Algorithmic Diagnosis
of
 Symptoms and Signs:
A Cost-Effective Approach
2

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Fourth Edition
Copyright © 2017 by Wolters Kluwer.
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Library of Congress Cataloging-in-Publication Data
Names: Collins, R. Douglas, author.
Title: Algorithmic diagnosis of symptoms and signs : a 
cost-effective
 approach / R.
Douglas Collins.
Description: Fourth edition. | Philadelphia : Wolters Kluwer Heath, [2017] |
Includes index.
Identifiers: LCCN 2016051998 | eISBN 9781496362810
Subjects: | MESH: Diagnosis | Signs and Symptoms | Algorithms | Cost Savings |
Handbooks
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4

This work is no substitute for individual patient assessment based upon healthcare
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5

1. 
  2. 
  3. 
  4. 
PREFACE TO THE FOURTH EDITION
When asked to do a fourth edition of this text, I was faced with the
question of how to make it even more useful than the third edition.
I believe we have accomplished this by the following additions:
Getting the most out of your history and physical examination. Here
we added many pearls of wisdom regarding the examination of
patients with the most common complaints plus tips to improve your
bedside manner.
Additional algorithms of symptoms and laboratory tests.
Algorithms of diseases that are symptoms of other diseases.
Differential diagnostic tables of the most common symptoms
encountered in your daily practice of medicine.
Finally, as in any new edition, I have brought all aspects of the text up to
date. A word of advice regarding a cost-effective approach: in today’s
world of the high cost of medical diagnostic procedure, you should order a
test only if you believe the results will affect your management of the
patient.
I thank my wife Norie for assisting in the preparation of this edition as
well as my editors, Rebecca Gaertner and Kristina Oberle, and the staff at
Wolters Kluwer for their patience, kindness, and diligence in the
production of this work.
 
R. Douglas Collins, MD, FACP
6

PREFACE TO THE FIRST EDITION
The average textbook of medicine is not very useful to the busy practicing
physician because all of the information in these texts is catalogued
according to specific diseases. Until the physician has a diagnosis, he or
she cannot look up diagnostic tests or treatment that would address the
patient’s problem.
This book applies algorithms to the clinical diagnosis of symptoms and
signs. It is aimed at organizing the approach to diagnosis and reducing the
cost of a diagnostic workup. To facilitate this procedure, the symptoms
and signs are arranged alphabetically. Under a certain symptom or sign,
the physician will find not just a list of diseases, but the diseases arranged
in an algorithm. At a glance he or she will be able to find what other
historical and clinical data is needed, to pin down the diagnosis. Then in
the accompanying text, the physician will find the tests to order for a
diagnostic workup.
A highlight of this book is a discussion on when to refer to the
appropriate specialist. Once a specific diagnosis has been established, the
clinician can move on to treatment. I have written this book to provide
primary care physicians and specialists with a useful tool in the rapid
diagnosis of symptoms and signs that they can use in their offices, in the
emergency room, or in the hospital wards.
 
7

INTRODUCTION
HOW TO USE THESE ALGORITHMS
The algorithms presented in these pages are, at the very least, a list of the
most common disorders that may cause a given symptom or sign. As such,
however, they are not all inclusive. Rare or unusual conditions are
excluded; the reader is referred to other treatises of differential diagnosis,
such as 
French’s Index of Differential Diagnosis
, edited by I.A.D.
Bouchier, H. Ellis, and P.R. Fleming, 
and Handbook of Difficult
Diagnosis
, edited by A.A. Louis, for a more complete list of diagnostic
possibilities.
The list of diagnostic possibilities is broken down by the presence or
absence of additional symptoms and signs. The reader should be aware
that any specific patient may not present with an additional symptom
necessary for this analysis, and, therefore, the entire list of possibilities
must still be entertained. Alternatively, the patient may present with the
additional symptom but still have one of the other disorders on the
diagnostic tree; therefore, at all times, the clinician should maintain an
index of suspicion that the patient could have any one of the disorders
listed on the page and not exclude any of the possibilities completely until
a positive laboratory, x-ray, or tissue diagnosis is ready. For example:
A 47-year-old white female reported progressive numbness and
tingling and weakness of the lower extremities. Examination
showed loss of vibratory and position sense in the lower
extremities and positive Babinski’s sign. A tentative diagnosis of
pernicious anemia was made. However, tests for serum B
12
 and
folic acid were normal. Magnetic resonance imaging (MRI) of the
thoracic spine showed a neurofibroma at the T6-7 level.
From this example, one can see that had the clinician not kept an open
mind about the entire list of diagnostic possibilities, he or she would not
have ordered an MRI of the thoracic spine and would have missed the
diagnosis.
Finally, the text accompanying each algorithm contains valuable
information on how to approach the patient with each presenting symptom
and sign and how to proceed with the diagnostic workup. For example:
A 35-year-old white female presents to the emergency room with
acute abdominal pain and diffuse tenderness and rebound.
8

The text on acute abdominal pain shows that the routine diagnostic tests
are a flat and upright plate of the abdomen, a complete blood cell count,
urinalysis, amylase, and chemistry panel. Most clinicians would remember
to order these tests without referring to this handbook. However, some
clinicians might forget to order a chest x-ray or electrocardiogram and
pregnancy test. Furthermore, there are additional tests to order in case the
routine tests are unrevealing. The clinician is reminded to order x-ray
contrast studies and ultrasound of the gallbladder and pelvis, and he or she
is reminded to do a peritoneal tap to diagnose a ruptured ectopic
pregnancy.
Most of the time, this little handbook will not present anything new to
the experienced diagnostician. However, the materials presented here will
jog the memory and help the diagnostician proceed with a thorough
workup.
9

CONTENTS
Introduction
Part 1
 Getting the Most out of Your History and Physical Examination
Part 2
 Algorithms of Symptoms and Signs
Abdominal Pain, Acute
Abdominal Pain, Chronic Recurrent
Abdominal Rigidity
Abdominal Swelling, Focal
Abdominal Swelling, Generalized
Absent or Diminished Pulse
Acid Phosphatase Elevation
Acidosis (Decreased pH)
Alkaline Phosphatase Elevation
Alkalosis (Increased pH)
Alopecia
Alterations in Serum Iron
Alteration in Serum Uric Acid
Amenorrhea
Amnesia
Anemia
Ankle Clonus
Anorexia
Anosmia or Unusual Odors
Anuria or Oliguria
Anxiety
Aphasia, Apraxia, and Agnosia
Ascites
Aspartate Aminotransferase Elevation
Ataxia
Athetosis
Axillary Mass
Babinski’s Sign
Back Pain
Bleeding Gums
Blindness
Blurred Vision
10

Bone Mass or Swelling
Borborygmi
Bradycardia
Breast Discharge
Breast Mass
Breast Pain
Cardiac Arrhythmia
Cardiac Murmurs
Cardiomegaly
Chest Deformity
Chest Pain
Chest Tenderness
Chills
Choreiform Movements
Clubbing of the Fingers
Coma
Constipation
Convulsions
Cough
Cramps, Menstrual
Cramps, Muscular
C-Reactive Protein
Crepitus
Cyanosis
Deafness
Delayed Puberty
Delirium
Delusions
Dementia
Depression
Diaphoresis
Diarrhea, Acute
Diarrhea, Chronic
Difficulty Urinating
Diplopia
Dizziness
Drop Attacks
Dwarfism
Dysarthria
Dysmenorrhea
11

Dyspareunia
Dysphagia
Dyspnea
Dysuria
Ear Discharge
Earache
Edema, Generalized
Edema, Localized
Enophthalmos
Enuresis
Epiphora
Epistaxis
Euphoria
Exophthalmos
Extremity Pain, Lower Extremity
Extremity Pain, Upper Extremity
Eye Pain
Face Pain
Facial Flushing
Facial Mass
Facial Paralysis
Facial Swelling
Facies, Abnormal
Failure to Thrive
Fatigue
Femoral Mass or Swelling
Fever, Acute
Fever, Chronic
Flank Mass
Flank Pain
Flatulence
Foot and Toe Pain
Foot Deformities
Foot Ulceration
Forehead Enlargement
Free Thyroxine (T
4
)
Frequency of Urination
Frigidity
Gait Disturbances
Gangrene
12

Gigantism
Girdle Pain
Glycosuria
Gynecomastia
Halitosis
Hallucinations
Head Mass or Swelling
Headache
Heartburn
Heel Pain
Hematemesis
Hematuria
Hemianopsia
Hemiparesis/Hemiplegia
Hemoptysis
Hemorrhoids
Hepatomegaly
Hiccups
Hip Pain
Hirsutism
Hoarseness
Horner’s Syndrome
Hydroxy Vitamin D
2
 and D
3
Hyperactive Reflexes
Hypercalcemia
Hypercholesterolemia
Hyperglycemia
Hyperkalemia
Hyperkinesis
Hypernatremia
Hyperpigmentation
Hypersomnia
Hypertension
Hypertriglyceridemia
Hypoactive Reflexes
Hypoalbuminemia
Hypocalcemia
Hypochondriasis
Hypoglycemia
Hypokalemia
13

Hyponatremia
Hypotension, Chronic
Hypothermia
Hypoxemia
Impotence (Erectile Dysfunction)
Incontinence of Feces
Incontinence of Urine
Increased Serum Bilirubin
Indigestion
Infertility, Female
Infertility, Male
Inguinal Swelling
Insomnia
Intermittent Claudication
Intracranial or Cervical Bruit
Jaundice
Jaw Pain
Jaw Swelling
Joint Pain
Joint Swelling
Knee Pain
Knee Swelling
Kyphosis
Lactic Dehydrogenase Elevation
Leg Ulceration
Leucocytosis
Leucopenia
Lip Pain
Lip Swelling
Lordosis
Lymphadenopathy
Melena
Memory Loss
Menorrhagia
Mental Retardation
Meteorism
Metrorrhagia
Monoplegia
Mouth Pigmentation
Muscular Atrophy
14

Musculoskeletal Pain, Generalized
Nail Abnormalities
Nasal Discharge
Nasal Obstruction
Nausea and Vomiting
Neck Pain
Neck Stiffness
Neck Swelling
Nightmares
Nocturia
Nose, Regurgitation of Food Through
Nystagmus
Obesity, Pathologic
ODOR
Opisthotonus
Orthopnea
Pain in the Penis
Pallor
Palpitations
Papilledema
Paresthesias of the Lower Extremity
Paresthesias of the Upper Extremity
Pathologic Reflexes
Pelvic Mass
Pelvic Pain
Penile Sores
Perineum Pain
Periorbital Edema
Peristalsis, Visible
Photophobia
Plasma Cortisol
Pneumaturia
Polycythemia
Polydipsia
Polyphagia
Polyuria
Popliteal Swelling
Precocious Puberty
Precordial Thrill
Premenstrual Tension
15

Priapism
Prolonged Prothrombin Time
Proteinuria
Pruritus, Ani
Pruritus, Generalized
Pruritus, Vulvae
Ptosis
Ptyalism
Pulsatile Swelling
Pulse Irregularity
Pulses, Unequal
Pupil Abnormalities
Purpura and Abnormal Bleeding
Pyuria
Rales
Rash—Distribution
Rash—Morphology
Raynaud’s Phenomena
Rectal Bleeding
Rectal Discharge
Rectal Mass
Rectal Pain
Red Eye
Regurgitation, Esophageal
Respiration Abnormalities
Restless Leg Syndrome
Risus Sardonicus
Scalp Tenderness
Scoliosis
Scotoma
Scrotal Swelling
Sedimentation Rate
Sensory Loss
Serum Albumin
Shoulder Pain
Skin Thickening
Sleep Apnea
Sleepwalking
Sneezing
Snoring
16

Sore Throat
Spasticity
Speech Abnormalities
Splenomegaly, Acute or Subacute
Splenomegaly, Chronic
Squint
Steatorrhea
Strangury
Stress Incontinence
Stretch Marks (Striae)
Stridor
Stupor
Succussion Sounds
Syncope
Tachycardia
Taste Abnormalities
Testicular Atrophy
Testicular Pain
Testicular Swelling
Thirst
Thrombocytopenia
Thyroid Enlargement
Tinnitus
Tongue Mass or Swelling
Tongue Pain
Tongue Ulcers
Tooth and Gum Abnormalities
Transient Ischemic Attacks
Tremor
Trismus
Uremia
Urethral Discharge
Urine Color Changes
Vaginal Bleeding
Vaginal Discharge
Varicose Veins
Vitamin B
12
Vulval or Vaginal Mass
Vulval or Vaginal Ulcerations
Weight Loss
17

Wheezing
Part 3
 Diseases That Are Symptoms of Other Diseases
Acne Vulgaris
Asthma
Atrial Fibrillation
Carpal Tunnel Syndrome
Cataracts
Cirrhosis
Congestive Heart Failure
Neuropathy
Peptic Ulcer
Pharyngitis
Pleural Effusion
Recurrent Renal Calculi
Recurrent Urinary Tract Infection
Stroke
Upper Respiratory Infection (URI)
Appendix A
Suggested Orders for the Workup of Common Symptoms
Appendix B
The Laboratory Workup of Disease
Index
18

Part 1
Getting the Most out of Your
History and Physical
Examination
19

GETTING THE MOST OUT OF YOUR HISTORY
AND PHYSICAL EXAMINATION
The main body of this chapter has been designed to get the most out of
your history and physical examination in the shortest period of time. If you
are like most busy primary care clinicians you are seeing 25 to 40 or more
patients in a day. Not long ago, I was covering an Urgent Care practice in
Palm Desert California and saw 37 patients in one 8-hour day. In this
section, we will address the techniques of performing a history and
physical examination like you have never witnessed before.
In medical school, you learned to methodically take your patients’
history beginning with the development of the chief complaint, following
that with the review of system and medical, family, and social history.
Then after having the patient undress and properly draped and placed on
the exam table, you perform your physical examination methodically from
head to toe, gathering all the necessary information you need to make a
Thereafter, you sit down and add up the positive findings and develop
a list of possible diagnoses that could explain the patient’s chief
complaints and proceed with your workup or treatment plan. This whole
process could take an hour or more and in my opinion is putting the cart
before the horse! How can you see 25 to 40 patients in an 8-hour day with
this methodology?
Here is a cost-effective approach that will save you time and the
patient money! But before we discuss this approach, I want to discuss
something which you have probably never had a formal discussion about
in your training or read in any medical text book. That is 
bedside manner
.
First, make sure you are properly dressed. Street clothes or jeans
should be replaced by an appropriate clean uniform, a shirt and tie or at
least covered with a lab coat. Make sure you don’t have bad breath or a
bad body odor. I keep a bottle of Benaca spray and an aftershave lotion
handy at all times, so I can freshen up when needed.
Greet the patient with a warm smile and an energetic “Hello!”
Introduce yourself properly if it’s the first time you have seen them. Never
act like you’re in a hurry! The patient wants to know you care about
him/her, so you must do everything you can to convince him/her that you
do! Not just about his/her illness, but about him/her as a person. The
patient needs to feel that he/she is the only patient you’ve got! To
20

accomplish this, sit down and address his/her problem eye ball to eye ball,
if possible. This is why I like to have two chairs at least in the examination
room. Standing over a patient who is sitting or lying down on the exam
table while you are doing your interview is a no–no in my opinion!
When you are talking to the patient maintaining as continuous eye
contact as possible is axiomatic. Spending all your time looking at the
computer or your notes conveys the impression that you care more about
your records than them.
Do all you can to convey your compassion about their illness! A warm
“I’m so sorry you’ve had to suffer” at the right time is a God-send to the
patient and an integral part of therapy. Perhaps you’re the first person
they’ve encountered who cares or even believes they are suffering.
Again, your 
examination
 of the patient needs to be slow, deliberate,
and gentle. Explain what you are doing and when possible convey the
results of the examination of each part. When you’re done with the history
and physical examination, tell them what you believe is wrong and what
you’re going to do about it.
Besides writing a prescription, write down a list of instructions they
need to do themselves if appropriate. If you simply give them verbal
orders, they may forget! For the most common disorders I encounter in my
practice, I have typed copies of instructions that I give to the patient and
explain each thing on the list I want them to do.
Now, to the techniques of a 
rapid history and physical
 examination.
Before you begin asking questions or examining the patient, formulate a
list of possible diagnoses in your mind based on the chief complaint. Then
you will ask questions to rule in or rule out each possibility! With this
technique, your history and physical examination will be more meaningful
and enjoyable rather than the “robotic” method you learned in medical
school.
I use the mnemonic 
MINT
 (M—malformation, I—inflammation, N—
neoplasm, T—trauma) to formulate a list of possibilities in many cases,
but you can use any mnemonic that suits you. Another way to form a list
of possibilities is to visualize the anatomy of the area where the chief
complaint is located. For example, if the patient is complaining of chest
pain, you would visualize skin (abscess, herpes zoster, etc.), ribs (fracture,
costochondritis, etc.), pleura (pleurisy), pericardium (pericarditis), heart
and blood vessels (myocardial infarction, coronary insufficiency,
dissecting aneurysm, etc.), lungs (pneumonia, pulmonary infarct, etc.),
esophagus (reflux esophagitis, etc.), thoracic spine (herniated disk,
fracture, osteoarthritis, etc.), and nerves (radiculopathy, herpes zoster,
21

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
10. 
11. 
12. 
13. 
14. 
etc.).
Now, you will eliminate some of these on your history and physical
examination. Then, you will be left with the ones you need to evaluate
with your diagnostic workup or you can immediately treat without a
workup.
Now, with the above techniques in mind, let’s apply them to the most
common complaints you encounter daily in your primary care practice.
ACUTE ABDOMINAL PAIN
The author recommends using anatomy to formulate your lists of
possibilities before you see the patient. Only the commonest causes will be
dealt with here:
Gastroenteritis
Appendicitis
Cholecystitis
Peptic ulcer
Pancreatitis
Diverticulitis
Intestinal obstruction
Perforated viscus
Ectopic pregnancy
Pelvic inflammatory disease (PID)
Reflux esophagitis
Myocardial infarction
Renal calculus
Hepatitis
With these possibilities in mind, you will begin your interview by asking
for the location of the pain. If it’s right upper quadrant (RUQ), consider
cholecystitis or duodenal ulcer. If it’s epigastric, consider the possibility of
pancreatitis, gastric ulcer, reflux esophagitis, and myocardial infarction.
Pain in the right lower quadrant brings up the possibility of appendicitis,
ectopic pregnancy, and PID, whereas pain in the left lower quadrant
suggests diverticulitis, ectopic pregnancy, and PID. Diffuse 
abdominal
pain is consistent with gastroenteritis and peritonitis either primary or
secondary to a ruptured viscus (ruptured peptic ulcer, etc.). Diffuse
abdominal pain also suggests intestinal obstruction. Next, determine if the
pain is constant (cholecystitis, appendicitis, diverticulitis, etc.) or
intermittent (biliary colic, renal colic, intestinal obstruction).
22

The severity of the pain may shed some light on the diagnosis. The
most severe pain will be caused by acute pancreatitis, ruptured viscus,
biliary or renal colic. Is the pain associated with meals? Pain from peptic
ulcer and reflux esophagitis occurs 1 to 2 hours after meals, while pain
from cholecystitis or cholelithiasis typically occurs 2 to 3 hours after
meals.
Associated symptoms
 are usually the key to the diagnosis. Diarrhea,
nausea, and vomiting are typical of gastroenteritis, while loss of appetite,
mild nausea, and fever are more typical of appendicitis. Severe nausea and
vomiting is common with cholecystitis, intestinal obstruction, pancreatitis,
and renal colic. Look for a vaginal discharge if you suspect PID, and
amenorrhea, morning sickness, and tender breasts if you suspect an ectopic
pregnancy. A myocardial infarction should be suspected if there is severe
diaphoresis without significant fever and a history of diabetes,
hyperlipemia, or hypertension. Acute pancreatitis is suspected if there is a
history of alcoholism, while reflux esophagitis should be suspected if there
is a history of recurrent regurgitation of food or acid especially on lying
down after a meal.
On your physical examination, always check for 
rebound tenderness
.
If this is in the RUQ, suspect cholecystitis. If it is localized to the right
lower quadrant, suspect acute appendicitis. Rebound tenderness in the left
lower quadrant is suspicious of diverticulitis. PID and ectopic pregnancy
may also be associated with rebound tenderness in one or both lower
quadrants. Diffuse rebound tenderness suggests pancreatitis or ruptured
viscus, especially a ruptured peptic ulcer and peritonitis.
A tender mass in the RUQ suggests cholecystitis or hepatitis, while a
mass in the right lower quadrant suggests a ruptured appendix. Look for a
mass in the groin or umbilicus (hernia) in intestinal obstruction. Icteric
sclera points to cholecystitis and hepatitis. 
Hyperactive bowel sounds
 are
the rule in intestinal obstruction, while decreased or absent bowel sounds
is highly suggestive of peritonitis or a ruptured viscus. Vaginal
examination will reveal a tender adnexal mass in PID, ectopic pregnancy,
and inflamed pelvic appendix. Look for Murphy’s sign if you suspect
cholecystitis and Rovsing’s sign in appendicitis. A reverse Rovsing’s sign
may be found in diverticulitis of the sigmoid colon. Years ago, the author
discovered that a retracted testicle on the right was consistent with
appendicitis, while a retracted testicle on the left was consistent with
diverticulitis (not in females, of course). If both testicles are retracted,
suspect peritonitis! Rectal examination may reveal gross blood in
intussusception or mesenteric thrombosis, or occult blood in these
23

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
conditions plus peptic ulcer disease, diverticulitis, and carcinoma of the
bowel.
Your diagnostic workup is essential to confirm your impressions after
a history and physical examination as well as to rule out other possibilities
(
page 16
).
CHEST PAIN
Before you see the patient, develop a list of most likely possibilities using
a mnemonic for the anatomy (skin, ribs, lungs, heart, thoracic spine, etc.):
Skin—cellulitis, herpes zoster, etc.
Ribs—fractures, contusions, costochondritis
Pleura—pneumonia with pleurisy
Lung—pneumothorax, pulmonary embolism, etc.
Heart—pericarditis, myocardial infarction, coronary insufficiency, etc.
Esophagus—reflux esophagitis (gastroesophageal reflux disease),
cardiospasm, carcinoma
Thoracic spine—fractures, herniated disk, space-occupying lesion
Now, in your history, you ask the location of the pain: left precardium
(myocardial insufficiency or infarct, pericarditis, etc.), while the pain with
the rest of the conditions can be almost anywhere. You ask if the pain is
precipitated by inspiration (pleurisy, costochondritis, pulmonary
embolism, rib fractures, reflux esophagitis, etc.) or by extension or rotation
of the spine (vertebral fracture, herniated disk, etc.). You ask if it is acute
(pulmonary embolism, pneumothorax, pneumonia with pleurisy, fractures,
costochondritis, myocardial infarction) or chronic or recurring (coronary
insufficiency, reflux esophagitis, thoracic spondylosis, etc.). Does the pain
radiate to the neck, jaw, or left upper extremity (myocardial infarction,
coronary insufficiency)? Is it associated with diaphoresis (myocardial
infarction, pulmonary embolism), hemoptysis (pulmonary embolism),
regurgitation of food or acid (reflux esophagitis), or a rash (herpes zoster)?
On your 
physical examination
, you can quickly identify
costochondritis by palpating the costochondral junctions at the 2nd, 3rd, or
4th ribs (usually). You can identify rib fractures by palpating the ribs. You
can identify pneumothorax by tracheal deviation and pulmonary embolism
or pneumonia with pleurisy on auscultation of the lungs. Loss of sensation
in the thoracic dermatomes and sensory, motor, and reflex changes in the
lower extremities may help identify thoracic spondylosis, a herniated
thoracic disk, or space-occupying lesion of the thoracic spine. Reflux
24

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
10. 
esophagitis can be identified by reproducing the pain with pressure in the
mid-epigastrium or relief of the pain with a swallow of 5 to 10 mL of
lidocaine viscous. Further differentiation of these conditions may require a
diagnostic workup (
page 93
) or referral to a specialist.
COUGH
Again, before you see a patient with cough, you develop a list of
conditions to look for like this:
Acute bronchitis
Pneumonia
Tuberculosis (TB)
Bronchiectasis
Asthma
Pulmonary embolism
Congestive heart failure (CHF)
Chronic obstructive pulmonary disease (COPD)
Neoplasm
Now, in your history, you are looking for fever and chills and night sweats
(an infections process) or if the cough is of recent onset (bronchitis
pneumonia, CHF, and pulmonary embolism), chronic or long standing
(TB, bronchiectasis, CHF, asthma, or COPD); purulent sputum
(pneumonia, TB, or bronchiectasis); hemoptysis (TB, neoplasm,
bronchiectasis, pulmonary embolism), shortness of breath (CHF, asthma,
COPD, pulmonary embolism), and regurgitation of acid or food (reflux
esophagitis). You are also looking for weight loss (neoplasm and TB).
On your 
, you are looking for crepitant rales and
signs of consolidation or effusion (pneumonia, TB, CHF, pulmonary
embolism); sibilant 
and sonorous rales or hyperresonance (asthma,
bronchitis, COPD); edema of one extremity and positive Homan’s sign
(pulmonary embolism) or edema of both extremities; cardiomegaly,
hypertension, hepatomegaly, jugular venous distension (CHF), or
decreased oxygen saturation (CHF, COPD and pulmonary embolism).
DIARRHEA
Here again, have a list of possible causes in your mind before you examine
the patient! Since most cases of diarrhea that you will see in a primary care
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practice are infectious, I like to make the list beginning with the smallest
organisms and working up to the largest:
Viral gastroenteritis
Bacterial gastroenteritis (
Shigella
, 
Salmonella
, 
Campylobacter
, etc.)
Giardiasis
Amebiasis
Cryptosporidium parvum
Then the rest of your list is developed using the mnemonic vindicate:
V—Vascular—ischemic colitis
I—Intoxication—Staphylococcal toxins, 
Clostridium difficile
 toxin
N—Neoplasm—villous adenoma, carcinoma, carcinoid, Zollinger–
Ellison syndrome
D—Degenerative—malabsorption syndrome, vitamin deficiency—
pellagra
I—Inflammatory bowel disease—(noninfectious) ulcerative colitis,
Crohn’s disease, etc.
C—Congenital—lactose deficiency, other enzyme deficiencies
A—Anxiety—irritable bowel syndrome
T—Toxic diarrhea due to drugs
E—Endocrine disorders—diabetic enteropathy, hyperthyroidism
Now, having this list in mind, your history begins with asking whether the
diarrhea is acute (viral, bacterial, staphylococcal, toxins) or chronic
(lactose intolerance, inflammatory bowel disease, carcinoid, Zollinger–
Ellison syndrome, irritable bowel, etc.). If it is acute, is there nausea and
vomiting (more likely viral gastroenteritis), or significant fever and chills
(more likely bacterial gastroenteritis)? Has the patient been on antibiotics
recently (
C. difficile
 
toxin) or other drugs (toxic diarrhea)? Is there bloody
diarrhea (inflammatory bowel disease, bacterial gastroenteritis, ischemic
colitis, neoplasm)? Is there a history of diabetes mellitus (diabetic
enteropathy) or AIDS (
C. parvum
)? Has the patient been out of the country
recently (
Escherichia coli
, traveler’s diarrhea)? Is there weight loss
(neoplasm, hyperthyroidism, malabsorption syndrome) or do the stools
float in the commode (malabsorption syndrome)? Is there flushing
(carcinoid syndrome), a history of peptic ulcers (Zollinger–Ellison
syndrome), or intolerance to milk and milk products (lactose intolerance)?
On your 
, you are looking for tremor, tachycardia,
and a thyroid mass (hyperthyroidism); a rash (pellagra, carcinoid
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syndrome, inflammatory bowel disease); peripheral neuropathy (diabetic
enteropathy, pellagra, etc.); and an abdominal mass (neoplasm or
inflammatory bowel disease). You must use your diagnostic workup to
rule out the other conditions, but you will undoubtedly treat patients with
acute diarrhea either symptomatically or based on your history and
physical examination.
DIZZINESS
Here again, formulate a list of possibilities in your mind before you
approach the patient. You may use your favorite mnemonic, but I prefer to
use the anatomy of the ear to develop a list of causes related to true
vertigo, and physiology and biochemistry to develop a list of causes
related to the decrease or change in the quality of the blood supply to the
brain.
A. True vertigo:
Cerumen or foreign body in the ear
Otitis media
Labyrinthitis
Vestibular neuronitis
Benign positional vertigo
Ménière’s disease
Cholesteatoma
Acoustic neuroma
Vertebral–basilar artery insufficiency
Multiple sclerosis
Migraine
Epilepsy
Post-concussion syndrome
B. Dizziness which is not true vertigo:
Carotid stenosis
Subclavian steal
Aortic stenosis
Cardiac arrhythmia
Postural hypotension
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10. 
11. 
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14. 
15. 
Anemia
Anoxia
Drug reaction
Hyperventilation syndrome
On taking your history, the first thing you need to do is differentiate
between true vertigo and dizziness or light-headedness that is not true
vertigo. True vertigo is a sensation of rotation of the patient or his
surroundings. One other sensation that is regarded as true vertigo is a
feeling of moving laterally to the right or left (called lateral pulsion). Now
having established that your patient has true vertigo, you want to know if it
is acute or recent onset (acute labyrinthitis, impacted cerumen, foreign
body, otitis media, vestibular neuronitis, etc.) or chronic recurrent (benign
positional vertigo, Ménière’s disease, cholesteatoma, acoustic neuroma,
multiple sclerosis, vertebral–basilar insufficiency, migraine).
Are there associated symptoms such as tinnitus and hearing loss (otitis
media, Ménière’s disease, cholesteatoma, acoustic neuroma) or neurologic
signs of ataxia, 
weakness, numbness, or tingling of the extremities or face
(acoustic neuroma, vertebral–basilar artery insufficiency, multiple
sclerosis)? Nausea and vomiting can be associated with any of the causes
of true vertigo, so these symptoms are of no help. Moving on to your
physical examination, you can rule out many of the causes of true vertigo.
If your ENT examination is normal, you can exclude impacted cerumen,
foreign body, otitis media, and cholesteatoma.
If a whisper test at 6 feet away with each ear is normal, you can
probably exclude Ménière’s disease and acoustic neuroma. If in doubt,
refer the patient for an audiogram. Weber and Rinne’s tests will help you
decide if you have a vertigo from a middle ear disorder or inner ear and
nerve damage (Ménière’s disease or acoustic neuroma). If your gross
neurologic examination is normal, you can probably exclude multiple
sclerosis and vertebral–basilar artery insufficiency and other space-
occupying lesions.
To exclude benign positional vertigo, perform Hallpike maneuvers.
With the patient sitting sideways on the exam table, turn his or her head to
the right and quickly lower the head and torso so that the head is below the
edge of the table and observe for nystagmus or vertigo for at least 2 to 3
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minutes. Then raise the patient’s head and torso back to the upright
position and again observe for nystagmus or vertigo. Repeat the same
procedure with the patient’s head straight and turned to the left. If the
patient experiences vertigo or you observe nystagmus in one of these
positions, a diagnosis of benign positional vertigo is likely. With other
form of vertigo, you may precipitate the sensation in many of these
positions or vertigo will not be precipitated at all.
Your history in the patient that does not have true vertigo is not going
to be as helpful as your physical examination and diagnostic workup.
However, it is important to look for a history of diabetes (hypoglycemia
from insulin or drugs), hypertension, and any drugs the patient may be on.
It is important to know if the patient has COPD or chronic anxiety
(hyperventilation syndrome) or anemia because of blood loss.
Your examination may reveal a cervical bruit (carotid stenosis),
hypertension, a difference in the blood pressure in each upper extremity
(subclavian steal), a drop in blood pressure on standing (postural
hypotension), a slow pulse (sick sinus syndrome, heart block), a heart
murmur (aortic stenosis, etc.), a rapid irregular heart rate (auricular
fibrillation), or a positive Chvostek’s or Trousseau’s sign (hypocalcemia).
Your diagnostic workup will be necessary to differentiate the rest of the
causes on this list. But aren’t you amazed at how many conditions can be
picked up on a good history and physical examination? However, the
clinical evaluation of a patient with dizziness can be time consuming, so if
no cause is immediately apparent, the author suggests you either
reschedule these patients for a full hour of your time or refer them to an
otolaryngologist or neurologist.
HEADACHE
Formulate your list of possibilities in your mind before you see the patient.
Here is a list I like to use:
Migraine
Cluster headache
Tension headache
Temporal arteritis
Hypertensive headaches
Sinusitis
Meningitis
Subarachnoid hemorrhage
Occipital neuralgia
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16. 
Cervical spondylosis
Space-occupying lesion
Postspinal tap headache
Postconcussion syndrome
Systemic infectious disease
Glaucoma
Myopia, astigmatism
Now, conducting your history, you will ask if the headache is intermittent
(migraine, cluster headache) or constant (sinusitis, meningitis,
subarachnoid hemorrhage, tension headache). Is it acute onset (meningitis,
subarachnoid hemorrhage, migraine, cluster headache, or acute bacterial
sinusitis)? Is there a history of trauma (subdural or epidural hematoma,
postconcussion syndrome)? Is it unilateral (migraine, cluster headache,
temporal arteritis), bilateral (common migraine, postconcussion
syndrome), or occipital and suboccipital (tension headache, meningitis,
subarachnoid hemorrhage, cervical spondylosis, hypertensive headaches,
occipital neuralgia)? For associated symptoms, is there fever (meningitis,
sinusitis, infectious disease), is there photophobia, noise sensitivity, or
nausea and vomiting (migraine, infectious disease, subarachnoid
hemorrhage, space-occupying lesion)? Is there an elevated blood pressure
(hypertensive headache, subarachnoid hemorrhage)? Are there visual
disturbances (migraine, refractive errors, astigmatism, space-occupying
lesion)? Are there other neurologic symptoms such as numbness, tingling
or weakness of one or more extremities, ataxia, hearing loss, visual loss,
facial paralysis, etc. (stroke, space-occupying lesion of the brain)?
If there is no fever, no history of trauma, and no other neurologic
symptomatology, you can quickly move on to the physical examination
where you should test visual acuity (glaucoma, refractive error), look for
papilledema
 
(space-occupying
 
lesion), check for nuchal rigidity
(subarachnoid hemorrhage and viral meningitis), and focal changes in
power, reflexes, or sensation on your neurologic examination (space-
occupying lesions). If the headache is relieved by superficial temporal
artery compression, it is most likely
 
migraine
 
or some other type of
vascular headache. On the contrary, if one of the temporal arteries is tender
or enlarged, consider the possibility of
 
temporal arteritis
. 
Pressure on both
jugular veins will relieve a
 
postspinal tap headache
. 
One or more sinuses
may fail to transilluminate in acute sinusitis. If there is tenderness of an
occipital nerve root, consider the possibility of occipital neuralgia, and
confirm your suspicion with an occipital nerve block. There will be
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15. 
watering of one eye and possibly a running nose in acute cluster headache.
However, this will also be present in acute maxillary sinusitis. Limited
range of motion (ROM) of the cervical spine in the absence of nuchal
rigidity supports a diagnosis of cervical spondylosis (osteoarthritis). Relief
of the headache with a
 
Neo-Synephrine
 
spray confirms the diagnosis of
allergic rhinitis and sinusitis in many cases. Finally, be sure to check the
blood pressure yourself and in both
 
upper
 
extremities to rule out
hypertensive headaches.
JOINT PAIN
Your list of possibilities can be made with a mnemonic like MINT or
visualizing the anatomy of the joint. Regardless of what method you use,
have a list of possibilities in mind before you see the patient:
Sprain
Fracture
Dislocation
Bursitis
Tendonitis
Septic arthritis
Rheumatic fever
Rheumatoid arthritis
Osteoarthritis
Psoriatic arthritis
Gout
Pseudogout
Reiter’s syndrome
Lupus erythematosus
Inflammatory bowel disease
Now, with this list in mind, in your history, you will consider the patient’s
age (over 50—osteoarthritis, 30 to 40—rheumatoid arthritis, etc.) and if
there is recent trauma (sprain, fracture, dislocation) or repetitive use of the
joint (bursitis, tendonitis, traumatic arthritis). You will ask if there has
been fever or chills (septic arthritis, rheumatic fever). Is the pain in a
single joint (septic arthritis, osteoarthritis, gout, pseudogout, trauma) or
multiple joints (rheumatoid arthritis, psoriatic arthritis, rheumatic fever,
systemic lupus erythematosus [SLE], gonococcal arthritis, etc.)? Is there a
rash (rheumatic fever, SLE, gonococcal arthritis, psoriasis) or red eye
(conjunctivitis or iritis from Reiter’s syndrome or scleritis from
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rheumatoid arthritis)? Is there a history of diabetes mellitus (pseudogout,
osteoarthritis) or family history of gout? Has there been a recent urethral
discharge (gonococcal arthritis, Reiter’s syndrome)?
On your examination, you need to find if the joint is red and hot (septic
arthritis, gout, rheumatic fever, and early rheumatoid arthritis) or just
swollen and tender (osteoarthritis). Other forms of arthritis will have
limited ROM on both active and passive movement, but bursitis and
tendonitis will usually have limited ROM on active movement only. Look
for subcutaneous nodules (rheumatoid arthritis, rheumatic fever) and heart
murmurs or cardiomegaly (rheumatic fever, SLE). If the pain is localized
to the knee, check for loose collateral ligaments, McMurray’s test (torn
meniscus), Lachman’s maneuver, and a drawer sign (anterior cruciate
ligament tear). If the pain is in the hip, palpate for a tender greater
trochanter bursa (greater trochanter bursitis) and a positive Patrick’s test
(bursitis and arthritis). One of the best ways to determine if the pain is due
to bursitis or tendonitis is to inject the area with 1% to 2% lidocaine with
or without 20 to 40 mg of triamcinolone acetonide. If you get total or
nearly total relief and ROM is restored, then bursitis or tendonitis is almost
certain.
LOW BACK PAIN
Visualizing the structures in the lower back, lower abdomen, and pelvis,
you come up with the following possibilities:
Lumbosacral sprain
Fracture
Herniated disk
Lumbar spondylosis or spinal stenosis
Space-occupying lesion of the cauda equina
Spondylolisthesis
Prostatitis, prostatic carcinoma (males)
PID (females)
Pelvic tumor (females)
Endometriosis (females)
Abdominal aortic aneurysm
Rheumatoid spondylitis
Scoliosis
Now, with this list in mind, when you take the history, you won’t forget to
look for trauma (sprain, fracture, herniated disk), onset of the back pain at
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11. 
12. 
an early age (rheumatoid spondylitis, spondylolisthesis), late onset of the
back pain (lumbar spondylosis, aortic aneurysm), back pain in a female
(pelvic tumor, PID, endometriosis), back pain in a male (prostatitis,
prostatic carcinoma, with metastasis), numbness, tingling or weakness in
one or both lower extremities (herniated disk, spondylolisthesis, space-
occupying lesion of the cauda equina, spinal stenosis), neurogenic
claudication (spinal stenosis), and fever (PID, prostatitis epidural abscess).
You must ask about difficulty voiding (prostatism, cauda equina
syndrome). On your
 
, 
you won’t forget to look for
erector spinae tenderness and spasm (lumbosacral sprain, fracture,
herniated disk, lumbar spondylosis), tender sacroiliac joints (rheumatoid
spondylitis), a positive straight leg raising (SLR) test or femoral stretch
test (herniated disk, other causes of radiculopathy), dermatomal sensory
loss, weakness, atrophy or reflex changes in one or both lower extremities
(herniated disk, other space-occupying lesions, spondylolisthesis), tender
boggy prostate (acute prostatitis), unilateral short leg (scoliosis), enlarged
abdominal aorta with or without a bruit (aortic aneurysm), tender enlarged
adnexa (PID, endometriosis), and pelvic mass (ovarian cyst or neoplasm,
uterine fibroids or neoplasm, etc.). Do not forget to evaluate for
malingering or hysteria when your basic examination is normal. This is
suggested when the back pain is produced or aggravated when both the
hips and the spine are rotated simultaneously. Also a negative SLR when
sitting in the face of a positive SLR while recumbent suggests malingering.
PAINFUL SHOULDER
Before you see the patient use MINT or a similar mnemonic to develop the
following list of possibilities:
Sprain
Subacromial bursitis
Osteoarthritis or other forms of arthritis of the glenohumeral joint
Frozen shoulder (adhesive capsulitis)
Fracture
Osteomyelitis
Cervical radiculopathy
Referred pain from coronary insufficiency
Cholecystitis or subdiaphragmatic abscess
Biceps tendonitis
Sympathetic dystrophy
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Acromioclavicular arthritis
Your 
history
 is designed to eliminate some of these. If there is no history
of trauma, then a sprain, fracture, or dislocation can be ruled out. If there is
no fever, osteomyelitis and subdiaphragmatic abscess can probably be
excluded. Look for abdominal pain, nausea, or vomiting if you suspect
cholecystitis. Pain radiating to 
the forearm, hand, and fingers associated
with weakness or numbness and tingling would suggest cervical
radiculopathy from a herniated disk or cervical spondylosis or 
space-
occupying
 lesion. It may also suggest a thoracic outlet syndrome.
Your 
physical examination should
 help rule in or rule out most of the
other conditions. Palpate the subacromial bursa for tenderness. Then have
the patient raise his or her shoulder until they experience pain. Then let
them drop the arm into your hands. If the pain disappears, subacromial
bursitis from a torn rotator cuff is likely. Confirm this by testing passive
ROM of extension and abduction. If passive ROM is full or almost full,
subacromial bursitis is likely. However, if both active and passive ROM is
impaired, the patient likely has arthritis (gout, rheumatoid arthritis,
osteoarthritis, etc.). To rule out biceps tendonitis, flex the biceps. If this
causes pain in the anterior shoulder biceps tendonitis is likely. You can
confirm this by palpating the biceps tendon at its origin in the shoulder.
Frozen shoulder can also be confirmed by the restriction of ROM on both
active and passive motion. Sympathetic dystrophy can be confirmed by
mild diffuse atrophy of the upper extremities along with trophic changes in
the skin. Acromioclavicular pathology can be confirmed by tenderness in
this joint.
Many of these conditions can be further verified by relief of pain with
an injection of 3 to 5 mL of 1% to 2% lidocaine into the appropriate bursa,
tendon, or joint.
RECTAL BLEEDING
Use the mnemonic MINT to formulate your list of possibilities before you
see the patient:
M—hemorrhoids, anal fistula
I—anal fissure, proctitis, ulcerative colitis, diverticulitis, Crohn’s
disease
N—neoplasm of the anus, rectum or colon
T—trauma from sodomy, etc.
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Don’t forget coagulation disorders. Now, the questions to ask in your
history are easier to recall. Is the rectal bleeding associated with pain on
defecation (thrombosed hemorrhoids, anal fissure) or is the bleeding
painless (carcinoma, internal or external hemorrhoids without
thrombosis)? Is the bleeding mixed with stools (colon neoplasm,
diverticulitis)? Is the bleeding associated with diarrhea (ulcerative colitis,
Crohn’s disease, amebic dysentery)? Is the rectal bleeding associated with
intestinal obstruction (intussusception, mesenteric thrombosis)? Is there
ecchymosis or bleeding elsewhere (coagulation disorder)?
Actually, the clinician could proceed directly to the rectal and
anoscopic examination in many of these patients with acute rectal bleeding
without diarrhea or evidence of intestinal obstruction. Hemorrhoids will be
obvious on inspection and a sentinel pile will help identify an anal fissure
that usually occurs at 6 o’clock. Anoscopic and proctoscopic examination
will identify rectal carcinomas, internal hemorrhoids, and anal fissures
when inspection and palpation are unable to do so. Rectal bleeding with
diarrhea, mixed with stool or evidence of intestinal obstruction requires a
more extensive workup (
page 439
) or referral to a proctologist or
gastroenterologist.
SORE THROAT
Whatever method you use, if you are following my advice you have a list
of conditions in mind when you approach the patient with this condition
like this:
Viral upper respiratory infection (URI)
Strep pharyngitis
Infectious mononucleosis
Diphtheria
Measles
Agranulocytosis
Subacute thyroiditis
Thus in your history, you will be asking about fever and chills to cover the
various infectious conditions, a rash (measles, infectious mononucleosis,
etc.), a history of drug use (agranulocytosis), running nose (viral URI,
measles), and tremor and palpitations (subacute thyroiditis).
On your 
, you will be looking for pharyngeal
exudates (strep pharyngitis, infectious mononucleosis, agranulocytosis,
diphtheria, etc.), a strawberry tongue (strep pharyngitis), Koplik spots, rash
35

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and conjunctivitis (measles), posterior cervical adenopathy and rash
(infectious mononucleosis), a tender possibly enlarged thyroid (subacute
thyroiditis), and enlarged spleen (leukemia, infectious mononucleosis).
URINARY FREQUENCY AND BURNING
This is another very common symptom in primary care practice.
Frequently, the nurse or medical assistant has already done a urine dipstick
before you see the patient and if it is positive for a urinary tract infection
(UTI) it is tempting to simply write a prescription without doing a history
and physical examination.
It is better to be thorough and consider a list of possible causes before
you see the patient and tailor your history and physical examination
accordingly. Here is a list the author uses but you can formulate your own.
It is easy if you consider the anatomy of the genitourinary tract and work
from the bottom up.
Urethritis
Prostatitis
Cystitis
Pyelonephritis
Bladder or renal calculus
Obstructive uropathy
Systemic causes of polyuria
With these conditions in mind, you begin your history by asking if the
burning or frequency is acute (urethritis, acute prostatitis, acute cystitis, or
pyelonephritis) or chronic and recurrent (chronic cystitis, chronic
prostatitis, bladder or renal calculi, bladder neck obstruction, other forms
of obstructive uropathy, systemic causes of polyuria). Is there a urethral
discharge (gonorrhea, chlamydia, prostatitis) or a vaginal discharge
(gonorrhea, chlamydia, bacterial vaginosis)? Is there hematuria (bladder or
renal calculus, honeymoon cystitis, neoplasm)? Is there conjunctivitis,
iritis, or arthritis (gonorrhea, Reiter’s syndrome)? Has the patient recently
had a new sexual partner or been sexually promiscuous (gonorrhea)? Is
there history of polydipsia, polyphagia, weakness, or weight loss (diabetes
mellitus, hyperthyroidism)? Is there fever or chills (pyelonephritis)?
On your 
, you will palpate and percuss for flank
tenderness or bladder and kidney enlargement (pyelonephritis, obstructive
uropathy, neoplasm). You will examine the external genitalia and do a
rectal examination on males looking for a urethral discharge (acute
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prostatitis and benign prostatic hypertrophy). If chronic prostatitis is
suspected, you may massage the prostate and make a smear of any urethra
discharge and look for leukocytes. However, do not massage the prostate 
if
the prostate is large, boggy, and tender. In females, do a vaginal
examination to look for vaginitis, cervicitis, and a uterine or adnexal mass.
At this point, you may proceed with your treatment or a diagnostic
workup depending on your findings.
VAGINAL DISCHARGE
Here’s the list of the most likely causes that you should be thinking of
before you see the patient with a vaginal discharge. The author formulated
this list by contemplating the largest organism to the smallest and also
considering anatomy but you can use a mnemonic that may suit you better
like “vindicate”:
Candida vaginitis
Trichomoniasis
Gonorrhea
Bacterial vaginosis
Chlamydia vaginitis
Pregnancy
Rectovaginal fistula
Foreign body
With these conditions in mind, you begin your 
history
 by asking the
character of the discharge. Is it cheesy (candidiasis), yellow
(trichomoniasis, gonorrhea, bacterial vaginitis), frothy (trichomoniasis),
mucopurulent (cervicitis), thin and slightly yellow (chlamydia), white,
mucoid but copious (pregnancy)? Has the patient had new or multiple
partners (gonorrhea, trichomoniasis, chlamydia)? Is there a history of
diabetes or use of oral contraceptives (candidiasis)? Are there other
symptoms of pregnancy such as swollen tender breasts, morning sickness,
etc.? Is there a history of Crohn’s disease (rectovaginal fistula)? Does the
patient use tampons (foreign body)?
On your vaginal examination, you will confirm if the discharge is
cheesy (candidiasis), yellow and frothy (trichomoniasis), or yellow and
mucopurulent (gonorrhea, bacterial vaginosis). You will do a saline prep to
look for motile organisms (trichomoniasis), a KOH prep to look for
hyphae and yeast cells (candidiasis) and a Gram’s stain to look for bacteria
(gonorrhea, bacterial vaginitis). Look for cervical erosions and a
37

mucopurulent discharge (gonorrhea) and cervical erosions with a milky
white discharge in chronic cervicitis and cervical carcinoma. If the patient
is pregnant, the cervix will be soft (Hegar’s sign) and bluish (Chadwick’s
sign) and of course the uterus will be enlarged. You will confirm this with
a pregnancy test. Cultures of the vaginal discharge or a urine sample may
be needed to confirm the presence of gonorrhea and chlamydia.
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ABDOMINAL PAIN, ACUTE
CASE HISTORY
A 67-year-old white woman presents to the emergency department with
generalized abdominal pain that began this morning. Following the
algorithm, you check her for cough, shortness of breath, and an unusual
odor to her breath, and find none of these signs. She is not aware of being
bitten by a spider, and you do not find any bite-like lesions on her body.
Her blood pressure is 95/60 and her pulse is 110 per minute, so you keep
in mind the possibility of an inferior wall myocardial infarct.
Examination of the abdomen reveals generalized rebound tenderness
and guarding and hypoactive bowel sounds. You perform a rectal
examination and find bloody stools. You suspect a mesenteric thrombosis
and you would be correct.
ASK THE FOLLOWING QUESTIONS:
Where is the pain located?
 If it is diffuse, one should consider
pancreatitis, mesenteric artery occlusion, or ruptured peptic ulcer. In
addition, another viscus may be perforated, such as a ruptured ectopic,
and there may be peritonitis. Pain out of proportion to the objective
findings suggests mesenteric artery occlusion. If it is focal, we need to
know what quadrant it is in. For example, acute cholecystitis is in the
right upper quadrant, whereas diverticulitis is usually in the left lower
quadrant (LLQ).
What is the nature of the pain?
 Colicky abdominal pain suggests
intestinal obstruction, renal calculus, and cholelithiasis or common
duct stone, whereas constant pain is typical of pancreatitis, a ruptured
peptic ulcer, appendicitis, diverticulitis, and a ruptured ectopic
Does the pain radiate?
 The pain of acute cholecystitis typically
radiates to the right scapula or right shoulder. The pain of a ruptured
peptic ulcer may also radiate to the shoulder. The pain of acute renal
calculus may radiate to the testicle.
What are the associated signs and symptoms?
 Shock with
generalized tenderness and rebound and diminished or absent bowel
sounds should suggest a ruptured peptic ulcer or acute pancreatitis.
However, acute right upper quadrant pain with nausea and vomiting
should suggest acute cholecystitis. On the other hand, appendicitis is
40

5. 
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more insidious in onset and is associated with anorexia and nausea,
rarely vomiting, as well as constipation. Renal colic presents with
hematuria.
Could this patient’s abdominal pain be caused by an extra-
abdominal condition?
 Remember, lobar pneumonia, myocardial
infarction, diabetic acidosis, and porphyria may be responsible for
acute abdominal pain. There are numerous other conditions that need
to be considered.
If the patient is an infant, is there projectile vomiting or current
jelly stools?
 Projectile vomiting suggests pyloric stenosis, whereas
bloody stools would suggest intussusception.
DIAGNOSTIC WORKUP
Except in patients with obvious gastroenteritis, it is wise to consult a
general surgeon at the outset. All patients with acute abdominal pain
should have a stat, flat, and upright plate of the abdomen; a chest x-ray to
rule out pneumonia; an electrocardiogram (EKG) to rule out myocardial
infarction; and a complete blood count (CBC), urinalysis, amylase, lipase,
lactic acid, and chemistry panel. In cases of trauma, the 
radiological
examination of choice is a computed tomography (CT) scan with and
without contrast as well as CT angiography (CTA), although abdominal
ultrasound is also used to demonstrate blood in the peritoneal cavity.
Sometimes, lateral decubitus films of the abdomen are necessary to show
the step ladder pattern of intestinal obstruction. A pregnancy test is ordered
when age and sex dictate it!
When these tests fail to confirm the clinical diagnosis, x-ray contrast
studies or ultrasound may be necessary. For example, a CT scan of the
abdomen can be done for a suspected renal calculus. Serial cardiac
enzymes may confirm a myocardial infarction. Gallbladder ultrasound can
be done to confirm cholecystitis and cholelithiasis. A nuclear scan of the
gallbladder with iminodiacetic acid derivatives is very accurate in
detecting acute cholecystitis. An angiogram is done for suspected
mesenteric thrombosis. Ultrasonography may also help diagnose
impending rupture of an abdominal aneurysm, appendicitis, or ectopic
pregnancy. A peritoneal tap may diagnose a ruptured ectopic pregnancy.
Laparoscopy should also be considered. A urine porphobilinogen helps
exclude porphyria. A double enema may help diagnose intestinal
obstruction. Magnetic resonance imaging (MRI) can be done when the
diagnosis remains obscure, but it is cheaper to consult a general surgeon
first.
41

If the diagnosis remains in doubt, an exploratory laparotomy must be
done before the patient’s condition deteriorates. The only case where this
might be risky is acute pancreatitis. If this is suspected and the serum
amylase is repeatedly normal, a quantitative urine amylase or peritoneal
tap may confirm the diagnosis. Endoscopy may need to be done to
diagnose a peptic ulcer, gastritis, gastric tumor, or reflux esophagitis. In
obscure cases of appendicitis and diverticulitis, a contrast barium enema
may help confirm the diagnosis. Angiography can diagnose an aneurysm
or mesenteric infarction.
Table 01: Abdominal Pain
The reader needs to keep in mind that exceptions to these findings do occur.
GERD, gastroesophageal reflux disease; LLQ, left lower quadrant; LQ, left quadrant; PID,
pelvic inflammatory disease; RLQ, right lower quadrant; RUQ, right upper quadrant.
42

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
ABDOMINAL PAIN, CHRONIC RECURRENT
Is there a family history of migraine or epilepsy?
 Migraine and
epilepsy both present with abdominal pain.
Is the pain colicky or persistent?
 
Chronic colicky abdominal pain
may be caused by chronic cholecystitis, cholelithiasis, renal calculus,
or partial intestinal obstruction.
What is the location of the pain?
 
If the pain is located in the upper
abdomen, then one should consider peptic ulcer disease, pancreatitis,
cholecystitis, and cholelithiasis. If the pain is located in the flanks, one
should consider renal calculus and pyelonephritis. If the pain is located
in the lower abdomen, one should consider diverticulitis, salpingitis,
endometritis, and chronic appendicitis. Regional ileitis also may be
located in the lower abdomen, particularly in the right lower quadrant.
What is the relationship to meals?
 Abdominal pain relieved by food
may be caused by a peptic ulcer. Abdominal pain brought on by food
may be caused by abdominal angina. If the pain comes on 2 to 3 hours
after a meal, it may be caused by a peptic ulcer. On the other hand,
pain that comes on 1 to 2 hours after meals, especially if it is a fatty
meal, may be related to cholecystitis and cholelithiasis.
Is there fever associated with the abdominal pain?
 Fever and
abdominal pain may be caused by pyelonephritis, diverticulitis, or
appendicitis.
Is there a history of chronic alcoholism?
 The history of chronic
alcoholism suggests acute and chronic pancreatitis.
Is there blood in the stool?
 The presence of blood in the stool would,
of course, suggest peptic ulcer disease and diverticulitis.
Is there an abdominal mass?
 The presence of an abdominal mass,
particularly in the midepigastrium, suggests a pancreatic cyst related
to chronic pancreatitis. A mass in the right lower quadrant might be
related to regional ileitis or salpingitis. A mass in the LLQ may be
related to diverticulitis and salpingitis.
Routine laboratory tests include a CBC, sedimentation rate, urinalysis,
urine culture, sensitivity, colony count, chemistry panel, stool for antigen
or serologic tests for 
Helicobacter pylori
, serum amylase and lipase,
44

pregnancy test, stool for occult blood, and stools for ovum and parasites. A
chest x-ray, EKG, and flat plate of the abdomen should also be done. A
urine porphobilinogen will help exclude porphyria. Chronic pancreatitis
can be diagnosed by a cholecystokinin-secretin test.
If these tests are negative, then an upper gastrointestinal (GI) series,
esophagogram, and gallbladder ultrasound would be done for upper
abdominal pain; an intravenous pyelogram (IVP) or CT scan would be
done for flank pain; and a barium enema and sigmoidoscopy would be
performed for lower abdominal pain. At this point, a trial of H
2
 antagonists
or proton pump inhibitors may be appropriate.
If these studies are inconclusive, a gastroenterologist should be
consulted for endoscopic procedures. If there is upper abdominal pain,
esophagoscopy, gastroscopy, and duodenoscopy would be performed.
Endoscopic retrograde cholangiopancreatography (ERCP) may be required
to diagnose cholangitis, chronic pancreatitis, or common duct stones. If
there is lower abdominal pain, colonoscopy would be performed. A CT
scan of the abdomen and pelvis is a useful diagnostic tool also. Gallium
scans may detect a diverticular abscess or other localized area of chronic
inflammation. Ultrasonography is useful in diagnosing a mesenteric artery
occlusion. Pelvic ultrasound may be useful in lower abdominal pain,
especially in females. Aortography and angiography will be useful 
in
abdominal angina. Lymphangiography can be helpful in discovering
retroperitoneal tumors. Ultimately, exploratory laparotomy may still be
necessary in some cases. In chronic lower abdominal pain in females, a
therapeutic trial of antibiotics may resolve pelvic inflammatory disease
(PID), or an intramuscular injection of medroxyprogesterone acetate
(depo-Provera) may determine whether endometriosis is the
 problem.
45

1. 
  2. 
  3. 
ABDOMINAL RIGIDITY
Is there tenderness and rebound tenderness?
 If this is absent,
consider voluntary rigidity. If this is present, the finding must be
considered serious.
Is there a history of trauma?
 A history of trauma brings to mind the
possibility of a ruptured spleen or other abdominal organ rupture or
laceration.
Is there a history of recurrent abdominal pain?
 This finding should
make one think of a ruptured peptic ulcer or diverticulum or a
perforated gallbladder, although appendicitis may occasionally be
preceded by bouts of abdominal pain. If there is no history of trauma
or abdominal pain, consider ruptured appendix, PID, ruptured ectopic
pregnancy, peritonitis, pancreatitis, mesenteric thrombosis, and
ruptured abdominal aneurysm.
A stat CBC, urinalysis, chemistry panel, amylase and lipase, and flat plate
and upright film of the abdomen should be done. Immediate consult with a
general surgeon is in order. If surgery is to be delayed or when the exact
cause of the rigidity is in doubt, consider ordering a chest x-ray to rule out
pneumonia and a peritoneal tap to exclude ruptured ectopic pregnancy,
generalized peritonitis, and laparoscopy. Blood cultures, abdominal
ultrasound, and CT scans of the abdomen may be necessary to diagnose
cholecystitis, diverticulitis, aortic aneurysm, and various neoplasms
associated with rupture. Exploratory laparotomy must be considered in any
case of unexplained tenderness and rigidity when the diagnosis is in doubt.
47

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
ABDOMINAL SWELLING, FOCAL
Is it in the right upper quadrant?
 A mass in the right upper quadrant
is most often an enlarged liver. However, the liver may be pushed
down by a subphrenic abscess, and there may be an enlarged
gallbladder due to cholecystitis or bile duct obstruction. There may be
perinephric abscesses, tumors of the colon, renal tumors, adrenal
tumors, hydrops of the gallbladder, fecal impaction, or an abdominal
wall hematoma.
Is it in the epigastrium?
 A mass in the epigastrium also may be an
enlarged liver, but other types of masses must be considered, including
an omental hernia, pancreatic tumor, pancreatic cyst, gastric
carcinoma, pyloric stenosis, aortic aneurysm, and retroperitoneal
sarcoma.
Is it in the left upper quadrant?
 Left upper quadrant masses are
often a splenomegaly, but abdominal wall hematomas occur in this
area, as well as pancreatic tumors, pancreatic cysts, gastric tumors,
colon tumors, kidney tumors or enlargement, and fecal impaction.
Is it in the right lower quadrant?
 A mass in the right lower quadrant
is frequently a carcinoma of the colon, appendiceal abscess, psoas
abscess, pyosalpinx, regional ileitis, intussusception, or an ovarian
tumor.
Is it in the hypogastrium?
 A mass in the hypogastrium may be
bladder, pregnant uterus, uterine fibroids, regional ileitis, urachal cyst,
omental cyst, and, rarely, endometrial carcinoma.
Is it in the LLQ?
 An LLQ mass is most often a palpable sigmoid
colon, but pathologic conditions such as diverticulitis with abscess,
carcinoma of the colon, and ovarian tumors may be present.
Is the mass tender?
 The presence of a tender mass in the right upper
quadrant often means congestive heart failure, a tender liver from
hepatitis, or a tender gallbladder from cholecystitis, subphrenic
abscess, perinephric abscess, or an abdominal wall hematoma. A
tender mass in the epigastrium may be a pancreatic cyst. A tender
mass in the left upper quadrant may be an abdominal wall hematoma
or a perinephric abscess. A tender mass in the right lower quadrant
may be appendiceal abscess, psoas abscess, pyosalpinx, regional
ileitis, or intussusception. A tender mass in the LLQ may be a
49

8. 
  9. 
diverticulitis or pyosalpinx.
Is there blood in the urine or stool?
 The presence of blood in the
urine, of course, would suggest a tumor of the kidney such as
hypernephroma or Wilms’ tumor. The presence of blood in the GI
tract would suggest either a gastric carcinoma or colon carcinoma but
may also be seen in intussusception, diverticulitis, and regional ileitis.
Occasionally, it is seen in carcinoma of the ampulla of Vater.
Is there fever?
 The presence of fever would suggest that the mass is
an abscess such as subphrenic abscess, perinephric abscess,
diverticular abscess, appendiceal abscess, or pyosalpinx. Fever also
suggests hepatitis, cholecystitis, or cholangitis.
Routine diagnostic tests include a CBC, sedimentation rate, urinalysis,
chemistry panel with electrolytes, amylase and lipase, stool for occult
blood, EKG, chest 
x-rays,
 and a CT scan of the abdomen and pelvis with
and without contrast. A carcinoembryonic antigen test may diagnose colon
cancer. Alpha-1-fetoprotein may diagnose carcinoma of the liver. If there
are chills and fever, blood cultures ought to be done. 
Next in line are
contrast radiographic studies such as upper GI series, barium enema, small
bowel series, IVP, or cholecystogram.
At this point, before ordering more expensive tests, a surgeon or
gastroenterologist should be consulted. An abdominal ultrasound will be
helpful in differentiating cholecystitis and other cystic masses of the
pancreas, kidneys, and reproductive organs.
Endoscopic procedures will help diagnose carcinoma of the stomach
and colon and diverticulitis. ERCP is useful in diagnosing carcinoma of
the pancreas and bile ducts.
Lymphangiography will help differentiate retroperitoneal tumors. An
MRI may provide better visualization of the biliary and pancreatic ductal
systems. Gallium scans will help uncover subdiaphragmatic, perinephric,
diverticular, and pelvic abscesses. Peritoneal taps will help differentiate
ascites, pancreatitis, and peritoneal bleeding. Needle biopsy of the liver or
any mass lesion under laparoscopic guidance may be diagnostic. A
laparoscopy is useful in differentiating many types of masses also.
Ultimately, exploratory laparotomy is still an excellent way of establishing
a diagnosis.
50

1. 
  2. 
  3. 
  4. 
ABDOMINAL SWELLING, GENERALIZED
Is there hepatomegaly?
 If there is hepatomegaly, one should suspect
congestive heart failure, emphysema, constrictive pericarditis, hepatic
vein thrombosis, and cirrhosis of the liver.
Is there dyspnea or cardiomegaly?
 If there is dyspnea or
cardiomegaly, one should suspect congestive heart failure or
emphysema.
Is there hypertension or proteinuria?
 The presence of hypertension
or proteinuria should arouse suspicion of nephritis or nephrosis.
Is there diffuse abdominal tenderness and rebound?
 These findings
are suggestive of tuberculous peritonitis, ruptured viscus, pancreatic
cyst, advanced intestinal obstruction, mesenteric thrombosis or
embolism, acute pancreatitis, and ruptured ectopic pregnancy.
microscopic examination of the urine sediment, chemistry panel, amylase
and lipase, tuberculin test, stool for occult blood, chest x-ray, EKG, and
flat plate of the abdomen with lateral decubitus. In women of child-bearing
age, a pregnancy test should be done.
The presence of ascites or smaller amounts of fluid can be established
by ultrasonography or CT scan. If peritoneal fluid is established, a
peritoneal tap is done and the fluid analyzed and cultured. Cultures should
be done for both routine and acid-fast bacilli (AFB). The fluid may be
spun down and a Papanicolaou (Pap) smear made or cell block study done.
Contrast radiographic studies may identify a primary neoplasm or primary
source for infection. Gallium scans may be utilized to identify a source of
infection. Laparoscopy or exploratory laparotomy is useful in establishing
the diagnosis. A general surgeon or gastroenterologist should be consulted
early in the diagnostic evaluation.
52

1. 
  2. 
  3. 
ABSENT OR DIMINISHED PULSE
A 62-year-old white man complained of pain, numbness, and tingling in
both lower extremities that is increased by walking more than one-half a
block for the past 6 months. He also complains of erectile dysfunction. On
physical examination, his blood pressure is 110/80, but he demonstrates
weak dorsalis pedis, tibialis, popliteal, and femoral pulses in both lower
extremities. There was a loud bruit over both femoral arteries. Following
the algorithm, you suspect a Leriche’s syndrome and you would be
correct.
Is it in the upper or lower extremities?
 
Diminished pulse in the
upper extremities should suggest dissecting aneurysm, embolism,
fracture, arteriovenous fistula, coarctation of the aorta, aortic
aneurysm, thoracic outlet syndrome, and subclavian steal syndrome.
Diminished pulse in the lower extremities should suggest embolism,
fracture, arteriovenous fistula, peripheral arteriosclerosis, Leriche’s
syndrome, and coarctation of the aorta, as well as dissecting aneurysm.
Diminished pulses in all four extremities would suggest shock or
constrictive pericarditis.
Is it unilateral or bilateral?
 The presence of unilateral absent or
diminished pulse should suggest dissecting aneurysm, embolism,
fracture, arteriovenous fistula, some cases of coarctation of the aorta,
aortic aneurysm, thoracic outlet syndrome, and subclavian steal if it is
in the upper extremity. In the lower extremities, unilateral decrease in
the pulse may be caused by arteriosclerosis or arterial embolism.
Bilateral diminished pulses would suggest Leriche’s syndrome, saddle
embolism, dissecting aneurysm, and coarctation of the aorta if it is in
the lower extremity; and if it is in the upper extremity, it may also be
related to a dissecting aneurysm and rarely arteriosclerosis.
Is it sudden in onset?
 
The presence of a sudden onset in diminished
pulse should suggest an embolism or dissecting aneurysm regardless
of where the diminished or absent pulse may be. However, if it is just
the lower extremities, it could be Leriche’s syndrome as well. If all
four extremities are involved, of course, it could be shock.
54

Routine tests include a CBC, sedimentation rate, urinalysis, chemistry
panel, venereal disease research laboratory (VDRL) test, EKG, and chest
x-ray. If there is a history of trauma, x-rays of the involved extremity or
extremities should be done. If it is acute onset with fever, a blood culture
should be done to rule out bacterial endocarditis. Because an acute onset
suggests an embolism, a search for the embolic source should be
undertaken. This would include serial EKGs and cardiac enzymes to rule
out myocardial infarction, echocardiography to rule out a thrombus in the
atrium or ventricle, and 24-hour Holter monitoring to rule out auricular
fibrillation of the paroxysmal variety. A cardiologist should be consulted
for further guidance in determining whether there is an embolic source.
If there are transient ischemic attacks, ultrasonography or four-vessel
angiography should be done to determine whether there is a subclavian
steal. If a dissecting aneurysm is suspected, a CT scan of the chest or
angiography is the diagnostic procedure of choice, and this must be done
without delay. Doppler studies are of assistance in diagnosing the
peripheral arteriosclerosis regardless of where it is, but angiography will
ultimately need to be done to determine the exact location of the blockage
and whether surgery could be effective in alleviating the condition.
55

1. 
  2. 
  3. 
ACID PHOSPHATASE ELEVATION
Is there a prostatic mass or prostate-specific antigen (PSA)
elevation?
 These findings point to a diagnosis of prostatic carcinoma.
If there is also an elevated alkaline phosphatase, there may be bony
metastasis. If there is no prostatic mass or elevated PSA, one should
look for Gaucher’s disease, liver disease, Niemann–Pick disease, or
various hematologic disorders.
Is the alkaline phosphatase elevated?
 As stated previously, an
elevated alkaline phosphatase with a prostatic mass or elevated PSA
points to prostatic carcinoma with bony metastasis. If both the alkaline
phosphatase and acid phosphatase are elevated in the absence of a
prostatic mass or elevated PSA, one should suspect Paget’s disease,
osteogenic sarcoma, and advanced Gaucher’s disease.
Is there no prostatic mass, no elevation of PSA, and no elevation of
the alkaline phosphatase?
 This picture may occur in liver disease,
early Gaucher’s disease, and multiple myeloma.
Initially, this may include a prostatic examination, a CBC, PSA, chemistry
panel, protein electrophoresis, liver profile, skeletal survey, and bone scan.
If the diagnosis is in doubt at this point, an urologist should be consulted.
The urologist may order ultrasonography of the prostate, CT scan of the
abdomen and pelvis, and a biopsy of the prostate.
56

1. 
  2. 
ACIDOSIS (DECREASED pH)
What is the blood glucose and serum acetone level?
 If these are
increased, consider diabetic acidosis. If these are normal, consider
other causes of acidosis.
What is the bicarbonate level?
 An increased bicarbonate level points
to respiratory acidosis, whereas a decreased bicarbonate level points to
renal disease, diarrhea, and the use of certain diuretics.
This should include a CBC, chemistry panel, electrolytes, arterial blood
gas (ABG) analysis, serum and urine ketones, lactic acid, pulmonary
function tests, EKG, and consultation with a pulmonologist or
nephrologist.
58

1. 
  2. 
  3. 
  4. 
ALKALINE PHOSPHATASE ELEVATION
What is the calcium level?
 If this is increased, one should look for
primary hyperparathyroidism and bone metastasis. These two findings
can be further differentiated with parathyroid hormone (PTH) assay. If
calcium is decreased, the patient may have vitamin D deficiency,
malabsorption syndrome, Fanconi’s syndrome, or other renal diseases.
Are there abnormalities of liver function tests?
 If the calcium is
normal but liver function tests are abnormal, think of liver disease,
obstructive jaundice, and liver metastasis. If the patient is not
pregnant, sepsis, Paget’s disease, osteogenic sarcoma, gynecologic
malignancies, and liver and bone metastasis may be considered.
What is the phosphate level?
 In the face of a low calcium level, a
low phosphate level will help distinguish vitamin D deficiency,
malabsorption syndrome, and Fanconi’s syndrome from other renal
diseases in which the phosphate level will be high.
Is there a high 5
′
-nucleotidase or gamma-glutamyltransferase
level?
 This will help distinguish liver disease from Paget’s disease,
metastatic bone disease, and osteogenic sarcoma.
The workup should include a CBC, sedimentation rate, urinalysis,
chemistry panel, protein electrophoresis, liver profile, PTH assay, skeletal
survey, bone scan, CT scan of the abdomen, alkaline phosphatase
isoenzymes, acid phosphatase, and a PSA to rule out prostatic carcinoma.
59

1. 
  2. 
ALKALOSIS (INCREASED pH)
 If this is elevated, the patient has a
metabolic alkalosis. If this is decreased, the patient has a respiratory
alkalosis associated with salicylate intoxication or hyperventilation
syndrome.
Has the patient been vomiting?
 If so, look for gastric outlet
obstruction, intestinal obstruction, and other causes of vomiting. If
there is no history of vomiting, the alkalosis may be caused by
diuretics, Cushing’s disease, or chronic antacid use.
The workup of alkalosis should include a CBC, chemistry panel,
urinalysis, electrolytes, ABG analysis, flat plate of the abdomen, chest x-
ray, and consultation with an endocrinologist.
61

ALOPECIA
The clinician faced with a patient with hair loss must decide whether it is
focal or diffuse. If it is focal, one should determine whether there is a rash
in the area of hair loss. If there is a rash, one should consider conditions
such as tinea capitis, lupus erythematosus, psoriasis, and seborrheic
dermatitis. If there is no rash, one should consider alopecia areata, syphilis,
burns, and other injuries to the skin.
If the area of hair loss is diffuse, one must consider that it might be
male pattern baldness, as well as female pattern baldness in later years. If
it is not typically a male pattern baldness, then one must consider that it
might be caused by a systemic disease myxedema, hyperpituitarism,
hyperthyroidism, anticoagulant drug therapy, or cancer chemotherapy.
If you are looking for pyoderma or a fungal infection, then a smear and
culture of the scrapings for bacteria and fungi should be done. If these are
negative, a skin biopsy should be performed. The skin biopsy will help
identify lupus erythematosus, psoriasis, and alopecia areata. Systemic
disorders may need to be ruled out with thyroid function tests, antinuclear
antibody (ANA) assay, VDRL test, CBC, and serum iron and ferritin. A
dermatologist should be consulted in difficult cases.
62

1. 
  1. 
ALTERATIONS IN SERUM IRON
INCREASED
ASK THE FOLLOWING QUESTION:
What is the red cell count?
 If it is decreased, think of aplastic anemia
and hemolytic anemia. If it is normal, look for hemochromatosis or a
side effect from pyridoxine (B
6
) therapy.
DECREASED
What is the serum ferritin?
 If it is increased, look for chronic
infection or malignancy. If it is decreased, then iron deficiency anemia
is confirmed.
Aplastic anemia will be confirmed by a bone marrow examination as well
as iron deficiency anemia and malignancy. Hemochromatosis is best
confirmed by a liver biopsy. Hemolytic anemia will show elevated serum
haptoglobins and reticulocyte count.
63

1. 
  2. 
  3. 
  4. 
ALTERATION IN SERUM URIC ACID
INCREASED
Is the patient an infant or child?
 If so, the patient may have Lesch–
Nyhan syndrome or Down’s syndrome.
Is the blood urea nitrogen (BUN) increased?
 Under these
circumstances, look for renal failure, obstructive uropathy, or multiple
myeloma.
Is there associated increase of the white or red cell count?
 This
would indicate leukemia or polycythemia.
If none of the foregoing questions can be answered positively, the
patient probably has gout. Other conditions to be considered are drugs
(thiazides, cytotoxics, and ethambutol) and various hematologic
conditions (lymphoma, megaloblastic anemia, etc.).
DECREASED
A decreased uric acid is found in renal tubular acidosis and associated with
diuretics and other drugs.
Order a CBC to diagnose leukemia and polycythemia. An arthrocentesis
may be indicated to diagnose gout, although a therapeutic trial of
colchicine will be useful if there are significant arthritic symptoms. A
chemistry panel and urinalysis will help pin down a diagnosis of renal
disease. Serum protein electrophoresis should be ordered in cases of
suspected multiple myeloma. A hematologist or nephrologist should be
consulted if the diagnosis is still in doubt.
64

1. 
  2. 
  3. 
AMENORRHEA
Is there galactorrhea?
 Of course, the most common cause of
galactorrhea would be the galactorrhea following pregnancy and
delivery. However, if there is galactorrhea, one should consider the
possibility that the patient is taking drugs, including contraceptive pills
and marijuana. Also, one should consider pituitary tumors and
hypothalamic tumors.
Are there abnormal or absent secondary sex characteristics?
 If
there is masculinization, then an adrenal or ovarian tumor or
polycystic ovaries should be considered. If there is simply absence of
female secondary sex characteristics, one should consider Turner’s
syndrome or Simmonds’ disease and other pituitary disorders.
Are there abnormal findings on the vaginal examination?
 
The
amenorrhea may be caused by an imperforate hymen, an imperforate
vagina, absence of the vagina, a cervical stenosis with hematometra,
and absence of a uterus, as in testicular dysgenesis. If there are normal
female secondary sex characteristics and a normal vaginal
examination and no galactorrhea, then some systemic disease such as
anemia, leukemia, or Hodgkin’s disease must be considered as well as
psychogenic causes. Perhaps the amenorrhea is secondary to a
neurologic disorder.
The first thing to do is a pregnancy test, as pregnancy is the most common
cause of secondary amenorrhea. If the pregnancy test is negative, referral
to a gynecologist may be done at this time. If a specialist is not handy, one
may proceed with the workup. A trial of medroxyprogesterone acetate
(Provera) may be done by intramuscular injection or by mouth. If bleeding
occurs on withdrawal of the progesterone, then it is established that the
uterus is functional. It also establishes that the cervix and vagina are
patent. If bleeding does not occur, uterine pathology is likely, and referral
to a gynecologist is necessary.
If there is no galactorrhea, a normal response to progesterone, and the
patient is a teenager, one may simply discontinue studies at this point and
observe for the normal onset of the menstrual cycle.
If the patient with primary amenorrhea has already reached her 20s or
66

if there is definite secondary amenorrhea, then further diagnostic studies
should be done. If there is galactorrhea, a serum for prolactin should be
done. If that is elevated, a CT scan or MRI of the brain should be done to
look for a pituitary tumor or hypothalamic tumor. If there is no
galactorrhea, one should still order a prolactin, but also order a thyroid-
stimulating hormone (TSH) test and tests for follicle-stimulating hormone
(FSH), luteinizing hormone (LH), and serum estradiol. If the FSH and LH
are elevated and the estradiol is decreased, primary ovarian failure must be
considered. A buccal smear for sex chromogens should be done to rule out
Turner’s syndrome. Other causes of primary ovarian failure are ovarian
agenesis and polycystic ovary syndrome. An elevated free testosterone will
support the diagnosis of polycystic ovary syndrome (Stein–Leventhal
syndrome). Perhaps a CT scan of the abdomen and pelvis is indicated.
If the FSH, LH, and estradiol are all decreased, then hypopituitarism
should be considered, as well as hypothalamic disorders. Referral to an
endocrinologist is wise at this point. When an adrenocortical tumor is
suspected, a serum cortisol and cortisol suppression test should be done.
67

1. 
  2. 
AMNESIA
Is the amnesia transient or persistent?
 If it is transient, one should
look for evidence of a head injury. If there is no evidence of a head
injury, then one should consider epilepsy, transient ischemic attacks,
and migraine. If there is evidence of a head injury, one would consider
concussion and some of the other more serious conditions of the brain
that occur with a head injury.
Is there a fever?
 If the amnesia is persistent and there is a fever, one
needs to consider encephalitis, meningoencephalitis, cerebral
abscesses, and encephalomyelitis. If there is no fever, one must ask if
there is a reduction of memory for recent events. If there is reduction
of memory for recent events, one should consider some of the more
serious diseases of the brain, such as cerebral tumors, chronic drug or
alcohol use, Alzheimer’s disease, cerebral arterial sclerosis, and
neurosyphilis. If there is no reduction of memory for recent events,
then a psychiatric disorder such as hysteria, dissociated reaction, or
schizophrenia must be considered.
All patients with a history of amnesia deserve a CT scan or MRI. The CT
scan would be more cost-effective and would be the diagnostic test of
choice because it also helps detect acute brain hemorrhages. Patients with
fever should have a spinal tap as well as CBC, urinalysis, and chemistry
panel. These patients also probably should have a blood culture. An
electroencephalogram (EEG) should be ordered to rule out epilepsy and
toxic, metabolic, and inflammatory diseases of the brain.
If all these studies are negative and an organic cause is still considered,
then referral to a neurosurgeon or neurologist is in order. If these studies
are negative and a psychiatric disorder is suspected, a psychiatrist should
be consulted.
69

1. 
  2. 
  3. 
  4. 
  5. 
ANEMIA
A 59-year-old white man complains of difficulty with his memory and
tingling of his hands and feet for the past year. His physical examination
reveals a slight decrease in vibratory sense below the knees and a smooth
tongue. His hemoglobin in your office is 13.1 g. Although this is not
striking, you know that this is below the normal of 14 to 17 for males.
Following the algorithm, you find he denies alcohol abuse and has not
noted bloody or tarry stools in the past year. He is not jaundiced. You
order a CBC and find, among other things, that his white count is low. You
suspect pernicious anemia, and further studies confirm your diagnosis.
Is there a history of chronic blood loss?
 A history of peptic ulcer,
ulcerative colitis, or other causes of chronic GI bleeding would
indicate the anemia is most likely caused by iron deficiency. Likewise,
chronic hypermenorrhea or metrorrhagia in women of child-bearing
age may lead to iron deficiency anemia.
Are there neurologic signs?
 Paresthesias, loss of vibratory sense,
ataxia, and mild dementia should lead one to suspect pernicious
anemia.
Is there jaundice?
 Clinical jaundice should arouse the suspicion of a
hemolytic anemia, but mild clinical jaundice may be seen in
pernicious anemia also. Chronic liver disease, such as alcoholic
cirrhosis, is often associated with folate deficiency or sideroblastic
anemia.
What is the white count?
 A decreased white count should alert one to
the possibility of aplastic anemia, myelofibrosis, or infiltrative
diseases of the bone marrow, such as carcinomatosis, Gaucher’s
disease, or lymphoma. It may also be related to pernicious anemia. An
increased white count would suggest leukemia, chronic infections,
anemia, or bacteremia.
Is the tourniquet test positive?
 This would suggest disseminated
intravascular coagulation or thrombocytopenia purpura of various
etiologies.
71

The most important thing to do initially is to examine a blood smear for
red cell morphology. If the anemia is microcytic, one would consider iron
deficiency or chronic blood loss. If it is macrocytic, consideration should
be given to pernicious anemia or folate deficiency. If there are
schistocytes, look for disseminated intravascular coagulation. Further
workup should include a CBC, red cell indices, chemistry panel, sickle cell
prep, Hb electrophoresis, stool for occult blood, liver function tests,
reticulocyte count, serum homocysteine, serum ferritin, serum iron and
iron-binding capacity, serum B
12
 and folic acid, serum haptoglobin, and
platelet count. A urine test for methylmalonic acid will help diagnose
pernicious anemia. A positive stool for occult blood would prompt a GI
workup. If these studies are inconclusive, a hematologist should be
consulted. A hematologist will perform a bone marrow examination for a
more definitive diagnosis. Perhaps a liver–spleen scan, CT scan of the
abdomen, or therapeutic trial of iron, B
12
, or folic acid is indicated.
72

1. 
  2. 
ANKLE CLONUS
What other symptoms and signs are present?
 Ankle clonus rarely
occurs by itself. Usually, there are pathologic reflexes such as a
Babinski’s sign on the lower extremities. The patient usually will also
complain of weakness and may be found to have weakness when the
muscles are tested. If the ankle clonus is long-standing, there will be
atrophy. There will also frequently be sensory findings as well as
sensory complaints. Finally, with bilateral ankle clonus there will
often be hyperactive reflexes throughout the lower extremities and
sometimes in the upper extremities.
Is the ankle clonus unilateral or bilateral?
 If it is unilateral, then it
is a sign of either hemiparesis or monoplegia; and if it is hemiplegia or
hemiparesis, one should consider the possibility of a cerebral disorder.
If there is headache and papilledema, that disorder is most likely a
space-occupying lesion of the brain such as a brain tumor, abscess, or
hematoma. If there is hemiparesis and it is acute in onset, there is most
likely an occlusion of one of the cerebral arteries, whereas if the
hemiparesis is gradual in onset, one should consider multiple sclerosis
and, once again, a brain tumor. Ankle clonus associated with
monoplegia is more likely related to a spinal cord tumor, but a
parasagittal tumor could also be present. Bilateral ankle clonus is more
likely caused by a disorder of the spinal cord such as a spinal cord
tumor, amyotrophic lateral sclerosis, or multiple sclerosis.
Syringomyelia and Friedreich’s ataxia may also present with bilateral
ankle clonus. However, if there are cranial nerve signs, one must
consider a brain stem tumor as well as other degenerative diseases of
the brain and brain stem.
Ankle clonus is a significant clinical sign, especially when it is unilateral.
Therefore, if a brain disorder is suspected, a CT scan or MRI of the brain
should be done. If a spinal cord lesion is suspected, then a CT scan at the
appropriate level of the spinal cord should be done. If there are no findings
on the examination to indicate a level, then, of course, the entire spine
would have to be covered. MRI is a more cost-effective method for the
cervical and thoracic levels of the cord. The spinal tap with analysis of the
74

fluid for myelin basic protein and gamma globulin levels should be done if
multiple sclerosis is suspected. In addition, somatosensory evoked
potentials (SSEPs) and visual evoked potentials should also be done if
multiple sclerosis is suspected. Finally, the most cost-effective approach to
a patient with ankle clonus is to refer the patient to a neurologic specialist.
75

1. 
  2. 
  3. 
  4. 
  5. 
ANOREXIA
A 32-year-old white woman presents to your office with the chief
complaint of anorexia and weight loss over the past 3 months. Following
the algorithm, you ask about a history of drug or alcohol use or abuse.
There is no cough or night sweats to suggest tuberculosis, carcinoma, or
other pulmonary conditions.
Your examination fails to reveal an abdominal mass or hepatomegaly.
You suspect anorexia nervosa, hypopituitarism, and adrenal insufficiency.
Is it acute or chronic?
 Acute anorexia would most likely be caused
by an acute febrile disease or acute psychiatric disturbance.
Is there a history of drug or alcohol ingestion?
 Alcoholics
frequently have a loss of appetite. Patients on aspirin and digitalis and
many other drugs may lose their appetite.
 The abdominal mass may be either an
enlarged liver or other mass. The most likely abdominal mass to
produce anorexia as the only symptom would be an early pancreatic
neoplasm. When the neoplasm advances, jaundice should be present.
Other neoplasms may be felt and/or metastasize to the liver and cause
hepatomegaly.
Is there a cough?
 If there is a chronic cough, one should consider
tuberculosis or carcinoma of the lung.
 Hepatomegaly without any other masses
present in the abdomen would certainly bring to mind cirrhosis. This
could be of cardiac origin, so congestive heart failure should be ruled
out. Also, the hepatomegaly may be related to a collagen disease or
metastatic carcinoma.
If the general physical examination is normal, it may be wise to obtain a
psychiatric consultation at the outset. All patients with anorexia as the
major sign should have a CBC, sedimentation rate, chemistry panel,
thyroid profile (free thyroxine index [FT
4
I] and thyroid-stimulating
hormone–sensitive assay [S-TSH]), and a chest 
x-ray.
 A referral to a
76

gastroenterologist may be wise if these are negative. However, if the
clinician wishes to proceed on his own, then a search for a neoplasm
should be conducted and should include an upper GI series, barium enema,
abdominal CT scan, and bone scan. If these are negative, a gastroscopy or
colonoscopy may be required.
A complete endocrinologic workup by an endocrinologist may be
indicated if all the above studies are negative. Patients with a normal
physical examination and normal diagnostic studies should be referred to a
psychiatrist.
77

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
ANOSMIA OR UNUSUAL ODORS
 Acute loss of smell would certainly suggest an
acute upper respiratory infection. It would also suggest recent
exposure to toxic fumes or recent head injury. If the anosmia or
unusual odor is intermittent, then one should consider psychomotor
epilepsy.
 A skull fracture, particularly if it
involves the cribriform plate, may interrupt the olfactory nerves and
cause anosmia.
Is there a history of drug use or overuse of nasal sprays?
 Captopril
and penicillamine may cause anosmia. Overuse of alcohol or tobacco
may also be the problem. Antirheumatic and antiproliferative drugs
are also known to cause anosmia.
Is the anosmia unilateral or bilateral?
 If there is unilateral anosmia,
one should consider an olfactory groove meningioma.
Are there other neurologic signs?
 Multifocal neurologic signs
should suggest multiple sclerosis, and additional neurologic signs such
as memory loss should suggest an olfactory groove meningioma or
parietal lobe tumor.
Are there signs of a systemic disease?
 Many systemic diseases may
cause anosmia, including hypothyroidism, diabetes, renal failure,
hepatic failure, and pernicious anemia.
If the disorder is acute and associated with an upper respiratory infection,
nothing needs to be done. However, if the condition has been of gradual
onset, the nasopharyngeal examination is negative, and the history of drugs
is negative, then a CT scan of the brain should be done. If this is negative,
a workup for systemic disease should be done, and that should include a
CBC and chemistry panel, thyroid profile, serum B
12
 and folic acid,
glucose tolerance test, and liver profile. If the anosmia or unusual odors
are intermittent, a wake-and-sleep EEG should be done. This symptom is
often delusional, so a psychiatrist may need to be consulted at the outset.
78

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
ANURIA OR OLIGURIA
Has the patient been on any drugs?
 Sulfonamides are notorious for
causing renal failure, but one must also consider amphotericin B, gold
compounds that might be administered in arthritis, and lead and other
drugs or heavy metals.
What is the blood pressure?
 
If there is hypertension and anuria, one
should consider acute or chronic glomerulonephritis, polycystic
kidneys, and acute tubular necrosis. If there is a low blood pressure,
one should consider prerenal causes of anuria such as dehydration,
blood loss, the acute abdomen, and other causes of shock.
Is there cardiomegaly or chest pain?
 If there is an enlarged heart,
one should consider congestive heart failure. If there is chest pain, one
should consider myocardial infarction or pulmonary infarction. If there
is chest or abdominal pain with hypertension, then one should
consider dissecting aneurysm.
Is there enlargement of the kidneys?
 Enlargement of both kidneys
should suggest bilateral hydronephrosis or polycystic kidneys.
Unilateral enlargement of the kidneys is not usually associated with
anuria.
Is there bladder enlargement?
 Enlarged bladder would make one
think of bladder neck obstructions due to prostatic hypertrophy or
carcinoma or a urethral stricture. Occasionally, what is thought to be
an enlarged bladder is actually a pelvic mass that is obstructing the
ureters.
Is there hematuria?
 Hematuria would suggest glomerulonephritis,
acute tubular necrosis, intravascular hemolysis, and nephrolithiasis.
What has been the patient’s recent intake of fluid?
 Dehydration is a
frequent cause of oliguria and anuria.
The first thing to determine is whether the patient really has anuria or
oliguria. A Foley catheter should be passed and attached to drainage to
determine the urine output. If there is obstructive uropathy due to bladder
neck obstruction, this will obviously determine the diagnosis, as there will
be a large volume of urine and it should be taken off gradually. Then
studies of obstructive uropathy can be done, including cystoscopy and
80

retrograde pyelography. If the obstructive uropathy is caused by
obstruction of the ureter, renal ultrasonography can be reliable in detecting
the dilated calyces or dilated ureter.
If the patient presents with anuria and hypotension, the most important
thing is to reestablish the blood pressure with a bolus of normal saline or
dopamine drip. If the anuria does not cease at this point, high-dose
furosemide or a mannitol infusion can be started. Meanwhile, a CBC,
chemistry panel, urinalysis, spot urine sodium, serum protein
electrophoresis, an ANA assay, an EKG, and chest x-ray should be done.
A flat plate of the abdomen should give an idea of the kidney size, but a
CT scan of the abdomen is even better. The clinician should examine the
urinary sediment himself, and this will identify cases of acute
glomerulonephritis, lupus erythematosus, and acute tubular necrosis with
considerable accuracy. The BUN and creatinine ratio are helpful in
distinguishing prerenal from renal azotemia.
If intravascular hemolysis is suspected, serum haptoglobins and serum
hemoglobin tests should be done. Eosinophilia of the blood or urine will
be found in drug-induced nephritis. Renal angiography and aortography
should be done in 
cases of suspected dissecting aneurysm or bilateral renal
artery stenosis. Abdominal ultrasound will also be helpful in diagnosing
polycystic kidneys and pelvic masses that may be obstructing the ureter. A
CT scan may be necessary as well.
In difficult cases, a renal biopsy may be necessary to diagnose the
various collagen diseases and the various forms of glomerulonephritis.
Referral to a nephrologist would be best at this point.
81

1. 
  2. 
  3. 
  4. 
  5. 
ANXIETY
Is the anxiety intermittent or constant?
 Intermittent anxiety
suggests the possibility of psychomotor epilepsy, a
pheochromocytoma, or insulinoma. It is also possible that the patient
is suffering from an intermittent cardiac arrhythmia such as
paroxysmal supraventricular tachycardia or atrial fibrillation.
What is the patient’s age?
 Be alert for sexual abuse in children with
anxiety. The young or middle-aged patient is more likely to be
suffering from a psychiatric disorder, whereas the older patient may be
suffering from cerebral arteriosclerosis or some other type of
dementia.
If there is tachycardia, is it sustained during sleep?
 Tachycardia
that is sustained during sleep would suggest hyperthyroidism, caffeine
effects, or other drug effects.
Is there associated weight loss?
 Sustained tachycardia with weight
loss makes hyperthyroidism a very likely possibility.
What drugs or addictive substances is the patient on?
 You would
not want to miss alcohol, caffeine, or cocaine abuse.
Routine workup begins with a CBC, chemistry panel, and thyroid panel. If
routine laboratory studies and physical examination are normal, a trial of
selective serotonin reuptake inhibitors may be warranted before launching
on an expensive diagnostic workup. Patients with intermittent anxiety with
long periods of calmness in between should have a wake-and-sleep EEG
and possibly a CT scan to rule out a cerebral tumor. A 24-hour urine
collection for catecholamines should also be done to rule out a
pheochromocytoma. Twenty-four-hour Holter monitoring may be
necessary to rule out a paroxysmal cardiac arrhythmia. In difficult cases, a
24-hour
 EEG or an EEG with nasopharyngeal electrodes inserted may be
necessary.
Patients with constant anxiety should have a thyroid profile, a drug
screen, and an EKG. If these are not revealing, perhaps 24-hour Holter
monitoring may be of some value. With a negative workup, a referral to a
psychiatrist is in order. It may be even wiser to consult a psychiatrist
before undertaking an expensive workup.
83

1. 
  2. 
  3. 
  4. 
APHASIA, APRAXIA, AND AGNOSIA
Is it intermittent?
 Episodic aphasia, apraxia, or agnosia would
suggest epilepsy, transient ischemic attacks, migraine, or hypertensive
encephalopathy.
Is it acute or gradual in onset?
 Acute onset of aphasia, apraxia, or
agnosia would suggest a cerebral vascular accident, or if there is fever,
the onset of a cerebral abscess. It may also mark the onset of acute
encephalitis. The gradual onset of aphasia, apraxia, and agnosia would
suggest a tumor or other type of space-occupying lesion.
Is there associated headache or papilledema?
 Headaches with
aphasia, apraxia, and agnosia might suggest migraine, but one should
not forget a brain tumor. Obviously, papilledema is a sign of a space-
occupying lesion.
Is there significant dementia?
 The development of dementia along
with the aphasia, apraxia, and agnosia suggest Alzheimer’s disease,
Pick’s disease, herpes encephalitis, multiple sclerosis, or Korsakoff’s
psychosis.
All patients should have a CBC, sedimentation rate, chemistry panel, a
VDRL test, and a CT scan of the brain. The CT scan may demonstrate an
infarct, a 
space-occupying
 lesion, a degenerative disease, or multiple
sclerosis. If this is negative, a neurologist should be consulted before
ordering an MRI or a spinal tap.
If the patient presents with intermittent aphasia, apraxia, or agnosia, an
EEG should be done to rule out epilepsy, and a carotid scan should be
done to rule out carotid stenosis or carotid plaques with ulceration. Four-
vessel angiography may need to be considered, but a neurologist should be
consulted before this is done.
85

1. 
  2. 
  3. 
  4. 
ASCITES
Is there associated dyspnea?
 If there is associated dyspnea, one
should look for congestive heart failure, pulmonary emphysema, and
other cardiopulmonary conditions.
 If there is associated hepatomegaly, certainly
cirrhosis of the liver has to top the list of possibilities, but additional
causes of ascites with hepatomegaly are constrictive pericarditis, the
cardiomyopathies, Budd–Chiari syndrome, metastatic carcinoma, and
hydatid cyst.
Is there edema of the lower extremities or significant proteinuria?
Edema in the lower extremities along with significant proteinuria
certainly suggests a nephrotic syndrome, whether it is caused by
glomerulonephritis, diabetes, or a collagen disease. It also suggests
end-stage nephritis. If there is no significant proteinuria, then a
primary peritoneal condition such as tuberculous peritonitis or
peritoneal carcinomatosis must be considered. Remember, a large
ovarian cyst can simulate ascites.
Is there a history of a primary tumor elsewhere?
 GI tumors may
spread to the peritoneal surface and cause ascites, but a malignant
melanoma may do the same thing.
Ultrasonography may help confirm the presence of ascites and
differentiate it from other conditions such as pregnancy or ovarian cysts. A
peritoneal tap with analysis of the fluid to determine whether it is a
transudate or exudate, and cell block studies as well as amylase, culture
and sensitivity should be done; an elevated amylase indicates pancreatic
disease. A CBC, chemistry panel, urinalysis, spot urine sodium and
sedimentation rate need to be done in all cases, and the urinary sediment
should be examined under the microscope.
To rule out congestive heart failure, a brain natriuretic peptide (BNP),
circulation time, EKG, pulmonary function studies, echocardiography, and
chest x-ray should be done. To rule out pulmonary emphysema, pulmonary
function studies, ABGs, and chest x-rays should be done. To rule out liver
disease, a liver profile may be done along with a serum protein
electrophoresis and a CT scan of the liver. A tuberculin test can be done to
87

rule out tuberculous peritonitis, but the ascitic fluids should be studied
with an AFB smear and culture. Guinea pig inoculation is sometimes
necessary for a positive diagnosis. Laparoscopy is useful in differentiating
peritoneal carcinomatosis from tuberculous peritonitis. A CT scan of the
abdomen should be done to determine whether there is peritoneal
carcinomatosis or a primary malignancy of the GI tract and other
structures in the abdomen. An upper GI series and barium enema may
need to be done. Also, colonoscopy and gastroscopy may need to be done.
As the diagnostic tests become more expensive, the clinician should
consider a referral to a gastroenterologist, nephrologist, or hepatologist
before proceeding.
88

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
ASPARTATE AMINOTRANSFERASE
ELEVATION
Is the patient receiving heparin therapy?
 As many as 27% of
patients taking heparin have an elevated aspartate aminotransferase
(AST, or serum glutamine-oxaloacetic transaminase), and 60% have
an elevated alanine aminotransferase.
Are the results of liver function tests abnormal?
 This indicates that
the elevated AST is caused by liver disease.
Is the creatine phosphokinase (CPK) or troponin elevated?
 An
elevated CPK would indicate that the elevated AST is related to
muscle damage or disease or a myocardial infarction. Further
differentiation of these two conditions is made by ordering CPK
isoenzymes and an EKG.
What is the arm-to-tongue circulation time?
 This is increased in
congestive heart failure.
Is the serum amylase elevated?
 This would point to pancreatitis as
the cause of the AST elevation. If all of the above related tests are
normal, the AST elevation is most likely caused by liver disease or
renal infarction.
Is the patient participating in risky sexual behavior?
 In this case,
look for Hepatitis B or C.
What drugs is the patient on?
 Isoniazid, statins, alcohol, and
depakote cause elevated AST.
Additional tests to order that will help pin down the diagnosis include a
CBC, troponin, BNP, serum amylase, chemistry panel, lactic acid
dehydrogenase isoenzymes, gamma-glutamyltransferase, urinalysis, serial
EKGs, echocardiography, pulmonary function tests, chest x-ray, flat plate
of the abdomen, electromyography, liver biopsy, and muscle biopsy.
Consultation with a cardiologist or hepatologist would be prudent before
ordering expensive diagnostic tests.
89

1. 
  2. 
  3. 
  4. 
  5. 
ATAXIA
A 67-year-old white man complains of increasing loss of balance for
several months. He denies headaches, vertigo, tinnitus, or deafness.
Neurologic examination discloses no nystagmus or papilledema, but there
is definite loss of vibratory and position sense in the lower extremities and
a smooth tongue. You suspect pernicious anemia and you would be
correct.
Is there vertigo, tinnitus, or deafness?
 Any one of these three signs
and symptoms should suggest Ménière’s disease or other labyrinthine
disease as well as eighth nerve pathology.
Are there headaches, nystagmus, or papilledema?
 These signs
should suggest a cerebellar tumor or acoustic neuroma.
 If there are long tract signs such as
hyperactive reflexes and loss of vibratory or position sense, one
should consider multiple sclerosis, pernicious anemia, or basilar artery
insufficiency. If there are glove and stocking hypoesthesia and
hypoactive reflexes, one should consider peripheral neuropathy or
tabes dorsalis. Normal pressure hydrocephalus often presents with
ataxia and dementia.
Is the ataxia worse in the dark?
 This is a sign that the dorsal column
or peripheral nerve is affected, and one should look for peripheral
neuropathy, pernicious anemia, multiple sclerosis, and Friedreich’s
ataxia. One should also look for tabes dorsalis.
Is there a secondary gain?
 Hysterical patients and patients who are
malingering will often show a completely normal neurologic
examination, but be unable to walk or stand without staggering. The
author has been particularly impressed with patients applying for long-
term disability who stagger a great deal without support, but as soon
as support in the form of a cane is given, their ataxia completely clears
up.
A wise clinician should consider a neurologic referral at the outset. If there
91

is vertigo, tinnitus, or deafness, then an audiogram and caloric testing
should be done. If these suggest eighth nerve damage, then a CT scan or
MRI of the brain should be done. Headaches, sustained nystagmus, or
papilledema are other indications for a CT scan or MRI. If multiple
sclerosis is suspected, MRI of the brain is very useful, as well as spinal
fluid for gamma globulin and myelin basic protein. Perhaps visual evoked
potential, brain stem evoked potential, or SSEP studies should be done. If
vascular disease is suspected, magnetic resonance angiography will allow
assessment of the vertebral-basilar arteries. If this is not available, four-
vessel cerebral angiography may be utilized. Patients with hypoactive
reflexes and glove and stocking hypesthesia and hypalgesia will need a
neuropathy workup (see 
page 378
). When there is ataxia in the presence of
a normal neurologic examination, referral to a psychologist for
psychometric testing should be done.
92

ATHETOSIS
Athetosis is an involuntary, smooth, sinuous, writhing movement of the
upper limbs and, less commonly, the face and lower extremity. The pill-
rolling of Parkinson’s disease is an example. Athetosis is caused by a
lesion of the basal ganglia. It may be the result of cerebral palsy,
encephalitis, Wilson’s disease, Parkinson’s disease, dystonia musculorum
deformans, or a cerebral infarct.
Patients presenting with this complaint should have MRI, a serum copper
and ceruloplasmin, a CBC, and liver function tests. A spinal tap should be
performed if central nervous system lues is suspected.
94

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
AXILLARY MASS
 Unilateral masses are usually an abscess
or enlarged lymph nodes due to some infectious process in the
extremity served by the axillary nodes or the breast served by the
axillary nodes. The unilateral mass may also be a tuberculous abscess,
lipoma, a sebaceous cyst, metastatic carcinoma, or Hodgkin’s disease.
Rarely, it is caused by an aneurysm. When the masses are bilateral,
one should consider a systemic infection, leukemia, or advanced
lymphoma. Rheumatoid arthritis and tuberculosis may be associated
with bilateral axillary nodes.
Is it painful or painless?
 A painful axillary mass is usually an acute
abscess or an acute inflammation of the lymph node caused by
infection on the extremity or breast supplied by the lymph node or
hidradenitis suppurativa.
Is there a discharge from the mass?
 A discharge from an axillary
mass usually means hidradenitis suppurativa.
 Fever with a bilateral axillary mass would suggest an
acute systemic infection or infectious mononucleosis. Fever with a
unilateral axillary mass would suggest that there is mastitis, a breast
abscess, or lymphangitis of the extremity supplied by the axillary
lymph nodes.
If the mass is unilateral, are there signs of an infection on the
extremity or breast supplied by the axillary nodes?
 In tularemia,
there will be a bubo on the extremity supplied by the axillary nodes,
and in lymphadenitis, there should be an infectious lesion on the
extremity involved. If the lymphadenitis is caused by mastitis, there
should be a breast discharge or extreme tenderness and enlargement of
the breast.
Does the mass pulsate?
 A pulsatile mass in the axilla is usually an
aneurysm.
If the mass is fluctuant or exudes a discharge, then needle aspiration or an
Incision and drainage (I&D) should be done and the material retrieved to
have culture and sensitivity performed on it. The discharge may also be
cultured for an organism. A surgeon may need to be consulted for
95

diagnosis and treatment. All patients with bilateral axillary masses should
have a CBC, sedimentation rate, chemistry panel, and urinalysis. Skin
testing for tuberculosis, sarcoidosis, and various fungi should be done. A
chest x-ray should be done to look for tuberculosis or malignancy.
Mammography should be done in cases of unilateral axillary masses that
suggest lymphadenopathy. In the final analysis, a biopsy of the mass may
need to be done to make the diagnosis.
96

1. 
  2. 
  3. 
  4. 
  5. 
BABINSKI’S SIGN
Is the onset acute?
 Babinski’s sign of acute onset is because of
trauma or vascular diseases in most cases. If there is fever, one should
consider an infectious process, most likely a cerebral abscess. Multiple
sclerosis may also cause Babinski’s sign of recent or acute onset.
Is Babinski’s sign unilateral or bilateral?
 Unilateral Babinski’s
signs suggest a space-occupying lesion of the brain such as hematoma,
abscess, or tumor. It also suggests a cerebral vascular accident. If
Babinski’s signs are bilateral, it may be because of a toxic or
degenerative condition of the brain such as encephalitis. It may also be
because of a spinal cord tumor or other space-occupying lesion of the
spinal cord.
Are there associated cranial nerve signs?
 If there is associated
central facial palsy on the ipsilateral side, one should consider an
infarct or a 
 lesion of the opposite cerebral
hemisphere. If there are cranial nerve signs aside from a facial palsy,
one should consider a brain stem lesion, especially if they are
contralateral.
Are there hypoactive reflexes?
 Babinski’s sign with hypoactive
reflexes, if it is of acute onset, would be considered a traumatic or
vascular lesion of the brain if it is unilateral and an acute vascular or
traumatic lesion of the spinal cord if it is bilateral. Hypoactive reflexes
of relatively insidious onset should make one think of pernicious
anemia or Friedreich’s ataxia.
Are there hyperactive reflexes?
 Unilateral hyperactive reflexes of
the upper and lower extremity with cranial nerve signs should bring to
mind middle cerebral artery thrombosis or hemorrhage, carotid
stenosis, and a 
 lesion of the brain. Hyperactive
reflexes of the upper and lower extremities with no cranial nerve signs
should suggest a high spinal cord tumor or a herniated cervical disk,
especially if it is unilateral. Unilateral hyperactive reflexes of the
lower extremity only would suggest an anterior cerebral artery
thrombosis or parasagittal meningioma. Hyperactive reflexes of all
extremities with cranial nerve signs should suggest a basilar artery
thrombosis, brain stem tumor, or other lesion of the brain stem.
Weakness and hyperactive reflexes of all four extremities without
97

6. 
  7. 
  8. 
  9. 
cranial nerve signs and without any sensory changes should suggest a
primary lateral sclerosis, although multiple sclerosis may occasionally
present in this manner.
Are there sensory changes?
 Hyperactive reflexes with sensory
changes confined to the trunk and extremities would make one think
of a spinal cord lesion such as multiple sclerosis, pernicious anemia, or
Friedreich’s ataxia, and, especially if it is unilateral, one would
consider a space-occupying lesion of the spinal cord. Other
considerations are transverse myelitis and anterior spinal artery
occlusion.
Is there involvement of the lower extremity only?
 This is an
important question to ask, as this would suggest a spinal cord tumor of
the thoracic level or a parasagittal meningioma.
Is there radicular pain?
 The association of radicular pain in the
cervical or thoracic area would make one think of a spinal cord tumor
or other 
 lesions of the spinal cord.
Is there associated fever?
 The finding of fever along with a unilateral
Babinski’s sign should make one think of a cerebral abscess or an
epidural abscess 
somewhere in the spinal column. The finding of fever
with bilateral Babinski’s signs should make one think of encephalitis,
particularly if there are disturbances of consciousness. However, fever
may be associated with a cerebral vascular accident, so don’t be
misled.
It is wise to consult a neurologist at the outset. The diagnostic workup
depends on other symptoms and signs that help the physician determine
what level the neurologic lesion might be. If there is an acute unilateral
Babinski’s sign with hemiplegia and cranial nerve signs, a space-
occupying lesion or vascular lesion of the brain must be considered. In that
case, a CT scan or MRI of the brain should be done, and this may be
followed with a spinal tap and carotid scans if a vascular lesion is
suspected. A spinal tap would not be done if there is any possibility of
increased intracranial pressure.
If a cerebral vascular disease is suspected, then a source for an
embolism should be looked for. Useful studies include echocardiography
and possibly blood cultures and an EKG. If the patient’s condition had an
insidious onset and there are no cranial nerve signs, an MRI of the cervical
or thoracic sign should be done to look for a tumor, multiple sclerosis, or
degenerative diseases.
98

Babinski’s sign associated with trauma and without cranial nerve signs
should prompt one to do x-rays of the cervical, thoracic, and lumbar spine
for fracture and other traumatic lesions. If there are associated disturbances
of consciousness, one must look for a cerebral lesion, and MRI of the brain
must be done in these traumatic conditions.
The fact that Babinski’s sign is a definite sign of neurologic disease is
reason enough to call a neurologic specialist in before undertaking any
diagnostic studies. A neurologic consultation is much less expensive than a
CT scan or MRI.
99

1. 
  2. 
  3. 
  4. 
BACK PAIN
A 72-year-old black male presents to your office with a 3-month history of
low back pain. Following the algorithm, you find there is no history of
trauma, fever, or chills. The pain radiates down the back of both legs and
he has had difficulty with urination for the past month.
Your examination shows a suprapubic mass, a small nodule of the right
lobe of the prostate, saddle hypesthesia and hypalgesia, and absent
Achilles reflexes bilaterally. The suprapubic mass disappears after you
catheterize him and remove 625 mL of urine. You suspect a cauda equina
tumor and you would be correct.
Is the pain of acute onset or gradual onset?
 If it is of acute onset,
one must consider the possibility of epidural abscess, pyelonephritis,
or other abdominal conditions as the cause of the back pain. If it is of
gradual onset, one should consider that it may be a tumor, particularly
of the spinal cord or cauda equina, a pelvic tumor, or an aortic
aneurysm that is compressing one of the nerve roots. In addition,
chronic conditions such as lumbar spondylosis, rheumatoid
spondylitis, and prostatitis must be considered.
 If there is a history of trauma, one
should consider a compression fracture of the spine, a sprain or
herniated disk, as well as spondylolisthesis. Without a history of
trauma, one should consider a tumor, herpes zoster, or dissecting
aneurysm. Lumbar spondylosis might be silent for a while only to
cause pain after a significant traumatic event.
Is there radiation of the pain around the trunk or into the
extremities?
 Radiation of the pain would certainly be more likely to
signify a 
 lesion of the spinal column such as a tumor,
an epidural abscess, or a herniated disk. If there is no radiation, one
would consider osteoarthritis or lumbar spondylosis and rheumatoid
spondylitis.
Finally, are there bladder symptoms associated with the pain?
 If
there are, then one must consider the possibility of a spinal cord
tumor, cauda equina tumor, or kidney disease.
100

The first thing to do is rule out malingering. With the patient standing
straight and one of your hands on his shoulder and the other on the
opposite hip, rotate his body. If he complains of pain he is probably
malingering. Next, measure the leg length. At least one-fourth of the
patients with back pain have one leg shorter than the other. All patients
with back pain need to have a CBC, urinalysis, and probably a urine
culture, as well as a chemistry panel. A sedimentation rate and arthritis
panel should be done if rheumatoid arthritis is suspected. All patients
should also have plain x-rays of the thoracic and/or lumbar spine. It is very
important to get anteroposterior (A-P) views, as well as oblique and lateral
views. A standing upright A-P will help diagnose a short leg syndrome as
well. At this point, it is wise to observe the results of conservative therapy
before ordering expensive diagnostic tests. If there is doubt about the
diagnosis at this point, a neurologic or orthopedic specialist may be
consulted. If there is radiation of the pain into the extremities or around the
trunk and definite neurologic findings, one should proceed to a CT scan 
or
MRI immediately. The CT scan costs about half as much as the MRI and
usually will show any significant herniated disks, primary or metastatic
tumor. The CT scan is the procedure of choice in severe trauma. Even
without radiation of pain into the extremities or definite neurologic
findings, a patient with persistent back pain should have a CT scan or
MRI. EMG will be useful in identifying radiculopathy.
When all these studies are negative, it might be wise to get a bone scan
because this will show the increased uptake of the sacroiliac joints in
rheumatoid spondylitis. Also, one should test for the HLA B27 antigen.
Bone scans are also more likely to show metastatic tumors but can be
negative in patients with multiple myeloma. In the event that all of the
above studies are negative, the possibility of a non-neurologic condition or
nonorthopedic condition causing the back pain should be considered.
Perhaps abdominal ultrasound should be done to rule out an aortic
aneurysm. Perhaps a pelvic tumor or prostatic tumor should be
reconsidered. Perhaps there is a pancreatic tumor that is causing the back
pain. Occasionally, combined myelography and CT scan is the only way to
identify a lesion. Exploratory surgery is rarely necessary. Older patients
should have a serum protein electrophoresis (for multiple myeloma) and
acid phosphatase or PSA to rule out prostatic carcinoma.
Table 02: Low Back Pain
101

Radiation
Positive Femoral
Stretch Test or
SLR
Focal
Neurologic
Signs
Bladder
Symptoms
Sprain
No
No
No
No
Sacroiliitis
No
No
No
No
Fracture
No
Infrequent
Rare
No
Yes
Yes
Yes
No
Lumbar
spondylosis
Yes
Often
Occasional
No
Scoliosis
No
No
No
No
Yes
Yes
Often
No
Spinal stenosis
Yes
Yes
Yes
Rheumatoid
spondylitis
No
No
No
No
Pelvic tumor
Often
Rare
No
Yes
No
No
No
Yes
Cauda equina
tumor or abscess
Yes
Yes
Yes
Yes
102

1. 
  2. 
  3. 
BLEEDING GUMS
Are there abnormalities on examination of the teeth or gums?
 The
gums may be swollen, as in phenytoin use and early scurvy, and bleed
on slight pressure, as in pyorrhea or other conditions. There may be
ulceration of the tongue, gums, and buccal mucosa. There may be
isolated dental caries that are causing bleeding. Excessive tartar may
be noted on the teeth.
Is there an enlarged spleen or a systemic rash?
 The presence of an
enlarged spleen should bring to mind Hodgkin’s disease, leukemia,
lupus erythematosus, thrombocytopenia purpura, and aplastic anemia.
A systemic rash that is because of petechiae is common in any
disorder that might cause thrombocytopenia.
Is there a positive Rumpel–Leede test?
 This would test for capillary
fragility, and it may be positive in scurvy, thrombocytopenia purpura,
leukemia, and other disorders that depress the platelet count. It will
also be positive in disorders of platelet function such as von
Willebrand’s disease.
A CBC, sedimentation rate, chemistry panel, ANA titer, and coagulation
profile are basic studies that need to be done. If these are negative, referral
to a dentist or periodontist would be appropriate. X-rays of the teeth need
to be done to look for dental caries, abscesses, and pyorrhea. X-rays of the
teeth will also help identify scurvy. A plasma or platelet ascorbic acid
level needs to be done if scurvy is suspected. If syphilis is suspected, a
VDRL test needs to be done.
103

1. 
  2. 
  3. 
BLINDNESS
A 72-year-old Hispanic male is brought to the emergency room because of
sudden onset of blindness in the left eye which has persisted for several
hours. Your examination shows weakness and hypoactive reflexes in the
right extremities but a normal ophthalmoscopic examination. There is a
left carotid bruit, so you suspect a carotid artery thrombosis. A carotid
duplex scan confirms your suspicions.
Is it transient?
 Transient blindness may occur in transient ischemic
attacks, epilepsy, migraine, and hypertension.
Is it a sudden onset?
 The sudden onset of blindness may occur in
optic neuritis, retinal vein thrombosis, central retinal artery occlusion,
vitreous hemorrhage, detached retina, carotid artery thrombosis,
temporal arteritis, injuries to the optic nerve, retrobulbar neuritis,
fracture of the skull, glaucoma, posterior cerebral artery occlusion,
multiple sclerosis, and hysteria.
 Unilateral blindness may occur in
glaucoma, vitreous hemorrhage, optic neuritis, retinal vein thrombosis,
central retinal artery thrombosis, carotid artery thrombosis, temporal
arteritis, injury to the optic nerve, fractured skull, brain tumors,
retinoblastomas, and sphenoid ridge meningiomas. Bilateral blindness
may occur in posterior cerebral artery occlusion, pituitary tumors,
retinitis pigmentosa, hereditary optic atrophy, uveitis, toxic amblyopia,
104

4. 
  5. 
cataracts, glaucoma, multiple sclerosis, and iritis. Head trauma may
cause transient cortical blindness in children.
Is there papilledema?
 The presence of papilledema should make one
suspect optic neuritis, retinal vein thrombosis, and space-occupying
lesions of the brain.
Are there abnormalities on ophthalmoscopic examination?
 Besides
papilledema, there may be changes on the ophthalmoscopic
examination in iritis, glaucoma, papillitis from optic neuritis, retinal
vein thrombosis, central retinal artery occlusion, vitreous hemorrhage,
detached retina, and retinoblastoma.
Referral to an ophthalmologist is usually the first step in a good workup. If
one is not available, a careful eye examination including slit lamp
examination, visual acuity evaluation, tonometry, and visual field studies
should be done. If these are unrevealing, referral to an ophthalmologist or
neurologist should be made without further delay. Additional studies
would include a CT scan or MRI of the brain and orbits, carotid scans,
spinal tap, magnetic resonance angiography (MRA), VEP studies, and
four-vessel cerebral angiography. An EEG would be useful in diagnosing
hysterical blindness and malingering. Ocular ultrasonography may be
helpful in diagnosing intraocular lesions.
105

1. 
  2. 
  3. 
  4. 
  5. 
BLURRED VISION
 The presence of unilateral blurred vision
should suggest such local ocular conditions as cataract, refractive
error, iritis, glaucoma, keratitis, retinal detachment, foreign body, and
optic neuritis. Transient blurred vision may occur in migraine and
carotid artery insufficiency. Orbital fracture and vitreous hemorrhage
may also cause unilateral blurred vision.
Bilateral blurred vision may result from cocaine use, methyl alcohol
poisoning, tobacco, barbiturates, quinine, and other drugs. However,
cataracts, glaucoma, chorioretinitis, retinitis pigmentosa, optic
atrophy, papilledema, papillitis, optic neuritis, refractive error,
pituitary tumors, posterior cerebral artery occlusion, concussion,
migraine, and hysteria must also be considered.
Is there a positive history for drug or alcohol ingestion?
 If this
history is positive, then cocaine, tobacco, barbiturates, methyl alcohol,
quinine, and other drugs may be responsible.
 Sudden onset of blurred vision should make
one suspect migraine, optic neuritis, vitreous hemorrhage, iritis,
keratitis, glaucoma, retinal detachment, foreign body, retrobulbar
neuritis, orbital fracture, carotid artery insufficiency, and hysteria.
Is the eye examination abnormal?
 Local ocular diseases such as
cataracts, refractive errors, iritis, keratitis, glaucoma, retinal
detachment, foreign bodies, retinitis pigmentosa, chorioretinitis, and
papilledema should be detected by the primary care physician.
A referral to an ophthalmologist is usually the first step in a workup. If an
ophthalmologist is not available, a careful eye examination including slit
lamp evaluation, tonometry, visual acuity evaluation, and visual fields
should be done. A toxicology screen may be indicated by history. If these
studies are unremarkable, referral to a neurologist may be made. Further
studies would include a CT scan or MRI of the brain, carotid scans, spinal
tap, VEP studies, and four-vessel cerebral angiography. Ocular
ultrasonography may be helpful in diagnosing intraocular lesions.
106

1. 
  2. 
  3. 
  4. 
BONE MASS OR SWELLING
 Trauma, of course, may cause fractures
and subperiosteal hematomas.
Is the patient a child or an adult?
 Children are more likely to have
Ewing’s tumors, scurvy, rickets, syphilis, battered baby syndrome,
osteosarcoma, osteomas, and osteochondromas. Adults are more likely
to have giant cell tumor, metastasis, osteomyelitis, osteogenic
sarcoma, fibrosarcoma, multiple myeloma, generalized fibrocystic
disease, Paget’s disease, acromegaly, and chondromas.
Are the lesions single or focal or are they multiple or diffuse?
Multiple and diffuse lesions in children are often because of scurvy,
rickets, syphilis, and battered baby syndrome. Multiple lesions or
diffuse lesions in adults are often because of metastasis, multiple
myeloma, generalized fibrocystic disease, Paget’s disease,
acromegaly, and chondroma. Single lesions in children are more likely
to be fracture, osteomyelitis, hematoma, Ewing’s tumor,
osteosarcoma, osteomas, and osteochondromas. Single lesions in
adults are often because of a giant cell tumor, osteomyelitis, fracture,
hematoma, osteogenic sarcoma, and fibrosarcoma, but may be because
of a metastasis.
Are the lesions usually painful?
 Painful lesions in children are more
likely to be because of fracture, osteomyelitis, hematoma, Ewing’s
tumors, scurvy, syphilis, battered baby syndrome, and rickets. Painful
lesions in adults may be because of a giant cell tumor, metastasis,
osteomyelitis, fracture, hematomas, osteogenic sarcoma,
fibrosarcomas, and multiple myeloma.
Routine diagnostic studies include a CBC, sedimentation rate, urinalysis,
chemistry panel, arthritis panel, serum protein electrophoresis, and plain
films of the involved bones. A skeletal survey may be necessary. If the
diagnosis remains in doubt, consult an orthopedic surgeon at this point.
Bone scans are often useful. A search for a primary tumor may require
chest x-ray, upper GI series, barium enema, IVP, CT scan of the abdomen
mammography, prostatic examination, PSA titer, thyroid scans, lymph
node biopsy, and bone marrow examinations.
108

CT scans of the area may help differentiate the mass or swelling.
Needle biopsy or exploratory surgery and bone biopsy may be necessary
before deciding what surgical approach should be undertaken.
109

1. 
  2. 
  3. 
BORBORYGMI
Is there abdominal distention?
 If there is abdominal distention, an
intestinal obstruction should be considered.
Is there obvious diarrhea?
 If there is diarrhea, one should look for
malabsorption syndrome, lactase deficiency, and carcinoid syndrome.
Other causes of chronic diarrhea are discussed in 
page 134
.
Is there flushing of the face?
 If there is significant flushing of the
face along with diarrhea, carcinoid syndrome is the most likely
possibility.
If there is significant distention of the abdomen, a flat plate of the
abdomen with lateral decubitus should be done to rule out intestinal
obstruction. A stool examination for occult blood, culture, quantitative fat
and ovum and parasites should be done. If there is flushing, a urine test for
5-hydroxyindoleacetic acid (5-HIAA) should be done to rule out carcinoid
syndrome. A lactose tolerance test may be indicated. After these tests are
done, further workup can proceed. An upper GI series with an
esophagogram, a small bowel series, and a barium enema would be next in
line. If all these studies are negative, perhaps referral to a
gastroenterologist or psychiatrist would be indicated. Endoscopy is rarely
110

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
BRADYCARDIA
 If there is fever, one should look for yellow fever,
diphtheria, cerebral abscess, or meningitis. Perhaps the fever and
bradycardia are related to increased intracranial pressure from
apoplexy.
Are there episodes of syncope?
 The addition of syncope should make
one think of a sick sinus syndrome, complete heart block, vasovagal
syncope, or carotid sinus syncope.
Is there a heart murmur present?
 Heart murmurs are found in
complete heart block, but they are also a sign of aortic stenosis, which
can cause bradycardia.
Is there a history of drug ingestion?
 Several drugs can induce
bradycardia, the most notable being digitalis; propranolol, quinidine,
calcium channel blockers, amitriptyline, and various cholinergic drugs
also may induce bradycardia. Opium poisoning may cause
bradycardia.
Is there nonpitting edema?
 Obviously, this is a sign of myxedema
and should be looked for in any patient presenting with bradycardia.
Is there chest pain?
 An acute myocardial infarction may present with
bradycardia, although it is more typical for tachycardia to be
associated with this condition. Heart disease, most notably, Chagas
disease, sarcoidosis, and Lyme disease, can cause a second- and third-
degree block, which may result in bradycardia, but also various other
types of arrhythmia that cause slowing of the pulse.
If there is fever without any definite focal signs, a CBC, sedimentation
rate, blood culture, chemistry panel, febrile agglutinins, and tests for other
antibodies may be done. Digoxin levels are helpful for patients on this
drug. If there is fever with nuchal rigidity, a spinal tap should be done,
preferably after a CT scan. An EKG will need to be done on all patients,
and if this shows simple sinus bradycardia and there is no history of drug
ingestion, a thyroid profile should be done. If there is chest pain, serial
EKGs and cardiac enzymes should be done. If there is a heart murmur,
echocardiography would be an important ancillary study. If the EKG
shows various types of arrhythmia, a cardiologist should be consulted for
112

further evaluation. A trial of glucagon IM or IV is helpful for beta-blocker
overdose.
113

1. 
  2. 
  3. 
  4. 
BREAST DISCHARGE
Is the discharge unilateral or bilateral?
 If it is unilateral and watery
or bloody, one should look for a neoplasm in the breast. If it is
bilateral and milky, one should look for the various conditions that
cause hyperprolactinemia or pregnancy.
Is the discharge bloody?
 A unilateral bloody discharge is most
suggestive of carcinoma of the breast. Other types of lesions of the
breast, such as Paget’s disease, papillary cystadenoma, and
epithelioma of the nipple, are also causes of a bloody discharge.
Is there a focal mass in the breast?
 A bloody discharge with a focal
mass makes a neoplasm almost certain. If there is a focal mass, fever,
and a nonbloody discharge, one should consider abscess.
 Fever or chills along with a purulent discharge from
the breast is most likely acute mastitis or an abscess.
If there is a bloody discharge, one should not hesitate to refer the patient to
a general surgeon, who will probably order mammography and perform a
biopsy. The type of biopsy may be either a fine-needle aspiration or fine-
needle biopsy or excisional biopsy, but the general surgeon can decide
which is appropriate for any given patient. A unilateral nonbloody
discharge may be studied further by ordering tests for occult blood,
cytology, and mammography before referral. If infection is suspected,
order a CBC, culture of the discharge, and trial of antibiotic therapy.
Remember that exploratory surgery may be the only way to get a
If the discharge is bilateral and milky, a serum prolactin should be
ordered. If the prolactin is high, referral to an endocrinologist is probably
the best step to take next. The endocrinologist will probably order a CT
scan of the brain and pituitary and do further workup studies based on his
or her examination.
114

1. 
  2. 
  3. 
  4. 
  5. 
BREAST MASS
 
A tender mass is most likely because of an
infectious process such as mastitis or an abscess. However, chronic
cystic mastitis may present with a tender mass. Also, advanced
carcinoma of the breast usually produces a tender mass.
Is there a discharge?
 A bloody discharge from the breast means that
the mass is most likely because of a malignant process. If there is a
purulent discharge, abscess or mastitis must be considered. A watery
discharge is often associated with chronic cystic mastitis, and this
occasionally may become bloody.
Does it transilluminate?
 Cysts of the breasts and galactoceles
customarily transilluminate. A mass that does not transilluminate is
probably a benign or malignant tumor.
Is there a deformity of the breast associated with the mass?
 An
orange peel appearance of the skin over a tumor certainly suggests that
it is a carcinoma. Retraction of the skin or the nipple suggests
carcinoma. Also, in carcinoma there may be necrosis and ulceration of
the tissues overlying the tumor.
 Fever would suggest an acute mastitis or abscess.
A breast mass is usually a clear indication for referral to a general surgeon.
However, if the mass is tender a course of antibiotics and/or I&D may be
initiated first if infection is suspected. The general surgeon will probably
perform mammography and a biopsy before proceeding with surgery. If a
cystic lesion is suspected, ultrasonography may be done, followed by fine-
needle aspiration and biopsy. When there is a definite mass on physical
examination, surgery is indicated even if mammography and other tests are
negative.
116

1. 
  2. 
  3. 
  4. 
BREAST PAIN
 Unilateral breast pain should make one
think of an infectious process or advanced carcinoma. Bilateral breast
pain should make one think of pregnancy. This may be a normal
pregnancy or an ectopic pregnancy.
Is there an associated mass?
 A tender breast mass is most likely a
mastitis or abscess, but advanced carcinoma can also produce a tender
breast mass. If there are tender masses in both breasts, chronic cystic
mastitis should be considered.
 A bloody discharge associated with a tender
breast should make one think of a carcinoma. A nonbloody discharge
suggests a breast abscess.
 Fever associated with a tender breast or tender breast
mass is most likely acute mastitis or abscess.
If there is fever and discharge, a culture and sensitivity of the discharge
should be done before beginning antibiotics. When there is a localized
tender mass, referral to a general surgeon should be made. Patients with
bilateral breast pain without any masses identified should have a
pregnancy test. If this is negative and the pain is associated with menstrual
cycle, they should be treated as having premenstrual tension. A
gynecologist may need to be consulted. If there is persistent bilateral breast
pain in a young unmarried female, perhaps a psychiatrist should be
consulted. Mammography is done first for localized masses followed up
with ultrasonography and biopsy as indicated.
118

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
CARDIAC ARRHYTHMIA
 An acute cardiac arrhythmia should make one
consider a myocardial infarction first.
Is the heart rate slow, normal, or fast?
 A rapid cardiac arrhythmia
may be associated with hyperthyroidism, congestive heart failure, or
drug toxicity. A slow cardiac arrhythmia is more likely to be
associated with heart block and syncope. A myocardial infarction may
produce either rapid or slow cardiac arrhythmia.
Is the rhythm regular or irregular?
 A tachycardia with a regular
rhythm is more likely to be a supraventricular tachycardia or
ventricular tachycardia. Carotid sinus massage can be used to
distinguish sinus tachycardia from supraventricular arrhythmias. A
tachycardia with an irregular rhythm is more likely to be atrial
fibrillation, but atrial flutter can also cause a rapid irregular rhythm.
Irregular premature contractions and ventricular premature
contractions may be associated with rapid, slow, or normal cardiac
rates. A slow, fairly regular heart rate is associated with complete
heart block.
Is there chest pain associated with the cardiac arrhythmia?
 Chest
pain should make one think of myocardial infarction, pericarditis, or
coronary insufficiency.
 If there is fever, one should consider rheumatic fever,
subacute bacterial endocarditis, and thyroid storm.
Is there a heart murmur associated with the arrhythmia?
 A heart
murmur associated with arrhythmia should make one think of
rheumatic fever or subacute bacterial endocarditis, myocardiopathy, or
acute congestive heart failure.
Are there signs of congestive heart failure?
 Hepatomegaly, jugular
vein distention, crepitant rales, and pitting edema of the extremities
would make one think that congestive heart failure was the cause of
the arrhythmia.
Is there a thyroid enlargement?
 An enlarged thyroid gland would
certainly make one think of thyrotoxicosis.
Is there hypertension?
 Hypertension is another important cause of
cardiac arrhythmias that should not be forgotten.
120

All patients should have an EKG, chest x-ray, and a CBC to rule out
anemia. A thyroid profile should be done to look for both hyperthyroidism
and hypothyroidism. In acute arrhythmias, serial EKGs and tests for
cardiac enzymes need to be done to exclude an acute myocardial
infarction. Venous pressure and circulation time or BNP should be
determined to rule out congestive heart failure; pulmonary function tests
may be helpful, as they may rule out both congestive heart failure and
emphysema. Echocardiograms should be done to rule out valvular disease
and cardiomyopathy. If there are paroxysmal arrhythmias, Holter
monitoring needs to be done. An exercise tolerance test may allow the
recording of an arrhythmia that is only induced on exercise. Signal-
averaged EKG and electrophysiologic testing should also be considered.
Patients on digitalis, quinidine, or other cardiac drugs should have blood
levels of these drugs measured to determine if their levels are toxic. If
there is fever, blood cultures should be done to rule out bacterial
endocarditis. Referral to a cardiologist can be made at any point in the
121

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
10. 
CARDIAC MURMURS
Could the murmur be extracardiac in origin?
 Extracardiac
murmurs include the pericardial friction rub and cardiorespiratory
murmurs.
Is the murmur continuous?
 A continuous murmur is most often
because of a patent ductus arteriosus or combined valvular stenosis
and insufficiency. However, arteriovenous aneurysms and ruptured
aneurysm of the sinus of Valsalva must also be considered.
Is the murmur systolic or diastolic?
 Diastolic murmurs include
aortic regurgitation and mitral stenosis and are always organic. Many
systolic murmurs are functional in nature.
Is there associated cardiomegaly?
 An enlarged heart associated with
the murmur makes it more likely that it is pathologic. One would
consider mitral regurgitation, aortic regurgitation, and aortic stenosis
and various forms of congenital heart disease.
 Hepatomegaly associated with the murmur
would make one think of congestive heart failure or tricuspid
regurgitation and tricuspid stenosis.
 Cardiac murmurs occurring with fever
suggest acute rheumatic fever and subacute bacterial endocarditis.
Is there dyspnea?
 Dyspnea associated with a cardiac murmur
suggests congestive heart failure.
 If there is chest pain associated with a cardiac
murmur, one must consider pericarditis and myocardial infarction.
Is there an enlarged thyroid or intention tremor?
suggest hyperthyroidism.
Is there cyanosis or clubbing?
 These findings suggest congenital
heart disease.
If the murmur is believed to be organic, the most cost-effective approach
would be to consult a cardiologist at the outset. If the astute clinician
wishes to pursue the diagnostic workup on his own, it is suggested that a
CBC, sedimentation rate, chemistry panel, VDRL test, and thyroid profile
should be done for the initial blood work. In addition, a chest x-ray
including obliques, to rule out congestive heart failure, phonocardiograms,
122

and EKG should be performed. These findings may provide a diagnosis. If
there is fever, a streptozyme test, antistreptolysin-O (ASO) titer, and serial
blood culture should be performed. If congestive heart failure is suspected,
venous pressure and circulation time and BNP should be determined.
Pulmonary function studies are also helpful. Echocardiography will be
extremely helpful in diagnosing the various forms of valvular disease and
will also help in identifying a pericardial effusion, congestive heart failure,
or the various cardiomyopathies. The recent development of CTA and
MRA may eliminate the need for an invasive study. Nevertheless, cardiac
catheterization and angiography and angiocardiography will identify the
various congenital heart lesions and valvular disease. These studies,
however, are most important when surgery is being considered.
123

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
CARDIOMEGALY
Is there a murmur?
 Cardiomegaly with cardiac murmur suggests
valvular disease, but it also suggests congestive heart failure and
advanced cardiomyopathies. One should also be sure that the murmur
is not a pericardial friction rub.
 Fever with cardiomegaly should suggest rheumatic
heart disease and bacterial endocarditis. However, it may also suggest
an acute myocarditis or acute pericarditis.
 Cardiomegaly with chest pain would certainly
suggest a myocardial infarction, but it may also suggest an acute
pericarditis.
 Cardiomegaly and hepatomegaly suggest
congestive heart failure. Hepatomegaly may also suggest one of the
systemic diseases that cause a myocardiopathy such as amyloidosis.
Is there edema?
 The presence of peripheral edema would suggest
congestive heart failure, and if it is nonpitting, it would suggest
myxedema.
 Cardiomegaly with hypertension would
suggest that the cardiomegaly is because of left ventricular
enlargement from chronic hypertension.
Is there cyanosis?
 Cardiomegaly with cyanosis, particularly if there is
an associated murmur, suggests congenital heart disease of the
cyanotic type.
A CBC, sedimentation rate, ANA, chemistry panel, VDRL test, thyroid
profile, EKG, and chest x-ray should be done on all patients. An
echocardiogram or CTA will be helpful in diagnosing valvular disease,
myocardiopathies, congestive heart failure, and pericardial effusion. If
congestive heart failure is suspected, BNP, venous pressure, and
circulation time can be measured, and one should do pulmonary function
studies. If there is fever, then one should do a streptozyme test, ASO titer,
and serial blood cultures. If there is hypertension, a hypertensive workup
may be indicated (see 
page 268
). Patients with cyanosis need a workup for
congenital heart disease, which will probably include cardiac
catheterization and angiocardiography.
125

Most prudent physicians will refer the patient with cardiomegaly to a
cardiologist before pursuing this extensive diagnostic workup.
126

CHEST DEFORMITY
Many deformities of the chest may be observed on inspection of the
patient and provide a clue to lung or systemic disease. Scoliosis may be a
clue to syringomyelia, old poliomyelitis, muscular dystrophy, and
Friedreich’s ataxia. The “rachitic rosary” seen in rickets is because of
swelling of the costochondral junctions. Expansion of one side of the chest
may be seen in acute pneumothorax. A barrel chest is typical of
emphysema. Empyema may produce a localized swelling of the chest. An
aortic aneurysm may cause a pulsatile swelling of the upper anterior chest.
Hodgkin’s disease, carcinoma of the lung, tuberculosis, actinomycosis, and
various benign tumors of the lung will cause localized swellings in the
chest.
Plain films of the chest, thoracic spine, and ribs will usually be diagnostic
of chest deformities. Sputum culture and sensitivity, pleural fluid analysis,
culture, and CT scans will be helpful in confusing cases. Referral to a
pulmonologist will also help clear up the confusion.
127

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
10. 
CHEST PAIN
Is the chest pain acute or chronic?
 If it is acute, one must consider
acute myocardial infarction, dissecting aneurysm, pulmonary
embolism, pneumothorax, pericarditis, and fractures. If the chest pain
is chronic, one must consider chronic coronary insufficiency,
esophagitis, hiatal hernia, and various chest wall conditions. The
endocardium is the source of chest pain in mitral valve prolapse.
Is the pain constant or intermittent?
 Constant pain suggests acute
myocardial infarction, pulmonary infarction, dissecting aneurysm, and
pneumonia. Intermittent pain would suggest coronary insufficiency,
Tietze’s disease, and Da Costa’s syndrome. Intermittent chest pain at
rest may be because of Prinzmetal angina.
Is there associated significant hypertension?
 Significant
hypertension would make one think of dissecting aneurysm, but it is
also found occasionally in acute myocardial infarction.
Is the pain relieved by antacids?
 Relief by antacids should prompt
one to consider reflux esophagitis and hiatal hernia.
Is the pain precipitated or increased by breathing?
 The pain of
pleurisy, costochondritis, rib fractures, and pneumothorax is
precipitated or increased by breathing. In costochondritis, there is
tenderness of the costochondral junctions.
Is there associated hemoptysis?
 Hemoptysis should make one
consider a pulmonary embolism.
Is there fever and purulent sputum?
 Fever and purulent sputum
should make one consider pneumonia.
 Dyspnea should make one consider pneumothorax,
pulmonary embolism, and pneumonia, as well as congestive heart
failure secondary to acute myocardial infarction.
Is it aggravated by movement?
 Aggravation of the chest pain by
movement should suggest pericarditis. Remember, myocardial
infarctions may also have extension into the pericardium and must be
considered at times.
Is it relieved by nitroglycerin?
 Relief by nitroglycerin should suggest
a coronary insufficiency, but esophagospasm may be relieved by
nitroglycerin also. Relief with 5 to 10 mL of lidocaine viscous will
128

help diagnose reflux esophagitis.
All patients should have a CBC, sedimentation rate, CRP, ANA, chemistry
panel, lipid profile, VDRL test, chest x-ray, and EKG. If there is sputum, a
smear and culture should be done as soon as possible. A urine drug screen
should be done in young adults. Coronary artery disease in the young
should prompt an investigation for collagen disease.
If a myocardial infarction is suspected, then serial EKGs and tests for
the isoenzyme of creatine kinase (CK-MB) should be done if the initial
EKG and enzymes do not show any significant changes. Serum cardiac
troponin levels may also be diagnostic of a myocardial infarct. Thallium-
201 scintigraphy is useful in diagnosing both myocardial infarction and
coronary insufficiency. Exercise tolerance tests may help diagnose
coronary insufficiency. Immediate coronary angiography should be
undertaken if the condition deteriorates and in the cases of ST segment
elevation myocardial infarction (STEMI). This can be followed by
immediate balloon angioplasty, reperfusion therapy, or bypass surgery.
Non-STEMI chest pain can be evaluated by CCTA (coronary CT
angiography) first.
If a pulmonary embolism is suspected, arterial blood gases and a
ventilation–perfusion scan or a spiral CT of the chest should be done,
which may also pick up a dissecting aneurysm. D-dimer testing of whole
blood is a sensitive test of pulmonary embolus. It is also elevated in
patients with a dissecting aneurysm. Pulmonary angiography may need to
be done if these are negative and pulmonary embolism is still strongly
suspected. Ultrasonography of the lower extremities will be helpful in
picking up an embolic source as will an MRI of the pelvis. CTA will easily
diagnose a dissecting aneurysm.
If esophageal disease is suspected, an upper GI series with
esophagogram should be done; this can be followed by esophagoscopy and
gastroscopy if needed. A Bernstein test (acid perfusion of the esophagus)
may reproduce the exact pain and distinguish esophageal reflux from a
cardiac source of the pain. Ambulatory pH monitoring may also diagnose
reflux esophagitis. A trial of proton pump inhibitors may obviate the
necessity for all of these tests if it is successful in making the patient
asymptomatic.
If pericarditis is suspected, echocardiography and possibly a CT scan
of the chest and pericardium may be necessary. Coronary angiography
may be necessary to diagnose coronary insufficiency. CCTA and a CT
129

scan for coronary calcium have been helpful in distinguishing which
patients may benefit most from invasive coronary angiography. A negative
CCTA can essentially rule out coronary artery disease. Echocardiography
is also helpful in diagnosing mitral valve prolapse and the various
myocardiopathies. Twenty-four-hour Holter monitoring is useful in
diagnosing many causes of intermittent chest pain.
Referral to a cardiologist or pulmonologist may be appropriate at any
point in this workup. Dissecting aneurysm may be confirmed by a CT
scan, transesophageal echocardiography, or MRI of the chest.
Table 03: Chest Pain
130

1. 
  2. 
  3. 
  4. 
CHEST TENDERNESS
 Fractured or bruised ribs head the list
of traumatic conditions that can cause chest tenderness. Intercostal
myositis and burns may cause tenderness.
Are there significant signs of systemic diseases?
 Signs of petechiae
or ecchymoses elsewhere may suggest blood dyscrasia. Splenomegaly
and hepatomegaly may also suggest a systemic disease. Evidence of
arthritic changes of the joints may suggest ankylosing spondylitis.
Is there a rash in the area of the tenderness?
 A rash in the area of
tenderness suggests herpes zoster. At times only a few vesicles or
bullae may be present, and it is easy to miss this diagnosis in the early
stages.
Are there abnormalities on auscultation and percussion of the
lung?
 The pleura and pericardium may elicit a friction rub that
indicates pericarditis or pleurisy. Flatness or dullness to percussion
may indicate pleural effusion, lobar pneumonia, or empyema. There
may be a murmur beneath the area of tenderness suggesting an aortic
aneurysm.
In any case of unexplained tenderness of the chest, x-ray of the chest and
the ribs will be extremely useful in the diagnosis. If a systemic disease is
suspected, a CBC and sedimentation rate, chemistry panel, and arthritis
profile should be done. If cardiac disease is suspected, serial EKGs and
serial cardiac enzymes may be necessary. A bone scan may diagnose
subtle fractures or metastatic neoplasm of the ribs. A CT scan may be
helpful in mediastinal tumors. Trigger point injections may help diagnose
costochondritis. In confusing cases, a cardiologist should be consulted.
132

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
CHILLS
Is there a heart murmur?
 The presence of a heart murmur should
suggest bacterial endocarditis.
 The presence of jaundice should suggest ascending
cholangitis and cholecystitis. Viral hepatitis is not usually associated
with chills.
Is there frequency or burning of urination?
 The presence of
frequency or burning of urination should suggest pyelonephritis,
perinephric abscess, and prostatic abscess.
 The presence of an enlarged liver usually
without jaundice is indicative of amebic abscess. The liver may be
palpable, but not significantly enlarged in subdiaphragmatic abscess.
 Neurologic findings would indicate a
brain abscess, sinus thrombosis, various forms of encephalitis, and
epidural abscess. Don’t forget that an epidural abscess of the spine
may have its onset with chills. This type of abscess should be looked
for in diabetics.
Is there cough or rales?
 The presence of cough or rales should
prompt a search for a lung abscess, lobar pneumonia, bronchiectasis,
and tuberculosis.
Is there bone pain or a bone mass?
 These findings are typical of
osteomyelitis.
Are there no focal signs of infection?
 Without focal signs of
infection, one should suspect septicemia, malaria, acute hemolytic
anemia, relapsing fever, subdiaphragmatic abscess, and dental
abscesses. However, chills may occur at the onset of any acute
infection.
This is identical to the diagnostic workup for acute fever on 
page 198
.
134

1. 
  2. 
  3. 
  4. 
CHOREIFORM MOVEMENTS
 Children are likely to develop
Sydenham’s chorea, Tourette’s syndrome, or Wilson’s disease.
Huntington’s chorea and senile chorea usually occur in adults.
Is there associated fever or joint pain?
 The presence of fever or
joint pain would make one think of Sydenham’s chorea, encephalitis
lethargica, or systemic lupus erythematosus.
Is there a family history?
 A family history will be found in patients
with Huntington’s chorea, Tourette’s syndrome, and Wilson’s disease.
 
Several drugs can lead to
choreiform movements, including the phenothiazines, levodopa,
anticonvulsants, and birth control pills.
A toxicology screen is usually the first thing to be done. A sedimentation
rate, ASO titer, streptozyme test, and EKG will help diagnose Sydenham’s
chorea. Serum copper and ceruloplasmin will help diagnose Wilson’s
disease. An ANA assay may be done in patients suspected of having lupus
erythematosus. Young adults with high-risk sexual behavior require
human immunodeficiency virus (HIV) testing. If these tests are
unrewarding, a neurologist should be consulted.
136

1. 
  2. 
  3. 
CLUBBING OF THE FINGERS
A 42-year-old executive is found to have clubbing on a routine physical.
Following the algorithm, you look for cyanosis, heart murmurs, and
cardiomegaly and find none of these. There is a history of chronic
productive cough but no fever, chills, or night sweats. A CT scan of the
chest reveals bronchiectasis.
 Cyanosis should make one think of cyanotic
congenital heart disease and pulmonary arteriovenous aneurysms.
Is there a cough or dyspnea?
 A cough or shortness of breath should
make one think of a pulmonary condition such as bronchiectasis,
chronic interstitial fibrosis, asbestosis, emphysema, or carcinoma of
the lung. Lung abscesses and tuberculosis must also be considered,
although they are less frequent.
 A fever along with the clubbing should make one
think of empyema, lung abscess, tuberculosis, or subacute bacterial
endocarditis.
An EKG and chest x-ray will identify the most common causes of
clubbing. A CBC, sedimentation rate, and chemistry panel should also be
done routinely. If there is fever, a sputum smear, culture and sensitivity,
and blood culture should be done. An upper GI series, an esophagogram,
and a barium enema will identify most GI disorders. Cyanotic congenital
heart disease will require further workup, including a cardiology
consultation, cardiac catheterization, and angiocardiography. A
thoracentesis may be necessary to diagnose empyema. Sputum cytology is
the first step if a neoplasm is suspected. Bronchoscopy may be necessary
to diagnose carcinoma of the lung. A CT scan of the chest can be used to
diagnose bronchiectasis.
If a more extensive workup is necessary, referral to a pulmonologist or
cardiologist should be considered.
138

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
COMA
 This is a very
important question to ask, as many cases of coma are because of acute
alcohol intoxication, delirium tremens, opium poisoning, barbiturate
poisoning, and other toxic cerebral depressants.
 Most of the time it will be obvious that
the patient has suffered a blow to the head. However, there are many
times when one must contact the family or other people who witnessed
the onset of the coma to determine if there was trauma.
Are there focal neurologic signs?
 Focal neurologic signs would
make one think of a stroke, brain abscess, brain tumor, or epidural or
subdural hematoma.
 Papilledema certainly would indicate a
possible 
 lesion such as a brain tumor, brain abscess,
or subdural hematoma.
Is there a sweet odor to the breath?
 A sweet odor to the breath
should make one think of a diabetic coma or alcoholism.
 If there is fever, one should be thinking of meningitis,
subarachnoid hemorrhage, or acute encephalitis. However, aspiration
pneumonia, urinary tract infection, or septicemia may explain the
fever.
Is there nuchal rigidity?
 The presence of nuchal rigidity suggests a
meningitis or subarachnoid hemorrhage.
Are there sibilant or crepitant rales on examination of the lung?
Sibilant rales would suggest the possibility that pulmonary
emphysema is responsible for the coma, whereas crepitant rales would
suggest that there is congestive heart failure or possibly pneumonia.
When one encounters a patient with coma, the first thing to do is to
establish an airway. Next, the blood pressure is taken. If there are any
signs of shock, an intravenous access is established, and the shock is
treated appropriately. A cardiology and surgical consult are obtained.
Blood should then be drawn for a CBC, type and cross-match,
sedimentation rate, chemistry panel, electrolytes, serum osmolality to rule
out hyperosmolar nonketotic diabetic coma, blood ammonia level, and
140

blood alcohol levels. Before removing the syringe, 50 mL of 50% dextrose
is given unless the patient is suspected of having hyperosmolar nonketotic
diabetic coma. Patients suspected of hypoglycemia may also be given 1
mg of glucagon parentally to assist in the diagnosis. Urinalysis and urine
drug screen must also be done. Administer naloxone IV if opioid
intoxication is suspected. Arterial blood gas analysis should be done. If the
situation is urgent or emergent, a CT scan of the brain is done before the
results of the laboratory tests are available. If the laboratory tests are
inconclusive, a CT scan must be done anyway. D-dimer and fibrinogen
levels will rule out DIC.
If all of the above studies are negative, a spinal tap is done for cell
count, protein, glucose, FTA-ABS, smear, and culture and sensitivity. This
is especially true when there is fever or nuchal rigidity.
If the diagnosis is still in doubt, blood tests for other toxic materials,
such as lead level, and blood cultures and EEG are done. A neurologist or
neurosurgeon is usually consulted as soon as one is available.
141

143

1. 
  2. 
  3. 
  4. 
CONSTIPATION
Is the constipation acute or chronic?
 If the constipation is acute and
there is abdominal pain or vomiting, one must consider the possibility
of intestinal obstruction. An examination may disclose an empty
rectum, in which case it is more likely complete intestinal obstruction;
or there may be some feces in the rectum, in which case there may be
incomplete intestinal obstruction. If the constipation is a chronic
problem, one should investigate the patient’s diet and emotional status
and toilet habits over the life span.
What kind of a diet is the patient on?
 Many patients today eat on the
run, and they eat mostly fast foods, which are devoid of fiber.
Frequently, they don’t take the time to go to the bathroom. Some
patients are on special diets to lose weight or have a fear of gaining
weight; therefore, they don’t eat well at all. If what the patient labels
as constipation is simply infrequent bowel movements, but the bowel
movements are normal in consistency, this is not really true
constipation.
Does the patient take drugs of any kind?
 Patients should be
questioned first about chronic use of laxatives. Americans have the
misconception that they must have a bowel movement every day and,
therefore, they get in the habit of using something to stimulate the
bowels, which can lead them to believe they have chronic
constipation. Chronic narcotic use can lead to constipation, as can the
use of antispasmodics for ulcer or urinary incontinence.
What are the associated symptoms?
 We have already mentioned
that abdominal pain and vomiting may be a sign of acute intestinal
obstruction, and occasionally this is a sign of chronic intestinal
obstruction. If there is alternating diarrhea and constipation, one must
consider the possibility of irritable bowel syndrome or a colon
carcinoma. Blood in the stool along with painful defecation may
indicate hemorrhoids and anal fissure. A person who is suffering from
these conditions may delay moving his bowels for fear of the pain that
accompanies this situation, and the hard stool that caused the
hemorrhoids and anal fissure in the first place perpetuates the
condition because it contributes to the constipation. If blood is found
in the stool, well mixed with the stool, and defecation is basically
144

5. 
painless, then colon carcinoma and diverticulitis must be considered.
Blood and mucus in the stool would indicate an irritable bowel
syndrome.
What are the findings on physical examination?
 The finding of an
empty rectum indicates an intestinal obstruction. The finding of an
abdominal mass or a rectal mass would certainly indicate carcinoma of
the colon. Rectal examination may disclose hemorrhoids or anal
fissure as causing the chronic constipation and allows one to test the
stool for occult blood.
If the constipation is acute, a flat plate of the abdomen or CT scan and a
CBC would be in order to determine if the patient has intestinal
obstruction. The workup of chronic constipation begins with eliminating
all drugs that may be the cause unless this is contraindicated. The next
steps should include stool for occult blood, sigmoidoscopy, barium enema,
or a colonoscopy. A chemistry panel and other diagnostic studies may be
necessary to rule out systemic causes of constipation such as diabetes,
hypothyroidism, and various conditions associated with hypercalcemia. If
diagnostic tests yield no positive findings, referral to a psychiatrist or a
gynecologist 
may be in order. A trial of a fiber diet may be helpful. At the
same time, one should eliminate chronic laxative usage. Anorectal
manometry will help diagnose rectal and anal sphincter dysfunction.
Defecography will also help diagnose anorectal dysfunction. A neurologist
should be consulted if urinary retention is also a problem.
145

1. 
  2. 
  3. 
  4. 
  5. 
CONVULSIONS
Are the episodes of loss of consciousness really seizures?
 Real
seizures, especially grand mal, present with incontinence and/or
tongue biting and postictal somnolence. Hysterical seizures with actual
tonic or clonic movements may occur, but there is no tongue biting or
incontinence or postictal somnolence. Syncope usually is not
accompanied by convulsive movements, but it occasionally can be
after the drop in blood pressure or anoxia to the brain that has
continued for a period of time. If there are no convulsive movements
to the blackouts, then the possibility of syncope must be considered
(
page 493
). In addition, cerebrovascular accidents, narcolepsy, and
breath-holding attacks must be considered when there are no definite
convulsive movements.
Is there a history of drug or alcohol abuse?
 Alcohol withdrawal
seizures and seizures because of cocaine abuse are becoming more
common. Patients frequently lie about their use of illicit drugs or
alcohol. In young adults and teenagers, a urine drug screen should be
done.
 Fever should make one think of meningitis or
encephalitis, or if it has been extended over a longer period of time, a
cerebral abscess. In children, one should consider the possibility of
febrile convulsions.
What type of seizure disorder is it?
 If there are convulsions, are they
focal or Jacksonian type? That would certainly suggest a space-
occupying lesion as opposed to a generalized convulsion. Loss of
awareness with no actual collapse for 1 minute or less is suggestive of
a petit mal–type seizure. In these seizures, the patient just simply
stares. Longer attacks of loss of awareness are more likely to be
because of complex partial seizures and occasionally an observer will
note unusual behavior during these episodes. The patient may note
unusual odors.
Are there focal neurologic signs and papilledema?
are more typical of a space-occupying lesion such as a cerebral tumor,
cerebral abscess, or a subdural hematoma.
147

All patients should receive a CBC, urinalysis, sedimentation rate, ANA,
VDRL test, and chemistry panel. Do a serum prolactin to rule out
hysterical seizures. (It’s only elevated in real seizures.) Patients with high-
risk behavior should have HIV testing. In older patients, a chest x-ray
should be done to look for the possibility of a primary lung tumor. A urine
drug screen is useful especially in young adults. All patients also need a
wake-and-sleep EEG. Ambulatory EEG monitoring can now be done in
the hospital or an outpatient setting with a Digitrace device. In the elderly,
a carotid duplex scan or MRA may be needed to distinguish transient
ischemic attacks from epilepsy. There is some argument over whether a
CT scan or MRI should be done on all patients with definite convulsions.
The author believes that a CT scan should be done on all patients, even
those without focal neurologic signs or papilledema. Isotope brain scans,
arteriography, and pneumoencephalography are no longer indicated unless
something is found on the CT scan that needs further clarification. A
spinal tap should also be done when there is fever or when central nervous
system lues or multiple sclerosis is suspected. VEP and BSEP tests may
also help diagnose multiple sclerosis. It should be noted that seizures occur
in 7% of cases with multiple sclerosis. In patients with frequent attacks, a
trial of anticonvulsant drugs may be 
diagnostic. Have the family take a
video of the patient during a seizure especially when conversion hysteria is
suspected. Then a psychiatrist should be consulted.
A consultation with a neurologic specialist can be done at any point in
this workup. Certainly, it would be very important to have it done early if
there are focal neurologic signs or papilledema.
148

1. 
  2. 
  3. 
  4. 
  5. 
COUGH
 Acute onset of a cough would suggest an acute
URI, viral pneumonia, or bronchopneumonia. A chronic cough is
more suggestive of pneumoconiosis, chronic bronchitis, emphysema,
bronchiectasis, tuberculosis, carcinoma of the lung, or bronchial
asthma.
Is there exposure to toxic fumes?
 
The most common toxic fume is
cigarette smoke. However, if one asks the patient’s occupation, one
might find that he/she is a miner, and therefore pneumoconiosis comes
to mind. One might find that he/she is an aircraft maker or shipbuilder,
in which case berylliosis and asbestosis would come to mind; or that
he/she is a farmer, and therefore farmer’s lung would come to mind.
Is there significant sputum production?
 If so, what is the nature of
the sputum? Purulent sputum would suggest a pneumonia, abscess,
tuberculosis, or bronchiectasis; bloody sputum would suggest
carcinoma of the lung, tuberculosis, and bronchiectasis; mucoid
sputum would suggest asthma. Advanced acquired immunodeficiency
syndrome (AIDS) may manifest as a productive cough because of
Pneumocystis jiroveci
. If the sputum is foamy, one would consider
congestive heart failure, mitral stenosis, and inhalation of poison gas.
 If there is fever associated with the cough, obviously
one would suspect an infectious process to be present. This could be
viral or bacterial. Most likely the patient has bronchopneumonia, but
the possibility of an abscess or pulmonary infarct would still have to
be entertained.
What other symptoms and signs are associated with the cough?
The first thing to be considered would be dyspnea. In acute cases,
dyspnea would be a sign of congestive heart failure, pulmonary
embolism, and, of course, advancing pneumonia. In chronic cases,
dyspnea would be a sign of emphysema, chronic pulmonary fibrosis,
and chronic congestive heart failure. Wheezing would be a sign of
asthma or congestive heart failure, but of course it is also found in
pulmonary emphysema. Cardiomegaly would suggest congestive heart
failure and if there is an associated murmur, that makes congestive
heart failure even more likely. If there is hepatosplenomegaly, one
would suspect a systemic disease involving the lungs such as
150

6. 
periarteritis nodosa or other collagen diseases.
Is the patient taking drugs?
 Angiotensin-converting enzyme
inhibitors such as captopril are well known to cause cough.
If there is nasal stuffiness and a postnasal drip, a trial of antihistamines or
decongestants is indicated before starting an expensive workup. All
patients require a CBC and differential count, a sedimentation rate, and a
chemistry panel. For chronic cough, a 24-hour sputum volume should be
ordered. A sputum for routine smear and culture should be done, and in
chronic cases a sputum for AFB culture and smear must be done. In
children, collect a specimen of gastric aspirate for AFB culture. One
should keep a high index of suspicion for
 
Mycoplasma pneumoniae
 
and
Legionnaire’s disease. A therapeutic trial of a macrolide is useful in
suspected cases of mycoplasma or Legionnaire’s. Also, sputum for fungi
culture should be done in chronic cases. For diagnosing TB, a skin test
may be done but recently a QuantiFERON-TB gold blood test has received
attention to resolve issues of false-positive tuberculin skin tests.
Asthma can be further elucidated and confirmed by doing a sputum for
eosinophils. Carcinoma of the lung can be confirmed with a sputum for
Pap smear. If there 
is fever, blood cultures may be useful and febrile
agglutinins should also be done. An x-ray of the chest with A-P, lateral,
and apical lordotic views should be done, and when a tumor is suspected,
tomography should be done or a CT scan. In cases of chronic cough, skin
testing for coccidioidomycosis, cystoplasmosis, tuberculosis, and
blastomycosis should be done. A Kveim test to rule out sarcoidosis may be
necessary. When these tests fail to make a diagnosis, bronchoscopy and
possibly bronchograms to look for a bronchiectasis should be done. Lung
biopsy may also be necessary. Pulmonary function tests should be done in
suspected cases of emphysema and asthma. Pulmonary function testing
before and after a methacholine challenge or bronchodilator is also useful.
Allergy skin testing is extremely valuable in cases of asthma. Look for
alpha-1-antitrypsin deficiency in difficult cases. If congestive heart failure
is suspected, echocardiography would be valuable. A trial of diuretics may
also assist in the diagnosis. If reflux esophagitis is suspected, prolonged
monitoring of esophageal pH may be diagnostic. A trial of therapy with an
H
2
 antagonist or proton pump inhibitor may also be diagnostic.
151

Table 05: Cough
152

CRAMPS, MENSTRUAL
There are usually physiologic cramps occurring during menstruation and
not associated with pathology of the female reproductive organs. If there is
associated menorrhagia, the differential diagnosis of this symptom should
be consulted (
page 332
).
Menstrual cramps occur more frequently in the virginal uterus, but
may establish themselves after the first pregnancy. All women have
experienced menstrual cramps at some time in their life. These cramps
may be the first sign of endometriosis, PID, or ectopic pregnancy.
153

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
CRAMPS, MUSCULAR
A 67-year-old black male complains of severe muscular cramps for the
past year, especially at night. Following the algorithm, you ask about drug
or alcohol use and find there is none.
On examination, he has normal peripheral and femoral pulses and a
blood pressure of 110/70. The cramps are not isolated to one extremity and
he has a positive Trousseau’s sign. You correctly suspect
hypoparathyroidism and other causes of hypocalcemia.
 Many drugs produce muscular
cramps. The most notable are the diuretics.
Are there absent or diminished peripheral pulses?
 Absent or
diminished peripheral pulses suggest the cramps are because of
ischemia from peripheral arteriosclerosis or arterial embolism.
Are the femoral pulses diminished?
 Diminished femoral pulses
suggest Leriche syndrome or saddle embolism of the terminal aorta.
 Hypertension suggests aldosteronism and
chronic glomerulonephritis.
Are the cramps limited to one extremity?
 Limitation of the cramps
to one extremity suggests an occupational neurosis (professional
cramps).
Is there a positive Chvostek’s and/or Trousseau’s sign?
 These are
signs of tetany, as might be associated with hypoparathyroidism,
uremia, alkalosis, and other causes of hypocalcemia.
 Fever is associated with dehydration, heat stroke, and
many infectious diseases that cause cramps.
Is there low back pain?
 This would suggest that spinal stenosis is the
cause.
All patients should have a CBC, sedimentation rate, CRP, chemistry panel,
electrolytes, and urinalysis. If there is associated diminished or absent
peripheral pulses, then Doppler studies and arteriography should be done.
If the cramps are acute in onset, time should not be wasted in performing
154

these studies. MRA is an excellent alternative to invasive angiography, but
it is expensive. If there is associated hypertension, then 24-hour urine
aldosterone and plasma renin studies should be done. If there are positive
Trousseau’s and/or Chvostek’s signs, a thorough investigation for
hypoparathyroidism should be done. A single serum calcium and
phosphorus and alkaline phosphatase are not enough, but repeated studies
should be done. In addition, 24-hour urine collection for calcium and
serum PTH should be done. An endocrinologist should probably be
consulted if there is any doubt about the existence of hypoparathyroidism
or any of the other causes of hypocalcemia.
155

1. 
  2. 
  3. 
  4. 
C-REACTIVE PROTEIN
What is the ASO titer?
 An elevated ASO titer points to rheumatic
fever.
Is the RA factor positive?
 This would suggest rheumatoid arthritis.
Is there an elevated MB-CPK or cardiac troponins?
 If so, then a
diagnosis of myocardial infarction should be considered!
Is there growth on serial blood cultures?
 Consider subacute
bacterial endocarditis or septicemia.
All patients should have a CBC, sedimentation rate, chemistry panel,
urinalysis, chest x-ray, and EKG.
If these tests are normal, a rheumatologist or infectious disease specialist
may need to be consulted. If the clinical examination fails to reveal the
cause, one may order an arthritis panel, serum protein electrophoresis, a
CT scan of the abdomen and pelvis, a bone scan, and CEA.
157

CREPITUS
The most classic example of crepitus is subcutaneous emphysema
following a chest injury, especially a fractured rib. This may also occur
around a tracheotomy site. Crepitus is felt over arthritic joints, especially
when there is synovitis. In tenosynovitis of the wrist, there is often a
marked crepitus over the flexor tendons. A grating sound or crepitus may
be felt over fractured bones if an effort is made to move the two portions
of fractured bones. Palpation of a malignant bone tumor will elicit crepitus
if the bone cortex has been penetrated. In patients with gas gangrene,
crepitus may be felt over the infected area because of subcutaneous gas.
This will depend on the type of crepitus felt. Plain films will verify the
presence of gas, fractures, and tumors. Undoubtedly, other symptoms and
signs will be present to key the rest of the diagnostic workup using the
pages in this book.
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1. 
  2. 
  3. 
  4. 
  5. 
  6. 
CYANOSIS
 Potassium chlorate,
sulfanilamide, and coal tar products are only a few of the drugs that
may cause methemoglobinemia and sulfhemoglobinemia.
Is the cyanosis limited to one extremity?
 If the cyanosis is limited to
one extremity, one should suspect an arterial embolism or
phlebothrombosis.
Is the cyanosis limited to the extremities or is it generalized?
Cyanosis that is limited to the extremities only suggests Raynaud’s
disease, Raynaud’s phenomena, shock, and acrocyanosis.
 If there is significant dyspnea, one
should consider a pulmonary or cardiac origin for the cyanosis such as
cyanotic congenital heart disease, pulmonary emphysema, pulmonary
fibrosis, or pulmonary embolism.
 Certain causes of cyanosis are
limited to children, such as laryngismus stridulus, laryngotracheitis,
and acute subglottic laryngitis.
Is there a heart murmur or cardiomegaly?
 A heart murmur or
cardiomegaly suggests rheumatic carditis, congenital heart disease, or
It is wise to order a cardiology consult at the outset. Arterial blood gases,
EKG, chest x-ray, and pulmonary function studies will diagnose most
cases that are because of pulmonary or cardiac causes. If there is a history
of drug ingestion, the blood should be drawn for methemoglobin and
sulfhemoglobin testing. If a pulmonary embolism is suspected, a
ventilation–perfusion scan or spiral CT scan and pulmonary arteriography
may need to be done. If a peripheral embolism is suspected, angiography
of the vessel involved will be diagnostic. Sputum or nose and throat
cultures will be useful in diagnosing the infectious diseases associated with
cyanosis.
160

1. 
  2. 
  3. 
  4. 
DEAFNESS
A 48-year-old white female complains of progressive loss of hearing and
tinnitus in her left ear over the past 2 years.
Following the algorithm, you find that she has had occasional attacks
of vertigo during that time. There is a family history of neurofibromatosis.
Your examination reveals no other neurologic signs but she has coffee-
colored areas of discoloration on her abdomen and thorax. What is your
diagnosis?
 Unilateral deafness may be because of
local conditions, such as wax, a foreign body, otitis media, or ruptured
drum, or it may be because of neurologic conditions such as Ménière’s
disease, acoustic neuroma, or multiple sclerosis. Bilateral deafness is
more likely because of otosclerosis, acoustic trauma, presbycusis, or
drug toxicity.
Are there abnormalities on otoscopic examination of the ear?
 It is
very important to do a thorough examination of the ear as one may
find wax, foreign body, otitis media, cholesteatoma, or ruptured drum.
Is there associated vertigo?
 The presence of vertigo should make one
think of Ménière’s disease or some neurologic condition such as
acoustic neuroma, multiple sclerosis, or basilar artery insufficiency.
What are the results of the Rinne’s test?
 Normally, the Rinne’s test
should show a 2:1 ratio of air to bone hearing. In otosclerosis, the ratio
approaches 1:1, but in sensory neural deafness the ratio is preserved at
2:1. In unilateral deafness, the Weber’s test is helpful. This will
lateralize to the affected ear if the problem is a conductive deafness,
and it will lateralize to the good ear if the problem is a sensory neural
deafness.
Audiometry and caloric testing or electronystagmography should be done
in almost all cases where the ear examination is normal. It is probably wise
to consult an otolaryngologist at this point of time. Tympanography will be
helpful in diagnosing subtle cases of serous otitis media. A CT scan of the
162

mastoids, petrous bones, and internal auditory canal should be done for
chronic otitis media, cholesteatoma, mastoiditis, and acoustic neuroma.
However, if an acoustic neuroma is suspected, an MRI of the brain and
auditory canals must be done. If basilar artery insufficiency is suspected,
four-vessel cerebral angiography should be done. MRA is an excellent
noninvasive alternative for diagnosing vertebral–basilar artery disease. If
multiple sclerosis is suspected, MRI of the brain, BSEP and VEP studies,
and a spinal tap for spinal fluid analysis may be done.
Rather than performing these tests, the most cost-effective approach
would be to refer the patient to a neurologist if other focal neurologic
findings are evident.
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1. 
  2. 
  3. 
  4. 
DELAYED PUBERTY
Is there a positive drug history?
 Boys and girls may take anabolic
steroids or androgens and thyroid hormones. These hormones may
cause a delay in puberty.
Is there a significant weight loss?
 Significant weight loss would
suggest anorexia nervosa, hyperthyroidism, celiac disease, cystic
fibrosis, and uncontrolled diabetes, among other conditions.
Is there a short stature?
 The presence of a short stature would
suggest pituitary tumors, hypothalamic syndromes, gonadal
dysgenesis, adrenal tumors, hyperplasia, hypothyroidism, and ovarian
tumors.
Is there a hemianopic field defect?
 The presence of a hemianopic
field defect would suggest a pituitary tumor. The presence of a normal
or tall stature would suggest constitutional delayed puberty among
other more rare conditions.
Before proceeding with an expensive diagnostic workup, it is perhaps best
to consult an endocrinologist. If one is not available, routine tests would be
a CBC, chemistry panel, and thyroid profile. Blood tests for a serum FSH,
LH, and testosterone or estradiol may be done, although urine
gonadotropins may be a cheaper screening test.
Pelvic ultrasound and CT scans of the abdomen and pelvis will help
identify ovarian and adrenal tumors and abnormal configuration of the
uterus. CT scans of the brain will help identify pituitary tumors. If all these
studies are negative, a psychiatrist may need to be consulted. Remember,
the family may be in more need of the psychiatrist than the child.
165

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
DELIRIUM
 Delirium with fever may simply indicate a
self-limited
 infectious process, but it should bring to mind encephalitis
and meningitis as well as cerebral abscess and cerebral hemorrhage.
 A history of head trauma would make
one suspect a subdural or epidural hematoma and concussion.
 This is probably the
most important single question to ask in the average case coming into
the emergency room these days without a good history. Very often,
the problem is alcoholism or various popular drugs such as cocaine,
lysergic acid diethylamide (LSD), and phencyclidine (PCP).
 Focal neurologic signs along with
the delirium would make one think of subdural or epidural hematoma,
cerebral abscess, or cerebral hemorrhage. Remember, a cerebral
thrombosis or embolism may present with delirium also.
 If there is nuchal rigidity, the patient may
have meningitis or subarachnoid hemorrhage.
should make one think of diabetic coma or alcoholism.
What is the response to intravenous thiamine?
 If the patient
responds to intravenous thiamine, the diagnosis is usually Wernicke’s
encephalopathy or Korsakoff’s syndrome.
Intermittent delirium should suggest psychomotor epilepsy and
transient global amnesia.
Routine laboratory tests include a CBC, sedimentation rate, ANA,
chemistry panel including electrolytes and BUN and VDRL tests, serum
osmolality to rule out syndrome of inappropriate secretion of antidiuretic
hormone (SIADH), a blood alcohol level, urinalysis, and urine drug
screen. A CT scan of the brain and EEG are also usually indicated. Acute
delirium may be an indication to administer intravenous glucose and
thiamine. If there is fever, blood cultures and a spinal tap for analysis and
culture need to be done. Arterial blood gases and carboxyhemoglobin
should be determined. Generally, a neurologist or neurosurgeon should be
consulted early.
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1. 
  2. 
DELUSIONS
 Many drugs may be
associated with delusions, especially cocaine, PCP, and LSD. The
confabulations of Korsakoff’s psychosis may be confused with
delusions.
Is there impairment of memory?
 If there is impairment of memory,
an organic psychosis should be suspected, such as senile and presenile
dementia or general paresis. When there is no impairment of memory,
the problem is probably a psychiatric disorder such as schizophrenia
or manic-depressive psychosis.
If there is a history of alcohol or drug ingestion, a blood alcohol level and
urine for drug screen should be done. A CT scan, EEG, and spinal fluid
analysis will often need to be done before referring a patient to a
psychiatrist for further evaluation.
169

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
DEMENTIA
A 68-year-old Hispanic is brought to your office for evaluation because his
family says he has become very forgetful lately. Following the algorithm,
you ask about alcohol abuse and inquire about the medication he is taking.
He has an occasional glass of wine and is on no medication other than an
occasional aspirin for headache.
Your examination reveals no papilledema or focal neurologic signs.
Serum B
12
 and folic acid are normal. A trial of vitamin B complex fails to
initiate improvement. The patient continues to insist he is okay. What is
your diagnosis?
 Chronic barbiturate
intoxication, ergotism, and other psychotropic or antidepressant drugs
may cause dementia. Alcoholism may cause dementia in the form of
Korsakoff’s psychosis or Wernicke’s encephalopathy.
Is there headache, papilledema, or focal neurologic signs?
 The
most important condition to rule out in this category would be a space-
occupying lesion, but normal pressure hydrocephalus, cerebral
arteriosclerosis, acute cerebrovascular accident, and general paresis
may present with focal neurologic signs.
Is there a response to niacin, thiamine, vitamin B
12
, or thyroid?
Response to these drugs would indicate that the patient has pellagra,
Korsakoff’s psychosis, pernicious anemia, or myxedema. However,
laboratory tests should be done before administering the medications.
Laboratory tests include serum B
12
 and folic acid, and a thyroid
profile. Unfortunately, most laboratories do not have a test for niacin
or thiamine.
Is there insight?
 In patients with cerebral arteriosclerosis, the patient
notices that his memory is slipping. This is also true of AIDS.
Are there extrapyramidal tract signs?
 Extrapyramidal tract signs
should suggest Huntington’s chorea or Parkinson’s disease.
Are there pyramidal tract signs or myoclonus?
 Pyramidal tract
signs are seen in general paresis and Jakob–Creutzfeldt syndrome, but
myoclonus is also seen in Jakob–Creutzfeldt syndrome.
170

First, eliminate as many drugs as possible and observe! Routine laboratory
tests include a CBC, CRP, sedimentation rate, chemistry panel, lipid panel,
apolipoprotein E testing, VDRL test, HIV antibody titer, ANA, blood
alcohol level, urine drug screens, thyroid profile, serum B
12
, and folic acid.
An MRI should probably be done in all cases. An EEG may be helpful in
demonstrating drug intoxication. A spinal tap may need to be done to
diagnose central nervous system lues, the best test for which is the
fluorescent treponemal antibody-absorption (FTA-ABS) test. An MRA
may be useful in distinguishing Alzheimer’s disease from cerebral
arteriosclerosis, as in cerebral arteriosclerosis small infarcts may be
demonstrated. A radioiodinated serum albumin (RISA) cisternography
study is useful to diagnose normal pressure hydrocephalus. Arterial blood
gases should be drawn. There is increasing use of positron emission
tomography (PET) scans to help determine treatment options in dementia.
Psychometric testing will help differentiate organic brain syndrome from
other psychiatric disorders and malingering. A neurologist or psychiatrist
should be consulted before ordering expensive diagnostic tests. In mild
cognitive disturbances, consider a trial of antidepressants or hormone
therapy, especially in postmenopausal women.
171

1. 
  2. 
  3. 
  4. 
DEPRESSION
Is there associated headache, papilledema, dementia, or focal
neurologic signs?
 These findings would suggest a space-occupying
lesion. This is something the clinician does not want to miss.
Are there endocrine changes?
 A number of endocrinologic diseases
may present with depression, including Cushing’s disease, myxedema,
hyperthyroidism, and menopause.
Is there marked loss of appetite, weight, and libido?
 Endogenous
depression, unipolar depression, and the depressive phase of manic–
depressive psychosis may present with these findings. On the contrary,
neurotic-depressive reaction usually is not associated with significant
loss of appetite, weight, or libido.
 Remember,
patients are reluctant to admit the latter.
If the patient is suicidal, one should not hesitate to make a psychiatric
referral or plan hospitalization immediately. To rule out organic causes,
routine laboratory studies include a CBC, sedimentation rate, chemistry
panel, urine drug screen, VDRL test, and thyroid profile. If Cushing’s
syndrome is suspected, a 24-hour 
urine-free
 cortisol and cortisol
suppression test should be done. If menopause is suspected, order a serum
FSH and estradiol level. A trial of estrogen therapy may be warranted in
women or a trial of testosterone therapy in men. A CT scan of the brain
should probably be done in all cases to exclude a brain tumor, especially if
there is no response to treatment! Office tests to evaluate nonorganic
depression include the Beck Depression Inventory and the Hamilton
Depression Scale. A referral to a psychiatrist should also be considered
early if the depression is severe or if there is suicidal ideation.
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1. 
  2. 
  3. 
  4. 
  5. 
  6. 
DIAPHORESIS
 Many drugs can
cause diaphoresis, but caffeine and nicotine head the list. Alcohol can
also be associated with significant diaphoresis. Organophosphate
intoxication is associated with profuse diaphoresis.
 Obviously, infectious disease is a very
important cause of diaphoresis, particularly when the fever breaks.
Look for tuberculosis, malaria, acute rheumatic fever, and bacterial
endocarditis. Thyroid storm can also be associated with fever.
Is there associated chest pain or hypotension?
 Chest pain with
diaphoresis would make one think of an acute myocardial infarction,
but this combination is also found in coronary insufficiency. Shock,
whatever the cause, produces significant diaphoresis.
Is there associated weight loss, hypertension, or both?
 Weight loss
and hypertension should make one think of hyperthyroidism and
pheochromocytoma. Peripheral neuropathy is also associated with
sweating because of involvement of the autonomic nervous system.
Is there associated weight gain?
 The triad of obesity, diaphoresis,
and increased appetite is typical of an insulinoma. Diabetics taking
excessive insulin will also sweat.
Is there a rash?
 Several skin diseases may cause hyperhidrosis.
Routine diagnostic studies include a CBC, sedimentation rate, chemistry
panel, electrolytes, thyroid profile, blood alcohol level, EKG, and chest x-
ray. Serial EKGs and cardiac enzymes should be done if a myocardial
infarction is suspected. A 
24-hour
 urine collection for catecholamines can
be done if a pheochromocytoma is suspected. A glucose tolerance test, a
36- to 72-hour fast, and insulin tolerance test may be done for an
insulinoma. If infectious disease is strongly suspected, a workup for fever
of unknown origin can be done (see 
page 198
).
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1. 
  2. 
  3. 
  4. 
  5. 
  6. 
DIARRHEA, ACUTE
 From the algorithm, blood in the stool
should indicate that there is 
, 
Shigella
, 
jejuni
, ulcerative colitis, Crohn’s disease, and amebic dysentery.
Without blood in the stool, it is more likely that the acute diarrhea is
because of a staphylococcal toxin, giardiasis, traveler’s diarrhea, a
virus, or contaminated food.
 Fever, especially with an elevated white count and
blood in the stool, would suggest 
, 
Shigella
, 
C. jejuni
, or
ulcerative colitis in its acute stage. The absence of fever would suggest
amebic dysentery or giardiasis, although there may be fever in amebic
dysentery in severe cases. Even traveler’s diarrhea and toxic
staphylococcal gastroenteritis do not usually give more than a low-
grade temperature at best. Pseudomembranous colitis may result in a
significant elevation of the temperature once the patient becomes
severely dehydrated.
Is there severe vomiting?
 Severe vomiting is seen in toxic
staphylococcal gastroenteritis! This follows 2 to 4 hours after eating
food poisoned with the toxin. Traveler’s diarrhea and viral
gastroenteritis may also cause severe vomiting, as may food that is
contaminated. On the contrary, there is little or no vomiting in
giardiasis and pseudomembranous colitis.
Did several members of the family also experience acute diarrhea?
This is a key question because it indicates whether there is a
possibility of toxic staphylococcal gastroenteritis, botulism, or a
contagious condition such as infection with 
, 
Shigella
, or
Campylobacter.
 If only one member of the family was suffering from
diarrhea and everyone is eating the same food, then it is less likely to
be a contagious condition, and one must consider ulcerative colitis,
pseudomembranous colitis, and conditions listed under chronic
diarrhea.
Was there recent foreign travel?
 Recent foreign travel would
suggest the possibility of traveler’s diarrhea, cholera, shigellosis,
salmonellosis, and giardiasis.
Is there neurologic symptomatology?
 This should point one in the
direction of botulism, and generally a little epidemiologic research
177

will disclose that other people in the community have been suffering
from the same condition. If there is no fever and no blood in the stool,
one should also suspect prescription drugs as a cause.
The first thing to do is a stool for occult blood. This will help distinguish
those patients who are having obvious infectious disease of the large
intestine or maybe even the small intestine. It will also make one
suspicious of ulcerative colitis. All patients need a stool culture and stool
for ova and parasites. A stool for 
Giardia
 antigen can also be done.
Serologic studies will not be of much help in the acute condition, but they
may help later on in cases of salmonellosis and amebiasis. The clinician
himself/herself should do a methylene blue smear for leukocytes and
examine a wet saline preparation of the stool. If there is a history of
antibiotic use, the stool should be tested for 
 toxin B.
Leukocytes on a smear suggest bacterial cause and a culture should be
done. The laboratory should be alerted if 
 or 
Yersinia
 is
suspected because special culture media are needed. If the diarrhea persists
or if there is blood, sigmoidoscopy or colonoscopy should be performed. It
is always important to examine the rectum for hemorrhoids and anal
fissures that may be causing the positive stool for occult blood. When the
diarrhea persists and becomes chronic, the diagnostic workup should
include the studies that are listed under chronic diarrhea (
page 134
).
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1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
DIARRHEA, CHRONIC
Is there a positive drug or alcohol history?
 It is well known that
alcohol can cause diarrhea, as do drugs in common use, such as
digitalis, diuretics, beta-blockers, aspirin, colchicine, and other
nonsteroidal 
anti-inflammatory
 drugs. Perhaps there is overuse of
laxatives. Remember, patients may lie about the use of laxatives.
 Blood in the stool certainly is significant
for ulcerative colitis, Crohn’s disease, carcinoma, and diverticulitis,
but it is also found in amebiasis and Zollinger–Ellison syndrome.
Is there a lot of mucus in the stool?
 Mucus is often found in
ulcerative colitis, Crohn’s disease, and irritable bowel syndrome.
Is there evidence of steatorrhea?
 Large volumes of stools that are
partially formed or formed and float in the commode suggest
steatorrhea. Stool analysis can be done, as is discussed later.
would suggest carcinoma or diverticulitis. Tenderness in the left lower
quadrant with or without a significant mass would be suggestive of
ulcerative colitis, diverticulitis, and irritable bowel syndrome. A mass
in the area of the ascending or descending colon or the transverse
colon should also be looked for, as these would suggest carcinoma.
Are there signs of systemic disease?
cause diarrhea. Among them are thyrotoxicosis, in which case one
would be looking for a thyroid tumor and a tremor and tachycardia;
carcinoid syndrome, which would cause considerable flushing;
Addison’s disease, which would cause hyperpigmentation of the skin;
and pellagra, which may cause dermatitis and dementia.
Does significant diarrhea persist on fasting?
 Diarrhea that persists
after fasting suggests a secretory diarrhea from a polypeptide-secreting
tumor, such as villous adenoma, a gastrinoma, or a carcinoid tumor.
Most patients will be diagnosed by a stool culture, stool for occult blood,
and stool for ovum and parasites, along with sigmoidoscopy and barium
enema. Colonoscopy has largely replaced the latter two procedures. Serum
lactoferrin and calprotectin will distinguish inflammatory bowel disease
from irritable bowel syndrome. Giardiasis may be best diagnosed by the
179

finding of 
Giardia
 antigen in the stool. Perform a hydrogen breath test if
lactose intolerance is suspected. In patients who have been on antibiotics,
the stool should be tested for 
 toxin B. If a systemic disease is
suspected, CBC, sedimentation rate, chemistry panel, and thyroid profile
should be done. An HIV antibody test may be indicated depending on the
history. A urine test for 5-HIAA will uncover a carcinoid syndrome. A
serum gastrin will usually reveal a gastrinoma. Perinuclear staining
antineutrophil cytoplasmic antibodies (p-ANCA) are found in 70% of
patients with ulcerative colitis. If these tests do not provide a diagnosis, the
most cost-effective approach at this point is to refer the patient to a
gastroenterologist who will undoubtedly perform a colonoscopy as part of
the workup. Small bowel aspiration and biopsy will be useful in
diagnosing 
Giardia
 infection or celiac sprue; angiography will confirm
mesenteric ischemia or infarcts. A swallowed string test may pick up
Giardia
, but when all else fails, a 
trial of metronidazole will be diagnostic.
A course of metronidazole will also help diagnose 
 colitis.
If a gastroenterologist is not available, the clinician may proceed with a
quantitative 24-hour stool analysis for fat. If there is 10 g or more of fat in
the stool in a day, then steatorrhea can be diagnosed and one can proceed
with the workup of steatorrhea (
page 482
). If there is less than 7 g of fat
per day in the stool, the stool volume after fasting should be done. If it is
large and we have ruled out surreptitious laxative abuse, a polypeptide-
secreting tumor should be considered. Here again, it would be best to refer
the patient to a gastroenterologist. If the volume after a fast is small, the
problem is most likely lactose or other food intolerance or an irritable
bowel syndrome. Occasionally, the problem is dysfunction of the anal
sphincter. Once again, a GI specialist is probably best consulted for
workup of a dysfunctional anal sphincter.
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1. 
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  3. 
DIFFICULTY URINATING
Is there pain on urination?
 The presence of pain on urination should
suggest cystitis, urethritis, urethral caruncle, vesicular calculus,
urethral stricture, and acute prostatitis.
 The presence of focal neurologic
signs should suggest multiple sclerosis, poliomyelitis, cauda equina
tumor, acute spinal cord injury, tabes dorsalis, and diabetic
neuropathy.
Is the prostate enlarged?
 The presence of an enlarged prostate would
suggest benign prostatic hypertrophy or an advanced malignancy. A
small nodular prostate may suggest an early carcinoma of the prostate.
Chronic prostatitis would present with a normal-sized or small prostate
that is firm.
It should go without saying that a complete physical, rectal, and neurologic
examination should be done at the outset. A pelvic examination is essential
in females. Routine laboratory tests include a CBC, sedimentation rate,
PSA, urinalysis, VDRL test, urine culture, colony count, and sensitivity. If
there is a urethral discharge, a Gram’s stain and culture for gonococcus
should be done. If this is negative, a culture for Chlamydia should be done.
The patient may be catheterized for residual urine. Alternatively,
ultrasonography may be done to demonstrate residual urine. If there is a
significant amount of residual urine, referral to an urologist for cystoscopy
and cystometric testing is done. A CT scan of the pelvis may be indicated
but not before consulting an urologist. The urologist may elect to do a
voiding cystourethrogram, especially in children with recurrent urinary
tract infections (UTIs).
If there are focal neurologic signs, a neurologist is consulted. An
enlarged prostate or a prostate that is nodular should be an indication for a
consultation with an urologist and ordering a PSA titer.
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1. 
  2. 
  3. 
  4. 
  5. 
  6. 
DIPLOPIA
Is it unilateral?
 Diplopia that is unilateral is rare, but it can be
encountered in ectopia lentis as associated with Marfan’s disease as
well as in congenital double pupil, cataracts, and corneal opacities.
 Intermittent diplopia would make one think of
myasthenia gravis, but remember, Eaton–Lambert syndrome can do
the same thing.
Is there associated proptosis?
 If there is associated proptosis, one
should consider hyperthyroidism or pituitary exophthalmos, especially
if it is bilateral. However, when it is associated with chemosis and
ecchymosis, one should consider an infectious process.
Is there chemosis, ecchymosis, or periorbital edema?
 These
findings should make one think immediately of cavernous sinus
thrombosis, but an arteriovenous aneurysm can produce unilateral
chemosis, ecchymosis, and exophthalmos.
Are there associated long tract neurologic signs?
 The findings of
associated pyramidal tract or other long tract signs would make one
think of a brain stem infarct or a brain stem tumor. Advanced
intracranial pressure will put pressure on the sixth nerve and cause
diplopia. Multiple sclerosis and basilar artery thrombosis on
insufficiency may cause long tract signs along with extraocular muscle
palsies.
Is there fever or chills?
 Findings of fever and chills and diplopia
should make one think of an orbital abscess, a brain abscess, or a
cavernous sinus thrombosis. There is also the possibility of diphtheria.
An expensive diagnostic workup may be avoided by referring the patient
to an ophthalmologist or a neurologist at the outset. If there is associated
exophthalmos, a free T
4
 and TSH are ordered. If the diplopia is
intermittent, a Tensilon test would be indicated. If there are fever and
chills, one should do a CBC, sedimentation rate, possibly blood cultures,
skull x-ray, and x-rays of the sinuses. However, under these circumstances,
it will usually be necessary to perform a CT scan of the brain, sinuses, and
orbits. If there is chemosis or ecchymosis, a cavernous sinus thrombosis is
184

likely, and immediate admission to the hospital and administration of
antibiotics after blood culture has been drawn are indicated. MRI of the
brain may be necessary to diagnose multiple sclerosis and some of the
brain stem infarcts.
185

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
DIZZINESS
Is it true vertigo?
 True vertigo is characterized by the fact that the
person feels he/she or his/her environment is turning. One other form
of true vertigo is lateral pulsion, in which the person feels as if he/she
is moving to the left or right or may be moving forward or backward.
True vertigo is a sign of neurologic or otologic disease, whereas
dizziness that is not true vertigo is more likely a sign of cardiovascular
disease, drug toxicity, or hypoglycemia.
Is there associated tinnitus or deafness?
 The presence of tinnitus or
deafness, especially if the ear examination is negative, is a sign of a
more serious otologic or neurologic condition. Disorders such as
cholesteatoma, acoustic neuroma, and Ménière’s disease must be
considered. On the contrary, vertigo without tinnitus or deafness
should prompt consideration of benign positional vertigo and
vestibular neuronitis.
Are there other neurologic findings?
 The finding of abnormalities of
other cranial nerves or the long tracts, such as the pyramidal tracts,
would suggest multiple sclerosis, an advanced brain stem tumor,
acoustic neuroma, or basilar artery insufficiency.
Are there findings on otoscopic examination?
 A normal neurologic
examination with an abnormal ear examination would suggest otitis
media, cholesteatoma, or petrositis.
Is there tachypnea during the attack?
 If there is hyperventilation
during the attack, then hyperventilation syndrome should be
considered.
 A history of trauma would suggest a
postconcussion syndrome.
Are there abnormalities of the blood pressure?
 If the dizziness is
really light-headedness, hypertension may be present, but hypertension
may also cause true vertigo. Hypotension is more likely to cause light-
headedness, which is not true vertigo. Be sure to take the blood
pressures while the patient is lying down and again after rapidly rising
to the standing position.
Are there abnormal cardiac findings?
 A thorough cardiovascular
examination should be done. Irregularities of the heartbeat, heart
murmurs, or cardiac enlargement will suggest cardiac arrhythmia,
186

9. 
aortic stenosis and insufficiency, mitral stenosis, prolapse of the mitral
valve, and congestive heart failure. A slow pulse may indicate heart
block or a sick sinus syndrome.
Is there pallor?
 Moderate to severe anemia will cause light-
headedness and dizziness, but usually not true vertigo.
If there is true vertigo, an audiogram and a caloric test or
electronystagmography should be done. Hallpike maneuver should also be
done to exclude benign positional vertigo. If these are abnormal, an x-ray
of the mastoids, petrous bones, and internal auditory canals should be
done. At this point, a neurologist should be consulted. If an acoustic
neuroma is strongly suspected, an MRI of the brain stem and auditory
canals should be done. If the MRI of the brain is negative, a spinal fluid
examination can be done to exclude such disorders as central nervous
system lues and multiple sclerosis. An MRI of the brain needs to be done
to distinguish multiple sclerosis. BSEPs, VEPs, and SSEPs will also be
helpful in making the diagnosis of multiple 
sclerosis, along with the spinal
fluid analysis mentioned earlier. A 
wake-and-sleep
 EEG needs to be done
to exclude temporal lobe epilepsy. If migraine or migraine equivalents are
suspected, perhaps a trial of beta-blockers would help make this diagnosis.
If vertebral–basilar artery ischemia is suspected, MRA may be indicated.
If the dizziness is not true vertigo, a CBC and chemistry panel, thyroid
profile, and 5-hour glucose tolerance test should be done at the outset.
Additional studies in the form of 24-hour blood pressure monitoring,
Holter monitoring, and echocardiography all have a valuable place in the
diagnostic workup of dizziness without true vertigo. Perhaps a tilt table
test should be ordered to rule out orthostatic hypotension. However,
referral to a cardiologist is wise before undertaking these expensive
studies. If all studies are negative, perhaps a psychiatrist should be
consulted.
Table 06: Dizziness
187

188

1. 
  2. 
  3. 
DROP ATTACKS
Is there loss of consciousness?
 If there is loss of consciousness, the
differential diagnosis for syncope should be considered (
page 493
).
Are there other neurologic signs and symptoms?
 Focal neurologic
signs and symptoms should make one think of basilar artery
insufficiency, cerebral arteriosclerosis, Ménière’s disease, and
cerebellar atrophy. A brain tumor should also be considered if there
are focal signs.
Is there hypotension, cardiomegaly, or a heart murmur?
 These
findings should make one think of orthostatic hypotension, aortic
stenosis and insufficiency, and cardiac arrhythmia.
Basic studies for the workup of drop attacks are CBC, sedimentation rate,
chemistry panel, VDRL test, chest x-ray, tilt table test, and EKG. These
will help identify anemia, hypoglycemia, and cardiovascular diseases. An
EEG should also be done to rule out epilepsy. If there are focal neurologic
signs, a CT scan or MRI should be done. Remember, the MRI is double
the cost of a CT scan and the diagnostic yield is only slightly higher. A
neurologist should be consulted to help decide which study is appropriate.
A 5-hour glucose tolerance test can be done to help diagnose
hypoglycemia. Four-vessel angiography or MRA is necessary to diagnose
vertebral–basilar disease. Holter monitoring will be useful to diagnose
complete heart block and other cardiac arrhythmias. If the chest x-ray or
EKG has revealed possible cardiac findings, a referral to a cardiologist
would be
 wise.
190

1. 
  2. 
  3. 
  4. 
  5. 
DWARFISM
Is there disproportion of the trunk and extremities?
would suggest achondrodysplasia.
Is there obesity?
 The finding of obesity would suggest Fröhlich’s
syndrome, Laurence–Moon–Bardet–Biedl syndrome, and Brissaud’s
infantilism.
Is there appearance of wasting and/or malnutrition?
 The presence
of wasting or other signs of malnutrition suggests chronic nephritis,
congenital heart disease, progeria, malnutrition, and rickets.
Is there an unusual appearance to the skull or face?
suggest mongolism, cretinism, microcephaly, hydrocephalus, and
cleidocranial dysostosis, among other conditions.
Are there abnormal secondary sex characteristics?
 The
development of secondary sex characteristics is impaired in Turner’s
syndrome and pituitary dwarfism.
Routine studies should include a CBC, sedimentation rate, urinalysis,
chemistry panel, thyroid profile, VDRL test, quantitative stool fat, a sweat
test, and x-ray of the skull and long bones.
If Turner’s syndrome is suspected, a buccal smear for sex chromogen
may be done. If pituitary dwarfism is suspected, a CT scan of the skull
may be helpful. Hypothyroidism can be distinguished by a delayed bone
age. Additional endocrine tests include a serum growth hormone level
before and after exercise, a resting somatomedin C level, and an overnight
dexamethasone suppression test. In patients suspected of having rickets
and hypoparathyroidism, 24-hour urine calcium test may be done.
However, it is best to consult a pediatrician, endocrinologist, or orthopedic
surgeon before proceeding with expensive diagnostic tests.
192

1. 
  2. 
  3. 
  4. 
DYSARTHRIA
 Intermittent dysarthria should make one think of
myasthenia gravis, epilepsy, and transient ischemic attacks.
Is there associated ataxia or nystagmus?
 The findings of nystagmus
or ataxia should make one think of a cerebellar disorder such as
multiple sclerosis, drug intoxication, or cerebellar ataxia.
 Alcohol and
phenytoin (Dilantin®) are just two of the toxic substances that may
affect speech.
Is there tremor or rigidity?
 If there is tremor or rigidity, one should
suspect Parkinson’s disease, hepatolenticular degeneration, and
phenothiazine toxicity.
The yield for diagnoses of dysarthria is high for a blood alcohol level and
urine drug screen. If the dysarthria is intermittent, an EEG and Tensilon
test or acetylcholine receptor antibody titer should be done. If transient
ischemic attacks are suspected, a carotid scan should be done, but the only
way to completely exclude this possibility is by doing four-vessel cerebral
angiography. A CT scan or MRI should be done in all cases of persistent
dysarthria. A neurologist can help decide which study would be most
appropriate. If Wilson’s disease is suspected, a test for serum copper and
ceruloplasmin should be done. A spinal tap may help diagnose multiple
sclerosis and intracranial hemorrhage.
194

1. 
  2. 
  3. 
DYSMENORRHEA
Are there abnormalities on pelvic examination?
 A tubo-ovarian
mass on pelvic examination should suggest salpingo-oophoritis,
endometriosis with a chocolate cyst, or ectopic pregnancy. Perhaps the
uterus is abnormal, in which case one should suspect fibroids,
endometrial carcinoma, uterine pregnancy, retroverted uterus,
endometrial cast, or cervical polyp. A normal examination should
suggest ovarian dysfunction, endocrine imbalance, and psychogenic
causes.
What is the age of the patient?
 If the patient is young, she probably
has a virginal uterus and may be considered to have primary
dysmenorrhea. These cases are usually because of uterine hypoplasia,
congenital malformations, ovarian dysfunction, or psychogenic causes.
Does the patient have an intrauterine device?
 This may be the
cause.
Routine studies should include a CBC, sedimentation rate, chemistry
panel, and thyroid profile. If there is vaginal discharge, a smear and culture
should be done for gonorrhea and Chlamydia. A cervical and rectal culture
for these organisms may also be necessary. If there is a tubo-ovarian mass
or enlarged uterus, abdominal ultrasound or a CT scan of the abdomen
may help in differentiating the cause. A pregnancy test should be done.
The pregnancy test of choice is radioimmunoassay for the beta subunit of
human chorionic gonadotropin (hCG), which will be positive within a
week of fertilization. If a ruptured ectopic pregnancy is expected, a
peritoneal tap or culdocentesis may help if abdominal ultrasound is not
conclusive. Laparoscopy may also be helpful in the diagnosis. A fern test
and basal body temperature may help diagnose endometriosis. An
exploratory laparotomy may be the only way to make a diagnosis in cases
of a pelvic mass. If the pelvic examination is perfectly normal, sometimes
a course of progesterone hormones is useful in alleviating the problem. A
dilation and curettage may also be done to address the problem. Referral to
a gynecologist is usually made before doing expensive diagnostic tests.
196

1. 
  2. 
  3. 
  4. 
DYSPAREUNIA
Does the history indicate that the difficulty is on penetration?
Difficulties on penetration usually point to a vulval or vaginal origin
for the problem. In that case, bartholinitis, vulvitis, vulvar dystrophy,
cystitis, urethritis, and urethral caruncle should be suspected.
Is the urinalysis abnormal?
 An abnormal urinalysis may indicate
cystitis or a bladder calculus.
Are there abnormalities on rectal examination?
 Hemorrhoids, anal
fissures, and impacted feces may cause dyspareunia.
Is the pelvic examination totally normal?
 If this is true, one would
consider functional dyspareunia, or it may be that the patient does not
have dyspareunia at all and simply has no sexual desire or dislikes the
sexual act.
It is extremely important to look for evidence of sexual abuse both on
history and on physical examination before undertaking an expensive
workup. Routine studies include a CBC, sedimentation rate, urinalysis,
urine culture and sensitivity, and vaginal smear and culture. A Pap smear
should also be done. A pregnancy test should be done if pregnancy is
suspected. If there is a pelvic mass, pelvic ultrasound may be helpful.
However, referral to a gynecologist is usually made before ordering this
study. If vulvar dystrophy is suspected, a vaginal biopsy may be useful. If
the vaginal examination is normal, perhaps a psychiatrist should be
198

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
DYSPHAGIA
Are there abnormalities on oropharyngeal examination?
 If so, then
of course the cause may be local. This is particularly true if there are
painful ulcerations of the mouth, glossitis, or tonsillitis. There may be
neoplasms in the oropharynx or larynx that may be either obstructing
swallowing or causing pain on swallowing.
Is the dysphagia constant or intermittent?
 Intermittent dysphagia
would make one think of myasthenia gravis, and if there are other
neurologic findings to suggest that, it would be the most likely
working diagnosis. Without neurologic findings, a Schatzki ring may
be present.
Does the patient have difficulty swallowing both liquids and solids
or only solids?
 If the patient has difficulty with both liquids and
solids, a diagnosis of achalasia, scleroderma, or diffuse esophageal
spasm should be entertained. Patients who have difficulty swallowing
solids only usually should be considered to have esophageal
carcinoma until proven otherwise.
Is heartburn present?
 If there is heartburn as well as dysphagia, a
diagnosis of reflux esophagitis with or without hiatal hernia should be
entertained. Many conditions, including achalasia, diffuse esophageal
spasm, and even advanced esophageal carcinoma, may be associated
with pain on swallowing or chest pain.
Is the patient male or female?
 Dysphagia in a male is suggestive of
esophageal carcinoma; this would be especially true with a history of
significant smoking and drinking. Dysphagia in a female would
suggest esophageal web, as in Plummer–Vinson syndrome.
Is there significant weight loss?
 Significant weight loss is very often
associated with esophageal carcinoma, but not until it is advanced to a
significant degree. One often forgets that weight loss is also associated
with achalasia.
Is there a history of syphilis?
 Obviously, this would suggest an aortic
aneurysm, and in considering aortic aneurysm, one should also
consider other mediastinal masses that might be associated with this
condition.
Are there dermatologic signs and symptoms?
 This would bring up
the possibility of scleroderma.
200

In a patient with definite dysphagia, it is wise to consult a
gastroenterologist at the outset! The most useful diagnostic test (and most
inexpensive) is the barium swallow, and an upper GI series might be done
as well. The barium swallow will often display fairly definitive features of
carcinoma of the esophagus, esophageal diverticulum, achalasia, hiatal
hernia, and esophagitis. Ask the radiologist for a dynamic swallowing
study as well. The barium swallow, however, must be frequently followed
by esophagoscopy to obtain a more definitive diagnosis and a tissue
biopsy, particularly in the case of carcinoma of the esophagus. If both of
these tests are negative, the possibility of myasthenia gravis should be
considered, and a Tensilon test should be done. Esophageal manometry
may detect achalasia or diffuse esophageal spasm. When a mediastinal
mass is suspected, a CT scan of the neck or mediastinum should be done.
The problem may be a retropharyngeal abscess or large adenoids. When all
testing is negative, hysteria should be considered. Ultrasonography can be
used to diagnose abnormal movements of the tongue and larynx.
Videofluoroscopy is also useful in diagnosing oropharyngeal causes.
Reflux esophagitis can be diagnosed with ambulatory pH monitoring. A
therapeutic trial of a
 
proton-pump
 
inhibitor may be
 useful.
201

1. 
  2. 
  3. 
  4. 
  5. 
DYSPNEA
Is the dyspnea acute?
 If the dyspnea is of acute onset, one should ask
if there is a drug history, particularly a history of mainlining narcotics.
If so, adult respiratory distress syndrome should be considered.
Furthermore, is there an embolic source for a possible pulmonary
embolism? If the onset is gradual, one should move on to consider
chronic diseases such as congestive heart failure and pulmonary
emphysema and fibrosis. Exposure to heavy metals such as cadmium
or mercury can cause severe lung damage, while bleach and
phosphoric acid can cause acute respiratory distress syndrome
(ARDS).
Is there fever or purulent sputum?
 Obviously, fever and purulent
sputum should make one think of pneumonia.
What kind of rales are there?
 If there are crepitant rales, one should
consider congestive heart failure or pneumonia. If there are sibilant
and sonorous rales or wheezing, one should consider bronchial asthma
or pulmonary emphysema.
 Hepatomegaly would be a sign of congestive
heart failure. However, in the acute stages it may not manifest
immediately. Hepatomegaly may also be an indication of other
systemic diseases that are associated with either lung disease or heart
disease. The collagen diseases, in particular, come to mind.
Is there an abnormal neurologic examination?
 Look for myasthenia
gravis and muscular dystrophy.
The basic workup of acute-onset dyspnea should include a CBC to exclude
anemia; a chest x-ray and arterial blood gases to exclude pneumothorax,
pneumonia, and other pulmonic diseases; and an EKG and serial cardiac
enzymes to exclude myocardial infarction and some of the causes of
congestive heart failure. A sputum smear and culture should always be
done when there is adequate sputum. Eosinophils should be sought. It is
important to make sure that you have an adequate specimen and, therefore,
leukocytes should be reported on the smear.
If there is chest pain accompanied by hemoptysis, a D-dimer, arterial
blood gases, and a ventilation–perfusion scan or spiral CT of the chest
203

should be done to rule out pulmonary embolism. Even without chest pain
and hemoptysis, a pulmonary embolism may need to be excluded. If the
ventilation–perfusion scan is inconclusive, a pulmonary angiography may
still need to be done in difficult cases. Look for an embolic source in the
extremities or pelvis. If routine smears and cultures are negative, cultures
for AFB and fungi may need to be done, especially when there is
continuing purulent sputum. The clinician should also consider doing skin
testing for these diseases.
If congestive heart failure is suspected, an arm-to-tongue circulation
time, BNP, and pulmonary function testing should also be done.
Echocardiography may also be diagnostic. A therapeutic trial of a diuretic
may be valuable. When there is significant wheezing, a trial of epinephrine
0.3 mL subcutaneously may clear up the confusion. If ARDS is suspected,
look for sepsis from an abdominal source or IV drug abuse.
In chronic dyspnea, the chest x-ray and EKG should be complemented
by pulmonary function testing, exercise testing, and arterial blood gases.
Serum protein electrophoresis to check for alpha-1-antitrypsin deficiency
and a sweat test to rule 
out cystic fibrosis may be indicated especially in
nonsmokers. Pulmonary function testing will be very useful in diagnosing
asthma and distinguishing pulmonary emphysema from pulmonary
fibrosis. A diagnosis of pulmonary fibrosis is substantiated by a reduction
in a single-breath carbon monoxide diffusing capacity. The advice of a
pulmonologist should be sought when extensive pulmonary function
testing, such as compliance and diffusing capacity, needs to be determined.
Bronchoscopy may need to be done to exclude a foreign body, neoplasm,
or bronchiectasis. Cardiac catheterization and pulmonary angiography may
be needed to identify chronic recurrent pulmonary embolism, intracardiac
shunts, and pulmonary hypertension. Dyspnea without objective findings
on physical examination should prompt a referral to a psychiatrist.
204

1. 
  2. 
  3. 
  4. 
  5. 
DYSURIA
 A significant fever would suggest either
pyelonephritis, particularly in females, or acute prostatitis in males.
Is the urine grossly bloody or are there a significant number of
red cells on microscopic examination?
 Grossly bloody urine in a
young female should suggest acute cystitis, particularly if she has just
returned from a honeymoon. In older patients it may indicate bladder
carcinoma, but generally these patients have blood in their urine
before they develop dysuria. Really significant blood in the urine may
also indicate schistosomiasis or tuberculous cystitis. Dysuria and
hematuria can occur in renal or vesicular calculi as well.
Is there a urethral or vaginal discharge?
 If either of these signs is
present, one must consider that the patient may have gonorrhea until
proven otherwise. Repeated negative smears and cultures for
gonococcus should suggest that the patient may have female urethral
syndrome or nonspecific urethritis because of Chlamydia.
Are there systemic symptoms?
 If there are systemic symptoms, one
must consider the possibility of Reiter’s syndrome or collagen disease.
One should not forget that systemic symptoms of arthritis and rash
may also be present in gonorrhea.
Is the pain very severe?
 Severe pain, particularly a need to stay close
to the restroom so one can empty one’s bladder, may indicate tabes
dorsalis, although this condition is rarely seen today.
Obviously, a urinalysis and Gram’s stain of the unspun urine should be
done in all cases. A dipstick test is often negative and the only way to rule
out a UTI with certainty is to look at a drop of urine under the microscope!
The author can’t count the number of times he has picked up a UTI this
way. If this is positive, treatment can be initiated. Urine cultures are only
necessary for resistant or repeated episodes. I also recommend a urethral
smear and a vaginal smear and culture if sufficient material can be
obtained. This may mean massaging the prostate for an adequate
specimen. Even four white cells per high-powered field on a urethral
smear probably indicate urethritis. Cultures for both gonorrhea and
Chlamydia should be done. DNA probe testing has become a useful tool in
206

detecting Chlamydia and gonorrhea. In persistent cases of dysuria, a
helical CT scan, ultrasonography, and a cystoscopy must be done. In
children, a voiding cystogram is essential. An urologist needs to be
consulted before ordering these tests. Blood cultures should be done in
cases of acute pyelonephritis. Cultures for anaerobic bacilli and
tuberculosis may be necessary in persistent pyuria. It should go without
saying that a rectal and vaginal examination should be done in all cases.
However, this is frequently neglected. A therapeutic trial of antibiotics is
useful. In particular, a course of ciprofloxacin is useful in diagnosing
prostatitis
Table 07: Dyspnea
207

a
Unless right heart failure.
208

1. 
  2. 
  3. 
  4. 
EAR DISCHARGE
Is it acute?
 Acute ear discharge suggests acute otitis media with
rupture or an otitis externa, especially if it is painful. If the patient is
diabetic, look for malignant otitis externa from a pseudomonas
infection. A chronic discharge would suggest cholesteatoma, chronic
otitis media, and possibly cerebrospinal fluid.
Is it painful?
 A painful ear with a discharge is most likely acute otitis
media with rupture. It may, however, be because of otitis externa, a
foreign body, or serous otitis media.
 An ear discharge with fever suggests otitis
media, mastoiditis, and petrositis.
What is the character of the discharge?
 A mucopurulent discharge
suggests chronic otitis media and mastoiditis, whereas a fetid
discharge with whitish debris suggests a cholesteatoma. If the
discharge is clear, a cerebrospinal fluid otorrhea should be suspected.
The most important test to do is a smear, culture, and sensitivity of the
discharge. If there is fever, a CBC, sedimentation rate, and chemistry panel
should be done. The ears should be examined after thorough irrigation. X-
ray of the mastoids and petrous bones should be done if a deep source for
the discharge is suspected. Audiograms are helpful if there is hearing loss.
If the discharge is thought to be cerebrospinal fluid, a RISA study and CT
scan of the brain may need to be done. An ear, nose, and throat specialist
should be consulted before ordering expensive diagnostic tests.
209

1. 
  2. 
  3. 
  4. 
EARACHE
Are there abnormalities on the ear examination?
 The ear
examination may reveal severe otitis externa, an epithelioma of the
pinna, a foreign body, or impacted wax. It may also show
inflammation and bulging of the eardrum. Be sure to do pneumatic
otoscopy for drum mobility. A vesicular rash of the drum and external
auditory canal may indicate herpes zoster.
Is there pain on moving the pinna?
 Pain on moving the ear suggests
otitis externa, foreign body, impacted wax, or keratosis obturans.
Is there hearing loss?
 Hearing loss with an abnormal drum would
suggest serous or bacterial otitis media. It may also suggest a
cholesteatoma. Hearing loss with a normal ear examination suggests
aero-otitis.
Could the pain be a referred pain?
 Dental caries, dental abscesses,
impacted teeth, tonsillitis, and temporomandibular joint syndrome may
refer pain to the ear.
It should go without saying that diagnosis begins with an adequate
otoscopic examination. If the drum is obscured by wax, gentle lavage after
using Debrox will usually clear the canal. If there is an exudate, a culture
and sensitivity should be ordered. Perhaps a throat culture should also be
done. X-ray of the mastoids and petrous bones should be done if the
exudate is believed to be from a deeper source. Perhaps a CT scan is also
needed. If there is hearing loss, an audiogram needs to be done and a
tympanogram will be useful in diagnosing serous otitis media. A trial of
carbamazepine (Tegretol) or phenytoin (Dilantin) may be useful in
diagnosing glossopharyngeal neuralgia or tic douloureux. In children, a
trial of antibiotics may be worthwhile especially if the drum is not
visualized. If the discharge is thought to be cerebrospinal fluid, a CT scan
and RISA study should be done.
Referral to an ear, nose, and throat specialist or neurologist should be
considered before ordering expensive diagnostic tests.
211

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
EDEMA, GENERALIZED
Does the edema pit on pressure?
 Edema that pits on pressure is more
likely to be because of heart, liver, or kidney disease. Edema that does
not pit on pressure is more likely because of myxedema or
lymphedema.
 If there is hepatomegaly, one should consider
liver disease such as cirrhosis or cardiac disease.
Is there ascites?
 If there is ascites along with hepatomegaly, cirrhosis
of the liver is the most likely cause of the edema. However, one should
not forget constrictive pericarditis. If there is no ascites along with the
hepatomegaly, then congestive heart failure should be considered.
Is there jugular vein distention?
 Jugular vein distention certainly
would be most suggestive of congestive heart failure, but other causes
of jugular vein distention include superior vena cava syndrome
because of a mediastinal mass such as carcinoma of the lung and
constrictive pericarditis. Right heart failure secondary to pulmonary
emphysema and fibrosis can also cause jugular vein distention.
Is there abnormal urinary sediment?
 If there is abnormal urinary
sediment, consider nephritis, whether it might be because of chronic
glomerulonephritis or whether it is secondary to diabetes mellitus or a
collagen disease.
Is the patient taking any drugs that could cause the edema?
Among the drugs that should be considered are corticosteroids,
progesterone, estrogen, anti-inflammatory drugs such as naproxen
(Naprosyn) and ibuprofen (Motrin), antihypertensive drugs such as
methyldopa (Aldomet) and clonidine hydrochloride, calcium channel
blockers, beta-adrenergic blockers, and antidepressants.
A CBC should be done to rule out significant anemia that may be the cause
of the edema. If there is anemia, we need to determine its source (
page 43
).
Liver function tests are done to rule out liver disease; serum protein
electrophoresis and tests for BUN and creatinine should be done to
exclude renal disease. The urinalysis is very important both for routine
studies and also to examine the urinary sediment for diseases such as
chronic glomerulonephritis and collagen disease. If there is significant loss
213

of protein in the urine, one should be considering nephrosis. An EKG,
chest x-ray, BNP, and venous pressure and circulation time will be
extremely helpful in diagnosing congestive heart failure, but pulmonary
function tests can be done as the vital capacity is significantly reduced in
this disease. When there is a strong suspicion of congestive heart failure,
echocardiography or radionuclide-gated blood pool scintigraphy should be
done to determine the left ventricular ejection fraction. A value of less than
45% is considered abnormal. A thyroid profile should be done to diagnose
myxedema. A serum and urine osmolality will help diagnose SIADH. A
CT scan of the chest will help diagnose constrictive pericarditis.
Occasionally, the edema is because of an abdominal tumor. A CT scan of
the abdomen and pelvis will be helpful in those cases. Contrast
lymphangiography may be necessary to diagnose lymphedema.
214

1. 
  2. 
  3. 
  4. 
EDEMA, LOCALIZED
Is the edema acute or chronic?
 Acute edema, if it is localized,
should always bring to mind a deep vein thrombophlebitis. Look for a
Baker’s cyst obstructing the vein. It also should bring to mind acute
lymphangitis, particularly if there is erythema in the area. Finally, it
should also make one think of trauma or a focal infection such as
cellulitis. Chronic localized edema, however, is more likely related to
varicose veins or lymphedema.
Is the edema pitting or nonpitting?
 If the edema pits, it is more
likely related to inflammation or venous incompetence. If it is
nonpitting, it is more likely because of obstruction of the lymphatics,
that is, lymphedema.
Is there erythema, a rash, or focal tenderness, or all three?
Erythema and focal tenderness would suggest cellulitis, lymphangitis,
thrombophlebitis, angioneurotic edema, insect bite, or snake bite. It
also would suggest a sprain or contusion. Focal tenderness alone with
pitting edema and no significant erythema or rash would suggest a
deep vein thrombophlebitis. When there is no erythema or tenderness
in a case of pitting edema of a localized nature, one should consider
varicose veins or, in the lower extremities, a popliteal cyst that might
be obstructing the veins on a chronic basis.
If the edema is of the lower extremities, is there a positive
Homans’ sign?
 A positive Homans’ sign should always be looked for
because this would suggest a deep vein thrombophlebitis. Action must
be taken immediately in such cases.
A venous ultrasound study, impedance plethysmography, and contrast
venography are very useful in the diagnosis of deep vein thrombophlebitis.
D-dimer testing is also a sensitive indicator of active deep vein
thrombophlebitis and the need for anticoagulants. If a pelvic vein
thrombosis is suspected, it is wise to do an MRI of the pelvis, diagnosing
osteomyelitis and fractures. Lymphangiography will be helpful in the
diagnosis of carcinomatosis or lymphedema from other causes. A CT scan
of the abdomen or pelvis may also demonstrate the malignant lymph
nodes. A thyroid profile will diagnose cases of pretibial myxedema
215

because of thyrotoxicosis. Patients with upper extremity edema should
have a chest x-ray and CT scan of the mediastinum to determine the causes
of superior vena cava syndrome.
Table 08: Pedal Edema
216

ENOPHTHALMOS
If the condition is unilateral, it is almost always because of paralysis of the
cervical sympathetic ganglion and part of Horner’s syndrome. Horner’s
syndrome includes enophthalmos, partial ptosis, constricted pupil, absence
of sweating, and the presence of blushing on the side of the sympathetic
paralysis. The various causes of Horner’s syndrome can be found in 
page
256
. Prolonged endophthalmitis may cause unilateral enophthalmos
because of shrinkage of the eyeball. Bilateral enophthalmos may be
because of starvation or cachexia (in which case the cause should be
obvious) or congenital.
217

1. 
  2. 
  3. 
  4. 
  5. 
ENURESIS
Is the bed-wetting frequent or only occasional?
 Frequent bed-
wetting should signify pathology in the urogenital tract or endocrine
system. If the 
bed-wetting
 is infrequent, one should consider epilepsy.
Are there abnormalities found on the urogenital examination?
There are many causes of enuresis that can be found on a simple
examination, such as phimosis, balanitis, meatal stricture, vulvitis, or
intestinal worms.
Are there abnormalities on the urinalysis?
 Urinalysis alone is
usually not adequate, and a urine culture should be done to rule out
cystitis and pyelonephritis. The simple examination of the urine
sediment for bacteria is also helpful. Sugar in the urine may indicate
diabetes mellitus, but it may also indicate Fanconi’s syndrome.
Is there polyuria?
 Polyuria might indicate diabetes insipidus, diabetes
mellitus, hyperthyroidism, and hypoparathyroidism.
Are there abnormalities on the neurologic examination?
 Here one
would be looking for cerebral palsy and congenital anomalies of the
Finally, if the neurologic examination, urogenital examination, and
urinalysis are normal, perhaps the patient has a simple neurosis or
situational maladjustment.
Patients who are suspected of having a urologic condition as the cause of
their enuresis should have a urinalysis, IVP, and voiding cystogram with a
urine culture and colony count. Referral to an urologist for cystometric
testing may be required. If there is polyuria, a glucose tolerance test, a
thyroid profile, and tests for calcium, phosphorus, alkaline phosphatase,
and PTH level should be done. If epilepsy is suspected, an EEG should be
ordered. If the neurologic examination is abnormal, referral to a neurologic
specialist would be in order. If all the studies and examinations are within
normal limits, a referral to a psychiatrist or psychologist may be in order.
However, the child may have simple enuresis, in which case all that is
required is to reassure the parents that the child will grow out of it by
puberty. Enuresis that develops after a substantial period of dryness may
indicate sexual abuse.
218

1. 
  2. 
EPIPHORA
Is the epiphora unilateral or bilateral?
 If it is bilateral, it is most
likely because of emotional weeping or because of the effects of drugs
such as bromides, arsenic, and mercury.
Is the eye examination normal?
 If the eye examination is abnormal,
there are most likely obvious findings of conjunctivitis, foreign
bodies, corneal ulcer, or other problems. A foreign body may be
difficult to find, as may a corneal ulcer, and referral to an
ophthalmologist would be in order. In any event, the conjunctiva will
be red and inflamed. In addition, there may be lid problems,
particularly in the elderly, and these may constitute ectropion or
entropion. There is also the possibility of Bell’s palsy causing
incomplete closure of the eye, and therefore the eye will be
chronically inflamed from constant exposure to air.
If the eye examination is normal, one must consider the possibility of
obstruction of the nasolacrimal duct because of trauma, congenital causes,
a calculus, neoplasm, or dacryocystitis. Crocodile tears may occur when,
because of aberrant nerve regeneration following facial paralysis, the
lacrimal gland is stimulated to produce excessive tears while eating.
The first thing to do if the epiphora is bilateral is to determine if the patient
has been on any particular drugs or has emotional problems. If the eye
examination is abnormal or there are problems with the lids, referral to an
ophthalmologist is in order. Even if the eye examination is normal, referral
to an ophthalmologist would be necessary to determine if obstruction of
the nasolacrimal duct is the problem.
220

1. 
  2. 
  3. 
  4. 
EPISTAXIS
 The patient with hypertension could have
either essential or symptomatic hypertension. Be sure to recheck the
blood pressure, as other health professionals may miss the auscultatory
gap. Next, treat the hypertension and examine the patient for
symptomatic hypertension later (
page 268
).
Is the bleeding from Little’s area or is it farther up the nasal
passageway?
 Ninety percent of epistaxis results from bleeding in
Little’s area (Kiesselbach’s plexus), and this area is most easily
controlled. Be sure to ask about the use of cocaine or nasal sprays.
Bleeding from this area is usually not a serious problem. However,
when the bleeding is from the posterior nasal areas, one must always
consider the possibility of carcinoma.
Is there a history or are there clinical signs of a coagulation
disorder?
 There may be a history of hemophilia or leukemia. There
may be splenomegaly. There may be bleeding sites elsewhere to
indicate that there is a systemic disorder associated with the epistaxis.
One can easily perform a Rumpel–Leede test to determine if there is a
platelet deficiency or dysfunction.
 Aspirin, warfarin sodium, and
numerous other drugs can cause epistaxis.
The diagnostic workup of epistaxis should include a coagulation profile
with prothrombin time, partial thromboplastin time, bleeding time, platelet
count, Rumpel–Leede test, and CBC. If these tests suggest a coagulation
disorder, referral to a hematologist can be done for further diagnostic
workup.
A nasal smear should be done for eosinophils to determine if the
patient has chronic allergic rhinitis.
When a carcinoma of the nasal pharynx or sinuses is suspected, x-ray
of the paranasal sinuses can be done as well as nasopharyngoscopy. A CT
scan of the sinuses is also of value in difficult diagnostic problems.
222

1. 
  2. 
  3. 
  4. 
EUPHORIA
 The patient will frequently not
tell the truth about drug ingestion, but one should ask family and
friends about whether the patient uses any illicit drugs such as LSD,
marijuana, or cocaine. Other drugs that are prescribed by physicians
may cause euphoria, such as corticosteroids and various narcotics.
Is the neurologic examination abnormal?
 The patient may
demonstrate simple disorientation or disturbance in the thought
process or excessive jocularity, as may be seen in Witzelsucht. All
these findings may suggest a frontal lobe tumor, a general paresis, or
other forms of dementia. When there are long tract signs, such as
posterior column or pyramidal tract involvement, one must consider
the possibility of multiple sclerosis or a pontine glioma.
Is there significant incoherence, delusions, or hallucinations?
These findings would most likely suggest schizophrenia.
Is the euphoria sustained for long periods, or is it very short-
lived?
 If the euphoria is intermittent and very brief, one should
consider temporal lobe epilepsy. If it is more sustained, one would
consider manic-depressive psychosis.
A drug screen should be axiomatic on all patients, as the patient may lie. If
this is negative, one may proceed with the more expensive testing, such as
MRI, or at least a CT scan to rule out a brain tumor. If these tests are
negative and the problem persists, the patient should be referred to a
224

1. 
  2. 
  3. 
  4. 
  5. 
EXOPHTHALMOS
Is it bilateral or unilateral?
 Bilateral exophthalmos would suggest
hyperthyroidism. Unilateral exophthalmos suggests orbital tumor,
abscess, or aneurysm.
If it is bilateral, are there signs of hyperthyroidism?
 If there are
other indications of hyperthyroidism, Graves’ disease would be the
If it is unilateral, does the eyeball pulsate?
 A pulsating eyeball
would suggest an arteriovenous fistula, and there should be a loud
blowing murmur over the orbit.
 Fever would suggest acute cellulitis, acute sinusitis,
periostitis, or a cavernous sinus thrombosis.
Is there chemosis or ecchymosis?
 These signs are suggestive of a
cavernous sinus thrombosis.
In cases of bilateral exophthalmos, particularly if there is no fever or
chemosis or ecchymosis, a thyroid profile is the most valuable test. Orbital
MRI may also be done. However, Graves’ disease may be present with
normal thyroid function tests. Testing for thyrotropin receptor antibody
and peroxidase antibodies should be done in these cases. Other endocrine
studies may be necessary once hyperthyroidism has been excluded. In
cases of unilateral exophthalmos, ultrasonography and plain films of the
orbits and sinuses may be helpful, but a CT scan of the brain and sinuses is
the most valuable diagnostic aid. Carotid angiography will need to be done
to diagnose an arteriovenous fistula.
226

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
EXTREMITY PAIN, LOWER EXTREMITY
Is the extremity pain of acute or gradual onset?
 Acute onset would
suggest arterial embolism, deep vein thrombophlebitis, and cellulitis.
If there is a history of trauma, it would suggest a fracture, sprain, or
torn ligament.
Is there limitation of motion of the joints?
 A positive Patrick’s test
would indicate hip pathology, including greater trochanter bursitis. A
positive McMurray test would indicate a torn meniscus.
Are there positive neurologic findings?
 A positive femoral stretch
test would suggest a herniated disk at L2–3 or L3–4, whereas a
positive Lasègue’s sign would indicate a herniated disk at L4–5 or L5
to S1. Combined motor and sensory deficits may indicate
radiculopathy or neuropathy.
Is there a positive Homans’ sign?
 This is a very important
examination, as one would not want to miss a deep vein
thrombophlebitis.
Is there diminished or absent peripheral pulses?
 Diminished or
absent pulses would suggest arterial embolism, peripheral
arteriosclerosis, or Leriche’s syndrome (thrombosis of the terminal
aorta).
Is there focal tenderness, swelling, or erythema of the extremity?
This would suggest cellulitis, superficial thrombophlebitis,
osteomyelitis, lymphangitis, and other types of infections. Tenderness
without significant swelling or erythema would be suggestive of
bursitis or deep vein thrombophlebitis.
Often bursitis and myofascitis can be diagnosed by the dramatic relief
obtained from a lidocaine injection. If there is clear-cut joint pathology, an
x-ray of the joints, arthritis profile, and synovial fluid analysis will usually
provide a diagnosis. MRI is useful in the diagnosis of a torn meniscus. If a
deep vein thrombophlebitis is suspected, venous Doppler ultrasound,
impedance plethysmography, or a contrast venogram may be done. Order a
phospholipid antibody titer in patients with frequent episodes of
thrombophlebitis. Frequently, a D-dimer test will determine if
thrombophlebitis is the problem. If the pelvis is suspected of being the
228

embolic source, order an MRI. If an arterial embolism is suspected,
femoral angiography can be done. In cases of chronic peripheral
arteriosclerosis, the ankle-brachial index and arterial Doppler
ultrasonography are studies to be ordered first. If these are inconclusive, a
CTA or MRA may be more definitive. If a herniated disk or other
pathology of the lumbar spine is suspected, plain films of the lumbar spine
should be obtained. It might be wise at this point to also obtain a CBC,
sedimentation rate, and chemistry panel to determine the alkaline
phosphatase, calcium, and phosphorus. In older males, tests for acid
phosphatase and PSA should be done.
If these tests are unrevealing, it is wise to refer the patient to a
neurologic specialist before more expensive tests are ordered. The
specialist will probably order a CT scan or MRI of the lumbar spine and
may do nerve conduction velocity studies, EMG examinations, or
dermatomal SSEP studies as indicated. In difficult neurologic problems, a
combined myelography and CT scan is preferred over MRI. Bone scans
will help diagnose obscure fractures and osteomyelitis, both of the lumbar
spine and of the lower extremities.
229

231

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
EXTREMITY PAIN, UPPER EXTREMITY
 Limitation of motion of a
joint would suggest not only various types of arthritis, fracture, or torn
ligaments, but also inflammation of surrounding structures such as the
bursa or tendons. For example, limitation of motion of the shoulder
would suggest impingement syndrome, frozen shoulder, rheumatoid
arthritis or osteoarthritis, subacromial bursitis, and a torn rotator cuff.
Is the limitation of motion both active and passive, or active only?
If the limitation of motion is only active, one should suspect tendinitis
or bursitis. If the limitation of motion is both active and passive, one
should suspect the various forms of arthritis, as well as bone tumors,
osteomyelitis, and adhesive capsulitis.
Is there weakness or paresthesia?
 Weakness and especially
paresthesia suggest a neurologic origin for the pain, and one should be
considering brachial plexus neuritis, carpal tunnel syndrome, ulnar
entrapment, and radiculopathy.
Are there vasomotor or trophic changes?
 Vasomotor changes
would suggest Raynaud’s phenomena and sympathetic dystrophy.
Trophic changes along with vasomotor changes would also suggest a
peripheral neuropathy.
Are there positive neurologic signs in the lower extremities?
Diffuse hypoactive reflexes with stocking deficits in the lower
extremities would suggest a peripheral neuropathy, whereas
hyperactive reflexes in the lower extremities would suggest a cervical
cord tumor, cervical spondylosis, or multiple sclerosis.
Is there a positive Tinel’s sign at the wrist or elbow?
 Tinel’s sign at
the wrist would suggest carpal tunnel syndrome, whereas Tinel’s sign
at the elbow would suggest ulnar entrapment if it is over the ulnar
nerve or pronator syndrome if it is over the median nerve.
Are Adson’s tests positive?
 Adson’s tests are positive in thoracic
outlet syndrome, whether it is because of a cervical rib, scalenus-
anticus syndrome, Wright syndrome (pectoralis minor syndrome), or a
costoclavicular compression.
X-ray of the affected joints needs to be done if there is tenderness or
232

limitation of motion. Further workup of joint pain can be found in page
310.
 
When there are abnormal neurologic findings, an x-ray of the cervical
spine (always with A-P, laterals, and obliques), nerve conduction velocity
studies, and EMG examinations need to be done. Referral to a neurologist
should be made for these tests. If there is a typical radicular pain and a
herniated cervical disk is strongly suspected, MRI of the cervical spine
should be done. This is an expensive test, but when there are obvious signs
of radiculopathy, it is worthwhile. Perhaps dermatomal somatosensory
studies should be done when there is confusion about whether a herniated
disk is pathologic. If a vascular lesion is suspected, angiography and
venography should be ordered. ANA and nailfold capillary loop dilation
and dropout study may diagnose Raynaud’s phenomena; a small injection
of lidocaine and steroids locally may be diagnostic in cases of carpal
tunnel syndrome.
When there is intermittent pain, an exercise tolerance test should be
done to exclude coronary insufficiency. A stellate ganglion block may be
helpful in diagnosing reflex sympathetic dystrophy. Remember that other
nerve blocks may be done and one should not hesitate to call an
anesthesiologist for help in this area. Various forms of bursitis may be
diagnosed by a therapeutic trial of lidocaine and corticosteroid injections.
233

235

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
EYE PAIN
Is there redness of the eye?
 Redness of the eye suggests definite eye
pathology. Besides conjunctivitis and scleritis, be sure to look for
closed angle glaucoma (dilated pupil) which is associated with nausea
and vomiting and is a medical emergency. This is why visual acuity
should always be checked. Without redness, one should suspect
disease in the adjacent structures or retrobulbar neuritis. However,
contact lens wearers may present with eye pain without redness, but
there will be white spots on the cornea.
If there is redness, is there periorbital edema as well?
 Periorbital
edema should suggest a cavernous sinus thrombosis or herpes zoster.
If there is periorbital edema, is there a rash?
 A rash, particularly
vesicular rash, would suggest herpes zoster.
In cases without redness of the eye, is there any abnormality on
examination both with the naked eye and with the
ophthalmoscope?
 A dilated pupil would certainly suggest glaucoma;
ophthalmoscopic examination may show optic neuritis or retinal
detachment. A visual field examination may detect optic neuritis,
retrobulbar neuritis, and retinal artery occlusion. A visual acuity check
may pick up a refractive error.
Finally, is there headache associated with the eye pain?
 This would
be suggestive of migraine or cluster headache.
 In children with fever and conjunctivitis, look for
measles and Kawasaki disease.
The primary care specialist may want to treat cases of obvious
conjunctivitis without a culture and sensitivity. However, a smear and
culture is useful especially if 
Neisseria
 is suspected. A smear may also
reveal eosinophils suggesting allergic conjunctivitis. The primary care
specialist may also use fluorescein dye to diagnose a foreign body. Most
primary care physicians feel competent to use tonometry to diagnose
glaucoma and may feel competent to use a slit lamp. If all tests are
negative, a trial of sumatriptan orally or by nasal spray may help diagnose
migraine or histamine headaches. However, when there is any doubt about
the diagnosis, the most cost-effective approach is to refer the patient to an
236

1. 
  2. 
  3. 
  4. 
FACE PAIN
 Intermittent pain would suggest
trigeminal neuralgia, cluster headaches, or atypical migraine. Constant
pain would suggest any local abnormalities in the structures
underlying the face, such as an abscessed sinus, an abscessed tooth, or
a neoplasm in these areas.
Is the pain increased by chewing?
 Pain that is increased by chewing
very often may be related to the temporomandibular joint syndrome,
but it could be related to trigeminal neuralgia or dental caries. An
elongated styloid process may cause face pain (Eagle’s syndrome).
Is there an associated nasal discharge?
 An associated bloody nasal
discharge would make one think of a nasopharyngeal carcinoma, but a
purulent discharge would make one think of acute or chronic sinusitis.
A watery nasal discharge often accompanies cluster headaches or
atypical migraine.
Are there abnormal neurologic findings?
 Face pain sometimes
accompanies multiple sclerosis, acute Wallenberg’s syndrome, and
advanced acoustic neuromas. The pain in the trigeminal distribution
associated with multiple sclerosis often is intermittent and suggests
trigeminal neuralgia.
The first thing to determine is whether there is an infectious or neoplastic
process in the structures underlying the face. X-ray of the sinuses and teeth
and CT scan of the sinuses and brain may be necessary to further elucidate
this. An x-ray of the temporomandibular joint may be helpful. An MRI of
the temporomandibular joint is the procedure of choice to rule out
pathology of this joint. Referral to a dentist to evaluate the patient’s teeth
or to an ear, nose, and throat specialist to evaluate sinusitis may be
To rule out cluster headaches or atypical migraine, a histamine test
may be done. It may be wise to see the patient during an attack so that
superficial temporal artery compression can be done to rule out migraine
and/or a shot of sumatriptan succinate can be given, which should provide
immediate results in cluster headache and atypical migraine.
A trial of carbamazepine (Tegretol) can be given in cases of suspected
238

trigeminal neuralgia, but referral to a neurosurgeon for an alcoholic
injection of the maxillary or mandibular branches of trigeminal nerve will
more likely make the diagnosis and solve the patient’s problem.
239

1. 
  2. 
  3. 
  4. 
FACIAL FLUSHING
Is the flushing constant or intermittent?
 Intermittent flushing
suggests menopause, carcinoid syndrome, systemic mastocytosis,
pheochromocytoma, and Zollinger–Ellison syndrome. Constant
flushing might suggest alcoholism, polycythemia, or the malar flush of
mitral stenosis.
Is there associated obesity?
 Associated obesity would certainly bring
to mind Cushing’s syndrome, but it may also be associated with
alcoholism.
Is there associated rash on the face or elsewhere?
 A rash would
most likely bring to mind rosacea if it is on the face, but if it is
elsewhere, one might consider systemic mastocytosis or
dermatomyositis.
Are there associated systemic symptoms and signs?
 
Diarrhea would
suggest carcinoid or Zollinger–Ellison syndrome. A headache along
with the flushing would suggest a systemic mastocytosis. Fainting
might suggest pheochromocytoma or epilepsy.
Urinalysis for 5-HIAA should be done, if carcinoid syndrome is suspected.
Urine samples may be taken for drug and alcohol screen in all cases in
which there is any doubt about drug or alcohol history. Tests for serum
FSH and estradiol should be done in patients suspected of having
menopause. A 24-hour urine collection for catecholamines should be done
for patients suspected of having pheochromocytoma. Serum gastrin tests
should be done for patients suspected of having Zollinger–Ellison
syndrome. In patients with systemic mastocytosis or dermatomyositis, a
skin biopsy or muscle biopsy can be done. In patients with suspected
Cushing’s disease, a serum cortisol and cortisol suppression test can be
done.
240

FACIAL MASS
A facial mass may come from the skin, the subcutaneous tissue, the teeth,
the sinuses, the bones, or the salivary glands. In the skin there may be
moles, simple nevi, sebaceous cysts, papillomas, carcinoma, comedones,
and urticaria. In the subcutaneous tissue, there may be angioneurotic
edema, trauma, and erysipelas and actinomycosis.
Swelling in the teeth includes dental abscess or dental cyst. The sinuses
may become infected and cause swelling over the surface. The bones may
develop an odontoma, a sarcoma, or a dermoid cyst. The bones may be
fractured and there may be bruising with considerable swelling. If the
bones of the sinuses are broken, there may be subcutaneous emphysema.
Mumps and uveoparotid fever may cause swelling of the salivary
glands. Mixed tumors of the parotid gland cause unilateral swelling of the
face. A stone may obstruct Stensen’s or Wharton’s ducts, causing
intermittent swelling. Nonspecific inflammation of the parotid glands
occurs in the elderly and malnourished individuals. Sjögren’s syndrome
usually causes bilateral parotid swelling and diminished saliva.
Most of the skin lesions will be obvious, but a skin biopsy can be
performed when in doubt. Smears and cultures should be done when
infection is suspected. A therapeutic trial of epinephrine or antihistamines
can be tried in angioneurotic edema or urticaria. X-ray of the skull, jaw,
and sinuses may be necessary. A CT scan may be needed to identify some
fractures, salivary gland tumors, and sinus infections. Referral to an oral
surgeon or otolaryngologist should be made early in confusing cases.
242

1. 
  2. 
  3. 
FACIAL PARALYSIS
Is it acute or gradual onset?
 If it is acute onset, Bell’s palsy, diabetic
neuropathy, and cerebral vascular accident must be considered. If it is
gradual onset, one must consider an acoustic neuroma, advancing
petrositis, or a brain tumor or abscess.
Is there associated hemiplegia or hemiparesis?
hemiplegia or hemiparesis and it is acute onset, one should consider
cerebral vascular accident or extradural or subdural hematoma. If the
hemiparesis, however, is contralateral, one should consider a brain
stem thrombosis or hemorrhage. There are two clinical syndromes that
are due to basilar artery lesions: Foville’s syndrome and Millard–
Gubler syndrome. If the hemiparesis is gradual onset, one should
consider brain tumor or abscess or degenerative disease.
Is there earache or hearing loss?
 Associated earache or hearing loss
should make one think of acoustic neuroma, petrositis, mastoiditis,
herpes zoster, and cholesteatoma.
Immediate referral to a neurologist is indicated. One should do a complete
examination of the ear, nose, and throat to determine if there is any rupture
of the drum, discharge, evidence of otitis media, etc. Thereafter, x-ray of
the mastoids and petrous bones should be done along with tomography. An
MRI or CT scan of the brain with or without contrast and with emphasis
on the internal auditory foramina should be done if acoustic neuroma is
suspected. Culture of the discharge from the ears and blood culture should
be done, if there are associated signs of an infectious process. Testing for
Lyme disease may be indicated. Spinal fluid analysis should be done to
look for Guillain–Barré syndrome. If myasthenia gravis is suspected, a
Tensilon test may be done. Spinal fluid culture should be done in cases of
brain abscess. Carotid scans and a workup for an embolic source should be
done in cases of cerebral vascular accident. Of course, when there is a
brain tumor or abscess or a cerebral vascular accident is suspected, CT
scans of the brain should be done. If these are not helpful or are
inconclusive, MRI of the brain can be done. Glucose tolerance testing
should be done to rule out diabetic neuropathy. If lead poisoning is
suspected, a blood level for lead should be done.
243

1. 
  2. 
  3. 
  4. 
  5. 
FACIAL SWELLING
Is the facial swelling focal or diffuse?
 If it is focal, one should
consider a local condition in the structures underlying the face such as
the salivary glands, the teeth, or the sinuses. Mumps is a common
condition, of course, especially in children. If it is diffuse facial
swelling, one should consider a systemic disease such as
glomerulonephritis, myxedema, or Cushing’s disease.
Is the swelling associated with generalized edema?
 If there is
generalized edema, one must consider acute glomerulonephritis,
nephrotic syndrome, congestive heart failure, or cirrhosis. If the
generalized edema is nonpitting, one would consider myxedema and
cretinism. If there is no generalized edema, one must consider
conditions such as Cushing’s syndrome, dermatomyositis,
acromegaly, mongolism, and Paget’s disease.
If the edema is generalized, is it pitting edema or nonpitting
edema?
 Nonpitting edema would suggest myxedema and cretinism.
Is there associated flushing?
 With flushing one would consider
Cushing’s syndrome, dermatomyositis, and a superior vena cava
syndrome. If there is no flushing, one should consider acromegaly,
mongolism, or Paget’s disease.
 If there is associated fever, look for
infections in the structures underlying the skin such as mumps,
abscess of the salivary gland, an abscessed tooth, sinusitis, or syphilis.
Cases of focal swelling should have a routine CBC and sedimentation rate.
X-ray
 of the sinuses and teeth should be done. If mumps is suspected, a
mumps skin test or antibody titer may be done. If all these tests are
negative and there is a focal swelling, referral to an oral surgeon may be
wise at this point.
If the swelling is diffuse, the basic workup is a CBC, chemistry panel,
and urinalysis. A streptozyme test or ASO titer can be done if
glomerulonephritis is suspected, but a microscopic examination of the
urine is extremely important in this condition. If congestive heart failure is
suspected, a chest x-ray, EKG, 
arm-to-tongue
 circulation time, and
pulmonary function testing should be done. In cases of Cushing’s disease,
245

a 24-hour urine-free cortisol and cortisol suppression test may be done. X-
ray of the skull and long bones should be done in suspected cases of
acromegaly or Paget’s disease.
246

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
10. 
11. 
12. 
13. 
14. 
15. 
FACIES, ABNORMAL
Perhaps every clinician has at one time or another experienced the joy of
seeing a patient’s face and making the diagnosis. The round flushed face
of Cushing’s disease, the pop-eyes of hyperthyroidism, or the
expressionless face of Parkinson’s disease quickly come to mind. There
are many other abnormal facies you will want to remember. Let’s
enumerate them.
In glomerulonephritis, the face is pale and puffy with edematous bags
under the eyes.
In myxedema, the facial features become coarse; consequently, the
nostrils are broad, and the lips are thick. The face is expressionless and
puffy.
In mongolism, there is epicanthus, and the face is oriental in
appearance with the tongue protruding.
In mental retardation, the face is often dull and expressionless.
In tetanus, we see the sarcastic smile of risus sardonicus.
In myasthenia gravis, the face is also expressionless, but the variable
degree of ptosis should be a warning.
In mitral stenosis, the malar flush is very helpful in making the
The flushing of the face in alcoholism, carcinoid syndrome, and
menopause is also helpful.
In acromegaly, the features are coarse, but the brows are enlarged and
the jaw protrudes. The spaces between the lower teeth widen.
In myotonic dystrophy, the face is hatchet-shaped due to the facial
wasting and weakness, and there is bilateral partial ptosis.
In bulbar and pseudobulbar palsy, regardless of the cause, the face is
expressionless, the mouth remains open most of the time, and there is
drooling.
In Bell’s palsy, the mouth is drawn to the unaffected side during a
smile, and the nasolabial fold is flat. The eye does not close
completely.
In Paget’s disease, the forehead protrudes, and the face appears
disproportionately small.
In scleroderma, there is smoothing out of all the wrinkles of the face
along with thinning of the skin, giving a waxy appearance.
In cachectic states, the face begins to appear like a skull with skin over
247

16. 
17. 
18. 
it.
In hypertelorism, the eyes are wide apart.
In Wilson’s disease, the face looks like it is ready to crack a smile, and
the mouth is open with frequent drooling.
The cyanosis of congenital heart disease would hardly be missed.
There are many other rare facies that, once seen, won’t be forgotten.
248

1. 
  2. 
  3. 
  4. 
  5. 
FAILURE TO THRIVE
Is there a history of an abnormal gestation?
 There may be a history
that the mother was a chronic alcoholic or ingested such drugs as
phenytoin, trimethadione, or narcotics. The mother may have had
toxoplasmosis, rubella, herpes simplex, or other diseases during her
gestation.
Is the child’s environment abnormal?
 Careful investigation may
disclose that the child has been neglected or that there are economic
circumstances to indicate that the child is not getting enough food.
Investigation may also indicate that the child is not getting adequate
love or practicing good hygiene.
Are there abnormalities found on the neurologic examination?
Neurologic examination may reveal findings to suggest microcephaly,
muscular atrophy, hydrocephalus, spastic diplegia, and other
neurologic causes of mental retardation.
Are there endocrine abnormalities?
 Cretinism, pituitary tumors, and
genital abnormalities may be suggested from the endocrine
examination.
Are there findings to suggest a GI disorder?
 Wasting and a
distended abdomen may suggest a malabsorption syndrome. The
history of frequent pneumonia may indicate fibrocystic disease.
Cataracts may suggest galactosemia.
The routine diagnostic workup should include a CBC, sedimentation rate,
urinalysis, urine culture, chemistry panel, thyroid profile, sweat test, stool
for quantitative fat, chest x-ray, and an EKG. Bone age x-ray is often
helpful in indicating a growth delay.
If there are focal neurologic signs or a pituitary tumor is suspected, a
CT scan of the brain may be necessary. Additional endocrinologic tests
include serum growth hormone level before and after exercise,
somatomedin-C level, and overnight dexamethasone suppression test.
However, an endocrinologist, pediatrician, or orthopedic surgeon should
be consulted before ordering expensive diagnostic tests. When the workup
fails to yield a diagnosis, consider constitutional growth delay.
249

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
FATIGUE
Is there weight loss?
 If there is weight loss, one must consider a
neoplasm, endocrine disorders, such as hyperthyroidism or diabetes
mellitus, malnutrition or malabsorption, and chronic infectious
diseases such as tuberculosis or subacute bacterial endocarditis.
 If there is fever, one should consider an infectious
disease, such as tuberculosis, subacute bacterial endocarditis,
toxoplasmosis, infectious mononucleosis, or brucellosis.
 If there is pallor, the most likely cause is a type of
anemia such as that associated with malabsorption syndrome or iron
deficiency anemia, pernicious anemia, or anemia blood loss.
Is the fatigue intermittent or constant?
 Intermittent fatigue would
make one suspect myasthenia gravis or Eaton–Lambert syndrome.
Constant fatigue would be related to any of the conditions we have
already discussed. Constant fatigue, however, with no weight loss
would make one consider a psychiatric disorder.
 Alcoholism, cocaine
abuse, and chronic aspirin ingestion are just a few of the disorders that
can be associated with chronic fatigue. Statins may cause myalgia and
frank rhabdomyolysis. Don’t forget caffeine abuse!
Are there associated neurologic findings?
 Many neurologic
disorders are associated with fatigue, and they include muscular
dystrophy, amyotrophic lateral sclerosis, and Parkinson’s disease.
 Polyuria would make one think of
hyperthyroidism, diabetes mellitus, hyperparathyroidism, and chronic
renal failure.
All patients should have routine laboratory studies, including CBC,
sedimentation rate, chemistry panel, VDRL test, a chest x-ray, and a
urinalysis including analysis for myoglobin. CPK, LDH, AST, and urine
creatine and creatinine should be done to rule out muscle disease. A
thyroid profile should be done to rule out hyperthyroidism. Further,
endocrine workup including serum cortisol will help differentiate
Addison’s disease and hypopituitarism. Because fatigue is associated with
aldosteronism, a 24-hour urine aldosterone determination should be done.
251

If SIADH is suspected, order a serum and urine osmolality. A serum PTH
may be indicated to rule out hyperparathyroidism.
Tests for chronic infectious disease, such as febrile agglutinins,
brucellin antibody titer, heterophile antibody titer or Monospot test,
sputum for AFB, and various skin tests for tuberculosis and fungi, can be
done. HIV testing may be appropriate, if there is a history of high-risk
sexual behavior. Serial blood cultures also would be of value if there is
significant fever. Tests for chronic organ failure such as BUN, creatinine,
serum electrolytes, and liver function tests should be done. A workup of
anemia including a workup of malabsorption syndrome may be necessary.
Consequently, stool analysis for fat content as well as D-xylose absorption
testing may be done.
A search for neoplasm will include chest x-ray, x-ray of the skull and
long bones, a bone scan, an upper GI series, and small bowel follow-
through as well as a barium enema and IVP. A muscle biopsy will help
differentiate certain collagen diseases, muscular dystrophy, and trichinosis.
An ANA test and serum complement to screen 
for collagen disease should
be done. A Tensilon test or acetylcholine receptor antibody titer may be
necessary to differentiate myasthenia gravis. Lambert–Eaton syndrome is
diagnosed by voltage-gated calcium channel radioimmunoassay. If a
neurologic disease is suspected, referral to a neurologist would be in order.
Consider EMG also. If sleep apnea is a possibility, overnight
polysomnography is indicated. An MRI of the brain or spinal cord may be
indicated to rule out multiple sclerosis.
If all the tests prove negative, referral to a psychiatrist would be
appropriate. On the contrary, it may be appropriate to refer the patient to a
psychiatrist earlier in the course of the workup. The diagnosis of chronic
fatigue syndrome is sometimes made when all the diagnostic tests are
negative, but whether it is truly a disease is questionable.
252

1. 
  2. 
  3. 
  4. 
  5. 
FEMORAL MASS OR SWELLING
Is it reducible?
 If the mass is reducible, it is most likely a femoral
hernia or saphenous varix.
Is there an associated kyphotic curvature of the spine?
 The
findings of a kyphotic curvature of the spine suggest a psoas abscess,
which is usually tuberculous.
Is the mass firm and ovoid?
 A firm, ovoid mass suggests an enlarged
lymph node or an ectopic testis.
Is there resonance or bowel sounds over the mass?
suggest a femoral hernia.
Is the corresponding half of the scrotum empty?
suggest an ectopic testis.
Surgical consultation may be wise at the outset. A reducible mass would
suggest a femoral hernia, but an upper GI series with a small bowel
follow-through would confirm this diagnosis. Of course, if it is felt that the
femoral hernia is irreducible, this study would not be done, and
exploratory surgery would be indicated. If the mass is suspected to be a
lymph node, a biopsy should be done. If the mass is suspected to be an
abscess, an incision and drainage should be done. If tuberculosis is
suspected, a tuberculin test as well as an AFB smear and culture should be
done. If the mass is suspected to be a saphenous varix, venography will
confirm the diagnosis. Exploratory surgery of the groin will clarify the
diagnosis in confusing cases.
254

1. 
  2. 
  3. 
  4. 
  5. 
FEVER, ACUTE
Is there a history of drug ingestion or injection?
 This will help
diagnose drug reactions and serum sickness, which are common and
easily discovered in the history. Patients with glucose-6-phosphate
dehydrogenase deficiency may develop fever after receiving certain
drugs.
 The presence of a rash should make one think of a
drug reaction, meningococcemia, the various exanthems, and subacute
bacterial endocarditis.
Is there localized pain?
 If there is a sore throat, obviously
streptococcal pharyngitis or a viral URI is likely. If there is headache,
then meningitis or encephalitis must be considered. If there is chest
pain, one should consider a pulmonary infarct, myocardial infarction,
or Bornholm disease. If there is abdominal pain, one would consider
pyelonephritis, cholecystitis, and appendicitis among the various
conditions. If there is joint pain, one should consider rheumatic fever,
rheumatoid arthritis, or septic arthritis.
Is there a focal discharge?
 A productive cough would make one
consider pneumonia. A rectal discharge would make one consider a
perirectal abscess. A urethral discharge should make one think of
gonorrhea.
Are there other localizing signs?
 Frequency of urination should
make one think of pyelonephritis. A productive cough should make
one think of pneumonia, whereas jaundice would make one think of
hepatitis.
Routine studies include a CBC, sedimentation rate, chemistry panel,
urinalysis, chest x-ray, VDRL test, and tuberculin skin test. A normal
sedimentation rate suggests factitious fever. Serial blood cultures should
be done on all patients. Febrile agglutinins usually should be done. An
ASO titer or streptozyme test should be done to exclude rheumatic fever.
Rheumatoid factor, ANA, and DNA tests should be done to look for lupus
and other connective tissue disease. An HIV antibody titer may need to be
ordered. Serologic tests for Lyme disease may be indicated. A serum
procalcitonin will often distinguish bacterial infections from viral
256

infections.
The next step is to culture any discharge or various body fluids that
might be suspect. Thus, a urinalysis and urine culture should be done. A
nose and throat culture should be done. A sputum smear and culture may
need to be done. The next consideration is to do various serologic tests. A
heterophile antibody titer should be done in teenagers. Febrile agglutinin
tests may need to be done. Acute and convalescent phase sera for viral
studies may need to be done. In persistent fever associated with cough, do
a urine test for legionella antigen.
Next one should do skin testing. Thus, histoplasmin, coccidioidin, and
blastomycin skin testing should be done on patients with a cough.
Trichinella
 skin testing may need to be done, as well as brucellin skin
testing. A Kveim test might need to be done for suspected sarcoidosis.
The next step is to do plain x-ray of suspected areas. For instance, x-
ray of the teeth may disclose an abscessed tooth. X-ray of the long bones
may disclose a metastatic carcinoma.
The next step is contrast x-ray studies of various organ systems. An
IVP may show a hypernephroma. A cholecystogram may show gallstones.
An upper GI series 
and barium enema may show chronic pancreatitis or
diverticulitis. Angiography may disclose periarteritis nodosa, aortitis, or
giant cell arteritis.
The next step is to do a CT scan of the abdomen and pelvis. If this is
negative, consider a CT scan of the chest and mediastinum.
Echocardiography may disclose valvular vegetations or an atrial myxoma.
Next, consider biopsying various organ systems. For instances, a
lymph node biopsy may disclose a lymphoma or sarcoidosis. A muscle
biopsy may disclose periarteritis nodosa, polymyositis, or trichinella.
Next one should do bone scans and gallium scans for possible
metastasis, osteomyelitis, or localized abscesses.
If all these procedures fail to turn up a lesion, then an exploratory
laparotomy may need to be done. A fibrin test may indicate Mediterranean
fever, or urine for etiocholanolone may also indicate a relapsing type of
fever. A urine test for porphobilinogen may diagnose porphyria.
The wisest move is to conduct this investigation with the help of an
infectious disease specialist or a specialist in the body organ system most
likely suspected of harboring the infection.
257

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
FEVER, CHRONIC
 Of course, the
history should reveal that the patient has been on a certain drug or has
received certain antitoxins, serums, or vaccines.
 If there is a rash, one should suspect subacute
bacterial endocarditis, Rocky Mountain spotted fever, secondary
syphilis, rat-bite fever, pemphigus, a drug reaction, lupus
erythematosus, dermatomyositis, or typhoid fever. There are other
conditions associated with a rash also.
Is there a characteristic pattern to the fever?
 The various forms of
malaria give a characteristic pattern of the fever, as well as undulant
fever in Hodgkin’s disease.
 Abdominal pain should suggest a
cholecystitis, hepatic abscess, diverticulitis, etc. A sore throat should
suggest infectious mononucleosis, leukemia, and subacute thyroiditis.
Joint pain should suggest rheumatoid arthritis, rheumatic fever, or
gonococcal arthritis. Earache should suggest otitis media or
mastoiditis. Chest pain should suggest tuberculosis, pleurisy, or
empyema.
Is there a localized discharge?
 Purulent sputum should suggest
pneumonia, tuberculosis, or chronic fungal disease in the lung. A
urethral discharge would suggest gonorrhea or Reiter’s disease.
Is there a localized mass or swelling?
 An abdominal mass would
suggest hepatic abscess, pancreatic cyst, or diverticular abscess. A
flank mass might suggest hypernephroma or perinephric abscess.
The diagnostic workup is similar to that for acute fever on 
page 198
.
259

1. 
  2. 
  3. 
  4. 
FLANK MASS
Are there bilateral flank masses?
 If the masses are bilateral, one
should consider polycystic kidney or early bilateral hydronephrosis.
Is there associated hypertension?
 If there is hypertension, one
should consider polycystic kidneys, hypernephroma,
pheochromocytoma, or adrenocortical carcinoma.
Is the mass painful?
 A painful flank mass should make one think of
perinephric abscess, hydronephrosis with partial obstruction, or
tuberculosis.
Is there blood in the urine?
 Hematuria should make one think of
hypernephroma, a Wilms’ tumor, tuberculosis, renal calculus, or
polycystic kidneys.
If the mass is unilateral, the most cost-effective approach would be to refer
the patient to an urologist at the outset. If the urologist is not available or if
the mass is bilateral, one might proceed with a workup. This should
include a CBC, chemistry panel, VDRL test, urinalysis or urine culture,
and a flat plate of the abdomen. Catheterization for residual urine may be
done to determine if there is bladder neck obstruction with associated
hydronephrosis. An IVP would be the next step although this is
increasingly being replaced by CT urography.
If these tests fail to make a definitive diagnosis, perhaps abdominal
ultrasound may help with the diagnosis of a renal cyst. A CT scan or MRI
of the abdomen would be the next logical step in confusing cases. Renal
angiography and cystoscopy with retrograde pyelography are not usually
261

1. 
  2. 
  3. 
FLANK PAIN
 The presence of fever along with chest
pain should make one think of a perinephric abscess or pyelonephritis.
Occasionally, however, hypernephroma can cause fever and flank
pain, as can bilateral hydronephrosis. If there is no fever, be sure to
ask about trauma.
Is there a flank mass?
 The presence of flank pain along with a flank
mass should make one think of a hypernephroma, hydronephrosis,
polycystic kidneys, or perinephric abscess.
 The presence of pain and hematuria should make
one think of renal calculus first, but the possibility of a renal
infarction, polycystic kidneys, and tuberculosis of the kidneys must be
considered also. Hematuria is also found in a hypernephroma.
Routine tests include a CBC, sedimentation rate, chemistry panel,
urinalysis, and urine culture. A non-contrast helical CT scan of the
abdomen is the next logical step. If these fail to make a definitive
diagnosis, one should consider ordering an abdominal ultrasound of the
abdomen. This would be the procedure of choice in pregnancy. MR
urography is also very useful when the results of other studies are
inconclusive. Alternatively, a trial of antibiotic may be indicated. If a renal
infarction is suspected, aortography and renal angiography may be
ordered. When the above tests are all negative, one should consider x-ray
of the lumbosacral spine and MRI of the thoracic and lumbar spine.
Consulting an urologist is prudent before ordering expensive diagnostic
tests.
263

1. 
  2. 
  3. 
  4. 
FLATULENCE
Is the flatulence associated with heartburn or regurgitation?
 The
presence of flatulence with heartburn or regurgitation should suggest
reflux esophagitis, gastric or duodenal ulcer, or chronic cholecystitis.
Is there a history of a gastrectomy?
 History of a gastrectomy may
indicate that there is gastric dilatation due to the fact that the stomach
fails to drain adequately.
Is there abdominal pain or distention?
 The presence of abdominal
pain or distention would indicate the possibility of partial intestinal
obstruction, steatorrhea, or diverticulitis.
Are there other signs of a nervous disorder?
 If there is a history of
emotional trauma or there is hyperkinesis, increased sweating,
insomnia, loss of appetite, or other signs of a nervous disorder,
aerophagia should be considered.
If the gas is eructated, stools for occult blood and an upper GI series and
esophagogram should be ordered. These may disclose a hiatal hernia and
esophagitis, a gastric or duodenal ulcer, and other upper intestinal
disorders. A gallbladder series may be done if the upper GI series is
unremarkable. Gastroscopy and esophagoscopy may be necessary, as well
as a gastric analysis.
If the excessive gas is passed rectally, stools for occult blood, stools for
ovum and parasite, and stool cultures should be done. A flat plate of the
abdomen may disclose evidence of intestinal obstruction. If these are
negative, a barium enema may be done and that may be followed with a
small bowel series. Colonoscopy may be indicated. Analysis of flatus for
volume and composition of intestinal gases may be helpful. A quantitative
stool-fat analysis should be done to determine if there is steatorrhea, and if
so, the workup would proceed (
page 482
). A lactose tolerance test can be
done in cases suspected of lactase deficiency. Hydrogen breath testing is
useful in detecting lactase deficiency and other carbohydrate intolerance
and bacterial overgrowth. A trial of PPIs may be all that is needed. When
extensive testing is negative, a psychiatrist may need to be consulted.
264

1. 
  2. 
  3. 
  4. 
FOOT AND TOE PAIN
Is there fever or localized erythema?
 Localized erythema would
suggest phlebitis, gout, osteomyelitis, cellulitis, ingrown toenail, and
paronychia. Achilles bursitis and tendonitis may be associated with
Reiter’s syndrome and ankylosing spondylitis. The presence of fever
would make one suspect osteomyelitis and cellulitis.
Is there associated deformity of the foot?
 Hallux valgus,
hammertoe, hallux rigidus, arthritis, and displaced fracture are the
main causes of a deformity of the foot.
Are the peripheral pulses palpable?
 Diminished arterial pulses
would make one think of arterial embolism, peripheral arteriosclerosis,
and diabetes.
 The presence of loss of
sensation to touch and pain should make one think of peripheral
neuropathy and tarsal tunnel syndrome. Numbness or loss of sensation
in the third and fourth toes is often associated with a Morton’s
neuroma.
Routine diagnostic tests include a CBC, sedimentation rate, chemistry
panel, VDRL test, and an x-ray of the foot. Consult a radiologist for what
views are most appropriate. If the peripheral pulses are diminished,
Doppler studies and angiography should be considered. If there is diffuse
swelling and erythema, venography may need to be done. If there are
neurologic findings, nerve conduction velocity studies and
electromyograms (EMGs) may be helpful. Consider bone scans, CT scans,
MRI, and arthroscopy if the above tests are negative. An MRI may be
needed to diagnose stress fractures. Stress fractures, Achilles tendonitis,
and tarsal tunnel syndrome are common in runners. Abnormal weight
distribution is diagnosed by quantitative scintigraphs. It is wise to refer the
patient to an orthopedic surgeon or podiatrist before ordering expensive
diagnostic tests.
266

1. 
FOOT DEFORMITIES
Are there signs of a neurologic disease?
 Many foot deformities are
associated with neurologic disease. For example, a pes cavus may be
associated with a peroneal muscular atrophy, poliomyelitis, and
Friedreich’s ataxia. Muscular dystrophy produces an equinovarus
deformity. Friedreich’s ataxia may produce a talipes equinovarus.
Amyotrophic lateral sclerosis and progressive muscular atrophy may
also cause foot deformities.
Rather than undertaking an extensive diagnostic workup, it is wise to refer
the patient to the appropriate specialist. If there are neurologic signs, the
patient should be referred to a neurologist. Otherwise, the patient should
be referred to an orthopedic surgeon or podiatrist.
268

1. 
  2. 
  3. 
  4. 
FOOT ULCERATION
Are there diminished or absent peripheral pulses?
 The finding of
poor peripheral pulses would suggest that the lesion is secondary to
ischemia from arteriosclerosis, Buerger’s disease, diabetic arteriolar
sclerosis, familial hyperlipidemia, and cryoproteinemia.
Are there abnormalities on neurologic examination?
of good peripheral pulses should make one look for a neurologic
explanation for the ulcer, and if there is diminished sensation to touch
and pain in the periphery, peripheral neuropathy is very likely. Ulcers
may also form in paraplegia of any cause, leprosy, and tabes dorsalis.
Is there a history of diabetes?
 A history of diabetes makes the
diagnosis of diabetic arteriolar sclerosis very likely. Remember, the
pulses may be normal in this condition.
Is there a positive smear or culture?
 The presence of good
peripheral pulses should prompt one to do a smear and culture of
material from the lesion, and if this is positive, then the diagnosis is
made. We would consider, in addition to the normal bacteria,
blastomycosis, sporotrichosis, maduromycosis, and syphilis.
Diminished pulses are a clear indication for Doppler ultrasound studies.
panel, VDRL test, and glucose tolerance test. An x-ray of the involved foot
should be done to rule out osteomyelitis. A bone scan or CT scan is even
more sensitive to osteomyelitis and other disorders of the bone that may be
causing the ulcer. A smear should be made of the ulcer material and a
culture done also, not just for the common pathogens, but for AFB and
fungi. A dark field preparation may be necessary. Skin testing for
blastomycosis and other fungi should be done. A nerve conduction
velocity study of the lower extremities will be helpful in differentiating
neurologic causes. Femoral angiography may be valuable in determining
the exact level of the lesion and whether it can be approached surgically.
269

FOREHEAD ENLARGEMENT
In adults, forehead enlargement is seen in Paget’s disease, fibrous
dysplasia, leontiasis ossea, and acromegaly. It may also be a normal
process as the frontal air sinuses develop over the years. In children,
forehead enlargement may be due to hydrocephalus, rickets, congenital
syphilis, and a large hematoma.
An x-ray of the skull; tests for calcium, phosphorus, and acid alkaline
phosphatase; and a VDRL test should be performed in all cases. When
other signs of acromegaly are present, serum growth hormone level should
be measured. Children may need a referral to a pediatrician.
271

1. 
  2. 
  1. 
  2. 
FREE THYROXINE (T
4
)
INCREASED
Is there an elevated sedimentation rate?
 An elevated sedimentation
rate coupled with an increased Free T
4
 suggests subacute thyroiditis.
Is the radioactive iodine (RAI) uptake increased?
 This would
indicate Grave’s disease or toxic nodular goiter. If the RAI uptake is
normal or decreased, look for iatrogenic hyperthyroidism.
DECREASED
What is the TSH level?
 If the TSH is elevated, the patient has
myxedema (hypothyroidism).
What are the results of a thyroid releasing factor stimulation test?
If there is no response to this test, the patient has pituitary
insufficiency. If there is a response, the patient probably has tertiary
hypothyroidism (a lesion in the hypothalamus) or T3 thyrotoxicosis.
To further evaluate an increased free thyroxine, it would be wise to order a
CT scan of the brain and thyroid as well as an endocrinology consult or a
trial of therapy. The same holds true for a low free thyroxine except, in
addition, one may need to order ultrasonography of the thyroid, a needle
biopsy, or exploratory surgery.
272

1. 
  2. 
  3. 
FREQUENCY OF URINATION
Is the 24-hour urine volume increased?
 If the 24-hour urine volume
is increased, then one has identified polyuria. The differential
diagnosis of this condition is found on 
page 400
.
Is there dysuria?
 
If there is dysuria, one should consider cystitis,
urethritis, prostatitis, bladder calculi, and tuberculosis of the bladder.
If there is no dysuria, then a bladder neck obstruction from conditions
such as prostatic hypertrophy or urethral stricture might be considered.
One should also consider a spastic neurogenic bladder.
 If there is fever along with frequency of urination, this
could be due to a systemic condition, but it is more important to look
for pyelonephritis.
The first thing to do is a urinalysis and examine the urinary sediment. This
will help determine if there is a UTI and if there is diabetes or one of the
other causes of polyuria. A sterile sample of the urine should be sent to the
lab for culture regardless of whether the urinalysis is normal.
If these studies are unremarkable, a 24-hour urine volume is
determined. If the urine volume is substantially increased, the workup may
proceed for polyuria (see 
page 400
). If the 24-hour urine volume is normal,
a pelvic and rectal examination must be done for a mass that might be
pressing on the bladder. Even if the pelvic and rectal examination is
negative, pelvic ultrasound may disclose a pelvic mass.
The next step would be to catheterize for residual urine or order
ultrasonography of the urinary bladder. If the residual urine is large,
bladder neck obstruction is probably the problem, and prostatic
hypertrophy, median bar hypertrophy, and urethral stricture must be
Further studies include an IVP, CT urography, cystogram, cystoscopy,
and retrograde pyelography, but these should be done in consultation with
an urologist. If a spastic neurogenic bladder is suspected, order cystometric
tests and a neurology consult.
274

1. 
  2. 
  3. 
  4. 
FRIGIDITY
Are there abnormalities on the vaginal examination?
 Imperforated
hymen, a mass in the cul-de-sac, a retroverted uterus, pregnancy, PID,
and cystitis are just a few of the conditions that might be found.
Are there abnormalities on the rectal examination?
 The rectal
examination may disclose anal fissures, hemorrhoids, or perirectal
abscess.
Are there abnormalities of the secondary sexual characteristics?
Turner’s syndrome and testicular feminization are two of the
conditions that may be associated with these abnormalities.
Is there a history of emotional trauma?
 Childhood sexual
molestations and marital difficulties are among the conditions that
may be found on a careful history.
First, one should do a good pelvic and rectal examination. If abnormalities
are found on these examinations, referral to a gynecologist or a
proctologist can be made. If the pelvic and rectal examinations are normal,
the patient should probably be referred to a psychiatrist or psychologist for
treatment. If there are abnormalities of the secondary sexual
characteristics, the clinician may undertake studies of these disorders, but
referral to an endocrinologist is probably more cost-effective.
276

1. 
  2. 
  3. 
  4. 
GAIT DISTURBANCES
 An abnormal
neurologic examination should make one think of multiple sclerosis,
peripheral neuropathy, muscular dystrophy, Parkinson’s disease,
Huntington’s chorea, and a host of degenerative neurologic conditions.
Is there a painful limp?
 The findings of a painful limp should make
one suspect hip, knee, or an ankle joint pathology. In children,
consider child abuse. A herniated lumbar disk may also cause a
characteristic antalgic gait.
Is the gait characteristic of a particular type?
 Characteristic gaits
include the short-stepped shuffling gait of Parkinson’s disease, the
ataxic gait of multiple sclerosis and cerebellar disorders, the reeling,
clownish gait of Huntington’s chorea, the pelvic tilt of muscular
dystrophy, and the steppage gait of peripheral neuropathy.
Could the gait disturbance be because of malingering or hysteria?
The gait of conversion hysteria is quite remarkable. The patient has a
normal neurologic examination and has no difficulty maintaining
balance while sitting down, but there is total inability to walk or stand
without reeling about.
Routine orders would include a CBC, sedimentation rate, chemistry panel,
VDRL test, and urinalysis. If there is a painful limp, x-ray of the hip, knee,
or an ankle on the affected side should be performed. An x-ray of the
lumbar spine will not usually be of great assistance, however. If plain x-
ray is negative, a CT scan or an MRI of the lumbar spine, hip, knee, or
ankle may be of assistance in the diagnosis. A bone scan may pick up
obscure fractures and other pathology.
If there are abnormalities on the neurologic examination, an MRI or a
CT scan of the appropriate level of suspected pathology will be done. A
spastic gait with abnormal cranial nerve findings would suggest a cerebral
tumor or other brain disease, and a CT scan or an MRI of the brain should
be done. Keep in mind that an MRI is almost double the cost of a CT scan,
and the diagnostic yield is not that much greater in many cases.
A spastic gait without cranial nerve signs or papilledema would
suggest a spinal cord disorder, and an MRI or a CT scan of the appropriate
278

level of the spinal cord should be done. A CT scan of the cervical spine,
however, is not very useful and an MRI is preferred.
If multiple sclerosis is suspected, a spinal tap for myelin basic protein
or 
gamma-globulin
 levels should be done. A VEP study, a BSEP study, or
a SSEP study will also be useful in diagnosing multiple sclerosis.
If there is an ataxic gait, cerebellar disorder should be suspected, and a
CT scan of the brain may be done. However, an ataxic gait may also
suggest multiple sclerosis, pernicious anemia, and tabes dorsalis. If the
VDRL test is negative, a FTA–ABS test should be done. Blood levels for
vitamin B
12
 and folic acid will help diagnose pernicious anemia. A
Schilling test, however, is sometimes necessary to facilitate this diagnosis.
If muscular dystrophy is suspected, electromyographic examination and
muscle biopsy will help confirm the diagnosis. If the patient has a steppage
gait, the workup of peripheral neuropathy should be done, as noted on
page 378
.
279

1. 
  2. 
  3. 
  4. 
  5. 
GANGRENE
Does it involve the upper or lower extremity?
 Involvement of the
upper extremities should suggest Raynaud’s disease, scleroderma, and
other collagen diseases. The Allen test will be helpful in diagnosing
Raynaud’s disease.
Are there good peripheral pulses?
 The complete absence of a
peripheral pulse, particularly if it is sudden onset, should suggest an
arterial embolism. If it is gradual onset, suspect arteriosclerosis or
diabetic ulcer.
 If there are other signs of
systemic disease, collagen disease, macroglobulinemia, and
cryoglobulinemia should be suspected.
Is the gangrene sudden in onset?
 A sudden onset of the gangrene
should make one suspect clostridia infections or arterial embolism.
Is there a positive culture?
 The culture will be positive in clostridia
infections, anthrax, and cancrum oris.
Routine orders include a CBC, sedimentation rate, chemistry panel, VDRL
test, serum protein electrophoresis, ANA titer, and glucose tolerance test.
The gangrenous area should be cultured. Plain x-ray of the area sometimes
is helpful. If there are diminished pulses, especially if the onset is acute,
angiography will be useful. A muscle biopsy or skin biopsy will be useful
in diagnosing collagen diseases. The Sia water test and serum
immunoelectrophoresis will be useful in diagnosing macroglobulinemia
and cryoglobulinemia.
280

1. 
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  3. 
GIGANTISM
 Patients with
Klinefelter’s syndrome, supermale, superfemale, sexual precocity, and
virilism have abnormal secondary sex characteristics and a tall stature.
Is there arachnodactyly?
 Arachnodactyly is associated with
Marfan’s syndrome and homocystinuria.
 Patients with a family history of tall stature
often have constitutional tall stature and not pituitary gigantism.
X-ray and CT scan of the skull will help identify a pituitary eosinophilic
adenoma, but serum growth hormone will also be elevated early, and FSH
and LH may be depressed later. An MRI will be necessary to pick up
microadenomas. Serum FSH and LH will be elevated in Klinefelter’s
syndrome. A chromosome study should be done to identify Klinefelter’s
syndrome, supermale, and superfemale. A serum testosterone,
dihydrotestosterone, and dehydroepiandrosterone sulfate will be helpful in
diagnosing sexual precocity and virilism caused by tumors and hyperplasia
of the adrenal gland. Echocardiography and urinary hydroxyproline will
help identify Marfan’s syndrome, whereas a urine for homocysteine will
help diagnose homocystinuria. A thyroid profile should be done to rule out
thyrotoxicosis.
282

1. 
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GIRDLE PAIN
Is there an associated rash?
 Presence of a rash, whether it is macular
or vesicular, especially if it is in a dermatomal distribution, would
suggest herpes zoster. Occasionally, herpes zoster occurs without a
rash and should still be considered in the differential diagnosis.
Are there pyramidal tract or other long tract signs?
 The findings
of long tract signs would indicate compression, degeneration, or
inflammation of the spinal cord, and conditions such as multiple
sclerosis, acute transverse myelitis, spinal cord tumor, herniated disk,
and pernicious anemia should be considered. If there are no long tract
signs and no rash, one should consider early spinal cord tumor or
herniated disk, intercostal neuralgia, fractured ribs, and sometimes a
compression fracture of the vertebra.
Patients with a rash, particularly if it is vesicular and in a dermatomal
distribution, may be treated for herpes zoster before doing an extensive
diagnostic workup. However, one should remember that herpes zoster may
be associated with an underlying neoplasm, particularly Hodgkin’s
disease.
If a patient does not have a rash, routine laboratory tests include a
CBC, chemistry panel, sedimentation rate, VDRL test, serum B
12
, and
folic acid. In addition, 
x-ray
 of the chest, ribs, and thoracic spine should be
done. If these are normal and the diagnosis remains in doubt, one should
consult a neurologist. If none is available, an MRI of the thoracic spine
may be ordered. A spinal tap may be done to help rule out multiple
sclerosis and tabes dorsalis. SSEP studies can be done to diagnose multiple
sclerosis. A thoracic myelogram is occasionally necessary in confusing
cases.
284

1. 
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GLYCOSURIA
Was the test used specific for glucose?
 Glucose oxidase tests
(Clinistix, etc.) are specific for glucose, whereas other tests
(Benedict’s, etc.) are not. Thus, the latter will give false positives for
lactose, fructose, galactose, and salicylates.
What is the blood sugar?
 If the blood sugar is elevated or a glucose
tolerance test is positive, one should suspect diabetes mellitus. If these
tests are normal, one should suspect renal glycosuria, pregnancy, or
renal tubular acidosis.
The investigation of glycosuria should include a glucose tolerance test,
HbA1c, chemistry panel, and electrolyte panel. If there are clinical features
of an endocrine disorder, the various tests for these disorders should be
ordered.
286

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
GYNECOMASTIA
 Digitalis,
phenothiazine, amphetamine, marijuana, and many other drugs may
cause gynecomastia.
Is there a testicular mass?
 Leydig’s cell and Sertoli’s cell tumors of
the testicle may cause gynecomastia.
 Klinefelter’s
syndrome, male pseudohermaphroditism, and testicular feminization
syndrome may cause gynecomastia.
Is there a bronze skin?
 If there is a bronze skin, one should consider
hemochromatosis, as this may be associated with gynecomastia.
Are there other endocrine abnormalities?
 Cushing’s syndrome,
Addison’s disease, and hyperthyroidism may cause gynecomastia.
 Myotonic
dystrophy, paraplegias of various types, and Friedreich’s ataxia are
among the many neurologic disorders that may be associated with
gynecomastia.
A urine drug screen, serum prolactin, and thyroid profile should be done at
the outset. Liver function studies, liver biopsy, and serum iron and iron-
binding capacity will help rule out hemochromatosis and cirrhosis of the
liver. A serum FSH, LH, hCG, testosterone, and estradiol will help
diagnose testicular tumors, Klinefelter’s syndrome, and testicular
feminization syndrome. Further, evidence of Klinefelter’s syndrome is
obtained by a buccal smear (Barr bodies). Normal gonadotropin and sex
hormone levels make serious pathology unlikely. A serum cortisol, cortisol
suppression test, and rapid adrenocorticotropic hormone (ACTH) test will
help diagnose Cushing’s syndrome and Addison’s disease. There is a
specific beta-hCG assay that can be done to rule out an hCG-secreting
tumor such as carcinoma of the lung.
287

1. 
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  3. 
  4. 
HALITOSIS
Is there a history of ingestion or use of a foul substance?
 Such a
history may suggest that the cause is onions, garlic, alcohol, tobacco,
paraldehyde, mercury, or other substances. A garlic odor to the breath
is common to many poisonings (arsenic, organophosphates, etc.).
Are there abnormalities of examination of the mouth, nose, and
throat?
 Abnormalities that may be found on examination of the
mouth, nose, and throat include gingivitis, carious teeth, pyorrhea,
stomatitis, sinusitis, pharyngitis, and tonsillitis.
Is there a chronic productive cough?
 The presence of a chronic
productive cough should suggest bronchiectasis, lung abscess,
gangrene of the lungs, tuberculosis, and other lung infections.
Is there esophageal regurgitation?
 The history of esophageal
regurgitation should suggest reflux esophagitis, peptic ulcer, partial
intestinal obstruction, and esophageal diverticula. If there are none of
these findings, one should look for uremia or cirrhosis.
Routine tests include a CBC and sedimentation rate to rule out chronic
inflammation; a chemistry panel to rule out uremia and cirrhosis; and
sputum, nose, and throat cultures to rule out chronic infections of the
sinuses, nose, throat, and lungs. Cultures of any suspicious area of
inflammation in the mouth, nose, and throat should be done. X-rays of the
teeth, sinuses, and chest should also be done. An upper GI series and
esophagogram will help diagnose reflux esophagitis, peptic ulcer, partial
intestinal obstruction, and esophageal diverticula.
A 24-hour sputum collection may help differentiate bronchiectasis and
lung abscesses. A tuberculin test and sputum for AFB smear, culture, and
possible guinea pig inoculation may identify tuberculosis.
289

1. 
  2. 
  3. 
  4. 
  5. 
HALLUCINATIONS
 Hallucinations are
common during alcohol withdrawal but may also be noted in cocaine
addiction, marijuana addiction, LSD intoxication, and PCP
intoxication.
Are the hallucinations primarily visual in nature?
 This would
suggest an organic cause such as organic brain syndrome, epilepsy,
brain tumor, etc.
Are the hallucinations episodic?
 If the hallucinations occur in
episodes with normal behavior in between, one should consider
epilepsy or narcolepsy.
Are the hallucinations associated with early stages of falling asleep
or awakening?
 These types of hallucinations are called 
hypnagogic
and are common in narcolepsy but may also be seen in normal people.
Are the hallucinations primarily auditory in nature?
 This is the
type of hallucination most commonly associated with schizophrenia.
A blood alcohol level and urine drug screen are essential at the outset. A
therapeutic trial of IV thiamine should be tried if Wernicke’s
encephalopathy or Korsakoff’s psychosis is suspected. Most physicians
will want to refer the patient to a psychiatrist if these studies are negative.
However, the interested physician may proceed further with a wake-and-
sleep EEG to identify psychomotor epilepsy, or a CT scan and MRI to
identify brain tumors and other causes of organic brain syndrome.
Remember, the MRI costs twice as much as a CT scan. A spinal tap will
be helpful in diagnosing central nervous system lues. A sleep study will
help diagnose narcolepsy. Psychometric testing will help identify
schizophrenia and other psychiatric disorders.
291

HEAD MASS OR SWELLING
Smaller localized, freely movable masses are the sebaceous cysts,
hematomas, lipomas, and lymph nodes. Masses that seem to be attached to
the skull are osteomas, dermoid cysts, and sarcomas. Brain tumor tissue
may occasionally protrude out beneath the scalp through a craniotomy
defect. Mastoiditis may also spread to the subcutaneous tissues. In the
newborn, there may be edema of the scalp (called 
caput succedaneum
)
following a vertex delivery due to molding or a large hematoma over one
or both parietal bones (called 
cephalhematoma
) due to the trauma of
delivery. There may be meningoceles or encephalomeningoceles due to
imperfect closure of the skull (cranium bifidum). Vascular abnormalities
of the skin may be found and include angiomas, arteriovenous fistulas, and
telangiectasis.
A skull x-ray will help distinguish the bone lesions, whereas aspiration or
biopsy will help distinguish the others. Referral to the appropriate
specialist would be the most cost-effective approach.
293

1. 
  2. 
  3. 
HEADACHE
A 29-year-old obese Hispanic female, gravid 2, para 2, complains of
generalized headache for the past 3 months. It is usually worse in the
morning and occasionally is associated with nausea but no vomiting. She
also complains of blurred vision for the past 6 weeks. Following the
algorithm, you ask about a history of drugs, caffeine, or alcohol ingestion
with negative results. She denies a history of trauma. There is no nuchal
rigidity or focal neurologic signs, but funduscopic examination reveals
papilledema and a visual field examination reveals an inferior nasal
quadrantanopia and enlarged blind spot. You suspect pseudotumor cerebri
and an MRI confirms your suspicion.
Is there a history of drug, caffeine, or alcohol ingestion?
 The
hangover headache is well known and should not present a problem in
diagnosis. Caffeine withdrawal headaches are also common because of
the large amount of caffeine consumed in coffee, various soft drinks,
and chocolate. Drugs that may induce headache include the
nonsteroidal anti-inflammatory drugs such as indomethacin (Indocin)
and the antihypertensives such as clonidine, aspirin, quinidine, and
bromides.
 Trauma may cause concussion and
postconcussion headaches, intracranial neoplasms such as subdural
hematoma, and cervical sprain, all of which can induce headaches.
Is the headache acute or chronic?
 An acute onset of a headache can
be a serious problem. It should be taken seriously because it may mean
a subarachnoid hemorrhage or meningitis. This can be easily
confirmed by checking for nuchal rigidity. Whenever there is an acute
onset of a headache, this must be done. Chronic headaches, on the
other hand, are most likely due either to migraine if they occur in
exacerbations or remissions, or to tension headaches if they are fairly
constant, mild, and chronic. The headache of a brain tumor is rarely
severe and is rarely the presenting symptom of a brain tumor.
Headaches that occur in clusters almost daily for 6 to 8 weeks with
interruptions of several months must make one consider cluster
headaches. Unilateral headaches in the elderly with acute onset should
294

4. 
  5. 
  6. 
  7. 
  8. 
  9. 
make one think of temporal arteritis.
 The presence of nuchal rigidity should make
one think of a subarachnoid hemorrhage or meningitis, but it may also
be due to cerebral hemorrhage or cerebral abscess.
 If the headache is associated with fever, the possibility
of acute sinusitis should be considered, and the sinuses should be
transilluminated. Other sources of the fever should be looked for, and
meningitis or encephalitis should be considered.
Is there papilledema or are there focal neurologic signs?
 With
acute headache and focal neurologic signs and/or papilledema, one
should consider cerebral abscess or cerebral hemorrhage. With a
chronic headache and papilledema or focal neurologic signs, one
should consider a space-occupying lesion such as a primary brain
tumor or metastatic neoplasm.
Do the sinuses transilluminate well?
 A sinus transilluminator should
be in the armamentarium of every physician who expects to diagnose
headache. If the sinuses fail to transilluminate, one should consider
acute sinusitis as the diagnosis.
Is there tenderness of the superficial temporal artery?
 The
presence of a tender superficial temporal artery should make one think
of temporal arteritis, particularly in the elderly, but it may also be
related to a long-standing migraine attack.
Is the headache relieved by superficial temporal artery
compression?
 Relief of the headache on superficial temporal artery
compression should suggest classical or common migraine. If one can
relieve the headache by compression of the occipital artery, occipital
migraine should be considered. When there is no relief on
compression of the superficial temporal artery, one should consider
tension headaches, occipital neuralgia, cervical spondylosis, and
cluster headaches as the cause. An aura before or photophobia during
a headache is almost diagnostic of migraine.
Routine diagnostic tests include a CBC to rule out severe anemia, a
sedimentation rate to rule out temporal arteritis, a chemistry panel to rule
out liver and kidney disease, a VDRL test to rule out central nervous
system syphilis, an x-ray of the sinuses to rule out sinusitis, and an x-ray of
the cervical spine to exclude cervical spondylosis. A chest x-ray should
also be done to rule out the possibility of metastatic neoplasm. A
tonometry study may be done if glaucoma is suspected. 
X-rays
 or SPECT
295

scans of the temporomandibular joints and referral to an oral surgeon
should be done if temporomandibular joint syndrome is suspected. Visual
acuity should always be evaluated because chronic headache is often due
to a refractive error or astigmatism.
If there are focal neurologic signs, referral should be made to a
neurologist or neurosurgeon as soon as possible. If one is not readily
available, a CT scan or MRI may be done, the CT scan being the preferred
procedure if cost is a consideration.
If there is nuchal rigidity, a CT scan should be done to rule out a 
space-
occupying
 lesion before proceeding with a spinal tap. If the CT scan is
negative, a spinal tap can be done, and this will ascertain whether there is
intracranial bleeding or meningitis. It is usually best to refer the patient to
a neurologist or neurosurgeon if there is nuchal rigidity.
If the headaches are chronic and episodic, and there are no focal
neurologic signs, papilledema, or nuchal rigidity, an imaging study can be
postponed for a while until the response to treatment is evaluated.
However, if the response to treatment is poor, one should not hesitate to
order a CT scan or MRI.
Difficult cases of headache should also be studied with 24-hour blood
pressure monitoring, a 24-hour urine for catecholamines, and lumbar
puncture to diagnose central nervous system lues. Histamine phosphate 0.5
mL subcutaneously may help diagnose cluster headaches. If the patient
presents with an acute headache, it is wise to assess the response to
sumatriptan orally or by nasal spray. Relief will usually be achieved in
patients with migraine or histamine headaches. Response to beta-blockers
may help diagnose migraine. Cerebral angiography or MRA may be
necessary to diagnose aneurysms and arteriovenous malformations.
Patients with chronic headache, unresponsive to therapy, should be
referred to a psychiatrist.
296

Table 11: Headache
297

1. 
  2. 
  3. 
  4. 
  5. 
HEARTBURN
A 52-year-old white male laboratory technician is brought to the
emergency room with acute chest pain and pain on swallowing. He gives a
long history of heartburn relieved by antacids. Following the algorithm,
you administer nitroglycerin without relief. The heartburn is associated
with regurgitation, so you administer a GI “cocktail” which includes
lidocaine viscous, and his pain is relieved. You suspect reflux esophagitis
and your diagnosis is confirmed by esophageal pH monitoring and
esophagoscopy.
Is there frequent regurgitation?
 If there is frequent regurgitation, the
most likely diagnosis is reflux esophagitis and hiatal hernia. Gastritis
and a previous gastrectomy will also cause frequent regurgitation.
Is there recurrent nausea or vomiting?
 If there is recurrent nausea
or vomiting, the most likely diagnosis is cholecystitis and
cholelithiasis. Chronic pancreatitis can cause the same symptoms,
however.
Is the heartburn precipitated by exercise and/or relieved by
nitroglycerin?
 These findings suggest coronary insufficiency.
Is there associated hematemesis or recurrent black stool?
 The
presence of hematemesis or recurrent black stools should suggest a
peptic ulcer.
Is there relief with lidocaine hydrochloride (Xylocaine viscous
solution)?
 The relief of the pain on viscous lidocaine suggests reflux
esophagitis, hiatal hernia, and previous gastrectomy with bile
esophagitis. Gastritis is not usually relieved by viscous Xylocaine.
The workup begins with an upper GI series and esophagram and stools for
occult blood. If these studies are negative, it may be prudent to give the
patient a trial of proton pump inhibitors. If there is recurrent vomiting and
right upper quadrant pain, a gallbladder ultrasound or cholecystogram
should be done. If these are negative, it is best to refer the patient to a
gastroenterologist for esophagoscopy and gastroscopy. The
298

gastroenterologist may do a Bernstein test, which will reproduce
symptoms by an infusion of dilute hydrochloric acid into the distal
esophagus, or perform esophageal manometry or pH monitoring of the
distal esophagus. An exercise tolerance test and coronary angiography also
have their place in the diagnostic armamentarium. A breath test or a stool
for 
 antigen should be ordered in persistent cases.
299

1. 
  2. 
  3. 
  4. 
HEEL PAIN
Are there abnormalities on inspection of the heel?
 Inspection of the
heel may disclose an ulcer, foreign body, cellulitis, plantar wart, and
other disorders.
Is the patient a child?
 Children often have Sever’s disease
(osteochondritis of the heel).
Is there tenderness or deformity of the Achilles tendon?
Tenderness or deformity of the Achilles tendon should suggest
Achilles tendinitis, rupture, or bursitis.
Are there abnormalities on x-ray examination?
 An x-ray may
disclose a calcaneal fracture, osteomyelitis, a tumor, or calcaneal spur.
If the x-ray is negative, plantar fasciitis is the most likely diagnosis,
but one should also consider gout.
In addition to a plain x-ray of the foot, a CBC, sedimentation rate,
chemistry panel, and arthritis panel should be done. A bone scan may
disclose an occult fracture. Response to a trigger point injection should be
evaluated. If the diagnosis is still in doubt, referral to an orthopedic
surgeon or podiatrist should be made before ordering expensive diagnostic
tests such as a CT scan or MRI.
300

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
HEMATEMESIS
A 44-year-old white female is brought in the middle of the night to the
emergency room with a history of vomiting bright red blood. Following
the algorithm, you look for a history of fever and chills, and find none. Her
temperature is 97.8°F. There is no history of drug or alcohol ingestion, but
she ate out the evening prior to admission and the food did not agree with
her. There is no abdominal pain. On further questioning, you find out that
there was no blood in the initial episodes of vomiting. You suspect a
Mallory–Weiss syndrome, and esophagoscopy confirms your suspicion.
 The presence of fever should suggest scarlet fever,
measles, malaria, leptospirosis, yellow fever, and other acute and
chronic infectious diseases.
Is there a history of ingestion of poison, drugs, or alcohol?
 Poison,
many drugs, and alcohol may cause acute gastritis, gastric ulcer, and
corrosive esophagitis.
Is there associated abdominal pain?
 Abdominal pain associated with
the hematemesis suggests the possibility of gastric or duodenal ulcer, a
hiatal hernia, and esophagitis or carcinoma of the stomach. Of course,
any of these conditions may occur without abdominal pain.
Was the hematemesis preceded by blood-free vomitus?
 If in the
initial stages of vomiting the vomitus was blood free, one should
consider Mallory–Weiss syndrome, which is a tear of the distal
esophagus due to severe vomiting.
Is there hepatomegaly or splenomegaly?
 Hepatomegaly would
suggest cirrhosis of the liver, whereas a portal vein thrombosis may
occur without hepatomegaly but almost certainly is associated with
splenomegaly. Splenomegaly should suggest Banti’s syndrome with
depression of platelets, leukocytes, and anemia. Splenomegaly also
suggests other blood dyscrasias.
Is there a positive tourniquet test or Ivy skin bleeding time?
 These
tests may indicate thrombocytopenia and other blood dyscrasias. If
these tests are negative and there is no hepatomegaly, splenomegaly,
or abdominal pain, one should consider hereditary hemorrhagic
telangiectasia, an aortic aneurysm, and pseudoxanthoma elasticum.
302

Hematemesis, no matter how small, is a clear indication for immediate
consultation with a gastroenterologist and esophagoscopy, gastroscopy,
and duodenoscopy. To delay this while ordering an upper GI series and
other diagnostic tests may place the patient in serious jeopardy. The
clinician would be prudent to order a CBC and coagulation profile, type,
and cross-match of several units of blood while waiting for the
gastroenterologist to see the patient. If endoscopy fails to locate the site of
bleeding, order a CT scan of the abdomen or better yet a CT angiography
of the abdomen. Catheter angiography is often employed. A technetium-
99m bleeding scan may be ordered to detect suspected bleeding but will
not often locate the exact site of bleeding. Video capsule endoscopy can
visualize the entire small intestine for bleeding sites. Liver function tests
should be ordered to rule out cirrhosis in all cases.
303

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
HEMATURIA
A 28-year-old white male is found to have blood in his urine on a routine
physical examination. Your investigation follows the algorithm. He denies
a history of abdominal pain or dysuria, but you order a urine culture
anyway. There is no history of fever or chills.
Your examination reveals bilateral flank masses and hypertension. You
suspect polycystic kidney disease and you would be correct.
Is there abdominal pain?
 The presence of abdominal pain with
hematuria should first suggest renal calculus, but other causes, such as
renal embolism, renal contusion, or laceration, must be considered.
Is there dysuria or frequency of micturition associated with the
hematuria?
 The presence of dysuria and frequency with the
hematuria should suggest a bladder stone, prostatic disease, or a UTI.
 The presence of fever with the hematuria would
suggest pyelonephritis.
 The presence of bilateral flank masses with
hematuria should suggest polycystic kidneys and hydronephrosis,
whereas a unilateral flank mass would suggest a hypernephroma or
unilateral hydronephrosis. A solitary cyst or renal vein thrombosis
may also present with a flank mass and hematuria.
 The presence of hypertension with the
hematuria suggests glomerulonephritis, polycystic kidneys, and
collagen diseases.
Are there other systemic signs and symptoms?
 If there are other
systemic signs and symptoms, one should be looking for collagen
disease, coagulation disorders, leukemia, and sickle cell anemia. When
there is no hypertension or other signs and symptoms of systemic
diseases, one should be looking for a benign or malignant tumor of the
bladder, tuberculosis, or parasitic infection.
Hematuria associated with flank pain should be evaluated as already
discussed on 
page 205
. The workup of hematuria without flank pain begins
305

with a urinalysis and microscopic examination of the urinary sediment.
The physician can easily do this in his office. If there is proteinuria,
granular cast, and red cell cast, glomerulonephritis or collagen disease
should be suspected. A culture and sensitivity and colony count should be
done if a UTI is suspected. A three-glass test may be done. If there is
blood in the initial specimen, the cause is most likely in the urethra or male
genitalia. If it is in the final specimen, the cause is most likely a bladder
lesion. Bladder cancer can be diagnosed by urine cytology (FISH test).
Phase-contrast microscopy may also be helpful in identifying hematuria
from a glomerular lesion. If this is negative, an anaerobic culture should be
done and then an AFB smear and culture and guinea pig inoculation to rule
out tuberculosis. Instead of doing an IVP, CT urography or a spiral CT
scan of the abdomen is done at this point because it yields much more
information. A CBC, sedimentation rate, chemistry panel, coagulation
profile, and ANA test will help rule out blood dyscrasias, collagen
diseases, and other systemic diseases. Ultrasonography may help diagnose
a renal cyst. If the microscopic examination of the urinary sediment is
negative be sure to suspect hemoglobinuria.
If the above are not revealing, referral to an urologist is indicated.
He/she will probably do a cystoscopy and retrograde pyelography. He/she
may also want to order a renal biopsy. Renal MRA, angiography, and
aortography may be necessary to evaluate renovascular hypertension and
renal embolism.
306

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
HEMIANOPSIA
 Intermittent hemianopsia, whether it is bitemporal
or homonymous in type, would suggest migraine, carotid artery
insufficiency, or vertebral basilar artery insufficiency.
Is the hemianopsia of sudden or gradual onset?
 Sudden onset of
hemianopsia would suggest a vascular disorder such as cerebral
thrombosis, embolism, or hemorrhage, but it may also suggest
multiple sclerosis or a ruptured aneurysm. Gradual onset of
hemianopsia would suggest a space-occupying lesion.
What type of hemianopsia is it?
 A bitemporal hemianopsia often
suggests a pituitary tumor, especially if there are endocrine changes,
but it may also be due to an aneurysm compressing the optic chiasm.
Homonymous hemianopsia suggests involvement of the optic tract or
occipital cortex. This may be by a space-occupying lesion, an
aneurysm, arterial thrombosis, an embolism, or a hemorrhage.
Are there long tract signs?
 Neurologic signs of pyramidal tract
involvement or posterior column involvement would suggest anterior
or middle cerebral artery occlusion, epidural hematoma, or multiple
sclerosis if it is acute, and compression of the cortex by a subdural
hematoma or brain tumor if it is chronic.
 The presence of weight loss, hair loss,
or diabetes insipidus would suggest a chromophobe adenoma of the
pituitary. On the other hand, a protruding jaw, enlargement of the
hands and fingers, and hypertrophy of the other tissues suggest
acromegaly.
Is there macular sparing?
 The presence of macular sparing suggests
that the lesion is in the optic cortex. This is most often a space-
Referral to an ophthalmologist for a thorough visual field examination is
suggested at the outset. A neurology consultation also needs to be
obtained. The neurologist will probably order a CT scan of the brain to
rule out a space-occupying lesion unless multiple sclerosis is suspected.
If multiple sclerosis is suspected, MRI would be the study of choice,
even though it is more expensive. In addition, VEP studies and spinal fluid
308

analysis may be ordered to rule out multiple sclerosis.
A carotid duplex scan will help diagnose carotid vascular
insufficiency, but four-vessel cerebral angiography or an MRA will most
likely be done so that both carotid and vertebral basilar artery diseases can
be evaluated. If there are endocrine changes, an endocrinologist should be
If a cerebral embolism is suspected, a source for the embolism should
be sought. A cardiologist can best determine what tests to order to search
for an embolic source.
309

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
HEMIPARESIS/HEMIPLEGIA
 Intermittent hemiparesis or hemiplegia would
suggest migraine or transient ischemic attacks from basilar artery or
carotid artery disease.
Is it sudden or gradual in onset?
 Sudden onset of hemiparesis would
suggest a cerebral thrombosis, hemorrhage, or embolism. However,
contusion or concussion of the spinal cord can occasionally produce a
sudden onset of hemiparesis or hemiplegia. If there is a history of
trauma, a subdural or epidural hematoma must be suspected. Gradual
onset of hemiparesis or hemiplegia would suggest a space-occupying
lesion.
Is there facial paralysis or other cranial nerve signs?
 If there is a
central facial palsy or other cranial nerve signs, one would look for a
lesion above the foramen magnum (i.e., in the brain). If there are no
cranial nerve signs, a spinal cord lesion should be suspected.
 The presence of fever should suggest a cerebral
abscess, venous sinus thrombosis, or encephalitis.
 The history of trauma with hemiparesis
or hemiplegia would suggest a subdural or epidural hematoma or a
hemorrhage in the brain itself.
Is there a history of hypertension?
 The history of hypertension
along with hemiparesis or hemiplegia suggests a cerebral hemorrhage.
However, a cerebral thrombosis or cerebral aneurysm may also occur
with a history of hypertension.
Is there auricular fibrillation or another embolic source?
 The
presence of auricular fibrillation, cardiac murmur, or other signs of an
embolic source would suggest a cerebral embolism.
A neurologist should be consulted at the outset because he/she can best
determine what type of imaging study should be done and whether
thrombolytic therapy is indicated. A spinal tap is no longer done without
first doing an imaging study. It may pick up a subarachnoid hemorrhage
when the CT scan is negative. CT angiography can be ordered to
definitively diagnose an ischemic stroke. Carotid scans can be done to rule
out carotid artery insufficiency. Four-vessel cerebral angiography may be
310

indicated, especially in transient ischemic attacks. Magnetic resonance
angiography has become an acceptable noninvasive technique for
evaluating the cerebral blood flow, especially in vertebral–basilar arteries.
EKG, echocardiography, and blood cultures will help identify an embolic
source, but a cardiologist should be consulted to investigate this further.
SSEP, BSEP, and VEP studies along with a spinal tap will help diagnose
multiple sclerosis.
311

1. 
  2. 
  3. 
  4. 
HEMOPTYSIS
A 32-year-old black female complains of a recurrent cough which has
recently been productive of blood-tinged sputum. She did not complain of
chest pain. She denies fever and chills and your nurse recorded a
temperature of 97.9°F making pneumonia, lung abscess, or tuberculosis
unlikely. She is, however, experiencing exertional dyspnea.
Your examination reveals bilateral crepitant rales at both bases and a
presystolic murmur with a sharp first heart sound. You suspect mitral
stenosis and congestive heart failure. Further studies confirm your
suspicion.
 If there is chest pain along with the hemoptysis,
one should suspect a pulmonary embolism.
Is there fever and/or purulent sputum?
 The presence of fever and
purulent sputum suggests pneumonia, lung abscess, tuberculosis, and
bronchiectasis. However, bronchiectasis does not usually occur with
fever.
Is there dyspnea, cardiomegaly, or a heart murmur?
 These
findings suggest congestive heart failure or mitral stenosis.
Is there copious sputum?
 The presence of copious sputum should
suggest bronchiectasis or lung abscess. If there is fever along with it,
lung abscess is more likely. Copious foamy sputum suggests
panel, coagulation profile, sputum smear, culture and sensitivity, a chest x-
ray, and an EKG.
If a pulmonary embolism or infarction is suspected, arterial blood
gases, 
D-dimer
 and a ventilation–perfusion scan or helical CT scan of the
chest should be ordered. In some cases, a pulmonary angiogram may be
necessary. Objective testing for deep vein thrombosis with
ultrasonography or impedance plethysmography may help confirm
suspicion of a pulmonary embolism.
312

If tuberculosis is suspected, one should order a sputum or gastric
washings for AFB smear, culture, and guinea pig inoculation. A tuberculin
test should also be done. Apical lordotic views of the lung as well as
lateral and oblique views may help identify a tuberculous cavity. There are
serologic tests for antibodies against specific mycobacterial antigens.
Sputum cultures for fungi and skin tests for various fungi may need to
be done. If congestive heart failure is suspected, venous pressure and
circulation time should be measured, and a pulmonary function test should
be done. Echocardiography will help diagnose mitral stenosis.
A consultation with a pulmonologist and bronchoscopy need to be
done if bronchogenic carcinoma or bronchiectasis is suspected. Other
studies that are helpful in diagnosing bronchogenic carcinoma are sputum
for Pap smear, transbronchial needle biopsy, and CT. MRI may confirm
vascular etiologies for the bleeding such as pulmonary aneurysm.
Serologic studies (ANA, antineutrophil cytoplasmic antibody [ANCA],
etc.) may be useful in detecting collagen diseases. A bronchogram will be
helpful in diagnosing bronchiectasis and foreign bodies.
313

HEMORRHOIDS
Hemorrhoids are dilated perianal veins that become thrombosed or can
rupture, producing subcutaneous or submucosal hematomas. They are
usually due to chronic constipation but may also be the cause of
constipation. Although they are usually considered to be a disease, it is
important to remember that they may be a sign of cirrhosis of the liver and
other conditions associated with portal hypertension. As such, they may
point to the diagnosis of esophageal varices in cases of hematemesis, and
their absence would make this diagnosis unlikely.
314

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
HEPATOMEGALY
 Hepatomegaly with jaundice may make one think
of hemolytic anemias; toxic or infectious hepatitis; bile duct
obstruction due to stones, carcinoma of the pancreas, or ampulla of
Vater; and biliary cirrhosis.
 Hepatomegaly with fever should make one think of
viral hepatitis, infectious mononucleosis, ascending cholangitis, and
other infectious diseases.
Is there splenomegaly?
 Hepatomegaly and splenomegaly should
make one think of alcoholic cirrhosis, amyloidosis,
reticuloendotheliosis, various hemolytic anemias, biliary cirrhosis, and
myeloid metaplasia. It should also make one think of various parasitic
diseases.
Is there an enlarged gallbladder?
 The presence of hepatomegaly
with jaundice and enlarged gallbladder is characteristic of bile duct
obstruction due to carcinoma of the pancreas, bile ducts, or ampulla of
Vater. The clinician should remember that hydrops of the gallbladder
with a common duct stone can mimic the same clinical presentation.
Is the splenomegaly massive?
 Massive splenomegaly is characteristic
of Gaucher’s disease, kala azar, and myeloid metaplasia. Occasionally,
other forms of reticuloendotheliosis may also be associated with
massive splenomegaly.
Is there another abdominal mass?
 The presence of another
abdominal mass suggests metastatic carcinoma.
Is the liver tender?
 Tenderness of the liver is seen with viral or toxic
hepatitis, congestive heart failure, and ascending cholangitis.
Routine diagnostic studies include a CBC, sedimentation rate, ANA test,
alpha-
fetoprotein assay, Monospot test, chemistry panel, chest x-ray, EKG,
and flat plate of the abdomen.
If viral hepatitis is suspected, a hepatitis profile should be ordered. If
congestive heart failure is suspected, a venous pressure and circulation
time or BNP and pulmonary function tests should be done. A CT scan or
MRI of the abdomen will assist in the diagnosis of metastatic carcinoma
and often find a primary source for the metastasis. Metastatic neoplasms
315

and the various forms of cirrhosis may be diagnosed by liver biopsy, but
one should keep in mind that it is dangerous to do a liver biopsy if biliary
cirrhosis is suspected. Gallbladder ultrasound or cholecystography should
be done if cholecystitis and cholelithiasis are suspected. Transhepatic
cholangiography or endoscopic retrograde cholangiopancreatography
(ERCP) may need to be done but an MRCP (magnetic resonance
retrograde cholangiopancreatography) is usually done first. Exploratory
surgery may be the only way to get a diagnosis, especially in obstructive
jaundice.
The various infectious diseases will need antibody titers and skin tests
to pin down the diagnosis. For example, a brucellin antibody titer or a
Monospot test can be done. Skin tests for the various fungi and
tuberculosis can be done.
The various hemolytic anemias may be diagnosed by blood smears, a
sickle cell preparation, serum haptoglobin, and hemoglobin
electrophoresis. The reticuloendothelioses require liver biopsy.
Hemochromatosis is also diagnosed by liver biopsy, but a test for serum
iron and iron-binding capacity should also be done. Wilson’s disease is
diagnosed by serum copper and ceruloplasmin tests. Venography will
diagnose hepatic vein thrombosis.
Most physicians prefer to refer the patient with hepatomegaly to a
gastroenterologist once the preliminary studies have been done. This
would be the most cost-effective approach.
316

1. 
  2. 
  3. 
  4. 
  5. 
HICCUPS
Is there a history of alcoholism?
 Alcoholic gastritis is a frequent
cause of hiccups.
 The presence of fever should make one think of
pneumonia with pleurisy, pericarditis, subdiaphragmatic abscess, and
peritonitis. It should also make one think of epidemic hiccups.
Is there heartburn or regurgitation?
 The presence of heartburn and
regurgitation should make one think of a hiatal hernia and esophagitis.
Is there a mediastinal mass?
 Because they irritate the phrenic nerve,
mediastinal masses such as Hodgkin’s disease, bronchogenic
carcinoma, and esophageal carcinoma may cause hiccups.
 Hiccups may
occur in tabes dorsalis, syringomyelia, encephalitis, chorea, and
cerebral hemorrhage.
The basic workup includes a CBC, sedimentation rate, chemistry panel, a
VDRL test, tuberculin test, EKG, chest x-ray, and a flat plate of the
abdomen. If these are negative, an upper GI series and esophagram should
be done. If these are negative, it may be wise to evaluate the response to
Pepto-Bismol or lidocaine viscous. If there is relief from one of these, the
patient may well have a reflux esophagitis.
If there is still confusion at this point, a gastroenterologist should be
consulted before ordering other expensive diagnostic tests. The
gastroenterologist will probably do an esophagoscopy, gastroscopy, and
duodenoscopy and may order a CT scan of the abdomen and mediastinum.
A Bernstein test may help diagnose reflux esophagitis. Esophageal
manometry and pH monitoring of the distal esophagus may also help in
this regard.
317

1. 
  2. 
  3. 
  4. 
  5. 
HIP PAIN
A 62-year-old Hispanic female complains of low back and hip pain of 6
weeks duration. She has curtailed her activities and uses a cane. Following
the algorithm, you do a neurologic examination and perform a straight leg
raising test with negative results. In fact, you find that all of the tenderness
is confined to her right hip. She has a positive Patrick’s sign and exquisite
tenderness over the greater trochanter. You diagnose greater trochanter
bursitis and infiltrate the bursa with 1% lidocaine, which relieves her pain
and restores her range of motion of the right hip.
Is there a positive straight leg raising test or other neurologic
signs?
 The presence of positive straight leg raising tests or other
neurologic signs would suggest a herniated disk, a cauda equina
tumor, or other neurologic disorders of the lumbar spine. Meralgia
paresthetica will cause characteristic loss of sensation in the
distribution of the lateral femoral cutaneous nerve.
Is there a positive Patrick’s test or limitation of the range of
motion of the hip?
 These findings suggest a greater trochanter
bursitis or hip joint pathology such as fracture, osteoarthritis,
rheumatoid arthritis, metastasis, slipped femoral epiphysis, Legg–
Calvé–Perthes disease, rheumatic fever, or transient synovitis.
Iliotibial band syndrome is a common cause of hip pain in runners.
Is there tenderness of the greater trochanter bursa?
 Tenderness of
the greater trochanter bursa will help differentiate greater trochanter
bursitis. It is also seen in hysteria.
 If the patient is a child, transient
synovitis, slipped femoral epiphysis, Legg–Calvé–Perthes disease, and
rheumatic fever should be considered. If the patient is an adult, it is
more likely that the problem is osteoarthritis, a fracture, rheumatoid
arthritis, metastasis, or avascular necrosis.
 A history of trauma would suggest that
there is a fracture or a sprain of the hip joint, but the clinician should
remember that a fracture in the elderly often occurs with no history of
trauma.
319

A CBC, sedimentation rate, chemistry panel, arthritis panel, tuberculin
test, and 
x-rays
 of the lumbosacral spine and hip will diagnose 90% of the
cases. These are relatively inexpensive in comparison to MRI. A bone scan
or CT scan may be necessary to diagnose occult fractures. A serum protein
electrophoresis will help diagnose multiple myeloma. A trigger point
injection of the greater trochanter bursa or ischiogluteal bursa will assist in
the diagnosis of these conditions. An orthopedic surgeon should be
consulted before ordering an MRI of the lumbar spine or hip. However,
MRI is especially important if the diagnosis of avascular necrosis is
suspected.
320

1. 
  2. 
  3. 
  4. 
HIRSUTISM
Is there clitoral enlargement or other signs of virilism?
 These
findings would suggest an ovarian tumor, an adrenal tumor or
hyperplasia, chromosome mosaicism, and true hermaphroditism,
which is rare.
 The presence of obesity and hirsutism should bring
to mind Cushing’s syndrome. However, it is also a sign of polycystic
ovaries.
Is there a history of the use of the steroids or other drugs?
Adrenocortical steroids, testosterone, phenytoin, minoxidil, and
diazoxide are just a few of the drugs that may cause hirsutism.
Is there an ovarian mass?
 The presence of an ovarian mass should
make one think of polycystic ovaries, an arrhenoblastoma, or
granulosis cell tumor. Remember, there may be no ovarian mass in
polycystic ovary syndrome (Stein–Leventhal syndrome).
The routine diagnostic workup includes a serum-free testosterone, free
cortisol, prolactin, serum DHEAS and androstenedione, a skull x-ray
(much more economical than a CT scan or MRI of the brain), and a
urinary gonadotropin assay. If a pituitary tumor or lesion is strongly
suspected, an FSH and LH should be done regardless of results of routine
tests. An overnight dexamethasone suppression test is more accurate than a
routine free cortisol in diagnosing Cushing’s syndrome. A 
24-hour
 urine-
free cortisol may also be used. Pelvic ultrasound and CT scan of the
abdomen and pelvis would complete the workup, but why order these
expensive diagnostic tests before consulting a gynecologist or
endocrinologist?
321

1. 
  2. 
  3. 
  4. 
HOARSENESS
 Acute hoarseness is usually due to a viral URI, but acute
simple laryngitis and acute subglottic laryngitis or rarely laryngeal
diphtheria may be responsible. Simple strain may be responsible
because of the patient’s occupation.
 Intermittent hoarseness would suggest myasthenia
gravis, urticaria, occupational causes, reflux esophagitis, tobacco, and
 If there
are other abnormalities on the neurologic examination, one should
consider peripheral neuropathy, poliomyelitis, Guillain–Barré
syndrome, brain stem tumors, and cerebrovascular disease.
Are there abnormalities on the laryngoscopic examination?
Laryngoscopy will identify many intrinsic lesions of the vocal cords
such as carcinoma, singer’s nodes, polyps, tuberculosis, or syphilis. It
will also identify vocal cord paralysis due to carcinoma of the lung,
aortic aneurysm, cardiac enlargement, or other mediastinal tumors.
A normal laryngoscopic examination would suggest hysteria,
myxedema, or acromegaly.
Acute hoarseness will require only a CBC, sedimentation rate, nose and
throat culture, and sputum culture if sputum is available. A chest x-ray
may also be ordered. Laryngoscopic examination is rarely necessary unless
the acute hoarseness becomes chronic.
The laryngoscopic examination is the single most important test for
chronic hoarseness. It will identify most intrinsic lesions. If vocal cord
paralysis is found, a chest x-ray and possibly a CT scan of the
mediastinum may be ordered. However, an ear, nose, and throat specialist
should be consulted before ordering these expensive tests. If the chords are
edematous, hypothyroidism or angioneurotic edema may be the cause. The
latter may be excluded by ordering a C1 esterase inhibitor level. A barium
swallow or esophagoscopy can be done to exclude a hiatal hernia or reflux
esophagitis. If there are other neurologic abnormalities, a referral to a
neurologist should be made before ordering a CT scan or MRI of the brain.
323

In cases of intermittent hoarseness, a Tensilon test or acetylcholine
receptor antibody titer should be done.
324

1. 
  2. 
  3. 
HORNER’S SYNDROME
Is there pain in the ipsilateral upper extremity?
 If there is pain in
the ipsilateral upper extremity, one should consider brachial plexus
neuritis, thoracic outlet syndrome, Pancoast’s tumor, and spinal cord
tumor.
Is there hemiplegia or other long tract neurologic signs?
 If there is
hemiplegia or other long tract signs, one should consider carotid artery
thrombosis, Wallenberg’s syndrome, or syringomyelia.
 A chest x-ray or an imaging study may
be necessary to disclose a mediastinal mass, but this will establish the
diagnosis of Horner’s syndrome and carcinoma of the lung,
lymphoma, aortic aneurysms, and mediastinitis. If there is no pain in
the extremities, the neurologic examination is normal, and there is no
mediastinal mass, one should consider the possibility of migraine and
histamine headaches.
A neurologist should probably be consulted at the outset. If there is pain in
the upper extremities along with the Horner’s syndrome, x-rays of the
chest should be done to rule out a Pancoast’s tumor, and x-rays of the
cervical spine should be done to rule out a cervical rib. Nerve conduction
velocity studies, SSEP studies, and EMGs of the upper extremities may
help diagnose brachial plexus neuralgia. MRI will be necessary to
diagnose a tumor of the cervical spinal cord.
If there is hemiplegia or other long tract neurologic signs, a CT scan or
MRI of the brain or cervical spinal cord needs to be done. If these tests are
negative and there is an isolated Horner’s syndrome, a CT scan of the
mediastinum should be ordered. Esophagograms, aortography, and
mediastinoscopy may all be necessary to establish the diagnosis in difficult
cases.
325

1. 
  2. 
  3. 
HYDROXY VITAMIN D
2
 AND D
3
Are there abnormal liver function tests?
 This would suggest
cirrhosis is the cause.
Is there significant proteinuria?
 This would suggest that the
nephrotic syndrome is the cause.
Is the D-xylose absorption test positive?
 One should test further for
malabsorption syndrome.
In the absence of the above conditions, it may be that the patient’s
anticonvulsant therapy or lack of sunlight is the cause. However,
hyperthyroidism and diabetes are other disorders that need to be
If the clinical picture does not suggest any of the above disorders, then a
therapeutic trail of 2,000 units of vitamin D
3
 is warranted before launching
on an expensive workup.
327

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
HYPERACTIVE REFLEXES
Are they intermittent or persistent?
 If the hyperactive reflexes are
intermittent, one should consider multiple sclerosis and cerebral
vascular insufficiency.
Are they focal?
 If the hyperactive reflexes are focal, and especially if
they are unilateral, one should consider vascular diseases, space-
occupying lesions, or multiple sclerosis. Certain degenerative diseases
such as amyotrophic lateral sclerosis may also present with focal
hyperactive reflexes.
If the hyperactive reflexes are focal, are they unilateral?
 Unilateral
hyperactive reflexes are characteristic of hemiplegia. Hemiplegia is
usually associated with a cerebral vascular disease or space-occupying
lesion of the brain, especially if there are cranial nerve signs.
However, early spinal cord tumors may present with unilateral
Are there cranial nerve signs?
 The presence of cranial nerve signs
suggests that the lesion is above the foramen magnum, and a cerebral
or brain stem tumor is the first thing to be considered. A cerebral
vascular lesion or multiple sclerosis must also be considered.
Is there dementia?
 The presence of dementia along with the
hyperactive reflexes, especially if they are diffuse, suggests
Alzheimer’s disease, Pick’s disease, general paresis, and Korsakoff’s
syndrome. There are many other causes of dementia to consider.
Are there other long tract signs?
 The presence of hyperactive
reflexes with sensory changes should suggest pernicious anemia,
syringomyelia, and Friedreich’s ataxia. It may also indicate multiple
sclerosis, a spinal cord tumor, a brain stem tumor, or basilar artery
insufficiency.
Hyperactive reflexes, especially if they are unilateral, are a clear indication
for an imaging study. It is wise to consult a neurologist or neurosurgeon
before determining which imaging study to order. If there are cranial nerve
findings and dementia, a CT scan or MRI of the brain should be ordered.
If there are hyperactive reflexes of all four extremities without
dementia or cranial nerve signs, MRI of the cervical spine would probably
328

be the most appropriate procedure. It may, however, be necessary to get a
CT scan or MRI of the brain anyway.
If only the lower extremities are involved, MRI of the thoracic cord
would probably be most appropriate, but then MRI of the cervical spine
should be done if the thoracic MRI is negative. Spinal fluid analysis will
help diagnose multiple sclerosis, central nervous system syphilis, cerebral
hemorrhages, or abscess. A CBC, serum B
12
 and folic acid, and Schilling
test will help diagnose pernicious anemia. Plain films of the appropriate
level of the spine are necessary in trauma cases. An EEG and
psychometric testing should be done in cases of dementia. SSEP, VEP, and
BSEP studies are helpful in diagnosing multiple sclerosis. Carotid duplex
scans and four-vessel angiography may be necessary for diagnosing
cerebral vascular disease.
329

1. 
  2. 
HYPERCALCEMIA
Is the parathyroid hormone (PTH) assay increased?
 This would
point to a parathyroid tumor or hyperplasia and ectopic PTH secretion.
In any case of elevated PTH, look for type I or type II multiple
endocrine neoplasm syndrome.
 Hypercalcemia and an
increased alkaline phosphatase without an increase in PTH assay
suggest metastatic carcinoma of the bone, Paget’s disease, and other
bone tumors. Hypercalcemia without an elevated alkaline phosphatase
is suggestive of multiple myeloma and hyperproteinemia due to other
causes. A serum protein electrophoresis will help define this further.
A CBC, chemistry panel, 24-hour urine calcium, PTH assay, serum 25-
(OH) vitamin D
3
, free thyroxine (T
4
), serum protein electrophoresis,
skeletal survey, bone scan, and endocrinology consult may be part of any
workup of hypercalcemia. The 
24-hour
 urine calcium is low in familial
hypocalciuric hypercalcemia in contrast to primary hyperparathyroidism.
331

1. 
  2. 
  3. 
HYPERCHOLESTEROLEMIA
What is the serum albumin?
 A decreased serum albumin associated
with an increased cholesterol strongly suggests the nephrotic
syndrome or liver disease. These two conditions may be further
differentiated by the finding of proteinuria in the nephrotic syndrome.
What is the free T
4
?
 Hypercholesterolemia associated with a low T
4
suggests myxedema.
What is the triglyceride level?
 An elevated cholesterol coupled with
a marked increase in the triglyceride is typical of type I and type II
lipoproteinemia. Type IIB, type III, and type IV lipoproteinemias are
associated with a high cholesterol but only mild increase of
triglyceride. Oral contraceptive use, atherosclerosis, and
xanthomatosis may present the same picture. These may be further
differentiated by lipoprotein electrophoresis.
First repeat the lipid panel after a 14-hour fast. If the total cholesterol is
still elevated, proceed with a workup of hypercholesterolemia. This should
include a CBC, CRP, urinalysis, chemistry panel, overnight refrigeration
of plasma, free T
4
, TSH, apolipoprotein, and lipoprotein electrophoresis.
An elevated CRP is especially helpful in evaluating the risk for stroke or
myocardial infarction. If these tests suggest liver disease, liver function
tests and liver biopsy may be indicated. If these tests suggest kidney
disease, a nephrologist should be consulted for consideration of renal
function tests or renal biopsy. A metabolic disease specialist or an
endocrinologist may need to be consulted for further diagnostic evaluation
and management.
332

1. 
  2. 
  3. 
  4. 
HYPERGLYCEMIA
4
?
 If this is elevated, think of hyperthyroidism.
What is the plasma cortisol?
 If this is elevated, think of Cushing’s
syndrome.
What is the plasma growth hormone?
 If this is elevated, think of
acromegaly or gigantism.
What is the 24-hour urine catecholamine level?
 If this is high, think
of a pheochromocytoma.
If all of the above tests are normal, diabetes mellitus is usually the
diagnosis, although some of these patients could have a glucagonoma or
pancreatic disease. Certain drugs can also cause a spurious hyperglycemia.
Further workup may include a CBC, urinalysis, chemistry panel, lipid
panel, HbA
1c
, glucose tolerance test, plasma cortisol, free T
4
, TSH, plasma
and urine catecholamines, skull x-ray or CT scan of the brain, 24-hour
urine vanillylmandelic acid, and endocrinology consult.
334

1. 
  2. 
  3. 
  4. 
HYPERKALEMIA
Is there hemolysis in the test tube?
 This is just one of the spurious
causes of hyperkalemia. Leukocytosis, thrombocytosis, and the use of
an excessively tight tourniquet to draw blood may also be the cause.
What is the BUN?
 Increased potassium is most often due to renal
failure, especially acute renal failure. Hyperkalemia can occur in some
renal diseases even without an elevated BUN.
 
Hyperkalemia with a low plasma
cortisol suggests Addison’s disease is the cause. Adrenogenital
syndrome and chronic renal disease may be associated with a defect in
aldosterone synthesis causing the same picture.
 Metabolic acidosis, especially
diabetic acidosis, is often associated with hyperkalemia.
Additional tests to order include a CBC, urinalysis, chemistry panel, serial
electrolytes, plasma cortisol, plasma renin, 24-hour urine aldosterone,
renal function tests, and endocrinology and nephrology consults. As a
precaution, it may be wise to hold all unnecessary drugs until the diagnosis
is certain.
336

1. 
  2. 
  3. 
HYPERKINESIS
 Phenothiazines, amphetamines,
tricyclic drugs, lithium, and other substances may cause hyperkinesis.
Is there a tremor, a goiter, or tachycardia?
 The findings would
other neurologic signs and symptoms would suggest Wilson’s disease,
Huntington’s chorea, Sydenham’s chorea, and Parkinson’s disease. If
there are no other neurologic signs and symptoms, one should look for
an attention deficit disorder or Gilles de la Tourette’s syndrome.
Routine studies include a CBC, sedimentation rate, ASO titer, chemistry
panel, urine drug screen, and a thyroid panel. A serum copper and
ceruloplasmin will usually diagnose Wilson’s disease. If all of the above
studies are negative, MRI of the brain may be done to rule out tumors or
degenerative disease of the nervous system, but why not consult a
neurologist first? An EEG may identify epilepsy and brain damage.
Referral to a psychiatrist or psychologist is made if all of the above studies
are normal.
338

1. 
  2. 
HYPERNATREMIA
What is the chloride level?
 Hypernatremia with an elevated chloride
is almost certainly due to dehydration, but renal and hypothalamic
diabetes insipidus, heat exhaustion, and hypertonic fluid
administration may also be responsible. A low chloride level with
hypernatremia may be seen in aldosteronism or Cushing’s syndrome.
What is the serum antidiuretic hormone (ADH) assay?
 If this is
low or absent, hypothalamic diabetes insipidus must be considered. If
this is normal, one should consider dehydration, heat exhaustion,
prolonged vomiting, renal diabetes insipidus, and hypertonic saline
administration as likely causes.
The workup should include a CBC, urinalysis, chemistry panel, serum and
urine osmolality, plasma cortisol, serum ADH, plasma volume studies,
serial electrolytes, and consultation with an endocrinologist or
339

1. 
  2. 
  3. 
  4. 
  5. 
HYPERPIGMENTATION
 Argyria, arsenic poisoning, and
methemoglobinemia are among the considerations in taking a drug
history.
 The presence of hepatomegaly would make
one think of hemochromatosis.
 The presence of significant weight
loss would suggest Addison’s disease, pellagra, hyperthyroidism, or
an ectopic hormone–secreting tumor.
Is there a history of seizures or neuropathy?
 The history of seizures
or neuropathy should make one consider porphyria.
Is the hyperpigmentation focal?
 In addition to melanotic cancer, this
should bring to mind acanthosis nigricans and the café au lait spots of
neurofibromatosis.
The serum iron and iron-binding capacity should be measured to rule out
hemochromatosis. A thyroid profile will exclude hyperthyroidism. A
serum cortisol and ACTH stimulation test will identify Addison’s disease.
A urine for porphyrins and porphobilinogen will diagnose porphyria. A
urine 
N
-methyl niacinamide will help diagnose pellagra.
If there is still doubt after these studies are done, a skin or liver biopsy
may be done to rule out hemochromatosis, and a CT scan of the abdomen
will help identify Addison’s disease.
340

1. 
  2. 
  3. 
  4. 
HYPERSOMNIA
Is there a history of drug or alcohol use?
 Alcoholism and
barbiturate intoxication are just two of the causes of hypersomnia.
Are there hallucinations, sleep paralysis, and cataplexy?
 These
findings suggest narcolepsy.
Is there associated loss of appetite and/or libido?
suggest endogenous depression.
 Abnormal
neurologic findings suggest multiple sclerosis, encephalitis,
neurosyphilis, and other disorders.
The routine workup includes a CBC, sedimentation rate, chemistry panel,
VDRL test, and urine drug screen. If there are abnormal neurologic signs,
MRI of the brain and spinal tap can be done, but it is advisable to consult a
neurologist first. An EEG and sleep study complete the workup.
If all of the above studies are normal, referral to a psychiatrist would
be in order.
342

1. 
  2. 
  3. 
  4. 
  5. 
HYPERTENSION
A 34-year-old obese white female presents with a 2-year history of
uncontrolled hypertension. Following the algorithm, you find there is
elevation of both her systolic and diastolic blood pressure to 180/115. The
blood pressure is slightly above that in the lower extremities. There is no
flank mass palpable. Examination of the urinary sediment is unremarkable.
However, you notice purple abdominal striae. A plasma cortisol level
confirms your suspicion of Cushing’s syndrome.
Is there systolic hypertension only?
 The presence of an elevated
systolic pressure only would suggest hyperthyroidism, aortic
insufficiency, and atherosclerotic aortitis. Systolic hypertension in the
elderly must always be taken seriously.
Is the hypertension paroxysmal?
 The presence of paroxysmal
hypertension should suggest a pheochromocytoma.
Is there a normal or low blood pressure in the lower extremities?
These findings would suggest a coarctation of the aorta.
 The presence of a flank mass should suggest
hypernephroma, hydronephrosis, and polycystic kidneys.
Are there abnormalities of the urinary sediment?
suggest glomerulonephritis, collagen disease, Henoch–Schönlein
purpura, and chronic nephritis. All primary care physicians should
have this capability in their office. Is the patient ingesting large
amounts of cocaine, caffeine, or other stimulating drugs? This is an
increasing concern of most physicians.
panel, total and high-density lipoprotein cholesterol, a VDRL test,
microscopic urinalysis, a urine culture with colony count and sensitivity, a
urine drug screen, and an EKG, chest x-ray, and flat plate of the abdomen
for kidney size. Remember overuse of diuretics is a cause of resistant
hypertension.
If these are normal, a nephrologist should be consulted before
344

undertaking expensive diagnostic tests. It may be wise to observe the
results of treatment before further testing.
Additional tests that may be ordered are an intravenous pyelogram or
CT scan of the abdomen to look for hydronephrosis, neoplasms or
congenital anomalies of the kidney, a 24-hour urine catecholamine, a
serum cortisol, a plasma renin level, a 24-hour urine aldosterone
determination, a cystoscopy, and retrograde pyelography. A 24-hour urine-
free cortisol may be more useful in diagnosing Cushing’s syndrome than
serum-free cortisol. Cases of Cushing’s syndrome due to an ACTH
secreting tumor may be differentiated by a poor response to a
dexamethasone suppression test. Ultrasonography may pick up a renal
artery stenosis. Renal angiography used to be done more frequently, but
should be considered in sudden onset of hypertension in the elderly and in
hypertension that is resistant to treatment. A CTA (CT angiography) or
MRA may obviate the need for this study.
A 24-hour blood pressure monitoring can be useful both in diagnosis
and in evaluating the results of therapy.
345

1. 
  2. 
  3. 
  4. 
  1. 
  2. 
  3. 
HYPERTRIGLYCERIDEMIA
Algorithm A
4
?
 If this is decreased, hypothyroidism should
come to mind.
What is a serum albumin and urine protein?
 If the serum albumin
is low and there is proteinuria, one should consider nephrotic
syndrome.
What is the fasting blood sugar?
 Hyperglycemia coupled with an
elevated triglyceride makes diabetes mellitus the most likely cause.
Hypoglycemia should prompt consideration of insulinomas and
glycogen storage disease.
If all of the above tests are normal, a familial disorder of lipid
metabolism (see Algorithm B) should be considered.
Algorithm B
Are the chylomicrons increased?
 An increased triglyceride coupled
with increased chylomicrons suggest type V and type I
lipoproteinemia. Normal chylomicrons suggest the possibility of type
III lipoproteinemia.
What is the cholesterol?
 An increased triglyceride and chylomicrons
should identify type V lipoproteinemia. Normal cholesterol with both
increased triglyceride and a marked increase in chylomicrons
identifies type I lipoproteinemia. Increased cholesterol with increased
triglyceride but normal chylomicrons identifies type III
lipoproteinemia. A mild to moderate increased triglyceride with
increased cholesterol but normal chylomicrons should identify type
IIB lipoproteinemia without chylomicrons, and normal or mildly
increased cholesterol should point to type IV lipoproteinemia.
If neither the chylomicrons nor the triglyceride is elevated, consider
type IIA lipoproteinemia or familial hypercholesterolemia. Remember,
regular alcohol consumption, estrogen therapy, nicotinic acid
treatment, and phenytoin treatment can also produce triglyceridemia.
346

First confirm that the hypertriglyceridemia is real by repeating the test
after a 
14-hour
 fast. The workup of triglyceridemia includes a CBC, CRP,
urinalysis, chemistry panel, free T
4
, glucose tolerance test, 24-hour urine
protein, serum apolipoprotein, lipoprotein electrophoresis,
ultracentrifugation, renal biopsy, liver biopsy, and consultation with a
metabolic disease specialist. As stated before, the CRP is important in
assessing the risk for stroke and MI.
347

1. 
  2. 
  3. 
  4. 
HYPOACTIVE REFLEXES
Is it focal?
 Hypoactive reflexes limited to one extremity suggest a
herniated disk, plexopathy, or early cauda equina or spinal cord tumor.
If focal, are the hypoactive reflexes involving both the upper and
lower extremities?
 If the hypoactive reflexes are in both the upper
and lower extremities on one side, this may be a normal phenomenon
suggesting that the opposite side is pathologic. It may also be a finding
in early cerebral vascular accident.
If the hypoactive reflexes are diffuse, was there a sudden onset?
Sudden onset of hypoactive reflexes would suggest acute spinal cord
conditions, such as spinal fractures, transverse myelitis, Guillain–
Barré syndrome, or poliomyelitis, or acute central nervous system
disorders, such as toxic metabolic disease of the central nervous
system, concussion, subdural hematoma, or acute increased
intracranial pressure. Early basilar artery thrombosis may be
associated with hypoactive reflexes also.
 The presence of other neurologic
signs, particularly cranial nerve involvement, would suggest an early
basilar artery thrombosis, cerebral vascular accident, or subdural
hematoma. If there are no other neurologic findings or there is simply
a disordered state of consciousness, then a head injury or toxic
metabolic disease of the central nervous system, increased intracranial
pressure, or poliomyelitis might be suspected.
Focal hypoactive reflexes of the lower extremity require plane x-rays of
the lumbosacral spine, a CT scan or MRI of the lumbosacral spine, and
nerve conduction velocity and EMG studies. Dermatomal SSEP studies
will occasionally show radiculopathy when EMGs are negative.
Hypoactive reflexes of one upper extremity can be worked up with x-
rays of the cervical spine, MRI of the cervical spine, nerve conduction
velocity studies, EMGs, and dermatomal SSEP studies. X-rays of the chest
may be useful to rule out Pancoast’s tumor.
Diffuse hypoactive reflexes associated with other neurologic signs or
symptoms require a neuropathy workup (see 
page 378
). A serum B
12
 and
349

folic acid and possibly a Schilling test may need to be done to rule out
pernicious anemia. An EMG and muscle biopsy may be done to rule out
muscular dystrophy. A spinal tap will be helpful in cases of poliomyelitis
and Guillain–Barré syndrome. If the hypoactive reflexes are part of a toxic
metabolic or inflammatory disease of the nervous system, the workup will
be similar to that of coma (
page 103
).
350

1. 
  2. 
  3. 
  4. 
HYPOALBUMINEMIA
What is the urine protein?
 Significant protein in the urine should
suggest nephrotic syndrome and other chronic renal disorders as the
likely cause.
Are there abnormalities of the liver function tests?
 This would
point to cirrhosis, viral hepatitis, and other liver diseases as possible
causes.
What does the D-xylose absorption test show?
 Decreased 
D-xylose
absorption points to malabsorption syndrome.
If all of the above tests are normal, look for starvation, 
protein-losing
enteropathy, acute burns, hemodilution states such as congestive heart
failure, and hypermetabolic states such as hyperthyroidism and
metastatic neoplasm. Chronic infectious disease can also lower the
albumin.
Routine tests include a CBC, urinalysis, 24-hour urine protein, chemistry
panel, protein electrophoresis, sedimentation rate, a chest x-ray, and EKG.
Further considerations include renal function tests, liver and renal biopsy,
a CT scan of the abdomen, and consultation with a nephrologist and a
hepatologist.
351

1. 
  2. 
  3. 
HYPOCALCEMIA
What is the PTH assay?
 If this is low, hypoparathyroidism ought to
be considered the most likely diagnosis. If it is normal or increased,
other causes of hypocalcemia should be investigated.
What is the phosphorus level?
 A decreased phosphorus level should
prompt a search for malabsorption syndrome, rickets, osteomalacia,
renal tubular acidosis, cirrhosis, and nephrotic syndrome. An elevated
phosphorus level would be most suggestive of renal disease, but
pseudohypoparathyroidism must also be considered.
What is the alkaline phosphatase level?
 This would be elevated in
hypocalcemia because of malabsorption syndrome, rickets,
osteomalacia, renal tubular acidosis, and other chronic renal disease. It
would be normal in cirrhosis, nephrosis, alkalosis, and
pseudohypoparathyroidism.
CBC, urinalysis, chemistry panel, 24-hour urine calcium, PTH assay,
serum protein electrophoresis, serum 25-(OH) vitamin D
3
, skeletal survey,
bone scan, 
D-xylose
 absorption test, serum l,25-(OH)
2
 vitamin D, and an
endocrinology consult should be considered in the workup.
Pseudohypoparathyroidism can be further differentiated from primary
hypoparathyroidism by the Ellsworth–Howard test, which involves
injecting PTH intravenously. The blood values of calcium and phosphorus
will improve in primary hypoparathyroidism but remain the same in
pseudohypoparathyroidism. There is a phosphate diuresis in primary
hypoparathyroidism.
353

1. 
  2. 
  3. 
HYPOCHONDRIASIS
Is there loss of libido and/or appetite?
 The findings of loss of libido
and appetite would suggest endogenous depression. There may also be
insomnia.
Is there loss of memory or concentration?
 These findings suggest
the possibility of an organic brain syndrome or cerebral
arteriosclerosis. Epilepsy may also be involved.
Does extensive testing fail to convince the patient he or she is well?
If extensive testing fails to convince the patient he or she is well, the
diagnoses of delusional hypochondriasis and schizophrenia must be
The diagnostic workup need not be extensive, but certain routine tests
should be done. These include a CBC, sedimentation rate, chemistry panel,
thyroid profile, EKG, chest x-ray, and flat plate of the abdomen. If there
are complaints of memory loss and/or poor concentration, an EEG and CT
scan of the brain may be done. A neurologist should be consulted. If the
above tests fail to disclose an organic cause for the complaints and the
patient is still not convinced he/she is well, referral to a psychiatrist is
indicated.
355

1. 
  2. 
  3. 
  4. 
  5. 
HYPOGLYCEMIA
A 36-year-old white male presents to the emergency room with
generalized weakness and fatigue that has suddenly gotten worse over the
past 24 hours. A stat blood sugar is 48 mg%.
Following the algorithm, you find he is not diabetic and, consequently,
does not take insulin or oral hypoglycemic agents. There is no history of
weight gain and in fact he has lost weight over the past 3 months. He
denies any episodes of loss of consciousness. He has a nice tan with
hyperpigmentation of the palmar creases. A decreased plasma cortisol
confirms your suspicion of Addison’s disease.
Is the patient taking oral hypoglycemic drugs or insulin?
 If so, the
dosage may be too high.
Is there a history of weight gain and/or episodes of loss of
consciousness?
 This would strongly suggest an insulinoma is the
cause.
 If this is decreased, look for Addison’s
disease!
 If this is decreased, look for
Simmonds’ disease.
What does a D-xylose absorption test show?
 If this is abnormal,
look for malabsorption syndrome. If the diagnosis is still in doubt, the
patient may have cirrhosis, glycogen storage disease, hypothyroidism,
or functional hypoglycemia.
The finding of hypoglycemia on routine blood analysis requires nothing in
an asymptomatic patient. If there is doubt, a repeat analysis should be
done. If the patient is symptomatic, a 5-hour glucose tolerance test or
hospitalization for repeated blood sugar during a 72-hour fast should be
done. Genetic testing and liver biopsy for glucose-6-phosphatase activity
will be useful in diagnosing glycogen storage disease. If these are
negative, the patient most likely has functional hypoglycemia. Additional
tests to order include a T
4
, plasma cortisol, plasma growth hormone assay,
357

plasma proinsulin, C-peptide, plasma insulin, CT scan of the abdomen, and
a tolbutamide tolerance test. Obtain an endocrinology consult.
358

1. 
  2. 
  3. 
HYPOKALEMIA
What is the sodium level?
 If the sodium is normal or increased,
consider aldosteronism, Cushing’s syndrome, periodic paralysis, or IV
fluid administration without supplemental potassium. If the sodium
level is decreased, consider pyloric obstruction, diuretics, severe
vomiting, diabetic acidosis, diarrhea, renal tubular acidosis, starvation,
and malabsorption syndrome as possibilities.
 If it is elevated, look for Cushing’s
syndrome.
 If this is increased with both a low
sodium and potassium, look for pyloric obstruction, persistent
vomiting, and diuretic administration. If this is low with both a low
sodium and potassium, look for diabetic acidosis, renal tubular
acidosis, diarrhea, starvation, diuretic effects, and malabsorption
syndrome.
The diagnosis can be pursued by ordering a CBC, urinalysis, 24-hour urine
potassium, serial electrolytes, a chemistry panel, plasma renin, 24-hour
urine aldosterone, D-xylose absorption test, and plasma cortisol and
obtaining an endocrinology or nephrology consult.
359

1. 
  2. 
  3. 
  4. 
HYPONATREMIA
 An increased chloride points to diabetic
acidosis, Addison’s disease, renal tubular acidosis, nephritis, and use
of certain diuretics as the cause. A decreased chloride suggests
congestive heart failure, syndrome of inappropriate secretion of
antidiuretic hormone (SIADH), pyloric obstruction, vomiting,
malabsorption syndrome, and diuretic use as the possible cause.
SIADH is found in carcinoma of the lung, porphyria, and numerous
pulmonary and neurologic conditions.
 An elevated blood sugar level suggests
diabetic acidosis or hyperosmolar coma.
 A low plasma cortisol coupled with a
low sodium and elevated chloride suggests Addison’s disease. A low
sodium and elevated chloride but normal plasma cortisol should
suggest renal tubular acidosis, nephritis, and use of certain diuretics.
What is the blood volume?
 Hyponatremia with an increased blood
volume is associated with congestive heart failure and SIADH.
The diagnostic workup should include a CBC, chemistry panel, serial
electrolytes, serum and urine osmolality, plasma cortisol, serum ADH
assay, plasma renin, arterial blood gases, and consultation with an
endocrinologist and a nephrologist.
360

1. 
  2. 
  3. 
  4. 
  5. 
HYPOTENSION, CHRONIC
Is the hypotension found only on standing?
hypotension on standing suggests orthostatic hypotension, which may
be due to several causes, including hypopituitarism, diabetic
neuropathy, anemia, and various cardiovascular disorders.
 Many drugs induce
hypotension, including nitroglycerin and its analogs, vasodilators,
quinidine, and tricyclic drugs.
Is there cardiomegaly or a heart murmur?
mitral valvular disease, aortic stenosis, and congestive heart failure.
 The finding of pallor suggests anemia.
Is there hyperpigmentation?
 The presence of hyperpigmentation
suggests Addison’s disease.
urinalysis, thyroid panel, EKG, and chest x-ray. A tilt table test is the best
way to establish the diagnosis of orthostatic hypotension. Blood volume
and arterial blood gas studies may be useful. A urine drug screen should be
done. If there is cardiomegaly or a murmur, echocardiography and venous
pressure and circulation time should be done. A cardiologist should also be
If there is hyperpigmentation, a serum cortisol and ACTH stimulation
test should be done. A skull x-ray can be done to rule out pituitary tumors.
A visual field examination by a qualified ophthalmologist may also be
helpful in this regard. A 
24-hour
 blood pressure monitoring may also be
useful in the workup.
362

1. 
  2. 
  3. 
  4. 
HYPOTHERMIA
 Alcoholic
intoxication, opium poisoning, tricyclic antidepressants, and
phenothiazine may cause hypothermia.
Is there a history of severe vomiting or diarrhea?
 Severe vomiting
or diarrhea may induce dehydration and electrolyte disturbances,
which will induce hypothermia. Intestinal obstruction, cholera, and
peritonitis are among the many disorders that may lead to severe
vomiting or diarrhea.
 Signs of hypothyroidism and
Addison’s disease may be obvious, but hypopituitarism,
hypoglycemia, and diabetes mellitus may also be the cause of
hypothermia.
 Focal
neurologic findings may be seen in a cerebral vascular accident or
epidural or subdural hematoma. However, thiamine deficiency may
also result in hypothermia.
Routine laboratory tests include a CBC and differential count, a
sedimentation rate and chemistry panel, electrolytes, thyroid profile, blood
cultures, urinalysis, and a urine drug screen. An EKG and chest x-ray
should also be done. A CT scan of the brain is done if there are focal
neurologic abnormalities or disorders of consciousness.
An infusion of dextrose intravenously and thiamine are given as soon
as blood studies are drawn in case there is hypoglycemia or thiamine
deficiency.
If the above studies are normal, a thorough endocrine workup is
indicated, including tests for serum cortisol, FSH, lutein-stimulating
hormone, and growth hormone. A cardiologist, neurologist, or
endocrinologist may need to be consulted to help solve the diagnostic
dilemma.
364

1. 
  2. 
  3. 
  4. 
  5. 
HYPOXEMIA
What is the carbon dioxide level?
 An increased carbon dioxide level
suggests pulmonary emphysema, asthma, Pickwickian syndrome,
respiratory paralysis, central nervous system disease, kyphoscoliosis,
drug effects, and disorders of the chest wall and spine.
What does spirometry show?
 If spirometry shows a decreased 
1-
second
 timed vital capacity with an increased carbon dioxide level,
consider emphysema and asthma likely. If the timed vital capacity is
normal, a diagnosis of Pickwickian syndrome, respiratory paralysis,
central nervous system disease, drug effects, and chest wall and spine
disorders should be considered.
If the carbon dioxide level is normal or decreased, what does the
chest radiograph show?
 A focal infiltrate suggests pulmonary infarct,
congestive heart failure, or pneumonia. A diffuse infiltrate or negative
chest x-ray suggests congestive heart failure, pulmonary fibrosis,
shock, pulmonary or intracardiac shunt, sarcoidosis, pneumoconiosis,
or alveolar proteinosis.
What does a perfusion scan show?
 If this is positive, consider
pulmonary infarction.
What does the pulmonary capillary wedge pressure show?
 If this is
increased, consider congestive heart failure. If this is decreased, the
patient may have hypovolemic shock. If it is normal, consider a right-
to-left shunt, pulmonary fibrosis, pneumoconiosis, or sarcoidosis.
Repeated arterial blood gases should be done. A CBC, urinalysis,
chemistry panel, methemoglobin, sulfhemoglobin, carboxyhemoglobin,
venous pressure and circulation time, blood volume, serial ECGs, CT scan
of the chest, lung biopsy, additional pulmonary function tests, and
consultation with a pulmonologist or cardiologist will be necessary in
many cases.
366

1. 
  2. 
  3. 
  4. 
IMPOTENCE (ERECTILE DYSFUNCTION)
Is there a history of alcohol or drug ingestion?
 A host of
antihypertensive drugs, including the beta-blockers, may cause
impotence. In addition, tricyclic drugs, nicotine, and alcohol
intoxication may cause impotence.
Is there loss of secondary sex characteristics?
suggest Fröhlich’s syndrome, Klinefelter’s syndrome, and other
congenital disorders.
Are there abnormalities on urologic examination?
 Various
conditions, such as Peyronie’s disease, atrophied testes, prostatitis, and
Leriche’s syndrome may be found on urologic examination.
Neurologic examination may reveal diabetic neuropathy, spinal cord
tumor, multiple sclerosis, and other neurologic disorders.
A thorough psychiatric and sexual history is necessary before undertaking
expensive laboratory tests. However, recent studies suggest that emotional
problems are the cause in less than 10% of the cases. It is wise to interview
the spouse or sexual partner also because the symptom may be
exaggerated by the patient. Do not hesitate to order a drug screen. Routine
tests include a CBC and differential count, a urinalysis, a urine culture and
colony count, a chemistry panel, VDRL test, thyroid profile, serum
testosterone, serum prolactin, and gonadotropin assay. A referral to an
urologist is probably wise at this point. He/she will work up the patient
further with a nocturnal tumescent study, Doppler ultrasonography, and
penile blood pressure studies. In addition, he/she may want to do a
cystoscopy. It may be wise to perform a postage stamp test before referral
for a formal tumescence study. A therapeutic trial of sildenafil may be
diagnostic!
Nerve conduction velocity studies and EMGs may be needed to rule
out diabetic neuropathy. An MRI of the spine, cystometric studies, and
SSEP studies will help rule out multiple sclerosis and other spinal cord
lesions. A sacral reflex latency time may be very helpful in diagnosing
sacral nerve injury. A spinal tap may help rule out central nervous system
lues. An angiography may be needed to exclude a Leriche’s syndrome.
368

1. 
  2. 
  3. 
  4. 
INCONTINENCE OF FECES
Is the stool volume small or large?
 A small volume of stool should
suggest anal fissure; hemorrhoids, diarrhea, or postoperative
incontinence from a fistulectomy; or other types of surgery in the
perirectal area.
Is the incontinence intermittent?
 Intermittent incontinence suggests
epilepsy or organic brain syndrome.
Are there hyperactive reflexes in the lower extremities?
 Presence
of hyperactive reflexes in the lower extremities should suggest a spinal
cord tumor or trauma to the spinal cord, multiple sclerosis, a
parasagittal meningioma, transverse myelitis, and syringomyelia.
Are there hypoactive reflexes in the lower extremities?
 The
presence of hypoactive reflexes in the lower extremities should
suggest tabes dorsalis, a cauda equina tumor, spinal stenosis, and other
conditions of the lumbar spine and lumbosacral area.
Routine studies include a CBC, sedimentation rate, chemistry panel, and
VDRL test. Sigmoidoscopy and barium enema are needed to exclude
malignancy. The anorectal area should be carefully inspected for lesions
and the sphincter competence determined by a digital examination. If these
findings are normal, it would be wise to consult a neurologist. If one is not
available, further workup may be done.
If there are hyperactive reflexes with cranial nerve signs, a CT scan or
an MRI of the brain should be done. If there are hyperactive reflexes of all
four extremities with no cranial nerve signs, an MRI of the cervical spine
should be done. With hyperactive reflexes of the lower extremities only,
an MRI of the thoracic cord should be done. If there are hypoactive
reflexes in the lower extremities, an MRI or a CT scan of the lumbar spine
should be done. If increased intracranial pressure has been excluded, a
spinal tap may be done to help diagnose multiple sclerosis or tabes
dorsalis. Anorectal manometry and defecography may be used to detect
anal and rectal muscle dysfunction.
If the general physical examination and neurologic examination are
negative, psychogenic causes should be considered, and cystometric
studies might be helpful. The patient should be referred to a psychiatrist.
370

1. 
  2. 
  3. 
  4. 
  5. 
INCONTINENCE OF URINE
Is the volume of urine large or small?
 If the volume of urine
released is small, stress incontinence and vesicovaginal fistula should
be considered. If the amount released is large, one should consider a
neurologic condition or an enlarged prostate with bladder neck
obstruction as the cause.
Neurologic disorders to be considered are spastic neurogenic bladder
because of multiple sclerosis, spinal cord tumor, and spinal cord
trauma, as well as incompetent sphincter because of cauda equina
syndrome, spinal stenosis, poliomyelitis, diabetic neuropathy, and
tabes dorsalis. Dementia and Parkinson’s disease are significant causes
of an overactive bladder.
 This helps distinguish the disorders
of the spinal cord and parasagittal area, such as spastic neurogenic
bladder because of multiple sclerosis, spinal cord tumor, spinal cord
trauma, normal pressure hydrocephalus, and parasagittal meningioma.
Are the reflexes hypoactive?
 Hypoactive reflexes suggest
poliomyelitis, cauda equina syndrome, spinal stenosis, diabetic
neuropathy, and tabes dorsalis.
Is there an enlarged bladder or prostate?
 If an enlarged bladder or
prostate is palpated, one should consider overflow incontinence from
bladder neck obstruction, prostatic hypertrophy, and tuberculosis of
the bladder.
Routine laboratory tests include a CBC, a urinalysis, a urine culture and
sensitivity, a chemistry panel, and a VDRL test. An IVP and a voiding
cystogram may be helpful. A Q-tip test or stress test may be helpful in
diagnosing stress incontinence. The bladder may be catheterized for
residual urine, or abdominal ultrasonography may be employed to evaluate
residual urine. Fifty milliliters or more is considered abnormal.
Cystoscopy may also be necessary to determine, if there is chronic bladder
inflammation or bladder neck obstruction. Office cystometrography can be
considered, but it is usually best to refer the patient to an urologist for
cystometric studies. Prostatic size can be determined by transrectal
372

prostatic ultrasonography.
The simplest and most cost-effective approach is to refer the patient to
a neurologist if there are abnormalities on the neurologic examination, or
refer the patient to an urologist if there are not. If there is stress
incontinence and a cystocele is found on vaginal examination, the patient
should be referred to a gynecologist. It is not cost-effective to begin
ordering MRIs or CT scans of the brain and spinal cord without the
assistance of these specialists.
373

1. 
  2. 
  3. 
INCREASED SERUM BILIRUBIN
Is the alkaline phosphatase increased?
 An increased alkaline
phosphatase along with an increased bilirubin would point to liver
disease or obstructive jaundice. An elevated bilirubin without alkaline
phosphatase increase is more likely to be associated with hemolytic
anemia, Gilbert’s disease, or Dubin–Johnson syndrome.
Are the liver enzymes elevated?
 If so, the patient likely has hepatitis
or cirrhosis of the liver, although occasionally elevation of the liver
enzymes is seen in obstructive jaundice.
What is the serum haptoglobin?
 An elevated serum haptoglobin
indicates hemolytic anemia. If the serum haptoglobin is normal, look
for Gilbert’s disease or Dubin–Johnson syndrome.
Hepatitis can be further evaluated by ordering a hepatitis profile,
Monospot test, and serologic tests for leptospirosis and various other liver
disorders. Cirrhosis of the liver can be diagnosed by a liver biopsy.
Cholestatic hepatitis can be diagnosed by the lowering of serum bilirubin
by a course of corticosteroids. Obstructive jaundice is best diagnosed by
ultrasound, ERCP or a CT scan of the abdomen, although transhepatic
cholangiography is occasionally necessary. Hemolytic anemia can be
further evaluated by a CBC, reticulocyte count, direct and indirect Coombs
test, and hemoglobin electrophoresis.
374

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
INDIGESTION
 Alcohol, tobacco,
aspirin, other nonsteroidal anti-inflammatory drugs, steroids, caffeine,
and antibiotics are just a few of the drugs that may irritate the
stomach.
Is the indigestion brought on by exertion?
 A history of indigestion
brought on by exertion should suggest angina pectoris.
Is there a loss of appetite and weight?
 These findings would suggest
not only a GI neoplasm, but also pernicious anemia, chronic
pancreatitis and pyloric obstruction, and chronic gastritis. Chronic
organ failure should also be entertained, such as uremia, cirrhosis, or
Is the indigestion or pain relieved by food or antacids?
 These
findings would suggest a duodenal ulcer, hiatal hernia, and
esophagitis.
Is the indigestion or pain brought on by food?
would suggest cholecystitis, gastric ulcer, or toxins in food such as
monosodium glutamate or sulfites.
Is the indigestion or pain unrelated to meals?
 These findings would
suggest a chronic appendicitis, chronic intestinal obstruction, or tabes
dorsalis. It may also suggest air swallowing from chronic anxiety or
excessive talking.
Is there no pain associated with the indigestion?
 This finding would
suggest functional dyspepsia.
If your physical examination is unremarkable, a trial of PPIs would be
wise before launching and expensive workup. Routine tests include a
CBC, urinalysis, chemistry panel, VDRL test, thyroid profile, serum B
12
and folic acid, an upper GI series, esophagogram, and stools for occult
blood and ovum and parasites. A lactose tolerance test can be helpful. The
next step is a cholecystogram or gallbladder ultrasound.
If these studies are negative, a gastroenterologist should be consulted.
He/she will do esophagoscopy, gastroscopy, and duodenoscopy. He/she
may also perform esophageal motility studies or esophageal pH
375

monitoring. A Bernstein test may be of value in solving the diagnostic
dilemma. He/she may also want to order a CT scan of the abdomen or a
small bowel series.
376

1. 
  2. 
  3. 
INFERTILITY, FEMALE
 Abnormalities
found on the pelvic examination are cervicitis, stenosis of the cervix,
fibroids, retroverted uterus, tubo-ovarian abscesses, and polycystic
ovaries.
Turner’s syndrome, Simmonds’ disease, Fröhlich’s syndrome, and
virilism may exhibit abnormal secondary sex characteristics.
Are there other abnormalities in endocrine examination?
 The
physical examination may disclose hypothyroidism, hyperthyroidism,
Simmonds’ disease, or acromegaly.
Routine studies include a CBC, urinalysis, urine culture and colony count,
chemistry panel, thyroid profile, VDRL test, and a vaginal smear and
culture. Cervicitis should be biopsied and treated. The next logical step is
to obtain a specimen of semen from the husband for sperm count.
If the above tests are negative, referral to a gynecologist is in order. If
one is not available, further workup can be done, including a serum FSH
and LH, serum estradiol, and serum progesterone to determine the
presence of pituitary or ovarian causes of ovulatory dysfunction. A
hysterosalpingogram can be done. The patient can keep a temperature
chart to determine if ovulation occurs. Cervical mucus studies can be done
for spinnbarkeit testing and ferning, and the presence of significant white
cells should be noted. Pelvic ultrasound may be done, and laparoscopy
may be necessary to rule out other conditions that may affect fertility. A
trial of clomiphene citrate may be given. Endometrial biopsy may also
contribute to solving the diagnostic dilemma.
377

1. 
  2. 
  3. 
INFERTILITY, MALE
Are there abnormalities on examination of the external genitalia
and prostate?
 The abnormalities that need to be looked for are
Klinefelter’s syndrome, epididymitis, testicular atrophy, urethritis, and
prostatitis.
Are there abnormalities on the endocrine examination?
 The
general endocrine examination may reveal hypothyroidism,
hyperthyroidism, or hypopituitarism.
Are there stress factors that need to be considered such as marital
difficulties or overwork?
 Overwork and marital difficulties may lead
to drug addiction and alcoholism, among other problems. All these
affect fertility.
Routine laboratory tests include a CBC, urinalysis, chemistry panel,
thyroid profile, VDRL test, and sperm count. If there is a urethral
discharge, a smear and culture should be done. If the sperm count reveals
oligospermia or antisperm autoantibodies on two separate specimens,
referral should be made to an urologist or endocrinologist for further
evaluation.
Additional tests that can be ordered include blood tests for LH, FSH,
and testosterone. Additional tests of pituitary function may be indicated.
Karyotype testing and sperm function tests may be needed. If these are
normal, a testicular biopsy may need to be done. Ultrasonography of the
testicles may be helpful.
379

1. 
  2. 
  3. 
INGUINAL SWELLING
 If the inguinal swelling is reducible, a femoral hernia
or inguinal hernia should be suspected.
 If the mass transilluminates, it is probably a
hydrocele and may be a hydrocele of the cord or a hydrocele of
Nuck’s canal.
Is it tender?
 Tenderness in the groin may signify an abscess,
hematoma, lymphadenitis, a strangulated hernia, or an obturated
hernia.
VDRL test, and an x-ray of the hips and pelvis. A bone scan may be
helpful in ruling out a psoas abscess. Arteriography may be helpful for
diagnosing aneurysm. Venography or Doppler ultrasonography will help
diagnose saphenous varix. Needle aspiration may be necessary to diagnose
an abscess. Exploratory surgery will be necessary in most cases for both
diagnosis and treatment.
381

1. 
  2. 
  3. 
  4. 
INSOMNIA
 If there is a history of dyspnea, heart disease or
lung disease should be suspected.
 There are many
drugs that may cause insomnia, including the amphetamines,
theophylline, caffeine, anticonvulsants, nicotine, thyroid hormones,
and the sympathomimetics. Alcohol may induce sleep, but patients
complain of early morning wakening.
Is there a history of a painful condition?
 Abscessed teeth, arthritis,
sciatica, bone metastasis, hiatal hernia, and esophagitis are just a few
of the conditions that may keep a patient awake because of pain.
Are there other psychiatric symptoms?
 Anxiety, loss of libido, loss
of appetite, and depression may be associated with hyperthyroidism,
general paresis, organic brain syndrome, chronic anxiety, and
endogenous depression. In the elderly, look for restless leg syndrome
and periodic limb movement disorder.
The first thing to do is to eliminate caffeinated beverages and chocolate.
Routine studies include a CBC, sedimentation rate, urinalysis and drug
screen, chemistry panel, thyroid profile, VDRL test, EKG, and a chest x-
ray. Arterial blood gases and pulmonary function testing should be done to
rule out pulmonary disease. A venous pressure and circulation time will
help rule out early congestive heart failure. Blood pressure monitoring can
be used to rule out paroxysmal hypertension. If an organic brain syndrome
is suspected, a CT scan or an MRI of the brain should be done. If
psychiatric symptoms are present, the patient should be referred to a
psychiatrist. Alternatively, a therapeutic trial of psychotherapeutic agents
may be initiated if the patient is not suicidal. When all of the above
diagnostic tests are negative, a sleep study must be done. However, home
monitors for apnea and oxygen desaturation are available and may be an
inexpensive alternative to rule out obstructive sleep apnea.
383

1. 
  2. 
INTERMITTENT CLAUDICATION
Are the tibialis or dorsalis pedis pulses diminished?
 If so, you
should consider peripheral arteriosclerosis or thrombosis of the
terminal aorta (Leriche’s syndrome) as the cause.
Are the femoral pulses diminished or is there a bruit over the
femoral artery?
 This would further confirm that the cause is
Leriche’s syndrome.
If the pulses are not diminished, is there a history of low back pain? If
yes, then there is a strong possibility that spinal stenosis is the cause. If no,
consider the possibility of peripheral neuropathy, drugs, hypocalcemia or
hypomagnesemia, even though the cramping pain is atypical in these
conditions.
Rule out systemic causes with a CBC, chemistry panel, serum magnesium,
Lipid panel, T
4
 and TSH and urinalysis. Regardless of whether the
peripheral pulses are diminished ultrasonography of the aorta, femoral,
dorsalis pedis, and tibialis arteries is the next step. An ankle-brachial index
is an excellent screening test but this alone will miss the diagnosis in
lumbar spine disorders. If the ultrasound study is equivocal, CT
angiography or MRA may settle the issue but catheter contrast
angiography may still be necessary. If these studies are negative, an MRI
of the lumbar spine should be done. In fact if the patient’s chief complaint
includes low back pain, this may be the study to order first. An NCV may
be ordered to rule out peripheral neuropathy. Some authorities would also
order a CT scan of the pelvis to rule out pelvic tumor, especially if a
thorough vaginal exam is difficult (as in obese patients).
385

INTRACRANIAL OR CERVICAL BRUIT
Intracranial bruits may be because of a carotid cavernous sinus fistula or a
cerebral angioma. It may also be because of a congenital arteriovenous
anomaly. A cerebral aneurysm is rarely big enough to cause a bruit. Severe
anemia may cause intracranial bruits without localized pathology being
responsible. All intracranial bruits should be investigated with an MRI and
angiography unless some systemic disease is found (e.g., anemia) that
would explain the sign.
Cervical bruits may be because of carotid stenosis, hyperthyroidism, a
venous hum, or aortic stenosis with transmission of the bruit to the vessels
in the neck. If hyperthyroidism and aortic stenosis can be excluded, a
carotid duplex scan, an MRA and possibly 4-vessel angiography can be
done to look for significant carotid stenosis. There is a controversy over
whether asymptomatic carotid stenosis should be operated on.
Nevertheless, a thorough workup should be done so the clinician knows
what he/she is dealing with.
387

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
JAUNDICE
A 42-year-old white male presents to your office because his family noted
a yellowish tinge to his skin and eyeballs. You ask about fever and chills
or abdominal pain, and he has none.
On examination, he shows icteric sclera, mild hepatomegaly, but no
enlargement of the gallbladder or spleen. There is no ascites or pedal
edema. Looking at the algorithm, you see that there are three possibilities
left: Primary or metastatic carcinoma, toxic hepatitis, and biliary cirrhosis.
On further questioning, you find out he has been on ranitidine for reflux
esophagitis. Withdrawal of the medication results in the clearing of his
jaundice.
Is the jaundice associated with hepatomegaly?
 There is little or no
hepatomegaly associated with hemolytic anemia, pernicious anemia,
Gilbert’s disease, and Dubin–Johnson syndrome.
Is the hepatomegaly massive?
 Massive hepatomegaly is associated
with Gaucher’s disease.
Is there associated fever, right upper quadrant pain, or a tender
liver?
 These findings would suggest viral hepatitis, cholecystitis,
infectious mononucleosis, leptospirosis, ascending cholangitis, hepatic
vein thrombosis, and toxic hepatitis.
Is the gallbladder enlarged?
 The finding of an enlarged gallbladder
with the jaundice suggests obstructive jaundice, carcinoma of the
pancreas, carcinoma of the bowel ducts, or ampulla of Vater.
Is there skin pigmentation?
 The presence of skin pigmentation that
is not bilirubin suggests hemochromatosis.
 The presence of significant splenomegaly
suggests infectious mononucleosis, cirrhosis of the liver, hemolytic
anemia, Gaucher’s disease, kala azar, or agnogenic myeloid
metaplasia.
Is there edema and ascites?
 The presence of edema and ascites
suggests alcoholic cirrhosis.
388

The basic workup includes a CBC, sedimentation rate, reticulocyte count,
red cell fragility test, coagulation profile, urinalysis, chemistry panel, lipid
panel, VDRL test, EKG, a chest x-ray, and flat plate of the abdomen.
If infectious hepatitis is suspected, a hepatitis profile, febrile
agglutinins, Monospot test, cytomegalic virus antibody titer, and
leptospirosis antibody titer should be done. The diagnosis of viral hepatitis
is confirmed by the finding if IgM antibodies to the type of virus (A, B,
etc.). If lupoid hepatitis is suspected, a test for antinuclear antibodies and a
smooth muscle antibody should be done. Toxic hepatitis, as in the case
above, may be confirmed by a steroid white wash.
If hemochromatosis is suspected, a serum iron, iron-binding capacity,
and ferritin should be done. Wilson’s disease is confirmed by ordering a
serum copper and ceruloplasmin.
If hemolytic anemia is suspected, serum haptoglobins, hemoglobin
electrophoresis, and sickle cell preparations may be done.
If obstructive jaundice is suspected, a gallbladder ultrasound should be
done to rule out gallstones and a CT scan or an MRI of the abdomen may
be done to look for GI neoplasm. An upper GI series may assist in finding
a primary neoplasm in the GI tract.
ERCP or percutaneous transhepatic cholangiography will assist in
determining whether there is definitely obstructive jaundice and whether it
is because of a surgically resectable lesion. Peritoneoscopy can also be
helpful. An exploratory laparotomy will probably be necessary regardless
of whether one performs the above tests. Magnetic resonance
cholangiopancreatography and endoscopic ultrasonography are the two
newer methods that may be used to evaluate the biliary tree and pancreatic
ducts, especially when a neoplasm is suspected.
Hepatocellular jaundice will often require a needle biopsy of the liver
to pin down the diagnosis. Antimitochondrial antibodies will need to be
ordered to screen for biliary cirrhosis. An alpha-1-fetoprotein will help
diagnose hepatocellular carcinoma. By the time you have reached this
point, you have gone to considerable expense in the diagnostic workup. It
would be much more prudent to ask for a gastroenterology consultation
before ordering all these expensive diagnostic tests.
389

1. 
  2. 
  3. 
JAW PAIN
 A
thorough examination of the teeth and gums may disclose dental
caries, gingivitis, oral tumors, or alveolar abscess.
Is the pain intermittent?
 Intermittent pain should suggest a
trigeminal neuralgia or glossopharyngeal neuralgia.
 The presence of a rash would suggest herpes zoster.
Be sure to examine the eardrum for Ramsay Hunt’s syndrome.
panel, arthritis panel, and an x-ray of the teeth and jaw. An x-ray of the
sinuses may be helpful. At this point of time, referral to a dentist or oral
surgeon should be made if there is still diagnostic difficulty. He may order
an MRI of the temporomandibular joint, which is the procedure of choice
in evaluating this joint. If all tests are negative or equivocal, perhaps a
psychiatric referral is in order.
391

1. 
  2. 
  3. 
  4. 
JAW SWELLING
Is the swelling focal or diffuse?
 Focal jaw swelling should suggest
alveolar abscess, gingivitis, adamantinoma, actinomycosis,
epithelioma, a cyst, osteoma, odontoma, or epulis.
 Painful jaw swelling should suggest alveolar abscess,
gingivitis, actinomycosis, adamantinoma, cellulitis, fracture,
hematoma, necrosis of the jaw, or osteomyelitis.
Is there enlargement of the hands and feet?
 Enlargement of the
hands and feet should suggest acromegaly.
 This would point to a stone in Stensen’s duct.
Routine tests include a CBC, urinalysis, sedimentation rate, chemistry
panel, arthritis panel, and an x-ray of the jaw and teeth. An x-ray of the
skull and long bones and a serum growth hormone should be done, if
acromegaly is suspected. PTH assay and x-ray of the skull and long bones
should be done, if osteitis fibrosa cystica is suspected. Referral to a dentist
or oral surgeon should be made, if there is still diagnostic confusion at this
point of time.
393

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
JOINT PAIN
A 23-year-old white male complains of painful wrists and knees of 4 days
duration. Following the algorithm, you look for fever and his temperature
is 101.3°F.
Your examination shows that his right conjunctiva is red and he has a
purulent urethral discharge which on microscopic examination shows
Gram-positive diplococci. What is your diagnosis?
Is the joint pain localized to a single joint?
 Localization to a single
joint should suggest a septic arthritis, gout, tuberculosis, hemophilia,
sickle cell disease, trauma, avascular necrosis, and pseudogout.
Monoarthritis that is sudden in onset should be considered a septic
joint until proven otherwise.
 The presence of fever should make one think of septic
arthritis, rheumatic fever, gonococcal arthritis, Reiter’s syndrome,
lupus erythematosus, Lyme arthritis, polymyalgia rheumatica, Still’s
disease, and rheumatoid arthritis.
Is there a urethral discharge?
 The presence of a urethral discharge
should make one think of Reiter’s syndrome or gonococcal arthritis.
 The presence of low back pain should
suggest rheumatoid spondylitis, ochronosis, and gout.
Is the arthritis migratory?
 The presence of migratory arthritis should
make one think of rheumatic fever and rat-bite fever. Multiple joint
involvement with oral or genital ulcers suggests Behçet’s disease.
 Younger patients may have sickle
cell disease, hemophilia, trauma, rheumatic fever, Still’s disease, and
gonococcal arthritis. Older patients are more likely to have
osteoarthritis, polymyalgia rheumatica, and gout. It should be noted
that there is considerable overlap here.
Routine studies include a CBC, sedimentation rate, ASO titer, ANA,
ANCA, CRP, uric acid, urinalysis, chemistry panel, arthritis panel, and x-
ray of the involved joints. The anti-citrullinated protein antibody (ACPA)
395

is more specific for rheumatoid arthritis than the R-A titer. It is also wise
at times to order a bone survey. Synovial fluid analysis and culture should
be done, if there is sufficient joint effusion. A trial of therapy may be
initiated at this point and will assist in the diagnosis. For example, a course
of colchicine may be given to rule out gout.
If there is still doubt, a rheumatology consultation should be made.
Other tests that may be done include a gonococcal antibody titer and a
coagulation profile. If there is a urethral discharge, a smear and culture of
the material should be made. If there is fever, febrile agglutinins, serologic
tests for Lyme disease, brucellin antibody titer, blood cultures, and a
Monospot test may be done. If collagen disease is suspected, antinuclear
antibodies and anti-DNA antibodies may be sought. If sickle cell anemia is
suspected, a sickle cell preparation should be done. A bone scan will help
diagnose rheumatoid spondylitis and ochronosis. A urine for homogentisic
acid will also diagnose ochronosis. An MRI may diagnose a torn meniscus
and other conditions.
396

Table 12: Joint Pain
a
Especially gonococcal.
397

1. 
  2. 
  3. 
  4. 
  5. 
JOINT SWELLING
Is it painless?
 The presence of joint swelling without pain, especially
on motion, would suggest Charcot’s disease.
Is the involvement primarily in small or large joints?
 Involvement
of the small joints is characteristic of rheumatoid arthritis, gonococcal
arthritis, and Reiter’s syndrome. Involvement of the larger joints is
more characteristic of gout and osteoarthritis. However, osteoarthritis
and rheumatoid arthritis may involve both.
Is the involvement symmetrical or asymmetrical?
 Asymmetrical
involvement is more typical of gout, rheumatic fever, hemophilia,
neoplasm, septic arthritis, and trauma. Symmetrical involvement is
more characteristic of rheumatoid arthritis and osteoarthritis.
rheumatic fever, gonococcal arthritis or other types of septic arthritis,
Reiter’s syndrome, rheumatoid arthritis, and lupus erythematosus.
 The younger patients with joint
swelling most likely have gonococcal arthritis, lupus erythematosus,
rheumatoid arthritis, and hemophilia. Gout, osteoarthritis, and
neoplasm are more common in older patients. However, there is
considerable overlap here.
Routine tests include a CBC, sedimentation rate, ASO titer, CRP, ANA,
urinalysis, chemistry panel, arthritis panel, and x-ray of the involved joints.
It is also wise to do a bone survey when there is multiple joint
involvement. A synovial fluid analysis and culture may be done, if there is
sufficient joint fluid. A trial of therapy can be initiated and may be
diagnostic particularly in gonococcal arthritis. At this point, it is wise to
refer the patient to a rheumatologist for further evaluation. Additional tests
that may be ordered are found on 
page 310
. Polarized microscopy may
reveal positive birefringent crystals of pseudogout.
398

1. 
  2. 
  3. 
  4. 
  5. 
KNEE PAIN
 Transient knee pain may be because of rheumatic
fever, sarcoidosis, palindromic rheumatism, or trauma.
 Unilateral knee pain would suggest gout,
septic arthritis, bursitis, hemophilia, pseudogout, osteogenic sarcoma,
and traumatic conditions, such as torn meniscus, hemarthrosis, sprain
of collateral ligaments, and fracture.
 History of trauma would suggest a
sprain, torn meniscus, bruise, or fracture. Perform a McMurray test,
posterior drawer test, and Lachman test. Iliotibial band syndrome,
compartment syndrome, and patellofemoral syndrome are important to
consider in athletes, especially gymnasts and ballet artists.
Are there prominent systemic symptoms?
 If there are prominent
systemic symptoms, one should consider lupus erythematosus,
Reiter’s disease, rheumatoid arthritis, other collagen disease, scurvy,
and rheumatic fever.
 Younger patients are more likely to
have traumatic conditions, such as fracture, sprains, bruises, or a torn
meniscus. Osgood–Schlatter disease would be more typical of patients
in their early teens. Patients in their 20s are more likely to have
rheumatoid arthritis, Reiter’s disease, and lupus erythematosus,
whereas patients in the fourth or fifth decade and older would be more
likely to have osteoarthritis, gout, and pseudogout.
Routine studies include a CBC, sedimentation rate, ASO titer, ANA, CRP,
urinalysis, chemistry panel, arthritis panel, and x-ray of the involved joint.
An x-ray may show a fracture, osteoarthritic changes, and punched-out
lesion of gout or chondrocalcinosis (suggesting pseudogout). Stress
fractures usually will not be evident on plain films. In these cases, a
nuclear bone scan is necessary. It is also wise to do a bone survey.
Synovial fluid analysis and culture may be done, if there is sufficient joint
fluid. The ACPA is a new test that is more sensitive than the rheumatoid
arthritis test. A trial of therapy can be initiated and may be diagnostic.
If further diagnostic workup needs to be done at this point of time, it is
most cost-effective to refer the patient to a rheumatologist or an orthopedic
400

surgeon before ordering an MRI or other studies. He/she may want to do
an arthroscopic examination before proceeding with other tests for arthritic
conditions. For further workup of knee pain, see 
page 310
.
401

1. 
  2. 
  3. 
  4. 
  5. 
KNEE SWELLING
 Painless swelling of the knee is probably a Charcot’s
joint.
 Unilateral knee swelling is most likely
because of trauma, gout, pseudogout, hemophilia, septic arthritis,
tuberculosis, osteogenic sarcoma, torn meniscus, or osteomyelitis.
Bilateral swelling of the knee is more commonly seen in osteoarthritis,
lupus erythematosus, Reiter’s disease, and rheumatoid arthritis.
 The presence of fever suggests septic arthritis,
rheumatic fever, rheumatoid arthritis, osteomyelitis, lupus
erythematosus, and Reiter’s disease.
 Systemic symptoms suggest lupus
erythematosus, rheumatoid arthritis, and Reiter’s disease, as well as
rheumatic fever.
 Knee swelling in younger patients is
more likely to be because of rheumatic fever, septic arthritis, lupus
erythematosus, Reiter’s disease, and rheumatoid arthritis. Older
patients are more likely to be affected with gout, pseudogout, and
osteoarthritis. Osteogenic sarcoma seems to occur between the ages of
5 and 25 years in most cases.
Routine diagnostic tests include CBC, sedimentation rate, urinalysis,
chemistry panel, arthritis panel, VDRL test, and x-ray of the involved joint
or joints. A bone survey should probably also be done. If there is
significant swelling, an arthrocentesis for synovial fluid should be done
and the fluid analyzed and cultured. A therapeutic trial may be initiated at
this point and can assist in the diagnosis.
If there is still doubt about the diagnosis, referral to a rheumatologist or
an orthopedic surgeon should be made before ordering an MRI or
expensive diagnostic tests. An orthopedic surgeon may perform fiberoptic
arthroscopy to diagnose the problem. Additional diagnostic tests to order
in cases of knee swelling may be found on 
page 310
.
402

1. 
  2. 
  3. 
KYPHOSIS
Is there a history of chronic cough?
 A history of cough would
suggest tuberculosis of the spine, emphysema, and metastatic
carcinoma.
What is the sex of the patient?
 If the patient is a woman in her 40s,
menopausal osteoporosis should be suspected.
kyphosis because of rickets, leukopolysaccharidosis, Hurler’s disease,
Scheuermann’s disease, Pott’s disease, or Morquio’s disease. Adults
are more likely to suffer from osteoarthritis, Paget’s disease,
Parkinson’s disease, osteomalacia, osteoporosis, and ankylosing
chemistry panel, arthritis panel, tuberculin test, and x-ray of the chest,
thoracic spine, lumbar spine, and the hips. If there is a productive cough, a
sputum for AFB smear and culture should be made.
If muscular disease is suspected, a muscle biopsy may be done. If
menopause is suspected, a serum FSH and LH and serum estradiol can be
done. A bone scan may identify pathologic fractures and ankylosing
spondylitis. An HLA B27 antigen test should be ordered, if ankylosing
spondylitis is suspected. A bone biopsy may clear up the diagnostic
dilemma.
404

1. 
  2. 
  3. 
  4. 
LACTIC DEHYDROGENASE ELEVATION
What is the level of creatine phosphokinase isoenzyme containing
M and B subunits (MB-CPK)?
 An elevated MB-CPK combined
with elevated LDH is most likely because of a myocardial infarction,
although myocarditis and pericarditis can produce a similar picture.
What is the AST level?
 If the MB-CPK or CPK are not also
increased, an elevation of both the LDH and AST would point to liver
disease.
What are the serum and urine creatine levels?
 If these are elevated,
muscle disease must be considered likely.
What does the lung scan show?
 If positive, a lung scan separates
pulmonary infarction from the other conditions in this group.
The diagnostic workup should include a CBC, urinalysis, chemistry panel,
sedimentation rate, CRP, ANA, urine and serum creatine, urine
myoglobin, serial EKGs, blood gas analysis, LDH isoenzymes, troponin C,
a chest x-ray, lung scan, EMG, and cardiology and neurology consults. A
liver scan, CT scan of the abdomen and liver, and muscle biopsy may be
406

1. 
  2. 
  3. 
LEG ULCERATION
Are the peripheral pulses diminished or absent?
 Presence of poor
peripheral pulses suggests arteriosclerosis, diabetes mellitus,
Buerger’s disease, and femoral artery thrombosis.
Neurologic disorders associated with leg ulceration include tabes
dorsalis, diabetic neuropathy, hemiplegia, and many other disorders.
Is there a positive smear or culture of the material from the ulcer?
A positive smear or culture of material from the ulcer may be found in
osteomyelitis, tuberculosis, syphilis, anthrax, and other fungal
diseases.
Routine studies include a CBC, sedimentation rate, sickle cell preparation,
urinalysis, chemistry panel, VDRL test, smear and culture of the material
from the ulcer, and x-ray of the involved area. A biopsy may be necessary
to establish the diagnosis. Rarely, a dark field examination will be
necessary. Ultrasonography, catheter arteriography or venography may
establish the level of arterial or venous obstruction. A bone scan or an MRI
will help pin down the diagnosis of osteomyelitis.
408

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
LEUCOCYTOSIS
Is the red cell count and platelet elevated?
polycythemia vera or hemoconcentration.
Are the neutrophils increased?
 This would suggest a bacterial
infection, leukemia, or corticosteroid therapy.
Is there an increased percentage of lymphocytes?
 This would
suggest a viral infection, infectious mononucleosis, or lymphatic
leukemia.
Is there an increased percentage of monocytes?
 Obviously, in this
situation one should consider a monocytic leukemia, but severe
infections can also present this picture.
Is the percentage of eosinophils increased?
 Allergic disorders
(asthma, etc.) and parasitic disease present this picture.
Is the percentage of basophils increased?
chronic myelogenous leukemia and other blood dyscrasias.
On physical examination, one should look for a source of infection.
Prostatic abscess and tubo-ovarian abscess are often missed. If there is a
massive splenic enlargement, the possibility of myeloid metaplasia or
chronic myelogenous leukemia must be considered. Cultures should be
taken of all body fluids and an unspun drop of urine looked at under the
microscope. If there are motile bacteria, it is safe to say that there are more
than 100,000 colonies/mL, which is a clear indication of a UTI. A
sedimentation rate, chemistry panel, blood and bone marrow smear
examination, serial blood cultures, blood smears for malarial parasites, and
Monospot test, all have their place in the workup, but a hematology
consult is wise before undertaking more expensive tests.
410

1. 
  2. 
  3. 
LEUCOPENIA
Are the red blood cell (RBC) and platelet counts decreased?
 If so,
this suggests hypersplenism, aplastic anemia, aleukemic leukemia,
myelophthisic anemia, megaloblastic anemia, or paroxysmal nocturnal
hemoglobinuria. If not, one should look for a viral infection,
agranulocytosis, or idiopathic leucopenia.
Is there an enlarged spleen?
 An enlarged spleen should suggest
hypersplenism of various causes, even though it may be associated
with the other disorders listed above on occasion.
What is the serum B
12
 
level?
 A decreased serum B
12
 will separate
pernicious anemia from the other disorders on the list.
A CBC, sedimentation rate, chemistry panel, serum protein
electrophoresis, urinalysis, platelet count, serum haptoglobins, serum B
12
and folic acid, and Donath–Landsteiner test may need to be done. A
hematologist should be consulted before ordering a bone marrow
examination, liver–spleen scan, CT scan, or other expensive tests.
412

1. 
  2. 
  3. 
LIP PAIN
Is there ulceration or swelling?
 Presence of ulceration would suggest
herpes simplex, syphilis, and carcinoma. Swelling would suggest there
was trauma, a carbuncle, insect bites or stings, and angioneurotic
edema.
 The presence of a rash would suggest herpes zoster,
particularly if it is unilateral.
Is there a history of trauma, insect bite, or sting?
 These historical
findings are important in determining, if the swelling is because of
trauma, insect bites, or stings.
Routine studies include a CBC, sedimentation rate, urinalysis, chemistry
panel, VDRL test, and culture of any material that can be obtained from
ulceration, if present. A therapeutic trial of antibiotics or antiviral
medication can be done at this point. If this is unsuccessful, the patient
should be referred to an oral surgeon or a dermatologist.
414

1. 
LIP SWELLING
Is it painful or nonpainful?
 Painful swelling of the lip is more likely
to be herpes zoster, herpes simplex, pyoderma granulosa, insect bites
or stings, alveolar abscess, and trauma. Painless swellings of the lip
are more likely because of syphilis, allergic urticaria, angioneurotic
edema, contact dermatitis, carcinoma, myxedema, and cretinism.
chemistry panel, VDRL test, and culture of any material that can be
obtained from an ulcer if present. An x-ray of the teeth and jaw also may
be necessary. A therapeutic trial of antibiotics or antiviral therapy can be
tried. If this is unsuccessful, a referral to an oral surgeon or a dermatologist
should be made.
415

LORDOSIS
This is often a congenital effusion or backward curvature of the spine
causing the person to appear “high and mighty.” However, it may be seen
in untreated bilateral congenital dislocation of the hips, muscular
dystrophy, tuberculosis, and spondylolisthesis. Lordosis is also seen in
orthostatic albuminuria and chondrodystrophy.
An x-ray of the lumbosacral spine and hips will usually establish the
diagnosis in cases of congenital dislocation of the hips and
spondylolisthesis. A family history and muscle biopsy will assist in the
diagnosis of muscular dystrophy.
416

1. 
  2. 
  3. 
LYMPHADENOPATHY
 Many drugs can cause
lymphadenopathy; the most notable is Dilantin, but the antibiotics,
aspirin, iodides, and certain antihypertensive drugs can also cause
lymphadenopathy.
Is the lymphadenopathy focal or diffuse?
 If the adenopathy is focal,
one should look for an infectious process in the area supplied by the
respective lymph nodes. For example, if there is occipital node
enlargement, one would look for ringworm, dermatitis of the scalp,
furunculosis, pediculosis, and cellulitis. However, infectious
mononucleosis and rubella may begin with enlargement of these
nodes.
infectious mononucleosis, brucellosis, dengue fever, toxoplasmosis,
and Still’s disease, among other diseases. Is the adenopathy primarily
cervical? In these cases, consider infectious mononucleosis, strep
throat, and Kawasaki disease.
Routine diagnostic tests include a CBC, sedimentation rate, nose and
throat culture, and culture of material from any area supplied by the
enlarged lymph nodes. Blood cultures are indicated in generalized
lymphadenopathy. In addition, a chemistry panel should be done, as well
as a heterophile antibody titer, brucellin antibody titer, febrile agglutinins,
and VDRL test. A chest x-ray and flat plate of the abdomen may be
helpful in diagnosing generalized lymphadenopathy. HIV testing is done in
patients with a history of high-risk sexual behavior.
An x-ray of the long bones or a bone scan may identify metastatic
carcinoma, and an x-ray of the hands may identify sarcoidosis. A bone
marrow examination may identify leukemia or lymphoma. If an infectious
process has been ruled out, biopsy of the local node may turn up metastatic
carcinoma, Hodgkin’s disease, and sarcoidosis. A tuberculin skin test
should be done; a Brucellergen skin test and Kveim test may also need to
be done. ANA and rheumatoid arthritis factor testing may need to be done
to rule out a collagen disease. A lymphangiogram may turn up a
lymphosarcoma or multiple metastatic lymph nodes. Liver biopsy is also
417

occasionally necessary. Imaging studies of the abdomen and pelvis and the
mediastinum are occasionally necessary. Mediastinoscopy may facilitate
getting a tissue diagnosis. Before ordering these, consultation with a
hematologist or an infectious disease specialist would be prudent.
418

1. 
  2. 
  3. 
  4. 
MELENA
Is it true or false melena?
 False melena may be induced by iron
ingestion, bismuth ingestion, charcoal ingestion, red wine ingestion,
and many other substances.
 It is surprising how
often the ingestion of alcohol is overlooked. Aspirin, other NSAIDs,
caffeine, anticoagulants, and reserpine are among the other drugs that
may cause melena.
Is there associated hematemesis?
 The presence of hematemesis
should prompt a search for esophageal varices, peptic ulcer, gastritis,
and many other conditions. For a more thorough discussion of this
topic, one is referred to the section on hematemesis (
page 236
).
 The presence of abdominal pain and
heartburn should make one think of duodenal ulcer, esophagitis,
gastritis, gastric ulcer, mesenteric embolism or thrombosis, and
Meckel’s diverticulum. However, the absence of abdominal pain
would be more consistent with a blood dyscrasia or hereditary
telangiectasia.
chemistry panel, coagulation panel, VDRL test, and stool for occult blood.
Recently, a more sensitive test for blood in the stool called the fecal
immunochemical test has been introduced. A stool for ovum and parasites
may also need to be done. If these tests are inconclusive, an upper GI
series and esophagogram would be the next step. Perhaps a small bowel
series should be added to the above studies.
If all of these tests are negative or still inconclusive, referral to a
gastroenterologist should be made. The gastroenterologist will probably
perform panendoscopy and resolve the diagnostic dilemma. Occasionally,
a fluorescein string test may be useful. A radioactive scan following
intravenous chromium or technetium-99 may show the site of bleeding in
obscure cases. CT angiography is another excellent method that may be
utilized to show the site of bleeding. When bleeding continues despite
therapy, mesenteric angiography, or splenic venography may assist in the
diagnosis. Exploratory laparotomy may be necessary in some cases.
419

Needless to say, a gastroenterologist should be consulted before
undertaking this.
420

1. 
  2. 
  3. 
  4. 
MEMORY LOSS
You are called to the urology ward to evaluate a 52-year-old Hispanic
male who developed confusion and disorientation following a radical
prostatectomy for prostatic carcinoma 4 weeks ago.
Following the algorithm, you find no history of trauma. His family
denies he has ever abused alcohol or drugs. Looking over the list of drugs
he is on, you fail to find anything that will likely cause delirium or
memory loss. However, he has had frequent loose stools post-operatively
and examination of his extremities discloses a maculopapular eruption.
You suspect pellagra and begin him on a course of vitamin B complex
which clears his symptoms.
 A history of trauma would suggest
concussion, intracranial hematoma, and posttraumatic epilepsy, among
other conditions.
 Chronic alcoholism
is associated with Korsakoff’s syndrome and Wernicke’s
encephalopathy. Drugs such as bromides, barbiturates, cocaine, and
LSD may induce memory loss. Heavy metals such as lead may cause a
chronic encephalopathy with memory loss.
Are there systemic signs and symptoms?
 If there is anemia and
memory loss, one should consider pernicious anemia. Pellagra,
beriberi, myxedema, lupus erythematosus, uremia, and liver failure
may be associated with memory loss.
Are there other focal neurologic signs?
 Extrapyramidal symptoms
may be found in Wilson’s disease, Huntington’s chorea, and
Parkinson’s disease. Long tract signs may be found in multiple
sclerosis, Creutzfeldt–Jakob disease, general paresis, and normal
pressure hydrocephalus. When there is memory loss without focal
neurologic signs, Alzheimer’s disease and Pick’s disease should be
considered, as well as malingering.
It is wise to start with simple tests of mental status such as the Kendrick
421

cognitive tests for the elderly or Mini-Mental Status Examination. Routine
laboratory tests include a CBC, sedimentation rate, urinalysis, chemistry
panel, ANA, serum B
12
 and folic acid, and VDRL test. In the elderly, a
chest x-ray should be done to look for a primary neoplasm. A urine drug
screen is essential.
If these studies are negative, the patient may be referred to a
neurologist, or a CT scan or an MRI may be done. The neurology
consultation is much less expensive. Ultimately, a spinal tap may need to
be done to look for multiple sclerosis and central nervous system lues. A
lumbar isotope cisternography may need to be done to rule out normal
pressure hydrocephalus. A referral to a psychologist can be made for
psychometric testing.
422

1. 
  2. 
  3. 
MENORRHAGIA
Is there persistent or recurring abdominal or pelvic pain?
 The
presence of pain with menorrhagia should make one suspect PID,
endometriosis, and ectopic pregnancy.
Are there abnormalities on the pelvic examination?
 The pelvic
examination will usually be positive in cases of uterine fibroid,
pregnancy, cervical polyp, PID, and ectopic pregnancy. Endometriosis
may not always be detected on pelvic examination.
Is there anemia or other systemic symptoms or signs?
 The clinician
should remember that iron deficiency anemia, hypothyroidism, lupus
erythematosus, and cirrhosis of the liver are just a few of the systemic
conditions that may present with menorrhagia.
Routine studies include a CBC, sedimentation rate, urinalysis, pregnancy
test, chemistry panel, ANA titer, VDRL test, coagulation profile, thyroid
profile, and flat plate of the abdomen. A Pap smear and vaginal smear and
culture should be done.
If these tests are negative, referral to a gynecologist should be made
before undertaking expensive tests such as pelvic ultrasound or CT scan of
the abdomen and pelvis. Some clinicians will probably ignore this advice.
A gynecologist will often be able to resolve the diagnostic dilemma with a
good pelvic examination. Laparoscopy, culdocentesis, endometrial biopsy,
and dilation and curettage are just a few of the diagnostic tools at his/her
disposal.
424

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
MENTAL RETARDATION
Is there decreased hair and skin pigment?
suggest phenylketonuria.
would suggest Klinefelter’s syndrome, Turner’s syndrome, and
Laurence–Moon–Bardet–Biedl syndrome.
Are there abnormalities of the skull present?
 Findings of
deformities or enlargement of the skull should suggest rickets,
microcephaly, hypertelorism, oxycephaly, and hydrocephalus, among
other things.
Is there hepatosplenomegaly?
 The findings of hepatosplenomegaly
suggest galactosemia, Hurler’s disease, and Gaucher’s disease, among
other diagnostic possibilities.
Are there skin changes?
 Sturge–Weber syndrome, tuberous sclerosis,
neurofibromatosis, and cretinism may present with skin changes.
Kernicterus is associated with jaundice.
 Tay–Sachs disease, congenital
syphilis, Arnold–Chiari malformation, and cerebral diplegia are just a
few of the causes of mental retardation that may present with other
neurologic signs.
Routine laboratory tests include a CBC, sedimentation rate, chemistry
panel, serum galactose level, VDRL test, thyroid profile, and urine screen
for carbohydrates, amino acids, and organic acids. Chromosomal analysis
may detect Klinefelter’s syndrome, Turner’s syndrome, mongolism, and
other disorders. If there are deformities of the skull present, a skull x-ray
should be done.
An EEG, a CT scan of the brain, and psychometric testing will often
need to be done, but a referral to a neurologist should be made before
ordering these expensive tests.
426

1. 
  2. 
  3. 
  4. 
METEORISM
Are there hyperactive bowel sounds?
 These findings should suggest
intestinal obstruction, and in that case one would look for strangulated
hernia, adhesions, volvulus, mesenteric embolism or thrombosis, and
other disorders. Perhaps the problem is a fecal impaction.
 Blood in the stool along with hyperactive
bowel sounds would suggest a mesenteric embolism or thrombosis or
intussusception.
 The clinician should keep in mind
that systemic diseases may present with meteorism. These include
diabetes mellitus, lobar pneumonia, typhoid fever, acute pancreatitis,
and steatorrhea.
 Spinal cord trauma and transverse
myelitis are among the many disorders that may present with
meteorism.
Routine laboratory tests include a stat CBC, sedimentation rate, serum
amylase and lipase, urinalysis, chemistry panel, stool for occult blood,
culture, ovum and parasites, and quantitative fat. A chest x-ray and flat
plate of the abdomen should also be done. If these tests are negative,
referral to a gastroenterologist or general surgeon is in order before
ordering CT scans, ultrasonography, or contrast radiography.
428

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
METRORRHAGIA
A 26-year-old white female, gravid 3 para 3 comes to your office for a
routine annual physical examination. On examination, you note a slight
amount of vaginal bleeding but no other abnormalities. When you bring
this to her attention, she admits she’s had irregular periods and spotting
between periods for some time now. She is not on birth control pills.
Following the algorithm, you look for pallor and find none. However,
she has a slight tension tremor and her pulse is 110 per minute. You
examine her neck and palpate a diffusely enlarged thyroid. A TSH and
 free
T
4
 
confirm your suspicion of hyperthyroidism.
Are there abnormalities found on the vaginal examination?
 An
enlarged uterus suggests pregnancy, fibroids, retained secundina,
hydatiform mole, choriocarcinoma, endometrial carcinoma, or
endometrial polyp. An adnexal mass suggests a granulosa cell tumor,
salpingitis, or ectopic pregnancy. Cervical lesions that cause
metrorrhagia are cervicitis, carcinoma of the cervix, and cervical
polyp. Vaginal lesions include vaginal carcinoma and senile vaginitis.
Is there a history of hormone therapy?
 If the patient has been taking
estrogen or progesterone, withdrawal or breakthrough bleeding should
be considered.
Is there pallor or other signs of anemia?
 Most types of anemia, but
particularly iron deficiency anemia, are associated with metrorrhagia.
Is there a history of tremor, tachycardia, or edema?
 Both
hyperthyroidism and hypothyroidism may be associated with
metrorrhagia.
Is there hirsutism or virilism?
 Look for an adrenal or ovarian
neoplasm and polycystic ovary syndrome in these cases.
If all of these questions fail to turn up any positive answers, then
dysfunctional uterine bleeding, collagen disease, or a coagulation
disorder should be strongly considered.
Is the patient past menopause?
 If so, then endometrial carcinoma
should be strongly considered.
430

In the authors experience ultrasonography should be performed when the
pelvic examination can’t be adequately performed especially in obese
women. Routine studies include a CBC, sedimentation rate, urinalysis,
pregnancy test, chemistry panel, ANA test, coagulation profile, thyroid
profile. A Pap smear and vaginal smear and culture for gonorrhea and
chlamydia should also be done.
If these are negative, referral to a gynecologist should be made before
undertaking expensive diagnostic tests such as pelvic or transvaginal
ultrasound, MRI or CT scans of the abdomen and pelvis. Alternatively, a
trial of cyclical estrogen and progesterone hormones may be done, if
dysfunctional bleeding is suspected before a referral is made. A
gynecologist may be able to resolve the diagnostic dilemma with a good
pelvic examination or, if that is unsuccessful, may perform laparoscopy or
culdocentesis. A dilation and curettage or office endometrial biopsy are
among the additional procedures at the gynecologist’s disposal. An
endocrinologist may be of help in deciding whether pituitary or ovarian
dysfunction is responsible. An FSH of greater than 40 mIU/mL suggests
ovarian failure. The endocrinologist may note hirsutism and order a free
testosterone and 17-hydroxy progesterone to rule out adrenal or ovarian
neoplasm.
431

1. 
  2. 
  3. 
  4. 
MONOPLEGIA
Are there hyperactive or pathologic reflexes of the involved
extremity?
 These findings suggest spinal cord tumor, parasagittal
tumor, amyotrophic lateral sclerosis, anterior cerebral artery occlusion,
spinal cord injury, transverse myelitis, and multiple sclerosis.
Are there decreased or absent reflexes of the involved extremity?
These findings suggest a herniated disk, a cauda equina tumor or early
cervical cord tumor, progressive muscular atrophy, brachial plexus
neuropathy, sciatic neuritis, or peripheral neuropathy.
Is the onset acute or gradual?
 An acute onset would suggest a
vascular lesion such as anterior cerebral artery occlusion, a spinal cord
injury, transverse myelitis, and multiple sclerosis. A gradual onset
suggests a space-occupying lesion such as spinal cord tumor,
parasagittal tumor, and degenerative diseases such as amyotrophic
lateral sclerosis.
Are there exacerbations or remissions?
exacerbations or remissions should suggest multiple sclerosis,
transient ischemic attack, and migraine.
Monoplegia of the upper extremities with hyperactive reflexes should
suggest the need to order a CT scan or an MRI of the brain and/or an MRI
of the cervical spine.
Monoplegia of the lower extremities with hyperactive reflexes or
pathologic reflexes would suggest the need to order MRI of the thoracic
spine. However, because an anterior cerebral artery occlusion or
parasagittal tumor may cause similar findings, a CT scan of the brain may
be necessary. Rather than make this difficult choice yourself, a neurologist
should be consulted. He/she may want to do a spinal fluid analysis or
evoked potential studies as well. If he/she believes a vascular lesion is
possible, then he/she may want to do a four-vessel angiography, MRA or
simply a carotid scan.
The findings of monoplegia with hypoactive reflexes, especially of
gradual onset, would suggest a radiculopathy, peripheral neuropathy, or
plexopathy. In the lower extremities, these findings would indicate the
need for a CT scan or an MRI of the lumbosacral spine. In the upper
432

extremities, these findings would suggest the need for an MRI of the
cervical spine.
A neuropathy workup is also indicated in monoplegia of the upper or
lower extremity (
page 378
). Nerve conduction velocity studies and EMG
studies of the involved extremities are also extremely valuable. The most
cost-effective approach is to refer the patient to a neurologist at the outset.
433

1. 
  2. 
MOUTH PIGMENTATION
Is there generalized pigmentation?
 The findings of generalized
pigmentation would suggest Addison’s disease, arsenic poisoning, and
occasionally hemochromatosis. When there is no generalized
pigmentation, one should suspect Peutz–Jeghers syndrome, chronic
cachectic conditions, and acanthosis nigricans.
Is there hypotension or weight loss?
Addison’s disease and arsenic poisoning. If there is no hypotension or
weight loss, then the mouth pigmentation and generalized
pigmentation may be associated with African ancestry or Fabry’s
disease.
Routine laboratory workup includes a CBC, sedimentation rate, urinalysis,
chemistry panel, and VDRL test. If arsenic poisoning is suspected, hair
analysis for arsenic should be done. If Addison’s disease is suspected, a
24-hour urine collection for 17-hydroxysteroids and 17-ketosteroids
should be done. The rapid ACTH test is a suitable alternative but usually
more expensive. If Peutz–Jeghers syndrome or acanthosis nigricans is
suspected, a GI series with a small bowel 
follow-through
 and a barium
enema may be necessary. Endoscopy procedures may also be useful in
certain cases.
434

1. 
  2. 
  3. 
  4. 
MUSCULAR ATROPHY
Is it focal or diffuse?
 Focal muscular atrophy would suggest
poliomyelitis, early spinal muscular atrophy, peripheral vascular
disease, and sympathetic dystrophy. However, occasionally it is an
indication of an early spinal cord tumor, herniated disk, or peroneal
muscular atrophy. It can also be a sign of an entrapment syndrome of
one of the peripheral nerves. Focal muscular atrophy with hyperactive
reflexes suggests amyotrophic lateral sclerosis, multiple sclerosis,
spinal cord tumors, or syringomyelia.
Are the reflexes hypoactive or hyperactive?
 Muscular atrophy with
hypoactive reflexes suggests peripheral neuropathy, poliomyelitis,
spinal muscular atrophy, myasthenia gravis, peripheral vascular
disease, sympathetic dystrophy, herniated disk, early spinal cord
tumor, and peroneal muscular atrophy. Muscular atrophy with
hyperactive reflexes suggests multiple sclerosis, spinal cord tumors,
syringomyelia, and amyotrophic lateral sclerosis.
Are there associated sensory changes?
 The finding of muscular
atrophy with sensory changes suggests a peripheral neuropathy,
Guillain–Barré syndrome, Friedreich’s ataxia, multiple sclerosis,
transverse myelitis, a herniated disk, spinal cord tumor, and peroneal
muscular atrophy. It may also suggest syringomyelia.
Are the reflexes normal?
 The presence of normal reflexes suggests
anorexia nervosa, tuberculosis, metastatic malignancy, and
hyperthyroidism.
The basic workup includes a CBC, sedimentation rate, urinalysis,
chemistry panel, ANA titer, serum protein electrophoresis, and VDRL test.
Additional muscle enzymes may be ordered such as serum aldolase and
CPK. A 24-hour urine collection for creatinine and creatine may be done.
At this point of time, it is best to consult a neurologist. He/she will
probably order nerve conduction velocity studies and EMGs of the
involved extremities. Genetic testing is now available to rule out
amyotrophic lateral sclerosis and the various myopathies. He also will be
best qualified to determine the need for CT scans or MRIs of the brain or
spine, as well as the particular study to order in each individual case. At
435

times, spinal fluid analysis and muscle biopsies may be necessary to solve
the problem. Also, a Tensilon test or acetylcholine receptor antibody titer
may be ordered in suspected myasthenia gravis.
436

1. 
  2. 
  3. 
  4. 
  5. 
MUSCULOSKELETAL PAIN, GENERALIZED
 Musculoskeletal pain with fever suggests dengue
fever, which is also called break-bone fever, poliomyelitis, Bornholm
disease, acute trichinosis, epidemic myalgia, viral influenza, and
meningitis, as well as almost any other febrile illness.
Is there paralysis?
 The presence of paralysis, especially if it is focal,
would suggest poliomyelitis, but porphyria, polyneuritis, Guillain–
Barré syndrome, dermatomyositis, and other collagen diseases may
present with generalized musculoskeletal pain and paralysis. If there is
diffuse pain without paralysis, one should consider trichinosis and
chronic fibromyositis. Polymyalgia rheumatica may also present in
this fashion.
 Transient musculoskeletal pain may occur with fever,
but it may also occur after injury, fatigue, and anxiety, and especially
extensive physical workouts.
Are there electrolyte abnormalities?
 One should always remember
that electrolyte abnormalities, such as hypokalemia, hyponatremia,
and hypocalcemia, will cause generalized musculoskeletal pain.
 The statins and other drugs can cause
myalgia and frank muscle necrosis.
panel including electrolytes, ANA test, serum protein electrophoresis,
febrile agglutinins, chest x-ray, and EKG.
If muscular disease is strongly suspected, then a 24-hour collection for
urine creatine and creatinine should be done, as well as serial muscle
enzymes. A urine myoglobin should be done to exclude muscle injury.
Perhaps a 
 skin test or antibody titer will be helpful. An EMG
and a nerve conduction velocity study may be helpful in both muscular
disease and peripheral neuropathies.
A muscle biopsy may be necessary to diagnose dermatomyositis,
trichinosis, cysticercosis, and various collagen diseases. Urine for
porphyrins and porphobilinogen should be done in difficult diagnostic
cases also.
Twenty-four-hour urine quantitative potassium, sodium, or calcium
437

will be helpful in the electrolyte disorders, as the serum electrolytes do not
always reflect the decrease in intracellular electrolytes.
A spinal tap will help diagnose poliomyelitis, meningitis, and
Guillain–Barré syndrome. It may be necessary to seek the help of a
rheumatologist, a neurologist, or an infectious disease specialist. If chronic
fibromyositis is suspected, a psychiatrist should be consulted. There is no
convincing proof that this is an organic disease.
438

1. 
NAIL ABNORMALITIES
Are the abnormalities focal or diffuse?
 Focal abnormalities include
thickening, which is often due to fungus infections; inflammation,
which is usually due to a paronychia, onychia, fungal infection, or
syphilis; hemorrhages under the nail, which may be due to trauma,
subacute bacterial endocarditis, or trichinosis; pitting of the nail,
which may be due to psoriasis; and atrophy or dystrophy of the nail,
which may be due to peripheral vascular diseases, epidermolysis
bullosa, nail biting, peripheral neuropathy, and various other
dermatoses. Diffuse abnormalities of the nail may include thickening
due to syphilis, hyperthyroidism or hypothyroidism, clubbing,
cyanotic heart disease, bronchiectasis, carcinoma of the lungs, and
other disorders; yellow nails due to lymphedema or chest conditions;
and spoon nails due to iron-deficiency anemia.
Diffuse spoon nails may be caused by iron-deficiency anemia. Yellow
nails may be due to lymphedema or chest conditions. Clubbing may be due
to cyanotic heart disease, bronchiectasis, or carcinoma of the lung (see
page 101
). Thickening may result from syphilis, hyperthyroidism, or
hypothyroidism. Hemorrhages may be due to trauma, subacute bacterial
endocarditis, or trichinosis. Pitting may be due to psoriasis. Focal
thickening may be due to fungus infections. Focal inflammation may be
due to paronychia, onychia, or syphilis. Focal atrophy or dystrophy may be
due to peripheral vascular disease, peripheral neuropathy, epidermolysis
bullosa, nail biting, or other dermatoses.
Focal abnormalities of one nail warrant a culture and sensitivity of any
scrapings or exudates from the area, as well as an x-ray of the digit or
extremity. A CBC and sedimentation rate will help identify an infectious
process. A glucose tolerance test will help identify diabetes mellitus.
Careful assessment of the area for vascular insufficiency includes Doppler
studies and possibly arteriography. A nerve conduction velocity study and
EMG may be necessary if peripheral neuropathy is suspected. A skin or
nail biopsy may be helpful.
Routine tests for diffuse nail changes include a CBC, sedimentation
439

rate, chemistry panel, VDRL test, ANA, thyroid profile, a chest x-ray, and
EKG. Arterial blood gases and pulmonary function studies should be done
if clubbing is suspected. Other tests for clubbing will be found on 
page
101
. Serial blood cultures should be done, if subacute bacterial
endocarditis is suspected. 
 skin test or antibody titer should be
done in cases, in which there are splintered nails with negative cultures for
subacute bacterial endocarditis. Muscle or skin biopsy will be useful not
only for trichinosis, but also for collagen disease. Nerve conduction
velocity studies and EMGs will be helpful in diagnosing peripheral
440

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
NASAL DISCHARGE
 Unilateral nasal discharge, especially if it
is purulent, suggests acute sinusitis, Wegener’s granulomatosis,
neoplasm, foreign body, and syphilis. If the discharge is clear or
mucoid, it could be just simply chronic sinusitis. Bilateral nasal
discharge suggests a URI, especially if it is an acute onset. If it is a
chronic condition and is mucoid or clear, allergic rhinitis, chronic
sinusitis, or vasomotor rhinitis should be suspected. Rarely, cerebral
spinal fluid rhinorrhea is the problem.
 The presence of fever makes acute sinusitis most
likely if the discharge is unilateral, but if it is bilateral, one should
suspect an acute viral URI. However, if there is significant pain
associated with the fever, one should consider the possibility that there
is an acute sinusitis.
Is it purulent, mucoid, or clear?
 The presence of a purulent
discharge suggests acute sinusitis, chronic bacterial sinusitis,
mucormycosis, Wegener’s granulomatosis, neoplasm, foreign body,
and syphilis. The presence of a mucoid discharge suggests allergic
rhinitis or a chronic sinusitis. The presence of a clear discharge
suggests cerebral spinal fluid rhinorrhea and senile rhinorrhea,
especially if the patient is older. If there is unilateral face pain, one
should consider cluster headache or migraine.
Is there pain?
 The presence of pain with fever or purulent discharge
certainly suggests acute sinusitis. However, when there is pain with a
clear discharge, one should think of cluster headache or migraine.
Is there sneezing or an allergy history?
 The presence of sneezing or
an allergic history should suggest allergic rhinitis and sinusitis.
However, allergic rhinitis and sinusitis may also occur without
sneezing or an allergic history.
Is the patient abusing cocaine or nasal sprays?
 These are common
causes of a chronic nasal discharge.
Routine orders for the workup of a nasal discharge include a CBC,
sedimentation rate, chemistry panel, VDRL test, smear and culture of the
nasal discharge, and x-ray of the sinuses. A CT scan of the sinus is the
441

preferred imaging study to diagnose sinusitis. If the discharge is chronic
and mucoid or clear, one should do a nasal smear for eosinophils and
serum IgE level to look for allergic rhinitis. A trial of therapy may be
indicated in these cases also. If Wegener’s granulomatosis is suspected,
serum for ANCA should be done. A RISA study can be done to rule out
cerebrospinal rhinorrhea.
If there is still diagnostic confusion after the above tests have been
done, referral to an ear, nose, and throat specialist or an allergist is
indicated. The specialist will perform nasopharyngoscopy and is in a better
position to evaluate whether CT scan or bone scan is required. Also, the
specialist can better evaluate when the patient should undergo allergy skin
testing, inhalation testing, or radioallergosorbent tests (RASTs). Idiopathic
vasomotor rhinitis can be diagnosed by a trial of Atrovent.
442

1. 
  2. 
  3. 
NASAL OBSTRUCTION
 The presence of acute nasal obstruction should
suggest acute sinusitis, acute rhinitis, a viral URI, allergic rhinitis,
nasal diphtheria, cluster headache, migraine, foreign body, and trauma.
The presence of chronic nasal obstruction, particularly if it is
unilateral, would suggest sinusitis, foreign bodies, neoplasm, deviated
septum, polyps, Wegener’s granulomatosis, mucormycosis, and nasal
gumma. If it is bilateral, it would suggest allergic rhinitis, vasomotor
rhinitis, adenoid enlargement, rhinitis medicamentosa, and ingestion
of drugs such as reserpine.
 The presence of unilateral nasal
obstruction suggests acute purulent sinusitis, foreign body, neoplasm,
mucormycosis, Wegener’s granulomatosis, polyps, and neoplasms. It
also suggests a deviated septum. The presence of bilateral nasal
obstruction suggests allergic rhinitis, acute viral URI, nasal diphtheria,
rhinitis medicamentosa, adenoids, and vasomotor rhinitis.
 The presence of fever with unilateral nasal obstruction
would suggest acute sinusitis. The presence of fever with bilateral
nasal obstruction would suggest acute rhinitis and acute viral URI.
Nasal diphtheria may occasionally present with this picture, even in
modern times.
panel, VDRL test, ANA, a nasal smear and culture for bacteria and fungi,
and x-ray of the sinus. If allergy is suspected, a nasal smear for eosinophils
and serum IgE antibodies should be done. A trial of antibiotics or
antihistamines may assist in the diagnosis. If Wegener’s granulomatosis is
suspected, serum for ANCA should be done.
If there is still confusion regarding the diagnosis at this point, a referral
to an ear, nose, and throat specialist or allergist would be indicated. The
ear, nose, and throat specialist may do a nasopharyngoscopy and is in a
better position to determine when CT scan or bone scan is indicated. The
allergist can best determine whether allergy skin testing, inhalation testing,
or RAST studies would be indicated.
444

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
NAUSEA AND VOMITING
 Alcohol and many
drugs, such as digitalis, aspirin, nonsteroidal anti-inflammatory agents,
antihypertensives, and antibiotics may cause gastric irritation or
gastritis.
 Fever may point to a localized abdominal condition
such as acute cholecystitis or acute appendicitis, as well as a systemic
condition, such as tuberculosis, brucellosis, yellow fever, and other
febrile illnesses.
 Abdominal pain suggests the possibility of
acute cholecystitis, acute appendicitis, pyelonephritis, pancreatitis,
renal calculus, and peritonitis.
 The presence of an abdominal mass
suggests pyloric or intestinal obstruction, a pancreatic neoplasm, acute
cholecystitis, Crohn’s disease, perinephric abscess, diverticulitis, and
other abscesses and neoplasms.
Is there vertigo?
 The clinician should remember that inner ear
diseases such as Ménière’s disease and labyrinthitis may be associated
with vomiting, and sometimes the patient does not mention vertigo.
Is there headache?
 Migraine, concussion, cerebral tumors or other
 lesions, meningitis, and subarachnoid hemorrhage
are associated with headaches, nausea, and vomiting. Migraine has
been known to cause vomiting without headache.
A patient presenting with nausea, vomiting, and diarrhea almost always
has a viral or bacterial gastroenteritis. However, appendicitis, pancreatitis,
and cholecystitis must always be kept in mind as does botulism. The basic
workup includes a CBC, sedimentation rate, urinalysis, urine drug screen,
chemistry panel and electrolytes, serum amylase, arterial blood gases,
stools for occult blood, chest x-ray, EKG, and flat plate of the abdomen.
Acute onset of nausea and vomiting with ataxia requires an immediate CT
scan of the brain to rule out a cerebellar hemorrhage. A pregnancy test
should be routine in women of child-bearing age. If there is fever, febrile
agglutinins and a heterophile antibody titer should be done. If there is an
abdominal mass, a gallbladder ultrasound and IVP may need to be done.
446

Isotope scanning with iminodiacetic acid derivatives is extremely useful to
detect acute cholecystitis. If there is chronic vomiting and abdominal pain,
the diagnosis can often be made with an upper GI series, small bowel
series, or barium enema.
When there is persistent vomiting with abdominal pain, an exploratory
laparotomy may need to be considered. The presence of an abdominal
mass or suspected pancreatic or biliary disease merits consideration of a
CT scan. However, before ordering expensive diagnostic tests, a general
surgeon or gastroenterologist ought to be consulted. Laparoscopy,
gastroscopy, esophagoscopy, duodenoscopy, and colonoscopy all need to
be considered in the workup. Gastroparesis and intestinal pseudo-
obstruction can be ruled out by radioisotope studies and manometry of the
stomach and small intestine. A CT angiography or conventional
angiography is useful to diagnose mesenteric artery ischemia.
447

1. 
  2. 
  3. 
NECK PAIN
Is there radiation of the pain to one or both upper extremities?
The finding of radiation of the pain to one or both upper extremities
would suggest a space-occupying lesion, such as a herniated disk,
spinal cord tumor, fracture, or cervical spondylosis.
Are there focal neurologic findings?
 The presence of focal
neurologic findings makes a space-occupying lesion even more likely
and the conditions that should be considered are fracture, herniated
disk, spinal cord tumor, and cervical spondylosis. One should not
forget a Pancoast’s tumor.
 The finding of nuchal rigidity suggests
Pain in the neck without radiation or focal neurologic signs can be
addressed with a routine workup only. Routine tests include a CBC,
sedimentation rate, urinalysis, chemistry panel, arthritis panel, and plain
films of the cervical spine. At this point, it is best to observe the results of
conservative treatment before an expensive workup is begun. If there are
focal neurologic findings, an MRI of the cervical spine, as well as EMG
examinations, nerve conduction velocity studies, and dermatomal SSEP
studies may need to be done.
It is wise to consult a neurologist or neurosurgeon before ordering
these expensive tests. If there is nuchal rigidity, a CT scan of the brain
should be done before performing a spinal tap unless there are clear-cut
clinical findings of meningitis. If possible, a neurologist should be
consulted first in these circumstances.
449

Table 13: Neck Pain
The reader needs to keep in mind that alternative findings do occur.
450

1. 
  2. 
  3. 
  4. 
NECK STIFFNESS
 Acute stiffness of the neck should make one
look for nuchal rigidity. If there is nuchal rigidity, meningitis or
subarachnoid hemorrhage would be high on the list of possibilities. If
there is chronic neck stiffness, one should consider rheumatoid
arthritis, cervical spondylosis, and idiopathic torticollis. With a history
of trauma, the possibility of flexion–extension injury and fracture is
more likely.
Is there nuchal rigidity or fever?
 The presence of nuchal rigidity or
fever should make one think of meningitis, subarachnoid hemorrhage,
or meningismus due to some systemic infectious disease.
Retropharyngeal abscess must also be considered.
Is it congenital or acquired?
 The presence of congenital stiffness of
the neck should make one think of congenital torticollis or Klippel–
Feil syndrome. Chronic acquired neck stiffness should make one think
of cervical spondylosis, Parkinson’s disease, idiopathic torticollis,
rheumatoid arthritis, tuberculosis, fractures of the spine, flexion–
extension injuries, and inflammation of the lymph nodes.
Are there x-ray changes?
 Plain films of the cervical spine will often
reveal cervical spondylosis, fractures, and tuberculosis. However, one
should not jump to the conclusion that this is the cause of the
If there is nuchal rigidity and fever, a CT scan of the brain should be done
to rule out a space-occupying lesion, and, following that, a spinal tap for
analysis, smear, and culture should be done.
If there is no nuchal rigidity or fever, plain films of the cervical spine
are a good place to start the diagnostic workup. A CBC, sedimentation
rate, urinalysis, chemistry panel, and arthritis profile may also be helpful.
If the stiffness is associated with pain radiating into the upper extremities,
EMG and nerve conduction velocity studies may be useful. If the stiffness
persists, an MRI of the cervical spine may be necessary. A bone scan may
identify a subtle fracture or osteomyelitis. A neurologic specialist should
be consulted before ordering expensive diagnostic tests.
451

1. 
  2. 
  3. 
  4. 
  5. 
NECK SWELLING
 Focal masses or swellings may be thyroglossal
cyst, branchial cleft cyst, aneurysm, an enlarged lymph node due to
Hodgkin’s disease, metastatic carcinoma, sarcoidosis, a cystic
hygroma, carotid body tumor, Riedel’s struma, and thyroid adenomas
and carcinomas. Diffuse masses would be Graves’ disease, subacute
thyroiditis, nontoxic goiter, venous distention of congestive heart
failure or superior vena cava syndrome, and subcutaneous
emphysema. An acute diffuse neck swelling must be considered
Ludwig’s angina (neck extension of an abscessed tooth) until proven
otherwise.
If the lesion is focal, is it in the midline or lateral to the midline?
Midline masses are thyroglossal cysts, adenoma of the thyroid,
Riedel’s struma, and thyroid cyst. Lateral masses include a pharyngeal
pouch, bronchial cyst, pulsion diverticulum, stone of Wharton’s duct,
Virchow’s node, cervical rib, metastatic lymph nodes or Hodgkin’s
lymphoma, metastatic carcinoma, cystic hygroma, carotid body tumor,
and some thyroid masses.
Is the swelling intermittent?
 The presence of an intermittent swelling
suggests a pulsion diverticulum, venous distention of congestive heart
failure, a bronchial cyst, a stone of Wharton’s duct, and aneurysms.
Is there crepitus?
 Subcutaneous crepitus is present in subcutaneous
Is the swelling associated with a tremor or tachycardia?
 The
presence of tremor or tachycardia would make one think of Graves’
disease and subacute thyroiditis.
panel, thyroid profile, a chest x-ray, and EKG. If these are negative, the
next best step is a CT scan of the neck.
Measurement of venous pressure and circulation time, BNP and
pulmonary function studies will help differentiate congestive heart failure.
A radioactive iodine uptake and scan will help differentiate thyroid tumors
and enlargements. Ultrasound and needle aspiration will be needed in
differentiating cystic adenomas. A lymph node biopsy will be useful in
453

diagnosing sarcoidosis, lymphomas, and metastatic carcinoma.
Esophagogram will help detect Zenker’s diverticulum. Ultrasonography,
MRA, and four-vessel contrast angiography will be useful in diagnosing
aortic aneurysms, innominate aneurysms, and subclavian aneurysms. A CT
scan of the mediastinum will help diagnose superior vena cava syndrome.
A PET scan is useful in differentiating lymphomas and metastatic
carcinomas.
454

1. 
  2. 
  3. 
  4. 
NIGHTMARES
Are they acute or chronic?
 The presence of acute nightmares should
make one think of the possibility of infectious disease, acute
situational maladjustment, or a head injury. Remember, there may be
amnesia from the head injury. Chronic nightmares may be associated
with drug or alcohol use, epilepsy, and neuroses or psychoses.
 Nightmares following trauma may be
due to the acute anxiety associated with the trauma or actually to a
head injury.
 Acute alcoholic
intoxication can create hallucinations and nightmares. Chronic
alcoholism can lead to delirium tremens. Benzodiazepines and
numerous other drugs may cause nightmares.
Is there a history of tongue biting or incontinence?
suggest grand mal epilepsy. Nightmares may result from complex
partial seizures without tongue biting or incontinence.
A CBC, sedimentation rate, and chemistry panel will help rule out
infectious diseases. A urine drug screen will help rule out the possibility of
drug-induced nightmares. A wake-and-sleep EEG will help diagnose
epilepsy. If epilepsy is strongly suspected, a therapeutic trial of
anticonvulsants may be necessary. If the workup is negative, referral to a
psychiatrist or psychologist is in order.
455

1. 
  2. 
  3. 
NOCTURIA
Is there daytime frequency of urination also?
 If there is daytime
frequency, the differential diagnosis of polyuria should be considered
(
page 400
).
Is there associated pain or difficulty voiding?
suggest cystitis, prostatitis, and urethritis.
Is there dyspnea, orthopnea, or peripheral edema?
would suggest congestive heart failure. If there is no dyspnea or
edema, one should consider chronic nephritis.
Routine laboratory tests should include a CBC, sedimentation rate,
urinalysis, chemistry panel, and urine culture and sensitivity. A
quantitative 24-hour urine volume should be determined. If this is above
normal, the differential diagnosis of polyuria should be considered and
additional workup can be found on 
page 400
.
Catheterization for residual urine will help determine if there is bladder
neck obstruction. If congestive heart failure is suspected, a chest x-ray,
EKG, and venous pressure and circulation time should be done. For further
evaluation, a nephrologist or urologist may be consulted.
457

1. 
  2. 
  3. 
  4. 
  5. 
NOSE, REGURGITATION OF FOOD THROUGH
Are there structural abnormalities on examination of the
nasopharynx?
 Structural abnormalities of the palate indicate cleft
palate, congenital short soft palate, trauma, tuberculosis, syphilis,
carcinoma, leprosy, and 
post-tonsillectomy
 scarring.
Are the abnormalities congenital or acquired?
 Congenital
abnormalities of the palate include cleft palate and congenital short
soft palate. Acquired abnormalities of the palate include trauma,
syphilis, tuberculosis, carcinoma, leprosy, and post-tonsillectomy
scarring.
Is there paralysis of the soft palate?
 The finding of paralysis of the
soft palate may suggest myasthenia gravis, poliomyelitis, Guillain–
Barré syndrome, pseudobulbar palsy, brain tumor, basilar artery
insufficiency, and syphilitic meningitis.
Is the paralysis of the soft palate intermittent or constant?
Intermittent paralysis of the soft palate should suggest myasthenia
gravis.
Are there associated hypoactive or hyperactive reflexes?
 The
presence of hypoactive reflexes would suggest poliomyelitis or
Guillain–Barré syndrome. The presence of hyperactive reflexes or
sensory findings would suggest pseudobulbar palsy, a brain tumor,
basilar artery insufficiency, and syphilitic meningitis, among other
chemistry panel, VDRL test, smear and culture from the lesions in the
nasopharynx, and a tuberculin test. A chest x-ray also should be done if
tuberculosis is suspected. A neurologic workup consists of an MRI of the
brain, EMG and nerve conduction velocity studies, spinal fluid analysis,
acetylcholine receptor antibody titers, and Tensilon tests. It is best to
consult an ear, nose, and throat specialist or a neurologic specialist before
459

1. 
  2. 
  3. 
  4. 
  5. 
NYSTAGMUS
Is the nystagmus pendular?
 Pendular nystagmus without a fast or
slow component suggests ocular nystagmus due to albinism, partial
blindness, or other ocular disorders.
Is it intermittent or fatigable?
 Intermittent or fatigable nystagmus
suggests otologic disorders, such as acoustic neuroma, Ménière’s
disease, vestibular neuronitis, and acute labyrinthitis.
 The presence of nystagmus
with tinnitus or deafness also suggests otologic disorders, such as
acoustic neuroma, Ménière’s disease, or cholesteatoma. If there are
long tract signs, multiple sclerosis and brain stem tumors must be
Is the nystagmus brought on by change of position?
 Nystagmus
brought on by certain changes of position suggests benign positional
vertigo. However, this also may be found in post-traumatic
labyrinthitis and postconcussion syndrome.
Are there associated long tract signs?
 The presence of long tract
signs suggests multiple sclerosis, basilar artery insufficiency,
syringomyelia, and Friedreich’s ataxia. Certain brain stem tumors may
also be associated with long tract signs.
The basic diagnostic workup includes visual acuity, visual fields,
audiogram, caloric testing, and x-ray of the skull, mastoids, and petrous
bones. If these are negative or indefinite, a CT scan or an MRI of the brain
should be done. A spinal fluid analysis will help diagnose central nervous
system lues and multiple sclerosis. A BSEP or VEP study may be needed
to diagnose multiple sclerosis. The help of a neurologic specialist should
be sought before ordering expensive diagnostic tests. Cisternography,
tomography, and vertebral–basilar angiography are occasionally necessary
to establish the diagnosis. MRA is an excellent noninvasive means of
visualizing the vertebral–basilar circulation.
461

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
OBESITY, PATHOLOGIC
Is there associated hyperphagia?
 If the patient recognizes that he or
she has a ravenous appetite or eats more than is necessary, the
possibility of an insulinoma or Fröhlich’s syndrome should be
Is the obesity centripetal?
 The presence of centripetal obesity,
especially with moon facies, should suggest Cushing’s syndrome.
Is the obesity mainly of the lower extremities?
suggest lipodystrophy.
Is there mental retardation?
 The presence of mental retardation
should suggest Laurence–Moon–Bardet–Biedl syndrome.
 In male patients, one should consider
Klinefelter’s syndrome, and in female patients, one should consider
polycystic ovary.
Many drugs may cause obesity, most notably the tricyclic
antidepressants and corticosteroids.
Routine laboratory tests include a CBC, urinalysis, chemistry panel, 2-hour
postprandial blood sugar, and thyroid profile. If an insulinoma is strongly
suspected, plasma insulin, C-peptide, a 24- to 36-hour fast, a 5-hour
glucose tolerance test, and tolbutamide tolerance test may be done. If
Cushing’s syndrome is suspected, a 24-hour urine free cortisol and cortisol
suppression test should be done. Pelvic ultrasound will help diagnose
polycystic ovaries. Chromosomal analysis will help diagnose Klinefelter’s
syndrome. Perhaps a psychiatrist should be consulted.
463

1. 
  2. 
  3. 
ODOR
Is there coma or disturbances of consciousness?
coma or disturbances of consciousness should suggest alcoholism,
diabetic acidosis, uremia, and hepatic coma.
Is the odor sweet?
 The presence of a sweet odor to the breath should
suggest diabetic acidosis, alcoholism, and maple syrup urine disease.
Is the odor unpleasant or foul?
 The presence of an unpleasant or
foul odor should suggest uremia, hepatic coma, anaerobic infections in
the mouth or nasopharynx, and isovaleric aciduria.
Routine laboratory work includes a CBC, urinalysis, chemistry panel,
blood alcohol level, and tests for serum acetone and serum amino acids.
Urine for chromatography may help pick up certain keto acids. A culture
of the mouth, gums, and nasopharynx may be necessary to diagnose
anaerobic infections.
465

1. 
  2. 
  3. 
  4. 
  5. 
OPISTHOTONUS
 If it is acute, strychnine poisoning, tetanus, and
phenothiazine intoxication should be considered. Also, consider
meningitis and uremia.
Is there a history of oral or intravenous drug use or a recent
wound infection?
 If there is a recent wound infection, one should
consider tetanus. If there is no recent wound infection, but a history of
oral or intravenous drug use, tetanus, and strychnine poisoning are
both possibilities. Phenothiazine intoxication must also be considered.
Is the opisthotonus chronic or recurring?
 The presence of chronic
or recurring opisthotonus should suggest epilepsy, Stiffman syndrome,
and hysteria.
If it is chronic and recurring, is there incontinence or tongue
biting?
 The presence of incontinence or tongue biting in a chronic
recurring form of opisthotonus should suggest epilepsy.
 If the opisthotonus is acute and there is a significant
fever, one should consider meningitis. However, strychnine poisoning
and tetanus may also induce fever in the later stages.
panel including electrolytes, blood cultures, urine drug screen, and
 VDRL
test. A spinal fluid analysis, smear, and culture are indicated if meningitis
is suspected. An
 EEG 
is indicated in the chronic recurring form.
466

ORTHOPNEA
A patient with orthopnea is able to breathe without significant subjective
difficulty in the sitting or upright position but almost invariably develops
shortness of breath in the recumbent position. This symptom is the most
characteristic of congestive heart failure, especially left ventricular failure.
The differential diagnosis and workup are the same as for dyspnea (
page
155
).
468

1. 
  2. 
  3. 
  4. 
  5. 
PAIN IN THE PENIS
Is the pain mostly during micturition?
 If the pain is mostly during
micturition, one should consider the possibilities of urethritis, cystitis,
bladder calculus, prostatitis, urethral stricture, carcinoma of the
bladder, seminal vesiculitis, anal fissure, and hemorrhoids.
If the pain is during micturition, is it mostly at the end of
micturition?
 If the pain in the penis is at the end of micturition,
chronic prostatitis, seminal vesiculitis, anal fissure, hemorrhoids, and
bladder calculi should be suspected.
Is the pain mostly during an erection?
an erection, Peyronie’s disease should be considered.
Is the pain unrelated to micturition or erection?
 If the pain is not
related to micturition or erection, renal colic, epithelioma,
appendicitis, anxiety, chancroid, and herpes simplex should be
 The presence of a urethral discharge should
make one think of gonorrhea and nonspecific urethritis.
The most important diagnostic procedure is a urinalysis, urine culture and
sensitivity, and smear and culture of any urethral discharge. It may be
necessary to massage the prostate to obtain an adequate specimen! An IVP
or CT scan of the abdomen should be done if obstructive uropathy or
bladder or renal calculi are suspected. If the above studies are negative,
referral to an urologist should be made. He will probably do cystoscopy
and retrograde pyelography as well as other diagnostic tests.
469

1. 
  2. 
PALLOR
Is the pallor acute?
 This would indicate vasovagal syncope or heart
block if the pulse is slow or shock, acute cardiac arrhythmias, trauma,
or hypoglycemia if the pulse is normal or rapid.
Is the pallor chronic?
 If so, then consider the possibility of drug
abuse or prescription drugs such as digoxin or beta-blockers if the
blood pressure is low or the pulse is slow! Consider the possibility of
anemia of its many causes if the blood pressure and pulse are normal.
Chronic anxiety and other psychiatric disorders also need to be
This begins with CBC, chemistry panel, sedimentation rate, C-reactive
protein (CRP), urinalysis, electrocardiogram (EKG), and chest x-ray. If
anemia is found, a stool for occult blood, barium enema, and upper
gastrointestinal (GI) series, and esophagram to rule out anemia of blood
loss is necessary as well as a serum B
12
 and folate. A urine drug screen to
rule out drug abuse may be necessary. Holter monitoring, ambulatory
blood pressure monitoring, and monitoring blood glucose during a 48-hour
fast may be necessary.
471

1. 
  2. 
  3. 
PALPITATIONS
A 27-year-old stenographer complains of palpitations. Following the
algorithm, you examine for murmurs, cardiomegaly, pallor, and fever and
find none. Her blood pressure is 135/85 and pulse is 120 per minute. There
is no thyromegaly but her hands are sweaty and tremulous. On further
questioning, you find she has been drinking a pot of coffee a day and
working overtime for several months. Eliminating coffee, tea, and other
caffeinated beverages relieved her symptomatology.
Are the palpitations constant or intermittent?
 Constant palpitations
may signify tachycardia, and that would suggest hyperthyroidism or
overuse of caffeine and other drugs. Intermittent palpitations are more
likely related to a cardiac arrhythmia, particularly extrasystoles.
Wolff–Parkinson–White (WPW) syndrome and other disorders of the
conduction system need to be considered here. Also, constant
palpitations may indicate a fever of unknown origin.
Are there associated symptoms?
 Palpitations with weight loss,
increased appetite, and polyuria would suggest hyperthyroidism.
Palpitations with shortness of breath and pitting edema would suggest
Are there positive physical findings?
 If there is cardiomegaly, one
must think of the possibility of congestive heart failure or valvular
heart disease. If one finds a cardiac murmur, it is more likely that there
is valvular heart disease such as acute or chronic rheumatic fever.
Mitral valve prolapse is a cause of palpitations. Cardiomegaly,
murmur, and/or fever would suggest bacterial endocarditis.
Cardiomegaly without a murmur would suggest myocardiopathy,
congestive heart failure, and hypothyroidism. Palpitations with no
cardiomegaly but with hypertension would suggest
pheochromocytoma, particularly if it is systolic hypertension, but it
can also be found in hyperthyroidism. Persistent or intermittent
palpitations with a totally normal physical examination suggest
sensitivity to caffeine or the use of other drugs.
472

Before initiating an expensive workup, the patient should eliminate use of
all drugs, alcohol, caffeine, and nicotine, if possible, for several days. If
this does not eliminate the palpitations, a careful inquiry into the dietary
habits should be made, and a CBC should be done to eliminate anemia. A
routine EKG may confirm WPW syndrome, prolonged QT syndrome, and
other abnormalities. In the presence of tachycardia, weight loss, and
increased appetite, it is obvious that a thyroid profile should be drawn. If
there are palpitations and fever, a workup for an infectious disease,
particularly rheumatic fever and bacterial endocarditis, is in order. Blood
cultures, ASO titers, sedimentation rate, and echocardiography are useful.
If the palpitations are intermittent, a pheochromocytoma should be
considered and 24-hour urine collection for VMA or metanephrines should
be ordered. A drug screen may be necessary to ensure patient cooperation
in eliminating all drugs. Twenty-four-hour blood pressure monitoring is
also useful. In addition, 24-hour or 48-hour Holter monitoring is very
useful in the diagnosis of intermittent palpitations. Newer technology
involving a 
continuous-loop
 event recorder allows monitoring for 2 weeks
at a time. Stress testing is useful if palpitations seem to be exercise
induced. Arm-to-tongue 
circulation times as well as spirometry may
diagnose early congestive heart failure. If a panic disorder is suspected
consult a psychiatrist.
473

1. 
  2. 
  3. 
  4. 
PAPILLEDEMA
 An acute onset would suggest optic
neuritis, hypertensive encephalopathy, cerebral hemorrhage,
extradural hematoma, brain abscess, dural sinus thrombosis,
meningitis, and subarachnoid hemorrhage. On the contrary, a gradual
onset would suggest a space-occupying lesion such as brain tumor,
abscess, or subdural hematoma.
If the onset is acute, is there coma or focal neurologic signs?
Findings of coma or focal neurologic signs should suggest cerebral
hemorrhage, extradural hematoma, brain abscess, dural sinus
thrombosis, meningitis, and subarachnoid hemorrhage. An acute onset
without focal neurologic signs or coma would suggest hypertensive
encephalopathy and optic neuritis.
If the onset is gradual, are there focal neurologic signs?
 A gradual
onset of papilledema with focal neurologic signs suggests a brain
tumor, abscess, or subdural hematoma.
 The presence of hypertension and
papilledema suggests hypertensive encephalopathy, acute
glomerulonephritis, and certain collagen diseases. If there is no
hypertension and no focal neurologic signs, then a diagnosis of
pseudotumor cerebri or pseudopapilledema should be suspected.
Regardless of whether there are focal neurologic signs or hypertension, a
CT scan or an MRI should be done, and a consultation with a neurologist
should be made when papilledema is suspected.
If there is significant hypertension and the CT scan or MRI is negative,
a hypertensive workup should be done (see 
page 268
).
With a normal CT scan or MRI and no focal neurologic signs or
hypertension, a spinal tap and visual field examination will assist in the
diagnosis of pseudotumor cerebri. However, a blood lead level should be
done to rule out lead poisoning. Also, the visual field examination may
show optic neuritis when the clinical examination is inconclusive.
An ophthalmologist will help diagnose optic neuritis and
pseudopapilledema.
475

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
PARESTHESIAS OF THE LOWER EXTREMITY
Are the pulses diminished?
 The presence of diminished pulses
should suggest peripheral arteriosclerosis or Leriche’s syndrome.
Is there associated pain in the involved extremity?
pain in the involved extremity should suggest lumbar spondylosis,
spinal stenosis, cauda equina tumor, spondylolisthesis, herniated disk,
and pelvic tumors.
Is there a positive straight-leg raising test and/or decreased
Achilles reflex?
 These findings suggest a herniated disk of L4 to 5 or
L5 to S1, lumbar spondylosis, spinal stenosis, a cauda equina tumor,
or spondylolisthesis.
Is there a positive femoral stretch test or decreased knee jerk?
These findings suggest a herniated disk of L3 to 4 or L2 to 3 or lumbar
spondylosis.
Are there diffuse hyperactive reflexes?
multiple sclerosis, pernicious anemia, degenerative diseases of the
spinal cord, such as syringomyelia, spinal cord tumor, or other space-
occupying lesions. It may also suggest anterior spinal artery occlusion.
Are there diffuse hypoactive reflexes?
 The presence of diffuse
hypoactive reflexes would suggest poliomyelitis, Guillain–Barré
syndrome, cauda equina tumor, metastatic tumor of the lumbar spine,
and, occasionally, pernicious anemia or peroneal neuropathy. Also,
peripheral neuropathy will present with diffuse hypoactive reflexes.
Is there incontinence associated with the hypoactive reflexes?
 The
presence of incontinence with the hypoactive reflexes may indicate
poliomyelitis, cauda equina tumor, or metastatic tumors to the lumbar
spine.
Paresthesias limited to the foot and toes may indicate Morton’s
neuroma or tarsal tunnel syndrome. If there is a positive Tinel’s sign
over the tibial nerve or a positive cuff test a tarsal tunnel syndrome is
even more likely.
The basic diagnostic workup includes a CBC, CRP, sedimentation rate,
urinalysis, chemistry panel, arthritis panel, VDRL test, and x-ray of the
477

lumbosacral spine. Serum B
12
 and folic acid tests should be done if
pernicious anemia is suspected. If these tests are negative, an orthopedic or
neurologic specialist should be consulted. A CT scan of the lumbosacral
spine, a nerve conduction velocity study, and an EMG may all be
necessary in the workup. An MRI is more expensive and often
unnecessary.
Combined myelography and a CT scan is often useful in evaluating the
need for surgery. A bone scan may be helpful in diagnosing occult
fractures, metastases, or osteomyelitis.
If multiple sclerosis, Guillain–Barré syndrome, or central nervous
system lues is suspected, a spinal tap may be done. Somatosensory evoked
potential (SSEP) studies are useful in diagnosing multiple sclerosis.
A neuropathy workup may be necessary. This involves a HbA
1c
 or a
glucose tolerance test to rule out diabetes; urine tests for porphyrins and
porphobilinogen to rule out porphyria; quantitative urine niacin, thiamine,
pyridoxine, and other B vitamins after loading, an ANA and anti-dsDNA
test to rule out collagen disease; serum protein electrophoresis and
immunoelectrophoresis to diagnose various collagen diseases and
macroglobulinemia; a lymph node biopsy and Kveim test for sarcoidosis;
nerve conduction velocity studies and EMG to establish the presence of 
a
neuropathy; thyroid profile to rule out hypothyroidism or hyperthyroidism;
HIV antibody titers; blood levels for heavy metals such as lead to rule out
lead or arsenic neuropathy; and skin and muscle biopsies to rule out
various collagen diseases. Blood tests are now available to rule out all the
various vitamin deficiencies that may cause paresthesias. Nevertheless, a
trial of therapy is often necessary to rule out the nutritional neuropathies.
Lumbar puncture, as already mentioned, is useful in diagnosing
Guillain–Barré syndrome. Remember that the cerebrospinal fluid (CSF)
protein is also elevated in diabetic neuropathy and hypothyroidism. Nerve
biopsy may be necessary when all the above procedures are negative.
RBC transketolase activity is decreased in beriberi and the serum
pyruvate and lactate levels are elevated.
478

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
PARESTHESIAS OF THE UPPER EXTREMITY
Are there paresthesias of the face or cranial nerve signs?
 These
findings would suggest a diagnosis of cerebral vascular disease, a
space-occupying lesion of the brain, migraine, or multiple sclerosis.
Is there pain in the involved extremity?
 Pain in the involved
extremity, particularly radicular pain, should suggest a herniated
cervical disk, spinal cord tumor, or cervical spondylosis. However,
many other conditions, such as brachial plexus neuropathy, thoracic
outlet syndrome, a cervical rib, Pancoast’s tumor, Raynaud’s disease,
and sympathetic dystrophy, should also be considered. Finally, the
various entrapment syndromes should be considered, such as carpal
tunnel syndrome and ulnar nerve entrapment at the elbow.
Are the Adson’s tests positive?
 If the radial pulse diminishes in
certain positions of the neck and shoulders, a thoracic outlet syndrome
or cervical rib should be considered.
Is the Tinel’s sign positive at the wrist or elbow?
 A positive Tinel’s
sign at the wrist would suggest a carpal tunnel syndrome and can be
confirmed by a positive Phalen’s test. A positive Tinel’s sign at the
elbow would suggest ulnar entrapment syndrome. The ulnar nerve
may also be entrapped in Guyon’s canal and the median nerve may be
trapped at the elbow in a pronator syndrome.
Is the cervical compression test positive?
 The presence of a positive
cervical compression test or a positive Spurling’s test would suggest
cervical spondylosis and herniated cervical disk.
 The presence of hyperactive reflexes
in the upper or lower extremity would suggest a spinal cord tumor,
multiple sclerosis, degenerative disease of the spinal cord, such as
syringomyelia or amyotrophic lateral sclerosis, anterior spinal artery
occlusion, and cervical spondylosis.
Are there normal or hypoactive reflexes noted?
normal or hypoactive reflexes in the involved extremity should prompt
consideration of peripheral neuropathy, pernicious anemia, and
brachial plexus neuropathy.
480

A CBC, sedimentation rate, urinalysis, chemistry panel, serum B
12
 and
folic acid, arthritis panel, and plain films of the cervical spine constitute
the basic workup of paresthesias of the upper extremities. If these are
negative, the next logical step is to consult a neurologist or neurosurgeon.
If there are paresthesias of the face or cranial nerve signs, an MRI or a
CT scan of the brain will probably be the most logical test to order next. If
not, an MRI of the cervical spine will be useful. Nerve conduction velocity
studies, EMG, and dermatomal SSEP studies complete the workup in most
cases. However, SSEP studies and a spinal tap may be necessary to
diagnose multiple sclerosis. If tabes dorsalis is suspected, a blood or spinal
fluid fluorescent 
Treponema pallidum
 antibody test may be done.
Immunoelectrophoresis may diagnose a monoclonal gammopathy. A
therapeutic trial of vitamin B6 or corticosteroids may diagnose carpal
tunnel syndrome if a neurologist is not available.
481

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
PATHOLOGIC REFLEXES
Are the findings intermittent?
 If the pathologic reflexes come and
go, transient ischemic attacks, multiple sclerosis, migraine, epilepsy,
and hypoglycemia should be considered in the differential diagnosis.
Are they unilateral or bilateral?
 Unilateral pathologic reflexes
should signify either a brain tumor or vascular lesion. Bilateral
pathologic reflexes should suggest an inflammatory or degenerative
disease. However, multiple sclerosis may present with either unilateral
or bilateral pathologic reflexes. Vascular lesions in the basilar
circulation may also present with bilateral pathologic reflexes. It
should be pointed out that there is no hard-and-fast rule.
Is there associated facial palsy or other cranial nerve signs?
 The
presence of facial palsy or other cranial nerve signs should make one
look for a lesion in the brain or brain stem.
Is there headache or papilledema?
 The presence of headache or
papilledema should prompt the investigation for a space-occupying
lesion of the brain or brain stem.
Is there hypertension or a possible source for an embolism?
 These
findings would suggest a cerebral vascular accident such as cerebral
hemorrhage or embolism.
Is the sensory examination normal?
 The findings of bilateral
pathologic reflexes or unilateral pathologic reflexes with a normal
sensory exam and no cranial nerve signs would suggest amyotrophic
lateral sclerosis or primary lateral sclerosis.
panel, ANA assay, serum B
12
 and folic acid, VDRL test, chest x-ray, and
EKG. If there are cranial nerve signs, a CT scan or an MRI of the brain
will usually be necessary. However, it is wise to get a neurology
consultation before undertaking these expensive tests. A spinal tap may be
done if the imaging study is negative.
If vascular disease is suspected, carotid scans to rule out carotid
stenosis or plaque and a search for an embolic source using
echocardiography and blood culture should be done. A cardiologist can
482

assist in this search. Four-vessel cerebral angiography or MRA may be
necessary. In fact, if a cerebral hemorrhage has been ruled out and there is
no significant hypertension, a four-vessel cerebral angiographic study
should probably be done. Evoked potential studies and HIV antibody titers
should also be done. If there are no cranial nerve signs, an MRI of the
cervical spine or thoracic spine should be done, depending on the level of
the lesion. Myelography may also be helpful. Serum protein
electrophoresis and immunoelectrophoresis all may be necessary in the
workup.
483

1. 
  2. 
  3. 
  4. 
PELVIC MASS
 The presence of abdominal pain suggests
PID, ectopic pregnancy, and endometriosis, among other things. It
should also suggest pelvic appendix.
Is there fever or vaginal discharge?
 The presence of fever or vaginal
discharge would be most suggestive of PID.
Is there a history of menorrhagia or metrorrhagia?
 The history of
menorrhagia or metrorrhagia should suggest ectopic pregnancy,
endometriosis, and threatened abortion, as well as retained secundinae.
Is the pregnancy test positive?
 A positive pregnancy test is the key
to a diagnosis of ectopic pregnancy when there is abdominal pain
along with the abdominal mass. If there is no pain, the pregnancy test
will help diagnose a normal pregnancy.
Routine diagnostic studies include a CBC, sedimentation rate, pregnancy
test, cancer antigen (CA)-125, urinalysis, urine culture, chemistry panel,
VDRL test, and Pap smear. Urinary human chorionic gonadotropin (hCG)
is increased in embryonal cell carcinoma. If there is a vaginal discharge, a
smear and culture of the material should be made. If a distended bladder is
suspected, catheterization for residual urine must be done. Pelvic
ultrasound or a CT scan will often be useful, but why not consult a
gynecologist before ordering these more expensive tests? The gynecologist
may do a laparoscopy, a culdocentesis, and, ultimately, an exploratory
laparotomy.
484

1. 
  2. 
  3. 
  4. 
  5. 
PELVIC PAIN
A 39-year-old female, gravid 3, para 2, presents to your office with a
history of recurrent hypogastric pain. Following the algorithm, you look
for a vaginal discharge and fever. These are absent. There is a history of
heavy periods and on examination, she had an enlarged asymmetrical
uterus. The pregnancy test is negative so, you suspect either uterine
fibroids or endometriosis. Pelvic ultrasound confirms the diagnosis of
uterine fibroids.
Is there a pelvic mass?
 The presence of a pelvic mass would suggest
salpingo-oophoritis,
 ectopic pregnancy, endometriosis, uterine fibroid,
or an ovarian tumor that is twisting on its pedicle. Be sure to do a
rectovaginal examination as there may be a mass or fluid in the 
cul-de-
sac.
Is there fever or purulent vaginal discharge?
 The presence of fever
or purulent vaginal discharge would suggest PID, diverticulitis, and
Is there a history of metrorrhagia or menorrhagia?
metrorrhagia or menorrhagia would suggest ectopic pregnancy,
threatened abortion, retained secundinae, uterine fibroids, and
endometriosis.
Is there a positive pregnancy test?
pregnancy test would suggest an ectopic pregnancy or threatened
abortion.
Is the pain related to the menstrual cycle?
 If the pain is related to
the menstrual cycle, mittelschmerz should be considered.
Routine studies include a CBC, sedimentation rate, pregnancy test,
urinalysis, urine culture, chemistry panel, VDRL test, and Pap smear. A
vaginal smear and culture should also be done routinely.
The next step would logically be a pelvic or transvaginal ultrasound,
but it is wise to consult a gynecologist before ordering expensive tests. The
gynecologist may proceed with laparoscopy, culdocentesis, and,
486

ultimately, an exploratory laparotomy. A CT scan of the abdomen and
pelvis may also be necessary. If there is fever, a trial of antibiotics may be
appropriate even if the workup is negative.
487

1. 
  2. 
PENILE SORES
 The presence of a painful penile sore suggests
chancroid, herpes simplex, herpes zoster, and balanitis. On the
contrary, a painless penile sore should suggest chancre,
lymphogranuloma venereum, epithelioma, granuloma inguinale, and
papilloma.
Is there inguinal adenopathy?
 If there is inguinal adenopathy,
lymphogranuloma venereum, epithelioma, and chancre should be
Routine studies include a smear and culture of material from the sore and a
dark field examination. All patients deserve a test for HIV especially if
there is risky sexual behavior. A VDRL test should be performed if
syphilis is suspected. Many cases require a biopsy of the lesion or a biopsy
of the lymph node.
A Frei test will help diagnose lymphogranuloma venereum. A Tzanck
test, serologic test, and viral isolation will help diagnose herpes zoster and
herpes simplex. There are also serologic tests for lymphogranuloma
venereum, if necessary. A lygranum test may help diagnose
lymphogranuloma inguinale. Difficult diagnostic problems should be
referred to an urologist.
488

1. 
  2. 
PERINEUM PAIN
Is there dysuria or a vaginal or urethral discharge?
suggest prostatitis, urethritis, cystitis, bladder calculus, bladder
carcinoma, vaginitis, and abscesses of Cowper’s glands.
Is there a rectal or anal mass or discharge?
hemorrhoids, perirectal abscess, anal fissure, anal ulcer, rectal
carcinoma, and condylomata lata.
Routine laboratory tests include a CBC, sedimentation rate, urinalysis and
urine culture, and a smear and culture of any discharge that is available. If
prostatitis is suspected, a serum PSA should be done. An anoscopy and
proctoscopy will help diagnose most rectal conditions. Pelvic ultrasound
will be helpful in diagnosing endometriosis, ectopic pregnancy, and pelvic
appendicitis. Referral to a gynecologist or urologist may be necessary in
some cases.
489

1. 
  2. 
  3. 
  4. 
PERIORBITAL EDEMA
Is there a periorbital or facial rash?
 The presence of a periorbital or
facial rash should suggest contact dermatitis, angioneurotic edema,
trichinosis, and herpes zoster. Remember, herpes zoster is usually
unilateral.
Is there a generalized edema?
 The presence of generalized edema
suggests myxedema, cirrhosis, acute and chronic glomerulonephritis,
congestive heart failure, and other disorders.
 The presence of fever suggests acute sinusitis,
cavernous sinus thrombosis, orbital cellulitis, meningitis, and
neurosyphilis.
(ACE) inhibitors and angiotensin II receptor blockers may cause
angioneurotic edema.
chemistry panel, thyroid profile, chest x-ray, VDRL test, and x-ray of the
sinuses and orbits. If there is fever, a nose and throat culture and blood
culture should be done and antibiotics begun without delay. A CT scan of
the brain and sinuses probably ought to be done in these cases, but why not
get an ear, nose, and throat or neurologic consultation first?
If there is generalized edema, the workup should proceed as outlined
on 
page 162
.
Trichinosis can be diagnosed by the skin test, serologic studies, or a
muscle biopsy. Superior vena cava syndrome may be diagnosed by a chest
x-ray in many cases, but a CT scan of the mediastinum may be necessary.
490

PERISTALSIS, VISIBLE
Visible peristalsis may be either gastric or intestinal, but it is invariably
associated with vomiting and other signs of intestinal obstruction.
In infants with pyloric obstruction, the vomiting is projectile, and the
severe dehydration that follows, along with the right upper quadrant mass
(a hypertrophied pylorus), helps to make the diagnosis.
In adults with pyloric obstruction, the enlarged stomach with peristaltic
waves going downward from left to right and a succussion splash are
useful diagnostic signs. A flat plate of the abdomen (demonstrating the
dilated stomach) and significant electrolyte alteration of metabolic
alkalosis and potassium depletion will help confirm the diagnosis, but an
exploratory laparotomy will remove all doubts.
Intestinal peristalsis is also associated with vomiting. The peristalsis is
transverse in small intestinal obstruction and vertical in large intestinal
obstruction. The abdomen is markedly distended. Once again, a flat plate
of the abdomen will confirm the diagnosis.
492

1. 
  2. 
  3. 
  4. 
PHOTOPHOBIA
Is there a history of exposure to drugs or toxins?
 Quinine, cocaine,
atropine, and Apresoline are just a few of the drugs that may cause
photophobia.
Are there abnormalities on the eye examination?
 Almost any
condition of the eye may cause photophobia, including conjunctivitis,
blepharitis, keratitis, iritis, corneal ulcers, and retinitis.
Are there abnormal tonometry readings?
 The eye may appear
normal, but the tonometry may disclose glaucoma.
 The presence of nuchal rigidity, especially
with fever, would suggest meningitis. Without fever or with only a
low-grade fever, the presence of nuchal rigidity should suggest
subarachnoid hemorrhage.
A careful eye examination including tonometry and slit lamp examination
should be done. A referral to an ophthalmologist may be necessary to
accomplish this. If there is nuchal rigidity, a CT scan followed by a spinal
tap should be done in conjunction with a neurologic consultation. If there
is fever without nuchal rigidity, the workup can proceed as outlined on
page 198
. A histamine test may be helpful in diagnosing migraine.
493

1. 
  2. 
  1. 
PLASMA CORTISOL
INCREASED
What is the ACTH level?
 An increased ACTH in the face of an
elevated plasma cortisol suggests a basophilic adenoma of the pituitary
or ectopic 
ACTH-producing
 tumors. A decreased ACTH coupled with
an increased plasma cortisol suggests adrenocortical hyperplasia,
adenoma, or carcinoma.
What are the results of a high-dose dexamethasone suppression
test?
 If there is suppression, look for adrenal hyperplasia. If no
response, look for adrenal adenoma or carcinoma.
DECREASED
 An increased ACTH coupled with a low
plasma cortisol is indicative of adrenal insufficiency, while a
decreased ACTH combined with a decreased plasma cortisol suggests
hypopituitarism or a hypothalamic disorder causing a drop in
corticotropin-releasing hormone secretion.
A basophilic adenoma is diagnosed by an MRI of the brain. Further testing
for hypopituitarism includes a metyrapone test, serum growth hormone,
FSH, LH, and TSH as well as an MRI or a CT scan of the brain. A CT
scan of the abdomen will help diagnose adrenal hyperplasia, adenoma, or
carcinoma. An ACTH stimulation test is an excellent test to diagnose
adrenal insufficiency but the CT scan of the abdomen is useful as well.
495

PNEUMATURIA
This condition is the passage of gas through the urethra. First, there may
be a rectovesical fistula. In these cases, usually there are feces in the urine
as well. The fistula results from ruptured diverticulitis, ruptured appendix,
or a neoplasm that forms a pelvic abscess that gradually eats its way into
Second, there may be a UTI with gas-producing organisms, usually
Escherichia coli.
 The patients are usually elderly diabetic females.
Urinalysis shows pus and often blood in both types. The fistula may be
diagnosed by an IVP, a barium enema, or cystoscopy. A urine culture may
show 
E. coli
, 
Enterobacter aerogenes
, or yeasts in those cases without a
communicating fistula. A course of antibiotic therapy will usually clear up
the UTI and stop the pneumaturia. If it does not, the search should
continue for a fistula.
497

1. 
  2. 
  3. 
POLYCYTHEMIA
A 36-year-old white female presents for an annual physical, and you are
immediately struck by how flushed her face is. You ask about chronic use
of alcohol and she assures you that she rarely drinks. Looking through her
chart, you find laboratory results that show an increase in hemoglobin and
hematocrit. Following the algorithm, you check for clinical signs of
dehydration, and there are none. Her oxygen saturation is 96%, so
pulmonary fibrosis or emphysema is an unlikely cause. You order a serum
erythropoietin and it is normal. You suspect polycythemia vera, but note
that she is obese and has purple abdominal striae. You suspect Cushing’s
syndrome and the plasma cortisol confirms your diagnosis.
What is the plasma volume?
 If the plasma volume is decreased,
think of dehydration, diuretic use, or other factors.
What is the arterial oxygen saturation?
 Decreased oxygen
saturation would suggest emphysema, pulmonary fibrosis, or
cardiovascular disorder.
Is the blood erythropoietin level increased?
 An increase in the
blood erythropoietin would suggest an erythropoietin-secreting tumor
such as renal carcinoma or pheochromocytoma. A normal or
decreased erythropoietin would point to polycythemia vera, heavy
cigarette smoking, or methemoglobinemia.
In addition to blood gas analysis, blood volume studies, CBC, platelet
count, serum erythropoietin, chemistry panel, urinalysis, and
sedimentation rate, most patients should have an IVP or CT scan of the
abdomen and pulmonary function tests and a chest x-ray. A hematology
consult would be wise before undertaking any of the more expensive
studies.
498

1. 
  2. 
  3. 
  4. 
POLYDIPSIA
 Diuretics and arsenic poisoning
are among the many causes of excessive thirst.
Is there associated polyphagia and weight loss?
these symptoms would suggest diabetes mellitus and hyperthyroidism.
Is there massive polyuria?
 The presence of massive polyuria
suggests diabetes insipidus or psychogenic polydipsia.
Is there mild polyuria?
 The presence of mild polyuria should suggest
chronic renal failure, renal tubular acidosis, hyperparathyroidism, and
The basic workup includes a CBC, sedimentation rate, urinalysis, 24-hour
urine volume, a serum and urine osmolality, a thyroid profile, and x-ray of
the skull and long bones.
The diagnosis of hyperparathyroidism may be assisted by ordering a
serum PTH level. Also, a 24-hour urine collection for calcium may be
done to help diagnose this condition. Microscopic examination of the
urinary sediment will help diagnose renal disease, as will renal biopsies. If
pituitary diabetes insipidus is suspected, a CT scan of the brain and blood
tests for serum growth hormone, FSH, LH, ACTH, and TSH may be done.
The Hickey–Hare test and monitoring intake and output before and after
vasopressin (Pitressin) will be useful in differentiating pituitary diabetes
insipidus from nephrogenic diabetes insipidus. The concentrations of
circulating vasopressin may be measured by immunoassay.
An endocrinologist should be consulted before ordering these
expensive diagnostic tests.
500

1. 
  2. 
  3. 
  4. 
POLYPHAGIA
Is there associated polydipsia, polyuria, and weight loss?
 The
presence of these symptoms would suggest diabetes mellitus or
 This symptom would indicate that
the patient has an insulinoma, Cushing’s disease, or idiopathic obesity.
Is there associated anxiety, depression, or other emotional
problems?
 These symptoms would signal that the polyphagia is
related to bulimia, hysteria, or other psychic disorder.
Is there associated diarrhea?
 This would suggest that the disorder is
related to a malabsorption syndrome, intestinal bypass, or
gastrointestinal (GI) fistula.
The basic workup of polyphagia should include a CBC, sedimentation rate,
chemistry panel, thyroid profile, and stool for ovum and parasites.
If diabetes mellitus is suspected, a glucose tolerance test may be done.
If Cushing’s disease is suspected, a serum-free cortisol should be done. If
an insulinoma is suspected, plasma insulin or C-peptide levels may be
done, or the patient may be hospitalized for a 72-hour fast with frequent
blood sugar determinations. If hyperthyroidism, diabetes mellitus,
insulinoma, and intestinal disorders have been ruled out, a referral to a
psychiatrist would be indicated.
502

1. 
  2. 
  3. 
  4. 
  5. 
POLYURIA
 Migraine, asthma, and drugs such as diuretics may
produce transient polyuria.
Is it massive?
 Massive polyuria is usually because of pituitary or
nephrogenic diabetes insipidus and psychogenic polydipsia. It may
also be because of diabetes mellitus.
Is there polyphagia and polydipsia?
 The presence of polyphagia and
polydipsia suggests the possibility of diabetes mellitus and
Is the polyuria mild?
 The presence of a mild polyuria suggests
chronic nephritis, renal tubular acidosis, hyperparathyroidism,
Fanconi’s syndrome, and mild diabetes mellitus.
Is there glycosuria?
 The presence of glycosuria suggests diabetes
mellitus, hyperthyroidism, and Fanconi’s syndrome.
Routine tests include a CBC, sedimentation rate, urinalysis, urine culture
and colony count, chemistry panel, thyroid panel, serum PTH, and x-ray of
the skull and long bones. The 24-hour intake and output should be
measured. A serum and urine osmolality will be helpful, as would a spot
urine sodium.
If pituitary diabetes insipidus is suspected, a CT scan of the brain and
tests for pituitary hormones should be done. The intake and output before
and after Pitressin may be measured. Alternatively, a water deprivation test
may be done but under close supervision!
If renal disease is suspected, the urinary sediment should be examined
microscopically and renal biopsy may be necessary. An endocrinologist
and nephrologist should be consulted before undertaking expensive
503

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
POPLITEAL SWELLING
Is it soft or firm?
 A soft popliteal swelling may be an abscess,
varicose vein, Baker’s cyst, popliteal aneurysm, or swollen bursa. A
firm popliteal swelling may be an osteosarcoma, periostitis, giant cell
tumor, exostoses, lymphadenitis, lipoma, or fibroma.
If the mass is firm, is it connected to the bone?
 Masses that are
connected to the bone are more likely exostoses, osteosarcomas,
periostitis, or giant cell tumors. They may also be a subperiosteal
hematoma.
 The presence of fever with a popliteal swelling would
suggest an acute abscess.
 If the popliteal swelling is reducible, a varicose vein
is most likely.
Is there associated arthritis of the knee joint?
associated arthritis of the knee joint suggests a Baker’s cyst.
Is it pulsatile?
 If the mass is pulsatile, a popliteal aneurysm should be
Routine tests include a CBC, sedimentation rate, and x-ray of the knee. If
these are negative, an MRI or a CT scan of the knee may be ordered, and
aspiration of the mass may be undertaken if the mass is not pulsatile or
there is no bruit over the mass. However, it is more cost-effective to seek
an orthopedic consultation before ordering these tests or undertaking
aspiration of the swelling. If the mass is pulsatile, ultrasonography or
angiography may be performed. If osteomyelitis is suspected, a bone scan
will be helpful.
505

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
PRECOCIOUS PUBERTY
Is there a history of anabolic steroid ingestion?
 Children may take
birth control pills early in life, and young boys may want to take
anabolic steroids to increase their muscular mass.
Is there headache, papilledema, or other neurologic signs?
 These
findings would suggest a brain tumor, and a pinealoma is one that
should be excluded.
Is there unilateral hyperpigmentation?
 This finding suggests
McCune–Albright syndrome.
 The presence of a testicular mass would
suggest Leydig cell tumor or hyperplasia.
Is there an adnexal mass?
 The presence of an adnexal mass would
suggest a granulosa cell tumor or arrhenoblastoma.
Is there an adrenal mass?
 The presence of an adrenal mass would
suggest adrenocortical hyperplasia or tumor.
Is there masculinization?
 This finding would suggest an
arrhenoblastoma.
Is there no mass detected on physical examination?
 The absence of
any mass would suggest constitutional precocious puberty.
chemistry panel, VDRL test, rapid ACTH test, serum testosterone,
dihydrotestosterone, dehydroepiandrosterone, and a flat plate of the
abdomen. If a brain tumor is suspected, a CT scan of the brain may be
done. If an adrenal tumor is suspected, a CT scan of the abdomen and
pelvis may be performed. Pelvic ultrasound or a CT scan of the pelvis may
identify an ovarian tumor. Ultrasound may help evaluate a testicular mass.
It is best to consult an endocrinologist, urologist, or gynecologist before
ordering these expensive diagnostic tests.
507

PRECORDIAL THRILL
Because a thrill is essentially a murmur that is bold enough to be felt by
the hand placed on the precordium, the differential diagnosis of this sign is
the same as for murmurs (
page 88
). Conditions more often associated with
a thrill are ventricular septal defect, pulmonic stenosis, and the
combination of the two that is found with tetralogy of Fallot. The
diagnostic workup is the same as for murmurs.
509

PREMENSTRUAL TENSION
This is the emotional tension, insomnia, depression, and irritability
associated with the premenstrual week. Somatic sensations associated with
this syndrome are similar to pregnancy and include bloating, cramping,
tenderness of the breasts, swelling of the hands and feet, and temporary
weight gain. The regular association of these symptoms with a certain
period of the menstrual cycle makes the diagnosis almost a certainty.
510

1. 
  2. 
  3. 
  4. 
PRIAPISM
Is there paraplegia or other neurologic signs?
 Neurologic findings
would suggest spinal cord trauma, tumor or inflammation, multiple
sclerosis, and several other disorders.
Is there splenomegaly or lymphadenopathy?
suggest leukemia and other blood dyscrasias.
Is there African ancestry?
 This finding would suggest sickle cell
anemia.
 Urethral tumors,
traumatic hematomas of the penis, thrombosis of the corpora
cavernosa, and prostatism may cause priapism.
The basic workup includes a CBC, sedimentation rate, urinalysis, urine
culture and colony count, sickle cell preparation, coagulation profile,
chemistry panel, and serum protein electrophoresis. An urologist should
also be consulted.
If there are neurologic signs, an MRI of the brain or appropriate level
of the spinal cord should probably be done. However, a neurologist should
be consulted before ordering these expensive tests. A spinal tap will be
helpful in diagnosing multiple sclerosis and central nervous system
syphilis.
511

1. 
  2. 
  3. 
PROLONGED PROTHROMBIN TIME
 Cirrhosis of the liver and
obstructive jaundice are associated with a prolonged prothrombin
time.
Is the thrombin time prolonged?
 A prolonged prothrombin and
thrombin time should make one suspect DIC, heparin therapy, or
polycythemia vera.
What is the platelet count?
 A decreased platelet count associated
with a prolonged prothrombin time is found in acute leukemia and
myelophthisic anemia and occasionally DIC.
Further workup of a patient who presents with a prolonged prothrombin
time requires a CBC and platelet count to rule out acute leukemia and
polycythemia vera, fibrin split product tests to pick up DIC and a bone
marrow examination or liver biopsy.
513

1. 
  2. 
  3. 
  4. 
PROTEINURIA
Are there significant numbers of white blood cells (WBCs) in the
urine?
 This would suggest a UTI. If there are white cell casts or
clumps, the infection may be a pyelonephritis. A urine culture and
colony count should be ordered. Sterile urine with persistent
proteinuria and pyuria may be seen in toxic nephritis.
Are there increased RBCs in the urine?
glomerulonephritis, collagen disease, polycystic kidney, tuberculosis,
renal calculus, trauma, or neoplasm. The presence of red cell casts
would make glomerulonephritis or collagen disease more likely.
Is glucose present in the urine?
 This would point to diabetic
nephritis or nephrosis.
If none of the above associated findings are present, one should look
for hypertension, toxemia of pregnancy, fever, cardiac disease,
poisoning, orthostatic proteinuria, multiple myeloma, or amyloidosis.
When faced with a report of protein in the urine, the first thing to do is
look at the urine under the microscope. If there are significant numbers of
bacteria and WBCs, one only has to order a urine culture and colony count
and begin therapy. Recurrent UTIs warrant an IVP and a referral to an
urologist, especially in males. If no infection is found, a more thorough
workup is warranted, including CBC, chemistry panel, serum protein
electrophoresis, ANA, sedimentation rate, urine for Bence Jones protein,
Addis count, ASO titer, CRP, and a CT scan of the abdomen. An urologist
may need to be consulted for cystoscopy and retrograde pyelography. A
nephrologist may need to be consulted for renal biopsy and further
515

PRURITUS, ANI
Itching at the anus is almost always because of anal or rectal conditions,
the most likely of which is hemorrhoids. If there is frequent passage of
bright red blood in the stool along with a painful bowel movement, one
should look for an anal fissure. If there is a chronic discharge, one should
look for an anal fissure or rectal prolapse. Pinworms must be sought in
children. Finally, contact dermatitis and candidiasis are always possible. If
candidiasis is the cause, a search for diabetes mellitus should be made.
If the physical examination is normal, examination with an anoscope is
essential. Sigmoidoscopy should also be done but is not adequate to detect
hemorrhoids, anal fissures, and fistulas. If these are negative, a trial of
antifungal creams (Lotrimin, etc.) should be given before other expensive
diagnostic tests are ordered. A Scotch tape test and stool for ovum and
parasites are useful, especially in children.
517

1. 
  2. 
  3. 
  4. 
  5. 
PRURITUS, GENERALIZED
Is the pruritus associated with a generalized rash?
 Almost every
generalized rash may be associated with pruritus, but the most
common ones are urticaria, dermatitis herpetiformis, eczema, scabies,
and pemphigus.
Is there hepatomegaly or jaundice?
or jaundice should make one think of obstructive jaundice, hepatitis,
metastatic carcinoma to the liver, and biliary cirrhosis. However,
almost any form of liver disease may be associated with pruritus.
Is there polyuria, polydipsia, and polyphagia?
would suggest diabetes mellitus, hyperthyroidism, and pregnancy.
Pruritus during the first trimester is called pruritus gravidarum of
unknown origin.
Is there an unusual odor?
 The presence of an unusual odor should
bring to mind the possibility of uremia, liver failure, or diabetic
acidosis.
Is there plethoric facies?
 The presence of plethoric facies suggests
If there is an associated skin rash, microscopic examination of a potassium
hydroxide preparation of curetted burrows will be helpful. Additional
examinations include Wood’s lamp evaluation, a patch test, and skin
biopsies. Therapeutic trials for scabies, fungal disease, or other disorders,
however, are justified if testing is not economically feasible. Routine
laboratory tests for the various systemic diseases that may cause pruritus
include a CBC, sedimentation rate, urinalysis, chemistry panel, ANA
assay, thyroid profile, and serum protein electrophoresis. Don’t forget to
order an antimitochondrial antibody titer to rule out primary biliary
cirrhosis. A bone marrow examination and lymph node biopsy may be
useful. A dermatologist, hematologist, or endocrinologist may help solve
the diagnostic dilemma. Further workup may include plain films of the
chest and abdomen and CT scans of the abdomen and pelvis. A bone scan
may be useful in diagnosing metastatic carcinoma. HIV testing may be
indicated if the patient has a history of high-risk sexual behavior.
518

1. 
  2. 
  3. 
PRURITUS, VULVAE
Is there a vaginal discharge?
 The presence of a vaginal discharge
should suggest candidiasis, trichomoniasis vaginitis, and bacterial
vaginitis.
 The presence of a rash would suggest eczema, herpes
simplex, folliculitis, scabies, and tinea infections.
Are there vulval or vaginal lesions?
 The presence of a lesion in the
vulva or vagina would suggest kraurosis vulvae, leukoplakia or vulval
carcinoma, condylomata lata, and condylomata acuminata.
If there is a discharge, microscopic examination of a potassium hydroxide
preparation and saline preparation is necessary. A smear and culture of the
discharge should be done for bacteria and fungi. Scrapings of the burrows
for scabies may be useful. Skin biopsy may help diagnose the cause of a
rash. Lesions should also be biopsied. If senile vaginitis is suspected,
serum FSH and estradiol and a Pap smear may help determine if there is
estrogen deficiency. A gynecologist should be consulted in all difficult
diagnostic problems.
520

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
PTOSIS
Are there abnormalities on eye examination?
 Pseudoptosis occurs
when there is inflammation of the eyelid, cornea, or other ocular
structures. Periorbital edema, conjunctivitis, and trachoma are among
the many disorders to consider.
 Intermittent ptosis would suggest myasthenia
gravis, ophthalmoplegic migraine, and transient ischemic attacks.
Is it partial?
 The presence of partial ptosis would suggest Horner’s
syndrome, especially if there is a constricted pupil. However,
myotonic dystrophy, myasthenia gravis, and progressive muscular
atrophy are just three of the disorders that may present with partial
ptosis.
Is there a dilated pupil?
 The presence of a dilated pupil, especially
with a unilateral ptosis, suggests a ruptured cerebral aneurysm.
However, if the dilated pupil is associated with many other neurologic
signs, then there are many other conditions to consider.
Is there a constricted pupil?
 The presence of a constricted pupil with
unilateral complete ptosis would suggest diabetic neuropathy.
However, if there is bilateral complete ptosis, chronic progressive
external ophthalmoplegia and myasthenia gravis should be considered.
Are there other cranial nerves involved?
 The presence of other
cranial nerve signs should suggest cavernous sinus thrombosis,
cerebral aneurysm, tuberculous meningitis, syphilitic meningitis,
Wernicke’s encephalopathy, diphtheria, and subdural hematoma.
would suggest syringomyelia, platybasia, brain stem tumors, vertebral
basilar occlusion or insufficiency, multiple sclerosis, epidemic
encephalitis, and general paresis.
 The presence of hypoactive reflexes
would suggest myotonic dystrophy, tabes dorsalis, and progressive
muscular atrophy.
If there are local conditions responsible for the ptosis, then a smear and
culture of the exudate and slit lamp examination or tonometry can be done,
or the patient should be referred to an ophthalmologist. If a neurologic
522

disease is suspected, a neurologist should be consulted, especially if the
onset is acute.
chemistry panel, glucose tolerance test, ANA, VDRL test, and x-ray of the
skull and sinuses. A CT scan or an MRI of the brain must be done in most
cases. If myasthenia gravis is suspected, a Tensilon test and acetylcholine
receptor antibody titer can be done.
If encephalitis, meningitis, central nervous system lues, or multiple
sclerosis are suspected, a spinal tap may be useful. Intravenous thiamine is
administered in Wernicke’s encephalopathy. If Horner’s syndrome is
suspected, the workup may be found on 
page 256
. If muscular dystrophy is
suspected, a 24-hour urine collection for creatinine and creatine and a
muscle biopsy may be done. Cerebral angiography will be necessary to
diagnose most cerebral aneurysms and cerebral vascular disease, including
transient ischemic attacks.
523

1. 
  2. 
  3. 
  4. 
  5. 
PTYALISM
 Mercury, iodides, and
mouthwash are some of the substances that may cause ptyalism.
Is the oral examination abnormal?
 Peritonsillar abscess, carious
tooth, ulcerating tumor, herpes simplex, aphthous stomatitis, and ill-
fitting dental plates are all conditions that may cause ptyalism. In
addition, fracture and dislocation of the jaw may cause ptyalism.
 The presence of intermittent ptyalism should
suggest myasthenia gravis.
 The
presence of abnormalities on the neurologic examination should
suggest pseudobulbar palsy, bulbar palsy, Parkinsonism, dementia,
idiocy, rabies, and facial palsies.
Is there atrophy of the tongue?
 Atrophy of the tongue will
differentiate bulbar palsy from pseudobulbar palsy.
If there are abnormalities on the examination of the mouth, a referral to a
dentist or oral surgeon should be considered. However, many of these
conditions can be treated by the family physician. If there are neurologic
abnormalities, a referral to a neurologist should be considered before
ordering a CT scan or an MRI of the brain and other expensive diagnostic
tests. In addition to imaging studies, the basic workup of ptyalism might
include a spinal tap, nerve conduction velocity studies, EMG, Tensilon
tests, and evoked potential studies. A neurologist is in a better position to
determine which of these studies is appropriate in any given case.
525

PULSATILE SWELLING
A pulsatile swelling anywhere is an aneurysm until proven otherwise.
However, frequently, there is simply a benign or malignant tumor over a
large artery that gives the false impression that the mass is an aneurysm
when it is not. In the abdomen, a normal abdominal aorta may be mistaken
for an aortic aneurysm, especially in thin patients. In the neck, normal
carotid, brachial, or innominate arteries may pulsate vigorously when there
is aortic regurgitation. Eggshell cracking along with the pulsation in a
mass should suggest an osteosarcoma. A pulsating mass in the right upper
quadrant is most likely the enlarged liver because of tricuspid regurgitation
or stenosis. The presence of dependent edema and ascites will support the
diagnosis. A pulsating tumor of the orbit is most likely a carotid cavernous
fistula.
In cases of suspected abdominal aortic aneurysms, abdominal ultrasound
will help differentiate the normal aorta or a tumor from a true aneurysm.
When in doubt, a CT scan or aortography should be done. It will be
necessary before surgery anyway.
All other cases of pulsatile masses suggesting an aneurysm should
receive angiography of the artery or arteries supplying the area.
527

1. 
  2. 
  3. 
PULSE IRREGULARITY
Is the rate normal, rapid, or slow?
 A rapid rate would suggest
supraventricular tachycardia, ventricular tachycardia, atrial flutter, and
fibrillation. A slow rate would suggest atrioventricular (AV) nodal
rhythm, third-degree AV block, sinoatrial block, Wenckebach
phenomena, and sick sinus syndrome. A normal rate would suggest
atrial and ventricular premature contractions, AV dissociation,
bigeminal rhythm, and controlled flutter or fibrillation.
If the rate is rapid, is it regular or irregular?
 A rapid regular rate
would suggest supraventricular tachycardia or ventricular tachycardia,
whereas a rapid irregular rate would suggest atrial flutter or
fibrillation.
If the rate is slow, is it regular or irregular?
 A slow regular rhythm
would suggest AV nodal rhythm, third-degree AV block, or sinoatrial
block. A slow irregular rhythm would suggest Wenckebach
phenomena or sick sinus syndrome.
Some physicians will want to refer the patient with a pulse irregularity to a
cardiologist at the outset. Other clinicians would rather investigate the
patient further.
Routine tests ordered include CBC, sedimentation rate, urinalysis,
chemistry panel, serial cardiac enzymes, thyroid profile, ANA test, EKG,
and chest x-ray with lateral and anterior oblique views. If there is fever, an
ASO titer or streptozyme test should be done to rule out rheumatic fever,
and blood cultures should be done to rule out bacterial endocarditis. If the
EKG is normal and the symptoms are intermittent, 24-hour Holter
monitoring should be done. The patient also can be hospitalized for a few
days for telemetry. Newer technology includes using a continuous-loop
event recorder to allow monitoring for 2 weeks at a time.
Echocardiography will disclose valvular diseases and myocardiopathies.
His bundle studies may be necessary in some cases. Also, angiography and
catheterization studies should be considered in difficult cases. Before
expensive tests are ordered, it is wise to consult a cardiologist.
528

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
PULSES, UNEQUAL
 Acute reduction of the pulse of an extremity may be
because of an arterial embolism, dissecting aneurysm, or fracture of
the limb.
Does it involve the upper extremities only?
 The upper extremities
are involved selectively in the subclavian steal syndrome, Takayasu’s
disease, a few cases of coarctation of the aorta, congenital anomalies,
thoracic outlet syndrome, aneurysm of the arch of the aorta, and
supravalvular aortic stenosis.
Is there a history of transient ischemic attacks?
transient ischemic attacks should suggest subclavian steal syndrome
and Takayasu’s disease.
 The presence of hypertension should suggest
coarctation of the aorta.
Does it involve the lower extremities only?
 Involvement of the lower
extremities only would suggest peripheral arteriosclerosis, Buerger’s
disease, arteriovenous fistula, and Leriche’s syndrome.
Are both the proximal and distal pulses in the lower extremities
diminished?
 These findings would suggest a Leriche’s syndrome.
Does it involve the upper and lower extremities?
 Involvement of
both the upper and lower extremities would suggest coarctation of the
aorta and dissecting aneurysm.
If the onset is acute, angiography must be done without delay. With a
history of trauma, plain films of the involved extremity are essential to rule
out fracture. If the onset is gradual, then Doppler studies may be done
before angiography. However, angiography will ultimately be necessary in
most cases. It is wise to consult a cardiovascular surgeon at the outset. If
an arterial embolism is suspected, the source for the embolism must be
sought. Serial EKGs and serial cardiac enzymes may disclose an acute
myocardial infarction with a mural thrombus. An EKG may disclose
auricular fibrillation. Blood cultures may disclose subacute bacterial
530

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
PUPIL ABNORMALITIES
Are both pupils dilated?
 The presence of dilated pupils in an
otherwise normal subject would suggest drug intoxication, such as
phenobarbital, marijuana, and PCP. However, the patient may not
know that he or she had a concussion recently. Also, glaucoma may
cause dilatation of both pupils.
Are both pupils constricted?
 The presence of constricted pupils
would suggest narcotic intoxication. It should also suggest
organophosphate intoxication.
Is one pupil dilated?
 The presence of a dilated pupil should suggest
oculomotor nerve palsy such as may be because of a ruptured
aneurysm or intracranial hematoma. However, if the pupil reacts to
light and accommodation, a local condition such as iritis, glaucoma,
anisocoria, or irritation of the cervical sympathetic nerves must be
considered. If the pupil reacts to accommodation but not to light, then
central nervous system syphilis must be suspected. If there is no
reaction to light or accommodation, blindness must be considered
because of optic nerve lesions.
If one pupil is dilated, does it react to light and accommodation?
This finding would suggest a local condition, such as iritis, glaucoma,
anisocoria, or irritation of the cervical sympathetic nerves.
Is one pupil constricted?
 The presence of a constricted pupil would
suggest Horner’s syndrome.
Is there ptosis?
 The presence of ptosis with a constricted pupil would
suggest Horner’s syndrome. If there is no ptosis with the constricted
pupil, a brain stem lesion, such as syringomyelia, tumor, abscess, or
encephalitis must be considered.
Is there blindness?
 The presence of blindness with a dilated pupil
would suggest optic nerve lesions.
Patients with bilateral dilated or constricted pupils should have a urine
drug screen and possibly a blood test for alcohol level. If there is fever or a
history of trauma with dilated or constricted pupils or other pupillary
abnormalities, a neurologist or neurosurgeon should be consulted
immediately before ordering expensive diagnostic tests.
532

Primary eye conditions can be excluded by tonometry, slit lamp
examination, or ophthalmology consultation. Intracranial neoplasms and
aneurysms must be excluded by CT scans, MRIs, and possibly
angiography. A spinal tap will help diagnose central nervous system lues
or multiple sclerosis. VEP studies will help diagnose multiple sclerosis.
The workup for Horner’s syndrome can be found on 
page 256
.
533

1. 
  2. 
  3. 
  4. 
PURPURA AND ABNORMAL BLEEDING
Is there a petechial rash?
 The presence of a petechial rash suggests
either a thrombocytopenic purpura, which may be idiopathic or
secondary to leukemia, aplastic anemia, collagen disease, or drugs. In
addition, petechiae may suggest platelet dysfunction, in which case the
platelet count will be normal, or vasculitis, such as from collagen
diseases, hereditary telangiectasia, scurvy, or drugs.
Is there ecchymosis or bruises?
 The presence of ecchymosis or
bruises would suggest hemophilia, Christmas disease, or other major
coagulation defects, but it may also be related to platelet disorders or
DIC.
If there is a petechial rash, is the platelet count normal?
 The
presence of a normal platelet count would suggest either
thrombocytopathy or vasculitis.
Is there significant mucosal bleeding?
 The presence of mucosal
bleeding along with ecchymosis and bruises suggests platelet disorders
or DIC.
If a coagulation disorder is suspected, consult a hematologist first. Routine
diagnostic studies include a CBC, platelet count, sedimentation rate, blood
smear for red cell morphology, urinalysis, chemistry panel, coagulation
profile, rheumatoid arthritis factor, ANA test, serum protein
electrophoresis, VDRL test, EKG, chest x-ray, and flat plate of the
abdomen. The coagulation profile should include a platelet count, a
bleeding time, a coagulation time, a partial thromboplastin time, and a
prothrombin time.
If there is fever, blood cultures should be done. A bone marrow
examination and bone marrow culture may be useful. If DIC is suspected,
a fibrinogen assay and estimation of fibrin degradation products should be
done. Platelet function may be assessed by clot retraction tests. Spleen and
liver scans and bone scans may be needed. A CT scan of the abdomen and
pelvis may also be necessary. Skin, muscle, and even kidney biopsies are
often done to complete the workup.
It can be seen from the above array of diagnostic tests that a
hematologist should be consulted at the outset. Various forms of vasculitis
534

1. 
  2. 
  3. 
PYURIA
Are there significant RBCs in the urine?
 If so, one should consider
glomerulonephritis, collagen disease, tuberculosis, neoplasm, trauma,
renal calculus, and polycystic kidney disease. If not, the most likely
etiology is a UTI.
Are there WBC casts in the urine?
 This would make pyelonephritis
or interstitial nephritis more likely.
Are there RBC casts in the urine?
 This would help differentiate
glomerulonephritis and collagen diseases from the other conditions
associated with hematuria.
First, look at the urinary sediment under a microscope. Further workup
should include a urine culture and colony count, AFB smear and culture,
CBC, sedimentation rate, ANA test, chemistry panel, serum protein
electrophoresis, IVP, and a urology consultation. In cases of sterile pyuria
don’t forget to consider renal tuberculosis. A chest x-ray and sputum
culture for AFB should be done. An urologist may do cystoscopy and
retrograde pyelography. He may order a CT scan of the abdomen to rule
out renal carcinomas and other kidney diseases. A nephrologist may need
to be consulted in difficult cases. An urologist should be consulted in all
cases of recurrent or persistent pyuria.
536

1. 
  2. 
  3. 
  4. 
RALES
Are they crepitant, sibilant, or sonorous?
 Crepitant rales signify
congestive heart failure, pneumonia, tuberculosis, pulmonary
embolism, adult respiratory distress syndrome, and aspiration
pneumonitis. Carcinoma of the lung may also present with crepitant
rales. Sibilant or sonorous rales, on the other hand, signify
bronchiectasis, asthma, emphysema, pneumoconiosis, and a foreign
body. Carcinoma of the lung is more likely to be associated with
sibilant and sonorous rales than crepitant rales.
Are they focal or diffuse?
 Focal crepitant rales may signify
pulmonary embolism, lobar pneumonia, or tuberculosis, whereas
diffuse crepitant rales are more likely to be associated with congestive
heart failure, adult respiratory distress syndrome, and aspiration
pneumonitis. Focal sibilant and sonorous rales are more likely to be
associated with foreign bodies, bronchiectasis, and carcinoma of the
lung, whereas diffuse sibilant and sonorous rales are more likely to be
associated with asthma, emphysema, or pneumoconiosis.
Is there associated chest pain?
 The presence of crepitant rales with
chest pain suggests pulmonary embolism, but it may also be
associated with congestive heart failure secondary to an acute
myocardial infarction.
Is there cardiomegaly?
 The presence of cardiomegaly suggests
congestive heart failure or pericardial effusion.
chemistry panel, ANA titer, VDRL test, chest x-ray, electrocardiogram
(EKG), and pulmonary function test. If sputum can be obtained, a smear
and culture of the sputum should be done. Sputum for eosinophils may
also be necessary if asthma is suspected.
If congestive heart failure is suspected, a venous pressure and
circulation time or BNP should be done. Echocardiography may be done to
determine the left ventricular ejection fraction (LVEF). If pulmonary
embolism is suspected, a ventilation–perfusion scan and possibly
pulmonary angiography may be necessary. Arterial blood gases are also
helpful. If tuberculosis is suspected, the appropriate skin tests and AFB
538

culture and guinea pig inoculation may be required. Skin tests and cultures
for the various fungi may be useful. Bronchoscopy and biopsy will be
helpful in diagnosing carcinoma of the lung. A consultation with a
pulmonologist, if not already done, is certainly necessary at this point.
539

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
RASH—DISTRIBUTION
 Focal rashes suggest dermatophytoses, scabies,
actinic dermatitis, herpes zoster, warts, contact dermatitis, erythema
nodosum, actinic dermatosis, dyshidrosis, skin tumors, nummular
eczema, stasis dermatitis, pyoderma, acne vulgaris, herpes simplex,
impetigo, and tuberous sclerosis. Diffuse rashes suggest xanthoma,
erythema multiforme, psoriasis, lichen planus, eczema, drug eruptions,
dermatitis herpetiformis, secondary syphilis, exfoliative dermatitis,
and pemphigus. A diffuse rash also may be due to pityriasis rosea and
tinea versicolor.
If diffuse, is it primarily the extremities that are involved?
 A
diffuse rash that involves primarily the extremities would suggest
smallpox and erythema multiforme, eczema, milium, lichen planus,
and psoriasis.
If diffuse, does it involve primarily the face and trunk?
 A diffuse
rash that involves primarily the face and trunk suggests chicken pox,
typhoid fever, German measles, pityriasis rosea, tinea versicolor, and
pemphigus.
If focal, does it primarily involve the extremities?
 A focal rash that
involves primarily the extremities suggests dermatophytosis, erythema
nodosum, contact dermatitis, warts, discoid lupus, actinic dermatosis,
scabies, dyshidrosis, skin tumors, nummular eczema, stasis dermatitis,
and pyoderma.
If focal, is it primarily involving the face and head?
 A rash that
involves primarily the face and head should suggest acne vulgaris,
acne rosacea, seborrheic dermatitis, herpes simplex, actinic
dermatosis, carcinoma, impetigo, contact dermatitis, Sturge–Weber
syndrome, tuberous sclerosis, and tinea capitis.
Is it equally distributed to the trunk and extremities?
 A rash that is
equally distributed to the trunk and extremities would suggest herpes
zoster, neurofibromatosis, scarlet fever, drug eruptions, dermatitis
herpetiformis, secondary syphilis, measles, and exfoliative dermatitis.
Before launching an expensive diagnostic workup, look for systemic
symptoms and signs. For example, a rash with bloody diarrhea suggests
540

ulcerative colitis or Crohn’s disease. A rash with joint pain would suggest
lupus erythematosus or gonorrhea. If there are any exudates, a smear and
culture for fungi and routine bacteria should be done. Skin scrapings may
be examined microscopically with a saline or potassium hydroxide
preparation to rule out scabies and fungi. A Wood’s lamp examination is
very useful in diagnosing various fungi. All isolated lesions should be
biopsied.
Diffuse rashes require routine CBC, sedimentation rate, urinalysis,
chemistry panel, ANA test, and VDRL test. If there is fever, blood cultures
should probably be done. Skin biopsies in consultation with a
dermatologist should be done in a timely fashion. Patch testing and
intradermal skin testing should be done when appropriate. A dark field
examination may be necessary. Gastrointestinal (GI) series, CT scan of the
abdomen, and barium enemas may be necessary to look for GI neoplasms,
Crohn’s disease, and ulcerative colitis.
541

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
RASH—MORPHOLOGY
Is the rash macular or papular?
 A macular or papular rash would
suggest scarlet fever, measles, erythema multiforme, exfoliative
dermatitis, pityriasis rosea, eczema, contact dermatitis, secondary
syphilis, drug eruption, and actinic dermatoses.
Is the rash pustular?
 A pustular rash suggests staphylococcus,
scabies, secondary syphilis, acne, folliculitis, and dermatophytosis.
Is the rash vesicular or bullous?
 A bullous or vesicular rash would
suggest chicken pox, smallpox, dermatitis herpetiformis, contact
dermatitis, pemphigus, herpes zoster, bullous impetigo, herpes
simplex, dyshidrosis, and nummular eczema. Hand, foot and mouth
disease is associated with a vesicular rash of the hands and feet along
with a stomatitis. It is caused by a coxsackie virus.
Is the rash scaly?
 A scaly rash suggests ichthyosis, psoriasis, lichen
planus, neurodermatitis, dermatophytosis, exfoliative dermatitis, and
drug eruptions. Seborrheic dermatitis is usually scaly with an
erythematous base. Sudden onset of this condition should prompt a
search for HIV.
Are there ulcers?
 The presence of ulcers in the lesions would suggest
basal cell carcinoma, syphilis, lupus erythematosus, diabetic ulcers,
ischemic ulcers, pyoderma gangrenosum, and ecthyma.
 The presence of fever suggests scarlet fever, measles,
erythema multiforme, exfoliative dermatitis, serum sickness, chicken
pox, and smallpox.
Could the rash be complicated by a secondary infection?
 Always a
good question to ask.
Does it itch?
 Pruritus is associated with urticaria, contact dermatitis,
and eczema. It is not common with psoriasis, lichen planus, and herpes
zoster.
This can be found under Rash—Distribution (
page 433
).
542

1. 
  2. 
  3. 
  4. 
  5. 
RAYNAUD’S PHENOMENA
 Ergotamine, methysergide, and
beta-adrenergic
 receptor blockers are just a few of the drugs that may
cause Raynaud’s phenomena.
Is there involvement of only one upper extremity?
 When there is
involvement of only one upper extremity, thoracic outlet syndrome,
especially cervical rib, arteriosclerosis of the subclavian artery, and
embolism should be considered.
Is there thickening of the skin?
 Thickening of the skin should bring
to mind scleroderma.
 The presence of hypertension might suggest
periarteritis nodosa and other collagen diseases, polycythemia vera,
macroglobulinemia, cold agglutinins, and sickle-cell anemia.
Are there abnormalities of the blood cells, red cell mass, or serum
proteins?
 These findings would suggest polycythemia vera,
chemistry panel, serum protein electrophoresis, ANA titer, chest x-ray, and
EKG.
If macroglobulinemia is suspected, a Sia water test and serum
immunoelectrophoresis may be done. If cold agglutinins are suspected, a
test for cold agglutinins may be done. A sickle-cell preparation may be
necessary if the patient is black. Collagen diseases may be further
evaluated by skin and muscle biopsy and esophageal manometry.
Raynaud’s phenomena may be demonstrated by immersing the hands
in water at a temperature of 10°C to 15°C. Whole body exposure to cold is
an even better way of demonstrating the actual Raynaud’s phenomena.
The finding of 
nail-fold
 capillary-loop dilation and drop out may also help
diagnose Raynaud’s phenomena. If scleroderma is suspected, an
antisclerodermal antibody titer is done.
Doppler studies and arteriography will rule out subclavian artery
occlusions. A rheumatology or neurology consultation may be helpful.
544

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
Is it severe?
 The presence of severe rectal bleeding would suggest
ulcerative colitis, amebic dysentery, bacillary dysentery,
intussusception, mesenteric thrombosis or embolism, diverticulitis,
ischemic colitis, and coagulation disorders.
Is there diarrhea and/or mucus?
 The presence of diarrhea with or
without mucus would suggest ulcerative colitis, amebic dysentery, or
bacillary dysentery.
Are there signs of intestinal obstruction?
 The presence of signs of
intestinal obstruction would suggest intussusception, mesenteric
thrombosis, or embolism.
If the bleeding is mild, is the bleeding mixed well with the stools?
Rectal bleeding that is mixed well with the stools suggests carcinoma
of the colon, ulcerative colitis, Crohn’s disease, Meckel’s
diverticulum, diverticulitis, and coagulation disorder.
Are there painful bowel movements?
 The presence of painful bowel
movements, especially with bright-red bleeding, would suggest anal
fissure or thrombosed hemorrhoid.
Is there a rectal mass?
 The presence of a rectal mass would suggest a
polyp, carcinoma, or internal hemorrhoids.
Most cases can be diagnosed by anoscopy, sigmoidoscopy, and a barium
enema. A stool culture and examination for ovum and parasites should also
be done. If the diagnosis is uncertain after these studies, referral to a
gastroenterologist should be done for colonoscopy and other diagnostic
studies. Recently, virtual colonoscopy (CT colonoscopy) has been
developed as an alternative to conventional colonoscopy. Ask your
radiologist about this important test. This is a procedure, where a CT scan
is performed while the colon is distended with air or CO
2
. This no doubt
will replace the barium enema in the near future. A CT scan of the
abdomen is a lot more expensive than a GI consult. The gastroenterologist
may order angiography or small intestinal enteroscopy as well as
radioisotope studies.
546

1. 
  2. 
  3. 
RECTAL DISCHARGE
Is it mucopurulent or feculent?
 A mucopurulent discharge suggests
an anal fistula, perirectal abscess, proctitis, anal ulcer, or rectal
prolapse. A feculent discharge suggests anal incontinence, internal
hemorrhoids, chronic anal fissure, or ulcer.
 Painful discharge suggests a perirectal abscess, proctitis,
anal ulcer, or rectal prolapse.
neurologic examination suggests that there is anal incontinence from
an upper or lower motor neuron lesion. This may be due to spinal cord
trauma, multiple sclerosis, spinal cord tumor, transverse myelitis, and
many other disorders.
chemistry panel, and smear and culture of the discharge. A Frei test may
be necessary to rule out lymphogranuloma venereum. Sigmoidoscopy,
colonoscopy, and a barium enema may be needed in selected cases. A
proctologist or gastroenterologist should be consulted in difficult
diagnostic problems. If there are abnormalities on the neurologic
examination, a neurologist should be consulted.
548

1. 
  2. 
  3. 
  4. 
RECTAL MASS
 A painful rectal mass should suggest perirectal abscess,
thrombosed hemorrhoid, anal ulcer, ruptured ectopic pregnancy, tubo-
ovarian abscess, and pelvic appendix.
Is it soft or cystic?
 The presence of a soft or cystic mass would
suggest internal hemorrhoids, polyps, intussusception, villous tumor,
granular proctitis, ovarian cyst, and blood or pus in the 
cul-de-sac.
Is it hard?
 The presence of a hard lesion would suggest a fecal
impaction, foreign body, retroverted uterus, enlarged prostate,
malignant deposits in the pouch of Douglas, stricture, and carcinoma.
Is there associated bleeding?
 The presence of bleeding should make
one suspect carcinoma above all else, but it may be due to internal
hemorrhoids, polyps, intussusception, villous tumors, or granular
proctitis.
Routine laboratory tests include a CBC, sedimentation rate, and urinalysis.
A smear and culture should be made of any rectal or vaginal discharge.
Most cases will be diagnosed by anoscopy and proctoscopy. A pelvic
ultrasound and a CT scan of the abdomen and pelvis may be useful in
evaluating ectopic pregnancy and other gynecologic disorders. Ultrasound
of the prostate may also be done to evaluate a prostatic mass. A
gynecologist, proctologist, or urologist should be consulted in difficult
cases.
549

1. 
  2. 
  3. 
RECTAL PAIN
Is there bleeding?
 The presence of bleeding with pain suggests an
anal fissure, hemorrhoids, carcinoma, rectal prolapse, and
Is there a mass?
 The presence of rectal pain along with a mass would
suggest internal and external hemorrhoids, rectal carcinoma, and
perirectal or ischiorectal abscesses. However, in females, masses in
the cul-de-sac, such as an acute salpingitis, ectopic pregnancy, or
endometriosis, will cause rectal pain. In males, prostatic abscess,
foreign bodies, and seminal vesiculitis may cause rectal pain.
Is there a purulent discharge?
 Fistula-in-ano, perirectal abscess,
ischiorectal abscess, and submucous abscess may cause a purulent
discharge.
chemistry panel, VDRL test, anoscopy, sigmoidoscopy, and barium
enema. In females, a pregnancy test and vaginal smear and culture should
be done. Ultimately, culdocentesis, pelvic ultrasound, a CT scan of the
pelvis, and laparoscopy may be necessary, but a gynecologist should be
consulted before considering these tests. In males, prostatic massage may
yield a urethral discharge for smear and culture. An IVP or cystoscopy
with retrograde pyelography may also be helpful.
551

1. 
  2. 
  3. 
  4. 
RED EYE
 Unilateral redness of the eye is more
likely bacterial conjunctivitis, a foreign body, herpes corneal ulcer,
corneal abrasion but be sure to look for herpes zoster, or cluster
headache. Visual acuity is usually normal in conjunctivitis and cluster
headache.
If there is only unilateral redness but the redness is circumcorneal
or focal, is the pupil dilated or constricted?
 A dilated pupil suggests
glaucoma, while a constricted or irregular pupil is more likely iritis. If
the pupil is normal and reacts to light and accommodation, look for
episcleritis, herpes simplex, or a corneal abrasion.
If there is bilateral redness, is it diffuse?
 Diffuse bilateral redness
makes viral or allergic conjunctivitis more likely than bacterial
conjunctivitis. If the palpebral conjunctiva are not involved, consider
the possibility of scleritis.
If there is bilateral redness, is it focal or circumcorneal?
 This
finding would suggest iritis, glaucoma, or keratitis which can again be
differentiated by the appearance of the pupil. Visual acuity is usually
affected in these disorders but not in conjunctivitis.
In cases of unilateral red eye with normal visual acuity in the involve eye,
a diagnostic workup is unnecessary other than a fluorescence dye test to
rule out a foreign body or corneal abrasion. If the visual acuity is affected
or the pupil is dilated or constricted, immediately referral to an
ophthalmologist is indicated. The same is true of bilateral red eye. Many
emergency rooms are equipped with a slit lamp and a tonometer, but these
examinations are best performed by an eye specialist.
Patients with scleritis or episcleritis need a workup for systemic
disease such as rheumatoid arthritis and various collagen diseases.
552

1. 
  2. 
  3. 
REGURGITATION, ESOPHAGEAL
Is there dysphagia?
 The presence of difficulty swallowing should
suggest carcinoma of the esophagus, esophageal strictures, esophageal
diverticulum, achalasia, aortic aneurysm, and other mediastinal
masses.
loss suggests carcinoma of the esophagus and esophageal stricture. It
is also found in the late stages of achalasia.
Is there heartburn?
 Several of the conditions associated with
esophageal regurgitation may be accompanied by heartburn, but reflux
esophagitis and gastric ulcer are the most common.
Most disorders will be diagnosed by an upper GI series with an
esophagogram and esophagoscopy with a biopsy. A Bernstein test,
esophageal pH monitoring, and esophageal manometry may be useful in
diagnosing reflux esophagitis. A CBC, serum iron, ferritin, and iron-
binding capacity will help diagnose Plummer–Vinson syndrome. An ANA
titer and skin biopsy will help diagnose scleroderma. A CT scan of the
mediastinum will help diagnose most mediastinal masses, and angiography
will be useful in diagnosing an aortic aneurysm.
554

1. 
  2. 
  3. 
  4. 
RESPIRATION ABNORMALITIES
Is the respiration rapid?
 The presence of rapid respiration indicates
dyspnea (
page 155
), and may be caused by shock, congestive heart
failure, asthma, emphysema, and other disorders.
Is the respiration slow?
 The presence of slow respiration should
suggest diabetes mellitus, alcoholic stupor, uremia, opium poisoning,
cerebral concussion, and metabolic acidosis from other causes.
Are the breaths irregular or alternating fast and slow?
 This would
suggest Cheyne–Stokes respiration or Biot’s breathing, and the causes
to consider are coma, congestive heart failure, uremia, tuberculosis,
bacterial meningitis, typhoid fever, chorea, and many other conditions.
Are the breaths deep or shallow?
 The presence of deep respiration
should suggest metabolic acidosis due to diabetes mellitus, renal
failure, alcoholic stupor, or respiratory alkalosis from salicylate
intoxication. The presence of shallow respiration would suggest
uremia, opium poisoning, and concussion.
chemistry panel, EKG, chest x-ray, urine drug screen, blood alcohol level,
arterial blood gases, and pulmonary function tests. If there is fever, blood
cultures, febrile agglutinins, and tuberculin and other skin tests may be
ordered. If there is coma, further diagnostic workup may be found on 
page
103
. If there is dyspnea, further diagnostic workup may be found on 
page
155
.
555

1. 
  2. 
  3. 
RESTLESS LEG SYNDROME
Is there a history of drug use?
 Many drugs, including barbiturates
and benzodiazepines, may cause a restless leg syndrome.
 Various forms
of peripheral neuropathy and multiple sclerosis may be associated with
restless leg syndrome. Parkinson’s disease may also be associated with
the restless leg syndrome.
 Various types of anemia may be associated with
restless leg syndrome also.
Routine tests include a CBC, serum iron and iron-binding capacity,
sedimentation rate, urinalysis, urine drug screen, chemistry panel, glucose
tolerance test, and nerve conduction velocity studies. Somatosensory
evoked potential (SSEP) studies may be useful in detecting multiple
sclerosis. Doppler studies may detect peripheral vascular disease. A
pregnancy test should be done on a woman of child-bearing age. A
therapeutic trial of a combination of dopa and carbidopa or pramipexole
may be useful.
557

1. 
  2. 
RISUS SARDONICUS
Is there a history of recent wound infection or intravenous drug
use?
 The presence of these findings should suggest tetanus.
Is there a history of psychosis or suicidal ideation?
these findings should suggest strychnine poisoning and cataplexy.
urine drug screen, chemistry panel, blood cultures, chest x-ray, and EKG.
A careful search for a puncture wound or evidence of frequent intravenous
injections should be done and cultures of any exudate obtained. If tetanus
has been ruled out, a psychiatrist should be consulted.
558

SCALP TENDERNESS
The cause of scalp tenderness is usually obvious when there is dermatitis
or inflammatory disorders of the skin, such as herpes zoster, pediculosis,
tinea capitis, infected sebaceous cyst, and impetigo.
The tenderness is more subtle in temporal arteritis unless there is
associated homolateral blindness or obvious enlargement of the superficial
temporal artery. Tenderness in the occipital area is usually due to occipital
major or minor entrapment by the posterior cervical muscles. This is
common after flexion–extension injuries of the cervical spine or cervical
spondylosis. Referred tenderness from trigeminal neuralgia, sinusitis, otitis
media, mastoiditis, and disorders of the teeth may occur. When a patient
presents with scalp tenderness, especially at the top of the head, and the
physical examination is normal, the diagnosis of psychoneurosis should be
entertained.
When there are obvious skin lesions, cultures, potassium hydroxide
preparations, or biopsies will usually establish the diagnosis. A skull x-ray
should be done to exclude fracture, rickets, syphilitic periostitis, and
primary and secondary tumors of the cranium. A sedimentation rate should
be done to exclude temporal arteritis, especially in the elderly. If the
physical examination and diagnostic workup are normal and the patient
persists with the complaint, a referral to a psychiatrist is in order.
559

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
SCOLIOSIS
 Patients with scoliosis and a history of
trauma should be suspected of having a thoracic or lumbosacral sprain,
fracture, or herniated disk.
 Abnormal neurologic
findings should suggest poliomyelitis, muscular dystrophy, multiple
sclerosis, syringomyelia, Friedreich’s ataxia, and many other
disorders.
If the neurologic examination is abnormal, are there motor
findings only or both sensory and motor findings?
 Abnormal motor
findings would suggest poliomyelitis or muscular dystrophy, whereas
abnormal sensory and motor findings would suggest multiple
sclerosis, syringomyelia, and Friedreich’s ataxia, among other
Does the x-ray show bone disease?
 Diseases of the bone that may
cause scoliosis are Paget’s disease, osteoporosis, destructive disease of
the vertebrae, such as tuberculosis, osteogenesis imperfecta, rickets,
congenital hemivertebra, and Klippel–Feil syndrome.
If the x-ray shows bone disease, is the patient a child or an adult?
Children with scoliosis and bone disease may have rickets,
osteogenesis imperfecta, congenital hemivertebra, and Klippel–Feil
syndrome. Adults with x-ray changes of bone diseases may have
Paget’s disease, osteoporosis, destructive disease of the vertebrae, and
Is one leg shorter than the other?
 A short leg would suggest
congenital or acquired short-leg syndrome.
Clinically, the diagnosis of scoliosis can be made by having the patient
bend over. In this position, there will be asymmetry in the height of the
scapulae (Adam’s test). The vast majority of mild cases of scoliosis require
only x-ray and watchful expectancy or referral to an orthopedic surgeon.
Routine diagnostic workup may include a CBC, sedimentation rate,
urinalysis, chemistry panel, arthritis panel with ANA and human leukocyte
antigen (HLA) B27 antigen, tuberculin test, and a spinal survey including
both recumbent and upright views. A bone survey may also need to be
560

done. A bone scan may be necessary to detect subtle bone disease. If these
tests are negative, the patient should be referred to an orthopedic surgeon.
EMG examinations, nerve conduction velocity studies, CT scans, and
MRIs may be necessary. Remember, scoliosis is rarely the cause of back
pain unless the spinal angulation exceeds 40 degrees.
561

1. 
  2. 
  3. 
SCOTOMA
 If the scotomas are transient, then migraine, transient
ischemic attacks, and retrobulbar neuritis should be suspected.
Are there abnormalities on the eye examination other than the
optic nerve?
 
On a careful eye examination, the clinician may find
corneal opacities, muscae volitantes, cataracts, choroiditis, glaucoma,
retinitis, retinal hemorrhage, and detached retina.
signs may suggest multiple sclerosis, carotid artery thrombosis or
insufficiency, basilar artery thrombosis or insufficiency, and
pseudotumor cerebri, among other disorders.
This should include a careful eye examination with slit lamp, tonometry,
and visual field examinations. If the initial findings suggest an ocular
disorder, referral to an ophthalmologist should be made. If the neurologic
examination is abnormal, the patient should be referred to a neurologist,
rather than ordering expensive tests, such as a CT scan, an MRI scan, VEP
studies, angiography, and spinal fluid examinations.
562

1. 
  2. 
  3. 
  4. 
  5. 
SCROTAL SWELLING
A 32-year-old white male presents at your clinic with a 3-week history of
scrotal swelling. Following the algorithm, you note that it is only his left
scrotum, so systemic diseases, such as congestive heart failure, cirrhosis
and nephrosis can be ruled out. It is painless, so it is unlikely that he has
torsion of the testicle, or an incarcerated, or strangulated inguinal hernia.
On examination, you find that the mass fails to transilluminate ruling
out a hydrocele. However, it is reducible, so you suspect a sliding inguinal
hernia or varicocele. You would be correct.
Is it diffuse or focal?
 Diffuse scrotal swelling would suggest
congestive heart failure, nephrosis, uremia, and cirrhosis, as well as
focal diseases such as filariasis or bilateral hydrocele. Focal scrotal
swelling would suggest a hernia, hydrocele, torsion of the testicle,
abscesses, epididymitis, orchitis, varicoceles, and testicular tumors.
If it is diffuse, is there ascites or generalized edema?
of diffuse edema of the scrotum with ascites or generalized edema
would suggest congestive heart failure, nephrosis, uremia, or cirrhosis.
If it is focal, is it painful?
 The presence of painful scrotal swelling
would suggest an incarcerated or strangulated inguinal hernia, torsion
of the testicle, a hematoma, orchitis, epididymitis, furuncle, or abscess.
 If the mass transilluminates, it is very likely
a hydrocele of the testicle or a spermatocele.
 If the mass is reducible, it is most likely an inguinal
hernia or a varicocele.
urine culture, and urethral smear. If prostatic disease is suspected, a PSA
should be ordered. If intestinal obstruction is suspected, a flat plate of the
abdomen and lateral decubitus should be ordered. Ultrasonography or a
radionuclide testicular scan with technetium-99m are useful in
differentiating between testicular torsion and epididymitis. Scrotal
ultrasound may be done to evaluate any kind of testicular or scrotal mass.
564

However, it is much less costly to refer the patient to an urologist.
565

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
SEDIMENTATION RATE
The sedimentation rate is an integral part of the routine orders. When it is
abnormal:
Is the sedimentation increased?
 This would suggest a viral, bacterial
or autoimmune disorder somewhere in the body. It may also suggest
multiple myeloma, neoplasm, or some myeloproliferative disorder.
If the sedimentation rate is increased, is there headache?
 This
would suggest temporal arteritis, meningitis, or a brain abscess.
 If there is significant lower abdominal
pain, consider the possibility that the increased sedimentation rate is
due to pelvic inflammation disease, appendicitis, or diverticulitis. If
there is upper abdominal pain, consider the possibility of cholecystitis,
pancreatitis, or a diaphragmatic abscess.
Is there generalized muscle pain?
 In this case, the increased
sedimentation rate may be due to polymyalgia rheumatica although
dermatomyositis and other collagen disease need to be considered.
Is there significant bone or joint pain?
 If so, look for rheumatoid
arthritis, lupus erythematosus, and multiple myeloma as well as septic
arthritis or osteomyelitis. If none of these questions provide a positive
answer, consider the possibility of leukemia, macroglobulinemia,
metastatic carcinoma, or another collagen disease.
Is the sedimentation rate decreased?
 This would most often be due
to polycythemia vera or Cushing’s syndrome and corticosteroid
therapy.
Routine orders, such as CBC, chemistry panel, and urinalysis have
probably already been ordered. These may point to leukemia or
macroglobulinemia. To diagnose abdominal conditions, ultrasonography
and CT scan of the abdomen and pelvis may be necessary. Temporal
arteritis, polymyalgia rheumatica, and various collagen diseases may
require a biopsy. A serum protein electrophoresis and skeletal survey or
bone scan will help diagnose multiple myeloma, osteomyelitis, and
metastatic carcinoma. In cases of joint pain an R-F titer or ANA will help
diagnose rheumatoid arthritis and lupus erythematosus.
566

1. 
  2. 
  3. 
  4. 
SENSORY LOSS
 The presence of intermittent sensory changes
would suggest a transient ischemic attack, migraine, and epilepsy.
Is there loss of vibratory and position sense only?
loss of vibratory and position sense only, particularly if it involves all
four extremities, would suggest pernicious anemia. If the loss of
vibratory and position sense is on one side of the body only, a parietal
lobe tumor should be suspected. Diffuse loss of vibratory and position
sense only may also be seen in multiple sclerosis, cervical
spondylosis, and Friedreich’s ataxia.
Is there loss of pain or temperature only?
pain and temperature on one side of the body is more likely to occur
with posterior inferior cerebellar artery occlusions. Rarely,
syringomyelia may cause loss of pain and temperature only in the
lower extremities, if the syringomyelia is in the thoracic cord and in
the upper extremities, if it is in the cervical cord. Anterior spinal artery
occlusions may cause loss of pain and temperature in the lower
extremities. Multiple sclerosis can occasionally cause loss of pain and
temperature in a diffuse manner.
Is there loss of all modalities together?
 If all modalities are lost
together on one-half of the body, one should consider thalamic
syndrome because of vascular occlusion of the thalamogeniculate
artery or its branches. Loss of all modalities in the lower extremities
and up to a certain sensory level would probably because of spinal
cord trauma, a space-occupying lesion, or transverse myelitis.
However, this condition can also be seen with multiple sclerosis. Loss
of all modalities together in the upper extremity may be found in
brachial plexus neuropathy or injuries. It may be found with
malingering as well. Loss of all modalities in a glove and stocking
distribution would suggest peripheral neuropathy. Loss of all
modalities in a dermatomal distribution would suggest radiculopathy
because of herniated disk, tumor, or arthritic spurs. Platybasia and
foramen magnum tumors may cause selective loss of vibratory and
position sense in one or more extremities or loss of sensation to all
modalities in one or more extremities.
568

chemistry panel, ANA, serum protein electrophoresis, VDRL test, a chest
x-ray, and an x-ray of the spine. Findings of a clear-cut sensory loss are a
good reason to consult a neurologist at this point. When one is not
available, further workup depends on what part of the body is affected.
If only the lower extremities are involved, a CT scan or an MRI of the
lumbar or thoracic spine may be done. EMG and nerve conduction
velocity studies of the lower extremities will complement the diagnostic
If both the upper and lower extremities are involved, an MRI of the
cervical spine would be the best procedure to perform. A CT scan of the
cervical spine is not nearly as precise. EMG examination of the upper and
possibly the lower extremities should be done in these cases. Nerve
conduction velocity studies may also need to be done.
If the face is involved along with the extremities, a CT scan or an MRI
of the brain should be done. Skull x-ray is not very useful unless a fracture
of the skull is suspected.
Carotid scans, MRA, and four-vessel angiography are very useful in
evaluating cerebral vascular disease. If peripheral neuropathy is suspected,
a neuropathy workup (see 
page 378
) should be done. If multiple sclerosis
is suspected, a spinal tap and somatosensory evoked potential (SSEP) or
visual evoked response (VEP) studies will assist in the diagnosis. A spinal
tap will also be useful in diagnosing central nervous system lues. If
pernicious anemia is suspected, a serum B
12
 and folic acid and possibly a
Schilling test should be done. Guillain–Barré syndrome is diagnosed by a
spinal fluid examination, which will show a markedly elevated spinal fluid
protein in the face of a normal cell count.
Entrapment syndromes, such as carpal tunnel syndrome, ulnar nerve
entrapment, or tarsal tunnel syndrome are diagnosed by nerve conduction
velocity studies.
A wake-and-sleep EEG may diagnose complex partial seizures or
parietal lobe seizures. Sometimes, combined myelography and CT scan are
better than MRI studies in selected cases.
569

1. 
  2. 
  3. 
  4. 
SERUM ALBUMIN
Is the albumin increased?
 This almost invariably means dehydration.
Is the albumin decreased?
 If so, and there are abnormal liver
function tests then, cirrhosis and other liver disease must be
 This finding would suggest a
nephrotic syndrome (from diabetes, collagen disease, and many other
disorders).
Are the gamma globulins or other globulins increased?
 This would
suggest multiple myeloma, macroglobulinemia, among other
If the albumin is decreased along with the globulins one should
consider dilutional hypoalbuminemia from congestive heart failure or poor
nutrition, malabsorption syndrome and protein loosing enteropathy.
Obviously, a CBC, sedimentation rate, chemistry panel, urinalysis serum
and urine osmolality, serum protein electrophoresis, and liver function
studies are necessary although some of these have probably already been
ordered. Immunoelectrophoresis will assist in the diagnosis of multiple
myeloma and macroglobulinemia as well as skeletal survey. If
malabsorption syndrome is suspected, a D-xylose absorption and urine
 5-
HIAA 
will be helpful. Congestive heart failure can be ruled out by a
 BNP,
circulation time, and echocardiography. Ultimately, a bone marrow, liver,
or renal biopsy may be required. It is wise to consult a hematologist,
hepatologist, or nephrologist before ordering expensive diagnostic tests.
571

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
SHOULDER PAIN
A 29-year-old painter complains of increasing pain in his right shoulder.
Following the algorithm, you find that the pain is nonradiating, and is
constant. It is not relieved by nitroglycerin. Neurologic examination is
within normal limits. There is normal range of motion. Moreover, you find
that the pain only occurs on active motion. You suspect subacromial
bursitis and a torn rotator cuff and an MRI of the shoulder confirms your
Is there significant radiation of pain down the arm?
of significant radiation of pain down the arm would suggest thoracic
outlet syndrome, herpes zoster, herniated cervical disk, spinal cord
tumor, brachial plexus neuritis, myocardial infarction, sympathetic
dystrophy, Pancoast’s tumor, and aortic aneurysm.
Is the radiation down the arm transient?
 The presence of transient
radiation of pain down the arm would suggest coronary insufficiency.
Are there hypoactive reflexes or significant dermatomal loss of
sensation in the involved extremity?
spinal cord tumor, herniated cervical disk, and brachial plexus neuritis,
among other disorders.
Is there pain on active motion only?
 Pain on active motion only is
more frequently found in subacromial bursitis, calcific tendinitis, and
torn rotator cuff. Flexing the biceps will cause pain in biceps
tendonitis. Acromioclavicular inflammation is usually traumatic in
origin.
Is there pain on both active and passive motion?
 This finding
would suggest osteoarthritis, rheumatoid arthritis, gout, dislocation of
the shoulder, adhesive capsulitis, shoulder–hand syndrome, aseptic
bone necrosis, and osteomyelitis.
Is there normal range of motion of the shoulder and normal
neurologic examination?
 These findings would suggest that the pain
is referred from gallbladder disease, pancreatitis, ruptured peptic ulcer,
pleurisy, or tuberculosis.
Are there diminished pulses in the involved extremity?
 These
findings would suggest occlusion of the subclavian artery, thoracic
573

outlet syndrome, or dissecting aneurysm.
The first thing to do is an x-ray of the shoulder. If this is normal, a trial of
conservative therapy may be initiated before ordering an expensive
diagnostic workup. If the pain persists, routine diagnostic studies include a
CBC, sedimentation rate, urinalysis, chemistry panel, arthritis panel
including ANA, chest x-ray, and electrocardiogram (EKG). An MRI of the
shoulder may need to be done to rule out a torn rotator cuff. Shoulder MRI
arthrography, a new procedure, can also be used to diagnose this condition.
If there are abnormal neurologic findings, EMG, nerve conduction velocity
studies, and MRI of the cervical spine may need to be done. A neurologist
should be consulted before ordering these expensive diagnostic tests.
If there are focal trigger points in the bursa or shoulder joints, a
therapeutic trial of lidocaine hydrochloride (Xylocaine) and corticosteroid
injections should be done if the x-ray of the shoulder is negative or show
only calcific tendinitis. Stellate ganglion blocks may be diagnostic and
therapeutic for sympathetic dystrophy. If 
there are abnormalities of the
brachial or radial pulses, angiography may need to be done. When there is
intermittent pain down the arm, an exercise tolerance test may need to be
ordered. However, it may be wise to refer the patient to a cardiologist
before ordering this test. A gastroenterologist may need to be consulted to
rule out cholecystitis, pancreatitis, and peptic ulcer disease.
574

SKIN THICKENING
Thickening of the skin is most commonly seen in myxedema and
scleroderma. The association of Raynaud’s phenomena will help
distinguish scleroderma. Thickening of the skin of the lower legs may also
be seen in lymphedema, carcinoid syndrome, and vascular insufficiency.
Localized thickening in the pretibial area may be seen in hyperthyroidism.
Thickening of the skin of the face is seen in Chagas disease and porphyria
cutanea tarda.
In cases of diffuse thickening of the skin, a thyroid profile with
triiodothyronine (T
3
), thyroxine (T
4
), and TSH should be done. This
should also identify hypothyroidism. A positive ANA test with a speckled
pattern will help identify scleroderma, but a skin biopsy should also be
done. An antisclerodermal antibody titer is also useful if available.
Esophageal motility studies will be helpful in early diagnosis. A skin
biopsy will help identify many of the other conditions mentioned above.
Urine for porphyrins will help identify porphyria.
575

1. 
  2. 
  3. 
SLEEP APNEA
Is there excessive snoring?
 Excessive snoring would indicate
obstructive sleep apnea from large tonsils, deviated nasal septum, cleft
palate, other abnormalities, and obesity.
 More than 60% of patients with sleep apnea have
obesity, and Pickwickian syndrome should be considered in these
patients, as well as idiopathic obesity.
Are there abnormalities of the neurologic examination?
 The
presence of neurologic abnormalities should make one think of
poliomyelitis, Shy–Drager syndrome, brain stem tumors, and other
neurologic disorders.
The most important diagnostic test is an all-night polygraphic recording
(polysomnography). This will differentiate between obstructive and
nonobstructive sleep apnea. If obstructive sleep apnea is suspected, a
referral should be made to an ear, nose, and throat specialist. If there are
abnormalities on the neurologic examination, a neurologic consultation
should be sought. If idiopathic nonobstructive sleep apnea is suspected, the
patient should be referred to a pulmonologist. A therapeutic trial of
continuous positive airway pressure may be done. Some cases should have
evaluation for a pituitary tumor, a thyroid profile, and a trial of tricyclic
drugs and progesterone.
576

SLEEPWALKING
Occasional sleepwalking is normal in children and of no pathologic
significance. It is reported in at least 15% of normal children. It should be
distinguished from night terrors which occur in stages 3 and 4 of non-rapid
eye movement sleep. When it is frequent, it is a sign of significant
emotional disturbances, and a referral to a psychiatrist is in order. Before
you make a referral, a 
 EEG, preferably with
nasopharyngeal electrodes, should be done to exclude partial complex
seizures (psychomotor epilepsy).
578

SNEEZING
Acute sneezing is often seen in the early stage of the common cold and can
be found in almost all URIs. It is also seen in measles and other infectious
diseases.
Chronic sneezing is another matter. When environmental irritants, such
as tobacco (especially snuff), ammonia, and other irritant gases, have been
eliminated, it is almost invariably caused by allergy. The only exception is
prolonged repetitive sneezing, which is usually psychological.
The diagnostic workup is the same as for nasal discharge (
page 348
).
Patients with prolonged repetitive sneezing and a negative workup for
allergy should be referred to a psychiatrist.
579

1. 
  2. 
SNORING
Are there abnormalities on the ear, nose, and throat examination?
A careful ear, nose, and throat examination may disclose hypertrophic
tonsils and adenoids, deviated septum, bifid uvula, large floppy palate,
and hypertrophic turbinates, among other conditions.
 A careful
neurologic examination may disclose bulbar palsy, pseudobulbar
palsy, myasthenia gravis, and cerebral vascular disease, among other
A sleep diary should be kept by the patient and his or her spouse. A tape
recording during sleep will be helpful. Polysomnography is the most
important diagnostic test. It will often confirm the diagnosis of obstructive
sleep apnea. If there are ear, nose, and throat abnormalities, a referral to an
ear, nose, and throat specialist should be made. If there are neurologic
abnormalities, a referral to a neurologist should be made. A therapeutic
trial of continuous positive airway pressure may be useful (see 
page 469
).
580

1. 
  2. 
  3. 
  4. 
Are there exudates?
 This is a key question when evaluating a sore
throat. Most cases of sore throat with exudates will be found to have
streptococcal pharyngitis. Without exudates, one could still have a
streptococcal sore throat, but it is less likely.
Is there a temperature elevation?
 A significant elevation of the
temperature, with or without exudates, is also characteristic of
streptococcal pharyngitis.
Are there enlarged lymph nodes?
 If the lymph nodes are enlarged in
the peritonsillar area, it is often a sign of streptococcal sore throat, but
it certainly is not diagnostic. Interestingly enough, 90% of patients
with infectious mononucleosis have posterior cervical adenopathy.
Are there systemic symptoms and signs?
 Patients who present with
exudative tonsillitis and splenomegaly certainly should be considered
to have infectious mononucleosis until proven otherwise. Also, an
exudative tonsillitis along with a fever and heart murmur should make
one consider rheumatic fever. Systemic symptoms such as dry cough,
runny nose, and generalized malaise or fatigue should make one think
of a viral URI.
In a sore throat with typical exudates very suggestive of streptococcal
pharyngitis, a throat culture may be all one needs before starting definitive
antibiotic therapy. In atypical cases, direct antigen testing and molecular
diagnostic assays are available for rapid detection of Group A hemolytic
streptococcus. An ASO titer is particularly important when one suspects
rheumatic fever. If the patient’s streptococcal sore throat persists, a
monospot test and a culture for gonorrhea should be done. Although there
are hardly any false-negative monospot tests, there are 10% false positives,
and that should be kept in mind. A blood smear for atypical lymphocytes
may be helpful, as well as a heterophile antibody titer in those cases.
581

SPASTICITY
Spasticity may arise from pyramidal tract lesions anywhere from the spinal
cord to the cerebral cortex. Consequently, the differential diagnosis and
workup of this type of spasticity is the same as for hemiplegia (
page 242
).
Spasticity may also be due to extrapyramidal disorders such as
Parkinsonism. The differential diagnosis and workup of this type of
spasticity may be found under Tremor (
page 518
).
In the stiff-man syndrome, there is persistent muscle rigidity that is
often painful and gradually increases over months or years. The cause is
unknown, but a hereditary form is known to occur.
583

SPEECH ABNORMALITIES
These are a group of speech abnormalities that do not fit into the category
of aphasia (
page 56
) or dysarthria (
page 149
). These are almost always
psychogenic in origin. 
Stammering speech
 is found in emotionally high-
strung people and is probably due to psychological trauma in childhood. It
is common in left-handed children who were forced to use the right hand.
Lolling speech
 is typified by difficulty with consonants. It is more
common in mental retardation, but it can be found in otherwise normal
persons. 
Idioglossia
 is a substitution of consonants, making the speech
very difficult to understand. It may be associated with high-tone deafness.
Perseveration
 means the repetition of a word or sentence. When a patient
repeats a word or sentence that he or she just heard, it is called 
echolalia.
Both of the last two conditions occur in schizophrenia, but perseveration
may occur in organic brain syndrome, especially Korsakoff’s psychosis.
Mutism
 is often due to schizophrenia or hysteria, but occasionally it is due
to total motor aphasia.
584

1. 
  2. 
  3. 
  4. 
  5. 
SPLENOMEGALY, ACUTE OR SUBACUTE
 The presence of fever should suggest infectious
mononucleosis, infectious hepatitis, leptospirosis, acute leukemia,
lymphoma, malaria, and bacterial endocarditis, among other things.
 The presence of a rash should suggest
thrombocytopenic purpura, acute leukemia, typhoid fever, septicemia,
and lupus erythematosus.
 The presence of jaundice should suggest infectious
hepatitis, leptospirosis, malaria, hereditary spherocytosis and other
hemolytic anemias, and portal vein thrombosis secondary to chronic
liver disease.
Is there lymphadenopathy?
 The presence of lymphadenopathy
should suggest infectious mononucleosis, acute lymphatic leukemia,
lymphoma, brucellosis, and reticuloendotheliosis.
 The presence of a history of trauma
would suggest a traumatic rupture of the spleen.
Routine tests include a CBC, platelet count, sedimentation rate, chemistry
panel, febrile agglutinins, serum haptoglobins, ANA test, monospot test,
serum protein electrophoresis, tuberculin test, a chest x-ray, EKG, and flat
plate of the abdomen.
If there is jaundice, a hepatitis profile, red cell fragility test, and blood
smear for parasites should be done. If there is fever, serial blood cultures,
leptospirosis antibody titer, and smear for malarial parasites should be
done. If there is a petechial rash, a coagulation profile should be done.
Lymph node biopsies and bone marrow examinations may be necessary. A
CT scan of the abdomen and radionuclide scan for liver and spleen size
and ratio should be done. The assistance of a hematologist or infectious
disease expert should be sought. A surgeon may need to be consulted for
an exploratory laparotomy.
585

1. 
  2. 
  3. 
  4. 
  5. 
SPLENOMEGALY, CHRONIC
 Massive splenomegaly is characteristic of Gaucher’s
disease, chronic myeloid leukemia, kala azar, and agnogenic myeloid
 The presence of jaundice with massive
splenomegaly would suggest chronic malaria. The presence of
jaundice with mild to moderate splenomegaly would suggest alcoholic
cirrhosis, chronic hepatitis, and hereditary spherocytosis.
 The presence of massive splenomegaly and
hepatomegaly is characteristic of Gaucher’s disease, chronic myeloid
leukemia, kala azar, and agnogenic myeloid metaplasia.
 The presence of pallor, of course, suggests anemia
and that would make one think of hereditary spherocytosis and other
hemolytic anemias, collagen disease, and chronic malaria.
should make one think of chronic lymphatic leukemia, lymphomas,
and sarcoidosis.
The diagnostic workup of chronic splenomegaly is similar to that for acute
splenomegaly (
page 477
). A splenoportogram may be helpful in
diagnosing portal vein thrombosis. Angiography may be helpful in
diagnosing a splenic aneurysm. A liver biopsy, splenic aspiration and
biopsy, and bone marrow biopsy may all be helpful in diagnosing
reticuloendothelioses such as Gaucher’s disease.
587

SQUINT
Squint simply means the eyes do not line up evenly. In other words, one
eye deviates to the left or the right compared to the other. The eyes may be
concomitant, in which case the alignment remains the same during
extraocular movements, or they may be nonconcomitant, in which case the
alignment or amount of deviation changes with movement of the eyes.
Concomitant strabismus is almost always congenital and the result of
birth trauma or anoxia. Rather than performing a diagnostic workup, the
clinician should simply refer the patient to an ophthalmologist.
Nonconcomitant strabismus is due to paralysis of the extraocular
muscles. The differential diagnosis of this disorder is discussed under
Diplopia (
page 139
).
589

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
STEATORRHEA
 Children with steatorrhea may
have celiac disease, cystic fibrosis, or tropical sprue.
Are there associated respiratory symptoms?
respiratory symptoms should suggest cystic fibrosis, regardless of
whether the patient is an adult or a child.
 The presence of jaundice would suggest
obstructive jaundice such as that due to biliary cirrhosis and other
Is there pallor and anemia?
 The presence of pallor or anemia
suggests malabsorption syndrome, blind loop syndrome, intestinal
parasites such as 
Diphyllobothrium latum,
 scleroderma, amyloidosis,
and chronic obstructive jaundice.
 If there are signs of systemic
disease, scleroderma, amyloidosis, and cystic fibrosis should be
should suggest obstructive jaundice, pancreatic carcinoma, and
hemochromatosis. Chronic pancreatitis may also present with an
abdominal mass if there is a pseudocyst of the pancreas.
The basic workup includes a CBC, a blood smear for cell morphology,
sedimentation rate, urinalysis, chemistry panel, serum B
12
serum amylase and lipase, stool for occult blood, ovum and parasites, fat
and trypsin, and urine for 
5-HIAA.
 Serum carotene levels taken following
a loading dose of oral carotene for 3 to 7 days will diagnose malabsorption
syndrome in many instances.
A sweat test should be done if cystic fibrosis is suspected. A D-xylose
absorption test will help differentiate primary diseases of the small
intestines. An abnormal yield of labeled carbon dioxide after ingestion of a
meal with radioactive 
14
C-glycocholate
 will help diagnose bacterial
overgrowth. An upper gastrointestinal (GI) series and small bowel follow-
through may be helpful. Intubation and analysis of pancreatic secretion of
enzymes after pancreozymin or secretin injection will help differentiate
590

pancreatic disorders. Another useful test is the bentiromide test. It will
often diagnose chronic pancreatitis when other tests are not definitive.
Consult your clinical pathologist for details. A CT scan of the abdomen
and endoscopy may be useful. Intestinal biopsy with a Crosby capsule may
help differentiate primary intestinal diseases also. Consult a
gastroenterologist before ordering many of these expensive diagnostic
tests.
A therapeutic trial with pancreatic enzymes, antibiotics, or even a
gluten-free
 diet may also assist in the diagnosis.
591

1. 
  2. 
  3. 
  4. 
  5. 
STRANGURY
 The presence of fever suggests acute pyelonephritis or
acute prostatitis.
 The presence of a urethral discharge is
suspicious for urethritis, gonorrhea, or prostatitis.
 This makes cystitis, vesicular calculus, vesicular
tumor, or tuberculosis very likely.
 In this case, one should consider uterine
fibroids, ovarian cyst, or tumor pressing on the bladder.
If none of the above associated signs is present, one should consider
hemorrhoids, anal fissure, tabes dorsalis, or bladder neck obstruction
as the most likely cause.
This will include a CBC, urinalysis, chemistry panel, urine culture,
sensitivity and colony count, urethral smear, vaginal smear and culture in
females, and cultures for gonorrhea or chlamydia if the history dictates it.
If these tests fail to detect the cause, an urologist must be consulted for
cystoscopy and intravenous or retrograde pyelography. A vaginal and
rectal examination should be done in all cases.
592

STRESS INCONTINENCE
Stress incontinence occurs most commonly in women who have had many
pregnancies or who are in menopause. The patient loses control of the
bladder when he or she coughs, laughs, or sneezes and consequently leaks
small amounts of urine. Nocturia is rare in stress incontinence. There is
often an associated cystocele. In postmenopausal women, there is often an
atrophic vaginitis due to the deficiency of estrogen. Men occasionally
develop stress incontinence following a prostatectomy.
In most cases, the diagnosis will be obvious. You can ask the patient to
cough during a vaginal examination, and the urine will trickle out. If that
does not establish the diagnosis, have the patient drink a lot of water and
not void until he or she returns to the office. Then you can have him or her
cough in the recumbent or erect position, and the urine will be released.
This is called a stress test. In the Q-tip test, a 
Q-tip
 is inserted in the tip of
the urethra, and the patient is asked to cough or strain. The Q-tip will move
at least 30 degrees above the horizontal in cases of stress incontinence. A
therapeutic trial of local or systemic estrogen may be helpful. For further
discussion of incontinence, see 
page 292
.
594

STRETCH MARKS (STRIAE)
Stretch marks are common in obese patients or during pregnancy, in which
case they are of no pathologic significance. However, purple striae of the
abdomen, especially when they are associated with moon facies or a
buffalo hump, should immediately call to mind Cushing’s syndrome.
Patients on prolonged corticosteroid therapy also develop purple striae.
The workup is the same as for Cushing’s syndrome (
page 366
).
595

1. 
  2. 
  3. 
  4. 
  5. 
STRIDOR
Is the patient an adult or a child?
 If the patient is a child, acute
epiglottitis, acute laryngotracheitis, foreign body, congenital laryngeal
stridor, laryngismus stridulus, and a retropharyngeal abscess should be
considered. Diphtheria is rarely found nowadays. If the patient is an
adult, myasthenia gravis, bulbar and pseudobulbar palsy, recurrent
laryngeal palsy, pharyngitis, laryngotracheitis, carcinoma of the larynx
or trachea, angioneurotic edema, foreign bodies, thyroid disorders, and
disorders of the mediastinum should be considered.
 The presence of stridor of acute onset
would suggest acute epiglottitis, acute pharyngitis, laryngotracheitis,
angioneurotic edema, retropharyngeal abscess, laryngismus stridulus,
and foreign body.
 The presence of fever would suggest acute
laryngotracheitis, diphtheria, subacute thyroiditis, retropharyngeal
abscess, and mediastinitis.
On ear, nose, and throat examination, the clinician may find
pharyngitis, acute epiglottitis, a foreign body, tenderness of the thyroid
suggesting thyroiditis, and thyroid masses.
Are there neurologic abnormalities on examination?
 Neurologic
abnormalities may be found in myasthenia gravis, bulbar and
pseudobulbar palsy, bilateral recurrent laryngeal nerve palsy, and
comatose states.
Routine tests may include a CBC; sedimentation rate; smear and culture of
material from the nose, throat, and sputum; x-ray of the chest and sinuses;
and, in adults, an EKG. In adults, it might also be wise to order a
chemistry panel, thyroid profile, and VDRL test, depending on the clinical
picture. Direct laryngoscopy can now be done in the office with the
fiberoptic laryngoscope. In addition, fiberoptic bronchoscopy may be
valuable. A Tensilon test may need to be done. An ear, nose, and throat
specialist should be consulted before ordering expensive diagnostic tests.
If there are neurologic signs, a neurologist should be consulted.
596

1. 
  2. 
  3. 
  4. 
  5. 
STUPOR
 Intermittent stupor should suggest epilepsy,
chronic illicit drug use, transient ischemic attacks, migraine, and
insulinoma.
suggest cocaine, barbiturate, alcohol, morphine, LSD, or PCP abuse.
signs may mean cerebral vascular disease, advanced brain tumor,
cerebral abscess, encephalitis, subdural hematoma, central nervous
system lues, Wernicke’s encephalopathy, and subarachnoid
hemorrhage or meningitis.
 The presence of nuchal rigidity would
suggest a subarachnoid hemorrhage or meningitis, but it could
occasionally indicate an intracerebral hemorrhage.
Is there a distinguishing odor to the breath?
 Besides alcohol,
uremia, diabetic acidosis, and liver failure may be suggested by a
characteristic odor to the breath.
Routine tests may include a CBC, sedimentation rate, urinalysis, chemistry
panel with electrolytes, arterial blood gas analysis, blood and urine drug
and alcohol screen, EEG, and CT scan of the brain. A spinal tap may be
done if the CT scan is negative for a space-occupying lesion. A neurologist
or neurosurgeon should have been contacted by this time. A cerebral
vascular disease may need further investigation, including carotid duplex
scan and cerebral angiography.
598

SUCCUSSION SOUNDS
Most of us have heard these sounds on ourselves after consuming a large
quantity of liquid. If they are heard with the stethoscope in a patient with
abdominal disturbance, they are of pathologic significance. When there are
associated hyperactive and/or high-pitched bowel sounds, intestinal
obstruction should be considered. When there are hypoactive bowel
sounds, paralytic ileus or peritonitis should be considered.
Succussion sounds coming from the chest are because of
hydropneumothorax or hemopneumothorax. The chest x-ray should make
the diagnosis obvious. Other rare causes of succussion sounds are acute
gastric dilatation, chronic pyloric obstruction, subdiaphragmatic abscess,
and pneumoperitoneum. The diagnostic workup will be determined by
associated symptoms and signs (vomiting, 
page 352
; abdominal pain, 
page
16
; abdominal mass, 
page 24
).
600

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
SYNCOPE
A 32-year-old white female is brought to your office by her husband who
is very concerned about her frequent episodes of fainting during the past 3
months. Following the algorithm, you ask about convulsive movements,
incontinence, or tongue lacerations following these episodes and there are
none of these signs.
Examination shows a normal pulse, no murmurs or cardiomegaly, and
the conjunctivae are not pale. Neurologic examination is negative. On
further questioning the patient tells you, she gets numbness and tingling of
her lips and fingers just before she passes out. The husband confirms that
the patient has rapid deep breathing during these attacks confirming your
suspicions of hyperventilation syndrome.
Are there convulsive movements or incontinence?
convulsive movements should suggest convulsions, and the
differential diagnosis of this is discussed in 
page 108
. However,
convulsive movements can occur with other forms of syncope. A slow
recovery phase or Todd’s paralysis suggests epilepsy.
Is the pulse slow or absent?
 The presence of a slow or absent pulse
would suggest heart block, vasovagal syncope, and carotid sinus
syncope.
Is the pulse rate normal?
 The presence of a normal pulse rate would
suggest anemia, aortic stenosis, aortic insufficiency, and cyanotic
congenital heart disease.
Is the pulse rate rapid?
 The presence of a rapid pulse would suggest
the various types of ventricular and supraventricular tachycardias,
including auricular fibrillation and flutter, and it should also suggest
heat exhaustion or heat stroke.
If the pulse is rapid, is it regular?
 The presence of a rapid regular
pulse should suggest supraventricular or ventricular tachycardia, heat
exhaustion, or heat stroke. Carotid sinus massage can help distinguish
supraventricular tachycardia from sinus tachycardia.
suggest aortic stenosis, aortic insufficiency, and cyanotic congenital
601

7. 
  8. 
  9. 
 The presence of pallor should suggest shock or
severe anemia and acute bleeding.
signs should suggest cerebral vascular insufficiency, hypoglycemia,
and transient ischemic attacks.
 Many antihypertensive drugs are
associated with syncope.
The diagnostic workup includes a CBC, C-reactive protein (CRP),
sedimentation rate, urinalysis, chemistry panel, BNP, lipid panel,
pregnancy test, VDRL test, thyroid profile, glucose tolerance test, EKG,
and chest x-ray. Several blood pressure recordings in the recumbent and
upright positions should be made. If hypoglycemia is suspected, a 72-hour
fast and a tolbutamide tolerance test should be done. The drug history
should always be reviewed. A toxicology screen may be helpful. A serum
prolactin can be drawn to distinguish hysterical seizures from true
epilepsy.
Most cases will require 24-hour Holter monitoring or event Holter
monitoring. This may not only pick up heart block and tachyarrhythmias,
but also syncope, 
induced by exercise or the prolonged QT syndrome. In
addition, other cardiovascular studies, such as echocardiography and His
bundle, may need to be done. Exercise tolerance testing is useful when the
syncope seems to be exercise induced. An upright-tilt test is helpful when
vasodepressor syncope is suspected, especially when combined with
isoproterenol infusion. Signal-averaged EKG can be useful if a ventricular
arrhythmia is suspected. If transient ischemic attacks are suspected, a
carotid scan MRA and cerebral angiography may be necessary. If the
syncopal attacks are thought to be due to epilepsy, a wake-and-sleep EEG
may need to be done. A CT scan or an MRI of the brain may need to be
done.
A cardiologist or neurologist should be consulted before ordering
expensive diagnostic tests. A psychiatrist may also need to be consulted. In
patients suspected of having seizures, a therapeutic trial of an
anticonvulsant may be indicated. For suspected postural hypotension a
therapeutic trial of 20 mg of hydrocortisone daily may confirm the
diagnosis. A cardiologist may suggest a trial of an antiarrhythmic agent for
a patient with a suspected tachyarrhythmia.
602

Table 14: Syncope
603

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
TACHYCARDIA
Is there a positive alcohol or drug history?
alcohol can cause a myocardiopathy. Atropine, caffeine, and many
other substances can cause a tachycardia.
Is the heart rate below 160 and/or reduced by carotid sinus
massage?
 This finding would help confirm the diagnosis of sinus
tachycardia and lead to a consideration of fever, thyrotoxicosis, shock,
anemia, myocardial infarction, and other disorders as the cause of the
tachycardia.
 The presence of fever and tachycardia should make
one suspect acute infectious diseases, rheumatic fever, and thyroid
storm.
Is there a tremor, neck mass, or systolic hypertension?
 These
findings suggest thyrotoxicosis.
 The presence of chest pain should make one
suspect myocardial infarction, pulmonary embolism, and acute
Is there pallor or sweating?
 The presence of pallor or sweating
should make one think of anemia and shock.
Are there crepitant rales, an enlarged liver, or peripheral edema?
These findings suggest congestive heart failure.
Is there hypotension?
 The presence of hypotension should make one
think that there may be a pathologic tachycardia, such as
supraventricular tachycardia, auricular flutter, or auricular fibrillation.
Auricular fibrillation is especially likely to be associated with
significant hypotension.
Is the rate irregular?
 The presence of an irregular heart rate should
make one suspect auricular fibrillation, or alternating flutter and
Routine diagnostic tests should include a CBC, sedimentation rate,
urinalysis, chemistry panel, toxicology screen, thyroid profile, ANA titer,
VDRL test, chest 
x-ray,
 and electrocardiogram (EKG). If there is fever,
then an antistreptolysin-O (ASO) titer and C-reactive protein (CRP),
febrile agglutinins, and serial blood cultures should be done.
604

If a myocardial infarction is suspected, serial EKGs and cardiac
enzymes need to be ordered. If a pulmonary embolism or infarction is
suspected, arterial blood gases and lung scans need to be ordered, and,
ultimately, pulmonary angiography may need to be done.
circulation time, BNP and possibly pulmonary function studies may be
done. Echocardiography may be done to determine the LVEF.
If the tachycardia is paroxysmal, 24-hour Holter monitoring or
admission to the hospital for ambulatory telemetry and observation may be
necessary. A cardiologist should be consulted. Ultimately, a psychiatrist
may also need to be consulted.
605

1. 
  2. 
  3. 
  4. 
  5. 
TASTE ABNORMALITIES
Is there distortion of the taste?
 Distortion of the taste occurs
episodically in uncinate fits of epilepsy and is persistent in hysteria,
pregnancy, schizophrenia, glossitis, and jaundice.
If there is distortion, is it constant or intermittent?
 If the distortion
of the taste is episodic, one should look for uncinate fits of epilepsy.
Is there a positive history of drug or poison ingestion?
should suggest penicillamine, mercury, bismuth, iodine, or bromide
toxicity.
Is the ear, nose, and throat or oral examination abnormal?
Abnormalities that may be found on an ear, nose, and throat or oral
examination include glossitis, gingivitis, stomatitis, dental caries,
rhinitis, and hay fever.
 Abnormalities on the
neurologic examination may suggest Bell’s palsy, temporomandibular
joint syndrome, petrositis, and brainstem lesions.
panel, urinalysis, urine drug screen, and a chest x-ray. If the ear, nose, and
throat or oral examination is revealing, the patient should be referred to an
ear, nose, and throat specialist or oral surgeon. If the neurologic
examination is abnormal, referral to a neurologist should be considered. A
wake-and-sleep EEG with nasopharyngeal electrodes and a CT scan of the
brain may be necessary to determine the cause or the diagnosis of uncinate
fits. A psychiatrist may need to be consulted if the patient is suspected of a
neurosis.
607

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
TESTICULAR ATROPHY
 The presence of unilateral atrophy would suggest
hernia surgery, previous orchitis from mumps, gonorrhea, syphilis,
tuberculosis or elephantiasis, varicocele, hydrocele, and an
undescended testicle.
Is there a history of trauma or surgery?
 A history of surgery would
suggest that the testicular atrophy is related to hernia surgery or
surgery for undescended testicle, vasectomy, or prostatectomy.
History of trauma may suggest that the patient had an acute orchitis or
hemorrhage from trauma.
Is there a history of an infection?
 A history of infection would
suggest mumps, gonorrhea, syphilis, tuberculosis, or elephantiasis.
Is there a loss of secondary sex characteristics?
would suggest Klinefelter’s syndrome.
Is there an enlarged liver?
 The presence of an enlarged liver or other
signs of hepatic dysfunction would suggest cirrhosis or
hemochromatosis.
 The presence of abnormal
neurologic findings would suggest myotonia atrophica.
Unilateral testicular atrophy usually requires no workup as long as there
are no complaints of sexual infertility or impotence. A smear and culture
of any urethral discharge should be done. Sometimes, prostatic massage
may be necessary to obtain a good specimen.
The workup of bilateral testicular atrophy may include a serum
testosterone, FSH, urine gonadotrophins, and chromosome studies to rule
out Klinefelter’s syndrome; liver function tests and liver biopsy to rule out
cirrhosis and hemochromatosis; and EMG and muscle biopsies to rule out
myotonia atrophica. Ultimately, a testicular biopsy may be necessary. An
urologist will be consulted long before most of these tests would be
performed.
609

TESTICULAR PAIN
It is rare for pain in the testicle to occur without a mass. Therefore, the
algorithmic diagnosis is essentially the same as that of testicular swelling
(
page 503
). Keep in mind that there are cases of orchitis, epididymitis, and
torsion not associated with testicular swelling. Also, in cases of renal colic
(nephrolithiasis, etc.) and herniated lumbar disk, pain may be referred to
the testicle.
611

1. 
  2. 
  3. 
  4. 
TESTICULAR SWELLING
Is there pain or tenderness of the testicle?
 The presence of pain or
tenderness should suggest torsion of the testicle, orchitis, epididymitis,
and a strangulated inguinal hernia.
Is the testicle retracted or does elevation of the testicle aggravate
the pain?
 These findings would suggest torsion of the testicle. An
absent cremasteric reflex should also suggest torsion.
Does the swelling transilluminate?
 If the swelling transilluminates,
the mass or swelling is most likely a hydrocele or spermatocele.
Is the swelling reducible?
 If the swelling is reducible, the mass is
probably an inguinal hernia or varicocele. A mass that does not reduce
could still be an incarcerated inguinal hernia.
A CBC, sedimentation rate, urinalysis, chemistry panel, and VDRL test
should be done routinely. If a tumor of the testicle is suspected, 24-hour
urine gonadotrophins and alpha-fetoprotein levels may be ordered. If there
is a urethral discharge, a smear and culture for gonorrhea and chlamydia
should be done. If a hernia is strongly suspected, a general surgeon should
be consulted. Testicular scans with technetium-99m and ultrasonography
will help distinguish torsion of the testicle from orchitis or epididymitis.
Scrotal ultrasound may also be useful in differentiating a hematoma,
abscess, or rupture from orchitis. It may also be helpful in evaluating
testicular tumors. A CT scan of the abdomen and pelvis may be necessary
to rule out metastasis.
The expense of some or all of these tests may be avoided by consulting
an urologist early in the diagnostic workup.
612

1. 
  2. 
  3. 
  4. 
THIRST
 Alcohol, amitriptyline,
diuretics, and many other drugs may cause excessive thirst.
 The presence of fever would make one suspect an
infectious disease (see 
page 198
).
Is there pallor or shock?
 Pallor or shock should make one think of
gastrointestinal (GI) bleeding, ruptured ectopic pregnancy, trauma,
and other disorders associated with anemia or shock.
Is there significant polyuria?
 Polyuria that is either significant or
massive would suggest diabetes insipidus, diabetes mellitus, or
thyrotoxicosis. Mild or insignificant polyuria may be because of
hypercalcemia, hyperparathyroidism, and excessive salt intake.
panel, thyroid panel, glucose tolerance test, blood alcohol level, and 24-
hour urine collection for sodium, potassium, and calcium. If pituitary
diabetes insipidus is suspected, a CT scan of the brain, the Hickey–Hare
test, and a vasopressin (Pitressin) injection test may need to be done. If
hyperparathyroidism is suspected, a serum PTH assay and x-ray of the
skull and long bones may be done. A consultation with an endocrinologist
may be necessary.
614

1. 
  2. 
THROMBOCYTOPENIA
What is the WBC count?
 Thrombocytopenia with a high white count
suggests leukemia or myeloid metaplasia. Thrombocytopenia with a
normal white count suggests idiopathic thrombocytopenic purpura or
drug reaction. Thrombocytopenia with a low white count suggests
lupus erythematosus, aplastic anemia, myelofibrosis, drugs,
myelophthisic anemia, or pernicious anemia.
What is the ANA?
 A positive ANA in the face of thrombocytopenia
and a low white count suggests lupus erythematosus.
The diagnostic workup should include a CBC, blood smear, sedimentation
rate, urinalysis, serum B
12
, chemistry panel, ANA, serum haptoglobins,
red cell survival, liver spleen scan, CT scan of the abdomen, and a
hematology consult for bone marrow study.
616

1. 
  2. 
  3. 
  4. 
  5. 
THYROID ENLARGEMENT
 Focal masses in the thyroid, include
thyroglossal cyst, toxic adenoma, colloid cyst, Riedel’s struma,
nontoxic adenoma, and malignancies.
Is there movement with protrusion of the tongue?
 This is a typical
finding in cases of thyroglossal cyst.
If focal, are there signs of thyrotoxicosis?
thyrotoxicosis and a focal mass suggest toxic adenoma.
If diffuse, are there signs of thyrotoxicosis?
 Diffuse thyroid
enlargement with thyrotoxicosis indicates Graves’ disease.
 The presence of a tender enlarged thyroid suggests
subacute thyroiditis and Hashimoto’s thyroiditis.
Routine tests include a CBC, sedimentation rate, urinalysis, thyroid profile
with a TSH immunoassay, calcitonin, chemistry panel, chest 
x-ray,
 and
EKG. Thyroid antibodies may be tested if Hashimoto’s thyroiditis is
The most important study is a thyroid technetium-99m or iodine-123
uptake and scan. If the results of these are abnormal, then an
endocrinologist or general surgeon should be consulted to assist in the
interpretation. If the scan indicates a cold nodule, ultrasonography may be
done to determine whether the nodule is cystic or solid. If it is cystic,
generally it can be aspirated and followed. If it is solid, a CT scan or an
MRI is indicated before a biopsy or aspiration and biopsy are undertaken.
If there are malignant cells or at least suspicious cells for malignancy,
surgery should be done. If the scan reveals a hot nodule and there is
clinical and laboratory evidence of thyrotoxicosis, the patient should be
treated with radioactive iodine or surgery. If the scan shows diffuse uptake
of radioactive materials and there is clinical thyrotoxicosis, the patient also
may be treated with radioactive iodine or surgery.
617

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
TINNITUS
Is it subjective or objective?
 Objective tinnitus is unusual, but it may
indicate glomus tumors, arteriovenous malformations, carotid stenosis,
aneurysms, anemia, a patent Eustachian tube, or myoclonus. Objective
tinnitus means that both the patient and the examiner can hear the
noises.
If it is subjective, is it unilateral or bilateral?
 Unilateral subjective
tinnitus is more likely to be associated with a more serious disorder,
such as Ménière’s disease, acoustic neuroma, cholesteatoma, or
vascular disease. Since von Recklinghausen disease is associated with
acoustic neuromas, look for café au lait spots.
the tinnitus is because of whiplash, concussion, or trauma to the
middle or inner ear.
Is there a history of the use of ototoxic drugs?
 Drugs that may cause
tinnitus include aminoglycosides, tetracyclines, clindamycin, caffeine,
and the tricyclic antidepressants. Aspirin and quinine may also be
associated with tinnitus.
Are there abnormalities found on the ear examination?
Abnormalities on the ear examination include cerumen, otitis externa,
otitis media, mastoiditis, and cholesteatomas. The tympanic membrane
may be red in cases of glomus tumors.
Is there vertigo and deafness?
 The presence of vertigo with deafness
should suggest Ménière’s disease, acoustic neuroma, and
cholesteatoma, as well as multiple sclerosis, basilar artery
insufficiency, and brainstem tumors.
signs along with vertigo and deafness would suggest multiple
sclerosis, advanced acoustic neuroma, basilar artery occlusion or
insufficiency, brainstem tumors, and central nervous system syphilis.
chemistry panel, thyroid profile, VDRL test, audiometry, caloric tests
(electronystagmography), and x-ray of the mastoids and petrous bones.
Specialized audiometry may be performed, such as impedance audiometry,
619

Békésy audiometry, and BSEP studies.
If an acoustic neuroma is strongly suspected, a CT scan with iodine
infusion or instillation of 4 mL of oxygen in the subarachnoid space would
be indicated. 
Gadolinium-enhanced
 MRI may also diagnose an early
acoustic neuroma. Angiography and venography may help diagnose
objective tinnitus. A spinal tap may be helpful in diagnosing multiple
sclerosis and central nervous system syphilis. A glucose tolerance test may
be indicated to rule out diabetes mellitus.
620

1. 
  2. 
TONGUE MASS OR SWELLING
 Painful swellings of the tongue, include trauma, burns,
herpes simplex, pemphigus, erythema bullosum, carcinoma, Ludwig’s
angina, angioneurotic edema, bee stings, and hemorrhage because of
coagulation disorders.
Is the mass or swelling focal or diffuse?
 Focal masses, include
trauma, herpes simplex, pemphigus, erythema bullosum, carcinoma,
angioma, fibroma, lipoma, mucus cyst, papilloma, or syphilitic
gumma. Diffuse masses, include Ludwig’s angina, angioneurotic
edema, bee sting, hemorrhage, myxedema, acromegaly, cretinism,
mongolism, primary amyloidosis, diffuse lymphoma, and riboflavin
Focal lesions of the tongue should be referred to an oral surgeon or
dermatologist for biopsy or excision. Diffuse enlargement or swellings
require a workup including CBC, sedimentation rate, urinalysis, chemistry
panel, thyroid panel, VDRL test, and ANA titer. If a coagulation disorder
is suspected, a coagulation profile may be done. If a vitamin deficiency is
suspected, a therapeutic trial of vitamins is indicated. If amyloidosis is
suspected, a biopsy may be done. Other disorders also may require biopsy.
A trial of antibiotics or corticosteroids may be necessary.
622

TONGUE PAIN
Pain in the tongue is rarely an isolated symptom. There is usually a focal
or diffuse inflammation of the tongue or an ulcerating lesion. Diffuse
inflammation is found in antibiotic glossitis, glossitis of avitaminosis
(pernicious anemia), aphthous stomatitis, thrush, streptococcal glossitis,
and acute diffuse glossitis. Focal lesions include cuts and ulcerations from
trauma, such as the bitten tongue or burned tongue (hot pizza, etc.), or
injury from a sharp tooth or jagged dental plate. Other painful focal lesions
are carcinoma, tuberculosis, syphilis (often painless), and herpes simplex
ulcers. When the tongue is completely normal, trigeminal neuralgia,
polymyositis, trichinosis, and calculus of the submaxillary gland should be
Most lesions will respond to conservative treatment and time. In patients
with signs of systemic disease and vitamin deficiency, the workup includes
serum B
12
 and folate level, upper GI series, ANA, and 
antibody titer. Focal lesions that persist should command a referral to a
dentist or oral surgeon.
623

TONGUE ULCERS
Ulcerations of the tongue are most commonly because of aphthous
stomatitis (canker sore), but they may appear in various stages of syphilis,
in herpes zoster, as a result of repetitive trauma from a sharp or carious
tooth, in tuberculosis, and in carcinoma. The chancre of primary syphilis
rarely causes severe pain, so this will often distinguish the lesion from the
others. To differentiate the other causes, a smear and culture and,
ultimately, a biopsy must be done. Most physicians will find referral to a
dentist or oral surgeon is the best course of action when the ulcer persists.
624

TOOTH AND GUM ABNORMALITIES
As physicians, we often neglect inspection of the teeth. We seem to expect
the dentist to do this part of the examination for us. Multiple cavities are
found in diabetes mellitus, pernicious anemia, and multiparous women.
Separation of the teeth may be a clue to hypopituitarism, whereas teeth
that taper to a thin edge are typical of the screwdriver appearance of
Hutchinson teeth in congenital syphilis. Who has not heard of the dramatic
gum hypertrophy associated with phenytoin use in epileptic children? In
scurvy, the gums become swollen, and the teeth get loose, drop out, or
become misaligned. In dental ectodermal dysplasia, the teeth may be
partially or completely absent, and, at times, there is no evidence of
enamel formation. The dark blue line positioned where the gums meet the
teeth is a sign of lead intoxication.
Mothers frequently complain that their children grind their teeth, but
this is rarely of pathologic significance. Of course, it may be a sign of
malocclusion and temporomandibular joint syndrome, especially in adults.
Yellow teeth is a sign that a child has been affected by tetracyclines
either 
in utero
 or early childhood.
625

1. 
  2. 
  3. 
  4. 
TRANSIENT ISCHEMIC ATTACKS
Is there a carotid bruit?
 This would suggest a stenosis or ulcerative
plaque in the carotid circulation.
Is there a difference in blood pressure of the upper extremities?
This would make a subclavian steal syndrome likely causing vertebral-
basilar artery insufficiency.
Is the heart beat rate and rhythm irregular?
 If so, consider the
possibility of atrial fibrillation.
Is there a history of myocardial infarction?
 If so, this may have
caused a mural thrombus. If not, remember an atrial myxoma,
migraine, epilepsy, and subacute bacterial endocarditis are real
possibilities in a transient ischemic attack.
It is wise to consult a neurologist first. Routine laboratory and x-ray
examinations include a CBC, chemistry panel, urinalysis, coagulation
profile, ANA, sedimentation rate, CRP, cardiac troponins, serum protein
electrophoresis, EKG and chest x-ray. Carotid duplex scans,
echocardiography, and Holter monitoring would be wise if the above
studies are not revealing. Ambulatory blood pressure monitoring may be
useful in patients suspected of having paroxysmal hypertension or postural
hypotension. A CT scan of the brain or an MRI and MRA, wake-and-sleep
EEG can be ordered at the neurologist’s discretion. Ambulatory EEG
monitoring is now possible. A video of the attack may help diagnose
conversion hysteria.
626

1. 
  2. 
  3. 
TREMOR
You are asked to see a 46-year-old white female because of increasing
tremor of her hands for the past year. Following the algorithm, you ask
about weight loss, palpitations, and sweating, and she has none of these
symptoms.
On your examination, there is no tremor at rest and the tremor is most
pronounced on finger to nose testing bilaterally. There are no other
neurologic signs, so you rule out multiple sclerosis, hereditary, and
neoplastic diseases of the cerebellum. On further questioning, you find that
her mother has a similar condition, so you suspect familial or essential
tremor. You would be correct.
When does the tremor occur?
 Intention tremor, which means that the
tremor occurs on movement, would suggest that the patient is
suffering from a familial or senile tremor or multiple sclerosis,
Wilson’s disease, or hereditary familial ataxia. It also may suggest
alcoholism. Nothing is more dramatic than the intention tremor of
alcohol withdrawal. A tremor occurring at rest would suggest
Parkinson’s disease or manganese poisoning. A fine tremor of the
outstretched hands, which is sometimes described as 
tension tremor,
would suggest hyperthyroidism.
The next question to ask is whether there are associated neurologic
findings. A tremor with long tract findings, such as hyperactive
reflexes or Babinski’s sign, would suggest multiple sclerosis, whereas
a fairly symmetrical tremor with no long tract signs or other
neurologic findings would suggest a familial or senile tremor. A
tremor with mental deterioration would suggest Wilson’s disease.
Are there associated systemic findings?
 If the patient has
tachycardia and an enlarged thyroid, one should consider
hyperthyroidism. However, simply tachycardia alone might indicate
that the patient is very sensitive to caffeine. Kayser–Fleischer ring and
enlarged liver would suggest Wilson’s disease. An enlarged liver
alone would suggest alcoholism.
628

Certainly, a thyroid profile should be done on all cases that present with a
tremor alone. In addition, blood tests for serum copper and ceruloplasmin
should be done when Wilson’s disease is suspected. A drug and alcohol
screen should also be done. If multiple sclerosis, Wilson’s disease, or a
cerebellar tumor is suspected, a CT scan or an MRI of the brain should be
done. When there is doubt as to whether the tremor is a resting or active
tremor, an EMG may be done to separate the two. Most patients presenting
with a mild intention tremor that is symmetrical and not associated with
other neurologic findings will probably have familial or senile tremor, and
the response to beta-blockers can be determined.
629

TRISMUS
True trismus or lockjaw is found in tetanus, rabies, and trichinosis. In
strychnine poisoning, it is a late development, as the twitchings and
convulsions are well established before it appears. Intermittent trismus
may be found in epilepsy and cataplexy. Trismus may be simulated by
impacted wisdom teeth, temporomandibular joint syndrome, scleroderma,
and malingering or hysteria. The diagnostic workup will be obvious in
cases of true trismus. Cases not associated with a systemic disease should
have an EEG and x-ray of the teeth and temporomandibular joints. A
referral to a dental specialist is often in order.
630

1. 
  2. 
  3. 
UREMIA
What is the BUN/creatinine ratio?
 If this ratio is 20:1 or greater, one
should look for prerenal azotemia. Confirmation with a serum and
urine osmolality will be helpful. If this ratio is 10:1 or less, one should
look for renal diseases or obstructive uropathy.
Is the bladder enlarged, or is there significant residual urine?
These findings point to obstructive uropathy, particularly bladder neck
obstruction. If these findings are absent, the cause of the uremia is
most likely a renal disease in cases in which the BUN/creatinine ratio
is 10:1 or less.
 ACE inhibitors, diuretics, and
nonsteroidal anti-inflammatory drugs (NSAIDs) can cause renal
failure.
Two things to do at the outset are a microscopic examination of the urine
and renal and bladder ultrasound. Further workup should include a CBC,
urinalysis, urine culture and colony count, serum and urine osmolality,
chemistry panel, sedimentation rate, arterial blood gas analysis, blood
volume, cystoscopy and retrograde pyelography, a nephrology consult, and
a urology consult. Additional studies include abdominal CT scan and a
renal biopsy.
631

URETHRAL DISCHARGE
Most cases of urethral discharge in both males and females are because of
gonorrhea or 
Chlamydia trachomatis.
 When the smear and culture are
negative for gonorrhea, a course of tetracycline can be given as a
therapeutic trial to diagnose 
Chlamydia
 infection. Alternatively, the urine
can be cultured for chlamydia. A therapeutic trial may not be necessary
because recently, DNA probe testing, nucleic acid amplification and rapid
antigen testing of the urine have become available for gonorrhea and
chlamydia. A swab of the discharge can be utilized for the same testing. If
there are joint pains or uveitis, look for Reiter’s syndrome. Other
etiologies for nongonococcal urethritis are 
Ureaplasma genitalium
 and
Trichomonas vaginalis.
 Alert the laboratory, in advance, if these
organisms are suspected because they may require special culture media
for isolation. A prostate examination should always be done in males, as
acute and chronic prostatitis are common causes of urethral discharge. In
teenagers, a urethral discharge may develop from prolonged abstinence or
excessive masturbation. Rarer causes of urethral discharge are syphilis,
tuberculosis, foreign body, and herpes. Carcinoma of the urethra is
extremely rare. Anyone with a urethral discharge needs a VDRL test and
HIV antibody titer. Sexual partners should be tested as well.
633

URINE COLOR CHANGES
Red urine may be because of hematuria (
page 238
), hemoglobinuria
(hemolytic anemia), myoglobinuria (muscle trauma, myocardial
infarction), and coproporphyria or uroporphyria (porphyria).
Phenazopyridine hydrochloride (Pyridium) also colors the urine red or
orange. Ingestion of large amounts of beets will also color the urine red.
Brown urine is usually because of hepatitis or obstructive jaundice, but
myoglobin and melanuria may also color the urine brown. Black urine is
found in malignant melanoma. Porphyrins may also color the urine black.
In alkaptonuria, the urine turns black on standing. Green or blue urine may
be found in patients taking methylene blue, indigo carmine, or indigo blue.
Pseudomonas aeruginosa
 infection may also turn urine green. The key to
the diagnostic workup is to send the urine to the laboratory for complete
analysis and culture. Most of the conditions listed above will have another
symptom that will offer additional keys to the diagnostic workup using
these pages.
634

1. 
  2. 
  3. 
  4. 
  5. 
VAGINAL BLEEDING
Is the vaginal examination normal?
 Cervical, endometrial, and
ovarian carcinomas are the most important possibilities to rule out.
Chronic cervicitis or vaginal trauma are just a few of the other
conditions to consider.
 This test should always be done in
cases of vaginal bleeding. A positive test suggests threatened abortion,
ectopic pregnancy, or missed abortion among other conditions.
Is there a history of use of oral contraceptives or other
contraceptive devices?
 These most certainly may cause dysfunctional
uterine bleeding.
Is there pale conjunctiva or poor nutrition?
 Consider iron
deficiency anemia or anemia of other causes.
Is there tremor, tachycardia, or nonpitting edema?
 If so, a thyroid
disorder may be the cause.
Negative answers to all these questions prompt an investigation for
blood dyscrasias and collagen disease, but menopause and dysfunctional
uterine bleeding may be the cause.
A pregnancy test is a must in women of child-bearing age even if the
pelvic examination is normal. A pelvic ultrasound examination is ordered
next. A CBC and serum iron and ferritin should be done because, even
though the initial cause of vaginal bleeding may be dysfunctional bleeding,
the continued blood loss leads to iron deficiency anemia which may
perpetuate the bleeding. For the same reason, a thyroxine (T
4
) and TSH
should be ordered. An ANA, coagulation profile, and serum protein
electrophoresis may be useful to rule out other systemic causes, but at this
point of time a gynecologist should have been consulted.
635

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
Is it purulent?
 A purulent vaginal discharge suggests nonspecific
bacterial vaginitis and gonorrhea. In contrast, the discharge of
bacterial vaginitis is white and has a fishy odor.
Is it frothy and yellow?
 This type of discharge is very often because
of trichomoniasis vaginitis.
Is it cheesy and associated with itching?
candidiasis vaginitis.
Is it watery and bloodstained?
 This type of discharge suggests
carcinoma of the cervix or endometrium, polyps, hydatidiform mole,
and chronic cervicitis. If a frankly bloody discharge is noted, consult
the differential diagnosis discussed on 
page 337
.
Is it offensive smelling?
 An offensive smelling discharge would
suggest foreign body in the vagina.
Is there inflammation of the cervix?
 The presence of cervical
inflammation would suggest chronic cervicitis and gonorrhea.
The most important test is microscopic examination of a saline and
potassium hydroxide preparation. This will diagnose most cases of
trichomoniasis and candidiasis. 
Gardnerella vaginalis
 can be diagnosed if
clue cells are found, and the pH of the discharge will be greater than 4.7. If
this is unrevealing, a Gram’s stain for gonorrhea and cultures for
trichomoniasis, candidiasis, chlamydia, 
G. vaginalis,
 and gonorrhea may
be done. Recently, DNA probe or rapid antigen testing of urine may be
used to diagnose gonorrhea or chlamydia. If the results of these tests are
negative, look for pinworms. A Pap smear should be done to rule out
malignancy. Polyps or inflamed areas of the cervix should be biopsied.
Colposcopy may help further differentiate a cervical lesion. A dilation and
curettage may be necessary to diagnose endometrial carcinoma and
hydatidiform mole. Occasionally, pelvic ultrasound and CT scan are
necessary. However, before ordering these expensive diagnostic tests, a
gynecologist should be consulted. Patients with documented evidence of
gonorrhea should have a VDRL test and HIV testing. A therapeutic trial of
tetracycline or metronidazole may be successful in bacterial vaginitis.
637

VARICOSE VEINS
Varicose veins are common in the lower extremities and are usually not a
sign of other disease. Varicose veins of the rectum are called hemorrhoids
and can be a sign of cirrhosis of the liver or portal vein obstruction from
other causes. Distention of the abdominal veins may be because of
cirrhosis of the liver, thrombosis of the inferior vena cava, or distention of
the abdomen because of a large tumor (e.g., ovarian cyst), ascites, or
massive hepatic or splenic enlargement. Varicose veins of the thorax and
upper extremities are seen in mediastinal malignancies (primary or
metastatic), thoracic aortic aneurysms, and chronic fibrous mediastinitis.
Obviously, a liver profile will be important. Chest x-ray and a flat plate of
the abdomen should be routine. When these fail to identify a lesion—and
even when they do identify a lesion—it is often necessary to get a CT scan
of the thorax or abdomen. Exploratory surgery may be necessary to
establish a tissue diagnosis, as biopsy may be dangerous.
639

1. 
  2. 
VITAMIN B
12
Is the Vitamin B
12
 
increased?
 This would suggest leukemia, if the
WBC is increased or polycythemia if the RBC is increased as well as
the WBC. If these studies are normal, consider the possibility of liver
disease or oral contraceptive use.
Is the vitamin B
12
 
decreased?
 One would immediately suspect
pernicious anemia, but if the folic acid is also decreased the
malabsorption syndrome must be considered. A decreased vitamin B
12
is also found in hypothyroidism, gastric atrophy, and gastric
To further evaluate a high serum B
12
, a bone marrow should be done or a
hematologist may be consulted. Further, evaluation of a low serum B
12
may require a Urine methylmalonic acid or Schilling test to confirm the
diagnosis of pernicious anemia! A D-xylose absorption test and urine 5-
HIAA will confirm the diagnosis of malabsorption syndrome. Liver
function tests, thyroid function tests, and a consultation with a
gastroenterologist may be indicated. A therapeutic trial of B
12
 may assist
in diagnosing pernicious anemia.
640

1. 
  2. 
  3. 
VULVAL OR VAGINAL MASS
 A tender vulval or vaginal mass would suggest vulvitis,
hematoma, acute bartholinitis, or urethral caruncle.
 A reducible vulval or vaginal mass would suggest
pudendal hernia, varicocele, cystocele, rectocele, and uterine prolapse.
Is the rectal examination abnormal?
 The rectal examination will be
abnormal when there are impacted feces or a rectal carcinoma.
Referral to a gynecologist or urologist can obviate an expensive diagnostic
workup in most cases. However, a primary care physician may wish to
treat acute bartholinitis or vulvitis. A culture and sensitivity is the only
procedure required in those cases.
641

1. 
  2. 
VULVAL OR VAGINAL ULCERATIONS
Is the lesion or are the surrounding lymph nodes tender?
 The
presence of tenderness of the lesion or the surrounding lymph nodes
would suggest chancroid, lymphogranuloma venereum, herpes
genitalis, and carcinoma. On the contrary, if the lesions or the
surrounding lymph nodes are nontender, chancre, yaws, condyloma
latum, and lupus should be suspected.
Is there only itching and erythema?
 Look for candidiasis or
pinworms.
The workup includes a CBC, sedimentation rate, urinalysis, and VDRL
test. A smear and culture of material from the ulceration should be done. A
dark field examination may also be necessary. The Frei test may diagnose
lymphogranuloma venereum, but a serologic test for this disorder may also
be ordered. Biopsy may be ultimately necessary. It is wise to enlist the
help of an urologist or gynecologist in difficult cases.
642

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
  7. 
  8. 
  9. 
WEIGHT LOSS
 The presence of fever would suggest an infectious
disease, such as tuberculosis, AIDS, brucellosis, and typhoid fever, but
collagen diseases and neoplasms should not be forgotten.
Is there anorexia?
 The presence of anorexia may be related to a
febrile process, but if there is no fever one should consider the
possibility of Addison’s disease, anorexia nervosa, Simmonds’
disease, drug abuse, poisoning, such as arsenic poisoning, scurvy,
malabsorption syndrome, uremia, and liver failure. There may also be
a neoplasm.
 The presence of generalized
lymphadenopathy should suggest leukemia, sarcoidosis, and
lymphoma, as well as infectious disease processes.
 An abdominal mass may be an
enlarged spleen, a pancreatic carcinoma, an enlarged liver, or renal
mass. These masses would suggest disease of those organs. The mass
also may be a carcinoma of the stomach or intestine.
would suggest Addison’s disease.
Is the appetite normal or increased?
 The presence of a normal or
increased appetite in the presence of weight loss should suggest
hyperthyroidism and diabetes mellitus. The patient also may be taking
thyroid hormone medication in increased quantities.
Is the thyroid gland enlarged?
 The presence of an enlarged thyroid
would suggest hyperthyroidism. One should also look for a focal
thyroid mass which might be a toxic adenoma.
Is the chest x-ray abnormal?
 Abnormalities found on x-ray that may
induce weight loss are carcinoma of the lung, tuberculosis, congestive
heart failure, pulmonary emphysema, and fibrosis.
Is there a history of risky sexual behavior?
 This should always
prompt the consideration of the possibility of AIDS.
chemistry panel, thyroid panel, serum amylase and lipase, febrile
agglutinins, tuberculin test, ANA titer, serum protein electrophoresis,
643

serum B
12
 and folic acid, chest x-ray, electrocardiogram (EKG), and a flat
plate of the abdomen. An HIV antibody titer needs to be done in selected
clinical circumstances.
A stool for fat, trypsin, occult blood, and ovum and parasites should be
done. Further tests for steatorrhea are listed on 
page 482
. If these tests are
within normal limits or are unrevealing, it is best to refer the patient to a
gastroenterologist or oncologist for further evaluation. Sometimes, clinical
clues suggest the need for an endocrinologist or psychiatrist as well.
However, if the primary care physician wishes to proceed further, he/she
may order an upper gastrointestinal (GI) series and esophagogram, a small
bowel series, barium enema, and a sigmoidoscopic examination. A CT
scan of the chest, abdomen, and pelvis may be useful, but it is an
expensive procedure.
Twenty-four-hour urine collection for free cortisol or rapid ACTH
stimulation test will diagnose Addison’s disease and hypopituitarism.
Quantitative stool fat and D-xylose absorption or a simple glucose
tolerance test will diagnose some cases of malabsorption syndrome.
Endoscopic procedures, including laparoscopy, and even an exploratory
laparotomy, have their place in the diagnostic workup. However, it is
always best to enlist the help of specialists before considering these
procedures, even if one is located in an isolated community. If a trial of a
nutritional supplement halts the weight loss, depression is most likely the
cause.
Table 15: Weight Loss
644

WHEEZING
Wheezing is classically due to bronchial asthma, but there is a danger in
jumping to that conclusion because it occurs in a few other conditions as
well. The wheezing of bronchial asthma is heard primarily on expiration,
whereas the wheezing of tracheal or laryngeal obstruction is heard on
inspiration, such as tracheobronchitis in children. The wheezing of cardiac
asthma (in congestive heart failure with acute pulmonary edema) is
associated with pink, frothy sputum, whereas the sputum of bronchial
asthma is thick and tenacious. Acute infectious bronchitis may simulate
bronchial asthma, but the response to epinephrine is poor. This is also true
of pulmonary emphysema, but the history will usually differentiate this
condition from bronchial asthma. A foreign body may often be
distinguished because the wheezing is unilateral. Look for occupational
causes of asthma such as methane exposure and animal dander.
The CBC, sedimentation rate, BNP, arterial blood gases (ABGs), C-
reactive protein (CRP), serum alpha-1-trypsin deficiency, sweat test, chest
x-ray, EKG, sputum analysis and culture, and pulmonary function testing
will usually assist with the clinical diagnosis. High-resolution CT scan will
be superior in confirming chronic obstructive pulmonary disease and
identifying bullous lung disease. Hereditary angioneurotic edema may be
diagnosed by a deficiency of C1 esterase inhibitor. Bronchoscopy may
also be needed, especially when there is hemoptysis (see 
page 244
). A trial
of epinephrine 1/1,000, 0.3 mL. subcutaneously or an albuterol inhaler
may resolve the dilemma.
646

1. 
  2. 
  3. 
  4. 
ACNE VULGARIS
Is the patient on drugs?
 Many drugs can cause or contribute to acne,
particularly phenytoin and corticosteroids.
In females, is there unusual hair growth?
 This would suggest either
Cushing’s syndrome or polycystic ovary syndrome.
Is there significant obesity or hypertension?
 This would make
Cushing’s syndrome more likely.
Is the patient of menopause age?
 This would suggest acne rosacea
which is treated, differently than acne vulgaris. Always consider the
possibility of lupus erythematosus.
Patients who respond poorly to treatment, deserve a referral to a
dermatologist or a diagnostic workup including serum cortisol,
dexamethasone suppression test, serum follicle-stimulating hormone
(FSH) and estradiol (in females) and an antinuclear antibody (ANA) and
double-strand DNA. A CT scan of the abdomen and brain may be required
to rule out Cushing’s syndrome and a CT scan of the pelvis may be
required to exclude polycystic ovary syndrome.
648

1. 
  2. 
  3. 
  4. 
  5. 
ASTHMA
Is there pitting edema or hepatomegaly?
suggest congestive heart failure (CHF) (“Cardiac Asthma”).
Does the patient have frequent acid regurgitation or heartburn?
 If
so, consider gastroesophageal reflux disease (GERD).
What is the patient’s occupation?
 Coal miners, workers exposed to
asbestos, and other work place irritants are subject to asthmatic
attacks.
Is there a history of steatorrhea and other abdominal complaints
or diabetic mellitus?
 If so, consider cystic fibrosis.
Is there significant eosinophilia or chronic constipation or loose
stool?
 These symptoms and signs suggest parasitic infestation. If the
answer to all these questions is “No,” then rule out chronic obstructive
pulmonary disease (COPD), alpha-1-trypsin deficiency, AIDS and
other possibilities (sarcoidosis, tuberculosis [TB], mycosis, etc.).
Patients with diagnosis of asthma, who have a poor response to
conventional treatment, need routine laboratory testing including a
complete blood count (CBC), HIV antibody titer, ANA, blood chemistry,
electrocardiogram (EKG), chest x-ray, and pulmonary function testing
before and after epinephrine. A brain natriuretic peptide (BNP) and
circulation time will help rule out CHF but if these tests are negative and
CHF is still suspected, echocardiography can be done or a cardiologist
consulted. If a sputum smear for eosinophils is positive a stool for ovum
and parasites should be done. Serum protein electrophoresis will help rule
out alpha-1-antitrypsin deficiency. Sarcoidosis can be diagnosed by a
Kveim test, scalene node biopsy, angiotensin-converting enzyme blood
level, and negative tuberculin test. Cystic fibrosis can be diagnosed by a
sweat test or quantitative pilocarpine iontophoresis. GERD (reflux
esophagitis) is best diagnosed by a trial of proton pump inhibitors or
gastroenterology consult.
649

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
ATRIAL FIBRILLATION
 Alcohol, illegal, and many legal
drugs (digoxin, sympathomimetics, etc.) can cause atrial fibrillation.
Is there a fine tremor, exophthalmus or thyroid enlargement or
mass?
 Grave’s disease and a toxic nodular goiter are often associated
with atrial fibrillation.
Is there high blood pressure?
 If so, hypertensive cardiovascular
disease and a pheochromocytoma should be considered.
Does the patient have episodic chest pain (angina) or a history of
myocardial infarction?
 A positive response would suggest coronary
artery disease as the cause.
Does the patient have a heart murmur?
congenital heart disease, rheumatic heart disease, or mitral valve
prolapse.
If none of these questions give a positive answer, consider
cardiomyopathy, atrial myxoma, or collagen disease.
Routine laboratory workup including CBC, chemistry panel, free thyroxine
(T
4
) and thyroid-stimulating hormone (TSH), urinalysis, ANA, and urine
drug screen needs to be done. Serial EKG’s and chest x-ray and
echocardiography need to be performed. If the atrial fibrillation is acute,
cardiac troponin, BNP and serial cardiac enzymes should be done. Patients
with hypertension deserve a workup for renal and adrenal causes. A
cardiologist should be consulted before ordering an expensive diagnostic
workup.
651

1. 
  2. 
  3. 
  4. 
  5. 
CARPAL TUNNEL SYNDROME
Is there joint pain?
 If so, then possible causes are rheumatoid
arthritis, lupus erythematosus, osteoarthritis, and gout.
If not, is there nonpitting edema?
 If so, consider hypothyroidism
and scleroderma as possible causes.
If not, are there hot flashes, amenorrhea, or other symptoms that
would suggest menopause may be the etiology?
Is there bone pain, anemia, or osteoporosis with lytic bone lesions?
If the answer is yes, then consider the possibility of multiple myeloma.
If none of these questions help in the diagnosis consider the possibility
of acromegaly or amyloidosis.
Routine workup includes a CBC, a chemistry panel including uric acid, T
4
and TSH, sedimentation rate, rheumatoid factor titer, ANA, and x-ray of
the wrists. Nerve conduction velocity of both upper extremities needs to be
done to confirm the diagnosis but this will not detect the cause. Protein
electrophoresis and a bone scan will assist in diagnosing multiple
myeloma. A serum growth hormone, FSH and luteinizing hormone, and a
CT scan of the brain should be ordered if acromegaly is suspected.
Menopause can be confirmed by a trial of estradiol.
653

1. 
  2. 
  3. 
  4. 
CATARACTS
Is there hyperglycemia or history of diabetes mellitus?
 Look for
the prognathism and other facial features of acromegaly as well as a
family history of diabetes.
Is there bilateral partial ptosis?
 This would suggest myotonic
muscular dystrophy.
Is there mental deficiency?
 Look for galactosemia, Down’s
syndrome, and Lawrence–Moon–Biedel syndrome.
Has the patient been on any drugs lately especially corticosteroids,
phenothiazines, and calcium channel blockers?
drugs that can cause hyperglycemia and if used long enough can
contribute to the development of cataracts.
Routine laboratory tests should be done including CBC, chemistry panel,
hemoglobin A1c (HbA
1c
), and urinalysis. DNA testing for common
mutations and chromosomal analysis can now be done to rule out Down’s
syndrome, myotonic dystrophy, and other disorders. X-ray of the skull and
long bones and CT scan of the brain will help rule out acromegaly. Red
cell analysis for galactose-1-phosphate uridyl transferase and urinalysis for
galactose will diagnose galactosemia.
655

1. 
  2. 
  3. 
  4. 
CIRRHOSIS
Is there a history of heavy alcohol intake?
 This would indicate
alcoholic hepatitis.
Is there a history of hepatitis?
 This would suggest cirrhosis due to
hepatitis B or C.
Is there tremor or dementia?
 Unless there is hepatic failure this
would point to Wilson’s disease.
Is there spontaneous tanning of the skin, impotence or
hyperglycemia?
 This would suggest hemochromatosis although
diabetes mellitus can be associated with impotence.
If none of the above questions yield positive answers, look for lupoid
hepatitis, hemosiderosis, and biliary cirrhosis.
Routine workup involves a CBC, ANA, sedimentation rate, urinalysis,
lipid panel and a comprehensive metabolic panel, a urine drug screen
should be performed as well as a hepatitis profile. Wilson’s disease can be
diagnosed with a serum copper and ceruloplasmin. Hemochromatosis can
be diagnosed by ordering a serum iron and iron binding capacity. A liver
biopsy may ultimately be necessary for a definitive diagnosis, but a
hepatologist should be consulted first.
657

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
CONGESTIVE HEART FAILURE
Is there a history of hypertension? If so, consider hypertensive
cardiovascular disease. These patients deserve a workup for renal and
adrenal causes of hypertension (
page 268
).
Is the patient taking drugs that may have toxic effects on the heart?
Beta-blockers,
 quinine, and procainamide are just a few of the drugs
that may cause CHF.
Is there tremor and a thyroid mass? Consider the possibility of
Is there a history of alcoholism? This is a significant cause of
cardiomyopathy.
Is there a heart murmur? This would suggest rheumatic carditis,
congenital heart disease, subacute bacterial endocarditis (SBE), and
atherosclerotic aortic stenosis.
If there is no heart murmur, consider the possibility of COPD, other
forms of cardiomyopathy and pericarditis.
To confirm CHF, a BNP, circulation time, chest x-ray and
echocardiography may be required. To determine the cause order a CBC,
C-reactive protein (CRP), ANA, sedimentation rate, chemistry panel,
urinalysis, serologic test for syphilis, T
4
 and TSH, cardiac troponin, and
antistreptolysin-O titer. A cardiologist should be consulted before ordering
more expensive tests, such as a CT scan, an MRI, and cardiac
catheterization.
659

1. 
  2. 
  3. 
  4. 
  5. 
  6. 
NEUROPATHY
Is there a history of poor nutrition either in a homeless individual,
poor postoperative appetite, etc.?
 This would suggest Pellagra or
beriberi neuropathy.
Is there hyperglycemia or a history of diabetes in the patient or his
or her family?
 Obviously, this would suggest diabetic neuropathy.
 This would suggest alcoholic or
nutritional neuropathy.
Is there a history of prescription drug use?
neuropathy only a few of which have been listed in the algorithm.
Is there a history of colicky abdominal pain, psychiatric
disturbances in the patient and/or relatives?
suggest porphyria.
Is there a history of tick bite?
 This would mean that Lyme disease
must be ruled out.
CMP (Comprehensive Metabolic Panel), HbA
1c
, blood lead level, serum
B
12
, serologic test for Lyme disease and ANA. A urine drug screen should
be done as well as urine porphyrins and porphobilinogen. A high
urobilinogen on the dipstick means a test for porphobilinogen should be
done. Consultation with a neurologist is wise from the outset.
661

1. 
  2. 
  3. 
  4. 
PEPTIC ULCER
Is there a history of moderate to heavy alcohol consumption?
 This
is a definite irritant to the lining of the stomach.
Has the patient been taking steady doses of nonsteroidal
 
anti-
inflammatory drugs (NSAIDs) or corticosteroids lately?
 These
drugs as well as some potassium chloride preparations are well known
to cause ulcers.
Does the patient have chronic diarrhea?
 Zollinger–Ellison
syndrome and multiple endocrine neoplasias are associated with
gastrinomas which increase the output of hydrochloric acid and cause
ulcers.
How many cups of coffee or cola beverages does the patient
consume each day?
 This is another cause of peptic ulcers that we can
avoid. There is no doubt that chronic anxiety and anger are associated
with peptic ulcers.
Presumably, the ulcer has already been diagnosed by an upper
gastrointestinal series or endoscopy. An 
Helicopter pylori
 infection should
have already been ruled out by a stool for 
H. pylori
 antigen or urea breath
test. A urine drug screen should be performed to rule out alcoholism. A
serum gastrin, secretin injection test, and calcium infusion test will help
rule out Zollinger–Ellison syndrome. Referral to a psychiatrist is necessary
if chronic anxiety or depression is suspected.
663

1. 
  2. 
  3. 
PHARYNGITIS
In patients with exudative pharyngitis who do not respond to antibiotics.
Is there a generalized adenopathy or splenomegaly?
 If so, consider
the possibility of infectious mononucleosis or leukemia.
 Many drugs have been associated
with agranulocytosis particularly chemotherapeutic agents.
 Oral sex may cause a
gonococcal pharyngitis. If there is no history of drug use or risky
sexual behavior, consider a possibility of diphtheria, Vincent’s angina
or candidiasis.
If there are obvious exudates on the tonsils or tonsillar pillars, many
clinicians would prescribe antibiotics without a diagnostic workup.
However, if a rapid strep test is immediately available, it is worthwhile to
perform this. In persistent cases of pharyngitis, a CBC, chemistry panel,
Monospot test, smear and culture should be done. 
Neisseria gonorrhea
requires a special nutrient-rich selective agar for culture so now a nucleic
acid amplification test is used to diagnose this disorder.
665

1. 
  2. 
  3. 
  4. 
  5. 
PLEURAL EFFUSION
Is there a cough with significant nonbloody sputum production?
Consider pneumonia if the sputum is yellow, TB if it is grayish and
thick, and CHF if the sputum is foamy.
Is there a cough with hemoptysis? This would suggest pulmonary
embolism, TB, a mesothelioma, or other primary or metastatic
neoplasm.
Is there chest pain? Chest pain with cough and hemoptysis is most
suggestive of pulmonary embolism, but the other causes of hemoptysis
would still have to be considered.
If there is no cough, is there significant shortness of breath? This
would suggest CHF and a hemopneumothorax.
If these questions fail to reveal a cause, then consider cirrhosis, drug
toxicity, subdiaphragmatic abscess, and collagen disease.
Routine laboratory tests include a CBC, sedimentation rate, CRP,
chemistry panel, ANA, tuberculin test, sputum smear and culture, sputum
for acid-fast bacilli smear and culture or guinea pig inoculation, and spiral
CT scan of the chest. If congestive heart failure is suspected, you may
order a BNP or echocardiography. Pleural fluid analysis will often reveal
the cause. If a pulmonary embolism is suspected, order a D-dimer test and
arterial blood gases. A CT scan of the abdomen and pelvis may be
necessary but these should not be ordered without consulting a
gastroenterologist or gynecologist.
666

1. 
  2. 
  3. 
  4. 
RECURRENT RENAL CALCULI
Is there a history of joint pain?
 This would suggest primary or
secondary gout (polycythemia, leukemia).
Is there hypercalcemia?
 This finding would suggest
hyperparathyroidism, hypervitaminosis-D, or milk-alkali syndrome.
Is there a fine tremor associated with tachycardia?
 Look for
 Look for hypernephroma, obstructive uropathy
or a congenital anomaly of the kidney, horse-shoe kidney, etc.
Routine laboratory including a CBC, sedimentation rate, urinalysis and
culture, CMP, thyroid profile, and vitamin D
3
 levels should be done. The
uric acid is not usually included in the CMP so it must be ordered
separately. A CT scan of the abdomen and neck with contrast should be
done in any case with recurrent calculi. Analysis of the stone and a urology
consult are usually necessary.
667

1. 
  2. 
  3. 
RECURRENT URINARY TRACT INFECTION
Is there low back pain or positive neurologic findings in the lower
 Consider a neurogenic bladder from multiple sclerosis,
spinal cord tumor, or cauda equina syndrome.
Is there difficulty voiding or chronic frequency of urination even
in between infections?
 If so, consider the possibility of benign
prostatic hypertrophy (in men), bladder neck obstruction, urethral
stricture or pelvic tumor (in women).
Is there recurrent hematuria?
 This would suggest a renal or bladder
calculus, hypernephroma, bladder neoplasm, or polycystic kidney. If
there is no recurrent hematuria, consider other congenital anomalies of
the urinary tract, diabetes mellitus, poor hygiene (in women) and
pelvic inflammatory disease (PID).
The best thing to do is consult an urologist before beginning an expensive
workup. If one is not available, get a CBC, chemistry panel, HbA
1c
,
tuberculin skin test, and ultrasonography of the bladder for residual urine.
Further studies include a CT scan of the abdomen and pelvis and
cystometric studies.
668

1. 
  2. 
  3. 
  4. 
  5. 
STROKE
 This would arouse suspicion for a carotid
thrombosis, stenosis, or plaque.
 In addition to essential hypertension, one
should look for secondary causes such as renal and adrenal causes of
Is there a cardiac arrhythmia?
 Look for atrial fibrillation, atrial
myxoma, and cardiomyopathy.
Is there a history of chest pain?
 Look for a myocardial infarction.
Is there fever, heart murmur, splinter hemorrhages, or emboli
elsewhere?
 Look for SBE and atrial myxoma.
A CBC, erythrocyte sedimentation rate, chemistry panel, cardiac
troponins, serial cardiac enzymes, serial blood cultures, serial EKGs, and
chest x-ray. Ultrasonography studies of the carotids and heart, and a CT
scan of the brain are essential. A neurologist and cardiologist need to be
consulted. A coagulation profile needs to be done, especially if tissue
plasminogen activator therapy is contemplated.
669

1. 
  2. 
  3. 
  4. 
  5. 
UPPER RESPIRATORY INFECTION
 This would be consistent with a viral urinary tract
infection (URI) but measles, infectious mononucleosis, other
exanthema, bacterial sinusitis, mucormycosis, Wegener’s
granulomatosis, and a foreign body in the nasal passages should be
considered in a persistent “URI.”
 This would make measles, other exanthema, and
infectious mononucleosis more likely.
Is the fever with headache and/or a purulent nasal discharge?
 This
would suggest bacterial sinusitis, mucormycosis, and a foreign body
of the nasal passages as well as a persistent viral URI.
If there is no fever, is there sneezing or a clear nasal discharge?
This would bring to mind the possibility of allergic rhinitis or sinusitis,
histamine cephalalgia, migraine, and rhinitis medicamentosus.
Is there significant or recurrent headache?
 This would help to
distinguish histamine cephalalgia, migraine, and allergic sinusitis from
the other causes of a URI.
Since most cases of URI are viral in origin a workup is usually not
necessary. However, if the “URI” persists then, a CBC, sedimentation rate,
CRP, chemistry panel, smear and culture of the throat or nasal discharge,
nasal smear for eosinophils, serum IgE, and x-ray or a CT scan of the
sinuses should be done as well as a Monospot test. Referral to an
otolaryngologist or infectious disease specialist may be indicated. A trial
of corticosteroids may help distinguish allergic rhinitis or sinusitis also.
670

A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
APPENDIX A
The author wants to emphasize that these orders are only suggestions and not
meant to be just automatically copied onto the order sheet in the hospital or
office. Rather, the clinician should select the orders most appropriate, à la carte
to fit the individual patient.
These orders are divided into those that can be cost effective for the
primary care provider without the help of a consultant and those that should be
ordered only after consultation with a specialist. It is almost always cheaper to
consult a specialist before ordering a CT scan, MRIs, and other expensive
diagnostic tests. For example, you should not order an MRI of the brain in a
patient with headache and no focal neurologic signs, without consulting a
neurologist first.
Initial Workup
CBC
Urinalysis
Chemistry panel
Sedimentation rate
Serum amylase and lipase
Pregnancy test
Flat plate of abdomen and upright
Chest 
x-ray
ECG
Expanded Workup
Consultation with a surgeon or gastroenterologist
Gallbladder ultrasonography
HIDA scan
CT scan of the abdomen with contrast
Lateral decubitus films
Serial cardiac enzymes
Peritoneal tap
Double enema
Gastroscopy
Laparoscopy
Gallium scan
Exploratory laparotomy
672

A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
A.
1.
2.
3.
4.
5.
Abdominal Pain, Chronic
CBC
Urine culture and colony count
Stool for occult blood X3
Stool for ovum and parasites
Stool for 
Giardia
 antigen
Stool for
 
antigen
Urea breath test
Abdominal film series
Chest 
x-ray
ECG
Therapeutic trial of antibiotics, amebicides, or anthelmintics
Gastroenterology consult
CT scan of abdomen and pelvis
Barium enema
Upper GI series and esophagram
Small bowel series
IVP
Esophagoscopy gastroscopy
Colonoscopy
Gallium or indium scan
Mesenteric angiography
Lymphangiography
Back Pain
CBC
Radiographs of thoracic or lumbar spine
673

B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
A.
1.
2.
3.
4.
5.
6.
Orthopedic or neurology consult
CT scan or MRI of spine
EMG and NCV of lower extremities
Bone scan
HLA-B27 antigen
RA test
ANA
PSA (in men)
Serum protein electrophoresis
Gynecology consult
Ultrasonography of pelvis
Aortography
Therapeutic trial of NSAIDs
Trigger point injections or nerve blocks
Blurred Vision and Blindness
Ophthalmology consult
Visual acuity
Visual field examination
Tonometry
Slit lamp examination
Carotid duplex scan
Sedimentation rate and VDRL
Neurology consult
CT scan or MRI of the brain
MRA
Spinal fluid analysis
Cerebral angiography
Pituitary function studies
Uveitis workup
CBC
Culture of discharge
Mammography
Ultrasonography
Surgical consult
674

B.
1.
2.
3.
4.
5.
6.
7.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
A.
1.
2.
3.
4.
Aspiration of cystic fluid
Biopsy
Serum prolactin
Skull x-ray or CT scan of brain
Serum FSH and LH
Endocrinology consult
CBC
CRP
ASO titer
Troponins
D-dimer
Thyroid profile
ECG
Chest 
x-ray
BNP
Cardiology consult
Echocardiography
Holter monitoring
Arterial blood gases
Spirometry
Blood cultures
24-hour urine catecholamines
Exercise tolerance test
Cardiac catheterization and angiocardiography
Chest Pain
CBC
Sedimentation rate, CRP
675

5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Troponins
D-dimer
BNP
Serial ECGs
Sputum smear and culture
Chest 
x-ray
Response to nitroglycerin
Response to lidocaine viscous
Ventilation–perfusion scan
Spiral CT scan of chest
Thallium-201 scan
24-hour Holter monitoring
Cardiac catheterization and coronary angiography
Esophagoscopy and gastroscopy
Bernstein test
Trigger point injection
Coma
CBC
Urine drug screen
Blood ammonia level
Serum and urine osmolality
IV dextrose or glucagon IM
IV thiamine
CT scan of brain
Blood lead level
EEG
MRI of brain
676

17.
18.
19.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
B.
1.
2.
3.
4.
5.
6.
7.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
Urine porphobilinogen
Trial of naloxone IV
Trial of benzodiazepine antagonist
CBC
Plain films of abdomen
Quantitative stool fat
PTH
PSA
Glucose tolerance test
Anoscopy and sigmoidoscopy
VDRL
Pelvic ultrasonography
Psychiatric consult
Therapeutic trial of Metamucil or stool softener
CBC
VDRL
CT scan
EEG, wake, and sleep
677

1.
2.
3.
4.
5.
6.
7.
8.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
ANA
HIV antibody titer
Therapeutic trial of anticonvulsants
Cough
Withdrawal of all medications if possible
CBC
AFB smear and culture
Cold agglutinins
Influenza rapid screen test
Chest 
x-ray
Legionella
 culture
Tuberculin test
Therapeutic trial of antibiotics or antihistamines
Pulmonary consult
Bronchoscopy
CT scan of chest
Fungal skin tests and cultures
ECG
Kveim test
ANA
Alpha-1-antitrypsin test
Allergy skin test
24-hour sputum volume
Sputum for eosinophils
Bronchography
Sweat test
678

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
A.
1.
2.
3.
4.
5.
6.
7.
CBC
VDRL
Eliminate as many medications as possible
Serum cortisol
Serum FSH
Serum estradiol
Therapeutic trial of estrogen if menopause is suspected
EEG
CBC
Electrolytes
Stool for occult blood
Stool for smear and culture
Stool for leukocytes
Stool for 
Giardia
 antigen
Stool for
 
Clostridia difficile
 
toxin
Sigmoidoscopy
CBC
VDRL
679

8.
9.
10.
11.
12.
13.
14.
15.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
Stool smear and culture
Stool for 
Giardia
 antigen
Stool for 
 toxin
Therapeutic trial of metronidazole
Lactose tolerance test
Urine 
5-HIAA
D-xylose absorption test
Serum gastrin
Stool for quantitative fat and trypsin
Stool volume after fasting
Upper GI series and small bowel follow through
CT scan of abdomen
Neurology consult and search for anal sphincter incompetence
Dizziness
CBC
VDRL
Audiogram
Caloric testing
EKG
X-ray of skull and mastoids
ENT consult
EEG
Electronystagmography
680

8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
A.
1.
ECG
MRA
24-hour blood pressure monitoring
Tilt table test
5-hour glucose tolerance test
2-hour fast with glucose monitoring
Plasma insulin and 
C-peptide
Dyspnea
CBC
BNP
D-dimer
Arterial blood gas analysis
Chest 
x-ray
EKG
Troponins
Spiral CT scan of the chest
Trial of diuretics
Trial of epinephrine
Dysuria
CBC
681

2.
3.
4.
5.
6.
7.
8.
B.
1.
2.
3.
4.
5.
6.
7.
8.
A.
1.
2.
3.
4.
5.
6.
7.
B.
1.
2.
3.
4.
5.
A.
1.
2.
3.
4.
5.
Urinalysis with microscopic
Urethral smear and culture
Vaginal smear and culture
Prostatic massage and examination of exudates
Urology consult
IVP and cystogram
Cystoscopy and retrograde pyelography
Cultures for 
Neisseria gonorrhea, Chlamydia,
 and 
Mycobacterium
tuberculosis
Therapeutic trial of ciprofloxacin or sulfonamides
Earache
CBC
Culture and sensitivity of exudates
Tympanogram
Audiogram
Radiographs of mastoids and petrous bones
Rapid strep test
Trial of antibiotics
Edema
CBC
682

6.
7.
8.
9.
10.
11.
12.
13.
14.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
B.
1.
2.
3.
4.
5.
6.
7.
Addis count
ANA
BNP
D-dimer
ECG
Chest 
x-ray
24-hour urine protein
Pulmonary function studies
Venous ultrasonography
Muscle biopsy
Extremity Pain, Lower
CBC
VDRL
D-dimer
ANA, RA
Radiography of extremities and joints
Ankle/brachial index
X-ray of lumbosacral spine
Bone scan
Orthopedic consult
CT scan or MRI of lumbar spine
Femoral angiography
Contrast venography
Synovial fluid analysis and culture
683

8.
9.
10.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Nerve blocks
Epidural blocks
Extremity Pain, Upper
CBC
VDRL
ANA
RA
Radiographs of the extremity and joints
X-ray of cervical spine
Chest 
x-ray
Bone scan
ECG
CT scan of extremity and joints
MRI of shoulder
MRI of cervical spine
EMG and NCV of upper extremities
Stellate ganglion block
Trigger point injections
Venography
Angiography
Eye Pain
CBC
Tonometry
Fluorescein dye test for foreign body or corneal abrasion
Culture and sensitivity of exudate
Trial of sumatriptan
684

10.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Trial of corticosteroids
CBC
Liver profile
Sweat test
Stool for quantitative fat
Chest 
x-ray
ECG
Skeletal survey for bone age
Serum growth hormone analysis
Chromosome analysis
Somatomedin C
Overnight dexamethasone suppression test
Bone scan
Fatigue
CBC
VDRL
ANA
RA antibody titer
Monospot test
PPD, intermediate
685

15.
16.
17.
18.
19.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
EKG and chest 
x-ray
Response to vitamins and corrective diet
Psychometric testing
Therapeutic trial of thyroid medication
Therapeutic trial of hormone replacement therapy
Infectious disease consult
Rheumatology consult
Discontinue all medications if possible
Drug screen
Lyme disease serology
Febrile agglutinins
Brucellin antibody titer
Skeletal survey
Bone scan
Muscles biopsy
CT scan of abdomen and chest
Acetylcholine receptor antibody titer
Fever of Unknown Origin
CBC
VDRL
ANA
RA titer
Lyme disease antibody titer
Chest 
x-ray
ASO titer
CRP
686

18.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
A.
1.
2.
3.
4.
5.
6.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Culture of all available body fluids
CSF analysis and culture
CT scan of chest, abdomen, and pelvis
Bone scan
Fibrin test
Urine for etiocholanolone
Urine for porphobilinogen
Oncology consult
CBC
Urinalysis and microscopic
Flat plate of abdomen
Ultrasonography of bladder and pelvis
Prostatic massage and microscopic
Catheterize for residual urine
Urine culture for anaerobic organisms
AFB urine smear and culture
IVP
Plasma ADH
Hickey–Hare test
Serum PTH
687

A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
B.
1.
2.
3.
4.
5.
6.
7.
8.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
Headache
Initial Work
CBC
VDRL
Radiographs of sinuses
Radiographs of cervical spine
Tonometry
Therapeutic trial of sumatriptan
Histamine test
CT scan or MRI of brain
Therapeutic trial of 
beta-blockers
Occipital nerve block
Heartburn
CBC
H. pylori
 antibody titer
Therapeutic trial of lidocaine viscous
Therapeutic trial of proton pump inhibitors
Esophagoscopy, gastroscopy, and biopsy
688

5.
6.
7.
1.
2.
3.
4.
5.
6.
7.
8.
9.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
A.
1.
Esophageal manometry
Esophageal pH monitoring
CBC
Coagulation profile
Type and cross match four units of blood
Esophagoscopy, gastroscopy, and duodenoscopy
Ultrasonography for esophageal varices
Hematuria
CBC
Strain all urine for stones
ASO titer
Renal ultrasonography
Nephrology consult
IVP
Urine culture for anaerobic organism
Urine for AFB culture
Renal angiography
MRI
Renal biopsy
CBC
689

2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
5.
6.
7.
8.
D-dimer
Chest 
x-ray
ECG
Ventilation/perfusion scan
MRI of chest
Needle biopsy of lesions
Hip Pain
CBC
RA test
ANA test
Radiograph of both hips
Radiograph of lumbosacral spine
Bursal or hip injection of lidocaine
CT scan of hips
CT scan of lumbosacral spine
MRI of lumbosacral spine
Bone scan
PSA
690

9.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
A.
1.
2.
3.
4.
5.
6.
7.
8.
EMG and nerve conduction studies
CBC
Throat culture
Viral antigen test for influenza
Sputum culture
Chest 
x-ray
X-ray of sinuses
Fiberoptic laryngoscopy
CT scan of chest, neck, and mediastinum
Tensilon test
MRI of the chest
Esophagram
Allergy skin testing
Therapeutic trial of antibiotics
Therapeutic trial of antihistamines
Therapeutic trial of corticosteroids
CBC
Serial electrolytes
ANA
ECG
691

9.
10.
11.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
A.
1.
2.
3.
4.
5.
6.
7.
8.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
A.
1.
Chest 
x-ray
Plain abdominal films
Spiral CT angiography or MRA
Plasma renin and aldosterone and potassium after salt loading
24-hour urine cortisol
Plasma and 24-hour urine metanephrine or catecholamines
Chest MRI
Renal ultrasound
CBC
Serum B
12
 and folic acid
Withhold as many drugs as possible
Avoid alcohol and caffeine
Hepatitis profile
Jaundice
CBC
692

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Serum haptoglobins
Chest 
x-ray
Ultrasonography of gallbladder
Upper GI series
ERCP
Antimitochondrial antibodies
Leptospirosis antibody titer
Serum iron and 
iron-binding
 capacity
Blood smear for parasites
ANA
Smooth muscle antibody titer
Liver biopsy
Steroid whitewash
Peritoneoscopy
Joint Pain or Swelling
CBC
RA titer
ANA
CRP
ASO titer
Radiographs of involved joints
693

10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Therapeutic trial of colchicine or NSAIDs
intra-articular
 steroids
MRI of joint
Bone scan
Arthroscopy
Arthrography
Gonococcal antibody titer
VDRL
Serologic test for Lyme disease
Sickle cell prep
Urine for homogentisic acid
Melena
CBC
Immunoglobulin 
G-serologic
 test for 
H. pylori
Liver function tests
Fluorescein string test
Nuclear scan after intravenous injection of 
chromium-tagged
 red cells
Ultrasonography of esophageal varices and portal venous system
694

A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
CBC
Sedimentation
VDRL
Serum B
12
 and folate
Withhold as many medications as possible, preferably one at a time
Therapeutic trial of vitamin B complex
Wake and sleep EEG
Radionuclide cisternography
Therapeutic trial of removal of spinal fluid
CBC
Chest 
x-ray
695

B.
1.
2.
3.
4.
5.
6.
7.
8.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
A.
1.
2.
3.
4.
5.
6.
B.
1.
2.
Esophagoscopy, gastroscopy, duodenoscopy, ERCP
HIDA scan
Neck Pain
CBC
Arthritis panel
Plain films of the cervical spine
Chest 
x-ray
ECG
MRI of the cervical spine
MRI of the neck
Facet injections
Obesity
CBC
Thyroid profile including TSH
72-hour fast with glucose monitoring
CT scan of brain and abdomen
696

3.
4.
5.
6.
7.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
A.
1.
2.
3.
4.
5.
6.
Plasma insulin
C-peptide
Chromosomal analysis
CBC
ASO titer
CRP
BNP
ECG
Chest 
x-ray
Avoid caffeine, alcohol, and nicotine
Discontinue all unnecessary drugs if possible, preferably one at a time
24-hour urine metanephrines or catecholamines
Coronary angiography
Therapeutic trial of diuretics
Paresthesias of the Lower Extremities
CBC
VDRL
697

7.
8.
9.
10.
11.
12.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Serum B
12
Radiographs of lumbosacral spine
ANA
Therapeutic trial of vitamin B
12
 injections
MRI of lumbar spine
EMG and NCV
Quantitative urine thiamine, niacin, and pyridoxine after loading
Blood viscosity
Lymph node biopsy
Kveim test
CBC
ANA
Radiographs of the cervical spine and chest
Serum B
12
VDRL
EMG and NCV
MRI of the brain
ECG
698

10.
11.
12.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
B.
1.
2.
Therapeutic trial of shoulder halter or cervical collar
CBC
Chemistry
Smear and culture of exudates
Dark field examination
Frei test
Biopsy of lesion
Tzanck test
Serologic test for lymphogranuloma venereum
Dermatology consult
Fluorescent treponema pallidum antibody
Therapeutic trial of acyclovir
Therapeutic trial of penicillin
Therapeutic trial of other antibiotics
Rash
CBC
VDRL
Routine smear and culture of exudates
Microscopic examination of KOH preparation for fungi and scabies
Wood’s lamp examination
ANA
Therapeutic trial of local antibiotics
Therapeutic trial of antifungal preparations
Therapeutic trial of scabicides
Skin biopsy
699

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
A.
1.
2.
Patch tests
RAST
Intradermal allergy skin testing
Weil–Felix reaction
Dark-field examination
CBC
Anoscopy
Stool culture
Gastroscopy and duodenoscopy
Nuclear scan after intravenous chromium ragged red cells
Frei test
Red Eye
CBC
700

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
B.
1.
2.
3.
4.
5.
6.
7.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
A.
1.
2.
3.
4.
5.
6.
Fluorescein dye test for foreign body or corneal abrasions
Check for urethral discharge
Nose and throat culture
Tonometry
Smear of exudates for eosinophils
Trial of antibiotic drops
CT scan of brain and sinuses
Refraction
Uveitis workup (as ordered by ophthalmologist)
HLA typing
CBC
PSA
Smear and culture of prostatic exudates
Ultrasonography of scrotum
Radionuclide scan of testicle
Testicular biopsy
CBC
X-ray of shoulder
Radiograph of chest
701

7.
8.
9.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Radiograph of cervical spine
Lidocaine injection of bursa or shoulder joint
Arthrogram
EMG and NCV studies
CBC
ASO titer or streptozyme
Culture for 
N. gonorrhea
Culture for diphtheria bacilli
Thyroid panel
Syncope
CBC
C-peptide or plasma insulin
ECG
Chest 
x-ray
Several blood pressure readings in recumbent and upright positions
702

B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
EEG
MRI and MRA of brain
Ambulatory EEG monitoring
Hospitalization for telemetry and video monitoring
Trial of anticonvulsants
Tremor
CBC
Blood alcohol level
Serum copper and ceruloplasmin
EEG
Vaginal and rectovaginal examination and Pap smear
CBC
 capacity
ANA
703

13.
14.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
B.
1.
2.
3.
4.
5.
6.
A.
1.
2.
3.
DNA probe or rapid antigen testing for gonorrhea and chlamydia
VDRL
Endometrial biopsy
D & C
Trial of cyclic progesterone
CA-125 test
CBC
DNA probe or rapid antigen testing of urine for gonorrhea and
chlamydia
Microscopic examination of saline and KOH preparations of discharge
Endocervical smear and culture
Search for clue cells in exudates
Pap smear
Candida
VDRL
FTA-ABS
D & C
CBC
704

4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
ANA
RA test
Chest 
x-ray
Urine 
5-HIAA
Plasma cortisol
Rapid ACTH stimulation test
Serum growth hormone
Serum FSH, LH
705

APPENDIX B
A
Abortion, threatened:
 Serum B–human chorionic gonadotropin (hCG), serum
progesterone levels, urine, hCG, pregnanediol, sonogram
Achalasia:
 Barium swallow, Mecholyl test, esophagoscopy, esophageal
manometry
Acoustic neuroma:
 Skull x-ray, computed tomography (CT) scan, posterior
fossa myelogram, magnetic resonance imaging (MRI)
Acquired immunodeficiency syndrome (AIDS):
 Human immunodeficiency
virus (HIV) antibody titer, 
enzyme-linked
 immunosorbent assay (ELISA),
western blot, viral load, CD4 count
Acromegaly:
 Skull x-ray, CT scan, serum growth hormone, MRI
Actinomycosis:
 Smear for sulfur granules, culture skin lesions
Addison disease:
 Serum cortisol before and after corticotrophin, antiadrenal
antibodies, CT scan of abdomen, metyrapone test
Adrenogenital syndrome:
 Serum cortisol, hydroxyprogesterone, 
11-
deoxycortisol,
 urine 17-ketosteroids and pregnanetriol, dexamethasone
suppression test, CT scan of the abdomen
Adult respiratory distress syndrome:
 Chest x-ray, CT scan of the chest,
sputum culture, blood culture, Swan–Ganz catheterization, arterial blood
gases (ABGs)
Agammaglobulinemia:
 Serum electrophoresis and immunoelectrophoresis,
blood type, lymph node biopsy, 
B-lymphocyte
 and T-lymphocyte counts
Agranulocytosis, idiopathic:
 Complete blood count (CBC), bone marrow
examination, spleen scan
AIDS:
 See Acquired immunodeficiency syndrome
Albright syndrome:
 X-ray of long bones, bone biopsy
Alcaptonuria:
 Urinary homogentisic acid, x-ray of spine
Alcoholism:
 Blood alcohol level, liver function tests, liver biopsy
Aldosteronism, primary:
 Electrolytes before and after spironolactone, plasma
renin, plasma aldosterone, 
24-hour
 urine aldosterone, CT scan, exploratory
laparotomy
Allergic rhinitis:
 Nasal smear for eosinophils, serum immunoglobulin E (IgE)
antibody, radioallergosorbent test (RAST), skin test
Alveolar proteinosis:
 Luteinizing hormone (LH), sputum for periodic 
acid-
Schiff
–positive material (PSP), lung biopsy
Alzheimer disease:
 CT scan or MRI, genetic testing
706

Amebiasis:
 
Stool for ova and parasites, rectal biopsy, hemagglutinin inhibition
test
Amyloidosis:
 Congo red test, rectal biopsy, liver biopsy, gingival biopsy,
subcutaneous fat aspiration and stain
Angina pectoris:
 Troponins, CRP, graded exercise tolerance test (GXT),
thallium-201
 scintigraphy, CT angiography or conventional coronary
angiogram, cardiac MRI, trial of nitroglycerin
Angioneurotic edema:
 C1 esterase inhibitor
Ankylosing spondylitis:
 Human leukocyte antigen (HLA) B27 tissue antigen
Anthrax:
 Smear and culture of lesion, skin biopsy, serologic test
Antitrypsin deficiency:
 Serum protein electrophoresis
Aortic aneurysm:
 Sonogram, CT scan, aortogram
Aortic valvular disease:
 Echocardiogram, CT scan, MRI, cardiac
catheterization
Aplastic anemia:
 Bone marrow, lymph node biopsy, immunoelectrophoresis
Appendicitis:
 CBC, flat plate of abdomen, CT scan, ultrasonography
Ascaris lumbricoides
:
 Cathartic stool for ova and parasites, eosinophil count
Asthma:
 Spirometry, sputum for eosinophils, serum IgE antibodies, RAST,
skin test
Atherosclerosis:
 CRP, lipid panel, apolipoprotein A-1 and B
Attention deficit disorder:
 Clinical diagnosis
Atrial arrhythmias:
 Free thyroxine, TSH, electrocardiogram (ECG), Holter
monitoring, His bundle study
Atypical pneumonia, primary:
 See 
B
Bacillary dysentery:
 Stool smear (for leukocytes) and culture, febrile
agglutinins
Balantidiasis:
 Stool for ova and parasites
Banti’s syndrome:
 Liver function tests, liver–spleen scan, bone marrow
examination, hepatic vein catheterization
Barbiturate poisoning:
 Blood or urine for barbiturates, electroencephalogram
(EEG)
Basilar artery insufficiency:
 
Four-vessel
 cerebral angiogram, magnetic
resonance angiogram
Bell palsy:
 CT scan of mastoids and petrous bones, electromyogram (EMG)
Beriberi:
 Transketolase activity coefficient, serum thiamine, urine thiamine
afterload, therapeutic trial
Bilharziasis:
 Stool or urine sediment for eggs, rectal biopsy
Biliary cirrhosis:
 Liver function tests, antimitochondrial antibodies, serum
bile acids, MRCP, endoscopic retrograde cholangiopancreatography
(ERCP), liver biopsy
707

Blastomycosis:
 Potassium hydroxide (KOH) prep, culture, chest x-ray, skin
test, serologic test
Boeck’s sarcoid:
 Chest x-ray, transbronchial lung biopsy, lymph node biopsy,
Kveim test, liver biopsy, angiotensin-converting enzyme, liver gallium scan
Botulism:
 Culture of food and stool, mouse assay of toxin
Brain tumor:
 CT scan, MRI
Brill–Symmers disease:
 Lymph node biopsy
Bromide poisoning:
 Blood bromide level
Bronchiectasis:
 high-resolution CT scan of lung
Bronchitis:
 Sputum culture, chest 
x-ray
Bronchopneumonia:
 Sputum smear and culture, chest x-ray, CBC, cold
Brucellosis:
 Blood cultures, serologic tests, skin test
Bubonic plague:
 Culture of bubo, blood, or sputum; animal inoculation;
serologic test
Buerger’s disease:
 Phlebogram, arteriogram, biopsy of affected vessels,
ultrasonography
C
Carbon monoxide poisoning:
 Carboxyhemoglobin determination
Carbon tetrachloride poisoning:
 Liver function tests, infrared spectrometry,
liver biopsy, blood carbon tetrachloride
Carcinoid syndrome:
 Serum serotonin, urine 5-hydroxyindoleacetic acid (5-
HIAA), exploratory laparotomy, bronchoscopy
Carcinoma of the breast:
 Mammogram, CEA, sonogram, fine-needle
aspiration, biopsy
Carcinoma of the cervix:
 Papanicolaou (Pap) smears, cervical biopsy,
colposcopy
Carcinoma of the colon:
 Stool for occult blood, sigmoidoscopy, barium
enema, colonoscopy, carcinoembryonic antigen (CEA), CT scan
Carcinoma of endometrium:
 Pap smear, endometrial biopsy, dilatation and
curettage (D & C)
Carcinoma of the esophagus:
 Barium swallow, esophagoscopy, biopsy
Carcinoma of the lung:
 Chest 
x-ray,
 CEA, CT scan, sputum Pap smears,
bronchoscopy and biopsy, needle biopsy, open-lung biopsy, scalene node
biopsy
Carcinoma of the ovary:
 CA-125, CT scan of the pelvis
Carcinoma of the pancreas:
 Sonogram, CEA, CT scan of abdomen, liver
function tests, ERCP, exploratory laparotomy, cancer antigen (CA) 
19-9
Carcinoma of the stomach:
 Gastrointestinal (GI) series, gastroscopy and
biopsy, gastric cytology
Carcinoma of the thyroid:
 calcitonin, CT scan of the neck, MRI
708

Cardiac arrhythmias:
 ECG, Holter monitoring, echocardiogram,
electrophysiologic study
Cardiomyopathy:
 See Myocarditis/Myocardiopathy
Carpal tunnel syndrome:
 Nerve conduction velocity (NCV) study, MRI
Cat-scratch disease:
 Skin test, lymph node biopsy
Celiac disease:
 D-xylose absorption, mucosal biopsy, urine 5-HIAA, 
small-
bowel
 series, tissue transglutaminase autoantibody titer by ELISA
Cellulitis:
 Smear and culture of wound exudates, antistreptolysin O (ASO)
titer
Cerebellar ataxia:
Cerebral abscess:
Cerebral aneurysm:
 CT scan, MRI, MRA, arteriogram
Cerebral embolism:
 CT scan, MRI blood culture, echocardiogram, carotid
scan, four-vessel cerebral angiogram, ECG
Cerebral hemorrhage:
Cerebral thrombosis:
 CT scan, MRI, MRA, carotid scan, digital subtraction
angiogram, four-vessel cerebral angiogram, hypercoagulable profile
Cervical spondylosis:
 X-ray of cervical spine, EMG, MRI, myelogram with
simultaneous CT scan
Chagas disease:
 Blood smear and culture, cerebrospinal fluid (CSF) smear
and culture, bone marrow or tissue biopsy, animal inoculation, serologic
tests
Chancroid:
 Smear and culture of lesion, skin biopsy, serology tests
Child abuse:
 Skeletal survey, chest 
x-ray,
 vaginal smear and culture
Chlamydia pneumonia:
 Chest 
x-ray,
 serologic tests
Cholangioma:
 Liver function tests, transhepatic cholangiogram, MRCP,
ERCP, CT scan of abdomen, exploratory laparotomy
Cholangitis:
 Liver function tests, transhepatic cholangiogram, MRCP, ERCP,
exploratory laparotomy
Cholecystitis:
 Sonogram, cholecystogram, liver function tests, hepatobiliary
iminodiacetic acid scan (HIDA) test
Choledocholithiasis:
 Liver function tests, duodenal drainage, ERCP,
transhepatic cholangiogram, sonogram
Cholelithiasis:
 Sonogram, cholecystogram, liver function tests, ERCP
Cholera:
 Stool smear and culture, dark field microscopy
Choriocarcinoma:
 Plasma B-subunit hCG, urine chorionic gonadotropin, D
& C
Cirrhosis:
 Liver function tests, liver scan, CT scan, liver biopsy
Coarctation of the aorta:
 
Chest
 
x-ray,
 
clinical evaluation, aortograms rarely
required
Coccidioidomycosis:
 Smear, animal inoculation, serology, skin test, chest 
x-
ray
709

Concussion:
 CT scan, MRI, EEG, evoked potentials, psychometric tests
Congestive heart failure:
 ECG, chest x-ray, spirometry, circulation time,
ABGs, echocardiogram, B-type natriuretic peptide (BNP) CT scan, MRI
Coronary insufficiency:
 See Angina pectoris
Costochondritis (Tietze syndrome):
 Lidocaine infiltration
Craniopharyngioma:
 Skull x-ray, CT scan, MRI
Cretinism:
 Free T
4
, thyrotropin, radioactive iodine (RAI) uptake and scan, x-
ray for bone age
Crigler–Najjar syndrome:
 See Gilbert disease
Cryoglobulinemia:
 Serum protein electrophoresis and immunoelectrophoresis
(SIA) water test, cold agglutinins, rheumatoid arthritis (RA) test, hepatitis C
antibody titer
Cryptococcosis:
 Spinal fluid smear and culture, sputum or blood cultures,
CSF cryptococcal antigen
Cushing syndrome:
 
Twenty-four-hour
 urine free cortisol, plasma cortisol,
single-dose overnight dexamethasone suppression test, plasma ACTH, CRH
stimulation test, CT scan of brain or abdomen
Cystic fibrosis:
 Quantitative pilocarpine iontophoresis, sweat test
Cysticercosis:
 Serologic test, CT scan of brain, MRI, biopsy of subcutaneous
cysticerci
Cystinosis:
 Slit-lamp examination, liver biopsy
Cystinuria:
 Serum and urine cystine and arginine, cyanide–nitroprusside test,
thin-layer chromatography
Cytomegalic inclusion disease:
 Blood smear for atypical lymphs,
cytomegalovirus (CMV), IgM antibody titer, human fibroblastic cell culture
inoculation, immunofluorescence technique for viral demonstration
D
Dehydration:
 Intake and output of fluid, electrolytes, blood urea nitrogen
(BUN) to creatinine ratio, serum/urine osmolality
Dementia:
 Free T
4
, TSH, serum B
12
, CRP, chromosomal analysis, serum
thiamine
Dengue:
 Viral isolation from blood, serology test
Dermatomyositis:
 Aldolase, serum, antinuclear antibody (ANA), aspartate
aminotransferase (AST), lactate dehydrogenase (LDH), creatine
phosphokinase (CPK),urine myoglobin, EMG, muscle biopsy
Diabetes insipidus:
 
Hickey–Hare test, serum/urine osmolality intake and
output before and after pitressin, CT scan, serum antidiuretic hormone
(ADH)
Diabetes mellitus:
 Glucose tolerance test, insulin antibodies, cortisone
glucose tolerance test, glycosylated hemoglobin (HbA
lc
)
Digitalis intoxication:
 Serum digoxin level, ECG
710

Di Guglielmo disease:
 Bone marrow, peripheral blood study
Diphtheria:
 Nose and throat culture
Diphyllobothrium latum:
 Stool for ova and parasites, serum B
12
 level
Dissecting aneurysm:
 Chest 
x-ray,
 ultrasonography, CT scan or MRI of aorta,
aortogram
Disseminated intravascular coagulation (DIC):
 Decreased fibrinogen,
increased fibrin degradation products, D-dimer assay
Diverticulosis:
 Sigmoidoscopy, barium enema, colonoscopy, CT scan of
abdomen, gallium scan, sonogram, exploratory laparotomy
Down syndrome:
 Chromosome study, urinary B-aminoisobutyric acid
Dracunculiasis:
 Noting presence of worms in subcutaneous tissues, serum
IgE, antifilarial antibody titer
Dubin–Johnson syndrome:
 Liver function tests, liver biopsy
Ductus arteriosus, patent:
 MRI or CT scan, cardiac catheterization,
angiocardiogram, echocardiogram
Duodenal ulcer:
 See Peptic ulcer
Dwarfism:
 X-ray of bones; endocrine, renal, and GI function tests
Dysfunctional uterine bleeding:
 D & C, endometrial biopsy, progesterone
challenge
E
Eaton–Lambert syndrome:
 EMG, Tensilon test, muscle biopsy, chest 
x-ray
Echinococcosis:
 CT scan of abdomen, x-ray of long bones, Casoni skin test,
serologic tests, liver biopsy
Eclampsia:
 Uric acid, renal function tests, renal biopsy
Ectopic pregnancy:
 Serum β-hCG by immunoassay, sonogram, laparoscopy,
culdocentesis, exploratory laparotomy, serum progesterone levels
Eczema:
 Serum IgE levels
Ehlers–Danlos syndrome:
 Capillary fragility test, bleeding time, skin biopsy
Emphysema:
 Pulmonary function tests, chest x-ray, ABGs, α-antitrypsin
level, single breath diffusing capacity for carbon monoxide
Empyema:
 Chest x-ray, sputum cultures, gallium scan, thoracentesis
Encephalitis:
 Viral isolation from brain tissue and spinal fluid, MRI, HSV and
HIV antibody titers, acute and chronic phase serum for viral studies
Encephalomyelitis:
 Viral isolation from brain tissue and spinal fluid, MRI,
serologic tests
Endocardial fibroelastosis:
 ECG, chest x-ray, echocardiogram, cardiac MRI,
angiocardiogram
Endocarditis:
 See Subacute bacterial endocarditis
Endometriosis:
 Sonogram, CA-125, MRI, therapeutic trial
Epilepsy:
 Wake-and-sleep EEG, CT scan or MRI, positron emission
tomography (PET) scan, ambulatory EEG monitoring, therapeutic trial
711

Erectile dysfunction:
 
Penile blood pressure nocturnal tumescence testing,
sonogram
Erythema multiforme:
 Skin biopsy, patch test
Erythroblastosis fetalis:
 Bilirubin, direct Coombs test, amniocentesis
Esophageal varices:
 Esophagoscopy, splenovenogram, ultrasonography
Esophagitis:
 Bernstein test, esophagoscopy and biopsy, esophageal
manometry, ambulatory pH monitoring
Extradural hematoma:
Epididymitis:
 Sonogram, radionuclide scan
F
Fanconi syndrome:
 
X-ray (pelvis, scapula, femur, ribs), urinary amino acids,
glucose, electrolytes, serum uric acid, alkaline phosphatase, renal biopsy
Filariasis:
 Blood smear for microfilariae, skin test, complement fixation test
Folic acid deficiency:
 Serum folic acid, therapeutic trial
Friedlander pneumonia:
 Sputum smear and culture, blood cultures, lung
puncture, serial chest 
x-rays
Friedreich’s ataxia:
G
Galactosemia:
 Paigon assay of blood galactose, red blood cell (RBC) assay of
(GAL-1-PUT) transferase
Gallstone:
 See Cholelithiasis
Gargoylism:
 Urinary chondroitin sulfuric acid, serum assay of α
-L-
iduronidase,
 tissue culture, enzyme assay
Gastric ulcer:
Gastritis:
 Serology for 
, urea breath test, gastroscopy,
biopsy
Gastroenteritis:
 Stool for culture, smear, and ova and parasites
Gaucher’s disease:
 Assay of leukocytes for β-glucosidase, angiotensin-
converting enzyme, bone marrow examination, x-ray of long bones
General paresis:
 Blood and spinal fluid fluorescent treponemal antibody
absorption (FTA–ABS) test
Giardia lamblia:
 Cathartic stool for ova and parasites, duodenal analysis,
Giardia
 antigen, string test
Gigantism:
 CT scan or MRI of brain, serum growth hormone, 
insulin-like
growth factor
Gilbert disease:
Gilles de la Tourette syndrome:
 Urinary catecholamines
Glanders:
 Culture of skin lesion, skin test, serologic tests, animal inoculation
Glanzmann’s disease:
 Platelet counts, clot retraction, prothrombin time,
bleeding time, capillary fragility test; see also Thrombocythemia
Glaucoma:
 Tonometry, gonioscopy, visual fields
712

Glomerulonephritis:
 Serum complement, streptozyme test, ANA, renal
biopsy
Glossitis:
 Culture, biopsy, therapeutic trial of vitamins and iron
Glycogen storage disease:
 Glucose tolerance test, epinephrine test, liver
biopsy and analysis for glucose-6-phosphatase
Goiter:
 Ultrasonography, Free T
4
, RAI uptake and scan, thyrotropin, serum
antibodies
Gonorrhea:
 Urethral, rectal, vaginal, or throat smear and cultures; urine DNA
probes and polymerase chain reaction (PCR)
Goodpasture’s syndrome:
 Circulating antiglomerular antibodies, chest 
x-ray,
renal biopsy
Gout:
 Serum uric acid, synovial fluid analysis, x-ray of bones and joints
Granuloma inguinale:
 Wright stain of scrapings from lesion and biopsy
Graves disease:
 See Hyperthyroidism
Guillain–Barré syndrome:
 EMG, spinal fluid analysis
Gumma:
 FTA–ABS
H
Haemophilus influenzae:
 Nose, throat, and sputum culture or spinal fluid
smear and culture
Hamman–Rich syndrome:
 Chest 
x-ray,
 pulmonary function tests, lung
biopsy
Hand–Schüller–Christian disease:
 
X-ray
 of skull, bone biopsy, bone marrow
Hansen disease:
 See Leprosy
Hartnup disease:
 Urinary amino acid, indican, and indoleacetic acid; FT
4
index; thyrotropin
Hashimoto’s disease:
 FT
4
 index, thyrotropin, serum thyroglobulin antibodies
Haverhill fever:
 Agglutination titer, aspiration of affected joint or abscess for
Streptobacillus moniliformis
Hay fever:
 See Allergic rhinitis
Heart failure:
 See Congestive heart failure
Helminth infections:
 Stool for ova and parasites, serologic tests, skin tests,
liver function tests
Hemangioblastoma:
 CT scan or MRI
Hemochromatosis:
 Serum ferritin, serum iron and iron-binding capacity, liver
or skin biopsy
Hemoglobin C disease:
 Blood smear for target cells, hemoglobin
electrophoresis
Hemoglobinuria, paroxysmal cold:
 CBC, Coombs test, Donath–Landsteiner
test, FTA–ABS, serum haptoglobins
Hemoglobinuria, paroxysmal nocturnal:
 CBC, Ham test, sucrose hemolysis
713

test
Hemolytic anemia:
 Serum haptoglobins, direct and indirect bilirubin,
radioactive chromium–tagged red cell survival, urine and fecal
urobilinogen, Coombs test, blood smear
Hemophilia:
 Coagulation profile, thromboplastin generation test, assay of
factors VIII, IX, XI Henoch–Schönlein purpura: skin biopsy, coagulation
profile
Hepatitis:
 Liver function test, hepatitis profile, IgM, anti–hepatitis A virus
(HAV), hepatitis B surface antigen 
(HBsAg), liver biopsy, anti–hepatitis C
virus (HCV)
Hepatitis, chronic active:
 HBsAg, liver function tests, ANA, liver biopsy,
anti–smooth muscle antibody
Hepatolenticular degeneration:
 See Wilson’s disease
Hepatoma:
 Ultrasonography, CT scan, α-fetoprotein, liver biopsy,
arteriogram, MRI
Hernia, diaphragmatic:
 See Hiatal hernia
Herniated disc:
 EMG, MRI, CT scan, myelogram, discogram
Herpangina:
 Serologic tests, viral isolation
Herpes genitalis:
 Examination of skin scrapings, Tzanck test, culture,
Herpes simplex:
 Serologic tests, viral isolation, Tzanck test
Herpes zoster:
 Tzanck test, serologic tests
Hiatal hernia:
 Bernstein test, esophagram, esophagoscopy and biopsy,
esophageal manometry, therapeutic trial
Hirschsprung’s disease:
 Rectal or colonic biopsy
Histamine cephalgia:
 Test trial of histamine subcutaneously, response to
sumatriptan
Histoplasmosis:
 Sputum culture, bone marrow culture, animal inoculation,
skin test, serologic tests, chest 
x-ray
HIV infections:
Hodgkin’s lymphoma:
 Lymph node biopsy, bone marrow lymphangiogram,
CT scan, liver–spleen scan, exploratory laparotomy
Huntington’s chorea:
 Clinical diagnosis, genetic markers, CT scan
Hurler syndrome:
 See Gargoylism
Hydronephrosis:
 CT scan of abdomen Intravenous pyelogram (IVP),
sonogram
Hyperaldosteronism:
 See Aldosteronism, primary
Hypercholesterolemia, familial:
 Lipoprotein electrophoresis, lipid profile
Hyperlipemia, idiopathic:
 Lipoprotein electrophoresis, ultracentrifugation
Hypernephroma:
 IVP or retrograde pyelogram, CT scan, angiogram
Hyperparathyroidism:
 Serum calcium, phosphorus, and alkaline
phosphatase; urine calcium; serum parathyroid hormone (PTH); 1,25-
714

(OH)2D; phosphate reabsorption test; ultrasonography, exploratory surgery
Hyperprolactinemia:
 CT scan, MRI of brain serum prolactin
Hypersplenism:
 
CBC, blood smear, red cell survival, spleen/liver ratio, bone
marrow, epinephrine test, exploratory laparotomy
Hyperthyroidism:
 
Thyroid-stimulating
 hormone (TSH), free T
3
, FT
4
 index,
free T
4
, radioactive I-123 uptake and scan
Hypogonadism:
 Serum testosterone, FSH, LH
Hypoparathyroidism:
 Serum calcium and phosphorus, 24-hour urine
calcium, skull x-ray, phosphate reabsorption, therapeutic trial, PTH assay,
urine cyclic adenosine monophosphate (AMP), Hypersensitivity angiitis:
ESR, serum complement
Hypopituitarism:
 Serum cortisol, serum thyroxine, serum growth hormone,
serum corticotrophin, thyrotropin, follicle-stimulating hormone (FSH), LH,
CT scan, MRI
Hypotension, idiopathic postural:
 Clinical observation, tilt table test,
response to vasopressin injection (Pitressin), tests to rule out causes of
secondary hypotension
Hypothermia:
 EKG (
J
 waves [Osborn waves])
Hypothyroidism:
 Free T
4
, thyrotropin-sensitive assay, thyroid microsomal
antibodies, therapeutic trial
I
Idiopathic hypertrophic subaortic stenosis:
 EKG, echocardiography
Ileitis:
 See Regional enteritis
Inappropriate ADH secretion:
 Plasma and urine osmolality, spot urinary
sodium, serum ADH
Infectious mononucleosis:
 Monospot test, heterophile antibody titer, smear
for atypical lymphocytes, liver function tests, repeat tests, Epstein–Barr
virus (EBV) antibody titer
Influenza, viral:
 Culture of nasopharyngeal washing, complement fixation
tests, rapid antigen test
Insulinoma:
 See Islet cell tumor
Interstitial cystitis:
 Cystoscopy and biopsy
Intestinal obstruction:
 Flat plate of the abdomen with lateral decubitus films,
double enema, sonogram, CT scan, GI series with diatrizoate meglumine
and diatrizoate sodium (Hypaque), exploratory laparotomy
Iron deficiency anemia:
 Serum ferritin, serum iron and iron-binding capacity,
free erythrocyte protoporphyrins (FEP), bone marrow, therapeutic trial
Irritable bowel syndrome:
Islet cell tumor:
 Glucose tolerance test, 72-hour fast, plasma insulin, 
C-
peptide,
 tolbutamide tolerance test, CT scan or MRI, exploratory
715

K
Kala azar:
 Blood smear, bone marrow or splenic aspirate for parasites,
culture, serologic tests (ELISA)
Kaposi sarcoma:
 Human herpesvirus 8 (HHV8) antibody titer, biopsy
Kawasaki syndrome:
 CRP, ESR, CBC, UA, spinal tap
Klinefelter’s syndrome:
 Sex chromatin pattern, testicular biopsy, serum FSH
and LH
Kwashiorkor:
 Serum albumin, CBC
L
Lactase deficiency:
 
Lactose tolerance test, mucosal biopsy, hydrogen breath
test
Laennec cirrhosis:
 See Cirrhosis
Larva migrans, visceral:
 Eosinophil count, serum globulin, skin testing,
Lambert–Eaton syndrome:
 GVC radioimmunoassay
Laryngeal carcinoma:
 Laryngoscopy
Laryngitis:
 Nose and throat culture, washings for viral studies, laryngoscopy
Lead intoxication:
 Serum and urine lead content, urine for γ
-aminolevulinic
acid (ALA), coproporphyria FEP, test dose of diaminoethanetetraacetic acid
(EDTA), x-ray of long bones
Legionnaire disease:
 Sputum culture, serology, urinary Ag assay
Leishmaniasis:
 CBC, blood spleen and bone marrow smears for parasites,
biopsy, serologic tests
Leprosy:
 Wade’s scraped incision procedure, culture of lesion, biopsy of skin
nerves, x-ray of hands and feet, histamine tests, lepromin skin test
Leptospirosis:
 See Weil disease
Letterer–Siwe disease:
 X-ray of bones, bone marrow, lymph node biopsy
Leukemia:
 Blood smear, bone marrow, uric acid, serum B
12
 concentration,
iron-binding capacity, Philadelphia chromosome
Listeriosis:
 Blood or spinal fluid smear and spinal fluid agglutination titer,
bone marrow biopsy
Liver abscess:
 
Liver scan with technetium or gallium, liver aspiration and
biopsy, CT scan, amebic hemagglutinin inhibition titer, cathartic stool for
ova and parasites
Loeffler’s syndrome:
 Eosinophil count, sputum for eosinophils, stool for ova
and parasites
Lung abscess:
 Chest x-ray, tomogram, CT scan, sputum culture,
bronchoscopy, sputum cytology, needle aspiration, biopsy, and culture
Lupoid hepatitis:
 See Hepatitis, chronic active
Lupus erythematosus:
 ANA, anti–
double-stranded
 DNA antibody titer (not
usually positive in drug-induced lupus), anti-Sm antibodies, Coombs test,
716

lupus erythematosus prep, coagulation profile, biopsy of skin, muscle,
lymph node, or kidney
Lyme disease:
 Serologic tests
Lymphangitis:
 CBC, sedimentation rate
Lymphogranuloma inguinale:
 Lygranum test, Giemsa-stained smear,
serologic tests, tissue or lymph node biopsy
Lymphogranuloma venereum:
 Serologic tests, lymph node biopsy,
aspiration of bubo for culture
Lymphoma:
 See Hodgkin’s disease
Lymphosarcoma:
 CT scan, x-rays of chest and abdomen, lymphangiogram
M
Macroglobulinemia:
ultracentrifugation, Sia water test, bone marrow
Malabsorption syndrome:
 
D-xylose
 absorption test, urine 5-HIAA, mucosal
biopsy, small-bowel series
Malaria:
 Blood smear for parasites, bone marrow, serologic tests
Mallory–Weiss syndrome:
 Esophagoscopy
Marfan syndrome:
 X-ray of long bones and ribs, slit-lamp examination of
eyes, IVP, urinary hydroxyproline, CT scan of aorta
Marie–Strumpell spondylitis:
 X-ray of lumbosacral spine, bone scan, HLA
typing
Mastocytosis:
 Skin biopsy, Darier’s sign, long-bone x-ray, bone marrow
biopsy
Mastoiditis:
 X-ray of mastoid, CT scan
McArdle syndrome:
 Liver biopsy, enzyme assay of muscle phosphorylase,
muscle biopsy, urine myoglobin
Measles:
 Smear of nasal secretions for giant cells, serologic tests
Meckel’s diverticulum:
 Technetium scan, sonogram, exploratory laparotomy
Mediastinitis:
 CT scan or MRI of chest, mediastinoscopy, exploratory surgery
Medullary sponge kidney:
 IVP, CT scan
Medulloblastoma:
Megaloblastic anemia:
 See Pernicious anemia
Meigs syndrome:
 Thoracentesis, culdoscopy, laparoscopy, exploratory
laparotomy, sonogram
Melanoma:
 Serum or urinary melanin, biopsy
Ménière’s disease:
 CT scan, audiogram, caloric tests, electronystagmography
(ENG)
Meningioma:
 CT scan, MRI, x-ray of skull or spine, myelogram
Meningitis:
 Spinal fluid examination, smear and culture, serum for viral
serologic studies, blood culture
Meningococcemia:
 Blood culture spinal fluid examination, smear and culture,
717

Gram’s stain of punctured petechiae
Menopause syndrome:
 Serum LH, FSH, serum estradiol, vaginal smear for
estrogen effects, therapeutic trial
Mental retardation:
 CT scan or MRI, EEG, psychometric testing, skull 
x-ray,
phenylketonuria (PKU), FT
4
 index, thyrotropin, urinary amino acids,
chromosomal analysis
Methemoglobinemia:
 Erythrocyte methemoglobin, ABG, blood diaphorase I,
spectrophotometry
Migraine:
 Nitroglycerin test, histamine test, sedimentation rate to rule out
Mikulicz’s disease:
 CBC, bone marrow, tuberculin test, biopsy of lesion,
ANA, lymph node biopsy
Milk–alkali syndrome:
 Serum calcium, phosphorus, alkaline phosphatase,
urinary calcium and phosphates
Milroy disease:
Mitral insufficiency or stenosis:
 ECG, chest x-ray, echocardiogram,
phonocardiogram, cardiac catheterization
Moniliasis:
 Vaginal smear or culture, skin scrapings with KOH prep, biopsy
Mononucleosis, infectious:
 See Infectious mononucleosis
Mucormycosis:
 Nose and throat culture, biopsy
Mucoviscidosis:
 See Cystic fibrosis
Multiple myeloma:
 Serum protein electrophoresis, 24-hour urine
electrophoresis, bone marrow, x-ray of skull and spine, MRI
Multiple sclerosis:
 Somatosensory evoked potentials (SSEP), visual evoked
potential (VEP), spinal fluid oligoclonal IgG bands, and myelin basic
protein, MRI
Mumps:
 Skin test, serologic tests, viral isolation from throat washings
Muscular dystrophy:
 EMG, muscle biopsy, urine creatine, chromosome
analysis, serum enzymes (creatine phosphokinase, and so forth)
Myasthenia gravis:
 EMG, Tensilon test, acetylcholine receptor antibody titer,
CT scan of chest to rule out thymoma
M. pneumoniae:
 Cold agglutinins, (MG) streptococcal agglutinins, culture
Mycosis fungoides:
 Skin biopsy
Myeloid metaplasia, agnogenic:
 Red cell morphology, CBC, bone marrow,
leukocyte alkaline phosphatase, urine and serum erythropoietin
Myelophthisic anemia:
 CBC, bone marrow, bone scan, lymph node biopsy
Myocardial infarction:
 Serial enzymes (MB, creatine phosphokinase [CPK],
and so forth), serial ECGs serum 
troponin-1,
 thallium-201 scintigraphy,
pyrophosphate imaging, coronary angiogram, echocardiogram
Myocarditis/Myocardiopathy:
 Echocardiogram, cardiac MRI,
endomyocardial biopsy, cardiac catheterization
Myotonia atrophica:
 EMG, urine creatinine and creatine, muscle biopsy
718

Myxoma, cardiac:
 Echocardiogram, angiocardiogram
N
Narcolepsy:
 Sleep study, EEG, 
HLA-DR2
 Nematodes: gastric analysis,
muscle biopsy, eosinophil count, skin test, serologic tests, stools for ova and
parasites, duodenal aspiration for ova and parasites, GI series, rectal swabs
with Scotch tape
Nephritis:
 See Glomerulonephritis
Nephrocalcinosis:
 Serum PTH, serum calcium, phosphorus and alkaline
phosphatase, IVP, CT scan of abdomen renal biopsy
Nephrotic syndrome:
 Urinalysis serum complement, sedimentation rate,
serum protein electrophoresis, renal function tests, ANA, renal biopsy
Neurinoma, acoustic:
 See Acoustic neuroma
Neuritis, peripheral:
 See Neuropathy
Neuroblastoma:
 Urinary vanillylmandelic acid (VMA) and homovanillic acid
(HVA), CT scan, bone marrow, exploratory laparotomy
Neurofibromatosis:
 Biopsy, skeletal survey, CT scan, spinal fluid analysis,
myelogram
Neuropathy:
 Glucose tolerance test, HbA
1c
, blood lead level, urine
porphobilinogen, blood and urine arsenic levels, serum thiamine and
nicotinic acid levels, ANA, serum B
12
 and folic acid, spinal fluid
examination, NCV, EMG, serum transketolase activity coefficient, nerve
biopsy
Neurosyphilis:
 Blood and spinal fluid FTA–ABS
Niacin deficiency:
 See Pellagra
Niemann–Pick disease:
 Demonstration of sphingomyelin in
reticuloendothelial cells, bone marrow biopsy, tissue biopsy, skeletal
survey, culture of skin fibroblasts
Nocardiosis:
 Sputum smear and culture, spinal fluid examination, smear and
culture
Nonketotic hyperosmolar coma:
 Blood sugar, plasma osmolality
Normal pressure hydrocephalus:
 CT scan, nuclear flow study (radioactive
iodinated albumin [RISA])
Nutritional neuropathy:
O
Ochronosis:
 Urinalysis (Benedict solution, isolation of homogentisic acid), x-
ray of spine
Oppenheim’s disease:
 EMG, muscle biopsy
Optic atrophy:
 CT scan of brain and orbits, visual fields, spinal tap, serum
B
12
, x-ray of skull and optic foramina
Optic neuritis:
 FTA–ABS antibody titer, visual fields, MRI of the brain
719

Osteitis deformans:
skeletal survey, bone scan, bone biopsy, urine hydroxyproline
Osteoarthritis:
 X-ray of spine and joints, exclusion of other forms of arthritis
Osteogenic sarcoma:
 Alkaline and acid phosphatase, x-ray of bone, bone
scan, bone biopsy
Osteomalacia:
 Serum calcium phosphorus, alkaline phosphatase, 
x-ray
 of
long bones, response to vitamin D and calcium, serum vitamin D levels
Osteomyelitis:
 Sedimentation rate, blood culture, culture of bone biopsy, 
x-
ray
 of bone, bone scan, CT scan, teichoic acid antibody titer (TAAB)
Osteopetrosis:
 Bone marrow, x-ray of bones, bone biopsy
Osteoporosis:
 Serum, calcium, phosphorus, alkaline phosphatase, bone
biopsy, x-ray of spine, quantitative computerized tomogram, bone mineral
density (BMD), bone densitometry
Otitis media:
 Nasopharyngeal or aural smear and culture, CBC, sedimentation
rate, tympanometry, audiogram
Otosclerosis:
 Audiometry
Ovarian cancer:
 Serum CA-125, pelvic sonogram, CT scan of abdomen and
pelvis
P
Paget’s disease:
 See Osteitis deformans
Pancreatic carcinoma:
 See Carcinoma of the pancreas
Pancreatitis, acute:
 Serum amylase and lipase, blood sugar, serum calcium,
paracentesis, flat plate of abdomen, 2-hour urinary amylase
Pancreatitis, chronic:
 Serum bentiromide test, serum and urinary amylase
and lipase before and after secretin, glucose tolerance test, duodenal
analysis for bicarbonate and enzyme concentration, CT scan, ERCP, fecal
fat, triolein iodine 131 (
131
I) uptake
Panniculitis:
 Bone marrow, skin and subcutaneous tissue biopsy
Paralysis agitans:
Pediculosis:
 Woods lamp, microscopic examination of hair shafts
Pellagra:
 Urine 
N
-methylnicotinamide, urine niacin after loading dose
therapeutic trial
Pelvic inflammatory disease (PID):
 Laparoscopy, culture of cervical mucus,
Pemphigus:
 Skin biopsy, Tzanck test, immunofluorescence studies
Penicillin allergy:
 Skin testing with penicilloyl polylysine
Peptic ulcer:
 Upper GI series, stool for occult blood, gastroscopy and
duodenoscopy, gastric analysis, serology for 
H. pylori
Periarteritis nodosa:
 ESR, CRP, ANA; eosinophil count; CBC; urinalysis;
muscle, skin, subcutaneous tissue, and testicular biopsy; nerve biopsy;
angiography
720

Pericarditis:
 ECG, echocardiogram, chest x-ray, angiocardiogram, pericardial
tap, CT scan, or MRI
Periodic paralysis, familial:
 
Serum potassium, ECG, EMG, response to
glucose
Peritonitis:
 CBC, flat plate of abdomen, CT scan, sonogram, peritoneal tap,
Pernicious anemia:
 CBC, blood smear, serum B
12
 and folic acid, Schilling
test, gastric analysis with histamine, bone marrow
Pertussis:
 CBC, nasopharyngeal smear and culture
Petit mal:
 Sleep EEG, CT scan
Peutz–Jeghers syndrome:
 
Small-bowel
 series, exploratory laparotomy
Pharyngitis:
 Nose and throat culture, rapid agglutination test of throat swab
(Abbott test pack strep A, Abbott Laboratories, Abbott Park, IL),
streptozyme test
Phenylpyruvic oligophrenia:
 Urine for PKU and phenylalanine, Guthrie test,
serum phenylalanine
Pheochromocytoma:
 Plasma and urine catecholamines, 24-hour urine VMA,
Phlebitis:
 See Thrombophlebitis
Phlebotomus fever:
Pickwickian syndrome:
 Pulmonary function tests, ABG, sleep study
Pinealoma:
Pinworms:
 Scotch tape swab of perianal area with microscopic examination
for eggs
Pituitary adenoma:
 CT scan, MRI, serum thyrotropin, corticotrophin, LH and
FSH, Free T
4
, serum cortisol, growth hormone, serum prolactin
Placenta previa:
 Ultrasonography
Plague:
 See Bubonic plague
Platyhelminthes:
 Stool for ova and parasites, serologic tests, skin test, urine
sediment for eggs, eosinophil count
Pleurisy:
 Chest x-ray, thoracentesis, pleural biopsy, bronchoscopy, CT scan,
Pleurodynia, epidemic:
 Serologic tests, stool and throat cultures for
Coxsackie B virus
Pneumococcal pneumonia:
 See Pneumonia
Pneumoconiosis:
 Chest x-ray, pulmonary function tests, ABG, sputum smear,
lung biopsy, lung scan, scalene node biopsy
Pneumonia:
 Stat sputum smear, culture, blood cultures, chest 
x-ray
Pneumothorax:
 Chest x-ray, ABG, CT scan
Poliomyelitis:
 Viral isolation from stool, serologic tests, spinal fluid analysis
Polyarteritis:
 See Periarteritis nodosa
Polycystic kidney:
 Sonogram, CT scan
721

Polycystic ovary:
 See Stein–Leventhal syndrome
Polycythemia vera:
 CBC, platelet count, uric acid, ABG, pulmonary function
tests, serum erythropoietin, bone marrow
Polymyalgia rheumatica:
 Sedimentation rate, CRP
Polyneuritis:
Porphyria:
 Urine porphyrins and porphobilinogen
Portal cirrhosis:
Pott disease:
 X-ray of the spine, aspiration and culture of synovial fluid,
synovial or bone biopsy, purified protein derivative (PPD) skin test
Preeclampsia:
 See Eclampsia
Pregnancy:
 Blood or urine test for pregnancy
Prostate carcinoma:
 Serum acid and alkaline phosphatase, 
prostate-specific
antigen (PSA) skeletal survey, bone scan, biopsy of prostate
Prostatic hypertrophy:
 Sonogram, cystoscopy, IVP
Protein-losing enteropathy:
 
131
I polyvinylpyrrolidone test, serum protein
Pseudogout:
 Synovial analysis, 
x-ray
 of knees
Pseudomembranous colitis:
 
 toxin B
Pseudohypoparathyroidism:
 Serum calcium, phosphorus, alkaline
phosphatase, urine calcium, Ellsworth–Howard test, PTH, parathyroid
tissue biopsy
Pseudotumor cerebri:
 CT scan, MRI, spinal tap
Psittacosis:
 Chest x-ray, serologic test, virus isolation
Psoriatic arthritis:
 ESR, CRP, HLA testing
Pulmonary embolism:
 See Pulmonary infarction
Pulmonary emphysema:
 See Emphysema
Pulmonary fibrosis:
 Diffusion capacity, bronchoscopy, lung biopsy, CT scan
Pulmonary hypertension, idiopathic:
 ABG, pulmonary function test, cardiac
catheterization, pulmonary angiogram
Pulmonary infarction:
 ABG, V/Q lung scan, pulmonary angiogram,
impedance plethysmogram, helical CT scan, rapid D-dimer assay
Pyelonephritis:
 Urine culture, colony count, IVP, cystoscopy, renal biopsy
Pyloric stenosis:
 GI series, gastroscopy, sonogram
Pyridoxine deficiency:
 Serum iron and iron-binding capacity, blood
pyridoxine, urine pyridoxic acid
Q
Q fever:
R
Rabies:
 
Observation or autopsy of infected animals, isolation of virus from
saliva, serum and CSF antibody titer, fluorescent antibody stain of corneal
or skin cells
722

Rat-bite fever:
 Dark field examination, culture of lesion, aspiration and
culture of regional lymph node, animal inoculation, serologic tests
Raynaud’s disease:
 ANA, lupus erythematosus prep, immunoelectrophoresis,
cold agglutinins, cryoglobulins, skin or muscle biopsy, cold challenge
Reflux esophagitis:
 See Esophagitis
Regional enteritis:
 Sedimentation rate, small-bowel series, sigmoidoscopy or
colonoscopy and biopsy, CT scan of abdomen, surgical exploration
Reiter disease:
 HLA typing, ESR. CRP, bone scan, synovial analysis
Relapsing fever:
 Peripheral blood smear for Borrelia organisms, animal
inoculation, serologic tests, total leukocytes, spinal tap
Renal calculus:
 IVP, noncontrast helical CT scan, cystoscopy, retrograde
pyelogram, sonogram, stone analysis
Renal tubular acidosis:
 Serum electrolytes, calcium, phosphorus, alkaline
phosphatase, urine calcium, phosphatase and bicarbonate, urine pH after
ammonium chloride load
Respiratory distress syndrome:
 Ratio of PaO
2
 to FiO
2
, pulmonary artery
Reticuloendotheliosis:
 
X-ray, CBC, tissue cholesterol content, biopsy of
skeletal lesion, bone marrow or lymph nodes
Reticulum cell sarcoma:
 Alkaline phosphatase, lymph node biopsy, x-ray of
chest, skeletal survey, GI series, IVP, cytologic examination of pleural or
ascitic fluid
Rheumatic fever:
 Throat culture, streptozyme test, C-reactive protein (CRP),
sedimentation rate, ECG, echocardiogram, serial ASO titer
Rheumatoid arthritis:
 Anti-CCP, RA test, sedimentation rate, ANA, x-ray of
joints, synovial fluid analysis
Riboflavin deficiency:
 Activity coefficient of erythrocyte glutathione
reductase
Rickets:
 Serum calcium, phosphorus, alkaline phosphatase, urine calcium, x-
ray of bones, serum PTH, serum 25-OHD, bone biopsy
Rickettsialpox:
Rocky Mountain spotted fever:
 Specific serologic tests, Weil–Felix test,
fluorescent antibody staining of skin lesions
Rubella:
 Viral isolation, latex agglutination card assay, other serologic tests
Rubeola:
 See Measles
S
Saddle embolus of aorta:
 Oscillometry, Doppler flow study, aortogram
Salicylate intoxication:
 Serum or urine salicylates, electrolytes
Salmonellosis:
 Stool culture, febrile agglutinins
Salpingitis:
 Vaginal smear and culture, sonogram, CT scan of pelvis,
laparoscopy, exploratory surgery
723

Sarcoidosis:
 
Chest x-ray, Kveim test, lymph node biopsy, elevated
angiotensin-converting enzymes, gallium scan
Scabies:
 KOH prep
Scalenus anticus syndrome:
 X-ray of cervical spine, arteriogram
Scarlet fever:
 Nose and throat culture, streptozyme test, Schultz–Charlton
reaction
Schilder’s disease:
 EEG, CT scan, MRI, spinal tap, brain biopsy
Schistosomiasis:
 
Stool or urine for ova, rectal biopsy, liver biopsy, serologic
tests
Schönlein–Henoch purpura:
 Urinalysis, platelet count, coagulation profile,
bleeding time, capillary fragility
Schüller–Christian disease:
 See Hand–Schüller–Christian disease
Scleroderma:
 ANA, RA test, 
anti-SCL
 antibodies, anticentromere antibody
titer, skin biopsy, esophagram, malabsorption workup
Scurvy:
 Serum ascorbic acid, capillary fragility, x-ray of bones, therapeutic
trial
Seminoma:
 Urine hCG, sonogram, exploratory surgery, α
-fetoprotein
Septicemia:
 Blood culture
Sexual precocity:
 Skull x-ray, CT scan, urine 17-ketosteroids and 
17-
hydroxysteroids,
 plasma cortisol, metyrapone test, exploratory surgery
Shigellosis:
 Stool examination for leukocytes, stool culture
SIADH:
 serum antidiuretic hormone, serum and urine osmolality
Sickle cell anemia:
 CBC, blood smear, sickle cell preparation, hemoglobin
Silicosis:
 Chest x-ray, pulmonary function tests, ABG, lung biopsy, CT scan
Silo-filler’s disease:
 Chest x-ray, clinical observations
Simmonds disease:
 See Hypopituitarism
Sinusitis:
 X-ray of sinuses, CT scan of sinuses, nose and throat culture,
erythrocyte sedimentation rate (ESR), CRP
Sjögren’s syndrome:
 Schirmer’s test for tear production, ANA, RA titer,
HLA typing, thyroglobulin antibody titer, anti-Sjögren’s syndrome B (La)
antibody titer, lip biopsy, 
anti-Ro/SSA
 and anti-La/SSB antibodies
Smallpox:
 Smear of vesicular fluid for virus particles, viral isolation, serologic
test
Spherocytosis, hereditary:
 CBC, blood smear, red cell fragility test,
reticulocyte count, serum haptoglobins, bilirubin
Spinal cord tumor:
 X-ray of spine, CT scan of spine, MRI
Spinal stenosis:
 CT scan, MRI, myelogram
Sporotrichosis:
 
Cultures of exudates from ulcer, serologic tests, skin tests,
chest
 
x-ray
Staphylococcal pneumonia:
 Sputum smear and culture, chest 
x-ray
Steatorrhea:
 See Celiac disease
724

Stein–Leventhal syndrome:
 Culdoscopy, laparoscopy, serum LH, urine 
17-
ketosteroids,
 sonogram, exploratory surgery, biopsy of ovaries
Stevens–Johnson syndrome:
 Streptozyme test, nose and throat culture
Still’s disease:
 RA test, sedimentation rate, CRP, synovianalysis
Stokes–Adams syndrome:
 ECG, Holter monitoring, event monitoring,
electrophysiologic testing
Streptococcal pharyngitis:
 See Pharyngitis
Strongyloidiasis:
 Stool or duodenal aspirate for ova and parasites
Sturge–Weber syndrome:
 Skull 
x-ray,
Subacute bacterial endocarditis:
 Blood culture, bone marrow cultures,
echocardiogram, RA test, FTA–ABS, transesophageal echocardiography
Subarachnoid hemorrhage:
 CT scan of brain, spinal tap, arteriogram
Subdiaphragmatic abscess:
 Chest 
x-ray,
 gallium scan, indium scan, CT scan,
needle aspiration, exploratory surgery
Subdural hematoma:
 CT scan, MRI, arteriogram
Subphrenic abscess:
 See Subdiaphragmatic abscess
Substance abuse:
 
Blood alcohol level, urine drug screen, CAGE
questionnaire
Sulfhemoglobinemia:
 Shaking of venous blood in test tube, spectroscopic
examination of blood
Syphilis:
 
Blood and spinal fluid venereal disease research laboratory (VDRL)
test or FTA–ABS, dark field microscopy
Syringomyelia:
 CT scan, myelogram, MRI
T
Tabes dorsalis:
 Blood and spinal fluid, FTA–ABS
Takayasu’s disease:
 ESR, CT scan of aorta, aortogram, serum protein
electrophoresis, urinary estrogens
Tapeworm infections:
 
Stool for ova and parasites, serology, sonogram, CT
scan
Tay–Sachs disease:
 Cortical biopsy
Temporal arteritis:
 
Sedimentation rate, CRP, platelet count, biopsy of
temporal artery
Tetanus:
 Clinical diagnosis, positive culture does not establish diagnosis
Thalassemia:
 CBC, blood smear, reticulocyte count, serum haptoglobin,
hemoglobin electrophoresis
Thromboangiitis obliterans:
 See Buerger’s disease
Thrombocythemia (thrombasthenia):
 Platelet count, bleeding time, clotting
time, clot retraction, capillary fragility
Thrombocytopenic purpura, idiopathic:
 Coagulation profile, platelet count,
platelet antibody titer, bone marrow, liver–spleen scan, capillary fragility
Thrombophlebitis:
 Impedance plethysmography, compression
725

ultrasonography, fibrinogen I-125 scan, venogram, thermogram,
Thymoma:
 Chest x-ray, CT scan of mediastinum, mediastinoscopy,
exploratory thoracotomy
Thyroiditis, subacute:
 FT
4
 index, RAI uptake and scan, sedimentation rate,
antithyroid autoantibodies
Thyroid carcinoma:
 Serum calcitonin, RAI uptake and scan, CT scan of the
neck
Thyroid nodule:
 RAI uptake and scan, fine-needle aspiration, biopsy, FT
4
index, sonogram, trial of thyroid suppression therapy
Tonsillitis:
Torsion of testicle:
 Ultrasonography, radionuclide scintigraphy
Tourette syndrome:
Torulosis:
 See Cryptococcosis
Toxemia of pregnancy:
Toxoplasmosis:
 Indirect fluorescent antibody (IFA) titer, passive
hemagglutination test (PHA), skin test, animal inoculation
Trachoma:
 Smear of conjunctival scrapings, culture for 
Chlamydia
, tears for
microimmunofluorescent antibodies
Transfusion reaction:
 Serum hemoglobins and methemalbumin, Coombs test
Transient ischemic attack (TIA):
 
Carotid scan, digital subtraction
angiogram, CT scan, four-vessel cerebral angiogram, MRI
Trichinosis:
 Eosinophil count, skin test, serologic tests, muscle biopsy
Trypanosomiasis:
 Smears and culture of blood, CSF, lymph node aspirate for
parasites, animal inoculation, serology
Tuberculosis:
 Smear and culture of sputum and gastric washings, Guinea pig
inoculation, skin test, chest 
x-ray,
 CT scan
Tuberous sclerosis:
 Skull x-ray, CT scan, skin biopsy, cortical biopsy, EEG
Tularemia:
 Smear and culture of ulcer, lymph nodes, or nasopharynx; Foshay
skin test; serologic tests
Turner syndrome:
 Buccal smear for chromatins (Barr bodies), chromosome
analysis, FSH
Typhoid fever:
 Culture of stool, blood, or bone marrow; febrile agglutinins
Typhus, epidemic:
 Serologic tests, Weil–Felix reaction
Typhus scrub:
 Isolation from blood, serologic tests, Weil–Felix reaction
U
Ulcer:
Ulcerative colitis:
 Barium enema, sigmoidoscopy or colonoscopy, biopsy
Urethritis:
 Urethral smear and culture, vaginal smear and culture, urine
culture, 
Chlamydia
 culture, cystoscopy
Uterine fibroids:
 Sonogram, CT scan, MRI
726

Urticaria:
 RAST, allergic skin testing, elimination diet, C1 esterase inhibitor
Uveitis:
 Slit-lamp examination, ANA, HLA-B27 typing, VDRL, lyme
serology
V
Varicella:
Varicose veins:
 Phlebogram, thermogram
Variola:
 See Smallpox
Ventricular septal defects:
 ECG, echocardiogram, cardiac catheterization
Visceral larva migrans:
 Blood typing, serologic tests, biopsy
Vitamin A deficiency:
 Serum vitamin A or carotene, skin biopsy
Vitamin B deficiency:
 See Beriberi
Vitamin C deficiency:
 See Scurvy
Vitamin D deficiency:
 See Rickets
Vitamin K deficiency:
 Coagulation profile including prothrombin time
von Gierke disease:
 See Glycogen storage disease
von Willebrand disease:
 Coagulation profile, thromboplastin generation test,
factor VIII assay
W
Waterhouse–Friderichsen syndrome:
 
Blood cultures, spinal fluid
examination, nose and throat culture, plasma cortisol
Wegener’s granulomatosis:
 X-ray or CT scans of nose, sinuses, and chest;
urinalysis; renal biopsy; lung biopsy; nasal biopsy; antineutrophil
cytoplasmic antigen (ANCA)
Weil’s disease:
 Dark field examination of blood, Guinea pig inoculation,
serologic tests, spinal tap
Wernicke’s encephalopathy:
 Response to intravenous thiamine
Whipple’s disease:
 Small-bowel series, lymph node biopsy, jejunal biopsy,
malabsorption tests
Whooping cough:
 See Pertussis
Wilson’s disease:
 Urine copper and amino acids, serum copper and
ceruloplasmin, liver biopsy, slit-lamp examination of cornea, uric acid
Y
Yaws:
 Dark field examination, serologic tests
Yellow fever:
 Viral isolation, serologic tests, liver biopsy
Z
Zollinger–Ellison syndrome:
 
Twelve-hour
 quantitative and basal gastric acid
output (BAO) gastric analysis, serum gastrin, GI series, gastroscopy,
727

INDEX
Note
: Page numbers followed by 
t
 indicate tables
A
A
bdomen
anuria or oliguria, 51, 53
pain (
See
 
Abdominal pain
)
rigidity (
See
 
Abdominal rigidity
)
swelling (
See
 
Abdominal swelling
)
Abdominal aortic aneurysm, back pain, 11
, 17
t
, 198, 200, 201, 202, 206, 207
acute
algorithm, 18–19
case history, 16
diagnostic workup, 16–17
questions to ask, 16
chronic recurrent
algorithm, 21
diagnostic workup, 20–21
questions to ask, 20
algorithm, 23
diagnostic workup, 22
peritonitis, 22, 23
questions to ask, 22
focal
algorithm, 26
diagnostic workup, 24–25
questions to ask, 24
generalized
algorithm, 28
diagnostic workup, 27
questions to ask, 27
Abnormal bleeding and purpura
algorithm, 429
diagnostic workup, 428
idiopathic thrombocytopenic, 428, 429
epistaxis, 170
thrombocytopenia, 507
questions to ask, 428
728

thrombocytopenic, hematemesis, 237
vascular, due to collagen disease, 428, 429
Abnormal facies
, 191
Abortion, threatened
pelvic mass, 385
pelvic pain, 385
Abscess
alveolar
jaw pain, 308
jaw swelling, 309
lip swelling, 324
amebic, 98, 99
appendiceal, 24, 26
brain
aphasia, apraxia, and agnosia, 56, 57
chills, 98, 99
coma, 103, 104
facial paralysis, 187, 188
papilledema, 376, 377
sedimentation rate, 458, 459
breast
discharge, 83
lymphadenopathy, 327
mass, 84
pain, 85
cerebral
amnesia, 41, 42
bradycardia, 81, 82
convulsions, 108, 109
delirium, 123, 124
headache, 229, 231
hemiparesis/hemiplegia, 242, 243
stupor, 490, 491
chest tenderness, 97
cough, 110, 111
Cowper’s gland, 389
dental, 98, 99 (
See also
 
Tooth or teeth
, 
abscessed
)
diaphragmatic, sedimentation rate, 458, 459
epidural
back pain, 70, 72
monoplegia, 340
hepatic, 201, 202
inguinal swelling, 300
729

intracranial, 426, 427
ischiorectal, 444
lung
clubbing of the fingers, 101, 102
halitosis, 225, 226
hemoptysis, 244, 245
orbital, 139, 140
parietal lobe, 460, 462
perinephric
abdominal swelling, focal, 24, 26
fever, chronic, 201, 202
flank mass, 203, 204
nausea and vomiting, 352, 353
perineum pain, 389
perirectal
pain, 444
rectal discharge, 441
rectal mass, 442, 443
peritonsillar, 419, 420
popliteal swelling, 402, 403
prostatic, 98, 99
psoas
femoral mass or swelling, 197
renal, 202
retropharyngeal
neck stiffness, 356, 357
stridor, 488, 489
salivary gland, 189, 190
scrotal swelling, 456, 457
subdiaphragmatic
hiccups, 249, 250
pleural effusion, 553, 554
shoulder pain, 11
submucous, 444
subphrenic, 24, 26
tuberculous, 65, 66
tubo-ovarian
infertility, female, 297, 298
730

Absent or diminished pulse
algorithm, 30
case history, 29
diagnostic workup, 29
questions to ask, 29
Abuse
alcohol (
See
 
Alcoholism
)
child (
See
 
Child abuse
)
drug (
See
 
Drug use and abuse
)
Acanthosis nigricans, 341
Achalasia
dysphagia, 153, 154
regurgitation, esophageal, 448
Achilles tendonitis
foot and toe pain, 208
heel pain, 235
Achondrodysplasia, 130, 147, 148
Acidosis
 (decreased pH)
algorithm, 32
bicarbonate level, 32
diagnostic workup, 32
questions to ask, 32
Acid phosphatase elevation
algorithm, 31
diagnostic workup, 31
questions to ask, 31
Aciduria, isovaleric, 368
Acne, 435, 436
Acne rosacea, 433, 434
acne vulgaris, 536
Acne vulgaris
, 433, 434
algorithm, 537
diagnostic workup, 536
questions to ask, 536
Acoustic neuroma, 364, 365
advanced
deafness, 119, 120
dizziness, 144
face pain, 183, 184
tinnitus, 510, 511
ataxia, 62, 63
dizziness, 7, 141, 143
t
, 144
early, 120
731

Acquired immunodeficiency syndrome (AIDS), 110
dementia, 126, 127
weight loss, 531, 533
Acrocyanosis, 117, 118
Acromegaly
bone mass or swelling, 78, 79
carpal tunnel syndrome, 542
cataract, 543
diaphoresis, 131
facial swelling, 189, 190
hirsutism, 253
hoarseness, 254, 255
hyperglycemia, 262
joint swelling, 313
kyphosis, 318
tongue mass or swelling, 512
Acromioclavicular arthritis, shoulder pain, 11, 12
ACTH level, 393, 394
Actinic dermatosis, rashes, 433
Actinomycosis, 309
Acute abdominal pain, history and physical examination, 3–4
Acute bronchitis, cough, 5
Acute respiratory distress syndrome (ARDS), dyspnea, 155, 156, 158
t
Adamantinoma, 309
Addiction
alcohol (
See
 
)
drug (
See
 
)
Addison’s disease
diarrhea, chronic, 134, 136
fatigue, 194, 196
gynecomastia, 223, 224
hyperkalemia, 263
hyperpigmentation, 266
hypoglycemia, 278, 279
hyponatremia, 281
hypotension, chronic, 282, 283
hypothermia, 284, 285
mouth pigmentation, 341
muscular atrophy, 343
syncope, 495
weight loss, 531, 532
Adenoids
732

enlargement, 350, 351
hypertrophied, 472
Adenoma
bronchial, 245
pituitary, 220
thyroid
enlargement, 508, 509
toxic, 508, 509
neck swelling, 358, 359
Adenopathy, pharyngitis, 552
Adhesions, meteorism, 336
Adrenal hyperplasia. 
See
 
Hyperplasia
, 
adrenal
Adrenal hypertension, congestive heart failure, 546, 547
Adrenal insufficiency, plasma cortisol, 393, 394
Adrenal tumors. 
See
 
Tumors
, 
adrenal
Adrenocortical adenoma, plasma cortisol, 393, 394
Adrenocortical carcinoma, 203, 204
plasma cortisol, 393, 394
Adrenocortical hyperplasia. 
See also
 
, 
adrenocortical
Adrenocortical tumors, 39, 40. 
See also
 
Tumors
, 
Aerophagia, 206, 207
Aerotitis, 161
Agglutinins, cold, 437, 438
Aging and impotence, 289
Agnogenic myeloid metaplasia, 479, 480
Agnosia, aphasia, and apraxia
algorithm, 57
diagnostic workup, 56
questions to ask, 56
Agranulocytosis, 322
pharyngitis, 552
sore throat, 12
Air swallowing, 80
Albinism, 364, 365
Alcohol
blurred vision, 76, 77
cirrhosis, 544, 545
failure to thrive, 192, 193
indigestion, 295, 296
insomnia, 301, 302
intoxication
733

chronic, 551
dysarthria, 149, 150
impotence, 288, 289
memory loss, 330, 331
methyl, 76, 77
poisoning, 455
tachycardia, 496, 497
thirst, 505, 506
Alcoholic cardiomyopathy, congestive heart failure, 546, 547
congestive heart failure, 546, 547
diaphoresis, 130, 131
facial flushing, 185
hallucinations, 227
hypersomnia, 267
infertility, male, 299
melena, 328, 329
menorrhagia, 333
neuropathy, 548, 549
odor, 368
peptic ulcer, 550, 551
tremor, 518
Aldosteronism
cramps, muscular, 113, 114
hypernatremia, 265
hypertension, 268, 269
hypokalemia, 280
Alkaline phosphatase elevation
γ
-glutamyltransferase level, 33
5
′
-nucleotidase, 33
algorithm, 34
calcium level, 33
diagnostic workup, 33
liver function tests, 33, 34
phosphate level, 33, 34
734

questions to ask, 33
Alkaloids, ergot, 438
Alkalosis
 (increased pH)
algorithm, 35
bicarbonate level, 35
diagnostic workup, 35
questions to ask, 35
vomitting, 35
Allergic disorders
dermatitis, 433, 434
leucocytosis, 321
rhinitis (
See
 
Rhinitis
, 
allergic
)
sinusitis, 348, 349
urticaria, 324
Allergic rhinitis, upper respiratory infection, 561, 562
Allergic sinusitis, upper respiratory infection, 561, 562
Alopecia
algorithm, 36
diagnostic workup, 36
diffuse hair loss, 36
focal hair loss, 36
Alpha-1-fetoprotein, 24
Alterations in serum iron. 
See
 
Serum iron, alterations in
Alterations in serum uric acid. 
See
 
Serum uric acid, alterations in
Alveolar abscess. 
See
 
Abscess
, 
alveolar
Alzheimer’s disease
hyperactive reflexes, 258, 259
Amblyopia, toxic, 74, 75
Amebiasis, 134, 136
diarrhea, 6
Amebic abscess, 98, 99
Amebic dysentery, rectal bleeding, 439
algorithm, 40
diagnostic workup, 39
infertility, female, 298
questions to ask, 39
Aminoglycosides, 510, 511
Amitriptyline, 505, 506
Amnesia
735

algorithm, 42
diagnostic workup, 41
persistent, 41
questions to ask, 41
transient, 41, 42
Amphetamines
euphoria, 172
hyperkinesis, 264
Amyloidosis
diarrhea, chronic, 136
hepatomegaly, 247, 248
splenomegaly, chronic, 480
steatorrhea, 482, 483
Amyotrophic lateral sclerosis
ankle clonus, 45, 46
Babinski’s sign, 69
monoplegia, 339, 340
muscular atrophy, 342, 343
pathologic reflexes, 383, 384
Anal fissure
chronic, 441
constipation, 106, 107
dyspareunia, 152
frigidity, 215
incontinence of feces, 290, 291
pain in penis, 371, 372
rectal bleeding, 12, 439, 440
rectal pain, 444, 445
Anal fistula, 444, 445
rectal bleeding, 12
Anal stricture
mass, 442, 443
pain, 445
Anal ulcer
736

Androgens
delayed puberty, 121, 122
precocious puberty, 404, 405
Anemia
abdominal pain, acute, 16–19
acquired hemolytic, 44
acute hemolytic, 98, 99
algorithm, 44
amenorrhea, 39, 40
anorexia, 48
aplastic, 43, 44, 373
bleeding gums, 73
leucopenia, 322
purpura and abnormal bleeding, 428, 429
cardiac murmurs, 89
case history, 43
chronic, 43, 44
chronic blood loss, 373
diagnostic workup, 43
dizziness, 7, 8, 141, 145
dyspnea, 155, 158
t
hemolytic
acquired, 43, 44
acute, 98, 99
jaundice, 305, 307
lactic dehydrogenase elevation, 319
splenomegaly, acute or subacute, 477, 478
splenomegaly, chronic, 479, 480
iron deficiency, 43, 44
menorrhagia, 332, 333
nail abnormalities, 346, 347
megaloblastic, 319
metrorrhagia, 337, 338
myelophthisic, prolonged prothrombin time, 410
myelophthisis, 44
737

nutritional, 44, 373
palpitations, 374, 375
pernicious, 43, 44
Babinski’s sign, 67, 69
gait disturbances, 216, 217
girdle pain, 221
hypoactive reflexes, 273, 274
paresthesias of lower extremity, 378, 380
pathologic reflexes, 384
vitamin B
12
, 528
questions to ask, 43
restless leg syndrome, 450
severe
coma, 104
syncope, 493, 495
sickle cell (
See
 
Sickle cell disease
)
syncope, 494
t
Aneurysm
aortic
abdominal swelling, 24, 26
absent or diminished pulse, 29, 30
back pain, 70–72
chest tenderness, 96, 97
hematemesis, 236, 237
shoulder pain, 465, 467
stridor, 489
arch of aorta, 424, 425
arteriovenous
738

cardiac murmurs, 88, 89
diplopia, 139, 140
exophthalmos, 173, 184
pulmonary, 101, 102
axillary mass, 65, 66
basilar artery, 364, 365
carotid, 510, 511
cerebral, 417, 418
dissecting
abdominal rigidity, 22, 23
anuria or oliguria, 51–53
chest pain, 93–95
pulses, unequal, 424, 425
hemianopsia, 240, 241
ruptured, 88, 89
splenic, 478
splenic, 478, 479, 480
Angina pectoris
chest pain, 95
extremity pain, upper extremity, 179
Angiography, 17, 20–21, 29, 51–52, 56, 62
Angioma, 512
Angioneurotic edema
localized, 164, 165
periorbital edema, 390
Anisocoria, 426, 427
Ankle-brachial index, 175
intermittent claudication, 303
Ankle clonus
algorithm, 46
bilateral, 45, 46
diagnostic workup, 45
739

questions to ask, 45
unilateral, 45, 46
Ankle joint pathology, 216, 217
Ankylosing spondylitis, kyphosis, 318
Anorexia
algorithm, 48
case history, 47
diagnostic workup, 47
questions to ask, 47
Anosmia or unusual odors
algorithm, 50
diagnostic workup, 49
questions to ask, 49
taste abnormalities, 498, 499
toxic, 49, 50
trauma, 49
unilateral, 49, 50
Anoxia, dizziness, 7
Antacid use, chronic, 35
Anterior cerebral artery occlusion
Anterior cerebral artery thrombosis, 67, 69
Anterior spinal artery occlusion
hyperactive reflexes, 259
sensory loss, 460, 462
Anthrax
gangrene, 218, 219
leg ulceration, 327
Antibiotics
lymphadenopathy, 326, 327
Anti-citrullinated protein antibody (ACPA), 310
Anticoagulants, 328, 329
Anticonvulsants, 100, 108
therapy, hydroxy vitamin D
2
 and D
3
, 257
Antidepressants, 126, 127, 131
Antihypertensives
Antinuclear antibody (ANA), 36, 100, 178, 194–195, 326, 448, 468
740

thrombocy topenia, 507
vaginal bleeding, 523
Antiproliferative drugs, 49
Antirheumatic drugs, 49
Anuria or oliguria
algorithm, 53
diagnostic workup, 51–52
questions to ask, 51
Anus neoplasm, rectal bleeding, 12
Anxiety
algorithm, 55
chronic
diagnostic workup, 54
fatigue, 196
neurosis, chronic, 551
questions to ask, 54
tremor, 499
Aorta, coarctation of, 29, 30
Aortic insufficiency
dizziness, 141, 145
drop attacks, 146
Aortic regurgitation, 88, 89
Aortic stenosis, 81, 82
Aortitis, atherosclerotic, 268, 269
Aortography, 20–21
Aphasia, apraxia, and agnosia
Aplastic anemia, 37
chronic pallor, 373
Appendiceal abscess, 24, 26
abdominal pain, acute, 17
741

acute, 352, 353
acute abdominal pain, 3, 4
chronic, 295, 296
fever, acute, 198, 200
pelvic pain, 386, 387
salpingitis, 19
Appendix
appendicitis (
See
 
)
pelvic
abdominal pain, chronic recurrent, 20–21
ruptured, 22, 23
Apresoline, 392
Arch of aorta, 424, 425
Areata, 36
Argyll-Robertson pupil, 426, 427
Argyria, 266
Arnold-Chiari malformation, 334, 335
Arrhenoblastoma
amenorrhea, 40
Arrhythmia, cardiac
algorithm, 87
anxiety, 54, 55
diagnostic workup, 86
dizziness, 141, 143
t
, 145
questions to ask, 86
Arsenic poisoning
polydipsia, 398
Arterial Doppler ultrasonography, 175
Arteriosclerosis
amnesia, 42
cerebral
742

hypochondriasis, 277
stupor, 491
foot ulceration, 210, 211
leg ulceration, 320
peripheral
extremity pain, lower extremity, 175, 176, 177
t
Arteriosus, 88, 89
Arteriovenous fistula
Arteriovenous malformation, 510, 511
Arteritis, temporal
blindness, 74
headache, 8, 9, 229–231, 232
t
Artery insufficiency
carotid artery, 76, 77
dizziness, 141, 144
vertebral basilar artery
dizziness, 7–8
ptosis, 417, 418
Arthritis
extremity pain
lower extremity, 175, 176, 177
t
upper extremity, 178, 179
gonococcal (
See
 
Gonococcal arthritis
)
hip joint, 176
Lyme disease, 310, 311
panel, C-reactive protein, 115
rheumatoid (
See
 
)
septic (
See
 
)
Arthrocentesis, 38
743

Asbestosis, 101, 102
Ascites
algorithm, 59
chylous, 59
diagnostic workup, 58
questions to ask, 58
ASHD, congestive heart failure, 547
Aspartate aminotransferase elevation
algorithm, 61
diagnostic workup, 60
questions to ask, 60
Aspirin
intoxication, 231
Asthenia, 496, 497
Asthma
algorithm, 539
bronchial, 110, 118
cardiac
dyspnea, 155, 156
rales, 431, 432
cough, 5, 6, 110, 111
cyanosis, 118
diagnostic workup, 538
dyspnea, 155, 156, 158
t
hypoxemia, 286, 287
polyuria, 400, 401
questions to ask, 538
respiration abnormalities, 449
Astigmatism, headache, 9
Ataxia
algorithm, 63
case history, 62
cerebellar, 149, 150
diagnostic workup, 62
hereditary cerebellar, 63
questions to ask, 62
Atherosclerosis, 438
744

Atherosclerotic aortic stenosis, congestive heart failure, 546
Athetosis
, diagnostic workup, 64
Atrial fibrillation
, 517
algorithm, 541
cardiac arrhythmia, 86, 87
controlled, 422, 423
diagnostic workup, 540
pulse irregularity, 422, 423
questions to ask, 540
stroke, 559, 560
transient ischemic attacks, 516
Atrial flutter
with variable degree of atrioventricular block, 87
Atrial myxoma, stroke, 559, 560
Atrial septal defect, 89
Atrioventricular dissociation, 87
with block bigeminal rhythm, 422, 423
Atrophic vaginitis, 486
Atrophy
cerebellar, 146
muscular (
See
 
Muscular atrophy
)
optic (
See
 
Optic atrophy
)
peroneal muscular, 342, 343
sensory loss, 460, 463
progressive muscular, 343
spinal muscular, 342, 343
testicular (
See
 
Testicular atrophy
)
Atropine
photophobia, 392
Attention deficit disorder, 264
Auricular fibrillation
Auricular flutter, 496, 497
Avascular necrosis
hip pain, 251, 252
joint pain, 310, 311
Avitaminosis, neuropathy, 549
Axillary mass
algorithm, 66
745

diagnostic workup, 65
questions to ask, 65
Azotemia, 520
B
Babinski’s sign
algorithm, 69
diagnostic workup, 68
questions to ask, 67–68
Bacillary dysentery, rectal bleeding, 439
Back pain
algorithm, 72
case history, 70
diagnostic workup, 70–71
low, 71
t
history and physical examination, 10–11
recurrent urinary tract infection, 557, 558
questions to ask, 70
Bacteremia, 43, 200
Bacterial conjunctivitis, red eye, 446, 447
Bacterial endocarditis
cardiomegaly, 90–91
clubbing of fingers, 101, 102
C-reactive protein, 115
subacute
hemiparesis/hemiplegia, 243
Bacterial gastroenteritis, diarrhea, 6
Bacterial sinusitis, upper respiratory infection, 561
Bacterial vaginosis, vaginal discharge, 14
Bacteria, toxigenic, 136
Baker’s cyst, 402, 403
Balanitis
enuresis, 167, 168
penile sores, 388
Baldness, 36
Barbiturates
746

insomnia, 302
Bartholinitis
vulval or vaginal mass, 529
Basal cell carcinoma, 435, 436
Basilar artery
aneurysm, 364, 365
insufficiency, 240, 241
nose, regurgitation of food through, 362, 363
meningitis
nystagmus, 364, 365
occlusion
vertebral-basilar, 417, 418
thrombosis
early basilar artery, 273, 274
vertebral basilar insufficiency
vertebral-basilar occlusion, 417, 418
Basophilic adenoma, plasma cortisol, 393, 394
Battered baby syndrome, 78, 79
Bee stings, 512
Bell’s palsy
epiphora, 169
Benign positional vertigo, dizziness, 7
747

Benign prostatic hypertrophy, recurrent urinary tract infection, 557, 558
Benzodiazepines
nightmares, 360
Beriberi
edema, generalized, 163
foot ulceration, 211
neuropathy, 548
Biceps tendonitis, shoulder pain, 11, 12
Bilateral recurrent laryngeal palsy, 488, 489
Bile ducts carcinoma
jaundice, 307
Biliary cirrhosis
jaundice, 305–307
Biliary colic, 352, 353
Biliary tree carcinoma, 48
Birth control pills, 100
Bismuth, 498, 499
Bites
black widow spider (
See
 
Black widow spider bites
)
insect (
See
 
Insect bites
)
Biting nails, 346, 347
abdominal pain, acute, 18
abdominal rigidity, 23
Bladder
calculus
abdominal pain, chronic recurrent, 21
frequency of urination, 214
pain in the penis, 371, 372
urinary frequency and burning, 13
cancer, 238
carcinoma
dysuria, 157, 158
distended, 385
748

enlargement, 51
intestinal obstructions, 27, 28
neck obstructions
incontinence of urine, 292, 293
neoplasm, recurrent urinary tract infection, 557, 558
neurogenic, 214
spastic neurogenic, due to multiple sclerosis, 292, 293
stone, 238, 239
tumors
benign, 238, 239
malignant, 238, 239
Blastomycosis, 210, 211
Bleeding
abnormal. 
See
 
anovulatory, 333
breakthrough, 337, 338
dysfunctional uterine
gastrointestinal, 505
hematoma. 
See
 
Hematoma
hemophilia. 
See
 
Hemophilia
hemorrhage. 
See
 
Hemorrhage
rectal. 
See
 
Rectal bleeding
Bleeding gums
. 
See also
 
Gingivitis
algorithm, 73
diagnostic workup, 73
questions to ask, 73
Blepharitis, 392
red eye, 446, 447
Blind loop syndrome, 482, 483
Blindness
algorithm, 75
case history, 74
diagnostic workup, 74
eclipse, 463
questions to ask, 74
Blood loss
749

anemia of, chronic pallor, 373
Blood pressure, 51, 53
Blood sugar, neuropathy, 549
Blood urea nitrogen (BUN), 38
Blurred vision
algorithm, 77
diagnostic workup, 76
questions to ask, 76
Bone mass or swelling
algorithm, 79
diagnostic workup, 78
questions to ask, 78
Bone scan, 118
Bone tumors
lower extremity, 175, 176
facial swelling, 190
algorithm, 80
diagnostic workup, 80
questions to ask, 80
Botulism
diarrhea, acute, 132
diplopia, 140
dysphagia, 154
Brachial plexus neuralgia, 354, 355
Brachial plexus neuritis
Horner’s syndrome, 256
hypoactive reflexes, 274
Brachial plexus neuropathy
neck pain, 354, 355
paresthesias of the upper extremity, 381, 382
algorithm, 82
diagnostic workup, 81
questions to ask, 81
Brain
abscess (
See also
 
Abscess
, 
brain
)
750

damage at birth, 220
diseases
brain stem, 364, 365
foot deformities, 209
space-occupying lesions, 45, 258, 259
Babinski’s sign, 67–69
blindness, 74, 75
depression, 128, 129
headache, 229–231, 232
t
tumors, 356, 357
advanced, 490, 491
brain stem (
See
 
Brain stem
)
Brain natriuretic peptide (BNP), 58
asthma, 538
Brain stem
lesions, 498, 499
tumors
sleep apnea, 469
Breast discharge
algorithm, 83
751

diagnostic workup, 83
questions to ask, 83
Breast mass
algorithm, 84
diagnostic workup, 84
questions to ask, 84
Breast pain
algorithm, 85
diagnostic workup, 85
questions to ask, 85
Brissaud’s infantilism, 147, 148
Bromides
Bronchiectasis, 101, 431
cough, 5
pleural effusion, 554
Bursitis
upper extremity, 178, 179, 180
t
greater trochanter
extremity pain, lower extremity, 175, 176
ischiogluteal, 251, 252
joint pain, 10
knee pain, 314, 315
knee swelling, 316, 317
olecranon, 178, 179
subacromial
extremity pain, upper extremity, 178, 179
shoulder pain, 465
C
C
affeinated beverages, peptic ulcer, 551
Caffeine
intoxication, 518
752

Calcific tendonitis, 465, 467
Calculus
bladder. 
See
 
Bladder
, 
calculus
neoplasms, 169
renal. 
See
 
vesicular. 
See
 
Vesicular calculus
Callus, suppurating, 211
Calprotectin, diarrhea, chronic, 134
Campylobacter jejuni,
 132, 133
Cancer
advanced melanotic, 266
leukemia. 
See
 
Leukemia
metastatic
anorexia, 47, 48
ascites, 58, 59
weight loss, 533
Candida vaginitis, vaginal discharge, 14
Candidiasis, pharyngitis, 552
Carbamazepine (Tegretol), 160, 183
Carbon monoxide poisoning
coma, 104
Carcinoembryonic antigen (CEA) test, 24
Carcinoid syndrome
borborygmi, 80
skin thickening, 468
Carcinoma
chest pain, 5
of esophagus, regurgitation, esophageal, 448
Cardiac arrhythmia. 
See also
 
acute pallor, 373
dizziness, 7
t
Cardiac asthma, wheezing of, 534
Cardiac murmurs
algorithm, 89
diagnostic workup, 88
questions to ask, 88
Cardiac troponins, C-reactive protein, 115
753

algorithm, 91
diagnostic workup, 90
questions to ask, 90
rales, 431
Cardiomyopathy
atrial fibrillation, 540, 541
stroke, 559
Cardiospasm, chest pain, 5
Carotid bruit
transient ischemic attacks, 516, 517
dizziness, 7, 8
Carpal tunnel syndrome
algorithm, 542
diagnostic workup, 542
questions to ask, 542
Cataracts
algorithm, 543
diagnostic workup, 543
questions to ask, 543
Cauda equina syndrome
back pain, 10, 11
Cellulitis
chest pain, 4
t
Cerebral vascular disease, 67–68
Cerumen, dizziness, 7
Cervical carcinomas, vaginal bleeding, 523
extremity pain, upper extremity, 180
t
Cervical spondylosis, headache, 9
Chest deformity
, diagnostic workup, 92
Chest pain
, 51, 53, 94
t
algorithm, 95
diagnostic workup, 93–94
history and physical examination, 4–5
754

questions to ask, 93
rales, 431
Chest tenderness
algorithm, 97
diagnostic workup, 96
questions to ask, 96
Chicken pox, rashes, 433
battered baby syndrome, 78, 79
molestation, 215
Chills
algorithm, 99
diagnostic workup, 98
questions to ask, 98
Chlamydia vaginitis, vaginal discharge, 14
Cholesteatoma, dizziness, 7
Choreiform movements
algorithm, 100
diagnostic workup, 100
questions to ask, 100
Chronic hepatitis, cirrhosis, 544, 545
Chronic obstructive pulmonary disease
cough, 5
Chronic peripheral arteriosclerosis, 175
Cirrhosis
alcoholic
advanced, 247, 248
algorithm, 545
biliary
755

jaundice, 306, 307
diagnostic workup, 544
early, 248
edema
generalized, 162, 163
localized, 165
t
hydroxy vitamin D
2
 and D
3
, 257
hypoalbuminemia, 275
hypocalcemia, 276
liver
abdominal swelling, generalized, 27, 28
anuria or oliguria, 53
clubbing of the fingers, 102
prolonged prothrombin time, 410
questions to ask, 544
serum albumin, 464
testicular atrophy, 500, 501
Clostridium botulinum
, diarrhea, acute, 133
Clubbing of fingers
algorithm, 102
case history, 101
diagnostic workup, 101
questions to ask, 101
Cluster headache, 229–231, 232
t
eye pain, 181, 182
face pain, 183, 184, 187
headache, 8, 9
nasal discharge, 348, 349
756

nasal obstruction, 350, 351
Coagulation disorders
rectal bleeding, 439
stroke, 560
Coagulation profile, vaginal bleeding, 523
Colchicine, 38
Colicky abdominal pain, neuropathy, 548, 549
Collagen disease
neuropathy, 549
Colon neoplasm, rectal bleeding, 12
Colonoscopy, diarrhea, chronic, 134
Coma
, 105
t
algorithm, 104
diabetic, 103, 104
diagnostic workup, 103
hepatic, odor, 103, 104
hyperosmolar, 281
questions to ask, 103
uremic, 104
Computed tomography angiography (CTA), 17
Computed tomography (CT) scan, 17, 20, 101, 117, 118
Concomitant strabismus, 481
Congenital adrenal hyperplasia, plasma cortisol, 393, 394
Congenital anomaly, of kidney, recurrent renal calculi, 555, 556
Congenital heart disease
atrial fibrillation, 540
Congenital syphilis, mental retardation, 334, 335
, 51, 53
abdominal swelling
focal, 24, 26
generalized, 27, 28
algorithm, 547
alkaline phosphatase elevation, 34
aspartate aminotransferase elevation, 60, 61
757

cardiomegaly, 90, 91
cyanosis, 117, 118
diagnostic workup, 546
edema, generalized, 162, 163
hypoxemia, 286
nocturia, 361
orthopnea, 370
questions to ask, 546
Conjunctivitis
allergic, red eye, 446, 447
bacterial, red eye, 446, 447
viral, red eye, 446, 447
algorithm, 107
diagnostic workup, 106–107
questions to ask, 106
Contusions, chest pain, 4
algorithm, 109
diagnostic workup, 108–109
febrile, 108, 109
questions to ask, 108
Corneal abrasion, red eye, 446, 447
Coronary artery disease, atrial fibrillation, 540
758

Coronary CT angiography (CCTA), 93–94
Coronary insufficiency
neck pain, 355
Corticosteroid
peptic ulcer, 551
Costochondritis, chest pain, 4, 5
Cough
, 111
t
algorithm, 111
diagnostic workup, 110–111
history and physical examination, 5–6
questions to ask, 110
whooping, 118
Cramps
athletic, 114
menstrual, 112
muscular
algorithm, 114
case history, 113
diagnostic workup, 113
questions to ask, 113
night, 113, 114
professional, 113, 114
Cranial nerve signs, 67–69
C-reactive protein
algorithm, 115
diagnostic workup, 115
questions to ask, 115
Creatine phosphokinase (CPK), 60, 61
Crepitant rales, 431
Crepitus
, diagnostic workup, 116
Cretinism, mental retardation, 334, 335
Crohn’s disease
rectal bleeding, 12, 439
Cushing’s syndrome
stretch marks (striae), 487
759

Cyanosis
algorithm, 118
diagnostic workup, 117
questions to ask, 117
Cystic fibrosis, asthma, 538
Cystitis
acute
chronic, 20–21
hematuria, 238, 239
interstitial, 158
penis pain, 371, 372
pyuria, 430
rectal pain, 445
strangury, 484, 485
tuberculous, 157, 158
urination difficulty, 137
Cystocele, 529
D
D
a Costa’s syndrome, chest pain, 93
Deafness
algorithm, 120
case history, 119
diagnostic workup, 119
hereditary sensory neural, 504
questions to ask, 119
tinnitus, 510
Decreased pH (acidosis). 
See
 
Acidosis (decreased pH)
Dehydration, 51, 53
Delirium
algorithm, 124
diagnostic workup, 123
760

questions to ask, 123
Delirium tremens
Delusions
algorithm, 125
diagnostic workup, 125
questions to ask, 125
Dementia
advanced, stupor, 491
algorithm, 127
Alzheimer’s (
See
 
)
antidepressants, 131
case history, 126
cirrhosis, 544
delusions, 125
diagnostic workup, 126–127
presenile, 125
ptyalism, 419, 420
questions to ask, 126
senile, 125, 127
algorithm, 129
dementia, 127
diagnostic workup, 128
endogenous, 128, 129
questions to ask, 128
senile, 129
unipolar, 128, 129
Dermatitis
allergic, 433, 434
contact
pruritus, vulvae, 416
rash—distribution, 433, 434
rash—morphology, 435, 436
761

exfoliative
herpetiformis
pruritus, generalized, 414, 415
scalp, 326, 327
seborrheic
alopecia, 36
stasis, 433, 434
Dermatophytosis, rashes, 433
Dexamethasone suppression test, 393, 394
Diabetes insipidus
nephrogenic, 400, 401
pituitary, 400, 401
renal, 265
Diabetes mellitus
glycosuria, 222
2
 and D
3
, 257
hypercholesterolemia, 261
hypertriglyceridemia, 270, 271
insipidus. 
See
 
insulin-dependent, 185, 400, 401
mellitus. 
See
 
meteorism, 336
mild, 400, 401
priapism, 408, 409
proteinuria, 411, 412
762

pruritus
generalized, 414, 415
vulvae, 416
uncontrolled, 121, 122
Diabetic enteropathy, diarrhea, 6
algorithm, 131
diagnostic workup, 130
questions to ask, 130
Diaphragmatic abscess, sedimentation rate, 458, 459
Diarrhea
acidosis (decreased pH), 32
acute
algorithm, 133
diagnostic workup, 132–133
traveler’s, 132–133
chronic
algorithm, 136
diagnostic workup, 134–135
questions to ask, 134
history and physical examination, 6
Diet and nutrition
constipation and, 106–107
deficiency, 299
Difficulty urinating
. 
See
 
Urination difficulty
Diffuse crepitant rales, 431
Diffuse rashes, 433
Diffuse sibilant rales, 431
Diffuse sonorous rales, 431
Dilantin®, 149
Dilated pupil, red eye, 446, 447
763

Diplopia
algorithm, 140
diagnostic workup, 139
questions to ask, 139
Dizziness
, 143
t
algorithm, 144–145
diagnostic workup, 141–142
history and physical examination, 7–8
questions to ask, 141
Dorsalis pedis pulses, intermittent claudication, 303
Down’s syndrome, cataract, 543
Drop attacks
algorithm, 146
diagnostic workup, 146
Drugs
abuse, weight loss, 531
eruption, rashes, 433
induced, syncope, 494
t
ingestion, atrial fibrillation, 540
reaction
acute fever, 198, 200
chronic fever, 201, 202
toxicity
recurrent renal calculi, 556
amphetamines (
See
 
)
anosmia or unusual odors, 49, 50
barbiturates (
See
 
)
764

constipation, 106–107
gangrene, 219
intoxication, 149, 150
marijuana (
See
 
Marijuana
)
nonsteroidal anti-inflammatory nausea and vomiting, 352, 353
opium poisoning (
See
 
Opium poisoning
)
pallor, 373
prescription, 548, 549
pupil abnormalities, 426, 427
tricyclic antidepressants
Dubin-Johnson syndrome, 294, 305, 307
Duodenal ulcer, abdominal pain, acute, 17
Dwarf
pituitary, 147, 148
primordial, 148
Dwarfism
algorithm, 148
diagnostic workup, 147
questions to ask, 147
D-xylose absorption
2
 and D
3
, 257
algorithm, 150
diagnostic workup, 149
765

questions to ask, 149
Dyshidrosis, rashes, 433
algorithm, 151
diagnostic workup, 151
questions to ask, 151
algorithm, 152
diagnostic workup, 152
functional, 152
questions to ask, 152
Dysphagia
algorithm, 154
diagnostic workup, 153
Dyspnea
, 58, 59, 158
t
algorithm, 156
diagnostic workup, 155–156
questions to ask, 155
Dysuria
algorithm, 158
diagnostic workup, 157
questions to ask, 157
E
Earache
algorithm, 161
diagnostic workup, 160
questions to ask, 160
Ear discharge
algorithm, 159
diagnostic workup, 159
questions to ask, 159
abdominal pain, acute, 16–17, 19
breast pain, 85
dysmenorrhea, 151
ruptured
766

Ectopic PTH secretion, hypercalcemia, 260
Eczema, rashes, 433
Edema
, 58
algorithm, 163
diagnostic workup, 162
idiopathic, 163
questions to ask, 162
localized
algorithm, 165
diagnostic workup, 164
questions to ask, 164
pedal, 165
t
Edema angioneurotic (
See
 
)
Ehlers–Danlos syndrome, joint pain, 311
Electrocardiogram (EKG), 16
Electroencephalogram (EEG), 41
Electromyography (EMG), 71
Emphysema, rales, 431
Endometrial carcinomas, vaginal bleeding, 523
Endometriosis
back pain, 11
Endometritis, abdominal pain, chronic recurrent, 20
Endophthalmitis, prolonged, 166
Endoscopic retrograde cholangiopancreatography (ERCP), 20, 25, 247
Endoscopy, 17
procedures, 25
, unilateral, 166
Enteropathy, 275
Enuresis
algorithm, 168
767

diagnostic workup, 167
questions to ask, 167
simple, 167, 168
Epigastrium, mass in, 24
Epilepsy
abdominal pain
acute, 18
chronic recurrent, 20, 21
dizziness, 7, 142, 144
grand mal, 360
idiopathic, 108, 109
opisthotonus, 369
posttraumatic, 330, 331
temporal lobe, 171, 172
Epinephrine, 534
Epiphora
algorithm, 169
diagnostic workup, 169
questions to ask, 169
Episcleritis, red eye, 446, 447
Epistaxis
algorithm, 170
diagnostic workup, 170
questions to ask, 170
Erythema multiforme, rashes, 433
Erythema nodosum, rashes, 433
Esophageal diverticulum, regurgitation, esophageal, 448
768

Esophageal strictures, regurgitation, esophageal, 448
Esophagitis
corrosive, 236, 237
reflux, 193, 206, 207
with aspiration, 111
flatulence, 206, 207
heartburn, 233, 234
after partial gastrectomy, 448
Esophagospasm, diffuse, 448
Estrogen
withdrawal, 337, 338
Euphoria
algorithm, 172
diagnostic workup, 171
questions to ask, 171
Eustachian tube, patulous, 510, 511
Ewing’s tumor, 78, 79
algorithm, 174
diagnostic workup, 173
pituitary
exophthalmos, 174
questions to ask, 173
Exploratory laparotomy, 17, 21, 22, 25, 27
Exploratory surgery, 527
Extremity pain
lower extremity, 177
t
algorithm, 176
diagnostic workup, 175
questions to ask, 175
upper extremity
algorithm, 179
769

diagnostic workup, 178
questions to ask, 178
Eye pain
algorithm, 182
diagnostic workup, 181
questions to ask, 181
Eye, redness of. 
See
 
Red eye
F
F
abry’s disease, 341
Face pain
algorithm, 184
diagnostic workup, 183
questions to ask, 183
Facet syndrome
back pain, 72
Facial flushing
algorithm, 185
diagnostic workup, 185
questions to ask, 185
Facial mass
, diagnostic workup, 186
Facial paralysis
algorithm, 188
diagnostic workup, 187
questions to ask, 187
Facial swelling
algorithm, 190
diagnostic workup, 189
questions to ask, 189
Facies, abnormal
, 191
Failure to thrive
diagnostic workup, 192
questions to ask, 192
Fanconi’s syndrome
alkaline phosphatase elevation, 33, 34
Fasting blood sugar (FBS), 270, 271
Fatigue
algorithm, 196
diagnostic workup, 194–195
questions to ask, 194
Feces
impacted
770

incontinence
algorithm, 291
diagnostic workup, 290
questions to ask, 290
Feculent rectal discharge, 441
Felty’s syndrome, 478
Female secondary sex characteristics, 39, 40
Femoral artery thrombosis, 320
Femoral hernia, 197
Femoral mass or swelling
algorithm, 197
diagnostic workup, 197
questions to ask, 197
Fever
acute
algorithm, 200
diagnostic workup, 198–199
questions to ask, 198
rheumatic, 130, 131
chronic
acute, 201
algorithm, 20
diagnostic workup, 201
questions to ask, 201
Rocky Mountain spotted, 201, 202
dengue, 344, 345
rat-bite
acute, 200, 201, 202
chronic, 201, 202
relapsing, 98, 99
rheumatic (
See
 
)
scarlet (
See
 
Scarlet fever
)
typhoid (
See
 
Typhoid fever
)
upper respiratory infection, 561, 562
yellow, 352, 353
771

Flank mass
algorithm, 204
diagnostic workup, 203
questions to ask, 203
recurrent renal calculi, 555, 556
Flank pain
algorithm, 205
diagnostic workup, 205
questions to ask, 205
algorithm, 207
diagnostic workup, 206
questions to ask, 206
Fluorescent treponemal antibody-absorption (FTA-ABS) test, 126
Focal crepitant rales, 431
Focal rashes, 433
Focal sibilant rales, 431
Focal sonorous rales, 431
Follicle-stimulating hormone (FSH), 39
Food
contaminated, 132, 133
flatulence and, 207
lack of, 192, 193
Foot and toe pain
algorithm, 208
diagnostic workup, 208
questions to ask, 208
Foot deformities
algorithm, 209
diagnostic workup, 209
question, 209
Foot ulceration
algorithm, 211
diagnostic workup, 210
questions to ask, 210
Forehead enlargement
, diagnostic workup, 212
Foreign body, upper respiratory infection, 561, 562
Foville’s syndrome
Fractures
arm, 424, 425
back pain, 10, 11, 70–72
772

calcaneal, 235
chest pain, 4, 5
compression, 70, 72
displaced, 208
extremity pain, upper extremity, 178
joint pain, 9, 10
knee swelling, 317
leg, 424, 425
orbital
scoliosis, 453, 454
skull
spinal, 273, 274
Free thyroxine
algorithm, 213
diagnostic workup, 213
questions to ask, 213
Frei test, 530
Friedreich’s ataxia, 45, 62, 63
Frigidity
773

algorithm, 215
diagnostic workup, 215
questions to ask, 215
Frozen shoulder, shoulder pain, 11, 12
Fungal infections
ear discharge, 159
Furuncle, 456, 457
G
Gait disturbances
algorithm, 217
diagnostic workup, 216
questions to ask, 216
Galactocele, 84
Galactorrhea, 39
Galactosemia, 334, 335
Gallbladder
courvoisier, 26
perforated, 22, 23
ultrasound, 17
Gallium scans, 20, 25, 27
Gangrene
algorithm, 219
diagnostic workup, 218
lungs, 225, 226
questions to ask, 218
Garlic, 225, 226
Gastrectomy, previous, 233, 234
Gastric atrophy, vitamin B
12
, 528
Gastric carcinoma
vitamin B
12
, 528
Gastric ulcer
Gastritis
774

acute, 236, 237
alcoholic, 249, 250
flatulence, 207
toxic staphylococcal, 132, 133
viral, 132, 133
Gastroenterologist, 20, 25
Gastroesophageal reflux disease (GERD)
Gastrointestinal neoplasms
tract, 327
Gaucher’s disease
acid phosphatase elevation, 31
mental retardation, 334, 335
German measles, 433, 434
Giant cell tumors
acute, 132, 133
chronic, 134, 136
Gigantism
algorithm, 220
diagnostic workup, 220
questions to ask, 220
Girdle pain
775

algorithm, 221
diagnostic workup, 221
questions to ask, 221
Glaucoma
headache, 9, 230–231
scotoma, 455
Glioma, pontine, 171, 172
Glomerulosclerosis, 53
Glomus tumors, 510, 511
Glossitis
Glucagonoma, 262
Glycogen storage disease
hepatomegaly, 248
algorithm, 222
diagnostic workup, 222
questions to ask, 222
renal, 222
fever
acute, 200
joint swelling, 312, 313
Gonococcal pharyngitis, pharyngitis, 552
Gonorrhea
sore throat, 473, 474
urethral discharge, 521
vaginal discharge, 14, 525, 526
Gout
776

joint pain, 10, 310, 311, 311
t
Granuloma
inguinale, 388
pyoderma, 324
Granulosa cell tumors
Graves’ disease
thyroid enlargement, 508, 509
Guillain–Barré syndrome
dysarthria, 150
musculoskeletal pain, generalized, 344, 345
paresthesias of lower extremity, 378, 379, 380
sensory loss, 461, 463
Gum abnormalities, 515
algorithm, 224
diagnostic workup, 223
questions to ask, 223
H
Halitosis
algorithm, 226
diagnostic workup, 225
questions to ask, 225
algorithm, 227
diagnostic workup, 227
777

questions to ask, 227
Hallux rigidus, 208
Hallux valgus, 208
Hammertoe, 208
Hashimoto’s thyroiditis, 508, 509
Hay fever
Headaches
, 232
t
algorithm, 231
caffeine withdrawal, 229, 231
case history, 229
cluster (
See
 
Cluster headaches
)
histamine (
See
 
Histamine headaches
)
history and physical examination, 8–9
diagnostic workup, 230
migraine (
See
 
Migraine
)
questions to ask, 229–230
tension (
See
 
Tension headaches
)
Head injury
Head mass or swelling
, diagnostic workup, 228
Hearing loss, noise-induced, 510, 511
Heart block
complete
second-degree, 81, 82
Heartburn
algorithm, 234
case history, 233
diagnostic workup, 233
questions to ask, 233
Heart diseases/disorders
athletic heart, 86, 87
congenital
778

acyanotic, 90, 91
dwarfism, 147, 148
congestive heart failure (
See
 
Congestive heart failure
)
cyanotic congenital, 117, 118
cyanotic, nail disorders, 346, 347
heart block (
See
 
)
Heart failure, congestive. 
See
 
Heart murmur
Heat exhaustion
Heat stroke
coma, 104
Heel pain
algorithm, 235
diagnostic workup, 235
questions to ask, 235
Hemarthrosis
algorithm, 237
case history, 236
diagnostic workup, 236
questions to ask, 236
Hematoma
abdominal wall, 24, 26
epidural
extradural
779

intracranial
coma, 104
penis, 408, 409
subdural
Hematometra, 39, 40
Hematuria
algorithm, 239
case history, 238
diagnostic workup, 238–239
questions to ask, 238
Hematuria, 522
algorithm, 241
diagnostic workup, 240
questions to ask, 240
Hemiatrophy, facial, 188
Hemiballism, 100
Hemiparesis/hemiplegia
algorithm, 243
diagnostic workup, 242
questions to ask, 242
Hemivertebra, congenital, 453, 454
Hemochromatosis, 37
780

Hemoconcentration, 321
Hemodilution states, 275
Hemoglobinuria, 322, 522
Hemolytic anemia. 
See
 
Anemia
, 
hemolytic
Hemopneumothorax, pleural effusion, 553, 554
algorithm, 245
case history, 244
cough, 111
diagnostic workup, 244
questions to ask, 244
cerebral
headache, 229–231
retinal, 455
subarachnoid
headache, 229, 231, 232
t
vitreous
781

, 246
internal
thrombosed
rectal bleeding, 439, 440
varicose veins, 527
Hemosiderosis, cirrhosis, 544, 545
Henoch-Schönlein purpura, 268, 269
Heparin, 60, 61
Hepatic abscess, 201, 202
Hepatic coma, 104
odor, 368
Hepatic disease, 261
Hepatic failure, 285
Hepatic vein thrombosis. 
See
 
Thrombosis
, 
hepatic vein
Hepatitis
infectious, 247, 248
toxic
viral, 305, 307
782

focal, 26
algorithm, 248
diagnostic workup, 247
questions to ask, 247
Hermaphroditism, 253
Hernia
femoral, 197
hiatal
chest pain, 93, 95
inguinal
testicular swelling, 503, 504
obturator
omental, 24, 26
pudendal, 529
strangulated
Herniated disk. 
See also
 
Spinal disks
, 
herniated
Herniorrhaphy, 500, 501
Herpes corneal ulcer, red eye, 446
Herpes genitalis, 530
Herpes simplex
lip pain, 323
Herpes zoster
783

earache, 160, 161
paresthesias of upper extremity, 381, 382
rash—distribution, 433
Herpetiformis dermatitis, 433, 434, 435, 436
Hiatal hernia. 
See
 
Hernia
, 
hiatal
Hiccups
algorithm, 250
diagnostic workup, 249
epidemic, 249, 250
peritonitis, 249, 250
postoperative, 250
questions to ask, 250
Hidradenitis, 65, 66
Hips
congenital dislocation, 217
pain
algorithm, 252
case history, 251
diagnostic workup, 251
questions to ask, 251
Hirsutism
algorithm, 253
diagnostic workup, 253
idiopathic, 253
questions to ask, 253
Histamine cephalalgia, upper respiratory infection, 561, 562
algorithm, 255
784

diagnostic workup, 254
questions to ask, 254
Hodgkin’s disease
Homocystinuria, 220
Homosexuality and frigidity, 215
Hordeolum, red eye, 446, 447
Horner’s syndrome
algorithm, 256
diagnostic workup, 256
occipital, neck pain, 354, 355
ophthalmoplegic, 417, 418
questions to ask, 256
Human chorionic gonadotropin (hCG), 151
Huntington’s chorea
choreiform movements, 100
Hurler’s disease
Hydatid disease, 248
Hydatidiform mole
vaginal discharge, 525, 526
Hydralazine use, 549
Hydrocele
785

testicular
atrophy, 500, 501
swelling, 503, 504
Hydrocephalus
normal pressure
Hydronephrosis
flank pain, 205
Hydrophobia, 154
Hydrops of gallbladder, 24, 26
Hydroxy vitamin D
2
 and D
3
algorithm, 257
diagnostic workup, 257
questions to ask, 257
Hygiene, poor, recurrent urinary tract infection, 557, 558
Hygroma, cystic
axillary mass, 66
Hymenal orifice, inflamed, 152
Hymen, imperforate
Hyperactive reflexes
algorithm, 259
diagnostic workup, 258
questions to ask, 258
algorithm, 260
diagnostic workup, 260
questions to ask, 260
algorithm, 261
786

diagnostic workup, 261
questions to ask, 261
algorithm, 262
cirrhosis, 545
diagnostic workup, 262
questions to ask, 262
algorithm, 263
diagnostic workup, 263
questions to ask, 263
spurious, 263
algorithm, 264
diagnostic workup, 264
questions to ask, 264
Hyperlipidemia, 210, 211
Hypermetabolic states, 275
algorithm, 265
diagnostic workup, 265
questions to ask, 265
Hypernephroma
peripheral abscess, 205
Hyperosmolar coma, 281
Hyperparathyroidism
hypercalcemia, 260
primary, 33
787

algorithm, 266
diagnostic workup, 266
questions to ask, 266
adrenal, 121, 122
Hyperprolactinemia
breast discharge, 83
Hyperproteinemia, 260
algorithm, 267
diagnostic workup, 267
questions to ask, 267
Hypersplenism, 322
Hypertelorism, 334, 355
algorithm, 269
case history, 268, 269
diagnostic workup, 268, 269
dizziness, 7, 8, 145
essential, 269
headache, 231, 232
t
questions to ask, 268, 269
symptomatic, 170
Hypertensive cardiovascular disease (HCVD)
congestive heart failure, 547
Hypertensive encephalopathy
788

Hypertensive headaches, 8, 9
Hyperthyroidism
exophthalmos, 173, 174
2
 and D
3
, 257
iatrogenic, 533
algorithms, 271–272
diagnostic workup, 270
questions to ask, 270
alkalosis (increased pH), 35
dyspnea, 156, 158
t
Hypervitaminosis-D, recurrent renal calculi, 555, 556
Hypnagogic, hallucinations, 227
789

Hypoactive reflexes
algorithm, 274
diagnostic workup, 273, 274
questions to ask, 273, 274
algorithm, 275
diagnostic workup, 275
questions to ask, 275
algorithm, 276
diagnostic workup, 276
questions to ask, 276
algorithm, 277
delusional, 277
diagnostic workup, 277
obsessive, 277
questions to ask, 277
Hypogastrium, mass in, 24
, 103
algorithm, 279
case history, 278, 279
diagnostic workup, 278, 279
palpitations, 375
questions to ask, 278, 279
syncope, 493, 494
t
, 495
Hypogonadism, 367
algorithm, 280
diagnostic workup, 280
questions to ask, 280
Hypomagnesemia, 114
790

Hypomania, 172
algorithm, 281
diagnostic workup, 281
questions to ask, 281
Hypoparathyroidism
Hypopituitarism
hypoglycemia, 279
Hypoplasia, 151
Hypotension
chronic
algorithm, 283
diagnostic workup, 282
questions to ask, 282
orthostatic
chronic, 282, 283
postural, 143
t
, 145
Hypothalamic syndrome, 121, 122
algorithm, 285
diagnostic workup, 284
questions to ask, 284
Hypothyroidism
edema, localized, 165
t
hypotension, chronic, 283
infertility
female, 297, 298
male, 299
791

obesity, pathologic, 367
and scleroderma, carpal tunnel syndrome, 542
vitamin B
12
, 528
Hypotonus, 146
Hypovolemia, 53
Hypoxemia
algorithm, 287
diagnostic workup, 286, 287
questions to ask, 286, 287
Hysteria
ataxia, 63
coma, 104
cramps, muscular, 114
hiccups, 250
risus sardonicus, 451
I
I
buprofen (Motrin), 162
Ichthyosis, 435, 436
Idiocy, 419, 420
Idioglossia, 476
Idiopathic thrombocytopenic purpura, 428, 429
Ileitis, regional
abdominal pain, acute, 19
abdominal pain, chronic recurrent, 20, 21
Ileus, paralytic, 336
Impacted feces. 
See
 
Feces
, 
impacted
Impetigo
bullous, 435, 436
792

rashes, 433
Impingement syndrome, 178, 179, 180
t
Impotence
algorithm, 289
diagnostic workup, 288
psychogenic, 289
questions to ask, 288
Incontinence
. 
See also
 
Feces
, 
algorithm, 293
diagnostic workup, 292
questions to ask, 292
stress, 292, 293
algorithm, 296
diagnostic workup, 295
questions to ask, 295
Infarct/infarction
acute adrenal, 205
acute myocardial
myocardial
abdominal pain, acute, 16–18
parasagittal, 460, 462
pulmonary
renal
793

Infections
acute systemic, 65, 66
anaerobic, 368
bacterial, 321
clostridia, 218, 219
fungal. 
See
 
genitalia, 327
larynx, 327
lower extremity, 327
lung, 225, 226
neck, 327
parasitic, 245
severe
coma, 104
streptococcal pharyngitis, viral upper respiratory
thyroid, 327
upper extremity, 327
upper respiratory, 49, 50
viral upper respiratory. 
See
 
Upper respiratory infections
, 
viral
Infectious diseases
acute
chronic, diaphoresis, 131
headache, 231
Infectious mononucleosis, pharyngitis, 552
Infertility
female
algorithm, 298
diagnostic workup, 297
questions to ask, 297
male
algorithm, 299
794

diagnostic workup, 299
questions to ask, 299
Inflammation
lymph nodes, 356, 357
spinal cord, 408, 409
Inflammatory disease and frigidity, 215
Inflammatory encephalopathy, 491
Influenza
eye pain, 182
Ingestion
aspirin, chronic, 194, 196
bismuth, 328, 329
caffeine, 54, 55
charcoal, 328, 329
drug
iron, 328, 329
red wine, 328, 329
Inguinal swelling
. 
See
 
Hernia
, 
inguinal swelling
Injury
acute spinal cord, 137, 138
flexion-extension, 356, 357
head. 
See
 
optic nerve, 74, 75
spinal cord, 339, 340
edema, localized, 164, 165
Insect stings
Insomnia
algorithm, 302
diagnostic workup, 301
questions to ask, 301
Insulin, 130, 131
Insulinoma, 130, 131
795

obesity, pathologic, 366, 367
Intercostal myositis, 96, 97
Intercostal neuralgia, 221
Intercostal neuritis, 97
Intermittent claudication
algorithm, 303
diagnostic workup, 303
questions to ask, 303
Interstitial fibrosis, chronic, 101, 102
Intestinal carcinoma, 531, 533
acute, 3, 4, 16–17, 19
advanced
chronic intestinal, 295, 296
complete intestinal, 106, 107
incomplete intestinal, 106, 107
partial
strangulated hernia, due to, 336
Intoxication
alcohol
barbiturate
796

caffeine, 518
chronic aspirin, 231
digitalis, 352, 353
drug, 149, 150
lead, 330, 331
phenothiazine, 369
Intracranial abscess, 426, 427
Intracranial hematoma. 
See
 
Hematoma
, 
Intracranial or cervical bruit
, 304
Intracranial pressure, increased, 81, 82
Intrathoracic tumors, 102
Intravenous pyelogram (IVP), 20
Intussusception
colon, 204
flank mass, 204
polyp, 442, 443
Iodides
mercury, 419, 420
Iodine, 498, 499
Iritis
acute, 74, 75
Iron deficiency anemia. 
See
 
Anemia
, 
iron deficiency
Irritable bowel syndrome
chronic, 134–136
Ischemic attacks
transient. 
See
 
Transient ischemic attacks
Ischemic colitis, 439, 440
Ischemic ulcer, 435, 436
797

Isolated luteinizing hormone deficiency, 122
Isoniazid use, 549
Itch, winter, 414, 415
J
J
akob–Creutzfeldt syndrome, 126
Jaundice
algorithm, 307
case history, 305
diagnostic workup, 305–306
liver disease, obstructive, 33, 34
obstructive, 305–307
liver disease, 33, 34
questions to ask, 305
Jaw pain
algorithm, 308
diagnostic workup, 308
questions to ask, 308
Jaw swelling
algorithm, 309
diagnostic workup, 309
questions to ask, 309
Jaw tumors, 308
Joint pain
, 311
t
algorithm, 311
case history, 310
diagnostic workup, 310
fever
acute, 198, 200
history and physical examination, 9–10
questions to ask, 310
Joint swelling
algorithm, 313
diagnostic workup, 312
questions to ask, 312
K
K
ala azar
798

Keratitis
red eye, 446
Keratosis obturans, 160, 161
Kernicterus, 334, 335
Kidneys
congenital anomaly of, recurrent renal calculi, 555, 556
enlargement, 24, 26
polycystic
renal calculus (
See
 
)
renal carcinoma, 396, 397
renal colic (
See
 
Renal colic
)
renal disease (
See
 
Renal disease
)
renal failure (
See
 
Renal failure
)
renal infarction (
See
 
, 
renal
)
renal tubular acidosis (
See
 
Renal tubular acidosis (decreased pH))
tumors, 24, 25, 26
Klinefelter’s syndrome
gigantism, 220
Klippel–Feil syndrome
Knee
799

pain
algorithm, 315
diagnostic workup, 314
questions to ask, 314
swelling
algorithm, 317
diagnostic workup, 316
questions to ask, 316
Korsakoff’s psychosis
Korsakoff’s syndrome
Kyphoscoliosis, 286, 287
Kyphosis
algorithm, 318
diagnostic workup, 318
questions to ask, 318
L
L
abyrinthitis
acute, 364, 365
ataxia, 63
dizziness, 7, 143
t
, 144
toxic, 143
t
, 144
viral, 143
t
, 144
Lactase deficiency
chronic, 136
Lactic dehydrogenase elevation
algorithm, 319
diagnostic workup, 319
questions to ask, 319
Lambert–Eaton syndrome, 195
Laparoscopy, 17, 25, 27
Large floppy palate, 472
Laryngismus stridulus
800

Laryngitis
acute simple, 254, 255
acute subglottic, 117, 118, 254, 255
Laryngotracheitis
acute, 488, 489
Larynx, carcinoma of
Lateral decubitus films, of abdomen, 17
Lateral medullary syndrome, 63
Laurence–Moon–Bardet–Biedl syndrome
Lawrence–Moon–Biedel syndrome, cataract, 543
Lead intoxication, 330, 331
Lead poisoning
Legg-Calvé-Perthes disease, 251, 252
Leg ulceration
algorithm, 320
diagnostic workup, 320
questions to ask, 320
Leontiasis ossea, 309
Leprosy
Leptospirosis
Leriche’s syndrome
801

paresthesias of the lower extremity, 378, 380
Lesions. 
See also
 
Brain
, 
space-occupying lesions
early space-occupying, 231, 232
t
optic nerve, 426, 427
algorithm, 321
diagnostic workup, 321
questions to ask, 321
algorithm, 322
diagnostic workup, 322
idiopathic, 322
questions to ask, 322
Leukemia
acute, 477, 478
lymphatic, 477, 478
aleukemic, 322
anemia, 43, 44
chronic
lymphatic, 479, 480
myelogenous, 321
myeloid
lymphatic
monocytic, 321
priapism, 408
802

vitamin B
12
, 528
Leukoplakia, 416
Leukopolysaccharidosis, kyphosis, 318
Leydig cell tumors, 404, 405
Lichen planus
Lipodystrophy
Lipoma
Lipoproteinemia
type I
hypertriglyceridemia, 270, 272
type II
type IIA
type IIB
type III
type IV
type V
Lip pain
algorithm, 323
diagnostic workup, 323
questions to ask, 323
Lip swelling
algorithm, 324
diagnostic workup, 324
803

question, 324
Lithium, 264
Little’s area, irritation of, 170
Liver, cirrhosis of. 
See
 
Cirrhosis
, 
liver
Liver disease. 
See also
 
Hepatic
 
entries
cirrhosis. 
See
 
Liver, cirrhosis of
Liver function tests, 257
Localized edema. 
See
 
Edema
, 
localized
Lolling speech, 476
Lorain–Lévi syndrome, 148
Lordosis
, 325
Lower extremity pain
Low sodium syndrome, 114
Ludwig’s angina
Lues
delirium, 124
Lumbar spine, space-occupying lesion, 303
Lumbar spondylosis
Lumbosacral sprain, 453, 454
Lung abscess. 
See
 
Abscess
, 
lung
Lung disease/disorders
carcinoma
emphysema. 
See
 
Emphysema
804

mycotic, 202
pulmonary fibrosis. 
See
 
Pulmonary fibrosis
pulmonary infarction. 
See
 
, 
pulmonary
tumors, 110, 111
Lupus
discoid, 433, 434
hepatitis, cirrhosis, 544, 545
vulval or vaginal ulcerations, 530
Lupus erythematosus, systemic. 
See
 
Systemic lupus erythematosus
Luteinizing hormone (LH), 39
Lye poisoning, 154
Lyme disease, neuropathy, 548, 549
Lymphadenitis
algorithm, 327
diagnostic workup, 326
questions to ask, 326
Lymphangiography, 21, 25
Lymphangitis
acute, 164, 165
Lymphatic leukemia. 
See
 
Leukemia
, 
lymphatic
Lymphedema
localized, 164, 165, 165
t
Lymph node, enlarged, 197
Lymphogranuloma venereum
Lymphoma
diffuse, 512
805

Lymphosarcoma
Lysergic acid diethylamide (LSD)
delirium, 123
euphoria, 171, 172
M
M
acroglobulinemia
Raynaud’s phenomenon, 437, 438
Maduromycosis, 210, 211
Magnetic resonance imaging (MRI), 17, 25
Magnetic resonance retrograde cholangiopancreatography (MRCP), 247
Major coagulation defect, 428, 429
Malabsorption syndrome
abdominal swelling, generalized, 28
2
 and D
3
, 257
weight loss, 531, 532, 533
Maladjustment
806

acute situational, 360
situational, 167, 168
Malaria
splenomegaly
acute or subacute, 477, 478
chronic, 479, 480
Malignancies
gastric, 329
gynecologic, 33, 34
pouch of Douglas, 442, 443
urination difficulty, 137, 138
Malingering
extremity pain, lower extremity, 176
fever, chronic, 202
Mallory–Weiss syndrome, 236, 237
Malnutrition
2
 and D
3
, 257
hypothermia, 285
Mammillitis, 83
Mammography, 85
Manganese poisoning, 518
Mania, 172
Maple syrup urine disease, 368
Marfan’s syndrome, 220
Marijuana
807

Mastitis
acute
breast mass, 84
chronic
cystic, 84
cystic
chronic, 84
Mastocytosis, systemic, 185
Mastodynia, 85
Mastoiditis
McCune–Albright syndrome, 404, 405
Measles
German, 433, 434
nasal discharge, 349
scarlet, 435, 436
Meatal stricture, 167, 168
Meckel’s diverticulum
Mediastinal tumors
cough, 111
Mediastinitis, stridor, 488, 489
Medroxyprogesterone acetate (depo-Provera), 21
Megacolon, congenital, 28
Meigs’ syndrome
ascites, 59
808

Melena
algorithm, 329
diagnostic workup, 328
questions to ask, 328
Memory loss
. 
See also
 
Dementia
Alzheimer’s disease. 
See
 
algorithm, 331
amnesia. 
See
 
Amnesia
case history, 330
diagnostic workup, 330
questions to ask, 330
Menarche, delayed, 40
t
, 144
Meningioma
olfactory groove, 49, 50
parasagittal. 
See
 
Parasagittal meningioma
sphenoid ridge, 74, 75
Meningismus, 356, 357
bacterial, 449
basilar
t
809

syphilitic, 362, 363
tuberculous, papilledema, 376, 377
Meningocele, 174
Meningococcemia, 198, 200
upper respiratory infection, 562
Meniscus, torn
Menopause
algorithm, 333
diagnostic workup, 332
questions to ask, 332
Menstrual cramps, 112
Mental retardation
algorithm, 335
diagnostic workup, 334
questions to ask, 334
Meralgia paresthetica
Mercury, 498, 499
Mescaline, 172
Mesenteric embolism, 328, 329, 336
Mesenteric thrombosis. 
See
 
, 
, 
mesenteric
Mesothelioma, pleural effusion, 553, 554
Metabolic acidosis (decreased pH), 32
Metabolic encephalopathy
convulsions, 109
810

Metaplasia
agnogenic myeloid, 479, 480
Metastasis
bone
mass or swelling, 78, 79
liver, 33, 34
Metastatic carcinoma, sedimentation rate, 458, 459
Metastatic neoplasm, 229, 230, 247, 260, 275
Metastatic tumors
back pain, 71, 72
to lumbar spine, 378, 380
Metatarsalgia, 208
Metatarsus, varus, 209
Meteorism
algorithm, 336
diagnostic workup, 336
questions to ask, 336
Methemoglobinemia
dyspnea, 156
polycythemia, 396, 397
         Methyldopa (Aldomet), 162
Metronidazole use, 549
algorithm, 338
case history, 337
diagnostic workup, 337
questions to ask, 337
Microcephaly
Middle cerebral artery thrombosis, 67, 69
Mieg’s syndrome, 554
Migraine
acute, 18
811

atypical, 183, 184
classical, 230, 231, 232
t
common, 230, 231, 232
t
t
headache, 8, 9, 229–231
monoplegia, 319, 339, 340
occipital, headache, 230, 231
Migraine equivalent, 142, 143
t
, 144
Milium, 433, 434
Milk-alkali syndrome, recurrent renal calculi, 555, 556
Millard–Gubler syndrome
Milroy’s disease
edema
generalized, 163
Minocycline, 510, 511
Mitral regurgitation, 88, 89
Mitral stenosis
Mitral valve disease, 282, 283
Mitral valve prolapse
Mittelschmerz
812

Molestation of child, 215
Mongolism
Mononeuritis, 460, 463
Mononucleosis
infectious
fever, acute, 200
algorithm, 340
diagnostic workup, 339
questions to ask, 339
Morphine, stupor, 490, 491
Morquio’s disease. 
See
 
Pott’s disease
Morton’s neuroma, 208
Mosaicism, chromosomal, 253
Mouth pigmentation
algorithm, 341
diagnostic workup, 341
questions to ask, 341
Mouthwash, 419, 420
MSG, 296
Mucopurulent rectal discharge, 441
Mucormycosis
Müllerian duct anomaly, 122
Multiple endocrine neoplasia
Multiple myeloma
813

difficulty urinating, 137, 138
t
, 144
early, 258, 259
fatigue, 195, 196
paresthesias of
lower extremity, 378, 380
upper extremity, 381, 382
recurrent urinary tract infection, 557
Mumps
deafness, 120
814

testicular atrophy, 500
Mural thrombus, transient ischemic attacks, 516, 517
Murmurs
cardiac, 88, 89
cardiorespiratory, 88, 89
Muscae volitantes, 455
Muscle biopsy, kyphosis, 318
Muscle diseases
aspartate aminotransferase elevation, 61
algorithm, 343
diagnostic workup, 342
peroneal muscular, 342, 343, 460, 463
questions to ask, 342
Muscular dystrophy
late, 273, 274
progressive muscular, 417, 418
Musculoskeletal pain, generalized
algorithm, 345
diagnostic workup, 344
questions to ask, 344
Mutism, 476
Myalgia, epidemic
Myasthenia gravis
fatigue, 194–196
815

snoring, 472
Myelitis, transverse
Myelofibrosis, 43, 44
Myeloma, multiple
Myelophthisic anemia, prolonged prothrombin time, 410
Myocardial infarction. 
See also
 
, 
;
, 
Myocardiopathy
Myocarditis, 319
Myoclonus, 510, 511
Myoglobinuria, 522
Myopia, headache, 9
Myotonic dystrophy
facial paralysis, 188
Myotonic muscular dystrophy, cataract, 543
Myxedema
816

pretibial, of thyrotoxicosis, 164, 165
Myxoma, 102
N
Nail abnormalities
algorithm, 347
diagnostic workup, 346
questions to ask, 346
Naproxen (Naprosyn), 162
Narcolepsy
Narcotics. 
See
 
Nasal discharge
algorithm, 349
diagnostic workup, 348
questions to ask, 348
upper respirator y infection, 561, 562
Nasal gumma, 350, 351
Nasal obstruction
algorithm, 351
diagnostic workup, 350
questions to ask, 350
Nasal polyps
priapism, 409
Nasal tumors, 170
Nasopharyngeal abnormalities, 469
Nausea and vomiting
algorithm, 353
diagnostic workup, 352
817

peritonitis, 352, 353
questions to ask, 352
severe, 280
Neck pain
algorithm, 355
diagnostic workup, 354
questions to ask, 354
Neck stiffness
algorithm, 357
diagnostic workup, 356
questions to ask, 356
Neck swelling
algorithm, 359
diagnostic workup, 358
questions to ask, 358
Necrosis
avascular. 
See
 
Needle biopsy, of liver, 25
Neglect, 192, 193
Neoplasms
calculus, 169
cough, 5
early pancreatic, 47, 48
gastrointestinal. 
See
 
jaundice, 306–307
metastatic, 305, 307
nasopharynx, 184
818

ovarian, 337, 338
pancreatic. 
See
 
Pancreatic neoplasms
primary, 305–307
Nephritis
chronic
end-stage, 58, 59
interstitial, 430
Nephrolithiasis
Nephroptosis, 204
Nephrosis
Nephrotic syndrome
edema
t
2
 and D
3
, 257
Neuralgia
brachial plexus, 354, 355
819

glossopharyngeal, 160, 161
intercostal, 221
plantar, 208
trigeminal. 
See
 
Trigeminal neuralgia
Neuritis
brachial plexus
optic. 
See
 
Optic neuritis
retrobulbar. 
See
 
Retrobulbar neuritis
sciatic. 
See
 
Sciatic neuritis
Neurodermatitis, 435, 436
Neurofibromatosis
Neurogenic bladder, 557, 558
Neurologic disorders
lumbar spine, 251, 252
Neuroma
acoustic. 
See
 
Morton’s, 208
Neuronitis, vestibular
t
, 144
alcoholic, 549
algorithm, 549
brachial plexus. 
See
 
diagnostic workup, 548
peripheral. 
See
 
Peripheral neuropathy
peroneal, 378, 380
questions to ask, 548
sciatic plexus, 378, 380
uremic, 450
Neurosis
anxiety, 55
cardiac, 97
820

dizziness, 145
Neurosyphilis
Nicotine
Niemann–Pick disease, 31
algorithm, 360
diagnostic workup, 360
questions to ask, 360
Nitroglycerin, 282, 283
Nocturia
algorithm, 361
diagnostic workup, 361
questions to ask, 361
Nocturia, 486
Nodes, singer’s, 254, 255
Nonbloody sputum production, 553, 554
Nose
deviated septum
nasal discharge
nasal gumma, 350, 351
nasal obstruction
regurgitation of food through
algorithm, 363
diagnostic workup, 362
questions to ask, 362
Nummular eczema
821

Nutrition. 
See
 
; 
Nutritional anemia, 373
Nystagmus
algorithm, 365
diagnostic workup, 364
ocular, 364, 365
questions to ask, 364
O
Obesity
gynecomastia, 224
idiopathic
pathologic
algorithm, 367
diagnostic workup, 366
questions to ask, 366
Obstructions
advanced intestinal
bladder intestinal, 28
bladder neck. 
See
 
Bladder
, 
intestinal. 
See
 
Intestinal obstructions
nasolacrimal duct, congenital causes, 169
present gastric outlet, 35
pyloric. 
See
 
Pyloric obstructions
Obstructive jaundice, 410
Obturator hernia. 
See
 
Hernia
, 
obturator
Occipital lobe tumors, 455
Occipital neuralgia, 9
Occlusion
anterior cerebral artery
822

anterior spinal artery
basilar artery
central retinal artery, 74, 75
middle cerebral artery, 240, 241
posterior cerebral artery
posterior inferior cerebellar artery, 460, 462
Ocular ultrasonography, 74, 76
Oculomotor nerve palsy, 426, 427
Odontoma, 309
Odor
algorithm, 368
diagnostic workup, 368
questions to ask, 368
Oliguria or anuria. 
See
 
Omental hernia, 24, 26
Onychia, 346, 347
Opacities, corneal
Ophthalmoplegia, 417, 418
algorithm, 369
diagnostic workup, 369
questions to ask, 369
hereditary, 455
823

Optic cortex tumors, 240, 241
Optic nerve
injury, 74, 75
lesions, 426, 427
Optic tract tumors, 240, 241
Oral contraceptives, 261
Oral tumors, 308
Orbital abscess, 139, 140
Orbital fractures
Orbital tumors, 140
Orchitis
Organic brain syndrome
Orthopnea
, 370
Orthostatic hypotension. 
See
 
, 
Osteitis fibrosa cystica, 309
lower extremity, 176
t
shoulder pain, 11, 465, 467
Osteochondritis, 235
Osteochondroma, 78, 79
Osteogenesis imperfecta, 453, 454
Osteogenic sarcoma
824

Osteoma
Osteomalacia
Osteoporosis
menopausal, 318
Osteosarcoma
Otitis externa
acute, with rupture, 159
bacterial, before perforation, 160, 161
chronic, 159
dizziness, 7, 141, 144
fever
acute, 200
825

with perforation, 160, 161
serious, 159
before perforation, 160, 161
Otorrhea
earache, 161
Otosclerosis
Ovarian carcinomas, 523
Ovarian cyst
advanced, 28
Ovarian dysgenesis, 39, 40
Ovarian tumors
strangury, 485
Ovaries, polycystic
Ovary fibromas, 28
Overdose
phenothiazine, 285
tricyclic, 284, 285
Oxycephaly, 334, 335
P
P
aget’s disease
826

Palate
cleft, 154, 362, 363
congenital short soft, 362, 363
large floppy, 472
Pallor
acute, 373
chronic, 373
diagnostic workup, 373
questions to ask, 373
algorithm, 375
case history, 374
diagnostic workup, 374–375
questions to ask, 374
Palsy
Bell’s, 169, 187, 188
bilateral recurrent laryngeal, 488, 489
bulbar, 150, 154, 420
facial, 419, 420
oculomotor nerve, 426, 427
pseudobulbar. 
See
 
Pseudobulbar palsy
Pancoast’s tumor, 179
Pancreatic carcinoma
Pancreatic cyst
Pancreatic disease, 262
Pancreatic tumors, 24, 26
827

acute
abdominal pain, acute, 3–4, 16–17, 19
chronic
fever, acute, 199, 200
Panic disorder
algorithm, 377
diagnostic workup, 376
questions to ask, 376
Papilledema abscess, 376, 377
Papillitis, 76, 77
Papilloma
Paraldehyde, 225, 226
Paralysis
congenital bilateral facial, 188
familial periodic, 196
periodic, 280
respiratory, 286, 287
Paraplegia
Parasagittal tumors
gait disturbances, 217
828

Parasites, 219, 220
Parasitic infestation, 538
Parasympathomimetics, 131
Paresis, general
Paresthesias
of lower extremity
algorithm, 380
diagnostic workup, 378–379
questions to ask, 378
of upper extremity
algorithm, 382
diagnostic workup, 381
questions to ask, 381
Parietal lobe abscess, 460, 462
Parietal lobe tumors, 460, 462
Parkinsonism, 419, 420
Parkinson’s disease
Paronychia
Parotid gland tumors, 190
Pathologic reflexes
algorithm, 384
diagnostic workup, 383
questions to ask, 383
Pedicle, twisting, 386, 387
Pediculosis, 326, 327
Pellagra
829

Pelvic congestion, 333, 387
Pelvic inflammatory disease
acute, 3–4, 17
chronic recurrent, 21
fever
acute, 200
chronic, 202
Pelvic mass
algorithm, 385
diagnostic workup, 385
t
questions to ask, 385
Pelvic pain
algorithm, 387
case history, 386
diagnostic workup, 386
questions to ask, 386
Pelvic pathology, 176
Pelvic tumors
back pain, 11, 70–72
Pelvic ultrasound, 20
Pemphigus
830

Penicillamine, 498, 499
Penile sores
algorithm, 388
diagnostic workup, 388
questions to ask, 388
Penis pain
diagnostic workup, 371
questions to ask, 371
acute, 3–4
chronic recurrent, 20–21
algorithm, 550
diagnostic workup, 550
heartburn, 223, 224
questions to ask, 550
Perforated ulcer
peptic, 17
Perforated viscus, 3
Periarteritis nodosa, 437, 438
Pericardial effusion, 90, 91, 431, 432
Pericarditis
adhesive, 248
chest pain, 5, 93–95
constrictive
Perinephric abscess. 
See
 
Abscess
, 
Perineum pain
algorithm, 389
diagnostic workup, 389
831

questions to ask, 389
Periorbital edema
, 417, 418
algorithm, 390
diagnostic workup, 390
questions to ask, 390
Periostitis, orbital, 173, 174
Peripheral arteriosclerosis. 
See
 
, 
hypoactive reflexes, 274, 374
Peripheral vascular disease. 
See
 
Vascular disease, peripheral
Perirectal abscess. 
See
 
Abscess
, 
Peristalsis, visible
, 391
Peritoneal fluid, 27
Peritonitis
infectious, 22, 23
tuberculous
Peritonsillar abscess, 419, 420
Pernicious anemia. 
See
 
Anemia
, 
pernicious
Peroneal muscular atrophy, 342, 343
Peroneal neuropathy, 378, 380
Pes cavus, 209
Petrositis
832

Peutz–Jeghers syndrome
Peyronie’s disease
pH
decreased (acidosis). 
See
 
increased (alkalosis). 
See
 
Alkalosis (increased pH)
algorithm, 552
diagnostic workup, 552
questions to ask, 552
streptococcal
in children, 352, 353
Phenazopyridine hydrochloride, 522
Phencyclidine (PCP)
Phenobarbital, 426, 427
Phenothiazine
intoxication, 369
Phenylketonuria, 334, 335
Phenytoin use, 73, 160, 536, 549
Pheochromocytoma
hypertension, 262, 268, 269
Phimosis, 167, 168
Phlebitis, 208
833

Phlebothrombosis, 117, 118
algorithm, 392
diagnostic workup, 392
questions to ask, 392
Pick’s disease
Pickwickian syndrome
Pinworms, 416
Pituitary exophthalmos
Pituitary tumors
Pityriasis rosea
Plantar fasciitis
heel pain, 215
Plantar neuralgia, 208
Plaque, 416
algorithm, 394
diagnostic workup, 393
questions to ask, 393
Platelet disorders, 428, 429
Platybasia, 384
Pleural effusion
algorithm, 554
diagnostic workup, 553
questions to ask, 553
Pleurisy
834

rales, 432
, 395
Pneumoconiosis
polycythemia, 397
Pneumocystis jiroveci, 110
Pneumonia
abdominal pain, acute, 16, 18
cough, 5, 110, 111
t
early primary atypical, 111
lobar
with pleurisy, 4, 249, 250
Pneumonitis, 431, 432
Pneumoperitoneum, 28
Pneumothorax, 118
chest pain, 4, 5, 93–95
t
Poisoning
alcohol, 455
arsenic. 
See
 
carbon monoxide. 
See
 
food, 352, 353. 
See also
 
Botulism
lead. 
See
 
lye, 154
manganese, 518
opium. 
See
 
quinine, 392
sodium fluoride, 154
835

strychnine. 
See
 
Strychnine poisoning
tobacco, 455
Poliomyelitis
amyotonia congenita, 209
Polycystic kidney, 557, 558
Polycystic ovaries. 
See
 
Polycystic ovary syndrome, 39
algorithm, 397
case history, 396
diagnostic workup, 396
questions to ask, 396
vitamin B
12
, 528
Polycythemia vera
algorithm, 398
diagnostic workup, 398
psychogenic, 398
questions to ask, 398
Polymyalgia rheumatica
musculoskeletal pain, generalized, 334, 335
836

Polymyositis, 343
Polyneuritis, 334, 345
Polyneuropathy, 179
diagnostic workup, 399
questions to ask, 399
Polyps
endometrial, 337, 338
intussusception, 442, 443
nasal, 408, 409
Polyuria
algorithm, 401
diagnostic workup, 400
questions to ask, 400
systemic causes of, 13
Popliteal cyst, 164, 165
Popliteal swelling
algorithm, 403
diagnostic workup, 402
questions to ask, 402
Porphyria
rash—distribution, 434
Porphyrins, 522
Portal vein thrombosis. 
See
 
, 
portal vein
t
, 144
headache, 9, 229, 231, 232
t
Posterior cerebral artery thrombosis. 
See
 
, 
Posterior fossa tumors, 69
Postictal state, 104
Postneurotic cirrhosis, 545
Post-prostatectomy, 293
Postspinal tap headache, 9
Postural defect, 72
837

Postural hypertension, 494
t
Postural hypotension, 7, 8
Posture, faulty, 318
Potassium
IV fluid administration without, 280
over use of IV, 263
Pott’s disease, 308
Pouch, pharyngeal, 358, 359
Precocious puberty
algorithm, 405
constitutional, 404, 405
diagnostic workup, 404
questions to ask, 404
Precordial thrill
, 406
Pregnancy
ectopic. 
See
 
fear of, 215
idiopathic, 450
uterine, 151
uterus
vaginal discharge, 14
Premenstrual tension
, 407
Presbycusis, 119, 120, 510, 511
838

Priapism
algorithm, 409
chronic intermittent, 409
diagnostic workup, 408
questions to ask, 408
Primary lateral sclerosis
Proctitis
rectal bleeding, 12, 440
Progeria, 147, 148
Progressive muscular atrophy, 343
Prolapse, 119, 120
Prolonged prothrombin time
algorithm, 410
diagnostic workup, 410
questions to ask, 410
Pronator syndrome, 178, 179
Propranolol, 81, 82
Prostatectomy, 500, 501
Prostate disease, 220
Prostate, enlarged, 442, 443
Prostate-specific antigen (PSA) elevation, 31
Prostatic abscess, 98, 99
Prostatic carcinoma, 10, 11
Prostatic hypertrophy
Prostatism, 408, 409
acute
839

chronic, 137, 138
algorithm, 412
diagnostic workup, 411
orthostatic, 411, 412
questions to ask, 411
fever, 411, 412
2
 and D
3
, 257
poisoning and, 411, 412
Pruritus
ani, 413
algorithm, 415
diagnostic workup, 414
psychogenic, 414, 415
questions to ask, 414
vulvae
algorithm, 416
diagnostic workup, 416
questions to ask, 416
Babinski’s sign, 67
vascular neoplastic or degenerative etiology, 150
joint pain, 10, 310–311, 311
t
840

knee pain, 310, 311, 311
t
Pseudohermaphroditism, 223, 224
Pseudohypoparathyroidism, 276
Pseudomembranous colitis
diarrhea
 infection, 522
Pseudotumor cerebri
Pseudoxanthoma elasticum, 236, 237
Psoriasis
Psoriatic arthritis, 10
Psychiatric disturbance, 548, 549
Psychogenic causes
for amenorrhea, 39, 40
for dysmenorrhea, 151
Psychosis
depression, generally. 
See
 
depressive phase of manic-depressive, 128, 129
functional, 124
manic-depressive, 125, 128
schizophrenia. 
See
 
Schizophrenia
Ptosis
algorithm, 418
diagnostic workup, 417
questions to ask, 417
Ptyalism
algorithm, 420
diagnostic workup, 419
questions to ask, 419
Ptyalorrhea, hysterical, 419, 420
Puberty
delayed
algorithm, 122
constitutional, 121, 122
diagnostic workup, 121
questions to ask, 121
841

precocious
Pudendal hernia, 529
Pulmonary embolism, 93–95, 110, 111, 117, 118, 244, 245, 431, 432, 497
cough, 5, 6
t
Pulmonary emphysema, 58, 59, 103, 110, 117, 118, 377, 533
chronic, 110, 111
scoliosis, 454
Pulmonary function testing, 111
Pulmonary infarction. 
See
 
, 
pulmonary
Pulmonic regurgitation, 89
Pulmonic stenosis, 89
Pulsatile swelling
, diagnostic workup, 421
Pulse
absent or diminished
irregularity
algorithm, 423
diagnostic workup, 422
questions to ask, 422
unequal
algorithm, 425
diagnostic workup, 424
questions to ask, 424
Pulsus alternans, 422, 423
Pulsus paradoxus, 422, 423
Pupil abnormalities
algorithm, 427
congenital double, 139, 140
diagnostic workup, 426
questions to ask, 426
842

Purpura and abnormal bleeding
. 
See
 
Purpura, thrombocytopenic, splenomegaly, acute or subacute, 477, 478
Pus, 442, 443
chronic, recurrent renal calculi, 556
fever
hematuria, 219, 220
Pyloric stenosis, 24, 26
Pylorospasm, 193
Pyoderma, 433, 434
Pyoderma gangrenosum, 320
Pyorrhea
Pyosalpinx, 24, 26
Pyuria
algorithm, 430
diagnostic workup, 430
questions to ask, 430
Q
Q
uinidine, 282, 283
Quinine, 510, 511
poisoning, 392
843

R
R
abies, 419, 420
Radiographic studies, 27
Radioiodinated serum albumin (RISA), 126
RA factor, C-reactive protein, 115
Rales
algorithm, 432
diagnostic workup, 431
questions to ask, 431
Ramsay Hunt’s syndrome, 188
Rash
distribution
algorithm, 434
diagnostic workup, 433
questions to ask, 433
morphology
algorithm, 436
diagnostic workup, 435
questions to ask, 435
Rash, 561, 562
Rat-bite fever
acute, 200
Raynaud’s disease
Raynaud’s phenomena
, 438
algorithm, 438
diagnostic workup, 437
questions to ask, 437
, 12
algorithm, 440
diagnostic workup, 439
questions to ask, 439
Rectal carcinoma
bleeding, 439, 440
pain, 444, 445
844

Rectal discharge
algorithm, 441
diagnostic workup, 441
questions to ask, 441
Rectal fistula
bleeding, 440
discharge, 441
Rectal mass
algorithm, 443
diagnostic workup, 442
questions to ask, 442
Rectal pain
algorithm, 445
diagnostic workup, 444
questions to ask, 444
Rectal prolapse
Rectal stricture
pain, 445
Rectocele, 529
Rectovaginal fistula, 14
Rectum neoplasm, 12
Recurrent renal calculi
algorithm, 556
diagnostic workup, 555
questions to ask, 555
Recurrent urinary tract infection
algorithm, 558
diagnostic workup, 557
questions to ask, 557
Red eye
algorithm, 447
diagnostic workup, 446
questions to ask, 446
Referred pain
cholecystitis, 465, 467
pancreatitis, 465, 467
pleurisy, 465, 467
tuberculosis, 465, 467
845

Reflexes. 
See
 
; 
; 
Reflux. 
See
 
cough, 5
Refractive error, 76, 77
Regurgitation
aortic, 88, 89
esophageal
algorithm, 448
diagnostic workup, 448
questions to ask, 448
food through nose
mitral, 88, 89
pulmonic, 89
tricuspid
cardiomegaly, 91
Reiter’s disease
t
t
red eye, 447
Relapsing fever, 98, 99
Renal artery stenosis, 220, 248
Renal carcinoma, 396
846

failure to thrive, 193
uremia, 520
chronic
hyperkalemia, 253
Renal hypertension, 546, 547
Renal infarction. 
See
 
, 
renal
Renal tubular acidosis (decreased pH)
Renal tumors, 24, 26
Respiration abnormalities
algorithm, 449
diagnostic workup, 449
questions to ask, 449
Respiratory acidosis (decreased pH), 32
Respiratory distress syndrome, 431, 432
Restless leg syndrome
algorithm, 450
diagnostic workup, 450
questions to ask, 450
Retardation. 
See
 
Reticuloendothelioses
Retina, detached
847

Retinal hemorrhage, 455
Retinal vein thrombosis, 74, 75
Retinitis
Retinitis pigmentosa
Retinoblastoma, 74, 75
Retropharyngeal abscess. 
See
 
Abscess
, 
Retroverted uterus. 
See
 
Uterus
, 
retroverted
Rheumatic carditis, 546, 547
t
Rheumatic heart disease, 540
Rheumatism, palindromic, 314, 315
fever
t
848

Rheumatoid spondylitis, 70–72
Rheumatologist, 115
Rhinitis
acute, 350, 351
allergic
anosmia or unusual odors, 50
chronic, 50
medicamentosa, 350, 351
vasomotor
Rhinitis medicamentosus, 561, 562
Rhinorrhea
cerebrospinal, 348, 349
senile, 348, 349
Rhythm, AV nodal, 422, 423
Riboflavin deficiency, 512
Ribs
bruised, 96, 97
cervical, 178, 256, 358, 381, 437
fractured, 93–95, 116
Rickets
Riedel’s struma
advanced, 508, 509
Ringworm, 326, 327
849

Risus sardonicus
algorithm, 451
diagnostic workup, 451
questions to ask, 451
Rocky Mountain spotted fever, 201, 202
Rosacea, 185
Rotator cuff, torn, 465, 467
Rubella, 326, 327
S
S
acroiliitis, 252
acute, 71, 72
, 132, 133
Salpingitis
acute, 444, 445
Salpingo-oophoritis
Salt intake, excessive, 505, 506
Saphenous varix
Sarcoidosis
Sarcoma
melanotic, 326, 327
osteogenic. 
See
 
retroperitoneal, 24, 26
Scabies
pruritus
Scalp dermatitis, 326, 327
850

Scalp tenderness
, diagnostic workup, 452
Scarlet measles, 435, 436
Schatzki ring, 153, 154
Scheuermann’s disease, 308
Schilling test, 528
Schistosomiasis
paranoid delusions, 125
and insomnia, 301, 302
Sciatic plexus neuropathy, 378, 380
Scleritis, 181, 182
Scleroderma
Scoliosis
algorithm, 454
diagnostic workup, 453
idiopathic, 454
questions to ask, 453
Scoliosis, 11
Scotoma
algorithm, 455
851

diagnostic workup, 455
questions to ask, 455
Scrotal swelling
algorithm, 457
case history, 456
diagnostic workup, 456
questions to ask, 456
Scurvy
early, 73
infantile, 390
Sebaceous cyst
scrotal swelling, 457
Seborrheic dermatitis
Secretion of antidiuretic hormone (SIADH), 123
Secundina, retained, 337, 338
algorithm, 459
diagnostic workup, 458
question to ask, 458
Seizure disorder
presenile dementia, 124
senile dementia, 124
t
Seizures
alcohol withdrawal, 108, 109
complex partial, 360
epilepsy. 
See
 
Epilepsy
hysterical, 108, 109
Senile rhinorrhea, 348, 349
Sensorineural deafness, 119, 120
Sensory loss
algorithm, 462–463
diagnostic workup, 460–461
questions to ask, 460
852

Sepsis, 33, 34
t
t
Septicemia
anemia, 44
Septum, deviated
Serum albumin
algorithm, 464
diagnostic workup, 464
questions to ask, 464
Serum bilirubin, increased
algorithm, 294
diagnostic workup, 294
questions to ask, 294
Serum calcium, normal, 556
algorithm, 37
diagnostic workup, 37
questions to ask, 37
Serum lactoferrin, 134
Serum protein electrophoresis, 38, 71, 78
dyspnea, 155–156
Serum sickness
fever
Serum uric acid, alteration in
algorithm, 38
decreased, 38
diagnostic workup, 38
increased, 38
questions to ask, 38
853

Sever’s disease, 235
Sexual behavior, risky, 552
Shigella,
 132, 133
Shock
coma, 103, 107
decreased, 286, 287
insulin, 104
Short-leg syndrome
acquired, 453, 454
congenital, 453, 454
Shoulder dislocation, 465, 467
Shoulder, frozen, 178, 179, 180
t
Shoulder-hand syndrome, 179
Shoulder pain
algorithm, 467
bursitis. 
See
 
Bursitis
case history, 465
diagnostic workup, 465–466
history and physical examination, 11–12
questions to ask, 465
Shunt, right-to-left, 286, 287
Shy–Drager syndrome, 469
SIADH, 162, 281
Sibilant rales, 431
Sickle cell disease, 43, 44
854

Sick sinus syndrome
cardiac arrhythmia, 87
Silicosis, 111
Simmonds’ disease
Sinus
cavernous, 173, 174, 181, 182
thrombosis, 98, 99
Sinusitis
acute
allergic, 348, 349
chronic
Sjögren’s syndrome, 186
Skin thickening
, diagnostic workup, 468
Skin tumors
Skull fractures
Sleep apnea
algorithm, 469
diagnostic workup, 469
idiopathic, 469
855

questions to ask, 469
, 470
Smallpox
Smoking
heavy cigarette, 396, 397
Sneezing
, 471
diagnostic workup, 471
Snoring, 472
Sodium fluoride poisoning, 154
Sonorous rales, 431
Sore throat
algorithm, 474
diagnostic workup, 473
history and physical examination, 12–13
questions to ask, 473
. See also
 
Brain
, 
headache, 9
Spasm, diffuse esophageal, 153, 154
Spastic diplegia
, 475
Speech abnormalities
, 476
Spermatocele, 503, 504
Spherocytosis
anemia, 44
hereditary, 44
Spinal cord
cervical cord, 258, 259
diseases, 209
disks. 
See
 
856

high cord, 67, 69
injury, 339, 340
acute, 137, 138
trauma
tumors
cauda equina, 460, 463
herniated
muscular atrophy, 33, 342, 343
herniated cervical
herniated, L2-3, 378, 380
herniated, L3-4, 378, 380
857

herniated, L4-5, 378, 380
herniated, L5 to S1, 378, 380
herniated lumbar
extremity pain, lower extremity, 176, 177
t
large herniated, 72
Spinal muscular atrophy, 336, 342, 343
t
Spleen
enlarged, 204
Splenic infarct, 478
Splenomegaly
acute or subacute
algorithm, 478
diagnostic workup, 477
questions to ask, 477
chronic
algorithm, 480
diagnostic workup, 479
questions to ask, 479
Splinter hemorrhages, 559
Spondylitis
ankylosing, 96, 97, 208, 217, 318
kyphosis, 308
rheumatoid, 65, 66, 70–72
Spondylosis
cervical
headache, 230, 231
858

lumbar
Sporotrichosis, 210, 211
Sprain
cervical
lumbosacral, 453, 454
thoracic, 453, 454
Spur
arthritic
Squint
, 481
Stammering speech, 476
Staphylococcus, 435, 436
Starvation protein losing, 275
Stasis dermatitis, 433, 434
Stature, constitutional tall, 220
, 336
algorithm, 483
diagnostic workup, 482
diarrhea, chronic, 134, 135
questions to ask, 482
Stein–Leventhal syndrome, 39, 40
Stenosis
aortic. 
See
 
carotid, 67, 69, 510, 511
cervix, 298
mitral. 
See
 
859

pyloric, 24, 26
renal artery, 220, 248
spinal. 
See
 
supravalvular aortic, 424, 425
tricuspid, 88, 89
Stensen’s duct stone, 190
Steroids
anabolic, 121, 122
Stiffman syndrome, 369
Still’s disease
Stings
bee, 512
insect
Stomach carcinoma
Stomatitis
acute, 73
aphthous, 419, 420
chronic, 73
Stone
bladder, 219, 220
kidney, 24, 26
Stensen’s duct, 190
Wharton’s duct, 358, 359
Strangulated hernia. 
See
 
Hernia
, 
Strangury
algorithm, 485
diagnostic workup, 484
questions to ask, 484
Strep pharyngitis, 12, 13
Streptococcal pharyngitis. 
See
 
, 
860

Stress incontinence
, diagnostic workup, 486
Stretch marks
 (striae), 487
Stridor
algorithm, 489
congenital laryngeal, 488, 489
diagnostic workup, 488
questions to ask, 488
Stroke
algorithm, 560
diagnostic workup, 559
heat
questions to ask, 559
Stupor
alcoholic, 449
algorithm, 491
diagnostic workup, 490
questions to ask, 490
Sturge–Weber syndrome
shoulder pain, 11, 12, 465, 467
Subacute bacterial endocarditis (SBE)
Subacute thyroiditis, 12
Subarachnoid hemorrhage. 
See
 
, 
Subclavian steal syndrome, 29, 30, 63
Subdiaphragmatic abscess. 
See
 
Abscess
, 
Subdural hematoma. 
See
 
Hematoma
, 
subdural
Subphrenic abscess, 24, 26
Succussion sounds
, 492
Sulfhemoglobinemia, 117, 118
861

Sulfites, 295, 296
Sulfonamides, 51, 53
Superior vena cava syndrome
Supravalvular aortic stenosis, 424, 425
Supraventricular tachycardia, 496, 497
cardiac arrhythmia, 86–87
Surgery
hernia, 500, 501
previous cataract, 426, 427
recent, 321
undescended testicle, 500, 501
Sydenham’s chorea, 100
Syncope
algorithm, 495
carotid sinus, 493, 495
case history, 493
diagnostic workup, 493–494
micturition, 495
questions to ask, 493
tussive, 495
vasovagal, 493, 495
Synovitis, transient, 251, 252
Syphilis
bone mass or swelling, 73, 78, 79
CNS, 426, 427
862

secondary
lymphadenopathy, 319, 320
Syringomyelia
Systemic infectious disease, 9
Systemic lupus erythematosus, 36, 51, 53, 100
fever
acute, 200
t
spelnomegaly, acute or subacute, 477, 478
Systemic sclerosis, 448
T
T
abes dorsalis
863

algorithm, 497
diagnostic workup, 496
questions to ask, 496
supraventricular. 
See
 
Supraventricular tachycardia
ventricular. 
See
 
Ventricular tachycardia
Takayasu’s disease, 424, 425
Talipes calcaneovalgus, 209
Talipes equinovarus, 209
Talipes varus, 209
Tarsal tunnel syndrome
Tartar, 73
Taste abnormalities
algorithm, 499
diagnostic workup, 498
questions to ask, 498
Tay–Sachs disease, 334, 335
TB. 
See
 
Tuberculosis
Teeth. 
See
 
Telangiectasia, hereditary
Temporal arteritis. 
See
 
Temporomandibular syndrome
Achilles
864

calcific, 465, 467
Tension headaches, 8, 9, 229–231, 232
t
Testicle
atrophy. 
See
 
torsion
undescended
algorithm, 500, 501
diagnostic workup, 500
questions to ask, 500
Testicular dysgenesis, 39
Testicular feminization syndrome, 223, 224
Testicular pain
, 502
Testicular swelling
algorithm, 504
diagnostic workup, 503
questions to ask, 503
Testicular tumors
Tetanus
Tetany, acute, 451
Tetralogy, Fallot, 91
Thalassemia
anemia, 44
major, 480
Thiamine deficiency, 284, 285
Thirst
algorithm, 506
diagnostic workup, 505
questions to ask, 505
Thoracic outlet syndrome
865

extremity pain, upper extremity, 178, 179, 180
t
Thoracic spinal cord tumors, 258, 259
Thoracic sprain, 453, 454
algorithm, 507
diagnostic workup, 507
drug-induced, 428, 429
questions to ask, 507
Thrombophlebitis
upper extremity, 179
superficial, 175, 176
anterior cerebral artery, 67, 69
carotid artery
cavernous
cerebral
ankle clonus, 46
deep vein, 176
dural sinus, 376, 377
866

femoral artery, 320
rectal bleeding, 440
middle cerebral artery, 67, 69
retinal vein, 74–75
sinus, 98, 99
venous
Thyroglossal cyst
Thyroid carcinoma
Thyroid enlargement
algorithm, 509
diagnostic workup, 508
questions to ask, 508
Thyroiditis
867

subacute
sore throat, 474
Thyroid mass, congestive heart failure, 546, 547
Thyroid-stimulating hormone (TSH), 39
Thyroid storm, 496, 497
Thyrotoxicosis
congestive heart failure, 546
Tibialis, 303
Tic douloureux, 160, 161
Tick bite, 548, 549
Tietze’s syndrome, 97
Tinea capitis
Tinea versicolor
Tinnitus
algorithm, 511
diagnostic workup, 510
questions to ask, 510
Tobacco
Toe and foot pain
Toenail, ingrown, 208
Tongue, large, 469
Tongue mass or swelling
algorithm, 512
diagnostic workup, 512
868

questions to ask, 512
Tongue pain
, diagnostic workup, 513
Tongue ulcers
, 514
Tonsillitis, 225, 226
Tonsils, hypertrophied, 472
Toothbrush, injury with, 73
abnormalities
, 515
abscessed
carious, 225, 226, 419, 420
impacted wisdom, 308
pain referred from, 323
Torticollis, idiopathic, 356, 357
Tourette’s syndrome, 100
Toxemia of pregnancy, proteinuria, 411, 412
Toxic encephalopathy
Toxicity. 
See also
 
Poisoning
drug, 86
levodopa, 100
phenothiazine, 100
prochlorperazine, 100
salicylate, 35
Toxic metabolic disease, 273, 274
Toxic nodular goiter, 540
Toxins in food, 295, 296
Toxoplasmosis, 326, 327
Trachea carcinoma, 488, 489
Tracheobronchitis, 534
Trachoma, 417, 418
algorithm, 517
diagnostic workup, 516
dizziness, 143
t
869

questions to ask, 516
syncope, 494, 494
t
, 495
Transverse myelitis. 
See
 
Trauma
acoustic, 119, 120
leucocytosis, 44
spinal cord. 
See
 
, 
trauma
Tremor
case history, 518
dementia, cirrhosis, 545
diagnostic workup, 518
familial, 518
questions to ask, 518
senile, 518
Trichinosis
musculoskeletal pain, generalized, 323
Trichomonas vaginalis
, 521
Trichomoniasis, 14
870

Tricuspid regurgitation
Tricuspid stenosis, 88, 89
Trigeminal neuralgia, 392
Trismus
, 519
Troponins, 115
bladder
joint pain, 310–311
meningitis. 
See
 
, 
miliary, 478
peritonitis. 
See
 
, 
871

spine, 356, 357
Tuberous sclerosis
Tubo-ovarian abscess. 
See
 
Abscess
, 
Tularemia, 65, 66
Tumors
adrenal
advanced brain, 491
bladder
benign, 219, 220
malignant, 219, 220
bone. 
See
 
brain. 
See
 
Brain, tumors
brain stem. 
See
 
Brain stem
, 
tumors
carotid body, 358, 359
cauda equina, 137, 138
cauda equine, 70–72, 290, 291, 339, 340, 343, 380
cerebellar, 62, 63, 365
cerebral, 41, 42, 352, 353
cervical spinal cord, 258, 259
colon, 24–25
cord
early cervical cord, 258, 259
early pituitary, 455
early spinal cord
ectopic hormone-secreting, 266
erythropoietin-secreting, 396
frontal lobe, 171, 172
872

giant cell. 
See
 
glomus, 510, 511
granulosa cell. 
See
 
high spinal cord, 67, 69
intrathoracic, 102
jaw, 308
Leydig cell, 404, 405
lung, 110, 111
mediastinal. 
See
 
nasal, 170
occipital lobe, 455
optic cortex, 240, 241
optic tract, 240, 241
oral, 308
orbital, 140
ovarian. 
See
 
Pancoast. 
See
 
Pancoast’s tumor
pancreatic, 24–25, 26
See
 
parotid gland, 190
pelvic. 
See
 
pituitary. 
See
 
posterior fossa, 69
renal, 24, 26
skin. 
See
 
See
 
, 
tumors
testicular. 
See
 
thoracic spinal cord, 258, 259
ulcerating, 419, 420
urethral, 408, 409
vasoactive intestinal polypeptide, 136
vesicular, 484, 485
villous, 442, 443
Turbinates, hypertrophied, 472
Turner’s syndrome
873

U
U
lcer
anal. 
See
 
Anal ulcer
corneal, 169, 392
diabetic, 218, 219, 436
duodenal, 206, 207, 236, 237, 295, 296
gastric. 
See
 
herpes corneal, 446
ischemic, 435, 436
leg. 
See
 
peptic. 
See
 
perforated, 19
perforated peptic, 17
ruptured peptic, 22, 23
Ulcerating tumors, 419, 420
Ulcerative colitis
Ulcerative plaque, transient ischemic attacks, 516, 517
Ulnar entrapment, 178, 179, 381, 382
Ultrasonography, 17, 20
Upper extremity pain
, 180
t
Upper respiratory infection
, 49, 50
algorithm, 562
diagnostic workup, 561
questions to ask, 561
874

viral
cough, 111
hoarseness, 255
sore throat, 12, 13, 474
, 521
Uremia
algorithm, 520
diagnostic workup, 520
hypercalcemia, 352, 353
odor, 368
questions to ask, 520
Uremic coma, 104
Uremic neuropathy, 450
Urethral caruncle
diffculty urinating, 137, 138
vulvar or vaginal mass, 529
Urethral discharge
, 521
Urethral stricture
Urethral syndrome, 157, 158
Urethral tumors, 408, 409
875

nonspecific, 157, 158
Urinalysis, 103
Urinary frequency and burning, 13–14
Urinary incontinence. 
See
 
Urinary tract infection, 13, 137, 411, 412
algorithm, 138
diagnostic workup, 137
questions to ask, 137
Urination frequency
algorithm, 214
diagnostic workup, 214
questions to ask, 214
Urine 5-HIAA, malabsorption syndrome, 528
Urine color changes
, 522
Urine drug, 109
Urine methylmalonic acid, 528
Urologist, 137
Uropathy, obstructive, 520
Urticaria
pigmentosa, 185
Uterine bleeding, dysfunctional. 
See
 
Bleeding
, 
Uterine fibroids
Uterine prolapse, 529
Uterus
876

pregnant
pelvic, 215
UTI. 
See
 
Urinary tract infection
Uveitis, 74, 75
Uvula, 472
V
V
agina, imperforate, 39, 40
Vaginal bleeding
algorithm, 524
diagnostic workup, 523
questions to ask, 523
Vaginal carcinoma
Vaginal discharge
, 14
algorithm, 526
diagnostic workup, 525
questions to ask, 525
Vaginal or vulval mass
algorithm, 529
diagnostic workup, 529
questions to ask, 529
Vaginal or vulval ulcerations
algorithm, 530
diagnostic workup, 530
question, 530
Vaginismus, 215
Vaginitis
bacterial, 416
candidiasis, 525, 526
nonspecific, 525, 526
trichomoniasis, 416, 525, 526
877

Valvular disease
combined, 89
Valvulitis, 91
Varicocele
vulval or vaginal mass, 511
Varicose veins
, 527
diagnostic workup, 527
edema, localized, 164, 165, 165
t
Vasectomy, 500, 501
Vasoactive intestinal polypeptide tumors, 136
Vasodilators, 282, 283
Vasomotor rhinitis
Vasovagal syncope, 373, 494
t
Vena cava syndrome, 189, 190
Venereal disease, 319
Venous thrombosis. 
See
 
, 
venous
Ventilation–perfusion scan, 117
Ventricular premature contractions, 86, 87, 423
Ventricular septal defect, 89
Ventricular tachycardia, 496, 497
Vertebral basilar artery insufficiency. 
See
 
, 
vertebral basilar
artery
Vertigo, 364, 365
difficulty urinating, 137
dysuria, 157
Vesicular tumor, 484, 485
Vesiculitis
878

Vestibular neuronitis, 7
Villous adenoma, 6
Villous tumors, 442, 443
Vincent’s angina, 552
Viral gastroenteritis, 6
Viral pharyngitis, 552
Viral urinary tract infection, 561, 562
Viremia, 200
Virilism
Viscus, ruptured, 27, 28
Visible peristalsis, 391
Vision, blurred. 
See
 
Visual acuity, 446
Vitamin B
12
algorithm, 528
diagnostic workup, 528
questions to ask, 528
Vitamin D deficiency, 33, 34
Vitreous hemorrhage. 
See
 
, 
vitreous
Volkmann’s contracture, 209
Volvulus, 336
Vomiting. 
See
 
Vulvae
kraurosis, 416
pruritus. 
See
 
Pruritus
, 
vulvae
Vulval dystrophy, 152
Vulval or vaginal mass
. 
See
 
Vulval or vaginal ulcerations. 
See
 
Vulvitis
W
W
allenberg’s syndrome
Warts
plantar, 235
879

Wax, ear
discharge, 159
impacted, 160, 161
Wegener’s granuloma, 348, 349
Wegener’s granulomatosis, 350, 351
upper respiratory infection, 561
Weight loss
algorithm, 533
anorexia (
See
 
Anorexia
)
bulimia, 533
diagnostic workup, 531–532
questions to ask, 531
Wenckebach, pulse irregularity, 422, 423
Wernicke’s encephalopathy
Wharton’s duct stone, 358, 359
Wheezing
, diagnostic workup, 534
Whiplash, 510, 511
White count, 43, 44
Wilms’ tumor
Wilson’s disease
jaundice, 305
Winter itch, 414, 415
Worms, intestinal, 167, 168
X
X
anthoma, 433
Xanthomatosis, 261
X-ray treatment for delayed puberty, 122
880

Y
Y
aws, 530
Yellow fever, 81, 82, 352, 353
Z
Z
ollinger–Ellison syndrome
881

目录
Half Title Page
2
Title Page
3
Copyright Page
4
Preface to the Fourth Edition
6
Preface to the First Edition
7
8
Contents
10
Part 1 Getting the Most out of Your History and Physical
19
Part 2 Algorithms of Symptoms and Signs
39
40
44
47
49
52
54
56
58
59
61
Alopecia
62
63
64
66
Amnesia
69
Anemia
71
74
Anorexia
76
78
80
882

Anxiety
83
85
Ascites
87
89
Ataxia
91
Athetosis
94
95
97
Back Pain
100
103
Blindness
104
106
108
110
112
114
116
118
120
122
125
127
Chest Pain
128
132
Chills
134
136
138
Coma
140
144
147
Cough
150
153
154
157
883

Crepitus
159
Cyanosis
160
Deafness
162
165
Delirium
167
Delusions
169
Dementia
170
173
175
177
179
182
Diplopia
184
Dizziness
186
190
Dwarfism
192
194
196
198
Dysphagia
200
Dyspnea
203
Dysuria
206
209
Earache
211
213
215
217
Enuresis
218
Epiphora
220
Epistaxis
222
Euphoria
224
226
228
232
884

Eye Pain
236
Face Pain
238
240
242
243
245
247
249
Fatigue
251
254
256
259
Flank Mass
261
Flank Pain
263
264
266
268
269
271
Free Thyroxine (T4)
272
274
Frigidity
276
278
Gangrene
280
Gigantism
282
284
286
287
Halitosis
289
291
293
Headache
294
Heartburn
298
Heel Pain
300
885

302
Hematuria
305
308
310
312
314
315
Hiccups
317
Hip Pain
319
Hirsutism
321
323
325
Hydroxy Vitamin D2 and D3
327
328
331
332
334
336
338
339
340
342
344
346
349
351
353
355
357
359
360
362
364
Hypoxemia
366
886

368
370
372
374
375
377
379
381
Insomnia
383
385
387
Jaundice
388
Jaw Pain
391
393
Joint Pain
395
398
Knee Pain
400
402
Kyphosis
404
406
408
410
412
Lip Pain
414
415
Lordosis
416
417
Melena
419
421
424
426
Meteorism
428
430
432
887

434
435
437
439
441
444
446
Neck Pain
449
451
453
455
Nocturia
457
459
Nystagmus
461
463
ODOR
465
466
Orthopnea
468
469
Pallor
471
472
475
477
480
482
484
486
488
489
490
492
493
495
497
888

498
500
502
Polyuria
503
505
507
509
510
Priapism
511
513
515
517
518
520
Ptosis
522
Ptyalism
525
527
528
530
532
534
Pyuria
536
Rales
538
540
542
544
546
548
549
551
Red Eye
552
554
555
557
889

558
559
Scoliosis
560
Scotoma
562
564
566
568
571
573
575
576
578
Sneezing
579
Snoring
580
581
583
584
585
587
Squint
589
590
Strangury
592
594
595
Stridor
596
Stupor
598
600
Syncope
601
604
607
609
611
612
Thirst
614
890

616
617
Tinnitus
619
622
623
624
625
626
Tremor
628
Trismus
630
Uremia
631
633
634
635
637
639
Vitamin B12
640
641
642
643
Wheezing
646
Part 3 Diseases That Are Symptoms of Other Diseases
647
648
Asthma
649
651
653
Cataracts
655
Cirrhosis
657
659
661
663
665
666
667
891

668
Stroke
669
670
Appendix A
672
672
Appendix B
706
706
Index
728
892

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2019
CURRENT
Medical Diagnosis
 
& Treatment
FIFTY-EIGHTH EDITION
Edited by
Maxine A. Papadakis, MD
Professor of Medicine, Emeritus
Department of Medicine
University of California, San Francisco
Stephen J. McPhee, MD
Division of General Internal Medicine
Associate Editor
Michael W. Rabow, MD
Professor of Medicine and Urology
Division of Palliative Medicine
With Associate Authors
New York
 
Chicago
 
San Francisco
 
Athens
 
London
 
Madrid
 
Mexico City
 
Milan
 
New Delhi
 
Singapore
 
Sydney
 
T
oronto
a LANGE medical book

Copyright © 2019 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright 
Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database 
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Contents
Authors
 
v
Preface
 
xiii
 
1.
 
D
isease Prevention & Health Promotion
 
1
Michael Pignone MD, MPH, & René Salazar, MD
 
2.
 
Common Symptoms
 
20
Paul L. Nadler, MD, & Ralph Gonzales, MD, MSPH 
 
3.
  
P
reoperative Evaluation & Perioperative 
Management
 
46
Hugo Q. Cheng, MD 
 
4.
 
Geriatric Disorders
 
55
G. Michael Harper, MD, C. Bree Johnston, MD, MPH, 
& C. Seth Landefeld, MD 
 
5.
 
P
alliative Care & Pain Management
 
72
Michael W. Rabow, MD, Steven Z. Pantilat, MD, 
Scott Steiger, MD, & Ramana K. Naidu, MD 
 
6.
 
Dermatologic Disorders
 
103
Kanade Shinkai, MD, PhD, & Lindy P . Fox, MD
 
7.
 
D
isorders of the Eyes & Lids
 
174
Paul Riordan-Eva, FRCOphth 
 
8.
 
Ear
, Nose, & Throat Disorders
 
210
Lawrence R. Lustig, MD, & Joshua S. Schindler, MD 
 
9.
 
Pulmonary Disorders
 
252
Asha N. Chesnutt, MD, Mark S. Chesnutt, MD, Niall 
T. Prendergast, MD, & Thomas J. Prendergast, MD 
10.
 
H
eart Disease
 
334
Thomas M. Bashore, MD, Christopher B. Granger, MD, 
Kevin P . Jackson, MD, &  Manesh R. Patel, MD 
11.
 
S
ystemic Hypertension
 
451
Michael Sutters, MD, MRCP (UK) 
12.
 
Blo
od Vessel & Lymphatic Disorders
 
483
Warren J. Gasper, MD, Joseph H. Rapp, MD, & 
Meshell D. Johnson, MD 
13.
 
Blo
od Disorders
 
510
Lloyd E. Damon, MD, & 
 
Charalambos Babis Andreadis, MD, MSCE
14.
  
D
isorders of Hemostasis, Thrombosis, & 
Antithrombotic Therapy
 
556
Andrew D. Leavitt, MD, & Tracy Minichiello, MD
15.
 
G
astrointestinal Disorders
 
589
Kenneth R. McQuaid, MD
16.
 
Liv
er, Biliary Tract, & Pancreas Disorders
 
688
Lawrence S. Friedman, MD 
17.
 
Br
east Disorders
 
750
Armando E. Giuliano, MD, FACS, FRCSEd, & 
 
Sara A. Hurvitz, MD 
18.
 
G
ynecologic Disorders
 
776
Jason Woo, MD, MPH, FACOG, & 
 
Rachel K. Scott, MD, MPH, FACOG 
19.
 
O
bstetrics & Obstetric Disorders
 
811
Vanessa L. Rogers, MD, & Scott W. Roberts, MD
20.
  
R
heumatologic, Immunologic, & 
 
Allergic Disorders
 
840
David B. Hellmann, MD, MACP , &
 
John B. Imboden Jr., MD
21.
 
E
lectrolyte & Acid-Base Disorders
 
898
Kerry C. Cho, MD 
22.
 
Kidne
y Disease
 
926
Tonja C. Dirkx, MD, & Tyler Woodell, MD 
23.
 
Ur
ologic Disorders
 
966
Maxwell V. Meng, MD, FACS, 
 
Thomas J. Walsh, MD, MS, & Thomas D. Chi, MD 
24.
 
N
ervous System Disorders
 
990
Vanja C. Douglas, MD, & 
 
Michael J. Aminoff, MD, DSc, FRCP 
25.
 
P
sychiatric Disorders
 
1063
Kristin S. Raj, MD, Nolan Williams, MD, & 
 
Charles DeBattista, DMH, MD 
iii
CMDT2019_FM_pi-xx.indd   3

iv
 CMDT 2019
26.
 
Endo
crine Disorders
 
1119
Paul A. Fitzgerald, MD 
27.
 
D
iabetes Mellitus & Hypoglycemia
 
1220
Umesh Masharani, MB, BS, MRCP (UK) 
28.
 
Lipid D
isorders
 
1267
Robert B. Baron, MD, MS 
29.
 
Nutritional D
isorders
 
1276
30.
  
C
ommon Problems in Infectious 
 
Diseases & Antimicrobial Therapy
 
1294
Peter V. Chin-Hong, MD, &
 
B. Joseph Guglielmo, PharmD 
31.
 
HIV I
nfection & AIDS
 
1338
Mitchell H. Katz, MD
32.
 
V
iral & Rickettsial Infections
 
1377
Wayne X. Shandera, MD, &
 
Dima Dandachi, MD 
33.
 
B
acterial & Chlamydial Infections
 
1448
Bryn A. Boslett, MD, &
 
Brian S. Schwartz, MD 
34.
 
Spir
ochetal Infections
 
1493
Susan S. Philip, MD, MPH 
35.
 
P
rotozoal & Helminthic Infections
 
1510
Philip J. Rosenthal, MD
36.
 
My
cotic Infections
 
1550
Samuel A.  Shelburne III, MD, PhD, & 
 
Richard J. Hamill, MD 
37.
  
D
isorders Related to Environmental 
 
Emergencies
 
1564
Jacqueline A. Nemer, MD, FACEP , &  
 
Marianne A. Juarez, MD 
38.
 
Poisoning
 
1580
Kent R. Olson, MD 
39.
 
Cancer
 
1611
Patricia A. Cornett, MD, Tiffany O. Dea, PharmD, 
BCOP , Sunny Wang, MD, Lawrence S. Friedman, 
MD, Pelin Cinar, MD, MS, Kenneth R. McQuaid, MD, 
Maxwell V. Meng, MD, FACS, & Charles J. Ryan, MD 
40.
 
G
enetic & Genomic Disorders
 
1681
Reed E. Pyeritz, MD, PhD
41.
  
Sp
orts Medicine & Outpatient 
 
Orthopedics
 
1690
Anthony Luke, MD, MPH, & C. Benjamin Ma, MD
42.
  
L
esbian, Gay, Bisexual, & Transgender 
Health
 
1722
Juno Obedin-Maliver, MD, MPH, MAS, Patricia A. 
Robertson, MD, Kevin L. Ard, MD, MPH, Kenneth H. 
Mayer, MD, & Madeline B. Deutsch, MD, MPH
e1.
  
A
nti-Infective Chemotherapeutic & 
Antibiotic Agents 
 
O
nline*
Katherine Gruenberg, PharmD, & B. Joseph 
Guglielmo, PharmD
e2.
  
D
iagnostic Testing & Medical Decision 
Making
 
Online*
Chuanyi Mark Lu, MD
e3.
  
Information Technology in 
 
Patient Care
 
O
nline*
Russ Cucina, MD, MS
e4.
  
Integrative Medicine
 
O
nline*
Darshan Mehta, MD, MPH, &
 
 Kevin Barrows, MD
e5.
 
P
odiatric Disorders
 
O
nline*
Monara Dini, DPM
e6.
 
W
omen’s Health Issues
 
O
nline*
Megan McNamara, MD, MSc, & 
 
Judith Walsh, MD, MPH
e7.
  
A
ppendix: Therapeutic Drug Monitoring & 
Laboratory Reference Intervals, & 
Pharmacogenetic Testing
 
O
nline*
Index
 
1743
CONTENTS
*
Free access to online chapters at www.accessmedicine.com/cmdt
CMDT2019_FM_pi-xx.indd   4

Authors
N. Franklin Adkinson, Jr., MD
Professor of Medicine, Johns Hopkins Asthma & 
 
Allergy Center, Baltimore, Maryland 
fadkinso@jhmi.edu
Allergic & Immunologic Disorders (in Chapter 20)
Michael J. Aminoff, MD, DSc, FRCP
Distinguished Professor and Executive Vice Chair, 
Department of Neurology, University of California, 
 
San Francisco; Attending Physician, University of 
California Medical Center, San Francisco 
michael.aminoff@ucsf.edu
Nervous System Disorders 
Associate Professor of Clinical Medicine, Division of 
Hematology/Oncology, University of California, 
 
San Francisco 
Charalambos.Andreadis@ucsf.edu
Blood Disorders
Kevin L. Ard, MD, MPH
Faculty, Division of Infectious Diseases, Massachusetts 
General Hospital; Medical Director, National LGBT 
Health Education Center, Fenway Institute; Instructor 
in Medicine, Harvard Medical School, Boston, 
Massachusetts
kard@mgh.harvard.edu
Gay & Bisexual Men’s Health (in Chapter 42) 
Patrick Avila, MD
Clinical Fellow, Division of Gastroenterology, Department 
of Medicine, University of California, San Francisco
References
Antoine Azar, MD
Assistant Professor of Medicine, Division of Allergy & 
Clinical Immunology, Johns Hopkins Asthma & 
Allergy Center, Baltimore, Maryland
aazar4@jhmi.edu
David M. Barbour, PharmD, BCPS
Pharmacist, Denver, Colorado 
dbarbour99@gmail.com
Drug References
Robert B. Baron, MD, MS
Professor of Medicine; Associate Dean for Graduate and 
Continuing Medical Education; University of 
California, San Francisco 
baron@medicine.ucsf.edu
Lipid Disorders; Nutritional Disorders 
Kevin Barrows, MD
Clinical Professor of Family and Community Medicine, 
Director of Mindfulness Programs, Osher Center for 
Integrative Medicine; Department of Family and 
Community Medicine, University of California, San 
Francisco 
Kevin.Barrows@ucsf.edu
CMDT Online—Integrative Medicine 
Thomas M. Bashore, MD
Professor of Medicine; Senior Vice Chief, Division of 
Cardiology, Duke University Medical Center, Durham, 
North Carolina 
thomas.bashore@duke.edu
Heart Disease 
Sudhamayi Bhadriraju, MD, MPH
Clinical Fellow, Department of Medicine, University of 
California, San Francisco
Bryn A. Boslett, MD
Assistant Professor, Division of Infectious Diseases, 
Department of Medicine, University of California, 
 
Bryn.Boslett@ucsf.edu
Bacterial & Chlamydial Infections
Rachel Bystritsky, MD
Infectious Diseases Fellow, University of California, 
 
Hugo Q. Cheng, MD
Clinical Professor of Medicine, University of California, 
quinny.cheng@ucsf.edu
Preoperative Evaluation & Perioperative Management 
Asha N. Chesnutt, MD
Clinical Assistant Professor, Division of Pulmonary & 
Critical Care Medicine, Department of Medicine, 
Oregon Health & Science University, Portland, Oregon
Asha.Chesnutt2@providence.org
Pulmonary Disorders 
Mark S. Chesnutt, MD
Professor, Pulmonary & Critical Care Medicine, Dotter 
Interventional Institute, Oregon Health & Science 
University, Portland, Oregon; Director, Critical Care, 
Portland Veterans Affairs Health Care System 
chesnutm@ohsu.edu
v
CMDT2019_FM_pi-xx.indd   5

vi
 CMDT 2019
Thomas D. Chi, MD
Assistant Professor, Department of Urology, University of 
tom.chi@ucsf.edu 
Urologic Disorders
Peter V. Chin-Hong, MD
Professor, Division of Infectious Diseases, Department of 
Medicine, University of California, San Francisco 
peter.chin-hong@ucsf.edu 
Common Problems in Infectious Diseases & Antimicrobial 
Therapy 
Kerry C. Cho, MD
Clinical Professor of Medicine, Division of Nephrology, 
kerry.cho@ucsf.edu
Electrolyte & Acid-Base Disorders
Pelin Cinar, MD, MS
Clinical Assistant Professor of Medicine in Oncology, 
University of California San Francisco; Director of 
Quality Improvement, UCSF Helen Diller Family 
Comprehensive Cancer Center
pelin.cinar@ucsf.edu
Alimentary Tract Cancers (in Chapter 39)
Patricia A. Cornett, MD
Professor of Medicine, Division of Hematology/Oncology, 
University of California, San Francisco 
patricia.cornett@ucsf.edu
Cancer
Professor of Hospital Medicine; Chief Health Information 
Officer, UCSF Health System; University of California, 
russ.cucina@ucsf.edu
CMDT Online—Information Technology in Patient Care 
Lloyd E. Damon, MD
Professor of Clinical Medicine, Department of Medicine, 
Division of Hematology/Oncology; Director of Adult 
Hematologic Malignancies and Blood and Marrow 
Transplantation, Deputy Chief of the Division of 
Hematology and Medical Oncology, University of 
lloyd.damon@ucsf.edu
Dima Dandachi, MD
Infectious Diseases Fellow, Baylor College of Medicine, 
Houston, Texas  
Viral & Rickettsial Infections 
Tiffany O. Dea, PharmD, BCOP
Oncology Pharmacist, Veterans Affairs Health Care System, 
San Francisco, California; Adjunct Professor, Thomas J. 
Long School of Pharmacy and Health Sciences, Stockton, 
California 
tiffany.dea@va.gov
Cancer
Charles DeBattista, DMH, MD
Professor of Psychiatry and Behavioral Sciences; Director, 
Depression Clinic and Research Program; Director of 
Medical Student Education in Psychiatry, Stanford 
University School of Medicine, Stanford, California
debattista@stanford.edu
Psychiatric Disorders
Madeline B. Deutsch, MD, MPH
Associate Professor of Clinical Family & Community 
Medicine; Director, UCSF Transgender Care; Center of 
Excellence for Transgender Health, University of 
Madeline.Deutsch@ucsf.edu
Transgender Health & Disease Prevention (in Chapter 42)
Assistant Clinical Professor, Chief of Podiatric Surgery 
Division, Department of Orthopedic Surgery, 
monara.dini@ucsf.edu
CMDT Online—Podiatric Disorders
Tonja C. Dirkx, MD
Associate Professor of Medicine, Division of Nephrology, 
Department of Medicine, Oregon Health & Science 
University, Portland, Oregon; Acting Nephrology 
Division Chief, Portland Veterans Affairs Health Care 
System 
dirkxt@ohsu.edu
Kidney Disease 
Vanja C. Douglas, MD
Sara & Evan Williams Foundation Endowed 
Neurohospitalist Chair, Associate Professor of Clinical 
Neurology, Department of Neurology, University of 
Vanja.Douglas@ucsf.edu
Paul A. Fitzgerald, MD
Clinical Professor of Medicine, Department of Medicine, 
Division of Endocrinology, University of California, 
paul.fitzgerald@ucsf.edu
Endocrine Disorders 
Lindy P . Fox, MD 
Associate Professor, Department of Dermatology, 
Lindy.Fox@ucsf.edu
AUTHORS
CMDT2019_FM_pi-xx.indd   6

vii
 
CMDT 2019
Lawrence S. Friedman, MD
Professor of Medicine, Harvard Medical School; Professor 
of Medicine, Tufts University School of Medicine, 
Boston, Massachusetts; The Anton R. Fried, MD, Chair, 
Department of Medicine, Newton-Wellesley Hospital, 
Newton, Massachusetts; Assistant Chief of Medicine, 
Massachusetts General Hospital, Boston 
lfriedman@partners.org
Liver, Biliary Tract, & Pancreas Disorders; Hepatobiliary 
Cancers (in Chapter 39)
Warren J. Gasper, MD
Assistant Professor of Clinical Surgery, Division of 
Vascular and Endovascular Surgery, Department of 
Surgery, University of California, San Francisco
warren.gasper@ucsf.edu
Blood Vessel & Lymphatic Disorders
Armando E. Giuliano, MD, FACS, FRCSEd
Executive Vice Chair of Surgery, Associate Director of 
Surgical Oncology, Cedars-Sinai Medical Center, 
 
Los Angeles, California 
armando.giuliano@cshs.org
Breast Disorders
Ilya Golovaty, MD
Research Fellow, Department of Medicine, University of 
Ralph Gonzales, MD, MSPH
Associate Dean, Clinical Innovation and Chief Innovation 
Officer, UCSF Health; Professor of Medicine, Division 
of General Internal Medicine, Department of Medicine, 
ralph.gonzales@ucsf.edu
Common Symptoms 
Christopher B. Granger, MD
Professor of Medicine; Director, Cardiac Care Unit, Duke 
University Medical Center, Duke Clinical Research 
Institute, Durham, North Carolina 
christopher.granger@dm.duke.edu
Katherine Gruenberg, PharmD
Assistant Professor, School of Pharmacy, University of 
Katherine.Gruenberg@ucsf.edu
CMDT Online—Anti-Infective Chemotherapeutic & 
Antibiotic Agents
B. Joseph Guglielmo, PharmD
Professor and Dean, School of Pharmacy, University of 
BJoseph.Guglielmo@ucsf.edu
Therapy; CMDT Online—Anti-Infective 
Chemotherapeutic & Antibiotic Agents
Richard J. Hamill, MD
Professor, Division of Infectious Diseases, Departments of 
Medicine and Molecular Virology & Microbiology, 
Baylor College of Medicine, Houston, Texas 
rhamill@bcm.edu
Mycotic Infections
G. Michael Harper, MD
Professor, Division of Geriatrics, Department of Medicine, 
University of California San Francisco School of 
Medicine; San Francisco Veterans Affairs Health Care 
System, San Francisco, California 
Michael.Harper@ucsf.edu
Geriatric Disorders 
David B. Hellmann, MD, MACP
Aliki Perroti Professor of Medicine; Vice Dean for Johns 
Hopkins Bayview; Chairman, Department of Medicine, 
Johns Hopkins Bayview Medical Center, Johns Hopkins 
University School of Medicine, Baltimore, Maryland 
hellmann@jhmi.edu
Rheumatologic, Immunologic, & Allergic Disorders 
Sara A. Hurvitz, MD
Associate Professor; Director, Breast Oncology Program, 
Division of Hematology/Oncology, Department of 
Internal Medicine, University of California, 
 
Los Angeles
shurvitz@mednet.ucla.edu
John B. Imboden, Jr., MD
Alice Betts Endowed Chair for Arthritis Research; 
Professor of Medicine, University of California, 
 
San Francisco; Chief, Division of Rheumatology, 
Zuckerberg San Francisco General Hospital
John.Imboden@ucsf.edu
Kevin P . Jackson, MD
Assistant Professor of Medicine, Director of 
Electrophysiology, Duke Raleigh Hospital, Duke 
University Medical Center, Durham, North Carolina 
k.j@duke.edu
Heart Disease
Jane Jih, MD, MPH, MAS
Assistant Professor of Medicine, Division of General 
Internal Medicine, Department of Medicine, University 
of California, San Francisco
Meshell D. Johnson, MD
Associate Professor of Medicine, Division of Pulmonary 
and Critical Care Medicine; Director of Faculty 
Diversity, Department of Medicine, University of 
meshell.johnson@ucsf.edu
Blood Vessel & Lymphatic Disorders; Alcohol Use Disorder 
(Alcoholism) (in Chapter 25) 
AUTHORS
CMDT2019_FM_pi-xx.indd   7

AUTHORS

viii
 CMDT 2019
C. Bree Johnston, MD, MPH
Medical Director of Palliative and Supportive Care, 
PeaceHealth St. Joseph Medical Center, Bellingham, 
Washington; Clinical Professor of Medicine, University 
of Washington 
bjohnston@peacehealth.org
Marianne A. Juarez, MD
Assistant Clinical Professor, Department of Emergency 
Medicine, University of California, San Francisco
Marianne.Juarez@ucsf.edu
Disorders Related to Environmental Emergencies
Clinical Professor of Medicine, Epidemiology & 
Biostatistics, University of California, San Francisco; 
Director of Health Services, Los Angeles County 
mkatz@dhs.lacounty.gov
HIV Infection & AIDS 
Bhavika Kaul, MD
Clinical Fellow, Department of Pulmonary & Critical Care 
Elaine Khoong, MD, MS
Primary Care Research Fellow, Department of Medicine, 
Lucinda Kohn, MD
Dermatology Resident, Department of Dermatology, 
C. Seth Landefeld, MD
Professor of Medicine; Chair, Department of Medicine 
and Spencer Chair in Medical Science Leadership, 
University of Alabama at Birmingham 
sethlandefeld@uab.edu
Andrew D. Leavitt, MD
Professor, Departments of Medicine (Hematology) and 
Laboratory Medicine; Medical Director, UCSF Adult 
Hemophilia Treatment Center, University of California, 
andrew.leavitt@ucsf.edu
Disorders of Hemostasis, Thrombosis, & Antithrombotic 
Therapy
Professor, Department of Laboratory Medicine, University 
of California, San Francisco; Chief, Hematology, 
Hematopathology & Molecular Diagnostics, 
Laboratory Medicine Service, Veterans Affairs Health 
Care System, San Francisco, California 
mark.lu@va.gov
CMDT Online—Appendix: Therapeutic Drug Monitoring 
& Laboratory Reference Intervals, & Pharmacogenetic 
Testing; CMDT Online—Diagnostic Testing & Medical 
Decision Making
Anthony Luke, MD, MPH
Professor of Clinical Orthopaedics, Department of 
Orthopaedics; Director, UCSF Primary Care Sports 
Medicine; Director, Human Performance Center at the 
Orthopaedic Institute, University of California, 
 
anthony.luke@ucsf.edu
Sports Medicine & Outpatient Orthopedics
Lawrence R. Lustig, MD
Howard W . Smith Professor and Chair, Department of 
Otolaryngology—Head & Neck Surgery, Columbia 
University Medical Center & New Y ork Presbyterian 
Hospital, New Y ork, New Y ork
lrl2125@cumc.columbia.edu
Ear, Nose, & Throat Disorders
C. Benjamin Ma, MD
Professor, Department of Orthopaedic Surgery; Chief, 
Sports Medicine and Shoulder Service, University of 
MaBen@orthosurg.ucsf.edu
Anne Mardy, MD
Clinical Fellow, Maternal Fetal Medicine and Medical 
Genetics, University of California, San Francisco
Umesh Masharani, MB, BS, MRCP (UK)
Professor of Medicine, Division of Endocrinology and 
Metabolism, Department of Medicine, University of 
umesh.masharani@ucsf.edu
Diabetes Mellitus & Hypoglycemia 
Kenneth H. Mayer, MD
Co-Chair and Medical Research Director, The Fenway 
Institute; Director of HIV Prevention Research, Beth 
Israel Deaconess Medical Center; Professor of 
Medicine, Harvard Medical School, Boston, 
kmayer@fenwayhealth.org
Gay & Bisexual Men’s Health (in Chapter 42)
AUTHORS
CMDT2019_FM_pi-xx.indd   8

ix
 
CMDT 2019
Megan McNamara, MD, MSc
Associate Professor of Medicine, Case Western Reserve 
University School of Medicine; Louis Stokes Cleveland 
Veterans Affairs Medical Center, Cleveland, Ohio 
Megan.Mcnamara@va.gov
CMDT Online—Women’s Health Issues 
Chief, Gastroenterology and Medical Service, 
 
San Francisco Veterans Affairs Medical Center; 
Professor of Clinical Medicine, Marvin H. Sleisenger 
Endowed Chair and Vice-Chairman, Department of 
Kenneth.Mcquaid@va.gov
Gastrointestinal Disorders; Alimentary Tract Cancers 
 
(in Chapter 39) 
Darshan Mehta, MD, MPH
Medical Director, Benson-Henry Institute for Mind Body 
Medicine, Massachusetts General Hospital; Associate 
Director of Education, Osher Center for Integrative 
Medicine, Harvard Medical School and Brigham and 
Women’s Hospital, Boston
dmehta@mgh.harvard.edu
CMDT Online—Integrative Medicine
Maxwell V. Meng, MD, FACS
Professor, Chief of Urologic Oncology, Department of 
Urology, University of California, San Francisco
max.meng@ucsf.edu
Urologic Disorders; Cancers of the Genitourinary Tract 
 
Tracy Minichiello, MD
San Francisco; Chief, Anticoagulation and Thrombosis 
Services, San Francisco Veterans Affairs Medical 
Center
Tracy.Minichiello@ucsf.edu
Therapy
Paul L. Nadler, MD
Clinical Professor of Medicine; Director, Screening and 
Acute Care Clinic, Division of General Internal 
Medicine, Department of Medicine, University of 
Paul.Nadler@ucsf.edu
Ramana K. Naidu, MD
Assistant Professor, Department of Anesthesia and 
Perioperative Care, Division of Pain Medicine, 
University of California, San Francisco; Pain Physician 
& Anesthesiologist, California Orthopedics and Spine, 
Medical Director of Pain Management, Marin General 
Hospital, Greenbrae, California 
ramonaidu@me.com
Palliative Care & Pain Management  
Jacqueline A. Nemer, MD, FACEP
Professor of Emergency Medicine, Director of Quality & 
Safety, Director of Advanced Clinical Skills, 
Department of Emergency Medicine, University of 
jacqueline.nemer@ucsf.edu
Disorders Related to Environmental Emergencies 
Juno Obedin-Maliver, MD, MPH, MAS
Assistant Professor, Department of Obstetrics, 
Gynecology, and Reproductive Sciences, University of 
California, San Francisco and San Francisco Veterans 
Affairs Medical Center; Founder and Investigator, 
Lesbian, Gay, Bisexual, and Transgender Medical 
Education Research Group, Stanford University School 
of Medicine, Stanford, California
Juno.Obedin-Maliver@ucsf.edu
Lesbian & Bisexual Women’s Health (in Chapter 42)
Kent R. Olson, MD
Clinical Professor of Medicine, Pediatrics, and Pharmacy, 
University of California, San Francisco; Medical 
Director, San Francisco Division, California Poison 
Control System
kent.olson@ucsf.edu
Poisoning 
Steven Z. Pantilat, MD
Professor of Medicine, Department of Medicine; 
 
Kates-Burnard and Hellman Distinguished Professor of 
Palliative Care; Director, Palliative Care Program, 
steve.pantilat@ucsf.edu
Palliative Care & Pain Management 
Charles Brian Parks, DPM 
Charles.Parks@ucsf.edu
CMDT Online— Flatfoot (Pes Planus) (in Chapter e5)
Manesh R. Patel, MD
Associate Professor of Medicine, Division of Cardiology, 
Department of Medicine; Director of Interventional 
manesh.patel@duke.edu
Susan S. Philip, MD, MPH
Assistant Clinical Professor, Division of Infectious 
Diseases, Department of Medicine, University of 
California, San Francisco; Disease Prevention and 
Control Branch, Population Health Division,

Control Branch, Population Health Division, 
 
San Francisco Department of Public Health, 
 
San Francisco, California 
susan.philip@sfdph.org
Spirochetal Infections 
AUTHORS
CMDT2019_FM_pi-xx.indd   9

x
 CMDT 2019
Michael Pignone, MD, MPH
Professor of Medicine; Chair, Department of Medicine, 
Dell Medical School, The University of Texas at Austin
pignone@austin.utexas.edu
Disease Prevention & Health Promotion 
Toya Pratt, MD
Clinical Fellow, Female Pelvic Medicine & Reconstructive 
Surgery, Kaiser Permanente-University of California, 
Niall T. Prendergast, MD
Instructor in Medicine, Barnes-Jewish Hospital, 
Washington University School of Medicine, Saint 
Louis, Missouri; Fellow, Division of Pulmonary, Allergy 
and Critical Care Medicine, Department of Medicine, 
University of Pittsburgh School of Medicine. 
Pittsburgh, Pennsylvania
prendergastn@wustl.edu
Thomas J. Prendergast, MD
Clinical Professor of Medicine, Oregon Health & Science 
University; Pulmonary Critical Care Section Chief, 
Portland Veterans Affairs Health Care System, 
Portland, Oregon 
thomas.prendergast@va.gov
William Smilow Professor of Medicine and Genetics, 
Raymond and Ruth Perelman School of Medicine of 
the University of Pennsylvania, Philadelphia 
reed.pyeritz@uphs.upenn.edu
Genetic & Genomic Disorders 
Michael W. Rabow, MD, FAAHPM
Helen Diller Family Chair in Palliative Care, Professor of 
Clinical Medicine and Urology, Division of Palliative 
Medicine, Department of Medicine; Director, Symptom 
Management Service, Helen Diller Family 
Comprehensive Cancer Center, University of 
Mike.Rabow@ucsf.edu
Leena T. Rahmat, MD
Clinical Fellow, Department of Hematology and Bone 
Marrow Transplantation, University of California, 
 
Kristin S. Raj, MD
Clinical Instructor, Department of Psychiatry and 
Behavioral Sciences, Stanford University School of 
Medicine, Stanford, California
kraj@stanford.edu
Psychiatric Disorders 
Joseph H. Rapp, MD
Professor of Surgery, Emeritus, Division of Vascular and 
Endovascular Surgery, University of California, 
 
Joseph.Rapp@ucsf.edu
Blood Vessel & Lymphatic Disorders 
Paul Riordan-Eva, FRCOphth
Consultant Ophthalmologist, King’s College Hospital, 
London, United Kingdom
paulreva@doctors.org.uk
Disorders of the Eyes & Lids 
Scott W. Roberts, MD
Associate Professor, Obstetrics and Gynecology, 
University of Texas Southwestern Medical Center, 
Dallas, Texas 
scott.roberts@utsouthwestern.edu
Obstetrics & Obstetric Disorders
Patricia A. Robertson, MD
Professor, Department of Obstetrics, Gynecology, and 
Reproductive Sciences, University of California, 
 
Patricia.Robertson@ucsf.edu
Vanessa L. Rogers, MD
vanessa.rogers@utsouthwestern.edu
Professor, Department of Medicine, University of 
California, San Francisco; Associate Chief, Division of 
HIV , Infectious Diseases, and Global Health, 
Zuckerberg San Francisco General Hospital 
philip.rosenthal@ucsf.edu
Protozoal & Helminthic Infections 
Charles J. Ryan, MD
Professor of Clinical Medicine and Urology; Thomas 
Perkins Distinguished Professor in Cancer Research; 
Program Leader, Genitourinary Medical Oncology, 
Helen Diller Family Comprehensive Cancer Center, 
charles.ryan@ucsf.edu
Cancers of the Genitourinary Tract (in Chapter 39)
René Salazar, MD
Professor of Medical Education, Assistant Dean for 
Diversity, Dell Medical School, The University of Texas 
at Austin 
rene.salazar@austin.utexas.edu
Disease Prevention & Health Promotion
AUTHORS
CMDT2019_FM_pi-xx.indd   10

xi
 
CMDT 2019
Joshua S. Schindler, MD
Associate Professor, Department of Otolaryngology, 
Oregon Health & Science University, Portland, Oregon; 
Medical Director, OHSU-Northwest Clinic for Voice 
and Swallowing
schindlj@ohsu.edu
Brian S. Schwartz, MD
Associate Professor, Division of Infectious Diseases, 
 
brian.schwartz@ucsf.edu
Rachel K. Scott MD, MPH, FACOG
Scientific Director of Women’s Health Research, MedStar 
Health Research Institute Director, Women’s Center for 
Positive Living, MedStar Washington Hospital Center, 
Department of Women’s and Infants’ Services; Assistant 
Professor of Obstetrics and Gynecology, Georgetown 
University School of Medicine, Washington, D.C.
Rachel.K.Scott@Medstar.net
Gynecologic Disorders
Wayne X. Shandera, MD
Assistant Professor, Department of Internal Medicine, 
shandera@bcm.tmc.edu
Samuel A. Shelburne, III, MD, PhD
Associate Professor, Department of Infectious Diseases 
and Department of Genomic Medicine, The University 
of Texas MD Anderson Cancer Center, Houston, Texas 
sshelburne@mdanderson.org
Mycotic Infections 
Kanade Shinkai, MD, PhD
Kanade.Shinkai@ucsf.edu
Scott Steiger, MD
Associate Professor of Clinical Medicine and Psychiatry, 
Division of General Internal Medicine, Department of 
Medicine, University of California, San Francisco; 
Deputy Medical Director, Opiate Treatment Outpatient 
Program, Division of Substance Abuse and Addiction 
Medicine, Department of Psychiatry, Zuckerberg 
 
San Francisco General Hospital 
scott.steiger@ucsf.edu
Michael Sutters, MD, MRCP (UK)
Attending Nephrologist, Virginia Mason Medical Center, 
Seattle, Washington; Affiliate Assistant Professor of 
Medicine, Division of Nephrology, University of 
Washington School of Medicine, Seattle, Washington 
michael.sutters@vmmc.org
Systemic Hypertension 
Philip Tiso
Principal Editor, Division of General Internal Medicine, 
Professor of Clinical Medicine, Division of General 
Internal Medicine, Women’s Health Center of 
Excellence, University of California, San Francisco 
Judith.Walsh@ucsf.edu
Thomas J. Walsh, MD, MS
Associate Professor, Department of Urology, University of 
walsht@uw.edu
Sunny Wang, MD
Assistant Clinical Professor of Medicine, Division of 
 
San Francisco; San Francisco Veterans Affairs Health 
Care System 
sunny.wang@ucsf.edu
Lung Cancer (in Chapter 39)
Nolan Williams, MD
Instructor; Director, Brain Stimulation Laboratory, 
Department of Psychiatry, Stanford University School 
nolanw@stanford.edu
CAPT Jason Woo, MD, MPH, FACOG
Medical Officer, Office of Generic Drugs, Center for Drug 
Evaluation and Research, U.S. Food and Drug 
Administration, Silver Spring, Maryland 
woojjmd@gmail.com
Tyler Woodell, MD
Fellow, Division of Nephrology, Oregon Health & Science 
University, Portland Oregon
woodell@ohsu.edu
Kidney Disease
Wanning Zhao, MD
Resident Physician, Department of Otolaryngology—Head 
 
& Neck Surgery, University of California, San Francisco
CMDT2019_FM_pi-xx.indd   11

CMDT2019_FM_pi-xx.indd   12

Preface
Current Medical Diagnosis & Treatment 2019 (CMDT 2019)
 is the 58th edition of this single-source reference for
practitioners in both hospital and ambulatory settings. The book emphasizes the practical features of clinical diagnosis and
patient management in all fields of internal medicine and in specialties of interest to primary care practitioners and to
subspecialists who provide general care.
Our students have inspired us to look at issues of race and justice, which surely impact people’s health. We have therefore
reviewed the content of our work to ensure that it contains the dignity and equality that every patient deserves.
INTENDED AUDIENCE FOR 
CMDT
House officers, medical students, and all other health professions students will find the descriptions of diagnostic and
therapeutic modalities, with citations to the current literature, of everyday usefulness in patient care.
Internists, family physicians, hospitalists, nurse practitioners, physician assistants, and all primary care providers will
appreciate 
CMDT
 as a ready reference and refresher text. Physicians in other specialties, pharmacists, and dentists will find
the book a useful basic medical reference text. Nurses, nurse practitioners, and physician assistants will welcome the format
and scope of the book as a means of referencing medical diagnosis and treatment.
Patients and their family members who seek information about the nature of specific diseases and their diagnosis and
treatment may also find this book to be a valuable resource.
NEW IN THIS EDITION OF 
CMDT
•	
New color figures throughout the book
•	
Rewritten section on pain management at the end of life
•	
Updated American College of Cardiology/American Heart Association (ACC/AHA) guidelines for treatment of
valvular heart disease
•	
ACC consensus document providing decision pathway for use of transcatheter aortic valve replacement
•	
Extensively revised sections on long QT syndrome; AV block; and sinus arrhythmia, bradycardia, and tachycardia
•	
Rewritten section on atrial tachycardia
•	
Substantial revision of ventricular tachycardia management
•	
New algorithms for managing mitral regurgitation and heart failure with reduced ejjection fraction
•	
New table outlining management strategies for women with valvular heart disease, complex congenital heart disease,
pulmonary hypertension, aortopathy, and dilated cardiomyopathy
•	
New ACC/AHA and Hypertension Canada blood pressure guidelines
•	
New table outlining blood pressure values across a range of measurement methods (ie, home and ambulatory
monitoring)
•	
New table comparing blood pressure treatment thresholds and targets in the 2017 ACC/AHA guidelines with the 2017
Hypertension Canada guidelines
•	
New FDA-approved medications for relapsing or refractory forms of leukemia
•	
Rewritten section on monoclonal gammopathy of uncertain significance
•	
New FDA-approved direct-acting oral anticoagulant
•	
Information regarding commercially available freeze-dried capsule fecal formulation for treatment of recurrent and
refractory 
 infection
•	
New FDA-approved medications for treatment of breast cancer
•	
Cancer Care Ontario and American Society of Clinical Oncology jointly published guidelines outlining adjuvant
therapy plan for postmenopausal breast cancer patients
•	
Substantial revision of the targeted therapies for hormone receptor–positive metastatic breast cancer
•	
American College of Obstetricians and Gynecologists support for considering use of low-dose aspirin to prevent
preeclampsia
xiii
CMDT2019_FM_pi-xx.indd   13

xiv
 CMDT 2019
•	
Revised recommendations for treating hepatitis C virus–associated kidney disease
•	
New chronic tubulointerstitial disease called Mesoamerican nephropathy 
•	
Detailed discussion of available treatment options for refractory trigeminal neuralgia
•	
New classification of epilepsy
•	
Updated information about treating spinal muscular atrophy
•	
Substantial revision of Psychiatric Disorders chapter
•	
New section on incidentally discovered adrenal masses
•	
Updated treatment section for classic Turner syndrome
•	
New FDA-approved integrase inhibitor for treatment of HIV-1 infection
•	
Extensive revision of Viral & Rickettsial Infections chapter
•	
New FDA-approved medication for gastric adenocarcinoma 
•	
New colon cancer screening recommendations from the US Multi-Society Task Force
OUTSTANDING FEATURES OF
 CMDT
•	
Medical advances up to time of annual publication
•	
Detailed presentation of primary care topics, including gynecology, obstetrics, dermatology, ophthalmology, 
otolaryngology, psychiatry, neurology, toxicology, urology, geriatrics, orthopedics, women’s health, preventive medicine, 
and palliative care
•	
Concise format, facilitating efficient use in any practice setting
•	
More than 1000 diseases and disorders
•	
Annual update on HIV/AIDS and other newly emerging infections
•	
Specific disease prevention information
•	
Easy access to medication dosages, with trade names indexed and costs updated in each edition
•	
Recent references, with unique identifiers (PubMed, PMID numbers) for rapid downloading of article abstracts and, in 
some instances, full-text reference articles
E-CHAPTERS, 
CMDT ONLINE
, & AVAILABLE APPS
E-Chapters
 mentioned in the table of contents can be accessed at www.AccessMedicine.com/CMDT. The seven online-only 
chapters available without need for subscription at www.AccessMedicine.com/CMDT include
•	
 
A
nti-Infective Chemotherapeutic & Antibiotic Agents
•	
 
Di
agnostic Testing & Medical Decision Making
•	
 
I
nformation Technology in Patient Care
•	
 
I
ntegrative Medicine
•	
 
P
•	
 
W
omen’s Health Issues 
•	
 
A
ppendix: Therapeutic Drug Monitoring & Laboratory Reference Intervals, & Pharmacogenetic Testing 
Institutional or individual subscriptions to AccessMedicine will also have full electronic access to 
CMDT 2019
.
Subscribers to 
CMDT Online
 receive full electronic access to 
CMDT 2019
 as well as
•	
 
A
n expanded, dedicated media gallery
•	
 
Q
uick Medical Diagnosis & Treatment
 (
QMDT
)—a concise, bulleted version of 
CMDT 2019
•	
 
Guide to Diagnostic Tests
—for quick reference to the selection and interpretation of commonly used diagnostic tests
•	
  
CURRENT P
ractice Guidelines in Primary Care—delivering concise summaries of the most relevant guidelines in 
primary care
•	
 
Diagnosaurus
—consisting of 1000+ differential diagnoses
CMDT 2019, QMDT, Guide to Diagnostic Tests
, and 
 are also available as individual apps for your smartphone 
or tablet and can be found in the Apple App Store and Google Play.
PREFACE
CMDT2019_FM_pi-xx.indd   14

xv
 
CMDT 2019
SPECIAL RECOGNITION
After preparing his annual contribution for this 2019 edition of 
CMDT
, Dr. Paul Riordan-Eva announced his retirement 
from the book. Dr. Riordan-Eva has contributed each year to 
CMDT
 for 30 years (since 1989). In addition, he has 
contributed to 
Vaughan & Asbury’s General Ophthalmology
 since 1989 and has been 
its senior editor since 2004. 
Dr. Riordan-Eva has had a distinguished career in ophthalmology. He studied at 
Cambridge University and St. Thomas Hospital Medical School, London. He then 
pursued his ophthalmology training in London, followed by a Fellowship at the 
Proctor Foundation in San Francisco. Dr. Riordan-Eva’s first consultant appointment 
in 1995 was as Consultant Neuro-Ophthalmologist at Moorfields Eye Hospital and 
the National Hospital for Neurology and Neurosurgery. His work there was 
combined with Consultant Clinical Scientist at the Medical Research Council Human 
Movement and Balance Unit, researching brainstem control of eye movements. In 
1999, Dr. Riordan-Eva moved to King’s College Hospital, London, to set up the neuro-
ophthalmology service in the regional neurosciences center. His publications include 
46 peer-reviewed original papers and 13 reviews. Dr. Riordan-Eva retired from 
clinical practice in 2017. Currently, he is the Chairman of the Medical Defence Union, 
the leading medical indemnity provider in the United Kingdom. 
On behalf of our readers and the entire staff at McGraw-Hill Education, we send 
our warmest congratulations to Paul for his retirement. As his editors, we offer our 
heartfelt gratitude for his 30 years of contribution to 
CMDT
. We will sorely miss 
working with him each year. Felicitations, Paul!
ACKNOWLEDGMENTS
We wish to thank our associate authors for participating once again in the annual updating of this important book. We are 
especially grateful to Natalie J.M. Dailey Garnes, MD, MPH, C. Diana Nicoll, MD, PhD, MPA, and Suzanne Watnick, MD, 
who are leaving 
CMDT
 this year. We have all benefited from their clinical wisdom and commitment. 
Many students and physicians also have contributed useful suggestions to this and previous editions, and we are grateful. 
We continue to welcome comments and recommendations for future editions in writing or via electronic mail. The editors’ 
e-mail addresses are below and author e-mail addresses are included in the Authors section. 
Maxine.Papadakis@ucsf.edu
Stephen.McPhee@ucsf.edu
Michael W . Rabow, MD
San Francisco, California
CMDT2019_FM_pi-xx.indd   15

CMDT2019_FM_pi-xx.indd   16

From inability to let well alone; from too much zeal for the new and 
contempt for what is old; from putting knowledge before wisdom, 
science before art and cleverness before common sense; from treating 
patients as cases; and from making the cure of the disease more 
grievous than the endurance of the same, Good Lord, deliver us.
—Sir Robert Hutchison
CMDT2019_FM_pi-xx.indd   17

CMDT2019_FM_pi-xx.indd   18

1
 
CMDT 2019
 
º
GENERAL APPROACH TO THE PATIENT
The medical interview serves several functions. It is used to 
collect information to assist in diagnosis (the “history” of 
the present illness), to understand patient values, to assess 
and communicate prognosis, to establish a therapeutic 
relationship, and to reach agreement with the patient about 
further diagnostic procedures and therapeutic options. It 
also serves as an opportunity to influence patient behavior, 
such as in motivational discussions about smoking cessa
-
tion or medication adherence. Interviewing techniques 
that avoid domination by the clinician increase patient 
involvement in care and patient satisfaction. Effective clini
-
cian-patient communication and increased patient involve
-
ment can improve health outcomes.
 
»
Patient Adherence
For many illnesses, treatment depends on difficult funda
-
mental behavioral changes, including alterations in diet, 
taking up exercise, giving up smoking, cutting down drink
-
ing, and adhering to medication regimens that are often 
complex. Adherence is a problem in every practice; up to 
50% of patients fail to achieve full adherence, and one-third 
never take their medicines. Many patients with medical 
problems, even those with access to care, do not seek appro
-
priate care or may drop out of care prematurely. Adherence 
rates for short-term, self-administered therapies are higher 
than for long-term therapies and are inversely correlated 
with the number of interventions, their complexity and 
cost, and the patient’s perception of overmedication.
As an example, in HIV-infected patients, adherence to 
antiretroviral therapy is a crucial determinant of treatment 
success. Studies have unequivocally demonstrated a close 
relationship between patient adherence and plasma HIV 
RNA levels, CD4 cell counts, and mortality. Adherence 
levels of more than 95% are needed to maintain virologic 
suppression. However, studies show that over 60% of 
patients are less than 90% adherent and that adherence 
tends to decrease over time.
1
Michael Pignone MD, MPH
1
 
Disease Prevention & 
Health Promotion
1
Dr. Pignone is a former member of the US Preventive Services 
Task Force (USPSTF). The views expressed in this chapter are his 
and Dr. Salazar’s and not necessarily those of the USPSTF.
Patient reasons for nonadherence include simple 
forgetfulness, being away from home, being busy, and 
changes in daily routine. Other reasons include psychi
-
atric disorders (depression or substance misuse), 
uncertainty about the effectiveness of treatment, lack of 
knowledge about the consequences of poor adherence, 
regimen complexity, and treatment side effects. The rising 
costs of medications, including generic drugs, and the 
increase in patient cost-sharing burden, has made adher
-
ence even more difficult, particularly for those with lower 
incomes.
Patients seem better able to take prescribed medica
-
tions than to adhere to recommendations to change their 
diet, exercise habits, or alcohol intake or to perform vari
-
ous self-care activities (such as monitoring blood glucose 
levels at home). For short-term regimens, adherence to 
medications can be improved by giving clear instructions. 
Writing out advice to patients, including changes in medi
-
cation, may be helpful. Because low functional health 
literacy is common (almost half of English-speaking US 
patients are unable to read and understand standard 
health education materials), other forms of communica
-
tion—such as illustrated simple text, videotapes, or oral 
instructions—may be more effective. For non–English-
speaking patients, clinicians and health care delivery sys
-
tems can work to provide culturally and linguistically 
appropriate health services.
To help improve adherence to long-term regimens, cli
-
nicians can work with patients to reach agreement on the 
goals for therapy, provide information about the regimen,

-
goals for therapy, provide information about the regimen, 
ensure understanding by using the “teach-back” method, 
counsel about the importance of adherence and how to 
organize medication-taking, reinforce self-monitoring, 
provide more convenient care, prescribe a simple dosage 
regimen for all medications (preferably one or two doses 
daily), suggest ways to help in remembering to take doses 
(time of day, mealtime, alarms) and to keep appoint
-
ments, and provide ways to simplify dosing (medication 
boxes). Single-unit doses supplied in foil wrappers can 
increase adherence but should be avoided for patients 
who have difficulty opening them. Medication boxes with 
compartments (eg, Medisets) that are filled weekly are 
useful. Microelectronic devices can provide feedback to 
CMDT19_Ch01_p0001-p0019.indd   1
05/07/18   2:04 PM

C
HAPTER
 1
2
 CMDT 2019
Table 1–1.
 
Leading causes of death in the United States, 
2015.
Category
Estimate
All causes
2,712,630
 
1.
 
Diseases of 
the heart
633,842
 
2.
 
Malignant neoplasms
595,930
 
3.
 
Chr
onic lower respiratory diseases
155,041
 
4.
 
Unintentional injuries
146,571
 
5.
 
Cerebrovascular diseases
140,323
 
6.
 
Alzheimer disease
110,561
 
7.
 
79,535
 
8.
 
I
nfluenza and pneumonia
57,062
 
9.
  
Nephritis
, nephrotic syndrome, and 
nephrosis
49,959
10.
 
I
ntentional self-harm (suicide)
44,193
Data from National Center for Health Statistics 2016.
show patients whether they have taken doses as scheduled 
or to notify patients within a day if doses are skipped. 
Reminders, including cell phone text messages, are another 
effective means of encouraging adherence. The clinician 
can also enlist social support from family and friends, 
recruit an adherence monitor, provide a more convenient 
care environment, and provide rewards and recognition for 
the patient’s efforts to follow the regimen. Collaborative 
programs that utilize pharmacists to help ensure adherence 
are also effective.
Adherence is also improved when a trusting doctor-
patient relationship has been established and when 
patients actively participate in their care. Clinicians can 
improve patient adherence by inquiring specifically about 
the behaviors in question. When asked, many patients 
admit to incomplete adherence with medication regimens, 
with advice about giving up cigarettes, or with engaging 
only in “safer sex” practices. Although difficult, sufficient 
time must be made available for communication of health 
messages.
Medication adherence can be assessed generally with 
a single question: “In the past month, how often did you 
take your medications as the doctor prescribed?” Other 
ways of assessing medication adherence include pill 
counts and refill records; monitoring serum, urine, or 
saliva levels of drugs or metabolites; watching for 
appointment nonattendance and treatment nonresponse; 
and assessing predictable drug effects, such as weight 
changes with diuretics or bradycardia from beta-blockers. 
In some conditions, even partial adherence, as with drug 
treatment of hypertension and diabetes mellitus, improves 
outcomes compared with nonadherence; in other cases, 
such as HIV antiretroviral therapy or tuberculosis treat
-
ment, partial adherence may be worse than complete 
nonadherence.
 
»
Guiding Principles of Care
Ethical decisions are often called for in medical practice, at 
both the “micro” level of the individual patient-clinician 
relationship and at the “macro” level of the allocation of 
resources. Ethical principles that guide the successful 
approach to diagnosis and treatment are honesty, benefi
-
cence, justice, avoidance of conflict of interest, and the 
pledge to do no harm. Increasingly, Western medicine 
involves patients in important decisions about medical 
care, eg, which colorectal screening test to obtain or which 
modality of therapy for breast cancer or how far to proceed 
with treatment of patients who have terminal illnesses (see 
Chapter 5).
The clinician’s role does not end with diagnosis and 
treatment. The importance of the empathic clinician in 
helping patients and their families bear the burden of seri
-
ous illness and death cannot be overemphasized. “To cure 
sometimes, to relieve often, and to comfort always” is a 
French saying as apt today as it was five centuries ago—as is 
Francis Peabody’s admonition: “The secret of the care of the 
patient is in caring for the patient. ” Training to improve 
mindfulness and enhance patient-centered communication 
increases patient satisfaction and may also improve clini
-
cian satisfaction.
Choudhry NK et al. Improving adherence to therapy and clinical 
outcomes while containing costs: opportunities from the 
greater use of generic medications: best practice advice from

greater use of generic medications: best practice advice from 
the Clinical Guidelines Committee of the American College of 
Physicians. Ann Intern Med. 2016 Jan 5;164(1):41–9. [PMID: 
26594818]
Thakkar J et al. Mobile telephone text messaging for medication 
adherence in chronic disease: a meta-analysis. JAMA Intern 
Med. 2016 Mar;176(3):340–9. [PMID: 26831740]
 
º
HEALTH MAINTENANCE & DISEASE 
PREVENTION
Preventive medicine can be categorized as primary, sec
-
ondary, or tertiary. Primary prevention aims to remove or 
reduce disease risk factors (eg, immunization, giving up or 
not starting smoking). Secondary prevention techniques 
promote early detection of disease or precursor states (eg, 
routine cervical Papanicolaou screening to detect carci
-
noma or dysplasia of the cervix). Tertiary prevention mea
-
sures are aimed at limiting the impact of established 
disease (eg, partial mastectomy and radiation therapy to 
remove and control localized breast cancer).
Tables 1–1 and 1–2 give leading causes of death in the 
United States and estimates of deaths from preventable 
causes. Recent data suggest increased rates of death, mainly 
from suicide and substance misuse, particularly among less 
well-educated middle-aged white adults.
Many effective preventive services are underutilized, 
and few adults receive all of the most strongly recom
-
mended services. Several methods, including the use of 
provider or patient reminder systems (including interac
-
tive patient health records), reorganization of care environ
-
ments, and possibly provision of financial incentives to 
clinicians (though this remains controversial), can increase 
utilization of preventive services, but such methods have 
not been widely adopted.
CMDT19_Ch01_p0001-p0019.indd   2

DISEASE PREVENTION & HEALTH PROMOTION
3
 
CMDT 2019
Table 1–2.
 
Deaths from all causes attributable to common preventable risk factors. (Numbers given in the thousands.)
Risk Factor
Male (95% CI)
Female (95% CI)
Both Sexes (95% CI)
Tobacco smoking
248 (226–269)
219 (196–244)
467 (436–500)
High blood pressure
164 (153–175)
231 (213–249)
395 (372–414)
Overweight–obesity (high BMI)
114 (95–128)
102 (80–119)
216 (188–237)
Physical inactivity
88 (72–105)
103 (80–128)
191 (164–222)
High blood glucose
102 (80–122)
89 (69–108)
190 (163–217)
High LDL cholesterol
60 (42–70)
53 (44–59)
113 (94–124)
High dietary salt (sodium)
49 (46–51)
54 (50–57)
102 (97–107)
Low dietary omega-3 fatty acids (seafood)
45 (37–52)
39 (31–47)
84 (72–96)
High dietary trans fatty acids
46 (33–58)
35 (23–46)
82 (63–97)
Alcohol use
45 (32–49)
20 (17–22)
64 (51–69)
Low intake of fruits and vegetables
33 (23–45)
24 (15–36)
58 (44–74)
Low dietary polyunsaturated fatty acids 
 
(in place of saturated fatty acids)
9 (6–12)
6 (3–9)
15 (11–20)
BMI, body mass index; CI, confidence interval; LDL, low-density lipoprotein.
Note: Numbers of deaths cannot be summed across categories.
Used, with permission, from Danaei G et al. The preventable causes of death in the United States: comparative risk assessment of dietary, 
lifestyle, and metabolic risk factors. PLoS Med. 2009 Apr 28;6(4):e1000058.
Case A et al. Rising morbidity and mortality in midlife among 
white non-Hispanic Americans in the 21st century. Proc Natl 
Acad Sci U S A. 2015 Dec 8;112(49):15078–83. [PMID: 
26575631]
Forman-Hoffman VL et al. Disability status, mortality, and lead
-
ing causes of death in the United States community popula
-
tion. Med Care. 2015 Apr;53(4):346–54. [PMID: 25719432]
García MC et al. Potentially preventable deaths among the five 
leading causes of death—United States, 2010 and 2014. 
MMWR Morb Mortal Wkly Rep. 2016 Nov 18;65(45):1245–55. 
[PMID: 27855145]
Levine DM et al. The quality of outpatient care delivered to 
adults in the United States, 2002 to 2013. JAMA Intern Med. 
2016 Dec 1;176(12):1778–90. [PMID: 27749962]
Ma J et al. Temporal trends in mortality in the United States, 
1969–2013. JAMA. 2015 Oct 27;314(16):1731–9. [PMID: 
26505597]
Murphy SL et al. Deaths: final data for 2015. National Vital 
Statistics Reports. Hyattsville, MD. 2017 Nov 27;66(6):1–76.
National Center for Health Statistics. Health, United States, 
2015: with special feature on racial and ethnic health dispari
-
ties. Hyattsville, MD. 2016 May. [PMID: 27308685]
PREVENTION OF INFECTIOUS DISEASES
Much of the decline in the incidence and fatality rates of 
infectious diseases is attributable to public health mea
-
sures—especially immunization, improved sanitation, and 
better nutrition.
Immunization
 remains the best means of preventing 
many infectious diseases. Recommended immunization 
schedules for children and adolescents can be found 
online at http://www.cdc.gov/vaccines/schedules/hcp/
child-adolescent.html, and the schedule for adults is at 
http://www.cdc.gov/vaccines/schedules/hcp/adult.html 
(see also Chapter 30). Substantial morbidity and mortality 
from vaccine-preventable diseases, such as hepatitis A, 
hepatitis B, influenza, and pneumococcal infections, con
-
tinue to occur among adults. Increases in the number of 
vaccine-preventable diseases in the United States highlight 
the need to understand the association of vaccine refusal 
and the epidemiology of these diseases. 
Evidence suggests annual 
influenza vaccination
 is safe 
and effective with potential benefit in all age groups, and 
the Advisory Committee on Immunization Practices 
(ACIP) recommends routine influenza vaccination for all 
persons aged 6 months and older, including all adults. 
When vaccine supply is limited, certain groups should be 
given priority, such as adults 50 years and older, individuals 
with chronic illness or immunosuppression, and pregnant 
women. An alternative high-dose inactivated vaccine is

women. An alternative high-dose inactivated vaccine is 
available for adults 65 years and older. Adults 65 years and 
older can receive either the standard-dose or high-dose 
vaccine, whereas those younger than 65 years should 
receive a standard-dose preparation.
The ACIP recommends two doses of measles, mumps, 
and rubella (MMR) vaccine in adults at high risk for expo
-
sure and transmission (eg, college students, health care 
workers). Otherwise, one dose is recommended for adults 
aged 18 years and older. Physician documentation of dis
-
ease is not acceptable for evidence of MMR immunity.
Routine use of 13-valent pneumococcal conjugate vac
-
cine (PCV13) is recommended among adults aged 65 and 
older. Individuals 65 years of age or older who have never 
received a pneumococcal vaccine should first receive 
PCV13 followed by a dose of 23-valent pneumococcal 
polysaccharide vaccine (PPSV23) 6–12 months later. Indi
-
viduals who have received more than one dose of PPSV23 
should receive a dose of PCV13 more than 1 year after the 
last dose of PPSV23 was administered.
CMDT19_Ch01_p0001-p0019.indd   3

C
HAPTER
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4
 CMDT 2019
 The ACIP recommends routine use of a single dose of 
tetanus, diphtheria, and 5-component acellular pertussis 
vaccine (Tdap) for adults aged 19–64 years to replace the 
next booster dose of tetanus and diphtheria toxoids 
vaccine (Td). Due to increasing reports of pertussis in the 
United States, clinicians may choose to give Tdap to per
-
sons aged 65 years and older (particularly to those who 
might risk transmission to at-risk infants who are most 
susceptible to complications, including death), despite lim
-
ited published data on the safety and efficacy of the vaccine 
in this age group.
Both 
hepatitis A vaccine
 and 
immune globulin
 pro
-
vide protection against hepatitis A; however, administra
-
tion of immune globulin may provide a modest benefit 
over vaccination in some settings. Hepatitis B vaccine 
administered as a three-dose series is recommended for all 
children aged 0–18 years and high-risk individuals (ie, 
health care workers, injection drug users, people with end-
stage renal disease). Adults with diabetes are also at 
increased risk for hepatitis B infection. The ACIP recom
-
mends 
vaccination for hepatitis B
 in diabetic patients aged 
19–59 years. The hepatitis B vaccine should also be consid
-
ered in diabetic persons age 60 and older.
Human papillomavirus (HPV) virus-like particle 
(VLP) vaccines
 have demonstrated effectiveness in pre
-
venting persistent HPV infections and thus may impact the 
rate of cervical intraepithelial neoplasia (CIN) II–III. The 
ACIP recommends routine HPV vaccination (with three 
doses of the 9-valent [9vHPV], 4-valent [4vHPV], or 
2-valent [2vHPV] vaccine) for girls aged 11–12 years. The 
ACIP also recommends that all unvaccinated girls and 
women through age 26 years receive the three-dose HPV 
vaccination. Studies suggest that one dose of vaccine may 
be as effective as three. The ACIP also recommends the 
routine vaccination with three doses of the 4vHPV or 
9vHPV vaccine for boys aged 11 or 12 years, males through 
age 21 years, and men who have sex with men and immu
-
nocompromised men (including those with HIV infec
-
tion) through age 26 years. Vaccination of males with 
HPV may lead to indirect protection of women by reducing 
transmission of HPV and may prevent anal intraepithelial 
neoplasia and squamous cell carcinoma in men who have 
sex with men. 
Persons traveling to countries where infections are 
endemic should take the precautions described in Chapter 
30 and at http://wwwnc.cdc.gov/travel/destinations/list. 
Immunization registries—confidential, population-based, 
computerized information systems that collect vaccination 
data about all residents of a geographic area—can be used 
to increase and sustain high vaccination coverage.
Until recently, the rate of tuberculosis in the United 
States had been declining. The Centers for Disease Control 
and Prevention (CDC) reports that after 2 decades of prog
-
ress toward tuberculosis elimination—with annual 
decreases of greater than or equal to 0.2 case per 100,000 
persons—its incidence in the United States plateaued at 
approximately 3.0 cases per 100,000 persons during 2013–
2015. Two blood tests, which are not confounded by prior 
bacillus Calmette-Guérin (BCG) vaccination, have been 
developed to detect tuberculosis infection by measuring in 
vitro T-cell interferon-gamma release in response to two 
antigens (one, the enzyme-linked immunospot [ELISpot], 
[T-SPOT.TB], and the other, a quantitative ELISA [Quan
-
tiFERON-TBGold] test). These T-cell–based assays have 
an excellent specificity that is higher than tuberculin skin 
testing in BCG-vaccinated populations.
The US Preventive Services Task Force (USPSTF) rec
-
ommends behavioral counseling for adolescents and adults 
who are sexually active and at increased risk for sexually 
transmitted infections. Sexually active women aged 24 years 
or younger and older women who are at increased risk for

or younger and older women who are at increased risk for 
infection should be screened for chlamydia. Screening 
HIV-positive men or men who have sex with men for 
syphilis every 3 months is associated with improved syphilis 
detection.
HIV infection
 remains a major infectious disease prob
-
lem in the world. The CDC recommends universal HIV 
screening of all patients aged 13–64, and the USPSTF rec
-
ommends that clinicians screen adolescents and adults 
aged 15 to 65 years. Clinicians should integrate biomedical 
and behavioral approaches for HIV prevention. In addition 
to reducing sexual transmission of HIV , initiation of anti
-
retroviral therapy reduces the risk for AIDS-defining 
events and death among patients with less immunologi
-
cally advanced disease.
Daily preexposure prophylaxis (PrEP) with the fixed-
dose combination of tenofovir disoproxil 300 mg and 
emtricitabine 200 mg (Truvada) should be considered for 
people who are HIV-negative but at substantial of risk for 
HIV infection. Studies of men who have sex with men sug
-
gest that PrEP is very effective in reducing the risk of con
-
tracting HIV . Patients taking PrEP should be encouraged 
to use other prevention strategies, such as consistent con
-
dom use and choosing less risky sexual behaviors (eg, oral 
sex), to maximally reduce their risk. Postexposure prophy
-
laxis (PEP) with combinations of antiretroviral drugs is 
widely used after occupational and nonoccupational con
-
tact, and may reduce the risk of transmission by approxi
-
mately 80%. PEP should be initiated within 72 hours of 
exposure.
In immunocompromised patients, live vaccines are 
contraindicated, but many killed or component vaccines 
are safe and recommended. 
Asymptomatic
 HIV-infected 
patients have not shown adverse consequences when given 
live MMR and influenza vaccinations as well as tetanus, 
hepatitis B, 
H influenza
 type b, and pneumococcal vaccina
-
tions—all should be given. However, if poliomyelitis 
immunization is required, the inactivated poliomyelitis 
vaccine is indicated. In 
symptomatic
 HIV-infected patients, 
live-virus vaccines, such as MMR, should generally be 
avoided, but annual influenza vaccination is safe.
Herpes zoster,
 caused by reactivation from previous 
varicella zoster virus infection, affects many older adults 
and people with immune system dysfunction. It can cause 
postherpetic neuralgia, a potentially debilitating chronic 
pain syndrome. Two vaccines are available for the preven
-
tion of herpes zoster, a live virus vaccine (Zostavax) and a 
herpes zoster subunit vaccine (HZ/su; Shingrix) (approved 
by the US Food and Drug Administration [FDA] in 
October 2017). The ACIP recommends the HZ/su vaccine 
CMDT19_Ch01_p0001-p0019.indd   4

5
 
CMDT 2019
be used for the prevention of herpes zoster and related 
complications in immunocompetent adults age 50 and 
older and in individuals who previously received Zostavax. 
The ACIP prefers the use of the new HZ/su vaccine over 
the older live virus vaccine.
In May 2015, the World Health Organization reported 
the first local transmission of Zika virus in the Western 
Hemisphere. Zika virus spreads to people primarily 
through mosquito bites but can also spread during sex by a 
person infected with Zika to his or her partner. Although 
clinical disease is usually mild, Zika virus infections in 
women infected during pregnancy have been linked to fetal 
microcephaly and loss, and newborn and infant blindness 
and other neurologic problems (see Chapter 32). Pregnant 
women should consider postponing travel to areas where 
Zika virus transmission is ongoing.
American Academy of Family Practitioners. ACIP recommends 
new herpes zoster subunit vaccine. 2017 Oct 31. http://www
 
.aafp.org/news/health-of-the-public/20171031acipmeeting
 
.html
Basta NE et al. Immunogenicity of a meningococcal B vaccine 
during a university outbreak. N Engl J Med. 2016 Jul 21;
 
375(3):220–8. [PMID: 27468058]
Blackstock OJ et al. A cross-sectional online survey of HIV pre-
exposure prophylaxis adoption among primary care physi
-
cians. J Gen Intern Med. 2017 Jan;32(1):62–70. [PMID: 
27778215]
Cantor AG et al. Screening for syphilis: updated evidence 
report and systematic review for the U.S. Preventive Services 
Task Force. JAMA. 2016 Jun 7;315(21):2328–37. [PMID: 
27272584]
Centers for Disease Control and Prevention (CDC). Adult 
Immunization Schedules: United States, 2016. http://www
 
.cdc.gov/vaccines/schedules/hcp/adult.html
Centers for Disease Control and Prevention (CDC). Pertussis 
outbreak trends, 2015. http://www.cdc.gov/pertussis/out
-
breaks/trends.html
Centers for Disease Control and Prevention (CDC). HIV/AIDS, 
2017. http://www.cdc.gov/hiv/basics/index.html
Centers for Disease Control and Prevention (CDC). Zika virus. 
http://www.cdc.gov/zika/index.html
Jin J. JAMA patient page. Screening for syphilis. JAMA. 2016 
Jun 7;315(21):2367. [PMID: 27272600]
Mayer KH et al. Antiretroviral preexposure prophylaxis: oppor
-
tunities and challenges for primary care physicians. JAMA. 
2016 Mar 1;315(9):867–8. [PMID: 26893026]
Phadke VK et al. Association between vaccine refusal and 
vaccine-preventable diseases in the United States: a review of 
measles and pertussis. JAMA. 2016 Mar 15;315(11):1149–58. 
Erratum in: JAMA. 2016 May 17;315(19):2125. [PMID: 
26978210]
PrEP (preexposure prophylaxis), 2017. http://www.cdc.gov/hiv/
basics/prep.html 
PEP (postexposure prophylaxis), 2017. http://www.cdc.gov/hiv/
basics//pep.html.
Sultan B et al. Current perspectives in HIV post-exposure 
prophylaxis. HIV AIDS (Auckl). 2014 Oct 24;6:147–58. 
[PMID: 25368534]
PREVENTION OF CARDIOVASCULAR DISEASE
Cardiovascular diseases, including coronary heart disease 
(CHD) and stroke, represent two of the most important 
causes of morbidity and mortality in developed countries. 
Several risk factors increase the risk for coronary disease 
and stroke. These risk factors can be divided into those that 
are modifiable (eg, lipid disorders, hypertension, cigarette 
smoking) and those that are not (eg, age, sex, family history 
of early coronary disease). Impressive declines in age-specific 
mortality rates from heart disease and stroke have been 
achieved in all age groups in North America during the 
past two decades, in large part through improvement of 
modifiable risk factors: reductions in cigarette smoking, 
improvements in lipid levels, and more aggressive detec
-
tion and treatment of hypertension. This section considers 
the role of screening for cardiovascular risk and the use of 
effective therapies to reduce such risk. Key recommenda
-
tions for cardiovascular prevention are shown in Table 1–3.

-
tions for cardiovascular prevention are shown in Table 1–3. 
Guidelines encourage regular assessment of global cardio
-
vascular risk in adults 40–79 years of age without known 
cardiovascular disease.
Goff DC Jr et al. 2013 ACC/AHA guideline on the assessment of 
cardiovascular risk: a report of the American College of Car
-
diology/American Heart Association Task Force on Practice 
Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S49–73. 
[PMID: 24222018]
Gómez-Pardo E et al. A comprehensive lifestyle peer group-
based intervention on cardiovascular risk factors: the ran
-
domized controlled fifty-fifty program. J Am Coll Cardiol. 
2016 Feb 9;67(5):476–85. Erratum in: J Am Coll Cardiol. 2016 
Mar 22;67(11):1385. [PMID: 26562047]
Jin J. JAMA patient page. Counseling on healthy living to pre
-
vent cardiovascular disease in adults without risk factors. 
JAMA. 2017 Jul 11;318(2):210. [PMID: 28697255]
Kavousi M et al. Comparison of application of the ACC/AHA 
guidelines, Adult Treatment Panel III guidelines, and Euro
-
pean Society of Cardiology guidelines for cardiovascular dis
-
ease prevention in a European cohort. JAMA. 2014 Apr 9;
 
311(14):1416–23. [PMID: 24681960]
U.S. Preventive Services Task Force. Behavioral counseling to 
promote a healthful diet and physical activity for cardiovascu
-
lar disease prevention in adults without cardiovascular risk 
factors: U.S. Preventive Services Task Force Recommendation 
Statement. JAMA. 2017 Jul 11;318(2):167–74. [PMID: 
28697260]
 
»
Abdominal Aortic Aneurysm
One-time screening for abdominal aortic aneurysm (AAA) 
by ultrasonography in men aged 65–75 years is associated 
with a relative reduction in odds of AAA-related mortality 
of almost 50% and possibly a small reduction in all-cause 
mortality. Women do not appear to benefit from screening, 
and most of the benefit in men appears to accrue among 
current or former smokers. Screening men aged 65 years 
and older is highly cost effective.
Canadian Task Force on Preventive Health Care. Recommen
-
dations on screening for abdominal aortic aneurysm in 
primary care. CMAJ. 2017 Sep 11;189(36):E1137–45. [PMID: 
28893876]
Wanhainen A et al; Swedish Aneurysm Screening Study Group 
(SASS). Outcome of the Swedish nationwide abdominal 
aortic aneurysm screening program. Circulation. 2016 Oct 18;
 
134(16):1141–8. [PMID: 27630132]
CMDT19_Ch01_p0001-p0019.indd   5

C
HAPTER
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6
 CMDT 2019
Table 1–3.
 
Expert recommendations for cardiovascular risk prevention methods: US Preventive Services Task Force 
(USPSTF).
1
Prevention Method
Recommendation/[Year Issued]
Screening for abdominal 
aortic aneurysm (AAA)
Recommends one-time screening for AAA by ultrasonography in men aged 65–75 years who have ever 
smoked. (B)
Selectively offer screening for AAA in men aged 65–75 years who have never smoked. (C)
Current evidence is insufficient to assess the balance of benefits and harms of screening for AAA in women 
aged 65–75 years who have ever smoked. (I)
Recommends against routine screening for AAA in women who have never smoked. 
(D) [2014]
Aspirin use
Recommends initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and 
colorectal cancer (CRC) in adults aged 50–59 years who have a 10% or greater 10-year CVD risk, are not at 
increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose 
aspirin daily for at least 10 years. (B)
The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 
 
60–69 years who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are 
 
not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take 
 
low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on 
 
the potential benefits than the potential harms may choose to initiate low-dose aspirin. (C)
The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the 
primary prevention of CVD and CRC in adults younger than 50 years or older than age 70. (I)
[2016]
Blood pressure screening
The USPSTF recommends screening for high blood pressure in adults aged 18 years or older. The USPSTF rec
-
ommends obtaining measurements outside of the clinical setting for diagnostic confirmation before start
-
ing treatment. (A)
[2015]
Serum lipid screening and 
use of statins for 
prevention
The USPSTF recommends that adults without a history of CVD use a low- to moderate-dose statin for the 
 
prevention of CVD events and mortality when all of the following criteria are met: (1) they are aged 
 
40–75 years; (2) they have one or more CVD risk factors (ie, dyslipidemia, diabetes mellitus, hypertension, or 
smoking); and (3) they have a calculated 10-year risk of a cardiovascular event of 10% or greater.
Identification of dyslipidemia and calculation of 10-year CVD event risk requires universal lipids screening in 
adults aged 40–75 years. See the “Clinical Considerations” section of the USPSTF recommendations
2
 for more 
information on lipids screening and the assessment of cardiovascular risk. (B)
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of 
 
initiating statin use for the primary prevention of CVD events and mortality in adults aged 76 years and older 
without a history of heart attack or stroke. (I)
[2016]
Counseling about health
-
ful diet and physical 
activity for CVD 
Recommends offering or referring adults who are overweight or obese and have additional CVD risk factors to 
intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD 
 
prevention. (B)
[2014]
Recommends that primary care professionals individualize the decision to offer or refer adults without obesity 
who do not have hypertension, dyslipidemia, abnormal blood glucose levels, or diabetes to behavioral 
 
counseling to promote a healthful diet and physical activity. (C)
[2017]
Screening for diabetes 
mellitus
Recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 
40–70 years who are overweight or obese. Clinicians should offer or refer patients with abnormal blood

40–70 years who are overweight or obese. Clinicians should offer or refer patients with abnormal blood 
 
glucose to intensive behavioral counseling interventions to promote a healthful diet and physical activity. (B)
[2015]
Screening for smoking and 
counseling to promote 
cessation
Recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide 
behavioral interventions and US Food and Drug Administration (FDA)–approved pharmacotherapy for 
 
cessation to adults who use tobacco. (A)
[2015]
1
Recommendation A:
 The USPSTF strongly recommends that clinicians routinely provide the service to eligible patients. (The USPSTF found 
good evidence that the service improves important health outcomes and concludes that benefits substantially outweigh harms.)
Recommendation B:
 The USPSTF recommends that clinicians routinely provide the service to eligible patients. (The USPSTF found at least 
fair evidence that the service improves important health outcomes and concludes that benefits substantially outweigh harms.)
Recommendation C:
 The USPSTF makes no recommendation for or against routine provision of the service.
Recommendation D:
 The USPSTF recommends against routinely providing the service to asymptomatic patients. (The USPSTF found at 
least fair evidence that the service is ineffective or that harms outweigh benefits.)
Recommendation I:
 The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing the service.
2
http://www.uspreventiveservicestaskforce.org/BrowseRec/Index/browse-recommendations
CMDT19_Ch01_p0001-p0019.indd   6

7
 
CMDT 2019
 
»
Cigarette Smoking
Cigarette smoking remains the most important cause of 
preventable morbidity and early mortality. In 2015, there 
were an estimated 6.4 million premature deaths in the 
world attributable to smoking and tobacco use; smoking is 
the second leading cause of disability adjusted life years 
lost. Cigarettes are responsible for one in every five deaths 
in the United States. From 2005 to 2009, more than 
480,000 deaths per year (more than 278,000 in men and 
more than 201,000 in women) were attributable to smok
-
ing. Annual cost of smoking-related health care is approxi
-
mately $130 billion in the United States, with another 
$150 billion in productivity losses. Fortunately, US smoking 
rates are declining; in 2015, 15.1% of US adults were smok
-
ers. Global direct health care costs from smoking in 2012 
were estimated at $422 billion, with total costs of over 
$1.4 trillion.
Nicotine is highly addictive, raises brain levels of dopa
-
mine, and produces withdrawal symptoms on discontinua
-
tion. Smokers die 5–8 years earlier than never-smokers. 
They have twice the risk of fatal heart disease; 10 times the 
risk of lung cancer; and several times the risk of cancers of 
the mouth, throat, esophagus, pancreas, kidney, bladder, 
and cervix; a twofold to threefold higher incidence of 
stroke and peptic ulcers (which heal less well than in non
-
smokers); a two- to fourfold greater risk of fractures of the 
hip, wrist, and vertebrae; four times the risk of invasive 
pneumococcal disease; and a twofold increase in cataracts. 
In the United States, over 90% of cases of chronic obstruc
-
tive pulmonary disease (COPD) occur among current or 
former smokers.
Both active smoking and passive smoking are associ
-
ated with deterioration of the elastic properties of the aorta 
(increasing the risk of aortic aneurysm) and with progres
-
sion of carotid artery atherosclerosis. Smoking has also 
been associated with increased risks of leukemia, of colon 
and prostate cancers, of breast cancer among postmeno
-
pausal women who are slow acetylators of N-acetyltrans
-
ferase-2 enzymes, of osteoporosis, and of Alzheimer 
disease. In cancers of the head and neck, lung, esophagus, 
and bladder, smoking is linked to mutations of the 
P53
 
gene, the most common genetic change in human cancer. 
Patients with head and neck cancer who continue to 
smoke during radiation therapy have lower rates of 
response than those who do not smoke. Olfaction and taste 
are impaired in smokers, and facial wrinkles are increased. 
Heavy smokers have a 2.5 greater risk of age-related macu
-
lar degeneration.
The children of smokers have lower birth weights, are 
more likely to be mentally retarded, have more frequent 
respiratory infections and less efficient pulmonary func
-
tion, have a higher incidence of chronic ear infections than 
children of nonsmokers, and are more likely to become 
smokers themselves. In addition, exposure to environmen
-
tal tobacco smoke has been shown to increase the risk of 
cervical cancer, lung cancer, invasive pneumococcal dis
-
ease, and heart disease; to promote endothelial damage and 
platelet aggregation; and to increase urinary excretion of 
tobacco-specific lung carcinogens. The incidence of breast 
cancer may be increased as well. Over 41,000 deaths per 
year in the United States are attributable to environmental 
tobacco smoke.
Smoking cessation reduces the risks of death and of 
myocardial infarction in people with coronary artery dis
-
ease; reduces the rate of death and acute myocardial infarc
-
tion in patients who have undergone percutaneous 
coronary revascularization; lessens the risk of stroke; and is 
associated with improvement of COPD symptoms. On 
average, women smokers who quit smoking by age 35 add 
about 3 years to their life expectancy, and men add more 
than 2 years to theirs. Smoking cessation can increase life

than 2 years to theirs. Smoking cessation can increase life 
expectancy even for those who stop after the age of 65.
Although tobacco use constitutes the most serious 
common medical problem, it is undertreated. Almost 40% 
of smokers attempt to quit each year, but only 4% are suc
-
cessful. Persons whose clinicians advise them to quit are 
1.6 times as likely to attempt quitting. Over 70% of smokers 
see a physician each year, but only 20% of them receive any 
medical quitting advice or assistance.
Factors associated with successful cessation include 
having a rule against smoking in the home, being older, 
and having greater education. Several effective interven
-
tions are available to promote smoking cessation, including 
counseling, pharmacotherapy, and combinations of the 
two. The five steps for helping smokers quit are summa
-
rized in Table 1–4.
Common elements of supportive smoking cessation 
treatments are reviewed in Table 1–5. A system should be 
implemented to identify smokers, and advice to quit should 
be tailored to the patient’s level of readiness to change. All 
patients trying to quit should be offered pharmacotherapy 
except those with medical contraindications, women who 
are pregnant or breast-feeding, and adolescents. Weight 
gain occurs in most patients (80%) following smoking ces
-
sation. Average weight gain is 2 kg, but for some (10–15%), 
major weight gain—over 13 kg—may occur. Planning for 
the possibility of weight gain, and means of mitigating it, 
may help with maintenance of cessation.
Several pharmacologic therapies have been shown to 
be effective in promoting cessation. Nicotine replacement 
therapy doubles the chance of successful quitting. The 
nicotine patch, gum, and lozenges are available over the 
counter and nicotine nasal spray and inhalers by prescrip
-
tion. The sustained-release antidepressant drug bupro
-
pion (150–300 mg/day orally) is an effective smoking 
cessation agent and is associated with minimal weight 
gain, although seizures are a contraindication. It acts by 
boosting brain levels of dopamine and norepinephrine, 
mimicking the effect of nicotine. More recently, vareni
-
cline, a partial nicotinic acetylcholine-receptor agonist, 
has been shown to improve cessation rates; however, its 
adverse effects, particularly its effects on mood, are not 
completely understood and warrant careful consideration. 
No single pharmacotherapy is clearly more effective than 
others, so patient preferences and data on adverse effects 
should be taken into account in selecting a treatment. 
Combination therapy is more effective than a single phar
-
macologic modality. The efficacy of e-cigarettes in smok
-
ing cessation has not been well evaluated, and some users 
may find them addictive.
CMDT19_Ch01_p0001-p0019.indd   7

C
HAPTER
 1
8
 CMDT 2019
Table 1–4.
 
Actions and strategies for the primary care clinician to help patients quit smoking.
Action
Strategies for Implementation
Step 1. Ask—Systematically Identify All Tobacco Users at Every Visit
Implement an officewide system that ensures 
 
that for 
every
 patient at 
every
 clinic visit, 
tobacco-use status is queried and 
 
documented
1
Expand the vital signs to include tobacco use.
Data should be collected by the health care team.
The action should be implemented using preprinted progress note paper that includes 
the expanded vital signs, a vital signs stamp or, for computerized records, an item 
assessing tobacco-use status.
Alternatives to the vital signs stamp are to place tobacco-use status stickers on all 
patients’ charts or to indicate smoking status using computerized reminder systems.
Step 2. Advise—Strongly Urge All Smokers to Quit
In a clear, strong, and personalized 
 
manner, urge every smoker to quit
Advice should be
Clear
: “I think it is important for you to quit smoking now, and I will help you. Cutting 
down while you are ill is not enough. ”
Strong:
 “As your clinician, I need you to know that quitting smoking is the most impor
-
tant thing you can do to protect your current and future health. ”
Personalized:
 Tie smoking to current health or illness and/or the social and economic 
costs of tobacco use, motivational level/readiness to quit, and the impact of smoking 
on children and others in the household.
Encourage clinic staff to reinforce the cessation message and support the patient’s quit 
attempt.
Step 3. Attempt—Identify Smokers Willing to Make a Quit Attempt
Ask every smoker if he or she is willing to make a 
quit attempt at this time
If the patient is willing to make a quit attempt at this time, provide assistance 
 
(see step 4).
If the patient prefers a more intensive treatment or the clinician believes more 
intensive treatment is appropriate, refer the patient to interventions adminis
-
tered by a smoking cessation specialist and follow up with him or her regarding 
quitting (see step 5).
If the patient clearly states he or she is not willing to make a quit attempt at this time, 
provide a motivational intervention.
Step 4. Assist—Aid the Patient in Quitting
A. Help the patient with a quit plan
Set a quit date.
 Ideally, the quit date should be within 2 weeks, taking patient prefer
-
ence into account.
Help the patient prepare for quitting.
 The patient must:
Inform
 family, friends, and coworkers of quitting and request understanding and 
support.
Prepare the environment
 by removing cigarettes from it. Prior to quitting, the patient 
should avoid smoking in places where he or she spends a lot of time (eg, home, car).
Review
 previous quit attempts. What helped? What led to relapse?
Anticipate
 challenges to the planned quit attempt, particularly during the critical first 
few weeks.
B. Encourage nicotine replacement therapy except 
in special circumstances
Encourage the use of the nicotine patch or nicotine gum therapy for smoking cessation.
C. Give key advice on successful quitting
Abstinence:
 Total abstinence is essential. Not even a single puff after the quit date.
Alcohol:
 Drinking alcohol is highly associated with relapse. Those who stop smoking 
should review their alcohol use and consider limiting or abstaining from alcohol use 
during the quit process.
Other smokers in the household:
 The presence of other smokers in the household, 
particularly a spouse, is associated with lower success rates. Patients should consider 
quitting with their significant others and/or developing specific plans to maintain 
abstinence in a household where others still smoke.
D. Provide supplementary materials
Source:
 Federal agencies, including the National Cancer Institute and the Agency for 
Health Care Policy and Research; nonprofit agencies (American Cancer Society, 
 
American Lung Association, American Heart Association); or local or state health

American Lung Association, American Heart Association); or local or state health 
departments.
Selection concerns:
 The material must be culturally, racially, educationally, and age 
appropriate for the patient.
Location:
 Readily available in every clinic office.
(
continued
)
CMDT19_Ch01_p0001-p0019.indd   8

9
 
CMDT 2019
Table 1–4.
 
Action
Step 5. Arrange—Schedule Follow-Up Contact
Schedule follow-up contact, either in person 
 
or via telephone
Timing:
 Follow-up contact should occur soon after the quit date, preferably during the 
first week. A second follow-up contact is recommended within the first month. 
Schedule further follow-up contacts as indicated.
Actions during follow-up:
 Congratulate success. If smoking occurred, review the cir
-
cumstances and elicit recommitment to total abstinence. Remind the patient that a 
lapse can be used as a learning experience and is not a sign of failure. Identify the 
problems already encountered and anticipate challenges in the immediate future. 
Assess nicotine replacement therapy use and problems. Consider referral to a more 
intense or specialized program.
1
Repeated assessment is not necessary in the case of the adult who has never smoked or not smoked for many years and for whom the 
information is clearly documented in the medical record.
Adapted and reproduced, with permission, from The Agency for Health Care Policy and Research. Smoking Cessation Clinical Practice 
Guideline. JAMA. 1996 Apr 24;275(16):1270–80. Copyright © 1996 American Medical Association. All rights reserved.
Individualized or group counseling is very cost effec
-
tive, even more so than in treating hypertension. Smoking 
cessation counseling by telephone (“quitlines”) and text 
messaging–based interventions have both proved effective. 
An additional strategy is to recommend that any smoking 
take place outdoors to limit the effects of passive smoke on 
housemates and coworkers. This can lead to smoking 
reduction and quitting.
The clinician’s role in smoking cessation is summarized 
in Tables 1–4 and 1–5. Public policies, including higher 
cigarette taxes and more restrictive public smoking laws, 
have also been shown to encourage cessation, as have 
financial incentives directed to patients.
GBD 2015 Risk Factors Collaborators. Global, regional, and 
national comparative risk assessment of 79 behavioural, envi
-
ronmental and occupational, and metabolic risks or clusters of 
risks, 1990–2015: a systematic analysis for the Global Burden of 
Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1659–724. 
[PMID: 27733284]
Goodchild M et al. Global economic cost of smoking-
 
attributable diseases. Tob Control. 2018 Jan;27(1):58–64. 
[PMID: 28138063]
Jamal A et al. Current cigarette smoking among adults—United 
States, 2005–2015. MMWR Morb Mortal Wkly Rep. 2016 
Nov 11;65(44):1205–11. [PMID: 27832052]
Martín Cantera C et al. Effectiveness of multicomponent inter
-
ventions in primary healthcare settings to promote continu
-
ous smoking cessation in adults: a systematic review. BMJ 
Open. 2015 Oct 1;5(10):e008807. [PMID: 26428333]
Mons U et al. Impact of smoking and smoking cessation on 
cardiovascular events and mortality among older adults: 
meta-analysis of individual participant data from prospective 
cohort studies of the CHANCES Consortium. BMJ. 2015 
Apr 20;350:h1551. [PMID: 25896935]
Rahman MA et al. E-cigarettes and smoking cessation: evidence 
from a systematic review and meta-analysis. PLoS One. 2015 
Mar 30;10(3):e0122544. [PMID: 25822251]
Rostron BL et al. Estimation of cigarette smoking-attributable 
morbidity in the United States. JAMA Intern Med. 2014 Dec;
 
174(12):1922–8. [PMID: 25317719]
Stead LF et al. Combined pharmacotherapy and behavioural 
interventions for smoking cessation. Cochrane Database Syst 
Rev. 2016 Mar 24;3:CD008286. [PMID: 27009521]
Table 1–5.
 
Common elements of supportive smoking 
Component
Examples
Encouragement of 
the patient in the 
quit attempt
Note that effective cessation treatments 
are now available.
Note that half the people who have 
ever
 
smoked have now quit.

Component
Examples
ever
 
Communicate belief in the patient’s ability 
to quit.
Communication of 
caring and 
concern
Ask how the patient feels about quitting.
Directly express concern and a willingness 
to help.
Be open to the patient’s expression of fears 
of quitting, difficulties experienced, and 
ambivalent feelings.
the patient to talk 
about the quitting 
process
Ask about:
 
Reasons tha
t the patient wants to quit.
 
Difficulties 
encountered while quitting.
 
Suc
cess the patient has achieved.
 
C
oncerns or worries about quitting.
Provision of basic 
information about 
smoking and 
 
successful quitting
Inform the patient about:
 
T
he nature and time course of 
withdrawal.
 
T
he addictive nature of smoking.
 
T
he fact that any smoking (even a single 
puff) increases the likelihood of full 
relapse.
Adapted, with permission, from The Agency for Health Care Policy 
and Research. Smoking Cessation Clinical Practice Guideline. 
JAMA. 1996 Apr 24;275(16):1270–80. Copyright © 1996 American 
Medical Association. All rights reserved.
Clinicians should not show disapproval of patients who 
failed to stop smoking or who are not ready to make a quit 
attempt. Thoughtful advice that emphasizes the benefits of 
cessation and recognizes common barriers to success can 
increase motivation to quit and quit rates. An intercurrent 
illness or hospitalization may motivate even the most 
addicted smoker to quit.
 
(continued)
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»
Lipid Disorders (see Chapter 28)
Higher low-density lipoprotein (LDL) cholesterol concen
-
trations and lower high-density lipoprotein (HDL) levels 
are associated with an increased risk of CHD. Measurement 
of total and high-density lipoprotein cholesterol levels can 
help assess the degree of CHD risk. The best age to start 
screening is controversial, as is its frequency. Cholesterol-
lowering therapy reduces the relative risk of CHD events, 
with the degree of reduction proportional to the reduction 
in LDL cholesterol achieved. The absolute benefits of 
screening for—and treating—abnormal lipid levels depend 
on the presence and level of other cardiovascular risk fac
-
tors, including hypertension, diabetes mellitus, smoking, 
age, and sex. If other risk factors are present, atherosclerotic 
cardiovascular disease risk is higher and the potential ben
-
efits of therapy are greater. Patients with known cardiovas
-
cular disease are at higher risk and have larger benefits 
from reduction in LDL cholesterol. The optimal risk 
threshold for initiating statins for primary prevention 
remains somewhat controversial, although most guidelines 
now suggest statin therapy when the 10-year atherosclerotic 
cardiovascular risk is greater than 10%.
Evidence for the effectiveness of statin-type drugs is 
better than for the other classes of lipid-lowering agents or 
dietary changes specifically for improving lipid levels. Mul
-
tiple large, randomized, placebo-controlled trials have 
demonstrated important reductions in total mortality, 
major coronary events, and strokes with lowering levels of 
LDL cholesterol by statin therapy for patients with known 
cardiovascular disease. Statins also reduce cardiovascular 
events for patients with diabetes mellitus. For patients with 
no previous history of cardiovascular events or diabetes, 
meta-analyses have shown important reductions of cardio
-
vascular events.
New antilipidemic monoclonal antibody agents (eg, 
evolocumab and alirocumab) lower LDL cholesterol by 
50–60% by binding proprotein convertase subtilisin 
kexin type 9 (PCSK9), which decreases the degradation 
of LDL receptors. PCSK9 inhibitors also decrease Lp(a) 
levels. These new agents are very expensive so are often 
used mainly when statin therapy does not reduce the 
LDL cholesterol sufficiently at maximally tolerated doses 
or when patients are intolerant of statins. So far, few side 
effects have been reported with PCSK9 inhibitor use. To 
date, there has been only one large placebo-controlled 
trial of alirocumab as add-on therapy to maximal statin 
doses.
Guidelines for statin and PCSK9 therapy are discussed 
in Chapter 28.
Cholesterol Treatment Trialists’ (CTT) Collaboration; Fulcher J 
et al. Efficacy and safety of LDL-lowering therapy among men 
and women: meta-analysis of individual data from 174,000 
participants in 27 randomised trials. Lancet. 2015 Apr 11;
 
385(9976):1397–405. [PMID: 25579834]
Pagidipati NJ et al. Comparison of recommended eligibility 
for primary prevention statin therapy based on the U.S. Preven
-
tive Services Task Force Recommendations vs the ACC/AHA 
Guidelines. JAMA. 2017 Apr 18;317(15):1563–7. [PMID: 
28418481]
U.S. Preventive Services Task Force. Statin use for the primary 
prevention of cardiovascular disease in adults: U.S. Preventive 
Services Task Force Recommendation Statement. JAMA. 
2016 Nov 15;316(19):1997–2007. [PMID: 27838723]
 
»
Hypertension (see Chapter 11)
Over 67 million adults in the United States have hyperten
-
sion, representing 29% of the adult US population. Hyper
-
tension in nearly half of these adults is not controlled (ie, 
less than 140/90 mm Hg). Among those whose hyperten
-
sion is not well controlled, nearly 40% are not aware of 
their elevated blood pressure; almost 16% are aware but not 
being treated; and 45% are being treated but the hyperten
-
sion is not controlled. In every adult age group, higher

-
sion is not controlled. In every adult age group, higher 
values of systolic and diastolic blood pressure carry greater 
risks of stroke and heart failure. Systolic blood pressure is a 
better predictor of morbid events than diastolic blood pres
-
sure. Home monitoring is better correlated with target 
organ damage than clinic-based values. Clinicians can 
apply specific blood pressure criteria, such as those of the 
Joint National Committee or American Heart Association 
guidelines, along with consideration of the patient’s cardio
-
vascular risk and personal values, to decide at what levels 
treatment should be considered in individual cases. One 
trial suggests additional benefit from more intensive blood 
pressure control (goal systolic blood pressure of 120 mm Hg) 
in patients at higher risk; however, another found no ben
-
efit from more aggressive treatment in patients at interme
-
diate risk.
Primary prevention of hypertension can be accom
-
plished by strategies aimed at both the general population 
and special high-risk populations. The latter include per
-
sons with high-normal blood pressure or a family history of 
hypertension, blacks, and individuals with various behav
-
ioral risk factors, such as physical inactivity; excessive con
-
sumption of salt, alcohol, or calories; and deficient intake of 
potassium. Effective interventions for primary prevention 
of hypertension include reduced sodium and alcohol con
-
sumption, weight loss, and regular exercise. Potassium 
supplementation lowers blood pressure modestly, and a diet 
high in fresh fruits and vegetables and low in fat, red meats, 
and sugar-containing beverages also reduces blood pres
-
sure. Interventions of unproven efficacy include pill supple
-
mentation of potassium, calcium, magnesium, fish oil, or 
fiber; macronutrient alteration; and stress management.
Improved identification and treatment of hypertension 
is a major cause of the recent decline in stroke deaths as 
well as the reduction in incidence of heart failure–related 
hospitalizations. Because hypertension is usually asymp
-
tomatic, screening is strongly recommended to identify 
patients for treatment. Elevated office readings should be 
confirmed with repeated measurements, ideally from 
ambulatory monitoring or home measurements. Despite 
strong recommendations in favor of screening and treat
-
ment, hypertension control remains suboptimal. An inter
-
vention that included both patient and provider education 
was more effective than provider education alone in 
achieving control of hypertension, suggesting the benefits 
of patient participation; another trial found that home 
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monitoring combined with telephone-based nurse support 
was more effective than home monitoring alone for blood 
pressure control. Pharmacologic management of hyperten
-
sion is discussed in Chapter 11.
Ettehad D et al. Blood pressure lowering for prevention of car
-
diovascular disease and death: a systematic review and meta-
analysis. Lancet. 2016 Mar 5;387(10022):957–67. [PMID: 
26724178]
James PA et al. 2014 evidence-based guideline for the manage
-
ment of high blood pressure in adults: report from the panel 
members appointed to the Eighth Joint National Committee 
(JNC 8). JAMA. 2014 Feb 5;311(5):507–20. Erratum in: 
JAMA. 2014 May 7;311(17):1809. [PMID: 24352797]
Lonn EM et al; HOPE-3 Investigators. Blood-pressure lowering 
in intermediate-risk persons without cardiovascular disease. 
N Engl J Med. 2016 May 26;374(21):2009–20. [PMID: 
27041480]
Piper MA et al. Diagnostic and predictive accuracy of blood 
pressure screening methods with consideration of rescreen
-
ing intervals: a systematic review for the U.S. Preventive Ser
-
vices Task Force. Ann Intern Med. 2015 Feb 3;162(3):192–204. 
[PMID: 25531400]
SPRINT Research Group; Wright JT Jr et al. A randomized trial 
of intensive versus standard blood-pressure control. N Engl J 
Med. 2015 Nov 26;373(22):2103–16. [PMID: 26551272]
Weiss J et al. Benefits and harms of intensive blood pressure 
treatment in adults aged 60 years or older: a systematic review 
and meta-analysis. Ann Intern Med. 2017 Mar 21;166(6):
 
419–29. [PMID: 28114673]
Whelton PK et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/
ASH/ASPC/NMA/PCNA guideline for the prevention, detec
-
tion, evaluation, and management of high blood pressure in 
adults: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice 
Guidelines. Hypertension. 2017 Nov 13. [Epub ahead of 
print] [PMID: 29133356]
Y oon SS et al. Trends in blood pressure among adults with 
hypertension: United States, 2003 to 2012. Hypertension. 
2015 Jan;65(1):54–61. [PMID: 25399687]
 
»
Chemoprevention
Regular use of low-dose aspirin (81–325 mg) can reduce 
cardiovascular events but increases gastrointestinal bleed
-
ing. Aspirin may also reduce the risk of death from several 
common types of cancer (colorectal, esophageal, gastric, 
breast, prostate, and possibly lung). The potential benefits 
of aspirin appear to exceed the harms for those at increased 
cardiovascular risk, which can be defined as a 10-year risk 
of greater than 10%.
Results from a meta-analysis suggest that aspirin could 
also reduce the risk of death from several common types of 
cancer (colorectal, esophageal, gastric, breast, prostate, and 
possibly lung). Nonsteroidal anti-inflammatory drugs may 
reduce the incidence of colorectal adenomas and polyps 
but may also increase heart disease and gastrointestinal 
bleeding, and thus are not recommended for colon cancer 
prevention in average-risk patients.
Antioxidant vitamin (vitamin E, vitamin C, and beta-
carotene) supplementation produced no significant reduc
-
tions in the 5-year incidence of—or mortality 
from—vascular disease, cancer, or other major outcomes 
in high-risk individuals with coronary artery disease, other 
occlusive arterial disease, or diabetes mellitus.
Dehmer SP et al. Aspirin for the primary prevention of cardio
-
vascular disease and colorectal cancer: a decision analysis for 
the U.S. Preventive Services Task Force. Ann Intern Med. 
2016 Jun 21;164(12):777–86. [PMID: 27064573]
Guirguis-Blake JM et al. Aspirin for the primary prevention of 
cardiovascular events: a systematic evidence review for the 
U.S. Preventive Services Task Force [Internet]. 2015 Sep. 
Rockville, MD: Agency for Healthcare Research and Quality; 
2015 Sep. http://www.ncbi.nlm.nih.gov/books/NBK321623/ 
[PMID: 26491760]
Moyer V A et al. Vitamin, mineral, and multivitamin supple
-
ments for the primary prevention of cardiovascular disease

-
ments for the primary prevention of cardiovascular disease 
and cancer: U.S. Preventive Services Task Force recommenda
-
tion statement. Ann Intern Med. 2014 Apr 15;160(8):558–64. 
[PMID: 24566474]
PREVENTION OF OSTEOPOROSIS
See Chapter 26.
Osteoporosis, characterized by low bone mineral den
-
sity, is common and associated with an increased risk of 
fracture. The lifetime risk of an osteoporotic fracture is 
approximately 50% for women and 30% for men. Osteopo
-
rotic fractures can cause significant pain and disability. As 
such, research has focused on means of preventing osteo
-
porosis and related fractures. Primary prevention strategies 
include calcium supplementation, vitamin D supplementa
-
tion, and exercise programs. The effectiveness of calcium 
and vitamin D for fracture prevention remain controver
-
sial, particularly in noninstitutionalized individuals.
Screening for osteoporosis on the basis of low bone 
mineral density is recommended for women over age 65, 
based on indirect evidence that screening can identify 
women with low bone mineral density and that treatment 
of women with low bone density with bisphosphonates is 
effective in reducing fractures. However, real-world adher
-
ence to pharmacologic therapy for osteoporosis is low: 
one-third to one-half of patients do not take their medica
-
tion as directed. The effectiveness of screening for osteopo
-
rosis in younger women and in men has not been 
established. Concern has been raised that bisphosphonates 
may increase the risk of certain uncommon atypical types 
of femoral fractures and rare osteonecrosis of the jaw, mak
-
ing consideration of the benefits and risks of therapy 
important when considering osteoporosis screening.
Black DM et al. Clinical Practice. Postmenopausal osteoporosis. 
N Engl J Med. 2016 Jan 21;374(3):254–62. [PMID: 26789873]
Golob AL et al. Osteoporosis: screening, prevention, and man
-
agement. Med Clin North Am. 2015 May;99(3):587–606. 
[PMID: 25841602]
PREVENTION OF PHYSICAL INACTIVITY
Lack of sufficient physical activity is the second most 
important contributor to preventable deaths, trailing only 
tobacco use. A sedentary lifestyle has been linked to 28% of 
deaths from leading chronic diseases. Sedentary behavior 
and physical inactivity have also been linked to decreases 
in midlife cognition. Worldwide, approximately 30% of 
adults are physically inactive. Inactivity rates are higher in 
women, in those from high-income countries (such as the 
Americas), and in aged individuals. Alarmingly, among 
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teens aged 13–15, 80% report doing fewer than 60 minutes 
of physical activity of moderate to vigorous intensity per 
day; boys are more active than girls.
The US Department of Health and Human Services and 
the CDC recommend that adults (including older adults) 
engage in 150 minutes of moderate-intensity (such as brisk 
walking) or 75 minutes of vigorous-intensity (such as jog
-
ging or running) aerobic activity or an equivalent mix of 
moderate- and vigorous-intensity aerobic activity each 
week. In addition to activity recommendations, the CDC 
recommends activities to strengthen all major muscle 
groups (abdomen, arms, back, chest, hips, legs, and shoul
-
ders) at least twice a week.
Patients who engage in regular moderate to vigorous 
exercise have a lower risk of myocardial infarction, stroke, 
hypertension, hyperlipidemia, type 2 diabetes mellitus, 
diverticular disease, and osteoporosis. Evidence supports 
the recommended guidelines of 30 minutes of moderate 
physical activity on most days of the week in both the pri
-
mary and secondary prevention of CHD.
In longitudinal cohort studies, individuals who report 
higher levels of leisure-time physical activity are less likely to 
gain weight. Conversely, individuals who are overweight are 
less likely to stay active. However, at least 60 minutes of daily 
moderate-intensity physical activity may be necessary to 
maximize weight loss and prevent significant weight regain. 
Moreover, adequate levels of physical activity appear to be 
important for the prevention of weight gain and the develop
-
ment of obesity. Physical activity also appears to have an 
independent effect on health-related outcomes, such as devel
-
opment of type 2 diabetes mellitus in patients with impaired 
glucose tolerance when compared with body weight, suggest
-
ing that adequate levels of activity may counteract the nega
-
tive influence of body weight on health outcomes.
Physical activity can be incorporated into any person’s 
daily routine. For example, the clinician can advise a 
patient to take the stairs instead of the elevator, to walk or 
bike instead of driving, to do housework or yard work, to 
get off the bus one or two stops earlier and walk the rest of 
the way, to park at the far end of the parking lot, or to walk 
during the lunch hour. The basic message should be the 
more the better, and anything is better than nothing.
To be more effective in counseling about exercise, clini
-
cians can also incorporate motivational interviewing tech
-
niques, adopt a whole-practice approach (eg, use practice 
nurses to assist), and establish linkages with community 
agencies. Clinicians can incorporate the “5 As” approach:
1.
 
Ask (identify those who can benefit).
2.
 
Assess (current activity level).
3.
 
Advise (individualize plan).
4.
 
Assist (provide a written exercise prescription and sup
-
port material).
5.
 
Arrange (appropriate referral and follow-up).
Such interventions have a moderate effect on self-
reported physical activity and cardiorespiratory fitness, 
even if they do not always help patients achieve a predeter
-
mined level of physical activity. In their counseling, clini
-
cians should advise patients about both the benefits and 
risks of exercise, prescribe an exercise program appropriate 
for each patient, and provide advice to help prevent injuries 
and cardiovascular complications.
Although primary care providers regularly ask patients 
about physical activity and advise them with verbal coun
-
seling, few providers provide written prescriptions or per
-
form fitness assessments. Tailored interventions may 
potentially help increase physical activity in individuals. 
Exercise counseling with a prescription, eg, for walking at 
either a hard intensity or a moderate intensity with a high 
frequency, can produce significant long-term improve
-
ments in cardiorespiratory fitness. To be effective, exercise

-
ments in cardiorespiratory fitness. To be effective, exercise 
prescriptions must include recommendations on type, fre
-
quency, intensity, time, and progression of exercise and 
must follow disease-specific guidelines. Several factors 
influence physical activity behavior, including personal, 
social (eg, family and work), and environmental (eg, access 
to exercise facilities and well-lit parks). Walkable neighbor
-
hoods around workplaces support physical activity such as 
walking and bicycling. A community-based volunteer 
intervention resulted in increased walking activity among 
older women, who were at elevated risk for both inactivity 
and adverse health outcomes.
Broad-based interventions targeting various factors are 
often the most successful, and interventions to promote 
physical activity are more effective when health agencies 
work with community partners, such as schools, businesses, 
and health care organizations. Enhanced community 
awareness through mass media campaigns, school-based 
strategies, and policy approaches are proven strategies to 
increase physical activity.
Adlakha D et al. Home and workplace built environment 
supports for physical activity. Am J Prev Med. 2015 Jan;
 
48(1):104–7. [PMID: 25442233]
Bouchard C et al. Less sitting, more physical activity, or higher 
fitness? Mayo Clin Proc. 2015 Nov;90(11):1533–40. [PMID: 
26422244]
Centers for Disease Control and Prevention (CDC). How much 
physical activity do adults need? 2015 Jun 4. http://www.cdc.
gov/physicalactivity/basics/adults/index.htm
Hoang TD et al. Effect of early adult patterns of physical activity 
and television viewing on midlife cognitive function. JAMA 
Psychiatry. 2016 Jan;73(1):73–9. [PMID: 26629780]
Varma VR et al. Effect of community volunteering on physical 
activity: a randomized controlled trial. Am J Prev Med. 
2016 Jan;50(1):106–10. [PMID: 26340864]
PREVENTION OF OVERWEIGHT & OBESITY
Obesity is now a true epidemic and public health crisis that 
both clinicians and patients must face. Normal body 
weight is defined as a body mass index (BMI), calculated as 
the weight in kilograms divided by the height in meters 
squared, of less than 25; overweight is defined as a BMI = 
25.0–29.9, and obesity as a BMI greater than 30. Between 
1980 and 2013, there was an 8% increase worldwide in the 
proportion of men and women with a BMI greater than 25. 
The most recent national data reveal that one-third of 
adults in the United States are obese, and prevalence rates 
are higher in blacks and Hispanics compared to 
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non-Hispanic whites. This trend has been linked both to 
declines in physical activity and to increased caloric intake.
Risk assessment of the overweight and obese patient 
begins with determination of BMI, waist circumference for 
those with a BMI of 35 or less, presence of comorbid condi
-
tions, and a fasting blood glucose and lipid panel. Obesity 
is clearly associated with type 2 diabetes mellitus, hyper
-
tension, hyperlipidemia, cancer, osteoarthritis, cardiovas
-
cular disease, obstructive sleep apnea, and asthma. In 
addition, almost one-quarter of the US population cur
-
rently has the metabolic syndrome.
Metabolic syndrome is defined as the presence of any 
three of the following: waist measurement of 40 inches or 
more for men and 35 inches or more for women, triglycer
-
ide levels of 150 mg/dL (1.70 mmol/L) or above, HDL 
cholesterol level less than 40 mg/dL (less than 1.44 mmol/L) 
for men and less than 50 mg/dL (less than 1.80 mmol/L) 
for women, blood pressure of 130/85 mm Hg or above, and 
fasting blood glucose levels of 100 mg/dL (5.55 mmol/L) or 
above. The relationship between overweight and obesity 
and diabetes, hypertension, and coronary artery disease is 
thought to be due to insulin resistance and compensatory 
hyperinsulinemia.
Obesity is associated with a higher all-cause mortality 
rate. Data suggest an increase among those with grades 2 
and 3 obesity (BMI more than 35); however, the impact on 
all-cause mortality among overweight (BMI 25–30) and 
grade 1 obesity (BMI 30–35) is questionable. Persons with 
a BMI 40 or higher have death rates from cancers that are 
52% higher for men and 62% higher for women than the 
rates in men and women of normal weight. Significant 
trends of increasing risk of death with higher BMIs are 
observed for cancers of the stomach and prostate in men 
and for cancers of the breast, uterus, cervix, and ovary in 
women, and for cancers of the esophagus, colon and rec
-
tum, liver, gallbladder, pancreas, and kidney, non-Hodgkin 
lymphoma, and plasma cell myeloma (previously called 
multiple myeloma) in both men and women.
In the Framingham Heart Study, overweight and obe
-
sity were associated with large decreases in life expectancy. 
For example, 40-year-old female nonsmokers lost 3.3 years 
and 40-year-old male nonsmokers lost 3.1 years of life 
expectancy because of overweight, and 7.1 years and 5.8 years 
of life expectancy, respectively, because of obesity. Obese 
female smokers lost 7.2 years and obese male smokers lost 
6.7 years of life expectancy compared with normal-weight 
smokers, and 13.3 years and 13.7 years, respectively, com
-
pared with normal-weight nonsmokers.
Prevention of overweight and obesity involves both 
increasing physical activity and dietary modification to 
reduce caloric intake. Adequate levels of physical activity 
appear to be important for the prevention of weight gain 
and the development of obesity. Physical activity programs 
consistent with public health recommendations may pro
-
mote modest weight loss (~2 kg); however, the amount of 
weight loss for any one individual is highly variable. Only 
49% of Americans are physically active at a moderate level 
and 20% at a more vigorous level. In addition, only 3% of 
Americans meet four of the five USDA recommendations 
for the intake of grains, fruits, vegetables, dairy products, 
and meat. Only one of four Americans eats the recom
-
mended five or more fruits and vegetables per day.
Clinicians can help guide patients to develop personal
-
ized eating plans to reduce energy intake, particularly by 
recognizing the contributions of fat, concentrated carbohy
-
drates, and large portion sizes (see Chapter 29). Patients 
typically underestimate caloric content, especially when 
consuming food away from home. Providing patients with 
caloric and nutritional information may help address the

caloric and nutritional information may help address the 
current obesity epidemic. To prevent the long-term chronic 
disease sequelae of overweight and obesity, clinicians must 
work with patients to modify other risk factors, eg, by 
smoking cessation (see above) and strict blood pressure 
and glycemic control (see Chapters 11 and 27).
Lifestyle modification, including diet, physical activity, 
and behavior therapy, has been shown to induce clinically 
significant weight loss. Other treatment options for obesity 
include pharmacotherapy and surgery (see Chapter 29). In 
overweight and obese persons, at least 60 minutes of mod
-
erate- to high-intensity physical activity per day may be 
necessary to maximize weight loss and prevent significant 
weight regain. Counseling interventions or pharmacother
-
apy can produce modest (3–5 kg) sustained weight loss 
over 6–12 months. Counseling appears to be most effective 
when intensive and combined with behavioral therapy. 
Pharmacotherapy appears safe in the short term; long-term 
safety is still not established. Lorcaserin, a selective 
5-hydroxytryptamine 2C (5-HT
2C
) agonist, has been 
shown to reduce body weight through a reduction of 
energy intake without influencing energy expenditure. It 
was approved by the FDA for adults with a BMI 30 or 
higher or adults with a BMI 27 or higher who have at least 
one obesity-related condition, such as hypertension, type 2 
diabetes mellitus, or hypercholesterolemia.
Commercial weight loss programs are effective in pro
-
moting weight loss and weight loss management. A ran
-
domized controlled trial of over 400 overweight or obese 
women demonstrated the effectiveness of a free prepared 
meal and incentivized structured weight loss program 
compared with usual care.
Weight loss strategies using dietary, physical activity, or 
behavioral interventions can produce significant improve
-
ments in weight among persons with prediabetes and a 
significant decrease in diabetes incidence. Lifestyle inter
-
ventions including diet combined with physical activity are 
effective in achieving weight loss and reducing cardiometa
-
bolic risk factors among patients with severe obesity.
Bariatric surgical procedures, eg, adjustable gastric band, 
sleeve gastrectomy, and Roux-en-Y gastric bypass, are 
reserved for patients with morbid obesity whose BMI exceeds 
40, or for less severely obese patients (with BMIs between 35 
and 40) with high-risk comorbid conditions such as life-
threatening cardiopulmonary problems (eg, severe sleep 
apnea, Pickwickian syndrome, and obesity-related cardiomy
-
opathy) or severe diabetes mellitus. In selected patients, sur
-
gery can produce substantial weight loss (10 to 159 kg) over 
1 to 5 years, with rare but sometimes severe complications. 
Nutritional deficiencies are one complication of bariatric 
surgical procedures and close monitoring of a patient’s meta
-
bolic and nutritional status is essential.
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Finally, clinicians seem to share a general perception 
that almost no one succeeds in long-term maintenance of 
weight loss. However, research demonstrates that approxi
-
mately 20% of overweight individuals are successful at 
long-term weight loss (defined as losing 10% or more of 
initial body weight and maintaining the loss for 1 year or 
longer). National Weight Control Registry members who 
lost an average of 33 kg and maintained the loss for more 
than 5 years have provided useful information about how 
to maintain weight loss. Members report engaging in high 
levels of physical activity (approximately 60 min/day), eat
-
ing a low-calorie, low-fat diet, eating breakfast regularly, 
self-monitoring weight, and maintaining a consistent eat
-
ing pattern from weekdays to weekends.
Clinicians must work to identify and provide the best 
prevention and treatment strategies for patients who are 
overweight and obese. Clinician advice on weight loss can 
have a significant impact on patient attempts to adjust 
weight-related behaviors. Unfortunately, many clinicians 
are poorly prepared to address obesity. Clinician bias and 
lack of training in behavior-change strategies impair the 
care of obese patients. Strategies to address these issues 
should be incorporated into innovative treatment and care-
delivery strategies.
Dietz WH et al. Management of obesity: improvement of health-
care training and systems for prevention and care. Lancet. 
2015 Jun 20;385(9986):2521–33. [PMID: 25703112]
Evert AB et al. Lifestyle intervention: nutrition therapy and 
physical activity. Med Clin North Am. 2015 Jan;99(1):69–85. 
[PMID: 25456644]
Flegal KM et al. Association of all-cause mortality with over
-
weight and obesity using standard body mass index catego
-
ries: a systematic review and meta-analysis. JAMA. 2013 Jan 2; 
309(1):71–82. [PMID: 23280227]
Guth E. JAMA patient page. Healthy weight loss. JAMA. 
2014 Sep 3;312(9):974. [PMID: 25182116]
Hartmann-Boyce J et al. Self-help for weight loss in overweight 
and obese adults: systematic review and meta-analysis. Am J 
Public Health. 2015 Mar;105(3):e43–57. [PMID: 25602873]
Jin J. JAMA patient page. Obesity and the heart. JAMA. 2013 
Nov 20;310(19):2113. [PMID: 24240948]
Ng M et al. Global, regional, and national prevalence of over
-
weight and obesity in children and adults during 1980–2013: 
a systematic analysis for the Global Burden of Disease Study 
2013. Lancet. 2014 Aug 30;384(9945):766–81. Erratum in: 
Lancet. 2014 Aug 30;384(9945):746. [PMID: 24880830]
Ogden CL et al. Prevalence of childhood and adult obesity in the 
United States, 2011–2012. JAMA. 2014 Feb 26;311(8):806–14. 
[PMID: 24570244]
Rose SA et al. Physician weight loss advice and patient weight 
loss behavior change: a literature review and meta-analysis of 
survey data. Int J Obes (Lond). 2013 Jan;37(1):118–28. 
[PMID: 22450855]
Swift DL et al. The role of exercise and physical activity in weight 
loss and maintenance. Prog Cardiovasc Dis. 2014 Jan–Feb;
 
56(4):441–7. [PMID: 24438736]
CANCER PREVENTION
 
»
Primary Prevention
Cancer mortality rates continue to decrease in the 
United States; part of this decrease results from reduc
-
tions in tobacco use, since cigarette smoking is the most 
important preventable cause of cancer. Primary preven
-
tion of skin cancer consists of restricting exposure to 
ultraviolet light by wearing appropriate clothing and use 
of sunscreens. Persons who engage in regular physical 
exercise and avoid obesity have lower rates of breast and 
colon cancer. Prevention of occupationally induced cancers 
involves minimizing exposure to carcinogenic substances, 
such as asbestos, ionizing radiation, and benzene com
-
pounds. Chemoprevention has been widely studied for 
primary cancer prevention (see above Chemoprevention 
section and Chapter 39). Use of tamoxifen, raloxifene, 
and aromatase inhibitors for breast cancer prevention is

and aromatase inhibitors for breast cancer prevention is 
discussed in Chapters 17 and 39. Hepatitis B vaccination 
can prevent hepatocellular carcinoma (HCC), and screen
-
ing and vaccination programs may be cost effective and 
useful in preventing HCC in high-risk groups, such as 
Asians and Pacific Islanders. The use of HPV vaccine to 
prevent cervical and possibly anal cancer is discussed 
above. In addition to preventing anogenital cancers, 
HPV vaccines may have a role in the prevention of HPV-
related head and neck cancers. Guidelines for optimal 
cancer screening in adults over the age of 75 are unsettled; 
thus, an individualized approach that considers differ
-
ences in disease risk rather than chronological age is 
recommended.
Breslau ES et al. An individualized approach to cancer screening 
decisions in older adults: a multilevel framework. J Gen 
Intern Med. 2016 May;31(5):539–47. [PMID: 26941042]
Smith RA et al. Cancer screening in the United States, 2016: a 
review of current American Cancer Society guidelines and 
current issues in cancer screening. CA Cancer J Clin. 2016 
Mar–Apr;66(2):96–114. [PMID: 26797525]
Wernli KJ et al. Screening for skin cancer in adults: updated 
evidence report and systematic review for the U.S. Preventive 
Services Task Force. JAMA. 2016 Jul 26;316(4):436–47. 
[PMID: 27458949]
 
»
Screening & Early Detection
Screening prevents death from cancers of the breast, colon, 
and cervix. Current cancer screening recommendations 
from the USPSTF are shown in Table 1–6. Despite an 
increase in rates of screening for breast, cervical, and colon 
cancer over the last decade, overall screening for these 
cancers is suboptimal. Interventions effective in promoting 
recommended cancer screening include group education, 
one-on-one education, patient reminders, reduction of 
structural barriers, reduction of out-of-pocket costs, and 
provider assessment and feedback.
Evidence from randomized trials suggests that screen
-
ing mammography has both benefits and downsides. A 
2011 Cochrane review estimated that screening with mam
-
mography led to a reduction in breast cancer mortality of 
15% but resulted in 30% overdiagnosis and overtreatment. 
Currently, the appropriate form and frequency of screening 
for breast cancer remains controversial, and screening 
guidelines vary. Clinicians should discuss the risks and 
benefits with each patient and consider individual patient 
preferences when deciding when to begin screening (see 
Chapters 17 and e6).
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Table 1–6.
 
Cancer screening recommendations for average-risk adults: US Preventive Services Task Force (USPSTF).
1
Test
USPSTF Recommendation/[Year Issued]
Breast self-examination
Recommends against teaching breast self-examination. (D)
[2009]
Clinical breast examination
Insufficient evidence to recommend for or against clinical breast examination. (I)
[2009]
Recommends biennial screening mammography for women aged 50–74 years. (B)
The decision to start screening mammography in women prior to age 50 years should be an individ
-
ual one. Women who place a higher value on the potential benefit than the potential harms may 
choose to begin biennial screening between the ages of 40 and 49 years. (C)
[2016]
Cervical cancer screening
Recommends screening for cervical cancer in women aged 21–65 years with cytology (Pap smear) 
every 3 years or, for women aged 30–65 years who want to lengthen the screening interval, 
screening with a combination of cytology and human papillomavirus (HPV) testing every 5 years. (A)
Recommends against screening for cervical cancer in women younger than 21 years. (D)
Recommends against screening for cervical cancer in women older than 65 years who have had 
 
adequate prior screening and are not otherwise at high risk for cervical cancer. (D)
Recommends against screening for cervical cancer in women who have had a hysterectomy with 
removal of the cervix and who do not have a history of a high-grade precancerous lesion 
 
(ie, cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer. (D)
[2017]
Colorectal cancer (CRC) screening
Recommends screening for CRC starting at age 50 years and continuing until age 75 years. (A)
The decision to screen for CRC in adults aged 76–85 years should be an individual one, taking into 
account the patient’s overall health and prior screening history. (C)
[2016]
 
Char
acteristics of colorectal 
 
canc
er screening strategies
Reviews the following tests: fecal occult blood tests (gFOBT, FIT) every year; FIT-DNA every 1 or 
 
3 years; colonoscopy every 10 years; CT colonography every 5 years; flexible sigmoidoscopy 
 
every 5 years; flexible sigmoidoscopy every 10 years plus FIT every 1 year.
Lung cancer screening
Recommends annual lung cancer screening using low-dose CT in current smokers aged 55–80 years 
with a 30-pack-year smoking history, or in smokers who quit within the past 15 years. (B)
Recommends stopping screening once a person has not smoked for 15 years or a health problem 
that significantly limits life expectancy has developed.
[2013]
Prostate cancer screening
Recommends that clinicians inform men ages 55–69 years about the potential benefits and harms of 
prostate-specific antigen (PSA)–based screening for prostate cancer. (C)
Recommends against prostate specific antigen PSA–based screening for prostate cancer in men age 
70 years and older. (D)
[2017]
Testicular cancer screening
Recommends against screening for testicular cancer in adolescent or adult males.
[2011]
1
United States Preventive Services Task Force recommendations available at http://www.uspreventiveservicestaskforce.org/BrowseRec/
Index/browse-recommendations.
 The USPSTF recommends against routinely providing the service. There may be considerations that support providing 
the service in an individual patient. There is at least moderate certainty that the net benefit is small.

 The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing the service. 
Digital mammography is more sensitive in women 
with dense breasts and younger women; however, studies 
exploring outcomes are lacking. MRI is not currently 
recommended for general screening, and its impact on 
breast cancer mortality is uncertain; nevertheless, the 
American Cancer Society recommends it for women at 
high risk (20–25% or more), including those with a 
strong family history of breast or ovarian cancer. Screen
-
ing with both MRI and mammography might be superior 
to mammography alone in ruling out cancerous lesions 
in women with an inherited predisposition to breast 
cancer.
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All current recommendations call for cervical and 
colorectal cancer screening. Screening for testicular cancers 
among asymptomatic adolescent or adult males is not rec
-
ommended by the USPSTF. Prostate cancer screening 
remains controversial, since no completed trials have 
answered the question of whether early detection and 
treatment after screen detection produce sufficient benefits 
to outweigh harms of treatment. A 2013 Cochrane system
-
atic review revealed that prostate cancer screening with 
PSA testing did not decrease all-cause mortality and may 
not decrease prostate cancer–specific mortality. Any bene
-
fits in terms of reduction in prostate cancer–related mor
-
tality would take more than 10 years to become evident. 
Men with less than 10–15 years’ life expectancy should be 
informed that screening for prostate cancer is unlikely to 
be beneficial. In 2017, the USPSTF recommended against 
PSA-based prostate cancer screening for men older than 
age 70 years (grade D recommendation).
Annual or biennial fecal occult blood testing reduces 
mortality from colorectal cancer by 16–33%. Fecal immu
-
nochemical tests (FIT) are superior to guaiac-based fecal 
occult blood tests (gFOBT) in detecting advanced adeno
-
matous polyps and colorectal cancer, and patients are more 
likely to favor FIT over gFOBT. Randomized trials using 
sigmoidoscopy as the screening method found 20–30% 
reductions in mortality from colorectal cancer. Colonos
-
copy has also been advocated as a screening examination. 
It is more accurate than flexible sigmoidoscopy for detect
-
ing cancer and polyps, but its value in reducing colon 
cancer mortality has not been studied directly. CT colo
-
nography (virtual colonoscopy) is a noninvasive option in 
screening for colorectal cancer. It has been shown to have a 
high safety profile and performance similar to colonos
-
copy. The American College of Physicians (ACP) recom
-
mends clinicians stop screening for colorectal cancer in 
individuals over the age of 75 years or with a life expec
-
tancy of less than 10 years. The USPSTF recommends 
screening for colorectal cancer starting at age 50 years and 
continuing until age 75 years (grade A recommendation) 
but says that the decision to screen for colorectal cancer in 
adults aged 76–85 years should be an individual one, taking 
into account the patient’s overall health and prior screening 
history (grade C recommendation).
The USPSTF recommends screening for cervical cancer 
in women aged 21–65 years with a Papanicolaou smear 
(cytology) every 3 years or, for women aged 30–65 years 
who desire longer intervals, screening with cytology and 
HPV testing every 5 years. The USPSTF recommends 
against screening in women younger than 21 years of age 
and average-risk women over 65 with adequate negative 
prior screenings. Receipt of HPV vaccination has no 
impact on screening intervals.
In 2012, the American Cancer Society, the American 
Society for Colposcopy and Cervical Pathology, and the 
American Society for Clinical Pathology published updated 
guidelines for management of abnormal results. Women 
whose cervical specimen HPV tests are positive but cytol
-
ogy results are otherwise negative should repeat co-testing 
in 12 months (option 1) or undergo HPV-genotype–specific 
testing for types 16 or 16/18 (option 2). Colposcopy is 
recommended in women who test positive for types 16 or 
16/18. Women with atypical squamous cells of undeter
-
mined significance (ASCUS) on cytology and a negative 
HPV test result should continue routine screening as per 
age-specific guidelines.
In a randomized, controlled trial, transvaginal ultra
-
sound combined with serum cancer antigen 125 (CA-125) 
as screening tools to detect ovarian cancer did not reduce 
mortality. Furthermore, complications were associated with 
diagnostic evaluations to follow up false-positive screening 
test results. Thus, screening for ovarian cancer with trans
-

-
vaginal ultrasound and CA-125 is not recommended.
Evidence suggests that chest CT is significantly more 
sensitive than chest radiography in identifying small 
asymptomatic lung cancers; however, controversy exists 
regarding the efficacy and cost-effectiveness of low-dose 
CT screening in high-risk individuals. In the United States, 
the National Lung Screening Trial (NLST), a randomized 
clinical trial of over 53,000 individuals at high risk for lung 
cancer, revealed a 20% relative reduction and 6.7% absolute 
reduction in lung cancer mortality in those who were 
screened with annual low-dose CTs for 3 years compared 
with those who had chest radiographs. There were a 
greater number of false-positive results in the low-dose CT 
group compared with those in the radiography group 
(23.3% vs 6.5%) (see Chapter 39). In Italy, the Multicentric 
Italian Lung Detection (MILD) study, a randomized trial of 
over 4000 participants comparing annual or biennial low-
dose CT with observation revealed no evidence of a protec
-
tive effect with annual or biennial low-dose CT screening.
The USPSTF recommends annual lung cancer screening 
with low-dose CT in current smokers aged 55 to 80 years 
with a 30-pack-year smoking history or smokers who quit 
within the past 15 years. Screening should stop once a per
-
son has not smoked for 15 years or a health problem that 
significantly limits life expectancy has developed. Screening 
should not be viewed as an alternative to smoking 
cessation.
Hayes JH et al. Screening for prostate cancer with the prostate-
specific antigen test: a review of current evidence. JAMA. 
2014 Mar 19;311(11):1143–9. [PMID: 24643604]
Holme Ø et al. Effect of flexible sigmoidoscopy screening on 
colorectal cancer incidence and mortality: a randomized 
clinical trial. JAMA. 2014 Aug 13;312(6):606–15. [PMID: 
25117129]
Jin J. JAMA patient page. Screening tests for colorectal cancer. 
JAMA. 2016 Jun 21;315(23):2636. [PMID: 27305292]
Lieberman D et al. Screening for colorectal cancer and evolving 
issues for physicians and patients: a review. JAMA. 2016 
 
Nov 22;316(20):2135–45. [PMID: 27893135]
Melnikow J et al. Supplemental screening for breast cancer in 
women with dense breasts: a systematic review for the U.S. 
Preventive Services Task Force. Ann Intern Med. 2016 
Feb 16;164(4):268–78. [PMID: 26757021]
Moyer V A; U.S. Preventive Services Task Force. Screening for 
lung cancer: U.S. Preventive Services Task Force recommen
-
dation statement. Ann Intern Med. 2014 Mar 4;160(5):330–8. 
[PMID: 24378917]
Nelson HD et al. Effectiveness of breast cancer screening: sys
-
tematic review and meta-analysis to update the 2009 U.S. 
Preventive Services Task Force Recommendation. Ann Intern 
Med. 2016 Feb 16;164(4):244–55. [PMID: 26756588]
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Soung MC. Screening for cancer: when to stop? A practical 
guide and review of the evidence. Med Clin North Am. 
2015 Mar;99(2):249–62. [PMID: 25700582]
Tanoue LT et al. Lung cancer screening. Am J Respir Crit Care 
Med. 2015 Jan 1;191(1):19–33. [PMID: 25369325]
Wood DE. National Comprehensive Cancer Network (NCCN) 
clinical practice guidelines for lung cancer screening. Thorac 
Surg Clin. 2015 May;25(2):185–97. [PMID: 25901562]
PREVENTION OF INJURIES & VIOLENCE
Injuries remain the most important cause of loss of poten
-
tial years of life before age 65. Homicide and motor vehicle 
accidents are a major cause of injury-related deaths among 
young adults, and accidental falls are the most common 
cause of injury-related death in older adults. Approxi
-
mately one-third of all injury deaths include a diagnosis of 
traumatic brain injury. Other causes of injury-related 
deaths include suicide and accidental exposure to smoke, 
fire, and flames.
Although motor vehicle accident deaths per miles 
driven have declined in the United States, there has been 
an increase in motor vehicle accidents related to distracted 
driving (using a cell phone, texting, eating). Evidence also 
suggests that motorists’ use of sleeping medications (such 
as zolpidem) almost doubles the risk of motor vehicle acci
-
dents. Clinicians should discuss this risk when selecting a 
sleeping medication. For 16- and 17-year-old drivers, the 
risk of fatal crashes increases with the number of 
passengers.
Each year in the United States, more than 500,000 
people are nonfatally injured while riding bicycles. The rate 
of helmet use by bicyclists and motorcyclists is significantly 
increased in states with helmet laws. Y oung men appear 
most likely to resist wearing helmets.
Males aged 16–35 are at especially high risk for serious 
injury and death from accidents and violence, with blacks 
and Latinos at greatest risk. Deaths from firearms have 
reached epidemic levels in the United States. In 2015, a 
total of 13,286 people were killed in the United States in a 
gun homicide, unintentional shooting, or murder/suicide. 
Having a gun in the home increases the likelihood of 
homicide nearly threefold and of suicide fivefold. Educat
-
ing clinicians to recognize and treat depression as well as 
restricting access to lethal methods have been found to 
reduce suicide rates.
In addition, clinicians should try to educate their 
patients about always wearing seat belts and safety helmets, 
about the risks of using cellular telephones or texting while 
driving, of drinking and driving—or of using other intoxi
-
cants (including marijuana) or long-acting benzodiaze
-
pines and then driving—and about the risks of having guns 
in the home.
Clinicians have a critical role in the detection, preven
-
tion, and management of intimate partner violence (see 
Chapter e6.). The USPSTF recommends screening women 
of childbearing age for intimate partner violence and 
providing or referring women to intervention services 
when needed. Inclusion of a single question in the medi
-
cal history—” At any time, has a partner ever hit you, 
kicked you, or otherwise physically hurt you?”—can 
increase identification of this common problem. Assess
-
ment for abuse and offering of referrals to community 
resources create the potential to interrupt and prevent 
recurrence of domestic violence and associated trauma. 
Clinicians should take an active role in following up with 
patients whenever possible, since intimate partner vio
-
lence screening with passive referrals to services may not 
be adequate. Evaluation of services available to patients 
after identification of intimate partner violence should be 
a priority.
Physical and psychological abuse, exploitation, and 
neglect of older adults are serious, underrecognized prob
-
lems; they may occur in up to 10% of elders. Risk factors

-
lems; they may occur in up to 10% of elders. Risk factors 
for elder abuse include a culture of violence in the family; 
a demented, debilitated, or depressed and socially isolated 
victim; and a perpetrator profile of mental illness, alcohol 
or drug abuse, or emotional and/or financial dependence 
on the victim. Clues to elder mistreatment include the 
patient’s ill-kempt appearance, recurrent urgent-care visits, 
missed appointments, suspicious physical findings, and 
implausible explanations for injuries.
Centers for Disease Control and Prevention (CDC). CDC Grand 
Rounds: reducing severe traumatic brain injury in the United 
States. MMWR Morb Mortal Wkly Rep. 2013 Jul 12; 62(27):
 
549–52. [PMID: 23842444]
Dicola D et al. Intimate partner violence. Am Fam Physician. 
2016 Oct 15;94(8):646–51. [PMID: 27929227]
Ellsberg M et al. Prevention of violence against women and girls: 
what does the evidence say? Lancet. 2015 Apr 18;385(9977):
 
1555–66. [PMID: 25467575]
Haegerich TM et al. Prevention of injury and violence in the 
USA. Lancet. 2014 Jul 5;384(9937):64–74. [PMID: 24996591]
Hansen RN et al. Sedative hypnotic medication use and the risk 
of motor vehicle crash. Am J Public Health. 2015 Aug;
 
105(8):e64–9. [PMID: 26066943]
Keall MD et al. Home modifications to reduce injuries from falls 
in the Home Injury Prevention Intervention (HIPI) study: a 
cluster-randomised controlled trial. Lancet. 2015 Jan 17;
 
385(9964):231–8. [PMID: 25255696]
Lachs MS et al. Elder abuse. N Engl J Med. 2015 Nov 12; 
373(20):1947–56. [PMID: 26559573]
Lyons BH et al. Surveillance for violent deaths—National Violent 
Death Reporting System, 17 States, 2013. MMWR Surveill 
Summ. 2016 Aug 19;65(10):1–42. [PMID: 27537325]
Moyer V A. Screening for intimate partner violence and abuse of 
elderly and vulnerable adults: U.S. Preventive Services Task 
Force recommendation statement. Ann Intern Med. 2013 
Mar 19;158(6):478–86. [PMID: 23338828]
National Center for Statistics and Analysis. Distracted Driving: 
2013 Data, in Traffic Safety Research Note. DOT HS 812 132. 
April 2015, National Highway Traffic Safety Administration: 
Washington, D.C. http://www.distraction.gov/downloads/
pdfs/Distracted_Driving_2013_Research_note.pdf
Riley CL et al; Society of Critical Care Medicine. Critical 
violent injury in the United States: a review and call to 
action. Crit Care Med. 2015 Nov;43(11):2460–7. [PMID: 
26327199]
Stowe JD et al. A randomized crash injury prevention trial of 
transitioning high-risk elders from driving. J Trauma Acute 
Care Surg. 2015 Jul;79(1):132–7. [PMID: 26091326]
Sumner SA et al. Violence in the United States: status, challenges, 
and opportunities. JAMA. 2015 Aug 4;314(5):478–88. [PMID: 
26241599]
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PREVENTION OF SUBSTANCE ABUSE: 
ALCOHOL & ILLICIT DRUGS
Substance abuse is a major public health problem in the 
United States, where approximately 51% of adults 18 years 
and older are current regular drinkers (at least 12 drinks in 
the past year). Maximum recommended consumption for 
adult women and those older than 65 years is three or 
fewer drinks per day (seven per week), and for adult men, 
four or fewer drinks per day (14 per week). The spectrum 
of alcohol misuse includes risky drinking (alcohol con
-
sumption above the recommended daily, weekly, or per-
occasion amounts), harmful use (a pattern causing damage 
to health), alcohol abuse (a pattern leading to clinically 
significant impairment or distress), and alcohol depen
-
dence (defined as three or more of the following: tolerance, 
withdrawal, increased consumption, desire to cut down 
use, giving up social activities, increased time using alcohol 
or recovering from use, continued use despite known 
adverse effects). Underdiagnosis and under-treatment of 
alcohol misuse is substantial, both because of patient 
denial and lack of detection of clinical clues. Treatment 
rates for alcohol dependence have slightly declined over 
the last several years. Only a quarter of alcohol-dependent 
patients have ever been treated.
As with cigarette use, clinician identification and coun
-
seling about alcohol misuse is essential. An estimated 
15–30% of hospitalized patients have problems with alco
-
hol abuse or dependence, but the connection between 
patients’ presenting complaints and their alcohol use is 
often missed. The USPSTF recommends screening adults 
aged 18 years and older for alcohol misuse.
The Alcohol Use Disorder Identification Test (AUDIT) 
consists of questions on the quantity and frequency of 
alcohol consumption, on alcohol dependence symptoms, 
and on alcohol-related problems (Table 1–7). The AUDIT 
questionnaire is a cost-effective and efficient diagnostic 
tool for routine screening of alcohol use disorders in 
primary care settings. Brief advice and counseling with
-
out regular follow-up and reinforcement cannot sustain 
significant long-term reductions in unhealthy drinking 
behaviors.
Time restraints may prevent clinicians from using the 
AUDIT to screen patients, but single-question screening 
tests for unhealthy alcohol use may help increase the fre
-
quency of subsequent AUDIT screening in primary care 
settings. The National Institute on Alcohol Abuse and 
Alcoholism recommends the following single-question 
screening test (validated in primary care settings): “How 
many times in the past year have you had X or more drinks 
Table 1–7.
 
Screening for alcohol abuse using the Alcohol Use Disorder Identification Test (AUDIT).
(Scores for response categories are given in parentheses. Scores range from 0 to 40, with a cutoff score of 5 or more indicating 
 
hazardous drinking, harmful drinking, or alcohol dependence.)
 
1.
 
Ho
w often do you have a drink containing alcohol?
(0) Never
(1) Monthly or less
(2) Two to four times a month
(3) Two or three times a week
(4) Four or more times a week
 
2.
 
Ho
w many drinks containing alcohol do you have on a typical day when you are drinking?
(0) 1 or 2
(1) 3 or 4
(2) 5 or 6
(3) 7 to 9
(4) 10 or more
 
3.
 
Ho
w often do you have six or more drinks on one occasion?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
 
4.
 
Ho
w often during the past year have you found that you were not able to stop drinking once you had started?
(0) Never
(3) Weekly
 
5.
 
Ho
w often during the past year have you failed to do what was normally expected of you because of drinking?
(0) Never
(3) Weekly
 
6.
 
Ho
w often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking session?
(0) Never

(3) Weekly
 
6.
 
Ho
(0) Never
(3) Weekly
 
7.
 
Ho
w often during the past year have you had a feeling of guilt or remorse after drinking?
(0) Never
(3) Weekly
 
8.
 
Ho
w often during the past year have you been unable to remember what happened the night before because you had been drinking?
(0) Never
(3) Weekly
 
9.
 
Ha
ve you or has someone else been injured as a result of your drinking?
(0) No
(2) Yes, but not in the past year
(4) Yes, during the past year
10.
 
Has a r
elative or friend or a doctor or other health worker been concerned about your drinking or suggested you cut down?
(0) No
Adapted, with permission, from BMJ Publishing Group Ltd. and Piccinelli M et al. Efficacy of the alcohol use disorders identification test as 
a screening tool for hazardous alcohol intake and related disorders in primary care: a validity study. BMJ. 1997 Feb 8;314(7078):420–4.
CMDT19_Ch01_p0001-p0019.indd   18

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CMDT 2019
in a day?” (X is 5 for men and 4 for women, and a response 
of more than 1 time is considered positive.)
Clinicians should provide those who screen positive for 
hazardous or risky drinking with brief behavioral counsel
-
ing interventions to reduce alcohol misuse. Use of screen
-
ing procedures and brief intervention methods (see 
Chapter 25) can produce a 10–30% reduction in long-term 
alcohol use and alcohol-related problems.
Several pharmacologic agents are effective in reducing 
alcohol consumption. In acute alcohol detoxification, long-
acting benzodiazepines are preferred because they can be 
given on a fixed schedule or through “front-loading” or 
“symptom-triggered” regimens. Adjuvant sympatholytic 
medications can be used to treat hyperadrenergic symp
-
toms that persist despite adequate sedation. Three drugs 
are FDA approved for treatment of alcohol dependence: 
disulfiram, naltrexone, and acamprosate. Disulfiram, an 
aversive agent, has significant adverse effects and conse
-
quently, compliance difficulties have resulted in no clear 
evidence that it increases abstinence rates, decreases relapse 
rates, or reduces cravings. Compared with placebo, naltrex
-
one can lower the risk of treatment withdrawal in alcohol-
dependent patients, and the long-acting intramuscular 
formulation of naltrexone has been found to be well toler
-
ated and to reduce drinking significantly among treat
-
ment-seeking alcoholics over a 6-month period. In a 
randomized, controlled trial, patients receiving medical 
management with naltrexone, a combined behavioral 
intervention, or both, fared better on drinking outcomes, 
whereas acamprosate showed no evidence of efficacy with 
or without combined behavioral intervention. Persons who 
receive short-term treatment with naltrexone have a lower 
chance of alcoholism relapse. Topiramate is a promising 
treatment for alcohol dependence. A 6-month randomized 
trial of topiramate versus naltrexone revealed a greater 
reduction of alcohol intake and cravings in participants 
receiving topiramate. Topiramate’s side effect profile is 
favorable, and its benefits appear to increase over time. 
Clinicians should be aware that although topiramate 
appears to be an effective treatment for alcohol depen
-
dence, the manufacturer has not pursued FDA approval for 
this indication.
Over the last decade, the rate of prescription drug abuse 
has increased dramatically, particularly at both ends of the 
age spectrum. The most commonly abused classes of medi
-
cations are pain relievers, tranquilizers, stimulants, and 
sedatives. Opioid-based prescription drug abuse, misuse, 
and overdose has reached epidemic proportions in the 
United States. Deaths due to prescription opioid overdose 
have dramatically increased. Opioid risk mitigation strate
-
gies include use of risk assessment tools, treatment agree
-
ments (contracts), and urine drug testing. Additional 
strategies include establishing and strengthening prescrip
-
tion drug monitoring programs, regulating pain manage
-
ment facilities, and establishing dosage thresholds requiring 
consultation with pain specialists. The FDA supports 
greater access to naloxone and is currently exploring 
options to make naloxone more available to treat opioid 
overdose. (See Chapter 5.)
Use of illegal drugs—including cocaine, methamphet
-
amine, and so-called designer drugs—either sporadically 
or episodically remains an important problem. Lifetime 
prevalence of drug abuse is approximately 8% and is gener
-
ally greater among men, young and unmarried individuals, 
Native Americans, and those of lower socioeconomic sta
-
tus. As with alcohol, drug abuse disorders often coexist 
with personality, anxiety, and other substance abuse disor
-
ders. Abuse of anabolic-androgenic steroids has been asso
-
ciated with use of other illicit drugs, alcohol, and cigarettes 
and with violence and criminal behavior.

-
-
As with alcohol abuse, the lifetime treatment rate for 
drug abuse is low (8%). The recognition of drug abuse 
presents special problems and requires that the clinician 
actively consider the diagnosis. Clinical aspects of sub
-
stance abuse are discussed in Chapter 25.
Buprenorphine has potential as a medication to amelio
-
rate the symptoms and signs of withdrawal from opioids 
and has been shown to be effective in reducing concomi
-
tant cocaine and opioid abuse. The risk of overdose is lower 
with buprenorphine than methadone and it is preferred for 
patients at high risk for methadone toxicity (see Chapter 5). 
Rapid opioid detoxification with opioid antagonist induc
-
tion using general anesthesia has emerged as an approach 
to treat opioid dependence. However, a randomized com
-
parison of buprenorphine-assisted rapid opioid detoxifica
-
tion with naltrexone induction and clonidine-assisted 
opioid detoxification with delayed naltrexone induction 
found no significant differences in rates of completion of 
inpatient detoxification, treatment retention, or propor
-
tions of opioid-positive urine specimens, and the anesthe
-
sia procedure was associated with more potentially 
life-threatening adverse events. Finally, cognitive-behavior 
therapy, contingency management, couples, and family 
therapy, and other types of behavioral treatment have been 
shown to be effective interventions for drug addiction.
Berger D et al. Primary care management of alcohol misuse. 
Med Clin North Am. 2015 Sep;99(5):989–1016. [PMID: 
26320043]
Delker E et al. Alcohol consumption in demographic subpopula
-
tions: an epidemiologic overview. Alcohol Res. 2016;38(1):7–15. 
[PMID: 27159807]
Dowell D et al. CDC guideline for prescribing opioids for 
chronic pain—United States, 2016. JAMA. 2016 Apr 
19;315(15):1624–45. [PMID: 26977696]
Moyer V A; U.S. Preventive Services Task Force. Screening and 
behavioral counseling interventions in primary care to reduce 
alcohol misuse: U.S. Preventive Services Task Force recom
-
mendation statement. Ann Intern Med. 2013 Aug 6;159(3): 
210–8. [PMID: 23698791]
U.S. Food and Drug Administration. FDA supports greater access 
to naloxone to help reduce opioid overdose deaths. 2016 
August 10. http://blogs.fda.gov/fdavoice/index.php/2016/08/
fda-supports-greater-access-to-naloxone-to-help-reduce-
opioid-overdose-deaths/
CMDT19_Ch01_p0001-p0019.indd   19

20
 CMDT 2019
COUGH
ESSENTIAL INQUIRIES
 
»
Age, tobacco or cannabis use, occupational history, 
environmental exposures, and duration of cough.
 
»
Dyspnea (at rest or with exertion).
 
»
Vital signs (heart rate, respiratory rate, body 
temperature).
 
»
Chest examination.
 
»
Chest radiography when unexplained cough lasts 
more than 3–6 weeks.
 
»
General Considerations
Cough is the most common symptom for which patients 
seek medical attention. Cough adversely affects personal 
and work-related interactions, disrupts sleep, and often 
causes discomfort of the throat and chest wall. Most people 
seeking medical attention for acute cough desire symptom 
relief; few are worried about serious illness. Cough results 
from stimulation of mechanical or chemical afferent nerve 
receptors in the bronchial tree. Effective cough depends on 
an intact afferent–efferent reflex arc, adequate expiratory 
and chest wall muscle strength, and normal mucociliary 
production and clearance.
 
»
Clinical Findings
A. Symptoms
Distinguishing 
acute
 (less than 3 weeks), 
persistent
 
(3–8 weeks), and 
chronic
 (more than 8 weeks) cough illness 
syndromes is a useful first step in evaluation. Postinfec
-
tious cough lasting 3–8 weeks has also been referred to as 
subacute
 cough to distinguish this common, distinct 
clinical entity from acute and chronic cough.
1. Acute cough—
In healthy adults, most acute cough syn
-
dromes are due to viral respiratory tract infections. Addi
-
tional features of infection such as fever, nasal congestion, 
and sore throat help confirm this diagnosis. Dyspnea (at 
rest or with exertion) may reflect a more serious condition, 
and further evaluation should include assessment of oxy
-
genation (pulse oximetry or arterial blood gas measure
-
ment), airflow (peak flow or spirometry), and pulmonary 
parenchymal disease (chest radiography). The timing and 
character of the cough are not very useful in establishing 
the cause of acute cough syndromes, although cough-
variant asthma should be considered in adults with promi
-
nent nocturnal cough, and persistent cough with phlegm 
increases the likelihood of chronic obstructive pulmonary 
disease (COPD). The presence of posttussive emesis or 
inspiratory whoop in adults modestly increases the likeli
-
hood of pertussis, and the absence of paroxysmal cough 
and the presence of fever decreases its likelihood. Uncom
-
mon causes of acute cough should be suspected in those 
with heart disease (heart failure) or hay fever (allergic rhinitis) 
and those with occupational risk factors (such as 
farmworkers).
2. Persistent and chronic cough—
Cough due to acute 
respiratory tract infection resolves within 3 weeks in the 
vast majority (more than 90%) of patients. Pertussis should 
be considered in adolescents and adults with persistent or 
severe cough lasting more than 3 weeks, and in selected 
geographic areas where its prevalence approaches 20% 
(although its exact prevalence is difficult to ascertain due 
to the limited sensitivity of diagnostic tests).
When angiotensin-converting enzyme (ACE) inhibitor 
therapy, acute respiratory tract infection, and chest radio
-
graph abnormalities are absent, most cases of persistent and 
chronic cough are due to (or exacerbated by) postnasal drip 
(upper airway cough syndrome), asthma, or gastroesopha
-
geal reflux disease (GERD), or some combination of these 
three entities. Approximately 10% of cases are caused by 
nonasthmatic eosinophilic bronchitis. A history of nasal or 
sinus congestion, wheezing, or heartburn should direct sub
-
sequent evaluation and treatment, though these conditions 
frequently cause persistent cough in the absence of typical 
symptoms. Dyspnea at rest or with exertion is not com
-
monly reported among patients with persistent cough; dys
-
pnea requires assessment for chronic lung disease, HF, 
anemia, pulmonary embolism, or pulmonary hypertension.2
 
-
 
Ralph Gonzales, MD, MSPH 
CMDT19_Ch02_p0020-p0045.indd   20
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COMMON SYMPTOMS
21
 
CMDT 2019
Table 2–1.
 
Positive and negative likelihood ratios for 
history, physical examination, and laboratory findings 
in the diagnosis of pneumonia.
Finding
Positive 
Likelihood 
Ratio
Negative 
Ratio
Medical history
 
Fever
1.7–2.1
0.6–0.7
 
Chills
1.3–1.7
0.7–0.9
Physical examination
 
T
achypnea (RR > 25 breaths/min)
1.5–3.4
0.8
 
T
achycardia (> 100 beats/min 
 
in t
wo studies or 
 
> 120 bea
ts/min in one study)
1.6–2.3
0.5–0.7
 
H
yperthermia (> 37.8°C)
1.4–4.4
0.6–0.8
Chest examination
 
D
ullness to percussion
2.2–4.3
0.8–0.9
 
D
ecreased breath sounds
2.3–2.5
0.6–0.8
 
Crackles
1.6–2.7
0.6–0.9
 
Rhonchi
1.4–1.5
0.8–0.9
 
Egophony
2.0–8.6
0.8–1.0
Laboratory findings
 
L
eukocytosis (> 11 × 10
9
/L in 
 
o
ne study or ≥ 10.4 × 10
9
/L 
 
in another 
study)
1.9–3.7
0.3–0.6
RR, respiratory rate.
Bronchogenic carcinoma is suspected when cough is 
accompanied by unexplained weight loss, hemoptysis, and 
fevers with night sweats, particularly in persons with sig
-
nificant tobacco or occupational exposures (asbestos, 
radon, diesel exhaust, and metals). Persistent and chronic 
cough accompanied by excessive mucus secretions 
increases the likelihood of COPD, particularly among 
smokers, or of bronchiectasis if accompanied by a history 
of recurrent or complicated pneumonia; chest radiographs 
are helpful in diagnosis.
B. Physical Examination
Examination can direct subsequent diagnostic testing for 
acute cough. Pneumonia is suspected when acute cough is 
accompanied by vital sign abnormalities (tachycardia, 
tachypnea, fever). Findings suggestive of airspace consoli
-
dation (rales, decreased breath sounds, fremitus, egoph
-
ony) are significant predictors of community-acquired 
pneumonia but are present in the minority of cases. Puru
-
lent sputum is associated with bacterial infections in 
patients with structural lung disease (eg, COPD, cystic 
fibrosis), but it is a poor predictor of pneumonia in the 
otherwise healthy adult. Wheezing and rhonchi are fre
-
quent findings in adults with acute bronchitis and do not 
indicate consolidation or adult-onset asthma in most cases.
Examination of patients with persistent cough should 
look for evidence of chronic sinusitis, contributing to post
-
nasal drip syndrome or asthma. Chest and cardiac signs 
may help distinguish COPD from HF. In patients with 
cough and dyspnea, a normal match test (ability to blow 
out a match from 25 cm away) and maximum laryngeal 
height greater than 4 cm (measured from the sternal notch 
to the cricoid cartilage at end expiration) substantially 
decrease the likelihood of COPD. Similarly, normal jugular 
venous pressure and no hepatojugular reflux decrease the 
likelihood of biventricular HF.
C. Diagnostic Studies
Chest radiography should be considered 
for any adult with acute cough whose vital signs are abnor
-
mal or whose chest examination suggests pneumonia. The 
relationship between specific clinical findings and the 
probability of pneumonia is shown in Table 2–1. A large, 
multicenter randomized clinical trial found that elevated 
serum C-reactive protein (levels greater than 30 mg/dL) 
improves diagnostic accuracy of clinical prediction rules 
for pneumonia in adults with acute cough; procalcitonin 
added no clinically relevant information. A meta-analysis 
found that lung ultrasonography had better accuracy than 
chest radiography for the diagnosis of adult community-
acquired pneumonia. Lung ultrasonography had a pooled 
sensitivity of 0.95 (95% confidence interval [CI], 0.93–0.97) 
and a specificity of 0.90 (95% CI, 0.86–0.94). Chest radiog
-
raphy had a pooled sensitivity of 0.77 (95% CI, 0.73–0.80) 
and a specificity of 0.91 (95% CI, 0.87–0.94). In patients 
with dyspnea, pulse oximetry and peak flow help exclude 
hypoxemia or obstructive airway disease. However, a nor
-
mal pulse oximetry value (eg, greater than 93%) does not

-
mal pulse oximetry value (eg, greater than 93%) does not 
rule out a significant alveolar–arterial (A–a) gradient when 
patients have effective respiratory compensation. During 
documented outbreaks, clinical diagnosis of influenza has 
a positive predictive value of ~70%; this usually obviates 
the need for rapid diagnostic tests.
Chest radiography is 
indicated when ACE inhibitor therapy–related and postin
-
fectious cough are excluded. If pertussis is suspected, poly
-
merase chain reaction testing should be performed on a 
nasopharyngeal swab or nasal wash specimen—although 
the ability to detect pertussis decreases as the duration of 
cough increases. When the chest film is normal, postnasal 
drip, asthma, or GERD are the most likely causes. The 
presence of typical symptoms of these conditions directs 
further evaluation or empiric therapy, though typical 
symptoms are often absent. Definitive tests for determin
-
ing the presence of each are available (Table 2–2). However, 
empiric treatment with a maximum-strength regimen for 
postnasal drip, asthma, or GERD for 2–4 weeks is one rec
-
ommended approach since documenting the presence of 
postnasal drip, asthma, or GERD does not mean they are 
the cause of the cough. Alternative approaches to identify
-
ing patients who have asthma with its corticosteroid-
responsive cough include examining induced sputum for 
increased eosinophil counts (greater than 3%) or providing 
an empiric trial of prednisone, 30 mg daily orally for 2 weeks. 
Spirometry may help identify large airway obstruction in 
CMDT19_Ch02_p0020-p0045.indd   21

Cha
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 2
22
 CMDT 2019
Table 2–2.
 
Empiric treatments or tests for persistent 
cough.
Suspected 
Condition
Step 1 (
e
mpiric 
Therapy)
Step 2 (Definitive 
Testing)
Postnasal drip
Therapy for allergy or 
chronic sinusitis
Sinus CT scan; 
 
ENT referral
Asthma
Beta-2-agonist
Spirometry; consider 
methacholine chal
-
lenge if normal
GERD
Lifestyle and diet 
modifications with 
or without proton 
pump inhibitors
Esophageal pH 
monitoring
ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease.
patients who have persistent cough and wheezing and who 
are not responding to asthma treatment. When empiric 
treatment trials are not successful, additional evaluation 
with pH manometry, endoscopy, barium swallow, sinus 
CT, or high-resolution chest CT may identify the cause.
 
»
Differential Diagnosis
A. Acute Cough
Acute cough may be a symptom of acute respiratory tract 
infection, asthma, allergic rhinitis, and HF, as well as many 
less common causes.
B. Persistent and Chronic Cough
Causes of persistent cough include environmental expo
-
sures (cigarette smoke, air pollution), occupational expo
-
sures, pertussis, postnasal drip, asthma (including 
cough-variant asthma), GERD, COPD, bronchiectasis, 
eosinophilic bronchitis, tuberculosis or other chronic infec
-
tion, interstitial lung disease, and bronchogenic carcinoma. 
COPD is a common cause of persistent cough among 
patients older than 50 years. Persistent cough may also be 
due to somatic cough syndrome (previously called “psycho
-
genic cough”) or tic cough (previously called “habit cough”).
 
»
Treatment
Treatment of acute cough should target the underlying 
etiology of the illness, the cough reflex itself, and any addi
-
tional factors that exacerbate the cough. Cough duration is 
typically 1–3 weeks, yet patients frequently expect cough to 
last fewer than 10 days. Limited studies on the use of dex
-
tromethorphan suggest a minor or modest benefit; dextro
-
methorphan should be avoided in children and adolescents 
because of concerns about misuse.
When influenza is diagnosed (including H1N1 influ
-
enza), oral oseltamivir or zanamivir or intravenous pera
-
mivir are equally effective (1 less day of illness) when 
initiated within 30–48 hours of illness onset; treatment is 
recommended regardless of illness duration when patients 
have severe influenza requiring hospitalization. In 
Chlamydophila-
 or 
Mycoplasma
-documented infection or 
outbreaks, first-line antibiotics include erythromycin or 
doxycycline. However, antibiotics do not improve cough 
severity or duration in patients with uncomplicated acute 
bronchitis. In patients with bronchitis and wheezing, 
inhaled beta-2-agonist therapy reduces severity and dura
-
tion of cough. In patients with acute cough, treating the 
accompanying postnasal drip (with antihistamines, decon
-
gestants, or nasal corticosteroids) can be helpful. A 
Cochrane review (n = 163) found codeine to be no more 
effective than placebo in reducing cough symptoms.
Evaluation and management of persistent cough often 
require multiple visits and therapeutic trials, which fre
-
quently lead to frustration, anger, and anxiety. When per
-
tussis infection is suspected early in its course, treatment 
with a macrolide antibiotic (see Chapter 33) is appropriate 
to reduce organism shedding and transmission. When 
pertussis has lasted more than 7–10 days, antibiotic treat
-
ment does not affect the duration of cough, which can last 
up to 6 months. Early identification, revaccination with 
Tdap, and treatment of adult patients who work or live with 
persons at high risk for complications from pertussis (preg
-
nant women, infants [particularly younger than 1 year], 
and immunosuppressed individuals) are encouraged.
Table 2–2 outlines empiric treatments for persistent 
cough. There is no evidence to guide how long to continue 
treatment for persistent cough due to postnasal drip,

treatment for persistent cough due to postnasal drip, 
asthma, or GERD. Studies have not found a consistent 
benefit of inhaled corticosteroid therapy in adults with 
persistent cough. Eight weeks of thrice-weekly azithromy
-
cin did not improve cough in patients without asthma.
When empiric treatment trials fail, consider other 
causes of chronic cough such as obstructive sleep apnea, 
tonsillar or uvular enlargement, and environmental fungi. 
The small percentage of patients with idiopathic chronic 
cough should be managed in consultation with an otolar
-
yngologist or a pulmonologist; consider a high-resolution 
CT scan of the lungs. Treatment options include nebulized 
lidocaine therapy and morphine sulfate, 5–10 mg orally 
twice daily. Sensory dysfunction of the laryngeal branches 
of the vagus nerve may contribute to persistent cough syn
-
dromes and may help explain the effectiveness of gabapen
-
tin in patients with chronic cough. Speech pathology 
therapy combined with pregabalin has some benefit in 
chronic refractory cough. In patients with reflex cough 
syndrome, therapy aimed at shifting the patient’s atten
-
tional focus from internal stimuli to external focal points 
can be helpful. Proton pump inhibitors are not effective on 
their own; most benefit appears to come from lifestyle 
modifications and weight reduction.
 
»
When to Refer
•	
Failure to control persistent or chronic cough following 
empiric treatment trials.
•	
Patients with recurrent symptoms should be referred to 
an otolaryngologist, pulmonologist, or gastroenterologist.
CMDT19_Ch02_p0020-p0045.indd   22

23
 
CMDT 2019
 
»
When to Admit
•	
Patient at high risk for tuberculosis for whom compli
-
ance with respiratory precautions is uncertain.
•	
Need for urgent bronchoscopy, such as suspected for
-
eign body.
•	
Smoke or toxic fume inhalational injury.
•	
Gas exchanged is impaired by cough.
•	
Patients at high risk for barotrauma (eg, recent 
pneumothorax).
Gibson P et al; CHEST Expert Cough Panel. Treatment of unex
-
plained chronic cough: CHEST Guideline and Expert Panel 
Report. Chest. 2016 Jan;149(1):27–44. [PMID: 26426314]
Kahrilas PJ et al; CHEST Expert Cough Panel. Chronic cough 
due to gastroesophageal reflux in adults: CHEST guideline 
and expert panel report. Chest. 2016 Dec;150(6):1341–60. 
[PMID: 27614002]
Michaudet C et al. Chronic cough: evaluation and management. 
Am Fam Physician. 2017 Nov 1;96(9):575–80. [PMID: 
29094873]
Moore A et al. Clinical characteristics of pertussis-associated 
cough in adults and children: a diagnostic systematic review 
and meta-analysis. Chest. 2017 Aug;152(2):353–67. [PMID: 
28511929]
Smith JA et al. Chronic cough. N Engl J Med. 2016 Oct 20;
 
375(16):1544–51. [PMID: 27797316]
Tarlo SM et al. Evaluation of occupational and environmental 
factors in the assessment of chronic cough in adults: a system
-
atic review. Chest. 2016 Jan;149(1):143–60. [PMID: 26501943]
Teepe J et al; GRACE Consortium. Predicting the presence of 
bacterial pathogens in the airways of primary care patients 
with acute cough. CMAJ. 2016 Oct 24. [Epub ahead of print] 
[PMID: 27777252]
DYSPNEA
 
»
Fever, cough, and chest pain.
 
»
Vital sign measurements; pulse oximetry.
 
»
Cardiac and chest examination.
 
»
Chest radiography and arterial blood gas mea
-
surement in selected patients.
 
»
Dyspnea is a subjective experience or perception of uncom
-
fortable breathing. There is a lack of empiric evidence on 
the prevalence, etiology, and prognosis of dyspnea in gen
-
eral practice. The relationship between level of dyspnea 
and the severity of underlying disease varies widely among 
individuals. Dyspnea can result from conditions that 
increase the mechanical effort of breathing (eg, COPD, 
restrictive lung disease, respiratory muscle weakness), con
-
ditions that produce compensatory tachypnea (eg, hypox
-
emia, acidosis), primary pulmonary vasculopathy 
(pulmonary hypertension), or psychogenic conditions. The 
following factors play a role in how and when dyspnea 
presents in patients: rate of onset, previous dyspnea, medi
-
cations, comorbidities, psychological profile, and severity 
of underlying disorder.
 
»
The duration, severity, and periodicity of dyspnea influ
-
ence the tempo of the clinical evaluation. Rapid onset or 
severe dyspnea in the absence of other clinical features 
should raise concern for pneumothorax, pulmonary embo
-
lism, or increased left ventricular end-diastolic pressure 
(LVEDP). Spontaneous pneumothorax is usually accompa
-
nied by chest pain and occurs most often in thin, young 
males and in those with underlying lung disease. Pulmo
-
nary embolism should always be suspected when a patient 
with new dyspnea reports a recent history (previous 4 
weeks) of prolonged immobilization or surgery, estrogen 
therapy, or other risk factors for deep venous thrombosis 
(DVT) (eg, previous history of thromboembolism, cancer, 
obesity, lower extremity trauma) and when the cause of 
dyspnea is not apparent. Silent myocardial infarction, 
which occurs more frequently in diabetic persons and 
women, can result in increased LVEDP , acute HF, and 
dyspnea.
Accompanying symptoms provide important clues to 
causes of dyspnea. When cough and fever are present, pul
-
monary disease (particularly infection) is the primary 
concern; myocarditis, pericarditis, and septic emboli can 
present in this manner. Chest pain should be further char
-
acterized as acute or chronic, pleuritic or exertional.

-
acterized as acute or chronic, pleuritic or exertional. 
Although acute pleuritic chest pain is the rule in acute 
pericarditis and pneumothorax, most patients with pleu
-
ritic chest pain in the outpatient clinic have pleurisy due to 
acute viral respiratory tract infection. Periodic chest pain 
that precedes the onset of dyspnea suggests myocardial 
ischemia or pulmonary embolism. When associated with 
wheezing, most cases of dyspnea are due to acute bronchi
-
tis; however, other causes include new-onset asthma, for
-
eign body, and vocal cord dysfunction. Interstitial lung 
disease and pulmonary hypertension should be considered 
in patients with symptoms (or history) of connective tissue 
disease.
When a patient reports prominent dyspnea with mild 
or no accompanying features, consider noncardiopulmo
-
nary causes of impaired oxygen delivery (anemia, methe
-
moglobinemia, cyanide ingestion, carbon monoxide), 
metabolic acidosis, panic disorder, neuromuscular disor
-
ders, and chronic pulmonary embolism.
Platypnea-orthodeoxia syndrome is characterized by 
dyspnea and hypoxemia on sitting or standing that 
improves in the recumbent position. It may be caused by 
an intracardiac shunt, pulmonary vascular shunt, or venti
-
lation-perfusion mismatch.
A focused physical examination should include evaluation 
of the head and neck, chest, heart, and lower extremities. 
Visual inspection of the patient can suggest obstructive 
CMDT19_Ch02_p0020-p0045.indd   23

Cha
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24
 CMDT 2019
airway disease (pursed-lip breathing, use of accessory 
respiratory muscles, barrel-shaped chest), pneumothorax 
(asymmetric excursion), or metabolic acidosis (Kussmaul 
respirations). Patients with impending upper airway 
obstruction (eg, epiglottitis, foreign body) or severe 
asthma exacerbation sometimes assume a tripod position. 
Focal wheezing raises the suspicion for a foreign body or 
other bronchial obstruction. Maximum laryngeal height 
(the distance between the top of the thyroid cartilage and 
the suprasternal notch at end expiration) is a measure of 
hyperinflation. Obstructive airway disease is virtually 
nonexistent when a nonsmoking patient younger than 45 
years has a maximum laryngeal height greater than 4 cm 
(Table 2–3). Absent breath sounds suggest a pneumotho
-
rax. An accentuated pulmonic component of the second 
heart sound (loud P2) is a sign of pulmonary hypertension 
and pulmonary embolism.
Table 2–4 shows clinical predictors of increased LVEDP 
in dyspneic patients with no prior history of HF. When 
none is present, there is a very low probability (less than 
10%) of increased LVEDP , but when two or more are pres
-
ent, there is a very high probability (greater than 90%) of 
increased LVEDP .
Causes of dyspnea that can be managed without chest radi
-
ography are few: ingestions causing lactic acidosis, anemia, 
methemoglobinemia, and carbon monoxide poisoning. 
The diagnosis of pneumonia should be confirmed by chest 
radiography in most patients, and elevated blood levels of 
procalcitonin or C-reactive protein can support the diag
-
nosis of pneumonia in equivocal cases or in the presence of 
interstitial lung disease. Conversely, a low procalcitonin 
can help exclude pneumonia in dyspneic patients present
-
ing with HF. Lung ultrasonography is more accurate than 
chest radiography for the diagnosis of pneumonia in 
patients admitted to an acute geriatric ward. Chest radiog
-
raphy is fairly sensitive and specific for new-onset HF 
(represented by redistribution of pulmonary venous circu
-
lation) and can help guide treatment of patients with other 
cardiac diseases. NT-proBNP can assist in the diagnosis of 
HF; the Acute Diagnostic Cut-Offs in the Emergency 
Department study defines best diagnostic cutoff points. 
End-expiratory chest radiography enhances detection of 
small pneumothoraces.
A normal chest radiograph has substantial diagnostic 
value. When there is no physical examination evidence of 
COPD or HF and the chest radiograph is normal, the major 
remaining causes of dyspnea include pulmonary embolism, 
Pneumocystis jirovecii
 infection (initial radiograph may be 
normal in up to 25%), upper airway obstruction, foreign 
body, anemia, and metabolic acidosis. If a patient has tachy
-
cardia and hypoxemia but a normal chest radiograph and 
electrocardiogram (ECG), then tests to exclude pulmonary 
emboli, anemia, or metabolic acidosis are warranted. High-
resolution chest CT is particularly useful in the evaluation 
of interstitial and alveolar lung disease. Helical (“spiral”) CT 
is useful to diagnose pulmonary embolism since the images 
are high resolution and require only one breathhold by the 
patient, but to minimize unnecessary testing and radiation 
exposure, the clinician should first consider a clinical deci
-
sion rule (with or without D-dimer testing) to estimate the 
pretest probability of a pulmonary embolism. It is appropri
-
ate to forego CT scanning in patients with very low proba
-
bility of pulmonary embolus when other causes of dyspnea 
are more likely (see Chapter 9).
Table 2–4 shows clinical findings suggesting increased 
LVEDP . Elevated serum or B-type natriuretic peptide (BNP 
or NT-proBNP) levels are both sensitive and specific for 
increased LVEDP in symptomatic persons. BNP has been 
shown to reliably diagnose severe dyspnea caused by HF 
and to differentiate it from dyspnea due to other conditions.

and to differentiate it from dyspnea due to other conditions. 
However, systematic use of BNP in evaluation of dyspnea in 
the emergency department does not appear to have a clini
-
cally significant impact on patient or system outcomes, and 
it does not conclusively affect hospital mortality rates. 
Newer cardiac biomarkers such as ST2 may have better 
prognostic value for mortality and may help titrate medical 
therapy.
Table 2–3.
 
Clinical findings suggesting obstructive 
 
airway disease.
a
djust
ed Likelihood Ratios
Factor Present
Factor 
a
bsen
t
> 40 pack-years 
smoking
11.6
0.9
Age ≥ 45 years
1.4
0.5
Maximum laryngeal 
height ≤ 4 cm
3.6
0.7
All three factors
58.5
0.3
Reproduced, with permission, from Straus SE et al. The accuracy of 
patient history, wheezing, and laryngeal measurements in diag
-
nosing obstructive airway disease. CARE-COAD1 Group. Clinical 
Assessment of the Reliability of the Examination—Chronic 
Obstructive Airways Disease. JAMA. 2000 Apr 12;283(14):1853–7. 
© 2000 American Medical Association. All rights reserved.
Table 2–4.
 
Clinical findings suggesting increased left 
ventricular end-diastolic pressure.
Systolic hypotension
Jugular venous distention (> 5–7 cm H
2
O)
1
Hepatojugular reflux (> 1 cm)
2
Crackles, especially bibasilar
Third heart sound
3
Lower extremity edema
Radiographic pulmonary vascular redistribution or cardiomegaly
1
1
These findings are particularly helpful.
2
Proper abdominal compression for evaluating hepatojugular 
reflux requires > 30 seconds of sustained right upper quadrant 
abdominal compression.
3
Auscultation of the heart at 45-degree angle in left lateral decubi
-
tus position doubles the detection rate of third heart sounds.
Data from Badgett RG et al. Can the clinical examination diagnose 
left-sided heart failure in adults? JAMA. 1997 Jun 4;277(21):1712–9.
CMDT19_Ch02_p0020-p0045.indd   24

25
 
CMDT 2019
Arterial blood gas measurement may be considered if 
clinical examination and routine diagnostic testing are 
equivocal. With two notable exceptions (carbon monoxide 
poisoning and cyanide toxicity), arterial blood gas mea
-
surement distinguishes increased mechanical effort causes 
of dyspnea (respiratory acidosis with or without hypox
-
emia) from compensatory tachypnea (respiratory alkalosis 
with or without hypoxemia or metabolic acidosis) and 
from psychogenic dyspnea (respiratory alkalosis). An 
observational study, however, found that arterial blood gas 
measurement had little value in determining the cause of 
dyspnea in patients presenting to the emergency depart
-
ment. Carbon monoxide and cyanide impair oxygen deliv
-
ery with minimal alterations in Po
2
; percent 
carboxyhemoglobin identifies carbon monoxide toxicity. 
Cyanide poisoning should be considered in a patient with 
profound lactic acidosis following exposure to burning 
vinyl (such as a theater fire or industrial accident). Sus
-
pected carbon monoxide poisoning or methemoglobin
-
emia can also be confirmed with venous carboxyhemoglobin 
or methemoglobin levels. Venous blood gas testing is also 
an option for assessing respiratory and acid-base status by 
measuring venous pH and P
co
2
 but is unable to provide 
information on oxygenation status. To correlate with arte
-
rial blood gas values, venous pH is typically 0.03–0.05 units 
lower, and venous P
co
2
 is typically 4–5 mm Hg higher than 
arterial samples.
Because arterial blood gas testing is impractical in most 
outpatient settings, 
pulse oximetry
 has assumed a central 
role in the office evaluation of dyspnea. Oxygen saturation 
values above 96% almost always correspond with a Po
2
 
greater than 70 mm Hg, whereas values less than 94% may 
represent clinically significant hypoxemia. Important 
exceptions to this rule include carbon monoxide toxicity, 
which leads to a normal oxygen saturation (due to the 
similar wavelengths of oxyhemoglobin and carboxyhemo
-
globin), and methemoglobinemia, which results in an 
oxygen saturation of about 85% that fails to increase with 
supplemental oxygen. A delirious or obtunded patient with 
obstructive lung disease warrants immediate measurement 
of arterial blood gases to exclude hypercapnia and the need 
for intubation, regardless of the oxygen saturation. If a 
patient reports dyspnea with exertion, but resting oximetry 
is normal, assessment of desaturation with ambulation (eg, 
a brisk walk around the clinic) can be useful for confirming 
impaired gas exchange.
A study found that for adults without known cardiac or 
pulmonary disease reporting dyspnea on exertion, spirom
-
etry, NT-proBNP , and CT imaging were the most informa
-
tive tests.
Episodic dyspnea can be challenging if an evaluation 
cannot be performed during symptoms. Life-threatening 
causes include recurrent pulmonary embolism, myocardial 
ischemia, and reactive airway disease. When associated 
with audible wheezing, vocal cord dysfunction should be 
considered, particularly in a young woman who does not 
respond to asthma therapy. Spirometry is very helpful in 
further classifying patients with obstructive airway disease 
but is rarely needed in the initial or emergent evaluation of 
patients with acute dyspnea.
 
»
Urgent and emergent conditions causing acute dyspnea 
include pneumonia, COPD, asthma, pneumothorax, pul
-
monary embolism, cardiac disease (eg, HF, acute myocar
-
dial infarction, valvular dysfunction, arrhythmia, 
intracardiac shunt), pleural effusion, diffuse alveolar hem
-
orrhage, metabolic acidosis, cyanide toxicity, methemoglo
-
binemia, and carbon monoxide poisoning. Chronic 
dyspnea may be caused by interstitial lung disease and 
pulmonary hypertension.
 
»
Treatment
The treatment of urgent or emergent causes of dyspnea 
should aim to relieve the underlying cause. Pending diag
-

»
Treatment
-
nosis, patients with hypoxemia should be immediately 
provided supplemental oxygen unless significant hyper
-
capnia is present or strongly suspected pending arterial 
blood gas measurement. Dyspnea frequently occurs in 
patients nearing the end of life. Opioid therapy, anxiolytics, 
and corticosteroids can provide substantial relief indepen
-
dent of the severity of hypoxemia. However, inhaled opi
-
oids are not effective. Oxygen therapy is most beneficial to 
patients with significant hypoxemia (Pao
2
 less than 55 mm 
Hg) (see Chapter 5). In patients with severe COPD and 
hypoxemia, oxygen therapy improves mortality and exer
-
cise performance. Pulmonary rehabilitation programs are 
another therapeutic option for patients with moderate to 
severe COPD or interstitial pulmonary fibrosis. A small 
study showed that patients with pulmonary hypertension 
had less dyspnea and lower plasma norepinephrine and 
interleukin-6 (IL-6) with slow paced respiration therapy. 
Noninvasive ventilation may be considered for patients 
with dyspnea caused by an acute COPD exacerbation, but 
the efficacy of this treatment is still uncertain.
 
»
•	
Following acute stabilization, patients with advanced 
COPD should be referred to a pulmonologist, and 
patients with HF or valvular heart disease should be 
referred to a cardiologist.
•	
Cyanide toxicity or carbon monoxide poisoning should 
be managed in conjunction with a toxicologist.
•	
Lung transplantation can be considered for patients 
with advanced interstitial lung disease.
 
»
•	
Impaired gas exchange from any cause or high risk of 
pulmonary embolism pending definitive diagnosis.
•	
Suspected cyanide toxicity or carbon monoxide 
poisoning.
Alba GA et al; Global Research on Acute Conditions Team 
(GREAT) Network. Diagnostic and prognostic utility of pro
-
calcitonin in patients presenting to the emergency depart
-
ment with dyspnea. Am J Med. 2016 Jan;129(1):96–104.e7. 
[PMID: 26169892]
CMDT19_Ch02_p0020-p0045.indd   25

Cha
PT
e
R
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26
 CMDT 2019
Gaggin HK et al; ICON-RELOADED Investigators. Rationale 
and design of the ICON-RELOADED study: International 
Collaborative of N-terminal pro-B-type Natriuretic Peptide 
Re-evaluation of Acute Diagnostic Cut-Offs in the Emer
-
gency Department. Am Heart J. 2017 Oct;192:26–37. [PMID: 
28938961]
Le Gal et al. D-dimer for pulmonary embolism. JAMA. 2015 Apr 
28;313(16):1668–9. [PMID: 25919531]
Miner B et al. Dyspnea in community-dwelling older persons: a 
multifactorial geriatric health condition. J Am Geriatr Soc. 
2016 Oct;64(10):2042–50. [PMID: 27549914]
Oelsner EC et al. Noninvasive tests for the diagnostic evaluation 
of dyspnea among outpatients: the Multi-Ethnic Study of 
Atherosclerosis lung study. Am J Med. 2015 Feb;128(2):171–80. 
[PMID: 25447621]
Taggart C. Shortness of breath: looking beyond the usual sus
-
pects. J Fam Pract. 2016 Aug;65(8):526–33. [PMID: 27660836]
Ticinesi A et al. Lung ultrasound and chest x-ray for detecting 
pneumonia in an acute geriatric ward. Medicine (Baltimore). 
2016 Jul;95(27):e4153. [PMID: 27399134]
Viniol A et al. Studies of the symptom dyspnoea: a systematic 
review. BMC Fam Pract. 2015 Oct 24;16:152. [PMID: 26498502]
 
»
Fever, cough, and other symptoms of lower respi
-
ratory tract infection.
 
»
Smoking history.
 
»
Nasopharyngeal or gastrointestinal bleeding.
 
»
Chest radiography and complete blood count 
(and, in some cases, INR).
 
»
Hemoptysis is the expectoration of blood that originates 
below the vocal cords. It is commonly classified as trivial, 
mild, or massive—the latter defined as more than 200–600 mL 
(about 1–2 cups) in 24 hours. Massive hemoptysis can be 
usefully defined as any amount that is hemodynamically 
significant or threatens ventilation. Its in-hospital mortal
-
ity was 6.5% in one study. The initial goal of management 
of massive hemoptysis is therapeutic, not diagnostic.
The causes of hemoptysis can be classified anatomically. 
Blood may arise from the airways in COPD, bronchiecta
-
sis, and bronchogenic carcinoma; from the pulmonary 
vasculature in left ventricular failure, mitral stenosis, pul
-
monary embolism, pulmonary arterial hypertension, and 
arteriovenous malformations; or from the pulmonary 
parenchyma in pneumonia, fungal infections, inhalation of 
crack cocaine, or granulomatosis with polyangiitis (for
-
merly Wegener granulomatosis). Diffuse alveolar hemor
-
rhage—manifested by alveolar infiltrates on chest 
radiography—is due to small vessel bleeding usually caused 
by autoimmune or hematologic disorders, or rarely precipi
-
tated by warfarin. Most cases of hemoptysis presenting in 
the outpatient setting are due to infection (eg, acute or 
chronic bronchitis, pneumonia, tuberculosis, aspergillo
-
sis). Hemoptysis due to lung cancer increases with age, 
causing up to 20% of cases among older adults. Less com
-
monly (less than 10% of cases), pulmonary venous hyper
-
tension (eg, mitral stenosis, pulmonary embolism) causes 
hemoptysis. Most cases of hemoptysis that have no visible 
cause on CT scan or bronchoscopy will resolve within 
6 months without treatment, with the notable exception of 
patients at high risk for lung cancer (smokers older than 
40 years). Iatrogenic hemorrhage may follow transbron
-
chial lung biopsies, anticoagulation, or pulmonary artery 
rupture due to distal placement of a balloon-tipped catheter. 
Obstructive sleep apnea may be a risk factor for hemoptysis. 
No cause is identified in up to 15–30% of cases.
 
»
Blood-tinged sputum in the setting of an upper respiratory 
tract infection in an otherwise healthy, young (age under 
40 years) nonsmoker does not warrant an extensive diag
-
nostic evaluation if the hemoptysis subsides with resolu
-
tion of the infection. However, hemoptysis is frequently a 
sign of serious disease, especially in patients with a high

-
-
sign of serious disease, especially in patients with a high 
prior probability of underlying pulmonary pathology. 
Hemoptysis is the only symptom found to be a specific 
predictor of lung cancer. There is no value in distinguish
-
ing blood-streaked sputum and cough productive of blood 
during evaluation; the goal of the history is to identify 
patients at risk for one of the disorders listed above. Perti
-
nent features include duration of symptoms, presence of 
respiratory infection, and past or current tobacco use. 
Nonpulmonary sources of hemorrhage—from the sinuses 
or the gastrointestinal tract—must be excluded.
Elevated pulse, hypotension, and decreased oxygen satura
-
tion suggest large-volume hemorrhage that warrants emer
-
gent evaluation and stabilization. The nares and oropharynx 
should be carefully inspected to identify a potential upper 
airway source of bleeding. Chest and cardiac examination 
may reveal evidence of HF or mitral stenosis.
Diagnostic evaluation should include a chest radiograph 
and complete blood count. Kidney function tests, urinalysis, 
and coagulation studies are appropriate in specific circum
-
stances. Hematuria that accompanies hemoptysis may be a 
clue to Goodpasture syndrome or vasculitis. Flexible bron
-
choscopy reveals endobronchial cancer in 3–6% of patients 
with hemoptysis who have a normal (non-lateralizing) chest 
radiograph. Nearly all of these patients are smokers over 
the age of 40, and most will have had symptoms for more 
than 1 week. High-resolution chest CT scan complements 
bronchoscopy; it can visualize unsuspected bronchiectasis 
and arteriovenous malformations and will show central 
endobronchial cancers in many cases. It is the test of choice 
for suspected small peripheral malignancies. Helical CT 
pulmonary angiography is the initial test of choice for 
evaluating patients with suspected pulmonary embolism, 
although caution should be taken to avoid large contrast 
CMDT19_Ch02_p0020-p0045.indd   26

27
 
CMDT 2019
loads in patients with even mild chronic kidney disease 
(serum creatinine greater than 2.0 g/dL or rapidly rising 
creatinine in normal range). Helical CT scanning can be 
avoided in patients who are at “unlikely” risk for pulmo
-
nary embolism using the Wells score for pulmonary embo
-
lism and the sensitive D-dimer test. Echocardiography may 
reveal evidence of HF or mitral stenosis.
 
»
Treatment
Management of mild hemoptysis consists of identifying 
and treating the specific cause. Massive hemoptysis is life-
threatening. The airway should be protected with endotra
-
cheal intubation, ventilation ensured, and effective 
circulation maintained. If the location of the bleeding site 
is known, the patient should be placed in the decubitus 
position with the involved lung dependent. Uncontrolla
-
ble hemorrhage warrants rigid bronchoscopy and surgical 
consultation. In stable patients, flexible bronchoscopy 
may localize the site of bleeding, and angiography can 
embolize the involved bronchial arteries. Embolization is 
effective initially in 85% of cases, although rebleeding 
may occur in up to 20% of patients during the following 
year. The anterior spinal artery arises from the bronchial 
artery in up to 5% of people, and paraplegia may result if 
it is inadvertently cannulated and embolized. There is 
some evidence that antifibrinolytics may reduce the dura
-
tion of bleeding.
 
»
•	
Patients should be referred to a pulmonologist when 
bronchoscopy of the lower respiratory tract is needed.
•	
Patients should be referred to an otolaryngologist when 
an upper respiratory tract bleeding source is identified.
•	
Patients with severe coagulopathy complicating man
-
agement should be referred to a hematologist.
 
»
•	
To stabilize bleeding process in patients at risk for or 
experiencing massive hemoptysis.
•	
To correct disordered coagulation (using clotting fac
-
tors or platelets, or both).
•	
To stabilize gas exchange.
Earwood JS et al. Hemoptysis: evaluation and management. Am 
Fam Physician. 2015 Feb 15;91(4):243–9. [PMID: 25955625]
Ittrich H et al. The diagnosis and treatment of hemoptysis. Dtsch 
Arztebl Int. 2017 Jun 5;114(21):371–81. [PMID: 28625277]
Ketai LH et al; Expert Panel on Thoracic Imaging. ACR appro
-
priateness criteria® hemoptysis. J Thorac Imaging. 2014 May;
 
29(3):W19–22. [PMID: 24717602]
Latimer KM et al. Lung cancer: diagnosis, treatment principles, 
and screening. Am Fam Physician. 2015 Feb 15;91(4):250–6. 
[PMID: 25955626]
Uyar M et al. Obstructive sleep apnea is the triggering factor for 
massive hemoptysis: obstructive sleep apnea and hemoptysis. 
Sleep Breath. 2017 May;21(2):475–8. [PMID: 27995436]
Worrell SG et al. Thoracic emergencies. Surg Clin North Am. 
2014 Feb;94(1):183–91. [PMID: 24267505]
CHEST PAIN
 
»
Pain onset, character, location/size, duration, peri
-
odicity, and exacerbators; shortness of breath.
 
»
Vital signs; chest and cardiac examination.
 
»
Electrocardiography and biomarkers of myocar
-
dial necrosis in selected patients.
 
»
Chest pain (or chest discomfort) is a common symptom 
that can occur as a result of cardiovascular, pulmonary, 
pleural, or musculoskeletal disease, esophageal or other 
gastrointestinal disorders, herpes zoster, cocaine use, or 
anxiety states. The frequency and distribution of life-
threatening causes of chest pain, such as acute coronary 
syndrome (ACS), pericarditis, aortic dissection, vasospas
-
tic angina, pulmonary embolism, pneumonia, and esopha
-
geal perforation, vary substantially between clinical 
settings. Systemic lupus erythematosus, rheumatoid arthri
-
tis, reduced estimated glomerular filtration rate, and HIV 
infection are conditions that confer a strong risk of coro
-
nary artery disease. Precocious ACS may represent acute 
thrombosis independent of underlying atherosclerotic dis
-

-
-
ease. In patients aged 35 years or younger, risk factors for 
ACS are obesity, hyperlipidemia, and smoking.
Chest pain characteristics that can lead to early diagno
-
sis of acute myocardial infarction do not differ in fre
-
quency or strength of association between men and 
women. Because pulmonary embolism can present with a 
wide variety of symptoms, consideration of the diagnosis 
and rigorous risk factor assessment for venous thrombo
-
embolism (VTE) is critical. Classic VTE risk factors 
include cancer, trauma, recent surgery, prolonged immobi
-
lization, pregnancy, oral contraceptives, and family history 
and prior history of VTE. Other conditions associated with 
increased risk of pulmonary embolism include HF and 
COPD. Sickle cell anemia can cause acute chest syndrome. 
Patients with this syndrome often have chest pain, fever, 
and cough.
 
»
Myocardial ischemia is usually described as a dull, aching 
sensation of “pressure, ” “tightness, ” “squeezing, ” or “gas, ” 
rather than as sharp or spasmodic. Ischemic symptoms 
usually subside within 5–20 minutes but may last longer. 
Progressive symptoms or symptoms at rest may represent 
unstable angina. Prolonged chest pain episodes might rep
-
resent myocardial infarction, although up to one-third of 
patients with acute myocardial infarction do not report 
chest pain. When present, pain due to myocardial ischemia 
is commonly accompanied by a sense of anxiety or uneasi
-
ness. The location is usually retrosternal or left precordial. 
CMDT19_Ch02_p0020-p0045.indd   27

Cha
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28
 CMDT 2019
Because the heart lacks somatic innervation, precise local
-
ization of pain due to cardiac ischemia is difficult; the pain 
is commonly referred to the throat, lower jaw, shoulders, 
inner arms, upper abdomen, or back. Ischemic pain may be 
precipitated or exacerbated by exertion, cold temperature, 
meals, stress, or combinations of these factors and is usu
-
ally relieved by rest. However, many episodes do not con
-
form to these patterns, and atypical presentations of ACS 
are more common in older adults, women, and persons 
with diabetes mellitus. Other symptoms that are associated 
with ACS include shortness of breath; dizziness; a feeling of 
impending doom; and vagal symptoms, such as nausea and 
diaphoresis. In older persons, fatigue is a common present
-
ing complaint of ACS. Likelihood ratios (LRs) for cardinal 
symptoms considered in the evaluation of acute myocar
-
dial infarction are summarized in Table 2–5.
A meta-analysis found the clinical findings and risk fac
-
tors most suggestive of ACS were prior abnormal stress test 
(specificity, 96%; LR, 3.1 [95% CI, 2.0–4.7]), peripheral 
arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5–
4.8]), and pain radiation to both arms (specificity, 96%; LR, 
2.6 [95% CI, 1.8–3.7]). The ECG findings associated with 
ACS were ST-segment depression (specificity, 95%; LR, 5.3 
[95% CI, 2.1–8.6]) and any evidence of ischemia (specific
-
ity, 91%; LR, 3.6 [95% CI, 1.6–5.7]). Risk scores derived 
from both the History, Electrocardiogram, Age, Risk Fac
-
tors, Troponin (HEART) and Thrombolysis in Myocardial 
Infarction (TIMI) trials performed well in detecting ACS 
(LR, 13 [95% CI, 7.0–24] for HEART score of 7–10, and 
LR, 6.8 [95% CI, 5.2–8.9] for TIMI score of 5–7).
Hypertrophy of either ventricle or aortic stenosis may 
also give rise to chest pain with less typical features. Peri
-
carditis produces pain that may be greater when supine 
than upright and increases with respiration, coughing, or 
swallowing. Pleuritic chest pain is usually not ischemic, 
and pain on palpation may indicate a musculoskeletal 
cause. Aortic dissection classically produces an abrupt 
onset of tearing pain of great intensity that often radiates to 
the back; however, this classic presentation occurs in a 
small proportion of cases. Anterior aortic dissection can 
also lead to myocardial or cerebrovascular ischemia.
Pulmonary embolism has a wide range of clinical pre
-
sentations, with chest pain present in about 75% of cases. 
The chief objective in evaluating patients with suspected 
pulmonary embolism is to assess the patient’s clinical risk 
for VTE based on medical history and associated signs and 
symptoms (see above and Chapter 9). Rupture of the tho
-
racic esophagus iatrogenically or secondary to vomiting is 
another cause of chest pain.
Findings on physical examination can occasionally yield 
important clues to the underlying cause of chest pain; how
-
ever, a normal physical examination should never be used 
as the sole basis for ruling out most diagnoses, particularly 
ACS and aortic dissection. Vital signs (including pulse 
oximetry) and cardiopulmonary examination are always 
the first steps for assessing the urgency and tempo of the 
subsequent examination and diagnostic workup.
Findings that increase the likelihood of ACS include 
diaphoresis, hypotension, S
3
 or S
4
 gallop, pulmonary crack
-
les, or elevated jugular venous pressure (see Table 2–5). 
Although chest pain that is reproducible or worsened with 
palpation strongly suggests a musculoskeletal cause, up to 
15% of patients with ACS will have reproducible chest wall 
tenderness. Pointing to the location of the pain with one 
finger has been shown to be highly correlated with non
-
ischemic chest pain. Aortic dissection can result in differ
-
ential blood pressures (greater than 20 mm Hg), pulse 
amplitude deficits, and new diastolic murmurs. Although

-
-
amplitude deficits, and new diastolic murmurs. Although 
hypertension is considered the rule in patients with aortic 
dissection, systolic blood pressure less than 100 mm Hg is 
present in up to 25% of patients.
A cardiac friction rub represents pericarditis until 
proven otherwise. It can best be heard with the patient sit
-
ting forward at end-expiration. Tamponade should be 
excluded in all patients with a clinical diagnosis of pericar
-
ditis by assessing pulsus paradoxus (a decrease in systolic 
Table 2–5.
 
Likelihood ratios (LRs) for clinical features 
associated with acute myocardial infarction.
Clinical Feature
LR+ (95% CI)
h
ist
ory
 
Chest pain 
that radiates to the left arm
2.3 (1.7–3.1)
 
Chest pain tha
t radiates to the right 
 
shoulder
2.9 (1.4–3.0)
 
Chest pain 
that radiates to both arms
7.1 (3.6–14.2)
 
P
leuritic chest pain
0.2 (0.2–0.3)
 
Sharp or stabbing chest 
pain
0.3 (0.2–0.5)
 
P
ositional chest pain
0.3 (0.2–0.4)
 
Nausea 
or vomiting
1.9 (1.7–2.3)
 
2.0 (1.9–2.2)
 
S
ystolic blood pressure ≤ 80 mm Hg
3.1 (1.8–5.2)
 
Chest pain 
reproduced by palpation
0.2–0.41
 
P
ulmonary crackles
2.1 (1.4–3.1)
 
T
hird heart sound
3.2 (1.6–6.5)
e
lectrocardiogram
 
An
y ST-segment elevation (≥ 1 mm)
11.2 (7.1–17.8)
 
An
y ST-segment depression
3.2 (2.5–4.1)
 
An
y Q wave
3.9 (2.7–7.7)
 
An
y conduction defect
2.7 (1.4–5.4)
 
New ST
-segment elevation (≥ 1 mm)
(5.7–53.9)
1
 
New ST
-segment depression
(3.0–5.2)
1
 
New Q w
ave
(5.3–24.8)
1
 
New c
onduction defect
6.3 (2.5–15.7)
1
Heterogeneous studies do not allow for calculation of a point 
estimate.
Adapted, with permission, from Panju AA et al. The rational clinical 
examination. Is this patient having a myocardial infarction? JAMA. 
1998 Oct 14;280(14):1256–63. © 1998 American Medical Association. 
All rights reserved.
CMDT19_Ch02_p0020-p0045.indd   28

29
 
CMDT 2019
blood pressure during inspiration greater than 10 mm Hg) 
and inspection of jugular venous pulsations. Subcutaneous 
emphysema is common following cervical esophageal per
-
foration but present in only about one-third of thoracic 
perforations (ie, those most commonly presenting with 
chest pain).
The absence of abnormal physical examination findings 
in patients with suspected pulmonary embolism usually 
serves to 
increase
 the likelihood of pulmonary embolism, 
although a normal physical examination is also compatible 
with the much more common conditions of panic/anxiety 
disorder and musculoskeletal disease.
Unless a competing diagnosis can be confirmed, an ECG is 
warranted in the initial evaluation of most patients with 
acute chest pain to help exclude ACS. ST-segment elevation 
is the ECG finding that is the strongest predictor of acute 
myocardial infarction (see Table 2–5); however, up to 20% 
of patients with ACS can have a normal ECG. In the emer
-
gency department, patients with suspected ACS can be 
safely removed from cardiac monitoring if they are pain-
free at initial physician assessment and have a normal or 
nonspecific ECG. This decision rule had 100% sensitivity 
for serious arrhythmia (95% CI, 80–100%). Clinically sta
-
ble patients with cardiovascular disease risk factors, nor
-
mal ECG, normal cardiac biomarkers, and no alternative 
diagnoses (such as typical GERD or costochondritis) 
should be followed up with a timely exercise stress test that 
includes perfusion imaging. However, more than 25% of 
patients with stable chest pain referred for noninvasive 
testing will have normal coronary arteries and no long-
term clinical events. The ECG can also provide evidence 
for alternative diagnoses, such as pericarditis and pulmo
-
nary embolism. Chest radiography is often useful in the 
evaluation of chest pain, and is always indicated when 
cough or shortness of breath accompanies chest pain. Find
-
ings of pneumomediastinum or new pleural effusion are 
consistent with esophageal perforation. Stress echocar
-
diography is useful in risk stratifying patients with chest 
pain, even among those with significant obesity.
Diagnostic protocols using a single high-sensitivity 
troponin assay combined with a standardized clinical 
assessment are an efficient strategy to rapidly determine 
whether patients with chest pain are at low risk and may be 
discharged from the emergency department. Five estab
-
lished risk scores are (1) the modified Goldman Risk Score, 
(2) Thrombolysis in Myocardial Infarction (TIMI) Risk 
Score, (3) Global Registry of Acute Cardiac Events 
(GRACE) Risk Score, (4) HEART Risk Score, and (5) Van
-
couver Chest Pain Rule. A study compared these risk 
scores for predicting acute myocardial infarction within 
30 days and reported a sensitivity of 98% (which correlates 
with a negative predictive value of greater than or equal to 
99.5%). Patients eligible for discharge (about 30%) were 
those with a TIMI score of less than or equal to 1, modified 
Goldman score of less than or equal to 1 with normal high-
sensitivity (hs-) troponin T, TIMI score of 0, or HEART 
score of less than or equal to 3 with normal high-sensitivity 
hs-troponin I.
While some studies of high-sensitivity cardiac troponin 
suggest that it may be the best cardiac biomarker, it may 
not outperform conventional troponin assays if an appro
-
priate cutoff is used. Copeptin, beta
2
-microglobulin, and 
heart-type fatty-acid–binding protein may also have a role 
in increasing diagnostic sensitivity.
Patients who arrive at the emergency department with 
chest pain of intermediate or high probability for ACS 
without electrocardiographic or biomarker evidence of a 
myocardial infarction can be safely discharged from an 
observation unit after stress cardiac MRI. Sixty-four–slice 
CT coronary angiography (CTA) is an alternative to stress

CT coronary angiography (CTA) is an alternative to stress 
testing in the emergency department for detecting ACS 
among patients with normal or nonspecific ECG and nor
-
mal biomarkers. A meta-analysis of nine studies found 
ACS in 10% of patients, and an estimated sensitivity of 
CTA for ACS of 95%, specificity of 87%, yielding a negative 
LR of 0.06 and a positive LR of 7.4. Coronary CTA applied 
early in the evaluation of suspected ACS does not identify 
more patients with significant CAD requiring coronary 
revascularization, shorten hospital stay, or allow for more 
direct discharge from the emergency department com
-
pared to hs-troponins. Thus, functional testing appears to 
be the best initial noninvasive test in symptomatic patients 
with suspected coronary artery disease. CTA is an option 
for patients who do not have access to functional testing.
A minimal-risk model developed by the PROMISE 
investigators includes 10 clinical variables that correlate 
with normal coronary CTA results and no clinical events 
(C statistic = 0.725 for the derivation and validation sub
-
sets; 95% CI, 0.705–0.746). These variables include (1) 
younger age; (2) female sex; (3) racial or ethnic minority; 
(4–6) no history of hypertension, diabetes, or dyslipidemia; 
(7) no family history of premature coronary artery disease; 
(8) never smoking; (9) symptoms unrelated to physical or 
mental stress; and (10) higher high-density lipoprotein 
cholesterol level.
In the evaluation of pulmonary embolism, diagnostic 
test decisions and results must be interpreted in the context 
of the clinical likelihood of VTE. A negative D-dimer test 
is helpful for excluding pulmonary embolism in patients 
with low clinical probability of VTE (3-month incidence = 
0.5%); however, the 3-month risk of VTE among patients 
with intermediate and high risk of VTE is sufficiently high 
in the setting of a negative D-dimer test (3.5% and 21.4%, 
respectively) to warrant further imaging given the life-
threatening nature of this condition if left untreated. CT 
angiography (with helical or multidetector CT imaging) 
has replaced ventilation-perfusion scanning as the pre
-
ferred initial diagnostic test, having approximately 90–95% 
sensitivity and 95% specificity for detecting pulmonary 
embolism (compared with pulmonary angiography). How
-
ever, for patients with high clinical probability of VTE, 
lower extremity ultrasound or pulmonary angiogram may 
be indicated even with a normal helical CT.
Panic disorder is a common cause of chest pain, 
accounting for up to 25% of cases that present to emer
-
gency departments and a higher proportion of cases pre
-
senting in primary care office practices. Features that 
correlate with an increased likelihood of panic disorder 
CMDT19_Ch02_p0020-p0045.indd   29

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include absence of coronary artery disease, atypical quality 
of chest pain, female sex, younger age, and a high level of 
self-reported anxiety. Depression is associated with recur
-
rent chest pain with or without coronary artery disease 
(odds ratio [OR] = 2.11, 95% CI 1.18–3.79).
 
»
Treatment
Treatment of chest pain should be guided by the underly
-
ing etiology. The term “noncardiac chest pain” is used 
when a diagnosis remains elusive after patients have 
undergone an extensive workup. Almost half reported 
symptom improvement with high-dose proton-pump 
inhibitor therapy. A meta-analysis of 15 trials suggested 
modest to moderate benefit for psychological (especially 
cognitive-behavioral) interventions. It is unclear whether 
tricyclic or selective serotonin reuptake inhibitor antide
-
pressants have benefit in noncardiac chest pain. Hypno
-
therapy may offer some benefit.
 
»
•	
Refer patients with poorly controlled, noncardiac chest 
pain to a pain specialist.
•	
Refer patients with sickle cell anemia to a hematologist.
 
»
•	
Failure to adequately exclude life-threatening causes of 
chest pain, particularly myocardial infarction, dissect
-
ing aortic aneurysm, pulmonary embolism, and esoph
-
ageal rupture.
•	
High risk of pulmonary embolism and a positive sensi
-
tive D-dimer test.
•	
TIMI score of 1 or more, abnormal electrocardiogram, 
and abnormal 0- and 2-hour troponin tests.
•	
Pain control for rib fracture that impairs gas exchange.
Bandstein N et al. Undetectable high-sensitivity cardiac tropo
-
nin T level in the emergency department and risk of myocar
-
dial infarction. J Am Coll Cardiol. 2014 Jun 17;63(23):2569–78. 
[PMID: 24694529]
Carlton EW et al. Identifying patients suitable for discharge after 
a single-presentation high-sensitivity troponin result: a com
-
parison of five established risk scores and two high-sensitivity 
assays. Ann Emerg Med. 2015 Dec;66(6):635–45.e1. [PMID: 
26260100]
Dedic A et al. Coronary CT angiography for suspected ACS in 
the era of high-sensitivity troponins: randomized multicenter 
study. J Am Coll Cardiol. 2016 Jan 5;67(1):16–26. [PMID: 
26764061]
Douglas PS et al; PROMISE Investigators. Outcomes of anatomi
-
cal versus functional testing for coronary artery disease. N 
Engl J Med. 2015 Apr 2;372(14):1291–300. [PMID: 25773919]
Fanaroff AC et al. Does this patient with chest pain have acute 
coronary syndrome? The Rational Clinical Examination Sys
-
tematic Review. JAMA. 2015 Nov 10;314(18):1955–65. [PMID: 
26547467]
Fordyce CB et al; Prospective Multicenter Imaging Study for 
Evaluation of Chest Pain (PROMISE) Investigators. Identifi
-
cation of patients with stable chest pain deriving minimal 
value from noninvasive testing: the PROMISE minimal-risk 
tool, a secondary analysis of a randomized clinical trial. 
JAMA Cardiol. 2017 Apr 1;2(4):400–8. [PMID: 28199464]
Hoorweg BB et al. Frequency of chest pain in primary care, 
diagnostic tests performed and final diagnoses. Heart. 2017 
Nov;103(21):1727–32. [PMID: 28634285]
Januzzi JL et al. Sensitive troponin assays in patients with sus
-
pected acute coronary syndrome: results from the multicenter 
Rule Out Myocardial Infarction using Computer Assisted 
Tomography II trial. Am Heart J. 2015 Apr;169(4):572–8. 
[PMID: 25819865]
Kim Y et al. Depression is associated with recurrent chest pain 
with or without coronary artery disease: a prospective cohort 
study in the emergency department. Am Heart J. 2017 
Sep;191:47–54. [PMID: 28888269]
Syed S et al. Prospective validation of a clinical decision rule to 
identify patients presenting to the emergency department 
with chest pain who can safely be removed from cardiac 
monitoring. CMAJ. 2017 Jan 30;189(4):E139–145. [PMID: 
28246315]
 
»
Forceful, rapid, or irregular beating of the heart.
 
»
Rate, duration, and degree of regularity of heart
-
beat; age at first episode.
 
»

28246315]
 
»
 
»
-
 
»
Factors that precipitate or terminate episodes.
 
»
Light-headedness or syncope; neck pounding.
 
»
Chest pain; history of myocardial infarction or 
structural heart disease.
 
»
Palpitations are defined as an unpleasant awareness of the 
forceful, rapid, or irregular beating of the heart. They are 
the primary symptom for approximately 16% of patients 
presenting to an outpatient clinic with a cardiac complaint. 
Palpitations represent 5.8 of every 1000 emergency depart
-
ment visits, with an admission rate of 24.6%. While palpita
-
tions are usually benign, they are occasionally the symptom 
of a life-threatening arrhythmia. To avoid missing a dan
-
gerous cause of the patient’s symptom, clinicians some
-
times pursue expensive and invasive testing when a 
conservative diagnostic evaluation is sufficient. The con
-
verse is also true; in one study, 54% of patients with supra
-
ventricular tachycardia were initially wrongly diagnosed 
with panic, stress, or anxiety disorder. A disproportionate 
number of these misdiagnosed patients are women. 
Table 2–6 lists history, physical examination, and ECG find
-
ings suggesting a cardiovascular cause for the palpitations.
 
»
Although described by patients in a myriad of ways, guid
-
ing the patient through a careful description of their palpi
-
tations may indicate a mechanism and narrow the 
differential diagnosis. Pertinent questions include the age 
at first episode; precipitants; and rate, duration, and degree 
CMDT19_Ch02_p0020-p0045.indd   30

31
 
CMDT 2019
of regularity of the heartbeat during the subjective palpita
-
tions. Palpitations lasting less than 5 minutes and a family 
history of panic disorder reduce the likelihood of an 
arrhythmic cause (LR = 0.38 and LR = 0.26, respectively). 
To better understand the symptom, the examiner can ask 
the patient to “tap out” the rhythm with his or her fingers. 
The circumstances associated with onset and termination 
can also be helpful in determining the cause. Palpitations 
that start and stop abruptly suggest supraventricular or 
ventricular tachycardias. Termination of palpitations using 
vagal maneuvers (eg, Valsalva maneuver) suggests supra
-
ventricular tachycardia.
Three common descriptions of palpitations are (1) 
“flip-flopping” (or “stop and start”), often caused by pre
-
mature contraction of the atrium or ventricle, with the 
perceived “stop” from the pause following the contraction, 
and the “start” from the subsequent forceful contraction; 
(2) rapid “fluttering in the chest, ” with regular “fluttering” 
suggesting supraventricular or ventricular arrhythmias 
(including sinus tachycardia) and irregular “fluttering” 
suggesting atrial fibrillation, atrial flutter, or tachycardia 
with variable block; and (3) “pounding in the neck” or neck 
pulsations, often due to “cannon” A waves in the jugular 
venous pulsations that occur when the right atrium con
-
tracts against a closed tricuspid valve.
Palpitations associated with chest pain suggest ischemic 
heart disease, or if the chest pain is relieved by leaning 
forward, pericardial disease is suspected. Palpitations asso
-
ciated with light-headedness, presyncope, or syncope sug
-
gest hypotension and may signify a life-threatening cardiac 
arrhythmia. Palpitations that occur regularly with exertion 
suggest a rate-dependent bypass tract or hypertrophic car
-
diomyopathy. If a benign etiology for these concerning 
symptoms cannot be ascertained at the initial visit, then 
ambulatory monitoring or prolonged cardiac monitoring 
in the hospital might be warranted.
Noncardiac symptoms should also be elicited since the 
palpitations may be caused by a normal heart responding 
to a metabolic or inflammatory condition. Weight loss sug
-
gests hyperthyroidism. Palpitations can be precipitated by 
vomiting or diarrhea that leads to electrolyte disorders and 
hypovolemia. Hyperventilation, hand tingling, and ner
-
vousness are common when anxiety or panic disorder is 
the cause of the palpitations. Palpitations associated with 
flushing and diaphoresis may be caused by a 
pheochromocytoma.
A family history of palpitations or sudden death sug
-
gests an inherited etiology such as long QT syndrome or 
Brugada syndrome. Chagas disease may cause palpitations 
and acute myocarditis.
Rarely does the clinician have the opportunity to examine 
a patient during an episode of palpitations. However, care
-
ful cardiovascular examination can find abnormalities that 
can increase the likelihood of specific cardiac arrhythmias. 
The midsystolic click of mitral valve prolapse can suggest 
the diagnosis of a supraventricular arrhythmia. The harsh 
holosystolic murmur of hypertrophic cardiomyopathy, 
which occurs along the left sternal border and increases 
with the Valsalva maneuver, suggests atrial fibrillation or 
ventricular tachycardia. The presence of dilated cardiomy
-
opathy, suggested on examination by a displaced and 
enlarged cardiac point-of-maximal impulse, increases the 
likelihood of ventricular tachycardia and atrial fibrillation. 
In patients with chronic atrial fibrillation, in-office exercise 
(eg, a brisk walk in the hallway) may reveal an intermittent 
accelerated ventricular response as the cause of the palpita
-
tions. The clinician should also look for signs of hyperthy
-
roidism (eg, tremulousness, brisk deep tendon reflexes, or 
fine hand tremor), or signs of stimulant drug use (eg,

-
-
fine hand tremor), or signs of stimulant drug use (eg, 
dilated pupils or skin or nasal septal perforations). Visible 
neck pulsations (LR, 2.68; 95% CI, 1.25–5.78) in associa
-
tion with palpitations increases the likelihood of atrioven
-
tricular nodal reentry tachycardia.
1. ECG—
A 12-lead ECG should be performed on all 
patients reporting palpitations because it can provide evi
-
dence for a wide variety of causes. Although in most 
instances a specific arrhythmia will not be detected on the 
tracing, a careful evaluation of the ECG can help the clini
-
cian deduce a likely etiology in certain circumstances.
For instance, bradyarrhythmias and heart block can be 
associated with ventricular ectopy or escape beats that may 
be experienced as palpitations by the patient. Evidence of 
prior myocardial infarction on ECG (eg, Q waves) increases 
the patient’s risk for nonsustained or sustained ventricular 
tachycardia. Ventricular preexcitation (Wolff-Parkinson-
White syndrome) is suggested by a short PR interval (less 
than 0.20 ms) and delta waves (upsloping PR segments). Left 
ventricular hypertrophy with deep septal Q waves in I, AVL, 
and V4 through V6 is seen in patients with hypertrophic 
obstructive cardiomyopathy. The presence of left atrial 
enlargement as suggested by a terminal P-wave force in V1 
more negative than 0.04 msec and notching in lead II reflects 
a patient at increased risk for atrial fibrillation. A prolonged 
QT interval and abnormal T-wave morphology suggest the 
long QT syndrome, which puts patients at increased risk for 
ventricular tachycardia. Persistent ST-segment elevations in 
Table 2–6.
 
Palpitations: Patients at high risk for a 
 
cardiovascular cause.
h
ist
orical risk factors
 
F
amily history of significant arrhythmias
 
P
ersonal or family history of syncope or resuscitated sudden 
 
death
 
H
istory of myocardial infarction (and likely scarred myocardium)
 
P
alpitations that occur during sleep
Physical examination findings
 
S
tructural heart disease such as dilated or hypertrophic 
 
cardiomyopathies
 
V
alvular disease (stenotic or regurgitant)
e
CG findings
 
L
ong QT syndrome
 
S
econd- or third-degree heart block
 
Sustained 
ventricular arrhythmias
CMDT19_Ch02_p0020-p0045.indd   31

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 CMDT 2019
ECG leads V1–V3 (particularly with a coved or saddle-back 
pattern) suggest Brugada syndrome.
2.
 
Monit
oring devices—
For high-risk patients (Table 2–6), 
further diagnostic studies are warranted. A step-wise 
approach has been suggested—starting with ambulatory 
monitoring devices (Holter monitoring if the palpitations 
are expected to occur within the subsequent 72-hour 
period, event monitoring if less frequent). A single-lead, 
lightweight, continuously recording ambulatory adhesive 
patch monitor (Zio Patch) worn for 14 days has been 
shown to be superior to 24-hour Holter monitoring. This is 
then followed by inpatient continuous monitoring if seri
-
ous arrhythmias are strongly suspected despite normal 
findings on the ambulatory monitoring, and by invasive 
electrophysiologic testing if the ambulatory or inpatient 
monitor records a worrisome arrhythmia.
In patients with a prior myocardial infarction, ambula
-
tory cardiac monitoring or signal-averaged ECG are appro
-
priate next steps to help exclude ventricular tachycardia. 
ECG exercise testing is appropriate in patients with sus
-
pected coronary artery disease and in patients who have 
palpitations with physical exertion. Echocardiography is 
useful when physical examination or ECG suggests struc
-
tural abnormalities or decreased ventricular function.
 
»
When assessing a patient with palpitations in an urgent 
care setting, the clinician must ascertain whether the 
symptoms represent (1) an arrhythmia that is minor and 
transient, (2) a significant cardiovascular disease, (3) a 
cardiac manifestation of a systemic disease such as thyro
-
toxicosis, or (4) a benign somatic symptom that is ampli
-
fied by the patient’s underlying psychological state.
Patients with palpitations who seek medical attention 
in an emergency department instead of a medical clinic 
are more likely to have a cardiac cause (47% versus 21%), 
whereas psychiatric causes are more common among 
those who seek attention in office practices (45% versus 
27%). In a study of patients who went to a university medi
-
cal clinic with the chief complaint of palpitations, causes 
were cardiac in 43%, psychiatric in 31%, and miscella
-
neous in 10%.
The most common psychiatric causes of palpitations 
are anxiety and panic disorder. The release of catechol
-
amines during a significant stress or panic attack can trig
-
ger an arrhythmia. Asking a single question, “Have you 
experienced brief periods, for seconds or minutes, of an 
overwhelming panic or terror that was accompanied by 
racing heartbeats, shortness of breath, or dizziness?” can 
help identify patients with panic disorder.
Miscellaneous causes of palpitations include fever, 
dehydration, hypoglycemia, anemia, thyrotoxicosis, mas
-
tocytosis, and pheochromocytoma. Drugs such as cocaine, 
alcohol, caffeine, pseudoephedrine, and illicit ephedra can 
precipitate palpitations, as can prescription medications, 
including digoxin, amitriptyline, erythromycin and other 
drugs that prolong the QT interval, class 1 antiarrhythmics, 
dihydropyridine calcium channel blockers, phenothi
-
azines, theophylline, and beta-agonists.
 
»
Treatment
After ambulatory monitoring, most patients with palpita
-
tions are found to have benign atrial or ventricular ectopy 
or nonsustained ventricular tachycardia. In patients with 
structurally normal hearts, these arrhythmias are not asso
-
ciated with adverse outcomes. Abstention from caffeine 
and tobacco may help. Often, reassurance suffices. If not, 
or in very symptomatic patients, a trial of a beta-blocker 
may be prescribed. A three-session course of cognitive-
behavioral therapy that includes some physical activity has 
proven effective for patients with benign palpitations with 
or without chest pain. For treatment of specific atrial or 
ventricular arrhythmias, see Chapter 10.
 
»
•	
For electrophysiologic studies.
•

»
•	
•	
For advice regarding treatment of atrial or ventricular 
arrhythmias.
 
»
•	
Palpitations associated with syncope or near-syncope, 
particularly when the patient is aged 75 years or older 
and has an abnormal ECG, hematocrit less than 30%, 
shortness of breath, respiratory rate higher than 24/min, 
or a history of HF.
•	
Patients with risk factors for a serious arrhythmia.
Abi Khalil C et al. Investigating palpitations: the role of Holter 
monitoring and loop recorders. BMJ. 2017 Jul 27;358:j3123. 
[PMID: 28751495]
Gale CP et al. Assessment of palpitations. BMJ. 2016 Jan 6;
 
352:h5649. [PMID: 26739319]
Probst MA et al. Emergency physicians’ perceptions and deci
-
sion-making processes regarding patients presenting with 
palpitations. J Emerg Med. 2015 Aug;49(2):236–43. [PMID: 
25943288]
LOWER EXTREMITY EDEMA
 
»
History of venous thromboembolism.
 
»
Symmetry of swelling.
 
»
Pain.
 
»
Change with dependence.
 
»
Skin findings: hyperpigmentation, stasis dermatitis, 
lipodermatosclerosis, atrophie blanche, ulceration.
 
»
Acute and chronic lower extremity edema present impor
-
tant diagnostic and treatment challenges. Lower extremi
-
ties can swell in response to increased venous or lymphatic 
pressures, decreased intravascular oncotic pressure, 
increased capillary leak, and local injury or infection. 
CMDT19_Ch02_p0020-p0045.indd   32

33
 
CMDT 2019
Chronic venous insufficiency
 is by far the most common 
cause, affecting up to 2% of the population, and the inci
-
dence of venous insufficiency has not changed during the 
past 25 years. Venous insufficiency is a common complica
-
tion of DVT; however, only a small number of patients with 
chronic venous insufficiency report a history of this disor
-
der. Venous ulceration commonly affects patients with 
chronic venous insufficiency, and its management is labor-
intensive and expensive. Normal lower extremity venous 
pressure (in the erect position: 80 mm Hg in deep veins, 
20–30 mm Hg in superficial veins) and cephalad venous 
blood flow require competent bicuspid venous valves, 
effective muscle contractions, normal ankle range of 
motion, and normal respirations. When one or more of 
these components fail, venous hypertension may result. 
Chronic exposure to elevated venous pressure by the post
-
capillary venules in the legs leads to leakage of fibrinogen 
and growth factors into the interstitial space, leukocyte 
aggregation and activation, and obliteration of the cutane
-
ous lymphatic network.
 
»
A. Symptoms and Signs
1. Unilateral lower extremity edema—
Among common 
causes of unilateral lower extremity swelling, DVT is the 
most life-threatening. Clues suggesting DVT include a 
history of cancer, recent limb immobilization, or confine
-
ment to bed for at least 3 days following major surgery 
within the past month (Table 2–7). Lower extremity swell
-
ing and inflammation in a limb recently affected by DVT 
could represent anticoagulation failure and thrombus 
recurrence but more often are caused by 
postphlebitic 
syndrome
 with valvular incompetence. A search for 
alternative explanations is equally important in exclud
-
ing DVT. Other causes of a painful, swollen calf 
include cellulitis, musculoskeletal disorders (Baker cyst 
rupture (“pseudothrombophlebitis”), gastrocnemius tear 
or rupture, calf strain or trauma, and left common iliac 
vein compression (May-Thurner syndrome), as well as 
other sites of nonthrombotic venous outflow obstruction, 
such as the inguinal ligament, iliac bifurcation, and popli
-
teal fossa.
2. Bilateral lower extremity edema—
Bilateral involve
-
ment and significant improvement upon awakening favor 
systemic causes (eg, venous insufficiency) and can be a 
presenting symptom of volume overload (HF, cirrhosis, 
kidney disease (eg, nephrotic syndrome). The sensation of 
“heavy legs” is the most frequent symptom of chronic 
venous insufficiency, followed by itching. Chronic expo
-
sure to elevated venous pressure accounts for the brawny, 
fibrotic skin changes observed in patients with chronic 
venous insufficiency as well as the predisposition toward 
skin ulceration, particularly in the medial malleolar area. 
Pain, particularly if severe, is uncommon in uncomplicated 
venous insufficiency.
Lower extremity swelling is a familiar complication of 
therapy with calcium channel blockers (particularly felo
-
dipine and amlodipine), pioglitazone, gabapentin, and 
minoxidil. Prolonged airline flights (longer than 10 hours) 
are associated with edema even in the absence of DVT. 
Lymphedema and lipoedema are other causes of bilateral 
lower extremity edema.
Physical examination should include assessment of the 
heart, lungs, and abdomen for evidence of pulmonary 
hypertension (primary or secondary to chronic lung dis
-
ease), HF, or cirrhosis. Some patients with cirrhosis have 
pulmonary hypertension without lung disease. There is a 
spectrum of skin findings related to chronic venous insuf
-
ficiency that depends on the severity and chronicity of the 
disease, ranging from hyperpigmentation and stasis der
-
matitis to abnormalities highly specific for chronic venous 
insufficiency: lipodermatosclerosis (thick, brawny skin; in 
advanced cases, the lower leg resembles an inverted cham
-

-
-
pagne bottle) and atrophie blanche (small depigmented 
macules within areas of heavy pigmentation). The size of 
both calves should be measured 10 cm below the tibial 
tuberosity and pitting and tenderness elicited. Leg edema 
may also be measured by ultrasonography with a gel pad if 
physical examination is equivocal. Swelling of the entire leg 
or of one leg 3 cm more than the other suggests deep 
venous obstruction. The left calf is normally slightly larger 
than the right as a result of the left common iliac vein 
coursing under the aorta.
Table 2–7.
 
Risk stratification of adults referred for 
ultrasound to rule out DVT.
Step 1: Calculate risk factor score
Score 1 point for each
 
Un
treated malignancy
 
P
aralysis, paresis, or recent plaster immobilization
 
Rec
ently bedridden for > 3 days due to major surgery within 
 
4 w
eeks
 
L
ocalized tenderness along distribution of deep venous system
 
En
tire leg swelling
 
S
welling of one calf > 3 cm more than the other (measured 
 
10 cm 
below tibial tuberosity)
 
I
psilateral pitting edema
 
C
ollateral superficial (nonvaricose) veins
 
P
reviously documented DVT
a
lt
ernative diagnosis as likely as or more likely than DVT: 
 
subtract 2 points
Step 2: Obtain ultrasound
Score
Ultrasound Positive
Ultrasound Negative
0
Confirm with venogram
DVT ruled out
1–2
Treat for DVT
Repeat ultrasound in 
 
3–7 days
≥ 3
DVT, deep venous thrombosis.
CMDT19_Ch02_p0020-p0045.indd   33

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An ulcer located over the medial malleolus is a hall
-
mark of chronic venous insufficiency but can be due to 
other causes. Shallow, large, modestly painful ulcers are 
characteristic of venous insufficiency, whereas small, deep, 
and more painful ulcers are more apt to be due to arterial 
insufficiency, vasculitis, or infection (including cutaneous 
diphtheria). Diabetic vascular ulcers, however, may be 
painless. When an ulcer is on the foot or above the mid-
calf, causes other than venous insufficiency should be 
Patients without an obvious cause of acute lower extremity 
swelling (eg, calf strain) should have an ultrasound per
-
formed, since DVT is difficult to exclude on clinical 
grounds. A prediction rule allows a clinician to exclude a 
lower extremity DVT in patients without an ultrasound if 
the patient has low pretest probability for DVT and a nega
-
tive sensitive D-dimer test (the “Wells prediction rule”). 
Assessment of the ankle-brachial pressure index (ABPI) is 
important in the management of chronic venous insuffi
-
ciency, since peripheral arterial disease may be exacerbated 
by compression therapy. This can be performed at the same 
time as ultrasound. Caution is required in interpreting the 
results of ABPI in older patients and diabetics due to the 
decreased compressibility of their arteries. A urine dipstick 
test that is strongly positive for protein can suggest 
nephrotic syndrome, and a serum creatinine can help esti
-
mate kidney function.
 
»
Treatment
Treatment of lower extremity edema should be guided by 
the underlying cause. See relevant chapters for treatment of 
edema in patients with HF (Chapter 10), nephrosis 
(Chapter 22), cirrhosis (Chapter 16), and lymphedema and 
venous stasis ulcers (Chapter 12). Edema resulting from 
calcium channel blocker therapy responds to concomitant 
therapy with ACE inhibitors or angiotensin receptor 
blockers.
In patients with chronic venous insufficiency without a 
comorbid volume overload state (eg, HF), it is best to avoid 
diuretic therapy. These patients have relatively decreased 
intravascular volume, and administration of diuretics may 
first enhance sodium retention through increased secre
-
tion of renin and angiotensin and then result in acute kid
-
ney injury and oliguria. Instead, the most effective 
treatment involves (1) leg elevation, above the level of the 
heart, for 30 minutes three to four times daily, and during 
sleep; (2) compression therapy; and (3) ambulatory exer
-
cise to increase venous return through calf muscle contrac
-
tions. There is no evidence for benefit or harm of 
valvuloplasty in the treatment of patients with deep venous 
insufficiency secondary to primary valvular 
incompetence.
A wide variety of stockings and devices are effective in 
decreasing swelling and preventing ulcer formation. They 
should be put on with awakening, before hydrostatic forces 
result in edema. To control simple edema, 20–30 mm Hg is 
usually sufficient, whereas 30–40 mm Hg is usually 
required to control moderate to severe edema associated 
with ulcer formation. To maintain improvement, consider 
switching from an elastic stocking to one made of inelastic 
grosgrain material. Patients with decreased ABPI should be 
managed in concert with a vascular surgeon. Compression 
stockings (12–18 mm Hg at the ankle) are effective in pre
-
venting edema and asymptomatic thrombosis associated 
with long airline flights in low- to medium-risk persons. 
For lymphedema, bandaging systems applied twice weekly 
can be effective. Short-term manual lymphatic drainage 
treatment may improve chronic venous insufficiency 
severity, symptoms, and quality of life.
 
»
•	
Chronic lower extremity ulcerations requiring specialist 
wound care.
•	
Refer patients with nephrotic syndrome to a 
•	
Refer patients with coexisting severe arterial insuffi
-

•	
•	
•	
-
ciency (claudication) that would complicate treatment 
with compression stockings to a vascular surgeon.
 
»
•	
Pending definitive diagnosis in patients at high risk for 
DVT despite normal lower extremity ultrasound.
•	
Severe, acute swelling raising concern for an impending 
compartment syndrome.
•	
Severe edema that impairs ability to ambulate or per
-
form activities of daily living.
Clarke MJ et al. Compression stockings for preventing deep vein 
thrombosis in airline passengers. Cochrane Database Syst 
Rev. 2016 Sep 14;9:CD004002. [PMID: 27624857]
dos Santos Crisóstomo RS et al. Influence of manual lymphatic 
drainage on health-related quality of life and symptoms of 
chronic venous insufficiency: a randomized controlled trial. 
Arch Phys Med Rehabil. 2015 Feb;96(2):283–91. [PMID: 
25308883]
Fox JD et al. Ankle range of motion, leg pain, and leg edema 
improvement in patients with venous leg ulcers. JAMA Der
-
matol. 2016 Apr;152(4):472–4. [PMID: 26818102]
Goel RR et al. Surgery for deep venous incompetence. Cochrane 
Database Syst Rev. 2015 Feb 23;2:CD001097. [PMID: 25702915]
FEVER & HYPERTHERMIA
 
»
Age; injection substance use.
 
»
Localizing symptoms; weight loss; joint pain.
 
»
Immunosuppression or neutropenia; history of 
cancer.
 
»
Medications.
 
»
Travel.
CMDT19_Ch02_p0020-p0045.indd   34

35
 
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»
The average normal oral body temperature taken in mid-
morning is 36.7°C (range 36–37.4°C). This range includes 
a mean and 2 standard deviations, thus encompassing 95% 
of a normal population (normal diurnal temperature varia
-
tion is 0.5–1°C). The normal rectal or vaginal temperature 
is 0.5°C higher than the oral temperature, and the axillary 
temperature is 0.5°C lower. Interestingly, in a pooled meta-
analysis comparing peripheral with central body tempera
-
ture measurement, peripheral thermometers (tympanic 
membrane, temporal artery, axillary, oral) showed low 
sensitivity, but high specificity. This suggests that a normal 
body temperature based on a peripheral measurement 
does not always exclude the presence of a fever. Thus, to 
exclude a fever, a rectal temperature is more reliable than 
an oral temperature (particularly in patients who breathe 
through their mouth or are tachypneic or who are in an 
intensive care unit setting where a rectal temperature probe 
can be placed to detect fever). Wearable digital thermom
-
eters may detect early mild increased temperature in 
patients with low white blood counts.
Fever is a regulated rise to a new “set point” of body 
temperature in the hypothalamus induced by pyrogenic 
cytokines. The elevation in temperature results from 
either increased heat production (eg, shivering) or 
decreased heat loss (eg, peripheral vasoconstriction). 
Body temperature in cytokine-induced fever seldom 
exceeds 41.1°C unless there is structural damage to hypo
-
thalamic regulatory centers.
 
»
A. Fever
Fever as a symptom provides important information about 
the presence of illness—particularly infections—and about 
changes in the clinical status of the patient. Fever may be 
more predictive of bacteremia in elderly patients. The fever 
pattern, however, is of marginal value for most specific 
diagnoses except for the relapsing fever of malaria, bor
-
reliosis, and occasional cases of lymphoma, especially 
Hodgkin disease. Furthermore, the degree of temperature 
elevation does not necessarily correspond to the severity of 
the illness. Contrary to common perceptions, a Swedish 
study found that increased body temperature in the emer
-
gency department was strongly associated with lower mor
-
tality and shorter hospital stays in patients with severe 
sepsis or septic shock subsequently admitted to the ICU 
even after adjustment for quality of care measures.
In general, the febrile response tends to be greater in 
children than in adults. In older persons, neonates, and in 
persons receiving certain medications (eg, NSAIDs, corti
-
costeroids), a normal temperature or even hypothermia 
may be observed. Markedly elevated body temperature may 
result in profound metabolic disturbances. High tempera
-
ture during the first trimester of pregnancy may cause birth 
defects, such as anencephaly. Fever increases insulin 
requirements and alters the metabolism and disposition of 
drugs used for the treatment of the diverse diseases associ
-
ated with fever.
Fever in the neurointensive care unit can occur directly 
from brain injury (called “central fever”). One model pre
-
dicted “central fever” with 90% probability if a patient met 
all of the following criteria: (1) less than 72 hours of neuro
-
logic intensive care unit admission, (2) presence of sub
-
arachnoid hemorrhage, intraventricular hemorrhage or 
brain tumor, (3) absence of infiltrate on chest radiograph, 
and (4) negative cultures.
The prevalence of intrapartum fever of 38°C or greater 
in pregnancies of 36 weeks’ gestation or more is 6.8% or 1 
in 15 women in labor. The neonatal sepsis rate among 
affected mothers is 0.24%, or less than 1 in 400 babies. 
Therefore, universal laboratory work, cultures, and antibi
-
otic treatment pending culture results for this newborn 
population need further examination.
Fever is common postoperatively following posterior

-
Fever is common postoperatively following posterior 
spinal fusion in pediatric patients; infection is an uncom
-
mon cause.
B. Hyperthermia
Hyperthermia—not mediated by cytokines—occurs when 
body metabolic heat production (as in thyroid storm) or 
environmental heat load exceeds normal heat loss capacity 
or when there is impaired heat loss; heat stroke is an 
example. Body temperature may rise to levels (more than 
41.1°C) capable of producing irreversible protein denatur
-
ation and resultant brain damage; no diurnal variation is 
observed.
Malignant catatonia is a disorder consisting of catatonic 
symptoms, hyperthermia, autonomic instability, and 
altered mental status.
Neuroleptic malignant syndrome,
 a variant of malig
-
nant catatonia, is a rare and potentially lethal idiosyncratic 
reaction to neuroleptic medications, particularly haloperi
-
dol and fluphenazine; however, it has also been reported 
with the atypical neuroleptics (such as olanzapine or ris
-
peridone) (see Chapter 25). 
Serotonin syndrome
 resem
-
bles neuroleptic malignant syndrome but occurs within 
hours of ingestion of agents that increase levels of sero
-
tonin in the central nervous system, including serotonin 
reuptake inhibitors, monoamine oxidase inhibitors, tricy
-
clic antidepressants, meperidine, dextromethorphan, bro
-
mocriptine, tramadol, lithium, and psychostimulants (such 
as cocaine, methamphetamine, and MDMA) (see Chapter 38). 
Clonus and hyperreflexia are more common in serotonin 
syndrome, whereas “lead pipe” rigidity is more common in 
neuroleptic malignant syndrome. Neuroleptic malignant 
and serotonin syndromes share common clinical and 
pathophysiologic features with 
malignant hyperthermia
 of 
anesthesia (see Chapter 38).
C. Fever of Undetermined Origin
See Fever of Unknown Origin, Chapter 30.
 
»
Treatment
Most fever is well tolerated. When the temperature is less 
than 40°C, symptomatic treatment only is required. A tem
-
perature greater than 41°C is likely to be hyperthermia 
rather than cytokine mediated, and 
emergent management 
CMDT19_Ch02_p0020-p0045.indd   35

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 CMDT 2019
is indicated
. (See Heat Stroke, Chapter 37.) The treatment 
of fever with antipyretics does not appear to affect mortal
-
ity of critically ill patients or affect the number of intensive 
care unit–free days.
A. General Measures for Removal of Heat
Regardless of the cause of the fever, alcohol sponges, cold 
sponges, ice bags, ice-water enemas, and ice baths will 
lower body temperature (see Chapter 37). They are more 
useful in hyperthermia, since patients with cytokine-
related fever will attempt to override these therapies.
B. Pharmacologic Treatment of Fever
1. Antipyretic drugs—
Antipyretic therapy is not needed 
except for patients with marginal hemodynamic status. 
Early administration of acetaminophen to treat fever due 
to probable infection did not affect the number of ICU-free 
days. Aspirin or acetaminophen, 325–650 mg every 4 hours, 
is effective in reducing fever. These drugs are best admin
-
istered around the clock, rather than as needed, since “as 
needed” dosing results in periodic chills and sweats due to 
fluctuations in temperature caused by varying levels of 
drug.
2. Antimicrobial therapy—
Antibacterial and antifungal 
prophylactic regimens are recommended only for patients 
expected to have less than 100 neutrophils/mcL for more 
than 7 days, unless other factors increase risks for compli
-
cations or mortality. In most febrile patients, empiric anti
-
biotic therapy should be deferred pending further 
evaluation. However, empiric antibiotic therapy is some
-
times warranted. Prompt broad-spectrum antimicrobials 
are indicated for febrile patients who are clinically unstable, 
even before infection can be documented. These include 
patients with hemodynamic instability, those with neutro
-
penia (neutrophils less than 500/mcL), others who are 
asplenic (surgically or secondary to sickle cell disease) or 
immunosuppressed (including individuals taking systemic 
corticosteroids, azathioprine, cyclosporine, or other immu
-
nosuppressive medications) (Tables 30–4 and 30–5), and 
those who are HIV infected (see Chapter 31).
Febrile neutropenic patients should receive initial doses 
of empiric antibacterial therapy within an hour of triage 
and should either be monitored for at least 4 hours to 
determine suitability for outpatient management or be 
admitted to the hospital (see Infections in the Immuno
-
compromised Patient, Chapter 30). Inpatient treatment is 
standard to manage febrile neutropenic episodes, although 
carefully selected patients may be managed as outpatients 
after systematic assessment beginning with a validated risk 
index (eg, Multinational Association for Supportive Care 
in Cancer [MASCC] score or Talcott rules). In the MASCC 
index calculation, low-risk factors include the following: 
age under 60 years (2 points), burden of illness (5 points for 
no or mild symptoms and 3 points for moderate symp
-
toms), outpatient status (3 points), solid tumor or hemato
-
logic malignancy with no previous fungal infection (4 points), 
no COPD (4 points), no dehydration requiring parenteral 
fluids (3 points), and systolic blood pressure greater than 
90 mm Hg (5 points). Patients with MASCC scores 21 or 
higher or in Talcott group 4 (presentation as an outpatient 
without significant comorbidity or uncontrolled cancer), 
and without other risk factors, can be managed safely as 
outpatients.
The carefully selected outpatients determined to be at 
low risk by MASCC score (particularly in combination 
with a normal serum C-reactive protein level) or by Talcott 
rules can be managed with an oral fluoroquinolone plus 
amoxicillin/clavulanate (or clindamycin, if penicillin aller
-
gic), unless fluoroquinolone prophylaxis was used before 
fever developed. For treatment of fever during neutropenia 
following chemotherapy, outpatient parenteral antimicro
-
bial therapy can be provided effectively and safely (in low-
risk patients) with a single agent such as cefepime,

-
risk patients) with a single agent such as cefepime, 
piperacillin/tazobactam, imipenem, meropenem or 
doripenem; or (in high-risk patients) with a combination 
of agents such as an aminoglycoside 
plus
 one of the follow
-
ing agents: piperacillin/tazobactam, cefepime (or ceftazi
-
dime), imipenem, or meropenem (or doripenem); 
or
 
vancomycin 
plus
 one of the following: either piperacillin/
tazobactam, cefepime (or ceftazidime), imipenem, merope
-
nem, or aztreonam 
and
 an aminoglycoside, or ciprofloxa
-
cin 
and
 an aminoglycoside. If a fungal infection is suspected 
in patients with prolonged fever and neutropenia, flucon
-
azole is an equally effective but less toxic alternative to 
amphotericin B.
C. Treatment of Hyperthermia
Discontinuation of the offending agent is mandatory. 
Treatment of neuroleptic malignant syndrome includes 
dantrolene in combination with bromocriptine or levodopa 
(see Chapter 25). Treatment of serotonin syndrome 
includes administration of a central serotonin receptor 
antagonist—cyproheptadine or chlorpromazine—alone or 
in combination with a benzodiazepine (see Chapter 38). In 
patients for whom it is difficult to distinguish which syn
-
drome is present, treatment with a benzodiazepine may be 
the safest therapeutic option.
 
»
•	
Presence of additional vital sign abnormalities or evi
-
dence of end-organ dysfunction in clinical cases when 
early sepsis is suspected.
•	
For measures to control a temperature higher than 41°C 
or when fever is associated with seizure or other mental 
status changes.
•	
Heat stroke.
•	
Neuroleptic malignant syndrome; serotonin syndrome; 
malignant hyperthermia of anesthesia.
Abbasi J. Wearable digital thermometer improves fever detec
-
tion. JAMA. 2017 Aug 8;318(6):510. [PMID: 28787489]
Combariza JF et al. C-reactive protein and the MASCC risk 
index identify high-risk patients with febrile neutropenia and 
hematologic neoplasms. Support Care Cancer. 2015 
Apr;23(4):1009–13. [PMID: 25270070]
Cunha BA et al. Fever of unknown origin: a clinical approach. 
Am J Med. 2015 Oct;128(10):1138.e1–15. [PMID: 26093175]
CMDT19_Ch02_p0020-p0045.indd   36

37
 
CMDT 2019
DeWitt S et al. Evaluation of fever in the emergency depart
-
ment. Am J Emerg Med. 2017 Nov;35(11):1755–8. [PMID: 
28822610]
Sundén-Cullberg J et al. Fever in the emergency department 
predicts survival of patients with severe sepsis and septic 
shock admitted to the ICU. Crit Care Med. 2017 Apr;45(4):
 
591–9. [PMID: 28141683]
Y oung P et al; HEAT Investigators; Australian and New Zealand 
Intensive Care Society Clinical Trials Group. Acetaminophen 
for fever in critically ill patients with suspected infection. N 
Engl J Med. 2015 Dec 3;373(23):2215–24. [PMID: 26436473]
INVOLUNTARY WEIGHT LOSS
 
»
Age; caloric intake; secondary confirmation (eg, 
changes in clothing size).
 
»
Fever; change in bowel habits.
 
»
Substance abuse.
 
»
Age-appropriate cancer screening history.
 
»
Body weight is determined by a person’s caloric intake, 
absorptive capacity, metabolic rate, and energy losses. 
Body weight normally peaks by the fifth or sixth decade 
and then gradually declines at a rate of 1–2 kg per decade. 
In NHANES II, a national survey of community-dwelling 
elders (aged 50–80 years), recent involuntary weight loss 
(more than 5% usual body weight) was reported by 7% of 
respondents, and this was associated with a 24% higher 
mortality. In contrast, one study found that a BMI of 33 or 
less is not associated with an increased mortality in adults 
aged 65 years or older. In postmenopausal women, unin
-
tentional weight loss was associated with increased rates of 
hip and vertebral fractures.
 
»
Etiology
Involuntary weight loss is regarded as clinically significant 
when it exceeds 5% or more of usual body weight over a 
6- to 12-month period. It often indicates serious physical 
or psychological illness. Physical causes are usually evident 
during the initial evaluation. The most common causes are 
cancer (about 30%), gastrointestinal disorders (about 15%), 
and dementia or depression (about 15%). When an ade
-
quately nourished–appearing patient complains of weight 
loss, inquiry should be made about exact weight changes 
(with approximate dates) and about changes in clothing 
size. Family members can provide confirmation of weight 
loss, as can old documents such as driver’s licenses. A mild, 
gradual weight loss occurs in some older individuals 
because of decreased energy requirements. However, rapid 
involuntary weight loss is predictive of morbidity and mor
-
tality. In addition to various disease states, causes in older 
individuals include loss of teeth and consequent difficulty 
with chewing, medications interfering with taste or causing 
nausea, alcoholism, and social isolation.
 
»
Once the weight loss is established, the history, medication 
profile, physical examination, and conventional laboratory 
and radiologic investigations (eg, complete blood count, 
liver biochemical tests, kidney panel, serologic tests includ
-
ing HIV , thyroid-stimulating hormone [TSH] level, uri
-
nalysis, fecal occult blood test, chest radiography, and 
upper gastrointestinal series) usually reveal the cause. 
When these tests are normal, the second phase of evalua
-
tion should focus on more definitive gastrointestinal inves
-
tigation (eg, tests for malabsorption, endoscopy) and 
cancer screening (eg, Papanicolaou smear, mammography, 
prostate specific antigen [PSA]). A prospective case study 
in patients with unintentional weight loss showed that 
colonoscopy did not find colorectal cancer if weight loss 
was the sole indication for the test.
If the initial evaluation is unrevealing, follow-up is pref
-
erable to further diagnostic testing. Death at 2-year follow-
up was not nearly as common in patients with unexplained 
involuntary weight loss (8%) as in those with weight loss 
due to malignant (79%) and established nonmalignant 
diseases (19%). Psychiatric consultation should be consid
-

-
ered when there is evidence of depression, dementia, 
anorexia nervosa, or other emotional problems. Ultimately, 
in approximately 15–25% of cases, no cause for the weight 
loss can be found.
 
»
Malignancy, gastrointestinal disorders (poorly fitting den
-
tures, cavities, swallowing or malabsorption disorders, 
pancreatic insufficiency), HF, psychological problems 
(dementia, depression, paranoia), endocrine disorders 
(hyperthyroidism, hypothyroidism, hyperparathyroidism, 
hypoadrenalism), eating problems (dietary restrictions, 
lack of money for food), social problems (alcohol use dis
-
order, social isolation), and medication side effects are all 
established causes.
 
»
Treatment
Weight stabilization occurs in most surviving patients with 
both established and unknown causes of weight loss 
through treatment of the underlying disorder and caloric 
supplementation. Nutrient intake goals are established in 
relation to the severity of weight loss, in general ranging 
from 30 to 40 kcal/kg/day. In order of preference, route of 
administration options include oral, temporary nasojeju
-
nal tube, or percutaneous gastric or jejunal tube. Parenteral 
nutrition is reserved for patients with serious associated 
problems. A variety of pharmacologic agents have been 
proposed for the treatment of weight loss. These can be 
categorized into appetite stimulants (corticosteroids, pro
-
gestational agents, dronabinol, and serotonin antagonists); 
anabolic agents (growth hormone and testosterone deriva
-
tives); and anticatabolic agents (omega-3 fatty acids, pent
-
oxifylline, hydrazine sulfate, and thalidomide). There is no 
evidence that appetite stimulants decrease mortality, and 
they may have severe adverse side effects. Although inflam
-
mation plays a role in the pathophysiology of cancer 
CMDT19_Ch02_p0020-p0045.indd   37

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anorexia-cachexia syndrome, guidelines conclude that 
evidence is insufficient regarding the benefits and harms of 
NSAIDs. Exercise training may prevent or even reverse the 
process of muscle wasting in HF (“cardiac cachexia”).
 
»
•	
Weight loss caused by malabsorption.
•	
Persistent nutritional deficiencies despite adequate 
supplementation.
•	
Weight loss as a result of anorexia or bulimia.
 
»
•	
Severe protein-energy malnutrition, including the syn
-
dromes of kwashiorkor and marasmus.
•	
Vitamin deficiency syndromes.
•	
Cachexia with anticipated progressive weight loss sec
-
ondary to unmanageable psychiatric disease.
•	
Careful electrolyte and fluid replacement in protein-
energy malnutrition and avoidance of “re-feeding 
syndrome. ”
Gaddey HL et al. Unintentional weight loss in older adults. Am 
Fam Physician. 2014 May 1;89(9):718–22. [PMID: [PMID: 
24784334]
Garcia JM et al. Nonsteroidal anti-inflammatory drugs in patients 
with anorexia-cachexia syndrome associated with malignancy 
and its treatments. Am J Med. 2017 Sep;130(9):1033–6. 
[PMID: 29016346]
Saitoh M et al. Sarcopenia, cachexia, and muscle performance in 
heart failure: review update 2016. Int J Cardiol. 2017 Jul 1;
 
238:5–11. [PMID: 28427849]
Venturelli M et al. Possible predictors of involuntary weight loss 
in patients with Alzheimer’s disease. PLoS One. 2016 Jun 27;
 
11(6):e0157384. [PMID: 27347878]
FATIGUE & CHRONIC FATIGUE SYNDROME
 
»
Weight loss; fever.
 
»
Sleep-disordered breathing.
 
»
Medications; substance use.
 
»
Fatigue, as an isolated symptom, accounts for 1–3% of vis
-
its to generalists. The symptom of fatigue is often poorly 
described and less well defined by patients than symptoms 
associated with specific dysfunction of organ systems. 
Fatigue or lassitude and the closely related complaints of 
weakness, tiredness, and lethargy are often attributed to 
overexertion, poor physical conditioning, sleep distur
-
bance, obesity, undernutrition, and emotional problems. A 
history of the patient’s daily living and working habits may 
obviate the need for extensive and unproductive diagnostic 
studies.
The diagnosis of chronic fatigue syndrome remains 
hotly debated because of the lack of a gold standard. Per
-
sons with chronic fatigue syndrome meeting specific crite
-
ria (such as those from the CDC) report a greater frequency 
of childhood trauma and psychopathology and demon
-
strate higher levels of emotional instability and self-
reported stress than persons who do not have chronic 
fatigue. Neuropsychological and neuroendocrine studies 
reveal abnormalities in most patients but no consistent pat
-
tern. Sleep disorders have been reported in 40–80% of 
patients with chronic fatigue syndrome, but polysomno
-
graphic studies have not shown a greater incidence of pri
-
mary sleep disorders in those with chronic fatigue 
syndrome than in controls, suggesting that the sleep disor
-
ders are comorbid rather than causative. Older patients 
with chronic fatigue syndrome demonstrate a greater dis
-
ease impact than younger patients, perhaps secondary to 
their greater autonomic dysfunction, decreased baroreflex 
sensitivity, and prolonged left ventricular ejection time. A 
study found that atopy (especially numerous atopic syn
-
dromes) is associated with chronic fatigue syndrome.
 
»
A. Fatigue
Clinically relevant fatigue is composed of three major com
-
ponents: generalized weakness (difficulty in initiating 
activities); easy fatigability (difficulty in completing activi
-
ties); and mental fatigue (difficulty with concentration and 
memory). Important diseases that can cause fatigue include 
hyperthyroidism and hypothyroidism, HF, infections 
(endocarditis, hepatitis), COPD, sleep apnea, anemia, auto
-
immune disorders, multiple sclerosis, irritable bowel syn
-
drome, Parkinson disease, cerebral vascular accident, and

-
-
drome, Parkinson disease, cerebral vascular accident, and 
cancer. Solution-focused therapy has a significant initial 
beneficial effect on the severity of fatigue and quality of life 
in patients with quiescent inflammatory bowel disease.
Alcohol use disorder, side effects from medications (eg, 
sedatives and beta-blockers), and psychological conditions 
(eg, insomnia, depression, anxiety, panic attacks, dysthmia, 
and somatization disorder) may be the cause. Common 
outpatient infectious causes include mononucleosis and 
sinusitis. These conditions are usually associated with 
other characteristic signs, but patients may emphasize 
fatigue and not reveal their other symptoms unless directly 
asked. The lifetime prevalence of significant fatigue (pres
-
ent for at least 2 weeks) is about 25%. Fatigue of unknown 
cause or related to psychiatric illness exceeds that due to 
physical illness, injury, alcohol, or medications.
Although frequently associated with Lyme disease, 
severe fatigue as a long-term sequela is rare.
B. Chronic Fatigue Syndrome
A working case definition of chronic fatigue syndrome 
indicates that it is not a homogeneous abnormality, there is 
no single pathogenic mechanism (Figure 2–1), and no 
physical finding or laboratory test can be used to confirm 
the diagnosis.
The evaluation of chronic fatigue syndrome includes a 
history and physical examination as well as complete blood 
CMDT19_Ch02_p0020-p0045.indd   38

39
 
CMDT 2019
Symptoms of prolonged or chronic 
fa
tigue 
History and physical 
ex
amination
If abnormal (findings of infection,
neoplasm, or thyroid disease),
pursue appropriate diagnostic 
te
sts
If abnormal, 
ev
aluate with
p
sy
chiatric or neurologic
ex
amination
If abnormal, pursue appropriate
further diagnostic 
ev
aluation 
If fatigue persists or relapses for 
≥6
 months, diagnose either 
chronic fatigue syndrome or idiopathic chronic 
fa
tigue, accordingly
Laboratory 
te
sting (CBC, ESR; serum electrolytes, glucos
e,
 BUN,
creatinine, alkaline phosphatase, AL
T,
 
Ca
2+
, PO
4
3–
, 
to
tal protein,
globulin, albumin, TSH; and UA)   
Mental Status Examination
Idiopathic Chronic 
Fa
tigue
Criteria for fatigue se
ve
ri
ty
 or 
sy
mptoms
of chronic fatigue syndrome are NOT met 
Chronic Fatigue Syndrome
Criteria for se
ve
ri
ty
 of fatigue are met AND four or more of the
following symptoms are concurrently present 
fo
r > 6 months
: 
• 
• 
Tender cervical or axillary lymph nodes
• 
Myalgias
• 
Po
lya
rthralgia
• 
New headaches
• 
Sleep that patient reports as unrefreshing
• 
Post-
exe
rtion malaise
• 
Memory or concentration impairment
▲
  
Figure 2–1.
 
Classification of chronic fatigue patients. 
ALT, alanine aminotransferase; BUN, blood urea nitrogen; 
Ca
2+
, calcium; CBC, complete blood count; ESR, erythro
-
cyte sedimentation rate; PO
4
3–
, phosphate; TSH, thyroid-
stimulating hormone; UA, urinalysis.
count, erythrocyte sedimentation rate, chemistries (blood 
urea nitrogen [BUN]), serum electrolytes, glucose, creati
-
nine, calcium, liver biochemical tests, and thyroid function 
tests), urinalysis, and tuberculin skin test, and screening 
questionnaires for psychiatric disorders. Other tests to be 
performed as clinically indicated are serum cortisol, anti
-
nuclear antibody, rheumatoid factor, immunoglobulin lev
-
els, Lyme serology in endemic areas (although rarely a 
long-term complication of this infection), and HIV anti
-
body. More extensive testing is usually unhelpful, including 
antibody to Epstein-Barr virus. There may be an abnor
-
mally high rate of postural hypotension. Brain MRI is not 
routinely recommended.
 
»
Treatment
A. Fatigue
Management of fatigue involves identification and treat
-
ment of conditions that contribute to fatigue, such as can
-
cer, pain, depression, disordered sleep, weight loss, and 
anemia. Resistance training and aerobic exercise lessens 
fatigue and improves performance for a number of chronic 
conditions associated with a high prevalence of fatigue, 
including HF, COPD, arthritis, and cancer. Continuous 
positive airway pressure is an effective treatment for 
obstructive sleep apnea. Psychostimulants such as methyl
-
phenidate have shown inconsistent results in randomized 
trials of treatment of cancer-related fatigue. Modafinil and 
armodafinil appear to be effective, well-tolerated agents in 
HIV-positive patients with fatigue and as adjunctive 
agents in patients with depression or bipolar disorder with 
fatigue. Testosterone therapy to raise levels from moder
-
ately low to mid-normal in men 65 years or older had no 
benefit for vitality or walking distance. Methylphenidate, 
as well as cognitive behavioral therapy, may improve men
-
tal fatigue and cognitive functions in patients with trau
-
matic brain injury. The TRUST study found that treatment 
of subclinical hypothyroidism did not improve symptoms 
of fatigue as measured by the Tiredness score (3.2±17.7 
and 3.8±18.4, respectively; between-group difference, 0.4; 
95% CI, –2.1–2.9). Vitamin D treatment significantly 
improved fatigue in otherwise healthy persons with vita
-
min D deficiency. Testosterone replacement in hypoandro
-
genic men over 65 had no significant benefit with respect to 
vitality, as assessed by the Functional Assessment of Chronic 
Illness Therapy-Fatigue scale, but men who received testos
-
terone reported slightly better mood and lower severity of

-
terone reported slightly better mood and lower severity of 
depressive symptoms than those who received placebo.
A variety of agents and modalities have been tried for the 
treatment of chronic fatigue syndrome. Acyclovir, intrave
-
nous immunoglobulin, nystatin, clonidine (in adolescent 
chronic fatigue syndrome), peripheral IL-1 inhibition with 
anakinra, and low-dose hydrocortisone do not improve 
symptoms. Some patients with postural hypotension report 
response to increases in dietary sodium as well as fludro
-
cortisone, 0.1 mg orally daily. The immune modulator 
rintatolimod improved some measures of exercise perfor
-
mance compared with placebo in two trials (low strength 
of evidence). There is very limited evidence that dietary 
modification is beneficial.
There is a greater prevalence of past and current psychi
-
atric diagnoses in patients with this syndrome. Affective 
disorders are especially common. Patients with chronic 
fatigue syndrome have benefited from a comprehensive 
multidisciplinary intervention, including optimal medi
-
cal management, treating any ongoing affective or anxi
-
ety disorder pharmacologically, and implementing a 
comprehensive cognitive-behavioral treatment program. 
At present, cognitive-behavioral therapy and graded 
exercise are the treatments of choice for patients with 
chronic fatigue syndrome. 
Cognitive-behavioral therapy,
 
a form of nonpharmacologic treatment emphasizing 
CMDT19_Ch02_p0020-p0045.indd   39
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self-help and aiming to change perceptions and behaviors 
that may perpetuate symptoms and disability, is helpful. 
Although few patients are cured, the treatment effect is 
substantial. Response to cognitive-behavioral therapy is 
not predictable on the basis of severity or duration of 
chronic fatigue syndrome. Patients with high neuroticism 
or low acceptance show more improvement in mental 
quality of life with cognitive-behavioral therapy.
Graded exercise
 has also been shown to improve func
-
tional work capacity and physical function. A 2011 ran
-
domized trial (PACE trial) confirmed the independent 
benefits of cognitive-behavioral therapy and graded exer
-
cise; it found no benefit of adaptive pacing therapy. Physi
-
ologic studies find an altered immune response to exercise 
in patients with chronic fatigue syndrome.
In addition, the clinician’s sympathetic listening and 
explanatory responses can help overcome the patient’s 
frustrations and debilitation by this still mysterious illness. 
All patients should be encouraged to engage in normal 
activities to the extent possible and should be reassured 
that full recovery is eventually possible in most cases. 
Chronic fatigue syndrome is not associated with increased 
all-cause mortality, but one study showed a substantial 
increased risk of completed suicide.
 
»
•	
Infections not responsive to standard treatment.
•	
Difficult to control hyperthyroidism or hypothyroidism.
•	
Severe psychological disease.
•	
Malignancy.
 
»
•	
Failure to thrive.
•	
Fatigue severe enough to impair activities of daily living.
Larun L et al. Exercise therapy for chronic fatigue syndrome. 
Cochrane Database Syst Rev. 2017 Apr 25;4:CD003200. 
[PMID: 28444695]
Nguyen S et al. Cognitive behavior therapy to treat sleep distur
-
bance and fatigue after traumatic brain injury: a pilot ran
-
domized controlled trial. Arch Phys Med Rehabil. 2017 Aug;
 
98(8):1508–17.e2. [PMID: 28400181]
Nowak A et al. Effect of vitamin D3 on self-perceived fatigue: a 
double-blind randomized placebo-controlled trial. Medicine 
(Baltimore). 2016 Dec;95(52):e5353. [PMID: 28033244]
Roberts E et al. Mortality of people with chronic fatigue syn
-
drome: a retrospective cohort study in England and Wales 
from the South London and Maudsley NHS Foundation Trust 
Biomedical Research Centre (SLaM BRC) Clinical Record 
Interactive Search (CRIS) Register. Lancet. 2016 Apr 16;
 
387(10028):1638–43. [PMID: 26873808]
Roerink ME et al. Cytokine inhibition in patients with chronic 
fatigue syndrome: a randomized trial. Ann Intern Med. 2017 
Apr 18;166(8):557–64. [PMID: 28265678]
Snyder PJ et al; Testosterone Trials Investigators. Effects of tes
-
tosterone treatment in older men. N Engl J Med. 2016 Feb 18;
 
374(7):611–24. [PMID: 26886521]
Speer L et al. “Doctor, I’m so tired!” Refining your work-up for 
chronic fatigue. J Fam Pract. 2015 Feb;64(2):84–91. [PMID: 
25671535]
Stott DJ et al; TRUST Study Group. Thyroid hormone therapy 
for older adults with subclinical hypothyroidism. N Engl J 
Med. 2017 Jun 29;376(26):2534–44. [PMID: 28402245]
Unger ER et al. CDC Grand Rounds: chronic fatigue syn
-
drome—advancing research and clinical education. MMWR 
Morb Mortal Wkly Rep. 2016 Dec 30;65(5051):1434–8. 
[PMID: 28033311]
Wormser GP et al. Long-term assessment of fatigue in patients 
with culture-confirmed Lyme disease. Am J Med. 2015 Feb;
 
128(2):181–4. [PMID: 25447620]
ACUTE HEADACHE
 
»
Age older than 40 years.
 
»
Rapid onset and severe intensity (ie, “thunderclap” 
headache); trauma, onset during exertion.
 
»
Fever; vision changes, neck stiffness.
 
»
HIV infection.
 
»
Current or past history of hypertension.
 
»
Neurologic findings (mental status changes, 
motor or sensory deficits, loss of consciousness).
 
»
Headache is a common reason that adults seek medical 
care, accounting for approximately 13 million visits each

»
care, accounting for approximately 13 million visits each 
year in the United States to physicians’ offices, urgent care 
clinics, and emergency departments. It is the fifth most 
common reason for emergency department visits, and sec
-
ond most common reason for neurologic consultation in 
the emergency department. A broad range of disorders can 
cause headache (see Chapter 24). This section deals only 
with acute nontraumatic headache in adolescents and 
adults. The challenge in the initial evaluation of acute 
headache is to identify which patients are presenting with 
an uncommon but life-threatening condition; approxi
-
mately 1% of patients seeking care in emergency depart
-
ment settings and considerably less in office practice 
settings fall into this category.
Diminution of headache in response to typical migraine 
therapies (such as serotonin receptor antagonists or ketoro
-
lac) does not rule out critical conditions such as subarach
-
noid hemorrhage or meningitis as the underlying cause.
 
»
A careful history and physical examination should aim to 
identify causes of acute headache that require immediate 
treatment. These causes can be broadly classified as immi
-
nent or completed 
vascular events
 (intracranial hemor
-
rhage, thrombosis, cavernous sinus thrombosis, vasculitis, 
malignant hypertension, arterial dissection, cerebral 
venous thrombosis, or aneurysm), 
infections
 (abscess, 
encephalitis, or meningitis), 
intracranial masses
 causing 
CMDT19_Ch02_p0020-p0045.indd   40

41
 
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Table 2–8.
 
Clinical features associated with acute 
headache that warrant urgent or emergent 
neuroimaging.
Prior to lumbar puncture
 
Abnormal 
neurologic examination
 
Abnormal 
mental status
 
Abnormal 
funduscopic examination (papilledema; loss of 
 
v
enous pulsations)
 
M
eningeal signs
e
mergent (conduct prior to leaving office or emergency 
department)
 
Abnormal 
 
Abnormal 
 
“
Thunderclap” headache
Urgent (scheduled prior to leaving office or emergency 
 
HIV
-positive patient
1
 
A
ge > 50 years (normal neurologic examination)
1
Use CT with or without contrast or MRI if HIV positive.
Data from American College of Emergency Physicians. Clinical 
policy: critical issues in the evaluation and management of 
patients presenting to the emergency department with acute 
headache. Ann Emerg Med. 2002 Jan;39(1):108–22.
intracranial hypertension, 
preeclampsia,
 and 
carbon 
monoxide poisoning.
 Having the patient carefully describe 
the onset of headache can be helpful in diagnosing a seri
-
ous cause. Report of a sudden-onset headache that reaches 
maximal and severe intensity within seconds or a few min
-
utes is the classic description of a “thunderclap” headache; 
it should precipitate workup for subarachnoid hemorrhage, 
since the estimated prevalence of subarachnoid hemor
-
rhage in patients with thunderclap headache is 43%. Thun
-
derclap headache during the postpartum period 
precipitated by the Valsalva maneuver or recumbent posi
-
tioning may indicate reversible cerebral vasoconstriction 
syndrome. Other historical features that raise the need for 
diagnostic testing include headache brought on by the Val
-
salva maneuver, cough, exertion, or sexual activity.
The medical history can also guide the need for addi
-
tional workup. Under most circumstances (including a 
normal neurologic examination), new headache in a 
patient older than 50 years or with HIV infection warrants 
immediate neuroimaging (Table 2–8). When the patient 
has a history of hypertension—particularly uncontrolled 
hypertension—a complete search for other features of 
“malignant hypertension” is appropriate to determine the 
urgency of control of hypertension (see Chapter 11). Head
-
ache and hypertension associated with pregnancy may be 
due to preeclampsia. Episodic headache associated with the 
triad of hypertension, heart palpitations, and sweats is sug
-
gestive of pheochromocytoma. In the absence of thunder
-
clap headache, advanced age, and HIV infection, a careful 
physical examination and detailed neurologic examination 
will usually determine acuity of the workup and need for 
further diagnostic testing. A history consistent with hyper
-
coagulability is associated with an increased risk of cerebral 
venous thrombosis.
Symptoms can also be useful for diagnosing migraine 
headache in the absence of the “classic” migraine pattern of 
scintillating scotoma followed by unilateral headache, pho
-
tophobia, and nausea and vomiting (Table 2–9). The pres
-
ence of three or more of these symptoms (nausea, 
photophobia, phonophobia, and exacerbation by physical 
activity) can establish the diagnosis of migraine (in the 
absence of other clinical features that warrant neuroimag
-
ing studies), and the presence of only one or two symptoms 
(provided one is not nausea) can help rule out migraine.
Critical components of the physical examination of the 
patient with acute headache include vital signs, neurologic 
examination, and vision testing with funduscopic examina
-
tion. The finding of fever with acute headache warrants 
additional maneuvers to elicit evidence of meningeal 
inflammation, such as Kernig and Brudzinski signs. The 
absence of jolt accentuation of headache cannot accurately 
rule out meningitis. Patients older than 60 years should be 
examined for scalp or temporal artery tenderness.

Careful assessment of visual acuity, ocular gaze, visual 
fields, pupillary defects, optic disks, and retinal vein pulsa
-
tions is crucial. Diminished visual acuity is suggestive of 
glaucoma, temporal arteritis, or optic neuritis. Ophthal
-
moplegia or visual field defects may be signs of venous 
sinus thrombosis, tumor, or aneurysm. Afferent pupillary 
defects can be due to intracranial masses or optic neuritis. 
In the setting of headache and hypertension, retinal cotton 
wool spots, flame hemorrhages, and disk swelling indicate 
acute severe hypertensive retinopathy. Ipsilateral ptosis and 
miosis suggest Horner syndrome and in conjunction with 
acute headache may signify carotid artery dissection. 
Finally, papilledema or absent retinal venous pulsations are 
signs of elevated intracranial pressure—findings that 
should be followed by neuroimaging prior to performing 
lumbar puncture (Table 2–8). On nonmydriatic fundos
-
copy, up to 8.5% of patients who arrive at the emergency 
department complaining of headache had abnormalities; 
although few had other significant physical examination 
findings, 59% had abnormal neuroimaging studies.
Complete neurologic evaluations are also critical 
and should include assessment of mental status, motor and 
sensory systems, reflexes, gait, cerebellar function, and 
pronator drift. Any abnormality on neurologic evaluation 
(especially mental status) warrants emergent neuroimag
-
ing (Table 2–8).
Table 2–9.
 
Summary likelihood ratios (LRs) for individ
-
ual clinical features associated with migraine 
LR– (95% CI)
Nausea
19 (15–25)
0.19 (0.18–0.20)
5.8 (5.1–6.6)
0.24 (0.23–0.26)
Phonophobia
5.2 (4.5–5.9)
0.38 (0.36–0.40)
Exacerbation by 
physical activity
3.7 (3.4–4.0)
CMDT19_Ch02_p0020-p0045.indd   41

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Neuroimaging is summarized in Table 2–8. Under most 
circumstances, a noncontrast head CT is sufficient to 
exclude intracranial hypertension with impending herni
-
ation, intracranial hemorrhage, and many types of intra
-
cranial masses (notable exceptions include lymphoma 
and toxoplasmosis in HIV-positive patients, herpes sim
-
plex encephalitis, and brain abscess). When needed, a 
contrast study can be ordered to follow a normal noncon
-
trast study. A normal neuroimaging study does not 
exclude subarachnoid hemorrhage and should be fol
-
lowed by lumbar puncture. One study supported a change 
of practice wherein a lumbar puncture can be withheld 
when a head CT scan was performed less than 6 hours 
after headache onset and showed no evidence of sub
-
arachnoid hemorrhage (negative predictive value 99.9% 
[95% CI, 99.3–100.0%]).
In patients for whom there is a high level of suspicion 
for subarachnoid hemorrhage or aneurysm, a normal CT 
and lumbar puncture should be followed by angiography 
within the next few days (provided the patient is medically 
stable). Lumbar puncture is also indicated to exclude infec
-
tious causes of acute headache, particularly in patients with 
fever or meningeal signs. Cerebrospinal fluid tests should 
routinely include Gram stain, white blood cell count with 
differential, red blood cell count, glucose, total protein, and 
bacterial culture. In appropriate patients, also consider 
testing cerebrospinal fluid for VDRL (syphilis), cryptococ
-
cal antigen (HIV-positive patients), acid-fast bacillus stain 
and culture, and complement fixation and culture for coc
-
cidioidomycosis. Storage of an extra tube with 5 mL of 
cerebrospinal fluid is also prudent for conducting unantici
-
pated tests in the immediate future. Polymerase chain reac
-
tion tests for specific infectious pathogens (eg, herpes 
simplex 2) should also be considered in patients with evi
-
dence of central nervous system infection but no identifi
-
able pathogen.
The Ottawa subarachnoid hemorrhage clinical decision 
rule had 100% sensitivity (and 13–15% specificity in differ
-
ent studies) in predicting subarachnoid hemorrhage. 
According to it, patients who seek medical attention in an 
emergency department complaining of an acute nontrau
-
matic headache should be evaluated for subarachnoid 
hemorrhage if they have one or more of the following fac
-
tors: age 40 years or older, neck pain or stiffness, witnessed 
loss of consciousness, onset during exertion, thunderclap 
headache (instantly peaking pain), or limited neck flexion 
on examination.
In addition to neuroimaging and lumbar puncture, 
additional diagnostic tests for exclusion of life-threatening 
causes of acute headache include erythrocyte sedimenta
-
tion rate (temporal arteritis; endocarditis), urinalysis 
(malignant hypertension; preeclampsia), and sinus CT 
(bacterial sinusitis, independently or as a cause of venous 
sinus thrombosis).
A prospective multicenter observational cohort study 
found that the biomarker copeptin was associated with 
serious secondary headache (OR 2.03, 95%CI 1.52–2.70, 
 
P
 < 0.0001).
 
»
Treatment
Treatment should be directed at the cause of acute head
-
ache. In patients in whom migraine or migraine-like head
-
ache has been diagnosed, early treatment with NSAIDs 
(oral, nasal, or intramuscular ketorolac), metoclopramide, 
dihydroergotamine, or triptans (oral, nasal, subcutaneous) 
can often abort or provide significant relief of symptoms 
(see Chapter 24). There appears to be no benefit of adding 
intravenous diphenhydramine to intravenous metoclo
-
pramide. Sumatriptan may be less effective as immediate 
therapy for migraine attacks with aura compared to attacks 
without aura. In a double-blind, randomized-controlled 
trial of 100 patients with migraine, ginger powder appeared 
to be as efficacious as sumatriptan. Injectable morphine

to be as efficacious as sumatriptan. Injectable morphine 
and hydromorphone are best avoided as first-line therapy.
Subanesthetic ketamine infusions may be beneficial in 
individuals with chronic migraine and new daily persistent 
headache that has not responded to other aggressive treat
-
ments. Peripheral nerve blocks may be a safe and effective 
way to treat headaches in older adults. Noninvasive vagus 
nerve stimulation has shown promise in the management 
of migraine and acute cluster headaches.
High-flow oxygen therapy may also provide effective 
treatment for all headache types in the emergency depart
-
ment setting. Peripheral nerve blocks for treatment-
refractory migraine may be an effective therapeutic option 
in pregnancy. The oral 5-HT
1F
 receptor agonist, lasmiditan, 
is currently in clinical trials for the treatment of acute 
migraine. Other causes of acute headache, such as sub
-
arachnoid hemorrhage, intracranial mass, or meningitis, 
require emergent treatment in the hospital.
 
»
•	
Frequent migraines not responsive to standard therapy.
•	
Migraines with atypical features.
•	
Chronic daily headaches due to medication overuse.
 
»
•	
Need for repeated doses of parenteral pain medication.
•	
To facilitate an expedited workup requiring a sequence 
of neuroimaging and procedures.
•	
To monitor for progression of symptoms and to obtain 
neurologic consultation when the initial emergency 
department workup is inconclusive.
•	
Pain severe enough to impair activities of daily living or 
impede follow-up appointments or consultations.
•	
Patients with subarachnoid hemorrhage, intracranial 
mass, or meningitis.
Blum CA et al. Copeptin for risk stratification in non-traumatic 
headache in the emergency setting: a prospective multicenter 
observational cohort study. J Headache Pain. 2017 Dec;
 
18(1):21. [PMID: 28197843]
Buttgereit F et al. Polymyalgia rheumatica and giant cell arteritis: 
a systematic review. JAMA. 2016 Jun 14;315(22):2442–58. 
[PMID: 27299619]
CMDT19_Ch02_p0020-p0045.indd   42

43
 
CMDT 2019
Derry S et al. Ibuprofen for acute treatment of episodic tension-
type headache in adults. Cochrane Database Syst Rev. 2015 
Jul 31;7:CD011474. [PMID: 26230487]
Easter JS et al. Will neuroimaging reveal a severe intracranial 
injury in this adult with minor head trauma? The rational 
clinical examination. JAMA. 2015 Dec 22–29;314(24):2672–81. 
[PMID: 26717031]
Lawton MT et al. Subarachnoid hemorrhage. N Engl J Med. 2017 
Jul 20;377(3):257–66. [PMID: 28723321]
Marmura MJ et al. The acute treatment of migraine in adults: the 
American Headache Society Evidence Assessment of 
Migraine Pharmacotherapies. Headache. 2015 Jan;55(1):3–20. 
[PMID: 25600718]
Najjar M et al. Metoclopramide for acute migraine treatment in 
the emergency department: an effective alternative to opioids. 
Cureus. 2017 Apr 20;9(4):e1181. [PMID: 28533997]
Orr SL et al. Management of adults with acute migraine in the 
emergency department: the American Headache Society evi
-
dence assessment of parenteral pharmacotherapies. Head
-
ache. 2016 Jun;56(6):911–40. [PMID: 27300483]
Pringsheim T et al. How to apply the AHS evidence assessment 
of the acute treatment of migraine in adults to your patient 
with migraine. Headache. 2016 Jul;56(7):1194–200. [PMID: 
27322907]
Rivara FP et al. Use of clinical prediction rules for guiding use of 
computed tomography in adults with head trauma. JAMA. 
2015 Dec 22–29;314(24):2629–31. [PMID: 26717029]
DYSURIA
 
»
Fever; new back or flank pain; nausea or vomiting.
 
»
Vaginal discharge.
 
»
Pregnancy risk.
 
»
Structural abnormalities.
 
»
Instrumentation of urethra or bladder.
 
»
Dysuria (painful urination) is a common reason for adoles
-
cents and adults to seek urgent medical attention. An 
inflammatory process (eg, urinary tract infection [UTI], 
autoimmune disorder) underlies most causes of dysuria. In 
women, cystitis will be diagnosed in up to 50–60% of cases. 
Cystitis has an incidence of 0.5–0.7% per year in sexually 
active young women. The key objective in evaluating 
women with dysuria is to exclude serious upper urinary 
tract disease, such as acute pyelonephritis, and sexually 
transmitted diseases. In elderly men, dysuria may be a 
symptom of prostatitis. In contrast, in younger men, ure
-
thritis accounts for the vast majority of cases of dysuria.
 
»
Well-designed cohort studies have shown that some 
women can be reliably diagnosed with uncomplicated cys
-
titis without a physical examination or urinalysis, and 
randomized controlled trials show that telephone manage
-
ment of uncomplicated cystitis is safe and effective. An 
increased likelihood of cystitis is present when women 
report multiple irritative voiding symptoms (dysuria, 
urgency, frequency), fever, or back pain (LRs = 1.6–2.0). 
Inquiring about symptoms of vulvovaginitis is imperative. 
When women report dysuria and urinary frequency, and 
deny vaginal discharge and irritation, the LR for culture-
confirmed cystitis is 24.5. In contrast, when vaginal dis
-
charge or irritation is present, as well as dysuria or urinary 
frequency, the LR is 0.7. Gross hematuria in women with 
voiding symptoms usually represents hemorrhagic cystitis 
but can also be a sign of bladder cancer (particularly in 
older patients) or upper tract disease. Failure of hematuria 
to resolve with antibiotic treatment should prompt further 
evaluation of the bladder and kidneys. Chlamydial infec
-
tion should be strongly considered among women aged 
25 years or younger who are sexually active and seeking 
medical attention for a suspected UTI for the first time or 
who have a new partner.
Because fever and back pain, as well as nausea and vom
-
iting, are considered harbingers of (or clinical criteria for) 
acute pyelonephritis, women with these symptoms should 
usually be examined by a clinician prior to treatment in 
order to exclude coexistent urosepsis, hydronephrosis, or

order to exclude coexistent urosepsis, hydronephrosis, or 
nephrolithiasis that would affect management decisions. 
Risk factors for acute pyelonephritis among women 
18–49 years of age relate to sexual behaviors (frequent 
sexual intercourse (3 times per week or more), new sexual 
partner in previous year, recent spermicide use), as well as 
diabetes mellitus and recent UTI or incontinence. Finally, 
pregnancy, underlying structural factors (polycystic kidney 
disease, nephrolithiasis, neurogenic bladder), immunosup
-
pression, diabetes mellitus, and a history of recent bladder 
or urethral instrumentation usually alter the treatment 
regimen (antibiotic choice or duration of treatment, or 
both) of cystitis. Presence of UTI during pregnancy is 
strongly associated with preeclampsia (particularly during 
the third trimester).
Fever, tachycardia, or hypotension suggest the possibility of 
urosepsis and potential need for hospitalization. A focused 
examination in women, in uncomplicated circumstances, 
could be limited to ascertainment of costovertebral angle 
tenderness and to a lower abdominal and pelvic examina
-
tion if the history suggests vulvovaginitis or cervicitis.
1. Urinalysis—
Urinalysis is probably overutilized in the 
evaluation of dysuria. The probability of culture-confirmed 
UTI among women with a history and physical examina
-
tion compatible with uncomplicated cystitis is about 
70–90%. Urinalysis is most helpful in atypical presenta
-
tions of cystitis. Dipstick detection (greater than trace) of 
leukocytes, nitrites, or blood supports a diagnosis of 
cystitis. When both leukocyte and nitrite tests are posi
-
tive, the LR is 4.2, and when both are negative, the LR is 0.3. 
CMDT19_Ch02_p0020-p0045.indd   43

Cha
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 CMDT 2019
The negative predictive value of urinalysis is not sufficient 
to exclude culture-confirmed UTI in women with multiple 
and typical symptoms; and randomized trial evidence 
shows that antibiotic treatment is beneficial to women with 
typical symptoms and negative urinalysis dipstick tests. 
Microscopy of unspun urine may also be helpful in diagno
-
sis and reduces unnecessary use of antibiotics. The combi
-
nation of urgency, dysuria, and pyuria, assessed with the 
high-power objective (40 ×) for pus cells (more than 1 pus 
cell/7 high-power fields) had a positive predictive value of 
71 and LR of 2.97.
2. Urine culture—
Urine culture should be considered for 
all women with upper tract symptoms (prior to initiating 
antibiotic therapy), as well as those with dysuria and a 
negative urine dipstick test. In symptomatic women, a 
clean-catch urine culture is considered positive when 10
2
–10
3
 
colony-forming units/mL of a uropathogenic organism is 
detected.
3. Renal imaging—
When severe flank or back pain is pres
-
ent, the possibility of complicated kidney infection (peri
-
nephric abscess, nephrolithiasis) or of hydronephrosis 
should be considered. Renal ultrasound or CT scanning 
should be done to rule out abscess and hydronephrosis. To 
exclude nephrolithiasis, noncontrast helical CT scanning is 
more accurate than intravenous urography and is the diag
-
nostic test of choice. In a meta-analysis, the positive and 
negative LRs of helical CT scanning for diagnosis of neph
-
rolithiasis were 23.2 and 0.05, respectively.
 
»
The differential diagnosis of dysuria in women includes 
acute cystitis, acute pyelonephritis, vaginitis (
Candida
, bac
-
terial vaginosis, 
Trichomonas
, herpes simplex), urethritis/
cervicitis (
Chlamydia
, gonorrhea), and interstitial cystitis/
painful bladder syndrome. Nucleic acid amplification tests 
from first-void urine or vaginal swab specimens are highly 
sensitive for detecting chlamydial infection. Other infectious 
pathogens associated with dysuria and urethritis in men 
include 
Mycoplasma genitalium
 and Enterobacteriaceae.
 
»
Treatment
Definitive treatment is directed to the underlying cause of 
the dysuria. An evidence-informed algorithm for manag
-
ing suspected UTI in women is shown in Figure 2–2. This 
algorithm supports antibiotic treatment of most women 
with multiple and typical symptoms of UTI without per
-
forming urinalysis or urine culture. Antibiotic selection 
should be guided by local resistance patterns; major 
options for uncomplicated cystitis include nitrofurantoin, 
cephalosporins, ciprofloxacin, fosfomycin, and trime
-
thoprim-sulfamethoxazole. According to the American 
Academy of Pediatrics’ Committee on Drugs, antibiotics 
that are usually acceptable when treating women who are 
breastfeeding include trimethoprim-sulfamethoxazole 
(unless G6PD deficiency is present), amoxicillin, nitrofu
-
rantoin, ciprofloxacin, and ofloxacin.
In men, prolonged treatment of UTIs (more than 7 days) 
out of concern for delayed clearance of infection within the 
prostate does not appear to reduce early or late recurrences. 
A 5-day course of fluoroquinolones in outpatient men with 
UTI is as effective as a 10-day course.
Symptomatic relief can be provided with phenazopyri
-
dine, a urinary analgesic that is available over the counter; 
it is used in combination with antibiotic therapy (when a 
UTI has been confirmed) but for no more than 2 days. 
Patients should be informed that phenazopyridine will 
cause orange/red discoloration of their urine and other 
body fluids (eg, some contact lens wearers have reported 
discoloration of their lenses). Rare cases of methemoglo
-
binemia and hemolytic anemia have been reported, usually 
with overdoses or underlying kidney dysfunction. Ibupro
-
fen has also been shown to be of symptomatic benefit. If a 
broad-spectrum antibiotic was initially prescribed empiri
-

-
-
cally for UTI and urine culture results return establishing 
efficacy of a narrow-spectrum antibiotic, treatment should 
be “de-escalated” to the narrow-spectrum antimicrobial. In 
patients with recurrent UTIs and asymptomatic renal cal
-
culi, 50% may be rendered infection-free following stone 
extraction.
In cases of interstitial cystitis/painful bladder syndrome 
(see Chapter 23), patients will often respond to a multi
-
modal approach that may include urethral/vesicular dila
-
tion, biofeedback, cognitive-behavioral therapy, 
antidepressants, dietary changes, vaginal emollients, and 
other supportive measures. Vaginal estrogen effectively 
relieves urinary urgency and frequency as well as recurrent 
UTIs related to vulvovaginal atrophy of menopause (also 
known as genitourinary syndrome of menopause).
A meta-analysis found that for most people with asymp
-
tomatic bacteriuria, antibiotic treatment is not beneficial 
and may be harmful. Antibiotic treatment does provide 
benefit to women in pregnancy with asymptomatic bacteri
-
uria and to those about to undergo urologic surgery.
 
»
•	
Anatomic abnormalities leading to repeated urinary 
•	
Infections associated with nephrolithiasis.
•	
Persistent interstitial cystitis/painful bladder syndrome.
 
»
•	
Severe pain requiring parenteral medication or impair
-
ing ambulation or urination (such as severe primary 
herpes simplex genitalis).
•	
Dysuria associated with urinary retention or 
obstruction.
•	
Pyelonephritis with ureteral obstruction.
•	
Signs and symptoms suggesting urosepsis.
Gágyor I et al. Ibuprofen versus fosfomycin for uncomplicated 
urinary tract infection in women: randomised controlled 
trial. BMJ. 2015 Dec 23;351:h6544. [PMID: 26698878]
Grigoryan L et al. Diagnosis and management of urinary tract 
infections in the outpatient setting: a review. JAMA. 2014 Oct 
22–29;312(16):1677–84. [PMID: 25335150]
CMDT19_Ch02_p0020-p0045.indd   44

45
 
CMDT 2019
Woman with 
≥
 1 symptom of UTI
1
Risk factors for complicated infection?
2
Back pain or 
fev
er?
Vaginal discharge?
Most elements of the history
(and physical 
ex
amination
3
) positive?
Pe
rform dipstick urina
ly
sis
Dipstick results positive?
Consider urine culture 
to
 esta
bl
ish diagnosis
Consider initiating empiric treatment
Pr
obabilit
y of UTI modera
te
 (~60%) and
 probability of 
py
elonephritis unknown
to
 esta
bl
Consider empiric treatment
Low 
to
 in
te
rmediate probability of UTI (~20%)
Pe
lv
ic 
ex
amination (including cervical cultures
 when appropriate) and urine
 culture 
to
 esta
bl
High probability of UTI (~90%)
Consider empiric treatment without urine
 culture
High probability of UTI (~80%)
 culture
Low 
to
 in
te
Consider urine culture or close clinical 
fo
llow-up and pelvic
 
ex
amination (including ce
rv
ical cultures when appropriate)
Ye
s
Ye
s
No
No
No
No
No
Ye
s
Ye
s
Ye
s
1
In women who ha
ve
 risk factors for sexual
ly
 transmitted diseases, consider testing for 
Chlam
yd
ia
. 
The US 
Pr
ev
entive Services Task 
Fo
rce recommends screening for 
Chlam
yd
ia
 for all women 25 years or younger 
and women of any age with mo
re
 than one sexual partner, a history of sexually transmi
tt
ed disease, or 
inconsistent use of condoms.
2
A complicated UTI is one in an individual with a functional or anatomic abnormality of the urinary tract, 
including a history of po
lycy
stic renal disease, nephrolithiasis, neurogenic 
bl
adder, diabetes mellitus, 
immunosuppression, pregnanc
y,
 indwelling urinary catheter, or recent urinary tract instrumentation.
3
The only ph
ys
ical 
ex
amination finding that increases the likelihood of UTI is cost
ov
ertebral angle 
te
nderness, and clinicians may consider not performing this test in patients with typical symptoms of acute 
uncomplicated UTI (as in telephone management).
▲
 
Figure 2–2.
 
Proposed algorithm for evaluating women with symptoms of acute urinary tract infection (UTI). 
(Modified and reproduced, with permission, from Bent S et al. Does this woman have an acute uncomplicated urinary 
tract infection? JAMA. 2002 May 22–29;287(20):2701–10. © 2002 American Medical Association. All rights reserved.)
Gupta K et al. Urinary tract infection. Ann Intern Med. 2017 Oct 
3;167(7):ITC49–64. [PMID: 28973215]
Holroyd KB et al. Misanalysis of urinalysis: a teachable moment. 
JAMA Intern Med. 2016 Apr;176(4):432–3. [PMID: 26954774]
Johnston CL et al. A likely urinary tract infection in a pregnant 
woman. BMJ. 2017 Apr 27;357:j1777. [PMID: 28450291]
Köves B et al. Benefits and harms of treatment of asymptomatic 
bacteriuria: a systematic review and meta-analysis by the Euro
-
pean Association of Urology Urological Infection Guidelines 
Panel. Eur Urol. 2017 Dec;72(6):865–8. [PMID: 28754533]
Michels TC et al. Dysuria: evaluation and differential diagnosis 
in adults. Am Fam Physician. 2015 Nov 1;92(9):778–86. 
[PMID: 26554471]
Schaeffer AJ et al. Clinical Practice. Urinary tract infections in 
older men. N Engl J Med. 2016 Feb 11;374(6):562–71. [PMID: 
26863357]
Weiskopf J et al. Asymptomatic bacteriuria, what are you treat
-
ing? JAMA Intern Med. 2015 Mar;175(3):344–5. [PMID: 
25581848]
CMDT19_Ch02_p0020-p0045.indd   45

46
 CMDT 2019
EVALUATION OF THE 
 
ASYMPTOMATIC PATIENT
Patients without significant medical problems—especially 
those under age 50—are at very low risk for perioperative 
complications. Their preoperative evaluation should 
include a history and physical examination. Special empha
-
sis is placed on obtaining a careful pharmacologic history 
and assessment of functional status, exercise tolerance, and 
cardiopulmonary symptoms and signs in an effort to reveal 
previously unrecognized disease that may require further 
evaluation prior to surgery. In addition, a directed bleeding 
history (Table 3–1) should be taken to uncover coagulopa
-
thy that could contribute to excessive surgical blood loss. 
Routine preoperative laboratory tests in asymptomatic 
healthy patients under age 50 have 
not
 been found to help 
predict or prevent complications. Even elderly patients 
undergoing minor or minimally invasive procedures (such 
as cataract surgery) are unlikely to benefit from preopera
-
tive screening tests.
O’Neill F et al. Routine preoperative tests for elective surgery: 
summary of updated NICE guidance. BMJ. 2016 Jul 14;
 
354:i3292. [PMID: 27418436]
Oresanya LB et al. Preoperative assessment of the older patient: a 
narrative review. JAMA. 2014 May;311(20):2110–20. [PMID: 
24867014]
CARDIAC RISK ASSESSMENT & REDUCTION 
IN NONCARDIAC SURGERY
The most important perioperative cardiac complications 
are myocardial infarction (MI) and cardiac death. Other 
complications include heart failure (HF), arrhythmias, and 
unstable angina. The principal patient-specific risk factor 
is the presence of end-organ cardiovascular disease. This 
includes not only coronary artery disease and HF but also 
cerebrovascular disease and chronic kidney disease. Diabe
-
tes mellitus, especially if treated with insulin, is considered 
a cardiovascular disease equivalent that increases the risk 
of cardiac complications. Major abdominal, thoracic, and 
vascular surgical procedures (especially abdominal aortic 
aneurysm repair) carry a higher risk of postoperative car
-
diac complications, likely due to their associated major 
fluid shifts, hemorrhage, and hypoxemia. These risk factors 
were identified in a validated, multifactorial risk prediction 
tool: The 
Revised Cardiac Risk Index (RCRI)
 (Table 3–2). 
Another risk prediction tool, derived from the 
American 
College of Surgeons’ National Surgical Quality Improve
-
ment Program (NSQIP)
 patient database, identified 
patient age, the location or type of operation, serum creati
-
nine greater than 1.5 mg/dL (132.6 mcmol/L), dependency 
in activities of daily living, and the patient’s American 
Society of Anesthesiologists physical status classification as 
predictors for postoperative MI or cardiac arrest. An online 
risk calculator using the NSQIP tool can be found at http://
www.qxmd.com/calculate-online/cardiology/gupta-
 
perioperative-cardiac-risk. The American College of Car
-
diology and American Heart Association endorse both 
prediction tools. Patients with two or more RCRI predic
-
tors or a cardiac risk in excess of 1% as calculated by the 
NSQIP prediction tool are deemed to be at elevated risk for 
cardiac complications.
Limited exercise capacity (eg, the inability to walk for 
two blocks at a normal pace or climb a flight of stairs with
-
out resting) also predicts higher cardiac risk. Emergency 
operations are also associated with greater cardiac risk, but 
should not be delayed for extensive cardiac evaluation. 
Instead, patients facing emergency surgery should be medi
-
cally optimized for surgery as quickly as possible and 
closely monitored for cardiac complications during the 
perioperative period.
 
»
Role of Preoperative Noninvasive 
 
Ischemia Testing
Most patients can be accurately risk-stratified by history and 
physical examination. A resting electrocardiogram (ECG) 
should also be obtained in patients with at least one RCRI

should also be obtained in patients with at least one RCRI 
predictor prior to major surgery but generally omitted in 
asymptomatic patients undergoing minor operations. Addi
-
tional noninvasive stress testing rarely improves risk stratifi
-
cation or management, especially in patients without 
cardiovascular disease undergoing minor operations, or 
who have at least fair functional capacity. Stress testing has 
more utility in patients with elevated risk-based clinical 
prediction tools, especially if they also have poor functional 3
Preoperative Evaluation & 
Perioperative Management
CMDT19_Ch03_p0046-p0054.indd   46
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PREOPERATIVE EVALUATION & PERIOPERATIVE MANAGEMENT
47
 
CMDT 2019
Table 3–1.
 
Directed bleeding history: Findings 
 
suggestive of a bleeding disorder.
Unprovoked bruising on the trunk of > 5 cm in diameter
Frequent unprovoked epistaxis or gingival bleeding
Menorrhagia with iron deficiency
Hemarthrosis with mild trauma
Prior excessive surgical blood loss or reoperation for bleeding
Family history of abnormal bleeding
Presence of severe kidney or liver disease
Use of medications that impair coagulation, including nutritional 
supplements and herbal remedies
Table 3–2.
 
Revised Cardiac Risk Index.
Independent Predictors of Postoperative Cardiac 
Complications
1.
 
I
ntrathoracic, intraperitoneal, or suprainguinal vascular surgery
2.
 
H
istory of ischemic heart disease
3.
 
H
istory of heart failure
4.
 
I
nsulin treatment for diabetes mellitus
5.
 
S
erum creatinine level > 2 mg/dL [> 176.8 mcmol/L]
6.
 
H
istory of cerebrovascular disease
Scoring (Number of 
 
Predictors Present)
Risk of Major Cardiac 
1
None
0.4%
One
1%
Two
2.4%
More than two
5.4%
1
Cardiac death, myocardial infarction, or nonfatal cardiac arrest.
Data from Devereaux PJ et al. Perioperative cardiac events in patients 
undergoing noncardiac surgery: a review of the magnitude of the 
problem, the pathophysiology of the events and methods to 
estimate and communicate risk. CMAJ. 2005 Sept 13;173(6):627–34.
status. The absence of ischemia on dipyridamole scintigra
-
phy or dobutamine stress echocardiography is reassuring in 
these patients. In contrast, extensive inducible ischemia in 
this population predicts a high risk of cardiac complications, 
particularly with vascular surgery, which may not be modi
-
fiable by either medical management or coronary revascu
-
larization. The predictive value of an abnormal stress test 
result for nonvascular surgery patients is less well estab
-
lished. An approach to perioperative cardiac risk assessment 
and management in patients with known or suspected stable 
coronary artery disease is shown in Figure 3–1.
 
»
Perioperative Management of Patients 
with Coronary Artery Disease
Patients with acute coronary syndromes require immediate 
management of their cardiac disease prior to any preopera
-
tive evaluation (see Chapter 10). In a large cohort study, 
postoperative MI typically occurred within 3 days of sur
-
gery and was associated with a 30-day mortality rate of 
11.6%. Postoperative MI often presents without chest pain. 
Symptoms and signs that should prompt consideration of 
postoperative MI include unexplained hypotension, hypox
-
emia, and delirium. Screening asymptomatic patients for 
postoperative MI through the use of ECG or cardiac 
enzyme monitoring remains controversial, since it has not 
yet been demonstrated to improve outcomes.
A. Medications
Preoperative antianginal medications, including beta-
blockers, calcium channel blockers, and nitrates, should be 
continued throughout the perioperative period. Several 
trials have shown that beta-blockers reduce the risk of 
nonfatal myocardial infarction in patients at elevated car
-
diac risk. However, in the largest trials, a high, fixed dose of 
metoprolol succinate 
increased
 total mortality and the risk 
of stroke. Because of the uncertain benefit-to-risk ratio of 
perioperative beta-blockade, it should be considered only 
in patients with a high risk of cardiac complications. If 
used, beta-blockers should be started well in advance of 
surgery, to allow time to gradually titrate up the dose with
-
out causing excessive bradycardia or hypotension. They 
should not be started on the day of surgery. Possible indica
-
tions and starting doses for prophylactic beta-blockade are 
presented in Table 3–3.
Several randomized trials and retrospective studies found 
that the use of HMG-CoA reductase inhibitors (statins) pre
-
vents MI in patients undergoing noncardiac surgery. Safety 
concerns, such as liver failure or rhabdomyolysis, have not

-
concerns, such as liver failure or rhabdomyolysis, have not 
materialized in these studies. It is unclear how far in advance 
of surgery statins must be started to see benefits. Statins 
should be considered in all patients undergoing vascular 
surgery and other patients deemed to be at high risk for 
cardiac complications, regardless of lipid levels. Patients 
already taking statins should continue these agents during 
the perioperative period. In patients without coronary stents, 
initiation of aspirin therapy before noncardiac surgery is not 
recommended because it did not reduce cardiac risk and 
caused increased bleeding in a large randomized trial.
B. Coronary Revascularization
Patients who have previously had coronary artery bypass 
grafting (CABG) surgery or percutaneous coronary inter
-
ventions (PCI) have a relatively low risk of cardiac compli
-
cations when undergoing subsequent noncardiac surgery. 
However, a trial that randomized over 500 patients with 
angiographically proven coronary artery disease to either 
coronary revascularization (with either CABG or PCI) or 
medical management alone before vascular surgery found 
no difference in postoperative MI, 30-day mortality, and 
long-term mortality. Thus, 
preoperative CABG or PCI 
should be performed only on patients who have guideline-
concordant indications independent of the planned 
noncardiac operation.
 In addition, surgical patients who 
have undergone recent coronary stenting are at high risk 
for stent thrombosis, especially if antiplatelet therapy is 
stopped prematurely. Therefore, elective surgery should be 
deferred for at least 30 days after placement of a bare-metal 
stent and ideally for 6 months after placement of a drug-
eluting stent. If this delay poses significant risks, such as in 
CMDT19_Ch03_p0046-p0054.indd   47

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 CMDT 2019
patients undergoing an operation for cancer, surgery could 
be considered 3 months after drug-eluting stent implanta
-
tion. If antiplatelet agents must be held before surgery, they 
should be resumed as soon as possible postoperatively.
 
»
Heart Failure & Left Ventricular 
Dysfunction
Decompensated HF, manifested by an elevated jugular 
venous pressure, an audible third heart sound, or evidence 
of pulmonary edema on physical examination or chest 
radiography, significantly increases the risk of periopera
-
tive cardiac complications. 
Elective surgery should be 
postponed in patients with decompensated HF until it 
can be evaluated and brought under control.
The risk of perioperative cardiac complications is simi
-
lar in patients with ischemic or nonischemic cardiomyopa
-
thy. HF with reduced ejection fraction likely confers more 
risk than HF with preserved ejection fraction. Patients 
with a history of symptomatic HF are at higher risk than 
those with asymptomatic left ventricular systolic dysfunc
-
tion. Guidelines recommend preoperative echocardiogra
-
phy in patients without known HF with unexplained 
dyspnea and in patients with known HF with clinical dete
-
rioration. A small observational study found that routine 
Ele
va
ted risk
Low risk
Go 
to
 OR
Ye
s
Go 
to
 OR
No impact on
management
Go 
to
 OR
or consider
alternatives
to
 sur
gery
No or unknown
Assess for ele
va
ted cardiac 
risk 
by
 using a prediction tool:
RCRI sco
re
 
≥
 2 points
or
NSQIP risk calculation > 1%
Assess functional capacity:
Can patient walk 2 blocks at 
normal pace or climb 
fl
ight of 
stairs without symptoms?
Determine whether stress test 
result will alter management:
• 
Ca
ncel or modify surge
ry
?
• Change medical management?
• 
Co
ronary 
rev
ascularization?
Normal
Go 
to
 OR
Ye
s
Abnormal
Obtain pharmacologic stress 
te
st
• Cancel or modify sur
gery if r
isk is unacceptable
• Consider beta-bloc
ker therapy (see 
Ta
ble 3–3)
• P
erform coronary 
rev
ascularization if patient has 
indications independent of sur
gery
▲
 
Figure 3–1.
 
Assessment and management of patients with known or suspected stable coronary artery disease 
(CAD) undergoing major elective noncardiac surgery. (OR, operating room; RCRI, Revised Cardiac Risk Index [Table 3–2]; 
NSQIP , National Surgical Quality Improvement Program: http://www.qxmd.com/calculate-online/cardiology/
gupta-perioperative-cardiac-risk)
Table 3–3.
 
Indications for prophylactic perioperative 
beta-blockade.
1
Strong 
indications
Patient already taking beta-blocker to treat 
ischemia, arrhythmia, or hypertension
Possible 
Patient with myocardial ischemia detected on 
preoperative stress testing
Patient with 3 or more Revised Cardiac Risk 
Index predictors (see Table 3–2)
1
Initial dose recommendations: atenolol 25 mg orally daily, biso
-
prolol 2.5 mg orally daily, or metoprolol 25 mg orally twice daily. 
The dose of beta-blocker should be carefully titrated to keep heart 
rate < 70 beats per minute and systolic blood pressure > 100 mm 
Hg. Avoid initiating beta-blockade on the day of surgery.
CMDT19_Ch03_p0046-p0054.indd   48
05/07/18   2:07 PM

49
 
CMDT 2019
echocardiography in patients with suspected heart disease or 
those aged 65 years or older prior to emergency noncardiac 
surgery frequently led to a change in diagnosis or manage
-
ment plan. While this is not an established practice, 
preop
-
erative echocardiography should be considered when 
there is uncertainty about the patient’s cardiac status.
Patients receiving diuretics and digoxin should have 
serum electrolyte and digoxin levels measured prior to sur
-
gery because abnormalities in these levels may increase the 
risk of perioperative arrhythmias. Clinicians must be cau
-
tious not to give too much diuretic, since the volume-
depleted patient will be much more susceptible to 
intraoperative hypotension. The surgeon and anesthesiolo
-
gist should be made aware of the presence and severity of 
left ventricular dysfunction so that appropriate decisions 
can be made regarding perioperative fluid management and 
intraoperative monitoring.
 
»
Valvular Heart Disease
If the nature or severity of valvular lesions is unknown, or if 
there has been a recent change in clinical status, echocar
-
diography should be performed prior to noncardiac sur
-
gery. Candidates for valve replacement or repair independent 
of the planned noncardiac surgery should have the valve 
correction procedure performed first. Patients with uncor
-
rected severe or symptomatic aortic stenosis are at particu
-
lar risk for cardiac complications. They should undergo 
surgery only after consultation with a cardiologist and 
anesthesiologist. Patients with mitral stenosis require heart 
rate control to prolong diastolic filling time. Regurgitant 
valvular lesions are generally less problematic during sur
-
gery because the vasodilatory effect of anesthetics promotes 
forward flow. Patients with aortic or mitral regurgitation 
likely benefit from afterload reduction and careful attention 
to volume status, but negative chronotropes should be 
avoided to reduce the regurgitant volume.
 
»
Arrhythmias
The finding of a rhythm disturbance on preoperative eval
-
uation should prompt consideration of further cardiac 
evaluation, particularly when the finding of structural 
heart disease would alter perioperative management. 
Patients with a rhythm disturbance without evidence of 
underlying heart disease are at low risk for perioperative 
 There is no evidence that the use of 
antiarrhythmic medications to suppress an asymptomatic 
arrhythmia alters perioperative risk.
Patients with symptomatic arrhythmias should not 
undergo elective surgery until their cardiac condition has 
been addressed. Thus, in patients with atrial fibrillation or 
other supraventricular arrhythmias, adequate rate control 
should be established prior to surgery. Symptomatic ven
-
tricular tachycardia must be thoroughly evaluated and 
controlled prior to surgery. Patients who have independent 
indications for a permanent pacemaker or implanted defi
-
brillator should have it placed prior to noncardiac sur
-
gery. The anesthesiologist must be notified that a patient has 
an implanted pacemaker or defibrillator so that steps may 
be taken to prevent device malfunction caused by 
electromagnetic interference from the intraoperative use of 
electrocautery.
 
»
Mild to moderate hypertension (systolic blood pressure 
below 180 mm Hg and diastolic blood pressure below 110 
mm Hg) does not appear to be an independent risk factor 
for postoperative MI or cardiac death. No evidence sup
-
ports delaying surgery in order to better control mild to 
moderate hypertension. Most medications for chronic 
hypertension should generally be continued up to and 
including the day of surgery. Consideration should be 
given to holding angiotensin-converting enzyme inhibitors 
and angiotensin receptor blockers on the day of surgery in 
the absence of HF, since these agents may increase the risk

the absence of HF, since these agents may increase the risk 
of intraoperative hypotension and potentiate postoperative 
acute kidney injury. Diuretic agents are also frequently 
held on the day of surgery to prevent hypovolemia and 
electrolyte disorders if they are not needed to control HF; 
however, the benefit of this practice is uncertain.
Severe hypertension, defined as a systolic pressure 
greater than 180 mm Hg or diastolic pressure greater than 
110 mm Hg, does appear to be an independent predictor of 
perioperative cardiac complications, including MI and HF. 
It is reasonable to consider delaying surgery in patients 
with such severe hypertension until blood pressure can be 
controlled, although it is not known whether the risk of 
cardiac complications is reduced with this approach.
Devereaux PJ et al. Cardiac complications in patients undergo
-
ing major noncardiac surgery. N Engl J Med. 2015 Dec 3;
 
373(23):2258–69. [PMID: 26630144]
Fleisher LA et al. 2014 ACC/AHA guideline on perioperative 
cardiovascular evaluation and management of patients 
undergoing noncardiac surgery: A report of the American 
College of Cardiology/American Heart Association Task 
Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 9;
 
64(22):e77–137. [PMID: 25091544]
Levine GN et al. 2016 ACC/AHA guideline focused update on 
duration of dual antiplatelet therapy in patients with coronary 
artery disease: A report of the American College of Cardiol
-
ogy/American Heart Association Task Force on Clinical 
Practice Guidelines. J Am Coll Cardiol. 2016 Sep;68(10):
 
1082–115. [PMID: 27036918]
PULMONARY EVALUATION IN NON–LUNG 
RESECTION SURGERY
Pneumonia and respiratory failure requiring prolonged 
mechanical ventilation are the most important postopera
-
tive pulmonary complications. The occurrence of these 
complications has been associated with a significant 
increase in mortality and hospital length of stay. Pulmo
-
nary thromboembolism is another serious complication; 
prophylaxis against venous thromboembolic disease is 
described in Chapter 14.
 
»
Risk Factors for the Development of 
Postoperative Pulmonary Complications
Procedure-related risk factors for postoperative pulmonary 
complications include location of surgery (with highest 
CMDT19_Ch03_p0046-p0054.indd   49

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APTER
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 CMDT 2019
rates occurring in cardiac, thoracic, and upper abdominal 
cases), prolonged anesthesia, and emergency cases. Opera
-
tions not requiring general anesthesia tend to have lower 
rates of postoperative pulmonary complications, and lapa
-
roscopic procedures tend to have lower risk than compa
-
rable open procedures.
It remains unclear which of the many patient-specific 
risk factors that have been identified are independent pre
-
dictors. Advanced age appears to confer increased risk. The 
presence and severity of systemic disease of any type is asso
-
ciated with pulmonary complications. In particular, patients 
with chronic obstructive pulmonary disease (COPD) or HF 
have at least twice the risk of postoperative pulmonary com
-
plications compared with patients without these conditions. 
As with preoperative cardiac risk assessment, physical debil
-
ity and poor functional capacity predict higher risk of post
-
operative pulmonary complications. A summary of risk 
factors for pulmonary complications is presented in Table 3–4. 
A risk calculator for predicting postoperative respiratory 
failure derived from the NSQIP patient database (http://
www.qxmd.com/calculate-online/respirology/postoperative-
respiratory-failure-risk-calculator) includes the type of 
surgery, emergency surgery, preoperative sepsis, depen
-
dency in activities of daily living, and the patient’s American 
Society of Anesthesiologists physical status classification.
 
»
Pulmonary Function Testing & 
 
Laboratory Studies
The main role for preoperative pulmonary function tests 
(PFTs) is to characterize pulmonary disease in patients 
with unexplained symptoms prior to major abdominal or 
cardiothoracic surgery. In patients with diagnosed lung 
disease, PFTs often add little information above clinical 
assessment. Furthermore, there is no clear degree of PFT 
abnormality that can be used as an absolute contraindica
-
tion to non–lung resection surgery. Chest radiographs in 
unselected patients also rarely add clinically useful infor
-
mation. Some experts have advocated polysomnography to 
diagnose obstructive sleep apnea prior to bariatric surgery, 
but the benefits of this approach are unproven. Arterial 
blood gas measurement is not routinely recommended 
except in patients with known lung disease and suspected 
hypoxemia or hypercapnia.
 
»
Retrospective studies have shown that smoking cessation 
reduced the incidence of pulmonary complications, but 
only if it was initiated at least 1–2 months before surgery. A 
meta-analysis of randomized trials found that preoperative 
smoking cessation programs reduced both pulmonary and 
surgical wound complications, especially if smoking cessa
-
tion was initiated at least 4 weeks prior to surgery. 
The 
preoperative period may be an optimal time to initiate 
smoking cessation efforts.
 A systematic review found that 
smoking cessation programs started in a preoperative 
evaluation clinic increased the odds of abstinence at 
3–6 months by nearly 60%. Smoking cessation less than 1 
month before surgery does 
not
 appear to 
increase
 the risk 
of postoperative complications.
Postoperative risk reduction strategies have centered on 
promoting lung expansion through the use of incentive 
spirometry, continuous positive airway pressure (CPAP), 
intermittent positive-pressure breathing (IPPB), and deep 
breathing exercises. Although trial results have been mixed, 
all these techniques have been shown to reduce the inci
-
dence of postoperative atelectasis and, in a few studies, to 
reduce the incidence of postoperative pulmonary compli
-
cations. In most comparative trials, these methods were 
equally effective. Given the higher cost of CPAP and IPPB, 
incentive spirometry and deep breathing exercises are 
the preferred methods for most patients.
 A single-center 
study found that a multicomponent postoperative respira
-
tory care program termed “I COUGH”—an acronym for 
I

-
I
ncentive spirometry, 
C
oughing and deep breathing, 
O
ral 
care, 
U
nderstanding (patient education), 
G
et out of bed 
(early ambulation), and 
H
ead of bed elevation—reduced 
the rates of pneumonia and unplanned intubation after 
general and vascular surgery.
Marseu K et al. Peri-operative pulmonary dysfunction and pro
-
tection. Anaesthesia. 2016 Jan;71(Suppl 1):46–50. [PMID: 
26620146]
Taylor A et al. Prevention of postoperative pulmonary complica
-
tions. Surg Clin North Am. 2015 Apr;95(2):237–54. [PMID: 
25814104]
Thomsen T et al. Interventions for preoperative smoking cessa
-
tion. Cochrane Database Syst Rev. 2014 Mar 27;3:CD002294. 
[PMID: 24671929]
EVALUATION OF THE PATIENT WITH 
 
LIVER DISEASE
Patients with serious liver disease are at increased risk for 
perioperative morbidity and demise. Appropriate preop
-
erative evaluation requires consideration of the effects of 
anesthesia and surgery on postoperative liver function and 
of the complications associated with anesthesia and sur
-
gery in patients with preexisting liver disease.
 
»
Risk Assessment in Surgical Patients with 
Liver Disease
Screening unselected patients with liver biochemical tests 
has a low yield and is not recommended. Patients with 
suspected or known liver disease based on history or 
Table 3–4.
 
Clinical risk factors for postoperative 
 
pulmonary complications.
Upper abdominal or cardiothoracic surgery
Prolonged anesthesia time (> 4 hours)
Emergency surgery
Age > 60 years
Heart failure
Severe systemic disease
Tobacco use (> 20 pack-years)
Impaired cognition or sensorium
Functional dependency or prior stroke
Preoperative sepsis
Low serum albumin level
Obstructive sleep apnea
CMDT19_Ch03_p0046-p0054.indd   50

51
 
CMDT 2019
physical examination, however, should have measurement 
of liver enzyme levels as well as tests of hepatic synthetic 
function performed prior to surgery.
Acute hepatitis increases surgical mortality risk. In 
three small series of patients with acute viral hepatitis who 
underwent abdominal surgery, the mortality rate was 
roughly 10%. Similarly, patients with undiagnosed alco
-
holic hepatitis had high mortality rates when undergoing 
abdominal surgery. Thus, elective surgery in patients with 
acute viral or alcoholic hepatitis should be delayed until the 
acute episode has resolved. In the absence of cirrhosis or 
synthetic dysfunction, chronic viral hepatitis is unlikely to 
increase risk significantly. Similarly, nonalcoholic fatty 
liver disease without cirrhosis probably does not pose a 
serious risk in surgical patients.
In patients with cirrhosis, postoperative complication 
rates correlate with the severity of liver dysfunction.
 Tra
-
ditionally, severity of dysfunction has been assessed with the 
Child-Pugh score (see Chapter 16). A conservative approach 
would be to avoid elective surgery in patients with Child-
Pugh class C cirrhosis and pursue it with great caution in 
class B patients. The Model for End-stage Liver Disease 
(MELD) score, based on serum bilirubin and creatinine 
levels, and the prothrombin time expressed as the Interna
-
tional Normalized Ratio, also predicted surgical mortality 
and outperformed the Child-Pugh classification in some 
studies. A web-based risk assessment calculator incorporat
-
ing age and MELD score can predict both perioperative and 
long-term mortality (http://www.mayoclinic.org/medical-
professionals/model-end-stage-liver-disease/post-operative-
mortality-risk-patients-cirrhosis). Generally, a MELD score 
less than 10 predicts low risk, whereas a score greater than 
15 is a contraindication to elective surgery.
When surgery is elective, controlling ascites, encepha
-
lopathy, and coagulopathy preoperatively is prudent. Asci
-
tes is a particular problem in abdominal operations, where 
it can lead to wound dehiscence, hernias, or both. Great 
care should be taken when using analgesics and sedatives, 
since these can worsen hepatic encephalopathy. In general, 
short-acting agents and lower doses should be used. Patients 
with coagulopathy should receive vitamin K (if there is 
concern for concomitant malnutrition) and may need fresh 
frozen plasma transfusion at the time of surgery.
Abbas N et al. Perioperative care of patients with liver cirrhosis: 
a review. Health Serv Insights. 2017 Feb 24;10:1–12. [PMID: 
28469455]
Im GY et al. Surgery in patients with portal hypertension: a 
preoperative checklist and strategies for attenuating risk. Clin 
Liver Dis. 2014 May;18(2):477–505. [PMID: 24679507]
PREOPERATIVE HEMATOLOGIC EVALUATION
Three of the more common clinical situations faced by the 
medical consultant are the patient with anemia, the assess
-
ment of bleeding risk, and the perioperative management 
of long-term anticoagulation.
Preoperative anemia is common, with a prevalence of 
43% in a large cohort of elderly veterans undergoing sur
-
gery. The main goals of the preoperative evaluation of the 
anemic patient are to determine the need for preoperative 
diagnostic evaluation and the need for transfusion. 
When 
feasible, the diagnostic evaluation of the patient with 
previously unrecognized anemia should be done prior to 
surgery because certain types of anemia (particularly 
those due to sickle cell disease, hemolysis, and acute 
blood loss) have implications for perioperative manage
-
ment.
 These types of anemia are typically associated with 
an elevated reticulocyte count. While preoperative anemia 
is associated with higher perioperative morbidity and mor
-
tality, it is not known whether correction of preoperative 
anemia with transfusions or erythropoiesis-stimulating

-
anemia with transfusions or erythropoiesis-stimulating 
agents will improve postoperative outcomes. Determina
-
tion of the need for preoperative transfusion in an indi
-
vidual patient must consider factors other than the absolute 
hemoglobin level, including the presence of cardiopulmo
-
nary disease, the type of surgery, and the likely severity of 
surgical blood loss. The few studies that have compared 
different postoperative transfusion thresholds failed to 
demonstrate improved outcomes with a more aggressive 
transfusion strategy. Based on available evidence, the 
AABB (formerly American Association of Blood Banks) 
recommends transfusion for a hemoglobin level less than 
8 g/dL (80 g/L) or for symptomatic anemia in patients 
undergoing orthopedic or cardiac surgery.
The most important component of the bleeding risk 
assessment is a directed bleeding history (see Table 3–1). 
Patients who provide a reliable history of no abnormal 
bleeding on directed bleeding history and have no sugges
-
tion of abnormal bleeding on physical examination are at 
very low risk for having an occult bleeding disorder. Labo
-
ratory tests of hemostatic parameters in these patients are 
generally not needed. When the directed bleeding history 
is unreliable or incomplete, or when abnormal bleeding is 
suggested, a formal evaluation of hemostasis should be 
done prior to surgery and should include measurement of 
the prothrombin time, activated partial thromboplastin 
time, and platelet count (see Chapter 13).
Patients receiving long-term oral anticoagulation are 
at risk for thromboembolic complications when an 
operation requires interruption of this therapy. “Bridging 
anticoagulation, ” where unfractionated or low-molecular-
weight heparin is administered parenterally while oral 
anticoagulants are held, is commonly practiced, but its 
benefit is unproven and there is the potential for harm. A 
randomized trial of bridging anticoagulation in surgical 
patients taking warfarin for atrial fibrillation demonstrated 
no difference in thromboembolism. Bleeding complica
-
tions were twice as common in patients who received bridg
-
ing anticoagulation. 
Most experts recommend bridging 
therapy only in patients at high risk for thromboembo
-
lism.
 An approach to perioperative anticoagulation 
management is shown in Table 3–5, but the recommenda
-
tions must be considered in the context of patient prefer
-
ence and hemorrhagic risk. Direct-acting oral anticoagulants 
should be withheld several days prior to surgery, based on 
the patient’s kidney function (Table 3–6). Because these 
agents take effect immediately, bridging is generally not 
needed when they are resumed, but they should be restarted 
after surgery only when adequate hemostasis is ensured 
(see Chapter 14).
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Ch
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 3
52
 CMDT 2019
Table 3–5.
 
Recommendations for management of perioperative anticoagulation with warfarin.
Thromboembolic Risk without Anticoagulation
Recommendation
Low
 (eg, atrial fibrillation with CHADS
2
 score 0–4
1
, 
mechanical bileaflet aortic valve prosthesis, or 
 
single venous thromboembolism > 3 months ago 
without hypercoagulability condition
2
)
1.
 
S
top warfarin 5 days before surgery
2.
  
M
easure INR the day before surgery to confirm that it is acceptable 
 
(< 1.6 for most operations)
3.
 
Resume w
arfarin when hemostasis permits
4.
 
No bridg
ing with parenteral anticoagulants before or after surgery
h
igh
 (eg, atrial fibrillation or mechanical heart valve 
with stroke < 3 months prior, atrial fibrillation with 
CHADS
2
 score 5 or 6, mechanical mitral valve pros
-
thesis, caged-ball or tilting disk valve prosthesis, or 
venous thrombosis < 3 months ago or associated 
with hypercoagulability condition
2
)
1.
 
S
2.
  
B
egin bridging with therapeutic dose UFH infusion or LMWH 2 days after stop
-
ping oral anticoagulation
3.
  
A
dminister last dose of LMWH 24 hours before surgery; discontinue UFH 4–6 
hours before surgery
4.
  
M
 
5.
 
Resume w
6.
  
I
f hemostasis permits, resume bridging with therapeutic dose UFH infusion or 
LMWH beginning 48–72 hours after surgery and continuing until the INR is 
therapeutic
1
1 point each for heart failure, hypertension, diabetes mellitus, age > 75 years, and 2 points for stroke or transient ischemic attack.
2
Patients should receive venous thromboembolism prophylaxis after surgery (see Chapter 14).
INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
Doherty JU et al. 2017 ACC Expert consensus decision pathway 
for periprocedural management of anticoagulation in patients 
with nonvalvular atrial fibrillation. A report of the American 
College of Cardiology Clinical Expert Consensus Document 
Task Force. J Am Coll Cardiol. 2017 Feb 21;69(7):871–98. 
[PMID: 28081965]
Lai A et al. Perioperative management of patients on new oral 
anticoagulants. Br J Surg. 2014 Jun;101(7):742–9. [PMID: 
24777590]
Muñoz M et al. Pre-operative haematological assessment in 
patients scheduled for major surgery. Anaesthesia. 2016 Jan;
 
71(Suppl 1):19–28. [PMID: 26620143]
NEUROLOGIC EVALUATION
Delirium can occur after any major operation but is par
-
ticularly common after hip fracture repair and cardiovas
-
cular surgery, where the incidence is 30–60%. 
Postoperative 
delirium has been associated with higher rates of major 
postoperative cardiac and pulmonary complications, 
poor functional recovery, increased length of hospital 
stay, increased risk of subsequent dementia and func
-
tional decline, and increased mortality.
 Numerous risk 
factors have been associated with the development of post
-
operative delirium. The American Geriatrics Society rec
-
ommends screening preoperative patients for age greater 
than 65 years, chronic cognitive impairment or dementia, 
severe illness, poor vision or hearing, and the presence of 
infection. Patients with any of these risk factors should be 
enrolled in a multi-component, nonpharmacologic delir
-
ium prevention program after surgery, which includes 
interventions such as reorientation, sleep hygiene, bowel 
and bladder care, mobilization and physical therapy, and 
the elimination of unnecessary medications. Moderate 
quality evidence supports the use of these nonpharmaco
-
logic interventions.
Only a minority of patients with postoperative delirium 
will have a single, reversible etiology for their condition. 
Evaluation of delirious patients should exclude electrolyte 
derangements, occult urinary tract infection, and adverse 
effects from psychotropic medications. Opioids, benzodi
-

-
azepines, anticholinergic agents, and antispasmodics are 
often implicated in postoperative delirium. Conservative 
management includes reassuring and reorienting the 
patient; eliminating unneeded psychotropic medication, 
intravenous lines, and urinary catheters; and keeping the 
patient active during the day while allowing uninterrupted 
sleep at night. When agitation jeopardizes patient or pro
-
vider safety, neuroleptic agents, given at the lowest effective 
dose for the shortest duration needed, are preferred over 
the use of benzodiazepines or physical restraints.
Stroke complicates less than 1% of all surgical proce
-
dures but may occur in 1–6% of patients undergoing 
Table 3–6.
 
Recommendations for preoperative management of direct-acting oral anticoagulants.
1
Creatinine Clearance
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
> 50 mL/min/1.73 m
2
 (0.83 mL/s/m
2
)
Hold 4–6 doses
Hold 2 doses
Hold 4 doses
30–50 mL/min/1.73 m
2
 (0.5–0.83 mL/s/m
2
)
Hold 6–8 doses
Hold 6 doses
1
Recommendations are for the number of doses to hold before the day of surgery for complete reversal of anticoagulant effect. If mild to 
moderate anticoagulant effect at time of procedure is desired, the number of held doses should be reduced by 50%.
CMDT19_Ch03_p0046-p0054.indd   52

53
 
CMDT 2019
cardiac or carotid artery surgery. Most of the strokes in 
cardiac surgery patients are embolic in origin, and about 
half occur within the first postoperative day. Stroke after 
cardiac surgery is associated with significantly increased 
mortality, up to 22% in some studies. A retrospective 
analysis found that patients who had previously suffered a 
stroke had an 18% risk of MI, recurrent stroke, or cardiac 
death if they underwent noncardiac surgery within 3 months 
of the stroke. This risk declined over time and reached its 
nadir 9 months after the stroke, suggesting a benefit to 
delaying elective surgery.
Symptomatic carotid artery stenosis is associated with a 
high risk of stroke in patients undergoing cardiac surgery. 
In general, 
 carotid lesions should be treated 
prior
 to elective cardiac surgery. In contrast, most studies 
suggest that asymptomatic carotid bruits and asymptom
-
atic carotid stenosis are associated with little or no increased 
risk of stroke in surgical patients. Prophylactic carotid 
endarterectomy or stenting in patients with asymptomatic 
carotid artery disease is unlikely to be beneficial in most 
patients, as the stroke risk of the carotid procedure likely 
outweighs any risk reduction it provides in a subsequent 
operation. On the other hand, patients with independent 
indications for such procedures (see Chapter 12) should 
probably have the carotid operation prior to the elective 
surgery.
American Geriatrics Society Expert Panel on Postoperative 
Delirium in Older Adults. Postoperative delirium in older 
adults: best practice statement from the American Geriatrics 
Society. J Am Coll Surg. 2015 Feb;220(2):136–48. [PMID: 
25535170]
Mashour GA et al. Neurological complications of surgery and 
anaesthesia. Br J Anaesth. 2015 Feb;114(2):194–203. [PMID: 
25204699]
MANAGEMENT OF ENDOCRINE DISEASES
 
»
Diabetes Mellitus
The most challenging issue in diabetic patients is the main
-
tenance of glucose control during the perioperative period. 
The increased secretion of cortisol, epinephrine, glucagon, 
and growth hormone during surgery is associated with 
insulin resistance and hyperglycemia in diabetic patients. 
The goal of management is the prevention of severe 
hyperglycemia or hypoglycemia in the perioperative 
period.
Cohort studies demonstrate that poor preoperative 
glycemic control, as indicated by an elevated hemoglobin 
A
1c
 level, is associated with a greater risk of surgical com
-
plications, particularly infections. However, a strategy of 
delaying surgery until glycemic control improves has not 
been rigorously studied. The ideal postoperative blood 
glucose target is also unknown. Based on trials that showed 
increased mortality in patients randomized to very tight 
control, the American College of Physicians recommends 
maintaining serum glucose between 140 mg/dL and 
200 mg/dL (7.8–11.1 mmol/L), whereas the British 
National Health Service guidelines recommend a range of 
108–180 mg/dL (6–10 mmol/L).
The specific pharmacologic management of diabetes 
during the perioperative period depends on the type of 
diabetes (insulin-dependent or not), the level of glycemic 
control, and the type and length of surgery. Oral hypogly
-
cemic agents should be held on the day of surgery. They 
should not be restarted after surgery until oral intake is 
adequate and unlikely to be interrupted. For patients tak
-
ing insulin, a common practice is to reduce the last preop
-
erative dose of long-acting, basal insulin by 30–50% and 
hold short-acting nutritional insulin. Use of correctional 
insulin only (without basal or nutritional insulin after sur
-
gery) is discouraged. A trial comparing correctional insu
-
lin with basal-bolus dosing found that the latter strategy 
led to fewer postoperative complications. Most patients 
with type 1 diabetes and some with type 2 diabetes will

-
with type 1 diabetes and some with type 2 diabetes will 
need an intravenous insulin infusion perioperatively. 
Con
-
sultation with an endocrinologist should be strongly 
considered when patients with type 1 diabetes mellitus 
undergo major surgery.
 All diabetic patients require fre
-
quent blood glucose monitoring to prevent hypoglycemia 
and to ensure prompt treatment of hyperglycemia. Periop
-
erative use of corticosteroids, common in neurosurgical 
and organ transplant procedures, increases glucose intoler
-
ance. Patients receiving corticosteroids often require addi
-
tional short-acting insulin with meals, while their fasting 
glucose levels and basal insulin requirements may remain 
relatively unchanged.
 
»
Corticosteroid Replacement
Perioperative complications (predominantly hypotension) 
resulting from primary or secondary adrenocortical insuf
-
ficiency are rare. The common practice of administering 
high-dose corticosteroids during the perioperative period 
in patients at risk for adrenocortical insufficiency has not 
been rigorously studied. While definitive recommenda
-
tions regarding perioperative corticosteroid therapy can
-
not be made, a conservative approach would be to 
consider 
any patient who has received the equivalent of at least 
7.5 mg of prednisone daily for 3 weeks within the past 
year to be at risk for having adrenocortical insufficiency.
 
Patients who have been taking less than 5 mg of prednisone 
daily and those receiving alternate-day corticosteroid dos
-
ing are unlikely to require supplemental coverage. A com
-
monly used regimen is 100 mg of hydrocortisone given 
intravenously daily, divided every 8 hours, beginning 
before induction of anesthesia and continuing for 
24–48 hours. Tapering the dose is not necessary. Patients 
receiving long-term maintenance corticosteroid therapy 
should also continue their usual dose throughout the 
 
»
Thyroid Disease
Severe symptomatic hypothyroidism has been associated 
with perioperative complications, including intraoperative 
hypotension, HF, cardiac arrest, and death. Elective surgery 
should be delayed in patients with severe hypothyroidism 
until adequate thyroid hormone replacement can be 
achieved. Similarly, patients with symptomatic hyperthy
-
roidism are at risk for perioperative thyroid storm and 
CMDT19_Ch03_p0046-p0054.indd   53

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 3
54
 CMDT 2019
Table 3–7.
 
Risk factors for the development of acute 
kidney injury after general surgery.
1
Age > 55 years
Male sex
Chronic kidney disease
Ascites
Intraperitoneal surgery
1
Presence of 5 or more risk factors associated with > 3% risk of 
creatinine elevation greater than 2 mg/dL (176.8 mcmol/L) above 
baseline or requirement for dialysis.
Reproduced, with permission, from Kheterpal S et al. Development 
and validation of an acute kidney injury risk index for patients 
undergoing general surgery: results from a national data set. 
Anesthesiology. 2009;110(3):505–15.
should not undergo elective surgery until their thyrotoxico
-
sis is controlled. An endocrinologist should be consulted if 
emergency surgery is needed in such patients. Conversely, 
patients with asymptomatic or mild hypothyroidism gener
-
ally tolerate surgery well, with only a slight increase in the 
incidence of intraoperative hypotension; surgery need not 
be delayed for the month or more required to ensure ade
-
quate thyroid hormone replacement.
MacKenzie CR et al. Stress dose steroids: myths and periopera
-
tive medicine. Curr Rheumatol Rep. 2016 Jul;18(7):47. 
[PMID: 27351679]
KIDNEY DISEASE
Approximately one-third of patients undergoing general 
surgery will suffer some degree of acute kidney injury, and 
3% of patients will develop a creatinine elevation greater 
than 2 mg/dL (176.8 mcmol/L) above baseline or require 
renal replacement therapy. 
The development of acute kid
-
ney injury is an independent predictor of mortality, even 
if mild or if kidney dysfunction resolves.
 The mortality 
associated with the development of perioperative acute 
kidney injury that requires dialysis exceeds 50%. Risk fac
-
tors associated with postoperative deterioration in kidney 
function are shown in Table 3–7. Several medications, 
including “renal-dose” dopamine, mannitol, 
N
-acetylcysteine, 
and clonidine, have been evaluated in an attempt to pre
-
serve kidney function during the perioperative period. 
None of these has proved effective in clinical trials and 
should not be used for this indication. 
Maintenance of 
adequate intravascular volume is likely to be the most 
effective method to reduce the risk of perioperative dete
-
rioration in kidney function.
 Exposure to renal-toxic 
agents, such as nonsteroidal anti-inflammatory drugs and 
intravenous contrast, should be minimized or avoided. 
Angiotensin-converting enzyme inhibitors and angiotensin 
receptor blockers reduce renal perfusion and may increase 
the risk of perioperative acute kidney injury. Although 
firm evidence is lacking, it may be useful to temporarily 
discontinue these medications in patients at risk for 
perioperative acute kidney injury.
Although the mortality rate for elective major surgery is 
low (1–4%) in patients with dialysis-dependent chronic 
kidney disease, the risk for perioperative complications, 
including postoperative hyperkalemia, pneumonia, fluid 
overload, and bleeding, is substantially increased. Postop
-
erative hyperkalemia requiring emergent hemodialysis has 
been reported to occur in 20–30% of patients. Patients 
should undergo dialysis preoperatively within 24 hours 
before surgery, and their serum electrolyte levels should be 
measured just prior to surgery and monitored closely dur
-
ing the postoperative period.
Golden D et al. Peri-operative renal dysfunction: prevention and 
management. Anaesthesia. 2016 Jan;71(Suppl 1):51–7. [PMID: 
26620147]
ANTIBIOTIC PROPHYLAXIS OF SURGICAL 
SITE INFECTIONS
Surgical site infection is estimated to occur in roughly 4% 
of general or vascular operations. Although the type of 
procedure is the main factor determining the risk of devel
-
oping a surgical site infection, certain patient factors have 
been associated with increased risk, including diabetes 
mellitus, older age, obesity, heavy alcohol consumption,

-
mellitus, older age, obesity, heavy alcohol consumption, 
admission from a long-term care facility, and multiple 
medical comorbidities. 
For most major procedures, the 
use of prophylactic antibiotics has been demonstrated to 
reduce the incidence of surgical site infections signifi
-
cantly.
 Several general conclusions can be drawn from 
studies of different antibiotic regimens for surgical proce
-
dures. First, substantial evidence suggests that a single dose 
of an appropriate intravenous antibiotic—or combination 
of antibiotics—is as effective as multiple-dose regimens 
that extend into the postoperative period. Second, for most 
procedures, a first-generation cephalosporin is as effective 
as later-generation agents. Third, prophylactic antibiotics 
should be given intravenously at induction of anesthesia or 
roughly 30–60 minutes prior to the skin incision.
Guidelines for antibiotic prophylaxis against infective 
endocarditis in patients undergoing invasive procedures 
are presented in Chapter 33. Given the lack of evidence for 
antibiotic prophylaxis against prosthetic joint infection 
before dental procedures, guidelines from the American 
Academy of Orthopedic Surgeons and the American Dental 
Association recommend against this practice.
Berríos-Torres SI et al; Healthcare Infection Control Practices 
Advisory Committee. Centers for Disease Control and Pre
-
vention guideline for the prevention of surgical site infection, 
2017. JAMA Surg. 2017 Aug 1;152(8):784–91. [PMID: 
28467526]
CMDT19_Ch03_p0046-p0054.indd   54

55
 
CMDT 2019
GENERAL PRINCIPLES OF GERIATRIC CARE
The following principles help in caring for older adults:
1.
 
Many disorders are multifactorial in origin and are best 
managed by multifactorial interventions.
2.
 
Diseases often present atypically or with nonspecific 
symptoms (eg, confusion, functional decline).
3.
 
Not all abnormalities require evaluation and treatment.
4.
 
Complex medication regimens, adherence problems, 
and polypharmacy are common challenges.
5.
 
Multiple chronic conditions often coexist and should be 
managed in concert with one another.
COMPREHENSIVE ASSESSMENT OF THE 
OLDER ADULT
In addition to conventional assessment of symptoms and 
diseases, comprehensive assessment addresses three topics: 
prognosis, values and preferences
, and 
ability to func
-
tion independently
. Comprehensive assessment is war
-
ranted before major clinical decisions are made.
 
»
Assessment of Prognosis
When an older person’s life expectancy is longer than 10 years 
(ie, 50% of similar persons live longer than 10 years), it is 
reasonable to consider effective tests and treatments much 
as they are considered in younger persons. When life 
expectancy is less than 10 years (and especially when it is 
much less), choices of tests and treatments should be made 
based on their ability to improve that patient’s prognosis 
and quality of life given that patient’s shorter life expec
-
tancy. The relative benefits and harms of tests and treat
-
ments often change as prognosis worsens, and net benefit 
often worsens.
When an older patient’s clinical situation is dominated 
by a single disease process (eg, lung cancer metastatic to 
brain), prognosis can be estimated well with a disease-specific 
instrument. Even in this situation, however, prognosis 
generally worsens with age (especially over age 90 years) 
and with the presence of serious age-related conditions, 
such as dementia, malnutrition, or impaired ability to walk.
When an older patient’s clinical situation is not domi
-
nated by a single disease process, prognosis can be esti
-
mated initially by considering basic demographic and 
health elements (Figure 4–1). For example, less than 25% of 
men aged 95 will live 5 years, whereas nearly 75% of 
women aged 70 will live 10 years. The prognosis of older 
persons living at home can be estimated by considering 
age, sex, comorbid conditions, and function (Table 4–1). 
The prognosis of older persons discharged from the hospi
-
tal is worse than that of those living at home and can be 
estimated by considering sex, comorbid conditions, and 
function at discharge (Table 4–2).
 
»
Assessment of Values & Preferences
Although patients vary in their values and preferences, 
most frail older patients prioritize maintaining their inde
-
pendence over prolonging survival. Values and preferences 
are determined by speaking directly with a patient or, when 
the patient cannot express preferences reliably, with the 
patient’s surrogate.
In assessing values and preferences, it is important to 
keep in mind the following:
1.
 
Patients are experts about their preferences for out
-
comes and experiences; however, they often do not have 
adequate information to express informed preferences 
for specific tests or treatments.
2.
 
Patients’ preferences often change over time. For exam
-
ple, some patients find living with a disability more 
acceptable than they thought before experiencing it.
 
»
Assessment of Function
People often lose function in multiple domains as they age, 
with the result that they may not be able to do some activi
-
ties as quickly or capably and may need assistance with 
other activities. Assessment of function improves prognos
-
tic estimates. 
Assessment of function is essential to deter
-
mining an individual’s needs in the context of his or her 
values and preferences and the possible effects of pre
-
scribed treatment.
About one-fourth of patients over age 65 and half of

-
-
About one-fourth of patients over age 65 and half of 
persons older than 85 need help performing their 
basic 4
G. Michael Harper, MD 
 
 C. Seth Landefeld, MD 
CMDT19_Ch04_p0055-p0071.indd   55
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Chapter 4
56
 CMDT 2019
30 30
Man Man
Woman Woman
95 95
Top 25th 
Pe
rcentile
Top 25th 
Pe
rcentile
50th 
Pe
rcentile
50th 
Pe
rcentile
Lo
west 25th 
Pe
rc
entile
Lo
west 25th 
Pe
rc
entile
90 90
85 85
Age (years)
Number of years
80 80
75 75
70 70
65 65
25 25
20 20
15 15
10 10
5 5
0 0
30 30
95 95
Top 25th 
Pe
rcentile
Top 25th 
Pe
rcentile
50th 
Pe
rcentile
50th 
Pe
rcentile
Lo
west 25th 
Pe
rc
entile
Lo
west 25th 
Pe
rc
entile
90 90
85 85
Number of 
ye
ars
Number of 
ye
ars
80 80
75 75
70 70
65 65
25 25
20 20
15 15
10 10
5 5
0 0
▲
 
Figure 4–1.
 
Median life expectancy of older men 
and women. 
(Data derived from Arias E. United States Life 
Tables, 2011. Natl Vital Stat Rep. 2015 Sep 22;64(11):1–63.)
Table 4–1.
 
Prognostic factors, “risk points, ” and 4-year 
mortality rates for older persons living at home.
p
r
ognostic Factor
r
isk 
p
oin
ts
a
ge
 
60–64 y
ears
1
 
65–69 y
ears
2
 
70–74 y
ears
3
 
75–79 y
ears
4
 
80–84 y
ears
5
 
85 y
ears and older
7
Male sex
2
Comorbid conditions reported by 
patients
 
Diabet
es mellitus
1
 
Cancer
2
 
L
ung disease
2
 
Hear
t failure
2
 
B
ody mass index < 25
1
 
C
urrent smoker
2
Function
 
Ba
thing difficulty
2
 
Difficult
y handling finances
2
 
Difficult
y walking several blocks
2
Sum of 
r
isk 
p
oin
ts
4-Year Mortality 
r
a
te
1–2
2%
3–6
7%
7–10
19%
> 10
53%
Reprinted, with permission, from Lee SJ et al. Development and 
validation of a prognostic index for 4-year mortality in older adults. 
JAMA. 2006 Feb 15;295(7):801–8. Copyright © 2006 American 
activities of daily living (ADLs)
: bathing, dressing, eat
-
ing, transferring from bed to chair, continence, toileting, 
or 
instrumental activities of daily living (IADLs)
: 
transportation, shopping, cooking, using the telephone, 
managing money, taking medications, housecleaning, 
laundry.
Functional screening
 should include assessment of 
ADLs and IADLs and questions to detect weight loss, falls, 
incontinence, depressed mood, self-neglect, fear for per
-
sonal safety, and common serious impairments (eg, hear
-
ing, vision, cognition, and mobility). Standard functional 
screening measures may not be useful in capturing subtle 
impairments in highly functional independent elders. One 
technique for these patients is to identify and regularly ask 
about a target activity, such as bowling or gardening. If the 
patient begins to have trouble with or discontinues such an 
“advanced” ADL, it may indicate early impairment, such as 
onset of cognitive impairment, incontinence, or worsening 
hearing loss, which may be uncovered with additional 
gentle questioning or assessment.
 
»
Frailty
Frailty is a syndrome characterized by loss of physiologic 
reserve and dysregulation across multiple systems, ulti
-
mately resulting in greater risk of poor health outcomes. 
One well-recognized model defines frailty as a phenotype 
that includes 
weakness, slow gait speed, decreased physi
-
cal activity, weight loss, and exhaustion or low energy
. 
While there is not one universally agreed upon definition or 
assessment tool for frailty, an individual is defined as frail 
when three or more of the above features are present. Per
-
sons with frailty are at increased risk for falls, hospitaliza
-
tion, functional decline, and death. Frailty is also recognized 
as a risk of worse outcomes following surgery. The ideal 
strategies for preventing and treating the frailty syndrome 
are unknown. At present, treatment is largely supportive, 
multifactorial, and individualized based on patient goals, 
CMDT19_Ch04_p0055-p0071.indd   56

G
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I
atr
IC DISO
r
D
er
S
57
 
CMDT 2019
Table 4–2.
 
Prognostic factors, “risk points, ” and 1-year 
mortality rates for older patients discharged from the 
hospital after an acute medical illness.
p
r
r
isk 
p
oin
ts
Male sex
1
patients
 
C
ancer, metastatic
8
 
C
ancer, not metastatic
3
 
S
erum creatinine > 3 mg/dL
2
 
Albumin 
< 3 mg/dL
2
 
Albumin 
3.0–3.4 mg/dL
1
Function
 
D
ependent in 1–4 ADL
1
2
 
D
ependent in 5 ADL
1
5
Sum of 
r
isk 
p
oin
ts
1-Year Mortality 
r
a
te
0–1
4%
2–3
19%
4–6
34%
> 6
64%
1
ADL refers to five activities of daily living: bathing, dressing, trans
-
ferring, using the toilet, and eating.
Reprinted, with permission, from Walter LC et al. Development and 
validation of a prognostic index for 1-year mortality in older adults 
after hospitalization. JAMA. 2001 Jun 20;285(23):2987–94. Copyright 
© 2001 American Medical Association. All rights reserved.
life expectancy, and comorbidities. 
Exercise, particularly 
strength and resistance training, is the intervention with 
the strongest evidence for benefit.
 Sometimes, transition
-
ing a patient to a palliative care only approach is the most 
appropriate clinical intervention when efforts to prevent 
functional decline fail. Under Centers for Medicare and 
Medicaid Services, frailty cannot be used as a primary hos
-
pice diagnosis but can be listed as a secondary diagnosis 
supporting an estimated prognosis of less than 6 months.
Bleijenberg N et al. Difficulty managing medications and 
finances in older adults: a 10-year cohort study. J Am Geriatr 
Soc. 2017 Jul;65(7):1455–61. [PMID: 28378345]
Cohen AB et al. Do-not-hospitalize orders in nursing homes: 
“Call the family instead of calling the ambulance” . J Am Geriatr 
Soc. 2017 Jul;65(7):1573–7. [PMID: 28369740]
Jiang S et al. Current development in elderly comprehensive 
assessment and research methods. Biomed Res Int. 2016;
 
2016:3528248. [PMID: 27042661]
Kim DH et al. Preoperative frailty assessment and outcomes at 
6 months or later in older adults undergoing cardiac surgical 
procedures: a systematic review. Ann Intern Med. 2016 Nov 1;
 
165(9):650–60. [PMID: 27548070]
Wong TW et al. Prognosis communication in late-life disability: a 
mixed methods study. J Am Geriatr Soc. 2017 Nov;65(11):
 
2496–501. [PMID: 28905358]
MANAGEMENT OF COMMON 
 
GERIATRIC PROBLEMS
1. Dementia
ESSENTIALS OF DIAGNOSIS
 
»
Progressive decline of intellectual function.
 
»
Loss of short-term memory and at least one other 
cognitive deficit.
 
»
Deficit severe enough to cause impairment of 
function.
 
»
Not delirious.
 
»
Dementia is an acquired, persistent, and progressive 
impairment in intellectual function, with compromise of 
memory
 and at least one other cognitive domain, most 
commonly 
aphasia
 (typically, word-finding difficulty), 
apraxia
 (inability to perform motor tasks, such as cutting a 
loaf of bread, despite intact motor function), 
agnosia
 
(inability to recognize objects), and 
impaired executive 
function
 (poor abstraction, mental flexibility, planning, 
and judgment). The diagnosis of dementia requires a sig
-
nificant decline in function that is severe enough to inter
-
fere with work, social life, or performance of routine 
activities.
While dementia prevalence doubles every 5 years in the 
older population, reaching 30–50% at age 85, the preva
-
lence among US adults 65 years or older has been declin
-
ing. This improvement has been attributed to higher 
education levels and better control of cardiovascular risk 
factors. Alzheimer disease accounts for roughly two-thirds 
of dementia cases in the United States, with vascular 
dementia (either alone or combined with Alzheimer dis
-
ease) and dementia with Lewy bodies accounting for much 
of the rest.
Depression and delirium are also common in elders, 
may coexist with dementia, and may also present with 
cognitive impairment.
 Depression is a common concomi
-

-
tant of early dementia. A patient with depression and cog
-
nitive impairment whose intellectual function improves 
with treatment of the mood disorder has an almost fivefold 
greater risk of suffering irreversible dementia later in life. 
Delirium, characterized by acute confusion, occurs much 
more commonly in patients with underlying dementia.
 
»
A. Screening
1. Cognitive impairment—
The Medicare Annual Wellness 
Visit mandates that clinicians assess patients for cognitive 
impairment. However, according to the United States Pre
-
ventive Services Task Force, there is insufficient evidence 
to recommend for or against screening all older adults for 
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cognitive impairment. While there is logic in the argument 
that early detection may improve future planning and 
patient outcomes, empiric evidence that demonstrates a 
clear benefit for either patients or caregivers is lacking.
At-home genetic testing for a susceptibility gene that is 
associated with late-onset Alzheimer disease (APOE-e4) 
has FDA approval. While the presence of the APOE-e4 
allele increases the risk of developing Alzheimer disease, 
quantifying such risk for an individual is difficult. Because 
it is possible to have one or two copies of the APOE-e4 
allele and not develop Alzheimer disease or to have no cop
-
ies and yet still become stricken, genetic testing is not 
widely recommended and, if considered, should not pro
-
ceed without genetic counseling.
When there is suspicion of cognitive impairment, sev
-
eral cognitive tests have been validated for clinical use. The 
mini-cog
 is a combination of a three-item word recall with 
a clock drawing task, and it can be completed in 3 minutes. 
When a patient fails this simple test, further cognitive 
evaluation with a standardized instrument is warranted. 
The 
Montreal Cognitive Assessment (MoCA©)
 is a 
30-point test that takes about 10 minutes to administer and 
examines several areas of cognitive function. A score below 
26 has a sensitivity of 0.94 or more and a specificity of .060 
or less. Free downloadable versions in multiple languages 
are available at http://www.mocatest.org.
2. Decision-making capacity—
Older adults with cognitive 
impairment commonly face serious medical decisions, and 
the clinicians involved in their care must ascertain whether 
the capacity exists to make medical decisions. The follow
-
ing five elements should be considered in a thorough 
assessment: (1) ability to express a choice; (2) understand
-
ing relevant information about the risks and benefits of 
planned therapy and the alternatives (including no treat
-
ment), in the context of one’s values; (3) comprehension of 
the problem and its consequences; (4) ability to reason; and 
(5) consistency of choice. A patient’s choice should follow 
from an understanding of the consequences.
Sensitivity must be used in applying these five compo
-
nents to people of various cultural backgrounds. Decision-
making capacity varies over time. Furthermore, the 
capacity to make a decision is a function of the decision in 
question. A woman with mild dementia may lack the 
capacity to consent to coronary artery bypass grafting yet 
retain the capacity to designate a surrogate decision maker.
B. Symptoms and Signs
The clinician can gather important information about the 
type of dementia by asking about (1) the rate of progression 
of the deficits as well as their nature (including any person
-
ality or behavioral change); (2) the presence of other neu
-
rologic and psychiatric symptoms, particularly motor 
problems and psychotic symptoms; (3) risk factors for HIV; 
(4) family history of dementia; and (5) medications, with 
particular attention to recent changes.
Workup is directed at identifying any potentially revers
-
ible causes of dementia. However, such cases are rare. For a 
detailed description of the symptoms and signs of different 
forms of dementia, see Chapter 24.
C. Physical Examination
The neurologic examination emphasizes assessment of 
mental status but should also include evaluation for sen
-
sory deficits, previous strokes, parkinsonism, or peripheral 
neuropathy. The remainder of the physical examination 
should focus on identifying comorbid conditions that may 
aggravate the individual’s disability. For a detailed descrip
-
tion of the neuropsychological assessment, see Chapter 24.
D. Laboratory Findings
Laboratory studies should include a complete blood count 
and serum electrolytes, calcium, creatinine, glucose, thy
-
roid-stimulating hormone (TSH), and vitamin B
12
 levels. 
While hypothyroidism or vitamin B
12
 deficiency may con
-

-
12
 levels. 
12
-
tribute to the cognitive impairment, treating these condi
-
tions typically does not completely reverse the dementia. 
HIV and rapid plasma reagin (RPR) tests, a heavy metal 
screen, and liver biochemical tests may be informative in 
selected patients but are not part of routine testing. For a 
detailed description of laboratory findings, see Chapter 24.
E. Imaging
Most patients should receive neuroimaging as part of the 
workup to rule out subdural hematoma, tumor, previous 
stroke, and hydrocephalus (usually normal pressure). 
Those who are younger; those who have focal neurologic 
symptoms or signs, seizures, or gait abnormalities; and 
those with an acute or subacute onset are most likely to 
have positive findings and most likely to benefit from MRI 
scanning. In older patients with a more classic picture of 
Alzheimer disease for whom neuroimaging is desired, a 
noncontrast CT scan is sufficient. For a detailed descrip
-
tion of imaging, see Chapter 24.
 
»
Older individuals experience occasional difficulty retriev
-
ing items from memory (usually word-finding difficulty) 
and experience a slowing in their rate of information pro
-
cessing. In the amnestic type of 
mild cognitive impair
-
ment,
 a patient complains of memory problems, 
demonstrates mild deficits (most commonly in short-term 
memory) on formal testing, but the impairment does not 
significantly impact function. Annual dementia conversion 
rates vary from less than 5% to 20%. No medications have 
been demonstrated to delay the progression of mild cogni
-
tive impairment to Alzheimer disease. An elderly patient 
with intact cognition but with severe impairments in vision 
or hearing commonly becomes confused in an unfamiliar 
medical setting and consequently may be falsely labeled as 
demented.
Delirium can be distinguished from dementia by its 
acute onset, fluctuating course, and deficits in attention 
rather than memory.
 Because delirium and dementia 
often coexist, it may not be possible to determine how 
much impairment is attributable to each condition until 
the patient has resolved the delirium and is back in his or 
her usual setting. Many medications have been associated 
with delirium and other types of cognitive impairment in 
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older patients. Anticholinergic agents, hypnotics, neuro
-
leptics, opioids, nonsteroidal anti-inflammatory drugs 
(NSAIDs), antihistamines (both H
1
- and H
2
-antagonists), 
and corticosteroids are just some of the medications that 
have been associated with cognitive impairment in elders.
 
»
Treatment
Patients and families should be made aware of the Alzheim
-
er’s Association (http://www.alz.org) as well as the wealth 
of helpful community and online resources and publica
-
tions available. Caregiver support, education, and counsel
-
ing may prevent or delay nursing home placement. 
Education should include the manifestations and natural 
history of dementia as well as the availability of local sup
-
port services, such as respite care. Even under the best of 
circumstances, caregiver stress can be substantial.
A. Cognitive Impairment
1. Acetylcholinesterase inhibitors—
Many experts recom
-
mend a trial of acetylcholinesterase inhibitors (eg, donepe
-
zil, galantamine, rivastigmine) in most patients with mild 
to moderate Alzheimer disease. These medications pro
-
duce a modest improvement in cognitive function that is 
not likely to be detected in routine clinical encounters. 
However, acetylcholinesterase inhibitors have not convinc
-
ingly been shown to delay functional decline or institution
-
alization. There is insufficient evidence to recommend 
their use in mild cognitive impairment to slow the progres
-
sion toward dementia.
Starting (and maximum) doses are donepezil, 5 mg 
orally once daily (maximum 10 mg once daily); galan
-
tamine, 4 mg orally twice daily (maximum 12 mg twice 
daily); and rivastigmine, 1.5 mg orally twice daily (maxi
-
mum 6 mg twice daily). Dosages are increased gradually as 
tolerated. The most bothersome side effects include diar
-
rhea, nausea, anorexia, weight loss, and syncope. While 
some patients with moderate to severe cognitive impair
-
ment may experience benefits from acetylcholinesterase 
inhibitors, the medication should be discontinued in those 
patients who have had no apparent benefit, who experience 
side effects, or for whom the financial outlay is a burden. 
While there are no published guidelines that describe what 
constitutes an adequate treatment trial, evaluation after 
2 months at the highest tolerated dose is reasonable.
2. Memantine—
In clinical trials, patients with more 
advanced disease have been shown to have statistical ben
-
efit from the use of memantine (5 mg orally daily to 10 mg 
twice daily), an 
N
-methyl-D-aspartate (NMDA) antago
-
nist, with or without concomitant use of an acetylcholines
-
terase inhibitor. Long-term and meaningful functional 
outcomes have yet to be demonstrated and evidence sug
-
gests there is no benefit to giving memantine in addition to 
an acetylcholinesterase inhibitor.
B. Behavioral Problems
1. Nonpharmacologic approaches—
Behavioral problems 
in patients with dementia are often best managed nonphar
-
macologically. Initially, it should be established that the 
problem is not unrecognized delirium, pain, urinary 
obstruction, or fecal impaction. Determining whether the 
caregiver or institutional staff can tolerate the behavior is 
also helpful, since it is often easier to find ways to accom
-
modate the behavior than to modify it. If not, the caregiver 
should keep a brief log in which the behavior is described 
along with antecedent events and consequences. This may 
uncover patterns that delineate precipitants of the behavior 
or perhaps that the behavior is being rewarded. Caregivers 
are taught to use simple language when communicating 
with the patient, to break down activities into simple com
-
ponent tasks, and to use a “distract, not confront” approach 
when the patient seems disturbed by a troublesome issue. 
Additional steps to address behavioral problems include 
providing structure and routine, discontinuing all medica
-

-
tions except those considered absolutely necessary, and 
correcting, if possible, sensory deficits.
2. Pharmacologic approaches—
There is no clear consen
-
sus about pharmacologic approaches to the treatment of 
behavioral problems in patients who have not benefited 
from nonpharmacologic therapies. Pharmacologic treat
-
ment should be reserved for those patients who pose an 
imminent danger to others or themselves or when symp
-
toms are substantially distressing to the patient.
Despite the lack of strong evidence, antipsychotic medi
-
cations have remained a mainstay for the treatment of 
behavioral disturbances, particularly agitation and aggres
-
sion, largely because of the lack of alternatives. The atypical 
antipsychotic agents (eg, risperidone, olanzapine, quetiap
-
ine, aripiprazole) are increasingly becoming the first choice 
because of an overall better safety profile compared to typi
-
cal agents (eg, haloperidol) but should be used with cau
-
tion in patients with vascular risk factors due to an 
increased risk of stroke; they can also cause weight gain 
and are also associated with hyperglycemia in diabetic 
patients and are considerably more expensive. 
Both typical 
and atypical antipsychotics increase mortality compared 
with placebo when used to treat elderly patients with 
dementia and behavioral disturbances.
 Starting and tar
-
get dosages should be much lower than those used in 
schizophrenia (eg, haloperidol, 0.5–2 mg orally; risperi
-
done, 0.25–2 mg orally).
A randomized placebo-controlled trial in patients with 
Alzheimer disease showed that citalopram (30 mg orally 
daily) improves symptoms of agitation. However, during 
the study, the U.S. Food and Drug Administration issued a 
warning against using doses greater than 40 mg daily 
because of the risk of dysrhythmia from QT interval pro
-
longation. For patients older than age 60, the maximum 
recommended dose is 20 mg daily. Thus, while citalopram 
may be used to treat agitation, safe and effective dosing for 
patients older than age 60 has not been established. In the 
specific instance of patients with dementia with Lewy bod
-
ies, treatment with acetylcholinesterase inhibitors has been 
shown to improve behavioral symptoms.
C. Driving
Although drivers with dementia are at an increased risk for 
motor vehicle accidents, many patients continue to drive 
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safely well beyond the time of initial diagnosis, making the 
timing of when to recommend that a patient stop driving 
particularly challenging.
There is no clear-cut evidence to suggest a single best 
approach to determining an individual patient’s capability, 
and there is no accepted “gold-standard” test. The result is 
that clinicians must consider several factors upon which to 
base their judgment. For example, determining the severity 
of dementia can be useful. Patients with very mild or mild 
dementia according to the Clinical Dementia Rating Scale 
were able to pass formal road tests at rates of 88% and 69%, 
respectively. 
Experts agree that patients with moderately 
severe or more advanced dementia should be counseled 
to stop driving.
 Although not well studied, clinicians 
should also consider the effects of comorbid conditions 
and medications and the role each may play in contributing 
to the risk of driving by a patient with dementia. Assess
-
ment of the ability to carry out IADLs may also assist in the 
determination of risk. Finally, in some cases of mild 
dementia, referral may be needed to a driver rehabilitation 
specialist for evaluation. Although not standardized, this 
evaluation often consists of both off- and on-road testing. 
The cost for this assessment can be substantial, and it is 
typically not covered by health insurance. Experts recom
-
mend such an evaluation for patients with mild dementia, 
for those with dementia for whom new impairment in 
driving skills is observed, and for those with significant 
deficits in cognitive domains, such as attention, executive 
function, and visuospatial skills.
Clinicians must also be aware of the reporting require
-
ments in their individual jurisdictions. When a clinician 
has made the decision to report an unsafe driver to the 
Department of Motor Vehicles, he or she must consider the 
impact of a potential breach in confidentiality and must 
weigh and address, in advance when possible, the conse
-
quences of the loss of driving independence.
D. Advance Financial Planning
Difficulty in managing financial affairs often develops 
early in the course of dementia. Although expertise is not 
expected, clinicians should have some proficiency to 
address financial concerns. Just as clinicians counsel 
patients and families about advance care planning, the 
same should be done to educate about the need for advance 
financial planning and to recommend that patients com
-
plete a durable power of attorney for finance matters 
(DPOAF) when the capacity to do so still exists. Other 
options to assist in managing and monitoring finances 
include online banking, automatic bill payments, direct 
deposits, and joint bank accounts.
No gold-standard test is available to identify when a 
patient with dementia no longer has financial capacity. 
However, the clinician should be on the lookout for signs 
that a patient is either at risk for or actually experiencing 
financial incapacity. Because financial impairment can 
occur when dementia is mild, making that diagnosis 
should alone be enough to warrant further investigation. 
Questioning patients and caregivers about late, missed, or 
repeated bill payments, unusual or uncharacteristic pur
-
chases or gifts, overdrawn bank accounts, or reports of 
missing funds can provide evidence of suspected financial 
impairment. Patients with dementia are also at increased 
risk for becoming victims of financial abuse, and some 
answers to these same questions might also be signs of 
potential financial abuse. When financial abuse is sus
-
pected, clinicians should be aware of the reporting require
-
ments in their local jurisdictions.
 
»
Prognosis
Life expectancy after a diagnosis of Alzheimer disease is 
typically 3–15 years; it may be shorter than previously 
reported. Other neurodegenerative dementias, such as 
dementia with Lewy bodies, show more rapid decline. Hos
-

-
pice care is often appropriate for patients with end-stage 
dementia.
 
»
Referral for neuropsychological testing may be helpful to 
distinguish dementia from depression, to diagnose demen
-
tia in persons of very poor education or very high premor
-
bid intellect, and to aid diagnosis when impairment is mild.
Davis DH et al. Montreal Cognitive Assessment for the diagnosis 
of Alzheimer’s disease and other dementias. Cochrane Data
-
base Syst Rev. 2015 Oct 29;(10):CD010775. [PMID: 26513331]
Jin J. JAMA patient page. Alzheimer disease. JAMA. 2015 
Apr 14;313(14):1488. [PMID: 25871685]
Langa KM et al. A comparison of the prevalence of dementia in 
the United States in 2000 and 2012. JAMA Intern Med. 2017 
Jan 1;177(1):51–8. [PMID: 27893041]
Langa KM et al. The diagnosis and management of mild cog
-
nitive impairment: a clinical review. JAMA. 2014 Dec 17;
 
312(23):2551–61. [PMID: 25514304]
Y ohanna D et al. Antipsychotics to treat agitation or psychosis in 
patients with dementia. JAMA. 2017 Sep 19;318(11):1057–58. 
[PMID: 28975291]
2. Depression
 
»
Depressed elders may not admit to depressed 
mood.
 
»
Depression screening in elders should include a 
question about anhedonia.
 
»
Major depressive disorder occurs in 2% of adults aged 
55 years and older, and its prevalence rises with increasing 
age. Clinically significant depressive symptoms—often 
related to loss, disease, and life changes—are present in up 
to 14% of older adults. Depression rates rise as illness bur
-
den increases. Depression is particularly common among 
hospitalized and institutionalized elders. Older single men 
have the highest suicide rate of any demographic group.
Older patients with depression are more likely to have 
somatic complaints, less likely to report depressed mood, 
and more likely to experience psychotic features than 
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younger patients. In addition, depression may be an early 
symptom of dementia. Depressed patients who have 
comorbid conditions (eg, heart failure) are at higher risk for 
hospitalization, tend to have longer hospital stays, and have 
worse outcomes than their nondepressed counterparts.
 
»
A simple two-question screen—which consists of asking 
“During the past 2 weeks, have you felt down, depressed, or 
hopeless?” and “During the past 2 weeks, have you felt little 
interest or pleasure in doing things?”—is highly sensitive 
for detecting major depression in persons over age 65. 
Positive responses should be followed up with more com
-
prehensive, structured interviews, such as the Geriatric 
Depression Scale (http://www.stanford.edu/~yesavage/
GDS.html) or the nine items regarding depression on the 
Patient Health Questionnaire (PHQ-9).
Elderly patients with depressive symptoms should be 
questioned about use of alcohol and medications (eg, ben
-
zodiazepines, corticosteroids), since these may contribute 
to the clinical picture. Similarly, many medical problems 
can cause fatigue, lethargy, or hypoactive delirium, all of 
which may be mistaken for depression.
 
»
Treatment
Treatment may involve psychosocial interventions, 
increased physical activity, psychotherapy, problem-
solving therapy, cognitive-behavioral therapy, reduction of 
alcohol or medication intake, antidepressant medications, 
or a combination approach. Depressed elders may do bet
-
ter with a collaborative or multidisciplinary care model 
that includes socialization and other support elements than 
with usual care. In older patients with depressive symp
-
toms who do not meet criteria for major depressive disor
-
der, nonpharmacologic treatment approaches should be 
used.
Choice of antidepressant agent is usually based on side-
effect profile, cost, and patient-specific factors, such as 
presenting symptoms and comorbidities. Selective sero
-
tonin reuptake inhibitors (SSRIs) are often used as first-
line agents because they are relatively well-tolerated (see 
Table 25–7). Mirtazapine is often used for patients with 
weight loss, anorexia, or insomnia. Duloxetine is useful in 
patients who also have neuropathic pain. Regardless of the 
medication chosen, many experts recommend starting 
elders at a relatively low dose, titrating to full dose slowly, 
and continuing for a longer trial (at least 8 weeks) before 
trying a different medication. Augmentation therapy (eg, 
with lithium, methylphenidate, or aripiprazole) can 
enhance clinical response in treatment-resistant depres
-
sion. For patients with severe or catatonic depression, 
electroconvulsive therapy should be considered.
For patients experiencing their first episode of depres
-
sion, pharmacologic treatment should continue for at least 
6 months after remission of the depression. Recurrence of 
major depression is common enough among elders that 
long-term maintenance medication therapy should be 
 
»
Any patient who might be considered for electroconvulsive 
therapy should be referred for psychiatric evaluation. Con
-
sider referral for patients who have mania, psychosis, cata
-
tonia, or treatment-resistant depression.
 
»
Consider psychiatric evaluation and admission for patients 
who are psychotic, suicidal, homicidal, catatonic, or gravely 
disabled.
Kok RM et al. Management of depression in older adults: a review. 
JAMA. 2017 May 23;317(20):2114–22. [PMID: 28535241]
Gilbody S et al. Effect of collaborative care vs usual care on 
depressive symptoms in older adults with subthreshold 
depression: the CASPER randomized clinical trial. JAMA. 
2017 Feb 21;317(7):728–37. [PMID: 28241357]
3. Delirium
 
»
Rapid onset and fluctuating course.
 
»
Primary deficit in attention rather than memory.
 
»
May be hypoactive or hyperactive.
 
»
Dementia frequently coexists.
 
»

»
 
»
 
»
 
»
 
»
Delirium is an acute, fluctuating disturbance of conscious
-
ness, associated with a change in cognition or development 
of perceptual disturbances (see also Chapter 25). It is the 
pathophysiologic consequence of an underlying general 
medical condition, such as infection, coronary ischemia, 
hypoxemia, or metabolic derangement. Delirium occurs in 
29–64% of hospitalized older adults, persists in 25% or 
more, and is associated with worse clinical outcomes 
(higher in-hospital and postdischarge mortality, longer 
lengths of stay, delayed and limited recovery of physical 
function, greater probability of placement in a nursing 
facility).
Although the acutely agitated elderly patient often 
comes to mind when considering delirium, many episodes 
are subtler. Such 
hypoactive delirium
 may be suspected 
only if one notices new cognitive slowing or inattention.
Cognitive impairment is an important risk factor for 
delirium. Other risk factors include severe illness, poly
-
pharmacy, use of psychoactive medications, sensory 
impairment, depression, and alcoholism.
 
»
Several bedside instruments are available for the assess
-
ment of delirium (http://www.hospitalelderlifeprogram.
org/delirium-instruments/). The 
confusion assessment 
method (CAM),
 available as the Long CAM, Short CAM, 
and 3D CAM (3-minute diagnostic CAM), requires (1) 
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acute onset and fluctuating course and (2) inattention and 
either
 (3) disorganized thinking 
or
 (4) altered level of con
-
sciousness. All three instruments perform well; the Short 
CAM and 3D CAM are particularly useful for clinical 
assessment of delirium. Two variations, the CAM-ICU and 
the CAM-S, are useful for the intensive care unit setting 
and in assessing delirium severity, respectively.
A key component of a delirium workup is review of 
medications because many medications, the addition of a 
new medication, an increase in dose of a medication, or the 
discontinuation of a medication known to cause with
-
drawal symptoms are all associated with the development 
of delirium. Medications that are particularly likely to 
increase the risk of delirium include sedative/hypnotics, 
anticholinergics, opioids, benzodiazepines, and H
1
- and 
H
2
-antihistamines.
Evaluation of most patients should include a complete 
blood count; blood urea nitrogen (BUN); serum electro
-
lytes, creatinine, glucose, calcium, albumin, and liver bio
-
chemical tests; urinalysis; and ECG. In selected cases, 
serum magnesium, medication levels, arterial blood gas 
measurements, blood cultures, chest radiography, urinary 
toxin screen, and lumbar puncture may be helpful. When 
delirium develops during a hospitalization in the absence 
of trauma or new localizing neurologic signs, a head CT is 
rarely revealing.
 
»
Prevention
The best evidence for prevention comes from nonpharma
-
cologic multicomponent interventions. These components 
include improving cognition (frequent reorientation, activ
-
ities, socialization with family and friends when possible), 
sleep (massage, noise reduction, minimizing interruptions 
at night), mobility, vision (visual aids and adaptive equip
-
ment), hearing (portable amplifiers, cerumen disimpac
-
tion), and hydration status (volume repletion). No 
medications, including antipsychotics, have been consis
-
tently shown to prevent delirium or improve outcomes 
such as length of stay or mortality should delirium develop.
 
»
Treatment
Management of established episodes of delirium is largely 
supportive and includes reassurance and reorientation, 
treatment of underlying causes, eliminating unnecessary 
medications, and avoidance of indwelling catheters and 
restraints. The role of antipsychotic agents (eg, haloperidol, 
0.5–1 mg orally, or quetiapine, 25 mg orally, at bedtime or 
twice daily) is uncertain because the evidence of benefit 
has been inconsistent. While these agents may reduce 
symptoms of hyperactive delirium, improvements in com
-
plication rates, length of stay, or mortality have not been 
shown. As with dementia, caution should be used when 
prescribing antipsychotic medications, including checking 
the QTc interval on the ECG, eliminating other QTc-
prolonging medications, and correcting any electrolyte 
abnormalities. Benzodiazepines should be avoided except 
in the circumstance of alcohol or benzodiazepine with
-
drawal. In ventilated patients in the intensive care unit 
setting, dexmedetomidine or propofol (or both) may also 
be useful alternatives or adjuncts to antipsychotic therapy 
in patients with delirium.
Most episodes of delirium clear in a matter of days after 
correction of the precipitant, but some patients suffer epi
-
sodes of much longer duration, and a significant percent
-
age never return to their former baseline level of 
functioning.
 
»
If an initial evaluation does not reveal the cause of delirium 
or if entities other than delirium are in the differential 
diagnosis, referral to a neuropsychologist, neurologist, or 
geropsychiatrist should be considered.
 
»
Patients with delirium of unknown cause should be admit
-
ted for an expedited workup if consistent with the patient’s 
goals of care.
Hshieh TT et al. Effectiveness of multicomponent nonpharma
-
cological delirium interventions: a meta-analysis. JAMA

-
-
cological delirium interventions: a meta-analysis. JAMA 
Intern Med. 2015 Apr;175(4):512–20. [PMID: 25643002]
Marcantonio ER. 3D-CAM: derivation and validation of a 
3-minute diagnostic interview for CAM-defined delirium: a 
cross-sectional diagnostic test study. Ann Intern Med. 2014 
Oct 21;161(8):554–61. [PMID: 25329203]
Neufeld KJ et al. Antipsychotic medication for prevention and 
treatment of delirium in hospitalized adults: a systematic 
review and meta-analysis. J Am Geriatr Soc. 2016 Apr;
 
64(4):705–14. [PMID: 27004732]
4. Immobility
Mobility limitation is common in older adults and is asso
-
ciated with increased rates of morbidity, hospitalization, 
disability, and mortality. Structured physical activity pro
-
grams may help reduce mobility-related disability among 
community-dwelling elders. Hospital-associated bed rest is 
a common precipitant of immobility and functional 
decline. Among hospitalized medical patients over age 70, 
about 10% experience a decline in function, and those who 
experience critical illness are at particularly high risk.
The hazards of bed rest in older adults are multiple, 
serious, quick to develop, and slow to reverse.
 Within 
days after being confined to bed, deconditioning of the 
cardiovascular system occurs and involves fluid shifts, 
decreased cardiac output, decreased peak oxygen uptake, 
increased resting heart rate, and postural hypotension. 
More striking changes occur in skeletal muscle, with loss of 
strength. Pressure injuries (previously called “pressure 
ulcers”), deep venous thrombosis, pulmonary embolism, 
and falls are additional serious risks. Recovery from these 
changes usually takes weeks to months.
 
»
Prevention & Treatment
Physical activity should be encouraged for all elders, par
-
ticularly sedentary elders. Protocols for hospitalized elders 
that promote walking two to three times daily and sitting 
upright for much of the day can minimize unnecessary 
immobility. When immobilization cannot be avoided, 
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several measures can be used to minimize its consequences. 
To reduce the risks of contracture and weakness, range-of-
motion and strengthening exercises should be started 
immediately and continued as long as the patient is in bed. 
Avoiding restraints and discontinuing intravenous lines and 
urinary catheters will increase opportunities for early 
mobility. Graduated ambulation should begin as soon as it 
is feasible. Prior to discharge, physical therapists can recom
-
mend appropriate exercises and assistive devices; after dis
-
charge, they can recommend safety modifications and 
maintenance exercises.
Pahor M et al. Effect of structured physical activity on preven
-
tion of major mobility disability in older adults: the LIFE 
study randomized clinical trial. JAMA. 2014 Jun 18;
 
311(23):2387–96. [PMID: 24866862]
5. Falls & Gait Disorders
About one-third of people over age 65 fall each year, and 
the frequency of falls increases markedly with advancing 
age. About 10% of falls result in serious injuries, such as 
fractures, soft tissue injuries, and traumatic brain injuries. 
Complications from falls are the leading cause of death 
from injury in persons over age 65.
 Hip fractures are 
common precursors to functional impairment, nursing 
home placement, and death.
Every older person should be asked about falls. Assess
-
ment of patients who fall should include postural blood 
pressure and pulse; cardiac examination; evaluations of 
strength, range of motion, cognition, and proprioception; 
and examination of feet and footwear. A thorough gait 
assessment should be performed in all older people. Gait 
and balance can be readily assessed by the 
“Up and Go 
Te s t ,”
 in which the patient is asked to stand up from a sit
-
ting position without use of hands, walk 10 feet, turn 
around, walk back, and sit down. Patients who take less 
than 10 seconds are usually normal, while patients who 
take longer than 13.5 seconds are considered at increased 
risk for falling. The ability to recognize common patterns 
of gait disorders is an extremely useful clinical skill to 
develop. Examples of gait abnormalities and their causes 
are listed in Table 4–3.
 
»
Causes of Falls
Balance and ambulation require a complex interplay of 
cognitive, neuromuscular, and cardiovascular function. 
With age, balance mechanisms can become compro
-
mised, reaction time lengthens, and postural sway 
increases. These changes predispose the older person to a 
fall when challenged by an additional insult to any of these 
systems.
Falls in older people are rarely due to a single cause, and 
effective intervention entails a comprehensive assessment 
of the patient’s intrinsic deficits (eg, diseases and medica
-
tions), the activity engaged in at the time of the fall, and 
environmental obstacles.
Intrinsic deficits are those that impair sensory input, 
judgment, blood pressure regulation, reaction time, and 
balance and gait. Dizziness may be closely related to the 
deficits associated with falls and gait abnormalities. 
While it may be impossible to isolate a sole “cause” or a 
“cure” for falls, gait abnormalities, or dizziness, it is often 
possible to identify and ameliorate some of the underlying 
contributory conditions and improve the patient’s overall 
function.
Medication use is one of the most common, significant, 
and reversible causes of falling. A meta-analysis found that 
sedative/hypnotics, antidepressants, and benzodiazepines 
were the classes of medications most likely to be associated 
with falling. The use of multiple medications simultane
-
ously has also been associated with an increased fall risk. 
Table 4–3.
 
Evaluation of gait abnormalities.
Gait 
a
bnormalit
y
p
ossible C
ause
Inability to stand without use of hands
Deconditioning
Myopathy (hyperthyroidism, alcohol, statin-induced)
Hip or knee pain
Unsteadiness upon standing
Orthostatic hypotension

y
p
ossible C
ause
Balance problem (peripheral neuropathy, vision problem, vestibular, other central nervous 
 
system causes)
Generalized weakness
Stagger with eyes closed
Often indicates that vision is compensating for another deficit
Short steps
Weakness
Parkinson disease or related condition
Asymmetry
Cerebrovascular accident
Focal pain or arthritis
Wide-based gait
Fear, balance problems
Flexed knees
Contractures, quadriceps weakness
Slow gait
Fear of falling, weakness, deconditioning, peripheral vascular disease, chronic obstructive 
 
pulmonary disease, heart failure, angina pectoris
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Other often overlooked but treatable contributors include 
postural hypotension (including postprandial, which peaks 
30–60 minutes after a meal), insomnia, use of multifocal 
lenses, and urinary urgency.
Since most falls occur in or around the home, a visit by 
a visiting nurse, physical therapist, or health care provider 
for a 
home safety evaluation
 reaps substantial benefits in 
identifying environmental obstacles and is generally 
reimbursed by third-party payers, including Medicare.
 
»
Complications of Falls
The most common fractures resulting from falls are of the 
wrist, hip, and vertebrae. There is a high mortality rate 
(approximately 20% in 1 year) in elderly women with hip 
fractures, particularly if they were debilitated prior to the 
time of the fracture.
Fear of falling again is a common, serious, but treatable 
factor in the elderly person’s loss of confidence and inde
-
pendence. Referral to a physical therapist for gait training 
with special devices is often all that is required.
Chronic subdural hematoma is an easily overlooked 
complication of falls that must be considered in any elderly 
patient presenting with new neurologic symptoms or signs. 
Headache and known history of trauma may both be absent.
Patients who are unable to get up from a fall are at risk 
for dehydration, electrolyte imbalance, pressure injuries, 
rhabdomyolysis, and hypothermia.
 
»
Prevention & Management
The risk of falling and consequent injury, disability, and 
potential institutionalization can be reduced by modifying 
the factors outlined in Table 4–4. Emphasis is placed on 
treating all contributory medical conditions, minimizing 
environmental hazards, and eliminating medications 
where the harms may outweigh the benefits—particularly 
those that induce orthostasis and parkinsonism (eg, alpha-
blockers, nitrates, antipsychotics). Also important are 
strength, balance, and gait training as well as screening and 
treatment for osteoporosis, if present. Vitamin D supple
-
mentation may reduce falls in patients who are vitamin D 
deficient, but the impact of supplementation on non–
vitamin-D-deficient adults is not clear. High-dose vitamin 
D (60,000 international units per month) has been shown 
to 
increase
 the incidence of falls.
Assistive devices, such as canes and walkers, are useful 
for many older adults but are often used incorrectly. Canes 
should be used on the “good” side. The height of walkers 
and canes should generally be about the level of the wrist. 
Physical therapists are invaluable in assessing the need for 
an assistive device, selecting the best device, and training a 
patient in its correct use.
Eyeglasses, particularly bifocal or graduated lenses, may 
increase the risk of falls, particularly in the early weeks of 
use. Patients should be counseled about the need to take 
extra care when new eyeglasses are being used.
Table 4–4.
 
Fall risk factors and targeted interventions.
t
o C
onsider for 
a
ll 
p
a
tients
Exercise or physical therapy
Tai Chi, gait training, balance training, strength training
Multifactorial intervention
Home safety assessment, medication review, review or specific conditions 
(below), advice on appropriate footwear, vision check, adaptive aids as 
appropriate, physical therapy or exercise as appropriate
Condition
t
ar
geted Intervention
Postural hypotension (> 20 mm Hg drop in systolic blood 
 
pressure, or systolic blood pressure < 90 mm Hg)
Behavioral recommendations, such as hand clenching, elevation of head 
 
of bed; discontinuation or substitution of high-risk medications
Use of benzodiazepine or sedative/hypnotic agent
Education about sleep hygiene; discontinuation or substitution of 
medications
Use of multiple prescription medications
Review of medications
Environmental hazards
Appropriate changes; installation of safety equipment (eg, grab bars)
Gait impairment
Gait training, assistive devices, balance or strengthening exercises

Impairment in transfer or balance
Balance exercises, training in transfers, environmental alterations 
 
(eg, grab bars)
Impairment in leg or arm muscle strength or limb 
 
range of motion
Exercise with resistance bands or putty, with graduated increases in 
resistance
Vision impairment
Cataract surgery or other interventions as appropriate
Inability to get up after a fall
Medic-alert system, physical therapy training for strategies
High-risk footwear
Education on appropriate footwear (eg, avoid slippers, high heels)
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Patients with repeated falls are often reassured by the 
availability of telephones at floor level, a mobile telephone 
on their person, or a lightweight radio call system. Their 
therapy should also include training in techniques for aris
-
ing after a fall.
 
»
Patients with a recent history of falls should be referred for 
physical therapy, eye examination, and home safety 
 
»
If the patient has new falls that are unexplained, particu
-
larly in combination with a change in the physical exami
-
nation or an injury requiring surgery, hospitalization 
should be considered.
Bischoff-Ferrari HA et al. Monthly high-dose vitamin D treat
-
ment for the prevention of functional decline: a randomized 
clinical trial. JAMA Intern Med. 2016 Feb;176(2):175–83. 
[PMID: 26747333]
Uusi-Rasi K et al. Exercise and vitamin D in fall prevention 
among older women: a randomized clinical trial. JAMA 
Intern Med. 2015 May;175(5):703–11. [PMID: 25799402]
6. Urinary Incontinence
 
»
Involuntary loss of urine.
 
»
Stress
 incontinence: leakage of urine upon cough
-
ing, sneezing, or standing.
 
»
Urge
 incontinence: urgency and inability to delay 
urination.
 
»
Overflow
 incontinence: variable presentation.
 
»
Urinary incontinence in older adults is common, and 
interventions can improve most patients. Many patients 
fail to tell their providers about it. A simple question about 
involuntary leakage of urine is a reasonable annual screen: 
“Do you have a problem with urine leaks or accidents?”
 
»
Classification
A. Transient Causes
Use of the mnemonic “DIAPPERS” may be helpful in 
remembering the categories of “transient” urinary 
incontinence.
1. Delirium—
A clouded sensorium impedes recognition of 
both the need to void and the location of the nearest toilet. 
Delirium is the most common cause of incontinence in 
hospitalized patients; once it clears, incontinence usually 
resolves.
2. Infection—
Symptomatic urinary tract infection com
-
monly causes or contributes to urgency and incontinence. 
Asymptomatic bacteriuria does not.
3. Atrophic urethritis and vaginitis—
Atrophic urethritis 
and vaginitis can usually be diagnosed presumptively by 
the presence of vaginal mucosal telangiectasia, petechiae, 
erosions, erythema, or friability. Urethral inflammation, if 
symptomatic, may contribute to incontinence in some 
women. Some experts suggest a trial of topical estrogen in 
these cases.
4. Pharmaceuticals—
Medications are one of the most 
common causes of transient incontinence. Typical offend
-
ing agents include potent diuretics, anticholinergics, psy
-
chotropics, opioid analgesics, alpha-blockers (in women), 
alpha-agonists (in men), and calcium channel blockers.
5. Psychological factors—
Severe depression with psycho
-
motor retardation may impede the ability or motivation to 
reach a toilet.
6. Excess urinary output—
Excess urinary output may 
overwhelm the ability of an older person to reach a toilet in 
time. In addition to diuretics, common causes include 
excess fluid intake; metabolic abnormalities (eg, hypergly
-
cemia, hypercalcemia, diabetes insipidus); and disorders 
associated with peripheral edema, with its associated heavy 
nocturia when previously dependent legs assume a hori
-
zontal position in bed.
7.
 
Restric
ted mobility—
(See Immobility, above.) If mobil
-
ity cannot be improved, access to a urinal or commode (eg, 
at the bedside) may improve continence.
8.
 
Stoo
l impaction—
This is a common cause of uri
-
nary incontinence in hospitalized or immobile patients. 
Although the mechanism is still unknown, a clinical 
clue to its presence is the onset of both urinary and fecal 
incontinence. Disimpaction usually restores urinary 
continence.
B. Established Causes
Causes of “established” incontinence should be addressed 
after the “transient” causes have been uncovered and man
-

-
aged appropriately.
1. Detrusor overactivity (urge incontinence)—
Detrusor 
overactivity refers to uninhibited bladder contractions that 
cause leakage. It is the most common cause of established 
geriatric incontinence, accounting for two-thirds of cases, 
and is usually idiopathic. Women will complain of urinary 
leakage after the onset of an intense urge to urinate that 
cannot be forestalled. In men, the symptoms are similar, 
but detrusor overactivity commonly coexists with urethral 
obstruction from benign prostatic hyperplasia. Because 
detrusor overactivity also may be due to bladder stones or 
tumor, the abrupt onset of otherwise unexplained urge 
incontinence—especially if accompanied by perineal or 
suprapubic discomfort or sterile hematuria—should be 
investigated by cystoscopy and cytologic examination of a 
urine specimen.
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2. Urethral incompetence (stress incontinence)—
Urethral incompetence is the second most common cause 
of established urinary incontinence in older women. Stress 
incontinence is most commonly seen in men after radical 
prostatectomy. Stress incontinence is characterized by 
instantaneous leakage of urine in response to a stress 
maneuver. It commonly coexists with detrusor overactivity. 
Typically, urinary loss occurs with laughing, coughing, or 
lifting heavy objects. Leakage is worse or occurs only dur
-
ing the day, unless another abnormality (eg, detrusor over
-
activity) is also present. To test for stress incontinence, have 
the patient relax her perineum and cough vigorously (a 
single cough) while standing with a full bladder. Instanta
-
neous leakage indicates stress incontinence (if urinary 
retention has been excluded by postvoiding residual deter
-
mination using ultrasound). A delay of several seconds or 
persistent leakage suggests that the problem is instead 
caused by an uninhibited bladder contraction induced by 
coughing.
3. Urethral obstruction—
Urethral obstruction (due to 
prostatic enlargement, urethral stricture, bladder neck con
-
tracture, or prostatic cancer) is a common cause of estab
-
lished incontinence in older men but is rare in older 
women. It can present as dribbling incontinence after void
-
ing, urge incontinence due to detrusor overactivity (which 
coexists in two-thirds of cases), or overflow incontinence 
due to urinary retention.
4. Detrusor underactivity (overflow incontinence)—
Detrusor underactivity is the least common cause of incon
-
tinence. It may be idiopathic or due to sacral lower motor 
nerve dysfunction. When it causes incontinence, detrusor 
underactivity is associated with urinary frequency, noctu
-
ria, and frequent leakage of small amounts. The elevated 
postvoiding residual urine (generally over 450 mL) distin
-
guishes it from detrusor overactivity and stress inconti
-
nence, but only urodynamic testing differentiates it from 
urethral obstruction in men. Such testing usually is not 
required in women, in whom obstruction is rarely 
present.
 
»
Treatment
Each identified transient cause should be treated regardless 
of whether an established cause coexists. For patients with 
urinary retention induced by an anticholinergic agent, 
discontinuation of the medication should first be consid
-
ered. If this is not feasible, substituting a less anticholiner
-
gic agent may be useful.
1. Detrusor overactivity—
The cornerstone of treatment is 
bladder training.
 Patients start by voiding on a schedule 
based on the shortest interval recorded on a bladder 
record. They then gradually lengthen the interval between 
voids by 30 minutes each week using relaxation techniques 
to postpone the urge to void. Lifestyle modifications, 
including weight loss and caffeine reduction, may also 
improve incontinence symptoms. For cognitively impaired 
patients and nursing home residents who are unable to 
manage on their own, 
timed and prompted voiding
 initi
-
ated by caregivers is effective. 
Pelvic floor muscle (“Kegel”) 
exercises
 can reduce the frequency of incontinence epi
-
sodes when performed correctly and sustained.
If behavioral approaches prove insufficient, 
antimusca
-
rinic agents
 may provide additional benefit. Tolterodine 
and oxybutynin are the two oral medications for which 
there is the most experience. Available regimens of these 
agents include short-acting tolterodine, 1–2 mg orally twice 
a day; long-acting tolterodine, 2–4 mg orally daily; short-
acting oxybutynin, 2.5–5 mg orally twice or three times a 
day; long-acting oxybutynin, 5–15 mg orally daily; and 
oxybutynin transdermal patch, 3.9 mg/day applied twice 
weekly. All of these agents can produce delirium, dry 
mouth, or urinary retention; long-acting preparations may 
be better tolerated. Agents such as fesoterodine (4–8 mg

be better tolerated. Agents such as fesoterodine (4–8 mg 
orally once daily), trospium chloride (20 mg orally once or 
twice daily), long-acting trospium chloride (60 mg orally 
daily), darifenacin (7.5–15 mg orally daily), and solifenacin 
(5–10 mg orally daily) appear to have similar efficacy, but 
only fesoterodine has been demonstrated to have tolerabil
-
ity in medically complex older adults that is comparable to 
younger adults.
The beta-3-agonist
 mirabegron,
 25–50 mg orally daily, 
is approved for overactive bladder symptoms, which 
include urge urinary incontinence. In trials comparing 
mirabegron with antimuscarinic agents, the efficacy and 
safety profiles have been comparable, with less dry mouth 
reported in persons who received mirabegron. While its 
potential cardiac effects warrant ongoing surveillance, the 
experience accruing among adults over the age of 70 shows 
that adherence rates may be superior to the antimuscarinic 
medications. For frail older adults and those with hyper
-
tension or cardiac conditions, the long-term safety remains 
to be determined.
An alternative to oral agents is an injection of 
onabotu
-
linum toxin A
 into the detrusor muscle. In a head-to-head 
comparison of onabotulinum toxin A with antimuscarinic 
medications, patients had similar rates of reduction of 
incontinence episodes. Persons who received onabotuli
-
num toxin A had higher rates of complete resolution of 
incontinence and lower rates of dry mouth but were more 
likely to experience urinary retention and urinary tract 
infections than those who did not receive onabotulinum 
toxin A.
The combination of behavioral therapy and antimusca
-
rinics appears to be more effective than either alone, 
although one study in a group of younger women showed 
that adding behavioral therapy to individually titrated 
doses of extended-release oxybutynin was no better than 
with medication treatment alone.
In men with both benign prostatic hyperplasia and 
detrusor overactivity and with postvoiding residual vol
-
umes of 150 mL or less, an antimuscarinic agent added to 
an alpha-blocker may provide additional relief of lower 
urinary tract symptoms.
Lifestyle modifications,
 including limiting caffeine and 
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fluid intake, may be helpful for some women, particu
-
larly women with mixed stress/urge incontinence; strong 
evidence supports weight loss in obese women. 
Pelvic 
floor muscle exercises
 are effective for women with 
mild to moderate stress incontinence; the exercises can 
be combined, if necessary, with biofeedback or electrical 
stimulation. Instruct the patient to pull in the pelvic 
floor muscles and hold for 6–10 seconds and to perform 
three sets of 8–12 contractions daily. Benefits may not be 
seen for 6 weeks. 
Pessaries
 or 
vaginal cones
 may be 
helpful in some women but should be prescribed only by 
providers who are experienced with using these 
modalities.
No medications are approved for the treatment of 
stress incontinence, and a clinical practice guideline 
from the American College of Physicians recommends 
against pharmacologic treatment. Although a last resort, 
surgery is the most effective treatment for stress inconti
-
nence; cure rates as high as 96% can result, even in older 
women.
Surgical decompression is the 
most effective treatment for obstruction, especially in the 
setting of urinary retention due to benign prostatic hyper
-
plasia. A variety of nonsurgical techniques make decom
-
pression feasible even for frail men. For the nonoperative 
candidate with urinary retention, intermittent or indwell
-
ing catheterization is used. For a man with prostatic 
obstruction who does not require or desire immediate 
surgery, treatment with alpha-blocking agents (eg, terazosin, 
1–10 mg orally daily; prazosin, 1–5 mg orally twice daily; 
tamsulosin, 0.4–0.8 mg orally daily taken 30 minutes after 
the same meal) can improve symptoms and delay obstruc
-
tion. Finasteride, 5 mg orally daily, can provide additional 
benefit to an alpha-blocking agent in men with an enlarged 
prostate.
4. Detrusor underactivity—
For the patient with a poorly 
contractile bladder, augmented voiding techniques (eg, 
double voiding, suprapubic pressure) can prove effective. If 
further emptying is needed, intermittent or indwelling 
catheterization is the only option. Antibiotics should be 
used only for symptomatic urinary tract infection or as 
prophylaxis against recurrent symptomatic infections in a 
patient using intermittent catheterization; they should not 
be used as prophylaxis in a patient with an indwelling 
catheter.
 
»
•	
Men with urinary obstruction who do not respond to 
medical therapy should be referred to a urologist.
•	
Women who do not respond to medical and behavioral 
therapy should be referred to a urogynecologist or 
urologist.
Culbertson S et al. Nonsurgical management of urinary inconti
-
nence in women. JAMA. 2017 Jan 3;317(1):79–80. [PMID: 
28030686]
Dubeau CE et al. Effect of fesoterodine in vulnerable elderly 
subjects with urgency incontinence: a double-blind, placebo 
controlled trial. J Urol. 2014 Feb;191(2):395–404. [PMID: 
23973522]
Qaseem A et al. Nonsurgical management of urinary inconti
-
nence in women: a clinical practice guideline from the 
American College of Physicians. Ann Intern Med. 2014 
Sep 16;161(6):429–40. [PMID: 25222388]
7. Involuntary Weight Loss
 
»
Aging, even in the absence of disease, is associated with 
reduced appetite. Involuntary weight loss affects substan
-
tial numbers of elders. Most studies of involuntary weight 
loss in community-dwelling older adults define it as loss of 
5% of body weight in 6 months or 10% of body weight in 
1 year.
 
»
The causes of involuntary weight loss are many but gener
-
ally break down along medical (60–70%) and psychiatric 
(10–20%) causes, while up to 25% of the time a cause will 
not be identified. Social factors such as access to food and 
dental health should also be explored. The history and 
physical examination should guide the evaluation looking

physical examination should guide the evaluation looking 
for symptoms and signs that could point to a potential cause 
(eg, abdominal pain—peptic ulcer disease, tachycardia—
hyperthyroidism). When the history, physical examination, 
and basic laboratory studies do not suggest a possible diag
-
nosis, additional evaluation (eg, total body CT scan) is usu
-
ally low yield. When no other cause is identified, the frailty 
syndrome should be considered in the differential 
 
»
Treatment
Initial treatment should focus on any identified causes of 
involuntary weight loss while also addressing social barri
-
ers that may impact the patient’s access to food. Oral nutri
-
tional supplements of 200–1000 kcal/day can increase 
weight and improve outcomes in malnourished hospital
-
ized elders but have 
not
 been shown to have benefits in 
community-dwelling older adults. Sodium-containing fla
-
vor enhancers (eg, iodized salt) can improve food intake 
without adverse health effects when there is no contraindi
-
cation to their use. Megestrol acetate as an appetite stimu
-
lant has not been shown to increase lean body mass or 
lengthen life among elders and has significant side effects. 
For those patients with advanced dementia, percutaneous 
tube feeding is not recommended, but rather assiduous 
hand feeding may allow maintenance of weight and pro
-
vide more comfort.
Abu RA et al. PEG insertion in patients with dementia does not 
improve nutritional status and has worse outcomes as com
-
pared with PEG insertion for other indications. J Clin Gas
-
troenterol. 2016 Aug 8. [Epub ahead of print] [PMID: 
27505401]
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8. 
p
r
essure Injury
 
»
Examine at-risk patients on admission to the 
 
hospital and daily thereafter.
 
»
Pressure injury is classified into one of six 
categories:
●
 
Stage 1: Non-blanchable erythema of intact skin
●
  
Stage 2: Partial-thickness skin loss with exposed 
dermis
●
 
Stage 3: Full-thickness skin loss
●
 
Stage 4: Full-thickness skin and tissue loss
●
  
Unstageable: Obscured full-thickness skin and 
tissue loss
●
  
Deep tissue: Persistent non-blanchable deep red, 
maroon, or purple discoloration
 
»
The National Pressure Ulcer Advisory Panel changed the 
term “pressure ulcer” to “pressure injury” to more accu
-
rately reflect the fact that stage 1 and deep tissue 
injury describe injuries to intact skin, compared to the 
ulcers described in the other 4 stages. Most pressure injuries 
develop during a hospital stay for an acute illness. Incidence 
ranges from 12% to 16%. The primary risk factor for 
pressure injuries is immobility. Other contributing risk fac
-
tors include reduced sensory perception, moisture (urinary 
and fecal incontinence), poor nutritional status, and friction 
and shear forces.
Deep tissue and unstageable pressure injury are included 
in the six pressure injury stages. An area of purple or 
maroon discolored intact skin or blood-filled blister is char
-
acteristic of deep tissue injury. The area may be preceded by 
tissue that is painful, firm, mushy, boggy, warmer, or cooler 
compared with adjacent tissue. Ulcers in which the base is 
covered by slough (yellow, tan, gray, green, or brown) or 
eschar (tan, brown, or black) are considered unstageable.
Several risk assessment instruments including the 
Braden Scale and the Norton score can be used to assess 
the risk of developing pressure injury.
While Medicare does not reimburse for hospital-
acquired pressure injury, there is a higher reimbursement 
for pressure injury present on admission. Clinicians should 
include a full skin assessment on every admission 
 
»
Using specialized support surfaces (including mattresses, 
beds, and cushions), patient repositioning, optimizing 
nutritional status, and moisturizing sacral skin are strate
-
gies that have been shown to reduce pressure injury. For 
moderate- to high-risk patients, mattresses or overlays that 
reduce tissue pressure below that of a standard mattress 
appear to be superior to standard mattresses.
 
»
Evaluation
Evaluation of pressure injuries should include patient’s risk 
factors and goals of care; injury stage, size, and depth; 
absence or presence (and type) of exudate; appearance of 
the wound bed and possible surrounding infection; and 
sinus tracking, or cellulitis.
 
»
Treatment
Treatment is aimed toward pressure reduction, removing 
necrotic debris and maintaining a moist wound bed that 
will promote healing and formation of granulation tissue. 
The type of dressing that is recommended depends on 
the location and depth of the wound, whether necrotic 
tissue or dead space is present, and the amount of exudate 
(Table 4–5). Pressure-reducing devices (eg, air-fluid beds 
and low-air-loss beds) are associated with improved heal
-
ing rates. Although poor nutritional status is a risk factor 
for the development of pressure injury, there is no evidence 
that nutritional supplementation helps correct pressure 
injury.
Providers can become easily overwhelmed by the array 
of products available for the treatment of established pres
-
sure injuries. Most institutions should designate a wound 
care expert or team to select a streamlined wound care 
product line that has simple guidelines. In a patient with 
end-stage disease who is receiving end-of-life care, appro
-
priate treatment might be directed toward palliation 
(including minimizing dressing changes and odors) rather 
than efforts directed at healing.
Table 4–5.
 
Treatment of pressure injury.
Injury 
t
ype
Dressing 
t

Table 4–5.
 
Injury 
t
ype
Dressing 
t
ype and C
onsiderations
Stage 1 and deep 
tissue injury
Polyurethane film
Hydrocolloid wafer
Semipermeable foam dressing
Stage 2
Hydrocolloid wafers
Stages 3 and 4
For highly exudative wounds, use highly 
absorptive dressing or packing, such as 
calcium alginate
Wounds with necrotic debris must be 
debrided
Debridement can be autolytic, enzymatic, 
or surgical
Shallow, clean wounds can be dressed with 
hydrocolloid wafers, semipermeable 
foam, or polyurethane film
Deep wounds can be packed with gauze; if 
the wound is deep and highly exudative, 
an absorptive packing should be used
Heel injury
Do not remove eschar on heel ulcers 
because it can help promote healing 
(eschar in other locations should be 
debrided)
Unstageable
Debride before deciding on further therapy
Deep tissue injury
Avoid pressure to the area
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»
Bacteria contaminate all chronic pressure injuries with skin 
loss, but it can be difficult to identify those wounds that are 
infected. Suspicion for infection should rise if there is pain, 
increased or foul-smelling wound drainage, erythema of 
the skin around the wound, or if the wound will not heal. 
Fever and leukocytosis are other indicators of systemic 
infection but are not always present. Culture from a super
-
ficial swab adds little valuable diagnostic information. For 
nonhealing infected wounds without evidence of systemic 
involvement, topical antiseptics (eg, silver sulfadiazine) are 
recommended and may need to be accompanied by 
debridement of necrotic tissue. When systemic infections 
such as cellulitis and osteomyelitis are present, oral or par
-
enteral antibiotics are warranted and medication choice 
should be guided by tissue culture, but this can be painful 
and is not always readily available.
 
»
Pressure injuries that are large or nonhealing should be 
referred to a plastic or general surgeon or dermatologist for 
biopsy, debridement, and possible skin grafting.
 
»
Patients with pressure injury should be admitted if the 
primary residence is unable to provide adequate wound 
care or pressure reduction, or if the wound is infected or 
requires complex or surgical care.
Qaseem A et al. Treatment of pressure ulcers: a clinical practice 
guideline from the American College of Physicians. Ann 
Intern Med. 2015 Mar 3;162(5):370–9. [PMID: 25732279]
Ricci JA et al. Evidence-based medicine: the evaluation and 
treatment of pressure injuries. Plast Reconstr Surg. 2017 Jan;
 
139(1):275–86. [PMID: 28027261]
Tran JP et al. Prevention of pressure ulcers in the acute care set
-
ting: new innovations and technologies. Plast Reconstr Surg. 
2016 Sep;138(3 Suppl):232–40S. [PMID: 27556767]
9. 
p
harmacotherapy & 
p
olypharmac
y
There are several reasons for the greater incidence of iatro
-
genic medication reactions in the elderly population, the 
most important of which is the large number of medica
-
tions that elders take. Medication metabolism is often 
impaired in elders due to a decrease in glomerular filtra
-
tion rate, reduced hepatic clearance, and changes in body 
composition. Older individuals often have varying 
responses to a given serum medication level. Most emer
-
gency hospitalizations for recognized adverse medication 
events among older persons result from only a few com
-
mon medications used alone or in combination.
 
»
Precautions in Administering Medications
Nonpharmacologic interventions can often be a first-line 
alternative to medications (eg, diet for mild hypertension 
or type 2 diabetes mellitus). Pharmacologic therapy is 
begun with less than the medication’s usual adult dosage, 
and the dosage increased slowly, consistent with its phar
-
macokinetics in older patients. However, age-related 
changes in medication distribution and clearance are vari
-
able among individuals, and some require full doses. After 
determining acceptable measures of success and toxicity, 
the dose is increased until one or the other is reached.
Despite the importance of beginning new medications 
in a slow, measured fashion, all too often an inadequate 
trial is attempted (in terms of duration or dose) before 
discontinuation. Antidepressants, in particular, are fre
-
quently stopped before therapeutic dosages are reached for 
sufficient durations.
A number of simple interventions can help improve 
adherence to the prescribed medical regimen. When possi
-
ble, the clinician should keep the dosing schedule simple, the 
number of pills low, the medication changes as infrequent as 
possible, and encourage the patient to use a single pharmacy. 
Pillboxes or “medi-sets” help some patients with adherence.
Having the patient or caregiver bring in all medications 
at each visit can help the clinician perform 
medication

medication 
reconciliation
 and reinforce reasons for medication use, 
dosage, frequency of administration, and possible adverse 
effects. Medication reconciliation is particularly important 
if the patient sees multiple providers.
The risk of toxicity goes up with the number of medica
-
tions prescribed. Certain combinations of medications (eg, 
warfarin and many types of antibiotics, angiotensin-
converting enzyme inhibitors and NSAIDs) are particu
-
larly likely to cause drug-drug interactions and should be 
watched carefully.
Trials of individual medication discontinuation should 
be considered when the original indication is unclear, the 
goals of care have changed, or the patient might be experi
-
encing side effects. Medication discontinuation is particu
-
larly important in patients with limited life expectancy who 
may experience increasing burdens and modest, if any, 
benefits from many classes of medications (eg, bisphos
-
phonates, cholesterol-lowering medications). Clinical tools 
such as “STOPP/START” and the Beers Criteria can 
improve medication prescribing and clinical outcomes.
 
»
Patients with poor or uncertain adherence may benefit 
from referral to a pharmacist or a home health nurse.
Hill-Taylor B et al. Effectiveness of the STOPP/START (Screen
-
ing Tool of Older Persons’ potentially inappropriate Prescrip
-
tions/Screening Tool to Alert doctors to the Right Treatment) 
criteria: systematic review and meta-analysis of randomized 
controlled studies. J Clin Pharm Ther. 2016 Apr;4(2):158–69. 
[PMID: 26990017]
Koronkowski MJ et al. Recent literature update on medication 
risk in older adults, 2015–2016. J Am Geriatr Soc. 2017 Jul;
 
65(7):1401–5. [PMID: 28369729]
Morin L et al. Choosing wisely? Measuring the burden of medi
-
cations in older adults near the end of life: nationwide, longi
-
tudinal cohort study. Am J Med. 2017 Aug;130(8):927–36.e9. 
[PMID: 28454668]
10. Vision Impairment
Visual impairment due to age-related refractive error 
(“presbyopia”), macular degeneration, cataracts, glaucoma, 
and diabetic retinopathy is associated with significant 
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Table 4–6.
 
Phrases and actions that may be helpful in 
situations of suspected abuse or neglect.
Questions for the 
e
lder
1.
 
Has an
yone hurt you?
2.
 
Ar
e you afraid of anybody?
3.
  
Is an
yone taking or using your money without your 
permission?
Questions for the Caregiver
1.
 
Ar
e your relative’s needs more than you can handle?
2.
 
Ar
e you worried that you might hit your relative?
3.
 
Ha
ve you hit your relative?
If abuse is suspected
Tell the patient that you are concerned, want to help, and will 
call Adult Protective Services to see if there is anything that 
they can do to help
Document any injuries
Document the patient’s words
Document whether the patient has decision-making capacity 
using a tool such as “Aid to Capacity Evaluation”
physical and mental health comorbidities, falls, mobility 
impairment, and reduced quality of life. The prevalence of 
serious and correctable visual disorders in elders is suffi
-
cient to warrant a complete eye examination by an ophthal
-
mologist or optometrist annually or biannually for most 
elders. Many patients with visual loss benefit from a refer
-
ral to a low-vision program.
Naël V et al. Visual impairment, undercorrected refractive 
errors, and activity limitations in older adults: findings from 
the three-city alienor study. Invest Ophthalmol Vis Sci. 2017 
Apr 1;58(4):2359–65. [PMID: 28437525]
Pelletier AL et al. Vision loss in older adults. Am Fam Physician. 
2016 Aug 1;94(3):219–26. Erratum in: Am Fam Physician. 
2016 Sep 1;94(5):344. [PMID: 27479624]
11. 
h
earing Impairment
Over one-third of persons over age 65 and half of those 
over age 85 have some hearing loss. Hearing loss is associ
-
ated with social isolation, depression, disability, cognitive 
impairment, and excess risk of hospitalization and nursing 
home placement. A reasonable screen is to ask patients if 
they have hearing impairment. Those who answer “yes” 
should be referred for audiometry. Those who answer “no” 
may still have hearing impairment and can be screened by 
a handheld audioscope or the whispered voice test. The 
whispered voice test is administered by standing 2 feet 
behind the subject, whispering three random numbers 
while simultaneously rubbing the external auditory canal 
of the non-tested ear to mask the sound. If the patient is 
unable to identify all three numbers, the test should be 
repeated with different numbers, and if still abnormal, a 
referral should be made for an audiogram. To determine 
the degree to which hearing impairment interferes with 
functioning, the provider may ask if the patient becomes 
frustrated when conversing with family members, is 
embarrassed when meeting new people, has difficulty 
watching TV , or has problems understanding conversa
-
tions. Caregivers or family members often have important 
information on the impact of hearing loss on the patient’s 
social interactions.
Hearing amplification or cochlear implantation can 
improve hearing-related quality of life and reduce depres
-
sive symptoms in patients with hearing loss. Compliance 
with hearing amplification can be a challenge because of 
dissatisfaction with performance, stigma associated with 
hearing aid use, and cost. Newer digital devices may per
-
form better but are considerably more expensive. Cochlear 
implantation is increasingly being recommended for 
selected elders with profound sensory hearing loss. Special 
telephones, amplifiers for the television, and other devices 
are helpful to many patients. Portable amplifiers are pager-
sized units with earphones attached; they can be purchased 
inexpensively at many electronics stores and can be useful 
in health care settings for improving communication with 
hearing-impaired patients. In general, facing the patient 
and speaking slowly in a low tone is a more effective com
-
munication strategy than shouting.
Chen DS et al. Health ABC study. Association of hearing impair
-

-
-
ment with declines in physical functioning and the risk of 
disability in older adults. J Gerontol A Biol Sci Med Sci. 2015 
May;70(5):654–61. [PMID: 25477427]
Choi JS et al. Association of using hearing aids or cochlear 
implants with changes in depressive symptoms in older 
adults. JAMA Otolaryngol Head Neck Surg. 2016 Jul 1;
 
142(7):652–7. [PMID: 27258813]
Goman AM et al. Prevalence of hearing loss by severity in the 
United States. Am J Public Health. 2016 Oct;106(10):1820–2. 
[PMID: 27552261]
12. 
e
lder Mistreatment & Self-Neglect
Elder mistreatment
 is defined as “actions that cause harm 
or create a serious risk of harm to an older adult by a care
-
giver or other person who stands in a trust relationship to 
the older adult, or failure by a caregiver to satisfy the elder’s 
basic needs or to protect the elder from harm. ” 
Self-neglect
 
is the most common form of elder mistreatment and 
occurs among all demographic strata of the aging popula
-
tion. In the United States, about 14% of adults over age 70 
experience some sort of abuse annually, with about 12% 
experiencing psychological abuse and almost 2% experi
-
encing physical abuse. Each year, 5–7% of elders may be 
victims of financial abuse or scams.
Clues to the possibility of elder abuse include behav
-
ioral changes in the presence of the caregiver, delays 
between occurrences of injuries and when treatment was 
sought, inconsistencies between an observed injury and its 
associated explanation, lack of appropriate clothing or 
hygiene, and not filling prescriptions. Many elders with 
cognitive impairment become targets of financial abuse. 
Both elder abuse and self-neglect are associated with an 
increased risk of mortality.
It is helpful to observe and talk with every older person 
alone for at least part of a visit to ask questions directly 
about possible abuse and neglect (Table 4–6). When self-
neglect is suspected, it is critical to establish whether a 
patient has decision-making capacity in order to determine 
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what course of action needs to be taken. A patient who has 
full decision-making capacity should be provided with 
help and support but can choose to live in conditions of 
self-neglect, providing that the public is not endangered 
by the actions of the person. In contrast, a patient who 
lacks decision-making capacity who lives in conditions of 
self-neglect will require more aggressive intervention, 
which may include guardianship, in-home help, or place
-
ment in a supervised setting. Mental state scores, such as 
the MoCA, may provide some insight into the patient’s 
cognitive status but are not designed to assess decision-
making capacity. A standardized tool, such as the “ Aid to 
Capacity Evaluation, ” is easy to administer, has good per
-
formance characteristics for determining decision-making 
capacity, and is available free online at http://www.jcb.uto
-
ronto.ca/tools/documents/ace.pdf.
 
»
•	
Refer elders with suspected abuse or self-neglect to 
Adult Protective Services, as required by law in most 
states (consult the National Center on Elder Abuse at 
http://www.ncea.aoa.gov).
•	
Refer elders to a mental health professional when it is 
unclear whether they have decision-making capacity 
after an initial assessment or whether an untreated men
-
tal health disorder is contributing to their problem.
 
»
Admit elders who would be unsafe in the community when 
an alternative plan cannot be put into place in a timely 
manner.
Burnes D et al. Prevalence of financial fraud and scams among 
older adults in the United States: a systematic review and 
meta-analysis. Am J Public Health. 2017 Aug;107(8):1295. 
[PMID: 28700284]
Lachs MS et al. Elder abuse. N Engl J Med. 2015 Nov 12;
 
Rosay AB. Prevalence estimates and correlates of elder abuse in 
the United States: the National Intimate Partner and Sexual 
Violence Survey. J Elder Abuse Negl. 2017 Jan–Feb;29(1):
 
1–14. [PMID: 27782784]
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º
PALLIATIVE CARE
DEFINITION & SCOPE
Palliative care is medical care focused on improving 
quality of life for people living with serious illness. Pal
-
liative care addresses and treats symptoms, supports 
patients’ families and loved ones, and helps ensure that 
care aligns with patients’ preferences, values, and goals. 
Near the end of life, palliative care may become the sole 
focus of care, but palliative care alongside cure-focused 
treatment or disease management is beneficial throughout 
the course of a serious illness, regardless of its prognosis.
Palliative care includes management of physical symp
-
toms, such as pain, dyspnea, nausea and vomiting, consti
-
pation, delirium, and agitation; emotional distress, such as 
depression, anxiety, and interpersonal strain; and existen
-
tial distress, such as spiritual crisis. While palliative care is 
a medical subspecialty recognized by the American Board 
of Medical Specialties (“specialty palliative care”) and is 
typically provided by an interdisciplinary team of experts, 
all
 clinicians should have the skills to provide “primary pal
-
liative care” including managing pain; treating dyspnea; 
identifying mood disorders; communicating about prog
-
nosis and patient preferences for care; and helping address 
spiritual distress.
During any stage of illness, patients should be screened 
routinely for symptoms. Any symptoms that cause signifi
-
cant suffering are a medical emergency that should be 
managed aggressively with frequent elicitation and reas
-
sessment as well as individualized treatment. While 
patients at the end of life may experience a host of distress
-
ing symptoms, pain, dyspnea, and delirium are among the 
most feared and burdensome. Management of these com
-
mon symptoms is described later in this chapter. Random
-
ized studies have shown that palliative care provided 
alongside disease-focused treatment can improve quality of 
life, promote symptom management, and even prolong life.
Basch E et al. Overall survival results of a trial assessing patient-
reported outcomes for symptom monitoring during routine 
cancer treatment. JAMA. 2017 Jul 11;318(2):197–8. [PMID: 
28586821]5
 
Steven Z. Pantilat, MD 
 
Ramana K. Naidu, MD 
Palliative Care & Pain 
El-Jawahri A et al. Effect of inpatient palliative care during 
hematopoietic stem-cell transplant on psychological distress 
6 months after transplant: results of a randomized clinical trial. 
J Clin Oncol. 2017 Nov 10;35(32):3714–21. [PMID: 28926288]
Ferrell BR et al. Integration of palliative care into standard oncol
-
ogy care: American Society of Clinical Oncology Clinical 
Practice Guideline Update. J Clin Oncol. 2017 Jan;35(1):
 
96–112. [PMID: 28034065]
Gaertner J et al. Effect of specialist palliative care services on 
quality of life in adults with advanced incurable illness in hos
-
pital, hospice, or community settings: systematic review and 
meta-analysis. BMJ. 2017 Jul 4;357:j2925. [PMID: 28676557]
Haun MW et al. Early palliative care for adults with advanced 
cancer. Cochrane Database Syst Rev. 2017 Jun 12;6:CD011129. 
[PMID: 28603881]
Kavalieratos D et al. Association between palliative care and 
patient and caregiver outcomes: a systematic review and 
meta-analysis. JAMA. 2016 Nov 22;316(20):2104–14. [PMID: 
27893131]
Temel JS et al. Effects of early integrated palliative care in 
patients with lung and GI cancer: a randomized clinical trial. 
J Clin Oncol. 2017 Mar 10;35(8):834–41. [PMID: 28029308]
PALLIATION OF COMMON NONPAIN 
SYMPTOMS
DYSPNEA
Dyspnea is the subjective experience of difficulty breathing 
and may be characterized by patients as tightness in the 
chest, shortness of breath, breathlessness, or a feeling of 
suffocation. Up to half of people at the end of life may 
experience severe dyspnea.
Treatment of dyspnea is usually first directed at the 
cause (see Chapter 9). At the end of life, dyspnea is often

cause (see Chapter 9). At the end of life, dyspnea is often 
treated nonspecifically with opioids, which are the single 
best class of medications for dyspnea with demonstrated 
effectiveness in multiple randomized trials. Starting doses 
are typically lower than would be necessary for the relief 
of moderate pain. Immediate-release morphine given 
orally (2–4 mg every 4 hours) or intravenously (1–2 mg 
every 4 hours) treats dyspnea effectively. Sustained-release 
morphine given orally at 10 mg daily is safe and effective 
for most patients with ongoing dyspnea. Supplemental 
oxygen may be useful for the dyspneic patient 
who is hypoxic
. 
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However, a nasal cannula and face mask are sometimes not 
well tolerated, and fresh air from a window or fan may 
provide relief for patients who are not hypoxic. Judicious 
use of noninvasive ventilation as well as nonpharmacologic 
relaxation techniques, such as meditation and guided 
imagery, may be beneficial for some patients. Benzodiaze
-
pines may be useful adjuncts for treatment of dyspnea-
related anxiety.
NAUSEA & VOMITING
Nausea and vomiting are common and distressing symp
-
toms. As with pain, the management of nausea may be 
optimized by regular dosing and often requires multiple 
medications. An understanding of the four major inputs 
to the vomiting center may help direct treatment (see 
Chapter 15).
Vomiting associated with opioids is discussed below. 
Nasogastric suction may provide rapid, short-term relief 
for vomiting associated with constipation (in addition to 
laxatives), gastroparesis, or gastric outlet or bowel obstruc
-
tion. Prokinetic agents, such as metoclopramide (5–20 mg 
orally or intravenously four times a day), can be helpful in 
the setting of partial gastric outlet obstruction. Transder
-
mal scopolamine (1.5-mg patch every 3 days) can reduce 
peristalsis and cramping pain, and ranitidine (50 mg intra
-
venously every 6 hours) can reduce gastric secretions. 
Octreotide (starting at 50–100 mcg subcutaneously every 
8 hours or as continuous intravenous or subcutaneous 
infusion, beginning at 10–20 mcg/h) can reduce gastric 
secretions and may have a role in relieving nausea and 
vomiting from malignant bowel obstruction. High-dose 
corticosteroids (eg, dexamethasone, 20 mg orally or intra
-
venously daily in divided doses) can be used in refractory 
cases of nausea or vomiting or when it is due to bowel 
obstruction or increased intracranial pressure.
Vomiting due to disturbance of the vestibular apparatus 
may be treated with anticholinergic and antihistaminic 
agents (including diphenhydramine, 25 mg orally or intra
-
venously every 8 hours, or scopolamine, 1.5-mg patch 
every 3 days).
Benzodiazepines (eg, lorazepam, 0.5–1.0 mg given 
orally every 6–8 hours) can be effective in preventing the 
anticipatory
 nausea associated with chemotherapy. For 
emetogenic chemotherapy, therapy includes combinations 
of 5-HT
3
-antagonists (eg, ondansetron, granisetron, dolas
-
etron, or palonosetron), neurokinin-1 receptor antagonists 
(eg, aprepitant, fosaprepitant, or rolapitant), the N-receptor 
antagonist netupitant combined with palonosetron (NEPA), 
olanzapine, dexamethasone, and prochlorperazine. In 
addition to its effect on mood, mirtazepine, 15–45 mg orally 
nightly may help with nausea and improve appetite. 
Finally, dronabinol (2.5–20 mg orally every 4–6 hours) can 
be helpful in the management of nausea and vomiting. 
Some patients report relief from medical cannabis.
Given the frequent use of opioids, poor dietary intake, 
physical inactivity, and lack of privacy, constipation is a 
common problem in seriously ill and dying patients. 
Clinicians must inquire about any difficulty with hard or 
infrequent stools. Constipation is an easily preventable and 
treatable cause of discomfort, distress, and nausea and 
vomiting (see Chapter 15).
Constipation may be prevented or relieved if patients 
can increase their activity and their intake of fluids. Simple 
considerations, such as privacy, undisturbed toilet time, 
and a bedside commode rather than a bedpan may be 
important for some patients.
A prophylactic bowel regimen with a stimulant laxative 
(senna or bisacodyl) should be started when opioid treat
-
ment is begun. Table 15–4 lists other agents (including 
osmotic laxatives such as polyethylene glycol) that can be 
added as needed. Docusate, a stool softener, is not recom
-
mended. Naloxegol, an oral peripherally acting receptor 
antagonist, and lubiprostone are FDA approved to treat

-
antagonist, and lubiprostone are FDA approved to treat 
opioid-induced constipation in patients with chronic non
-
cancer pain. Methylnaltrexone, a subcutaneous medica
-
tion, is a peripherally acting mu-receptor antagonist and is 
available for severe, unrelieved, opioid-induced constipa
-
tion. Patients who report being constipated and then have 
diarrhea typically are passing liquid stool around impacted 
stool.
FATIGUE
Fatigue is a distressing symptom and is the most common 
complaint among cancer patients. Specific abnormalities 
that can contribute to fatigue, including anemia, hypothy
-
roidism, hypogonadism, cognitive and functional impair
-
ment, and malnutrition, should be corrected. Because pain, 
depression, and fatigue often coexist in patients with cancer, 
pain and depression should be managed appropriately in 
patients with fatigue. Fatigue from medication adverse 
effects and polypharmacy is common and should be 
addressed. For nonspecific fatigue, exercise and physical 
rehabilitation may be most effective. Although commonly 
used, strong evidence for psychostimulants, such as methyl
-
phenidate, 5–10 mg orally in the morning and afternoon, or 
modafinil, 200 mg orally in the morning, for cancer-related 
fatigue is lacking. American Ginseng (
Panax quinquefolius
) 
has been shown to be effective for cancer-related fatigue but 
may have an estrogenic effect. Corticosteroids may have a 
short-term benefit. Caffeinated beverages can help.
DELIRIUM & AGITATION
Many patients die in a state of delirium—a waxing and 
waning in level of consciousness and a change in cognition 
that develops over a short time and is manifested by misin
-
terpretations, illusions, hallucinations, sleep-wake cycle 
disruptions, psychomotor disturbances (eg, lethargy, rest
-
lessness), and mood disturbances (eg, fear, anxiety). Delir
-
ium may be hyperactive, hypoactive, or mixed. Agitated 
delirium at the end of life has been called 
terminal 
restlessness.
Some delirious patients may be “pleasantly confused, ” 
although it is difficult to know what patients experience. In 
the absence of obvious distress in the patient, a decision by 
the patient’s family and the clinician not to treat delirium 
may be considered. More commonly, however, agitated 
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delirium at the end of life is distressing to patients and fam
-
ily and requires treatment. Delirium may interfere with the 
family’s ability to interact with or feel comforting to the 
patient and may prevent a patient from being able to recog
-
nize and report important symptoms. Reversible causes of 
delirium include urinary retention, constipation, anticho
-
linergic medications, and pain; these should be addressed 
whenever possible. There is no evidence that hydration 
relieves or dehydration causes delirium. Careful attention 
to patient safety and nonpharmacologic strategies to help 
the patient remain oriented (clock, calendar, familiar envi
-
ronment, reassurance and redirection from caregivers) 
may be sufficient to prevent or manage mild delirium. A 
randomized trial of placebo compared to risperidone or 
haloperidol in delirious patients demonstrated increased 
mortality with neuroleptics. Thus, the benefits of neurolep
-
tic agents (eg, haloperidol, 1–10 mg orally, subcutaneously, 
intramuscularly, or intravenously twice or three times a 
day, or risperidone, 1–3 mg orally twice a day) in the treat
-
ment of agitated delirium must be weighed carefully 
against their potential harms. When delirium is refractory 
to treatment and remains intolerable, sedation may be 
required to provide relief.
Agar MR et al. Efficacy of oral risperidone, haloperidol, or placebo 
for symptoms of delirium among patients in palliative care: a 
randomized clinical trial. JAMA Intern Med. 2017 Jan 1;
 
177(1):34–42. [PMID: 27918778]
Currow DC et al. Double-blind, placebo-controlled, randomized 
trial of octreotide in malignant bowel obstruction. J Pain 
Symptom Manage. 2015 May;49(5):814–21. [PMID: 25462210]
Hui D et al. Effect of lorazepam with haloperidol vs haloperidol 
alone on agitated delirium in patients with advanced cancer 
receiving palliative care: a randomized clinical trial. JAMA. 
2017 Sep 19;318(11):1047–56. [PMID: 28975307]
Mitchell GK et al. The effect of methylphenidate on fatigue in 
advanced cancer: an aggregated N-of-1 trial. J Pain Symptom 
Manage. 2015 Sep;50(3):289–96. [PMID: 25896104]
Singer AE et al. Symptom trends in the last year of life from 1998 
to 2010: a cohort study. Ann Intern Med. 2015 Feb 3;162(3):
 
175–83. [PMID: 25643305]
CARE OF PATIENTS AT T
h
E END OF LIFE
In the United States, nearly 2.5 million people die each 
year. Caring for patients at the end of life is an important 
responsibility and a rewarding opportunity for clinicians. 
From the medical perspective, the end of life may be 
defined as that time when death—whether due to terminal 
illness or acute or chronic illness—is expected within hours 
to months and can no longer be reasonably forestalled by 
medical intervention. Palliative care at the end of life 
focuses on relieving distressing symptoms and promoting 
quality of life (as with all other stages of illness). For 
patients at the end of life, palliative care may become the 
sole focus of care.
 
»
Prognosis at the End of Life
Clinicians must help patients understand when they are 
approaching the end of life. Most patients (and their family 
caregivers) want accurate prognostic information. This 
information influences patients’ treatment decisions, may 
change how they spend their remaining time, and does not 
negatively impact patient survival. One-half or more of 
cancer patients do not understand that many treatments 
they might be offered are palliative and not curative.
While certain diseases, such as cancer, are more ame
-
nable to prognostic estimates regarding the time course to 
death, the other common causes of mortality—including 
heart disease, stroke, chronic lung disease, and dementia—
have more variable trajectories and difficult-to-predict 
prognoses. Even for patients with cancer, clinician esti
-
mates of prognosis are often inaccurate and generally 
overly optimistic. Nonetheless, clinical experience, epide
-

-
-
miologic data, guidelines from professional organizations, 
and computer modeling and prediction tools (eg, the Pal
-
liative Performance Scale or http://eprognosis.ucsf.edu/
index.php) may be used to help offer patients more realistic 
estimates of prognosis. Clinicians can also ask themselves 
“Would I be surprised if this patient died in the next year?” 
to determine whether a discussion of prognosis would be 
appropriate. If the answer is “no, ” then the clinician should 
initiate a discussion. Recognizing that patients may have 
different levels of comfort with prognostic information, 
clinicians can introduce the topic by simply saying, “I have 
information about the likely time course of your illness. 
Would you like to talk about it?”
 
»
Expectations About the End of Life
Death is often regarded by clinicians, patients, and families 
as a failure of medical science. This attitude can create or 
heighten a sense of guilt about the failure to prevent dying. 
Both the general public and clinicians often view death as 
an enemy to be battled furiously in hospitals rather than as 
an inevitable outcome to be experienced as a part of life at 
home. As a result, approximately 75% of people in the 
United States die in hospitals or long-term care facilities.
Even when the clinician and patient continue to pursue 
cure of potentially reversible disease, relieving suffering, 
providing support, and helping the patient make the most 
of their life should be foremost considerations. Patients at 
the end of life and their families identify a number of ele
-
ments as important to quality end-of-life care: managing 
pain and other symptoms adequately, avoiding inappropri
-
ate prolongation of dying, communicating clearly, preserv
-
ing dignity, preparing for death, achieving a sense of 
control, relieving the burden on others, and strengthening 
relationships with loved ones.
 
»
Communication & Care of the Patient
Caring for patients at the end of life requires the same 
skills clinicians use in other tasks of medical care: diag
-
nosing treatable conditions, providing patient education, 
facilitating decision making, and expressing understand
-
ing and caring. Communication skills are vitally impor
-
tant and can be improved through training. Higher-quality 
communication is associated with greater satisfaction 
and awareness of patient wishes. Clinicians must become 
proficient at delivering serious news and then dealing with 
its consequences (Table 5–1). Smartphone and Internet 
CMDT19_Ch05_p0072-p0102.indd   74

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communication resources are available to support clini
-
cians (www.vitaltalk.org), and evidence suggests that com
-
munication checklists or guides can be effective. When the 
clinician and patient do not share a common language, the 
use of a professional interpreter is needed to facilitate clear 
communication and help broker cultural issues.
Three further obligations are central to the clinician’s 
role at this time. First, he or she must work to identify, 
understand, and relieve physical, psychological, social, and 
spiritual distress or suffering. Second, clinicians can serve 
as facilitators or catalysts for hope. While hope for a par
-
ticular outcome such as cure may fade, it can be refocused 
on what is 
still
 possible. Although a patient may hope for a 
“miracle, ” other more likely hopes can be encouraged and 
supported, including hope for relief of pain, for reconcilia
-
tion with loved ones, for discovery of meaning, and for 
spiritual growth. With such questions as “What is still pos
-
sible now for you?” and “When you look to the future, what 
do you hope for?” clinicians can help patients uncover 
hope, explore meaningful and realistic goals, and develop 
strategies to achieve them.
Finally, dying patients’ feelings of isolation and fear 
demand that clinicians assert that they will care for the 
patient throughout the final stage of life. The promise of 
nonabandonment
 is the central principle of end-of-life care 
and is a clinician’s pledge to serve as a caring partner, a 
resource for creative problem solving and relief of suffering, 
a guide during uncertain times, and a witness to the 
patient’s experiences—no matter what happens. Clinicians 
can say to a patient, “I will care for you whatever happens. ”
 
»
Caring for the Family
While significant others may support and comfort a patient 
at the end of life, the threatened loss of a loved one may also 
create or reveal dysfunctional or painful family dynamics. 
Clinicians must be attuned to the potential impact of illness 
on the patient’s family: substantial physical caregiving 
responsibilities and financial burdens as well as increased 
rates of anxiety, depression, chronic illness, and even mor
-
tality. Family caregivers, typically women, commonly pro
-
vide the bulk of care for patients at the end of life, yet their 
work is often not acknowledged, supported, or compen
-
sated. Simply acknowledging and praising the caregiver can 
provide much needed and appreciated support.
Clinicians can help families confront the imminent loss 
of a loved one (Table 5–2) and often must negotiate amid 
complex and changing family needs. Identifying a spokes
-
person for the family, conducting family meetings, allow
-
ing all to be heard, and providing time for consensus may 
help the clinician work effectively with the family. Provid
-
ing good palliative care to the patient can reduce the risk of 
depression and complicated grief in loved ones after the 
patient’s death. Palliative care support directly for caregiv
-
ers improves caregiver depression.
 
»
Clinician Self-Care
Many clinicians find caring for patients at the end of life to 
be one of the most rewarding aspects of practice. However, 
working with the dying requires tolerance of uncertainty, 
ambiguity, and existential challenges. Clinicians must rec
-
ognize and respect their own limitations and attend to their 
own needs in order to avoid being overburdened, overly 
distressed, or emotionally depleted.
Back AL et al. Building resilience for palliative care clinicians: an 
approach to burnout prevention based on individual skills 
and workplace factors. J Pain Symptom Manage. 2016 Aug;
 
52(2):284–91. [PMID: 26921494]
Dionne-Odom JN et al. Benefits of early versus delayed palliative 
care to informal family caregivers of patients with advanced 
cancer: outcomes from the ENABLE III randomized con
-

-
trolled trial. J Clin Oncol. 2015 May 1;33(13):1446–52. [PMID: 
25800762]
Jin J. JAMA patient page. Caregiver support. JAMA. 2014 Mar 12;
 
311(10):1082. [PMID: 24618980]
Kamal AH et al. Prevalence and predictors of burnout among 
hospice and palliative care clinicians in the U.S. J Pain Symp
-
tom Manage. 2016 Apr;51(4):690–6. [PMID: 26620234]
Kearney MK et al. Self-care of physicians caring for patients at 
the end of life: “Being connected . . . a key to my survival. ” 
JAMA. 2009 Mar 18;301(11):1155–64. [PMID: 19293416]
Table 5–1.
 
Suggestions for the delivery of 
 
serious news.
Prepare an appropriate place and time.
Address basic information needs.
Be direct; avoid jargon and euphemisms.
Allow for silence and emotional ventilation.
Assess and validate patient reactions.
Respond to immediate discomforts and risks.
Listen actively and express empathy.
Achieve a common perception of the problem.
Reassure about pain relief.
Ensure follow-up and make specific plans for the future.
Table 5–2.
 
Clinician interventions helpful to families of 
dying patients.
Excellent communication,
 including clinician willingness to 
talk about death, to supply timely and clear information, to 
give proactive guidance, to listen, and to provide empathic 
responses
Advance care planning and clear decision making,
 including 
ensuring culturally sensitive communication, and achieving 
consensus among family members and an understanding that 
surrogate decision makers are trying to determine what the 
patient
 would have wanted, not what the surrogate would 
want
Support for home care,
 including orienting family members to 
the scope and details of family caregiving, providing clear 
direction about how to contact professional caregivers, and 
informing patients and families of the benefits of hospice care
Empathy for family emotions and relationships,
 including 
recognizing and validating common positive and negative 
feelings
Attention to grief and bereavement,
 including support for 
anticipatory grief and follow-up with the family after the 
patient’s death
Data from Rabow MW et al. Supporting family caregivers at the end 
of life: “they don’t know what they don’t know.” JAMA. 2004 Jan 28;
 
291(4):483–91.
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Razmaria AA. JAMA patient page. End-of-life care. JAMA. 2016 
Jul 5;316(1):115. [PMID: 27380364]
Rodenbach RA et al. Promoting end-of-life discussions in 
advanced cancer: effects of patient coaching and question 
prompt lists. J Clin Oncol. 2017 Mar 10;35(8):842–51. [PMID: 
28135140]
White DB et al. Prevalence of and factors related to discordance 
about prognosis between physicians and surrogate decision 
makers of critically ill patients. JAMA. 2016 May 17;315(19):
 
2086–94. [PMID: 27187301]
Wright AA et al. Family perspectives on aggressive cancer care 
near the end of life. JAMA. 2016 Jan 19;315(3):284–92. 
[PMID: 26784776]
 
»
Decision Making, Advance Care Planning, 
& Advance Directives
The idea that patients must choose between quality and 
length of life is an outmoded concept that presents patients 
with a false choice. Clinicians should discuss with patients 
that an approach that provides concurrent palliative and 
disease-focused care is the one most likely to achieve 
improvements in both quality and quantity of life. Patients 
deserve to have their health care be consistent with their 
values, preferences, and goals of care. Well-informed, com
-
petent adults have a right to refuse life-sustaining interven
-
tions even if this would result in death. In order to promote 
patient autonomy, clinicians are obligated to inform 
patients about the risks, benefits, alternatives, and expected 
outcomes of medical interventions, such as cardiopulmo
-
nary resuscitation (CPR), mechanical ventilation, hospital
-
ization and ICU care, and artificial nutrition and hydration. 
Advance directives
 are oral or written statements made by 
patients when they are competent that project their auton
-
omy into the future and are intended to guide care should 
they lose the ability to make and communicate their own 
decisions. Advance directives are an important part of 
advance care planning
—defined by an international Del
-
phi panel as “a process that supports adults at any age or 
stage of health in understanding and sharing their personal 
values, life goals, and preferences regarding future medical 
care. The goal of advance care planning is to help ensure 
that people receive medical care that is consistent with 
their values, goals and preferences during serious and 
chronic illness. ” Advance directives take effect when the 
patient can no longer communicate his or her preferences 
directly. While oral statements about these matters are 
ethically binding, they are not legally binding in all states. 
State-specific advance directive forms are available from a 
number of sources, including http://www.caringinfo.org.
Clinicians should facilitate the process for all patients—
ideally, well before the end of life—to consider their prefer
-
ences, to appoint a surrogate, to talk to that person about 
their preferences, and to complete a formal advance direc
-
tive. Most patients with a serious illness have already thought 
about end-of-life issues, want to discuss them with their 
clinician, want the clinician to bring up the subject, and 
feel better for having had the discussion. Patients who have 
such discussions with their clinicians are perceived by their 
family as having a better quality of life at the end of life, are 
less likely to die in the hospital, and more likely to utilize 
hospice care. With advance care planning discussions, 
patients’ loved ones are less likely to suffer from depression 
during bereavement. In the United States, Medicare pro
-
vides payment to clinicians for having advance care plan
-
ning discussions with patients.
One type of advance directive is the 
Durable Power of 
Attorney for Health Care (DPOA-HC)
 that allows the 
patient to designate a surrogate decision maker. The 
DPOA-HC is particularly useful because it is often difficult 
to anticipate what specific decisions will need to be made. 
The responsibility of the surrogate is to provide “substi
-

-
tuted judgment”—to decide as the 
patient
 would, not as the 
surrogate
 wants. Clinicians should encourage patients to 
talk with their surrogates about their preferences generally 
and about scenarios that are likely to arise, such as the need 
for mechanical ventilation in a patient with end-stage 
emphysema. Clear clinician communication is important 
to correct misunderstandings and address biases. In the 
absence of a designated surrogate, clinicians usually turn to 
family members or next of kin. Regulations require health 
care institutions to inform patients of their rights to formu
-
late an advance directive. 
Physician (
or 
Medical) Orders 
for Life-Sustaining Treatment (POLST
 or 
MOLST)
 or 
or 
Medical) Orders for Scope of Treatment 
(POST
 or 
MOST)
 forms are clinician orders that accom
-
pany patients wherever they are cared for—home, hospital, 
or nursing home. They are available in most states—and 
used to complement advance directives for patients at the 
end of life.
 
»
Do Not Attempt Resuscitation Orders
Because the “default” in US hospitals is that patients will 
undergo CPR in the event of cardiopulmonary arrest, as 
part of advance care planning, clinicians should elicit 
patient preferences about CPR. Most patients and many 
clinicians overestimate the chances of success of CPR. Only 
about 17% of all patients who undergo CPR in the hospital 
survive to hospital discharge and, among people with mul
-
tisystem organ failure, metastatic cancer, and sepsis, the 
likelihood of survival to hospital discharge following CPR 
is virtually nil. Patients may ask their clinician to write an 
order that CPR not be attempted on them. Although this 
order initially was referred to as a 
“DNR” (do not resuscitate)
 
order, many clinicians prefer the term 
“DNAR” (do not 
attempt resuscitation)
 to emphasize the low likelihood of 
success.
For most patients at the end of life, decisions about CPR 
may not be about 
whether
 they will live but about 
how
 they 
will die. Clinicians should correct the misconception that 
withholding CPR in appropriate circumstances is tanta
-
mount to “not doing everything” or “just letting someone die. ” 
While respecting the patient’s right ultimately to make 
the decision—and keeping in mind their own biases and 
prejudices—clinicians should offer explicit recommen
-
dations about DNAR orders and protect dying patients 
and their families from feelings of guilt and from the sor
-
row associated with vain hopes. Clinicians should dis
-
cuss what interventions will be continued and started to 
promote quality of life rather than focusing only on what is 
CMDT19_Ch05_p0072-p0102.indd   76

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not
 to be done. For patients with implantable cardioverter 
defibrillators (ICDs), clinicians must also address issues of 
turning off these devices, while leaving the pacemaker 
function on, as death approaches to prevent the uncom
-
mon but distressing situation of the ICD discharging dur
-
ing the dying process.
 
»
Hospice & Other Palliative Care Services
In the United States, hospice is a specific type of palliative 
care service focused on comprehensively addressing the 
needs of the dying. In the United States, about 45% of 
people who die use hospice, and about 66% of hospice 
patients die at home where they can be cared for by their 
family and visiting hospice staff. Hospice care can also be 
provided in institutional residences and hospitals. As is 
true of all types of palliative care, hospice emphasizes indi
-
vidualized attention and human contact, and uses an inter
-
disciplinary team approach. Hospice care can include 
arranging for respite for family caregivers and assisting 
with referrals for legal, financial, and other services. 
Patients in hospice require a physician, preferably their 
primary care clinician, to oversee their care.
Hospice care is rated highly by families and has been 
shown to increase patient satisfaction and to decrease fam
-
ily caregiver mortality. Despite evidence that suggests that 
hospice care does not shorten, and may even extend, length 
of life, hospice care tends to be used very late, often near 
the very end of life. The mean average length of stay in 
hospice care in the United States is 71 days, but the median 
length of stay is 18.5 days, and 36% of patients die within 
7 days of starting it.
In the United States, most hospice organizations require 
clinicians to estimate the patient’s prognosis to be less than 
6 months, since this is a criterion for eligibility under the 
Medicare hospice benefit that is typically the same for 
other insurance coverage.
 
»
Cultural Issues
The individual patient’s experience of dying occurs in the 
context of a complex interaction of personal, philosophic, 
and cultural values. Various religious, ethnic, gender, class, 
and cultural traditions influence a patient’s style of com
-
munication, comfort in discussing particular topics, expec
-
tations about dying and medical interventions, and 
attitudes about the appropriate disposition of dead bodies. 
While there are differences in beliefs regarding advance 
directives, autopsy, organ donation, hospice care, and with
-
drawal of life-sustaining interventions among patients of 
different ethnic groups, clinicians should be careful not to 
make assumptions about individual patients. Clinicians 
must appreciate that palliative care is susceptible to the 
same biases documented in other medical disciplines. 
Being sensitive to a person’s cultural beliefs and respecting 
traditions are important responsibilities of the clinician 
caring for a patient at the end of life. A clinician may ask a 
patient, “What do I need to know about you and your 
beliefs that will help me take care of you?” and “How do 
you deal with these issues in your family?”
Bischoff KE et al. A video is worth a thousand words. J Hosp 
Med. 2017 Sep;12(9):773–4. [PMID: 28914286]
Bischoff KE et al. Care planning for inpatients referred for 
palliative care consultation. JAMA Intern Med. 2018 Jan 1;
 
178(1):48–54. [PMID: 29159371]
El-Jawahri A et al. Randomized, controlled trial of an advance 
care planning video decision support tool for patients with 
advanced heart failure. Circulation. 2016 Jul 5;134(1):52–60. 
[PMID: 27358437]
Hanson LC et al. Effect of the goals of care intervention for 
advanced dementia: a randomized clinical trial. JAMA Intern 
Med. 2017 Jan 1;177(1):24–31. [PMID: 27893884]
Sudore RL et al. Defining advance care planning for adults: a 
consensus definition from a multidisciplinary Delphi panel. J

consensus definition from a multidisciplinary Delphi panel. J 
Pain Symptom Manage. 2017 May;53(5):821–32.e1. [PMID: 
28062339]
Sudore RL et al. Effect of the PREPARE website vs an easy-to-
read advance directive on advance care planning documenta
-
tion and engagement among veterans: a randomized clinical 
trial. JAMA Intern Med. 2017 Aug 1;177(8):1102–9. [PMID: 
28520838]
Thompson AE. JAMA patient page. Advance directives. JAMA. 
2015 Feb 24;313(8):868. [PMID: 25710673]
 
»
Nutrition & Hydration
People approaching the end of life often lose their appetite 
and most stop eating and drinking in their last days. Clini
-
cians should explain to families that the dying patient is not 
suffering from hunger or thirst; rather, the discontinuation 
of eating and drinking is part of dying. The anorexia-
cachexia syndrome frequently occurs in patients with 
advanced cancer, and cachexia is common and a poor 
prognostic sign in patients with heart failure. Seriously ill 
people often have no hunger despite not eating at all and 
the associated ketonemia can produce a sense of well-
being, analgesia, and mild euphoria. Although it is unclear 
to what extent withholding hydration at the end of life cre
-
ates an uncomfortable sensation of thirst, any such sensa
-
tion is usually relieved by simply moistening the dry 
mouth. Ice chips, hard candy, swabs, popsicles, or minted 
mouthwash may be effective. Although this normal process 
of diminishing oral intake and accompanying weight loss is 
very common, it can be distressing to patients and families 
who may associate the offering of food with compassion 
and love and lack of eating with distressing images of star
-
vation. In response, patients and families often ask about 
supplemental enteral or parenteral nutrition.
Supplemental artificial nutrition and hydration offer no 
benefit to those at the end of life and rarely achieve patient 
and family goals. The American Geriatrics Society recom
-
mends against liquid artificial nutrition (“tube feeding”) in 
people with advanced dementia because it does not pro
-
vide any benefit. Furthermore, enteral feeding may cause 
nausea and vomiting in ill patients and can lead to diarrhea 
in the setting of malabsorption. Artificial nutrition and 
hydration may increase oral and airway secretions as well 
as increase the risk of choking, aspiration, and dyspnea; 
ascites, edema, and effusions may be worsened.
Individuals at the end of life have a right to voluntarily 
refuse all nutrition and hydration. Because they may have 
deep social and cultural significance for patients, families, 
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and clinicians themselves, decisions about artificial nutri
-
tion and hydration are not simply medical. Eliciting per
-
ceived goals of artificial nutrition and hydration and 
correcting misperceptions can help patients and families 
make clear decisions.
 
»
Withdrawal of Curative Efforts
Requests from appropriately informed and competent 
patients or their surrogates for withdrawal of life-sustaining 
interventions must be respected. Limitation of life-sustain
-
ing interventions prior to death is common practice in 
ICUs. The withdrawal of life-sustaining interventions, such 
as mechanical ventilation, must be approached carefully to 
avoid patient suffering and distress for those in atten
-
dance. Clinicians should educate the patient and family 
about the expected course of events and the difficulty of 
determining the precise timing of death after withdrawal 
of interventions. Sedative and analgesic agents should be 
administered to ensure patient comfort even at the risk of 
respiratory depression or hypotension. While “death rattle, ” 
the sound of air flowing over airway secretions, is common 
in actively dying patients and can be distressing to families, 
it is doubtful that it causes discomfort to the patient. Turn
-
ing the patient can decrease the sound of death rattle. 
There is no evidence that any medications reduce death 
rattle, and suctioning should be avoided as it can cause 
patient discomfort.
 
»
Physician-Assisted Death
Physician-assisted death is the legally sanctioned process 
by which patients who have a terminal illness may request 
and receive a prescription from a physician for a lethal dose 
of medication that they themselves would self-administer 
for the purpose of ending their own life. Terminology for 
this practice varies. “Physician-assisted death” is used here 
to clarify that a willing physician provides assistance in 
accordance with the law (by writing a prescription for a 
lethal medication) to a patient who meets strict criteria and 
who chooses to end his or her own life. Patients, family 
members, nonmedical and medical organizations, clini
-
cians, lawmakers, and the public frequently use other 
terms, namely, “physician or medical aid in dying, ” “aid in 
dying, ” “death with dignity, ” “compassionate death, ” or 
“physician-assisted suicide. ” This latter term is not pre
-
ferred because when this action is taken according to the 
law, it is not considered suicide and people who are actively 
depressed and suicidal are not eligible for this process.
Public support for physician-assisted death has grown 
in the United States, but it is still opposed by a number of 
medical organizations and no state court has recognized 
physician-assisted death as a fundamental right. However, 
as of 2017, physician-assisted death has been legalized with 
careful restriction and specific procedures for residents in 
six US states (Oregon, Washington, Montana, Vermont, 
Colorado, and California) and in the District of Columbia. 
During 2017, 20 state legislatures or courts considered and 
rejected it; physician-assisted death remains illegal or 
criminalized in all other states. Internationally, physician-
assisted death (and/or euthanasia, the administration a 
lethal dose of medication by a clinician) is legal in nine 
countries (the Netherlands, Belgium, Luxembourg, 
Switzerland, Colombia, Canada, Germany, Japan, and the 
Australian state of Victoria). There are no universal stan
-
dards about whether patients who request lethal medica
-
tion for self-administration require a particular prognosis 
or about what types and levels of suffering qualify them for 
it, although the current US laws require a prognosis of 
6 months or less. Laws in the United States authorizing 
physician-assisted death distinguish it from euthanasia, 
which is illegal in the United States.
Most requests for physician-assisted death come from

Most requests for physician-assisted death come from 
patients with cancer. In the United States, most patients 
requesting it are male, well-educated, and receiving hospice 
care. Requests for physician-assisted death are relatively 
rare. Internationally, less than 5% of deaths are due to 
either physician-assisted death or euthanasia in locales 
where one or both of these are legal. In Oregon, the first US 
state to legalize physician-assisted death, approximately 
0.39% of deaths in 2015 resulted from this practice. Patient 
motivations for physician-assisted death generally revolve 
around preserving dignity, self-respect, and autonomy 
(control), and maintaining personal connections at the end 
of life rather than experiencing intolerable pain or suffer
-
ing. Notably, despite initial concerns, there has been no 
evidence of greater use or abuse of physician-assisted death 
in vulnerable populations compared with the general popu
-
lation. Some patients who have requested medication to 
self-administer for a physician-assisted death later withdraw 
their request when provided palliative care interventions.
Each clinician must decide his or her personal approach 
in caring for patients who ask about physician-assisted 
death. Regardless of the clinician’s personal feelings about 
the process, the clinician can respond initially by exploring 
the patient’s reasons and concerns that prompted the 
request (Table 5–3). During the dialog, the clinician should 
Table 5–3.
 
Exploring inquiries about physician-
assisted death.
Patient Concerns
Useful Clinician Questions
Patient is worried about 
future suffering: “I can 
see what’s going to 
 
happen and I don’t 
like it. ”
•  “What
 
ar
e
 
y
ou
 
most
 
w
orried
 
about?”
• 
 
“
Tell
 
me
 
mor
e
 
about
 
e
xactly
 
wha
t
 
frightens you. ”
• 
 
“
What
 
k
inds
 
of
 
dea
ths
 
ha
ve
 
y
ou
 
seen
 
in
 
y
our
 
family?”
• 
 
“Ho
w
 
ar
e
 
y
ou
 
hoping
 
I
 
can
 
help
 
y
ou?”
Patient feels quality of 
life is intolerable: “I’ve 
suffered enough. ”
• 
 
“
What
 
mak
es
 
y
our
 
situa
tion
 
most
 
intolerable
 
righ
t
 
no
w?”
• 
 
“
Tell
 
me
 
mor
e
 
about
 
the
 
w
orst
 
par
t.”
• 
 
“Ho
w
 
do
 
y
ou
 
think
 
y
our
 
family
 
f
eels
 
or would feel about your wish to end 
your
 
o
wn
 
lif
e?”
• 
 
“Exac
tly
 
ho
w
 
ar
e
 
y
ou
 
hoping
 
I
 
can
 
help
 
y
ou?”
Adapted, with permission, from Quill TE et al. Responding to 
patients requesting physician-assisted death: physician involve
-
ment at the very end of life. JAMA. 2016 Jan 19;315(3):245–6. 
Copyright © 2016 American Medical Association. All rights reserved.
CMDT19_Ch05_p0072-p0102.indd   78

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inform the patient about palliative options, including hos
-
pice care; access to expert symptom management; and psy
-
chological, social, and spiritual support, as needed, and 
provide reassurance and commitment to address future 
problems that may arise. For clinicians who object to phy
-
sician-assisted death on moral or ethical grounds, referral 
to another clinician may be necessary and may help the 
patient avoid feeling abandoned. That clinician must be 
willing to provide the prescription for lethal medication, to 
care for the patient until death (though it is not necessary 
to be present at the death), to sign the death certificate list
-
ing the underlying terminal condition as the cause of 
death, and in some jurisdictions to complete a mandatory 
follow-up form.
Blanke C et al. Characterizing 18 years of the Death With Dig
-
nity Act in Oregon. JAMA Oncol. 2017 Oct 1;3(10):1403–6. 
[PMID: 28384683]
Emanuel EJ et al. Attitudes and practices of euthanasia and 
physician-assisted suicide in the United States, Canada, and 
Europe. JAMA. 2016 Jul 5;316(1):79–90. [PMID: 27380345]
Flaschner E et al. American Geriatrics Society Position State
-
ment on feeding tubes in advanced dementia. J Am Geriatr 
Soc. 2015;63(7):1490–1. [PMID: 26189864]
Gostin LO et al. Physician-assisted dying: a turning point? 
JAMA. 2016 Jan 19;315(3):249–50. [PMID: 26784764]
Petrillo LA et al. How California prepared for implementation 
of physician-assisted death: a primer. Am J Public Health. 
2017 Jun;107(6):883–8. [PMID: 28426307]
Quill TE et al. Responding to patients requesting physician-
assisted death: physician involvement at the very end of life. 
JAMA. 2016 Jan 19;315(3):245–6. [PMID: 26784762]
Snyder Sulmasy L et al. Ethics, Professionalism and Human 
Rights Committee of the American College of Physicians. 
Ethics and the legalization of physician-assisted suicide: an 
American College of Physicians Position Paper. Ann Intern 
Med. 2017 Oct 17;167(8):576–8. [PMID: 28975242]
Y ang YT et al. Why physicians should oppose assisted suicide. 
JAMA. 2016 Jan 19;315(3):247–8. [PMID: 26784763]
 
»
Ethical & Legal Issues
Clinicians’ care of patients at the end of life is guided by the 
same ethical and legal principles that inform other types of 
medical care. Foremost among these are (1) truthtelling, 
(2) nonmaleficence, (3) beneficence, (4) autonomy, (5) 
confidentiality, and (6) procedural and distributive justice. 
Important ethical principles may come into conflict when 
caring for patients. For example, many treatments that 
promote beneficence and autonomy, such as surgery or 
bone marrow transplant, may violate the clinician’s obliga
-
tion for nonmaleficence; thus, balancing the benefits and 
risks of treatments is a fundamental ethical responsibility. 
Similarly, while a patient may express his or her auton
-
omy as a desire for a particular medical intervention such 
as CPR in the setting of multisystem organ failure, the 
clinician may decline to provide the intervention because 
it is futile (ie, of no therapeutic benefit and thus violates 
both beneficence and nonmaleficence). However, clini
-
cians must use caution in invoking futility, since strict 
futility is rare and what constitutes futility is often a mat
-
ter of controversy and subject to bias. While in the vast 
majority of cases clinicians and patients and families will 
agree on the appropriateness of and decisions to withdraw 
life-sustaining interventions, in rare cases, such as CPR in 
multisystem organ failure, clinicians may determine uni
-
laterally that a particular intervention is medically inap
-
propriate. In such cases, the clinician’s intention to 
withhold CPR should be communicated to the patient and 
family and documented, and the clinician must consult 
with another clinician not involved in the care of the 
patient. If differences of opinion persist about the appro
-

-
priateness of particular care decisions, the assistance of an 
institutional ethics committee should be sought. Because 
such unilateral actions violate the autonomy of the patient, 
clinicians should rarely resort to such unilateral actions. 
Studies confirm that most disagreements between patients 
and families and clinicians can be resolved with good com
-
munication. Although clinicians and family members 
often feel differently about withholding versus withdraw
-
ing life-sustaining interventions, there is consensus among 
ethicists, supported by legal precedent, of their ethical 
equivalence.
The ethical principle of 
“double effect”
 argues that the 
potential to hasten imminent death is acceptable if it comes 
as the known but unintended consequence of a primary 
intention to provide comfort and relieve suffering. For 
example, it is acceptable to provide high doses of opioids if 
needed to control pain even if there is the known and unin
-
tended effect of depressing respiration.
 
»
Psychological, Social, & Spiritual Issues
Dying is not exclusively or even primarily a biomedical 
event. It is an intimate personal experience with profound 
psychological, interpersonal, and existential meanings. For 
many people at the end of life, the prospect of impending 
death stimulates a deep and urgent assessment of their 
identity, the quality of their relationships, the meaning and 
purpose of their life, and their legacy.
A. Psychological Challenges
In 1969, Dr. Elisabeth Kübler-Ross identified five psycho
-
logical reactions or patterns of emotions that patients at the 
end of life may experience: denial and isolation, anger, 
bargaining, depression, and acceptance. Not every patient 
will experience all these emotions, and typically not in an 
orderly progression. In addition to these five reactions are 
the perpetual challenges of anxiety and fear of the 
unknown. Simple information, listening, assurance, and 
support may help patients with these psychological chal
-
lenges. In fact, patients and families rank emotional sup
-
port as one of the most important aspects of good 
end-of-life care. Psychotherapy and group support may be 
beneficial as well.
Despite the significant emotional stress of facing death, 
clinical depression is not normal at the end of life and 
should be treated. Cognitive and affective signs of depres
-
sion, such as feelings of worthlessness, hopelessness, or 
helplessness, may help distinguish depression from the 
low energy and other vegetative signs common with end-
stage illness. Although traditional antidepressant treat
-
ments such as selective serotonin reuptake inhibitors are 
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Table 5–4.
 
Five statements often necessary for the 
completion of important interpersonal relationships.
1.
 
“F
orgive me. ”
2.
 
“I f
orgive you. ”
3.  “Thank
 
y
ou.”
4.
 
“I lo
ve you. ”
5.
 
“Goodbye. ”
(An expression of regret)
(An expression of acceptance)
(An expression of gratitude)
(An expression of affection)
(Leave-taking)
Source: Byock I. 
Dying Well: Peace and Possibilities at the End of Life.
 
New York: Riverhead Books, an imprint of Penguin Group (USA) 
LLC, 1997.
Table 5–5.
 
An existential review of systems.
Intrapersonal
 
“
What
 
does
 
y
our
 
illness/dying
 
mean
 
t
o
 
y
ou?”
 
“
What
 
do
 
y
ou
 
think
 
caused
 
y
our
 
illness?”
 
“Ho
w
 
ha
ve
 
y
ou
 
been
 
healed
 
in
 
the
 
past?”
 
“
What
 
do
 
y
ou
 
think
 
is
 
needed
 
f
or
 
y
ou
 
t
o
 
be
 
healed
 
no
w?”
 
“
What
 
is
 
righ
t
 
with
 
y
ou
 
no
w?”
 
“
What
 
do
 
y
ou
 
hope
 
f
or?”
 
“
Are
 
y
ou
 
a
t
 
peac
e?”
Interpersonal
 
“
Who
 
is
 
impor
tant
 
t
o
 
y
ou?”
 
“
To
 
whom
 
does
 
y
our
 
ma
tter?”
 
“D
o
 
y
ou
 
ha
ve
 
an
y
 
unfinished
 
business
 
with
 
sig
nificant
 
others?”
Transpersonal
 
“
What
 
is
 
y
our
 
sour
ce
 
of
 
str
ength,
 
help
,
 
or
 
hope?”
 
“D
o
 
y
ou
 
ha
ve
 
spiritual
 
c
oncerns
 
or
 
a
 
spiritual
 
pr
actice?”
  
“I
f so, how does your spirituality relate to your illness/dying, and 
how
 
can
 
I
 
help
 
in
tegrate
 
y
our
 
spiritualit
y
 
in
to
 
y
our
 
health
 
car
e?”
 
“
What
 
do
 
y
ou
 
think
 
happens
 
af
ter
 
w
e
 
die?”
 
“
What
 
purpose
 
migh
t
 
y
our
 
ser
ve?”
 
“
What
 
do
 
y
ou
 
think
 
is
 
tr
ying
 
t
o
 
happen
 
her
e?”
effective, more rapidly acting medications, such as dextro
-
amphetamine (2.5–7.5 mg orally at 8 
am
 and noon) or 
methylphenidate (2.5–10 mg orally at 8 
am
 and noon), 
may be particularly useful when the end of life is near or 
while waiting for another antidepressant medication to 
take effect. Oral ketamine and hallucinogens are being 
explored as rapid-onset treatment for anxiety and depres
-
sion at the end of life. Some research suggests a mortality 
benefit from treating depression in the setting of serious 
illness.
B. Social Challenges
At the end of life, patients should be encouraged to dis
-
charge personal, professional, and business obligations. 
These tasks include completing important work or per
-
sonal projects, distributing possessions, writing a will, and 
making funeral and burial arrangements. The prospect of 
death often prompts patients to examine the quality of 
their interpersonal relationships and to begin the process 
of saying goodbye (Table 5–4). Concern about estranged 
relationships or “unfinished business” with significant oth
-
ers and interest in reconciliation may become paramount 
at this time.
C. Spiritual Challenges
Spirituality is the attempt to understand or accept the 
underlying meaning of life, one’s relationships to oneself 
and other people, one’s place in the universe, one’s legacy, 
and the possibility of a “higher power” in the universe. 
People may experience spirituality as part of or distinct 
from particular religious practices or beliefs.
Unlike physical ailments, such as infections and frac
-
tures, which usually require a clinician’s intervention to be 
treated, the patient’s spiritual concerns often require only a 
clinician’s attention, listening, and witness. Clinicians can 
inquire about the patient’s spiritual concerns and ask 
whether the patient wishes to discuss them. For example, 
asking, “How are you within yourself?” or “ Are you at 
peace?” communicates that the clinician is interested in the 
patient’s whole experience and provides an opportunity for 
the patient to share perceptions about his or her inner life. 
Questions that might constitute an existential “review of 
systems” are presented in Table 5–5. Formal legacy work 
and dignity therapy have been shown to be effective in

and dignity therapy have been shown to be effective in 
improving quality of life and spiritual well-being.
The end of life offers an opportunity for psychological, 
interpersonal, and spiritual development. Individuals may 
grow—even achieve a heightened sense of well-being or 
transcendence—in the process of dying. Through listening, 
support, and presence, clinicians may help foster this learn
-
ing and be a catalyst for this transformation. Rather than 
thinking of dying simply as the termination of life, clini
-
cians and patients may be guided by a developmental 
model of life that recognizes a series of lifelong develop
-
mental tasks and landmarks and allows for growth at the 
Best M et al. Doctors discussing religion and spirituality: a sys
-
tematic literature review. Palliat Med. 2016 Apr;30(4):327–37. 
[PMID: 26269325]
Bovero A et al. Spirituality, quality of life, psychological adjust
-
ment in terminal cancer patients in hospice. Eur J Cancer 
Care (Engl). 2016 Nov;25(6):961–9. [PMID: 26215314]
Egan R et al. Spiritual beliefs, practices, and needs at the end of 
life: results from a New Zealand national hospice study. Palliat 
Support Care. 2017 Feb; 31(2):140–6.
Ernecoff NC et al. Health care professionals’ responses to religious 
or spiritual statements by surrogate decision makers during 
goals-of-care discussions. JAMA Intern Med. 2015 Oct;
 
175(10):1662–9. [PMID: 26322823]
Johnson J et al. The impact of faith beliefs on perceptions of end-
of-life care and decision making among African American 
church members. J Palliat Med. 2016 Feb;19(2):143–8. 
[PMID: 26840849]
Rosenfeld B et al. Adapting Meaning-Centered Psychotherapy 
for the palliative care setting: results of a pilot study. Palliat 
Med. 2017 Feb;31(2):140–6. [PMID: 27435603]
Sun A et al. Efficacy of a church-based, culturally-tailored pro
-
gram to promote completion of advance directives among 
Asian Americans. J Immigr Minor Health. 2017 Apr;
 
19(2):381–91. [PMID: 27103618]
Swinton M et al. Experiences and expressions of spirituality at 
the end of life in the intensive care unit. Am J Respir Crit Care 
Med. 2017 Jan 15;195(2):198–204. [PMID: 27525361]
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TASKS AFTER DEATH
After the death of a patient, the clinician is called upon to 
perform a number of tasks, both required and recom
-
mended. The clinician must plainly and directly inform the 
family of the death, complete a death certificate, contact an 
organ procurement organization, and request an autopsy. 
Providing words of sympathy and reassurance, time for 
questions and initial grief and, for people who die in the 
hospital or other health care facility, a quiet private room for 
the family to grieve is appropriate and much appreciated.
 
»
The Pronouncement & Death Certificate
In the United States, state policies direct clinicians to con
-
firm the death of a patient in a formal process called “pro
-
nouncement. ” The diagnosis of death is typically easy to 
make, and the clinician need only verify the absence of 
spontaneous respirations and cardiac activity. Attempting to 
elicit pain in a patient who has died is unnecessary and dis
-
respectful and should be avoided. A note describing these 
findings, the time of death, and that the family has been 
notified is entered in the patient’s medical record. In many 
states, when a patient whose death is expected dies outside 
of the hospital (at home or in prison, for example), nurses 
may be authorized to report the death over the telephone to 
a physician who assumes responsibility for signing the death 
certificate within 24 hours. For traumatic deaths, some 
states allow emergency medical technicians to pronounce a 
patient dead at the scene based on clearly defined criteria 
and with physician telephonic or radio supervision.
While the pronouncement may often seem like an awk
-
ward and unnecessary formality, clinicians may use this 
time to reassure the patient’s loved ones at the bedside that 
the patient died peacefully and that all appropriate care had 
been given. Both clinicians and families may use the ritual 
of the pronouncement as an opportunity to begin to pro
-
cess emotionally the death of the patient.
Physicians are legally required to report certain deaths 
to the coroner and to accurately report the underlying 
cause of death on the death certificate. This reporting is 
important both for patients’ families (for insurance pur
-
poses and the need for an accurate family medical history) 
and for the epidemiologic study of disease and public 
health. The physician should be specific about the major 
cause of death being the condition without which the 
patient would not have died (eg, “decompensated cirrhosis”) 
and its contributory cause (eg, “hepatitis B and hepatitis C 
infections, chronic alcoholic hepatitis, and alcoholism”) as 
well as any associated conditions (eg, “acute kidney 
injury”)—and not simply put down “cardiac arrest” as the 
cause of death.
 
»
Autopsy & Organ Donation
Discussing the options and obtaining consent for autopsy 
and organ donation with patients prior to death is a good 
practice as it advances the principle of patient autonomy 
and lessens the responsibilities of distressed family mem
-
bers during the period immediately following the death. 
In the case of brain death, designated organ transplant 
personnel are more successful than treating clinicians at 
obtaining consent for organ donation from surviving 
family members. In the United States, federal regulations 
require that a designated representative of an organ pro
-
curement organization approach the family about organ 
donation if the organs are appropriate for transplanta
-
tion. Most people in the United States support the dona
-
tion of organs for transplants. Currently, however, organ 
transplantation is severely limited by the availability of 
donor organs. The families of donors experience a sense 
of reward in contributing, even through death, to the lives 
of others.
Clinicians must be sensitive to ethnic and cultural dif
-
ferences in attitudes about autopsy and organ donation.

of others.
-
ferences in attitudes about autopsy and organ donation. 
Patients or their families should be reminded of their right 
to limit autopsy or organ donation in any way they choose, 
although such restriction may limit the utility of autopsy. 
Pathologists can perform autopsies without interfering 
with funeral plans or the appearance of the deceased.
The results of an autopsy may help surviving family 
members and clinicians understand the exact cause of a 
patient’s death and foster a sense of closure. Despite the use 
of more sophisticated diagnostic tests, the rate of unexpected 
findings at autopsy has remained stable and thus, an autopsy 
can provide important health information to families. A 
clinician–family conference to review the results of the 
autopsy provides a good opportunity for clinicians to assess 
how well families are grieving and to answer questions.
 
»
Follow-Up & Grieving
Proper care of patients at the end of life includes following 
up with surviving family members after the patient has 
died. Contacting loved ones by telephone enables the clini
-
cian to assuage any guilt about decisions the family may 
have made, assess how families are grieving, reassure them 
about the nature of normal grieving, and identify compli
-
cated grief or depression. Clinicians can recommend sup
-
port groups and counseling as needed. A card or telephone 
call from the clinician to the family days to weeks after the 
patient’s death (and perhaps on the anniversary of the 
death) allows the clinician to express concern for the family 
and the deceased.
After a patient dies, the clinician also may need to 
grieve. Although clinicians may be relatively unaffected by 
the deaths of some patients, other deaths may cause feel
-
ings of sadness, loss, and guilt. These emotions should be 
recognized as the first step toward processing and healing 
them. Each clinician may find personal or communal 
resources that help with the process of grieving. Shedding 
tears, sharing with colleagues, time for reflection, and tra
-
ditional or personal mourning rituals all may be effective. 
Attending the funeral of a patient who has died can be a 
satisfying personal experience that is almost universally 
appreciated by families and that may be the final element 
in caring well for people at the end of life.
Morris SE et al. Adding value to palliative care services: the 
development of an institutional bereavement program. 
 
J Palliat Med. 2015 Nov;18(11):915–22. [PMID: 26275079]
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º
PAIN MANAGEMENT
TAXONOMY OF PAIN
The International Association for the Study of Pain (IASP) 
defines 
pain
 as an unpleasant sensory and emotional expe
-
rience associated with actual or potential tissue damage, or 
described in terms of such damage. 
Acute pain
 resolves 
within the expected period of healing and is self-limited. 
Chronic pain
 persists beyond the expected period of heal
-
ing and is itself a disease state. In general, chronic pain is 
defined as extending beyond 3–6 months, although defini
-
tions vary in terms of the time period from initial onset of 
nociception. 
Cancer pain
 is in its own special category 
because of the unique ways neoplasia and its therapies 
(such as surgery, chemotherapy, or radiation therapy) can 
lead to burdensome pain. Finally, related to cancer pain, 
there is 
pain at the end of life
, for which measures to alle
-
viate suffering may take priority over promoting restora
-
tion of function.
Pain is a worldwide burden; across the globe, one in five 
adults suffers from pain. In 2010, members from 130 countries 
signed the Declaration of Montreal stating that access to 
pain management is a fundamental human right. The first 
CDC guidelines on opioid prescribing for chronic pain, 
including chronic noncancer pain, cancer pain, and pain at 
the end of life, were published in March of 2016.
Centers for Disease Control and Prevention (CDC). CDC guide
-
line for prescribing opioids for chronic pain. 2017 Aug 29. 
http://www.cdc.gov/drugoverdose/prescribing/guideline.
html
chronic pain—United States, 2016. JAMA. 2016 Apr 19;
 
315(15):1624–45. [PMID: 26977696]
Henschke N et al. The epidemiology and economic conse
-
quences of pain. Mayo Clin Proc. 2015 Jan;90(1):139–47. 
[PMID: 25572198]
Williams AC et al. Updating the definition of pain. Pain. 
2016 Nov;157(11):2420–23. [PMID: 27200490]
ACUTE PAIN
Acute pain resolves within the expected period of healing 
and is self-limited. Common examples include pain from 
dental caries, kidney stones, surgery, or trauma. Manage
-
ment of acute pain depends on comprehending the type of 
pain (somatic, visceral, or neuropathic) and on under
-
standing the risks and benefits of potential therapies. Not 
relieving acute pain can have consequences beyond the 
immediate suffering. Acute pain that is not adequately 
treated develops into chronic pain in some patients. This 
transition from acute to chronic pain (so-called “chronifi
-
cation” of pain) depends on the pain’s cause, type and 
severity and on the patient’s age, psychological status, and 
genetics, among other factors. This transition is an area of 
increasing study because chronic pain leads to such signifi
-
cant societal costs beyond the individual’s experiences of 
suffering, helplessness, and depression.
The Oxford League Table of Analgesics is a useful 
guide; for example, it lists the number-needed-to-treat for 
specific doses of various medications to relieve acute pain. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclo
-
oxygenase (COX) inhibitors are at the top of the list, with 
the lowest number-needed-to-treat. These medications can 
be delivered via oral, intramuscular, intravenous, intrana
-
sal, rectal, and other routes of administration. They gener
-
ally work by inhibiting COX-1 and -2 and therefore reduce 
the levels of prostaglandins involved in inflammatory 
nociception (eg, PGI2 and PGE2). These oxygenase 
enzymes also determine levels of other breakdown prod
-
ucts such as other prostaglandins, thromboxane, and pros
-
tacyclins that play a role in renal, gastrointestinal, and 
cardiovascular homeostasis. For this reason, the primary 
limitation of the COX inhibitors is their side effect profile 
of gastritis, kidney dysfunction, bleeding, hypertension, 
and cardiovascular adverse events such as myocardial 
infarction or stroke. Ketorolac is primarily a COX-1 inhibi
-

-
tor that has an analgesic effect as potent as morphine at the 
appropriate dosage. The limitation of the COX inhibitors is 
that they have a “ceiling” effect, meaning beyond a certain 
dose, there is no additional benefit.
Acetaminophen (paracetamol) is effective as a sole 
agent, or in combination with a COX inhibitor or an opioid 
in acute pain. Its mechanism of action remains undeter
-
mined. It is one of the most widely used and best tolerated 
analgesics; its primary limitation is hepatoxicity when 
given in high doses or to patients with underlying impaired 
liver function.
Opioids were once thought not to have a ceiling effect; 
this is not true. Even full mu opioid receptor agonists such 
as morphine or fentanyl have a ceiling effect; however, this 
effect is not seen until high and sometimes extraordinary 
doses are reached. Use of opioids for acute pain is limited 
by their side-effect profile; measures to avoid respiratory 
depression are paramount. Opioids are not particularly 
effective in 
dynamic pain
 (pain associated with move
-
ment) but are effective for 
static pain
 (pain occurring even 
when one is immobilized). NSAIDs are effective for 
dynamic pain and are first-line agents for acute arthralgias 
or myalgias.
Postoperatively, 
patient-controlled analgesia (PCA)
 
with intravenous morphine, hydromorphone, or another 
opioid can achieve analgesia faster and with less medica
-
tion requirement than with standard “as needed” or even 
scheduled intermittent dosing. PCA has been adapted for 
use with oral analgesic opioid medications. The goal of 
PCA is to maintain a patient’s plasma concentration of 
opioid in the “therapeutic window, ” between the minimum 
effective analgesic concentration and a toxic dose.
Chou R et al. Management of postoperative pain: a clinical prac
-
tice guideline from the American Pain Society, the American 
Society of Regional Anesthesia and Pain Medicine, and the 
American Society of Anesthesiologists’ Committee on 
Regional Anesthesia, Executive Committee, and Administra
-
tive Council. J Pain. 2016 Feb;17(2):131–57. Erratum in: J 
Pain. 2016 Apr;17(4):508–10. Dosage error in article text. 
[PMID: 26827847]
Helander EM et al. Multimodal analgesia, current concepts, and 
acute pain considerations. Curr Pain Headache Rep. 2017 Jan;
 
21(1):3. [PMID: 28132136]
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83
 
CMDT 2019
Mędrzycka-Dąbrowska W et al. Problems and barriers in ensur
-
ing effective acute and post-operative pain management—an 
international perspective. Adv Clin Exp Med. 2015 Sep–Oct;
 
24(5):905–10. [PMID: 26768644]
Polomano RC et al. Multimodal analgesia for acute postoperative 
and trauma-related pain. Am J Nurs. 2017 Mar;117(3 Suppl 1):
 
S12–26. [PMID: 28212146]
CHRONIC NONCANCER PAIN
Chronic noncancer pain may begin as acute pain that then 
fails to resolve and extends beyond the expected period of 
healing or it may be a primary disease state, rather than the 
symptom residual from another condition. Common 
examples include chronic low-back pain and arthralgias 
(often somatic in origin), chronic abdominal pain and 
chronic pelvic pain (often visceral in origin), and chronic 
headaches, peripheral neuropathy, and postherpetic neu
-
ralgia (neuropathic origin) as well as other less common 
but debilitating syndromes such as trigeminal neuralgia 
(neuropathic origin) and complex regional pain syndrome 
(mixed origin). Chronic noncancer pain is common, with 
the World Health Organization estimating a worldwide 
prevalence of 20%. In the United States, 11% of adults suf
-
fer from chronic noncancer pain, and the Institute of Medi
-
cine estimates that it costs $635 billion annually in 
treatment and lost productivity.
Chronic noncancer pain requires interdisciplinary 
management. Generally, no one therapy by itself is suffi
-
cient to manage such chronic pain. In no particular order, 
pharmacologic therapy, interventional modalities, physi
-
cal/functional therapy, pain psychology, and complemen
-
tary/integrative approaches are useful in caring for affected 
patients.
Chronic low-back pain
 is one example of a common 
chronic noncancer pain. It causes more disability globally 
than any other condition. Chronic low-back pain includes 
spondylosis, spondylolisthesis, and spinal canal stenosis 
(Chapter 24), and the “failed back surgical syndrome, ” a 
term used to refer to patients in whom chronic pain devel
-
ops and persists after lumbar spine surgery. Also referred 
to as the post-laminectomy pain syndrome, it can affect 
10–40% of patients after lumbar spine surgery.
The importance of clinicians knowing the many causes 
of chronic low-back pain and, in particular, understanding 
how anatomic structures relate to one another and how 
they can cause the different types of low-back pain, has 
been highlighted by the epidemic of opioid abuse in the 
United States since the year 2000. In fact, current evidence-
based practice does 
not
 support the use of prolonged opioid 
therapy for chronic low-back pain.
Beal BR et al. An overview of pharmacologic management of 
chronic pain. Med Clin North Am. 2016 Jan;100(1):65–79. 
[PMID: 26614720]
Chapman CR et al. The transition of acute postoperative pain to 
chronic pain: an integrative overview of research on mechanisms. 
J Pain. 2017 Apr;18(4):359.e1–38. [PMID: 27908839]
Enthoven WT et al. Non-steroidal anti-inflammatory drugs 
for chronic low back pain. Cochrane Database Syst Rev. 2016 
Feb 10;2:CD012087. [PMID: 26863524]
Manchikanti L et al. Responsible, safe, and effective pre
-
scription of opioids for chronic non-cancer pain: American 
Society of Interventional Pain Physicians (ASIPP) guide
-
lines. Pain Physician. 2017 Feb;20(2S):S3–92. [PMID: 
28226332]
Qaseem A et al. Clinical Guidelines Committee of the American 
College of Physicians. Noninvasive treatments for acute, sub
-
acute, and chronic low back pain: a clinical practice guideline 
from the American College of Physicians. Ann Intern Med. 
2017 Apr 4;166(7):514–30. [PMID: 28192789]
Ray W A et al. Prescription of long-acting opioids and mortality 
in patients with chronic noncancer pain. JAMA. 2016 Jun 14;
 
315(22):2415–23. [PMID: 27299617]
Ringwalt C et al. A randomized controlled trial of an emer
-
gency department intervention for patients with chronic

-
gency department intervention for patients with chronic 
noncancer pain. J Emerg Med. 2015 Dec;49(6):974–83. 
[PMID: 26423915]
CANCER PAIN
Cancer pain deserves its own category because it is unique 
in cause and in therapies. Cancer pain consists of both 
acute pain and chronic pain from the neoplasm itself and 
from the therapies associated with it, such as surgery, che
-
motherapy, and radiation. In addition, patients with cancer 
pain may also have acute or chronic noncancer-related 
pain, and this possibility should not be overlooked when 
taking care of cancer patients.
Cancer pain includes somatic pain (eg, neoplastic inva
-
sion of tissue such as painful fungating chest wall masses in 
breast cancer), visceral pain (eg, painful hepatomegaly 
from liver metastases, stretching the liver capsule), neuro
-
pathic pain (eg, neoplastic invasion of sacral nerve roots), 
or pain from a paraneoplastic syndrome (eg, peripheral 
neuropathy related to anti-Hu antibody production). Che
-
motherapy can cause peripheral neuropathies, radiation 
can cause neuritis or skin allodynia, and surgery can cause 
persistent postsurgical pain syndromes such as post-mas
-
tectomy or post-thoracotomy pain syndromes.
Generally, patients with cancer pain do not exhibit a 
single type of pain—they may have multiple reasons for 
pain and thus benefit from a comprehensive and multi
-
modal strategy. The WHO Analgesic Ladder, first pub
-
lished in 1986, suggests starting medication treatment with 
nonopioid analgesics, then weak opioid agonists, followed 
by strong opioid agonists. While opioid therapy can be 
helpful for a majority of patients living with cancer pain, 
therapy must be individualized depending on the individ
-
ual patient, their family, and the clinician. For example, if 
one of the goals of care is to have a lucid and coherent 
patient, opioids may not be the optimal choice; interven
-
tional therapies such as implantable devices may be an 
option, weighing their risks and costs against their poten
-
tial benefits. Alternatively, in dying patients, provided there 
is careful documentation of continued, renewed, or accel
-
erating pain, use of opioid doses exceeding those recom
-
mended as standard for acute (postoperative) pain is 
acceptable.
Radiation therapy (including single-fraction external 
beam treatments) or radionuclide therapy (eg, strontium-89), 
which can be used to relieve bone pain from metastases, is 
one of the unique options in cancer.
CMDT19_Ch05_p0072-p0102.indd   83

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Table 5–6.
 
Pain assessment scales.
A. Numeric Rating Scale
No pain
01234 56
78
91
0
Wo
rst pain
None, mild, moderate, severe
B.
 
Numeric Rating Scale Translated into Word and Behavior Scales
Pain Intensity
Word Scale
Nonverbal Behaviors
0
No pain
Relaxed, calm expression
1–2
Least pain
Stressed, tense expression
3–4
Mild pain
Guarded movement, grimacing
5–6
Moderate pain
Moaning, restless
7–8
Severe pain
Crying out
9–10
Excruciating pain
Increased intensity of above
C. Wong Baker FACES Pain Rating Scale
1
1
Especially useful for patients who cannot read English (and for pediatric patients).
©1983 Wong-Baker FACES Foundation. www.WongBakerFACES.org. Used with permission. Originally published in 
Whaley & Wong’s Nursing 
Care of Infants and Children
 (Mosby Elsevier).
0
No hurt
1
Hurts
Little Bit
2
Hurts
Little More
3
Hu
rt
s
Even More
4
Hu
rt
s
Whole Lot
5
Hu
rt
s
Wo
rs
t
Neufeld NJ et al. Cancer pain: a review of epidemiology, clinical 
quality and value impact. Future Oncol. 2017 Apr;13(9):
 
833–41. [PMID: 27875910]
Paice JA. Under pressure: the tension between access and 
abuse of opioids in cancer pain management. J Oncol Pract. 
2017 Sep;13(9):595–6. [PMID: 28813190]
Paice JA et al. Management of chronic pain in survivors of adult 
cancers: American Society of Clinical Oncology clinical prac
-
tice guideline. J Clin Oncol. 2016 Sep 20;34(27):3325–45. 
[PMID: 27458286]
Prommer EE. Pharmacological management of cancer-related 
pain. Cancer Control. 2015 Oct;22(4):412–25. [PMID: 
26678968]
PAIN AT THE END OF LIFE
Pain is what many people say they fear most about dying, 
and pain at the end of life is consistently undertreated. Up 
to 75% of patients dying of cancer, heart failure, chronic 
obstructive pulmonary disease, AIDS, or other diseases 
experience pain. In the United States, the Joint Commis
-
sion includes pain management standards in its reviews of 
health care organizations and, in 2018, it began mandating 
that each hospital have a designated leader in pain 
management.
The ratio of risk versus benefit changes in end-of-life 
pain management. Harms from the use of opioid analge
-
sics, including death from accidental or intentional over
-
dose or diversion of medication, are less of a concern in 
patients approaching the end of life. In all cases, clinicians 
must be prepared to use appropriate doses of opioids in 
order to relieve this distressing symptom for these patients. 
Typically, for ongoing cancer pain, a long-acting opioid 
analgesic can be given around the clock with a short-acting 
opioid medication as needed for “breakthrough” pain.
Some clinicians fear legal repercussions from prescrib
-
ing the high doses of opioids sometimes necessary to con
-
trol pain at the end of life. However, governmental and 
professional medical groups, regulators (including the 
CDC and FDA), and the US Supreme Court have made it 
clear that appropriate treatment of pain is the right of the 
seriously or terminally ill patient and is a fundamental 
responsibility of the clinician. Although clinicians may feel 
trapped between consequences of overprescribing or 
underprescribing opioids, there remains a wide range of 
practice in which clinicians can safely and appropriately 
treat pain for patients with such advanced, serious illness.
PRINCIPLES OF PAIN MANAGEMENT
The experience of pain is unique to each person and influ
-
enced by many factors, including the patient’s prior experi
-
ences with pain, meaning given to the pain, emotional 
stresses, and family and cultural influences. Pain is a sub
-
jective and multi-faceted phenomenon, and clinicians can
-
not reliably detect its existence or quantify its severity 
without asking the patient directly. A brief means of assess
-
ing pain and evaluating the effectiveness of analgesia is to 
ask the patient to rate the degree of pain along a numeric 
or visual pain scale (Table 5–6), assessing trends over time. 
CMDT19_Ch05_p0072-p0102.indd   84

85
 
CMDT 2019
Clinicians should ask about the nature, severity, timing, 
location, quality, and aggravating and relieving factors of 
the pain.
General guidelines for diagnosis and management of 
pain are recommended for the treatment of all patients with 
pain but clinicians must comprehend that such guidelines 
may not be suited for every individual. Because of pain’s 
complexity, it is important to understand benefits and risks 
of treatment with growing evidence for each patient. Dis
-
tinguishing between nociceptive (somatic or visceral) and 
neuropathic pain is essential to proper management.
In addition, while clinicians should seek to diagnose the 
underlying cause of pain and then treat it, they must bal
-
ance the burden of diagnostic tests or therapeutic interven
-
tions with the patient’s suffering. For example, 
single-fraction radiation therapy for painful bone metasta
-
ses or nerve blocks for neuropathic pain may obviate the 
need for ongoing treatment with analgesics and their side 
effects. Regardless of decisions about seeking and treating 
the underlying cause of pain, every patient should be 
offered prompt pain relief.
The aim of effective pain management is to meet specific 
goals, such as preservation or restoration of function or 
quality of life, and this aim must be discussed between pro
-
vider and patient, as well as their family. For example, some 
patients may wish to be completely free of pain even at the 
cost of significant sedation, while others will wish to control 
pain to a level that still allows maximal functioning.
Whenever possible, the oral route of analgesic adminis
-
tration is preferred because it is easier to manage at home, 
is not itself painful, and imposes no risk from needle 
exposure.
Finally, pain management should not automatically 
indicate opioid therapy. While many individuals fare better 
with opioid therapy in specific situations, this does not 
mean that opioids are the answer for every patient. There 
are situations where opioids actually make the quality of life 
worse for individuals, due to their side effects, or due to a 
lack of effect.
 
»
Barriers to Good Care
One barrier to good pain control is that many clinicians 
have limited training and clinical experience with pain 
management and thus are reluctant to attempt to manage 
severe pain. Lack of knowledge about the proper selection 
and dosing of analgesic medications carries with it atten
-
dant and typically exaggerated fears about the side effects 
of pain medications, such as the possibility of respiratory 
depression from opioids. Most clinicians, however, can 
develop good pain management skills, and nearly all pain, 
even at the end of life, can be managed without hastening 
death through respiratory depression.
P
h
ARMACOLOGIC PAIN MANAGEMENT 
STRATEGIES
Pain generally can be well controlled with nonopioid and 
opioid analgesic medications, complemented by nonphar
-
macologic adjunctive and interventional treatments. For 
mild to moderate pain, acetaminophen, aspirin, and 
NSAIDs (also known as COX inhibitors) may be sufficient. 
For moderate to severe pain, especially for those with acute 
pain, short courses of opioids are sometimes necessary; for 
those with cancer pain or pain from advanced, progressive 
serious illness, opioids are generally required and interven
-
tional modalities should be considered. In all cases, the 
choice of an analgesic medication must be guided by care
-
ful attention to the physiology of the pain and the benefits 
and risks of the particular analgesic being considered.
 
»
Acetaminophen & NSAIDs (COX Inhibitors)
Table 5–7 provides comparison information for acetamino
-
phen, aspirin, the COX-2 inhibitor celecoxib and the 
NSAIDs. Appropriate doses of acetaminophen may be just as 
effective an analgesic and antipyretic as NSAIDs but without 
the risk of gastrointestinal bleeding or ulceration. Acetamin
-

-
ophen can be given at a dosage of 500–1000 mg orally every 
6 hours, not to exceed 4000 mg/day maximum for short-
term use. Total acetaminophen doses should not exceed 
3000 mg/day for long-term use or 2000 mg/day for older 
patients and for those with liver disease. Hepatotoxicity is of 
particular concern because of how commonly acetamino
-
phen is also an ingredient in various over-the-counter medi
-
cations and because of failure to account for the 
acetaminophen dose in combination acetaminophen-opioid 
medications such as Vicodin or Norco. The FDA has limited 
the amount of acetaminophen available in combination anal
-
gesics (eg, in acetaminophen plus codeine preparations).
Aspirin (325–650 mg orally every 4 hours) is an effec
-
tive analgesic, antipyretic, and anti-inflammatory medica
-
tion. Gastrointestinal irritation and bleeding are side 
effects that are lessened with enteric-coated formulation
-
sand by concomitant use of proton pump inhibitor medica
-
tion. Bleeding, allergy, and an association with Reye 
syndrome in children and teenagers further limit its use.
NSAIDs are antipyretic, analgesic, and anti-inflamma
-
tory. Treatment with NSAIDs increases the risk of gastro
-
intestinal bleeding 1.5 times; the risks of bleeding and 
nephrotoxicity are both increased in elders. Gastrointesti
-
nal bleeding and ulceration may be prevented with the 
concurrent use of proton pump inhibitors (eg, omeprazole, 
20–40 mg orally daily) or with use of celecoxib (100 mg 
orally daily to 200 mg orally twice daily), the only COX-2 
inhibitor available. Celecoxib and the NSAIDs can lead to 
fluid retention, kidney injury, and exacerbations of heart 
failure and should be used with caution in patients with 
that condition. Topical formulations of NSAIDs (such as 
diclofenac 1.3% patch or 1% gel), placed over the painful 
body part for treatment of musculoskeletal pain, are associ
-
ated with less systemic absorption and fewer side effects 
than oral administration and are likely underutilized in 
patients at risk for gastrointestinal bleeding.
Chang AK et al. Effect of a single dose of oral opioid and nono
-
pioid analgesics on acute extremity pain in the emergency 
department: a randomized clinical trial. JAMA. 2017 Nov 7;
 
318(17):1661–7. [PMID: 29114833]
Wiffen PJ et al. Oral paracetamol (acetaminophen) for cancer 
pain. Cochrane Database Syst Rev. 2017 Jul 12;7:CD012637. 
[PMID: 28700092]
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Table 5–7.
 
Acetaminophen and useful nonsteroidal anti-inflammatory drugs and COX inhibitors.
Medication 
(alphabetic order)
Usual Dose for 
Adults ≥ 50 kg
Adults < 50 kg
1
Cost per Unit
Cost for 
 
30 Days
2
Comments
3
Acetaminophen 
(Ofirmev)
1000 mg intrave
-
nously every 
 
6–8 hours
 
$45.02 per vial of 
1000 mg
$5402.40
 
Acetaminophen or 
paracetamol
4
 
(Tylenol,
 
Da
tril,
 
etc)
325–500 mg orally 
every 4 hours or 
500–1000 mg 
orally every 
 
6 hours, up to 
2000–4000 mg/
day
10–15 mg/kg every 
 
4 hours orally; 
15–20 mg/kg 
every 4 hours 
 
rectally, up to 
2000–3000 mg/
day
$0.02/500 mg 
(oral)
 
O
TC;
 
$0.43/650 mg 
(rectal)
 
O
TC
$3.60 (oral); 
$77.40 
(rectal)
Not an NSAID because it lacks 
peripheral anti-inflammatory 
effects. Equivalent to aspirin 
as analgesic and antipyretic 
agent.
Limit dose to 4000 mg/day in 
acute pain, and to 3000 mg/
day in chronic pain. Limit 
doses to 2000 mg/day in 
older patients and those with 
Be mindful of multiple sources 
of acetaminophen as in com
-
bination analgesics, cold 
remedies, and sleep aids.
Aspirin
5
325–650 mg orally 
every 4 hours
 
rectally
$0.02/325 mg 
OTC;
 
$1.51/600
 
mg
 
(r
ectal)
 
O
TC
$7.20 (oral); 
$271.80 
(rectal)
Available also in enteric-coated 
form that is more slowly 
absorbed but better 
tolerated.
Celecoxib
4
 (Celebrex)
200 mg orally once 
daily (osteoarthri
-
tis); 100–200 mg 
orally twice daily 
(RA)
100 mg orally once 
or twice daily
$4.62/100 mg; 
$7.58/200 mg
$227.40 OA; 
$454.80 
RA
Cyclooxygenase-2 inhibitor. No 
antiplatelet effects. Lower 
doses for elderly who weigh 
 
< 50 kg. Lower incidence of 
endoscopic gastrointestinal 
ulceration than NSAIDs. Not 
known if true lower incidence 
of gastrointestinal bleeding. 
Celecoxib is contraindicated 
in sulfonamide allergy.
Choline magnesium 
salicylate
6
 
(
Trila
-
sate, others)
1000–1500 mg 
orally three times 
daily
25 mg/kg orally 
three times daily
$0.46/500 mg
$124.20
Salicylates cause less gastroin
-
testinal distress and kidney 
impairment than NSAIDs but 
are probably less effective in 
pain management than 
NSAIDs.
Diclofenac (Flector)
1.3% topical patch 
applied twice daily
 
$14.92/patch
$895.20
Apply patch to most painful area
Diclofenac (Voltaren, 
Cataflam, others)
50–75 mg orally two 
or three times 
daily; 1% gel 
 
2–4 g four times 
daily
 
$0.95/50 mg; 
$1.14/75 mg; 
$0.52/g gel
$85.50; 
$102.60
 
$249.60 
gel
May impose higher risk of hepa
-
totoxicity. Enteric-coated 
product;
 
slo
w
 
onset
.
 
T
opical
 
formulations may result in 
fewer side effects than oral 
formulations.
Diclofenac sustained 
release (Voltaren-
XR, others)
100–200 mg orally 
once daily
 
$2.81/100 mg
$168.60
 
Diflunisal
7
 (Dolobid, 
others)
500 mg orally every 
12 hours
 
$2.07/500 mg
$124.20
Fluorinated acetylsalicylic acid 
derivative.
Etodolac (Lodine, 
others)
200–400 mg orally 
every 6–8 hours
 
$1.32/400 mg
$158.40
 
Fenoprofen calcium 
(Nalfon, others)
300–600 mg orally 
every 6 hours
 
$3.40/600 mg
$408.00
Perhaps more side effects than 
others, including tubulointer
-
stitial nephritis.
(
continued
)
CMDT19_Ch05_p0072-p0102.indd   86

87
 
CMDT 2019
Table 5–7.
 
1
Cost for 
 
30 Days
2
Comments
3
Flurbiprofen (Ansaid)
50–100 mg orally 
three or four times 
daily
 
$0.78/50 mg; 
$1.18/100 mg
$93.60; 
$141.60
Adverse gastrointestinal effects 
may be more common 
among elderly.
Ibuprofen (Caldolor)
400–800 mg intrave
-
 
6 hours
 
$18.02/800 mg 
vial
$2163.00
 
Ibuprofen (Motrin, 
Advil, Rufen, 
others)
400–800 mg orally 
10 mg/kg orally 
$0.28/600 mg Rx; 
$0.05/200 mg 
OTC
$33.60; $9.00
Relatively well tolerated and 
inexpensive.
Indomethacin 
(Indocin, Indo
-
meth, others)
25–50 mg orally two 
to four times daily
 
$0.38/25 mg; 
$0.64/50 mg
$45.60; 
$76.80
Higher
 
incidenc
e
 
of
 
dose
-related
 
toxic effects, especially 
 
gastrointestinal and bone 
marrow effects.
Ketoprofen (Orudis, 
Oruvail, others)
25–75 mg orally 
every 6–8 hours 
(max 300 mg/day)
 
$1.12/50 mg Rx; 
$1.24/75 mg Rx
$134.40; 
$148.80
Lower doses for elderly.
Ketorolac 
tromethamine
10 mg orally every 
4–6 hours to a 
maximum of 
 
40 mg/day orally
 
$2.16/10 mg
Not 
recom
-
mended
Short-term use (< 5 days) only; 
otherwise, increased risk of 
gastrointestinal side effects.
Ketorolac 
8
60 mg intramuscu
-
larly or 30 mg 
intravenously ini
-
tially, then 30 mg 
every 6 hours 
intramuscularly or 
intravenously
 
$1.45/30 mg
Not 
recom
-
mended
Intramuscular or intravenous 
NSAID as alternative to 
 
opioid. Lower doses for 
elderly. Short-term use 
 
(< 5 days) only.
Magnesium salicy
-
late (various)
 
$0.23/325 mg 
 
OTC
$55.20
 
Meclofenamate 
sodium
9
 
(Meclomen)
 
$7.74/100 mg
$928.80
Diarrhea more common.
Mefenamic acid 
(Ponstel)
250 mg orally every 
 
6 hours
 
$17.41/250 mg
$2089.20
Meloxicam (Mobic)
7.5 mg orally every 
12 hours
 
$4.84/7.5 mg
$290.40
Intermediate COX-2/COX-1 ratio 
similar to diclofenac
Nabumetone 
(Relafen)
500–1000 mg orally 
once daily (max 
dose 2000 mg/
day)
 
$1.30/500 mg; 
$1.53/750 mg
$78.00; 
$91.80
May be less ulcerogenic than 
ibuprofen, but overall side 
effects may not be less.
Naproxen (Naprosyn, 
Anaprox, Aleve 
[OTC],
 
others)
250–500 mg orally 
5 mg/kg every 
 
8 hours
$1.29/500 mg Rx; 
$0.09/220 mg 
OTC
$154.80; 
$8.10
 
O
TC
Generally well tolerated. Lower 
doses for elderly.
Oxaprozin (Daypro, 
others)
600–1200 mg orally 
once daily
 
$1.50/600 mg
$90.00
Similar to ibuprofen. May cause 
rash, pruritus, 
photosensitivity.
Piroxicam (Feldene, 
others)
20 mg orally 
 
once daily
 
$4.49/20 mg
$134.70
Not recommended in the elderly 
due to high adverse drug 
reaction rate. Single daily 
 
dose convenient. Long half-
life. May cause higher rate of 
gastrointestinal bleeding and 
dermatologic side effects.
(
continued
)
 
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»
Opioids
A. Formulations and Regimens
For many patients, opioids are the mainstay of pain man
-
agement (Table 5–8). Opioids are appropriate for managing 
severe pain due to any cause, including the following: neu
-
ropathic pain, cancer pain, pain from other serious ill
-
nesses, and pain at the end of life. Full opioid agonists such 
as morphine, hydromorphone, oxycodone, methadone, 
fentanyl, hydrocodone, tramadol, and codeine are used 
most commonly. Hydrocodone and codeine are typically 
combined with acetaminophen or an NSAID, although 
acetaminophen in these combinations is restricted to 
300–325 mg per unit dose due to the risk of hepatotoxicity. 
Extended-release hydrocodone without acetaminophen is 
also available. 
Short-acting formulations
 of oral morphine 
sulfate (starting dosage 4–8 mg orally every 3–4 hours), 
hydromorphone (1–2 mg orally every 3–4 hours), or oxy
-
codone (5 mg orally every 3–4 hours) are useful for severe 
acute pain not controlled with other analgesics. The trans
-
mucosal intermediate-release fentanyl products, such as 
oral transmucosal fentanyl (200 mcg oralet dissolved in the 
mouth) or buccal fentanyl (100 mcg dissolved in the 
mouth), can be used for treating patients with cancer pain 
that breaks through long-acting medications, or it can be 
administered before activity known to cause more pain 
(such as burn wound dressing changes). The use of 
buprenorphine as a short-acting analgesic generally should 
be reserved for pain management specialists.
For chronic stable pain, 
long-acting medications
 are 
preferred, such as oral sustained-release formulations of 
morphine (one to three times a day), hydromorphone 
(once daily), oxymorphone (two times a day), oxycodone 
(two or three times a day), or hydrocodone (two times a 
day), or the long-acting medication methadone (three or 
four times a day) (Table 5–8).
Clinicians prescribing opioids must understand the 
concept of 
equianalgesic dosing.
 The dosages of any full 
opioid agonists used to control pain can be converted into 
an equivalent dose of any other opioid. This approach is 
helpful in estimating the appropriate dose of a long-acting 
opioid based on the amount of short-acting opioid required 
over the preceding days. For example, 24-hour opioid 
requirements established using short-acting opioid medi
-
cations can be converted into equivalent dosages of long-
acting medications or formulations. Cross-tolerance is 
often incomplete, however, so generally only two-thirds to 
three-quarters of the full, calculated equianalgesic dosage 
is administered initially when switching between opioid 
Methadone
 deserves special consideration among the 
long-acting opioids because it is inexpensive, available in a 
liquid formulation, and may have added efficacy for neu
-
ropathic pain. However, equianalgesic dosing is complex 
because it varies with the patient’s opioid dose, and cau
-
tion must be used at higher methadone doses (generally 
more than 100–150 mg/day) because of the risk of QT 
prolongation. Baseline electrocardiography is recom
-
mended before starting methadone and repeated up to 
monthly except at the end of life where comfort is the only 
goal. Given the complexities of management, consultation 
with a palliative medicine or pain specialist may be 
appropriate.
Transdermal fentanyl
 is appropriate for patients 
already tolerant to other opioids for at least 1 week at a dose 
equivalent to at least 60 mg/day of oral morphine 
Table 5–7.
 
1
Cost for 
 
30 Days
2
Comments
3
Sulindac (Clinoril, 
others)
150–200 mg orally 
twice daily
 
$0.98/150 mg; 
$1.21/200 mg
$58.80; 
$72.60
May cause higher rate of 
 
gastrointestinal bleeding. 
 
May have less nephrotoxic 
potential.
Tolmetin
 
(

others)
 
$58.80; 
$72.60
 
Tolmetin
 
(
Tolectin)
200–600 mg orally 
four times daily
 
$0.75/200 mg; 
$3.98/600 mg
$90.00; 
$477.60
Perhaps more side effects 
 
than others, including 
 
anaphylactic reactions.
1
Acetaminophen and NSAID dosages for adults weighing < 50 kg should be adjusted for weight.
2
Average wholesale price (AWP , for AB-rated generic when available) for quantity listed. Source: 
Red Book
 (electronic version), Truven Health 
Analytics Information, http://www.micromedexsolutions.com, accessed March 1, 2018. AWP may not accurately represent the actual phar
-
macy cost because wide contractual variations exist among institutions.
3
The adverse effects of headache, tinnitus, dizziness, confusion, rashes, anorexia, nausea, vomiting, gastrointestinal bleeding, diarrhea, 
nephrotoxicity, visual disturbances, etc, can occur with any of these drugs. Tolerance and efficacy are subject to great individual variations 
among patients. Note: All NSAIDs can increase serum lithium levels.
4
Acetaminophen and celecoxib lack antiplatelet effects.
5
May inhibit platelet aggregation for 1 week or more and may cause bleeding.
6
May have minimal antiplatelet activity.
7
Administration with antacids may decrease absorption.
8
Has the same gastrointestinal toxicities as oral NSAIDs.
9
Coombs-positive autoimmune hemolytic anemia has been associated with prolonged use.
OA, osteoarthritis; RA, rheumatoid arthritis; OTC, over the counter; Rx, prescription.
 
CMDT19_Ch05_p0072-p0102.indd   88

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CMDT 2019
Table 5–8.
 
Opioid analgesics.
Approximate Equianalgesic Dose 
 
(compared to morphine 30 mg orally or 
 
10 mg intravenously/subcutaneously)
1
Usual Starting Dose
Potential Advantages
Potential 
Disadvantages
Adults ≥ 50 kg Body Weight
Adults < 50 kg Body Weight
Medication
Oral
Parenteral
Oral
Oral
Opioid Agonists
2
Buprenorphine 
parenteral 
(Buprenex)
300 mcg intrave
-
nously slowly 
once, may be 
repeated after 
30–60 minutes 
once; or 600 mcg 
intramuscularly 
once
-
once $18.20/300 
mcg
 
transdermal 
(BuTrans®)
Not available
Not available orally.
Transdermal
 
doses
 
available: 5, 10, and 
20 mcg/h. Initiate 
 
5 mcg/h patch for 
opioid-naïve 
patients (may 
 
currently be 
 
using nonopioid 
analgesics); 
$120.80/10 mcg/h
7-day
analgesia; may be initi
-
ated in opioid-naïve 
patients with 5 mcg/h.
Can titrate up dose by 
 
5 mcg/h after 72 hours, 
to a maximum dose of 
20 mcg/h.
Concomitant use 
of other opioids 
for acute pain 
could be diffi
-
cult due to 
strong receptor 
binding of 
buprenorphine, 
although this is 
often not 
 
found in clinical 
practice.
QT
 
pr
olongation.
(
continued
)
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Table 5–8.
 
Opioid analgesics. (continued)
 
1
Potential 
Oral
Oral
Oral
sublingual 
(Belbuca®)
Sublingual strip 
approved for pain
 
In opioid-naive or opi
-
oid-intolerant 
patients, individual
-
ize dose every 12 h. 
Start: 75 mcg buc
-
cally every 12–24 h 
for at least 4 days, 
then increase to 
 
150 mcg buccally 
every 12 h, then 
may increase by no 
more than 150 mcg 
buccally every 12 h 
no more frequently 
than every 4 days.
Maximum: 900 
 
mcg/12 h;
$6.07/75 mcg.
 
Used by pain 
management 
specialists.
Do no cut, chew, 
swallow strip. 
Taper
 
slo
wly
 
t
o
 
discontinue.
Use lowest effec
-
tive dose, 
shortest effec
-
tive treatment 
duration. 
 
Titrate
 
slo
wly
 
in patients age 
> 65 yrs.
See footnote
3
 for 
dosing in opi
-
oid-experi
-
enced patients.
Fentanyl
100 mcg every hour
50–100 mcg intrave
-
nously/intramus
-
cularly every hour 
or 0.5–1.5 mcg/
kg/h intravenous 
infusion 
$1.51/100 mcg
0.5–1 mcg/kg 
intravenously 
every 1–4 
hours or 1–2 
mcg/kg intra
-
venously × 1, 
then 0.5–1 
mcg/kg/h 
infusion
Possibly less neuroexcit
-
atory effects, including 
in kidney failure.
 
Fentanyl oral 
transmucosal 
(Actiq); buccal 
(Fentora)
200 mcg 
 
transmucosal; 
 
100 mcg buccal; 
$18.80/200 mcg 
$74.58/200 mcg 
buccal
For pain breaking 
through long-acting 
opioid medication.
Transmucosal
 
and buccal 
 
formulations 
are not bio
-
equivalent; 
there is higher 
bioavailability 
in buccal 
formulation.
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Fentanyl 
transdermal
Conversion to fentanyl 
patch is based on 
total daily dose of 
oral morphine:
2
 mor
-
phine 60–134 mg/
day orally = fentanyl 
25 mcg/h patch; mor
-
phine 135–224 mg/
50 mcg/h patch; mor
-
phine 225–314 mg/
75 mcg/h patch; and 
morphine 315–404 
mg/day orally = fen
-
tanyl 100 mcg/h 
patch
Not available orally
12.5–25 mcg/h patch 
every 72 hours; 
$14.43/25 mcg/h
12.5–25 mcg/h 
patch every 
72 hours
Stable medication blood 
levels.
Not for use in 
 
patients. Mini
-
mum starting 
dose is 25 
mcg/h patch in 
patients who 
have been tak
-
ing stable dose 
of opioids for 
 
at least 1 week 
at the equiva
-
lent of at least 
60 mg/day of 
oral morphine.
Hydrocodone,
 
extended 
release 
(Zohydro ER)
20 mg
1
10 mg every 12 hours; 
$10.28/10 mg
Available as an extended-
release formulation 
without 
acetaminophen.
 
Hydromorphone
4
 
(Dilaudid)
7.5 mg every 3–4 hours
1.5 mg every 
 
3–4 hours
1–2 mg every 3–4 
hours; $0.48/2 mg
1.5 mg every 3–4 
hours; $1.80/2 mg
0.06 mg/every 
3–4 hours
0.015 mg/kg 
every 3–4 
hours
Similar to morphine. 
Available in injectable 
high-potency prepara
-
tion, rectal 
suppository.
Short duration.
 
extended 
release 
(Exalgo)
45–60 mg every 
 
24 hours
8 mg every 24 hours; 
$16.73/8 mg
Similar to morphine.
Taper
 
dose
 
25–50% every 
2–3 days to 
 
8 mg/day to 
(
continued
)
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Table 5–8.
 
1
Potential 
Oral
Oral
Oral
Levorphanol 
(Levo-Dromo
-
ran)
4 mg every 6–8 hours
4 mg every 6–8 hours; 
$49.20/2 mg
0.04 mg/kg 
every 
 
6–8 hours
Longer acting than mor
-
phine sulfate.
 
Meperidine
5
 
(Demerol)
300 mg every 2–3 
hours; usual dose 
50–150 mg every 
 
3–4 hours
100 mg every 
 
3 hours
Not recommended
 
3 hours; 
$4.24/100 mg
Not 
recom
-
mended
0.75 mg/kg every 
2–3 hours
Use only when single-
dose, short-duration 
analgesia is needed, as 
for outpatient proce
-
dures like colonoscopy. 
Not recommended for 
chronic pain or for 
repeated dosing.
Short duration. 
Normeperidine 
metabolite 
accumulates in 
kidney failure 
and other 
 
situations, and 
in high 
 
concentrations 
may cause 
 
irritability and 
seizures.
Methadone 
(Dolophine, 
others)
10–20 mg every 
 
6–8 hours (when 
 
converting from 
 
< 100 mg long-term 
daily oral morphine
6
)
5–10 mg every 
 
6–8 hours
5–20 mg every 6–8 
hours; $0.31/10 mg
2.5–10 mg every 
6–8 hours; 
$23.34/10 mg
0.2 mg/kg every 
6–8 hours
0.1 mg/kg every 
6–8 hours
Somewhat longer acting 
than morphine. Useful 
in cases of intolerance 
to morphine.
May be particularly 
 
useful for neuropathic 
pain. Available in 
 
liquid formulation.
Analgesic dura
-
tion shorter 
than plasma 
duration. May 
accumulate, 
requiring close 
monitoring 
during first 
weeks of 
 
treatment. 
Equianalgesic 
ratios vary 
 
with opioid 
dose. Risk of 
 
QT
 
pr
olonga
-
tion at doses 
>100–150 mg/
day. Baseline 
ECG 
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Morphine
4
 
immediate 
release 
 
(Morphine 
 
sulfate tablets, 
Roxanol liquid)
30 mg every 3–4 hours 
(around-the-clock 
dosing); 60 mg every 
3–4 hours (single or 
intermittent dosing)
10 mg every 
 
3–4 hours
4–8 mg every 3–4 
hours; used for 
breakthrough pain 
in patients already 
taking controlled-
release preparations; 
$0.44/15 mg tab; 
$0.84/20 mg liquid
10 mg every 
 
3–4 hours; 
$12.90/10 mg
0.3 mg/kg every 
3–4 hours
3–4 hours
Standard of comparison; 
multiple dosage forms 
available.
No unique prob
-
lems when 
compared with 
other opioids.
Active metabolite 
kidney 
dysfunction.
Morphine 
 
controlled 
release
4
 (MS 
Contin, 
Oramorph)
90–120 mg every 
 
12 hours
15–60 mg every 
 
12 hours; 
 
$1.50/30 mg
 
Morphine 
extended 
release 
(Kadian, 
Avinza)
180–240 mg every 
 
24 hours
20–30 mg every 
 
24 hours; 
 
$5.69/30 mg
Once-daily dosing 
possible.
 
Oxycodone 
 
(Roxicodone, 
OxyIR)
 
3–4 hours
 
3–4 hours; 
 
$0.54/5 mg
3–4 hours
 
Oxycodone 
 
release 
(Oxycontin)
40 mg every 12 hours
20–40 mg every 
 
12 hours; 
 
$5.84/20 mg
 
Physical and 
chemical pill 
formulation to 
deter misuse 
(injection or 
intranasal 
administra
-
tion).
Oxymorphone
7
 
oral, immedi
-
ate release 
(Opana)
10 mg every 6 hours
 
6 hours; 
 
$2.95/5 mg
 
Taking
 
with
 
f
ood
 
can increase 
serum levels 
 
by 50%.
dosing conver
-
sion range is 
wide.
(
continued
)
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Table 5–8.
 
1
Potential 
Oral
Oral
Oral
Combination Opioid Agonist–Nonopioid Preparations
7
 
extended 
release (Opana 
ER)
30–40 mg every 
 
12 hours
15–30 mg every 
 
12 hours; 
 
$4.79/10 mg
 
Taking
 
with
 
f
ood
 
by 50%.
-
wide.
Codeine
8,9
 
(with aspirin 
 
or 
acetamino
-
phen)
10
180–200 mg every 
 
3–4 hours; commonly 
available dose in 
combination with 
acetaminophen, 
15–60 mg of codeine 
every 4–6 hours
130 mg every 
 
3–4 hours
60 mg every 
 
4–6 hours; 
 
$0.64/60 mg
60 mg every 
 
2 hours 
 
intramuscularly/
subcutaneously; 
price not avail
-
able in the 
 
United States
0.5–1 mg/kg 
every 3–4 
hours
Not 
recommended
Closely monitor 
for efficacy as 
patients vary in 
their ability to 
convert the 
prodrug 
codeine to 
morphine.
Hydrocodone
7
 
(in Lorcet, 
Lortab, 
 
Vicodin, 
others)
10
30 mg every 3–4 hours
10 mg every 
 
3–4 hours; 
 
$0.54/5 mg
3–4 hours
 
Combination with 
acetaminophen 
limits dosage 
titration.
Oxycodone
8
 (in 
Percodan, 
Tylox,
 
others)
10
10 mg every 
 
3–4 hours; 
 
$1.37/5 mg
3–4 hours
and aspirin 
 
Combination Opioid Agonist–Norepinephrine Reuptake Inhibitor Preparations
Tapentadol
 
(Nucynta)
Not known
Not known
Start 50–100 mg once, 
may repeat dose in 
 
1 hour. Can increase 
to 50–100 mg every 
4 hours. Maximum 
daily dose 600 mg; 
$10.82/100 mg
 
Avoid in severe 
kidney or liver 
impairment.
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Tapentadol,
 
extended 
release 
(Nucynta ER)
Not known
Not known
Start 50 mg orally 
every 12 hours. Can 
increase by 50-mg 
increments twice 
daily every 3 days to 
dose of 100–250 mg 
twice daily; 
$13.83/100 mg
 
Tramadol
 
(Ultram)
Not known
Not known
Start 25 mg orally daily. 
Can increase by 25 
mg every 3 days to 
25 mg orally 4 times 
daily, then may 
increase by 50 mg/
day every 3 days to 
100 mg orally 4 
times daily. Limit of 
300 mg/day in 
patients > 75 years 
old; $0.83/50 mg
 
If creatinine 
 
clearance less 
than 30, limit 
 
to 200 mg/day; 
with cirrhosis, 
limit to 100 
mg/day.
1
Published tables vary in the suggested doses that are equianalgesic to morphine. Clinical response is the criterion that must be applied for each patient; titration to clinical efficacy is necessary. Because 
there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower than equianalgesic dose initially when changing drugs and to retitrate to response.
2
Conversion is conservative; therefore, do not use these equianalgesic doses for converting back from fentanyl patch to other opioids because they may lead to inadvertent overdose. Patients may 
require breakthrough doses of short-acting opioids during conversion to transdermal fentanyl.
3
In opioid-experienced patients, taper current opioids to 30 mg/day oral morphine equivalent prior to starting buprenorphine. Thereafter, buprenorphine dosing schedule depends on prior current 
oral morphine equivalent:
< 30 mg/day, 75 mcg buccally every 12 h;
30–89 mg/day, 150 mcg buccally every 12 h;
90–160 mg/ day, 300 mcg buccally every 12 h;
In all patients, use same dose escalation and maximum dose as shown for opioid-naïve patients.
4
Caution:
 For morphine, hydromorphone, and oxymorphone, rectal administration is an alternative route for patients unable to take oral medications. Equianalgesic doses may differ from oral and 
parenteral doses. A short-acting opioid should normally be used for initial therapy.
5
Not recommended for chronic pain. Doses listed are for brief therapy of acute pain only. Switch to another opioid for long-term therapy.
6
Methadone conversion varies depending on the equivalent total daily dose of morphine. Consult with a pain management or palliative care expert for conversion.
7
Caution:
 Recommended doses do not apply for adult patients with kidney or liver impairment or other conditions affecting drug metabolism.
8
Caution:
 Doses of aspirin and acetaminophen in combination products must also be adjusted to the patient's body weight.
9
Caution:
 Doses of codeine above 60 mg often are not appropriate because of diminishing incremental analgesia with increasing doses but continually increasing nausea, constipation, and other side 
effects.
10
Caution:
 Monitor total acetaminophen dose carefully, including any OTC use. Total acetaminophen dose maximum 3 g/day. If liver impairment or heavy alcohol use, maximum is 2 g/day. Available 
dosing formulations of these combination medications are being adjusted to reflect increased caution about acetaminophen toxicity. Acetaminophen doses in a single combination tablet or capsule 
will be limited to no more than 325 mg.
Note:
 Average wholesale price (AWP , generic when available) for quantity listed. Source: 
Red Book
 (electronic version), Truven Health Analytics Information, http://www.micromedexsolutions.com, 
accessed March 1, 2018. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
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(equivalent to a transdermal fentanyl 25 mcg/h patch 
applied topically every 72 hours) and therefore should not 
be used in the postoperative setting or be the first opioid 
used. Since transdermal fentanyl can require 24–48 hours 
to achieve pharmacologic “steady state, ” patients should be 
weaned off their current opioid and given short-acting 
opioids while awaiting the full analgesic effect of a new 
transdermal fentanyl patch, and changes in dose of trans
-
dermal fentanyl should be made no more frequently than 
every 6 days.
Buprenorphine
 has been FDA-approved for treatment 
of moderate to severe chronic pain and is available in par
-
enteral, transdermal, and buccal formulations. The usual 
dosages of the 
parenteral
 formulation (Buprenex®) are 300 
mcg intravenously once (may be repeated once after 30–60 
minutes) or as 600 mcg intramuscularly once. The 
trans
-
dermal patch
 (BuTrans®) is available in dosages of 5, 10, 
and 20 mcg/h. The benefits of transdermal buprenorphine 
include its long half-life, once weekly change of patch, and 
lower risk of respiratory depression during treatment and 
lower likelihood of withdrawal upon discontinuation than 
with other opioids. The 
buccal buprenorphine
 strip for
-
mulation (Belbuca®
) is sometimes used by pain manage
-
ment specialists for moderate to severe constant pain. It 
can be more frequently up-titrated since it is given twice 
daily. Depending on the patient’s current opioid usage, it 
can be started at 75–300 mcg once or twice daily, then 
escalated by 150- to 450-mcg doses twice daily to a maxi
-
mum of 900 mcg twice daily. Although there is a theoretical 
concern about decreased efficacy of short-acting opioid 
agents unable to compete with buprenorphine at the opioid 
receptor, this is not a major issue with the formulations 
available in the United States.
In addition, buprenorphine comes in significantly more 
potent formulations generally reserved for the treatment of 
opioid use disorder with or without comorbid constant 
pain: a 
sublingual tablet
 (Subutex and others), a 
sublin
-
gual film
 (Suboxone) in which the buprenorphine is com
-
bined with naloxone, and 
subdermal implant
 of 
buprenorphine alone (Probuphine), each of which is used 
in maintenance treatment to reduce problematic use of 
While some clinicians and patients inexperienced with 
the management of severe pain may feel more comfortable 
with combined nonopioid-opioid agents, full agonist opi
-
oids are typically a better choice in patients with severe 
pain because the dose of opioid is not limited by the toxici
-
ties of the acetaminophen, aspirin, or NSAID component 
of combination preparations. There may be no maximal 
allowable or effective dose for full opioid agonists. Gener
-
ally, the dose can be gradually increased to whatever is 
necessary to relieve pain, as long as the side effects are tol
-
erable. Clinicians should confirm that increasing doses of 
opioid provide additional pain relief and remember that 
not all pain is opioid sensitive and that certain types of 
pain, such as neuropathic pain, may respond better to 
agents other than opioids, or to combinations of opioids 
with co-analgesics (Table 5–9).
Table 5–9.
 
Pharmacologic management of neuropathic pain.
1
Starting Dose
Typical Dose
Antidepressants
2
Nortriptyline
10 mg orally at bedtime
10–150 mg orally at bedtime
Desipramine
Calcium-channel Alpha2-delta Ligands
Gabapentin
3
100–300 mg orally once to three times daily
300–1200 mg orally three times daily
Pregabalin
4
50 mg orally three times daily
100 mg orally three times daily
Selective Serotonin Norepinephrine Reuptake Inhibitors
Duloxetine
60 mg orally daily or 20 mg orally twice daily in elders
60–120 mg orally daily
Venlafaxine
5
75 mg orally daily divided into two or three doses
150–225 mg orally daily divided into two or three 
doses
Opioids
(
see

5
doses
Opioids
(
see 
Table
 
5–8
)
(
see 
Table
 
5–8
)
Other Medications
Lidocaine transdermal
5% patch applied daily, for a maximum of 12 hours
1–3 patches applied daily for a maximum of 12 hours
Tramadol
 
h
ydrochloride
6
50 mg orally four times daily
100 mg orally two to four times daily
1
Begin at the starting dose and titrate up every 4 or 5 days. Within each category, drugs listed in order of prescribing preference.
2
Begin with a low dose. Use the lowest effective dose. Pain relief may be achieved at doses below antidepressant doses, thereby minimizing 
adverse side effects.
3
Common side effects include nausea, somnolence, and dizziness. Take medication on a full stomach. Do not combine with serotonin or 
norepinephrine uptake inhibitors, or with tricyclic antidepressants.
4
Common side effects include dizziness, somnolence, peripheral edema, and weight gain. Must adjust dose for kidney impairment.
5
Caution:
 Can cause hypertension and ECG changes. Obtain baseline ECG and monitor.
6
Tramadol is classified by the DEA as a Schedule IV controlled substance.
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While physiologic tolerance is possible with opioids, 
failure of a previously effective opioid dose to adequately 
relieve pain in a patient with cancer is usually due to wors
-
ening of the underlying condition causing pain, such as 
tumor growth or new metastasis. In this case, for moderate 
unrelieved pain, the dose of opioid can be increased by 
25–50%. For severe unrelieved pain, a dose increase of 
50–100% may be appropriate. The frequency of dosing 
should be adjusted so that pain control is continuous. 
Long-term dosing may then be adjusted by adding the 
average daily amount of short-acting opioid necessary for 
breakthrough pain over the preceding 72–96 hours to the 
long-acting medication dose. In establishing or reestablish
-
ing adequate dosing, frequent reassessments of the patient’s 
pain and medication side effects are necessary.
B. Assessing Benefits of Opioids
The potential benefits and harms of daily opioid therapy 
for patients with chronic noncancer pain differ than for 
patients with cancer pain and for patients receiving pallia
-
tive care or end-of-life care. For example, research demon
-
strates that the beneficial effect of opioids for chronic 
noncancer pain is modest at best, and no measures have 
been identified to predict a good response. The improve
-
ments are generally measured in terms of a reduction in the 
analog pain score of 2–3 points on a 10-point scale (see 
Table 5–6) or in improvements in the important but less 
precise outcome of function. Prior to considering a trial of 
daily opioids, clinicians should discuss these modest pos
-
sible benefits with patients to help set realistic goals of 
therapy (eg, moving from an average pain level of a “7” to 
a “4”). Clinicians should also set a deadline for reaching the 
patient’s goals. Since the published trials have generally 
lasted less than 16 weeks, it is reasonable to set a deadline 
before that, with some experts advocating a 90-day trial 
period. Limiting the time of a trial also helps prevent dose 
escalation to levels associated with increased risk of adverse 
effects, including overdose. Many experts recommend 
developing a specific goal of improved function (eg, return 
to work or to an exercise regimen), and tracking the 
patient’s progress toward achieving this goal.
For the many patients who do not have specific, mea
-
surable goals—or who come to the clinician already tak
-
ing daily opioid medication—monitoring response to 
treatment over time can be difficult. A useful tracking 
measure derived from the Brief Pain Inventory and vali
-
dated for use in primary care is the “PEG, ” which directs 
patients to quantify on a scale of 0–10 the following three 
outcomes over the last week: average pain intensity, how 
much the pain has affected their enjoyment of life, and 
how much their pain has impacted their general activity. 
Patients who do not progress toward their goal or whose 
PEG scores remain high over time may have pain that is 
unresponsive to opioids, and clinicians should reconsider 
the original diagnosis and use other modalities (both 
pharmacologic and nonpharmacologic) to provide anal
-
gesia. Without a clear analgesic benefit from opioids for 
chronic noncancer pain, the risks may predominate, and 
the ineffective therapy should be discontinued in a 
patient-centered manner.
C. Common Side Effects of Opioids
Opioid-related 
constipation
 should be anticipated and 
prevented in all patients. Constipation is common at any 
dose of opioid, and tolerance to this side effect does not 
develop over time. Prescribing a bowel regimen (see 
Chapter 15) to a patient taking opioids long term is a qual
-
ity of care measure supported by the National Quality 
Forum.
Sedation
 can be expected with opioids, although toler
-
ance to this effect and to side effects other than constipa
-
tion typically develops within 24–72 hours at a stable dose.

Forum.
Sedation
-
-
tion typically develops within 24–72 hours at a stable dose. 
Sedation typically appears well before significant respira
-
tory depression. If treatment for sedation is desired, 
dextroamphetamine (2.5–7.5 mg orally at 8 
am
 and noon) 
or methylphenidate (2.5–10 mg orally at 8 
am
 and noon) 
may be helpful. Caffeinated beverages can also ameliorate 
minor opioid sedation.
Opioid-induced 
neurotoxicity,
 including myoclonus, 
hyperalgesia, delirium with hallucinosis, and seizures, may 
develop in patients who take high doses of opioids for a 
prolonged period. Opioid-induced hyperalgesia appears to 
be a result of changes in both the peripheral and central 
nervous systems such that typically benign or even sooth
-
ing stimuli (eg, light massage) may be perceived as painful 
(allodynia); increasing the opioid dose may exacerbate the 
problem. Opioid-induced neurotoxicity symptoms typi
-
cally resolve after lowering the dose or switching opioids 
(“opioid rotation”), especially to opioids that do not have 
active metabolites (such as fentanyl or methadone). While 
waiting for the level of the offending opioid to fall, low 
doses of clonazepam, baclofen, or gabapentin may be help
-
ful for treating myoclonus; haloperidol may be useful for 
treating delirium. Avoiding or correcting dehydration may 
be helpful for avoiding opioid-induced neurotoxicity.
Nausea
 may occur with initiation of opioid therapy and 
resolve after a few days. Notably, unrelieved constipation 
may be a more likely cause of nausea in the setting of opioid 
use than opioid-induced nausea. Severe or persistent nau
-
sea despite treatment of constipation can be managed by 
switching opioids or by giving haloperidol, 0.5–4 mg orally, 
subcutaneously, or intravenously every 6 hours or prochlor
-
perazine, 10 mg orally or intravenously or 25 mg rectally 
every 6 hours. Ondansetron, 4–8 mg orally or intravenously 
every 6 hours, also relieves nausea but can contribute to 
constipation. Mirtazapine and medical cannabis may each 
have a role in treating opioid-induced nausea. Most anti
-
emetic treatments can contribute to sedation.
Although clinicians may worry about 
respiratory 
depression
 with opioids, this side effect is uncommon 
when a low dose is given initially and titrated upward 
slowly. Patients at particular risk for respiratory depres
-
sion include those with obstructive sleep apnea or central 
sleep apnea, chronic obstructive pulmonary disease, and 
baseline CO
2
 retention; those with liver or kidney or com
-
bined liver-kidney failure; and those with adrenal insuffi
-
ciency or frank myxedema. Y et, even patients with severe 
pulmonary disease and obstructive sleep apnea can toler
-
ate low-dose opioids, although patients should be moni
-
tored carefully. Hospitalized patients with these conditions 
who require increased doses of opioids should be 
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monitored with continuous pulse oximetry. Clinicians 
should not allow unfounded concerns about respiratory 
depression to prevent them from treating pain adequately 
with opioids.
As opioids are titrated upward and continued long 
term, increasing difficulty with the side effects can be 
expected. A misunderstanding of the physiologic effects of 
opioids can lead to unfounded concerns on the part of cli
-
nicians, patients, or family members that patients will 
become addicted to opioids. While physiologic 
tolerance
 
(requiring increasing dosage to achieve the same analgesic 
effect) and 
dependence
 (requiring continued dosing to 
prevent symptoms of medication withdrawal) are expected 
with regular opioid use, the use of opioids at the end of life 
for relief of pain and dyspnea is not generally associated 
with a risk of psychological 
addiction
 (use of a substance 
despite negative health or social consequences, cravings to 
use a substance, compulsive use or loss of control over level 
or time of use). The risk of problematic use of pain medica
-
tions is higher, however, in patients with a history of addic
-
tion to other substances. However, patients with such a 
history need pain relief and may benefit from opioids, 
albeit with closer monitoring.
D. Adverse Effects and Risks of Opioids
In an effort to treat chronic pain more aggressively, clini
-
cians in the United States dramatically increased the pre
-
scription of opioids beginning in the mid-1990s and 
peaking in 2010. After a modest decline, the amount of 
opioids prescribed per capita in 2015 remained triple the 
amount prescribed in 1999. The increased attention to 
treating chronic noncancer pain undoubtedly improved 
the lives of many patients, but the increase in prescribed 
opioids also had a deleterious effect on the health of the 
population as a whole. The increased population exposure 
to prescription opioids appears to have expanded the mar
-
ket for illicit opioids (heroin, fentanyl and its derivatives), 
with concomitant increase in opioid use disorder and opi
-
oid overdoses, which caused more than 60,000 deaths in 
2016. The CDC named both misuse of prescription medi
-
cations and opioid overdoses as epidemics in the United 
States and released guidelines in 2016 to limit the risks of 
prescribed opioids (https://www.cdc.gov/drugoverdose/
prescribing/guideline.html). Also in 2016, the US Surgeon 
General directly appealed to prescribing physicians to focus 
on combating the opioid epidemic and issued a report titled 
“Facing Addiction in America” (https://www.surgeonge
-
neral.gov/library/2016alcoholdrugshealth/index.html).
In addition to the grave risks of addiction and overdose 
and the common side effects of constipation and sedation, 
long-term opioid use leads to increased risk of many other 
problems, including hypogonadism, fracture, hyperalgesia, 
psychosocial problems, and fraught interactions with the 
health care system. When considering whether to initiate 
or continue opioids for chronic noncancer pain, clinicians 
should delineate these specific risks for patients so that an 
informed decision can be made.
Finally, diversion of medication from patients to whom 
they are prescribed into other hands is an additional risk that 
must be considered when prescribing long-term opioids for 
chronic noncancer pain. Diversion can represent opportun
-
ism, eg, when a patient sells medication in order to make 
money. Family members (including children), acquain
-
tances, or strangers may steal or extort medication for their 
own use or gain.
E. Limiting Risks of Opioids
A number of interventions have been used in an effort to 
limit the risks of opioids for patients with chronic noncancer 
pain. Data demonstrating the effectiveness of such measures 
are limited, but nearly all medical society consensus panels 
and expert guidelines recommend using a risk assessment

and expert guidelines recommend using a risk assessment 
tool, patient-provider agreements, urine drug testing, dose 
limitations, and limits on the use of some medications.
1. Risk assessment tool—
There are no highly predictive 
models for who will benefit from long-term opioids for 
chronic noncancer pain, and no models adequately predict 
harms. Some models can identify patients most likely to 
exhibit aberrant or addictive behaviors. Most published 
guidelines recommend using an instrument like the Opioid 
Risk Tool (available at http://www.opioidrisk.com/
node/884) to determine how closely to monitor patients 
who are receiving opioids long term, or whether to offer 
long-term opioids at all.
2. Patient-provider agreements—
Also known as “pain 
contracts, ” these agreements have a modest effect, with a 
7–23% reduction in aberrant behaviors reported. They do 
represent an opportunity for the clinician to discuss explic
-
itly the risks and benefits of opioids for chronic noncancer 
pain, protocols and procedural requirements for refills and 
monitoring, and consequences of worrisome behaviors.
3. Urine drug testing—
Toxicology testing is a tool bor
-
rowed from addiction treatment with goals of limiting 
diversion and identifying risky secondary drug use. Guide
-
lines recommend more frequent testing with any increased 
risk as determined by dose, risk assessment tool, or recent 
behavior. It is imperative that clinicians choose the tests 
appropriately and understand the limitations of toxicology 
testing when using this tool. Universal testing is recom
-
mended
,
 given provider inability to judge misuse of medi
-
cation and documented racial differences in monitoring.
4. Dose limitations—
Risk of overdose increases approxi
-
mately linearly with dose in observational studies. The 
CDC considers doses above the equivalent of 50 mg of 
morphine per day to be risky, and specifically recommends 
against prescribing more than 120 mg of morphine per day. 
Clinicians must be cautious when tapering a patient’s long-
term dose to meet these limits in order to avoid withdrawal. 
No data support one tapering regimen over another, but for 
patients taking opioids for years, the CDC recommends a 
monthly decrease of 10% of the original daily dose. Taper
-
ing too quickly may result in dissolution of the therapeutic 
relationship or risky patient behavior, such as use of non
-
prescribed prescription medications or heroin.
5. Special medication limitations—
The FDA requires 
companies making extended-release opioid formulations 
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to provide trainings for prescribers, although these train
-
ings have not reduced the increase in opioid overdoses. 
Many guidelines recommend that the prescription of 
methadone and fentanyl be limited to specialists, and 
because of the increased incidence of opioid overdose, the 
CDC recommends against concurrent prescription of opi
-
oids and benzodiazepines.
6. Antidote to overdose—
Distributing naloxone, a quick-
onset opioid-receptor antagonist, has long been known to 
reduce overdose deaths in people who use heroin. More 
recently, prescribing naloxone to patients taking opioids 
for chronic noncancer pain has been demonstrated to 
reduce rates of opioid overdose death. Educating both 
patients and their caregivers on the use of rescue naloxone 
is important, since those experiencing sedation and respi
-
ratory suppression from opioid overdose will not be able to 
self-administer the naloxone. In addition to preloaded 
needle-tipped syringes, intranasal and intramuscular auto
-
injector naloxone preparations are approved for sale in the 
United States, where an increasing number of states autho
-
rize pharmacies to dispense naloxone in the absence of a 
prescription. CDC guidelines recommend prescribing nal
-
oxone for any patient with history of overdose, substance 
use disorder, concomitant benzodiazepine use, or daily 
doses above 50 mg morphine equivalent.
F. A Shared Decision-Making 
 
Approach to Opioid Use
As opposed to using opioids in patients with cancer or at 
the end of life, prescribing opioids for patients with chronic 
noncancer pain is fraught with challenges for clinicians. 
But taking the approach of carefully evaluating benefits 
and risks allows the opportunity for shared decision mak
-
ing between patient and clinician in individual cases. Clini
-
cal trials do not suggest that the majority of people with 
chronic noncancer pain benefit significantly from daily 
opioid therapy, and the dramatic increase in morbidity and 
mortality witnessed with the increased availability of these 
medications now warrants very careful patient selection. It 
is incumbent upon the clinician to provide frank advice to 
patients prescribed long-term opioids for chronic noncan
-
cer pain and to offer safer alternatives when the benefit is 
insufficient or the risks are too high.
Chen JH et al. Effect of opioid prescribing guidelines in primary 
care. Medicine (Baltimore). 2016 Aug;95(35):e4760. [PMID: 
27583928]
Coffin PO et al. Nonrandomized intervention study of naloxone 
coprescription for primary care patients receiving long-term 
opioid therapy for pain. Ann Intern Med. 2016 Aug 16;
 
165(4):245–52. [PMID: 27366987]
Cordier Scott L et al. JAMA patient page. Opioids for chronic 
pain. JAMA. 2016 Apr 19;315(15):1672. [PMID: 26978825]
Dart RC et al. Trends in opioid analgesic abuse and mortality in 
the United States. N Engl J Med. 2015 Apr 16;372(16):1573–4. 
[PMID: 25875268]
Dowell D et al. CDC guideline for prescribing opioids for chronic 
pain—United States, 2016. JAMA. 2016 Apr 19;315(15):1624–15. 
[PMID: 26977696] http://www.cdc.gov/drugoverdose/
 
prescribing/guideline.html
Dowell D et al. Underlying factors in drug overdose deaths. 
JAMA. 2017 Dec 19;318(23):2295–6. [PMID: 29049472]
Frank JW et al. Patient outcomes in dose reduction or discontinu
-
ation of long-term opioid therapy: a systematic review. Ann 
Intern Med. 2017 Aug 1;167(3):181–91. [PMID: 28715848]
Gaither JR et al. The association between receipt of guideline-
concordant long-term opioid therapy and all-cause mortality. 
J Gen Intern Med. 2016 May;31(5):492–501. [PMID: 
26847447]
Garg RK et al. Patterns of opioid use and risk of opioid overdose 
death among Medicaid patients. Med Care. 2017 Jul;
 
55(7):661–8. [PMID: 28614178]
Guy GP Jr. et al. Vital Signs: changes in opioid prescribing in the 
United States, 2006–2015. MMWR Morb Mortal Wkly Rep 
2017 Jul 7;66:697–704. [PMID: 28683056]

Manchikanti L et al. Responsible, safe, and effective prescription 
of opioids for chronic non-cancer pain: American Society of 
Interventional Pain Physicians (ASIPP) guidelines. Pain 
Physician. 2017 Feb;20(2S):S3–92. [PMID: 28226332]
 
»
Medications for Neuropathic Pain
When taking a patient’s history, listening for pain descrip
-
tions such as “burning, ” “shooting, ” “pins and needles, ” or 
“electricity, ” and for pain associated with numbness is 
essential because such a history suggests neuropathic pain. 
While opioids are effective for neuropathic pain, a number 
of nonopioid medications have also been found to be effec
-
tive in randomized trials (Table 5–9). Successful manage
-
ment of neuropathic pain often requires the use of more 
than one effective medication.
The calcium channel alpha2-delta ligands, gabapentin 
and pregabalin, are first-line therapies for neuropathic 
pain. Both medications have no significant medication 
interactions but can cause sedation, dizziness, ataxia, and 
gastrointestinal side effects. Both medications require dose 
adjustments in patients with kidney dysfunction. Gabapen
-
tin should be started at low dosages of 100–300 mg orally 
three times a day and titrated upward by 300 mg/day every 
4 or 5 days with a typical effective dose of 1800–3600 mg/day. 
Pregabalin should be started at 150 mg/day in two or three 
divided doses. If necessary, the dose of pregabalin can be 
titrated upward to 300–600 mg/day in two or three divided 
doses. Both medications are relatively safe in accidental 
overdose and may be preferred over tricyclic antidepres
-
sants for a patient with a history of heart failure or arrhyth
-
mia or if there is a risk of suicide. Prescribing both 
gabapentin and an opioid for neuropathic pain may pro
-
vide better analgesia at lower doses than if each is used as a 
single agent.
The selective serotonin norepinephrine reuptake inhib
-
itors (SSNRIs) duloxetine and venlafaxine are also first-line 
treatments for neuropathic pain. Patients should be advised 
to take duloxetine on a full stomach because nausea is a 
common side effect. Duloxetine may provide increased 
benefit for neuropathic pain up to a total daily dose of 
120 mg, beyond the 60-mg limit used for depression. 
Duloxetine generally should not be combined with other 
serotonin or norepinephrine uptake inhibitors, but it can 
be combined with gabapentin or pregabalin. Because ven
-
lafaxine can cause hypertension and induce ECG changes, 
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patients with cardiovascular risk factors should be carefully 
monitored when starting this medication.
Among the tricyclic antidepressants that are effective 
for neuropathic pain, nortriptyline and desipramine are 
preferred because they cause less orthostatic hypotension 
and have fewer anticholinergic effects than amitriptyline. 
Start with a low dosage (10–25 mg orally daily) and titrate 
upward in 10-mg increments every 4 or 5 days aiming to 
use the lowest effective dose and to titrate up to a maxi
-
mum of no greater than 100 mg daily. It may take several 
weeks for a tricyclic antidepressant to have its full analgesic 
effect for neuropathic pain.
Other medications effective for neuropathic pain 
include tramadol, tapentadol, and the 5% lidocaine patch. 
The 5% lidocaine patch is particularly effective in posther
-
petic neuralgia and may be effective in other types of local
-
ized neuropathic pain that causes hypesthesia; it is not 
effective for other causes of pain. Medical cannabis strains 
high in cannabidiol have proven efficacy for some types of 
neuropathic pain.
Fornasari D. Pharmacotherapy for neuropathic pain: a review. 
Pain Ther. 2017 Dec;6(Suppl 1):25–33. [PMID: 29178034]
 
»
Adjuvant Pain Medications & Treatments
If pain cannot be controlled without uncomfortable medi
-
cation side effects, clinicians should consider using lower 
doses of multiple medications, which is done commonly 
for neuropathic pain, rather than larger doses of one or two 
medications.
For metastatic bone pain, the anti-inflammatory effect 
of NSAIDs can be helpful. Futhermore, bisphosphonates 
(such as pamidronate and zoledronic acid) and receptor 
activator of NF-kappa-B ligand (RANKL) inhibitors (such 
as denosumab) may relieve such bone pain.
Corticosteroids, such as dexamethasone, prednisone, 
and methylprednisolone, can be helpful for patients with 
headache due to increased intracranial pressure, pain 
from spinal cord compression, metastatic bone pain, and 
neuropathic pain due to invasion or infiltration of nerves 
by tumor. Because of the side effects of long-term cortico
-
steroid administration, they are most appropriate for 
short-term use and in patients with end-stage disease. 
Low-dose intravenous, oral, and nasal ketamine has been 
used successfully for neuropathic and other pain syn
-
dromes refractory to opioids, although research data are 
limited.
Chen F et al. Safety of denosumab versus zoledronic acid in 
patients with bone metastases: a meta-analysis of randomized 
controlled trials. Oncol Res Treat. 2016;39(7–8):453–9. 
[PMID: 27487236]
Niesters M et al. Ketamine for chronic pain: risks and benefits. Br 
J Clin Pharmacol. 2014 Feb;77(2):357–67. [PMID: 23432384]
Paulsen O et al. Efficacy of methylprednisolone on pain, fatigue, 
and appetite loss in patients with advanced cancer using opi
-
oids: a randomized, placebo-controlled, double-blind trial. J 
Clin Oncol. 2014 Oct 10;32(29):3221–8. [PMID: 25002731]
Rasu RS et al. Assessing prescribing trends of adjuvant medication 
therapy in outpatients with a diagnosis of noncancer chronic 
pain. Clin J Pain. 2017 Sep;33(9):786–92. [PMID: 28002095]
Y ang L et al. Efficacy and safety of zoledronic acid and pamidronate 
disodium in the treatment of malignant skeletal metastasis: a 
meta-analysis. Medicine (Baltimore). 2015 Oct;94(42):e1822. 
[PMID: 26496320]
INTEGRATIVE T
h
ERAPIES & OT
h
ER PAIN 
MANAGEMENT
Nonpharmacologic and noninterventional therapies are 
valuable in treating pain. Hot or cold packs, massage, and 
physical therapy can be helpful for musculoskeletal pain. 
Similarly, integrative medicine therapies of acupuncture, 
chiropractic, biofeedback, meditation, music therapy, cog
-
nitive-behavioral therapy, guided imagery, cognitive dis
-
traction, and framing may be of help in treating pain. 
Because mood and psychological issues play an important 
role in the patient’s perception of and response to pain,

-
role in the patient’s perception of and response to pain, 
psychotherapy, support groups, prayer, and pastoral coun
-
seling can also help in the management of pain. Depres
-
sion, which may be instigated by chronic pain or may alter 
the response to pain, should be treated aggressively with 
antidepressants.
Martorella G et al. Tailored web-based interventions for pain: 
systematic review and meta-analysis. J Med Internet Res. 
2017 Nov 10;19(11):e385. [PMID: 29127076]
Zhao M et al. Acupressure therapy for acute ankle sprains: a 
randomized clinical trial. PM R Phys Med Rehab. 2018 Jan;
 
10(1):36–44. [PMID: 28634002]
INTERVENTIONAL MODALITIES FOR 
PAIN RELIEF
Interventional pain management modalities involve neuro
-
modulating therapies to a specific target in order to allevi
-
ate acute, chronic, and cancer pain. They are undertaken 
by pain management specialists. Interventional procedures 
may include percutaneous needle injection of local anes
-
thetics and/or corticosteroids; radiofrequency (thermal), 
cryotherapy, or chemical neurolysis; or implantation of 
intrathecal drug delivery pump systems or neurostimula
-
tion devices. Neurostimulation devices may deliver spinal 
cord (dorsal column) stimulation, dorsal root ganglion 
stimulation, peripheral nerve/field stimulation, deep brain 
stimulation, and stimulation of other neural targets. While 
implantation procedures carry their own inherent risks 
(such as bleeding or infection), they can drastically reduce 
and obviate the need for other therapies (eg, opioid or 
other medications), which may have side effects that are 
burdensome to the individual.
For some patients, a nerve block (eg, a celiac plexus 
block for pain from pancreatic cancer) can provide sub
-
stantial relief. Intrathecal pumps delivering opioids (some
-
times mixed with adjuvant medications) may be useful 
for patients with severe pain responsive to opioids but 
who require such large doses that systemic side effects 
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(eg, sedation, urinary retention and constipation) have 
become limiting. In the palliative care setting, these pumps 
are appropriate when life expectancy is long enough to 
justify the discomfort and cost of their surgical insertion.
Clinicians do not need to know all of the details of 
interventional pain procedures but should consider referral 
of their patients to pain management specialists if such 
procedures might be of benefit. For example, a common 
question is whether long-term opioid therapy with its 
inherent risks is better than an injection, a neurolytic pro
-
cedure, or an implanted device. Beyond knowing the ben
-
efits and risks of the various interventions, pain 
management specialists understand the fiscal implications 
since some of these therapies can be quite costly. The 
S.A.F.E. principles of safety, appropriateness, fiscal neutral
-
ity, and efficacy create a framework for decision-making 
about interventional modalities.
Tables 5–10 and 5–11 list some of the procedures and 
agents typically used in these interventional modalities for 
pain relief.
Deer TR et al. Dorsal root ganglion stimulation yielded higher 
treatment success rate for complex regional pain syndrome 
and causalgia at 3 and 12 months: a randomized comparative 
trial. Pain. 2017 Apr;158(4):669–81. [PMID: 28030470]
Deer TR et al. The Neurostimulation Appropriateness Consen
-
sus Committee (NACC): recommendations for infection 
prevention and management. Neuromodulation. 2017 
Jan;20(1):31–50. Erratum in: Neuromodulation. 2017 Jul;
 
20(5):516. [PMID: 28042909]
-
sus Committee (NACC): recommendations on bleeding and 
coagulation management in neurostimulation devices. Neu
-
romodulation. 2017 Jan;20(1):51–62. Erratum in: Neuro
-
modulation. 2017 Jun;20(4):407. [PMID: 28042905]
Deer TR et al. The Polyanalgesic Consensus Conference (PACC): 
recommendations on intrathecal drug infusion systems best 
practices and guidelines. Neuromodulation. 2017 Feb;20(2):
 
96–132. Erratum in: Neuromodulation. 2017 Jun;20(4):405–6. 
[PMID: 28042904]
Eghtesadi M et al. Neurostimulation for refractory cervicogenic 
headache: a three-year retrospective study. Neuromodula
-
tion. 2017 Nov 27. [Epub ahead of print] [PMID: 29178511]
Morgalla MH et al. Dorsal root ganglion stimulation used for the 
treatment of chronic neuropathic pain in the groin: a single-
center study with long-term prospective results in 34 cases. 
Neuromodulation. 2017 Dec;20(8):753–60. [PMID: 29131488]
Patel N et al. ‘Was it worth it?’ Intrathecal analgesia for cancer pain: 
a qualitative study exploring the views of family carers. Palliat 
Med.  2018 Jan;32(1):287–93. [PMID: 28832240]
Sharan A et al. An overview of chronic spinal pain: revisiting 
diagnostic categories and exploring an evolving role for 
neurostimulation. Spine (Phila Pa 1976). 2017 Jul 15;42
 
(Suppl 14):S35–40. [PMID: 28441315]
Zheng S et al. Evaluation of intrathecal drug delivery system for 
intractable pain in advanced malignancies: a prospective 
cohort study. Medicine (Baltimore). 2017 Mar;96(11):e6354. 
[PMID: 28296770]
Table 5–10.
 
Interventional techniques (injection and 
stimulation) for chronic pain by anatomic location.
Neuraxial
Intrathecal
Epidural (caudal, lumbar, thoracic, cervical)
Interlaminar
Transforaminal
Paraneuraxial (planar blockade)
Paravertebral (intercostal)
Transversus
 
abdominis
 
plane/quadr
atus
 
lumborum
Peripheral nerve (perineural blockade)
Brachial plexus and branches
Lumbar plexus and branches
Joints
Intra-articular injections
Joint denervating procedures
Intrathecal drug delivery (via refillable subcutaneous 
 
implanted pump)
Sympathetic ganglion
Gasserian ganglion
Sphenopalatine ganglion
Stellate ganglion (cervical sympathetic blockade)
Splanchnic or celiac plexus or both
Superior hypogastric plexus
Ganglion impar
Neurostimulation

Dorsal column stimulation (spinal cord stimulation)
Dorsal root ganglion stimulation
Peripheral nerve or field stimulation or both
Noninvasive stimulation of various targets
Table 5–11.
 
Agents used in neuromodulatory 
therapies.
Voltage-gated sodium channel blockade—local anesthetics
1
Lidocaine
Mepivacaine
Bupivacaine
Ropivacaine
Corticosteroids
1
Dexamethasone
Betamethasone
Triamcinolone
Methylprednisolone
Opioids
1
Morphine
Fentanyl
Adjuvants
1
Clonidine
Dexmedetomidine
Chemical neurolysis
Alcohol
Phenol
Glycerol
Thermal neurolysis
Radiofrequency ablation
Cryoanalgesia
Various:
•  Patterns
•  Frequencies
•  Amplitudes
•  Pulse
 
widths
1
List is not comprehensive but includes most commonly used 
agents.
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»
•	
Pain does not respond to opioids at typical doses or 
causes major adverse effects at typical doses.
•	
Pain cannot be controlled expeditiously or safely by 
other clinicians.
•	
Neuropathic pain does not respond to first-line 
•	
Complex methadone or buprenorphine management 
issues arise.
•	
Severe pain occurs from bone metastases.
 
»
•	
Severe exacerbation of pain that is not responsive to 
previous stable oral opioids given around the clock plus 
breakthrough doses.
•	
Patients’ pain is so severe that they cannot be cared for 
at home.
•	
Uncontrollable side effects from opioids occur, including 
nausea, vomiting, myoclonus, and altered mental status.
•	
A surgical or anesthesia-based procedure, such as 
implantation of an intrathecal drug delivery pump or 
neurostimulation device, performance of a nerve block 
or indwelling catheter.
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CMDT 2019
Dermatologic diseases are diagnosed by the types of lesions 
they cause. To make a diagnosis: (1) identify the type of 
lesion(s) the patient exhibits by morphology establishing a 
differential diagnosis (Table 6–1); and (2) obtain the ele
-
ments of the history, physical examination, and appropriate 
laboratory tests to confirm the diagnosis. Specific clinical 
situations, such as an immunocompromised or critically ill 
patient, lead to different diagnostic considerations.
PRINCIPLES OF DERMATOLOGIC THERAPY
 
»
Frequently Used Treatment Measures
A. Bathing
Soap should be used only in the axillae and groin and on 
the feet by persons with dry or inflamed skin. Soaking in 
water for 10–15 minutes before applying topical corticoste
-
roids or emollient enhances their efficacy (Soak and 
Smear).
B. Topical Therapy
Nondermatologists should become familiar with a repre
-
sentative agent in each category for each indication (eg, 
topical corticosteroid, topical retinoid, etc).
1. Corticosteroids—
Topical corticosteroid creams, lotions, 
ointments, gels, foams, and sprays are presented in Table 6–2. 
Topical corticosteroids are divided into classes based on 
potency. Agents within the same class are equivalent thera
-
pies; however, prices of even generic topical corticosteroids 
vary dramatically. 
For a given agent, an ointment is more 
potent than a cream
. The potency of a topical corticoste
-
roid may be dramatically increased by occlusion (covering 
with a water-impermeable barrier) for at least 4 hours. 
Depending on the location of the skin condition, gloves, 
plastic wrap, moist pajamas covered by dry pajamas (wet 
wraps), or plastic occlusive suits for patients can be used. 
Caution should be used in applying topical corticosteroids 
to areas of thin skin (face, scrotum, vulva, skin folds). Topi
-
cal corticosteroid use on the eyelids may result in glaucoma 
or cataracts. One may estimate the amount of topical corti
-
costeroid needed by using the “rule of nines” (as in burn 
evaluation; see Figure 37–2). Approximately 20–30 g is 
needed to cover the entire body surface of an adult. Sys
-
temic absorption does occur, but adrenal suppression, 
diabetes mellitus, hypertension, osteoporosis, and other 
complications of systemic corticosteroids are very rare with 
topical corticosteroid therapy.
2. Emollients for dry skin (“moisturizers”)—
Dry skin is a 
result of abnormal function of the epidermis. Emollients 
restore the epidermis by promoting keratinocyte differen
-
tiation and production of innate antimicrobials in skin. 
Many types of emollients are available. Petrolatum, mineral 
oil, Aquaphor, CeraVe, Cetaphil, and Eucerin cream are the 
heaviest and best. 
Emollients are most effective when 
applied to wet skin but can also be used on dry skin.
 If 
the skin is too greasy after application, pat dry with a damp 
towel. Vanicream is relatively allergen-free and can be used 
if allergic contact dermatitis to topical products is 
The scaly appearance of dry skin may be improved by 
emollients with concomitant use of keratolytics including 
urea, lactic acid, or glycolic acid–containing products pro
-
vided no inflammation (erythema or pruritus) is present.
3. Drying agents for weepy dermatoses—
If the skin is 
weepy from infection or inflammation, drying agents may 
be beneficial. The best drying agent is water, applied as 
repeated compresses for 15–30 minutes, alone or with alu
-
minum salts (Burow solution, Domeboro tablets).
4. Topical antipruritics—
Lotions that contain 0.5% each of 
camphor and menthol (Sarna) or pramoxine hydrochloride 
1% (with or without 0.5% menthol, eg, Prax, PrameGel, 
Aveeno Anti-Itch lotion) are effective antipruritic agents. 
Hydrocortisone, 1% or 2.5%, may be incorporated for its 
anti-inflammatory effect (Pramosone cream, lotion, or 
ointment). Doxepin cream 5% may reduce pruritus but may 
cause drowsiness. Pramoxine and doxepin are most effec
-

-
tive when applied with topical corticosteroids. Topical cap
-
saicin can be effective in some forms of neuropathic itch.
C. Systemic Antipruritic Drugs
1. Antihistamines and antidepressants—
H
1
-blockers are 
the agents of choice for pruritus when due to histamine, 
such as in urticaria. Otherwise, they appear to benefit itchy 6
 
Lindy P . Fox, MD
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Table 6–1.
 
Morphologic categorization of skin lesions and diseases.
Pigmented
Freckle, lentigo, seborrheic keratosis, nevus, blue nevus, halo nevus, atypical nevus, melanoma
Scaly
Psoriasis, dermatitis (atopic, stasis, seborrheic, chronic allergic contact or irritant contact), xerosis 
 
(dry skin), lichen simplex chronicus, tinea pedis/cruris/corporis, tinea versicolor, secondary syphilis, 
 
pityriasis rosea, discoid lupus erythematosus, exfoliative dermatitis, actinic keratoses, Bowen disease, 
Paget disease, drug eruption
Vesicular
Herpes simplex, varicella, herpes zoster, pompholyx (vesicular dermatitis of palms and soles), vesicular 
tinea, autoeczematization, dermatitis herpetiformis, miliaria crystallina, scabies, photosensitivity, acute 
contact allergic dermatitis, drug eruption
Weepy or encrusted
Impetigo, acute contact allergic dermatitis, any vesicular dermatitis
Pustular
Acne vulgaris, acne rosacea, folliculitis, candidiasis, miliaria pustulosa, pustular psoriasis, any vesicular 
 
dermatitis, drug eruption
Figurate (“shaped”) erythema
Urticaria, erythema multiforme, erythema migrans, cellulitis, erysipelas, erysipeloid, arthropod bites
Bullous
Impetigo, blistering dactylitis, pemphigus, pemphigoid, porphyria cutanea tarda, drug eruptions, ery
-
thema multiforme, toxic epidermal necrolysis
Papular
Hyperkeratotic: warts, corns, seborrheic keratoses
Purple-violet: lichen planus, drug eruptions, Kaposi sarcoma, lymphoma cutis, Sweet syndrome
Flesh-colored, umbilicated: molluscum contagiosum
Pearly: basal cell carcinoma, intradermal nevi
Small, red, inflammatory: acne, rosacea, miliaria rubra, candidiasis, scabies, folliculitis
Pruritus
1
Xerosis, scabies, pediculosis, lichen planus, lichen simplex chronicus, bites, systemic causes, 
 
anogenital pruritus
Nodular, cystic
Erythema nodosum, furuncle, cystic acne, follicular (epidermal) inclusion cyst, metastatic tumor to skin
Photodermatitis 
 
(photodistributed rashes)
Drug eruption, polymorphic light eruption, lupus erythematosus
Morbilliform
Drug eruption, viral infection, secondary syphilis
Erosive
Any vesicular dermatitis, impetigo, aphthae, lichen planus, erythema multiforme, intertrigo
Ulcerated
Decubiti, herpes simplex, skin cancers, parasitic infections, syphilis (chancre), chancroid, vasculitis, stasis, 
arterial disease, pyoderma gangrenosum
1
Not a morphologic class but included because it is one of the most common dermatologic presentations.
Table 6–2.
 
Useful topical dermatologic therapeutic agents.
a
gen
t
Formulations, Strengths, 
and 
p
ric
es
1
Frequency of 
a
pplic
ation
p
ot
ency 
Class
Common 
Indications
Comments
Corticosteroids (Listed in Order of Increasing 
p
ot
ency)
Hydrocortisone 
acetate
Cream 1%: $3.99/30 g
Ointment 1%: $3.99/30 g
Solution 1%: $6.12/44 mL
Twice daily
Low
Pruritus ani
Intertrigo
Not the same as hydrocorti
-
sone butyrate or valerate
Not for poison oak, OTC lotion 
(Aquanil HC), OTC solution 
(Scalpicin, T Scalp)
Cream 2.5%: $11.00/30 g
As for 1% 
hydrocortisone
Perhaps better for pruritus ani
Not clearly better than 1%
More expensive
Not OTC
Alclometasone 
dipropionate 
(Aclovate)
Cream 0.05%: $48.07/15 g
Ointment 0.05%: 
 
$20.00/15 g
Low
As for hydrocortisone
More efficacious than 
Perhaps causes less atrophy
Desonide
Cream 0.05%: $80.29/15 g
 
$60.10/15 g
Lotion 0.05%: 
 
$296.10/60 mL
Low
For lesions on face or 
body folds resis
-
tant to 
Can cause rosacea or atrophy
Not fluorinated
(
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)
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Table 6–2.
 
a
gen
t
and 
p
ric
es
1
a
pplic
ation
p
ot
ency 
Class
Common 
Comments
Clocortolone 
(Cloderm)
Cream 0.1%: $322.47/45 g
Three times daily
Medium
Contact dermatitis
Atopic dermatitis
Does not cross-react with other 
corticosteroids chemically 
and can be used in patients 
allergic to other 
corticosteroids
Prednicarbate 
(Dermatop)
Emollient cream 0.1%: 
$137.10/60 g
Ointment 0.1%: $30.00/15 g
Medium
As for triamcinolone
May cause less atrophy
No generic formulations
Preservative-free
Triamcinolone 
acetonide
Cream 0.1%: $3.89/15 g
Ointment 0.1%: $5.57/15 g
Lotion 0.1%: $42.42/60 mL
Medium
Eczema on extensor 
areas
Used for psoriasis 
with tar
Seborrheic dermatitis 
and psoriasis on 
scalp
Caution in body folds, face
Economical in 0.5-lb and 1-lb 
sizes for treatment of large 
body surfaces
Economical as solution for 
scalp
Cream 0.025%: $4.50/15 g
Ointment 0.025%: 
$11.15/80 g
Medium
As for 0.1% strength
Possibly less efficacy and few 
advantages over 0.1% 
formulation
Fluocinolone 
acetonide
Cream 0.025%: $33.77/15 g
$33.77/15 g
Medium
 
Solution 0.01%: 
 
$180.00/60 mL
Medium
As for triamcinolone 
solution
Mometasone 
furoate (Elocon)
Cream 0.1%: $6.05/15 g
Ointment 0.1%: $24.30/15 g
Lotion 0.1%: $55.45/60 mL
Once daily
Medium
Often used inappropriately on 
the face or on children
Diflorasone 
diacetate
Cream 0.05%: $209.68/15 g
$209.68/15 g
High
Nummular dermatitis
Allergic contact 
dermatitis
Lichen simplex 
chronicus
Fluocinonide 
(Lidex)
Cream 0.05%: $45.55/15 g
Gel 0.05%: $59.56/15 g
Ointment 0.05%: $28.53/15 g
Solution 0.05%: 
 
$97.19/60 mL
High
As for 
betamethasone
Gel useful for poison 
oak
Economical generics
Lidex cream can cause stinging 
on eczema
Lidex emollient cream 
preferred
Betamethasone 
(Diprolene)
Cream 0.05%: $41.60/15 g
 
$50.45/15 g
Lotion 0.05%: $45.00/60 mL
Ultra-high
For lesions resistant 
to high-potency 
Economical generics available
Clobetasol propio
-
nate (Temovate)
Cream 0.05%: $128.23/15 g
$155.45/15 g
 
$288.96/60 mL
As for betametha
-
sone dipropionate
Somewhat more potent than 
diflorasone
Limited to 2 continuous weeks 
of use
Limited to 50 g or less per week
Cream may cause stinging; use 
“emollient cream” 
Generic available
Halobetasol 
 
propionate 
(Ultravate)
Cream 0.05%: $79.58/15 g
 
$79.58/15 g
As for clobetasol
Same restrictions as clobetasol
Cream does not cause stinging
Compatible with calcipotriene 
(Dovonex)
(
continued
)
 
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Table 6–2.
 
a
gen
t
and 
p
ric
es
1
a
pplic
ation
p
ot
ency 
Class
Common 
Comments
Desoximetasone
Cream 0.05%: $62.43/15 g
Cream 0.25%: $58.28/15 g
Gel 0.05%: $298.38/60 g
Ointment 0.25%: 
 
$18.00/15 g
High
Comparable potency to 
fluocinonide
Suggested for use when allergic 
contact dermatitis to topical 
corticosteroid is suspected; 
ointment useful when aller
-
gic contact dermatitis to pro
-
pylene glycol is suspected
Flurandrenolide 
(Cordran)
Tape: $763.04/24” × 3” roll
 
$394.68/60 mL
Every 12 hours
chronicus
Tape version protects the skin 
and prevents scratching
Nonsteroidal 
a
n
ti-inflammatory 
a
gen
ts (Listed 
a
lphabetic
ally)
Crisaborole 
(Eucrisa)
Ointment 2%: 
 
$737.76/60 g 
N/A
Steroid substitute not causing 
atrophy or striae
May sting or burn on initial 
application
Pimecrolimus
2
 
(Elidel)
Cream 1%: $677.10/60 g
N/A
Tacrolimus
2
 
(Protopic)
Ointment 0.1%: 
 
$520.90/60 g
Ointment 0.03%: 
N/A
Burns in ≥ 40% of patients 
with eczema
a
n
tibiotics (for 
a
cne) (List
ed 
a
lphabetic
ally)
Clindamycin 
phosphate
Solution 1%: $28.94/30 mL
Gel 1%: $86.38/30 mL
Lotion 1%: $120.18/60 mL
Pledget 1%: $46.40/60
N/A
Mild papular acne
Lotion is less drying for 
patients with sensitive skin
Recommend use with benzoyl 
peroxide to avoid antibiotic 
resistance from 
monotherapy
Clindamycin/Ben
-
zoyl peroxide 
(BenzaClin)
Gel: $204.19/25 g
Gel: $408.35/50 g
N/A
As for benzamycin
No generic
More effective than either 
agent alone
Dapsone
Gel 5%: $585.50/60 g
Once daily
N/A
Mild papulopustular 
acne
More expensive, well tolerated
Erythromycin
Solution 2%: $47.63/60 mL
Gel 2%: $149.20/30 g
Pledget 2%: $94.55/60
N/A
As for clindamycin
Many different manufacturers
Economical
Erythromycin/Ben
-
(Benzamycin)
Gel: $199.08/23.3 g
Gel: $398.18/46.6 g
N/A
Can help treat come
-
donal acne
No generics
More effective than other topi
-
cal antibiotics
Main jar requires refrigeration
a
n
tibiotics (for Impetigo)
Mupirocin 
(Bactroban)
Ointment 2%: $11.25/22 g
Cream 2%: $124.93/15 g
N/A
Impetigo, folliculitis
Because of cost, use limited to 
tiny areas of impetigo
Used in the nose twice daily 
for 5 days to reduce staphy
-
lococcal carriage
 
(
continued
)
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Table 6–2.
 
a
gen
t
and 
p
ric
es
1
a
pplic
ation
p
ot
ency 
Class
Common 
Comments
Retapamulin 
(Altabax)
Ointment 1%: $328/15 g 
N/A
Impetigo
For 
Staphylococcus aureus
 or 
Streptococcus pyogenes
 
infection
Typically reserved for mupiro
-
cin resistant infections
a
n
tifungals: Imidazoles (Listed 
a
lphabetic
ally)
Clotrimazole
Cream 1%: $5.29/15 g OTC
Solution 1%: $45.13/10 mL
N/A
Dermatophyte and 
Candida
 
Available OTC
Inexpensive generic cream 
available
Econazole 
(Spectazole)
Cream 1%: $30.04/15 g
Once daily
N/A
As for clotrimazole
Somewhat more effective than 
clotrimazole and miconazole
Ketoconazole
Cream 2%: $30.90/15 g
Once daily
N/A
Miconazole
Cream 2%: $5.50/30 g OTC
N/A
Oxiconazole 
(Oxistat)
Cream 1%: $614.73/30 g
Lotion 1%: $771.91/30 mL
N/A
Sertaconazole 
(Ertaczo)
Cream 2%: $1079.41/60 g
N/A
Refractory tinea 
pedis
By prescription
Sulconazole 
(Exelderm)
Cream 1%: $72.38/15 g
Solution 1%: $412.60/30 mL
N/A
No generic
Other 
a
n
tifungals (Listed 
a
lphabetic
ally)
Butenafine 
(Mentax)
Cream 1%: $117.68/15 g
Once daily
N/A
Dermatophytes
Fast response; high cure rate; 
expensive
Ciclopirox (Loprox) 
(Penlac)
Cream 0.77%: $51.10/30 g
Lotion 0.77%: $80.68/30 g
Solution 8%: $52.95/6.6 mL
N/A
No generic
Efinaconazole 
(Jublia)
Solution 10%: $687.38/4 mL
Once daily for 
 
48 weeks
N/A
Onychomycosis
No generic; more effective than 
ciclopirox for nail disease
Naftifine (Naftin)
Cream 1%: $375.38/60 g
Gel 1%: $473.82/60 mL
Once daily
N/A
No generic
Tavaborole 
(Kerydin)
Solution 5%: $725.21/4 mL
 
48 weeks
N/A
No generic available
Terbinafine 
(Lamisil)
Cream 1%: $8.72/12 g OTC
Once daily
N/A
Fast clinical response
OTC
a
n
tipruritics (Listed 
a
lphabetic
ally)
Camphor/menthol 
(Sarna)
Lotion 0.5%/0.5%: 
$7.80/222 mL
Two to three 
times daily
N/A
Mild eczema, xerosis, 
mild contact 
Capsaicin (various)
Cream 0.025–0.1%
Cream 0.025%: $9.95/60 g
Cream 0.075%: $10.39/56 g
Three to four 
N/A
Topical antipruritic, 
best used for neu
-
ropathic itching
Burning/stinging with initial 
application that subsides 
with consistent ongoing use
Doxepin (Zonalon)
Cream 5%: $663.89/45 g
Four times daily
N/A
best used in com
-
bination with 
appropriate topical 
corticosteroid to 
enhance efficacy
Can cause sedation
(
continued
)
 
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Table 6–2.
 
a
gen
t
and 
p
ric
es
1
a
pplic
ation
p
ot
ency 
Class
Common 
Comments
Pramoxine hydro
-
chloride (Prax)
Lotion 1%: $17.86/120 mL 
OTC
N/A
Dry skin, varicella, 
mild eczema, pru
-
ritus ani
OTC formulations (Prax, Aveeno 
Anti-Itch Cream or Lotion; 
Itch-X Gel)
By prescription mixed with 1% 
or 2% hydrocortisone
e
mollients (Listed 
a
lphabetic
ally)
Aqua glycolic
Cream, lotion, shampoo, 
others: $17.94/60 g
Once to three 
N/A
Xerosis, ichthyosis, 
keratosis pilaris
Mild facial wrinkles
Mild acne or sebor
-
rheic dermatitis
Contains 8% glycolic acid
Available from other makers, 
eg, Alpha Hydrox, or generic 
8% glycolic acid lotion
May cause stinging on 
 
eczematous skin
Aquaphor
Ointment: $5.49/50 g
N/A
Xerosis, eczema
For protection of area 
in pruritus ani
Not as greasy as petrolatum
Aveeno
Cream, lotion, cleanser, 
others: $8.14/354 mL
N/A
Many formulations made
Some facial and body moistur
-
izers contain sunscreen
Ceratopic cream
Cream: $77.00/6 oz
N/A
Contains ceramide; anti-
inflammatory and 
nongreasy moisturizer
CeraVe
others: $13.29/453 g
N/A
CeraVe SA formulation contains 
salicylic acid, ammonium 
lactate as keratolytics
-
Cetaphil
$10.50/480 mL
N/A
-
Complex 15
3
Lotion: $6.48/240 mL
Cream: $4.82/75 g
N/A
Xerosis
Lotion or cream rec
-
ommended for 
split or dry nails
Active ingredient is a 
phospholipid
DML
Cream, lotion, facial mois
-
turizer: $5.95/240 mL
N/A
As for Complex 15
Face cream has sunscreen
Eucerin
Cream: $13.99/454 g
Lotion: $3.75/120 mL
N/A
Eucerin Plus contains alphahy
-
droxy acid and may cause 
stinging on eczematous skin
Facial moisturizer has SPF 25 
sunscreen
Lac-Hydrin-Five
Lotion: $13.25/226 g OTC
N/A
Most effective strength is 12%
May sting on eczematous skin
Lubriderm
Lotion: $6.13/473 mL
N/A
Unscented usually preferred
Neutrogena
-
turizer: $7.58/240 mL
N/A
Face cream has titanium-based 
sunscreen
U-Lactin
Lotion: $15.74/480 mL OTC
Once daily
N/A
Hyperkeratotic heels
Moisturizes and removes 
keratin
(
continued
)
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Table 6–2.
 
a
gen
t
and 
p
ric
es
1
a
pplic
ation
p
ot
ency 
Class
Common 
Comments
Urea (various)
Cream 20%: $10.37/85 g
Lotion 10%: $8.64/240 mL
N/A
Xerosis
Contains urea as humectant
Nongreasy hydrating agent 
(10%); debrides keratin 
(20%, 40%)
Vanicream
Lotion, cream, cleanser, 
others: $11.20/453 g
N/A
Many formulations available
Branded as hypoallergenic
1
Average wholesale price (AWP , for AB-rated generic when available) for quantity listed. AWP may not accurately represent the actual 
pharmacy cost because wide contractual variations exist among institutions. Source: 
Red Book Online
, (electronic version), Truven 
Health Analytics Information, http://www.micromedexsolutions.com, accessed March 1, 2018.
2
Topical tacrolimus and pimecrolimus should be used only when other topical treatments are ineffective. Treatment should be limited to 
an area and duration to be as brief as possible. Treatment with these agents should be avoided in persons with known immunosuppression, 
HIV infection, bone marrow and organ transplantation, lymphoma, at high risk for lymphoma, and those with a prior history of lymphoma.
3
Discontinued in the United States; available in Canada.
N/A, not applicable; OTC, over-the-counter.
patients only by their sedating effects. Hydroxyzine 25–50 mg 
nightly is a typical dose. Sedating and nonsedating antihis
-
tamines are of limited value for the treatment of pruritus 
associated with inflammatory skin disease. Agents that 
may treat pruritus better include antidepressants (such as 
doxepin, mirtazapine, and paroxetine) as well as agents 
that may act either centrally or peripherally directly on the 
neurons that perceive or modulate pruritus (such as gaba
-
pentin, pregabalin, and duloxetine). Aprepitant and opioid 
antagonists, such as naltrexone and butorphenol, can be 
very effective in select patients, but their exact role in the 
management of the pruritic patient is not yet defined.
2. Systemic corticosteroids—
(See Chapter 26.)
American Academy of Dermatology. Medical student core cur
-
riculum. http://www.aad.org/education-and-quality-care/
medical-student-core-curriculum
Jewell JR et al. Topical therapy primer for nondermatologists. 
Med Clin North Am. 2015 Nov;99(6):1167–82. [PMID: 
26476246]
van Zuuren EJ et al. Emollients and moisturisers for eczema: 
abridged Cochrane systematic review including GRADE 
assessments. Br J Dermatol. 2017 Nov;177(5):1256–71. 
[PMID: 28432721]
van Zuuren EJ et al. No high level evidence to support the use of 
oral H
1
 antihistamines as monotherapy for eczema: a sum
-
mary of a Cochrane systematic review. Cochrane Database 
Syst Rev. 2014 Mar 13;3:25. [PMID: 24625301]
Y osipovitch G et al. Clinical practice. Chronic pruritus. N Engl J 
Med. 2013 Apr 25;368(17):1625–34. [PMID: 23614588]
 
»
Sunscreens
Protection from ultraviolet light should begin at birth 
and will reduce the incidence of actinic keratoses, mela
-
noma, and some nonmelanoma skin cancers when initi
-
ated at any age and in any skin type
. The best protection 
is shade, but protective clothing, avoidance of direct sun 
exposure during the peak hours of the day, and daily use of 
sunscreens are important.
Fair-complexioned persons should use a sunscreen with 
a 
sun protective factor (SPF) of at least 30
 every day. Cli
-
nicians should reinforce regular sunscreen use. Sunscreens 
with SPF values greater than 30 usually afford some protec
-
tion against UV A as well as UVB and are helpful in manag
-
ing photosensitivity disorders. The actual SPF achieved is 
about one-quarter or less than that listed on the product 
due to insufficient application compared with the amount 
used in tests to determine the listed SPF. Repeated daily 
applications enhance sunscreen efficacy. Aggressive sun
-

-
screen use should be accompanied by vitamin D supple
-
mentation in persons at risk for osteopenia.
Agbai ON et al. Skin cancer and photoprotection in people of 
color: a review and recommendations for physicians and the 
public. J Am Acad Dermatol. 2014 Apr;70(4):748–62. [PMID: 
24485530]
Akamine KL et al. Trends in sunscreen recommendation among 
US physicians. JAMA Dermatol. 2014 Jan;150(1):51–5. 
[PMID: 24005847]
Mancuso JB et al. Sunscreens: an update. Am J Clin Dermatol. 
2017 Oct;18(5):643–50. [PMID: 28510141]
 
»
Complications of Topical Dermatologic 
Therapy
Complications of topical therapy can be largely avoided. 
They fall into several categories: allergy, irritation, and 
other side effects.
A. Allergy
Of the topical antibiotics, neomycin and bacitracin have 
the greatest potential for sensitization. Diphenhydramine, 
benzocaine, vitamin E, aromatic oils, preservatives, fra
-
grances, tea tree oil, and even the topical corticosteroids 
themselves can cause allergic contact dermatitis.
B. Irritation
Preparations of tretinoin, benzoyl peroxide, and other acne 
medications should be applied sparingly to the skin.
 
CMDT19_Ch06_p0103-p0173.indd   109

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110
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▲
Figure 6–2.
 
Atypical (dysplastic) nevus on the 
chest. Note irregular border and variegation in color. 
(Used, with permission, from Richard P . Usatine, MD in 
Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H. 
The 
Color Atlas of Family Medicine,
 2nd ed. McGraw-Hill, 2013.)
 
▲
Figure 6–1.
 
Benign, compound nevus on the back. 
The Color 
Atlas of Family Medicine,
C. Other Side Effects
Topical corticosteroids may induce acne-like lesions on the 
face (steroid rosacea) and atrophic striae in body folds.
 
º
COMMON D
er
M
a
t
OS
e
S
p
IGM
e
N
te
D L
e
SIONS
MELANOCYTIC NEVI (
Normal Moles
)
In general, a benign mole is a small (less than 6 mm) mac
-
ule or papule with a well-defined border and homogeneous 
beige or pink to dark brown pigment. They represent 
benign melanocytic growths.
Moles have a typical natural history. Early in life, moles 
often appear as flat, small, brown lesions and are termed 
“junctional nevi” because the nevus cells are at the junction 
of the epidermis and dermis. Over time, these moles 
enlarge and often become raised, reflecting the appearance 
of a dermal component, giving rise to “compound nevi” 
(Figure 6–1). Moles may darken and grow during preg
-
nancy. As white patients enter their eighth decade, most 
moles have lost their junctional component and dark pig
-
mentation. At every stage of life, normal moles should be 
well demarcated, symmetric, and uniform in contour and 
color. Regular mole screening is not an evidence-based 
recommendation for all adults although rates of screening 
continue to rise.
Linos E et al. Skin cancer—the importance of prevention. JAMA 
Intern Med. 2016 Oct 1;176(10):1435–6. [PMID: 27459394]
Livingston EH. JAMA patient page. Screening for skin cancer. 
JAMA. 2016 Jul 26;316(4):470. [PMID: 27458970]
Mayer JE et al. Screening, early detection, education, and trends 
for melanoma: current status (2007–2013) and future direc
-
tions: part I. Epidemiology, high-risk groups, clinical strategies, 
and diagnostic technology. J Am Acad Dermatol. 2014 Oct;
 
71(4):599.e1–12. [PMID: 25219716]
-
tions: part II. Screening, education, and future directions. J Am 
Acad Dermatol. 2014 Oct;71(4):611.e1–10. [PMID: 25219717]
Watts CG et al. Clinical practice guidelines for identification, 
screening and follow-up of individuals at high risk of primary 
cutaneous melanoma: a systematic review. Br J Dermatol. 
2015 Jan;172(1):33–47. [PMID: 25204572]
ATYPICAL NEVI
The term “atypical nevus” or “atypical mole” has sup
-
planted “dysplastic nevus. ” The diagnosis of atypical moles 
is made clinically and not histologically, and moles should 
be removed only if they are suspected to be melanomas. 
Dermoscopy by a trained clinician may be a useful tool in 
the evaluation of atypical nevi. Clinically, these moles are 
large (6 mm or more in diameter), with an ill-defined, 
irregular border and irregularly distributed pigmentation 
(Figure 6–2). It is estimated that 5–10% of the white popu
-
lation in the United States has one or more atypical nevi, 
and recreational sun exposure is a primary risk for the 
development of atypical nevi in nonfamilial settings. Stud
-
ies have defined an increased risk of melanoma in the fol
-
lowing populations: patients with 50 or more nevi with one 
or more atypical moles and one mole at least 8 mm or 
larger, and patients with any number of definitely atypical 
moles. These patients should be educated in how to recog
-
nize changes in moles and be monitored regularly (every 
6–12 months) by a clinician. Kindreds with familial mela
-
noma (numerous atypical nevi and a family history of two 
first-degree relatives with melanoma) deserve even closer

-
first-degree relatives with melanoma) deserve even closer 
attention, as the risk of developing single or even multiple 
melanomas in these individuals approaches 50% by age 50.
Kim CC et al. Addressing the knowledge gap in clinical recom
-
mendations for management and complete excision of clini
-
cally atypical nevi/dysplastic nevi: Pigmented Lesion 
Subcommittee consensus statement. JAMA Dermatol. 2015 
Feb 1;151(2):212–8. [PMID: 25409291]
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▲
Figure 6–3.
 
Blue nevus on the left cheek, a darkly-
pigmented blue-black macule with some resemblance 
to a melanoma due to its dark pigmentation. 
(Used, with 
permission, from Richard P . Usatine, MD in Usatine RP , 
Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. 
 
The Color Atlas of Family Medicine
. McGraw-Hill, 2009.)
Truong A et al. Reduction in nevus biopsies in patients monitored 
by total body photography. J Am Acad Dermatol. 2016 Jul;
 
75(1):135–43. [PMID: 26947450]
Winkelmann RR et al. Management of dysplastic nevi: a 14-year 
follow-up survey assessing practice trends among US derma
-
tologists. J Am Acad Dermatol. 2015 Dec;73(6):1056–9. 
[PMID: 26568339]
BLUE NEVI
Blue nevi are small, slightly elevated, blue-black lesions 
(Figure 6–3) that favor the dorsal hands. They are common 
in persons of Asian descent, and an individual patient may 
have several of them. If the lesion has remained unchanged 
for years, it may be considered benign, since malignant 
blue nevi are rare. However, blue-black papules and nod
-
ules that are new or growing must be evaluated to rule out 
nodular melanoma.
Cabral ES et al. Acquired blue nevi in older individuals: retro
-
spective case series from a Veterans Affairs population, 1991 
to 2013. JAMA Dermatol. 2014 Aug;150(8):873–6. [PMID: 
24788980]
Zembowicz A. Blue nevi and related tumors. Clin Lab Med. 
2017 Sep;37(3):401–15. [PMID: 28802492]
FRECKLES & LENTIGINES
Freckles (ephelides) and lentigines are flat brown macules, 
typically between 3 mm and 5 mm in diameter. Freckles 
first appear in young children, darken with ultraviolet 
exposure, and fade with cessation of sun exposure. They are 
determined by genetic factors. In adults, lentigines gradu
-
ally appear in sun-exposed areas, particularly the face, 
dorsal hands, upper back, and upper chest, starting in the 
fourth to fifth decade of life, and are associated with photo
-
aging as well as estrogen and progesterone use. On the 
upper back, they may have a very irregular border (inkspot 
lentigines). They do not fade with cessation of sun expo
-
sure. They should be evaluated like all pigmented lesions: if 
the pigmentation is homogeneous and they are symmetric 
and flat, they are most likely benign. They can be treated 
with topical retinoids such as 0.1% tretinoin or 0.1% tazaro
-
tene, hydroquinone, laser/light therapy, or cryotherapy.
Hexsel D et al. Triple combination as adjuvant to cryotherapy in 
the treatment of solar lentigines: investigator-blinded, ran
-
domized clinical trial. J Eur Acad Dermatol Venereol. 
 
2015 Jan;29(1):128–33. [PMID: 24684165]
Praetorius C et al. Sun-induced freckling: ephelides and solar 
lentigines. Pigment Cell Melanoma Res. 2014 May;27(3):
 
339–50. [PMID: 24517859]
SEBORRHEIC KERATOSES
Seborrheic keratoses are benign papules and plaques, beige 
to brown or even black, 3–20 mm in diameter, with a vel
-
vety or warty surface (Figure 6–4). They appear to be stuck 
or pasted onto the skin. They are extremely common—
especially in older adults—and may be mistaken for mela
-
nomas or other types of cutaneous neoplasms. Although 
they may be frozen with liquid nitrogen or curetted if they 
itch or are inflamed, no treatment is needed.
Jackson JM et al. Current understanding of seborrheic keratosis: 
prevalence, etiology, clinical presentation, diagnosis, and 
management. J Drugs Dermatol. 2015 Oct;14(10):1119–25. 
[PMID: 26461823]
MALIGNANT MELANOMA
 
»
May be flat or raised.
 
»
Should be suspected in any pigmented skin lesion 
with recent change in appearance.
 
»
Examination with good light may show varying 
colors, including red, white, black, and blue.
 
»
Borders typically irregular.
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▲
Figure 6–4.
 
Seborrheic keratosis with light pig
-
mentation, with waxy, dry, “stuck-on appearance. ” 
(Used, 
with permission, from Richard P . Usatine, MD in Usatine RP , 
Smith MA, Mayeaux EJ Jr, Chumley H. 
The Color Atlas of 
Family Medicine
, 2nd ed. McGraw-Hill, 2013.)
 
»
Malignant melanoma is the leading cause of death due to 
skin disease. The reported incidence of melanoma has 
doubled over the past 30 years. In 2016, approximately 
76,380 new melanomas were diagnosed in the United 
States, with 46,870 cases in men and 29,510 in women. 
Each year melanoma causes an estimated 10,130 deaths 
(two-thirds in men). One in four cases of melanoma occurs 
before the age of 40. Increased detection of early melano
-
mas has led to increased survival, but melanoma fatalities 
continue to increase, especially in men older than 70 years. 
The lifetime risk of melanoma is 2% in whites, and 0.1–0.5% 
in nonwhites.
Tumor thickness is the single most important prognos
-
tic factor. Ten-year survival rates—related to thickness in 
millimeters—are as follows: less than 1 mm, 95%; 1–2 mm, 
80%; 2–4 mm, 55%; and greater than 4 mm, 30%. With 
lymph node involvement, the 5-year survival rate is 62%; 
with distant metastases, it is 16%.
 
»
Primary malignant melanomas may be classified into vari
-
ous clinicohistologic types, including 
lentigo maligna 
melanoma
 (arising on chronically sun-exposed skin of 
older individuals); 
superficial spreading malignant 
melanoma
 (two-thirds of all melanomas arising on 
intermittently sun-exposed skin); 
nodular malignant 
melanoma;
 
acral-lentiginous melanomas
 (arising on 
palms, soles, and nail beds); 
ocular melanoma;
 and 
malignant melanomas on mucous membranes.
 These 
different clinical types of melanoma appear to have 
different oncogenic mutations, which may be important in 
the treatment of patients with advanced disease. Clinical 
features of pigmented lesions suspicious for melanoma are 
an irregular, notched border where the pigment appears to 
be spreading into the normal surrounding skin; surface 
topography that may be irregular, ie, partly raised and 
partly flat (Figure 6–5). Color variegation is present and is 
an important indication for referral. A useful mnemonic is 
the ABCDE rule: “ ABCDE = Asymmetry, Border irregular
-
ity, Color variegation, Diameter greater than 6 mm, and 
Evolution. ” 
The history of a changing mole (evolution) is 
the single most important historical reason for close 
evaluation and possible referral.
 Bleeding and ulceration 
are ominous signs. A mole that appears distinct from the 
patient’s other moles deserves special scrutiny—the “ugly 
duckling sign. ” A patient with a large number of moles is 
statistically at increased risk for melanoma and deserves 
annual total body skin examination by a primary care clini
-
cian or dermatologist, particularly if the lesions are atypi
-
cal. Referral of suspicious pigmented lesions is always 
While superficial spreading melanoma is largely a dis
-
ease of whites, persons of other races are at risk for this and 
other types of melanoma, particularly acral lentiginous 
melanomas. These occur as dark, irregularly shaped lesions 
on the palms and soles and as new, often broad and soli
-
tary, darkly pigmented, longitudinal streaks in the nails, 
typically with involvement of the proximal nail fold. Acral 
lentiginous melanoma may be a difficult or delayed diag
-
nosis because benign pigmented lesions of the hands, feet, 
and nails occur commonly in more darkly pigmented 
persons, and clinicians may hesitate to biopsy these sites. 
Clinicians should give special attention to new or changing 
lesions in these areas.
 
▲
Figure 6–5.
 
Malignant melanoma. Note the classic 
“ABCD” features: lack of symmetry, irregular border, mul
-
tiple colors and diameter greater than 6 mm. 
(Used, with

▲
 
-
Family Medicine,
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»
Treatment
Treatment of melanoma starts with excision. After histo
-
logic diagnosis, reexcision is recommended with margins 
dictated by the thickness of the tumor. Surgical margins of 
0.5–1 cm for melanoma in situ and 1 cm for lesions less 
than 1 mm in thickness are recommended.
Sentinel lymph node biopsy (selective lymphadenec
-
tomy) using preoperative lymphoscintigraphy and intraop
-
erative lymphatic mapping is effective for staging melanoma 
patients with intermediate risk without clinical adenopathy 
and is recommended for all patients with lesions over 1 mm 
in thickness or with high-risk histologic features (ulcer
-
ation, high mitotic index). This procedure may not confer 
a survival advantage. Referral of intermediate-risk and 
high-risk patients to centers with expertise in melanoma is 
strongly recommended. Identifying the oncogenic muta
-
tions in patients with advanced melanoma may dictate 
targeted therapy, most commonly to specific BRAF muta
-
tions. Additionally, immunotherapy treatments directed 
toward immune costimulatory molecules such as PD-1 can 
activate systemic immune-directed destruction of meta
-
static melanoma.
Faries MB et al. Completion dissection or observation for sentinel-
node metastasis in melanoma. N Engl J Med. 2017 Jun 8;
 
376(23):2211–22. [PMID: 28591523]
Luke JJ et al. Targeted agents and immunotherapies: optimizing 
outcomes in melanoma. Nat Rev Clin Oncol. 2017 Aug;
 
14(8):463–82. [PMID: 28374786]
SC
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ATOPIC DERMATITIS
 
»
Pruritic, xerotic, exudative, or lichenified eruption 
on face, neck, upper trunk, wrists, and hands and 
in the antecubital and popliteal folds.
 
»
Personal or family history of allergic manifestations 
(eg, asthma, allergic rhinitis, atopic dermatitis).
 
»
Tendency to recur.
 
»
Onset in childhood in most patients. Onset after 
age 30 is very uncommon.
 
»
Atopic dermatitis (also known as eczema) has distinct pre
-
sentations in people of different ages and races. Diagnostic 
criteria for atopic dermatitis must include pruritus, typical 
morphology and distribution (flexural lichenification, 
hand eczema, nipple eczema, and eyelid eczema in adults), 
onset in childhood, and chronicity. Also helpful are (1) a 
personal or family history of atopy (asthma, allergic rhini
-
tis, atopic dermatitis), (2) xerosis-ichthyosis, (3) facial pal
-
lor with infraorbital darkening, (4) elevated serum IgE, and 
(5) repeated skin infections.
 
»
Itching is a key clinical feature and may be severe and pro
-
longed. Ill-defined, scaly, red plaques affect the face, neck, 
and upper trunk. The flexural surfaces of elbows and knees 
are often involved. In chronic cases, the skin is dry and 
lichenified. In dark-skinned patients with severe disease, 
pigmentation may be lost in lichenified areas. During acute 
flares, widespread redness with weeping, either diffusely or 
in discrete plaques, is common. Since virtually all patients 
with atopic dermatitis have skin disease before age 5, a new 
diagnosis of atopic dermatitis in an adult over age 30 should 
be made only after consultation with a dermatologist.
B. Laboratory Findings
Food allergy is an uncommon cause of flares of atopic der
-
matitis in adults. Eosinophilia and increased serum IgE 
levels may be present.
 
»
Atopic dermatitis must be distinguished from seborrheic 
dermatitis (less pruritic, frequent scalp and central face 
involvement, greasy and scaly lesions, and quick response 
to therapy). Psoriasis is marked by sharply demarcated 
thickly scaled plaques on elbows, knees, scalp, and inter
-
gluteal cleft. Secondary staphylococcal or herpetic infec
-
tions may exacerbate atopic dermatitis and should be 
considered during hyperacute, weeping flares of atopic 
dermatitis. An infra-auricular fissure is a cardinal sign of

-
dermatitis. An infra-auricular fissure is a cardinal sign of 
secondary infection.
 
»
Treatment
Patient education regarding gentle skin care and exactly 
how to use medications is critical to successful manage
-
ment of atopic dermatitis.
A. General Measures
Atopic patients have hyperirritable skin. Anything that 
dries or irritates the skin will potentially trigger dermatitis. 
Atopic individuals are sensitive to low humidity and often 
flare in the winter. Adults with atopic disorders should not 
bathe more than once daily. Soap should be confined to the 
armpits, groin, scalp, and feet. Washcloths and brushes 
should not be used. After rinsing, the skin should be patted 
dry (not rubbed) and then immediately—within minutes—
covered with a thin film of an emollient or a corticosteroid 
as needed. Vanicream can be used if contact dermatitis 
resulting from additives in medication is suspected. Atopic 
patients may be irritated by rough fabrics, including wools 
and acrylics. Cottons are preferable, but synthetic blends 
also are tolerated. Other triggers of atopic dermatitis in 
some patients include sweating, ointments, and heat.
B. Local Treatment
Corticosteroids should be applied sparingly to the derma
-
titis once or twice daily and rubbed in well. Their potency 
should be appropriate to the severity of the dermatitis. In 
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general, for treatment of lesions on the body (excluding 
genitalia, axillary or crural folds), one should begin with 
triamcinolone 0.1% or a stronger corticosteroid then taper 
to hydrocortisone or another slightly stronger mild corti
-
costeroid (alclometasone, desonide). 
It is vital that 
patients taper off corticosteroids and substitute emol
-
lients as the dermatitis clears to avoid side effects of cor
-
ticosteroids
. Tapering is also important to avoid rebound 
flares of the dermatitis that may follow their abrupt cessa
-
tion. Tacrolimus ointment (Protopic 0.03% or 0.1%) and 
pimecrolimus cream (Elidel 1%) can be effective in manag
-
ing atopic dermatitis when applied twice daily. Burning on 
application occurs in about 50% of patients using Protopic 
and in 10–25% of Elidel users, but it may resolve with con
-
tinued treatment. These noncorticosteroid medications do 
not cause skin atrophy or striae, avoiding the complications 
of long-term topical corticosteroid use. They are safe for 
application on the face and even the eyelids but are more 
expensive than generic topical corticosteroids.
The US Food and Drug Administration (FDA) has 
issued a black box warning for both topical tacrolimus and 
pimecrolimus due to concerns about the development of 
T-cell lymphoma. The agents should be used sparingly and 
only in locations where less expensive corticosteroids can
-
not be used. They should be avoided in patients at high risk 
for lymphoma (ie, those with HIV , iatrogenic immunosup
-
pression, or prior lymphoma).
The treatment of atopic dermatitis is dictated by the 
pattern and stage of the dermatitis—acute/weepy, sub
-
acute/scaly, or chronic/lichenified.
1. Acute weeping lesions—
Staphylococcal or herpetic 
superinfection should be formally excluded. Use water or 
aluminum subacetate solution (Domeboro tablets, one in a 
pint of cool water), or colloidal oatmeal (Aveeno; dispense 
one box, and use as directed on box) as a bath or as wet 
dressings for 10–30 minutes two to four times daily. Lesions 
on extremities may be bandaged for protection at night. Use 
high-potency corticosteroids after soaking, but spare the 
face and body folds. Tacrolimus is usually not tolerated at 
this stage. Systemic corticosteroids may be required.
2. Subacute or scaly lesions—
At this stage, the lesions are 
dry but still red and pruritic. Mid- to high-potency corti
-
costeroids in ointment form should be continued until skin 
lesions are cleared and itching is decreased substantially. At 
that point, patients should begin a 2- to 4-week taper from 
twice-daily to daily dosing with topical corticosteroids to 
reliance on emollients, with occasional use of corticoste
-
roids only to inflamed areas. It is preferable to switch to 
daily use of a low-potency corticosteroid instead of further 
tapering the frequency of usage of a more potent cortico
-
steroid. Tacrolimus and pimecrolimus may be substituted if 
corticosteroids cannot be stopped completely.
3. Chronic, dry, lichenified lesions—
Thickened and usu
-
ally well demarcated, they are best treated with high-
potency to ultra–high-potency corticosteroid ointments. 
Nightly occlusion for 2–6 weeks may enhance the initial 
response. Adding tar preparations, such as liquor carbonis 
detergens (LCD) 10% in Aquaphor or 2% crude coal tar 
may be beneficial.
4. Maintenance treatment—
Once symptoms have 
improved, constant application of effective moisturizers is 
recommended to prevent flares. In patients with moderate 
disease, use of topical anti-inflammatories only on week
-
ends or three times weekly can prevent flares.
C. Systemic and Adjuvant Therapy
Systemic corticosteroids are indicated only for severe acute 
exacerbations. Oral prednisone dosages should be high 
enough to suppress the dermatitis quickly, usually starting 
with 1 mg/kg daily. The dosage is then tapered off over a 
period of 2–4 weeks. Owing to the chronic nature of atopic

period of 2–4 weeks. Owing to the chronic nature of atopic 
dermatitis and the side effects of long-term systemic corti
-
costeroids, 
ongoing use of these agents is not recom
-
mended for maintenance therapy.
 Bedtime doses of 
hydroxyzine, diphenhydramine, or doxepin may be helpful 
via their sedative properties to mitigate perceived pruritus. 
Fissures, crusts, erosions, or pustules indicate staphylococ
-
cal or herpetic infection clinically. Systemic antistaphylo
-
coccal antibiotics—such as a first-generation cephalosporin 
or doxycycline if methicillin-resistant 
Staphylococcus 
aureus
 is suspected—should be given only if indicated and 
guided by bacterial culture. Cultures to exclude methicil
-
lin-resistant 
S aureus
 are recommended. In this setting, 
continuing and augmenting the topical anti-inflammatory 
treatment often improves the dermatitis despite the pres
-
ence of infection. Dupilumab is a targeted immunomodu
-
lator with minimal systemic adverse effects and requires 
minimal laboratory monitoring. Oral cyclosporine, myco
-
phenolate mofetil, methotrexate, interferon gamma, tofaci
-
tinib, or azathioprine may also be used for the most severe 
and recalcitrant cases.
 
»
Complications of Treatment
The clinician should monitor for skin atrophy. Eczema 
herpeticum, a generalized herpes simplex infection mani
-
fested by monomorphic vesicles, crusts, or scalloped ero
-
sions superimposed on atopic dermatitis or other extensive 
eczematous processes, is treated successfully with oral 
acyclovir, 200 mg five times daily, or intravenous acyclovir 
in a dose of 10 mg/kg intravenously every 8 hours (500 mg/m
2
 
every 8 hours).
 
»
Prognosis
Atopic dermatitis runs a chronic or intermittent course. 
Affected adults may have only hand dermatitis. Poor prog
-
nostic factors for persistence into adulthood in atopic der
-
matitis include generalized disease or onset early in 
childhood and asthma. Only 40–60% of these patients have 
lasting remissions.
Simpson EL et al; SOLO 1 and SOLO 2 Investigators. Two phase 
3 trials of dupilumab versus placebo in atopic dermatitis. N 
Engl J Med. 2016 Dec 15;375(24):2335–48. [PMID: 27690741]
Stein SL et al. Management of atopic dermatitis. JAMA. 2016 
Apr 12;315(14):1510–1. [PMID: 27115267]
Weidinger S et al. Atopic dermatitis. Lancet. 2016 Mar 12;
 
387(10023):1109–22. [PMID: 26377142]
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PSORIASIS
 
»
Silvery scales on bright red, well-demarcated 
plaques, usually on the knees, elbows, and scalp.
 
»
Nails: pitting and onycholysis (separation of the 
nail plate from the bed).
 
»
Mild itching is common.
 
»
May be associated with psoriatic arthritis.
 
»
Increased risk of cardiovascular events, type 2 
diabetes mellitus, metabolic syndrome, and 
lymphoma.
 
»
Histopathology helpful.
 
»
Psoriasis is a common benign, chronic inflammatory skin 
disease with both a genetic basis and known environmental 
triggers. Injury or irritation of normal skin tends to induce 
lesions of psoriasis at the site (Koebner phenomenon). 
Obesity worsens psoriasis, and significant weight loss in 
obese persons may lead to substantial improvement of 
their psoriasis. Psoriasis has several variants—the most 
common is the plaque type. Eruptive (guttate) psoriasis 
consisting of myriad lesions 3–10 mm in diameter occurs 
occasionally after streptococcal pharyngitis. Rarely, grave, 
occasionally life-threatening forms (generalized pustular 
and erythrodermic psoriasis) may occur.
 
»
There are often no symptoms, but itching may occur and 
be severe. Favored sites include the scalp, elbows, knees, 
palms and soles, and nails. The lesions are red, sharply 
defined plaques covered with silvery scale (Figure 6–6). 
The glans penis and vulva may be affected. The combina
-
tion of red plaques with silvery scales on elbows and 
knees, with scaliness in the scalp or nail findings, is diag
-
nostic. Occasionally, only the flexures (axillae, inguinal 
areas) are involved (termed inverse psoriasis). Fine stip
-
pling (“pitting”) in the nails is highly suggestive of psoria
-
sis (Figure 6–7). Patients with psoriasis often have a pink 
or red intergluteal fold (Figure 6–6). Not all patients have 
findings in all locations, but the occurrence of a few may 
help make the diagnosis when other lesions are not typi
-
cal. Some patients have mainly hand or foot dermatitis 
and only minimal findings elsewhere. There may be asso
-
ciated arthritis that is most commonly distal and oligoar
-
ticular, although the rheumatoid variety with a negative 
rheumatoid factor may occur. The psychosocial impact of 
psoriasis is a major factor in determining the treatment of 
the patient.
 
»
Psoriasis lesions are well demarcated and affect extensor 
surfaces—in contrast to atopic dermatitis, with poorly 
demarcated plaques in flexural distribution. In body folds, 
scraping and culture for 
Candida
 and examination of scalp 
and nails will distinguish inverse psoriasis from intertrigo 
and candidiasis. Dystrophic changes in nails may mimic 
onychomycosis, and a potassium hydroxide (KOH) 
 
▲
Figure 6–6.
 
Plaque psoriasis in the sacral region and 
intergluteal fold. 
(Used, with permission, from Richard P . 
Usatine, MD in Usatine RP , Smith MA, Mayeaux EJ Jr, 
Chumley H, Tysinger J. 
. 
McGraw-Hill, 2009.)
 
▲
Figure 6–7.
 
Nail pitting due to psoriasis. 
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preparation or fungal culture is valuable in diagnosis. 
The cutaneous features of reactive arthritis, pityriasis 
rosea, systemic lupus erythematosus, and syphilis mimic 
psoriasis.
 
»
Treatment
There are many therapeutic options in psoriasis to be cho
-
sen according to the extent (body surface area [BSA] 
affected) and the presence of other findings (for example, 
arthritis). 
Systemic corticosteroids should never be used 
to treat flares of psoriasis
. Even tiny doses of systemic 
corticosteroids given to patients with psoriasis may lead to 
severe rebound flares of their disease when they are 
tapered. Certain other medications, such as beta-blockers, 
antimalarials, statins, and lithium, may flare or worsen 
psoriasis. Patients with moderate to severe psoriasis should 
be managed by or in conjunction with a dermatologist.
A. Limited Disease
High- to ultra–high-potency 
topical corticosteroids
 are 
the mainstay for limited disease (less than 10% BSA). For 
patients with numerous small plaques, phototherapy is the 
best therapy. For patients with large plaques and less than 
10% of the BSA involved, the easiest regimen is to use a 
high-potency to ultra–high-potency topical corticosteroid 
cream or ointment. It is best to restrict the ultra–high-
potency corticosteroids to 2–3 weeks of twice-daily use and 
then use them in a pulse fashion three or four times on 
weekends or switch to a mid-potency corticosteroid. Topi
-
cal corticosteroids rarely induce a lasting remission. Addi
-
tional measures are therefore commonly added to topical 
corticosteroid therapy. Calcipotriene ointment 0.005% or 
calcitriol ointment 0.003%, both 
vitamin D analogs
, are 
used twice daily for plaque psoriasis. Initially, patients are 
treated with twice-daily topical corticosteroids plus a 
vitamin D analog twice daily. This rapidly clears the 
lesions; eventually, the topical corticosteroids are stopped, 
and once- or twice-daily application of the vitamin D ana
-
log is continued long-term. Calcipotriene usually cannot 
be applied to the groin or face because of irritation. Treat
-
ment of extensive psoriasis with vitamin D analogs may 
result in hypercalcemia, so that the maximum dose for 
calcipotriene is 100 g/week and for calcitriol it is 200 g/week. 
Calcipotriene is incompatible with many topical cortico
-
steroids (but not halobetasol), so if used concurrently, it 
must be applied at a different time.
For thick plaques on the scalp, start with a tar shampoo, 
used daily if possible. Additional treatments include 6% 
salicylic acid gel (eg, Keralyt), P & S solution (phenol, min
-
eral oil, and glycerin), or fluocinolone acetonide 0.01% in 
oil (Derma-Smoothe/FS) under a shower cap at night, and 
shampoo in the morning. In order of increasing potency, 
triamcinolone 0.1%, fluocinolone, betamethasone dipro
-
pionate, amcinonide, and clobetasol are available in solu
-
tion form for use on the scalp twice daily. Tacrolimus 
ointment 0.1% or 0.03% or pimecrolimus cream 1% may be 
effective in intertriginous, genital, and facial psoriasis, 
since potent corticosteroids cannot be used.
B. Moderate Disease
Psoriasis affecting 10–30% of the patient’s BSA is fre
-
quently treated with UV phototherapy, either in a medical 
office or via a home light unit. Systemic agents listed below 
may also be used.
C. Generalized Disease
If psoriasis involves more than 30% of the body surface, it 
is difficult to treat with topical agents. The treatment of 
choice is outpatient narrowband UVB (NB-UVB) three 
times weekly. Clearing occurs in an average of 7 weeks, and 
maintenance may be required.
Psoralen plus UV A (PUV A) photochemotherapy may 
be effective even in patients who have not responded to 
standard NB-UVB treatment. Long-term use of PUV A 
(greater than 250 doses) is associated with an increased 
risk of skin cancer (especially squamous cell carcinoma 
and perhaps melanoma) in persons with fair complexions.

and perhaps melanoma) in persons with fair complexions. 
Thus, periodic examination (every 3–6 months) of the skin 
is imperative. Atypical lentigines are a common complica
-
tion. There can be rapid aging of the skin in fair individu
-
als. Cataracts have not been reported with proper use of 
protective glasses. PUV A may be used in combination with 
other therapy, such as acitretin or methotrexate.
Methotrexate is very effective for severe psoriasis in 
doses up to 25 mg once weekly according to published 
protocols. Long-term methotrexate use may be associated 
with cirrhosis. After receiving a 3.5–4-g cumulative dose, 
the patient should be referred to a hepatologist for evalua
-
tion. Administration of folic acid, 1–2 mg daily, can elimi
-
nate nausea caused by methotrexate without compromising 
efficacy.
Acitretin, a synthetic retinoid, is most effective for pus
-
tular psoriasis in oral dosages of 0.5–0.75 mg/kg/day. Liver 
enzymes and serum lipids must be checked periodically. 
Because acitretin is a teratogen and persists for 2–3 years in 
fat, women of childbearing age must wait at least 3 years 
after completing acitretin treatment before considering 
pregnancy. When used as single agents, retinoids will flat
-
ten psoriatic plaques, but will rarely result in complete 
clearing. Retinoids find their greatest use when combined 
with phototherapy—either UVB or PUV A, with which they 
are synergistic.
Cyclosporine dramatically improves psoriasis and may 
be used to control severe cases. Rapid relapse (rebound) is 
the rule after cessation of therapy, so another agent must be 
added if cyclosporine is stopped. The tumor necrosis factor 
(TNF) inhibitors etanercept (Enbrel), infliximab (Remicade), 
and adalimumab (Humira) are effective in pustular and 
chronic plaque psoriasis and are also effective for the asso
-
ciated arthritis. Infliximab provides the most rapid 
response and can be used for severe pustular or erythro
-
dermic flares. Etanercept is used more frequently for long-
term treatment at a dose of 50 mg subcutaneously twice 
weekly for 3 months, then 50 mg once weekly. All three 
TNF inhibitors can also induce or worsen psoriasis. 
IL-12/23 monoclonal antibodies (ustekinumab [Stelara], 
guselkumab), Janus kinase inhibitors (tofacitinib, approved 
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▲
Figure 6–8.
 
Pityriasis rosea with scaling lesions fol
-
lowing skin lines and resembling a Christmas tree. 
(From 
EJ Mayeaux, MD; used, with permission, from Usatine RP , 
The Color 
Atlas of Family Medicine
for use in rheumatoid arthritis but with strong data sup
-
porting its use in psoriasis), and IL-17 monoclonal anti
-
bodies (secukinumab, brodalumab, and ixekizumab) are 
also highly effective treatments. The oral phosphodiester
-
ase 4 inhibitor apremilast is an approved option for plaque-
type psoriasis with minimal immunosuppressive effects 
and requires no laboratory monitoring. Given the large 
number of psoriasis treatments available, consultation with 
a dermatologist is recommended when considering sys
-
temic treatment for moderate to severe psoriasis.
 
»
Prognosis
The course tends to be chronic and unpredictable, and the 
disease may be refractory to treatment. Patients (especially 
those older than 40 years) should be monitored for meta
-
bolic syndrome, which correlates with the severity of their 
skin disease.
Armstrong AW et al. Combining biologic therapies with other 
systemic treatments in psoriasis: evidence-based, best-practice 
recommendations from the Medical Board of the National 
Psoriasis Foundation. JAMA Dermatol. 2015 Apr;151(4):
 
432–8. [PMID: 25517130]
Boehncke WH et al. Psoriasis. Lancet. 2015 Sep 5;386(9997):
 
983–94. [PMID: 26025581]
Nast A et al. Efficacy and safety of systemic long-term treat
-
ments for moderate-to-severe psoriasis: a systematic review 
and meta-analysis. J Invest Dermatol. 2015 Nov;135(11):
 
2641–8. [PMID: 26046458]
PITYRIASIS ROSEA
 
»
Oval, fawn-colored, scaly eruption following cleav
-
age lines of trunk.
 
»
Herald patch precedes eruption by 1–2 weeks.
 
»
Occasional pruritus.
 
»
This is a common mild, acute inflammatory disease that is 
50% more common in females. Y oung adults are princi
-
pally affected, mostly in the spring or fall. Concurrent 
household cases have been reported.
 
»
Itching is common but is usually mild. The diagnosis is 
made by finding one or more classic lesions. The lesions 
consist of oval, fawn-colored plaques up to 2 cm in diameter. 
The centers of the lesions have a crinkled or “cigarette 
paper” appearance and a collarette scale, ie, a thin bit of 
scale that is bound at the periphery and free in the center. 
Only a few lesions in the eruption may have this character
-
istic appearance, however. Lesions follow cleavage lines on 
the trunk (so-called Christmas tree pattern, Figure 6–8), 
and the proximal portions of the extremities are often 
involved. A variant that affects the flexures (axillae and 
groin), so-called inverse pityriasis rosea, and a papular vari
-
ant, especially in black patients, also occur. An initial lesion 
(“herald patch”) that is often larger than the later lesions 
often precedes the general eruption by 1–2 weeks. The erup
-
tion usually lasts 6–8 weeks and heals without scarring.
 
»
Serologic testing for syphilis should be performed if at least 
a few perfectly typical lesions are not present and especially 
if there are palmar and plantar or mucous membrane 
lesions or adenopathy, features that are suggestive of sec
-
ondary syphilis. Tinea corporis may present with red, 
slightly scaly plaques, but rarely are there more than a few 
lesions of tinea corporis compared to the many lesions of 
pityriasis rosea. A potassium hydroxide examination 
should be performed to exclude a fungal cause. Seborrheic 
dermatitis on occasion presents on the body with poorly 
demarcated patches over the sternum, in the pubic area, 
and in the axillae. Tinea versicolor lacks the typical collar
-
ette rimmed lesions. Certain medications (eg, angiotensin-
converting enzyme [ACE] inhibitors and metronidazole)

-
converting enzyme [ACE] inhibitors and metronidazole) 
and immunizations rarely may induce a skin eruption 
mimicking pityriasis rosea.
 
»
Treatment
Pityriasis rosea often requires no treatment. In darker-
skinned individuals, more aggressive management may be 
indicated because dyspigmentation of lesions may remain 
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for some time. Treatment is, otherwise, indicated only if 
the patient is symptomatic. While adequately controlled 
and reproduced trials have not demonstrated widely effec
-
tive treatments, most dermatologists recommend UVB 
treatments or a short course of prednisone for severe or 
severely symptomatic cases. For mild to moderate cases, 
topical corticosteroids of medium strength (triamcinolone 
0.1%) and oral antihistamines may also be used if pruritus 
is bothersome. The role of macrolide antibiotics is not 
evidence based.
 
»
Prognosis
Pityriasis rosea is usually an acute self-limiting illness that 
typically disappears in about 6 weeks, although prolonged 
variants have been reported.
Chuh A et al. A position statement on the management of 
patients with pityriasis rosea. J Eur Acad Dermatol Venereol. 
2016 Oct;30(10):1670–81. [PMID: 27406919]
Urbina F et al. Clinical variants of pityriasis rosea. World J Clin 
Cases. 2017 Jun 16;5(6):203–11. [PMID: 28685133]
SEBORRHEIC DERMATITIS
 
»
Dry scales and underlying erythema.
 
»
Scalp, central face, presternal, interscapular areas, 
umbilicus, and body folds.
 
»
Seborrheic dermatitis is an acute or chronic papulosqua
-
mous dermatitis that often coexists with psoriasis.
 
»
The scalp, face, chest, back, umbilicus, eyelid margins, 
genitalia, and body folds have dry scales (dandruff) or oily 
yellowish scurf (Figure 6–9). Pruritus is a variable finding. 
Patients with Parkinson disease, HIV infection, and 
patients who become acutely ill often have seborrheic 
dermatitis.
 
»
There is a spectrum from seborrheic dermatitis to scalp 
psoriasis. Extensive seborrheic dermatitis may simulate 
intertrigo in flexural areas, but scalp, face, and sternal 
involvement suggests seborrheic dermatitis.
 
»
Treatment
A. Seborrhea of the Scalp
Shampoos that contain zinc pyrithione or selenium are 
used daily if possible. These may be alternated with keto
-
conazole shampoo (1% or 2%) used twice weekly. A com
-
bination of shampoos is used in refractory cases. Tar 
shampoos are also effective for milder cases and for scalp 
psoriasis. Topical corticosteroid solutions or lotions are 
then added if necessary and are used twice daily. (See treat
-
ment for scalp psoriasis, above.)
B. Facial Seborrheic Dermatitis
The mainstay of therapy is a mild corticosteroid (hydrocor
-
tisone 1%, alclometasone, desonide) used intermittently 
and not near the eyes. If the disorder cannot be controlled 
with intermittent use of a mild topical corticosteroid alone, 
ketoconazole (Nizoral) 2% cream is added twice daily. 
Topical tacrolimus (Protopic) and pimecrolimus (Elidel) 
are steroid-sparing alternatives.
C. Seborrheic Dermatitis of Nonhairy Areas
Low-potency corticosteroid creams—ie, 1% or 2.5% hydro
-
cortisone, desonide, or alclometasone dipropionate—are 
highly effective.
D. Seborrhea of Intertriginous Areas
Apply low-potency corticosteroid lotions or creams twice 
daily for 5–7 days and then once or twice weekly for main
-
tenance as necessary. Selenium lotion, ketoconazole, or 
clotrimazole gel or cream may be a useful adjunct. Tacroli
-
mus or pimecrolimus topically may avoid corticosteroid 
atrophy in chronic cases.
E. Involvement of Eyelid Margins
“Marginal blepharitis” usually responds to gentle cleaning 
of the lid margins nightly as needed, with undiluted John
-
son & Johnson Baby Shampoo using a cotton swab.
 
»
Prognosis
The tendency is for lifelong recurrences. Individual out
-
breaks may last weeks, months, or years.
 
▲
Figure 6–9.
 
Seborrheic dermatitis with classic crust
-
ing in the nasolabial crease and beard area. 
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Budding
yeast
Pseudohyphae
 
▲
Figure 6–10.
 
KOH preparation of fungus demon
-
strating pseudohyphae and budding yeast forms. 
(Reproduced, with permission, from Nicoll D et al. 
Pocket 
Guide to Diagnostic Tests,
 6th ed. McGraw-Hill, 2012.)
Clark GW et al. Diagnosis and treatment of seborrheic dermati
-
tis. Am Fam Physician. 2015 Feb 1;91(3):185–90. [PMID: 
25822272]
Gupta AK et al. Topical treatment of facial seborrheic dermatitis: 
a systematic review. Am J Clin Dermatol. 2017 Apr;18(2):
 
193–213. [PMID: 27804089]
FUNGAL INFECTIONS OF THE SKIN
The diagnosis of fungal infections of the skin is usually 
based on the location and characteristics of the lesions and 
on the following laboratory examinations: (1) Direct dem
-
onstration of fungi in 10% KOH evaluation of suspected 
lesions. 
“If it’s scaly, scrape it” is a time-honored maxim
 
(Figure 6–10). (2) Cultures of organisms from skin scrap
-
ings. (3) Histologic sections of biopsies stained with peri
-
odic acid-Schiff technique may be diagnostic if scrapings 
and cultures are falsely negative.
 
»
Principles of Treatment
A diagnosis should always be confirmed by KOH prepara
-
tion, culture, or biopsy. Many other diseases cause scaling, 
and use of an antifungal agent without a firm diagnosis 
makes subsequent diagnosis more difficult. In general, 
fungal infections are treated topically except for those with 
extensive involvement or involving the nails or hair folli
-
cles. In these situations, oral agents may be useful, with 
special attention to their side effects and complications, 
including hepatic toxicity.
 
»
General Measures & Prevention
Since moist skin favors the growth of fungi, dry the skin 
carefully after bathing or after perspiring heavily. Talc or 
other drying powders may be useful with the exception of 
powders containing corn starch, which may exacerbate 
fungal infections. The use of topical corticosteroids for 
other diseases may be complicated by intercurrent tinea 
or candidal infection, and topical antifungals are often 
used in intertriginous areas with corticosteroids to pre
-
vent this.
1. 
t
inea C
orporis or 
t
inea Cir
cinata
 
»
Ring-shaped lesions with an advancing scaly bor
-
der and central clearing or scaly patches with a 
distinct border.
 
»
Microscopic examination of scrapings or culture 
confirms the diagnosis.
 
»
The lesions are often on exposed areas of the body such as 
the face and arms. A history of exposure to an infected pet 
(who may have scaly rash or patches of alopecia) may occa
-
sionally be obtained, usually indicating 
Microsporum
 infec
-
tion. 
Trichophyton rubrum
 is the most common pathogen, 
usually representing extension onto the trunk or extremi
-
ties of tinea cruris, pedis, or manuum.
 
»
Itching may be present. In classic lesions, rings of ery
-
thema have an advancing scaly border and central 
clearing.
The diagnosis should be confirmed by KOH preparation or 
culture.
 
»
Positive fungal studies distinguish tinea corporis from 
other skin lesions with annular configuration, such as the 
annular lesions of psoriasis, lupus erythematosus, syphilis, 
granuloma annulare, and pityriasis rosea. Psoriasis has 
typical lesions on elbows, knees, scalp, and nails. Second
-
ary syphilis is often manifested by characteristic palmar, 
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plantar, and mucous membrane lesions. Tinea corporis 
rarely has the large number of symmetric lesions seen in 
pityriasis rosea. Granuloma annulare lacks scale.
 
»
Complications include extension of the disease down the 
hair follicles (which presents as papules and pustules and is 
more difficult to cure) and pyoderma.
 
»
Treat infected household pets (
 infections). To 
prevent recurrences, the use of foot powder and keeping 
feet dry by wearing sandals, or changing socks can be 
useful.
 
»
Treatment
A. Local Measures
Tinea corporis responds to most topical antifungals, including 
terbinafine, butenafine, econazole, miconazole, and clotrima
-
zole, most of which are available over the counter in the 
United States (see Table 6–2). Terbinafine and butenafine 
require shorter courses and lead to the most rapid response. 
Treatment should be continued for 1–2 weeks after clinical 
clearing
. Betamethasone dipropionate with clotrimazole 
(Lotrisone) is not recommended. Long-term improper use 
may result in side effects from the high-potency corticosteroid 
component, especially in body folds.
B. Systemic Measures
Itraconazole as a single weeklong pulse of 200 mg orally 
daily is effective in tinea corporis. Terbinafine, 250 mg orally 
daily for 1 month, is an alternative.
 
»
Prognosis
Tinea corporis usually responds promptly to conservative 
topical therapy or to an oral agent within 4 weeks.
van Zuuren EJ et al. Evidence-based topical treatments for tinea 
cruris and tinea corporis: a summary of a Cochrane system
-
atic review. Br J Dermatol. 2015 Mar;172(3):616–41. [PMID: 
25294700]
2. 
t
inea Cruris (
Jock Itch)
 
»
Marked itching in intertriginous areas, usually 
sparing the scrotum.
 
»
Peripherally spreading, sharply demarcated, 
 
centrally clearing erythematous lesions.
 
»
May have associated tinea infection of feet or 
toenails.
 
»
Laboratory examination with microscope or culture 
confirms diagnosis.
 
»
Tinea cruris lesions are confined to the groin and gluteal 
cleft. Intractable pruritus ani may occasionally be caused 
by a tinea infection.
 
»
Itching may be severe, or the rash may be asymptomatic. 
The lesions have sharp margins, cleared centers, and active, 
spreading scaly peripheries. Follicular pustules are some
-
times encountered. The area may be hyperpigmented on 
resolution.
Hyphae can be demonstrated microscopically in KOH 
preparations or skin biopsy. The organism may be 
cultured.
 
»
Tinea cruris must be distinguished from other lesions 
involving the intertriginous areas, such as candidiasis, seb
-
orrheic dermatitis, intertrigo, psoriasis of body folds 
(“inverse psoriasis”), and erythrasma (corynebacterial 
infection of intertriginous areas). Candidiasis is generally 
bright red and marked by satellite papules and pustules 
outside of the main border of the lesion. 
Candida
 typically 
involves the scrotum. Seborrheic dermatitis also often 
involves the face, sternum, and axillae. Intertrigo tends to 
be more red, less scaly, and present in obese individuals in 
moist body folds with less extension onto the thigh. 
“Inverse psoriasis” is characterized by distinct plaques. 
Other areas of typical psoriatic involvement should be 
checked, and the KOH examination will be negative. Ery
-
thrasma is best diagnosed with Wood (ultraviolet) light—a 
brilliant coral-red fluorescence is seen.
 
»
Treatment
Drying powder (eg, miconazole nitrate [Zeasorb-AF]) can 
be dusted into the involved area in patients with excessive 
perspiration or occlusion of skin due to obesity as a preven
-
tive measure.
B. Local Measures
Any of the topical antifungal preparations listed in Table 
6–2 may be used. Terbinafine cream is curative in over 80% 
of cases after once-daily use for 7 days.

-
C. Systemic Measures
One week of either itraconazole, 200 mg daily, or terbin
-
afine, 250 mg daily, can be effective.
 
»
Prognosis
Tinea cruris usually responds promptly to topical or sys
-
temic treatment but often recurs.
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3. 
t
inea M
anuum & 
t
inea 
p
edis 
 
(
t
inea of 
p
alms & S
oles)
 
»
Most often presents with asymptomatic scaling.
 
»
May progress to fissuring or maceration in toe 
web spaces.
 
»
May be a portal of entry for bacteria causing lower 
extremity cellulitis.
 
»
Itching, burning, and stinging of interdigital web; 
scaling palms and soles; vesicles of soles in inflam
-
matory cases.
 
»
The fungus is shown in skin scrapings examined 
microscopically or by culture of scrapings.
 
»
Tinea of the feet (athlete’s foot) is an extremely common 
acute or chronic dermatosis. Most infections are caused by 
Trichophyton
 species.
 
»
The presenting symptom may be itching, burning, or sting
-
ing. Pain may indicate secondary infection with complicat
-
ing cellulitis. Interdigital tinea pedis is the most common 
predisposing cause of lower extremity cellulitis in healthy 
individuals. Regular examination of the feet of diabetic 
patients for evidence of scaling and fissuring and treatment 
of any identified tinea pedis may prevent complications. 
Tinea pedis has several presentations that vary with the 
location. On the sole and heel, tinea may appear as chronic 
noninflammatory scaling, occasionally with thickening 
and fissuring. This may extend over the sides of the feet in 
a “moccasin” distribution (Figure 6–11). The KOH prepa
-
ration is usually positive. Tinea pedis often appears as a 
scaling or fissuring of the toe webs, often with maceration 
(Figure 6–12). As the web spaces become more macerated, 
the KOH preparation and fungal culture are less often posi
-
tive because bacterial species begin to dominate. Finally, 
there may also be vesicles, bullae, or generalized exfoliation 
of the skin of the soles, or nail involvement in the form of 
discoloration, friability, and thickening of the nail plate.
KOH and culture do not always demonstrate pathogenic 
fungi from macerated areas.
 
»
Differentiate from other skin conditions involving the same 
areas, such as interdigital erythrasma (use Wood light). Pso
-
riasis may be a cause of chronic scaling on the palms or soles 
and may cause nail changes. Repeated fungal cultures should 
be negative, and the condition will not respond to antifungal 
therapy. Contact dermatitis will often involve the dorsal 
surfaces and will respond to topical or systemic corticoste
-
roids. Vesicular lesions should be differentiated from pom
-
pholyx (dyshidrosis) and scabies by proper scraping of the 
roofs of individual vesicles. Rarely, gram-negative organisms 
may cause toe web infections, manifested as an acute erosive 
flare of interdigital disease. This entity is treated with alumi
-
num salts and imidazole antifungal agents or ciclopirox. 
Candida
 may also cause erosive interdigital disease.
 
»
The essential factor in prevention is personal hygiene. 
Wear open-toed sandals if possible. Use of sandals in com
-
munity showers and bathing places is often recommended, 
though the effectiveness of this practice has not been 
studied. Careful drying between the toes after showering is 
essential. A hair dryer used on low setting may be used. 
 
▲
Figure 6–11.
 
Tinea pedis in the moccasin distribu
-
tion. 
(Used, with permission, from Richard P . Usatine, MD 
in Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H. 
The 
Color Atlas of Family Medicine, 
2nd ed. McGraw-Hill, 2013.)
 
▲
Figure 6–12.
 
Tinea pedis in the interdigital space 
between fourth and fifth digits. The differential diagno
-
sis includes a bacterial primary or secondary infection 
with gram-negative organisms. 
(Used, with permission, 
from Richard P . Usatine, MD in Usatine RP , Smith MA, 
Mayeaux EJ Jr, Chumley H, Tysinger J. 
Family Medicine.
 McGraw-Hill, 2009.)
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Socks should be changed frequently, and absorbent non
-
synthetic socks are preferred. Apply dusting and drying 
powders as necessary. The use of powders containing anti
-
fungal agents (eg, Zeasorb-AF) or long-term use of anti
-
fungal creams may prevent recurrences of tinea pedis.
 
»
Treatment
1. Macerated stage—
Treat with aluminum subacetate 
solution soaks for 20 minutes twice daily. Broad-spectrum 
antifungal creams and solutions (containing imidazoles or 
ciclopirox) (Table 6–2) will help combat diphtheroids and 
other gram-positive organisms present at this stage and 
alone may be adequate therapy. If topical imidazoles fail, 
1 week of once-daily topical allylamine treatment (terbin
-
afine or butenafine) will often result in clearing.
2. Dry and scaly stage—
Use any of the antifungal agents 
listed in Table 6–2. The addition of urea 10–20% lotion or 
cream may increase the efficacy of topical treatments in 
thick (“moccasin”) tinea of the soles.
Itraconazole, 200 mg orally daily for 2 weeks or 400 mg 
daily for 1 week, or terbinafine, 250 mg orally daily for 
2–4 weeks, may be used in refractory cases. If the infection 
is cleared by systemic therapy, the patient should be 
encouraged to begin maintenance with topical therapy, 
since recurrence is common.
 
»
Prognosis
For many individuals, tinea pedis is a chronic affliction, 
temporarily cleared by therapy only to recur.
Canavan TN et al. Identifying signs of tinea pedis: a key to 
understanding clinical variables. J Drugs Dermatol. 2015 Oct;
 
14(10):s42–7. [PMID: 26461834]
Kaushik N et al. Superficial fungal infections. Prim Care. 
 
2015 Dec;42(4):501–16. [PMID: 26612371]
4. 
t
inea V
ersicolor (
p
it
yriasis Versicolor)
 
»
Velvety, tan, pink, or white macules or white mac
-
ules that do not tan with sun exposure.
 
»
Fine scales that are not visible but are seen by 
scraping the lesion.
 
»
Central upper trunk the most frequent site.
 
»
Yeast and short hyphae observed on microscopic 
examination of scales.
 
»
Tinea versicolor is a mild, superficial 
Malassezia
 infection of 
the skin (usually of the upper trunk). This yeast is a colonizer 
of all humans, which accounts for the high recurrence rate 
after treatment. The eruption is often called to patients’ atten
-
tion by the fact that the involved areas will not tan, and the 
resulting hypopigmentation may be mistaken for vitiligo. A 
hyperpigmented form is not uncommon.
 
»
Lesions are asymptomatic, but a few patients note itching. 
The lesions are velvety, tan, pink, or white macules or thin 
papules that vary from 4 mm to 5 mm in diameter to large 
confluent areas. The lesions initially do not look scaly, but 
scales may be readily obtained by scraping the area. Lesions 
may appear on the trunk, upper arms, neck, and groin.
Large, blunt hyphae and thick-walled budding spores 
(“spaghetti and meatballs”) are seen on KOH. Fungal cul
-
ture is not useful.
 
»
Vitiligo usually presents with larger periorificial and acral 
lesions and is also characterized by total (not partial) depig
-
mentation. Vitiligo does not scale. Pink and red-brown 
lesions on the chest are differentiated from seborrheic der
-
matitis of the same areas by the KOH preparation.
 
»
Treatment & Prognosis
Topical treatments include selenium sulfide lotion, which may 
be applied from neck to waist daily and left on for 5–15 minutes 
for 7 days; this treatment is repeated weekly for a month and 
then monthly for maintenance. Ketoconazole shampoo, 1% or 
2%, lathered on the chest and back and left on for 5 minutes 
may also be used weekly for treatment and to prevent recur
-
rence. Clinicians must stress to the patient that the raised and 
scaly aspects of the rash are being treated; the alterations in

-
scaly aspects of the rash are being treated; the alterations in 
pigmentation may take months to fade or fill in.
Two doses of oral fluconazole, 300 mg, 14 days apart, is 
first-line treatment; the risk of hepatitis is minimal. Keto
-
conazole, 200 mg daily orally for 1 week or 400 mg as a 
single oral dose, with exercise to the point of sweating for 
30–60 minutes after ingestion, results in short-term cure of 
90% of cases but is no longer recommended as first-line 
treatment because of the risk of drug-induced hepatitis. 
Patients should be instructed not to shower for 8–12 hours 
after taking ketoconazole, because it is delivered in sweat to 
the skin. An additional dose may be required in severe cases 
or humid climates. Without maintenance therapy, recur
-
rences will occur in over 80% of “cured” cases over the 
subsequent 2 years. Imidazole creams, solutions, and lotions 
are quite effective for localized areas but are too expensive 
for use over large areas such as the chest and back.
Gupta AK et al. Systematic review of systemic treatments for 
tinea versicolor and evidence-based dosing regimen recom
-
mendations. J Cutan Med Surg. 2014 Mar–Apr;18(2):79–90. 
[PMID: 24636433]
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CUTANEOUS LUPUS ERYTHEMATOSUS
 
»
Localized violaceous red plaques, usually on the 
face and scalp.
 
»
Scaling, follicular plugging, atrophy, dyspigmenta
-
tion, and telangiectasia of involved areas.
 
»
Distinctive histology.
 
»
Photosensitivity.
 
»
Common forms of cutaneous lupus include chronic cuta
-
neous lupus erythematosus (CCLE), typically chronic scar
-
ring (discoid) lupus lesions (DLE), and erythematous 
nonscarring red plaques of subacute cutaneous LE (SCLE). 
All occur most frequently in photoexposed areas. Perma
-
nent hair loss and loss of pigmentation are common 
sequelae of discoid lesions. Systemic lupus erythematosus 
(SLE) is discussed in Chapter 20. Patients with SLE may 
have DLE or SCLE lesions.
 
»
Symptoms are usually mild. The lesions consist of violaceous 
red, well-localized, single or multiple plaques, 5–20 mm in 
diameter, usually on the head in DLE and the trunk in 
SCLE. In DLE, the scalp, face, and external ears (conchal 
bowl) may be involved. In discoid lesions, there is atrophy, 
telangiectasia, central depigmentation, a hyperpigmented 
rim, and follicular plugging. On the scalp, significant per
-
manent hair loss may occur in lesions of DLE. In SCLE, the 
lesions are erythematous annular or psoriasiform plaques 
up to several centimeters in diameter and favor the upper 
chest and back.
In patients with DLE, the possibility of SLE should be con
-
sidered if the following findings are present: positive anti
-
nuclear antibody (ANA), other positive serologic studies 
(eg, anti-double-stranded DNA or anti-Smith antibody), 
high erythrocyte sedimentation rate, arthralgias/arthritis, 
presence of hypocomplementemia, widespread lesions (not 
localized to the head), or nailfold changes (dilated or 
thrombosed nailfold capillary loops). Patients with marked 
photosensitivity and a picture otherwise suggestive of 
lupus may have negative ANA tests but are positive for 
antibodies against Ro/SSA or La/SSB (SCLE).
 
»
The diagnosis is based on the clinical appearance con
-
firmed by skin biopsy in all cases. In DLE, the scales are dry 
and “thumbtack-like” and can thus be distinguished from 
those of seborrheic dermatitis and psoriasis. Older lesions 
that have left depigmented scarring or areas of hair loss will 
also differentiate lupus from these diseases. Ten percent of 
patients with SLE have discoid skin lesions, and 5% of 
patients with discoid lesions have SLE. Medications (most 
commonly, hydrochlorothiazide, calcium channel block
-
ers, H
2
-blockers and proton pump inhibitors, ACE inhibi
-
tors, TNF inhibitors, and terbinafine) may induce SCLE 
with a positive Ro/SSA.
 
»
Treatment
Use photoprotective clothing and sunblock with UVB and 
UV A coverage daily. 
Caution:
 Avoid using radiation ther
-
apy or medications that are potentially photosensitizing 
when possible.
For limited lesions, the following should be tried before 
systemic therapy: high-potency corticosteroid creams 
applied each night and covered with airtight, thin, pliable 
plastic film (eg, Saran Wrap); Cordran tape; or ultra–high-
potency corticosteroid cream or ointment applied twice 
daily without occlusion.
C. Local Infiltration
Triamcinolone acetonide suspension, 2.5–10 mg/mL, may 
be injected into the lesions of DLE once a month.
D. Systemic Treatment
1. Antimalarials—
Caution
: these medications should be 
used only when the diagnosis is secure because they have 
been associated with flares of psoriasis, which may be in 
the differential diagnosis.
a. 
H
ydroxychloroquine sulfate—
0.2–0.4 g orally 
daily for several months may be effective and is often used 
prior to chloroquine. A minimum 3-month trial is recom
-
mended. Screening for ocular toxicity is needed.
b. 
C
hloroquine sulfate—

-
b. 
C
250 mg orally daily may be 
effective in some cases when hydroxychloroquine is not.
c. 
Q
uinacrine (atabrine)
—
100 mg orally daily may be 
the safest of the antimalarials, since ocular toxicity has not 
been reported. It colors the skin yellow and is therefore not 
acceptable to some patients. It may be added to the other 
antimalarials for patients with incomplete responses.
2. Isotretinoin—
Isotretinoin, 1 mg/kg/day orally, is effec
-
tive in hypertrophic DLE lesions.
3. Thalidomide—
Thalidomide is effective in refractory 
cases in doses of 50–300 mg orally daily. Monitor for neu
-
ropathy. Lenalidomide (5–10 mg orally daily) may also be 
effective with less risk for neuropathy.
Isotretinoin, thalidomide, and lenalidomide are terato
-
gens and should be used with appropriate contraception 
and monitoring in women of childbearing age.
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»
Prognosis
The disease is persistent but not life-endangering unless 
systemic lupus is present. Treatment with one or more 
antimalarials is effective in more than half of cases. 
Although the only morbidity may be cosmetic, this can be 
of overwhelming significance in more darkly pigmented 
patients with widespread disease. Scarring alopecia can be 
prevented or lessened with close attention and aggressive 
therapy. Over years, DLE tends to become inactive. Drug-
induced SCLE usually resolves over months when the 
inciting medication is stopped.
Hejazi EZ et al. Cutaneous lupus erythematosus: an update on 
pathogenesis, diagnosis and treatment. Am J Clin Dermatol. 
2016 Apr;17(2):135–46. [PMID: 26872954]
Wieczorek IT et al. Systemic symptoms in the progression of 
cutaneous to systemic lupus erythematosus. JAMA Dermatol. 
2014 Mar;150(3):291–6. [PMID: 24477339]
CUTANEOUS T-CELL LYMPHOMA 
 
(
Mycosis Fungoides
)
 
»
Localized or generalized erythematous scaling 
patches that progress to plaques and nodules.
 
»
Pruritus.
 
»
Lymphadenopathy.
 
»
 
»
Mycosis fungoides is a cutaneous T-cell lymphoma that 
begins on the skin and may involve only the skin for years 
or decades. It may progress to systemic disease, including 
Sézary syndrome (erythroderma with circulating malig
-
nant T cells).
 
»
Localized or generalized erythematous scaly patches or 
plaques are present usually on the trunk. Plaques are 
almost always over 5 cm in diameter. Pruritus is a frequent 
complaint and can be severe. The lesions often begin as 
nondescript or nondiagnostic patches, and it is not unusual 
for the patient to have skin lesions for more than a decade 
before the diagnosis can be confirmed. Follicular involve
-
ment with hair loss is characteristic of mycosis fungoides, 
and its presence should raise the suspicion of mycosis 
fungoides for any pruritic eruption. In more advanced 
cases, tumors appear. Lymphadenopathy may occur locally 
or widely. Lymph node enlargement may be due to benign 
expansion of the node (dermatopathic lymphadenopathy) 
or by specific involvement with mycosis fungoides.
The skin biopsy remains the basis of diagnosis, though at 
times numerous biopsies are required before the diagnosis 
can be confirmed. In more advanced disease, circulating 
malignant T cells (Sézary cells) can be detected in the 
blood (T-cell gene rearrangement test). Eosinophilia may 
 
»
Mycosis fungoides may be confused with psoriasis, a drug 
eruption (including to serotonin reuptake inhibitors), pho
-
toallergy, an eczematous dermatitis, or tinea corporis. 
Histologic examination can distinguish these conditions.
 
»
Treatment
The treatment of mycosis fungoides is complex. Early and 
aggressive treatment has not been proven to cure or pre
-
vent disease progression. Skin-directed therapies, includ
-
ing topical corticosteroids, topical mechlorethamine, 
bexarotene gel, and UV phototherapy, are used initially. If 
the disease progresses, PUV A plus retinoids, PUV A plus 
interferon, extracorporeal photophoresis, bexarotene, 
alpha-interferon with or without retinoids, interleukin 12, 
denileukin, targeted immunomodulators, and total skin 
electron beam treatment are used.
 
»
Prognosis
Mycosis fungoides is usually slowly progressive (over 
decades). Prognosis is better in patients with patch or 
plaque stage disease and worse in patients with erythro
-
derma, tumors, and lymphadenopathy. Survival is not 
reduced in patients with limited patch disease. Elderly 
patients with limited patch and plaque stage disease com
-
monly die of other causes. Overly aggressive treatment may 
lead to complications and premature demise.
Devata S et al. Cutaneous T-cell lymphoma: a review with a focus 
on targeted agents. Am J Clin Dermatol. 2016 Jun;17(3):

225–37. [PMID: 26923912]
Olsen EA et al. Guidelines for phototherapy of mycosis fungoi
-
des and Sézary syndrome: a consensus statement of the 
United States Cutaneous Lymphoma Consortium. J Am Acad 
Dermatol. 2016 Jan;74(1):27–58. [PMID: 26547257]
Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diag
-
nosis, risk-stratification, and management. Am J Hematol. 
2016 Jan;91(1):151–65. [PMID: 26607183]
EXFOLIATIVE DERMATITIS 
 
(
Exfoliative Erythroderma
)
 
»
Scaling and erythema over most of the body.
 
»
Itching, malaise, fever, chills, weight loss.
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Erythroderma describes generalized redness and scaling of 
the skin of more than 30% BSA. A preexisting dermatosis 
is the cause of exfoliative dermatitis in two-thirds of cases, 
including psoriasis, atopic dermatitis, contact dermatitis, 
pityriasis rubra pilaris, and seborrheic dermatitis. Reac
-
tions to topical or systemic medications account for about 
15% of cases, cancer (underlying lymphoma, solid tumors 
and, most commonly, cutaneous T-cell lymphoma) for 
about 10%, and 10% are idiopathic. Widespread scabies is 
an important diagnostic consideration since patients with 
erythrodermic presentation are highly contagious. At the 
time of acute presentation, without a clear-cut prior history 
of skin disease or medication exposure, it may be impos
-
sible to make a specific diagnosis of the underlying condi
-
tion, and diagnosis may require continued observation.
 
»
Symptoms may include itching, weakness, malaise, fever, 
and weight loss. Chills are prominent. Erythema and scal
-
ing are widespread. Loss of hair and nails can occur. Gen
-
eralized lymphadenopathy may be due to lymphoma or 
leukemia or may be reactive. The mucosae are typically 
spared.
A skin biopsy is required and may show changes of a spe
-
cific inflammatory dermatitis or cutaneous T-cell lym
-
phoma. Peripheral leukocytes may show clonal 
rearrangements of the T-cell receptor in Sézary syndrome.
 
»
Protein and electrolyte loss as well as dehydration may 
develop in patients with generalized inflammatory exfolia
-
tive erythroderma; or sepsis may occur.
 
»
Treatment
A. Topical Therapy
Home treatment is with cool to tepid baths and application 
of mid-potency corticosteroids under wet dressings or with 
the use of an occlusive plastic suit. If the exfoliative eryth
-
roderma becomes chronic and is not manageable in an 
outpatient setting, the patient should be hospitalized. Keep 
the room at a constant warm temperature and provide the 
same topical treatment as for an outpatient.
B. Specific Measures
Stop all medications, if possible. Systemic corticosteroids 
may provide marked improvement in severe or fulminant 
exfoliative dermatitis, but long-term therapy should be 
avoided (see Chapter 26). In addition, systemic corticoste
-
roids must be used with caution because some patients 
with erythroderma have psoriasis and could develop pus
-
tular flare. For cases of psoriatic erythroderma and pityria
-
sis rubra pilaris, acitretin, methotrexate, cyclosporine, or a 
TNF inhibitor may be indicated. Erythroderma secondary 
to lymphoma or leukemia requires specific topical or sys
-
temic chemotherapy. Suitable antibiotic medications with 
coverage for 
Staphylococcus
 should be given when there is 
evidence of bacterial infection.
 
»
Prognosis
Careful follow-up is necessary because identifying the 
cause of exfoliative erythroderma early in the course of the 
disease may be impossible. Most patients recover com
-
pletely or improve greatly over time but may require long-
term therapy. Deaths are rare in the absence of cutaneous 
T-cell lymphoma. A minority of patients will suffer from 
undiminished erythroderma for indefinite periods.
César A et al. Erythroderma. A clinical and etiological study of 
103 patients. J Dermatol Case Rep. 2016 Mar 31;10(1):1–9. 
[PMID: 27119000]
MISCELLANEOUS SCALING DERMATOSES
Isolated scaly patches may represent actinic (solar) kerato
-
ses, nonpigmented seborrheic keratoses, or Bowen or Paget 
disease.
1. 
a
c
tinic Keratoses
Actinic keratoses are small (0.2–0.6 cm) macules or papules—
flesh-colored, pink, or slightly hyperpigmented—that feel 
like sandpaper and are tender to palpation. They occur on 
sun-exposed parts of the body in persons of fair complex
-
ion. Actinic keratoses are considered premalignant, but 
only 1:1000 lesions per year progress to become squamous

-
only 1:1000 lesions per year progress to become squamous 
cell carcinomas.
Application of liquid nitrogen is a rapid method of 
eradication. The lesions crust and disappear in 10–14 days. 
“Field treatment” with a topical agent to the anatomic area 
where the actinic keratoses are most prevalent (eg, fore
-
head, dorsal hands, etc) can be considered in patients with 
multiple lesions in one region. The topical agents used for 
field treatment include fluorouracil, imiquimod, and 
ingenol mebutate. Photodynamic therapy can be effective 
in cases refractory to topical treatment. Any lesions that 
persist should be evaluated for possible biopsy.
Arenberger P et al. New and current preventive treatment 
options in actinic keratosis. J Eur Acad Dermatol Venereol. 
2017 Sep;31(Suppl 5):13–7. [PMID: 28805940]
Pomerantz H et al; Veterans Affairs Keratinocyte Carcinoma 
Chemoprevention (V AKCC) Trial Group. Long-term efficacy 
of topical fluorouracil cream, 5%, for treating actinic keratosis: 
a randomized clinical trial. JAMA Dermatol. 2015 Sep;
 
151(9):952–60. [PMID: 25950503]
Siegel JA et al. Current perspective on actinic keratosis: a review. 
Br J Dermatol. 2017 Aug;177(2):350–8. [PMID: 27500794]
Werner RN et al. Evidence- and consensus-based (S3) guidelines 
for the treatment of actinic keratosis—International League of 
Dermatological Societies in cooperation with the European 
Dermatology Forum—short version. J Eur Acad Dermatol 
Venereol. 2015 Nov;29(11):2069–79. [PMID: 26370093]
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▲
Figure 6–13.
 
Paget disease of the breast surrounding 
the nipple. 
(From the University of Texas Health Sciences 
Center, Division of Dermatology; used, with permission, 
from Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H, 
 
Tysinger J. 
. McGraw-Hill, 
2009.)
2. Bowen Disease & 
p
aget D
isease
Bowen disease
 (intraepidermal squamous cell carcinoma) 
can develop on both sun-exposed and non–sun-exposed 
skin. The lesion is usually a small (0.5–3 cm), well-demarcated, 
slightly raised, pink to red, scaly plaque and may resemble 
psoriasis or a large actinic keratosis. These lesions may 
progress to invasive squamous cell carcinoma. Excision or 
other definitive treatment is indicated.
Extramammary Paget disease
, a manifestation of 
intraepidermal carcinoma or underlying genitourinary or 
gastrointestinal cancer, resembles chronic eczema and usu
-
ally involves apocrine areas such as the genitalia. 
Mam
-
mary Paget disease of the nipple
, a unilateral or rarely 
bilateral red scaling plaque that may ooze, is associated 
with an underlying intraductal mammary carcinoma 
(Figure 6–13). While these lesions appear as red patches 
and plaques in fair-skinned persons, in darker-skinned 
individuals, hyperpigmentation may be prominent.
Cohen JM et al. Risk stratification in extramammary Paget 
disease. Clin Exp Dermatol. 2015 Jul;40(5):473–8. [PMID: 
26011765]
Herrel LA et al. Extramammary Paget’s disease in males: survival 
outcomes in 495 patients. Ann Surg Oncol. 2015 May;
 
22(5):1625–30. [PMID: 25384700]
Morton CA et al. British Association of Dermatologists’ guide
-
lines for the management of squamous cell carcinoma in situ 
(Bowen’s disease) 2014. Br J Dermatol. 2014 Feb;170(2):
 
245–60. [PMID: 24313974]
INTERTRIGO
Intertrigo is caused by the macerating effect of heat, mois
-
ture, and friction. It is especially likely to occur in obese 
persons and in humid climates. The symptoms are itching, 
stinging, and burning. The body folds develop fissures, 
erythema, maceration, and superficial denudation. Candi
-
diasis may complicate intertrigo. “Inverse psoriasis, ” 
seborrheic dermatitis, tinea cruris, erythrasma, and candi
-
diasis must be ruled out.
Maintain hygiene in the area, and keep it dry. Com
-
presses may be useful acutely. Hydrocortisone 1% cream 
plus an imidazole or clotrimazole 1% cream is effective. 
Recurrences are common.
Kalra MG et al. Intertrigo and secondary skin infections. Am 
Fam Physician. 2014 Apr 1;89(7):569–73. [PMID: 24695603]
V
e
SICUL
ar
 D
er
M
a
t
OS
e
S
HERPES SIMPLEX (
Cold or Fever 
 
Sore; Genital Herpes
)
 
»
Recurrent small grouped vesicles (especially orola
-
bial and genital) on an erythematous base.
 
»
May follow minor infections, trauma, stress, or sun 
exposure; regional lymph nodes may be swollen 
and tender.
 
»
Direct fluorescent antibody tests are positive.
 
»
Over 85% of adults have serologic evidence of herpes sim
-
plex type 1 (HSV-1) infections, most often acquired 
asymptomatically in childhood. Occasionally, primary 
infections may be manifested as severe gingivostomatitis. 
Thereafter, the patient may have recurrent self-limited 
attacks, provoked by sun exposure, orofacial surgery, fever, 
or a viral infection.
About 25% of the US population has serologic evidence 
of infection with herpes simplex type 2 (HSV-2). HSV-2 
causes lesions whose morphology and natural history are 
similar to those caused by HSV-1 but are typically located 
on the genitalia of both sexes. The infection is acquired by 
sexual contact. In monogamous heterosexual couples 
where one partner has HSV-2 infection, seroconversion of 
the noninfected partner occurs in 10% over a 1-year 
period. Up to 70% of such infections appeared to be trans
-
mitted during periods of asymptomatic shedding. Genital 
herpes may also be due to HSV-1.
 
»

-
 
»
The principal symptoms are burning and stinging. Neural
-
gia may precede or accompany attacks. The lesions consist 
of small, grouped vesicles on an erythematous base that 
can occur anywhere but which most often occur on the 
vermilion border of the lips (Figure 6–14), the penile shaft, 
the labia, the perianal skin, and the buttocks. Any erosion 
or fissure in the anogenital region can be due to herpes 
simplex. Regional lymph nodes may be swollen and tender. 
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▲
Figure 6–14.
 
Orolabial herpes simplex showing 
deroofed blisters (ulcer). 
(Used, with permission, from 
Richard P . Usatine, MD in Usatine RP , Smith MA, Mayeaux 
EJ Jr, Chumley H. 
The Color Atlas of Family Medicine,
 2nd ed. 
McGraw-Hill, 2013.)
The lesions usually crust and heal in 1 week. Immunosup
-
pressed patients may have unusual variants, including ver
-
rucous or nodular herpes lesions at typical sites of 
involvement. Lesions of herpes simplex must be distin
-
guished from chancroid, syphilis, pyoderma, or trauma.
Direct fluorescent antibody slide tests offer rapid, sensitive 
diagnosis. Viral culture may also be helpful. Herpes serol
-
ogy is not used in the diagnosis of an acute genital ulcer. 
However, specific HSV-2 serology by Western blot assay or 
enzyme-linked immunosorbent assay (ELISA) can deter
-
mine who is HSV-infected and potentially infectious, but 
routine HSV-2 screening is not recommended.
 
»
Complications include pyoderma, eczema herpeticum, 
herpetic whitlow, herpes gladiatorum (epidemic herpes in 
wrestlers transmitted by contact), proctitis, esophagitis, 
neonatal infection, keratitis, and encephalitis.
 
»
Treatment
A. Systemic Therapy
Three systemic agents are available for the treatment of 
acute herpes infections: acyclovir, its valine analog valacy
-
clovir, and famciclovir. All three agents are very effective, 
and when used properly, virtually nontoxic. Only acyclovir 
is available for intravenous administration. In the immu
-
nocompetent, with the exception of severe orolabial her
-
pes, only genital disease is treated.
1. For first clinical episode—
For first clinical episodes of 
herpes simplex, the dosage of acyclovir is 400 mg orally five 
times daily (or 800 mg three times daily); of valacyclovir, 
1000 mg orally twice daily; and of famciclovir, 250 mg 
orally three times daily. The duration of treatment is from 
7 to 10 days depending on the severity of the outbreak.
2. For mild recurrences—
Most cases do not require therapy. 
In addition, pharmacotherapy of recurrent HSV is of limited 
benefit, with studies finding a reduction in the average out
-
break by only 12–24 hours. 
To be effective, the treatment 
must be initiated by the patient at the first sign of recur
-
rence
. If treatment is desired, recurrent genital herpes out
-
breaks may be treated with 3 days of valacyclovir, 500 mg 
orally twice daily, 5 days of acyclovir, 200 mg orally five times 
a day, or 5 days of famciclovir, 125 mg orally twice daily. 
Valacyclovir, 2 g twice daily for 1 day, or famciclovir, 1 g once 
or twice in 1 day, are equally effective short-course alterna
-
tives and can abort impending recurrences of both orolabial 
and genital herpes. The addition of a potent topical cortico
-
steroid three times daily reduces the duration, size, and pain 
of orolabial herpes treated with an oral antiviral agent.
3. For frequent or severe recurrences—
Suppressive ther
-
apy may be effective in controlling disease. Suppressive 
treatment will reduce outbreaks by 85% and reduces viral 
shedding by more than 90%. This results in about a 50% 
reduced risk of transmission. The recommended suppres
-
sive doses, taken continuously, are acyclovir, 400 mg orally 
twice daily; valacyclovir, 500 mg orally once daily; or fam
-
ciclovir, 125–250 mg orally twice daily. Pritelivir may have 
superior reduction of viral shedding in HSV-2. Long-term 
suppression appears very safe, and after 5–7 years a sub
-
stantial proportion of patients can discontinue treatment.
The use of latex condoms and patient education have 
proved effective in reducing genital herpes transmission in 
some studies but have not proved beneficial in others. No 
single or combination intervention absolutely prevents 
transmission. Sunscreens are useful adjuncts in preventing 
sun-induced HSV-1 recurrences. A preventive antiviral

sun-induced HSV-1 recurrences. A preventive antiviral 
medication should be started beginning 24 hours prior to 
ultraviolet light exposure, dental surgery, or orolabial cos
-
metic surgery.
In general, topical therapy has only limited efficacy and is 
generally not recommended because evidence shows that it 
only minimally reduces skin healing time.
 
»
Prognosis
Aside from the complications described above, recurrent 
attacks last several days, and patients recover without 
sequelae.
Chi CC et al. Interventions for prevention of herpes simplex 
labialis (cold sores on the lips). Cochrane Database Syst Rev. 
2015 Aug 7;(8):CD010095. [PMID: 26252373]
Feltner C et al. Serologic screening for genital herpes: an updated 
evidence report and systematic review for the US Preventive 
Services Task Force. JAMA. 2016 Dec 20;316(23):2531–43. 
[PMID: 27997660]
Sauerbrei A. Optimal management of genital herpes: current 
perspectives. Infect Drug Resist. 2016 Jun 13;9:129–41. 
[PMID: 27358569]
Wald A et al. Effect of pritelivir compared with valacyclovir on 
genital HSV-2 shedding in patients with frequent recurrences: 
a randomized clinical trial. JAMA. 2016 Dec 20;316(23):
 
2495–503. [PMID: 27997653]
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▲
Figure 6–15.
 
Herpes zoster.
 (Used, with permission, 
from Berger TG, Dept Dermatology, UCSF.)
HERPES ZOSTER (
Shingles
)
 
»
Dermatomal pain followed by grouped vesicular 
lesions.
 
»
Involvement is unilateral; some lesions (fewer than 
20) may occur outside the affected dermatome.
 
»
Lesions are usually on face or trunk.
 
»
Direct fluorescent antibody positive, especially in 
vesicular lesions.
 
»
Herpes zoster is an acute vesicular eruption due to the 
varicella-zoster virus. It usually occurs in adults and inci
-
dence rises with age. With rare exceptions, patients suffer 
only one attack. While dermatomal herpes zoster is com
-
mon, generalized disease raises the suspicion of an associ
-
ated immunosuppressive disorder, such as HIV infection. 
HIV-infected patients are 20 times more likely to develop 
zoster, often before other clinical findings of HIV disease 
are present. 
A history of HIV risk factors and HIV testing 
when appropriate should be considered, especially in 
patients with zoster who are younger than 55 years
.
 
»
Pain along a dermatome usually precedes the eruption by 
48 hours or more and may persist after the lesions have 
disappeared. The lesions consist of grouped, tense, deep-
seated vesicles distributed unilaterally along a dermatome 
(Figure 6–15). The most common distributions are on the 
trunk or face. Up to 20 lesions may be found outside the 
affected dermatomes, even in immunocompetent persons. 
Regional lymph nodes may be tender and swollen.
 
»
Since poison oak and poison ivy dermatitis can occur uni
-
laterally, they must be differentiated at times from herpes 
zoster. Allergic contact dermatitis is pruritic; zoster is pain
-
ful. One must differentiate herpes zoster from lesions of 
herpes simplex, which rarely occurs in a dermatomal dis
-
tribution. Facial zoster may simulate erysipelas initially, but 
zoster is unilateral and shows vesicles after 24–48 hours. 
Depending on the dermatome involved, the pain of 
preeruptive herpes zoster may lead the clinician to diag
-
nose migraine, myocardial infarction, acute abdomen, 
herniated disk, etc.
 
»
Sacral zoster may be associated with bladder and bowel 
dysfunction. Persistent neuralgia, anesthesia or scarring of 
the affected area, facial or other nerve paralysis, and 
encephalitis may occur. Postherpetic neuralgia is most 
common after involvement of the trigeminal region and in 
patients over the age of 55. 
Early (within 72 hours after 
onset) and aggressive antiviral treatment of herpes zos
-
ter reduces the severity and duration of postherpetic 
neuralgia.
 Zoster ophthalmicus (V1) can result in visual 
impairment. Increased risk of transient ischemic attack and 
stroke has been demonstrated.
 
»
An effective live herpes zoster vaccine (Zostavax) is recom
-
mended in persons aged 60 and older, even in those who 
have had zoster. It reduces the risk of developing herpes zos
-
ter by approximately 50% and postherpetic neuralgia by 67%.
 
»
Treatment
1. Immunocompetent patient—
Antiviral treatment 
within 72 hours of rash decreases the duration and severity 
of acute herpes zoster. Since such treatment also reduces 
postherpetic neuralgia, those with a risk of developing this 
complication should be treated (ie, those over age 50 and 
those with nontruncal eruption). In addition, patients with 
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acute moderate to severe pain or rash may benefit from 
antiviral therapy. Treatment can be given with oral acyclo
-
vir, 800 mg five times daily; famciclovir, 500 mg three times 
daily; or valacyclovir, 1 g three times daily—all for 7 days 
(see Chapter 32). For reasons of increased bioavailability 
and ease of dosing schedule, the preferred agents are those 
given three times daily. Patients should maintain good 
hydration. The dose of antiviral should be adjusted for 
kidney function as recommended. Nerve blocks may be 
used in the management of initial severe pain. Ophthalmo
-
logic consultation is vital for involvement of the first 
branch of the trigeminal nerve, even if the patient has no 
ocular symptoms.
Systemic corticosteroids are effective in reducing acute 
pain, improving quality of life, and returning patients to 
normal activities much more quickly. They do not increase 
the risk of dissemination in immunocompetent persons. If 
not contraindicated, a tapering 3-week course of oral pred
-
nisone, starting at 60 mg/day, should be considered for its 
adjunctive benefit in immunocompetent patients. Oral 
corticosteroids do not reduce the prevalence, severity, or 
duration of postherpetic neuralgia beyond that achieved by 
effective antiviral therapy. Adequate analgesia, including 
the use of opioids, tricyclic antidepressants, and gabapen
-
tin as necessary, should be given for zoster-associated pain.
2. Immunocompromised patient—
Given the safety and 
efficacy of currently available antivirals, most immuno
-
compromised patients with herpes zoster are candidates 
for antiviral therapy. The dosage schedule is as listed above, 
but treatment should be continued until the lesions have 
completely crusted and are healed or almost healed (up to 
2 weeks). 
Because corticosteroids increase the risk of dis
-
semination in immunosuppressed patients, they should 
not be used in these patients.
 Progression of disease may 
necessitate intravenous therapy with acyclovir, 10 mg/kg 
intravenously, three times daily. After 3–4 days, oral ther
-
apy may be substituted if there has been a good response to 
intravenous therapy. Adverse effects include decreased 
kidney function from crystallization, nausea and vomiting, 
and abdominal pain.
Foscarnet, administered in a dosage of 40 mg/kg two or 
three times daily intravenously, is indicated for treatment 
of acyclovir-resistant varicella-zoster virus infections.
Calamine or aluminum salt compresses (Domeboro, 
Burow soaks) may be helpful for dry weeping lesions.
C. Postherpetic Neuralgia Therapy
The most effective treatment is prevention with vaccina
-
tion of those at risk for developing zoster and early and 
aggressive antiviral therapy once zoster has occurred. Once 
established, postherpetic neuralgia may be treated with 
capsaicin ointment, 0.025–0.075%, or lidocaine (Lido
-
derm) topical patches. Chronic postherpetic neuralgia may 
be relieved by regional blocks (stellate ganglion, epidural, 
local infiltration, or peripheral nerve), with or without 
corticosteroids added to the injections. Tricyclic antide
-
pressants, such as amitriptyline, 25–75 mg orally as a single 
nightly dose, are the first-line therapy beyond simple anal
-
gesics. Gabapentin, up to 3600 mg orally daily (starting at 
300 mg orally three times daily), or duloxetine, up to 
60–120 mg orally daily (starting at 30–60 mg orally daily) 
may be added for additional pain relief. Long-acting opi
-
oids may be appropriate. Referral to a pain management 
clinic should be considered in moderate to severe cases and 
in those who do not respond to the above treatments.
 
»
Prognosis
The eruption persists 2–3 weeks and usually does not 
recur. Motor involvement in 2–3% of patients may lead to 
temporary palsy.
Gagliardi AM et al. Vaccines for preventing herpes zoster in 
older adults. Cochrane Database Syst Rev. 2016 Mar 3;3:

CD008858. [PMID: 26937872]
Schmader K. Herpes zoster. Clin Geriatr Med. 2016 Aug;32(3):
 
539–53. [PMID: 27394022]
Schutzer-Weissmann J et al. Post-herpetic neuralgia—a review 
of current management and future directions. Expert Opin 
Pharmacother. 2017 Nov;18(16):1739–50. [PMID: 29025327]
POMPHOLYX
 
»
Pruritic “tapioca” vesicles of 1–2 mm on the palms, 
soles, and sides of fingers.
 
»
Vesicles may coalesce to form multiloculated 
blisters.
 
»
Scaling and fissuring may follow drying of the 
blisters.
 
»
Appearance in the third decade, with lifelong 
recurrences.
 
»
Pompholyx, or vesiculobullous dermatitis of the palms and 
soles, is formerly known as dyshidrosis or dyshidrotic eczema. 
About half of patients have an atopic background, and many 
patients report flares with stress. Patients with widespread 
dermatitis due to any cause may develop pompholyx-like 
eruptions as a part of an autoeczematization response.
 
»
Small clear vesicles resembling grains of tapioca stud 
the skin at the sides of the fingers and on the palms 
(Figure 6–16) and may also affect the soles, albeit less 
frequently. They may be associated with intense itching. 
Later, the vesicles dry and the area becomes scaly and 
fissured.
 
»
Unroofing the vesicles and examining the blister roof with 
a KOH preparation will reveal hyphae in cases of bullous 
tinea. Always examine the feet of a patient with a hand 
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▲
Figure 6–16.
 
Severe pompholyx. (
Used, with 
 
▲
Figure 6–17.
 
Porphyria cutanea tarda. 
permission, from Lewis Rose, MD in Usatine RP , Smith MA, 
eruption because patients with inflammatory tinea pedis 
may have a vesicular autoeczematization of the palms. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) may pro
-
duce an eruption very similar to that of vesiculobullous 
dermatitis on the hands.
 
»
There is no known way to prevent attacks if the condition 
is idiopathic. About one-third to one-half of patients with 
vesiculobullous hand dermatitis have a relevant contact 
allergen, especially nickel. Patch testing and avoidance of 
identified allergens can lead to improvement.
 
»
Treatment
Topical and systemic corticosteroids help some patients 
dramatically. Since this is a chronic problem, systemic cor
-
ticosteroids are generally not appropriate therapy. A high-
potency topical corticosteroid used early in the attack may 
help abort the flare and ameliorate pruritus. Topical cortico
-
steroids are also important in treating the scaling and fissur
-
ing that are seen after the vesicular phase. It is essential that 
patients avoid anything that irritates the skin; they should 
wear cotton gloves inside vinyl gloves when doing dishes or 
other wet chores and use a hand cream after washing the 
hands. Patients respond to PUV A therapy and injection of 
botulinum toxin into the palms as for hyperhidrosis.
 
»
Prognosis
For most patients, the disease is an inconvenience. For 
some, vesiculobullous hand eczema can be incapacitating.
Brans R et al. Clinical patterns and associated factors in patients 
with hand eczema of primarily occupational origin. J Eur 
Acad Dermatol Venereol. 2016 May;30(5):798–805. [PMID: 
26660508]
Crane MM et al. Hand eczema and steroid-refractory chronic hand 
eczema in general practice: prevalence and initial treatment. Br J 
Dermatol. 2017 Apr;176(4):955–64. [PMID: 27534443]
Halling-Overgaard AS et al. Management of atopic hand derma
-
titis. Dermatol Clin. 2017 Jul;35(3):365–72. [PMID: 28577805]
PORPHYRIA CUTANEA TARDA
 
»
Noninflammatory blisters on sun-exposed sites, 
especially the dorsal surfaces of the hands.
 
»
Hypertrichosis, skin fragility.
 
»
Associated liver disease.
 
»
Elevated urine porphyrins.
 
»
Porphyria cutanea tarda is the most common type of por
-
phyria. Cases are sporadic or hereditary. The disease is 
associated with ingestion of certain medications (eg, estro
-
gens) and alcoholic liver disease, hemochromatosis, or 
hepatitis C.
 
»
Patients complain of painless blistering and fragility of the 
skin of the dorsal surfaces of the hands (Figure 6–17). Facial 
hypertrichosis and hyperpigmentation are common.
Urinary uroporphyrins are elevated twofold to fivefold 
above coproporphyrins. Patients may also have abnormal 
liver bichemical tests, evidence of hepatitis C infection, 
increased liver iron stores, and hemochromatosis gene 
mutations.
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▲
Figure 6–18.
 
Bullous impetigo. 
(Used, with permis
-
sion, from Jack Resneck, Sr, MD in Usatine RP , Smith MA, 
Mayeaux EJ Jr, Chumley H. 
The Color Atlas of Family 
Medicine,
 
»
Skin lesions identical to those of porphyria cutanea tarda 
may be seen in patients who undergo dialysis and in those 
who take certain medications (tetracyclines, voriconazole, 
and NSAIDs, especially naproxen). In this so-called 
pseu
-
doporphyria
, the biopsy results are the same as those 
associated with porphyria cutanea tarda, but urine porphy
-
rins are normal.
 
»
Barrier sun protection with clothing is required. Although 
the lesions are triggered by sun exposure, the wavelength of 
light triggering the lesions is beyond that absorbed by 
sunscreens.
 
»
Treatment
Stopping all triggering medications and substantially reduc
-
ing or stopping alcohol consumption may alone lead to 
improvement in most cases. Phlebotomy without oral iron 
supplementation at a rate of 1 unit every 2–4 weeks will 
gradually lead to improvement. Very low-dose antimalarial 
medication (as low as 200 mg of hydroxychloroquine twice 
weekly), alone or in combination with phlebotomy, will 
increase the excretion of porphyrins, improving the skin 
disease. Deferasirox, an iron chelator, can also improve 
porphyria cutanea tarda. Treatment is continued until the 
patient is asymptomatic. Urine porphyrins may be 
monitored.
 
»
Prognosis
Most patients improve with treatment. Sclerodermoid skin 
lesions may develop on the trunk, scalp, and face.
Handler NS et al. Porphyria cutanea tarda: an intriguing genetic 
disease and marker. Int J Dermatol. 2017 Jun;56(6):e106–17. 
[PMID: 28321838]
Schulenburg-Brand D et al. The cutaneous porphyrias. Derma
-
tol Clin. 2014 Jul;32(3):369–84. [PMID: 24891059]
DERMATITIS HERPETIFORMIS
Dermatitis herpetiformis is an uncommon disease mani
-
fested by pruritic papules, vesicles, and papulovesicles 
mainly on the elbows, knees, buttocks, posterior neck, and 
scalp. It appears to have its highest prevalence in Northern 
Europe and is associated with HLA antigens -B8, -DR3, and 
-DQ2. The histopathology is distinctive. Circulating anti
-
bodies to tissue transglutaminase are present in 90% of 
cases. NSAIDs may cause flares. Patients have gluten-
sensitive enteropathy, but it is subclinical in the great major
-
ity. However, ingestion of gluten is the cause of the disease, 
and strict long-term avoidance of dietary gluten has been 
shown to decrease the dose of dapsone (usually 100–200 mg 
daily) required to control the disease and may even eliminate 
the need for treatment. Patients with dermatitis herpetifor
-
mis are at increased risk for development of gastrointestinal 
lymphoma, and this risk is reduced by a gluten-free diet.
Collin P et al. Dermatitis herpetiformis: a cutaneous manifesta
-
tion of coeliac disease. Ann Med. 2017 Feb;49(1):23–31. 
[PMID: 27499257]
W
eep
ING O
r
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r
US
te
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e
SIONS
IMPETIGO
 
»
Superficial blisters filled with purulent material 
that rupture easily.
 
»
Crusted superficial erosions.
 
»
Positive Gram stain and bacterial culture.
 
»
Impetigo is a contagious and autoinoculable infection of 
the skin (epidermis) caused by staphylococci or 
streptococci.
 
»
The lesions consist of macules, vesicles, bullae, pustules, 
and honey-colored crusts that when removed leave 
denuded red areas (Figure 6–18). The face and other 
exposed parts are most often involved. 
Ecthyma
 is a deeper 
form of impetigo caused by staphylococci or streptococci, 
with ulceration and scarring that occurs frequently on the 
extremities.
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Gram stain and culture confirm the diagnosis. In temper
-
ate climates, most cases are associated with 
S aureus
 infec
-
tion. 
Streptococcus
 species are more common in tropical 
 
»
The main differential diagnoses are acute allergic contact 
dermatitis and herpes simplex. Contact dermatitis may be 
suggested by the history or by linear distribution of the 
lesions, and culture should be negative for staphylococci and 
streptococci. Herpes simplex infection usually presents with 
grouped vesicles or discrete erosions and may be associated 
with a history of recurrences. Viral cultures are positive.
 
»
Treatment
Soaks and scrubbing can be beneficial, especially in unroof
-
ing lakes of pus under thick crusts. Topical agents, such as 
bacitracin, mupirocin, and retapamulin, are first-line treat
-
ment options for infections limited to small areas. In wide
-
spread cases, or in immunosuppressed individuals, systemic 
antibiotics are indicated. Cephalexin, 250 mg orally four 
times daily, is usually effective. Doxycycline, 100 mg orally 
twice daily, is a reasonable alternative. Community-
associated methicillin-resistant 
S aureus
 (CA-MRSA) may 
cause impetigo, and initial coverage for MRSA could 
include doxycycline or trimethoprim-sulfamethoxazole 
(TMP-SMZ). About 50% of CA-MRSA cases are quinolone 
resistant. Recurrent impetigo is associated with nasal car
-
riage of 
S aureus
 and is treated with rifampin, 600 mg daily 
for 5 days. Intranasal mupirocin ointment twice daily for 
 
5 days clears the carriage of 40% of MRSA strains. Bleach 
baths (¼ to ½ cup per 20 liters of bathwater for 15 minutes 
3–5 times weekly) for all family members, and the use of 
dilute household bleach to clean showers and other bath 
surfaces may help reduce the spread. Individuals should not 
share towels if there is a case of impetigo in the household.
Bowen AC et al. Short-course oral co-trimoxazole versus intra
-
muscular benzathine benzylpenicillin for impetigo in a highly 
endemic region: an open-label, randomised, controlled, non-
inferiority trial. Lancet. 2014 Dec 13;384(9960):2132–40. 
[PMID: 25172376]
Hartman-Adams H et al. Impetigo: diagnosis and treatment. Am 
Fam Physician. 2014 Aug 15;90(4):229–35. [PMID: 25250996]
CONTACT DERMATITIS
 
»
Erythema and edema, with pruritus, vesicles, bul
-
lae, weeping or crusting.
 
»
Irritant contact dermatitis:
 occurs only in area of 
direct contact with irritant.
 
»
Allergic contact dermatitis:
 extends beyond area 
of direct contact with allergen; positive patch test.
 
»
Contact dermatitis (irritant or allergic) is an acute or 
chronic dermatitis that results from direct skin contact 
with chemicals or allergens. Eighty percent of cases are due 
to excessive exposure to or additive effects of universal 
irritants (eg, soaps, detergents, organic solvents) and are 
called 
irritant contact dermatitis
. The most common 
causes of 
allergic contact dermatitis
 are poison ivy or 
poison oak, topically applied antimicrobials (especially 
bacitracin and neomycin), anesthetics (benzocaine), pre
-
servatives, jewelry (nickel), rubber, essential oils, propolis 
(from bees), vitamin E, and adhesive tape. Occupational 
exposure is an important cause of allergic contact 
 
»
1. Allergic contact dermatitis—
The acute phase is charac
-
terized by intense pruritus, tiny vesicles and weepy and 
crusted lesions. The lesions, distributed on exposed parts 
or in bizarre asymmetric patterns, consist of erythematous 
macules, papules, and vesicles and may occur beyond the 
contact area, distinguishing it from irritant dermatitis. The 
affected area may also be edematous and warm, simulat
-
ing—and at times complicated by—infection. The pattern 
of the eruption may be diagnostic (eg, typical linear

-
of the eruption may be diagnostic (eg, typical linear 
streaked vesicles on the extremities in poison oak or ivy 
dermatitis [Figure 6–19]). The location will often suggest 
the cause: Scalp involvement suggests hair dyes or sham
-
poos; face involvement, creams, cosmetics, soaps, shaving 
materials, nail polish; and neck involvement, jewelry, hair 
dyes. Reactions may not develop for 48–72 hours after 
exposure.
2. Irritant contact dermatitis—
The rash is erythematous 
and scaly (but less likely vesicular) and occurs only in the 
direct sites of contact with the irritant. Resolving or 
chronic contact dermatitis presents with scaling, erythema, 
and possibly thickened skin. Itching, burning, and stinging 
may be severe in both allergic and irritant contact derma
-
titis. Reactions may develop within 24 hours of contact 
exposure.
Gram stain and culture will rule out impetigo or secondary 
infection (impetiginization). After the episode of allergic 
contact dermatitis has cleared, patch testing may be useful 
if the triggering allergen is not known.
 
»
Asymmetric distribution, blotchy erythema around the 
face, linear lesions, and a history of exposure help distin
-
guish acute contact dermatitis from other skin lesions. The 
most commonly mistaken diagnosis is impetigo or celluli
-
tis. Chronic allergic contact dermatitis must be differenti
-
ated from scabies, particularly if itching is generalized; 
atopic dermatitis; and pompholyx.
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▲
Figure 6–19.
 
Contact dermatitis with linear pattern 
due to poison ivy. 
(Used, with permission, from Berger TG, 
Dept Dermatology, UCSF.)
 
»
Prompt and thorough removal of the causative oil by 
washing with liquid soap may be effective if done within 
30 minutes after exposure to poison oak or ivy. Goop and 
Tecnu are also effective but much more expensive without 
increased efficacy. Over-the-counter barrier creams may 
be effective when applied prior to exposure and prevent/
reduce the severity of the dermatitis.
The mainstay of prevention is identification of the agent 
causing the dermatitis and strict avoidance of exposure or 
use of protective clothing and gloves. In industry-related 
cases, prevention may be accomplished by moving or 
retraining the worker.
 
»
Treatment
A. Overview
While local measures are important, severe or widespread 
involvement is difficult to manage without systemic corti
-
costeroids because even the highest-potency topical 
corticosteroids seem not to work well on vesicular and 
weepy lesions. Localized involvement (except on the face) 
can often be managed solely with topical agents. Irritant 
contact dermatitis is treated by protection from the irritant 
and use of topical corticosteroids as for atopic dermatitis 
(described above). The treatment of allergic contact der
-
matitis is detailed below.
1. Acute weeping dermatitis—
Gentle cleansing and dry
-
ing compresses (such as Domeboro) are recommended. 
Calamine lotion or zinc oxide paste may be used between 
wet dressings, especially for involvement of intertriginous 
areas or when oozing is not marked. Lesions on the 
extremities may be bandaged with wet dressings for 
30–60 minutes several times a day. High-potency topical 
corticosteroids in gel or cream form (eg, fluocinonide, 
clobetasol, or halobetasol) may help suppress acute contact 
dermatitis and relieve itching. This treatment should be 
followed by tapering of the number of applications per day 
or use of a mid-potency corticosteroid, such as triamcino
-
lone 0.1% cream to prevent rebound of the dermatitis. A 
soothing formulation is 2 oz of 0.1% triamcinolone aceton
-
ide cream in 7.5 oz Sarna lotion (0.5% camphor, 0.5% 
menthol, 0.5% phenol) mixed by the patient.
2. Subacute dermatitis (subsiding)—
Mid-potency 
(triamcinolone 0.1%) to high-potency corticosteroids 
(clobetasol, fluocinonide, desoximetasone) are the main
-
stays of therapy.
3. Chronic dermatitis (dry and lichenified)—
High-
potency to superpotency corticosteroids are used in ointment 
form. Occlusion may be helpful on the hands.
C. Systemic Therapy
For acute severe cases, prednisone may be given orally for 
12–21 days. Prednisone, 60 mg for 4–7 days, 40 mg for 
4–7 days, and 20 mg for 4–7 days without a further taper is 
one useful regimen. The key is to use enough corticosteroid 
(and as early as possible) to achieve a clinical effect and to 
taper slowly over 2–3 weeks to avoid rebound.
 
»
Prognosis
Allergic contact dermatitis is self-limited if reexposure is 
prevented but often takes 2–3 weeks for full resolution. 
Removal of the causative agent is paramount to avoid 
Mowad CM. Contact dermatitis: practice gaps and challenges. 
Dermatol Clin. 2016 Jul;34(3):263–7. [PMID: 27363882]
Mowad CM et al. Allergic contact dermatitis: patient diagnosis 
and evaluation. J Am Acad Dermatol. 2016 Jun;74(6):1029–40. 
[PMID: 27185421]
Mowad CM et al. Allergic contact dermatitis: patient manage
-
ment and education. J Am Acad Dermatol. 2016 Jun;
 
74(6):1043–54. [PMID: 27185422]
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▲
Figure 6–20.
 
Acne vulgaris, severe papulopustular 
and nodular cystic form with scarring. 
 
The Color 
p
US
t
UL
ar
 DISO
r
D
er
S
 
»
The most common skin condition.
 
»
Almost universal in puberty, though may begin in 
premenarchal girls and present or persist into the 
fourth or fifth decade.
 
»
Comedones are the hallmark. Severity varies from 
purely comedonal to papular or pustular inflam
-
matory acne to cysts or nodules.
 
»
Face, neck, and upper trunk may be affected.
 
»
Scarring may be a sequela of the disease or pick
-
ing by the patient.
 
»
Acne vulgaris is polymorphic. Open and closed comedo
-
nes, papules, pustules, and cysts are found.
In younger persons, acne vulgaris is more common and 
more severe in males. It does not always clear spontaneously 
when maturity is reached. Twelve percent of women and 3% 
of men over age 25 have acne vulgaris. This rate does not 
decrease until the fourth or fifth decade of life. The skin 
lesions parallel sebaceous activity. Pathogenic events include 
plugging of the infundibulum of the follicles, retention of 
sebum, overgrowth of the acne bacillus (
Propionibacterium 
acnes
) with resultant release of and irritation by accumu
-
lated fatty acids, and foreign-body reaction to extrafollicu
-
lar sebum. Antibiotics may help control acne because of 
their antibacterial or anti-inflammatory properties.
Hyperandrogenism may be a cause of acne in women 
and may or may not be accompanied by hirsutism, irregu
-
lar menses, or signs of virilism. Polycystic ovary syndrome 
(PCOS) is the most common identifiable cause. Acne may 
develop in patients who use systemic corticosteroids or 
topical fluorinated corticosteroids on the face. Acne may 
be exacerbated or caused by cosmetic creams or oils.
 
»
There may be mild tenderness, pain, or itching. The lesions 
occur mainly over the face, neck, upper chest, back, and 
shoulders. Comedones (tiny, flesh-colored, white or black 
noninflamed superficial papules that give the skin a rough 
texture or appearance) are the hallmark of acne vulgaris. 
Inflammatory papules, pustules, ectatic pores, acne cysts, 
and scarring are also seen (Figure 6–20).
Acne may have different presentations at different ages. 
Preteens often present with comedones as their first 
lesions. Inflammatory lesions in young teenagers are often 
found in the middle of the face, extending outward as the 
patient becomes older. Women in their third and fourth 
decades (often with no prior history of acne) commonly 
present with papular lesions on the chin and jawline.
 
»
In adults, rosacea presents with papules and pustules in the 
middle third of the face, but absence of truncal involvement, 
telangiectasia, flushing, and the absence of comedones dis
-
tinguish rosacea from acne vulgaris. A pustular eruption on 
the face in patients receiving antibiotics or with otitis externa 
should be investigated with culture to rule out a gram-
negative folliculitis. Pustules on the face can also be caused 
by tinea infections. Lesions on the back are more problem
-
atic. When they occur alone, staphylococcal folliculitis, mili
-
aria (“heat rash”) or, uncommonly, 
Malassezia (Pityrosporum)
 
folliculitis should be suspected. Bacterial culture, trial of an 
antistaphylococcal antibiotic, and observing the response to 
therapy will help in the differential diagnosis. In patients 
with HIV infection, folliculitis is common and may be either 
staphylococcal folliculitis or eosinophilic folliculitis (typi
-
cally pruritic tumid papules on the face and neck).
 
»
Cyst formation, pigmentary changes, scarring, and poor 
quality of life may result.
 
»
Treatment

-
 
»
 
»
Treatment
1. Education of the patient—
Education on proper use of 
medications and cosmetics is paramount. 
Because lesions 
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take 4–6 weeks to improve, clinical improvement should 
be measured by the number of new lesions forming after 
6–8 weeks of therapy.
 Additional time (3–4 months) will 
be required to see improvement on the back and chest, as 
these areas are slowest to respond. Avoid topical exposure 
to oils, cocoa butter (theobroma oil), and greases in cos
-
metics, including hair products. Scarring may occur with 
or without the patient manipulating the lesions. It is essen
-
tial that the patient be educated in a supportive way about 
this complication. Anxiety and depression are common in 
patients with excoriated acne.
2. Diet—
A low glycemic diet has been associated with 
improvement and lower incidence of acne. This improve
-
ment was associated with a reduction in insulin resistance. 
Hyperinsulinemia has also been associated with acne in 
both eumenorrheic women and individuals with PCOS.
B. Comedonal Acne
Treatment of acne is based on the type and severity of 
lesions. Comedones require treatment different from that 
of pustules and cystic lesions. In assessing severity, take the 
sequelae of the lesions into account. An individual who 
gets only a few new lesions per month that scar or leave 
postinflammatory hyperpigmentation must be treated 
much more aggressively than a comparable patient whose 
lesions clear without sequelae. Hygiene plays little role in 
acne treatment, and a mild soap is almost always recom
-
mended. The agents effective in comedonal acne are listed 
below in the order in which they should be tried.
1. Topical retinoids—
Tretinoin is very effective for come
-
donal acne or for treatment of the comedonal component 
of more severe acne, but its usefulness is limited by irrita
-
tion. Start with 0.025% cream (not gel) and have the patient 
use it at first twice weekly at night, increasing frequency to 
nightly as tolerated. A few patients cannot use even this 
low-strength preparation more than three times weekly but 
even that may cause improvement. A lentil-sized amount is 
sufficient to cover the entire face. To avoid irritation, have 
the patient wait 20 minutes after washing to apply. Ada
-
palene gel 0.1% and reformulated tretinoin (Renova, Retin 
A Micro, Avita) are other options for patients irritated by 
standard tretinoin preparations. Although the absorption 
of tretinoin is minimal, its use during pregnancy is contra
-
indicated. Patients should be warned that their acne may 
flare in the first 4 weeks of treatment.
2. Benzoyl peroxide—
Benzoyl peroxide products are 
available in concentrations of 2.5%, 4%, 5%, 8%, and 10%, 
but 2.5% is as effective as 10% and less irritating. In gen
-
eral, water-based and not alcohol-based gels should be 
used to decrease irritation. Benzoyl peroxide in combina
-
tion with several other topical agents, including adapalene 
and topical antibiotics (erythromycin, clindamycin phos
-
phate), are available as a single formulation.
C. Papular or Cystic Inflammatory Acne
Brief treatment (3 weeks to 3 months) with topical or oral 
antibiotics is the mainstay for treatment of inflammatory 
acne that does not respond to topical therapy 
with retinoids or benzoyl peroxide. Topical clindamycin 
phosphate and erythromycin are used only for mild papu
-
lar acne that can be controlled by topicals alone or for 
patients who refuse or cannot tolerate oral antibiotics. To 
decrease resistance, benzoyl peroxide should be used in 
combination with the topical antibiotic.
1. Mild acne—
The first choice of topical antibiotics in terms 
of efficacy and relative lack of induction of resistant 
P acnes
 
is the combination of erythromycin or clindamycin with 
benzoyl peroxide topical gel or wash. These may be used 
once or twice daily. The addition of tretinoin cream or gel at 
night may increase improvement, since it works via a differ
-
ent mechanism. Topical retinoids ideally are used after acne

-
ent mechanism. Topical retinoids ideally are used after acne 
clearance is achieved as a long-term maintenance therapy.
2. Moderate acne—
Common oral antibiotics used for 
acne include doxycycline (100 mg twice daily), minocy
-
cline (50–100 mg once or twice daily), TMP-SMZ (one 
double-strength tablet twice daily), or a cephalosporin 
(cefadroxil or cephalexin 500 mg twice daily), which 
should be used in combination with benzoyl peroxide to 
minimize development of antibiotic resistance. Once the 
patient’s skin is clear, instructions should be given for 
tapering the dose by 50% every 6–8 weeks—while treating 
with topical antibiotics or retinoids—to arrive at the lowest 
systemic dose needed to maintain clearing. In general, 
discontinuing antibiotics immediately without adjunctive 
topical therapy results in prompt recurrence. Topical reti
-
noids are excellent for long-term maintenance following 
antibiotics. Subantimicrobial dosing of doxycycline can be 
used in patients who require long-term systemic therapy. 
Combination oral contraceptives or spironolactone 
(50–200 mg/day) are highly effective alternatives in women 
with treatment-resistant acne. Tetracycline, minocycline, 
and doxycycline are contraindicated in pregnancy, but cer
-
tain oral erythromycins or cephalosporins may be used.
3. Severe acne—
a. 
I
sotretinoin—
A vitamin A analog, isotretinoin is 
used for the treatment of severe acne that has not responded 
to conventional therapy. A dosage of 0.5–1 mg/kg/day for 
20 weeks for a cumulative dose of at least 120 mg/kg is usu
-
ally adequate for severe cystic acne. Patients should be 
offered isotretinoin therapy before they experience signifi
-
cant scarring if they are not promptly and adequately con
-
trolled by antibiotics. 
The medication is absolutely 
contraindicated during pregnancy because of its terato
-
genicity.
 Two forms of effective contraception must be 
used; abstinence is an acceptable alternative. Informed 
consent must be obtained before its use, and patients must 
be enrolled in a monitoring program (iPledge). In addition 
to its teratogenicity, isotretinoin has numerous serious side 
effects and should only be prescribed by clinicians (usually 
dermatologists) well aware of these issues. Consider order
-
ing laboratory tests, including total cholesterol levels, tri
-
glyceride levels, and liver enzyme tests (particularly alanine 
aminotransferase, which is the most liver-specific enzyme) 
in patients before treatment and after achieving therapeu
-
tic dosing; monitoring through the entire treatment may 
not be high value.
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▲
Figure 6–21.
 
Rosacea in a 34-year-old woman 
showing erythema, papules, and pustules covering 
much of the face.
 (Used, with permission, from Richard P . 
Chumley H. 
, 2nd ed. 
Abnormal laboratory tests, especially elevated liver 
enzymes and triglyceride levels, return to normal quickly 
upon conclusion of therapy. The medication may induce 
long-term remissions in 40–60%, or acne may recur that is 
more easily controlled with conventional therapy. Occa
-
sionally, a second course is needed if acne does not respond 
or recurs.
b. 
I
ntralesional injection—
Intralesional injection of 
dilute suspensions of triamcinolone acetonide (2.5 mg/mL, 
0.05 mL per lesion) will often hasten the resolution of 
deeper papules and occasional cysts.
c. 
S
car revision—
Cosmetic improvement may be 
achieved by excision and punch-grafting of deep scars and 
by physical or chemical abrasion of inactive acne lesions, 
particularly flat, superficial scars.
 
»
Prognosis
Acne vulgaris eventually remits spontaneously, but when 
this will occur cannot be predicted. The condition may 
persist throughout adulthood and may lead to severe scar
-
ring if left untreated. Patients treated with antibiotics con
-
tinue to improve for the first 3–6 months of therapy. 
Relapse during treatment may suggest the emergence of 
resistant 
P acnes
. The disease is chronic and tends to flare 
intermittently in spite of treatment. Remissions following 
systemic treatment with isotretinoin may be lasting in up 
to 60% of cases. Relapses after isotretinoin usually occur 
within 3 years and require a second course in up to 20% of 
patients. Immediate relapse after isotretinoin discontinua
-
tion may suggest hyperandrogenism or other underlying 
hormonal disorders in a female patient.
Bienenfeld A et al. Oral antibacterial therapy for acne vulgaris: 
an evidence-based review. Am J Clin Dermatol. 2017 
Aug;18(4):469–90. [PMID: 28255924]
Zaenglein AL et al. Guidelines of care for the management of 
acne vulgaris. J Am Acad Dermatol. 2016 Feb;4:945–73. 
[PMID: 26897386]
ROSACEA
 
»
A chronic disorder affecting the face.
 
»
Neurovascular component: erythema and telangi
-
ectasis and a tendency to flush easily.
 
»
Acneiform component: papules and pustules may 
 
»
Glandular component: sebaceous hyperplasia and 
fibrosis of affected areas (eg, rhinophyma).
 
»
Rosacea is a common condition that presents in adulthood. 
The pathogenesis of this chronic disorder is not known. 
Topical corticosteroids applied to the face can induce 
rosacea-like conditions.
 
»
Patients frequently report flushing or exacerbation of their 
rosacea due to heat, hot drinks, spicy food, sunlight, exer
-
cise, alcohol, emotions, or menopausal flushing. The 
cheeks, nose, chin, and ears —at times the entire face—may 
be affected. No comedones are seen. In its mildest form, 
erythema and telangiectasias are seen on the cheeks. 
Inflammatory papules may be superimposed on this back
-
ground and may evolve to pustules (Figure 6–21). Associ
-
ated seborrhea may be found. The patient often complains 
of burning or stinging with episodes of flushing and 
extremely cosmetic-intolerant skin. Patients may have 
associated ophthalmic disease, including blepharitis, kera
-
titis, and chalazion, which often requires topical or sys
-
temic antibiotic or immunosuppressive therapy.
 
»
Rosacea is distinguished from acne by the presence of the 
neurovascular component and the absence of comedones. 
Lupus is often misdiagnosed, but the presence of pustules 
excludes that diagnosis.
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»
Treatment
Educating patients to avoid the factors they know to pro
-
duce exacerbations is important. Patients should wear a 
broad-spectrum mineral-based sunscreen; zinc- or tita
-
nium-based sunscreens are tolerated best. Medical man
-
agement is most effective for the inflammatory papules and 
pustules and the erythema that surrounds them. Rosacea is 
usually a lifelong condition, so maintenance therapy is 
required. Telangiectases are benefited by laser therapy, and 
phymatous overgrowth of the nose can be treated by surgi
-
cal reduction.
A. Local Therapy
Avoidance of triggers (especially alcohol and spicy or hot 
foods) and drinking ice water may be effective in reducing 
facial erythema and flushing. Metronidazole (available as 
creams, gels, or lotions), 0.75% applied twice daily or 1% 
applied once daily, and ivermectin 1% cream applied 
once daily are effective topical treatments. Another effec
-
tive treatment includes topical clindamycin (solution, 
gel, or lotion) 1% applied twice daily. Response is noted in 
4–8 weeks. Sulfur-sodium sulfacetamide-containing topi
-
cals are helpful in patients only partially responsive to topi
-
cal antibiotics. Topical retinoids can be carefully added for 
maintenance. Topical brimonidine tartrate gel 0.33% or 
oxymetazoline 1% cream can temporarily reduce the 
erythema.
B. Systemic Therapy
Oral tetracyclines should be used when topical therapy is 
inadequate. Minocycline or doxycycline, 50–100 mg orally 
once or twice daily, is effective. Metronidazole or amoxicil
-
lin, 250–500 mg orally twice daily, or rifaximin, 400 mg 
orally three times daily (for 10 days), may be used in refrac
-
tory cases. Side effects are few, although metronidazole 
may produce a disulfiram-like effect when the patient 
ingests alcohol, and it may cause neuropathy with long-
term use. Long-term maintenance with subantimicrobial 
dosing of minocycline or doxycycline is recommended 
once the initial flare of rosacea has resolved. Isotretinoin 
may succeed where other measures fail. A dosage of 
0.5 mg/kg/d orally for 12–28 weeks is recommended, 
although very low-dose isotretinoin may also be effective. 
See precautions above.
 
»
Prognosis
Rosacea tends to be a persistent process. With the regimens 
described above, it can usually be controlled adequately.
Two AM et al. Rosacea: part I. Introduction, categorization, 
histology, pathogenesis, and risk factors. J Am Acad Dermatol. 
2015 May;72(5):749–58. [PMID: 25890455]
Two AM et al. Rosacea: part II. Topical and systemic therapies in 
the treatment of rosacea. J Am Acad Dermatol. 2015 May;
 
72(5):761–70. [PMID: 25890456]
Van Zuuren EJ et al. Interventions for rosacea: abridged updated 
Cochrane systematic review including GRADE assessments. 
Br J Dermatol. 2015 Sep;173(3):651–62. [PMID: 26099423]
FOLLICULITIS (
Including Sycosis
)
 
»
Itching and burning in hairy areas.
 
»
Pustule surrounding and including the hair 
follicle.
 
»
Folliculitis
 has multiple causes. It is frequently caused by 
staphylococcal infection and may be more common in the 
diabetic patient. When the lesion is deep-seated, chronic, 
and recalcitrant on the head and neck, it is called 
sycosis.
Gram-negative folliculitis,
 which may develop during 
antibiotic treatment of acne, may present as a flare of acne 
pustules or nodules. 
Klebsiella, Enterobacter, Escherichia 
coli
, and 
Proteus
 have been isolated from these lesions.
Hot tub folliculitis (
Pseudomonas
 folliculitis)
, caused 
by 
, is characterized by pruritic or 
tender follicular, pustular lesions occurring within 1–4 days 
after bathing in a contaminated hot tub, whirlpool, or 
swimming pool. Systemic flu-like symptoms may accom
-
pany cutaneous lesions. Rarely, systemic infections may 
result. Neutropenic patients should avoid these exposures.
Nonbacterial folliculitis

-
 may also be caused by friction 
and oils. Occlusion, perspiration, and rubbing, such as that 
resulting from tight jeans and other heavy fabrics on the 
upper legs can worsen this type of folliculitis.
Steroid acne
 may be seen during topical or systemic 
corticosteroid therapy and presents as eruptive monomor
-
phous papules and papulopustules on the face and trunk. It 
responds to topical benzoyl peroxide.
Eosinophilic folliculitis
 is a sterile folliculitis that pres
-
ents with urticarial papules with prominent eosinophilic 
infiltration. It is common in patients with AIDS. It may 
appear first with institution of highly active antiretroviral 
therapy (ART) and be mistaken for a drug eruption.
Pseudofolliculitis
 is caused by ingrowing hairs in the 
beard area. It occurs in men and women with tightly curled 
beard hair. In this entity, the papules and pustules are 
located at the side of and not in follicles. It may be treated 
by growing a beard, by using chemical depilatories, or by 
shaving with a foil-guard razor. Laser hair removal, medi
-
cally indicated, is dramatically beneficial in patients with 
pseudofolliculitis, requires limited maintenance, and can 
be done on patients of any skin color.
 folliculitis
 presents as 
1–2-mm pruritic pink papulopustules on the upper trunk 
and arms. It is often pruritic and tends to develop during 
periods of excessive sweating.
Demodex folliculitis
 is caused by the mite 
Demodex 
folliculorum
 and presents as 1–2 mm papules and pustules 
on an erythematous base, often on the background of 
rosacea-like changes, in patients who have not responded 
to conventional treatment for rosacea. It is more common 
in immunosuppressed patients. KOH from the pustules 
will demonstrate 
Demodex folliculorum
 mites.
CMDT19_Ch06_p0103-p0173.indd   137

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▲
Figure 6–22.
 
Bacterial folliculitis. Note the hair emi
-
nating from the center of the pustule, the clinical hall
-
mark of folliculitis. 
Chumley H. 
 2nd ed. 
 
»
The symptoms range from slight burning and tenderness 
to intense itching. The lesions consist of pustules of hair 
follicles (Figure 6–22).
 
»
It is important to differentiate bacterial from nonbacterial 
folliculitis. The history is important for pinpointing the 
causes of nonbacterial folliculitis, and a Gram stain and 
culture are indispensable. One must differentiate folliculitis 
from acne vulgaris or pustular miliaria (heat rash) and 
from infections of the skin, such as impetigo or fungal 
infections, especially 
 folliculitis. 
 folliculitis is often suggested by the history of 
hot tub use. Eosinophilic folliculitis in AIDS often requires 
biopsy for diagnosis.
 
»
Abscess formation is the major complication of bacterial 
folliculitis.
 
»
Correct any predisposing local causes, such as oils or fric
-
tion. Be sure that the water in hot tubs and spas is treated 
properly. If staphylococcal folliculitis is persistent, treat
-
ment of nasal or perineal carriage with rifampin, 600 mg 
daily for 5 days, or with topical mupirocin ointment 2% 
twice daily for 5 days, may help. Prolonged oral clindamy
-
cin, 150–300 mg/day for 4–6 weeks, or oral TMP-SMZ 
given 1 week per month for 6 months can be effective in 
preventing recurrent staphylococcal folliculitis and 
furunculosis. Bleach baths (¼ to ½ cup per 20 liters of 
bathwater for 15 minutes 3–5 times weekly) may reduce 
cutaneous staphylococcal carriage and not contribute to 
antibiotic resistance. Control of blood glucose in diabetes 
may reduce the number of these infections.
 
»
Treatment
Anhydrous ethyl alcohol containing 6.25% aluminum 
chloride (Xerac AC), applied three to seven times weekly to 
lesions and environs, may be helpful, especially for chronic 
frictional folliculitis of the buttocks. Topical antibiotics are 
generally ineffective if bacteria have invaded the hair folli
-
cle but may be prophylactic if used as an aftershave in 
patients with recurrent folliculitis after shaving.
 folliculitis will clear spontaneously in non-
neutropenic patients if the lesions are superficial. It may 
be treated with ciprofloxacin, 500 mg orally twice daily for 
5 days.
Systemic antibiotics are recommended for bacterial fol
-
liculitis due to other organisms. Extended periods of treat
-
ment (4–8 weeks or more) with antistaphylococcal 
antibiotics are required if infection has involved the scalp 
or densely hairy areas, such as the axilla, beard, or groin 
(see Table 30–4).
Gram-negative folliculitis in acne patients may be 
treated with isotretinoin in compliance with all precautions 
discussed above (see Acne Vulgaris).
Eosinophilic folliculitis may be treated initially by the 
combination of potent topical corticosteroids and oral anti
-
histamines. In more severe cases, treatment is with one of 
the following: topical permethrin (application for 12 hours 
every other night for 6 weeks); itraconazole, 200–400 mg 
orally daily; UVB or PUV A phototherapy; or isotretinoin, 
0.5 mg/kg/day orally for up to 5 months. A remission may 
be induced by some of these therapies, but long-term treat
-
ment may be required.
 folliculitis is treated with 
topical sulfacetamide lotion twice a day, alone or in combi
-
nation with itraconazole or fluconazole.
Demodex folliculitis is treated with topical 5% perme
-
thrin applied every other night or ivermectin either by 
daily topical or weekly oral administration.
 
»
Prognosis

-
 
»
Prognosis
Bacterial folliculitis is occasionally stubborn and persis
-
tent, requiring prolonged or intermittent courses of 
antibiotics.
Bachmeyer C et al. Demodex folliculitis. CMAJ. 2017 Jun 26;
 
189(25):E865. [PMID: 28652482]
Laureano AC et al. Facial bacterial infections: folliculitis. Clin 
Dermatol. 2014 Nov–Dec;32(6):711–4. [PMID: 25441463]
Pedrosa AF et al. Malassezia infections: a medical conundrum. J 
Am Acad Dermatol. 2014 Jul;71(1):170–6. [PMID: 24569116]
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MILIARIA (
Heat Rash
)
 
»
Burning, itching, superficial aggregated small 
vesicles, papules, or pustules on covered areas of 
the skin, usually the trunk.
 
»
More common in hot, moist climates.
 
»
Rare forms associated with fever and even heat 
prostration.
 
»
Miliaria occurs most commonly on the trunk and inter
-
triginous areas. A hot, moist environment is the most fre
-
quent cause. Occlusive clothing required for certain 
occupations may increase the risk. Bedridden febrile 
patients are susceptible. Plugging of the ostia of sweat ducts 
occurs, with ultimate rupture of the sweat duct, producing 
an irritating, stinging reaction. Increase in numbers of resi
-
dent aerobes, notably cocci, plays a role. Medications that 
enhance sweat gland function (eg, clonidine, beta-blockers, 
opioids) may contribute.
 
»
The usual symptoms are burning and itching. The histo
-
logic depth of sweat gland obstruction determines the 
clinical presentation: 
miliaria crystallina
 in the superficial 
(subcorneal) epidermis, 
miliaria rubra
 in the deep epider
-
mis, and 
miliaria profunda
 in the dermis. The lesions 
consist of small (1–3 mm) nonfollicular lesions. Subcor
-
neal thin-walled, discrete clear fluid-filled vesicles are 
termed “miliaria crystallina. ” When fluid is turbid and 
lesions present as vesicopustules or pustules, they are called 
miliaria pustulosa.
 Miliaria rubra (prickly heat) presents 
as pink papules. Miliaria profunda presents as nonfollicu
-
lar skin-colored papules that develop after multiple bouts 
of miliaria rubra. In a hospitalized patient, the reaction 
virtually always affects the back.
 
»
Miliaria is to be distinguished from a drug eruption and 
 
»
Use of a topical antibacterial preparation, such as chlorhex
-
idine, prior to exposure to heat and humidity may help 
prevent the condition. Frequent turning or sitting of the 
hospitalized patient may reduce miliaria on the back.
 
»
Treatment
The patient should keep cool and wear light clothing. 
Triamcinolone acetonide, 0.1% in Sarna lotion, or a 
mid-potency corticosteroid in a lotion or cream may be 
applied two to four times daily. Secondary infections 
(superficial pyoderma) are treated with appropriate anti
-
staphylococcal antibiotics. Anticholinergic medications 
(eg, glycopyrrolate 1 mg orally twice a day) may be help
-
ful in severe cases.
 
»
Prognosis
Miliaria is usually a mild disorder, but severe forms (tropi
-
cal anhidrosis and asthenia) result from interference with 
the heat-regulating mechanism.
Tey HL et al. In vivo imaging of miliaria profunda using high-
definition optical coherence tomography: diagnosis, pathogen
-
esis, and treatment. JAMA Dermatol. 2015 Mar 1;151(3):
 
346–8. [PMID: 25390622]
Y anamandra U et al. Miliaria crystallina: relevance in patients 
with hemato-oncological febrile neutropenia. BMJ Case Rep. 
2015 Nov 26;5:212231. [PMID: 26611484]
MUCOCUTANEOUS CANDIDIASIS
 
»
Severe pruritus of vulva, anus, or body folds.
 
»
Superficial denuded, beefy-red areas with or with
-
out satellite vesicopustules.
 
»
Whitish curd-like concretions on the oral and vagi
-
nal mucous membranes.
 
»
Yeast and pseudohyphae on microscopic exami
-
nation of scales or curd.
 
»
Mucocutaneous candidiasis is a superficial fungal infection 
that may involve almost any cutaneous or mucous surface 
of the body. It is particularly likely to occur in diabetic 
patients, during pregnancy, in obese persons, and in the 
setting of immunosuppression. Systemic antibiotics, oral 
corticosteroids, hormone replacement therapy, and oral 
contraceptive agents may be contributory. Oral and inter
-
digital candidiasis may be the first sign of HIV infection 
(see Chapter 31). Denture use predisposes the elderly to 
 
»

-
 
»
Itching may be intense. Burning is reported, particularly 
around the vulva and anus. The lesions consist of superfi
-
cially denuded, beefy-red areas in the depths of the body 
folds, such as in the groin and the intergluteal cleft, beneath 
the breasts, at the angles of the mouth, in the webspaces of 
digits, and in the umbilicus. The peripheries of these 
CMDT19_Ch06_p0103-p0173.indd   139

Chapter 6
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▲
Figure 6–23.
 
Oral mucosal candidiasis. 
(Used with 
permission from Sol Silverman, Jr, DDS, Public Health 
Image Library, CDC.)
denuded lesions are superficially undermined, and there 
may be satellite vesicopustules. Whitish, curd-like concre
-
tions may be present on mucosal lesions (Figure 6–23). 
Paronychia may occur.
Clusters of budding yeast and pseudohyphae can be seen 
under high power (400×) when skin scales or curd-like 
lesions are mounted in 10% KOH. Culture can confirm the 
 
»
Intertrigo, seborrheic dermatitis, tinea cruris, “inverse pso
-
riasis” , and erythrasma involving the same areas may 
mimic mucocutaneous candidiasis.
 
»
Systemic invasive candidiasis with candidemia may be seen 
with immunosuppression and in patients receiving broad-
spectrum antibiotic and hypertonic glucose solutions, as in 
hyperalimentation. There may or may not be clinically 
evident mucocutaneous candidiasis.
 
»
Treatment
Affected parts should be kept dry and exposed to air as 
much as possible. Water immersion should be minimized 
and gloves should be worn for those with infected nails or 
digital skin. If possible, discontinue systemic antibiotics. For 
treatment of systemic invasive candidiasis, see Chapter 36.
1. Nails and paronychia—
Apply clotrimazole solution 1% 
twice daily. Thymol 4% in ethanol applied once daily is an 
alternative.
2. Skin—
Apply nystatin ointment or clotrimazole cream 
1%, either with hydrocortisone cream 1%, twice daily. 
Gentian violet 0.5% solution is economical and highly 
effective in treating mucocutaneous candidiasis, but the 
purple discoloration may represent a cosmetic issue. 
Severe or widespread cutaneous disease responds to flu
-
conazole, 100–200 mg orally daily, for 1 week.
3. Vulvar and anal mucous membranes—
For vaginal 
candidiasis, single-dose fluconazole (150 mg orally) is 
effective. Intravaginal clotrimazole, miconazole, tercon
-
azole, or nystatin may also be used. Long-term suppressive 
therapy may be required for recurrent or “intractable” 
cases. Non-albicans candidal species may be identified by 
culture in some refractory cases and may respond to oral 
itraconazole, 200 mg twice daily for 2–4 weeks.
4. Balanitis—
This is most frequent in uncircumcised men, 
and 
Candida
 usually plays a role. Topical nystatin ointment 
is the initial treatment if the lesions are mildly erythema
-
tous or superficially erosive. Soaking with dilute aluminum 
acetate for 15 minutes twice daily may quickly relieve burn
-
ing or itching. Chronicity and relapses, especially after 
sexual contact, suggest reinfection from a sexual partner 
who should be treated. Severe purulent balanitis is usually 
due to bacteria. If it is so severe that phimosis occurs, oral 
antibiotics—some with activity against anaerobes—are 
required; if rapid improvement does not occur, urologic 
consultation is indicated.
5. Mastitis—
Lancinating breast pain and nipple dermatitis 
in breast-feeding women may be a manifestation of 
Candida
 colonization/infection of the breast ducts. Topical 
nystatin cream and clotrimazole 0.1% cream are safe dur
-
ing lactation. Topical gentian violet 0.5% daily for 7 days is 
also useful. Oral fluconazole, 200 mg daily for 2 weeks, can 
be dramatically effective.
 
»
Prognosis
Cases of cutaneous candidiasis range from the easily cured 
to the intractable and prolonged.
Gonçalves B et al. Vulvovaginal candidiasis: epidemiology, 
microbiology and risk factors. Crit Rev Microbiol. 2016 Nov;
 
42(6):905–27. [PMID: 26690853]
Millsop JW et al. Oral candidiasis. Clin Dermatol. 2016 Jul–Aug;
 
34(4):487–94. [PMID: 27343964]
Pappas PG et al. Executive summary: clinical practice guideline 
for the management of candidiasis: 2016 update by the Infectious 
Diseases Society of America. Clin Infect Dis. 2016 Feb 15;
 
62(4):409–17. [PMID: 26810419]

Pichard DC et al. Primary immunodeficiency update: part II. 
Syndromes associated with mucocutaneous candidiasis and 
noninfectious cutaneous manifestations. J Am Acad Dermatol. 
2015 Sep;73(3):367–81. [PMID: 26282795]
Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet 
Gynecol. 2016 Jan;214(1):15–21. [PMID: 26164695]
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Figure 6–24.
 
Urticaria. 
Berger TG, Dept Dermatology, UCSF.)
er
Y
the
M
a
S
REACTIVE ERYTHEMAS
1. Urticaria & 
a
ngioedema
 
»
Eruptions of evanescent wheals or hives.
 
»
Itching is intense but, rarely, may be absent.
 
»
Special forms of urticaria have special features 
(dermatographism, cholinergic urticaria, solar 
urticaria, or cold urticaria).
 
»
Most incidents are acute and self-limited 
 
(1–2 weeks).
 
»
Chronic urticaria (episodes lasting longer than 
 
6 weeks) may have an autoimmune basis.
 
»
Urticaria is defined as acute (less than 6 weeks’ duration) or 
chronic (more than 6 weeks’ duration). Urticaria can result 
from many different stimuli on an immunologic or nonim
-
munologic basis. The most common immunologic mecha
-
nism is mediated by IgE, as seen in the majority of patients 
with acute urticaria; another involves activation of the 
complement cascade. Some patients with chronic urticaria 
demonstrate autoantibodies directed against mast cell IgE 
receptors. ACE inhibitor and angiotensin receptor blocker 
therapy may be complicated by urticaria or angioedema. In 
general, extensive costly workups are not indicated in 
patients who have urticaria. A careful history and physical 
examination are more helpful.
 
»
Lesions are itchy, red swellings of a few millimeters to many 
centimeters (Figure 6–24). The morphology of the lesions 
may vary over a period of minutes to hours, resulting in 
geographic or bizarre patterns. Individual lesions in true 
urticaria last less than 24 hours, and often only 2–4 hours. 
Angioedema is involvement of deeper subcutaneous tissue 
with swelling of the lips, eyelids, palms, soles, and genitalia. 
Angioedema is no more likely than urticaria to be associ
-
ated with systemic complications, such as laryngeal edema 
or hypotension.
 In cholinergic urticaria, which is triggered 
by a rise in core body temperature (hot showers, exercise), 
wheals are 2–3 mm in diameter with a large surrounding red 
flare. Cold urticaria is acquired or inherited and triggered by 
exposure to cold and wind (see Chapter 37).
The most common causes of acute urticaria are foods, 
infections, and medications. The cause of chronic urticaria 
is often not found. Although laboratory studies are not 
likely to be helpful in the evaluation of acute or chronic 
urticaria, a complete blood count with differential, eryth
-
rocyte sedimentation rate, C-reactive protein, thyroid-
stimulating hormone, and liver biochemical tests might be 
appropriate for some patients with chronic urticaria. In 
patients with individual lesions that persist past 24 hours, 
skin biopsy may confirm neutrophilic urticaria or urticar
-
ial vasculitis. A functional ELISA test looking for antibod
-
ies against the high-affinity receptor for IgE (Fc-Epislon RI) 
can detect patients with an autoimmune basis for their 
chronic urticaria.
 
»
Papular urticaria resulting from insect bites persists for 
days. A central punctum can usually be seen. Streaked 
urticarial lesions may be seen in the 24–48 hours before 
blisters appear in acute allergic plant dermatitis, eg, poi
-
son ivy, oak, or sumac. Urticarial responses to heat, sun, 
water, and pressure are quite rare. Urticarial vasculitis 
may be seen as part of serum sickness, associated with 
fever and arthralgia. In this setting, a low serum comple
-
ment level may be associated with severe systemic 
disease.
In hereditary angioedema, there is generally a positive 
family history and gastrointestinal or respiratory symp
-
toms. Urticaria is not part of the syndrome, and lesions are 
not pruritic.
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»
Treatment
A detailed search by history for a cause of acute urticaria 
should be undertaken, and treatment may then be tailored 
to include the provocative condition. The chief causes are 
medications—eg, aspirin, NSAIDs, ACE inhibitor, angio
-
tensin receptor blocker, morphine, and codeine; arthropod 
bites—eg, insect bites and bee stings (though the latter may 
cause anaphylaxis as well as angioedema); physical factors, 
such as heat, cold, sunlight, and pressure; and, presumably, 
neurogenic factors, as in cholinergic urticaria induced by 
exercise, excitement, hot showers, etc. Other causes may 
include penicillins and other medications; inhalants such 
as feathers and animal danders; ingestion of shellfish, 
tomatoes, or strawberries; infections, such as viral hepatitis 
(causing urticarial vasculitis); and in selected patients 
salicylates and tartrazine dyes.
B. Systemic Treatment
The mainstay of treatment initially includes H
1
-antihista
-
mines. Initial therapy is hydroxyzine, 10 mg orally twice 
daily to 25 mg three times daily, or as a single nightly dose 
of 50–75 mg to reduce daytime sedation. Cyproheptadine, 
4 mg orally four times daily, may be especially useful for 
cold urticaria. “Nonsedating” or less sedating antihista
-
mines are added if the generic sedating antihistamines are 
not effective. Options include fexofenadine, 180 mg orally 
once daily; or cetirizine or loratadine, 10 mg orally daily. 
Higher doses of these second-generation antihistamines 
may be required to suppress urticaria (up to four times the 
standard recommended dose) than are required for allergic 
rhinitis. Combining antihistamines (eg, fexofenadine plus 
cetirizine) at these higher doses can be done safely to 
achieve remission in refractory cases, since less than 40% 
of cases of chronic urticaria respond to standard to H
1
 
blockade. Montelukast (10 mg orally daily) in combination 
with antihistamines appears to have a therapeutic benefit.
Doxepin (a tricyclic antidepressant with potent antihis
-
taminic properties), 10–75 orally mg at bedtime, can be 
very effective in chronic urticaria. It has anticholinergic 
side effects.
H
2
-antihistamines in combination with H
1
-blockers 
may be helpful in patients with symptomatic dermatogra
-
phism and to a lesser degree in chronic urticaria. UVB 
phototherapy can suppress some cases of chronic urti
-
caria. If a skin biopsy of a lesion of chronic urticaria iden
-
tifies neutrophils as a significant component of the 
inflammatory infiltrate, dapsone or colchicine (or both) 
A few patients with chronic urticaria may respond to 
elimination of salicylates and tartrazine (a coloring agent). 
Asymptomatic foci of infection—sinusitis, vaginal candidi
-
asis, cholecystitis, and intestinal parasites—may rarely cause 
chronic urticaria. Although systemic corticosteroids in a 
dose of about 40 mg daily will usually suppress acute and 
chronic urticaria, the use of corticosteroids is rarely indi
-
cated and, once withdrawn, the urticaria virtually always 
returns. Instead of instituting systemic corticosteroids, 
consultation should be sought from a dermatologist or an 
allergist with experience in managing severe urticaria. 
Cyclosporine (3–5 mg/kg/day), mycophenolate mofetil, and 
other immunosuppressives may be effective in severe cases 
of chronic urticaria. Omalizumab is approved for the treat
-
ment of refractory chronic urticaria and should be consid
-
ered when severe chronic urticaria fails to respond to 
high-dose antihistamines.
C. Local Treatment
Local treatment is rarely rewarding.
 
»
Prognosis
Acute urticaria usually lasts only a few days to weeks. Half 
of patients whose urticaria persists for longer than 6 weeks 
will have it for years. Patients in whom angioedema devel
-
ops with an ACE inhibitor may be switched to an angioten
-
sin receptor blocker with caution (estimated cross-reaction 
about 10%).

-
-
Fine LM et al. Guideline of chronic urticaria beyond. Allergy 
Asthma Immunol Res. 2016 Sep;8(5):396–403. [PMID: 
27334777]
Gill P et al. The clinical evaluation of angioedema. Immunol 
Allergy Clin North Am. 2017 Aug;37(3):449–66. [PMID: 
28687102]
Guillén-Aguinaga S et al. Updosing nonsedating antihistamines in 
patients with chronic spontaneous urticaria: a systematic 
review and meta-analysis. Br J Dermatol. 2016 Dec;175(6):
 
1153–65. [PMID: 27237730]
Rutkowski K et al. How to manage chronic urticaria ‘beyond’ 
guidelines: a practical algorithm. Clin Exp Allergy. 2017 
Jun;47(6):710–8. [PMID: 28452145]
Saini SS et al. Efficacy and safety of omalizumab in patients with 
chronic idiopathic/spontaneous urticaria who remain symp
-
tomatic on H
1
 antihistamines: a randomized, placebo-con
-
trolled study. J Invest Dermatol. 2015 Mar;135(3):925. [PMID: 
25501032]
2. 
e
rythema Multiforme/Stevens-Johnson 
Syndrome/
t
o
xic 
e
pidermal Necrolysis
Erythema multiforme
 
»
Herpes simplex is most common cause.
 
»
Cutaneous lesions are true three ring targets.
 
»
Presents on the extensor surfaces, palms, soles, or 
mucous membranes.
 
»
Disease remains localized.
Stevens-Johnson syndrome and toxic epidermal 
necrolysis
 
»
Stevens-Johnson syndrome:
 Less than 10% BSA 
detachment
 
»
Toxic epidermal necrolysis:
 Greater than 10% BSA 
 
»
Medications are most common cause.
 
»
Cutanoues lesions are targetoid but often not true 
three ring targets.
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▲
Figure 6–25.
 
Erythema multiforme with classic tar
-
get lesions. Note the three zones of color change. 
(Used, 
 
»
Favors the trunk.
 
»
Involves two or more mucous membranes.
 
»
May progress so that significant body surface is 
involved and may be life-threatening.
 
»
Erythema multiforme is an acute inflammatory skin disease 
that was traditionally divided clinically into minor and 
major types based on the clinical findings. Approximately 
90% of cases of erythema multiforme minor follow out
-
breaks of herpes simplex, and so is preferably termed 
her
-
pes-associated erythema multiforme.
 The term “erythema 
multiforme major” has largely been abandoned. 
Stevens-
Johnson syndrome
 
(SJS)
 is defined as atypical target lesions 
with less than 10% BSA detachment; 
toxic epidermal 
 
(TEN)
 when there is greater than 30% BSA 
detachment; and 
SJS/TEN overlap
 for cases with between 
10% and 30% BSA detachment. The abbreviation SJS/TEN 
is often used to refer to these three variants of what is con
-
sidered one syndrome. All these clinical scenarios are char
-
acterized by toxicity and involvement of two or more 
mucosal surfaces (often oral and conjunctival but can 
involve any mucosal surface, including respiratory epi
-
thelium). SJS/TEN is most often caused by medications, 
especially sulfonamides, NSAIDs, allopurinol, and anticon
-
vulsants. In certain races, polymorphisms of antigen-pre
-
senting major histocompatibility (MHC) loci increase the 
risk for the development of SJS/TEN; for example, screening 
for HLA-B
*
5801, which is associated with allopurinol-
induced SJS/TEN, is recommended in Han Chinese, those 
of Thai descent, and Koreans with stage 3 or worse chronic 
kidney disease before initiation of allopurinol (see Chapter 20). 
The exposure to medications associated with SJS/TEN may 
be systemic or, less commonly, topical (eg, eyedrops). 
 may trigger a mucocutaneous 
reaction with skin and oral lesions closely resembling SJS in 
up to 50% of children/young adults in some series. This 
syndrome tends not to progress to TEN-like diseases and 
carries an overall good prognosis.
 
»
A classic target lesion, as in herpes-associated erythema 
multiforme, consists of three concentric zones of color 
change, most often found acrally on the hands and feet 
(Figure 6–25). Medication-associated bullous eruptions in 
the SJS/TEN spectrum present with raised purpuric target-
like lesions, with only two zones of color change and a 
central blister, or nondescript reddish or purpuric mac
-
ules favoring the trunk and proximal upper extremities 
(Figure 6–26). Pain on eating, swallowing, and urination 
can occur if relevant mucosae are involved.
Blood tests are not useful for diagnosis. Skin biopsy is diag
-
nostic. Direct immunofluorescence studies are negative.
 
»
Urticaria and drug eruptions are the chief entities that 
must be differentiated from erythema multiforme minor. 
In true urticaria, lesions are not purpuric or bullous, last 
less than 24 hours, and respond to antihistamines. The dif
-
ferential diagnosis of SJS/TEN includes autoimmune bul
-
lous diseases (eg, pemphigus, pemphigoid, and linear IgA 
bullous dermatosis), acute systemic lupus erythematosus, 
vasculitis, and Sweet syndrome. The presence of a blister
-
ing eruption requires biopsy and consultation for appropri
-
ate diagnosis and treatment.
 
»
The tracheobronchial mucosa, conjunctiva, and urethral 
mucosa may be involved in severe cases with resultant 
scarring. 
Ophthalmologic consultation is required if ocular 
involvement is present because vision loss is the major conse
-

scarring. 
-
quence of SJS/TEN.
 
▲
Figure 6–26.
 
Stevens-Johnson syndrome. 
permission, from Berger TG, Dept Dermatology, UCSF.)
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▲
Figure 6–27.
 
Erythema migrans due to 
Borrelia 
burgdorferi
 (Lyme disease). 
Thomas Corson, MD in Usatine RP , Smith MA, Mayeaux EJ 
Jr, Chumley H. 
, 2nd ed. 
 
»
Treatment
Toxic epidermal necrolysis is best treated in an acute care 
environment, which may include an ICU or a burn unit. 
Patients should be admitted if mucosal involvement inter
-
feres with hydration and nutrition or extensive blistering 
develops. Open lesions should be managed like second-
degree burns. Immediate discontinuation of the inciting 
medication (before blistering occurs) is a significant pre
-
dictor of outcome. Delay in establishing the diagnosis and 
inadvertently continuing the offending medication results 
in higher morbidity and mortality.
The most important aspect of treatment is to stop the 
offending medication and to move patients with greater 
than 25–30% BSA involvement to an appropriate acute care 
environment. Nutritional and fluid support and high vigi
-
lance for infection are the most important aspects of care. 
Reviews of systemic treatments for SJS and TEN have been 
conflicting. Some data support the use of high-dose cortico
-
steroids. If corticosteroids are to be tried, they should be 
used early, before blistering occurs, and in moderate to high 
doses (prednisone, 1–2 mg/kg/day) and stopped within 
days if there is no dramatic response. Intravenous immuno
-
globulin (IVIG) (1 g/kg/day for 4 days) has become stan
-
dard of care at some centers for toxic epidermal necrolysis 
cases. IVIG used early in the course and at a total dose of at 
least 2 g/kg may result in decreased mortality, although not 
all studies support this finding. Cyclosporine (3–5 mg/kg/day 
for 7 days) may also be effective. Tumor necrosis factor 
inhibitors are used at some centers as well. Oral and topical 
corticosteroids are useful in the oral variant of erythema 
multiforme. Oral acyclovir prophylaxis of herpes simplex 
infections may be effective in preventing recurrent herpes-
associated erythema multiforme minor.
C. Local Measures
Topical therapy is not very effective in this disease.
 
»
Prognosis
Erythema multiforme minor usually lasts 2–6 weeks and 
may recur. SJS/TEN may be serious with a mortality of 
about 30% in cases with greater than 30% BSA involvement. 
SCORTEN (a severity of illness scale) predicts mortality in 
SJS/TEN.
Barron SJ et al. Intravenous immunoglobulin in the treatment of 
Stevens-Johnson syndrome and toxic epidermal necrolysis: a 
meta-analysis with meta-regression of observational studies. 
Int J Dermatol. 2015 Jan;54(1):108–15. [PMID: 24697283]
Canavan TN et al. 
–induced rash and 
mucositis as a syndrome distinct from Stevens-Johnson syn
-
drome and erythema multiforme: a systematic review. J Am 
Acad Dermatol. 2015 Feb;72(2):239–45. [PMID: 25592340]
Cheng L et al. HLA-B
*
58:01 is strongly associated with allopuri
-
nol-induced severe cutaneous adverse reactions in Han Chinese 
patients: a multicentre retrospective case-control clinical study. 
Br J Dermatol. 2015 Aug;173(2):555–8. [PMID: 26104483]
Creamer D et al. U.K. guidelines for the management of Stevens-
Johnson syndrome/toxic epidermal necrolysis in adults 2016. 
Br J Dermatol. 2016 Jun;174(6):1194–227. [PMID: 27317286]
Hsu DY et al. Morbidity and mortality of Stevens-Johnson syn
-
drome and toxic epidermal necrolysis in United States adults. 
J Invest Dermatol. 2016 Jul;136(7):1387–97. [PMID: 27039263]
Law EH et al. Corticosteroids in Stevens-Johnson syndrome/
toxic epidermal necrolysis: current evidence and implications 
for future research. Ann Pharmacother. 2015 Mar;49(3):
 
335–42. [PMID: 25406459]
Zimmermann S et al. Systemic immunomodulating therapies 
for Stevens-Johnson syndrome and toxic epidermal necrolysis: 
a systematic review and meta-analysis. JAMA Dermatol. 2017

a systematic review and meta-analysis. JAMA Dermatol. 2017 
Jun 1;153(6):514–22. [PMID: 28329382]
3. 
e
rythema Migrans (See also Chapter 34)
Erythema migrans is a unique cutaneous eruption that char
-
acterizes the localized or generalized early stage of Lyme 
disease (caused by 
Borrelia burgdorferi
) (Figure 6–27).
INFECTIOUS ERYTHEMAS
1. 
e
rysipelas
 
»
Edematous, circumscribed, hot, erythematous 
area, with raised advancing border.
 
»
Central face or lower extremity frequently 
involved.
 
»
Pain and systemic toxicity may be striking.
 
»
Erysipelas is a superficial form of cellulitis that is caused by 
beta-hemolytic streptococci.
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»
The symptoms are pain, malaise, chills, and moderate 
fever. A bright red spot appears and then spreads to form a 
tense, sharply demarcated, glistening, smooth, hot plaque. 
The margin characteristically makes noticeable advances 
in days or even hours. The lesion is edematous with a 
raised edge and may pit slightly with the finger. Vesicles or 
bullae occasionally develop on the surface. The lesion does 
not usually become pustular or gangrenous and heals with
-
out scar formation. The disease may complicate any break 
in the skin that provides a portal of entry for the organism. 
On the face, erysipelas begins near a fissure at the angle of 
the nose. On the lower extremity, tinea pedis with inter
-
digital fissuring is a common portal of entry.
Leukocytosis is almost invariably present; blood cultures 
may be positive.
 
»
Erysipeloid is a benign bacillary infection producing cel
-
lulitis of the skin of the fingers or the backs of the hands in 
fishermen and meat handlers.
 
»
Unless erysipelas is promptly treated, death may result 
from bacterial dissemination, particularly in older adults.
 
»
Treatment
Intravenous antibiotics effective against group A beta-
hemolytic streptococci and staphylococci should be consid
-
ered, but outpatient treatment with oral antibiotics has 
demonstrated equal efficacy. Oral regimens include a 7-day 
course with penicillin VK (250 mg), dicloxacillin (250 mg), or 
a first-generation cephalosporin (250 mg) orally four times a 
day. Alternatives in penicillin-allergic patients are clindamy
-
cin (250 mg twice daily orally for 7–14 days) or erythromycin 
(250 mg four times daily orally for 7–14 days), the latter only 
if the infection is known to be due to streptococci.
 
»
Prognosis
With appropriate treatment, rapid improvement is 
expected. The presence of lymphedema carries the greatest 
risk of recurrence.
2. Cellulitis
 
»
Edematous, expanding, erythematous, warm 
plaque with or without vesicles or bullae.
 
»
Lower leg is frequently involved.
 
»
Pain, chills, and fever are commonly present.
 
»
Septicemia may develop.
 
»
Cellulitis, a diffuse spreading infection of the dermis 
and subcutaneous tissue, is usually on the lower leg 
(Figure 6–28) and most commonly due to gram-positive 
cocci, especially group A beta-hemolytic streptococci and 
S aureus
. Rarely, gram-negative rods or even fungi can 
produce a similar picture. In otherwise healthy persons, the 
most common portal of entry for lower leg cellulitis is toe 
web intertrigo with fissuring, usually a complication of 
interdigital tinea pedis. Other diseases that predispose to 
cellulitis are prior episodes of cellulitis, chronic edema, 
venous insufficiency with secondary edema, lymphatic 
obstruction, saphenectomy, and other perturbations of the 
skin barrier. Bacterial cellulitis is almost never bilateral.
 
»
Cellulitis begins as a tender small patch. Swelling, ery
-
thema, and pain are often present. The lesion expands over 
hours, so that from onset to presentation is usually 6 to 
36 hours. As the lesion grows, the patient becomes more ill 
with progressive chills, fever, and malaise. Lymphangitis 
and lymphadenopathy are often present. If septicemia 
develops, hypotension may develop, followed by shock.
Leukocytosis or at least a neutrophilia (left shift) may be 
present from early in the course. Blood cultures are positive 
in only 8% of patients. If a central ulceration, pustule, or 
abscess is present, culture may be of value. Aspiration of the 
advancing edge has a low yield (less than 20%) and is usu
-
ally not performed. In immunosuppressed patients, or if an 
unusual organism is suspected and there is no loculated site

-
unusual organism is suspected and there is no loculated site 
to culture, a full-thickness skin biopsy taken before antibi
-
otics are given can be useful. Either two specimens or one 
divided in half should be sent for routine histologic evalua
-
tion and for culture (bacterial, fungal, and mycobacterial). 
Skin biopsy is particularly important in the immunocom
-
promised patient in whom cellulitis may be due to an 
 
▲
Figure 6–28.
 
Cellulitis. 
(Used, with permission, Lindy 
Fox, MD.)
CMDT19_Ch06_p0103-p0173.indd   145
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Chapter 6
146
 CMDT 2019
uncommon organism. If a primary source for the infection 
is identified (wound, leg ulcer, toe web intertrigo), cultures 
from these sites isolate the causative pathogen in half of 
cases and can be used to guide antibiotic therapy.
 
»
Two potentially life-threatening entities that can mimic cel
-
lulitis (ie, present with a painful, red, swollen lower extrem
-
ity) include deep venous thrombosis and necrotizing 
fasciitis. The diagnosis of necrotizing fasciitis should be 
suspected in a patient who has a very toxic appearance, bul
-
lae, crepitus or anesthesia of the involved skin, overlying 
skin necrosis, and laboratory evidence of rhabdomyolysis 
(elevated creatine kinase [CK]) or disseminated intravascu
-
lar coagulation. While these findings may be present with 
severe cellulitis and bacteremia, it is essential to rule out 
necrotizing fasciitis because rapid surgical debridement is 
essential. Other skin lesions that may resemble cellulitis 
include sclerosing panniculitis, an acute, exquisitely tender 
red plaque on the medial lower legs above the malleolus in 
patients with venous stasis or varicosities, and acute severe 
contact dermatitis on a limb, which produces erythema, 
vesiculation, and edema, as seen in cellulitis, but with itch
-
ing instead of pain. Bilateral lower leg bacterial cellulitis is 
exceedingly rare, and other diagnoses, especially severe 
stasis dermatitis (see Figure 12–2), should be considered in 
this setting. Severe lower extremity stasis dermatitis usually 
develops over days to weeks rather than the hours of cel
-
lulitis. It is also not as tender to palpation as cellulitis. 
Cryptococcal cellulitis in the organ transplant recipient is 
often bilateral.
 
»
Treatment
Intravenous or parenteral antibiotics may be required for 
the first 2–5 days, with adequate coverage for 
 
and 
. Methicillin-susceptible 
S aureus
 
(MSSA) can be treated with nafcillin, cefazolin, clindamy
-
cin, dicloxacillin, cephalexin, doxycycline, or TMP-SMZ. If 
MRSA is suspected or proven, treatment options include 
vancomycin, linezolid, clindamycin, daptomycin, doxycy
-
cline, or TMP-SMZ. In mild cases or following the initial 
parenteral therapy, oral dicloxacillin or cephalexin, 
250–500 mg four times daily for 5–10 days, is usually ade
-
quate. In patients in whom intravenous treatment is not 
instituted, the first dose of oral antibiotic can be doubled to 
achieve high blood levels rapidly. In patients with recurrent 
lower leg cellulitis (3–4 episodes per year), oral penicillin 
250 mg twice daily or erythromycin can delay the appear
-
ance of the next episode. Prior episodes of cellulitis, lymph
-
edema, chronic venous insufficiency, peripheral vascular 
disease, and deep venous thrombosis are associated with an 
increased risk of recurrent cellulitis.
 
»
•	
Severe local symptoms and signs.
•	
Systemic inflammatory response syndrome (SIRS) criteria 
are met.
•	
Elevated white blood cell count with marked left shift.
•	
Failure to respond to oral antibiotics.
Dalal A et al. Interventions for the prevention of recurrent erysipelas 
and cellulitis. Cochrane Database Syst Rev. 2017 Jun 20;6:
 
CD009758. [PMID: 28631307]
Quirke M et al. Risk factors for nonpurulent leg cellulitis: a sys
-
tematic review and meta-analysis. Br J Dermatol. 2017 Aug;
 
177(2):382–94. [PMID: 27864837]
Raff AB et al. Cellulitis: a review. JAMA. 2016 Jul 19;316(3):
 
325–37. [PMID: 27434444]
Stevens DL et al. Practice guidelines for the diagnosis and man
-
agement of skin and soft tissue infections: 2014 update by the 
Infectious Diseases Society of America. Clin Infect Dis. 2014 
Jul 15;59(2):147–59. [PMID: 24947530]
Talan DA et al. Factors associated with decision to hospitalize 
emergency department patients with skin and soft tissue 
infection. West J Emerg Med. 2015 Jan;16(1):89–97. [PMID: 
25671016]
BLIS
ter
ING DIS
ea
S
e
S
PEMPHIGUS

25671016]
BLIS
ter
ING DIS
ea
S
e
S
PEMPHIGUS
 
»
Relapsing crops of bullae, often fragile and lead
-
ing to erosions.
 
»
Often preceded by mucous membrane bullae, 
erosions, and ulcerations.
 
»
Superficial detachment of the skin after pressure 
or trauma variably present (Nikolsky sign).
 
»
Acantholysis on biopsy.
 
»
Immunofluorescence studies and serum ELISA for 
pathogenic antibodies are confirmatory.
 
»
Pemphigus is an uncommon intraepidermal blistering dis
-
ease occurring on skin and mucous membranes. It is 
caused by autoantibodies to adhesion molecules expressed 
in the skin and mucous membranes. The cause is unknown, 
and in the preantibiotic, presteroid era, the condition was 
usually fatal within 5 years. The bullae appear spontane
-
ously and are tender and painful when they rupture. Drug-
induced pemphigus from penicillamine, captopril, and 
others has been reported. There are several forms of pem
-
phigus: 
pemphigus vulgaris
 and its variant, 
pemphigus 
vegetans
; and the more superficially blistering 
pemphigus 
foliaceus
pemphigus erythematosus.
 All 
forms may occur at any age, but most present in middle 
age. The vulgaris form begins in the mouth in over 50% of 
cases. The foliaceus form is especially apt to be associated 
with other autoimmune diseases, or it may be drug-
induced. 
Paraneoplastic pemphigus,
 a unique form of the 
disorder, is associated with numerous types of benign and 
malignant neoplasms but most frequently non-Hodgkin 
lymphoma.
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▲
Figure 6–29.
 
Pemphigus vulgaris on the back with 
crusted and intact bullae. Downward pressure on a 
bulla demonstrates a positive Asboe-Hansen sign with 
lateral spread of a fresh bullae. 
from Eric Kraus, MD in Usatine RP , Smith MA, Mayeaux EJ Jr, 
Chumley H. 
 2nd ed. 
 
»
Pemphigus is characterized by an insidious onset of flaccid 
bullae, crusts, and erosions in crops or waves (Figure 6–29). 
In pemphigus vulgaris, lesions often appear first on the 
oral mucous membranes. These rapidly become erosive. 
The scalp is another site of early involvement. Rubbing a 
cotton swab or finger laterally on the surface of unin
-
volved skin may cause easy separation of the epidermis 
(Nikolsky sign). Pemphigus vegetans presents as erosive 
vegetating plaques, most often in intertriginous areas. 
Pemphigus foliaceus is a superficial form of pemphigus 
where cutaneous lesions often present as flaccid bullae 
that quickly evolve into superficial erosions and thin pink 
plaques with overlying scale. Mucosal lesions are rare in 
pemphigus foliaceus. Pemphigus erythematosus has over
-
lapping features of pemphigus foliaceus and lupus erythe
-
matosus. It presents with flaccid bullae that develop 
overlying scale and crust in a photodistributed area. 
Again, mucosal lesions are rare. Paraneoplastic pemphigus 
is clinically, histologically, and immunologically distinct 
from other forms of the disease. Oral erosions and ery
-
thematous plaques resembling erythema multiforme are 
seen. Survival rates are low because of the underlying 
malignancy.
The diagnosis is made by light microscopy and by direct 
and indirect immunofluorescence (IIF) microscopy. Auto
-
antibodies to intercellular adhesion molecules (desmoglien 
3 and 1) can be detected with ELISA assays and have 
replaced the use of IIF in some centers.
 
»
Blistering diseases include erythema multiforme (Figure 
6–25), SJS/TEN, drug eruptions, bullous impetigo, contact 
dermatitis, dermatitis herpetiformis, and bullous pemphi
-
goid, but flaccid blisters are not typical of these diseases, 
and acantholysis is not seen on biopsy. All of these dis
-
eases have clinical characteristics and different immuno
-
fluorescence test results that distinguish them from 
 
»
Secondary infection commonly occurs; this is a major 
cause of morbidity and mortality. Disturbances of fluid, 
electrolyte, and nutritional intake can occur as a result of 
painful oral ulcers.
 
»
Treatment
When the disease is severe, hospitalize the patient at bed 
rest and provide antibiotics and intravenous feedings as 
indicated. Anesthetic troches used before eating ease pain
-
ful oral lesions.
Pemphigus requires systemic therapy as early in its course 
as possible. However, the main morbidity in this disease is 
due to the side effects of such therapy. Initial therapy is with 
prednisone, 60–80 mg daily. In all but the mildest cases, a 
steroid-sparing agent is added from the beginning, since 
the course of the disease is long and the steroid-sparing 
agents take several weeks to exert their activity. Azathio
-
prine (100–200 mg orally daily) or mycophenolate mofetil 
(1–1.5 g orally twice daily) are often used. Rituximab treat
-
ment (1 g intravenously on days 1 and 15), especially early 
in the course, appears to be associated with therapeutic 
induction of a complete remission and is increasingly being 
used as first-line therapy. Repeated courses are efficacious 
and well tolerated in patients who do not achieve complete 
remission or relapse. Monthly IVIG at 2 g/kg intravenously 
over 3–4 days frequently is beneficial. In refractory cases, 
cyclophosphamide, pulse intravenous corticosteroids, and

cyclophosphamide, pulse intravenous corticosteroids, and 
plasmapheresis can be used. Other anti-CD20 medications 
may be future therapeutic options.
In patients with limited disease, skin and mucous mem
-
brane lesions should be treated with topical corticosteroids. 
Complicating infection requires appropriate systemic and 
local antibiotic therapy.
 
»
Prognosis
The course tends to be chronic in most patients, though 
about one-third appear to experience remission. Infection 
is the most frequent cause of death, usually from 
S aureus
 
septicemia.
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Atzmony L et al. The role of adjuvant therapy in pemphigus: a 
systematic review and meta-analysis. J Am Acad Dermatol. 
2015 Aug;73(2):264–71. [PMID: 26088689]
Cholera M et al. Management of pemphigus vulgaris. Adv Ther. 
2016 Jun;33(6):910–58. [PMID: 27287854]
Huang A et al. Future therapies for pemphigus vulgaris: ritux
-
imab and beyond. J Am Acad Dermatol. 2016 Apr;74(4):
 
746–53. [PMID: 26792592]
Ishii K. Importance of serological tests in diagnosis of autoim
-
mune blistering diseases. J Dermatol. 2015 Jan;42(1):3–10. 
[PMID: 25558946]
Jonkman MF. JAMA Dermatology patient page. Pemphigus. 
JAMA Dermatol. 2014 Jun;150(6):680. [PMID: 24919519]
Kasperkiewicz M et al. Pemphigus. Nat Rev Dis Primers. 2017 
May 11;3:17026. [PMID: 28492232]
BULLOUS PEMPHIGOID
Many autoimmune skin disorders are characterized by 
formation of bullae, or blisters. These include bullous pem
-
phigoid, cicatricial pemphigoid, dermatitis herpetiformis, 
and pemphigoid gestationis.
Bullous pemphigoid is a relatively benign pruritic dis
-
ease characterized by tense blisters in flexural areas, usually 
remitting in 5 or 6 years, with a course characterized by 
exacerbations and remissions. Most affected persons are 
over the age of 60 (often in their 70s or 80s), and men are 
affected twice as frequently as women. The appearance of 
blisters may be preceded by pruritic urticarial or edema
-
tous lesions for months. Oral lesions are present in about 
one-third of affected persons. The disease may occur in 
various forms, including localized, vesicular, vegetating, 
erythematous, erythrodermic, and nodular.
The diagnosis is made by biopsy and direct immuno
-
fluorescence examination. Light microscopy shows a sub
-
epidermal blister. With direct immunofluorescence, IgG 
and C3 are found at the dermal-epidermal junction. ELISA 
tests for bullous pemphigoid antibodies (BP 180 or BP 230) 
are 87% sensitive and 95% specific. If the patient has mild 
disease, ultrapotent topical corticosteroids may be ade
-
quate. Prednisone at a dosage of 0.75 mg/kg orally daily is 
often used to achieve rapid control of more widespread 
disease. Tetracycline (500 mg orally three times daily), 
alone or combined with nicotinamide—not nicotinic acid 
or niacin—(up to 1.5 g orally daily), may control the dis
-
ease in patients who cannot use corticosteroids or may 
allow for decreasing or eliminating corticosteroids after 
control is achieved. Dapsone is particularly effective in 
mucous membrane pemphigoid. If these medications are 
not effective, methotrexate (5–25 mg orally weekly), aza
-
thioprine (50 mg one to three times orally daily), or myco
-
phenolate mofetil (1–1.5 g orally twice daily) may be used 
as steroid-sparing agents. Intravenous immunoglobulin, 
rituximab, and omalizumab have been used with success in 
refractory cases.
Bağcı IS et al. Bullous pemphigoid. Autoimmun Rev. 2017 May;
 
16(5):445–55. [PMID: 28286109]
Bernard P et al. Bullous pemphigoid: a review of its diagnosis, 
associations and treatment. Am J Clin Dermatol. 2017 Aug;
 
18(4):513–28. PMID: 28247089
Cho YT et al. First-line combination therapy with rituximab and 
corticosteroids provides a high complete remission rate in 
moderate-to-severe bullous pemphigoid. Br J Dermatol. 
 
2015 Jul;173(1):302–4. [PMID: 25529394]
-
Yu KK et al. Omalizumab therapy for bullous pemphigoid. J Am 
Acad Dermatol. 2014 Sep;71(3):468–74. [PMID: 24954907]
pap
UL
e
S
WARTS
 
»
Verrucous papules anywhere on the skin or 
mucous membranes, usually no larger than 1 cm 
in diameter.
 
»
Prolonged incubation period (average 2–18 months).
 
»
Spontaneous “cures” of common warts in 50% at 
 
2 years.
 
»
“Recurrences” (new lesions) are frequent.
 
»
Warts (common, plantar, and genital) are caused by human

»
 
2 years.
 
»
 
»
Warts (common, plantar, and genital) are caused by human 
papillomaviruses (HPVs). Typing of HPV lesions is not a 
part of standard medical evaluation except in the case of 
anogenital dysplasia.
 
»
There are usually no symptoms. Tenderness on pressure 
occurs with plantar warts; itching occurs with anogenital 
warts (Figure 6–30). Flat warts are most evident under 
oblique illumination. Periungual warts may be dry, fis
-
sured, and hyperkeratotic and may resemble hangnails. 
Plantar warts resemble plantar corns or calluses.
 
»
Some warty-looking lesions are actually hypertrophic 
actinic keratoses or squamous cell carcinomas. Some 
genital warty lesions are condylomata lata of secondary 
syphilis. Molluscum contagiosum lesions are pearly with a 
central dell. In AIDS, wart-like lesions may be caused by 
varicella zoster virus.
 
»
Administration of a vaccine against certain anogenital 
HPV types (including 6, 11, 16, 18, 31, 33, 45, 52, and 58) 
can prevent infection with these wart types and reduce 
anogenital, oropharyngeal, and cervical cancer. It is recom
-
mended for teenagers and young adults, men who have sex 
with men, and immunocompromised patients (see 
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▲
Figure 6–30.
 
Condyloma around the clitoris, labia 
minor, and opening of the vagina. 
-
sion, from Richard P . Usatine, MD in Usatine RP , Smith MA, 
 
Chapters 1 and 18). There may be a role for adjuvant vac
-
cination in HPV-infected patients.
 
»
Treatment
Treatment is aimed at inducing “wart-free” intervals for as 
long as possible without scarring, since no treatment can 
guarantee a remission or prevent recurrences. In immuno
-
compromised patients, the goal is even more modest, ie, to 
control the size and number of lesions present.
A. Removal
For common warts of the hands, patients are usually 
offered liquid nitrogen or keratolytic agents. The former 
may work in fewer treatments but requires office visits and 
is painful.
1. Liquid nitrogen—
Liquid nitrogen is applied to achieve 
a thaw time of 30–45 seconds. Two freeze-thaw cycles are 
given every 2–4 weeks for several visits. Scarring will occur 
if it is used incorrectly. Liquid nitrogen may cause perma
-
nent depigmentation in pigmented individuals. Cryother
-
apy is first-line clinician-applied surgical treatment for 
genital warts (
condyloma acuminata
).
2. Keratolytic agents and occlusion—
Salicylic acid prod
-
ucts may be used against common warts or plantar warts. 
They are applied, then occluded. Plantar warts may be 
treated by applying a 40% salicylic acid plaster after paring. 
The plaster may be left on for 5–6 days, then removed, the 
lesion pared down, and another plaster applied. Although 
it may take weeks or months to eradicate the wart, the 
method is safe and effective with almost no side effects. 
Chronic occlusion alone with water-impermeable tape 
(duct tape, adhesive tape) is less effective than 
cryotherapy.
3. Podophyllum resin—
For genital warts, the purified 
active component of the podophyllum resin, podofilox, 
is applied by the patient twice daily 3 consecutive days a 
week for cycles of 4–6 weeks. It is less irritating and more 
effective than “clinician-applied” podophyllum resin. 
After a single 4-week cycle, 45% of patients were wart-
free; but of these, 60% relapsed at 6 weeks. Thus, multiple 
cycles of treatment are often necessary. Patients unable to 
obtain the take-home podofilox may be treated in the 
clinician’s office by painting each wart carefully (protect
-
ing normal skin) every 2–3 weeks with 25% podophyl
-
lum resin (podophyllin) in compound tincture of 
benzoin. Podophyllin is ineffective for common warts 
and plantar warts and contraindicated in pregnant 
women.
4. Imiquimod—
A 5% cream of this local interferon inducer 
has moderate activity in clearing external genital warts. 
Treatment is once daily on 3 alternate days per week. 
Response may be slow, with patients who eventually 
cleared having responses at 8 weeks (44%) or 12 weeks 
(69%). There is a marked difference between the sexes with 
respect to response, with 77% of women and 40% of men 
having complete clearing of their lesions. Once cleared, 
about 13% have recurrences in the short term.
Although imiquimod is considerably more expensive 
than podophyllotoxin, its high rate of response in women 
and its safety make it the “patient-administered” treat
-
ment of choice for external genital warts in women. In 
men, the more rapid response, lower cost, and similar 
efficacy make podophyllotoxin the initial treatment of 
choice, with imiquimod used for recurrences or refrac
-
tory cases. Imiquimod has no demonstrated efficacy 
for—and should not be used to treat—plantar or common 
warts.
5. Operative removal—
Plantar warts may be removed by 
blunt dissection. For genital warts, snip biopsy (scissors) 
removal followed by light electrocautery is more effective 
than cryotherapy, especially for patients with pedunculated 
or large lesions.
6. Laser therapy—
The CO
2
 laser can be effective for

The CO
2
 laser can be effective for 
treating recurrent warts, periungual warts, plantar warts, 
and condylomata acuminata. It leaves open wounds that 
must fill in with granulation tissue over 4–6 weeks and is 
best reserved for warts resistant to all other modalities. 
Lasers with emissions of 585, 595, or 532 nm may also be 
used every 3–4 weeks to gradually ablate common, plan
-
tar, facial, and anogenital warts. This is no more effective 
than cryotherapy in controlled trials. For genital warts, it 
has not been shown that laser therapy is more effective 
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▲
Figure 6–31.
 
A group of molluscum contagiosum 
lesions on the abdomen. 
, 2nd ed. 
than electrosurgical removal. Photodynamic therapy 
can be considered in refractory widespread flat and genital 
warts.
7. Other agents—
Bleomycin, diluted to 1 unit/mL, 
injected into common and plantar warts has been shown to 
have a high cure rate. It should be used with caution on 
digital warts because of the potential complications of 
Raynaud phenomenon, nail loss, and terminal digital 
necrosis. 5-Fluorouracil 5% cream applied once or twice 
daily, usually with occlusion, may be applied to warts with 
the similar efficacy to other treatment methods.
B. Immunotherapy
Squaric acid dibutylester may be applied in a concentra
-
tion of 0.2–2% directly to the warts from once weekly to 
five times weekly to induce a mild contact dermatitis. 
Between 60% and 80% of warts clear over 10–20 weeks. 
Injection of 
Candida
 antigen starting at 1:50 dilution 
and repeated every 3–4 weeks may be similarly effective 
in stimulating immunologic regression of common and 
plantar warts.
C. Physical Modalities
Soaking warts in hot (42.2°C) water for 10–30 minutes 
daily for 6 weeks has resulted in involution in some cases.
 
»
Prognosis
There is a striking tendency to develop new lesions. 
Warts may disappear spontaneously or may be unre
-
sponsive to treatment. Combining therapies (eg, liquid 
nitrogen plus immunotherapy) may improve therapeutic 
response.
Aldahan AS et al. Efficacy of intralesional immunotherapy for 
the treatment of warts: a review of the literature. Dermatol 
Ther. 2016 May;29(3):197–207. [PMID: 26991521]
Alikhan A et al. Use of 
Candida
 antigen injections for the treat
-
ment of verruca vulgaris: a two-year Mayo Clinic experience. 
J Dermatolog Treat. 2016 Aug;27(4):355–8. [PMID: 26558635]
Bertolotti A et al. Cryotherapy to treat anogenital warts in non
-
immunocompromised adults: systematic review and meta-
analysis. J Am Acad Dermatol. 2017 Sep;77(3):518–26. 
[PMID: 28651824]
Grillo-Ardila CF et al. Imiquimod for anogenital warts in non-
immunocompromised adults. Cochrane Database Syst Rev. 
2014 Nov 1;1:CD010389. [PMID: 25362229]
Veitch D et al. Pulsed dye laser therapy in the treatment of warts: 
a review of the literature. Dermatol Surg. 2017 Apr;43(4):
 
485–93. [PMID: 28272080]
MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum, caused by a poxvirus, presents as 
single or multiple dome-shaped, waxy papules 2–5 mm in 
diameter that are umbilicated (Figure 6–31). Lesions at 
first are firm, solid, and flesh-colored but upon reaching 
maturity become soft, whitish, or pearly gray and may sup
-
purate. The principal sites of involvement are the face, 
lower abdomen, and genitals.
The lesions are autoinoculable and spread by wet skin-
to-skin contact. In sexually active individuals, they may be 
confined to the penis, pubis, and inner thighs and are con
-
sidered a sexually transmitted infection.
Molluscum contagiosum is common in patients with 
AIDS, usually with a helper T-cell count less than 100/mcL. 
Extensive lesions tend to develop over the face and neck as 
well as in the genital area.
The diagnosis is easily established in most instances 
because of the distinctive central umbilication of the dome-
shaped lesion. Estimated time to remission is 13 months. 
The best treatment is by curettage or applications of liquid 
nitrogen as for warts—but more briefly. When lesions are 
frozen, the central umbilication often becomes more 
apparent. Light electrosurgery with a fine needle is also 
effective. Cantharadin (applied in the office and then 
washed off by the patient 4 hours later) is a safe and effec
-
tive option. Ten percent potassium hydroxide solution 
applied twice daily until lesions clear is another treatment

-
applied twice daily until lesions clear is another treatment 
option. Other options include salicylic acid, tretinoin, 
imiquimod, and pulsed dye laser are additional treatment 
options. Lesions are difficult to eradicate in patients with 
AIDS unless immunity improves; however, with highly 
effective antiretroviral treatment, molluscum will usually 
spontaneously clear.
Forbat E et al. Molluscum contagiosum: review and update on 
management. Pediatr Dermatol. 2017 Sep;34(5):504–15. 
[PMID: 28884917]
Martin P . Interventions for molluscum contagiosum in people 
infected with human immunodeficiency virus: a systematic 
review. Int J Dermatol. 2016 Sep;55(9):956–66. [PMID: 
26991246]
van der Wouden JC et al. Interventions for cutaneous molluscum 
contagiosum. Cochrane Database Syst Rev. 2017 May 17;5:
 
CD004767. [PMID: 28513067]
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▲
Figure 6–32.
 
Pearly nodular basal cell carcinoma on 
the face of a 52-year-old woman present for 5 years. 
The Color 
Atlas of Family Medicine, 
BASAL CELL CARCINOMA
 
»
Pearly papule, erythematous patch greater than 
 
6 mm, or nonhealing ulcer in sun-exposed 
 
areas (face, trunk, lower legs).
 
»
History of bleeding.
 
»
Fair-skinned person with a history of sun exposure 
(often intense, intermittent).
 
»
Basal cell carcinomas are the most common form of cancer. 
They occur on sun-exposed skin in otherwise normal, fair-
skinned individuals; ultraviolet light is the cause. Basal cell 
carcinomas can be divided into clinical and histologic 
subtypes, which determine both clinical behavior and 
treatment. The clinical subtypes include superficial, nodu
-
lar, pigmented, and morpheaform. Ths histologic subtypes 
include superficial, nodular, micronodular, and infiltrative. 
Morpheaform, micronodular, and infiltrative basal cell 
carcinomas are not amenable to topical therapy or electro
-
desiccation and curettage and typically require surgical 
excision or Mohs micrographic surgery.
 
»
The most common presentation is a papule or nodule that 
may have a central scab or erosion (Figure 6–32). Occa
-
sionally the nodules have stippled pigment (pigmented 
basal cell carcinoma). Intradermal nevi without pigment 
on the face of older white individuals may resemble basal 
cell carcinomas. Basal cell carcinomas grow slowly, 
attaining a size of 1–2 cm or more in diameter, usually only 
after years of growth. There is a 
waxy, “pearly” appear
-
ance,
 with telangiectatic vessels easily visible. It is the 
pearly or translucent quality of these lesions that is most 
diagnostic, a feature best appreciated if the skin is 
stretched. On the back and chest, basal cell carcinomas 
appear as reddish, somewhat shiny, scaly patches. Mor
-
pheaform basal cell carcinomas are scar-like in appear
-
ance. Basal cell carcinomas are more common and more 
likely to recur in immunosuppressed patients, including 
those with non-Hodgkin lymphoma and those who have 
undergone solid organ or allogeneic hematopoietic stem 
cell transplantation.
 
»
Treatment
Lesions suspected to be basal cell carcinomas should be 
biopsied, by shave or punch biopsy. Therapy is then aimed 
at eradication with minimal cosmetic deformity. Excision 
and suturing has a recurrence rate of 5% or less. The tech
-
nique of three cycles of curettage and electrodesiccation 
(ED+C) depends on the skill of the operator and is not 
recommended for head and neck lesions or basal cell carci
-
nomas with morpheaform, infiltrative, or micronodular 
histopathology. After 4–6 weeks of healing, it leaves a 
broad, hypopigmented, at times hypertrophic scar. Radio
-
therapy is effective and sometimes appropriate for older 
individuals (over age 65), but recurrent tumors after radia
-
tion therapy are more difficult to treat and may be more 
aggressive. Radiation therapy is the most expensive method 
to treat basal cell carcinoma and should be used only if 
other treatment options are not appropriate. 
Mohs micro
-
graphic surgery
—removal of the tumor followed by 
immediate frozen section histopathologic examination of 
margins with subsequent reexcision of tumor-positive 
areas and final closure of the defect—gives the highest cure 
rates (98%) and results in least tissue loss. It is an appropri
-
ate therapy for tumors of the eyelids, nasolabial folds, can
-
thi, external ear, and temple; for recurrent lesions; where 
tissue sparing is needed for cosmesis; and those with mor
-
pheaform, infiltrative, or micronodular histopathology in 
certain locations.
The histopathologic classification of basal cell carcino
-

-
-
mas determines therapy. Superficial or nodular type lesions 
can be treated with ED+C, excision, or Mohs micrographic 
surgery, while those that are classified as micronodular or 
infiltrative should be treated with excision or Mohs micro
-
graphic surgery depending on the size and location of the 
lesion. Imiquimod (applied topically 5 nights per week for 
6–10 weeks depending on patient reaction) and 5-fluorouracil 
(applied topically twice daily for up to 12 weeks) may be 
appropriate for select patients with superficial basal cell 
carcinomas, but the treated area must be observed for evi
-
dence of complete cure. Photodynamic therapy is approved 
in Europe, Australia, and New Zealand for the treatment of 
superficial and nodular basal cell carcinomas.
Hedgehog pathway inhibitors (vismodegib, sonidegib) 
are reserved for the treatment of advanced or metastatic 
basal cell carcinoma or in patients with extensive tumor 
burden (eg, basal cell nevus syndrome). Since a second 
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▲
Figure 6–33.
 
Squamous cell carcinoma: an irregular 
shaped pink plaque with overlong hemorrhagic crust in 
a chronically sun exposed area. 
 
Medicine,
lesion will develop in up to half of patients with a basal cell 
carcinoma, patients with basal cell carcinomas must be 
monitored at least yearly to detect new or recurrent lesions.
Basset-Seguin N et al. Vismodegib in patients with advanced 
basal cell carcinoma (STEVIE): a pre-planned interim analysis 
of an international, open-label trial. Lancet Oncol. 2015 Jun;
 
16(6):729–36. [PMID: 25981813]
Kauvar AN et al; American Society for Dermatologic Surgery. 
Consensus for nonmelanoma skin cancer treatment: basal cell 
carcinoma, including a cost analysis of treatment methods. 
Dermatol Surg. 2015 May;41(5):550–71. [PMID: 25868035]
Tolkachjov SN et al. Understanding Mohs micrographic surgery: 
a review and practical guide for the nondermatologist. Mayo 
Clin Proc. 2017 Aug;92(8):1261–71. [PMID: 28778259]
Verkouteren JAC et al. Epidemiology of basal cell carcinoma: 
scholarly review. Br J Dermatol. 2017 Aug;177(2):359–72. 
[PMID: 28220485]
Williams HC et al; Surgery Versus Imiquimod for Nodular and 
Superficial Basal Cell Carcinoma (SINS) Study Group. Sur
-
gery versus 5% imiquimod for nodular and superficial basal 
cell carcinoma: 5-year results of the SINS randomized con
-
trolled trial. J Invest Dermatol. 2017 Mar;137(3):614–9. 
[PMID: 27932240]
Wiznia LE et al. Treatment of basal cell carcinoma in the elderly: 
what nondermatologists need to know. Am J Med. 2016 Jul;
 
129(7):655–60. [PMID: 27046242]
SQUAMOUS CELL CARCINOMA
 
»
Nonhealing ulcer or warty nodule.
 
»
Skin damage due to long-term sun exposure.
 
»
Common in fair-skinned organ transplant 
recipients.
Squamous cell carcinoma usually occurs subsequent to 
prolonged sun exposure on exposed parts in fair-skinned 
individuals who sunburn easily and tan poorly. It may arise 
from an actinic keratosis. The lesions appear as small red, 
conical, hard nodules that occasionally ulcerate (Figure 6–33). 
In actinically induced squamous cell cancers, rates of 
metastasis are estimated from retrospective studies to be 
3–7%. Squamous cell carcinomas of the ear, temple, lip, 
oral cavity, tongue, and genitalia have much higher rates of 
recurrence or metastasis and require special management. 
Patients with multiple squamous cell carcinomas (espe
-
cially more than 10) have higher rates of local recurrence 
and nodal metastases.
Examination of the skin and therapy are essentially the 
same as for basal cell carcinoma. The preferred treatment 
of squamous cell carcinoma is excision. Electrodesiccation 
and curettage and x-ray radiation may be used for some 
lesions. Mohs micrographic surgery is recommended for 
high-risk lesions (lips, temples, ears, nose), recurrent 
tumors, aggressive histologic subtypes (perineural or peri
-
vascular invasion), large lesions (greater than 1.0 cm face, 
greater than 2.0 cm trunk or extremities), immunosup
-
pressed patients, lesions developing within a scar, and for 
tumors arising in the setting of genetic diseases. Follow-up 
for squamous cell carcinoma must be more frequent and 
thorough than for basal cell carcinoma, starting at every 
3 months, with careful examination of lymph nodes for 
1 year, then twice yearly thereafter. In addition, palpation 
of the lips is essential to detect hard or indurated areas that 
represent early squamous cell carcinoma. All such cases 
must be biopsied.
Transplant patients with squamous cell carcinomas 
represent a highly specialized patient population. Biologic 
behavior of skin cancer in organ transplant recipients may 
be aggressive, and careful management is required. Multi
-
ple squamous cell carcinomas are very common on the

-
ple squamous cell carcinomas are very common on the 
sun-exposed skin of organ transplant patients. The inten
-
sity of immunosuppression, not the use of any particular 
immunosuppressive agent, is the primary risk factor in 
determining the development of skin cancer after trans
-
plant. The tumors begin to appear after 5 years of immuno
-
suppression. Voriconazole treatment appears to increase 
the risk of development of squamous cell carcinoma, espe
-
cially in lung transplant patients. Regular dermatologic 
evaluation in at-risk organ transplant recipients is recom
-
mended. Other forms of immunosuppression, such as 
allogeneic hematopoietic stem cell transplants, chronic 
lymphocytic leukemia, HIV/AIDS, and chronic iatrogenic 
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▲
Figure 6–34.
 
Lichen planus. 
immunosuppression, may also increase skin cancer risk 
and be associated with more aggressive skin cancer 
behavior.
Burton KA et al. Cutaneous squamous cell carcinoma: a review 
of high-risk and metastatic disease. Am J Clin Dermatol. 
 
2016 Oct;17(5):491–508. [PMID: 27358187]
Eigentler TK et al. Survival of patients with cutaneous squamous 
cell carcinoma: results of a prospective cohort study. J Invest 
Dermatol. 2017 Nov;137(11):2309–15. [PMID: 28736229]
Harwood CA et al; KeraCon Consortium. The pathogenesis of 
cutaneous squamous cell carcinoma in organ transplant 
recipients. Br J Dermatol. 2017 Nov;177(5):1217–24. [PMID: 
29086420]
Kauvar AN et al. Consensus for nonmelanoma skin cancer treat
-
ment, part II: squamous cell carcinoma, including a cost 
analysis of treatment methods. Dermatol Surg. 2015 Nov;
 
41(11):1214–40. [PMID: 26445288]
Levine DE et al. Outcomes of patients with multiple cutaneous 
squamous cell carcinomas: a 10-year single-institution cohort 
study. JAMA Dermatol. 2015 Nov;151(11):1220–5. [PMID: 
26177278]
Stratigos A et al; European Dermatology Forum (EDF); Euro
-
pean Association of Dermato-Oncology (EADO); European 
Organization for Research and Treatment of Cancer (EORTC). 
Diagnosis and treatment of invasive squamous cell carcinoma 
of the skin: European consensus-based interdisciplinary 
guideline. Eur J Cancer. 2015 Sep;51(14):1989–2007. [PMID: 
26219687]
VIOL
a
C
e
OUS 
t
O
 
p
U
rp
L
e
 
pap
UL
e
S & NODUL
e
S
LICHEN PLANUS
 
»
Pruritic, violaceous, flat-topped papules with fine 
white streaks and symmetric distribution.
 
»
Lacy or erosive lesions of the buccal, vulvar, and 
vaginal mucosa; nail dystrophy.
 
»
Commonly seen along linear scratch marks (Koeb
-
ner phenomenon) on anterior wrists, penis, and 
legs.
 
»
Histopathologic examination is diagnostic.
 
»
Lichen planus is an inflammatory pruritic disease of the 
skin and mucous membranes characterized by distinctive 
papules with a predilection for the flexor surfaces and 
trunk. The three cardinal findings are typical skin lesions, 
mucosal lesions, and histopathologic features of band-like 
infiltration of lymphocytes in the upper dermis. The most 
common medications causing lichen planus–like reactions 
include sulfonamides, tetracyclines, quinidine, NSAIDs, 
beta-blockers, and hydrochlorothiazide. Lichenoid drug 
eruptions can resemble lichen planus clinically and histo
-
logically. Hepatitis C infection is found with greater fre
-
quency in lichen planus patients than in controls. Allergy 
to mercury and other metal-containing amalgams can 
trigger oral lesions identical to lichen planus.
 
»
The lesions are violaceous, flat-topped, angulated papules, 
up to 1 cm in diameter, discrete or in clusters, with very 
fine white streaks (Wickham striae) on the flexor surfaces 
of the wrists and on the penis, lips, tongue as well as buccal, 
vulvar, vaginal, esophageal, and anorectal mucous mem
-
branes (Figure 6–34). Itching is mild to severe. The papules 
may become bullous or eroded. The disease may be gener
-
alized. Mucous membrane lesions have a lacy white net
-
work overlying them that may be confused with leukoplakia. 
The presence of oral and vulvo-vaginal lichen planus in the 
same patient is common. Patients with both these mucous 
membranes involved are at much higher risk for esopha
-
geal lichen planus. The 
Koebner phenomenon
 (appear
-
ance of lesions in areas of trauma) may be seen.
A special form of lichen planus is the erosive or ulcer
-
ative variety, a major problem in the mouth or genitalia. 
Squamous cell carcinoma develops in up to 5% of patients 
with erosive oral or genital lichen planus and may occur in 
esophageal lichen planus. There is also an increased risk of

esophageal lichen planus. There is also an increased risk of 
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squamous cell carcinoma developing in lesions of hyper
-
trophic lichen on the lower extremities.
 
»
Lichen planus must be distinguished from similar lesions 
produced by medications and other papular lesions, such 
as psoriasis, lichen simplex chronicus, graft-versus-host 
disease, and syphilis. Lichen planus on the mucous mem
-
branes must be differentiated from leukoplakia. Erosive 
oral lesions require biopsy and often direct immunofluo
-
rescence for diagnosis since lichen planus may simulate 
other erosive diseases.
 
»
Treatment
Superpotent topical corticosteroids applied twice daily are 
most helpful for localized disease in nonflexural areas. 
Alternatively, high-potency corticosteroid cream or oint
-
ment may be used nightly under thin, pliable plastic film.
Topical tacrolimus appears effective in oral and vaginal 
erosive lichen planus, but long-term therapy is required to 
prevent relapse. If tacrolimus is used, lesions must be 
observed carefully for development of cancer. Since absorp
-
tion can occur through mucous membranes, serum tacro
-
limus levels should be checked at least once if widespread 
mucosal application (more than 5–10 cm
2
) is used. If the 
erosive oral lichen planus lesions are adjacent to a metal-
containing amalgam, removal of the amalgam may result 
in clearing of the erosions.
NB-UVB, bath PUV A, oral PUV A, and the combination of 
an oral retinoid plus PUV A (re-PUV A) are all forms of pho
-
totherapy that can improve lichen planus. Hydroxychloro
-
quine, 200 mg orally twice daily, acitretin 10–25 mg orally 
daily, cyclosporine 3–5 mg/kg orally, and mycophenolate 
mofetil, 1 g orally twice daily, can also be effective in muco
-
sal and cutaneous lichen planus. Corticosteroids may be 
required in severe cases or in circumstances where the most 
rapid response to treatment is desired. Unfortunately, 
relapse almost always occurs as the corticosteroids are 
tapered, making systemic corticosteroid therapy an imprac
-
tical option for the management of chronic lichen planus.
 
»
Prognosis
Lichen planus is a benign disease, but it may persist for 
months or years and may be recurrent. Hypertrophic 
lichen planus and oral lesions tend to be especially persis
-
tent, and neoplastic degeneration has been described in 
chronically eroded lesions.
Ashack KA et al. Assessing the clinical effectiveness of an algo
-
rithmic approach for mucosal lichen planus (MLP): a retro
-
spective review. J Am Acad Dermatol. 2016 Jun;74(6):1073–6.
e2. [PMID: 27185423]
García-Pola MJ et al. Treatment of oral lichen planus. Systematic 
review and therapeutic guide. Med Clin (Barc). 2017 Oct 23;
 
149(8):351–62. [PMID: 28756997]
Gupta S et al. Interventions for the management of oral lichen 
planus: a review of the conventional and novel therapies. Oral 
Dis. 2017 Nov;23(8):1029–42. [PMID: 28055124]
Knackstedt TJ et al. Squamous cell carcinoma arising in hyper
-
trophic lichen planus: a review and analysis of 38 cases. 
Dermatol Surg. 2015 Dec;41(12):1411–8. [PMID: 26551772]
Mauskar M. Erosive lichen planus. Obstet Gynecol Clin North 
Am. 2017 Sep;44(3):407–20. [PMID: 28778640]
Olson MA et al. Oral lichen planus. Clin Dermatol. 2016 
Jul–Aug;34(4):495–504. [PMID: 27343965]
KAPOSI SARCOMA
 
»
Human herpes virus 8 (HHV-8), or Kaposi sarcoma–asso
-
ciated herpes virus, is the cause of all forms of Kaposi 
sarcoma.
Before 1980 in the United States, this rare, malignant 
skin lesion was seen mostly in elderly men, had a chronic 
clinical course, and was rarely fatal. Kaposi sarcoma occurs 
endemically in an often aggressive form in young black 
men of equatorial Africa, but it is rare in American blacks. 
Kaposi sarcoma continues to occur largely in homosexual 
men with HIV infection as an AIDS-defining illness. 
Kaposi sarcoma may complicate immunosuppressive ther
-

-
apy, and stopping the immunosuppression may result in 
improvement.
Red or purple plaques or nodules on cutaneous or 
mucosal surfaces are characteristic. Marked edema may 
occur with few or no skin lesions. Kaposi sarcoma com
-
monly involves the gastrointestinal tract and can be 
screened for by fecal occult blood testing. In asymptomatic 
patients, these lesions are not sought or treated. Pulmonary 
Kaposi sarcoma can present with shortness of breath, 
cough, hemoptysis, or chest pain; it may be asymptomatic, 
appearing only on chest radiograph. Bronchoscopy may be 
indicated. The incidence of AIDS-associated Kaposi sar
-
coma is diminishing; however, chronic Kaposi sarcoma can 
develop in patients with HIV infection, high CD4 counts, 
and low viral loads. In this setting, the Kaposi sarcoma usu
-
ally resembles the endemic form, being indolent and local
-
ized. At times, however, it can be clinically aggressive. The 
presence of Kaposi sarcoma at the time of antiretroviral 
initiation is associated with Kaposi sarcoma–immune 
reconstitution inflammatory syndrome (KS-IRIS), which 
has an especially aggressive course in patients with visceral 
disease.
 
»
Treatment
For Kaposi sarcoma in elders, palliative local therapy with 
intralesional chemotherapy or radiation is usually all that is 
required. In the setting of iatrogenic immunosuppression, 
the treatment of Kaposi sarcoma is primarily reduction of 
doses of immunosuppressive medications. In AIDS-
associated Kaposi sarcoma, the patient should first be given 
ART. Other therapeutic options include cryotherapy or 
intralesional vinblastine (0.1–0.5 mg/mL) for cosmetically 
objectionable lesions; radiation therapy for accessible and 
space-occupying lesions; and laser surgery for certain 
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intraoral and pharyngeal lesions. Systemic therapy is indi
-
cated in patients with rapidly progressive skin disease 
(more than 10 new lesions per month), with edema or 
pain, and with symptomatic visceral disease or pulmonary 
disease. ART plus chemotherapy appears to be more effec
-
tive than ART alone (see Table 39–3). Liposomal doxoru
-
bicin is highly effective in severe cases and may be used 
alone or in combination with bleomycin and vincristine. 
Alpha-interferon may also be used. Paclitaxel and other 
taxanes can be effective even in patients who do not 
respond to anthracycline treatment. Targeted immuno
-
therapy is under active investigation.
Cancer Project Working Group for the Collaboration of Obser
-
vational HIV Epidemiological Research Europe (COHERE) 
study in EuroCoord. Changing incidence and risk factors for 
Kaposi sarcoma by time since starting antiretroviral therapy: 
collaborative analysis of 21 European cohort studies. Clin 
Infect Dis. 2016 Nov 15;63(10):1373–9. [PMID: 27535953]
Gbabe OF et al. Treatment of severe or progressive Kaposi’s sar
-
coma in HIV-infected adults. Cochrane Database Syst Rev. 
2014 Aug 13;8:CD003256. [PMID: 25221796]
Schneider JW et al. Diagnosis and treatment of Kaposi sarcoma. 
Am J Clin Dermatol. 2017 Aug;18(4):529–39. [PMID: 
28324233]
pr
U
r
I
t
US (I
t
C
h
ING)
Pruritus is the sensation that provokes a desire to scratch. 
It is modulated by multiple factors, including anxiety, 
depression, and amphetamine and cocaine use. Pruritus as 
a medical complaint is 40% as common as low back pain. 
Elderly Asian men are most significantly affected with 20% 
of all health care visits in Asian men over the age of 65 
involving the complaint of itch. The quality of life of a 
patient with chronic pruritus is the same as a patient 
undergoing hemodialysis. Evidence suggests that increased 
interleukin-31 (IL-31) signaling through the IL-31 receptor 
on epithelial cells and keratinocytes is associated with itch, 
especially in allergic skin disease.
Dry skin is the first cause of itch that should be 
sought,
 since it is common and easily treated. The next 
step in physical evaluation of the itchy patient is deciding 
whether a primary skin lesion is present or absent. If a 
primary skin lesion is present, then the patient has a pri
-
mary cutaneous disease with associated pruritus. Examples 
of primary cutaneous diseases include scabies, atopic der
-
matitis, insect bites, pediculosis, contact dermatitis, drug 
reactions, urticaria, psoriasis, lichen planus, and fiberglass 
dermatitis. These conditions all present with recognizable 
cutaneous morphologies, and the treatment of the skin 
condition usually results in control of the associated 
pruritus.
Persistent pruritus not explained by cutaneous disease 
or association with a primary skin eruption should prompt 
a staged workup for systemic causes. Common causes of 
pruritus associated with systemic diseases include endo
-
crine disorders (eg, hypothyroidism, hyperthyroidism, or 
hyperparathyroidism), psychiatric disturbances, lym
-
phoma, leukemia, and other internal malignant disorders, 
iron deficiency anemia, HIV , hypercalcemia, cholestasis, 
and certain neurologic disorders. Calcium channel block
-
ers can cause pruritus with or without eczema, even years 
after they have been started, and it may take up to 1 year for 
the pruritus to resolve after the calcium channel blocker 
has been stopped.
 
»
Treatment
The treatment of chronic pruritus can be frustrating. 
Most 
cases of pruritus are not mediated by histamine,
 hence 
the poor response of many pruritic patients to antihista
-
mines. Emollients for dry skin are listed in Table 6–2. 
Emollient creams (preferred over lotions) should be gener
-
ously applied from neck to toe immediately after towel 
drying and again one more time per day. Neuropathic dis
-
ease, especially in diabetic patients, is associated with pru
-

-
-
-
ritus, making neurally acting agents such as gabapentin 
(starting at 300 mg orally at around 4 
pm
 and a second dose 
of 600 mg orally at bedtime) or pregabalin (150 mg orally 
daily) attractive approaches to the management of pruritus. 
Combinations of antihistamines, sinequan, gabapentin, 
pregabalin, mirtazapine, and opioid antagonists can be 
attempted in refractory cases. In cancer-associated and 
other forms of pruritus, aprepitant (Emend) 80 mg orally 
daily for several days can be dramatically effective. The 
uremia in conjunction with hemodialysis and to a lesser 
degree the pruritus of liver disease may be helped by pho
-
totherapy with ultraviolet B or PUV A. Naltrexone and 
nalmefene have been shown to relieve the pruritus of liver 
disease. Naltrexone is not effective in pruritus associated 
with advanced chronic kidney disease, but gabapentin or 
mirtazapine may be effective. Il-31 blockade (nemoli
-
zumab) may represent a future target of itch therapy. Some 
medications recently approved for the treatment of atopic 
dermatitis (crisaborole a topical phosphodiesterase 4 
inhibitor) and dupilumab (an interleukin-4 inhibitor) are 
demonstrating some efficacy in the treatment of itch.
 
»
Prognosis
Elimination of external factors and irritating agents may 
give complete relief. Pruritus accompanying a specific skin 
disease will subside when the skin disease is controlled. 
Pruritus accompanying serious internal disease may not 
respond to any type of therapy.
Leslie TA. Itch management in the elderly. Curr Probl Dermatol. 
2016;0:192–201. [PMID: 27578088]
Matsuda KM et al. Gabapentin and pregabalin for the treatment 
of chronic pruritus. J Am Acad Dermatol. 2016 Sep;75(3):
 
619–25.e6. [PMID: 27206757]
Metz M et al. Itch management: topical agents. Curr Probl 
 
Dermatol. 2016;0:40–5. [PMID: 27578070]
Pereira MP et al. Chronic pruritus in the absence of skin disease: 
pathophysiology, diagnosis and treatment. Am J Clin Derma
-
tol. 2016 Aug;17(4):337–48. [PMID: 27216284]
Şavk E. Neurologic itch management. Curr Probl Dermatol. 
2016;50:116–23. [PMID: 27578080]
Silverberg JI. Practice gaps in pruritus. Dermatol Clin. 2016 Jul;
 
34(3):257–61. [PMID: 27363881]
Stull C et al. Advances in therapeutic strategies for the treatment 
of pruritus. Expert Opin Pharmacother. 2016;17(5):671–87. 
[PMID: 26630350]
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▲
Figure 6–35.
 
Erythrasma of the axilla. 
The Color 
ANOGENITAL PRURITUS
 
»
Itching, chiefly nocturnal, of the anogenital area.
 
»
Examination is highly variable, ranging from no 
skin findings to excoriations and inflammation of 
any degree, including lichenification.
 
»
Anogenital pruritus may be due to a primary inflammatory 
skin disease (intertrigo, psoriasis, lichen simplex chroni
-
cus, seborrheic dermatitis, lichen sclerosus), contact der
-
matitis (soaps, colognes, douches, and topical treatments), 
irritating secretions (diarrhea, leukorrhea, or trichomoniasis), 
infections (candidiasis, dermatophytosis, erythrasma), or 
oxyuriasis (pinworms). Erythrasma (Figure 6–35) is diag
-
nosed by coral-red fluorescence with Wood light and cured 
with erythromycin. Squamous cell carcinoma of the anus 
and extramammary Paget disease are rare causes of genital 
pruritus.
In pruritus ani, hemorrhoids are often found, and leak
-
age of mucus and bacteria from the distal rectum onto the 
perianal skin may be important in cases in which no other 
skin abnormality is found.
Many women experience pruritus vulvae. Pruritus 
vulvae does not usually involve the anal area, though 
anal itching may spread to the vulva. In men, pruritus of 
the scrotum is most commonly seen in the absence of 
pruritus ani.
Up to one-third of unidentified causes of anogenital 
pruritus may be due to nerve impingements of the lumbo
-
sacral spine, so referral for evaluation of lumbosacral spine 
disease is appropriate if no skin disorder is identified and 
topical therapy is ineffective.
 
»
The only symptom is itching. Physical findings are usually 
not present, but there may be erythema, fissuring, macera
-
tion, lichenification, excoriations, or changes suggestive of 
candidiasis or tinea.
Microscopic examination or culture of tissue scrapings may 
reveal yeasts or fungi. Stool examination may show pin
-
worms. Radiologic studies may demonstrate spinal disease.
 
»
The etiologic differential diagnosis consists of 
Candida
 
infection, parasitosis, local irritation from contactants or 
irritants, nerve impingement, and other primary skin dis
-
orders of the genital area, such as psoriasis, seborrhea, 
intertrigo, or lichen sclerosus.
 
»
Instruct the patient in proper anogenital hygiene after 
treating systemic or local conditions. If appropriate, physi
-
cal therapy and exercises to support the lower spine are 
 
»
Treatment
Treating constipation, preferably with high-fiber manage
-
ment (psyllium), may help. Instruct the patient to use very 
soft or moistened tissue or cotton after bowel movements 
and to clean the perianal area thoroughly with cool water if 
possible. Women should use similar precautions after uri
-
nating. Patch testing most commonly reveals clinically 
relevant allergy in about 20% of patients, often to methyl
-
chloroisothiazolinone or methylisothiazolinone, preserva
-
tives commonly found in “baby wipes” and other personal 
care products.
Pramoxine cream or lotion or hydrocortisone-pramox
-
ine (Pramosone), 1% or 2.5% cream, lotion, or ointment, is 
helpful for anogenital pruritus and should be applied after 
a bowel movement. Topical doxepin cream 5% is similarly 
effective, but it may be sedating. Topical calcineurin inhibi
-
tors (tacrolimus 0.03%) improve pruritus ani in patients 
with atopic dermatitis. Underclothing should be changed 
daily, and in men, the seam of their “boxers” should not 
rub against or contact the scrotum. Balneol Perianal 
Cleansing Lotion or Tucks premoistened pads, ointment, 
or cream may be very useful for pruritus ani. About one-

third of patients with scrotal or anal pruritus will respond 
to capsaicin cream 0.006%. In cases where underlying spi
-
nal neurologic disease is suspected, gabapentin or pregaba
-
lin may be helpful. The use of high-potency topical 
corticosteroids should be avoided in the genital area.
 
»
Prognosis
Although benign, anogenital pruritus is often persistent 
and recurrent.
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▲
Figure 6–36.
 
Scabies. 
Abu-Asi MJ et al. Patch testing is clinically important for 
patients with peri-anal dermatoses and pruritus ani. Contact 
Dermatitis. 2016 May;74(5):298–300. [PMID: 27040873]
Ansari P . Pruritus ani. Clin Colon Rectal Surg. 2016 Mar;
 
29(1):38–42. [PMID: 26929750]
Chibnall R. Vulvar pruritus and lichen simplex chronicus. 
Obstet Gynecol Clin North Am. 2017 Sep;44(3):379–88. 
[PMID: 28778638]
2016;0:116–23. [PMID: 27578080]
SCABIES
 
»
Generalized very severe itching.
 
»
Burrows, vesicles, and pustules, especially on 
 
finger webs and in wrist creases.
 
»
Mites, ova, and brown dots of feces (scybala) 
 
visible microscopically.
 
»
Red papules or nodules on the scrotum and on 
the penile glans and shaft are pathognomonic.
 
»
Scabies is caused by infestation with 
Sarcoptes scabiei
. 
Close physical contact for 15–20 minutes with an infected 
person is the typical mode of transmission. However, sca
-
bies may be acquired by contact with the bedding of an 
infested individual. Facility-associated scabies is common, 
primarily in long-term care facilities and misdiagnosis is 
common. Index patients are usually elderly and immuno
-
suppressed. When these patients are hospitalized, hospital-
based epidemics can occur. These epidemics are difficult to 
eradicate since many health care workers become infected 
and spread the infestation to other patients.
 
»
Itching is almost always present and can be severe. The 
lesions consist of more or less generalized excoriations with 
small pruritic vesicles, pustules, and “burrows” in the inter
-
digital spaces of the hands and feet, on the heels of the 
palms, wrists (Figure 6–36), elbows, umbilicus, around the 
axillae, on the areolae in women, or on the penile shaft and 
scrotum in men. The burrow appears as a short irregular 
mark, 2–3 mm long and the width of a hair. Characteristic 
nodular lesions may occur on the scrotum or penis and 
along the posterior axillary line. The infestation 
usually 
spares the head and neck
 (though these areas may be 
involved in infants, older adults, and patients with AIDS).
Hyperkeratotic or crusted scabies presents as thick flak
-
ing scale. These areas contain millions of mites, and these 
patients are highly infectious. Pruritus is often absent. 
Patients with widespread hyperkeratotic scabies are at risk 
for superinfection with 
S aureus
, which in some cases pro
-
gresses to sepsis if left untreated. Crusted scabies is the 
cause of 83% of scabies outbreaks in institutions.
The diagnosis should be confirmed by microscopic dem
-
onstration of the organism, ova, or feces in a mounted 
specimen, examined with tap water, mineral oil, or KOH. 
Best results are obtained when multiple lesions are scraped, 
choosing the best unexcoriated lesions from interdigital 
webs, wrists, elbows, or feet. A No. 15 blade is used to 
scrape each lesion until it is flat. Patients with crusted/
hyperkeratotic scabies must be evaluated for immunosup
-
pression (especially HIV and HTLV-1 infections) if no 
iatrogenic cause of immunosuppression is present. Patients 
with hyperkeratotic scabies and associated bacterial super
-
infection may have laboratory findings consistent with 
infection and, if severe, sepsis.
 
»
Scabies must be distinguished from the various forms of 
pediculosis, from bedbug and flea bites, and from other 
causes of pruritus.
 
»
Treatment is aimed at killing scabies mites and controlling 
the dermatitis, which can persist for months after effective 
eradication of the mites. Bedding and clothing should be 
laundered or cleaned or set aside for 14 days in plastic bags.

laundered or cleaned or set aside for 14 days in plastic bags. 
High heat (60°C) is required to kill the mites and ova. 
Treatment is aimed at all infected persons in a family or 
institutionalized group. Otherwise, reinfestations will 
likely occur, which is why scabies in nursing home patients, 
institutionalized or mentally impaired patients, and AIDS 
patients may be much more difficult to treat.
1. Permethrin 5% cream—
Treatment with permethrin, a 
highly effect and safe agent, consists of a single application 
from the neck down for 8–12 hours then washed off, 
repeated in 1 week. Patients often continue to itch for sev
-
eral weeks after treatment. Use of triamcinolone 0.1% 
cream helps resolve the dermatitis. Pregnant patients 
should be treated only if they have documented scabies 
themselves. Permethrin 5% cream once for 12 hours—or 
5% or 6% sulfur in petrolatum applied nightly for 3 nights 
from the collarbones down—may be used.
Most failures in normal persons are related to incorrect 
use or incomplete treatment of the housing unit. In these 
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cases, repeat treatment with permethrin once weekly for 
2 weeks, with re-education regarding the method and 
extent of application, is suggested.
2. Ivermectin—
In immunocompetent individuals, 200 
mcg/kg orally is effective in about 75% of cases with a sin
-
gle dose and 95% of cases with two doses 2 weeks apart.
Ivermectin is often used in combination with perme
-
thrin. In immunosuppressed persons and those with 
crusted (hyperkeratotic) scabies, multiple doses of iver
-
mectin (every 2 weeks for 2 or 3 doses) plus topical therapy 
with permethrin every 3 days to once weekly, depending 
on degree of involvement, may be effective when topical 
treatment and oral therapy alone fail. A topical keratolytic 
(urea) should be used to help remove the scale, thereby 
decreasing the mite load, of hyperkeratotic scabies.
Ivermectin can be very beneficial in mass treatment to 
eradicate infections in institutions or villages. In endemic 
areas, mass intervention with ivermectin is effective in 
controlling both scabies and associated bacterial 
If secondary pyoderma is present, it is treated with sys
-
temic antibiotics. Staphylococcal superinfection may lead 
to sepsis. In areas where nephritogenic streptococcal 
strains are prevalent, infestation with scabies or exposure 
to scabies-infested dogs may be followed by acute post-
streptococcal glomerulonephritis.
Persistent pruritic postscabietic papules may be treated 
with mid- to high-potency corticosteroids or with intrale
-
sional triamcinolone acetonide (2.5–5 mg/mL).
Anderson KL et al. Epidemiology, diagnosis, and treatment of 
scabies in a dermatology office. J Am Board Fam Med. 
 
2017 1/2;30(1):78–84. [PMID: 28062820]
Goldust M. Treatment of scabies, comparing the different medi
-
cations. Ann Parasitol. 2016 Oct 1;62(3):243. [PMID: 
27770765]
Hardy M et al. Scabies: a clinical update. Aust Fam Physician. 
2017;46(5):264–68. [PMID: 28472570]
Panahi Y et al. The efficacy of topical and oral ivermectin in the 
treatment of human scabies. Ann Parasitol. 2015;61(1):11–6. 
[PMID: 25911032]
Romani L et al. Mass drug administration for scabies control in 
a population with endemic disease. N Engl J Med. 2015 Dec 10;
 
373(24):2305–13. [PMID: 26650152]
White LC et al. The management of scabies outbreaks in residential 
care facilities for the elderly in England: a review of current 
health protection guidelines. Epidemiol Infect. 2016 Nov;
 
144(15):3121–30. [PMID: 27734781]
PEDICULOSIS
 
»
Pruritus with excoriation.
 
»
Nits on hair shafts; lice on skin or clothes.
 
»
Occasionally, sky-blue macules (maculae ceruleae) 
on the inner thighs or lower abdomen in pubic 
louse infestation.
 
»
Pediculosis is a parasitic infestation of the skin of the scalp, 
trunk, or pubic areas. Body lice usually occur among peo
-
ple who live in overcrowded dwellings with inadequate 
hygiene facilities. Pubic lice may be sexually transmitted. 
Head lice may be transmitted by shared use of hats or 
combs. Adults in contact with children with head lice fre
-
quently acquire the infestation.
There are three different varieties (1) 
pediculosis capitis,
 
caused by 
Pediculus humanus
 var 
capitis
 (head louse); (2) 
pediculosis corporis,
 caused by 
 var 
corporis
 (body louse); and (3) 
pediculosis pubis,
 caused by 
Phthirus pubis
 (pubic louse, “crabs”).
Head and body lice are similar in appearance and are 
3–4 mm long. The body louse can seldom be found on the 
body, because the insect comes onto the skin only to feed 
and must be looked for in the seams of the clothing. Trench 
fever, relapsing fever, and typhus are transmitted by the 
body louse in countries where those diseases are endemic. 
In the United States, 
Bartonella quintana
, the organism that 
causes trench fever, has been found in lice infesting the 
homeless population.
 
»

»
In body louse infestations, itching may be very intense, and 
scratching may result in deep excoriations, especially over 
the upper shoulders, posterior flanks, and neck. In some 
cases, only itching is present, with few excoriations seen. 
Pyoderma may be the presenting sign. Diagnosis is made 
by examining the seams of clothing for nits and lice. Head 
lice presents as scalp pruritus often accompanied by ero
-
sions on the occipital scalp, posterior neck, and upper back. 
Diagnosis is made by finding lice on the scalp or small nits 
resembling pussy willow buds on the scalp hairs close to 
the skin. Nits are easiest to see above the ears and at the 
nape of the neck. Pubic louse infestations are occasionally 
generalized, particularly in hairy individuals; the lice may 
even be found on the eyelashes and in the scalp. Diagnosis 
is made by finding lice or nits on pubic hair, body hair, or 
eyelashes.
 
»
Head louse infestation must be distinguished from sebor
-
rheic dermatitis, body louse infestation from scabies and 
bedbug bites, and pubic louse infestation from anogenital 
pruritus and eczema.
 
»
Treatment
1. Pediculosis capitis—
Permethrin 1% cream rinse (Nix) 
is a topical over-the-counter pediculicide and ovicide. It is 
applied to the scalp and hair and left on for 8 hours before 
being rinsed off. Although it is the treatment of choice for 
head lice, permethrin resistance is common. Malathion 
lotion 1% (Ovide) is very effective, but it is highly volatile 
and flammable, so application must be done in a well-
ventilated room or out of doors. Topical ivermectin 0.5% 
lotion, benzyl alcohol 5%, Oxyphthirine® lotion, spinosad 
0.9% suspension, and dimethicone are additional agents 
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that appear to have efficacy against pediculosis capitis; of 
these agents, topical ivermectin is the most effective. All 
infested persons in a household, school, or other facility 
should ideally be treated at the same time. Other than topi
-
cal ivermectin, topical therapies should be repeated 7–9 days 
after the initial treatment. For involvement of eyelashes, 
petrolatum is applied thickly twice daily for 8 days, and 
remaining nits are then plucked off. Systemic treatment 
options, often used in combination with topical agents) are 
oral ivermectin (200 mcg/kg orally, repeated in 7 days) (for 
children older than 5 years and more than 15 kg) and oral 
TMP-SMZ (10 mg TMP/kg/day and 50 mg SMZ/kg/day 
divided twice daily for 10 days).
2. Pediculosis corporis—
Body lice are treated by disposing 
of the infested clothing and addressing the patient’s social 
situation.
3. Pediculosis pubis—
Application of permethrin rinse 1% 
for 10 minutes or permethrin cream 5% for 8 hours to the 
pubis is effective. Sexual contacts should be treated. Clothes 
and bedclothes should be washed and dried at high 
temperature.
Dadabhoy I et al. Parasitic skin infections for primary care phy
-
sicians. Prim Care. 2015 Dec;42(4):661–75. [PMID: 26612378]
Devore CD et al; Council on School Health and Committee on 
Infectious Diseases, American Academy of Pediatrics. Head 
lice. Pediatrics. 2015 May;135(5):e1355–65. [PMID: 25917986]
Feldmeier H. Treatment of pediculosis capitis: a critical appraisal 
of the current literature. Am J Clin Dermatol. 2014 Oct;
 
15(5):401–12. [PMID: 25223568]
Salavastru CM et al. European guideline for the management of 
pediculosis pubis. J Eur Acad Dermatol Venereol. 2017 Sep;
 
31(9):1425–8. [PMID: 28714128]
Sangaré AK et al. Management and treatment of human lice. 
Biomed Res Int. 2016;6:8962685. [PMID: 27529073]
SKIN LESIONS DUE TO OTHER ARTHROPODS
 
»
Localized urticarial papules with pruritus.
 
»
Lesions in linear groups of three (“breakfast, lunch, 
and dinner”) is characteristic of bedbugs.
 
»
Furuncle-like lesions containing live arthropods.
 
»
Tender erythematous patches that migrate (“larva 
migrans”).
 
»
Some arthropods (eg, mosquitoes and biting flies) are 
readily detected as they bite. Many others are not because 
they are too small, because there is no immediate reaction, 
or because they bite during sleep. Reactions are allergic and 
may be delayed for hours to days. Patients are most apt to 
consult a clinician when the lesions are multiple and pruri
-
tus is intense.
Many persons will react severely only to their earliest 
contacts with an arthropod, thus presenting with pruritic 
lesions when traveling, moving into new quarters, etc. 
Body lice, fleas, bedbugs, and mosquitoes should be con
-
sidered. Bedbug exposure typically occurs in hotels and in 
housing with inadequate hygiene but also may occur in 
stable domiciles. Spiders are often incorrectly believed to 
be the source of bites; they rarely attack humans, though 
the brown recluse spider (
Loxosceles laeta
, 
L reclusa
) may 
cause severe necrotic reactions and death due to intravas
-
cular hemolysis, and the black widow spider (
Latrodectus 
mactans
) may cause severe systemic symptoms and death. 
(See also Chapter 38.) The majority of patient-diagnosed, 
clinician-diagnosed, and even published cases of brown 
recluse spider bites (or loxoscelism) are incorrect, espe
-
cially if made in areas where these spiders are not endemic. 
Many of these lesions are actually due to CA-MRSA.
In addition to arthropod bites, the most common 
lesions are venomous stings (wasps, hornets, bees, ants, 
scorpions) or bites (centipedes), furuncle-like lesions due 
to fly maggots or sand fleas in the skin, and a linear creep
-
ing eruption due to a migrating larva.
 
»
The diagnosis may be difficult when the patient has not

-
 
»
The diagnosis may be difficult when the patient has not 
noticed the initial attack but suffers a delayed reaction. 
Individual bites are often in clusters and tend to occur 
either on exposed parts (eg, midges and gnats) or under 
clothing, especially around the waist or at flexures (eg, 
small mites or insects in bedding or clothing). The reaction 
is often delayed for 1–24 hours or more. Pruritus is almost 
always present and may be all but intolerable once the 
patient starts to scratch. Secondary infection may follow 
scratching. Urticarial wheals are common. Papules may 
become vesicular. The diagnosis is aided by searching for 
exposure to arthropods and by considering the patient’s 
occupation and recent activities.
The principal arthropods are as follows:
1.
 
Fleas:
 Fleas are bloodsucking ectoparasites that feed on 
dogs, cats, humans, and other species. Flea saliva pro
-
duces papular urticaria in sensitized individuals. To 
break the life cycle of the flea, one must treat the home 
and pets, using quick-kill insecticides, residual insecti
-
cides, and a growth regulator.
2.
 
Bedbugs:
 In crevices of beds or furniture; bites tend to 
occur in lines or clusters. Papular urticaria is a charac
-
teristic lesion of bedbug (
Cimex lectularius
) bites. 
Bedbugs are not restricted to any socioeconomic group 
and are a major health problem in some major metro
-
politan areas, especially in commercial and residential 
hotels.
3.
 
Ticks:
 Usually picked up by brushing against low 
vegetation.
4.
 
Chiggers or red bugs:
 These are larvae of trombiculid 
mites. A few species confined to particular regions and 
locally recognized habitats (eg, berry patches, wood
-
land edges, lawns, brush turkey mounds in Australia, 
poultry farms) attack humans, often around the waist, 
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on the ankles, or in flexures, raising intensely itching 
erythematous papules after a delay of many hours. The 
red chiggers may sometimes be seen in the center of 
papules that have not yet been scratched.
5.
 
Bird and rodent mites:
 Larger than chiggers, bird mites 
infest birds and their nests. Bites are multiple anywhere 
on the body. Room air conditioning units may suck in 
bird mites and infest the inhabitants of the room. 
Rodent mites from mice or rats may cause similar 
effects. If the domicile has evidence of rodent activity, 
then rodent mite dermatitis should be suspected, as the 
mites are rarely found. Pet rodents or birds may be 
infested with mites, maintaining the infestation.
6.
 
Mites in stored products:
 These are white and almost 
invisible and infest products, such as copra, vanilla 
pods, sugar, straw, cottonseeds, and cereals. Persons 
who handle these products may be attacked, especially 
on the hands and forearms and sometimes on the feet.
7.
 
Caterpillars of moths with urticating hairs:
 The hairs 
are blown from cocoons or carried by emergent moths, 
causing severe and often seasonally recurrent outbreaks 
after mass emergence. The gypsy moth is a cause in the 
eastern United States.
8.
 
Tungiasis:
 Tungiasis is due to the burrowing flea 
known as 
Tunga penetrans
 and is found in Africa, the 
West Indies, and South and Central America. The 
female burrows under the skin, sucks blood, swells to 
0.5 cm, and then ejects her eggs onto the ground. 
Ulceration, lymphangitis, gangrene, and septicemia 
may result, in some cases with lethal effect. Simple sur
-
gical removal is usually performed.
 
»
Arthropod infestations are best prevented by avoidance of 
contaminated areas, personal cleanliness, and disinfection 
of clothing, bedclothes, and furniture as indicated. Chig
-
gers and mites can be repelled by permethrin applied to the 
head and clothing. (It is not necessary to remove clothing.) 
Bedbugs are no longer repelled by permethrin and can 
survive for up to 1 year without feeding. Aggressive clean
-
ing, usually requiring removal of the affected occupant 
from the domicile, may be necessary to eradicate bedbug 
infestation in a residence.
 
»
Treatment
Living arthropods should be removed carefully with twee
-
zers after application of alcohol and preserved in alcohol 
for identification. In endemic Rocky Mountain spotted 
fever areas, ticks should not be removed with the bare 
fingers.
Corticosteroid lotions or creams are helpful. Topical 
antibiotics may be applied if secondary infection is sus
-
pected. Localized persistent lesions may be treated with 
intralesional corticosteroids.
Stings produced by many arthropods may be alleviated 
by applying papain powder (Adolph’s Meat Tenderizer) 
mixed with water, or aluminum chloride hexahydrate 
(Xerac AC).
Extracts from venom sacs of bees, wasps, yellow jackets, 
and hornets are available for immunotherapy of patients at 
risk for anaphylaxis.
McMenaman KS et al. 
 (“bed bugs”): recognition, 
management, and eradication. Pediatr Emerg Care. 2016 Nov;
 
32(11):801–6. [PMID: 27811535]
Vasievich MP et al. Got the travel bug? A review of common 
infections, infestations, bites, and stings among returning 
travelers. Am J Clin Dermatol. 2016 Oct;17(5):451–62. [PMID: 
27344566]
INFL
a
MM
a
t
O
r
Y
 NODUL
e
S
ERYTHEMA NODOSUM
 
»
Painful nodules without ulceration on anterior 
aspects of legs.
 
»
Slow regression over several weeks to resemble 
contusions.
 
»
Women are predominantly affected by a ratio of 
10:1 compared to men.
 
»
Some cases associated with infection, inflamma
-
tory bowel disease, or medication exposure.
 
»
Erythema nodosum is a symptom complex characterized 
by tender, erythematous nodules that appear most com
-
monly on the extensor surfaces of the lower legs. It usually 
lasts about 6 weeks and may recur. The disease may be

-
lasts about 6 weeks and may recur. The disease may be 
associated with various infections—streptococcosis, pri
-
mary coccidioidomycosis, other deep fungal infections, 
tuberculosis, 
Yersinia pseudotuberculosis
 and 
Y enterocolitica
 
infection, diverticulitis, or syphilis. It may accompany sar
-
coidosis, Behçet disease, and inflammatory bowel disease. 
Erythema nodosum may be associated with pregnancy or 
with use of oral contraceptives.
 
»
The subcutaneous swellings are exquisitely tender and may 
be preceded by fever, malaise, and arthralgia. They are 
most often located on the anterior surfaces of the legs 
below the knees but may occur on the arms, trunk, and 
face. The lesions, 1–10 cm in diameter, are at first pink to 
red; with regression, all the various hues seen in a contu
-
sion can be observed (Figure 6–37) but, as a rule, the 
lesions do not ulcerate.
Evaluation of patients presenting with acute erythema 
nodosum should include a careful history (including 
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▲
Figure 6–37.
 
Erythema nodosum. 
 
medication exposures) and physical examination for prior 
upper respiratory infection or diarrheal illness, symptoms 
of any deep fungal infection endemic to the area, a chest 
radiograph, a PPD, and two consecutive ASO/DNAse B 
titers at 2- to 4-week intervals. If no underlying cause is 
found, only a small percentage of patients will go on to 
develop a significant underlying illness (usually sarcoid
-
osis) over the next year.
 
»
Unlike other forms of panniculitis, a defining feature of 
erythema nodosum is that it does not ulcerate. Erythema 
induratum from tuberculosis is seen on the posterior sur
-
faces of the legs and may ulcerate. Lupus panniculitis pres
-
ents as tender nodules in fatty areas of the buttocks and 
posterior arms and heals with depressed scars. In polyar
-
teritis nodosa, the subcutaneous nodules are often associ
-
ated with fixed livedo reticularis. In its late stages, erythema 
nodosum must be distinguished from simple bruises and 
 
»
Treatment
First, the underlying cause should be identified and treated. 
Primary therapy is with NSAIDs in usual doses. Saturated 
solution of potassium iodide, 5–15 drops three times daily, 
results in prompt involution in many cases. Complete bed 
rest may be advisable if the lesions are painful. Systemic 
therapy directed against the lesions themselves may include 
corticosteroid therapy (see Chapter 26) (unless contraindi
-
cated by associated infection), dapsone, colchicine, or 
hydroxychloroquine.
 
»
Prognosis
The lesions usually disappear after about 6 weeks, but they 
may recur.
Chen S et al. 
Mycobacterium tuberculosis
 infection is associated 
with the development of erythema nodosum and nodular 
vasculitis. PLoS One. 2013 May 1;8(5):e62653. [PMID: 
23650522]
Chowaniec M et al. Erythema nodosum—review of the litera
-
ture. Reumatologia. 2016;54(2):79–82. [PMID: 27407284]
De Simone C et al. Clinical, histopathological, and immunologi
-
cal evaluation of a series of patients with erythema nodosum. 
Int J Dermatol. 2016 May;55(5):e289–94. [PMID: 26917228]
FURUNCULOSIS (
Boils
) & CARBUNCLES
 
»
Extremely painful inflammatory swelling based on 
a hair follicle that forms an abscess.
 
»
Coagulase-positive 
S aureus
 is the causative 
organism.
 
»
Predisposing condition (diabetes mellitus, HIV 
disease, injection drug use) sometimes present.
 
»
A 
furuncle (boil)
 is a deep-seated infection (abscess) 
caused by 
S aureus
 and involving the entire hair follicle and 
adjacent subcutaneous tissue. The most common sites of 
occurrence are the hairy parts exposed to irritation and 
friction, pressure, or moisture. Because the lesions are 
autoinoculable, they are often multiple. Diabetes mellitus 
(especially if using insulin injections), injection drug use, 
allergy injections, and HIV disease all increase the risk of 
staphylococcal infections by increasing the rate of carriage. 
Certain other exposures including hospitalization, athletic 
teams, prisons, military service, and homelessness may 
also increase the risk of infection.
A 
carbuncle
 consists of several furuncles developing in 
adjoining hair follicles and coalescing to form a conglom
-
erate, deeply situated mass with multiple drainage points.
Recurrent furunculosis (three or more episodes in 
12 months) tends to occur in those with direct contact with 
other infected individuals, especially family members.
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▲
Figure 6–38.
 
Acute paronychia. 
from E.J. Mayeaux Jr, MD in Usatine RP , Smith MA, Mayeaux 
, 2nd ed. 
 
»
Pain and tenderness may be prominent. The abscess is 
either rounded or conical. It gradually enlarges, becomes 
fluctuant, and then softens and opens spontaneously after 
a few days to 1–2 weeks to discharge a core of necrotic tis
-
sue and pus. The inflammation occasionally subsides 
before necrosis occurs. Infection of the soft tissue around 
the nails (paronychia) may be due to staphylococci when it 
is acute (Figure 6–38).
There may be slight leukocytosis, but a white blood cell 
count is rarely required. Pus can be cultured to rule out 
MRSA or other bacteria. Culture of the anterior nares and 
anogenital area (including the rectum to test for gastroin
-
testinal carriage) may identify chronic staphylococcal car
-
riage in cases of recurrent cutaneous infection.
 
»
The most common entity in the differential is an inflamed 
epidermal inclusion cyst
 that suddenly becomes red, ten
-
der, and expands greatly in size over one to a few days. The 
history of a prior cyst in the same location, the presence of 
a clearly visible cyst orifice, and the extrusion of malodor
-
ous cheesy material (rather than purulent material) helps 
in the diagnosis. Tinea profunda (deep dermatophyte 
infection of the hair follicle) may simulate recurrent furun
-
culosis. Furuncle is also to be distinguished from deep 
mycotic infections, such as sporotrichosis; from other 
bacterial infections, such as anthrax and tularemia (rare); 
from atypical mycobacterial infections; and from acne 
cysts. Hidradenitis suppurativa (acne inversa) presents 
with recurrent tender, sterile abscesses in the axillae and 
groin, on the buttocks, or below the breasts. The presence 
of old scars or sinus tracts plus negative cultures suggests 
this diagnosis.
 
»
Serious and sometimes fatal complications of staphylococ
-
cal infection such as septicemia can occur.
 
»
Identifying and eliminating the source of infection is criti
-
cal to prevent recurrences after treatment. The source 
individual may have chronic dermatitis or be an asymp
-
tomatic carrier. Nasal carriage of MRSA and the number of 
children in a household are risk factors for transmission 
between household members. Local measures, such as 
meticulous handwashing; no sharing of towels, clothing, 
and personal hygiene products; avoiding loofas or sponges 
in the bath or shower; changing underwear, sleepwear, 
towels and washcloths daily; aggressive scrubbing of 
showers, bathrooms, and surfaces with bleach; bleach 
baths (¼–½ cup per 20 liters of bathwater for 15 minutes 
3–5 times weekly), 4% chlorhexidine washes, and isolation 
of infected patients who reside in institutions to prevent 
spread are all effective measures.
 
»
Treatment
A. Specific Measures
Incision and drainage is recommended for all loculated sup
-
purations and is the mainstay of therapy. Systemic antibiot
-
ics are usually given. Patients who receive antibiotics 
(specifically, TMP-SMZ [160/800 or 320/1600 mg orally 
twice a day for 10 days or 7 days, respectively] or clindamy
-
cin [300 mg orally three times daily for 10 days]) at the time 
of drainage have higher cure rates and lower new infection 
rates. Other oral antibiotic options include dicloxacillin or 
cephalexin, 1 g daily in divided doses for 10 days. For suspected 
MRSA, doxycycline 100 mg twice daily, TMP-SMZ double-
strength one tablet twice daily, clindamycin 150–300 mg 
twice daily, and linezolid 400 mg twice daily are effective. 
Recurrent furunculosis may be effectively treated with a 
combination of cephalexin (250–500 mg four times daily) or 
doxycycline (100 mg twice daily) for 2–4 weeks plus either

doxycycline (100 mg twice daily) for 2–4 weeks plus either 
rifampin (300 mg twice daily for 5 days) or long-term 
clindamycin (150–300 mg daily for 1–2 months). Shorter 
courses of antibiotics (7–14 days) plus longer-term daily 4% 
chlorhexidine whole body washing and intranasal, axilla, 
and anogenital mupirocin or retapamulin may also cure 
recurrent furunculosis. Oral vancomycin (1 g twice daily for 
5 days) can treat gastrointestinal carriage of 
S aureus
. Family 
members, pets, and intimate contacts may need evaluation 
for staphylococcal carrier state and perhaps concomitant 
treatment. Stopping high-risk behavior, such as injection 
drug use, can also prevent recurrence of furunculosis.
Immobilize the part and avoid overmanipulation of 
inflamed areas. Use moist heat to help larger lesions “localize. ” 
Use surgical incision and drainage after the lesions are 
“mature. ” To incise and drain an acute staphylococcal paro
-
nychia, insert a flat metal spatula or sharpened hardwood 
stick into the nail fold where it adjoins the nail. This will 
release pus from a mature lesion.
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»
Prognosis
Recurrent crops may harass the patient for months or years.
Creech CB et al. Prevention of recurrent staphylococcal skin 
infections. Infect Dis Clin North Am. 2015 Sep;29(3):429–64. 
[PMID: 26311356]
Daum RS et al; DMID 07-0051 Team. A placebo-controlled trial 
of antibiotics for smaller skin abscesses. N Engl J Med. 2017 
Jun 29;376(26):2545–55. PMID: 28657870
Ibler KS et al. Recurrent furunculosis—challenges and manage
-
ment: a review. Clin Cosmet Investig Dermatol. 2014 Feb 18;
 
7:59–64. [PMID: 24591845]
Talan DA et al. Trimethoprim-sulfamethoxazole versus placebo 
for uncomplicated skin abscess. N Engl J Med. 2016 Mar 3;
 
374(9):823–32. [PMID: 26962903]
ep
ID
er
M
a
L INCLUSION CYS
t
 
»
Firm dermal papule or nodule.
 
»
Overlying black comedone or “punctum. ”
 
»
Expressible foul-smelling cheesy material.
 
»
May become red and drain, mimicking an abscess.
 
»
Epidermal inclusion cysts (EICs) are common, benign 
growths of the upper portion of the hair follicle. They are 
common in Gardner syndrome and may be the first stig
-
mata of the condition.
EICs favor the face and trunk and may complicate 
nodulocystic acne vulgaris. Individual lesions range in size 
from 0.3 cm to several centimeters. An overlying pore or 
punctum is characteristic. Dermoscopy can aid in observ
-
ing a tiny punctum when not visible to the naked eye. 
Lateral pressure may lead to extrusion of a foul-smelling, 
cheesy material.
 
»
EICs are distinguished from lipomas by being more super
-
ficial (in the dermis, not the subcutaneous fat) and by their 
overlying punctum. Many other benign and malignant 
tumors may superficially resemble EICs, but all lack the 
punctum.
 
»
EICs may rupture, creating an acute inflammatory nodule 
very similar to an abscess. Cultures of the expressed mate
-
rial will be sterile.
 
»
Treatment
Treatment is not required if asymptomatic. Inflamed 
lesions may be treated with incision and drainage or intra
-
lesional triamcinolone acetomide 5–10 mg/mL. For large 
or symptomatic cysts, surgical excision is curative.
Mun JH et al. Importance of keen observation for the diagnosis 
of epidermal cysts: dermoscopy can be a useful adjuvant tool. 
J Am Acad Dermatol. 2014 Oct;71(4):e138–40. [PMID: 
25219733]
ph
O
t
OD
er
M
a
t
I
t
IS
 
»
Painful or pruritic erythema, edema, or vesicula
-
tion on sun-exposed surfaces (face, neck, hands, 
and “V” of the chest).
 
»
Inner upper eyelids and area under the chin are 
spared.
 
»
Photodermatitis is a cutaneous reaction to ultraviolet 
radiation. Photodermatitis is classified into four groups: (1) 
primary photodermatoses that are immunologically 
mediated but are idiopathic in etiology; (2) drug- or 
chemical-induced photodermatoses; (3) dermatoses that 
are worsened or aggravated by ultraviolet exposure; and 
(4) genetic diseases with mutations predisposing to 
photodermatitis.
Primary photodermatoses include polymorphic light 
eruption, chronic actinic dermatitis, and actinic prurigo. 
Drug- or chemical-induced photodermatitis may be either 
exogenous or endogenous in origin. Porphyria cutanea 
tarda and pellagra are examples of endogenous phototoxic 
dermatoses. Exogenous drug- or chemical-induced photo
-
dermatitis manifests either as phototoxicity (a tendency 
for the individual to sunburn more easily than expected) 
or as photoallergy (a true immunologic reaction that pres
-
ents with dermatitis). Drug-induced phototoxicity is trig
-
gered by UV A. Contact photosensitivity may occur with 
plants, perfumes, and sunscreens. The sunscreen oxyben
-
zone (a benzophenone) is a common cause of photoaller
-
gic dermatitis. Dermatoses that are worsened or aggravated 
by ultraviolet exposure include systemic lupus erythemato
-
sus and dermatomyositis. Three percent of persons with

-
-
sus and dermatomyositis. Three percent of persons with 
atopic dermatitis, especially middle-aged women, are 
photosensitive.
 
»
The acute inflammatory phase of phototoxicity, if severe 
enough, is accompanied by pain, fever, gastrointestinal 
symptoms, malaise, and even prostration. Signs include 
erythema, edema, and possibly vesiculation and oozing on 
exposed surfaces. Peeling of the epidermis and pigmentary 
changes often result. The key to diagnosis is localization of 
the rash to photoexposed areas, though these eruptions 
may become generalized with time to involve even photo
-
protected areas. The lower lip may be affected.
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Blood and urine tests are generally not helpful unless por
-
phyria cutanea tarda is suggested by the presence of blister
-
ing, scarring, milia (white cysts 1–2 mm in diameter) and 
skin fragility of the dorsal hands, and facial hypertrichosis. 
Eosinophilia may be present in chronic photoallergic 
responses.
 
»
The differential diagnosis is long. If a clear history of the 
use of a topical or systemic photosensitizer is not available 
and if the eruption is persistent, then a workup including 
biopsy and light testing may be required. Photodermatitis 
must be differentiated from contact dermatitis that may 
develop from one of the many substances in suntan lotions 
and oils, as these may often have a similar distribution. 
Sensitivity to actinic rays may also be part of a more serious 
condition, such as porphyria cutanea tarda or lupus erythe
-
matosus. These disorders are diagnosed by appropriate 
blood or urine tests. The most common medications caus
-
ing a phototoxic reaction are tetracyclines, quinolones, and 
TMP-SMZ. The most common medications causing a 
photoallergic reaction are hydrochlorothiazide, amioda
-
rone, and chlorpromazine. Other potent photosensitizers 
include quinine or quinidine, griseofulvin, NSAIDs, vori
-
conazole, eculizumab, topical and systemic retinoids (treti
-
noin, isotretinoin, acitretin), and calcium channel blockers. 
Polymorphous light eruption (PMLE) is a very common 
idiopathic photodermatitis and often has its onset in the 
third to fourth decades, except in Native Americans and 
Latinos, in whom it may present in childhood. PMLE is 
chronic in nature. Transitory periods of spontaneous 
remission do occur.
 
»
Some individuals continue to be chronic light reactors even 
when they apparently are no longer exposed to photosensi
-
tizing medications.
 
»
While sunscreens are useful agents in general and should 
be used by persons with photosensitivity, patients may 
react to such low amounts of energy that sunscreens alone 
may not be sufficient. Sunscreens with an SPF of 30–60 and 
broad UV A coverage, containing dicamphor sulfonic acid 
(Mexoryl SX), avobenzone (Parasol 1789), titanium diox
-
ide, and micronized zinc oxide, are especially useful in 
patients with photoallergic dermatitis. Photosensitivity due 
to porphyria is not prevented by sunscreens and requires 
barrier protection (clothing) to prevent outbreaks.
 
»
Treatment
Medications should be suspected in cases of photosensitiv
-
ity even if the particular medication (such as hydrochloro
-
thiazide) has been used for months.
When the eruption is vesicular or weepy, treatment is simi
-
lar to that of any acute dermatitis, using cooling and sooth
-
ing wet dressings.
Sunscreens should be used as described above. Mid-
potency to high-potency topical corticosteroids are of 
limited benefit in phototoxic reactions but may help in 
PMLE and photoallergic reactions. Since the face is often 
involved, close monitoring for corticosteroid side effects is 
Aspirin may have some value for fever and pain of acute 
sunburn. Systemic corticosteroids in doses as described for 
acute contact dermatitis may be required for severe photo
-
sensitivity reactions. Otherwise, different photodermatoses 
are treated in specific ways.
Patients with severe photoallergy may require immuno
-
suppressives, such as azathioprine, in the range of 50–300 
mg/day, or cyclosporine, 3–5 mg/kg/day.
 
»
Prognosis
The most common phototoxic sunburn reactions are usu
-
ally benign and self-limited. PMLE and some cases of 
photoallergy can persist for years.
Choi D et al. Evaluation of patients with photodermatoses. 
Dermatol Clin. 2014 Jul;32(3):267–75. [PMID: 24891050]
Coffin SL et al. Photodermatitis for the allergist. Curr Allergy 
Asthma Rep. 2017 Jun;17(6):36. [PMID: 28477263]

Dawe RS et al. Drug-induced photosensitivity. Dermatol Clin. 
2014 Jul;32(3):363–8. [PMID: 24891058]
Gozali MV et al. Update on treatment of photodermatosis. Der
-
matol Online J. 2016 Feb 17;22(2). pii: 13030/qt1rx7d228. 
[PMID: 27267185]
Kutlubay Z et al. Photodermatoses, including phototoxic and 
photoallergic reactions (internal and external). Clin Derma
-
tol. 2014 Jan–Feb;32(1):73–9. [PMID: 24314379]
ULC
er
S
LEG ULCERS SECONDARY TO VENOUS 
INSUFFICIENCY
 
»
Past history of varicosities, thrombophlebitis, or 
postphlebitic syndrome.
 
»
Irregular ulceration, often on the medial lower 
legs above the malleolus.
 
»
Edema of the legs, varicosities, hyperpigmenta
-
tion, red and scaly areas (stasis dermatitis), and 
scars from old ulcers support the diagnosis.
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▲
Figure 6–39.
 
Venous stasis ulcer near the medial 
malleolus. 
(Used, with permission, from Maureen Sheehan, 
MD in Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H, 
2009.)
 
»
Patients at risk may have a history of venous insufficiency, 
either with obvious varicosities or with a past history of 
thrombophlebitis, or with immobility of the calf muscle 
group (paraplegics, etc). Red, pruritic patches of stasis der
-
matitis often precede ulceration. Because venous insuffi
-
ciency plays a role in between 75% and 90% of lower leg 
ulcerations, testing of venous competence is a required part 
of a leg ulcer evaluation even when no changes of venous 
insufficiency are present. The left leg is usually more 
severely affected than the right.
 
»
Classically, chronic edema is followed by a dermatitis, 
which is often pruritic. These changes are followed by 
hyperpigmentation, skin breakdown, and eventually scle
-
rosis of the skin of the lower leg (Figure 6–39). The ulcer 
base may be clean, but it often has a yellow fibrin eschar 
that may require surgical removal. Ulcers that appear on 
the feet, toes, or above the knees should be approached 
with other diagnoses in mind.
Thorough evaluation of the patient’s vascular system 
(including measurement of the ankle/brachial index 
[ABI]) is essential. An ABI less than 0.7 indicates the pres
-
ence of significant arterial disease and therefore requires 
vascular surgery consultation to address the component of 
arterial insufficiency. Doppler examination is usually 
sufficient (except in the diabetic patient) to evaluate 
venous competence.
 
»
The differential includes vasculitis, pyoderma gangreno
-
sum, arterial ulcerations, infection, trauma, skin cancer, 
arachnid bites, and sickle cell anemia. When the diagnosis 
is in doubt, a punch biopsy from the border (not base) of 
the lesion may be helpful.
 
»
Compression stockings to reduce edema are the most 
important means of prevention. Compression should 
achieve a pressure of 30 mm Hg below the knee and 40 mm 
Hg at the ankle. The stockings should not be used in 
patients with arterial insufficiency with an ABI less than 
0.7. Pneumatic sequential compression devices may be of 
great benefit when edema is refractory to standard com
-
pression dressings.
 
»
Treatment
Clean the base of the ulcer with saline or cleansers, such as 
Saf-Clens®. A curette or small scissors can be used to 
remove the yellow fibrin eschar; local anesthesia may be 
used if the areas are very tender.
Overall, there is little evidence to support topical antibi
-
otics other than cadexomer iodine for the treatment of 
venous insufficiency ulcerations. In dermatology clinics, 
metronidazole gel is used to reduce bacterial growth and 
odor. Red dermatitic skin is treated with a medium- to 
high-potency corticosteroid ointment such as triamcino
-
lone acetonide 0.1% ointment. The ulcer is then covered 
with an occlusive hydroactive dressing (DuoDerm® or 
Cutinova®) or a polyurethane foam (Allevyn) followed by 
an Unna zinc paste boot. This is changed weekly. The ulcer 
should begin to heal within weeks, and healing should be 
complete within 4–6 months. If the patient is diabetic, 
becaplermin (Regranex) may be applied to those ulcers 
that are not becoming smaller or developing a granulating 
base. Some ulcerations require grafting. Full- or split-
thickness grafts often do not take, and pinch grafts (small 
shaves of skin laid onto the bed) may be effective. Cultured 
epidermal cell grafts may accelerate wound healing, but 
they are very expensive. They should be considered in 
refractory ulcers, especially those that have not healed after 
a year or more of conservative therapy.

No topical intervention has evidence to suggest that it 
will improve healing of arterial leg ulcers.
Pentoxifylline, 400 mg orally three times daily adminis
-
tered with compression dressings, is beneficial in accelerat
-
ing healing of venous insufficiency leg ulcers. Zinc 
supplementation is occasionally beneficial in patients with 
low serum zinc levels. In the absence of cellulitis, there is 
no role for systemic antibiotics in the treatment of venous 
insufficiency ulcers. The diagnosis of cellulitis in the 
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setting of a venous insufficiency ulcer can be very difficult. 
Surface cultures are of limited value. 
The diagnosis of cel
-
lulitis should be considered in the following settings: 1) 
expanding warmth and erythema surrounding the ulcer
-
ation, with or without 2) increasing pain of the ulcer
-
ation.
 The patient may also report increased exudate from 
the ulceration, but this without the other cardinal findings 
of cellulitis does not confirm the diagnosis of cellulitis. If 
cellulitis accompanies the ulcer, oral antibiotics are recom
-
mended: dicloxacillin, 250 mg four times a day, or levo
-
floxacin, 500 mg once daily for 1–2 weeks, is usually 
adequate. Routine use of antibiotics and treating bacteria 
isolated from a chronic ulcer without clinical evidence of 
infection is discouraged. If the ulcer fails to heal or there is 
a persistent draining tract in the ulcer, an underlying osteo
-
myelitis should be sought.
 
»
Prognosis
The combination of limited debridement, compression 
dressings or stockings, and moist dressings will heal the 
majority of venous stasis ulcers within an average of 18 months. 
These need to be applied at least 80% of the time to opti
-
mize ulcer healing. Topical growth factors, antibiotics, 
debriding agents, and xenografts and autografts can be 
considered in recalcitrant cases, but they are usually not 
required in most patients. The failure of venous insuffi
-
ciency ulcerations to heal is most often related to not using 
the basic treatment methods consistently, rather than fail
-
ure to use these specific modalities. Ongoing control of 
edema is essential to prevent recurrent ulceration. The use 
of compression stockings following ulcer healing is critical 
to prevent recurrence, with recurrence rates 2–20 times 
higher if patients do not comply with compression stocking 
use. If the ABI is less than 0.5, the prognosis for healing is 
poor. Patients with an ABI below 0.5 or refractory ulcer
-
ations (or both) should be considered for surgical proce
-
dure (artery-opening procedures or ablation of the 
incompetent superficial vein).
Attaran RR et al. Compression therapy for venous disease. 
Phlebology. 2017 Mar;32(2):81–8. [PMID: 26908640]
Broussard KC et al. Wound dressings: selecting the most appro
-
priate type. Am J Clin Dermatol. 2013 Dec;14(6):449–59. 
[PMID: 24062083]
Couch KS et al. The international consolidated venous ulcer 
guideline update 2015: process improvement, evidence analysis, 
and future goals. Ostomy Wound Manage. 2017 May;63(5):
 
42–6. [PMID: 28570248]
Gould LJ et al. Modalities to treat venous ulcers: compression, 
surgery, and bioengineered tissue. Plast Reconstr Surg. 2016 Sep;
 
138(3 Suppl):199S–208S. [PMID: 27556762]
Neumann HA et al. Evidence-based (S3) guidelines for diag
-
nostics and treatment of venous leg ulcers. J Eur Acad Derma
-
tol Venereol. 2016 Aug 25. [Epub ahead of print] [PMID: 
27558548]
O’Meara S et al. Antibiotics and antiseptics for venous leg ulcers. 
Cochrane Database Syst Rev. 2014 Jan 10;1:CD003557. 
[PMID: 24408354]
Sundaresan S et al. Stasis dermatitis: pathophysiology, evaluation, 
and management. Am J Clin Dermatol. 2017 Jun;18(3):
 
383–90. [PMID: 28063094]
1
Hirsutism is discussed in Chapter 26.
 
º
MISC
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PIGMENTARY DISORDERS
Although the color of skin may be altered by many diseases 
and agents, the vast majority of patients have either an 
increase or decrease in pigment secondary to an inflamma
-
tory disease, such as acne or atopic dermatitis.
Other pigmentary disorders include those resulting 
from exposure to exogenous pigments, such as caroten
-
emia, argyria, and tattooing. Other endogenous pigmen
-
tary disorders are attributable to metabolic substances (eg, 
hemosiderin [iron]) in purpuric processes, to homogen
-
tisic acid in ochronosis, and bile pigments.
 
»
First, determine whether the disorder is hyperpigmenta
-

-
 
»
-
tion or hypopigmentation, ie, an increase or decrease in 
normal skin colors. Each may be considered to be primary 
or to be secondary to other disorders. Depigmentation, the 
absence of all pigment, should also be differentiated from 
hypopigmentation, in which the affected skin is lighter 
than baseline skin color, but not completely devoid of 
pigment.
The evaluation of pigmentary disorders is helped by 
Wood light, which accentuates epidermal pigmentation in 
hyperpigmented disorders and highlights depigmentation. 
Depigmentation, as seen in vitiligo, enhances with Wood 
light examination, whereas postinflammatory hypopig
-
mentation does not.
A. Primary Pigmentary Disorders
1. Hyperpigmentation—
The disorders in this category are 
nevoid, congenital or acquired, and include pigmented 
nevi, ephelides (juvenile freckles), and lentigines (senile 
freckles). Hyperpigmentation occurs also in arsenical 
melanosis or in association with Addison disease. Melasma 
(chloasma) occurs as patterned hyperpigmentation of the 
face, usually as a direct effect of estrogens. It occurs not 
only during pregnancy but also in 30–50% of women tak
-
ing oral contraceptives, and rarely in men.
2. Hypopigm
entation and depigmentation—
The disor
-
ders in this category are vitiligo, albinism, and piebald
-
ism. In 
vitiligo
, pigment cells (melanocytes) are 
destroyed (Figure 6–40). Vitiligo, present in approxi
-
mately 1% of the population, may be associated with 
other autoimmune disorders, such as autoimmune thyroid 
disease, pernicious anemia, diabetes mellitus, and Addison 
disease.
B. Secondary Pigmentary Disorders
Any damage to the skin (irritation, allergy, infection, exco
-
riation, burns, or dermatologic therapy, such as chemical 
peels and freezing with liquid nitrogen) may result in 
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▲
Figure 6–40.
 
Vitiligo of the hands. 
 
The Color 
hyperpigmentation or hypopigmentation. Several disor
-
ders of clinical importance are described below.
The most common type of sec
-
ondary hyperpigmentation occurs after another inflamma
-
tory dermatologic condition, such as acne, lichen planus, 
or eczema, and is most commonly seen in moderately 
complexioned persons (Asians, Hispanics, and light-
skinned black individuals). It is called post-inflammatory 
hyperpigmentation.
Pigmentation may be produced by certain medications, 
eg, chloroquine, chlorpromazine, minocycline, and amio
-
darone. Fixed drug eruptions to phenolphthalein (in laxatives), 
TMP-SMZ, NSAIDs, and tetracyclines also lead to hyper
-
pigmentation, typically in annular patches.
2. Hypopigmentation—
Hypopigmentation may compli
-
cate atopic dermatitis, lichen planus, psoriasis, discoid 
lupus, and lichen simplex chronicus. It may also be post
-
traumatic. 
Clinicians must exercise special care in using liq
-
uid nitrogen on any patient with olive or darker complexions, 
since doing so may result in hypopigmentation or depigmen
-
tation, at times permanent
. Intralesional or intra-articular 
injections of high concentrations of corticosteroids may 
also cause localized temporary hypopigmentation.
 
»
Actinic keratoses and skin cancers are more likely to 
develop in persons with vitiligo. Severe emotional trauma 
may occur in extensive vitiligo and other types of hypopig
-
mentation and hyperpigmentation, particularly in natu
-
rally dark-skinned persons.
 
»
A. Hyperpigmentation
Therapeutic bleaching preparations generally contain 
hydroquinone. Hydroquinone has occasionally caused 
unexpected hypopigmentation, hyperpigmentation, or 
even secondary ochronosis and pigmented milia, particu
-
larly with prolonged use.
The role of exposure to ultraviolet light cannot be 
overstressed as a factor promoting or contributing to 
most disorders of hyperpigmentation, and such expo
-
sure should be minimized.
 Melasma, ephelides, and 
postinflammatory hyperpigmentation may be treated with 
varying success with 4% hydroquinone and a sunscreen 
containing UV A photoprotectants (Avobenzone, Mexoryl, 
zinc oxide, titanium dioxide). Tretinoin cream, 0.025–
0.05%, may be added. Adjuvant topical options for melasma 
include kojic acid, ascorbic acid, and niacinamide. Superfi
-
cial melasma responds well, but if there is predominantly 
dermal deposition of pigment (does not enhance with 
Wood light), the prognosis is poor. Response to therapy 
may take months and requires avoidance of sunlight. 
Hyperpigmentation often recurs after treatment if the skin 
is exposed to ultraviolet light. Acne with postinflammatory 
hyperpigmentation responds well to azelaic acid and 
tretinoin, as both address both acne and hyperpigmen
-
tation. Solar lentigines respond to liquid nitrogen 
application. Tretinoin 0.1% cream or tazarotene 0.1% used 
over 10 months can fade solar lentigines, facial hyperpig
-
mentation, and postinflammatory hyperpigmentation. 
Lasers are available for the removal of epidermal and der
-
mal pigment, and referral should be considered for patients 
whose responses to medical treatment are inadequate.
B. Hypopigmentation
In secondary hypopigmentation, repigmentation may 
occur spontaneously. Cosmetics such as Covermark and 
Dermablend are highly effective for concealing disfiguring 
patches. Therapy of vitiligo is long and tedious, and the 
patient must be strongly motivated. If less than 20% of the 
skin is involved (most cases), topical tacrolimus 0.1% twice 
daily is the first-line therapy. A superpotent corticosteroid 
may also be used, but local skin atrophy from prolonged

may also be used, but local skin atrophy from prolonged 
use may ensue. With 20–25% involvement, narrowband 
UVB or oral PUV A is the best option. Severe phototoxic 
response (sunburn) may occur with PUV A. The face and 
upper chest respond best, and the fingertips and the genital 
areas do not respond as well to treatment. Y ears of treat
-
ment may be required. There is some emerging evidence 
that JAK inhibitors (tofactinib) may have a role in the treat
-
ment of vitiligo.
Bastonini E et al. Skin pigmentation and pigmentary disorders: 
focus on epidermal/dermal cross-talk. Ann Dermatol. 
2016 Jun;28(3):279–89. [PMID: 27274625]
Gill L et al. Comorbid autoimmune diseases in patients 
with vitiligo: a cross-sectional study. J Am Acad Dermatol. 
2016 Feb;74(2):295–302. [PMID: 26518171]
Mohammad TF et al. Practice and educational gaps in abnormal 
pigmentation. Dermatol Clin. 2016 Jul;34(3):291–301. [PMID: 
27363886]
Nicolaidou E et al. Pigmentation disorders: hyperpigmentation 
and hypopigmentation. Clin Dermatol. 2014 Jan–Feb;
 
32(1):66–72. [PMID: 24314378]
Ogbechie-Godec OA et al. Melasma: an up-to-date comprehen
-
sive review. Dermatol Ther (Heidelb). 2017 Sep;7(3):305–18. 
[PMID: 28726212]
Passeron T. Medical and maintenance treatments for vitiligo. 
Dermatol Clin. 2017 Apr;35(2):163–70. [PMID: 28317526]
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Rodrigues M et al; Vitiligo Working Group. Current and emerging 
treatments for vitiligo. J Am Acad Dermatol. 2017 Jul;77(1):
 
17–29. [PMID: 28619557]
Whitton M et al. Evidence-based management of vitiligo: sum
-
mary of a Cochrane systematic review. Br J Dermatol. 2016 
May;174(5):962–9. [PMID: 26686510]
ALOPECIA
 
»
Alopecias are divided into scarring and nonscarring forms. 
When first evaluating a patient who complains of hair loss, 
it is most important on physical examination to determine 
if follicular markings (the opening where hair exits the 
skin) are present or absent. Present follicular markings 
suggest a nonscarring alopecia; absent follicular markings 
suggest a scarring alopecia.
 
»
Nonscarring Alopecia
Nonscarring alopecia may occur in association with vari
-
ous systemic diseases, such as SLE, secondary syphilis, 
hyperthyroidism or hypothyroidism, iron deficiency ane
-
mia, vitamin D deficiency, and pituitary insufficiency. The 
only treatment necessary is prompt and adequate control of 
the underlying disorder, which usually leads to regrowth of 
the hair.
Androgenetic alopecia,
 the most common form of 
alopecia, is of genetic predetermination. In men, the earli
-
est changes occur at the anterior portions of the calvarium 
on either side of the “widow’s peak” and on the crown 
(vertex). The extent of hair loss is variable and unpredict
-
able. Minoxidil 5% is available over the counter and can be 
specifically recommended for persons with recent onset 
(less than 5 years) and smaller areas of alopecia. Approxi
-
mately 40% of patients treated twice daily for a year will 
have moderate to dense growth. Finasteride (Propecia), 
1 mg orally daily, has similar efficacy and may be additive 
to minoxidil.
Androgenetic alopecia also occurs in women. Classi
-
cally, there is retention of the anterior hairline while there 
is diffuse thinning of the vertex scalp hair and a widening 
of the part. Treatment includes topical minoxidil and, in 
women not of childbearing potential, finasteride at doses 
up to 2.5 mg/day. A workup consisting of determination of 
serum testosterone, DHEAS, iron, total iron-binding 
capacity, thyroid function tests, vitamin D level, and a com
-
plete blood count will identify most other causes of hair 
thinning in premenopausal women. Women who complain 
of thin hair but show little evidence of alopecia need fol
-
low-up, because more than 50% of the scalp hair can be lost 
before the clinician can perceive it.
Telogen effluvium
 is a transitory increase in the num
-
ber of hairs in the telogen (resting) phase of the hair 
growth cycle. This may occur spontaneously, may appear 
at the termination of pregnancy, may be precipitated by 
“crash dieting, ” high fever, stress from surgery or shock, 
malnutrition, or may be provoked by hormonal contra
-
ceptives. Whatever the cause, telogen effluvium usually 
has a latent period of 4 months. The prognosis is generally 
good. The condition is diagnosed by the presence of large 
numbers of hairs with white bulbs coming out upon gentle 
tugging of the hair. Counts of hairs lost by the patient on 
combing or shampooing often exceed 150 per day, com
-
pared to an average of 70–100. In one study, a major cause 
of telogen effluvium was found to be iron deficiency, and 
the hair counts bore a clear relationship to serum iron lev
-
els. If iron deficiency is suspected, a serum ferritin should 
be obtained, and any value less than 40 ng/mL followed 
with supplementation.
Alopecia areata
 is of unknown cause but is believed to 
be an immunologic process. Typically, there are patches 
that are perfectly smooth and without scarring. Tiny hairs 
2–3 mm in length, called “exclamation hairs, ” may be seen. 
Telogen hairs are easily dislodged from the periphery of 
active lesions. The beard, brows, and lashes may be 
involved. Involvement may extend to all of the scalp hair 
(
alopecia totalis

(
) or to all scalp and body hair (
alopecia 
universalis
). Severe forms may be treated by systemic cor
-
ticosteroid therapy, although recurrences follow discon
-
tinuation of therapy. Alopecia areata is occasionally 
associated with autoimmune disorders, including Hashi
-
moto thyroiditis, pernicious anemia, Addison disease, and 
vitiligo. Additional comorbidities may include SLE, atopy, 
and mental health disease.
Intralesional corticosteroids are frequently effective for 
alopecia areata. Triamcinolone acetonide in a concentra
-
tion of 2.5–10 mg/mL is injected in aliquots of 0.1 mL at 
approximately 1- to 2-cm intervals, not exceeding a total 
dose of 30 mg per month for adults. Alopecia areata is usu
-
ally self-limiting, with complete regrowth of hair in 80% of 
patients with focal disease. Some mild cases are resistant to 
treatment, as are the extensive totalis and universalis types. 
Support groups for patients with extensive alopecia areata 
are very beneficial. JAK inhibitors (ruxolitinib, tofacitinib) 
are therapeutic options for patients with highly morbid 
disease, although relapse is the rule once the medication 
In 
trichotillomania
 (the pulling out of one’s own hair), 
the patches of hair loss are irregular, with short, growing 
hairs almost always present, since they cannot be pulled 
out until they are long enough. The patches are often uni
-
lateral, occurring on the same side as the patient’s domi
-
nant hand. The patient may be unaware of the habit.
 
»
Scarring (Cicatricial) Alopecia
Cicatricial alopecia may occur following any type of 
trauma or inflammation that may scar hair follicles. Exam
-
ples include chemical or physical trauma, lichen planopila
-
ris, bacterial or fungal infections, severe herpes zoster, 
chronic discoid lupus erythematosus (DLE), scleroderma, 
and excessive ionizing radiation. The specific cause is often 
suggested by the history, the distribution of hair loss, and 
the appearance of the skin, as in DLE. Biopsy is useful in 
the diagnosis of scarring alopecia, but specimens must be 
taken from the active border and not from the scarred 
central zone. Scarring alopecias are irreversible and perma
-
nent. It is important to diagnose and treat the scarring 
process as early in its course as possible.
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Adil A et al. The effectiveness of treatments for androgenetic 
alopecia: a systematic review and meta-analysis. J Am Acad 
Dermatol. 2017 Jul;77(1):136–41.e5. [PMID: 28396101]
Bolduc C et al. Primary cicatricial alopecia: lymphocytic pri
-
mary cicatricial alopecias, including chronic cutaneous lupus 
erythematosus, lichen planopilaris, frontal fibrosing alopecia, 
and Graham-Little syndrome. J Am Acad Dermatol. 2016 Dec;
 
75(6):1081–99. [PMID: 27846944]
Bolduc C et al. Primary cicatricial alopecia: other lymphocytic 
primary cicatricial alopecias and neutrophilic and mixed 
primary cicatricial alopecias. J Am Acad Dermatol. 2016 Dec;
 
75(6):1101–17. [PMID: 27846945]
Kennedy Crispin M et al. Safety and efficacy of the JAK inhibitor 
tofacitinib citrate in patients with alopecia areata. JCI Insight. 
2016 Sep 22;1(15):e89776. [PMID: 27699252]
Lee S et al. Management of alopecia areata: updates and algorith
-
mic approach. J Dermatol. 2017 Nov;44(11):1199–211. 
[PMID: 28635045]
Mackay-Wiggan J et al. Oral ruxolitinib induces hair regrowth in 
patients with moderate-to-severe alopecia areata. JCI Insight. 
2016 Sep 22;1(15):e89790. [PMID: 27699253]
Pratt CH et al. Alopecia areata. Nat Rev Dis Primers. 2017 Mar 16;
 
3:17011. [PMID: 28300084]
van Zuuren EJ et al. Interventions for female pattern hair loss. 
Cochrane Database Syst Rev. 2016 May 26;(5):CD007628. 
[PMID: 27225981]
NAIL DISORDERS
1. Morphologic 
a
bnormalities of the Nails
 
»
Acquired nail disorders may be classified as local or those 
associated with systemic or generalized skin diseases.
A. Local Nail Disorders
1.
 
Onycholysis (distal separation of the nail plate from the 
nail bed, usually of the fingers) is caused by excessive 
exposure to water, soaps, detergents, alkalies, and 
industrial cleaning agents. Candidal infection of the 
nail folds and subungual area, nail hardeners, drug-
induced photosensitivity, hyperthyroidism, hypothy
-
roidism, and psoriasis may cause onycholysis.
2.
 
Distortion of the nail occurs as a result of chronic 
inflammation or infiltration of the nail matrix underly
-
ing the eponychial fold. Such changes may be caused by 
impingement on the nail matrix by inflammatory dis
-
eases (eg, psoriasis, lichen planus, eczema), warts, 
tumors, or cysts.
3.
 
Discoloration and crumbly thickened nails are noted in 
dermatophyte infection and psoriasis.
4.
 
Allergic reactions (to resins in undercoats and polishes 
or to nail glues) are characterized by onycholysis or by 
grossly distorted, hypertrophic, and misshapen nails.
B. Nail Changes Associated with Systemic or 
Generalized Skin Diseases
1.
 
Beau lines (transverse furrows) affect all nails and clas
-
sically develop after a serious systemic illness.
2.
 
Atrophy of the nails may be related to trauma or to 
vascular or neurologic disease.
3.
 
Clubbed fingers may be due to the prolonged hypox
-
emia associated with cardiopulmonary disorders 
(Figure 6–41) (See Chapter 9).
4.
 
Spoon nails may be seen in anemic patients.
5.
 
Stippling or pitting of the nails is seen in psoriasis, alo
-
pecia areata, and hand eczema.
6.
 
Nail hyperpigmentation may be caused by many che
-
motherapeutic agents, but especially the taxanes.
 
»
Onychomycosis may cause nail changes identical to those 
seen in psoriasis. Careful examination for more character
-
istic lesions elsewhere on the body is essential to the diag
-
nosis of the nail disorders. Cancer should be suspected 
(eg, Bowen disease or squamous cell carcinoma) as the 
cause of any persistent solitary subungual or periungual 
lesion.
 
»
Toenail changes may lead to an ingrown nail—in turn 
often complicated by bacterial infection and occasionally 
by exuberant granulation tissue. Poor manicuring and 
poorly fitting shoes may contribute to this complication. 
Cellulitis may result.
 
»

»
Treatment consists usually of careful debridement and 
manicuring and, above all, reduction of exposure to irri
-
tants (soaps, detergents, alkali, bleaches, solvents, etc). 
Longitudinal grooving due to temporary lesions of the 
matrix, such as warts, synovial cysts, and other impinge
-
ments, may be cured by removal of the offending lesion.
 
▲
Figure 6–41.
 
Clubbing of the fingers in congenital 
heart disease. 
. 
CMDT19_Ch06_p0103-p0173.indd   169

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2. 
t
inea Unguium (
Onychomycosis)
Tinea unguium is a trichophyton infection of one or more 
(but rarely all) fingernails or toenails. The species most 
commonly found is 
T rubrum
. “Saprophytic” fungi may 
rarely cause onychomycosis (less than 5% of cases). Evi
-
dence supporting a genetic defect in the innate and adap
-
tive immune system may explain why some people suffer 
from chronic tinea pedis and onychomycosis.
The nails are lusterless, brittle, and hypertrophic, and 
the substance of the nail is friable. Laboratory diagnosis is 
mandatory since only 50% of dystrophic nails are due to 
dermatophytosis. Portions of the nail should be clipped, 
digested with 10% KOH, and examined under the micro
-
scope for hyphae. Fungi may also be cultured from debris 
collected from underneath the nail plate. Periodic acid-
Schiff stain of a histologic section of the nail plate will also 
demonstrate the fungus readily. Each technique is positive 
in only 50% of cases so several different tests may need to 
be performed. Periodic acid-Schiff staining of nail plate 
coupled with fungal culture has a sensitivity of 96%.
Onychomycosis is difficult to treat because of the long 
duration of therapy required and the frequency of recur
-
rences. Fingernails respond more readily than toenails. For 
toenails, treatment is indicated for patients with discomfort, 
inability to exercise, diabetes, and immune compromise.
In general, systemic therapy is required to effectively 
treat nail onychomycosis. Although historically topical 
therapy has had limited value, efinaconazole 10% has been 
approved as a topical therapy; evidence suggests that it 
performs better than prior topical treatment options. Tava
-
borole 5% solution has also been approved for the treat
-
ment of onychomycosis, but its clearance rates do not 
appear to be as good as those of efinaconazole. Adjunctive 
value of surgical procedures is unproven, and the efficacy 
of laser treatments is lacking, especially with regard to 
long-term cures.
Fingernails can virtually always be cured, and toenails are 
cured 35–50% of the time and are clinically improved about 
75% of the time. In all cases, before treatment, the diagnosis 
should be confirmed. The costs of the various treatment 
options should be known and the most cost-effective treat
-
ment chosen. Medication interactions must be avoided. 
Ketoconazole, due to its higher risk for hepatotoxicity, is not 
recommended to treat any form of onychomycosis. For fin
-
gernails, ultramicronized griseofulvin 250 mg orally three 
times daily for 6 months can be effective. Alternative treat
-
ments are (in order of preference) oral terbinafine 250 mg 
daily for 6 weeks, oral itraconazole 400 mg daily for 7 days 
each month for 2 months, and oral itraconazole 200 mg daily 
for 2 months. Off-label use of fluconazole, 400 mg once 
weekly for 6 months, can also be effective, but there is lim
-
ited evidence for this option. Once clear, fingernails usually 
remain free of disease for some years.
Onychomycosis of the toenails does not respond to 
griseofulvin therapy. The best treatment, which is also FDA 
approved, is oral terbinafine 250 mg daily for 12 weeks. 
Liver biochemical tests and a complete blood count with 
platelets are performed 4–6 weeks after starting treatment, 
although because the risk of idiosyncratic injury is very low 
(transaminitis occurs in less than 0.5% of patients), the 
need for routine monitoring is being questioned. Pulse oral 
itraconazole 200 mg twice daily for 1 week per month for 
3 months is inferior to standard terbinafine treatments, but 
it is an acceptable alternative for those unable to take terbi
-
nafine. The courses of terbinafine or itraconazole may need 
to be repeated 6 months after the first treatment cycle if 
fungal cultures of the nail are still positive.
Elewski BE et al. Topical treatment for onychomycosis: is it more

Elewski BE et al. Topical treatment for onychomycosis: is it more 
effective than the clinical data suggests? J Clin Aesthet Der
-
matol. 2016 Nov;9(11):34–9. [PMID: 28210388]
Ghannoum M et al. Examining the importance of laboratory 
and diagnostic testing when treating and diagnosing 
 
onychomycosis. Int J Dermatol.  2018 Feb;57(2):131–8. 
[PMID: 28653769]
Iorizzo M. Tips to treat the 5 most common nail disorders: 
brittle nails, onycholysis, paronychia, psoriasis, onychomyco
-
sis. Dermatol Clin. 2015 Apr;33(2):175–83. [PMID: 25828710]
Kanzler MH. Reevaluating the need for laboratory testing in the 
treatment of onychomycosis: safety and cost-effectiveness 
considerations. JAMA Dermatol. 2016 Mar;152(3):263–4. 
[PMID: 26719999]
Kreijkamp-Kaspers S et al. Oral antifungal medication for toe
-
nail onychomycosis. Cochrane Database Syst Rev. 2017 Jul 14;
 
7:CD010031. [PMID: 28707751]
Mikailov A et al. Cost-effectiveness of confirmatory testing before 
treatment of onychomycosis. JAMA Dermatol. 2016 Mar;
 
152(3):276–81. [PMID: 26716567]
Park JH et al. Nail neoplasms. J Dermatol. 2017 Mar;44(3):
 
279–87. [PMID: 28256766]
DRUG ERUPTION (
Dermatitis Medicamentosa
)
 
»
Usually, abrupt onset of widespread, symmetric 
erythematous eruption.
 
»
May mimic any inflammatory skin condition.
 
»
Constitutional symptoms (malaise, arthralgia, 
headache, and fever) may be present.
 
»
Rashes are among the most common adverse reactions to 
medications and occur in 2–3% of hospitalized patients. 
There are multiple different types of cutaneous reactions 
to medications. Penicillin and other beta-lactam antibiot
-
ics and TMP-SMZ are the most common causes of urti
-
carial and maculopapular reactions. Drug-induced 
hypersensitivity reaction (DIHS) (also known as drug 
eruption with eosinophilia and systemic symptoms 
[DRESS]) is most often caused by anticonvulsants, allopu
-
rinol, and sulfonamides. SJS and TEN most commonly 
occur in response to antibiotics, sulfonamides, anticonvul
-
sants, allopurinol, and NSAIDs. Phenolphthalein, pyrazo
-
lone derivatives, tetracyclines, NSAIDs, TMP-SMZ, and 
barbiturates are the major causes of fixed drug eruptions. 
Calcium channel blockers are a common cause of pruritus 
and eczemas in older adults.
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Certain genetic polymorphisms of antigen-presenting 
major histocompatibility (MHC) loci increase the risk for 
the development of severe drug eruptions, including SJS/
TEN and DIHS. Pharmacogenetic testing is increasingly 
utilized to predict who is at risk for and therefore should 
avoid certain medication exposures. For example, in Han 
Chinese, HLA typing is indicated before institution of car
-
bamazepine treatment.
 
»
Drug eruptions are generally classified as “simple” or “com
-
plex, ” referring to the risk of morbidity and mortality asso
-
ciated with the specific eruption. Simple drug eruptions 
involve an exanthem, usually appear in the second week of 
medication therapy, and have no associated constitutional 
symptoms or abnormal laboratory findings. Antibiotics, 
including the penicillins and quinolones, are the most 
common causes. Complex drug eruptions include DIHS 
and SJS/TEN.
DIHS occurs later than the simple morbilliform drug 
eruptions with signs and symptoms developing 2–6 weeks 
after the medication has been started and has associated 
constitutional symptoms or abnormal laboratory findings. 
These may include fevers, chills, hematologic abnormali
-
ties (especially eosinophilia and atypical lymphocystosis), 
and abnormal liver or kidney function. Coexistent reacti
-
vation of certain viruses, especially HHV-6, but also 
Epstein-Barr virus, cytomegalovirus, HHV-7, and parvovi
-
rus B19 may be present and may be important in the 
pathogenesis of these complex drug eruptions. Table 6–3 
summarizes the types of skin reactions, their appearance 
and distribution, and the common offenders in each case.
Table 6–3.
 
Skin reactions due to systemic medications.
r
eaction
a
ppear
ance
Distribution and Comments
Common Offenders
Allergic vasculitis
The primary lesion is typically 
a 2–3 mm purpuric papule. 
Other morphologies include 
urticaria that lasts over 
 
24 hours, vesicles, bullae, or 
necrotic ulcers.
Most severe on the legs.
Sulfonamides, phenytoin, 
propylthiouracil.
Drug exanthem
Morbilliform, maculopapular, 
exanthematous reactions.
The most common skin reaction 
 
to medications. Initially begins 
 
on trunk 7–10 days after the 
medication has been started. 
Spreads to extremities and 
begins to clear on the trunk over 
3–5 days. In previously exposed 
patients, the rash may start in 
2–3 days. Fever may be present.
Antibiotics (especially ampicillin and 
TMP-SMZ), sulfonamides and related 
compounds (including thiazide 
diuretics, furosemide, and sulfonyl
-
urea hypoglycemic agents), and 
barbiturates.
Drug-related subacute 
cutaneous lupus 
erythematosus
(Drug-induced SLE rarely 
produces a skin 
reaction)
May present with a 
 
photosensitive rash, 
 
annular lesions, or psoriasis 
on upper trunk.
Less severe than SLE, sparing the 
kidneys and central nervous sys
-
tem. Recovery often follows 
medication withdrawal.
Diltiazem, etanercept, hydrochlorothia
-
zide, infliximab, lisinopril, 
terbinafine.
Erythema nodosum
Inflammatory cutaneous 
nodules.
Usually limited to the extensor 
aspects of the legs. May be 
accompanied by fever, arthral
-
gias, and pain.
Oral contraceptives.
Exfoliative dermatitis and 
erythroderma
(Drug-induced hypersensi
-
tivity syndrome)
Red and scaly.
Entire skin surface. Typically associ
-
ated with elevated liver bio
-
chemical tests, eosinophilia, and 
acute kidney injury. Eruption 
begins between 2 and 6 weeks 
after first dose of medication.
Allopurinol, sulfonamides, isoniazid, 
anticonvulsants, or carbamazepine.
Fixed drug eruptions
Single or multiple demarcated, 
round, erythematous 
plaques that often become 
hyperpigmented.
Recur at the same site when the 
medication is repeated. Hyper
-
pigmentation, if present, remains 
after healing.
Antimicrobials, analgesics (acetamino
-
phen, ibuprofen, and naproxen), 
barbiturates, cardiovascular drugs,

-
-
barbiturates, cardiovascular drugs, 
heavy metals, antiparasitic agents, 
antihistamines, phenolphthalein.
(
continued
)
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Table 6–3.
 
r
eaction
a
ppear
ance
Lichenoid and lichen 
 
planus–like eruptions
Pruritic, erythematous to viola
-
ceous polygonal papules 
that coalesce or expand to 
form plaques.
May be in photo- or nonphotodis
-
tributed pattern.
Carbamazepine, furosemide, hydroxy
-
chloroquine, phenothiazines, beta-
blockers, quinidine, quinine, 
sulfonylureas, tetracyclines, 
 
thiazides, and triprolidine.
Photosensitivity: increased 
sensitivity to light, often 
of ultraviolet A wave
-
lengths, but may be due 
to UVB or visible light as 
well
Sunburn, vesicles, papules in 
photodistributed pattern.
Exposed skin of the face, the neck, 
and the backs of the hands and, 
in women, the lower legs. Exag
-
gerated response to ultraviolet 
light.
Sulfonamides and sulfonamide-related 
compounds (thiazide diuretics, furo
-
semide, sulfonylureas), tetracyclines, 
phenothiazines, sulindac, amioda
-
rone, voriconazole, and NSAIDs.
Pigmentary changes
Flat hyperpigmented areas.
Forehead and cheeks (chloasma, 
melasma). The most common 
pigmentary disorder associated 
with drug ingestion. Improve
-
ment is slow despite stopping 
the medication.
Oral contraceptives are the usual cause. 
Diltiazem causes facial hyperpig
-
mentation that may be difficult to 
distinguish from melasma.
Blue-gray discoloration.
Light-exposed areas.
Chlorpromazine and related 
phenothiazines.
Brown or blue-gray 
pigmentation.
Generalized.
Heavy metals (silver, gold, bismuth, 
and arsenic).
Yellow color.
Quinacrine.
Blue-black patches on the 
shins.
Minocycline, chloroquine.
Blue-black pigmentation 
 
of the nails and palate and 
depigmentation of the hair.
Chloroquine.
Slate-gray color.
Primarily in photoexposed areas.
Amiodarone.
Brown discoloration of the 
nails.
Especially in more darkly 
 
pigmented patients.
Hydroxyurea.
Pityriasis rosea–like 
eruptions
Oval, red, slightly raised 
patches with central scale.
Mainly on the trunk.
Barbiturates, bismuth, captopril, 
clonidine, methopromazine, meto
-
prolol, metronidazole, and 
tripelennamine.
Psoriasiform eruptions
Scaly red plaques.
May be located on trunk and 
extremities. Palms and soles may 
be hyperkeratotic. May cause 
psoriasiform eruption or worsen 
Antimalarials, lithium, beta-blockers, 
and TNF inhibitors.
SJS/TEN
Target-like lesions.
Bullae may occur.
Mucosal involvement.
Usually trunk and proximal 
Sulfonamides, anticonvulsants, allopu
-
rinol, NSAIDs, lamotrigine.
Urticaria
Red, itchy wheals that vary in 
size from less than 1 cm to 
many centimeters. May be 
accompanied by 
angioedema.
Chronic urticaria is rarely caused by 
Acute urticaria: penicillins, NSAIDs, sul
-
fonamides, opioids, and salicylates. 
Angioedema is common in patients 
receiving ACE inhibitors and angio
-
tensin receptor blockers.
ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal 
necrolysis; SLE, systemic lupus erythematosus; TMP-SMZ, trimethoprim-sulfamethoxazole; TNF, tumor necrosis factor.
 
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Routinely ordered blood work is of no value in the diagno
-
sis of simple drug eruptions. In complex drug eruptions, 
the complete blood count, liver biochemical tests, and 
kidney function tests should be monitored. Skin biopsies 
may be helpful in making the diagnosis. Serum PCR for 
HHV-6, HHV-7, Epstein-Barr virus, cytomegalovirus, and 
parvovirus B19 are routinely performed in some centers.
 
»
Observation after discontinuation, which may be a slow 
process, helps establish the diagnosis. Rechallenge, though 
of theoretical value, may pose a danger to the patient and is 
best avoided.
 
»
Some cutaneous drug reactions may be associated with 
visceral involvement. The organ systems involved depend 
on the individual medication or drug class. Most common 
is an infectious mononucleosis-like illness and hepatitis 
associated with administration of anticonvulsants. Myo
-
carditis may be a serious complication of drug-induced 
hypersensitivity syndrome. Months after recovering from 
DIHS patients may suffer hypothyroidism.
 
»
Treatment
Systemic manifestations are treated as they arise (eg, ane
-
mia, icterus, purpura). Antihistamines may be of value in 
urticarial and angioneurotic reactions. Epinephrine 1:1000, 
0.5–1 mL intravenously or subcutaneously, should be used 
as an emergency measure. In DIHS, corticosteroids are 
typically required, most commonly oral prednisone at a 
dose of 1–1.5 mg/kg/day and tapering very slowly over a 
minimum of 6 weeks, since rapid taper leads to rebound 
and more recalcitrant disease. In the case of allopurinol-
induced DIHS, starting steroid-sparing agent (eg, myco
-
phenolate mofetil) at the time of prednisone initiation is 
recommended because allopurinol-induced DIHS tends to 
rebound after corticosteroid discontinuation. Treatment in 
this special case often takes up to 12 months.
SJS/TEN with extensive blistering eruptions resulting in 
erosions and superficial ulcerations demands hospitaliza
-
tion and nursing care as for burn patients.
 
»
Prognosis
Drug rash usually disappears upon withdrawal of the 
medication and proper treatment. DIHS may be associated 
with autoimmune phenomena, including abnormal thy
-
roid function. This can occur months after the hypersensi
-
tivity syndrome has resolved.
Ahronowitz I et al. Severe drug-induced dermatoses. Semin 
Cutan Med Surg. 2014 Mar;33(1):49–58. [PMID: 25037258]
Cheng CY et al. HLA associations and clinical implications in 
T-cell mediated drug hypersensitivity reactions: an updated 
review. J Immunol Res. 2014;4:565320. [PMID: 24901010]
Chung WH et al. Severe cutaneous adverse drug reactions. 
J Dermatol. 2016 Jul;43(7):758–66. [PMID: 27154258]
Dodiuk-Gad RP et al. Epidemiology of severe drug hypersensi
-
tivity. Semin Cutan Med Surg. 2014 Mar;33(1):2–9. [PMID: 
25037253]
Duong TA et al. Severe cutaneous adverse reactions to drugs. 
Lancet. 2017 Oct 28;390(10106):1996–2011. [PMID: 28476287]
Harp JL et al. Severe cutaneous adverse reactions: impact of 
immunology, genetics, and pharmacology. Semin Cutan Med 
Surg. 2014 Mar;33(1):17–27. [PMID: 25037255]
Wolverton SE. Practice gaps: drug reactions. Dermatol Clin. 
2016 Jul;34(3):311–8. [PMID: 27363888]
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REFRACTIVE ERRORS
Refractive error is the most common cause of reduced clar
-
ity of vision (visual acuity) and may be a readily treatable 
component of poor vision in patients with other 
diagnoses.
Use of a pinhole will overcome most refractive errors 
and thus allows their identification as a cause of reduced 
visual acuity.
 
»
Treatment
A. Contact Lenses
An estimated 40.9 million US adults wear contact lenses, 
mostly for correction of refractive errors, for which they 
provide better optical correction than glasses. Decorative 
contact lenses are increasingly being used.
The major risk from contact lens wear is corneal infec
-
tion, potentially a blinding condition. Such infections 
occur more often with soft lenses, particularly extended 
wear, for which there is at least a fivefold increase in risk of 
corneal infection compared with daily wear. Decorative 
contact lenses have a high prevalence of microbial con
-
tamination. Contact lens wearers should be made aware of 
the risks they face and ways to minimize them, such as 
avoiding overnight wear or use of lenses past their replace
-
ment date and maintaining meticulous lens hygiene, 
including not using tap water or saliva for lens cleaning. 
Contact lenses should be removed whenever there is ocular 
discomfort or redness.
Cope JR et al. Risk behaviors for contact lens-related eye infec
-
tions among adults and adolescents—United States, 2016. 
MMWR Morb Mortal Wkly Rep. 2017 Aug 18;66(32):841–5. 
[PMID: 28817556]
Razmaria AA. JAMA patient page. Proper care of contact lenses. 
JAMA. 2015 Oct 13;314(14):1534. [PMID: 26462011]
B. Surgery
Various surgical techniques are available to reduce refrac
-
tive errors, particularly nearsightedness.Laser corneal 
refractive surgery reshapes the middle layer (stroma) of the 
cornea with an excimer laser. Other refractive surgery 
techniques are extraction of the clear crystalline lens with 
insertion of a single vision, multifocal, or accommodative 
intraocular lens; insertion of an intraocular lens without 
removal of the crystalline lens (phakic intraocular lens); 
intrastromal corneal ring segments (INTACS); collagen 
cross-linking; laser thermal keratoplasty; and conductive 
keratoplasty (CK).
Wilkinson JM et al. Refractive eye surgery: helping patients 
make informed decisions about LASIK. Am Fam Physician. 
2017 May 15;95(10):637–44. [PMID: 28671403]
C. Reduction of Rate of Progression of 
Nearsightedness
Topical atropine and pirenzepine, a selective muscarinic 
antagonist; rigid contact lens wear during sleep (orthokera
-
tology); and various types of soft contact lenses and spec
-
tacles reduce the rate of progression of nearsightedness but 
their long-term efficacy and safety are uncertain.
 
»
Any contact lens wearer with an acute painful red eye must 
be referred emergently to an ophthalmologist.
DISORDERS OF THE LIDS & LACRIMAL 
APPARATUS
1. Hordeolum
Hordeolum is a common staphylococcal abscess that is 
characterized by a localized red, swollen, acutely tender 
area on the upper or lower lid. Internal hordeolum is a 
meibomian gland abscess that usually points onto the con
-
junctival surface of the lid; external hordeolum or sty usu
-
ally is smaller and on the margin.
Warm compresses are helpful. Incision may be indi
-
cated if resolution does not begin within 48 hours. An 
antibiotic ointment (bacitracin or erythromycin) applied to 
the lid every 3 hours may be beneficial during the acute 
stage. Internal hordeolum may lead to generalized cellulitis 
of the lid.7
Disorders of the 
 
Eyes & Lids
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2. Chalazion
Chalazion is a common granulomatous inflammation of a 
meibomian gland that may follow an internal hordeolum. 
It is characterized by a hard, nontender swelling on the 
upper or lower lid with redness and swelling of the adjacent 
conjunctiva. Treatment is usually by incision and curettage 
but corticosteroid injection may also be effective.
3. Blepharitis
Blepharitis is a common chronic bilateral inflammatory 
condition of the lid margins. 
Anterior blepharitis
 involves 
the lid skin, eyelashes, and associated glands. It may be 
ulcerative, because of infection by staphylococci, or sebor
-
rheic in association with seborrhea of the scalp, brows, and 
ears. 
Posterior blepharitis
 results from inflammation of 
the meibomian glands. There may be bacterial infection, 
particularly with staphylococci, or primary glandular dys
-
function, in which there is a strong association with acne 
rosacea.
 
»
Symptoms are irritation, burning, and itching. In 
anterior 
blepharitis,
 the eyes are “red-rimmed” and scales or gran
-
ulations can be seen clinging to the lashes. In 
posterior 
 the lid margins are hyperemic with telangiec
-
tasias, and the meibomian glands and their orifices are 
inflamed. The lid margin is frequently rolled inward to 
produce a mild entropion, and the tears may be frothy or 
abnormally greasy.
Blepharitis is a common cause of recurrent conjunctivi
-
tis. Both anterior and, more particularly, posterior blepha
-
ritis may be complicated by hordeola or chalazia; abnormal 
lid or lash positions, producing trichiasis; epithelial kerati
-
tis of the lower third of the cornea; marginal corneal infil
-
trates; and inferior corneal vascularization and thinning.
 
»
Treatment
 is usually controlled by cleanliness of 
the lid margins, eyebrows, and scalp. Scales should be 
removed from the lids daily with a hot wash cloth or a 
damp cotton applicator and baby shampoo. In acute exac
-
erbations, an antistaphylococcal antibiotic eye ointment, 
such as bacitracin or erythromycin, is applied daily to the 
lid margins. Antibiotic sensitivity studies may be helpful in 
severe cases.
In mild 
posterior blepharitis
, regular meibomian 
gland expression may be sufficient to control symptoms. 
Inflammation of the conjunctiva and cornea indicates a 
need for more active treatment, including long-term low-
dose oral antibiotic therapy, usually with tetracycline 
(250 mg twice daily), doxycycline (100 mg daily), minocy
-
cline (50–100 mg daily), or erythromycin (250 mg three 
times daily), and possibly short-term topical corticoste
-
roids, eg, prednisolone, 0.125% twice daily. Topical therapy 
with antibiotics, such as ciprofloxacin 0.3% ophthalmic 
solution twice daily, may be helpful but should be restricted 
to short courses.
Eberhardt M et al. Blepharitis. StatPearls [Internet]. Treasure 
Island (FL): StatPearls Publishing; 2017 Oct 17. [PMID: 
29083763] http://www.ncbi.nlm.nih.gov/books/NBK459305/
4. Entropion & Ectropion
Entropion (inward turning of usually the lower lid) occurs 
occasionally in older people as a result of degeneration of 
the lid fascia, or may follow extensive scarring of the con
-
junctiva and tarsus. Surgery is indicated if the lashes rub on 
the cornea. Botulinum toxin injections may also be used 
for temporary correction of the involutional lower lid 
entropion of older people.
Ectropion (outward turning of the lower lid) is common 
with advanced age. Surgery is indicated if there is excessive 
tearing, exposure keratitis, or a cosmetic problem.
Hahn S et al. Lower lid malposition: causes and correction. 
Facial Plast Surg Clin North Am. 2016 May;24(2):163–71. 
[PMID: 27105802]
5. Tumors
Lid tumors are usually benign. Basal cell carcinoma is the 
most common malignant tumor. Squamous cell carci
-
noma, meibomian gland carcinoma, and malignant mela
-

5. Tumors
-
-
noma also occur. Surgery for any lesion involving the lid 
margin should be performed by an ophthalmologist or 
suitably trained plastic surgeon to avoid deformity of the 
lid. Histopathologic examination of eyelid tumors should 
be routine, since 2% of lesions thought to be benign clini
-
cally are found to be malignant. The Mohs technique of 
intraoperative examination of excised tissue is particularly 
valuable in ensuring complete excision so that the risk of 
recurrence is reduced. Medications such as vismodegib (an 
oral inhibitor of the hedgehog pathway), imiquimod (an 
immunomodulator), and 5-fluorouracil occasionally are 
used instead of or as an adjunct to surgery.
Silverman N et al. What’s new in eyelid tumors. Asia Pac J 
Ophthalmol (Phila). 2017 Mar–Apr;6(2):143–52. [PMID: 
28399340]
6. Dacryocystitis
Dacryocystitis is infection of the lacrimal sac usually due to 
congenital or acquired obstruction of the nasolacrimal 
system. It may be acute or chronic and occurs most often 
in infants and in persons over 40 years. It is usually unilat
-
eral. The usual infectious organisms are 
aureus
 and streptococci in acute dacryocystitis and 
Staphy
-
lococcus epidermidis
, streptococci, or gram-negative bacilli 
in chronic dacryocystitis.
Acute dacryocystitis is characterized by pain, swelling, 
tenderness, and redness in the tear sac area; purulent mate
-
rial may be expressed. In chronic dacryocystitis, tearing 
and discharge are the principal signs, and mucus or pus 
may also be expressed.
Acute dacryocystitis responds well to systemic antibi
-
otic therapy. To relieve the underlying obstruction, surgery 
is usually done electively but may be performed urgently in 
acute cases. The chronic form may be kept latent with 
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antibiotics, but relief of the obstruction is the only cure. In 
adults, the standard procedure is dacryocystorhinostomy, 
which involves surgical exploration of the lacrimal sac and 
formation of a fistula into the nasal cavity and, if necessary, 
supplemented by nasolacrimal intubation. Congenital 
nasolacrimal duct obstruction is common and often 
resolves spontaneously. It can be treated by probing the 
nasolacrimal system, supplemented by nasolacrimal intu
-
bation or balloon catheter dilation, if necessary. Dacryo
-
cystorhinostomy is rarely required.
CONJUNCTIVITIS
Conjunctivitis is the most common eye disease. It may be 
acute or chronic. Most cases are due to viral or bacterial 
(including gonococcal and chlamydial) infection. Other 
causes include keratoconjunctivitis sicca, allergy, chemical 
irritants, and deliberate self-harm. The mode of transmis
-
sion of infectious conjunctivitis is usually direct contact via 
fingers, towels, handkerchiefs, etc, to the fellow eye or to 
other persons. It may be through contaminated eye drops.
Conjunctivitis must be differentiated from acute uve
-
itis, acute glaucoma, and corneal disorders (Table 7–1).
1. Viral Conjunctivitis
Adenovirus is the most common cause of viral conjunctivi
-
tis. There is usually bilateral disease with copious watery 
discharge, often with marked foreign body sensation, and a 
follicular conjunctivitis. Infection spreads easily, some
-
times in eye clinics and contaminated swimming pools. 
Epidemic keratoconjunctivitis, which may result in visual 
loss due to corneal subepithelial infiltrates, is usually caused 
by adenovirus types 8, 19, and 37. The disease lasts at least 
2 weeks. Infection with adenovirus types 3, 4, 7, and 11 is 
typically associated with pharyngitis, fever, malaise, and 
preauricular adenopathy (pharyngoconjunctival fever). The 
disease usually lasts 10 days. Viral conjunctivitis may also 
be due to herpes simplex virus (HSV), when it is usually 
unilateral and may be associated with lid vesicles, and 
enterovirus 70 or coxsackievirus A24 that characteristically 
cause acute hemorrhagic conjunctivitis (see Chapter 32).
Except for HSV infection for which treatment with 
topical (eg, ganciclovir 0.15% gel) and/or systemic (eg, oral 
acyclovir) antivirals is recommended (Table 32–1), there is 
no specific treatment. Cold compresses reduce discomfort 
and topical sulfonamides (or oral antibiotics) can be pre
-
scribed to prevent secondary bacterial infection. The value 
of weak topical corticosteroids or topical cyclosporine for 
corneal infiltrates due to adenoviral infection is uncertain.
Jhanji V et al. Adenoviral keratoconjunctivitis. Surv Ophthalmol. 
2015 Sep–Oct;60(5):435–43. [PMID: 26077630]
2. Bacterial Conjunctivitis
The organisms isolated most commonly in bacterial con
-
junctivitis are staphylococci, including methicillin-resistant 
S aureus
 (MRSA); streptococci, particularly 
S pneumoniae
; 
Haemophilus
 species; 
Pseudomonas;
 and 
Moraxella
. All 
may produce a copious purulent discharge. There is no 
blurring of vision and only mild discomfort. In severe 
(hyperpurulent) cases, examination of stained conjunctival 
scrapings and cultures is recommended, particularly to 
identify gonococcal infection that requires emergent 
treatment.
The disease is usually self-limited, lasting about 
10–14 days if untreated. A topical antibiotic will usually 
clear the infection in 2–3 days. Except in special circum
-
stances, the use of topical fluoroquinolones is rarely justified 
for treatment of a generally self-limiting, benign infection.
A. Gonococcal Conjunctivitis
Gonococcal conjunctivitis, usually acquired through 
contact with infected genital secretions, typically causes 
Table 7–1.
 
The inflamed eye: differential diagnosis of common causes.
a
cut
e Conjunctivitis
a
cut
e 
a
n
terior Uveitis 
(Iritis)
a
cut
e 
a
ngle
-Closure 
Glaucoma
Corneal Trauma or 
Infection
Incidence
Extremely common

a
cut
a
cut
e 
a
n
(Iritis)
a
cut
e 
a
ngle
-Closure 
Glaucoma
Infection
Incidence
Common
Uncommon
Common
Discharge
Moderate to copious
None
None
Watery or purulent
Vision
No effect on vision
Often blurred
Markedly blurred
Usually blurred
Pain
Mild
Moderate
Severe
Moderate to severe
Conjunctival injection
Diffuse; more toward 
fornices
Mainly circumcorneal
Cornea
Clear
Usually clear
Cloudy
Clarity change related to 
cause
Pupil size
Normal
Small
Moderately dilated
Normal or small
Pupillary light response
Normal
Poor
None
Normal
Intraocular pressure
Normal
Usually normal but may 
be elevated
Markedly elevated
Normal
Smear
Causative organisms
No organisms
Organisms found only in 
corneal infection
CMDT19_Ch07_p0174-p0209.indd   176

177
 
CMDT 2019
copious purulent discharge. It is an ophthalmologic emer
-
gency because corneal involvement may rapidly lead to 
perforation. The diagnosis should be confirmed by stained 
smear and culture of the discharge. Systemic treatment is 
required. A single 1-g dose of intramuscular ceftriaxone is 
usually adequate. (Fluoroquinolone resistance is common.) 
Topical antibiotics such as erythromycin and bacitracin 
may be added. Other sexually transmitted diseases, includ
-
ing chlamydiosis, syphilis, and HIV infection, should be 
considered. Routine treatment for chlamydial infection is 
Costumbrado J et al. Conjunctivitis, Gonococcal. StatPearls 
[Internet]. Treasure Island (FL): StatPearls Publishing; 
2017 Oct 11. [PMID: 29083770]
B. Chlamydial Keratoconjunctivitis
1. Trachoma—
Trachoma is the most common infectious 
cause of blindness worldwide, with approximately 
 
40 million people affected and 1.2 million blind. Recurrent 
episodes of infection in childhood manifest as bilateral 
follicular conjunctivitis, epithelial keratitis, and corneal 
vascularization (pannus). Scarring (cicatrization) of the 
tarsal conjunctiva leads to entropion and trichiasis in 
adulthood with secondary central corneal scarring.
Immunologic tests or polymerase chain reaction on 
conjunctival samples will confirm the diagnosis but treat
-
ment should be started on the basis of clinical findings. A 
single 1-g dose of oral azithromycin is the preferred drug 
for mass treatment campaigns, but improvements in 
hygiene and living conditions probably have contributed 
more to the marked reduction in the prevalence of tra
-
choma during the past 25 years. Local treatment is not 
necessary. Surgical treatment includes correction of lid 
deformities and corneal transplantation.
2. Inclusion conjunctivitis—
The eye becomes infected 
after contact with infected genital secretions. The disease 
starts with acute redness, discharge, and irritation. The eye 
findings consist of follicular conjunctivitis with mild kera
-
titis. A nontender preauricular lymph node can often be 
palpated. Healing usually leaves no sequelae. Diagnosis can 
be rapidly confirmed by immunologic tests or polymerase 
chain reaction on conjunctival samples. Treatment is with 
a single dose of azithromycin, 1 g orally. All cases should be 
assessed for genital tract infection and other sexually trans
-
mitted diseases.
Satpathy G et al. Chlamydial eye infections: current perspec
-
tives. Indian J Ophthalmol. 2017 Feb;65(2):97–102. [PMID: 
28345563]
3. Dry Eyes (Keratoconjunctivitis Sicca)
This is a common disorder, affecting around 50% of older 
women. Hypofunction of the lacrimal glands, causing loss 
of the aqueous component of tears, may be due to aging, 
hereditary disorders, systemic disease (eg, Sjögren syn
-
drome), or systemic drugs. Excessive evaporation of tears 
may be due to environmental factors (eg, a hot, dry, or 
windy climate) or abnormalities of the lipid component of 
the tear film, as in blepharitis. Mucin deficiency may be 
due to vitamin A deficiency, or conjunctival scarring from 
trachoma, Stevens-Johnson syndrome and related condi
-
tions, mucous membrane pemphigoid, burns, or topical 
drugs or their preservatives.
 
»
The patient complains of dryness, redness, or foreign body 
sensation. In severe cases, there is persistent marked dis
-
comfort, with photophobia, difficulty in moving the lids, 
and often excessive mucus secretion. In many cases, 
inspection reveals no abnormality, but on slit-lamp exami
-
nation there are subtle abnormalities of tear film stability 
and reduced volume of the tear film meniscus along the 
lower lid. In more severe cases, damaged corneal and con
-
junctival cells stain with the vital stains rose bengal and 
lissamine green. In the most severe cases, there is marked 
conjunctival injection, loss of the normal conjunctival and

-
conjunctival injection, loss of the normal conjunctival and 
corneal luster, epithelial keratitis that stains with fluores
-
cein and may progress to frank ulceration, and mucous 
strands. The Schirmer test, which measures the rate of 
production of the aqueous component of tears, may be 
helpful.
 
»
Treatment
Aqueous deficiency can be treated with various types of 
artificial tears. The simplest preparations are physiologic 
(0.9%) or hypo-osmotic (0.45%) solutions of sodium chlo
-
ride, which can be used as frequently as every half-hour, 
but in most cases are needed only three or four times a day. 
More prolonged duration of action can be achieved with 
drop preparations containing a mucomimetic such as 
hydroxypropyl methylcellulose (HPMC), carboxymethyl
-
celluose (carmellose), sodium hyaluronate, polyvinyl alco
-
hol, or polyacrylic acid (carbomers), or by using petrolatum 
ointment or a hydroxypropyl cellulose (Lacrisert) insert. 
Autologous serum eye drops may be used in severe cases. 
All these mucomimetics are particularly indicated when 
there is mucin deficiency. If there is tenacious mucus, 
mucolytic agents (eg, acetylcysteine 10% or 20%, one drop 
six times daily) may be helpful.
Artificial tear preparations are generally very safe and 
without side effects. However, preservatives included in 
some preparations to maintain sterility are potentially 
toxic and allergenic and may cause keratitis and cicatrizing 
conjunctivitis in frequent users. The development of such 
reactions may be misinterpreted as a worsening of the dry 
eye state requiring more frequent use of the artificial tears 
and leading in turn to further deterioration, rather than 
being recognized as a need to change to a preservative-free 
preparation.
Disease modification can be achieved with topical anti-
inflammatory agents such as lifitegrast 5%, an integrin 
antagonist; corticosteroids, of which loteprednol (Lotemax) 
is favored because of its low risk of intraocular adverse 
effects; or calcineurin inhibitors, of which cyclosporine 
0.05% ophthalmic emulsion (Restasis) twice a day has been 
used most widely. Diquafosol eye drops promote water 
transfer, rebamipide eye drops increase mucin secretion, 
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and vitamin A is included in some artificial tear prepara
-
tions. Increased dietary intake of omega-3 fatty acids has 
been reported to be beneficial.
Lacrimal punctal occlusion by canalicular plugs or cau
-
tery is useful in severe cases. Blepharitis is treated as 
described above. Associated blepharospasm may benefit 
from botulinum toxin injections.
Mathews PM et al. Functional impairment of reading in patients 
with dry eye. Br J Ophthalmol. 2017 Apr;101(4):481–6. 
[PMID: 27450145]
Pflugfelder SC et al. The pathophysiology of dry eye disease: 
what we know and future directions for research. Ophthal
-
mology. 2017 Nov;124(11S):S4–13. [PMID: 29055361]
4. 
a
ller
gic Eye Disease
Allergic eye disease is common and takes a number of dif
-
ferent forms but all are expressions of atopy, which may 
also manifest as atopic asthma, atopic dermatitis, or allergic 
rhinitis.
 
»
Symptoms include itching, tearing, redness, stringy dis
-
charge, and occasionally, photophobia and visual loss.
Allergic conjunctivitis
 is a benign disease, occurring 
usually in late childhood and early adulthood. It may be 
seasonal (hay fever), developing usually during the spring 
or summer, or perennial. Clinical signs are limited to con
-
junctival hyperemia and edema (chemosis), the latter at 
times being marked and sudden in onset. 
Vernal kerato
-
conjunctivitis
 also tends to occur in late childhood and 
early adulthood. It is usually seasonal, with a predilection 
for the spring. Large “cobblestone” papillae are noted on 
the upper tarsal conjunctiva. There may be lymphoid fol
-
licles at the limbus. 
Atopic keratoconjunctivitis
 is a more 
chronic disorder of adulthood. Both the upper and the 
lower tarsal conjunctivas exhibit a fine papillary conjuncti
-
vitis with fibrosis, resulting in forniceal shortening and 
entropion with trichiasis. Staphylococcal blepharitis is a 
complicating factor. Corneal involvement, including 
refractory ulceration, is frequent during exacerbations of 
both vernal and atopic keratoconjunctivitis. The latter may 
be complicated by herpes simplex keratitis.
 
»
Treatment
A. Mild and Moderately Severe 
 
Allergic Eye Disease
Topical treatments include emedastine and levocabastine, 
which are antihistamines; cromolyn, lodoxamide, nedocro
-
mil, and pemirolast, which are mast cell stabilizers; alcafta
-
dine, azelastine, bepotastine, epinastine, ketotifen, and 
olopatadine, which are combined antihistamines and mast 
cell stabilizers; and bromfenac, diclofenac, flurbiprofen, 
indomethacin, ketorolac, and nepafenac, which are nonste
-
roidal anti-inflammatory drugs (see Treatment of Ocular 
Disorders). Mast cell stabilization takes longer to act than 
antihistamine and nonsteroidal anti-inflammatory effects 
but is useful for prophylaxis. Topical vasoconstrictors 
such as ephedrine, naphazoline, tetrahydrozoline, and 
phenylephrine, alone or in combination with antihistamines 
such as antazoline and pheniramine, are available as over-
the-counter medications but are of limited efficacy and may 
produce rebound hyperemia and follicular conjunctivitis. 
Systemic antihistamines (eg, loratadine 10 mg orally daily) 
may be useful in prolonged atopic keratoconjunctivitis. In 
allergic conjunctivitis, specific allergens may be avoidable. 
In vernal keratoconjunctivitis, a cooler climate often pro
-
vides significant benefit.
B. Acute Exacerbations and Severe 
 
Topical corticosteroids (Table 7–2) are essential to control 
acute exacerbations of both vernal and atopic keratocon
-
junctivitis. Corticosteroid-induced side effects, including 
cataracts, glaucoma, and exacerbation of herpes simplex 
keratitis, are major problems but may be attenuated by the 
ester corticosteroid, loteprednol. Topical cyclosporine or 
tacrolimus is also effective. Systemic corticosteroid or 
other immunosuppressant therapy and even plasmaphere
-

-
sis may be required in severe atopic keratoconjunctivitis.
Castillo M et al. Topical antihistamines and mast cell stabilisers 
for treating seasonal and perennial allergic conjunctivitis. 
Cochrane Database Syst Rev. 2015 Jun 1;6:CD009566. [PMID: 
26028608]
Mounsey AL et al. Topical antihistamines and mast cell stabiliz
-
ers for treating allergic conjunctivitis. Am Fam Physician. 
2016 Jun 1;93(11):915–6. [PMID: 27281835]
PINGUECULA & PTERYGIUM
Pinguecula is a yellow, elevated conjunctival nodule, more 
commonly on the nasal side, in the area of the palpebral 
fissure. It is common in persons over age 35 years. Pteryg
-
ium is a fleshy, triangular encroachment of the conjunctiva 
onto the nasal side of the cornea and is usually associated 
with prolonged exposure to wind, sun, sand, and dust. 
Pinguecula and pterygium are often bilateral.
Pingueculae rarely grow but may become inflamed (pin
-
gueculitis). Pterygia become inflamed and may grow. No 
treatment is usually required for inflammation of pinguec
-
ula or pterygium but artificial tears are often beneficial.
The indications for excision of pterygium are growth 
that threatens vision by encroaching on the visual axis, 
marked induced astigmatism, or severe ocular irritation. 
Recurrence is common and often more aggressive than the 
primary lesion.
Clearfield E et al. Conjunctival autograft for pterygium. 
Cochrane Database Syst Rev. 2016 Feb 11;2:CD011349. 
[PMID: 26867004]
Hovanesian JA et al; ASCRS Cornea Clinical Committee. 
Surgical techniques and adjuvants for the management of 
primary and recurrent pterygia. J Cataract Refract Surg. 
2017 Mar;43(3):405–19. [PMID: 28410726]
CORNEAL ULCER
Corneal ulcers are most commonly due to infection by 
bacteria, viruses, fungi, or amebas. Noninfectious causes—
all of which may be complicated by infection—include 
CMDT19_Ch07_p0174-p0209.indd   178

179
 
CMDT 2019
Table 7–2.
 
Topical ophthalmic agents.
a
gen
t
Cost/Size
1
Recommended Regimen
a
n
tibiotics
2
Amikacin 2.5% (fortified) solution
Compounding pharmacy
Azithromycin (AzaSite)
$213.41/2.5 mL
1 drop two times daily for 2 days, 
then once daily for 5 days
Bacterial conjunctivitis
Bacitracin 500 units/g ointment 
(various)
3
$112.80/3.5 g
Apply small amount (0.5 inch) 
 
into lower conjunctival sac 
 
or to eyelids three to four 
 
times daily for 7–10 days
Bacterial conjunctivitis, 
 
blepharitis, sty
Bacitracin/Polymyxin ointment 
 
(Polysporin, AK-Poly)
$26.12/3.5 g
 
and then three to four 
 
times daily, then as required
Corneal abrasion
Following corneal foreign body 
removal
Besifloxacin ophthalmic suspension, 
0.6% (Besivance)
$191.72/5 mL
1–2 drops every 2 hours while 
awake for 2 days, then every 
 
4 hours for 5 days
1 drop every hour during the day 
and every 2 hours during the 
night for 48 hours, then 
 
gradually reducing
Bacterial keratitis
Cefazolin 5–10% (fortified) solution
Ceftazidime 5% (fortified) solution
Cefuroxime 5% (fortified) solution
Chloramphenicol 1% ointment
4
Chloramphenicol 0.5% solution
4
Ciprofloxacin HCl 0.3% solution 
(Ciloxan)
$47.31/5 mL
 
night for 48 hours, then gradu
-
ally reducing
Ciprofloxacin HCl 0.3% ointment
$257.23/3.5 g
 
three times daily for 2 days, 
then two times daily for 5 days
Erythromycin 0.5% ointment (various)
5
$17.96/3.5 g
1-cm ribbon up to six times daily 
(depending on severity of 
infection)
Bacterial infection of the eye
Fusidic acid 1% gel (Fucithalmic)
Not available in 
 
1 drop two times daily
 
blepharitis, sty, keratitis
Gatifloxacin 0.5% solution (Zymaxid)
$118.16/2.5 mL
1 drop every 2 hours while 
 
awake, up to eight times on 
 
day 1, then two to four times 
daily while awake, days 2–7
 
Gentamicin sulfate 0.3% solution 
(various)
$19.18/5 mL
1–2 drops every 4 hours up to 
 
2 drops every hour for severe 
Ocular surface infection
Gentamicin sulfate 0.3% ointment 
(various)
$19.67/3.5 g
 
two to three times daily
(
continued
)
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Table 7–2.
 
a
gen
t
Cost/Size
1
Gentamicin sulfate 1.5% (fortified 
preparation)
-
Levofloxacin 0.5% solution (various)
$74.76/5 mL
awake for 2 days (maximum 
eight times per day), then every 
4 hours for 5 days (maximum 
four times per day)
-
Moxifloxacin 0.5% solution (Vigamox)
$167.35/3 mL
1 drop three times daily for 7 days
-
Neomycin/Polymyxin B/Gramicidin 
(Neosporin)
$61.26/10 mL
1–2 drops every 4 hours for 
 
7–10 days or more frequently, 
as required
Norfloxacin 0.3% solution
 
-
Ofloxacin 0.3% solution (Ocuflox)
$20.94/5 mL
1–2 drops every 2–4 hours for 
 
2 days, then four times daily for 
5 days
-
Polymyxin B 10,000 U/mL/Trimethoprim 
sulfate 1 mg/mL (Polytrim) 
6
$12.90/10 mL
1 drop every 3 hours for 7–10 days 
(maximum of 6 doses per day)
Propamidine isethionate 0.1% solution
Not available in the 
 
2 days, then four times daily 
 
for 5 days
Ocular surface infection (includ
-
ing 
Ancathamoeba
 keratitis)
Propamidine isethionate 0.1% ointment
 
into lower conjunctival sac up 
Sulfacetamide sodium 10% solution 
(various)
$55.65/15 mL
1 or 2 drops every 2–3 hours ini
-
tially; taper by increasing time 
intervals as condition responds; 
usual duration 7–10 days
Sulfacetamide sodium 10% ointment 
(various)
$65.86/3.5 g
Apply small amount (0.5 inch) into 
lower conjunctival sac once 
every 3–4 hours and at bed
-
time; taper by increasing time 
Bacterial infections of the eye
Tobramycin 0.3% solution (various)
$14.10/5 mL
1–2 drops every 4 hours for a mild 
to moderate infection or hourly 
until improvement (then reduce 
prior to discontinuation) for a 
severe infection
(
continued
)
 
CMDT19_Ch07_p0174-p0209.indd   180

181
 
CMDT 2019
Table 7–2.
 
a
gen
t
Cost/Size
1
Tobramycin 1.5% (fortified) solution
-
Tobramycin 0.3% ointment (Tobrex)
lower conjunctival sac two to 
three times daily for a mild to 
moderate infection or every 
3–4 hours until improvement 
(then reduce prior to discontin
-
uation) for a severe infection
a
n
tifungal 
a
gen
ts
Amphotericin 0.1–0.5% solution
Natamycin 5% suspension (Natacyn)
$395.00/15 mL
1 drop every 1–2 hours initially; 
see prescribing information for 
further recommendations
Fungal blepharitis, conjunctivi
-
tis, keratitis
Voriconazole 1% solution
a
n
tiviral 
a
gen
ts
Acyclovir 3% ointment (Zovirax)
 
Five times daily
Herpes simplex virus keratitis
Ganciclovir 0.15% gel (Zirgan)
$397.66/5 g
Herpetic keratitis
Trifluridine 1% solution (Viroptic)
$178.28/7.5 mL
1 drop onto cornea every 2 hours 
while awake for a maximum 
daily dose of 9 drops until 
 
resolution occurs; then an addi
-
tional 7 days of 1 drop every 
 
4 hours while awake (minimum 
five times daily)
a
n
ti-Inflammatory 
a
gen
ts
a
n
tihistamines
7
Emedastine difumarate 0.05% solution 
(Emadine)
$159.20/5 mL
1 drop four times daily
Allergic eye disease
Levocabastine (Livostin)
 
1 drop twice daily
Mast cell stabilizers
Cromolyn sodium 4% solution (Crolom)
$28.12/10 mL
1 drop four to six times daily
Lodoxamide tromethamine 0.1% 
 
solution (Alomide)
$205.28/10 mL
1 or 2 drops four times daily 
 
(up to 3 months)
Nedocromil sodium 2% solution (Alocril)
$256.58/5 mL
Pemirolast potassium 0.1% solution 
(Alamast)
 
Combined antihistamines and mast cell stabilizers
Alcaftadine 0.25% ophthalmic solution 
(Lastacaft)
$257.83/3 mL
1 drop once daily
Azelastine HCl 0.05% ophthalmic solu
-
tion (Optivar)
$102.90/6 mL
1 drop two to four times daily 
 
(up to 6 weeks)
Bepotastine besilate 1.5% solution 
(Bepreve)
$470.02/10 mL
Epinastine hydrochloride 0.05% oph
-
thalmic solution (Elestat)
$106.99/5 mL
1 drop twice daily (up to 8 weeks)
(
continued
)
 
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Table 7–2.
 
a
gen
t
Cost/Size
1
Ketotifen fumarate 0.025% solution 
(Zaditor)
OTC $11.70/5 mL
1 drop two to four times daily
Olopatadine hydrochloride 0.1% solu
-
tion (Patanol)
$256.50/5 mL
Nonsteroidal anti-inflammatory agents
8
Bromfenac 0.09% solution (Xibrom)
$202.52/1.7 mL
1 drop to operated eye twice daily 
beginning 24 hours after cata
-
ract surgery and continuing 
through first 2 postoperative 
weeks
Treatment of postoperative 
inflammation following 
 
cataract extraction
Diclofenac sodium 0.1% solution 
(Voltaren)
$73.03/5 mL
1 drop to operated eye four times 
daily beginning 24 hours after 
surgery and continuing through 
first 2 postoperative weeks.
 
cataract extraction and laser 
corneal surgery
Flurbiprofen sodium 0.03% solution 
(various)
$8.73/2.5 mL
1 drop every half hour beginning 
2 hours before surgery; 1 drop 
to operated eye four times daily 
-
ract surgery
Inhibition of intraoperative mio
-
sis. Treatment of cystoid mac
-
ular edema and inflammation 
after cataract surgery
Indomethacin 1% solution (Indocid)
 
Treatment of allergic eye dis
-
ease, postoperative inflam
-
mation following cataract 
extraction and laser corneal 
surgery
Ketorolac tromethamine 0.5% solution 
(Acular)
$106.87/5 mL
-
-
surgery
Nepafenac 0.1% suspension (Nevanac)
$305.64/3 mL
1 drop to operated eye three 
times daily beginning 24 hours 
after cataract surgery and con
-
tinuing through first 2 postop
-
erative weeks
inflammation following cata
-
ract extraction
9
Dexamethasone sodium phosphate 
0.1% solution (various)
$21.10/5 mL
1 or 2 drops as often as indicated 
by severity; use every hour dur
-
ing the day and every 2 hours 
during the night in severe 
inflammation; taper off as 
inflammation decreases
Treatment of steroid-responsive 
inflammatory conditions
0.05% ointment
Apply thin coating on lower con
-
junctival sac three or four times 
daily
Fluorometholone 0.1% suspension 
(various)
10
$170.50/10 mL
-
Fluorometholone 0.25% suspension 
(FML Forte)
10
$349.51/10 mL
Fluorometholone 0.1% ointment (FML 
S.O.P .)
$174.74/3.5 g
-
daily
(
continued
)
 
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183
 
CMDT 2019
Table 7–2.
 
a
gen
t
Cost/Size
1
Loteprednol etabonate 0.5% (Lotemax)
$538.18/10 mL
1 or 2 drops four times daily
Prednisolone acetate 0.12% suspension 
(Pred Mild)
$303.98/10 mL
by severity of inflammation; use 
every hour during the day and 
every 2 hours during the night 
in severe inflammation; taper 
off as inflammation decreases
Prednisolone sodium phosphate 
 
0.125% solution
Prednisolone acetate 1% suspension 
(various)
$105.60/10 mL
2 drops four times daily
Prednisolone sodium phosphate 1% 
solution (various)
$63.25/10 mL
1–2 drops two to four times daily
Immunomodulators
Cyclosporine 0.05% emulsion (Restasis) 
0.4 mL/container
$305.59/30 containers
Dry eyes and severe allergic eye 
disease
Tacrolimus 0.1% ointment
$260.45/30 g tube
Not yet established (no label to 
support)
Severe allergic eye disease; no 
indication in United States
a
gen
ts for Glaucoma and Ocular Hypertension
Sympathomimetics
Apraclonidine HCl 0.5% solution 
(Iopidine)
$86.77/5 mL
1 drop three times daily
Reduction of intraocular pres
-
sure; expensive; reserve for 
treatment of resistant cases
Apraclonidine HCl 1% solution 
$33.27/unit dose
1 drop 1 hour before and immedi
-
ately after anterior segment 
laser surgery
To control or prevent elevations 
of intraocular pressure after 
laser trabeculoplasty or 
iridotomy
Brimonidine tartrate 0.2% solution 
(Alphagan, Alphagan P [benzalko
-
nium chloride-free])
$18.13/5 mL
1 drop two or three times daily
Reduction of intraocular 
pressure
Beta-adrenergic blocking agents
Betaxolol HCl 0.5% solution (Betoptic) 
and 0.25% suspension (Betoptic S)
11
0.5%: $117.91/10 mL
0.25%: $372.64/10 mL
pressure
Carteolol HCl 1% and 2% solution 
 
(various, Teoptic)
12
1%: $40.16/10 mL
Levobunolol HCl 0.25% and 0.5% 
 
solution (Betagan)
13
0.5%: $11.94/10 mL
1 drop once or twice daily
Metipranolol HCl 0.3% solution 
(OptiPranolol)
13
$50.17/10 mL
Timolol 0.25% and 0.5% solution 
(Betimol)
13
0.5%: $155.40/10 mL
Timolol maleate 0.25% and 0.5% solu
-
tion (Istalol, Ocudose [preservative-
free], Timoptic) and 0.1%, 0.25% and 
0.5% gel (Timoptic-XE, Timoptic 
GFS)
13
0.5% solution: 
 
$8.80/10 mL
0.5% gel: $217.27/5 mL
Miotics
Pilocarpine HCl 1-4% solution
1% solution: 
 
$98.56/15 mL
1 drop up to 4 times daily for 
elevated intraocular pressure
 
pressure, treatment of 
 
acute or chronic angle-
 
closure glaucoma, and 
 
pupillary constriction
(
continued
)
 
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Table 7–2.
 
a
gen
t
Cost/Size
1
Carbonic anhydrase inhibitors
Brinzolamide 1% suspension (Azopt)
$341.45/10 mL
pressure
Dorzolamide HCl 2% solution (Trusopt)
$45.89/10 mL
p
r
ostaglandin analogs
Bimatoprost 0.03% solution (Lumigan)
$144.65/3 mL
1 drop once daily at night
pressure
Latanoprost 0.005% solution (Xalatan, 
Monopost [preservative-free])
$15.00/2.5 mL
(Monopost not available 
in United States)
1 drop once or twice daily at 
night
Tafluprost 0.0015% solution (Saflutan 
[preservative-free], Taflotan, Zioptan 
[preservative-free])
$220.45/30 units
(Saflutan not available in 
United States)
Travoprost 0.004% solution (Travatan, 
Travatan Z [benzalkonium 
chloride-free])
$204.30/2.5 mL
Unoprostone isopropyl 0.15% solution 
(Rescula)
$153.84/5 mL
Combined preparations
Bimatoprost 0.03% and timolol 0.5% 
(Ganfort)
 
1 drop daily in the morning
pressure
Brimonidine 0.2% and timolol 0.5% 
(Combigan)
$386.50/10 mL
Brimonidine 0.2% and brinzolamide 1% 
(Simbrinza)
$180.82/8 mL
1 drop three times a day
Brinzolamide 1% and timolol 0.5% 
(Azarga)
 
Dorzolamide 2% and timolol 0.5% 
(Cosopt, Cosopt PF 
$238.41/10 mL
Latanoprost 0.005% and timolol 0.5% 
(Xalacom)
 
Tafluprost 0.0015% and timolol 0.5% 
(Taptiqom [preservative-free])
 
1 drop daily
Travoprost 0.004% and timolol 0.5% 
(DuoTrav)
 
1
Average wholesale price (AWP , for AB-rated generic when available) for quantity listed. Source: Red Book Online, Truven Health Analytics 
Information, www.micromedexsolutions.com, accessed March 1, 2018. AWP may not accurately represent the actual pharmacy cost 
because wide contractual variations exist among institutions.
2
Many combination products containing antibiotics or antibiotics and corticosteroids are available.
3
Little efficacy against gram-negative organisms (except 
Neisseria
).
4
Aplastic anemia has been reported with prolonged ophthalmic use.
5
Also indicated for prophylaxis of neonatal conjunctivitis due to 
Neisseria gonorrhoeae
 or 
Chlamydia trachomatis
.
6
No gram-positive coverage.
7
May produce rebound hyperemia and local reactions.
8
Cross-sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs.
9
Long-term use increases intraocular pressure, causes cataracts, and predisposes to bacterial, herpes simplex virus, and fungal keratitis. 
These problems may be attenuated by the ester corticosteroid, loteprednol.
10
Less likely to elevate intraocular pressure.
11
Cardioselective (beta-1) beta-blocker.
12
Teoptic is not available in the United States.
13
Nonselective (beta-1 and beta-2) beta-blocker. Monitor all patients for systemic side effects, particularly exacerbation of asthma.
14
Decreased night vision and headaches possible.
 
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neurotrophic keratitis (resulting from loss of corneal 
sensation), exposure keratitis (due to inadequate lid clo
-
sure), severe dry eye, severe allergic eye disease, and vari
-
ous inflammatory disorders that may be purely ocular or 
part of a systemic vasculitis. Delayed or ineffective treat
-
ment of corneal ulceration may lead to devastating conse
-
quences with corneal scarring or intraocular infection. 
Prompt referral is essential.
Patients complain of pain, photophobia, tearing, and 
reduced vision. The eye is red, with predominantly circum
-
corneal injection, and there may be purulent or watery 
discharge. The corneal appearance varies according to the 
underlying cause.
 
»
Any patient with an acute painful red eye and corneal abnor
-
mality should be referred emergently to an ophthalmologist.
Austin A et al. Update on the management of infectious kera
-
titis. Ophthalmology. 2017 Nov;124(11):1678–89. [PMID: 
28942073]
Gomes BA et al. Corneal involvement in systemic inflammatory 
diseases. Eye Contact Lens. 2015 May;41(3):141–4. [PMID: 
25794330]
INFECTIOUS KERATITIS
1. Bacterial Keratitis
Bacterial keratitis usually pursues an aggressive course. 
Precipitating factors include contact lens wear—especially 
overnight wear—and corneal trauma, including refractive 
surgery. The pathogens most commonly isolated are staph
-
ylococci, including MRSA; streptococci; and 
Pseudomonas 
aeruginosa, Moraxella
 species, and other gram-negative 
bacilli. The cornea is hazy, with an ulcer and adjacent stro
-
mal abscess. Hypopyon is often present. The ulcer is 
scraped to recover material for Gram stain and culture prior 
to starting treatment with high-concentration topical anti
-
biotic drops applied hourly day and night for at least the 
first 48 hours. Fluoroquinolones, such as levofloxacin 0.5%, 
ofloxacin 0.3%, norfloxacin 0.3%, or ciprofloxacin 0.3%, are 
commonly used as first-line agents as long as local preva
-
lence of resistant organisms is low (Table 7–2). The fourth-
generation fluoroquinolones (moxifloxacin 0.5% and 
gatifloxacin 0.3%) may be preferable because they are also 
active against mycobacteria. Gram-positive cocci can also 
be treated with a cephalosporin, such as fortified cefazolin 
10%, but vancomycin may be required for MRSA; and 
gram-negative bacilli can be treated with an aminoglyco
-
side, such as fortified tobramycin 1.5%. If no organisms are 
seen on the Gram stain, a cephalosporin and an aminogly
-
coside can be used together in areas where resistance to 
fluoroquinolones is common. Although early adjunctive 
topical corticosteroid therapy may improve visual outcome, 
it should be prescribed only by an ophthalmologist.
 
»
Any patient with suspected bacterial keratitis must be 
referred emergently to an ophthalmologist.
Herretes S et al. Topical corticosteroids as adjunctive therapy for 
bacterial keratitis. Cochrane Database Syst Rev. 2014 Oct 16;
 
10:CD005430. [PMID: 25321340]
Peng MY et al. Bacterial keratitis: isolated organisms and 
antibiotic resistance patterns in San Francisco. Cornea. 
2018 Jan;37(1):84–7. [PMID: 29053557]
Tam ALC et al. Bacterial keratitis in Toronto: a 16-year review of 
the microorganisms isolated and the resistance patterns 
observed. Cornea. 2017 Dec;36(12):1528–34. [PMID: 28938380]
2. Herpes Simplex Keratitis
Primary ocular herpes simplex virus infection may mani
-
fest as lid, conjunctival, or corneal ulceration. The ability of 
the virus to colonize the trigeminal ganglion leads to recur
-
rences that may be precipitated by fever, excessive exposure 
to sunlight, or immunodeficiency. The dendritic (branching) 
corneal ulcer is the most characteristic manifestation of 
recurrent ocular disease. More extensive (“geographic”) 
ulcers also occur, particularly if topical corticosteroids have 
been used. The corneal ulcers are most easily seen after

been used. The corneal ulcers are most easily seen after 
instillation of fluorescein and examination with a blue 
light. Such corneal epithelial disease in itself generally 
does not lead to corneal scarring. It responds well to sim
-
ple debridement and patching. More rapid healing can be 
achieved by the addition of topical antivirals, such as tri
-
fluridine drops, ganciclovir gel, or acyclovir ointment 
(Table 7–2), or oral antivirals, such as acyclovir, 
400–800 mg five times daily. Long-term oral acyclovir, 
400 mg twice daily; famciclovir, 250 mg once daily; or vala
-
cyclovir, 500 mg once daily, reduces the rate of recurrent 
epithelial disease, particularly in atopic individuals.
Stromal herpes simplex keratitis produces increasingly 
severe corneal opacity with each recurrence. Topical antivi
-
rals alone are insufficient to control stromal disease, so 
topical corticosteroids are used as well but they may 
enhance viral replication, exacerbating epithelial disease, 
and steroid dependence is common. Oral acyclovir, 
200–400 mg five times a day, is often helpful in the treat
-
ment of severe herpetic keratitis. Severe stromal scarring 
may require corneal grafting, but the overall outcome is 
relatively poor. 
Caution:
 For patients with known or pos
-
sible herpetic disease, topical corticosteroids should be 
prescribed only with ophthalmologic supervision.
 
»
Any patient with a history of herpes simplex keratitis and 
an acute red eye should be referred urgently to an 
ophthalmologist.
Azher TN et al. Herpes simplex keratitis: challenges in diagnosis 
and clinical management. Clin Ophthalmol. 2017 Jan 19;
 
11:185–91. [PMID: 28176902]
Prakash G et al. The three faces of herpes simplex epithelial kera
-
titis: a steroid-induced situation. BMJ Case Rep. 2015 Apr 2;
 
2015. [PMID: 25837655]
Reynaud C et al. Persistent impairment of quality of life in 
patients with herpes simplex keratitis. Ophthalmology. 
2017 Feb;124(2):160–9. [PMID: 27863844]
Tsatsos M et al. Herpes simplex virus keratitis: an update of the 
pathogenesis and current treatment with oral and topical anti
-
viral agents. Clin Exp Ophthalmol. 2016 Dec;44(9):824–37. 
[PMID: 27273328]
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3. Herpes Zoster Ophthalmicus
Herpes zoster frequently involves the ophthalmic division 
of the trigeminal nerve. It presents with malaise, fever, 
headache, and periorbital burning and itching. These 
symptoms may precede the eruption by a day or more. The 
rash is initially vesicular, quickly becoming pustular and 
then crusting. Involvement of the tip of the nose or the lid 
margin predicts involvement of the eye. Ocular signs 
include conjunctivitis, keratitis, episcleritis, and anterior 
uveitis, often with elevated intraocular pressure. Recurrent 
anterior segment inflammation, neurotrophic keratitis, 
and posterior subcapsular cataract are long-term complica
-
tions. Optic neuropathy, cranial nerve palsies, acute retinal 
necrosis, and cerebral angiitis occur infrequently. HIV 
infection is an important risk factor for herpes zoster oph
-
thalmicus and increases the likelihood of complications.
High-dose oral acyclovir (800 mg five times a day), 
valacyclovir (1 g three times a day), or famciclovir (500 mg 
three times a day) for 7–10 days started within 72 hours 
after the appearance of the rash reduces the incidence of 
ocular complications but not of postherpetic neuralgia. 
Keratitis can be treated with a topical antiviral such as gan
-
ciclovir 0.15% gel. Anterior uveitis requires treatment with 
topical corticosteroids and cycloplegics. Neurotrophic ker
-
atitis is an important cause of long-term morbidity. Vari
-
cella vaccination reduces the overall incidence but may 
trigger herpes zoster ophthalmicus.
 
»
Any patient with herpes zoster ophthalmicus and ocular 
symptoms or signs should be referred urgently to an 
Cohen EJ. Management and prevention of herpes zoster ocular 
disease. Cornea. 2015 Oct;34(Suppl 10):S3–8. [PMID: 26114827]
Jastrzebski A et al. Reactivation of herpes zoster keratitis 
with corneal perforation after zoster vaccination. Cornea. 
2017 Jun;36(6):740–2. [PMID: 28410358]
Johnson JL et al. Herpes zoster ophthalmicus. Prim Care. 
2015 Sep;42(3):285–303. [PMID: 26319339]
Vrcek I et al. Herpes zoster ophthalmicus: a review for the 
internist. Am J Med. 2017 Jan;130(1):21–6. [PMID: 27644149]
4. Fungal Keratitis
Fungal keratitis tends to occur after corneal injury involv
-
ing plant material or in an agricultural setting, in eyes with 
chronic ocular surface disease, and increasingly in contact 
lens wearers. It is usually an indolent process, with the 
cornea characteristically having multiple stromal abscesses 
and relatively little epithelial loss. Intraocular infection is 
common. Corneal scrapings should be cultured on media 
suitable for fungi whenever the history or corneal appear
-
ance is suggestive of fungal disease. Diagnosis is often 
delayed and treatment is difficult. Natamycin 5%, ampho
-
tericin 0.1–0.5%, and voriconazole 0.2–1% are the most 
commonly used topical agents. Systemic azoles are proba
-
bly not helpful unless there is scleritis or intraocular infec
-
tion. Corneal grafting is often required.
Maharana PK et al. Recent advances in diagnosis and manage
-
ment of mycotic keratitis. Indian J Ophthalmol. 2016 May;
 
64(5):346–57. [PMID: 27380973]
Prajna NV et al. Effect of oral voriconazole on fungal keratitis in 
the Mycotic Ulcer Treatment Trial II (MUTT II): a random
-
ized clinical trial. JAMA Ophthalmol. 2016 Dec 
1;134(12):1365–72. [PMID: 27787540]
Prajna NV et al. Predictors of corneal perforation or need 
for therapeutic keratoplasty in severe fungal keratitis: A 
secondary analysis of the Mycotic Ulcer Treatment Trial II. 
JAMA Ophthalmol. 2017 Sep 1;135(9):987–91. [PMID: 
28817744]
Prajna VN et al. Fungal keratitis: the Aravind experience. Indian 
J Ophthalmol. 2017 Oct;65(10):912–9. [PMID: 29044053]
5. 
a
mebic K
eratitis
Amebic infection, usually due to 
Acanthamoeba
, is an 
important cause of keratitis in contact lens wearers. 
Although severe pain with perineural and ring infiltrates in

5. 
a
mebic K
eratitis
, is an 
Although severe pain with perineural and ring infiltrates in 
the corneal stroma is characteristic, it is not specific and 
earlier forms with changes confined to the corneal epithe
-
lium are identifiable. Diagnosis is facilitated by confocal 
microscopy. Culture requires specialized media. Long-
term treatment is required. Intensive topical biguanide 
(polyhexamethylene or chlorhexidine) and diamidine 
(propamidine or hexamidine) is the standard initial treat
-
ment with addition of an azole such as voriconazole if 
necessary. Delayed diagnosis and prior treatment with 
topical steroids adversely affect the visual outcome. Cor
-
neal grafting may be required after resolution of infec
-
tion to restore vision. If there is scleral involvement, 
monotherapy or combination therapy with systemic anti-
inflammatory and immunosuppressant medication is 
helpful but the prognosis is poor.
Carrijo-Carvalho LC et al. Therapeutic agents and biocides for 
ocular infections by free-living amoebae of 
 
genus. Surv Ophthalmol. 2017 Mar-Apr;62(2):203-18.
Lee MH et al. Risk factors, demographics and clinical profile of 
 keratitis in Melbourne: an 18-year retrospec
-
tive study. Br J Ophthalmol. 2017 Aug 27. [Epub ahead of 
print] [PMID: 28844988]
Pinna A et al. Free-living amoebae keratitis. Cornea. 2017 Jul;
 
36(7):785–90. [PMID: 28486311]
Zhong J et al. Associated factors, diagnosis and manage
-
ment of 
 keratitis in a referral center in 
Southern China. BMC Ophthalmol. 2017 Oct 2;17(1):175. 
[PMID: 28969610]
ACUTE ANGLE-CLOSURE GLAUCOMA
 
»
Older age group, particularly farsighted individuals.
 
»
Rapid onset of severe pain and profound visual 
loss with “halos around lights. ”
 
»
Red eye, cloudy cornea, dilated pupil.
 
»
Hard eye on palpation.
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▲
Figure 7–1.
 
Laser peripheral iridotomy at 2 o’clock 
position seen by direct illumination. 
(Reproduced, with 
permission, from Riordan-Eva P , Augsburger JJ. 
Vaughan & 
Asbury’s General Ophthalmology,
 19th ed. McGraw-Hill, 2018.)
 
»
Primary acute angle-closure glaucoma (acute angle-closure 
crisis) results from closure of a preexisting narrow anterior 
chamber angle. The predisposing factors are shallow ante
-
rior chamber, which may be associated with farsightedness 
or short stature (or both); enlargement of the crystalline 
lens with age; and inheritance, such as among Inuits and 
Asians. Closure of the angle is precipitated by pupillary 
dilation and thus can occur from sitting in a darkened 
theater, during times of stress, following nonocular admin
-
istration of anticholinergic or sympathomimetic agents (eg, 
nebulized bronchodilators, atropine for preoperative medi
-
cation, antidepressants, bowel or bladder antispasmodics, 
nasal decongestants, or tocolytics) or, rarely, from pharma
-
cologic mydriasis (see Precautions in Management of Ocu
-
lar Disorders, below). Subacute primary angle-closure 
glaucoma may present as recurrent headache. Secondary 
acute angle-closure glaucoma, which does not require a 
preexisting narrow angle, may occur in anterior uveitis, 
dislocation of the lens, or due to various drugs (see Adverse 
Ocular Effects of Systemic Drugs, below). Symptoms are 
the same as in primary acute angle-closure glaucoma, but 
differentiation is important because of differences in man
-
agement. Acute glaucoma, for which the mechanism may 
not be the same in all cases, can occur in association with 
hemodialysis. (Chronic angle-closure glaucoma presents in 
the same way as chronic open-angle glaucoma.)
 
»
Patients with acute glaucoma usually seek treatment imme
-
diately because of extreme pain and blurred vision, though 
there are subacute cases. Typically, the blurred vision is 
associated with halos around lights. Nausea and abdominal 
pain may occur. The eye is red, the cornea cloudy, and the 
pupil moderately dilated and nonreactive to light. Intraoc
-
ular pressure is usually over 50 mm Hg, producing a hard 
eye on palpation.
 
»
Acute glaucoma must be differentiated from conjunctivitis, 
acute uveitis, and corneal disorders (Table 7–1).
 
»
Treatment
Initial treatment is reduction of intraocular pressure. A 
single 500-mg intravenous dose of acetazolamide, followed 
by 250 mg orally four times a day, together with topical 
medications is usually sufficient. Osmotic diuretics, such as 
oral glycerin and intravenous urea or mannitol—the dos
-
age of all three being 1–2 g/kg—may be necessary if there 
is no response to acetazolamide.
A. Primary
In primary acute angle-closure glaucoma, once the intra
-
ocular pressure has started to fall, topical 4% pilocarpine, 
1 drop every 15 minutes for 1 hour and then four times a 
day, is used to reverse the underlying angle closure. The 
definitive treatment is laser peripheral iridotomy (Figure 7–1) 
or surgical peripheral iridectomy. Cataract extraction is a 
possible alternative. If it is not possible to control the intra
-
ocular pressure medically, the angle closure may be over
-
come by corneal indentation, laser treatment (argon laser 
peripheral iridoplasty), cyclodiode laser treatment, or 
paracentesis; or by glaucoma drainage surgery as for 
uncontrolled open-angle glaucoma.
All patients with primary acute angle-closure should 
undergo prophylactic laser peripheral iridotomy to the unaf
-
fected eye, unless that eye has already undergone cataract or 
glaucoma surgery. Whether prophylactic laser peripheral 
iridotomy should be undertaken in asymptomatic patients 
with narrow anterior chamber angles is mainly influenced 
by the risk of the more common chronic angle-closure.
B. Secondary
In secondary acute angle-closure glaucoma, additional

In secondary acute angle-closure glaucoma, additional 
treatment is determined by the cause.
 
»
Prognosis
Untreated acute angle-closure glaucoma results in severe 
and permanent visual loss within 2–5 days after onset of 
symptoms. Affected patients need to be monitored for 
development of chronic glaucoma.
 
»
Any patient with suspected acute angle-closure glaucoma 
must be referred emergently to an ophthalmologist.
Ah-Kee EY et al. A review of drug-induced acute angle closure 
glaucoma for non-ophthalmologists. Qatar Med J. 2015 May 
10;2015(1):6. [PMID: 26535174]
Gracitelli CP et al. Ability of non-ophthalmologist doctors to 
detect eyes with occludable angles using the flashlight test. Int 
Ophthalmol. 2014 Jun; 34(3):557–61. [PMID: 24081914]
Khazaeni B et al. Glaucoma, acute closed angle. StatPearls [Inter
-
net]. Treasure Island (FL): StatPearls Publishing; 2017 Apr 9. 
[PMID: 28613607]
Zhang X et al. Why does acute primary angle closure happen? 
Potential risk factors for acute primary angle closure. Surv 
Ophthalmol. 2017 Sep–Oct;62(5):635–47. [PMID: 28428109]
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CHRONIC GLAUCOMA
 
»
No symptoms in early stages.
 
»
Insidious progressive bilateral loss of peripheral 
vision, resulting in tunnel vision but preserved 
visual acuities until advanced disease.
 
»
Pathologic cupping of the optic disks.
 
»
Intraocular pressure is usually elevated.
 
»
Chronic glaucoma is characterized by gradually progres
-
sive excavation (“cupping”) of the optic disk with loss of 
vision progressing from slight visual field loss to complete 
blindness. In chronic open-angle glaucoma, primary or 
secondary, intraocular pressure is elevated due to reduced 
drainage of aqueous fluid through the trabecular mesh
-
work. In chronic angle-closure glaucoma, which is particu
-
larly common in Inuits and eastern Asians, flow of aqueous 
fluid into the anterior chamber angle is obstructed. In 
normal-tension glaucoma, intraocular pressure is not ele
-
vated but the same pattern of optic nerve damage occurs.
Primary (chronic) open-angle glaucoma is usually 
bilateral. There is an increased prevalence in first-degree 
relatives of affected individuals and in diabetic patients. In 
Afro-Caribbeans and Africans, and probably in Hispanics, 
it is more frequent, occurs at an earlier age, and results in 
more severe optic nerve damage. Secondary open-angle 
glaucoma may result from ocular disease, eg, pigment dis
-
persion, pseudoexfoliation, uveitis, or trauma; or cortico
-
steroid therapy, whether it is intraocular, topical, inhaled, 
intranasal or systemic.
In the United States, it is estimated that 2% of people 
over 40 years of age have glaucoma, affecting over 2.5 million 
individuals. At least 25% of cases are undetected. Over 90% 
of cases are of the open-angle type. Worldwide, about 
45 million people have open-angle glaucoma, of whom 
about 4.5 million are bilaterally blind. About 4 million 
people, of whom approximately 50% live in China, are 
bilaterally blind from chronic angle-closure glaucoma.
 
»
Because initially there are no symptoms, chronic glaucoma 
is often first suspected at a routine eye test. Diagnosis 
requires consistent and reproducible abnormalities in at 
least two of three parameters—optic disk or retinal nerve 
fiber layer (or both), visual field, and intraocular pressure. 
Optic disk cupping is identified as an absolute increase or 
an asymmetry between the two eyes of the ratio of the 
diameter of the optic cup to the diameter of the whole optic 
disk (cup-disk ratio). (Cup-disk ratio greater than 0.5 or 
asymmetry between eyes of 0.2 or more is suggestive.) 
Detection of optic disk cupping and associated abnormali
-
ties of the retinal nerve fiber layer is facilitated by optical 
coherence tomography scans. Visual field abnormalities 
initially develop in the paracentral region, followed by 
constriction of the peripheral visual field. Central vision 
remains good until late in the disease. The normal range of 
intraocular pressure is 10–21 mm Hg.
In many individuals (about 4.5 million in the United States), 
elevated intraocular pressure is not associated with optic 
disk or visual field abnormalities (ocular hypertension). 
Treatment to reduce intraocular pressure is justified if 
there is a moderate to high risk of progression to glaucoma, 
but monitoring for development of glaucoma is required in 
all cases. A significant proportion of eyes with primary 
open-angle glaucoma have normal intraocular pressure 
when it is first measured, and only repeated measurements 
identify the abnormally high pressure. In normal-tension 
glaucoma, intraocular pressure is always within the normal 
range.
 
»
There are many causes of optic disk abnormalities or visual 
field changes that mimic glaucoma and visual field testing 
may prove unreliable in some patients, particularly in the 
older age group. Hence, the diagnosis of glaucoma is not 
always straightforward and screening programs need to

always straightforward and screening programs need to 
involve ophthalmologists.
Although all persons over age 50 years may benefit 
from intraocular pressure measurement and optic disk 
examination every 3–5 years, screening for chronic open-
angle glaucoma should be targeted at individuals with an 
affected first-degree relative, at persons who have diabetes 
mellitus, and at older individuals with African or Hispanic 
ancestry. Screening may also be warranted in patients tak
-
ing long-term oral or combined intranasal and inhaled 
corticosteroid therapy. Screening for chronic angle-closure 
glaucoma should be targeted at Inuits and Asians.
 
»
Treatment
A. Medications (Table 7–2)
Prostaglandin analog eye drops are commonly used as 
first-line therapy because of their efficacy, lack of systemic 
side effects, and convenient once-daily dose (except 
unoprostone) (Table 7–2). All may produce conjunctival 
hyperemia, permanent darkening of the iris and eyebrow 
color, increased eyelash growth, and reduction of perior
-
bital fat (prostaglandin-associated periorbitopathy). Topi
-
cal beta-adrenergic blocking agents may be used alone or 
in combination with a prostaglandin analog. They may be 
contraindicated in patients with reactive airway disease or 
heart failure. Betaxolol is theoretically safer in reactive 
airway disease but less effective at reducing intraocular 
pressure. Brimonidine 0.2%, a selective alpha-2-agonist, 
and topical carbonic anhydrase inhibitors also can be used 
in addition to a prostaglandin analog or a beta-blocker 
(twice daily) or as initial therapy when prostaglandin ana
-
logs and beta-blockers are contraindicated (brimonidine 
twice daily, carbonic anhydrase inhibitors three times 
daily). All three are associated with allergic reactions. Bri
-
monidine may cause uveitis. Apraclonidine, 0.5–1%, 
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CMDT 2019
another alpha-2-agonist, can be used three times a day to 
postpone the need for surgery in patients receiving maxi
-
mal medical therapy, but long-term use is limited by 
adverse reactions. It is more commonly used to control 
acute rise in intraocular pressure, such as after laser ther
-
apy. Pilocarpine 1–4% is rarely used because of adverse 
effects. Oral carbonic anhydrase inhibitors (acetazolamide 
[Diamox], methazolamide [Neptazane], and dichlorphena
-
mide [Daranide]) may still be used on a long-term basis if 
topical therapy is inadequate and surgical or laser therapy 
is inappropriate.
Various eye drop preparations combining two agents 
out of the prostaglandin analogs, beta-adrenergic blocking 
agents, brimonidine and topical carbonic anhydrase inhib
-
itors are available to improve compliance when multiple 
medications are required. Formulations of one or two 
agents without preservative or not including benzalkonium 
chloride as the preservative are increasingly used to reduce 
adverse effects on the ocular surface.
B. Laser Therapy and Surgery
Laser trabeculoplasty is used as an adjunct to topical ther
-
apy to defer surgery and is also advocated as primary treat
-
ment. Surgery is generally undertaken when intraocular 
pressure is inadequately controlled by medical and laser 
therapy, but it may also be used as primary treatment. Tra
-
beculectomy remains the standard procedure. Adjunctive 
treatment with subconjunctival mitomycin or fluorouracil 
is used perioperatively or postoperatively in worse progno
-
sis cases. Viscocanalostomy, deep sclerectomy with collagen 
implant and Trabectome—alternative procedures that avoid 
a full-thickness incision into the eye—are associated with 
fewer complications but are more difficult to perform.
In chronic angle-closure glaucoma, laser peripheral iri
-
dotomy or surgical peripheral iridectomy may be helpful. In 
patients with asymptomatic narrow anterior chamber 
angles, which includes about 10% of Chinese adults, prophy
-
lactic laser peripheral iridotomy can be performed to reduce 
the risk of acute and chronic angle-closure glaucoma. How
-
ever, there are concerns about the efficacy of such treatment 
and the risk of cataract progression and corneal decompen
-
sation. In the United States, about 1% of people over age 
35 years have narrow anterior chamber angles, but acute and 
chronic angle-closure are sufficiently uncommon that pro
-
phylactic therapy is not generally advised.
 
»
Prognosis
Untreated chronic glaucoma that begins at age 40–45 years 
will probably cause complete blindness by age 60–65. 
Early diagnosis and treatment can preserve useful vision 
throughout life. In primary open-angle glaucoma and if 
treatment is required in ocular hypertension, the aim is to 
reduce intraocular pressure to a level that will adequately 
reduce progression of visual field loss. In eyes with marked 
visual field or optic disk changes, intraocular pressure 
must be reduced to less than 16 mm Hg. In normal-tension 
glaucoma with progressive visual field loss, it is necessary 
to achieve even lower intraocular pressure such that surgery 
is often required.
 
»
All patients with suspected chronic glaucoma should be 
referred to an ophthalmologist.
Feroze KB et al. Glaucoma, secondary glaucoma, steroid. Stat
-
Pearls [Internet]. Treasure Island (FL): StatPearls Publishing; 
2017 Apr 16. [PMID: 28613653]
Foris LA et al. Glaucoma, open angle. StatPearls [Internet]. Trea
-
sure Island (FL): StatPearls Publishing; 2017 Oct 13. [PMID: 
28722917]
Jonas JB et al. Glaucoma. Lancet. 2017 Nov 11;390(10108):
 
2183–93. [PMID: 28577860]
Prum BE Jr et al. Primary open-angle glaucoma Preferred Practice 
Pattern(
®
) Guidelines. Ophthalmology. 2016 Jan;123(1):
 
P41–111. [PMID: 26581556]
Prum BE Jr et al. Primary open-angle glaucoma suspect Pre
-
ferred Practice Pattern(
®
) Guidelines. Ophthalmology. 2016

®
 
-
®
) Guidelines. Ophthalmology. 2016 
Jan;123(1):P112–51. [PMID: 26581560]
UVEITIS
 
»
Usually immunologic but possibly infective or 
neoplastic.
 
»
Acute nongranulomatous anterior uveitis:
 pain, 
redness, photophobia, and visual loss.
 
»
Granulomatous anterior uveitis:
 blurred vision in 
a mildly inflamed eye.
 
»
Posterior uveitis:
 gradual loss of vision in a mini
-
mally inflamed eye.
 
»
Intraocular inflammation (uveitis) is classified as acute or 
chronic and as nongranulomatous or granulomatous, 
according to the clinical signs, and by its involvement of 
the anterior, intermediate, posterior, or all (panuveitis) seg
-
ments of the eye. The common types are acute nongranu
-
lomatous anterior, granulomatous anterior, and posterior.
In most cases the pathogenesis of uveitis is primarily 
immunologic, but infection may be the cause, particularly 
in immunodeficiency states. The systemic disorders associ
-
ated with acute nongranulomatous anterior uveitis are the 
HLA-B27-related conditions (ankylosing spondylitis, reac
-
tive arthritis, psoriasis, ulcerative colitis, and Crohn dis
-
ease). Chronic nongranulomatous anterior uveitis occurs 
in juvenile idiopathic arthritis. Behçet syndrome produces 
both anterior uveitis, with recurrent hypopyon but little 
discomfort, and posterior uveitis, characteristically with 
branch retinal vein occlusions. Both herpes simplex and 
herpes zoster infections may cause nongranulomatous 
anterior uveitis as well as retinitis (acute retinal necrosis).
Diseases producing granulomatous anterior uveitis 
also tend to be causes of posterior uveitis. These include 
sarcoidosis, toxoplasmosis, tuberculosis, syphilis, Vogt-
Koyanagi-Harada disease (bilateral uveitis associated with 
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A
B
 
▲
Figure 7–2.
 
Vogt–Koyanagi–Harada (VKH) disease. 
A:
 Poliosis of the eyelashes. 
B:
 Alopecia, vitiligo and 
poliosis of the hair. 
(Reproduced, with permission, from 
A: Lueder GT. 
Pediatric Practice: Ophthalmology
. 
McGraw-Hill, 2011; B: Riordan-Eva P , Augsburger JJ. 
Vaughan & Asbury’s General Ophthalmology,
 19th ed. 
McGraw-Hill, 2018.)
alopecia, poliosis [depigmented eyelashes, eyebrows, or 
hair], vitiligo, and hearing loss) (Figure 7–2), and sympa
-
thetic ophthalmia that occurs after penetrating ocular 
trauma. In toxoplasmosis, there may be evidence of previ
-
ous episodes of retinochoroiditis. Syphilis characteristically 
produces a “salt and pepper” fundus but may present with 
a wide variety of clinical manifestations. The other princi
-
pal pathogens responsible for ocular inflammation in HIV 
infection are cytomegalovirus (CMV), herpes simplex and 
herpes zoster viruses, mycobacteria, 
Cryptococcus, Toxo
-
plasma,
 and 
Candida
.
Retinal vasculitis and intermediate uveitis predomi
-
nantly manifest as posterior uveitis with central or periph
-
eral retinal abnormalities in retinal vasculitis and far 
peripheral retinal abnormalities (pars planitis) in interme
-
diate uveitis. Retinal vasculitis can be caused by a wide 
variety of infectious agents and noninfectious systemic 
conditions but also may be idiopathic. Intermediate uveitis 
is often idiopathic but can be due to multiple sclerosis or 
sarcoidosis.
 
»
Anterior uveitis
 is characterized by inflammatory cells 
and flare within the aqueous. In severe cases, there may be 
hypopyon (layered collection of white cells) and fibrin 
within the anterior chamber. Cells may also be seen on the 
corneal endothelium as keratic precipitates (KPs). In 
granulomatous uveitis, there are large “mutton-fat” KPs, 
and sometimes iris nodules. In nongranulomatous uveitis 
the KPs are smaller with no iris nodules. The pupil is usu
-
ally small, and with the development of posterior synechiae 
(adhesions between the iris and anterior lens capsule) it 
also becomes irregular.
Nongranulomatous anterior uveitis tends to present 
acutely with unilateral pain, redness, photophobia, and 
visual loss. However, in juvenile idiopathic arthritis there 
tends to be an indolent, often initially asymptomatic pro
-
cess with a high risk of sight-threatening complications. 
Granulomatous anterior uveitis is usually indolent, causing 
blurred vision in a mildly inflamed eye.
In 
posterior uveitis,
 there are cells in the vitreous and 
there may be inflammatory retinal or choroidal lesions. 
Fresh retinal lesions are yellow with indistinct margins and 
there may be retinal hemorrhages, whereas older lesions 
have more definite margins and are commonly pigmented. 
Retinal vessel sheathing may occur adjacent to such lesions 
or more diffusely. In severe cases, vitreous opacity pre
-
cludes visualization of retinal details.
Posterior uveitis tends to present with gradual visual loss 
in a minimally inflamed eye. Bilateral involvement is com
-
mon. Visual loss may be due to vitreous haze and opacities, 
inflammatory lesions involving the macula, macular edema, 
retinal vein occlusion, or rarely optic neuropathy.
 
»
Retinal detachment, intraocular tumors, and central ner
-
vous system lymphoma may all masquerade as uveitis.
 
»
Treatment
 usually responds to topical corticoste
-
roids. Occasionally periocular corticosteroid injections or 
even systemic corticosteroids are required. Dilation of the 
pupil is important to relieve discomfort and prevent per
-
manent posterior synechiae. 
Posterior uveitis
 more com
-
monly requires systemic, periocular, or intravitreal 
corticosteroid therapy and occasionally systemic immuno
-
suppression with agents such as azathioprine, cyclosporine, 
mycophenolate, methotrexate, tacrolimus, or sirolimus, of 
which some can be administered by intraocular injection.

-
which some can be administered by intraocular injection. 
The use of biologic therapies is increasing. Pupillary dila
-
tion is not usually necessary.
If an infectious cause is identified, specific antimicro
-
bial therapy is often needed. In general, the prognosis for 
anterior uveitis, particularly the nongranulomatous type, is 
better than for posterior uveitis.
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»
•	
Any patient with suspected acute uveitis should be 
referred urgently to an ophthalmologist or emergently 
if visual loss or pain is severe.
•	
Any patient with suspected chronic uveitis should be 
referred to an ophthalmologist, urgently if there is more 
than mild visual loss.
 
»
Patients with severe uveitis, particularly those requiring 
intravenous therapy, may require hospital admission.
Foster CS et al. The Ocular Immunology and Uveitis Foundation 
preferred practice patterns of uveitis management. Surv Oph
-
thalmol. 2016 Jan–Feb;61(1):1–17. [PMID: 26164736]
Jabs DA. Immunosuppression for the uveitides. Ophthalmology. 
2018 Feb;125(2):193–202.
Krishna U et al. Uveitis: a sight-threatening disease which can 
impact all systems. Postgrad Med J. 2017 Dec;93(1106):
 
766–73. [PMID: 28942431]
Sève P et al. Uveitis: diagnostic work-up. A literature review and 
recommendations from an expert committee. Autoimmun 
Rev. 2017 Dec;16(12):1254–64. [PMID: 29037906]
Thorne JE et al. Prevalence of noninfectious uveitis in the 
United States: a claims-based analysis. JAMA Ophthalmol. 
2016 Nov 1;134(11):1237–45. [PMID: 27608193]
CATARACT
 
»
Gradually progressive blurred vision.
 
»
No pain or redness.
 
»
Lens opacities (may be grossly visible).
 
»
Cataracts are opacities of the crystalline lens and are usu
-
ally bilateral. They are the leading cause of blindness 
worldwide. Age-related cataract is by far the most common 
cause. Other causes include (1) congenital (owing to intra
-
uterine infections, such as rubella and CMV , or inborn 
errors of metabolism, such as galactosemia); (2) traumatic; 
(3) secondary to systemic disease (diabetes mellitus, myo
-
tonic dystrophy, atopic dermatitis); (4) topical, systemic or 
inhaled corticosteroid treatment; (5) uveitis; or (6) radia
-
tion exposure. Most persons over age 60 have some degree 
of lens opacity. Cigarette smoking increases the risk of cata
-
ract formation. Multivitamin/mineral supplements and 
high dietary antioxidants may prevent the development of 
age-related cataract.
 
»
The predominant symptom is progressive blurring of 
vision. Glare, especially in bright light or when driving at 
night; change of focusing, particularly development of near
-
sightedness; and monocular double vision may also occur.
Even in its early stages, a cataract can be seen through a 
dilated pupil with an ophthalmoscope or slit lamp. As the 
cataract matures, the retina will become increasingly diffi
-
cult to visualize, until finally the fundus reflection is absent 
and the pupil is white.
 
»
Treatment
Functional visual impairment, specifically its effect on 
daily activities such as increased falls, is the prime criterion 
for surgery. The cataract is usually removed by one of the 
techniques in which the posterior lens capsule remains 
(extracapsular), thus providing support for a prosthetic 
intraocular lens. Laser treatment may be used during sur
-
gery and may be required subsequently if the posterior 
capsule opacifies. Ultrasonic fragmentation (phacoemulsi
-
fication) of the lens nucleus and foldable intraocular lenses 
allow cataract surgery to be performed through a small 
incision without the need for sutures, thus reducing the 
postoperative complication rate and accelerating visual 
rehabilitation. Multifocal and accommodative intraocular 
lenses reduce the need for both distance and near vision 
correction. In the developing world, manual small-incision 
surgery, in which the lens nucleus is removed intact, is 
popular because less equipment is required.
 
»
Prognosis
Cataract surgery is cost-effective in improving survival and 
quality of life. In the developed world, it improves visual 
acuity in 95% of cases. In the other 5%, there is preexisting 
retinal damage or operative or postoperative complica
-

-
tions. In less developed areas, the improvement in visual 
acuity is not as high, in part due to uncorrected refractive 
error postoperatively. A large number of drugs, such as 
alpha-1-antagonists for benign prostatic hyperplasia or 
systemic hypertension and antipsychotics, increase the risk 
of complications during surgery (floppy iris syndrome) 
and in the early postoperative period. Stopping the drug for 
1–2 weeks prior to surgery may be beneficial. Nasolacrimal 
duct obstruction increases the risk of intraocular infection 
(endophthalmitis).
 
»
Patients with cataracts should be referred to an ophthal
-
mologist when their visual impairment adversely affects 
their everyday activities.
Enright JM et al. Floppy iris syndrome and cataract surgery. 
Curr Opin Ophthalmol. 2017 Jan;28(1):29–34. [PMID: 
27653607]
Lee CM et al. The global state of cataract blindness. Curr Opin 
Ophthalmol. 2017 Jan;28(1):98–103. [PMID: 27820750]
Nanji KC et al. Preventing adverse events in cataract surgery: 
Recommendations from a Massachusetts expert panel. 
Anesth Analg. 2017 Oct 4. [Epub ahead of print] [PMID: 
28991115]
Roberto SA et al. Patient harm in cataract surgery: a series of 
adverse events in Massachusetts. Anesth Analg. 2017 Oct 5. 
[Epub ahead of print] [PMID: 28991108]
Thompson J et al. Cataracts. Prim Care. 2015 Sep;42(3):409–23. 
[PMID: 26319346]
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RETINAL DETACHMENT
 
»
Loss of vision in one eye that is usually rapid, pos
-
sibly with “curtain” spreading across field of vision.
 
»
 
»
Detachment seen by ophthalmoscopy.
 
»
Most cases of retinal detachment are due to development of 
one or more peripheral retinal tears or holes (rhegmatog
-
enous retinal detachment). This is usually spontaneous, 
related to degenerative changes in the vitreous, and gener
-
ally occurs in persons over 50 years of age. Nearsightedness 
and cataract extraction are the two most common predis
-
posing causes. It may also be caused by penetrating or 
blunt ocular trauma.
Tractional retinal detachment occurs when there is 
preretinal fibrosis, such as in proliferative retinopathy due 
to diabetic retinopathy or retinal vein occlusion or as a 
complication of rhegmatogenous retinal detachment. Exu
-
dative retinal detachment results from accumulation of 
subretinal fluid, such as in neovascular age-related macular 
degeneration or secondary to choroidal tumor.
 
»
Rhegmatogenous retinal detachment usually starts in the 
superior temporal area, spreading rapidly to cause visual 
field loss that starts inferiorly and expands upward. Pre
-
monitory symptoms of the predisposing vitreous degenera
-
tion and vitreo-retinal traction are recent onset of or 
increase in floaters (moving spots or streaks in the visual 
field) and photopsias (flashes of light). Central vision 
remains intact until the macula becomes detached. On 
ophthalmoscopic examination, the retina is seen hanging 
in the vitreous like a gray cloud (Figure 7–3). One or more 
retinal tears or holes will usually be found on further 
examination. In traction retinal detachment, there is irreg
-
ular retinal elevation. In exudative retinal detachment, the 
retina is dome-shaped and the subretinal fluid shifts posi
-
tion with changes in posture. Ocular ultrasonography 
assists the detection and characterization of retinal 
detachment.
 
»
Treatment
Treatment of rhegmatogenous retinal detachments is 
directed at closing all of the retinal tears and holes by form
-
ing a permanent adhesion between the neurosensory ret
-
ina, the retinal pigment epithelium, and the choroid with 
laser photocoagulation to the retina or cryotherapy to the 
sclera. The following may be required to achieve apposi
-
tion of the neurosensory retina to the retinal pigment epi
-
thelium while the adhesion is developing: indentation of 
the sclera with a silicone sponge or buckle, subretinal fluid 
drainage via an incision in the sclera, or injection of an 
expansile gas or silicone oil into the vitreous cavity follow
-
ing intraocular surgery to remove the vitreous (pars plana 
vitrectomy). Certain types of uncomplicated retinal detach
-
ment may be treated by pneumatic retinopexy, in which an 
expansile gas is injected into the vitreous cavity followed by 
positioning of the patient’s head to facilitate reattachment 
of the retina. Once the retina is repositioned, the defects 
are sealed by laser photocoagulation or cryotherapy; these 
two methods are also used to seal retinal defects without 
associated detachment.
In complicated retinal detachments, particularly trac
-
tion retinal detachments, retinal reattachment can be 
accomplished only by pars plana vitrectomy, direct manip
-
ulation of the retina, and internal tamponade of the retina 
with air, expansile gas, or silicone oil. (The presence of an 
expansile gas within the eye is a contraindication to air 
travel, mountaineering at high altitude, and nitrous oxide 
anesthesia. Such gases persist in the globe for weeks after 
surgery.) Treatment of exudative retinal detachments is 
determined by the underlying cause.
 
»
Prognosis
About 90% of uncomplicated rhegmatogenous retinal 
detachments can be cured with one operation. The visual 
prognosis is worse if the macula is detached or if the

»
Prognosis
prognosis is worse if the macula is detached or if the 
detachment is of long duration.
 
»
All cases of retinal detachment must be referred urgently to 
an ophthalmologist, emergently if central vision is good 
because this indicates that the macula has not detached. 
During transportation, the patient’s head is positioned so 
that the detached portion of the retina will fall back with 
the aid of gravity.
 
▲
Figure 7–3.
 
Inferior retinal detachment as seen on 
direct or indirect ophthalmoscopy.
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Bond-Taylor M et al. Posterior vitreous detachment—prevalence 
of and risk factors for retinal tears. Clin Ophthalmol. 2017 
 
Sep 18;11:1689–95. [PMID: 29075095]
de Jong JH et al. Preoperative posturing of patients with 
macula-on retinal detachment reduces progression toward 
the fovea. Ophthalmology. 2017 Oct;124(10):1510–22. 
[PMID: 28499747]
Hatef E et al. Pneumatic retinopexy versus scleral buckle for 
repairing simple rhegmatogenous retinal detachments. 
Cochrane Database Syst Rev. 2015 May 7;5:CD008350. 
[PMID: 25950286]
Kreissig I. Primary retinal detachment: a review of the develop
-
ment of techniques for repair in the past 80 years. Taiwan J 
Ophthalmol. 2016 Oct–Dec;6(4):161–9. [PMID: 29018735]
Park DH et al. Factors associated with visual outcome after 
macula-off rhegmatogenous retinal detachment surgery. 
Retina. 2018 Jan;38(1):137–47. [PMID: 28099315]
VITREOUS HEMORRHAGE
Patients with vitreous hemorrhage complain of sudden 
visual loss, abrupt onset of floaters that may progressively 
increase in severity, or occasionally, “bleeding within the 
eye. ” Visual acuity ranges from 20/20 (6/6) to light percep
-
tion. The eye is not inflamed, and clues to diagnosis are 
inability to see fundal details or localized collection of 
blood in front of the retina. Causes of vitreous hemorrhage 
include retinal tear (with or without detachment), diabetic 
or sickle cell retinopathy, retinal vein occlusion, retinal 
vasculitis, neovascular age-related macular degeneration, 
blood dyscrasia, therapeutic anticoagulation, trauma, sub
-
arachnoid hemorrhage, and severe straining.
 
»
All patients with suspected vitreous hemorrhage must be 
referred urgently to an ophthalmologist.
Shieh WS et al. Ophthalmic complications associated with direct 
oral anticoagulant medications. Semin Ophthalmol. 
2017;32(5):614–9. [PMID: 27367495]
Zhang T et al. Early vitrectomy for dense vitreous hemorrhage in 
adults with non-traumatic and non-diabetic retinopathy. J Int 
Med Res. 2017 Dec;45(6):2065–71. [PMID: 28627981]
AGE-RELATED MACULAR DEGENERATION
 
»
Older age group.
 
»
Acute or chronic deterioration of central vision in 
one or both eyes.
 
»
Distortion or abnormal size of images.
 
»
 
»
Macular abnormalities seen by ophthalmoscopy.
 
»
In developed countries, age-related macular degeneration 
is the leading cause of permanent visual loss in the older 
population. Its prevalence progressively increases over age 
50 years (to almost 30% by age 75). Its occurrence and 
response to treatment are possibly influenced by geneti
-
cally determined variations in the complement pathway 
and lipoprotein metabolism. Other associated factors are 
race (usually white), sex (slight female predominance), 
family history, cigarette smoking, and possibly regular 
aspirin use.
Age-related macular degeneration is classified into dry 
(“atrophic, ” “geographic”) and wet (“neovascular, ” “exudative”). 
Although both are progressive and usually bilateral, they 
differ in manifestations, prognosis, and management.
 
»
The precursor to age-related macular degeneration is age-
related maculopathy that is characterized by retinal drusen. 
Hard drusen appear ophthalmoscopically as discrete yel
-
low deposits. Soft drusen are larger, paler, and less distinct. 
Large, confluent soft drusen are particularly associated 
with neovascular (wet) age-related macular degeneration. 
Age-related macular degeneration results in loss of central 
field of vision only. Peripheral fields, and hence naviga
-
tional vision, are maintained.
“Dry” age-related macular degeneration
 is character
-
ized by gradually progressive bilateral visual loss of moder
-
ate severity due to atrophy and degeneration of the outer 
retina and retinal pigment epithelium. In “
wet” age-
related macular degeneration,
 choroidal new vessels grow

-
wet” age-
 choroidal new vessels grow 
between the retinal pigment epithelium and Bruch mem
-
brane, leading to accumulation of exudative fluid, hemor
-
rhage, and fibrosis. The onset of visual loss is more rapid 
and more severe than in atrophic degeneration. The two 
eyes are frequently affected sequentially over a period of a 
few years. Although “dry” age-related macular degenera
-
tion is much more common, “wet” age-related macular 
degeneration accounts for about 90% of all cases of legal 
blindness due to age-related macular degeneration.
 
»
Treatment
No dietary modification has been shown to prevent the 
development of age-related maculopathy, but its progres
-
sion may be reduced by oral treatment with antioxidants 
(vitamins C and E), zinc, copper, and carotenoids (lutein 
and zeaxanthin, rather than vitamin A [beta-carotene]). 
Oral omega-3 fatty acids do not provide additional benefit.
In wet degeneration, inhibitors of vascular endothelial 
growth factors (VEGF), such as ranibizumab (Lucentis), 
pegaptanib (Macugen), bevacizumab (Avastin), and 
aflibercept (VEGF Trap-Eye, Eylea), reverse choroidal neo
-
vascularization with stabilization of vision. Long term 
repeated intraocular injections are required. Treatment is 
well tolerated with minimal adverse effects, but there is a 
risk of intraocular complications and up to one-third of 
eyes have a poor outcome. In bilateral severe disease, 
macular surgery may be beneficial.
There is no specific treatment for dry degeneration but, 
as for wet degeneration, rehabilitation including low-vision 
aids is important.
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»
Older patients with sudden visual loss due to macular dis
-
ease, particularly paracentral distortion or scotoma with 
preservation of central acuity, should be referred urgently 
to an ophthalmologist.
Evans JR et al. Antioxidant vitamin and mineral supplements for 
preventing age-related macular degeneration. Cochrane Data
-
base Syst Rev. 2017 Jul 30;7:CD000253. [PMID: 28756617]
slowing the progression of age-related macular degeneration. 
Cochrane Database Syst Rev. 2017 Jul 31;7:CD000254. 
[PMID: 28756618]
Jonas JB et al. Updates on the epidemiology of age-related 
macular degeneration. Asia Pac J Ophthalmol (Phila). 2017 
Nov–Dec;6(6):493–7. [PMID: 28906084]
Kataja M et al. Outcome of anti-vascular endothelial growth 
factor therapy for neovascular age-related macular degen
-
eration in real-life setting. Br J Ophthalmol. 2017 Oct 26. 
[Epub ahead of print] [PMID: 29074495]
Mehta S. Age-related macular degeneration. Prim Care. 
2015 Sep;42(3):377–91. [PMID: 26319344]
CENTRAL & BRANCH RETINAL VEIN 
OCCLUSIONS
 
»
Sudden monocular loss of vision.
 
»
 
»
Widespread or sectoral retinal hemorrhages.
 
»
Central and branch retinal vein occlusion are common 
causes of acute loss of vision with branch being four times 
more common. The major predisposing factors are the 
etiologic factors associated with arteriosclerosis.
 
»
Ophthalmoscopic signs of 
central retinal vein occlusion
 
include widespread retinal hemorrhages, retinal venous 
dilation and tortuosity, retinal cotton-wool spots, and optic 
disk swelling (Figure 7–4).
Branch retinal vein occlusion
 may present in a variety 
of ways. Sudden loss of vision may occur at the time of 
occlusion if the fovea is involved or some time afterward 
from vitreous hemorrhage due to retinal new vessels. More 
gradual visual loss may occur with development of macular 
edema. In acute branch retinal vein occlusion, the retinal 
abnormalities (hemorrhages, venous dilation and tortuos
-
ity, and cotton-wool spots) are confined to the area drained 
by the obstructed vein.
To assess possible reversible risk factors, check blood 
pressure and ask about tobacco smoking in all patients and 
ask women about estrogen therapy (including combined 
oral contraceptives).
Obtain screening laboratory studies for diabetes mellitus, 
hyperlipidemia, and hyperviscosity (especially in simulta
-
neous bilateral disease), including serum protein electro
-
phoresis for paraproteinemia. Particularly in younger 
patients, consider obtaining antiphospholipid antibodies, 
lupus anticoagulant, tests for inherited thrombophilia, and 
plasma homocysteine levels.
 
»
If central retinal vein occlusion is associated with wide
-
spread retinal ischemia, manifesting as poor visual acuity 
(20/200 [6/60] or worse), florid retinal abnormalities, and 
extensive areas of capillary closure on fluorescein angiogra
-
phy, there is a high risk of development of neovascular 
(rubeotic) glaucoma, typically within the first 3 months. 
Branch retinal vein occlusion may be complicated by periph
-
eral retinal neovascularization or chronic macular edema.
 
»
Treatment
Eyes at risk for neovascular glaucoma following ischemic 
central retinal vein occlusion can be treated by panretinal 
laser photocoagulation prophylactically or as soon as there 
is evidence of neovascularization, the latter approach 
necessitating frequent monitoring. Regression of iris neo
-
vascularization has been achieved with intravitreal injec
-
tions of bevacizumab. In branch retinal vein occlusion 
complicated by retinal neovascularization, the ischemic 
retina should be laser photocoagulated.
Intravitreal injection of ranibizumab (Lucentis), pegap
-
tanib (Macugen), bevacizumab (Avastin), or aflibercept

-
tanib (Macugen), bevacizumab (Avastin), or aflibercept 
(VEGF Trap-Eye, Eylea), is beneficial in 
chronic macular 
edema
 due to either branch or nonischemic central retinal 
vein occlusion. Intravitreal triamcinolone improves vision 
in chronic macular edema due to nonischemic central reti
-
nal vein occlusion, whereas an intravitreal implant con
-
taining dexamethasone is beneficial in both central and 
branch retinal vein occlusion. Retinal laser photocoagula
-
tion may be indicated in chronic macular edema due to 
branch, but not central, retinal vein occlusion.
 
▲
Figure 7–4.
 
Central retinal vein occlusion.
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»
Prognosis
In central retinal vein occlusion, severity of visual loss ini
-
tially is a good guide to visual outcome. Initial visual acuity 
of 20/60 (6/18) or better indicates a good prognosis. Visual 
prognosis is poor for eyes with neovascular glaucoma. In 
branch retinal vein occlusion, visual outcome is deter
-
mined by the severity of macular damage from hemor
-
rhage, ischemia, or edema.
 
»
All patients with retinal vein occlusion should be referred 
urgently to an ophthalmologist.
Ehlers JP et al. Therapies for macular edema associated with 
branch retinal vein occlusion: a report by the American Academy 
of Ophthalmology. Ophthalmology. 2017 Sep;124(9):1412–23. 
[PMID: 28551163]
Jonas JB et al. Retinal vein occlusions. Dev Ophthalmol. 
2017;58:139–67. [PMID: 28351046]
Li J et al. New developments in the classification, pathogenesis, 
risk factors, natural history, and treatment of branch retinal 
vein occlusion. J Ophthalmol. 2017;2017:4936924. [PMID: 
28386476]
Pesin N et al. The role of occult hypertension in retinal vein 
occlusions and diabetic retinopathy. Can J Ophthalmol. 
2017 Apr;52(2):225–8. [PMID: 28457296]
Sinawat S et al. Systemic abnormalities associated with retinal 
vein occlusion in young patients. Clin Ophthalmol. 2017 
Feb 23;11:441–7. [PMID: 28260858]
CENTRAL & BRANCH RETINAL ARTERY 
 
»
 
»
 
»
Widespread or sectoral pallid retinal swelling.
 
»
In patients 50 years of age or older with central retinal 
artery occlusion, giant cell arteritis must be considered 
(see Ischemic Optic Neuropathy and Chapter 20). Other
-
wise, even if no retinal emboli are identified on ophthal
-
moscopy, urgent investigation for carotid and cardiac 
sources of emboli must be undertaken in central and par
-
ticularly in branch retinal artery occlusion, so that timely 
treatment can be given to reduce the risk of stroke (see 
Chapters 12, 14, and 24). Diabetes mellitus, hyperlipid
-
emia, and systemic hypertension are common etiologic 
factors. Migraine, oral contraceptives, systemic vasculitis, 
congenital or acquired thrombophilia, and hyperhomo
-
cysteinemia are also causes, particularly in young patients. 
Internal carotid artery dissection should be considered 
especially when there is neck pain or a recent history of 
neck trauma.
 
»
Central retinal artery occlusion
 presents as sudden pro
-
found monocular visual loss. Visual acuity is usually 
reduced to counting fingers or worse, and visual field is 
restricted to an island of vision in the temporal field. Oph
-
thalmoscopy reveals pallid swelling of the retina with a 
cherry-red spot at the fovea. The retinal arteries are attenu
-
ated, and “box-car” segmentation of blood in the veins may 
be seen. Occasionally, emboli are seen in the central retinal 
artery or its branches. The retinal swelling subsides over a 
period of 4–6 weeks, leaving a pale optic disk with thinning 
of the inner retina on optical coherence tomography scans.
Branch retinal artery occlusion
 may also present with 
sudden loss of vision if the fovea is involved, but more 
commonly sudden loss of visual field is the presenting 
complaint. Fundal signs of retinal swelling and sometimes 
adjacent cotton-wool spots are limited to the area of retina 
supplied by the occluded artery.
Identify risk factors for cardiac source of emboli includ
-
ing arrhythmia, particularly atrial fibrillation, and cardiac 
valvular disease, and check the blood pressure. Nonocular 
clinical features of giant cell arteritis are age 50 years or 
older, headache, scalp tenderness, jaw claudication, general 
malaise, weight loss, symptoms of polymyalgia rheumatica, 
and tenderness, thickening, or absence of pulse of the 
superficial temporal arteries. Table 20–12 lists the clinical

superficial temporal arteries. Table 20–12 lists the clinical 
manifestations of vasculitis.
Erythrocyte sedimentation rate and C-reactive protein are 
usually elevated in giant cell arteritis but one or both may 
be normal. Consider screening for other types of vasculitis 
(see Table 20–11). Screen for diabetes mellitus and hyper
-
lipidemia in all patients. Particularly in younger patients, 
consider testing for antiphospholipid antibodies, lupus 
anticoagulant, inherited thrombophilia, and elevated plasma 
homocysteine.
C. Imaging
To identify carotid and cardiac sources of emboli, obtain 
duplex ultrasonography of the carotid arteries, ECG, and 
echocardiography, with transesophageal studies (if neces
-
sary). When indicated, obtain CT or MR studies for inter
-
nal carotid artery dissection.
 
»
Treatment
If the patient is seen within a few hours after onset, emer
-
gency treatment, comprising laying the patient flat, ocular 
massage, high concentrations of inhaled oxygen, intrave
-
nous acetazolamide, and anterior chamber paracentesis, 
may influence the visual outcome. Early thrombolysis, 
particularly by local intra-arterial injection but also intra
-
venously, has shown good results in central retinal artery 
occlusion not due to giant cell arteritis, but the former 
method has a high incidence of adverse effects and may be 
difficult to accomplish within the required time.
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In giant cell arteritis, there is risk of involvement of the 
other eye without prompt treatment. Recommended initial 
empiric treatment is intravenous methylprednisolone 
0.5–1 g/day for 1–3 days but intravenous hydrocortisone 
250–500 mg may be easier to administer. Whether oral 
methylprednisolone is similarly effective is unknown. All 
patients require subsequent long-term corticosteroid ther
-
apy (eg, oral prednisolone 1–1.5 mg/kg/day) and possibly 
low-dose aspirin (~81 mg/day orally). There must be close 
monitoring to ensure that symptoms resolve and do not 
recur. Temporal artery biopsy should be performed 
promptly, and if necessary, assistance sought from a rheu
-
matologist (see Polymyalgia Rheumatica & Giant Cell 
Arteritis, Chapter 20).
Patients with embolic retinal artery occlusion and 
70–99% ipsilateral carotid artery stenosis and possibly 
those with 50–69% stenosis should be considered for 
carotid endarterectomy or possibly angioplasty with stent
-
ing to be performed within 2 weeks (see Chapters 12 and 
24). Retinal embolization due to cardiac disease such as 
atrial fibrillation or a hypercoagulable state usually requires 
anticoagulation. Cardiac valvular disease and patent fora
-
men ovale may require surgical treatment.
 
»
•	
Patients with central retinal artery occlusion should be 
•	
Patients with branch retinal artery occlusion should be 
referred urgently.
 
»
Patients with visual loss due to giant cell arteritis may 
require emergency admission for high-dose corticosteroid 
therapy and close monitoring to ensure that treatment is 
adequate.
Abel AS et al. Practice patterns after acute embolic retinal artery 
occlusion. Asia Pac J Ophthalmol (Phila). 2017 Jan–Feb;
 
6(1):37–9. [PMID: 28161924]
Hayreh SS et al. Ocular arterial occlusive disorders and carotid 
artery disease. Ophthalmol Retina. 2017 Jan–Feb;1(1):12–8. 
[PMID: 28547004]
Mehta N et al. Central retinal artery occlusion: acute manage
-
ment and treatment. Curr Ophthalmol Rep. 2017 Jun;
 
5(2):149–59. [PMID: 29051845]
Soriano A et al. Visual loss and other cranial ischaemic compli
-
cations in giant cell arteritis. Nat Rev Rheumatol. 2017 Aug;
 
13(8):476–84. [PMID: 28680132]
Vodopivec I et al. Management of transient monocular vision 
loss and retinal artery occlusions. Semin Ophthalmol. 
2017;32(1):125–33. [PMID: 27780399]
TRANSIENT MONOCULAR VISUAL LOSS
 
»
Monocular loss of vision usually lasting a few 
minutes with complete recovery.
Transient monocular visual loss (“ocular transient ischemic 
attack [TIA]”) is usually caused by a retinal embolus from 
ipsilateral carotid disease or the heart. The visual loss is 
characteristically described as a curtain passing vertically 
across the visual field with complete monocular visual loss 
lasting a few minutes and a similar curtain effect as the 
episode passes (amaurosis fugax; also called “fleeting 
blindness”). An embolus is rarely seen on ophthalmoscopy. 
Other causes of transient, often recurrent, visual loss due to 
ocular ischemia are giant cell arteritis, hypercoagulable 
state (such as antiphospholipid syndrome), hyperviscosity, 
and severe occlusive carotid disease. More transient visual 
loss, lasting only a few seconds to 1 minute, usually recur
-
rent, and affecting one or both eyes, occurs in patients with 
optic disk swelling, for example in those with raised intra
-
cranial pressure.
 
»
Diagnostic Studies
In most cases, clinical assessment and investigations are 
much the same as for retinal artery occlusion with empha
-
sis on identification of a source of emboli. Optic disk swell
-
ing requires different investigations.
 
»
Treatment
All patients with possible embolic transient visual loss 
should be treated immediately with oral aspirin (at least 
81 mg daily), or another antiplatelet drug, until the cause

»
Treatment
81 mg daily), or another antiplatelet drug, until the cause 
has been determined. Affected patients with 70–99% (and 
possibly those with 50–69%) ipsilateral carotid artery 
stenosis should be considered for urgent carotid endarter
-
ectomy or possibly angioplasty with stenting (see 
Chapters 12 and 24). In all patients, vascular risk factors 
(eg, hypertension) need to be controlled. Retinal emboliza
-
tion due to cardiac arrhythmia, such as atrial fibrillation, or 
hypercoagulable state usually requires anticoagulation. 
Cardiac valvular disease and patent foramen ovale may 
require surgical treatment.
 
»
In all cases of episodic visual loss, early ophthalmologic 
consultation is advisable.
 
»
Hospital admission is advisable in embolic transient visual 
loss if there have been two or more episodes in the preced
-
ing week (“crescendo TIA ”) or the underlying cause is car
-
diac or a hypercoagulable state.
Bagheri N et al. Acute vision loss. Prim Care. 2015 Sep;
 
42(3):347–61. [PMID: 26319342]
Kvickström P et al. Amaurosis fugax: risk factors and prevalence 
of significant carotid stenosis. Clin Ophthalmol. 2016 Oct 31;
 
10:2165–70. [PMID: 27826182]
Pula JH et al. Update on the evaluation of transient vision loss. 
Clin Ophthalmol. 2016 Feb 11;10:297–303. [PMID: 26929593]
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RETINAL DISORDERS ASSOCIATED WITH 
SYSTEMIC DISEASES
1. Diabetic Retinopathy
 
»
Present in about 35% of all diagnosed diabetic 
patients.
 
»
Present in about 20% of type 2 diabetic patients at 
 
»
Background retinopathy:
 mild retinal abnormali
-
ties without visual loss.
 
»
Maculopathy:
 macular edema, exudates, or 
ischemia.
 
»
Proliferative retinopathy:
 new retinal vessels.
 
»
Diabetic retinopathy is broadly classified as 
nonproliferative,
 
which is subclassified as mild, moderate, or severe, or 
pro
-
liferative,
 which is less common but causes more severe 
visual loss. Diabetic retinopathy is present in about one-
third of patients in whom diabetes has been diagnosed, 
and about one-third of those have sight-threatening dis
-
ease. In the United States, it affects about 4 million people; 
it is the leading cause of new blindness among adults aged 
20–65 years; and the number of affected individuals aged 
65 years or older is increasing. Worldwide, there are 
approximately 93 million people with diabetic retinopa
-
thy, including 28 million with vision-threatening disease. 
Retinopathy increases in prevalence and severity with 
increasing duration and poorer control of diabetes. In type 
1 diabetes, retinopathy is not detectable for at least 3 years 
after diagnosis. In type 2 diabetes, retinopathy is present in 
about 20% of patients at diagnosis and may be the present
-
ing feature.
 
»
Clinical assessment comprises visual acuity testing, stereo
-
scopic examination of the retina, retinal imaging with opti
-
cal coherence tomography, and sometimes fluorescein 
angiography.
Nonproliferative retinopathy manifests as microaneu
-
rysms, retinal hemorrhages, venous beading, retinal 
edema, and hard exudates. Reduction of vision is most 
commonly due to diabetic macular edema, which may be 
focal or diffuse, but it can also be due to macular isch
-
emia. Macular involvement is the most common cause of 
legal blindness in type 2 diabetes. Macular edema may be 
associated with treatment with thiazolidinediones 
(glitazones).
Proliferative retinopathy is characterized by neovascu
-
larization, arising from either the optic disk or the major 
vascular arcades. Vitreous hemorrhage is a common 
sequela. Proliferation into the vitreous of blood vessels, 
with their associated fibrous component, may lead to trac
-
tional retinal detachment.
 
»
Screening
Visual symptoms and visual acuity are poor guides to the 
presence of diabetic retinopathy. Adult and adolescent 
patients with diabetes mellitus should undergo regular 
screening by fundal photography, commonly with central
-
ized screening that may involve computer detection soft
-
ware programs, or slit-lamp examination. More frequent 
monitoring is required in women during pregnancy and in 
those planning pregnancy. Patients with type 2 diabetes 
mellitus should be screened shortly after diagnosis.
 
»
Treatment
Treatment includes optimizing blood glucose, blood pres
-
sure, kidney function, and serum lipids, although such 
measures are probably more important in preventing the 
development of retinopathy than in influencing its subse
-
quent course. Fenofibrate and renin-angiotensin system 
inhibitors are beneficial even in established retinopathy.
Macular edema and exudates, but not ischemia, may 
respond to laser photocoagulation; to intravitreal adminis
-
tration of a VEGF inhibitor (ranibizumab [Lucentis], 
pegaptanib [Macugen], bevacizumab [Avastin], or afliber
-
cept [VEGF Trap-Eye, Eylea]) or corticosteroid (triamcin
-
olone, dexamethasone implant [Ozurdex], or fluocinolone 
implant [Retisert, Iluvien]); to vitrectomy; or to intravitreal 
injection of a serine protease (ocriplasmin [Jetrea]) to 
release vitreo-retinal traction.
Proliferative retinopathy
 is usually treated by panreti
-
nal laser photocoagulation, preferably before vitreous hem

-
-
orrhage or tractional detachment has occurred. Regression 
of neovascularization can also be achieved by intravitreal 
injection of a VEGF inhibitor. In patients with severe 
non
-
proliferative retinopathy,
 fluorescein angiography can 
help determine whether panretinal laser photocoagulation 
should be undertaken prophylactically by determining the 
extent of retinal ischemia. Vitrectomy is necessary for 
removal of persistent vitreous hemorrhage, to improve 
vision and allow panretinal laser photocoagulation for the 
underlying retinal neovascularization, for treatment of trac
-
tional retinal detachment involving the macula, and for 
management of rapidly progressive proliferative disease.
Proliferative diabetic retinopathy, especially after suc
-
cessful laser treatment, is not a contraindication to treat
-
ment with thrombolytic agents, aspirin, or warfarin unless 
there has been recent intraocular hemorrhage.
 
»
•	
All diabetic patients with sudden loss of vision or reti
-
nal detachment should be referred emergently to an 
•	
Proliferative retinopathy or macular involvement 
requires urgent referral to an ophthalmologist.
•	
Severe nonproliferative retinopathy or unexplained 
reduction of visual acuity requires early referral to an 
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Hendrick AM et al. Diabetic retinopathy. Prim Care. 2015 Sep;
 
42(3):451–64. [PMID: 26319349]
Liu Y et al. Risk factors of diabetic retinopathy and sight-
threatening diabetic retinopathy: a cross-sectional study of 13 
473 patients with type 2 diabetes mellitus in mainland China. 
BMJ Open. 2017 Sep 1;7(9):e016280. [PMID: 28864696]
Mbata O et al. Obesity, metabolic syndrome and diabetic 
retinopathy: Beyond hyperglycemia. World J Diabetes. 
2017 Jul 15;8(7):317–29. [PMID: 28751954]
National Collaborating Centre for Women’s and Children’s 
Health (UK). Diabetes in pregnancy: management of diabetes 
and its complications from preconception to the postnatal 
period. 2015 Feb. [PMID: 25950069]
Shah AR et al. Diabetic retinopathy: research to clinical practice. 
Clin Diabetes Endocrinol. 2017 Oct 19;3:9. [PMID: 29075511]
2. Hypertensive Retinochoroidopathy
Systemic hypertension affects both the retinal and choroi
-
dal circulations. The clinical manifestations vary accord
-
ing to the degree and rapidity of rise in blood pressure 
and the underlying state of the ocular circulation. The 
most florid ocular changes occur in young patients with 
abrupt elevations of blood pressure, such as may occur 
in pheochromocytoma, malignant hypertension, or 
 
preeclampsia-eclampsia. Hypertensive retinopathy can be 
a surrogate marker for current and future nonocular end-
organ damage. Its detection is aided by nonmydriatic fun
-
dal photography.
Chronic hypertension accelerates the development of 
atherosclerosis. The retinal arterioles become more tortu
-
ous and narrower and develop abnormal light reflexes 
(“silver-wiring” and “copper-wiring”). There is increased 
venous compression at the retinal arteriovenous crossings 
(“arteriovenous nicking”), predisposing to branch retinal 
vein occlusions. Flame-shaped hemorrhages occur in the 
nerve fiber layer of the retina.
Acute elevations of blood pressure result in loss of auto
-
regulation in the retinal circulation, leading to breakdown 
of endothelial integrity and occlusion of precapillary arteri
-
oles and capillaries that manifest as cotton-wool spots, reti
-
nal hemorrhages, retinal edema, and retinal exudates, often 
in a stellate appearance at the macula. Vasoconstriction and 
ischemia in the choroid result in exudative retinal detach
-
ments and retinal pigment epithelial infarcts that later 
develop into pigmented lesions that may be focal, linear, or 
wedge-shaped. The abnormalities in the choroidal circula
-
tion may also affect the optic nerve head, producing isch
-
emic optic neuropathy with optic disk swelling. Fundal 
abnormalities are the hallmark of hypertensive crisis with 
retinopathy (previously known as malignant hypertension) 
that requires emergency treatment. Marked fundal abnor
-
malities are likely to be associated with permanent retinal, 
choroidal, or optic nerve damage. Precipitous reduction of 
blood pressure may exacerbate such damage.
Aissopou EK et al. The Keith-Wagener-Barker and Mitchell-
Wong grading systems for hypertensive retinopathy: associa
-
tion with target organ damage in individuals below 55 years. 
J Hypertens. 2015 Nov;33(11):2303–9. [PMID: 26335430]
Fraser-Bell S et al. Hypertensive eye disease: a review. Clin Exp 
Ophthalmol. 2017 Jan;45(1):45–53. [PMID: 27990740]
Kolman SA et al. Consideration of hypertensive retinopathy as 
an important end-organ damage in patients with hyperten
-
sion. J Hum Hypertens. 2017 Feb;31(2):121-5.
Omotoso AB et al. Relationship between retinopathy and renal 
abnormalities in black hypertensive patients. Clin Hypertens. 
2016 Oct 21;22:19. [PMID: 28828178]
Shantsila A et al. Malignant hypertension revisited—does this 
still exist? Am J Hypertens. 2017 Jun 1;30(6):543–9. [PMID: 
28200072]
3. Blood Dyscrasias
Severe 
thrombocytopenia
 or 
anemia
 may result in various 
types of retinal or choroidal hemorrhages, including white 
centered retinal hemorrhages (Roth spots) that occur in

Severe 
 or 
anemia
centered retinal hemorrhages (Roth spots) that occur in 
leukemia and other situations besides bacterial endocardi
-
tis. Involvement of the macula may result in permanent 
visual loss.
Sickle cell retinopathy
 is particularly common in 
hemoglobin SC disease but may also occur with other 
hemoglobin S variants. Manifestations include “salmon-
patch” preretinal/intraretinal hemorrhages, “black sun
-
bursts” resulting from intraretinal hemorrhage, and new 
vessels. Severe visual loss is rare but more common in 
patients with pulmonary hypertension. Retinal laser photo
-
coagulation reduces the frequency of vitreous hemorrhage 
from new vessels. Surgery is occasionally needed for persis
-
tent vitreous hemorrhage or tractional retinal detachment.
Do BK et al. Sickle cell disease and the eye. Curr Opin Ophthal
-
mol. 2017 Nov;28(6):623–8. [PMID: 28984727]
Talcott KE et al. Ophthalmic manifestations of leukemia. Curr 
Opin Ophthalmol. 2016 Nov;27(6):545–51. [PMID: 27585213]
4. HIV Infection/
a
IDS
HIV retinopathy
 causes cotton-wool spots, retinal hemor
-
rhages, and microaneurysms but may also lead to reduced 
contrast sensitivity and retinal nerve fiber layer and outer 
retinal damage (HIV neuroretinal disorder).
CMV retinitis
 is less common since the availability of 
antiretroviral therapy (ART) but continues to be prevalent 
where resources are limited. It usually occurs when CD4 
counts are below 50/mcL (or 0.05 × 10
9
/L) and is character
-
ized by progressively enlarging yellowish-white patches of 
retinal opacification, accompanied by retinal hemorrhages, 
and usually beginning adjacent to the major retinal vascu
-
lar arcades. Patients are often asymptomatic until there is 
involvement of the fovea or optic nerve, or until retinal 
detachment develops. Choices for initial therapy are (1) 
valganciclovir 900 mg orally twice daily for 3 weeks; (2) 
ganciclovir 5 mg/kg intravenously twice a day, foscarnet 
60 mg/kg intravenously three times a day, or cidofovir 
5 mg/kg intravenously once weekly, for 2–3 weeks; or (3) 
local administration, using either intravitreal injection of 
ganciclovir or foscarnet, or the sustained-release ganciclo
-
vir intravitreal implant. All available agents are virostatic. 
Maintenance therapy can be achieved with lower-dose 
therapy (oral valganciclovir 900 mg once daily, intravenous 
ganciclovir 5 mg/kg/day, intravenous foscarnet 90 mg/kg/day, 
or intravenous cidofovir 5 mg/kg once every 2 weeks) or 
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CMDT 2019
with intravitreal therapy. Systemic therapy has a greater 
risk of nonocular adverse effects but reduces mortality, 
incidence of nonocular CMV disease (but this is less com
-
mon with ART), and incidence of retinitis in the fellow eye 
and avoids intraocular complications of intravitreal admin
-
istration. Pharmacologic prophylaxis against CMV retinitis 
in patients with low CD4 counts or high CMV burdens has 
not been found to be worthwhile. In all patients with CMV 
retinitis, ART needs to be instituted or adjusted. This may 
lead to the 
immune reconstitution inflammatory syn
-
drome
 
(IRIS),
 of which the immune recovery uveitis may 
lead to visual loss, predominantly due to cystoid macular 
edema. If the CD4 count is maintained above 100/mcL 
(0.1 × 10
9
/L), it may be possible to discontinue maintenance 
anti-CMV therapy.
Other ophthalmic manifestations of opportunistic 
infections occurring in AIDS patients include herpes sim
-
plex retinitis, which usually manifests as acute retinal 
necrosis; toxoplasmic and candidal chorioretinitis possibly 
progressing to endophthalmitis; herpes zoster ophthal
-
micus and herpes zoster retinitis, which can manifest as 
acute retinal necrosis or progressive outer retinal necrosis; 
and various entities due to syphilis, tuberculosis, or crypto
-
coccosis. Kaposi sarcoma of the conjunctiva (see Chapter 31) 
and orbital lymphoma may also be seen on rare occasions. 
Chronic HIV infection is associated with increased preva
-
lence of age-related macular degeneration.
Hassan-Moosa R et al. Cytomegalovirus retinitis and HIV: case 
reviews from KwaZulu-Natal Province, South Africa. S Afr 
Med J. 2017 Sep 22;107(10):843–6. [PMID: 29022526]
Kim DY et al. Comparison of visual prognosis and clinical fea
-
tures of cytomegalovirus retinitis in HIV and non-HIV 
patients. Retina. 2017 Feb;37(2):376–81. [PMID: 28118285]
ISCHEMIC OPTIC NEUROPATHY
 
»
Sudden painless visual loss with signs of optic 
nerve dysfunction.
 
»
Optic disk swelling in anterior ischemic optic 
Anterior ischemic optic neuropathy
—due to inadequate 
perfusion of the posterior ciliary arteries that supply the 
anterior portion of the optic nerve—produces sudden 
visual loss, usually with an altitudinal field defect, and optic 
disk swelling. In older patients, it may be caused by giant 
cell arteritis (arteritic anterior ischemic optic neuropathy). 
The predominant factor predisposing to nonarteritic ante
-
rior ischemic optic neuropathy, which subsequently affects 
the fellow eye in around 15% of cases, is a congenitally 
crowded optic disk. Other predisposing factors are sys
-
temic hypertension, diabetes mellitus, hyperlipidemia, 
systemic vasculitis, inherited or acquired thrombophilia, 
interferon-alpha therapy, obstructive sleep apnea, and 
phosphodiesterase type 5 inhibitors.
Ischemic optic neuropathy, usually involving the retro
-
bulbar optic nerve and thus not causing any optic disk 
swelling 
(posterior ischemic optic neuropathy),
 may 
occur with severe blood loss; nonocular surgery, particu
-
larly prolonged lumbar spine surgery in the prone position; 
severe burns; or in association with dialysis. In all such 
situations, there may be several contributory factors.
 
»
Treatment
Arteritic anterior ischemic optic neuropathy necessitates 
emergency high-dose systemic corticosteroid treatment to 
prevent visual loss in the other eye. (See Central & Branch 
Retinal Artery Occlusions, above, and Polymyalgia Rheu
-
matica & Giant Cell Arteritis, Chapter 20.) It is uncertain 
whether systemic or intravitreal corticosteroid therapy 
influences the outcome in nonarteritic anterior ischemic 
optic neuropathy or whether oral low-dose (~81 mg daily) 
aspirin reduces the risk of fellow eye involvement. In isch
-
emic optic neuropathy after nonocular surgery, treatment 
of marked anemia by blood transfusion may be beneficial.
 
»

-
 
»
Patients with ischemic optic neuropathy should be referred 
 
»
Patients with ischemic optic neuropathy due to giant cell 
arteritis or other vasculitis may require emergency admis
-
sion for high-dose corticosteroid therapy and close moni
-
toring to ensure that treatment is adequate.
Berry S et al. Nonarteritic anterior ischemic optic neuropathy: 
cause, effect, and management. Eye Brain. 2017 Sep 27;9:23–8. 
[PMID: 29033621]
Fandino W . Strategies to prevent ischemic optic neuropathy fol
-
lowing major spine surgery: a narrative review. J Clin Anesth. 
2017 Oct 3;43:50–8. [PMID: 28985584]
Mendel E et al. Revisiting postoperative vision loss following 
non-ocular surgery: a short review of etiology and legal con
-
siderations. Front Surg. 2017 Jun 26;4:34. [PMID: 28695122]
OPTIC NEURITIS
 
»
Subacute usually unilateral visual loss.
 
»
Pain exacerbated by eye movements.
 
»
Optic disk usually normal in acute stage but sub
-
sequently develops pallor.
 
»
Inflammatory optic neuropathy is strongly associated with 
demyelinating disease (typical optic neuritis), particularly 
multiple sclerosis but also acute disseminated encephalo
-
myelitis. It also occurs in sarcoidosis; in neuromyelitis 
optica spectrum disorder, which is characterized by serum 
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antibodies to aquaporin-4; in association with serum anti
-
bodies to myelin oligodendrocyte glycoprotein; following 
viral infection (usually in children); in varicella zoster virus 
infection; in various autoimmune disorders, particularly 
systemic lupus erythematosus and Sjögren syndrome; dur
-
ing treatment with biologics; and by spread of inflamma
-
tion from the meninges, orbital tissues, or paranasal 
sinuses.
 
»
Optic neuritis in demyelinating disease is characterized by 
unilateral loss of vision developing over a few days. Visual 
acuity ranges from 20/30 (6/9) to no perception of light, 
with more severe visual loss being associated with low 
serum vitamin D. In almost all cases there is pain behind 
the eye, exacerbated by eye movements. Field loss is usually 
central. There is particular loss of color vision and a rela
-
tive afferent pupillary defect. In about two-thirds of cases, 
the optic nerve is normal during the acute stage (retrobul
-
bar optic neuritis). In the remainder, the optic disk is swol
-
len (papillitis) with occasional flame-shaped peripapillary 
hemorrhages. Visual acuity usually improves within 2–3 weeks 
and returns to 20/40 (6/12) or better in 95% of previously 
unaffected eyes. Optic atrophy subsequently develops if 
there has been damage to sufficient optic nerve fibers. Any 
patient with presumed demyelinating optic neuritis in 
which visual recovery does not occur or there are other 
atypical features, including continuing deterioration of 
vision or persisting pain after 2 weeks, should undergo 
further investigation, including MRI of the head and orbits 
to exclude a lesion compressing the optic nerve and to 
identify atypical optic neuritis.
 
»
Treatment
In acute demyelinating optic neuritis, intravenous methyl
-
prednisolone (1 g daily for 3 days followed by a tapering 
course of oral prednisolone) has been shown to accelerate 
visual recovery, although in clinical practice, the oral taper 
is not often prescribed and oral methylprednisolone may 
be used. Use in an individual patient is determined by the 
degree of visual loss, the state of the fellow eye, and the 
patient’s visual requirements. Phenytoin and amiloride 
may be neuroprotective in typical optic neuritis.
Atypical optic neuritis due to sarcoidosis, neuromye
-
litis optica, herpes zoster, or systemic lupus erythemato
-
sus generally has a poorer prognosis, requires immediate 
and more prolonged corticosteroid therapy, may require 
plasma exchange, and may necessitate long-term 
immunosuppression.
 
»
Prognosis
Among patients with a first episode of clinically isolated 
optic neuritis, multiple sclerosis will develop in 50% 
within 15 years but the visual and neurologic prognoses 
are good. The major risk factors are female sex and mul
-
tiple white matter lesions on brain MRI. Many disease-
modifying drugs are available to reduce the risk of further 
neurologic episodes and potentially the accumulation of 
disability but each has adverse effects that in some instances 
are life-threatening. Fingolimod is associated with macular 
edema. Retinal nerve fiber layer optical coherence tomog
-
raphy quantifies axonal damage that can be used to moni
-
tor disease progression.
 
»
All patients with optic neuritis should be referred urgently 
for ophthalmologic or neurologic assessment.
Deschamps R et al. Etiologies of acute demyelinating optic neu
-
ritis: an observational study of 110 patients. Eur J Neurol. 
2017 Jun;24(6):875–9. [PMID: 28477397]
Kale N. Optic neuritis as an early sign of multiple sclerosis. Eye 
Brain. 2016 Oct 26;8:195–202. [PMID: 28539814]
Morrow MJ et al. Should oral corticosteroids be used to treat 
demyelinating optic neuritis? J Neuroophthalmol. 2017 Dec;
 
37(4):444–50. [PMID: 28857910]
Patterson SL et al. Neuromyelitis optica. Rheum Dis Clin North 
Am. 2017 Nov;43(4):579–91. [PMID: 29061244]
OPTIC DISK SWELLING

Optic disk swelling may result from intraocular disease, 
orbital and optic nerve lesions, severe hypertensive retino
-
choroidopathy, or raised intracranial pressure, the last 
necessitating urgent imaging to exclude an intracranial 
mass or cerebral venous sinus occlusion. Intraocular causes 
include central retinal vein occlusion, posterior uveitis, and 
posterior scleritis. Optic nerve lesions causing disk swell
-
ing include anterior ischemic optic neuropathy; optic neu
-
ritis; optic nerve sheath meningioma; and infiltration by 
sarcoidosis, leukemia, or lymphoma. Any orbital lesion 
causing nerve compression may produce disk swelling.
 (optic disk swelling due to raised intracra
-
nial pressure) is usually bilateral and most commonly pro
-
duces enlargement of the blind spot without loss of acuity. 
Chronic papilledema, as in idiopathic intracranial hyper
-
tension and cerebral venous sinus occlusion, or severe acute 
papilledema may be associated with visual field loss and 
occasionally with profound loss of acuity. All patients with 
chronic papilledema must be monitored carefully—
especially their visual fields—and cerebrospinal fluid shunt 
or optic nerve sheath fenestration should be considered in 
those with progressive visual failure not controlled by 
medical therapy (weight loss where appropriate and usually 
acetazolamide). In idiopathic intracranial hypertension, 
transverse venous sinus stenting is also an option.
Optic disk drusen
 and congenitally crowded optic 
disks, which are associated with farsightedness, cause optic 
disk elevation that may be mistaken for swelling (pseudo-
papilledema). Exposed optic disk drusen may be obvious 
clinically or can be demonstrated by their autofluores
-
cence. Buried drusen are best detected by orbital ultra
-
sound or CT scanning. Other family members may be 
similarly affected.
Chan JW . Current concepts and strategies in the diagnosis and 
management of idiopathic intracranial hypertension in 
adults. J Neurol. 2017 Aug;264(8):1622–33. [PMID: 28144922]
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▲
Figure 7–5.
 
Left partial third nerve palsy with ptosis 
(A),
 reduced adduction 
(B),
 elevation 
(C),
 and depression 
(D)
 but normal abduction 
(E)
 of the left eye.
A
B
C
D
E
Ottridge R et al. Randomised controlled trial of bariatric sur
-
gery versus a community weight loss programme for the sus
-
tained treatment of idiopathic intracranial hypertension: 
the Idiopathic Intracranial Hypertension Weight Trial 
(IIH:WT) protocol. BMJ Open. 2017 Sep 27;7(9):e017426. 
[PMID: 28963303]
Wall M. Update on idiopathic intracranial hypertension. Neurol 
Clin. 2017 Feb;35(1):45–57. [PMID: 27886895]
Wall M et al; NORDIC Idiopathic Intracranial Hypertension 
Study Group. The longitudinal Idiopathic Intracranial Hyper
-
tension Trial: outcomes from months 6–12. Am J Ophthal
-
mol. 2017 Apr;176:102–7. [PMID: 28104417]
OCULAR MOTOR CRANIAL NERVE PALSIES
In complete 
third nerve palsy,
 there is ptosis with a diver
-
gent and slightly depressed eye (Figure 7–5). Extraocular 
movements are restricted in all directions except laterally 
(preserved lateral rectus function). Intact fourth nerve 
(superior oblique) function is detected by inward rotation 
on attempted depression of the eye. Pupillary involvement, 
manifesting as a relatively dilated pupil that does not con
-
strict normally to light, usually means compression, which 
may be due to aneurysm of the posterior communicating 
artery or uncal herniation due to a supratentorial mass 
lesion. In acute painful isolated third nerve palsy with 
pupillary involvement, posterior communicating artery 
aneurysm must be excluded. Pituitary apoplexy is a rarer 
cause. Causes of isolated third nerve palsy without pupil
-
lary involvement include diabetes mellitus, hypertension, 
giant cell arteritis, and herpes zoster.
Fourth nerve palsy
 causes upward deviation of the eye 
with failure of depression on adduction. In acquired cases, 
there is vertical and torsional diplopia that is most apparent 
on looking down. Trauma is a major cause of acquired—
particularly bilateral—fourth nerve palsy, but posterior 
fossa tumor and medical causes, such as in third nerve 
palsy, should also be considered. Similar clinical features 
are seen in congenital cases due to developmental anomaly 
of the nerve, muscle, or tendon.
Sixth nerve palsy
 causes convergent squint in the pri
-
mary position with failure of abduction of the affected eye, 
producing horizontal diplopia that increases on gaze to the 
affected side and on looking into the distance. It is an 
important sign of raised intracranial pressure and may also 
be due to trauma, neoplasms, brainstem lesions, petrous 
apex lesions, or medical causes (such as diabetes mellitus, 
hypertension, giant cell arteritis, and herpes zoster).
In isolated ocular motor nerve palsy presumed to be due 
a medical cause, brain MRI is not always required initially, 
but it is necessary if recovery has not begun within 3 months.
Ocular motor nerve palsy accompanied by other neuro
-
logic signs may be due to lesions in the brainstem, cavern
-
ous sinus, or orbit. Lesions around the cavernous sinus 
involve the first and second divisions of the trigeminal 
nerve, the ocular motor nerves, and occasionally the optic 
chiasm. Orbital apex lesions involve the optic nerve and 
the ocular motor nerves.
Myasthenia gravis and thyroid eye disease (Graves oph
-
thalmopathy) should be considered in the differential 
diagnosis of disordered extraocular movements.
 
»
•	
In recent onset isolated third nerve palsy, particularly if 
there is pupillary involvement or pain, emergency referral 
is required for neurologic assessment and possibly CT, 
MRI, or catheter angiography for intracranial aneurysm.
•	
All patients with recent onset double vision should be 
referred urgently to a neurologist or ophthalmologist, 
particularly if there are multiple cranial nerve dysfunc
-
tions or other neurologic abnormalities.
 
»

-
 
»
Patients with double vision due to giant cell arteritis may 
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▲
Figure 7–6.
 
Thyroid eye disease. Inferior rectus fibro
-
sis causing 
(A)
 downward deviation and 
(B)
 limitation of 
elevation of right eye. 
Riordan-Eva P , Augsburger JJ. 
Vaughan & Asbury’s General 
Ophthalmology, 
19th ed. McGraw-Hill, 2018.)
A
B
adequate. (See Central & Branch Retinal Artery Occlusions 
and Chapter 20.)
Huff JS et al. Neuro-ophthalmology in emergency medicine. 
Emerg Med Clin North Am. 2016 Nov;34(4):967–86. [PMID: 
27741997]
Klein Hesselink T et al. Neurological imaging in acquired cranial 
nerve palsy: ophthalmologists vs. neurologists. Strabismus. 
2017 Sep;25(3):134–9. [PMID: 28759288]
Kung NH et al. Isolated ocular motor nerve palsies. Semin Neu
-
rol. 2015 Oct;35(5):539–48. [PMID: 26444399]
Prasad S. A window to the brain: neuro-ophthalmology for the 
primary care practitioner. Am J Med.  2018 Feb;131(2):120–8. 
[PMID: 29079403]
THYROID EYE DISEASE 
 
(Graves Ophthalmopathy
)
Thyroid eye disease is a syndrome of clinical and orbital 
imaging abnormalities caused by deposition of mucopoly
-
saccharides and infiltration with chronic inflammatory 
cells of the orbital tissues, particularly the extraocular 
muscles. It usually occurs in association with autoimmune 
hyperthyroidism. Clinical or laboratory evidence of thy
-
roid dysfunction and thyroid antibodies may not be detect
-
able at presentation or even on long-term follow-up, but 
their absence requires consideration of other disease enti
-
ties. Radioiodine therapy, possibly indirectly due to induc
-
tion of hypothyroidism, and cigarette smoking increase the 
severity of thyroid eye disease and ethanol injection of 
thyroid nodules has been reported to be followed by severe 
disease (see Chapter 26). Ocular myasthenia and thyroid 
eye disease are associated and may coexist, the presence of 
ptosis rather than lid retraction being more characteristic 
of the former.
 
»
The primary clinical features are proptosis, lid retraction 
and lid lag, conjunctival chemosis and episcleral inflamma
-
tion, and extraocular muscle dysfunction (Figure 7–6). 
Resulting symptoms are cosmetic abnormalities, surface 
irritation, which usually responds to artificial tears, and 
diplopia, which should be treated conservatively (eg, with 
prisms) in the active stages of the disease and only by sur
-
gery when the disease has been static for at least 6 months. 
The important complications are corneal exposure and optic 
nerve compression, both of which may lead to marked 
visual loss. The primary imaging features are enlargement of 
the extraocular muscles, usually affecting both orbits. The 
clinical and imaging abnormalities of thyroid eye disease 
may be mimicked by dural carotico-cavernous sinus fistula.
 
»
Treatment
See Graves Ophthalmopathy, Chapter 26.
 
»
All patients with thyroid eye disease should be referred to 
an ophthalmologist, urgently if there is reduced vision.
Blandford AD et al. Dysthyroid optic neuropathy: update on 
pathogenesis, diagnosis, and management. Expert Rev Oph
-
thalmol. 2017;12(2):111–21. [PMID: 28775762]
Smith TJ et al. Graves’ disease. N Engl J Med. 2016 Oct 20;
 
375(16):1552–65. [PMID: 27797318]
Strianese D. Update on Graves disease: advances in treatment of 
mild, moderate and severe thyroid eye disease. Curr Opin 
Ophthalmol. 2017 Sep;28(5):505–13. [PMID: 28700384]
Wiersinga WM. Advances in treatment of active, moderate-to-
severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol. 
2017 Feb;5(2):134–42. [PMID: 27346786]
ORBITAL CELLULITIS
Orbital cellulitis is characterized by fever, proptosis, restric
-
tion of extraocular movements, and swelling with redness 
of the lids. Immediate treatment with intravenous antibiot
-
ics is necessary to prevent optic nerve damage and spread 
of infection to the cavernous sinuses, meninges, and brain.

-
of infection to the cavernous sinuses, meninges, and brain. 
Infection of the paranasal sinuses is the usual underlying 
cause. Infecting organisms include 
, the 
incidence of which has been reduced by the administra
-
tion of pneumococcal vaccine; other streptococci, such as 
the anginosus group; 
H influenzae
 and, less commonly, 
S aureus
 including MRSA. Penicillinase-resistant penicil
-
lin, such as nafcillin, is recommended, possibly together 
with metronidazole or clindamycin to treat anaerobic 
infections. If trauma is the underlying cause, a cephalospo
-
rin, such as cefazolin or ceftriaxone, should be added to 
ensure coverage for 
S aureus
 and group A beta-hemolytic 
streptococci. If MRSA infection is a concern, vancomycin 
or clindamycin may be required. For patients with penicil
-
lin hypersensitivity, vancomycin, levofloxacin, and metro
-
nidazole are recommended. The response to antibiotics is 
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usually excellent, but surgery may be required to drain the 
paranasal sinuses or orbital abscess. In immunocompro
-
mised patients, zygomycosis must be considered.
 
»
All patients with suspected orbital cellulitis must be 
Amin N et al. Assessment and management of orbital cellulitis. 
Br J Hosp Med (Lond). 2016 Apr;77(4):216–20. [PMID: 
27071427]
Marchiano E et al. Characteristics of patients treated for orbital 
cellulitis: an analysis of inpatient data. Laryngoscope. 
2016 Mar;126(3):554–9. [PMID: 26307941]
OCULAR TRAUMA
Ocular trauma, which occurs in many different circum
-
stances and by a variety of mechanisms, is an important 
cause of avoidable severe visual impairment at all ages but 
particularly in young adult males and is the leading cause 
of monocular blindness in the United States. Thorough but 
safe clinical assessment, supplemented when necessary by 
imaging, is crucial to effective management. Ocular dam
-
age and the possible need for early assessment by an oph
-
thalmologist need to be borne in mind in the assessment of 
any patient with mid-facial injury.
Keel S et al. The prevalence of vision loss due to ocular trauma 
in the Australian National Eye Health Survey. Injury. 
2017 Nov;48(11):2466–9. [PMID: 28964509]
Li EY et al. Epidemiology of open-globe injuries in Hong Kong. 
Asia Pac J Ophthalmol (Phila). 2017 Jan–Feb;6(1):54–8. [PMID: 
28161926]
Sahraravand A et al. Ocular traumas in working age adults in 
Finland—Helsinki Ocular Trauma Study. Acta Ophthalmol. 
2017 May;95(3):288–94. [PMID: 27935236]
Wang W et al. Epidemiology and clinical characteristics of 
patients hospitalized for ocular trauma in South-Central 
China. Acta Ophthalmol. 2017 Sep;95(6):e503–10. [PMID: 
28371405]
1. Conjunctival & Corneal Foreign Bodies
If a patient complains of “something in my eye” and gives a 
consistent history, a foreign body is usually present on the 
cornea or under the upper lid even though it may not be 
visible. Visual acuity should be tested before treatment is 
instituted, to assess the severity of the injury and as a basis 
for comparison in the event of complications.
After a local anesthetic (eg, proparacaine, 0.5%) is 
instilled, the eye is examined with a slit lamp or with a 
hand flashlight, using oblique illumination, and loupe. 
Corneal foreign bodies may be made more apparent by the 
instillation of sterile fluorescein. They are then removed 
with a sterile wet cotton-tipped applicator or hypodermic 
needle. Bacitracin-polymyxin ophthalmic ointment should 
be instilled. It is not necessary to patch the eye. All patients 
need to be advised to return promptly for reassessment if 
there is any increase in pain, redness, or impairment of 
vision.
Iron foreign bodies usually leave a diffuse rust ring. 
This requires excision and is best done under local anes
-
thesia using a slit lamp. 
Caution:
 Anesthetic drops should 
not be given to the patient for self-administration.
If there is no infection, a layer of corneal epithelial 
cells will line the crater within 24 hours. While the epi
-
thelium is defective, the cornea is extremely susceptible 
to infection. Early infection is manifested by a white 
necrotic area around the crater and a small amount of 
gray exudate.
In the case of a foreign body under the upper lid, a local 
anesthetic is instilled and the lid is everted by grasping the 
lashes gently and exerting pressure on the mid portion of 
the outer surface of the upper lid with an applicator 
(Figure 7–7). If a foreign body is present, it can easily be 
removed by passing a wet sterile cotton-tipped applicator 
across the conjunctival surface.
 
»
Urgent referral to an ophthalmologist should be arranged 
if a corneal foreign body cannot be removed or if there is 
suspicion of corneal infection.
Fraenkel A et al. Managing corneal foreign bodies in office-based

Fraenkel A et al. Managing corneal foreign bodies in office-based 
general practice. Aust Fam Physician. 2017 Mar;46(3):89–93. 
[PMID: 28260265]
2. Intraocular Foreign Body
Intraocular foreign body requires emergency treatment by 
an ophthalmologist. Patients giving a history of “something 
hitting the eye”—particularly while hammering on metal 
or using grinding equipment—must be assessed for this 
possibility, especially when no corneal foreign body is seen, 
a corneal or scleral wound is apparent, or there is marked 
visual loss or media opacity. Such patients must be treated 
as for open globe injury and referred without delay. Intra
-
ocular foreign bodies significantly increase the risk of 
intraocular infection.
 
»
Patients with suspected intraocular foreign body must be 
Loporchio D et al. Intraocular foreign bodies: a review. Surv 
Ophthalmol. 2016 Sep–Oct;61(5):582–96. [PMID: 26994871]
3. Corneal 
a
br
asions
A patient with a corneal abrasion complains of severe pain 
and photophobia. There is often a history of trauma to the 
eye, commonly involving a fingernail, piece of paper, or 
contact lens. Visual acuity is recorded, and the cornea and 
conjunctiva are examined with a light and loupe to rule out 
a foreign body. If an abrasion is suspected but cannot be 
seen, sterile fluorescein is instilled into the conjunctival 
sac: the area of corneal abrasion will stain more than the 
surrounding cornea.
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A
B
C
D
 
▲
Figure 7–7.
 
Technique of lid eversion. 
A:
 With the patient looking down, the upper lashes are grasped with one 
hand as an applicator stick is positioned at the superior edge of the upper tarsus (at the upper lid crease). 
B
 and 
C:
 
As the lashes are lifted, slight downward pressure is simultaneously applied with the applicator stick. 
D:
 The thumb 
pins the lashes against the superior orbital rim, allowing examination of the undersurface of the tarsus. 
(Photos by 
Richard Leung and Matthew Richardson. Used with permission from King’s College Hospital, London in Riordan-Eva P , 
Augsburger JJ. 
, 19th ed. McGraw-Hill, 2018.)
Treatment includes bacitracin-polymyxin ophthalmic 
ointment, mydriatic (cyclopentolate 1%), and analgesics 
either topical or oral nonsteroidal anti-inflammatory 
agents. Padding the eye is probably not helpful for small 
abrasions. Corneal abrasions heal more slowly in persons 
who smoke cigarettes. Recurrent corneal erosion may fol
-
low corneal abrasions.
Although topical tetracaine for 24 hours in the treat
-
ment of corneal abrasion has been reported to be safe and 
effective, there is a risk of severe corneal disease from misuse 
of topical anesthetics.
Ahmed F et al. Corneal abrasions and corneal foreign bodies. 
Prim Care. 2015 Sep;42(3):363–75. [PMID: 26319343]
Wakai A et al. Topical non-steroidal anti-inflammatory drugs for 
analgesia in traumatic corneal abrasions. Cochrane Database 
Syst Rev. 2017 May 18;5:CD009781. [PMID: 28516471]
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4. Contusions
Contusion injury of the eye (closed globe injury) and sur
-
rounding structures may cause ecchymosis (“black eye”), 
subconjunctival hemorrhage, edema of the cornea, hemor
-
rhage into the anterior chamber (hyphema), rupture of the 
root of the iris (iridodialysis), paralysis of the pupillary 
sphincter, paralysis of the muscles of accommodation, cat
-
aract, dislocation of the lens, vitreous hemorrhage, retinal 
hemorrhage and edema (most common in the macular 
area), detachment of the retina, rupture of the choroid, 
fracture of the orbital floor (“blowout fracture”), or optic 
nerve injury. Many of these injuries are immediately obvi
-
ous; others may not become apparent for days or weeks. 
The possibility of globe injury must always be considered 
in patients with facial injury, particularly if there is an 
orbital fracture. Patients with moderate to severe contu
-
sions should be seen by an ophthalmologist.
Any injury causing hyphema involves the danger of 
secondary hemorrhage, which may cause intractable glau
-
coma with permanent visual loss. The patient should be 
advised to rest until complete resolution has occurred. 
Frequent ophthalmologic assessment is essential. Aspirin 
and any drugs inhibiting coagulation increase the risk of 
secondary hemorrhage and are to be avoided. Sickle cell 
anemia or trait adversely affects outcome.
 
»
Patients with moderate or severe ocular contusion should 
be referred to an ophthalmologist, emergently if there is 
hyphema.
Bansal S et al. Controversies in the pathophysiology and man
-
agement of hyphema. Surv Ophthalmol. 2016 May–Jun;
 
61(3):297–308. [PMID: 26632664]
5. Lacerations
A. Lids
If the lid margin is lacerated, the patient should be referred 
for specialized care, since permanent notching may result. 
Lacerations of the lower eyelid near the inner canthus often 
sever the lower canaliculus, for which canalicular intuba
-
tion is likely to be required. Lid lacerations not involving 
the margin may be sutured like any skin laceration.
Kalin-Hajdu E et al. Controversies of the lacrimal system. Surv 
Ophthalmol. 2016 May–Jun;61(3):309–13. [PMID: 26700821]
Ko AC et al. Eyelid and periorbital soft tissue trauma. Facial Plast 
Surg Clin North Am. 2017 Nov;25(4):605–16. [PMID: 
28941512]
B. Conjunctiva
In lacerations of the conjunctiva, sutures are not necessary. 
To prevent infection, topical sulfonamide or other antibi
-
otic is used until the laceration is healed.
C. Cornea or Sclera
Patients with suspected corneal or scleral laceration or 
rupture (open globe injury) must be seen emergently by an 
ophthalmologist. Manipulation is kept to a minimum, 
since pressure may result in extrusion of intraocular con
-
tents. The eye is bandaged lightly and covered with a shield 
that rests on the orbital bones above and below. The patient 
should be instructed not to squeeze the eye shut and to 
remain still. If there may be a metallic intraocular foreign 
body, a radiograph or CT scan is obtained to identify and 
localize it. 
MRI is contraindicated because of the risk of 
movement of any metallic foreign body but may be useful for 
non-metallic foreign body.
 Endophthalmitis occurs in over 
5% of open globe injuries.
 
»
Patients with suspected open globe injury must be referred 
emergently to an ophthalmologist.
Beshay N et al. The epidemiology of open globe injuries 
presenting to a tertiary referral eye hospital in Australia. 
Injury. 2017 Jul;48(7):1348–54. [PMID: 28438416]
Page RD et al. Risk factors for poor outcomes in patients with 
open-globe injuries. Clin Ophthalmol. 2016 Aug 1;10:1461–6. 
[PMID: 27536059]
ULTRAVIOLET KERATITIS 
 
(
Actinic Keratitis
)
Ultraviolet burns of the cornea are usually caused by use of a 
sunlamp without eye protection, exposure to a welding arc, 
or exposure to the sun when skiing (“snow blindness”). There

)
or exposure to the sun when skiing (“snow blindness”). There 
are no immediate symptoms, but about 6–12 hours later the 
patient complains of agonizing pain and severe photophobia. 
Slit-lamp examination after instillation of sterile fluorescein 
shows diffuse punctate staining of both corneas.
Treatment consists of binocular patching and instillation 
of 1–2 drops of 1% cyclopentolate (to relieve the discomfort 
of ciliary spasm). All patients recover within 24–48 hours 
without complications. Local anesthetics should not be 
prescribed because they delay corneal epithelial healing.
CHEMICAL CONJUNCTIVITIS & KERATITIS
Chemical burns are treated by copious irrigation of the eyes 
as soon as possible after exposure, with tap water, saline 
solution, or buffering solution if available. Neutralization of 
an acid with an alkali or vice versa may cause further dam
-
age. Alkali injuries are more serious and require prolonged 
irrigation, since alkalies are not precipitated by the proteins 
of the eye as are acids. It is important to remove any retained 
particulate matter, such as is typically present in injuries 
involving cement and building plaster. This may require 
double eversion of the upper lid. The pupil should be dilated 
with 1% cyclopentolate, 1 drop twice a day, to relieve dis
-
comfort, and prophylactic topical antibiotics should be 
started. In moderate to severe injuries, intensive topical 
corticosteroids and topical and systemic vitamin C are also 
necessary. Complications include mucus deficiency, scarring 
of the cornea and conjunctiva, symblepharon (adhesions 
between the tarsal and bulbar conjunctiva), tear duct 
obstruction, and secondary infection. It is difficult to assess 
severity of chemical burns without slit-lamp examination.
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▲
Figure 7–8.
 
Periocular contact dermatitis due to eye 
drop preservative.
Haring RS et al. Epidemiologic trends of chemical ocular burns 
in the United States. JAMA Ophthalmol. 2016 Oct 1;
 
134(10):1119–24. [PMID: 27490908]
Sharma N et al. Treatment of acute ocular chemical burns. Surv 
Ophthalmol. 2018 Mar–Apr; 63(2):214–35. [PMID: 28935121]
TREATMENT OF OCULAR DISORDERS
Table 7–2 lists commonly used ophthalmic drugs and their 
indications and costs.
PRECAUTIONS IN MANAGEMENT OF OCULAR 
DISORDERS
1. Use of Local 
a
nesthetics
Unsupervised self-administration of local anesthetics is 
dangerous because they are toxic to the corneal epithelium 
and the patient may further injure an anesthetized eye 
without knowing it.
Tok OY et al. Toxic keratopathy associated with abuse of topical 
anesthetics and amniotic membrane transplantation for treat
-
ment. Int J Ophthalmol. 2015 Oct 18;8(5):938–44. [PMID: 
26558205]
2. 
p
upillar
y Dilation
Dilating the pupil can very occasionally precipitate acute 
glaucoma if the patient has a narrow anterior chamber 
angle and should be undertaken with caution if the ante
-
rior chamber is obviously shallow (readily determined by 
oblique illumination of the anterior segment of the eye). A 
short-acting mydriatic, such as tropicamide, should be 
used and the patient warned to report immediately if ocu
-
lar discomfort or redness develops. Angle closure is more 
likely to occur if pilocarpine is used to overcome pupillary 
dilation than if the pupil is allowed to constrict naturally.
3. Corticosteroid Therapy
Repeated use of local corticosteroids presents several haz
-
ards: herpes simplex (dendritic) and fungal keratitis, open-
angle glaucoma, and cataract formation. Furthermore, 
perforation of the cornea may occur when corticosteroids 
are used for herpes simplex keratitis. Topical nonsteroidal 
anti-inflammatory agents can be a good alternative. The 
potential for causing or exacerbating systemic hypertension, 
diabetes mellitus, gastritis, osteoporosis, or glaucoma must 
always be borne in mind when systemic corticosteroids are 
prescribed, such as for uveitis or giant cell arteritis.
4. Contaminated Eye Medications
Ophthalmic solutions are prepared with the same degree of 
care as fluids intended for intravenous administration, but 
once bottles are opened there is always a risk of contamina
-
tion, particularly with solutions of tetracaine, proparacaine, 
fluorescein, and any preservative-free preparations. The 
most dangerous is fluorescein, as this solution can be con
-
taminated with 
P aeruginosa
, which can rapidly destroy the 
eye. Single-use fluorescein eye drops or sterile fluorescein 
filter paper strips are recommended for use in place of 
multiple-use fluorescein solutions.
Whether in plastic or glass containers, eye solutions 
should not remain in use for long periods after the bottle is 
opened. Four weeks after opening is the usual maximum 
time for use of a solution containing preservatives before 
discarding. Preservative-free preparations should be kept 
refrigerated and usually discarded within 1 week after 
opening. Single-use products should not be reused.
If the eye has been injured by accident or by surgical 
trauma, it is of the greatest importance to use freshly opened 
bottles of sterile medications or single-use products.
5. Toxic & Hypersensitivity Reactions to Topical 
Therapy
In patients receiving long-term topical therapy, local toxic 
or hypersensitivity reactions to the active agent or preserva
-
tives may develop (Figure 7–8), especially if there is inade
-
quate tear secretion. Preservatives in contact lens cleaning 
solutions may produce similar problems. Burning and sore
-
ness are exacerbated by drop instillation or contact lens

-
-
ness are exacerbated by drop instillation or contact lens 
insertion; occasionally, fibrosis and scarring of the conjunc
-
tiva and cornea may occur. Preservative-free topical medi
-
cations, increasingly used in the treatment of glaucoma, and 
preservative-free contact lens solutions are available.
An antibiotic instilled into the eye can sensitize the 
patient to that drug and cause an allergic reaction upon 
subsequent systemic administration. Potentially fatal ana
-
phylaxis is known to occur in up to 0.3% of patients after 
intravenous fluorescein for fluorescein angiography. Ana
-
phylaxis also has been reported after topical fluorescein.
6. Systemic Effects of Ocular Drugs
The systemic absorption of certain topical drugs (through 
the conjunctival vessels and lacrimal drainage system) 
must be considered when there is a systemic medical con
-
traindication to the use of the drug. Ophthalmic solutions 
of the nonselective beta-blockers, eg, timolol, may worsen 
bradycardia, heart failure, or asthma. Phenylephrine eye 
drops may precipitate hypertensive crises and angina. Also 
to be considered are adverse interactions between sys
-
temically administered and ocular drugs. Using only 1 or 
2 drops at a time and a few minutes of nasolacrimal 
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Table 7–3.
 
Adverse ophthalmic effects of systemic drugs.
Drug
p
ossible Side E
ffects
Ophthalmic drugs
Carbonic anhydrase inhibitors (eg, 
 
acetazolamide, methazolamide)
Epidermal necrolysis, nearsightedness, angle-closure glaucoma due to ciliary body swelling
Respiratory drugs
Anticholinergic bronchodilators 
 
(eg, ipratropium)
Angle-closure glaucoma due to mydriasis, blurring of vision due to cycloplegia, dry eyes
Oxygen
Retinopathy of prematurity
Sympathomimetic bronchodilators 
 
(eg, salbutamol) and decongestants 
(eg, ephedrine)
Angle-closure glaucoma due to mydriasis
Cardiovascular system drugs
Amiodarone
Corneal deposits (vortex keratopathy), optic neuropathy, thyroid eye disease
Amlodipine
Chemosis (conjunctival edema)
Anticoagulants
Conjunctival, retinal and vitreous hemorrhage
Warfarin taken during pregnancy may cause fetal facial deformity with nasolacrimal duct 
obstruction, microphthalmos, cataract, optic atrophy
Chlorthalidone
Angle-closure glaucoma due to ciliary body swelling
Digitalis
Disturbance of color vision, photopsia
Furosemide
Phosphodiesterase type 5 inhibitors (eg, 
sildenafil, tadalafil, vardenafil)
Disturbance of color vision, ischemic optic neuropathy
Statins
Extraocular muscle palsy (myasthenic syndrome)
Thiazides (eg, indapamide)
Angle-closure glaucoma due to ciliary body swelling, nearsightedness, xanthopsia (yellow 
vision)
Gastrointestinal drugs
Anticholinergic agents
Urinary tract drugs
Alpha-2-antagonists (eg, alfuzosin, doxa
-
zosin, prazosin, tamsulosin, terazosin, 
silodosin)
Complications during (floppy iris syndrome) and after cataract surgery
Finasteride
Central nervous system drugs
Widening of palpebral fissure, blurring of vision due to mydriasis, elevated intraocular pressure
Anticholinergic agents including 
 
preoperative medications
Aripiprazole
Diazepam
Nystagmus
Haloperidol
Capsular cataract
Lithium carbonate
Proptosis, oculogyric crisis, nystagmus
Monoamine oxidase inhibitors
Nystagmus
Morphine
Miosis
Neostigmine
Nystagmus, miosis
Olanzapine
Phenothiazines (eg, chlorpromazine)
Pigmentary deposits in conjunctiva, cornea, lens, and retina, oculogyric crisis
Chlorpromazine causes complications during (floppy iris syndrome) and after cataract surgery
(
continued
)
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Table 7–3.
 
Drug
p
ffects
Phenytoin
Nystagmus
Quetiapine
Retigabine
Ocular pigmentation and retinopathy
Risperidone, paliperidone
Selective serotonin reuptake inhibitors 
(SSRIs) (eg, paroxetine, sertraline)
Angle-closure glaucoma, optic neuropathy
Serotonin and noradrenaline reuptake 
inhibitors (eg, venlafaxine)
Angle-closure glaucoma
Thioridazine
Corneal and lens deposits, retinopathy, oculogyric crisis
Topiramate
Angle-closure glaucoma due to ciliary body swelling, nearsightedness, macular folds, anterior 
uveitis
Tricyclic agents (eg, imipramine)
Angle-closure glaucoma due to mydriasis, blurring of vision due to cycloplegia
Triptans (sumatriptan, zolmitriptan)
Angle-closure glaucoma due to ciliary body swelling, nearsightedness
Vigabatrin
Visual field constriction
Zonisamide
Obstetric drugs
Sympathomimetic tocolytics
Hormonal agents
Aromatase inhibitors (eg, anastozole)
Dry eye, vitreo-retinal traction, retinal hemorrhages
Cabergoline
Female sex hormones
Retinal artery occlusion, retinal vein occlusion, papilledema, cranial nerve palsies, ischemic optic 
neuropathy
Tamoxifen
Crystalline retinal and corneal deposits, altered color perception, cataract, optic neuropathy
Alpha-interferon
Retinopathy, keratoconjunctivitis, dry eyes, optic neuropathy
Cataract (posterior subcapsular); susceptibility to viral (herpes simplex), bacterial, and fungal 
infections; steroid-induced glaucoma
Cyclosporine
Posterior reversible leukoencephalopathy
Fingolimod
Macular edema
Optic neuropathy, posterior reversible leukoencephalopathy
a
n
tibiotics
Chloramphenicol
Optic neuropathy
Clofazimine
Crystalline deposits (conjunctiva, cornea, iris)
Ethambutol
Fluoroquinolones
Diplopia, retinal detachment
Isoniazid
Linezolid
Rifabutin
Uveitis
Streptomycin
Optic neuropathy, epidermal necrolysis
Sulfonamides
Tetracycline, doxycycline, minocycline
a
n
tivirals
Cidofovir
Uveitis
a
n
timalarial agents
Chloroquine, hydroxychloroquine
Retinal degeneration principally involving the macula, keratopathy
(
continued
)
 
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Table 7–3.
 
Drug
p
ffects
Quinine
Retinal toxicity, pupillary abnormalities
a
mebicides
Iodochlorhydroxyquin
Chemotherapeutic agents
Bortezomib
Chalazia
Chlorambucil
Cisplatin
Docetaxel
Lacrimal (canalicular) obstruction
Fluorouracil
Vincristine
Chelating agents
Deferoxamine, deferasirox
Retinopathy, optic neuropathy, lens opacity
Penicillamine
Ocular pemphigoid, optic neuropathy, extraocular muscle palsy (myasthenic syndrome)
Oral hypoglycemic agents
Chlorpropamide
Refractive error, epidermal necrolysis, optic neuropathy
Thiazolidinediones (glitazones)
Increase in diabetic macular edema
Vitamins
Vitamin A
Vitamin D
Band-shaped keratopathy
a
n
tirheumatic agents
Allopurinol
Epidermal necrolysis
Retinal degeneration principally involving the macula, vortex keratopathy
Gold salts
Deposits in the cornea, conjunctiva, and lens
Nonsteroidal anti-inflammatory drugs 
(NSAIDs) (eg, ibuprofen, naproxen, 
indomethacin)
Vortex keratopathy (ibuprofen, naproxen), corneal deposits (indomethacin), retinal degeneration 
principally involving the macula (indomethacin)
Phenylbutazone
Retinal hemorrhages
Salicylates
Subconjunctival and retinal hemorrhages, nystagmus
Dermatologic agents
Retinoids (eg, isotretinoin, tretinoin, 
acitretin, and etretinate)
Papilledema, blepharoconjunctivitis, corneal opacities, decreased contact lens tolerance, 
decreased dark adaptation, teratogenic ocular abnormalities
Bisphosphonates
Alendronate, pamidronate
Scleritis, episcleritis, uveitis
occlusion or eyelid closure ensure maximum efficacy and 
decrease systemic side effects of topical agents.
ADVERSE OCULAR EFFECTS OF 
 
SYSTEMIC DRUGS
Systemically administered drugs produce a wide variety of 
adverse effects on the visual system. Table 7–3 lists the 
major examples. Repeated screening for toxic retinopathy 
is recommended in patients receiving long-term chloro
-
quine or hydroxychloroquine therapy.
Chatziralli IP et al. Risk factors for intraoperative floppy iris 
syndrome: a prospective study. Eye (Lond). 2016 Aug;
 
30(8):1039–44. [PMID: 27367744]
Ding HJ et al. Hydroxychloroquine-related retinal toxicity. 
Rheumatology (Oxford). 2016 Jun;55(6):957–67. [PMID: 
26428520]
Fraunfelder FW et al. Ocular & systemic side effects of drugs. In: 
Ophthalmology,
 19th ed. McGraw-Hill, 2018.
Raizman MB et al. Drug-induced corneal epithelial changes. 
Surv Ophthalmol. 2017 May–Jun;62(3):286–301. [PMID: 
27890620]
 
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º
DISEASES OF THE EAR
HEARING LOSS
 
»
Two main types of hearing loss: conductive and 
sensorineural.
 
»
Most commonly due to cerumen impaction, 
transient eustachian tube dysfunction from upper 
respiratory tract infection, or age-related hearing 
loss.
 
»
Classification & Epidemiology
Table 8–1 categorizes hearing loss as normal, mild, moder
-
ate, severe, and profound and outlines the vocal equivalent 
as well as the decibel range.
A. Conductive Hearing Loss
Conductive hearing loss results from external or middle 
ear dysfunction. Four mechanisms each result in impair
-
ment of the passage of sound vibrations to the inner ear: 
(1) obstruction (eg, cerumen impaction), (2) mass loading 
(eg, middle ear effusion), (3) stiffness (eg, otosclerosis), 
and (4) discontinuity (eg, ossicular disruption). Conduc
-
tive losses in adults are most commonly due to cerumen 
impaction or transient eustachian tube dysfunction from 
upper respiratory tract infection. Persistent conductive 
losses usually result from chronic ear infection, trauma, or 
otosclerosis. Conductive hearing loss is often correctable 
with medical or surgical therapy, or both.
B. Sensorineural Hearing Loss
Sensory and neural causes of hearing loss are difficult to 
differentiate due to testing methodology, thus often 
referred to as “sensorineural. ” Sensorineural hearing losses 
in adults are common.8
 
Joshua S. Schindler, MD 
Ear, Nose, & Throat 
Disorders
Sensory hearing loss results from deterioration of the 
cochlea, usually due to loss of hair cells from the organ of 
Corti. The most common form is a gradually progressive, 
predominantly high-frequency loss with advancing age 
(presbyacusis); other causes include excessive noise expo
-
sure, head trauma, and systemic diseases. Sensory hearing 
loss is usually not correctable with medical or surgical 
therapy but often may be prevented or stabilized. An excep
-
tion is a sudden sensory hearing loss, which may respond to 
corticosteroids if delivered within several weeks of onset.
Neural hearing loss lesions involve the eighth cranial 
nerve, auditory nuclei, ascending tracts, or auditory cortex. 
Neural hearing loss is much less commonly recognized. 
Causes include acoustic neuroma, multiple sclerosis, and 
auditory neuropathy.
Kaga K. Auditory nerve disease and auditory neuropathy spec
-
trum disorders. Auris Nasus Larynx. 2016 Feb;43(1):10–20. 
[PMID: 26209259]
Ouda L et al. Age-related changes in the central auditory system. 
Cell Tissue Res. 2015 Jul;361(1):337–58. [PMID: 25630878]
Roberts B et al. What can 35 years and over 700,000 measure
-
ments tell us about noise exposure in the mining industry? Int 
J Audiol. 2016 Nov 22:1–9. [PMID: 27871188]
Vaden KI Jr et al. Longitudinal changes in audiometric pheno
-
types of age-related hearing loss. J Assoc Res Otolaryngol. 
2017 Apr;18(2):371–5. [PMID: 27830350]
 
»
Evaluation of Hearing (Audiology)
In a quiet room, the hearing level may be estimated by 
having the patient repeat aloud words presented in a soft 
whisper, a normal spoken voice, or a shout. A 512-Hz tun
-
ing fork is useful in differentiating conductive from senso
-
rineural losses. In the 
Weber test,
 the tuning fork is placed 
on the forehead or front teeth. In conductive losses, the 
sound appears louder in the poorer-hearing ear, whereas 
in sensorineural losses it radiates to the better side. In the 
Rinne test,
 the tuning fork is placed alternately on the 
mastoid bone and in front of the ear canal. In conductive 
losses greater than 25 dB, bone conduction exceeds air 
conduction; in sensorineural losses, the opposite is true.
Formal audiometric studies are performed in a sound
-
proofed room. Pure-tone thresholds in decibels (dB) are 
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CMDT 2019
Table 8–1.
 
Hearing loss classification.
Vocal Equivalent
Decibel (dB) 
Range
Normal
Soft whisper
0–20 dB
Mild
Soft spoken voice
20–40 dB
Moderate
Normal spoken voice
40–60 dB
Severe
Loud spoken voice
60–80 dB
Profound
Shout
> 80 dB
obtained over the range of 250–8000 Hz for both air and 
bone conduction. Conductive losses create a gap between 
the air and bone thresholds, whereas in sensorineural 
losses, both air and bone thresholds are equally dimin
-
ished. Speech discrimination measures the clarity of hear
-
ing, reported as percentage correct (90–100% is normal). 
Auditory brainstem-evoked responses may determine 
whether the lesion is sensory (cochlea) or neural (central). 
However, MRI scanning is more sensitive and specific in 
detecting central lesions.
Every patient who complains of a hearing loss should be 
referred for audiologic evaluation unless the cause is easily 
remediable (eg, cerumen impaction, otitis media). Imme
-
diate audiometric referral is indicated for patients with 
idiopathic sudden sensorineural hearing loss because it 
requires treatment (corticosteroids) within a limited sev
-
eral-week time period. Routine audiologic screening is 
recommended for adults with prior exposure to potentially 
injurious noise levels of noise or in adults at age 65, and 
every few years thereafter.
Musiek FE et al. Perspectives on the pure-tone audiogram. J Am 
Acad Audiol. 2017 Jul/Aug;28(7):655–71. [PMID: 28722648]
Phan NT et al. Diagnosis and management of hearing loss in 
elderly patients. Aust Fam Physician. 2016 Jun;45(6):366–9. 
[PMID: 27622223]
 
»
Hearing Amplification
Patients with hearing loss not correctable by medical ther
-
apy may benefit from hearing amplification. Contempo
-
rary hearing aids are comparatively free of distortion and 
have been miniaturized to the point where they often may 
be contained entirely within the ear canal or lie inconspicu
-
ously behind the ear.
For patients with conductive loss or unilateral pro
-
found sensorineural loss, bone-conducting hearing aids 
directly stimulate the ipsilateral cochlea (for conductive 
losses) or contralateral ear (profound unilateral sensori
-
neural loss).
In most adults with severe to profound sensory hearing 
loss, the cochlear implant—an electronic device that is sur
-
gically implanted into the cochlea to stimulate the auditory 
nerve—offers socially beneficial auditory rehabilitation.
Barker F et al. Interventions to improve hearing aid use in adult 
auditory rehabilitation. Cochrane Database Syst Rev. 2016 
Aug 18;(8):CD010342. [PMID: 27537242]
McRackan TR et al. Meta-analysis of quality-of-life improve
-
ment after cochlear implantation and associations with 
speech recognition abilities. Laryngoscope. 2018 Apr;128(4):
 
982–990. [PMID: 28731538]
Michaud HN et al. Aural rehabilitation for older adults with 
hearing loss: impacts on quality of life—a systematic review of 
randomized controlled trials. J Am Acad Audiol. 2017 Jul/Aug;
 
28(7):596–609. [PMID: 28722643]
DISEASES OF THE AURICLE
Disorders of the auricle include skin cancers due to sun 
exposure. Traumatic auricular hematoma must be drained 
to prevent significant cosmetic deformity (cauliflower ear) 
or canal blockage resulting from dissolution of supporting 
cartilage. Similarly, cellulitis of the auricle must be treated 
promptly to prevent perichondritis and resultant defor
-
mity. Relapsing polychondritis is characterized by recur
-
rent, frequently bilateral, painful episodes of auricular 
erythema and edema and sometimes progressive involve
-
ment of the cartilaginous tracheobronchial tree. Treatment 
with corticosteroids may help forestall cartilage dissolu
-
tion. Polychondritis and perichondritis may be differenti
-
ated from cellulitis by sparing of involvement of the lobule, 
which does not contain cartilage.
Shakeel M et al. Open surgical management of auricular haema
-

-
-
toma: incision, evacuation and mattress sutures. J Laryngol 
Otol. 2015 May;129(5):496–501. [PMID: 25994384]
DISEASES OF THE EAR CANAL
1. Cerumen Impaction
Cerumen is a protective secretion produced by the outer por
-
tion of the ear canal. In most persons, the ear canal is self-
cleansing. Recommended hygiene consists of cleaning the 
external opening only with a washcloth over the index finger. 
Cerumen impaction is most often self-induced through ill-
advised cleansing attempts by entering the canal itself. It may 
be relieved by the patient using detergent ear drops (eg, 3% 
hydrogen peroxide; 6.5% carbamide peroxide) and irrigation, 
or by the clinician using mechanical removal, suction, or 
irrigation. Irrigation is performed with water at body tem
-
perature to avoid a vestibular caloric response. The stream 
should be directed at the posterior ear canal wall adjacent to 
the cerumen plug. Irrigation should be performed only when 
the tympanic membrane is known to be intact.
Use of jet irrigators (eg, WaterPik) should be avoided 
since they may result in tympanic membrane perforations. 
Following irrigation, the ear canal should be thoroughly 
dried (eg, by the patient using a hair blow-dryer on low-
power setting or by the clinician instilling isopropyl alcohol) 
to reduce the likelihood of external otitis. Specialty referral 
is indicated if impaction is frequently recurrent, if it has 
not responded to routine measures, or if there is tympanic 
membrane perforation or chronic otitis media.
Schwartz SR et al. Clinical Practice Guideline (Update): Earwax 
(cerumen impaction). Otolaryngol Head Neck Surg. 2017 Jan;
 
156(1 Suppl):S1–29. [PMID: 28045591]
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2. Foreign Bodies
Foreign bodies in the ear canal are more frequent in chil
-
dren than in adults. Firm materials may be removed with a 
loop or a hook, taking care not to displace the object medi
-
ally toward the tympanic membrane; microscopic guid
-
ance is helpful. Aqueous irrigation should not be performed 
for organic foreign bodies (eg, beans, insects), because 
water may cause them to swell. Living insects are best 
immobilized before removal by filling the ear canal with 
lidocaine.
Friedman EM. Videos in clinical medicine. Removal of foreign 
bodies from the ear and nose. N Engl J Med. 2016 Feb 18;
 
374(7):e7. [PMID: 26886547]
Shunyu NB et al. Ear, nose and throat foreign bodies removed 
under general anaesthesia: a retrospective study. J Clin Diagn 
Res. 2017 Feb;11(2):MC01–4. [PMID: 28384894]
3. External Otitis
 
»
Painful erythema and edema of the ear canal skin.
 
»
Purulent exudate.
 
»
In diabetic or immunocompromised patients, 
osteomyelitis of the skull base (“malignant exter
-
nal otitis”) may occur.
 
»
External otitis presents with otalgia, frequently accompa
-
nied by pruritus and purulent discharge. There is often a 
history of recent water exposure (ie, swimmer’s ear) or 
mechanical trauma (eg, scratching, cotton applicators). 
External otitis is usually caused by gram-negative rods (eg, 
Pseudomonas, Proteus
) or fungi (eg, 
Aspergillus
), which 
grow in the presence of excessive moisture. In diabetic or 
immunocompromised patients, persistent external otitis 
may evolve into osteomyelitis of the skull base (so-called, 
malignant external otitis). Usually caused by 
aeruginosa
, osteomyelitis begins in the floor of the ear 
canal and may extend into the middle fossa floor, the cli
-
vus, and even the contralateral skull base.
 
»
Examination reveals erythema and edema of the ear canal 
skin, often with a purulent exudate (Figure 8–1). Manipu
-
lation of the auricle elicits pain. Because the lateral surface 
of the tympanic membrane is ear canal skin, it is often 
erythematous. However, in contrast to acute otitis media, it 
moves normally with pneumatic otoscopy. When the canal 
skin is very edematous, it may be impossible to visualize 
the tympanic membrane. Malignant external otitis typi
-
cally presents with persistent foul aural discharge, granula
-
tions in the ear canal, deep otalgia, and in advanced cases, 
progressive palsies of cranial nerves VI, VII, IX, X, XI, or 
XII. Diagnosis is confirmed by the demonstration of osse
-
ous erosion on CT scanning.
 
»
Treatment
Treatment of external otitis involves protection of the ear 
from additional moisture and avoidance of further 
mechanical injury by scratching. In cases of moisture in 
the ear (eg, swimmer’s ear), acidification with a drying 
agent (ie, a 50/50 mixture of isopropyl alcohol/white vin
-
egar) is often helpful. When infected, an otic antibiotic 
solution or suspension of an aminoglycoside (eg, neomy
-
cin/polymyxin B) or fluoroquinolone (eg, ciprofloxacin), 
with or without a corticosteroid (eg, hydrocortisone), is 
usually effective. Purulent debris filling the ear canal 
should be gently removed to permit entry of the topical 
medication. Drops should be used abundantly (five or 
more drops three or four times a day) to penetrate the 
depths of the canal. When substantial edema of the canal 
wall prevents entry of drops into the ear canal, a wick is 
placed to facilitate their entry. In recalcitrant cases—
particularly when cellulitis of the periauricular tissue has 
developed—oral fluoroquinolones (eg, ciprofloxacin, 
500 mg twice daily for 1 week) are used because of their 
effectiveness against 
. Any case of persistent 
 
▲
Figure 8–1.
 
Malignant external otitis in a 40-year-
old woman with diabetes mellitus, with typical swelling 
and honey-colored crusting of the pinna. Both the

▲
 
and honey-colored crusting of the pinna. Both the 
external auditory canal and temporal bone were 
involved in the pseudomonal infection. 
 
permission, from E.J. Mayeaux Jr, MD in Usatine RP , 
 
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CMDT 2019
otitis externa in an immunocompromised or diabetic indi
-
vidual must be referred for specialty evaluation.
Treatment of “malignant external otitis” requires pro
-
longed antipseudomonal antibiotic administration, often 
for several months. Although intravenous therapy is often 
required initially (eg, ciprofloxacin 200–400 mg every 
12 hours), selected patients may be graduated to oral cip
-
rofloxacin (500–1000 mg twice daily). To avoid relapse, 
antibiotic therapy should be continued, even in the asymp
-
tomatic patient, until gallium scanning indicates marked 
reduction or resolution of the inflammation. Surgical 
debridement of infected bone is reserved for cases of dete
-
rioration despite medical therapy.
Bola S et al. Optimising the use of otowicks in otitis externa. 
J Laryngol Otol. 2017 Sep;131(9):809–12. [PMID: 28693628]
Chawdhary G et al. Current management of necrotising otitis 
externa in the UK: survey of 221 UK otolaryngologists. Acta 
Otolaryngol. 2017 Aug;137(8):818–22. [PMID: 28301961]
Rosenfeld RM et al. Clinical practice guideline: acute otitis 
externa. Otolaryngol Head Neck Surg. 2014 Feb;150(1 Suppl):
 
S1–24. Erratum in: Otolaryngol Head Neck Surg. 2014 Mar;
 
150(3):504. [PMID: 24491310]
4. 
p
ruritus
Pruritus of the external auditory canal, particularly at the 
meatus, is common. While it may be associated with exter
-
nal otitis or with seborrheic dermatitis or psoriasis, most 
cases are self-induced from excoriation or overly zealous 
ear cleaning. To permit regeneration of the protective ceru
-
men blanket, patients should be instructed to avoid use of 
soap and water or cotton swabs in the ear canal and avoid 
any scratching. Patients with excessively dry canal skin 
may benefit from application of mineral oil, which helps 
counteract dryness and repel moisture. When an inflam
-
matory component is present, topical application of a cor
-
ticosteroid (eg, 0.1% triamcinolone) may be beneficial.
Babakurban ST et al. Therapeutic effect of Castellani’s paint in 
patients with an itchy ear canal. J Laryngol Otol. 2016 Oct;
 
130(10):934–8. [PMID: 27774921]
5. Exostoses & Osteomas
Bony overgrowths of the ear canal are a frequent incidental 
finding and occasionally have clinical significance. Clini
-
cally, they present as skin-covered bony mounds in the 
medial ear canal obscuring the tympanic membrane to a 
variable degree. Solitary osteomas are of no significance as 
long as they do not cause obstruction or infection. Multiple 
exostoses, which are generally acquired from repeated 
exposure to cold water (eg, “surfer’s ear”), may progress 
and require surgical removal.
Grinblat G et al. Outcomes of drill canalplasty in exostoses and 
osteoma: analysis of 256 cases and literature review. Otol 
Neurotol. 2016 Dec;37(10):1565–72. [PMID: 27755370]
Morris S et al. Awareness and attitudes towards external auditory 
canal exostosis and its preventability in surfers in the UK: 
cross-sectional study. J Laryngol Otol. 2016 Jul;130(7):628–34. 
[PMID: 2726234]
6. Neoplasia
The most common neoplasm of the ear canal is squamous 
cell carcinoma. When an apparent otitis externa does not 
resolve on therapy, a malignancy should be suspected and 
biopsy performed. This disease carries a very high 5-year 
mortality rate because the tumor tends to invade the lym
-
phatics of the cranial base and must be treated with wide 
surgical resection and radiation therapy. Adenomatous 
tumors, originating from the ceruminous glands, generally 
follow a more indolent course.
Beyea JA et al. Squamous cell carcinoma of the temporal bone. 
Otolaryngol Clin North Am. 2015 Apr;48(2):281–92. [PMID: 
25769352]
Mazzoni A et al. En bloc temporal bone resections in 
squamous cell carcinoma of the ear. Technique, principles, 
and limits. Acta Otolaryngol. 2016;136(5):425–32. [PMID: 
26824405]
Wang Z et al. The contribution of CT and MRI in staging, treat
-

26824405]
-
ment planning and prognosis prediction of malignant tumors 
of external auditory canal. Clin Imaging. 2016 Nov–Dec;
 
40(6):1262–8. [PMID: 27639864]
DISEASES OF THE EUSTACHIAN TUBE
1. Eustachian Tube Dysfunction
 
»
Aural fullness.
 
»
Fluctuating hearing.
 
»
Discomfort with barometric pressure change.
 
»
At risk for serous otitis media.
The tube that connects the middle ear to the nasopharynx—
the eustachian tube—provides ventilation and drainage 
for the middle ear cleft. It is normally closed, opening only 
during swallowing or yawning. When eustachian tube 
function is compromised, air trapped within the middle 
ear becomes absorbed and negative pressure results. 
The most common causes of eustachian tube dysfunc
-
tion are diseases associated with edema of the tubal 
lining, such as viral upper respiratory tract infections 
and allergy. The patient usually reports a sense of full
-
ness in the ear and mild to moderate impairment of 
hearing. When the tube is only partially blocked, swal
-
lowing or yawning may elicit a popping or crackling 
sound. Examination may reveal retraction of the tym
-
panic membrane and decreased mobility on pneumatic 
otoscopy. Following a viral illness, this disorder is usually 
transient, lasting days to weeks. Treatment with systemic 
and intranasal decongestants (eg, pseudoephedrine, 60 mg 
orally every 4–6 hours; oxymetazoline, 0.05% spray every 
8–12 hours) combined with autoinflation by forced exhala
-
tion against closed nostrils may hasten relief. Autoinflation 
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should not be recommended to patients with active intra
-
nasal infection, since this maneuver may precipitate mid
-
dle ear infection. Allergic patients may also benefit from 
intranasal corticosteroids (eg, beclomethasone dipropio
-
nate, two sprays in each nostril twice daily for 2–6 weeks). 
Air travel, rapid altitudinal change, and underwater diving 
should be avoided until resolution.
Conversely, an overly patent eustachian tube (“patu
-
lous eustachian tube”) is a relatively uncommon, though 
quite distressing problem. Typical complaints include full
-
ness in the ear and autophony, an exaggerated ability to 
hear oneself breathe and speak. A patulous eustachian 
tube may develop during rapid weight loss, or it may be 
idiopathic. In contrast to eustachian tube dysfunction, the 
aural pressure is often made worse by exertion and may 
diminish during an upper respiratory tract infection. 
Although physical examination is usually normal, respira
-
tory excursions of the tympanic membrane may occasion
-
ally be detected during vigorous breathing. Treatment 
includes avoidance of decongestant products, insertion of 
a ventilating tube to reduce the outward stretch of the 
eardrum during phonation and, rarely, surgery on the 
eustachian tube itself.
Huisman JML et al. Treatment of eustachian tube dysfunction 
with balloon dilation: a systematic review. Laryngoscope. 
2018 Jan;128(1):237–47. [PMID: 28799657]
Ward BK et al. Patulous eustachian tube dysfunction: patient 
demographics and comorbidities. Otol Neurotol. 2017 Oct;
 
38(9):1362–9. [PMID: 28796094]
2. Serous Otitis Media
 
»
Eustachian tube remains blocked for a prolonged 
period.
 
»
Resultant negative pressure results in transuda
-
tion of fluid.
Prolonged eustachian tube dysfunction with resultant 
negative middle ear pressure may cause a transudation of 
fluid. In adults, serous otitis media usually occurs with an 
upper respiratory tract infection, with barotrauma, or with 
chronic allergic rhinitis, but when persistent and unilateral, 
nasopharyngeal carcinoma must be excluded. The tym
-
panic membrane is dull and hypomobile, occasionally 
accompanied by air bubbles in the middle ear and conduc
-
tive hearing loss. The treatment of serous otitis media is 
similar to that for eustachian tube dysfunction. When 
medication fails to bring relief after several months, a ven
-
tilating tube placed through the tympanic membrane may 
restore hearing and alleviate the sense of aural fullness. 
Endoscopically guided laser expansion of the nasopharyn
-
geal orifice of the eustachian tube or balloon dilation may 
improve function in recalcitrant cases.
Roditi RE et al. Otitis media with effusion: our national practice. 
Otolaryngol Head Neck Surg. 2017 Aug;157(2):171–2. 
[PMID: 28535139]
Schilder AG et al. Otitis media. Nat Rev Dis Primers. 2016 
Sep 8;2:16063. [PMID: 27604644]
3. Barotrauma
Persons with poor eustachian tube function (eg, congeni
-
tal narrowness or acquired mucosal edema) may be unable 
to equalize the barometric stress exerted on the middle ear 
by air travel, rapid altitudinal change, or underwater div
-
ing. The problem is generally most acute during airplane 
descent, since the negative middle ear pressure tends to 
collapse and block the eustachian tube, causing pain. Sev
-
eral measures are useful to enhance eustachian tube func
-
tion and avoid otic barotrauma. The patient should be 
advised to swallow, yawn, and autoinflate frequently dur
-
ing descent. Oral decongestants (eg, pseudoephedrine, 
60–120 mg) should be taken several hours before antici
-
pated arrival time so that they will be maximally effective 
during descent. Topical decongestants such as 1% phenyl
-
ephrine nasal spray should be administered 1 hour before 
arrival.
For acute negative middle ear pressure that persists on 
the ground, treatment includes decongestants and attempts

-
arrival.
the ground, treatment includes decongestants and attempts 
at autoinflation. Myringotomy (creation of a small ear
-
drum perforation) provides immediate relief and is appro
-
priate in the setting of severe otalgia and hearing loss. 
Repeated episodes of barotrauma in persons who must fly 
frequently may be alleviated by insertion of ventilating 
tubes.
Underwater diving may represent an even greater 
barometric stress to the ear than flying. Patients should be 
warned to avoid diving when they have an upper respira
-
tory infection or episode of nasal allergy. During the 
descent phase of the dive, if inflation of the middle ear via 
the eustachian tube has not occurred, pain will develop 
within the first 15 feet; the dive must be aborted. In all 
cases, divers must descend slowly and equilibrate in 
stages to avoid the development of severely negative pres
-
sures in the tympanum that may result in hemorrhage 
(hemotympanum) or in perilymphatic fistula. In the latter, 
the oval or round window ruptures, resulting in sensory 
hearing loss and acute vertigo. During the ascent phase of 
a saturation dive, sensory hearing loss or vertigo may 
develop as the first (or only) symptom of decompression 
sickness. Immediate recompression will return intravascu
-
lar gas bubbles to solution and restore the inner ear 
microcirculation.
Tympanic membrane perforation is an absolute contra
-
indication to diving, as the patient will experience an 
unbalanced thermal stimulus to the semicircular canals 
and may experience vertigo, disorientation, and even 
emesis.
Jansen S et al. Prevalence of barotrauma in recreational 
scuba divers after repetitive saltwater dives. Otol Neurotol. 
2016 Oct;37(9):1325–31. [PMID: 27636390]
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DISEASES OF THE MIDDLE EAR
1. Acute Otitis Media
 
»
Otalgia, often with an upper respiratory tract 
 
»
Erythema and hypomobility of tympanic membrane.
 
»
Acute otitis media is a bacterial infection of the mucosally 
lined air-containing spaces of the temporal bone. Purulent 
material forms not only within the middle ear cleft but also 
within the pneumatized mastoid air cells and petrous apex. 
Acute otitis media is usually precipitated by a viral upper 
respiratory tract infection that causes eustachian tube 
obstruction. This results in accumulation of fluid and 
mucus, which becomes secondarily infected by bacteria. The 
most common pathogens are 
Streptococcus pneumoniae, 
Haemophilus influenzae,
 and 
Streptococcus pyogenes.
 
»
Acute otitis media may occur at any age. Presenting symp
-
toms and signs include otalgia, aural pressure, decreased 
hearing, and often fever. The typical physical findings are 
erythema and decreased mobility of the tympanic mem
-
brane (Figure 8–2). Occasionally, bullae will appear on the 
tympanic membrane.
Rarely, when middle ear empyema is severe, the tym
-
panic membrane bulges outward. In such cases, tympanic 
membrane rupture is imminent. Rupture is accompanied 
by a sudden decrease in pain, followed by the onset of otor
-
rhea. With appropriate therapy, spontaneous healing of the 
tympanic membrane occurs in most cases. When perfora
-
tion persists, chronic otitis media may develop. Mastoid 
tenderness often accompanies acute otitis media and is due 
to the presence of pus within the mastoid air cells. This 
alone does not indicate suppurative (surgical) mastoiditis. 
Frank swelling over the mastoid bone or the association of 
cranial neuropathies or central findings indicates severe 
disease requiring urgent care.
 
»
Treatment
The treatment of acute otitis media is specific antibiotic 
therapy, often combined with nasal decongestants. The 
first-choice oral antibiotic treatment is amoxicillin (80–90 
mg/kg/day divided twice daily) (
or
 erythromycin [50 mg/
kg/day]) plus sulfonamide (150 mg/kg/day) for 10 days. 
Alternatives useful in resistant cases are cefaclor (20–40 
mg/kg/day) or amoxicillin-clavulanate (20–40 mg/kg/day).
Tympanocentesis for bacterial (aerobic and anaerobic) 
and fungal culture may be performed by any experienced 
physician. A 20-gauge spinal needle bent 90 degrees to the 
hub attached to a 3-mL syringe is inserted through the 
inferior portion of the tympanic membrane. Interposition 
of a pliable connecting tube between the needle and 
syringe permits an assistant to aspirate without inducing 
movement of the needle. Tympanocentesis is useful for 
otitis media in immunocompromised patients and when 
infection persists or recurs despite multiple courses of 
Surgical drainage of the middle ear (myringotomy) is 
reserved for patients with severe otalgia or when complica
-
tions of otitis (eg, mastoiditis, meningitis) have occurred.
Recurrent acute otitis media may be managed with 
long-term antibiotic prophylaxis. Single daily oral doses of 
sulfamethoxazole (500 mg) or amoxicillin (250 or 500 mg) 
are given over a period of 1–3 months. Failure of this regi
-
men to control infection is an indication for insertion of 
ventilating tubes.
Laulajainen Hongisto A et al. Severe acute otitis media and acute 
mastoiditis in adults. J Int Adv Otol. 2016 Dec;12(3):224–30. 
[PMID: 27895000]
Schilder AG et al. Panel 7: Otitis media: treatment and compli
-
cations. Otolaryngol Head Neck Surg. 2017 Apr;156(4 Suppl):
 
S88–105. [PMID: 28372534]
2. Chronic Otitis Media
 
»
Chronic otorrhea with or without otalgia.
 
»
Tympanic membrane perforation with conductive 
hearing loss.
 
»
Often amenable to surgical correction.
 
▲
Figure 8–2.
 
Acute otitis media with effusion of right

»
 
»
 
▲
 
Acute otitis media with effusion of right 
ear, with multiple air-fluid levels visible through a translu
-
cent, slightly retracted, nonerythematous tympanic mem
-
brane. 
(Used, with permission, from Frank Miller, MD in 
The Color 
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»
Chronic infection of the middle ear and mastoid generally 
develops as a consequence of recurrent acute otitis media, 
although it may follow other diseases and trauma. Perfora
-
tion of the tympanic membrane is usually present. The 
bacteriology of chronic otitis media differs from that of 
acute otitis media. Common organisms include 
P aeruginosa, 
Proteus
 species, 
Staphylococcus aureus,
 and mixed anaerobic 
 
»
The clinical hallmark of chronic otitis media is purulent 
aural discharge. Drainage may be continuous or intermit
-
tent, with increased severity during upper respiratory tract 
infection or following water exposure. Pain is uncommon 
except during acute exacerbations. Conductive hearing loss 
results from destruction of the tympanic membrane or 
ossicular chain, or both.
 
»
Treatment
The medical treatment of chronic otitis media includes 
regular removal of infected debris, use of earplugs to pro
-
tect against water exposure, and topical antibiotic drops 
(ofloxacin 0.3% or ciprofloxacin with dexamethasone) for 
exacerbations. Oral ciprofloxacin, active against 
Pseudo
-
monas
, 500 mg twice a day for 1–6 weeks may help dry a 
chronically discharging ear.
Definitive management is surgical in most cases. Suc
-
cessful reconstruction of the tympanic membrane may be 
achieved in about 90% of cases, often with elimination of 
infection and significant improvement in hearing. When 
the mastoid air cells are involved by irreversible infection, 
they should be exenterated at the same time through a 
mastoidectomy.
Harris AS et al. Why are ototopical aminoglycosides still first-
line therapy for chronic suppurative otitis media? A system
-
atic review and discussion of aminoglycosides versus 
quinolones. J Laryngol Otol. 2016 Jan;130(1):2–7. [PMID: 
26584651]
 
»
Complications of Otitis Media
A. Cholesteatoma
Cholesteatoma is a special variety of chronic otitis media 
(Figure 8–3). The most common cause is prolonged eusta
-
chian tube dysfunction, with inward migration of the 
upper flaccid portion of the tympanic membrane. This 
creates a squamous epithelium-lined sac, which—when its 
neck becomes obstructed—may fill with desquamated 
keratin and become chronically infected. Cholesteatomas 
typically erode bone, with early penetration of the mastoid 
and destruction of the ossicular chain. Over time they may 
erode into the inner ear, involve the facial nerve, and on 
rare occasions spread intracranially. Otoscopic examina
-
tion may reveal an epitympanic retraction pocket or a 
marginal tympanic membrane perforation that exudes 
keratin debris, or granulation tissue. The treatment of cho
-
lesteatoma is surgical marsupialization of the sac or its 
complete removal. This may require the creation of a “mas
-
toid bowl” in which the ear canal and mastoid are joined 
into a large common cavity that must be periodically 
cleaned.
Jackler RK et al. A new theory on the pathogenesis of acquired 
cholesteatoma: mucosal traction. Laryngoscope. 2015 Aug;
 
125(Suppl 4):S1–14. [PMID: 26013635]
Rutkowska J et al. Cholesteatoma definition and classification: a 
literature review. J Int Adv Otol. 2017 Aug;13(2):266–71. 
[PMID: 28274903]
B. Mastoiditis
Acute suppurative mastoiditis usually evolves following 
several weeks of inadequately treated acute otitis media. It 
is characterized by postauricular pain and erythema 
accompanied by a spiking fever. CT scan reveals coales
-
cence of the mastoid air cells due to destruction of their 
bony septa. Initial treatment consists of intravenous antibi
-
otics (eg, cefazolin 0.5–1.5 g every 6–8 hours) directed against 
the most common offending organisms (
S pneumoniae, 
H influenzae,
 and 
S pyogenes),
 and myringotomy for culture 
and drainage. Failure of medical therapy indicates the need

 and 
and drainage. Failure of medical therapy indicates the need 
for surgical drainage (mastoidectomy).
C. Petrous Apicitis
The medial portion of the petrous bone between the inner 
ear and clivus may become a site of persistent infection 
when the drainage of its pneumatic cell tracts becomes 
blocked. This may cause foul discharge, deep ear 
 
▲
Figure 8–3.
 
Cholesteatoma. 
(From Vladimir Zlinsky, 
MD, in Roy F. Sullivan, PhD: Audiology Forum: Video Otos
-
copy, www.RCSullivan.com; used with permission from 
Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger 
J. 
The Color Atlas of Family Medicine.
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and retro-orbital pain, and sixth nerve palsy (Gradenigo 
syndrome); meningitis may be a complication. Treatment 
is with prolonged antibiotic therapy (based on culture 
results) and surgical drainage via petrous apicectomy.
Gadre AK et al. The changing face of petrous apicitis-a 40-year 
experience. Laryngoscope. 2018 Jan;128(1):195–201. [PMID: 
28378370]
Vitale M et al. Gradenigo’s syndrome: a common infection with 
uncommon consequences. Am J Emerg Med. 2017 Sep;
 
35(9):1388.e1–2. [PMID: 28720403]
D. Facial Paralysis
Facial palsy may be associated with either acute or chronic 
otitis media. In the acute setting, it results from inflamma
-
tion of the seventh nerve in its middle ear segment. Treat
-
ment consists of myringotomy for drainage and culture, 
followed by intravenous antibiotics (based on culture 
results). The use of corticosteroids is controversial. The 
prognosis is excellent, with complete recovery in most cases.
Facial palsy associated with chronic otitis media usually 
evolves slowly due to chronic pressure on the seventh nerve 
in the middle ear or mastoid by cholesteatoma. Treatment 
requires surgical correction of the underlying disease. The 
prognosis is less favorable than for facial palsy associated 
with acute otitis media.
Prasad S et al. Facial nerve paralysis in acute suppurative otitis 
media—management. Indian J Otolaryngol Head Neck Surg. 
2017 Mar;69(1):58–61. [PMID: 28239580]
E. Sigmoid Sinus Thrombosis
Trapped infection within the mastoid air cells adjacent to 
the sigmoid sinus may cause septic thrombophlebitis. This 
is heralded by signs of systemic sepsis (spiking fevers, 
chills), at times accompanied by signs of increased intra
-
cranial pressure (headache, lethargy, nausea and vomiting, 
papilledema). Diagnosis can be made noninvasively by 
magnetic resonance venography (MRV). Primary treat
-
ment is with intravenous antibiotics (based on culture 
results). Surgical drainage with ligation of the internal 
jugular vein may be indicated when embolization is 
Sharma KM et al. Cerebral venous sinus thrombophlebitis as a 
complication of acute otitis media. J Emerg Med. 2015 Jan;
 
48(1):e9–13. [PMID: 25440866]
F. Central Nervous System Infection
Otogenic meningitis is by far the most common intracra
-
nial complication of ear infection. In the setting of acute 
suppurative otitis media, it arises from hematogenous 
spread of bacteria, most commonly 
 and 
 
S pneumoniae.
 In chronic otitis media, it results either from 
passage of infection along preformed pathways, such as the 
petrosquamous suture line, or from direct extension of dis
-
ease through the dural plates of the petrous pyramid.
Epidural abscesses arise from direct extension of dis
-
ease in the setting of chronic infection. They are usually 
asymptomatic but may present with deep local pain, head
-
ache, and low-grade fever. They are often discovered as an 
incidental finding at surgery. Brain abscess may arise in the 
temporal lobe or cerebellum as a result of septic thrombo
-
phlebitis adjacent to an epidural abscess. The predominant 
causative organisms are 
S aureus, S pyogenes
, and 
S pneu
-
moniae.
 Rupture into the subarachnoid space results in 
meningitis and often death. (See Chapter 30.)
Laulajainen Hongisto A et al. Otogenic intracranial abscesses, 
our experience over the last four decades. J Int Adv Otol. 
2017 Apr;13(1):40–6. [PMID: 28084999]
3. Otosclerosis
Otosclerosis is a progressive disease with a marked familial 
tendency that affects the bony otic capsule. Lesions involv
-
ing the footplate of the stapes result in increased imped
-
ance to the passage of sound through the ossicular chain, 
producing conductive hearing loss. This may be treated 
either through the use of a hearing aid or surgical replace
-
ment of the stapes with a prosthesis (stapedectomy). When 
otosclerotic lesions impinge on the cochlea (“cochlear oto
-

-
-
sclerosis”), permanent sensory hearing loss occurs.
Ishai R et al. Long-term incidence and degree of sensorineural 
hearing loss in otosclerosis. Otol Neurotol. 2016 Dec;
 
37(10):1489–96. [PMID: 27755362]
Rudic M et al. The pathophysiology of otosclerosis: review of 
current research. Hear Res. 2015 Dec;330(Pt A):51–6. [PMID: 
26276418]
4. Trauma to the Middle Ear
Tympanic membrane perforation may result from impact 
injury or explosive acoustic trauma (Figure 8–4). Sponta
-
neous healing occurs in most cases. Persistent perforation 
may result from secondary infection brought on by expo
-
sure to water. Patients should be advised to wear earplugs 
 
▲
Figure 8–4.
 
Traumatic perforation of the left tym
-
panic membrane. 
(Used, with permission, from William 
Clark, MD in Usatine RP , Smith MA, Mayeaux EJ Jr, 
 
. 
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while swimming or bathing during the healing period. 
Hemorrhage behind an intact tympanic membrane (hemo
-
tympanum) may follow blunt trauma or extreme baro
-
trauma. Spontaneous resolution over several weeks is the 
usual course. When a conductive hearing loss greater than 
30 dB persists for more than 3 months following trauma, 
disruption of the ossicular chain should be suspected. 
Middle ear exploration with reconstruction of the ossicular 
chain, combined with repair of the tympanic membrane 
when required, will usually restore hearing.
Delrue S et al. Surgical management and hearing outcome of 
traumatic ossicular injuries. J Int Adv Otol. 2016 Dec;
 
12(3):231–36. [PMID: 8031153]
5. Middle Ear Neoplasia
Primary middle ear tumors are rare. Glomus tumors arise 
either in the middle ear (glomus tympanicum) or in the 
jugular bulb with upward erosion into the hypotympanum 
(glomus jugulare). They present clinically with pulsatile 
tinnitus and hearing loss. A vascular mass may be visible 
behind an intact tympanic membrane. Large glomus jugu
-
lare tumors are often associated with multiple cranial neu
-
ropathies, especially involving nerves VII, IX, X, XI, and 
XII. Treatment usually requires surgery, radiotherapy, or 
both. Pulsatile tinnitus thus warrants magnetic resonance 
angiography (MRA) and MRV to rule out a vascular mass.
Pelosi S et al. Adenomatous tumors of the middle ear. Otolar
-
yngol Clin North Am. 2015 Apr;48(2):305–15. [PMID: 
25769353]
Sweeney AD et al. Glomus tympanicum tumors. Otolaryngol 
Clin North Am. 2015 Apr;48(2):293–304. [PMID: 25659513]
EARACHE
Earache can be caused by a variety of otologic problems, 
but external otitis and acute otitis media are the most com
-
mon. Differentiation of the two should be apparent by 
pneumatic otoscopy. Pain out of proportion to the physical 
findings may be due to herpes zoster oticus, especially 
when vesicles appear in the ear canal or concha. Persistent 
pain and discharge from the ear suggest osteomyelitis of 
the skull base or cancer, and patients with these complaints 
should be referred for specialty evaluation.
Nonotologic causes of otalgia are numerous. The sen
-
sory innervation of the ear is derived from the trigemi
-
nal, facial, glossopharyngeal, vagal, and upper cervical 
nerves. Because of this rich innervation, referred otalgia 
is quite frequent. Temporomandibular joint dysfunction 
is a common cause of referred ear pain. Pain is exacer
-
bated by chewing or psychogenic grinding of the teeth 
(bruxism) and may be associated with dental malocclu
-
sion. Repeated episodes of severe lancinating otalgia may 
occur in glossopharyngeal neuralgia. Infections and 
neoplasia that involve the oropharynx, hypopharynx, 
and larynx frequently cause otalgia. Persistent earache 
demands specialty referral to exclude cancer of the upper 
aerodigestive tract.
Harrison E et al. Otalgia. Aust Fam Physician. 2016 Jul;
 
45(7):493–7. [PMID: 27610432]
DISEASES OF THE INNER EAR
1. Sensory Hearing Loss
Diseases of the cochlea result in sensory hearing loss, a 
condition that is usually irreversible. Most cochlear dis
-
eases result in bilateral symmetric hearing loss. The pres
-
ence of unilateral or asymmetric sensorineural hearing loss 
suggests a lesion proximal to the cochlea. Lesions affecting 
the eighth cranial nerve and central auditory system are 
discussed in the section on neural hearing loss. The pri
-
mary goals in the management of sensory hearing loss are 
prevention of further losses and functional improvement 
with amplification and auditory rehabilitation.
A. Presbyacusis
Presbyacusis, or age-related hearing loss, is the most fre
-
quent cause of sensory hearing loss and is progressive, 
predominantly high-frequency, and symmetrical. Various 
etiologic factors (eg, prior noise trauma, drug exposure, 
genetic predisposition) may contribute to presbyacusis. 
Most patients notice a loss of speech discrimination that is

Most patients notice a loss of speech discrimination that is 
especially pronounced in noisy environments. About 25% 
of people between the ages of 65 and 75 years and almost 
50% of those over 75 experience hearing difficulties.
Golub JS. Brain changes associated with age-related hearing 
loss. Curr Opin Otolaryngol Head Neck Surg. 2017 Oct;
 
25(5):347–52. [PMID: 28661962]
Homans NC et al. Prevalence of age-related hearing loss, includ
-
ing sex differences, in older adults in a large cohort study. 
Laryngoscope. 2017 Mar;127(3):725–30. [PMID: 27377351]
B. Noise Trauma
Noise trauma is the second most common cause of sensory 
hearing loss. Sounds exceeding 85 dB are potentially injuri
-
ous to the cochlea, especially with prolonged exposures. The 
loss typically begins in the high frequencies (especially 4000 Hz) 
and, with continuing exposure, progresses to involve the 
speech frequencies. Among the more common sources of 
injurious noise are industrial machinery, weapons, and exces
-
sively loud music. Personal music devices (eg, MP3 and CD 
players) used at excessive loudness levels may also be injuri
-
ous. Monitoring noise levels in the workplace by regulatory 
agencies has led to preventive programs that have reduced 
the frequency of occupational losses. Individuals of all ages, 
especially those with existing hearing losses, should wear 
earplugs when exposed to moderately loud noises and spe
-
cially designed earmuffs when exposed to explosive noises.
Le TN et al. Current insights in noise-induced hearing loss: a 
literature review of the underlying mechanism, pathophysiol
-
ogy, asymmetry, and management options. J Otolaryngol 
Head Neck Surg. 2017 May 23;46(1):41. [PMID: 28535812]
Liberman MC et al. Toward a differential diagnosis of hidden 
hearing loss in humans. PLoS One. 2016 Sep 12;11(9):
 
e0162726. [PMID: 27618300]
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C. Physical Trauma
Head trauma (eg, deployment of air bags during an auto
-
mobile accident) has effects on the inner ear similar to 
those of severe acoustic trauma. Some degree of sensory 
hearing loss may occur following simple concussion and is 
frequent after skull fracture.
Diaz RC et al. Treatment of temporal bone fractures. J Neurol 
Surg B Skull Base. 2016 Oct;77(5):419–29. [PMID: 27648399]
D. Ototoxicity
Ototoxic substances may affect both the auditory and ves
-
tibular systems. The most commonly used ototoxic medi
-
cations are aminoglycosides; loop diuretics; and several 
antineoplastic agents, notably cisplatin. These medications 
may cause irreversible hearing loss even when adminis
-
tered in therapeutic doses. When using these medications, 
it is important to identify high-risk patients, such as those 
with preexisting hearing losses or kidney disease. Patients 
simultaneously receiving multiple ototoxic agents are at 
particular risk owing to ototoxic synergy. Useful measures 
to reduce the risk of ototoxic injury include serial audiom
-
etry, monitoring of serum peak and trough levels, and 
substitution of equivalent nonototoxic drugs whenever 
possible.
It is possible for topical agents that enter the middle ear 
to be absorbed into the inner ear via the round window. 
When the tympanic membrane is perforated, use of poten
-
tially ototoxic ear drops (eg, neomycin, gentamicin) is best 
avoided.
Crundwell G et al. Ototoxicity (cochleotoxicity) classifications: a 
review. Int J Audiol. 2016 Feb;55(2):65–74. [PMID: 26618898]
E. Sudden Sensory Hearing Loss
Idiopathic sudden loss of hearing in one ear may occur 
at any age, but typically it occurs in persons over age 
20 years. The cause is unknown; however, one hypothesis 
is that it results from a viral infection or a sudden vascular 
occlusion of the internal auditory artery. Prognosis is 
mixed, with many patients suffering permanent deafness 
in the involved ear, while others have complete recovery. 
Prompt treatment with corticosteroids has been shown to 
improve the odds of recovery. A common regimen is oral 
prednisone, 1 mg/kg/day, followed by a tapering dose over 
a 10-day period. Intratympanic administration of cortico
-
steroids alone or in association with oral corticosteroids 
has been associated with an equal or more favorable prog
-
nosis. Because treatment appears to be most effective as 
close to the onset of the loss as possible, and appears not 
to be effective after 6 weeks, a prompt audiogram should 
be obtained in all patients who present with sudden hear
-
ing loss without obvious middle ear pathology.
El Sabbagh NG et al. Intratympanic dexamethasone in sudden 
sensorineural hearing loss: a systematic review and meta-
analysis. Laryngoscope. 2017 Aug;127(8):1897–1908. [PMID: 
27861924]
Li H et al. Intratympanic steroid therapy as a salvage treatment 
for sudden sensorineural hearing loss after failure of con
-
ventional therapy: a meta-analysis of randomized, con
-
trolled trials. Clin Ther. 2015 Jan 1;37(1):178–87. [PMID: 
25542075]
Sara SA et al. Bilateral sudden sensorineural hearing loss: 
review. J Laryngol Otol. 2014 Jan;128(Suppl 1):S8–15. [PMID: 
24331736]
F. Hereditary Hearing Loss
Sensory hearing loss with onset during adult life is often 
familial. The mode of inheritance may be either autosomal 
dominant or recessive. The age at onset, the rate of progres
-
sion of hearing loss, and the audiometric pattern (high-
frequency, low-frequency, or flat) can often be predicted by 
studying family members. The connexin-26 mutation, the 
most common cause of genetic deafness, may be tested 
clinically, as can most other single gene mutations known 
to cause hearing loss.
Abou Tayoun AN et al. Improving hearing loss gene testing: a 
systematic review of gene evidence toward more efficient 
next-generation sequencing-based diagnostic testing and

next-generation sequencing-based diagnostic testing and 
interpretation. Genet Med. 2016 Jun;18(6):545–53. [PMID: 
26562227]
Chen MM et al. Diagnosis and management of congenital senso
-
rineural hearing loss. Curr Treat Options Pediatr. 2016 Sep;
 
2(3):256–65. [PMID: 28083467]
G. Autoimmune Hearing Loss
Sensory hearing loss may be associated with a wide array of 
systemic autoimmune disorders, such as systemic lupus 
erythematosus, granulomatosis with polyangiitis (formerly 
Wegener granulomatosis), and Cogan syndrome (hearing 
loss, keratitis, aortitis). The loss is most often bilateral and 
progressive. The hearing level often fluctuates, with peri
-
ods of deterioration alternating with partial or even com
-
plete remission. Usually, there is the gradual evolution of 
permanent hearing loss, which often stabilizes with some 
remaining auditory function but occasionally proceeds to 
complete deafness. Vestibular dysfunction, particularly 
dysequilibrium and postural instability, may accompany 
the auditory symptoms. A syndrome resembling Ménière 
disease may also occur with intermittent attacks of severe 
vertigo.
In many cases, the autoimmune pattern of audioves
-
tibular dysfunction presents in the absence of recognized 
systemic autoimmune disease. Responsiveness to oral cor
-
ticosteroid treatment is helpful in making the diagnosis 
and constitutes first-line therapy. If stabilization of hearing 
becomes dependent on long-term corticosteroid use, ste
-
roid-sparing immunosuppressive regimens may become 
Atturo F et al. Can unilateral, progressive or sudden hearing loss 
be immune-mediated in origin? Acta Otolaryngol. 2017 Aug;
 
137(8):823–8. [PMID: 28296514]
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2. Tinnitus
 
»
Perception of abnormal ear or head noises.
 
»
Persistent tinnitus often, though not always, indi
-
cates the presence of sensory hearing loss.
 
»
Intermittent periods of mild, high-pitched tinnitus 
lasting seconds to minutes are common in nor
-
mal-hearing persons.
 
»
Tinnitus is defined as the sensation of sound in the absence 
of an exogenous sound source. Tinnitus can accompany 
any form of hearing loss, and its presence provides no diag
-
nostic value in determining the cause of a hearing loss. 
Approximately 15% of the general population experiences 
some type of tinnitus, with prevalence beyond 20% in 
aging populations.
 
»
Though tinnitus is commonly associated with hearing loss, 
tinnitus severity correlates poorly with the degree of hear
-
ing loss. About one in seven tinnitus sufferers experiences 
severe annoyance, and 4% are severely disabled. When 
severe and persistent, tinnitus may interfere with sleep and 
ability to concentrate, resulting in considerable psychologi
-
cal distress.
Pulsatile tinnitus—often described by the patient as 
listening to one’s own heartbeat—should be distinguished 
from tonal tinnitus. Although often ascribed to conductive 
hearing loss, pulsatile tinnitus may be far more serious and 
may indicate a vascular abnormality, such as glomus 
tumor, venous sinus stenosis, carotid vaso-occlusive dis
-
ease, arteriovenous malformation, or aneurysm. In con
-
trast, a staccato “clicking” tinnitus may result from middle 
ear muscle spasm, sometimes associated with palatal 
myoclonus. The patient typically perceives a rapid series of 
popping noises, lasting seconds to a few minutes, accompa
-
nied by a fluttering feeling in the ear.
B. Diagnostic Testing
For routine, nonpulsatile tinnitus, audiometry should be 
ordered to rule out an associated hearing loss. For unilateral 
tinnitus, particularly associated with hearing loss in the 
absence of an obvious causative factor (ie, noise trauma), an 
MRI should be obtained to rule out a retrocochlear lesion, 
such as vestibular schwannoma. MRA and MRV and tem
-
poral bone computed tomography (CT) should be consid
-
ered for patients who have pulsatile tinnitus to exclude a 
causative vascular lesion or sigmoid sinus abnormality.
 
»
Treatment
The most important treatment of tinnitus is avoidance 
of exposure to excessive noise, ototoxic agents, and other 
factors that may cause cochlear damage. Masking the tin
-
nitus with music or through amplification of normal 
sounds with a hearing aid may also bring some relief. 
Among the numerous drugs that have been tried, oral anti
-
depressants (eg, nortriptyline at an initial dosage of 50 mg 
orally at bedtime) have proved to be the most effective. 
Habituation techniques, such as tinnitus retraining ther
-
apy, and masking techniques may prove beneficial in those 
with refractory symptoms. Transcranial magnetic stimula
-
tion of the central auditory system has been shown to 
improve symptoms in some patients.
McCormack A et al. A systematic review of the reporting of tin
-
nitus prevalence and severity. Hear Res. 2016 Jul;337:70–9. 
[PMID: 27246985]
Zenner HP et al. A multidisciplinary systematic review of the 
treatment for chronic idiopathic tinnitus. Eur Arch Otorhino
-
laryngol. 2017 May;274(5):2079–91. [PMID: 27995315]
3. Hyperacusis
Excessive sensitivity to sound may occur in normal-hearing 
individuals, either in association with ear disease, follow
-
ing noise trauma, in patients susceptible to migraines, or 
for psychological reasons. Patients with cochlear dysfunc
-
tion commonly experience “recruitment, ” an abnormal 
sensitivity to loud sounds despite a reduced sensitivity to 
softer ones. Fitting hearing aids and other amplification 
devices to patients with recruitment requires use of com
-
pression circuitry to avoid uncomfortable overamplifica
-

-
-
tion. For normal-hearing individuals with hyperacusis, use 
of an earplug in noisy environments may be beneficial, 
though attempts should be made at habituation.
Jastreboff PJ et al. Decreased sound tolerance: hyperacusis, 
misophonia, diplacusis, and polyacusis. Handb Clin Neurol. 
2015;129:375–87. [PMID: 25726280]
4. Vertigo
 
»
Either a sensation of motion when there is no 
motion or an exaggerated sense of motion in 
response to movement.
 
»
Duration of vertigo episodes and association with 
hearing loss are the key to diagnosis.
 
»
Must differentiate peripheral from central etiolo
-
gies of vestibular dysfunction.
 
»
Peripheral:
 Onset is sudden; often associated with 
tinnitus and hearing loss; horizontal nystagmus 
may be present.
 
»
Central:
 Onset is gradual; no associated auditory 
symptoms.
 
»
Evaluation includes audiogram and electronystag
-
mography (ENG) or videonystagmography (VNG) 
and head MRI.
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Table 8–2.
 
Causes of vertigo.
p
eripher
al causes
 
V
estibular neuritis/labyrinthitis
 
M
énière disease
 
B
enign positional vertigo
 
E
thanol intoxication
 
I
nner ear barotraumas
 
S
emicircular canal dehiscence
Central causes
 
Seizure
 
Multiple 
sclerosis
 
W
ernicke encephalopathy
 
Chiari malf
ormation
 
C
erebellar ataxia syndromes
Mixed central and peripheral causes
 
Migraine
 
S
troke and vascular insufficiency
  
P
osterior inferior cerebellar artery stroke
  
An
terior inferior cerebellar artery stroke
  
V
ertebral artery insufficiency
  
Vasculitides
   
Cogan syndrome
   
Susac syndrome
    
Gr
anulomatosis with polyangiitis (formerly Wegener 
 
granulomatosis)
   
Behçet disease
 
C
erebellopontine angle tumors
  
V
estibular schwannoma
  
Lyme disease
  
Syphilis
 
V
ascular compression
 
H
yperviscosity syndromes
  
W
aldenström macroglobulinemia
 
Endocrinopathies
  
Pendred syndrome
Table 8–3.
 
Common vestibular disorders: differential 
diagnosis based on classic presentations.
Duration of 
 
Typical Vertigi
-
nous Episodes
Auditory 
 
Symptoms 
p
r
esent
Auditory Symptoms 
Absent
Seconds
Perilymphatic 
fistula
Positioning vertigo 
(cupulolithiasis), 
 
vertebrobasilar 
 
insufficiency, 
migraine-associated 
vertigo
Hours
Endolymphatic 
hydrops 
 
(Ménière syn
-
drome, syphilis)
Migraine-associated 
vertigo
Days
Labyrinthitis, 
 
labyrinthine 
 
concussion, 
 
autoimmune 
inner ear disease
Vestibular neuronitis, 
vertigo
Months
Acoustic neuroma, 
ototoxicity
Multiple sclerosis, cere
-
bellar degeneration
 
»
Vertigo can be caused by either a peripheral or central eti
-
ology, or both (Table 8–2).
 
»
Vertigo is the cardinal symptom of vestibular disease. Ver
-
tigo is typically experienced as a distinct “spinning” 
sensation or a sense of tumbling or of falling forward or 
backward. It should be distinguished from imbalance, 
light-headedness, and syncope, all of which are nonvestib
-
ular in origin (Table 8–3).
1. Peripheral vestibular disease—
Peripheral vestibulopa
-
thy usually causes vertigo of sudden onset, may be so 
severe that the patient is unable to walk or stand, and is 
frequently accompanied by nausea and vomiting. Tinnitus 
and hearing loss may be associated and provide strong sup
-
port for a peripheral (ie, otologic) origin.
Critical elements of the history include the duration of 
the discrete vertiginous episodes (seconds, minutes to 
hours, or days), and associated symptoms. Triggers should 
be sought, including diet (eg, high salt in the case of 
Ménière disease), stress, fatigue, and bright lights (eg, 
migraine-associated dizziness).
The physical examination of the patient with vertigo 
includes evaluation of the ears, observation of eye motion 
and nystagmus in response to head turning, cranial nerve 
examination, and Romberg testing. In acute peripheral 
lesions, nystagmus is usually horizontal with a rotatory 
component; the fast phase usually beats away from the 
diseased side. Visual fixation tends to inhibit nystagmus 
except in very acute peripheral lesions or with CNS disease. 
In benign paroxysmal positioning vertigo, Dix-Hallpike 
testing (quickly lowering the patient to the supine position 
with the head extending over the edge and placed 30 degrees 
lower than the body, turned either to the left or right) will 
elicit a delayed onset (~10 sec) fatiguable nystagmus. 
Nonfatigable nystagmus in this position indicates CNS 
disease.
Since visual fixation often suppresses observed nystag
-
mus, many of these maneuvers are performed with Frenzel 
goggles, which prevent visual fixation, and often bring out 
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subtle forms of nystagmus. The Fukuda test can demon
-
strate vestibular asymmetry when the patient steps in place 
with eyes closed and consistently rotates.
2. Central disease—
In contrast to peripheral forms of 
vertigo, dizziness arising from CNS disease (Table 8–2) 
tends to develop gradually and then becomes progressively 
more severe and debilitating. Nystagmus is not always 
present but can occur in any direction and may be dissoci
-
ated in the two eyes. The associated nystagmus is often 
nonfatigable, vertical rather than horizontal in orientation, 
without latency, and unsuppressed by visual fixation. ENG 
is useful in documenting these characteristics. Evaluation 
of central audiovestibular dysfunction requires MRI of the 
brain.
Episodic vertigo can occur in patients with diplopia 
from external ophthalmoplegia and is maximal when the 
patient looks in the direction where the separation of 
images is greatest. Cerebral lesions involving the temporal 
cortex may also produce vertigo; it is sometimes the initial 
symptom of a seizure. Finally, vertigo may be a feature of a 
number of systemic disorders and can occur as a side effect 
of certain anticonvulsant, antibiotic, hypnotic, analgesic, 
and tranquilizer medications or of alcohol.
Laboratory investigations, such as audiologic evaluation, 
caloric stimulation, ENG, VNG, vestibular-evoked myo
-
genic potentials (VEMPs), and MRI, are indicated in 
patients with persistent vertigo or when CNS disease is 
suspected. These studies help distinguish between central 
and peripheral lesions and identify causes requiring spe
-
cific therapy. ENG consists of objective recording of the 
nystagmus induced by head and body movements, gaze, 
and caloric stimulation. It is helpful in quantifying the 
degree of vestibular hypofunction.
Bertholon P et al. Otologic disorders causing dizziness, includ
-
ing surgery for vestibular disorders. Handb Clin Neurol. 2016;
 
137:279–93. [PMID: 27638078]
Cohen JM et al. Headache and dizziness: how to differentiate 
vestibular migraine from other conditions. Curr Pain Head
-
ache Rep. 2015 Jul;19(7):31. [PMID: 26049771]
Sandhu JS et al. Clinical examination and management of the 
dizzy patient. Br J Hosp Med (Lond). 2016 Dec 2;77(12):692–8. 
[PMID: 27937029]
 
»
Vertigo Syndromes Due to Peripheral 
Lesions
A. Endolymphatic Hydrops (Ménière Syndrome)
The cause of Ménière syndrome is unknown. Distention of 
the endolymphatic compartment of the inner ear is thought 
to be part of the pathogenesis of the disorder. Although a 
precise cause of hydrops cannot be established in most 
cases, two known causes are syphilis and head trauma. The 
classic syndrome consists of episodic vertigo, with discrete 
vertigo spells lasting 20 minutes to several hours in associa
-
tion with fluctuating low-frequency sensorineural hearing 
loss, tinnitus (usually low-tone and “blowing” in quality), 
and a sensation of unilateral aural pressure (Table 8–3). 
These symptoms in the absence of hearing fluctuations 
suggest migraine-associated dizziness. Symptoms wax and 
wane as the endolymphatic pressure rises and falls. Caloric 
testing commonly reveals loss or impairment of thermally 
induced nystagmus on the involved side. Primary treat
-
ment involves a low-salt diet and diuretics (eg, acetazol
-
amide). For symptomatic relief of acute vertigo attacks, 
oral meclizine (25 mg) or diazepam (2–5 mg) can be used. 
In refractory cases, patients may undergo intratympanic 
corticosteroid injections, endolymphatic sac decompres
-
sion, or vestibular ablation, either through transtympanic 
gentamicin, vestibular nerve section, or surgical 
labyrinthectomy.
Nakashima T et al. Meniere’s disease. Nat Rev Dis Primers. 2016 
May 12;2:16028. [PMID: 27170253]
Tabet P et al. Meniere’s disease and vestibular migraine: updates 
and review of the literature. J Clin Med Res. 2017 Sep;9(9):
 
733–44. [PMID: 28811849]
B. Labyrinthitis

Patients with labyrinthitis suffer from acute onset of con
-
tinuous, usually severe vertigo lasting several days to a 
week, accompanied by hearing loss and tinnitus. During a 
recovery period that lasts for several weeks, the vertigo 
gradually improves. Hearing may return to normal or 
remain permanently impaired in the involved ear. The 
cause of labyrinthitis is unknown. Treatment consists of 
antibiotics if the patient is febrile or has symptoms of a 
bacterial infection, and supportive care. Vestibular sup
-
pressants are useful during the acute phase of the attack 
(eg, diazepam or meclizine) but should be discontinued as 
soon as feasible to avoid long-term dysequilibrium from 
inadequate compensation.
Kaya S et al. Quantitative assessment of cochlear histopathologic 
findings in patients with suppurative labyrinthitis. JAMA 
Otolaryngol Head Neck Surg. 2016 Apr;142(4):364–9. [PMID: 
26987015]
C. Benign Paroxysmal Positioning Vertigo
Patients suffering from recurrent spells of vertigo, lasting a 
few minutes per spell, associated with changes in head posi
-
tion (often provoked by rolling over in bed), usually have 
benign paroxysmal positioning vertigo (BPPV). The term 
“positioning vertigo” is more accurate than “positional ver
-
tigo” because it is provoked by changes in head position 
rather than by the maintenance of a particular posture.
The typical symptoms of BPPV occur in clusters that 
persist for several days. There is a brief (10–15 sec) latency 
period following a head movement before symptoms 
develop, and the acute vertigo subsides within 10–60 seconds, 
though the patient may remain imbalanced for several 
hours. Constant repetition of the positional change leads to 
habituation. Since some CNS disorders can mimic BPPV 
(eg, vertebrobasilar insufficiency), recurrent cases warrant 
head MRI. In central lesions, there is no latent period, fatiga
-
bility, or habituation of the symptoms and signs. Treatment 
of BPPV involves physical therapy protocols (eg, the Epley 
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maneuver or Brandt-Daroff exercises), based on the theory 
that it results from free-floating otoconia within a semicircu
-
lar canal.
Balatsouras DG et al. Benign paroxysmal positional vertigo 
secondary to mild head trauma. Ann Otol Rhinol Laryngol. 
2017 Jan;126(1):54–60. [PMID: 27780909]
Pérez-Vázquez P et al. Practice Guidelines for the Diagnosis and 
Management of Benign Paroxysmal Positional Vertigo Oto
-
neurology Committee of Spanish Otorhinolaryngology and 
Head and Neck Surgery Consensus Document. Acta Otorri
-
nolaringol Esp. 2017 Aug 18. [Epub ahead of print] [PMID: 
28826856]
D. Vestibular Neuronitis
In vestibular neuronitis, a paroxysmal, usually single attack 
of vertigo occurs without accompanying impairment of 
auditory function and will persist for several days to a week 
before gradually abating. During the acute phase, examina
-
tion reveals nystagmus and absent responses to caloric 
stimulation on one or both sides. The cause of the disorder 
is unclear though presumed to be viral. Treatment consists 
of supportive care, including oral diazepam, 2–5 mg every 
6–12 hours, or meclizine, 25–100 mg divided 2–3 times 
daily, during the acute phases of the vertigo only, followed 
by vestibular therapy if the patient does not completely 
compensate.
Batuecas-Caletrío A et al. Glucocorticoids improve acute dizzi
-
ness symptoms following acute unilateral vestibulopathy. 
J Neurol. 2015 Nov;262(11):2578–82. [PMID: 26459091]
Strupp M et al. Acute unilateral vestibulopathy. Neurol Clin. 
2015 Aug;33(3):669–85. [PMID: 26231279]
E. Traumatic Vertigo
Labyrinthine concussion is the most common cause of 
vertigo following head injury. Symptoms generally dimin
-
ish within several days but may linger for a month or more. 
Basilar skull fractures that traverse the inner ear usually 
result in severe vertigo lasting several days to a week and 
deafness in the involved ear. Chronic posttraumatic vertigo 
may result from cupulolithiasis. This occurs when trau
-
matically detached statoconia (otoconia) settle on the 
ampulla of the posterior semicircular canal and cause an 
excessive degree of cupular deflection in response to head 
motion. Clinically, this presents as episodic positioning 
vertigo. Treatment consists of supportive care and vestibu
-
lar suppressant medication (diazepam or meclizine) during 
the acute phase of the attack, and vestibular therapy.
Szczupak M et al. Posttraumatic dizziness and vertigo. Handb 
Clin Neurol. 2016;137:295–300. [PMID: 27638079]
F. Perilymphatic Fistula
Leakage of perilymphatic fluid from the inner ear into the 
tympanic cavity via the round or oval window is a rare 
cause of vertigo and sensory hearing loss. Most cases result 
from either physical injury (eg, blunt head trauma, hand 
slap to ear); extreme barotrauma during airflight, scuba 
diving, etc; or vigorous Valsalva maneuvers (eg, during 
weight lifting). Treatment may require middle ear explora
-
tion and window sealing with a tissue graft.
Foster PK. Autologous intratympanic blood patch for presumed 
perilymphatic fistulas. J Laryngol Otol. 2016 Dec;130(12):
 
1158–61. [PMID: 27894374]
Meldrum JA et al. Perilymph fistula: the patients’ experience. J 
Laryngol Otol. 2016 Jun;130(6):526–31. [PMID: 27112544]
Morvan JB et al. Perilymphatic fistula after underwater diving: a 
series of 11 cases. Diving Hyperb Med. 2016 Jun;46(2):72–5. 
[PMID: 27334993]
G. Cervical Vertigo
Position receptors located in the facets of the cervical spine 
are important physiologically in the coordination of head 
and eye movements. Cervical proprioceptive dysfunction is 
a common cause of vertigo triggered by neck movements. 
This disturbance often commences after neck injury, par
-
ticularly hyperextension; it is also associated with degenera
-
tive cervical spine disease. Although symptoms vary, vertigo 
may be triggered by assuming a particular head position as

-
-
may be triggered by assuming a particular head position as 
opposed to moving to a new head position (the latter typical 
of labyrinthine dysfunction). Cervical vertigo may often be 
confused with migraine-associated vertigo, which is also 
associated with head movement. Management consists of 
neck movement exercises to the extent permitted by ortho
-
pedic considerations.
Hain TC. Cervicogenic causes of vertigo. Curr Opin Neurol. 
2015 Feb;28(1):69–73. [PMID: 25502050]
H. Migrainous Vertigo
Episodic vertigo is frequently associated with migraine 
headache. Head trauma may also be a precipitating feature. 
The vertigo may be temporally related to the headache and 
last up to several hours, or it may also occur in the absence 
of any headache. Migrainous vertigo may resemble Ménière 
disease but without associated hearing loss or tinnitus. 
Accompanying symptoms may include head pressure; 
visual, motion, or auditory sensitivity; and photosensitiv
-
ity. Symptoms typically worsen with lack of sleep and anxi
-
ety or stress. Food triggers include caffeine, chocolate, and 
alcohol, among others. There is often a history of motion 
intolerance (easily carsick as a child). Migrainous vertigo 
may be familial. Treatment includes dietary and lifestyle 
changes (improved sleep pattern, avoidance of stress) and 
antimigraine prophylactic medication.
Sohn JH. Recent advances in the understanding of vestibular 
migraine. Behav Neurol. 2016;2016:1801845. [PMID: 27821976]
and review of the literature. J Clin Med Res. 2017 Sep;9(9):733–44. 
[PMID: 28811849]
von Brevern M et al. Vestibular migraine. Handb Clin Neurol. 
2016;137:301–16. [PMID: 27638080]
I. Superior Semicircular Canal Dehiscence
Deficiency in the bony covering of the superior semicircu
-
lar canal may be associated with vertigo triggered by loud 
noise exposure, straining, and an apparent conductive 
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hearing loss. Autophony is also a common feature. Diagno
-
sis is with coronal high-resolution CT scan and VEMPs. 
Surgically resurfacing or plugging the dehiscent canal can 
improve symptoms.
Palma Diaz M et al. Superior semicircular canal dehiscence syn
-
drome—diagnosis and surgical management. Int Arch Oto
-
rhinolaryngol. 2017 Apr;21(2):195–8. [PMID: 28382131]
Ziylan F et al. A comparison of surgical treatments for superior 
semicircular canal dehiscence: a systematic review. Otol Neu
-
rotol. 2017 Jan;38(1):1–10. [PMID: 27861193]
 
»
Vertigo Syndromes Due to Central Lesions
CNS causes of vertigo include brainstem vascular disease, 
arteriovenous malformations, tumor of the brainstem and 
cerebellum, multiple sclerosis, and vertebrobasilar migraine 
(Table 8–2). Vertigo of central origin often becomes unre
-
mitting and disabling. The associated nystagmus is often 
is useful in documenting these characteristics. There are 
commonly other signs of brainstem dysfunction (eg, cra
-
nial nerve palsies; motor, sensory, or cerebellar deficits in 
the limbs) or of increased intracranial pressure. Auditory 
function is generally spared. The underlying cause should 
be treated.
Bronstein AM. Multisensory integration in balance control. 
Handb Clin Neurol. 2016;137:57–66. [PMID: 27638062]
Tsang BK et al. Acute evaluation of the acute vestibular syn
-
drome—differentiating posterior circulation stroke from 
acute peripheral vestibulopathies. Intern Med J. 2017 Dec;
 
47(12):1352–60. [PMID: 28696571]
DISEASES OF THE CENTRAL AUDITORY & 
VESTIBULAR SYSTEMS
Lesions of the eighth cranial nerve and central audioves
-
tibular pathways produce neural hearing loss and vertigo 
(Table 8–3). One characteristic of neural hearing loss is 
deterioration of speech discrimination out of proportion to 
the decrease in pure tone thresholds. Another is auditory 
adaptation, wherein a steady tone appears to the listener to 
decay and eventually disappear. Auditory evoked responses 
are useful in distinguishing cochlear from neural losses 
and may give insight into the site of lesion within the cen
-
tral pathways.
The evaluation of central audiovestibular disorders usu
-
ally requires imaging of the internal auditory canal, cere
-
bellopontine angle, and brain with enhanced MRI.
1. Vestibular Schwannoma (Acoustic Neuroma)
Eighth cranial nerve schwannomas are among the most 
common intracranial tumors. Most are unilateral, but 
about 5% are associated with the hereditary syndrome 
neurofibromatosis type 2, in which bilateral eighth nerve 
tumors may be accompanied by meningiomas and other 
intracranial and spinal tumors. These benign lesions arise 
within the internal auditory canal and gradually grow to 
involve the cerebellopontine angle, eventually compressing 
the pons and resulting in hydrocephalus. Their typical 
auditory symptoms are unilateral hearing loss with a dete
-
rioration of speech discrimination exceeding that pre
-
dicted by the degree of pure tone loss. Nonclassic 
presentations, such as sudden unilateral hearing loss, are 
fairly common. Any individual with a unilateral or asym
-
metric sensorineural hearing loss should be evaluated for 
an intracranial mass lesion. Vestibular dysfunction more 
often takes the form of continuous dysequilibrium than 
episodic vertigo. Diagnosis is made by enhanced MRI. 
Treatment consists of observation, microsurgical excision, 
or stereotactic radiotherapy, depending on such factors as 
patient age, underlying health, and size of the tumor. Beva
-
cizumab (vascular endothelial growth factor blocker) has 
shown promise for treatment of tumors in neurofibroma
-
tosis type 2.
Apicella G et al. Radiotherapy for vestibular schwannoma: 
review of recent literature results. Rep Pract Oncol Radiother. 
2016 Jul–Aug;21(4):399–406. [PMID: 27330427]

-
Gao X et al. Anti-VEGF treatment improves neurological func
-
tion and augments radiation response in NF2 schwannoma 
model. Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):
 
14676–81. [PMID: 26554010]
Kirchmann M et al. Ten-year follow-up on tumor growth and 
hearing in patients observed with an intracanalicular vestibular 
schwannoma. Neurosurgery. 2017 Jan 1;80(1):49–56. [PMID: 
27571523]
2. Vascular Compromise
Vertebrobasilar insufficiency is a common cause of vertigo 
in the elderly. It is often triggered by changes in posture or 
extension of the neck. Reduced flow in the vertebrobasilar 
system may be demonstrated noninvasively through MRA. 
Empiric treatment is with vasodilators and aspirin.
Choi KD et al. Ischemic syndromes causing dizziness and ver
-
tigo. Handb Clin Neurol. 2016;137:317–40. [PMID: 27638081]
Lee H. Isolated vascular vertigo. J Stroke. 2014 Sep;16(3):124–30. 
[PMID: 25328871]
3. Multiple Sclerosis
Patients with multiple sclerosis may suffer from episodic 
vertigo and chronic imbalance. Hearing loss in this disease 
is most commonly unilateral and of rapid onset. Spontane
-
ous recovery may occur.
Kim HA et al. Recent advances in understanding audiovestibular 
loss of a vascular cause. J Stroke. 2017 Jan;19(1):61–6. [PMID: 
28030893]
OTOLOGIC MANIFESTATIONS OF AIDS
The otologic manifestations of AIDS are protean. The 
pinna and external auditory canal may be affected by 
Kaposi sarcoma and by persistent and potentially invasive 
fungal infections (particularly 
Aspergillus fumigatus
)
.
 
Serous otitis media due to eustachian tube dysfunction 
may arise from adenoidal hypertrophy (HIV lymphade
-
nopathy), recurrent mucosal viral infections, or an 
obstructing nasopharyngeal tumor (eg, lymphoma). 
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Unfortunately, ventilating tubes are seldom helpful and 
may trigger profuse watery otorrhea. Acute otitis media is 
usually caused by typical bacterial organisms, including 
Proteus, Staphylococcus,
 and 
Pseudomonas,
 and rarely, by 
. Sensorineural hearing loss is com
-
mon and, in some cases, results from viral CNS infection. 
In cases of progressive hearing loss, cryptococcal meningi
-
tis and syphilis must be excluded. Acute facial paralysis due 
to herpes zoster infection (Ramsay Hunt syndrome) occurs 
commonly and follows a clinical course similar to that in 
nonimmunocompromised patients. Treatment is with 
high-dose acyclovir (see Chapter 32). Corticosteroids may 
also be effective as an adjunct.
Matas CG et al. Audiological and electrophysiological alterations 
in HIV-infected individuals subjected or not to antiretroviral 
therapy. Braz J Otorhinolaryngol. 2017 Aug 2. [Epub ahead of 
print] [PMID: 28823692]
Riancho J et al. Clinical spectrum of peripheral facial paralysis in 
HIV-infected patients according to HIV status. Int J STD 
AIDS. 2013 Jan;24(1):39–41. [PMID: 23467294]
van der Westhuizen Y et al. Auditory and otological manifesta
-
tions in adults with HIV/AIDS. Int J Audiol. 2013 Jan;
 
52(1):37–43. [PMID: 23043519]
 
º
DISEASES OF THE NOSE & 
 
p
AR
ANASAL SINUSES
INFECTIONS OF THE NOSE & 
 
PARANASAL SINUSES
1. Acute Viral Rhinosinusitis (Common Cold)
 
»
Nasal congestion, clear rhinorrhea, and hyposmia.
 
»
Associated malaise, headache, and cough.
 
»
Erythematous, engorged nasal mucosa without 
intranasal purulence.
 
»
Symptoms are self-limited, lasting less than 4 weeks 
and typically less than 10 days.
 
»
Because there are numerous serologic types of rhinovi
-
ruses, adenoviruses, and other viruses, patients remain 
susceptible to the common cold throughout life. These 
infections, while generally quite benign and self-limited, 
have been implicated in the development or exacerbation 
of more serious conditions, such as acute bacterial sinusitis 
and acute otitis media, asthma, cystic fibrosis, and bronchi
-
tis. Nasal congestion, decreased sense of smell, watery rhi
-
norrhea, and sneezing, accompanied by general malaise, 
throat discomfort and, occasionally, headache are typical in 
viral infections. Nasal examination usually shows ery
-
thematous, edematous mucosa and a watery discharge. The 
presence of purulent nasal discharge suggests bacterial 
rhinosinusitis.
 
»
Treatment
There are no effective antiviral therapies for either the pre
-
vention or treatment of most viral rhinitis despite a com
-
mon misperception among patients that antibiotics are 
helpful. Prevention of influenza virus infection by boosting 
the immune system using the annually created vaccine may 
be the most effective management strategy. Oseltamivir is 
the first neuramidase inhibitor approved for the treatment 
and prevention of influenza virus infection, but its use is 
generally limited to those patients considered high risk. 
These high-risk patients include young children, pregnant 
women, and adults older than 65 years of age. Oseltamivir 
is hard to use because it must be started within 48 hours for 
optimal effect. Other specific antiviral medications are 
available or in clinical trials but have not achieved signifi
-
cant use. Zinc for the treatment of viral rhinitis has been 
controversial. Buffered hypertonic saline (3–5%) nasal 
irrigation has been shown to improve symptoms and 
reduce the need for nonsteroidal anti-inflammatory drugs 
(NSAIDs). Other supportive measures, such as oral decon
-
gestants (pseudoephedrine, 30–60 mg every 4–6 hours or 
120 mg twice daily), may provide some relief of rhinorrhea 
and nasal obstruction. Nasal sprays, such as oxymetazoline 
or phenylephrine, are rapidly effective but should not be 
used for more than a few days to prevent rebound conges
-

-
tion. Withdrawal of the drug after prolonged use leads to 
rhinitis medicamentosa,
 an almost addictive need for 
continuous usage. Treatment of rhinitis medicamentosa 
requires mandatory cessation of the sprays, and this is 
often extremely frustrating for patients. Topical intranasal 
corticosteroids (eg, flunisolide, 2 sprays in each nostril 
twice daily), intranasal anticholinergic (ipratropium 0.06% 
nasal spray, 2–3 sprays every 8 hours as needed), or a short 
tapering course of oral prednisone may help during the 
withdrawal process.
 
»
Other than mild eustachian tube dysfunction or transient 
middle ear effusion, complications of viral rhinitis are 
unusual. Secondary acute bacterial rhinosinusitis is a well-
accepted complication of acute viral rhinitis and is sug
-
gested by persistence of symptoms beyond 10 days with 
purulent green or yellow nasal secretions and unilateral 
facial or tooth pain.
Bergmark RW et al. Diagnosis and first-line treatment of chronic 
sinusitis. JAMA. 2017 Dec 19;318(23):2344–5. [PMID: 
29260210]
Harris AM et al; High Value Care Task Force of the American 
College of Physicians and for the Centers for Disease Control 
and Prevention. Appropriate antibiotic use for acute respira
-
tory tract infection in adults: advice for high-value care from 
the American College of Physicians and the Centers for Dis
-
ease Control and Prevention. Ann Intern Med. 2016 Mar 15;
 
164(6):425–34. [PMID: 26785402]
King D et al. Saline nasal irrigation for acute upper respiratory 
tract infections. Cochrane Database Syst Rev. 2015 Apr 20;
 
(4):CD006821. [PMID: 25892369]
Rudmik L et al. JAMA patient page. Adult chronic sinusitis. 
JAMA. 2015 Sep 1;314(9):964. [PMID: 26325574]
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Tan KS et al. Impact of respiratory virus infections in exacerba
-
tion of acute and chronic rhinosinusitis. Curr Allergy Asthma 
Rep. 2017 Apr;17(4):24. [PMID: 28389843]
2. Acute Bacterial Rhinosinusitis (Sinusitis)
 
»
Purulent yellow-green nasal discharge or 
expectoration.
 
»
Facial pain or pressure over the affected sinus or 
sinuses.
 
»
Nasal obstruction.
 
»
Acute onset of symptoms (between 1 and 4 weeks’ 
duration).
 
»
Associated cough, malaise, fever, and headache.
 
»
Compared with viral rhinitis, acute bacterial rhinosinusitis 
infections are uncommon, but they still affect nearly 20 million 
Americans annually and account for over 2 billion dollars 
in health care expenditures.
Acute bacterial rhinosinusitis usually is a result of 
impaired mucociliary clearance, inflammation of the nasal 
cavity mucosa, and obstruction of the ostiomeatal com
-
plex, or sinus “pore. ” Edematous mucosa causes obstruc
-
tion of the complex, resulting in the accumulation of 
mucus in the sinus cavity that becomes secondarily infected 
by bacteria. The largest of these ostiomeatal complexes is 
deep to the middle turbinate in the middle meatus. This 
complex is actually a confluence of complexes draining the 
maxillary, ethmoid, and frontal sinuses. The sphenoid 
drains from a separate complex between the septum and 
superior turbinate.
The typical pathogens of bacterial rhinosinusitis are 
S 
pneumoniae
, other streptococci, 
 and less 
commonly, 
S aureus
 and 
Moraxella catarrhalis.
 Pathogens 
vary regionally in both prevalence and drug resistance; 
about 25% of healthy asymptomatic individuals may, if 
sinus aspirates are cultured, harbor such bacteria as well.
 
»
There are no agreed-upon criteria for the diagnosis of acute 
bacterial rhinosinusitis in adults. Major symptoms include 
purulent nasal drainage, nasal obstruction or congestion, 
facial pain/pressure, altered smell, cough, and fever. Minor 
symptoms include headache, otalgia, halitosis, dental pain, 
and fatigue. Many of the more specific symptoms and signs 
relate to the affected sinus(es). Bacterial rhinosinusitis can 
be distinguished from viral rhinitis by persistence of symp
-
toms for more than 10 days after onset or worsening of 
symptoms within 10 days after initial improvement. Acute 
rhinosinusitis is defined as lasting less than 4 weeks, and 
subacute rhinosinusitis, as lasting 4–12 weeks.
Acute maxillary sinusitis
 is the most common form of 
acute bacterial rhinosinusitis because the maxillary is the 
largest sinus with a single drainage pathway that is easily 
obstructed. Unilateral facial fullness, pressure, and tender
-
ness over the cheek are common symptoms, but may not 
always be present. Pain may refer to the upper incisor and 
canine teeth via branches of the trigeminal nerve, which 
traverse the floor of the sinus. Purulent nasal drainage 
should be noted with nasal airway obstruction or facial 
pain (pressure). Maxillary sinusitis may result from dental 
infection, and teeth that are tender should be carefully 
examined for signs of abscess. Drainage of the periapical 
abscess or removal of the diseased tooth typically resolves 
the sinus infection.
Acute ethmoiditis
 in adults is often accompanied by 
maxillary sinusitis, and symptoms are similar to those 
described above. Localized ethmoid sinusitis may present 
with pain and pressure over the high lateral wall of the nose 
between the eyes that may radiate to the orbit.
Sphenoid sinusitis
 is usually seen in the setting of pan
-
sinusitis or infection of all the paranasal sinuses on at least 
one side. The patient may complain of a headache “in the 
middle of the head” and often points to the vertex.
Acute frontal sinusitis
 may cause pain and tenderness 
of the forehead. This is most easily elicited by palpation of

of the forehead. This is most easily elicited by palpation of 
the orbital roof just below the medial end of the eyebrow.
Hospital-associated sinusitis
 is a form of acute bacte
-
rial rhinosinusitis that may present without the usual 
symptoms. Instead, it may be a cause of fever in critically ill 
patients. It is often associated with prolonged presence of a 
nasogastric or, rarely, nasotracheal tube causing nasal 
mucosal inflammation and ostiomeatal complex obstruc
-
tion. Pansinusitis on the side of the tube is common on 
imaging studies.
B. Imaging
The diagnosis of acute bacterial rhinosinusitis can usually 
be made on clinical grounds alone. Although more sensi
-
tive than clinical examination, routine radiographs are not 
cost-effective and are not recommended by the Agency for 
Health Care Policy and Research or American Association 
of Otolaryngology Guidelines. Consensus guidelines rec
-
ommend imaging when clinical criteria are difficult to 
evaluate, when the patient does not respond to appropriate 
therapy or has been treated repeatedly with antibiotics, 
when intracranial involvement or cerebrospinal fluid rhi
-
norrhea is suspected, when complicated dental infection is 
suspected, or when symptoms of more serious infection 
are noted.
When necessary, noncontrast screening coronal CT 
scans are more cost-effective and provide more informa
-
tion than conventional sinus films. CT provides a rapid and 
effective means to assess all of the paranasal sinuses, iden
-
tify areas of greater concern (such as bony dehiscence, 
periosteal elevation or maxillary tooth root exposure 
within the sinus), and speed appropriate therapy.
CT scans are reasonably sensitive but are not specific. 
Swollen soft tissue and fluid may be difficult to distinguish 
when opacification of the sinus is due to other conditions, 
such as chronic rhinosinusitis, nasal polyposis, or mucus 
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retention cysts. Sinus abnormalities can be seen in most 
patients with an upper respiratory infection, while bacte
-
rial rhinosinusitis develops in only 2%.
If malignancy, intracranial extension, or opportunistic 
infection is suspected, MRI with gadolinium should be 
ordered instead of, or in addition to, CT. MRI will distin
-
guish tumor from fluid, inflammation, and inspissated 
mucus far better than CT, and will better delineate tumor 
extent (eg, involvement of adjacent structures, such as the 
orbit, skull base, and palate). Bone destruction can be dem
-
onstrated as well by MRI as by CT.
 
»
Treatment
All patients with acute bacterial rhinosinusitis should have 
careful evaluation of pain. NSAIDs are generally recom
-
mended. Sinus symptoms may be improved with oral or 
nasal decongestants (or both)—eg, oral pseudoephedrine, 
30–60 mg every 6 hours, up to 240 mg/day; nasal oxy
-
metazoline, 0.05% or oxymetazoline, 0.05–0.1%, one or 
two sprays in each nostril every 6–8 hours for up to 3 days. 
Intranasal corticosteroids (high-dose mometasone furoate 
200 mcg each nostril twice daily for 21 days) can help 
reduce facial pain and congestion.
Between 40% and 69% of patients with acute bacterial 
rhinosinusitis improve symptomatically within 2 weeks with
-
out antibiotic therapy. Antibiotic treatment is controversial in 
uncomplicated cases of clinically diagnosed acute bacterial 
rhinosinusitis because only 5% of patients will note a shorter 
duration of illness with treatment, and antibiotic treatment is 
associated with nearly twice the number of adverse events 
compared with placebo. Antibiotics may be considered when 
symptoms last more than 10 days or when symptoms (includ
-
ing fever, facial pain, and swelling of the face) are severe or 
when cases are complicated (such as immunodeficiency). In 
these patients, administration of antibiotics does reduce the 
incidence of clinical failure by 50% and represents the most 
cost-effective treatment strategy.
Selection of antibiotics is usually empiric and based on 
a number of factors, including regional patterns of antibi
-
otic resistance, antibiotic allergy, cost, and patient toler
-
ance. For adults younger than 65 years with mild to 
moderate acute bacterial rhinosinusitis, the recom
-
mended first-line therapy is amoxicillin-clavulanate 
 
(500 mg/125 mg orally three times daily or 875 mg/125 mg 
orally twice daily for 5–7 days), or in those with severe 
sinusitis, high-dose amoxicillin-clavulanate (2000 mg/125 mg 
extended-release orally twice daily for 7–10 days). In 
patients with a high risk for penicillin-resistant 
 
(age over 65 years, hospitalization in the prior 5  days, 
antibiotic use in the prior month, immunocompromised 
status, multiple comorbidities or severe sinus infection), 
the recommended first-line therapy is the high-dose 
amoxicillin-clavulanate option (2000 mg/125 mg 
extended-release orally twice daily for 7–10 days). For 
those with penicillin allergy or hepatic impairment, then 
doxycycline (100 mg orally twice daily or 200 mg orally 
once daily for 5–7 days), or clindamycin (150–300 mg 
every 6 hours) plus a cephalosporin (cefixime 400 mg 
orally once daily or cefpodoxime proxetil 200 mg 
 
orally twice daily) for 10 days are options. Macrolides, 
 
trimethoprim-sulfamethoxazole, and second- or third-
generation cephalosporins are not recommended for 
empiric therapy.
Hospital-associated infections in critically ill patients 
are treated differently from community-acquired infec
-
tions. Removal of a nasogastric tube and improved nasal 
hygiene (nasal saline sprays, humidification of supplemen
-
tal nasal oxygen, and nasal decongestants) are critical 
interventions and often curative in mild cases without 
aggressive antibiotic use. Endoscopic or transantral cul
-
tures may help direct medical therapy in complicated cases.

-
tures may help direct medical therapy in complicated cases. 
In addition, broad-spectrum antibiotic coverage directed at 
P aeruginosa, S aureus
 (including methicillin-resistant 
strains), and anaerobes may be required.
 
»
Local complications of acute bacterial rhinosinusitis 
include orbital cellulitis and abscess, osteomyelitis, cavern
-
ous sinus thrombosis, and intracranial extension.
Orbital complications typically occur by extension of 
ethmoid sinusitis through the lamina papyracea, a thin 
layer of bone that comprises the medial orbital wall. Any 
change in the ocular examination necessitates immediate 
CT imaging. Extension in this area may cause orbital cellu
-
litis leading to proptosis, gaze restriction, and orbital pain. 
Select cases are responsive to intravenous antibiotics, with 
or without corticosteroids, and should be managed in close 
conjunction with an ophthalmologist or otolaryngologist, 
or both. Extension through the lamina papyracea can also 
lead to subperiosteal abscess formation (orbital abscess). 
Such abscesses cause marked proptosis, ophthalmoplegia, 
and pain with medial gaze. While some cases respond to 
antibiotics, such findings should prompt an immediate 
referral to a specialist for consideration of decompression 
and evacuation. Failure to intervene quickly may lead to 
permanent visual impairment and a “frozen globe. ”
Osteomyelitis requires prolonged antibiotics as well as 
removal of necrotic bone. The frontal sinus is most com
-
monly affected, with bone involvement suggested by a 
tender swelling of the forehead (Pott puffy tumor). Follow
-
ing treatment, secondary cosmetic reconstructive proce
-
dures may be necessary.
Intracranial complications of sinusitis can occur either 
through hematogenous spread, as in cavernous sinus 
thrombosis and meningitis, or by direct extension, as in 
epidural and intraparenchymal brain abscesses. Fortu
-
nately, they are rare today. Cavernous sinus thrombosis is 
heralded by ophthalmoplegia, chemosis, and visual loss; 
the diagnosis is most commonly confirmed by MRI. When 
identified early, cavernous sinus thrombosis typically 
responds to intravenous antibiotics. Frontal epidural and 
intracranial abscesses are often clinically silent, but may 
present with altered mental status, persistent fever, or 
severe headache.
 
»
Failure of acute bacterial rhinosinusitis to resolve after an 
adequate course of oral antibiotics necessitates referral to 
an otolaryngologist for evaluation. Endoscopic cultures 
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may direct further treatment choices. Nasal endoscopy and 
CT scan are indicated when symptoms persist longer than 
4–12 weeks. Any patients with suspected extension of dis
-
ease outside the sinuses should be evaluated urgently by an 
otolaryngologist and imaging should be obtained.
 
»
•	
Facial swelling and erythema indicative of facial 
cellulitis.
•	
Proptosis.
•	
Vision change or gaze abnormality indicative of orbital 
•	
Abscess or cavernous sinus involvement.
•	
Mental status changes suggestive of intracranial 
extension.
•	
Immunocompromised status.
•	
Failure to respond to appropriate first-line treatment or 
symptoms persisting longer than 4 weeks.
Ahovuo-Saloranta A et al. Antibiotics for acute maxillary sinus
-
itis in adults. Cochrane Database Syst Rev. 2014 Feb 11;
 
(2):CD000243. Update in: Cochrane Database Syst Rev. 
2015;(10):CD000243. [PMID: 24515610]
Carr TF. Complications of sinusitis. Am J Rhinol Allergy. 
 
2016 Jul;30(4):241–5. [PMID: 27456592]
Dass K et al. Diagnosis and management of rhinosinusitis: high
-
lights from the 2015 Practice Parameter. Curr Allergy Asthma 
Rep. 2016 Apr;16(4):29. [PMID: 26949223]
-
-
 
Rosenfeld RM et al. Clinical practice guideline (update): adult 
sinusitis. Otolaryngol Head Neck Surg. 2015 Apr;152(Suppl 2):
 
S1–39. [PMID: 25832968]
Smith SS et al. The prevalence of bacterial infection in acute 
rhinosinusitis: a systematic review and meta-analysis. Laryn
-
goscope. 2015 Jan;125(1):57–69. [PMID: 24723427]
Snidvongs K et al. Update on intranasal medications in rhinosi
-
nusitis. Curr Allergy Asthma Rep. 2017 Jul;17(7):47. [PMID: 
28602009]
3. Nasal Vestibulitis & 
S aureus
 Nasal 
Colonization
Inflammation of the nasal vestibule may result from fol
-
liculitis of the hairs that line this orifice and is usually the 
result of nasal manipulation or hair trimming. Systemic 
antibiotics effective against 
S aureus
 (such as dicloxacillin, 
250 mg orally four times daily for 7–10 days) are indicated. 
Topical mupirocin 2% nasal ointment (applied two or three 
times daily) may be a helpful addition and may prevent 
future occurrences. If recurrent, the addition of rifampin 
(10 mg/kg orally twice daily for the last 4 days of dicloxacil
-
lin treatment) may eliminate the 
S aureus
 carrier state. If a 
furuncle exists, it should be incised and drained, preferably 
intranasally. Adequate treatment of these infections is 
important to prevent retrograde spread of infection 
through valveless veins into the cavernous sinus and intra
-
cranial structures.
S aureus
 is the leading nosocomial pathogen, and nasal 
carriage is a well-defined risk factor in the development 
and spread of nosocomial infections. Nasal and extranasal 
methicillin-resistant 
S aureus
 (MRSA) colonization are 
associated with a 30% risk of developing an invasive MRSA 
infection during hospital stays. While the vast majority 
have no vestibulitis symptoms, screening by nasal swabs 
and PCR-based assays has a demonstrated 30% rate of 
 
S aureus
 colonization in hospital patients and an 11% rate 
of MRSA colonization in intensive care unit patients. 
Elimination of the carrier state is challenging, but studies 
of mupirocin 2% nasal ointment application with chlorhex
-
idine facial washing (40 mg/mL) twice daily for 5 days have 
demonstrated decolonization in 39% of patients.
Sai N et al. Efficacy of the decolonization of methicillin-resistant 
 carriers in clinical practice. Antimicrob

 carriers in clinical practice. Antimicrob 
Resist Infect Control. 2015 Dec 18;4:56. [PMID: 26688720]
Vigil DI et al. Risk of MRSA infection in patients with intermit
-
tent versus persistent MRSA nares colonization. Infect Con
-
trol Hosp Epidemiol. 2015 Nov;36(11):1292–7. [PMID: 
26289065]
4. Invasive Fungal Sinusitis
Invasive fungal sinusitis is rare and includes both rhinocer
-
ebral mucormycosis (
Mucor, Absidia,
 and 
Rhizopus sp.
) and 
other invasive fungal infections, such as 
. The 
fungus spreads rapidly through vascular channels and may 
be lethal if not detected early. Patients with mucormycosis 
almost invariably have some degree of immunocompro
-
mise, such as diabetes mellitus, long-term corticosteroid 
therapy, or end-stage renal disease, and particularly pro
-
found immunocompromise such as for the treatment of 
hematologic malignancies. Occasional cases have been 
reported in patients with AIDS, though 
 sp. is 
more common in this setting. The initial symptoms may be 
similar to those of acute bacterial rhinosinusitis, although 
facial pain is often more severe. Nasal drainage is typically 
clear or straw-colored, rather than purulent, and visual 
symptoms may be noted at presentation in the absence of 
significant nasal findings. On examination, the classic 
finding of mucormycosis is a black eschar on the middle 
turbinate, but this finding is not universal and may not be 
apparent if the infection is deep or high within the nasal 
bones. Often the mucosa appears normal or simply pale 
and dry. Early diagnosis requires suspicion of the disease 
and nasal biopsy with silver stains, revealing broad nonsep
-
tate hyphae within tissues and necrosis with vascular 
occlusion. Because CT or MRI may initially show only soft 
tissue changes, biopsy and ultimate debridement should be 
based on the clinical setting rather than radiographic dem
-
onstration of bony destruction or intracranial changes.
Invasive fungal sinusitis represents a medical and surgi
-
cal emergency. Once recognized, amphotericin B by intra
-
venous infusion and prompt wide surgical debridement are 
indicated for patients with reversible immune deficiency 
(eg, poorly controlled hyperglycemia in diabetes). Lipid-
based amphotericin B (Ambisome) may be used in patients 
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who have kidney disease or who develop it secondary to 
nephrotoxicity of nonlipid amphotericin. Other antifun
-
gals, including voriconazole and caspofungin, may be 
appropriate therapy depending on the fungus. Surgical 
management, while necessary for any possibility of cure, 
often results in tremendous disfigurement and functional 
deficits (eg, often resulting in the loss of at least one eye). 
Even with early diagnosis and immediate appropriate 
intervention, the prognosis is guarded. In persons with 
diabetes, the mortality rate is about 20%. If kidney disease 
is present or develops, mortality is over 50%; in the setting 
of AIDS or hematologic malignancy with neutropenia, 
mortality approaches 100%. Whether to undertake aggres
-
sive surgical management should be considered carefully 
because many patients are gravely ill at the time of diagno
-
sis, and overall disease-specific survival is only about 57%.
Payne SJ et al. Acute invasive fungal rhinosinusitis: a 15-year 
experience with 41 patients. Otolaryngol Head Neck Surg. 
2016 Apr;154(4):759–64. [PMID: 26884367]
ALLERGIC RHINITIS
 
»
Clear rhinorrhea, sneezing, tearing, eye irritation, 
and pruritus.
 
»
Associated symptoms include cough, broncho
-
spasm, and eczematous dermatitis.
 
»
Environmental allergen exposure in the presence 
of allergen-specific IgE.
 
»
Allergic rhinitis is very common in the United States with 
population studies reporting a prevalence of ~20% (range: 
14–40%). Allergic rhinitis adversely affects school and 
work performance, costing about $6 billion annually in the 
United States. Seasonal allergic rhinitis is most commonly 
caused by pollens and spores. Flowering shrub and tree 
pollens are most common in the spring, flowering plants 
and grasses in the summer, and ragweed and molds in the 
fall. Dust, household mites, air pollution, and pet dander 
may produce year-round symptoms, termed “perennial 
rhinitis. ”
 
»
The symptoms of “hay fever” are similar to those of viral 
rhinitis but are usually persistent and may show seasonal 
variation. Nasal symptoms are often accompanied by eye 
irritation, pruritus, conjunctival erythema, and excessive 
tearing. Many patients have a strong family history of atopy 
or allergy.
The clinician should be careful to distinguish allergic 
rhinitis from vasomotor (nonallergic) rhinitis. 
Vasomotor 
rhinitis
 is caused by increased sensitivity of the vidian 
nerve and is a common cause of clear rhinorrhea in elderly 
persons. Often patients will report that they have troubling 
rhinorrhea in response to numerous nasal stimuli, includ
-
ing warm or cold air, odors or scents, light, or particulate 
matter.
On physical examination, the mucosa of the turbinates 
is usually pale or violaceous because of venous engorge
-
ment. This is in contrast to the erythema of viral rhinitis. 
Nasal polyps, which are yellowish boggy masses of hyper
-
trophic mucosa, are associated with long-standing allergic 
rhinitis.
 
»
Treatment
A. Intranasal Corticosteroids
Intranasal corticosteroid sprays are the mainstay of treat
-
ment of allergic rhinitis. They are more effective—and fre
-
quently less expensive—than nonsedating antihistamines, 
though patients should be reminded that there may be a 
delay in onset of relief of 2 or more weeks. Corticosteroid 
sprays may also shrink hypertrophic nasal mucosa and nasal 
polyps, thereby providing an improved nasal airway and 
ostiomeatal complex drainage. Because of this effect, intra
-
nasal corticosteroids are critical in treating allergy in patients 
prone to recurrent acute bacterial rhinosinusitis or chronic 
rhinosinusitis. Available preparations include beclometha
-
sone (42 mcg/spray twice daily per nostril), flunisolide 
(25 mcg/spray twice daily per nostril), mometasone furoate 
(200 mcg once daily per nostril), budesonide (100 mcg twice

-
(200 mcg once daily per nostril), budesonide (100 mcg twice 
daily per nostril), and fluticasone propionate (200 mcg 
once daily per nostril). All are considered equally effective. 
Probably the most critical factors are compliance with regu
-
lar use and proper introduction into the nasal cavity. In order 
to deliver medication to the region of the middle meatus, 
proper application involves holding the bottle straight up 
with the head tilted forward and pointing the bottle toward 
the ipsilateral ear when spraying. Side effects are limited, the 
most annoying being epistaxis (perhaps related to incorrect 
delivery of the drug toward the nasal septum).
B. Antihistamines
Antihistamines offer temporary, but immediate, control of 
many of the most troubling symptoms of allergic rhinitis. 
Effective antihistamines include nonsedating loratadine 
(10 mg orally once daily), desloratadine (5 mg once daily), 
and fexofenadine (60 mg twice daily or 120 mg once daily), 
and minimally sedating cetirizine (10 mg orally once 
daily). Brompheniramine or chlorpheniramine (4 mg 
orally every 6–8 hours, or 8–12 mg orally every 8–12 hours 
as a sustained-release tablet) and clemastine (1.34–2.68 mg 
orally twice daily) may be less expensive but are usually 
associated with some drowsiness. The H
1
-receptor antago
-
nist nasal spray azelastine (1–2 sprays per nostril daily) is 
also effective, but many patients object to its bitter taste. 
Other side effects of oral antihistamines besides sedation 
include xerostomia and antihistamine tolerance (with 
eventual return of allergy symptoms despite initial benefit 
after several months of use). In such patients, typically those 
with perennial allergy, alternating effective antihistamines 
periodically can control symptoms over the long term.
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C. Adjunctive Treatment Measures
Antileukotriene medications, such as montelukast 
 
(10 mg/day orally), alone or with cetirizine (10 mg/day 
orally) or loratadine (10 mg/day orally), may improve 
nasal rhinorrhea, sneezing, and congestion. Cromolyn 
sodium and sodium nedocromil are also useful adjunct 
agents for allergic rhinitis. They work by stabilizing mast 
cells and preventing proinflammatory mediator release. 
Topical agents, they have very few side effects. The most 
useful form of cromolyn is probably the ophthalmologic 
preparation. Intranasal cromolyn is cleared rapidly and 
must be administered four times daily for continued 
symptom relief, and it is not nearly as effective as inhaled 
corticosteroid.
Intranasal anticholinergic agents, such as ipratropium 
bromide 0.03% or 0.06% sprays (42–84 mcg per nostril 
three times daily), may be helpful adjuncts when rhinor
-
rhea is a major symptom. They are not as effective for treat
-
ing allergic rhinitis but are more useful for treating 
vasomotor rhinitis.
Avoiding or reducing exposure to airborne allergens is 
the most effective means of alleviating symptoms of aller
-
gic rhinitis. Depending on the allergen, this can be 
extremely difficult. Maintaining an allergen-free environ
-
ment by covering pillows and mattresses with plastic cov
-
ers, substituting synthetic materials (foam mattress, 
acrylics) for animal products (wool, horsehair), and remov
-
ing dust-collecting household fixtures (carpets, drapes, 
bedspreads, wicker) is worth the attempt to help more 
troubled patients. Air purifiers and dust filters may also aid 
in maintaining an allergen-free environment. Nasal saline 
irrigations are a useful adjunct in the treatment of allergic 
rhinitis to mechanically flush the allergens from the nasal 
cavity. There is no clear benefit to hypertonic saline over 
commercially available normal saline preparations (eg, Ayr 
or Ocean Spray). When symptoms are extremely bother
-
some, a search for offending allergens may prove helpful. 
This can either be done by serum radioallergosorbent test 
(RAST) testing or skin testing by an allergist.
In some cases, allergic rhinitis symptoms are inade
-
quately relieved by medication and avoidance measures. 
Often, such patients have a strong family history of atopy 
and may also have lower respiratory manifestations, such 
as allergic asthma. Referral to an allergist may be appropri
-
ate for consideration of immunotherapy. This treatment 
course is quite involved, with proper identification of 
offending allergens, progressively increasing doses of 
allergen(s), and eventual maintenance dose administration 
over a period of 3–5 years. Immunotherapy has been 
proven to reduce circulating IgE levels in patients with 
allergic rhinitis and reduce the need for allergy medica
-
tions. Both subcutaneous and sublingual immunotherapy 
have been shown to be effective in the long-term treatment 
of refractory allergic rhinitis. Treatments are initiated at a 
suitable medical facility with monitoring following treat
-
ment because of the risk of anaphylaxis during dose escala
-
tion; later, sublingual immunotherapy may be administered 
at home. Local reactions from subcutaneous injections are 
common and usually self-limited.
Caimmi D et al. Allergen immunotherapy outcomes and unmet 
needs: a critical review. Immunol Allergy Clin North Am. 
2016 Feb;36(1):181–9. [PMID: 26617234]
Durham SR et al. Sublingual or subcutaneous immunotherapy 
for allergic rhinitis? J Allergy Clin Immunol. 2016 Feb;
 
137(2):339–49. [PMID: 26853126]
Hoyte FC et al. Recommendations for the pharmacologic man
-
agement of allergic rhinitis. Allergy Asthma Proc. 2014 
 
May–Jun;35(Suppl 1):S20–7. [PMID: 25582158]
Nankervis H et al. House dust mite reduction and avoidance 
measures for treating eczema. Cochrane Database Syst Rev. 
2015 Jan 19;1:CD008426. [PMID: 25598014]
OLFACTORY DYSFUNCTION
 
»

»
Subjective diminished smell or taste sensation.
 
»
Lack of objective nasal obstruction.
 
»
Objective decrease in olfaction demonstrated by 
testing.
 
»
Anatomic blockage of the nasal cavity with subsequent 
airflow disruption is the most common cause of olfactory 
dysfunction (hyposmia or anosmia). Polyps, septal defor
-
mities, and nasal tumors may be the cause. Transient olfac
-
tory dysfunction often accompanies the common cold, 
nasal allergies, and perennial rhinitis through changes in 
the nasal and olfactory epithelium. About 20% of olfactory 
dysfunction is idiopathic, although it often follows a viral 
illness. Central nervous system neoplasms, especially those 
that involve the olfactory groove or temporal lobe, may 
affect olfaction and must be considered in patients with no 
other explanation for their hyposmia or other neurologic 
signs. Head trauma is a rare but severe cause of olfactory 
dysfunction. Shearing of the olfactory neurites accounts for 
less than 5% of cases of hyposmia but is more commonly 
associated with anosmia. Absent, diminished, or distorted 
smell or taste has been reported in a wide variety of endo
-
crine, nutritional, and nervous disorders. In particular, 
olfactory dysfunction in Parkinson disease and Alzheimer 
disease has been the subject of research as neurofibrillary 
tangles and Lewy bodies are found throughout the olfac
-
tory system. Quantitation of olfactory dysfunction may 
serve as a useful marker of disease progression and 
response to specific treatment.
 
»
Evaluation of olfactory dysfunction should include a thor
-
ough history of systemic illnesses and medication use as 
well as a physical examination focusing on the nose and 
nervous system. Nasal obstruction (from polyps, trauma, 
foreign bodies, or nasal masses) can cause functional 
hyposmia and should be excluded before concluding that 
the disruption of olfaction is primary. Most clinical offices 
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are not set up to test olfaction, but such tests may at times 
be worthwhile if only to assess whether a patient possesses 
any sense of smell at all. The University of Pennsylvania 
Smell Identification Test (UPSIT) is available commercially 
and is a simple, self-administered “scratch-and-sniff ” test 
that is useful in differentiating hyposmia, anosmia, and 
malingering. Odor threshold can be tested at regional spe
-
cialty centers using increasing concentrations of various 
odorants.
 
»
Treatment
Hyposmia secondary to nasal polyposis, obstruction, and 
chronic rhinosinusitis may respond to endoscopic sinus 
surgery. Unfortunately, there is no specific treatment for 
primary disruption of olfaction; some disturbances sponta
-
neously resolve. The degree of hyposmia is the greatest 
predictor of recovery, with less severe hyposmia recovering 
at a much higher rate. In permanent hyposmia, counseling 
should be offered about seasoning foods (such as using 
pepper that stimulates the trigeminal as well as olfactory 
chemoreceptors, rather than table salt) and safety issues 
(such as installing home smoke alarms and using electric 
rather than gas appliances).
Coelho DH et al. Posttraumatic olfactory dysfunction. Auris 
Nasus Larynx. 2016 Apr;43(2):137–43. [PMID: 26441369]
Doty RL. Olfactory dysfunction and its measurement in the 
clinic. World J Otorhinolaryngol Head Neck Surg. 2015 
 
Oct 26;1(1):28–33. [PMID: 29204537]
Riga M et al. Hyposmia: an underestimated and frequent adverse 
effect of chemotherapy. Support Care Cancer. 2015 Oct;
 
23(10):3053–8. [PMID: 25739754]
Thompson CF et al. Olfaction in endoscopic sinus and skull base 
surgery. Otolaryngol Clin North Am. 2015 Oct;48(5):795–804. 
[PMID: 26117298]
EPISTAXIS
 
»
Bleeding from a unilateral anterior nasal cavity 
most common.
 
»
Most cases may be successfully treated by direct 
pressure on the bleeding site for 15 minutes. 
When this is inadequate, topical sympathomimet
-
ics and various nasal tamponade methods are 
usually effective.
 
»
Posterior, bilateral, or large-volume epistaxis 
should be triaged immediately to a specialist in a 
critical care setting.
 
»
Epistaxis is an extremely common problem in the primary 
care setting. Predisposing factors include nasal trauma 
(nose picking, foreign bodies, forceful nose blowing), rhi
-
nitis, nasal mucosal drying from low humidity or supple
-
mental nasal oxygen, deviation of the nasal septum, 
atherosclerotic disease, hereditary hemorrhagic telangiec
-
tasia (Osler-Weber-Rendu syndrome), inhaled nasal 
cocaine or other drug use, and alcohol use. Poorly con
-
trolled hypertension has traditionally been associated 
with epistaxis, although confounding factors during 
bleeding events make establishing a causal relationship 
impossible. Anticoagulation or antiplatelet medications 
may be associated with a higher incidence of epistaxis, 
more frequent recurrence of epistaxis, and greater diffi
-
culty controlling bleeding, but they do not cause epistaxis. 
Bleeding is most common in the anterior septum where a 
confluence of veins creates a superficial venous plexus 
(Kiesselbach plexus).
 
»
It is important in all patients with epistaxis to consider 
underlying causes of the bleeding. Laboratory assessment of 
bleeding parameters may be indicated, especially in recur
-
rent cases. Once the acute episode has passed, careful 
examination of the nose and paranasal sinuses to rule out 
neoplasia and hereditary hemorrhagic telangiectasia is wise.
Patients presenting with epistaxis often have higher 
blood pressures than control patients, but in many cases, 
blood pressure returns to normal following treatment of 
acute bleeding. Repeat evaluation for clinically significant 
hypertension and treatment should be performed follow
-
ing control of epistaxis and removal of any packing.
 
»
Treatment

-
 
»
Treatment
Most cases of anterior epistaxis may be successfully treated 
by direct pressure on the site by compression of the nares 
continuously for 15 minutes. Venous pressure is reduced in 
the sitting position, and slight leaning forward lessens the 
swallowing of blood. Short-acting topical nasal deconges
-
tants (eg, phenylephrine, 0.125–1% solution, one or two 
sprays), which act as vasoconstrictors, may also help. 
When the bleeding does not readily subside, the nose 
should be examined, using good illumination and suction, 
in an attempt to locate the bleeding site. Topical 4% cocaine 
applied either as a spray or on a cotton strip serves both as 
an anesthetic and a vasoconstrictor. If cocaine is unavail
-
able, a topical decongestant (eg, oxymetazoline) and a topi
-
cal anesthetic (eg, tetracaine or lidocaine) provide similar 
results. When visible, the bleeding site may be cauterized 
with silver nitrate, diathermy, or electrocautery. A supple
-
mental patch of Surgicel or Gelfoam may be helpful with a 
moisture barrier, such as petroleum-based ointment, to 
prevent drying and crusting. Warfarin may be continued in 
the setting of controlled epistaxis, although resorbable 
packing may preferable in these patients.
Occasionally, a site of bleeding may be inaccessible to 
direct control, or attempts at direct control may be unsuc
-
cessful. In such cases, there are a number of alternatives. 
When the site of bleeding is anterior, a hemostatic sealant, 
pneumatic nasal tamponade, or anterior packing may suf
-
fice. There are a number of ways to do this, such as with 
several feet of lubricated iodoform packing systematically 
placed in the floor of the nose and then the vault of the 
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nose, or with various manufactured products designed for 
nasal tamponade.
About 5% of nasal bleeding originates in the posterior 
nasal cavity. Such bleeds are more commonly associated with 
atherosclerotic disease and hypertension. If an anteriorly 
placed pneumatic nasal tamponade is unsuccessful, it may be 
necessary to consult an otolaryngologist for a pack to occlude 
the choana before placing a pack anteriorly. In emergency 
settings, double balloon packs (Epistat) may facilitate rapid 
control of bleeding with little or no mucosal trauma. Because 
such packing is uncomfortable, bleeding may persist, and 
vasovagal syncope is quite possible, hospitalization for moni
-
toring and stabilization is indicated. Opioid analgesics are 
needed to reduce the considerable discomfort and elevated 
blood pressure caused by a posterior pack.
Surgical management of epistaxis, through ligation of 
the nasal arterial supply (internal maxillary artery and 
ethmoid arteries) is an alternative to posterior nasal pack
-
ing. Endovascular embolization of the internal maxillary 
artery or facial artery is also quite effective and can allow 
very specific control of hemorrhage. Such alternatives are 
necessary when packing fails to control life-threatening 
hemorrhage. On very rare occasions, ligation of the exter
-
nal carotid artery may be necessary.
After control of epistaxis, the patient is advised to avoid 
straining and vigorous exercise for several days. Nasal 
saline should be applied to the packing frequently to keep 
the packing moist. Avoidance of hot or spicy foods and 
tobacco is also advisable, since these may cause nasal vaso
-
dilation. Avoiding nasal trauma, including nose picking, is 
an obvious necessity. Lubrication with petroleum jelly or 
bacitracin ointment and increased home humidity may 
also be useful ancillary measures. Finally, antistaphylococ
-
cal antibiotics (eg, cephalexin, 500 mg orally four times 
daily, or clindamycin, 150 mg orally four times daily) are 
indicated to reduce the risk of toxic shock syndrome devel
-
oping while the packing remains in place (at least 5 days).
 
»
•	
Patients with recurrent epistaxis, large-volume epi
-
staxis, and episodic epistaxis with associated nasal 
obstruction should be referred to an otolaryngologist 
for endoscopic evaluation and possible imaging.
•	
Those with ongoing bleeding beyond 15 minutes should 
be taken to a local emergency department if the clini
-
cian is not prepared to manage acute epistaxis.
Bola S et al. Does the continuation of warfarin change manage
-
ment outcomes in epistaxis patients? J Laryngol Otol. 
 
2016 Mar;130(3):256–60. [PMID: 26707504]
Chin CJ et al. Epistaxis in hereditary hemorrhagic telangiectasia: 
an evidence based review of surgical management. J Otolar
-
yngol Head Neck Surg. 2016 Jan 12;45:3. [PMID: 26754744]
Dupuis-Girod S et al. Effect of bevacizumab nasal spray on epi
-
staxis duration in hereditary hemorrhagic telangectasia: a 
randomized clinical trial. JAMA. 2016 Sep 6;316(9):934–42. 
[PMID: 27599328]
Whitehead KJ et al. Effect of topical intranasal therapy on epi
-
staxis frequency in patients with hereditary hemorrhagic tel
-
angiectasia: a randomized clinical trial. JAMA. 2016 Sep 6;
 
316(9):943–51. [PMID: 27599329]
NASAL TRAUMA
The nasal pyramid is the most frequently fractured bone in 
the body. Fracture is suggested by crepitance or palpably 
mobile bony segments. Epistaxis and pain are common, as 
are soft-tissue hematomas (“black eye”). It is important to 
make certain that there is no palpable step-off of the infra
-
orbital rim, which would indicate the presence of a zygo
-
matic complex fracture. Radiologic confirmation may at 
times be helpful but is not necessary in uncomplicated nasal 
fractures. It is also important to assess for possible concomi
-
tant additional facial, spine, pulmonary, or intracranial 
injuries when the circumstances of injury are suggestive, as

-
injuries when the circumstances of injury are suggestive, as 
in the case of automobile and motorcycle accidents.
Treatment is aimed at maintaining long-term nasal 
airway patency and cosmesis. Closed reduction can be 
performed under local or general anesthesia; closed reduc
-
tion under general anesthesia appears to afford better 
patient satisfaction and decreased need for subsequent 
revision septoplasty or rhinoplasty.
Intranasal examination should be performed in all 
cases to rule out septal hematoma, which appears as a wid
-
ening of the anterior septum, visible just posterior to the 
columella. The septal cartilage receives its only nutrition 
from its closely adherent mucoperichondrium. An 
untreated subperichondrial hematoma will result in loss of 
the nasal cartilage with resultant saddle nose deformity. 
Septal hematomas may become infected, with 
S aureus
 
most commonly, and should be drained with an incision in 
the inferior mucoperichondrium on both sides.
Packing for 2–5 days is often helpful to help prevent re-
formation of the hematoma. Antibiotics with antistaphylo
-
coccal efficacy (eg, cephalexin, 500 mg four times daily, or 
clindamycin, 150 mg four times daily) should be given for 
3–5 days or the duration of the packing to reduce the risk 
of toxic shock syndrome and the drained fluid sent for 
culture.
Basheeth N et al. Acute nasal fracture management: a prospec
-
tive study and literature review. Laryngoscope. 2015 Dec;
 
125(12):2677–84. [PMID: 25959006]
TUMORS & GRANULOMATOUS DISEASE
1. Benign Nasal Tumors
A. Nasal Polyps
Nasal polyps are pale, edematous, mucosally covered 
masses commonly seen in patients with allergic rhinitis. 
They may result in chronic nasal obstruction and a dimin
-
ished sense of smell. In patients with nasal polyps and a 
history of asthma, aspirin should be avoided as it may 
precipitate a severe episode of bronchospasm, known as 
triad asthma
 (Samter triad). Such patients may have an 
immunologic salicylate sensitivity.
Use of topical intranasal corticosteroids improves the 
quality of life in patients with nasal polyposis and chronic 
rhinosinusitis. Initial treatment with topical nasal cortico
-
steroids (see Allergic Rhinitis section for specific drugs) for 
1–3 months is usually successful for small polyps and may 
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reduce the need for operation. A short course of oral corti
-
costeroids (eg, prednisone, 6-day course using 21 [5-mg] 
tablets: 6 tablets [30 mg] on day 1 and tapering by 1 tablet 
[5 mg] each day) may also be of benefit. When polyps are 
massive or medical management is unsuccessful, polyps 
may be removed surgically. In healthy persons, this is a 
minor outpatient procedure. In recurrent cases or when 
surgery itself is associated with increased risk (such as in 
patients with asthma), a more complete procedure, such as 
ethmoidectomy, may be advisable. In recurrent polyposis, it 
may be necessary to remove polyps from the ethmoid, 
sphenoid, and maxillary sinuses to provide longer-lasting 
relief. Intranasal corticosteroids should be continued fol
-
lowing polyp removal to prevent recurrence, and the clini
-
cian should consider allergen testing to determine the 
offending allergen and avoidance measures. Biologic thera
-
pies with interleukin-specific blocking antibodies are cur
-
rently in preclinical and clinical trials and may be a valuable 
means of controlling nasal mucosal polyps in the future.
Rivero A et al. Anti-IgE and anti-IL5 biologic therapy in the 
treatment of nasal polyposis: a systematic review and meta-
analysis. Ann Otol Rhinol Laryngol. 2017 Nov;126(11):
 
739–47. [PMID: 28918644]
Stevens W et al. Aspirin-exacerbated diseases: advances in 
asthma with nasal polyposis, urticaria, angioedema, and ana
-
phylaxis. Curr Allergy Asthma Rep. 2015 Dec;15(12):69. 
[PMID: 26475526]
B. Inverted Papilloma
Inverted papillomas are benign tumors caused by human 
papillomavirus (HPV) that usually arise on the lateral nasal 
wall. They present with unilateral nasal obstruction and 
occasionally hemorrhage. They are often easily seen on ante
-
rior rhinoscopy as cauliflower-like growths in or around the 
middle meatus. Because squamous cell carcinoma is seen in 
about 10% of inverted or schneiderian papillomas, complete 
excision is strongly recommended. This usually requires a 
medial maxillectomy, but in selected cases an endoscopic 
approach may be possible. Because recurrence rates for 
inverted papilloma are reported to be as high as 20%, subse
-
quent clinical and radiologic follow-up is imperative. All 
excised tissue (not just a portion) should be carefully reviewed 
by the pathologist to be sure no carcinoma is present.
Adriaensen GF et al. Endoscopic treatment of inverted 
 
papilloma attached in the frontal sinus/recess. Rhinology. 
2015 Dec;53(4):317–24. [PMID: 26345107]
Thavaraj S. Human papillomavirus-associated neoplasms of 
 
the sinonasal tract and nasopharynx. Semin Diagn Pathol. 
2016 Mar;33(2):104–11. [PMID: 26482046]
2. Malignant Nasopharyngeal & 
p
ar
anasal 
 
Sinus Tumors
Though rare, malignant tumors of the nose, nasopharynx, 
and paranasal sinuses are quite problematic because they 
tend to remain asymptomatic until late in their course. 
Squamous cell carcinoma is the most common cancer 
found in the sinuses and nasopharynx. It is especially com
-
mon in the nasopharynx, where it obstructs the eustachian 
tube and results in serous otitis media. Nasopharyngeal 
carcinoma (nonkeratinizing squamous cell carcinoma or 
lymphoepithelioma) is usually associated with elevated IgA 
antibody to the viral capsid antigen of the Epstein-Barr 
virus (EBV). It is particularly common in patients of south
-
ern Chinese descent and has a weaker association with 
tobacco exposure than other head and neck squamous cell 
carcinomas. Adenocarcinomas, mucosal melanomas, sar
-
comas, and non-Hodgkin lymphomas are less commonly 
encountered neoplasms of this area.
Early symptoms are nonspecific, mimicking those of 
rhinitis or sinusitis. Unilateral nasal obstruction, otitis 
media, and discharge are common, with pain and recurrent 
hemorrhage often clues to the diagnosis of cancer. Any 
adult with persistent unilateral nasal symptoms or new

adult with persistent unilateral nasal symptoms or new 
otitis media should be thoroughly evaluated with nasal 
endoscopy and nasopharyngoscopy. A high index of suspi
-
cion remains a key to early diagnosis of these tumors. 
Patients often present with advanced symptoms, such as 
proptosis, expansion of a cheek, or ill-fitting maxillary 
dentures. Malar hypesthesia, due to involvement of the 
infraorbital nerve, is common in maxillary sinus tumors. 
Biopsy is necessary for definitive diagnosis, and MRI is the 
best imaging study to delineate the extent of disease and 
plan appropriate surgery and radiation.
Treatment depends on the tumor type and the extent of 
disease. Very early stage disease may be treated with mega
-
voltage radiation therapy alone, but advanced nasopharyn
-
geal carcinoma is best treated with concurrent radiation 
and cisplatin followed by adjuvant chemotherapy with cis
-
platin and fluorouracil. This chemoradiation therapy pro
-
tocol significantly decreases local, nodal, and distant 
failures and increases progression-free and overall survival 
in advanced stage disease. Locally recurrent nasopharyn
-
geal carcinoma may in selected cases be treated with repeat 
irradiation protocols or surgery with moderate success and 
a high degree of concern about local wound healing. Other 
squamous cell carcinomas are best treated—when resectable—
with a combination of surgery and irradiation. Cranial base 
surgery, which can be done endoscopically using image 
navigation, appears to be an effective modality in improv
-
ing the overall prognosis in paranasal sinus malignancies 
eroding the ethmoid roof. Although the prognosis is poor 
for advanced tumors, the results of treating resectable 
tumors of paranasal sinus origin have improved with the 
wider use of skull base resections and intensity-modulated 
radiation therapy. Cure rates are often 45–60%.
Lee AW et al. Management of nasopharyngeal carcinoma: current 
practice and future perspective. J Clin Oncol. 2015 Oct 10;
 
33(29):3356–64. [PMID: 26351355]
Sze H et al. Chemotherapy for nasopharyngeal carcinoma—
 
current recommendation and controversies. Hematol Oncol 
Clin North Am. 2015 Dec;29(6):1107–22. [PMID: 26568551]
3. Sinonasal Inflammatory Disease 
(Granulomatosis with 
p
oly
angiitis & Sarcoidosis)
The nose and paranasal sinuses are involved in over 90% of 
cases of 
granulomatosis with polyangiitis
. It is often not 
realized that involvement at these sites is more common 
CMDT19_Ch08_p0210-p0251.indd   233

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▲
Figure 8–5.
 
Leukoplakia with moderate dysplasia on 
the lateral border of the tongue. 
from Ellen Eisenberg, DMD in Usatine RP , Smith MA, 
than involvement of lungs or kidneys. Examination shows 
bloodstained crusts and friable mucosa. Biopsy, when posi
-
tive, shows necrotizing granulomas and vasculitis. Other 
recognized sites of granulomatosis with polyangiitis in the 
head and neck include the subglottis and the middle ear.
 commonly involves the paranasal sinuses 
and is clinically similar to other chronic sinonasal inflam
-
matory processes. Sinonasal symptoms, including rhinor
-
rhea, nasal obstruction, and hyposmia or anosmia may 
precede diagnosis of sarcoidosis in other organ systems. 
Clinically, the turbinates appear engorged with small white 
granulomas. Biopsy shows classic noncaseating granulo
-
mas. Notably, patients with sinonasal involvement gener
-
ally have more trouble managing sarcoidosis in other organ 
systems.
Polymorphic reticulosis
 (midline malignant reticulo
-
sis, idiopathic midline destructive disease, lethal midline 
granuloma)—as the multitude of apt descriptive terms sug
-
gests—is not well understood but appears to be a nasal 
T-cell or NK-cell lymphoma. In contrast to granulomatosis 
with polyangiitis, involvement is limited to the mid-face, 
and there may be extensive bone destruction. Many 
destructive lesions of the mucosa and nasal structures 
labeled as polymorphic reticulosis are in fact non-Hodgkin 
lymphoma of either NK-cell or T-cell origin. Immunophe
-
notyping, especially for CD56 expression, is essential in the 
histologic evaluation. Even when apparently localized, 
these lymphomas have a poor prognosis, with progression 
and death within a year the rule.
For treatment of granulomatosis with polyangiitis, see 
Chapter 20.
Badhey AK et al. Sarcoidosis of the head and neck. Head Neck 
Pathol. 2015 Jun;9(2):260–8. [PMID: 25183456]
Knopf A et al. Clinical aspects of granulomatosis with polyangi
-
itis affecting the head and neck. Eur Arch Otorhinolaryngol. 
2015 Jan;272(1):185–93. [PMID: 24609734]
Lawson W et al. Sinonasal sarcoidosis: a new system of classifica
-
tion acting as a guide to diagnosis and treatment. Am J Rhinol 
Allergy. 2014 Jul–Aug;28(4):317–22. [PMID: 25197919]
Pakalniskis MG et al. The many faces of granulomatosis with 
polyangiitis: a review of the head and neck imaging manifes
-
tations. AJR Am J Roentgenol. 2015 Dec;205(6):W619–29. 
[PMID: 26587951]
 
º
DISEASES OF THE ORAL CAVITY & 
p
HARYNX
LEUKOPLAKIA, ERYTHROPLAKIA, ORAL 
LICHEN PLANUS, & ORAL CANCER
 
»
Leukoplakia:
 A white lesion that cannot be 
removed by rubbing the mucosal surface.
 
»
Erythroplakia:
 Similar to leukoplakia except that it 
has a definite erythematous component.
 
»
Oral Lichen Planus:
 Most commonly presents as 
lacy leukoplakia but may be erosive; definitive 
diagnosis requires biopsy.
 
»
Oral Cancer:
 Early lesions appear as leukoplakia or 
erythroplakia; more advanced lesions will be 
larger, with invasion into the tongue such that a 
mass lesion is palpable. Ulceration may be 
present.
 
»
Oropharynx Cancer:
 Unilateral throat masses, 
typically presenting with painful swallowing and 
weight loss.
Leukoplakic regions
 range from small to several centi
-
meters in diameter (Figure 8–5). Histologically, they are 
often hyperkeratoses occurring in response to chronic 
irritation (eg, from dentures, tobacco, lichen planus); about 
2–6%, however, represent either dysplasia or early invasive 
squamous cell carcinoma. Distinguishing between 
leuko
-
plakia
 and 
erythroplakia
 is important because about 90% 
of cases of erythroplakia are either dysplasia or carcinoma. 
Squamous cell carcinoma
 accounts for 90% of oral cancer. 
Alcohol and tobacco use are the major epidemiologic risk 
factors.

factors.
The differential diagnosis may include oral candidiasis, 
necrotizing sialometaplasia, pseudoepitheliomatous hyper
-
plasia, median rhomboid glossitis, and vesiculoerosive 
inflammatory disease, such as erosive lichen planus. This 
should not be confused with the brown-black gingival 
melanin pigmentation—diffuse or speckled—common in 
nonwhites, blue-black embedded fragments of dental 
amalgam, or other systemic disorders associated with gen
-
eral pigmentation (neurofibromatosis, familial polyposis, 
Addison disease). Intraoral melanoma is extremely rare 
and carries a dismal prognosis.
Any area of 
, enlarging area of 
leukoplakia
, 
or a lesion that has submucosal depth on palpation should 
CMDT19_Ch08_p0210-p0251.indd   234

235
 
CMDT 2019
 
▲
Figure 8–6.
 
Oral hairy leukoplakia on the side of the 
tongue in AIDS. 
Usatine, MD, in Usatine RP , Smith MA, Mayeaux EJ Jr, 
 
have an incisional biopsy or an exfoliative cytologic exami
-
nation. Ulcerative lesions are particularly suspicious and 
worrisome. Specialty referral should be sought early both 
for diagnosis and treatment. A systematic intraoral exami
-
nation—including the lateral tongue, floor of the mouth, 
gingiva, buccal area, palate, and tonsillar fossae—and pal
-
pation of the neck for enlarged lymph nodes should be part 
of any general physical examination, especially in patients 
over the age of 45 who smoke tobacco or drink immoder
-
ately. Indirect or fiberoptic examination of the nasophar
-
ynx, oropharynx, hypopharynx, and larynx by an 
otolaryngologist, head and neck surgeon, or radiation 
oncologist should also be considered for such patients 
when there is unexplained or persistent throat or ear pain, 
oral or nasal bleeding, or oral erythroplakia. Fine-needle 
aspiration (FNA) biopsy may expedite the diagnosis if an 
enlarged lymph node is found.
To date, there remain no approved therapies for revers
-
ing or stabilizing leukoplakia or erythroplakia. Clinical 
trials have suggested a role for beta-carotene, celecoxib, 
vitamin E, and retinoids in producing regression of leuko
-
plakia and reducing the incidence of recurrent squamous 
cell carcinomas. None have demonstrated benefit in large 
studies and these agents are not in general use today. The 
mainstays of management are surveillance following elimi
-
nation of carcinogenic irritants (eg, smoking tobacco, 
chewing tobacco or betel nut, drinking alcohol) along with 
serial biopsies and excisions.
Oral lichen planus
 is a relatively common (0.5–2% of 
the population) chronic inflammatory autoimmune dis
-
ease that may be difficult to diagnose clinically because 
of its numerous distinct phenotypic subtypes. For exam
-
ple, the reticular pattern may mimic candidiasis or 
hyperkeratosis, while the erosive pattern may mimic 
squamous cell carcinoma. Management begins with dis
-
tinguishing it from other oral lesions. Exfoliative cytol
-
ogy or a small incisional or excisional biopsy is indicated, 
especially if squamous cell carcinoma is suspected. 
Therapy of lichen planus is aimed at managing pain and 
discomfort. Corticosteroids have been used widely both 
locally and systemically. Cyclosporines and retinoids 
have also been used, but tacrolimus shows the most 
promise in recent studies. Many experts think there is a 
low rate (1%) of squamous cell carcinoma arising within 
lichen planus (in addition to the possibility of clinical 
misdiagnosis).
Hairy leukoplakia
 occurs on the lateral border of the 
tongue and is a common early finding in HIV infection 
(see Chapter 31). It often develops quickly and appears as 
slightly raised leukoplakic areas with a corrugated or 
“hairy” surface (Figure 8–6). While much more prevalent 
in HIV-positive patients, hairy leukoplakia can occur fol
-
lowing solid organ transplantation and is associated with 
Epstein-Barr virus infection and long-term systemic corti
-
costeroid use. Hairy leukoplakia waxes and wanes over 
time with generally modest irritative symptoms. Acyclovir, 
valacyclovir, and famciclovir have all been used for treat
-
ment but produce only temporary resolution of the condi
-
tion. It does not appear to predispose to malignant 
transformation.
Oral cavity squamous cell carcinoma
 can be hard to 
distinguish from other oral lesions, but early detection is 
the key to successful management (Figure 8–7). Raised, 
firm, white lesions with ulcers at the base are highly suspi
-
cious and generally quite painful on even gentle palpation. 
Lesions less than 4 mm in depth have a low propensity to

-
Lesions less than 4 mm in depth have a low propensity to 
metastasize. Most patients in whom the tumor is detected 
before it is 2 cm in diameter are cured by local resection. 
Radiation is reserved for patients with positive margins or 
metastatic disease. Large tumors are usually treated with a 
combination of resection, neck dissection, and external 
beam radiation. Reconstruction, if required, is done at the 
time of resection and can involve the use of myocutaneous 
flaps or vascularized free flaps with or without bone.
 
▲
Figure 8–7.
 
Squamous cell carcinoma of the palate. 
(Used, with permission, from Frank Miller, MD in Usatine 
RP , Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. 
The 
Color Atlas of Family Medicine
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Oropharyngeal squamous cell carcinoma
 generally 
presents later than oral cavity squamous cell carcinoma. 
The lesions tend to be larger and are often buried within 
the lymphoid tissue of the palatine or lingual tonsils. Most 
patients note only unilateral odynophagia and weight loss, 
but ipsilateral cervical lymphadenopathy is often identified 
by the careful clinician. While these tumors are typically 
associated with known carcinogens such as tobacco and 
alcohol, their epidemiology has changed dramatically over 
the past 20 years. Despite demonstrated reductions in 
tobacco and alcohol use within developed nations, the 
incidence of oropharyngeal squamous cell carcinoma has 
not declined over this period. Known as a possible cause of 
head and neck cancer since 1983, the human papillomavi
-
rus (HPV)—most commonly, type 16—is now believed to 
be the cause of up to 70% of all oropharyngeal squamous 
cell carcinoma. HPV-positive tumors are readily distin
-
guished by immunostaining of primary tumor or fine-
needle aspiration biopsy specimens for the p16 protein, a 
tumor suppressor protein that is highly correlated with the 
presence of HPV . These tumors often present in advanced 
stages of the disease with regional cervical lymph node 
metastases (stages III and IV), but have a better prognosis 
than similarly staged lesions in tobacco and alcohol users. 
This difference in disease control is so apparent in multi
-
center studies that, based on the presence or absence of the 
p16 protein, two distinct staging systems for oropharyngeal 
squamous cell carcinoma were introduced in 2018. Ongo
-
ing clinical trials are trying to determine if a reduction in 
treatment intensity is warranted for HPV-associated 
cancers.
Chamani G et al. Efficacy of tacrolimus and clobetasol in the 
treatment of oral lichen planus: a systematic review and meta-
analysis. Int J Dermatol. 2015 Sep;54(9):996–1004. [PMID: 
26204904]
Chera BS et al. Current status and future directions of treatment 
deintensification in human papilloma virus–associated oro
-
pharyngeal squamous cell carcinoma. Semin Radiat Oncol. 
2018 Jan;28(1):27–34. [PMID: 29173753]
Chi AC et al. Oral cavity and oropharyngeal squamous cell 
carcinoma—an update. CA Cancer J Clin. 2015 Sep–Oct;
 
65(5):401–21. [PMID: 26215712]
Gooi Z et al. The epidemiology of the human papillomavirus 
related to oropharyngeal head and neck cancer. Laryngo
-
scope. 2016 Apr;126(4):894–900. [PMID: 26845348]
Greenspan JS et al. Hairy leukoplakia; lessons learned: 30-plus 
years. Oral Dis. 2016 Apr;22(Suppl 1):120–7. [PMID: 
27109280]
Huang SH et al. Overview of the 8th edition TNM classification 
for head and neck cancer. Curr Treat Options Oncol. 2017 Jul;
 
18(7):40. [PMID: 28555375]
Jones KB et al. White lesions in the oral cavity: clinical presenta
-
tion, diagnosis, and treatment. Semin Cutan Med Surg. 
 
2015 Dec;34(4):161–70. [PMID: 26650693]
Lodi G et al. Interventions for treating oral leukoplakia to pre
-
vent oral cancer. Cochrane Database Syst Rev. 2016 Jul 29;
 
7:CD001829. [PMID: 27471845]
Lowy DR et al. Preventing cancer and other diseases caused by 
human papillomavirus infection: 2017 Lasker-DeBakey Clini
-
cal Research Award. JAMA. 2017 Sept 12;318(10):901–2. 
[PMID: 28876435]
ORAL CANDIDIASIS
 
»
Fluctuating throat or mouth discomfort.
 
»
Systemic or local immunosuppression, such as 
recent corticosteroid, chemotherapy, or antibiotic 
use.
 
»
Erythema of the oral cavity or oropharynx with 
creamy-white, curd-like patches.
 
»
Rapid resolution of symptoms with appropriate 
 
»
Oral candidiasis (thrush) is usually painful and looks like 
creamy-white curd-like patches overlying erythematous 
mucosa (see Figure 6–23). Because these white areas are 
easily rubbed off (eg, by a tongue depressor)—unlike leu
-
koplakia or lichen planus—only the underlying irregular

-
koplakia or lichen planus—only the underlying irregular 
erythema may be seen. Oral candidiasis is commonly asso
-
ciated with the following risk factors: (1) use of dentures, 
(2) debilitated state with poor oral hygiene, (3) diabetes 
mellitus, (4) anemia, (5) chemotherapy or local irradiation, 
(6) corticosteroid use (oral or systemic) or (7) broad-
spectrum antibiotics. Another manifestation of candidiasis 
is angular cheilitis (also seen in nutritional deficiencies) 
(Figure 8–8).
B. Diagnostic Studies
The diagnosis is made clinically. A wet preparation using 
potassium hydroxide will reveal spores and may show non
-
septate mycelia. Biopsy will show intraepithelial pseudo
-
mycelia of 
Candida albicans
.
Candidiasis is often the first manifestation of HIV 
infection, and HIV testing should be considered in patients 
 
▲
Figure 8–8.
 
Severe angular cheilitis in HIV-positive 
man with oral thrush. 
Richard P . Usatine, MD, in Usatine RP , Smith MA, Mayeaux 
EJ Jr, Chumley H, Tysinger J. 
 
Medicine
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CMDT 2019
with no known predisposing cause for 
Candida
 over
-
growth (see also Chapter 31). The US Department of 
Health Services Clinical Practice Guideline for Evaluation 
and Management of Early HIV Infection recommends 
examination of the oral mucosa with each clinician visit as 
well as at a dental examination every 6 months for indi
-
viduals infected with HIV .
 
»
Treatment
Effective antifungal therapy may be achieved with any of 
the following: fluconazole (100 mg orally daily for 7 days), 
ketoconazole (200–400 mg orally with breakfast [requires 
acidic gastric environment for absorption] for 7–14 days), 
clotrimazole troches (10 mg dissolved orally five times 
daily), or nystatin mouth rinses (500,000 units [5 mL of 
100,000 units/mL] held in the mouth before swallowing 
three times daily). In patients with HIV infection, however, 
longer courses of therapy with fluconazole may be needed, 
and oral itraconazole (200 mg/day) may be indicated in 
fluconazole-refractory cases. Many of the 
Candida
 species 
in these patients are resistant to first-line azoles and may 
require newer drugs, such as voriconazole. In addition, 
0.12% chlorhexidine or half-strength hydrogen peroxide 
mouth rinses may provide local relief. Nystatin powder 
(100,000 units/g) applied to dentures three or four times 
daily and rinsed off for several weeks may help denture 
wearers.
Patton LL. Current strategies for prevention of oral manifestations 
of human immunodeficiency virus. Oral Surg Oral Med Oral 
Pathol Oral Radiol. 2016 Jan;121(1):29–38. [PMID: 26679357]
Singh A et al. Oral candidiasis: an overview. J Oral Maxillofac 
Pathol. 2014 Sep;18(Suppl 1):S81–5. [PMID: 25364186]
GLOSSITIS, GLOSSODYNIA, DYSGEUSIA, & 
BURNING MOUTH SYNDROME
Inflammation of the tongue with loss of filiform papillae 
leads to a red, smooth-surfaced tongue (glossitis). Rarely 
painful, it may be secondary to nutritional deficiencies (eg, 
niacin, riboflavin, iron, or vitamin E), drug reactions, 
dehydration, irritants, or foods and liquids, and possibly to 
autoimmune reactions or psoriasis. If the primary cause 
cannot be identified and corrected, empiric nutritional 
replacement therapy may be of value.
Glossodynia is burning and pain of the tongue, which 
may occur with or without glossitis. In the absence of any 
clinical findings, it has been termed “burning mouth syn
-
drome. ” Glossodynia with glossitis has been associated 
with diabetes mellitus, drugs (eg, diuretics), tobacco, xero
-
stomia, and candidiasis as well as the listed causes of glos
-
sitis. The burning mouth syndrome typically has no 
identifiable associated risk factors and seems to be most 
common in postmenopausal women. Treating possible 
underlying causes, changing long-term medications to 
alternative ones, and smoking cessation may resolve symp
-
toms of glossitis. Effective treatments for the burning 
mouth syndrome include alpha-lipoic acid and clonaze
-
pam. Clonazepam is most effective as a rapid-dissolving 
tablet placed on the tongue in doses from 0.25 mg to 0.5 mg 
every 8–12 hours. Behavioral therapy has also been shown 
to be effective. Both glossodynia and the burning mouth 
syndrome are benign, and reassurance that there is no 
infection or tumor is likely to be appreciated. Unilateral 
symptoms, symptoms that cannot be related to a specific 
medication, and symptoms and signs involving regions 
supplied by other cranial nerves all may suggest neuropa
-
thology, and imaging of the brain, brainstem, and skull 
base with MRI should be considered.
Brescoll J et al. A review of vitamin B12 in dermatology. Am J 
Clin Dermatol. 2015 Feb;16(1):27–33. [PMID: 25559140]
Klasser GD et al. Burning mouth syndrome. Oral Maxillofac Surg 
Clin North Am. 2016 Aug;28(3):381–96. [PMID: 27475513]
Salerno C et al. An overview of burning mouth syndrome. Front 
Biosci (Elite Ed). 2016 Jan 1;8:213–8. [PMID: 26709657]

Silvestre FJ et al. Burning mouth syndrome: a review and update. 
Rev Neurol. 2015 May 16;60(10):457–63. [PMID: 25952601]
Syed Q et al. The impact of aging and medical status on dysgeu
-
sia. Am J Med. 2016 Jul;129(7):753.e1–6. [PMID: 26899755]
INTRAORAL ULCERATIVE LESIONS
1. Necrotizing Ulcerative Gingivitis 
 
(Trench Mouth, Vincent Angina)
Necrotizing ulcerative gingivitis, often caused by an infec
-
tion with both spirochetes and fusiform bacilli, is common 
in young adults under stress (classically in students at 
examination time). Underlying systemic diseases may also 
predispose to this disorder. Clinically, there is painful acute 
gingival inflammation and necrosis, often with bleeding, 
halitosis, fever, and cervical lymphadenopathy. Warm half-
strength peroxide rinses and oral penicillin (250 mg three 
times daily for 10 days) may help. Dental gingival curettage 
may prove necessary.
Atout RN et al. Managing patients with necrotizing ulcerative 
gingivitis. J Can Dent Assoc. 2013;79:d46. [PMID: 23763733]
2. Aphthous Ulcer (Canker Sore, 
 
Ulcerative Stomatitis)
Aphthous ulcers are very common and easy to recognize. 
Their cause remains uncertain, although an association 
with human herpesvirus 6 has been suggested. Found on 
freely moving, nonkeratinized mucosa (eg, buccal and 
labial mucosa and not attached gingiva or palate), they may 
be single or multiple, are usually recurrent, and appear as 
painful small round ulcerations with yellow-gray fibrinoid 
centers surrounded by red halos. Minor aphthous ulcers 
are less than 1 cm in diameter and generally heal in 
10–14 days. Major aphthous ulcers are greater than 1 cm in 
diameter and can be disabling due to the degree of associ
-
ated oral pain. Stress seems to be a major predisposing 
factor to the eruptions of aphthous ulcers. A study found 
that the frequency of viral rhinitis and bedtime after 11 
pm
 
were independent predictors of aphthous ulcer frequency 
and severity in college students.
Treatment is challenging because no single systemic 
treatment has proven effective. Topical corticosteroids (triam
-
cinolone acetonide, 0.1%, or fluocinonide ointment, 0.05%) 
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in an adhesive base (Orabase Plain) do appear to provide 
symptomatic relief in many patients. Other topical thera
-
pies shown to be effective in controlled studies include 
diclofenac 3% in hyaluronan 2.5%, doxymycine-cyanoac
-
rylate, mouthwashes containing the enzymes amylogluco
-
sidase and glucose oxidase, and amlexanox 5% oral paste. A 
1-week tapering course of prednisone (40–60 mg/day) has 
also been used successfully. Cimetidine maintenance ther
-
apy may be useful in patients with recurrent aphthous 
ulcers. Thalidomide has been used selectively in recurrent 
aphthous ulcerations in HIV-positive patients.
Large or persistent areas of ulcerative stomatitis may be 
secondary to erythema multiforme or drug allergies, acute 
herpes simplex, pemphigus, pemphigoid, epidermolysis 
bullosa acquisita, bullous lichen planus, Behçet disease, or 
inflammatory bowel disease. Squamous cell carcinoma 
may occasionally present in this fashion. When the diagno
-
sis is not clear, incisional biopsy is indicated.
Altenburg A et al. The treatment of chronic recurrent oral aph
-
thous ulcers. Dtsch Arztebl Int. 2014 Oct 3;111(40):665–73. 
[PMID: 25346356]
Belenguer-Guallar I et al. Treatment of recurrent aphthous stoma
-
titis: a literature review. J Clin Exp Dent. 2014 Apr 1;6(2):
 
e168–74. [PMID: 24790718]
Ranganath SP et al. Is optimal management of recurrent aph
-
thous stomatitis possible? A reality check. J Clin Diagn Res. 
2016 Oct;10(10):ZE08–13. [PMID: 27891490]
3. Herpes Stomatitis
Herpes gingivostomatitis is common, mild, and short-
lived and requires no intervention in most adults. In 
immunocompromised persons, however, reactivation of 
herpes simplex virus infection is frequent and may be 
severe. Clinically, there is initial burning, followed by 
typical small vesicles that rupture and form scabs. Lesions 
are most commonly found on the attached gingiva and 
mucocutaneous junction of the lip, but lesions can also 
form on the tongue, buccal mucosa, and soft palate. Acy
-
clovir (200–800 mg orally five times daily for 7–10 days) 
or valacyclovir (1000 mg orally twice daily for 7–10 days) 
may shorten the course and reduce postherpetic pain. 
These treatments may be effective only when started 
within 24–48 hours of the onset of initial symptoms 
(pain, itching, burning) and are not effective once vesicles 
have erupted. Differential diagnosis includes aphthous 
stomatitis, erythema multiforme, syphilitic chancre, and 
Balasubramaniam R et al. Update on oral herpes virus infec
-
tions. Dent Clin North Am. 2014 Apr;58(2):265–80. [PMID: 
24655522]
Patton LL. Current strategies for prevention of oral manifesta
-
tions of human immunodeficiency virus. Oral Surg Oral Med 
Oral Pathol Oral Radiol. 2016 Jan;121(1):29–38. [PMID: 
26679357]
PHARYNGITIS & TONSILLITIS
 
»
Sore throat.
 
»
Fever.
 
»
Anterior cervical adenopathy.
 
»
Tonsillar exudate.
 
»
Focus is to treat group A beta-hemolytic strepto
-
coccus infection to prevent rheumatic sequelae.
 
»
Pharyngitis and tonsillitis account for over 10% of all office 
visits to primary care clinicians and 50% of outpatient anti
-
biotic use. The main concern is determining who is likely 
to have a group A beta-hemolytic streptococcal (GABHS) 
infection, as this can lead to subsequent complications, 
such as rheumatic fever and glomerulonephritis. A second 
public health policy concern is reducing the extraordinary 
cost (both in dollars and in the development of antibiotic-
resistant 
) in the United States associated 
with unnecessary antibiotic use. Questions being asked: 
Have the rapid antigen tests supplanted the need to culture 
a throat under most circumstances? Are clinical criteria

a throat under most circumstances? Are clinical criteria 
alone a sufficient basis for decisions about which patients 
should be given antibiotics? Should any patient receive any 
antibiotic other than penicillin (or erythromycin if penicillin-
allergic)? For how long should treatment be continued? 
Numerous well-done studies and experience with rapid 
laboratory tests for detection of streptococci (eliminating 
the delay caused by culturing) informed a consensus 
experience.
 
»
The clinical features most suggestive of GABHS pharyngi
-
tis include fever over 38°C, tender anterior cervical ade
-
nopathy, lack of a cough, and pharyngotonsillar exudate 
(Figure 8–9). These four features (the Centor criteria), 
when present, strongly suggest GABHS. When two or three 
of the four are present, there is an intermediate likelihood 
of GABHS. When only one criterion is present, GABHS is 
unlikely. Sore throat may be severe, with odynophagia, 
tender adenopathy, and a scarlatiniform rash. An elevated 
white count and left shift are also possible. Hoarseness, 
cough, and coryza are not suggestive of this disease.
Marked lymphadenopathy and a shaggy, white-purple 
tonsillar exudate, often extending into the nasopharynx, 
suggest mononucleosis, especially if present in a young 
adult. With about 90% sensitivity, lymphocyte-to-white-
blood-cell ratios of greater than 35% suggest EBV infection 
and not tonsillitis. Hepatosplenomegaly and a positive 
heterophile agglutination test or elevated anti-EBV titer are 
corroborative. However, about one-third of patients with 
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CMDT 2019
infectious mononucleosis have secondary streptococcal 
tonsillitis, requiring treatment. Ampicillin should routinely 
be avoided if mononucleosis is suspected because it induces 
a rash that might be misinterpreted by the patient as a 
penicillin allergy. Diphtheria (extremely rare but described 
in the alcoholic population) presents with low-grade fever 
and an ill patient with a gray tonsillar pseudomembrane.
The most common pathogens other than GABHS in the 
differential diagnosis of “sore throat” are viruses, 
Neisseria 
gonorrhoeae, Mycoplasma,
 and 
 
Rhinorrhea and lack of exudate would suggest a virus, but 
in practice it is not possible to confidently distinguish viral 
upper respiratory infection from GABHS on clinical 
grounds alone. Infections with 
Corynebacterium diphtheria,
 
anaerobic streptococci, and 
Corynebacterium haemolyticum
 
(which responds better to erythromycin than penicillin) 
may also mimic pharyngitis due to GABHS.
A single-swab throat culture is 90–95% sensitive and the 
rapid antigen detection testing (RADT) is 90–99% sensi
-
tive for GABHS. Results from the RADT are available in 
about 15 minutes.
 
»
Treatment
The Infectious Diseases Society of America recommends 
laboratory confirmation of the clinical diagnosis by means 
of either throat culture or RADT of the throat swab. The 
American College of Physicians–American Society of 
Internal Medicine (ACP-ASIM), in collaboration with the 
Centers for Disease Control and Prevention, advocates use 
of a clinical algorithm alone—in lieu of microbiologic 
testing—for confirmation of the diagnosis in adults for 
whom the suspicion of streptococcal infection is high. Oth
-
ers examine the assumptions of the ACP-ASIM guideline 
for using a clinical algorithm alone and question whether 
those recommendations will achieve the stated objective of 
dramatically decreasing excess antibiotic use. A reasonable 
strategy to follow is that patients with zero or one Centor 
criteria are at very low risk for GABHS and therefore do 
not need throat cultures or RADT of the throat swab and 
should not receive antibiotics. Patients with two or three 
Centor criteria need throat cultures or RADT of the throat 
swab, since positive results would warrant antibiotic treat
-
ment. Patients who have four Centor criteria are likely to 
have GABHS and can receive empiric therapy without 
throat culture or RADT.
A single intramuscular injection of benzathine penicil
-
lin or procaine penicillin, 1.2 million units is an effective 
antibiotic treatment, but the injection is painful. It is now 
used for patients if compliance with an oral regimen is an 
issue. Currently, oral treatment is effective and preferred. 
Penicillin V potassium (250 mg orally three times daily or 
500 mg twice daily for 10 days) or cefuroxime axetil (250 mg 
orally twice daily for 5–10 days) are both effective. The 
efficacy of a 5-day regimen of penicillin V potassium 
appears to be similar to that of a 10-day course, with a 94% 
clinical response rate and an 84% streptococcal eradication 
rate. Erythromycin (also active against 
 and 
Chlamydia
) is a reasonable alternative to penicillin in aller
-
gic patients. Cephalosporins are somewhat more effective 
than penicillin in producing bacteriologic cures; 5-day 
courses of cefpodoxime and cefuroxime have been success
-
ful. The macrolide antibiotics have also been reported to be 
successful in shorter-duration regimens. Azithromycin 
(500 mg once daily), because of its long half-life, need be 
taken for only 3 days.
Adequate antibiotic treatment usually avoids the strep
-
tococcal complications of scarlet fever, glomerulonephritis, 
rheumatic myocarditis, and local abscess formation.
Antibiotics for treatment failures are also somewhat 
controversial. Surprisingly, penicillin-tolerant strains are

controversial. Surprisingly, penicillin-tolerant strains are 
not isolated more frequently in those who fail treatment 
than in those treated successfully with penicillin. The 
reasons for failure appear to be complex, and a second 
course of treatment with the same drug is reasonable. 
Alternatives to penicillin include cefuroxime and other 
cephalosporins, dicloxacillin (which is beta-lactamase–
resistant), and amoxicillin with clavulanate. When there 
is a history of penicillin allergy, alternatives should be 
used, such as erythromycin. Erythromycin resistance—
with failure rates of about 25%—is an increasing problem 
in many areas. In cases of severe penicillin allergy, cepha
-
losporins should be avoided as the cross-reaction is com
-
mon (8% or more).
Ancillary treatment of pharyngitis includes analgesics 
and anti-inflammatory agents, such as aspirin, acetamino
-
phen, and corticosteroids. In meta-analysis, corticosteroids 
increased the likelihood of complete pain resolution at 
24 hours by threefold without an increase in recurrence or 
adverse events. Some patients find that salt water gargling 
is soothing. In severe cases, anesthetic gargles and lozenges 
(eg, benzocaine) may provide additional symptomatic 
relief. Occasionally, odynophagia is so intense that hospi
-
talization for intravenous hydration and antibiotics is nec
-
essary. (See Chapter 33.)
 
▲
Figure 8–9.
 
Streptococcal pharyngitis showing ton
-
sillar exudate and erythema. 
(From Michael Nguyen, MD; 
reproduced, with permission, from Usatine RP , Smith MA, 
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Patients who have had rheumatic fever should be 
treated with a continuous course of antimicrobial prophy
-
laxis (erythromycin, 250 mg twice daily orally, or penicillin 
G, 500 mg once daily orally) for at least 5 years.
Anjos LM et al. Streptococcal acute pharyngitis. Rev Soc Bras 
Med Trop. 2014 Jul;47(4):409–13. [PMID: 25229278]
-
-
 
Stewart EH et al. Rapid antigen group A streptococcus test to 
diagnose pharyngitis: a systematic review and meta-analysis. 
PLoS One. 2014 Nov 4;9(11):e111727. [PMID: 25369170]
Weber R. Pharyngitis. Prim Care. 2014 Mar;41(1):91–8. Erratum 
in: Prim Care. 2015 Mar;42(1):xvii. [PMID: 24439883]
PERITONSILLAR ABSCESS & CELLULITIS
When infection penetrates the tonsillar capsule and 
involves the surrounding tissues, peritonsillar cellulitis 
results. Peritonsillar abscess (
quinsy
) and cellulitis present 
with severe sore throat, odynophagia, trismus, medial 
deviation of the soft palate and peritonsillar fold, and an 
abnormal muffled (“hot potato”) voice. Following therapy, 
peritonsillar cellulitis usually either resolves over several 
days or evolves into peritonsillar abscess. Ultrasound may 
be a useful adjunct to clinical suspicion, but imaging is not 
required for the diagnosis. The existence of an abscess may 
be confirmed by aspirating pus from the peritonsillar fold 
just superior and medial to the upper pole of the tonsil. A 
19-gauge or 21-gauge needle should be passed medial to 
the molar and no deeper than 1 cm, because the internal 
carotid artery may lie more medially than its usual location 
and pass posterior and deep to the tonsillar fossa. Most 
commonly, patients with peritonsillar abscess present to 
the emergency department and receive a dose of parenteral 
amoxicillin (1 g), amoxicillin-sulbactam (3 g), or clindamy
-
cin (600–900 mg). Less severe cases and patients who are 
able to tolerate oral intake may be treated for 7–10 days 
with oral antibiotics, including amoxicillin, 500 mg three 
times a day; amoxicillin-clavulanate, 875 mg twice a day; or 
clindamycin, 300 mg four times daily. Although antibiotic 
treatment is generally undisputed, there is controversy 
regarding the surgical management of peritonsillar abscess. 
Methods include needle aspiration, incision and drainage, 
and tonsillectomy. Some clinicians incise and drain the 
area and continue with parenteral antibiotics, whereas oth
-
ers aspirate only and monitor as an outpatient. To drain the 
abscess and avoid recurrence, it may be appropriate to 
consider immediate tonsillectomy (quinsy tonsillectomy). 
About 10% of patients with peritonsillar abscess exhibit 
relative indications for tonsillectomy. All three approaches 
are effective. Regardless of the method used, one must be 
sure the abscess is adequately treated, since complications 
such as extension to the retropharyngeal, deep neck, and 
posterior mediastinal spaces are possible. Bacteria may also 
be aspirated into the lungs, resulting in pneumonia. There 
is controversy about whether a single abscess is a sufficient 
indication for tonsillectomy; about 30% of patients aged 
17–30 who do not undergo early planned tonsillectomy 
following peritonsillar abscess ultimately undergo surgery, 
and only about 13% of those over 30 have their tonsils 
removed.
Blair AB et al. A unifying theory of tonsillitis, intratonsillar 
abscess and peritonsillar abscess. Am J Otolaryngol. 2015 
Jul–Aug;36(4):517–20. [PMID: 25865201]
Hildreth AF et al. Evidence-based evaluation and management

Hildreth AF et al. Evidence-based evaluation and management 
of patients with pharyngitis in the emergency department. 
Emerg Med Pract. 2015 Sep;17(9):1–16. [PMID: 26276908]
Holm K et al. The role of 
Fusobacterium necrophorum
 in pharyn
-
gotonsillitis—a review. Anaerobe. 2016 Sep 28;42:89–97. 
[PMID: 27693542]
Lee YJ et al. The efficacy of corticosteroids in the treatment of 
peritonsillar abscess: a meta-analysis. Clin Exp Otorhinolar
-
yngol. 2016 Jun;9(2):89–97. [PMID: 27090283]
Nogan S et al. The use of ultrasound imaging in evaluation of 
peritonsillar infections. Laryngoscope. 2015 Nov;125(11):
 
2604–7. [PMID: 25946659]
DEEP NECK INFECTIONS
 
»
Marked acute neck pain and swelling.
 
»
Abscesses are emergencies because rapid airway 
compromise may occur.
 
»
May spread to the mediastinum or cause sepsis.
 
»
Ludwig angina
 is the most commonly encountered neck 
space infection. It is a cellulitis of the sublingual and sub
-
maxillary spaces, often arising from infection of the man
-
dibular dentition. 
Deep neck abscesses
 most commonly 
originate from odontogenic infections. Other causes 
include suppurative lymphadenitis, direct spread of pha
-
ryngeal infection, penetrating trauma, pharyngoesopha
-
geal foreign bodies, cervical osteomyelitis, and intravenous 
injection of the internal jugular vein, especially in drug 
abusers. Recurrent deep neck infection may suggest an 
underlying congenital lesion, such as a branchial cleft cyst. 
Suppurative lymphadenopathy in middle-aged persons 
who smoke and drink alcohol regularly should be consid
-
ered a manifestation of malignancy (typically metastatic 
squamous cell carcinoma) until proven otherwise.
 
»
Patients with 
 have edema and erythema of 
the upper neck under the chin and often of the floor of the 
mouth. The tongue may be displaced upward and backward 
by the posterior spread of cellulitis, and coalescence of pus is 
often present in the floor of mouth. This may lead to occlu
-
sion of the airway. Microbiologic isolates include strepto
-
cocci, staphylococci, 
Bacteroides,
 and 
Fusobacterium
. 
Patients with diabetes may have different flora, including 
Klebsiella
, and a more aggressive clinical course.
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deep neck abscesses
 usually present with 
marked neck pain and swelling. Fever is common but not 
always present. 
Deep neck abscesses are emergencies because 
they may rapidly compromise the airway.
 Untreated or inad
-
equately treated, they may spread to the mediastinum or 
cause sepsis.
Contrast-enhanced CT usually augments the clinical 
examination in defining the extent of the infection. It often 
will distinguish inflammation and phlegmon (requiring 
antibiotics) from abscess (requiring drainage) and define 
for the surgeon the extent of an abscess. CT with MRI may 
also identify thrombophlebitis of the internal jugular vein 
secondary to oropharyngeal inflammation. This condition, 
known as 
Lemierre syndrome
, is rare and usually associ
-
ated with severe headache. The presence of pulmonary 
infiltrates consistent with septic emboli in the setting of a 
neck abscess should lead one to suspect Lemierre syn
-
drome or injection drug use, or both.
 
»
Treatment
Usual doses of penicillin plus metronidazole, ampicillin-
sulbactam, clindamycin, or selective cephalosporins are 
good initial choices for treatment of 
. Cul
-
ture and sensitivity data are then used to refine the choice. 
Dental consultation is advisable to address the offending 
tooth or teeth. External drainage via bilateral submental 
incisions is required if the airway is threatened or when 
medical therapy has not reversed the process.
Treatment of 
 includes securing the 
airway, intravenous antibiotics, and incision and drainage. 
When the infection involves the floor of the mouth, base of 
the tongue, or the supraglottic or paraglottic space, the 
airway may be secured either by intubation or tracheot
-
omy. Tracheotomy is preferable in the patients with sub
-
stantial pharyngeal edema, since attempts at intubation 
may precipitate acute airway obstruction. Bleeding in 
association with a deep neck abscess is very rare but sug
-
gests carotid artery or internal jugular vein involvement 
and requires prompt neck exploration both for drainage of 
pus and for vascular control.
 require prompt insti
-
tution of antibiotics appropriate for 
Fusobacterium nec
-
rophorum
 as well as the more usual upper airway pathogens. 
The use of anticoagulation in treatment is of no proven 
benefit.
Brito TP et al. Deep neck abscesses: study of 101 cases. Braz J 
Otorhinolaryngol. 2017 May–Jun;83(3):341–8. [PMID: 
27236632]
Hidaka H et al. Clinical and bacteriological influence of diabetes 
mellitus on deep neck infection: systematic review and meta-
analysis. Head Neck. 2015 Oct;37(10):1536–46. [PMID: 
24844194]
Horváth T et al. Severe neck infections that require wide external 
drainage: clinical analysis of 17 consecutive cases. Eur Arch 
Otorhinolaryngol. 2015 Nov;272(11):3469–74. [PMID: 
25359195]
Mejzlik J et al. Univariate and multivariate models for the pre
-
diction of life-threatening complications in 586 cases of deep 
neck space infections: retrospective multi-institutional study. 
J Laryngol Otol. 2017 Sep;131(9):779–84. [PMID: 28578716]
SNORING
 
»
Noise produced on inspiration during sleep.
 
»
Snoring is associated with obstructive sleep apnea 
(OSA) but has no disruption of sleep on clinical 
sleep evaluation.
 
»
Ventilation disorders during sleep are extremely common. 
While OSA occurs in 5–10% of Americans, clinically rele
-
vant snoring may occur in as many as 59%. In general, 
sleep-disordered breathing problems are attributed to nar
-
rowing of the upper aerodigestive tract during sleep due to 
changes in position, muscle tone, and soft tissue hypertro
-
phy or laxity. The most common sites of obstruction are 
the oropharynx and the base of the tongue. The spectrum 
of the problem ranges from simple snoring without cessa
-

-
-
tion of airflow to OSA with long periods of apnea and life-
threatening physiologic sequelae. OSA is discussed in 
Chapter 9. In contrast to OSA, snoring is almost exclusively 
a social problem, and despite its prevalence and association 
with OSA, there is comparatively little known about the 
management of this problem.
 
»
All patients who complain of snoring should be evaluated 
for OSA as discussed in Chapter 9. Symptoms of OSA 
(including snoring, excessive daytime somnolence, day
-
time headaches, and weight gain) may be present in as 
many as 30% of patients without demonstrable apnea or 
hypopnea on formal testing. Clinical examination should 
include examination of the nasal cavity, nasopharynx, oro
-
pharynx, and larynx to help exclude other causes of 
dynamic airway obstruction. In many cases of isolated 
snoring, the palate and uvula appear enlarged and elon
-
gated with excessive mucosa hanging below the muscular 
portion of the soft palate.
B. Imaging and Diagnostic Testing
Sleep examination with polysomnography is strongly 
advised in the evaluation of a patient with complaints of 
snoring. Radiographic imaging of the head or neck is gen
-
erally not necessary.
 
»
Treatment
Expeditious and inexpensive management solutions of 
snoring are sought, often with little or no benefit. Diet 
modification and physical exercise can lead to improve
-
ment in snoring through the weight loss and improvement 
in pharyngeal tone that accompanies overall physical con
-
ditioning. Position change during sleep can be effective, 
and time-honored treatments, such as taping or sewing a 
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tennis ball to the back of a shirt worn during sleep, may 
satisfactorily eliminate symptoms by ensuring recumbency 
on one side. Although numerous pharmacologic therapies 
have been endorsed, none demonstrate any significant util
-
ity when scrutinized.
Anatomic management of snoring can be challenging. As 
with OSA, snoring can come from a number of sites in the 
upper aerodigestive tract. While medical or surgical correc
-
tion of nasal obstruction may help alleviate snoring prob
-
lems, most interventions aim to improve airflow through the 
nasopharynx and oropharynx. Nonsurgical options include 
mandibular advancement appliances designed to pull the 
base of the tongue forward and continuous positive airway 
pressure via face or nasal mask. Compliance with both of 
these treatment options is problematic because snorers with
-
out OSA do not notice the physiologic benefits of these 
devices noted by patients with sleep apnea.
Surgical correction of snoring is most commonly 
directed at the soft palate. Historical approaches involved 
resection of redundant mucosa and the uvula similar to 
uvulopalatopharyngoplasty that is used for OSA. Regard
-
less of how limited the procedure or what technique was 
used, postoperative pain, the expense of general anesthesia, 
and high recurrence rates limit the utility of these proce
-
dures. Office-based approaches are more widely used 
because of these limitations. Most of these procedures aim 
to stiffen the palate to prevent vibration rather than remove 
it. A series of procedures, including injection snoreplasty, 
radiofrequency thermal fibrosis, and an implantable pala
-
tal device, have been used with variable success and patient 
tolerance. The techniques can be technically challenging. 
Persistent symptoms may occur following initial treatment 
necessitating costly (and sometimes painful) repeat proce
-
dures. The durability of these procedures in alleviating 
symptoms is also poorly understood, and late failures can 
lead to patient and clinician frustration.
Achuthan S et al. A systematic review of the pharmacological 
approaches against snoring: can we count on the chickens that 
have hatched? Sleep Breath. 2015 Sep;19(3):1035–42. [PMID: 
25680547]
Bratton DJ et al. CPAP vs mandibular advancement devices and 
blood pressure in patients with obstructive sleep apnea: a 
systematic review and meta-analysis. JAMA. 2015 Dec 1;
 
314(21):2280–93. [PMID: 26624827]
Rivas M et al. Obstructive sleep apnea and its effects on car
-
diovascular diseases: a narrative review. Anatol J Cardiol. 
2015 Nov;15(11):944–50. [PMID: 26574763]
 
º
DISEASES OF THE SALIVARY GLANDS
ACUTE INFLAMMATORY SALIVARY 
 
GLAND DISORDERS
1. Sialadenitis
Acute bacterial sialadenitis most commonly affects either 
the parotid or submandibular gland. It typically presents 
with acute swelling of the gland, increased pain and swell
-
ing with meals, and tenderness and erythema of the duct 
opening. Pus often can be massaged from the duct. 
Sialadenitis often occurs in the setting of dehydration or in 
association with chronic illness. Underlying Sjögren syn
-
drome and chronic periodontitis may contribute. Ductal 
obstruction, often by an inspissated mucous plug, is fol
-
lowed by salivary stasis and secondary infection. The most 
common organism recovered from purulent draining 
saliva is 
S aureus.
 Treatment consists of intravenous antibi
-
otics, such as nafcillin (1 g intravenously every 4–6 hours), 
measures to increase salivary flow, including hydration, 
warm compresses, sialagogues (eg, lemon drops), and mas
-
sage of the gland. Treatment can usually then be switched 
to an oral agent based on clinical improvement and micro
-
biologic results to complete a 10-day treatment course. Less 
severe cases can often be treated with oral antibiotics with 
similar spectrum. Complete resolution of parotid swelling 
and pain can take 2–3 weeks. Failure of the process to

and pain can take 2–3 weeks. Failure of the process to 
improve and ultimately resolve on this regimen suggests 
abscess formation, ductal stricture, stone, or tumor causing 
obstruction. Ultrasound or CT scan may be helpful in 
establishing the diagnosis. In the setting of acute illness, a 
severe and potentially life-threatening form of sialadenitis, 
sometimes called 
suppurative sialadenitis
, may develop. 
The causative organism is usually 
S aureus
, but often no 
pus will drain from Stensen papilla. These patients often do 
not respond to rehydration and intravenous antibiotics and 
thus may require operative incision and drainage to resolve 
the infection.
2. Sialolithiasis
Calculus formation is more common in Wharton duct 
(draining the submandibular glands) than in Stensen duct 
(draining the parotid glands). Clinically, a patient may note 
postprandial pain and local swelling, often with a history of 
recurrent acute sialadenitis. Stones in Wharton duct are 
usually large and radiopaque, whereas those in Stensen duct 
are usually radiolucent and smaller. Those very close to the 
orifice of Wharton duct may be palpated manually in the 
anterior floor of the mouth and removed intraorally by 
dilating or incising the distal duct. Those more than 1.5–2 cm 
from the duct are too close to the lingual nerve to be 
removed safely in this manner. Similarly, dilation of Stensen 
duct, located on the buccal surface opposite the second 
maxillary molar, may relieve distal stricture or allow a small 
stone to pass. Sialoendoscopy for the management of 
chronic sialolithiasis is superior to extracorporeal shock-
wave lithotripsy and fluoroscopically guided basket 
retrieval. Repeated episodes of sialadenitis are usually asso
-
ciated with stricture and chronic infection. If the obstruc
-
tion cannot be safely removed or dilated, excision of the 
gland may be necessary to relieve recurrent symptoms.
Atienza G et al. Management of obstructive salivary disorders by 
sialendoscopy: a systematic review. Br J Oral Maxillofac Surg. 
2015 Jul;53(6):507–19. [PMID: 25823614]
Delagnes EA et al. Sialadenitis without sialolithiasis: prospective 
outcomes after sialendoscopy-assisted salivary duct surgery. 
Laryngoscope. 2017 May;127(5):1073–9. [PMID: 27701754]
Xiao JQ et al. Evaluation of sialendoscopy-assisted treatment 
of submandibular gland stones. J Oral Maxillofac Surg. 
2017 Feb;75(2):309–16. [PMID: 27663537]
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CHRONIC INFLAMMATORY & INFILTRATIVE 
DISORDERS OF THE SALIVARY GLANDS
Numerous infiltrative disorders may cause unilateral or 
bilateral parotid gland enlargement. Sjögren syndrome and 
sarcoidosis are examples of lymphoepithelial and granulo
-
matous diseases that may affect the salivary glands. Meta
-
bolic disorders, including alcoholism, diabetes mellitus, 
and vitamin deficiencies, may also cause diffuse enlarge
-
ment. Several drugs have been associated with parotid 
enlargement, including thioureas, iodine, and drugs with 
cholinergic effects (eg, phenothiazines), which stimulate 
salivary flow and cause more viscous saliva.
SALIVARY GLAND TUMORS
Approximately 80% of salivary gland tumors occur in 
the parotid gland. In adults, about 80% of these are 
benign. In the submandibular triangle, it is sometimes 
difficult to distinguish a primary submandibular gland 
tumor from a metastatic submandibular space node. 
Only 50–60% of primary submandibular tumors are 
benign. Tumors of the minor salivary glands are most 
likely to be malignant, with adenoid cystic carcinoma 
predominating, and may be found throughout the oral 
cavity or oropharynx.
Most parotid tumors present as an asymptomatic mass 
in the superficial part of the gland. Their presence may 
have been noted by the patient for months or years. Facial 
nerve involvement correlates strongly with malignancy. 
Tumors may extend deep to the plane of the facial nerve or 
may originate in the parapharyngeal space. In such cases, 
medial deviation of the soft palate is visible on intraoral 
examination. MRI and CT scans have largely replaced sia
-
lography in defining the extent of tumor.
When the clinician encounters a patient with an oth
-
erwise asymptomatic salivary gland mass where tumor is 
the most likely diagnosis, the choice is whether to simply 
excise the mass via a parotidectomy with facial nerve dis
-
section or submandibular gland excision or to first 
obtain an FNA biopsy. Although the accuracy of FNA 
biopsy for malignancy has been reported to be quite 
high, results vary among institutions. If a negative FNA 
biopsy would lead to a decision not to proceed to surgery, 
then it should be considered. Poor overall health of the 
patient and the possibility of inflammatory disease as the 
cause of the mass are situations where FNA biopsy might 
be helpful. In otherwise straightforward nonrecurrent 
cases, excision is indicated. In benign and small, low-
grade malignant tumors, no additional treatment is 
needed. Postoperative irradiation is indicated for larger 
and high-grade cancers.
Becker C et al. Prognostic value of comorbidities in patients with 
carcinoma of the major salivary glands. Eur Arch Otorhino
-
laryngol. 2017 Mar;274(3):1651–57. [PMID: 27888340]
Sood S et al. Management of salivary gland tumours: United 
Kingdom national multidisciplinary guidelines. J Laryngol 
Otol. 2016 May;130(S2):S142–9. [PMID: 27841127]
 
º
DISEASES OF THE LARYNX
DYSPHONIA, HOARSENESS, & STRIDOR
The primary symptoms of laryngeal disease are hoarseness 
and stridor. Hoarseness is caused by an abnormal vibration 
of the vocal folds. The voice is breathy when too much air 
passes incompletely apposed vocal folds, as in unilateral 
vocal fold paralysis or vocal fold mass. The voice is harsh 
when the vocal folds are stiff and vibrate irregularly, as is 
the case in laryngitis or malignancy. Heavy, edematous 
vocal folds produce a rough, low-pitched vocal quality. 
Stridor (a high-pitched, typically inspiratory, sound) is the 
result of turbulent airflow from a narrowed upper airway. 
Airway narrowing at or above the vocal folds produces 
inspiratory stridor. Airway narrowing below the vocal fold 
level produces either expiratory or biphasic stridor. The 
timing and rapidity of onset of stridor are critically impor
-
tant in determining the seriousness of the airway problem.

-
tant in determining the seriousness of the airway problem. 
All cases of stridor should be evaluated by a specialist and 
rapid-onset stridor should be evaluated emergently.
Evaluation of an abnormal voice begins with obtaining 
a history of the circumstances preceding its onset and an 
examination of the airway.
Any patient with hoarseness that has persisted beyond 
2 weeks should be evaluated by an otolaryngologist with 
laryngoscopy. Especially when the patient has a history of 
tobacco use, laryngeal cancer or lung cancer (leading to 
paralysis of a recurrent laryngeal nerve) must be strongly 
considered. In addition to structural causes of dysphonia, 
laryngoscopy can help identify functional problems with 
the voice, including vocal fold paralysis, muscle tension 
dysphonia, and spasmodic dysphonia.
Reiter R et al. Hoarseness—causes and treatments. Dtsch Arztebl 
Int. 2015 May 8;112(19):329–37. [PMID: 26043420]
van Esch BF et al. Effect of botulinum toxin and surgery among 
spasmodic dysphonia patients: a systematic review. Otolaryngol 
Head Neck Surg. 2017 Feb;156(2):238–54. [PMID: 27803079]
COMMON LARYNGEAL DISORDERS
1. Acute Laryngitis
Acute laryngitis is probably the most common cause of 
hoarseness, which may persist for a week or so after other 
symptoms of an upper respiratory infection have cleared. 
The patient should be warned to avoid vigorous use of the 
voice (singing, shouting) until their voice returns to nor
-
mal, since persistent use may lead to the formation of 
traumatic vocal fold hemorrhage, polyps, and cysts. 
Although thought to be usually viral in origin, both 
 
M catarrhalis
 and 
 may be isolated from the 
nasopharynx at higher than expected frequencies. Despite 
this finding, a meta-analysis has failed to demonstrate any 
convincing evidence that antibiotics significantly alter the 
natural resolution of acute laryngitis. Erythromycin may 
speed improvement of hoarseness at 1 week and cough at 
2 weeks when measured subjectively. Oral or intramuscular 
corticosteroids may be used in highly selected cases of 
professional vocalists to speed recovery and allow 
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scheduled performances. Examination of the vocal folds 
and assessment of vocal technique are mandatory prior to 
corticosteroid initiation, since inflamed vocal folds are at 
greater risk for hemorrhage and the subsequent develop
-
ment of traumatic vocal fold pathology.
Reveiz L et al. Antibiotics for acute laryngitis in adults. Cochrane 
Database Syst Rev. 2015 May 23;(5):CD004783. [PMID: 
26002823]
2. Laryngopharyngeal Reflux
 
»
Commonly associated with hoarseness, throat 
irritation, and chronic cough.
 
»
Symptoms typically occur when upright, and half 
of patients do not experience heartburn.
 
»
Laryngoscopy is critical to exclude other causes of 
hoarseness.
 
»
Diagnosis is made based following response to 
proton-pump inhibitor therapy.
 
»
Treatment failure with proton-pump inhibitors is 
common and suggests other etiologies.
Gastroesophageal reflux into the larynx (laryngopharyn
-
geal reflux) is considered a cause of chronic hoarseness 
when other causes of abnormal vocal fold vibration (such 
as tumor or nodules) have been excluded by laryngoscopy. 
Gastroesophageal reflux disease (GERD) has also been 
suggested as a contributing factor to other symptoms, such 
as throat clearing, throat discomfort, chronic cough, a sen
-
sation of postnasal drip, esophageal spasm, and some cases 
of asthma. Since less than half of patients with laryngeal 
acid exposure have typical symptoms of heartburn and 
regurgitation, the lack of such symptoms should not be 
construed as eliminating this cause. Indeed, most patients 
with symptomatic laryngopharyngeal reflux, as it is now 
called, do not meet criteria for GERD by pH probe testing 
and these entities must be considered separately. The 
prevalence of this condition is hotly debated in the litera
-
ture, and laryngopharyngeal reflux may not be as common 
as once thought.
Evaluation should initially exclude other causes of dys
-
phonia through laryngoscopy; consultation with an oto
-
laryngologist is advisable. Many clinicians opt for an 
empiric trial of a proton-pump inhibitor since no gold 
standard exists for diagnosing this condition. Such an 
empiric trial should not precede visualization of the vocal 
folds to exclude other causes of hoarseness. When used, 
the American Academy of Otolaryngology—Head and 
Neck Surgery recommends twice-daily therapy with full-
strength proton-pump inhibitor (eg, omeprazole 40 mg 
orally twice daily, or equivalent) for a minimum of 3 months. 
Patients may note improvement in symptoms after 3 months, 
but the changes in the larynx often take 6 months to 
resolve. If symptoms improve and cessation of therapy 
leads to symptoms again, then a proton-pump inhibitor is 
resumed at the lowest dose effective for remission, usually 
daily but at times on a demand basis. Although H
2
-receptor 
antagonists are an alternative to proton-pump inhibitors, 
they are generally both less clinically effective and less 
cost-effective. Nonresponders should undergo pH testing 
and manometry. Twenty-four-hour pH monitoring of the 
pharynx should best document laryngopharyngeal reflux 
and is advocated by some as the initial management step, 
but it is costly, more difficult, and less available than 
lower esophageal monitoring alone. Double pH probe 
(proximal and distal esophageal probes) testing is the best 
option for evaluation, since lower esophageal pH monitor
-
ing alone does not correlate well with laryngopharyngeal 
reflux symptoms. Oropharyngeal pH probe testing is 
available, but its ability to predict response to reflux treat
-
ment in patients with laryngopharyngeal reflux is not 
known.
Dhillon VK et al. How to approach laryngopharyngeal reflux: 
an otolaryngology perspective. Curr Gastroenterol Rep. 
 
2016 Aug;18(8):44. [PMID: 27417389]
Lechien JR et al. Voice outcomes of laryngopharyngeal reflux 
treatment: a systematic review of 1483 patients. Eur Arch

treatment: a systematic review of 1483 patients. Eur Arch 
Otorhinolaryngol. 2017 Jan;274(1):1–23. [PMID: 27007132]
Wei C. A meta-analysis for the role of proton pump inhibitor 
therapy in patients with laryngopharyngeal reflux. Eur Arch 
Otorhinolaryngol. 2016 Nov;273(11):3795–801. [PMID: 
27312992]
3. Recurrent Respiratory 
p
apilloma
tosis
Papillomas are common lesions of the larynx and other 
sites where ciliated and squamous epithelia meet. Unlike 
oral papillomas, recurrent respiratory papillomatosis typi
-
cally becomes symptomatic, with hoarseness that occasion
-
ally progresses over weeks to months. These papillomas are 
almost always due to HPV types 6 and 11. Repeated laser 
vaporizations or cold knife resections via operative laryn
-
goscopy are the mainstay of treatment. Severe cases can 
cause airway compromise in adults and may require treat
-
ment as often as every 6 weeks to maintain airway patency. 
Extension can occur into the trachea and lungs. Tracheot
-
omy should be avoided, if possible, since it introduces an 
additional squamociliary junction for which papillomas 
appear to have an affinity. Interferon treatment has been 
under investigation for many years but is only indicated in 
severe cases with pulmonary involvement. Rarely, cases of 
malignant transformation have been reported (often in 
smokers), but recurrent respiratory papillomatosis should 
generally be thought of as a benign condition. Cidofovir (a 
cytosine nucleotide analog in use to treat cytomegalovirus 
retinitis) has been used with success as intralesional ther
-
apy for recurrent respiratory papillomatosis. Because cido
-
fovir causes adenocarcinomas in laboratory animals, its 
potential for carcinogenesis is being monitored. The quad
-
rivalent and new 9 serotype recombinant human HPV 
vaccines (Gardasil and Gardasil 9) offer hope for the even
-
tual prevention of this benign, but terribly morbid, 
disease.
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Donne A et al. Prevalence and management of recurrent respira
-
tory papillomatosis (RRP) in the UK: cross sectional study. 
Clin Otolaryngol. 2017 Feb;42(1):86-91. [PMID: 27208548]
San Giorgi MR et al. Quality of life of patients with recurrent respi
-
ratory papillomatosis. Laryngoscope. 2017 Aug;127(8):1826–31. 
[PMID: 27861969]
4. Epiglottitis
Epiglottitis (or, more correctly, supraglottitis) should be 
suspected when a patient presents with a rapidly develop
-
ing sore throat or when odynophagia (pain on swallowing) 
is out of proportion to apparently minimal oropharyngeal 
findings on examination. It is more common in diabetic 
patients and may be viral or bacterial in origin. Rarely in 
the era of 
 type b vaccine is this bacterium 
isolated in adults. Unlike in children, indirect laryngoscopy 
is generally safe and may demonstrate a swollen, erythema
-
tous epiglottis. Lateral plain radiographs may demonstrate 
an enlarged epiglottis (the epiglottis “thumb sign”). Initial 
treatment is hospitalization for intravenous antibiotics—
eg, ceftizoxime, 1–2 g intravenously every 8–12 hours; or 
cefuroxime, 750–1500 mg intravenously every 8 hours; and 
dexamethasone, usually 4–10 mg as initial bolus, then 4 mg 
intravenously every 6 hours—and observation of the air
-
way. Corticosteroids may be tapered as symptoms and 
signs resolve. Similarly, substitution of oral antibiotics may 
be appropriate to complete a 10-day course. Less than 10% 
of adults require intubation. Indications for intubation are 
dyspnea, rapid pace of sore throat (where progression to 
airway compromise may occur before the effects of corti
-
costeroids and antibiotics), and endolaryngeal abscess 
noted on CT imaging. If the patient is not intubated, pru
-
dence suggests monitoring oxygen saturation with contin
-
uous pulse oximetry and initial admission to a monitored 
unit.
Chroboczek T et al. Long-term outcome of critically ill adult 
patients with acute epiglottitis. PLoS One. 2015 May 6;
 
10(5):e0125736. [PMID: 25945804]
Lee SH et al. Do we need a change in ED diagnostic strategy for 
adult acute epiglottitis? Am J Emerg Med. 2017 Oct;35(10):
 
1519–24. [PMID: 28460811]
MASSES OF THE LARYNX
1. Traumatic Lesions of the Vocal Folds
Vocal fold nodules
 are smooth, paired lesions that form at 
the junction of the anterior one-third and posterior two-
thirds of the vocal folds. They are a common cause of 
hoarseness resulting from vocal abuse. In adults, they are 
referred to as “singer’s nodules” and in children as “scream
-
er’s nodules. ” Treatment requires modification of voice 
habits, and referral to a speech therapist is indicated. While 
nearly all true nodules will resolve with behavior modifica
-
tion, recalcitrant nodules may require surgical excision. 
Often, additional pathology, such as a polyp or cyst, may be 
encountered.
Vocal fold polyps
 are unilateral masses that form 
within the superficial lamina propria of the vocal fold. 
They are related to vocal trauma and seem to follow resolu
-
tion of vocal fold hemorrhage. Small, sessile polyps may 
resolve with conservative measures, such as voice rest and 
corticosteroids, but larger polyps are often irreversible and 
require operative removal to restore normal voice.
Vocal fold cysts
 are also considered traumatic lesions 
of the vocal folds and are either true cysts with an epithelial 
lining or pseudocysts. They typically form from mucus-
secreting glands on the inferior aspect of the vocal folds. 
Cysts may fluctuate in size from week to week and cause a 
variable degree of hoarseness. They rarely, if ever, resolve 
completely and may leave behind a sulcus, or vocal fold 
scar, if they decompress or are marsupialized. Such scar
-
ring can be a frustrating cause of permanent dysphonia.
Polypoid corditis
 is different from vocal fold polyps 
and may form from loss of elastin fibers and loosening of

-
and may form from loss of elastin fibers and loosening of 
the intracellular junctions within the lamina propria. This 
loss allows swelling of the gelatinous matrix of the super
-
ficial lamina propria (called 
Reinke edema
). These 
changes in the vocal folds are strongly associated with 
smoking, but also with vocal abuse, chemical industrial 
irritants, and hypothyroidism. While this problem is com
-
mon in both male and female smokers, women seem more 
troubled by the characteristic decline in modal pitch 
caused by the increased mass of the vocal folds. If the 
patient stops smoking or the lesions cause stridor and 
airway obstruction, surgical resection of the hyperplastic 
vocal fold mucosa may be indicated to improve the voice 
or airway, or both.
A common but often unrecognized cause of hoarseness 
and odynophonia are 
contact ulcers
 or their close relatives, 
granulomas
. Both lesions form on the vocal processes of 
the arytenoid cartilages, and patients often can correctly 
inform the clinician which side is affected. The cause of 
these ulcers and granulomas is disputed, but they are 
clearly related to trauma and may be related to exposure of 
the underlying perichondrium. They are common follow
-
ing intubation and generally resolve quite quickly. Chronic 
ulceration or granuloma formation has been associated 
with gastroesophageal reflux but is also common in patients 
with muscle tension dysphonia. Treatment is often multi
-
modal, and an inhaled corticosteroid (eg, fluticasone 440 mcg 
twice daily) may be the most effective pharmacologic 
therapy. Adjunctive treatment measures include proton-
pump inhibitor therapy (omeprazole 40 mg orally twice 
daily, or equivalent) and voice therapy with special atten
-
tion to vocal hygiene. Rare cases can be quite stubborn and 
persistent without adequate therapy. Surgical removal is 
rarely, if ever, required for nonobstructive lesions.
Jeong WJ et al. Conservative management for vocal fold polyps. 
JAMA Otolaryngol Head Neck Surg. 2014 May;140(5):448–52. 
[PMID: 24676626]
Ogawa M et al. Is voice therapy effective for the treatment of 
dysphonic patients with benign vocal fold lesions? Auris 
Nasus Larynx. 2017 Aug 22. [Epub ahead of print] [PMID: 
28844607]
Zhukhovitskaya A et al. Gender and age in benign vocal fold 
lesions. Laryngoscope. 2015 Jan;125(1):191–6. [PMID: 
25216037]
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2. Laryngeal Leukoplakia
Leukoplakia of the vocal folds is commonly found in asso
-
ciation with hoarseness in smokers. Direct laryngoscopy 
with biopsy is advised in almost all cases. Histologic exami
-
nation usually demonstrates mild, moderate, or severe 
dysplasia. In some cases, invasive squamous cell carcinoma 
is present in the initial biopsy specimen. Cessation of 
smoking may reverse or stabilize mild or moderate dyspla
-
sia. Some patients—estimated to be less than 5% of those 
with mild dysplasia and about 35–60% of those with severe 
dysplasia—will subsequently develop squamous cell carci
-
noma. Treatment options include proton-pump inhibitor 
therapy, close follow-up with laryngovideostroboscopy, 
serial resection, and external beam radiation therapy.
Ahn A et al. Serial full-thickness excision of dysplastic vocal 
fold leukoplakia: diagnostic or therapeutic? Laryngoscope. 
2016 Apr;126(4):923–7. [PMID: 26527122]
3. Squamous Cell Carcinoma of the Larynx
 
»
New and persistent (more than 2 weeks’ duration) 
hoarseness in a smoker.
 
»
Persistent throat or ear pain, especially with 
swallowing.
 
»
Neck mass.
 
»
Hemoptysis.
 
»
Stridor or other symptoms of a compromised 
airway.
 
»
Squamous cell carcinoma of the larynx, the most common 
malignancy of the larynx, occurs almost exclusively in 
patients with a history of significant tobacco use. Squa
-
mous cell carcinoma is usually seen in men aged 50–70 years; 
an estimated 13,150 new cases in both sexes (10,490 in 
men) will be seen in United States in 2018. There may be 
an association between laryngeal cancer and HPV type 16 
or 18 infection, but this association is much less strong 
than that between HPV 16 or 18 and oropharyngeal cancer. 
In both cancer types, the association with HPV seems to be 
strongest in nonsmokers. Laryngeal cancer is very treatable 
and early detection is the key to maximizing posttreatment 
voice, swallowing, and breathing function.
 
»
A change in voice quality is most often the presenting com
-
plaint, although throat or ear pain, hemoptysis, dysphagia, 
weight loss, and airway compromise may occur. Because of 
their early impact on vocal quality, glottic cancers are 
among the smallest detectable human malignancies and 
treatment success is very high with early lesions. Neck 
metastases are not common in early glottic (true vocal 
fold) cancer in which the vocal folds are mobile, but a third 
of patients in whom there is impaired fold mobility will 
also have involved lymph nodes at neck dissection. Supra
-
glottic carcinoma (false vocal folds, aryepiglottic folds, 
epiglottis), on the other hand, often metastasizes to both 
sides of the neck early in the disease. Complete head and 
neck examination, including laryngoscopy, by an experi
-
enced clinician is mandated for any person with the con
-
cerning symptoms listed under Essentials of Diagnosis.
B. Imaging and Laboratory Studies
Radiologic evaluation by CT or MRI is helpful in assessing 
tumor extent. Imaging evaluates neck nodes, tumor vol
-
ume, and cartilage sclerosis or destruction. A chest CT scan 
is indicated if there are level VI enlarged nodes (around the 
trachea and the thyroid gland) or level IV enlarged nodes 
(inferior to the cricoid cartilage along the internal jugular 
vein), or if a chest film is concerning for a second primary 
lesion or metastases. Laboratory evaluation includes com
-
plete blood count and liver biochemical tests. Formal car
-
diopulmonary evaluation may be indicated, especially if 
partial laryngeal surgery is being considered. All partial 
laryngectomy candidates should have good to excellent 
lung function and exercise tolerance because chronic 
microaspiration may be expected following the procedure. 
A positron emission tomography (PET) scan or CT-PET 
scan may be indicated to assess for distant metastases when

scan may be indicated to assess for distant metastases when 
there appears to be advanced local or regional disease.
C. Biopsy
Diagnosis is made by biopsy at the time of laryngoscopy 
when true fold mobility and arytenoid fixation, as well as 
surface tumor extent, can be evaluated. Most otolaryngolo
-
gists recommend esophagoscopy and bronchoscopy at the 
same time to exclude synchronous primary tumor. Although 
an FNA biopsy of an enlarged neck node may have already 
been done, it is generally acceptable to assume radiographi
-
cally enlarged neck nodes (greater than 1–1.5 cm) or nodes 
with necrotic centers are neck metastases. Open biopsies of 
nodal metastases should be discouraged because they may 
lead to higher rates of tumor treatment failure.
D. Tumor Staging
The American Joint Committee on Cancer (AJCC) staging 
of laryngeal cancers uses the TNM system to describe 
tumor extent and can be used for prognosis. Early laryn
-
geal cancers, T1 and T2 (stage I and II) lesions, involve 1–2 
laryngeal subsites locally and have no nodal metastases or 
profound functional abnormalities. T3 and T4 lesions may 
involve multiple laryngeal subsites with limitation of laryn
-
geal mobility. These locally advanced lesions are stage III or 
IV cancers, and any size tumor with regional nodal metas
-
tases is at least a stage III tumor. Stage I and II lesions are 
generally treated with single-modality therapy (surgery or 
radiation), while multimodality therapy, usually including 
chemotherapy with radiation therapy, is reserved for more 
advanced stage III and IV lesions.
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»
Treatment
Treatment of laryngeal carcinoma has four goals: cure, pres
-
ervation of safe and effective swallowing, preservation of 
useful voice, and avoidance of a permanent tracheostoma. 
For early glottic and supraglottic cancers, radiation therapy 
is the standard of care since cure rates are greater than 95% 
and 80%, respectively. That said, radiation therapy carries 
substantial morbidity, and many early tumors (T1 and T2 
lesions, without involved nodes) and selected advanced 
tumors (T3 and T4) may be treated with partial laryngec
-
tomy if at least one cricoarytenoid unit can be preserved. 
Five-year locoregional cure rates exceed 80–90% with sur
-
gery, and patient-reported satisfaction is excellent. In supra
-
glottic tumors, even when clinically N0, elective limited 
neck dissection is indicated following surgical resection 
because of the high risk of neck node involvement.
Advanced stage III and IV tumors represent a challeng
-
ing and ever-changing treatment dilemma. Twenty-five 
years ago, total laryngectomy was often recommended for 
such patients. However, the 1994 V A study (with induction 
cisplatin and 5-fluorouracil followed by irradiation alone in 
responders) demonstrated that two-thirds of patients could 
preserve their larynx. Subsequent studies have further 
defined multimodal therapy. Cisplatin-based chemotherapy 
concomitant with radiation therapy has been shown to be 
superior to either irradiation alone or induction chemo
-
therapy followed by radiation. The same benefits have been 
demonstrated with the epidermal growth factor receptor 
blocker cetuximab with lower overall systemic toxicity and 
better patient tolerance. However, chemoradiation using 
either cetuximab or cisplatin is associated with prolonged 
gastrostomy-dependent dysphagia.
The high rate of dysphagia and morbidity associated 
with severe laryngeal stenosis following chemoradiation 
has prompted a reevaluation of the role of extended, but 
less-than-total, laryngeal resection for selected advanced 
laryngeal carcinoma in which at least one cricoarytenoid 
unit is intact (organ preservation surgery). In addition to 
the late complications, clinicians have noted that the over
-
all success in the treatment of larynx cancer has declined in 
parallel with the increase in organ preservation chemora
-
diation therapy over the past 20 years. Some experts have 
proposed that this decline is the direct result of the shift in 
management of advanced laryngeal cancer away from sur
-
gery. Organ preservation surgery should be considered and 
discussed as an alternative to chemoradiation but may 
require referral to an appropriate regional center where 
such techniques are offered. After thorough evaluation of 
candidacy and discussion of the treatment options, patient 
choice plays a critical role in the ultimate decision to pur
-
sue surgery or chemoradiation as a definitive treatment 
modality. The patient and treating clinicians must carefully 
consider different early and late side effects and complica
-
tions associated with different treatment modalities.
The presence of malignant adenopathy in the neck 
affects the prognosis greatly. Supraglottic tumors metasta
-
size early and bilaterally to the neck, and this must be 
included in the treatment plans even when the neck is 
apparently uninvolved. Glottic tumors in which the true 
vocal folds are mobile (T1 or T2) have less than a 5% rate 
of nodal involvement; when a fold is immobile, the rate of 
ipsilateral nodal involvement climbs to about 30%. An 
involved neck is treated by surgery or chemoradiation, or 
both. This decision will depend on the treatment chosen 
for the larynx and the extent of neck involvement.
Total laryngectomy is largely reserved for patients with 
advanced resectable tumors with extralaryngeal spread or 
cartilage involvement, for those with persistent tumor fol
-

-
lowing chemoradiation, and for patients with recurrent or 
second primary tumor following previous radiation therapy. 
Voice rehabilitation via a primary (or at times secondary) 
tracheoesophageal puncture produces intelligible and 
serviceable speech in about 75–85% of patients. Indwelling 
prostheses that are changed every 3–6 months are a com
-
mon alternative to patient-inserted prostheses, which need 
changing more frequently.
Long-term follow-up is critical in head and neck cancer 
patients. In addition to the 3–4% annual rate of second 
tumors and monitoring for recurrence, psychosocial aspects 
of treatment are common. Dysphagia, impaired communi
-
cation, and altered appearance may result in patient diffi
-
culties adapting to the workplace and to social interactions. 
In addition, smoking cessation and alcohol abatement are 
common challenges. Nevertheless, about 65% of patients 
with larynx cancer are cured, most have useful speech, and 
many resume their prior livelihoods with adaptations.
Castellsagué X et al; ICO International HPV in Head and Neck 
Cancer Study Group. HPV involvement in head and neck 
cancers: comprehensive assessment of biomarkers in 3680 
patients. J Natl Cancer Inst. 2016 Jan 28;108(6):djv403. 
[PMID: 26823521]
Marchiano E et al. Subglottic squamous cell carcinoma: a popu
-
lation-based study of 889 cases. Otolaryngol Head Neck Surg. 
2016 Feb;154(2):315–21. [PMID: 26607281]
Marur S et al. Head and neck squamous cell carcinoma: update 
on epidemiology, diagnosis, and treatment. Mayo Clin Proc. 
2016 Mar;91(3):386–96. [PMID: 26944243]
Xing Y et al. Relation between the level of lymph node metastasis 
and survival in locally advanced head and neck squamous cell 
carcinoma. Cancer. 2016 Feb 15;122(4):534–45. [PMID: 
26554754]
VOCAL FOLD PARALYSIS
Vocal fold paralysis can result from a lesion or damage to 
either the vagus or recurrent laryngeal nerve and usually 
results in breathy dysphonia and effortful voicing. Com
-
mon causes of 
unilateral recurrent laryngeal nerve
 
involvement include thyroid surgery (and occasionally 
thyroid cancer), other neck surgery (anterior discectomy 
and carotid endarterectomy), and mediastinal or apical 
involvement by lung cancer. Skull base tumors often 
involve or abut upon lower cranial nerves and may affect 
the vagus nerve directly, or the vagus nerve may be dam
-
aged during surgical management of the lesion. While iat
-
rogenic injury is the most common cause of unilateral 
vocal fold paralysis, the second most common cause is 
idiopathic. However, before deciding whether the paralysis 
is due to iatrogenic injury or is idiopathic, the clinician 
must exclude other causes, such as malignancy. In the 
absence of other cranial neuropathies, a CT scan 
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with contrast from the skull base to the aorto-pulmonary 
window (the span of the recurrent laryngeal nerve) should 
be performed. If other cranial nerve deficits or high vagal 
weakness with palate paralysis is noted, an MRI scan of the 
brain and brainstem is warranted.
Unlike unilateral fold paralysis, 
bilateral fold paralysis
 
usually causes inspiratory stridor with deep inspiration. If 
the onset of bilateral fold paralysis is insidious, it may be 
asymptomatic at rest, and the patient may have a normal 
voice. However, the acute onset of bilateral vocal fold 
paralysis with inspiratory stridor at rest should be managed 
by a specialist immediately in a critical care environment. 
Causes of bilateral fold paralysis include thyroid surgery, 
esophageal cancer, and ventricular shunt malfunction. 
Unilateral or bilateral fold immobility may also be seen in 
cricoarytenoid arthritis secondary to advanced rheumatoid 
arthritis, intubation injuries, glottic and subglottic stenosis, 
and, of course, laryngeal cancer. The goal of intervention is 
the creation of a safe airway with minimal reduction in 
voice quality and airway protection from aspiration. A 
number of fold lateralization procedures for bilateral 
paralysis have been advocated as a means of removing the 
tracheotomy tube.
Unilateral vocal fold paralysis is occasionally temporary 
and may take over a year to resolve spontaneously. Surgical 
management of persistent or irrecoverable symptomatic 
unilateral vocal fold paralysis has evolved over the last 
several decades. The primary goal is medialization of the 
paralyzed fold in order to create a stable platform for vocal 
fold vibration. Additional goals include advancing diet and 
improving pulmonary toilet by facilitating cough. Success 
has been reported for years with injection laryngoplasty 
using Teflon, Gelfoam, fat, and collagen. Teflon is the only 
permanent injectable material, but its use is discouraged 
because of granuloma formation within the vocal folds of 
some patients. Temporary injectable materials, such as col
-
lagen or fat, provide excellent temporary restoration of 
voice and can be placed under local or general anesthesia. 
Once the paralysis is determined to be permanent, formal 
medialization thyroplasty may be performed by creating a 
small window in the thyroid cartilage and placing an 
implant between the thyroarytenoid muscle and inner 
table of the thyroid cartilage. This procedure moves the 
vocal fold medially and creates a stable platform for bilat
-
eral, symmetric mucosal vibration.
Kandil E et al. Assessment of vocal fold function using transcu
-
taneous laryngeal ultrasonography and flexible laryngoscopy. 
JAMA Otolaryngol Head Neck Surg. 2016 Jan;142(1):74–8. 
[PMID: 26632676]
Paddle PM et al. Diagnostic yield of computed tomography in 
the evaluation of idiopathic vocal fold paresis. Otolaryngol 
Head Neck Surg. 2015 Sep;153(3):414–9. [PMID: 26156423]
Rosow DE. Trends in utilization of vocal fold injection proce
-
dures. Otolaryngol Head Neck Surg. 2015 Nov;153(5):812–4. 
[PMID: 26220059]
TRACHEOSTOMY & CRICOTHYROTOMY
There are two primary indications for tracheotomy: airway 
obstruction at or above the level of the larynx and respira
-
tory failure requiring prolonged mechanical ventilation. In 
an acute emergency, cricothyrotomy secures an airway 
more rapidly than tracheotomy, with fewer potential 
immediate complications, such as pneumothorax and 
hemorrhage. Percutaneous dilatational tracheotomy as an 
elective bedside (or intensive care unit) procedure has 
undergone scrutiny in recent years as an alternative to tra
-
cheotomy. In experienced hands, the various methods of 
percutaneous tracheotomy have been documented to be 
safe in carefully selected patients. Simultaneous videobron
-
choscopy can reduce the incidence of major complications. 
The major cost reduction comes from avoiding the operat
-

-
-
ing room. Bedside tracheotomy (in the intensive care unit) 
achieves similar cost reduction and is advocated by some 
experts as slightly less costly than the percutaneous 
procedures.
The most common indication for elective tracheotomy 
is the need for prolonged mechanical ventilation. There is 
no firm rule about how many days a patient must be intu
-
bated before conversion to tracheotomy should be advised. 
The incidence of serious complications, such as subglottic 
stenosis increases with extended endotracheal intubation. 
As soon as it is apparent that the patient will require pro
-
tracted ventilatory support, tracheotomy should replace 
the endotracheal tube. Less frequent indications for trache
-
ostomy are life-threatening aspiration pneumonia, the 
need to improve pulmonary toilet to correct problems 
related to insufficient clearing of tracheobronchial secre
-
tions, and sleep apnea.
Posttracheotomy care requires humidified air to pre
-
vent secretions from crusting and occluding the inner can
-
nula of the tracheotomy tube. The tracheotomy tube 
should be cleaned several times daily. The most frequent 
early complication of tracheotomy is dislodgment of the 
tracheotomy tube. Surgical creation of an inferiorly based 
tracheal flap sutured to the inferior neck skin may make 
reinsertion of a dislodged tube easier. It should be recalled 
that the act of swallowing requires elevation of the larynx, 
which is limited by tracheotomy. Therefore, frequent tra
-
cheal and bronchial suctioning is often required to clear 
the aspirated saliva as well as the increased tracheobron
-
chial secretions. Care of the skin around the stoma is 
important to prevent maceration and secondary infection.
Dempsey GA et al. Long-term outcome following tracheostomy 
in critical care: a systematic review. Crit Care Med. 2016 Mar;
 
44(3):617–28. [PMID: 26584197]
 
º
FOREIGN BODIES IN THE U
pp
ER 
 
AERODIGESTIVE TRACT
FOREIGN BODIES OF THE TRACHEA & 
BRONCHI
Aspiration of foreign bodies occurs much less frequently in 
adults than in children. Older adults and denture wearers 
appear to be at greatest risk. Wider familiarity with the 
Heimlich maneuver has reduced deaths. If the maneuver is 
unsuccessful, cricothyrotomy may be necessary. Plain chest 
radiographs may reveal a radiopaque foreign body. Detec
-
tion of radiolucent foreign bodies may be aided by 
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inspiration-expiration films that demonstrate air trapping 
distal to the obstructed segment. Atelectasis and pneumo
-
nia may occur later.
Tracheal and bronchial foreign bodies should be 
removed under general anesthesia with rigid bronchoscopy 
by a skilled endoscopist working with an experienced 
anesthesiologist.
Altuntas B et al. Foreign bodies in trachea: 25 years of experience. 
Eurasian J Med. 2016 Jun;48(2):119–23. [PMID: 27551175]
ESOPHAGEAL FOREIGN BODIES
Foreign bodies in the esophagus create urgent but not life-
threatening situations as long as the airway is not compro
-
mised. There is probably time to consult an experienced 
clinician for management. It is a useful diagnostic sign of 
complete obstruction if the patient is drooling or cannot 
handle secretions. Patients may often point to the exact 
level of the obstruction. Indirect laryngoscopy often shows 
pooling of saliva at the esophageal inlet. Plain films may 
detect radiopaque foreign bodies, such as chicken bones. 
Coins tend to align in the coronal plane in the esophagus 
and sagittally in the trachea. If a foreign body is suspected, 
a barium swallow may help make the diagnosis.
The treatment of an esophageal foreign body depends 
very much on identification of its nature. In children, swal
-
lowed nonfood objects are common. In adults, however, 
food foreign bodies are more common, and there is the 
greater possibility of underlying esophageal pathology. 
Endoscopic removal and examination is usually best via 
flexible esophagoscopy or rigid laryngoscopy and esopha
-
goscopy. If there is nothing sharp, such as a bone, some 
clinicians advocate a hospitalized 24-hour observation 
period prior to esophagoscopy, noting that spontaneous 
passage of the foreign body will occur in 50% of adult 
patients. In the management of meat obstruction, the use 
of papain (meat tenderizer) should be discouraged because 
it can damage the esophageal mucosa and lead to stenosis 
or perforation.
Bekkerman M et al. Endoscopic management of foreign bodies 
in the gastrointestinal tract: a review of the literature. Gastro
-
enterol Res Pract. 2016;2016:8520767. [PMID: 27807447]
Geraci G et al. Retrospective analysis of management of ingested 
foreign bodies and food impactions in emergency endoscopic 
setting in adults. BMC Emerg Med. 2016 Nov 4;16(1):42. 
[PMID: 27809769]
Zhong Q et al. Esophageal foreign body ingestion in adults on 
weekdays and holidays: a retrospective study of 1058 patients. 
Medicine (Baltimore). 2017 Oct;96(43):e8409. [PMID: 
29069038]
DISEASES PRESENTING AS NECK MASSES
The differential diagnosis of neck masses is heavily depen
-
dent on the location in the neck, the age of the patient, and 
the presence of associated disease processes. Rapid growth 
and tenderness suggest an inflammatory process, while 
firm, painless, and slowly enlarging masses are often neo
-
plastic. In young adults, most neck masses are benign 
(branchial cleft cyst, thyroglossal duct cyst, reactive 
lymphadenitis), although malignancy should always be 
considered (lymphoma, metastatic thyroid carcinoma). 
Lymphadenopathy is common in HIV-positive persons, 
but a growing or dominant mass may well represent lym
-
phoma. In adults over age 40, cancer is the most common 
cause of persistent neck mass. A metastasis from squamous 
cell carcinoma arising within the mouth, pharynx, larynx, 
or upper esophagus should be suspected, especially if there 
is a history of tobacco or significant alcohol use. Especially 
among patients younger than 30 or older than 70, lym
-
phoma should be considered. In any case, a comprehensive 
otolaryngologic examination is needed. Cytologic evalua
-
tion of the neck mass via FNA biopsy is likely to be the next 
step if an obvious primary tumor is not obvious on physical 
CONGENITAL LESIONS PRESENTING AS NECK 
MASSES IN ADULTS
1. Branchial Cleft Cysts

Branchial cleft cysts usually present as a soft cystic mass 
along the anterior border of the sternocleidomastoid mus
-
cle. These lesions are usually recognized in the second or 
third decades of life, often when they suddenly swell or 
become infected. To prevent recurrent infection and pos
-
sible carcinoma, they should be completely excised, along 
with their fistulous tracts.
First branchial cleft cysts present high in the neck, 
sometimes just below the ear. A fistulous connection with 
the floor of the external auditory canal may be present. 
Second branchial cleft cysts, which are far more common, 
may communicate with the tonsillar fossa. Third branchial 
cleft cysts, which may communicate with the piriform 
sinus, are rare and present low in the neck.
Derks LS et al. Surgery versus endoscopic cauterization in 
patients with third or fourth branchial pouch sinuses: a sys
-
tematic review. Laryngoscope. 2016 Jan;126(1):212–7. 
[PMID: 26372400]
Ha EJ et al. Efficacy and safety of ethanol ablation for branchial 
cleft cysts. AJNR Am J Neuroradiol. 2017 Dec;38(12):2351–6. 
[PMID: 28970243]
2. Thyroglossal Duct Cysts
Thyroglossal duct cysts occur along the embryologic 
course of the thyroid’s descent from the tuberculum impar 
of the tongue base to its usual position in the low neck. 
Although they may occur at any age, they are most com
-
mon before age 20. They present as a midline neck mass, 
often just below the hyoid bone, which moves with swal
-
lowing. Surgical excision is recommended to prevent 
recurrent infection. This requires removal of the entire 
fistulous tract along with the middle portion of the hyoid 
bone through which many of the fistulas pass. Preoperative 
evaluation should include a thyroid ultrasound to confirm 
anatomic position of the thyroid.
Rayess HM et al. Thyroglossal duct cyst carcinoma: a systematic 
review of clinical features and outcomes. Otolaryngol Head 
Neck Surg. 2017 May;156(5):794–802. [PMID: 28322121]
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Ross J et al. Thyroglossal duct cyst surgery: a ten-year single 
institution experience. Int J Pediatr Otorhinolaryngol. 2017 
Oct;101:132–6. [PMID: 28964283]
INFECTIOUS & INFLAMMATORY 
 
NECK MASSES
1. Reactive Cervical Lymphadenopathy
Normal lymph nodes in the neck are usually less than 1 cm 
in length. Infections involving the pharynx, salivary glands, 
and scalp often cause tender enlargement of neck nodes. 
Enlarged nodes are common in HIV-infected persons. 
Except for the occasional node that suppurates and requires 
incision and drainage, treatment is directed against the 
underlying infection. An enlarged node (larger than 1.5 cm) 
or node with a necrotic center that is not associated with an 
obvious infection should be further evaluated, especially if 
the patient has a history of smoking, alcohol use, or prior 
cancer. Other common indications for FNA biopsy of a 
node include its persistence or continued enlargement. 
Common causes of cervical adenopathy include tumor 
(squamous cell carcinoma, lymphoma, occasional metas
-
tases from non-head and neck sites) and infection (eg, 
reactive nodes, mycobacteria, and cat-scratch disease). 
Rare causes of adenopathy include Kikuchi disease (his
-
tiocytic necrotizing lymphadenitis) and autoimmune 
adenopathy.
Białek EJ et al. Mistakes in ultrasound diagnosis of superficial 
lymph nodes. J Ultrason. 2017 Mar;17(68):59–65. [PMID: 
28439430]
Celenk F et al. Predictive factors for malignancy in patients with 
persistent cervical lymphadenopathy. Eur Arch Otorhinolar
-
yngol. 2016 Jan;273(1):251–6. [PMID: 26187739]
2. Tuberculous & Nontuberculous Mycobacterial 
Granulomatous neck masses are not uncommon. The dif
-
ferential diagnosis includes mycobacterial adenitis, sarcoid
-
osis, and cat-scratch disease due to 
Bartonella henselae.
 The 
incidence of mycobacterial lymphadenitis is on the rise both 
in immunocompromised and immunocompetent individu
-
als. The usual presentation of granulomatous disease in the 
neck is simply single or matted nodes. Although mycobacte
-
rial adenitis can extend to the skin and drain externally (as 
described for atypical mycobacteria and referred to as 
scrofula), this late presentation is no longer common.
FNA biopsy is usually the best initial diagnostic 
approach: cytology, smear for acid-fast bacilli, mycobacte
-
rial culture, and a sensitivity test can all be done. PCR from 
FNA (or from excised tissue) is the most sensitive test and 
is particularly useful when conventional methods have not 
been diagnostic but clinical impression remains consistent 
for tuberculous infection. While FNA has a high sensitivity 
(about 88%), its specificity is low (49%); thus, an excisional 
biopsy is often required to confirm the diagnosis.
See Table 9–15 for current recommended treatment of 
tuberculosis, including tuberculous lymphadenopathy. For 
atypical (nontuberculous) lymphadenopathy, treatment 
depends on the sensitivity results of culture, but antibiotics 
likely to be useful include 6 months of isoniazid and 
rifampin and, for at least the first 2 months, ethambutol—all 
in standard dosages. Some would totally excise the involved 
nodes prior to chemotherapy, depending on location and 
other factors, but this can lead to chronic draining fistulas.
28439430]
Gonzalez CD et al. Complex nontuberculous mycobacterial 
cervicofacial lymphadenitis: what is the optimal approach? 
Laryngoscope. 2016 Jul;126(7):1677–80. [PMID: 26372159]
Kim KH et al. The efficacy of the interferon-γ release assay for 
diagnosing cervical tuberculous lymphadenitis: a prospective 
controlled study. Laryngoscope. 2016 Feb;126(2):378–84. 
[PMID: 26267599]
Meghji S et al. What is the optimal diagnostic pathway in 
tuberculous lymphadenitis in the face of increasing

tuberculous lymphadenitis in the face of increasing 
resistance: cytology or histology? Am J Otolaryngol. 2015 
Nov–Dec;36(6):781–5. [PMID: 26545471]
3. Lyme Disease
Lyme disease, caused by the spirochete 
 
and transmitted by ticks of the 
Ixodes
 genus, may have pro
-
tean manifestations, but over 75% of patients have symptoms 
involving the head and neck. Facial paralysis, dysesthesias, 
dysgeusia, or other cranial neuropathies are most common. 
Headache, pain, and cervical lymphadenopathy may occur. 
See Chapter 34 for a more detailed discussion.
Sanchez JL. Clinical manifestations and treatment of Lyme dis
-
ease. Clin Lab Med. 2015 Dec;35(4):765–78. [PMID: 26593256]
TUMOR METASTASES
In older adults, 80% of firm, persistent, and enlarging neck 
masses are metastatic in origin. The great majority of these 
arise from squamous cell carcinoma of the upper aerodi
-
gestive tract. A complete head and neck examination may 
reveal the tumor of origin, but examination under anesthe
-
sia with direct laryngoscopy, esophagoscopy, and bron
-
choscopy is usually required to fully evaluate the tumor 
and exclude second primaries.
It is often helpful to obtain a cytologic diagnosis if ini
-
tial head and neck examination fails to reveal the primary 
tumor. An open biopsy should be done only when neither 
physical examination by an experienced clinician special
-
izing in head and neck cancer nor FNA biopsy performed 
by an experienced cytopathologist yields a diagnosis. In 
such a setting, one should strongly consider obtaining an 
MRI or PET scan prior to open biopsy, as these methods 
may yield valuable information about a possible presumed 
primary site or another site for FNA.
With the exception of papillary thyroid carcinoma, 
non–squamous cell metastases to the neck are infrequent. 
While tumors that are not primary in the head or neck 
seldom metastasize to the cervical lymph nodes, the supra
-
clavicular lymph nodes are quite often involved by lung, 
gastroesophageal, and breast tumors. Infradiaphragmatic 
tumors, with the exception of renal cell carcinoma and 
testicular cancer, rarely metastasize to the neck.
CMDT19_Ch08_p0210-p0251.indd   250

251
 
CMDT 2019
Arosio AD et al. Neck lymph node metastases from unknown 
primary. Cancer Treat Rev. 2017 Feb;53:1–9. [PMID: 
28027480]
Bochtler T et al. Diagnosis and management of metastatic neo
-
plasms with unknown primary. Semin Diagn Pathol. 2017 
Nov 26. [Epub ahead of print] [PMID: 29203116]
Green B et al. Current surgical management of metastases in the 
neck from mucosal squamous cell carcinoma of the head and 
neck. Br J Oral Maxillofac Surg. 2016 Feb;54(2):135–40. 
[PMID: 26432197]
Liang L et al. A meta-analysis on selective versus comprehensive 
neck dissection in oral squamous cell carcinoma patients with 
clinically node-positive neck. Oral Oncol. 2015 Dec;
 
51(12):1076–81. [PMID: 26500065]
LYMPHOMA
About 10% of lymphomas present in the head and neck. 
Multiple rubbery nodes, especially in young adults or in 
patients who have AIDS, are suggestive of this disease. A 
thorough physical examination may demonstrate other 
sites of nodal or organ involvement. FNA biopsy may be 
diagnostic, but open biopsy is often required to determine 
architecture and an appropriate treatment course.
Oishi N et al. Head and neck lymphomas in HIV patients: a 
clinical perspective. Int Arch Otorhinolaryngol. 2017 Oct;
 
21(4):399–407. [PMID: 29018505]
CMDT19_Ch08_p0210-p0251.indd   251

252
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º
DISORDERS OF THE AIRWAYS
Airway disorders have diverse causes but share certain com
-
mon pathophysiologic and clinical features. Airflow limitation 
is characteristic and frequently causes dyspnea and cough. 
Other symptoms are typically disease-specific. Disorders of 
the airways can be classified as those that involve the upper 
airways—loosely defined as those above and including the 
vocal folds—and those that involve the lower airways.
DISORDERS OF THE UPPER AIRWAYS
Acute obstruction of the upper airway
 can be immedi
-
ately life-threatening and must be relieved promptly to 
avoid asphyxia. Causes of acute upper airway obstruction 
include trauma to the larynx or pharynx, foreign body 
aspiration, laryngospasm, laryngeal edema from thermal 
injury or angioedema, infections (acute epiglottitis, Ludwig 
angina, pharyngeal or retropharyngeal abscess), and acute 
allergic laryngitis.
Chronic obstruction of the upper airway
 may be 
caused by carcinoma of the pharynx or larynx, laryngeal or 
subglottic stenosis, laryngeal granulomas or webs, or bilat
-
eral vocal fold paralysis. Laryngeal or subglottic stenosis 
may become evident weeks or months after translaryngeal 
endotracheal intubation. Inspiratory stridor, intercostal 
retractions on inspiration, a palpable inspiratory thrill over 
the larynx, and wheezing localized to the neck or trachea 
on auscultation are characteristic findings. Flow-volume 
loops may show characteristic flow limitations. Soft-tissue 
radiographs of the neck may show supraglottic or infra
-
glottic narrowing. CT and MRI scans can reveal exact sites 
of obstruction. Flexible endoscopy may be diagnostic, but 
caution is necessary to avoid exacerbating upper airway 
edema and precipitating critical airway narrowing.
Vocal fold dysfunction syndrome
 is characterized by 
paradoxical vocal fold adduction, resulting in both acute 
and chronic upper airway obstruction. It can cause dys
-
pnea and wheezing that may be distinguished from asthma 
or exercise-induced asthma by the lack of response to 
bronchodilator therapy, normal spirometry immediately 
after an attack, spirometric evidence of upper airway 
obstruction, a negative bronchial provocation test, or direct 
visualization of adduction of the vocal folds on both 9
Asha N. Chesnutt, MD 
 
Niall T. Prendergast, MD 
 
Thomas J. Prendergast, MD 
inspiration and expiration. The condition appears to be 
psychogenic in nature. Treatment consists of speech ther
-
apy, which uses breathing, voice, and neck relaxation exer
-
cises to abort the symptoms.
Denipah N et al. Acute management of paradoxical vocal fold 
motion (vocal cord dysfunction). Ann Emerg Med. 2017 Jan;
 
69(1):18–23. [PMID: 27522309]
Idrees M et al. Vocal cord dysfunction in bronchial asthma. 
A review article. J Asthma. 2015 May;52(4):327–35. [PMID: 
25365113]
DISORDERS OF THE LOWER AIRWAYS
Tracheal obstruction
 may be intrathoracic (below the 
suprasternal notch) or extrathoracic. Fixed tracheal 
obstruction may be caused by acquired or congenital tra
-
cheal stenosis, primary or secondary tracheal neoplasms, 
extrinsic compression (tumors of the lung, thymus, or 
thyroid; lymphadenopathy; congenital vascular rings; 
aneurysms; etc), foreign body aspiration, tracheal granulo
-
mas and papillomas, and tracheal trauma. Tracheomalacia, 
foreign body aspiration, and retained secretions may cause 
variable tracheal obstruction.
Acquired 
tracheal stenosis
 is usually secondary to pre
-
vious tracheotomy or endotracheal intubation. Dyspnea, 
cough, and inability to clear pulmonary secretions occur 
weeks to months after tracheal decannulation or extuba
-
tion. Physical findings may be absent until tracheal diam
-
eter is reduced 50% or more, when wheezing, a palpable 
tracheal thrill, and harsh breath sounds may be detected. 
The diagnosis is usually confirmed by plain films or CT of

-
The diagnosis is usually confirmed by plain films or CT of 
the trachea. Complications include recurring pulmonary 
infection and life-threatening respiratory failure. Manage
-
ment is directed toward ensuring adequate ventilation and 
oxygenation and avoiding manipulative procedures that 
may increase edema of the tracheal mucosa. Surgical 
reconstruction, endotracheal stent placement, or laser pho
-
toresection may be required.
Bronchial obstruction
 may be caused by retained pul
-
monary secretions, aspiration, foreign bodies, bronchoma
-
lacia, bronchogenic carcinoma, compression by extrinsic 
masses, and tumors metastatic to the airway. Clinical and 
radiographic findings vary depending on the location of 
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PULMONARY DISORDERS
253
 
CMDT 2019
the obstruction and the degree of airway narrowing. Symp
-
toms include dyspnea, cough, wheezing, and, if infection is 
present, fever and chills. A history of recurrent pneumonia 
in the same lobe or segment or slow resolution (more than 
3 months) of pneumonia on successive radiographs sug
-
gests the possibility of bronchial obstruction and the need 
for bronchoscopy.
Radiographic findings include 
atelectasis
 (local paren
-
chymal collapse), postobstructive infiltrates, and air trap
-
ping caused by unidirectional expiratory obstruction. CT 
scanning may demonstrate the nature and exact location of 
obstruction of the central bronchi. MRI may be superior to 
CT for delineating the extent of underlying disease in the 
hilum, but it is usually reserved for cases in which CT find
-
ings are equivocal. Bronchoscopy is the definitive diagnos
-
tic study, particularly if tumor or foreign body aspiration is 
suspected. The finding of bronchial breath sounds on 
physical examination or an air bronchogram on chest 
radiograph in an area of atelectasis rules out complete air
-
way obstruction. Bronchoscopy is unlikely to be of thera
-
peutic benefit in this situation.
Murgu SD et al. Central airway obstruction: benign strictures, 
tracheobronchomalacia, and malignancy-related obstruction. 
Chest. 2016;150(2):426–41. [PMID: 26874192]
ASTHMA
 
»
Episodic or chronic symptoms of wheezing, dyspnea, 
or cough.
 
»
Symptoms frequently worse at night or in the 
early morning.
 
»
Prolonged expiration and diffuse wheezes on 
 
»
Limitation of airflow on pulmonary function test
-
ing or positive bronchoprovocation challenge.
 
»
Reversibility of airflow obstruction, either sponta
-
neously or following bronchodilator therapy.
 
»
Asthma is a common disease, affecting approximately 
8–10% of the population. It is slightly more common in 
male children (younger than 14 years) and in female adults. 
There is a genetic predisposition to asthma. Prevalence, 
hospitalizations, and fatal asthma have all increased in the 
United States over the past 20 years. Each year, approxi
-
mately 10 million office visits, 1.8 million emergency 
department visits, and more than 3500 deaths in the 
United States are attributed to asthma. Hospitalization 
rates have been highest among blacks and children, and 
death rates are consistently highest among blacks aged 
15–24 years.
 
»
Definition & Pathogenesis
Asthma is a chronic disorder of the airways characterized 
by variable airway obstruction, airway hyperresponsive
-
ness, and airway inflammation. No single histopathologic 
feature is pathognomonic but common findings include 
airway inflammatory cell infiltration with eosinophils, 
neutrophils, and lymphocytes (especially T cells); goblet 
cell hyperplasia, sometimes plugging of small airways with 
mucus; collagen deposition beneath the basement mem
-
brane; hypertrophy of bronchial smooth muscle; airway 
edema; mast cell activation; and denudation of airway epi
-
thelium. IgE plays a central role in the pathogenesis of 
allergic asthma. IL-5 is important in promoting eosino
-
philic inflammation.
The strongest identifiable predisposing factor for the 
development of asthma is atopy, but obesity is increasingly 
recognized as a risk factor. Exposure of sensitive patients to 
inhaled allergens increases airway inflammation, airway 
hyper-responsiveness, and symptoms. Symptoms may 
develop immediately (immediate asthmatic response) or 
4–6 hours after allergen exposure (late asthmatic response). 
Common allergens include house dust mites (often found 
in pillows, mattresses, upholstered furniture, carpets, and 
drapes), cockroaches, cat dander, and seasonal pollens. 
Substantially reducing exposure reduces pathologic find
-
ings and clinical symptoms.
Nonspecific precipitants
 of asthma include exercise,

-
 of asthma include exercise, 
upper respiratory tract infections, rhinosinusitis, postnasal 
drip, aspiration, gastroesophageal reflux, changes in the 
weather, and stress. Exposure to 
products of combustion
 
(eg, from tobacco, crack cocaine, methamphetamines, and 
other agents) increases asthma symptoms and the need for 
medications and reduces lung function. 
Air pollution
 
(increased air levels of respirable particles, ozone, SO
2
, and 
NO
2
) precipitate asthma symptoms and increase emer
-
gency department visits and hospitalizations. Selected 
individuals may experience asthma symptoms after expo
-
sure to aspirin (aspirin exacerbated respiratory disease), 
nonsteroidal anti-inflammatory drugs, or tartrazine dyes. 
Other 
 may precipitate asthma symptoms (see 
Table 9–24). 
Occupational asthma
 is triggered by various 
agents in the workplace and may occur weeks to years after 
initial exposure and sensitization. Women may experience 
catamenial asthma
 at predictable times during the men
-
strual cycle. 
Exercise-induced bronchoconstriction
 begins 
during exercise or within 3 minutes after its end, peaks 
within 10–15 minutes, and then resolves by 60 minutes. This 
phenomenon is thought to be a consequence of the airways’ 
attempt to warm and humidify an increased volume of 
expired air during exercise. 
“Cardiac asthma”
 is wheezing 
precipitated by decompensated heart failure. Cough-variant 
asthma has cough instead of wheezing as the predominant 
symptom of bronchial hyperreactivity.
 
»
Symptoms and signs vary widely among patients as well as 
individually over time. General clinical findings in stable 
asthma patients are listed in Figure 9–1 and Table 9–1; 
Table 9–2 lists findings seen during asthma exacerbations.
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C
HAPTER
 9
254
 CMDT 2019
Asthma is characterized by episodic wheezing, difficulty in 
breathing, chest tightness, and cough. Excess sputum pro
-
duction is common. The frequency of asthma symptoms is 
highly variable. Some patients have infrequent, brief attacks 
of asthma while others may suffer nearly continuous symp
-
toms. Asthma symptoms may occur spontaneously or be 
and consider short course of
oral
systemic corticosteroids
St
ep 4 
or 
5
St
ep 
3
Step
 2
Step
 1
Recommended Step
for Initiating Treatment
(S
ee Figure 
9
−
2 
for treatment steps.
)
In 
2
−
6 weeks, evalua
te
 leve
l of 
ast
hma control that
 is achieved and adjust therapy 
acco
rdingly.
 
•N
ormal FE
V
1
between 
ex
acerbation
s
Extremely limited
Some limit
at
io
n
Minor limit
at
io
n
None
Interference with
 
normal activity
Several time
s
per da
y
Dail
y
> 2 days/week
bu
t not daily, and 
not more than
1
×
 on any da
y
≤
 2 days/week
Short-ac
ti
ng
β
2
-agonis
t use for 
symptom control (not
 
prevention of EIB)
≥
 2/year (see note
)
0
−
1/year (see 
no
te
)
•F
EV
1
< 60%
predicte
d
•F
EV
1
> 60% but 
< 80% predicted
•F
EV
1
> 80%
pr
ed
ic
te
d
•F
EV
1
> 80%
predicte
d
•F
EV
1
/FVC
reduced > 5%
•F
EV
1
/FVC
 
redu
ce
d 5%
•F
EV
1
/F
VC
 normal
•F
EV
1
/FVC norm
al
Ris
k
Relative annual ri
sk
 of exac
erbations may be related to FE
V
1
.
Classification of Asthma Severity
≥
 12 years of ag
e
Consider severity and in
terv
al since last exacerbation
.
Fr
equency and severity may fluctuate over time for patients in any severity category
.
Impairment
Normal FE
V
1
/FVC:
8
−
19 yr
85%
20
−
39 
yr
80%
40
−
59 
yr
75%
60
−
80 
yr
70%
Persist
en
t
Components of Severity
Exa
cerbatio
ns
requiring oral
 
systemic
 
Lung 
fu
nction
Of
te
n 
7
×
/wee
k
> 1
×
/week bu
t
not nigh
tl
y
3
−
4
×
/mont
h
≤
 2
×
/mont
h
Ni
gh
ttime 
awakeni
ng
s
Throughout the da
y
Dail
y
> 2 days/week bu
t 
not dail
y
≤
Symptom
s
Se
ve
re
Modera
te
Mild
Intermittent
 
EIB, exercise-induced bronchospasm; FE
V
1
, forced expiratory volume in 1 second; FVC, forced vital capac
ity; ICU,
intensive care unit.
Notes:
• 
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient
needs.
• 
Level of severity is determined by assessment of both impairment and risk. Assess impairment domain by patient’s/
caregiver’s recall of previous 2–4 weeks and spirometry. Assign severity to the most severe category in which any
feature occurs.
• 
At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity.
In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or IC
U
admission) indicate greater underlying disease severity. For tr
eatment purposes, patients who had 
≥
 2 exacerbations
requiring oral systemic corticosteroids in the past year may be considered the same as patients who have persistent
asthma, even in the absence of impairment levels consistent with persistent asthma.
 
▲
Figure 9–1.
 
Classifying asthma severity and initiating treatment. 
(Adapted from National Asthma Education and 
Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes 
of Health Pub. No. 08-4051. Bethesda, MD, 2007.)
precipitated or exacerbated by many different triggers as 
discussed above. Asthma symptoms are frequently worse at 
night; circadian variations in bronchomotor tone and 
bronchial reactivity reach their nadir between 3 
am
 and 
4 
am
, increasing symptoms of bronchoconstriction.
Some physical examination findings increase the 
probability of asthma. Nasal mucosal swelling, increased 
secretions, and polyps are often seen in patients with 
CMDT19_Ch09_p0252-p0333.indd   254

255
 
CMDT 2019
Table 9–1.
 
Assessing asthma control.
Components of Control
Classification of Asthma Control (≥ 12 years of age)
Well Controlled
Not Well Controlled
Very Poorly Controlled
Symptoms
≤ 2 days/week
Throughout the day
Nighttime awakenings
≤ 2×/month
1–3×/week
≥ 4×/week
Interference with normal 
activity
None
Some limitation
Short-acting beta-2-agonist 
 
use for symptom control 
 
(not prevention of EIB)
Several times/day
FEV
1
 or peak flow
> 80% predicted/
 
personal best
60–80% predicted/
 
< 60% predicted/
 
Validated Questionnaires
 
ATAQ
1
 
ACQ
1
 
ACT
1
0
≤ 0.75
≥ 20
1–2
≥ 1.5
16–19
3–4
N/A
≤ 15
Risk
Exacerbations requiring 
 
oral systemic 
0–1/year
≥ 2/year (see note)
Consider severity and interval since last exacerbation
Loss of lung function
Evaluation requires long-term follow-up care
Treatment-related adverse 
effects
Medication side effects can vary in intensity from none to very troublesome and 
worrisome. The level of intensity does not correlate to specific levels of control but 
should be considered in the overall assessment of risk.
Recommended Action for Treatment 
 
(see Figure 9–2 for steps)
• 
 
Maintain current step
• 
 
Regular follow-ups 
every 1–6 months to 
maintain control.
• 
 
Consider step down if 
well controlled for at 
least 3 months.
• 
 
Step up 1 step, and
• 
 
Reevaluate in 
2–6 weeks.
• 
 
For side effects, 
consider alternative 
treatment options.
• 
 
Consider short course of oral 
systemic corticosteroids,
• 
 
Step up 1–2 steps, and
• 
 
Reevaluate in 2 weeks.
• 
 
For side effects, consider 
alternative options.
1
Minimal importance differences: 1.0 for the ATAQ; 0.5 for the ACQ with values of 0.76–1.4 considered indeterminate; not determined for 
the ACT.
ACQ, Asthma Control Questionnaire
©
; ACT, Asthma Control Test
TM”
; ATAQ = Asthma Therapy Assessment Questionnaire
©
; EIB, exercise-
induced bronchospasm; FEV
1
, forced expiratory volume in 1 second; ICU, intensive care unit.
Notes:
• 
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
• 
 
The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient’s recall of previous 
2–4 weeks and by spirometry or peak flow measures. Symptom assessment for longer periods should reflect a global assessment, such 
as inquiring whether the patient’s asthma is better or worse since the last visit.
• 
 
Inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense 
exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer control. For therapy purposes, 
patients with ≥ 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have 
not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.
• 
Before step up in therapy:
 
—R
eview adherence to medication, inhaler.
 
—I
f an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step.
Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management 
of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007.
allergic asthma. Eczema, atopic dermatitis, or other allergic 
skin disorders may also be present. Wheezing or a pro
-
longed expiratory phase during normal breathing corre
-
lates well with the presence of airflow obstruction. 
(Wheezing during forced expiration does not.) Chest 
examination may be normal between exacerbations in 
patients with mild asthma. During severe asthma exacer
-
bations, airflow may be too limited to produce wheezing,

-
bations, airflow may be too limited to produce wheezing, 
and the only diagnostic clue on auscultation may be glob
-
ally reduced breath sounds with prolonged expiration. 
Hunched shoulders and use of accessory muscles of respi
-
ration suggest an increased work of breathing.
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C
HAPTER
 9
256
 CMDT 2019
Arterial blood gas measurements may be normal during a 
mild asthma exacerbation, but respiratory alkalosis and an 
increase in the alveolar-arterial oxygen difference 
(A–a–D
o
2
) are common. During severe exacerbations, 
hypoxemia develops and the Pa
co
2
 returns to normal. The 
combination of an increased Pa
co
2
 and respiratory acido
-
sis may indicate impending respiratory failure and the need 
for mechanical ventilation.
C. Pulmonary Function Testing
Clinicians are able to identify airflow obstruction on exami
-
nation, but they have limited ability to assess its severity or 
to predict whether it is reversible. The evaluation for asthma 
should therefore include 
spirometry
 (forced expiratory vol
-
ume in 1 second [FEV
1
], forced vital capacity [FVC], FEV
1
/
FVC) before and after the administration of a short-acting 
bronchodilator. These measurements help determine the 
presence and extent of airflow obstruction and whether it is 
immediately reversible. Airflow obstruction is indicated by a 
reduced FEV
1
/FVC ratio. Significant reversibility of airflow 
obstruction is defined by an increase of 12% or more and 
200 mL in FEV
1
 or FVC after inhaling a short-acting 
bronchodilator. A positive bronchodilator response strongly 
confirms the diagnosis of asthma but a lack of responsive
-
ness in the pulmonary function laboratory does not preclude 
success in a clinical trial of bronchodilator therapy. Severe 
airflow obstruction results in significant air trapping, with 
an increase in residual volume and consequent reduction in 
FVC, resulting in a pattern that may mimic a restrictive 
ventilatory defect.
Bronchial provocation testing
 with inhaled histamine 
or methacholine may be useful when asthma is suspected 
but spirometry is nondiagnostic. Bronchial provocation is 
not recommended if the FEV
1
 is less than 65% of predicted. 
A positive methacholine test is defined as a fall in the FEV
1
 
of 20% or more at exposure to a concentration of less than 
or equal to 8 mg/mL. A negative test has a negative predic
-
tive value for asthma of 95%. Exercise challenge testing 
may be useful in patients with symptoms of exercise-
induced bronchospasm.
Peak expiratory flow (PEF)
 meters are handheld 
devices designed as personal monitoring tools. PEF moni
-
toring can establish peak flow variability, quantify asthma 
severity, and provide both patient and clinician with objec
-
tive measurements on which to base treatment decisions. 
There are conflicting data about whether measuring PEF 
Table 9–2.
 
Evaluation and classification of severity of asthma exacerbations.
Mild
Moderate
Severe
Respiratory Arrest 
Imminent
Symptoms
Breathlessness
While walking
At rest, limits 
activity
At rest, interferes with 
conversation
While at rest, mute
Talks in
Sentences
Phrases
Words
Silent
Alertness
May be agitated
Usually agitated
Drowsy or confused
Signs
Respiratory rate
Increased
Increased
Often > 30/minute
> 30/minute
Body position
Can lie down
Prefers sitting
Sits upright
Unable to recline
Use of accessory muscles; 
suprasternal retractions
Usually not
Commonly
Usually
Paradoxical thoracoabdomi
-
nal movement
Wheeze
Moderate, often only 
end expiratory
Loud; throughout 
exhalation
Usually loud; throughout 
inhalation and exhalation
Absent
Pulse/minute
< 100
100–120
> 120
Pulsus paradoxus
Absent < 10 mm Hg
May be present 
10–25 mm Hg
Often present > 25 mm Hg
Absence suggests respiratory 
muscle fatigue
Functional Assessment
PEF or FEV
1
 % predicted 
or % personal best
≥ 70%
40–69%
< 40%
< 25%
Pa
o
2
 (on air, mm Hg)
Normal
1
≥ 60
1
< 60: possible cyanosis
P
co
2
 (mm Hg)
< 42 mm Hg
1
< 42 mm Hg
1
≥ 42
1
≥ 42
1
Sa
o
2
 (on air, %)
> 95%
1
90–95%
1
< 90%
1
< 90%
1
1
Test not usually necessary.
FEV
1
, forced expiratory volume in 1 second; PEF, peak expiratory flow; Sa
o
2
, oxygen saturation.

1
≥ 42
1
≥ 42
1
Sa
o
2
 (on air, %)
> 95%
1
90–95%
1
< 90%
1
< 90%
1
1
FEV
1
o
2
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257
 
CMDT 2019
improves asthma outcomes, but doing so is recommended 
to help confirm the diagnosis of asthma, to improve 
asthma control in patients with poor perception of airflow 
obstruction, and to identify environmental and occupa
-
tional causes of symptoms. Predicted values for PEF vary 
with age, height, and sex but are poorly standardized. 
Comparison with reference values is less helpful than com
-
parison with the patient’s own baseline. PEF shows diurnal 
variation. It is generally lowest on first awakening and 
highest several hours before the midpoint of the waking 
day. PEF should be measured in the morning before the 
administration of a bronchodilator and in the afternoon 
after taking a bronchodilator. A 20% change in PEF values 
from morning to afternoon or from day to day suggests 
inadequately controlled asthma. PEF values less than 
200 L/min indicate severe airflow obstruction.
D. Additional Testing
Routine chest radiographs in patients with asthma are usu
-
ally normal or show only hyperinflation. Other findings 
may include bronchial wall thickening and diminished 
peripheral lung vascular shadows. Chest imaging is indi
-
cated when pneumonia, another disorder mimicking 
asthma, or a complication of asthma such as pneumotho
-
rax is suspected.
Skin testing or in vitro testing, including total serum IgE 
and allergen-specific IgE, to assess sensitivity to environ
-
mental allergens can identify atopy in patients with persis
-
tent asthma who may benefit from therapies directed at their 
allergic diathesis. Evaluations for paranasal sinus disease or 
gastroesophageal reflux should be considered in patients 
with pertinent, severe, or refractory asthma symptoms. An 
absolute eosinophil count can identify patients eligible for 
anti–IL-5 therapy to manage eosinophilic airway disease.
 
»
Complications of asthma include exhaustion, dehydration, 
airway infection, and tussive syncope. Pneumothorax 
occurs but is rare. Acute hypercapnic and hypoxemic respi
-
ratory failure occurs in severe disease.
 
»
Patients who have atypical symptoms or poor response to 
therapy may have a condition that mimics asthma. These 
disorders typically fall into one of five categories: upper 
airway disorders, lower airway disorders, systemic 
vasculitides, cardiac disorders, and psychiatric disorders. 
Upper airway disorders
 that mimic asthma include vocal 
fold paralysis, vocal fold dysfunction syndrome, foreign 
body aspiration, laryngotracheal masses, tracheal narrow
-
ing, tracheobronchomalacia, and airway edema (eg, angio
-
edema or inhalation injury). 
Lower airway disorders
 
include nonasthmatic chronic obstructive pulmonary 
disease (COPD) (chronic bronchitis or emphysema), 
bronchiectasis, allergic bronchopulmonary mycosis, cys
-
tic fibrosis, eosinophilic pneumonia, hypersensitivity 
pneumonitis, sarcoidosis, and bronchiolitis obliterans. 
Systemic vasculitides
 with pulmonary involvement may 
have an asthmatic component, such as eosinophilic 
granulomatosis with polyangiitis. 
Cardiac disorders
 
include heart failure and pulmonary hypertension. 
Psy
-
chiatric causes
 include conversion disorders (“func
-
tional” asthma), emotional laryngeal wheezing, vocal fold 
dysfunction, or episodic laryngeal dyskinesis. Rarely, 
Münchausen syndrome or malingering may explain a 
patient’s complaints.
 
»
NAEPP 3 Diagnosis & Management 
Guidelines
The third Expert Panel Report of the National Asthma Edu
-
cation and Prevention Program (NAEPP), in conjunction 
with the Global Initiative for Asthma, a collaboration 
between the National Institutes of Health/National Heart, 
Lung, and Blood Institute and the World Health Organiza
-
tion, provides guidelines for diagnosis and management of 
asthma (NAEPP 3) (Figure 9–2). This report identifies four 
components of chronic asthma diagnosis and management: 
(1) assessing and monitoring asthma severity and asthma

(1) assessing and monitoring asthma severity and asthma 
control, (2) patient education designed to foster a partner
-
ship for care, (3) control of environmental factors and 
comorbid conditions that affect asthma, and (4) pharmaco
-
logic therapy for asthma.
1. Assessing and monitoring asthma severity and asthma 
control—
Severity
 is the intrinsic intensity of the disease 
process. 
Control
 is the degree to which symptoms and 
limitations on activity are minimized by therapy. 
Respon
-
siveness
 is the ease with which control is achieved with 
therapy. NAEPP 3 guidelines emphasize control over clas
-
sifications of severity, since the latter is variable over time 
and in response to therapy. A measure of severity on initial 
presentation (Figure 9–1) is helpful, however, in guiding 
the initiation of therapy. Control of asthma is assessed in 
terms of 
impairment
 (frequency and intensity of symp
-
toms and functional limitations) and 
risk
 (the likelihood of 
acute exacerbations or chronic decline in lung function). A 
key insight is that these two domains of control may 
respond differently to treatment: some patients may have 
minimal impairment yet remain at risk for severe exacer
-
bations, for example, in the setting of an upper respiratory 
tract infection. Table 9–1 is used to assess the adequacy of 
asthma control and is used in conjunction with Figure 9–2 
to guide adjustments in therapy based on the level of 
control.
2. Patient education designed to foster a partnership for 
care—
Active self-management reduces urgent care visits 
and hospitalizations and improves perceived control of 
asthma. Therefore, an outpatient preventive approach that 
includes self-management education is an integral part of 
effective asthma care.
All patients, but particularly those with poorly con
-
trolled symptoms or history of severe exacerbations, should 
have a written 
asthma action plan
 that includes instruc
-
tions for daily management and measures to take in 
response to specific changes in status. Patients should be 
taught to recognize symptoms—especially patterns indi
-
cating inadequate asthma control or predicting the need 
for additional therapy.
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258
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▲
Figure 9–2.
 
Stepwise approach to managing asthma. 
(Adapted from National Asthma Education and Prevention 
Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health 
Pub. No. 08-4051. Bethesda, MD, 2007.)
Key: 
Alphabetical order is used when more than one treatment option is listed within either preferred or 
alternative therapy. 
EIB, exercise-induced bronchospasm; ICS, inhaled corticosteroid; LABA, inhaled 
long-acting beta-2-agonist; LTRA, leukotriene receptor antagonist; SABA, inhaled short-acting beta-2-
agonist.
 
Notes:
• 
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet 
individual patient needs.
• 
If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment 
before stepping up.
• 
Zileuton is a less desirable alternative as adjunctive therapy due to limited studies and the need to monitor 
liver function. Theophylline requires monitoring of serum concentration levels.
• 
In step 6, before oral systemic corticosteroids are introduced, a trial of high-dose ICS + LABA + either 
LTRA, theophylline, or zileuton may be considered, although this approach has not been studied in clinical 
trials.
• 
Step 1, 2, and 3 preferred therapies are based on Evidence A; step 3 alternative therapy is based on 
Evidence A for LTRA, Evidence B for theophylline, and Evidence D for zileuton. Step 4 preferred therapy  
is based on Evidence B, and alternative therapy is based on Evidence B for LTRA and theophylline and 
Evidence D for zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferred therapy is 
based on NAEPP Expert Panel Report 2, 1997 and Evidence B for omalizumab. 
• 
Immunotherapy for steps 2–4 is based on Evidence B for house-dust mites, animal danders, and pollens; 
evidence is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with 
single allergens. The role of allergy in asthma is greater in children than in adults. 
• 
Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and 
treat anaphylaxis that may occur.
Asthma
Persistent Asthma: Daily Medication
Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.
Step 1
Step 2
Step 3
Step 6
S
t
e
p
u
p
i
f
n
e
e
d
e
d
(
f
i
r
s
t
,
c
h
e
c
k
a
d
h
e
r
e
n
c
e
,
e
n
v
i
r
o
n
m
e
n
t
a
l
c
o
n
t
r
o
l
,
a
n
d
c
o
m
o
r
b
i
d
c
o
n
d
i
t
i
o
n
s
)
S
t
e
p
d
o
w
n
i
f
p
o
s
s
i
b
l
e
(
a
n
d
a
s
t
h
m
a
i
s
w
e
l
l
c
o
n
t
r
o
l
l
e
d
a
t
l
e
a
s
t
3
m
o
n
t
h
s
)
Step 4
Step 5
As
sess
co
nt
ro
l
Each step: Patient education, environmental control, and management of comorbidities.
Steps 2–4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma (see notes).
Preferred:
SABA PRN
Low-dose ICS
Alternative:
Cromolyn, LTRA,
nedocromil, or
theophylline
+ LABA
OR
Medium-dose ICS
+ either LTRA,
theophylline, or
zileuton
+ LABA
zileuton
High-dose ICS
+ LABA
AND
Consider 
omalizumab for
patients who have
allergies
+ LABA + oral
corticosteroid
AND
Consider 
allergies
Quick-Relief Medication for All Patients
• 
SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to three treatments at 20-minute intervals 
as needed. Short course of oral systemic corticosteroids may be needed.
• 
Use of SABA > 2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step 
up treatment.
CMDT19_Ch09_p0252-p0333.indd   258

259
 
CMDT 2019
3. Control of environmental factors and comorbid condi
-
tions that affect asthma—
Significant reduction in expo
-
sure to nonspecific airway irritants or to inhaled allergens 
in atopic patients may reduce symptoms and medication 
needs. Comorbid conditions that impair asthma manage
-
ment, such as rhinosinusitis, gastroesophageal reflux, obe
-
sity, and obstructive sleep apnea, should be identified and 
treated. This search for complicating conditions is particu
-
larly crucial in the initial evaluation of new asthma, and in 
patients who have difficult-to-control symptoms or fre
-
quent exacerbations.
4. Pharmacotherapy for asthma—
The goals of pharmaco
-
logic therapy are to minimize chronic symptoms that inter
-
fere with normal activity (including exercise), to prevent 
recurrent exacerbations, to reduce or eliminate the need for 
emergency department visits or hospitalizations, and to 
maintain normal or near-normal pulmonary function. 
These goals should be met while providing therapeutic 
agents with the fewest adverse effects and while satisfying 
patients’ and families’ expectations of asthma care.
 
»
Treatment
A. Pharmacologic Agents
Asthma medications can be divided into two categories: 
(1) quick-relief (
reliever
) medications that act principally 
by direct relaxation of bronchial smooth muscle, thereby 
promoting prompt reversal of acute airflow obstruction to 
relieve accompanying symptom; and (2) long-term control 
(
controller
) medications that act primarily to attenuate 
airway inflammation and that are taken daily independent 
of symptoms to achieve and maintain control of persistent 
asthma. Anti-inflammatory agents, long-acting bronchodi
-
lators, and leukotriene modifiers comprise the important 
long-term control medications (Tables 9–3 and 9–4). Other 
classes of agents are mentioned briefly below.
Most asthma medications are administered by inhala
-
tion or orally. Inhalation of an appropriate agent results in 
a more rapid onset of pulmonary effects as well as fewer 
systemic effects compared with oral administration of the 
same dose. Proper inhaler technique and the use of an 
inhalation chamber (a “spacer”) with metered-dose inhal
-
ers (MDIs) decrease oropharyngeal deposition and improve 
drug delivery to the lung. Nebulizer therapy is reserved for 
patients who are acutely ill and those who cannot use 
inhalers because of difficulties with coordination, under
-
standing, or cooperation.
1. 
Beta-adrenergic agonists—
Beta-agonists are divided 
into 
short-acting beta-agonists
 (SABAs) and 
long-
 
acting beta-agonists
 (LABAs). SABAs, including alb
-
uterol, levalbuterol, bitolterol, pirbuterol, and terbutaline 
(Table 9–5), are the mainstays of reliever or rescue ther
-
apy for asthma patients; all asthmatics should have imme
-
diate access to a SABA. SABAs are the most effective 
bronchodilators during exacerbations and provide imme
-
diate relief of symptoms. There is no convincing evidence 
to support the use of one agent over another. Administra
-
tion before exercise effectively prevents exercise-induced 
bronchoconstriction.
Inhaled SABA therapy is as effective as oral or paren
-
teral therapy in relaxing airway smooth muscle and 
improving acute asthma and offers the advantages of rapid 
onset of action (less than 5 minutes) with fewer systemic 
side effects. Repetitive administration produces incremen
-
tal bronchodilation. One or two inhalations of a SABA 
from an MDI are usually sufficient for mild to moderate 
symptoms. Severe exacerbations frequently require higher 
doses: 6–12 puffs every 30–60 minutes of albuterol by MDI 
with an inhalation chamber or 2.5 mg by nebulizer provide 
equivalent bronchodilation. Administration by nebuliza
-
tion does not offer more effective delivery than MDIs used 
correctly but does provide higher doses. With most SABAs, 
the recommended dose by nebulizer for acute asthma (alb
-

-
-
uterol, 2.5 mg) is 25–30 times that delivered by a single 
activation of the MDI (albuterol, 0.09 mg). This difference 
suggests that standard dosing of inhalations from an MDI 
are often insufficient in the setting of an acute exacerba
-
tion. Independent of dose, nebulizer therapy may be more 
effective in patients who are unable to coordinate inhala
-
tion of medication from an MDI because of age, agitation, 
or severity of the exacerbation.
Scheduled daily use of SABAs is not recommended. 
Increased use (more than one canister a month) or lack of 
expected effect indicates diminished asthma control and 
the need for additional long-term control therapy.
LABAs provide bronchodilation for up to 12 hours after 
a single dose. Salmeterol and formoterol are the LABAs 
available for asthma in the United States. They are admin
-
istered via dry powder delivery devices. They are indicated 
for long-term prevention of asthma symptoms (including 
nocturnal symptoms) and for prevention of exercise-
induced bronchospasm. When added to low and medium 
daily doses of inhaled corticosteroids (Table 9–4), LABAs 
provide control equivalent to what is achieved by doubling 
the inhaled corticosteroid dose. Side effects are minimal at 
standard doses. LABAs should not be used as monotherapy 
since they have no anti-inflammatory effect and since 
monotherapy has been associated with a small but statisti
-
cally significant increased risk of severe or fatal asthma 
attacks in two large studies. This increased risk has not 
been fully explained but may relate to genetic variation in 
the beta-adrenergic receptor; it remains an area of contro
-
versy. The efficacy of combined inhaled corticosteroid and 
LABA therapy has led to the marketing of combination 
medications that deliver both agents simultaneously 
(Table 9–3). Combination inhalers containing formoterol 
and budesonide have shown efficacy in both rescue (given 
formoterol’s short time to onset) and maintenance 
(budesonide).
2. Corticosteroids—
Corticosteroids are the most potent 
and consistently effective anti-inflammatory agents cur
-
rently available. They decrease both acute and chronic 
inflammation, resulting in reduced symptoms and 
improved lung function. These agents may also potentiate 
the action of beta-adrenergic agonists.
Inhaled corticosteroids
 are preferred, first-line agents 
for all patients with persistent asthma. Patients with per
-
sistent symptoms or asthma exacerbations who are not 
taking an inhaled corticosteroid should be started on one. 
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Table 9–3.
 
Long-term control medications for asthma.
Dosage Form
Adult Dose
Comments
Inhaled Corticosteroids
(See Table 9–4)
Systemic Corticosteroids
(Applies to all three corticosteroids)
Prednisolone
Prednisone
2-, 4-, 6-, 8-, 16-, 32-mg tablets
5-mg tablets; 5 mg/5 mL,
 
15 mg/5 mL
1-, 2.5-, 5-, 10-, 20-, 50-mg 
 
tablets; 5 mg/mL
7.5–60 mg
40–60 mg
• 
 
Administer single dose in 
am
 either daily or on 
alternate days (alternate-day therapy may produce 
less adrenal suppression) as needed for control.
• 
 
Short courses or “bursts” as single or 2 divided 
doses for 3–10 days are effective for establishing 
control when initiating therapy or during a period 
of gradual deterioration.
• 
 
There is no evidence that tapering the dose 
following improvement in symptom control and 
pulmonary function prevents relapse.
Inhaled Long-Acting Beta-2-Agonists
Should not be used for symptom relief or 
 
exacerbations. Use with inhaled 
 
corticosteroids.
Formoterol
Salmeterol
Inhalation 20 mcg/2 mL neb
(DPI discontinued by FDA in 
DPI 50 mcg/actuation
20 mcg every 12 hours
1 blister every 12 hours
• 
 
Additional doses should not be administered for 
at least 12 hours.
• 
 
Agents should be used only with their specific 
inhaler and should not be taken orally.
• 
 
Decreased duration of protection against EIB may 
occur with regular use.
Combined Medication
Budesonide/
HFA MDI
80 mcg/4.5 mcg
160 mcg/4.5 mcg
2 inhalations twice daily; 
dose depends on 
severity of asthma
• 
 
80/4.5 for asthma not controlled on low- to 
medium-dose inhaled corticosteroids
• 
 
160/4.5 for asthma not controlled on medium- to 
high-dose inhaled corticosteroids
Fluticasone/salmeterol
DPI
100 mcg/50 mcg
250 mcg/50 mcg, or
500 mcg/50 mcg
HFA
45 mcg/21 mcg
115 mcg/21 mcg
230 mcg/21 mcg
1 inhalation twice daily; 
• 
 
100/50 DPI or 45/21 HFA for patient not controlled 
on low- to medium-dose inhaled corticosteroids
• 
 
250/50 DPI or 115/21 HFA for patients not 
controlled on medium- to high-dose inhaled 
Fluticasone furoate/
vilanterol
100 mcg/25 mcg, 200 mcg/
 
25 mcg per blister DPI
1 puff inhaled daily
• 
Once-daily asthma maintenance
Mometasone/
formoterol
100 mcg/5 mcg/spray
200 mcg/5 mcg/spray
2 inhalation twice daily
Cromolyn and Nedocromil
Cromolyn
Nedocromil
MDI
0.8 mg/puff
Nebulizer
20 mg/ampule
MDI
1.75 mg/puff
2 puffs four times daily
1 ampule four times daily
• 
 
4–6 week trial may be needed to determine 
maximum benefit.
• 
 
Dose by MDI may be inadequate to affect 
hyperresponsiveness.
• 
 
One dose before exercise or allergen exposure 
provides effective prophylaxis for 1–2 hours. Not 
as effective for EIB as SABA.
• 
 
Once control is achieved, the frequency of dosing 
may be reduced.
Inhaled Long-Acting Anticholinergic
 
Tiotropium
DPI 18 mcg/blister
1 blister daily
(
continued
 
)
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261
 
CMDT 2019
The most important determinants of agent selection and 
appropriate dosing are the patient’s status and response to 
treatment. Dosages for inhaled corticosteroids vary 
depending on the specific agent and delivery device 
(Table 9–4). For most patients, twice-daily dosing provides 
adequate control of asthma. Once-daily dosing may be suf
-
ficient in selected patients. Maximum responses from 
inhaled corticosteroids may not be observed for months. 
The use of an inhalation chamber coupled with mouth 
washing after inhaled corticosteroid use decreases local 
side effects (cough, dysphonia, oropharyngeal candidiasis) 
and systemic absorption. Dry powder inhalers (DPIs) are 
not used with an inhalation chamber. Systemic effects 
(adrenal suppression, osteoporosis, skin thinning, easy 
bruising, and cataracts) may occur with high-dose inhaled 
corticosteroid therapy. Many combination inhalers with 
inhaled corticosteroid/LABA offer convenient treatment of 
persistent asthma.
Systemic corticosteroids
 (oral or parenteral) are most 
effective in achieving prompt control of asthma during 
exacerbations. Systemic corticosteroids are effective pri
-
mary treatment for patients with moderate to severe 
asthma exacerbations and for patients with exacerbations 
who do not respond promptly and completely to inhaled 
SABA therapy. These medications speed the resolution of 
airflow obstruction and reduce the rate of relapse. Delays 
in administering corticosteroids may result in delayed ben
-
efits from these important agents. Therefore, oral cortico
-
steroids should generally be prescribed to have available at 
home for early administration in patients with moderate to 
severe asthma. The minimal effective dose of systemic 
corticosteroids for asthma patients has not been identified. 
Outpatient prednisone “burst” therapy is 0.5–1 mg/kg/day 
(typically 40–60 mg) in 1–2 doses for 3–10 days. Severe 
exacerbations requiring hospitalization typically require 
1 mg/kg of prednisone or methylprednisolone every 
6–12 hours for 48 hours or until the FEV
1
 (or PEF rate) 
returns to 50% of predicted (or 50% of baseline). The dose 
is then decreased to 60–80 mg/day until the PEF reaches 
70% of predicted or personal best. No clear advantage has 
been found for higher doses of corticosteroids. It may be 
prudent to administer corticosteroids intravenously to 
critically ill patients to avoid concerns about altered gastro
-
intestinal absorption.
In patients with refractory, poorly controlled asthma, 
systemic corticosteroids may be required for the long-term 
suppression of symptoms. Repeated efforts should be made 
to reduce the dose to the minimum needed to control 
symptoms. Alternate-day treatment is preferred to daily 
treatment. Concurrent treatment with calcium supplements 
Table 9–3.
 
Adult Dose
Comments
Leukotriene Modifiers
Leukotriene Receptor Antagonists
Montelukast
4- or 5-mg chewable tablet; 
10-mg tablet
10 mg daily at bedtime
• 
 
Exhibits a flat dose-response curve. Doses > 10 mg 
will not produce a greater response in adults.
Zafirlukast
10- or 20-mg tablet
20-mg tablet twice daily
• 
 
Administration with meals decreases 
bioavailability; take at least 1 hour before or 
 
2 hours after meals.
• 
 
Monitor for symptoms and signs of hepatic 
5-Lipoxygenase Inhibitor
Zileuton
600-mg tablet
600 mg four times daily
• 
 
Monitor hepatic enzyme (ALT).
Methylxanthines
Theophylline
Liquids, sustained-release 
tablets, and capsules
Starting dose 10 mg/kg/
day up to 300 mg 
maximum; usual 
maximum dose 
 
800 mg/day
• 
 
Adjust dose to achieve serum concentration of 
5–15 mcg/mL after at least 48 hours on same 
dose.
• 
 
Due to wide interpatient variability in 
theophylline metabolic clearance, routine serum 
theophylline level monitoring is important.
Mepoluzimab
Subcutaneous injection
100 mcg every 4 weeks

Omalizumab
Subcutaneous injection, 
150 mg/1.2 mL following 
reconstitution with 1.4 mL 
sterile water for injection
150–375 mg subcutane
-
ously every 2–4 weeks, 
depending on body 
weight and pretreat
-
ment serum IgE level
• 
 
Do not administer more than 150 mg per 
injection site.
• 
 
Monitor for anaphylaxis for 2 hours following at 
least the first 3 injections.
Reslizumab
Intravenous injection
3 mg/kg intravenously 
every 4 weeks
• 
 
Eosinophilic subtype
(
continued
 
)
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Table 9–4.
 
Estimated comparative daily dosages for inhaled corticosteroids for asthma.
Low Daily Dose Adult
Medium Daily Dose Adult
High Daily Dose Adult
Beclomethasone HFA
 
40 or 80 
mcg/puff
80–240 mcg
> 240–480 mcg
> 480 mcg
Budesonide DPI
 
90, 180, 
or 200 mcg/inhalation
180–600 mcg
> 600–1200 mcg
> 1200 mcg
Flunisolide
 
250 mcg/puff
500–1000 mcg
> 1000–2000 mcg
> 2000 mcg
Flunisolide HFA
 
80 mcg/puff
320 mcg
> 320–640 mcg
> 640 mcg
Fluticasone
 
HFA/MDI:
 44, 110, or 220 mcg/puff
 
DPI:
 50, 100, or 250 mcg/inhalation
88–264 mcg
100–300 mcg
> 264–440 mcg
> 300–500 mcg
> 440 mcg
> 500 mcg
Mometasone DPI
 
200 mcg/puff
200 mcg
400 mcg
> 400 mcg
Triamcinolone acetonide
 
75 mcg/puff
300–750 mcg
> 750–1500 mcg
> 1500 mcg
DPI, dry powder inhaler; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkaline; MDI, metered-dose inhaler; SABA, short-acting 
beta-2-agonist.
Notes:
• 
The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy.
• 
Potential drug interactions:
  
A number of the inhaled cor
ticosteroids, including fluticasone, budesonide, and mometasone, are metabolized in the gastrointestinal 
tract and liver by CYP 3A4 isoenzymes. Potent inhibitors of CYP 3A4, such as ritonavir and ketoconazole, have the potential for increasing 
systemic concentrations of these inhaled corticosteroids by increasing oral availability and decreasing systemic clearance. Some cases of 
clinically significant Cushing syndrome and secondary adrenal insufficiency have been reported.
Table 9–5.
 
Quick-relief medications for asthma.
Adult Dose
Comments
Inhaled Short-Acting Beta-2-Agonists
MDI
Albuterol CFC
Albuterol HFA
Pirbuterol CFC
Levalbuterol HFA
90 mcg/puff, 200 puffs/
canister
canister
200 mcg/puff, 400 puffs/
canister
45 mcg/puff, 200 puffs/
canister
2 puffs 5 minutes before 
exercise
2 puffs every 4–6 hours 
as needed
• 
 
An increasing use or lack of expected effect indicates 
diminished control of asthma.
• 
 
Not recommended for long-term daily treatment. Regular 
use exceeding 2 days/week for symptom control (not pre
-
vention of EIB) indicates the need to step up therapy.
• 
 
Differences in potency exist, but all products are essentially 
comparable on a per-puff basis.
• 
 
May double usual dose for mild exacerbations.
• 
 
Prime the inhaler by releasing four actuations prior to use.
• 
 
Periodically clean HFA activator, as drug may block/plug 
orifice.
Nebulizer solution
Albuterol
0.63 mg/3 mL
1.25 mg/3 mL
2.5 mg/3 mL
5 mg/mL (0.5%)
1.25–5 mg in 3 mL 
 
of saline every 
 
4–8 hours as 
 
needed
• 
 
May mix with budesonide inhalant suspension, cromolyn 
or ipratropium nebulizer solutions.
• 
 
May double dose for severe exacerbations.
Levalbuterol 
(R-albuterol)
0.31 mg/3 mL
1.25 mg/0.5 mL
0.63 mg–1.25 mg every 
8 hours as needed
• 
 
Compatible with budesonide inhalant suspension. 
The product is a sterile-filled, preservative-free, unit dose 
vial.
(
continued
 
)
CMDT19_Ch09_p0252-p0333.indd   262

263
 
CMDT 2019
Table 9–5.
 
Adult Dose
Comments
Anticholinergics
MDI
Ipratropium HFA
17 mcg/puff, 200 puffs/
canister
2–3 puffs every 6 hours
• 
 
Evidence is lacking for anticholinergics producing added 
benefit to beta-2-agonists in long-term control asthma 
therapy.
0.25 mg/mL (0.025%)
0.25 mg every 6 hours
MDI
Ipratropium with 
albuterol
18 mcg/puff of ipratropium 
bromide and 90 mcg/
puff of albuterol, 
 
200 puffs/canister
0.5 mg/3 mL ipratropium 
bromide and 2.5 mg/
 
3 mL albuterol
3 mL every 4–6 hours
• 
 
Contains EDTA to prevent discolorations of the solution. 
This additive does not induce bronchospasm.
2-, 4-, 6-, 8-, 16-, 
 
32-mg tablets
40–60 mg/day as single 
or 2 divided doses
• 
 
Short courses or “bursts” are effective for establishing 
control when initiating therapy or during a period of 
gradual deterioration.
• 
 
The burst should be continued until symptoms resolve 
and the PEF is at least 80% of personal best. This usually 
requires 3–10 days but may require longer. There is no 
evidence that tapering the dose following improvements 
prevents relapse.
5-mg tablets, 5 mg/5 mL, 
15 mg/5 mL
Repository injection
Methylprednisolone 
acetate
40 mg/mL
80 mg/mL
240 mg intramuscularly 
once
• 
 
May be used in place of a short burst of oral corticosteroids 
in patients who are vomiting or if adherence is a problem.
CFC, chlorofluorocarbon; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; PEF, peak expiratory 
flow.
(
continued
 
)
and vitamin D should be initiated to prevent corticoste
-
roid-induced bone mineral loss in long-term administra
-
tion. Bone mineral density testing after 3 or more months 
of systemic corticosteroid lifetime use can guide the use of 
bisphosphonates for treatment of steroid-induced osteopo
-
rosis. Rapid discontinuation of systemic corticosteroids 
after long-term use may precipitate adrenal insufficiency.
3. Anticholinergics—
Anticholinergic agents reverse 
vagally mediated bronchospasm but not allergen- or 
 
exercise-induced bronchospasm. They may decrease 
mucus gland hypersecretion. Both 
short-acting musca
-
 (SAMAs) and 
long-acting muscarinic agents
 
(LAMAs) are available. Ipratropium bromide, a SAMA, is 
less effective than SABA for relief of acute bronchospasm, 
but it is the inhaled drug of choice for patients 
with intolerance to SABA or with bronchospasm due to 
beta-blocker medications. Ipratropium bromide reduces 
the rate of hospital admissions when added to inhaled 
SABAs in patients with moderate to severe asthma exacer
-
bations. Although LAMAs have long been the cornerstone 
of therapy for COPD, their role in asthma continues to 
evolve. Studies have shown that the addition of tiotropium 
to medium-dose inhaled corticosteroid and salmeterol 
improve lung function and reduce the frequency of asthma 
exacerbations. One study showed that the addition of once-
daily tiotropium to an inhaled corticosteroid is as effective 
as twice-daily salmeterol.
4. Leukotriene modifiers—
Leukotrienes are potent medi
-
ators that contribute to airway obstruction and asthma 
symptoms by contracting airway smooth muscle, 
CMDT19_Ch09_p0252-p0333.indd   263

C
HAPTER
 9
264
 CMDT 2019
increasing vascular permeability and mucus secretion, and 
attracting and activating airway inflammatory cells. Zileu
-
ton is a 5-lipoxygenase inhibitor that decreases leukotriene 
production, and zafirlukast and montelukast are cysteinyl 
leukotriene receptor antagonists. In randomized controlled 
trials, these agents caused modest improvements in lung 
function and reductions in asthma symptoms and lessened 
the need for SABA rescue therapy. These agents are alter
-
natives to low-dose inhaled corticosteroids in patients with 
mild persistent asthma, although, as monotherapy, their 
effect is generally less than inhaled corticosteroids. In real-
life community trials, leukotriene receptor antagonists 
were equivalent in efficacy to an inhaled corticosteroid as 
first-line long-term controller medication or to a LABA as 
add-on therapy. Zileuton can cause reversible elevations in 
plasma aminotransferase levels. Eosinophilic granuloma
-
tosis with polyangiitis has been diagnosed in a small num
-
ber of patients who have taken montelukast or zafirlukast, 
perhaps due to corticosteroid withdrawal rather than a 
direct drug effect.
5. Phosphodiesterase inhibitor—
Theophylline provides 
mild bronchodilation in asthmatic patients. Theophylline 
also has anti-inflammatory and immunomodulatory prop
-
erties, enhances mucociliary clearance, and strengthens 
diaphragmatic contractility. Sustained-release theophylline 
preparations are effective in controlling nocturnal symp
-
toms and as added therapy in patients with moderate or 
severe persistent asthma whose symptoms are inadequately 
controlled by inhaled corticosteroids. When added to an 
inhaled corticosteroid, theophylline may allow equivalent 
control at lower corticosteroid doses.
Theophylline serum concentrations need to be moni
-
tored closely owing to the medication’s narrow therapeutic- 
toxic range, individual differences in metabolism, and the 
effects of many factors on drug absorption and metabo
-
lism. At therapeutic doses, potential adverse effects include 
insomnia, aggravation of dyspepsia and gastroesophageal 
reflux, and urination difficulties in men with prostatic 
hyperplasia. Dose-related toxicities include nausea, vomit
-
ing, tachyarrhythmias, headache, seizures, hyperglycemia, 
and hypokalemia.
6. Mediator inhibitors—
Cromolyn sodium and nedocro
-
mil are long-term control medications that prevent asthma 
symptoms and improve airway function in patients with 
mild persistent or exercise-induced asthma. These agents 
modulate mast cell mediator release and eosinophil recruit
-
ment and inhibit both early and late asthmatic responses to 
allergen challenge and exercise-induced bronchospasm. 
They can be effective when taken before an exposure or 
exercise but do not relieve asthmatic symptoms once pres
-
ent. The clinical response to these agents is less predictable 
than to inhaled corticosteroids. Nedocromil may help 
reduce the dose requirements for inhaled corticosteroids. 
Both agents have excellent safety profiles.
Asthmatic patients who require omali
-
zumab, reslizumab, or mepoluzimab should be evaluated 
by either a pulmonologist or allergist. Omalizumab is a 
recombinant antibody that binds IgE without activating 
mast cells. In clinical trials in patients with moderate to 
severe asthma and elevated serum IgE levels, omalizumab 
reduced the need for corticosteroids. Reslizumab and 
mepoluzimab are interleukin-5 antagonist monoclonal 
antibodies that are approved for the treatment of severe 
asthma with peripheral blood eosinophilia that has not 
responded to other standard treatments.
B. Desensitization
Immunotherapy for specific allergens may be considered 
in selected asthma patients who have exacerbations when 
exposed to allergens to which they are sensitive and 
when unresponsive to environmental control measures 
or other therapies. Studies show a reduction in asthma

or other therapies. Studies show a reduction in asthma 
symptoms in patients treated with single-allergen immu
-
notherapy. Because of the risk of immunotherapy-
induced bronchoconstriction, it should be administered 
only in a setting where such complications can be imme
-
diately treated.
C. Vaccination
Patients with asthma should receive pneumococcal vacci
-
nation (Pneumovax) and annual influenza vaccinations. 
Inactive vaccines (Pneumovax) are associated with few side 
effects, but the use of the live attenuated influenza vaccine 
intranasally may be associated with asthma exacerbations 
in young children.
 
»
Treatment of Asthma Exacerbations
NAEPP 3 asthma treatment algorithms begin with an 
assessment of the severity of a patient’s baseline asthma. 
Adjustments to that algorithm follow a stepwise approach 
based on a careful assessment of asthma control. Educating 
patients to recognize symptoms of an exacerbation and use 
their action plan is an important aspect of asthma manage
-
ment. Symptoms of exacerbations include progressive 
breathlessness, increasing chest tightness, decreased peak 
flow, and lack of improvement after SABA therapy. Most 
instances of uncontrolled asthma are mild and can be man
-
aged successfully by patients at home with the telephone 
assistance of a clinician (Figure 9–3). More severe exacer
-
bations require evaluation and management in an urgent 
care or emergency department setting (Figure 9–4).
A. Mild Exacerbations
Mild asthma exacerbations are characterized by only 
minor changes in airway function (PEF more than 80%) 
and minimal symptoms and signs of airway dysfunction 
(see Table 9–2). Many such patients respond quickly and 
fully to an inhaled SABA alone. However, an inhaled SABA 
may need to be continued at increased doses, eg, every 
3–4 hours for 24–48 hours. In patients not taking an 
inhaled corticosteroid, initiating one should be considered 
during the mild exacerbation. In patients already taking an 
inhaled corticosteroid, a 7-day course of oral corticoste
-
roids (0.5–1.0 mg/kg/day) may be necessary. Doubling the 
dose of inhaled corticosteroid is not effective and is not 
recommended in the NAEPP 3 guidelines.
CMDT19_Ch09_p0252-p0333.indd   264

265
 
CMDT 2019
B. Moderate Exacerbations
The principal goals of treatment of moderate asthma exac
-
erbations are correction of hypoxemia, reversal of airflow 
obstruction, and reduction of the likelihood of recurrence 
of obstruction. Early intervention may lessen the severity 
and shorten the duration of an exacerbation. Airflow 
obstruction is treated with continuous administration of an 
inhaled SABA and the early administration of systemic 
corticosteroids. Systemic corticosteroids should be given to 
patients with a peak flow of less than 70% of baseline or 
who do not respond to several treatments of SABA. Serial 
measurements of lung function to quantify the severity of 
airflow obstruction and its response to treatment are 
useful. The improvement in FEV
1
 after 30 minutes of treat
-
ment correlates significantly with the severity of the 
asthma exacerbation. Serial measurement of airflow in the 
As
sess Se
ve
rit
y
Pa
tients at high ris
k for
 a 
fata
l att
ac
k 
requir
e im
medi
at
e 
medi
cal at
te
ntion after 
initi
al treatmen
t.
  
Sy
mp
toms 
an
d 
si
gn
s su
gg
es
ti
ve of a 
more
 se
ri
ous ex
acer
batio
n, 
su
ch as 
ma
rk
ed 
brea
th
le
ss
ness,
 
inabili
ty to spea
k 
mo
re than sh
or
t ph
ra
ses, 
us
e of accessory musc
le
s, 
or dr
ow
siness 
(s
ee
 
Table 9–2) shou
ld r
esult 
in
 initial treatment while im
me
diately
 co
nsul
ting 
wi
th a 
cl
inic
ia
n.
Less severe 
sympt
om
s 
and 
sig
ns ca
n 
be 
treated 
initia
ll
y wi
th assessment of re
sponse to 
therapy 
and further st
ep
s 
as
 listed 
be
lo
w.
If avai
la
bl
e, measure PEF—v
al
ue
s of 
50–79% pre
dicted or 
pe
rso
nal 
best 
in
di
ca
te
 the need for 
quick-relief 
me
dicati
on
. De
pe
nd
in
g 
on the 
re
sponse 
to
 tr
ea
tment, 
contact 
wi
th a cl
in
icia
n 
ma
y 
 
also be 
in
di
cat
ed. V
alu
es 
below
 50% indicate the ne
ed
 for im
me
di
ate 
me
dical care. 
Initial 
Treatm
en
t
Inhaled SABA
: 
up
 to two treat
me
nt
s 
20
 minu
tes apart of
 2–
6 
puff
s 
by MDI or ne
bu
li
ze
rt
reatm
en
ts
.
Note: 
Me
dica
tion delivery is hi
ghly varia
ble.
 Children and individua
ls
wh
o 
ha
ve exacerbat
ions of le
sser severity may 
ne
ed fe
we
r puffs th
an
su
gg
est
ed ab
ov
e. 
 
Good 
Response
No 
wh
ee
zi
ng or 
dy
spn
ea
(assess ta
ch
ypne
ai
n yo
un
g 
ch
il
dren).
PE
F 
≥
80% pr
edicte
d or 
personal be
st.
Contact clinician 
for 
foll
ow-up
instructions and 
further
 management.
Ma
y cont
inue in
ha
led 
SABA every 3–4 
hours for 
24–
48
 hours
.
Cons
id
er shor
t course of
 
oral systemi
c 
cort
ic
os
teroid
s.
Incomp
lete 
Re
sponse
Pers
is
te
nt 
wh
ee
zi
ng an
d 
dy
spne
a(
tach
yp
ne
a)
.
PEF 50–
79
% predicte
d or 
pe
rs
on
al
 be
st
.
Ad
d or
al systemi
c 
cort
ic
os
te
ro
id.
Continue 
inhale
d SA
BA.
Contact clin
ician 
urgently 
(this day) fo
r 
further 
instr
uct
ion
.
Poor Response
Ma
rked 
wh
eezing an
d d
ysp
nea.
PEF < 50% pr
edic
ted or 
pers
on
al
 best
.
Ad
d or
al sy
stemic
 
cort
ic
os
te
ro
id
.
Repeat
 in
ha
le
d SABA
 
im
me
diately.
If di
stress 
is severe
 and 
nonre
sp
on
sive
to 
in
it
ial 
trea
tm
en
t:
To
 ED
.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ED, emergency department; MDI, metered-dose inhaler; PEF, peak 
expiratory flow; SABA short-acting beta-2-agonist (quick-relief inhaler).
—C
all your 
doctor AN
D
—
PROCEED TO ED;
—
Consider calling 9-1-1
 
(amb
ulance
 tran
sport)
.
 
▲
Figure 9–3.
 
Management of asthma exacerbations: home treatment. 
CMDT19_Ch09_p0252-p0333.indd   265

C
HAPTER
 9
266
 CMDT 2019
 
▲
Figure 9–4.
 
Management of asthma exacerbations: emergency department and hospital-based treatment. 
(Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis 
and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007.)
In
itial Asse
ss
me
nt (see Tables 9–1, 
9–2)
Brief history, physical ex
am (auscultat
io
n,
 
us
e 
of
 a
cce
ssory
 musc
le
s, 
heart ra
te
, re
sp
irat
or
y 
rate),
 
PEF or FE
V
1
, ox
yg
en satur
at
ion, and ot
her 
te
sts 
as
 
in
dica
te
d
FE
V
1
or PEF 
≥
 40
% 
(Mild-to-Moderat
e)
Oxygen to achieve Sa
O
2
 ≥ 90%
Inha
led SABA by ne
buliz
er
or 
MDI with
 
va
lved
ho
lding 
chambe
r,
 up to three
do
se
s in fir
st 
hour
Oral systemic
 
cort
ic
os
te
ro
id
s if
 no 
immed
ia
te r
espon
se 
or if 
pa
ti
en
t 
recently
 took oral systemic
 
cort
ic
os
te
ro
id
s
FE
V
1
or PEF < 40
% 
(Severe)
Ox
yg
en 
to
 ac
hie
ve
 Sa
O
2
≥
90
%
High-
do
se
 in
haled SAB
A 
pl
us
 
ipratr
op
iu
mb
y 
ne
bu
li
ze
ro
r 
MDI plus valved
ho
lding 
ch
am
be
r,
 ev
er
y 
20
minute
s or
 
cont
inuously
 for 
1 ho
ur
 
cort
icos
te
ro
id
s
Impending or Actual 
Respirator
y 
Arrest
In
tu
ba
ti
on 
an
d 
me
chanical
 
ve
nt
il
at
ion 
wi
th 100%
 
oxygen
Ne
bu
lize
dS
ABA and 
ipratr
opiu
m
Intravenous co
rt
icost
eroi
ds
Co
ns
id
er 
adjunc
t therapie
s
Repeat 
As
se
ssment 
Symptoms, 
ph
ys
i
cal
 ex
am, PEF,
 oxygen sa
tu
ration, other 
te
st
s 
as
 
ne
eded
Ad
mit to Hospital 
Intensive Care
(see box 
be
low)
Severe Exacerbation
FE
V
1
 
or PEF 
< 
40
% predicte
d/
pers
on
al
 be
st
Physical ex
am: severe 
sympt
om
s 
at 
re
st
, 
accessory muscle
 us
e,
 
ch
es
t re
tracti
on
History: high-risk 
pa
tien
t
No
 
im
provement after 
initi
al
 tr
ea
tm
en
t
Ox
yg
en
Ne
bu
li
ze
dS
ABA 
+ ipr
at
ro
pi
um, hour
ly or 
co
ntin
uo
us
 
cort
ic
os
te
ro
id
s
Cons
id
er ad
ju
nc
t therapies
Moderate Exacerb
atio
n
FEV
1
 
or PEF 
40–69% 
pred
ic
ted/persona
l 
best
am: moderate sym
ptom
s
Inha
led SA
BA every 
60 min
ut
es
Oral systemic cortic
os
teroid
Continue trea
tm
ent 1–3 hours,
 
provide
d there is impr
ov
emen
t;
 
ma
ke 
ad
mi
t de
cision in < 4 
hours
Incom
pl
ete 
Re
spon
se
 
FE
V
1
 or PEF 
40
–69%
M
ild-to-mod
erat
e 
symp
toms
Po
or
 Response 
FE
V
1 
or 
PEF < 40
%
P
CO
2
≥
42 mm Hg
Ph
ys
ic
al ex
am: 
 
sympt
oms 
se
ve
re
, 
drow
siness, 
co
nfusio
n
Indi
vidu
alized 
deci
sion 
re
: 
hospitalizat
io
n 
(s
ee
 te
xt
)
Discharg
e Home
Conti
nu
e tr
ea
tm
en
t with inhaled SABA
.
Conti
nu
e 
cou
rs
e 
of or
al 
systemic
 
corti
co
steroid.
Consi
der 
initiation of 
an
 IC
S
Pati
en
t educ
atio
n
—Review
 m
edicati
on
s,
 in
cl
ud
in
g in
hale
r
  
te
chniq
ue
—Review
/initiat
e 
ac
ti
on 
pl
an
—Recommend 
cl
os
e 
me
di
cal 
fo
ll
ow
-u
p
Ad
mit to Hospital Ward
Ox
yg
en
Inha
led SABA
System
ic
 (o
ra
l or
 
intrav
enou
s) corticosteroid
Cons
id
er ad
ju
nc
Mo
nitor 
vi
tal 
si
gn
s, FE
V
1
 or
PEF, Sa
O
2
Ad
Inte
ns
iv
e 
Ca
re
Ox
yg
en
Inha
led SA
BA
 hourly or
 
con
ti
nu
ou
sl
y 
Intravenous cort
ic
os
te
roid
Cons
id
er ad
ju
nc
Possib
le
 intuba
tio
n 
and 
me
ch
an
ic
al vent
il
at
io
n
Improve
Impr
ov
e
Discharge Home
Continue tr
ea
tm
ent 
wi
th inha
le
d 
SABAs
Co
ntinue course 
of or
al 
syst
em
ic
 co
rt
icos
te
ro
id
Continue 
on ICS. 
For 
th
ose 
no
t on 
lo
ng
-ter
m 
co
ntrol th
erap
y,
 
co
ns
ider 
an 
IC
S
Patie
nt 
ed
ucat
io
n (e
g, 
rev
iew
 me
dica
ti
on
s,
 in
cl
ud
ing 
in
haler
 te
ch
nique an
d,
 
wh
enever poss
ib
le
, 
en
vi
ro
nm
en
tal 
co
ntrol me
as
ures
; review
/i
nitiate ac
ti
on 
pl
an; re
co
mm
en
d cl
os
e 
me
di
cal fo
ll
ow
-u
p)
Before 
disc
ha
rg
e,
 
sc
hedu
le
 fo
ll
ow
-u
pa
ppointment 
wi
th pr
im
ar
y 
care pr
ovider 
and/
or 
asth
ma 
specia
li
st
 in 1–
4 
we
ek
s
Good Response
FEV
1
 
or PEF 
≥ 
70
%
Resp
onse su
stai
ne
d 
60 
minutes 
after las

le
 fo
ll
ow
-u
pa
wi
th pr
im
ar
y 
care pr
ovider 
and/
or 
asth
ma 
specia
li
st
 in 1–
4 
we
ek
s
FEV
1
 
or PEF 
≥ 
70
%
Resp
onse su
stai
ne
d 
60 
minutes 
after las
t treatmen
t
No distre
ss
Physical exam: normal
•
•
•
FEV
1
, 
fo
rced expiratory volume in 1 second; ICS, inhaled corticosteroid; MDI, metered-dose inhaler
; 
PEF , 
peak expiratory 
flow
; 
SA
BA, short-acting beta-2-agonist; 
Sa
O
2
, 
ox
ygen saturation.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
CMDT19_Ch09_p0252-p0333.indd   266

267
 
CMDT 2019
emergency department may reduce the rate of hospital 
admissions for asthma exacerbations. The post-exacerba
-
tion care plan is important. Regardless of the severity, all 
patients should be provided with necessary medications 
and education in how to use them, instruction in self-
assessment, a follow-up appointment, and an action plan 
for managing recurrence.
C. Severe Exacerbations
Severe exacerbations of asthma can be life-threatening, so 
treatment should be started immediately. All patients with a 
severe exacerbation should immediately receive oxygen, high 
doses of an inhaled SABA, and systemic corticosteroids. A 
brief history pertinent to the exacerbation can be completed 
while such treatment is being initiated. More detailed assess
-
ments, including laboratory studies, usually add little early on 
and so should be postponed until after therapy is instituted. 
Early initiation of 
oxygen therapy
 is paramount because 
asphyxia is a common cause of asthma deaths. Supplemental 
oxygen should be given to maintain an Sa
o
2
 greater than 90% 
or a Pa
o
2
 greater than 60 mm Hg. Oxygen-induced hypoven
-
tilation is extremely rare, and concern for hypercapnia should 
never delay correction of hypoxemia.
Frequent high-dose delivery of an 
inhaled SABA
 is 
indicated and usually well tolerated in severe airway 
obstruction. Some studies suggest that continuous therapy 
is more effective than intermittent administration of these 
agents, but there is no clear consensus as long as similar 
doses are administered. At least three MDI or nebulizer 
treatments should be given in the first hour of therapy. 
Thereafter, the frequency of administration varies accord
-
ing to the improvement in airflow and symptoms and the 
occurrence of side effects. Ipratropium bromide reduces 
SABAs in patients with moderate to severe asthma 
exacerbations.
 are administered as detailed 
above. 
Intravenous magnesium sulfate
 (2 g intravenously 
over 20 minutes) produces a detectable improvement in 
airflow and may reduce hospitalization rates in acute 
severe asthma (FEV
1
 less than 25% of predicted on presen
-
tation or failure to respond to initial treatment).
Mucolytic agents (eg, acetylcysteine, potassium iodide) 
may worsen cough or airflow obstruction. Anxiolytic and 
hypnotic drugs are generally contraindicated in severe 
asthma exacerbations because of their potential respiratory 
depressant effects.
Multiple studies suggest that infections with viruses 
(rhinovirus) and bacteria (
Mycoplasma pneumoniae, Chla
-
mydophila pneumoniae
) predispose to acute exacerbations 
of asthma and may underlie chronic, severe asthma. The 
use of empiric antibiotics is, however, not recommended in 
routine asthma exacerbations because there is no consis
-
tent evidence to support improved clinical outcomes. Anti
-
biotics should be considered when there is a high likelihood 
of acute bacterial respiratory tract infection, such as 
patients with fever or purulent sputum and evidence of 
pneumonia or bacterial sinusitis.
In the 
emergency department setting,
 repeat assess
-
ment of patients with severe exacerbations should be done 
after the initial dose of an inhaled SABA and again after 
three doses of an inhaled SABA (60–90 minutes after initi
-
ating treatment). The response to initial treatment is a 
better predictor of the need for hospitalization than is the 
severity of an exacerbation on presentation. The decision 
to hospitalize a patient should be based on the duration 
and severity of symptoms, severity of airflow obstruction, 
arterial blood gas results (if available), course and severity 
of prior exacerbations, medication use at the time of the 
exacerbation, access to medical care and medications, 
adequacy of social support and home conditions, and pres
-
ence of psychiatric illness. In general, discharge to home is

-
ence of psychiatric illness. In general, discharge to home is 
appropriate if the PEF or FEV
1
 has returned to 60% or 
more of predicted or personal best and symptoms are mini
-
mal or absent. Patients with a rapid response to treatment 
should be observed for 30 minutes after the most recent 
dose of bronchodilator to ensure stability of response 
before discharge.
In the 
intensive care setting,
 a small subset of patients 
will not respond to treatment and will progress to impend
-
ing respiratory failure due to a combination of worsening 
airflow obstruction and respiratory muscle fatigue (see 
Table 9–2). Since such patients can deteriorate rapidly, they 
must be monitored in a critical care setting. Intubation of 
an acutely ill asthma patient is technically difficult and is 
best done semi-electively, before the crisis of a respiratory 
arrest. At the time of intubation, the patient’s intravascular 
volume should be closely monitored because hypotension 
commonly follows the administration of sedative medica
-
tions and the initiation of positive-pressure ventilation; 
these patients are often dehydrated due to poor recent oral 
intake and high insensible losses.
The main goals of mechanical ventilation are to ensure 
adequate oxygenation and to avoid barotrauma. Controlled 
hypoventilation with permissive hypercapnia is often 
required to limit airway pressures. Frequent high-dose 
delivery of inhaled SABAs should be continued along with 
anti-inflammatory agents as discussed above. Many ques
-
tions remain regarding the optimal delivery of inhaled 
SABAs to intubated, mechanically ventilated patients.
 
»
•	
Atypical presentation or uncertain diagnosis of asthma, 
particularly if additional diagnostic testing is required 
(bronchoprovocation challenge, allergy skin testing, 
rhinoscopy, consideration of occupational exposure).
•	
Complicating comorbid problems, such as rhinosinus
-
itis, tobacco use, multiple environmental allergies, 
suspected allergic bronchopulmonary mycosis.
•	
Uncontrolled symptoms despite LABA and high-dose 
inhaled corticosteroid.
•	
Patient not meeting goals of asthma therapy after 
3–6 months of treatment.
•	
More than two courses of oral prednisone therapy in 
the past 12 months.
•	
Any life-threatening asthma exacerbation or exacerba
-
tion requiring hospitalization in the past 12 months.
•	
Presence of social or psychological issues interfering 
with asthma management.
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Alzahrani YA et al. Asthma control assessment tools. Respir 
Care. 2016 Jan;61(1):106–16. [PMID: 26556901]
Fergeson JE et al. Acute asthma, prognosis and treatment. J Allergy 
Clin Immunol. 2017 Feb;139(2):438-47. [PMID: 27554811]
Hines KL et al. Management of the asthma-COPD overlap syn
-
drome (ACOS): a review of the evidence. Curr Allergy Asthma 
Rep. 2017 Mar;17(3):15. [PMID: 28283854]
Israel E et al. Severe and difficult-to-treat asthma in adults. 
N Engl J Med. 2017 Sep 7;377(10):965–76. [PMID: 28877019]
Jin J. JAMA patient page. Asthma attacks. JAMA. 2016 Feb 23;
 
315(8):832. [PMID: 26903352]
Lenaeus MJ et al. Primary care of the patient with asthma. Med 
Clin North Am. 2015 Sep;99(5):953–67. [PMID: 26320041]
McCracken J et al. Diagnosis and management of asthma in 
adults: a review. JAMA. 2017 Jul 18;318(3):279–90. [PMID: 
28719697]
CHRONIC OBSTRUCTIVE 
PULMONARY DISEASE
 
»
History of cigarette smoking.
 
»
Chronic cough, dyspnea, and sputum production.
 
»
Rhonchi, decreased intensity of breath sounds, 
and prolonged expiration on physical 
 
»
Airflow limitation on pulmonary function testing 
that is not fully reversible and is most often 
progressive.
 
»
The Global Initiative for Chronic Obstructive Lung Dis
-
ease (GOLD) defines COPD as a common, preventable, 
and treatable disease state characterized by persistent respi
-
ratory symptoms and airflow limitation due to airway and 
alveolar abnormalities usually caused by significant expo
-
sure to noxious particles or gases. Symptoms include 
cough, dyspnea, and sputum production. COPD is a major 
cause of chronic morbidity and mortality worldwide.
Most patients with COPD have features of both emphy
-
sema and chronic bronchitis. 
Chronic bronchitis
 is a clini
-
cal diagnosis defined by excessive secretion of bronchial 
mucus and is manifested by daily productive cough for 
 
3 months or more in at least 2 consecutive years. 
Emphy
-
sema
 is a pathologic diagnosis that denotes abnormal per
-
manent enlargement of air spaces distal to the terminal 
bronchiole, with destruction of alveolar walls and without 
obvious fibrosis. Both of these definitions are no longer 
included in GOLD because they comprise a minority of 
patients. Chronic respiratory symptoms also exist in 
people with normal spirometry, and a number of smokers 
without airflow limitation will have varying degrees of 
Cigarette smoking is clearly the most important cause 
of COPD in North America and Western Europe. Nearly 
all smokers suffer an accelerated decline in lung function 
that is dose- and duration-dependent. Fifteen percent 
develop progressively disabling symptoms in their 40s and 
50s. Approximately 80% of patients seen for COPD have 
significant exposure to tobacco smoke. The remaining 20% 
frequently have a combination of exposures to environ
-
mental tobacco smoke, occupational dusts and chemicals, 
and indoor air pollution from biomass fuel used for cook
-
ing and heating in poorly ventilated buildings. Outdoor air 
pollution, airway infection, environmental factors, and 
allergy have also been implicated in chronic bronchitis, and 
hereditary factors (deficiency of alpha-1-antiprotease 
[alpha-1-antitrypsin]) have been implicated in emphy
-
sema. Atopy and the tendency for bronchoconstriction to 
develop in response to nonspecific airway stimuli may be 
important risks. Evidence suggests that lung exposures to 
pollution and allergens early in life can lead to poor lung 
growth in childhood and expiratory airflow limitation, 
resulting in lower than predicted spirometric values in 
midlife.
 
»
Patients with COPD characteristically present in the fifth 
or sixth decade of life complaining of excessive cough, 
sputum production, and shortness of breath. Symptoms 
have often been present for 10 years or more. Dyspnea is

have often been present for 10 years or more. Dyspnea is 
noted initially only on heavy exertion, but as the condition 
progresses it occurs with mild activity. In severe disease, 
dyspnea occurs at rest. As the disease progresses, two symp
-
tom patterns tend to emerge, historically referred to as 
“pink puffers” and “blue bloaters” (Table 9–6). Most COPD 
patients have pathologic evidence of both disorders, and 
their clinical course may involve other factors, such as cen
-
tral control of ventilation and concomitant sleep-disordered 
breathing.
Pneumonia, pulmonary hypertension, cor pulmonale, 
and chronic respiratory failure characterize the late stage of 
COPD. A hallmark of COPD is the periodic exacerbation 
of symptoms beyond normal day-to-day variation, often 
including increased dyspnea, an increased frequency or 
severity of cough, and increased sputum volume or change 
in sputum character. These exacerbations are commonly 
precipitated by infection (more often viral than bacterial) 
or environmental factors. Exacerbations of COPD vary 
widely in severity but typically require a change in regular 
therapy.
Spirometry provides objective information about pulmo
-
nary function and assesses the response to therapy. Pulmo
-
nary function tests early in the course of COPD reveal only 
evidence of abnormal closing volume and reduced mid-
expiratory flow rates. Reductions in FEV
1
 and in the ratio of 
forced expiratory volume to vital capacity (FEV
1
% or FEV
1
/
FVC ratio) (Table 9–6) occur later. Post-bronchodilator 
FEV
1
/FVC less than 0.70 establishes the presence of air
-
flow obstruction (Global Initiative for Obstructive Lung 
Disease [GOLD] definition). In severe disease, the FVC is 
markedly reduced. Lung volume measurements reveal a 
CMDT19_Ch09_p0252-p0333.indd   268

269
 
CMDT 2019
marked increase in residual volume (RV), an increase 
in total lung capacity (TLC), and an elevation of the 
RV/TLC ratio, indicative of air trapping, particularly in 
Arterial blood gas measurements characteristically show 
no abnormalities early in COPD other than an increased 
A–a–D
o
2
. Indeed, measurement is unnecessary unless (1) 
hypoxemia or hypercapnia is suspected, (2) the FEV
1
 is less 
than 40% of predicted, or (3) there are clinical signs of right 
heart failure. Hypoxemia occurs in advanced disease, par
-
ticularly when chronic bronchitis predominates. Compen
-
sated respiratory acidosis occurs in patients with chronic 
respiratory failure, particularly in chronic bronchitis, with 
worsening of acidemia during acute exacerbations.
Positive sputum cultures are poorly correlated with acute 
exacerbations, and research techniques demonstrate evi
-
dence of preceding viral infection in a majority of patients 
with exacerbations. The ECG may show sinus tachycardia 
and, in advanced disease, chronic pulmonary hypertension 
may produce electrocardiographic abnormalities typical of 
cor pulmonale. Supraventricular arrhythmias (multifocal 
atrial tachycardia, atrial flutter, and atrial fibrillation) and 
ventricular irritability also occur.
C. Imaging
Radiographs of patients with chronic bronchitis typically 
show only nonspecific peribronchial and perivascular mark
-
ings. Plain radiographs are insensitive for the diagnosis of 
emphysema; they show hyperinflation with flattening of the 
diaphragm or peripheral arterial deficiency in about half of 
cases. CT of the chest, particularly using high-resolution CT, 
is more sensitive and specific than plain radiographs for its 
diagnosis. In advanced disease, pulmonary hypertension 
may be suggested by enlargement of central pulmonary 
arteries on radiographs, and Doppler echocardiography 
provides an estimate of pulmonary artery pressure.
 
»
Clinical, imaging, and laboratory findings should enable the 
clinician to distinguish COPD from other obstructive pul
-
monary disorders, such as asthma, bronchiectasis, cystic 
Table 9–6.
 
Patterns of disease in advanced COPD.
Type A: Pink Puffer (Emphysema Predominant)
Type B: Blue Bloater (Bronchitis Predominant)
Major complaint is dyspnea, often severe, usually 
presenting after age 50. Cough is rare, with 
scant clear, mucoid sputum. Patients are thin, 
with recent weight loss common. They appear 
uncomfortable, with evident use of accessory 
muscles of respiration. Chest is very quiet 
without adventitious sounds. No peripheral 
edema.
Major complaint is chronic cough, productive of 
mucopurulent sputum, with frequent exacerbations 
due to chest infections. Often presents in late 30s and 
40s. Dyspnea usually mild, though patients may note 
limitations to exercise. Patients frequently overweight 
and cyanotic but seem comfortable at rest. Peripheral 
edema is common. Chest is noisy, with rhonchi 
invariably present; wheezes are common.
Laboratory studies
Hemoglobin usually normal (12–15 g/dL). Pa
o
2
 
normal to slightly reduced (65–75 mm Hg) but 
Sa
o
2
 normal at rest. Pa
co
2
 normal to slightly 
reduced (35–40 mm Hg). Chest radiograph 
shows hyperinflation with flattened 
diaphragms. Vascular markings are 
diminished, particularly at the apices.
Hemoglobin usually elevated (15–18 g/dL). Pa
o
2
 reduced 
(45–60 mm Hg) and Pa
co
2
 slightly to markedly elevated 
(50–60 mm Hg). Chest radiograph shows increased 
interstitial markings (“dirty lungs”), especially at bases. 
Diaphragms are not flattened.
Pulmonary 
 
function tests
Airflow obstruction ubiquitous. Total lung 
capacity increased, sometimes markedly 
so. D
l
CO
 reduced. Static lung compliance 
increased.
Airflow obstruction ubiquitous. Total lung capacity 
generally normal but may be slightly increased. 
D
l
CO
 normal. Static lung compliance normal.

l
CO
D
l
CO
Special Evaluations
Ventilation-perfusion 
testing
Increased ventilation to high 
V
.
/
Q
.
 areas, ie, high 
dead space ventilation.
Increased perfusion to low 
V
.
/
Q
.
 areas.
Hemodynamics
Cardiac output normal to slightly low. Pulmonary 
artery pressures mildly elevated and increase 
with exercise.
Cardiac output normal. Pulmonary artery pressures 
elevated, sometimes markedly so, and worsen with 
exercise.
Nocturnal ventilation
Mild to moderate degree of oxygen desaturation 
not usually associated with obstructive sleep 
apnea.
Severe oxygen desaturation, frequently associated with 
obstructive sleep apnea.
Exercise ventilation
Increased minute ventilation for level of oxygen 
consumption; Pa
o
2
 tends to fall; Pa
co
2
 rises 
slightly.
Decreased minute ventilation for level of oxygen 
consumption. Pa
o
2
 may rise; Pa
co
2
 may rise 
significantly.
D
l
CO
, single-breath diffusing capacity for carbon monoxide; 
V
.
/
Q
.
 ventilation-perfusion.
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C
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270
 CMDT 2019
fibrosis, bronchopulmonary mycosis, and central airflow 
obstruction. Asthma is characterized by complete or near-
complete reversibility of airflow obstruction. Bronchiectasis 
is distinguished from COPD by recurrent pneumonia and 
hemoptysis, digital clubbing, and characteristic imaging 
abnormalities. Patients with severe alpha-1-antitrypsin defi
-
ciency have a family history of the disorder and the finding 
of panacinar bibasilar emphysema early in life, usually in the 
third or fourth decade; hepatic cirrhosis and hepatocellular 
carcinoma may develop. Cystic fibrosis occurs in children, 
adolescents, and young adults. Mechanical obstruction of 
the central airways can be distinguished from COPD by 
flow-volume loops.
 
»
Acute bronchitis, pneumonia, pulmonary thromboembo
-
lism, atrial dysrhythmias (such as atrial fibrillation, atrial 
flutter, and multifocal atrial tachycardia), and concomitant 
left ventricular failure may worsen otherwise stable COPD. 
Pulmonary hypertension, cor pulmonale, and chronic 
respiratory failure are common in advanced COPD. Spon
-
taneous pneumothorax occurs in a small fraction of 
patients with emphysema. Hemoptysis may result from 
chronic bronchitis or may signal bronchogenic carcinoma.
 
»
COPD is largely preventable through elimination of long-
term exposure to tobacco smoke, combustion of biomass 
fuels, and other inhaled toxins. Smokers with early evidence 
of airflow limitation can significantly alter their disease by 
smoking cessation. Smoking cessation slows the decline in 
FEV
1
 in middle-aged smokers with mild airways obstruc
-
tion. Influenza vaccination reduces the frequency and sever
-
ity of influenza-like illness as well as the number of COPD 
exacerbations. Pneumococcal vaccination appears to reduce 
both the frequency of community-acquired pneumonia and 
the number of COPD exacerbations.
 
»
Treatment
The treatment of COPD is guided by the severity of symp
-
toms or the presence of an exacerbation of stable symp
-
toms. Standards for the management of patients with stable 
COPD and COPD exacerbations from the American Tho
-
racic Society and GOLD, a joint expert committee of the 
NHLBI and the WHO, are incorporated in the recommen
-
dations below. The GOLD classification uses three ways to 
identify high-risk COPD patients who may require more 
intense treatment: (1) FEV
1
 less than 50% (GOLD III/IV), 
(2) more than two exacerbations within the previous 
12 months, and (3) one or more hospitalizations for COPD 
exacerbation.
See Chapter 37 for a discussion of air travel in patients 
with lung disease.
A. Ambulatory Patients
1. Smoking cessation—
The single most important inter
-
vention in smokers with COPD is to encourage smoking 
cessation
 (see Chapter 1). Simply telling a patient to quit 
succeeds 5% of the time. Behavioral approaches, ranging 
from clinician advice to intensive group programs, may 
improve cessation rates. Pharmacologic therapy includes 
bupropion, nicotine replacement (transdermal patch, gum, 
lozenge, inhaler, or nasal spray), varenicline (a partial ago
-
nist of nicotinic acetylcholine receptors), and cytisine. 
Combined pharmacotherapies (two forms of nicotine 
replacement, or nicotine replacement and bupropion), 
with or without behavioral approaches, have been recom
-
mended. Varenicline is effective but use has been limited 
by concerns of neuropsychiatric side effects. Electronic 
cigarettes are being aggressively marketed as an aid for 
tobacco cigarette cessation. One randomized controlled 
trial (RCT) showed electronic cigarettes to be noninferior 
to nicotine transdermal patches. Most pulmonologists do 
not recommend electronic cigarettes as a tobacco cessation 
aid, based on safety concerns (they are not regulated and 
contain a variety of chemicals), and limited clinical trial 
data, although some clinicians will not discourage moti
-

-
vated smokers who refuse to consider standard approaches 
from trying electronic cigarettes.
2. Oxygen therapy—
Supplemental oxygen for patients 
with resting hypoxemia (Pa
o
2
 < 56 mm Hg) is the only 
therapy with evidence of improvement in the natural his
-
tory of COPD.
 Proved benefits of home oxygen therapy in 
hypoxemic patients include longer survival, reduced hospi
-
talizations, and better quality of life. Survival in hypoxemic 
patients with COPD treated with supplemental oxygen 
therapy is directly proportionate to the number of hours per 
day oxygen is administered: in COPD hypoxemic patients 
treated with continuous oxygen for 24 hours daily, the sur
-
vival after 36 months is about 65%—significantly better than 
the survival rate of about 45% in those treated with only 
nocturnal oxygen. Oxygen by nasal prongs must be given for 
at least 15 hours a day unless therapy is specifically intended 
only for exercise or sleep. However, several studies of supple
-
mental oxygen therapy showed no survival benefit in COPD 
patients with borderline low-normal resting oxygen levels 
(Pa
o
2
 between 56 mm Hg and 69 mm Hg). In a study of 
patients with stable COPD and resting or exercise-induced 
moderate desaturation, the prescription of long-term sup
-
plemental oxygen did not result in a longer time to first 
hospitalization or death than no long-term supplemental 
oxygen, nor did it provide sustained benefit with regard to 
any of the other measured outcomes. Requirements for US 
Medicare coverage for a patient’s home use of oxygen and 
oxygen equipment are listed in Table 9–7. Arterial blood gas 
analysis is preferred over oximetry to guide initial oxygen 
therapy. Hypoxemic patients with pulmonary hypertension, 
chronic cor pulmonale, erythrocytosis, impaired cognitive 
function, exercise intolerance, nocturnal restlessness, or 
morning headache are particularly likely to benefit from 
home oxygen therapy.
Home oxygen may be supplied by liquid oxygen sys
-
tems, compressed gas cylinders, or oxygen concentrators. 
Most patients benefit from having both stationary and por
-
table systems. For most patients, a flow rate of 1–3 L/min 
 
achieves a Pa
o
2
 greater than 55 mm Hg. The monthly cost 
of home oxygen therapy ranges from $300 to $500 or more, 
higher for liquid oxygen systems. Medicare covers approxi
-
mately 80% of home oxygen expenses. Reservoir nasal 
CMDT19_Ch09_p0252-p0333.indd   270

271
 
CMDT 2019
cannulas or “pendants” and demand (pulse) oxygen deliv
-
ery systems are also available to conserve oxygen.
3. Inhaled bronchodilators—
Bronchodilators do not alter 
the inexorable decline in lung function that is a hallmark of 
COPD, but they improve symptoms, exercise tolerance, 
and overall health status. Aggressiveness of bronchodilator 
therapy should be matched to the severity of the patient’s 
disease. In patients who experience no symptomatic 
improvement, bronchodilators should be discontinued.
The most commonly prescribed short-acting broncho
-
dilators are the anticholinergic ipratropium bromide and 
SABAs (eg, albuterol, metaproterenol), delivered by MDI 
or as an inhalation solution by nebulizer. Ipratropium bro
-
mide is generally preferred to the SABAs as a first-line 
agent because of its longer duration of action and absence 
of sympathomimetic side effects. Some studies have sug
-
gested that ipratropium achieves superior bronchodilation 
in COPD patients. Typical doses are two to four puffs 
(36–72 mcg) every 6 hours. SABAs are less expensive and 
have a more rapid onset of action, commonly leading to 
greater patient satisfaction. At maximal doses, beta-2-
 
agonists have bronchodilator action equivalent to that of 
ipratropium but may cause tachycardia, tremor, or hypoka
-
lemia. There does not appear to be any advantage of sched
-
uled use of SABAs compared with as-needed administration. 
Use of both SABAs and anticholinergics at submaximal 
doses leads to improved bronchodilation compared with 
either agent alone but does not improve dyspnea.
LAMAs (eg, tiotropium, aclidinium, umeclidinium) 
and LABAs (eg, formoterol, salmeterol, indacaterol, 
arformoterol, vilanterol) appear to achieve bronchodilation 
that is equivalent or superior to what is experienced with 
ipratropium, in addition to similar improvements in health 
status. Although more expensive than short-acting agents, 
long-acting bronchodilators may have superior clinical 
efficacy in persons with advanced disease. One RCT of 
long-term administration of tiotropium added to standard 
therapy reported fewer exacerbations or hospitalizations, 
and improved dyspnea scores, in the tiotropium group. 
Tiotropium had no effect on long-term decline in lung 
function, however. Another RCT comparing the effects 
of tiotropium with those of salmeterol-fluticasone over 
 
2 years reported no difference in the risk of COPD exacer
-
bation. The incidence of pneumonia was higher in the sal
-
meterol-fluticasone group, yet dyspnea scores were lower 
and there was a mortality benefit compared with tiotro
-
pium. The combination of tiotropium and formoterol 
(LAMA/LABA) has been shown to improve FEV
1
 and FVC 
more than the inhaled corticosteroid/LABA combination 
salmeterol and fluticasone in patients with a baseline FEV
1
 
of less than 55% predicted.
The symptomatic benefits of long-acting bronchodila
-
tors are firmly established. Increased exacerbations and 
mortality in asthmatic patients treated with salmeterol 
have not been observed in COPD patients, and several 
studies report a trend toward lower mortality in patients 
treated with salmeterol alone, compared with placebo. In 
addition, a 4-year tiotropium trial reported fewer cardio
-
vascular events in the intervention group. Subsequent 
meta-analyses that include the 4-year tiotropium trial did 
not find an increase in cardiovascular events in treated 
patients. Most practitioners believe that the documented 
benefits of anticholinergic therapy outweigh any potential 
risks.
4. Corticosteroids—
Multiple large clinical trials have 
reported a reduction in the frequency of COPD exacerba
-
tions and an increase in self-reported functional status in 
COPD patients treated with inhaled corticosteroids. These 
same trials demonstrate no effect of inhaled corticosteroids 
on mortality or the characteristic decline in lung function

on mortality or the characteristic decline in lung function 
experienced by COPD patients. Thus, inhaled corticoste
-
roids alone should not be considered first-line therapy in 
stable COPD patients.
However, combination therapy with an inhaled cortico
-
steroid and a LABA reduces the frequency of exacerbations 
and improves self-reported functional status in COPD 
patients, compared with placebo or with sole use of inhaled 
corticosteroids, LABAs, or anticholinergics. In one RCT, 
addition of an inhaled corticosteroid/LABA to tiotropium 
therapy in COPD patients did not reduce the frequency of 
exacerbations but did improve hospitalization rates and 
functional status.
Apart from acute exacerbations, COPD is not generally 
responsive to oral corticosteroid therapy. Given the risks of 
adverse side effects, oral corticosteroids are not recom
-
mended for the long-term treatment of COPD.
5. Theophylline—
Oral theophylline is a fourth-line agent for 
treating COPD patients who do not achieve adequate symp
-
tom control with inhaled anticholinergic, beta-2-agonist, and 
Table 9–7.
 
Home oxygen therapy: requirements for 
Medicare coverage.
1
Group I (any of the following):
1.
   
Pa
o
2
 ≤ 55 mm Hg or Sa
o
2
 ≤ 88% taken while awake, at rest, 
breathing room air.
2.
   
D
uring sleep (prescription for nocturnal oxygen use only): 
a.
  
Pa
o
2
o
2
 ≤ 88% for a patient whose awake, 
resting, room air Pa
o
2
 is ≥ 56 mm Hg or Sa
o
2
 ≥ 89%, 
or
 
b.
  
D
ecrease in Pa
o
2
 > 10 mm Hg or decrease in Sa
o
2
 > 5% 
associated with symptoms or signs reasonably attributed to 
hypoxemia (eg, impaired cognitive processes, nocturnal 
restlessness, insomnia).
3.
   
D
uring exercise (prescription for oxygen use only during exercise):
a.
  
Pa
o
2
 ≤ 55 mg Hg or Sa
o
2
 ≤ 88% taken during exercise for a 
patient whose awake, resting, room air Pa
o
2
 is ≥ 56 mm Hg or 
Sa
o
2
 ≥ 89%, 
and
 
b.
  
T
here is evidence that the use of supplemental oxygen during 
exercise improves the hypoxemia that was demonstrated dur
-
ing exercise while breathing room air.
Group II
2
:
Pa
o
2
 = 56–59 mm Hg or Sa
o
2
 = 89% if there is evidence of any of 
the following:
1.
   
D
ependent edema suggesting heart failure.
2.
   
P pulmonale on EC
G (P wave > 3 mm in standard leads II, III, or 
aVF).
3.
   
Hematocrit > 56%.
1
Centers for Medicare & Medicaid Services, 2003.
2
Patients in this group must have a second oxygen test 3 months 
after the initial oxygen setup.
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 CMDT 2019
corticosteroid therapies. Sustained-release theophylline 
improves hemoglobin saturation during sleep in COPD 
patients and is a first-line agent for those with sleep-related 
breathing disorders. Theophylline improves dyspnea ratings, 
exercise performance, and pulmonary function in many 
patients with stable COPD. Its benefits result from bronchodi
-
lation; anti-inflammatory properties; and extrapulmonary 
effects on diaphragm strength, myocardial contractility, and 
kidney function. Theophylline toxicity is a significant concern 
due to the medication’s narrow therapeutic window, and long-
term administration requires careful monitoring of serum 
levels. Despite potential for adverse effects, theophylline con
-
tinues to have a beneficial role in carefully selected patients.
6. Antibiotics—
Antibiotics are commonly prescribed to 
outpatients with COPD for the following indications: (1) to 
treat an acute exacerbation, (2) to treat acute bronchitis, 
and (3) to prevent acute exacerbations of chronic bronchi
-
tis (prophylactic antibiotics). In patients with COPD, anti
-
biotics appear to improve outcomes slightly in all three 
situations. Patients with a COPD exacerbation associated 
with increased sputum purulence accompanied by dyspnea 
or an increase in the quantity of sputum are thought to 
benefit the most from antibiotic therapy. The choice of 
antibiotic depends on local bacterial resistance patterns 
and individual risk of 
 infection 
(history of 
 isolation, FEV
1
 less than 50% of 
predicted, recent hospitalization [2 or more days in the past 
3 months], more than three courses of antibiotics within 
the past year, use of systemic corticosteroids). Oral antibi
-
otic options include doxycycline (100 mg every 12 hours), 
trimethoprim-sulfamethoxazole (160/800 mg every 
12 hours), a cephalosporin (eg, cefpodoxime 200 mg every 
12 hours or cefprozil 500 mg every 12 hours), a macrolide 
(eg, azithromycin 500 mg followed by 250 mg daily for 
5 days), a fluoroquinolone (eg, ciprofloxacin 500 mg every 
12 hours), and amoxicillin-clavulanate (875/125 mg every 
12 hours). Suggested duration of therapy is 3–7 days and 
depends on response to therapy; some studies suggest that 
5 days is as effective as 7 days but with fewer adverse 
effects. There are few controlled trials of antibiotics in 
severe COPD exacerbations, but prompt administration is 
appropriate, particularly in persons with risk factors for 
poor outcomes (age older than 65 years, FEV
1
 less than 
50% of predicted, three or more exacerbations in the past 
year, antibiotic therapy within the past 3 months, comorbid 
conditions, such as cardiac disease). In COPD patients 
subject to frequent exacerbations despite optimal medical 
therapy, azithromycin (daily or three times weekly) and 
moxifloxacin (a 5-day course 1 week in 8 over 48 weeks) 
were modestly effective in clinical trials at reducing the 
frequency of exacerbations; monitoring for hearing loss 
and QT prolongation is essential.
7. Pulmonary rehabilitation—
Graded aerobic physical 
exercise programs (eg, walking 20 minutes three times 
weekly or bicycling) are helpful to prevent deterioration of 
physical condition and to improve patients’ ability to carry 
out daily activities. Training of inspiratory muscles by 
inspiring against progressively larger resistive loads reduces 
dyspnea and improves exercise tolerance, health status, and 
respiratory muscle strength in some but not all patients. 
Pursed-lip breathing to slow the rate of breathing and 
abdominal breathing exercises to relieve fatigue of acces
-
sory muscles of respiration may reduce dyspnea in some 
patients. Many patients undergo these exercise and educa
-
tional interventions in a structured rehabilitation program. 
In a number of studies, pulmonary rehabilitation has been 
shown to improve exercise capacity, decrease hospitaliza
-

-
-
tions, and enhance quality of life. Referral to a comprehen
-
sive rehabilitation program is recommended in patients 
who have severe dyspnea, reduced quality of life, or fre
-
quent hospitalizations despite optimal medical therapy.
8. Phosphodiesterase 4 inhibitor—
Roflumilast has been 
shown to reduce exacerbation frequency in patients who 
have moderate or severe (FEV
1
 less than 50% of predicted) 
COPD and chronic bronchitis, with frequent exacerbations 
and are taking LABA/inhaled corticosteroid with or with
-
out a LAMA.
9. Other measures—
In patients with chronic bronchitis, 
increased mobilization of secretions may be accomplished 
through the use of adequate systemic hydration, effective 
cough training methods, or the use of a handheld flutter 
device and postural drainage, sometimes with chest per
-
cussion or vibration. Postural drainage and chest percus
-
sion should be used only in selected patients with excessive 
amounts of retained secretions that cannot be cleared by 
coughing and other methods; these measures are of no 
benefit in pure emphysema. Expectorant-mucolytic ther
-
apy has generally been regarded as unhelpful in patients 
with chronic bronchitis. Cough suppressants and sedatives 
should be avoided. Morphine can reduce chronic dyspnea 
in patients with very severe COPD.
Human alpha-1-antitrypsin is available for replacement 
therapy in emphysema due to congenital deficiency 
(PiZZ or null genotype) of alpha-1-antiprotease (alpha-1-
 
antitrypsin). Patients over 18 years of age with airflow obstruc
-
tion by spirometry and serum levels less than 11 mcmol/L 
(~50 mg/dL) are potential candidates for replacement 
 
therapy. Alpha-1-antitrypsin is administered intravenously 
in a dose of 60 mg/kg body weight once weekly. Severe 
dyspnea in spite of optimal medical management may war
-
rant a clinical trial of an opioid (eg, morphine 5–10 mg 
orally every 3–4 hours, oxycodone 5–10 mg orally every 
4–6 hours, sustained-release morphine 10 mg orally once 
daily). Sedative-hypnotic drugs (eg, diazepam, 5 mg three 
times daily) marginally improve intractable dyspnea but 
cause significant drowsiness; they may benefit very anxious 
patients. Transnasal positive-pressure ventilation at home 
to rest the respiratory muscles is an approach to improve 
respiratory muscle function and reduce dyspnea in patients 
with severe COPD.
B. Hospitalized Patients
Management of the hospitalized patient with an acute exacer
-
bation of COPD includes (1) supplemental oxygen (titrated to 
maintain Sa
o
2
 between 90% and 94% or Pa
o
2
 between 
60 mm Hg and 70 mm Hg); (2) inhaled ipratropium bromide 
(500 mcg by nebulizer, or 36 mcg by MDI with spacer, every 
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4 hours as needed) plus beta-2-agonists (eg, albuterol 2.5 mg 
diluted with saline to a total of 3 mL by nebulizer, or MDI, 
90 mcg per puff, four to eight puffs via spacer, every 1–4 hours 
as needed); (3) corticosteroids (prednisone 30–40 mg orally 
per day for 7–10 days is usually sufficient, even 5 days may be 
adequate); (4) broad-spectrum antibiotics; and (5) in selected 
cases, chest physiotherapy.
For patients without risk factors for 
, man
-
agement options include a fluoroquinolone (eg, levofloxacin 
750 mg orally or intravenously per day, or moxifloxacin 
400 mg orally or intravenously every 24 hours) or a third-
generation cephalosporin (eg, ceftriaxone 1 g intravenously 
per day, or cefotaxime 1 g intravenously every 8 hours).
For patients with risk factors for 
, thera
-
peutic options include piperacillin-tazobactam (4.5 g intra
-
venously every 6 hours), ceftazidime (1 g intravenously 
every 8 hours), cefepime (1 g intravenously every 12 hours), 
or levofloxacin (750 mg orally or intravenously per day for 
3–7 days).
Theophylline should not be initiated in the acute set
-
ting, but patients taking theophylline prior to acute hospi
-
talization should have their theophylline serum levels 
measured and maintained in the therapeutic range. Oxy
-
gen therapy should 
not
 be withheld for fear of worsening 
respiratory acidemia; hypoxemia is more detrimental than 
hypercapnia. Cor pulmonale usually responds to measures 
that reduce pulmonary artery pressure, such as supplemen
-
tal oxygen and correction of acidemia; bed rest, salt restric
-
tion, and diuretics may add some benefit. Cardiac 
dysrhythmias, particularly multifocal atrial tachycardia, 
usually respond to aggressive treatment of COPD itself. 
Atrial flutter may require DC cardioversion after initiation 
of the above therapy. If progressive respiratory failure 
ensues, tracheal intubation and mechanical ventilation are 
necessary. In clinical trials of COPD patients with hyper
-
capnic acute respiratory failure, 
noninvasive positive-
pressure ventilation (NIPPV)
 delivered via face mask 
reduced the need for intubation and shortened lengths of 
stay in the intensive care unit (ICU). Other studies have 
suggested a lower risk of nosocomial infections and less use 
of antibiotics in COPD patients treated with NIPPV . These 
benefits do not appear to extend to hypoxemic respiratory 
failure or to patients with acute lung injury or acute respi
-
ratory distress syndrome (ARDS).
C. Surgery for COPD
1. Lung transplantation—
Requirements for lung trans
-
plantation are severe lung disease, limited activities of daily 
living, exhaustion of medical therapy, ambulatory status, 
potential for pulmonary rehabilitation, limited life expec
-
tancy without transplantation, adequate function of other 
organ systems, and a good social support system. Average 
total charges for lung transplantation through the end of the 
first postoperative year exceed $250,000. The 2-year survival 
rate after lung transplantation for COPD is 75%. Complica
-
tions include acute rejection, opportunistic infection, and 
obliterative bronchiolitis. Substantial improvements in pul
-
monary function and exercise performance have been 
noted after transplantation.
2. Lung volume reduction surgery—
Lung volume reduc
-
tion surgery (LVRS), or reduction pneumoplasty, is a surgi
-
cal approach to relieve dyspnea and improve exercise 
tolerance in patients with advanced diffuse emphysema 
and lung hyperinflation. Bilateral resection of 20–30% of 
lung volume in selected patients results in modest improve
-
ments in pulmonary function, exercise performance, and 
dyspnea. The duration of any improvement as well as any 
mortality benefit remains uncertain. Prolonged air leaks 
occur in up to 50% of patients postoperatively. Mortality 
rates in centers with the largest experience with LVRS 
range from 4% to 10%.

The National Emphysema Treatment Trial compared 
LVRS with medical treatment in a randomized, multicenter 
clinical trial of 1218 patients with severe emphysema. 
Overall, surgery improved exercise capacity but not mor
-
tality when compared with medical therapy. The persis
-
tence of this benefit remains to be defined. Subgroup 
analysis suggested that patients with upper lobe–predominant 
emphysema and low exercise capacity might have improved 
survival, while other groups suffered excess mortality 
when randomized to surgery.
3. Bullectomy—
Bullectomy is an older surgical procedure 
for palliation of dyspnea in patients with severe bullous 
emphysema. Bullectomy is most commonly pursued when 
a single bulla occupies at least 30–50% of the hemithorax.
 
»
Prognosis
The outlook for patients with clinically significant COPD 
is poor. The degree of pulmonary dysfunction at the time 
the patient is first seen is an important predictor of sur
-
vival: median survival of patients with FEV
1
 1 L or less is 
about 4 years. A multidimensional index (the BODE 
index), which includes body mass index (BMI), airway 
obstruction (FEV
1
), dyspnea (Medical Research Council 
dyspnea score), and exercise capacity, is a tool that predicts 
death and hospitalization better than FEV
1
 alone. Compre
-
hensive care programs, cessation of smoking, and supple
-
mental oxygen may reduce the rate of decline of pulmonary 
function, but therapy with bronchodilators and other 
approaches probably have little, if any, impact on the natural 
course of COPD.
Dyspnea at the end of life can be extremely uncomfort
-
able and distressing to the patient and family. As patients 
near the end of life, meticulous attention to palliative care 
is essential to effectively manage dyspnea (see Chapter 5).
 
»
•	
COPD onset occurs before the age of 40.
•	
Frequent exacerbations (two or more a year) despite 
optimal treatment.
•	
Severe or rapidly progressive COPD.
•	
Symptoms disproportionate to the severity of airflow 
•	
Need for long-term oxygen therapy.
•	
Onset of comorbid illnesses (eg, bronchiectasis, heart 
failure, or lung cancer).
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»
•	
Severe symptoms or acute worsening that fails to 
respond to outpatient management.
•	
Acute or worsening hypoxemia, hypercapnia, periph
-
eral edema, or change in mental status.
•	
Inadequate home care, or inability to sleep or maintain 
nutrition/hydration due to symptoms.
•	
The presence of high-risk comorbid conditions.
Global strategy for the diagnosis, management, and prevention 
of chronic obstructive lung disease 2018 report. http://gold
-
copd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-
FINAL-revised-20-Nov_WMS.pdf
The Global Initiative for Chronic Obstructive Lung Disease 
(GOLD). http://goldcopd.org/
The Long-Term Oxygen Treatment Trial Research Group. A 
randomized trial of long-term oxygen for COPD with moder
-
ate desaturation. N Engl J Med. 2016 Oct 27;375(17):1617–27. 
[PMID: 27783918]
Vogelmeier CF et al. Global strategy for the diagnosis, manage
-
ment, and prevention of chronic obstructive lung disease 
2017 report. GOLD executive summary. Am J Respir Crit 
Care Med. 2017 Mar 1;195(5):557–82. [PMID: 28128970]
Wedzicha JA et al. Management of COPD exacerbations: a Euro
-
pean Respiratory Society/American Thoracic Society guideline. 
Eur Respir J. 2017 Mar 15;49(3):1600791. [PMID: 28298398]
Wedzicha JA et al. Prevention of COPD exacerbations: a European 
Respiratory Society/American Thoracic Society guideline. Eur 
Respir J. 2017 Sept 9 50(3):1602265. [PMID: 28889106]
BRONCHIECTASIS
 
»
Chronic productive cough with dyspnea and 
wheezing.
 
»
Radiographic findings of dilated, thickened air
-
ways and scattered, irregular opacities.
 
»
Bronchiectasis is a congenital or acquired disorder of the 
large bronchi characterized by permanent, abnormal dila
-
tion and destruction of bronchial walls. It may be caused by 
recurrent inflammation or infection of the airways and 
may be localized or diffuse. Cystic fibrosis causes about 
half of all cases of bronchiectasis. Other causes include 
lung infection (tuberculosis, fungal infections, lung abscess, 
pneumonia), abnormal lung defense mechanisms (humoral 
immunodeficiency, alpha-1-antitrypsin deficiency with 
cigarette smoking, mucociliary clearance disorders, rheu
-
matic diseases), and localized airway obstruction (foreign 
body, tumor, mucoid impaction). Immunodeficiency states 
that may lead to bronchiectasis include congenital or 
acquired panhypogammaglobulinemia; common variable 
immunodeficiency; selective IgA, IgM, and IgG subclass 
deficiencies; and acquired immunodeficiency from cyto
-
toxic therapy, AIDS, lymphoma, plasma cell myeloma 
(previously called multiple myeloma), and leukemia. Most 
patients with bronchiectasis have panhypergammaglobu
-
linemia, however, presumably reflecting an immune sys
-
tem response to chronic airway infection.
 
»
Symptoms of bronchiectasis include chronic cough with 
production of copious amounts of purulent sputum, 
hemoptysis, and pleuritic chest pain. Dyspnea and wheez
-
ing occur in 75% of patients. Weight loss, anemia, and 
other systemic manifestations are common. Physical find
-
ings are nonspecific, but persistent crackles at the lung 
bases are common. Clubbing is infrequent in mild cases 
but is common in severe disease (Figure 6–41). Copious, 
foul-smelling, purulent sputum is characteristic. Obstruc
-
tive pulmonary dysfunction with hypoxemia is seen in 
moderate or severe disease.
B. Imaging
Radiographic abnormalities include dilated and thickened 
bronchi that may appear as “tram tracks” or as ring-like 
markings. Scattered irregular opacities, atelectasis, and 
focal consolidation may be present. High-resolution CT is 
the diagnostic study of choice.
C. Microbiology
 is the most common organism recovered 
from non–cystic fibrosis patients with bronchiectasis. 
P aeruginosa, S pneumoniae
, and 
 are

, and 
 are 
commonly identified. Nontuberculous mycobacteria are 
seen less commonly. Patients with 
 infection 
experience an accelerated course, with more frequent exac
-
erbations and more rapid decline in lung function.
 
»
Treatment
Treatment of acute exacerbations consists of antibiotics, 
daily chest physiotherapy with postural drainage and chest 
percussion, and inhaled bronchodilators. Handheld flutter 
valve devices may be as effective as chest physiotherapy in 
clearing secretions. Antibiotic therapy should be guided by 
sputum smears and prior cultures. If a specific bacterial 
pathogen cannot be isolated, then empiric oral antibiotic 
therapy for 10–14 days is appropriate. Common regimens 
include amoxicillin or amoxicillin-clavulanate (500 mg 
every 8 hours), ampicillin (250–500 mg four times 
daily), doxycycline (100 mg twice daily), trimethoprim-
sulfamethoxazole (160/800 mg every 12 hours), or cipro
-
floxacin (500–750 mg twice daily). It is important to screen 
patients for infection with nontuberculous mycobacteria 
because these organisms may underlie a lack of treatment 
response. Preventive or suppressive treatment is sometimes 
given to stable outpatients with bronchiectasis who have 
copious purulent sputum. Prolonged macrolide therapy 
(azithromycin 500 mg three times a week for 6 months or 
250 mg daily for 12 months) has been found to decrease the 
frequency of exacerbations compared to placebo. Alternat
-
ing cycles of the antibiotics listed above given orally for 
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2–4 weeks are also used in patients who are not colonized 
with 
, although this practice is not supported 
by clinical trial data. In patients with underlying cystic 
fibrosis, inhaled aerosolized aminoglycosides reduce colo
-
nization by 
 species, improve FEV
1
, and 
reduce hospitalizations; in patients with non–cystic fibrosis 
bronchiectasis, the role of inhaled aerosolized aminoglyco
-
sides is unclear. Complications of bronchiectasis include 
hemoptysis, cor pulmonale, amyloidosis, and secondary 
visceral abscesses at distant sites (eg, brain). Bronchoscopy 
is sometimes necessary to evaluate hemoptysis, remove 
retained secretions, and rule out obstructing airway lesions. 
Massive hemoptysis may require embolization of bronchial 
arteries or surgical resection. Surgical resection is other
-
wise reserved for the few patients with localized bronchiec
-
tasis and adequate pulmonary function in whom 
conservative management fails.
Chalmers JD et al. Management of bronchiectasis in adults. Eur 
Respir J. 2015 May;45(5):1446–62. [PMID: 25792635]
Fjaellegaard K et al. Antibiotic therapy for stable non-CF bron
-
chiectasis in adults—a systematic review. Chron Respir Dis. 
2017 May;14(2):174–86. [PMID: 27507832]
Tarrant BJ et al. Mucoactive agents for chronic, non-cystic fibrosis 
lung disease: a systematic review and meta-analysis. Respirol
-
ogy. 2017 Aug;22(6):1084–92. [PMID: 28397992]
Wilson R et al. Challenges in managing 
 
in non-cystic fibrosis bronchiectasis. Respir Med. 2016 Aug;
 
117:179–89. [PMID: 27492530]
ALLERGIC BRONCHOPULMONARY 
 
MYCOSIS
Allergic bronchopulmonary mycosis is a pulmonary hyper
-
sensitivity disorder caused by allergy to fungal antigens 
that colonize the tracheobronchial tree. It usually occurs in 
atopic asthmatic individuals who are 20–40 years of age or 
those with cystic fibrosis, in response to antigens of 
Asper
-
gillus
 species. For this reason, the disorder is commonly 
referred to as allergic bronchopulmonary aspergillosis 
(ABPA). Primary criteria for the diagnosis of ABPA include 
(1) a clinical history of asthma or cystic fibrosis; (2) ele
-
vated serum total IgE levels (typically greater than 1000 
international units/mL; a value less than 1000 international 
units/mL may be acceptable if all other criteria are met); 
(3) immediate cutaneous hypersensitivity to 
 
antigens or elevated serum IgE levels specific to 
Aspergillus 
fumigatus;
 and (4) at least two of the following: (a) precipi
-
tating serum antibodies to 
 antigen or elevated 
serum 
 IgG by immunoassay, (b) radiographic 
pulmonary opacities consistent with ABPA, or (c) periph
-
eral blood eosinophil count greater than 500 cells/mcL. 
High-dose prednisone (0.5–1 mg/kg orally per day) for at 
least 2 weeks is the initial treatment of choice. Depending 
on the clinical situation, prednisone dose can then be 
reduced or converted to every other day and slowly tapered 
over 3–6 months. Relapses are frequent, and protracted or 
repeated treatment with corticosteroids is not uncommon. 
Patients with corticosteroid-dependent disease may benefit 
from itraconazole (200 mg orally three times a day for 
 
3 days, followed by twice daily [with food if the capsule 
formulation is used] for at least 16 weeks) without added 
toxicity. Bronchodilators (see Table 9–5) are also helpful. 
Complications include hemoptysis, severe bronchiectasis, 
and pulmonary fibrosis.
Muldoon EG et al. Allergic and noninvasive infectious pulmo
-
nary aspergillosis syndromes. Clin Chest Med. 2017 Sep;38(3):
 
521–34. [PMID: 28797493]
Shah A et al. Allergic bronchopulmonary aspergillosis: a perplexing 
clinical entity. Allergy Asthma Immunol Res. 2016 Jul;8(4):
 
282–97. [PMID: 27126721]
CYSTIC FIBROSIS
 
»
Pulmonary problems: chronic or recurrent pro
-
ductive cough, dyspnea, and wheezing, recurrent

»
-
ductive cough, dyspnea, and wheezing, recurrent 
airway infections or chronic colonization of the 
airways with 
H influenzae, P aeruginosa, S aureus
, 
or 
Burkholderia cepacia
; bronchiectasis and scar
-
ring on chest radiographs; airflow obstruction on 
spirometry.
 
»
Gastrointestinal problems: pancreatic insuffi
-
ciency, recurrent pancreatitis, distal intestinal 
obstruction syndrome, or chronic liver disease.
 
»
Genitourinary problems: male infertility and uro
-
genital abnormalities.
 
»
Sweat chloride concentration greater than 60 
mEq/L on two occasions.
 
»
Presence of two (one from each parent) gene 
mutations known to cause cystic fibrosis.
 
»
Abnormal nasal potential difference.
 
»
Cystic fibrosis is the most common cause of severe chronic 
lung disease in young adults and the most common fatal 
hereditary disorder of whites in the United States. It is an 
autosomal-recessive disorder affecting about 1 in 3000 
whites; 1 in 25 is a carrier. Cystic fibrosis is caused by 
abnormalities in a membrane chloride channel (the cystic 
fibrosis transmembrane conductance regulator [CFTR] 
protein) that results in altered chloride transport and water 
flux across the apical surface of epithelial cells. Almost all 
exocrine glands produce an abnormal mucus that obstructs 
glands and ducts and leads to tissue damage. In the respira
-
tory tract, inadequate hydration of the tracheobronchial 
epithelium impairs mucociliary function. High concentra
-
tion of extracellular DNA in airway secretions (due to 
chronic airway inflammation and autolysis of neutrophils) 
increases sputum viscosity.
Over one-third of the nearly 30,000 cystic fibrosis 
patients in the United States are adults. Patients with cystic 
fibrosis have an increased risk of osteopenia, arthropathies, 
and malignancies of the gastrointestinal tract.
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»
Cystic fibrosis should be suspected in an adult with a his
-
tory of chronic lung disease (especially bronchiectasis), 
pancreatitis, or infertility. Cough, sputum production, 
decreased exercise tolerance, and recurrent hemoptysis are 
typical complaints. Patients also often complain of chronic 
rhinosinusitis symptoms, steatorrhea, diarrhea, and 
abdominal pain. Patients with cystic fibrosis are often mal
-
nourished with low body mass index. Digital clubbing, 
increased anteroposterior chest diameter, hyperresonance 
to percussion, and apical crackles are noted on physical 
examination. Sinus tenderness, purulent nasal secretions, 
and nasal polyps may also be seen. Nearly all men with 
cystic fibrosis have congenital bilateral absence of the vas 
deferens with azoospermia. Biliary cirrhosis and gallstones 
may occur.
Arterial blood gas studies often reveal hypoxemia and, in 
advanced disease, a chronic, compensated respiratory aci
-
dosis. Pulmonary function studies show a mixed obstruc
-
tive and restrictive pattern. There is a reduction in FVC, 
airflow rates, and TLC. Air trapping (high ratio of RV to 
TLC) and reduction in pulmonary diffusing capacity are 
common.
C. Imaging
Hyperinflation is seen early in the disease process. Peri
-
bronchial cuffing, mucus plugging, bronchiectasis (ring 
shadows and cysts), increased interstitial markings, small 
rounded peripheral opacities, and focal atelectasis are 
common findings. Pneumothorax can also be seen. Thin-
section CT scanning often confirms the presence of 
bronchiectasis.
D. Diagnosis
The 
quantitative pilocarpine iontophoresis sweat test
 
reveals elevated sodium and chloride levels (greater than 
60 mEq/L) in the sweat of patients with cystic fibrosis. Two 
tests on different days performed in experienced laborato
-
ries are required for accurate diagnosis. A normal sweat 
chloride test does not exclude the diagnosis, in which case 
genotyping or other alternative diagnostic studies (such as 
measurement of nasal membrane potential difference, 
semen analysis, or assessment of pancreatic function) 
should be pursued, especially if there is a high clinical sus
-
picion of cystic fibrosis. All patients with cystic fibrosis 
should undergo 
CFTR
 genotyping.
 
»
Treatment
Early recognition and comprehensive multidisciplinary 
therapy improve symptom control and the chances of sur
-
vival. Referral to a regional cystic fibrosis center is strongly 
recommended. Conventional treatment programs focus on 
the following areas: clearance and reduction of lower air
-
way secretions, reversal of bronchoconstriction, treatment 
of respiratory tract infections and airway bacterial burden, 
pancreatic enzyme replacement, and nutritional and psy
-
chosocial support (including genetic and occupational 
counseling). Oral CFTR modulator drugs, alone or in 
combination, are available for patients with specific genetic 
mutations. The Pulmonary Therapies Committee, estab
-
lished by the Cystic Fibrosis Foundation, has issued evi
-
denced-based recommendations regarding long-term use 
of medications for maintenance of lung function and 
reduction of exacerbations in patients with cystic fibrosis.
Clearance of lower airway secretions can be promoted 
by postural drainage, chest percussion or vibration tech
-
niques, positive expiratory pressure (PEP) or flutter valve 
breathing devices, directed cough, and other breathing 
techniques; these approaches require detailed patient 
instruction by experienced personnel. Inhaled recombi
-
nant human deoxyribonuclease (rhDNase, dornase alpha) 
cleaves extracellular DNA in sputum, decreasing sputum 
viscosity; when administered long-term at a daily nebu
-
lized dose of 2.5 mg, this therapy leads to improved FEV
1
 
and reduces the risk of cystic fibrosis–related respiratory 
exacerbations and the need for intravenous antibiotics.

-
1
 
exacerbations and the need for intravenous antibiotics. 
Inhalation of hypertonic (7%) saline twice daily has been 
associated with small improvements in pulmonary func
-
tion and fewer pulmonary exacerbations. The beneficial 
effects of hypertonic saline may derive from improved 
airway mucous clearance.
Short-term antibiotics
 are used to treat active airway 
infections based on results of culture and susceptibility 
testing of sputum. 
S aureus
strains) and a mucoid variant of 
 are com
-
monly present. 
H influenzae, Stenotrophomonas malto
-
philia
, and 
B cepacia
 (a highly drug-resistant organism) are 
occasionally isolated. 
Long-term antibiotic therapy
 is 
helpful in slowing disease progression and reducing exac
-
erbations in patients with sputum cultures positive for 
. These antibiotics include azithromycin 
500 mg orally three times a week, which has immuno
-
modulatory properties, and various inhaled antibiotics (eg, 
tobramycin, aztreonam, colistin, and levofloxacin) taken 
two to three times a day. The length of therapy depends on 
the persistent presence of 
 in the sputum. The 
incidence of atypical mycobacterial colonization is higher 
in cystic fibrosis patients, and directed antibiotic treatment 
is recommended for frequent exacerbations, progressive 
decline in lung function, or failure to thrive. Y early screen
-
ing with sputum acid-fast bacilli cultures is advised.
Inhaled bronchodilators
 (eg, albuterol, two puffs every 
4 hours as needed) should be considered in patients who 
demonstrate an increase of at least 12% in FEV
1
 after an 
inhaled bronchodilator. An inhaled corticosteroid should 
be added to the treatment regimen for patients who have 
cystic fibrosis with persistent asthma or allergic broncho
-
pulmonary mycosis.
Lung transplantation
 is the only definitive treatment 
for advanced cystic fibrosis. Double-lung or heart-lung 
transplantation is required. A few transplant centers offer 
living lobar lung transplantation to selected patients. The 
median survival following transplantation for cystic fibro
-
sis is 7.8 years.
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CMDT 2019
Vaccination
 against pneumococcal infection and 
annual influenza vaccination are advised. 
Screening
 of 
family members and genetic counseling are suggested.
 
»
Prognosis
The longevity of patients with cystic fibrosis is increasing, 
and the median survival age is over 39 years. Death occurs 
from pulmonary complications (eg, pneumonia, pneumo
-
thorax, or hemoptysis) or as a result of terminal chronic 
respiratory failure and cor pulmonale.
Elborn JS. Cystic fibrosis. Lancet. 2016 Nov 19;388(10059):
 
2519–31. [PMID: 27140670]
Farrell PM et al. Diagnosis of cystic fibrosis: consensus guide
-
lines from the Cystic Fibrosis Foundation. J Pediatr. 2017 
Feb;181S:S4–15. [PMID: 28129811]
Langton Hewer SC et al. Antibiotic strategies for eradicating 
 in people with cystic fibrosis. 
Cochrane Database Syst Rev. 2017 Apr 25;4:CD004197. 
[PMID: 28440853]
Quon BS et al. New and emerging targeted therapies for cystic 
fibrosis. BMJ. 2016 Mar 30;352:i859. [PMID: 27030675]
BRONCHIOLITIS
 
»
Insidious onset of cough and dyspnea.
 
»
Irreversible airflow obstruction on pulmonary 
function testing.
 
»
Minimal findings on chest radiograph.
 
»
Relevant exposure or risk factors: toxic fumes, viral 
infections, organ transplantation, connective tis
-
sue disease.
 
»
Bronchiolitis is a generic term applied to varied inflamma
-
tory processes that affect the bronchioles, which are small 
conducting airways less than 2 mm in diameter. Disorders 
associated with bronchiolitis include organ transplanta
-
tion, connective tissue diseases, and hypersensitivity pneu
-
monitis. Inhalational injuries as well as postinfectious and 
drug-induced causes are identified by association with a 
known exposure or illness prior to the onset of symptoms. 
Idiopathic cases are characterized by the insidious onset of 
dyspnea or cough.
 
»
Acute bronchiolitis
 can be seen seen following viral 
Constrictive bronchiolitis
 (also referred to as oblitera
-
tive bronchiolitis, or bronchiolitis obliterans) is relatively 
infrequent although it is the most common finding follow
-
ing inhalation injury. It may also be seen in rheumatoid 
arthritis; medication reactions; and chronic rejection fol
-
lowing heart-lung, lung, or bone marrow transplant. 
Patients with constrictive bronchiolitis have airflow 
obstruction on spirometry; minimal radiographic abnor
-
malities; and a progressive, deteriorating clinical course.
Proliferative bronchiolitis
 is associated with diverse 
pulmonary disorders, including infection, aspiration, 
ARDS, hypersensitivity pneumonitis, connective tissue 
diseases, and organ transplantation. Compared with con
-
strictive bronchiolitis, proliferative bronchiolitis is more 
likely to have an abnormal chest radiograph.
Cryptogenic organizing pneumonitis (COP)
 formerly 
referred to as 
bronchiolitis obliterans with organizing 
pneumonia (BOOP)
 affects men and women between the 
ages of 50 and 70 years, typically with a dry cough, dys
-
pnea, and constitutional symptoms that may be present for 
weeks to months prior to seeking medical attention. A his
-
tory of a preceding viral illness is present in half of cases. 
Pulmonary function testing typically reveals a restrictive 
ventilatory defect and impaired oxygenation. The chest 
radiograph frequently shows bilateral patchy, ground-glass 
or alveolar infiltrates, although other patterns have been 
described.
Follicular bronchiolitis
 is most commonly associated 
with connective tissue disease, especially rheumatoid arthritis 
and Sjögren syndrome, and with immunodeficiency states.
Respiratory bronchiolitis
 usually occurs without 
symptoms or physiologic evidence of lung impairment.
Diffuse panbronchiolitis
 is most frequently diagnosed 
in Japan. Men are affected about twice as often as women, 
two-thirds are nonsmokers, and most patients have a his
-

-
tory of chronic pansinusitis. Patients complain of dyspnea, 
cough, and sputum production, and chest examination 
shows crackles and rhonchi. Pulmonary function tests 
reveal obstructive abnormalities, and the chest radiograph 
shows a distinct pattern of diffuse, small, nodular shadows 
with hyperinflation.
 
»
Treatment
 is relatively unresponsive to 
corticosteroids and is frequently progressive. Corticoste
-
roids are effective in two-thirds of patients with 
prolifera
-
tive bronchiolitis,
 and improvement can be prompt. 
Therapy is initiated with prednisone at 1 mg/kg/day orally 
for 1–3 months. The dose is then tapered slowly to 20–40 
mg/day, depending on the response, and weaned over the 
subsequent 3–6 months as tolerated. Relapses are common 
if corticosteroids are stopped prematurely or tapered too 
quickly. Most patients with 
COP
 recover following cortico
-
steroid treatment. 
 is effectively 
treated with azithromycin.
Barker AF et al. Obliterative bronchiolitis. N Engl J Med. 2014 
May 8;370(19):1820–8. [PMID: 24806161]
Bergeron A et al. Budesonide/formoterol for bronchiolitis oblit
-
erans after hematopoietic stem cell transplantation. Am J 
Respir Crit Care Med. 2015 Jun 1;191(11):1242–9. [PMID: 
25835160]
Meyer KC et al. An international ISHLT/ATS/ERS clinical prac
-
tice guideline: diagnosis and management of bronchiolitis 
obliterans syndrome. Eur Respir J. 2014 Dec;44(6):1479–503. 
[PMID: 25359357]
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º
PULMONARY INFECTIONS
PNEUMONIA
Pneumonia has classically been considered in terms of the 
infecting organism (Table 9–8). This approach facilitates 
discussion of characteristic clinical presentations but is a 
limited guide to patient management since specific micro
-
biologic information is rarely available at initial presenta
-
tion. More recent classification schemes emphasize 
epidemiologic factors that predict etiology and guide initial 
therapy. Pneumonia may be classified as community-
acquired (CAP) or nosocomial and, within the latter, as 
hospital-acquired (HAP) or ventilator-associated (V AP). 
These categories are based on differing settings and infec
-
tious agents and require different diagnostic and therapeu
-
tic interventions. Anaerobic pneumonia and lung abscess 
can occur in both hospital and community settings and 
warrant separate consideration.
This section sets forth the evaluation and management 
of pulmonary infiltrates in immunocompetent persons 
separately from the approach to immunocompromised 
persons—defined as those with HIV disease, absolute neu
-
trophil counts less than 1000/mcL (1.0 × 10
9
/L), current or 
recent exposure to myelosuppressive or immunosuppres
-
sive medications, or those currently taking prednisone in a 
dosage greater than 5 mg/day.
1. Community-Acquired Pneumonia
 
»
Fever or hypothermia, tachypnea, cough with or 
without sputum, dyspnea, chest discomfort, 
sweats or rigors (or both).
 
»
Bronchial breath sounds or inspiratory crackles on 
chest auscultation.
 
»
Parenchymal opacity on chest radiograph.
 
»
Occurs outside of the hospital or within 48 hours 
of hospital admission in a patient not residing in a 
long-term care facility.
Table 9–8.
 
Characteristics of selected pneumonias.
Organism; Appearance on Smear of 
 
Sputum
Clinical Setting
Streptococcus pneumoniae
 (pneumococcus). 
Gram-positive diplococci.
Chronic cardiopulmonary disease; follows upper 
respiratory tract infection
Bacteremia, meningitis, endocarditis, 
pericarditis, empyema
Haemophilus influenzae
. Pleomorphic 
 
gram-negative coccobacilli.
Empyema, endocarditis
. Plump gram-positive 
cocci in clumps.
Residence in chronic care facility, hospital-
 
associated, influenza epidemics, cystic fibrosis, 
bronchiectasis, injection drug use
Empyema, cavitation
Klebsiella pneumoniae
. Plump gram-negative 
encapsulated rods.
Alcohol abuse, diabetes mellitus; 
hospital-associated
Cavitation, empyema
. Gram-negative rods.
Hospital-associated; rarely, community-acquired
Empyema
. 
 
Gram-negative rods.
Hospital-associated; cystic fibrosis, bronchiectasis
Cavitation
Anaerobes. Mixed flora.
Aspiration, poor dental hygiene
Necrotizing pneumonia, abscess, 
empyema
. PMNs and 
 
monocytes; no bacteria.
Young adults; summer and fall
Skin rashes, bullous myringitis; 
 
hemolytic anemia
 species.
Few PMNs; no bacteria.
Summer and fall; exposure to contaminated 
 
construction site, water source, air conditioner; 
community-acquired or hospital-associated
Empyema, cavitation, endocarditis, 
pericarditis
Chlamydophila pneumoniae
. Nonspecific.
Clinically similar to 
M pneumoniae
, 
 
but prodromal symptoms last longer 
 
(up to 2 weeks). Sore throat with hoarseness 
common. Mild pneumonia in teenagers and 
young adults.
Reinfection in older adults with 
underlying COPD or heart failure 
may be severe or even fatal
Moraxella catarrhalis
. Gram-negative 
 
diplococci.
Preexisting lung disease; elderly patients; 
 
corticosteroid or immunosuppressive therapy
Rarely, pleural effusions and 
bacteremia
AIDS, immunosuppressive or cytotoxic drug 
 
therapy, cancer
Pneumothorax, respiratory failure, 
ARDS, death

ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; PMN, polymorphonuclear leukocyte.
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»
Community-acquired pneumonia (CAP) is a common 
disorder, with approximately 4–5 million cases diagnosed 
each year in the United States, 25% of which require hospi
-
talization. It is the deadliest infectious disease in the United 
States and the eighth leading cause of death. Mortality in 
milder cases treated as outpatients is less than 1%. Among 
patients hospitalized for CAP , in-hospital mortality is 
approximately 10–12% and 1-year mortality (in those over 
age 65) is greater than 40%. Risk factors for the develop
-
ment of CAP include advanced age; alcoholism; tobacco 
use; comorbid medical conditions, especially asthma or 
COPD; and immunosuppression.
The patient’s history, physical examination, and imag
-
ing studies are essential to establishing a diagnosis of CAP . 
None of these efforts identifies a specific microbiologic 
cause, however. Sputum examination may be helpful in 
selected patients but 40% of patients cannot produce an 
evaluable sputum sample and Gram stain and culture lack 
sensitivity for the most common causes of pneumonia. 
Since patient outcomes improve when the initial antibiotic 
choice is appropriate for the infecting organism, the American 
Thoracic Society and the Infectious Diseases Society of 
America recommend empiric treatment based on epide
-
miologic data (Table 9–9). Such treatment improves initial 
antibiotic coverage, reduces unnecessary hospitalization, 
and appears to improve 30-day survival.
Decisions regarding hospitalization and ICU care 
should be based on prognostic criteria.
 
»
CAP is diagnosed outside of the hospital in ambulatory 
patients who are not residents of nursing homes or other 
long-term care facilities. It may also be diagnosed in a pre
-
viously ambulatory patient within 48 hours after admission 
to the hospital.
Pulmonary defense mechanisms (cough reflex, muco
-
ciliary clearance system, immune responses) normally pre
-
vent the development of lower respiratory tract infections 
following aspiration of oropharyngeal secretions containing 
bacteria or inhalation of infected aerosols. CAP occurs 
when there is a defect in one or more of these normal 
defense mechanisms or when a large infectious inoculum or 
a virulent pathogen overwhelms the immune response.
Prospective studies fail to identify the cause of CAP in 
40–60% of cases; two or more causes are identified in up to 
5% of cases. Bacteria are more commonly identified than 
viruses. The most common bacterial pathogen identified in 
most studies of CAP is 
, accounting for 
approximately two-thirds of bacterial isolates. 
Table 9–9.
 
Recommended empiric antibiotics for community-acquired pneumonia.
Outpatient management
1.
 
For previously healthy patients who have not taken antibiotics within the past 3 months:
a.
 
A macrolide (clarithromycin, 500 mg orally twice a day; or azithromycin, 500 mg orally as a first dose and then 250 mg orally daily for 
 
4 days, or 500 mg orally daily for 3 days), 
or
b.
 
Doxycycline, 100 mg orally twice a day.
2.
 
For patients with comorbid medical conditions such as chronic heart, lung, liver, or kidney disease; diabetes mellitus; alcoholism; malig
-
nancy; asplenia; immunosuppressant conditions or use of immunosuppressive drugs; or use of antibiotics within the previous 3 months 
(in which case an alternative from a different antibiotic class should be selected):
a.
 
A respiratory fluoroquinolone (moxifloxacin, 400 mg orally daily; gemifloxacin, 320 mg orally daily; levofloxacin, 750 mg orally daily) 
or
b.
 
A macrolide (as above) 
plus
 a beta-lactam (amoxicillin, 1 g orally three times a day; amoxicillin-clavulanate, 2 g orally twice a day are 
preferred to cefpodoxime, 200 mg orally twice a day; cefuroxime, 500 mg orally twice a day).
3.
 
In regions with a high rate (> 25%) of infection with high level (MIC ≥ 16 mcg/mL) macrolide-resistant

3.
 
In regions with a high rate (> 25%) of infection with high level (MIC ≥ 16 mcg/mL) macrolide-resistant 
, 
 
consider use of alternative agents listed above in (2) for patients with comorbidities.
Inpatient management not requiring intensive care
1.
 
A respiratory fluoroquinolone. See above for oral therapy. For intravenous therapy, moxifloxacin, 400 mg daily; levofloxacin, 750 mg daily; 
ciprofloxacin, 400 mg every 8–12 hours, 
or
2.
 
A macrolide 
plus
 a beta-lactam. See above for oral therapy. For intravenous therapy, ampicillin, 1–2 g every 4–6 hours; cefotaxime, 
 
1–2 g every 4–12 hours; ceftriaxone, 1–2 g every 12–24 hours.
Inpatient intravenous management requiring intensive care
1.
 
Azithromycin (500 mg orally as a first dose and then 250 mg orally daily for 4 days, or 500 mg orally daily for 3 days) or a respiratory 
 
fluoroquinolone plus an antipneumococcal beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam, 1.5–3 g every 6 hours).
2.
 
For patients allergic to beta-lactam antibiotics, a fluoroquinolone 
plus
 aztreonam (1–2 g every 6–12 hours).
3.
 
For patients at risk for 
 infection:
a.
 
An antipneumococcal, antipseudomonal beta-lactam (piperacillin-tazobactam, 3.375–4.5 g every 6 hours; cefepime, 1–2 g twice a day; 
imipenem, 0.5–1 g every 6–8 hours; meropenem, 1 g every 8 hours) 
plus
 ciprofloxacin (400 mg every 8–12 hours) or levofloxacin, 
or
b.
 
The above beta-lactam 
plus
 an aminoglycoside (gentamicin, tobramycin, amikacin, all weight-based dosing administered daily 
adjusted to appropriate trough levels) 
plus
 azithromycin or a respiratory fluoroquinolone.
4.
 
For patients at risk for methicillin-resistant 
 infection, add vancomycin (interval dosing based on kidney function 
to achieve serum trough concentration 15–20 mcg/mL) 
or
 linezolid (600 mg twice a day).
MIC, minimum inhibitory concentration.
Recommendations assembled from Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus 
guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44:S27–72.
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Other common bacterial pathogens include 
H influenzae, 
Mycoplasma pneumoniae, C pneumoniae, S aureus, Neisse
-
ria meningitidis, M catarrhalis, Klebsiella pneumoniae
, 
other gram-negative rods, and 
 species. Common 
viral causes of CAP include influenza virus, respiratory 
syncytial virus, adenovirus, and parainfluenza virus. A 
detailed assessment of epidemiologic risk factors may aid 
in diagnosing pneumonias due to the following uncom
-
mon causes: 
Chlamydophila psittaci
 (psittacosis), 
Coxiella 
burnetii
 (Q fever), 
Francisella tularensis
 (tularemia), 
endemic fungi (
Blastomyces, Coccidioides, Histoplasma
), 
and sin nombre virus (hantavirus pulmonary syndrome).
 
»
Most patients with CAP experience an acute or subacute 
onset of fever, cough with or without sputum production, 
and dyspnea. Other common symptoms include sweats, 
chills, rigors, chest discomfort, pleurisy, hemoptysis, 
fatigue, myalgias, anorexia, headache, and abdominal pain.
Common physical findings include fever or hypother
-
mia, tachypnea, tachycardia, and arterial oxygen desatura
-
tion. Many patients appear acutely ill. Chest examination 
often reveals inspiratory crackles and bronchial breath 
sounds. Dullness to percussion may be observed if lobar 
consolidation or a parapneumonic pleural effusion is pres
-
ent. The clinical evaluation is less than 50% sensitive com
-
pared to chest imaging for the diagnosis of CAP (see 
Imaging section below). In most patients, therefore, a chest 
radiograph is essential to the evaluation of suspected CAP .
Diagnostic testing for a specific infectious cause of CAP is 
not generally indicated in ambulatory patients treated as 
outpatients because empiric antibiotic therapy is almost 
always effective in this population. In ambulatory outpa
-
tients whose presentation (travel history, exposure) suggests 
an etiology not covered by standard therapy (eg, 
Coccidioi
-
des)
 or public health concerns (eg, 
Mycobacterium tubercu
-
losis
, influenza), diagnostic testing is appropriate. Diagnostic 
testing is recommended in hospitalized CAP patients for 
multiple reasons: the likelihood of an infectious cause unre
-
sponsive to standard therapy is higher in more severe ill
-
ness, the inpatient setting allows narrowing of antibiotic 
coverage as specific diagnostic information is available, and 
the yield of testing is improved in more acutely ill patients.
Diagnostic testing results are used to guide initial anti
-
biotic therapy, permit adjustment of empirically chosen 
therapy to a specific infectious cause or resistance pattern, 
and facilitate epidemiologic analysis. There are three 
widely available, rapid point-of-care diagnostic tests that 
may guide initial therapy: the sputum Gram stain, urinary 
antigen tests for 
 and 
 species, and 
rapid antigen detection tests for influenza. Sputum Gram 
stain is neither sensitive nor specific for 
, the 
most common cause of CAP . The usefulness of a sputum 
Gram stain lies in broadening initial coverage in patients to 
be hospitalized for CAP , most commonly to cover 
S aureus
 
(including community-acquired methicillin-resistant 
strains, CA-MRSA) or gram-negative rods. Urinary anti
-
gen assays for 
Legionella pneumophilia
 and 
 
are at least as sensitive and specific as sputum Gram stain 
and culture. Results are available immediately and are not 
affected by early initiation of antibiotic therapy. Positive 
tests may allow narrowing of initial antibiotic coverage. 
Urinary antigen assay for 
 should be ordered 
for patients with leukopenia, asplenia, active alcohol use, 
chronic severe liver disease, pleural effusion, and those 
requiring ICU admission. Urinary antigen assay for 
L 
pneumophilia
 should be ordered for patients with active 
alcohol use, travel within previous 2 weeks, pleural effu
-

L 
-
sion, and those requiring ICU admission. Rapid influenza 
testing has intermediate sensitivity but high specificity. 
Positive tests may reduce unnecessary antibacterial use and 
direct isolation of hospitalized patients.
Additional microbiologic testing including pre-antibi
-
otic sputum and blood cultures (at least two sets with needle 
sticks at separate sites) has been standard practice for 
patients with CAP who require hospitalization. The yield of 
blood and sputum cultures is low; however, false-positive 
results are common, and the impact of culture results on 
patient outcomes is small. As a result, targeted testing 
based on specific indications is recommended. Culture 
results are not available prior to initiation of antibiotic 
therapy. Their role is to allow narrowing of initial empiric 
antibiotic coverage, adjustment of coverage based on spe
-
cific antibiotic resistance patterns, to identify unsuspected 
pathogens not covered by initial therapy, and to provide 
information for epidemiologic analysis.
Apart from microbiologic testing, hospitalized patients 
should undergo complete blood count with differential and a 
chemistry panel (including serum glucose, electrolytes, urea 
nitrogen, creatinine, bilirubin, and liver enzymes). Hypox
-
emic patients should have arterial blood gases sampled. Test 
results help assess severity of illness and guide evaluation and 
management. HIV testing should be considered in all adult 
patients, and performed in those with risk factors.
C. Imaging
A pulmonary opacity on chest radiography or CT scan is 
required to establish a diagnosis of CAP . Chest CT scan is 
more sensitive and specific than chest radiography and may 
be indicated in selected cases. Radiographic findings range 
from patchy airspace opacities to lobar consolidation with 
air bronchograms to diffuse alveolar or interstitial opacities. 
Additional findings can include pleural effusions and cavi
-
tation. Chest imaging cannot identify a specific microbio
-
logic cause of CAP , however. No pattern of radiographic 
abnormalities is pathognomonic of any infectious cause.
Chest imaging may help assess severity and response to 
therapy over time. Progression of pulmonary opacities 
during antibiotic therapy or lack of radiographic improve
-
ment over time are poor prognostic signs and also raise 
concerns about secondary or alternative pulmonary pro
-
cesses. Clearing of pulmonary opacities in patients with 
CAP can take 6 weeks or longer. Clearance is usually quick
-
est in younger patients, nonsmokers, and those with only 
single-lobe involvement.
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CMDT 2019
D. Special Examinations
Patients with CAP who have significant pleural fluid col
-
lections may require diagnostic thoracentesis (glucose, 
lactate dehydrogenase [LD], and total protein levels; leuko
-
cyte count with differential; pH determination) with pleu
-
ral fluid Gram stain and culture. Positive pleural cultures 
indicate the need for tube thoracostomy drainage.
Patients with cavitary opacities should have sputum 
fungal and mycobacterial cultures.
Sputum induction and fiberoptic bronchoscopy to obtain 
samples of lower respiratory secretions are indicated in 
patients who cannot provide expectorated sputum samples 
or who may have 
P jirovecii
 or 
M tuberculosis
 pneumonia.
Serologic assays, polymerase chain reaction tests, spe
-
cialized culture tests, and other diagnostic tests for organ
-
isms such as viruses, 
, 
, and 
C 
 may be performed when these diagnoses are 
 
»
The differential diagnosis of lower respiratory tract infec
-
tion is extensive and includes upper respiratory tract infec
-
tions, reactive airway diseases, heart failure, cryptogenic 
organizing pneumonitis, lung cancer, pulmonary vasculi
-
tis, pulmonary thromboembolic disease, and atelectasis.
 
»
Treatment
Two general principles guide antibiotic therapy once the 
diagnosis of CAP is established: 
prompt
 initiation of a 
medication to which the etiologic pathogen is 
susceptible.
In patients who require specific diagnostic evaluation, 
sputum and blood culture specimens should be obtained 
prior to initiation of antibiotics. Since early administration of 
antibiotics to acutely ill patients is associated with improved 
outcomes, obtaining other diagnostic specimens or test 
results should not delay the initial dose of antibiotics.
Optimal antibiotic therapy would be pathogen directed, 
but a definitive microbiologic diagnosis is rarely available 
on or within 6 hours of presentation. A syndromic approach 
to therapy, based on clinical presentation and chest imag
-
ing, does not reliably predict the microbiology of CAP . 
Therefore, initial antibiotic choices are typically empiric, 
based on acuity (treatment as an outpatient, inpatient, or in 
the ICU), patient risk factors for specific pathogens, and 
local antibiotic resistance patterns (Table 9–9).
Since 
 remains a common cause of CAP 
in all patient groups, local prevalence of drug-resistant 
S 
 significantly affects initial antibiotic choice. 
Prior treatment with one antibiotic in a pharmacologic 
class (eg, beta-lactam, macrolide, fluoroquinolone) predis
-
poses the emergence of drug-resistant 
, with 
resistance developing against that class of antibiotics to 
which the pathogen was previously exposed. Definitions of 
resistance have shifted based on observations of continued 
clinical efficacy at achievable serum levels. In CAP , for 
parenteral penicillin G or oral amoxicillin, susceptible 
strains have a minimum inhibitory concentration (MIC) 
 
2 mcg/mL or less; intermediate resistance is defined as an 
MIC between 2 mcg/mL and 4 mcg/mL because treatment 
failures are uncommon with MIC 4 mcg/mL or less. Mac
-
rolide resistance has increased; approximately one-third of 
 isolates now show in vitro resistance to mac
-
rolides. Treatment failures have been reported but remain 
rare compared to the number of patients treated; current in 
vivo efficacy appears to justify maintaining macrolides as 
first-line therapy except in areas where there is a high 
prevalence of resistant strains. 
 resistant to 
fluoroquinolones is rare in the United States (1% to levo
-
floxacin, 2% to ciprofloxacin) but is increasing.
Community-acquired methicillin-resistant 
S aureus
 
(CA-MRSA) is genetically and phenotypically different 
from hospital-acquired MRSA strains. CA-MRSA is a rare

S aureus
 
from hospital-acquired MRSA strains. CA-MRSA is a rare 
cause of necrotizing pneumonia, empyema, respiratory 
failure, and shock; it appears to be associated with prior 
influenza infection. Linezolid may be preferred to vancomycin 
in treatment of CA-MRSA pulmonary infection. For expanded 
discussions of specific antibiotics, see Chapters 30 and e1.
A. Treatment of Outpatients
See Table 9–9 for specific medication dosages. The most 
common etiologies of CAP in outpatients who do not 
require hospitalization are 
; 
M pneumoniae; 
C pneumoniae;
 and respiratory viruses, including influ
-
enza. For previously healthy patients with no recent 
 
(90 days) use of antibiotics, the recommended treatment 
is a macrolide (clarithromycin or azithromycin) or 
doxycycline.
In patients at risk for drug resistance (antibiotic therapy 
within the past 90 days, age greater than 65 years, comor
-
bid illness, immunosuppression, exposure to a child in 
daycare), the recommended treatment is a respiratory fluo
-
roquinolone (moxifloxacin, gemifloxacin, or levofloxacin) 
or a macrolide plus a beta-lactam (high-dose amoxicillin 
and amoxicillin-clavulanate are preferred to cefpodoxime 
and cefuroxime).
In regions where there is a high incidence of macrolide-
resistant 
, initial therapy in patients with no 
comorbidities may include a respiratory fluoroquinolone 
or the combination of a beta-lactam added to a macrolide.
There are limited data to guide recommendations for 
duration of treatment. The decision should be influenced 
by the severity of illness, etiologic pathogen, response to 
therapy, other medical problems, and complications. Most 
experts recommend administering a minimum of 5 days of 
therapy and continuing antibiotics until the patient is 
afebrile for 48–72 hours.
B. Treatment of Hospitalized and ICU Patients
The most common etiologies of CAP in patients who require 
hospitalization but not intensive care are 
, 
 
M pneumoniae, C pneumoniae, H influenzae
, 
 
species, and respiratory viruses. Some patients have aspira
-
tion as an immediate precipitant to the CAP without a spe
-
cific bacterial etiology. First-line therapy in hospitalized 
patients is a respiratory fluoroquinolone (eg, moxifloxacin, 
gemifloxacin, or levofloxacin) or the combination of a mac
-
rolide (clarithromycin or azithromycin) plus a beta-lactam 
(cefotaxime, ceftriaxone, or ampicillin) (see Table 9–9).
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Almost all patients admitted to a hospital for treat
-
ment of CAP receive intravenous antibiotics. However, no 
studies in hospitalized patients demonstrated superior 
outcomes with intravenous antibiotics compared with 
oral antibiotics, as long as patients were able to tolerate 
the oral therapy and the medication was well absorbed. 
Duration of inpatient antibiotic treatment is the same as 
for outpatients.
The most common etiologies of CAP in patients who 
require admission to intensive care are 
, 
 species, 
H influenzae, Enterobacteriaceae
 spe
-
cies, 
S aureus
, and 
 species. First-line therapy 
in ICU patients with CAP is either azithromycin or a respi
-
ratory fluoroquinolone (moxifloxacin, gemifloxacin, or 
levofloxacin) combined with an antipneumococcal beta-
lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam). 
In patients at risk for 
 infection, one of two 
following regimens can be used: an antipneumococcal, 
antipseudomonal beta-lactam (piperacillin-tazobactam, 
cefepime, imipenem, meropenem) plus ciprofloxacin or 
levofloxacin 
or
 the above antipneumococcal beta-lactam 
plus an aminoglycoside (gentamicin, tobramycin, amika
-
cin) plus either azithromycin or a respiratory fluoroquino
-
lone (moxifloxacin, gemifloxacin, or levofloxacin).
 
»
Pneumococcal vaccines have the potential to prevent or 
lessen the severity of pneumococcal infections in immuno
-
competent patients. Two pneumococcal vaccines for adults 
are available and approved for use in the United States: one 
containing capsular polysaccharide antigens of 23 common 
strains of 
 in use for many years (Pneumovax 23) 
and a conjugate vaccine containing 13 common strains 
approved for adult use in 2011 (Prevnar-13). Current recom
-
mendations are for sequential administration of the two 
vaccines in those aged 65 years or older and in immunocom
-
promised persons. Adults with chronic illness that increases 
the risk of CAP (see Chapter 30) should receive the 23-valent 
vaccine regardless of age. Immunocompromised patients 
and those at highest risk for fatal pneumococcal infections 
should receive a single revaccination of the 23-valent vaccine 
5 years after the first vaccination regardless of age. Immuno
-
competent persons 65 years of age or older should receive a 
second dose of the 23-valent vaccine if the patient first 
received the vaccine 6 or more years previously and was 
under 65 years old at the time of first vaccination.
The seasonal influenza vaccine is effective in preventing 
severe disease due to influenza virus with a resulting posi
-
tive impact on both primary influenza pneumonia and 
secondary bacterial pneumonias. The seasonal influenza 
vaccine is administered annually to persons at risk for 
complications of influenza infection (aged 65 years or 
older, residents of long-term care facilities, patients with 
pulmonary or cardiovascular disorders, patients recently 
hospitalized with chronic metabolic disorders) as well as 
health care workers and others who are able to transmit 
influenza to high-risk patients.
Hospitalized patients who would benefit from pneumo
-
coccal and influenza vaccines should be vaccinated during 
hospitalization. The vaccines can be given simultaneously, and 
may be administered as soon as the patient has stabilized.
 
»
Once a diagnosis of CAP is made, the first management deci
-
sion is to determine the site of care: Is it safe to treat the 
patient at home or does he or she require hospital or intensive 
care admission? There are two widely used clinical prediction 
rules available to guide admission and triage decisions, the 
Pneumonia Severity Index (PSI)
 and the 
CURB-65.
A. Hospital Admission Decision
The PSI is a validated prediction model that uses 20 items 
from demographics, medical history, physical examination,

 and the 
CURB-65.
from demographics, medical history, physical examination, 
laboratory results, and imaging to stratify patients into five 
risk groups. The PSI is weighted toward discrimination at 
low predicted mortality. In conjunction with clinical judg
-
ment, it facilitates safe decisions to treat CAP in the outpa
-
tient setting. An online PSI risk calculator is available at 
https://www.thecalculator.co/health/Pneumonia-Severity-
Index-(PSI)-Calculator-977.html. The CURB-65 assesses 
five simple, independent predictors of increased mortality 
(
c
onfusion, 
u
remia, 
r
espiratory rate, 
b
lood pressure, and age 
greater than 
65
) to calculate a 30-day predicted mortality 
(https://www.mdcalc.com/curb-65-score-pneumonia-
severity). Compared with the PSI, the simpler CURB-65 is 
less discriminating at low mortality but excellent at identify
-
ing patients with high mortality who may benefit from ICU-
level care. A modified version (CRB-65) dispenses with 
serum blood urea nitrogen and eliminates the need for labo
-
ratory testing. Both have the advantage of simplicity: Patients 
with zero CRB-65 predictors have a low predicted mortality 
(less than 1%) and usually do not need hospitalization; hos
-
pitalization should be considered for those with one or two 
predictors, since they have an increased risk of death; and 
urgent hospitalization (with consideration of ICU admis
-
sion) is required for those with three or four predictors.
B. Intensive Care Unit Admission Decision
Expert opinion has defined major and minor criteria to 
identify patients at high risk for death. Major criteria are 
septic shock with need for vasopressor support and respi
-
ratory failure with need for mechanical ventilation. Minor 
criteria are respiratory rate 30 breaths or more per minute, 
hypoxemia (defined as Pa
o
2
/F
io
2
 250 or less), hypothermia 
(core temperature less than 36.0°C), hypotension requiring 
aggressive fluid resuscitation, confusion/disorientation, 
multilobar pulmonary opacities, leukopenia due to infec
-
tion with WBC less than 4000/mcL (less than 4.0 × 10
9
/L), 
thrombocytopenia with platelet count less than 100,000/
mcL (less than 100 × 10
9
/L), uremia with blood urea nitro
-
gen 20 mg/dL or more (7.1 mmol/L or more), metabolic 
acidosis, or elevated lactate level. Either one major crite
-
rion or three or more minor criteria of illness severity 
generally require ICU-level care.
In addition to pneumonia-specific issues, good clinical 
practice always makes an admission decision in light of the 
whole patient. Additional factors suggesting need for inpa
-
tient hospitalization include the following:
•	
Exacerbations of underlying disease (eg, heart failure) 
that would benefit from hospitalization.
•	
Other medical or psychosocial needs (such as cognitive 
dysfunction, psychiatric disease, homelessness, drug 
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abuse, lack of outpatient resources, or poor overall 
functional status).
•	
Failure of outpatient therapy, including inability to 
maintain oral intake and medications.
Lee JS et al. Antibiotic therapy for adults hospitalized with 
community-acquired pneumonia: a systematic review. JAMA. 
2016 Feb 9;315(6):593–602. [PMID: 26864413]
Prina E et al. Community-acquired pneumonia. Lancet. 2015 
Sep 12;386(9998):1097–108. [PMID: 26277247]
Uranga A et al. Duration of antibiotic treatment in community-
acquired pneumonia: a multicenter randomized clinical trial. 
JAMA Intern Med. 2016 Sep 1;176(9):1257–65. [PMID: 
27455166]
Wunderink RG et al. Clinical practice. Community-acquired 
pneumonia. N Engl J Med. 2014 Feb 6;370(6):543–51. [PMID: 
24499212]
2. Nosocomial Pneumonia (Hospital-Acquired & 
Ventilator-Associated)
 
»
Hospital-acquired pneumonia (HAP)
 occurs more 
than 48 hours after admission to the hospital or 
other health care facility and excludes any infec
-
tion present at the time of admission.
 
»
Ventilator-associated pneumonia (VAP)
 develops 
more than 48 hours following endotracheal intu
-
bation and mechanical ventilation.
 
»
At least two of the following: fever, leukocytosis, 
purulent sputum.
 
»
New or progressive parenchymal opacity on chest 
radiograph.
 
»
Especially common in patients requiring intensive 
care or mechanical ventilation.
 
»
Hospitalized patients carry different flora with different 
resistance patterns than healthy patients in the community, 
and their health status may place them at higher risk for 
more severe infection. The diagnostic approach and antibi
-
otic treatment of patients with HAP is, therefore, different 
from patients with CAP . Similarly, management of patients 
in whom V AP develops following endotracheal intubation 
and mechanical ventilation should address issues specific 
to this group of patients.
Considered together, these nosocomial pneumonias 
(HAP/V AP) represent an important cause of morbidity and 
mortality despite widespread use of preventive measures, 
advances in diagnostic testing, and potent new antimicrobial 
agents. HAP is the second most common cause of infection 
among hospital inpatients and is the leading cause of death 
due to infection with mortality rates ranging from 20% to 
50%. While a minority of cases occurs in ICU patients, the 
highest-risk patients are those in ICUs or who are being 
mechanically ventilated; these patients also experience higher 
morbidity and mortality from HAP . Definitive identification 
of the infectious cause of a lower respiratory infection is 
rarely available on presentation, thus, rather than pathogen-
directed antibiotic treatment, the choice of empiric therapy is 
usually informed by epidemiologic and patient data.
 
»
HAP develops more than 48 hours after admission to the 
hospital and V AP develops in a mechanically ventilated 
patient more than 48 hours after endotracheal intubation.
Three factors distinguish nosocomial pneumonia from 
CAP: (1) different infectious causes; (2) different antibiotic 
susceptibility patterns, specifically, a higher incidence of drug 
resistance; and (3) poorer underlying health status of patients 
putting them at risk for more severe infections. Since access to 
the lower respiratory tract occurs primarily through micro
-
aspiration, nosocomial pneumonia starts with a change in 
upper respiratory tract flora. Colonization of the pharynx and 
possibly the stomach with bacteria is the most important step 
in the pathogenesis of nosocomial pneumonia. Pharyngeal 
colonization is promoted by exogenous factors (eg, instru
-
mentation of the upper airway with nasogastric and endotra
-
cheal tubes; contamination by dirty hands, equipment, and 
contaminated aerosols; and treatment with broad-spectrum 
antibiotics that promote the emergence of drug-resistant

-
antibiotics that promote the emergence of drug-resistant 
organisms) and patient factors (eg, malnutrition, advanced 
age, altered consciousness, swallowing disorders, and under
-
lying pulmonary and systemic diseases). Within 48 hours of 
admission, 75% of seriously ill hospitalized patients have their 
upper airway colonized with organisms from the hospital 
environment. Impaired cellular and mechanical defense 
mechanisms in the lungs of hospitalized patients raise the risk 
of infection after aspiration has occurred.
Gastric acid may play a role in protection against noso
-
comial pneumonias. Observational studies have suggested 
that elevation of gastric pH due to antacids, H
2
-receptor 
antagonists, proton-pump inhibitors (PPIs), or enteral 
feeding is associated with gastric microbial overgrowth, 
tracheobronchial colonization, and HAP/V AP . Sucralfate, a 
cytoprotective agent that does not alter gastric pH, is asso
-
ciated with a trend toward a lower incidence of V AP . The 
Infectious Diseases Society of America and other profes
-
sional organizations recommend that acid-suppressive 
medications (H
2
-receptor antagonists and PPIs) be given 
only to patients at high risk for stress gastritis.
The microbiology of the nosocomial pneumonias dif
-
fers from CAP but is substantially the same among HAP 
and V AP . The most common organisms responsible for HAP 
include 
S aureus
 (both methicillin-sensitive 
S aureus
 and 
MRSA), 
, gram-negative rods, including non-
extended spectrum beta-lactamase (non-ESBL)–producing 
and ESBL-producing 
(Enterobacter
 species, 
K pneumoniae
, 
and 
Escherichia coli)
 organisms. V AP patients may be 
infected with 
Acinetobacter species
 and 
S maltophilia
. 
Anaerobic organisms (bacteroides, anaerobic streptococci, 
fusobacterium) may also cause pneumonia in the hospital
-
ized patient; when isolated, they are commonly part of a 
polymicrobial flora. Mycobacteria, fungi, chlamydiae, 
viruses, rickettsiae, and protozoal organisms are uncom
-
mon causes of nosocomial pneumonias.
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»
The symptoms and signs associated with nosocomial pneu
-
monias are nonspecific; however, two or more clinical find
-
ings (fever, leukocytosis, purulent sputum) in the setting of 
a new or progressive pulmonary opacity on chest radio
-
graph were approximately 70% sensitive and 75% specific 
for the diagnosis of V AP in one study. Other findings 
include those listed above for CAP .
The differential diagnosis of new lower respiratory 
tract symptoms and signs in hospitalized patients includes 
heart failure, atelectasis, aspiration, ARDS, pulmonary 
thromboembolism, pulmonary hemorrhage, and medica
-
tion reactions.
Diagnostic evaluation for suspected nosocomial pneumo
-
nia includes blood cultures from two different sites. Blood 
cultures can identify the pathogen in up to 20% of all 
patients with nosocomial pneumonias; positivity is associ
-
ated with increased risk of complications and other sites of 
infection. Blood counts and clinical chemistry tests do not 
establish a specific diagnosis; however, they help define the 
severity of illness and identify complications. The assess
-
ment of oxygenation by an arterial blood gas or pulse 
oximetry determination helps define the severity of illness 
and determines the need for assisted ventilation. Thora
-
centesis for pleural fluid analysis should be considered in 
patients with pleural effusions.
Examination of lower respiratory tract secretions is 
attended by the same disadvantages as in CAP . Gram stains 
and cultures of sputum are neither sensitive nor specific in 
the diagnosis of nosocomial pneumonias. The identifica
-
tion of a bacterial organism by culture of lower respiratory 
tract secretions does not prove that the organism is a lower 
respiratory tract pathogen. However, it can be used to help 
identify bacterial antibiotic sensitivity patterns and as a 
guide to adjusting empiric therapy.
C. Imaging
Radiographic findings in HAP/V AP are nonspecific and 
often confounded by other processes that led initially to 
hospitalization or ICU admission. (See CAP above.)
When HAP is suspected in a patient who subsequently 
requires mechanical ventilation, secretions obtained by 
spontaneous expectoration, sputum induction, nasotracheal 
suctioning, and endotracheal aspiration should be cultured. 
For patients with suspected V AP , endotracheal aspiration 
using a sterile suction catheter with semi-quantitative cul
-
tures of lower respiratory tract secretions is the recom
-
mended method of evaluation.
 
»
Treatment
The initial treatment of HAP and V AP is usually empiric, 
based on risk factors for MRSA and multiple drug-resistant 
pathogens (Table 9–10) as well as local antibiograms and 
mortality risk (Table 9–11). Each hospital should generate 
antibiograms to guide the optimal choice of antibiotics 
with the goals of reducing exposure to unnecessary antibi
-
otics and the development of antibiotic resistance and thus 
minimizing patient harm. Because of the high mortality 
rate, therapy should be started as soon as pneumonia is 
suspected. After results of sputum, blood, and pleural fluid 
cultures are available, it may be possible to change initially 
broad to more specific therapy. Endotracheal aspiration 
cultures have significant negative predictive value but lim
-
ited positive predictive value in the diagnosis of specific 
infectious causes of HAP/V AP . If an invasive diagnostic 
approach to suspected V AP using quantitative culture of 
bronchoalveolar lavage (BAL), protected specimen brush 
(PSB), or blind bronchial sampling (BBS) is used, antibiot
-
ics can be withheld when results are below a diagnostic 
threshold (BAL less than 10
4
 CFU/mL, PSB or BBS less than 
Table 9–10.
 
Risk factors for multidrug resistant (MDR) 
pathogens, methicillin-resistant 
 
(MRSA), and 
 and other gram-negative

4
 
 and other gram-negative 
bacilli in patients with hospital-acquired pneumonia 
(HAP) and ventilator-associated pneumonia (VAP).
Risk factors for MDR pathogens
 
An
tibiotic therapy in the preceding 90 days
 
S
eptic shock
 
A
cute respiratory distress syndrome preceding VAP
 
5 or mor
e days in hospital prior to occurrence of HAP/VAP
 
A
cute renal replacement therapy prior to HAP/VAP onset
 
T
reatment in a unit where > 10% of gram-negative isolates 
 
ar
e resistant to an agent being considered for monotherapy
 
T
reatment in a unit where local antibiotic susceptibility rates 
 
ar
e not known
Risk factors for MRSA
 
An
 
Renal r
eplacement therapy in the preceding 30 days
 
U
se of gastric acid suppressive agents
 
P
ositive culture or prior MRSA colonization, especially in the 
 
pr
eceding 90 days
 
Hospitaliza
tion in a unit where > 20% of 
S aureus
 isolates 
 
ar
e MRSA
 
tion in a unit where prevalence of MRSA is not known
Risk factors for 
 and other gram-
 
nega
tive bacilli
 
An
 
S
tructural lung disease (COPD, especially with recurrent 
 
e
xacerbations; bronchiectasis; or cystic fibrosis)
 
Rec
ent hospitalizations, especially with manipulation of the 
 
aer
odigestive tract (nasoenteric nutrition, intubation)
 
H
igh-quality Gram stain of respiratory secretions with 
 
numer
ous and predominant gram-negative bacilli
 
P
ositive culture for 
 in the past year
HAP , hospital-acquired pneumonia; MDR, multidrug resistant; 
MRSA, methicillin-resistant 
Staphylococcus aureus;
 VAP , ventilator-
associated pneumonia.
Data from Kalil AC et al. Management of adults with hospital-
acquired and ventilator-associated pneumonia: 2016 Clinical 
Practice Guidelines by the Infectious Diseases Society of America 
and the American Thoracic Society. Clin Infect Dis. 2016 Sept 1;
 
63(5):e61–111.
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CMDT 2019
Table 9–11.
 
Recommended initial empiric antibiotics for hospital-acquired pneumonia (HAP) and ventilator-
 
associated pneumonia (VAP).
HAP not at high risk for mortality, or VAP with no risk factors for MDR, MRSA, or 
 and other gram-negative bacilli
 
USE 
one
 of the following:
  
P
iperacillin-tazobactam 4.5 g intravenously every 6 hours
1
  
C
efepime, 2 g intravenously every 8 hours
1
  
L
evofloxacin, 750 mg intravenously daily
  
I
mipenem, 500 mg intravenously every 6 hours
1
  
M
eropenem, 1 g intravenously every 8 hours
1
HAP or VAP with risk factors for MRSA but no risk factors for MDR, 
, and other gram-negative bacilli
 
USE 
one
  
P
iperacillin-tazobactam, 4.5 g intravenously every 6 hours
1
  
C
1
  
C
eftazidime, 2 g intravenously every 8 hours
  
L
  
Cipr
ofloxacin, 400 mg intravenously every 8 hours
  
I
1
  
M
1
  
A
ztreonam, 2 g intravenously every 8 hours
 
PLUS 
one
   
V
ancomycin, 15 mg/kg intravenously every 8–12 hours with goal to target trough level = 15–20 mg/mL (consider a loading dose of 
 
25–30 mg/k
g once for severe illness)
2
  
Linez
olid, 600 mg intravenously every 12 hours
HAP with risk factors for 
 and other gram-negative bacilli, but no risk factors for MRSA and not at high risk for mortality
 
USE 
one
  
P
1
  
C
1
  
C
  
I
1
  
M
1
  
A
 
PLUS 
one
  
L
  
Cipr
  
G
entamicin, 5–7 mg/kg intravenously daily
2
  
T
obramycin, 5–7 mg/kg intravenously daily
2
  
A
HAP at high risk for mortality or VAP with risk factors for MRSA 
and
 risk factors for MDR, 
 
USE 
one
  
P
1
  
C
1
  
C
  
I
1
  
M
1
  
A
 
PLUS 
one
  
L
  
Cipr
  
Amik
acin, 15–20 mg/kg intravenously daily
2
  
G
2
  
T
2
  
M
1
  
C
olistin, 5 mg/kg intravenously once (loading dose) followed by 2.5 mg × (1.5 × CrCl + 30) intravenously every 12 hours (maintenance dose)
  
P
olymyxin B, 2.5–3.0 mg/kg per day divided in 2 daily intravenous doses
 
PLUS 
one
   
V
 
25–30 mg/k
2
  
Linez
CrCl, creatinine clearance; HAP , hospital-acquired pneumonia; MDR, multidrug resistant; MRSA, methicillin-resistant 
; 
VAP , ventilator-associated pneumonia.
1
Extended infusions may be appropriate.
2
Drug level monitoring and adjustment of dosing are required.
Data from Kalil AC et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice 
Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sept 1;63(5):e61–111.

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10
3
 CFU/mL). Duration of antibiotic therapy should be 
individualized based on the pathogen, severity of illness, 
response to therapy, and comorbid conditions. Data from 
one large trial assessing treatment outcomes in V AP sug
-
gested that 8 days of antibiotics is as effective as 15 days, 
except in cases caused by 
.
For expanded discussions of specific antibiotics, see 
Chapter 30.
Kalil AC et al. Management of adults with hospital-acquired and 
ventilator-associated pneumonia: 2016 Clinical Practice 
Guidelines by the Infectious Diseases Society of America and 
the American Thoracic Society. Clin Infect Dis. 2016 Sept 1;
 
63(5):e61–111. [PMID: 27418577]
Pugh R et al. Short-course versus prolonged-course antibiotic 
therapy for hospital-acquired pneumonia in critically ill 
adults. Cochrane Database Syst Rev. 2015 Aug 24;(8):
 
CD007577. [PMID: 26301604]
3. Anaerobic Pneumonia & Lung Abscess
 
»
History of or predisposition to aspiration.
 
»
Indolent symptoms, including fever, weight loss, 
and malaise.
 
»
Poor dentition.
 
»
Foul-smelling purulent sputum (in many patients).
 
»
Infiltrate in dependent lung zone, with single or 
multiple areas of cavitation or pleural effusion.
 
»
Aspiration of small amounts of oropharyngeal secretions 
occurs during sleep in normal individuals but rarely causes 
disease. Sequelae of aspiration of larger amounts of mate
-
rial include nocturnal asthma, chemical pneumonitis, 
mechanical obstruction of airways by particulate matter, 
bronchiectasis, and pleuropulmonary infection. Individu
-
als predisposed to disease induced by aspiration include 
those with depressed levels of consciousness due to drug or 
alcohol use, seizures, general anesthesia, or central nervous 
system disease; those with impaired deglutition due to 
esophageal disease or neurologic disorders; and those with 
tracheal or nasogastric tubes, which disrupt the mechani
-
cal defenses of the airways.
Periodontal disease and poor dental hygiene, which 
increase the number of anaerobic bacteria in aspirated 
material, are associated with a greater likelihood of anaero
-
bic pleuropulmonary infection. Aspiration of infected 
oropharyngeal contents initially leads to pneumonia in 
dependent lung zones, such as the posterior segments of 
the upper lobes and superior and basilar segments of the 
lower lobes. Body position at the time of aspiration deter
-
mines which lung zones are dependent. The onset of symp
-
toms is insidious. By the time the patient seeks medical 
attention, necrotizing pneumonia, lung abscess, or empy
-
ema may be apparent.
In most cases of aspiration and necrotizing pneumonia, 
lung abscess, and empyema, multiple species of anaerobic 
bacteria are causing the infection. Most of the remaining 
cases are caused by infection with both anaerobic and aero
-
bic bacteria. 
Prevotella melaninogenica
, 
Peptostreptococcus
, 
Fusobacterium nucleatum
, and 
Bacteroides
 species are 
commonly isolated anaerobic bacteria.
 
»
Patients with anaerobic pleuropulmonary infection usually 
present with constitutional symptoms, such as fever, weight 
loss, and malaise. Cough with expectoration of foul-smelling 
purulent sputum suggests anaerobic infection, though the 
absence of productive cough does not rule out such an infec
-
tion. Dentition is often poor. Patients are rarely edentulous; 
if so, an obstructing bronchial lesion is usually present.
Expectorated sputum is inappropriate for culture of anaer
-
obic organisms because of contaminating mouth flora. 
Representative material for culture can be obtained only by 
transthoracic aspiration, thoracentesis, or bronchoscopy 
with a protected brush. Transthoracic aspiration is rarely 
indicated, because drainage occurs via the bronchus and 
anaerobic pleuropulmonary infections usually respond 
well to empiric therapy.

C. Imaging
The different types of anaerobic pleuropulmonary infection 
are distinguished on the basis of their radiographic appear
-
ance. 
Lung abscess
 appears as a thick-walled solitary cavity 
surrounded by consolidation. An air-fluid level is usually 
present. Other causes of cavitary lung disease (tuberculosis, 
mycosis, cancer, infarction, granulomatosis with polyangi
-
itis [formerly Wegener granulomatosis]) should be 
excluded. 
Necrotizing pneumonia
 is distinguished by mul
-
tiple areas of cavitation within an area of consolidation. 
Empyema
 is characterized by the presence of purulent 
pleural fluid and may accompany either of the other two 
radiographic findings. Ultrasonography is of value in locat
-
ing fluid and may also reveal pleural loculations.
 
»
Treatment
Medications of choice are clindamycin (600 mg intrave
-
nously every 8 hours until improvement, then 300 mg orally 
every 6 hours) or amoxicillin-clavulanate (875 mg/125 mg 
orally every 12 hours). Penicillin (amoxicillin, 500 mg every 
8 hours, or penicillin G, 1–2 million units intravenously 
every 4–6 hours) plus metronidazole (500 mg orally or 
intravenously every 8–12 hours) is another option. Penicil
-
lin alone is inadequate treatment for anaerobic pleuropul
-
monary infections because an increasing number of 
anaerobic organisms produce beta-lactamases, and up to 
20% of patients do not respond to penicillins. Antibiotic 
therapy for anaerobic pneumonia should be continued until 
the chest radiograph improves, a process that may take a 
CMDT19_Ch09_p0252-p0333.indd   286

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CMDT 2019
month or more; patients with lung abscesses should be 
treated until radiographic resolution of the abscess cavity is 
demonstrated. Anaerobic pleuropulmonary disease requires 
adequate drainage with tube thoracostomy for the treat
-
ment of empyema. Open pleural drainage is sometimes 
necessary because of the propensity of these infections to 
produce loculations in the pleural space.
DiBardino DM et al. Aspiration pneumonia: a review of modern 
trends. J Crit Care. 2015 Feb;30(1):40–8. [PMID: 25129577]
PULMONARY INFILTRATES IN THE 
IMMUNOCOMPROMISED HOST
Pulmonary infiltrates in immunocompromised patients 
(patients with HIV disease, absolute neutrophil counts less 
than 1000/mcL [less than 1.0 × 10
9
/L], current or recent expo
-
sure to myelosuppressive or immunosuppressive medications, 
or those currently taking more than 5 mg/day of prednisone) 
may arise from infectious or noninfectious causes. Infection 
may be due to bacterial, mycobacterial, fungal, protozoal, 
helminthic, or viral pathogens. Noninfectious processes, such 
as pulmonary edema, alveolar hemorrhage, medication reac
-
tions, pulmonary thromboembolic disease, malignancy, and 
radiation pneumonitis, may mimic infection.
Although almost any pathogen can cause pneumonia in 
an immunocompromised host, two clinical tools help the 
clinician narrow the differential diagnosis. The first is knowl
-
edge of the underlying immunologic defect. Specific immu
-
nologic defects are associated with particular infections. 
Defects in humoral immunity predispose to bacterial infec
-
tions; defects in cellular immunity lead to infections with 
viruses, fungi, mycobacteria, and protozoa. Neutropenia and 
impaired granulocyte function predispose to infections from 
S aureus
, 
, gram-negative bacilli, and 
Candida
. 
Second, the time course of infection also provides clues to the 
etiology of pneumonia in immunocompromised patients. A 
fulminant pneumonia is often caused by bacterial infection, 
whereas an insidious pneumonia is more apt to be caused by 
viral, fungal, protozoal, or mycobacterial infection. Pneumo
-
nia occurring within 2–4 weeks after organ transplantation is 
usually bacterial, whereas several months or more after trans
-
plantation 
, viruses (eg, cytomegalovirus) and fungi 
(eg, 
) are encountered more often.
 
»
Chest radiography is rarely helpful in narrowing the differ
-
ential diagnosis. Examination of expectorated sputum for 
bacteria, fungi, mycobacteria, 
, and 
 is 
important and may preclude the need for expensive, inva
-
sive diagnostic procedures. Sputum induction is often nec
-
essary for diagnosis. The sensitivity of induced sputum for 
detection of 
 depends on institutional expertise, 
number of specimens analyzed, and detection methods.
Routine evaluation frequently fails to identify a caus
-
ative organism. The clinician may begin empiric antimicro
-
bial therapy before proceeding to invasive procedures, such 
as bronchoscopy, transthoracic needle aspiration, or open 
lung biopsy. The approach to management must be based 
on the severity of the pulmonary infection, the underlying 
disease, the risks of empiric therapy, and local expertise and 
experience with diagnostic procedures. BAL using the flex
-
ible bronchoscope is a safe and effective method for obtain
-
ing representative pulmonary secretions for microbiologic 
studies. It involves less risk of bleeding and other complica
-
tions than bronchial brushing and transbronchial biopsy. 
BAL is especially suitable for the diagnosis of 
 
pneumonia in patients with AIDS when induced sputum 
analysis is negative. Surgical lung biopsy, now often per
-
formed by video-assisted thoracoscopy, provides the defini
-
tive option for diagnosis of pulmonary infiltrates in the 
immunocompromised host. However, a specific diagnosis is

-
-
immunocompromised host. However, a specific diagnosis is 
obtained in only about two-thirds of cases, and the informa
-
tion obtained may not affect the outcome.
Alanio A et al; 5th European Conference on Infections in Leuke
-
mia (ECIL-5), a joint venture of The European Group for 
Blood and Marrow Transplantation (EBMT), The European 
Organization for Research and Treatment of Cancer 
(EORTC), the Immunocompromised Host Society (ICHS) 
and The European LeukemiaNet (ELN). ECIL guidelines for 
the diagnosis of 
 pneumonia in patients 
with haematological malignancies and stem cell transplant 
recipients. J Antimicrob Chemother. 2016 Sep;71(9):2386–96. 
[PMID: 27550991]
Bassetti M et al. Overview of fungal infections—the Italian expe
-
rience. Semin Respir Crit Care Med. 2015 Oct;36(5):796–805. 
[PMID: 26398544]
Letourneau AR et al. Pneumonia in the immunocompromised 
host. Curr Opin Pulm Med. 2014 May;20(3):272–9. [PMID: 
24626236]
Maschmeyer G et al; 6th European Conference on Infections in 
Leukemia (ECIL-6), a joint venture of The European Group 
for Blood and Marrow Transplantation (EBMT), The Euro
-
pean Organization for Research and Treatment of Cancer 
(EORTC), the International Immunocompromised Host 
Society (ICHS) and The European LeukemiaNet (ELN). ECIL 
guidelines for treatment of 
 pneumonia 
in non-HIV-infected haematology patients. J Antimicrob 
Chemother. 2016 Sep;71(9):2405–13. [PMID: 27550993]
PULMONARY TUBERCULOSIS
 
»
Fatigue, weight loss, fever, night sweats, and pro
-
ductive cough.
 
»
Risk factors for acquisition of infection: household 
exposure, incarceration, drug use, travel to an 
endemic area.
 
»
Chest radiograph: pulmonary opacities, most 
often apical.
 
»
Acid-fast bacilli on smear of sputum or sputum 
culture positive for 
.
 
»
Tuberculosis is one of the world’s most widespread and 
deadly illnesses. 
, the organism that causes 
tuberculosis infection and disease, infects one-third of the 
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world’s population. In 2014, there were 9.6 million new 
cases of tuberculosis worldwide with 1.5 million people 
dying of the disease. In the United States, an estimated 
 
11 million people are infected with 
 and in 
2014 there were 9421 active cases. By 2015, the number of 
cases of tuberculosis increased for the first time in 23 years 
in 29 US states, particularly in Texas, California, Florida, 
and New Y ork. Tuberculosis occurs disproportionately 
among disadvantaged populations, such as the malnour
-
ished, homeless, and those living in overcrowded and sub
-
standard housing. There is an increased occurrence of 
tuberculosis among HIV-positive individuals.
Infection with 
 begins when a susceptible 
person inhales airborne droplet nuclei containing viable 
organisms. Tubercle bacilli that reach the alveoli are ingested 
by alveolar macrophages. Infection follows if the inoculum 
escapes alveolar macrophage microbicidal activity. Once 
infection is established, lymphatic and hematogenous dis
-
semination of tuberculosis typically occurs before the 
development of an effective immune response. This stage 
of infection, 
primary tuberculosis,
 is usually clinically and 
radiographically silent. In most persons with intact cell-
mediated immunity, T-cells and macrophages surround 
the organisms in granulomas that limit their multiplication 
and spread. The infection is contained but not eradicated, 
since viable organisms may lie dormant within granulomas 
for years to decades.
Individuals with 
latent tuberculosis infection
 do not 
have active disease and cannot transmit the organism to 
others. However, reactivation of disease may occur if the 
host’s immune defenses are impaired. 
Active tuberculosis
 
will develop in approximately 6% of individuals with latent 
tuberculosis infection who are not given preventive therapy; 
half of these cases occur in the 2 years following primary 
infection. Diverse conditions such as gastrectomy, silicosis, 
diabetes mellitus, and an impaired immune response (eg, 
HIV infection; therapy with corticosteroids, tumor necrosis 
factor inhibitors or other immunosuppressive drugs) are 
associated with an increased risk of reactivation.
In approximately 5% of cases, the immune response is 
inadequate to contain the primary infection and 
progres
-
sive primary tuberculosis
 develops, accompanied by both 
pulmonary and constitutional symptoms as described 
below. The clinical presentation does not definitively dis
-
tinguish primary disease from reactivation of latent tuber
-
culosis infection. Standard teaching has held that 90% of 
tuberculosis in adults represents activation of latent dis
-
ease. However, DNA fingerprinting of the bacillus suggests 
that as many as one-third of new cases of tuberculosis in 
urban populations are primary infections resulting from 
person-to-person transmission.
The prevalence of drug-resistant strains is increasing 
worldwide; however, in the United States, the rate of drug-
resistant isolates has fallen to less than 1.3%. Risk factors 
for drug resistance include immigration from countries 
with a high prevalence of drug-resistant tuberculosis, close 
and prolonged contact with individuals with drug-resistant 
tuberculosis, unsuccessful previous therapy, and nonad
-
herence to treatment. Drug resistance may be single or 
multiple. 
Drug-resistant tuberculosis
 is resistant to one 
first-line antituberculous drug, either isoniazid or rifampin. 
Multidrug-resistant tuberculosis
 is resistant to isoniazid 
and rifampin, and possibly additional agents. 
Extensively 
drug-resistant tuberculosis
 is resistant to isoniazid, 
rifampin, fluoroquinolones, and either aminoglycosides or 
capreomycin or both. Outcomes of drug-resistant tubercu
-
losis treatment are worse than when the isolate is drug-
sensitive, but outcomes appear to vary with HIV status. In

-
sensitive, but outcomes appear to vary with HIV status. In 
a review of extensively drug-resistant tuberculosis cases in 
the United States, mortality was 10% and 68% in HIV-
negative and HIV-positive patients, respectively.
 
»
The patient with pulmonary tuberculosis typically presents 
with slowly progressive constitutional symptoms of malaise, 
anorexia, weight loss, fever, and night sweats. Chronic cough 
is the most common pulmonary symptom. It may be dry at 
first but typically becomes productive of purulent sputum as 
the disease progresses. Blood-streaked sputum is common, 
but significant hemoptysis is rarely a presenting symptom; 
life-threatening hemoptysis may occur in advanced disease. 
Dyspnea is unusual unless there is extensive disease. Rarely, 
the patient is asymptomatic. On physical examination, the 
patient appears chronically ill and malnourished. On chest 
examination, there are no physical findings specific for 
tuberculosis infection. The examination may be normal or 
may reveal classic findings such as posttussive apical rales.
Definitive diagnosis depends on recovery of 
 
from cultures or identification of the organism by DNA or 
RNA amplification techniques. Three consecutive morning 
sputum specimens are advised. Fluorochrome staining 
with rhodamine-auramine of concentrated, digested spu
-
tum specimens is performed initially as a screening 
method, with confirmation by the Kinyoun or Ziehl-
Neelsen stains. Demonstration of acid-fast bacilli on spu
-
tum smear does not establish a diagnosis of 
, 
since nontuberculous mycobacteria may colonize the air
-
ways and are increasingly recognized to cause clinical ill
-
ness in patients with underlying structural lung disease.
In patients thought to have tuberculosis who cannot 
produce satisfactory specimens or when the smear of the 
spontaneously expectorated sputum is negative for acid-
fast bacilli, sputum induction with 3% hypertonic saline 
should be performed. Flexible bronchoscopy with bron
-
chial washings has similar diagnostic yield to induced 
sputum; transbronchial lung biopsies do not significantly 
increase the diagnostic yield but may lead to earlier diag
-
nosis by identifying tissue granulomas. Post-bronchoscopy 
expectorated sputum specimens should be collected. Posi
-
tive blood cultures for 
 are uncommon in 
patients with normal CD4 cell counts, but the organism 
may be cultured from blood in up to 50% of HIV-seropos
-
itive patients with tuberculosis whose CD4 cell counts are 
less than 100/mcL (less than 0.1 × 10
9
/L).
Traditional light-microscopic examination of stained 
sputum for acid-fast bacilli and culture of sputum specimens 
CMDT19_Ch09_p0252-p0333.indd   288

289
 
CMDT 2019
remain the mainstay of tuberculosis diagnosis. The slow rate 
of mycobacterial growth, the urgency to provide early, 
appropriate treatment to patients to improve their outcomes 
and limit community spread, and concerns about potential 
drug toxicities in patients treated empirically who do not 
have tuberculosis infection have fostered the use of rapid 
diagnostic techniques (Table 9–12). Molecular diagnostics 
offer multiple options and many advantages at significantly 
increased expense. Nucleic acid amplification testing not 
only detects 
 (NAAT-TB) but it also identifies 
resistance markers (NAAT-R). NAAT-TB can identify 
M 
 within hours of sputum processing, allowing 
early isolation and treatment, but the negative predictive 
value is low in smear-negative patients. NAAT-R allows 
rapid identification of primary drug resistance and is indi
-
cated in the following patients: (1) those treated previously 
for tuberculosis, (2) those born (or who lived for more than 
1 year) in a country with moderate tuberculosis incidence or 
a high incidence of multiple drug-resistant isolates, (3) con
-
tacts of patients with multidrug-resistant tuberculosis, or (4) 
those who are HIV seropositive. Clinical suspicion remains 
the critical factor in interpreting all these studies. Standard 
drug susceptibility testing of culture isolates is considered 
routine for the first isolate of 
, when a treat
-
ment regimen is failing, and when sputum cultures remain 
positive after 2 months of therapy.
Needle biopsy of the pleura reveals granulomatous 
inflammation in approximately 60% of patients with pleu
-
ral effusions caused by 
. Pleural fluid cul
-
tures are positive for 
 in less than 23–58% of 
cases of pleural tuberculosis. Culture of three pleural 
biopsy specimens combined with microscopic examination 
of a pleural biopsy yields a diagnosis in up to 90% of 
patients with pleural tuberculosis. Tests for pleural fluid 
adenosine deaminase (approximately 90% sensitivity and 
specificity for pleural tuberculosis at levels greater than 
 
70 units/L) and interferon-gamma (89% sensitivity, 97% 
specificity in a recent meta-analysis) can be extremely 
helpful diagnostic aids, particularly in making decisions to 
pursue invasive testing in complex cases.
C. Imaging
Contrary to traditional teaching, molecular analysis dem
-
onstrates that radiographic abnormalities in pulmonary 
tuberculosis do not distinguish primary disease from 
Table 9–12.
 
Essential laboratory tests for the detection of 
.
1
Test
Time to Result
Test Characteristics
Acid-fast bacilli light microscopy
1 day
Three morning specimens recommended. Combined sensitivity of 70% 
(54% for the first specimen, 11% for the second specimen, and 5% for 
 
the third specimen). First morning specimen increased yield by 12% 
 
compared to spot specimen.
Nucleic acid amplification test, 
 
detection (NAAT-TB)
1 day
Sensitivity/specificity high for smear-positive specimens, 85–97% for both; 
sensitivity falls in smear-negative specimens to ~66%. A positive NAAT 
 
in smear-negative patients with intermediate to high (> 30%) pretest 
 
probability of 
 infection is helpful while a negative NAAT 
 
is not. Should not be ordered in patients with low pretest probability of 
 infection.
 
resistance markers (NAAT-R)
1–2 days
Multiple assays for rifampin and isoniazid are available. Specificity uniformly 
high, > 98%. Sensitivity varies from about 84% to 96%, increases with 
multiple specimens. See text for indications for testing.
Mycobacterial growth detection
 
Liquid 
(broth based) medium
 
S
olid (agar or egg based) medium
Up to 6–8 weeks
 
A
vg 10–14 days
 
A
vg 3–4 weeks
Liquid culture methods are more sensitive (~90% and 76%, respectively)

Liquid 
 
S
 
A
 
A
Liquid culture methods are more sensitive (~90% and 76%, respectively) 
with shorter time to detection but higher contamination with bacterial 
growth than solid culture methods. Specificity exceeds 99% for all 
methods.
Identification of 
 
complex by DNA probe or high 
 
performance liquid 
chromatography
1 day
1
May be useful in areas of low 
 incidence where nontuberculous 
mycobacteria are commonly isolated.
First-line drug susceptibility testing 
(liquid medium)
1–2 weeks
1
Gold standard. Should be performed routinely on the initial isolate.
Second-line and novel compound 
drug susceptibility testing
 
Liquid 
 
S
1–2 weeks
1
3–4 weeks
1
1
Following detection of mycobacterial growth.
Adapted from Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic 
Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was 
endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000 Apr; 161(4 Pt 1):
 
1376–95.
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reactivation of latent tuberculosis (Figure 9–5). The only 
independent predictor of an atypical pattern on chest 
radiograph—that is, not associated with upper lobe or cavi
-
tary disease—is an impaired host immune response. In 
elderly patients, lower lobe infiltrates with or without 
pleural effusion are frequently encountered. Lower lung 
tuberculosis may masquerade as pneumonia or lung can
-
cer. A “miliary” pattern (diffuse small nodular densities) 
can be seen with hematologic or lymphatic dissemination 
of the organism. Immunocompromised patients—partic
-
ularly those with late-stage HIV infection—often display 
lower lung zone, diffuse, or miliary infiltrates; pleural 
effusions; and involvement of hilar, and, in particular, 
mediastinal lymph nodes.
Resolution of active tuberculosis leaves characteristic 
radiographic findings. Dense nodules in the pulmonary 
hila, with or without obvious calcification, upper lobe 
fibronodular scarring, and bronchiectasis with volume loss 
are common findings. Ghon (calcified primary focus) and 
Ranke (calcified primary focus and calcified hilar lymph 
node) complexes are seen in a minority of patients.
Testing for latent tuberculosis infection is used to evaluate 
an asymptomatic person in whom 
 infection 
is suspected (eg, following contact exposure) or to establish 
the prevalence of tuberculosis infection in a population. 
Testing may be used in a person with symptoms of active 
tuberculosis, but a positive test does not distinguish 
between active and latent infection. Routine testing of indi
-
viduals at low risk for tuberculosis is not recommended.
The traditional approach to testing for latent tuberculo
-
sis infection is the 
tuberculin skin test.
 The Mantoux test 
is the preferred method: 0.1 mL of purified protein deriva
-
tive (PPD) containing 5 tuberculin units is injected intra
-
dermally on the volar surface of the forearm using a 
27-gauge needle on a tuberculin syringe. The 
transverse 
width in millimeters of induration
 at the skin test site is 
measured after 48–72 hours. To optimize test performance, 
criteria for determining a positive reaction vary depending 
on the likelihood of infection. Table 9–13 summarizes the 
criteria established by the Centers for Disease Control and 
Prevention (CDC) for interpretation of the Mantoux tuber
-
culin skin test. Sensitivity and specificity of the tuberculin 
skin test are high: 77% and 97%, respectively. Specificity 
falls to 59% in populations previously vaccinated with 
bacillus Calmette-Guérin (BCG, an attenuated form of 
Mycobacterium bovis
). False-negative tuberculin skin test 
reactions may result from improper testing technique; con
-
current infections, including fulminant tuberculosis; mal
-
nutrition; advanced age; immunologic disorders; 
malignancy; corticosteroid therapy; chronic kidney dis
-
ease; and HIV infection. Some individuals with latent 
tuberculosis infection may have a negative tuberculin skin 
test when tested many years after exposure. Anergy testing 
is not recommended for routine use to distinguish a true-
negative result from anergy. Poor anergy test standardiza
-
tion and lack of outcome data limit the evaluation of its 
effectiveness. Interpretation of the tuberculin skin test in 
persons who have previously received BCG vaccination is 
the same as in those who have not had BCG.
Interferon gamma release assays
 (including the Quan
-
tiFERON and T-SPOT tests) are in vitro assays of CD4+ 
T-cell–mediated interferon gamma release in response to 
stimulation by specific 
 antigens. The anti
-
gens are absent from all BCG strains and most nontubercu
-
lous mycobacteria; therefore, in whole blood, the specificity 
of interferon gamma release assays is superior to the tuber
-
culin skin test in BGC-vaccinated individuals. Sensitivity is 
comparable to the tuberculin skin test: 60–90% depending

-
comparable to the tuberculin skin test: 60–90% depending 
on the specific assay and study population. Sensitivity is 
reduced by HIV infection, particularly in patients with low 
A
B
 
▲
Figure 9–5.
 
Pulmonary tuberculosis. Primary pulmo
-
nary tuberculosis in a 20-year-old man with chest radio
-
graph 
(A)
 showing right upper lobe consolidation 
(white arrow) and right hilar and mediastinal lymphade
-
nopathy (black arrows) and contrast-enhanced CT scan 
(B)
 showing mediastinal lymphadenopathy (arrows). 
(Used, with permission, from Carlos Santiago Restrepo, 
MD in Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H. 
, 2nd ed. McGraw-Hill, 
2013.)
CMDT19_Ch09_p0252-p0333.indd   290

291
 
CMDT 2019
Table 9–13.
 
Classification of positive tuberculin skin test reactions.
1
Induration Size
Group
≥ 5 mm
1.
  
HIV-positive persons.
2.
  
Rec
ent contacts of a person with infectious tuberculosis disease.
3.
  
P
ersons with fibrotic changes on chest radiographs suggestive of prior tuberculosis.
4.
  
P
atients with organ transplants and other immunosuppressed patients (receiving the equivalent of > 15 mg/day 
of prednisone for 1 month or more, or those taking TNF-alpha antagonists).
≥ 10 mm
1.
  
Rec
ent immigrants (< 5 years) from countries with a high prevalence of tuberculosis (eg, Asia, Africa, Latin 
America).
2.
  
HIV
-negative injection drug users.
3.
  
M
ycobacteriology laboratory personnel.
4.
 
Residen
ts of and employees in high-risk congregate settings: correctional institutions; long-term care facilities; 
hospitals and other health care facilities; residential facilities for HIV/AIDS patients; and homeless shelters.
5.
 
P
ersons with medical conditions that increase the risk of progression to tuberculosis disease: gastrectomy, ≥ 10% below 
ideal body weight, jejunoileal bypass, diabetes mellitus, silicosis, advanced chronic kidney disease, some hematologic 
disorders, (eg, leukemias, lymphomas), and other specific malignancies (eg, carcinoma of the head or neck and lung).
6.
  
Childr
en younger than 4 years or infants, children, and adolescents exposed to adults at high risk.
≥ 15 mm
1.
  
P
ersons with no known risk factors for tuberculosis.
1
A tuberculin skin test reaction is considered positive if the transverse diameter of the 
indurated
 area reaches the size required for the 
specific group. All other reactions are considered negative.
Data from Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. Centers for Disease Control and Prevention. https://
www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf
CD4 counts. Specificity is high, greater than 95%. Potential 
advantages of interferon gamma release assay testing 
include fewer false-positive results from prior BCG vaccina
-
tion, better discrimination of positive responses due to 
nontuberculous mycobacteria, and the requirement for only 
one patient contact (ie, no need for the patient to return to 
have the tuberculin skin test read 48–72 hours later). Disad
-
vantages include the need for specialized laboratory equip
-
ment and personnel, and the substantially increased cost 
compared to the tuberculin skin test.
In endemic areas, interferon gamma release assays are no 
more sensitive than the tuberculin skin test in active tuber
-
culosis (20–40% false-negative rate) and cannot distinguish 
active from latent disease. Interferon gamma release assays 
should not be used to exclude active tuberculosis.
Guidelines established by the CDC allow interferon 
gamma release assays to be used interchangeably with the 
tuberculin skin testing in the diagnosis of latent tuberculosis 
infection. Interferon gamma release assays are preferred in 
patients with prior BCG vaccination; the tuberculin skin test 
is preferred in children under 5 years old. Routine use of both 
tests is not recommended. In individuals with a positive 
tuberculin skin test but a low prior probability of latent tuber
-
culosis infection and low risk for progression to active disease, 
the interferon gamma release assay may be helpful as a confir
-
matory test to exclude a false-positive tuberculin skin test.
 
»
Treatment
The goals of therapy are to cure the individual patient, 
minimize risk of morbidity and mortality related to treat
-
ment, reduce transmission of 
 to other per
-
sons, and prevent the emergence of clinically significant 
drug resistance in tubercle bacilli. The basic principles of 
antituberculous treatment are (1) to administer multiple 
medications to which the organisms are susceptible; (2) to 
provide the safest, most effective therapy in the shortest

provide the safest, most effective therapy in the shortest 
period of time; (3) to ensure adherence to therapy; and (4) 
to add at least two new antituberculous agents to a regimen 
when treatment failure is suspected.
All suspected and confirmed cases of tuberculosis should 
be reported promptly to local and state public health author
-
ities. Public health departments will perform case investiga
-
tions on sources and patient contacts to determine if other 
individuals with untreated, infectious tuberculosis are pres
-
ent in the community. They can identify infected contacts 
eligible for treatment of latent tuberculous infection and 
ensure that a plan for monitoring adherence to therapy is 
established for each patient with tuberculosis. Patients with 
tuberculosis should be treated by clinicians who are skilled 
in the management of this infection. Clinical expertise is 
especially important in cases of drug-resistant tuberculosis.
Nonadherence to antituberculous treatment is a major 
cause of treatment failure, continued transmission of tuber
-
culosis, and the development of medication resistance. 
Adherence to treatment can be improved by providing 
detailed patient education about tuberculosis and its treat
-
ment in addition to a case manager who oversees all aspects 
of an individual patient’s care. 
Directly observed therapy 
(DOT),
 which requires that a health care worker physically 
observe the patient ingest antituberculous medications in the 
home, clinic, hospital, or elsewhere, also improves adherence 
to treatment. The importance of direct observation of ther
-
apy cannot be overemphasized. The CDC recommends DOT 
for all patients with drug-resistant tuberculosis and for those 
receiving intermittent (twice- or thrice-weekly) therapy.
Hospitalization for initial therapy of tuberculosis is not 
necessary for most patients. It should be considered if a 
patient is incapable of self-care or is likely to expose new, 
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 CMDT 2019
susceptible individuals to tuberculosis. Hospitalized 
patients with active disease require a private room with 
negative-pressure ventilation until tubercle bacilli are no 
longer found in their sputum (“smear-negative”) on three 
consecutive smears taken on separate days.
Characteristics of antituberculous drugs are provided in 
Table 9–14. Additional treatment considerations can be 
found in Chapter 33. More complete information can be 
obtained from the CDC’s Division of Tuberculosis Elimi
-
nation Web site at https://www.cdc.gov/tb/.
B. Treatment of Tuberculosis in 
 
HIV-Negative Persons
Most patients with previously untreated pulmonary tuber
-
culosis can be effectively treated with either a 6-month or a 
9-month regimen, though the 6-month regimen is pre
-
ferred. The initial phase of a 6-month regimen consists of 
2 months of daily isoniazid, rifampin, pyrazinamide, and 
ethambutol. Once the isolate is determined to be isoniazid-
sensitive, ethambutol may be discontinued. If the 
M tuber
-
culosis
 isolate is susceptible to isoniazid and rifampin, the 
second phase of therapy consists of isoniazid and rifampin 
for a minimum of 4 additional months, with treatment to 
extend at least 3 months beyond documentation of conver
-
sion of sputum cultures to negative for 
. If 
DOT is used, medications may be given intermittently 
using one of three regimens: (1) Daily isoniazid, rifampin, 
pyrazinamide, and ethambutol for 2 months, followed by 
isoniazid and rifampin two or three times each week for 
4 months if susceptibility to isoniazid and rifampin is 
Table 9–14.
 
Characteristics of antituberculous medications.
Most Common Side 
Effects
Tests for Side 
Effects
Drug Interactions
Remarks
Isoniazid
Peripheral neuropathy, 
hepatitis, rash, mild 
CNS effects.
AST and ALT; 
neurologic 
Phenytoin (synergistic); disulfiram.
Bactericidal to both extracellular 
and intracellular organisms. 
 
Pyridoxine, 25–50 mg orally daily 
as prophylaxis for neuritis; 
50–100 mg orally daily as 
Rifampin
Hepatitis, fever, rash, 
 
flu-like illness, 
 
gastrointestinal 
 
upset, bleeding 
 
problems, kidney 
failure.
CBC, platelets, 
AST and ALT.
Rifampin inhibits the effect of oral con
-
traceptives, quinidine, corticosteroids, 
warfarin, methadone, digoxin, oral 
hypoglycemics; aminosalicylic acid 
may interfere with absorption of 
rifampin. Significant interactions 
with protease inhibitors and nonnu
-
cleoside reverse transcriptase 
inhibitors.
Bactericidal to all populations of 
organisms. Colors urine and 
other body secretions orange. 
Discoloring of contact lenses.
Rifapentine
Bone marrow 
 
suppression, 
 
hematuria/
 
pyuria, hepatitis, 
 
upset, flu-like illness.
Strong cytochrome P450 inducer with 
multiple drug interactions. Use in 
HIV patients receiving antiretroviral 
therapy should be limited to experts 
in antiretroviral therapy.
 
Colors urine and other body 
secretions orange. Long half-life, 
can be administered weekly in 
LTBI prophylaxis. Not for use in 
induction phase of therapy.
Pyrazinamide
Hyperuricemia, 
 
hepatotoxicity, rash, 
 
upset, joint aches.
Uric acid, AST, 
ALT.
Rare.
Bactericidal to intracellular 
organisms.
Optic neuritis 
 
(reversible with 
 
discontinuance of 
drug; rare at 
 
15 mg/kg); rash.
Red-green color 
discrimination 
and visual 
acuity.
Rare.
Bacteriostatic to both intracellular 
and extracellular organisms. 
Mainly used to inhibit develop
-
ment of resistant mutants. Use 
with caution in kidney disease or 
when ophthalmologic testing is 
not feasible.
Eighth nerve damage, 
nephrotoxicity.
Vestibular 
 
function 
(audiograms); 
BUN and 
creatinine.
Neuromuscular blocking agents may 
be potentiated and cause prolonged 
paralysis.

function 
BUN and 
Bactericidal to extracellular organ
-
isms. Use with caution in older 
patients or those with kidney 
disease.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; LTBI, latent tubercu
-
losis infection.
CMDT19_Ch09_p0252-p0333.indd   292

293
 
CMDT 2019
demonstrated. (2) Daily isoniazid, rifampin, pyrazinamide, 
and ethambutol for 2 weeks, then administration of the same 
agents twice a week for 6 weeks followed by administration 
of isoniazid and rifampin twice each week for 4 months if 
susceptibility to isoniazid and rifampin is demonstrated. 
(3) Isoniazid, rifampin, pyrazinamide, and ethambutol 
three times a week for 6 months.
Patients who cannot or should not (eg, pregnant women) 
take pyrazinamide should receive daily isoniazid and rifampin 
along with ethambutol for 4–8 weeks. If susceptibility to iso
-
niazid and rifampin is demonstrated or drug resistance is 
unlikely, ethambutol can be discontinued and isoniazid and 
rifampin may be given twice a week for a total of 9 months of 
therapy. If drug resistance is a concern, patients should receive 
isoniazid, rifampin, and ethambutol for 9 months. Patients 
with smear- and culture-negative disease (eg, pulmonary 
tuberculosis diagnosed on clinical grounds) and patients for 
whom drug susceptibility testing is not available can be 
treated with 6 months of isoniazid and rifampin combined 
with pyrazinamide for the first 2 months. This regimen 
assumes low prevalence of drug resistance. Previous guide
-
lines have used streptomycin interchangeably with ethambu
-
tol. Increasing worldwide streptomycin resistance has made 
this medication less useful as empiric therapy.
When a twice-weekly or thrice-weekly regimen is used 
instead of a daily regimen, the dosages of isoniazid, pyrazin
-
amide, and ethambutol or streptomycin must be increased. 
Recommended dosages for the initial treatment of tuberculo
-
sis are listed in Table 9–15. Fixed-dose combinations of iso
-
niazid and rifampin (Rifamate) and of isoniazid, rifampin, 
and pyrazinamide (Rifater) are available to simplify treat
-
ment. Single tablets improve compliance but are more expen
-
sive than the individual medications purchased separately.
C. Treatment of Tuberculosis in HIV-Positive Persons
Management of tuberculosis is complex in patients with 
concomitant HIV disease. Experts in the management of 
both tuberculosis and HIV disease should be involved in 
the care of such patients. The CDC has published detailed 
recommendations for the treatment of tuberculosis in 
HIV-positive patients (www.cdc.gov/tb/topic/basics/tbhiv
-
coinfection.htm).
The basic approach to HIV-positive patients with 
tuberculosis is similar to that detailed above for patients 
without HIV disease. Additional considerations in HIV-
positive patients include (1) longer duration of therapy 
and (2) drug interactions between rifamycin derivatives 
such as rifampin and rifabutin used to treat tuberculosis 
and some of the protease inhibitors and nonnucleoside 
reverse transcriptase inhibitors (NNRTIs) used to treat 
HIV (see www.cdc.gov/tb/topic/basics/tbhivcoinfection
 
.htm). DOT should be used for all HIV-positive tubercu
-
losis patients. Pyridoxine (vitamin B
6
), 25–50 mg orally 
each day, should be administered to all HIV-positive 
patients being treated with isoniazid to reduce central and 
peripheral nervous system side effects.
D. Treatment of Drug-Resistant Tuberculosis
Patients with drug-resistant 
 infection 
require careful supervision and management. Clinicians 
who are unfamiliar with the treatment of drug-resistant 
tuberculosis should seek expert advice. Tuberculosis resis
-
tant only to isoniazid can be successfully treated with a 
6-month regimen of rifampin, pyrazinamide, and etham
-
butol or streptomycin or a 12-month regimen of rifampin 
and ethambutol. When isoniazid resistance is documented 
during a 9-month regimen without pyrazinamide, isonia
-
zid should be discontinued. If ethambutol was part of the 
initial regimen, rifampin and ethambutol should be contin
-
ued for a minimum of 12 months. If ethambutol was not 
part of the initial regimen, susceptibility tests should be

-
part of the initial regimen, susceptibility tests should be 
repeated and two other medications to which the organism 
is susceptible should be added. Treatment of 
 
isolates resistant to agents other than isoniazid and treat
-
ment of drug resistance in HIV-infected patients require 
expert consultation.
Table 9–15.
 
Recommended dosages for the initial treatment of tuberculosis.
1
Daily
2
Cost
3
/Day
Twice a Week
2
Cost
3
/Wk
Three Times a Week
2
Cost
3
/Wk
Isoniazid
5 mg/kg
Max: 300 mg/dose
$0.31/300 mg
15 mg/kg
Max: 900 mg/dose
$1.86
15 mg/kg
$2.79
Rifampin
10 mg/kg
Max: 600 mg/dose
$2.66/600 mg
10 mg/kg
$5.32
10 mg/kg
$7.98
18.2–26.3 mg/kg
Max: 2 g/dose
$11.44/2 g
Weight-based dosing: 
see references below.
1
—
1
—
14.5–21.1 mg/kg
Max: 1.6 g/dose
$3.76/1.6 g
1
—
1
—
1
Data from Nahid P et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of 
America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–95.
2
All dosing regimens should be used with directly observed therapy.
3
Red Book
-
Also available at www.cdc.gov/tb/topic/treatment/guidelinehighlights.htm
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Multidrug-resistant tuberculosis and extensively drug-
resistant tuberculosis call for an individualized daily DOT 
plan under the supervision of an experienced clinician. 
Treatment regimens are based on the patient’s overall status 
and the results of susceptibility studies. Most drug-resistant 
isolates are resistant to at least isoniazid and rifampin and 
require a minimum of three drugs to which the organism is 
susceptible. These regimens are continued until culture con
-
version is documented, and then a two-drug regimen is 
continued for at least another 12 months. Some experts 
recommend at least 18–24 months of a three-drug regimen.
E. Treatment of Extrapulmonary Tuberculosis
In most cases, regimens that are effective for treating pul
-
monary tuberculosis are also effective for treating extra
-
pulmonary disease. However, many experts recommend 
9–12 months of therapy when miliary, meningeal, or bone 
and joint disease is present. Treatment of skeletal tubercu
-
losis is enhanced by early surgical drainage and debride
-
ment of necrotic bone. Corticosteroid therapy has been 
shown to help prevent constrictive pericarditis from 
tuberculous pericarditis and to reduce neurologic compli
-
cations from tuberculous meningitis (Chapter 33).
F. Treatment of Pregnant or Lactating Women
Tuberculosis in pregnancy is usually treated with isoniazid, 
rifampin, and ethambutol for 2 months, followed by isonia
-
zid and rifampin for an additional 7 months. Ethambutol 
can be stopped after the first month if isoniazid and 
rifampin susceptibility is confirmed. Since the risk of tera
-
togenicity with pyrazinamide has not been clearly defined, 
pyrazinamide should be used only if resistance to other 
drugs is documented and susceptibility to pyrazinamide is 
likely. Streptomycin is contraindicated in pregnancy because 
it may cause congenital deafness. Pregnant women taking 
isoniazid should receive pyridoxine (vitamin B
6
), 10–25 mg 
orally once a day, to prevent peripheral neuropathy.
Small concentrations of antituberculous drugs are pres
-
ent in breast milk. First-line therapy is not known to be 
harmful to nursing newborns at these concentrations. 
Therefore, breastfeeding is not contraindicated while receiv
-
ing first-line antituberculous therapy. Lactating women 
receiving other agents should consult a tuberculosis expert.
G. Treatment Monitoring
Adults should have measurements of a complete blood 
count (including platelets) and serum bilirubin, hepatic 
enzymes, urea nitrogen, and creatinine before starting 
therapy for tuberculosis. Visual acuity and red-green color 
vision tests are recommended before initiation of ethambu
-
tol and serum uric acid before starting pyrazinamide. 
Audiometry should be performed if streptomycin therapy 
is initiated.
Routine monitoring of laboratory tests for evidence of 
medication toxicity during therapy is not recommended, 
unless baseline results are abnormal or liver disease is sus
-
pected. Monthly questioning for symptoms of medication 
toxicity is advised. Patients should be educated about com
-
mon side effects of antituberculous medications and 
instructed to seek medical attention should these symp
-
toms occur. Monthly follow-up of outpatients is recom
-
mended, including sputum smear and culture for 
M 
, until cultures convert to negative. Patients 
with negative sputum cultures after 2 months of treatment 
should have at least one additional sputum smear and cul
-
ture performed at the end of therapy. Patients with drug-
resistant isolates should have sputum cultures performed 
monthly during the entire course of treatment. A chest 
radiograph at the end of therapy provides a useful baseline 
for any future films.
Patients whose cultures do not become negative or 
whose symptoms do not resolve despite 3 months of ther
-
apy should be evaluated for nonadherence to the regimen 
and for drug-resistant organisms. DOT is required for the

-
and for drug-resistant organisms. DOT is required for the 
remainder of the treatment regimen, and the addition of at 
least two drugs not previously given should be considered 
pending repeat drug susceptibility testing. The clinician 
should seek expert assistance if drug resistance is newly 
found, if the patient remains symptomatic, or if smears or 
cultures remain positive.
Patients with only a clinical diagnosis of pulmonary 
tuberculosis (smears and cultures negative for 
) 
whose symptoms and radiographic abnormalities are 
unchanged after 3 months of treatment usually either have 
another process or have had tuberculosis in the past.
H. Treatment of Latent Tuberculosis
Treatment of latent tuberculous infection is essential to 
controlling and eliminating tuberculosis. Treatment of 
latent tuberculous infection substantially reduces the risk 
that infection will progress to active disease. Targeted test
-
ing with the tuberculin skin test or interferon gamma 
release assays is used to identify persons who are at high 
risk for tuberculosis and who stand to benefit from treat
-
ment of latent infection. Table 9–13 gives the tuberculin 
skin test criteria for treatment of latent tuberculous infec
-
tion. In general, patients with a positive tuberculin skin test 
or interferon gamma release assay who are at increased risk 
for exposure or disease are treated. It is essential that each 
person who meets the criteria for treatment of latent tuber
-
culous infection undergo a careful assessment to exclude 
active disease. A history of past treatment for tuberculosis 
and contraindications to treatment should be sought. All 
patients at risk for HIV infection should be tested for HIV . 
Patients suspected of having tuberculosis should receive 
one of the recommended multidrug regimens for active 
disease until the diagnosis is confirmed or excluded.
Some close contacts of persons with active tuberculosis 
should be evaluated for treatment of latent tuberculous 
infection despite a negative tuberculin skin test reaction 
(less than 5 mm induration). These include immunosup
-
pressed persons and those who may develop disease 
quickly after tuberculous infection. Close contacts who 
have a negative tuberculin skin test reaction on initial test
-
ing should be retested 10–12 weeks later.
Several treatment regimens for both HIV-negative and 
HIV-positive persons are available for the treatment of latent 
tuberculous infection: (1) 
Isoniazid:
 A 9-month oral regi
-
men (minimum of 270 doses administered within 12 months) 
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is preferable to 6 months of therapy. Dosing options include 
a daily dose of 300 mg or twice-weekly doses of 15 mg/kg. 
Persons at risk for developing isoniazid-associated peripheral 
neuropathy (diabetes mellitus, uremia, malnutrition, alcohol
-
ism, HIV infection, pregnancy, seizure disorder) may be 
given supplemental pyridoxine (vitamin B
6
), 10–50 mg/day. 
(2) 
Isoniazid and rifampin:
 A 3-month oral regimen of daily 
isoniazid (300 mg) and rifampin (600 mg). (3) 
Isoniazid and 
rifapentine:
 A 3-month oral regimen of once weekly isonia
-
zid at 15 mg/kg and rifapentine at 15–30 mg/kg. (4) 
Rifampin:
 Patients who cannot tolerate isoniazid can be 
considered for a 4-month oral regimen of rifampin at 600 mg 
daily. HIV-positive patients receiving protease inhibitors or 
NNRTIs who are given rifampin or rifapentine require man
-
agement by experts in both tuberculosis and HIV disease (see 
Treatment of Tuberculosis in HIV-Positive Persons, above).
Contacts of persons with isoniazid-resistant, rifampin-
sensitive tuberculosis should receive a 2-month regimen of 
rifampin and pyrazinamide or a 4-month regimen of daily 
rifampin alone. Contacts of persons with drug-resistant 
tuberculosis should receive two drugs to which the infect
-
ing organism has demonstrated susceptibility. Contacts in 
whom the tuberculin skin test or interferon gamma release 
assay is negative and contacts who are HIV seronegative 
may be observed without treatment or treated for 6 months. 
HIV-positive contacts should be treated for 12 months. All 
contacts of persons with multidrug-resistant tuberculosis or 
extensively drug-resistant tuberculosis should have 2 years 
of follow-up regardless of treatment.
Persons with a positive tuberculin skin test (5 mm or 
more of induration) and fibrotic lesions suggestive of old 
tuberculosis on chest radiographs who have no evidence of 
active disease and no history of treatment for tuberculosis 
should receive 9 months of isoniazid or 4 months of 
rifampin (with or without isoniazid). Pregnant or breast
-
feeding women with latent tuberculosis should receive 
either daily or twice-weekly isoniazid with pyridoxine 
(vitamin B
6
).
Baseline laboratory testing is indicated for patients at 
risk for liver disease, patients with HIV infection, women 
who are pregnant or within 3 months of delivery, and per
-
sons who use alcohol regularly. Patients receiving treat
-
ment for latent tuberculous infection should be evaluated 
once a month to assess for symptoms and signs of active 
tuberculosis and hepatitis and for adherence to their treat
-
ment regimen. Routine laboratory testing during treatment 
is indicated for those with abnormal baseline laboratory 
tests and for those at risk for developing liver disease.
Vaccine BCG
 is an antimycobacterial vaccine devel
-
oped from an attenuated strain of 
M bovis
. Millions of 
individuals worldwide have been vaccinated with BCG. 
However, it is not generally recommended in the United 
States because of the low prevalence of tuberculous infec
-
tion, the vaccine’s interference with the ability to determine 
latent tuberculous infection using tuberculin skin test reac
-
tivity, and its variable effectiveness in prophylaxis of pul
-
monary tuberculosis. BCG vaccination in the United States 
should be undertaken only after consultation with local 
health officials and tuberculosis experts. Vaccination of 
health care workers should be considered on an individual 
basis in settings in which a high percentage of tuberculosis 
patients are infected with strains resistant to both isoniazid 
and rifampin, in which transmission of such drug-resistant 
 and subsequent infection are likely, and in 
which comprehensive tuberculous infection-control pre
-
cautions have been implemented but have not been suc
-
cessful. The BCG vaccine is contraindicated in persons 
with impaired immune responses due to disease or 
 
»

-
-
 
»
Prognosis
Almost all properly treated immunocompetent patients 
with tuberculosis can be cured. Relapse rates are less than 
5% with current regimens. The main cause of treatment 
failure is nonadherence to therapy.
Getahun H et al. Latent 
 infection. N 
Engl J Med. 2015 May 28;372(22):2127–35. [PMID: 26017823]
Kurz SG et al. Drug-resistant tuberculosis: challenges and prog
-
ress. Infect Dis Clin North Am. 2016 Jun;30(2):509–22. 
[PMID: 27208770]
Lewinsohn DM et al. Official American Thoracic Society/Infec
-
tious Diseases Society of America/Centers for Disease Con
-
trol and Prevention Clinical Practice Guidelines: diagnosis 
of tuberculosis in adults and children. Clin Infect Dis. 2017 
Jan 15;64(2):111–5. [PMID: 28052967]
Nahid P et al. Official American Thoracic Society/Centers for 
Disease Control and Prevention/Infectious Diseases Society 
of America Clinical Practice Guidelines: treatment of drug-
susceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):
 
e147–95. [PMID: 27516382]
Wilson JW et al. Extensively drug-resistant tuberculosis: princi
-
ples of resistance, diagnosis, and management. Mayo Clin 
Proc. 2016 Apr;91(4):482–95. [PMID: 26906649]
PULMONARY DISEASE CAUSED BY 
NONTUBERCULOUS MYCOBACTERIA
 
»
Chronic cough, sputum production, and fatigue; 
less commonly: malaise, dyspnea, fever, hemopty
-
sis, and weight loss.
 
»
Parenchymal opacities on chest radiograph, most 
often thin-walled cavities or multiple small nod
-
ules associated with bronchiectasis.
 
»
Isolation of nontuberculous mycobacteria in a 
sputum culture.
 
»
Mycobacteria other than 
—nontuberculous 
mycobacteria (NTM), sometimes referred to as 
 
“atypical” mycobacteria—are ubiquitous in water and soil 
and have been isolated from tap water. Marked geographic 
variability exists, both in the NTM species responsible for dis
-
ease and in the prevalence of disease. These organisms are not 
considered communicable from person to person, have dis
-
tinct laboratory characteristics, and are often resistant to 
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most antituberculous medications (Chapter 33). Long-
term epidemiologic data suggest that NTM disease has 
been increasing in the United States.
 
»
The diagnosis of lung disease caused by NTM is based on 
a combination of clinical, radiographic, and bacteriologic 
criteria and the exclusion of other diseases that can resem
-
ble the condition. Specific diagnostic criteria are discussed 
below. Complementary data are important for diagnosis 
because NTM organisms can reside in or colonize the air
-
ways without causing clinical disease.
Mycobacterium avium
 complex (MAC) is the most fre
-
quent cause of NTM pulmonary disease in humans in the 
United States. 
Mycobacterium kansasii
 is the next most 
frequent pulmonary pathogen. Other NTM causes of pul
-
monary disease include 
Mycobacterium abscessus, Myco
-
bacterium xenopi
, and 
Mycobacterium malmoense;
 the list 
of more unusual etiologic NTM species is long. Most NTM 
cause a chronic pulmonary infection that resembles tuber
-
culosis, but tends to progress more slowly. Disseminated 
disease is rare in immunocompetent hosts; however, dis
-
seminated MAC disease is common in patients with AIDS.
 
»
NTM infection among immunocompetent hosts frequently 
presents in one of three prototypical patterns: cavitary, 
upper lobe lesions in older male smokers that may mimic 
; nodular bronchiectasis affecting the mid 
lung zones in middle-aged women with chronic cough; and 
hypersensitivity pneumonitis following environmental 
exposure. Most patients with NTM infection experience a 
chronic cough, sputum production, and fatigue. Less com
-
mon symptoms include malaise, dyspnea, fever, hemopty
-
sis, and weight loss. Symptoms from coexisting lung 
disease (COPD, bronchiectasis, previous mycobacterial 
disease, cystic fibrosis, and pneumoconiosis) may con
-
found the evaluation. In patients with bronchiectasis, coin
-
fection with NTM and 
 is a negative prognostic 
factor. New or worsening infiltrates as well as adenopathy 
or pleural effusion (or both) are described in HIV-positive 
patients with NTM infection as part of the immune recon
-
stitution inflammatory syndrome following institution of 
antiretroviral therapy.
The diagnosis of NTM infection rests on recovery of the 
pathogen from cultures. Sputum cultures positive for atypi
-
cal mycobacteria do not prove infection because NTM may 
exist as saprophytes colonizing the airways or may be envi
-
ronmental contaminants. Bronchial washings are considered 
to be more sensitive than expectorated sputum samples; 
however, their specificity for clinical disease is not known.
Bacteriologic criteria have been proposed based on 
studies of patients with cavitary disease with MAC or 
M 
kansasii
. Diagnostic criteria in immunocompetent persons 
include the following: positive culture results from at least 
two separate expectorated sputum samples; or positive 
culture from at least one bronchial wash; or a positive cul
-
ture from pleural fluid or any other normally sterile site. 
The diagnosis can also be established by demonstrating 
NTM cultured from a lung biopsy, bronchial wash, or 
sputum plus histopathologic changes, such as granuloma
-
tous inflammation in a lung biopsy. Rapid species identifi
-
cation of some NTM is possible using DNA probes or 
high-pressure liquid chromatography.
Diagnostic criteria are less stringent for patients with 
severe immunosuppression. HIV-infected patients may show 
significant MAC growth on culture of bronchial washings 
without clinical infection; therefore, HIV patients being evalu
-
ated for MAC infection must be considered individually.
Medication susceptibility testing on cultures of NTM is 
recommended for the following NTM: (1) 
Mycobacterium 
avium intracellulare
 to macrolides only (clarithromycin and 
azithromycin); (2) 
M kansasii

M kansasii
 to rifampin; and (3) rapid 
growers (such as 
Mycobacterium fortuitum, Mycobacterium 
chelonae, and M abscessus
) to amikacin, doxycycline, imipe
-
nem, fluoroquinolones, clarithromycin, cefoxitin, and 
sulfonamides.
C. Imaging
Chest radiographic findings include infiltrates that are pro
-
gressive or persist for at least 2 months, cavitary lesions, and 
multiple nodular densities. The cavities are often thin-walled 
and have less surrounding parenchymal infiltrate than is 
commonly seen with MTB infections. Evidence of contigu
-
ous spread and pleural involvement is often present. High-
resolution CT of the chest may show multiple small nodules 
with or without multifocal bronchiectasis. Progression of 
pulmonary infiltrates during therapy or lack of radiographic 
improvement over time are poor prognostic signs and also 
raise concerns about secondary or alternative pulmonary 
processes. Clearing of pulmonary infiltrates due to NTM is 
slow.
 
»
Treatment
Establishing NTM infection does not mandate treatment in 
all cases, for two reasons. First, clinical disease may never 
develop in some patients, particularly asymptomatic 
patients with few organisms isolated from single specimens. 
Second, the spectrum of clinical disease severity is very 
wide; in patients with mild or slowly progressive symptoms, 
traditional chemotherapeutic regimens using a combina
-
tion of agents may lead to drug-induced side effects worse 
than the disease itself.
Specific treatment regimens and responses to therapy 
vary with the species of NTM. HIV-seronegative patients 
with MAC pulmonary disease usually receive a combina
-
tion of daily clarithromycin or azithromycin, rifampin or 
rifabutin, and ethambutol (Table 9–15). For patients with 
severe fibrocavitary disease, streptomycin or amikacin is 
added for the first 2 months. The optimal duration of treat
-
ment is unknown, but therapy should be continued for 
 
12 months after sputum conversion. Medical treatment is 
initially successful in about two-thirds of cases, but relapses 
after treatment are common; long-term benefit is 
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demonstrated in about half of all patients. Those who do 
not respond favorably generally have active but stable dis
-
ease. Surgical resection is an alternative for the patient with 
progressive disease that responds poorly to chemotherapy; 
the success rate with surgical therapy is good. Disease 
caused by 
M kansasii
 responds well to drug therapy. A daily 
regimen of rifampin, isoniazid, and ethambutol for at least 
18 months with a minimum of 12 months of negative cul
-
tures is usually successful. Rapidly growing mycobacteria 
(
M abscessus
, 
M fortuitum
, 
M chelonae
) are generally resis
-
tant to standard antituberculous therapy.
 
»
Patients with rapidly growing mycobacteria infection 
should be referred for expert management.
Stout JE et al. Update on pulmonary disease due to non-tubercu
-
lous mycobacteria. Int J Infect Dis. 2016 Apr;45:123–34. 
[PMID: 26976549]
Wassilew N et al. Pulmonary disease caused by non-tuberculous 
mycobacteria. Respiration. 2016;91(5):386–402. [PMID: 
27207809]
 
º
PULMONARY NEOPLASMS
See Chapter 39 for discussions of Lung Cancer, Second
-
ary Lung Cancer, and Mesothelioma.
SCREENING FOR LUNG CANCER
Two large RCTs reported findings in 2011 regarding the utility 
of lung cancer screening. The Prostate, Lung, Colorectal and 
Ovarian Randomized Trial (PLCO) randomized 154,901 
adults (52% current or former smokers) between the ages of 
55 and 74 years to receive either no screening or annual pos
-
terior-anterior chest radiographs for 4 consecutive years. The 
investigators monitored the participants after screening for an 
average of 12 years. Results showed no mortality benefit from 
four annual chest radiographs either in the whole cohort or in 
a subset of heavy smokers who met the entry criteria for the 
other major trial, the National Lung Screening Trial (NLST). 
The NLST enrolled 53,454 current or former smokers (mini
-
mum 30-pack year exposure history) between the ages of 55 
and 74 years who were randomly assigned to one of two 
screening modalities: three annual posterior-anterior chest 
radiographs or three annual low-dose chest CT scans. They 
were monitored for an additional 6.5 years after screening. 
Compared with chest radiography, low-dose chest CT 
detected more early-stage lung cancers and fewer advanced-
stage lung cancers, indicating that CT screening systematically 
shifted the time of diagnosis to earlier stages, thereby provid
-
ing more persons the opportunity for effective treatment. 
Furthermore, compared with chest radiographs, the cohort 
that received three annual CT scans had a statistically signifi
-
cant mortality benefit, with reductions in both lung cancer 
deaths (20.0%) and all-cause mortality (6.7%). This is the first 
time that evidence from an RCT demonstrated that lung 
cancer screening reduces all-cause mortality.
Additional information from PLCO, the NLST, and 
multiple other ongoing randomized trials is available. The 
Multicentric Italian Lung Detection (MILD) study, which 
was a randomized trial of more than 4000 participants that 
compared annual or biennial low-dose CT with observa
-
tion, found no evidence of a protective effect with the 
annual or biennial low-dose CT screening.
Salient issues that temper enthusiasm for widespread 
screening at this time include the following: 
(1) Generaliz
-
ability to community practice:
 NLST-participating insti
-
tutions demonstrated a high level of expertise in imaging 
interpretation and diagnostic evaluation. Ninety-six per
-
cent of findings on CT were false positives but the vast 
majority of patients were monitored with serial imaging. 
Invasive diagnostic evaluations were uncommon and were 
associated with a low complication rate (1.4%). 
(2) Dura
-
tion of screening:
 The rate of detection of new lung can
-
cers did not fall with each subsequent annual screening 
over 3 years. Since each year lung cancers first become

(2) Dura
-
-
over 3 years. Since each year lung cancers first become 
detectable during that screening interval, the optimal num
-
ber of annual CT scans is unknown as is the optimal 
screening interval. 
(3) Overdiagnosis:
 After 6.4 years of 
post-screening observation, there were more lung cancers 
in the NLST CT cohort than the chest radiography cohort 
(1089 and 969, respectively). Since the groups were ran
-
domized and well matched, lung cancer incidence should 
have been identical. Therefore, 18.5% of the lung cancers 
detected by CT remained clinically silent and invisible on 
chest radiograph for 6.4 years. Many, perhaps most, of 
these lung cancers will never cause clinical disease and 
represent overdiagnosis. 
(4) Cost effectiveness:
 The num
-
ber needed to screen with three annual chest CT scans to 
prevent one death from lung cancer was 320.
Given the level of evidence from US studies showing 
benefit, the US Preventive Services Task Force has been rec
-
ommending screening with low-dose chest CT in high-risk 
individuals since late 2013. There is no evidence of benefit in 
a mixed population screened with chest radiography.
Infante M et al; DANTE Study Group. Long-term follow-up 
results of the DANTE trial, a randomized study of lung cancer 
screening with spiral computed tomography. Am J Respir Crit 
Care Med. 2015 May 15;191(10):1166–75. [PMID: 25760561]
Ruparel M et al. Pulmonary nodules and CT screening: the past, 
present and future. Thorax. 2016 Apr;71(4):367–75. [PMID: 
26921304]
Tanoue LT. Lung cancer screening. Curr Opin Pulm Med. 2016 Jul;
 
22(4):327–35. [PMID: 27159896]
SOLITARY PULMONARY NODULE
A solitary pulmonary nodule, sometimes referred to as a 
“coin lesion, ” is a less-than-3-cm isolated, rounded opacity 
on chest imaging outlined by normal lung and not associ
-
ated with infiltrate, atelectasis, or adenopathy. Most are 
asymptomatic and represent an unexpected finding on 
chest radiography or CT scanning. The finding is impor
-
tant because it carries a significant risk of malignancy. The 
frequency of malignancy in surgical series ranges from 
10% to 68% depending on patient population. 
Benign 
neoplasms,
 such as hamartomas, account for less than 5% 
of solitary nodules. Most benign nodules are infectious 
granulomas.
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The goals of evaluation are to identify and resect 
malignant tumors in patients who will benefit from resec
-
tion while avoiding invasive procedures in benign disease. 
The task is to identify nodules with a sufficiently high 
probability of malignancy to warrant biopsy or resection 
or a sufficiently low probability of malignancy to justify 
observation.
Symptoms alone rarely establish the cause, but clinical 
and imaging data can be used to assess the probability of 
malignancy. Malignant nodules are rare in persons under 
age 30. Above age 30, the likelihood of malignancy increases 
with age. Smokers are at increased risk, and the likelihood of 
malignancy increases with the number of cigarettes smoked 
daily. Patients with a prior malignancy have a higher likeli
-
hood of having a malignant solitary nodule.
The first and most important step in the imaging evalu
-
ation is to review old imaging studies. Comparison with 
prior studies allows estimation of doubling time, which is 
an important marker for malignancy. Rapid progression 
(doubling time less than 30 days) suggests infection while 
long-term stability (doubling time greater than 465 days) 
suggests benignity. Certain radiographic features help in 
estimating the probability of malignancy. Size is correlated 
with malignancy. A study of solitary nodules identified by 
CT scan showed a 1% malignancy rate in those measuring 
2–5 mm, 24% in 6–10 mm, 33% in 11–20 mm, and 80% in 
21–45 mm. The appearance of a smooth, well-defined edge 
is characteristic of a benign process. Ill-defined margins or 
a lobular appearance suggest malignancy. A high-resolu
-
tion CT finding of spiculated margins and a peripheral 
halo are both highly associated with malignancy. Calcifica
-
tion and its pattern are also helpful clues. Benign lesions 
tend to have dense calcification in a central or laminated 
pattern. Malignant lesions are associated with sparser cal
-
cification that is typically stippled or eccentric. Cavitary 
lesions with thick (greater than 16 mm) walls are much 
more likely to be malignant. High-resolution CT offers bet
-
ter resolution of these characteristics than chest radiogra
-
phy and is more likely to detect lymphadenopathy or the 
presence of multiple lesions. Chest CT is indicated in any 
suspicious solitary pulmonary nodule.
 
»
Treatment
Based on clinical and radiologic data, the clinician should 
assign a specific probability of malignancy to the lesion. 
The decision whether to recommend a biopsy or surgical 
excision depends on the interpretation of this probability 
in light of the patient’s unique clinical situation. The prob
-
abilities in parentheses below represent guidelines only and 
should not be interpreted as prescriptive.
In the case of solitary pulmonary nodules, a continuous 
probability function may be grouped into three categories. 
In patients with a 
low probability (less than 5%) of malig
-
nancy
 (eg, age under 30, lesions stable for more than 
 
2 years, characteristic pattern of benign calcification), watch
-
ful waiting is appropriate. Management consists of serial 
imaging studies (CT scans or chest radiographs) at inter
-
vals that identify growth suggestive of malignancy. Three-
dimensional reconstruction of high-resolution CT images 
provides a more sensitive test for growth.
Patients with a 
high probability (greater than 60%) of 
malignancy
 should proceed directly to resection following 
staging, provided the surgical risk is acceptable. Biopsies 
rarely yield a specific benign diagnosis and are not indicated.
Optimal management of patients with an 
intermediate 
probability of malignancy (5–60%)
 remains controversial. 
The traditional approach is to obtain a diagnostic biopsy, 
either through transthoracic needle aspiration (TTNA) or 
bronchoscopy. Bronchoscopy yields a diagnosis in 10–80% 
of procedures depending on the size of the nodule and its

of procedures depending on the size of the nodule and its 
location. In general, the bronchoscopic yield for nodules 
that are less than 2 cm and peripheral is low, although com
-
plications are generally rare. Newer bronchoscopic modali
-
ties, such as electromagnetic navigation and ultrathin 
bronchoscopy are being studied, although their impact 
upon diagnostic yield remains uncertain. TTNA has a 
higher diagnostic yield, reported to be between 50% and 
97%. The yield is strongly operator-dependent, however, 
and is affected by the location and size of the lesion. Com
-
plications are higher than bronchoscopy, with pneumotho
-
rax occurring in up to 30% of patients, with up to one-third 
of these patients requiring placement of a chest tube.
Disappointing diagnostic yields and a high false-
negative rate (up to 20–30% in TTNA) have prompted 
alternative approaches. 
Positron emission tomography 
(PET)
 detects increased glucose metabolism within malig
-
nant lesions with high sensitivity (85–97%) and specificity 
(70–85%). Many diagnostic algorithms have incorporated 
PET into the assessment of patients with inconclusive 
high-resolution CT findings. A positive PET increases the 
likelihood of malignancy, and a negative PET correctly 
excludes cancer in most cases. False-negative PET scans can 
occur with tumors with low metabolic activity (well-
differentiated adenocarcinomas, carcinoids, and bronchio
-
loalveolar tumors), and follow-up CT imaging is typically 
performed at discrete intervals to ensure absence of growth. 
PET has several drawbacks, however: resolution below 1 cm 
is poor, the test is expensive, and availability remains limited.
Sputum cytology
 is highly specific but lacks sensitivity. 
It is used in central lesions and in patients who are poor 
candidates for invasive diagnostic procedures.
Some centers recommend 
video-assisted thoracoscopic 
surgery (V ATS)
 resection of all solitary pulmonary nodules 
with intermediate probability of malignancy. In some cases, 
the surgeon will remove the nodule and evaluate it in the 
operating room with frozen section. If the nodule is malig
-
nant, he or she will proceed to lobectomy and lymph node 
sampling, either thoracoscopically or through conversion to 
standard thoracotomy. This approach is less common when 
PET scanning is available.
All patients should be provided with an estimate of the 
likelihood of malignancy, and their preferences should be 
used to help guide diagnostic and therapeutic decisions. A 
strategy that recommends observation may not be preferred 
by a patient who desires a definitive diagnosis. Similarly, a 
surgical approach may not be agreeable to all patients unless 
the presence of cancer is definitive. Patient preferences 
should be elicited, and patients should be well informed 
regarding the specific risks and benefits associated with the 
recommended approach as well as the alternative strategies.
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Alpert JB et al. Imaging the solitary pulmonary nodule. Clin 
Chest Med. 2015 Jun;36(2):161–78. [PMID: 26024598]
MacMahon H et al. Guidelines for management of incidental 
pulmonary nodules detected on CT images: from the Fleis
-
chner Society 2017. Radiology. 2017 Jul;284(1):228–43. 
[PMID: 28240562]
26921304]
RIGHT MIDDLE LOBE SYNDROME
Right middle lobe syndrome is recurrent or persistent atel
-
ectasis of the right middle lobe. This collapse is related to 
the relatively long length and narrow diameter of the right 
middle lobe bronchus and the oval (“fish mouth”) opening 
to the lobe, in the setting of impaired collateral ventilation. 
Fiberoptic bronchoscopy or CT scan is often necessary to 
rule out obstructing tumor. Foreign body or other benign 
causes are common.
BRONCHIAL CARCINOID TUMORS
Carcinoid and bronchial gland tumors are sometimes 
termed “bronchial adenomas. ” This term should be avoided 
because it implies that the lesions are benign when, in fact, 
carcinoid tumors and bronchial gland carcinomas are low-
grade malignant neoplasms.
Carcinoid tumors
 are about six times more common 
than bronchial gland carcinomas, and most of them occur as 
pedunculated or sessile growths in central bronchi. Men and 
women are equally affected. Most patients are under 60 years 
of age. Common symptoms of bronchial carcinoid tumors 
are hemoptysis, cough, focal wheezing, and recurrent pneu
-
monia. Peripherally located bronchial carcinoid tumors are 
rare and present as asymptomatic solitary pulmonary nod
-
ules. 
 (flushing, diarrhea, wheezing, 
hypotension) is rare. Fiberoptic bronchoscopy may reveal a 
pink or purple tumor in a central airway. These lesions have 
a well-vascularized stroma, and biopsy may be complicated 
by significant bleeding. CT scanning is helpful to localize the 
lesion and to follow its growth over time. Octreotide scintig
-
raphy is also available for localization of these tumors.
Bronchial carcinoid tumors grow slowly and rarely 
metastasize. Complications involve bleeding and airway 
obstruction rather than invasion by tumor and metastases. 
Surgical excision of clinically symptomatic lesions is often 
necessary, and the prognosis is generally favorable. Most 
bronchial carcinoid tumors are resistant to radiation and 
chemotherapy (see Chapter 39).
Caplin ME et al; ENETS consensus conference participants. 
Pulmonary neuroendocrine (carcinoid) tumors: European 
Neuroendocrine Tumor Society expert consensus and recom
-
mendations for best practice for typical and atypical pulmo
-
nary carcinoids. Ann Oncol. 2015 Aug;26(8):1604–20. 
[PMID: 25646366]
Filosso PL et al; European Society of Thoracic Surgeons Lung 
Neuroendocrine Tumors Working-Group Steering Commit
-
tee. Multidisciplinary management of advanced lung neuro
-
endocrine tumors. J Thorac Dis. 2015 Apr;7(Suppl 2):S163–71. 
[PMID: 25984363]
Pusceddu S et al. Diagnosis and management of typical and 
atypical lung carcinoids. Crit Rev Oncol Hematol. 2016 Apr;
 
100:167–76. [PMID: 26917456]
MEDIASTINAL MASSES
Various developmental, neoplastic, infectious, traumatic, 
and cardiovascular disorders may cause masses that appear 
in the mediastinum on chest radiograph. A useful conven
-
tion arbitrarily divides the mediastinum into three com
-
partments—anterior, middle, and posterior—in order to 
classify mediastinal masses and assist in differential diag
-
nosis. Specific mediastinal masses have a predilection for 
one or more of these compartments; most are located in 
the anterior or middle compartment. The differential diag
-
nosis of an 
anterior mediastinal mass
 includes thymoma, 
teratoma, thyroid lesions, lymphoma, and mesenchymal 
tumors (lipoma, fibroma). The differential diagnosis of a 
middle mediastinal mass
 includes lymphadenopathy, pul
-

includes thymoma, 
-
monary artery enlargement, aneurysm of the aorta or 
innominate artery, developmental cyst (bronchogenic, 
enteric, pleuropericardial), dilated azygous or hemiazygous 
vein, and foramen of Morgagni hernia. The differential 
diagnosis of a 
posterior mediastinal mass
 includes hiatal 
hernia, neurogenic tumor, meningocele, esophageal 
tumor, foramen of Bochdalek hernia, thoracic spine dis
-
ease, and extramedullary hematopoiesis. The neurogenic 
tumor group includes neurilemmoma, neurofibroma, 
neurosarcoma, ganglioneuroma, and pheochromocytoma.
Symptoms and signs of mediastinal masses are nonspe
-
cific and are usually caused by the effects of the mass on 
surrounding structures. Insidious onset of retrosternal 
chest pain, dysphagia, or dyspnea is often an important clue 
to the presence of a mediastinal mass. In about half of cases, 
symptoms are absent, and the mass is detected on routine 
chest radiograph. Physical findings vary depending on the 
nature and location of the mass.
CT scanning is helpful in management; additional 
radiographic studies of benefit include barium swallow if 
esophageal disease is suspected, Doppler sonography or 
venography of brachiocephalic veins and the superior vena 
cava, and angiography. MRI is useful; its advantages include 
better delineation of hilar structures and distinction 
between vessels and masses. MRI also allows imaging in 
multiple planes, whereas CT permits only axial imaging. 
Tissue diagnosis is necessary if a neoplastic disorder is sus
-
pected. Treatment and prognosis depend on the underlying 
cause of the mediastinal mass.
Azizad S et al. Solid tumors of the mediastinum in adults. Semin 
Ultrasound CT MR. 2016 Jun;37(3):196–211. [PMID: 
27261345]
Carter BW et al. Approaching the patient with an anterior medi
-
astinal mass: a guide for clinicians. J Thorac Oncol. 2014 Sep;
 
9(9 Suppl 2):S102–9. [PMID: 25396306]
Ruffini E et al. Management of thymic tumors: a European per
-
spective. J Thorac Dis. 2014 May;6(Suppl 2):S228–37. [PMID: 
24868441]
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º
INTERSTITIAL LUNG DISEASE (
Diffuse 
Parenchymal Lung Disease
)
 
»
Insidious onset of progressive dyspnea and non
-
productive chronic cough; extrapulmonary find
-
ings may accompany specific diagnoses.
 
»
Tachypnea, small lung volumes, bibasilar dry rales; 
digital clubbing and right heart failure with 
advanced disease.
 
»
Chest radiographs with low lung volumes and 
patchy distribution of ground glass, reticular, nod
-
ular, reticulonodular, or cystic opacities.
 
»
Reduced lung volumes, pulmonary diffusing 
capacity and 6-minute walk distance; hypoxemia 
Interstitial lung disease, or diffuse parenchymal lung 
disease, comprises a heterogeneous group of disorders that 
share common presentations (dyspnea), physical findings 
(late inspiratory crackles), and chest radiographs (septal 
thickening and reticulonodular changes).
The term “interstitial” is misleading since the pathologic 
process usually begins with injury to the alveolar epithelial 
or capillary endothelial cells (alveolitis). Persistent alveolitis 
may lead to obliteration of alveolar capillaries and reorgani
-
zation of the lung parenchyma, accompanied by irreversible 
fibrosis. The process does not affect the airways proximal to 
the respiratory bronchioles. At least 180 disease entities may 
present as interstitial lung disease. Table 9–16 outlines a 
selected list of differential diagnoses of interstitial lung dis
-
ease. In most patients, no specific cause can be identified. In 
the remainder, medications, a variety of organic and inor
-
ganic dusts, and connective tissue disease are the principal 
causes. The history—particularly the occupational and 
medication history—may provide evidence of a specific 
cause.
Table 9–16.
 
Differential diagnosis of interstitial lung disease.
Medication-related
 
An
tiarrhythmic agents (amiodarone)
 
An
tibacterial agents (nitrofurantoin, sulfonamides)
 
An
tineoplastic agents (bleomycin, cyclophosphamide, methotrexate, nitrosoureas)
 
An
tirheumatic agents (gold salts, penicillamine)
 
Phenytoin
Environmental and occupational (inhalation exposures)
 
D
ust, inorganic (asbestos, silica, hard metals, beryllium)
 
D
ust, organic (thermophilic actinomycetes, avian antigens, 
 species)
 
G
ases, fumes, and vapors (chlorine, isocyanates, paraquat, sulfur dioxide)
 
Ionizing 
radiation
 
T
alc (injection drug users)
 
F
ungus, disseminated (
Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum
)
 
M
ycobacteria, disseminated
 
Viruses
Primary pulmonary disorders
 
Cr
yptogenic organizing pneumonia
 
Idiopa
thic interstitial pneumonia: acute interstitial pneumonia, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, 
 
usual in
terstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease
 
P
ulmonary alveolar proteinosis
Systemic disorders
 
A
cute respiratory distress syndrome
 
Ank
ylosing spondylitis
 
A
utoimmune disease: dermatomyositis, polymyositis, rheumatoid arthritis, systemic sclerosis (scleroderma), systemic lupus erythematosus
 
Chr
onic eosinophilic pneumonia
 
G
oodpasture syndrome
 
Idiopa
thic pulmonary hemosiderosis
 
I
nflammatory bowel disease
 
Langerhans 
cell histiocytosis (eosinophilic granuloma)
 
L
ymphangitic spread of cancer (lymphangitic carcinomatosis)
 
Lymphangioleiomyomatosis
 
P
ulmonary edema
 
P
ulmonary venous hypertension, chronic
 
Gr
anulomatosis polyangiitis (formerly Wegener granulomatosis)
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The presence of diffuse parenchymal lung disease in the 
setting of an established connective tissue disease, such as 
rheumatoid arthritis, systemic lupus erythematosus, sclero
-
derma, polymyositis-dermatomyositis, Sjögren syndrome, 
and other overlap conditions, is suggestive of the etiology. 
In some cases, lung disease precedes the more typical mani
-
festations of the underlying connective tissue disease by 
months or years.
Known causes of interstitial lung disease are dealt with 
in their specific sections. The important idiopathic forms 
are discussed below.
DIFFUSE INTERSTITIAL PNEUMONIAS
 
»
Important to identify specific fibrosing disorders.
 
»
Idiopathic disease may require biopsy for 
 
»
Accurate diagnosis identifies patients most likely 
to benefit from therapy.
 
»
The most common diagnosis among patients with diffuse 
interstitial lung disease is one of the interstitial pneumonias, 
including all the entities described in Table 9–17. Histori
-
cally, a diagnosis of interstitial lung disease was based on 
clinical and radiographic criteria with only a small number 
of patients undergoing surgical lung biopsy. When biopsies 
were obtained, the common element of fibrosis led to the 
grouping together of several histologic patterns under the 
category of interstitial pneumonia or idiopathic pulmonary 
fibrosis (IPF). Distinct histopathologic features are now 
understood to represent different natural histories and 
responses to therapy (Table 9–17). Therefore, in the evalua
-
tion of patients with diffuse interstitial lung disease, clini
-
cians should attempt to identify specific disorders.
Patients with diffuse interstitial pneumonia may have 
any of the histologic patterns described in Table 9–17. The 
first step in evaluation is to identify patients whose disease 
is truly idiopathic. As indicated in Table 9–16, most identi
-
fiable causes of diffuse interstitial pneumonia are medica
-
tion-related, environmental or occupational agent exposure, 
or infectious. Interstitial lung diseases associated with other 
systemic disorders (pulmonary renal syndromes, autoim
-
mune disease) may be identified through a careful medical 
history. Apart from acute interstitial pneumonia, the clini
-
cal presentations of the diffuse interstitial pneumonias are 
sufficiently similar to preclude a specific diagnosis. Chest 
radiographs and high-resolution CT scans are diagnostic in 
some patients. Ultimately, many patients with apparently 
idiopathic disease require surgical lung biopsy to make a 
definitive diagnosis. The importance of accurate diagnosis 
is twofold. First, it allows the clinician to provide accurate 
information about the cause and natural history of the ill
-
ness. Second, accurate diagnosis helps distinguish patients 
most likely to benefit from therapy.
 
»
A. Symptoms, Signs, and Imaging
The most common of the diffuse interstitial pneumonias is 
pulmonary fibrosis associated with the histopathologic 
pattern of 
usual interstitial pneumonia (UIP).
 When no 
associated cause is evident, this is 
IPF.
 A diagnosis of IPF/
UIP can be made with 90% confidence in patients over 
 
65 years of age who have (1) idiopathic disease by history 
and inspiratory crackles on physical examination; (2) 
restrictive physiology on pulmonary function testing; 
(3) characteristic radiographic evidence of progressive 
fibrosis over several years; and (4) diffuse, patchy fibrosis 
with pleural-based honeycombing on high-resolution CT 
scan (Figure 9–6). Such patients do not need surgical lung 
biopsy.
B. Special Studies
Three diagnostic techniques are in common use: BAL, 
transbronchial biopsy, and surgical lung biopsy, either 
through an open procedure or using V ATS.
BAL
 may provide a specific diagnosis in cases of infec
-
tion, particularly with 
 or mycobacteria, or when

BAL
-
 or mycobacteria, or when 
cytologic examination reveals the presence of malignant 
cells. The findings may be suggestive and sometimes diag
-
nostic of eosinophilic pneumonia, Langerhans cell histiocy
-
tosis, or alveolar proteinosis.
Transbronchial biopsy
 through the flexible broncho
-
scope is easily performed in most patients. The risks of 
pneumothorax (5%) and hemorrhage (1–10%) are low. 
However, the tissue specimens recovered are small, sam
-
pling error is common, and crush artifact may complicate 
diagnosis. Transbronchial biopsy can make a definitive 
diagnosis of sarcoidosis, lymphangitic spread of carci
-
noma, pulmonary alveolar proteinosis, miliary tuberculo
-
sis, and Langerhans cell histiocytosis. Note that the 
diagnosis of IPF cannot be confirmed on transbronchial 
lung biopsy since the histologic diagnosis requires a pat
-
tern of changes rather than a single pathognomonic find
-
ing. Transbronchial biopsy may exclude IPF by confirming 
a specific alternative diagnosis. Transbronchial biopsy also 
cannot establish a specific diagnosis of idiopathic intersti
-
tial pneumonia. These patients generally require surgical 
lung biopsy.
Surgical lung biopsy
 is the standard for diagnosis of 
diffuse interstitial lung disease. Two or three biopsies taken 
from multiple sites in the same lung, including apparently 
normal tissue, may yield a specific diagnosis as well as 
prognostic information regarding the extent of fibrosis 
versus active inflammation. Patients under age 60 without 
a specific diagnosis generally should undergo surgical lung 
biopsy. In older and sicker patients, the risks and benefits 
must be weighed carefully for three reasons: (1) the mor
-
bidity of the procedure can be significant; (2) a definitive 
diagnosis may not be possible even with surgical lung 
biopsy; and (3) when a specific diagnosis is made, there 
may be no effective treatment. Empiric therapy or no treat
-
ment may be preferable to surgical lung biopsy in some 
patients.
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Table 9–17.
 
Idiopathic interstitial pneumonias.
Name and Clinical Presentation
Histopathology
Radiographic Pattern
Response to Therapy and Prognosis
Usual interstitial pneumonia (UIP)
Age 55–60, slight male predominance. Insidious dry 
cough and dyspnea lasting months to years. Clubbing 
present at diagnosis in 25–50%. Diffuse fine late inspi
-
ratory crackles on lung auscultation. Restrictive venti
-
latory defect and reduced diffusing capacity on 
pulmonary function tests. ANA and RF positive in 
~25% in the absence of documented collagen-vascu
-
lar disease.
Patchy, temporally and geographically nonuniform 
distribution of fibrosis, honeycomb change, and 
normal lung. Type I pneumocytes are lost, and 
there is proliferation of alveolar type II cells. 
“Fibroblast foci” of actively proliferating fibro
-
blasts and myofibroblasts. Inflammation is gen
-
erally mild and consists of small lymphocytes. 
Intra-alveolar macrophage accumulation is 
 
present but is not a prominent feature.
Diminished lung volume. Increased linear or 
reticular bibasilar and subpleural opacities. 
Unilateral disease is rare. High-resolution 
CT scanning shows minimal ground-glass 
and variable honeycomb change. Areas of 
normal lung may be adjacent to areas of 
advanced fibrosis. Between 2% and 10% 
have normal chest radiographs and high-
resolution CT scans on diagnosis.
No randomized study has demonstrated 
improved survival compared with 
untreated patients. Inexorably progres
-
sive. Median survival approximately 
 
3 years, depending on stage at presenta
-
tion. Nintedanib and pirfenidone reduce 
rate of decline in lung function.
Respiratory bronchiolitis-associated interstitial lung 
disease (RB-ILD)
1
Age 40–45. Presentation similar to that of UIP though in 
younger patients. Similar results on pulmonary func
-
tion tests, but less severe abnormalities. Patients with 
respiratory bronchiolitis are invariably heavy smokers.
Increased numbers of macrophages evenly dis
-
persed within the alveolar spaces. Rare fibro
-
blast foci, little fibrosis, minimal honeycomb 
change. In RB-ILD the accumulation of macro
-
phages is localized within the peribronchiolar 
air spaces; in DIP
1
, it is diffuse. Alveolar architec
-
ture is preserved.
May be indistinguishable from UIP . More 
often presents with a nodular or reticulo
-
nodular pattern. Honeycombing rare. 
High-resolution CT more likely to reveal 
diffuse ground-glass opacities and upper 
lobe emphysema.
Spontaneous remission occurs in up to 20% of 
patients, so natural history unclear. Smoking 
cessation is essential. Prognosis clearly bet
-
ter than that of UIP: median survival greater 
than 10 years. Corticosteroids thought to be 
effective, but there are no randomized clini
-
cal trials to support this view.
Acute interstitial pneumonia (AIP)
Clinically known as Hamman-Rich syndrome. Wide age 
range, many young patients. Acute onset of dyspnea 
followed by rapid development of respiratory failure. 
Half of patients report a viral syndrome preceding 
lung disease. Clinical course indistinguishable from 
that of idiopathic ARDS.
Pathologic changes reflect acute response to 
injury within days to weeks. Resembles organiz
-
ing phase of diffuse alveolar damage. Fibrosis 
and minimal collagen deposition. May appear 
similar to UIP but more homogeneous and 
there is no honeycomb change—though this 
may appear if the process persists for more than 
a month in a patient on mechanical ventilation.
Diffuse bilateral airspace consolidation with 
areas of ground-glass attenuation on 
high-resolution CT scan.
Supportive care (mechanical ventilation) 
critical but effect of specific therapies 
unclear. High initial mortality: 50-90% 
die within 2 months after diagnosis. 
 
Not progressive if patient survives. Lung 
function may return to normal or may 
 
be permanently impaired.
Nonspecific interstitial pneumonia (NSIP)
Age 45–55. Slight female predominance. Similar to UIP

Age 45–55. Slight female predominance. Similar to UIP 
but onset of cough and dyspnea over months, not 
years.
Nonspecific in that histopathology does not fit into 
better-established categories. Varying degrees 
of inflammation and fibrosis, patchy in distribu
-
tion but uniform in time, suggesting response 
to single injury. Most have lymphocytic and 
plasma cell inflammation without fibrosis. Hon
-
eycombing present but scant. Some have advo
-
cated division into cellular and fibrotic subtypes.
May be indistinguishable from UIP . Most 
typical picture is bilateral areas of 
ground-glass attenuation and fibrosis on 
high-resolution CT. Honeycombing is 
rare.
Treatment thought to be effective, but no 
prospective clinical studies have been 
published. Prognosis overall good but 
depends on the extent of fibrosis at 
 
diagnosis. Median survival greater than 
10 years.
Cryptogenic organizing pneumonia (COP , formerly bron
-
chiolitis obliterans organizing pneumonia [BOOP])
Typically age 50–60 but wide variation. Abrupt onset, fre
-
quently weeks to a few months following a flu-like illness. 
Dyspnea and dry cough prominent, but constitutional 
symptoms are common: fatigue, fever, and weight loss. 
Pulmonary function tests usually show restriction, but up 
to 25% show concomitant obstruction.
Included in the idiopathic interstitial pneumonias 
on clinical grounds. Buds of loose connective 
tissue (Masson bodies) and inflammatory cells 
fill alveoli and distal bronchioles.
Lung volumes normal. Chest radiograph 
typically shows interstitial and parenchy
-
mal disease with discrete, peripheral 
alveolar and ground-glass infiltrates. 
Nodular opacities common. High-resolu
-
tion CT shows subpleural consolidation 
and bronchial wall thickening and 
dilation.
Rapid response to corticosteroids in two-
thirds of patients. Long-term prognosis 
generally good for those who respond. 
Relapses are common.
1
Includes desquamative interstitial pneumonia (DIP).
ANA, antinuclear antibody; ARDS, acute respiratory distress syndrome; RF, rheumatoid factor; UIP , usual interstitial pneumonia.
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»
Treatment
Clinical experience suggests that patients with RB-ILD, 
nonspecific interstitial pneumonia (NSIP), or COP (Table 
9–17) frequently respond to corticosteroids and should 
be given a trial of therapy—typically prednisone, 1–2 mg/
kg/day for a minimum of 2 months. The same therapy is 
ineffective in patients with IPF. Since this therapy carries 
significant morbidity, experts do not recommend routine 
use of corticosteroids in patients with IPF. A number of 
antifibrotic (interferon gamma 1b) and immunomodula
-
tor/immunosuppressant (cyclosporine A, azathioprine, 
etanercept) agents have been investigated and are not 
recommended for the treatment of IPF, either in mono
-
therapy or combination therapy. In 2014, two agents, 
nintedanib and pirfenidone, were approved for the treat
-
ment of IPF based on controlled trials showing a signifi
-
cant reduction in the rate of decline in lung function in 
the population studied. Neither agent improved survival 
or quality of life compared with no treatment, however. 
Both agents cost approximately $100,000 per patient per 
year in the United States. The only definitive treatment 
for IPF is lung transplantation, with a 5-year survival rate 
estimated at 50%.
Hansell DM et al. CT staging and monitoring of fibrotic intersti
-
tial lung diseases in clinical practice and treatment trials: a 
position paper from the Fleischner Society. Lancet Respir 
Med. 2015 Jun;3(6):483–96. [PMID: 25975761]
Raoof S et al. Cystic lung diseases: algorithmic approach. Chest. 
2016 Oct;150(4):945–65. [PMID: 27180915]
Sverzellati N et al. American Thoracic Society-European 
Respiratory Society classification of the idiopathic intersti
-
tial pneumonias: advances in knowledge since 2002. 
Radiographics. 2015 Nov–Dec;35(7):1849–71. [PMID: 
26452110]
SARCOIDOSIS
 
»
Symptoms related to the lung, skin, eyes, periph
-
eral nerves, liver, kidney, heart, and other tissues.
 
»
Demonstration of noncaseating granulomas in a 
biopsy specimen.
 
»
Exclusion of other granulomatous disorders.
 
»
Sarcoidosis is a systemic disease of unknown etiology char
-
acterized in about 90% of patients by granulomatous 
inflammation of the lung. The incidence is highest in North 
American blacks and northern European whites; among 
blacks, women are more frequently affected than men. 
Onset of disease is usually in the third or fourth decade.
 
»
Patients may have malaise, fever, and dyspnea of insidious 
onset. Symptoms from skin involvement (erythema nodo
-
sum, lupus pernio [Figure 9–7]), iritis, peripheral neuropa
-
thy, arthritis (Chapter 20), or cardiomyopathy may also 
cause the patient to seek care. Some individuals are asymp
-
tomatic and come to medical attention after abnormal 
findings (typically bilateral hilar and right paratracheal 
lymphadenopathy) on chest radiographs. Physical findings 
are atypical of interstitial lung disease in that crackles are 
uncommon on chest examination. Other symptoms and 
 
▲
Figure 9–6.
 
Idiopathic pulmonary fibrosis. 
CT scan of 
the lungs showing the typical radiographic pattern of 
idiopathic pulmonary fibrosis, with a predominantly basi
-
lar, peripheral pattern of traction bronchiectasis, reticula
-
tion, and early honeycombing.
 
▲
Figure 9–7.
 
Skin involvement in sarcoidosis (lupus 
pernio), here involving the nasal rim. 
-
Mayeaux EJ Jr, Chumley H, Tysinger J.
 
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findings may include parotid gland enlargement, hepato
-
splenomegaly, and lymphadenopathy.
Laboratory tests may show leukopenia, an elevated eryth
-
rocyte sedimentation rate, and hypercalcemia (about 5% of 
patients) or hypercalciuria (20%). Angiotensin-converting 
enzyme (ACE) levels are elevated in 40–80% of patients 
with active disease. This finding is neither sensitive nor 
specific enough to have diagnostic significance. Physio
-
logic testing may reveal evidence of airflow obstruction, 
but restrictive changes with decreased lung volumes and 
diffusing capacity are more common. Skin test anergy is 
present in 70%. ECG may show conduction disturbances 
and dysrhythmias.
C. Imaging
Radiographic findings are variable and include bilateral 
hilar adenopathy alone (radiographic stage I), hilar adenop
-
athy and parenchymal involvement (radiographic stage II), 
or parenchymal involvement alone (radiographic stage III). 
Parenchymal involvement is usually manifested radio
-
graphically by diffuse reticular infiltrates, but focal infil
-
trates, acinar shadows, nodules, and, rarely, cavitation may 
be seen. Pleural effusion is noted in less than 10% of patients. 
Stage IV disease refers to advanced fibrotic changes princi
-
pally in the upper lobes.
The diagnosis of sarcoidosis generally requires histologic 
demonstration of noncaseating granulomas in biopsies 
from a patient with other typical associated manifestations. 
Other granulomatous diseases (eg, berylliosis, tuberculo
-
sis, fungal infections) and lymphoma must be excluded. 
Biopsy of easily accessible sites (eg, palpable lymph nodes, 
skin lesions, or salivary glands) is likely to be positive. 
Transbronchial lung biopsy has a high yield (75–90%) as 
well, especially in patients with radiographic evidence of 
parenchymal involvement. Some clinicians believe that tis
-
sue biopsy is not necessary when stage I radiographic find
-
ings are detected in a clinical situation that strongly favors 
the diagnosis of sarcoidosis (eg, a young black woman with 
erythema nodosum). Biopsy is essential whenever clinical 
and radiographic findings suggest the possibility of an 
alternative diagnosis, such as lymphoma. BAL fluid in sar
-
coidosis is usually characterized by an increase in lympho
-
cytes and a high CD4/CD8 cell ratio. BAL does not 
establish a diagnosis but may be useful in following the 
activity of sarcoidosis in selected patients. All patients 
require a complete ophthalmologic evaluation.
 
»
Treatment
Indications for treatment with oral corticosteroids (predni
-
sone, 0.5–1.0 mg/kg/day) include disabling constitutional 
symptoms, hypercalcemia, iritis, uveitis, arthritis, central 
nervous system involvement, cardiac involvement, granu
-
lomatous hepatitis, cutaneous lesions other than erythema 
nodosum, and progressive pulmonary lesions. Long-term 
therapy is usually required over months to years. Immuno
-
suppressive medications, most commonly methotrexate, 
azathioprine, or infliximab, are used in patients who are 
intolerant of corticosteroids or who have corticosteroid-
refractory disease, but sound clinical research to support 
specific agents is lacking.
 
»
Prognosis
The outlook is best for patients with hilar adenopathy alone; 
radiographic involvement of the lung parenchyma is associ
-
ated with a worse prognosis. Erythema nodosum portends 
a good outcome. About 20% of patients with lung involve
-
ment suffer irreversible lung impairment, characterized by 
progressive fibrosis, bronchiectasis, and cavitation. Pneu
-
mothorax, hemoptysis, mycetoma formation in lung cavi
-
ties, and respiratory failure often complicate this advanced 
stage. Myocardial sarcoidosis occurs in about 5% of patients, 
sometimes leading to restrictive cardiomyopathy, cardiac 
dysrhythmias, and conduction disturbances. Death from 
respiratory insufficiency occurs in about 5% of patients.

Patients require long-term follow-up: at a minimum, 
yearly physical examination, pulmonary function tests, 
chemistry panel, ophthalmologic evaluation, chest radio
-
graph, and ECG.
Baughman RP et al. New treatment strategies for pulmonary 
sarcoidosis: antimetabolites, biological drugs, and other treat
-
ment approaches. Lancet Respir Med. 2015 Oct;3(10):813–22. 
[PMID: 26204816]
Birnie DH et al. Cardiac manifestations of sarcoidosis: diagnosis 
and management. Eur Heart J. 2017 Sep 14;38(35):2663–70. 
[PMID: 27469375]
Carmona EM et al. Pulmonary sarcoidosis: diagnosis and treat
-
ment. Mayo Clin Proc. 2016 Jul;91(7):946–54. [PMID: 
27378039]
Judson MA. Corticosteroids in sarcoidosis. Rheum Dis Clin 
North Am. 2016 Feb;42(1):119–35. [PMID: 26611555]
Shinn J et al. The management of sarcoidosis: a primary care 
approach. Med Clin North Am. 2015 Sep;99(5):1123–48. 
[PMID: 26320049]
PULMONARY ALVEOLAR PROTEINOSIS
Pulmonary alveolar proteinosis is a rare disease in which 
phospholipids accumulate within alveolar spaces. The 
condition may be primary (idiopathic) or secondary 
(occurring in immunodeficiency; hematologic malignan
-
cies; inhalation of mineral dusts; or following lung infec
-
tions, including tuberculosis and viral infections). 
Progressive dyspnea is the usual presenting symptom, and 
chest radiograph shows bilateral alveolar infiltrates sug
-
gestive of pulmonary edema. The diagnosis is based on 
demonstration of characteristic findings on BAL (milky 
appearance and PAS-positive lipoproteinaceous material) 
in association with typical clinical and radiographic fea
-
tures. In secondary disease, an elevated anti-GM-CSF titer 
in serum or BAL fluid is highly sensitive and specific. In 
some cases, transbronchial or surgical lung biopsy (reveal
-
ing amorphous intra-alveolar phospholipid) is necessary.
The course of the disease varies. Some patients experience 
spontaneous remission; others develop progressive 
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respiratory insufficiency. Pulmonary infection with 
Nocardia
 
or fungi may occur. Therapy for alveolar proteinosis con
-
sists of periodic whole-lung lavage. Patients who cannot 
tolerate whole lung lavage or who fail to respond may 
benefit from inhalational or subcutaneous GM-CSF.
Papiris SA et al. Pulmonary alveolar proteinosis: time to shift? 
Expert Rev Respir Med. 2015 Jun;9(3):337–49. [PMID: 
25864717]
Suzuki T et al. Pulmonary alveolar proteinosis syndrome. Clin 
Chest Med. 2016 Sep;37(3):431–40. [PMID: 27514590]
EOSINOPHILIC PULMONARY SYNDROMES
Eosinophilic pulmonary syndromes are a diverse group of 
disorders typically characterized by eosinophilic pulmonary 
infiltrates, dyspnea, and cough. Many patients have constitu
-
tional symptoms, including fever. Common causes include 
exposure to medications (nitrofurantoin, phenytoin, ampi
-
cillin, acetaminophen, ranitidine) or infection with hel
-
minths (eg, 
Ascaris
, hookworms, 
Strongyloides
) or filariae 
(eg, 
Wuchereria bancrofti, Brugia malayi
, tropical pulmo
-
nary eosinophilia). 
Löffler syndrome
 refers to acute eosino
-
philic pulmonary infiltrates in response to transpulmonary 
passage of helminth larvae. Pulmonary eosinophilia can also 
be a feature of other illnesses, including allergic bronchopul
-
monary mycosis, eosinophilic granulomatosis with polyan
-
giitis, systemic hypereosinophilic syndromes, eosinophilic 
granuloma of the lung (properly referred to as pulmonary 
Langerhans cell histiocytosis), neoplasms, and numerous 
interstitial lung diseases. If an extrinsic cause is identified, 
therapy consists of removal of the offending medication or 
treatment of the underlying parasitic infection.
One-third of cases are idiopathic, and there are two 
common syndromes. 
Chronic eosinophilic pneumonia
 is 
seen predominantly in women and is characterized by 
fever, night sweats, weight loss, and dyspnea. Asthma is 
present in half of cases. Chest radiographs often show 
peripheral infiltrates, the “photographic negative” of pulmo
-
nary edema. BAL typically has a marked eosinophilia; 
peripheral blood eosinophilia is present in greater than 80%. 
Therapy with oral prednisone (1 mg/kg/day for 1–2 weeks, 
followed by a gradual taper over many months) usually 
results in dramatic improvement; however, most patients 
require at least 10–15 mg of prednisone every other day for 
a year or more (sometimes indefinitely) to prevent relapses. 
Acute eosinophilic pneumonia
 is an acute, febrile illness 
characterized by cough and dyspnea, sometimes rapidly 
progressing to respiratory failure. The chest radiograph is 
abnormal but nonspecific. BAL frequently shows eosino
-
philia but peripheral blood eosinophilia is rare at the onset 
of symptoms. The response to corticosteroids is usually 
dramatic.
Cottin V . Eosinophilic lung diseases. Clin Chest Med. 2016 Sep;
 
37(3):535–56. [PMID: 27514599]
Sergew A et al. Current approach to diagnosis and management 
of pulmonary eosinophilic syndromes: eosinophilic pneumo
-
nias, eosinophilic granulomatosis with polyangiitis, and 
hypereosinophilic syndrome. Semin Respir Crit Care Med. 
2016 Jun;37(3):441–56. [PMID: 27231866]
 
º
DISORDERS OF THE PULMONARY 
CIRCULATION
PULMONARY VENOUS THROMBOEMBOLISM
 
»
Predisposition to venous thrombosis, usually of 
the lower extremities.
 
»
One or more of the following: dyspnea, chest pain, 
hemoptysis, syncope.
 
»
Tachypnea and a widened alveolar-arterial P
o
2
 
difference.
 
»
Elevated rapid D-dimer and characteristic defects 
on CT pulmonary angiography, ventilation-
 
perfusion lung scan, or pulmonary angiogram.
 
»
Pulmonary venous thromboembolism, often referred to as 
pulmonary embolism (PE), is a common, serious, and 
potentially fatal complication of thrombus formation 
within the deep venous circulation. PE is the third leading 
cause of death among hospitalized patients. Despite this

cause of death among hospitalized patients. Despite this 
prevalence, most cases are not recognized antemortem, 
and less than 10% of patients with fatal emboli have 
received specific treatment for the condition. Management 
demands a vigilant systematic approach to diagnosis and 
an understanding of risk factors so that appropriate pre
-
ventive therapy can be given.
Many substances can embolize to the pulmonary circu
-
lation, including air (during neurosurgery, from central 
venous catheters), amniotic fluid (during active labor), fat 
(long bone fractures), foreign bodies (talc in injection drug 
users), parasite eggs (schistosomiasis), septic emboli (acute 
infectious endocarditis), and tumor cells (renal cell carci
-
noma). The most common embolus is thrombus, which 
may arise anywhere in the venous circulation or heart but 
most often originates in the deep veins of the lower 
extremities. Thrombi confined to the calf rarely embolize 
to the pulmonary circulation. However, about 20% of calf 
vein thrombi propagate proximally to the popliteal and 
ileofemoral veins, at which point they may break off and 
embolize to the pulmonary circulation. Pulmonary emboli 
will develop in 50–60% of patients with proximal deep 
venous thrombosis (DVT); half of these embolic events 
will be asymptomatic. Approximately 50–70% of patients 
who have symptomatic pulmonary emboli will have lower 
extremity DVT when evaluated.
PE and DVT are two manifestations of the same dis
-
ease. The risk factors for PE are the risk factors for throm
-
bus formation within the venous circulation: venous stasis, 
injury to the vessel wall, and hypercoagulability (Virchow 
triad). Venous stasis increases with immobility (bed rest—
especially postoperative—obesity, stroke), hyperviscosity 
(polycythemia), and increased central venous pressures 
(low cardiac output states, pregnancy). Vessels may be 
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HAPTER
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damaged by prior episodes of thrombosis, orthopedic sur
-
gery, or trauma. Hypercoagulability can be caused by 
medications (oral contraceptives, hormonal replacement 
therapy) or disease (malignancy, surgery) or may be the 
result of inherited gene defects. The most common inher
-
ited cause in white populations is resistance to activated 
protein C, also known as factor V Leiden. The trait is pres
-
ent in approximately 3% of healthy American men and in 
20–40% of patients with idiopathic venous thrombosis. 
Other major risks for hypercoagulability include the fol
-
lowing: deficiencies or dysfunction of protein C, protein S, 
and antithrombin; prothrombin gene mutation; hyperho
-
mocysteinemia and the presence of antiphospholipid anti
-
bodies (lupus anticoagulant and anticardiolipin antibody).
PE has multiple physiologic effects. Physical obstruction 
of the vascular bed and vasoconstriction from neurohu
-
moral reflexes both increase pulmonary vascular resistance. 
Massive thrombus may cause right ventricular failure. Vas
-
cular obstruction increases physiologic dead space (wasted 
ventilation) and leads to hypoxemia through right-to-left 
shunting, decreased cardiac output, and surfactant depletion 
causing atelectasis. Reflex bronchoconstriction promotes 
wheezing and increased work of breathing.
 
»
The clinical diagnosis of PE is notoriously difficult for two 
reasons. First, the clinical findings depend on both the size 
of the embolus and the patient’s preexisting cardiopulmo
-
nary status. Second, common symptoms and signs of pul
-
monary emboli are not specific to this disorder (Table 9–18).
Indeed, no single symptom or sign or combination of 
clinical findings is specific to PE. Some findings are fairly 
sensitive: dyspnea and pain on inspiration occur in 75–85% 
and 65–75% of patients, respectively. Tachypnea is the only 
sign reliably found in more than half of patients. A com
-
mon clinical strategy is to use combinations of clinical 
findings to identify patients’ risk for PE. For example, 97% 
of patients in the original Prospective Investigation of Pul
-
monary Embolism Diagnosis (PIOPED I) study with 
angiographically proved pulmonary emboli had one or 
Table 9–18.
 
Frequency of specific symptoms and signs in patients at risk for pulmonary thromboembolism.
UPET
1
 PE+ 
 
(n = 327)
PIOPED I
2
 PE+ 
 
(n = 117)
PIOPED I
2
 
PE– (n = 248)
Symptoms
Dyspnea
84%
73%
72%
Respirophasic chest pain
74%
66%
59%
Cough
53%
37%
36%
Leg pain
NR
26%
24%
30%
13%
8%
NR
10%
18%
Wheezing
NR
9%
11%
Anginal pain
14%
4%
6%
Signs
Respiratory rate ≥ 16 UPET, ≥ 20 PIOPED I
92%
70%
68%
Crackles (rales)
58%
51%
40%
3
Heart rate ≥ 100/min
44%
30%
24%
Fourth heart sound (S
4
)
NR
24%
13%
3
Accentuated pulmonary component of second heart sound (S
2
P)
53%
23%
13%
3
T ≥ 37.5°C UPET, ≥ 38.5°C PIOPED
43%
7%
12%
Homans sign
NR
4%
2%
Pleural friction rub
NR
3%
2%
Third heart sound (S
3
)
NR
3%
4%
Cyanosis
19%
1%
2%
1
Data from the Urokinase-Streptokinase Pulmonary Embolism Trial (UPET), as reported in Bell WR et al. The clinical features of submassive 
and massive pulmonary emboli. Am J Med. 1977 Mar;62(3):355–60.
2
Data from patients enrolled in the PIOPED I study, as reported in Stein PD et al. Clinical, laboratory, roentgenographic, and electrocardio
-
graphic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest. 1991 Sep; 100(3):
 
598–603.
3
P
 < 0.05 comparing patients in the PIOPED I study.
PE+, confirmed diagnosis of pulmonary embolism; PE–, diagnosis of pulmonary embolism ruled out; NR, not reported.
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CMDT 2019
more of three findings: dyspnea, chest pain with breathing, 
or tachypnea. Wells and colleagues have published and 
validated a simple clinical decision rule that quantifies and 
dichotomizes this clinical risk assessment, allowing diver
-
sion of patients deemed unlikely to have PE to a simpler 
diagnostic algorithm (see Integrated Approach to Diagno
-
sis of Pulmonary Embolism).
The 
ECG
 is abnormal in 70% of patients with PE. However, 
the most common abnormalities are sinus tachycardia and 
nonspecific ST and T wave changes, each seen in approxi
-
mately 40% of patients. Five percent or less of patients in 
the PIOPED I study had P pulmonale, right ventricular 
hypertrophy, right axis deviation, and right bundle branch 
block.
 usually reveal acute respiratory 
alkalosis due to hyperventilation. The arterial P
o
2
 and the 
alveolar-arterial oxygen difference (A–a–D
o
2
) are usually 
abnormal in patients with PE compared with healthy, age-
matched controls. However, arterial blood gases are not 
diagnostic: among patients who were evaluated in the 
PIOPED I study, neither the P
o
2
 nor the A–a–D
o
2
 differ
-
entiated between those with and those without pulmonary 
emboli. Profound hypoxia with a normal chest radiograph 
in the absence of preexisting lung disease is highly suspi
-
cious for PE.
Plasma levels of 
D-dimer,
 a degradation product of 
cross-linked fibrin, are elevated in the presence of thrombus. 
Using a D-dimer threshold between 300 and 500 ng/mL 
(300 and 500 mcg/L), a rapid quantitative enzyme-linked 
immunosorbent assay (ELISA) has shown a sensitivity for 
venous thromboembolism of 95–97% and a specificity of 
45%. Therefore, a D-dimer less than 500 ng/mL (less than 
500 mcg/L) using a rapid quantitative ELISA provides 
strong evidence against venous thromboembolism, with a 
likelihood ratio of 0.11–0.13. Appropriate diagnostic 
thresholds have not been established for patients in whom 
D-dimer is elevated.
Serum troponin I, troponin T, and plasma B-type natri
-
uretic peptide (BNP) levels are typically higher in patients 
with PE compared with those without embolism; the pres
-
ence and magnitude of the elevation are not useful in diagno
-
sis, but correlate with adverse outcomes, including mechanical 
ventilation, prolonged hospitalization, and death.
C. Imaging and Special Examinations
1. Chest radiography—
The chest radiograph is necessary 
to exclude other common lung diseases and to permit 
interpretation of the ventilation-perfusion (
V
.
/
Q
.
) scan, but 
it does not establish the diagnosis by itself. The chest radio
-
graph was normal in only 12% of patients with confirmed 
PE in the PIOPED I study. The most frequent findings were 
atelectasis, parenchymal infiltrates, and pleural effusions. 
However, the prevalence of these findings was the same in 
hospitalized patients without PE. A prominent central pul
-
monary artery with local oligemia (Westermark sign) or 
pleural-based areas of increased opacity that represent 
intraparenchymal hemorrhage (Hampton hump) are 
uncommon. Paradoxically, the chest radiograph may be 
most suggestive of PE when normal in the setting of 
hypoxemia.
2. CT-pulmonary angiography (PA)—
Helical CT-PA is 
used as the initial diagnostic study in North America for 
suspected PE. CT-PA requires administration of intrave
-
nous radiocontrast dye but is otherwise noninvasive. A 
high-quality study is very sensitive for the detection of 
thrombus in the proximal pulmonary arteries. Comparing 
CT-PA to the 
V
.
/
Q
.
 scan as the initial test for PE, detection 
of thrombi is roughly comparable, although more alterna
-
tive pulmonary diagnoses are made with CT-PA scanning.
Test characteristics of CT-PA vary widely by study and 
facility. Factors influencing results include patient size and 
cooperation, the type and quality of the scanner, the imag
-

-
ing protocol, and the experience of the interpreting radi
-
ologist. The 2006 PIOPED II study, using multi-detector 
(four-row) helical CT and excluding the 6% of patients 
whose studies were “inconclusive, ” reported sensitivity of 
83% and specificity of 96%.
A 15–20% false-negative rate is high for a screening test, 
and raises the practical question whether it is safe to with
-
hold anticoagulation in patients with a negative CT-PA. 
Research data provide two complementary answers. The 
insight of PIOPED I, that the clinical assessment of pretest 
probability improves the performance of the 
V
.
/
Q
.
 scan, was 
confirmed with CT-PA in PIOPED II, where positive and 
negative predictive values were highest in patients with 
concordant clinical assessments but poor with conflicting 
assessments. The negative predictive value of a normal 
CT-PA in patients with a high pretest probability was only 
60%. Therefore, a normal CT-PA alone does not exclude 
PE in high-risk patients, and either empiric therapy or 
further testing is indicated.
A large, prospective trial, the Christopher Study, incor
-
porated objective, validated pretest clinical assessment into 
diagnostic algorithms using D-dimer measurement. In this 
study, patients with a high pretest probability and a nega
-
tive CT-PA who were not receiving anticoagulation had a 
low (less than 2%) 3-month incidence of subsequent PE. 
This low rate of complications supports the contention that 
many false-negative studies represent clinically insignifi
-
cant, small distal thrombi and provides support for moni
-
toring most patients with a high-quality negative CT-PA 
off therapy (see Integrated Approach to Diagnosis of Pul
-
monary Embolism below). The rate of false-positive CT-PA 
and overtreatment of PE has not been as well studied to 
date.
3. Ventilation-perfusion lung scanning—
A perfusion 
scan is performed by injecting radiolabeled microaggre
-
gated albumin into the venous system, allowing the parti
-
cles to embolize to the pulmonary capillary bed. To 
perform a ventilation scan, the patient breathes a radioac
-
tive gas or aerosol while the distribution of radioactivity in 
the lungs is recorded. A defect on perfusion scanning rep
-
resents diminished blood flow to that region of the lung. 
This finding is not specific for PE. Defects in the perfusion 
scan are interpreted in conjunction with the ventilation 
scan to give a high, low, or intermediate (indeterminate) 
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probability that PE is the cause of the abnormalities. 
Criteria for the combined interpretation of ventilation 
and perfusion scans (commonly referred to as a single 
test, the 
V
.
/
Q
.
 scan) are complex, confusing, and not com
-
pletely standardized. A normal perfusion scan excludes the 
diagnosis of clinically significant PE (negative predictive 
value of 91% in the PIOPED I study). A high-probability 
V
.
/
Q
.
 scan is most often defined as having two or more seg
-
mental perfusion defects in the presence of normal ventila
-
tion and is sufficient to make the diagnosis of PE in most 
instances (positive predictive value of 88% among PIOPED 
I patients). 
V
.
/
Q
.
 scans are most helpful when they are either 
normal or indicate a high probability of PE. Such readings 
are reliable—interobserver agreement is best for normal 
and high-probability scans—and they carry predictive 
power. The likelihood ratios associated with normal and 
high-probability scans are 0.10 and 18, respectively, indi
-
cating significant and frequently conclusive changes from 
pretest to posttest probability.
However, 75% of PIOPED I 
V
.
/
Q
.
 scans were nondiag
-
nostic, ie, of low or intermediate probability. At angiogra
-
phy, these patients had an overall incidence of PE of 14% 
and 30%, respectively.
One of the most important findings of PIOPED I was 
that the clinical assessment of pretest probability could be 
used to aid the interpretation of the 
V
.
/
Q
.
 scan. For patients 
with low-probability 
V
.
/
Q
.
 scans and a low (20% or less) 
clinical pretest probability of PE, the diagnosis was con
-
firmed in only 4%. Such patients may reasonably be 
observed off therapy without angiography. All other patients 
with nondiagnostic 
V
.
/
Q
.
 scans require further testing to 
determine the presence of venous thromboembolism.
4. Venous thrombosis studies—
Seventy percent of 
patients with PE will have DVT on evaluation, and approx
-
imately half of patients with DVT will have PE on angiog
-
raphy. Since the history and physical examination are 
neither sensitive nor specific for PE and since the results of 
V
.
/
Q
.
 scanning are frequently equivocal, documentation of 
DVT in a patient with suspected PE establishes the need 
for treatment and may preclude further testing.
Commonly available diagnostic techniques include 
venous ultrasonography, impedance plethysmography, and 
contrast venography. In most centers, 
venous ultrasonog
-
raphy
 is the test of choice to detect proximal DVT. Inability 
to compress the common femoral or popliteal veins in 
symptomatic patients is diagnostic of first-episode DVT 
(positive predictive value of 97%); full compressibility of 
both sites excludes proximal DVT (negative predictive 
value of 98%). The test is less accurate in distal thrombi, 
recurrent thrombi, or in asymptomatic patients. Imped
-
ance plethysmography relies on changes in electrical 
impedance between patent and obstructed veins to deter
-
mine the presence of thrombus. Accuracy is comparable 
though not quite as high as ultrasonography. Both ultraso
-
nography and impedance plethysmography are useful in 
the serial examination of patients with high clinical suspi
-
cion of venous thromboembolism but negative leg studies. 
In patients with suspected first-episode DVT and a 
negative ultrasound or impedance plethysmography 
examination, multiple studies have confirmed the safety of 
withholding anticoagulation while conducting two sequen
-
tial studies on days 1–3 and 7–10. Similarly, patients with 
nondiagnostic 
V
.
/
Q
.
 scans and an initial negative venous 
ultrasound or impedance plethysmography examination 
may be monitored off therapy with serial leg studies over 
 
2 weeks. When serial examinations are negative for proximal 
DVT, the risk of subsequent venous thromboembolism 
over the following 6 months is less than 2%.
Contrast venography remains the reference standard

Contrast venography remains the reference standard 
for the diagnosis of DVT. An intraluminal filling defect is 
diagnostic of venous thrombosis. However, venography 
has significant shortcomings and has been replaced by 
venous ultrasound as the diagnostic procedure of choice. 
Venography may be useful in complex situations where 
there is discrepancy between clinical suspicion and nonin
-
vasive testing.
5. Pulmonary angiography—
Pulmonary angiography 
remains the reference standard for the diagnosis of PE. An 
intraluminal filling defect in more than one projection 
establishes a definitive diagnosis. Secondary findings 
highly suggestive of PE include abrupt arterial cutoff, 
asymmetry of blood flow—especially segmental olige
-
mia—or a prolonged arterial phase with slow filling. Pul
-
monary angiography was performed in 755 patients in the 
PIOPED I study. A definitive diagnosis was established in 
97%; in 3% the studies were nondiagnostic. Four patients 
(0.8%) with negative angiograms subsequently had pulmo
-
nary thromboemboli at autopsy. Serial angiography has 
demonstrated minimal resolution of thrombus prior to day 
7 following presentation. Thus, negative angiography 
within 7 days of presentation excludes the diagnosis.
Pulmonary angiography is a safe but invasive procedure 
with well-defined morbidity and mortality data. Minor 
complications occur in approximately 5% of patients. Most 
are allergic contrast reactions, transient kidney injury, or 
percutaneous catheter–related injuries; cardiac perforation 
and arrhythmias are reported but rare. Among the PIOPED 
I patients who underwent angiography, there were five 
deaths (0.7%) directly related to the procedure.
The appropriate role of pulmonary angiography in the 
diagnosis of PE remains a subject of ongoing debate. There 
is wide agreement that angiography is indicated in any 
patient in whom the diagnosis is in doubt when there is a 
high clinical pretest probability of PE or when the diagno
-
sis of PE must be established with certainty, as when anti
-
coagulation is contraindicated or placement of an inferior 
vena cava filter is contemplated.
 
»
Integrated Approach to Diagnosis of 
Pulmonary Embolism
An integrated approach to the diagnosis of PE uses the 
clinical likelihood of venous thromboembolism derived 
from a clinical prediction rule (Table 9–19) along with the 
results of diagnostic tests to come to one of three decision 
points: to establish venous thromboembolism (PE or DVT) 
as the diagnosis, to exclude venous thromboembolism with 
sufficient confidence to discontinue anticoagulation 
CMDT19_Ch09_p0252-p0333.indd   308

309
 
CMDT 2019
therapy and monitor the patient, or to refer the patient for 
additional testing. An ideal diagnostic algorithm would 
proceed in a cost-effective, stepwise fashion to come to 
these decision points at minimal risk to the patient. Most 
North American centers use Wells’ clinical prediction rule 
(Table 9–19) or something similar to guide a rapid D-dimer 
and CT-PA–based diagnostic algorithm (Figure 9–8). This 
approach is highly effective when applied correctly. The 
Christopher Study, a rigorous study that used the Wells’ 
approach, found the incidence of venous thromboembo
-
lism was 1.3% and fatal PE occurred in 0.5% of persons who 
stopped anticoagulation therapy and were monitored for 
 
3 months. The incidence of PE following a negative inte
-
grated clinical, D-dimer, and CT-PA evaluation that 
excludes PE is comparable to that seen following the tradi
-
tional gold standard of a negative pulmonary angiography.
Concern over false-positive D-dimer measurements in 
low-risk patients that prompt unnecessary CT-PA has led 
researchers to develop the Pulmonary Embolism Rule-Out 
Criteria (PERC, Table 9–20). In a prospective analysis of 
8138 emergency department patients at risk for PE, 
researchers identified 20% (1666) who had 
both
 a low (less 
than 20%) pretest probability of PE 
and
 met all eight PERC 
criteria. This group had a 1.0% incidence of PE, with one 
fatality. Using the algorithm in Figure 9–8, patients with a 
Modified Wells Score of 4 or less who meet all eight PERC 
criteria do not need to undergo D-dimer testing and may 
be monitored clinically.
The standard 
V
.
/
Q
.
 scan based algorithm (Table 9–21) 
remains useful in many patients, especially those who are 
not able to undergo CT-PA (eg, those with advanced 
chronic kidney disease).
 
»
Venous thromboembolism is often clinically silent until it 
presents with significant morbidity or mortality. It is a 
prevalent disease, clearly associated with identifiable risk 
factors. For example, the incidence of proximal DVT, PE, 
and fatal PE in untreated patients undergoing hip fracture 
surgery is reported to be 10–20%, 4–10%, and 0.2–5%, 
respectively. There is unambiguous evidence of the efficacy 
of prophylactic therapy in this and other clinical situations, 
yet it remains underused. Only about 50% of surgical 
deaths from PE had received any form of preventive ther
-
apy. Discussion of strategies for the prevention of venous 
thromboembolism can be found in Chapter 14.
 
»
Treatment
A. Anticoagulation
Anticoagulation is not definitive therapy but a form of 
secondary prevention. Heparin binds to and accelerates the 
ability of antithrombin to inactivate thrombin, factor Xa, 
and factor IXa. It thus retards additional thrombus forma
-
tion, allowing endogenous fibrinolytic mechanisms to 
lyse-existing clot. The standard regimen of heparin fol
-
lowed by 6 months of oral warfarin results in an 80–90% 
reduction in the risk of both recurrent venous thrombosis 
and death from PE (see Tables 14–16, 14–19, 14–20). Low-
molecular-weight heparins (LMWHs) are as effective as 
unfractionated heparin in the treatment of venous throm
-
boembolism. The 2016 CHEST Guideline and Expert 
Panel Report recommends direct oral anticoagulants over 
vitamin K antagonist (warfarin) and LMWH in all patients 
with venous thromboembolism without a cancer diagnosis 
and recommends LMWH for patients with cancer.
The optimal duration of anticoagulation therapy for 
venous thromboembolism is unknown. There appears to 
be a protective benefit to continued anticoagulation in 
first-episode venous thromboembolism (twice the rate of 
recurrence in 6 weeks compared with 6 months of therapy) 
and recurrent disease (eightfold risk of recurrence in 
 
6 months compared with 4 years of therapy). These studies 
did not distinguish patients with reversible risk factors, 
such as surgery or transient immobility, from patients who

such as surgery or transient immobility, from patients who 
have a nonreversible hypercoagulable state, such as factor V 
Leiden, inhibitor deficiency, antiphospholipid syndrome, or 
malignancy. An RCT of low-dose warfarin (INR 1.5–2.0) 
versus no therapy following 6 months of standard ther
-
apy in patients with idiopathic DVT was stopped early. 
The protective benefits of continued anticoagulation 
include fewer DVTs in addition to a trend toward lower 
mortality despite more hemorrhage in the warfarin group. 
Table 9–19.
 
Clinical prediction rule for pulmonary 
embolism (PE).
Variable
Points
Clinical symptoms and signs of deep venous 
thrombosis (DVT) (leg swelling and pain with 
palpation of deep veins)
3.0
Alternative diagnosis less likely than PE
3.0
Heart rate > 100 beats/min
1.5
Immobilization for more than 3 days or surgery 
in previous 4 weeks
1.5
Previous PE or DVT
1.5
1.0
Cancer (with treatment within past 6 months or 
palliative care)
1.0
Three-tiered clinical probability assessment 
(Wells criteria)
Score
High
> 6.0
Moderate
2.0 to 6.0
Low
< 2.0
Dichotomous clinical probability assessment 
(Modified Wells criteria)
Score
PE likely
> 4.0
PE unlikely
< or = 4.0
Data from Wells PS et al. Derivation of a simple clinical model to 
categorize patients’ probability of pulmonary embolism: increasing 
the models’ utility with the SimpliRED D-dimer. Thromb Haemost. 
2000 Mar;83(3):416–20.
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Risk reductions were consistent across groups with and 
without inherited thrombophilia.
For many patients, venous thrombosis is a recurrent 
disease, and continued therapy results in a lower rate of 
recurrence at the cost of an increased risk of hemorrhage. 
Therefore, the appropriate duration of therapy needs to 
take into consideration the patient’s age, potentially revers
-
ible risk factors, likelihood and potential consequences of 
hemorrhage, and preferences for continued therapy. The 
2016 CHEST Guideline and Expert Panel Report recom
-
mends 3 months of anticoagulation after a first episode 
provoked by a surgery or a transient nonsurgical risk fac
-
tor. Extended therapy (no scheduled stop date) is recom
-
mended for an unprovoked episode with a low to moderate 
risk of bleeding. Patient sex and D-dimer level measured a 
month after stopping anticoagulant therapy may influence 
this treatment decision. Patients who continue to receive 
anticoagulation long term should be reassessed for venous 
thrombosis periodically (at least annually). For patients 
with cancer, extended therapy with LMWH is recom
-
mended regardless of bleeding risk. D-dimer testing has 
been suggested to identify those who may benefit from 
continued anticoagulation after 3 months of therapy but 
clinical data have not supported its utility in this regard.
The major complication of anticoagulation is hemor
-
rhage. Risk factors for hemorrhage include the intensity of 
the anticoagulation; duration of therapy; concomitant 
administration of medications, such as aspirin, that inter
-
fere with platelet function; and patient characteristics, 
particularly increased age, previous gastrointestinal hem
-
orrhage, and coexistent chronic kidney disease.
PE ex
cl
uded
Search
 for 
alternativ
e
di
ag
noses
Fo
llow of
f 
anticoagulatio
n
Nega
ti
ve
Al
l 8
< 
8
P
ositi
ve
PE
RC criteria from T
abl
e 
9–
20
R
api
d 
quantitati
ve ELIS
A
D-
dime
r 
assa
y
High
 
qualit
y,
 
normal
 
stud
y
Findin
gs
 of PE
In
de
te
rmin
ate st
ud
y for PE
CT
-P
A
> 
4.
0
PE 
li
ke
ly
Concern
 for PE
≤ 4.
0
PE 
unlik
el
y
LE US or 
PA
Di
ag
nosis
 
establishe
d
Tr
eat for 
PE
PE ex
cl
uded
Search
 for 
e
di
ag
noses
Fo
llow of
f 
n
Dich
otomous Clin
ical
 Pr
obabili
ty
 
Assessment
Modified
 
We
lls Score from T
abl
e 
9–
19
 
▲
Figure 9–8.
 
D-dimer and helical CT-PA–based diagnostic algorithm for PE. 
CT-PA, CT pulmonary angiogram; PE, 
pulmonary embolism; ELISA, enzyme-linked immunosorbent assay; PERC, pulmonary embolism rule-out criteria; VTE, 
venous thromboembolic disease; LE US, lower extremity venous ultrasound for deep venous thrombosis; PA, pulmonary 
angiogram. (Adapted, with permission, from van Belle A et al. Effectiveness of managing suspected pulmonary embolism 
using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006 Jan 11;295(2):
 
172–9. Copyright © 2006 American Medical Association. All rights reserved.)
Table 9–20.
 
Pulmonary embolism rule-out criteria 
(PERC) for low-risk patients.
For patients with a Modified Wells Score ≤ 4
1
 who meet ALL of the 
following criteria, PE is excluded, follow off anticoagulation, and 
search for alternative diagnoses.
 
• 
Age
 
<
 
50
 
y
ears
 
• 
Heart
 
r
ate
 
<
 
100
 
bpm
 
• 
Oxyhemoglobin
 
sa
turation
 
on
 
r
oom
 
air
 
≥
 
95%
 
• 
No
 
prior
 
hist
ory
 
of
 
v
enous
 
thr
omboembolism
 
• 
 
No
 
r
ecent
 
(within
 
4
 
w
eeks)
 
tr
auma
 
or
 
sur
gery
 
r
equiring
 
hospitalization
 
• 
No
 
pr
esenting
 
hemopt
ysis
 
• 
No
 
estr
ogen
 
ther
apy
 
• 
No
 
unila
teral
 
leg
 
sw
elling
1
See Table 9–19.
Data from: Kline JA et al. Impact of a rapid rule-out protocol for 
pulmonary embolism on the rate of screening, missed cases, and 
pulmonary vascular imaging in an urban US emergency room. 
Ann Emerg Med. 2004 Nov;44(5):490–502.
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CMDT 2019
The reported incidence of major hemorrhage following 
intravenous administration of unfractionated heparin is nil 
to 7%; that of fatal hemorrhage is nil to 2%. The incidence 
with LMWHs is not statistically different. There is no 
information comparing hemorrhage rates at different doses 
of heparin. The risk of death from another pulmonary 
embolism during subtherapeutic heparin administration 
in the first 24–48 hours after diagnosis is significant; it 
appears to outweigh the risk of short-term supratherapeu
-
tic heparin levels. The incidence of hemorrhage during 
therapy with warfarin is reported to be between 3% and 4% 
per patient year. The frequency varies with the target INR 
and is consistently higher when the INR exceeds 4.0. There 
is no apparent additional antithrombotic benefit in venous 
thromboembolism with a target INR above 2.0–3.0 (see 
Chapter 14).
B. Thrombolytic Therapy
Streptokinase, urokinase, and recombinant tissue plasmino
-
gen activator (rt-PA; alteplase) increase plasmin levels and 
thereby directly lyse intravascular thrombi. In patients with 
established PE, thrombolytic therapy accelerates resolution 
of emboli within the first 24 hours compared with standard 
heparin therapy. This is a consistent finding using angiogra
-
Table 9–21.
 
Pulmonary ventilation-perfusion scan based diagnostic algorithm for PE.
Clinical concern for PE:
1. Analyze by three-tiered clinical probability assessment (Table 9–19)
2. Obtain scan
3. Match results in the following table
Clinical suspicion for PE by clinical probability assessment
HIGH
MODERATE
LOW
 
High Probability 
scan
STOP .
Diagnosis established.
Treat for PE.
STOP .
Diagnosis likely (56% in PIOPED I, but 
small number of patients). Treat for PE 
or evaluate further with LE US or 
CT-PA.
 
Indeterminate 
Probability 
scan
Diagnosis highly likely 
 
(66% in PIOPED I).
Treat for PE or evaluate further with 
 
LE US or CT-PA.
Uncertain diagnosis. Evaluate 
 
further with LE US or CT-PA.
Uncertain diagnosis. Evaluate further 
with LE US or CT-PA.
 
Low 
 
scan
STOP .
Diagnosis excluded; monitor off 
 
anticoagulation. Consider 
 
alternative diagnoses.
 
Normal 
scan
STOP .
 
STOP .
 
STOP .
 
CT-PA, helical CT pulmonary angiography; LE US, lower extremity venous ultrasound for DVT; PE, pulmonary embolism.
Data from The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective 
Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990 May 23–30;263(20):2753–9.
phy, 
V
.
/
Q
.
 scanning, echocardiography, and direct measure
-
ment of pulmonary artery pressures. However, at 
 
1 week and 1 month after diagnosis, these agents show no 
difference in outcome compared with heparin and warfarin. 
Hemodynamically stable patients with echocardiographic 
evidence of right heart strain from acute PE show no long-
term improvement in function or mortality when given 
thrombolytic therapy. Indeed, clinical research shows no 
improvements in mortality in any patient population. Sub
-
tle improvements in pulmonary function, including 
improved single-breath diffusing capacity and a lower inci
-
dence of exercise-induced pulmonary hypertension, have 
been observed. The reliability and clinical importance of 
these findings is unclear. The major disadvantages of 
thrombolytic therapy compared with heparin are its greater 
cost and significant increase in major hemorrhagic compli
-
cations. The incidence of intracranial hemorrhage in

-
cations. The incidence of intracranial hemorrhage in 
patients with PE treated with alteplase is 2.1% compared 
with 0.2% in patients treated with heparin. Current practice 
supports thrombolytic therapy for PE in patients at high 
risk for death from refractory hypotension or hypoxemia 
despite heparin therapy, patients in whom the more rapid 
resolution of thrombus may be lifesaving.
Absolute contraindications to thrombolytic therapy 
include active internal bleeding and stroke within the past 
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2 months. Major contraindications include uncontrolled 
hypertension and surgery or trauma within the past 
 
6 weeks.
C. Additional Measures
Interruption of the inferior vena cava may be indicated in 
patients with a major contraindication to anticoagulation 
who have or are at high risk for development of proximal 
DVT or PE. Placement of an inferior vena cava filter is also 
recommended for recurrent thromboembolism despite 
adequate anticoagulation, for chronic recurrent embolism 
with a compromised pulmonary vascular bed (eg, in pul
-
monary hypertension), and with the concurrent perfor
-
mance of surgical pulmonary embolectomy or pulmonary 
thromboendarterectomy. Percutaneous transjugular place
-
ment of a mechanical filter is the preferred mode of infe
-
rior vena cava interruption. These devices reduce the 
short-term incidence of PE in patients presenting with 
proximal lower extremity DVT. However, they are associ
-
ated with a twofold increased risk of recurrent DVT in the 
first 2 years following placement so plans must be usually 
made for their subsequent removal.
In rare critically ill patients for whom thrombolytic 
therapy is contraindicated or unsuccessful, mechanical or 
surgical extraction of thrombus may be indicated. Pulmo
-
nary embolectomy is an emergency procedure of last resort 
with a very high mortality rate. It is performed only in a 
few specialized centers.
 
»
Prognosis
PE is estimated to cause more than 50,000 deaths annually. 
In the majority of deaths, PE is not recognized antemortem 
or death occurs before specific treatment can be initiated. 
These statistics highlight the importance of preventive 
therapy in high-risk patients (Chapter 14). The outlook for 
patients with diagnosed and appropriately treated PE is 
generally good. Overall prognosis depends on the underly
-
ing disease rather than the PE itself. Death from recurrent 
thromboemboli is uncommon, occurring in less than 3% of 
cases. Perfusion defects resolve in most survivors. Chronic 
thromboembolic pulmonary hypertension develops in 
approximately 1% of patients. Selected patients may benefit 
from pulmonary endarterectomy.
Couturaud F et al; PADIS-PE Investigators. Six months vs 
extended oral anticoagulation after a first episode of pulmo
-
nary embolism: the PADIS-PE randomized clinical trial. 
JAMA. 2015 Jul 7;314(1):31–40. [PMID: 26151264]
Jin J. JAMA patient page. Treatment duration for pulmonary 
embolism. JAMA. 2015 Jul 7;314(1):98. [PMID: 26151285]
Kearon C et al. Antithrombotic therapy for VTE disease: CHEST 
Guideline and Expert Panel Report. Chest. 2016 
Feb;149(2):315–52. [PMID: 26867832] 
Konstantinides SV et al. Management of pulmonary embolism: 
an update. J Am Coll Cardiol. 2016 Mar;67(8):976–90. 
[PMID:26916489]
Meinel FG et al. Predictive value of computed tomography in acute 
pulmonary embolism: systematic review and meta-analysis. 
 
Am J Med. 2015 Jul;128(7):747–59. [PMID: 25680885]
Raja AS et al. Evaluation of patients with suspected acute pulmo
-
nary embolism: best practice advice from the Clinical Guide
-
lines Committee of the American College of Physicians. Ann 
Intern Med. 2015 Nov 3;163(9):701–11. [PMID: 26414967]
Righini M et al. Age-adjusted D-dimer cutoff levels to rule out 
pulmonary embolism: the ADJUST-PE study. JAMA. 2014 
Mar 19;311(11):1117–24. [PMID: 24643601]
PULMONARY HYPERTENSION
 
»
Dyspnea, fatigue, chest pain, and syncope on 
exertion.
 
»
Narrow splitting of second heart sound with loud 
pulmonary component; findings of right ventricu
-
lar hypertrophy and heart failure in advanced 
disease.
 
»
Electrocardiographic evidence of right ventricular 
strain or hypertrophy and right atrial 
enlargement.
 
»
Enlarged central pulmonary arteries on chest 
 
»
Elevated right ventricular systolic pressure on 
two-dimensional echocardiography with Doppler 
flow studies.
 
»

»
 
»
 
»
Pulmonary hypertension is a complex problem character
-
ized by pathologic elevation in pulmonary arterial pres
-
sure. Normal pulmonary artery systolic pressure at rest is 
15–30 mm Hg, with a mean pressure between 10 mm Hg 
and 18 mm Hg. The pulmonary circulation is a low-
pressure, low-resistance system due to its large cross-
 
sectional area, and it can accommodate significant increase 
in blood flow during exercise. The primary pathologic 
mechanism in pulmonary hypertension is an increase in 
pulmonary vascular resistance that leads to an increase in 
the pulmonary systolic pressure greater than 30 mm Hg or 
the mean pressure greater than 25 mm Hg.
The World Health Organization currently classifies 
pulmonary hypertension based on similarities in patho
-
logic mechanisms and includes the following five groups.
Group 1
 (pulmonary arterial hypertension secondary to 
various disorders): This group gathers diseases that localize 
directly to the pulmonary arteries leading to structural 
changes, smooth muscle hypertrophy, and endothelial dys
-
function. This group includes idiopathic (formerly primary) 
pulmonary arterial hypertension, heritable pulmonary arte
-
rial hypertension, HIV infection, portal hypertension, drugs 
and toxins, connective tissue disorders, congenital heart 
disease, schistosomiasis, primary veno-occlusive disease, 
and pulmonary capillary hemangiomatosis.
Group 2
 (pulmonary venous hypertension secondary 
to left heart disease): Often referred to as pulmonary 
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venous hypertension or “post-capillary” pulmonary hyper
-
tension, this group includes left ventricular systolic or dia
-
stolic dysfunction and valvular heart disease.
Group 3
 (pulmonary hypertension secondary to lung 
disease or hypoxemia): This group is caused by advanced 
obstructive and restrictive lung disease, including COPD, 
interstitial lung disease, pulmonary fibrosis, bronchiecta
-
sis, as well as other causes of chronic hypoxemia, such as 
sleep-disordered breathing, alveolar hypoventilation syn
-
dromes, and high altitude exposure.
Group 4
 (pulmonary hypertension secondary to 
chronic thromboembolism): This group consists of patients 
with pulmonary hypertension due to thromboembolic 
occlusion of the proximal and distal pulmonary arteries. 
(This classification no longer includes patients with non-
thrombotic occlusion, such as tumors or foreign objects.)
Group 5
hematologic, systemic, metabolic, or miscellaneous causes): 
These patients have pulmonary hypertension secondary to 
hematologic disorders (eg, chronic hemolytic anemia, 
myeloproliferative disorders, splenectomy), systemic disor
-
ders (eg, sarcoidosis, vasculitis, pulmonary Langerhans cell 
histiocytosis, neurofibromatosis type 1), metabolic disor
-
ders (eg, glycogen storage disease, Gaucher disease, thyroid 
disease), and miscellaneous causes (tumor embolization, 
external compression of the pulmonary vasculature, end-
stage renal disease on dialysis).
The clinical severity of pulmonary hypertension is clas
-
sified according to the New Y ork Heart Association 
(NYHA) classification system, which was originally devel
-
oped for heart failure but subsequently modified by the 
World Health Organization; it is based primarily on symp
-
toms and functional status.
Class I:
 Pulmonary hypertension without limitation of 
physical activity. No dyspnea, fatigue, chest pain, or near 
syncope with exertion.
Class II:
 Pulmonary hypertension resulting in slight 
limitation of physical activity. No symptoms at rest but 
ordinary physical activity causes dyspnea, fatigue, chest 
pain, or near syncope.
Class III:
 Pulmonary hypertension resulting in marked 
limitation of physical activity. No symptoms at rest but less 
than ordinary activity causes dyspnea, fatigue, chest pain, 
or near syncope.
Class IV:
 Pulmonary hypertension with inability to 
perform any physical activity without symptoms. Evidence 
of right heart failure. Dyspnea and fatigue at rest and wors
-
ening of symptoms with any activity.
 
»
There are no specific symptoms or signs but patients with 
pulmonary hypertension typically experience dyspnea 
with exertion and even, with advanced disease, at rest. 
Anginal pain, nonproductive cough, malaise, and fatigue 
may be present. Syncope occurs with exertion when there 
is insufficient cardiac output or if there is an arrhythmia. 
Hemoptysis is a rare but life-threatening event in pulmonary 
hypertension usually caused by the rupture of a pulmonary 
artery.
Findings on physical examination can include jugular 
venous distention, accentuated pulmonary valve compo
-
nent of the second heart sound, right-sided third heart 
sound, tricuspid regurgitation murmur, hepatomegaly, and 
lower extremity edema. Cyanosis can occur in patients 
with an open patent foramen ovale and right-to-left shunt 
due to increased right atrial pressure.
Routine blood work is often normal; any abnormalities 
noted are usually related to the underlying disease in sec
-
ondary pulmonary hypertension. On arterial blood gas 
analysis, patients with idiopathic pulmonary arterial 
hypertension often have normal Pa
o
2
 at rest but show evi
-
dence of hyperventilation with a decrease in Pa
co
2
. All 
patients should be evaluated for HIV and collagen vascular 
disease.
The ECG is typically normal except in advanced dis
-

-
co
2
. All 
disease.
-
ease, where right ventricular hypertrophy (right axis devia
-
tion, incomplete right bundle branch block) and right atrial 
enlargement (peaked P wave in the inferior and right-sided 
leads) can be noted.
Radiographs and CT scans of the chest are useful in diagno
-
sis. Enlargement of the right and left main pulmonary arter
-
ies is common; right ventricular and right atrial enlargement 
is seen in advanced disease. Chest imaging and pulmonary 
function testing are also useful in determining the cause of 
pulmonary hypertension for patients in Group 3 (pulmo
-
nary hypertension due to lung disease). On pulmonary 
function testing, the combination of decreased single-
breath diffusing capacity, normal FVC on spirometry, nor
-
mal TLC on lung volume measurement, and increased 
wasted ventilation on cardiopulmonary exercise testing is 
suggestive of pathologically increased pulmonary arterial 
pressures.
Patients in whom pulmonary hypertension is suspected 
should undergo echocardiography with Doppler flow. The 
echocardiogram is useful in the assessment of underlying 
cardiac disease while Doppler flow can estimate the right 
ventricular systolic pressure. Right ventricular systolic 
pressure can be estimated based on tricuspid jet velocity 
and right atrial pressure. The severity of pulmonary hyper
-
tension can also be assessed based on the right ventricular 
size and function. Right-sided cardiac catheterization 
remains the gold standard for the diagnosis and quantifica
-
tion of pulmonary hypertension and should be performed 
prior to initiation of advanced therapies. Estimated pres
-
sures on echocardiogram correlate with right heart cathe
-
terization measurement but can vary by at least 10 mm Hg 
in more than 50% of cases so should not be used to direct 
therapy. Cardiac catheterization is particularly helpful in 
differentiating pulmonary arterial hypertension from pul
-
monary venous hypertension by assessment of the drop in 
pressure across the pulmonary circulation, also known as 
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the transpulmonary gradient. Vasodilator challenge is 
often performed during right heart catheterization and a 
significant acute vasodilator response consists of a drop in 
mean pulmonary pressure of greater than 10 mm Hg (or 
20%) to less than 40 mm Hg.
In patients with unexplained pulmonary hypertension 
who have a history of PE or risk factors for thromboem
-
bolic disease, chronic thromboembolic disease (Group 4 
pulmonary hypertension) should be excluded prior to 
diagnosing idiopathic pulmonary hypertension. 
V
.
/
Q
.
 lung 
scanning is a very sensitive test that can differentiate 
chronic thromboembolic pulmonary hypertension from 
idiopathic pulmonary arterial hypertension. Currently, 
pulmonary angiography is considered the most definitive 
diagnostic procedure for defining the distribution and 
extent of disease in chronic thromboembolic pulmonary 
 
»
Treatment
Primary therapy refers to treatment directed at the under
-
lying cause of pulmonary hypertension. Currently, there 
are no primary therapies available targeting the underlying 
lesion for patients in Group 1 (pulmonary arterial hyper
-
tension) but advanced therapies are available directly tar
-
geting the pulmonary hypertension itself. The advanced 
therapy chosen is typically based on patient symptoms and 
functional status according to the NYHA/WHO classifica
-
tion. Based on observational studies showing improved 
functional status and possible decreased mortality, first-
line therapy consists of oral calcium channel blockers. 
However, these medications should be given only to 
patients with positive acute vasodilator response when 
tested in the cardiac catheterization laboratory because 
they may be harmful to nonresponders. Preferred treat
-
ments for Group 1 patients in functional class II include 
oral endothelin receptor antagonists (ambrisentan, bosen
-
tan), and phosphodiesterase inhibitors (sildenafil, 
tadalafil). RCTs using either endothelin receptor antago
-
nists or phosphodiesterase inhibitors have shown improve
-
ment in symptoms, 6-minute walk distance, WHO 
functional status, and hemodynamic measurements. For 
Group 1 patients in functional classes III and IV or Group 
1 patients who are not responsive to previous therapies, 
prostanoid agents are available. Continuous long-term 
intravenous epoprostenol infusion improved mortality in a 
prospective RCT. Limitations to intravenous prostacyclins 
(epoprostenol, treprostinil) include short medication half-
life requiring a reliable continuous infusion, difficulty in 
titration, and high cost of therapy. Inhaled prostanoids 
(iloprost, treprostinil) and subcutaneous prostanoids 
(treprostinil) are available for patients unable to tolerate 
continuous intravenous infusion. One oral formulation of 
prostacyclin analogs has been approved for Group 1 dis
-
ease based on a clinical trial that demonstrated a small 
increase in 6-minute walk distance.
Treatment of patients with Group 2 pulmonary hyper
-
tension (secondary to left heart failure) is discussed in 
Chapter 10. The main goal is to decrease pulmonary venous 
pressure by treating heart failure and volume overload.
Patients with Group 3 pulmonary hypertension (due to 
lung disease) and hypoxemia at rest or with physical activ
-
ity should receive supplemental oxygen. In patients with 
COPD and hypoxemia, administration of supplemental 
oxygen for 15 hours or more per day has been shown to 
slow the progression of pulmonary hypertension.
For patients with Group 1 pulmonary hypertension and 
Group 4 pulmonary hypertension (due to thromboembolic 
disease), long-term anticoagulation is recommended and 
generally accepted, based solely on observational studies 
suggesting improvement in survival. For Group 4 patients 
in functional class IV and no response to other advanced 
therapies, thromboendarterectomy is recommended. Only 
patients with surgically accessible lesions and acceptable

patients with surgically accessible lesions and acceptable 
perioperative risk should undergo this procedure.
Lung transplantation is a treatment option for selected 
patients with pulmonary hypertension when medical ther
-
apy is no longer effective. Double-lung transplant is the 
preferred method, although single-lung transplant is rou
-
tinely done as well. In some cases, transplantation of the 
heart and both lungs is needed.
 
»
Prognosis
The prognosis of idiopathic (some Group 1) pulmonary 
hypertension is poor and is not affected by therapies pri
-
marily used to treat symptoms. Conversely, the prognosis 
for patients with secondary pulmonary hypertension 
(some Group 1 and Groups 2–5) depends on the underly
-
ing disease and its response to treatment. In all cases, right 
ventricular function is one of the most important prognos
-
tic factors. The presence of cor pulmonale carries a poor 
survival outcome regardless of the underlying cause.
 
»
Patients with pulmonary arterial hypertension and symp
-
toms of dyspnea, fatigue, chest pain, or near syncope 
should be referred to a pulmonologist or cardiologist at a 
specialized center for expert management.
 
»
•	
Patients with pulmonary hypertension, severe symp
-
toms, and evidence of decompensated right heart fail
-
ure with volume overload should be admitted to the 
hospital for aggressive diuresis.
•	
Patients with Group 1 pulmonary hypertension and 
functional class IV symptoms should be admitted to a 
specialized center for initiation of advanced therapies, 
such as intravenous prostacyclins.
Galiè N et al. 2015 ESC/ERS Guidelines for the diagnosis and 
treatment of pulmonary hypertension: The Joint Task Force 
for the Diagnosis and Treatment of Pulmonary Hypertension 
of the European Society of Cardiology (ESC) and the Euro
-
pean Respiratory Society (ERS) Endorsed by: Association for 
European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation 
(ISHLT). Eur Heart J. 2016 Jan 1;37(1):67–119. [PMID: 
26320113]
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Hill NS et al. New therapeutic paradigms and guidelines in the 
management of pulmonary arterial hypertension. J Manag 
Care Spec Pharm. 2016 Mar;22(3 Suppl A):S3–21. [PMID: 
27003666]
Taichman DB et al. Pharmacologic therapy for pulmonary arte
-
rial hypertension in adults: CHEST guideline and expert 
panel report. Chest. 2014 Aug;146(2):449–75. [PMID: 
24937180]
PULMONARY VASCULITIS
Granulomatosis with polyangiitis
 (formerly referred to as 
Wegener granulomatosis)
 is an idiopathic disease mani
-
fested by a combination of glomerulonephritis, necrotizing 
granulomatous vasculitis of the upper and lower respira
-
tory tracts, and varying degrees of small-vessel vasculitis. 
Chronic sinusitis, arthralgias, fever, skin rash, and weight 
loss are frequent presenting symptoms. Specific pulmonary 
complaints occur less often. The most common sign of 
lung disease is nodular pulmonary infiltrates, often with 
cavitation, seen on chest radiography. Tracheal stenosis 
and endobronchial disease are sometimes seen. The diag
-
nosis is most often based on serologic testing and biopsy of 
lung, sinus tissue, or kidney with demonstration of necro
-
tizing granulomatous vasculitis (Chapter 20).
Eosinophilic granulomatosis with polyangiitis
 (for
-
merly referred to as 
Churg-Strauss syndrome)
 is an idio
-
pathic multisystem vasculitis of small and medium-sized 
arteries that occurs in patients with asthma. The skin and 
lungs are most often involved, but other organs, including 
the paranasal sinuses, the heart, gastrointestinal tract, 
liver, and peripheral nerves, may also be affected. Periph
-
eral eosinophilia greater than 1500 cells/mcL (greater than 
1.5 × 10
9
/L) or greater than 10% of peripheral WBCs is the 
rule. Abnormalities on chest radiographs range from tran
-
sient opacities to multiple nodules. This illness may be part 
of a spectrum that includes polyarteritis nodosa. The diag
-
nosis requires demonstration of histologic features, includ
-
ing fibrinoid necrotizing epithelioid and eosinophilic 
 
»
Treatment
Treatment of pulmonary vasculitis usually requires cortico
-
steroids and cyclophosphamide. Oral prednisone (1 mg/kg 
ideal body weight per day initially, tapering slowly to 
alternate-day therapy over 3–6 months) is the corticoste
-
roid of choice; in granulomatosis with polyangiitis, some 
clinicians may use cyclophosphamide alone. For fulminant 
vasculitis, therapy may be initiated with intravenous meth
-
ylprednisolone (up to 1 g intravenously per day) for several 
days. Cyclophosphamide (1–2 mg/kg ideal body weight 
orally per day initially, with dosage adjustments to avoid 
neutropenia) is given until complete remission is obtained 
and then is slowly tapered, and often replaced with metho
-
trexate or azathioprine for maintenance therapy.
 
»
Prognosis
Five-year survival rates in patients with these vasculitis 
syndromes have been improved by combination therapy. 
Complete remission can be achieved in over 90% of 
patients with granulomatosis with polyangiitis. The addi
-
tion of trimethoprim-sulfamethoxazole (one double-
strength tablet by mouth twice daily) to standard therapy 
may help prevent relapses.
Cottin V et al; Groupe d’Etudes et de Recherche sur les Maladies 
Orphelines Pulmonaires (GERM”O”P). Revisiting the sys
-
temic vasculitis in eosinophilic granulomatosis with polyan
-
giitis (Churg-Strauss): a study of 157 patients. Autoimmun 
Rev. 2017 Jan;16(1):1–9. [PMID: 27671089]
Greco A et al. Churg-Strauss syndrome. Autoimmun Rev. 2015 Apr;
 
14(4):341–8. [PMID: 25500434]
Greco A et al. Goodpasture’s syndrome: a clinical update. Auto
-
immun Rev. 2015 Mar;14(3):246–53. [PMID: 25462583]
Lally L et al. Pulmonary vasculitis. Rheum Dis Clin North Am. 
2015 May;41(2):315–31. [PMID: 25836645]
Talarico R et al. Systemic vasculitis and the lung. Curr Opin 
Rheumatol. 2017 Jan;29(1):45–50. [PMID: 27755177]
ALVEOLAR HEMORRHAGE SYNDROMES

Diffuse alveolar hemorrhage may occur in a variety of 
immune and nonimmune disorders. Hemoptysis, alveolar 
infiltrates on chest radiograph, anemia, dyspnea, and occa
-
sionally fever are characteristic. Rapid clearing of diffuse 
lung infiltrates within 2 days is a clue to the diagnosis of 
diffuse alveolar hemorrhage. Pulmonary hemorrhage can 
be associated with an increased single-breath diffusing 
capacity for carbon monoxide (D
l
CO
).
Causes of diffuse 
immune alveolar hemorrhage
 have 
been classified as anti-basement membrane antibody dis
-
ease (Goodpasture syndrome), vasculitis and collagen 
vascular disease (systemic lupus erythematosus, granulo
-
matosis with polyangiitis, systemic necrotizing vasculitis, 
and others), and pulmonary capillaritis associated with 
idiopathic rapidly progressive glomerulonephritis. 
Nonim
-
mune causes
 of diffuse hemorrhage include coagulopathy, 
mitral stenosis, necrotizing pulmonary infection, drugs 
(penicillamine), toxins (trimellitic anhydride), and idio
-
pathic pulmonary hemosiderosis.
Goodpasture syndrome
 is idiopathic recurrent alveo
-
lar hemorrhage and rapidly progressive glomerulonephri
-
tis. The disease is mediated by anti-glomerular basement 
membrane antibodies. Goodpasture syndrome occurs 
mainly in men who are in their 30s and 40s. Hemoptysis is 
the usual presenting symptom, but pulmonary hemorrhage 
may be occult. Dyspnea, cough, hypoxemia, and diffuse 
bilateral alveolar infiltrates are typical features. Iron defi
-
ciency anemia and microscopic hematuria are usually pres
-
ent. The diagnosis is based on characteristic linear IgG 
deposits detected by immunofluorescence in glomeruli or 
alveoli and on the presence of anti-glomerular basement 
membrane antibody in serum. Combinations of immuno
-
suppressive drugs (initially methylprednisolone, 30 mg/kg 
intravenously over 20 minutes every other day for three 
doses, followed by daily oral prednisone, 1 mg/kg/day, with 
cyclophosphamide, 2 mg/kg orally per day) and plasma
-
pheresis have yielded excellent results.
Idiopathic pulmonary hemosiderosis
 is a disease of chil
-
dren or young adults characterized by recurrent pulmonary 
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hemorrhage; in contrast to Goodpasture syndrome, renal 
involvement and anti-glomerular basement membrane anti
-
bodies are absent, but iron deficiency is typical. It is frequently 
associated with celiac disease. Treatment of acute episodes of 
hemorrhage with corticosteroids may be useful. Recurrent 
episodes of pulmonary hemorrhage may result in interstitial 
fibrosis and pulmonary failure.
Lichtenberger JP III et al. Diffuse pulmonary hemorrhage: clues 
to the diagnosis. Curr Probl Diagn Radiol. 2014 May–Jun;
 
43(3):128–39. [PMID: 24791616]
Xi-Yuan C et al. Idiopathic pulmonary hemosiderosis in adults: 
review of cases reported in the latest 15 years. Clin Respir J. 
2017 Nov;11(6):677–81. [PMID: 26692115]
 
º
ENVIRONMENTAL & OCCUPATIONAL 
LUNG DISORDERS
SMOKE INHALATION
The inhalation of products of combustion may cause seri
-
ous respiratory complications. As many as one-third of 
patients admitted to burn treatment units have pulmonary 
injury from smoke inhalation. Morbidity and mortality 
due to smoke inhalation may exceed those attributed to the 
burns themselves. The death rate of patients with both 
severe burns and smoke inhalation exceeds 50%.
All patients in whom significant smoke inhalation is 
suspected must be assessed for three consequences of 
smoke inhalation: impaired tissue oxygenation, thermal 
injury to the upper airway, and injury to the lower airways 
and lung parenchyma. Impaired tissue oxygenation may 
result from inhalation of a hypoxemic gas mixture, carbon 
monoxide or cyanide, or from alterations in 
V
.
/
Q
.
 matching, 
and is an immediate threat to life. Immediate treatment 
with 100% oxygen is essential. The management of patients 
with carbon monoxide and cyanide poisoning is discussed 
in Chapter 38. The clinician must recognize that patients 
with carbon monoxide poisoning display a normal partial 
pressure of oxygen in arterial blood (Pa
o
2
), but have a low 
measured
 (ie, not oximetric) hemoglobin saturation (Sa
o
2
). 
Treatment with 100% oxygen should be continued until the 
measured carboxyhemoglobin level falls to less than 10% 
and concomitant metabolic acidosis has resolved.
Thermal injury to the mucosal surfaces of the upper 
airway occurs from inhalation of super-heated gases. Com
-
plications, including mucosal edema, upper airway 
obstruction, and impaired ability to clear oral secretions, 
usually become evident by 18–24 hours and produce inspi
-
ratory stridor. Respiratory failure occurs in severe cases. 
Early management (Chapter 37) includes the use of a high-
humidity face mask with supplemental oxygen, gentle 
suctioning to evacuate oral secretions, elevation of the head 
30 degrees to promote clearing of secretions, and topical 
epinephrine to reduce edema of the oropharyngeal mucous 
membrane. Helium-oxygen gas mixtures (Heliox) may 
reduce labored breathing due to critical upper airway nar
-
rowing. Close monitoring with arterial blood gases and 
later with oximetry is important. Examination of the upper 
airway with a fiberoptic laryngoscope or bronchoscope is 
superior to routine physical examination. Endotracheal 
intubation is often necessary to maintain airway patency 
and is likely to be necessary in patients with deep facial 
burns or oropharyngeal or laryngeal edema. Tracheotomy 
should be avoided if possible because of an increased risk 
of pneumonia and death from sepsis.
Injury to the lower airways and lung parenchyma 
results from inhalation of toxic gases and products of com
-
bustion, including aldehydes and organic acids. The site of 
lung injury depends on the solubility of the gases inhaled, 
the duration of exposure, and the size of inhaled particles 
that transport noxious gases to distal lung units. Bronchor
-
rhea and bronchospasm are seen early after exposure along 
with dyspnea, tachypnea, and tachycardia. Labored breath
-
ing and cyanosis may follow. Physical examination at this

-
-
ing and cyanosis may follow. Physical examination at this 
stage reveals diffuse wheezing and rhonchi. Bronchiolar and 
alveolar edema (eg, ARDS) may develop within 1–2 days 
after exposure. Sloughing of the bronchiolar mucosa may 
occur within 2–3 days, leading to airway obstruction, atel
-
ectasis, and worsening hypoxemia. Bacterial colonization 
and pneumonia are common by 5–7 days after the 
exposure.
Treatment of smoke inhalation consists of supplemental 
oxygen, bronchodilators, suctioning of mucosal debris and 
mucopurulent secretions via an indwelling endotracheal 
tube, chest physical therapy to aid clearance of secretions, 
and adequate humidification of inspired gases. Positive 
end-expiratory pressure (PEEP) has been advocated to 
treat bronchiolar edema. Judicious fluid management and 
close monitoring for secondary bacterial infection with 
daily sputum Gram stains round out the management 
protocol.
The routine use of corticosteroids for lung injury from 
smoke inhalation has been shown to be ineffective and may 
even be harmful. Routine or prophylactic use of antibiotics 
is not recommended.
Patients who survive should be watched for the late 
development of bronchiolitis obliterans.
Enkhbaatar P et al. Pathophysiology, research challenges, and 
clinical management of smoke inhalation injury. Lancet. 2016 
Oct 1;388(10052):1437–46. [PMID: 27707500]
Walker PF et al. Diagnosis and management of inhalation injury: 
an updated review. Crit Care. 2015 Oct 28;19:351. [PMID: 
26507130]
PULMONARY ASPIRATION SYNDROMES
Aspiration of material into the tracheobronchial tree 
results from various disorders that impair normal degluti
-
tion, especially disturbances of consciousness and esopha
-
geal dysfunction.
1. Acute Aspiration of Gastric Contents 
(Mendelson Syndrome)
Acute aspiration of gastric contents may be catastrophic. The 
pulmonary response depends on the characteristics and 
amount of gastric contents aspirated. The more acidic the 
material, the greater the degree of chemical pneumonitis. 
Aspiration of pure gastric acid (pH < 2.5) causes extensive 
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desquamation of the bronchial epithelium, bronchiolitis, 
hemorrhage, and pulmonary edema. Acute gastric aspira
-
tion is one of the most common causes of ARDS. The clini
-
cal picture is one of abrupt onset of respiratory distress, with 
cough, wheezing, fever, and tachypnea. Crackles may be 
audible at the bases of the lungs. Hypoxemia may be noted 
immediately after aspiration occurs. Radiographic abnor
-
malities, consisting of patchy alveolar opacities in dependent 
lung zones, appear within a few hours. If particulate food 
matter has been aspirated along with gastric acid, radio
-
graphic features of bronchial obstruction may be observed. 
Fever and leukocytosis are common even in the absence of 
Treatment of acute aspiration of gastric contents con
-
sists of supplemental oxygen, measures to maintain the 
airway, and the usual measures for treatment of acute respi
-
ratory failure. There is no evidence to support the routine 
use of prophylactic antibiotics or corticosteroids after gas
-
tric aspiration. Secondary pulmonary infection, which 
occurs in about one-fourth of patients, typically appears 
2–3 days after aspiration. Management of infection depends 
on the observed flora of the tracheobronchial tree. Hypo
-
tension secondary to alveolar capillary membrane injury 
and intravascular volume depletion is common and is 
managed with the judicious administration of intravenous 
fluids.
2. Chronic Aspiration of Gastric Contents
Chronic aspiration of gastric contents may result from 
primary disorders of the larynx or the esophagus, such as 
achalasia, esophageal stricture, systemic sclerosis (sclero
-
derma), esophageal carcinoma, esophagitis, and gastro
-
esophageal reflux. In the last condition, relaxation of the 
tone of the lower esophageal sphincter allows reflux of 
gastric contents into the esophagus and predisposes to 
chronic pulmonary aspiration, especially at night. Ciga
-
rette smoking, consumption of alcohol or caffeine, and use 
of theophylline are known to relax the lower esophageal 
sphincter. Pulmonary disorders linked to gastroesophageal 
reflux and chronic aspiration include asthma, chronic 
cough, bronchiectasis, and pulmonary fibrosis. Even in the 
absence of aspiration, acid in the esophagus may trigger 
bronchospasm or bronchial hyperreactivity through reflex 
mechanisms.
The diagnosis and management of gastroesophageal 
reflux and chronic aspiration is challenging. A discussion 
of strategies for the evaluation, prevention, and manage
-
ment of extraesophageal reflux manifestations can be 
found in Chapter 15.
3. “Café Coronary”
Acute obstruction of the upper airway by food is associated 
with difficulty swallowing, old age, dental problems that 
impair chewing, and use of alcohol and sedative drugs. The 
Heimlich procedure is lifesaving in many cases.
4. Retention of an Aspirated Foreign Body
Retention of an aspirated foreign body in the tracheobron
-
chial tree may produce both acute and chronic conditions, 
including atelectasis, postobstructive hyperinflation, both 
acute and recurrent pneumonia, bronchiectasis, and lung 
abscess. Occasionally, a misdiagnosis of asthma, COPD, or 
lung cancer is made in adult patients who have aspirated a 
foreign body. The plain chest radiograph usually suggests 
the site of the foreign body. In some cases, an expiratory 
film, demonstrating regional hyperinflation due to a check-
valve effect, is helpful. Bronchoscopy is usually necessary 
to establish the diagnosis and attempt removal of the for
-
eign body.
5. Aspiration of Inert Material
Most patients suffer no serious sequelae from aspiration of 
inert material. However, it may cause asphyxia if the 
amount aspirated is massive and if cough is impaired, in 
which case immediate tracheobronchial suctioning is 
6. Aspiration of Toxic Material
Aspiration of toxic material into the lung usually results in 
clinically evident pneumonia.

clinically evident pneumonia. 
Hydrocarbon pneumonitis
 
is caused by aspiration of ingested petroleum distillates, eg, 
gasoline, kerosene, furniture polish, and other household 
petroleum products. Lung injury results mainly from vom
-
iting of ingested products and secondary aspiration. Ther
-
apy is supportive. The lung should be protected from 
repeated aspiration with a cuffed endotracheal tube if 
necessary. 
Lipoid pneumonia
 is a chronic syndrome 
related to the repeated aspiration of oily materials, eg, min
-
eral oil, cod liver oil, and oily nose drops; it usually occurs 
in elderly patients with impaired swallowing. Patchy opaci
-
ties in dependent lung zones and lipid-laden macrophages 
in expectorated sputum are characteristic findings.
Prather AD et al. Aspiration-related lung diseases. J Thorac 
Imaging. 2014 Sep;29(5):304–9. [PMID: 24911122]
OCCUPATIONAL PULMONARY DISEASES
Many acute and chronic pulmonary diseases are directly 
related to inhalation of noxious substances encountered in 
the workplace. Disorders that are linked to occupational 
exposures may be classified as follows: (1) pneumoconio
-
ses, (2) hypersensitivity pneumonitis, (3) obstructive air
-
way disorders, (4) toxic lung injury, (5) lung cancer, (6) 
pleural diseases, and (7) other occupational pulmonary 
diseases.
1. Pneumoconioses
Pneumoconioses are chronic fibrotic lung diseases caused 
by the inhalation of inorganic dusts. Pneumoconioses due 
to inhalation of inert dusts may be asymptomatic disorders 
with diffuse nodular opacities on chest radiograph or may 
be severe, symptomatic, life-shortening disorders. Clini
-
cally important pneumoconioses include coal worker’s 
pneumoconiosis, silicosis, and asbestosis (Table 9–22). 
Treatment for each is supportive.
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A. Coal Worker’s Pneumoconiosis
In coal worker’s pneumoconiosis, ingestion of inhaled coal 
dust by alveolar macrophages leads to the formation of coal 
macules, usually 2–5 mm in diameter, that appear on chest 
radiograph as diffuse small opacities that are especially 
prominent in the upper lung. Simple coal worker’s pneumo
-
coniosis is usually asymptomatic; pulmonary function 
abnormalities are unimpressive. Cigarette smoking does not 
increase the prevalence of coal worker’s pneumoconiosis but 
may have an additive detrimental effect on ventilatory func
-
tion. In complicated coal worker’s pneumoconiosis 
(“pro
-
gressive massive fibrosis”),
 conglomeration and contraction 
in the upper lung zones occur, with radiographic features 
resembling complicated silicosis. 
Caplan syndrome
 is a rare 
condition characterized by the presence of necrobiotic rheu
-
matoid nodules (1–5 cm in diameter) in the periphery of the 
lung in coal workers with rheumatoid arthritis.
B. Silicosis
In silicosis, extensive or prolonged inhalation of free silica 
(silicon dioxide) particles in the respirable range (0.3–5 
mcm) causes the formation of small rounded opacities (sili
-
cotic nodules) throughout the lung. Calcification of the 
periphery of hilar lymph nodes (“eggshell” calcification) is 
an unusual radiographic finding that strongly suggests sili
-
cosis. Simple silicosis is usually asymptomatic and has no 
effect on routine pulmonary function tests; in complicated 
silicosis, large conglomerate densities appear in the upper 
lung and are accompanied by dyspnea and obstructive and 
restrictive pulmonary dysfunction. The incidence of pulmo
-
nary tuberculosis is increased in patients with silicosis. All 
patients with silicosis should have a tuberculin skin test and 
a current chest radiograph. If old, healed pulmonary tuber
-
culosis is suspected, multidrug treatment for tuberculosis 
(not single-agent preventive therapy) should be instituted.
C. Asbestosis
Asbestosis is a nodular interstitial fibrosis occurring in 
workers exposed to asbestos fibers (shipyard and 
construction workers, pipe fitters, insulators) over many 
years (typically 10–20 years). Patients with asbestosis usu
-
ally first seek medical attention at least 15 years after expo
-
sure with the following symptoms and signs: progressive 
dyspnea, inspiratory crackles, and in some cases, clubbing 
and cyanosis. The radiographic features of asbestosis 
include linear streaking at the lung bases, opacities of vari
-
ous shapes and sizes, and honeycomb changes in advanced 
cases. The presence of pleural calcifications may be a clue 
to diagnosis. High-resolution CT scanning is the best 
imaging method for asbestosis because of its ability to 
detect parenchymal fibrosis and define the presence of 
coexisting pleural plaques. Cigarette smoking in asbestos 
workers increases the prevalence of radiographic pleural 
and parenchymal changes and markedly increases the inci
-
dence of lung carcinoma. It may also interfere with the 
clearance of short asbestos fibers from the lung. Pulmo
-
nary function studies show restrictive dysfunction and 
reduced diffusing capacity. The presence of a ferruginous 
body in tissue suggests significant asbestos exposure; how
-
ever, other histologic features must be present for diagno
-
sis. There is no specific treatment.
Banks DE. Clinical aspects of asbestos-related diseases—what 
are the unresolved topics? J Occup Environ Med. 2014 Oct;
 
56(Suppl 10):S8–12. [PMID: 25285978]
Cohen RA et al. Lung pathology in U.S. coal workers with rap
-
idly progressive pneumoconiosis implicates silica and sili
-
cates. Am J Respir Crit Care Med. 2016 Mar 15;193(6):673–80. 
[PMID: 26513613]
Go LH et al. Lung disease and coal mining: what pulmonologists 
need to know. Curr Opin Pulm Med. 2016 Mar;22(2):170–8. 
[PMID: 26761630]
2. Hypersensitivity Pneumonitis
Hypersensitivity pneumonitis (also called extrinsic allergic

Hypersensitivity pneumonitis (also called extrinsic allergic 
alveolitis) is a nonatopic, nonasthmatic inflammatory pul
-
monary disease. It is manifested mainly as an occupational 
disease (Table 9–23), in which exposure to inhaled organic 
antigens leads to an acute illness. Prompt diagnosis is 
essential since symptoms are usually reversible if the 
Table 9–22.
 
Selected pneumoconioses.
Disease
Agent
Occupations
Asbestosis
Asbestos
Mining, insulation, construction, shipbuilding
Baritosis
Barium salts
Glass and insecticide manufacturing
Coal worker’s pneumoconiosis
Coal dust
Coal mining
Kaolin pneumoconiosis
Sand, mica, aluminum silicate
Mining of china clay; pottery and cement work
Shaver disease
Aluminum powder
Manufacture of corundum
Siderosis
Metallic iron or iron oxide
Mining, welding, foundry work
Silicosis
Free silica (silicon dioxide)
Rock mining, quarrying, stone cutting, tunneling, sandblasting, 
pottery, diatomaceous earth
Stannosis
Tin, tin oxide
Mining, tin-working, smelting
Talcosis
Magnesium silicate
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CMDT 2019
offending antigen is removed from the patient’s environ
-
ment early in the course of illness. Continued exposure 
may lead to progressive disease. The histopathology of 
acute hypersensitivity pneumonitis is characterized by 
interstitial infiltrates of lymphocytes and plasma cells, with 
noncaseating granulomas in the interstitium and air spaces.
 
»
A. Acute Illness
The symptoms are characterized by sudden onset of mal
-
aise, chills, fever, cough, dyspnea, and nausea 4–8 hours 
after exposure to the offending antigen. This may occur 
after the patient has left work or even at night and thus may 
mimic paroxysmal nocturnal dyspnea. Bibasilar crackles, 
tachypnea, tachycardia, and (occasionally) cyanosis are 
noted. Small nodular densities sparing the apices and bases 
of the lungs are noted on chest radiograph. Laboratory 
studies reveal an increase in the white blood cell count with 
a shift to the left, hypoxemia, and the presence of precipi
-
tating antibodies to the offending agent in serum. Hyper
-
sensitivity pneumonitis antibody panels against common 
offending antigens are available; positive results, while 
supportive, do not establish a definitive diagnosis. Pulmo
-
nary function studies reveal restrictive dysfunction and 
reduced diffusing capacity.
B. Subacute Illness
A subacute hypersensitivity pneumonitis syndrome (15% 
of cases) is characterized by the insidious onset of chronic 
cough and slowly progressive dyspnea, anorexia, and 
weight loss. Chronic exposure leads to progressive respira
-
tory insufficiency and the appearance of pulmonary fibro
-
sis on chest imaging. Surgical lung biopsy may be necessary 
for the diagnosis of subacute and chronic hypersensitivity 
pneumonitis. Even with surgical lung biopsy, however, 
chronic hypersensitivity pneumonitis may be difficult to 
diagnose because histopathologic patterns overlap with 
several idiopathic interstitial pneumonias.
 
»
Treatment
Treatment of acute hypersensitivity pneumonitis consists 
of identification of the offending agent and avoidance of 
further exposure. In severe acute or protracted cases, oral 
corticosteroids (prednisone, 0.5 mg/kg daily as a single 
morning dose for 2 weeks, tapered to nil over 4–6 weeks) 
may be given. Change in occupation is often unavoidable.
Elicker BM et al. Multidisciplinary approach to hypersensitivity 
pneumonitis. J Thorac Imaging. 2016 Mar;31(2):92–103. 
[PMID: 26479131]
Spagnolo P et al. Hypersensitivity pneumonitis: a comprehensive 
review. J Investig Allergol Clin Immunol. 2015;25(4):237–50. 
[PMID: 26310038]
3. Obstructive Airway Disorders
Occupational pulmonary diseases manifested as obstruc
-
tive airway disorders include occupational asthma, indus
-
trial bronchitis, and byssinosis.
A. Occupational Asthma
It has been estimated that from 2% to 5% of all cases of 
asthma are related to occupation. Offending agents in the 
workplace are numerous; they include grain dust, wood 
dust, tobacco, pollens, enzymes, gum arabic, synthetic 
dyes, isocyanates (particularly toluene diisocyanate), rosin 
(soldering flux), inorganic chemicals (salts of nickel, plati
-
num, and chromium), trimellitic anhydride, phthalic anhy
-
dride, formaldehyde, and various pharmaceutical agents. 
Diagnosis of occupational asthma depends on a high index 
of suspicion, an appropriate history, spirometric studies 
before and after exposure to the offending substance, and 
peak flow rate measurements in the workplace. Bronchial 
provocation testing may be helpful in some cases. Treat
-
ment consists of avoidance of further exposure to the 
offending agent and bronchodilators, but symptoms may 
persist for years after workplace exposure has been 
terminated.
B. Industrial Bronchitis
Industrial bronchitis is chronic bronchitis found in coal 
miners and others exposed to cotton, flax, or hemp dust. 
Chronic disability from industrial bronchitis is infrequent.
Table 9–23.

Selected causes of hypersensitivity 
pneumonitis.
Disease
Antigen
Source
Farmer’s lung
Micropolyspora 
faeni, Thermo
-
actinomyces 
vulgaris
Moldy hay
“Humidifier” lung
Thermophilic 
actinomycetes
Contaminated 
humidifiers, heat
-
ing systems, or air 
conditioners
Bird fancier’s lung
Avian proteins
Bird serum and 
excreta
Bagassosis
Thermoactinomy
-
ces sacchari
 and 
T vulgaris
Moldy sugar cane 
fiber (bagasse)
Sequoiosis
Graphium, Aureoba
-
sidium, and other 
fungi
Moldy redwood 
sawdust
Maple bark strip
-
per’s disease
Cryptostroma 
(Coniosporium) 
corticale
Rotting maple tree 
logs or bark
Mushroom picker’s 
disease
Same as farmer’s 
lung
Moldy compost
Suberosis
Penicillium 
frequentans
Moldy cork dust
Detergent worker’s 
lung
Bacillus subtilis
 
enzyme
Enzyme additives
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C. Byssinosis
Byssinosis is an asthma-like disorder in textile workers 
caused by inhalation of cotton dust. The pathogenesis is 
obscure. Chest tightness, cough, and dyspnea are charac
-
teristically worse on Mondays or the first day back at work, 
with symptoms subsiding later in the week. Repeated expo
-
sure leads to chronic bronchitis.
4. Toxic Lung Injury
Toxic lung injury from inhalation of irritant gases is dis
-
cussed in the section on smoke inhalation. 
Silo-filler’s 
disease
 is acute toxic high-permeability pulmonary edema 
caused by inhalation of nitrogen dioxide encountered in 
recently filled silos. Bronchiolitis obliterans is a common 
late complication, which may be prevented by early treat
-
ment of the acute reaction with corticosteroids. Extensive 
exposure to silage gas may be fatal. Inhalation of the com
-
pound diacetyl, a constituent of butter-flavoring, has been 
linked to the development of bronchiolitis obliterans 
among microwave popcorn production workers.
5. Lung Cancer
Many industrial pulmonary carcinogens have been identi
-
fied, including asbestos, radon gas, arsenic, iron, chro
-
mium, nickel, coal tar fumes, petroleum oil mists, isopropyl 
oil, mustard gas, and printing ink. Cigarette smoking acts 
as a cocarcinogen with asbestos and radon gas to cause 
bronchogenic carcinoma. Asbestos alone causes malignant 
mesothelioma. Almost all histologic types of lung cancer 
have been associated with these carcinogens. Chloromethyl 
methyl ether specifically causes small-cell carcinoma of the 
lung.
6. Pleural Diseases
Occupational diseases of the pleura may result from expo
-
sure to asbestos or talc. Inhalation of talc causes pleural 
plaques that are similar to those caused by asbestos. Benign 
asbestos pleural effusion occurs in some asbestos workers 
and may cause chronic blunting of the costophrenic angle 
on chest radiograph.
7. Other Occupational Pulmonary Diseases
Occupational agents are also responsible for other pulmo
-
nary disorders. These include exposure to beryllium, 
which now occurs in machining and handling of beryllium 
products and alloys. Beryllium miners are not at risk for 
berylliosis and beryllium is no longer used in fluorescent 
lamp production, which was a source of exposure before 
1950. 
Berylliosis,
 an acute or chronic pulmonary disorder, 
occurs from absorption of beryllium through the lungs or 
skin and wide dissemination throughout the body. Acute 
berylliosis is a toxic, ulcerative tracheobronchitis and 
chemical pneumonitis following intense and severe expo
-
sure to beryllium. Chronic berylliosis, a systemic disease 
closely resembling sarcoidosis, is more common. Chronic 
pulmonary beryllium disease is an alveolitis mediated by 
the proliferation of beryllium-specific CD4 T-cells in the 
lung.
Balmes JR et al; ATS Ad Hoc Committee on Beryllium Sensitiv
-
ity and Chronic Beryllium Disease. An official American 
Thoracic Society statement: diagnosis and management of 
beryllium sensitivity and chronic beryllium disease. Am J 
Respir Crit Care Med. 2014 Nov 15;190(10):e34–59. [PMID: 
25398119]
Markowitz S. Asbestos-related lung cancer and malignant meso
-
thelioma of the pleura: selected current issues. Semin Respir 
Crit Care Med. 2015 Jun;36(3):334–46. Erratum in: Semin 
Respir Crit Care Med. 2016 Feb;37(1):143–4. [PMID: 
26024342]
Omland O et al. Occupational chronic obstructive pulmonary 
disease: a systematic literature review. Scand J Work Environ 
Health. 2014 Jan;40(1):19–35. [PMID: 24220056]
Pralong JA et al. Review of diagnostic challenges in occupational 
asthma. Curr Allergy Asthma Rep. 2017 Jan;17(1):1. [PMID: 
28091866]
MEDICATION-INDUCED LUNG DISEASE
Typical patterns of pulmonary response to medications 
implicated in medication-induced respiratory disease are 
summarized in Table 9–24. Pulmonary injury due to medi
-
cations occurs as a result of allergic reactions, idiosyncratic

-
cations occurs as a result of allergic reactions, idiosyncratic 
reactions, overdose, or undesirable side effects. In most 
patients, the mechanism of pulmonary injury is unknown.
Precise diagnosis of medication-induced pulmonary 
disease is often difficult because results of routine labora
-
tory studies are not helpful and radiographic findings are 
not specific. A high index of suspicion and a thorough his
-
tory of medication usage are critical to establishing the 
diagnosis of medication-induced lung disease. The clinical 
response to cessation of the suspected offending agent is 
also helpful. Acute episodes of medication-induced pulmo
-
nary disease usually disappear 24–48 hours after the medi
-
cation has been discontinued, but chronic syndromes may 
take longer to resolve. Challenge tests to confirm the diag
-
nosis are risky and rarely performed.
Treatment of medication-induced lung disease consists 
of discontinuing the offending agent immediately and 
managing the pulmonary symptoms appropriately.
Inhalation of crack cocaine
 may cause a spectrum of 
acute pulmonary syndromes, including pulmonary infil
-
tration with eosinophilia, pneumothorax and pneumome
-
diastinum, bronchiolitis obliterans, and acute respiratory 
failure associated with diffuse alveolar damage and alveolar 
hemorrhage. Corticosteroids have been used with variable 
success to treat alveolar hemorrhage.
RADIATION LUNG INJURY
The lung is an exquisitely radiosensitive organ that can be 
damaged by external beam radiation therapy. The degree of 
pulmonary injury is determined by the volume of lung 
irradiated, the dose and rate of exposure, and potentiating 
factors (eg, concurrent chemotherapy, previous radiation 
therapy in the same area, and simultaneous withdrawal of 
corticosteroid therapy). Symptomatic radiation lung injury 
occurs in about 10% of patients treated for carcinoma of 
the breast, 5–15% of patients treated for carcinoma of the 
lung, and 5–35% of patients treated for lymphoma. Two 
phases of the pulmonary response to radiation are 
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apparent: an acute phase (radiation pneumonitis) and a 
chronic phase (radiation fibrosis).
1. Radiation Pneumonitis
Acute radiation pneumonitis usually occurs 2–3 months 
(range 1–6 months) after completion of radiotherapy and 
is characterized by insidious onset of dyspnea, intractable 
dry cough, chest fullness or pain, weakness, and fever. Late 
radiation pneumonitis may develop 6–12 months after 
completion of radiation. The pathogenesis of acute radia
-
tion pneumonitis is unknown, but there is speculation that 
hypersensitivity mechanisms are involved. The dominant 
histopathologic findings are a lymphocytic interstitial 
pneumonitis progressing to an exudative alveolitis. Inspira
-
tory crackles may be heard in the involved area. In severe 
disease, respiratory distress and cyanosis occur that are 
characteristic of ARDS. An increased white blood cell 
count and elevated sedimentation rate are common. Pul
-
monary function studies reveal reduced lung volumes, 
reduced lung compliance, hypoxemia, reduced diffusing 
capacity, and reduced maximum voluntary ventilation. 
Chest radiography, which correlates poorly with the pres
-
ence of symptoms, usually demonstrates alveolar or nodu
-
lar opacities limited to the irradiated area. Air bronchograms 
are often observed. Sharp borders of an opacity may help 
distinguish radiation pneumonitis from other conditions, 
such as infectious pneumonia, lymphangitic spread of car
-
cinoma, and recurrent tumor; however, the opacity may 
extend beyond the radiation field. No specific therapy is 
proved to be effective in radiation pneumonitis, but pred
-
nisone (1 mg/kg/day orally) is commonly given immedi
-
ately for about 1 week. The dose is reduced and maintained 
at 20–40 mg/day for several weeks, then slowly tapered. 
Radiation pneumonitis may improve in 2–3 weeks follow
-
ing onset of symptoms as the exudative phase resolves. 
Acute respiratory failure, if present, is treated supportively. 
Death from ARDS is unusual in radiation pneumonitis.
2. Pulmonary Radiation Fibrosis
Radiation fibrosis may occur with or without antecedent 
radiation pneumonitis. Cor pulmonale and chronic respira
-
tory failure are rare. Radiographic findings include oblitera
-
tion of normal lung markings, dense interstitial and pleural 
fibrosis, reduced lung volumes, tenting of the diaphragm, and 
sharp delineation of the irradiated area. No specific therapy is 
proven effective, and corticosteroids have no value. Pulmo
-
nary fibrosis may develop after an intervening period (6–12 
months) of well-being in patients who experience radiation 
pneumonitis. Pulmonary radiation fibrosis occurs in most 
patients who receive a full course of radiation therapy for 
cancer of the lung or breast. Most patients are asymptomatic, 
although slowly progressive dyspnea may occur.
3. Other Complications of Radiation Therapy
Other complications of radiation therapy directed to the 
thorax include pericardial effusion, constrictive pericardi
-
tis, tracheoesophageal fistula, esophageal candidiasis, radi
-
ation dermatitis, and rib fractures. Small pleural effusions, 
radiation pneumonitis outside the irradiated area, sponta
-
neous pneumothorax, and complete obstruction of central 
airways are unusual occurrences.
Giridhar P et al. Radiation induced lung injury: prediction, 
assessment and management. Asian Pac J Cancer Prev. 
2015;16(7):2613–7. [PMID: 25854336]
Y amashita H et al. Radiation pneumonitis after stereotactic radia
-
tion therapy for lung cancer. World J Radiol. 2014 Sep 28;
 
6(9):708–15. [PMID: 25276313]
 
º
PLEURAL DISEASES
PLEURITIS
Pain due to acute pleural inflammation is caused by irrita
-
tion of the parietal pleura. Such pain is localized, sharp, 
and fleeting; it is made worse by coughing, sneezing, deep 
Table 9–24.
 
Pulmonary manifestations of selected 
medication toxicities.
Asthma
 
Beta-blockers
 
Aspirin
 
Nonst
eroidal anti-
 
inflamma
tory drugs

Asthma
 
Aspirin
 
Nonst
 
inflamma
tory drugs
 
Histamine
 
Methacholine
 
Acetylcysteine
 
A
erosolized pentamidine
 
An
y nebulized medication
Chronic cough
 
Angiotensin-converting 
 
enz
yme inhibitors
Pulmonary infiltration
 
W
ithout eosinophilia
  
Amitriptyline
  
Azathioprine
  
W
ith eosinophilia
  
l
-Tryptophan
  
Nitrofurantoin
  
Penicillin
  
Methotrexate
  
Crack cocaine
Drug-induced systemic lupus 
 
Hydralazine
 
Procainamide
 
Isoniazid
 
Chlorpromazine
 
Phenytoin
Interstitial pneumonitis/fibrosis
 
Bleomycin
 
Busulfan
 
Cyclophosphamide
 
Methysergide
 
Phenytoin
Pulmonary edema
 
Noncardiogenic
  
Aspirin
  
Chlordiazepoxide
  
Cocaine
  
Ethchlorvynol
  
Heroin
 
Cardiogenic
  
Bromocriptine
 
An
y drug inducing systemic 
 
lupus er
ythematosus
 
Chemotherapeutic 
 
agen
ts (eg, carmustine, 
cyclophosphamide, 
 
dasatinib, docetaxel, 
 
GM-CSF, methotrexate)
Mediastinal widening
 
Phenytoin
 
Respiratory failure
 
Neur
omuscular blockade
  
Aminoglycosides
  
Paralytic agents
 
C
entral nervous system 
 
Sedatives
  
Hypnotics
  
Opioids
  
Alcohol
  
T
ricyclic antidepressants
 
Oxygen
GM-CSF, granulocyte-macrophage colony-stimulating factor.
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breathing, or movement. When the central portion of the 
diaphragmatic parietal pleura is irritated, pain may be 
referred to the ipsilateral shoulder. There are numerous 
causes of pleuritis. The setting in which pleuritic pain 
develops helps narrow the differential diagnosis. In young, 
otherwise healthy individuals, pleuritis is usually caused by 
viral respiratory infections or pneumonia. The presence of 
pleural effusion, pleural thickening, or air in the pleural 
space requires further diagnostic and therapeutic mea
-
sures. Simple rib fracture may cause severe pleurisy.
Treatment of pleuritis consists of treating the underly
-
ing disease. Analgesics and anti-inflammatory medications 
(eg, indomethacin, 25 mg orally two or three times daily) 
are often helpful for pain relief. Codeine (30–60 mg orally 
every 8 hours) or other opioids may be used to control 
cough associated with pleuritic chest pain if retention of 
airway secretions is not a likely complication. Intercostal 
nerve blocks are sometimes helpful but the benefit is usu
-
ally transient.
 
»
May be asymptomatic; chest pain frequently seen 
in the setting of pleuritis, trauma, or infection; 
dyspnea is common with large effusions.
 
»
Dullness to percussion and decreased breath 
sounds over the effusion.
 
»
Radiographic evidence of pleural effusion.
 
»
Diagnostic findings on thoracentesis.
 
»
There is constant movement of fluid from parietal pleural 
capillaries into the pleural space at a rate of 0.01 mL/kg 
body weight/h. Absorption of pleural fluid occurs through 
parietal pleural lymphatics. The resultant homeostasis 
leaves 5–15 mL of fluid in the normal pleural space. A 
pleural effusion is an abnormal accumulation of fluid in 
the pleural space. Pleural effusions may be classified by 
differential diagnosis (Table 9–25) or by underlying patho
-
physiology. Five pathophysiologic processes account for 
most pleural effusions: increased production of fluid in the 
setting of normal capillaries due to increased hydrostatic or 
decreased oncotic pressures 
(transudates);
 increased pro
-
duction of fluid due to abnormal capillary permeability 
(exudates);
 decreased lymphatic clearance of fluid from 
the pleural space (
exudates
); infection in the pleural space 
(empyema);
 and bleeding into the pleural space 
(hemo
-
thorax). Parapneumonic pleural effusions
 are exudates 
that accompany bacterial pneumonias.
Diagnostic thoracentesis
 should be performed when
-
ever there is a new pleural effusion and no clinically appar
-
ent cause. Observation is appropriate in some situations 
(eg, symmetric bilateral pleural effusions in the setting of 
heart failure), but an atypical presentation or failure of an 
effusion to resolve as expected warrants thoracentesis. 
Sampling allows visualization of the fluid in addition to 
chemical and microbiologic analyses to identify the under
-
lying pathophysiologic process.
 
»
Patients with pleural effusions most often report dyspnea, 
cough, or respirophasic chest pain. Symptoms are more 
common in patients with existing cardiopulmonary dis
-
ease. Small pleural effusions are less likely to be symptom
-
atic than larger effusions. Physical findings are usually 
absent in small effusions. Larger effusions may present 
with dullness to percussion and diminished or absent 
breath sounds over the effusion. Compressive atelectasis 
may cause bronchial breath sounds and egophony just 
above the effusion. A massive effusion with increased 
intrapleural pressure may cause contralateral shift of the 
trachea and bulging of the intercostal spaces. A pleural 
friction rub indicates infarction or pleuritis.
The gross appearance of pleural fluid helps identify several 
types of pleural effusion. Grossly purulent fluid signifies

types of pleural effusion. Grossly purulent fluid signifies 
empyema. Milky white pleural fluid should be centrifuged. 
A clear supernatant above a pellet of white cells indicates 
empyema, whereas a persistently turbid supernatant sug
-
gests a 
chylous effusion;
 analysis of this supernatant 
reveals chylomicrons and a high triglyceride level (greater 
than 100 mg/dL [1 mmol/L]), often from disruption of the 
thoracic duct. 
Hemorrhagic pleural effusion
 is a mixture 
of blood and pleural fluid. Ten thousand red cells per 
microliter create blood-tinged pleural fluid; 100,000 red 
cells/mcL create grossly bloody pleural fluid. 
Hemothorax
 
is the presence of gross blood in the pleural space, usually 
following chest trauma or instrumentation. It is defined as 
a ratio of pleural fluid hematocrit to peripheral blood 
hematocrit greater than 0.5.
Pleural fluid samples should be sent for measurement 
of protein, glucose, and LD in addition to total and differ
-
ential white blood cell counts. Chemistry determinations 
are used to classify effusions as transudates or exudates. 
This classification is important because the differential 
diagnosis and subsequent evaluation for each entity is 
vastly different (Table 9–25). A 
pleural exudate
 is an effu
-
sion that has one or more of the following laboratory fea
-
tures: (1) ratio of pleural fluid protein to serum protein 
greater than 0.5; (2) ratio of pleural fluid LD to serum LD 
greater than 0.6; (3) pleural fluid LD greater than two-
thirds the upper limit of normal serum LD. 
Pleural tran
-
sudates
 occur in the setting of normal capillary integrity 
and demonstrate none of the laboratory features of exu
-
dates. A transudate suggests the absence of local pleural 
disease; characteristic laboratory findings include a glucose 
equal to serum glucose, pH between 7.40 and 7.55, and 
fewer than 1000 white blood cells/mcL (1.0 × 10
9
/L) with a 
predominance of mononuclear cells.
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Heart failure accounts for 90% of transudates. Bacterial 
pneumonia and cancer are the most common causes of 
exudative effusion. Other causes of exudates with charac
-
teristic laboratory findings are summarized in Table 9–26.
Pleural fluid pH is useful in the assessment of parapneu
-
monic effusions. A pH < 7.30 suggests the need for drainage 
of the pleural space. An elevated amylase level in pleural 
fluid suggests pancreatitis, pancreatic pseudocyst, adeno
-
carcinoma of the lung or pancreas, or esophageal rupture.
Suspected tuberculous pleural effusion should be evalu
-
ated by thoracentesis with culture along with pleural 
biopsy, since pleural fluid culture positivity for 
M tubercu
-
losis
 is low (less than 23–58% of cases). Closed pleural 
biopsy reveals granulomatous inflammation in approxi
-
mately 60% of patients, and culture of three pleural biopsy 
specimens combined with histologic examination of a 
pleural biopsy for granulomas yields a diagnosis in up to 
90% of patients. Tests for pleural fluid adenosine deami
-
nase (approximately 90% sensitivity and specificity for 
pleural tuberculosis at levels greater than 70 units/L) and 
interferon-gamma (89% sensitivity, 97% specificity in a 
meta-analysis) can be extremely helpful diagnostic aids, 
particularly in making decisions to pursue invasive testing 
in complex patients.
Between 40% and 80% of exudative pleural effusions 
are malignant, while over 90% of malignant pleural effu
-
sions are exudative. Almost any form of cancer may cause 
effusions, but the most common causes are lung cancer 
(one-third of cases) and breast cancer. In 5–10% of malig
-
nant pleural effusions, no primary tumor is identified. The 
term 
“paramalignant”
 pleural effusion refers to an 
effusion in a patient with cancer when repeated attempts to 
identify tumor cells in the pleura or pleural fluid are non
-
diagnostic but when there is a presumptive relation to the 
underlying malignancy. For example, superior vena cava 
syndrome with elevated systemic venous pressures causing 
a transudative effusion would be “paramalignant. ”
Pleural fluid specimens should be sent for cytologic 
examination in all cases of exudative effusions in patients 
suspected of harboring an underlying malignancy. The 
diagnostic yield depends on the nature and extent of the 
underlying malignancy. Sensitivity is between 50% and 
65%. A negative cytologic examination in a patient with a 
high prior probability of malignancy should be followed by 
one repeat thoracentesis. If that examination is negative, 
thoracoscopy is preferred to closed pleural biopsy. The 
sensitivity of thoracoscopy is 92–96%.
C. Imaging
The lung is less dense than water and floats on pleural fluid 
that accumulates in dependent regions. Subpulmonary 
fluid may appear as lateral displacement of the apex of the 
diaphragm with an abrupt slope to the costophrenic sulcus 
or a greater than 2-cm separation between the gastric air 
bubble and the lung. On a standard upright chest radio
-
graph (Figure 9–9), approximately 75–100 mL of pleural 
fluid must accumulate in the posterior costophrenic sulcus 
to be visible on the lateral view, and 175–200 mL must be 
present in the lateral costophrenic sulcus to be visible on 
the frontal view. Chest CT scans may identify as little as 
 
10 mL of fluid. At least 1 cm of fluid on the decubitus view 
is necessary to permit blind thoracentesis. Ultrasonogra
-
phy is useful to guide thoracentesis in the setting of smaller 
effusions.
Pleural fluid may become trapped (loculated) by pleu
-
ral adhesions, thereby forming unusual collections along 
the lateral chest wall or within lung fissures. Round or oval 
fluid collections in fissures that resemble intraparenchymal 
masses are called pseudotumors. Massive pleural effusion 
causing opacification of an entire hemithorax is most com
-
monly caused by cancer but may be seen in tuberculosis 
and other diseases.
 
»

-
 
»
Treatment
A. Transudative Pleural Effusion
Transudative pleural effusions characteristically occur in 
the absence of pleural disease. Therefore, treatment is 
directed at the underlying condition. Therapeutic thora
-
centesis for severe dyspnea typically offers only transient 
benefit. Pleurodesis and tube thoracostomy are rarely 
B. Malignant Pleural Effusion
Chemotherapy or radiation therapy or both offer tempo
-
rary control in some malignant effusions but are generally 
ineffective in lung cancer in the pleural space except for 
small-cell lung cancer. Asymptomatic malignant effusions 
Table 9–25.
 
Causes of pleural fluid transudates and 
exudates.
Transudates
Exudates
Heart failure (> 90% of cases)
Cirrhosis with ascites
Peritoneal dialysis
Myxedema
Atelectasis (acute)
Constrictive pericarditis
Superior vena cava obstruction
Pneumonia (parapneumonic 
 
effusion, including empyema)
Cancer
Bacterial infection (including 
empyema)
Connective tissue disease
Viral infection
Fungal infection
Rickettsial infection
Parasitic infection
Asbestos
Meigs syndrome
Pancreatic disease
Uremia
Chronic atelectasis
Trapped lung
Chylothorax
Post–myocardial injury 
syndrome
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Table 9–26.
 
Characteristics of important exudative pleural effusions.
Etiology or Type 
of Effusion
Gross Appearance
White Blood Cell 
Count (cells/mcL)
Red Blood Cell 
Glucose
Comments
Malignancy
Turbid to bloody; 
occasionally 
 
serous
1000–100,000 M
100 to several 
 
hundred 
 
thousand
Equal to serum levels; 
< 60 mg/dL in 
15% of cases
Eosinophilia uncommon; 
positive results on 
cytologic examination
Uncomplicated 
parapneumonic
Clear to turbid
5000–25,000 P
< 5000
Equal to serum levels
Tube thoracostomy 
unnecessary
Empyema
Turbid to purulent
25,000–100,000 P
< 5000
Less than serum 
 
levels; often 
 
very low
Drainage necessary; 
putrid odor suggests 
anaerobic infection
Serous to 
serosanguineous
5000–10,000 M
< 10,000
Equal to serum 
 
levels; occasionally 
< 60 mg/dL
Protein > 4.0 g/dL 
 
(may exceed 5 g/dL); 
eosinophils (> 10%) 
 
or mesothelial cells 
 
(> 5%) make diagnosis 
unlikely; see text for 
additional diagnostic 
tests
Turbid; greenish 
yellow
1000–20,000 M or P
< 1000
< 40 mg/dL
Secondary empyema 
common; high LD, 
 
low complement, 
 
high rheumatoid factor, 
cholesterol crystals are 
characteristic
Pulmonary 
 
infarction
Serous to grossly 
bloody
1000–50,000 M or P
100 to > 100,000
Variable findings; no 
pathognomonic 
features
Esophageal 
 
rupture
Turbid to purulent; 
red-brown
< 5000 to > 50,000 P
1000–10,000
Usually low
High amylase level 
 
(salivary origin); 
 
pneumothorax in 
 
25% of cases; effusion 
usually on left side; pH 
< 6.0 strongly suggests 
diagnosis
Turbid to 
1000–50,000 P
Usually left-sided; high 
amylase level
LD, lactate dehydrogenase; M, mononuclear cell predominance; P , polymorphonuclear leukocyte predominance.
usually do not require specific treatment. Symptomatic 
patients should have a therapeutic thoracentesis. If symp
-
toms are relieved but the effusion returns, the options are 
serial thoracenteses, attempted pleurodesis, or placement 
of an indwelling drainage catheter that the patient can 
access at home. Choice among these options depends on 
the rate of reaccumulation in addition to the functional 
status, tolerance for discomfort, and life expectancy of the 
patient. Consultation with a thoracic specialist is advised 
(Chapter 39).
C. Parapneumonic Pleural Effusion
Parapneumonic pleural effusions are divided into three 
categories: simple or uncomplicated, complicated, and 
empyema. 
Uncomplicated parapneumonic effusions
 are 
free-flowing sterile exudates of modest size that resolve 
quickly with antibiotic treatment of pneumonia. They do 
not need drainage. 
Empyema
 is gross infection of the pleu
-
ral space indicated by positive Gram stain or culture. 
Empyema should always be drained by tube thoracostomy 
to facilitate clearance of infection and to reduce the prob
-
ability of fibrous encasement of the lung, causing perma
-
nent pulmonary impairment.
Complicated parapneumonic effusions
 present the 
most difficult management decisions. They tend to be 
larger than simple parapneumonic effusions and to show 
more evidence of inflammatory stimuli, such as low glucose 
level, low pH, or evidence of loculation. Inflammation 
probably reflects ongoing bacterial invasion of the pleural 
space despite rare positive bacterial cultures. The morbidity 
associated with complicated effusions is due to their 
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CMDT 2019
tendency to form a fibropurulent pleural “peel, ” trapping 
otherwise functional lung and leading to permanent 
impairment. Tube thoracostomy is indicated when pleural 
fluid glucose is less than 60 mg/dL (less than 3.3 mmol/L) 
or the pH is < 7.2. These thresholds have not been prospec
-
tively validated and should not be interpreted strictly. The 
clinician should consider drainage of a complicated effusion 
if the pleural fluid pH is between 7.2 and 7.3 or the LD is 
greater than 1000 units/L (greater than 20 mckat/L). Pleural 
fluid cell count and protein have little diagnostic value in 
this setting.
Tube thoracostomy drainage of empyema or compli
-
cated parapneumonic effusions is frequently complicated 
by loculation that prevents adequate drainage. Intrapleural 
instillation of fibrinolytic agents has not been shown in 
controlled trials to improve drainage. The combination of 
intrapleural tissue plasminogen activator and deoxyribo
-
nuclease (DNase), an enzyme that catalyses extracellular 
DNA and degrades biofilm formation within the pleural 
cavity, has been found to improve clinical outcome 
(increased drainage, decreased length of stay and surgical 
referral) compared with placebo or either agent alone.
D. Hemothorax
A small-volume hemothorax that is stable or improving on 
chest radiographs may be managed by close observation. In 
all other cases, hemothorax is treated by immediate inser
-
tion of a large-bore thoracostomy tube to (1) drain existing 
blood and clot, (2) quantify the amount of bleeding, (3) 
reduce the risk of fibrothorax, and (4) permit apposition of 
the pleural surfaces in an attempt to reduce hemorrhage. 
 
▲
Figure 9–9.
 
Left pleural effusion. 
Frontal chest 
radiograph showing a meniscus-shaped density at the 
left costophrenic angle sulcus indicative of a moderate-
sized pleural effusion.
 
Lechner AJ, Matuschak GM, Brink DS. 
Respiratory: An Inte
-
grated Approach to Disease
. McGraw-Hill, 2012.)
Thoracotomy may be indicated to control hemorrhage, 
remove clot, and treat complications such as bronchopleu
-
ral fistula formation.
Fortin M et al. Pleural controversies: indwelling pleural catheter 
vs. pleurodesis for malignant pleural effusions. J Thorac Dis. 
2015 Jun;7(6):1052–7. [PMID: 26150918]
Kummerfeldt CE et al. Improving the predictive accuracy of 
identifying exudative effusions. Chest. 2014 Mar 1;145(3):
 
586–92. [PMID: 24008773]
Vorster MJ et al. Tuberculous pleural effusions: advances and 
controversies. J Thorac Dis. 2015 Jun;7(6):981–91. [PMID: 
26150911]
Wilcox ME et al. Does this patient have an exudative pleural 
effusion? The Rational Clinical Examination systematic 
review. JAMA. 2014 Jun 18;311(23):2422–31. [PMID: 
24938565]
SPONTANEOUS PNEUMOTHORAX
 
»
Acute onset of unilateral chest pain and dyspnea.
 
»
Minimal physical findings in mild cases; unilateral 
chest expansion, decreased tactile fremitus, 
hyperresonance, diminished breath sounds, medi
-
astinal shift, cyanosis and hypotension in tension 
pneumothorax.
 
»
Presence of pleural air on chest radiograph.
 
»
Pneumothorax, or accumulation of air in the pleural space, 
is classified as spontaneous (primary or secondary) or trau
-
matic. Primary spontaneous pneumothorax occurs in the 
absence of an underlying lung disease, whereas secondary 
spontaneous pneumothorax is a complication of preexist
-
ing pulmonary disease. Traumatic pneumothorax results 
from penetrating or blunt trauma. Iatrogenic pneumotho
-
rax may follow procedures such as thoracentesis, pleural 
biopsy, subclavian or internal jugular vein catheter place
-
ment, percutaneous lung biopsy, bronchoscopy with trans
-
bronchial biopsy, and positive-pressure mechanical 
ventilation. Tension pneumothorax usually occurs in the 
setting of penetrating trauma, lung infection, cardiopul
-

-
-
monary resuscitation, or positive-pressure mechanical 
ventilation. In tension pneumothorax, the pressure of air in 
the pleural space exceeds ambient pressure throughout the 
respiratory cycle. A check-valve mechanism allows air to 
enter the pleural space on inspiration and prevents egress 
of air on expiration.
Primary pneumothorax affects mainly tall, thin boys 
and men between the ages of 10 and 30 years. It is thought 
to occur from rupture of subpleural apical blebs in response 
to high negative intrapleural pressures. Family history and 
cigarette smoking may also be important factors.
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Secondary pneumothorax occurs as a complication of 
COPD, asthma, cystic fibrosis, tuberculosis, 
Pneumocystis
 
pneumonia, menstruation (catamenial pneumothorax), 
and a wide variety of interstitial lung diseases, including 
sarcoidosis, lymphangioleiomyomatosis, Langerhans cell 
histiocytosis, and tuberous sclerosis. Aerosolized pentami
-
dine and a prior history of 
 pneumonia are 
considered risk factors for the development of pneumotho
-
rax. One-half of patients with pneumothorax in the setting 
of recurrent (but not primary) 
 pneumonia 
will develop pneumothorax on the contralateral side. The 
mortality rate of pneumothorax in 
 pneumo
-
nia is high.
 
»
Chest pain ranging from minimal to severe on the affected 
side and dyspnea occur in nearly all patients. Symptoms 
usually begin during rest and usually resolve within 
 
24 hours even if the pneumothorax persists. Alternatively, 
pneumothorax may present with life-threatening respira
-
tory failure if underlying COPD or asthma is present.
If pneumothorax is small (less than 15% of a hemitho
-
rax), physical findings, other than mild tachycardia, are 
normal. If pneumothorax is large, diminished breath 
sounds, decreased tactile fremitus, and decreased move
-
ment of the chest are often noted. Tension pneumothorax 
should be suspected in the presence of marked tachycardia, 
hypotension, and mediastinal or tracheal shift.
Arterial blood gas analysis is often unnecessary but reveals 
hypoxemia and acute respiratory alkalosis in most patients. 
Left-sided primary pneumothorax may produce QRS axis 
and precordial T-wave changes on the ECG that may be 
misinterpreted as acute myocardial infarction.
C. Imaging
Demonstration of a visceral pleural line on chest radio
-
graph is diagnostic and may be seen only on an expiratory 
film. A few patients have secondary pleural effusion that 
demonstrates a characteristic air-fluid level on chest radi
-
ography. In supine patients, pneumothorax on a conven
-
tional chest radiograph may appear as an abnormally 
radiolucent costophrenic sulcus (the “deep sulcus” sign). In 
patients with tension pneumothorax, chest radiographs 
show a large amount of air in the affected hemithorax and 
contralateral shift of the mediastinum.
 
»
If the patient is a young, tall, thin, cigarette-smoking man, 
the diagnosis of primary spontaneous pneumothorax is 
usually obvious and can be confirmed by chest radiograph. 
In secondary pneumothorax, it is sometimes difficult to 
distinguish loculated pneumothorax from an emphysema
-
tous bleb. Occasionally, pneumothorax may mimic myo
-
cardial infarction, pulmonary embolism, or pneumonia.
 
»
Tension pneumothorax may be life-threatening. Pneumo
-
mediastinum and subcutaneous emphysema may occur as 
complications of spontaneous pneumothorax. If pneumo
-
mediastinum is detected, rupture of the esophagus or a 
bronchus should be considered in the differential 
 
»
Treatment
Treatment depends on the severity of the pneumothorax 
and the nature of the underlying disease. In a reliable 
patient with a small (less than 15% of a hemithorax), stable, 
spontaneous primary pneumothorax, observation alone 
may be appropriate. Many small pneumothoraces resolve 
spontaneously as air is absorbed from the pleural space; 
supplemental oxygen therapy may increase the rate of reab
-
sorption. Simple aspiration drainage of pleural air with a 
small-bore catheter (eg, 16-gauge angiocatheter or larger 
drainage catheter) can be performed for spontaneous pri
-
mary pneumothoraces that are large or progressive. Place
-
ment of a small-bore chest tube (7F to 14F) attached to a 
one-way Heimlich valve provides protection against devel
-
opment of tension pneumothorax and may permit obser
-
vation from home. The patient should be treated

-
-
vation from home. The patient should be treated 
symptomatically for cough and chest pain, and followed 
with serial chest radiographs every 24 hours.
Patients with secondary pneumothorax, large pneumo
-
thorax, tension pneumothorax, or severe symptoms or 
those who have a pneumothorax on mechanical ventilation 
should undergo chest tube placement (tube thoracostomy). 
The chest tube is placed under water-seal drainage, and 
suction is applied until the lung expands. The chest tube 
can be removed after the air leak subsides.
All patients who smoke should be advised to discon
-
tinue smoking and warned that the risk of recurrence is 
50% if cigarette smoking is continued. Future exposure to 
high altitudes, flying in unpressurized aircraft, and scuba 
diving should be avoided.
Indications for thoracoscopy or open thoracotomy 
include recurrences of spontaneous pneumothorax, any 
occurrence of bilateral pneumothorax, and failure of tube 
thoracostomy for the first episode (failure of lung to reex
-
pand or persistent air leak). Surgery permits resection of 
blebs responsible for the pneumothorax and pleurodesis by 
mechanical abrasion and insufflation of talc.
Management of pneumothorax in patients with 
Pneu
-
mocystis
 pneumonia is challenging because of a tendency 
toward recurrence, and there is no consensus on the best 
approach. Use of a small chest tube attached to a Heimlich 
valve has been proposed to allow the patient to leave the 
hospital. Some clinicians favor its insertion early in the 
course.
 
»
Prognosis
An average of 30% of patients with spontaneous pneumo
-
thorax experience recurrence of the disorder after either 
observation or tube thoracostomy for the first episode. 
Recurrence after surgical therapy is less frequent. 
CMDT19_Ch09_p0252-p0333.indd   326

327
 
CMDT 2019
Following successful therapy, there are no long-term 
complications.
Bintcliffe OJ et al. Spontaneous pneumothorax: time to rethink 
management? Lancet Respir Med. 2015 Jul;3(7):578–88. 
[PMID: 26170077]
Hsu HH et al. The etiology and therapy of primary spontaneous 
pneumothoraces. Expert Rev Respir Med. 2015 Oct;9(5):
 
655–65. [PMID: 26366808]
Imran JB et al. JAMA patient page. Pneumothorax. JAMA. 2017 
Sep 12;318(10):974. [PMID: 28898380]
Tschopp JM et al. ERS task force statement: diagnosis and treat
-
ment of primary spontaneous pneumothorax. Eur Respir J. 
2015 Aug;46(2):321–35. [PMID: 26113675]
Visouli AN et al. Catamenial pneumothorax. J Thorac Dis. 2014 Oct;
 
6(Suppl 4):S448–60. [PMID: 25337402]
 
º
DISORDERS OF CONTROL OF 
VENTILATION
The principal influences on ventilatory control are arterial 
P
co
2
, pH, P
o
2
, and brainstem tissue pH. These variables 
are monitored by peripheral and central chemoreceptors. 
Under normal conditions, the ventilatory control system 
maintains arterial pH and P
co
2
 within narrow limits; arte
-
rial P
o
2
 is more loosely controlled.
Abnormal control of ventilation can be seen with a 
variety of conditions ranging from rare disorders, such as 
central alveolar hypoventilation, Ondine curse, neuromus
-
cular disorders, myxedema, starvation, and carotid body 
resection to more common disorders, such as asthma, 
COPD, obesity, heart failure, and sleep-related breathing 
disorders. A few of these disorders will be discussed in this 
section.
Annane D et al. Nocturnal mechanical ventilation for chronic 
hypoventilation in patients with neuromuscular and chest 
wall disorders. Cochrane Database Syst Rev. 2014 Dec 13;
 
12:CD001941. [PMID: 25503955]
Böing S et al. Chronic hypoventilation syndromes and sleep-
related hypoventilation. J Thorac Dis. 2015 Aug;7(8):1273–85. 
[PMID: 26380756]
OBESITY-HYPOVENTILATION SYNDROME 
(
Pickwickian Syndrome
)
In obesity-hypoventilation syndrome, alveolar hypoventi
-
lation appears to result from a combination of blunted 
ventilatory drive and increased mechanical load imposed 
upon the chest by obesity. Voluntary hyperventilation 
returns the P
co
2
 and the P
o
2
 toward normal values, a cor
-
rection not seen in lung diseases causing chronic respira
-
tory failure, such as COPD. Most patients with 
obesity-hypoventilation syndrome also suffer from 
obstructive sleep apnea, which must be treated aggressively 
if identified as a comorbid disorder. Therapy of obesity-
hypoventilation syndrome consists mainly of weight loss, 
which improves hypercapnia and hypoxemia as well as the 
ventilatory responses to hypoxia and hypercapnia. NIPPV 
is helpful in some patients. Respiratory stimulants may be 
helpful and include progesterone acetate, 10–20 mg every 
 
8 hours orally, theophylline, and acetazolamide.
Jones SF et al. Obesity hypoventilation syndrome in the critically 
ill. Crit Care Clin. 2015 Jul;31(3):419–34. [PMID: 26118913]
Pierce AM et al. Obesity hypoventilation syndrome: current 
theories of pathogenesis. Curr Opin Pulm Med. 2015 Nov;
 
21(6):557–62. [PMID: 26390338]
Piper A. Obesity hypoventilation syndrome: weighing in on 
therapy options. Chest. 2016 Mar;149(3):856–68. [PMID: 
26292036]
HYPERVENTILATION SYNDROMES
Hyperventilation is an increase in alveolar ventilation that 
leads to hypocapnia. It may be caused by a variety of condi
-
tions, such as pregnancy, hypoxemia, obstructive and infil
-
trative lung diseases, sepsis, hepatic dysfunction, fever, and 
pain. The term “central neurogenic hyperventilation” 
denotes a monotonous, sustained pattern of rapid and deep 
breathing seen in comatose patients with brainstem injury 
of multiple causes. Functional hyperventilation may be 
acute or chronic. 
Acute hyperventilation
 presents with

 presents with 
hyperpnea, paresthesias, carpopedal spasm, tetany, and 
anxiety. 
Chronic hyperventilation
 may present with vari
-
ous nonspecific symptoms, including fatigue, dyspnea, 
anxiety, palpitations, and dizziness. The diagnosis of 
chronic hyperventilation syndrome is established if symp
-
toms are reproduced during voluntary hyperventilation. 
Once organic causes of hyperventilation have been 
excluded, treatment of acute hyperventilation consists of 
breathing through pursed lips or through the nose with 
one nostril pinched, or rebreathing expired gas from a 
paper bag held over the face in order to decrease respira
-
tory alkalemia and its associated symptoms. Anxiolytic 
drugs may also be useful.
Boulding R et al. Dysfunctional breathing: a review of the litera
-
ture and proposal for classification. Eur Respir Rev. 2016 Sep;
 
25(141):287–94. [PMID: 27581828]
SLEEP-RELATED BREATHING DISORDERS
Abnormal ventilation during sleep is manifested by apnea 
(breath cessation for at least 10 seconds) or hypopnea (dec
-
rement in airflow with drop in hemoglobin saturation of at 
least 4%). Episodes of apnea are 
central
 if ventilatory effort 
is absent for the duration of the apneic episode, 
obstructive
 
if ventilatory effort persists throughout the apneic episode 
but no airflow occurs because of transient obstruction of 
the upper airway, and 
mixed
 if absent ventilatory effort 
precedes upper airway obstruction during the apneic epi
-
sode. Pure central sleep apnea is uncommon; it may be an 
isolated finding or may occur in patients with primary 
alveolar hypoventilation or with lesions of the brainstem. 
Obstructive and mixed sleep apneas are more common and 
may be associated with life-threatening cardiac arrhyth
-
mias, severe hypoxemia during sleep, daytime somnolence, 
pulmonary hypertension, cor pulmonale, systemic hyper
-
tension, and secondary erythrocytosis.
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C
HAPTER
 9
328
 CMDT 2019
OBSTRUCTIVE SLEEP APNEA
 
»
Daytime somnolence or fatigue.
 
»
A history of loud snoring with witnessed apneic 
events.
 
»
Overnight polysomnography demonstrating 
apneic episodes with hypoxemia.
 
»
Upper airway obstruction during sleep occurs when loss of 
normal pharyngeal muscle tone allows the pharynx to col
-
lapse passively during inspiration. Patients with anatomi
-
cally narrowed upper airways (eg, micrognathia, 
macroglossia, obesity, tonsillar hypertrophy) are predis
-
posed to the development of obstructive sleep apnea. 
Ingestion of alcohol or sedatives before sleeping or nasal 
obstruction of any type, including the common cold, may 
precipitate or worsen the condition. Hypothyroidism and 
cigarette smoking are additional risk factors for obstructive 
sleep apnea. Before making the diagnosis of obstructive 
sleep apnea, a drug history should be obtained and a sei
-
zure disorder, narcolepsy, and depression should be 
excluded.
 
»
Most patients with obstructive or mixed sleep apnea are 
obese, middle-aged men. Arterial hypertension is common. 
Patients may complain of excessive daytime somnolence, 
morning sluggishness and headaches, daytime fatigue, cog
-
nitive impairment, recent weight gain, and impotence. Bed 
partners usually report loud cyclical snoring, breath cessa
-
tion, witnessed apneas, restlessness, and thrashing move
-
ments of the extremities during sleep. Personality changes, 
poor judgment, work-related problems, depression, and 
intellectual deterioration (memory impairment, inability to 
concentrate) may also be observed. The US Preventive Ser
-
vices Task Force does not recommend screening asymp
-
tomatic adults for sleep apnea.
Physical examination may be normal or may reveal 
systemic and pulmonary hypertension with cor pulmonale. 
The patient may appear sleepy or even fall asleep during 
the evaluation. The oropharynx is frequently found to be 
narrowed by excessive soft tissue folds, large tonsils, pen
-
dulous uvula, or prominent tongue. Nasal obstruction by a 
deviated nasal septum, poor nasal airflow, and a nasal 
twang to the speech may be observed. A “bull neck” 
appearance is common.
Erythrocytosis is common. Thyroid function tests (serum, 
TSH, FT
4
) should be obtained to exclude hypothyroidism.
C. Other Studies
Observation of the sleeping patient may reveal loud snor
-
ing interrupted by episodes of increasingly strong ventila
-
tory effort that fail to produce airflow. A loud snort often 
accompanies the first breath following an apneic episode. 
Definitive diagnostic evaluation for suspected sleep apnea 
includes otorhinolaryngologic examination and overnight 
polysomnography (the monitoring of multiple physiologic 
factors during sleep). Screening may be performed using 
home nocturnal pulse oximetry, which when normal has a 
high negative predictive value in ruling out significant 
sleep apnea. A complete 
polysomnography
 examination 
includes electroencephalography, electro-oculography, 
electromyography, ECG, pulse oximetry, and measurement 
of respiratory effort and airflow. Polysomnography reveals 
apneic episodes lasting as long as 60 seconds. Oxygen satu
-
ration falls, often to very low levels. Bradydysrhythmias, 
such as sinus bradycardia, sinus arrest, or atrioventricular 
block, may occur. Tachydysrhythmias, including paroxys
-
mal supraventricular tachycardia, atrial fibrillation, and 
ventricular tachycardia, may be seen once airflow is 
reestablished.
 
»
Treatment
 and strict avoidance of alcohol and hypnotic 
medications are the first steps in management. Weight loss 
may be curative, but most patients are unable to lose the 
10–20% of body weight required. 
Nasal continuous posi
-
tive airway pressure (nasal CP AP)
 at night is curative in 
many patients. Polysomnography is frequently necessary to

-
many patients. Polysomnography is frequently necessary to 
determine the level of CPAP (usually 5–15 cm H
2
O) neces
-
sary to abolish obstructive apneas. Unfortunately, only 
about 75% of patients continue to use nasal CPAP after 
 
1 year. Pharmacologic therapy for obstructive sleep apnea is 
disappointing. Supplemental oxygen may lessen the severity 
of nocturnal desaturation but may also lengthen apneas; it 
should not be routinely prescribed without polysomnogra
-
phy to assess the effects of oxygen therapy. Mechanical 
devices inserted into the mouth at bedtime to hold the jaw 
forward and prevent pharyngeal occlusion have modest 
effectiveness in relieving apnea; however, patient compli
-
ance is not optimal.
Uvulopalatopharyngoplasty (UPPP),
 a procedure con
-
sisting of resection of pharyngeal soft tissue and amputation 
of approximately 15 mm of the free edge of the soft palate 
and uvula, is helpful in approximately 50% of selected 
patients. It is more effective in eliminating snoring than 
apneic episodes. UPPP may be performed on an outpatient 
basis with a laser. 
Nasal septoplasty
 is performed if gross 
anatomic nasal septal deformity is present. 
Tracheostomy
 
relieves upper airway obstruction and its physiologic con
-
sequences and represents the definitive treatment for 
obstructive sleep apnea. However, it has numerous adverse 
effects, including granuloma formation, difficulty with 
speech, and stoma and airway infection. Furthermore, the 
long-term care of the tracheostomy, especially in obese 
patients, can be difficult. Tracheostomy and other maxil
-
lofacial surgery approaches are reserved for patients with 
life-threatening arrhythmias or severe disability who have 
CMDT19_Ch09_p0252-p0333.indd   328

329
 
CMDT 2019
not responded to conservative therapy. A randomized trial 
of adaptive servo-ventilation in sleep apnea patients with 
predominant central apnea and impaired left ventricular 
ejection fraction (less than 45%) reported increased car
-
diovascular and all-cause mortality in the treatment group.
Bratton DJ et al. CPAP vs. mandibular advancement devices and 
blood pressure in patient with obstructive sleep apnea: a sys
-
tematic review and meta-analysis. JAMA. 2015 Dec 1;314(21):
 
2280–93. [PMID: 26624827]
Cowie MR et al. Adaptive servo-ventilation for central sleep 
apnea in systolic heart failure. N Engl J Med. 2015 Sep 17;
 
373(12):1095–105. [PMID: 26323938]
Jun JC et al. Sleep apnoea. Eur Respir Rev. 2016 Mar;25(139):
 
12–8. [PMID: 26929416]
Mokhlesi B et al. Diagnostic testing for obstructive sleep apnea 
in adults. JAMA. 2017 Nov 28;318(20):2035–6. [PMID: 
29183053]
Qaseem A et al. Diagnosis of obstructive sleep apnea in adults: a 
clinical practice guideline from the American College of Phy
-
sicians. Ann Intern Med. 2014 Aug 5;161(3):210–20. [PMID: 
25089864]
 
º
ACUTE RESPIRATORY FAILURE
Respiratory failure is defined as respiratory dysfunction 
resulting in abnormalities of oxygenation or ventilation 
(CO
2
 elimination) severe enough to threaten the function 
of vital organs. Arterial blood gas criteria for respiratory 
failure are not absolute but may be arbitrarily established as 
a Po
2
 under 60 mm Hg (7.8 kPa) or a Pco
2
 over 50 mm Hg 
(6.5 kPa). Acute respiratory failure may occur in a variety 
of pulmonary and nonpulmonary disorders (Table 9–27). 
Only a few selected general principles of management will 
be reviewed here.
 
»
Symptoms and signs of acute respiratory failure are those 
of the underlying disease combined with those of hypox
-
emia or hypercapnia. The chief symptom of hypoxemia is 
dyspnea, though profound hypoxemia may exist in the 
absence of complaints. Signs of hypoxemia include cyano
-
sis, restlessness, confusion, anxiety, delirium, tachypnea, 
bradycardia or tachycardia, hypertension, cardiac dys
-
rhythmias, and tremor. Dyspnea and headache are the 
cardinal symptoms of hypercapnia. Signs of hypercapnia 
include peripheral and conjunctival hyperemia, hyperten
-
sion, tachycardia, tachypnea, impaired consciousness, pap
-
illedema, and asterixis. The symptoms and signs of acute 
respiratory failure are both insensitive and nonspecific; 
therefore, the clinician must maintain a high index of sus
-
picion and obtain arterial blood gas analysis if respiratory 
failure is suspected.
 
»
Treatment
Treatment of the patient with acute respiratory failure con
-
sists of (1) specific therapy directed toward the underlying 
disease, (2) respiratory supportive care directed toward the 
maintenance of adequate gas exchange, and (3) general 
supportive care. Only the last two aspects are discussed 
below.
Table 9–27.
 
Selected causes of acute respiratory 
 
failure in adults.
Airway disorders
 
Asthma
 
A
cute exacerbation of 
 
chr
onic bronchitis or 
emphysema
 
Obstruc
tion of pharynx, 
 
lar
ynx, trachea, main stem 
bronchus, or lobar bron
-
chus by edema, mucus, 
mass, or foreign body
 
I
ncreased hydrostatic 
 
pressure
 
L
eft ventricular dysfunc-
 
tion (eg, myocardial 
 
ischemia, heart failure)
 
M
itral regurgitation
 
L
eft atrial outflow obstruc-
 
tion (
eg, mitral stenosis)
 
V
olume overload states
 
I
ncreased pulmonary 
 
capillary permeability
 
A
cute respiratory distress 
 
syndrome
 
A
cute lung injury
Unclear etiology
 
Neurogenic
 
Nega
tive pressure (inspira-
 
t
ory airway obstruction)
 
Re-expansion
 
Tocolytic-associated
Parenchymal lung disorders
 
Pneumonia
 
I
nterstitial lung diseases
 
Diffuse alv
eolar hemorrhage 
 
syndromes
 
Aspiration
 
L
ung contusion
Pulmonary vascular disorders
 
Thromboembolism
 
Air embolism
 
Amniotic 
fluid embolism
Chest wall, diaphragm, and

syndromes
 
L
 
Amniotic 
Chest wall, diaphragm, and 
pleural disorders
 
R
ib fracture
 
F
lail chest
 
Pneumothorax
 
P
leural effusion
 
M
assive ascites
 
Abdominal 
distention and 
 
abdominal compartment 
syndrome
Neuromuscular and related 
disorders
 
P
rimary neuromuscular 
 
diseases
  
Guillain-Barré syndrome
  
Polymyositis
 
Drug- or t
oxin-induced
  
Botulism
  
Organophosphates
   
Neur
omuscular blocking 
 
agents
  
Spinal 
cord injury
 
P
hrenic nerve injury or 
 
dysfunction
 
Elec
trolyte disturbances
  
Hypophosphatemia
 
Myxedema
Central nervous system 
disorders
 
Drugs: 
sedatives, hypnotics, 
 
opioids
, anesthetics
 
Br
ainstem respiratory center 
 
disor
ders: trauma, tumor, 
vascular disorders, 
hypothyroidism
 
I
ntracranial hypertension
 
C
 
Increased CO
2
 production
 
Fever
 
Infection
 
H
yperalimentation with 
 
e
xcess caloric and 
 
carbohydrate intake
 
Seizures
 
Rigors
 
Drugs
A. Respiratory Support
Respiratory support has both nonventilatory and ventila
-
tory aspects.
1. Nonventilatory aspects—
The main therapeutic goal in 
acute hypoxemic respiratory failure is to ensure adequate 
oxygenation of vital organs. Inspired oxygen concentration 
CMDT19_Ch09_p0252-p0333.indd   329

C
HAPTER
 9
330
 CMDT 2019
should be the lowest value that results in an arterial hemo
-
globin saturation of 90% or more (Po
2
 60 mm Hg or more 
[7.8 kPa or more]). Higher arterial oxygen tensions are of 
no proven benefit and may be deleterious. Restoration of 
normoxia may rarely cause hypoventilation in patients 
with chronic hypercapnia; however, oxygen therapy should 
not be withheld for fear of causing progressive respiratory 
acidemia. Hypoxemia in patients with obstructive airway 
disease is usually easily corrected by administering low-
flow oxygen by nasal cannula (1–3 L/min) or Venturi mask 
(24–40%). Higher concentrations of oxygen are necessary 
to correct hypoxemia in patients with ARDS, pneumonia, 
and other parenchymal lung diseases. The high flow nasal 
cannula provides adjustable oxygen delivery and flow-
dependent clearance of carbon dioxide from the upper 
airway resulting in reduced work of breathing and better 
matching of respiratory demand during respiratory dis
-
tress. In hypoxemia due to acute respiratory failure, oxy
-
genation with use of a high flow nasal cannula has been 
shown to be similar, and in some cases superior, to conven
-
tional low flow oxygen supplementation and to noninva
-
sive positive pressure ventilation.
2. Ventilatory aspects—
Ventilatory support consists of 
maintaining patency of the airway and ensuring adequate 
alveolar ventilation. Mechanical ventilation may be provided 
via mask (noninvasive) or through tracheal intubation.
a.
 
N
oninvasive positive-pressure ventilation
—
NIPPV delivered via a full face mask or nasal mask is first-line 
therapy in COPD patients with hypercapnic respiratory fail
-
ure who can protect and maintain the patency of their airway, 
handle their own secretions, and tolerate the mask apparatus. 
Several studies have demonstrated the effectiveness of this 
therapy in reducing intubation rates and ICU stays in patients 
with ventilatory failure. A bilevel positive-pressure ventilation 
mode is preferred for most patients. Patients with acute lung 
injury or ARDS or those who suffer from severely impaired 
oxygenation are less likely to benefit and should be intubated 
if they require mechanical ventilation.
b.
 
T
racheal intubation
—
Indications for tracheal intu
-
bation include (1) hypoxemia despite supplemental oxygen; 
(2) upper airway obstruction; (3) impaired airway protec
-
tion; (4) inability to clear secretions; (5) respiratory acidosis; 
(6) progressive general fatigue, tachypnea, use of accessory 
respiratory muscles, or mental status deterioration; and (7) 
apnea. Patients in respiratory failure who undergo a trial of 
NIPPV and do not improve within 30–90 minutes should 
be intubated. In general, orotracheal intubation is preferred 
to nasotracheal intubation in urgent or emergency situa
-
tions because it is easier, faster, and less traumatic. The tip 
of the endotracheal tube should be positioned 2–4 cm above 
the carina and be verified by chest radiograph immediately 
following intubation. Only tracheal tubes with high-
volume, low-pressure air-filled cuffs should be used. Cuff 
inflation pressure should be kept below 20 mm Hg if pos
-
sible to minimize tracheal mucosal injury.
c.
 
M
echanical ventilation
—
Indications for mechani
-
cal ventilation include (1) apnea, (2) acute hypercapnia 
that is not quickly reversed by appropriate specific therapy, 
(3) severe hypoxemia, and (4) progressive patient fatigue 
despite appropriate treatment.
Several modes of positive-pressure ventilation are avail
-
able. Controlled mechanical ventilation (CMV; also known as 
assist-control [A-C]) and synchronized intermittent manda
-
tory ventilation (SIMV) are ventilatory modes in which the 
ventilator delivers a minimum number of breaths of a speci
-
fied tidal volume each minute. In both CMV and SIMV , the 
patient may trigger the ventilator to deliver additional breaths. 
In CMV , the ventilator responds to breaths initiated by the

-
In CMV , the ventilator responds to breaths initiated by the 
patient above the set rate by delivering additional full tidal 
volume breaths. In SIMV , additional breaths are not sup
-
ported by the ventilator unless the pressure support mode is 
added. Numerous alternative modes of mechanical ventila
-
tion now exist, the most popular being pressure support ven
-
tilation (PSV), pressure control ventilation (PCV), and CPAP .
PEEP is useful in improving oxygenation in patients with 
diffuse parenchymal lung disease, such as ARDS. It should 
be used cautiously in patients with localized parenchymal 
disease, emphysema, hyperinflation, or very high airway 
pressure requirements during mechanical ventilation.
d.
 
C
omplications of mechanical ventilation—
Potential complications of mechanical ventilation are numer
-
ous. Migration of the tip of the endotracheal tube into a main 
bronchus can cause atelectasis of the contralateral lung and 
overdistention of the intubated lung. Barotrauma refers to 
rupture and loss of integrity of the alveolar space secondary 
to high transmural pressures applied during positive pressure 
ventilation. Barotrauma is manifested by subcutaneous 
emphysema, pneumomediastinum, subpleural air cysts, 
pneumothorax, or systemic gas embolism. Volutrauma is 
sometimes used to refer to subtle parenchymal injury due to 
overdistention of alveoli from excessive tidal volumes with
-
out alveolar rupture, mediated through inflammatory rather 
than physical mechanisms. The principal strategy to avoid 
volutrauma is the use of low tidal volume ventilation.
Acute respiratory alkalosis caused by overventilation is 
common. Hypotension induced by elevated intrathoracic 
pressure that results in decreased return of systemic venous 
blood to the heart may occur in patients treated with PEEP , 
particularly those with intravascular volume depletion, and 
in patients with severe airflow obstruction at high respira
-
tory rates that promote “breath stacking” (dynamic hyper
-
inflation). Ventilator-associated pneumonia is another 
serious complication of mechanical ventilation.
B. General Supportive Care
Hypokalemia and hypophosphatemia may worsen hypoven
-
tilation due to respiratory muscle weakness. Sedative-hyp
-
notics and opioid analgesics should be titrated carefully to 
avoid oversedation, leading to prolongation of intubation. 
Temporary paralysis with a nondepolarizing neuromuscular 
blocking agent is used to facilitate mechanical ventilation and 
to lower oxygen consumption. Prolonged muscle weakness 
due to an acute myopathy is a potential complication of these 
agents. Myopathy is more common in patients with kidney 
injury and in those given concomitant corticosteroids.
Psychological and emotional support of the patient and 
family, skin care to avoid pressure injuries (previously 
CMDT19_Ch09_p0252-p0333.indd   330

331
 
CMDT 2019
called pressure ulcers), and meticulous avoidance of health 
care–associated infection and complications of tracheal 
tubes are vital aspects of comprehensive care for patients 
with acute respiratory failure.
Attention must also be paid to preventing complications 
associated with serious illness. Stress gastritis and ulcers may 
be avoided by administering sucralfate (1 g orally twice a 
day), histamine H
2
-receptor antagonists, or PPIs. There is 
some concern that the latter two agents, which raise gastric 
pH, may permit increased growth of gram-negative bacteria 
in the stomach, predisposing to pharyngeal colonization and 
ultimately HCAP; many clinicians therefore prefer sucral
-
fate. The risk of DVT and PE may be reduced by subcutane
-
ous administration of heparin (5000 units every 12 hours), 
the use of LMWH (see Table 14–14), or placement of 
sequential compression devices on the lower extremities.
 
»
Course & Prognosis
The course and prognosis of acute respiratory failure vary 
and depend on the underlying disease. The prognosis of 
acute respiratory failure caused by uncomplicated sedative 
or opioid overdose is excellent. Acute respiratory failure in 
patients with COPD who do not require intubation and 
mechanical ventilation has a good immediate prognosis. 
On the other hand, ARDS and respiratory failure associ
-
ated with sepsis have a poor prognosis.
Drake MG. High flow nasal cannula oxygen in adults: an evi
-
dence-based assessment. Ann Am Thorac Soc. 2018 
Feb;15(2):145–55. [PMID: 29144160]
Meeder AM et al. Noninvasive and invasive positive pressure 
ventilation for acute respiratory failure in critically ill patients: 
a comparative cohort study. J Thorac Dis. 2016 May;8(5):
 
813–25. [PMID: 27162654]
Pisani L et al. Management of acute hypercapnic respiratory 
failure. Curr Opin Crit Care. 2016 Feb;22(1):45–52. [PMID: 
26627537]
Rochwerg B et al. Official ERS/ATS clinical practice guidelines: 
noninvasive ventilation for acute respiratory failure. Eur 
Respir J 2017 Aug 31;50(2). [PMID: 28860265]
 
º
ACUTE RESPIRATORY DISTRESS 
SYNDROME
 
»
Onset of respiratory distress, often progressing to 
respiratory failure, within 7 days of a known clini
-
cal insult.
 
»
New, bilateral radiographic pulmonary opacities 
not explained by pleural effusion, atelectasis, or 
nodules.
 
»
Respiratory failure not fully explained by heart 
failure or volume overload.
 
»
Impaired oxygenation, with ratio of partial pres
-
sure of oxygen in arterial blood (Pao
2
) to fractional 
concentration of inspired oxygen (F
io
2
) less than 
300 mm Hg, with PEEP 5 cm H
2
O or more.
 
»
Acute respiratory distress syndrome (ARDS) as a clinical 
syndrome is based on three inclusion criteria plus one 
exclusion criterion, as detailed above. The severity of 
ARDS is based on the level of oxygenation impairment: 
mild,
 Pa
o
2
/F
io
2
 ratio between 200 and 300 mm Hg; 
mod
-
erate,
 Pa
o
2
/F
io
2
 ratio between 100 and 200 mm Hg; and 
severe,
 Pa
o
2
/F
io
2
 ratio less than 100 mm Hg.
ARDS may follow a wide variety of clinical events 
(Table 9–28). Common risk factors for ARDS include sep
-
sis, aspiration of gastric contents, shock, infection, lung 
contusion, nonthoracic trauma, toxic inhalation, near-
drowning, and multiple blood transfusions. About one-
third of ARDS patients initially have sepsis syndrome. 
Damage to capillary endothelial cells and alveolar epithelial 
cells is common to ARDS regardless of cause or mecha
-
nism of lung injury, resulting in increased vascular perme
-
ability and decreased production and activity of surfactant; 
these abnormalities lead to interstitial and alveolar pulmo
-
nary edema, alveolar collapse, and hypoxemia.
 
»
ARDS is marked by the rapid onset of profound dyspnea 
that usually occurs 12–48 hours after the initiating event. 
Labored breathing, tachypnea, intercostal retractions, and

»
Labored breathing, tachypnea, intercostal retractions, and 
crackles are noted on physical examination. Chest radiog
-
raphy shows diffuse or patchy bilateral infiltrates that rap
-
idly become confluent; these characteristically spare the 
costophrenic angles. Air bronchograms occur in about 
80% of cases. Heart size is usually normal, and pleural 
Table 9–28.
 
Selected disorders associated with ARDS.
Systemic Insults
Pulmonary Insults
Trauma
Sepsis
Shock
Multiple transfusions
Disseminated intravascular 
coagulation
Burns
Drugs and drug overdose
 
Opioids
 
Aspirin
 
Phenothiazines
 
T
 
Chemother
apeutic agents
 
Protamine
Thrombotic thrombocytopenic 
purpura
Cardiopulmonary bypass
Paraquat
Aspiration of gastric contents
Embolism of thrombus, fat, air, 
or amniotic fluid
Miliary tuberculosis
Diffuse pneumonia (eg, SARS)
Cryptogenic organizing 
pneumonitis
Upper airway obstruction
Free-base cocaine smoking
Near-drowning
Toxic gas inhalation
 
N
itrogen dioxide
 
Chlorine
 
Sulfur 
dioxide
 
Ammonia
 
Smoke
Oxygen toxicity
Lung contusion
Radiation exposure
High-altitude exposure
Lung reexpansion or 
reperfusion
ARDS, acute respiratory distress syndrome; SARS, severe acute 
respiratory syndrome.
CMDT19_Ch09_p0252-p0333.indd   331

C
HAPTER
 9
332
 CMDT 2019
effusions are small or nonexistent. Marked hypoxemia 
occurs that is refractory to treatment with supplemental 
oxygen. Many patients with ARDS demonstrate multiple 
organ failure, particularly involving the kidneys, liver, gut, 
central nervous system, and cardiovascular system.
 
»
Since ARDS is a physiologic and radiographic syndrome 
rather than a specific disease, the concept of differential 
diagnosis does not strictly apply. Normal-permeability 
(“cardiogenic” or hydrostatic) pulmonary edema must be 
excluded, however, because specific therapy is available for 
that disorder. Emergent echocardiogram or measurement 
of pulmonary capillary wedge pressure by means of a flow-
directed pulmonary artery catheter may be required in 
selected patients with suspected cardiac dysfunction; rou
-
tine use in ARDS is discouraged.
 
»
No measures that effectively prevent ARDS have been iden
-
tified; specifically, prophylactic use of PEEP in patients at 
risk for ARDS has not been shown to be effective. Intrave
-
nous methylprednisolone does not prevent ARDS when 
given early to patients with sepsis syndrome or septic shock.
 
»
Treatment
The first principle in management is to identify and treat 
the primary condition that has led to ARDS. Meticulous 
supportive care must then be provided to compensate for 
the severe dysfunction of the respiratory system associated 
with ARDS and to prevent complications.
Treatment of the hypoxemia seen in ARDS usually 
requires tracheal intubation and positive-pressure mechan
-
ical ventilation. The lowest levels of PEEP (used to recruit 
atelectatic alveoli) and supplemental oxygen required to 
maintain the Pao
2
 above 55 mm Hg (7.13 kPa) or the Sao
2
 
above 88% should be used. Efforts should be made to 
decrease F
i
o
2
 as soon as possible in order to avoid oxygen 
toxicity. PEEP can be increased as needed as long as cardiac 
output and oxygen delivery do not decrease and airway 
pressures do not increase excessively. Prone positioning 
frequently improves oxygenation by helping recruit atelec
-
tatic alveoli and may yield a mortality benefit in severe 
ARDS. In one placebo-controlled randomized trial, neuro
-
muscular blockade (by continuous infusion of cisatracu
-
rium at 37.5 mg/h) for 48 hours upon initiation of 
mechanical ventilation was associated with improved mor
-
tality and more ventilator-free days in patients with Pa
o
2
/
F
i
o
2
 ratio less than 120 mm Hg.
A variety of mechanical ventilation strategies are avail
-
able. The most significant advance in the treatment of 
ARDS over the past 20 years has been the recognition of 
the potential for excessive alveolar stretch to cause lung 
injury, and the widespread adoption of low tidal volume 
ventilation. A multicenter study of 800 patients demon
-
strated that a protocol using volume-control ventilation 
with low tidal volumes (6 mL/kg of ideal body weight) 
resulted in an 8.8% absolute mortality reduction over 
therapy with standard tidal volumes (defined as 12 mL/kg 
of ideal body weight).
Approaches to hemodynamic monitoring and fluid 
management in patients with acute lung injury have been 
carefully studied. A prospective RCT comparing hemody
-
namic management guided either by a pulmonary artery 
catheter or a central venous catheter using an explicit man
-
agement protocol demonstrated that a pulmonary artery 
catheter should not be routinely used for the management 
of acute lung injury. A subsequent randomized, prospec
-
tive clinical study of restrictive fluid intake and diuresis as 
needed to maintain central venous pressure less than 
 
4 mm Hg or pulmonary artery occlusion pressure less than 
8 mm Hg (conservative strategy group) versus a fluid 
management protocol to target a central venous pressure 
of 10–14 mm Hg or a pulmonary artery occlusion pressure 
14–18 mm Hg (liberal strategy group), showed that

14–18 mm Hg (liberal strategy group), showed that 
patients in the conservative strategy group experienced 
faster improvement in lung function and spent signifi
-
cantly fewer days on mechanical ventilation and in the 
ICU without an improvement in death by 60 days or wors
-
ening nonpulmonary organ failure at 28 days. Oxygen 
delivery can be increased in anemic patients by ensuring 
that hemoglobin concentrations are at least 7 g/dL (70 g/L); 
patients are not likely to benefit from higher levels. 
Increasing oxygen delivery to supranormal levels through 
the use of inotropes and high hemoglobin concentrations 
is not clinically useful and may be harmful. Strategies to 
decrease oxygen consumption include the appropriate use 
of sedatives, analgesics, and antipyretics.
A large number of innovative therapeutic interventions 
to improve outcomes in ARDS patients have been or are 
being investigated. Unfortunately, to date, none have consis
-
tently shown benefit in clinical trials. Systemic corticoste
-
roids have been studied extensively with variable and 
inconsistent results. While a few small studies suggest some 
specific improved outcomes when given within the first 
 
2 weeks after the onset of ARDS, mortality appears increased 
when corticosteroids are started more than 2 weeks after the 
onset of ARDS. Therefore, routine use of corticosteroids is 
not recommended.
 
»
Overall, ARDS mortality with low tidal volume ventilation 
is around 30% in ARDSnet studies. The major causes of 
death are the primary illness and secondary complications, 
such as multiple organ system failure or sepsis. Many 
patients who die of ARDS and its complications die after 
withdrawal of mechanical ventilation (see Chapter 5). One 
troubling aspect of ARDS care is that the actual mortality 
of ARDS in community hospitals continues to be higher 
than at academic hospitals. This may reflect the fact that a 
significant number of community hospital–based clini
-
cians have not adopted low lung volume ventilation.
Different clinical syndromes that lead to ARDS carry 
different prognoses. For example, patients with trauma-
associated ARDS have better prognosis, with a mortality 
rate close to 20%, whereas those with end-stage liver 
CMDT19_Ch09_p0252-p0333.indd   332

333
 
CMDT 2019
disease have an 80% mortality rate. This presumably 
reflects the effect of significant comorbidities (trauma 
patients tend to be younger and healthier) but may also 
represent different types/severities of inflammation associ
-
ated with different precipitants of ARDS.
Failure to improve in the first week of treatment is a 
poor prognostic sign. Survivors tend to be young and pul
-
monary function generally recovers over 6–12 months, 
although residual abnormalities often remain, including 
mild restrictive or obstructive defects, low diffusion 
capacity, and impaired gas exchange with exercise. Survi
-
vors of ARDS also have diminished health-related and 
pulmonary disease–specific quality of life as well as 
systemic effects, such as muscle wasting, weakness, and 
fatigue.
Anand S et al. Role of extracorporeal membrane oxygenation in 
adult respiratory failure: an overview. Hosp Pract (1995). 
2016;44(2):76–85. [PMID: 26848884]
Hager DN. Recent advances in the management of the acute 
respiratory distress syndrome. Clin Chest Med. 2015 Sep;
 
36(3):481–96. [PMID: 26304285]
Sweeney RM et al. Acute respiratory distress syndrome. Lancet. 
2016 Nov 12;388(10058):2416–30. [PMID: 27133972]
Villar J et al. Current incidence and outcome of the acute respira
-
tory distress syndrome. Curr Opin Crit Care. 2016 Feb;
 
22(1):1–6. [PMID: 26645551]
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10
Thomas M. Bashore, MD 
 
Christopher B. Granger, MD 
 
Kevin P . Jackson, MD 
 
Manesh R. Patel, MD 
 
º
ADULT CONGENITAL HEART DISEASE
In the United States, there are many more adults with 
 
congenital heart disease than children, with an estimated 
2  million adults in the United States surviving with con
-
genital heart disease.
Baumgartner H et al; Task Force on the Management of Grown-
up Congenital Heart Disease of the European Society of 
Cardiology (ESC); Association for European Paediatric Car
-
diology (AEPC); ESC Committee for Practice Guidelines 
(CPG). ESC guidelines for the management of grown-up 
congenital heart disease (new version 2010). Eur Heart J.
 
 2010 Dec;31(23):2915–57. [PMID: 20801927]
Bhatt AB et al. Congenital heart disease in the older adult: a scien
-
tific statement from the American Heart Association. Circula
-
tion. 2015 May 26;131(21):1884–931. [PMID: 25896865]
Canobbio MM et al; American Heart Association Council on 
Cardiovascular and Stroke Nursing; Council on Clinical Car
-
diology; Council on Cardiovascular Disease in the Y oung; 
Council on Functional Genomics and Translational Biology; 
and Council on Quality of Care and Outcomes Research. 
Management of pregnancy in patients with complex congeni
-
tal heart disease: a scientific statement for healthcare profes
-
sionals from the American Heart Association. Circulation. 
2017 Feb 21;135(8):e50–87. [PMID: 28082385]
PULMONARY VALVE STENOSIS
 
»
Severe cases may present with right-sided heart 
failure.
 
»
P
2
 delayed and soft or absent.
 
»
Pulmonary ejection click often present and 
decreases with inspiration—the only right heart 
sound that 
decreases
 with inspiration; all other 
right heart sounds increase.
 
»
Echocardiography/Doppler is diagnostic.
 
»
Patients with peak pulmonic valve gradients 
greater than 60 mm Hg or a mean of 40 mm Hg by 
echocardiography/Doppler should undergo inter
-
vention regardless of symptoms. Otherwise, oper
-
ate for symptoms or evidence for RV dysfunction.
 
»
Stenosis of the pulmonary valve or right ventricular (RV) 
infundibulum increases the resistance to RV outflow, raises 
the RV pressure, and limits pulmonary blood flow. Pul
-
monic stenosis is often congenital and associated with other 
cardiac lesions. Pulmonary blood flow preferentially goes to 
the left lung in valvular pulmonic stenosis. In the absence of 
associated shunts, arterial saturation is normal. Peripheral 
pulmonic stenosis can accompany valvular pulmonic steno
-
sis and may be part of a variety of clinical syndromes, 
including the congenital rubella syndrome. Patients who 
have had the 
Ross procedure
 for aortic valve disease (trans
-
fer of the pulmonary valve to the aortic position with a 
homograft pulmonary valve placed in the pulmonary 
 
position) may experience noncongenital postoperative 
p
 
u
lmonic valvular or main PA stenosis due to an immune 
response in the homograft. RV outflow obstructions can 
also occur when there is a conduit from the RV to the 
 
pulmonary artery (PA) that becomes stenotic from degen
-
erative changes over time or when there is degeneration of 
a bioprosthetic replacement pulmonary valve.
 
»
Mild cases of pulmonic stenosis are asymptomatic; moder
-
ate to severe pulmonic stenosis may cause symptoms of 
dyspnea on exertion, syncope, chest pain, and eventually 
RV failure.
On examination, there is often a palpable parasternal lift 
due to right ventricular hypertrophy (RVH) and the pulmo
-
nary outflow tract may be palpable if the PA is enlarged. A 
loud, harsh systolic murmur and occasionally a prominent 
thrill are present in the left second and third interspaces 
parasternally. The murmur radiates toward the left shoulder 
due to the flow pattern within the main PA and increases 
with inspiration. In mild to moderate pulmonic stenosis, a

with inspiration. In mild to moderate pulmonic stenosis, a 
loud ejection click can be heard to precede the murmur; 
this sound decreases with inspiration as the increased RV 
filling from inspiration prematurely opens the valve during 
atrial systole when inspiratory increased blood flow to the 
right heart occurs. The valve excursion during systole is 
thus less with inspiration than with expiration, and the click 
CMDT19_Ch10_p0334-p0450.indd   334
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HEART DISEASE
335
 
CMDT 2019
is therefore less audible with inspiration. 
This is the only 
right-sided auscultatory event that 
decreases
 with inspi
-
ration.
 All of the other auscultatory events increase with 
the increased right heart output that occurs with inspira
-
tion. In severe pulmonic stenosis, the second sound is 
obscured by the murmur and the pulmonary component of 
S
2
 may be diminished, delayed, or absent. A right-sided S
4
 
and a prominent 
a
 wave in the venous pulse are present 
when there is RV diastolic dysfunction or a 
c-v
 wave may be 
observed in the JVP if tricuspid regurgitation is present. 
Pulmonary valve regurgitation is relatively uncommon in 
primary pulmonic stenosis and may be very difficult to 
hear, as the gradient between the reduced PA diastolic pres
-
sure and the elevated RV diastolic pressure may be quite 
small (low-pressure pulmonary valve regurgitation).
B. ECG and Chest Radiography
Right axis deviation or RVH is noted; peaked P waves pro
-
vide evidence of right atrial (RA) overload. Heart size may be 
normal on radiographs, or there may be a prominent RV and 
RA or gross cardiac enlargement, depending on the severity. 
There is often poststenotic dilation of the main and left pul
-
monary arteries. Pulmonary vascularity is usually normal, 
although there tends to be preferential flow to the left lung.
Echocardiography/Doppler is the diagnostic tool of choice, 
can provide evidence for a doming valve versus a dysplastic 
valve, can determine the gradient across the valve, and can 
provide information regarding subvalvular obstruction and 
the presence or absence of tricuspid or pulmonic valvular 
regurgitation. Mild pulmonic stenosis is present if the peak 
gradient by echocardiography/Doppler is less than 30 mm Hg, 
moderate pulmonic stenosis is present if the peak gradient 
is between 30 mm Hg and 60 mm Hg, and severe pulmonic 
stenosis is present if the peak gradient is greater than 
60 mm Hg or the mean gradient is greater than 40 mm Hg. 
A lower gradient may be evident if there is RV dysfunction. 
Catheterization is usually unnecessary for the diagnosis; it 
should be used only if the data are unclear or in preparation 
for either percutaneous intervention or surgery.
 
»
Prognosis & Treatment
Patients with mild pulmonic stenosis have a normal life 
span with no intervention. Moderate stenosis may be 
asymptomatic in childhood and adolescence, but symp
-
toms often appear as patients grow older. The degree of 
stenosis does worsen with time in a few patients, so serial 
follow-up is important. Severe stenosis is rarely associated 
with sudden death but can cause right heart failure in 
patients as early as in their 20s and 30s. Pregnancy and 
exercise tend to be well tolerated except in severe stenosis.
Class I (definitive) indications for intervention include 
all symptomatic patients and all those with a resting peak-to-
peak gradient greater than 60 mm Hg or a mean greater than 
40 mm Hg, regardless of symptoms. Percutaneous balloon 
valvuloplasty is highly successful in domed valve patients 
and is the treatment of choice. Surgical commissurotomy 
can also be done, or pulmonary valve replacement (with 
either a bioprosthetic valve or homograft) when pulmonary 
valve regurgitation is too severe or the valve is dysplastic. 
Pulmonary outflow tract obstruction due to RV to PA con
-
duit obstruction or to homograft pulmonary valve stenosis 
can often be relieved with a percutaneously implanted pul
-
monary valve (both the Medtronic Melody valve and the 
Edwards Sapien XT valve have been FDA approved). Percu
-
taneous pulmonary valve replacement is also FDA approved 
for those with conduit stenosis or following the Ross proce
-
dure. Percutaneous valve replacements have also been per
-
formed off-label for native pulmonary valve disease.
Endocarditis prophylaxis is unnecessary for native 
valves even after valvuloplasty unless there has been prior

-
valves even after valvuloplasty unless there has been prior 
pulmonary valve endocarditis (an unusual occurrence) (see 
Table 33–3). It should be used if surgical or percutaneous 
valve replacement has occurred. There appears to be more 
pulmonary valve endocarditis following percutaneous pul
-
monary valve replacement with the Melody valve than 
expected, and this is being closely monitored by the FDA.
 
»
All symptomatic patients (regardless of gradient) and all 
asymptomatic patients whose peak pulmonary valve gradi
-
ent is greater than 60 mm Hg or whose mean gradient is 
greater than 40 mm Hg should be referred to a cardiologist 
with expertise in adult congenital heart disease.
Ansari MM et al. Percutaneous pulmonary valve replacement: 
present status and evolving future. J Am Coll Cardiol. 
2015 Nov 17;66(20):2246–55. [PMID: 26564602]
Boudjemline Y . Percutaneous pulmonary valve implantation: 
what have we learned over the years? EuroIntervention. 
2017 Sep 24;13(AA):AA60–7. [PMID: 28942387]
Hascoet S et al. Infective endocarditis risk after percutaneous 
pulmonary valve replacement with the Melody and Sapien 
valves. JACC Cardiovasc Interv. 2017 Mar 13;10(5):510–7. 
[PMID: 28279319]
Warnes CA et al. ACC/AHA 2008 guidelines for the manage
-
ment of adults with congenital heart disease: a report of the 
American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines. Circulation. 2008 Dec 2;
 
118(23):e714–833. [PMID: 18997169]
COARCTATION OF THE AORTA
 
»
Usual presentation is systemic hypertension.
 
»
Echocardiography/Doppler is diagnostic; a peak 
gradient of more than 20 mm Hg may be signifi
-
cant due to collaterals around the coarctation 
reducing gradient despite severe obstruction.
 
»
Associated bicuspid aortic valve in 50–80% of 
patients.
 
»
Delayed pulse in femoral artery compared to bra
-
chial artery.
 
»
Systolic pressure is higher in upper extremities than 
in lower extremities; diastolic pressures are similar.
CMDT19_Ch10_p0334-p0450.indd   335

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HA
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 1
0
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 CMDT 2019
 
»
Coarctation of the aorta consists of localized narrowing of 
the aortic arch just distal to the origin of the left subclavian 
artery. If the stenosis is severe, collateral circulation devel
-
ops around the coarctation site through the intercostal 
arteries and the branches of the subclavian arteries and can 
result in a lower transcoarctation gradient by enabling 
blood flow to bypass the obstruction. 
Coarctation is a 
cause of secondary hypertension and should be consid
-
ered in young patients with elevated blood pressure 
(BP).
 The renin-angiotensin system is often abnormal, 
however, and contributes to the hypertension occasionally 
seen even after coarctation repair. A bicuspid valve is seen 
in approximately 50–80% of the cases, and there is an 
increased incidence of cerebral berry aneurysms.
 
»
If cardiac failure does not occur in infancy, there are usually 
no symptoms until the hypertension produces left ventricu
-
lar (LV) failure. Cerebral hemorrhage, though rare, may 
occur. Strong arterial pulsations are seen in the neck and 
suprasternal notch. Hypertension is present in the arms, but 
the pressure is normal or low in the legs. This difference is 
exaggerated by exercise. Femoral pulsations are weak and 
are delayed in comparison with the brachial or radial pulse. 
A continuous murmur heard superiorly and midline in the 
back or over the left anterior chest may be present when 
large collaterals are present and is a clue that the coarctation 
is severe. The coarctation itself may result in systolic ejec
-
tion murmurs heard in the left upper lung field anteriorly 
and near the spine on the left side posteriorly. There may be 
an aortic regurgitation or stenosis murmur due to an associ
-
ated bicuspid aortic valve. Coarctation is associated with 
Turner syndrome (a sex chromosomal abnormality [XO]); 
a webbed neck may be present in these patients.
The ECG usually shows LV hypertrophy (LVH). Radiogra
-
phy may show scalloping of the inferior portion of the ribs 
(rib notching) due to enlarged collateral intercostal arter
-
ies. Dilation of the left subclavian artery and poststenotic 
aortic dilation along with LV enlargement may be present. 
The coarctation region and the poststenotic dilation of the 
descending aorta may result in a 
“3” sign
 along the aortic 
shadow on the PA chest radiograph (the notch in the “3” 
representing the area of coarctation).
Echocardiography/Doppler is usually diagnostic and may 
provide additional evidence for a bicuspid aortic valve. 
Both MRI and CT can provide excellent images of the 
coarctation anatomy, and one or the other should always be 
done to define the coarctation anatomic structure. MRI 
and echocardiography/Doppler can also provide estimates 
of the gradient across the lesion. Cardiac catheterization 
provides definitive gradient information and is necessary if 
percutaneous stenting is to be considered.
 
»
Cardiac failure is common in infancy and in older untreated 
patients when the coarctation is severe. Patients with a 
demonstrated peak gradient of greater than 20 mm Hg 
should be considered for intervention, especially if there is 
evidence of collateral blood vessels. Many untreated 
patients with severe coarctation die of hypertension, rup
-
ture of the aorta, infective endarteritis, or cerebral hemor
-
rhage before the age of 50. Aortic dissection also occurs 
with increased frequency. Coarctation of any significance 
may be poorly tolerated in pregnancy because of the inabil
-
ity to support the placental flow.
Resection of the coarctation site has a surgical mortality 
rate of 1–4% and includes risk of spinal cord injury. The 
percutaneous interventional procedure of choice is endovas
-
cular stenting; when anatomically feasible, self-expanding

-
cular stenting; when anatomically feasible, self-expanding 
and balloon-expandable covered stents have been shown to 
be advantageous over bare metal stents. These covered stents 
have been FDA approved. Most coarctation repair in adults 
is percutaneous. Otherwise, surgical resection (usually with 
end-to-end anastomosis) should be performed. About 25% 
of surgically corrected patients continue to be hypertensive 
years after surgery because of permanent changes in the 
renin-angiotensin system, endothelial dysfunction, aortic 
stiffness, altered arch morphology, and increased ventricular 
stiffness. Recurrence of the coarctation stenosis following 
intervention requires long-term follow-up.
 
»
All patients with coarctation and a detectable gradient 
should be referred to a cardiologist with expertise in adult 
Haji Zeinali AM et al. Midterm to long-term safety and efficacy 
of self-expandable nitinol stent implantation for coarctation 
of aorta in adults. Catheter Cardiovasc Interv. 2017 Sep 1;
 
90(3):425–31. [PMID: 28707350]
Rinnström D et al. Hypertension in adults with repaired coarcta
-
tion of the aorta. Am Heart J. 2016 Nov;181:10–5. [PMID: 
27823680]
Schneider H. Modern management of coarctation of the aorta: 
transcatheter and surgical options. J Cardiovasc Surg (Torino). 
2016 Aug;57(4):557–68. [PMID: 27243624]
-
 
ATRIAL SEPTAL DEFECT & 
PATENT FORAMEN OVALE
 
»
Often asymptomatic and discovered on routine 
 
»
With an atrial septal defect (ASD) and left to right 
shunt: RV lift; S
2
 widely split and fixed.
CMDT19_Ch10_p0334-p0450.indd   336

337
 
CMDT 2019
 
»
 
»
ASDs should be closed if there is evidence of an RV 
volume overload regardless of symptoms.
 
»
A patent foramen ovale (PFO), present in 25% of 
the population, rarely can lead to paradoxic 
emboli.
 
»
The most common form of ASD (80% of cases) is 
persis
-
tence of the ostium secundum
 in the mid-septum. A less 
common abnormality is 
persistence of the ostium pri
-
mum
 (low in the septum). In most patients with an 
ostium primum defect, there are mitral or tricuspid valve 
“clefts” as well as a ventricular septal defect (VSD) as part 
of the atrioventricular (AV) septal defect. A 
sinus veno
-
sus defect
 is a hole, usually at the upper (or rarely the 
lower) part of the atrial septum, due to failure of the 
embryonic superior vena cava or the inferior vena cava to 
merge with the atria properly. The superior vena cava 
sinus venosus defect is usually associated with an anoma
-
lous connection of the right upper pulmonary vein into 
the superior vena cava. The 
coronary sinus ASD
 is rare 
and is basically an unroofed coronary sinus that results in 
shunting from the LA to the coronary sinus and then to 
the RA.
In all cases, normally oxygenated blood from the 
higher-pressure LA shunts into the RA, increasing RV out
-
put and pulmonary blood flow. In children, the degree of 
shunting across these defects may be quite large (pulmo
-
nary to systemic blood flow ratios of 3:1 or so). As the RV 
compliance worsens from the chronic volume overload, the 
RA pressure may rise and the degree of left-to-right shunt
-
ing may decrease over time. Eventually, if the RA pressure 
exceeds the LA, the shunt may reverse and be primarily 
right-to-left. When this happens systemic cyanosis appears. 
The major factor in the direction of shunt flow is thus the 
compliance of the respective atrial chambers.
The pulmonary pressures are modestly elevated in 
most patients with an ASD due to the high pulmonary 
blood flow, but severe pulmonary hypertension with cya
-
nosis (
Eisenmenger physiology
) is actually unusual, 
occurring in only about 15% of the patients with an ASD 
alone. Increased pulmonary vascular resistance (PVR) and 
pulmonary hypertension secondary to pulmonary vascu
-
lar disease rarely occur in childhood or young adult life in 
secundum defects and are more common in primum 
defects. Eventual RV failure may occur with any atrial 
shunt of significant size, and most shunts should be cor
-
rected unless they are quite small (less than 1.5:1 left-to-
right shunt). In adults, a large left-to-right shunt may have 
begun to reverse, so the absolute left-to-right shunt mea
-
surement (Qp/Qs, where Qp = pulmonary flow and Qs = 
systemic flow) at the time the patient is studied may 
underestimate the original shunt size. In addition, in most 
people the LV and LA compliance normally declines more 
over time than the RV and RA compliance; for this reason, 
the natural history of small atrial septal shunts is to 
increase the left-to-right shunting as the patient ages. 
There is generally only trivial shunting with a PFO com
-
pared to a true ASD. ASDs predispose to atrial fibrillation 
due to RA enlargement, and paradoxic right-to-left emboli 
do occur.
Interestingly, paradoxic emboli may be more common 
in patients with a PFO than a true ASD, especially when 
there is an atrial septal aneurysm. An 
aneurysm of the 
atrial septum
 is not a true aneurysm but rather simply a 
redundancy of the atrial septum that causes it to swing 
back and forth (greater than 10 mm). When present with a 
PFO, the back-and-forth swinging tends to pull open the 
PFO, encouraging shunting. This helps explain why more 
right-to-left shunting occurs in patients with an atrial sep
-
tal aneurysm and PFO than in those with a PFO alone. 
This creates the anatomic substrate for the occurrence of 
paradoxical emboli. Other factors may distort the atrial

-
paradoxical emboli. Other factors may distort the atrial 
septum (such as an enlarged aorta) and result in an 
increase shunting in patients with a PFO. Right-to-left PFO 
shunting may be more prominent upright, creating ortho
-
static hypoxemia 
(platypnea orthodeoxia).
 There may 
also be increased shunting in patients with a PFO and sleep 
apnea as the RA compliance may worsen during apneic 
spells when pulmonary pressures increase.
 
»
Patients with a small or moderate ASD or with a PFO are 
asymptomatic unless a complication occurs. There is 
only trivial shunting in a PFO unless the RA pressure 
increases for some other reason or the atrial septum is 
distorted. With larger ASD shunts, exertional dyspnea or 
heart failure may develop, most commonly in the fourth 
decade of life or later. Prominent RV and PA pulsations 
are then readily visible and palpable. A moderately loud 
systolic ejection murmur can be heard in the second and 
third interspaces parasternally as a result of increased 
flow through the pulmonary valve. S
2
 is widely split and 
does not vary with respiration. The left-to-right shunt 
across the defect decreases with inspiration (as the RA 
pressure increases) and then increases with expiration 
(as the RA pressure decreases), thus keeping the RV 
stroke volume relatively constant in inspiration and expi
-
ration. A 
“fixed” splitting
 of the second sound results. In 
very large left-to-right shunts, a tricuspid rumble may be 
heard due to the high flow across the tricuspid valve in 
diastole.
Right axis deviation or RVH may be present depending on 
the size of the RV volume overload. Incomplete or com
-
plete right bundle branch block is present in nearly all cases 
of ASD, and superior axis deviation (left anterior fascicular 
block) is noted in the complete AV septal defect, where 
complete heart block is often seen as well. With sinus veno
-
sus defects, the P axis is leftward of +15° due to abnormal 
atrial activation with loss of the upper RA tissue from 
around the sinus node. This creates the negative P waves in 
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the inferior leads. The chest radiograph shows large pul
-
monary arteries, increased pulmonary vascularity, an 
enlarged RA and RV , and a small aortic knob as with all 
pre-tricuspid valve cardiac left-to-right shunts. The LA is 
not traditionally enlarged due to an ASD shunt because the 
chamber is being decompressed.
Echocardiography demonstrates evidence of RA and RV 
volume overload. The atrial defect is usually observed by 
echocardiography, although sinus venosus defects may be 
elusive since they are high in the atrial septum. Many 
patients with a PFO also have an atrial septal aneurysm 
(defined as greater than 10-mm excursion of the septum 
from the static position). Echocardiography with saline 
injection (bubble contrast) can demonstrate the right-to-
left component of the shunt, and both pulsed and color 
flow Doppler flow studies can demonstrate shunting in 
either direction. In platypnea orthodeoxia, the shunt may 
primarily result from inferior vena cava blood, and a femo
-
ral vein saline injection may be required to demonstrate 
the shunt. Transesophageal echocardiography (TEE) is 
helpful when transthoracic echocardiography quality is not 
optimal because it improves the sensitivity for detection of 
small shunts and provides a better assessment of PFO or 
ASD anatomy. Both CT and MRI can elucidate the atrial 
septal anatomy, better detect multiple fenestrations, and 
demonstrate associated lesions such as anomalous pulmo
-
nary venous connections. Atrial septal anatomy can be 
complex, and either MRI, TEE, or CT can reveal whether 
there is an adequate rim around the defect to allow for safe 
positioning of an atrial septal occluder device. These stud
-
ies can also help identify any anomalous pulmonary 
venous connections. Cardiac catheterization can define the 
size and location of the shunt and determine the pulmo
-
nary pressure and PVR.
 
»
Patients with small atrial shunts live a normal life span with 
no intervention. Large shunts usually cause disability by 
age 40 years. Because left-to-right shunts and RV overload 
tend to increase with normal age-related reduction in LV 
(and subsequently LA) compliance, guidelines suggest that 
closure of all left-to-right shunts greater than 1.5:1 should 
be accomplished either by a percutaneous device or by 
surgery. This situation always results in RV volume over
-
load if the lesion is left untreated. If the pulmonary systolic 
pressure is more than two-thirds the systemic systolic pres
-
sure, the pulmonary hypertension may preclude ASD clo
-
sure. Testing with transient balloon occlusion of the shunt 
and with pulmonary vasodilators may be required in the 
presence of pulmonary hypertension. Preservation of the 
cardiac output after transient balloon occlusion and evi
-
dence for preserved pulmonary vasoreactivity with pulmo
-
nary vasodilator testing all favor closure when pulmonary 
hypertension and at least a 1.5:1 left-to-right shunt are 
present. After age 40 years, cardiac arrhythmias (especially 
atrial fibrillation) and heart failure occur with increased 
frequency due to the chronic right heart volume overload. 
Paradoxical systemic arterial embolization also becomes 
more of a concern as RV compliance is lost and the left-to-
right shunt begins to reverse.
PFOs are usually not associated with significant shunt
-
ing, and therefore the patients are hemodynamically 
asymptomatic and the heart size is normal. However, PFOs 
can be responsible for paradoxical emboli and are a possi
-
ble cause of cryptogenic strokes in patients under age 
55 years. An associated atrial septal aneurysm increases the 
risk of right-to-left shunting in patients with a PFO and 
cryptogenic transient ischemic attack (TIA) or stroke. 
Interestingly, the risk of recurrent paradoxical emboli is 
low, and that observation has reduced the value of closing

low, and that observation has reduced the value of closing 
these defects in cryptogenic stroke. Further confounding 
the advantage of PFO closure for cryptogenic stroke/TIA 
has been the discovery of frequent bouts of paroxysmal 
atrial fibrillation using 30-day monitoring in these patients, 
suggesting atrial fibrillation is the real risk factor in some 
patients.
Occasionally, a PFO that has not been pathologic may 
become responsible for cyanosis, especially if the RA pres
-
sure is elevated from pulmonary or RV hypertension or 
from severe tricuspid regurgitation.
Surgery involves stitching or patching of the foramen. 
For ostium secundum ASDs, percutaneous closure by use 
of a variety of devices is preferred over surgery when the 
anatomy is appropriate (usually this means there must 
bean adequate atrial septal rim around the defect to secure 
the occluder device).
Patients who have hypoxemia (especially upon standing 
or with exercise) should have the PFO closed if no other 
cause for hypoxemia is evident and there is right-to-left 
shunting demonstrated through the PFO. For patients with 
cryptogenic stroke or TIA, it remains uncertain whether 
closure of the PFO, either by open surgical or percutaneous 
techniques, has any advantage over anticoagulation with 
either warfarin, one of the direct-acting oral anticoagu
-
lants, or aspirin. As of 2017, there were five major random
-
ized clinical trials evaluating the advantage of PFO closure 
in cryptogenic stroke (at ages greater than 55 years). Three 
of the five trials did not show an advantage of device clo
-
sure over medical therapy with antiplatelet or anticoagula
-
tion medication; however, two of the five suggested there 
may be a role. The FDA has approved one device for use 
when both a cardiologist and neurologist feel the PFO 
contributed to a TIA or stroke.
From a practical standpoint, patients younger than 55 
years with cryptogenic stroke/TIA and no other identifi
-
able cause except for the presence of a PFO should still be 
considered for PFO closure, albeit the data suggest medical 
therapy remains an equally viable option. A workup for any 
causes for hypercoagulability and a 30-day monitor should 
also be part of the clinical assessment to exclude other 
potential causes for cryptogenic stroke/TIA. There are no 
data suggesting warfarin is superior to antiplatelet medica
-
tions. There are also no data regarding the effectiveness of 
direct-acting oral anticoagulants (DOACs). The American 
Heart Association/American Stroke Association (AHA/
ASA) Stroke Guidelines moved PFO closure from a class IIb 
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indication to a class III based on data as of 2014. The new 
class III indication suggested PFO closure be done only if 
there was evidence of deep venous thrombosis and that risk 
was ongoing. Most clinicians would consider PFO closure 
in the presence of stroke or TIA if the event occurred while 
the patient was receiving adequate anticoagulant or anti
-
platelet therapy. As of 2017, the major neurologic and car
-
diologic governing bodies had yet to rule on an appropriate 
strategy following the publication of the Gore REDUCE 
and the CLOSE trials.
PFO closure is also occasionally recommended for deep 
sea divers to help prevent the “bends” due to nitrous oxide 
shunting. Despite much fanfare from small studies suggest
-
ing an advantage, there are no strong data to confirm an 
advantage in PFO closure for patients suffering from 
migraine headaches. One randomized, placebo-controlled 
trial did not show a lessening of migraine events with PFO 
closure.
 
»
•	
All patients with an ASD should be evaluated by a car
-
diologist with expertise in adult congenital disease to 
ensure no other structural disease is present and to 
investigate whether the RV is enlarged.
•	
If the RA and RV sizes remain normal, serial echocar
-
diography should be performed every 3–5 years.
•	
If the RA and RV volumes are increased, then referral to 
a cardiologist who performs percutaneous closure is 
warranted.
•	
Patients younger than 55 years with cryptogenic stroke 
when no other source is identified except for a PFO 
with right-to-left shunting should be considered for 
PFO closure or medical therapy. The indication for 
PFO closure in younger patients with either a TIA or 
stroke is evolving, since some randomized trials suggest 
there may be a role in selected patients.
•	
Patients with cyanosis and a PFO with evidence of a 
right-to-left shunt by agitated saline bubble contrast on 
echocardiography, especially if the cyanosis is worsened 
upon assuming the upright posture.
Gladstone DJ et al; EMBRACE Investigators and Coordinators. 
Atrial fibrillation in patients with cryptogenic stroke. N Engl 
J Med. 2014 Jun 26;370(26):2467–77. [PMID: 24963566]
Kent DM et al. Device closure of patent foramen ovale after 
stroke: pooled analysis of completed randomized trials. J Am 
Coll Cardiol. 2016 Mar 1;67(8):907–17. [PMID: 26916479]
Meese SR et al. Practice advisory: recurrent stroke with patent 
foramen ovale (update of practice parameter): report of the 
guideline development, dissemination and implementation 
subcommittee of the American Academy of Neurology. Neu
-
rology. 2016 Aug 23;87(8):815–21. [PMID: 27466464]
Saver JL et al; RESPECT Investigators. Long-term outcomes 
of  patent foramen ovale closure or medical therapy after 
stroke. N Engl J Med. 2017 Sep 14;377(11):1022–32. [PMID: 
28902590]
Søndergaard L et al; Gore REDUCE Clinical Study Investigators. 
Patent foramen ovale closure or antiplatelet therapy for cryp
-
togenic stroke. N Engl J Med. 2017 Sep 14;377(11):1033–42. 
[PMID: 28902580]
VENTRICULAR SEPTAL DEFECT
 
»
A restrictive VSD is small and makes a louder mur
-
mur than an unrestricted one, often with an accom
-
panying thrill. The higher the gradient across the 
septum, the smaller the left-to-right shunt.
 
»
Small defects may be asymptomatic.
 
»
Larger defects result in pulmonary hypertension 
(Eisenmenger physiology) if not repaired or the 
pulmonary circuit is not protected by RV outflow 
tract obstruction.
 
»
 
»
Congenital VSDs occur in various parts of the ventricular 
septum. Membranous and muscular septal defects may 
spontaneously close in childhood as the septum grows and 
hypertrophies. A left-to-right shunt is present, the degree 
depending on associated RV pressure. The smaller the 
defect, the greater the gradient from the LV to the RV and

defect, the greater the gradient from the LV to the RV and 
the louder the murmur. The presentation in adults depends 
on the size of the shunt and whether there is associated 
pulmonic or subpulmonic stenosis that has protected the 
lung from the systemic pressure and volume. Unprotected 
lungs with large shunts invariably lead to pulmonary vascu
-
lar disease and severe pulmonary hypertension (Eisen
-
menger physiology). VSD sizes are defined by comparison 
to the aortic root size; a small or restrictive VSD diameter is 
less than 25% of the aortic root diameter, a moderately 
restrictive VSD diameter is 25–75% of the aorta, and an 
unrestricted VSD size is greater than 75% of the aortic 
diameter. The size can also be quantitated based on the 
Qp/Qs (left-to-right shunt), with a restrictive lesion being 
less than 1.5:1, moderately restrictive VSD being 1.5–2.2:1, 
and an unrestricted lesion being greater than 2.2:1.
 
»
The clinical features depend on the size of the defect and the 
presence or absence of RV outflow obstruction or increased 
PVR. Small shunts are associated with loud, harsh holosys
-
tolic murmurs in the left third and fourth interspaces along 
the sternum. A systolic thrill is common. Larger shunts may 
create both LV and RV volume and pressure overload. If 
pulmonary hypertension occurs, high-pressure pulmonary 
valve regurgitation may result. Right heart failure may 
gradually become evident late in the course, and the shunt 
will begin to balance or reverse as RV and LV systolic pres
-
sures equalize with the advent of pulmonary hypertension. 
Cyanosis from a developing right-to-left shunt may then 
occur. Cyanosis with pulmonary hypertension and an intra
-
cardiac shunt define the 
Eisenmenger syndrome.
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The ECG may be normal or may show right, left, or biven
-
tricular hypertrophy, depending on the size of the defect and 
the PVR. With large shunts, the LV , the LA, and the pulmo
-
nary arteries are enlarged and pulmonary vascularity is 
increased on chest radiographs. The RV is often normal until 
late in the process. If an increased PVR (pulmonary hyperten
-
sion) evolves, an enlarged PA with pruning of the distal pul
-
monary vascular bed is seen. In rare cases of a VSD high in the 
ventricular septum, an aortic cusp (right coronary cusp) may 
prolapse into the VSD and reduce the VSD shunt but result in 
acute aortic regurgitation and acute heart failure.
Echocardiography can demonstrate the size of the over
-
loaded chambers and can usually define the defect anatomy. 
Doppler can qualitatively assess the magnitude of shunting 
by noting the gradient from LV to RV and, if some tricuspid 
regurgitation is present, the RV systolic pressure can be 
estimated. The septal leaflet of the tricuspid valve may be 
part of the VSD anatomy and the complex appears as a 
ventricular septal “aneurysm. ” These membranous septal 
aneurysms resemble a “windsock” and may fenestrate and 
result in a VSD shunt being present or they may remain 
intact. Color flow Doppler helps delineate the shunt severity 
and the presence of valvular regurgitation. MRI and cardiac 
CT can often visualize the defect and describe any other 
anatomic abnormalities. MRI can provide quantitative 
shunt data as well. Cardiac catheterization is usually 
reserved for those with at least moderate shunting, to quan
-
titate the PVR and the degree of pulmonary hypertension. 
A PVR of greater than 7.0 absolute units or a PVR/systemic 
vascular resistance ratio or a systolic PA pressure/systolic 
aortic pressure ratio greater than 0.67 (two-thirds) generally 
means the patient’s VSD is inoperable. The vasoreactivity of 
the pulmonary circuit may be tested at catheterization using 
agents such as inhaled nitric oxide, and if the pulmonary 
pressures can be lowered enough that the above ratios fall 
below the two-thirds value, then repair is reasonable as long 
as the left-to-right VSD shunt is greater than 1.5:1.
 
»
Patients with a small VSD have a normal life expectancy 
except for the small risk of infective endocarditis. Antibi
-
otic prophylaxis after dental work is recommended only 
when the VSD is residual from a prior patch closure or 
when there is associated pulmonary hypertension and cya
-
nosis (see Tables 33–3, 33–4, and 33–5). With large VSD 
shunts, heart failure may develop early in life, and survival 
beyond age 40 years is unusual without intervention.
The ACC/AHA guidelines for the management of 
patients with VSD include the following:
1.
 
Medical management (class IIb recommendation [ben
-
efit exceeds risk and may be considered]): Pulmonary 
vasodilatory therapy is appropriate for adults with a 
VSD and severe pulmonary hypertension. The response 
to inhaled nitric oxide is used to guide which agent 
would be the best option (Level of evidence [LOE] C).
2.
 
Surgical management (class I recommendation; LOE B): 
Closure is indicated when the left-to-right shunt ratio is 
greater than 2.0 or there is clinical LV volume overload. 
In addition, closure is recommended if there has been a 
history of infective endocarditis.
3.
 
Surgical management (class IIb recommendation; LOE C): 
Closure is reasonable if the left-to-right shunt is greater 
than 1.5 and pulmonary systolic pressure or the PVR is 
less than two-thirds systemic values, or both. Closure is 
also reasonable if the shunt ratio is greater than 1.5 with 
evidence of LV dysfunction.
Small shunts (pulmonary-to-systemic flow ratio less 
than 1.5) in asymptomatic patients do not require surgery 
or other intervention. The presence of RV infundibular

or other intervention. The presence of RV infundibular 
stenosis or pulmonary valve stenosis may protect the pul
-
monary circuit such that some patients, even with a large 
VSD, may still be surgical candidates as adults if there is no 
Surgical repair of a VSD is generally a low-risk proce
-
dure unless there is significant Eisenmenger physiology. 
Devices for nonsurgical closure of muscular VSDs are 
approved and those for membranous VSDs are being 
implanted with promising results; however, conduction 
disturbance is a major complication. The percutaneous 
devices are also approved for closure of a VSD related to 
acute myocardial infarction, although the results in this 
very high-risk patient population have not been encourag
-
ing. The medications used to treat pulmonary hyperten
-
sion secondary to VSD are similar to those used to treat 
idiopathic (“primary”) pulmonary hypertension and at 
times can be quite effective in relieving symptoms and 
cyanosis.
 
»
All patients with a VSD should be referred to a cardiologist 
with expertise in adult congenital disease to decide if long-
term follow-up is warranted.
Bhatt AB et al. Congenital heart disease in the older adult: a 
scientific statement from the American Heart Association. 
Circulation. 2015 May 26;131(21):1884–931. [PMID: 
25896865]
Hamilton MCK et al. The in vivo morphology of post-infarct 
ventricular septal defect and the implications for closure. 
JACC Cardiovasc Interv. 2017 Jun 26;10(12):1233–43. [PMID: 
28641844]
Menting ME et al. The unnatural history of the ventricular 
septal defect: outcome up to 40 years after surgical closure. 
 
J Am Coll Cardiol. 2015 May 12;65(18):1941–51. [PMID: 
25953746]
Saurav A et al. Comparison of percutaneous device closure ver
-
sus surgical closure of peri-membranous ventricular septal 
defects: a systematic review and meta-analysis. Catheter Car
-
diovasc Interv. 2015 Nov 15;86(6):1048–56. [PMID: 
26257085]
-
 
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TETRALOGY OF FALLOT
 
»
Five features are characteristic:
 
– VSD.
 
– Concentric RVH.
 
– 
 
R
V outflow obstruction due to infundibular 
stenosis.
 
– 
 
O
verriding aorta in half (requires less than 50% of 
the aorta to override the septum).
 
– A right-sided aortic arch in 25%.
 
»
Most adult patients with tetralogy of Fallot have 
been operated on, usually with an RV outflow 
patch and VSD closure.
 
»
Physical examination may be deceptive after classic 
tetralogy repair, with severe pulmonary valve regurgi
-
tation often present if a transannular patch was used.
 
»
Echocardiography/Doppler may underestimate 
significant pulmonary valve regurgitation. Be 
wary if the RV is enlarged.
 
»
Arrhythmias are common; periodic ambulatory 
monitoring is recommended.
 
»
Serious arrhythmias and sudden death may occur 
if the QRS is wide or the RV becomes quite large, 
or both.
 
»
Patients with tetralogy of Fallot have a VSD, RV infundibu
-
lar stenosis, RVH, and a dilated aorta (in about 50% of 
patients it overrides the septum). If there is an associated 
ASD, the complex is referred to as pentalogy of Fallot. 
There may or may not be pulmonary valve stenosis as well, 
usually due to a bicuspid pulmonary valve or RV outflow 
hypoplasia. The aorta can be quite enlarged and aortic 
regurgitation may occur. If more than 50% of the aorta 
overrides into the RV outflow tract, the anatomy is referred 
to as a “double outlet RV . ” Two vascular abnormalities are 
common: a right-sided aortic arch (in 25%) and an anoma
-
lous left anterior descending coronary artery from the right 
cusp (7–9%). The latter is important in that surgical cor
-
rection must avoid injuring the coronary artery when 
repairing the RV outflow obstruction. Pulmonary branch 
stenosis may also be present.
Most adult patients have undergone prior surgery. If 
significant RV outflow obstruction is present in the neona
-
tal period, a systemic arterial to pulmonary artery shunt 
may be the initial surgical procedure to improve pulmo
-
nary blood flow, though many infants undergo repair 
without this first step. Most adults will have had this initial 
palliative repair, however. The palliative procedure enables 
blood to reach the underperfused lung either by directly 
attaching one of the subclavian arteries to a main PA 
branch (
classic Blalock shunt
) or by creating a conduit 
between the two (
modified Blalock shunt
). In the adult, 
there may be a reduced upper extremity pulse on the side 
used for the classic Blalock procedure. 
Total repair
 of the 
tetralogy of Fallot generally includes a VSD patch and usu
-
ally an enlarging RV outflow tract patch, as well as a take-
down of any prior arterial-pulmonary artery shunt. Often 
the RV outflow tract patch extends through the pulmonary 
valve into the PA 
(transannular patch)
, and the patient 
then is left with varying degrees of pulmonary valve regur
-
gitation (although great effort is made to avoid pulmonary 
valve regurgitation if at all possible). Over the years, the 
volume overload from severe pulmonary valve regurgita
-
tion becomes the major hemodynamic problem seen in 
adults. Ventricular arrhythmias can also originate from the 
edge of the patch and tend to increase in frequency as the 
size of the RV increases.
 
»
Most adult patients in whom tetralogy of Fallot has been 
repaired are relatively asymptomatic unless right heart 
failure occurs or arrhythmias become an issue. Patients can 
be active and generally require no specific therapy.
Physical examination should include checking both arms 
for any loss of pulse from a prior shunt procedure in 
infancy. The jugular venous pulsations (JVP) may reveal an 
increased 
a
 wave from poor RV compliance or rarely a 
c-v
 
wave due to tricuspid regurgitation. The right-sided arch 
has no consequence. The precordium may be active, often

increased 
a
c-v
 
has no consequence. The precordium may be active, often 
with a persistent pulmonary outflow murmur. P
2
 may or 
may not be audible. A right-sided gallop may be heard. 
A residual VSD or an aortic regurgitation murmur may be 
present. At times, the insertion site of a prior Blalock or 
other shunt may create a stenotic area in the branch PA and 
a continuous murmur occurs as a result.
The ECG reveals RVH and right axis deviation; in repaired 
tetralogy, there is often a right bundle branch block pat
-
tern. The chest radiograph shows a classic boot-shaped 
heart with prominence of the RV and a concavity in the RV 
outflow tract. This may be less impressive following repair. 
The aorta may be enlarged and right-sided. Importantly, 
the width of the QRS should be examined yearly because 
persons at greatest risk for sudden death are traditionally 
those with a QRS width of more than 180 msec, although 
more recent data has suggested that this cutoff is not as 
specific as once thought. Most experts recommend ambu
-
latory monitoring periodically as well, especially if the 
patient experiences palpitations. Other identified risk fac
-
tors for ventricular arrhythmias include having multiple 
prior cardiac surgeries, an elevated LV end-diastolic pres
-
sure (LVEDP), and older age at time of repair.
Echocardiography/Doppler usually establishes the diagno
-
sis by noting the unrestricted (large) VSD, the RV infun
-
dibular stenosis, and the enlarged aorta. In patients who 
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have had tetralogy of Fallot repaired, echocardiography/
Doppler also provides data regarding the amount of resid
-
ual pulmonary valve regurgitation if a transannular patch 
is present, RV and LV function, and the presence of aortic 
regurgitation. Elevated N-terminal pro B-type natriuretic 
peptide (NT-proBNP) blood levels have also been corre
-
lated with increasing RV enlargement.
Cardiac MRI and CT can quantitate both the pulmo
-
nary regurgitation and the RV volumes. In addition, car
-
diac MRI and CT can identify whether there is either a 
native pulmonary arterial branch stenosis or a stenosis at 
the distal site of a prior arterial-to-PA shunt or other 
anomalies, such as an ASD. The ability of cardiac MRI to 
accurately quantitate the pulmonary regurgitation severity 
and provide more accurate RV volume measurements than 
other modalities has resulted in it having an advantage over 
other imaging studies. Cardiac catheterization may be 
required to document the degree of pulmonary valve 
regurgitation because noninvasive studies depend on 
velocity gradients. Pulmonary angiography demonstrates 
the degree of pulmonary valve regurgitation, and RV angi
-
ography helps assess any postoperative outflow tract 
aneurysm.
The need for electrophysiologic studies with ventricular 
stimulation and potential ventricular tachycardia ablation 
has been suggested by some experts for patients who have 
had evidence for ventricular tachycardia, unexplained syn
-
cope, a wide QRS, are older, or who are about to undergo 
pulmonary valve replacement.
 
»
A few patients with “just the right amount” of subpulmonic 
stenosis enter adulthood without having had surgical cor
-
rection. However, most adult patients have had surgical 
repair, including VSD closure, resection of infundibular 
muscle, and insertion of an outflow tract patch to relieve the 
subpulmonic obstruction. Many have a transannular patch 
resulting in pulmonary valve regurgitation. Patients with 
pulmonary valve regurgitation should be monitored to 
ensure the RV volume does not progressively increase. Low-
pressure pulmonary valve regurgitation is difficult to diag
-
nose due to the fact that the RV diastolic pressures tend to 
be high and the pulmonary arterial diastolic pressure low. 
This means there is little gradient between the PA and the 
RV in diastole, so that there may be little murmur or evi
-
dence of turbulence on color flow Doppler. If the RV begins 
to enlarge, it must be assumed that this is due to pulmonary 
valve regurgitation until proven otherwise. Early surgical 
pulmonary valve replacement is increasingly being favored. 
A percutaneous approach to pulmonary valve regurgitation 
remains limited as the available percutaneous valve diame
-
ters are frequently too small for the size of the pulmonary 
annulus. The Melody valve is a bovine jugular vein prosthe
-
sis with the largest size being 22 mm in diameter. Percuta
-
neous stented valves up to 26 mm in diameter are used in 
Europe and off-label in the United States.
If an anomalous coronary artery is present, then an 
extracardiac conduit around it from the RV to the PA may 
be necessary. By 20-year follow-up, reoperation of the 
common tetralogy repair is needed in about 10–15%, not 
only for severe pulmonary valve regurgitation but also for 
residual infundibular stenosis. Usually the pulmonary 
valve is replaced with a pulmonary homograft, although a 
porcine bioprosthetic valve is also suitable. Percutaneous 
valve-in-valve bioprosthetic valves have successfully been 
used when there is surgical bioprosthetic valve dysfunc
-
tion. Cryoablation of tissue giving rise to arrhythmias is 
sometimes performed at the time of reoperation. Branch 
pulmonary stenosis may be percutaneously opened by 
stenting. If a conduit has been used already for repair of the 
RV outflow obstruction, a percutaneous approach with a

RV outflow obstruction, a percutaneous approach with a 
stented pulmonary valve may be possible. All patients 
require endocarditis prophylaxis (see Tables 33–3, 33–4, 
and 33–5). Most adults with stable hemodynamics can be 
quite active, and most women can carry a pregnancy ade
-
quately if RV function is preserved.
Atrial fibrillation, reentrant atrial arrhythmias, and ven
-
tricular ectopy are common, especially after the age of 45. 
Left heart disease appears to cause these arrhythmias more 
often than right heart disease. Biventricular dysfunction is 
not an uncommon consequence as the patient ages. The 
cause of associated LV dysfunction is often multifactorial 
and frequently unclear. Similarly, the aorta may enlarge 
with accompanying aortic regurgitation, and these lesions 
can become severe enough to warrant surgical intervention. 
Patients with RV or LV dysfunction or with dysfunction of 
both ventricles may require a prophylactic defibrillator.
 
»
All patients with tetralogy of Fallot should be referred to a 
cardiologist with expertise in adult congenital heart 
disease.
25896865]
Buddhe S et al. Progression of right ventricular dilation in 
repaired tetralogy of Fallot. J Magn Reson Imaging. 2015 Mar;
 
41(3):730–7. [PMID: 24591270]
Downing TE et al. Tetralolgy of Fallot: general principles of 
management. Cardiol Clin. 2015 Nov;33(4):531–41. [PMID: 
26471818]
Fraser CD et al. Tetralogy of Fallot. Semin Thorac Cardiovasc 
Surg. 2015 Summer;27(2):189–204. [PMID: 26686447]
Paolino A et al. NT-proBNP as marker of ventricular dilatation 
and pulmonary regurgitation after surgical correction of 
tetralogy of Fallot: a MRI validation study. Pediatr Cardiol. 
2017 Feb;38(2):324–31. [PMID: 27872995]
 
º
VALVULAR HEART DISEASE
The 2014 AHA/ACC guidelines provide current informa
-
tion on valvular heart disease diagnosis and treatment. The 
typical findings of each native valve lesion are described in 
Table 10–1. Table 10–2 outlines bedside maneuvers to dis
-
tinguish among the various systolic murmurs. These 
guidelines were updated in 2017 to reflect the remarkable 
increase in the use of percutaneous valvular devices, some 
of the newer information regarding anticoagulation usage, 
and when to intervene.
CMDT19_Ch10_p0334-p0450.indd   342

343
 
CMDT 2019
Table 10–1.
 
Differential diagnosis of valvular heart disease.
Mitral Stenosis
Mitral Regurgitation
Aortic Stenosis
Aortic Regurgitation
Tricuspid Stenosis
Tricuspid Regurgitation
Inspection
Malar flush, precordial bulge, 
and diffuse pulsation in 
young patients.
Usually prominent and 
hyperdynamic apical 
impulse to left of MCL.
Sustained PMI, prominent 
atrial filling wave.
Hyperdynamic PMI to left of 
MCL and downward. Visible 
carotid pulsations. Pulsating 
nailbeds (Quincke), head bob 
(deMusset).
Giant 
a
 wave in jugular 
pulse with sinus 
rhythm. Peripheral 
edema or ascites, or 
both.
Large 
v
pulse; time with carotid 
pulsation. Peripheral 
both.
p
alpa
tion
“Tapping” sensation over 
area of expected PMI. 
Right ventricular pulsation 
in left third to fifth ICS 
parasternally when pul
-
monary hypertension is 
present. P
2
 may be 
palpable.
Forceful, brisk PMI; systolic 
thrill over PMI. Pulse 
normal, small, or 
slightly collapsing.
Powerful, heaving PMI to 
left and slightly below 
MCL. Systolic thrill over 
aortic area, sternal 
notch, or carotid arter
-
ies in severe disease. 
Small and slowly rising 
carotid pulse. If bicus
-
pid AS, check for delay 
at femoral artery to 
exclude coarctation.
Apical impulse forceful and dis
-
placed significantly to left 
and downward. Prominent 
carotid pulses. Rapidly rising 
and collapsing pulses 
 
(Corrigan pulse).
Pulsating, enlarged 
liver in ventricular 
systole.
Right ventricular pulsa
-
tion. Systolic pulsation 
of liver.
Heart sounds, 
rhythm, and 
blood pressure
S
1
 loud if valve mobile. 
Opening snap following 
S
2
. The worse the disease, 
the closer the S
2
-opening 
snap interval.
S
1
 normal or buried in early 
part of murmur (excep
-
tion in mitral prolapse 
where murmur may be 
late). Prominent third 
heart sound when 
severe MR. Atrial fibrilla
-
tion common. Blood 
pressure normal. Midsys
-
tolic clicks may be pres
-
ent and may be multiple.
A
2
 normal, soft, or absent. 
Prominent S
4
. Blood 
pressure normal, or sys
-
tolic pressure normal 
with high diastolic 
pressure.
S
1
 normal or reduced, A
2
 loud. 
Wide pulse pressure with dia
-
stolic pressure < 60 mm Hg.
When severe, gentle compres
-
sion of femoral artery with 
diaphragm of stethoscope 
may reveal diastolic flow 
(Duroziez) and pressure in leg 
on palpation > 40 mm Hg 
than arm (Hill).
S
1
 often loud.
Atrial fibrillation maybe 
present.
Murmurs
Location and 
transmission
Localized at or near apex. 
Diastolic rumble best 
heard in left lateral posi
-
tion; may be accentuated 
by having patient do sit-
ups. Rarely, short diastolic 
murmur along lower left 
sternal border (Graham 
Steell) in severe pulmo
-
nary hypertension.
Loudest over PMI; posteri
-
orly directed jets (ie, 
anterior mitral prolapse) 
transmitted to left 
axilla, left infrascapular 
area; anteriorly directed 
jets (ie, posterior mitral 
prolapse) heard over 
anterior precordium. 
Murmur unchanged 
after premature beat.
Right second ICS paraster
-
nally or at apex, heard 
in carotid arteries and 
occasionally in upper 
interscapular area. May 
sound like MR at apex 
(Gallaverdin phenome
-
non), but murmur 
occurs after S
1
 and 
stops before S
2
.
Diastolic: louder along left ster
-
nal border in third to fourth 
interspace. Heard over aortic 
area and apex. May be associ
-
ated with low-pitched mid-
diastolic murmur at apex 
(Austin Flint) due to func
-
tional mitral stenosis. If due 
to an enlarged aorta, murmur 
may radiate to right sternal 
border.
Third to fifth ICS along 
left sternal border 
out to apex. Murmur 
increases with 
inspiration.
Third to fifth ICS along left 
sternal border. Murmur 
hard to hear but 
increases with inspira
-
tion. Sit-ups can 
increase cardiac output 
and accentuate 
murmur.
(
continued
 
)
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Timing
Relation of opening snap to 
A
2
 important. The higher 
the LA pressure, the ear
-
lier the opening snap. Pre
-
systolic accentuation 
before S
1
 if in sinus 
rhythm. Graham Steell 
begins with P
2
 (early dias
-
tole) if associated pulmo
-
Pansystolic: begins with S
1
 
and ends at or after A
2
. 
May be late systolic in 
mitral valve prolapse.
Begins after S
1
, ends 
before A
2
. The more 
severe the stenosis, the 
later the murmur peaks.
Begins immediately after aortic 
second sound and ends 
before first sound (blurring 
both); helps distinguish from 
MR.
Rumble often follows 
audible opening 
snap.
At times, hard to hear. 
Begins with S
1
 and fills 
systole. Increases with 
Character
Low-pitched, rumbling; pre
-
systolic murmur merges 
with loud S
1
.
Blowing, high-pitched; 
occasionally harsh or 
musical.
Harsh, rough.
Blowing, often faint.
As for mitral stenosis.
Blowing, coarse, or 
musical.
Optimum ausculta
-
tory conditions
After exercise, left lateral 
recumbency. Bell chest 
piece lightly applied.
After exercise; use dia
-
phragm chest piece. In 
prolapse, findings may 
be more evident while 
standing.
Use stethoscope dia
-
phragm. Patient resting, 
leaning forward, breath 
held in full expiration.
Use stethoscope diaphragm. 
Patient leaning forward, 
breath held in expiration.
Use stethoscope bell. 
Murmur usually 
louder and at peak 
during inspiration. 
Patient recumbent.
-
phragm. Murmur usu
-
ally becomes louder 
during inspiration.
Radiography
Straight left heart border 
from enlarged LA append
-
age. Elevation of left 
mainstem bronchus. Large 
right ventricle and pulmo
-
nary artery if pulmonary 
hypertension is present. 
Calcification in mitral 
valve in rheumatic mitral 
stenosis or in annulus in 
calcific mitral stenosis.
Enlarged left ventricle and 
LA.
Concentric left ventricular 
hypertrophy. Prominent 
ascending aorta. Calci
-
fied aortic valve 
common.
Moderate to severe left ventric
-
ular enlargement. Aortic root 
often dilated.
Enlarged right atrium 
with prominent SVC 
and azygous 
shadow.
Enlarged right atrium and 
right ventricle.
ECG
Broad P waves in standard 
leads; broad negative 
phase of diphasic P in V
1
. 
If pulmonary hyperten
-
sion is present, tall peaked 
P waves, right axis devia
-
tion, or right ventricular 
hypertrophy appears.
Left axis deviation or frank 
left ventricular hyper
-
trophy. P waves broad, 
tall, or notched in stan
-
dard leads. Broad nega
-
tive phase of diphasic P 
in V
1
.
Left ventricular 
hypertrophy.
Left ventricular hypertrophy.
Tall, peaked P waves. 
Possible right ven
-
tricular hypertrophy.
Right axis usual.
 
Differential diagnosis of valvular heart disease. (continued)
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CMDT 2019
Two-dimensional 
echocardiography
Thickened, immobile mitral 
valve with anterior and 
posterior leaflets moving 
together. “Hockey stick” 
shape to opened anterior 
leaflet in rheumatic mitral 
stenosis. Annular calcium 
with thin leaflets in calcific 
mitral stenosis. LA 
enlargement, normal to 
small left ventricle. Orifice 
can be traced to approxi
-
mate mitral valve orifice 
area.
Thickened mitral valve in 
rheumatic disease; 
mitral valve prolapse; 
flail leaflet or vegeta
-
tions may be seen. 
Dilated left ventricle in 
volume overload. Oper
-
ate for left ventricular 
end-systolic dimension 
< 4.5 cm.
Dense persistent echoes 
from the aortic valve 
with poor leaflet excur
-
sion. Left ventricular 
hypertrophy late in the 
disease. Bicuspid valve 
in younger patients.
Abnormal aortic valve or dilated 
aortic root. Diastolic vibra
-
tions of the anterior leaflet of 
the mitral valve and septum. 
In acute aortic regurgitation, 
premature closure of the 
mitral valve before the QRS. 
When severe, dilated left ven
-
tricle with normal or 
decreased contractility. Oper
-
ate when left ventricular end-
systolic dimension > 5.0 cm.
In rheumatic disease, 
tricuspid valve thick
-
ening, decreased 
early diastolic filling 
slope of the tricus
-
pid valve. In carci
-
noid, leaflets fixed, 
but no significant 
thickening.
Enlarged right ventricle 
with paradoxical septal 
motion. Tricuspid valve 
often pulled open by 
displaced chordae.
Continuous and color 
flow 
 
Doppler and
 
TEE
Prolonged pressure half-time 
across mitral valve allows 
estimation of gradient. 
MVA estimated from pres
-
sure half-time. Indirect 
evidence of pulmonary 
hypertension by noting 
elevated right ventricular 
systolic pressure mea
-
sured from the tricuspid 
regurgitation jet.
Regurgitant flow mapped 
into LA. Use of PISA 
helps assess MR sever
-
ity. TEE important in 
prosthetic mitral valve 
regurgitation.
Increased transvalvular 
flow velocity; severe AS 
when peak jet > 4 m/sec 
(64 mm Hg). Valve area 
estimate using continu
-
ity equation is poorly 
reproducible.
Demonstrates regurgitation and 
qualitatively estimates sever
-
ity based on percentage of 
left ventricular outflow filled 
with jet and distance jet pen
-
etrates into left ventricle. TEE 
important in aortic valve 
endocarditis to exclude 
abscess. Mitral inflow pattern 
describes diastolic 
Prolonged pressure 
half-time across tri
-
cuspid valve can be 
used to estimate 
mean gradient. 
Severe tricuspid ste
-
nosis present when 
mean gradient 
 
> 5 mm Hg.
into right atrium and 
venae cavae. Right ven
-
tricular systolic pressure 
estimated by tricuspid 
regurgitation jet 
velocity.
A
2
, aortic second sound; AS, aortic stenosis; ICS, intercostal space; LA, left atrial; MCL, midclavicular line; MR, mitral regurgitation; MVA, measured valve area; P
2
, pulmonary second sound; PISA, proximal 
isovelocity surface area; PMI, point of maximal impulse; S
1
, first heart sound; S
2
, second heart sound; S
4
, fourth heart sound; SVC, superior vena cava; TEE, transesophageal echocardiography; V
1
, chest 
ECG lead 1.
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Table 10–2.
 
Effect of various interventions on systolic murmurs.
Intervention
Hypertrophic 
Mitral 
p
r
olapse
Valsalva
↑
↓
↓
 or ×
↑
 or 
↓
Standing
↑
↑
 or ×
↓
 or ×
↑
Handgrip or squatting
↓
↓
 or ×
↑
↓
Supine position with legs 
elevated
↓
↑
 or ×
×
↓
Exercise
↑
↑
 or ×
↓
↑
↑
, increased; 
↓
, decreased; ×, unchanged.
Modified, with permission, from Paraskos JA. Combined valvular disease. In: 
, 3e. Dalen JE, Alpert JS, Rahimtoola SH 
 
(editors). Philadelphia: Lippincott Williams & Wilkins, 2000.
The 2014 update of the AHA/ACC valvular guidelines 
suggests all lesions may be best classified clinically into one 
of six categories:
Stage A:
 Patients at risk for valvular heart disease.
Stage B:
 Patients with progressive valvular heart disease 
(mild to moderate severity) and asymptomatic.
Stage C:
 Asymptomatic patients who have reached crite
-
ria for severe valvular heart disease.
C1:
 Severe valve lesion. Asymptomatic. Normal LV 
function.
C2:
 Severe valve lesion. Asymptomatic. Abnormal LV 
function.
Stage D:
 Symptomatic patients as a result of valvular 
Nishimura RA et al. 2014 AHA/ACC guideline for the manage
-
ment of patients with valvular heart disease: executive sum
-
mary: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines. J Am Coll 
Cardiol. 2014 Jun 10;63(22):2438–88. Erratum in: J Am Coll 
Cardiol. 2014 Jun 10;63(22):2489. [PMID: 24603192]
Nishimura RA et al. 2017 AHA/ACC focused update of the 2014 
AHA/ACC guideline for the management of patients with 
valvular heart disease: a report of the American College of 
Cardiology/American Heart Association Task Force on Prac
-
tice Guidelines. Circulation. 2017 Jun 20;135(25):e1159–95. 
[PMID: 28298458]
MITRAL STENOSIS
 
»
Fatigue, exertional dyspnea, and orthopnea when 
the stenosis becomes severe.
 
»
Symptoms often precipitated by onset of atrial 
fibrillation or pregnancy.
 
»
Intervention indicated for symptoms, atrial fibrilla
-
tion, or evidence of pulmonary hypertension. 
Most symptomatic patients have a mitral valve 
area of less than 1.5 cm
2
.
 
»
Most patients with native valve mitral stenosis are pre
-
sumed to have had rheumatic heart disease, although a 
history of rheumatic fever is noted in only about one-third. 
(Also see section on Rheumatic Fever.) Rheumatic mitral 
stenosis results in thickening of the leaflets, fusion of the 
mitral commissures, retraction, thickening and fusion of 
the chordae, and calcium deposition in the valve. Mitral 
stenosis can also occur due to congenital disease with 
chordal fusion or papillary muscle malposition. The papil
-
lary muscles may be abnormally close together, sometimes 
so close that they merge into a single papillary muscle (the 
“parachute mitral valve”
). In these patients, the chordae or 
valvular tissue (or both) may also be fused. In older patients 
and in those undergoing dialysis, mitral annular calcifica
-
tion may stiffen the mitral valve and reduce its motion to 
the point where a mitral gradient is present. Calcium in the 
mitral annulus virtually invades the mitral leaflet from 
the annulus inward as opposed to the calcium buildup in 
the leaflets and commissures as seen in rheumatic heart 
disease. Mitral valve obstruction may also develop in 
patients who have had mitral valve repair with a mitral 
annular ring that is too small, or in patients who have had a 
surgical valve replacement (prosthetic valve-patient mis
-
match or degeneration of the prosthetic valve over time).
 
»
Two clinical syndromes classically occur in patients with 
mitral stenosis. In 
mild
 to 
moderate mitral stenosis,
 LA 
pressure and cardiac output may be essentially normal, and 
the patient is either asymptomatic or symptomatic only

mild
 to 
 LA 
the patient is either asymptomatic or symptomatic only 
with extreme exertion. The measured valve area is usually 
between 1.5 cm
2
 and 1.0 cm
2
. In 
severe mitral stenosis
 
(valve area less than 1.0 cm
2
), severe pulmonary hyperten
-
sion develops due to a “secondary stenosis” of the pulmo
-
nary vasculature. In this condition, pulmonary edema is 
uncommon, but symptoms of low cardiac output and right 
heart failure predominate.
A characteristic finding of rheumatic mitral stenosis is 
an 
opening snap
 following A
2
 due to the stiff mitral valve. 
CMDT19_Ch10_p0334-p0450.indd   346

347
 
CMDT 2019
The interval between the opening snap and aortic closure 
sound is long when the LA pressure is low, but shortens as 
the LA pressure rises and approaches the aortic diastolic 
pressure. As mitral stenosis worsens, there is a localized 
low-pitched diastolic murmur whose duration increases 
with the severity of the stenosis when the mitral gradient 
continues throughout more of diastole. The diastolic mur
-
mur is best heard at the apex with the patient in the left 
lateral position (Table 10–1). Mitral regurgitation may be 
present as well.
Paroxysmal or chronic atrial fibrillation eventually devel
-
ops in 50–80% of patients. Any increase in the heart rate 
reduces diastolic filling time and increases the mitral gradi
-
ent. A sudden increase in heart rate may precipitate pulmo
-
nary edema. Therefore, heart rate control is important, with 
slow heart rates allowing for more diastolic filling of the LV .
Echocardiography is the most valuable technique for 
assessing mitral stenosis (Table 10–1). LA size can also be 
determined by echocardiography; increased size denotes 
an increased likelihood of atrial fibrillation and thrombus 
formation.
Because echocardiography and careful symptom evalu
-
ation provide most of the needed information, cardiac 
catheterization is used primarily to detect associated coro
-
nary or myocardial disease—usually after the decision to 
intervene has been made.
 
»
 In most cases, there is a long asymptomatic phase after the 
initial rheumatic infection, followed by subtle limitation of 
activity. Pregnancy and its associated increase in stroke 
volume and heart rate results in an increased transmitral 
pressure gradient and may precipitate symptoms. In par
-
ticular, toward the end of pregnancy, the cardiac output 
continues to be maintained by an increase in heart rate, 
increasing the mitral gradient by shortening diastolic 
time. Patients with moderate to severe mitral stenosis 
should have the condition corrected prior to becoming 
pregnant if possible (when the measured valve area is less 
than 2.0 cm
2
). Pregnant patients who become symptom
-
atic can undergo successful surgery, preferably in the third 
trimester, although balloon valvuloplasty is the treatment 
of choice if the echocardiography valve score is low 
enough.
The onset of atrial fibrillation often precipitates symp
-
toms, which improve with control of the ventricular rate or 
restoration of sinus rhythm. Conversion to and subsequent 
maintenance of sinus rhythm are most commonly success
-
ful when the duration of atrial fibrillation is brief (less than 
6–12 months) and the LA is not severely dilated (diameter 
less than 4.5 cm). Once atrial fibrillation occurs, the patient 
should receive warfarin anticoagulation therapy even if 
sinus rhythm is restored, since atrial fibrillation often 
recurs even with antiarrhythmic therapy and 20–30% of 
these patients will have systemic embolization if untreated. 
Systemic embolization in the presence of only mild to 
moderate disease is not an indication for surgery but 
should be treated with warfarin anticoagulation. DOACs 
(dabigatran, apixaban, rivaroxaban, edoxaban) have not 
been studied for the prevention of stroke and non–central 
nervous system embolism in patients with moderate or 
severe mitral stenosis and atrial fibrillation, and the 2017 
valvular guidelines do not recommend them as an antico
-
agulant option for these patients.
Indications for intervention focus on symptoms such as 
an episode of pulmonary edema, a decline in exercise 
capacity, or any evidence of pulmonary hypertension (peak 
systolic pulmonary pressure greater than 50 mm Hg). 
Some experts believe that the presence of atrial fibrillation 
should also be a consideration for an intervention. Most 
interventions are not pursued until the patient is symptom
-
atic (stage D) (Figure 10–1). In some patients, symptoms

-
atic (stage D) (Figure 10–1). In some patients, symptoms 
develop with calculated mitral valve areas between 1.5 cm
2
 
and 1.0 cm
2
. Symptoms or evidence of pulmonary hyper
-
tension should drive the decision to intervene in these 
patients, not the estimated valve area.
Open mitral commissurotomy is now rarely performed 
and has given way to percutaneous balloon valvuloplasty. 
Ten-year follow-up data comparing surgery to balloon val
-
vuloplasty suggest no real difference in outcome between 
the two modalities. Replacement of the valve is indicated 
when combined stenosis and regurgitation are present or 
when the mitral valve echo score is greater than 8–10. Per
-
cutaneous balloon valvuloplasty has a very low mortality 
rate (less than 0.5%) and a low morbidity rate (3–5%). 
Operative mortality rates are also low: 1–3% in most insti
-
tutions. Repeat balloon valvuloplasty can be done if the 
morphology of the valve remains suitable. At surgery, a 
Maze procedure may be done at the same time to reduce 
recurrent atrial arrhythmias. It involves a number of endo
-
cardial incisions across the right and left atria to disrupt the 
electrical activity that sustains atrial arrhythmias.
Mechanical mitral prosthetic valves are more prone to 
thrombosis than mechanical aortic prosthetic valves. 
The 
recommended INR range is thus higher (INR 2.5–3.5) 
and low-dose aspirin should be used in conjunction.
 It is 
a IIa recommendation that warfarin be used for up to 
6 months after implantation of a bioprosthetic mitral 
valve. Bioprosthetic valves tend to degenerate after about 
10–15 years. Percutaneous balloon valvuloplasty is not 
effective when bioprosthetic valve stenosis occurs, but 
stented valve-in-valve procedures have been successful and 
will likely be used more often as more data become avail
-
able and the technique becomes more simplified. Y ounger 
patients and those with end-stage renal disease are gener
-
ally believed to do the poorest with bioprosthetic heart 
valves, although data have questioned the role of chronic 
kidney disease as a major risk factor. Endocarditis prophy
-
laxis is indicated for patients with prosthetic heart valves 
but is not indicated in native valve disease (see Tables 33–3, 
33–4, and 33–5).
 
»
•	
Patients with mitral stenosis should be monitored with 
yearly examinations, and echocardiograms should be 
performed more frequently as the severity of the 
obstruction increases.
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MITRAL REGURGITATION
 
»
May be asymptomatic for years (or for life).
 
»
Severe mitral regurgitation may cause left-sided 
heart failure.
 
»
For chronic primary mitral regurgitation, surgery is 
indicated for symptoms or when the LV ejection frac
-
tion (LVEF) is less than 60% or the echocardiographic 
LV end-systolic dimension is greater than 4.0 cm.
 
»
In patients with mitral prolapse and severe mitral 
regurgitation, earlier surgery is indicated if mitral 
repair can be performed.
 
»
Patients with functional mitral regurgitation may 
improve with biventricular pacing. Some may 
benefit from surgical intervention.
•	
All patients should initially be seen by a cardiologist, 
who can then decide how often the patient needs cardi
-
ology follow-up.
Ghosh-Dastidar M et al. Mitral valve-in-valve and valve-in-ring 
for failing surgical bioprosthetic valves and rings. J 
 
C
ardiovasc 
Surg (Torino). 2016 Jun;57(3):372–80. [PMID: 26923547]
-
-
-
Praz F et al. Expanding indications of transcatheter heart valve 
interventions. JACC Cardiovasc Interv. 2015 Dec 21;8(14):
 
1777–96. [PMID: 26718509]
YES
NO
Rheumatic MS
Class I
Class IIb
Ve
ry
 severe MS
MVA 
≤ 
1 .0 cm
2
∆
P
mean 
> 
10
 mm Hg
T
1
/
2 
≥  
220 msec
Symptomatic
(stage D)
New onset AF
(stage B or C)
Symptomatic with
no other cause
(stage C)
Fa
vo
rable 
va
lv
e
No LA clot
No or mild MR
Fa
vo
rable 
va
lv
e
No LA clot
NYHA class III/IV
symptoms with high
surgical 
ri
sk
Fa
vo
rable 
va
lv
e
No LA clot
PCWP > 25 mm Hg
∆
P
mean 
> 
15
 mm Hg
with 
exe
rcise
YES
AF , atrial fibrillation; LA, left atrial
; 
MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral 
va
lv
e area; MVR, mitral 
va
lv
e
replacement; NYHA, New 
Yo
rk
 Heart Association; PBMC, percutaneous balloon mitral commissurotomy; PCWP , pulmonary 
capilla
ry
 wedge pressure; 
∆
P
mean
, mean pressur
e gradient;
 T
1
/
2
, half-lif
e.
NO
Pe
riodic
moni
to
ring
PBMC (I)
MVR (I)
PBMC (IIb)
Pe
riodic monitoring
Severe 
MS
MVA 
≤ 
1 .5 cm
2
∆
P
mean
 
> 5 mm Hg
T
1
/
2
 ≥ 
150 msec
Pr
ogressive
 MS
MVA > 
1.
5 cm
2
∆
P
mean
 ≤ 
5 mm Hg
T
1
/
2
 
< 
15
0 msec
NO
YES
YES
YES
NO
NO
 
▲
Figure 10–1.
 
The 2014 AHA/ACC guidelines for intervention in mitral stenosis. 
(Reproduced, with permission, 
from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: 
A
 
Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 
2014 Jun 10;129(23):e521–643. © 2014 American Heart Association, Inc.)
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CMDT 2019
 
»
Mitral regurgitation (formerly called mitral insufficiency) 
results in a volume load on the heart (increases preload) 
but reduces afterload. The result is an enlarged LV with an 
increased EF. Over time, the stress of the volume overload 
reduces myocardial contractile function; when this occurs, 
there is a drop in EF and a rise in end-systolic volume.
 
»
In acute mitral regurgitation, the LA size is not large, and 
LA pressure rises abruptly, leading to pulmonary edema if 
severe. When chronic, the LA enlarges progressively and 
the increased volume can be handled without a major rise 
in the LA pressure; the pressure in pulmonary veins and 
capillaries may rise only during exertion. Exertional dys
-
pnea and fatigue progress gradually over many years.
Mitral regurgitation leads to chronic LA and LV 
enlargement and may result in subsequent atrial fibrillation 
and eventually LV dysfunction. Clinically, mitral regurgita
-
tion is characterized by a pansystolic murmur maximal at 
the apex, radiating to the axilla and occasionally to the 
base. The murmur does not change in intensity after a 
premature beat because the LV to LA gradient is unaf
-
fected. In addition, a hyperdynamic LV impulse and a brisk 
carotid upstroke may be present along with a prominent 
third heart sound due to the increased volume returning to 
the LV in early diastole (Tables 10–1 and 10–2). In acute 
mitral regurgitation, the murmur intensity may be modest 
due to little difference between the LA and LV systolic 
pressures. The mitral regurgitation murmur due to mitral 
valve prolapse tends to radiate anteriorly in the presence of 
posterior leaflet prolapse and posteriorly when the pro
-
lapse is primarily of the anterior leaflet. Mitral regurgita
-
tion may not be pansystolic in these patients but occur only 
after the mitral click (until late in the disease process when 
it then becomes progressively more holosystolic).
Echocardiographic information demonstrating the under
-
lying pathologic process (rheumatic, calcific, prolapse, flail 
leaflet, endocarditis, cardiomyopathy), LV size and func
-
tion, LA size, PA pressure, and RV function can be invalu
-
able in planning treatment as well as in recognizing 
associated lesions. The 2014 guidelines for valvular heart 
disease from the AHA/ACC provide details of the classifi
-
cation and measures of severity for primary and secondary 
mitral valve regurgitation. Doppler techniques provide 
qualitative and semiquantitative estimates of the severity of 
mitral regurgitation. TEE may help reveal the cause of 
regurgitation and is especially useful in patients who have 
had mitral valve replacement, in suspected endocarditis, 
and in identifying candidates for valvular repair. Echocar
-
diographic dimensions and measures of systolic function 
are critical in deciding the timing of surgery. Asymptom
-
atic patients with severe mitral regurgitation (stage C1) but 
preserved LV dimensions should undergo at least yearly 
echocardiography. Exercise hemodynamics with either 
Doppler echocardiography or cardiac catheterization may 
be useful when the symptoms do not fit the anatomic 
severity of mitral regurgitation. B-type natriuretic peptide 
(BNP or NT-proBNP) is useful in the early identification of 
LV dysfunction in the presence of mitral regurgitation and 
asymptomatic patients, and values that trend upward over 
time appear to have some prognostic importance.
Cardiac MRI is occasionally useful, especially if specific 
myocardial causes are being sought (such as amyloid or 
myocarditis) or if myocardial viability assessment is needed 
prior to deciding whether to add coronary artery bypass 
grafting to mitral valve surgery.
Cardiac catheterization provides a further assessment 
of regurgitation and its hemodynamic impact along with

of regurgitation and its hemodynamic impact along with 
LV function, resting cardiac output, and PA pressure. 
The 
2014 AHA/ACC guidelines recommend coronary angi
-
ography to determine the presence of incidental coro
-
nary artery disease (CAD) prior to valve surgery in all 
men over age 40 years and in menopausal women with 
coronary risk factors.
 In younger patients, cardiac multi
-
detector CT may be adequate to screen patients with valvu
-
lar heart disease for asymptomatic CAD. A normal CT 
coronary angiogram has a high predictive value for patients 
with normal or insignificant disease.
 
»
A. Primary Mitral Regurgitation
The degree of LV enlargement reflects the severity and 
chronicity of regurgitation. LV volume overload may ulti
-
mately lead to LV failure and reduced cardiac output. LA 
enlargement may be considerable in 
chronic mitral regur
-
gitation
 and a large amount of mitral regurgitation regur
-
gitant volume may be tolerated. Patients with chronic 
lesions may thus remain asymptomatic for many years. 
Surgery is necessary when symptoms develop or when 
there is evidence for LV dysfunction, since progressive and 
irreversible deterioration of LV function can occur prior to 
the onset of symptoms. Early surgery is indicated even in 
asymptomatic patients with a reduced EF (less than 60%) 
or marked LV dilation with reduced contractility (end-
systolic dimension greater than 4.0 cm) (Figure 10–2). The 
2017 update of the valvular guidelines has added a IIa 
indication for mitral valve surgery when the LVEF is 
greater than 60% and the LV end-systolic dimension is still 
less than 4.0 cm. The new guidelines suggest that mitral 
valve replacement should be done if serial imaging reveals 
a progressive increase in the LV end-systolic dimension or 
a decrease in the EF. This latter recommendation was based 
on information that LV function is more likely to return to 
normal when the LVEF was greater than 64% and the LV 
end-systolic dimension was less than 3.7 cm. Pulmonary 
hypertension development suggests the mitral regurgita
-
tion is severe and should prompt intervention.
Acute mitral regurgitation
 may develop abruptly, such 
as with papillary muscle dysfunction following myocardial 
infarction, valve perforation in infective endocarditis, in 
patients with hypertrophic cardiomyopathy, or when there 
are ruptured chordae tendineae in patients with mitral 
valve prolapse. Emergency surgery may be required.
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Some patients may become hemodynamically unstable 
and require treatment with vasodilators or intra-aortic bal
-
loon counterpulsation that reduce the amount of retro
-
grade regurgitant flow by lowering systemic vascular 
resistance. There is controversy regarding the role of after
-
load reduction in chronic mitral regurgitation, since the 
lesion inherently results in a reduction in afterload, and 
there are no data that chronic afterload reduction is effec
-
tive in avoiding LV dysfunction or surgical intervention. A 
heightened sympathetic state has led some experts to sug
-
gest that beta-blockade be considered routinely, though 
this also remains speculative. The mitral regurgitation in 
patients with tachycardia-related cardiomyopathy may 
improve with normalization of the heart rate.
B. Myocardial Disease and Mitral Regurgitation
When mitral regurgitation is due to papillary dysfunction, it 
may subside as the infarction heals or LV dilation dimin
-
ishes. The cause of the regurgitation in most of these situa
-
tions is displacement of the papillary muscles and an 
enlarged mitral annulus rather than papillary muscle isch
-
emia. The fundamental problem is the lack of leaflet coapta
-
tion during systole (due to either leaflet prolapse or 
retraction). In acute myocardial infarction, rupture of the 
papillary muscle may occur with catastrophic results. 
Transient—but sometimes severe—mitral regurgitation may 
occur during episodes of myocardial ischemia and contrib
-
ute to flash pulmonary edema. Patients with dilated cardio
-
myopathies of any origin may have 
secondary mitral 
regurgitation
 due to the papillary muscle displacement or 
dilation of the mitral annulus, or both. If mitral valve 
replacement is performed, preservation of the chordae to the 
native valve helps prevent further ventricular dilation fol
-
lowing surgery. Several groups have reported good results 
with mitral valve repair in patients with LVEF less than 30% 
and secondary mitral regurgitation. The 2014 AHA/ACC 
guidelines advise that mitral valve repair/replacement can be 
attempted in severe mitral regurgitation patients with an EF 
less than 30% or an LV end-systolic dimension greater than 
5.5 cm, or both, as long as repair and preservation of the 
chordae are possible. The 2017 update of these guidelines 
1
MV repair is preferred over MV replacement when possible.
AF, atrial fibrillation; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; EF, ejection fraction; ERO, effe
ctive regurgitant orifice; HF,
heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; M
R, mitral regurgitation; MV, mitral valve;
NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; RF, regurgitant fraction; RVol, regurgitant volume;
 and Rx, therapy.
Progressive MR
(stage B)
Vena contracta < 0.7 cm
 RVol < 60 mL
RF < 50%
ERO < 0.4 cm
2
Severe MR
Vena contracta ≥ 0.7 cm
RVol ≥ 60 mL
RF ≥ 50%
ERO ≥ 0.4 cm
2
LV dilation 
Periodic monitoring
(stage D)
(stage C) 
severe MR
(stage D)
MV surgery
1
(I) 
LVEF > 60% and
LVESD < 40 mm
 (stage C1)
 LVEF 30% to ≤ 60%
or LVESD ≥ 40 mm
(stage C2) 
MV repair
(IIa)
 Likelihood of successful
repair > 95% and
expected mortality < 1% 
Primary MR
LVEF > 30%
MV surgery
1
(IIb) 
severe MR
(stage C)
Progressive
MR
(stage B) 
 MV surgery
1
(IIb)
Periodic monitoring 
Persistent NYHA
class III-IV
symptoms
Class I
Class IIa
Class IIb
Yes
No
New-onset AF or
PASP > 50 mm Hg
(stage C1)
MR
Secondary MR
CAD Rx
HF Rx
Consider CRT
Yes
No
 Progressive increase
in LVESD or
decrease in EF
MV surgery
(IIa)
 
▲
Figure 10–2.
 
The 2017 Focused update AHA/ACC guidelines for intervention in mitral regurgitation. 
(Reproduced, 
with permission, Nishimura RA et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management

with permission, Nishimura RA et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management 
of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task 
Force on Practice Guidelines. Circulation. 2017 Jun 20;135(25):e1159–95 © 2017 American Heart Association, Inc.)
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(Figure 10–2) suggest the latest data favor mitral valve 
replacement with chordal preservation over mitral valve 
repair in patients with chronic ischemic cardiomyopathy. 
There may also be a role for cardiac resynchronization 
therapy with biventricular pacemaker insertion, which has 
been found to reduce mitral regurgitation related to cardio
-
myopathy in many patients. Guidelines recommend biven
-
tricular pacing prior to surgical repair in symptomatic 
patients who have functional mitral regurgitation as long as 
other criteria (eg, a QRS of greater than 150 msec or left 
bundle branch block or both) are present.
There are several ongoing trials of percutaneous 
approaches to reducing mitral regurgitation. These 
approaches include the use of a 
mitral clip
 device to create 
a double orifice mitral valve, various coronary catheter 
devices to reduce the mitral annular area, and devices to 
reduce the septal-lateral ventricular size and consequent 
mitral orifice size. Of these devices, the most success has 
been noted with the mitral clip device. The device, how
-
ever, is reserved for patients in whom surgical risk is con
-
sidered excessive and there is primary mitral valve disease 
with at least 3+ mitral regurgitation. In addition, vascular 
plugging and occluder devices are being used in selected 
patients to occlude perivalvular leaks around prosthetic 
mitral valves. A transcatheter stented valve, which is used 
as a 
transcatheter aortic valve replacement (TAVR)
 
device, can be used to open a degenerated mitral biopros
-
thetic valve in any position (aortic, mitral, tricuspid, or 
pulmonary). Transcatheter valve replacement has also 
been attempted in small series to repair mitral regurgita
-
tion following mitral valve repair with mixed results. 
Finally, the first cases of a stented mitral valve prosthesis to 
replace the entire mitral valve have been reported.
 
»
•	
All patients with more than mild mitral regurgitation 
should be referred to a cardiologist for an evaluation.
•	
Serial examinations and echocardiograms should be 
obtained and surgical referral made if there is an increase 
in the LV end-systolic dimensions, a fall in the LVEF to 
less than 60%, symptoms, evidence for pulmonary 
hypertension or the new onset of atrial fibrillation.
•	
There is growing evidence that mitral valve repair 
should be done early in the course of the disease to 
improve mortality and morbidity.
De Backer O et al. Percutaneous transcatheter mitral valve 
replacement: an overview of devices in preclinical and early 
clinical evaluation. Circ Cardiovasc Interv. 2014 Jun;7(3):
 
400–9. [PMID: 24944303]
-
-
mary: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guide
-
lines. J Am Coll Cardiol. 2014 Jun 10;63(22):2438–88. Erra
-
tum in: J Am Coll Cardiol. 2014 Jun 10;63(22):2489. [PMID: 
24603192]
 
C
ardiology/American Heart Association Task Force on Prac
-
O’Gara PT et al. 2017 ACC expert consensus decision pathway 
on the management of mitral regurgitation: a report of the 
American College of Cardiology Task Force on Expert Con
-
sensus Decision Pathways. J Am Coll Cardiol. 2017 Nov 7;
 
70(19):2421–49. [PMID: 29055505]
interventions. JACC Cardiovasc Interv. 2015 Dec 21;
 
8(14):1777–96. [PMID: 26718509]
MITRAL VALVE PROLAPSE SYNDROME
 
»
Single or multiple mid-systolic clicks often heard 
on auscultation.
 
»
Murmur may be pansystolic or only late in 
systole.
 
»

»
 
»
systole.
 
»
Often associated with skeletal changes (straight 
back, pectus excavatum, and scoliosis) or hyper
-
flexibility of joints.
 
»
Echocardiography is confirmatory with prolapse 
of mitral leaflets in systole into the LA.
 
»
Chest pain and palpitations are common symp
-
toms in the young adult.
 
»
The significance of mild mitral valve prolapse (“floppy” or 
myxomatous mitral valve), also commonly referred to as 
“degenerative” mitral valve disease,
 has been in dispute 
because of the frequency with which it is diagnosed by 
echocardiography in even healthy young women (10% or 
less). A controversial hyperadrenergic syndrome not too 
dissimilar to the 
postural orthostatic tachycardia 
syndrome
 has also been described (especially in young 
females) that may be responsible for some of the noncardiac 
symptoms observed. Fortunately, this hyperadrenergic 
component attenuates with age and is infrequent in persons 
older than 40–45 years. Some patients with mitral prolapse 
have findings of a systemic collagen abnormality (Marfan or 
Ehlers-Danlos syndrome). In these conditions, a dilated 
aortic root and aortic regurgitation may coexist. In many 
persons, the “degenerative” myxomatous mitral valve clearly 
leads to long-term sequelae and is the most common cause 
of mitral regurgitation in developed countries.
Patients who have only a mid-systolic click usually have 
no immediate clinical issues, but significant mitral regurgi
-
tation may develop, occasionally suddenly due to rupture 
of chordae tendineae (flail leaflet) or gradually due to pro
-
gressive annular and LV dilation. The need for valve repair 
or replacement increases with age, so that approximately 
2% per year of patients with mitral valve prolapse with 
clinically significant regurgitation over age 60 years will 
eventually require surgery.
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»
Mitral valve prolapse without significant mitral regurgita
-
tion is usually asymptomatic but may be associated with a 
syndrome of nonspecific chest pain, dyspnea, fatigue, or 
palpitations. Most patients are young, female, thin, and 
some have skeletal deformities, such as pectus excavatum 
or scoliosis. On auscultation, there are characteristic mid-
systolic clicks that may be multiple and emanate from the 
chordae or redundant valve tissue. If leaflets fail to come 
together properly, the clicks will be followed by a late sys
-
tolic murmur. As the mitral regurgitation worsens, the 
murmur is heard more and more throughout systole. The 
smaller the LV chamber, the greater the degree of leaflet 
prolapse, and thus auscultatory findings are often accentu
-
ated in the standing position or during the Valsalva 
maneuver. Whether sudden cardiac death presumably due 
to ventricular arrhythmias is more frequent in patients 
with mitral valve prolapse remains controversial. Mitral 
prolapse progresses to significant mitral regurgitation over 
3–16 years in about one-fourth of individuals.
The diagnosis is primarily clinical and confirmed echocar
-
diographically. Mitral prolapse is often associated with 
aortic root disease, and any evidence for a dilated aorta by 
chest radiography should prompt either CT or MRI angi
-
ography. If palpitations are an issue, an ambulatory moni
-
tor is often helpful to distinguish atrial from ventricular 
tachyarrhythmias.
 
»
Treatment
Beta-blockers in low doses are used to treat the hyperad
-
renergic state when present and are usually satisfactory for 
treatment of arrhythmias (see Table 11–7). Selective sero
-
tonin reuptake inhibitors have also been used, especially if 
orthostatic hypotension or anxiety is associated with mitral 
valve prolapse; results have been mixed. Some patients 
have associated postural orthostatic tachycardia syndrome. 
Afterload reduction has not been shown to change progno
-
sis when mitral regurgitation is present.
Mitral valve repair is strongly favored over valve replace
-
ment, and its efficacy has led many to recommend interven
-
tion earlier and earlier in the course of the disease process. 
Mitral repair may include shortening of chordae, chordae 
transfers, wedge resection of redundant valve tissue, the inser
-
tion of a mitral annular ring to reduce the annular size, or 
some combination of these techniques. Stitching the middle 
of the leaflets together to create a double-orifice mitral valve is 
also used at times 
(Alfieri procedure)
 and can be performed 
percutaneously 
(MitraClip)
. Mitral repair or replacement can 
usually be achieved through a right minithoracotomy with or 
without the use of a robotic device. Endocarditis prophylaxis 
is no longer recommended for most patients with mitral valve 
prolapse regardless of the degree of mitral regurgitation. A 
variety of percutaneous techniques and devices have been 
tried with some success, although results suggest that surgical 
repair is generally more durable.
 
»
•	
All patients with mitral valve prolapse and audible 
mitral regurgitation should be seen at least once by a 
cardiologist.
•	
Periodic echocardiography is warranted to assess LV 
size (especially end-systolic dimensions) and EF when 
mitral regurgitation is present. If only mitral clicks are 
audible, then serial echocardiography is not warranted.
Basso C et al. Arrhythmic mitral valve prolapse and sudden 
cardiac death. Circulation. 2015 Aug 18;132(7):556–66. 
[PMID: 26160859]
Delling FN et al. Evolution of mitral valve prolapse: insights 
from the Framingham Heart Study. Circulation. 2016 Apr 26;
 
133(17):1688–95. [PMID: 27006478]
Theofilogiannakos EK et al. Floppy mitral valve/mitral valve 
prolapse syndrome: beta-adrenergic receptor polymorphism 
may contribute to the pathogenesis of symptoms. J Cardiol.

may contribute to the pathogenesis of symptoms. J Cardiol. 
2015 May;65(5):434–8. [PMID: 25172623]
AORTIC STENOSIS
 
»
Congenital bicuspid aortic valve (usually asymp
-
tomatic until middle or old age).
 
»
“Degenerative” or calcific aortic stenosis; similar 
risk factors as atherosclerosis.
 
»
Visual observation of immobile aortic valve plus a 
valve area of less than 1.0 cm
2
 define severe dis
-
ease; low-gradient but severe aortic stenosis can 
thus be recognized.
 
»
 
»
Surgery typically indicated for symptoms. Percuta
-
neous valve replacement is being used increasingly.
 
»
Surgery considered for asymptomatic patients 
with severe aortic stenosis (mean gradient greater 
than 55 mm Hg) or when undergoing heart sur
-
gery for other reasons (eg, coronary artery bypass 
grafting [CABG]).
 
»
BNP is a marker of early LV myocardial failure, and 
high levels suggest poor prognosis.
 
»
There are two common clinical scenarios in which aortic 
stenosis is prevalent. The first is due to a congenitally 
abnormal 
unicuspid
 or 
bicuspid valve,
 rather than tricus
-
pid. Symptoms can occur in young or adolescent individu
-
als if the stenosis is severe, but more often emerge at age 
50–65 years when calcification and degeneration of the 
valve become manifest. A dilated ascending aorta, due to 
an intrinsic defect in the aortic root media and the hemo
-
dynamic effects of the eccentric aortic jet, may accompany 
the bicuspid valve in about half of these patients. 
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Coarctation of the aorta is also seen in a number of 
patients with congenital aortic stenosis. Offspring of 
patients with a bicuspid valve have a much higher inci
-
dence of the disease in either the valve, the aorta, or both 
(up to 30% in some series).
A second pathologic process, 
degenerative
 or 
calcific 
aortic stenosis
, is thought to be related to calcium deposi
-
tion due to processes similar to those that occur in athero
-
sclerotic vascular disease. Approximately 25% of patients 
over age 65 years and 35% of those over age 70 years have 
echocardiographic evidence of aortic valve thickening 
(sclerosis). About 10–20% of these will progress to hemo
-
dynamically significant aortic stenosis over a period of 
10–15 years. Certain genetic markers are associated with 
aortic stenosis (most notably Notch 1), so a genetic com
-
ponent appears a likely contributor, at least in some 
patients. Other associated genetic markers have also been 
Aortic stenosis has become the most common surgical 
valve lesion in developed countries, and many patients are 
elderly. The risk factors include hypertension, hypercholes
-
terolemia, and smoking. Hypertrophic cardiomyopathy 
may also coexist with valvular aortic stenosis.
 
»
Slightly narrowed, thickened, or roughened valves 
(aortic 
sclerosis)
 or aortic dilation may contribute to the typical 
ejection murmur of aortic stenosis. In mild or moderate 
cases where the valve is still pliable, an ejection click may 
precede the murmur and the closure of the valve (S
2
) is 
preserved. The characteristic systolic ejection murmur is 
heard at the aortic area and is usually transmitted to the 
neck and apex. In severe aortic stenosis, a palpable LV heave 
or thrill, a weak to absent aortic second sound, or reversed 
splitting of the second sound is present (see Table 10–1). In 
some cases, only the high-pitched components of the mur
-
mur are heard at the apex, and the murmur may sound like 
mitral regurgitation (the so-called Gallaverdin phenome
-
non). When the valve area is less than 0.8–1.0 cm
2
 (normal, 
3–4 cm
2
), ventricular systole becomes prolonged and the 
typical carotid pulse pattern of delayed upstroke and low 
amplitude is present. A delayed upstroke, though, is an 
unreliable finding in older patients with extensive arterio
-
sclerotic vascular disease and a stiff, noncompliant aorta. 
LVH increases progressively due to the pressure overload, 
eventually resulting in elevation of ventricular end-diastolic 
pressure. Cardiac output is maintained until the stenosis is 
severe. LV failure, angina pectoris, or syncope may be pre
-
senting symptoms of significant aortic stenosis; impor
-
tantly, all symptoms tend to first occur with exertion.
B. Redefining Severe Aortic Stenosis
There are four different anatomic syndromes that occur in 
patients with severe aortic stenosis. The common underly
-
ing measure of 
severe aortic stenosis
 is an aortic valve area 
of less than 1.0 cm
2
 and echocardiographic evidence of an 
immobile aortic valve. In patients with a normal LVEF and 
normal cardiac output, the threshold for intervention is a 
peak aortic gradient of greater than 64 mm Hg and mean 
aortic gradient of greater than 40 mm Hg. In the same situ
-
ation, 
super-severe aortic stenosis
 is defined as a mean 
gradient of greater than 55 mm Hg or peak aortic velocity 
greater than 5 m/sec by Doppler.
In some patients with an aortic valve area of less than 
1.0 cm
2
 with a low cardiac output and stroke volume, the 
mean gradient may be less than 40 mm Hg. This can occur 
when the LV systolic function is poor (
low-gradient severe 
aortic stenosis with low LVEF
) or when the LV systolic 
function is normal 
(
paradoxical
 low-flow severe aortic 
stenosis with a normal LVEF).
 Low flow (low output) in 
these situations is defined by an echocardiographic stroke 
volume index of less than 35 mL/min/m
2

(
2
. Prognosis in 
patients with low gradient, low valve area, low output, and 
a normal LVEF aortic stenosis may actually be worse than 
in patients with the traditional high gradient, low valve 
area, normal output, and normal LVEF aortic stenosis. If 
low-flow severe aortic stenosis is present in the face of a 
low LVEF, provocative testing with dobutamine or nitro
-
prusside is warranted to increase the stroke volume to dis
-
cover if a mean aortic valve gradient of at least 40 mm Hg 
can be demonstrated without increasing the aortic valve 
area. If the aortic valve area can be made to increase and a 
mean gradient of greater than 40 mm Hg cannot be dem
-
onstrated by inotropic challenge, the presumption is that 
the low gradient is due to an associated cardiomyopathy 
and not the aortic valve stenosis. In this latter situation 
intervention is not indicated. The 2014 AHA/ACC guide
-
lines acknowledge these four situations (Table 10–3). Inter
-
vention is indicated in supersevere aortic stenosis even 
without demonstrable symptoms (grade C) and in any of 
the other situations when symptoms are present: D1 
defines the symptomatic high gradient patient; D2 the 
symptomatic low-flow, low-gradient patient with low 
LVEF; and D3 the symptomatic low-flow, low-gradient 
patient with normal LVEF.
Symptoms of LV failure may be sudden in onset or may 
progress gradually. Angina pectoris frequently occurs in 
Table 10–3.
 
Summary of 2014 AHA/ACC guideline 
definitions of symptomatic severe aortic stenosis.
Category of Severe 
 
1
p
r
operties
High Gradient
 
H
igh gradient
> 4.0 m/sec Doppler jet velocity
> 40 mm Hg mean gradient
 
Super-severe
> 5.0 m/sec Doppler jet velocity
> 55 mm Hg mean gradient
Low Gradient
 
L
ow flow
Reduced LVEF (< 50%)
 
L
ow flow
Paradoxical with normal LVEF 
 
(> 50%)
1
All categories of severe aortic stenosis have abnormal systolic 
opening of the aortic valve and an aortic valve area < 1.0 cm
2
.
LVEF, left ventricular ejection fraction.
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aortic stenosis due to underperfusion of the endocardium. 
Of patients with calcific aortic stenosis and angina, half 
have significant associated CAD. Syncope, a late finding, 
occurs with exertion as the LV pressure rises, stimulating 
the LV baroreceptors to cause peripheral vasodilation. This 
vasodilation results in the need for an increase in stroke 
volume, which increases the LV systolic pressure again, 
creating a cycle of vasodilation and stimulation of the 
 
baroreceptors that eventually results in a drop in systemic 
BP , as the stenotic valve prevents further increase in stroke 
volume. Less commonly, syncope may be due to arrhyth
-
mias (usually ventricular tachycardia but sometimes AV 
block as calcific invasion of the conduction system from 
the aortic valve may occur).
The ECG reveals LVH or secondary repolarization changes 
in most patients but can be normal in up to 10%. The chest 
radiograph may show (1) a normal or enlarged cardiac sil
-
houette, (2) calcification of the aortic valve, and (3) dilation 
or calcification (or both) of the ascending aorta. The echo
-
cardiogram provides useful data about aortic valve calcifi
-
cation and leaflet opening, the severity of LV wall thickness, 
and overall ventricular function, while Doppler can provide 
an excellent estimate of the aortic valve gradient. Valve area 
estimation by echocardiography is less reliable but is a criti
-
cal component of the diagnosis of aortic stenosis due to 
issues such as paradoxical low-flow aortic stenosis (low-
gradient, low-flow, normal LVEF patients). Likewise, the 
echocardiography/Doppler can estimate the stroke volume 
index used to define the low-flow state when the valve area 
is small but the gradient is less than 40 mm Hg. Cardiac 
catheterization mostly provides an assessment of the hemo
-
dynamic consequence of the aortic stenosis, and the anat
-
omy of the coronary arteries. Catheterization data can be 
important when there is a discrepancy between symptoms 
and the echocardiography/Dopper information of aortic 
stenosis severity. In younger patients and in patients with 
high aortic gradients, the aortic valve need not be crossed at 
catheterization. Aortic regurgitation can be semiquantified 
by aortic root angiography. Some authors have suggested 
the use of BNP (or NT-proBNP) may provide additional 
prognostic data in the setting of poor LV function and aor
-
tic stenosis. A BNP greater than 550 pg/mL has been associ
-
ated with a poor outcome in these patients regardless of the 
results of dobutamine testing. Stress testing can be done 
cautiously in patients in whom the aortic stenosis severity 
does not match the reported symptoms in order to confirm 
the reported clinical status. It should 
not
 be done in patients 
with super-severe aortic stenosis.
 
»
Table 10–4 outlines the 2014 guidelines for surgical inter
-
vention in aortic stenosis. Valve intervention is warranted 
in all patients who have 
symptomatic severe aortic stenosis.
 
There are also times when asymptomatic aortic stenosis 
should undergo intervention. 
Asymptomatic patients 
with severe aortic stenosis
 (aortic valve area less than 1.0 cm
2
) 
should generally undergo intervention according to the 
following guidelines: (1) they are undergoing other cardiac 
surgery (ie, CABG), (2) there is evidence for a reduced 
LVEF (less than 50%), (3) when the mean gradient exceeds 
55 mm Hg (peak velocity greater than 5 m/sec), (4) when 
there is failure of the BP to rise more than 20 mm Hg 
Table 10–4.
 
2014 AHA/ACC guidelines for surgical indications in aortic stenosis.
Recommendations
COR
LOE
AVR is recommended in symptomatic patients with severe AS (stage D)
I
B
AVR is recommended for asymptomatic patients with severe AS (stage C2 or D) and LVEF < 50%
I
B
AVR is indicated for patients with severe AS (stage C or D) when undergoing other cardiac surgery
I
B

I
B
I
B
I
B
AVR is reasonable for asymptomatic patients with very severe AS (aortic velocity ≥ 5 m/s) (stage C2) 
 
and low surgical risk
IIa
B
AVR is reasonable in asymptomatic patients (stage C1) with severe AS and an abnormal exercise test
IIa
B
AVR is reasonable in symptomatic patients with low-flow/low-gradient severe AS with reduced LVEF 
(stage S1) with a low-dose dobutamine stress study that shows an aortic velocity ≥ 4 m/s (or mean 
gradient ≥ 40 mm Hg) with a valve area ≤ 1.0 cm
2
 at any dobutamine dose
IIa
B
AVR is reasonable for patients with moderate AS (stage B) (velocity 3.0–3.9 m/s) who are undergoing 
other cardiac surgery
IIa
C
AVR may be considered for asymptomatic patients with severe AS (stage C1) and rapid disease 
 
progression and low surgical risk
IIb
C
AVR may be considered in symptomatic patients who have low-flow/low-gradient severe AS (stage S2) 
who are normotensive and have an LVEF ≥ 50% if clinical, hemodynamic, and anatomic data support 
valve obstruction as the most likely cause of symptoms
IIb
C
AS, aortic stenosis; AVR, aortic valve replacement; COR, class of recommendation; LOE, level of evidence; LVEF, left ventricular ejection fraction.
Reproduced, with permission, from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart 
Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 
 
2014 Jun 10;129(23):e521–643. © 2014 American Heart Association, Inc.
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with exercise, (5) when there is severe valvular calcium, or 
(6) when there is evidence of a rapid increase in the peak 
aortic gradient (more than 0.3 m/sec/year). Following the 
onset of heart failure, angina, or syncope, the prognosis 
without surgery is poor (50% 3-year mortality rate). Medi
-
cal treatment may stabilize patients in heart failure, but 
intervention is indicated for all symptomatic patients with 
evidence of significant aortic stenosis.
The surgical mortality rate for valve replacement is low, 
even in older adults, and ranges from 2% to 5%. This low 
risk is due to the dramatic hemodynamic improvement 
that occurs with relief of the increased afterload. Mortality 
rates are substantially higher when there is an associated 
ischemic cardiomyopathy. Severe coronary lesions are usu
-
ally bypassed at the same time as aortic valve replacement 
(AVR), although there are few data to suggest this practice 
affects outcome. In some cases, a staged procedure with 
stenting of the coronaries prior to surgery may be consid
-
ered, especially if a percutaneous AVR approach is being 
considered. Around one-third to one-half of all patients 
with aortic stenosis have significant CAD, so this is a com
-
mon concern. With the success of 
transcatheter aortic 
valve replacement (TAVR)
 the treatment options have 
greatly expanded for many patients with severe aortic ste
-
nosis. For this reason, a 
Heart Valve Team
 approach bring
-
ing together invasive and noninvasive cardiologists, 
radiologists, anesthesiologists, and cardiac surgeons is 
mandatory; clinical factors (such as frailty) and anatomic 
features (such as a calcified aorta, vascular access, etc) can 
affect the decision making.
Medical therapy to reduce the progression of disease 
has 
not
 been effective to date. Statins have been assessed in 
four major clinical trials. None revealed any benefit on the 
the progression of aortic stenosis or on clinical outcomes 
despite the association of aortic stenosis with atherosclero
-
sis. If patients with aortic stenosis have concomitant CAD, 
the guidelines for the use of statins should be followed. 
Efforts to reduce stenosis progression by blockage of the 
renin-angiotensin system have also been ineffective. Con
-
trol of systemic hypertension, though, is an important 
adjunct, and inadequate systemic BP control is all too com
-
mon due to unreasonable concerns about providing too 
much afterload reduction in patients with aortic stenosis. 
Normal systemic BP is important to maintain as the LV is 
affected by the total afterload (systemic BP plus the aortic 
valve gradient).
The interventional options in patients with aortic valve 
stenosis has expanded with the use of TAVR and depend 
on the patient’s lifestyle and age. The algorithm to decide 
when an AVR is appropriate in various situations is out
-
lined in Figure 10–3. The 2017 ACC/AHA valvular guide
-
lines modify this only in that surgical AVR can be 
considered for any of the indications outlined in the figure, 
whether asymptomatic or not. TAVR should be reserved 
only for those patients with symptoms. These newest 
guidelines point out that TAVR is equivalent to surgical 
AVR in all of the randomized trials of symptomatic 
patients. As of 2017, TAVR for tricuspid valve aortic steno
-
sis can be applied to all except the lowest risk (less than 
4%). The lowest risk patients are being studied in trials 
randomizing between TAVR and surgical AVR.
In young and adolescent patients, percutaneous balloon 
valvuloplasty still has a small role. Balloon valvuloplasty is 
associated with early restenosis in the elderly population, 
and thus is rarely used except as a temporizing measure. 
Data suggest aortic balloon valvuloplasty in elderly people 
has an advantage only in those with preserved LV function, 
and such patients are usually excellent candidates for surgi
-
cal AVR. Middle-aged adults generally can tolerate the

-
cal AVR. Middle-aged adults generally can tolerate the 
anticoagulation therapy necessary for the use of mechani
-
cal aortic valves, so patients younger than 60 years gener
-
ally undergo AVR with a bileaflet mechanical valve. If the 
aortic root is severely dilated as well (greater than 4.5 cm), 
then the valve may be housed in a Dacron sheath (Bentall 
procedure) and the root replaced along with the aortic 
valve. Alternatively, a human homograft root and valve 
replacement can be used. In patients older than 60 years, 
bioprosthetic (either porcine or bovine pericardial) valves 
with a life expectancy of about 10–15 years are routinely 
used instead of mechanical valves to avoid need for antico
-
agulation. Data favor the bovine pericardial valve over the 
porcine aortic valve. As it is becoming clearer that biopros
-
thetic valve degeneration in the larger valves can be poten
-
tially repaired by percutaneous valve-in-valve TAVR, it is 
likely that the use of mechanical valves will continue to 
decline. If the aortic annulus is small, a bioprosthetic valve 
with a short sheath can be sewn to the aortic wall (the 
stentless AVR) rather than sewing the prosthetic annulus 
to the aortic annulus. (Annulus is a relative term when 
speaking of the aortic valve, since there is no true annulus.) 
Another popular surgical option when the aorta is enlarged 
is the use of the Wheat procedure; it involves aortic root 
replacement above the coronary arteries and replacement 
of the aortic valve below the coronary arteries. The coro
-
nary arteries thus remain attached to the native aorta 
between the new graft and prosthetic valve rather than 
being reimplanted onto an artificial sheath or homograft.
In patients with a bicuspid aortic valve, there is an asso
-
ciated ascending aortic aneurysm in about half. If the 
maximal dimension of the aortic root is greater than 5.5 cm, 
it is recommended to proceed with root replacement 
regardless of the severity of the aortic valve disease. It is 
also appropriate to intervene when the maximal aortic root 
size is greater than 5.0 cm in diameter if there is a family 
history of aortic dissection or the aortic root size increases 
by more than 0.5 cm in 1 year. The aortic valve may be 
replaced at the same time if at least moderate aortic steno
-
sis is present or may be either left alone or repaired (valve 
sparing operation). If there is an indication for AVR and 
the root is greater than 4.5 cm in diameter, root replace
-
ment is also recommended.
The use of mechanical versus bioprosthetic AVR has 
changed over time. A bioprosthetic valve is acceptable for 
patients at any age for whom anticoagulant therapy is con
-
traindicated, not desired, or cannot be managed, and is 
preferred in patients over the age of 70. An aortic mechani
-
cal valve should be used in patients younger than 50 years 
of age who can take warfarin (this recommendation is a 
decrease from age 60 in the recent updated guidelines). 
Either type of valve is acceptable between the ages of 50 
and 70 years depending on patient preference and any 
issues with warfarin usage.
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Anticoagulation
 is required with the use of mechanical 
aortic valves, and the international normalized ratio (INR) 
should be maintained between 2.0 and 3.0 for bileaflet 
valves. In general, mechanical aortic valves are less subject to 
thrombosis than mechanical mitral valves and do not need 
bridging with anticoagulation unless there are other throm
-
boembolic risk factors or there is an older generation AVR. 
Low-dose aspirin is recommended as well. Some newer 
bileaflet mechanical valves (On-X) allow for a lower INR 
range from 1.5 to 2.0. Clopidogrel is recommended for the 
first 6 months after TAVR in combination with lifelong aspi
-
rin therapy. DOACs are not recommended for any mechani
-
cal valves but may be used in patients with a bioprosthetic 
AVR if treating atrial fibrillation or venous thrombosis.
The estimated use of TAVR has grown dramatically, 
with over 300,000 implants worldwide reported by 2017. In 
the United States, the Food and Drug Administration 
(FDA) has granted approval for two devices, the Edwards 
SAPIEN and the Medtronic CoreValve, for use in patients 
with at least a 4% surgical risk (intermediate risk) as mea
-
sured by the Society of Thoracic Surgeons. These devices 
are fundamentally stents with a trileaflet bioprosthetic valve 
constructed within them. There are a variety of implanta
-
tion approaches, though most valves are placed via a femo
-
ral artery approach. Other options include an antegrade 
approach via transseptal across the atrial septum, via the LV 
apex with a small surgical incision, via the subclavian arter
-
ies, via the carotid, or via a minithoracotomy. The Edwards 
SAPIEN valve is a balloon-expandable valvular stent, while 
the CoreValve is a valvular stent that self-expands when 
pushed out of the catheter sheath. Multiple other devices are 
in trials, many with excellent early results. These devices 
will allow for a wider range of aortic valve sizes to be 
treated; can be delivered with smaller catheters, eliminating 
Abnormal aortic 
va
lve with
reduced 
sy
stolic opening
V
max
 
≥ 
4 m/s
∆
P
mean
 
≥ 
40 mm Hg
(stage D)
(stage C)
(stage B)
Other cardiac
surgery
AS
 likely cause
of symptoms
LVEF < 50%
(stage C2)
surgery
Abnormal ETT
V
max
 
≥ 
5 m/s
∆
P
mean
 
≥ 
60 mm Hg
Lo
w-
surgical risk
∆
V
max
 > 0.3 m/s/y
AVR (I)
AVR (IIa)
AVR (IIb)
Pe
LVEF < 50%
V
max
 3 m/s–3.9 m/s
∆
P
mean
 20–39 mm Hg
Stage S2*
AV
A 
≤ 
1 .0 cm
2
 and
LVEF
 
≥ 
50%
V
max
 < 3 m/s
∆
P
mean
 < 30 mm Hg
Class I
Class IIa
Class IIb
Ye
s
No
Ye
s
No
Stage S1: DSE with
AV
A 
≤ 
1.
0 cm
2
 and
V
max
  
≥ 
4.0 m/s
*AVR should be considered with stage S2 
AS
 only if 
va
lv
e obstruction is the most li
kely
 cause of 
sy
mp
to
ms, stroke
volume index is < 35 mL/m
2
, indexed 
AV
A is 
≤ 
0.6 cm
2
/m
2
, and data are recorded when the patient is normotensive (
systo
lic
BP < 140 mm Hg).
AS
, aortic stenosis; 
AV
A, aortic 
va
lv
e area;
 A
VR, aortic 
va
lv
e replacement; BP , blood pressure; DSE, do
bu
tamine
stress echocar
diograph
y; ETT, 
exe
rcise treadmill test; LVEF , left ventricular ejection fraction
; 
∆
P
mean
e gradient
;
V
max
, maximum velocit
y.
 
▲
Figure 10–3.
 
Algorithm for the management of aortic valve stenosis. 
Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of 
the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 10; 
129(23):e521–643. © 2014 American Heart Association, Inc.)
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Babaliarois V . Innovation in intervention: transcatheter aortic 
valve replacement focus issue. JACC Cardiol Interv. 2015 
 
Apr 27;8(5):758–9. [PMID: 25946454]
Bonow RO et al. 2017 appropriate use criteria for the treatment of 
patients with severe aortic stenosis: a report of the American 
College of Cardiology Appropriate Use Criteria Task Force, 
American Association for Thoracic Surgery, American Heart 
Association, American Society of Echocardiography, European 
Association for Cardio-Thoracic Surgery, Heart Valve Society, 
Society of Cardiovascular Anesthesiologists, Society for Car
-
diovascular Angiography and Interventions, Society of Cardio
-
vascular Computed Tomography, Society for Cardiovascular 
Magnetic Resonance, and Society of Thoracic Surgeons. J Am 
Coll Cardiol. 2017 Nov 14;70(20):2566–98. [PMID: 29054308]
Hakeem A et al. Outcomes of TAVR in bicuspid aortic valve 
stenosis. J Am Coll Cardiol. 2017 Sep 26;70(13):1684–5. 
[PMID: 28935046]
Moat NE. Will TAVR become the predominant method for 
treating severe aortic stenosis? N Engl J Med. 2016 Apr 28;
 
374(17):1682–3. [PMID: 27040006]
-
-
-
-
24603192]
-
Otto CM et al. 2017 ACC expert consensus decision pathway for 
transcatheter aortic valve replacement in the management of 
adults with aortic stenosis: a report of the American College 
of Cardiology Task Force on Clinical Expert Consensus 
Documents. J Am Coll Cardiol. 2017 Mar 14;69(10):1313–46. 
[PMID: 28063810]
Vahl TP et al. Transcatheter aortic valve replacement 2016: a 
modern day “through the looking-glass” adventure. J Am Coll 
Cardiol. 2016 Mar 29;67(12):1472–87. [PMID: 27012409]
the need for femoral artery cutdowns; will allow for reposi
-
tioning before permanent implantation; and appear to 
result in less paravalvular regurgitation and less injury to 
the conduction system. Cost remains a major issue. All of 
the professional societies stress the importance of a Heart 
Valve Team when considering aortic stenosis intervention. 
This is critically important because many patients referred 
for TAVR have serious comorbid conditions that will not 
improve with alleviation of the aortic stenosis. A 2017 con
-
sensus document from the ACC provides a decision path
-
way for the use of TAVR. This document summarizes 
background information and provides a checklist of items 
to consider when deciding between surgical AVR and 
TAVR. The importance of quality of life and frailty is 
emphasized because some of the most elderly or most 
debilitated patients may not benefit from any procedure.
Figure 10–4 outlines the suggested indications for 
TAVR based on the 2017 updated AHA/ACC guidelines.
TAVR is also being used more frequently in “valve-in-
valve” procedures to reduce the gradient in patients with 
prosthetic valve dysfunction (regardless of whether in the 
aortic, mitral, tricuspid, or pulmonary position). While the 
results of TAVR in patients with bicuspid aortic valves (as 
opposed to tricuspid) have been less impressive, newer 
modifications have improved the success rates in these 
anatomic situations as well.
 
»
•	
All patients with echocardiographic evidence for mild-
to-moderate aortic stenosis (estimated peak valve gra
-
dient greater than 30 mm Hg by echocardiography/

»
•	
-
Doppler) should be referred to a cardiologist for evalu
-
ation and to determine the frequency of follow-up.
•	
Any patients with symptoms suggestive of aortic stenosis 
(ie, exertional symptoms of chest pressure, shortness of 
breath, or presyncope) should be seen by a cardiologist.
AS, aortic stenosis; AVR, aortic valve replacement; TAVR, transcatheter aortic valve replacement.
Surgical AVR
 (Class I) 
Severe AS
(stage D)
Intermediate surgical
risk
(Class I) 
TAVR
(Class IIa)
Surgical AVR or TAVR
(Class I) 
TAVR
 (Class I) 
Low surgical
risk
High surgical
risk
Prohibitive surgical
risk
Class I
Class IIa
 
▲
Figure 10–4.
 
Choice of TAVR versus surgical AVR in patients with severe symptomatic AS. 
(Reproduced, with per
-
mission, from Nishimura RA et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of 
patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task 
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AORTIC REGURGITATION
 
»
Usually asymptomatic until middle age; presents 
with left-sided failure or rarely chest pain.
 
»
 
»
Surgery for symptoms, EF less than 50%, LV end-
systolic dimension greater than 50 mm or LV end-
diastolic dimension greater than 65 mm.
 
»
Of all patients with isolated aortic valve disease, about 13% 
have predominately aortic regurgitation. Rheumatic aortic 
regurgitation has become much less common than in the 
preantibiotic era, and nonrheumatic causes now predomi
-
nate. These include congenitally bicuspid valves, infective 
endocarditis, and hypertension. Many patients also have 
aortic regurgitation secondary to aortic root diseases, such 
as that associated with Marfan syndrome or aortic dissec
-
tion. Rarely, inflammatory diseases, such as ankylosing 
spondylitis, may be implicated.
 
»
The clinical presentation is determined by the rapidity with 
which regurgitation develops. In 
chronic aortic regurgita
-
tion,
 the only sign for many years may be a soft aortic 
diastolic murmur. As the severity of the aortic regurgita
-
tion increases, diastolic BP falls, and the LV progressively 
enlarges. Most patients remain asymptomatic for long 
periods even at this point. LV failure is a late event and may 
be sudden in onset. Exertional dyspnea and fatigue are the 
most frequent symptoms, but paroxysmal nocturnal dys
-
pnea and pulmonary edema may also occur. Angina pecto
-
ris or atypical chest pain may occasionally be present. 
Associated CAD and presyncope or syncope are less com
-
mon than in aortic stenosis.
Hemodynamically, because of compensatory LV dila
-
tion, patients eject a large stroke volume, which is adequate 
to maintain forward cardiac output until late in the course 
of the disease. LV diastolic pressure may rise when heart 
failure occurs. Abnormal LV systolic function (as mani
-
fested by reduced EF less than 50%) and increasing end-
systolic LV volume (greater than 5.0 cm) are signs that 
surgical intervention is warranted.
The major physical findings in chronic aortic regurgita
-
tion relate to the high stroke volume being ejected into the 
systemic vascular system with rapid runoff as the regurgi
-
tation takes place (see Table 10–1). This results in a 
wide 
arterial pulse pressure.
 The pulse has a rapid rise and fall 
(
water-hammer pulse
 or 
Corrigan pulse
), with an ele
-
vated systolic and low diastolic pressure. The large stroke 
volume and flow back into the heart are also responsible 
for characteristic findings, such as 
Quincke pulses
 (nailbed 
capillary pulsations), 
Duroziez sign
 (to-and-fro murmur 
over a partially compressed femoral peripheral artery), and 
Musset sign
 (head bob with each pulse). In younger 
patients, the increased stroke volume may summate with 
the pressure wave reflected from the periphery and create 
a higher than expected systolic pressure in the lower 
extremities compared with the central aorta. Since the 
peripheral bed is much larger in the leg than the arm, the 
BP in the leg may be over 40 mm Hg higher than in the arm 
(
Hill sign
) in severe aortic regurgitation. The apical 
impulse is prominent, laterally displaced, usually hyperdy
-
namic, and may be sustained. A systolic flow murmur is 
usually present and may be quite soft and localized; the 
aortic diastolic murmur is usually high-pitched and decre
-
scendo. A mid or late diastolic low-pitched mitral murmur 
(
Austin Flint murmur
) may be heard in advanced aortic 
regurgitation, owing to relative obstruction of mitral 
inflow produced by partial closure of the mitral valve by 
the rapidly rising LV diastolic pressure due to the aortic 
In acute aortic regurgitation (usually from aortic dis
-
section or infective endocarditis), LV failure is manifested

-
section or infective endocarditis), LV failure is manifested 
primarily as pulmonary edema and may develop rapidly; 
surgery is urgently required in such cases. Patients with 
acute aortic regurgitation do not have the dilated LV of 
chronic aortic regurgitation and the extra LV volume is 
handled poorly. For the same reason, the diastolic mur
-
mur is shorter, may be minimal in intensity, and the pulse 
pressure may not be widened—making clinical diagnosis 
difficult. The mitral valve may close prematurely even 
before LV systole has been initiated (
preclosure
) due to 
the rapid rise in the LV diastolic pressure, and the first 
heart sound is thus diminished or inaudible. Preclosure of 
the mitral valve can be readily detected on echocardiogra
-
phy and is considered an indication for urgent surgical 
intervention.
The ECG usually shows moderate to severe LVH. Radio
-
graphs show cardiomegaly with LV prominence and some
-
times a dilated aorta.
Echocardiography demonstrates the major diagnostic 
features, including whether the lesion includes the proxi
-
mal aortic root and what valvular pathology is present. 
Annual assessments of LV size and function are critical in 
determining the timing for valve replacement when the 
aortic regurgitation is severe. The 2014 AHA/ACC valvular 
guideline provides criteria for assessing the severity of aor
-
tic regurgitation. Cardiac MRI and CT can estimate aortic 
root size, particularly when there is concern for an ascend
-
ing aneurysm. MRI can provide a regurgitant fraction to 
help confirm severity. Cardiac catheterization may be 
unnecessary in younger patients, particularly those with 
acute aortic regurgitation, but can help define hemody
-
namics, aortic root abnormalities, and associated CAD 
preoperatively in older patients. Increasing data are emerg
-
ing that serum BNP or NT-proBNP may be an early sign of 
LV dysfunction, and it is possible that these data will be 
added to recommendations for surgical intervention in the 
future.
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»
Aortic regurgitation that appears or worsens during or 
after an episode of infective endocarditis or aortic dissec
-
tion may lead to acute severe LV failure or subacute pro
-
gression over weeks or months. The former usually 
presents as pulmonary edema; surgical replacement of the 
valve is indicated even during active infection. These 
patients may be transiently improved or stabilized by 
vasodilators.
Chronic aortic regurgitation may be tolerated for 
many years, but the prognosis without surgery becomes 
poor when symptoms occur. Since aortic regurgitation 
places both a preload (volume) and afterload increase on 
the LV , medications that decrease afterload can reduce 
regurgitation severity, although there are no convincing 
data that afterload reduction alters mortality. 
Recom
-
mendations advocate afterload reduction in aortic 
regurgitation only when there is associated systolic 
hypertension (systolic BP greater than 140 mm Hg).
 
Afterload reduction in normotensive patients does not 
appear warranted. Angiotensin receptor blockers (ARBs), 
rather than beta-blockers, are the preferred additions to 
the medical therapy in patients with an enlarged aorta, 
such as in Marfan syndrome, because of the theoretical 
ability of an ARB to reduce aortic stiffness (by blocking 
TGF-beta) and to slow the rate of aortic dilation. How
-
ever, clinical trials evaluating the efficacy of ARBs to 
reduce aortic stiffness and slow the rate of aortic dilation 
have not yielded a positive outcome to support their use 
Surgery is indicated once symptoms emerge or for any 
evidence of LV dysfunction (as exhibited by a reduction in 
the LVEF or increase in the LV end-systolic diameter). In 
addition, it is suggested that surgery should be considered 
when the LV becomes excessively enlarged (LV end-
diastolic diameter greater than 65 mm) (Table 10–5).
The issues with AVR covered in the above section con
-
cerning aortic stenosis pertain here. There are no percuta
-
neous approaches that specifically address aortic 
regurgitation, especially when the cause is an enlarged 
aortic root. TAVR results have been much more mixed 
when the percutaneous replacement has been used for 
primarily aortic regurgitation compared to TAVR used for 
aortic stenosis, though newer designed TAVR devices are 
being assessed to address the issue of aortic regurgitation 
in patients with native valve disease. Aortic regurgitation 
due to a paravalvular prosthetic valve defect can occasion
-
ally be occluded with percutaneous occluder devices. The 
choice of prosthetic valve for AVR depends on the patient’s 
age and compatibility with warfarin anticoagulation simi
-
lar to the choices for AVR in aortic stenosis.
The operative mortality for AVR is usually in the 3–5% 
range. Aortic regurgitation due to aortic root disease 
requires repair or replacement of the root as well as surgi
-
cal treatment of the aortic valve. Though valve-sparing 
operations have improved recently, most patients with 
root replacement undergo valve replacement at the same 
time. Root replacement in association with valve replace
-
ment may require reanastomosis of the coronary arteries, 
and thus the procedure is more complex than valve 
replacement alone. The Wheat procedure replaces the 
aortic root but spares the area where the coronaries attach 
to avoid the necessity for their reimplantation. Following 
any aortic valve surgery, LV size usually decreases and LV 
function generally improves even when the baseline EF is 
depressed.
The AHA/ACC 2014 valvular guidelines and a 2015 
consensus document recommend the “cutoff ” diameter 
that indicates repair of the aortic root in patients with a 
bicuspid valve should be 5.5 cm regardless of aortic valve 
disease severity. There are data that dissection is much 
more prevalent when the aortic root diameter exceeds 6.0

more prevalent when the aortic root diameter exceeds 6.0 
cm, and the general sense is not to let it approach that size. 
Patients with risk factors (family history of dissection or 
an increase in the diameter of the root greater than 0.5 cm 
in 1 year) should have the aorta repaired when the maxi
-
mal dimension exceeds 5.0 cm. The following classifica
-
tions summarize when to operate on the aortic root in 
patients with a bicuspid aortic valve based on the 
guidelines:
Class I
 indication (LOE C): aortic root diameter at 
sinuses or ascending aorta greater than 5.5 cm 
(regardless of need for AVR).
Class IIa
sinuses or ascending aorta greater than 5.0 cm when 
there are associated risk factors (family history of 
dissection or increase in size more than 0.5 cm in 
1 year).
Class IIa
 indication (LOE C): aortic root diameter 
greater than 4.5 cm if patient undergoing AVR for 
valvular reasons.
 
»
•	
Patients with audible aortic regurgitation should be 
seen, at least initially, by a cardiologist who can deter
-
mine whether the patient needs follow-up.
•	
Patients with a dilated aortic root should be monitored 
by a cardiologist, since imaging studies other than the 
chest radiograph or echocardiogram may be required to 
decide surgical timing.
Table 10–5.
 
When to operate in chronic severe aortic 
regurgitation (AR).
Indication for Surgery
Class and Level of 
 
Evidence (LOE)
Class I LOE B
 
Abnormal 
LVEF < 50%
 
Under
going other heart surgery
Class I LOE C
 
Normal 
LVEF, but LVESD > 50 mm
Class IIa LOE B
 
M
oderate AR and other heart surgery
Class IIa LOE C
 
Normal 
LVEF, but LVEDD > 65 mm
Class IIb LOE C
LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-
diastolic dimension; LVESD, left ventricular end-systolic dimension.
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Franzone A et al. Transcatheter aortic valve replacement for the 
treatment of pure native aortic valve regurgitation: a system
-
atic review. JACC Cardiovasc Interv. 2016 Nov 28;9(22):
 
2308–17. [PMID: 28026742]
Hiratzka LF et al. Surgery for aortic dilatation in patients with 
bicuspid aortic valves: a statement of clarification from the 
American College of Cardiology/American Heart Associa
-
tion Task Force on Clinical Practice Guidelines. J Am Coll 
Cardiol. 2016 Feb 16;67(6):724–31. [PMID: 26658475]
-
-
-
-
24603192]
-
TRICUSPID STENOSIS
 
»
Female predominance.
 
»
History of rheumatic heart disease most likely. 
Carcinoid disease and prosthetic valve degenera
-
tion are the most common etiologies in the 
 
United States.
 
»
 
»
Tricupsid stenosis is rare, affecting less than 1% of the 
population in developed countries and less than 3% world
-
wide. Native valve tricuspid valve stenosis is usually rheu
-
matic in origin. In the United States, tricuspid stenosis is 
more commonly due to prior tricuspid valve repair or 
replacement or to the carcinoid syndrome. Tricuspid 
regurgitation frequently accompanies the lesion. It should 
be suspected when right heart failure appears in the course 
of mitral valve disease or in the postoperative period after 
tricuspid valve repair or replacement. Congenital forms of 
tricuspid stenosis may also be rarely observed, as have case 
reports of multiple pacemaker leads creating RV inflow 
obstruction at the tricuspid valve.
 
»
Tricuspid stenosis is characterized by right heart failure 
with hepatomegaly, ascites, and dependent edema. In sinus 
rhythm, a giant 
a
 wave is seen in the JVP , which is also 
elevated (see Table 10–1). The typical diastolic rumble 
along the lower left sternal border mimics mitral stenosis, 
though in tricuspid stenosis the rumble increases with 
inspiration. In sinus rhythm, a presystolic liver pulsation 
may be found. It should be considered when patients 
exhibit signs of carcinoid syndrome.
In the absence of atrial fibrillation, the ECG reveals RA 
enlargement. The chest radiograph may show marked car
-
diomegaly with a normal PA size. A dilated superior vena 
cava and azygous vein may be evident.
The normal valve area of the tricuspid valve is 10 cm
2
, so 
significant stenosis must be present to produce a gradient. 
Hemodynamically, a mean diastolic pressure gradient 
greater than 5 mm Hg is considered significant, although 
even a 2 mm Hg gradient can be considered abnormal. This 
can be demonstrated by echocardiography or cardiac cathe
-
terization. The 2014 AHA/ACC guidelines suggest a tricus
-
pid valve area of less than 1.0 cm
2
 and a pressure half-time 
longer than 190 msec should be considered significant.
 
»
Tricuspid stenosis may be progressive, eventually causing 
severe right-sided heart failure. Initial therapy is directed at 
reducing the fluid congestion, with diuretics the mainstay 
(see Treatment, Heart Failure). When there is considerable 
bowel edema, torsemide or bumetanide may have an 
advantage over other loop diuretics, such as furosemide,

advantage over other loop diuretics, such as furosemide, 
because they are better absorbed from the gut. Aldosterone 
inhibitors also help, particularly if there is liver engorge
-
ment or ascites. Neither surgical nor percutaneous valvulo
-
plasty is particularly effective for relief of tricuspid stenosis, 
as residual tricuspid regurgitation is common. Tricuspid 
valve replacement is the preferred surgical approach. 
Mechanical tricuspid valve replacement is rarely done 
because the low flow predisposes to thrombosis and 
because the mechanical valve cannot be crossed should the 
need arise for right heart catheterization or pacemaker 
implantation. Therefore, bioprosthetic valves are almost 
always preferred. Often tricuspid valve replacement is per
-
formed in conjunction with mitral valve replacement for 
rheumatic mitral stenosis or regurgitation. Percutaneous 
transcatheter valve replacement (stented valve) has been 
used in degenerative prosthetic valve stenosis and a percu
-
taneous tricuspid valve replacement device is being inves
-
tigated. The indications for valve replacement in severe 
tricuspid stenosis are straightforward:
Class I
 indication (LOE C): at time of operation for left-
sided valve disease.
Class I
 indication (LOE C): if symptomatic.
Class IIb
 indication (LOE C): rarely percutaneous bal
-
loon commissurotomy for isolated tricuspid steno
-
sis in high-risk patients with no significant tricuspid 
 
»
All patients with any evidence for tricuspid stenosis on an 
echocardiogram should be seen and monitored by a cardi
-
ologist to assess when intervention may be required.
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Al-Hijii M et al. The forgotten valve: isolated severe tricuspid 
valve stenosis. Circulation. 2015 Aug 18;132(7):e123–5. 
[PMID: 26283605]
Cevasco M et al. Surgical management of tricuspid stenosis. Ann 
Cardiothorac Surg. 2017 May;6(3):275–82. [PMID: 28706872]
TRICUSPID REGURGITATION
 
»
Frequently occurs in patients with pulmonary or 
cardiac disease with pressure or volume overload 
on the right ventricle.
 
»
Tricuspid valve regurgitation from pacemaker lead 
placement is becoming more common.
 
»
Echocardiography useful in determining cause 
(low- or high-pressure tricuspid regurgitation).
 
»
Tricuspid valvular regurgitation often occurs whenever 
there is RV dilation from any cause. As tricuspid regurgita
-
tion increases, the RV size increases further pulling the valve 
open due to chordal and papillary muscle displacement. 
This, in turn, worsens the severity of the tricuspid regurgita
-
tion. In most cases, the cause of the tricuspid regurgitation is 
the RV geometry (functional) and not primary tricuspid 
valve disease. An enlarged, dilated RV may be present if 
there is RV systolic hypertension from valvular or subvalvu
-
lar pulmonary valve stenosis, pulmonary hypertension for 
any reason, in severe pulmonary valve regurgitation, or in 
cardiomyopathy. The RV may also be injured from myocar
-
dial infarction or may be inherently dilated due to infiltrative 
diseases (RV dysplasia or sarcoidosis). RV dilation often 
occurs secondary to left heart failure. Inherent abnormalities 
of the tricuspid valve include Ebstein anomaly (displace
-
ment of the septal and posterior, but not the anterior, leaflets 
into the RV), tricuspid valve prolapse, carcinoid plaque for
-
mation, collagen disease inflammation, valvular tumors, or 
tricuspid endocarditis. In addition, pacemaker lead valvular 
injury is becoming an increasingly frequent iatrogenic cause.
 
»
The symptoms and signs of tricuspid regurgitation are 
identical to those resulting from RV failure due to any 
cause. As a generality, the diagnosis can be made by careful 
inspection of the JVP . The JVP waveform should decline 
during ventricular systole (the 
x
 descent). The timing of 
this decline can be observed by palpating the opposite 
carotid artery. As tricuspid regurgitation worsens, more 
and more of this 
x
 descent valley in the JVP is filled with 
the regurgitant wave until all of the 
x
 descent is obliterated 
and a positive systolic waveform will be noted in the JVP . 
An associated tricuspid regurgitation murmur may or may 
not be audible and can be distinguished from mitral regur
-
gitation by the left parasternal location and an increase 
with inspiration (Carvallo sign). An S
3
 may accompany the 
murmur and is related to the high flow returning to the RV 
from the RA. Cyanosis may be present if the increased RA 
pressure stretches the atrial septum and opens a PFO or 
there is a true ASD (eg, in about 50% of patients with 
Ebstein anomaly). Severe tricuspid regurgitation results in 
hepatomegaly, edema, and ascites.
The ECG is usually nonspecific, though atrial flutter or atrial 
fibrillation is common. The chest radiograph may reveal 
evidence of an enlarged RA or dilated azygous vein and 
pleural effusion. The echocardiogram helps assess severity of 
tricuspid regurgitation (see the 2014 AHA/ACC valvular 
heart disease guidelines for definitions). In addition, 
echocardiography/Doppler provides RV systolic pressure as 
well as RV size and function. A paradoxically moving inter
-
ventricular septum may be present due to the volume over
-
load on the RV . Catheterization confirms the presence of the 
regurgitant wave in the RA and elevated RA pressures. If the 
PA or RV systolic pressure is less than 40 mm Hg, primary 
valvular tricuspid regurgitation should be suspected.
 
»

»
Mild tricuspid regurgitation is common and generally can 
be well managed with diuretics. When severe tricuspid 
regurgitation is present, bowel edema may reduce the 
effectiveness of diuretics, such as furosemide, and intrave
-
nous diuretics should be used initially. Torsemide or 
bumetanide is better absorbed in this situation when oral 
diuretics are added. Aldosterone antagonists have a role as 
well, particularly if ascites is present. At times, the efficacy 
of loop diuretics can be enhanced by adding a thiazide 
diuretic (see Treatment, Heart Failure). Aquapheresis has 
also been proven helpful to reduce the edema in marked 
right heart failure, although results have been inconsistent 
and worsening kidney function has often been noted using 
this method.
Since most tricuspid regurgitation is secondary, defini
-
tive treatment usually requires elimination of the cause of 
the RV dysfunction. If the problem is left heart disease, 
then treatment of the left heart issues may lower pulmo
-
nary pressures, reduce RV size, and resolve the tricuspid 
regurgitation. Treatment for primary and secondary causes 
of pulmonary hypertension will generally reduce the tri
-
cuspid regurgitation. It is a class I recommendation that 
tricuspid annuloplasty be performed when significant tri
-
cuspid regurgitation is present and mitral valve replace
-
ment or repair is being performed for mitral regurgitation. 
Annuloplasty without insertion of a prosthetic ring 
(DeVega annuloplasty) may also be effective in reducing 
the tricuspid annular dilation. The valve leaflet itself can 
occasionally be primarily repaired in tricuspid valve endo
-
carditis. If there is an inherent defect in the tricuspid valve 
apparatus that cannot be repaired, then replacement of the 
tricuspid valve is warranted. A bioprosthetic valve rather 
than a mechanical valve, is almost always used because the 
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risk of mechanical valve thrombosis is increased if the INR 
is not stable. Anticoagulation is not required for biopros
-
thetic valves unless there is associated atrial fibrillation or 
flutter. Tricuspid regurgitation due to bioprosthetic degen
-
eration has been shown to respond to transcatheter valve 
replacement. There are early reports of percutaneous tri
-
cuspid valve replacement for native valve tricuspid regur
-
gitation being successful, so this may emerge soon as a 
treatment option.
 
»
•	
Anyone with moderate or severe tricuspid regurgitation 
should be seen at least once by a cardiologist to deter
-
mine whether studies and intervention are needed.
•	
Severe tricuspid regurgitation requires regular follow-
up by a cardiologist.
Eicken A et al. Percutaneous tricuspid valve implantation: two 
center experience with mid-term results. Circ Cardiovasc 
Interv. 2015;8(4):e002155. [PMID: 25873731]
-
-
 
PULMONARY VALVE REGURGITATION
 
»
Most cases are due to pulmonary hypertension 
resulting in high-pressure pulmonary valve 
 
»
Echocardiogram is definitive in high-pressure, but 
may be less definitive in low-pressure pulmonary 
valve regurgitation.
 
»
Low-pressure pulmonary valve regurgitation is 
well tolerated.
 
»
Pulmonary valve regurgitation can be divided into 
high-
pressure causes
 (due to pulmonary hypertension) and 
low-pressure causes
 (usually due to a dilated pulmonary 
annulus, a congenitally abnormal [bicuspid or dysplastic] 
pulmonary valve, plaque from carcinoid disease, surgical 
pulmonary valve replacement, or the residual physiology 
following a surgical transannular patch used to reduce the 
outflow gradient in tetralogy of Fallot). Because the RV 
tolerates a volume load better than a pressure load, it tends 
to tolerate low-pressure pulmonary valve regurgitation for 
long periods of time without dysfunction.
 
»
Most patients are asymptomatic. Those with marked PR 
may exhibit symptoms of right heart volume overload. On 
examination, a hyperdynamic RV can usually be palpated 
(RV lift). If the PA is enlarged, it also may be palpated along 
the left sternal border. P
2
 will be palpable in pulmonary 
hypertension and both systolic and diastolic thrills are 
occasionally noted. On auscultation, the second heart 
sound may be widely split due to prolonged RV systole or 
an associated right bundle branch block. A pulmonary 
valve systolic click may be noted as well as a right-sided 
gallop. If pulmonic stenosis is also present, the ejection 
click may decline with inspiration, while any associated 
systolic pulmonary murmur will increase. In high-pressure 
pulmonary valve regurgitation, the pulmonary diastolic 
(
Graham Steell
) murmur is readily audible. It is often 
contributed to by a dilated pulmonary annulus. The mur
-
mur increases with inspiration and diminishes with the 
Valsalva maneuver. In low-pressure pulmonary valve 
regurgitation, the PA diastolic pressure may be only a few 
mm Hg higher than the RV diastolic pressure, and there is 
little diastolic gradient to produce a murmur or character
-
istic echocardiography/Doppler findings. At times, only 
contrast angiography or MRI of the main PA will show the 
free-flowing pulmonary valve regurgitation in low-
pressure pulmonary valve regurgitation. This situation is

pressure pulmonary valve regurgitation. This situation is 
common in patients following repair of tetralogy of Fallot 
where, despite little murmur, there may effectively be no 
pulmonary valve present. This can be suspected by noting 
an enlarging right ventricle.
The ECG is generally of little value, although right 
bundle branch block is common, and there may be ECG 
criteria for RVH. The chest radiograph may show only the 
enlarged RV and PA. Echocardiography may demonstrate 
evidence of RV volume overload (paradoxic septal motion 
and an enlarged RV), and Doppler can determine peak 
systolic RV pressure and reveal any associated tricuspid 
regurgitation. The interventricular septum may appear 
flattened if there is pulmonary hypertension. The size of 
the main PA can be determined and color flow Doppler 
can demonstrate the pulmonary valve regurgitation, par
-
ticularly in the high-pressure situation. Cardiac MRI and 
CT can be useful for assessing the size of the PA, for esti
-
mating regurgitant flow, for excluding other causes of pul
-
monary hypertension (eg, thromboembolic disease, 
peripheral PA stenosis), and for evaluating RV function. 
Cardiac catheterization is confirmatory only.
 
»
Pulmonary valve regurgitation rarely needs specific ther
-
apy other than treatment of the primary cause. In low-
pressure pulmonary valve regurgitation due to surgical 
transannular patch repair of tetralogy of Fallot, pulmonary 
valve replacement may be indicated if RV enlargement or 
dysfunction is present. In tetralogy of Fallot, the QRS will 
widen as RV function declines (a QRS greater than 180 msec 
suggests a higher risk for sudden death) and increasing RV 
volumes should trigger an evaluation for potential severe 
pulmonary valve regurgitation. In carcinoid heart disease, 
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pulmonary valve replacement with a porcine bioprosthesis 
may be undertaken, though the plaque from this disorder 
eventually coats the prosthetic pulmonary valve, which 
tends to limit the life span of these valves. In high-pressure 
pulmonary valve regurgitation, treatment to control the 
cause of the pulmonary hypertension is key. High-pressure 
pulmonary valve regurgitation is poorly tolerated and is a 
serious condition that needs a thorough evaluation for 
cause and choice of therapy. Pulmonary valve replacement 
requires a bioprosthetic valve in most cases. Pulmonary 
valve regurgitation due to an RV to PA conduit or due to a 
pulmonary autograft replacement as part of the Ross pro
-
cedure can be repaired with a percutaneous pulmonary 
valve (Melody valve). Bioprosthetic pulmonary valve 
regurgitation has also been treated using a percutaneous 
valve (Edwards Sapien).
 
»
Patients with pulmonary valve regurgitation that results in 
RV enlargement should be referred to a cardiologist regard
-
less of the estimated pulmonary pressures.
25896865]
pulmonary valve implantation with Melody and Sapien 
Warnes CA et al. ACC/AHA 2008 Guidelines for the Manage
-
ment of Adults With Congenital Heart Disease. A Report of 
the American College of Cardiology/American Heart Asso
-
ciation Task Force on Practice Guidelines. Circulation. 
2008 Dec 2;118(23):e714–833. [PMID: 18997169]
MANAGEMENT OF ANTICOAGULATION FOR 
PATIENTS WITH PROSTHETIC HEART VALVES
The risk of thromboembolism is much lower with biopros
-
thetic valves than mechanical prosthetic valves. Mechani
-
cal mitral valve prostheses pose a greater risk for thrombosis 
than mechanical aortic valves. For that reason, the INR 
should be kept between 2.5 and 3.5 for mechanical mitral 
prosthetic valves but can be kept between 2.0 and 2.5 for 
most mechanical aortic prosthetic valves. Several changes 
were recommended regarding anticoagulation use in val
-
vular heart disease with the publication of the 2017 update 
to the 2014 ACC/AHA valve guidelines, including (1) a 
recommendation (Class 2a) to expand the use of vitamin K 
antagonists (VKAs), such as warfarin, for up to 6 months 
after bioprosthetic valve replacement; (2) a lower target 
INR of 1.5–2.0 for a mechanical AVR using the On-X valve 
(Class 2b); and (3) a consideration of VKA use with an INR 
of 2.5 for 3 months after TAVR (Class 2a). The concern 
regarding thrombus formation on bioprosthetic valves also 
led to a Class 1 recommendation to use multimodality 
imaging to identify thrombus (Class 1).
In 2015 the European Registry of Pregnancy and Car
-
diac Disease (ROPAC) reported on a registry that compared 
pregnant women who had undergone mechanical and bio
-
prosthetic valve replacement to pregnant women who had 
not. Maternal mortality was similar between the mechani
-
cal and bioprosthetic valve patients (1.5% and 1.4%, respec
-
tively) but was much higher than those without an artificial 
valve (0.2%). When patients with either mechanical or bio
-
prosthetic valves were further assessed, it was found that 
pregnant women with mechanical valves were more likely 
to suffer adverse events than women with bioprosthetic 
valves. Hemorraghic events occurred in 23.1% versus 9.2%, 
miscarriage on warfarin occurred in 28.6% versus 9.2%, and 
late fetal death was noted in 7.1% versus 0.7%, respectively. 
These data suggest 
a high risk for mortality and morbidity

a high risk for mortality and morbidity 
for pregnant patients with mechanical heart valves,
 and 
in the WHO Classification of Maternal Cardiac Risk, the 
presence of a mechanical valve is considered a class III (out 
of IV) risk for pregnancy complications.
Stoppage of warfarin for noncardiac surgery is likewise 
dependent on which mechanical valve is involved, the 
patient-specific risk factors, and the procedure contem
-
plated. The risk of thromboembolism is highest in the first 
few months after valve replacement. While the interruption 
of warfarin therapy is generally safe, most cases of valve 
thrombosis occur during periods of inadequate anticoagu
-
lation, so the time interval without coverage should be kept 
as short as possible. High-risk features include atrial fibril
-
lation, a prior history of thromboembolism, heart failure or 
low LVEF, a hypercoagualable state, a mechanical valve in 
the mitral position, a known high-risk valve (ball-in-cage), 
or concomitant hypercoagulable state (such as with an 
associated cancer). The use of bridging VKAs, unfraction
-
ated heparin, low-molecular-weight heparin (LMWH) and 
antifibrinolytics in various clinical situations in patients 
with valvular heart disease is summarized in Table 10–6 
and the issues are covered in more depth in both the 2012 
European Society of Cardiology (ESC) and the 2017 update 
to the 2014 AHA/ACC valvular heart disease guidelines. In 
general, low-risk procedures (eg, pacemaker implantation 
and routine dental work) require no stoppage of VKAs, 
while in other situations the warfarin can be stopped 3 days 
ahead of the procedure and resumed the night after the 
procedure (ie, in patients with bileaflet aortic valves) with
-
out any bridging unfractionated heparin or LMWH. In 
high-risk patients, though, the warfarin should be stopped 
and 
bridging
 with either unfractionated heparin or LMWH 
begun once the INR falls below therapeutic levels. Fresh 
frozen plasma or prothrombin complex concentrate is rea
-
sonable in an emergency situation for acute reversal. Most 
patients with a mechanical valve should not have the war
-
farin reversed with vitamin K if it can be avoided because 
this can result in a transient hypercoagulable state, and it 
may take many days to reach a therapeutic INR again.
Warfarin causes fetal skeletal abnormalities in up to 2% 
of women who become pregnant while taking the medica
-
tion, so every effort is made to defer valve replacement in 
women until after childbearing age. However, if a woman 
with a mechanical valve becomes pregnant while taking 
warfarin, the risk of stopping warfarin may be higher for 
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the mother than the risk of continuing warfarin for the 
fetus. The risk of warfarin to the fetal skeleton is greatest 
during the first trimester and, remarkably, is more related 
to dose than to the INR level. Guidelines suggest it is rea
-
sonable to continue warfarin for the first trimester if the 
dose is 5 mg/day or less. If the dose is more than 5 mg/day, 
it is appropriate to consider either LMWH (as long as the 
anti-Xa is being monitored [range: 0.8 unit/mL to 1.2 
units/m 4–6 hours post-dose]) or continuous intravenous 
unfractionated heparin (if the activated partial thrombo
-
plastin time [aPTT] can be monitored and is at least two 
times control). Guidelines suggest warfarin and low-dose 
aspirin are safe during the second and third trimester, and 
then should be stopped upon anticipation of delivery. At 
time of vaginal delivery, unfractionated intravenous hepa
-
rin with aPTT at least two times control is desirable. 
DOACs (antithrombin or Xa inhibitors) should 
not
 be used 
in place of warfarin for mechanical prosthetic valves since 
there are no data they are safe during pregnancy.
Management of suspected mechanical valve thrombosis 
depends on whether a left-sided or right-sided valve is 
involved, the size of the thrombus, and the patient’s clinical 
Table 10–6.
 
Recommendations for administering vitamin K antagonist (VKA) therapy in patients undergoing 
 
procedures or patients with certain clinical conditions.
p
r
ocedures
General
Stop VKA 5 days prior and resume 12–24 hours after procedure
Bridging for mechanical heart valves
Required only for those at high risk for thromboembolism
Bridge with UFH or LMWH and stop UFH 4–6 hours before procedure or stop 
LMWH 24 hours before procedure
Resume 48–72 hours after the procedure
Clinical Situations
Atrial fibrillation and moderate or severe mitral stenosis
VKA (target INR 2.0–3.0)
If patient refuses, aspirin (50–100 mg) plus clopidogrel (75 mg)
Sinus rhythm and mitral stenosis
If left atrial size > 5.5 cm, then consider VKA (target 2.0–3.0)
Intermittent atrial fibrillation or history of systemic embolus 
and mitral stenosis
Endocarditis
 
Na
tive valve or bioprosthetic valve endocarditis
 
M
echanical valve endocarditis
No anticoagulation recommended
Hold VKA until “safe to resume” (generally when mycotic aneurysm is ruled 
out or there is no need for urgent surgery)
First 3 months following valve replacement
 
Biopr
osthetic aortic valve replacement
 
T
ranscatheter valve replacement
 
M
itral or aortic repair
 
Biopr
osthetic mitral valve
Aspirin (50–100 mg)
Aspirin (50–100 mg) plus clopidogrel (75 mg)
Long-term anticoagulation after valve replacement
 
Biopr
osthetic valve in normal sinus rhythm
 
M
echanical valve replacement
VKA (target INR 2.0–3.0 for aortic, target INR 2.5–3.5 for mitral) plus aspirin 
(50–100 mg)
Prosthetic valve thrombosis
 
R
ight-sided valve
 
L
eft-sided valve
Fibrinolytic therapy
Early surgery if thrombus large (> 0.8 cm
2
 area), otherwise either fibrinolytic 
therapy or UFH
Pregnancy and a mechanical heart valve
Add aspirin (50–100 mg) for high risk
Adjusted dose LMWH twice daily throughout pregnancy (follow anti-Xa 
4 hours after dose)
or
Adjusted dose UFH every 12 hours throughout pregnancy (aPTT > 2 times 
control or anti-Xa between 0.35 and 0.70)
or
Adjusted dose UFH or LMWH until 13th week of pregnancy then VKA until 
close to delivery, then resume UFH or LMWH
aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated 
heparin.
Data from Holbrook A et al. Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 
9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e152S–84S.

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condition. Simple fluoroscopy can help assess mechanical 
valve motion, although a TEE is indicated to assess thrombus 
size. Therapeutic unfractionated heparin should be given to 
all patients with a thrombosed valve, and this alone is gener
-
ally effective. Fibrinolytic therapy is indicated if heparin 
therapy is ineffective and the clinical onset has been less than 
2 weeks, the thrombus is smaller than 0.8 cm
2
, NYHA class 
symptoms are mild (functional class I or II) or the valve is 
right-sided. Surgery is rarely indicated, and reserved for 
those with left-sided mechanical valves in NYHA functional 
class III or IV heart failure or in whom TEE demonstrates a 
mobile thrombus larger than 0.8 cm
2
. The 2017 updated 
valvular heart disease guidelines added (Class 1) the use of 
urgent initial therapy for a thrombosed mechanical valve to 
include low-dose, slow-infusion fibrinolytic therapy or 
urgent surgery if the patient is symptomatic.
Alshawabkeh L et al. Anticoagulation during pregnancy: evolv
-
ing strategies with a focus on mechanical valves. J Am Coll 
Cardiol. 2016 Oct 18;68(16):1804–13. [PMID: 27737747]
-
Van Hagen IM et al. Pregnancy in women with a mechanical 
heart valve: data from the ESC Registry of Pregnancy and 
Cardiac Diseases (ROPAC). Circulation. 2015 Jul 14;
 
132(2):132–42. [PMID: 26100109]
 
º
CORONARY HEART DISEASE 
 
(Atherosclerotic 
CAD
, Ischemic 
 
Heart Disease)
Coronary heart disease (CHD), or atherosclerotic CAD, is 
the number one cause of death in the United States and 
worldwide. Every minute, an American dies of CHD. About 
37% of people who experience an acute coronary event, 
either angina or myocardial infarction, will die of it in the 
same year. Death rates of CHD have declined every year 
since 1968, with about half of the decline from 1980 to 2000 
due to treatments and half due to improved risk factors. 
CHD is still responsible for approximately one of five deaths 
and over 600,000 deaths per year in the United States. CHD 
afflicts nearly 16 million Americans and the prevalence 
rises steadily with age; thus, the aging of the US population 
promises to increase the overall burden of CHD.
 
»
Risk Factors for CAD
Most patients with CHD have some identifiable risk factor. 
These include a 
positive family history
 (the younger the 
onset in a first-degree relative, the greater the risk), 
male 
sex,
 
blood lipid abnormalities,
 
diabetes mellitus,
 
hyper
-
tension,
 
physical inactivity,
 
abdominal obesity,
 
cigarette 
smoking, psychosocial factors,
 and consumption of 
too 
few fruits and vegetables
 and 
too much alcohol
. Many of 
these risk factors are modifiable. 
Smoking remains the 
number one preventable cause of death and illness in the 
 Although smoking rates have declined in 
the United States in recent decades, 18% of women and 
21% of men still smoke. According to the World Health 
Organization, 1 year after quitting, the risk of CHD 
decreases by 50%. Various interventions have been shown 
to increase the likelihood of successful smoking cessation 
(see Chapter 1).
 is an important modifiable risk 
factor for CHD. Risk increases progressively with higher 
levels of low-density lipoprotein (LDL) cholesterol and 
declines with higher levels of high-density lipoprotein 
(HDL) cholesterol. Composite risk scores, such as the 
Framingham score and the 10-year atherosclerotic cardio
-
vascular disease risk calculator (http://my.americanheart
 
.org/cvriskcalculator), provide estimates of the 10-year 
probability of development of CHD that can guide primary

-
 
probability of development of CHD that can guide primary 
prevention strategies. The 2013 ACC/AHA Guideline on 
the Treatment of Blood Cholesterol to Reduce Atheroscle
-
rotic Cardiovascular Risk in Adults suggests statin therapy 
in four populations: patients with (1) clinical atherosclerotic 
disease, (2) LDL cholesterol 190 mg/dL or higher, (3) diabe
-
tes who are aged 40–75 years, and (4) an estimated 10-year 
atherosclotic risk of 7.5% or more aged 40–75 years (Figure 
10–5). Importantly, 
the guidelines do not recommend 
treating to a target LDL cholesterol.
 Patients in these cat
-
egories should be treated with moderate- or high-intensity 
statin, with high-intensity statin for the higher-risk popula
-
tions (Table 10–7). The ACC/AHA atherosclerotic cardio
-
vascular disease risk estimator allows clinicians to determine 
the 10-year CHD risk to determine treatment decisions 
(http://tools.cardiosource.org/ASCVD-Risk-Estimator/).
The 
metabolic syndrome
 is defined as a constellation 
of three or more of the following: abdominal obesity, tri
-
glycerides 150 mg/dL or higher, HDL cholesterol less than 
40 mg/dL for men and less than 50 mg/dL for women, fast
-
ing glucose 110 mg/dL or higher, and hypertension. This 
syndrome is increasing in prevalence at an alarming rate. 
Related to the metabolic syndrome, the epidemic of 
obesity
 in the United States is likewise a major factor con
-
tributing to CHD risk.
 
»
Myocardial Hibernation & Stunning
Areas of myocardium that are persistently underperfused 
but still viable may develop sustained contractile dysfunc
-
tion. This phenomenon, which is termed 
myocardial 
hibernation,
 appears to represent an adaptive response 
that may be associated with depressed LV function. It is 
important to recognize this phenomenon, since this form 
of dysfunction is reversible following coronary revascular
-
ization. Hibernating myocardium can be identified by 
radionuclide testing, positron emission tomography (PET), 
contrast-enhanced MRI, or its retained response to inotro
-
pic stimulation with dobutamine. A related phenomenon, 
termed 
myocardial stunning,
 is the occurrence of persis
-
tent contractile dysfunction following prolonged or repeti
-
tive episodes of myocardial ischemia. Clinically, myocardial 
stunning is often seen after reperfusion of acute myocar
-
dial infarction and is defined with improvement following 
revascularization.
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Age > 75 y OR if not candidate 
fo
r
high-intensity statin
Moderate-intensity statin
High-intensity statin
(Moderate-intensity statin if not
candidate for high-intensity statin)
Estimated 10-y ASCVD risk 
≥ 
7 .5%
1
Moderate- 
to
 high-intensity statin
ASCVD pr
ev
ention benefit of statin therapy may be less clear in other groups.
In selected individuals, consider additional factors influencing 
AS
CVD risk
3
 and potential 
AS
CVD
risk benefits and adverse effects, drug-drug interactions, and patient preferences 
fo
r statin treatment.
Estimate 10-y ASCVD risk
with pooled cohort equations
2
Clinical
ASCVD
LDL–C 
≥ 
19
0
mg/dL
Diabetes
Type 1 or 2
age 40–75 y
≥ 
7 .5% estimated
10-y ASCVD 
ri
sk
and age 40–75 y
Ye
s
Ye
s
Ye
s
Ye
s
Ye
s
Ye
s
Ye
s
No
No
No
No
Adults age > 21 y and a
candidate for statin therapy
Definitions of high- and
moderate-intensity statin the
ra
py
(See 
Ta
ble 10–9)
High
Daily dose lowers
LDL–C by approx.
≥ 
50%
Moderate
30% to < 50%
Age 
≤ 
75 y
ASCVD statin benefit groups
Heart healthy lifestyle habits are the foundation of 
AS
CVD pr
ev
ention.
In individuals not receiving cholesterol-lo
wer
ing drug therap
y,
 
re
calculate estimated 
10
-y 
AS
CVD risk 
ev
ery 4–6 y
in individuals aged 40–75 y without clinical ASCVD or diabetes and with LDL–C 70–189 mg/dL.
1
Pe
rcent reduction in LDL–C can be used as an indication of response and adherence 
to
 therapy but is not in
itself a treatment goal.
2
The 
Po
oled Cohort Equations can be used 
to
 estimate 
10
-year 
AS
CVD risk in individuals with and without
diabetes
. 
A downloadable spreadsheet enabling estimation of 
10
-year and lifetime 
ri
sk 
fo
r 
AS
CVD and a web-based
calculator are 
av
ailable at http://m
y.
americanheart.org/cvriskcalculator and http://www.cardiosource.org/science-and-
quality/practice-guidelines-and-qualit
y-
standards/20
13
-p
rev
ention-guideline-tools.aspx.
3
Pr
imary LDL–C 
≥ 
160 mg/dL or other evidence of genetic hyperlipidemias, 
fa
mi
ly
 history of premature 
AS
CVD
with onset < 55 years of age in a 
fi
r
st-degr
ee male relative or < 65 
ye
ars of age in a 
fi
rst-degree 
fe
male relativ
e,
high-sensitivi
ty
 C-reactive protein > 2 mg/L, 
CA
C score 
≥ 
300 
Ag
atston units or 
≥ 
75 percentile 
fo
r age, sex, and
ethnicit
y,
 ankle-brachial index < 0.9, or ele
va
ted lifetime risk of 
AS
CV
D.
AS
CV
D,
 atherosclerotic cardio
va
scular disease; 
CAC,
 corona
ry
 ar
te
ry
 calcium
; 
LDL–C, lo
w-
density lipoprotein
cholesterol.
 
▲
Figure 10–5.
 
Major recommendation for statin therapy for ASCVD prevention. 
Adapted from Stone NJ et al. 2013 
ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A 
Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 
 
Circulation. 2014 Jun 24;129(25 Suppl 2):S1–45.
CMDT19_Ch10_p0334-p0450.indd   366

367
 
CMDT 2019
for events (patients with diabetes and patients with peripheral 
artery disease), and those with elevated cholesterol without 
multiple risk factors, and those without vascular disease or 
diabetes with elevated high-sensitivity C-reactive protein 
(hsCRP) with normal LDL levels. The benefits of statin 
therapy at moderate and high doses (Table 10–7) are rec
-
ommended by the cholesterol treatment guidelines. The 
IMPROVE-IT study showed that ezetimibe, 10 mg daily, 
combined with simvastatin was modestly better than simv
-
astatin alone in reducing the risk of myocardial infarction 
and ischemic stroke, but not mortality, in stabilized patients 
following an acute coronary syndrome. This was associated 
with a reduction of LDL to 53.7 mg/dL compared to 
69.7 mg/dL. With this data, ezetimibe can be used in com
-
bination with statin therapy in patients who are not at tar
-
get choleseterol level or cannot tolerate high-dose statin 
therapy.
Benefits occurred regardless of age, race, baseline cho
-
lesterol levels, or the presence of hypertension. It is clear 
that for patients with vascular disease, statins provide ben
-
efit for those with normal cholesterol levels, and that more 
aggressive statin use is associated with greater benefits. 
All 
patients at significant risk for vascular events should 
receive a statin regardless of their cholesterol levels,
 and 
many recommend that with those who have prior cardio
-
vascular events should have their LDL lowered below 
70 mg/dL.
Novel monoclonal antibodies that inhibit proprotein 
convertase subtilisin/kexin type 9 (PCSK9) have been 
developed and have shown to reduce LDL cholesterol levels 
significantly beyond levels associated with traditional 
statin therapy. These therapies have been studied in initial 
randomized trials of patients with maximally tolerated 
Ridker PM et al. CANTOS Trial Group. Antiinflammatory 
therapy with canakinumab for atherosclerotic disease. N Engl 
J Med. 2017 Sep 21;377(12):1119–31. [PMID: 28845751]
Stone NJ et al. 2013 ACC/AHA guideline on the treatment of 
blood cholesterol to reduce atheroschlerotic cardiovascular 
risk in adults: a report of the American College of Cardiology/ 
-
lines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1–45. [PMID: 
24222016]
Yu Y . Four decades of obesity trends among non-hispanic whites 
and blacks in the United States: analyzing the influences of 
educational inequalities in obesity and population improve
-
ments in education. PLoS One. 2016 Nov 28;11(11):e0167193. 
[PMID: 27893853]
 
»
Primary & Secondary Prevention of CHD
Although many risk factors for CHD are not modifiable, it 
is now clear that interventions, such as smoking cessation, 
treatment of dyslipidemia, and lowering of BP can both 
prevent coronary disease and delay its progression and 
complications after it is manifest.
Lowering LDL levels delays the progression of athero
-
sclerosis and in some cases may produce regression. Even 
in the absence of regression, fewer new lesions develop, 
endothelial function may be restored, and coronary event 
rates are markedly reduced in patients with clinical evi
-
dence of vascular disease.
A series of clinical trials has demonstrated the efficacy 
of hydroxymethylglutaryl coenzyme A (HMG-CoA) 
reductase inhibitors (statins) in preventing death, coronary 
events, and strokes. Beneficial results have been found in 
patients who have already experienced coronary events 
(secondary prevention), in those at particularly high risk 
Table 10–7.
 
High-, moderate-, and low-intensity statin therapy (used in the RCTs reviewed by the expert panel).
1,2
High-Intensity Statin Therapy
Moderate-Intensity Statin Therapy
Low-Intensity Statin Therapy
Daily dose lowers LDL–C on average by 
approximately ≥ 50%
approximately 30% to < 50%
< 30%
Atorvastatin (40
3

< 30%
3
)–80 mg
Rosuvastatin 20 
(40)
 mg
Atorvastatin 10 
(20)
 mg
Rosuvastatin 
(5)
 10 mg
Simvastatin 20–40 mg
4
p
r
avastatin 40 
(80)
 mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg twice daily
Pitavastatin 2–4 mg
Simvastatin 10 mg
p
r
avastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastatin 1 mg
1
Statins and doses in 
boldface
 were evaluated in RCTs; all demonstrated a reduction in major cardiovascular events. Statins and doses that 
are approved by the US FDA but were not tested in the RCTs reviewed are listed in 
italics
.
2
Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis 
for a less-than-average response.
3
Evidence from one RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL.
4
Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA 
due to the increased risk of myopathy, including rhabdomyolysis.
FDA, Food and Drug Administration; IDEAL, Incremental Decrease through Aggressive Lipid Lowering study; LDL–C, low-density lipoprotein 
cholesterol; RCTs, randomized controlled trials.
Modified, with permission, from Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic 
Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 
Circulation. 2014 Jun 24;129(25 Suppl 2):S1–45. © 2014 American Heart Association, Inc.
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statin therapy (and for patients with statin intolerance) and 
have lowered LDL with signals of improved cardiovascular 
outcomes. The first outcomes trial, FOURIER, showed that 
the PCSK9 inhibitor evolocumab, on top of statin, reduced 
the composite of atherothrombotic outcomes by 20% but 
did not reduce mortality. Other outcome trials are ongoing. 
Alirocumab and evolocumab have been approved by the 
FDA for patients on maximally tolerated statin therapy 
with familial hypercholesterolemia and atherosclerotic 
vascular disease, or both, and who require additional low
-
ering of LDL. These medications cost approximately 
$14,000 per year in the United States.
The CANTOS trial has demonstrated as a proof of con
-
cept that canakinumab (antibody targeting IL-1 and lead
-
ing to IL-6 inhibition) can modestly reduce cardiovascular 
events by targeting inflammation—patients with con
-
trolled LDL cholesterol and elevated hsCRP . By the end of 
2017, this agent was not yet approved by the FDA for the 
CAD population.
Treatment to raise HDL levels has failed to show ben
-
efit.
 The AIM High trial found no benefit from the addi
-
tion of niacin in patients with vascular disease and a serum 
LDL near 70 mg/dL who were receiving statin therapy. The 
HPS2-THRIVE trial found no benefit but rather substan
-
tial harm of extended-release niacin (2 g) plus laropiprant 
(an antiflushing agent) for preventing vascular events in a 
population of over 25,000 patients with vascular disease 
who were taking simvastatin.
The value of medications that reduce elevated triglycer
-
ide levels is less clear, unless triglycerides are elevated to 
greater than 500 mg/dL despite diet intervention.
Antiplatelet therapy is another very effective preventive 
measure. Aspirin (325 mg every other day) in men over the 
age of 50 years reduces the incidence of myocardial infarc
-
tion. A similar approach (100 mg every other day), how
-
ever, did not prevent myocardial infarction in women age 
45 years or older, although stroke did appear to be reduced. 
Thus, the role of aspirin in primary prevention, including 
the dose, remains controversial. A prudent approach would 
be to 
administer 81–325 mg daily to men with multiple 
coronary risk factors or concomitant diabetes starting 
at age 45–50 years if no contraindication is present.
 The 
exact dose of aspirin in chronic CAD (81 mg vs 325 mg) 
 
is being evaluated in a large ongoing Pragmatic trial 
(ADAPTABLE). While clopidogrel was found to be effec
-
tive at preventing vascular events for 9–12 months after 
acute coronary syndromes, it was not found to be effective 
at preventing vascular events in combination with aspirin 
with longer-term treatment in the CHARISMA trial. This 
trial included patients with clinically evident stable athero
-
thrombosis or with multiple risk factors; all were treated 
with aspirin and observed for a median of 28 months.
In the COMPASS trial, rivaroxaban, a direct factor Xa 
inhibitor, at a dose of 2.5 mg twice daily in addition to 100 mg 
of aspirin, was shown to reduce cardiovascular death, myo
-
cardial infarction, and stroke by a relative risk reduction of 
24% compared to 100 mg aspirin monotherapy in stable 
patients with CAD and peripheral artery disease. All cause 
mortality was also reduced by 18%. This regimen awaits 
FDA review for this indication.
The HOPE and the EUROPA trials demonstrated that 
angiotensin-converting enzyme (ACE) inhibitors (ramipril 
10 mg/day and perindopril 8 mg/day, respectively) reduced 
fatal and nonfatal vascular events (cardiovascular deaths, 
nonfatal myocardial infarctions, and nonfatal strokes) by 
20–25% in patients at high risk, including patients with 
diabetes with additional risk factors or patients with clini
-
cal coronary, cerebral, or peripheral arterial atherosclerotic 
disease. An overview of these trials has demonstrated that 
while low-risk patients may 
not
 derive substantial benefits

-
not
 derive substantial benefits 
from ACE inhibitors, 
most patients with vascular disease, 
even in the absence of heart failure or LV dysfunction, 
should be treated with an ACE inhibitor.
Cannon CP et al; IMPROVE-IT Investigators. Ezetimibe added 
to statin therapy after acute coronary syndromes. N Engl J 
Med. 2015 Jun 18;372(25):2387–97. [PMID: 26039521]
Eikelboom JW et al; COMPASS Investigators. Rivaroxaban with 
or without aspirin in stable cardiovascular disease. N Engl J 
Med. 2017 Oct 5;377(14):1319–30. [PMID: 28844192]
Lloyd-Jones DM et al. 2017 focused update of the 2016 ACC 
expert consensus decision pathway on the role of non-statin 
therapies for LDL-cholesterol lowering in the management of 
atherosclerotic cardiovascular disease risk: a report of the 
-
sensus Decision Pathways. J Am Coll Cardiol. 2017 Oct 3;
 
70(14):1785–822. [PMID: 28886926]
Ridker PM et al; CANTOS Trial Group. Antiinflammatory 
Robinson JG et al; ODYSSEY LONG TERM Investigators. Effi
-
cacy and safety of alirocumab in reducing lipids and cardio
-
vascular events. N Engl J Med. 2015 Apr 16;372(16):1489–99. 
[PMID: 25773378]
Sabatine MS et al; FOURIER Steering Committee and Investiga
-
tors. Evolocumab and clinical outcomes in patients with car
-
diovascular disease. N Engl J Med. 2017 May 4;376(18):
 
1713–22. [PMID: 28304224]
CHRONIC STABLE ANGINA PECTORIS
 
»
Precordial chest pain, usually precipitated by stress 
or exertion, relieved rapidly by rest or nitrates.
 
»
ECG or scintigraphic evidence of ischemia during 
pain or stress testing.
 
»
Angiographic demonstration of significant 
obstruction of major coronary vessels.
 
»
Angina pectoris is usually due to atherosclerotic heart dis
-
ease. Coronary vasospasm may occur at the site of a lesion 
or, less frequently, in apparently normal vessels. Other 
unusual causes of coronary artery obstruction, such as 
congenital anomalies, emboli, arteritis, or dissection may 
cause ischemia or infarction. Angina may also occur in the 
absence of coronary artery obstruction as a result of severe 
CMDT19_Ch10_p0334-p0450.indd   368

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myocardial hypertrophy, severe aortic stenosis or regurgi
-
tation, or in response to increased metabolic demands, as 
in hyperthyroidism, marked anemia, or paroxysmal tachy
-
cardias with rapid ventricular rates.
 
»
The diagnosis of angina pectoris principally depends on 
the history, which should specifically include the following 
information: circumstances that precipitate and relieve 
angina, characteristics of the discomfort, location and 
radiation, duration of attacks, and effect of nitroglycerin.
1. Circumstances that precipitate and relieve angina—
Angina occurs most commonly during activity and is 
relieved by resting. Patients may prefer to remain upright 
rather than lie down, as increased preload in recumbency 
increases myocardial work. The amount of activity required 
to produce angina may be relatively consistent under com
-
parable physical and emotional circumstances or may vary 
from day to day. The threshold for angina is usually lower 
after meals, during excitement, or on exposure to cold. It is 
often lower in the morning or after strong emotion; the 
latter can provoke attacks in the absence of exertion. In 
addition, discomfort may occur during sexual activity, at 
rest, or at night as a result of coronary spasm.
2. Characteristics of the discomfort—
Patients often do 
not refer to angina as “pain” but as a sensation of tightness, 
squeezing, burning, pressing, choking, aching, bursting, 
“gas, ” indigestion, or an ill-characterized discomfort. It is 
often characterized by clenching a fist over the mid chest. 
The distress of angina is rarely sharply localized and is not 
spasmodic.
3. Location and radiation—
The distribution of the distress 
may vary widely in different patients but is usually the 
same for each patient unless unstable angina or myocardial 
infarction supervenes. In most cases, the discomfort is felt 
behind or slightly to the left of the mid sternum. When it 
begins farther to the left or, uncommonly, on the right, it 
characteristically moves centrally substernally. Although 
angina may radiate to any dermatome from C8 to T4, it 
radiates most often to the left shoulder and upper arm, 
frequently moving down the inner volar aspect of the arm 
to the elbow, forearm, wrist, or fourth and fifth fingers. It 
may also radiate to the right shoulder or arm, the lower jaw, 
the neck, or even the back.
4. Duration of attacks—
Angina is generally of short dura
-
tion and subsides completely without residual discomfort. 
If the attack is precipitated by exertion and the patient 
promptly stops to rest, it usually lasts under 3 minutes. 
Attacks following a heavy meal or brought on by anger 
often last 15–20 minutes. Attacks lasting more than 30 minutes 
are unusual and suggest the development of an acute coro
-
nary syndrome with unstable angina, myocardial infarction, 
or an alternative diagnosis.
5. Effect of nitroglycerin—
The diagnosis of angina pecto
-
ris is supported if sublingual nitroglycerin promptly and 
invariably shortens an attack and if prophylactic nitrates 
permit greater exertion or prevent angina entirely.
B. Signs
Examination during angina frequently reveals a significant 
elevation in systolic and diastolic BP , although hypotension 
may also occur, and may reflect more severe ischemia or 
inferior ischemia (especially with bradycardia) due to a 
Bezold-Jarisch reflex. Occasionally, a gallop rhythm and an 
apical systolic murmur due to transient mitral regurgita
-
tion from papillary muscle dysfunction are present during 
pain only. Supraventricular or ventricular arrhythmias may 
be present, either as the precipitating factor or as a result of 
ischemia.
It is important to detect signs of diseases that may con
-
tribute to or accompany atherosclerotic heart disease, eg, 
diabetes mellitus (retinopathy or neuropathy), xanthe
-
lasma tendinous xanthomas, hypertension, thyrotoxicosis,

-
-
lasma tendinous xanthomas, hypertension, thyrotoxicosis, 
myxedema, or peripheral artery disease. Aortic stenosis or 
regurgitation, hypertrophic cardiomyopathy, and mitral 
valve prolapse should be sought, since they may produce 
angina or other forms of chest pain.
C. Laboratory Findings
Other than standard laboratory tests to evaluate for acute 
coronary syndrome (troponin and CK-MB), factors con
-
tributing to ischemia (such as anemia), and to screen for 
risk factors that may increase the probability of true CHD 
(such as hyperlipidemia and diabetes mellitus), blood tests 
are not helpful to diagnose chronic angina.
D. ECG
The resting ECG is often normal in patients with angina. In 
the remainder, abnormalities include old myocardial 
infarction, nonspecific ST–T changes, and changes of LVH. 
During anginal episodes, as well as during asymptomatic 
ischemia, the characteristic ECG change is horizontal or 
downsloping ST-segment depression that reverses after the 
ischemia disappears. T wave flattening or inversion may 
also occur. Less frequently, transient ST-segment elevation 
is observed; this finding suggests severe (transmural) isch
-
emia from coronary occlusion, and it can occur with coro
-
nary spasm.
E. Pretest Probability
The history as detailed above, the physical examination 
findings, and laboratory and ECG findings are used to 
develop a pretest probability of CAD as the cause of the 
clinical symptoms. Other important factors to include in 
calculating the pretest probability of CAD are patient age, 
sex, and clinical symptoms. Patients with low to intermedi
-
ate pretest probability for CAD should undergo noninva
-
sive stress testing whereas patients with high pretest 
probability are generally referred for cardiac catheteriza
-
tion. National review of diagnostic cardiac catheterization 
findings in patients without known CAD undergoing 
angiography has shown that between 38% and 40% of 
patients do not have obstructive disease.
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F. Exercise ECG
Exercise ECG testing is the most commonly used noninva
-
sive procedure for evaluating for inducible ischemia in the 
patient with angina. Exercise ECG testing is often com
-
bined with imaging studies (nuclear or echocardiography), 
but in low-risk patients without baseline ST-segment 
abnormalities or in whom anatomic localization is not 
necessary, the exercise ECG remains the recommended 
initial procedure because of considerations of cost, conve
-
nience, and longstanding prognostic data.
Exercise testing can be done on a motorized treadmill 
or with a bicycle ergometer. A variety of exercise protocols 
are utilized, the most common being the 
Bruce protocol,
 
which increases the treadmill speed and elevation every 
 
3 minutes until limited by symptoms. At least two ECG 
leads should be monitored continuously.
1. Precautions and risks—
The risk of exercise testing is 
about one infarction or death per 1000 tests, but individu
-
als who have pain at rest or minimal activity are at higher 
risk and should not be tested. 
Many of the traditional 
exclusions, such as recent myocardial infarction or heart 
failure, are no longer used if the patient is stable and 
ambulatory, but symptomatic aortic stenosis remains a 
relative contraindication.
2. Indications—
Exercise testing is used (1) to confirm the 
diagnosis of angina; (2) to determine the severity of limita
-
tion of activity due to angina; (3) to assess prognosis in 
patients with known coronary disease, including those 
recovering from myocardial infarction, by detecting groups 
at high or low risk; and (4) to evaluate responses to therapy. 
Because false-positive tests often exceed true positives, 
leading to much patient anxiety and self-imposed or man
-
dated disability, exercise testing of asymptomatic individu
-
als should be done only for those whose occupations place 
them or others at special risk (eg, airline pilots) and older 
individuals commencing strenuous activity.
3. Interpretation—
The usual ECG criterion for a positive test 
is 1-mm (0.1-mV) horizontal or downsloping ST-segment 
depression (beyond baseline) measured 80 msec after the J 
point. By this criterion, 60–80% of patients with anatomi
-
cally significant coronary disease will have a positive test, 
but 10–30% of those without significant disease will also be 
positive. False positives are uncommon when a 2-mm 
depression is present. Additional information is inferred 
from the time of onset and duration of the ECG changes, 
their magnitude and configuration, BP and heart rate 
changes, the duration of exercise, and the presence of asso
-
ciated symptoms. In general, patients exhibiting more 
severe ST-segment depression (more than 2-mm) at low 
workloads (less than 6 minutes on the Bruce protocol) or 
heart rates (less than 70% of age-predicted maximum)—
especially when the duration of exercise and rise in BP are 
limited or when hypotension occurs during the test—have 
more severe disease and a poorer prognosis. Depending on 
symptom status, age, and other factors, such patients 
should be referred for coronary arteriography and possible 
revascularization. On the other hand, less impressive posi
-
tive tests in asymptomatic patients are often “false 
positives. ” Therefore, exercise testing results that do not 
conform to the clinical suspicion should be confirmed by 
stress imaging.
G. Myocardial Stress Imaging
Myocardial stress imaging (scintigraphy, echocardiogra
-
phy, or MRI) is indicated (1) when the resting ECG makes 
an exercise ECG difficult to interpret (eg, left bundle 
branch block, baseline ST–T changes, low voltage); (2) for 
confirmation of the results of the exercise ECG when they 
are contrary to the clinical impression (eg, a positive test in 
an asymptomatic patient); (3) to localize the region of isch
-
emia; (4) to distinguish ischemic from infarcted myocar
-
dium; (5) to assess the completeness of revascularization

-
-
dium; (5) to assess the completeness of revascularization 
following bypass surgery or coronary angioplasty; or (6) as 
a prognostic indicator in patients with known coronary 
disease. Published criteria summarize these indications for 
stress testing.
1. Myocardial perfusion scintigraphy—
This test, also 
known as 
radionuclide imaging,
 provides images in 
which radionuclide uptake is proportionate to blood flow 
at the time of injection.
Stress imaging is positive in about 75–90% of patients 
with anatomically significant coronary disease and in 
20–30% of those without it. Occasionally, other conditions, 
including infiltrative diseases (sarcoidosis, amyloidosis), 
left bundle branch block, and dilated cardiomyopathy, may 
produce resting or persistent perfusion defects. False-
positive radionuclide tests may occur as a result of dia
-
phragmatic attenuation or, in women, attenuation through 
breast tissue. Tomographic imaging (single-photon emis
-
sion computed tomography, SPECT) can reduce the sever
-
ity of artifacts.
2. Radionuclide angiography—
This procedure, also 
known as 
multi-gated acquisition scan,
 or 
MUGA scan,
 
uses radionuclide tracers to image the LV and measures its 
EF and wall motion. In coronary disease, resting abnor
-
malities usually represent infarction, and those that occur 
only with exercise usually indicate stress-induced isch
-
emia. Exercise radionuclide angiography has approxi
-
mately the same sensitivity as myocardial perfusion 
scintigraphy, but it is less specific in older individuals and 
those with other forms of heart disease. In addition, 
because of the precision around LVEF, the test is also used 
for monitoring patients exposed to cardiotoxic therapies 
(such as chemotherapeutic agents).
3. Stress echocardiography—
Echocardiograms per
-
formed during supine exercise or immediately following 
upright exercise may demonstrate exercise-induced seg
-
mental wall motion abnormalities as an indicator of isch
-
emia. In experienced laboratories, the test accuracy is 
comparable to that obtained with scintigraphy—though a 
higher proportion of tests is technically inadequate. While 
exercise is the preferred stress because of other information 
derived, pharmacologic stress with high-dose dobutamine 
(20–40 mcg/kg/min) can be used as an alternative to 
exercise.
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H. Other Imaging
1. Positron emission tomography—
PET and SPECT 
scanning can accurately distinguish transiently dysfunc
-
tional (“stunned”) myocardium from scar tissue.
2. CT and MRI scanning—
CT scanning can image the 
heart and, with contrast medium and multislice technol
-
ogy, the coronary arteries. 
Multislice CT angiography 
may be useful in evaluating patients with low likeli
-
hood of significant CAD to rule out disease.
 With lower 
radiation exposure than radionuclide SPECT imaging, 
CT angiography may also be useful for evaluating chest 
pain and suspected acute coronary syndrome. In the large 
randomized comparative effectiveness PROMISE trial, 
patients with stable chest pain undergoing anatomic 
imaging with CT angiography had similar outcomes to 
patients undergoing functional testing (stress ECG, stress 
radionuclide, or stress echocardiography). CT angiogra
-
phy with noninvasive functional assessment of coronary 
stenosis (fractional flow reserve), termed 
CT-FFR,
 has 
also been evaluated in patients with low-intermediate 
likelihood of CAD. CT-FFR has been shown to reduce the 
number of patients without coronary disease requiring 
invasive angiography. CT-FFR has been approved for 
clinical use and is being explored in clinical practice in 
the United States and Europe.
Electron beam CT (EBCT)
 can quantify coronary 
artery calcification, which is highly correlated with ath
-
eromatous plaque and has high sensitivity, but low speci
-
ficity, for obstructive coronary disease. Thus, although 
this test can stratify patients into lower- and higher-risk 
groups, the appropriate management of individual 
patients with asymptomatic coronary artery calcification—
beyond aggressive risk factor modification—is unclear. 
This test has not traditionally been used in symptomatic 
patients. According to the American Heart Association, 
persons who are at low risk (less than 10% 10-year risk) 
or at high risk (greater than 20% 10-year risk) for 
obstructive coronary disease do not benefit from coro
-
nary calcium assessment (class III, level of evidence: B). 
However, in clinically selected, intermediate-risk patients, 
it may be reasonable to determine the atherosclerosis 
burden using EBCT in order to refine clinical risk predic
-
tion and to select patients for more aggressive target 
values for lipid-lowering therapies (class IIb, level of evi
-
dence: B).
Cardiac MRI using gadolinium
 provides high-
resolution images of the heart and great vessels without 
radiation exposure or use of iodinated contrast media. 
Gadolinium has been associated with a rare but fatal 
complication in patients with severe kidney disease, 
called 
necrotizing systemic fibrosis.
 Gadolinium can 
demonstrate perfusion using dobutamine or adenosine to 
produce pharmacologic stress. Advances have been made 
in imaging the proximal coronary arteries. Perhaps the 
most clinically used indication of cardiac MRI is for iden
-
tification of myocardial fibrosis, either from myocardial 
infarction or infiltration, done with gadolinium contrast. 
This allows high-resolution imaging of myocardial viabil
-
ity and infiltrative cardiomyopathies.
I. Ambulatory ECG Monitoring
Ambulatory ECG recorders can monitor for ischemic ST-
segment depression, but this modality is rarely used for 
ischemia detection. In patients with CAD, these episodes 
usually signify ischemia, even when asymptomatic 
(“silent”).
J. Coronary Angiography
Selective coronary arteriography is the definitive diagnos
-
tic procedure for CAD. It can be performed with low mor
-
tality (about 0.1%) and morbidity (1–5%), but due to the 
invasive nature and cost, it is recommended only in 
patients with a high pretest probability of CAD.
Coronary arteriography should be performed in the 
following circumstances if percutaneous transluminal cor
-
onary angioplasty or bypass surgery is a consideration:
1.
 
Life-limiting stable angina despite an adequate medical

-
1.
 
Life-limiting stable angina despite an adequate medical 
regimen.
2.
 
Clinical presentation (unstable angina, postinfarction 
angina, etc) or noninvasive testing suggests high-risk 
disease (see Indications for Revascularization).
3.
 
Concomitant aortic valve disease and angina pectoris, 
to determine whether the angina is due to accompany
-
ing coronary disease.
4.
 
Asymptomatic older patients undergoing valve surgery 
so that concomitant bypass may be done if the anatomy 
is propitious.
5.
 
Recurrence of symptoms after coronary revasculariza
-
tion to determine whether bypass grafts or native ves
-
sels are occluded.
6.
 
Cardiac failure where a surgically correctable lesion, 
such as LV aneurysm, mitral regurgitation, or reversible 
ischemic dysfunction, is suspected.
7.
 
Survivors of sudden death, symptomatic, or life-threat
-
ening arrhythmias when CAD may be a correctable 
cause.
8.
 
Chest pain of uncertain cause or cardiomyopathy of 
unknown cause.
9.
 
Emergently performed cardiac catheterization with 
intention to perform primary PCI in patients with sus
-
pected acute myocardial infarction.
A narrowing of more than 50% of the luminal diameter 
is considered hemodynamically (and clinically) significant, 
although most lesions producing ischemia are associated 
with narrowing in excess of 70%. In those with strongly posi
-
tive exercise ECGs or scintigraphic studies, three-vessel or 
left main disease may be present in 75–95% depending on 
the criteria used. 
Intravascular ultrasound
 
(IVUS)
 is useful 
as an adjunct for assessing the results of angioplasty or stent
-
ing. In addition, IVUS is the invasive diagnostic method of 
choice for ostial left main lesions and coronary dissections. 
In 
fractional flow reserve (FFR),
 a pressure wire is used to 
measure the relative change in pressure across a coronary 
lesion after adenosine-induced hyperemia. Revasculariza
-
tion based on abnormal FFR improves clinical outcomes 
compared to revascularization of all angiographically ste
-
notic lesions. FFR is an important invasive tool to aid with 
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ischemia-driven revascularization and has become the stan
-
dard tool to evaluate borderline lesions in cases in which the 
clinical team is evaluating the clinical and hemodynamic 
significance of a coronary stenosis. Additionally, pressures 
distally/pressures proximally during a wave-free period in 
diastole have been shown to demonstrate similar clinical 
outcomes to FFR, without the use of adenosine.
LV angiography
 is usually performed at the same time 
as coronary arteriography. Global and regional LV function 
are visualized, as well as mitral regurgitation if present. LV 
function is a major determinant of prognosis in CHD.
 
»
When atypical features are present—such as prolonged 
duration (hours or days) or darting, or knifelike pains at 
the apex or over the precordium—ischemia is less likely.
Anterior chest wall syndrome
 is characterized by a 
sharply localized tenderness of the intercostal muscles. 
Inflammation of the chondrocostal junctions may result in 
diffuse chest pain that is also reproduced by local pressure 
(
Tietze syndrome
). Intercostal neuritis (due to herpes zos
-
ter or diabetes mellitus, for example) also mimics angina.
Cervical or thoracic spine disease involving the dorsal 
roots produces sudden sharp, severe chest pain suggesting 
angina in location and “radiation” but related to specific 
movements of the neck or spine, recumbency, and straining 
or lifting. Pain due to cervical or thoracic disk disease 
involves the outer or dorsal aspect of the arm and the thumb 
and index fingers rather than the ring and little fingers.
Reflux esophagitis, peptic ulcer, chronic cholecystitis, 
esophageal spasm, and functional gastrointestinal disease 
may produce pain suggestive of angina pectoris. The pic
-
ture may be especially confusing because ischemic pain 
may also be associated with upper gastrointestinal symp
-
toms, and esophageal motility disorders may be improved 
by nitrates and calcium channel blockers. Assessment of 
esophageal motility may be helpful.
Degenerative and inflammatory lesions of the left 
shoulder and thoracic outlet syndromes may cause chest 
pain due to nerve irritation or muscular compression; the 
symptoms are usually precipitated by movement of the arm 
and shoulder and are associated with paresthesias.
Pneumonia, pulmonary embolism, and spontaneous 
pneumothorax may cause chest pain as well as dyspnea. 
Dissection of the thoracic aorta can cause severe chest pain 
that is commonly felt in the back; it is sudden in onset, 
reaches maximum intensity immediately, and may be asso
-
ciated with changes in pulses. Other cardiac disorders, such 
as mitral valve prolapse, hypertrophic cardiomyopathy, 
myocarditis, pericarditis, aortic valve disease, or RVH, may 
cause atypical chest pain or even myocardial ischemia.
 
»
Treatment
Sublingual nitroglycerin is the medication of choice for 
acute management; it acts in about 1–2 minutes. As soon as 
the attack begins, one fresh tablet is placed under the 
tongue. This may be repeated at 3- to 5-minute intervals, 
but if pain is not relieved or improving after 5 minutes, the 
patient should call 9-1-1; pain not responding to three 
tablets or lasting more than 20 minutes may represent 
evolving infarction. The dosage (0.3, 0.4, or 0.6 mg) and the 
number of tablets to be used before seeking further medical 
attention must be individualized. Nitroglycerin buccal spray 
is also available as a metered (0.4 mg) delivery system. It has 
the advantage of being more convenient for patients who 
have difficulty handling the pills and of being more stable.
 
»
Prevention of Further Attacks
A. Aggravating Factors
Angina may be aggravated by hypertension, LV failure, 
arrhythmia (usually tachycardias), strenuous activity, cold 
temperatures, and emotional states. These factors should 
be identified and treated when possible.
B. Nitroglycerin

Nitroglycerin, 0.3–0.6 mg sublingually or 0.4–0.8 mg trans
-
lingually by spray, should be taken 5 minutes before any 
activity likely to precipitate angina. Sublingual isosorbide 
dinitrate (2.5–5 mg) is only slightly longer-acting than 
sublingual nitroglycerin.
C. Long-Acting Nitrates
Longer-acting nitrate preparations include isosorbide dini
-
trate, 10–40 mg orally three times daily; isosorbide mono
-
nitrate, 10–40 mg orally twice daily or 60–120 mg once 
daily in a sustained-release preparation; oral sustained-
release nitroglycerin preparations, 6.25–12.5 mg two to 
four times daily; nitroglycerin ointment, 2% ointment, 0.5 
to 2 inches (7.5 to 30 mg in the morning and six hours 
later); and transdermal nitroglycerin patches that deliver 
nitroglycerin at rates of 0.2, 0.4, and 0.6 mg/h rate 
(0.1–0.8 mg/h), and should be taken off after 12–14 hours 
of use for a 10–12 hour patch-free interval daily. The main 
limitation to long-term nitrate therapy is tolerance, which 
can be limited by using a regimen that includes a minimum 
8- to 10-hour period per day without nitrates. Isosorbide 
dinitrate can be given three times daily, with the last dose 
after dinner, or longer-acting isosorbide mononitrate once 
daily. Transdermal nitrate preparations should be removed 
overnight in most patients.
Nitrate therapy is often limited by headache. Other side 
effects include nausea, light-headedness, and hypotension. 
Importantly, phosphodiesterase inhibitors used commonly 
for erectile dysfunction should not be taken within 24 hours 
of nitrate use.
D. Beta-Blockers
Beta-blockers are the only antianginal agents that have 
been demonstrated to prolong life in patients with coro
-
nary disease (post–myocardial infarction). Beta-blockers 
should be considered for first-line therapy in most patients 
with chronic angina and are recommened as such by the 
stable ischemic heart disease guidelines (Figure 10–6).
Beta-blockers with intrinsic sympathomimetic activity, 
such as pindolol, are less desirable because they may exac
-
erbate angina in some individuals and have not been effec
-
tive in secondary prevention trials. The pharmacology and 
CMDT19_Ch10_p0334-p0450.indd   372

373
 
CMDT 2019
Lifestyle modi-
fication including diet,
weight loss, physical
activity
AS
A 75–162 mg
daily
Smoking
cessation
pr
ogra
m
Moderate-to
high-dose statin
Drug
therapy 
to
achie
ve
 BP < 140/90
mm Hg 
consider
 
AC
E
/
ARB
 
if
LV
 
dy
sfunction,
diabetes
CKD
Add/substitu
te
CCB and/or long-acting
nitrat
e if no contra
-
indication
Beta-b
lo
cke
r
if no contraindication
(
Espec. if prior MI, heart
fa
ilu
re
 or other
)
Sublingual NTG
Successful
treatment?
te
ranolazine
Appropriate
g
ly
cemic
control
Consider
adding bile-sequestrant
or niacin
Guideline-di
re
cted
medical therapy
with ongoing
patient education
Pe
rs
istent symptoms despi
te
adequate trial of guideline-
di
re
cted medical therapy
BP 
≥ 
140/90 mm
Hg after diet,
pr
ogram?
Hypertension?
Diabetes?
Ci
gare
tt
e
smoking?
See NHLBI ATP III
pr
ev
ention guideline
See JNC VII
and VIII
guidelines
See AHA/ACC
cardiovascular risk
reduction guideline
Stable ischemic heart disease
Anginal symp
to
ms?
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Yes
Clopidog
re
l
75 mg daily 
or
 
AS
A
desensitization
Serious adverse
effect or
contraindication
Co
nsider
reva
scularization
to
 impr
ov
e
symptoms
Contraindicated
or adverse effect
Se
ri
ous contraindication
Se
ri
Yes
Yes
Yes
ACE/AR
B,
 angiotensin-con
ve
rting enzyme/angiotensin receptor blo
cke
r;
 AHA/ACC, American Hea
rt
 A
ssociation/American 
Co
llege of 
Ca
rd
iology
; 
AS
A, 
aspirin; BP , blood pressure; CCB, calcium channel blo
cke
r;
 CKD, chronic kidney disease
; 
MI, 
my
ocardial in
fa
rction
; 
NTG, nitrogl
yc
erin.
 
▲
Figure 10–6.
 
Algorithm for guideline-directed medical therapy for patients with stable ischemic heart disease. The use of bile acid sequestrant is relatively contrain
-
dicated when triglycerides are 200 mg/dL or higher and contraindicated when triglycerides are 500 mg/dL or higher. Dietary supplement niacin must not be used as a 
substitute for prescription niacin. 
(Reproduced, with permission, from Fihn SD et al; American College of Cardiology Foundation/American Heart Association Task Force. 2012 
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation. 2012 Dec 18;126(25):e354–471. 
© 2012 American Heart Association, Inc.)
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side effects of the beta-blockers are discussed in Chapter 11 
(see Table 11–7). The dosages of all these medications 
when given for angina are similar. The major contraindica
-
tions are severe bronchospastic disease, bradyarrhythmias, 
and decompensated heart failure.
E. Ranolazine
Ranolazine is indicated for chronic angina. Ranolazine has 
no effect on heart rate and BP , and it has been shown in clini
-
cal trials to prolong exercise duration and time to angina, 
both as monotherapy and when administered with conven
-
tional antianginal therapy. It is safe to use with erectile dys
-
function drugs. The usual dose is 500 mg orally twice a day. 
Because it can cause QT prolongation, it is contraindicated in 
patients with existing QT prolongation; in patients taking QT 
prolonging medications, such as class I or III antiarrhythmics 
(eg, quinidine, dofetilide, sotalol); and in those taking potent 
and moderate CYP450 3A inhibitors (eg, clarithromycin and 
rifampin). Of interest, in spite of the QT prolongation, there 
is a significantly lower rate of ventricular arrhythmias with its 
use following acute coronary syndromes, as shown in the 
MERLIN trial. It also decreases occurrence of atrial fibrilla
-
tion and results in a small decrease in HbA
1c
. It is contraindi
-
cated in patients with significant liver and kidney disease. 
Ranolazine is not to be used for treatment of acute anginal 
episodes. Ranolazine does not improve outcomes of patients 
who do not get complete coronary revascularization.
F. Calcium Channel Blocking Agents
Unlike the beta-blockers, calcium channel blockers have 
not
 been shown to reduce mortality postinfarction and in 
some cases have increased ischemia and mortality rates. 
This appears to be the case with some dihydropyridines 
(eg, nifedipine) and with diltiazem and verapamil in 
patients with clinical heart failure or moderate to severe LV 
dysfunction. Meta-analyses have suggested that short-acting 
nifedipine in moderate to high doses causes an increase in 
mortality. It is uncertain whether these findings are rele
-
vant to longer-acting dihydropyridines. Nevertheless, con
-
sidering the uncertainties and the lack of demonstrated 
favorable effect on outcomes, calcium channel blockers 
should be considered third-line anti-ischemic medications 
in the postinfarction patient. Similarly, these agents, with 
the exception of amlodipine (which proved safe in patients 
with heart failure in the PRAISE-2 trial), should be avoided 
in patients with heart failure or low EFs.
The pharmacologic effects and side effects of the cal
-
cium channel blockers are discussed in Chapter 11 and 
summarized in Table 11–9. Diltiazem, amlodipine, and 
verapamil are preferable because they produce less reflex 
tachycardia and because the former, at least, may cause 
fewer side effects. Nifedipine, nicardipine, and amlodipine 
are also approved agents for angina. Isradipine, felodipine, 
and nisoldipine are not approved for angina but probably 
are as effective as the other dihydropyridines.
G. Ivabradine
Ivabradine selectively blocks the I
f
 current and specifically 
lowers heart rate. It has been shown to reduce angina in 
patients with chronic stable angina and is approved in 
Europe. However, the SIGNIFY trial found no overall dif
-
ference in clinical outcomes in patients without heart fail
-
ure and angina and that there may have been harm for 
patients with significant angina with regard to outcomes of 
cardiovascular death and myocardial infarction.
H. Alternative and Combination Therapies
Patients who do not respond to one class of antianginal 
medication often respond to another. It may, therefore, be 
worthwhile to use an alternative agent before progressing 
to combinations. The stable ischemic heart disease guide
-
lines recommend starting with a beta-blocker as initial 
therapy, followed by calcium channel blockers, long-acting

-
therapy, followed by calcium channel blockers, long-acting 
nitrates, or ranolazine. A few patients will have further 
response to a regimen including all four agents.
I. Platelet-Inhibiting Agents
Several studies have demonstrated the benefit of antiplate
-
let medications for patients with stable and unstable vascu
-
lar disease. Therefore, unless contraindicated, 
aspirin
 (81–325 
mg orally daily) should be prescribed for all patients with 
angina. 
Clopidogrel,
 75 mg orally daily, reduces vascular 
events in patients with stable vascular disease (as an alter
-
native to aspirin) and in patients with acute coronary syn
-
dromes (in addition to aspirin). Thus, it is also a good 
alternative in aspirin-intolerant patients. Clopidogrel in 
addition to aspirin did not reduce myocardial infarction, 
stroke, or cardiovascular death in the CHARISMA trial of 
patients with cardiovascular disease or multiple risk fac
-
tors, with about a 50% increase in bleeding. However, it 
might be reasonable to use combination clopidogrel and 
aspirin for certain high-risk patients with established coro
-
nary disease. Specifically, 
prolonged used of dual anti
-
platelet therapy with aspirin and clopidogrel may be 
beneficial in patients post–percutaneous stenting with 
drug-eluting stents, in patients with low bleeding risk.
Ticagrelor,
 a P2Y12 inhibitor, has been shown to 
reduce cardiovascular events in patients with acute coro
-
nary syndromes. Additionally, in patients with prior myo
-
cardial infarction, long-term treatment with ticagrelor plus 
aspirin reduced cardiovascular events compared to aspirin 
alone. In patients with peripheral artery disease, ticagrelor 
monotherapy did not reduce cardiovascular events com
-
pared to clopidogrel.
The latest antiplatelet agent to be approved by the FDA, 
vorapaxar,
 is an inhibitor of the protease-activated recep
-
tor-1. It was shown to reduce cardiovascular events for 
patients with stable atherosclerosis with a history of myocar
-
dial infarction or peripheral artery disease in the TRA 2P 
trial. It is contraindicated for patients with a history of stroke 
or TIA due to increased risk of intracranial hemorrhage. 
Therefore, current guidelines recommend dual antiplatelet 
therapy (aspirin + P2Y12 therapy) in patients with recent 
myocardial infarction (within 1 year) or recent stenting 
(within 6 months) and for prolonged therapy (more than 1 year) 
in patients at high ischemic risk (multi-vessel coronary disease 
or polyvascular disease) and low bleeding risk.
Rivaroxaban,
 a direct factor Xa inhibitor, when used at a 
dose of 2.5 mg twice daily in addition to low-dose aspirin 
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CMDT 2019
was found to reduce cardiovascular events including cardio
-
vascular death, myocardial infarction, or stroke when com
-
pared to aspirin monotherapy in patients with known CAD 
or peripheral artery disease. Once approved by the FDA, this 
regimen will provide another important option for patients.
J. Risk Reduction
Patients with coronary disease should undergo aggressive 
risk factor modification.
 This approach, with a particular 
focus on statin treatment, treating hypertension, stopping 
smoking, and exercise and weight control (especially for 
patients with metabolic syndrome or at risk for diabetes), 
may markedly improve outcomes. For patients with diabe
-
tes and cardiovascular disease, there is uncertainty about 
the optimal target blood sugar control. The ADV ANCE 
trial suggested some benefit for tight blood sugar control 
with target HbA
1C
 of 6.5% or less but the ACCORD trial 
found that routine aggressive targeting for blood sugar 
control to HbA
1C
 to less than 6.0% in patients with diabetes 
and coronary disease was associated with increased mor
-
tality. Therefore, tight blood sugar control should be 
avoided particularly in patients with a history of severe 
hypoglycemia, long-standing diabetes, and advanced vas
-
cular disease. Aggressive BP control (target systolic BP less 
than 120 mm Hg) in the ACCORD trial was not associated 
with reduction in CHD events despite reducing stroke. In 
contrast, the SPRINT trial, which did not include diabetic 
patients, demonstrated a reduction in cardiovascular 
events in patients with a reduction in death from any cause 
and reduction in myocardial infarction with a goal systolic 
BP of less than 120 mm Hg versus of goal of less than 
140 mm Hg. Some increase in adverse events was noted. 
Based on this and the totality of results, the AHA has rec
-
ommended defining hypertension at the 130 mm Hg level.
K. Revascularization
1. Indications—
There is general agreement that otherwise 
healthy patients in the following groups should undergo 
revascularization: (1) Patients with unacceptable symp
-
toms despite medical therapy to its tolerable limits; (2) 
Patients with left main coronary artery stenosis greater 
than 50% with or without symptoms; (3) Patients with 
three-vessel disease with LV dysfunction (EF less than 50% 
or previous transmural infarction); (4) Patients with unsta
-
ble angina who after symptom control by medical therapy 
continue to exhibit ischemia on exercise testing or moni
-
toring and; (5) Post–myocardial infarction patients with 
continuing angina or severe ischemia on noninvasive test
-
ing. The use of revascularization for patients with acute 
coronary syndromes and acute ST elevation myocardial 
infarction is discussed below.
Data from the COURAGE trial have shown that for 
patients with chronic angina and disease suitable for PCI, 
PCI in addition to stringent guideline-directed medical 
therapy aimed at both risk reduction and anti-anginal care 
offers no mortality benefit beyond excellent medical therapy 
alone, and relatively moderate long-term symptomatic 
improvement. Therefore, for patients with mild to moderate 
CAD and limited symptoms, revascularization may not 
provide significant functional status quality-of-life benefit. 
For patients with moderate to significant coronary stenosis, 
such as those who have two-vessel disease associated with 
underlying LV dysfunction, anatomically critical lesions 
(greater than 90% proximal stenoses, especially of the proxi
-
mal left anterior descending artery), or physiologic evidence 
of severe ischemia (early positive exercise tests, large exer
-
cise-induced thallium scintigraphic defects, or frequent epi
-
sodes of ischemia on ambulatory monitoring), a Heart Team 
consisting of revascularization physicians (interventional 
cardiologists and surgeons) may be required to review and 
provide patients with the best revascularization options.
2. Type of procedure
a. 
P

a. 
P
ercutaneous coronary intervention includ
ing 
stenting
—
PCI, including balloon angioplasty and coro
-
nary stenting, can effectively open stenotic coronary arter
-
ies. Coronary stenting, with either bare metal stents or 
drug-eluting stents, has substantially reduced restenosis. 
Stenting can also be used selectively for left main coronary 
stenosis, particularly when CABG is contraindicated or 
deemed high risk.
PCI is possible but often less successful in bypass graft 
stenoses. Experienced operators are able to successfully 
dilate more than 90% of lesions attempted. The major early 
complication is intimal dissection with vessel occlusion, 
although this is rare with coronary stenting. The use of 
intravenous platelet glycoprotein IIb/IIIa inhibitors 
(abciximab, eptifibatide, tirofiban)
 substantially reduces 
the rate of periprocedural myocardial infarction, and place
-
ment of intracoronary stents markedly improves initial and 
long-term angiographic results, especially with complex 
and long lesions. After percutaneous coronary intervention, 
all patients should have CK-MB and troponin measured. 
The definition of a periprocedural infarction has been 
debated, with many experts advocating for a clinical defini
-
tion that incorporates different enzyme cutpoints, angio
-
graphic findings, and electrocardiographic evidence. Acute 
thrombosis after stent placement can largely be prevented 
by aggressive antithrombotic therapy (long-term aspirin, 
81–325 mg, plus clopidogrel, 300–600 mg loading dose fol
-
lowed by 75 mg daily, for between 30 days and 1 year, and 
with acute use of platelet glycoprotein IIb/IIIa inhibitors).
A major limitation with PCI has been 
restenosis,
 which 
occurs in the first 6 months in less than 10% of vessels treated 
with drug-eluting stents, 15–30% of vessels treated with bare 
metal stents, and 30–40% of vessels without stenting. Factors 
associated with higher restenosis rates include diabetes, small 
luminal diameter, longer and more complex lesions, and 
lesions at coronary ostia or in the left anterior descending 
coronary artery. Drug-eluting stents that elute antiprolifera
-
tive agents, such as sirolimus, everolimus, zotarolimus, or 
paclitaxel, have substantially reduced restenosis. In-stent 
restenosis is often treated with restenting with drug-eluting 
stents, and rarely with brachytherapy. The nearly 2 million 
PCIs performed worldwide per year far exceed the number of 
CABG operations, but the rationale for many of the proce
-
dures performed in patients with stable angina should be for 
angina symptom reduction. The COURAGE trial has con
-
firmed earlier studies in showing that even for patients with 
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moderate anginal symptoms and positive stress tests PCI 
provides no benefit over medical therapy with respect to 
death or myocardial infarction. PCI was more effective at 
relieving angina, although most patients in the medical group 
had improvement in symptoms. PCI was also not more effec
-
tive than optimal medical therapy for exercise time in 
patients with one vessel coronary disease. Thus, 
in patients 
with mild or moderate stable symptoms, aggressive lipid-
lowering and antianginal therapy may be a preferable ini
-
tial strategy, reserving PCI for patients with significant 
and refractory symptoms or for those who are unable to 
take the prescribed medicines.
Several studies of PCI, including those with drug-
eluting stents, versus CABG in patients with multivessel 
disease have been reported. The SYNTAX trial as well as 
previously performed trials with drug-eluting stent use in 
PCI patients show comparable mortality and infarction 
rates over follow-up periods of 1–3 years but a high rate 
(approximately 40%) of repeat procedures following PCI. 
Stroke rates are higher with CABG. As a result, the choice 
of revascularization procedure may depend on details of 
coronary anatomy and is often a matter of patient prefer
-
ence. However, it should be noted that less than 20% of 
patients with multivessel disease meet the entry criteria for 
the clinical trials, so these results cannot be generalized to 
all multivessel disease patients. Outcomes with percutane
-
ous revascularization in patients with diabetes have gener
-
ally been inferior to those with CABG. The FREEDOM 
trial demonstrated that CABG surgery was superior to PCI 
with regards to death, myocardial infarction, and stroke for 
patients with diabetes and multivessel coronary disease at 
5 years across all subgroups of SYNTAX score anatomy.
b. 
C
oronary artery bypass grafting
—
CABG can be 
accomplished with a very low mortality rate (1–3%) in other
-
wise healthy patients with preserved cardiac function. How
-
ever, the mortality rate of this procedure rises to 4–8% in older 
individuals and in patients who have had a prior CABG.
Grafts using one or both internal mammary arteries 
(usually to the left anterior descending artery or its 
branches) provide the best long-term results in terms of 
patency and flow. Segments of the saphenous vein (or, less 
optimally, other veins) or the radial artery interposed 
between the aorta and the coronary arteries distal to the 
obstructions are also used. One to five distal anastomoses 
are commonly performed.
Minimally invasive surgical techniques
 may involve a 
limited sternotomy, lateral thoracotomy (MIDCAB), or tho
-
racoscopy (port-access). They are more technically demand
-
ing, usually not suitable for more than two grafts, and do not 
have established durability. Bypass surgery can be performed 
both on circulatory support (on-pump) and without direct 
circulatory support (off-pump). Randomized trial data 
have not shown a benefit with off-pump bypass surgery, 
but minimally invasive surgical techniques allow earlier 
postoperative mobilization and discharge.
The operative mortality rate is increased in patients 
with poor LV function (LVEF less than 35%) or those 
requiring additional procedures (valve replacement or ven
-
tricular aneurysmectomy). Patients over 70 years of age, 
patients undergoing repeat procedures, or those with 
important noncardiac disease (especially chronic kidney 
disease and diabetes) or poor general health also have 
higher operative mortality and morbidity rates, and full 
recovery is slow. Thus, CABG should be reserved for more 
severely symptomatic patients in this group. Early (1–6 months) 
graft patency rates average 85–90% (higher for internal 
mammary grafts), and subsequent graft closure rates are 
about 4% annually. Early graft failure is common in vessels 
with poor distal flow, while late closure is more frequent in

with poor distal flow, while late closure is more frequent in 
patients who continue smoking and those with untreated 
hyperlipidemia. Antiplatelet therapy with aspirin improves 
graft patency rates. Smoking cessation and vigorous treat
-
ment of blood lipid abnormalities (particularly with statins) 
are necessary. Repeat revascularization may be necessitated 
because of recurrent symptoms due to progressive native 
vessel disease and graft occlusions. Reoperation is techni
-
cally demanding and less often fully successful than the 
initial operation. In addition, in patients with ischemic 
mitral regurgitation, mitral repair at the time of a CABG 
does not offer any clinical benefit.
L. Mechanical Extracorporeal Counterpulsation
Extracorporeal counterpulsation entails repetitive infla
-
tion of a high-pressure chamber surrounding the lower 
half of the body during the diastolic phase of the cardiac 
cycle for daily 1-hour sessions over a period of 7 weeks. 
Randomized trials have shown that extracorporeal coun
-
terpulsation reduces angina, thus it may be considered for 
relief of refractory angina in patients with stable coronary 
disease.
M. Neuromodulation
Spinal cord stimulation can be used to relieve chronic 
refractory angina. Spinal cord stimulators are subcutane
-
ously implantable via a minimally invasive procedure 
under local anesthesia.
 
»
Prognosis
The prognosis of angina pectoris has improved with devel
-
opment of therapies aimed at secondary prevention. Mor
-
tality rates vary depending on the number of vessels 
diseased, the severity of obstruction, the status of LV func
-
tion, and the presence of complex arrhythmias. Mortality 
rates are progressively higher in patients with one-, two-, 
and three-vessel disease and those with left main coronary 
artery obstruction (ranging from 1% per year to 25% per 
year). The outlook in individual patients is unpredictable, 
and nearly half of the deaths are sudden. Therefore, risk 
stratification is attempted. Patients with accelerating symp
-
toms have a poorer outlook. Among stable patients, those 
whose exercise tolerance is severely limited by ischemia 
(less than 6 minutes on the Bruce treadmill protocol) and 
those with extensive ischemia by exercise ECG or scintig
-
raphy have more severe anatomic disease and a poorer 
prognosis. The Duke Treadmill Score, based on a standard 
Bruce protocol exercise treadmill test, provides an estimate 
of risk of death at 1 year. The score uses time on the tread
-
mill, amount of ST-segment depression, and presence of 
angina (Table 10–8).
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»
All patients with new or worsening symptoms believed to 
represent progressive angina or a positive stress test for 
myocardial ischemia with continued angina despite medi
-
cal therapy (or both) should be referred to a cardiologist.
 
»
•	
Patients with elevated cardiac biomarkers, ischemic 
ECG findings, or hemodynamic instability.
•	
Patients with new or worsened symptoms, possibly 
thought to be ischemic, but who lack high-risk features 
can be observed with serial ECGs and biomarkers, and 
discharged if stress testing shows low-risk findings.
Al-Lamee R et al; ORBITA Investigators. Percutaneous coronary 
intervention in stable angina (ORBITA): a double-blind, ran
-
domised controlled trial. Lancet. 2018 Jan 6;391(10115):
 
31–40. [PMID: 29103656]
Davies JE et al. Use of the instantaneous wave-free ratio or 
fractional flow reserve in PCI. N Engl J Med. 2017 May 11;
 
376(19):1824–34. [PMID: 28317458]
Douglas PS et al; PLATFORM Investigators. Clinical outcomes 
of fractional flow reserve by computed tomographic angiog
-
raphy-guided diagnostic strategies vs. usual care in patients 
with suspected coronary artery disease: the prospective longi
-
tudinal trial of FFRCT: outcome and resource impacts study. 
Eur Heart J. 2015 Dec 14;36(47):3359–67. [PMID: 26330417]
-
Fihn SD et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS 
guideline for the diagnosis and management of patients with 
stable ischemic heart disease: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force 
on Practice Guidelines, and the American College of Physicians, 
American Association for Thoracic Surgery, Preventive Cardio
-
vascular Nurses Association, Society for Cardiovascular Angiog
-
raphy and Interventions, and Society of Thoracic Surgeons. 
Circulation. 2012 Dec 18;126(25):e354–471. [PMID: 23166211]
Fox K et al; SIGNIFY Investigators. Ivabradine in stable coronary 
artery disease without clinical heart failure. N Engl J Med. 
2014 Sep 18;371(12):1091–9. [PMID: 25176136]
Table 10–8.
 
Duke Treadmill Score: calculation and 
interpretation.
Time in minutes on Bruce protocol
= ________________
–5 × amount of depression (in mm)
–4 × angina index
0 = no angina on test
1 = angina, not limiting
2 = limiting angina
Total Summed Score
Risk Group
Annual Mortality
≥ 5
Low
0.25%
–10 to 4
Intermediate
1.25%
≤ –11
High
5.25%
Götberg M et al; iFR-SWEDEHEART Investigators. Instanta
-
neous wave-free ratio versus fractional flow reserve to guide 
PCI. N Engl J Med. 2017 May 11;376(19):1813–23. [PMID: 
28317438]
Hiatt WR et al; EUCLID Trial Steering Committee and Investi
-
gators. Ticagrelor versus clopidogrel in symptomatic periph
-
eral artery disease. N Engl J Med. 2017 Jan 5;376(1):32–40. 
[PMID: 27959717]
artery disease: a report of the American College of Cardiology/
Guidelines: an update of the 2011 ACCF/AHA/SCAI guide
-
line for percutaneous coronary intervention, 2011 ACCF/
AHA guideline for coronary artery bypass graft surgery, 2012 
ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the 
diagnosis and management of patients with stable ischemic 
heart disease, 2013 ACCF/AHA guideline for the manage
-
ment of ST-elevation myocardial infarction, 2014 AHA/ACC 
guideline for the management of patients with non-ST-
elevation acute coronary syndromes, and 2014 ACC/AHA

-
elevation acute coronary syndromes, and 2014 ACC/AHA 
guideline on perioperative cardiovascular evaluation and 
management of patients undergoing noncardiac surgery. 
Circulation. 2016 Sep 6;134(10):e123–55. Erratum in: Circu
-
lation. 2016 Sep 6;134(10):e192–4. [PMID: 27026020]
Mauri L et al; DAPT Study Investigators. Twelve or 30 months of 
dual antiplatelet therapy after drug-eluting stents. N Engl J 
Med. 2014 Dec 4;371(23):2155–66. [PMID: 25399658]
Smith PK et al; Cardiothoracic Surgical Trials Network Investi
-
gators. Surgical treatment of moderate ischemic mitral regur
-
gitation. N Engl J Med. 2014 Dec 4;371(23):2178–88. [PMID: 
25405390]
Med. 2015 Nov 26;373(22):2103–16. Erratum in: N Engl J 
Med. 2017 Dec 21;377(25):2506. [PMID: 26551272]
Stone GW et al; EXCEL Trial Investigators. Everolimus-eluting 
stents or bypass surgery for left main coronary artery disease. 
N Engl J Med. 2016 Dec 8;375(23):2223–35. [PMID: 
27797291]
Weisz G et al; RIVER-PCI investigators. Ranolazine in patients 
with incomplete revascularisation after percutaneous coro
-
nary intervention (RIVER-PCI): a multicentre, randomised, 
double-blind, placebo-controlled trial. Lancet. 2016 Jan 9;
 
387(10014):136–45.
CORONARY VASOSPASM & ANGINA WITH 
NORMAL CORONARY ARTERIOGRAMS
 
»
Precordial chest pain, often occurring at rest dur
-
ing stress or without known precipitant, relieved 
rapidly by nitrates.
 
»
ECG evidence of ischemia during pain, sometimes 
with ST-segment elevation.
 
»
Angiographic demonstration of:
– 
 
No sig
nificant obstruction of major coronary 
vessels.
– 
 
C
oronary spasm that responds to intracoronary 
nitroglycerin or calcium channel blockers.
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»
Although most symptoms of myocardial ischemia result 
from fixed stenosis of the coronary arteries, intraplaque 
hemorrhage, or thrombosis at the site of lesions, some 
ischemic events may be precipitated or exacerbated by 
coronary vasoconstriction.
Spasm of the large coronary arteries with resulting 
decreased coronary blood flow may occur spontaneously 
or may be induced by exposure to cold, emotional stress, or 
vasoconstricting medications, such as ergot-derivative 
medications. Spasm may occur both in normal and in ste
-
nosed coronary arteries. Even myocardial infarction may 
occur as a result of spasm in the absence of visible obstruc
-
tive CHD, although most instances of such coronary spasm 
occur in the presence of coronary stenosis.
Cocaine can induce myocardial ischemia and infarction 
by causing coronary artery vasoconstriction or by increas
-
ing myocardial energy requirements. It also may contribute 
to accelerated atherosclerosis and thrombosis. The isch
-
emia in 
Prinzmetal (variant) angina
 usually results from 
coronary vasoconstriction. It tends to involve the right 
coronary artery and there may be no fixed stenoses. Myo
-
cardial ischemia may also occur in patients with normal 
coronary arteries as a result of disease of the coronary 
microcirculation or abnormal vascular reactivity. This has 
been termed “
syndrome X
.”
 
»
Ischemia may be silent or result in angina pectoris.
Prinzmetal (variant) angina is a clinical syndrome in 
which chest pain occurs without the usual precipitating fac
-
tors and is associated with ST-segment elevation rather than 
depression. It often affects women under 50 years of age. It 
characteristically occurs in the early morning, awakening 
patients from sleep, and is apt to be associated with arrhyth
-
mias or conduction defects. It may be diagnosed by chal
-
lenge with ergonovine (a vasoconstrictor), although the 
results of such provocation are not specific and it entails risk.
 
»
Treatment
Patients with chest pain associated with ST-segment eleva
-
tion should undergo coronary arteriography to determine 
whether fixed stenotic lesions are present. If they are, 
aggressive medical therapy or revascularization is indicated, 
since this may represent an unstable phase of the disease. If 
significant lesions are not seen and spasm is suspected, 
avoidance of precipitants, such as cigarette smoking and 
cocaine, is the top priority. Episodes of coronary spasm 
generally respond well to nitrates, and both nitrates and 
calcium channel blockers (including long-acting nifedipine, 
diltiazem, or amlopidine [see Table 11–9]) are effective 
prophylactically. By allowing unopposed alpha-1-mediated 
vasoconstriction, beta-blockers have exacerbated coronary 
vasospasm, but they may have a role in management of 
patients in whom spasm is associated with fixed stenoses.
 
»
All patients with persistent symptoms of chest pain that 
may represent spasm should be referred to a cardiologist.
ACUTE CORONARY SYNDROMES WITHOUT 
ST-SEGMENT ELEVATION
 
»
Distinction in acute coronary syndrome between 
patients with and without ST-segment elevation 
at presentation is essential to determine need for 
reperfusion therapy.
 
»
Fibrinolytic therapy is harmful in acute coronary 
syndrome without ST-segment elevation, unlike 
with ST-segment elevation, where acute reperfu
-
sion saves lives.
 
»
Antiplatelet and anticoagulation therapies and 
coronary intervention are mainstays of treatment.
 
»
Acute coronary syndromes
 comprise the spectrum of 
unstable cardiac ischemia from unstable angina to acute 
myocardial infarction. Acute coronary syndromes are clas
-
sified based on the presenting ECG as either 
“ST-segment 
elevation” (STEMI)
 or 
“non–ST-segment elevation” 
(NSTEMI)
. This allows for immediate classification and

-
 or 
(NSTEMI)
. This allows for immediate classification and 
guides determination of whether patients should be con
-
sidered for acute reperfusion therapy. The evolution of 
cardiac biomarkers then allows determination of whether 
myocardial infarction has occurred.
Acute coronary syndromes represent a dynamic state in 
which patients frequently shift from one category to 
another, as new ST elevation can develop after presentation 
and cardiac biomarkers can become abnormal with recur
-
rent ischemic episodes.
 
»
Patients with acute coronary syndromes generally have 
symptoms and signs of myocardial ischemia either at rest 
or with minimal exertion. These symptoms and signs are 
similar to the chronic angina symptoms described above, 
consisting of substernal chest pain or discomfort that may 
radiate to the jaw, left shoulder or arm. Dyspnea, nausea, 
diaphoresis, or syncope may either accompany the chest 
discomfort or may be the only symptom of acute coronary 
syndrome. About one-third of patients with myocardial 
infarction have no chest pain per se—these patients tend to 
be older, female, have diabetes, and be at higher risk for 
subsequent mortality. Patients with acute coronary syn
-
dromes have signs of heart failure in about 10% of cases, 
and this is also associated with higher risk of death.
Many hospitals have developed chest pain observation 
units to provide a systematic approach toward serial risk 
stratification to improve the triage process. In many cases, 
those who have not experienced new chest pain and have 
insignificant ECG changes and no cardiac biomarker eleva
-
tion undergo treadmill exercise tests or imaging 
CMDT19_Ch10_p0334-p0450.indd   378

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procedures to exclude ischemia at the end of an 8- to 
24-hour period and are discharged directly from the emer
-
gency department if these tests are negative.
Depending on the time from symptom onset to presenta
-
tion, initial laboratory findings may be normal. The markers 
of cardiac myocyte necrosis (myoglobin, CK-MB and 
tropnin I and T) may all be used to identify acute myocardial 
infarction. These markers have a well-described pattern of 
release over time in patients with myocardial infarction (see 
Laboratory Findings, Acute Myocardial Infarction with ST-
Segment Elevation, below). In patients with STEMI, these 
initial markers are often within normal limits as the patient 
is being rushed to immediate reperfusion. In patients with
-
out ST-segment elevation, it is the presence of abnormal 
CK-MB or troponin values that are associated with myocyte 
necrosis and the diagnosis of myocardial infarction. The 
universal definition of myocardial infarction is a rise of car
-
diac biomarkers with at least one value above the 99th per
-
centile of the upper reference limit together with evidence of 
myocardial ischemia with at least one of the following: 
symptoms of ischemia, ECG changes of new ischemia, new 
Q waves, or imaging evidence of new loss of viable myocar
-
dium or new wall motion abnormality.
Serum creatinine is an important determinant of risk, 
and estimated creatinine clearance is important to guide 
dosing of certain antithrombotics, including eptifibatide 
and enoxaparin.
C. ECG
Many patients with acute coronary syndromes will exhibit 
ECG changes during pain—either ST-segment elevation, 
ST-segment depression, or T wave flattening or inversion. 
Dynamic ST-segment shift is the most specific for acute 
coronary syndrome. ST-segment elevation in lead AVR 
suggests left main or three vessel disease.
 
»
Treatment
Treatment of acute coronary syndromes without ST eleva
-
tion should be multifaceted. Patients who are at medium or 
high risk should be hospitalized, maintained at bed rest or 
at very limited activity for the first 24 hours, monitored, 
and given supplemental oxygen. Sedation with a benzodi
-
azepine agent may help if anxiety is present.
Figure 10–7 provides an algorithm for initial management 
of non–ST-segment myocardial infarction.
C. Antiplatelet and Anticoagulation Therapy
Patients should receive a combination of antiplatelet and 
anticoagulant agents on presentation. Fibrinolytic therapy 
should be 
avoided
 in patients without ST-segment eleva
-
tion since they generally do not have an acute coronary 
occlusion, and the risk of such therapy appears to outweigh 
the benefit.
1. Antiplatelet therapy
a. 
A
spirin
—
Aspirin, 162–325 mg loading dose, then 
81–325 mg daily, should be commenced immediately and 
continued for the first month. The 2012 ACC/AHA guide
-
lines for longer-term aspirin treatment recommend aspirin 
75–162 mg/day as preferable to higher doses with or with
-
out coronary stenting.
b. 
P2Y
12
 inhibitors
—
ACC/AHA guidelines call for 
either a P2Y
12
 inhibitor (clopidogrel, prasugrel [at the time 
of PCI], or ticagrelor) as a class I recommendation. The 
ESC guidelines provide a stronger recommendation for a 
P2Y
12
 inhibitor up-front, as a class IA recommendation for 
all patients. Both sets of guidelines recommend postponing 
elective CABG surgery for at least 5 days after the last dose 
of clopidogrel or ticagrelor and at least 7 days after the last 
dose of prasugrel, due to risk of bleeding.
The Clopidogrel in Unstable Angina to Prevent Recur
-
rent Events (CURE) trial demonstrated a 20% reduction in 
the composite end point of cardiovascular death, myocar
-
dial infarction, and stroke with the addition of clopidogrel 
(300-mg loading dose, 75 mg/day for 9–12 months) to 
aspirin in patients with non–ST-segment elevation acute

-
aspirin in patients with non–ST-segment elevation acute 
coronary syndromes. The large CURRENT trial showed 
that “double-dose” clopidogrel (600-mg initial oral loading 
dose, followed by 150 mg orally daily) for 7 days reduced 
stent thrombosis with a modest increase in major (but not 
fatal) bleeding and, therefore, it is an option for patients 
with acute coronary syndrome undergoing PCI.
The ESC guidelines recommend ticagrelor for all 
patients at moderate to high risk for acute coronary syn
-
drome (class 1 recommendation). Prasugrel is recom
-
mended for patients who have not yet received another 
P2Y
12
 inhibitor, for whom a PCI is planned, and who are 
not at high risk for life-threatening bleeding. Clopidogrel is 
reserved for patients who cannot receive either ticagrelor or 
prasugrel. Some studies have shown an association between 
assays of residual platelet function and thrombotic risk dur
-
ing P2Y
12
 inhibitor therapy, and both the European and the 
US guidelines do not recommend routine platelet function 
testing to guide therapy (class IIb recommendation).
Prasugrel is both more potent and has a faster onset of 
action than clopidogrel. The TRITON trial compared pra
-
sugrel with clopidogrel in patients with STEMI or NSTEMI 
in whom PCI was planned; prasugrel resulted in a 19% 
relative reduction in death from cardiovascular causes, 
myocardial infarction, or stroke, at the expense of an 
increase in serious bleeding (including fatal bleeding). 
Stent thrombosis was reduced by half. Because patients 
with prior stroke or TIA had higher risk of intracranial 
hemorrhage, prasugrel is contraindicated in such patients. 
Bleeding was also higher in patients with low body weight 
(less than 60 kg) and age 75 years or older, and caution 
should be used in these populations. For patients with 
STEMI treated with PCI, prasugrel appears to be especially 
effective (compared to clopidogrel) without a substantial 
increase in bleeding. For patients who will not receive 
revascularization, prasugrel, when compared to clopido
-
grel, had no overall benefit in the TRILOGY trial (the dose 
of prasugrel was lowered for older adults).
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Ticagrelor has a faster onset of action than clopidogrel 
and a more consistent and potent effect. The PLATO trial 
showed that when ticagrelor was started at the time of pre
-
sentation in acute coronary syndrome patients (UA/
NSTEMI and STEMI), it reduced cardiovascular death, 
myocardial infarction, and stroke by 16% when compared 
with clopidogrel. In addition, there was a 22% relative risk 
reduction in mortality with ticagrelor. The overall rates of 
bleeding were similar between ticagrelor and clopidogrel, 
although non–CABG-related bleeding was modestly 
higher. The finding of a lesser treatment effect in the 
United States may have been related to use of higher-dose 
aspirin, and thus when using ticagrelor, low-dose aspirin 
(81 mg/day) is recommended.
c. 
G
lycoprotein 
II
b/
III
a inhibitors
—
Small-molecule 
inhibitors of the platelet glycoprotein IIb/IIIa receptor are 
useful adjuncts in high-risk patients (usually defined by 
fluctuating ST-segment depression or positive biomarkers) 
with acute coronary syndromes, particularly when they are 
undergoing PCI. Tirofiban, 25 mcg/kg over 3 minutes, fol
-
lowed by 0.15 mcg/kg/min, and eptifibatide, 180 mcg/kg 
bolus followed by a continuous infusion of 2 mcg/kg/min, 
have both been shown to be effective. Downward dose 
Diagnosis of UA/NSTEMI is likely or definite
AS
A (class I)
Clopidogrel if 
AS
A intolerant (class I)
Select management strategy
Initial conservative strategy or unknown
Invasiv
e strat
egy
Initiate anticoagulant therapy (class I) 
Acceptable options include 
• Eno
xaparin or UFH (class I) 
• F
ondaparinux (class I) 
• Eno
xaparin or fondaparinux preferred
 
ov
er UFH (class lIa)
Initiate anticoagulant therapy
(class I)
Acceptable options include
• Eno
xaparin or UFH (class I)
• Biv
alirudin (class I)
Initiate clopidogrel (class I)
Pr
ecatheterization:
 A
dd second
antiplatelet agent (class I)
• Clopidog
re
l (class I) 
or
• GP IIb/llla inhibit
or (class I)
• (IV eptif
ibatide or ti
ro
fi
ban preferred)
Next step per triage decision at
angiograph
y
PCI:
Class I:
• Clopidogr
el (if not begun
 precathe
te
rization) 
or
• 
Pr
asugrel 
or
• Selectiv
el
y,
 a GP Ilb/llIa inhibit
or
 (if not begun precathe
te
rization)
C
ABG:
Maintenance 
AS
A
(class I)
Medical Therapy:
discontinue
GP llb/llla
 inhibi
tors
 if begun
and gi
ve
 clopidog
re
l
per conservative
 strat
egy
 
▲
Figure 10–7.
 
Flowchart for class I and class IIa recommendations for initial management of unstable angina/non–
ST-segment elevation myocardial infarction (UA/NSTEMI). ASA, aspirin; CABG, coronary artery bypass grafting; GP IIb/
IIIa, glycoprotein IIb/IIIa; LOE, level of evidence; UFH, unfractionated heparin. 
Wright RS et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable 
Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 May 10; 
123(18):2022–60. Erratum in: Circulation. 2011 Sep 20;124(12):e337–40; Circulation. 2011 Jun 7;123(22):e625–6. © 2011 
American Heart Association, Inc.)
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adjustments of the infusions are required in patients with 
reduced kidney function. The bolus or loading dose remains 
unadjusted. For example, if the estimated creatinine clear
-
ance is below 50 mL/min, the eptifibatide infusion should 
be cut in half to 1 mcg/kg/min. The ISAR-REACT 2 trial 
showed that for patients undergoing PCI with high-risk 
acute coronary syndrome, especially with elevated tropo
-
nin, intravenous abciximab (added to a 600 mg loading 
dose of clopidogrel) reduces ischemic events by about 25%. 
The EARLY-ACS trial in over 10,000 patients with high-risk 
acute coronary syndrome found no benefit from eptifiba
-
tide started at the time of admission and higher rates of 
bleeding compared with eptifibatide treatment started at 
the time of invasive coronary angiography.
2. Anticoagulant therapy
a. 
H
eparin—
Several trials have shown that LMWH 
(enoxaparin 1 mg/kg subcutaneously every 12 hours) is 
somewhat more effective than unfractionated heparin in 
preventing recurrent ischemic events in the setting of acute 
coronary syndromes. However, the SYNERGY trial showed 
that unfractionated heparin and enoxaparin had similar 
rates of death or (re)infarction in the setting of frequent 
early coronary intervention.
b. 
F
ondaparinux
—
Fondaparinux, a specific factor Xa 
inhibitor given in a dose of 2.5 mg subcutaneously once a 
day, was found in the OASIS-5 trial to be equally effective 
as enoxaparin among 20,000 patients at preventing early 
death, myocardial infarction, and refractory ischemia, and 
resulted in a 50% reduction in major bleeding. This reduc
-
tion in major bleeding translated into a significant reduc
-
tion in mortality (and in death or myocardial infarction) at 
30 days. While catheter-related thrombosis was more com
-
mon during coronary intervention procedures with 
fondaparinux, the FUTURA trial found that it can be con
-
trolled by adding unfractionated heparin (in a dose of 
85 units/kg without glycoprotein IIb/IIIa inhibitors, and 
60 units/kg with glycoprotein IIb/IIIa inhibitors) during 
the procedure. Guidelines recommend fondaparinux, 
describing it as especially favorable for patients who are 
initially treated medically and who are at high risk for 
bleeding, such as elderly individuals.
c. 
D
irect thrombin inhibitors
—
The ACUITY trial 
showed that bivalirudin appears to be a reasonable alterna
-
tive to heparin (unfractionated heparin or enoxaparin) 
plus a glycoprotein IIb/IIIa antagonist for many patients 
with acute coronary syndromes who are undergoing early 
coronary intervention. Bivalirudin (without routine glyco
-
protein IIb/IIIa inhibitor) is associated with substantially 
less bleeding than heparin plus glycoprotein IIb/IIIa inhib
-
itor. The ISAR REACT-4 trial showed that bivalirudin has 
similar efficacy compared to abciximab but better bleeding 
outcomes in NSTEMI patients. Bivalrudin does not cur
-
rently have an FDA-approved indication for NSTEMI care.
D. Temporary Discontinuation of Antiplatelet 
Therapy for Procedures
Patients who have had recent coronary stents are at risk for 
thrombotic events, including stent thrombosis, if P2Y
12
 
inhibitors are discontinued for procedures (eg, dental pro
-
cedures or colonoscopy). If possible, these procedures 
should be delayed until the end of the necessary treatment 
period with P2Y
12
 inhibitors, which generally is at least 
1 month with bare metal stents and 3–6 months with drug-
eluting stents. Before that time, if a procedure is necessary, 
risk and benefit of continuing the antiplatelet therapy 
through the time of the procedure should be assessed. Aspi
-
rin should generally be continued throughout the period of 
the procedure. Patients with polymer-free drug coated 
stents who are at high risk for bleeding and receiving a short 
course of dual antiplatelet therapy had fewer cardiovascular 
and bleeding events. A cardiologist should be consulted

and bleeding events. A cardiologist should be consulted 
before temporary discontinuation of these agents.
E. Nitroglycerin
Nitrates are first-line therapy for patients with acute coro
-
nary syndromes presenting with chest pain. Nonparenteral 
therapy with sublingual or oral agents or nitroglycerin 
ointment is usually sufficient. If pain persists or recurs, 
intravenous nitroglycerin should be started. The usual ini
-
tial dosage is 10 mcg/min. The dosage should be titrated 
upward by 10–20 mcg/min (to a maximum of 200 mcg/min) 
until angina disappears or mean arterial pressure drops by 
10%. Careful—usually continuous—BP monitoring is 
required when intravenous nitroglycerin is used. Avoid 
hypotension (systolic BP less than 100 mm Hg). Tolerance 
to continuous nitrate infusion is common.
F. Beta-Blockers
Beta-blockers are an important part of the initial treatment 
of unstable angina unless otherwise contraindicated. The 
pharmacology of these agents is discussed in Chapter 11 
and summarized in Table 11–7. Use of agents with intrinsic 
sympathomimetic activity should be avoided in this set
-
ting. Oral medication is adequate in most patients, but 
intravenous treatment with metoprolol, given as three 
5-mg doses 5 minutes apart as tolerated and in the absence 
of heart failure, achieves a more rapid effect. Oral therapy 
should be titrated upward as BP permits.
G. Calcium Channel Blockers
Calcium channel blockers have not been shown to favor
-
ably affect outcome in unstable angina, and they should be 
used primarily as third-line therapy in patients with con
-
tinuing symptoms on nitrates and beta-blockers or those 
who are not candidates for these medications. In the pres
-
ence of nitrates and without accompanying beta-blockers, 
diltiazem or verapamil is preferred, since nifedipine and 
the other dihydropyridines are more likely to cause reflex 
tachycardia or hypotension. The initial dosage should be 
low, but upward titration should proceed steadily (see 
Table 11–9).
H. Statins
The PROVE-IT trial provides evidence for starting a statin 
in the days immediately following an acute coronary syn
-
drome. In this trial, more intensive therapy with atorvastatin 
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80 mg/day, regardless of total or LDL cholesterol level, 
improved outcome compared to pravastatin 40 mg/day, with 
the curves of death or major cardiovascular event separating 
as early as 3 months after starting therapy. High-dose statins 
are recommended for all patients with acute coronary syn
-
dromes (see Table 10–7).
 
»
Indications for Coronary Angiography
For patients with acute coronary syndrome, including 
non–ST-segment elevation myocardial infarction, risk 
stratification is important for determining intensity of care. 
Several therapies, including glycoprotein IIb/IIIa inhibi
-
tors, LMWH heparin, and early invasive catheterization, 
have been shown to have the greatest benefit in higher-risk 
patients with acute coronary syndrome. As outlined in the 
ACC/AHA guidelines, patients with any high-risk feature 
(Table 10–9) generally warrant an early invasive strategy 
with catheterization and revascularization. For patients 
without these high-risk features, either an invasive or non
-
invasive approach, using exercise (or pharmacologic stress 
for patients unable to exercise) stress testing to identify 
patients who have residual ischemia and/or high risk, can 
be used. Moreover, based on the ICTUS trial, a strategy 
based on selective coronary angiography and revascular
-
ization for instability or inducible ischemia, or both, even 
for patients with positive troponin, is acceptable (ACC/
AHA class IIb recommendation).
Two risk-stratification tools are available that can be 
used at the bedside, the GRACE Risk Score (http://www
 
.outcomes-umassmed.org/grace) and the TIMI Risk Score 
(available for download at http://www.timi.org). The 
GRACE Risk Score,
 which applies to patients with or with
-
out ST elevation, was developed in a more generalizable 
registry population and includes Killip class, BP , ST-segment 
deviation, cardiac arrest at presentation, serum creatinine, 
elevated creatine kinase (CK)-MB or troponin, and heart 
rate. The 
TIMI Risk Score
 includes seven variables: age 
65 years or older, three or more cardiac risk factors, prior 
coronary stenosis 50% or more, ST-segment deviation, two 
anginal events in prior 24 hours, aspirin in prior 7 days, 
and elevated cardiac markers.
 
»
•	
All patients with acute myocardial infarction should be 
•	
Patients who are taking a P2Y
12
 inhibitor following cor
-
onary stenting should consult a cardiologist before dis
-
continuing treatment for nonemergency procedures.
Fanaroff AC et al. JAMA patient page. Acute coronary syn
-
drome. JAMA. 2015 Nov 10;314(18):1990. [PMID: 26547478]
Hamm CW et al. ESC guidelines for the management of acute 
coronary syndromes in patients presenting without persistent 
ST-segment elevation: the Task Force for the Management of 
Acute Coronary Syndromes (ACS) in Patients Presenting 
Without Persistent ST-Segment Elevation of the European 
Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):
 
2999–3054. [PMID: 21873419]
Table 10–9.
 
Indications for catheterization and 
 
percutaneous coronary intervention.
1
Acute coronary syndromes (unstable angina and non-ST 
 
elevation MI)
Class I
Early invasive strategy for any of the following 
 
high-risk indicators:
Recurrent angina/ischemia at rest or with low-level 
activity
Elevated troponin
ST-segment depression
Recurrent ischemia with evidence of HF
High-risk stress test result
EF < 40%
Hemodynamic instability
Sustained ventricular tachycardia
PCI within 6 months
Prior CABG
In the absence of these findings, either an early 
 
conservative or early invasive strategy
Class IIa
Early invasive strategy for patients with repeated 
 
presentations for ACS despite therapy
Class III
Extensive comorbidities in patients in whom benefits 
of revascularization are not likely to outweigh the 
risks
Acute chest pain with low likelihood of ACS
Acute MI after fibrinolytic therapy
Class I

risks
Class I
Cardiogenic shock or acute severe heart failure that 
develops after initial presentation
Intermediate or high-risk findings on predischarge 
noninvasive ischemia testing
Spontaneous or easily provoked myocardial ischemia
Class IIa
Failed reperfusion or reocclusion after fibrinolytic 
therapy
Stable
2
 patients after successful fibrinolysis, before 
 
discharge and ideally between 3 and 24 hours
1
Class I indicates treatment is useful and effective, IIa indicates 
weight of evidence is in favor of usefulness/efficacy, class IIb indi
-
cates weight of evidence is less well established, and class III indi
-
cates intervention is not useful/effective and may be harmful. Level 
of evidence A recommendations are derived from large-scale ran
-
domized trials, and B recommendations are derived from smaller 
randomized trials or carefully conducted observational analyses.
2
Although individual circumstances will vary, clinical stability is 
defined by the absence of low output, hypotension, persistent 
tachycardia, apparent shock, high-grade ventricular or symptom
-
atic supraventricular tachyarrhythmias, and spontaneous recurrent 
ischemia.
ACCF/AHA, American College of Cardiology Foundation/American 
Heart Association; ACS, acute coronary syndrome; CABG, coronary 
artery bypass grafting; EF, ejection fraction; HF, heart failure; MI, 
myocardial infarction; PCI, percutaneous coronary intervention.
Data from O’Gara PT et al. 2013 ACCF/AHA guideline for the manage
-
ment of ST-elevation myocardial infarction: a report of the American 
College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. Circulation. 2013;127. e362–e425.
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Jneid H et al. 2012 ACCF/AHA focused update of the guideline 
for the management of patients with unstable angina/non–
ST-elevation myocardial infarction (updating the 2007 guide
-
line and replacing the 2011 focused update): a report of the 
American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines. Circulation. 
2012 Aug 14;126(7):875–910. [PMID: 22800849]
Levine GN et al. 2011 ACCF/AHA/SCAI guideline for percuta
-
neous coronary intervention: a report of the American Col
-
lege of cardiology foundation/American Heart Association 
Task Force on Practice Guidelines and the Society for Cardio
-
vascular Angiography and Interventions. Circulation. 2011 
 
Dec 6;124(23):e574–651. [PMID: 22064601]
Urban P et al; LEADERS FREE Investigators. Polymer-free drug-
coated coronary stents in patients at high bleeding risk. N Engl 
J Med. 2015 Nov 19;373(21):2038–47. [PMID: 26466021]
ACUTE MYOCARDIAL INFARCTION WITH 
 
»
Sudden but not instantaneous development of 
prolonged (more than 30 minutes) anterior chest 
discomfort (sometimes felt as “gas” or pressure).
 
»
Sometimes painless, masquerading as acute heart 
failure, syncope, stroke, or shock.
 
»
ECG: ST-segment elevation or left bundle branch 
block.
 
»
Immediate reperfusion treatment is warranted.
 
»
Primary PCI within 90 minutes of first medical contact 
is the goal and is superior to fibrinolytic therapy.
 
»
Fibrinolytic therapy within 30 minutes of hospital 
presentation is the goal, and reduces mortality if 
given within 12 hours of onset of symptoms.
 
»
STEMI results, in most cases, from an occlusive coronary 
thrombus at the site of a preexisting (though not necessar
-
ily severe) atherosclerotic plaque. More rarely, infarction 
may result from prolonged vasospasm, inadequate myocar
-
dial blood flow (eg, hypotension), or excessive metabolic 
demand. Very rarely, myocardial infarction may be caused 
by embolic occlusion, vasculitis, aortic root or coronary 
artery dissection, or aortitis. Cocaine, a cause of infarction, 
should be considered in young individuals without risk 
factors. A condition that may mimic STEMI is stress car
-
diomyopathy (also referred to as 
tako-tsubo
 or 
apical bal
-
looning
 syndrome). ST elevation connotes an acute 
coronary occlusion and warrants immediate reperfusion 
therapy with activation of emergency services.
 
»
1. Premonitory pain—
There is usually a worsening in the 
pattern of angina preceding the onset of symptoms of 
myocardial infarction; classically the onset of angina occurs 
with minimal exertion or at rest.
2. Pain of infarction—
Unlike anginal episodes, most 
infarctions occur 
at rest
, and more commonly in the early 
morning. The pain is similar to angina in location and 
radiation but it may be more severe, and it builds up rap
-
idly or in waves to maximum intensity over a few minutes 
or longer. Nitroglycerin has little effect; even opioids may 
not relieve the pain.
3. Associated symptoms—
Patients may break out in a 
cold sweat, feel weak and apprehensive, and move about, 
seeking a position of comfort. They prefer not to lie quietly. 
Light-headedness, syncope, dyspnea, orthopnea, cough, 
wheezing, nausea and vomiting, or abdominal bloating 
may be present singly or in any combination.
4. Painless infarction—
One-third of patients with acute 
myocardial infarction present without chest pain, and 
these patients tend to be undertreated and have poor out
-
comes. Older patients, women, and patients with diabetes 
mellitus are more likely to present without chest pain. As 
many as 25% of infarctions are detected on routine ECG 
without any recallable acute episode.
5. Sudden death and early arrhythmias—
Of all deaths 
from myocardial infarction, about 50% occur before the 
patients arrive at the hospital, with death presumably

patients arrive at the hospital, with death presumably 
caused by ventricular fibrillation.
B. Signs
1. General—
Patients may appear anxious and sometimes 
are sweating profusely. The heart rate may range from 
marked bradycardia (most commonly in inferior infarc
-
tion) to tachycardia, low cardiac output, or arrhythmia. 
The BP may be high, especially in former hypertensive 
patients, or low in patients with shock. Respiratory distress 
usually indicates heart failure. Fever, usually low grade, 
may appear after 12 hours and persist for several days.
2. Chest—
The 
Killip classification
 is the standard way to 
classify heart failure in patients with acute myocardial 
infarction and has powerful prognostic value. Killip class I 
is absence of rales and S
3
, class II is rales that do not clear 
with coughing over one-third or less of the lung fields or 
presence of an S
3
, class III is rales that do not clear with 
coughing over more than one-third of the lung fields, and 
class IV is cardiogenic shock (rales, hypotension, and signs 
of hypoperfusion).
3. Heart—
The cardiac examination may be unimpressive 
or very abnormal. Jugular venous distention reflects RA 
hypertension, and a Kussmaul sign (failure of decrease of 
jugular venous pressure with inspiration) is suggestive of 
RV infarction. Soft heart sounds may indicate LV dysfunc
-
tion. Atrial gallops (S
4
) are the rule, whereas ventricular 
gallops (S
3
) are less common and indicate significant LV 
dysfunction. Mitral regurgitation murmurs are not uncom
-
mon and may indicate papillary muscle dysfunction or, 
rarely, rupture. Pericardial friction rubs are uncommon in 
the first 24 hours but may appear later.
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4. Extremities—
Edema is usually not present. Cyanosis 
and cold temperature indicate low output. The peripheral 
pulses should be noted, since later shock or emboli may 
alter the examination.
Cardiac-specific markers of myocardial damage include 
quantitative determinations of CK-MB, highly sensitive 
and conventional troponin I, and troponin T. Each of these 
tests may become positive as early as 4–6 hours after the 
onset of a myocardial infarction and should be abnormal 
by 8–12 hours. Troponins are more sensitive and specific 
than CK-MB. “Highly sensitive” or “fourth-generation” 
troponin assays were approved in 2017, but are not yet 
widely used in the United States. However, they are the 
standard assays in most of Europe, with a 10- to 100-fold 
lower limit of detection, allowing myocardial infarction to 
be detected earlier, using the change in value over 3 hours.
Circulating levels of troponins may remain elevated for 
5–7 days or longer and therefore are generally not useful for 
evaluating suspected early reinfarction. Elevated CK-MB 
generally normalizes within 24 hours, thus being more help
-
ful for evaluation of reinfarction. Low-level elevations of 
troponin in patients with severe chronic kidney disease may 
not be related to acute coronary disease but rather a function 
of the physiologic washout of the marker. While many con
-
ditions including chronic heart failure are associated with 
elevated levels of the high-sensitivity troponin assays, these 
assays may be especially useful when negative to exclude 
myocardial infarction in patients reporting chest pain.
D. ECG
The extent of the ECG abnormalities, especially the sum of 
the total amount of ST-segment deviation, is a good indica
-
tor of the extent of acute infarction and risk of subsequent 
adverse events. The classic evolution of changes is from 
peaked (“hyperacute”) T waves, to ST-segment elevation, 
to Q wave development, to T wave inversion. This may 
occur over a few hours to several days. The evolution of 
new Q waves (longer than 30 msec in duration and 25% of 
the R wave amplitude) is diagnostic, but Q waves do not 
occur in 30–50% of acute infarctions (non-Q wave infarc
-
tions). Left bundle branch block, especially when new (or 
not known to be old), in a patient with symptoms of an 
acute myocardial infarction, is considered to be a “STEMI 
equivalent”; reperfusion therapy is indicated for the 
affected patient. Concordant ST elevation (ie, ST elevation 
in leads with an overall positive QRS complex) with left 
bundle branch block is a specific finding indicating STEMI.
E. Chest Radiography
The chest radiograph may demonstrate signs of heart fail
-
ure, but these changes often lag behind the clinical findings. 
Signs of aortic dissection, including mediastinal widening, 
should be sought as a possible alternative diagnosis.
F. Echocardiography
Echocardiography provides convenient bedside assessment 
of LV global and regional function. This can help with the 
diagnosis and management of infarction; echocardiogra
-
phy has been used successfully to make judgments about 
admission and management of patients with suspected 
infarction, including in patients with ST-segment elevation 
or left bundle branch block of uncertain significance, since 
normal wall motion makes an infarction unlikely. Doppler 
echocardiography is generally the most convenient proce
-
dure for diagnosing postinfarction mitral regurgitation or 
VSD.
G. Other Noninvasive Studies
Diagnosis of myocardial infarction and extent of myocar
-
dial infarction can be assessed by various imaging studies 
in addition to echocardiography. 
MRI with gadolinium 
contrast enhancement
 is the most sensitive test to detect 
and quantitate extent of infarction, with the ability to 
detect as little as 2 g of myocardial infarction. 
Technetium-
99m pyrophosphate scintigraphy,
 when injected at least

 when injected at least 
18 hours postinfarction, complexes with calcium in 
necrotic myocardium to provide a “hot spot” image of the 
infarction. This test is insensitive to small infarctions, and 
false-positive studies occur, so its use is limited to patients 
in whom the diagnosis by ECG and enzymes is not possible—
principally those who present several days after the event 
or have intraoperative infarctions. 
Scintigraphy with 
 or 
technetium-based perfusion tracers
 will 
demonstrate “cold spots” in regions of diminished perfu
-
sion, which usually represent infarction when the radio
-
tracer is administered at rest, but abnormalities do not 
distinguish recent from old damage. All of these tests may 
be considered after the patient has had revascularization.
H. Hemodynamic Measurements
These can be helpful in managing the patient with sus
-
pected cardiogenic shock. Use of PA catheters, however, 
has generally not been associated with better outcomes and 
should be limited to patients with severe hemodynamic 
compromise for whom the information would be antici
-
pated to change management.
 
»
Treatment
A. Aspirin, P2Y
12
 Inhibitors (Prasugrel, Ticagrelor, 
and Clopidogrel)
All patients with definite or suspected acute myocardial 
infarction should receive aspirin at a dose of 162 mg or 
325 mg at once regardless of whether fibrinolytic therapy is 
being considered or the patient has been taking aspirin. 
Chewable aspirin provides more rapid blood levels. Patients 
with a definite aspirin allergy should be treated with a 
P2Y
12
 inhibitor (clopidogrel, prasugrel, or ticagrelor).
P2Y
12
 inhibitors, in combination with aspirin, have 
been shown to provide important benefits in patients with 
acute STEMI. Thus, guidelines call for a P2Y
12
 inhibitor to 
be added to aspirin for all patients with STEMI, regardless 
of whether reperfusion is given, and continued for at least 
14 days, and generally for 1 year. The preferred P2Y
12
 
inhibitors are prasugrel (60 mg orally on day 1, then 10 mg 
daily) or ticagrelor (180 mg orally on day 1, then 90 mg 
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twice daily). Both of these medications demonstrated supe
-
rior outcomes to clopidogrel in clinical studies of primary 
PCI. Clopidogrel should be administered as a loading dose 
of 300–600 mg orally for faster onset of action than the 75 mg 
maintenance dose. With fibrinolytic therapy, there are no 
randomized trial data regarding when the early use of pra
-
sugrel or ticagrelor and clopidogrel is indicated (with a 300 mg 
loading dose for patients younger than 75 years and no 
loading dose for patients older than 75 years). Prasugrel is 
contraindicated in patients with history of stroke or who 
are older than 75 years.
B. Reperfusion Therapy
Patients with STEMI who seek medical attention within 
12 hours of the onset of symptoms should be treated with 
reperfusion therapy, either primary PCI or fibrinolytic 
therapy. Patients without ST-segment elevation (previously 
labeled “non-Q wave” infarctions) do not benefit, and may 
derive harm, from thrombolysis.
1. Primary percutaneous coronary intervention—
Immediate coronary angiography and primary PCI (includ
-
ing stenting) of the infarct-related artery have been shown 
to be 
superior
 to thrombolysis when done by experienced 
operators in high-volume centers with rapid time from first 
medical contact to intervention (“door-to-balloon”). US 
and European guidelines call for first medical contact or 
door-to-balloon times of 90 minutes or less. Several trials 
have shown that if efficient transfer systems are in place, 
transfer of patients with acute myocardial infarction from 
hospitals without primary PCI capability to hospitals with 
primary PCI capability with first door-to-device times of 
120 minutes or less can improve outcome compared with 
fibrinolytic therapy at the presenting hospital, although this 
requires sophisticated systems to ensure rapid identifica
-
tion, transfer, and expertise in PCI. Because PCI also car
-
ries a lower risk of hemorrhagic complications, including 
intracranial hemorrhage, it may be the preferred strategy in 
many older patients and others with contraindications to 
fibrinolytic therapy (see Table 10–10 for factors to consider 
in choosing fibrinolytic therapy or primary PCI).
a. 
S
tenting
—
PCI with stenting is standard for patients 
with acute myocardial infarction. Although randomized 
trials have shown a benefit with regard to fewer repeat 
interventions for restenosis with the use of drug-eluting 
stents in STEMI patients, and current generation drug elut
-
ing stents have similar or lower rates of stent thrombosis 
than bare metal stents, bare metal stents may still be used 
for selected patients without the ability to obtain and com
-
ply with P2Y
12
 inhibitor therapy. In the subgroup of patients 
with cardiogenic shock, early catheterization and percuta
-
neous or surgical revascularization are the preferred man
-
agement and have been shown to reduce mortality.
Table 10–10.
 
Fibrinolytic therapy for acute myocardial infarction.
Alteplase; Tissue 
p
lasminogen 
Activator (t-
p
A
)
Reteplase
Tenecteplase 
(TNK-t-
p
A
)
Streptokinase
Source
Recombinant DNA
Group C streptococcus
Half-life
5 minutes
15 minutes
20 minutes
20 minutes
Usual dose
100 mg
20 units
40 mg
1.5 million units
Administration
Initial bolus of 15 mg, followed by 
50 mg infused over the next 
30 minutes and 35 mg over the 
following 60 minutes
10 units as a bolus 
over 2 minutes, 
 
30 minutes
Single weight-
adjusted bolus, 
0.5 mg/kg
750,000 units over 20 minutes 
followed by 750,000 units 
over 40 minutes
Anticoagulation 
after infusion
Aspirin, 325 mg daily; heparin, 
 
5000 units as bolus, followed by 
1000 units per hour infusion, 
 
subsequently adjusted to maintain 
PTT 1.5–2 times control
Aspirin, 325 mg; 
 
heparin as 
 
with t-PA
Aspirin, 325 mg 
daily
Aspirin, 325 mg daily; there is 
no evidence that adjunctive 
heparin improves outcome 
following streptokinase

heparin as 
 
with t-PA
daily
Clot selectivity
High
High
High
Low
Fibrinogenolysis
+
+
+
+++
Bleeding
+
+
+
+
+
+
+
+++
Allergic reactions
+
+
+
++
Reocclusion
10–30%
—
5–20%
5–20%
Approximate cost
1
$10,560.43
$11,361.86
$7034.24
 
1
Average wholesale price (AWP , for AB-rated generic when available) for quantity listed.
PTT, partial thromboplastin time.
Source: 
Red Book
 (electronic version), Truven Health Analytics Information, http://www.micromedexsolutions.com, accessed April 10, 2018. 
AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
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“Facilitated” PCI, whereby a combination of medica
-
tions (full- or reduced-dose fibrinolytic agents, with or 
without glycoprotein IIb/IIIa inhibitors) is given followed 
by immediate PCI is not recommended. Patients should be 
treated either with primary PCI or with fibrinolytic agents 
(and immediate rescue PCI for reperfusion failure), if it can 
be done promptly as outlined in the ACC/AHA and Euro
-
pean guidelines. Timely access to most appropriate reper
-
fusion, including primary PCI, can be expanded with 
development of regional systems of care, including emer
-
gency medical systems and networks of hospitals. Patients 
treated with fibrinolytic therapy appear to have improved 
outcomes if transferred for routine coronary angiography 
and PCI within 24 hours. The American Heart Association 
has a program called “Mission: Lifeline” to support the 
development of regional systems of care (http://www.heart
 
.org/missionlifeline).
b. 
A
ntiplatelet therapy after drug-eluting or 
bare metal stents
—
In patients with an acute coronary 
syndrome, 
dual antiplatelet therapy
 is indicated for 1 year 
in all patients (including those with medical therapy and 
those patients undergoing revascularization irrespective of 
stent type). For patients undergoing elective or stable PCI, 
the duration of dual antiplatelet therapy is recommended 
for at least 1 month for patients receiving bare metal stents. 
For patients receiving drug-eluting stents for acute coro
-
nary syndromes, dual antiplatelet therapy is recommended 
for at least 1 year by the ACC/AHA and European guide
-
lines. These recommendations are based both on the dura
-
tions of therapies during the studies evaluating the stents, 
and the pathophysiologic understanding of the timing of 
endothelialization following bare metal versus drug-eluting 
stent implantation. The DAPT (dual antiplatelet therapy) 
study showed fewer death, myocardial infarction, and 
stroke events with longer (up to 30 months) dual antiplate
-
let therapy for patients who had received drug-eluting 
stents, but it also showed more bleeding and a tendency for 
higher mortality. Treatment with clopidogrel for longer 
than 1 year after drug-eluting stents, therefore, should be 
individualized based on thrombotic and bleeding risks.
2. Fibrinolytic therapy
a. 
B
enefit
—
Fibrinolytic therapy reduces mortality and 
limits infarct size in patients with STEMI (defined as 0.1 mV 
or more in two inferior or lateral leads or two contiguous 
precordial leads), or with left bundle branch block (not 
known to be old). The greatest benefit occurs if treatment 
is initiated within the first 3 hours after the onset of presen
-
tation, when up to a 50% reduction in mortality rate can be 
achieved. The magnitude of benefit declines rapidly there
-
after, but a 10% relative mortality reduction can be achieved 
up to 12 hours after the onset of chest pain. The survival 
benefit is greatest in patients with large—usually anterior—
infarctions. Primary PCI (including stenting) of the infarct-
related artery, however, is superior to thrombolysis when 
done by experienced operators with rapid time from first 
medical contact to intervention (“door-to-balloon”).
b. 
C
ontraindications
—
Major bleeding complications 
occur in 0.5–5% of patients, the most serious of which is 
intracranial hemorrhage. The major risk factors for intra
-
cranial bleeding are age 75 years or older, hypertension at 
presentation (especially over 180/110 mm Hg), low body 
weight (less than 70 kg), and the use of fibrin-specific fibri
-
nolytic agents (alteplase, reteplase, tenecteplase). Although 
patients over age 75 years have a much higher mortality 
rate with acute myocardial infarction and therefore may 
derive greater benefit, the risk of severe bleeding is also 
higher, particularly among patients with risk factors for 
intracranial hemorrhage, such as severe hypertension or

intracranial hemorrhage, such as severe hypertension or 
recent stroke. Patients presenting more than 12 hours after 
the onset of chest pain may also derive a small benefit, 
particularly if pain and ST-segment elevation persist, but 
rarely does this benefit outweigh the attendant risk.
Absolute contraindications to fibrinolytic therapy 
include previous hemorrhagic stroke, other strokes or cere
-
brovascular events within 1 year, known intracranial neo
-
plasm, recent head trauma (including minor trauma), active 
internal bleeding (excluding menstruation), or suspected 
aortic dissection. Relative contraindications are BP greater 
than 180/110 mm Hg at presentation, other intracerebral 
pathology not listed above as a contraindication, known 
bleeding diathesis, trauma within 2–4 weeks, major surgery 
within 3 weeks, prolonged (more than 10 minutes) or 
traumatic cardiopulmonary resuscitation, recent (within 
2–4 weeks) internal bleeding, noncompressible vascular 
punctures, active diabetic retinopathy, pregnancy, active 
peptic ulcer disease, a history of severe hypertension, cur
-
rent use of anticoagulants (INR greater than 2.0–3.0), and 
(for streptokinase) prior allergic reaction or exposure to 
streptokinase or anistreplase within 2 years.
c. 
F
ibrinolytic agents
—
The following fibrinolytic 
agents are available for acute myocardial infarction and are 
characterized in Table 10–10.
Alteplase
 (recombinant tissue plasminogen activator; 
t-PA) results in about a 50% reduction in circulating 
fibrinogen. In the first GUSTO trial, which compared a 
90-minute dosing of t-PA (with unfractionated heparin) 
with streptokinase, the 30-day mortality rate with t-PA was 
one absolute percentage point lower (one additional life 
saved per 100 patients treated), though there was also a 
small 
increase
 in the rate of intracranial hemorrhage. An 
angiographic substudy confirmed a higher 90-minute 
patency rate and a higher rate of normal (TIMI grade 3) 
flow in patients.
Reteplase
 is a recombinant deletion mutant of t-PA that 
is slightly less fibrin specific. In comparative trials, it 
appeared to have efficacy similar to that of alteplase, but it 
has a longer duration of action and can be administered as 
two boluses 30 minutes apart.
Tenecteplase
 (TNK-t-PA) is a genetically engineered 
substitution mutant of native t-PA that has reduced plasma 
clearance, increased fibrin sensitivity, and increased resis
-
tance to plasminogen activator inhibitor-1. It can be given 
as a single weight-adjusted bolus. In the ASSENT 2 trial, 
this agent was equivalent to t-PA with regard to efficacy 
and resulted in significantly less noncerebral bleeding.
, commonly used outside of the United 
States, is somewhat less effective at opening occluded 
 
arteries and less effective at reducing mortality. 
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It  is non–fibrin-specific, causes depletion of circulating 
fibrinogen, and has a tendency to induce hypotension, par
-
ticularly if infused rapidly. This can be managed by slowing 
or interrupting the infusion and administering fluids. There 
is controversy as to whether adjunctive heparin is beneficial 
in patients given streptokinase, unlike its administration 
with the more clot-specific agents. Allergic reactions, 
including anaphylaxis, occur in 1–2% of patients, and this 
agent should generally not be administered to patients with 
prior exposure.
(1) Selection of a fibrinolytic agent—
In the United 
States, most patients are treated with alteplase, reteplase, or 
tenecteplase. The differences in efficacy between them are 
small compared with the potential benefit of treating a 
greater proportion of appropriate candidates in a more 
prompt manner. The principal objective should be to 
administer a thrombolytic agent within 30 minutes of 
presentation—or even during transport. The ability to 
administer tenecteplase as a single bolus is an attractive fea
-
ture that may facilitate earlier treatment. The combination of 
a reduced-dose thrombolytic given with a platelet glycopro
-
tein IIb/IIIa inhibitor does not reduce mortality but does 
cause a modest increase in bleeding complications.
(2) Postfibrinolytic management—
After completion of 
the fibrinolytic infusion, aspirin (81–325 mg/day) and 
anticoagulation should be continued until revasculariza
-
tion or for the duration of the hospital stay (or up to 8 days). 
Anticoagulation with LMWH (enoxaparin or fondaparinux) 
is preferable to unfractionated heparin.
(a) 
L
ow-molecular-weight heparin
—
In the 
EXTRACT trial, enoxaparin significantly reduced death and 
myocardial infarction at day 30 (compared with unfraction
-
ated heparin), at the expense of a modest increase in bleed
-
ing. In patients younger than age 75, enoxaparin was given 
as a 30-mg intravenous bolus and 1 mg/kg subcutaneously 
every 12 hours; in patients aged 75 years and older, it was 
given with no bolus and 0.75 mg/kg subcutaneously every 
12 hours. This appeared to attenuate the risk of intracranial 
hemorrhage in older adults that had been seen with full-
dose enoxaparin. Another antithrombotic option is 
fondaparinux, given at a dose of 2.5 mg subcutaneously once 
a day. There is no benefit of fondaparinux among patients 
undergoing primary PCI, and fondaparinux is not recom
-
mended as a sole anticoagulant during PCI due to risk of 
catheter thrombosis.
(b) 
U
nfractionated heparin
—
with intravenous heparin (initial dose of 60 units/kg bolus 
to a maximum of 4000 units, followed by an infusion of 
12 units/kg/h to a maximum of 1000 units/hour, then 
adjusted to maintain an aPTT of 50–75 seconds beginning 
with an aPTT drawn 3 hours after thrombolytic) is contin
-
ued for at least 48 hours after alteplase, reteplase, or 
tenecteplase, and with continuation of an anticoagulant 
until revascularization (if performed) or until hospital 
discharge (or day 8).
The most recent (and perhaps most relevant) trial to 
compare bivalirudin to unfractionated heparin in acute 
myocardial infarction was the V ALIDATE trial, which 
found no benefit to bivalirudin regarding the outcome of 
death, myocardial infarction, or major bleeding.
(c) 
P
rophylactic therapy against gastrointes
 
tin
al
 
bleeding
—
For all patients with STEMI treated with 
intensive antithrombotic therapy, prophylactic treatment 
with proton-pump inhibitors, or antacids and an H
2
-
blocker, is advisable, although certain proton-pump inhib
-
itors, such as omeprazole and esomeprazole, decrease the 
effect of clopidogrel.
3. 
A
ssessment of myocardial reperfusion, recurrent 
 
ischemic pain, reinfarction—
Myocardial reperfusion can 
be recognized clinically by the early cessation of pain and 
the resolution of ST-segment elevation. Although at least

the resolution of ST-segment elevation. Although at least 
50% resolution of ST-segment elevation by 90 minutes may 
occur without coronary reperfusion, ST resolution is a 
strong predictor of better outcome. Even with anticoagula
-
tion, 10–20% of reperfused vessels will reocclude during 
hospitalization, although reocclusion and reinfarction 
appear to be reduced following intervention. Reinfarction, 
indicated by recurrence of pain and ST-segment elevation, 
can be treated by readministration of a thrombolytic agent 
or immediate angiography and PCI.
C. General Measures
Cardiac care unit monitoring should be instituted as soon 
as possible. Patients without complications can be trans
-
ferred to a telemetry unit after 24 hours. Activity should 
initially be limited to bed rest but can be advanced within 
24 hours. Progressive ambulation should be started after 
24–72 hours if tolerated. For patients without complica
-
tions, discharge by day 4 appears to be appropriate. Low-
flow oxygen therapy (2–4 L/min) should be given if oxygen 
saturation is reduced, but there is no value to routine use of 
oxygen.
D. Analgesia
An initial attempt should be made to relieve pain with 
sublingual nitroglycerin. However, if no response occurs 
after two or three tablets, intravenous opioids provide the 
most rapid and effective analgesia and may also reduce 
pulmonary congestion. Morphine sulfate, 4–8 mg, or 
meperidine, 50–75 mg, should be given. Subsequent small 
doses can be given every 15 minutes until pain abates.
Nonsteroidal anti-inflammatory agents, other than 
aspirin, should be avoided during hospitalization for 
STEMI due to increased risk of mortality, myocardial rup
-
ture, hypertension, heart failure, and kidney injury with 
their use.
E. Beta-Adrenergic Blocking Agents
Trials have shown modest short-term benefit from beta-
blockers started during the first 24 hours after acute myo
-
cardial infarction if there are no contraindications 
(metoprolol 25–50 mg orally twice daily). Aggressive beta-
blockade can increase shock, with overall harm in patients 
with heart failure. Thus, early beta-blockade should be 
avoided in patients with any degree of heart failure, evi
-
dence of low output state, increased risk of cardiogenic 
shock, or other relative contraindications to beta-blockade. 
Carvedilol (beginning at 6.25 mg twice a day, titrated to 
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25  mg twice a day) was shown to be beneficial in the 
CAPRICORN trial following the acute phase of large myo
-
cardial infarction.
F. Nitrates
Nitroglycerin is the agent of choice for continued or recur
-
rent ischemic pain and is useful in lowering BP or relieving 
pulmonary congestion. However, routine nitrate adminis
-
tration is not recommended, since no improvement in 
outcome has been observed in the ISIS-4 or GISSI-3 trials. 
Nitrates should be avoided in patients who received phos
-
phodiesterase inhibitors (sildenafil, vardenafil, and 
tadalafil) in the prior 24 hours.
G. Angiotensin-Converting Enzyme (ACE) Inhibitors
A series of trials (SAVE, AIRE, SMILE, TRACE, GISSI-III, 
and ISIS-4) have shown both short- and long-term 
improvement in survival with ACE inhibitor therapy. The 
benefits are greatest in patients with an EF of 40% or less, 
large infarctions, or clinical evidence of heart failure. 
Because substantial amounts of the survival benefit occur 
on the first day, ACE inhibitor treatment should be com
-
menced early in patients without hypotension, especially 
patients with large or anterior myocardial infarction. Given 
the benefits of ACE inhibitors for patients with vascular 
disease, it is reasonable to use ACE inhibitors for 
all
 
patients following STEMI who do not have 
contraindications.
H. Angiotensin Receptor Blockers
Although there has been inconsistency in the effects of dif
-
ferent ARBs on mortality for patients post–myocardial 
infarction with heart failure and/or LV dysfunction, the 
V ALIANT trial showed that valsartan 160 mg orally twice 
a day is equivalent to captopril in reducing mortality. Thus, 
valsartan should be used for all patients with ACE inhibitor 
intolerance, and is a reasonable, albeit more expensive, 
alternative to captopril. The combination of captopril and 
valsartan (at a reduced dose) was no better than either 
agent alone and resulted in more side effects.
I. Aldosterone Antagonists
The RALES trial showed that 25-mg spironolactone can 
reduce the mortality rate of patients with advanced heart 
failure, and the EPHESUS trial showed a 15% relative risk 
reduction in mortality with eplerenone 25 mg daily for 
patients post–myocardial infarction with LV dysfunction 
(LVEF of 40% or less) and either clinical heart failure or 
diabetes. Kidney dysfunction or hyperkalemia are contra
-
indications, and patients must be monitored carefully for 
development of hyperkalemia.
J. Calcium Channel Blockers
There are no studies to support the routine use of calcium 
channel blockers in most patients with acute myocardial 
infarction—and indeed, they have the potential to exacer
-
bate ischemia and cause death from reflex tachycardia or 
myocardial depression. Long-acting calcium channel 
blockers should generally be reserved for management of 
hypertension or ischemia as second- or third-line medica
-
tions after beta-blockers and nitrates.
K. Long-Term Antithrombotic Therapy
Discharge on aspirin, 81–325 mg/day, since it is highly 
effective, inexpensive, and well tolerated, is a key quality 
indicator of myocardial infarction care. Patients who 
received a coronary stent should also receive a P2Y
12
 
inhibitor (see Antiplatelet therapy after drug-eluting or 
bare metal stents, above).
Patients who have received a coronary stent and who 
require warfarin anticoagulation present a particular chal
-
lenge, since 
“triple therapy”
 with aspirin, clopidogrel, and 
warfarin has a high risk of bleeding. Triple therapy should 
be (1) limited to patients with a clear indication for warfa
-
rin (such as CHADS
2
 score of 2 or more or a mechanical 
prosthetic valve), (2) used for the shortest period of time 
(such as 1 month after placement of bare metal stent; drug-
eluting stents that would require longer clopidogrel dura
-
tion should be avoided if possible), (3) used with low-dose 
aspirin and with strategies to reduce risk of bleeding (eg,

-
aspirin and with strategies to reduce risk of bleeding (eg, 
proton-pump inhibitors for patients with a history of gas
-
trointestinal bleeding), and (4) used with consideration of 
a lower target anticoagulation intensity (INR 2.0 to 2.5, at 
least for the indication of atrial fibrillation) during the 
period of concomitant treatment with aspirin and P2Y
12
 
therapy. The PIONEER trial studied three treatment regi
-
mens for patients with atrial fibrillation who had coronary 
stent placement with a primary outcome of bleeding: (1) 
rivaroxaban 2.5 mg twice daily plus clopidogrel, (2) rivar
-
oxaban 15 mg once daily plus clopidogrel, and (3) warfarin 
plus aspirin plus clopidogrel. There was less bleeding in the 
patients who received rivaroxaban plus clopidogrel than in 
those who received “triple therapy, ” although the trial was 
not powered to assess efficacy, and thus the low dose of 
rivaroxaban may be inadequate. Consensus statements 
recommend oral anticoagulation (with either warfarin or a 
DOAC) be combined with clopidogrel and with a relatively 
short duration of aspirin for 1–3 months for the typical 
patient with atrial fibrillation and coronary stents. Dabiga
-
tran, 110 mg and 150 mg, was also studied in patients with 
atrial fibrillation who underwent PCI. Dual therapy with 
dabigatran and clopidogrel was shown to be beneficial for 
bleeding compared to triple therapy, with similar rates of 
thrombotic cardiovascular events. However, there were too 
few thrombotic events to be certain about efficacy of dis
-
continuing the aspirin, and there was a suggestion that 
myocardial infarction and stent thrombosis occurred more 
often with the 110-mg dose of dabigatran than with clopi
-
dogrel alone.
L. Coronary Angiography
For patients who do not reperfuse based on lack of at least 
50% resolution of ST elevation, rescue angioplasty should 
be performed and has been shown to reduce the composite 
risk of death, reinfarction, stroke, or severe heart failure. 
Patients treated with coronary angiography and PCI 
CMDT19_Ch10_p0334-p0450.indd   388

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3–24 hours after fibrinolytic therapy showed improved 
outcomes. Patients with recurrent ischemic pain prior to 
discharge should undergo catheterization and, if indicated, 
revascularization. PCI of a totally occluded infarct-related 
artery more than 24 hours after STEMI should generally 
not be performed in asymptomatic patients with one or 
two vessel disease without evidence of severe ischemia.
 
»
Cannon CP et al; RE-DUAL PCI Steering Committee and Inves
-
tigators. Dual antithrombotic therapy with dabigatran after 
PCI in atrial fibrillation. N Engl J Med. 2017 Oct 19;377(16):
 
1513–24. [PMID: 28844193]
Erlinge D et al. Bivalirudin versus heparin monotherapy in myo
-
cardial infarction. N Engl J Med. 2017 Sep 21;377(12):1132–42. 
 
[PMID: 28844201]
 
»
A variety of complications can occur after myocardial 
infarction even when treatment is initiated promptly.
A. Postinfarction Ischemia
In clinical trials of thrombolysis, recurrent ischemia 
occurred in about one-third of patients, was more common 
following non–ST elevation myocardial infarction than 
after STEMI, and had important short- and long-term 
prognostic implications. Vigorous medical therapy should 
be instituted, including nitrates and beta-blockers as well as 
aspirin 81–325 mg/day, anticoagulant therapy (unfraction
-
ated heparin, enoxaparin, or fondaparinux) and clopidogrel 
(75 mg orally daily). Most patients with postinfarction 
angina—and all who are refractory to medical therapy—
should undergo early catheterization and revascularization 
by PCI or CABG.
B. Arrhythmias
Abnormalities of rhythm and conduction are common.
1. Sinus bradycardia—
This is most common in inferior 
infarctions or may be precipitated by medications. Obser
-
vation or withdrawal of the offending agent is usually suf
-
ficient. If accompanied by signs of low cardiac output, 
atropine intravenously is usually effective. Temporary pac
-
ing is rarely required.
2. Supraventricular tachyarrhythmias—
Sinus tachycardia 
is common and may reflect either increased adrenergic 
stimulation or hemodynamic compromise due to hypovo
-
lemia or pump failure. In the latter, beta-blockade is con
-
traindicated. Supraventricular premature beats are 
common and may be premonitory for atrial fibrillation. 
Electrolyte abnormalities and hypoxia should be corrected 
and causative agents (especially aminophylline) stopped. 
Atrial fibrillation should be rapidly controlled or converted 
to sinus rhythm. Intravenous beta-blockers, such as meto
-
prolol (2.5–5 mg intravenously every 2–5 minutes, 
maximum 15 mg over 10–minutes) or short-acting esmolol 
(50–200 mcg/kg/min) are the agents of choice if cardiac 
function is adequate. Intravenous diltiazem (5–15 mg/h) 
may be used if beta-blockers are contraindicated or ineffec
-
tive. Electrical cardioversion (commencing with 100 J) may 
be necessary if atrial fibrillation is complicated by hypoten
-
sion, heart failure, or ischemia, but the arrhythmia often 
recurs. Amiodarone (150 mg intravenous bolus and then 
15–30 mg/h intravenously, or rapid oral loading dose for 
cardioversion of 400 mg three times daily) may be helpful 
to restore or maintain sinus rhythm.
3. Ventricular arrhythmias—
Ventricular arrhythmias are 
most common in the first few hours after infarction and are 
a marker of high risk. Ventricular premature beats may be 
premonitory for ventricular tachycardia or fibrillation, but 
generally should 
not
 be treated in the absence of frequent 
or sustained ventricular tachycardia. Lidocaine is 
not
 rec
-
ommended as a prophylactic measure.
Sustained ventricular tachycardia should be treated 
with a 1 mg/kg bolus of lidocaine if the patient is stable or 
by electrical cardioversion (100–200 J) if not. If the 
arrhythmia cannot be suppressed with lidocaine, procain
-

-
amide (100 mg boluses over 1–2 minutes every 5 minutes 
to a cumulative dose of 750–1000 mg) or intravenous 
amiodarone (150 mg over 10 minutes, which may be 
repeated as needed, followed by 360 mg over 6 hours and 
then 540 mg over 18 hours) should be initiated, followed by 
an infusion of 0.5 mg/min (720 mg/24 hours). Ventricular 
fibrillation is treated electrically (300–400 J). All patients 
taking antiarrhythmics should be monitored with teleme
-
try or ECGs during initiation. Unresponsive ventricular 
fibrillation should be treated with additional amiodarone 
and repeat cardioversion while cardiopulmonary resuscita
-
tion (CPR) is administered.
Accelerated idioventricular rhythm is a regular, wide-
complex rhythm at a rate of 60–120/min. It may occur with 
or without reperfusion and should not be treated with 
antiarrhythmics, which could cause asystole.
4. Conduction disturbances—
All degrees of AV block may 
occur in the course of acute myocardial infarction. Block at 
the level of the AV node is more common than infranodal 
block and occurs in approximately 20% of inferior myocar
-
dial infarctions. First-degree block is the most common 
and requires no treatment. Second-degree block is usually 
of the Mobitz type I form (Wenckebach), is often transient, 
and requires treatment only if associated with a heart rate 
slow enough to cause symptoms. Complete AV block 
occurs in up to 5% of acute inferior infarctions, usually is 
preceded by Mobitz I second-degree block, and generally 
resolves spontaneously, though it may persist for hours to 
several weeks. The escape rhythm originates in the distal AV 
node or AV junction and hence has a narrow QRS complex 
and is reliable, albeit often slow (30–50 beats/min). 
Treatment is often necessary because of resulting hypo
-
tension and low cardiac output. Intravenous atropine 
(1 mg) usually restores AV conduction temporarily, but if 
the escape complex is wide or if repeated atropine treat
-
ments are needed, temporary ventricular pacing is indi
-
cated. The prognosis for these patients is only slightly 
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worse than for patients in whom AV block does not 
develop.
In anterior infarctions, the site of block is distal, below 
the AV node, and usually a result of extensive damage of 
the His-Purkinje system and bundle branches. New first-
degree block (prolongation of the PR interval) is unusual in 
anterior infarction; Mobitz type II AV block or complete 
heart block may be preceded by intraventricular conduc
-
tion defects or may occur abruptly. The escape rhythm, if 
present, is an unreliable wide-complex idioventricular 
rhythm. Urgent ventricular pacing is mandatory, but even 
with successful pacing, morbidity and mortality are high 
because of the extensive myocardial damage. New conduc
-
tion abnormalities, such as right or left bundle branch 
block or fascicular blocks, may presage progression, often 
sudden, to second- or third-degree AV block. Temporary 
ventricular pacing is recommended for new-onset alternat
-
ing bilateral bundle branch block, bifascicular block, or 
bundle branch block with worsening first-degree AV block. 
Patients with anterior infarction who progress to second- 
or third-degree block even transiently should be consid
-
ered for insertion of a prophylactic permanent ventricular 
pacemaker before discharge.
C. Myocardial Dysfunction
Persons with hypotension not responsive to fluid resuscita
-
tion or refractory heart failure or cardiogenic shock should 
be considered for urgent echocardiography to assess left 
and right ventricular function and for mechanical compli
-
cations, right heart catheterization, and continuous mea
-
surements of arterial pressure. These measurements permit 
the accurate assessment of volume status and may facilitate 
decisions about volume resuscitation, selective use of pres
-
sors and inotropes, and mechanical support.
1. Acute LV failure—
Dyspnea, diffuse rales, and arterial 
hypoxemia usually indicate LV failure. General measures 
include supplemental oxygen to increase arterial saturation 
to above 95% and elevation of the trunk. Diuretics are usu
-
ally the initial therapy unless RV infarction is present. 
Intravenous furosemide (10–40 mg) or bumetanide 
(0.5–1 mg) is preferred because of the reliably rapid onset 
and short duration of action of these medications. Higher 
dosages can be given if an inadequate response occurs. 
Morphine sulfate (4 mg intravenously followed by incre
-
ments of 2 mg) is valuable in acute pulmonary edema.
Diuretics are usually effective; however, because most 
patients with acute infarction are not volume overloaded, 
the hemodynamic response may be limited and may be 
associated with hypotension. In mild heart failure, sublin
-
gual isosorbide dinitrate (2.5–10 mg every 2 hours) or 
nitroglycerin ointment (6.25–25 mg every 4 hours) may be 
adequate to lower PCWP . In more severe failure, especially 
if cardiac output is reduced and BP is normal or high, 
sodium nitroprusside may be the preferred agent. It should 
be initiated only with arterial pressure monitoring; the 
initial dosage should be low (0.25 mcg/kg/min) to avoid 
excessive hypotension, but the dosage can be increased by 
increments of 0.5 mcg/kg/min every 5–10 minutes up to 
5–10 mcg/kg/min until the desired hemodynamic response 
is obtained. Excessive hypotension (mean BP less than 
65–75 mm Hg) or tachycardia (greater than 10/min 
increase) should be avoided.
Intravenous nitroglycerin (starting at 10 mcg/min) also 
may be effective but may lower PCWP with less hypoten
-
sion. Oral or transdermal vasodilator therapy with nitrates 
or ACE inhibitors is often necessary after the initial 
24–48 hours.
Inotropic agents should be avoided if possible, because 
they often increase heart rate and myocardial oxygen 
requirements and worsen clinical outcomes. Dobutamine 
has the best hemodynamic profile, increasing cardiac out
-
put and modestly lowering PCWP , usually without exces
-
sive tachycardia, hypotension, or arrhythmias. The initial

-
-
sive tachycardia, hypotension, or arrhythmias. The initial 
dosage is 2.5 mcg/kg/min, and it may be increased by simi
-
lar increments up to 15–20 mcg/kg/min at intervals of 
5–10 minutes. Dopamine is more useful in the presence of 
hypotension, since it produces peripheral vasoconstriction, 
but it has a less beneficial effect on PCWP . Digoxin has not 
been helpful in acute infarction except to control the ven
-
tricular response in atrial fibrillation, but it may be benefi
-
cial if chronic heart failure persists.
2. Hypotension and shock—
Patients with hypotension 
(systolic BP less than 90 mm Hg, individualized depending 
on prior BP) and signs of diminished perfusion (low uri
-
nary output, confusion, cold extremities) that does not 
respond to fluid resuscitation should be presumed to have 
cardiogenic shock and should be considered for urgent 
catheterization and revascularization as well as selective 
use of 
intra-aortic balloon pump (IABP)
 support and 
hemodynamic monitoring with a PA catheter, although 
these later measures have not been shown to improve out
-
come. Up to 20% will have findings indicative of intravas
-
cular hypovolemia (due to diaphoresis, vomiting, decreased 
venous tone, medications—such as diuretics, nitrates, 
morphine, beta-blockers, calcium channel blockers, and 
thrombolytic agents—and lack of oral intake). These 
should be treated with successive boluses of 100 mL of 
normal saline until PCWP reaches 15–18 mm Hg to deter
-
mine whether cardiac output and BP respond. Pericardial 
tamponade due to hemorrhagic pericarditis (especially 
after thrombolytic therapy or cardiopulmonary resuscita
-
tion) or ventricular rupture should be considered and 
excluded by echocardiography if clinically indicated. RV 
infarction, characterized by a normal PCWP but elevated 
RA pressure, can produce hypotension. This is discussed 
below.
Most patients with cardiogenic shock will have moder
-
ate to severe LV systolic dysfunction, with a mean EF of 
30% in the SHOCK trial. If hypotension is only modest 
(systolic pressure higher than 90 mm Hg) and the PCWP is 
elevated, diuretics should be administered. If the BP falls, 
inotropic support will need to be added. A large random
-
ized trial showed no benefit of IABP support in cardiogenic 
shock.
Dopamine is generally considered to be the most 
appropriate vasopressor for cardiogenic hypotension. It 
should be initiated at a rate of 2–4 mcg/kg/min and 
increased at 5-minute intervals to the appropriate hemody
-
namic end point. At dosages lower than 5 mcg/kg/min, it 
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improves renal blood flow; at intermediate dosages 
(2.5–10 mcg/kg/min), it stimulates myocardial contractil
-
ity; at higher dosages (greater than 8 mcg/kg/min), it is a 
potent alpha-1-adrenergic agonist. In general, BP and car
-
diac index rise, but PCWP does not fall. Dopamine may be 
combined with nitroprusside or dobutamine (see above for 
dosing), or the latter may be used in its place if hypotension 
is not severe. Norepinephrine (0.1–0.5 mcg/kg/min) is 
generally reserved for failure of other vasopressors, since 
epinephrine produces less vasoconstriction and does not 
increase coronary perfusion pressure (aortic diastolic pres
-
sure), but it does tend to worsen the balance between 
myocardial oxygen delivery and utilization.
Patients with cardiogenic shock not due to hypovolemia 
have a poor prognosis, with 30-day mortality rates of 
40–80%. The IABP-SHOCK II trial found that the use of an 
IABP does not offer a mortality benefit at 30 days or 1 year, 
compared with routine care with rapid revascularization, 
and is likely not helpful. Surgically implanted (or percuta
-
neous) ventricular assist devices may be used in refractory 
cases. Emergent cardiac catheterization and coronary angi
-
ography followed by percutaneous or surgical revascular
-
ization offer the best chance of survival. Additionally, 
revascularization in shock should be aimed at the culprit 
artery only, avoiding multivessel PCI.
D. RV Infarction
RV infarction is present in one-third of patients with infe
-
rior wall infarction but is clinically significant in less than 
50% of these. It presents as hypotension with relatively 
preserved LV function and should be considered whenever 
patients with inferior infarction exhibit low BP , raised 
venous pressure, and clear lungs. Hypotension is often 
exacerbated by medications that decrease intravascular 
volume or produce venodilation, such as diuretics, nitrates, 
and opioids. RA pressure and JVP are high, while PCWP is 
normal or low and the lungs are clear. The diagnosis is sug
-
gested by ST-segment elevation in right-sided anterior 
chest leads, particularly RV
4
. The diagnosis can be con
-
firmed by echocardiography or hemodynamic measure
-
ments. Treatment consists of fluid loading beginning with 
500 mL of 0.9% saline over 2 hours to improve LV filling, 
and inotropic agents only if necessary.
E. Mechanical Defects
Partial or complete rupture of a papillary muscle or of the 
interventricular septum occurs in less than 1% of acute 
myocardial infarctions and carries a poor prognosis. These 
complications occur in both anterior and inferior infarc
-
tions, usually 3–7 days after the acute event. They are 
detected by the appearance of a new systolic murmur and 
clinical deterioration, often with pulmonary edema. The 
two lesions are distinguished by the location of the mur
-
mur (apical versus parasternal) and by Doppler echocar
-
diography. Hemodynamic monitoring is essential for 
appropriate management and demonstrates an increase in 
oxygen saturation between the RA and PA in VSD and, 
often, a large 
v
 wave with mitral regurgitation. Treatment 
by nitroprusside and, preferably, intra-aortic balloon 
counterpulsation (IABC) reduces the regurgitation or 
shunt, but surgical correction is mandatory. In patients 
remaining hemodynamically unstable or requiring contin
-
uous parenteral pharmacologic treatment or counterpulsa
-
tion, early surgery is recommended, though mortality rates 
are high (15% to nearly 100%, depending on residual 
 
ventricular function and clinical status). Patients who are 
stabilized medically can have delayed surgery with lower 
risks (10–25%), although this may be due to the death of 
sicker patients, some of whom may have been saved by 
earlier surgery.
F. Myocardial Rupture
Complete rupture of the LV free wall occurs in less than 1% 
of patients and usually results in immediate death. It occurs

of patients and usually results in immediate death. It occurs 
2–7 days postinfarction, usually involves the anterior wall, 
and is more frequent in older women. Incomplete or 
gradual rupture may be sealed off by the pericardium, cre
-
ating a pseudoaneurysm. This may be recognized by echo
-
cardiography, radionuclide angiography, or LV angiography, 
often as an incidental finding. It demonstrates a narrow-
neck connection to the LV . Early surgical repair is indi
-
cated, since delayed rupture is common.
G. LV Aneurysm
An LV aneurysm, a sharply delineated area of scar that 
bulges paradoxically during systole, develops in 10–20% of 
patients surviving an acute infarction. This usually follows 
anterior Q wave infarctions. Aneurysms are recognized by 
persistent ST-segment elevation (beyond 4–8 weeks), and a 
wide neck from the LV can be demonstrated by echocar
-
diography, scintigraphy, or contrast angiography. They 
rarely rupture but may be associated with arterial emboli, 
ventricular arrhythmias, and heart failure. Surgical resec
-
tion may be performed for these indications if other mea
-
sures fail. The best results (mortality rates of 10–20%) are 
obtained when the residual myocardium contracts well and 
when significant coronary lesions supplying adjacent 
regions are bypassed.
H. Pericarditis
The pericardium is involved in approximately 50% of 
infarctions, but pericarditis is often not clinically signifi
-
cant. Twenty percent of patients with Q wave infarctions 
will have an audible friction rub if examined repetitively. 
Pericardial pain occurs in approximately the same propor
-
tion after 2–7 days and is recognized by its variation with 
respiration and position (improved by sitting). Often, no 
treatment is required, but aspirin (650 mg every 4–6 hours) 
will usually relieve the pain. Indomethacin and corticoste
-
roids can cause impaired infarct healing and predispose to 
myocardial rupture, and therefore should generally be 
avoided in the early post–myocardial infarction period. 
Likewise, anticoagulation should be used cautiously, since 
hemorrhagic pericarditis may result.
One week to 12 weeks after infarction, 
Dressler syn
-
drome
 (post–myocardial infarction syndrome) occurs in 
less than 5% of patients. This is an autoimmune phenom
-
enon and presents as pericarditis with associated fever, 
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leukocytosis and, occasionally, pericardial or pleural effu
-
sion. It may recur over months. Treatment is the same as 
for other forms of pericarditis. A short course of nonsteroi
-
dal agents or corticosteroids may help relieve symptoms.
I. Mural Thrombus
Mural thrombi are common in large anterior infarctions 
but not in infarctions at other locations. Arterial emboli 
occur in approximately 2% of patients with known infarc
-
tion, usually within 6 weeks. Anticoagulation with heparin 
followed by short-term (3-month) warfarin therapy pre
-
vents most emboli and should be considered in all patients 
with large anterior infarctions. Mural thrombi can be 
detected by echocardiography or cardiac MRI, but these 
procedures should not be relied upon for determining the 
need for anticoagulation.
Thiele H et al; CULPRIT-SHOCK Investigators. PCI strategies 
in patients with acute myocardial infarction and cardiogenic 
shock. N Engl J Med. 2017 Dec 21;377(25):2419–32. [PMID: 
29083953]
 
»
Postinfarction Management
After the first 24 hours, the focus of patient management is 
to prevent recurrent ischemia, improve infarct healing and 
prevent remodeling, and prevent recurrent vascular events. 
Patients with hemodynamic compromise, who are at high 
risk for death, need careful monitoring and management of 
volume status.
A. Risk Stratification
Risk stratification is important for the management of 
STEMI. GRACE and TIMI risk scores can be helpful tools. 
Patients with recurrent ischemia (spontaneous or 
 
provoked), hemodynamic instability, impaired LV func
-
tion, heart failure, or serious ventricular arrhythmias 
should undergo cardiac catheterization (see Table 10–9). 
ACE inhibitor (or ARB) therapy is indicated in patients 
with clinical heart failure or LVEF of 40% or less. Aldoste
-
rone blockade is indicated for patients with an LVEF of 
40% or less and either heart failure or diabetes mellitus.
For patients not undergoing cardiac catheterization, 
submaximal exercise (or pharmacologic stress testing for 
patients unable to exercise) before discharge or a maximal 
test after 3–6 weeks (the latter being more sensitive for 
ischemia) helps patients and clinicians plan the return to 
normal activity. Imaging in conjunction with stress testing 
adds additional sensitivity for ischemia and provides local
-
izing information. Both exercise and pharmacologic stress 
imaging have successfully predicted subsequent outcome. 
One of these tests should be used prior to discharge in 
patients who have received thrombolytic therapy as a 
means of selecting appropriate candidates for coronary 
B. Secondary Prevention
Postinfarction management should begin with identification 
and modification of risk factors. Treatment of hyperlipidemia 
and smoking cessation both prevent recurrent infarction 
and death. Statin therapy should be started before the 
patient is discharged from the hospital to reduce recurrent 
atherothrombotic events. BP control as well as cardiac 
rehabilitation and exercise are also recommended. They 
can be of considerable psychological benefit and appear to 
improve prognosis.
Beta-blockers improve survival rates, primarily by 
reducing the incidence of sudden death in high-risk sub
-
sets of patients, though their value may be less in patients 
without complications with small infarctions and normal 
exercise tests. While a variety of beta-blockers have been 
shown to be beneficial, for patients with LV dysfunction 
managed with contemporary treatment, carvedilol titrated 
to 25 mg orally twice a day has been shown to reduce mor
-
tality. Beta-blockers with intrinsic sympathomimetic activ
-
ity have not proved beneficial in postinfarction patients.
Antiplatelet agents are beneficial; aspirin (81–325 mg 
daily, with 81 mg daily the preferred long-term dose) is 
recommended, and adding clopidogrel (75 mg daily) has 
been shown to provide additional short-term benefit after

been shown to provide additional short-term benefit after 
STEMI. Prasugrel provides further reduction in throm
-
botic outcomes compared with clopidogrel, at the cost of 
more bleeding. Likewise, ticagrelor provides benefit over 
clopidogrel but should be used with low-dose aspirin 
(81 mg/day). Warfarin anticoagulation for 3 months 
reduces the incidence of arterial emboli after large anterior 
infarctions and, according to the results of at least one 
study, it improves long-term prognosis; however, these 
studies were done before the routine use of aspirin and 
clopidogrel. An advantage to combining low-dose aspirin 
and warfarin has not been demonstrated, except perhaps in 
patients with atrial fibrillation.
Calcium channel blockers have 
not
 been shown to 
improve prognoses overall and should not be prescribed 
purely for secondary prevention. Antiarrhythmic therapy 
other than with beta-blockers has 
not
 been shown to be 
effective except in patients with symptomatic arrhythmias. 
Amiodarone has been studied in several trials of postin
-
farct patients with either LV dysfunction or frequent ven
-
tricular ectopy. Although survival was not improved, 
amiodarone was not harmful—unlike other agents in this 
setting. Therefore, it is the agent of choice for individuals 
with symptomatic postinfarction supraventricular arrhyth
-
mias. While implantable defibrillators improve survival for 
patients with postinfarction LV dysfunction and heart 
failure, the DINAMIT trial found no benefit to implantable 
defibrillators implanted in the 40 days following acute 
C. ACE Inhibitors and ARBs in Patients With 
LV Dysfunction
Patients who sustain substantial myocardial damage often 
experience subsequent progressive LV dilation and dys
-
function, leading to clinical heart failure and reduced long-
term survival. In patients with EFs less than 40%, long-term 
ACE inhibitor (or ARB) therapy prevents LV dilation and 
the onset of heart failure and prolongs survival. The HOPE 
trial, as well as an overview of trials of ACE inhibitors for 
secondary prevention, also demonstrated a reduction of 
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approximately 20% in mortality rates and the occurrence of 
nonfatal myocardial infarction and stroke with ramipril 
treatment of patients with coronary or peripheral vascular 
disease and without confirmed LV systolic dysfunction. 
Therefore, ACE inhibitor therapy should be strongly con
-
sidered in this broader group of patients—and especially in 
patients with diabetes and those with even mild systolic 
hypertension, in whom the greatest benefit was observed 
(see Table 11–8).
D. Revascularization
Postinfarction patients not treated with primary PCI who 
appear likely to benefit from early revascularization with 
CABG if the anatomy is appropriate are (1) those who have 
undergone fibrinolytic therapy, especially if they have high-
risk features (including systolic BP of less than 100 mm Hg, 
heart rate of greater than 100 bpm, Killip class II or III, and 
ST-segment depression of 2 mm or more in the anterior 
leads); (2) patients with LV dysfunction (EF less than 
30–40%); (3) patients with NSTEMI and high-risk features; 
and (4) patients with markedly positive exercise tests and 
multi-vessel disease. The value of revascularization in 
patients not treated with acute reperfusion therapy with 
preserved LV function who have mild ischemia and are not 
symptom limited is less clear. In general, patients without 
high-risk features who survive infarctions without compli
-
cations, have preserved LV function (EF greater than 50%), 
and have no exercise-induced ischemia have an excellent 
prognosis and do not require invasive evaluation.
Smaller randomized trials have demonstrated that 
patients with noninfarct-related artery disease may benefit 
from revascularization strategies at the time of acute myo
-
cardial infarction care, prior to hospital discharge.
O’Gara PT et al. 2013 ACCF/AHA guideline for the manage
-
ment of ST-elevation myocardial infarction: a report of the 
2013 Jan 29;127(4):e362–425. Erratum in: Circulation. 2013 Dec 
24;128(25):e481. [PMID: 23247304]
 
º
DISORDERS OF RATE & RHYTHM
Abnormalities of cardiac rhythm and conduction can be 
symptomatic (syncope, near syncope, dizziness, fatigue, or 
palpitations), or asymptomatic. In addition, they can be 
lethal (sudden cardiac death) or dangerous to the extent 
that they reduce cardiac output, so that perfusion of the 
brain and myocardium is impaired. Stable supraventricular 
tachycardia (SVT) is generally well tolerated in patients 
without underlying heart disease but may lead to myocar
-
dial ischemia or heart failure in patients with coronary 
disease, valvular abnormalities, and systolic or diastolic 
myocardial dysfunction. Ventricular tachycardia, if pro
-
longed, often results in hemodynamic compromise and 
may deteriorate into ventricular fibrillation if left untreated.
Whether slow heart rates produce symptoms at rest or 
with exertion depends on whether cerebral and peripheral 
perfusion can be maintained, which is generally a function 
of whether the patient is upright or supine and whether LV 
function is adequate to maintain stroke volume. If the heart 
rate abruptly slows, as with the onset of complete heart 
block or sinus arrest, syncope or convulsions (or both) may 
result. Unless a clear, reversible cause is found, most symp
-
tomatic patients require implantation of a permanent 
pacemaker.
The diagnosis of an abnormal tachyarrhythmia can 
generally be made via cardiac monitoring, including in-
hospital and ambulatory ECG monitoring, event recorders 
(instruments that can be used for prolonged periods to 
record and transmit rhythm tracings when infrequent epi
-
sodes occur), continuous mobile cardiac telemetry, or 
implantable loop recorders. More invasive testing, includ
-
ing catheter-based electrophysiologic studies (to assess 
sinus node function, AV conduction, and inducibility of

-
sinus node function, AV conduction, and inducibility of 
arrhythmias), and tests of autonomic nervous system func
-
tion (tilt-table testing) can also be performed.
Treatment of tachyarrhythmias varies and can include 
modalities such as antiarrhythmic medications and more 
invasive techniques such as catheter ablation.
 
»
Antiarrhythmic Medications (Table 10–11)
Antiarrhythmic medications are frequently used to treat 
arrhythmias, but have variable efficacy and produce fre
-
quent side effects. They are often divided into classes based 
on their electropharmacologic actions and many of these 
medications have multiple actions. The most frequently 
used classification scheme is the Vaughan-Williams, which 
consists of four classes.
Class I
 agents block membrane sodium channels. Three 
subclasses are further defined by the effect of the agents on 
the Purkinje fiber action potential. 
Class Ia
 medications 
(ie, quinidine, procainamide, disopyramide) slow the rate 
of rise of the action potential (V
max
) and prolong its dura
-
tion, thus slowing conduction and increasing refractori
-
ness (moderate depression of phase 0 upstroke of the 
action potential). 
Class Ib
 agents (ie, lidocaine, mexiletine) 
shorten action potential duration; they do not affect con
-
duction or refractoriness (minimal depression of phase 0 
upstroke of the action potential). 
Class Ic
 agents (ie, fle
-
cainide, propafenone) prolong V
max
 and slow repolariza
-
tion, thus slowing conduction and prolonging 
refractoriness, but more so than class Ia medications 
(maximal depression of phase 0 upstroke of the action 
potential).
Class II
 agents are the beta-blockers, which decrease 
automaticity, prolong AV conduction, and prolong 
refractoriness.
Class III
 agents (ie, amiodarone, dronedarone, sotalol, 
dofetilide, ibutilide) block potassium channels and prolong 
repolarization, widening the QRS and prolonging the QT 
interval. They decrease automaticity and conduction and 
prolong refractoriness.
Class IV
 agents are the calcium channel blockers, 
which decrease automaticity and AV conduction.
There are some antiarrhythmic agents that do not fall 
into one of these categories. The most frequently used are 
digoxin and adenosine. Digoxin inhibits the Na+, K+-
ATPase pump. Digoxin prolongs AV nodal conduction and 
the AV nodal refractory period, but it shortens the action 
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Table 10–11.
 
Antiarrhythmic medications (listed in alphabetical order within class).
Agent
Intravenous Dosage
Oral Dosage
Therapeutic 
p
lasma Level
Route of 
Elimination
Side Effects
Class Ia: Action: Sodium channel blockers: Depress phase 0 depolarization; slow conduction; prolong repolarization.
Indications:
 Supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats.
Disopyramide
Immediate release: 
 
100–200 mg every 6 h
Sustained release: 
 
200–400 mg every 12 h
2–8 mg/mL
Renal
Urinary retention, dry 
mouth, markedly 
↓
 LVF, 
QT prolongation
Loading: 10–17 mg/kg 
at 20–50 mg/min;
Maintenance: 
 
1–4 mg/min
50 mg/kg/day in divided 
doses every 4 h 
(short-acting)
4–10 mg/mL; 
 
NAPA (active 
metabolite), 
10–20 mcg/mL
Renal
Quinidine
6–10 mg/kg (intramus
-
cularly or intrave
-
nously) over 20 min 
(rarely used 
parenterally)
324–648 mg every 8 h
2–5 mg/mL
Hepatic
GI, 
↓
 LVF, 
↑
 Dig
Class Ib: Action: Shorten repolarization.
 Ventricular tachycardia, prevention of ventricular fibrillation, symptomatic ventricular premature beats.
Lidocaine
Loading: 1 mg/kg;
 
1–4 mg/min
1–5 mg/mL
Hepatic
CNS, GI, 
↓
 LVF
Mexiletine
100–300 mg every 8–12 h; 
maximum: 1200 mg/day
0.5–2 mg/mL
Hepatic
CNS, GI, leukopenia
Class Ic: Action: Depress phase 0 repolarization; slow conduction. (
p
r
opafenone is a weak calcium channel blocker and beta-blocker 
 
and pr
olongs action potential and refractoriness.)
 Ventricular tachycardia (in the absence of structural heart disease), refractory supraventricular tachycardia.
Flecainide
50–150 mg twice daily
0.2–1 mg/mL
Hepatic
CNS, GI, AFL with 1:1 con
-
duction, ventricular 
pro-arrhythmia
Propafenone
150–300 mg every 8–12 h
Note:
 Active 
metabolites
Hepatic
-
Class II: Action: Beta-blockers, slow AV conduction.
 Supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, long QT syndrome
Esmolol
Loading: 500 mcg/kg 
over 1–2 min
Maintenance: 50 mcg/
kg/min
Other beta-blockers may 
be used concomitantly
Not established
Hepatic
↓
 LVF, bradycardia, AV 
block
Metoprolol
5 mg every 5 min up 
to 3 doses
25–200 mg daily
Hepatic
↓
block, fatigue
Propranolol
1–3 mg every 5 min 
up to total of 5 mg
40–320 mg in 1–4 doses 
daily (depending on 
Hepatic
↓
block, bronchospasm
Class III: Action: 
p
r
olong action potential.
 
Amiodarone:
 refractory ventricular tachycardia, supraventricular tachycardia, prevention of ventricular tachycardia, atrial 
fibrillation, ventricular fibrillation; 
Dofetilide:
 atrial fibrillation and flutter; 
Dronedarone:
 atrial fibrillation (not persistent); 
Ibutilide:
 
conversion of atrial fibrillation and flutter; 
Sotalol:
 ventricular tachycardia, atrial fibrillation.
150–300 mg infused 
rapidly, followed by 
1 mg/min infusion 
for 6 h and then 
 
0.5 mg/min for 18 h
800–1600 mg/day for 
7–14 days; maintain at 
100–400 mg/day
1–5 mg/mL
Hepatic
Pulmonary fibrosis, hypo
-
thyroidism, hyperthy
-
roidism, photosensitivity, 
corneal and skin depos
-
its, hepatitis, 
↑
 Dig, 
 
neurotoxicity, GI
(
continued
 
)
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CMDT 2019
 
Agent
p
Route of 
Dofetilide
125–500 mcg every 12 h
Renal (dose must 
be reduced 
with kidney 
dysfunction)
Torsades de pointes in 3%; 
interaction with cyto
-
chrome P-450 inhibitors
Dronedarone
400 mg twice daily
Hepatic (contra
-
indicated in 
severe 
impairment)
QTc prolongation, HF. 
 
Contraindicated in HF 
(NYHA class IV or recent 
decompensation), 
 
persistent AF
Ibutilide
1 mg over 10 min, fol
-
lowed by a second 
infusion of 0.5–1 mg 
over 10 min
Hepatic and 
 
renal
Torsades de pointes in up 
to 5% of patients within 
3 h after administration; 
patients must be moni
-
tored with defibrillator 
nearby
Sotalol
75 mg every 12 h
80–160 mg every 12 h 
(maximum 320 mg 
daily)
Renal (dosing 
interval should 
be extended if 
creatinine 
clearance is 
< 60 mL/min)
Early incidence of torsades 
de pointes, 
↓
 LVF, brady
-
cardia, fatigue (and oth
-
erside effects associated 
with beta-blockers)
Class IV: Action: Slow calcium channel blockers.
 Supraventricular tachycardia, ventricular tachycardia (outflow tract, idiopathic).
Diltiazem
0.25 mg/kg over 2 min; 
second 0.35-mg/kg 
bolus after 15 min if 
response is inade
-
quate; infusion rate, 
5–15 mg/h
120–360 mg daily in 
 
1–3 doses depending 
on preparation
Hepatic metabo
-
lism, renal 
excretion
Hypotension, 
↓
 LVF, 
bradycardia
Verapamil
2.5 mg bolus followed 
by additional 
boluses of 2.5–5 mg 
every 1–3 min; total 
20 mg over 20 min; 
maintain at 
 
5 mg/kg/min
80–120 mg every 6–8 h; 
240–480 mg once daily 
with sustained-release 
preparation
0.1–0.15 mg/mL
Hepatic
↓
 LVF, 
 
constipation, 
↑
 Dig
Miscellaneous: Indications: Supraventricular tachycardia.
Adenosine
6 mg rapidly followed 
by 12 mg after 
1–2 min if needed; 
use half these doses 
if administered via 
central line
Adenosine recep
-
tor stimulation, 
metabolized in 
blood
Transient flushing, dys
-
pnea, chest pain, AV 
block, sinus bradycardia; 
effect 
↓
 by theophylline, 
↑
 by dipyridamole
Digoxin
0.5 mg over 20 min fol
-
lowed by increment 
of 0.25 or 0.125 mg 
to 1–1.5 mg over 
24 h
1–1.5 mg over 24–36 h in 
3 or 4 doses; 
 
maintenance, 
 
0.125–0.5 mg/day
0.7–2 mg/mL
Renal
AV block, arrhythmias, 
 
GI, visual changes
AF, atrial fibrillation; AV, atrioventricular; CNS, central nervous system; Dig, elevation of serum digoxin level; GI, gastrointestinal (nausea, 
vomiting, diarrhea); HF, heart failure; 
↓
LVF, reduced left ventricular function; NAPA, 
N
-acetylprocainamide; NYHA, New York Heart Association; 
SLE, systemic lupus erythematosus.
 
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potential and decreases the refractoriness of the ventricular 
myocardium and Purkinje fibers. Adenosine can block AV 
nodal conduction and shortens atrial refractoriness.
Although the in vitro electrophysiologic effects of most 
of these agents have been defined, their use remains largely 
empiric. 
All can exacerbate arrhythmias
 
(proarrhythmic 
effect), and many depress LV function.
The risk of antiarrhythmic agents has been highlighted 
by many studies, most notably the Coronary Arrhythmia 
Suppression Trial (CAST), in which two class Ic agents 
(flecainide, encainide) and a class Ia agent (moricizine) 
increased mortality rates in patients with asymptomatic 
ventricular ectopy after myocardial infarction. Class 1c 
antiarrhythmic agents should therefore 
not
 be used in 
patients with prior myocardial infarction or structural 
The use of antiarrhythmic agents for specific arrhyth
-
mias is discussed below.
 
»
Catheter Ablation for Cardiac Arrhythmias
Catheter ablation has become the primary modality of 
therapy for many symptomatic supraventricular arrhyth
-
mias, including AV nodal reentrant tachycardia, tachycar
-
dias involving accessory pathways, paroxysmal atrial 
tachycardia, and atrial flutter. Catheter ablation of atrial 
fibrillation is more complex and usually involves complete 
electrical isolation of the pulmonary veins (which are often 
the sites of initiation of atrial fibrillation) or placing linear 
lesions within the atria to prevent propagation throughout 
the atrial chamber. This technique is considered a reason
-
able second-line therapy (after pharmacologic treatment) 
for certain patients with symptomatic medication-refractory 
atrial fibrillation. Catheter ablation of ventricular arrhyth
-
mias has proved more difficult, but experienced centers 
have demonstrated reasonable success with all types of 
ventricular tachycardias including bundle-branch reentry, 
tachycardia originating in the ventricular outflow tract or 
papillary muscles, tachycardias originating in the special
-
ized conduction system (fascicular ventricular tachycar
-
dia), and ventricular tachycardias occurring in patients 
with ischemic or dilated cardiomyopathy. Ablation of many 
of these arrhythmias can be performed from the endocar
-
dial surface via endovascular catheter placement or on the 
epicardial surface of the heart via a percutaneous subxi
-
phoid approach.
Catheter ablation has also been successfully performed 
for the treatment of ventricular fibrillation when a uniform 
premature ventricular contraction (PVC) can be identified. 
In addition, patients with symptomatic PVCs or PVCs 
occurring at a high enough burden to result in a cardiomy
-
opathy (usually more than 10,000/day) are often referred 
for catheter ablation as well.
Catheter ablation procedures are generally safe, with an 
overall major complication rate ranging from 1% to 5%. 
Major vascular damage during catheter insertion occurs in 
less than 2% of patients. There is a low incidence of perfo
-
ration of the myocardial wall resulting in pericardial tam
-
ponade. Sufficient damage to the AV node to require 
permanent cardiac pacing occurs in less than 1% of 
patients. When transseptal access through the interatrial 
septum or retrograde LV catheterization is required, addi
-
tional potential complications include damage to the heart 
valves, damage to a coronary artery, or systemic emboli. A 
rare but potentially fatal complication after catheter abla
-
tion of atrial fibrillation is the development of an atrio-
esophageal fistula resulting from ablation on the posterior 
wall of the LA just overlying the esophagus, estimated to 
occur in less than 0.1% of procedures.
January CT et al. 2014 AHA/ACC/HRS guideline for the man
-
agement of patients with atrial fibrillation: a report of the 
-
tion Task Force on Practice Guidelines and the Heart Rhythm

-
-
tion Task Force on Practice Guidelines and the Heart Rhythm 
Society. J Am Coll Cardiol. 2014 Dec 2;64(21):e1–76. [PMID: 
24685669]
SINUS ARRHYTHMIA, BRADYCARDIA, & 
 
»
Wide variation in sinus rate is common in young, 
healthy individuals and generally not pathologic.
 
»
Symptomatic bradycardia may require permanent 
pacemaker implantation, especially in the elderly 
or patients with underlying heart disease.
 
»
Sinus tachycardia is usually secondary to another 
underlying process (ie, fever, pain, anemia, alcohol 
withdrawal).
 
»
Sick sinus syndrome manifests as sinus bradycardia, 
pauses, or inadequate heart rate response to physi
-
ologic demands (chronotropic incompetence).
 
»
Sinus arrhythmia
 is an irregularity of the normal heart 
rate defined as variation in the PP interval of more than 
120 ms. This occurs commonly in young, healthy people 
due to changes in vagal influence on the sinus node during 
respiration (phasic) or independent of respiration (non
-
phasic). This is generally 
not
 a pathologic arrhythmia and 
requires no specific cardiac evaluation.
Sinus bradycardia
 is defined as a heart rate slower than 
60 beats/min and may be due to increased vagal influence 
on the normal sinoatrial pacemaker or organic disease of 
the sinus node. In healthy individuals, and especially in 
patients who are in excellent physical condition, sinus bra
-
dycardia to rates of 50 beats/min or lower especially during 
sleep is a normal finding. However, in elderly patients and 
individuals with heart disease sinus bradycardia may be an 
indication of true sinus node pathology. When the sinus 
rate slows severely, the atrial-nodal junction or the nodal-
His bundle junction may assume pacemaker activity for 
the heart, usually at a rate of 35–60 beats/min.
Sinus tachycardia
 is defined as a heart rate faster than 
100 beats/min that is caused by rapid impulse formation 
CMDT19_Ch10_p0334-p0450.indd   396

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CMDT 2019
from the sinoatrial node. It is a normal physiologic 
response to exercise or other conditions in which catechol
-
amine release is increased. The rate infrequently exceeds 
160 beats/min but may reach 180 beats/min in young per
-
sons. The onset and termination are usually gradual, in 
contrast to paroxysmal supraventricular tachycardia 
(PSVT) due to reentry. In rare instances, otherwise healthy 
individuals may present with “inappropriate” sinus tachy
-
cardia where persistently elevated basal heart rates are not 
in-line with physiologic demands. Long-term conse
-
quences of this disorder are few.
 is a broad diagnosis applied to 
patients with sinus arrest, sinoatrial exit block (recognized 
by a pause equal to a multiple of the underlying PP interval 
or progressive shortening of the PP interval prior to a pause), 
or persistent sinus bradycardia. A common presentation in 
elderly patients is of recurrent SVTs (often atrial fibrillation) 
accompanied by bradyarrhythmias (
“tachy-brady syn
-
drome”
). The long pauses that often follow the termination 
of tachycardia cause the associated symptoms. Sick sinus 
syndrome may also manifest as 
chronotropic incompe
-
tence,
 defined as an inappropriate heart rate response to the 
physiologic demands of exercise or stress, and is an under
-
recognized cause of poor exercise tolerance.
 
»
In most patients, sinus arrhythmia (bradycardia or tachy
-
cardia) does not cause symptoms in the absence of under
-
lying cardiac disease or other comorbidities. When severe 
sinus bradycardia results in low cardiac output, however, 
patients may complain of weakness, confusion, or syncope 
if cerebral perfusion is impaired. Atrial, junctional and 
ventricular ectopic rhythms are more apt to occur with 
slow sinus rates. Sinus bradycardia is often exacerbated by 
medications (digitalis, calcium channel blockers, beta-
blockers, sympatholytic agents, antiarrhythmics), and 
agents that may be responsible should be withdrawn prior 
to making the diagnosis.
Sinus tachycardia is most often a normal response to 
many medications as well as to conditions that require an 
increase in cardiac output including fever, pain, anxiety, 
anemia, heart failure, hypovolemia, or thyrotoxicosis. 
Alcohol and alcohol withdrawal are common causes of 
sinus tachycardia and other supraventricular arrhythmias. 
In patients with underling cardiac disease, sinus tachycar
-
dia may cause dyspnea or chest pain due to increase myo
-
cardial oxygen demand or reduced coronary artery blood 
flow.
Symptoms from sinus node dysfunction are nonspecific 
and may be due to other causes. It is therefore essential that 
symptoms be demonstrated to coincide temporally with 
arrhythmias. This may require prolonged ambulatory 
monitoring or the use of an event recorder.
 
»
Treatment
Asymptomatic patients generally do not require treatment. 
For symptomatic patients with bradycardia or sick sinus 
syndrome, implantation of a permanent pacemaker is usu
-
ally indicated. For patients with “tachy-brady syndrome,” 
treatment of the associated tachyarrhythmia is often diffi
-
cult without first instituting pacing, since beta-blockers, 
calcium channel blockers, digoxin, and other antiarrhyth
-
mic agents may exacerbate the bradycardia. When a dual-
chamber pacemaker is implanted for sinus node 
dysfunction, unnecessary ventricular pacing must be 
avoided because it may exacerbate heart failure, especially 
in patients with preexisting LV dysfunction. In most situa
-
tions, sinus tachycardia will improve or resolve with treat
-
ment of the underlying cause. Inappropriate sinus 
tachycardia in the presence of symptoms (palpitations, 
dizziness, exertional intolerance) can be treated with a trial 
of beta-blockers or calcium channel blockers although 
treatment is often challenging. Ivabradine (5–7.5 mg twice 
daily), a selective inhibitor of the potassium funny channel 
(I
f

(I
f
) specific to the sinus node, appears to be an effective 
 
»
Patients with symptoms related to bradycardia or tachycar
-
dia when reversible etiologies have been excluded.
John RM et al. Sinus node and atrial arrhythmias. Circulation. 
2016 May 10;133(19):1892–900. [PMID: 27166347]
Koruth JS et al. The clinical use of ivabradine. J Am Coll Cardiol. 
2017 Oct 3;70(14):1777–84. [PMID: 28958335]
AV BLOCK
 
»
Conduction disturbance between the atrium and 
ventricle that can be physiologic (due to enhanced 
vagal tone) or pathologic.
 
»
Block occurs in the AV node (first-degree, second-
degree Mobitz type I) or below the AV node (second-
degree Mobitz type II, third-degree).
 
»
Symptomatic AV block or block below the AV 
node in the absence of a reversible cause usually 
warrants permanent pacemaker implantation.
 
»
AV block can be physiologic (due to increased vagal tone) 
or pathologic (due to underlying heart disease such as isch
-
emia, myocarditis, fibrosis of the conduction system, or 
after cardiac surgery). AV block is categorized as 
first-
degree
 (PR interval greater than 200 ms with all atrial 
impulses conducted), 
second-degree
 (intermittent blocked 
beats), or 
third-degree
 (complete heart block, in which no 
atrial impulses are conducted to the ventricles). Second-
degree AV block is further subclassified into 
Mobitz type I 
(Wenckebach),
 in which the AV conduction time (PR 
interval) progressively lengthens before the blocked beat 
and 
Mobitz type II,
 in which there are intermittently 
nonconducted atrial beats not preceded by lengthening 
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AV conduction. When only 2:1 AV block is present on the 
ECG, the differentiation between Mobitz type I or Mobitz 
type II is more difficult. If the baseline PR interval is pro
-
longed (greater than 200 ms) or the width of the QRS 
complex is narrow (less than 120 ms), the block is usually 
nodal (Mobitz type I); if the QRS complex is wide (greater 
than or equal to 120 ms), the block is more likely infrano
-
dal (Mobitz type II).
AV dissociation
 occurs when an intrinsic ventricular 
pacemaker is firing at a rate faster than or close to the sinus 
rate (accelerated idioventricular rhythm, ventricular pre
-
mature beats, or ventricular tachycardia), such that atrial 
impulses arriving at the AV node when it is refractory may 
not be conducted. This phenomenon does not necessarily 
indicate AV block. No treatment is required aside from 
management of the causative arrhythmia.
 
»
The clinical presentation of first-degree and Mobitz type I 
block is typically benign and rarely produces symptoms. 
Normal, physiologic block of this type occurs in response to 
increases in parasympathetic output. This is commonly 
seen during sleep, with carotid sinus massage, or in well-
trained athletes. It may also occur as a medication effect 
(calcium channel blockers, beta-blockers, digitalis, or anti
-
arrhythmics). Pathologic causes including myocardial isch
-
emia or infarction (discussed earlier), inflammatory 
processes (ie, Lyme disease), fibrosis, calcification, or infil
-
tration (ie, amyloidosis or sarcoidosis) should be excluded.
Mobitz type II block and complete (third-degree) heart 
block are almost always due to pathologic disease involving 
the infranodal conduction system, and symptoms includ
-
ing fatigue, dyspnea, presyncope or syncope are common. 
With complete heart block, where no atrial impulses reach 
the ventricle, the ventricular escape rate is usually slow 
(less than 50 beats/min) and severity of symptoms may 
vary depending on the rate and stability of the escape 
rhythm. The first heart sound varies in intensity; wide 
pulse pressure, a changing systolic BP level, and cannon 
venous pulsations in the neck are also present. As for lesser 
degrees of AV block, pathologic causes should be explored.
Intraventricular conduction block
 is relatively com
-
mon and may be transient (ie, related to increases in heart 
rate) or permanent. Right bundle branch block is often 
seen in patients with structurally normal hearts. The left 
bundle is composed of two components (anterior and pos
-
terior fascicles) and left bundle branch block is more often 
a marker of underlying cardiac disease, including ischemic 
heart disease, inflammatory or infiltrative disease, cardio
-
myopathy, and valvular heart disease. In asymptomatic 
patients with bifascicular block (block in two of three 
infranodal components—right bundle, left anterior, and 
left posterior fascicle), the incidence of occult complete 
heart block or progression to it is low.
 
»
Treatment
Asymptomatic patients with first- or second-degree Mob
-
itz type I AV block do not require any specific therapy. 
Patients should undergo treatment of any potentially 
reversible cause (ie, myocardial ischemia or medication 
effect). Symptomatic patients with any degree of heart 
block should be treated urgently with atropine (initial 
dose 0.5 mg given intravenously) or temporary pacing 
(transcutaneous or transvenous). The indications for per
-
manent pacing are symptomatic bradyarrhythmias with 
any degree of AV block or asymptomatic high-degree AV 
block (second-degree Mobitz type II or third-degree heart 
block). Patients with presumed cardiac syncope with nor
-
mal heart rates and rhythm but bifascicular or trifascicular 
block on ECG should also be considered for permanent 
pacing.
A standardized nomenclature for pacemaker generators 
is used, usually consisting of four letters. The first letter

pacing.
is used, usually consisting of four letters. The first letter 
refers to the chamber that is paced (A, atrium; V , ventricle; 
D, dual [for both]). The second letter refers to the chamber 
that is sensed (also A, V , or D). An additional option (O) 
indicates absence of sensing. The third letter refers to how 
the pacemaker responds to a sensed event (I, inhibition by 
a sensed impulse; T, triggering by a sensed impulse; D, dual 
modes of response; O, no response to sensed impulse). The 
fourth letter refers to the programmability or rate modula
-
tion capacity (R, rate modulation), a function that can 
increase the pacing rate in response to motion or respira
-
tory rate when the intrinsic heart rate is inappropriately 
low.
A dual-chamber pacemaker that senses and paces in 
both chambers is the most physiologic approach to pacing 
patients who remain in sinus rhythm. AV synchrony is 
particularly important in patients in whom atrial contrac
-
tion produces a substantial increment in stroke volume 
and in those in whom sensing the atrial rate to provide 
rate-responsive ventricular pacing is useful. In patients 
with single-chamber ventricular pacemakers, the lack of 
an atrial kick may lead to the so-called 
pacemaker syn
-
drome
, in which the patient experiences signs of low car
-
diac output while upright. In patients with complete heart 
block with left ventricular systolic dysfunction, implanta
-
tion of a pacemaker capable of simultaneous left and right 
ventricular pacing (CRT-P) may be indicated. Complica
-
tions from pacemaker implantation include infection, 
hematoma, cardiac perforation, pneumothorax, and lead 
dislodgement.
 
»
Patients with symptomatic AV block (any degree) or 
asymptomatic high-degree (second-degree Mobitz type II 
or third-degree) AV block after reversible causes have been 
excluded.
Epstein AE et al. 2012 ACCF/AHA/HRS focused update incor
-
porated into the ACCF/AHA/HRS 2008 guidelines for 
device-based therapy of cardiac rhythm abnormalities: a 
report of the American College of Cardiology Foundation/
-
lines and the Heart Rhythm Society. Circulation. 2013 Jan 22;
 
127(3):e283–352. [PMID: 23255456]
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PAROXYSMAL SUPRAVENTRICULAR 
 
»
Rapid, regular tachycardia most commonly seen 
in young adults and characterized by abrupt onset 
and offset.
 
»
QRS duration narrow (less than 120 ms) except in 
the presence of bundle branch block or accessory 
pathway.
 
»
Often responsive to vagal maneuvers, AV nodal 
blockers, or adenosine. Cardioversion rarely 
required.
 
»
Paroxysmal supraventricular tachycardia (PSVT) is an 
intermittent arrhythmia that is characterized by a sudden 
onset and offset and a regular ventricular response. Epi
-
sodes may last from a few seconds to several hours or lon
-
ger. PSVT often occurs in patients without structural heart 
disease. The most common mechanism for PSVT is reen
-
try, which may be initiated or terminated by a fortuitously 
timed atrial or ventricular premature beat. The reentrant 
circuit usually involves dual pathways (a slow and a fast 
pathway) within the AV node; this is referred to as 
AV 
nodal reentrant tachycardia (AVNRT)
 and accounts for 
60% of cases of PSVT. Less commonly (30% of cases), reen
-
try is due to an accessory pathway between the atria and 
ventricles, referred to as 
atrioventricular reciprocating 
tachycardia (AVRT)
. The pathophysiology and manage
-
ment of arrhythmias due to accessory pathways differ in 
important ways and are discussed separately below.
 
»
Symptoms of PSVT can be quite variable depending on the 
degree of heart rate elevation, resultant hypotension or the 
presence of other comorbidities. Symptoms may include 
palpitations, diaphoresis, dyspnea, dizziness, and mild 
chest pain (even in the absence of associated CHD). Syn
-
cope is rare.
B. ECG
Obtaining a 12-lead ECG when feasible is important to 
help determine the tachycardia mechanism. The QRS 
duration will be narrow (less than 120 ms) except in cases 
of PSVT with aberrant conduction (left bundle branch 
block, right bundle branch block, or bystander accessory 
pathway). The heart rate is regular and is usually 
160–220 beats/min but may be greater than 250 beats/min. 
The P wave usually differs in contour from sinus beats and is 
often simultaneous with or just after the QRS complex.
 
»
Treatment
In the absence of structural heart disease, serious effects 
are rare, and most episodes resolve spontaneously. Particu
-
lar effort should be made to terminate the episode quickly 
if cardiac failure, syncope, or anginal pain develops or if 
there is underlying cardiac or (particularly) coronary dis
-
ease. Because reentry is the most common mechanism for 
PSVT, effective therapy requires that conduction be inter
-
rupted at some point in the reentry circuit and the vast 
majority of these circuits involve the AV node.
A. Mechanical Measures
A variety of maneuvers have been used to interrupt epi
-
sodes, and patients may learn to perform these themselves. 
These maneuvers result in an acute increase in vagal tone 
and include the Valsalva maneuver, lowering the head 
between the knees, coughing, splashing cold water on the 
face, and breath holding. The 
Valsalva maneuver
 is per
-
formed with the patient semirecumbent (45 degrees), exert
-
ing around 40 mm Hg of intrathoracic pressure (by blowing 
through a 10 mL syringe) for at least 15 seconds. Moving 
the patient supine immediately following the strain maneu
-
ver and passively raising their legs for an additional 15 seconds 
may increase effectiveness of the maneuver. 
Carotid sinus 
massage
 is an additional technique often performed by 
physicians but should be avoided if the patient has carotid 
bruits or a history of transient cerebral ischemic attacks. 
Firm but gentle pressure and massage are applied first over 
the right carotid sinus for 10–20 seconds and, if unsuccess
-
ful, then over the left carotid sinus. Pressure should not be 
exerted on both sides at the same time. 
Facial contact with

-
Facial contact with 
cold water
 may cause transient bradycardia and termina
-
tion of sustained ventricular tachycardia, a phenomenon 
known as the diving reflex. When performed properly, 
these maneuvers result in abrupt termination of the arrhyth
-
mia in 20–50% of cases.
B. Medication Therapy
If mechanical measures fail to terminate the arrhythmia, 
pharmacologic agents should be tried. 
Intravenous ade
-
nosine
 is recommended as the first-line agent due to its 
brief duration of action and minimal negative inotropic 
activity (Table 10–11). Because the half-life of adenosine is 
less than 10 seconds, the medication is given rapidly (in 
1–2 seconds) as a 6 mg bolus followed by 20 mL of fluid. If 
this regimen is unsuccessful at terminating the arrhythmia, 
a second higher dose (12 mg) may be given. Adenosine 
causes block of electrical conduction through the AV node 
and results in termination of SVT in approximately 90% of 
cases. Minor side effects are common and include transient 
flushing, chest discomfort, nausea, and headache. Adenos
-
ine may excite both atrial and ventricular tissue causing 
atrial fibrillation (in up to 12% of patients) or rarely ven
-
tricular arrhythmias and therefore administration should 
be performed with continuous cardiac monitoring and 
availability of an external defibrillator. Adenosine must 
also be used with caution in patients with reactive airways 
disease because it can promote bronchospasm.
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When adenosine fails to terminate the arrhythmia or if a 
contraindication to its use is present, 
intravenous calcium 
channel blockers
, including verapamil and diltiazem
,
 may 
be used (Table 10–11). Verapamil in particular has been 
shown to be as effective at terminating SVT in the acute set
-
ting (approximately 90%) as adenosine. Calcium channel 
blockers should be used with caution in patients with heart 
failure due to their negative inotropic effects. Their longer 
half-life compared to adenosine may result in prolonged 
hypotension despite restoration of normal rhythm.
Intravenous beta-blockers
 include esmolol (a very 
short-acting beta-blocker), propranolol, and metoprolol. 
While beta-blockers cause less myocardial depression than 
calcium channel blockers, the evidence of their effective
-
ness to terminate SVT is limited. If the tachycardia is 
believed to be mediated by an accessory pathway, 
intrave
-
nous
 
procainamide
 may terminate the tachycardia by 
prolonging refractoriness in the accessory pathway; how
-
ever, because it facilitates AV conduction and an initial 
increase in rate may occur, it is usually not given until after 
a calcium channel blocker or a beta-blocker has been 
administered. Although 
intravenous amiodarone
 is safe, 
it is usually not required and often ineffective for treatment 
of these arrhythmias.
C. Cardioversion
If the patient is hemodynamically unstable or if adenosine, 
beta-blockers, and calcium channel blockers are contrain
-
dicated or ineffective, synchronized electrical cardiover
-
sion (beginning at 100 J) should be performed.
 
»
A. Catheter Ablation
Because of concerns about the safety and the intolerability 
of antiarrhythmic medications, 
radiofrequency ablation 
is the preferred approach to patients with recurrent 
symptomatic reentrant SVT,
 whether it is due to dual 
pathways within the AV node or to accessory pathways.
B. Medications
AV nodal blocking agents are the medications of choice as 
first-line medical therapy (Table 10–11). Beta-blockers or 
non-dihydropyridine calcium channel blockers, such as 
diltiazem and verapamil, are typically used first. Patients 
who do not respond to agents that increase refractoriness 
of the AV node may be treated with antiarrhythmics. The 
class Ic agents (flecainide, propafenone) can be used in 
patients without underlying structural heart disease. In 
patients with evidence of structural heart disease, class III 
agents, such as sotalol or amiodarone, should be used 
because of the lower incidence of ventricular proarrhyth
-
mia during long-term therapy.
 
»
All patients with sustained or symptomatic PSVT should 
be referred to a cardiologist or cardiac electrophysiologist 
for long-term treatment options (including observation, 
pharmacotherapy, or ablation).
Appelboam A et al. Postural modification to the standard 
 
Valsalva manoeuvre for emergency treatment of supraven
-
tricular tachycardias (REVERT): a randomised controlled 
trial. Lancet. 2015 Oct 31;386(10005):1747–53. [PMID: 
26314489]
Page RL et al. 2015 ACC/AHA/HRS guideline for the management 
of adult patients with supraventricular tachycardia: a report of 
-
ciation Task Force on Clinical Practice Guidelines and the 
Heart Rhythm Society. J Am Coll Cardiol. 2016 Apr 5;67(13):
 
e27–115. [PMID: 26409259]
SVT
s
 DUE TO ACCESSORY AV PATHWAYS 
(
Preexcitation Syndromes
)
 
»
Two classic features of Wolff-Parkinson-White 
(WPW) pattern on ECG are short PR interval and 
wide, slurred QRS complex due to manifest preex
-
citation (delta wave).
 
»
Most patients with WPW pattern do not have clini
-
cal history of arrhythmia but have a higher risk of 
sudden cardiac death due to rapidly conducted 
atrial fibrillation through the accessory pathway. 
Risk factors include age younger than 20, history

Risk factors include age younger than 20, history 
of tachycardia, and rapid conduction properties at 
electrophysiologic testing.
 
»
Accessory pathways or bypass tracts between the atrium 
and the ventricle bypass the compact AV node and can 
predispose to reentrant arrhythmias, such as AVRT and 
atrial fibrillation. When direct AV connections conduct 
antegrade (manifest preexcitation) they produce a classic 
WPW pattern
 on the baseline ECG consisting of a short 
PR interval and a wide, slurred QRS complex 
(delta wave)
 
owing to early ventricular depolarization of the region 
adjacent to the pathway. Although the morphology and 
polarity of the delta wave can suggest the location of the 
pathway, mapping by intracardiac recordings is required 
for precise anatomic localization.
Accessory pathways occur in 0.1–0.3% of the popula
-
tion and facilitate reentrant arrhythmias owing to the dis
-
parity in refractory periods of the AV node and accessory 
pathway. 
WPW syndrome
 refers to a patient with baseline 
WPW pattern on ECG with associated SVT. Whether the 
tachycardia is associated with a narrow or wide QRS com
-
plex is frequently determined by whether antegrade 
conduction is through the node (narrow) or the bypass 
tract (wide). Some bypass tracts only conduct in a retro
-
grade direction. In these cases, the bypass tract is 
termed “concealed” because it is not readily apparent on a 
baseline (sinus) ECG. 
Orthodromic
 reentrant tachycardia 
accounts for approximately 90% of AVRT episodes and is 
characterized by conduction antegrade down the AV node 
CMDT19_Ch10_p0334-p0450.indd   400

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CMDT 2019
and retrograde up the accessory pathway, resulting in a 
narrow QRS complex (unless an underlying bundle branch 
block or interventricular conduction delay is present). 
Antidromic
 reentrant tachycardia conducts antegrade 
down the accessory pathway and retrograde through the 
AV node, resulting in a wide and often bizarre appearing 
QRS complex which may be mistaken for ventricular 
tachycardia. Accessory pathways often have shorter refrac
-
tory periods than specialized conduction tissue and thus 
tachycardias involving accessory pathways have the poten
-
tial to be more rapid.
 
»
Patients with WPW in whom arrhythmia develops often 
have palpitations, dizziness, or mild chest pain. Most 
patients that have a delta wave found incidentally on ECG 
(WPW pattern) do not have a clinical history of arrhyth
-
mia and are therefore asymptomatic. However, these 
patients are still at higher risk for sudden cardiac death 
than the general population. Atrial fibrillation or flutter 
with antegrade conduction down the accessory pathway 
and a rapid ventricular response will develop in up to 30% 
of patients with WPW . If this conduction is very rapid, it 
can potentially degenerate to ventricular fibrillation. The 
10-year risk of sudden cardiac death in patients with WPW 
syndrome ranges from 0.15% to 0.24%. Risk factors include 
age younger than 20, a history of symptomatic tachycardia, 
and multiple accessory pathways.
Multiple risk stratification strategies have been pro
-
posed to identify asymptomatic patients with WPW pat
-
tern ECG who may be at higher risk for lethal cardiac 
arrhythmias. A sudden loss of preexcitation during exer
-
cise testing likely indicates an accessory pathway with 
poor conduction properties and therefore low risk for 
rapid anterograde conduction. In the absence of this find
-
ing or other signs of weak anterograde properties (inter
-
mittent preexcitation on resting or ambulatory ECG 
monitoring), patients may be referred for invasive electro
-
physiology testing. During the study, patients found to 
have the shortest preexcited R-R interval during atrial 
fibrillation of 250 ms or less or inducible SVT are at 
increased risk for sudden cardiac death and should 
undergo catheter ablation.
 
»
Treatment
A. Pharmacotherapy
Initial treatment of narrow-complex reentrant rhythms 
involving a bypass tract (orthodromic AVRT) is similar to 
other forms of SVT and includes vagal maneuvers, intra
-
venous adenosine, or verapamil. Treatment of wide-
complex tachycardia in the presence of an accessory 
pathway, be it reentrant-type (antidromic AVRT) or atrial 
fibrillation with antegrade conduction down the bypass 
tract, must be managed differently. Agents such as calcium 
channel blockers and beta-blockers may increase the 
refractoriness of the AV node with minimal or no effect on 
the accessory pathway, often leading to faster ventricular 
rates and increasing the risk of ventricular fibrillation. 
Therefore, these agents should be avoided. Intravenous 
class Ia (procainamide) and class III (ibutilide) antiar
-
rhythmic agents will increase the refractoriness of the 
bypass tract and are the medications of choice for wide-
complex tachycardias involving accessory pathways. If 
hemodynamic compromise is present, electrical cardio
-
version is warranted.
B. Catheter Ablation
For long-term management, catheter ablation is the proce
-
dure of choice in patients with accessory pathways and 
recurrent symptoms or asymptomatic patients with WPW 
pattern on ECG and high-risk features at baseline or dur
-
ing electrophysiology study. Success rates for ablation of 
accessory pathways with radiofrequency catheters exceed 
95% in appropriate patients. Major complications from 
catheter ablation are rare but include AV block, cardiac 
tamponade, and thromboembolic events. Minor complica
-
tions, including hematoma at the catheter access site, occur

-
tions, including hematoma at the catheter access site, occur 
in 1–2% of procedures. For patients not a candidate for 
catheter ablation, class Ic or class III antiarrhythmic medi
-
cation may be considered.
 
»
•	
Asymptomatic patients with an incidental finding of 
Wolff-Parkinson-White pattern on ECG with high-risk 
features.
•	
Symptomatic patients with recurrent or prolonged epi
-
sodes despite treatment with AV nodal blocking agents.
•	
Patients with preexcitation and a history of atrial fibril
-
lation or syncope.
Al-Khatib SM et al. Risk stratification for arrhythmic events in 
patients with asymptomatic pre-excitation: a systematic 
review for the 2015 ACC/AHA/HRS guideline for the man
-
agement of adult patients with supraventricular tachycardia. 
Circulation. 2016 Apr 5;133(14):e575–86. [PMID: 26399661]
 
»
Presents as an irregularly irregular heart rhythm 
on examination and ECG.
 
»
Prevention of stroke should be considered in all 
patients with risk factors for stroke (eg, heart fail
-
ure, hypertension, age 65 or older, diabetes melli
-
tus, prior history of stroke or TIA, and vascular 
disease).
 
»
Heart rate control with beta-blocker or calcium 
channel blockers generally required. Restoration 
of sinus rhythm with cardioversion, antiarrhyth
-
mic medications, or catheter ablation in symp
-
tomatic patients.
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»
Atrial fibrillation is the most common chronic arrhythmia, 
with an incidence and prevalence that rise with age, so that 
it affects approximately 9% of individuals over age 65 years. 
It occurs in rheumatic and other forms of valvular heart 
disease, dilated cardiomyopathy, ASD, hypertension, and 
CHD as well as in patients with no apparent cardiac disease; 
it may be the initial presenting sign in thyrotoxicosis, and 
this condition should be excluded with the initial episode. 
Atrial fibrillation often appears in a 
paroxysmal
 fashion 
before becoming the established rhythm. Pericarditis, chest 
trauma, thoracic or cardiac surgery, thyroid disorders, 
obstructive sleep apnea, or pulmonary disease (pneumonia, 
pulmonary embolism) as well as medications such as the
-
ophylline and beta-adrenergic agonists may cause attacks in 
patients with normal hearts. Acute alcohol excess and alco
-
hol withdrawal—and, in predisposed individuals, even 
consumption of small amounts of alcohol—may precipitate 
atrial fibrillation. This latter presentation, which is often 
termed 
holiday heart,
 is usually transient and self-limited. 
Short-term rate control usually suffices as treatment.
Atrial fibrillation, particularly when the ventricular rate 
is uncontrolled, can lead to LV dysfunction, heart failure or 
myocardial ischemia (when underlying CAD is present). 
Perhaps the most serious consequence of atrial fibrillation 
is the propensity for thrombus formation due to stasis in 
the atria (particularly the left atrial appendage) and conse
-
quent embolization, most devastatingly to the cerebral 
circulation. Untreated, the rate of stroke is approximately 
5% per year. However, patients with significant obstructive 
valvular disease, chronic heart failure or LV dysfunction, 
diabetes mellitus, hypertension, or age over 75 years and 
those with a history of prior stroke or other embolic events 
are at substantially higher risk (up to nearly 20% per year 
in patients with multiple risk factors) (Table 10–12). A 
substantial portion of the aging population with hyperten
-
sion has 
asymptomatic
 or 
“subclinical”
 atrial fibrillation 
that is also associated with increased risk of stroke.
 
»
Atrial fibrillation itself is rarely life-threatening; however, it 
can have serious consequences if the ventricular rate is suf
-
ficiently rapid to precipitate hypotension, myocardial isch
-
emia, or tachycardia-induced myocardial dysfunction. 
Moreover, particularly in patients with risk factors, atrial 
fibrillation is a major preventable cause of stroke. Although 
many patients—particularly older or inactive individuals—
have relatively few symptoms if the rate is controlled, some 
patients are aware of the irregular rhythm and may find it 
very uncomfortable. Most patients will complain of fatigue 
whether they experience other symptoms or not. The heart 
rate may range from quite slow to extremely rapid, but is 
uniformly irregular unless underlying complete heart 
block with junctional escape rhythm or a permanent ven
-
tricular pacemaker is in place. Atrial fibrillation is the only 
common arrhythmia in which the ventricular rate is rapid 
and the rhythm very irregular. Because of the varying 
stroke volumes resulting from fluctuating periods of 
diastolic filling, not all ventricular beats produce a palpable 
peripheral pulse. The difference between the apical rate 
and the pulse rate is the “pulse deficit”; this deficit is greater 
when the ventricular rate is high.
B. ECG
The surface ECG typically demonstrates erratic, disorga
-
nized atrial activity between discrete QRS complexes 
occurring in an irregular pattern. The atrial activity may be 
very fine and difficult to detect on the ECG, or quite coarse 
and often mistaken for atrial flutter.
C. Echocardiography
Echocardiography provides assessment of chamber vol
-

-
umes, left ventricular size and function, or the presence of 
concomitant valvular heart disease and should be per
-
formed in all patients with a new diagnosis of atrial fibrilla
-
tion. TEE is the most sensitive imaging modality to identify 
thrombi in the left atrium or left atrial appendage prior to 
any attempt at chemical or electrical cardioversion.
 
»
Treatment
A. Newly Diagnosed Atrial Fibrillation
1. Initial management
a. 
H
emodynamically unstable patient
—
If the 
patient is hemodynamically unstable—usually as a result of 
a rapid ventricular rate or associated cardiac or noncardiac 
Table 10–12.
 
CHADS
2
 Risk Score for assessing risk of 
stroke and for selecting antithrombotic therapy for 
Condition
p
oin
ts
C
1
H
Hypertension (current or treated)
1
A
Age ≥ 75 years
1
D
1
S
2
Stroke or transient ischemic attack
2
CHADS
2
 
Score
Adjusted Stroke Rate, %/year 
(95% Confidence Interval)
p
a
tients
1
 
(n = 1733)
0
1.9 (1.2 to 3.0)
120
1
2.8 (2.0 to 3.8)
463
2
4.0 (3.1 to 5.1)
523
3
5.9 (4.6 to 7.3)
337
4
8.5 (6.3 to 11)
220
5
12.5 (8.2 to 17.5)
65
1
Validation performed in a population of Medicare beneficiaries 
aged 65 to 95 years who were not prescribed warfarin at hospital 
Reproduced, with permission, from Gage BF et al. Validation of 
clinical classification schemes for predicting stroke: results from the 
National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-70. 
Copyright © 2001 American Medical Association. All rights reserved.
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conditions—hospitalization and immediate treatment of 
atrial fibrillation are required. Intravenous beta-blockers 
(esmolol, propranolol, and metoprolol) or calcium channel 
blockers (diltiazem and verapamil) are usually effective at 
rate control in the acute setting. Urgent electrical cardio
-
version is only indicated in patients with shock or severe 
hypotension, pulmonary edema, or ongoing myocardial 
infarction or ischemia. There is a potential risk of throm
-
boembolism in patients undergoing cardioversion who 
have not received anticoagulation therapy if atrial fibrilla
-
tion has been present for more than 48 hours or is of 
unknown duration; however, in hemodynamically unstable 
patients the need for immediate rate control outweighs that 
risk. An initial shock with 100–200 J is administered in 
synchrony with the R wave. If sinus rhythm is not restored, 
an additional attempt with 360 J is indicated. If this fails, 
cardioversion may be successful after loading with intrave
-
nous ibutilide (1 mg over 10 minutes, repeated in 10 minutes 
if necessary).
b. 
H
emodynamically stable patient
—
If the patient 
has no symptoms, hemodynamic instability, or evidence of 
important precipitating conditions (such as silent myocar
-
dial infarction or ischemia, decompensated heart failure, 
pulmonary embolism, or hemodynamically significant 
valvular disease), hospitalization is usually not necessary. 
In most of these cases, atrial fibrillation is an unrecognized 
chronic or paroxysmal condition and should be managed 
accordingly (see Subsequent Management, below). For 
new onset atrial fibrillation, thyroid function tests and 
echocardiography to assess for occult valvular or myocar
-
dial disease should be performed.
In stable patients with atrial fibrillation, a strategy of 
rate control
 and 
anticoagulation
 is appropriate. This is 
true whether the conditions that precipitated atrial fibrilla
-
tion are likely to persist (such as following cardiac or non
-
cardiac surgery, with respiratory failure, or with pericarditis) 
or might resolve spontaneously over a period of hours to 
days (such as atrial fibrillation due to excessive alcohol 
intake, electrolyte imbalance or atrial fibrillation due to 
exposure to excessive theophylline or sympathomimetic 
agents). The choice of agent is guided by the hemodynamic 
status of the patient, associated conditions, and the urgency 
of achieving rate control. In the stable patient with atrial 
fibrillation, a beta-blocker or calcium channel blocker 
(orally or intravenously) is usually the first-line agent for 
ventricular rate control. In the setting of myocardial infarc
-
tion or ischemia, beta-blockers are the preferred agent. The 
most frequently used agents are either metoprolol (admin
-
istered as a 5 mg intravenous bolus, repeated twice at inter
-
vals of 5 minutes and then given as needed by repeat 
boluses or orally at total daily doses of 25–200 mg) or, in 
unstable patients, esmolol (0.5 mg/kg intravenously, 
repeated once if necessary, followed by a titrated infusion 
of 0.05–0.2 mg/kg/min). If beta-blockers are contraindi
-
cated, calcium channel blockers are immediately effective. 
Diltiazem (10–20 mg bolus, repeated after 15 minutes if 
necessary, followed by a maintenance infusion of 5–15 mg/h) 
is the preferred calcium blocker if hypotension or LV 
dysfunction is present. Otherwise, verapamil (5–10 mg 
intravenously over 2–3 minutes, repeated after 30 minutes 
if necessary) may be used. Rate control using digoxin is 
slow (onset of action more than 1 hour with peak effect at 
6 hours) and may be inadequate and is usually not indi
-
cated for use in the acute setting. Similarly, amiodarone, 
even when administered intravenously, has a relatively 
slow onset and is most useful as an adjunct when rate con
-
trol with the previously cited agents is incomplete or con
-
traindicated or when cardioversion is planned in the near

-
-
traindicated or when cardioversion is planned in the near 
future. Care should be taken in patients with hypotension 
or heart failure because the rapid intravenous administra
-
tion of amiodarone may worsen hemodynamics.
If the onset of atrial fibrillation was more than 48 hours 
prior to presentation (or unknown) and early cardiover
-
sion is considered necessary due to inability to adequately 
rate control, a transesophageal echocardiogram should be 
performed prior to cardioversion to exclude left atrial 
thrombus. If thrombus is present, the cardioversion is 
delayed until after a 4-week period of therapeutic antico
-
agulation. In any case, because atrial contractile activity 
may not recover for several weeks after restoration of sinus 
rhythm in patients who have been in atrial fibrillation for 
more than several days, cardioversion should be followed 
by anticoagulation 
for at least 1 month
 unless there is a 
strong contraindication.
2. Subsequent management—
Up to two-thirds of 
patients experiencing a first episode of atrial fibrillation 
will spontaneously revert to sinus rhythm within 24 hours. 
In the absence of valvular heart disease, diabetes, hyperten
-
sion or other risk factors for stroke, these patients may not 
require long-term anticoagulation beyond aspirin. If atrial 
fibrillation has been present for more than a week, sponta
-
neous conversion is unlikely. In most cases immediate 
cardioversion is not required and management consists of 
rate control and anticoagulation whether or not the patient 
has been admitted to the hospital. Rate control is usually 
relatively easy to achieve with beta-blockers, rate-slowing 
calcium blockers and, occasionally, digoxin used in combi
-
nation with other agents. In older patients, who often have 
diminished AV nodal function and relatively limited activ
-
ity, modest rate control can often be achieved with a single 
agent. Many younger or more active individuals require a 
combination of two agents. Choice of the initial medication 
is best based on the presence of accompanying conditions: 
Hypertensive patients should be given beta-blockers or 
calcium blockers (see Tables 11–7 and 11–9); patients with 
CHD should receive a beta-blocker; and patients with 
heart failure should be given a beta-blocker with consider
-
ation of adding digoxin. Beta-blockers should be avoided 
in patients with severe COPD or asthma. Adequacy of rate 
control should be evaluated by recording the apical pulse 
rate both at rest and with an appropriate level of activity 
(such as after brisk walking around the corridor or climb
-
ing stairs).
a. 
A
nticoagulation
—
For patients with atrial fibrilla
-
tion, even when it is paroxysmal or occurs rarely, the need 
for oral anticoagulation should be evaluated and treatment 
initiated for those without strong contraindication. Patients 
with 
lone atrial fibrillation
 (eg, no evidence of associated 
heart disease, hypertension, atherosclerotic vascular 
CMDT19_Ch10_p0334-p0450.indd   403

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disease, diabetes mellitus, or history of stroke or TIA) 
under age 65 years need no antithrombotic treatment. 
transient atrial fibrillation
, such as in the 
setting of acute myocardial infarction or pneumonia, but 
no prior history of arrhythmia, are at high risk for future 
development of atrial fibrillation and appropriate anti
-
coagulation should be initiated based on risk factors 
(Table 10–12). If the cause is reversible, such as after coro
-
nary artery bypass surgery or associated with hyperthy
-
roidism, then long term anticoagulation is not necessary.
In addition to the traditional five risk factors that com
-
prise the 
CHADS
2
 score
 (heart failure, hypertension, age 
75 years or older, diabetes mellitus, and [2 points for] his
-
tory of stroke or TIA), the European and American guide
-
lines recommend that three additional factors included in 
the 
CHA
2
DS
2
- VA S c
 score be considered: age 65–74 years, 
female sex, and presence of vascular disease (Table 10–13). 
The CHA
2
DS
2
-V ASc score is especially relevant for patients 
who have a CHADS
2
 score of 0 or 1; if the CHA
2
DS
2
-V ASc 
score is greater than or equal to 2, oral anticoagulation is 
recommended, and if CHA
2
DS
2
-V ASc score is 1, oral anti
-
coagulation should be considered, taking into account risk, 
benefit, and patient preferences. (The use of warfarin is 
discussed in the section on Selecting Appropriate Antico
-
agulant Therapy in Chapter 14.) Unfortunately, studies 
show that 
only about half
 of patients with atrial fibrillation 
and an indication for oral anticoagulation are receiving it, 
and even when treated with warfarin, they are out of the 
target INR range nearly half the time. One reason for 
undertreatment is the 
misperception
 that aspirin is useful 
for prevention of stroke due to atrial fibrillation. In the 
2016 European guidelines, aspirin is given a class III A 
recommendation, indicating that it should not be used 
because of harm (and with no good evidence of benefit). 
Cardioversion, if planned, should be performed after at least 
3–4 weeks of anticoagulation at a therapeutic level (or after 
exclusion of left atrial appendage thrombus by transesoph
-
ageal echocardiogram as discussed above). Anticoagulation 
clinics with systematic management of warfarin dosing and 
adjustment have been shown to result in better maintenance 
of target anticoagulation.
Four DOACs—dabigatran, rivaroxaban, apixaban, and 
edoxaban—have been shown to be at least as effective as 
warfarin for stroke prevention in patients with atrial fibril
-
lation and have been approved by the FDA for this indica
-
tion (Table 10–14). These medications have not been 
studied in patients with moderate or severe mitral stenosis, 
and they should not be used for patients with mechanical 
prosthetic valves. The term “nonvalvular atrial fibrillation” 
is no longer used in the European guidelines since most 
patients with other types of valvular heart disease have 
been included in trials of DOACs, which are equally effec
-
tive in these patients.
 (studied in the RE-LY trial) is superior to 
warfarin at preventing stroke at the 150 mg twice daily 
dose, and it is noninferior at the 110 mg twice daily dose, 
although this dose is not approved for treatment of atrial 
fibrillation in the United States. Both doses result in 
less
 
intracranial hemorrhage than warfarin but also in 
more
 
gastrointestinal bleeding than warfarin. Neither dabigatran 
nor any of the DOACs should be used in patients with 
mechanical prosthetic heart valves where the medications 
are less effective and riskier.
 is noninferior to warfarin for stroke pre
-
vention in atrial fibrillation (in the ROCKET-AF trial). 
Rivaroxaban is dosed at 20 mg once daily, with a reduced 
Table 10–13.
 
CHA
2
DS
2
-VASc Risk Score for assessing 
risk of stroke and for selecting antithrombotic therapy

CHA
2
DS
2
risk of stroke and for selecting antithrombotic therapy 
for patients with atrial fibrillation.
CHA
2
DS
2
-VASc Risk Score
Heart failure or LVEF ≤ 40%
1
1
2
1
Stroke, transient ischemic attack, or 
thromboembolism
2
Vascular disease (previous myocardial 
infarction, peripheral artery disease, or 
aortic plaque)
1
Age 65–74 years
1
Female sex (but not a risk factor if female 
sex is the only factor)
1
Maximum score
9
Adjusted stroke rate according to CHA
2
DS
2
-VASc score
CHA
2
DS
2
-VASc 
Score
p
a
tients 
 
(n = 7329)
Adjusted stroke 
rate (%/year)
0
1
0%
1
422
1.3%
2
1230
2.2%
3
1730
3.2%
4
1718
4.0%
5
1159
6.7%
6
679
9.8%
7
294
9.6%
8
82
6.7 %
9
14
15.2%
CHA
2
DS
2
 = 
0:
 recommend no antithrombotic therapy
CHA
2
DS
2
 = 
1:
 recommend antithrombotic therapy 
with oral anticoagulation or antiplatelet therapy but preferably 
oral anticoagulation
CHA
2
DS
2
 = 
2:
 recommend oral anticoagulation
CHA
2
DS
2
-VASc, Cardiac failure, Hypertension, Age ≥ 75 years 
(doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, 
and Sex category (female); LVEF, left ventricular ejection fraction.
Data from Camm AJ et al. 2012 focused update of the ESC 
Guidelines for the management of atrial fibrillation: an update of 
the 2010 ESC Guidelines for the management of atrial fibrillation. 
Developed with the special contribution of the European Heart 
Rhythm Association. Eur Heart J. 2012 Nov;33(21) 2719–47.
CMDT19_Ch10_p0334-p0450.indd   404

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CMDT 2019
dose (15 mg/day) for patients with creatinine clearances 
between 15 and 50 mL/min. It should be administered 
with 
food
, since that results in a 40% higher drug absortion. 
Similar to dabigatran, there is substantially less intracranial 
hemorrhage with rivaroxaban than warfarin.
Apixaban
 is more effective than warfarin at stroke pre
-
vention while having a substantially lower risk of major 
bleeding (in the ARISOTLE trial) and a lower risk of all-
cause mortality. The apixaban dosage is 5 mg twice daily or 
2.5 mg twice daily for patients with two of three high-risk 
criteria (age 80 years or older, body weight 60 kg or less, 
and serum creatinine of 1.5 mg/dL or more). Apixaban is 
associated with less intracranial hemorrhage and is well 
tolerated. Apixaban was also shown to be superior to aspi
-
rin (and better tolerated) in the AVERROES trial of 
patients deemed not suitable for warfarin.
Edoxaban,
 60 mg once a day, is noninferior to warfarin 
for stroke prevention with lower rates of major bleeding 
and lower rates of hemorrhagic stroke (studied in the 
ENGAGE-AF trial). Edoxaban carries a boxed warning in 
FDA labelleling that it should not be used in patients 
whose creatinine clearance is more than 95 mL/min 
because it is less effective in this population. The dose is 
decreased to 30 mg/day for patients whose creatinine clear
-
ance is less than or equal to 50 mL/min.
These four DOACs have important advantages over 
warfarin, and therefore they are recommended preferen
-
tially over VKAs in the European Guidelines. In practice, 
these medications are often underdosed. They should be 
used at the doses shown to be effective in the clinical trials 
as shown in Table 10–14. Even though labeled for “nonval
-
vular” atrial fibrillation, the DOACs are safe and effective 
for patients with moderate or severe valvular abnormali
-
ties, with the exception of moderate or severe mitral steno
-
sis. In part because of lower rates of intracerebral 
hemorrhage, DOACs have particular advantage over war
-
farin in the elderly and the frail, including patients with 
history of falls. For patients who fall, oral anticoagulation 
should generally be used, except for patients who are suf
-
fering head trauma with falls.
There are some patients with atrial fibrillation, how
-
ever, who 
should
 be treated with VKAs. These patients 
include those who have mechanical prosthetic valves, 
advanced kidney disease (creatinine clearance less than 
30 mL/min), moderate or severe mitral stenosis, and those 
who cannot afford the newer medications. Patients who 
have been stable while receiving warfarin for a long time, 
with a high time in target INR range, and who are at lower 
risk for intracranial hemorrhage will have relatively less 
benefit with a switch to a newer medication. It is important 
to note, however, that most patients who have intracranial 
hemorrhage while taking warfarin have had a recent INR 
below 3.0, so that good INR control does not ensure avoid
-
ance of intracranial bleeding. One way to reduce bleeding 
for patients taking oral anticoagulants is to avoid concur
-
rent aspirin, unless the patient has a clear indication, like 
recent myocardial infarction or coronary stent. Even then, 
use of oral anticoagulant plus clopidogrel without aspirin, 
or with only a brief period of “triple” therapy and then 
discontinuation of aspirin, may be a reasonable approach, 
as has been shown in clinical trials comparing rivaroxaban 
and dabigatran with warfarin.
There are some important practical issues with using 
the DOACs. It is important to monitor kidney function at 
baseline and at least once a year, or more often for those 
with impaired kidney function. Each of the medications 
interacts with other medications affecting the P-glycoprotein 
pathway, like oral ketoconazole, verapamil, dronederone, 
and phenytoin. Each of the medications has a half-life of

and phenytoin. Each of the medications has a half-life of 
about 10–12 hours for patients with normal kidney func
-
tion. For elective procedures, stop the medications two to 
three half-lives (usually 24–48 hours) before procedures 
with low to moderate bleeding risk (ie, colonoscopy, dental 
extraction, cardiac catheterization), and five half-lives 
Table 10–14.
 
Direct-acting oral anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation.
Apixaban
Edoxaban
Class
Antithrombin
Factor Xa inhibitor
Bleeding risk compared 
to warfarin
Less intracranial bleeding
Higher incidence of gas
-
trointestinal bleeding
-
Substantially lower risk of 
major bleeding
Lower risk of major 
bleeding
Dosage
110 mg twice daily
150 mg twice daily
20 mg once daily (give 
with food)
5 mg twice daily
60 mg once daily
Dosage adjustments
75 mg twice daily for 
 
creatinine clearance
1
 
15–30 mL/min 
(approved in the 
United States but not 
tested in clinical trials)
15 mg once daily for cre
-
atinine clearance
1
 
< 50 mL/min
2.5 mg twice daily for 
patients with at least two 
of three risk factors:
1. Age ≥ 80 years
2. Body weight ≤ 60 kg
3. 
 
S
erum creatinine 
 
≥ 1.5 mg/dL
30 mg once daily for 
 
1
 
≤ 50 mL/min
FDA recommends not to 
use if creatinine 
 
clearance
1
 > 95 mL/min
1
Creatinine clearance calculated by Cockcroft-Gault equation.
Data from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 10;129(23):e521–643.
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before procedures like major surgery. Discontinuation 
times should be extended in patients with impaired renal 
function, particularly with dabigatran. There are no practi
-
cal tests to immediately measure the effect of the medica
-
tions, although a normal aPTT suggests little effect with 
dabigatran, and a normal prothrombin suggests little effect 
with rivaroxaban. For rivaroxaban and apixaban, chromo
-
genic Xa assays will measure the effect, but may not be 
readily available. For bleeding, standard measures (eg, 
diagnosing and controlling the source, stopping antithrom
-
botic agents, and replacing blood products) should be 
taken. If the direct-acting medication was taken in the 
prior 2–4 hours, use activated oral charcoal to reduce 
absorption. If the patient is taking aspirin, consider platelet 
transfusion. For life-threatening bleeding in patients taking 
factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), 
prothrombin complex concentrate may have an effect, but 
this should generally be used in consultation with a hema
-
tologist. For cardioversion, the target specific medications 
appear to have similar rates of subsequent stroke as warfa
-
rin, as long as patients have been taking the medications 
and adherent for at least several weeks. Like with warfarin, 
there appears to be a 1.5- to 2-fold increased rate of bleed
-
ing associated with the use of aspirin in combination with 
the DOACs. Therefore, aspirin should not be used with the 
DOACs unless there is a clear indication, like acute coro
-
nary syndrome within the prior year.
A patient with severe bleeding while taking dabigatran 
may be treated with the reversal agent 
idarucizumab,
 
which is a humanized monoclonal antibody approved by 
the FDA for rapid reversal of the anticoagulation effects, 
for use in the event of severe bleeding or the need for an 
urgent procedure. This treatment is widely available in the 
United States. Reversal agents are in development for the 
other DOACs. Until then, preliminary data suggest that 
administration of four-factor prothrombin complex con
-
centrate may partially reverse the effects of these agents. 
Due to the short half-life of the DOACs (10–12 hours with 
normal kidney function), supportive measures (local con
-
trol, packed red blood cells, platelets) may suffice until the 
medication has cleared.
Each of the DOACs appears to be safe and effective 
around the time of electrical cardioversion. In each of these 
trials, and in one modest-sized prospective randomized 
trial of rivaroxaban that specifically addressed cardiover
-
sion, the rates of stroke were low (and similar to warfarin) 
with the DOACs when given for at least 3–4 weeks prior to 
cardioversion. An advantage of the DOACs is that when 
stable anticoagulation is desired before elective cardiover
-
sion, it is achieved faster than with warfarin.
Devices to exclude the left atrial appendage have been 
shown to protect against stroke compared to warfarin in 
patients with atrial fibrillation; the Watchman device is 
also approved for this use, with restrictions including 
unsuitability for long-term anticoagulation.
b. 
R
ate control or elective cardioversion
—
Two 
large randomized controlled trials (the 4060-patient Atrial 
Fibrillation Follow-up Investigation of Rhythm Manage
-
ment, or AFFIRM trial; and the Rate Control Versus Elec
-
trical Cardioversion for Persistent Atrial Fibrillation, or 
RACE trial) compared strategies of rate control and rhythm 
control. In both, a strategy of rate control and long-term 
anticoagulation was associated with no higher rates of 
death or stroke—both, if anything, 
favored rate control
—
and only a modestly increased risk of hemorrhagic events 
over a strategy of restoring sinus rhythm and maintaining 
it with antiarrhythmic drug therapy. Of note is that exercise 
tolerance and quality of life were not significantly better in

tolerance and quality of life were not significantly better in 
the rhythm control group. Nonetheless, the decision of 
whether to attempt to restore sinus rhythm following the 
initial episode remains controversial. Elective cardiover
-
sion following an appropriate period of anticoagulation 
(minimum of 4 weeks) is generally recommended for the 
initial episode in patients in whom atrial fibrillation is 
thought to be of recent onset and when there is an identifi
-
able precipitating factor. Similarly, cardioversion is appro
-
priate in patients who remain symptomatic from the 
rhythm despite efforts to achieve rate control.
In cases in which elective cardioversion is required, it 
may be accomplished electrically or pharmacologically. A 
number of factors influence the success of electrical cardio
-
version. Biphasic energy waverform and anteroposterior 
electrode placement provide superior effectiveness. Pharma
-
cologic cardioversion with 
intravenous ibutilide
 may be 
used as described above in a setting in which the patient can 
undergo continuous ECG monitoring for at least 4–6 hours 
following administration. Pretreatment with intravenous 
magnesium (1–2 g) may prevent rare episodes of torsades de 
pointes associated with ibutilide administration. In patients 
in whom a decision has been made to continue antiarrhyth
-
mic therapy to maintain sinus rhythm (see next paragraph), 
cardioversion can be attempted with an agent that is being 
considered for long-term use. For instance, after therapeutic 
anticoagulation has been established, 
amiodarone
 can 
be initiated on an outpatient basis (400 mg twice daily for 
2 weeks, followed by 200 mg twice daily for at least 2–4 weeks 
and then a maintenance dose of 200 mg daily). Because 
amiodarone increases the prothrombin time in patients tak
-
ing warfarin and increases digoxin levels, careful monitoring 
of anticoagulation and medication levels is required.
Other agents that may be used for both cardioversion 
and maintenance therapy include dofetilide, propafenone, 
flecainide, and sotalol. 
 (125–500 mcg twice daily 
orally) must be initiated in hospital due to the potential risk 
of torsades de pointes and the downward dose adjustment 
that is required for patients with renal impairment. 
 (150–300 mg orally every 8 hours) should be 
avoided in patients with structural heart disease (CAD, 
systolic dysfunction, or significant LVH). 
 
(50–150 mg twice daily orally) should be used in conjunc
-
tion with an AV nodal blocking medication if there is a 
history of atrial flutter and should be avoided in patients with 
structural heart disease. 
Sotalol
 (80–160 mg orally twice 
daily) should be initiated in the hospital in patients with 
structural heart disease due to a risk of torsades de pointes; it 
is not very effective for converting atrial fibrillation but can 
be used to maintain sinus rhythm following cardioversion.
In patients treated long-term with an antiarrhythmic 
agent, sinus rhythm will persist in 30–50%. The most com
-
monly used medications are amiodarone, dronedarone, 
CMDT19_Ch10_p0334-p0450.indd   406

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CMDT 2019
sotalol, propafenone, flecainide, and dofetilide, but the lat
-
ter four agents are associated with a clear risk of proarrhyth
-
mia in certain populations; dronedarone has less efficacy 
than amiodarone, and amiodarone frequently causes other 
adverse effects. Therefore, after an initial presentation of 
atrial fibrillation, it may be prudent to determine whether 
atrial fibrillation recurs during a period of 6 months with
-
out antiarrhythmic medications. If it does recur, the deci
-
sion to restore sinus rhythm and initiate long-term 
antiarrhythmic therapy can be based on how well the 
patient tolerates atrial fibrillation. The decision to maintain 
long-term anticoagulation should be based on risk factors 
(CHADS
2
 or CHA
2
DSv-V ASc score, Tables 10–12 and 
10–13) and not on the perceived presence or absence of 
atrial fibrillation as future episodes may be asymptomatic.
B. Recurrent and Refractory Atrial Fibrillation
1. Recurrent paroxysmal atrial fibrillation—
recurrent paroxysmal atrial fibrillation are at similar stroke 
risk as those who are in atrial fibrillation chronically. Although 
these episodes may be apparent to the patient, many are not 
recognized and may be totally asymptomatic. Thus, extended 
continuous ambulatory monitoring or event recorders are 
indicated in those in whom paroxysmal atrial fibrillation is 
suspected. Long-term anticoagulation should be considered 
for all patients except in those who are under 65 years of age 
and have no additional stroke risk factors. Antiarrhythmic 
agents are first-line therapy for recurrent, symptomatic atrial 
fibrillation; however, they are not often successful in prevent
-
ing all paroxysmal atrial fibrillation episodes.
2. Refractory atrial fibrillation—
Atrial fibrillation should 
generally be considered refractory if it causes persistent 
symptoms or limits activity despite attempts at rate control. 
This is much more likely in younger individuals and those 
who are active or engage in strenuous exercise. Even in 
such individuals, medication combinations of a beta-
blocker, rate-slowing calcium blocker and, in some 
instances, digoxin can prevent excessive ventricular rates, 
though in some cases they are associated with excessive 
bradycardia during sedentary periods.
If antiarrhythmic or rate-control medications fail to 
improve the symptoms of atrial fibrillation, catheter abla
-
tion of foci in and around the pulmonary veins that initiate 
atrial fibrillation may be considered. 
Pulmonary vein iso
-
lation
 is a reasonable second-line therapy for individuals 
with symptomatic paroxysmal or persistent atrial fibrilla
-
tion that is refractory to pharmacologic therapy. Ablation is 
successful about 50–70% of the time but more than one 
procedure may be required. The procedure is routinely 
performed in the electrophysiology laboratory using a 
catheter-based approach and can also be performed via a 
subxiphoid approach thorascopically, via thoracotomy, or 
via median sternotomy in the operating room by experi
-
enced surgeons. In symptomatic patients with poor rate-
control and deemed inappropriate for pulmonary vein 
isolation, radiofrequency ablation of the AV node and 
permanent pacing ensure rate control and may facilitate a 
more physiologic rate response to activity, but this is used 
only as a last resort.
 
»
•	
Symptomatic atrial fibrillation with or without ade
-
quate rate control.
•	
Asymptomatic atrial fibrillation with poor rate control 
despite AV nodal blockers.
•	
Patients at risk for stroke who have not tolerated oral 
anticoagulants.
January CT et al. 2014 AHA/ACC/HRS Guideline for the Man
-
agement of Patients With Atrial Fibrillation: A Report of the 
-
24685669]

-
24685669]
Kirchhof P et al. 2016 ESC Guidelines for the management of 
atrial fibrillation developed in collaboration with EACTS. Eur 
Heart J. 2016 Oct 7;37(38):2893–962. [PMID: 27567408]
Piccini JP et al. Rhythm control in atrial fibrillation. Lancet. 
2016 Aug 20;388(10046):829–40. [PMID: 27560278]
Van Gelder IC et al. Rate control in atrial fibrillation. Lancet. 
2016 Aug 20;388(10046):818–28. [PMID: 27560277]
ATRIAL FLUTTER
 
»
Rapid, regular tachycardia presenting classically 
with 2 to 1 block in the AV node and ventricular 
heart rate of 150 beats/min. ECG shows “sawtooth” 
pattern of atrial activity (rate 300 beats/min).
 
»
Stroke risk should be considered equivalent to 
that with atrial fibrillation.
 
»
Catheter ablation is highly successful and is con
-
sidered the definitive treatment for typical atrial 
flutter.
 
»
Atrial flutter is less common than fibrillation. It may occur 
in patients with structurally normal hearts but is more 
commonly seen in patients with COPD, valvular or struc
-
tural heart disease, ASD, or surgically repaired congenital 
 
»
Patients typically present with complaints of palpitations, 
fatigue, or mild dizziness. In situations where the arrhyth
-
mia is unrecognized for a prolonged period of time, 
patients may present with symptoms and signs of heart 
failure (dyspnea, exertional intolerance, edema) due to 
tachycardia-induced cardiomyopathy. The ECG typically 
demonstrates a “sawtooth” pattern of atrial activity in the 
inferior leads (II, III, and AVF). The reentrant circuit gen
-
erates atrial rates of 250–350 beats/min, usually with trans
-
mission of every second, third, or fourth impulse through 
the AV node to the ventricles.
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»
Treatment
Ventricular rate control is accomplished using the same 
agents used in atrial fibrillation, but it is generally more dif
-
ficult. Conversion of atrial flutter to sinus rhythm with 
class I antiarrhythmic agents is also difficult to achieve, and 
administration of these medications has been associated 
with slowing of the atrial flutter rate to the point at which 1:1 
AV conduction can occur at rates in excess of 200 beats/min, 
with subsequent hemodynamic collapse. The intravenous 
class III antiarrhythmic agent ibutilide has been significantly 
more successful in converting atrial flutter (see Table 10–11). 
About 50–70% of patients return to sinus rhythm within 
60–90 minutes following the infusion of 1–2 mg of this 
agent. Electrical cardioversion is also very effective for atrial 
flutter, with approximately 90% of patients converting fol
-
lowing synchronized shocks of as little as 25–50 J.
Although the organization of atrial contractile function 
in this arrhythmia may provide some protection against 
thrombus formation, the risk of thromboembolism should 
be considered 
equivalent to that with atrial fibrillation
 due 
to the common coexistence of these arrhythmias. Precar
-
dioversion anticoagulation is not necessary for atrial flutter 
of less than 48 hours duration except in the setting of 
mitral valve disease. As with atrial fibrillation, anticoagula
-
tion should be continued for at least 4 weeks after electrical 
or chemical cardioversion and chronically in patients with 
risk factors for thromboembolism.
Catheter ablation is the treatment of choice for long-term 
management of atrial flutter owing to the high success rate 
and safety of the procedure. The anatomy of the typical cir
-
cuit is well defined and catheter ablation within the right 
atrium results in immediate and permanent elimination of 
atrial flutter in more than 90% of patients. Due to the frequent 
coexistence of atrial flutter with atrial fibrillation, however, 
some patients may require catheter ablation of both arrhyth
-
mias. If pharmacologic therapy is chosen, class III antiar
-
rhythmics (amiodarone or dofetilide) are generally preferred 
(see Table 10–11). Dofetilide is often given in conjunction 
with an AV nodal blocker (other than verapamil).
 
»
All patients with atrial flutter should be referred to a cardi
-
ologist or cardiac electrophysiologist for consideration of 
definitive treatment with catheter ablation.
ATRIAL TACHYCARDIA
 
»
Characterized by bursts of rapid, regular 
 
»
Multifocal atrial tachycardia commonly seen with 
severe COPD and presents with three or more 
distinct P wave morphologies on ECG, often con
-
fused for atrial fibrillation. Treatment of the under
-
lying lung disease is most effective therapy.
 
»
Atrial tachycardia
 is an uncommon form of SVT charac
-
terized by paroxysms or bursts of rapid, regular arrhyth
-
mia due to focal atrial impulses originating outside of the 
normal sinus node. Common sites include the tricuspid 
annulus, the crista terminalis of the right atrium and the 
coronary sinus. 
Multifocal atrial tachycardia
 is a partic
-
ular subtype seen in patients with severe COPD and 
characterized by varying P wave morphology (by defini
-
tion, three or more foci) and markedly irregular PP 
intervals. The rate is usually between 100 beats/min and 
140 beats/min, and it is often confused for atrial fibrilla
-
tion. Solitary 
atrial premature beats
 are benign and 
generally not associated with underlying cardiac disease. 
They occur when an ectopic focus in the atria fires before 
the next sinus node impulse. The contour of the P wave 
usually differs from the patient’s normal complex, unless 
the ectopic focus is near the sinus node. Acceleration of 
the heart rate by any means usually abolishes most pre
-
mature beats.
 
»

-
 
»
Focal atrial tachycardias are usually intermittent and self-
limiting although incessant forms do exist and may pres
-
ent with signs and symptoms of heart failure due to 
tachycardia-induced cardiomyopathy. Most patients 
report palpitations with an abrupt onset, similar to other 
forms of SVT. Patients with underlying cardiac pathology 
(eg, CHD) can present with dyspnea or angina. Close 
inspection of the P wave on 12-lead ECG suggests a focus 
away from the sinus node, although certain locations (eg, 
high right atrial crista terminalis) may mimic sinus tachy
-
cardia. In this situation, the abrupt onset and offset of the 
arrhythmia is helpful in distinguishing atrial from sinus 
tachycardia, although electrophysiologic study is some
-
times necessary.
 
»
Treatment
Initial management of atrial tachycardia is similar to other 
types of PSVT; however, vagal maneuvers and intravenous 
adenosine are generally less effective. Intravenous beta-
blockers or calcium channel blockers can be given in the 
hemodynamically stable patient with a change to oral for
-
mulations for long-term managment. Antiarrhythmic 
medications or catheter ablation should be considered in 
patients who continue to have symptomatic episodes. 
Long-term anticoagulation is not indicated in the absence 
of coexistant atrial fibrillation or atrial flutter.
For patients with multifocal atrial tachycardia, treat
-
ment of the underlying condition (eg, COPD) is para
-
mount; verapamil, 240–480 mg orally daily in divided 
doses may be effective in some patients.
 
»
All patients with atrial tachycardia in whom initial medical 
management fails should be referred to a cardiologist or 
cardiac electrophysiologist.
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VENTRICULAR PREMATURE BEATS 
(
Ventricular Extrasystoles)
 
»
Common but rarely symptomatic.
 
»
Ambulatory ECG monitoring to quantify daily bur
-
den of PVCs. Asymptomatic patients with greater 
than 10% PVC burden should have periodic echo
-
cardiogram to exclude development of LV 
 
»
Ventricular premature beats, also called 
PVCs
, are typically 
isolated beats originating from ventricular tissue. Sudden 
death occurs more frequently (presumably as a result of 
ventricular fibrillation) when ventricular premature beats 
occur in the presence of organic heart disease but not in 
individuals with no known cardiac disease.
 
»
The patient may or may not sense the irregular beat, usu
-
ally as a skipped beat. Exercise generally abolishes prema
-
ture beats in normal hearts, and the rhythm becomes 
regular. Ventricular premature beats are characterized by 
wide QRS complexes that differ in morphology from the 
patient’s normal beats. They are usually not preceded by a 
P wave, although retrograde ventriculoatrial conduction 
may occur. Bigeminy and trigeminy are arrhythmias in 
which every second or third beat is premature; these pat
-
terns confirm a reentry mechanism for the ectopic beat. 
Ambulatory ECG monitoring or monitoring during graded 
exercise may reveal more frequent and complex ventricular 
premature beats than occur in a single routine ECG. An 
increased frequency of ventricular premature beats during 
exercise is associated with a higher risk of cardiovascular 
mortality and should be investigated further.
 
»
Treatment
If no associated cardiac disease is present and if the ectopic 
beats are asymptomatic, no therapy is indicated. Mild 
symptoms or anxiety from palpitations may be allayed with 
reassurance to the patient of the benign nature of this 
arrhythmia. If PVCs are frequent (bigeminal or trigeminal 
pattern), electrolyte abnormalities (especially hypokalemia 
or hyperkalemia and hypomagnesemia), hyperthyroidism, 
and occult heart disease should be excluded. In addition, 
an echocardiogram should be performed in patients in 
whom a burden of PVCs of greater than 10,000 per day has 
been documented by ambulatory ECG monitoring. Phar
-
macologic treatment is indicated only for patients who are 
symptomatic or who develop cardiomyopathy thought due 
to high burden PVCs (generally greater than 10% of daily 
heart beats). Beta-blockers or non-dihydropyridine cal
-
cium channel blockers are appropriate as first-line therapy. 
The class I and III antiarrhythmic agents (see Table 10–11) 
may be effective in reducing ventricular premature beats 
but are often poorly tolerated and can be proarrhythmic in 
up to 5% of patients. Catheter ablation is a well-established 
therapy for symptomatic individuals who do not respond 
to medication or for those patients whose burden of ecto
-
pic beats has resulted in a cardiomyopathy.
 
»
Patients with symptomatic PVCs who do not respond to 
initial medical management or asymptomatic patients with 
daily PVC burden greater than 10% on ambulatory ECG 
monitoring should be referred to a cardiologist or cardiac 
electrophysiologist.
Tran CT et al. Premature ventricular contraction-induced car
-
diomyopathy: an emerging entity. Expert Rev Cardiovasc 
Ther. 2016 Nov;14(11):1227–34. [PMID: 27531417]
VENTRICULAR TACHYCARDIA
 
»
Fast, wide QRS complex on ECG.
 
»
Associated with ischemic heart disease, particu
-
larly in older patients.
 
»
In the absence of reversible cause, implantable 
cardioverter defibrillator (ICD) is recommended if 
meaningful life expectancy is longer than 1 year.
 
»
Ventricular tachycardia is defined as three or more consec
-
utive ventricular premature beats. It is classified as either 
nonsustained
 (lasting less than 30 seconds and terminating 
spontaneously) or 
sustained

-
sustained
 with a heart rate greater than 
100 beats/min. In individuals without heart disease, non
-
sustained ventricular tachycardia is generally associated 
with a benign prognosis. In patients with structural heart 
disease, nonsustained ventricular tachycardia is associated 
with an increased risk of subsequent symptomatic ventricu
-
lar tachycardia and sudden death, especially when seen 
more than 48 hours after myocardial infarction.
Ventricular tachycardia is a frequent complication of 
acute myocardial infarction and dilated cardiomyopathy 
but may occur in chronic coronary disease, hypertrophic 
cardiomyopathy, myocarditis, and in most other forms of 
myocardial disease. It can also be a consequence of atypical 
forms of cardiomyopathies, such as arrhythmogenic right 
ventricular cardiomyopathy. However, idiopathic ventricu
-
lar tachycardia can also occur in patients with structurally 
normal hearts. 
Accelerated idioventricular rhythm
 is a 
regular wide complex rhythm with a rate of 60–120 beats/
min, usually with a gradual onset. It occurs commonly in 
acute infarction and following reperfusion with thrombo
-
lytic medications. Treatment is not indicated unless there is 
hemodynamic compromise or more serious arrhythmias.
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Torsades de pointes,
 a form of ventricular tachycardia 
in which QRS morphology twists around the baseline, may 
occur in the setting of severe hypokalemia, hypomagnese
-
mia, or after administration of a medication that prolongs 
the QT interval. In nonacute settings, most patients with 
ventricular tachycardia have known or easily detectable 
cardiac disease, and the finding of ventricular tachycardia 
is an unfavorable prognostic sign.
 
»
Patients commonly experience palpitations, dyspnea, or 
lightheadedness, but on rare occasion may be asymptom
-
atic. Syncope or cardiac arrest can be presenting symptoms 
in patients with underlying cardiac disease or other severe 
comorbidities. Episodes may be triggered by exercise or 
emotional stress.
Comprehensive blood laboratory work should be per
-
formed because ventricular tachycardia can occur in the 
setting of hypokalemia and hypomagnesemia. Cardiac 
markers may be elevated when ventricular tachycardia 
presents in the setting of acute myocardial infarction or as 
a consequence of underlying CAD and demand ischemia. 
In patients with sustained, hemodynamically tolerated 
ventricular tachycardia, a 12-lead ECG during tachycardia 
should be obtained. Cardiac evaluation with echocardiog
-
raphy or cardiac MRI, ambulatory ECG monitoring, and 
exercise testing may be warranted depending on the clini
-
cal situation. In survivors of cardiac arrest or those with 
life-threatening ventricular arrhythmia, invasive coronary 
angiography is recommended to establish or exclude the 
presence of significant CAD.
There is generally no role for invasive electrophysio
-
logic study in patients with sustained ventricular tachycar
-
dia who otherwise meet criteria for ICD. In patients with 
structural heart disease and syncope of unknown cause, or 
in situations in which the mechanism of wide complex 
tachycardia is uncertain, electrophysiologic study may pro
-
vide important information.
C. Differentiation of Aberrantly Conducted 
Supraventricular Beats From Ventricular Beats
The distinction on 12-lead ECG of ventricular tachycardia 
from SVT with aberrant conduction may be difficult in 
patients with a wide-complex tachycardia; it is important 
because of the differing prognostic and therapeutic impli
-
cations of each type. Findings favoring a 
ventricular origin
 
include: (1) AV dissociation; (2) a QRS duration exceeding 
0.14 second; (3) capture or fusion beats (infrequent); (4) 
left axis deviation with right bundle branch block mor
-
phology; (5) monophasic (R) or biphasic (qR, QR, or RS) 
complexes in V
1
; and (6) a qR or QS complex in V
6
. 
Supra
-
 is favored by: (1) a triphasic QRS com
-
plex, especially if there was initial negativity in leads I and 
V
6
; (2) ventricular rates exceeding 170 beats/min; (3) QRS 
duration longer than 0.12 second but not longer than 
0.14 second; and (4) the presence of preexcitation syn
-
drome. Patients with a wide-complex tachycardia, espe
-
cially those with known cardiac disease, should be presumed 
to have ventricular tachycardia if the diagnosis is unclear.
 
»
Treatment
A. Initial Management
The treatment of acute ventricular tachycardia is deter
-
mined by the degree of hemodynamic compromise and the 
duration of the arrhythmia. In patients with structurally 
normal hearts, the prognosis is generally benign and syn
-
cope is uncommon. The etiology is often triggered activity 
from the right or left ventricular outflow tract and immedi
-
ate treatment with a short-acting intravenous beta-blocker 
or verapamil may terminate the episode.
In the presence of known or suspected structural heart 
disease, assessment of hemodynamic stability determines 
the need for urgent direct current cardioversion. When 
ventricular tachycardia causes hypotension, heart failure, 
or myocardial ischemia, immediate synchronized direct

or myocardial ischemia, immediate synchronized direct 
current cardioversion with 100–360 J should be performed. 
If ventricular tachycardia recurs, intravenous amiodarone 
(150-mg bolus followed by 1 mg/min infusion for 6 h and 
then 0.5 mg/min for 18 h) should be administered to 
achieve a stable rhythm with further attempts at cardiover
-
sion as necessary. Significant hypotension can occur with 
rapid infusions of amiodarone. The management of ven
-
tricular tachycardia in the setting of acute myocardial 
infarction is discussed in the Complications section of 
Acute Myocardial Infarction with ST-Segment Elevation.
In patients with sustained ventricular tachycardia who 
are hemodynamically stable, medical treatment with intra
-
venous amiodarone, lidocaine or procainamide can be 
used; however direct current cardioversion should be per
-
formed if the ventricular tachycardia fails to terminate or 
symptoms worsen. Empiric magnesium replacement 
(1–2 g intravenously) may help especially for polymorphic 
ventricular tachycardia. If polymorphic ventricular tachy
-
cardia recurs, increasing the heart rate with isoproterenol 
infusion (up to 20 mcg/min) or atrial pacing with a tempo
-
rary pacemaker (at 90–120 bpm) will effectively shorten 
the QT interval to prevent further episodes.
B. Long-term Management
Patients with symptomatic or sustained ventricular tachy
-
cardia in the absence of a reversible precipitating cause 
(acute myocardial infarction or ischemia, electrolyte imbal
-
ance, medication toxicity, etc) are at high risk for recur
-
rence. In patients with structurally normal hearts and 
ventricular tachycardia with typical outflow tract (left bun
-
dle branch block with inferior axis) or left posterior fascicle 
(right bundle branch block with superior axis) appearance 
on ECG, suppressive treatment with beta-blocker or a non-
dihydropyridine calcium channel blocker may be tried. 
Catheter ablation has a high success rate in these patients 
who fail initial medical treatment. In patients with signifi
-
cant LV dysfunction, subsequent sudden death is common 
and ICD implantation is recommended if meaningful sur
-
vival is expected to be longer than 1 year. Beta-blockers are 
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the mainstay for medical treatment of ventricular tachycar
-
dia in patients with structural heart disease. Antiarrhythmic 
medications have not been shown to lower mortality in 
these patients, but may decrease subsequent episodes and 
reduce the number of ICD shocks. Amiodarone is generally 
preferred in patients with structural heart disease but 
sotalol may be considered as well. Catheter ablation can be 
used as a palliative therapy for those patients with recurrent 
tachycardia who do not respond to or are intolerant of 
medical therapy; however, recurrence rates are high.
 
»
Any patient with sustained ventricular tachycardia or syn
-
cope of unknown cause in the presence of underlying 
structural cardiac disease.
Al-Khatib SM et al. 2017 AHA/ACC/HRS guideline for manage
-
ment of patients with ventricular arrhythmias and the preven
-
tion of sudden cardiac death: a report of the American College 
of Cardiology/American Heart Association Task Force on 
Clinical Practice Guidelines and the Heart Rhythm Society. 
J Am Coll Cardiol. 2017 Oct 25. pii: S0735-1097(17)41306-4. 
[PMID: 29097296]
Pedersen CT et al. EHRA/HRS/APHRS expert consensus on 
ventricular arrhythmias. Europace. 2014 Sep;16(9):1257–83. 
[PMID: 25172618]
VENTRICULAR FIBRILLATION & 
 
SUDDEN DEATH
 
»
Most patients with sudden cardiac death have 
underlying CHD.
 
»
In the absence of reversible cause, ICD is 
 
»
Sudden cardiac death
 is defined as unexpected nontrau
-
matic death in clinically well or stable patients who die 
within 1 hour after onset of symptoms. The causative 
rhythm in most cases is ventricular fibrillation. 
Sudden 
cardiac arrest
 is a term reserved for the successful resusci
-
tation of ventricular fibrillation, either spontaneously or 
via intervention (defibrillation).
 
»
Approximately 70% of cases of sudden cardiac death are 
attributable to underlying CHD; in up to 20% of patients, 
sudden cardiac death may be the initial manifestation of 
CHD. The initiating arrhythmia in most patients is unknown 
but is presumed to be sustained monomorphic ventricular 
tachycardia, polymorphic ventricular tachycardia, or pri
-
mary ventricular fibrillation (especially in the setting of 
acute ischemia). Complete heart block and sinus node arrest 
may also cause sudden death. A disproportionate number of 
sudden deaths occur in the early morning hours, which sug
-
gests that there is a strong interplay with the autonomic 
nervous system. Other forms of structural heart disease can 
predispose to sudden cardiac death including idiopathic 
cardiomyopathy, hypertrophic cardiomyopathy, valvular 
heart disease (aortic stenosis, pulmonic stenosis), congenital 
heart disease, arrhythmogenic right ventricular cardiomy
-
opathy, and myocarditis. Five to 10% of cases of sudden 
cardiac death are primarily arrhythmic and occur in the 
absence of structural heart disease. Etiologies include long 
QT syndrome, Brugada syndrome, catecholaminergic poly
-
morphic ventricular tachycardia, and WPW syndrome.
Prompt evaluation to exclude reversible causes of sudden 
cardiac arrest should begin immediately following resuscita
-
tion. Laboratory testing should be performed to exclude 
severe electrolyte abnormalities (particularly hypokalemia 
and hypomagnesemia) and acidosis and to evaluate cardiac 
biomarkers. Caution should be taken in attributing cardiac 
arrest solely to an electrolyte disturbance, however, because 
laboratory abnormalities may be secondary to resuscitation 
and not causative of the event. A 12-lead ECG should be 
performed to evaluate for ongoing ischemia or conduction 
system disease. Ventricular function should be evaluated 
with echocardiography. Coronary arteriography should be 
performed to exclude coronary disease as the underlying 
cause, since revascularization may prevent recurrence.
 
»
Treatment

»
Treatment
Unless ventricular fibrillation occurs shortly after myocar
-
dial infarction, is associated with ischemia, or is seen with 
a correctable process (such as an electrolyte abnormality or 
medication toxicity), surviving patients require interven
-
tion since recurrences are frequent. Survivors of cardiac 
arrest have improved long-term outcomes if a hypothermia 
protocol is rapidly initiated and continued for 24–36 hours 
after cardiac arrest.
Patients who survive sudden cardiac arrest have a high 
incidence of recurrence, so an ICD is generally indicated. 
Sudden cardiac arrest in the setting of acute ischemia or 
infarct should be managed with prompt coronary revascu
-
larization. However, implantation of a prophylactic ICD in 
patients early after myocardial infarction is associated with 
a trend toward worse outcomes. These patients may be 
managed with a wearable defibrillator vest until recovery of 
ventricular function can be assessed by echocardiogram at 
a later date (6–12 weeks following myocardial infarction or 
coronary intervention).
 
»
All survivors of sudden cardiac arrest should be referred to 
a cardiologist or cardiac electrophysiologist.
Piccini JP et al; American Heart Association Electrocardiogra
-
phy and Arrhythmias Committee of the Council on Clinical 
Cardiology and Council on Cardiovascular and Stroke Nurs
-
ing. Wearable cardioverter-defibrillator therapy for the pre
-
vention of sudden cardiac death. Circulation. 2016 Apr 26;
 
133(17):1715–27. [PMID: 27022063]
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LONG QT SYNDROME
 
»
Can be congenital or acquired.
 
»
Genetic testing for patients with high suspicion of 
congenital cause based on family history, ECG or 
exercise testing, or severely prolonged QT interval 
(greater than 500 ms) on serial ECGs.
 
»
Patients with congenital long QT syndrome should 
be managed long-term with an oral beta-blocker 
(propranolol or nadolol). ICD is indicated for 
patients with ventricular arrhythmia or syncope 
despite medical treatment.
 
»
Congenital long QT syndrome
 is an uncommon disease (1 
in 2000 live births) that is characterized by a long QT inter
-
val (usually greater than 470 ms) and ventricular arrhyth
-
mia, typically polymorphic ventricular tachycardia. It is due 
to a genetic abnormality in ion channel activity and may be 
associated with increased cardiac sympathetic activity. It 
may occur in the presence of congenital deafness (
Jervell-
Lange-Nielsen syndrome
) with autosomal recessive inheri
-
tance. 
Acquired long QT interval
 is usually secondary to 
use of antiarrhythmic agents, methadone, antidepressant 
medications, or certain antibiotics; electrolyte abnormali
-
ties; myocardial ischemia; or significant bradycardia. Nota
-
bly, many antiarrhythmic medications that are effective for 
the treatment of atrial and ventricular arrhythmias may 
significantly prolong the QT interval (sotalol, dofetilide).
 
»
The clinical presentation of congenital or acquired long QT 
syndrome is variable. Patients may be asymptomatic or have 
palpitations, sustained tachyarrhythmia, syncope, or sud
-
den cardiac arrest. In young patients with congenital long 
QT syndrome, syncopal episodes may be misdiagnosed as a 
primary seizure disorder. Personal and family history 
should be thoroughly reviewed in all patients with long QT 
syndrome (congenital or acquired). A 12-lead ECG should 
be performed as well as ambulatory ECG monitoring to 
evaluate for ventricular arrhythmias as well as dynamic 
changes to the QT interval or T wave. Exercise ECG testing 
should be performed in all patients to assess for lack of 
appropriate QT interval shortening with exercise or during 
recovery. Genetic testing is appropriate for patients with a 
high suspicion of congenital long QT syndrome based on 
the above findings, or for patients with severe (greater than 
500 ms) prolongation of the QT interval on serial ECGs.
 
»
Treatment
The management of acute torsades de pointes differs from 
that of other forms of ventricular tachycardia. Class Ia, Ic, 
or III antiarrhythmics, which prolong the QT interval, 
should be avoided—or withdrawn immediately if being 
used. Intravenous beta-blockers may be effective, espe
-
cially in congenital forms of long QT syndrome; intrave
-
nous magnesium should be given immediately. Increasing 
the heart rate, whether by infusion of beta-agonist (dopa
-
mine or isoproterenol) or temporary atrial or ventricular 
pacing, is an effective approach that can both break and 
prevent the rhythm.
Long-term management of acquired long QT syndrome 
generally involves withdrawal of the offending medication 
and correction of any electrolyte abnormalities. For con
-
genital long QT syndrome, prognosis is excellent if the 
arrhythmia is controlled. Long-term use of beta-blockers 
(particularly propranolol or nadolol) is the mainstay of 
treatment. Surgical cervicothoracic sympathectomy should 
be considered for patients who do not respond to or are 
intolerant of beta-blockers. ICD implantation is recom
-
mended for patients in whom recurrent syncope, sustained 
ventricular arrhythmias, or sudden cardiac death occurs 
despite medical therapy. An ICD should be considered as 
primary therapy in certain patients, such as those in whom 
sudden cardiac arrest is the initial presentation of the long 
QT syndrome syndrome.
 
»
Any patient with known or suspected congenital (familial)

»
Any patient with known or suspected congenital (familial) 
long QT syndrome or with severe QT interval prolongation 
(greater than 500 ms on serial ECGs) should be referred to 
Abrams DJ et al. Long QT syndrome. Circulation. 2014 Apr 8;
 
129(14):1524–9. [PMID: 24709866]
SYNCOPE
 
»
Transient loss of consciousness and postural tone 
from vasodepressor or cardiogenic causes with 
prompt recovery without resuscitative measures.
 
»
High-risk features include history of structural 
heart disease, abnormal ECG, and age older than 
60 years.
 
»
Syncope is a symptom defined as a transient, self-limited 
loss of consciousness, usually leading to a fall. Thirty per
-
cent of the adult population will experience at least one 
episode of syncope. It accounts for approximately 3% of 
emergency department visits. A specific cause of syncope is 
identified in about 50% of cases during the initial evalua
-
tion. The prognosis is relatively favorable except when 
accompanying cardiac disease is present. In many patients 
with recurrent syncope or near syncope, arrhythmias are 
not the cause. This is particularly true when the patient has 
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no evidence of associated heart disease by history, exami
-
nation, standard ECG, or noninvasive testing. The history 
is the most important component of the evaluation to 
identify the cause of syncope.
Reflex (neurally mediated) syncope
 may be due to 
excessive vagal tone or impaired reflex control of the periph
-
eral circulation. The most frequent type is 
vasovagal syn
-
cope
 or the “common faint, ” which is often initiated by a 
stressful, painful, or claustrophobic experience, especially in 
young women. Enhanced vagal tone with resulting hypoten
-
sion is the cause of syncope in 
carotid sinus hypersensitiv
-
ity
 and 
postmicturition syncope;
 vagal-induced sinus 
bradycardia, sinus arrest, and AV block are common accom
-
paniments and may themselves be the cause of syncope.
Orthostatic (postural) hypotension
 is another com
-
mon cause of vasodepressor syncope, especially in elderly 
patients; in diabetic patients or others with autonomic neu
-
ropathy; in patients with blood loss or hypovolemia; and in 
patients taking vasodilators, diuretics, and adrenergic-
blocking medications. In addition, a syndrome of chronic 
idiopathic orthostatic hypotension exists primarily in older 
men. In most of these conditions, the normal vasoconstric
-
tive response to assuming upright posture, which compen
-
sates for the abrupt decrease in venous return, is impaired.
Cardiogenic syncope
 can occur on a mechanical or 
arrhythmic basis. There is usually no prodrome; thus, 
injury secondary to falling is common. Mechanical prob
-
lems that can cause syncope include aortic stenosis (where 
syncope may occur from autonomic reflex abnormalities 
or ventricular tachycardia), pulmonary stenosis, hypertro
-
phic cardiomyopathy, congenital lesions associated with 
pulmonary hypertension or right-to-left shunting, and LA 
myxoma obstructing the mitral valve. Episodes are com
-
monly exertional or postexertional. More commonly, car
-
diac syncope is due to disorders of automaticity (sick sinus 
syndrome), conduction disorders (AV block), or tachyar
-
rhythmias (especially ventricular tachycardia and SVT 
with rapid ventricular rate).
 
»
Syncope is characteristically abrupt in onset, often 
resulting in injury, transient (lasting for seconds to a few 
minutes), and followed by prompt recovery of full 
consciousness.
Vasodepressor premonitory symptoms, such as nausea, 
diaphoresis, tachycardia, and pallor, are usual in the “com
-
mon faint. ” Episodes can be aborted by lying down or remov
-
ing the inciting stimulus. In orthostatic (postural) 
hypotension, a greater than normal decline (20 mm Hg) in 
BP immediately upon arising from the supine to the standing 
position is observed, with or without tachycardia depending 
on the status of autonomic (baroreceptor) function.
B. Diagnostic Tests
The evaluation for syncope depends on findings from the 
history and physical examination (especially orthostatic BP 
evaluation, auscultation of carotid arteries, and cardiac 
examination).
1. ECG—
A resting ECG is recommended for all patients 
undergoing evaluation for syncope. High-risk findings on 
ECG include non-sinus rhythm, complete or partial left 
bundle branch block, and voltage criteria indicating left 
ventricular hypertrophy. Patients with a normal initial 
evaluation, including unremarkable history and physical, 
absence of cardiac disease or significant comorbidities and 
normal baseline ECG may not need further testing. When 
initial evaluation suggests a possible cardiac arrhythmia, 
continuous ambulatory ECG monitoring, event recorder 
(for infrequent episodes), or an implantable cardiac moni
-
tor can be considered. Caution is required before attribut
-
ing a patient’s syncopal event to rhythm or conduction 
abnormalities observed during monitoring without con
-
comitant symptoms. For instance, dizziness or syncope in

-
-
comitant symptoms. For instance, dizziness or syncope in 
older patients may be unrelated to incidentally observed 
bradycardia, sinus node abnormalities, or ventricular 
ectopy.
2. Autonomic testing—
Tilt-table testing
 may be useful in 
patients with suspected vasovagal syncope where the diag
-
nosis is unclear after initial evaluation, especially when 
syncope is recurrent. The hemodynamic response to tilting 
determines whether there is a cardioinhibitory, vasode
-
pressor, or mixed response. The overall utility of the test is 
improved when there is a high pretest probability of neu
-
rally mediated syncope, since the sensitivity and specificity 
of the test in the general population is only moderate.
3. Electrophysiologic studies—
Electrophysiologic study 
has limited role in the evaluation of syncope, particularly 
in patients without structural heart disease or when there 
is a low suspicion for arrhythmic etiology. In patients with 
ischemic heart disease, LV dysfunction, known conduction 
disease or arrhythmia, electrophysiologic study may help 
elucidate the mechanism of syncope and guide treatment 
decisions. The diagnostic yield in patients with structural 
heart disease is approximately 50%.
 
»
Treatment
In patients with vasovagal syncope, treatment consists 
largely of education on the benign nature of the condition 
and counseling to avoid predisposing situations. Counter
-
pressure maneuvers (squatting, leg-crossing, abdominal 
contraction) can be helpful in limiting or terminating epi
-
sodes. Medical therapy is reserved for patients with symp
-
toms despite these measures. Midodrine is an alpha-agonist 
that can increase the peripheral sympathetic neural out
-
flow and decrease venous pooling during vasovagal epi
-
sodes. Fludrocortisone and beta-blockers have also been 
used but generally provide minimal benefit. Selective 
serotonin reuptake inhibitors have shown some benefit in 
select patients. There is generally no indication for perma
-
nent pacemaker implantation in patients with vasovagal 
syncope unless prolonged, spontaneous episodes of syn
-
cope are recorded, especially in the absence of vasodepres
-
sor response on tilt-table testing.
If symptomatic bradyarrhythmias or supraventricular 
tachyarrhythmias are detected and felt to be the cause of 
syncope, therapy can usually be initiated without addi
-
tional diagnostic studies. Permanent pacing is indicated in 
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patients with syncope and documented severe pauses 
(greater than 3 seconds), bradycardia, or high-degree AV 
block (second-degree Mobitz type II or complete heart 
block) when symptoms are correlated to the arrhythmia.
An important consideration in patients who have expe
-
rienced syncope, symptomatic ventricular tachycardia, or 
aborted sudden death is to provide recommendations con
-
cerning 
automobile
 
driving restrictions
. Patients with 
syncope thought to be due to temporary factors (acute 
myocardial infarction, bradyarrhythmias subsequently 
treated with permanent pacing, medication effect, electro
-
lyte imbalance) should be advised after recovery not to 
drive for at least 1 week. Other patients with symptomatic 
ventricular tachycardia or aborted sudden death, whether 
treated pharmacologically, with antitachycardia devices, or 
with ablation therapy, should not drive for at least 6 months. 
Longer restrictions are warranted in these patients if 
significant arrhythmias persist.
 
»
•	
Patients with syncope and underlying structural heart 
disease, documented arrhythmia or conduction 
disturbance.
•	
Unclear etiology of syncope with high-risk features 
(heart failure, abnormal ECG findings, advanced age, 
multiple unexplained episodes).
Shen WK et al. 2017 ACC/AHA/HRS guideline for the evalua
-
tion and management of patients with syncope: executive 
summary: a report of the American College of Cardiology/
Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 
2017 Aug 1;70(5):620–63. [PMID: 28286222]
 
º
HEART FAILURE
 
»
LV failure: Either due to systolic or diastolic dysfunc
-
tion. Predominant symptoms are those of low car
-
diac output and congestion, including dyspnea.
 
»
RV failure: Symptoms of fluid overload predomi
-
nate; usually RV failure is secondary to LV failure.
 
»
Assessment of LV function is a crucial part of diag
-
nosis and management.
 
»
Optimal management of chronic heart failure 
includes combination medical therapies, such as 
ACE inhibitors, aldosterone antagonists, and 
beta-blockers.
 
»
Heart failure is a common syndrome that is increasing in 
incidence and prevalence. Approximately 6.5 million 
patients in the United States have heart failure, and there 
are around 960,000 new cases each year, with 8 million or 
more patients projected to have heart failure by 2030. Each 
year in the United States, over 1 million patients are dis
-
charged from the hospital with a diagnosis of heart failure. 
It is primarily a disease of aging, with over 75% of existing 
and new cases occurring in individuals over 65 years of age. 
Seventy-five percent of heart failure patients have anteced
-
ent hypertension. The prevalence of heart failure rises from 
less than 1% in individuals below 60 years to nearly 10% in 
those over 80 years of age.
Heart failure may be right-sided or left-sided (or both). 
left heart failure
 may have symptoms of low 
cardiac output and elevated pulmonary venous pressure; 
dyspnea is the predominant feature. Signs of fluid retention 
predominate in 
right heart failure
. Most patients exhibit 
symptoms or signs of both right- and left-sided failure, and 
LV dysfunction is the primary cause of RV failure. Approx
-
imately half of patients with heart failure have 
preserved 
LV systolic function
 and usually have some degree of dia
-
stolic dysfunction. Patients with reduced or preserved sys
-
tolic function may have similar symptoms and it may be 
difficult to distinguish clinically between the two based on 
signs and symptoms. In developed countries, CAD with 
resulting myocardial infarction and loss of functioning 
myocardium 
(ischemic cardiomyopathy)
 is the most 
common cause of systolic heart failure. Systemic hyperten
-
sion remains an important cause of heart failure and, even

 is the most 
-
sion remains an important cause of heart failure and, even 
more commonly in the United States, an exacerbating fac
-
tor in patients with cardiac dysfunction due to other 
causes, such as CAD. Several processes may present with 
dilated 
or
 congestive cardiomyopathy
, which is charac
-
terized by LV or biventricular dilation and generalized 
systolic dysfunction. These are discussed elsewhere in this 
chapter, but the most common are alcoholic cardiomyopa
-
thy, viral myocarditis (including infections by HIV), and 
dilated cardiomyopathies with no obvious underlying 
cause (idiopathic cardiomyopathy). Rare causes of dilated 
cardiomyopathy include infiltrative diseases (hemochro
-
matosis, sarcoidosis, amyloidosis, etc), other infectious 
agents, metabolic disorders, cardiotoxins, and medication 
toxicity. Valvular heart diseases—particularly degenerative 
aortic stenosis and chronic aortic or mitral regurgitation—
are not infrequent causes of heart failure. Persistent tachy
-
cardia, often related to atrial arrhythmias, can cause 
systolic dysfunction that may be reversible with controlling 
the rate. 
Diastolic cardiac dysfunction
 is associated with 
aging and related myocardial stiffening, as well as LVH, 
commonly resulting from hypertension. Conditions such 
as 
hypertrophic
 or 
restrictive cardiomyopathy
, diabetes, 
and pericardial disease can produce the same clinical pic
-
ture. Atrial fibrillation with or without rapid ventricular 
response may contribute to impaired left ventricular 
filling.
Heart failure is often preventable by early detection of 
patients at risk and by early intervention. The importance of 
these approaches is emphasized by US guidelines that have 
incorporated a classification of heart failure that includes 
four stages. 
Stage A
 includes patients at risk for developing 
heart failure (such as patients with hypertension). In the 
majority of these patients, development of heart failure can 
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be prevented with interventions such as the aggressive treat
-
ment of hypertension, modification of coronary risk factors, 
and reduction of excessive alcohol intake. 
Stage B
 includes 
patients who have structural heart disease but no current or 
previously recognized symptoms of heart failure. Examples 
include patients with previous myocardial infarction, other 
causes of reduced systolic function, LVH, or asymptomatic 
valvular disease. Both ACE inhibitors and beta-blockers 
prevent heart failure in the first two of these conditions, and 
more aggressive treatment of hypertension and early surgi
-
cal intervention are effective in the latter two. 
Stages C
 and 
D
 include patients with clinical heart failure and the rela
-
tively small group of patients that has become refractory to 
the usual therapies, respectively.
 
»
The most common symptom of patients with 
left heart 
failure
 is shortness of breath, chiefly exertional dyspnea at 
first and then progressing to orthopnea, paroxysmal noctur
-
nal dyspnea, and rest dyspnea. Chronic nonproductive 
cough, which is often worse in the recumbent position, may 
occur. Nocturia due to excretion of fluid retained during the 
day and increased renal perfusion in the recumbent position 
is a common nonspecific symptom of heart failure, as is 
fatigue and exercise intolerance. These symptoms correlate 
poorly with the degree of cardiac dysfunction. Patients with 
 have predominate signs of fluid reten
-
tion, with the patient exhibiting edema, hepatic congestion 
and, on occasion, loss of appetite and nausea due to edema 
of the gut or impaired gastrointestinal perfusion and ascites. 
Surprisingly, some individuals with severe LV dysfunction 
will display few signs of left heart failure and appear to have 
isolated right heart failure. Indeed, they may be clinically 
indistinguishable from patients with 
cor pulmonale,
 who 
have right heart failure secondary to pulmonary disease.
Patients with acute heart failure from myocardial 
infarction, myocarditis, and acute valvular regurgitation 
due to endocarditis or other conditions usually present 
with pulmonary edema. Patients with episodic symptoms 
may be having LV dysfunction due to intermittent isch
-
emia. Patients may also present with acute exacerbations of 
chronic, stable heart failure. Exacerbations may be caused 
by alterations in therapy (or patient noncompliance), 
excessive salt and fluid intake, arrhythmias, excessive activ
-
ity, pulmonary emboli, intercurrent infection, or progres
-
sion of the underlying disease.
Patients with heart failure are often categorized by the 
NYHA classification as 
class I
 (asymptomatic), 
class II
 
(symptomatic with moderate activity), 
class III
 (symptom
-
atic with mild activity), or 
class IV
 (symptomatic at rest). 
This classification is important since some of the treat
-
ments are indicated based on NYHA classification.
B. Signs
Many patients with heart failure, including some with 
severe symptoms, appear comfortable at rest. Others will 
be dyspneic during conversation or minor activity, and 
those with long-standing severe heart failure may appear 
cachectic or cyanotic. The vital signs may be normal, but 
tachycardia, hypotension, and reduced pulse pressure may 
be present. Patients often show signs of increased sympa
-
thetic nervous system activity, including cold extremities 
and diaphoresis. Important peripheral signs of heart failure 
can be detected by examination of the neck, the lungs, the 
abdomen, and the extremities. RA pressure may be esti
-
mated through the height of the pulsations in the jugular 
venous system. With the patient at 45 degrees, measure the 
height of the pulsation about the sternal angle, and add 5 cm 
to estimate the height above the left atrium, with a pressure 
greater than 8 cm being abnormal. In addition to the height

greater than 8 cm being abnormal. In addition to the height 
of the venous pressure, abnormal pulsations, such as regur
-
gitant 
v
 waves, should be sought. Examination of the 
carotid pulse may allow estimation of pulse pressure as well 
as detection of aortic stenosis. Thyroid examination may 
reveal occult hyperthyroidism or hypothyroidism, which 
are readily treatable causes of heart failure. Crackles at the 
lung bases reflect transudation of fluid into the alveoli. 
Pleural effusions may cause bibasilar dullness to percus
-
sion. Expiratory wheezing and rhonchi may be signs of 
heart failure. Patients with severe right heart failure may 
have hepatic enlargement—tender or nontender—due to 
passive congestion. Systolic pulsations may be felt in tricus
-
pid regurgitation. Sustained moderate pressure on the liver 
may increase jugular venous pressure (a positive 
hepato
-
jugular reflux
 is an increase of greater than 1 cm, which 
correlates with elevated pulmonary capillary wedge pres
-
sure). Ascites may also be present. Peripheral pitting edema 
is a common sign in patients with right heart failure and 
may extend into the thighs and abdominal wall.
Cardinal cardiac examination signs are a parasternal lift, 
indicating pulmonary hypertension; an enlarged and sus
-
tained LV impulse, indicating LV dilation and hypertrophy; 
a diminished first heart sound, suggesting impaired con
-
tractility; and an S
3
 gallop originating in the LV and some
-
times the RV . An S
4
 is usually present in diastolic heart 
failure. Murmurs should be sought to exclude primary val
-
vular disease; secondary mitral regurgitation and tricuspid 
regurgitation murmurs are common in patients with dilated 
ventricles. In chronic heart failure, many of the expected 
signs of heart failure may be absent despite markedly abnor
-
mal cardiac function and hemodynamic measurements.
A blood count may reveal anemia and a high red-cell distri
-
bution width (RDW), both of which are associated with 
poor prognosis in chronic heart failure through poorly 
understood mechanisms. Kidney function tests can deter
-
mine whether cardiac failure is associated with impaired 
kidney function that may reflect poor kidney perfusion. 
Chronic kidney disease is another poor prognostic factor in 
heart failure and may limit certain treatment options. Serum 
electrolytes may disclose hypokalemia, which increases the 
risk of arrhythmias; hyperkalemia, which may limit the use 
of inhibitors of the renin–angiotensin system; or hyponatre
-
mia, an indicator of marked activation of the renin–
angiotensin system and a poor prognostic sign. Thyroid 
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function should be assessed to detect occult thyrotoxicosis 
or myxedema, and iron studies should be checked to test for 
hemochromatosis. In unexplained cases, appropriate biop
-
sies may lead to a diagnosis of amyloidosis. Myocardial 
biopsy may exclude specific causes of dilated cardiomyopa
-
thy but rarely reveals specific reversible diagnoses.
Serum BNP is a powerful prognostic marker that adds 
to clinical assessment in differentiating dyspnea due to 
heart failure from noncardiac causes. Two markers—
BNP
 
and 
NT-proBNP
—provide similar diagnostic and prog
-
nostic information. BNP is expressed primarily in the 
ventricles and is elevated when ventricular filling pressures 
are high. It is quite sensitive in patients with symptomatic 
heart failure—whether due to systolic or to diastolic 
dysfunction—but less specific in older patients, women, 
and patients with COPD. Studies have shown that BNP can 
help in emergency department triage in the diagnosis of 
acute decompensated heart failure, such that an NT-
proBNP less than 300 pg/mL or BNP less than 100 pg/mL, 
combined with a normal ECG, makes heart failure unlikely. 
BNP is less sensitive and specific to diagnose heart failure 
in the chronic setting. BNP may be helpful in guiding the 
intensity of diuretic and a more consistent use of disease-
modifying therapies, such as ACE inhibitors and beta-
blockers, for the management of chronic heart failure. BNP , 
but not NT-proBNP , is increased by neprilysin inhibitors, 
since neprilysin degrades BNP . Thus, while NT-proBNP is 
still reliable, BNP should 
not
 be used to monitor degree of 
heart failure when patients are treated with sacubitril/
 
valsartan. Worsening breathlessness or weight associated 
with a rising BNP (or both) might prompt increasing the 
dose of diuretics. However, there is no proven value in 
using serial natriuretic peptide measurements to guide 
therapy, as shown in the GUIDE-IT trial. Elevation of 
serum troponin, and especially of high-sensitivity tropo
-
nin, is common in both chronic and acute heart failure, 
and it is associated with higher risk of adverse outcomes.
D. ECG and Chest Radiography
ECG may indicate an underlying or secondary arrhyth
-
mia, myocardial infarction, or nonspecific changes that 
often include low voltage, intraventricular conduction 
defects, LVH, and nonspecific repolarization changes. 
Chest radiographs provide information about the size and 
shape of the cardiac silhouette. Cardiomegaly is an impor
-
tant finding and is a poor prognostic sign. Evidence of 
pulmonary venous hypertension includes relative dilation 
of the upper lobe veins, perivascular edema (haziness of 
vessel outlines), interstitial edema, and alveolar fluid. In 
acute heart failure, these findings correlate moderately 
well with pulmonary venous pressure. However, patients 
with chronic heart failure may show relatively normal 
pulmonary vasculature despite markedly elevated pres
-
sures. Pleural effusions are common and tend to be bilat
-
eral or right-sided.
E. Additional Studies
Many studies have indicated that the clinical diagnosis of 
systolic myocardial dysfunction is often inaccurate. The 
primary confounding conditions are diastolic dysfunction 
of the heart with decreased relaxation and filling of the LV 
(particularly in hypertension and in hypertrophic states) 
and pulmonary disease.
The most useful test is the echocardiogram because it 
can differentiate heart failure with and without preserved 
LV systolic function. The echocardiogram can define the 
size and function of both ventricles and of the atria. LVEF 
is the most commonly used measurement to define systolic 
function. RV function is assessed by contractility and other 
measures, such as tricuspid annular plane systolic excur
-
sion. Echocardiography will also allow detection of peri
-
cardial effusion, valvular abnormalities, intracardiac

-
-
cardial effusion, valvular abnormalities, intracardiac 
shunts, and segmental wall motion abnormalities sugges
-
tive of old myocardial infarction as opposed to more gen
-
eralized forms of dilated cardiomyopathy.
Radionuclide angiography as well as cardiac MRI also 
measure LVEF and permit analysis of regional wall motion. 
These tests are especially useful when echocardiography is 
technically suboptimal, such as in patients with severe pul
-
monary disease. MRI can assess for presence of scar tissue 
and of infiltrative disease. When myocardial ischemia is 
suspected as a cause of LV dysfunction, as it should be 
unless there is another clear cause, stress testing or coro
-
nary angiography should be performed.
F. Cardiac Catheterization
In most patients with heart failure, clinical examination 
and noninvasive tests can determine LV size and function 
and valve function to confirm the diagnosis. Left heart 
catheterization may be helpful to define the presence and 
extent of CAD, although CT angiography may also be 
appropriate, especially when the likelihood of coronary 
disease is low. Evaluation for coronary disease is particu
-
larly important when LV dysfunction may be partially 
reversible by revascularization. The combination of angina 
or noninvasive evidence of significant myocardial ischemia 
with symptomatic heart failure is often an indication for 
coronary angiography if the patient is a potential candidate 
for revascularization. Right heart catheterization may be 
useful to select and monitor therapy in patients refractory 
to standard therapy.
 
»
Treatment: Heart Failure With Reduced EF
The treatment of heart failure is aimed at relieving symp
-
toms, improving functional status, and preventing death 
and hospitalizations. Figure 10–8 outlines the role of the 
major pharmacologic and device therapies for heart failure 
with reduced LVEF (less than or equal to 40%). The evi
-
dence of clinical benefit, including reducing death and 
hospitalization, as well as reducing sudden cardiac death, 
of most therapies is limited to patients with heart failure 
with reduced LVEF. Treatment of heart failure with pre
-
served LVEF is aimed at improving symptoms and treating 
comorbidities. Achieving target (or maximally tolerated up 
to target) dosing to obtain the benefits of these treatments 
that have been shown in clinical trials is important 
(Table 10–15).
CMDT19_Ch10_p0334-p0450.indd   416

417
 
CMDT 2019
Continue GDMT with serial reassessment and optimized dosing/adherence
Palliative care
2
(COR I)
Transplant
2
(COR I)
LVAD
2
(COR IIa)
Investigational
studies
3
Step 1
Establish Dx of HFrEF;
assess volume;
initiate GDMT
Step 2
Consider the following
patient scenarios
Step 3
Implement indicated GDMT.
Choices are not mutually
exclusive, and no order is
inferred
Step 4
Reassess
symptoms
Step 5
Consider
additional
therapy
HFrEF
NYHA class I-IV
(Stage C)
1 
The combination of ISDN/HYD with ARNI has not been robustly studied, BP response should be carefully monitored.
2 
See 2013 HF guidelines.
3 
Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF.
ACEI or ARB AND
GDMT beta-blocker;
diuretics as needed
(COR I)
lvabradine
(COR lla)
NYHA class II–IV,
provided est. CrCI 
>3
0
mL/min and K
+
 < 5.0 mEq/L
NYHA class II–III HF
Adequate BP on
ACEI or ARB
1
; No C/I
to ARB or sacubitril
NYHA class III–IV,
in black patients
NYHA class II–III, LVEF
≤ 35%; (caveat: 
>1
 y
survival, > 40 d post Ml)
NYHA class II–IV, LVEF
≤ 35%, NSR and QRS
≥150 ms with LBBB
pattern
NYHA class II–III, NSR,
heart rate ≥70 bpm on
maximally tolerated
dose beta-blocker
Aldosterone
antagonist
(COR I)
Discontinue ACEI or
ARB; initiate ARNI
1
(COR I)
Hydral-Nitrates
1, 2
(COR I)
ICD
2
(COR I)
CRT or CRT-D
2
(COR I)
Refractory
NYHA class III-IV
(Stage D)
Symptoms
improved
 
▲
Figure 10–8.
 
Major pharmacologic and device therapies for heart failure with reduced left ventricular ejection 
fraction.
For all medical therapies, dosing should be optimized and serial assessment exercised.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor-blocker; ARNI, angiotensin receptor-neprilysin 
inhibitor; BP , blood pressure; bpm, beats per minute; C/I, contraindication; COR, Class of Recommendation; CrCl, creatinine 
clearance; CRT-D, cardiac resynchronization therapy–device; Dx, diagnosis; GDMT, guideline-directed management and 
therapy; HF, heart failure; HFr EF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; 
ISDN/HYD, isosorbide dinitrate hydral-nitrates; K+, potassium; LBBB, left bundle-branch block; LVAD, left ventricular assist 
device; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm; and NYHA, New York 
Heart Association.
(Figure reproduced, with permission, from Yancy CW et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA 
Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Associa
-
tion Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. 
Circulation
. 2017 Aug 
8;136(6):e137-e161. © 2017 American Heart Association, Inc.)
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A. Correction of Reversible Causes
The major reversible causes of heart failure with reduced 
EF, also called chronic systolic heart failure, include valvu
-
lar lesions, myocardial ischemia, uncontrolled hyperten
-
sion, arrhythmias (especially persistent tachycardias), 
alcohol- or drug-induced myocardial depression, hypothy
-
roidism, intracardiac shunts, and high-output states. Cal
-
cium channel blockers with negative inotropy (specifically 
verapamil or diltiazem), antiarrhythmic medications, thia
-
zolidinediones, and nonsteroidal anti-inflammatory agents 
may be important contributors to worsening heart failure. 
Some metabolic and infiltrative cardiomyopathies may be 
partially reversible, or their progression may be slowed; 
these include hemochromatosis, sarcoidosis, and amyloi
-
dosis. Once possible reversible components are being 
addressed, the measures outlined below are appropriate.
B. Pharmacologic Treatment
See also the following section Acute Heart Failure & Pul
-
monary Edema.
1. Diuretic therapy—
Diuretics are the most effective 
means of providing symptomatic relief to patients with 
moderate to severe heart failure with dyspnea and fluid 
overload, for heart failure with reduced and with preserved 
LVEF. Few patients with symptoms or signs of fluid reten
-
tion can be optimally managed without a diuretic. How
-
ever, excessive diuresis can lead to electrolyte imbalance 
and neurohormonal activation. A combination of a diuretic 
and an ACE inhibitor should be the initial treatment in 
most symptomatic patients with heart failure and reduced 
LVEF, with the early addition of a beta-blocker.
When fluid retention is mild, thiazide diuretics or a 
similar type of agent (hydrochlorothiazide, 25–100 mg; 
metolazone, 2.5–5 mg; chlorthalidone, 25–50 mg; etc) may 
be sufficient. Thiazide or related diuretics often provide 
better control of hypertension than short-acting loop 
agents. The thiazides are generally 
ineffective
 when the 
glomerular filtration rate falls below 30–40 mL/min, a not 
infrequent occurrence in patients with severe heart failure. 
Metolazone maintains its efficacy down to a glomerular 
filtration rate of approximately 20–30 mL/min. Adverse 
reactions include hypokalemia and intravascular volume 
depletion with resulting prerenal azotemia, skin rashes, 
neutropenia and thrombocytopenia, hyperglycemia, 
hyperuricemia, and hepatic dysfunction.
Patients with more severe heart failure should be 
treated with one of the oral loop diuretics. These include 
furosemide (20–320 mg daily), bumetanide (1–8 mg daily), 
and torsemide (20–200 mg daily). These agents have a 
rapid onset and a relatively short duration of action. In 
patients with preserved kidney function, two or more daily 
doses are preferable to a single larger dose. In acute situa
-
tions or when gastrointestinal absorption is in doubt, they 
should be given intravenously. Torsemide may be effective 
when furosemide is not, related to better absorption and a 
longer half life. Larger doses (up to 500 mg of furosemide 
or equivalent) may be required with severe renal impair
-
ment. The major adverse reactions include intravascular 
volume depletion, prerenal azotemia, and hypotension. 
Hypokalemia, particularly with accompanying digitalis 
therapy, is a major problem. Less common side effects 
include skin rashes, gastrointestinal distress, and ototoxic
-
ity (the latter more common with ethacrynic acid and pos
-
sibly less common with bumetanide).
The oral potassium-sparing agents are often useful in 
combination with the loop diuretics and thiazides. Triam
-
terene (37.5–75 mg daily) and amiloride (5–10 mg daily) 
act on the distal tubule to reduce potassium secretion. 
Their diuretic potency is only mild and not adequate for 
most patients with heart failure, but they may minimize the 
hypokalemia induced by more potent agents. Side effects 
include hyperkalemia, gastrointestinal symptoms, and kid
-

-
ney dysfunction.
Spironolactone (12.5–100 mg daily) and eplerenone 
(25–100 mg daily) are specific inhibitors of aldosterone, 
which is often increased in heart failure. These medications 
Table 10–15.
 
Evidence-based doses of disease-
 
modifying medications in key randomized trials in 
HFrEF (or after myocardial infarction).
Medications
Target Dose
ACE Inhibitors
Captopril
6.25 mg three times 
daily
50 mg three times 
daily
Enalapril
2.5 mg twice daily
10–20 mg twice 
daily
Lisinopril
2.5–5.0 mg once 
daily
20–35 once daily
Ramipril
2.5 mg once daily
10 mg once daily
Trandolapril
0.5 mg once daily
4 mg once daily
Beta-Blockers
Bisoprolol
1.25 mg once daily
Carvedilol
3.125 mg twice daily
25 mg twice daily
Metoprolol succi
-
nate (CR/XL)
12.5–25 mg once 
daily
200 mg once daily
Nebivolol
1.25 once daily
ARBs
Candesartan
4–8 mg once daily
32 mg once daily
Valsartan
40 mg twice daily
160 mg twice daily
Losartan
50 mg once daily
150 mg once daily
Aldosterone Antagonist
Eplerenone
25 mg once daily
Spironolactone
ARNI
Sacubitril/valsartan
49/51 mg twice daily
97/103 mg twice 
daily
I
f
 Channel Blocker
Ivabradine
7.5 mg twice daily
ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor 
blockers; ARNI, angiotensin receptor-neprilysin inhibitor; HFrEF, 
heart failure with reduced ejection fraction.
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spare loss of potassium, they have some diuretic effect 
(especially at higher doses), and they also improve clinical 
outcomes, including survival. Their onsets of action are 
slower than the other potassium-sparing agents, and spi
-
ronolactone’s side effects include gynecomastia. Combina
-
tions of potassium supplements or ACE inhibitors and 
potassium-sparing medications can produce hyperkalemia 
but have been used with success in patients with persistent 
hypokalemia.
Patients with refractory edema may respond to combi
-
nations of a loop diuretic and thiazide-like agents. Metola
-
zone, because of its maintained activity with chronic 
kidney disease, is the most useful agent for such a combi
-
nation. Extreme caution must be observed with this 
approach, since massive diuresis and electrolyte imbal
-
ances often occur; 2.5 mg of metolazone orally should be 
added to the previous dosage of loop diuretic. In many 
cases this is necessary only once or twice a week, but dos
-
ages up to 10 mg daily have been used in some patients.
2. Inhibitors of the renin–angiotensin–aldosterone 
sys
tem
—
Inhibition of the renin–angiotensin–aldosterone 
system with ACE inhibitors should be part of the initial 
therapy of this syndrome based on their mortality benefits.
a. 
ACE
—
At least seven ACE inhibitors have 
been shown to be effective for the treatment of heart failure 
or the related indication of postinfarction LV dysfunction 
(see Table 11–8). ACE inhibitors reduce mortality by 
approximately 20% in patients with symptomatic heart fail
-
ure and have also been shown to prevent hospitalizations, 
increase exercise tolerance, and reduce symptoms in these 
patients. As a result, ACE inhibitors generally should be part 
of first-line treatment of patients with symptomatic LV sys
-
tolic dysfunction (EF less than 40%), usually in combination 
with a diuretic. They are also indicated for the management 
of patients with reduced EFs without symptoms because 
they prevent the progression to clinical heart failure.
Because ACE inhibitors may induce significant hypo
-
tension, particularly following the initial doses, they must 
be started with caution. Hypotension is most prominent in 
patients with already low BPs (systolic pressure less than 
100 mm Hg), hypovolemia, prerenal azotemia (especially if 
it is diuretic induced), and hyponatremia (an indicator of 
activation of the renin–angiotensin system). These patients 
should generally be started at low dosages (captopril 6.25 mg 
orally three times daily, enalapril 2.5 mg orally daily, or the 
equivalent), but other patients may be started at twice these 
dosages. Within several days (for those with the markers of 
higher risk) or at most 2 weeks, patients should be ques
-
tioned about symptoms of hypotension, and both kidney 
function and potassium levels should be monitored.
ACE inhibitors should be titrated to the dosages proved 
effective in clinical trials (captopril 50 mg three times daily, 
enalapril 10 mg twice daily, ramipril 10 mg daily, lisinopril 
20 mg daily, or the equivalent) over a period of 1–3 months. 
Most patients will tolerate these doses. Asymptomatic 
hypotension is not a contraindication to up-titrating or 
continuing ACE inhibitors. Some patients exhibit increases 
in serum creatinine or potassium, but they do not require 
discontinuation if the levels stabilize—even at values as 
high as 3 mg/dL and 5.5 mEq/L, respectively. Kidney dys
-
function is more frequent in patients with diabetes, older 
patients, and those with low systolic pressures, and these 
groups should be monitored more closely. The most com
-
mon side effects of ACE inhibitors in heart failure patients 
are dizziness (often not related to the level of BP) and 
cough, though the latter is often due as much to heart fail
-
ure or intercurrent pulmonary conditions as to the ACE 
inhibitor. ACE inhibitor–induced cough is more common 
in women than in men.

-
b. 
A
ngiotensin 
II
 receptor blockers
—
Another 
approach to inhibiting the renin–angiotensin–aldosterone 
system is the use of specific ARBs (see Table 11–8), which 
will decrease adverse effects of angiotensin II by blocking 
the AT
1
 receptor. In addition, because there are alternative 
pathways of angiotensin II production in many tissues, the 
receptor blockers may provide more complete blockade of 
the AT
1
 receptor.
However, these agents do not share the effects of ACE 
inhibitors on other potentially important pathways that 
produce increases in bradykinin, prostaglandins, and nitric 
oxide in the heart, blood vessels, and other tissues. ARBs, 
specifically candesartan or valsartan, provide important 
benefits as an alternative to ACE inhibitors in chronic heart 
failure with reduced LVEF. (A large trial of patients with 
chronic heart failure and preserved LVEF found no benefit 
from the ARB irbesartan.) While they have the same level 
of recommendation in the guidelines, generally ACE 
inhibitors are preferred over ARBs for patients who tolerate 
them.
c. 
S
pironolactione and eplerenone
—
Inhibiting 
aldosterone has become a mainstay of management of 
symptomatic heart failure with reduced LVEF. The RALES 
trial compared spironolactone 25 mg daily with placebo in 
patients with advanced heart failure (current or recent 
class IV) already receiving ACE inhibitors and diuretics 
and showed a 29% reduction in mortality as well as similar 
decreases in other clinical end points. Based on the 
EMPHASIS-HF trial, the efficacy and safety of aldosterone 
antagonism—in the form of eplerenone, 25–50 mg orally 
daily—is established for patients with mild or moderate 
heart failure. Hyperkalemia was uncommon in severe heart 
failure clinical trial patients who received high doses of 
diuretic as maintenance therapy; however, hyperkalemia in 
patients taking spironolactone appears to be common in 
general practice. Potassium levels must be monitored 
closely during initiation of spironolactone (after 1 and 4 weeks 
of therapy) and periodically thereafter, particularly for 
patients with even mild degrees of kidney injury, and in 
patients receiving ACE inhibitors.
d. 
C
ombination sacubitril and v alsartan
—
The 
most recently approved medication to improve clinical out
-
come in patients with heart failure and reduced LVEF is the 
combination of valsartan and sacubitril, called an angioten
-
sin receptor-neprilysin inhibitor (ARNI). Compared to the 
ACE inhibitor enalapril, the ARNI was shown to reduce 
cardiovascular death and hospitalization for heart failure by 
20% for patients with heart failure and reduced LVEF in a 
large randomized trial (PARADIGM-HF) of patients who 
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had been taking an ACE inhibitor or ARB. Cardiovascular 
death itself was also reduced by 20%.
This has led to a class I recommendation by the ACC/
AHA and the ESC guidelines for the use of sacubitril/
 
valsartan as a replacement for ACE inhibitors for patients 
with heart failure with reduced EF 
who remain symptom
-
atic on an ACE inhibitor, beta-blocker, and mineralocorticoid 
inhibitor
. For some patients, cost will be a barrier to use, 
although analyses have shown that sacubitril/valsartan is 
cost effective. Patients with baseline systolic blood pressure 
less than 100 mmHg were not included in the PARADIGM 
trial, and symptomatic hypotension is more common with 
sacubitril/valsartan than ACE inhibitor.
3. Beta-blockers—
Beta-blockers are part of the founda
-
tion of care of chronic heart failure based on their life-
saving benefits. The mechanism of this benefit remains 
unclear, but it is likely that chronic elevations of catechol
-
amines and sympathetic nervous system activity cause 
progressive myocardial damage, leading to worsening LV 
function and dilation. The primary evidence for this 
hypothesis is that over a period of 3–6 months, beta-blockers 
produce consistent substantial rises in EF (averaging 10% 
absolute increase) and reductions in LV size and mass.
Three medications have strong evidence of reducing 
mortality: 
carvedilol
 (a nonselective beta-1- and beta-
2-receptor blocker), the beta-1-selective 
extended-release 
agent metoprolol succinate
 (but not short-acting meto
-
prolol tartrate), and 
bisoprolol
 (beta-1-selective agent).
This has led to a strong recommendation that stable 
patients (defined as having no recent deterioration or evi
-
dence of volume overload) with mild, moderate, and even 
severe heart failure should be treated with a beta-blocker 
unless there is a noncardiac contraindication. In the 
COPERNICUS trial, carvedilol was both well tolerated and 
highly effective in reducing both mortality and heart fail
-
ure hospitalizations in a group of patients with severe 
(NYHA class III or IV) symptoms, but care was taken to 
ensure that they were free of fluid retention at the time of 
initiation. In this study, one death was prevented for every 
13 patients treated for 1 year—as dramatic an effect as has 
been seen with a pharmacologic therapy in the history of 
cardiovascular medicine. One trial comparing carvedilol 
and (short-acting) metoprolol tartrate (COMET) found 
significant reductions in all-cause mortality and cardiovas
-
cular mortality with carvedilol. Thus, patients with chronic 
heart failure should be treated with extended-release meto
-
prolol succinate, bisoprolol, or carvedilol but 
not
 short-
acting metoprolol tartrate.
Because even apparently stable patients may deteriorate 
when beta-blockers are initiated, initiation must be done 
gradually and with great care. Carvedilol is initiated at a 
dosage of 3.125 mg orally twice daily and may be increased 
to 6.25, 12.5, and 25 mg twice daily at intervals of approxi
-
mately 2 weeks. The protocols for sustained-release meto
-
prolol use were started at 12.5 or 25 mg orally daily and 
doubled at intervals of 2 weeks to a target dose of 200 mg 
daily (using the Toprol XL sustained-release preparation). 
Bisoprolol was administered at a dosage of 1.25, 2.5, 3.75, 
5, 7.5, and 10 mg orally daily, with increments at 1- to 
4-week intervals. More gradual up-titration is often more 
convenient and may be better tolerated. The SENIORS trial 
of 2135 patients found that nebivolol was effective in 
elderly patients (70 years and older) with chronic heart 
failure, although the evidence of degree of benefit was not 
as strong as with the three proven beta-blockers carvedilol, 
metoprolol succinate, or bisoprolol.
Patients should be instructed to monitor their weight at 
home as an indicator of fluid retention and to report any 
increase or change in symptoms immediately. Before each

increase or change in symptoms immediately. Before each 
dose increase, patients should be seen and examined to ensure 
that there has not been fluid retention or worsening of symp
-
toms. If heart failure worsens, this can usually be managed by 
increasing diuretic doses and delaying further increases in 
beta-blocker doses, though downward adjustments or discon
-
tinuation is sometimes required. Carvedilol, because of its 
beta-blocking activity, may cause dizziness or hypotension. 
This can usually be managed by reducing the doses of other 
vasodilators and by slowing the pace of dose increases.
4. Digitalis glycosides—
The efficacy of digitalis glycosides 
in reducing the symptoms of heart failure has been estab
-
lished in at least four multicenter trials that have demon
-
strated that digoxin withdrawal is associated with 
worsening symptoms and signs of heart failure, more fre
-
quent hospitalizations for decompensation, and reduced 
exercise tolerance. Digoxin should be considered for 
patients who remain symptomatic when taking diuretics 
and ACE inhibitors as well as for patients with heart failure 
who are in atrial fibrillation and require rate control.
Digoxin has a half-life of 24–36 hours and is eliminated 
almost entirely by the kidneys. The oral maintenance dose 
may range from 0.125 mg three times weekly to 0.5 mg 
daily. It is lower in patients with kidney dysfunction, in 
older patients, and in those with smaller lean body mass. 
Although an oral loading dose of 0.75–1.25 mg (depending 
primarily on lean body size) over 24–48 hours may be 
given if an early effect is desired, in most patients with 
chronic heart failure it is sufficient to begin with the 
expected maintenance dose (usually 0.125–0.25 mg daily). 
Amiodarone, quinidine, propafenone, and verapamil are 
among the medications that may increase digoxin levels up 
to 100%. It is prudent to measure a blood level after 
7–14 days (and at least 6 hours after the last dose was admin
-
istered). Optimum serum digoxin levels are 0.7–1.2 ng/mL, 
though clinically evident toxicity is rare with levels less than 
1.8 ng/mL. Digoxin may induce ventricular arrhythmias, 
especially when hypokalemia or myocardial ischemia is pres
-
ent. Digoxin toxicity is discussed in Chapter 38.
5. Nitrates and hydralazine—
Although ACE inhibitors, 
which have vasodilating properties, improve prognosis, 
such a benefit is not established with the direct-acting 
vasodilators. The combination of hydralazine and isosor
-
bide dinitrate has been shown to improve outcome in 
African Americans, but the effect is less clear than the well-
established benefits of ACE inhibitors. ARBs or ARNIs 
have largely supplanted the use of the hydralazine–isosorbide 
dinitrate combination in ACE-intolerant patients.
See section Acute Myocardial Infarction earlier in this 
chapter for a discussion on the intravenous vasodilating 
medications and their dosages.
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a. 
N
itrates
—
Intravenous vasodilators (sodium nitro
-
prusside or nitroglycerin) are used primarily for acute or 
severely decompensated chronic heart failure, especially 
when accompanied by hypertension or myocardial isch
-
emia. If neither of the latter is present, therapy is best initi
-
ated and adjusted based on hemodynamic measurements. 
The starting dosage for nitroglycerin is generally about 
10 mcg/min, which is titrated upward by 10–20 mcg/min 
(to a maximum of 200 mcg/min) until mean arterial pres
-
sure drops by 10%. Hypotension (BP less than 100 mm Hg 
systolic) should be avoided. For sodium nitroprusside, the 
starting dosage is 5–10 mcg/min, with upward titration to 
a maximum dose of 400 mcg/min.
Isosorbide dinitrate, 20–40 mg orally three times daily, 
and nitroglycerin ointment, 2%, 15–16 mg (1.4 inches; 1 inch 
= 15 mg) every 6–8 hours, appears to be equally effective, 
although the ointment is generally reserved for inpatient 
use only. The nitrates are moderately effective in relieving 
shortness of breath, especially in patients with mild to 
moderate symptoms, but less successful—probably because 
they have little effect on cardiac output—in advanced heart 
failure. Nitrate therapy is generally well tolerated, but head
-
aches and hypotension may limit the dose of all agents. The 
development of tolerance to long-term nitrate therapy 
occurs. This is minimized by intermittent therapy, espe
-
cially if a daily 8- to 12-hour nitrate-free interval is used, 
but probably develops to some extent in most patients 
receiving these agents. Transdermal nitroglycerin patches 
have no sustained effect in patients with heart failure and 
should not be used for this indication.
b. 
H
ydralazine
—
Oral hydralazine is a potent arteriolar 
dilator; when used as a single agent, it has not been shown 
to improve symptoms or exercise tolerance during long-
term treatment. The combination of nitrates and oral 
hydralazine produces greater hemodynamic effects as well 
as clinical benefits.
6. Ivabradine—
Ivabradine inhibits the I
f
 channel in the 
sinus node and has the specific effect of slowing sinus rate. 
Ivabradine is approved by the FDA for use in stable patients 
with heart failure and heart rate of 70 beats per minute who 
are taking the maximally tolerated dose of beta-blockers or 
in patients in whom beta-blockers are contraindicated. It is 
approved by the European Medicines Agency for use in 
patients with a heart rate of 75 beats per minute or more. 
Both the US and the European guidelines give it a class IIa 
recommendation for patients in sinus rhythm with a heart 
rate of 70 beats per minute or more with an EF of 35% or 
less, and persisting symptoms despite treatment with an 
evidence-based dose of beta-blocker (or a maximum toler
-
ated dose below that), ACE inhibitor (or ARB), and an 
aldosterone antagonist (or ARB). In a trial of patients with 
chronic angina, ivabradine did not reduce cardiovascular 
events, and there may have been more events with 
ivabradine (than placebo) in patients with symptomatic 
angina.
7. Combination of medical therapies—
Optimal manage
-
ment of chronic heart failure involves using combinations 
of proven life-saving therapies. In addition to ACE inhibi
-
tors and beta-blockers, patients who remain symptomatic 
should be considered for mineralocorticoid (aldosterone) 
receptor antagonists and for sacubitril/valsartan. This 
combination, titrated to full tolerated doses, with careful 
monitoring of kidney function and potassium, will provide 
the greatest pharmacologic benefit to the majority of 
patients with heart failure with reduced EF.
8. Treatments that may cause harm in heart failure 
with 
reduced 
LVEF
—
Several therapies should be 
avoided,
 
when possible, in patients with systolic heart failure. These 
include thiazoladinediones (glitazones) that cause worsen
-
ing heart failure, most calcium channel blockers (with the

avoided,
 
-
ing heart failure, most calcium channel blockers (with the 
exception of amlodipine and felodipine), nonsteroidal anti-
inflammatory medications, and cyclooxygenase-2 inhibi
-
tors that cause sodium and water retention and renal 
impairment, and the combination of an ACE inhibitor, 
ARB, and aldosterone blocker that increases the risk of 
hyperkalemia.
9. Anticoagulation—
Patients with LV failure and reduced 
EF are at somewhat increased risk for developing intracar
-
diac thrombi and systemic arterial emboli. However, this 
risk appears to be primarily in patients who are in atrial 
fibrillation, who have had thromboemboli, or who have 
had a large recent anterior myocardial infarction. In gen
-
eral, these patients should receive warfarin for 3 months 
following the myocardial infarction. Other patients with 
heart failure have embolic rates of approximately two per 
100 patient-years of follow-up, which approximates the 
rate of major bleeding, and routine anticoagulation does 
not appear warranted except in patients with prior embolic 
events or mobile LV thrombi.
10. Antiarrhythmic therapy—
Patients with moderate to 
severe heart failure have a high incidence of both symptom
-
atic and asymptomatic arrhythmias. Although less than 10% 
of patients have syncope or presyncope resulting from ven
-
tricular tachycardia, ambulatory monitoring reveals that up 
to 70% of patients have asymptomatic episodes of nonsus
-
tained ventricular tachycardia. These arrhythmias indicate a 
poor prognosis independent of the severity of LV dysfunc
-
tion, but many of the deaths are probably not arrhythmia 
related. Beta-blockers, because of their marked favorable 
effect on prognosis in general and on the incidence of sud
-
den death specifically, should be initiated in these as well as 
all other patients with heart failure (see Beta-Blockers). 
Other evidence-based therapies for heart failure, including 
ACE inhibitors, ARBs, mineralocorticoid receptor antago
-
nists, and ARNIs, have all been shown to reduce sudden 
cardiac death. Empiric antiarrhythmic therapy with amioda
-
rone did not improve outcome in the SCD-HeFT trial, and 
most other agents are contraindicated because of their pro
-
arrhythmic effects in this population and their adverse effect 
on cardiac function. For patients with systolic heart failure 
and atrial fibrillation, a rhythm control strategy has not been 
shown to improve outcome compared to a rate control strat
-
egy and thus should be reserved for patients with a reversible 
cause of atrial fibrillation or refractory symptoms. Then, 
amiodarone is the drug of choice.
11. Statin therapy—
Even though vascular disease is pres
-
ent in many patients with chronic heart failure, the role of 
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statins has not been well defined in the heart failure popu
-
lation. The CORONA and the GISSI-HF trials show no 
benefits of statins in the chronic heart failure population.
C. Nonpharmacologic Treatment
1. Implantable cardioverter defibrillators—
Indications 
for ICDs include not only patients with symptomatic or 
asymptomatic arrhythmias but also patients with chronic 
heart failure and LV systolic dysfunction who are receiving 
contemporary heart failure treatments, including beta-
blockers. In the second Multicenter Automatic Defibrilla
-
tor Implantation Trial (MADIT II), 1232 patients with 
prior myocardial infarction and an EF less than 30% were 
randomized to an ICD or a control group. Mortality was 
31% lower in the ICD group, which translated into 9 lives 
saved for each 100 patients who received a device and were 
monitored for 3 years. The Centers for Medicare & Medic
-
aid Services provides reimbursement coverage to include 
patients with chronic heart failure and ischemic or non
-
ischemic cardiomyopathy with an EF of 35% or less.
2. Biventricular pacing (resynchronization)—
Many 
patients with heart failure due to systolic dysfunction have 
abnormal intraventricular conduction that results in dys
-
synchronous and hence inefficient contractions. Several 
studies have evaluated the efficacy of “multisite” pacing, 
using leads that stimulate the RV from the apex and the LV 
from the lateral wall via the coronary sinus. Patients with 
wide QRS complexes (generally 120 msec or more), 
reduced EFs, and moderate to severe symptoms have been 
evaluated. Results from trials with up to 2 years of follow-
up have shown an increase in EF, improvement in symp
-
toms and exercise tolerance, and reduction in death and 
hospitalization. The best responders to cardiac resynchro
-
nization therapy are patients with wider QRS, left bundle 
branch block, and nonischemic cardiomyopathy, and the 
lowest responders are those with narrow QRS and non–left 
bundle branch block pattern. Thus, as recommended in the 
2013 European guidelines, resynchronization therapy is 
indicated for patients with class II, III, and ambulatory 
class IV heart failure, EF of 35% or less, and left bundle 
branch block pattern with QRS duration of 120 msec or 
more. Patients with non–left bundle branch block pattern 
and prolonged QRS duration may be considered for 
3. Case management, diet, and exercise training—
Thirty 
to 50 percent of heart failure patients who are hospitalized 
will be readmitted within 3–6 months. Strategies to prevent 
clinical deterioration, such as case management, home 
monitoring of weight and clinical status, and patient 
adjustment of diuretics, can prevent rehospitalizations and 
should be part of the treatment regimen of advanced heart 
failure. Involvement of a multidisciplinary team (rather 
than a single physician) and in-person (rather than just 
telephonic) communication appear to be important fea
-
tures of successful programs.
Patients should routinely practice moderate salt restric
-
tion (2–2.5 g sodium or 5–6 g salt per day). More severe 
sodium restriction is usually difficult to achieve and unnec
-
essary because of the availability of potent diuretic agents.
Exercise training improves activity tolerance in signifi
-
cant part by reversing the peripheral abnormalities associ
-
ated with heart failure and deconditioning. In severe heart 
failure, restriction of activity may facilitate temporary rec
-
ompensation. A large trial showed no significant benefit 
(nor harm) from a structured exercise training program on 
death or hospitalization, although functional status and 
symptoms were improved. Thus, in stable patients, a pru
-
dent increase in activity or a regular exercise regimen can 
be encouraged. Indeed, a gradual exercise program is asso
-
ciated with diminished symptoms and substantial increases 
in exercise capacity.
4. Coronary revascularization—

-
Since underlying CAD is 
the cause of heart failure in the majority of patients, coro
-
nary revascularization has been thought to be able to both 
improve symptoms and prevent progression. While the 
STITCH trial failed to show an overall survival benefit 
from CABG among patients with multivessel coronary 
disease who were candidates for CABG, but who also had 
heart failure and an LVEF of 35% or less at 5 years, there 
was benefit at 10 years of follow-up. Thus, revasculariza
-
tion does appear warranted for some patients with heart 
failure, including those with more severe angina or left 
main coronary disease (excluded from the STITCH trial).
5. Cardiac transplantation—
Because of the poor progno
-
sis of patients with advanced heart failure, cardiac trans
-
plantation is widely used. Many centers have 1-year 
survival rates exceeding 80–90%, and 5-year survival rates 
above 70%. Infections, hypertension and kidney dysfunc
-
tion caused by cyclosporine, rapidly progressive coronary 
atherosclerosis, and immunosuppressant-related cancers 
have been the major complications. The high cost and lim
-
ited number of donor organs require careful patient selec
-
tion early in the course.
6. Other surgical treatment options—
Externally powered 
and implantable 
ventricular assist devices
 can be used in 
patients who require ventricular support either to allow the 
heart to recover or as a bridge to transplantation. The latest 
generation devices are small enough to allow patients unre
-
stricted mobility and even discharge from the hospital. Con
-
tinuous flow devices appear to be more effective than pulsatile 
flow devices. However, complications are frequent, including 
bleeding, thromboembolism, and infection, and the cost is 
very high, exceeding $200,000 in the initial 1–3 months.
Although 1-year survival was improved in the 
REMATCH randomized trial, all 129 patients died by 
26 months. Newer-generation continuous flow pump ven
-
tricular assist devices have been shown to result in better 
survival than the first-generation pulsatile flow device used 
in REMATCH.
7. Palliative care—
Despite the technologic advances of 
recent years, it should be remembered that many patients 
with chronic heart failure are elderly and have multiple 
comorbidities. Many of them will not experience meaningful 
improvements in survival with aggressive therapy. The goal 
of management for these patients and all those with serious 
illness should include symptomatic improvement and pallia
-
tive care as they approach the end of life (see Chapter 5).
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»
Treatment: Heart Failure With Preserved EF
Although half of all heart failure occurs among patients 
with normal LVEF, often with diastolic dysfunction, 
no
 
therapies have been shown to improve survival in this 
population. The mainstay of management of patients with 
heart failure with preserved EF is to manage fluid overload 
with diuretic therapy and to treat comorbidities like hyper
-
tension, diabetes, and arrhythmias.
Hypertension, pericardial disease, and atrial tachycardias 
are potentially reversible factors that can contribute to 
heart failure with preserved EF. Since tachycardia is associ
-
ated with shorter overall diastolic filling time, controlling 
accelerated heart rate may be important.
Diuretics are important to control 
symptoms of fluid overload in patients with heart failure 
with preserved EF, similar to symptoms from systolic heart 
failure.
2. Inhibitors of the renin-angiotensin-aldosterone 
 
system—
ACE inhibitors and ARBs have 
not
 been shown 
to improve outcome in patients with heart failure and pre
-
served EF, despite being good therapies for the comorbidity 
of hypertension. Spironolactone has not shown to improve 
outcome in a large trial of patients with heart failure and 
preserved EF, but there may have been some benefit in 
patients enrolled in the Americas who had more clearly 
defined heart failure. Spironolactone should remain a 
therapeutic option, especially for patients who also have 
Unlike in patients with heart failure and reduced EF, ICD 
and resynchronization device treatments do 
not
 have a role 
in patients with preserved EF. Revascularization for 
patients with heart failure and preserved EF should be 
guided by the same considerations as for patients with 
heart failure with reduced EF.
 
»
Prognosis
Once manifest, heart failure with reduced EF carries a 
poor prognosis. Even with modern treatment, the 5-year 
mortality is approximately 50%. Mortality rates vary from 
less than 5% per year in those with no or few symptoms to 
greater than 30% per year in those with severe and refrac
-
tory symptoms. These figures emphasize the critical 
importance of early detection and intervention. Higher 
mortality is related to older age, lower LVEF, more severe 
symptoms, chronic kidney disease, and diabetes. The 
prognosis of heart failure has improved in the past two 
decades, probably at least in part because of the more 
widespread use of ACE inhibitors and beta-blockers, 
which markedly improve survival in those with heart 
failure with reduced EF.
 
»
Patients with new symptoms of heart failure not explained 
by an obvious cause should be referred to a cardiologist. 
Patients with continued symptoms of heart failure and 
reduced LVEF (35% or less) should be referred to a cardi
-
ologist for consideration of placement of an ICD or cardiac 
resynchronization therapy (if QRS duration is 120 msec or 
more, especially with left bundle branch block pattern).
 
»
•	
Patients with unexplained new or worsened symptoms 
or positive cardiac biomarkers concerning for acute 
myocardial necrosis.
•	
Patients with hypoxia, fluid overload, or pulmonary 
edema not readily resolved in an outpatient setting.
Al-Khatib SM et al. 2017 AHA/ACC/HRS Guideline for Man
-
agement of Patients With Ventricular Arrhythmias and the 
Prevention of Sudden Cardiac Death: Executive Summary: a 
report of the American College of Cardiology/American 
Heart Association Task Force on Clinical Practice Guidelines 
and the Heart Rhythm Society. Circulation. 2017 Oct 30. pii: 
S1547–5271(17)31249–3 [PMID: 29084733]
Brignole M et al. 2013 ESC Guidelines on cardiac pacing and 
cardiac resynchronization therapy: the Task Force on Cardiac 
Pacing and Resynchronization Therapy of the European Soci
-

-
ety of Cardiology (ESC). Developed in collaboration with the 
European Heart Rhythm Association (EHRA). Eur Heart J. 
2013 Aug;34(29):2281–329. [PMID: 23801822]
Felker GM et al. Effect of natriuretic peptide-guided therapy on 
hospitalization or cardiovascular mortality in high-risk 
patients with heart failure and reduced ejection fraction: a 
randomized clinical trial. JAMA. 2017 Aug 22;318(8):713–20. 
[PMID: 28829876]
Gaziano TA et al. Cost-effectiveness analysis of sacubitril/valsar
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tan vs enalapril in patients with heart failure and reduced 
ejection fraction. JAMA Cardiol. 2016 Sep 1;1(6):666–72. 
[PMID: 27438344]
McMurray JJ et al; PARADIGM-HF Investigators and Commit
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tees. Angiotensin-neprilysin inhibition versus enalapril in 
heart failure. N Engl J Med. 2014 Sep 11;371(11):993–1004. 
[PMID: 25176015]
Mozaffarian D et al; on behalf of the American Heart Associa
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tion Statistics Committee and Stroke Statistics Subcommittee. 
Heart disease and stroke statistics—2016 update: a report 
from the American Heart Association. Circulation. 
2016;133:e38–360. [PMID: 26673558]
Pfeffer MA et al. Regional variation in patients and outcomes in 
the Treatment of Preserved Cardiac Function Heart Failure 
With an Aldosterone Antagonist (TOPCAT) trial. Circula
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tion. 2015 Jan 6;131(1):34–42. [PMID: 25406305]
Pitt B et al; TOPCAT Investigators. Spironolactone for heart 
failure with preserved ejection fraction. N Engl J Med. 
 
2014 Apr 10;370(15):1383–92. [PMID: 24716680]
Ponikowski P et al. 2016 ESC guidelines for the diagnosis and 
treatment of acute and chronic heart failure: the Task Force for 
the Diagnosis and Treatment of Acute and Chronic Heart Fail
-
ure of the European Society of Cardiology (ESC). Developed 
with the special contribution of the Heart Failure Association 
(HFA) of the ESC. Eur Heart J Fail. 2016 Aug;18(8):891–975. 
[PMID: 27207191]
Shen L et al. Declining risk of sudden death in heart failure. N 
Engl J Med. 2017 Jul 6;377(1):41–51. [PMID: 28679089]
Troughton RW et al. Effect of B-type natriuretic peptide-guided 
treatment of chronic heart failure on total mortality and 
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ospitalization: an individual patient meta-analysis. Eur 
Heart J. 2014 Jun 14;35(23):1559–67. [PMID: 24603309]
Y ancy CW et al. 2017 ACC/AHA/HFSA focused update of the 
2013 ACCF/AHA guideline for the management of heart 
failure: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical Prac
-
tice Guidelines and the Heart Failure Society of America. 
Circulation. 2017 Aug 8;136(6):e137–61. [PMID: 28455343]
ACUTE HEART FAILURE & 
PULMONARY EDEMA
 
»
Acute onset or worsening of dyspnea at rest.
 
»
Tachycardia, diaphoresis, cyanosis.
 
»
Pulmonary rales, rhonchi; expiratory wheezing.
 
»
Radiograph shows interstitial and alveolar edema 
with or without cardiomegaly.
 
»
Arterial hypoxemia.
 
»
Typical causes of acute cardiogenic pulmonary edema 
include acute myocardial infarction or severe ischemia, 
exacerbation of chronic heart failure, acute severe hyper
-
tension, acute kidney injury, acute volume overload of the 
LV (valvular regurgitation), and mitral stenosis. By far the 
most common presentation in developed countries is one 
of acute or subacute deterioration of chronic heart failure, 
precipitated by discontinuation of medications, excessive 
salt intake, myocardial ischemia, tachyarrhythmias (espe
-
cially rapid atrial fibrillation), or intercurrent infection. 
Often in the latter group, there is preceding volume over
-
load with worsening edema and progressive shortness of 
breath for which earlier intervention can usually avoid the 
need for hospital admission.
 
»
Acute pulmonary edema presents with a characteristic clini
-
cal picture of severe dyspnea, the production of pink, frothy 
sputum, and diaphoresis and cyanosis. Rales are present in 
all lung fields, as are generalized wheezing and rhonchi. 
Pulmonary edema may appear acutely or subacutely in the 
setting of chronic heart failure or may be the first manifesta
-
tion of cardiac disease, usually acute myocardial infarction, 
which may be painful or silent. Less severe decompensations 
usually present with dyspnea at rest, rales, and other evi
-
dence of fluid retention but without severe hypoxia.
Noncardiac causes of pulmonary edema include intrave
-
nous opioids, increased intracerebral pressure, high altitude, 
sepsis, medications, inhaled toxins, transfusion reactions, 
shock, and disseminated intravascular coagulation. These 
are distinguished from cardiogenic pulmonary edema by the 
clinical setting, history, and physical examination. 
Conversely, in most patients with cardiogenic pulmonary 
edema, an underlying cardiac abnormality can usually be 
detected clinically or by ECG, chest radiograph, or 
echocardiogram.
The chest radiograph reveals signs of pulmonary vascu
-
lar redistribution, blurriness of vascular outlines, increased 
interstitial markings, and, characteristically, the butterfly 
pattern of distribution of alveolar edema. The heart may be 
enlarged or normal in size depending on whether heart fail
-
ure was previously present. Assessment of cardiac function 
by echocardiography is important, since a substantial pro
-
portion of patients has normal EFs with elevated atrial pres
-
sures due to diastolic dysfunction. In cardiogenic pulmonary 
edema, BNP is elevated, and the PCWP is invariably ele
-
vated, usually over 25 mm Hg. In noncardiogenic pulmo
-
nary edema, the wedge pressure may be normal or even low.
 
»
Treatment
In full-blown pulmonary edema, the patient should be placed 
in a sitting position with legs dangling over the side of the 
bed; this facilitates respiration and reduces venous return. 
Oxygen
 is delivered by mask to obtain an arterial P
o
2
 greater 
than 60 mm Hg. Noninvasive pressure support ventilation 
may improve oxygenation and prevent severe CO
2
 retention 
while pharmacologic interventions take effect. However, if

o
2
 greater 
2
 retention 
while pharmacologic interventions take effect. However, if 
respiratory distress remains severe, endotracheal intubation 
and mechanical ventilation may be necessary.
Morphine
 is highly effective in pulmonary edema and 
may be helpful in less severe decompensations when the 
patient is uncomfortable. The initial dosage is 2–8 mg 
intravenously (subcutaneous administration is effective in 
milder cases) and may be repeated after 2–4 hours. Mor
-
phine increases venous capacitance, lowering LA pressure, 
and relieves anxiety, which can reduce the efficiency of 
ventilation. However, morphine may lead to CO
2
 retention 
by reducing the ventilatory drive. It should be avoided in 
patients with opioid-induced pulmonary edema, who may 
improve with opioid antagonists, and in those with neuro
-
genic pulmonary edema.
Intravenous diuretic therapy
 (furosemide, 40 mg, or 
bumetanide, 1 mg—or higher doses if the patient has been 
receiving long-term diuretic therapy) is usually indicated 
even if the patient has not exhibited prior fluid retention. 
These agents produce venodilation prior to the onset of 
diuresis. The DOSE trial has shown that, for acute decom
-
pensated heart failure, bolus doses of furosemide are of 
similar efficacy as continuous intravenous infusion, and 
that higher-dose furosemide (2.5 times the prior daily 
dose) resulted in more rapid fluid removal without a sub
-
stantially higher risk of kidney impairment.
Nitrate therapy
 accelerates clinical improvement by 
reducing both BP and LV filling pressures. Sublingual nitro
-
glycerin or isosorbide dinitrate, topical nitroglycerin, or 
intravenous nitrates will ameliorate dyspnea rapidly prior to 
the onset of diuresis, and these agents are particularly valu
-
able in patients with accompanying hypertension.
Intravenous nesiritide
, a recombinant form of human 
BNP , is a potent vasodilator that reduces ventricular filling 
pressures and improves cardiac output. Its hemodynamic 
effects resemble those of intravenous nitroglycerin with a 
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more predictable dose–response curve and a longer dura
-
tion of action. In clinical studies, nesiritide (administered 
as 2 mcg/kg by intravenous bolus injection followed by an 
infusion of 0.01 mcg/kg/min, which may be up-titrated if 
needed) produced a rapid improvement in both dyspnea 
and hemodynamics. The primary adverse effect is hypo
-
tension, which may be symptomatic and sustained. Because 
most patients with acute heart failure respond well to con
-
ventional therapy, the role of nesiritide may be primarily in 
patients who continue to be symptomatic after initial treat
-
ment with diuretics and nitrates.
A randomized placebo-controlled trial of 950 patients 
evaluating intravenous milrinone in patients admitted for 
decompensated heart failure who had no definite indica
-
tions for inotropic therapy showed no benefit in increasing 
survival, decreasing length of admission, or preventing 
readmission. In addition, rates of sustained hypotension 
and atrial fibrillation were significantly increased. Thus, 
the role of positive inotropic agents appears to be limited to 
patients with refractory symptoms and signs of low cardiac 
output, particularly if life-threatening vital organ hypoper
-
fusion (such as deteriorating kidney function) is present. In 
some cases, dobutamine or milrinone may help maintain 
patients who are awaiting cardiac transplantation.
Bronchospasm may occur in response to pulmonary 
edema and may itself exacerbate hypoxemia and dyspnea. 
Treatment with inhaled beta-adrenergic agonists or intra
-
venous aminophylline may be helpful, but both may also 
provoke tachycardia and supraventricular arrhythmias.
In most cases, pulmonary edema responds rapidly to 
therapy. When the patient has improved, the cause or pre
-
cipitating factor should be ascertained. In patients without 
prior heart failure, evaluation should include echocardiog
-
raphy and, in many cases, cardiac catheterization and coro
-
nary angiography. Patients with acute decompensation of 
chronic heart failure should be treated to achieve a 
euvolemic state and have their medical regimen optimized. 
Generally, an oral diuretic and an ACE inhibitor should be 
initiated, with efficacy and tolerability confirmed prior to 
discharge. In selected patients, early but careful initiation 
of beta-blockers in low doses should be considered.
 
º
MYOCARDITIS & THE 
CARDIOMYO
p
A
THIES
INFECTIOUS MYOCARDITIS
 
»
Often follows an upper respiratory infection.
 
»
May present with chest pain (pleuritic or nonspe
-
cific) or signs of heart failure.
 
»
Echocardiogram documents cardiomegaly and 
contractile dysfunction.
 
»
Myocardial biopsy, though not sensitive, may 
reveal a characteristic inflammatory pattern. MRI 
has a role in diagnosis.
 
»
Cardiac dysfunction due to primary myocarditis is pre
-
sumedly caused by either an acute viral infection or a 
postviral immune response. Secondary myocarditis is the 
result of inflammation caused by nonviral pathogens, 
medications, chemicals, physical agents, or inflammatory 
diseases (such as systemic lupus erythematosus). The list of 
both infectious and noninfectious causes of myocarditis is 
extensive (Table 10–16).
Early-phase myocarditis is initiated by infection of car
-
diac tissue. The currently accepted definition of myocardi
-
tis is biopsy dependent and includes the observation of 14 
or more lymphocytes/mcL including up to 4 monocytes/mcL 
Table 10–16.
 
Causes of myocarditis.
1. INFECTIOUS CAUSES
RNA viruses:
 Picornaviruses (coxsackie A and B, echovirus, 
poliovirus, hepatitis virus), orthomyxovirus (influenza), para
-
myxoviruses (respiratory syncytial virus, mumps), togaviruses 
(rubella), flaviviruses (dengue fever, yellow fever)
DNA viruses
:
 Adenovirus (A1, 2, 3, and 5), erythrovirus (Bi9V and 
2), herpesviruses (human herpes virus 6 A and B, cytomegalo
-

:
-
virus, Epstein-Barr virus, varicella-zoster), retrovirus (HIV)
Bacteria:
 Chlamydia (
Chlamydophila pneumoniae, C psittaci
), 
, 
Legionella, Pneumophilia, Brucella, 
Clostridium, Francisella tularensis, Neisseria meningitis, Myco
-
bacterium
 (tuberculosis), 
Salmonella, Staphylococcus,
 strepto
-
coccus A, 
Streptococcus pneumoniae,
 tularemia, tetanus, 
syphilis, 
Vibrio cholera
Spirocheta:
 
Borrelia recurrentis
, leptospira, 
Rickettsia:
 
Coxiella burnetti, R rickettsii, R prowazekii
Fungi:
 
Actinomyces, Aspergillus, Candida, Cryptococcus, Histo
-
plasma, Nocardia
p
r
otozoa:
 
Entamoeba histolytica, Plasmodium falciparum, Try
-
panosoma cruzi, T burcei, T gondii, Leishmania
Helminthic:
 
Ascaris, Echinococcus granulosus, Schistosoma, 
Trichenella spiralis, Wuchereria bancrofti
2. NONINFECTIOUS CAUSES
Autoimmune diseases:
 Dermatomyositis, inflammatory bowel 
disease, rheumatoid arthritis, Sjögren syndrome, systemic 
lupus erythematosus, granulomatosis with polyangiitis, giant 
cell myocarditis
Drugs:
 Aminophylline, amphetamine, anthracyclin, catecholamines, 
chloramphenicol, cocaine, cyclophosphamide, doxorubicin, 5-FU, 
mesylate, methysergide, phenytoin, trastuzumab, zidovudine
Hypersensitivity reactions due to drugs:
 Azithromycin, 
 
benzodiazepines, clozapine, cephalosporins, dapsone, 
 
dobutamine, lithium, diuretics, thiazide, methyldopa, mexi
-
letine, streptomycin, sulfonamides, nonsteroidal anti-inflam
-
matory drugs, tetanus toxoid, tetracycline, tricyclic 
antidepressants
Hypersensitivity reactions due to venoms:
 Bee, wasp, black 
widow spider, scorpion, snake
Systemic diseases:
 Eosinophilic granulomatosis with polyangiitis 
(formerly known as Churg-Strauss syndrome), collagen dis
-
eases, sarcoidosis, Kawasaki disease, scleroderma
Other:
 Heat stroke, hypothermia, transplant rejection, radiation 
injury
Modified, with permission, from Schultheiss HP et al. The manage
-
ment of myocarditis. Eur Heart J. 2011;32:2616–25. By permission 
of Oxford University Press and the European Society of Cardiology.
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with the presence of 7 or more CD3-positive T lymphocytes/
mcL. Injury can be fulminant, subclinical, or chronic. In 
severe myocarditis, soluble Fas ligand and interleukin may 
be expressed. Both cellular and humoral inflammatory 
processes contribute to the progression to chronic injury, 
and there are subgroups that appear to benefit from immu
-
nosuppression. The prevalence globally is about 22/100,000 
patients annually.
Genetic predisposition is a likely factor in at least a few 
cases. Autoimmune myocarditis (eg, giant cell myocarditis) 
may occur with no identifiable viral infection.
 
»
Patients may present several days to a few weeks after the 
onset of an acute febrile illness or a respiratory infection 
or they may present with heart failure without antecedent 
symptoms. The onset of heart failure may be gradual or 
may be abrupt and fulminant. In acute fulminant myocar
-
ditis, low output and shock may be present with severely 
depressed LV systolic function. A pericardial friction rub 
may be present. In the European Study of Epidemiology 
and Treatment of Inflammatory Heart Disease, 72% of 
participants had dyspnea, 32% had chest pain, and 18% 
had arrhythmias. Pulmonary and systemic emboli may 
occur. Pleural-pericardial chest pain is common. Exami
-
nation reveals tachycardia, a gallop rhythm, and other 
evidence of heart failure or conduction defects. At times, 
the presentation may mimic an acute myocardial infarc
-
tion with ST changes, positive cardiac markers, and 
regional wall motion abnormalities despite normal coro
-
naries. Microaneurysms may also occur and may be asso
-
ciated with serious ventricular arrhythmias. It has been 
estimated that approximately 10% of all dilated cardiomy
-
opathy patients have viral myocarditis as the cause.
ECG may show sinus tachycardia, other arrhythmias, non
-
specific repolarization changes, and intraventricular con
-
duction abnormalities. The presence of Q waves or left 
bundle branch block portends a higher rate of death or 
cardiac transplantation. Ventricular ectopy may be the 
initial and only clinical finding. The chest radiograph is 
nonspecific, but cardiomegaly is frequent, though not uni
-
versal. Evidence for pulmonary venous hypertension is 
common and frank pulmonary edema may be present.
There is no specific laboratory finding that is consistently 
present, though the white blood cell count is usually ele
-
vated and the sedimentation rate and CRP usually are 
increased. Troponin I or T levels are elevated in about one-
third of patients, but CK-MB is elevated in only 10%. Other 
biomarkers, such as BNP and NT-proBNP , are usually ele
-
vated. Echocardiography provides the most convenient 
way of evaluating cardiac function and can exclude many 
other processes. MRI with gadolinium enhancement 
reveals spotty areas of injury throughout the myocardium, 
but both T2- and T1-weighted images are needed to 
achieve optimal results; correlation with endomyocardial 
biopsy results is poor.
D. Endomyocardial Biopsy
Confirmation of myocarditis still requires histologic evi
-
dence. The AHA/ACC/ESC class I recommendations for 
biopsy are (1) in patients with heart failure, a normal-sized 
or dilated LV less than 2 weeks after onset of symptoms, 
and hemodynamic compromise; or (2) in patients with a 
dilated LV 2 weeks to 3 months after onset of symptoms, 
new ventricular arrhythmias or AV nodal block (Mobitz II 
or complete heart block) or who do not respond to usual 
care after 1–2 weeks. In some cases, the identification of 
inflammation without viral genomes by PCR suggests that 
immunosuppression might be useful. Because the cardiac 
involvement is often patchy, the diagnosis can be missed in 
up to one-half of cases.
 
»
Patients with fulminant myocarditis may present with acute

»
Patients with fulminant myocarditis may present with acute 
cardiogenic shock. Acute myocarditis has been implicated 
as a cause of sudden death in 5–22% of such cases in ath
-
letes younger than 35 years. The ventricles are usually not 
dilated, but thickened (possibly due to myoedema). There is 
a high death rate, but if the patients recover, they are often 
left with no residual cardiomyopathy. Patients with sub
-
acute disease have a dilated cardiomyopathy and generally 
make an incomplete recovery. Those who present with 
chronic disease tend to have only mild dilation of the LV 
and eventually present with a more restrictive cardiomyop
-
athy. Treatment is directed toward the clinical scenario with 
ACE inhibitors and beta-blockers if LVEF is less than 40%. 
Nonsteroidal anti-inflammatory medications should be 
used if myopericarditis-related chest pain occurs. Colchi
-
cine has been suggested if 
 
p
ericarditis predominates. 
Arrhythmias should be suppressed.
Specific antimicrobial therapy is indicated when an 
infecting agent is identified. Exercise should be limited 
during the recovery phase. Some experts believe digoxin 
should be avoided, and it likely has little value in this set
-
ting anyway. Controlled trials of immunosuppressive ther
-
apy with corticosteroids and intravenous immunoglobulin 
(IVIG) have not suggested a benefit, though some recom
-
mend IVIG given at 2 g/kg over 24 hours in proven cases. 
Uncontrolled trials suggest that interferon might have a 
supportive role. Similarly, antiviral medication (such as 
pleconaril for enteroviruses) has been tried empirically. 
Studies are lacking as to when to discontinue the chosen 
therapy if the patient improves. Patients with fulminant 
myocarditis require aggressive short-term support, includ
-
ing an IABP or an LV assist device. If severe pulmonary 
infiltrates accompany the fulminant myocarditis, extracor
-
poreal membrane oxygenation (ECMO) support may be 
temporarily required and has had notable success.
 
»
Patients in whom myocarditis is suspected should be seen 
by a cardiologist at a tertiary care center where facilities are 
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available for diagnosis and therapies available should a 
fulminant course ensue. The facility should have ventricu
-
lar support devices and transplantation options available.
Fung G et al. Myocarditis. Circ Res. 2016 Feb 5;118(3):496–514. 
[PMID: 26846643]
NONINFECTIOUS MYOCARDITIS
A variety of medications, illicit drugs, and toxic substances 
can produce acute or chronic myocardial injury; the clinical 
presentation varies widely. The phenothiazines, lithium, 
chloroquine, disopyramide, antimony-containing com
-
pounds, and arsenicals can also cause ECG changes, 
arrhythmias, or heart failure. Hypersensitivity reactions to 
sulfonamides, penicillins, and aminosalicylic acid as well as 
other medications can result in cardiac dysfunction. Radia
-
tion can cause an acute inflammatory reaction as well as a 
chronic fibrosis of heart muscle, usually in conjunction 
with pericarditis.
Cardiotoxicity from cocaine may occur from coronary 
artery spasm, myocardial infarction, arrhythmias, and 
myocarditis. Because many of these processes are believed 
to be mediated by cocaine’s inhibitory effect on norepi
-
nephrine reuptake by sympathetic nerves, beta-blockers 
have been used in patients with fixed stenosis. In docu
-
mented coronary spasm, calcium channel blockers and 
nitrates may be effective. Usual therapy for heart failure or 
conduction system disease is warranted when symptoms 
occur. Other recreational drug use has been associated 
with myocarditis in various case reports.
Systemic disorders are also associated with myocarditis. 
These include giant cell myocarditis, eosinophilic myocar
-
ditis, celiac disease, granulomatosis with polyangiitis, and 
sarcoidosis. A benefit from immunosuppressive therapy, 
especially in giant cell myocarditis has been suggested in a 
number of observational studies, including those directed 
primarily at T cells (ie, using muromonab-CD3). Treatment 
of eosinophilic myocarditis includes the use of high-dose 
corticosteroids and removal of the offending medication or 
underlying trigger. Most studies suggest that HIV is only 
indirectly responsible for HIV cardiomyopathy, and other 
factors, gp 120 protein, adverse reaction to antiretroviral 
therapy, and opportunistic infections have been implicated 
more often. Epstein Barr and herpex simplex viruses have 
been identified in some patients’ myocardium.
The problem of cardiovascular side effects from cancer 
chemotherapy agents is an ever growing one. Anthracy
-
clines (doxorubicin, daunorubicin, idarubicin, epirubicin, 
and mitoxantrone) remain the cornerstone of treatment of 
many malignancies. Heart failure can be expected in 5% of 
patients treated with a cumulative dose of 400–450 mg/m
2
, 
and this rate is doubled if the patient is over age 65. While 
symptoms and evidence for myocardial dysfunction usu
-
ally appear within 1 year of starting therapy, late onset 
manifestation of heart failure may appear up to a decade 
later. The major mechanism of cardiotoxicity is thought to 
be due to oxidative stress inducing both apoptosis and 
necrosis of myocytes. There is also disruption of the sarco
-
mere. This pathologic understanding is the rationale 
behind the superoxide dismutase mimetic and iron-chelating 
agent, dexrazoxane, to protect from the injury. The use of 
trastuzumab in combination with anthracyclines increases 
the risk of cardiac dysfunction up to 28%; this has been an 
issue since combined use of these agents is particularly 
HER
 2–positive breast cancer. Other risk fac
-
tors for patients receiving anthracyclines include the use of 
paxlitaxel, concurrent radiation, and preexisting cardiovas
-
cular disease (including hypertension, peripheral vascular 
disease, CAD and diabetes).
In patients receiving chemotherapy, it is important to 
look for subtle signs of cardiovascular compromise. Echo
-
cardiography, cardiac MRI, and serial MUGA studies can

-
cardiography, cardiac MRI, and serial MUGA studies can 
provide concrete data regarding LV function. Biomarkers 
such as BNP or NT-proBNP may be of some value when 
serial measures are obtained. Other biomarkers may appear 
early in the course of myocardial injury (especially tropo
-
nin and myeloperoxidase) and may allow for early detec
-
tion of cardiotoxicity before other signs become evident. 
There is some evidence that beta-blocker therapy may 
reduce the negative effects on myocardial function. There 
are anecdotal data from animal models that nonsteroidal 
anti-inflammatory drugs may be harmful in patients with 
myocarditis. They should be avoided along with alcohol 
and strenuous physical exercise.
 
»
Many patients with myocardial injury from toxic agents 
can be monitored safely if ventricular function remains 
relatively preserved (EF greater than 40%) and no heart 
failure symptoms occur. Diastolic dysfunction may be 
subtle.
Once heart failure or a reduced LVEF becomes evident 
or significant conduction system disease becomes mani
-
fest, the patient should be evaluated and monitored by a 
cardiologist in case myocardial dysfunction worsens and 
further intervention becomes warranted.
Chaudhry MA et al. Modern day management of giant cell myo
-
carditis. Int J Cardiol. 2015 Jan 15;178:82–4. [PMID: 
25464225]
Ky B et al. Early increases in multiple biomarkers predict subse
-
quent cardiotoxicity in patients with breast cancer treated 
with doxorubicin, taxanes, and trastuzumab. J Am Coll Car
-
diol. 2014 Mar 4;63(8):809–16. [PMID: 24291281]
Rosa GM et al. Update on cardiotoxicity of anti-cancer treatments. 
Eur J Clin Invest. 2016 Mar;46(3):264–84. [PMID: 26728634]
DILATED CARDIOMYOPATHY
 
»
Symptoms and signs of heart failure.
 
»
Echocardiogram confirms LV dilation, thinning, 
and global dysfunction.
 
»
Severity of RV dysfunction critical in long-term 
prognosis.
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»
Heart failure definitions have changed over the years and 
patients with a dilated cardiomyopathy are generally 
placed into the category of heart failure with reduced ejec
-
tion fraction where the LVEF is defined as less than or 
equal to 40%. In about half of the patients in this category 
there is LV enlargement and it is this group that defines 
dilated cardiomyopathy. This is a large group of heteroge
-
neous myocardial disorders characterized by reduced 
myocardial contractility in the absence of abnormal load
-
ing conditions such as with hypertension or valvular dis
-
ease. The prevalence averages 36 cases/100,000 in the 
United States and accounts for approximately 10,000 
deaths annually. Blacks are afflicted three times as often as 
whites. The prognosis is poor with 50% mortality at 5 years 
once symptoms emerge.
The causes are multiple and diverse. Up to 20–35% have a 
familial etiology. A large proportion is idiopathic. Endocrine, 
inflammatory, and metabolic causes include obesity, diabetes, 
thyroid disease, celiac disease, systemic lupus erythematosus, 
acromegaly, and growth hormone deficiency. Toxic, drug-
induced, and inflammatory causes are listed in the prior sec
-
tion. Nutritional diseases such as deficiency of thiamine, 
selenium, and carnitine have also been documented. Dilated 
cardiomyopathy may also be caused by prolonged tachycar
-
dia either from supraventricular arrhythmias, from very fre
-
quent PVCs (more than 15% of heart beats), or from frequent 
right ventricular pacing. Dilated cardiomyopathy is also 
associated with HIV , Chagas disease, rheumatologic disor
-
ders, iron overload, sleep apnea, amyloidosis, sarcoidosis, 
chronic alcohol usage, end-stage kidney disease, or cobalt 
exposure (“Quebec beer-drinkers cardiomyopathy”). 
 
Peripartum cardiomyopathy and stress-induced disease 
(tako-tsubo) are discussed separately.
 
»
In most patients, symptoms of heart failure develop gradu
-
ally. It is important to seek out a history of familial dilated 
cardiomyopathy and to identify behaviors that might pre
-
dispose patients to the disease. The physical examination 
reveals rales, an elevated JVP , cardiomegaly, S
3
 gallop 
rhythm, often the murmurs of functional mitral or tricus
-
pid regurgitation, peripheral edema, or ascites. In severe 
heart failure, Cheyne-Stokes breathing, pulsus alternans, 
pallor, and cyanosis may be present.
The major findings are listed in Table 10–17. Sinus tachy
-
cardia is common. Other common abnormalities include 
left bundle branch block and ventricular or atrial arrhyth
-
mias. The chest radiograph reveals cardiomegaly, evidence 
for left and/or right heart failure, and pleural effusions 
(right more frequently than left).
In the 2017 AHA/ACCF heart failure guideline focused 
update, patients with dyspnea should have a BNP or NT-
proBNP measured to help establish prognosis and disease 
severity (class I, LOE A).
Table 10–17.
 
Classification of the cardiomyopathies.
Dilated
Hypertrophic
Restrictive
Frequent causes
Idiopathic, alcoholic, major 
 
catecholamine discharge, myocardi
-
tis, postpartum, doxorubicin, endo
-
crinopathies, genetic diseases
Hereditary syndrome, possibly chronic 
hypertension in older adults
Amyloidosis, post-radiation, post–
open heart surgery, diabetes, 
endomyocardial fibrosis
Symptoms
Left or biventricular heart failure
Dyspnea, chest pain, syncope
Dyspnea, fatigue, right heart 
 
failure > left heart failure
Physical 
Cardiomegaly, S
3
, elevated jugular 
venous pressure, rales
Sustained point of maximal impulse, 
S
4
, variable systolic murmur, 
 
bisferiens carotid pulse
Elevated jugular venous 
 
pr
essure, 
Kussmaul sign
Electrocardiogram
ST–T changes, conduction abnormali
-
ties, ventricular ectopy
Left ventricular hypertrophy, 
 
exaggerated septal Q waves

pr
essure, 
-
 
ST–T changes, conduction abnor
-
malities, low voltage
Chest radiograph
Enlarged heart, pulmonary congestion
Mild cardiomegaly
Mild to moderate cardiomegaly
Echocardiogram, 
nuclear studies, 
MRI
Left ventricular dilation and 
Left ventricular hypertrophy, asymmet
-
ric septal hypertrophy, small left 
ventricular size, normal or supranor
-
mal function, systolic anterior mitral 
motion, diastolic dysfunction
Small or normal left ventricular 
size, normal or mildly 
reduced left ventricular 
 
function. 
 
Gadolinium-
 
hyperenhancement on MRI
Cardiac 
 
dysfunction, high diastolic pressures, 
low cardiac output. Coronary angi
-
ography 
 
impor
tant to exclude isch
-
emic cause
Small, hypercontractile left ventricle, 
dynamic outflow gradient, diastolic 
High diastolic pressure, “square 
root” sign, normal or mildly 
function
CMDT19_Ch10_p0334-p0450.indd   428

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An echocardiogram is indicated to exclude unsuspected 
valvular or other lesions and confirm the presence of ven
-
tricular dilatation, reduced LV systolic function and associ
-
ated RV systolic dysfunction, or pulmonary hypertension. 
Mitral Doppler inflow patterns also help in the diagnosis of 
concomitant diastolic dysfunction. Color flow Doppler can 
reveal tricuspid or mitral regurgitation, and continuous 
Doppler can estimate PA pressures. Intracavitary thrombosis 
is occasionally seen. Exercise or pharmacologic stress myo
-
cardial perfusion imaging may uncover underlying coronary 
disease. Radionuclide ventriculography provides a noninva
-
sive measure of the EF and both RV and LV wall motion, 
though its use has been supplanted by cardiac MRI in most 
institutions. Cardiac MRI is particularly helpful in inflamma
-
tory or infiltrative processes, such as sarcoidosis or hemo
-
chromatosis, and is the diagnostic study of choice for RV 
dysplasia. MRI can also help define an ischemic etiology by 
noting gadolinium hyperenhancement consistent with myo
-
cardial scar from infarction or prior myocarditis. Cardiac 
catheterization is seldom of specific value unless myocardial 
ischemia is suspected, although right heart catheterization 
should be considered to help guide therapy when the clinical 
syndrome is not clear cut (class I indication, LOE C). Myo
-
cardial biopsy is rarely useful in establishing the diagnosis, 
although occasionally the underlying cause (eg, sarcoidosis, 
hemochromatosis) can be discerned. Its use is considered a 
class IIa indication with LOE of C. It should not be used rou
-
tinely. Biopsy is most useful in transplant rejection.
 
»
Treatment
The management of heart failure is outlined in the section 
on heart failure in this chapter. Standard therapy includes 
control of BP and of contributing factors such as obesity, 
smoking, diabetes or potentially cardiotoxic agents. All 
patients with a remote history of myocardial infarction or 
acute coronary syndrome and reduced LVEF should be 
given ACE inhibitors or ARBs. Beta-blockers should be 
included in this population as well. All patients with dilated 
cardiomyopathy regardless of etiology should be treated 
with beta-blockers and ACE inhibitors. If still symptomatic, 
aldosterone antagonsits should be added, and ARNI used 
instead of an ACE inhibitor or ARB. The use of the combi
-
nation of all three of ACE inhibition, ARB, and aldosterone 
antagonists can create harm, though, and is discouraged 
due to concerns for hyperkalemia. A few beta-blockers, 
including bisoprolol, carvedilol, and sustained-release 
metoprolol, have been shown to reduce mortality and 
should be preferentially used. Calcium channel blockers 
should be avoided except as necessary to control ventricular 
response in atrial fibrillation or flutter. If congestive symp
-
toms are present, diuretics and an aldosterone antagonist 
should be added. In patients with class II–IV heart failure 
symptoms, an aldosterone receptor antagonist should be 
added when the LVEF is less than 35% (unless contraindi
-
cated). Care in the use of mineralocorticoid receptor 
antagonists is warranted when the glomerular filtration rate 
is less than 30 mL/min/1.73 m
2
 or when the potassium is 
elevated. All patients with diabetes should be taking miner
-
alocorticoid antagonists if the LVEF is less than or equal to 
40%. Systemic BP control is extremely important. Use of the 
angiotensin receptor-neprilysin inhibitor, sacubitril/valsar
-
tan, has been approved for NYHA Heart Failure of Func
-
tional class II–IV . If the resting HR is greater than 70 beats 
per minute, the LVEF is less than 35% and the patient has 
chronic stable heart failure, the use of a selective inhibitor of 
the sinus node “f-current, ” ivabradine, to slow the heart rate 
has also been approved. Ivabradine should not replace other 
beta-blockers, however. Digoxin is a second-line medica
-

-
tion but remains favored as an adjunct by some clinicians; 
digoxin may be beneficial to reduce recurrent hospitaliza
-
tions and to control the ventricular response in atrial fibril
-
lation in sedentary patients. Given the question of abnormal 
nitric oxide utilization in blacks, the use of hydralazine-
nitrate combination therapy is recommended in this popu
-
lation. Sodium restriction is helpful, especially in acute 
heart failure. Continuous positive airway pressure can 
improve LV function in patients with sleep apnea.
When atrial fibrillation is present, heart rate control is 
important if sinus rhythm cannot be established or main
-
tained. There are few data, however, to suggest an advan
-
tage of sinus rhythm over atrial fibrillation on long-term 
outcomes. Many patients may be candidates for cardiac 
synchronization therapy with biventricular pacing if there 
is significant mitral regurgitation and the QRS width is 
greater than 150 msec.
To help prevent sudden death, an ICD is reasonable 
(class IIa LOE B) in asymptomatic ischemic cardiomyopa
-
thy patients with an LVEF of less than 30% on appropriate 
medical therapy (at least 40 days post–myocardial infarc
-
tion). Cardiac rehabilitation and exercise training have 
consistently been found to improve clinical status.
Few cases of cardiomyopathy are amenable to specific 
therapy for the underlying cause. Alcohol use should be 
discontinued, since there is often marked recovery of cardiac 
function following a period of abstinence in alcoholic car
-
diomyopathy. Endocrine causes (hyperthyroidism or hypo
-
thyroidism, acromegaly, and pheochromocytoma) should be 
treated. Immunosuppressive therapy is not indicated in 
chronic dilated cardiomyopathy. There are some patients 
who may benefit from implantable LV assist devices either as 
a bridge to transplantation or as a temporary measure until 
cardiac function returns. LV assist devices can be considered 
as 
destination therapy
 in patients who are not candidates for 
cardiac transplantation. Arterial and pulmonary emboli are 
more common in dilated cardiomyopathy than in ischemic 
cardiomyopathy and suitable candidates may benefit from 
long-term anticoagulation. All patients with atrial fibrilla
-
tion should be so treated. 
DOACs are preferred over warfa
-
rin unless there is associated mitral stenosis.
 Either 
warfarin or a DOAC should be considered when a mobile 
LV thrombus is observed on the echocardiogram.
 
»
Prognosis
The prognosis of dilated cardiomyopathy without clinical 
heart failure is variable, with some patients remaining sta
-
ble, some deteriorating gradually, and others declining 
rapidly. Once heart failure is manifest, the natural history is 
similar to that of other causes of heart failure, with an 
annual mortality rate of around 11–13%. The underlying 
cause of heart failure has prognostic value in patients with 
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unexplained cardiomyopathy. Patients with peripartum 
cardiomyopathy or stress-induced cardiomyopathy appear 
to have a better prognosis than those with other forms of 
cardiomyopathy. Patients with cardiomyopathy due to 
infiltrative myocardial diseases, HIV infection, or doxoru
-
bicin therapy have an especially poor prognosis.
 
»
Patients with new or worsening symptoms of heart failure 
with dilated cardiomyopathy should be referred to a cardi
-
ologist. Patients with continued symptoms of heart failure 
and reduced LVEF (35% or less) should be referred for con
-
sideration of placement of an ICD or cardiac resynchroniza
-
tion therapy (if QRS duration is 150 msec or more, especially 
with a left bundle branch block pattern). Patients with 
advanced refractory symptoms should be referred for con
-
sideration of heart transplant or LV assist device therapy.
 
»
Patients with hypoxia, fluid overload, or pulmonary edema 
not readily resolved in an outpatient setting should be 
admitted.
Bozkurt B et al. Current diagnostic and treatment strategies for 
specific dilated cardiomyopathies: a scientific statement from 
the American Heart Association. Circulation. 2016 Dec 6;
 
134(23):e579–646. [PMID: 27832612]
Japp AG et al. The diagnosis and evaluation of dilated cardiomy
-
opathy. J Am Coll Cardiol. 2016 Jun 28;67(25):2996–3010. 
[PMID: 27339497]
Witt CT et al. Adding the implantable cardioverter-defibrillator 
to cardiac resynchronization therapy is associated with 
improved long-term survival in ischaemic, but not in non-
ischaemic cardiomyopathy. Europace. 2016 Mar;18(3):413–9. 
[PMID: 26378089]
Y ancy CW et al; American College of Cardiology Foundation/
-
lines. 2013 ACCF/AHA guideline for the management of 
heart failure. Circulation. 2013 Oct 15;128(16):e240–327. 
[PMID: 23741058]
Y ancy CW et al. 2016 ACC/AHA/HFSA focused update on new 
pharmacological therapy for heart failure: an update of the 
2013 ACCF/AHA guideline for the management of heart fail
-
ure. J Am Coll Cardiol. 2016 Sep 27;68(13):1476–88. [PMID: 
27216111]
Guidelines and the Heart Failure Society of America. Circula
-
tion. 2017 Aug 8;136(6):e137–61. [PMID: 28455343]
STRESS CARDIOMYOPATHY
 
»
Occurs after a major catecholamine discharge.
 
»
Acute chest pain or shortness of breath.
 
»
Predominately affects postmenopausal women.
 
»
Presents as an acute anterior myocardial infarction, 
but coronaries normal at cardiac catheterization.
 
»
Imaging reveals apical left ventricular ballooning 
due to anteroapical stunning of the myocardium.
 
»
Most patients recover completely, although there 
are complications similar to myocardial infarction.
 
»
Stress cardiomyopathy (Tako-Tsubo syndrome) generally 
follows a high catecholamine surge. The resulting shape of 
the LV acutely suggests a rounded ampulla form similar to 
a Japanese octopus pot (tako-tsubo pot). Mid-ventricular 
ballooning has also been described. The key feature is that 
the myocardial stunning that occurs does not follow the 
pattern suggestive of coronary ischemia (even though 
about 15% of patients will have coexisting CAD, and some 
may have concomitant plaque rupture myocardial infarc
-
tion). Over two-thirds of patients report a prior stressful 
event, either emotional or physical, including hypoglyce
-
mia, lightning strikes, earthquakes, postventricular tachy
-
cardia, during alcohol withdrawal, following surgery, 
during hyperthyroidism, after stroke, and following emo
-
tional stress (“broken-heart syndrome”). Virtually any 
event that triggers excess catecholamines has been impli
-

-
-
cated in a wide number of case reports. Pericarditis and 
even tamponade have been described in isolated cases. 
Recurrences have also been described. In Western coun
-
tries it predominantly affects women (up to 90%), primar
-
ily postmenopausal. Among patients with stress 
cardiomyopathy, compared to patients with acute coronary 
syndrome, there are more neurologic and psychiatric dis
-
orders. Patients with COPD, migraines, or affective disor
-
ders who take beta-agonists may have an increased risk 
of a poor outcome. Approximately 10% of patients will 
have cardiac and neurologic adverse outcomes over the 
next year.
 
»
The symptoms are similar to any acute coronary syndrome. 
Typical angina and dyspnea are usually present. Syncope is 
rare, although arrhythmias are not uncommon.
The ECG reveals ST-segment elevation as well as deep 
anterior T-wave inversion. The chest radiograph is either 
normal or reveals pulmonary congestion. The dramatic 
T-wave inversions gradually resolve over time.
The echocardiogram reveals LV apical dyskinesia usually 
not consistent with any particular coronary distribution. 
The urgent cardiac catheterization reveals the LV apical 
ballooning in association with normal coronaries. Initial 
cardiac enzymes are positive but often taper quickly. In 
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almost all cases, MRI hyperenhancement studies reveal no 
long-term scarring.
 
»
Treatment
Immediate therapy is similar to any acute myocardial 
infarction. Initiation of long-term therapy depends on 
whether LV dysfunction persists. Most patients receive 
aspirin, beta-blockers, and ACE inhibitors until the LV 
fully recovers. Despite the presumed association with high 
catecholamines, the use of ACE inhibitors or ARBs, but not 
beta-blockers has been associated with improved long-term 
survival. See Treatment of Heart Failure with Reduced EF.
 
»
Prognosis
In a 2015 registry of 1759 patients, the rate of severe in-
hospital complications, including shock and death, were 
similar between those with an acute coronary syndrome and 
tako-tsubo. Overall, prognosis is good unless there is a seri
-
ous complication (such as mitral regurgitation, ventricular 
rupture, or ventricular tachycardia). Recovery of the LVEF is 
expected in most cases after a period of weeks to months. At 
times, the LV function recovers fully in a few days.
 
»
All patients with an acute coronary syndrome should be 
urgently seen by a cardiologist for further evaluation and 
monitored until resolution of the ventricular dysfunction.
Goica A et al. Novel developments in stress cardiomyopathy: 
from pathophysiology to prognosis. Int J Cardiol 
2016;223:1053–58. [PMID: 27611570]
Templin C et al. Clinical features and outcome of takotsubo 
(stress) cardiomyopathy. N Engl J Med. 2015 Sep 3;
 
373(10):929–38. [PMID: 26332547]
Tornvall P et al. A case-control study of the risk markers and 
mortality in Takotsubo stress cardiomyopathy. J Am Coll 
Cardiol. 2016 Apr 26;67(16):1931–6. [PMID: 27102508]
HYPERTROPHIC CARDIOMYOPATHY
 
»
May present with dyspnea, chest pain, syncope.
 
»
Though LV outflow gradient is classic, symptoms 
are primarily related to diastolic dysfunction.
 
»
Echocardiogram is diagnostic. Any area of LV wall 
thickness greater than 1.5 cm defines the disease.
 
»
Increased risk of sudden death.
 
»
Hypertrophic cardiomyopathy is noted when there is LVH 
unrelated to any pressure or volume overload. The defini
-
tion has evolved over time; while it traditionally has been 
defined by LV outflow obstruction due to septal hypertro
-
phy, now it is considered present any time that any LV wall 
is measured at 
more than 1.5 cm thick
 on an echocardio
-
gram. This allows for many forms to be considered that do 
not create LV outflow obstruction. The increased wall 
thickness reduces LV systolic stress, increases the EF, and 
can result in an “empty ventricle” at end-systole. The inter
-
ventricular septum may be disproportionately involved 
(asymmetric septal hypertrophy), but in some cases the 
hypertrophy is localized to the mid-ventricle or to the apex. 
The LV outflow tract is usually narrowed during systole 
due to the hypertrophied septum and systolic anterior 
motion of the mitral valve occurs as the anterior mitral 
valve leaflet is pulled into the LV outflow. The obstruction 
is worsened by factors that increase myocardial contractil
-
ity (sympathetic stimulation, digoxin, and postextrasystolic 
beat) or that decrease LV filling (Valsalva maneuver, 
peripheral vasodilators). The amount of obstruction is 
preload and afterload dependent and can vary from day to 
day. The consequence of the hypertrophy is 
elevated LV 
diastolic pressures
 rather than systolic dysfunction. Rarely, 
systolic dysfunction develops late in the disease. The LV is 
usually more involved than the RV , and the atria are fre
-
quently significantly enlarged.
Hypertrophic cardiomyopathy is inherited as an auto
-
somal-dominant trait with variable penetrance and is 
caused by mutations of one of a large number of genes, 
most of which code for myosin heavy chains or proteins 
regulating calcium handling. The prognosis is related to

regulating calcium handling. The prognosis is related to 
the specific gene mutation. Patients usually present in early 
adulthood. Elite athletes may demonstrate considerable 
hypertrophy that can be confused with hypertrophic car
-
diomyopathy, but generally diastolic dysfunction is not 
present in the athlete and this finding helps separate patho
-
logic disease from 
athletic hypertrophy
. The apical variety 
is particularly common in those of Asian descent. A 
hyper
-
trophic cardiomyopathy
 in older adults (usually in asso
-
ciation with hypertension) has also been defined as a 
distinct entity (often a sigmoid interventricular septum is 
noted with a knob of cardiac muscle below the aortic 
valve). Mitral annular calcification is often present. Mitral 
regurgitation is variable and often dynamic, depending on 
the degree of outflow tract obstruction.
 
»
The most frequent symptoms are dyspnea and chest pain 
(see Table 10–17). Syncope is also common and is typically 
postexertional, when diastolic filling diminishes due to 
fluid loss and tachycardia increasing LV outflow tract 
obstruction. Residual circulating catecholamines accentu
-
ate the changes. Arrhythmias are an important problem. 
Atrial fibrillation is a long-term consequence of chronically 
elevated LA pressures and is a poor prognostic sign. Ven
-
tricular arrhythmias are also common, and sudden death 
may occur, often after extraordinary exertion.
Features on physical examination include a bisferiens 
carotid pulse, triple apical impulse (due to the prominent 
atrial filling wave and early and late systolic impulses), and 
a loud S
4
. The JVP may reveal a prominent 
a
 wave due to 
reduced RV compliance. In cases with LV outflow 
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obstruction, a loud systolic murmur is present along the 
left sternal border that increases with upright posture or 
Valsalva maneuver and decreases with squatting. These 
maneuvers help differentiate the murmur of hypertrophic 
cardiomyopathy from that of aortic stenosis. In hypertro
-
phic cardiomyopathy, reducing the LV volume 
increases
 the 
outflow obstruction and the murmur intensity; whereas in 
valvular aortic stenosis, reducing the stroke volume across 
the valve decreases the murmur. Mitral regurgitation is 
frequently present as well.
LVH is nearly universal in symptomatic patients, though 
entirely normal ECGs are present in up to 25%, usually in 
those with localized hypertrophy. Exaggerated septal Q 
waves inferolaterally may mimic myocardial infarction. 
The chest radiograph is often unimpressive. Unlike with 
aortic stenosis, the ascending aorta is not dilated.
The echocardiogram is diagnostic, revealing LVH (involv
-
ing the septum more commonly than the posterior walls), 
systolic anterior motion of the mitral valve, early closing 
followed by reopening of the aortic valve, a small and 
hypercontractile LV , and delayed relaxation and filling of 
the LV during diastole. The septum is usually 1.3–1.5 times 
the thickness of the posterior wall. Septal motion tends to 
be reduced. Doppler ultrasound reveals turbulent flow and 
a dynamic gradient in the LV outflow tract and, commonly, 
mitral regurgitation. Abnormalities in the diastolic filling 
pattern are present in 80% of patients.
Echocardiography can usually differentiate the disease 
from ventricular noncompaction, a congenital myocardial 
disease pattern with marked trabeculation that partially 
fills the LV cavity. Myocardial perfusion imaging may sug
-
gest septal ischemia in the presence of normal coronary 
arteries. Cardiac MRI confirms the hypertrophy and con
-
trast enhancement frequently reveals evidence of scar at 
the junction of the RV attachment to the interventricular 
septum. Cardiac catheterization confirms the diagnosis 
and defines the presence or absence of CAD. Frequently, 
coronary arterial bridging (squeezing of the coronary in 
systole) occurs, especially in the septal arteries. Exercise 
studies are recommended to assess for ventricular arrhyth
-
mias and to document the BP response. Loop monitoring 
is recommended for determination of ventricular ectopy.
 
»
Treatment
Beta-blockers should be the initial medication in symptom
-
atic individuals, especially when dynamic outflow obstruc
-
tion is noted on the echocardiogram. The resulting slower 
heart rates assist with diastolic filling of the stiff LV . Dyspnea, 
angina, and arrhythmias respond in about 50% of patients. 
Calcium channel blockers, especially verapamil, have also 
been effective in symptomatic patients. Verapamil is pre
-
ferred due to its more potent effects on the myocardium. 
Their effect is due primarily to improved diastolic function; 
however, their vasodilating actions can also increase outflow 
obstruction and cause hypotension. Disopyramide is also 
effective because of its negative inotropic effects; it is usually 
used as an addition to the medical regimen rather than as 
primary therapy or to help control atrial arrhythmias. Diuret
-
ics are frequently necessary due to the high LV diastolic pres
-
sure and elevated LA pressures, but should be used with 
caution to avoid dehydration that would increase obstruc
-
tion. Patients do best in sinus rhythm, and atrial fibrillation 
should be aggressively treated with antiarrhythmics or radio
-
frequency ablation. Dual-chamber pacing may help prevent 
the progression of hypertrophy and obstruction. There 
appears to be an advantage to the use of short-AV delay 
biventricular pacing.
Nonsurgical septal ablation can be performed by injec
-
tion of alcohol into septal branches of the left coronary

-
tion of alcohol into septal branches of the left coronary 
artery to create a controlled myocardial infarct in the regions 
of greatest wall thickness. Patients with malignant ventricu
-
lar arrhythmias and unexplained syncope in the presence of 
a positive family history for sudden death, with or without 
an abnormal BP response to exercise, are probably best man
-
aged with an implantable defibrillator. 
 
E
xcision of part of the 
outflow myocardial septum (myotomy–myomectomy) by 
experienced surgeons is successful in patients with severe 
symptoms unresponsive to medical therapy. A few surgeons 
advocate mitral valve replacement, since this results in reso
-
lution of the gradient and prevents associated mitral regur
-
gitation. In some cases, myomectomy has been combined 
with an Alfieri stitch on the mitral valve (a stitch that binds 
the midportion of the anterior and posterior mitral valve 
leaflets together). Rare cases of progression to LV dilation or 
patients with intractable symptoms can be considered for 
cardiac transplantation. Figure 10–9 provides an algorithm 
for the treatment of hypertrophic cardiomyopathy as defined 
in the 2011 AHA/ACC guidelines.
Pregnancy results in an increased risk in patients with 
symptoms or outflow tract gradients of greater than 50 mm Hg. 
Genetic counseling is indicated before planned conception. 
In pregnant patients with hypertrophic cardiomyopathy, 
continuation of beta-blocker therapy is recommended.
 
»
Prognosis
The natural history of hypertrophic cardiomyopathy is 
highly variable. Genetic testing is recommended if first-
degree relatives are available to participate. Some patients 
remain asymptomatic for many years or for life. Sudden 
death, especially during exercise, may be the initial event. 
The highest risk patients are those with (1) a personal his
-
tory of serious ventricular arrhythmias or survival of a 
sudden death episode; (2) a family history of sudden death; 
(3) unexplained syncope; (4) documented nonsustained 
ventricular tachycardia, defined as three or more beats of 
ventricular tachycardia at 120 beats per minute or more on 
ambulatory ECG monitoring; and (5) maximal LV wall 
thickness of 30 mm or more. In addition, patients in whom 
the systolic BP does not increase more than 20 mm Hg 
during treadmill stress testing are also at risk, as are those 
with double and compound genetic mutations and those 
with marked LV outflow tract obstruction. MRI data sug
-
gest that the extent of scarring on hyperenhancement may 
also be predictive of adverse events, and some studies sug
-
gest a substantial risk factor is defined if the amount of 
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CMDT 2019
Elliott PM et al. 2014 ESC guidelines on diagnosis and manage
-
ment of hypertrophic cardiomyopathy: the Task Force for the 
Diagnosis and Management of Hypertrophic Cardiomyopa
-
thy of the European Society of Cardiology (ESC). Eur Heart J. 
2014 Oct 14;35(39):2733–79. [PMID: 25173338]
Gersh BJ et al. 2011 ACCF/AHA guideline for the treatment of 
hypertrophic cardiomyopathy. J Am Coll Cardiol. 2011 Dec 
13;58(25):e212–60. [PMID: 22075469]
Maron BJ et al. How hypertrophic cardiomyopathy became a 
contemporary treatable genetic disease with low mortality 
shaped by 50 years of clinical research and practice. JAMA 
Cardiol. 2016 Apr 1;1(1):98–105. [PMID: 27437663]
Sen-Chowdry S et al. Update on hypertrophic cardiomyopathy 
and a guide to the guidelines. Nat Rev Cardiol. 2016 Nov;
 
13(11):651–75. [PMID: 27681577]
hyperenhancement scar exceeds 15% of the entire myocar
-
dium. Hypertrophic cardiomyopathy is the pathologic fea
-
ture most frequently associated with sudden death in 
athletes. Endocarditis prophylaxis is not indicated. A final 
stage may be a transition into a dilated cardiomyopathy in 
5–10% of patients due to the long-term effects of LV 
remodeling; treatment at that stage is similar to that for 
dilated cardiomyopathy.
 
»
Patients should be referred to a cardiologist when symp
-
toms are difficult to control, syncope has occurred, or there 
are any of the high-risk features present, which may denote 
the need for a prophylactic defibrillator.
HCM
Tr
eat comorbidities (high blood pressur
e,
hy
perlipidemia, diabetes mellitus) 
Obstructive
physiology
Av
oid vasodilators or
high-dose diuretics
HF or
angina
Class I
Ke
y:
HF or angina
Annual visit
Sy
stolic function
LVEF < 50%
LVEF 
≥
 50%
Standard HF
therapy
Beta-
bl
o
ckers
Ve
rapamil
Diuretics
ACE inhibi
to
r
ARB
Class IIa
Class IIb
Alcohol ablation
Ve
rapamil
Pe
rsistent symptoms
Invasive therapy
Surgical candidate
candidate
DDD pacing
1
1
See section on 
AV
 Block in the 
te
xt.
Beta-
bl
o
ckers
Surgical 
my
ectomy
No
No
Ye
s
Ye
s
Ye
s
Ye
s
Ye
s
No
No
No
 
▲
Figure 10–9.
 
Recommended therapeutic approach to the patient with hypertrophic cardiomyopathy (HCM). ACE, 
angiotensin-converting enzyme; ARB, angiotensin receptor blockers; HF, heart failure; LVEF, left ventricular ejection 
fraction. 
(Reproduced, with permission, from Gersh BJ et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of 
Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation/American Heart Association 
Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, American 
Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm 
Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 
2011 Dec 13;58(25):e212–60. Copyright © Elsevier.)
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RESTRICTIVE CARDIOMYOPATHY
 
»
Right heart failure tends to dominate over left 
 
»
Pulmonary hypertension is present.
 
»
Amyloidosis is the most common cause.
 
»
Echocardiography is key to diagnosis.
 
»
Myocardial biopsy or cardiac MRI can confirm 
amyloid.
 
»
Restrictive cardiomyopathy is characterized by impaired 
diastolic filling with reasonably preserved contractile func
-
tion. The condition is relatively uncommon, with the most 
frequent cause being amyloidosis. 
Cardiac amyloidosis
 is 
more common in men than in women and rarely manifests 
before the age of 40. While light-chain amyloid proteins 
can be toxic to cardiomyocytes, they may also internalize 
into many cell types and this may explain some of the car
-
diac dysfunction observed. The AL (light-chain) type is the 
most common, with cardiac involvement in 50%. Other 
forms include mutated transthyretin (ATTR) in familial 
amyloidosis (usually manifested in the elderly black popu
-
lation) and a wild-type transthyretin in senile amyloidosis. 
Transthyretin is produced almost entirely in the liver. Sec
-
ondary (AA) amyloidosis due to fragments of serum amy
-
loid A protein associated with chronic inflammatory 
disorders is a rare cause of cardiac disease. An isolated 
atrial amyloid form is also recognized.
The differential diagnosis of a restrictive cardiomyopa
-
thy includes infiltrative disorders beside amyloidosis, such 
as sarcoidosis, Gaucher disease, and Hurler syndrome. 
Storage diseases such as hemochromatosis, Fabry disease, 
and glycogen storage diseases can also produce the picture. 
Noninfiltrative diseases, such as familial cardiomyopathy 
and pseudoxanthoma elasticum, can be implicated rarely, 
and other secondary causes include diabetes, scleroderma, 
radiation, chemotherapy, CAD and longstanding 
 
»
Restrictive cardiomyopathy must be distinguished from 
constrictive pericarditis (see Table 10–17). The key feature 
is that ventricular interaction is 
accentuated
 with respira
-
tion in constrictive pericarditis and that interaction is 
absent
 in restrictive cardiomyopathy. In addition, the pul
-
monary arterial pressure is invariably elevated in restrictive 
cardiomyopathy due to the high PCWP and is normal in 
uncomplicated constrictive pericarditis. Symptoms may 
include angina, syncope, stroke, and peripheral neuropa
-
thy. Periorbital purpura, a thickened tongue, or hepato
-
megaly are all suggestive physical findings of amyloidosis.
Conduction disturbances are frequently present. Low volt
-
age on the ECG combined with ventricular hypertrophy on 
the echocardiogram is suggestive of disease. Cardiac MRI 
presents a distinctive pattern of diffuse hyperenhancement 
of the gadolinium image in amyloidosis and is a useful 
screening test. Late gadolinium hyperenhancement of a 
high degree suggests more extensive cardiac involvement. 
Technetium pyrophosphate imaging (bone scan imaging) 
can also identify amyloid deposition in the myocardium, as 
can 18F-florbetaben PET scanning. The echocardiogram 
reveals a small, thickened LV with bright myocardium 
(speckled), rapid early diastolic filling revealed by the 
mitral inflow Doppler, and biatrial enlargement. The LV 
chamber size is usually normal with a reduced LVEF. Atrial 
septal thickening may be evident. Rectal, abdominal fat, or 
gingival biopsies can confirm systemic involvement, but 
myocardial involvement may still be present if these are 
negative and requires endomyocardial biopsy for the con
-
firmation that cardiac amyloid is present. Demonstration 
of tissue infiltration on biopsy specimens using special 
stains followed by immunohistochemical studies and 
genetic testing are essential to define which specific protein 
is involved. Mass spectroscopy on all tissue in question and

is involved. Mass spectroscopy on all tissue in question and 
TTR gene sequencing in patients in whom the TTR wild 
type or TTR mutant variant is suspected is recommended. 
BNP and NT-proBNP are traditionally elevated and have 
been used to help distinguish constrictive pericarditis from 
a restrictive cardiomyopathy.
 
»
Treatment
Unfortunately, little useful therapy is available for either the 
causative conditions or the restrictive cardiomyopathy 
physiology. First-line treatment for AL amyloidosis 
includes alkylator-based chemotherapy or high-dose mel
-
phalan followed by autologous stem cell transplantation. In 
immunoglobin light chain amyloidosis, standard- or high-
dose chemotherapy with stem cell rescue is often pursued. 
In ATTR, therapies that decrease protein production, pre
-
vent dissociation, and promote clearance have the potential 
to slow or even halt the disease.
In acute cases, diuretics can help, but excessive diuresis 
can produce worsening kidney dysfunction. As with most 
patients with severe right heart failure, loop diuretics, thia
-
zides, and aldosterone antagonists are all useful. Ultrafiltra
-
tion devices may improve diuresis, although it is not clear 
if prognosis is improved. Atrial thrombi are not uncom
-
mon, although the role of anticoagulation in amyloidosis 
remains ill defined. Digoxin may precipitate arrhythmias 
and should not be used. Beta-blockers help slow heart rates 
and improve filling by increasing diastolic time. Verapamil 
presumably works by improving myocardial relaxation and 
increasing diastolic filling time. Slow heart rates are desired 
to allow for increased diastolic filling time. ACE inhibition 
or angiotensin II receptor blockade may improve diastolic 
filling at times and can be tried with caution if the systemic 
blood pressure is adequate. Corticosteroids may be helpful 
in sarcoidosis but they are more effective for conduction 
abnormalities than heart failure.
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In amyloidosis, the therapeutic strategy depends on the 
characterization of the type of amyloid protein and extent 
of disease and may include chemotherapy or bone marrow 
transplantation. In familial amyloidosis (ATTR) with 
transthyretin deposition, liver transplantation may be an 
option. In AL amyloidosis chemotherapy and autologous 
stem cell transplantation has been tried with mixed suc
-
cess. Cardiac transplantation has also been used in patients 
with primary cardiac amyloidosis and no evidence of sys
-
temic involvement.
 
»
All patients with the diagnosis of a restrictive cardiomy
-
opathy should be referred to a cardiologist to decide etiol
-
ogy and plan appropriate treatment. This is especially true 
if amyloidosis is suspected given its poor prognosis and 
available therapies.
Gertz MA et al. Pathophysiology and treatment of cardiac amy
-
loidosis. Nat Rev Cardiol. 2015 Feb;12(2):91–102. [PMID: 
25311231]
Ruberg FL et al. Cardiovascular magnetic resonance visualization 
of cardiac amyloid infiltration: challenges and opportunities. 
Circulation. 2015 Oct 20;132(16):1525–27. [PMID: 26362630]
 
º
RHEUMATIC FEVER
 
»
More common in developing countries (100 cases/
 
100,000 population) than in the United States 
 
(~2 cases/100,000 population).
 
»
Peak incidence between ages 5 and 15 years.
 
»
Revision of Jones criteria in 2015 includes echo
-
cardiographic findings.
 
»
May involve mitral and other valves acutely, rarely 
leading to heart failure.
 
»
Rheumatic fever is a systemic immune process that is a 
sequela of a beta-hemolytic streptococcal infection of the 
pharynx. It is a major scourge in developing countries and 
responsible for 250,000 deaths in young people worldwide 
each year. Over 15 million people have evidence for rheu
-
matic heart disease. Signs of 
acute rheumatic fever
 usually 
commence 2–3 weeks after infection but may appear as 
early as 1 week or as late as 5 weeks. The disease has 
become quite uncommon in the United States, except in 
immigrants; however, there have been reports of new out
-
breaks in several regions of the United States. The peak 
incidence is between ages 5 and 15 years; rheumatic fever 
is rare before age 4 years or after age 40 years. Rheumatic 
carditis and valvulitis may be self-limited or may lead to 
slowly progressive valvular deformity. The characteristic 
lesion is a perivascular granulomatous reaction with valvu
-
litis. The mitral valve is acutely attacked in 75–80% of 
cases, the aortic valve in 30% (but rarely as the sole valve 
involved), and the tricuspid and pulmonary valves in 
under 5% of cases.
The clinical profile of the infection includes carditis in 
50–70% and arthritis in 35–66%, followed by chorea 
(10–30% and predominantly in girls) then subcutaneous 
nodules (0–10%) and erythema marginatum (in less than 
6%). Echocardiography has been found to be superior to 
auscultation, and the 2015 guidelines introduced 
subclinical 
carditis
 to the Jones criteria to represent abnormal echo
-
cardiographic findings when auscultatory findings were 
either not present or not recognized.
Chronic rheumatic heart disease
 results from single 
or repeated attacks of rheumatic fever that produce rigid
-
ity and deformity of valve cusps, fusion of the commis
-
sures, or shortening and fusion of the chordae tendineae. 
Valvular stenosis or regurgitation results, and the two 
often coexist. In chronic rheumatic heart disease, the 
mitral valve alone is abnormal in 50–60% of cases; com
-
bined lesions of the aortic and mitral valves occur in 20%; 
pure aortic lesions are less common. Tricuspid involve
-
ment occurs in about 10% of cases, but only in association 
with mitral or aortic disease and is thought to be more 
common when recurrent infections have occurred. The 
pulmonary valve is rarely affected long term. A history of

pulmonary valve is rarely affected long term. A history of 
rheumatic fever is obtainable in only 60% of patients with 
rheumatic heart disease.
 
»
The presence of two major criteria—or one major and two 
minor criteria—establishes the diagnosis. While India, 
New Zealand, and Australia have all published revised 
guidelines since 2001, the 2015 recommendations have 
revised the Jones criteria (Table 10–18) in a scientific state
-
ment from the AHA where subclinical carditis is now recog
-
nized with the advent of echocardiography. The revised 
criteria also recognize that a lower threshold should be used 
to diagnosis acute rheumatic fever in high-risk populations.
A. Major Criteria
1. Carditis—
Carditis is most likely to be evident in chil
-
dren and adolescents. Any of the following suggests the 
presence of carditis: (1) pericarditis; (2) cardiomegaly, 
detected by physical signs, radiography, or echocardiogra
-
phy; (3) heart failure, right- or left-sided—the former per
-
haps more prominent in children, with painful liver 
engorgement due to tricuspid regurgitation; and (4) mitral 
or aortic regurgitation murmurs, indicative of dilation of a 
valve ring with or without associated valvulitis or morpho
-
logic findings on echocardiography of rheumatic valvulitis. 
The Carey–Coombs short mid-diastolic mitral murmur 
may be present due to inflammation of the mitral valve. It is 
a class I (LOE B) indication to perform echocardiography/
Doppler studies on all cases of suspected or confirmed 
acute rheumatic fever.
2. Erythema marginatum and subcutaneous nodules—
Erythema marginatum begins as rapidly enlarging macules 
that assume the shape of rings or crescents with clear cen
-
ters. They may be raised, confluent, and either transient or 
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persistent and usually on the trunk or proximal extremi
-
ties. Subcutaneous nodules are uncommon except in chil
-
dren. They are small (2 cm or less in diameter), firm, and 
nontender and are attached to fascia or tendon sheaths 
over bony prominences. They persist for days or weeks, are 
recurrent, and are indistinguishable from rheumatoid nod
-
ules. Neither the rash nor nodules ever occur as the sole 
manifestation of acute rheumatic fever.
3. Sydenham chorea—
This is the most definitive manifes
-
tation of acute rheumatic fever. Defined as involuntary 
choreoathetoid movements primarily of the face, tongue, 
and upper extremities, Sydenham chorea may be the sole 
manifestation of rheumatic fever. Girls are more frequently 
affected than boys, and occurrence in adults is rare.
4. Polyarthritis—
This is a migratory polyarthritis that 
involves the large joints sequentially. In adults and in cer
-
tain moderate- to high-risk populations, only a single joint 
may be affected. The arthritis lasts 1–5 weeks and subsides 
without residual deformity. Prompt response of arthritis to 
therapeutic doses of salicylates or nonsteroidal agents is 
characteristic.
B. Minor Criteria
These include fever, polyarthralgias, reversible prolonga
-
tion of the PR interval, and an elevated erythrocyte sedi
-
mentation rate or CRP . A lower threshold is set for patients 
at high risk (Table 10–18). The 2015 guidelines stipulate 
that evidence for a preceding streptococcal infection can be 
defined by an increase or rising anti-streptolysin O titer or 
streptococcal antibodies (anti-DNAase B), a positive throat 
culture for group A beta-hemolytic streptococcal or a posi
-
tive rapid group A streptococcal carbohydrate antigen test 
in a child with a high pretest probability of streptococcal 
pharyngitis.
 
»
Treatment
The patient should be kept at strict bed rest until the tem
-
perature returns to normal (without the use of antipyretic 
medications) and the sedimentation rate, plus the resting 
pulse rate, and the ECG have all returned to baseline.
B. Medical Measures
1. Salicylates—
The salicylates markedly reduce fever and 
relieve joint pain and swelling. They have no effect on the 
natural course of the disease. Adults may require large 
doses of aspirin, 0.6–0.9 g every 4 hours; children are 
treated with lower doses.
2. Penicillin—
Penicillin (benzathine penicillin, 1.2 million 
units intramuscularly once, or procaine penicillin, 600,000 
units intramuscularly daily for 10 days) is used to eradicate 
streptococcal infection if present. Erythromycin may be 
substituted (40 mg/kg/day).
3. Corticosteroids—
There is no proof that cardiac damage 
is prevented or minimized by corticosteroids. A short 
course of corticosteroids (prednisone, 40–60 mg orally 
daily, with tapering over 2 weeks) usually causes rapid 
improvement of the joint symptoms and is indicated when 
response to salicylates has been inadequate.
Table 10–18.
 
The 2015 revised Jones criteria.
1
p
opula
tion
Criteria
Major
Minor
Low risk
Carditis (clinical or subclinical)
Polyarthralgia
Arthritis (polyarthritis only)
Fever (≥ 38.5°C)
Chorea
ESR ≥ 60 mm/h or CRP ≥ 3.0 mg/dL (or both)
Erythema marginatum
Prolonged PR interval (unless carditis is major criterion)
Subcutaneous nodules
Moderate and high risk
Monoarthralgia
Arthritis (monoarthritis, polyarthritis, 
polyarthalgia)
Fever (≥ 38°C)
Chorea
ESR ≥ 30 mm/h or CRP ≥ 3.0 mg/dL (or both)
Prolonged PR interval (unless carditis is a major criterion)
1
For all patients with evidence of preceding group A streptococcal pharyngitis: initial acute rheumatic fever can be diagnosed when 2 major 
criteria or 1 major plus 2 minor criteria are met. Recurrent acute rheumatic fever can be diagnosed when 2 major or 1 major plus 2 minor 
or 3 minor criteria are met.

ESR, erythrocyte sedimentation rate; CRP , C-reactive protein.
Modified, with permission, from Gewitz, MH et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki 
Disease of the Council on Cardiovascular Disease in the Young. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in 
the era of Doppler echocardiography. A scientific statement from the American Heart Association. Circulation. 2015 May 19;131(20):1806–18. 
© 2015 American Heart Association, Inc.
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»
Prevention of Recurrent Rheumatic Fever
Improvement in socioeconomic conditions and public 
health are critical to reducing bouts of rheumatic fever. The 
initial episode of rheumatic fever can usually be prevented 
by early treatment of streptococcal pharyngitis with peni
-
cillin (see Chapter 33). Prevention of recurrent episodes of 
rheumatic fever is critical. Recurrences of rheumatic fever 
are most common in patients who have had carditis during 
their initial episode and in children, 20% of whom will 
have a second episode within 5 years. The preferred 
method of prophylaxis is with benzathine penicillin G, 
1.2 million units intramuscularly every 4 weeks. Oral 
penicillin (250 mg twice daily) is less reliable.
If the patient is allergic to penicillin, sulfadiazine (or 
sulfisoxazole), 1 g daily, or erythromycin, 250 mg orally 
twice daily, may be substituted. The macrolide azithromy
-
cin is similarly effective against group A streptococcal 
infection. If the patient has not had an immediate hyper
-
sensitivity (anaphylactic-type) reaction to penicillin, then 
cephalosporin may also be used.
Recurrences are uncommon after 5 years following the 
first episode and in patients over 21 years of age. Prophylaxis 
is usually discontinued after these times except in groups 
with a high risk of streptococcal infection—parents or teach
-
ers of young children, nurses, military recruits, etc. Second
-
ary prevention of rheumatic fever depends on whether 
carditis has occurred. Current guidelines suggest that if there 
is no evidence for carditis, preventive therapy can be stopped 
at age 21 years. If carditis has occurred but there is no residual 
valvular disease, it can be stopped at 10 years after the acute 
rheumatic fever episode. If carditis has occurred with resid
-
ual valvular involvement, it should be continued for 10 years 
after the last episode or until age 40 years if the patient is in a 
situation in which reexposure would be expected.
 
»
Prognosis
Initial episodes of rheumatic fever may last months in chil
-
dren and weeks in adults. The immediate mortality rate is 
1–2%. Persistent rheumatic carditis with cardiomegaly, 
heart failure, and pericarditis implies a poor prognosis; 
30% of children thus affected die within 10 years after the 
initial attack. After 10 years, two-thirds of patients will 
have detectable valvular abnormalities (usually thickened 
valves with limited mobility), but significant symptomatic 
valvular heart disease or persistent cardiomyopathy occurs 
in less than 10% of patients with a single episode. In devel
-
oping countries, acute rheumatic fever occurs earlier in life 
and recurs more frequently, thus the evolution to chronic 
valvular disease is both accelerated and more severe.
Gewitz MH et al; American Heart Association Committee on 
Rheumatic Fever, Endocarditis, and Kawasaki Disease of the 
Council on Cardiovascular Disease in the Y oung. Revision of 
the Jones criteria for the diagnosis of acute rheumatic fever in 
the era of Doppler echocardiography. A scientific statement 
from the American Heart Association. Circulation. 2015 May 
19;131(20):1806–18. [PMID: 25908771]
Y acoub M et al. Eliminating acute rheumatic fever and rheu
-
matic heart disease. Lancet. 2017 Jul 15;390(10091):212–3. 
[PMID: 28721865]
 
º
DISEASES OF THE 
p
ERICARDIUM
ACUTE INFLAMMATORY PERICARDITIS
 
»
Anterior pleuritic chest pain that is worse supine 
than upright.
 
»
Pericardial rub.
 
»
Fever common.
 
»
Erythrocyte sedimentation rate or inflammatory 
CRP usually elevated.
 
»
ECG reveals diffuse ST-segment elevation with 
associated PR depression.
 
»
Acute (less than 2 weeks) inflammation of the pericardium 
may be infectious in origin or may be due to systemic dis
-
eases (autoimmune syndromes, uremia), neoplasm, radia
-
tion, drug toxicity, hemopericardium, postcardiac surgery,

-
-
tion, drug toxicity, hemopericardium, postcardiac surgery, 
or contiguous inflammatory processes in the myocardium 
or lung. In many of these conditions, the pathologic pro
-
cess involves both the pericardium and the myocardium. 
Overall pericarditis accounts for 0.2% of hospital admis
-
sions and about 5% of patients with nonischemic chest 
pain seen in the emergency department. The ESC in 2015 
proposed four definitions for pericarditis and elucidated 
diagnostic criteria for each (Table 10–19). 
Viral infections
 
(especially infections with coxsackieviruses and echovi
-
ruses but also influenza, Epstein-Barr, varicella, hepatitis, 
mumps, and HIV viruses) are the most common cause of 
acute pericarditis and probably are responsible for many 
cases classified as idiopathic. Males—usually under age 
50 years—are most commonly affected. The differential 
diagnosis primarily requires exclusion of acute myocardial 
infarction. 
Tuberculous pericarditis
 is rare in developed 
countries but remains common in certain areas of the 
world. It results from direct lymphatic or hematogenous 
spread; clinical pulmonary involvement may be absent or 
minor, although associated pleural effusions are common. 
Bacterial pericarditis
 is equally rare and usually results 
from direct extension from pulmonary infections. Pneu
-
mococci, though, can cause a primary pericardial infec
-
tion. 
Borrelia burgdorferi,
 the organism responsible for 
Lyme disease, can also cause myopericarditis (and occa
-
sionally heart block). 
Uremic pericarditis
 is a common 
complication of chronic kidney disease. The pathogenesis 
is uncertain; it occurs both with untreated uremia and in 
otherwise stable dialysis patients. Spread of adjacent lung 
cancer as well as invasion by breast cancer, renal cell carci
-
noma, Hodgkin disease, and lymphomas are the most 
common 
neoplastic processes
 involving the 
 
p
ericardium 
and have become the most frequent causes of pericardial 
tamponade in many countries. Pericarditis may occur 
2–5 days after infarction due to an inflammatory reaction to 
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transmural myocardial necrosis 
(postmyocardial infarc
-
tion
 or 
postcardiotomy pericarditis [Dressler syn
-
drome]).
 
Radiation
 can initiate a fibrinous and fibrotic 
process in the pericardium, presenting as subacute pericar
-
ditis or constriction. Radiation pericarditis usually follows 
treatments of more than 4000 cGy delivered to ports 
including more than 30% of the heart.
Other causes of pericarditis include connective tissue 
diseases, such as lupus erythematosus and rheumatoid 
arthritis, drug-induced pericarditis (minoxidil, penicillins, 
clozapine), and myxedema. In addition, pericarditis may 
result from pericardial injury from invasive cardiac proce
-
dures (such as cardiac pacemaker and defibrillator perfora
-
tion and intracardiac ablation, especially atrial fibrillation 
ablation), and the implantation of intracardiac devices 
(such as ASD occluder devices).
Pericarditis and myocarditis may coexist in 20–30% of 
patients. Myocarditis is often suspected when there is an 
elevation of serum troponins, although there are no data 
that suggest troponin elevations are associated with a poor 
 
»
The presentation and course of inflammatory pericarditis 
depend on its cause, but most syndromes have associated 
chest pain, which is usually pleuritic and postural (relieved 
by sitting). The pain is substernal but may radiate to the 
neck, shoulders, back, or epigastrium. Dyspnea may also be 
present and the patient is often febrile. A pericardial 
friction 
rub
 is characteristic, with or without evidence of fluid accu
-
mulation or constriction. The presentation of tuberculous 
pericarditis tends to be subacute, but nonspecific symptoms 
(fever, night sweats, fatigue) may be present for days to 
months. Pericardial involvement develops in 1–8% of 
patients with pulmonary tuberculosis. Symptoms and signs 
of bacterial pericarditis are similar to those of other types of 
inflammatory pericarditides, but patients appear toxic and 
are often critically ill. Uremic pericarditis can present with or 
without symptoms; fever is absent. Often neoplastic pericar
-
ditis is painless, and the presenting symptoms relate to 
hemodynamic compromise or the primary disease. At times 
the pericardial effusion is very large, consistent with its 
chronic nature. Postmyocardial infarction or postcardiot
-
omy pericarditis (Dressler syndrome) usually presents as a 
recurrence of pain with pleural-pericardial features. A rub is 
often audible, and repolarization changes on the ECG may 
be confused with ischemia. Large effusions are uncommon, 
and spontaneous resolution usually occurs in a few days. 
Dressler syndrome occurs days to weeks to several months 
after myocardial infarction or open heart surgery, may be 
recurrent, and probably represents an autoimmune syn
-
drome. Patients present with typical pain, fever, malaise, and 
leukocytosis. Rarely, other symptoms of an autoimmune 
disorder, such as joint pain and fever, may occur. Tampon
-
ade is rare with Dressler syndrome after myocardial infarc
-
tion but not when it occurs postoperatively. The clinical 
onset of radiation pericarditis is usually within the first year 
but may be delayed for many years; often a full decade or 
more may pass before constriction becomes evident.
B. Laboratory Findings and Diagnostic Studies
The diagnosis of viral pericarditis is usually clinical, and leu
-
kocytosis is often present. Rising viral titers in paired sera 
may be obtained for confirmation but are rarely done. Car
-
diac enzymes may be slightly elevated, reflecting an epicar
-
dial myocarditis component. The echocardiogram is often 
normal or reveals only a trivial amount of extra fluid during 
the acute inflammatory process. The diagnosis of tubercu
-
lous pericarditis can be inferred if acid-fast bacilli are found 
elsewhere. The tuberculous pericardial effusions are usually

-
elsewhere. The tuberculous pericardial effusions are usually 
small or moderate but may be large when chronic. The yield 
of mycobacterial organisms by pericardiocentesis is low; 
pericardial biopsy has a higher yield but may also be negative, 
and pericardiectomy may be required. If bacterial pericarditis 
is suspected on clinical grounds, diagnostic pericardiocente
-
sis can be confirmatory. In uremic patients not on dialysis, 
the incidence of pericarditis correlates roughly with the level 
of blood urea nitrogen (BUN) and creatinine. The pericar
-
dium is characteristically “shaggy” in uremic pericarditis, and 
the effusion is hemorrhagic and exudative. The diagnosis of 
neoplastic pericarditis can occasionally be made by cytologic 
examination of the effusion or by pericardial biopsy, but it 
may be difficult to establish clinically if the patient has 
received mediastinal radiation within the previous year. Neo
-
plastic pericardial effusions develop over a long period of 
time and may become quite huge (more than 2 L). The sedi
-
mentation rate is high in postmyocardial infarction or post
-
cardiotomy pericarditis and can help confirm the diagnosis. 
Table 10–19.
 
Definitions and diagnostic criteria for 
p
eric
arditis
Definition and Diagnosis
Acute
At least two of the following four listed findings:
1. Pericardial chest pain
2. Pericardial rub
3. New widespread ST-elevation or PR depression
4. Pericardial effusion (new or worsening)
Additional supportive findings:
1. Elevated inflammatory markers (CRP , ESR, WBC)
2. Evidence for pericardial inflammation (CT or MRI)
Incessant
Pericarditis lasting longer than 4–6 weeks but less 
than 3 months without remission
Recurrent
Recurrence after a documented first espisode and 
a symptom-free interval of 4–6 weeks or longer
Chronic
Pericarditis lasting longer than 3 months
CRP , C-reactive protein; CT, computed tomography; ESR, erythro
-
cyte sedimentation rate; MRI, magnetic resonance imaging; WBC, 
white blood count.
Modified, with permission, from Adler Y et al. 2015 ESC guidelines 
for the diagnosis and management of pericardial diseases: the Task 
Force for the Diagnosis and Management of Pericardial Diseases of 
the European Society of Cardiology (ESC) endorsed by: the 
European Association for Cardio-Thoracic Surgery (EACTS). Eur 
Heart J. 2015 Nov 7;36(42):2921–64. By permission of Oxford 
University Press and the European Society of Cardiology.
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Large pericardial effusions and accompanying pleural effu
-
sions are frequent. Myxedema pericardial effusions due to 
hypothyroidism usually are characterized by the presence of 
cholesterol crystals within the fluid.
The ECG usually shows generalized ST and T wave 
changes and may manifest a characteristic progression 
beginning with diffuse ST elevation, followed by a return to 
baseline and then to T-wave inversion. Atrial injury is often 
present and manifested by PR depression, especially in the 
limb leads. The chest radiograph is frequently normal but 
may show cardiac enlargement (if pericardial fluid is pres
-
ent), as well as signs of related pulmonary disease. Mass 
lesions and enlarged lymph nodes may suggest a neoplastic 
process. About 60% of patients have a pericardial effusion 
(usually mild) detectable by echocardiography. MRI and 
CT scan can visualize neighboring tumor in neoplastic 
pericarditis. A screening chest CT or MRI is often recom
-
mended to ensure there are no extracardiac diseases con
-
tiguous to the pericardium. A consensus statement from 
the American Society of Echocardiography proposes add
-
ing an elevated CRP and late gadolinium enhancement of 
the pericardium to confirmatory criteria for the diagnosis 
of pericarditis. There are data that the degree of quantita
-
tive delayed enhancement of the pericardium is associated 
with a higher rate of recurrent pericarditis. PET scanning 
can also be used to help define pericardial inflammation.
 
»
Treatment
For acute pericarditis, experts suggest a restriction in activity 
until symptom resolution. For athletes the duration of exer
-
cise restriction should be until resolution of symptoms and 
normalization of all laboratory tests (generally 3 months). 
The 2015 ESC guidelines recommend aspirin 750–1000 mg 
every 8 hours for 1–2 weeks with a taper by decreasing the 
dose 250–500 mg every 1–2 weeks or ibuprofen 600 mg 
dose by 200–400 mg every 1–2 weeks. Gastroprotection 
should be included. Studies support initial treatment of the 
acute episode with colchicine to prevent recurrences. Col
-
chicine should be added to the nonsteroidal anti-inflamma
-
tory medication at 0.5–0.6 mg once (for patients less than 
70 kg) or twice (for patients more than 70 kg) daily and 
continued for at least 3 months. Tapering of colchicine is not 
mandatory; however, in the last week of treatment, the dos
-
age can be reduced every other day for patients less than 
70 kg or once a day for those more than 70 kg. Aspirin and 
colchicine should be used instead of nonsteroidal anti-
inflammatory medications in postmyocardial infarction 
pericarditis (Dressler syndrome), since nonsteroidal anti-
inflammatory medications and corticosteroids may have 
an adverse effect on myocardial healing. Aspirin in doses 
of 750–1000 mg three times daily for 1–2 weeks plus 
3 months of colchicine is the recommended treatment for 
Dressler syndrome.
Colchicine should be used for at least 6 months as 
therapy in all refractory cases and in recurrent pericarditis. 
At times longer therapy is required. The CRP is used to 
assess the effectiveness of treatment, and once it is 
normalized, tapering is initiated. Indomethacin in doses of 
25–50 mg every 8 hours can also be considered in recur
-
rent pericarditis in place of ibuprofen. Systemic corticoste
-
roids can be added in patients with severe symptoms, in 
refractory cases, or in patients with immune-mediated 
etiologies, but such therapy may entail a higher risk of 
recurrence and may actually prolong the illness. Colchicine 
is recommended in addition to corticosteroids, again for at 
least 3 months, to help prevent recurrences. Prednisone in 
doses of 0.25–0.5 mg/kg/day orally is generally suggested 
with tapering over a 4–6 week period.
As a rule, symptoms subside in several days to weeks. The

As a rule, symptoms subside in several days to weeks. The 
major early complication is tamponade, which occurs in less 
than 5% of patients. There may be recurrences in the first few 
weeks or months. Rarely, when colchicine therapy alone fails 
or cannot be tolerated (usually do to gastrointestinal symp
-
toms), the pericarditis may require more significant immu
-
nosuppression, such as cyclophosphamide, azathioprine, 
intravenous human immunoglobulins, interleukin-1 recep
-
tor antagonists (anakinra), or methotrexate. If colchicine plus 
more significant immunosuppression fails, surgical pericar
-
dial stripping may be considered in recurrent cases even 
without clinical evidence for constrictive pericarditis.
Standard antituberculous drug therapy is usually success
-
ful for tuberculous pericarditis (see Chapter 9), but constric
-
tive pericarditis can occur. Uremic pericarditis usually resolves 
with the institution of—or with more aggressive—dialysis. 
Tamponade is fairly common, and partial pericardiectomy 
(pericardial window) may be necessary. Whereas anti-inflam
-
matory agents may relieve the pain and fever associated with 
uremic pericarditis, indomethacin and systemic corticoste
-
roids do not affect its natural history. The prognosis with 
neoplastic effusion is poor, with only a small minority surviv
-
ing 1 year. If it is compromising the clinical comfort of the 
patient, the effusion is initially drained percutaneously. 
Attempts at balloon pericardiotomy have been abandoned 
because outcomes were not more effective than simple drain
-
age. A pericardial window, either by a subxiphoid approach or 
via video-assisted thoracic surgery, allows for partial pericar
-
diectomy. Instillation of chemotherapeutic agents or tetracy
-
cline may be used to reduce the recurrence rate. Symptomatic 
therapy is the initial approach to radiation pericarditis, but 
recurrent effusions and constriction often require surgery.
 
»
Patients who do not respond initially to conservative man
-
agement, who have recurrences, or who appear to be devel
-
oping constrictive pericarditis should be referred to a 
cardiologist for further assessment.
Adler Y et al. 2015 ESC guidelines for the diagnosis and manage
-
ment of pericardial diseases: The Task Force for the Diagnosis 
and Management of Pericardial Diseases of the European 
Society of Cardiology (ESC) endorsed by: the European Asso
-
ciation for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 
2015 Nov 7;36(42):2921–64. [PMID: 26320112]
Cremer PC et al. Complicated pericarditis: understanding risk 
factors and pathophysiology to inform imaging and treatment. 
J Am Coll Cardiol. 2016 Nov 29;68(21):2311–28. [PMID: 
27884251]
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Doctor NS et al. Acute pericarditis. Prog Cardiovasc Dis. 2017 
Jan–Feb;59(4):349–59. [PMID: 27956197]
Imazio M et al. Evaluation and treatment of pericarditis. A sys
-
tematic review. JAMA. 2015 Oct 13;314(14):1498–506. [PMID: 
26461998]
Kumar A et al. Quantitative pericardial delayed hyperenhancement 
informs clinical course in recurrent pericarditis. JACC Cardio
-
vasc Imaging. 2017 Nov;10(11):1337–46. [PMID: 28330665]
PERICARDIAL EFFUSION & TAMPONADE
Pericardial Effusion
 
»
Clinical impact determined by the speed of 
accumulation.
 
»
May or may not cause pain.
Tamponade
 
»
Tachycardia with an elevated JVP and either hypo
-
tension or a paradoxical pulse.
 
»
Low voltage or electrical alternans on ECG.
 
»
Echocardiography is diagnostic.
Pericardial effusion can develop during any of the acute 
pericarditis processes. Because the pericardium covers the 
ascending aorta and arch, aortic dissection and/or rupture 
can lead to tamponade as well. The 
speed of accumulation
 
determines the physiologic importance of the effusion. 
Because of pericardial stretch, effusions larger than 1000 mL 
that develop slowly may produce no hemodynamic effects. 
Conversely, smaller effusions that appear rapidly can cause 
tamponade due to the curvilinear relationship between the 
volume of fluid and the intrapericardial pressure. Tampon
-
ade is characterized by elevated intrapericardial pressure 
(greater than 15 mm Hg), which restricts venous return 
and ventricular filling. As a result, the stroke volume and 
arterial pulse pressure fall, and the heart rate and venous 
pressure rise. Shock and death may result.
 
»
Pericardial effusions may be associated with pain if they occur 
as part of an acute inflammatory process or may be painless, 
as is often the case with neoplastic or uremic effusion. Dys
-
pnea and cough are common, especially with tamponade. 
Cardiac tamponade can be a life-threatening syndrome evi
-
denced by tachycardia, hypotension, pulsus paradoxicus, 
raised JVP , muffled heart sounds, and decreased ECG voltage 
or electrical alternans. Other symptoms may result from the 
primary disease. The prognosis is a function of the cause. 
Large idiopathic chronic effusions (over 3 months) have a 
30–35% risk of progression to cardiac tamponade.
A pericardial friction rub may be present even with 
large effusions. In cardiac tamponade, tachycardia, tachy
-
pnea, a narrow pulse pressure, and a relatively preserved 
systolic pressure are characteristic. 
 is 
defined as a decline of greater than 10 mm Hg in systolic 
pressure during inspiration. Since the RV and LV share the 
same pericardium, when there is significant pericardial 
effusion, as the RV enlarges with inspiratory filling, septal 
motion toward the LV chamber reduces LV filling and 
results in an accentuated drop in the stroke volume and 
systemic BP with inspiration (the paradoxical pulse). Cen
-
tral venous pressure is elevated and, since the intrapericar
-
dial, and thus intracardiac, pressures are high even at the 
initiation of diastole, there is no evident 
y
 descent in the 
RA, RV , or LV hemodynamic tracings because the pericar
-
dial pressure prevents early ventricular filling. This differs 
from constriction where most of the initial filling of the RV 
and LV occurs during early diastole (rapid 
y
 descent), and 
it is only in mid to late diastole that the ventricles can no 
longer fill. In tamponade, ventricular filling is inhibited 
throughout diastole. Edema or ascites are rarely present in 
tamponade; these signs favor a more chronic process.
Laboratory tests tend to reflect the underlying processes (see 
causes of pericarditis under General Considerations above).
Chest radiograph can suggest chronic effusion by an 
enlarged cardiac silhouette with a globular configuration,

enlarged cardiac silhouette with a globular configuration, 
but may appear normal in acute situations. The ECG often 
reveals nonspecific T wave changes and reduced QRS volt
-
age. Electrical alternans is present only occasionally but is 
pathognomonic and is believed to be due to the heart swing
-
ing within the large effusion. Echocardiography is the pri
-
mary method for demonstrating pericardial effusion and is 
quite sensitive. If tamponade is present, the high intraperi
-
cardial pressure may collapse lower pressure cardiac struc
-
tures, such as the RA and RV . Cardiac CT and MRI also 
demonstrate pericardial fluid, pericardial thickening, and 
any associated contiguous lesions within the chest. Diagnos
-
tic pericardiocentesis or biopsy may be indicated for micro
-
biologic and cytologic studies; a pericardial biopsy may be 
performed relatively simply through a small subxiphoid 
incision or by use of a video-assisted thoracoscopic surgical 
procedure. Unfortunately, the quality of the pericardial fluid 
itself rarely leads to a diagnosis, and any type of fluid (serous, 
serosanguinous, bloody, etc) can be seen in most diseases. 
Pericardial fluid analysis is most useful in excluding a bacte
-
rial cause and is occasionally helpful in malignancies. Effu
-
sions due to hypothyroidism or lymphatic obstruction may 
contain cholesterol or be chylous in nature, respectively.
 
»
Treatment
Small effusions can be followed clinically by careful observa
-
tions of the JVP and by testing for a change in the paradoxi
-
cal pulse. The most common cause of a paradoxical pulse is 
severe pulmonary disease, especially asthma, where marked 
changes in intrapleural pressures occur with inspiration and 
expiration. Serial echocardiograms are indicated if no inter
-
vention is immediately contemplated. Vasodilators and 
diuretics should be avoided. When tamponade is present, 
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urgent pericardiocentesis or cardiac surgery is required. 
Because the pressure–volume relationship in the pericardial 
fluid is curvilinear and upsloping, removal of even a small 
amount of fluid often produces a dramatic fall in the intra
-
pericardial pressure and immediate hemodynamic benefit; 
but complete drainage with a catheter is preferable. Contin
-
ued or repeat drainage may be indicated, especially in malig
-
nant effusions. Pericardial windows via video-assisted 
thorascopy have been particularly effective in preventing 
recurrences and is more effective than subxiphoid surgical 
windows or percutaneous balloon pericardiotomy. Effusions 
related to recurrent inflammatory pericarditis can be treated 
as noted above (see Acute Inflammatory Pericarditis). The 
presence of pericardial fluid in patients with pulmonary 
hypertension is a poor prognostic sign.
 
»
•	
Any unexplained pericardial effusion should be referred 
to a cardiologist.
•	
Trivial pericardial effusions are common, especially in 
heart failure, and need not be referred unless symptoms 
of pericarditis are evident.
•	
Hypotension or a paradoxical pulse suggesting the peri
-
cardial effusion is hemodynamically compromising the 
patient is a medical emergency and requires immediate 
drainage.
•	
Any echocardiographic signs of tamponade.
-
ment of pericardial diseases: the Task Force for the Diagnosis 
-
Azarbal A et al. Pericardial effusion. Cardiol Clin. 2017 Nov;
 
35(4):515–24. [PMID: 29025543]
factors and pathophysiology to inform imaging and treat
-
ment. J Am Coll Cardiol. 2016 Nov 29;68(21):2311–28. 
[PMID: 27884251]]
Langdon SE et al. Contemporary outcomes after pericardial 
window surgery: impact of operative technique. J Cardiotho
-
rac Surg. 2016 Apr 26;11(1):73. [PMID: 27118051]
CONSTRICTIVE PERICARDITIS
 
»
Clinical evidence of right heart failure.
 
»
No fall or an elevation of the JVP with inspiration 
(Kussmaul sign).
 
»
Echocardiographic evidence for septal bounce and 
reduced mitral inflow velocities with inspiration.
 
»
At times may be difficult to differentiate from 
restrictive cardiomyopathy.
 
»
Cardiac catheterization may be necessary when clini
-
cal and echocardiographic features are equivocal.
 
»
Pericardial inflammation can lead to a thickened, fibrotic, 
adherent pericardium that restricts diastolic filling and 
produces chronically elevated venous pressures. In the 
past, tuberculosis was the most common cause of constric
-
tive pericarditis, but while it remains so in underdeveloped 
countries, it is rare now in the rest of the world. Constric
-
tive pericarditis rarely occurs following recurrent pericar
-
ditis. The risk of constrictive pericarditis due to viral or 
idiopathic pericarditis is less than 1%. Its occurrence 
increases following immune-mediated or neoplastic peri
-
carditis (2–5%) and is highest after purulent bacterial 
pericarditis (20–30%). Other causes include post cardiac 
surgery, radiation therapy, and connective tissue disorders. 
A small number of cases are drug-induced or secondary to 
trauma, asbestosis, sarcoidosis, or uremia. At times, both 
pericardial tamponade and constrictive pericarditis may 
coexist, a condition referred to as 
effusive-constrictive 
. The only definitive way to diagnose this con
-
dition is to reveal the underlying constrictive physiology 
once the pericardial fluid is drained. The differentiation of 
constrictive pericarditis from a restrictive cardiomyopathy 
may require cardiac catheterization and the utilization of

may require cardiac catheterization and the utilization of 
all available noninvasive imaging methods.
 
»
The principal symptoms are slowly progressive dyspnea, 
fatigue, and weakness. Chronic edema, hepatic conges
-
tion, and ascites are usually present. Ascites often seems 
out of proportion to the degree of peripheral edema. The 
examination reveals these signs and a characteristically 
elevated jugular venous pressure with a rapid 
y
 descent. 
This can be detected at bedside by careful observation of 
the jugular pulse and noting an apparent increased pulse 
wave at the end of ventricular systole (due to the relative 
accentuation of the 
v
 wave by the rapid 
y
 descent). 
—a failure of the JVP to fall with inspiration—
is also a frequent finding. The apex may actually retract 
with systole and a pericardial “knock” may be heard in 
early diastole. Pulsus paradoxus is unusual. Atrial fibrilla
-
tion is common.
At times constrictive pericarditis is extremely difficult to 
differentiate from restrictive cardiomyopathy and the two 
may coexist. When unclear, the use of both noninvasive 
testing and cardiac catheterization is required to sort out 
the difference.
1. Radiographic findings—
The chest radiograph may 
show normal heart size or cardiomegaly. Pericardial calci
-
fication is best seen on the lateral view and is uncommon. 
It rarely involves the LV apex, and finding of calcification 
at the LV apex is more consistent with LV aneurysm.
2. Echocardiography—
Echocardiography rarely demon
-
strates a thickened pericardium. A septal “bounce” reflect
-
ing the rapid early filling is common, though. RV/LV 
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interaction may be demonstrated by an inspiratory reduc
-
tion in the mitral inflow Doppler pattern of greater than 
25%, much as in tamponade. Usually the initial mitral 
inflow into the LV is very rapid and this can be demon
-
strated as well by the Doppler inflow (E wave) pattern. 
Other echocardiographic features can also help reveal 
constrictive physiology.
3. Cardiac CT and MRI—
These imaging tests are only occa
-
sionally helpful. Pericardial thickening of more than 4 mm 
must be present to establish the diagnosis, but no pericar
-
dial thickening is demonstrable in 20–25% of patients with 
constrictive pericarditis. Some MRI techniques demon
-
strate the septal bounce and can provide further evidence 
for ventricular interaction.
4. Cardiac catheterization—
This procedure is often con
-
firmatory or can be diagnostic in difficult cases where the 
echocardiographic features are unclear or mixed. As a 
generality, the pulmonary pressure is low in constriction 
(as opposed to restrictive cardiomyopathy). In constrictive 
pericarditis, because of the need to demonstrate RV/LV 
interaction, cardiac catheterization should include simulta
-
neous measurement of both the LV and RV pressure trac
-
ings with inspiration and expiration. This interaction can 
be demonstrated by cardiac MRI. Hemodynamically, 
patients with constriction have equalization of end-
diastolic pressures throughout their cardiac chambers, 
there is rapid early filling then an abrupt increase in dia
-
stolic pressure (“square-root” sign), the RV end-diastolic 
pressure is more than one-third the systolic pressure, 
simultaneous measurements of RV and LV systolic pres
-
sure reveal a discordance with inspiration (the RV rises as 
the LV falls), and there is usually a Kussmaul sign (failure 
of the RA pressure to fall with inspiration. In restrictive 
cardiomyopathy, there is concordance of RV and LV sys
-
tolic pressures with inspiration.
 
»
Treatment
Therapy should be aimed at the specific etiology initially. If 
there is laboratory evidence of ongoing inflammation, then 
anti-inflammatory medications may have a role. Once the 
hemodynamics are evident, the mainstay of treatment is 
diuresis. As in other disorders of right heart failure, the 
diuresis should be aggressive, using loop diuretics (oral 
torsemide or bumetanide if bowel edema is suspected or 
intravenous furosemide), thiazides, and aldosterone antag
-
onists (especially in the presence of ascites and liver con
-
gestion). Surgical pericardiectomy should be recommended 
when diuretics are unable to control symptoms. Pericardi
-
ectomy removes only the pericardium between the phrenic 
nerve pathways, however, and most patients still require 
diuretics after the procedure, though symptoms are usually 
dramatically improved. Morbidity and mortality after peri
-
cardiectomy are high (up to 15%) and are greatest in those 
with the most disability prior to the procedure. Poor prog
-
nostic predictors include prior radiation, renal dysfunc
-
tion, higher pulmonary systolic pressures, abnormal LV 
systolic function, a lower serum sodium level, liver dys
-
function, and older age. Pericardial calcium has no impact 
on survival.
 
»
If the diagnosis of constrictive pericarditis is unclear or the 
symptoms of fluid retention resist medical therapy, then 
referral to a cardiologist is warranted to both establish the 
diagnosis and recommend therapy.
-
-
-

-
[PMID: 27884251]
Geske JB et al. Differentiation of constriction and restriction: 
complex cardiovascular hemodynamics. J Am Coll Cardiol. 
2016 Nov 29;68(21):2329–47. [PMID: 27884252]
Syed FF et al. Constrictive pericarditis—a curable diastolic heart 
failure. Nat Rev Cardiol. 2014 Sep;11(9):530–44. [PMID: 
25072910]
 
º
p
ULMONARY HY
p
ERTENSION
 
»
Mean PA pressure of 25 mm Hg or more.
 
»
Dyspnea and often cyanosis.
 
»
Enlarged pulmonary arteries on chest radiograph.
 
»
Elevated JVP and RV heave.
 
»
Echocardiography is often diagnostic.
 
»
The normal pulmonary bed offers about one-tenth as 
much resistance to blood flow as the systemic arterial sys
-
tem. Experts recommend that a diagnosis of idiopathic 
pulmonary hypertension should be firmly based on a mean 
PA pressure of 
25 mm Hg or more
 in association with a 
PCWP of less than 16 mm Hg at rest.
The clinical classification of pulmonary hypertension 
by the Fourth World Symposium on Pulmonary Hyperten
-
sion is outlined in Table 10–20. It is a complex disorder due 
to multiple causes.
Group 1
 includes pulmonary arterial hypertension 
(PAH) related to an underlying pulmonary vasculopathy. It 
includes the former “primary” pulmonary hypertension 
under the term “idiopathic pulmonary hypertension” and 
is defined as pulmonary hypertension and elevated PVR in 
the absence of other disease of the lungs or heart. Its cause 
is unknown. About 6–10% have heritable PAH. Drug and 
toxic pulmonary hypertension have been described as 
associated with the use of anorexigenic agents that increase 
serotonin release and block its uptake. These include ami
-
norex fumarate, fenfluramine, and dexfenfluramine. In 
some cases, there is epidemiologic linkage to ingestion of 
CMDT19_Ch10_p0334-p0450.indd   442

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rapeseed oil or L-tryptophan and use of recreational drugs, 
such as amphetamines. Pulmonary hypertension associ
-
ated with connective tissue disease includes cases associ
-
ated with scleroderma—up to 8–12% of patients with 
scleroderma may be affected. Pulmonary hypertension has 
also been associated with HIV infection, portal hyperten
-
sion, congenital heart disease (Eisenmenger syndrome), 
schistosomiasis, and chronic hemolytic anemia (eg, sickle 
cell anemia). In rare instances, obstruction of the pulmo
-
nary venous circulation may occur (pulmonary veno-
occlusive disease and capillary hemangiomatosis).
Group 2
 includes all cases related to left heart disease. 
Group 3
 includes cases due to parenchymal lung disease, 
impaired control of breathing, or living at high altitude. This 
group encompasses those with idiopathic pulmonary fibro
-
sis and COPD. 
Group 4
 represents patients with chronic 
thromboemboli. 
Group 5
 includes multifactorial cases.
 
»
Common to all is exertional dyspnea, chest pain, fatigue, 
and lightheadedness as early symptoms; later symptoms 
include syncope, abdominal distention, ascites, and periph
-
eral edema as RV function worsens. Chronic lung disease, 
especially sleep apnea, often is overlooked as a cause for 
pulmonary hypertension as is chronic thromboembolic 
disease. Patients with idiopathic pulmonary hypertension 
are characteristically young women who have evidence of 
right heart failure that is usually progressive, leading to 
death in 2–8 years without therapy. This is a decidedly dif
-
ferent prognosis than patients with Eisenmenger physiol
-
ogy due to a left-to-right shunt; 40% of patients with 
Eisenmenger physiology are alive 25 years after the diagno
-
sis has been made. Patients have manifestations of low 
cardiac output, with weakness and fatigue, as well as edema 
and ascites as right heart failure advances. Peripheral cya
-
nosis is present, and syncope on effort may occur.
The European Society of Cardiology and European Respira
-
tory Society updated guidelines for the diagnosis and treat
-
ment of pulmonary hypertension in 2015 (published in 2016). 
The reader is referred to this document for further details, 
diagnostic and treatment algorithms, but the diagnostic steps 
include the typical clinical picture and the echocardiographic 
probability of PAH. All patients with a high risk for PAH 
should undergo confirmatory right heart catheterization.
The laboratory evaluation of idiopathic pulmonary 
hypertension must exclude a secondary cause. A hyperco
-
agulable state should be sought by measuring protein C 
and S levels, the presence of a lupus anticoagulant, the level 
of factor V Leiden, prothrombin gene mutations, and 
D-dimer. Chronic pulmonary emboli must be excluded 
(usually by ventilation-perfusion lung scan or contrast 
spiral CT); the ventilation-perfusion scan is the more sen
-
sitive test but not specific. If it is normal, then chronic 
thromboembolic pulmonary hypertension is very unlikely. 
The chest radiograph helps exclude a primary pulmonary 
etiology—evidence for patchy pulmonary edema may raise 
the suspicion of pulmonary veno-occlusive disease due to 
localized obstruction in pulmonary venous drainage. A 
sleep study may be warranted if sleep apnea is suspected. 
The ECG is generally consistent with RVH and RA 
enlargement. Echocardiography with Doppler helps 
exclude an intracardiac shunt and usually demonstrates an 
enlarged RV and RA—at times they may be huge and 
hypocontractile. Severe pulmonic or tricuspid valve regur
-
gitation may be present. Interventricular septal flattening 
seen on the echocardiogram is consistent with pulmonary 
hypertension. Doppler interrogation of the tricuspid regur
-
gitation jet provides an estimate of RV systolic pressure. 
Pulmonary function tests help exclude other disorders,

-
Pulmonary function tests help exclude other disorders, 
though primary pulmonary hypertension may present 
Table 10–20.
 
Clinical classification of pulmonary 
I. 
 p
ulmonar
y arterial hypertension from pulmonary 
vasculopathy
Idiopathic pulmonary arterial hypertension
Heritable gene mutations
 
BMPR2
 (bone morphogenic protein receptor type 2)
 
ALK1
 (activin A receptor type II-like kinase-1), 
endoglin
 (with or
 
without her
editary hemorrhagic telangiectasia)
Unknown
Drug and toxin-induced
Associated with
 
C
onnective tissue diseases
 
HIV inf
ection
 
P
ortal hypertension
 
C
ongenital heart disease
 
Chr
onic hemolytic anemia
 
P
ersistent pulmonary hypertension of the newborn
Pulmonary veno-occlusive disease and/or pulmonary capillary 
hemangiomatosis
II. 
p
ulmonar
y hypertension due to left heart disease
Systolic dysfunction
Diastolic dysfunction
III. 
 p
ulmonar
y hypertension due to lung disease and/or hypoxia
Interstitial lung disease
Other pulmonary disease with mixed restrictive and obstructive 
pattern
IV. Chronic thromboembolic pulmonary hypertension
V.  
 p
ulmonar
y hypertension with unclear multifactorial 
mechanisms
Hematologic disorders: myeloproliferative disorders, splenectomy
Systemic disorders: sarcoidosis, pulmonary Langerhans cell histio
-
cytosis: lymphangioleimyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, 
thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal 
failure on dialysis
Data from Simonneau G et al. Updated clinical classification of pul
-
monary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):
 
S43–54.
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with only a reduced carbon monoxide diffusing capacity of 
the lung (DL
CO
) or severe desaturation (particularly if a 
PFO has been stretched open and a right-to-left shunt is 
present). A declining DL
CO
 in a scleroderma patient may 
precede the development of pulmonary hypertension. 
Chest CT demonstrates enlarged pulmonary arteries and 
excludes other causes (such as emphysema or interstitial 
lung disease). Pulmonary angiography (or magnetic reso
-
nance angiography or CT angiography) reveals loss of the 
smaller acinar pulmonary vessels and tapering of the larger 
ones. Catheterization allows measurement of pulmonary 
pressures and testing for vasoreactivity using a variety of 
agents, but nitric oxide is the preferred testing agent due to 
its ease of use and short half-life. A positive response is 
defined as one that decreases the pulmonary mean pres
-
sure by greater than 10 mm Hg, with the final mean PA 
pressure less than 40 mm Hg. Abdominal ultrasound is 
recommended to exclude portal hypertension. A lung 
biopsy is no longer suggested as relevant for the diagnosis.
 
»
The treatment of PAH continues to evolve and depends on 
the etiology. For Group I patients with a normal PCWP , 
treatment is related to the response to nitric oxide chal
-
lenge with those responsive being initially treated with 
calcium channel blockers. Most patients, unfortunately, do 
not respond to the acute vasoreactivity testing. Specific 
PAH therapy is therefore recommended in this situation. 
This begins with monotherapy but expands to the use of 
sequential medication therapy when pulmonary pressures 
are not improved. In critically ill hypotensive patients ino
-
tropic support may be required and eventually lung trans
-
plantation considered. Balloon atrial septostomy is 
considered a IIb recommendation (on the notion that 
increased right to left shunting will improve cardiac out
-
put), but it is very rarely utilized.
Medication monotherapy varies in effectiveness 
depending on the etiologic classification. Only those in 
class 1 who respond to nitric oxide should get calcium 
channel blockers. The current alternative medication ther
-
apies include endothelin-receptor blockers (ambrisentan, 
bosentan, macitentan), phosphodiesterase type-5 inhibi
-
tors (sildenafil, tadalafil, and vardenafil), a guanylate 
cyclase stimulator (riociquat), prostanoids (epoprostenol, 
iloprost, teprostinil, and beraprost) and an IP-receptor 
agonist (selexipag). Various medication combinations have 
been approved and, when ineffective, sequential medica
-
tion therapies may be used. Anticoagulation is often rec
-
ommended and is required lifelong in chronic 
thromboembolic pulmonary hypertension; it should not be 
used if portal hypertension is present. Many medications 
interfere with HIV treatment and this needs to be assessed 
if relevant. Due to inherent lung disease or left heart dis
-
ease, there are no therapies that are specific to PAH.
Counseling and patient education are also important. 
Aerobic exercise is recommended but no heavy physical 
exertion or isometric exercise. Routine immunizations are 
advised. Pregancy should be strongly discouraged and pre
-
ventive measures taken to ensure it does not occur. Mater
-
nal mortality in severe PAH may be up to 50%.
Warfarin anticoagulation is recommended in all 
patients with idiopathic PAH and no contraindication. 
Diuretics are useful for the management of right-sided 
heart failure; clinical experience suggests loop diuretics 
(torsemide or butmetanide, which are absorbed if bowel 
edema is present), plus spironolactone are preferable. Oxy
-
gen should be used to maintain oxygen saturation greater 
than 90%. Acute vasodilator testing (generally with nitric 
oxide) should be performed in all patients with idiopathic 
PAH who may be potential candidates for long-term ther
-
apy with calcium channel blockers. Patients with PAH

-
apy with calcium channel blockers. Patients with PAH 
caused by conditions other than idiopathic PAH respond 
poorly to oral calcium channel blockers, and there is little 
value of acute vasodilator testing in these patients.
 
»
All patients with suspected pulmonary hypertension 
should be referred to either a cardiologist or pulmonologist 
who specializes in pulmonary hypertension.
Galiè N et al. 2015 ESC/ERS guidelines for the diagnosis and 
treatment of pulmonary hypertension: the Joint Task Force 
-
pean Respiratory Society (ERS). Eur Heart J. 2016 Jan 1;
 
37(1):67–119. [PMID: 26320113]
Liu HL et al. Efficacy and safety of pulmonary arterial hyperten
-
sion-specific therapy in pulmonary arterial hypertension: a 
meta-analysis of randomized controlled trials. Chest. 2016 Aug;
 
150(2):353–66. [PMID: 27048870]
 
º
NEO
p
LASTIC DISEASES OF THE HEART
PRIMARY CARDIAC TUMORS
Primary cardiac tumors are rare and constitute only a small 
fraction of all tumors that involve the heart or pericardium. 
The most common primary tumor is 
atrial myxoma
; it 
comprises about 50% of all tumors in adult case series. It is 
generally attached to the atrial septum and is more likely 
grow on the LA side of the septum rather than the RA. 
Patients with myxoma can rarely present with the charac
-
teristics of a systemic illness, with obstruction of blood 
flow at the mitral valve level or with signs of peripheral 
embolization. The syndrome includes fever, malaise, 
weight loss, leukocytosis, elevated sedimentation rate, and 
emboli (peripheral or pulmonary, depending on the loca
-
tion of the tumor). This is sometimes confused with infec
-
tive endocarditis, lymphoma, other cancers, or autoimmune 
diseases. In other cases, the tumor may grow to consider
-
able size and produce symptoms by simply obstructing 
mitral inflow. Episodic pulmonary edema (classically 
occurring when an upright posture is assumed) and signs 
of low output may result. Physical examination may reveal 
a diastolic sound related to motion of the tumor (“tumor 
plop”) or a diastolic murmur similar to that of mitral steno
-
sis. Right-sided myxomas may cause symptoms of right-
sided failure. Familial myxomas occur as part of the 
Carney complex, which consists of myxomas, pigmented 
skin lesions, and endocrine neoplasia.
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The diagnosis of atrial myxoma is established by echo
-
cardiography or by pathologic study of embolic material. 
Cardiac MRI is useful as an adjunct. Contrast angiography 
is frequently unnecessary, although it may demonstrate a 
“tumor blush” when the mass is vascular. Surgical excision 
is usually curative, though recurrences do occur and serial 
echocardiographic follow-up is recommended.
The second most common primary cardiac tumors are 
valvular papillary fibroelastomas
 and 
atrial septal lipo
-
mas.
 These tend to be benign and usually require no ther
-
apy, although large papillary fibroelastomas may embolize or 
cause valvular dysfunction and should be removed if large 
and mobile. Other primary cardiac tumors include rhabdo
-
myomas (that often appear multiple in both the RV and LV), 
fibrous histiocytomas, hemangiomas, and a variety of 
unusual sarcomas. Some sarcomas may be of considerable 
size before discovery. Primary pericardial tumors, such as 
mesotheliomas related to asbestos exposure, may also occur. 
The diagnosis may be supported by an abnormal cardiac 
contour on radiograph. Echocardiography is usually helpful 
but may miss tumors infiltrating the ventricular wall. Car
-
diac MRI is emerging as the diagnostic procedure of choice 
along with gated CT imaging for all cardiac tumors.
SECONDARY CARDIAC TUMORS
Metastases from malignant tumors can also affect the 
heart. Most often this occurs in malignant melanoma, but 
other tumors that are known to metastasize to the heart 
include bronchogenic carcinoma; carcinoma of the breast; 
lymphoma; renal cell carcinoma; sarcomas; and, in patients 
with AIDS, Kaposi sarcoma. These are often clinically 
silent but may lead to pericardial tamponade, arrhythmias 
and conduction disturbances, heart failure, and peripheral 
emboli. The ECG may reveal regional Q waves. The diag
-
nosis is often made by echocardiography, but cardiac MRI 
and CT scanning can often better delineate the extent of 
involvement. Metastatic tumors, especially lung or breast, 
may invade the pericardium and result in very large peri
-
cardial effusions as they result in slow accumulation of 
fluid. The prognosis is poor for all secondary cardiac 
tumors as treatment is generally palliative. On occasion, 
surgical resection for debulking or removal and chemo
-
therapy may be effective in relieving symptoms.
Many primary tumors may be resectable. Atrial myxo
-
mas should be removed surgically due to the high inci
-
dence of embolization from these friable tumors. 
Recurrences require lifelong monitoring with echocardiog
-
raphy. Papillary fibroelastomas are usually benign but they 
should be removed if they appear mobile and are larger 
than 10 mm in size or if there is evidence of embolization 
at the time of discovery. Large pericardial effusions from 
metastatic tumors may be drained for comfort, but the 
fluid invariably recurs. Rhabdomyomas may be surgically 
cured if the tumor is accessible and can be removed while 
still leaving enough functioning myocardium intact.
 
»
All patients with suspected cardiac tumors should be 
referred to a cardiologist or cardiac surgeon for evaluation 
and possible therapy.
Wang Y et al. Surgical treatment of primary cardiac valve tumor: 
early and late results in eight patients. J Cardiothorac Surg. 
2016 Feb 19;11:31. [PMID: 26891966]
 
º
TRAUMATIC HEART DISEASE
Trauma is the leading cause of death in patients aged 
1–44 years; cardiac and vascular trauma is second only to 
neurologic injury as the reason for these deaths. Penetrating 
wounds to the heart are often lethal unless surgically 
repaired. In a 20-year review of penetrating trauma at a 
single institution, it was found that gunshot wounds were 
fatal 13 times more often than stab wounds and that factors 
such as hypotension, Glasgow Coma Score less than 8, 
Revised Trauma Score less than 7.84, associated injuries and

Revised Trauma Score less than 7.84, associated injuries and 
the more severe the injuries (Injury Severity Score greater 
than 25) all added to the mortality and morbidity risk.
Blunt trauma is a more frequent cause of cardiac inju
-
ries. This type of injury is common in motor vehicle acci
-
dents and may occur with any form of chest trauma, 
including CPR efforts. The most common injuries are 
myocardial contusions or hematomas. Other forms of non
-
ischemic cardiac injury include metabolic injury due to 
burns, electrical current, or sepsis. These may be asymp
-
tomatic (particularly in the setting of more severe injuries) 
or may present with chest pain of a nonspecific nature or, 
not uncommonly, with a pericardial component. Elevations 
of cardiac enzymes are frequent but the levels do not cor
-
relate with prognosis. There are some data that the presence 
of certain other cardiac biomarkers, such as NT-proBNP , 
correlate better with significant myocardial injury. Echocar
-
diography may reveal an akinetic segment or pericardial 
effusion. Cardiac MRI may also suggest acute injury. Coro
-
nary CT angiography or angiography can reveal a coronary 
dissection or acute occlusion if that is a concern. Pericardio
-
centesis is warranted if tamponade is evident. As noted 
above, tako-tsubo transient segmental myocardial dysfunc
-
tion can occur due to the accompanying stress.
Severe trauma may also cause myocardial or valvular 
rupture. Cardiac rupture can involve any chamber, but sur
-
vival is most likely if injury is to one of the atria or the RV . 
Hemopericardium or pericardial tamponade is the usual 
clinical presentation, and surgery is almost always necessary. 
Mitral and aortic valve rupture may occur during severe 
blunt trauma—the former presumably if the impact occurs 
during systole and the latter if during diastole. Patients reach 
the hospital in shock or severe heart failure. Immediate sur
-
gical repair is essential. The same types of injuries may result 
in transection of the aorta, either at the level of the arch or 
distal to the takeoff of the left subclavian artery at the lig
-
mentum arteriosum. Transthoracic echocardiography and 
TEE are the most helpful and immediately available diagnos
-
tic techniques. CT and MRI may also be required to better 
define the injury before surgical intervention.
Blunt trauma may also result in damage to the coronary 
arteries. Acute or subacute coronary thrombosis is the 
most common presentation. The clinical syndrome is one 
of acute myocardial infarction with attendant ECG, enzy
-
matic, and contractile abnormalities. Emergent revascular
-
ization is sometimes feasible, either by the percutaneous 
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route or by coronary artery bypass surgery. LV aneurysms 
are common outcomes of traumatic coronary occlusions, 
likely due to sudden occlusion with no collateral vascular 
support. Coronary artery dissection or rupture may also 
occur in the setting of blunt cardiac trauma.
As expected, patients with severe preexisting condi
-
tions fare the least well after cardiac trauma. Data from 
ReCONECT, a trauma consortium, reveal that mortality is 
linked to volume of cases seen at various centers, preexist
-
ing coronary disease or heart failure, intubation, age, and a 
severity scoring index.
Bellister SA et al. Blunt and penetrating cardiac trauma. Surg 
Clin North Am. 2017 Oct;97(5):1065–76. [PMID: 28958358]
Gosavi S et al. Cardiac trauma. Angiology. 2016;67(10):896–901. 
[PMID: 26802100]
Soto JR et al. Penetrating cardiac injuries at a Level II trauma 
center: a 15-year review. Am Surg. 2015 Mar;81(3):324–5. 
[PMID: 25760212]
 
º
HEART DISEASE & 
p
REGNANCY
General principles to discuss with the patient include pre
-
conceptual counseling, pregnancy risk assessment, genetic 
risks, environmental risks, and pregnancy management. 
For some patients, it may also include a discussion regard
-
ing contraception, termination of a pregnancy, and a con
-
versation about not only the delivery but what will happen 
post-pregnancy (including issues such as an eventual need 
for heart surgery or transplantation).
The Cardiac Disease in Pregnancy Investigation 
(CARPREG) scoring system for risk from cardiac events for 
women with heart disease noted four major risk factors: (1) 
NYHA FC III or IV heart failure, (2) prior cardiac events, 
(3) mitral or aortic obstruction, and (4) LVEF less than 
40%. One point is assigned to each. Patients with no points 
had a 5% risk, those with 1 point had a complication rate of 
27%, while for those with 2 or more points, the risk was 
74%. Other reviews have suggested that the major risk for 
adverse outcomes or death to either the mother or fetus 
include pulmonary hypertension (with pulmonary pressure 
greater than three-quarters of systemic pressure), maternal 
cyanosis, systemic ventricular dysfunction, poor maternal 
functional class, severe left-sided valvular obstruction, aor
-
tic coarctation, significantly dilated aortic root, significant 
unrepaired heart defects, and warfarin therapy in patients 
with mechanical valves. In 2011, the World Health Organi
-
zation outlined guidelines for the management of preg
-
nancy in patients with congenital heart disease. This 
guideline also outlines risks to the fetus. Table 10–21 sum
-
maries the observations and recommendations. Medication 
usage during pregnancy is always a difficult decision, since 
most have not been studied. ACE inhibitors and amioda
-
rone are contraindicated. Beta-blockers (including labet
-
alol, metoprolol, and sotalol), digoxin, and calcium channel 
blockers are generally well tolerated (especially nifedipine, 
amlodipine, or verapamil, although there is controversy 
with diltiazem). There are concerns about the use of ateno
-
lol and premature birth, and it should not be used. Labetalol 
has been found to be particularly useful for treating 
hypertension as has methyldopa. Diuretics can generally be 
given safely. Pregnancy is a hypercoagulant state; the use of 
warfarin is discussed above under valvular disease, but fun
-
damentally the risk is dose related (not INR related) and can 
be used during the first trimester if the dose is 5 mg or less. 
For many patients, the most common potential complica
-
tion is an atrial arrhythmia or systemic hypertension 
(systemic blood pressure greater than 140/90 mm Hg). 
Patients should be hospitalized if blood pressure exceeds 
170/110 mm Hg.
Elkayam U et al. High-risk cardiac disease in pregnancy: part I. 
J Am Coll Cardiol. 2016 Jul 26;68(4):396–410. [PMID: 
27443437]
Elkayam U et al. High-risk cardiac disease in pregnancy: part II.

27443437]
Elkayam U et al. High-risk cardiac disease in pregnancy: part II. 
J Am Coll Cardiol. 2016 Aug 2;68(5):502–16. [PMID: 
27443948]
Regitz-Zagrosek V et al. Management of cardiovascular diseases 
during pregnancy. Curr Probl Cardiol. 2014 Apr–May;39
 
(4–5):85–151. [PMID: 24794710]
CARDIOVASCULAR COMPLICATIONS OF 
PREGNANCY
Pregnancy-related hypertension (eclampsia and pre
-
eclampsia) is discussed in Chapter 19.
1. Cardiomyopathy of 
p
r
egnancy (
p
eripar
tum 
Cardiomyopathy)
In approximately 1 in 3000 to 4000 live births, dilated cardio
-
myopathy develops in the mother in the final month of preg
-
nancy or within 6 months after delivery. Risk factors include 
preeclampsia, twin pregnancies, and African ethnicity.
The course of the disease is variable; most cases 
improve or resolve completely over several months, but 
others progress to refractory heart failure. About 60% of 
patients make a complete recovery. Serum BNP levels are 
routinely elevated in pregnancy, but serial values may be 
useful in predicting who may be at increased risk for a 
worse outcome. Beta-blockers have been administered 
judiciously to these patients, with at least anecdotal suc
-
cess. Diuretics, hydralazine, and nitrates help treat the 
heart failure with minimal risk to the fetus. Sotalol is 
acceptable for ventricular or atrial arrhythmias if other 
beta-blockers are ineffective. Some experts advocate anti
-
coagulation because of an increased risk of thrombotic 
events, and both warfarin and heparin have their propo
-
nents. In severe cases, transient use of extracorporeal oxy
-
genation (ECMO) has been lifesaving. Recurrence in 
subsequent pregnancies is common, particularly if cardiac 
function has not completely recovered, and subsequent 
pregnancies are to be discouraged if the EF remains less 
than 55%. The risk of recurrent heart failure in a subse
-
quent pregnancy has been estimated to be about 1 in 5 
(21%). Delivery of the baby is important, though the peak 
incidence of the problem is in the first week after delivery 
and a few cases appear up to 5 weeks after delivery.
Arany Z et al. Peripartum cardiomyopathy. Circulation. 2016 
Apr 5;133(14):1397–409. [PMID: 27045128]
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2. Coronary Artery & Aortic Vascular 
Abnormalities During 
p
r
egnancy
There have been a number of reports of myocardial 
infarction during pregnancy. It is known that pregnancy 
predisposes to dissection of the aorta and other arteries, 
perhaps because of the accompanying connective tissue 
changes. The risk may be particularly high in patients 
with Marfan, Ehlers-Danlos, or Loeys-Dietz syndromes. 
In a review from 2015, the risk is highest in the 
third trimester, and coronary dissection, thrombosis, and 
atherosclerosis had about equal prevalence. The very 
highest cause was dissection overall, and it had a peak 
incidence in the early postpartum period. Paradoxical 
emboli through a PFO have been implicated in a few 
instances. Clinical management is essentially similar to 
that of other patients with acute infarction, unless there is 
a connective tissue disorder. If nonatherosclerotic dissec
-
tion is present, coronary intervention may be risky, as 
further dissection can be aggravated. In most instances, 
Table 10–21.
 
Management strategies for women with valve disease, complex congenital heart disease, pulmonary 
hypertension, aortopathy, and dilated cardiomyopathy.
High-Risk Heart Disease in 
p
r
egnancy
•  Preconception
 
c
ounseling
 
and
 
pr
egnancy
 
risk
 
str
atification
 
f
or
 
all
 
w
omen
 
with
 
high-risk
 
hear
t
 
disease
 
of
 
childbearing
 
age
•  In
 
w
omen
 
c
onsidering
 
pr
egnancy:
 
S
witch
 
t
o
 
saf
er
 
car
diac
 
medica
tions
 
and
 
emphasiz
e
 
impor
tance
 
of
 
close
 
monit
oring
•  In
 
w
omen
 
a
voiding
 
pr
egnancy:
 
Discuss
 
saf
e
 
and
 
eff
ective
 
c
ontraception
 
choic
es
 
or
 
t
ermination
 
in
 
early
 
pr
egnancy
Management Strategy
Disease
p
r
egnancy Not Advised
p
r
egnancy Management
Delivery
Valve disease
•  Severe
 
mitr
al
 
and
 
aor
tic
 
v
alve
 
disease
•  Mechanical
 
pr
osthetic
 
v
alves
 
if effective anticoagulation not 
possible
•  Close
 
f
ollow-up
•  Drug
 
ther
apy
 
f
or
 
hear
t
 
failure or arrhythmias
•  Balloon
 
v
alvuloplasty
 
or
 
sur
-
gical valve replacement in 
refractory cases
•  Vaginal
 
deliv
ery
 
pr
eferred
•  C-section
 
in
 
case
 
of
 
f
etal
 
or
 
ma
ternal
 
instability
•  Early
 
deliv
ery
 
f
or
 
clinical
 
and
 
hemodynamic
 
deterioration
•  Consider
 
monit
oring
 
during
 
labor and delivery
Complex congenital 
heart disease
•  Significant
 
v
entricular
 
•  Severe
 
A
V
 
v
alve
 
dy
sfunction
•  Falling
 
F
ontan
 
cir
culation
•  Oxygen
 
sa
turation
 
<
 
85%
•  Close
 
f
ollow-up
•  Vaginal
 
deliv
ery
 
pr
eferred
 
in
 
case
 
of
 
f
etal
 
or
 
ma
ternal
 
•  Consider
 
monit
oring
 
during
 
Pulmonary 
hypertension
•  Established
 
pulmonar
y
 
ar
terial
 
•  Close
 
f
ollow-up
•  Early
 
institution
 
of
 
pulmo
-
nary vasodilators
•  Vaginal
 
deliv
ery
 
pr
eferred
 
in
 
case
 
of
 
f
etal
 
or
 
ma
ternal
 
•  Timing
 
of
 
deliv
ery
 
depends
 
on
 
clinical
 
and
 
R
V
 
function
•  Early
 
deliv
ery
 
advisable
•  Diuresis
 
af
ter
 
deliv
ery
 
t
o
 
pr
event
 
R
V
 
v
olume
 
overload
•  Extended
 
hospital
 
sta
y
 
af
ter
 
deliv
ery
Aortopathy
For some women—
•  Marfan
 
syndr
ome
•  Bicuspid
 
aor
tic
 
v
alve
•  Turner
 
syndr
ome
•  Rapid
 
g
rowth
 
of
 
aor
tic
 
diameter or family history of 
premature aortic dissection
•  Treat
 
h
ypertension
• 
 
B
eta-blockers
 
t
o
 
r
educe
 
heart rate
•  Frequent
 
echocar
diographic
 
assessment
• 
 
Sur
gery
 
during
 
pr
egnancy
 
or
 
after C-section if large 
increase in aortic diameter
 
in
 
cases
 
of
 
sig
nificant
 
aor
tic
 
dila
tion
– Marfan syndrome > 40 mm
– Bicuspid aortic valve > 45 mm
– Turner syndrome: aortic size index 
 
> 20 mm/m
2
Dilated 
cardiomyopathy
•  LVEF
 
<
 
40%
•  History
 
of
 
peripar
tum
 
•  Close
 
f
ollow-up

> 20 mm/m
2
Dilated 
•  LVEF
 
<
 
40%
•  History
 
of
 
peripar
tum
 
•  Close
 
f
ollow-up
•  Beta-blockers
•  Diuretic
 
agen
ts
 
f
or
 
v
olume
 
overload
•  Vasodilators
 
f
or
 
hemody
-
namic and symptomatic 
improvement
•  Vaginal
 
deliv
ery
 
pr
eferred
 
in
 
case
 
of
 
f
etal
 
or
 
ma
ternal
 
•  Consider
 
monit
oring
 
during
 
•  Early
 
deliv
ery
 
f
or
 
clinical
 
and
 
AV, atrioventricular; C-section, caesarean section; LV, left ventricular; RV right ventricular.
Modified, with permission, from Elkayam U et al. High-risk cardiac disease in pregnancy: Part I. J Am Coll Cardiol. 2016 Jul 26;68(4):396–410 
© 2016 by the American College of Cardiology Foundation.
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conservative management is warranted. At times, exten
-
sive aortic dissection requires surgical intervention. The 
2011 European guidelines suggest Marfan patients are 
particularly susceptible to further aortic expansion dur
-
ing pregnancy when the aortic diameter is more than 
4.5 cm (greater or equal to 27 mm/m
2
) and pregnancy be 
discouraged in these situations. Some data, however, sug
-
gest that there is an increased risk of dissection during 
pregnancy even when the aortic root is at 4.0 cm, since 
pregnancy appears to have a small, but significant, influ
-
ence on aortic growth even at this size. The earlier 2010 
ACC/AHA/AATS guidelines suggest elective repair is 
reasonable when the aortic root is greater than 4.0 cm in 
women with Marfan syndrome contemplating pregnancy; 
as the review notes, half of women with Marfan syndrome 
and this large an aorta will need surgery since they are at 
risk for rupture or life-threatening aortic root growth 
during pregnancy.
Acute infarction during pregnancy is associated with an 
8% maternal mortality and 56% incidence of premature 
delivery. If PCI is required, it is recommended that a bare 
metal stent be used to minimize antiplatelet usage. There 
are data that clopidogrel is safe, but ticagrelor, prasugrel, 
bivalirudin, and glycoprotein IIb/IIIa inhibitors should not 
be used. Statins are contraindicated in pregnancy.
27443437]
Elkayam U et al. High-risk cardiac disease in pregnancy: part II. J 
Am Coll Cardiol. 2016 Aug 2;68(5):502–16. [PMID: 27443948]
Lameijer H et al. Ischaemic heart disease during pregnancy or 
post-partum: systematic review and case series. Neth Heart J. 
2015 May;23(5):249–57. [PMID: 25911007]
Regitz-Zagrosek V et al. Management of cardiovascular disease 
in pregnancy. Curr Probl Cardiol 2014;39:85–151. [PMID: 
24794710]
3. 
p
r
ophylaxis for Infective Endocarditis During 
p
r
egnancy & Delivery
The 2007 ACC/AHA Task Force addressing adults with 
congenital heart disease has formulated guidelines outlin
-
ing recommendations for pregnant women during labor 
and delivery. Pregnancy itself is not considered a risk for 
endocarditis. Since vaginal delivery might include bactere
-
mia, the guidelines advocate endocarditis prophylaxis to 
cover the same high-risk groups as in the traditional endo
-
carditis recommendations from the ACC/AHA, acknowl
-
edging that data are lacking to support this approach. 
Antibiotic prophylaxis against infective endocarditis is 
considered reasonable (class IIa LOE C) in select patients 
with the highest risk of adverse outcomes before vaginal 
delivery at the time of membrane rupture. Indications for 
antibiotic use include (1) prosthetic cardiac valve or pros
-
thetic material used for cardiac valve repair, and (2) unre
-
paired and palliated cyanotic congenital heart disease, 
including surgically constructed palliative shunt conduits.
Brickner ME. Cardiovascular management in pregnancy: con
-
genital heart disease. Circulation. 2014 Jul 15;130(3):273–82. 
[PMID: 25024123]
-
-
tion Task Force on Practice Guidelines. Circulation. 2008 Dec 
2;118(23):e714–833. [PMID: 18997169]
 
»
Management of Labor
Although vaginal delivery is usually well tolerated, unsta
-
ble patients (including patients with severe hypertension 
and worsening heart failure) should have planned cesarean 
section. Spinal anesthesia results in a large drop in the sys
-
temic vascular resistant and can worsen right-to-left shunt
-
ing. An increased risk of aortic rupture has been noted 
during delivery in patients with coarctation of the aorta 
and severe aortic root dilation with Marfan syndrome, and

-
and severe aortic root dilation with Marfan syndrome, and 
vaginal delivery should be avoided in these patients. For 
most patients, even those with complex congenital heart 
disease, vaginal delivery is the preferred method however. 
Following delivery, there are numerous fluid shifts that 
occur with the initial blood-reducing preload accompanied 
by the loss of the afterload reduction provided by the pla
-
centa. Venous return increases as the uterus is no longer 
compressing the inferior vena cava and there is an infusion 
of fluid into the vascular system as the uterus quickly 
shrinks back toward its normal size. The sudden increase 
in preload and loss of afterload following delivery can 
result in heart failure during the first 48–72 hours after the 
delivery and that remains the high-risk time for susceptible 
patients.
 
º
CARDIOVASCULAR SCREENING OF 
ATHLETES
The sudden death of a competitive athlete inevitably 
becomes an occasion for local, if not national, publicity. 
On each occasion, the public and the medical community 
ask whether such events could be prevented by more care
-
ful or complete screening. Although each event is tragic, it 
must be appreciated that there are approximately 5 million 
competitive athletes at the high school level or above in 
any given year in the United States. The number of cardiac 
deaths occurring during athletic participation is unknown, 
but estimates at the high school level range from one in 
100,000 to one in 300,000 participants. Death rates among 
more mature athletes increase as the prevalence of CAD 
rises. These numbers highlight the problem of how best to 
screen individual participants. Even an inexpensive test 
such as an ECG would generate an enormous cost if 
required of all athletes, and it is likely that only a few at-
risk individuals would be detected. Echocardiography, 
either as a routine test or as a follow-up examination for 
abnormal ECGs, would be prohibitively expensive except 
for the elite professional athlete. Thus, the most feasible 
approach is that of a careful medical history and cardiac 
examination performed by personnel aware of the 
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conditions responsible for most sudden deaths in com
-
petitive athletes.
It is important to point out that sudden death is much 
more common in the older than the younger athlete. 
Older athletes will generally seek advice regarding their 
fitness for participation. These individuals should recog
-
nize that strenuous exercise is associated with an increase 
in risk of sudden cardiac death and that appropriate train
-
ing substantially reduces this risk. Preparticipation 
screening for risk of sudden death in the older athlete is a 
complex issue and at present is largely focused on identi
-
fying inducible ischemia due to significant coronary 
disease.
In a series of 158 athletic deaths in the United States 
between 1985 and 1995, hypertrophic cardiomyopathy 
(36%) and coronary anomalies (19%) were by far the most 
frequent underlying conditions. LVH was present in 
another 10%, ruptured aorta (presumably due to Marfan 
syndrome or cystic medial necrosis) in 6%, myocarditis or 
dilated cardiomyopathy in 6%, aortic stenosis in 4%, and 
arrhythmogenic RV dysplasia in 3%. In addition, commo
-
tio cordis, or sudden death due to direct myocardial injury, 
may occur. More common in children, ventricular tachy
-
cardia or ventricular fibrillation may occur even after a 
minor direct blow to the heart; it is thought to be due to the 
precipitation of a PVC just prior to the peak of the T wave 
on ECG.
A careful family and medical history and cardiovascular 
examination will identify most individuals at risk. An 
update in 2014 recommends that all middle school and 
higher athletes undergo a medical screen questionnaire 
and examination. The 12 elements in the examination are 
outlined in Table 10–22.
A family history of premature sudden death or cardio
-
vascular disease, or of any of these predisposing condi
-
tions should mandate further workup, including an ECG 
and echocardiogram. Symptoms of unexplained fatigue or 
dyspnea, exertional chest pain, syncope, or near-syncope 
also warrant further evaluation. A Marfan-like appear
-
ance, significant elevation of BP , abnormalities of heart 
rate or rhythm, and pathologic heart murmurs or heart 
sounds should also be investigated before clearance for 
athletic participation is given. Such an evaluation is rec
-
ommended before participation at the high school and 
college levels and every 2 years during athletic 
competition.
Stress-induced syncope or chest pressure may be the 
first clue to an anomalous origin of a coronary artery. Ana
-
tomically, this lesion occurs most often when the left ante
-
rior descending artery or left main coronary arises from 
the right coronary cusp and traverses between the aorta 
and pulmonary trunks. The “slit-like” orifice that results 
from the angulation at the vessel origin is thought to cause 
ischemia when the aorta and pulmonary arteries enlarge 
during rigorous exercise and tension is placed on the 
coronary.
The toughest distinction may be in sorting out the 
healthy athlete with LVH from the athlete with hypertro
-
phic cardiomyopathy. In general, the healthy athlete’s 
heart is 
less
 likely to have an unusual pattern of LVH 
(such as asymmetric septal hypertrophy), or to have LA 
enlargement, an abnormal ECG, an LV cavity less than 
45 mm in diameter at end-diastole, an abnormal diastolic 
filling pattern, or a family history of hypertrophic cardio
-
myopathy. The athlete is more likely to be male than the 
individual with hypertrophic cardiomyopathy, where 
women are equally at risk. Increased risk is also evident in 
patients with the Wolff-Parkinson-White syndrome, a 
prolonged QTc interval, or the Brugada syndrome on 
their ECG.
Selective use of routine ECG and stress testing is rec
-
ommended in men above age 40 years and women above 
age 50 years who continue to participate in vigorous exer
-
cise and at earlier ages when there is a positive family his
-

-
-
-
tory for premature CAD, hypertrophic cardiomyopathy, or 
multiple risk factors. Because at least some of the risk 
features (long QT, LVH, Brugada syndrome, WPW syn
-
drome) may be evident on routine ECG screening, several 
cost-effectiveness studies have been done. Most suggest 
that pre-participation ECGs are of potential value, though 
what to do when the QTc is mildly increased is unclear. 
Many experts feel the high incidence of false-positive ECG 
studies make it very ineffective as a screening tool. With 
the low prevalence of cardiac anomalies in the general 
public, it has been estimated that 200,000 individual ath
-
letes would need to be screened to identify the single 
individual who would die suddenly. The issue of routine 
screening, therefore, remains controversial. In 2017, a 
Table 10–22.
 
12-element AHA recommendations for 
preparticipation cardiovascular screening of competi
-
tive athletes.
Medical History
p
ersonal H
istory
  
1. Ex
ertional chest pain/discomfort
  
2. Une
xplained syncope/near-syncope
  
3. Ex
cessive exertional and unexplained dyspnea/fatigue
  
4. P
rior recognition of a heart murmur
  
5. Elev
ated systemic blood pressure
Family History
  
6. 
 
P
remature death (sudden and unexpected, or otherwise) 
before age of 50 years due to heart disease in one or more 
relatives
  
7. 
 
Disabilit
y from heart disease in a close relative before age of 
50 years
  
8. 
 
Specific 
knowledge of certain cardiac conditions in family 
members: hypertrophic cardiomyopathy, dilated cardiomy
-
opathy, long QT syndrome or other ion channelopathies, 
Marfan syndrome, or other important arrhythmias
p
hysical Examination
  
9. Hear
t murmur
 
10. Diminished f
emoral pulse (to exclude coarctation)
 
11. P
henotype of Marfan syndrome
 
12. Br
achial artery blood pressure (sitting position)
Reproduced, with permission, from Lawless CE et al. Protecting the 
heart of the American athlete: proceedings of the American 
College of Cardiology Sports and Exercise Cardiology Think Tank, 
October 18, 2012, Washington, DC. J Am Coll Cardiol. 2014 Nov 
18–25;64(20):2146–71. Copyright © Elsevier.
CMDT19_Ch10_p0334-p0450.indd   449

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consensus statement from the American Medical Society 
for Sports Medicine was published summarizing the cur
-
rent recommendations for the appropriate screening 
options in the various clinical scenarios. Once a high-risk 
individual has been identified, guidelines from the 
Bethesda conference and the ESC can be used to help 
determine whether the athlete may continue to participate 
in sporting events. Table 10–23 summarizes these 
recommendations.
Table 10–23.
 
Recommendations for competitive sports participation among athletes with potential causes of SCD.
Condition
36th Bethesda Conference
European Society of Cardiology
Structural cardiac abnormalities
HCM
Exclude athletes with a probable or definitive clinical diagnosis from all 
competitive sports.
Genotype-positive/phenotype-negative athletes may still compete.
Exclude athletes with a probable or definitive 
clinical diagnosis from all competitive sports.
Exclude genotype-positive/phenotype-negative 
individuals from competitive sports.
ARVC
Exclude athletes with a probable or definitive diagnosis from 
 
diagnosis from competitive sports.
CCAA
Exclude from competitive sports.
Not applicable.
Participation in all sports 3 months after successful surgery would be per
-
mitted for an athlete with ischemia, ventricular arrhythmia or tachyar
-
rhythmia, or LV dysfunction during maximal exercise testing.
Electrical cardiac abnormalities
WPW
Athletes without structural heart disease, without a history of palpita
-
tions, or without tachycardia can participate in all competitive 
sports.
In athletes with symptoms, electrophysiological study and ablation are 
recommended. Return to competitive sports is allowed after correc
-
tive ablation, provided that the ECG has normalized.
Athletes without structural heart disease, without 
a history of palpitations, or without tachycardia 
can participate in all competitive sports.
In athletes with symptoms, electrophysiological 
study and ablation are recommended. Return 
to competitive sports is allowed after corrective 
ablation, provided that the ECG has normalized.
LQTS
Exclude any athlete with a previous cardiac arrest or syncopal episode 
from competitive sports.
Asymptomatic patients restricted to competitive low-intensity sports.
Exclude any athlete with a clinical or genotype 
BrS
Exclude from all competitive sports except those of low intensity.
Exclude from all competitive sports.
CPVT
Exclude all patients with a clinical diagnosis from competitive sports.
Genotype-positive/phenotype-negative patients may still compete in 
low-intensity sports.
Exclude all patients with a clinical diagnosis from 
Genotype-positive/phenotype-negative patients 
are also excluded.
Acquired cardiac abnormalities
Commotio 
cordis
Eligibility for returning to competitive sport in survivors is a matter of 
individual clinical judgment. Survivors must undergo a thorough 
cardiovascular workup including 12-lead electrocardiography, 
ambulatory ECG monitoring, and echocardiography
Myocarditis
Convalescent period of 6 months.
Athletes may return to competition when test results normalize.
Athletes may return to competition when test 
results normalize.
ARVC, arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CCAA, congenital coronary artery anomalies; CPVT, 
cathecholaminergic polymorphic ventricular tachycardia; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LQTS, long QT 
syndrome; LV, left ventricular; SCD, sudden cardiac death; WPW, Wolff-Parkinson-White syndrome.

Reproduced, with permission, from Chandra N et al. Sudden cardiac death in young athletes: practical challenges and diagnostic dilemmas. 
J Am Coll Cardiol. 2013 Mar 12;61(10):1027–40. Copyright © Elsevier.
Chugh SS et al. Sudden cardiac death in the older athlete. J Am 
Coll Cardiol. 2015 Feb 10;65(5):493–502. [PMID: 25660928]
Drezner JA et al. AMSSM position statement on cardiovascular 
preparticipation screening in athletes: current evidence, knowl
-
edge gaps, recommendations and future directions. Br J Sports 
Med. 2017 Feb;51(3):153–67. [PMID: 27660369]
Risgaard B et al. Sports-related sudden cardiac death in a competitive 
and a noncompetitive athlete population aged 12 to 49 years: 
data from an unselected nationwide study in Denmark. Heart 
Rhythm. 2014 Oct;11(10):1673–81. [PMID: 24861446]
CMDT19_Ch10_p0334-p0450.indd   450

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Based on data from the 2011–2012 NHANES survey, about 
one-third of adults in the United States are hypertensive. 
Hypertension is uncontrolled in almost half of these 71 million 
people, and of those with uncontrolled hypertension, about 
36% or 13 million are unaware of the diagnosis. Even in 
patients in whom hypertension is diagnosed and treated, 
control is attained in only 60%. Cardiovascular morbidity 
and mortality increase as both systolic and diastolic blood 
pressures rise, but in individuals over age 50 years, the sys
-
tolic pressure and pulse pressure are better predictors of 
complications than diastolic pressure. The prevalence of 
hypertension increases with age, and it is more common in 
blacks than in whites. Adequate blood pressure control 
reduces the incidence of acute coronary syndrome by 
20–25%, stroke by 30–35%, and heart failure by 50%.
HOW IS BLOOD PRESSURE MEASURED & 
HYPERTENSION DIAGNOSED?
Blood pressure should be measured with a well-calibrated 
sphygmomanometer. The bladder width within the cuff 
should encircle at least 80% of the arm circumference. 
Readings should be taken after the patient has been resting 
comfortably, back supported in the sitting or supine posi
-
tion, for at least 5 minutes and at least 30 minutes after 
smoking or coffee ingestion. Office-based devices that 
permit multiple automated measurements after a pre-
programmed rest period produce blood pressure readings 
that are independent of digit preference bias and the “white 
coat” phenomenon (where blood pressure is elevated in the 
clinic but normal at home). Blood pressure measurements 
taken outside the office environment, either by intermit
-
tent self-monitoring (home blood pressure) or with an 
automated device programmed to take measurements at 
regular intervals (ambulatory blood pressure) are more 
powerful predictors of outcomes and are advocated in 
clinical guidelines. Home measurements are also helpful in 
differentiating white coat hypertension from hypertension 
that is resistant to treatment, and in diagnosis of “masked 
hypertension” (where blood pressure is normal in the clinic 
but elevated at home). The cardiovascular risk associated 
with masked hypertension is similar to that observed in 
sustained hypertension.
A single elevated blood pressure reading is not suffi
-
cient to establish the diagnosis of hypertension. The major 
exceptions to this rule are hypertensive presentations with 
unequivocal evidence of life-threatening end-organ dam
-
age, as seen in hypertensive emergency, or in hypertensive 
urgency where blood pressure is greater than 220/125 mm Hg 
but life-threatening end-organ damage is absent. In less 
severe cases, the diagnosis of hypertension depends on a 
series of measurements of blood pressure, since readings 
can vary and tend to regress toward the mean with time. 
Patients whose initial blood pressure is in the hypertensive 
range exhibit the greatest fall toward the normal range 
between the first and second encounters. However, the 
concern for diagnostic precision needs to be balanced by 
an appreciation of the importance of establishing the diag
-
nosis of hypertension as quickly as possible, since a 
3-month delay in treatment of hypertension in high-risk 
patients is associated with a twofold increase in cardiovas
-
cular morbidity and mortality. Based on epidemiological 
data, the conventional 140/90 mm Hg threshold for the 
diagnosis of hypertension is being questioned. The 2017 
guidelines from the American College of Cardiology and 
American Heart Association (ACC/AHA) suggest that, for 
conventional office-based measurement, 
normal
 be 
defined as less than 120/80 mm Hg, 
elevated
 as 120–129/
less than 80 mm Hg, 
stage 1
 as 130–139/80–89 mm Hg and 
stage 2
 as greater than or equal to 140/90 mm Hg. Blood 
pressure measurements using automated office devices, 
manual home cuffs, or ambulatory equipment are signifi
-

as 130–139/80–89 mm Hg and 
stage 2
-
cantly better predictors of cardiovascular outcomes than 
conventional clinic measurements. As exemplified by 
Hypertension Canada’s 2017 guidelines (Figure 11–1), 
automated and home blood pressure measurements are 
assuming greater prominence in the diagnostic algorithms 
published by many national hypertension workgroups. 
Equivalent blood pressure for these different modes of 
measurement are described in Table 11–1.
Ambulatory blood pressure readings are normally lowest 
at night and the loss of this nocturnal dip is a dominant 
predictor of cardiovascular risk, particularly risk of throm
-
botic stroke. An accentuation of the normal morning 
increase in blood pressure is associated with increased likeli
-
hood of cerebral hemorrhage. Furthermore, variability of 11
 
Systemic Hypertension
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Chapter 11 
452
 CMDT 2019
Ele
va
ted BP reading
(office
, 
home or pharmacy)
No
6
White coat hypertension
6
Dedicated office visit
1
Mean office BP ≥ 180/1
10
 mm Hg
No Diabetes Diabetes
3
1.
 
AOBP
2
 
≥ 135/85
 mm Hg (preferred)
2. 
Non-AOBP
2
 
≥ 140/90
 mm Hg (if AOBP
 unavailable)
AOBP or
non-AOBP
2
≥ 130/80
mm Hg
OR
Out-of-office measurement
4
1.
 
ABPM
 
(preferred)
 
Da
ytime mean ≥ 135/85 mm Hg 
 24-hour mean ≥ 130/80 mm Hg 
2. 
Home BP series
5
 Mean ≥ 135/85 mm Hg
OR
Ye
s
Ye
s
No
No
Ye
s
No
1. If AOBP is used, use the mean calculated and
 displayed by the device. If non-AOBP is used,
 take at least three readings, discard the first
 and calculate the mean of the remaining
 measurements. A history and physical
 examination should be performed and
 diagnostic tests ordered.
2. 
AOBP
 is performed with the patient
 unattended in a private area.
 
Non-AOBP
 is performed using an electronic
 upper arm device with the provider in the room.
3. Diagnostic thresholds for AOBP, ABPM, and
 home BP in patients with diabetes have yet
 to be established (and may be lower than
 130/80 mm Hg).
4. Serial office measurements over
 3–5 visits can be used if ABPM or home
 measurement not available.
5. Home BP series: Two readings taken each
 morning and evening for 7 days (28 total).
 Discard first day readings and average
 t
he last 6 days.
6. Annual BP measurement is recommended
 to detect progression to hypertension.
Notes:
ABPM, ambulatory blood pressure measurement; AOBP, automated office
blood pressure; BP, blood pressure.
 
▲
Figure 11–1.
 
According to these recommendations, if AOBP measurements are not available, blood pressures 
recorded manually in the office may be substituted if taken as the mean of the last two readings of three consec
-
utive readings. Note that the blood pressure threshold for diagnosing hypertension is higher if recorded manu
-
ally in these guidelines. If home blood pressure monitoring is unavailable, office measurements recorded over 
three to five separate visits can be substituted. 
(Reproduced, with permission, from Leung AA et al; Hypertension 
Canada. Hypertension Canada’s 2017 guidelines for diagnosis, risk assessment, prevention, and treatment of hyper
-
tension in adults. Can J Cardiol. 2017 May;33(5):557–76. Erratum in: Can J Cardiol. 2017 Dec;33(12):1733–4.)
Table 11–1.
 
Corresponding blood pressure values across a range of blood pressure measurement methods.
Manual Measurement 
in Clinic
1
h
ome Blood 
p
r
essure 
Measurement
a
mbula
tory Blood 
p
r
essure Measurement 
(Daytime)
a
mbula
tory Blood 
p
r
(Nighttime)
a
mbula
tory Blood 
p
r
(24-
h
our)
120/80 mm Hg
100/65 mm Hg
115/75 mm Hg
130/80 mm Hg
110/65 mm Hg
125/75 mm Hg
140/90 mm Hg
135/85 mm Hg
120/70 mm Hg
160/100 mm Hg
145/90 mm Hg
140/85 mm Hg
1
Clinic manual blood pressures are critically dependent on technique. The use of automated devices in an unattended setting typically 
result in systolic blood pressures 9–13 mm Hg lower than clinic manual pressures.
Data abstracted from Greenland P et al. The New 2017 ACC/AHA Guidelines “up the pressure” on diagnosis and treatment of hypertension. 
JAMA. 2017 Dec 5;318(21):2083–4.
CMDT19_Ch11_p0451-p0482.indd   452

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CMDT 2019
systolic blood pressure predicts cardiovascular events inde
-
pendently of mean systolic blood pressure.
It is important to recognize that the diagnosis of hyper
-
tension does not automatically entail drug treatment; this 
decision depends on the clinical setting, as discussed below.
Greenland P et al. The New 2017 ACC/AHA Guidelines “up the 
pressure” on diagnosis and treatment of hypertension. JAMA. 
2017 Dec 5;318(21):2083–4. [PMID: 29159417]
Jin J. JAMA patient page. Checking blood pressure at home. 
JAMA. 2017 Jul 18;318(3):310. [PMID: 28719694]
Leung AA et al; Hypertension Canada. Hypertension Canada’s 2017 
guidelines for diagnosis, risk assessment, prevention, and treat
-
ment of hypertension in adults. Can J Cardiol. 2017 May;33(5):
 
557–76. Erratum in: Can J Cardiol. 2017 Dec; 33(12):1733–4. 
[PMID: 28449828]
Myers MG. Automated office blood pressure—incorporating 
SPRINT into clinical practice. Am J Hypertens. 2017 Jan;
 
30(1):8–11. [PMID: 27551025]
APPROACH TO HYPERTENSION
 
»
Etiology & Classification
A. Primary Essential Hypertension
“Essential hypertension” is the term applied to the 95% of 
hypertensive patients in which elevated blood pressure 
results from complex interactions between multiple genetic 
and environmental factors. The proportion regarded as 
“essential” will diminish with improved detection of clearly 
defined secondary causes and with better understanding of 
pathophysiology. Essential hypertension occurs in 10–15% 
of white adults and 20–30% of black adults in the United 
States. The onset is usually between ages 25 and 50 years; it 
is uncommon before age 20 years. The best understood 
pathways underlying hypertension include overactivation 
of the sympathetic nervous and renin–angiotensin–
aldosterone systems, blunting of the pressure-natriuresis 
relationship, variation in cardiovascular and renal develop
-
ment, and elevated intracellular sodium and calcium levels.
Exacerbating factors
 include obesity, sleep apnea, 
increased salt intake, excessive alcohol use, cigarette smok
-
ing, polycythemia, nonsteroidal anti-inflammatory 
(NSAID) therapy, and low potassium intake. 
Obesity
 is 
associated with an increase in intravascular volume, ele
-
vated cardiac output, activation of the renin-angiotensin 
system, and, probably, increased sympathetic outflow. 
Lifestyle-driven weight reduction lowers blood pressure 
modestly, but the dramatic weight reduction following 
bariatric surgery results in improved blood pressure in 
most patients, and actual remission of hypertension in 
20–40% of cases. In patients with 
sleep apnea
, treatment 
with continuous positive airway pressure (CPAP) has been 
associated with improvements in blood pressure. 
Increased 
salt intake
 probably elevates blood pressure in some indi
-
viduals so dietary salt restriction is recommended in 
patients with hypertension. Excessive use of 
alcohol
 also 
raises blood pressure, perhaps by increasing plasma cate
-
cholamines. Hypertension can be difficult to control in 
patients who consume more than 40 g of ethanol (two 
drinks) daily or drink in “binges. ” 
Cigarette smoking
 
raises blood pressure by increasing plasma norepinephrine. 
Although the long-term effect of smoking on blood pres
-
sure is less clear, the synergistic effects of smoking and high 
blood pressure on cardiovascular risk are well documented. 
The relationship of 
exercise
 to hypertension is variable. 
Aerobic exercise lowers blood pressure in previously sed
-
entary individuals, but increasingly strenuous exercise in 
already active subjects has less effect. The relationship 
between stress and hypertension is not established. 
Polycythemia,
 whether primary, drug-induced, or due to 
diminished plasma volume, increases blood viscosity and 
may raise blood pressure. 
NSAIDs
 produce increases in 
blood pressure averaging 5 mm Hg and are best avoided in

NSAIDs
blood pressure averaging 5 mm Hg and are best avoided in 
patients with borderline or elevated blood pressures. 
Low potassium intake
 is associated with higher blood 
pressure in some patients; an intake of 90 mmol/day is 
The complex of abnormalities termed the 
“metabolic 
syndrome”
 (upper body obesity, insulin resistance, and 
hypertriglyceridemia) is associated with both the develop
-
ment of hypertension and an increased risk of adverse 
cardiovascular outcomes. Affected patients usually also 
have low high-density lipoprotein (HDL) cholesterol levels 
and elevated catecholamines and inflammatory markers 
such as C-reactive protein.
B. Secondary Hypertension
Approximately 5% of patients have hypertension secondary 
to identifiable specific causes (Table 11–2). Secondary 
hypertension should be suspected in patients in whom 
hypertension develops at an early age or after the age of 
 
50 years, and in those previously well controlled who 
become refractory to treatment. Hypertension resistant to 
three medications is another clue, although multiple medica
-
tions are usually required to control hypertension in persons 
with diabetes. Secondary causes include genetic syndromes; 
kidney disease; renal vascular disease; primary hyperaldoste
-
ronism; Cushing syndrome; pheochromocytoma; coarcta
-
tion of the aorta and hypertension associated with pregnancy, 
estrogen use, hypercalcemia, and medications.
1. Genetic causes—
Hypertension can be caused by muta
-
tions in single genes, inherited on a Mendelian basis. 
Although rare, these conditions provide important insight 
Table 11–2.
 
Identifiable causes of hypertension.
Drug-induced or drug-related
Primary aldosteronism
Renovascular disease
Long-term corticosteroid therapy and Cushing syndrome
Coarctation of the aorta
Thyroid or parathyroid disease
Data from Chobanian AV et al. The Seventh Report of the Joint 
National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003 
May 21;289(19):2560–72.
CMDT19_Ch11_p0451-p0482.indd   453

Chapter 11 
454
 CMDT 2019
into blood pressure regulation and possibly the genetic 
basis of essential hypertension. 
Glucocorticoid remedia
-
ble aldosteronism
 is an autosomal dominant cause of 
early-onset hypertension with normal or high aldosterone 
and low renin levels. It is caused by the formation of a 
chimeric gene encoding both the enzyme responsible for 
the synthesis of aldosterone (transcriptionally regulated by 
angiotensin II) and an enzyme responsible for synthesis of 
cortisol (transcriptionally regulated by ACTH). As a con
-
sequence, aldosterone synthesis becomes driven by ACTH, 
which can be suppressed by exogenous cortisol. In the 
syndrome of apparent mineralocorticoid excess
, early-
onset hypertension with hypokalemic metabolic alkalosis 
is inherited on an autosomal recessive basis. Although 
plasma renin is low and plasma aldosterone level is very 
low in these patients, aldosterone antagonists are effective 
in controlling hypertension. This disease is caused by loss 
of the enzyme 11beta-hydroxysteroid dehydrogenase, 
which normally metabolizes cortisol and thus protects the 
otherwise “promiscuous” mineralocorticoid receptor in 
the distal nephron from inappropriate glucocorticoid acti
-
vation. Similarly, glycyrrhetinic acid, found in licorice, 
causes increased blood pressure through inhibition of 
11beta-hydroxysteroid dehydrogenase. The syndrome of 
hypertension exacerbated in pregnancy
 is inherited as an 
autosomal dominant trait. In these patients, a mutation in 
the mineralocorticoid receptor makes it abnormally 
responsive to progesterone and, paradoxically, to spirono
-
lactone. 
Liddle syndrome
 is an autosomal dominant 
condition characterized by early-onset hypertension, 
hypokalemic alkalosis, low renin, and low aldosterone 
levels. This is caused by a mutation that results in constitu
-
tive activation of the epithelial sodium channel of the 
distal nephron, with resultant unregulated sodium reab
-
sorption and volume expansion. 
Gordon syndrome,
 or 
pseudohypoaldosteronism type II
, presents with early- 
onset hypertension associated with hyperkalemia, meta
-
bolic acidosis and relative suppression of aldosterone. 
Inheritence is most often autosomal dominant. The 
underlying mutations occur in one of several genes encod
-
ing proteins that regulate the thiazide-sensitive NaCl 
co-transporter in the distal nephron, leading to constitu
-
tive activation of sodium and chloride reabsorption. The 
abnormalities in this syndrome are corrected by thiazide 
diuretics.
2. Kidney disease—
Renal parenchymal disease is the most 
common cause of secondary hypertension and is related to 
increased intravascular volume and increased activity of 
the renin–angiotensin–aldosterone system. Increased sym
-
pathetic nerve activity may also contribute.
3. Renal vascular hypertension—
Renal artery stenosis is 
present in 1–2% of hypertensive patients. The most com
-
mon cause is atherosclerosis, but fibromuscular dysplasia 
should be suspected in women under 50 years of age. 
Excessive renin release occurs due to reduction in renal 
perfusion pressure, while attenuation of pressure natriure
-
sis contributes to hypertension in patients with a single 
kidney or bilateral lesions. Activation of the renal sympa
-
thetic nerves may also be important.
Renal vascular hypertension should be suspected in the 
following circumstances: (1) the documented onset is 
before age 20 or after age 50 years, (2) the hypertension 
is resistant to three or more drugs, (3) there are epigastric 
or renal artery bruits, (4) there is atherosclerotic disease of 
the aorta or peripheral arteries (15–25% of patients with 
symptomatic lower limb atherosclerotic vascular disease 
have renal artery stenosis), (5) there is an abrupt increase 
(more than 25%) in the level of serum creatinine after 
administration of angiotensin-converting enzyme (ACE) 
inhibitors, or (6) episodes of pulmonary edema are associ
-

-
ated with abrupt surges in blood pressure. (See Renal 
Artery Stenosis, Chapter 22.)
4. Primary hyperaldosteronism—
Hyperaldosteronism 
should be considered in people with resistant hyperten
-
sion, blood pressures consistently greater than 150/100 mm 
Hg, hypokalemia (irrespective of diuretic exposure), adre
-
nal incidentaloma, and in those with a family history of 
hyperaldosteronism. Hypersecretion of aldosterone is esti
-
mated to be present in 5–10% of hypertensive patients and, 
besides noncompliance, is the most common cause of 
resistant hypertension. The initial screening step is the 
simultaneous measurement of aldosterone and renin in 
blood in a morning sample collected after 30 minutes qui
-
etly seated. Hyperaldosteronism is suggested when the 
plasma aldosterone concentration is elevated (normal: 
1–16 ng/dL) in association with suppression of plasma 
renin activity (normal: 1–2.5 ng/mL/h). However, the 
plasma aldosterone/renin ratio (normal less than 30) is not 
highly specific as a screening test. This is because “bottom
-
ing out” of renin assays leads to exponential increases in 
the plasma aldosterone/renin ratio even when aldosterone 
levels are normal. Hence, an elevated plasma aldosterone/
renin ratio should probably not be taken as evidence of 
hyperaldosteronism unless the aldosterone level is actually 
supranormal.
During the workup for hyperaldosteronism, an initial 
plasma aldosterone/renin ratio can be measured while the 
patient continues taking usual medications. If under these 
circumstances the ratio proves negative or equivocal, medi
-
cations that alter renin and aldosterone levels, including 
ACE inhibitors, angiotensin receptor blockers (ARBs), 
diuretics, beta-blockers, and clonidine, should be discon
-
tinued for 2 weeks before repeating the plasma aldoste
-
rone/renin ratio; spironolactone and eplerenone should be 
held for 4 weeks. Slow-release verapamil and alpha-receptor 
blockers can be used to control blood pressure during this 
drug washout period. Patients with a plasma aldosterone 
level greater than 16 ng/dL and an aldosterone/renin ratio 
of 30 or more might require further evaluation for primary 
hyperaldosteronism.
The lesion responsible for hyperaldosteronism is an 
adrenal adenoma or bilateral adrenal hyperplasia. Approxi
-
mately 50% of aldosterone-secreting adenomas arise as a 
consequence of somatic mutations in genes encoding glo
-
merulosa cell membrane ion transporters, with resultant 
elevation of intracellular calcium concentration.
5. Cushing syndrome—
Hypertension occurs in about 80% 
of patients with spontaneous Cushing syndrome. Excess 
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CMDT 2019
glucocorticoid may act through salt and water retention 
(via mineralocorticoid effects), increased angiotensinogen 
levels, or permissive effects in the regulation of vascular 
tone.
Diagnosis and treatment of Cushing syndrome are dis
-
cussed in Chapter 26.
6. Pheochromocytoma—
Pheochromocytomas are uncom
-
mon; they are probably found in less than 0.1% of all 
patients with hypertension and in approximately two indi
-
viduals per million population. However, autopsy studies 
indicate that pheochromocytomas are very often undiag
-
nosed in life. The blood pressure elevation caused by the 
catecholamine excess results mainly from alpha-receptor–
mediated vasoconstriction of arterioles, with a contribution 
from beta-1-receptor-mediated increases in cardiac output 
and renin release. Chronic vasoconstriction of the arterial 
and venous beds leads to a reduction in plasma volume and 
predisposes to postural hypotension. Glucose intolerance 
develops in some patients. Hypertensive crisis in pheochro
-
mocytoma may be precipitated by a variety of drugs, includ
-
ing tricyclic antidepressants, antidopaminergic agents, 
metoclopramide, and naloxone. The diagnosis and treat
-
ment of pheochromocytoma are discussed in Chapter 26.
7. Coarctation of the aorta—
This uncommon cause of 
hypertension is discussed in Chapter 10. Evidence of radial-
femoral delay should be sought in all younger patients with 
8. Hypertension associated with pregnancy—
Hyperten
-
sion occurring de novo or worsening during pregnancy, 
including preeclampsia and eclampsia, is one of the most 
common causes of maternal and fetal morbidity and mor
-
tality (see Chapter 19). Autoantibodies with the potential 
to activate the angiotensin II type 1 receptor have been 
causally implicated in preeclampsia, in resistant hyperten
-
sion, and in progressive systemic sclerosis.
9. Estrogen use—
A small increase in blood pressure 
occurs in most women taking oral contraceptives. A more 
significant increase above 140/90 mm Hg is noted in about 
5% of women, mostly in obese individuals older than age 
35 who have been treated for more than 5 years. This is 
caused by increased hepatic synthesis of angiotensinogen. 
Postmenopausal estrogen does not generally cause hyper
-
tension but rather maintains endothelium-mediated 
vasodilation.
10. Other causes of secondary hypertension—
Hypertension 
has been associated with hypercalcemia, acromegaly, hyper
-
thyroidism, hypothyroidism, baroreceptor denervation, com
-
pression of the rostral ventrolateral medulla, and increased 
intracranial pressure. A number of medications may cause or 
exacerbate hypertension—most importantly cyclosporine, 
tacrolimus, angiogenesis inhibitors, and erythrocyte-
stimulating agents (such as erythropoietin). Decongestants, 
NSAIDs, cocaine and alcohol should also be considered. 
Over-the-counter products should not be overlooked, eg, a 
dietary supplement marketed to enhance libido was found to 
contain yohimbine, an alpha-2–antagonist, which can 
produce severe rebound hypertension in patients taking 
clonidine.
 
»
Referral to a hypertension specialist should be considered 
in cases of severe, resistant or early-/late-onset hyperten
-
sion or when secondary hypertension is suggested by 
screening.
Gyamlani G et al. Primary aldosteronism: diagnosis and man
-
agement. Am J Med Sci. 2016 Oct;352(4):391–8. [PMID: 
27776721]
Owen JG et al. Bariatric surgery and hypertension. Am J 
Hypertens. 2017 Dec 8;31(1):11–7. [PMID: 28985287]
Raman G et al. Comparative effectiveness of management strate
-
gies for renal artery stenosis: an updated systematic review. 
Ann Intern Med. 2016 Nov 1;165(9):635–49. [PMID: 
27536808]
 
»
Complications of Untreated Hypertension
Elevated blood pressure results in structural and functional 
changes in the vasculature and heart. Most of the adverse 
outcomes in hypertension are associated with thrombosis

outcomes in hypertension are associated with thrombosis 
rather than bleeding, possibly because increased vascular 
shear stress converts the normally anticoagulant endothe
-
lium to a prothrombotic state. The excess morbidity and 
mortality related to hypertension approximately doubles 
for each 6 mm Hg increase in diastolic blood pressure. 
However, target-organ damage varies markedly between 
individuals with similar levels of office hypertension; home 
and ambulatory pressures are superior to office readings in 
the prediction of end-organ damage.
A. Hypertensive Cardiovascular Disease
Cardiac complications are the major causes of morbidity and 
mortality in primary (essential) hypertension. For any level of 
blood pressure, left ventricular hypertrophy is associated with 
incremental cardiovascular risk in association with heart fail
-
ure (through systolic or diastolic dysfunction), ventricular 
arrhythmias, myocardial ischemia, and sudden death.
The occurrence of heart failure is reduced by 50% with 
antihypertensive therapy. Hypertensive left ventricular 
hypertrophy regresses with therapy and is most closely 
related to the degree of systolic blood pressure reduction. 
Diuretics have produced equal or greater reductions of left 
ventricular mass when compared with other drug classes. 
Conventional beta-blockers are less effective in reducing 
left ventricular hypertrophy but play a specific role in 
patients with established coronary artery disease or 
impaired left ventricular function.
B. Hypertensive Cerebrovascular Disease and 
Dementia
Hypertension is the major predisposing cause of hemor
-
rhagic and ischemic stroke. Cerebrovascular complications 
are more closely correlated with systolic than diastolic 
blood pressure. The incidence of these complications is 
markedly reduced by antihypertensive therapy. Preceding 
hypertension is associated with a higher incidence of sub
-
sequent dementia of both vascular and Alzheimer types. 
Home and ambulatory blood pressure may be a better 
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predictor of cognitive decline than office readings in older 
people. Effective blood pressure control may reduce the 
risk of development of cognitive dysfunction later in life, 
but once cerebral small-vessel disease is established, low 
blood pressure might exacerbate this problem.
C. Hypertensive Kidney Disease
Chronic hypertension is associated with injury to vascular, 
glomerular, and tubulointerstitial compartments within 
the kidney, accounting for about 25% of end-stage kidney 
disease. Nephrosclerosis is particularly prevalent in blacks, 
in whom susceptibility is linked to 
APOL1
 mutations and 
hypertension results from kidney disease rather than caus
-
ing it.
D. Aortic Dissection
Hypertension is a contributing factor in many patients with 
dissection of the aorta. Its diagnosis and treatment are 
discussed in Chapter 12.
E. Atherosclerotic Complications
Most Americans with hypertension die of complications of 
atherosclerosis, but antihypertensive therapy seems to have 
a lesser impact on atherosclerotic complications compared 
with the other effects of treatment outlined above. Preven
-
tion of cardiovascular outcomes related to atherosclerosis 
probably requires control of multiple risk factors, of which 
hypertension is only one.
Coca A et al. Can the treatment of hypertension in the middle-
aged prevent dementia in the elderly? High Blood Press 
Cardiovasc Prev. 2016 Jun;23(2):97–104. [PMID: 27075454]
Seccia TM et al. Hypertensive nephropathy. Moving from 
classic to emerging pathogenetic mechanisms. J Hypertens. 
2017 Feb;35(2):205–12. [PMID: 27782909]
 
»
The clinical and laboratory findings are mainly referable to 
involvement of the target organs: heart, brain, kidneys, 
eyes, and peripheral arteries.
Mild to moderate primary (essential) hypertension is 
largely asymptomatic for many years. The most frequent 
symptom, headache, is also very nonspecific. Accelerated 
hypertension is associated with somnolence, confusion, 
visual disturbances, and nausea and vomiting (hypertensive 
encephalopathy).
Hypertension in patients with 
pheochromocytomas
 
that secrete predominantly norepinephrine is usually sus
-
tained but may be episodic. The typical attack lasts from 
minutes to hours and is associated with headache, anxiety, 
palpitation, profuse perspiration, pallor, tremor, and nau
-
sea and vomiting. Blood pressure is markedly elevated, 
and angina or acute pulmonary edema may occur. In 
primary aldosteronism
, patients may have muscular 
weakness, polyuria, and nocturia due to hypokalemia; 
 
▲
Figure 11–2.
 
Severe, chronic hypertensive retinopa
-
thy with hard exudates, increased vessel light reflexes, 
and sausage-shaped veins. 
Richard E. Wyszynski, MD in Knoop KJ, Stack LB, Storrow 
AB, Thurman RJ.
 
The Atlas of Emergency Medicine,
 
4th ed. 
McGraw-Hill, 2016.)
malignant hypertension is rare. 
Chronic hypertension
 
often leads to left ventricular hypertrophy and diastolic 
dysfunction, which can present with exertional and parox
-
ysmal nocturnal dyspnea. Cerebral involvement causes 
stroke due to thrombosis or hemorrhage from microaneu
-
rysms of small penetrating intracranial arteries. 
Hyper
-
tensive encephalopathy
 is probably caused by acute 
capillary congestion and exudation with cerebral edema, 
which is reversible.
B. Signs
Like symptoms, physical findings depend on the cause of 
hypertension, its duration and severity, and the degree of 
effect on target organs.
1. Blood pressure—
Blood pressure is taken in both arms 
and, if lower extremity pulses are diminished or delayed, in 
the legs to exclude coarctation of the aorta. If blood pres
-
sure differs between right and left arms, the higher reading 
should be recorded as the actual blood pressure and subcla
-
vian stenosis suspected in the other arm. An orthostatic 
drop of at least 20/10 mm Hg is often present in pheochro
-

-
-
mocytoma. Older patients may have falsely elevated read
-
ings by sphygmomanometry because of noncompressible 
vessels. This may be suspected in the presence of Osler 
sign—a palpable brachial or radial artery when the cuff is 
inflated above systolic pressure. Occasionally, it may be 
necessary to make direct measurements of intra-arterial 
pressure, especially in patients with apparent severe hyper
-
tension who do not tolerate therapy.
2. Retinas—
Narrowing of arterial diameter to less than 
50% of venous diameter, copper or silver wire appear
-
ance, exudates, hemorrhages, or hypertensive retinopa
-
thy are associated with a worse prognosis. The typical 
changes of severe hypertensive retinopathy are shown in 
CMDT19_Ch11_p0451-p0482.indd   456

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3. Heart—
A left ventricular heave indicates severe hyper
-
trophy. Aortic regurgitation may be auscultated in up to 5% 
of patients, and hemodynamically insignificant aortic 
regurgitation can be detected by Doppler echocardiogra
-
phy in 10–20%. A presystolic (S
4
) gallop due to decreased 
compliance of the left ventricle is quite common in patients 
in sinus rhythm.
4. Pulses—
Radial-femoral delay suggests coarctation of the 
aorta; loss of peripheral pulses occurs due to atherosclero
-
sis, less commonly aortic dissection, and rarely Takayasu 
arteritis, all of which can involve the renal arteries.
Recommended testing includes the following: hemoglobin; 
urinalysis and serum creatinine; fasting blood sugar level 
(hypertension is a risk factor for the development of diabe
-
tes, and hyperglycemia can be a presenting feature of pheo
-
chromocytoma); plasma lipids (necessary to calculate 
cardiovascular risk and as a modifiable risk factor); serum 
uric acid (hyperuricemia is a relative contraindication to 
diuretic therapy); and serum electrolytes.
D. Electrocardiography and Chest Radiographs
Electrocardiographic criteria are highly specific but not very 
sensitive for left ventricular hypertrophy. The “strain” pat
-
tern of ST–T wave changes is a sign of more advanced 
disease and is associated with a poor prognosis. A chest 
radiograph is not necessary in the workup for uncomplicated 
E. Echocardiography
The primary role of echocardiography should be to evaluate 
patients with clinical symptoms or signs of cardiac disease.
F. Diagnostic Studies
Additional diagnostic studies are indicated only if the 
clinical presentation or routine tests suggest secondary or 
complicated hypertension. These may include 24-hour 
urine free cortisol, urine or plasma metanephrines, and 
plasma aldosterone and renin concentrations to screen for 
endocrine causes of hypertension. Renal ultrasound will 
detect structural changes (such as polycystic kidneys, asym
-
metry, and hydronephrosis); echogenicity and reduced 
cortical volume are reliable indicators of advanced chronic 
kidney disease. Evaluation for renal artery stenosis should 
be undertaken in concert with subspecialist consultation.
G. Summary
Since most hypertension is essential or primary, few studies 
are necessary beyond those listed above. If conventional 
therapy is unsuccessful or if secondary hypertension is 
suspected, further studies and perhaps referral to a hyper
-
tension specialist are indicated.
Katsi V et al. Impact of arterial hypertension on the eye. Curr 
Hypertens Rep. 2012 Dec;14(6):581–90. [PMID: 22673879]
 
»
Nonpharmacologic Therapy
Lifestyle modification may have an impact on morbidity and 
mortality. A diet rich in fruits, vegetables, and low-fat dairy 
foods and low in saturated and total fats (DASH diet) has been 
shown to lower blood pressure. Dietary fiber seems especially 
important. For every 7 g of dietary fiber ingested, cardiovascu
-
lar risk could be lowered by 9%. Increased dietary fiber lowers 
blood pressure. The effect of diet on blood pressure may be 
mediated by shifts in the microbial species in the gut, the intes
-
tinal microbiota. Additional measures, listed in Table 11–3, 
 
Table 11–3.
 
Lifestyle modifications to manage hypertension.
1
Modification
r
ecommendation
a
ppr
oximate Systolic B
p
 
r
eduction, 
r
ange
Weight reduction
Maintain normal body weight (BMI, 18.5–24.9)
5–20 mm Hg/10 kg weight 
loss
Adopt DASH eating plan
Consume a diet rich in fruits, vegetables, and low-fat dairy products 
 
with a reduced content of saturated fat and total fat
8–14 mm Hg
Dietary sodium reduction
Reduce dietary sodium intake to no more than 100 mEq/day 
 
(2.4 g sodium or 6 g sodium chloride)
2–8 mm Hg
Physical activity
Engage in regular aerobic physical activity such as brisk walking 
 
(at least 30 minutes per day, most days of the week)
4–9 mm Hg

2–8 mm Hg
 
4–9 mm Hg
Moderation of alcohol 
consumption
Limit consumption to no more than two drinks per day (1 oz or 
 
30 mL ethanol [eg, 24 oz beer, 10 oz wine, or 3 oz 80-proof 
 
whiskey]) in most men and no more than one drink per day in 
 
women and lighter-weight persons
2–4 mm Hg
1
For overall cardiovascular risk reduction, stop smoking. The effects of implementing these modifications are dose- and time-dependent 
and could be higher for some individuals.
BMI, body mass index calculated as weight in kilograms divided by the square of height in meters; BP , blood pressure; DASH, Dietary 
Approaches to Stop Hypertension.
Data from Chobanian AV et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure: the JNC 7 report. JAMA. 2003 May 21;289(19):2560–72.
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can prevent or mitigate hypertension or its cardiovascular 
consequences.
All patients with high-normal or elevated blood pressures 
and those with elevated cardiovascular risk should be coun
-
seled about nonpharmacologic approaches to lowering blood 
pressure. Approaches of proven but modest value include 
weight reduction, reduced alcohol consumption, and, in 
some patients, reduced salt intake (less than 5 g salt or 2 g 
sodium). Gradually increasing activity levels should be 
encouraged in previously sedentary patients, but strenuous 
exercise training programs in already active individuals may 
have less benefit. Alternative approaches that may be mod
-
estly effective include relaxation techniques and biofeedback. 
Calcium and potassium supplements have been advocated, 
but their ability to lower blood pressure is limited. Smoking 
cessation will reduce cardiovascular risk. Overall, the effects 
of lifestyle modification on blood pressure are modest.
Appel LJ. The effects of dietary factors on blood pressure. 
Cardiol Clin. 2017 May;35(2):197–212. [PMID: 28411894]
Marques FZ et al. Beyond gut feelings: how the gut microbiota regu
-
lates blood pressure. Nat Rev Cardiol. 2018 Jan;15(1):20–32. 
[PMID: 28836619]
 
»
Who Should Be Treated With Medications?
Treatment should ideally be offered to all persons in 
whom blood pressure reduction, irrespective of initial 
blood pressure levels, will appreciably reduce overall 
cardiovascular risk with an acceptably low rate of 
medication-associated adverse effects. Outcomes data 
indicate that patients with office-based blood pressure 
measurements that consistently exceed 160/100 mm Hg 
will benefit from antihypertensive therapy irrespective of 
cardiovascular risk. Several international guidelines sug
-
gest that treatment thresholds evaluated by home-based 
Table 11–4.
 
Comparison of blood pressure treatment thresholds and targets in the 2017 ACC/AHA guidelines with 
the 2017 Hypertension Canada guidelines.
t
hr
eshold for pharmacotherapy
3
 (mm 
h
g)
t
ar
get blood pressure
3
 (mm 
h
g)
Nonelevated CVD risk
1
: 
a
C
C/
aha
 2017
> 140/90
< 130/80 (“reasonable”)
2
: 
h
ypertension 
 
Canada 2017
> 160/100
< 140/90
e
levated CVD risk
1
: 
a
C
C/
aha
 2017
> 130/80
< 130/80 (“recommended”)
e
2
: 
h
 
> 140/90 (
“
Consider” lower threshold in 
 
certain populations: High-risk and 
 
age > 50 years: >130/80)
< 140/90 (
“Consider” lower goals in certain 
populations: Diabetes: < 130/80
; 
 
High-risk and age > 50 years: < 120/80)
It should be noted that the definition of elevated cardiovascular disease (CVD) risk differs in the two published 2017 guidelines.
1
The ACC/AHA guidelines define elevated risk as the presence of atherosclerotic cardiovascular disease (ASCVD) or a 10-year risk of cardio
-
vascular events exceeding 10% (Greenland P et al. The New 2017 ACC/AHA Guidelines “up the pressure” on diagnosis and treatment of 
hypertension. JAMA. 2017 Dec 5;318(21):2083–4).
2
Hypertension Canada defines elevated risk as one or more of the following: clinical or subclinical cardiovascular disease, chronic kidney 
 
disease, 10-year cardiovascular risk exceeding 15% and age 75 years or older (Leung AA et al; Hypertension Canada. Hypertension Canada’s 
2017 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults. Can J Cardiol. 2017 May;33(5):557–76. 
Erratum in: Can J Cardiol. 2017 Dec;33(12):1733–4).
3
In addition, the 2017 ACC/AHA guidelines for the prevention, detection, evaluation and management of hypertension suggest lower 
treatment thresholds and more aggressive blood pressure goals than other guidelines.
measurements should be lower, perhaps 150/95 mm Hg 
using home blood pressure or daytime ambulatory mea
-
surements. However, prospective outcomes data for 
treatment based on measurements taken outside the

-
treatment based on measurements taken outside the 
clinic are lacking. Most national guidelines indicate that 
treatment should be offered at lower thresholds in those 
with elevated cardiovascular risk or in the presence of 
existing end-organ damage (Table 11–4). The corollary of 
this is that treatment thresholds might reasonably be set 
higher for young people with extremely low cardiovascular 
risk, but specialty referral should be sought in these cases.
Since evaluation of total cardiovascular risk 
 
(Table 11–5) is important in deciding who to treat with 
antihypertensive medications, risk calculators are becom
-
ing essential clinical tools. The American College of Car
-
diology has developed an online toolkit relevant to 
primary prevention (http://www.acc.org/tools-and-practice-
 
support/clinical-toolkits/prevention), and an associated 
App called ASCVD plus (downloadable at http://www.acc.
org/tools-and-practice-support/mobile-resources/
features/2013-prevention-guidelines-ascvd-risk-estimator).
 
»
Goals of Treatment
Traditionally, the most widely accepted goal for blood pres
-
sure management has been less than 140/90 mm Hg. How
-
ever, observational studies suggest that there does not seem 
to be a blood pressure level below which decrements in 
cardiovascular risk taper off, and a number of randomized 
controlled trials have suggested that treatment to blood 
pressure targets considerably below 140 mm Hg may ben
-
efit certain patient groups.
The SPRINT study suggests that outcomes improve in 
nondiabetic patients with considerably elevated cardiovas
-
cular risk when treatment lowers systolic pressure to less 
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Table 11–5.
 
Cardiovascular risk factors.
Major risk factors
 
1
 
Cigar
ette smoking
 
Obesit
y (BMI ≥ 30)
1
 
P
hysical inactivity
 
Dyslipidemia
1
 
Diabet
1
 
M
icroalbuminuria or estimated GFR < 60 mL/min
 
A
ge (> 55 years for men, > 65 years for women)
 
F
amily history of premature cardiovascular disease 
 
(men < 55 
years or women < 65 years)
t
ar
get-organ damage
 
Heart
  
L
eft ventricular hypertrophy
  
Ang
ina or prior myocardial infarction
  
P
rior coronary revascularization
  
Brain
  
S
troke or transient ischemic attack
 
Chr
onic kidney disease
 
P
eripheral arterial disease
 
Retinopathy
1
Components of the metabolic syndrome.
BMI indicates body mass index calculated as weight in kilograms 
divided by the square of height in meters; GFR, glomerular filtration 
rate.
May 21; 289(19):2560–72.
than 120 mm Hg compared to less than 140 mm Hg. On 
the other hand, in the HOPE 3 study of largely nondiabetic 
patients at somewhat lower risk than those in SPRINT, 
reducing blood pressure by an average of 6/3 mm Hg sys
-
tolic from a baseline of 138/82 mm Hg provided no signifi
-
cant outcomes benefits. Therefore, it appears that blood 
pressure targets should be lower in people at greater esti
-
mated cardiovascular risk. In response to the SPRINT 
study, the 2017 Hypertension Canada guidelines urge pre
-
scribers to consider a blood pressure goal of less than 
120/80 mm Hg in patients considered at elevated risk for 
cardiovascular events. The 2017 ACC/AHA guidelines take 
a different approach by defining a 130/80 mm Hg goal as 
“reasonable” in nonelevated risk patients, strengthening 
this to “recommended” in elevated risk hypertensive 
patients. Some experts note that manual office measure
-
ments of around 130/80 mm Hg are likely to approximate 
the lower blood pressure targets specified in the SPRINT 
study, which used automated office blood pressure measur
-
ing devices that have been demonstrated to read 16/7 mm Hg 
lower than manual office readings. The 2017 Canadian 
guidelines acknowledge this disparity in measurement 
methods by specifying that automated office devices should 
be used in the monitoring of patients selected for the 
aggressive blood pressure goal of less than 120/80 mm Hg. 
Table 11–4 compares the treatment threshold and target 
recommendations published in the ACC/AHA and Hyper
-
tension Canada guidelines for 2017.
In the ACCORD study of diabetic patients, treat
-
ment of systolic pressures to below 130–135 mm Hg 
significantly increased the risk of serious adverse effects 
with no additional gain in terms of heart, kidney, or 
retinal disease. On the other hand, reducing systolic 
pressure below 130 mm Hg in this study seemed to fur
-
ther lower the risk of stroke, so lower targets might be 
justified in diabetic patients at high risk for cerebrovas
-
cular events.
Similarly, in the SPS3 trial in patients recovering from 
a lacunar stroke, treating the systolic blood pressure to 
less than 130 mm Hg (mean systolic blood pressure of 
127 mm Hg among treated versus mean systolic blood 
pressure 138 mm Hg among untreated patients) probably 
reduced the risk of recurrent stroke (and with an accept
-
ably low rate of adverse effects from treatment).
 
»
How Low To Go?
Although observational studies indicate that the blood 
pressure-risk relationship holds up at levels considerably 
below 120 mm Hg, there is uncertainty about whether this 
is true for treated blood pressure. This question was 
addressed in a secondary analysis of data from the ONTAR
-
GET and TRANSCEND studies in which participants with 
elevated cardiovascular risk but no history of stroke were 
treated with telmisartan (plus or minus ramipril), or pla

-
-
cebo. The risk of the composite cardiovascular endpoint 
was lowest at a treated systolic blood pressure range 
between 120 mm Hg and 140 mm Hg. Increased risk was 
observed at blood pressures below and above this range. 
The risk of stroke was the only exception, with incremental 
benefit observed below a treated systolic of 120 mm Hg. 
With respect to diastolic blood pressure on treatment, 
composite risk began to increase at levels below 70 mm Hg. 
This suggests that the blood pressure-cardiovascular risk 
relationship evident in observational studies may not hold 
in the case of treated blood pressure and that there are 
grounds for a degree of caution in treating below a systolic 
pressure of 120 mm Hg.
In seeking to simplify decision making in the treatment 
of hypertension, some authors have suggested that a sys
-
tolic blood pressure goal in the 120–130 mm Hg range 
would be safe and effective in high-risk patients, and a 
systolic blood pressure of around 130 mm Hg would be 
reasonable in lower-risk patients.
Data from multiple studies indicate that statins should 
be considered as part of the strategy to reduce overall car
-
diovascular risk. The HOPE3 study of persons at interme
-
diate cardiovascular risk showed that 10 mg of rosuvastatin 
reduced average low-density lipoprotein (LDL) cholesterol 
from 130 mg/dL to 90 mg/dL (3.36–2.33 mmol/L), and 
significantly reduced the risk of multiple cardiovascular 
events, including myocardial infarction and coronary 
revascularization. Low-dose aspirin (81 mg/day) is likely to 
be beneficial in patients older than age 50 with either tar
-
get-organ damage or elevated total cardiovascular risk 
(greater than 20–30%). Care should be taken to ensure that 
blood pressure is controlled to the recommended levels 
before starting aspirin to minimize the risk of intracranial 
hemorrhage.
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ACCORD Study Group; Cushman WC et al. Effects of intensive 
blood-pressure control in type 2 diabetes mellitus. N Engl J 
Med. 2010 Apr 29;362(17):1575–85. [PMID: 20228401]
Böhm M et al. Achieved blood pressure and cardiovascular out
-
comes in high-risk patients: results from ONTARGET and 
TRANSCEND trials. Lancet. 2017 Jun 3;389(10085):2226–37. 
[PMID: 28390695]
27041480]
Yusuf S et al; HOPE-3 Investigators. Cholesterol lowering in 
intermediate-risk persons without cardiovascular disease. N 
Engl J Med. 2016 May 26;374(21):2021–31. [PMID: 27040132]
DRUG THERAPY: CURRENT 
ANTIHYPERTENSIVE AGENTS
There are many classes of antihypertensive drugs of which 
six (diuretics, beta-blockers, renin inhibitors, ACE inhibi
-
tors, calcium channel blockers, and ARBs) are suitable for 
initial therapy based on efficacy and tolerability. A number 
of considerations enter into the selection of the initial 
regimen for a given patient. These include the weight of 
evidence for beneficial effects on clinical outcomes, the 
safety and tolerability of the drug, its cost, demographic 
differences in response, concomitant medical conditions, 
and lifestyle issues. The specific classes of antihypertensive 
medications are discussed below, and guidelines for the 
choice of initial medications are offered.
A. Diuretics
Thiazide diuretics (Table 11–6) are the antihypertensives 
that have been most extensively studied and most consis
-
tently effective in clinical trials. They lower blood pressure 
initially by decreasing plasma volume, but during long-term 
therapy, their major hemodynamic effect is reduction of 
peripheral vascular resistance. Most of the antihypertensive 
effect of these agents is achieved at lower dosages than used 
previously (typically, 12.5 mg of hydrochlorothiazide or 
equivalent), but their biochemical and metabolic effects are 
dose related. Chlorthalidone has the advantage of better 
24-hour blood pressure control than hydrochlorothiazide in 
clinical trials. Thiazides may be used at higher doses if 
plasma potassium is above 4.5 mmol/L. The loop diuretics 
(such as furosemide) may lead to electrolyte and volume 
depletion more readily than the thiazides and have short 
durations of action. Because of these adverse effects, loop 
diuretics should be reserved for use in patients with kidney 
dysfunction (serum creatinine greater than 2.5 mg/dL [208.3 
mcmol/L]; estimated glomerular filtration rate [eGFR] less 
than 30 mL/min) in which case they are more effective than 
thiazides. Relative to beta-blockers and ACE inhibitors, 
diuretics are more potent in blacks, older individuals, the 
obese, and other subgroups with increased plasma volume 
or low plasma renin activity (or both). They are relatively 
more effective in smokers than in nonsmokers. Long-term 
thiazide administration also mitigates the loss of bone min
-
eral content in older women at risk for osteoporosis.
Overall, diuretics administered alone control blood 
pressure in 50% of patients with mild to moderate hyper
-
tension and can be used effectively in combination with all 
other agents. They are also useful for lowering isolated or 
predominantly systolic hypertension. The adverse effects 
of diuretics relate primarily to the metabolic changes listed 
in Table 11–6. Erectile dysfunction, skin rashes, and photo
-
sensitivity are less frequent. Hypokalemia has been a con
-
cern but is uncommon at the recommended dosages. The 
risk can be minimized by limiting dietary salt or increasing 
dietary potassium; potassium replacement is not usually 
required to maintain serum K
+

+
 at greater than 3.5 mmol/L. 
Higher serum K+ levels are prudent in patients at special 
risk from intracellular potassium depletion, such as those 
taking digoxin or with a history of ventricular arrhythmias 
in which case a potassium-sparing agent could be used. 
Compared with ACE inhibitors and ARBs, diuretic therapy 
is associated with a slightly higher incidence of mild new-
onset diabetes. Diuretics also increase serum uric acid and 
may precipitate gout. Increases in blood glucose, triglycer
-
ides, and LDL cholesterol may occur but are relatively 
minor during long-term low-dose therapy. The potential 
for worsening of diabetes is outweighed by the advantages 
of blood pressure control, and diuretics should not be with
-
held from diabetic patients.
B. Beta-Adrenergic Blocking Agents
These drugs are effective in hypertension because they 
decrease the heart rate and cardiac output. The beta-block
-
ers also decrease renin release and are more efficacious in 
populations with elevated plasma renin activity, such as 
younger white patients. They neutralize the reflex tachy
-
cardia caused by vasodilators and are especially useful in 
patients with associated conditions that benefit from the 
cardioprotective effects of these agents. These include indi
-
viduals with angina pectoris, previous myocardial infarc
-
tion, and stable heart failure as well as those with migraine 
headaches and somatic manifestations of anxiety.
Although all beta-blockers appear to be similar in anti
-
hypertensive potency, they differ in a number of pharma
-
cologic properties (these differences are summarized in 
Table 11–7), including specificity to the cardiac beta-
1-receptors (cardioselectivity) and whether they also block 
the beta-2-receptors in the bronchi and vasculature; at 
higher dosages, however, all agents are nonselective. The 
beta-blockers also differ in their pharmacokinetics, lipid 
solubility—which determines whether they cross the 
blood-brain barrier predisposing to central nervous system 
side effects—and route of metabolism. Unlike the tradi
-
tional beta-blockers, carvedilol and nebivolol may produce 
a beneficial hemodynamic profile, reducing peripheral 
vascular resistance by concomitant alpha-blockade 
(carvedilol) and increased nitric oxide release (nebivolol).
The side effects of beta-blockers include inducing or 
exacerbating bronchospasm in predisposed patients; sinus 
node dysfunction and atrioventricular (AV) conduction 
depression (resulting in bradycardia or AV block); nasal 
congestion; Raynaud phenomenon; and central nervous 
system symptoms with nightmares, excitement, depression, 
and confusion. Fatigue, lethargy, and erectile dysfunction 
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Table 11–6.
 
Antihypertensive drugs: diuretics. (In descending order of preference).
Drugs
p
r
oprietary 
Names
Initial Oral 
Doses
Dosage 
r
ange
Cost of 30 
Days 
t
r
eat
-
ment
1
 (
a
ver
-
age Dosage)
a
dv
erse 
e
ff
ects
Comments
t
hiazides and 
r
elated Diuretics
Hydrochloro
-
thiazide 
(HCTZ)
Esidrix, 
Microzide
12.5 or 25 mg 
once daily
12.5–50 mg 
once daily
$0.08/25 mg
$2.40
↓
K
+
, 
↓
Mg
2+
, 
↑
Ca
2+
, 
↓
Na+, 
↑
uric acid, 
 
↑
glucose, 
↑
LDL cholesterol, 
 
↑
triglycerides; rash, erectile dysfunction.
Low dosages effective in many patients without 
associated metabolic abnormalities; metolazone 
more effective with concurrent kidney disease; 
indapamide does not alter serum lipid levels.
Thalitone
once daily
12.5–50 mg 
once daily
$1.21/25 mg
$36.30
 
Metolazone
Zaroxolyn
1.25 or 2.5 mg 
once daily
1.25–5 mg 
once daily
$2.36/5 mg
$70.80
 
Indapamide
Lozol
2.5 mg once 
daily
2.5–5 mg once 
daily
$0.83/2.5 mg
$24.90
 
Bendroflume
-
thiazide
Aprinox
Neo-Naclex
2.5 mg once 
daily
—
—
—
—
Not available in United States
Loop Diuretics
Lasix
20 mg twice 
daily
40–320 mg in 2 
or 3 doses
$0.16/40 mg
$9.60
Same as thiazides, but higher risk of 
excessive diuresis and electrolyte 
imbalance. Increases calcium 
excretion.
Furosemide: Short duration of action a disadvan
-
tage; should be reserved for patients with kidney 
disease or fluid retention. Poor antihypertensive.
Ethacrynic acid
Edecrin
50 mg once 
daily
50–100 mg 
once or 
$23.95/25 mg
$1437.00
Bumetanide
(generic)
0.25 mg twice 
daily
0.5–10 mg in 2 
or 3 doses
$1.09/1 mg
$65.40
Torsemide
Demadex
5 mg once 
daily
5–10 mg once 
daily
$0.70/10 mg
$21.00
Torsemide: Effective blood pressure medication at 
low dosage.
a
ldost
erone 
r
eceptor Blockers
Aldactone
once daily
12.5–100 mg 
once daily
$0.46/25 mg
$13.80
Hyperkalemia, metabolic acidosis, 
Can be useful add-on therapy in patients with 
refractory hypertension.
Amiloride
(generic)
5 mg once 
daily
daily
$1.28/5 mg
$38.40
(
continued
 
)
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Chapter 11 
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Drugs
p
r
oprietary 
Names
Doses
Dosage 
r
ange
Cost of 30 
Days 
t
r
eat
-
ment
1
 (
a
ver
-
a
dv
erse 
e
ff
ects
Comments
Inspra
25 mg once 
daily
25–100 mg 
once daily
$4.34/25 mg
$130.20
Combination 
p
r
oducts
HCTZ and 
triamterene
Dyazide, Max
-
zide-25 
(25/37.5 mg)
1 tab once 
daily
1 or 2 tabs 
once daily
$0.27
$8.10
Same as thiazides plus GI disturbances, 
hyperkalemia rather than hypokale
-
mia, headache; triamterene can cause 
kidney stones and kidney dysfunction; 
spironolactone causes gynecomastia. 
Hyperkalemia can occur if this combi
-
nation is used in patients with 
advanced kidney disease or those tak
-
ing ACE inhibitors.
Use should be limited to patients with demonstra
-
ble need for a potassium-sparing agent.
HCTZ and 
amiloride
(generic) (50/5 
mg)
½ tab once 
daily
1 or 2 tabs 
once daily
$1.16
$34.80
HCTZ and 
spironolac
-
tone
Aldactazide 
(25/25 mg; 
50/50 mg)
1 tab (25/25 
mg) once 
daily
1–4 tabs once 
daily
$1.24/(25/25 
mg)
$37.20
1
Source: 
Red Book
 (electronic version), Truven Health Analytics Information, http://www.micromedexsolutions.com, accessed March 1, 2018. AWP may not accurately represent the actual pharmacy cost 
ACE, angiotensin-converting enzyme; GI, gastrointestinal; LDL, low-density lipoprotein.
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Table 11–7.
 
Antihypertensive drugs: beta-adrenergic blocking agents.
Special 
p
r
operties
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
Cost per 
Unit
Cost of 30 Days 
t
r
eatment 
(Based on 
a
v
er
-
1
Beta-1 
Selec
-
tivity
2
IS
a
3
MS
a
4
Lipid 
Solubility
r
enal vs 
h
epatic 
e
limination
Comments
5
Acebutolol
Sectral
400 mg once 
daily
200–1200 mg in 1 or 
2 doses
$0.69/400 mg
$20.70
+
+
+
+
H > R
Positive ANA; rare LE syndrome; 
 
also indicated for arrhythmias. 
Doses > 800 mg have beta-
 
1 and beta-2 effects.
Atenolol
Tenormin
25 mg once 
daily
25–100 mg once 
daily
$0.83/50 mg
$24.90
+
0
0
0
R
Also indicated for angina pecto
-
ris and post-MI. Doses > 100 
mg have beta-1 and beta-2 
effects.
Atenolol/
chlorthali
-
done
Tenoretic
50 mg/25 mg 
once daily
50 mg/25 mg–100 mg
 
/25 mg once daily
$1.88/50 mg/
 
25 mg
$56.40
+
0
0
0
R
Betaxolol
Kerlone
10 mg once 
daily
10–40 mg once daily
$0.78/10 mg
$23.40
+
0
0
+
H > R
Zebeta
5 mg once 
daily
5–20 mg once daily
$1.22/10 mg
$36.60
+
0
0
0
R = H
Bisoprolol also effective for 
Bisoprolol 
and HCTZ
Ziac
2.5 mg/6.25 
mg once 
daily
2.5 mg/6.25 mg–10 
mg/6.25 mg once 
daily
$1.13/2.5/
 
6.25 mg
$33.90
+
0
0
0
R = H
Low-dose combination 
approved for initial therapy.
Coreg
 
Coreg CR
6.25 mg twice 
daily
20 mg ER 
once daily
12.5–50 mg in 
 
2 doses
20–80 mg ER once 
daily
$1.95/25 mg
 
$9.91/any 
tablet
$117.00 (25 mg 
twice a day)
$297.30
0
0
0
+++
H > R
Alpha:beta blocking activity 1:9; 
may cause orthostatic symp
-
toms; effective for heart fail
-
ure. Nitric oxide potentiating 
vasodilatory activity.
Labetalol
Trandate
100 mg twice 
daily
200–2400 mg in 
 
2 doses
$0.71/200 mg
$42.60
0
0/+
0
++
H
Alpha:beta blocking activity 
 
1:3; more orthostatic hypoten
-
sion, fever, hepatotoxicity.
Lopressor
 
Toprol-XL (SR 
prepara
-
tion)
50 mg twice 
daily
25 mg once 
daily
50–200 mg twice 
daily
25–400 mg once 
daily
$0.56/50 mg
 
$1.58/100 mg
$33.60
 
$47.40
+
0
+
+++
H
-
ris and post-MI. Approved for 
heart failure. Doses > 100 mg 
have beta-1 and beta-2 
effects.
Metoprolol 
and HCTZ
Lopressor 
HCT
50 mg/12.5 
mg twice 
daily
50 mg/25 mg–200 
mg/50 mg
$1.63/100 
mg/25 mg
$48.90
+
0
+
+++
H
(
continued
 
)
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Special 
p
r
operties
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
Cost per 
Unit
t
r
eatment 
(Based on 
a
v
er
-
1
Beta-1 
Selec
-
tivity
2
IS
a
3
MS
a
4
Lipid 
r
enal vs 
h
epatic 
e
Comments
5
Nadolol
Corgard
20 mg once 
daily
20–320 mg once 
daily
$3.97/40 mg
$119.10
0
0
0
0
R
Nadolol and 
bendro
-
flumetha
-
zide
Corzide
40 mg/5 mg 
once daily
40 mg/5 mg–80 
mg/5 mg once 
daily
$4.66/40 mg/
 
5 mg
$139.80
 
Nebivolol
Bystolic
5 mg once 
daily
40 mg once daily
$5.23/5 mg
$156.90
+
0
0
++
H
Nitric oxide potentiating 
 
Penbutolol
Levatol
20 mg once 
daily
20–80 mg once daily
$4.07/20 mg
$122.10
0
+
0
++
R > H
Pindolol
Visken
5 mg twice 
daily
10–60 mg in 2 doses
$1.32/5 mg
$79.20
0
++
+
+
H > R
In adults, 35% renal clearance.
Inderal
 
Inderal LA
 
InnoPran XL
20 mg twice 
daily
80 mg ER 
once daily
80 mg ER 
once 
nightly
40–640 mg in 2 doses
 
120–640 mg ER once 
daily
80–120 mg ER once 
nightly
$0.72/40 mg
 
$1.92/120 mg
 
$30.20/120 mg
$43.20
 
$57.60
 
$906.00
0
0
++
+++
H
-
ris and post-MI.
Propranolol 
and HCTZ
(generic)
40 mg/25 mg 
80 mg/25 mg 
 
$1.41/80 
mg/25 mg
$84.60
0
0
++
+++
H
Timolol
(generic)
5 mg twice 
daily
$1.70/10 mg
$102.00
0
0
0
++
H > R
Also indicated for post-MI; 80% 
hepatic clearance.
1
Source: 
Red Book
2
Agents with beta-1 selectivity are less likely to precipitate bronchospasm and decrease peripheral blood flow in low doses, but selectivity is only relative.
3
Agents with ISA cause less resting bradycardia and lipid changes.
4
MSA generally occurs at concentrations greater than those necessary for beta-adrenergic blockade. The clinical importance of MSA by beta-blockers has not been defined.
5
Adverse effects of all beta-blockers: bronchospasm, fatigue, sleep disturbance and nightmares, bradycardia and atrioventricular block, worsening of heart failure, cold extremities, gastrointestinal 
disturbances, erectile dysfunction, 
↑
 triglycerides, 
↓
 HDL cholesterol, rare blood dyscrasias.
ANA, antinuclear antibody; HCTZ, hydrochlorothiazide; ISA, intrinsic sympathomimetic activity; LE, lupus erythematosus; MI, myocardial infarction; MSA, membrane-stabilizing activity; SR, sustained 
release; 0, no effect; +, some effect; ++, moderate effect; +++, most effect.
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may occur. The traditional beta-blockers (but not the vaso
-
dilator beta-blockers carvedilol and nebivolol) have an 
adverse effect on lipids and glucose metabolism. Metoprolol 
reduces mortality and morbidity in patients with chronic 
stable heart failure with reduced ejection fraction (see 
Chapter 10). Carvedilol and nebivolol, which maintain car
-
diac output, are also beneficial in patients with systolic left 
ventricular dysfunction. Beta-blockers are used cautiously in 
patients with type 1 diabetes, since they can mask the symp
-
toms of hypoglycemia and prolong these episodes by inhibit
-
ing gluconeogenesis. These drugs should also be used with 
caution in patients with advanced peripheral vascular dis
-
ease associated with rest pain or nonhealing ulcers, but they 
are generally well tolerated in patients with mild claudica
-
tion. Nebivolol can be safely used in patients with stage II 
claudication (claudication at 200 m).
In treatment of pheochromocytoma, beta-blockers should 
not be administered until alpha-blockade has been established
. 
Otherwise, blockade of vasodilatory beta-2-adrenergic recep
-
tors will allow unopposed vasoconstrictor alpha-adrenergic 
receptor activation with worsening of hypertension. 
For the 
same reason, beta-blockers should not be used to treat hyper
-
tension arising from cocaine use
.
Because of the lack of efficacy in primary prevention of 
myocardial infarction and inferiority compared with other 
drugs in prevention of stroke and left ventricular hypertro
-
phy, traditional beta-blockers should not be regarded as 
ideal first-line agents in the treatment of hypertension 
without specific compelling indications (such as active 
coronary artery disease). It might be that vasodilating beta-
blockers will emerge as alternative first-line antihyperten
-
sives, but this possibility has yet to be rigorously tested in 
outcomes studies.
Great care should be exercised if the decision is made, 
in the absence of compelling indications, to remove beta-
blockers from the treatment regimen because abrupt with
-
drawal can precipitate acute coronary events and severe 
increases in blood pressure.
C. Renin Inhibitors
Since renin cleavage of angiotensinogen is the rate-limiting 
step in the renin-angiotensin cascade, the most efficient 
inactivation of this system would be expected with renin 
inhibition. Conventional ACE inhibitors and ARBs proba
-
bly offer incomplete blockade, even in combination. Aliski
-
ren, a renin inhibitor, binds the proteolytic site of renin, 
thereby preventing cleavage of angiotensinogen. As a conse
-
quence, levels of angiotensins I and II are reduced and renin 
concentration is increased. Aliskiren effectively lowers 
blood pressure, reduces albuminuria, and limits left ven
-
tricular hypertrophy, but it has yet to be established as a 
first-line drug based on outcomes data. The combination of 
aliskiren with ACE inhibitors or ARBs in persons with type 
2 diabetes mellitus offers no advantage and might even 
increase the risk of adverse cardiac or renal consequences.
D. Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors are commonly used as the initial medica
-
tion in mild to moderate hypertension (Table 11–8). Their 
primary mode of action is inhibition of the renin–angiotensin–
aldosterone system, but they also inhibit bradykinin degra
-
dation, stimulate the synthesis of vasodilating prostaglandins, 
and can reduce sympathetic nervous system activity. These 
latter actions may explain why they exhibit some effect 
even in patients with low plasma renin activity. ACE 
inhibitors appear to be more effective in younger white 
patients. They are relatively less effective in blacks and 
older persons and in predominantly systolic hypertension. 
Although as single therapy they achieve adequate antihy
-
pertensive control in only about 40–50% of patients, the 
combination of an ACE inhibitor and a diuretic or calcium

-
combination of an ACE inhibitor and a diuretic or calcium 
channel blocker is potent.
ACE inhibitors are the agents of choice in persons with 
type 1 diabetes with frank proteinuria or evidence of kid
-
ney dysfunction because they delay the progression to end-
stage kidney disease. Many authorities have expanded this 
indication to include persons with type 1 and type 2 diabetics 
with microalbuminuria who do not meet the usual criteria 
for antihypertensive therapy. ACE inhibitors may also 
delay the progression of nondiabetic kidney disease. The 
Heart Outcomes Prevention Evaluation (HOPE) trial dem
-
onstrated that the ACE inhibitor ramipril reduced the 
number of cardiovascular deaths, nonfatal myocardial 
infarctions, and nonfatal strokes and also reduced the inci
-
dence of new-onset heart failure, kidney dysfunction, and 
new-onset diabetes in a population of patients at high risk 
for vascular events. Although this was not specifically a 
hypertensive population, the benefits were associated with 
a modest reduction in blood pressure, and the results infer
-
entially support the use of ACE inhibitors in similar hyper
-
tensive patients. ACE inhibitors are a drug of choice 
(usually in conjunction with a diuretic and a beta-blocker) 
in patients with heart failure with reduced ejection fraction 
and are indicated also in asymptomatic patients with 
reduced ejection fraction. An advantage of the ACE inhibi
-
tors is their relative freedom from troublesome side effects. 
Severe hypotension can occur in patients with bilateral 
renal artery stenosis; sudden increases in creatinine may 
ensue but are usually reversible with discontinuation of 
ACE inhibition. Hyperkalemia may develop in patients 
with kidney disease and type IV renal tubular acidosis 
(commonly seen in patients with diabetes) and in older 
adults. A chronic dry cough is common, seen in 10% of 
patients or more, and may require stopping the drug. Skin 
rashes are observed with any ACE inhibitor. Angioedema 
is an uncommon but potentially dangerous side effect of all 
agents of this class because of their inhibition of kininase. 
Exposure of the fetus to ACE inhibitors during the second 
and third trimesters of pregnancy has been associated with 
a variety of defects due to hypotension and reduced renal 
blood flow.
E. Angiotensin II Receptor Blockers
ARBs can improve cardiovascular outcomes in patients 
with hypertension as well as in patients with related con
-
ditions such as heart failure and type 2 diabetes with 
nephropathy. ARBs have not been compared with ACE 
inhibitors in randomized controlled trials in patients with 
hypertension, but two trials comparing losartan with 
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Table 11–8.
 
Antihypertensive drugs: renin and ACE inhibitors and angiotensin II receptor blockers.
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
Cost of 30 
Days 
t
r
eat
-
ment (
a
v
er
-
1
a
dv
erse 
e
ff
ects
Comments
r
enin Inhibitors
Aliskiren
Tekturna
150 mg once 
daily
150–300 mg 
once daily
$7.20/150 mg
$216.00
Angioedema, hypotension, hyperkalemia.
Contraindicated in pregnancy.
Probably metabolized by CYP3A4. Absorption is 
inhibited by high-fat meal.
Aliskiren and 
HCTZ
Tekturna HCT
150 mg/
 
12.5 mg 
once daily
150 mg/12.5 mg
 
–300 mg/
 
25 mg 
 
once daily
$7.20/150 mg/
 
12.5 mg
$216.00
a
C
e
 Inhibitors
Benazepril
Lotensin
10 mg once 
daily
5–40 mg in 
 
1 or 2 doses
$1.05/20 mg
$31.50
Cough, hypotension, dizziness, kidney dys
-
function, hyperkalemia, angioedema; 
taste alteration and rash (may be more 
frequent with captopril); rarely, protein
-
uria, blood dyscrasia. Contraindicated in 
More fosinopril is excreted by the liver in 
patients with kidney dysfunction (dose 
reduction may or may not be necessary). 
Captopril and lisinopril are active without 
metabolism. Captopril, enalapril, lisinopril, 
and quinapril are approved for heart 
failure.
Benazepril and 
HCTZ
Lotensin HCT
5 mg/6.25 mg 
once daily
5 mg/
 
6.25 mg–
 
20 mg/25 mg
$2.07/any dose
$62.10
 
amlodipine
Lotrel
10 mg/2.5 mg 
once daily
10 mg/
 
2.5 mg–
 
40 mg/10 mg
$3.32/20 mg/
 
10 mg
$99.60
 
Captopril
Capoten
25 mg twice 
daily
50–450 mg in 
 
2 or 3 doses
$1.36/25 mg
$81.60
 
Captopril and 
HCTZ
Capozide
25 mg/15 mg 
25 mg/
 
15 mg–
 
50 mg/25 mg
$2.85/25 mg/
 
15 mg
$171.00
 
Enalapril
Vasotec
5 mg once 
daily
5–40 mg in 
 
1 or 2 doses
$1.48/20 mg
$44.40
 
Enalapril and 
HCTZ
Vaseretic
5 mg/12.5 mg 
once daily
5 mg/
 
12.5 mg–
 
10 mg/25 mg
$1.10/10 
mg/25 mg
$33.00
 
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(
continued
 
)
Fosinopril
Monopril
10 mg once 
daily
10–80 mg in
 
 1 or 2 doses
$1.19/20 mg
$35.70
 
Fosinopril and 
HCTZ
Monopril-HCT
10 mg/12.5 mg 
once daily
10 mg/12.5 mg
 
–20 mg/
 
12.5 mg
$1.26/any dose
$37.80
Prinivil, Zestril
daily
5–40 mg once 
daily
$0.57/20 mg
$17.10
Lisinopril and 
HCTZ
Prinzide or 
Zestoretic
once daily
 
–20 mg/
 
12.5 mg
$1.20/20 
mg/12.5 mg
$36.00
Moexipril
Univasc
7.5 mg once 
daily
7.5–30 mg in 
 
1 or 2 doses
$1.39/7.5 mg
$41.70
Moexipril and 
HCTZ
Uniretic
7.5 mg/12.5 
mg once 
daily
7.5 mg/12.5 mg
 
–15 mg/
 
25 mg
$1.34/7.5 
mg/12.5 mg
$40.20
Perindopril
Aceon
4 mg once 
daily
4–16 mg in 
 
1 or 2 doses
$2.80/8 mg
$84.00
Perindopril and 
Prestalia
3.5 mg/2.5 mg 
once daily
14 mg/10 mg 
once daily
$5.87/7 mg/5 
mg
$176.10
Quinapril
Accupril
10 mg once 
daily
10–80 mg in 
 
1 or 2 doses
$1.22/20 mg
$36.60
Quinapril and 
HCTZ
Accuretic
once daily
10 mg/
 
12.5 mg–
 
20 mg/25 mg
$1.22/20 
mg/12.5 mg
$36.60
Ramipril
Altace
2.5 mg once 
daily
2.5–20 mg in 
 
1 or 2 doses
$1.80/5 mg
$54.00
Mavik
1 mg once 
daily
1–8 mg once 
daily
$1.24/4 mg
$37.20
Trandolapril 
and 
verapamil
Tarka
2 mg/180 mg 
ER once 
daily
2 mg/180 mg 
ER–8 mg/
 
480 mg
 
 ER
$5.29/any dose
$158.70
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Chapter 11 
468
 CMDT 2019
a
ngiot
ensin II 
r
Azilsartan
Edarbi
40 mg once 
daily
40–80 mg 
 
once daily
$7.67/80 mg
$230.10
Azilsartan and 
-
done
Edarbychlor
40 mg/12.5 mg 
once daily
40 mg/
 
12.5–
 
40 mg/
 
25 mg 
 
once daily
$7.24/any dose
$217.20
Hyperkalemia, kidney dysfunction, rare 
angioedema. Combinations have addi
-
tional side effects. Contraindicated in 
Losartan has a flat dose-response curve. 
 
Valsartan and irbesartan have wider 
 
dose-response ranges and longer 
 
durations of action. Addition of low-dose 
diuretic (separately or as combination pills) 
increases the response.
Candesartan 
cilexitil
Atacand
16 mg 
 
once daily
8–32 mg 
 
once daily
$3.06/16 mg
$91.80
 
cilexitil and 
HCTZ
Atacand HCT
16 mg/12.5 mg 
once daily
32 mg/12.5 mg 
once daily
$4.72/16 
mg/12.5 mg
$141.60
 
Eprosartan
Teveten
600 mg 
 
once daily
400–800 mg in 
1–2 doses
$11.42/600 mg
$342.60
 
Irbesartan
Avapro
150 mg 
 
once daily
150–300 mg 
once daily
$3.07/150 mg
$92.10
Irbesartan and 
HCTZ
Avalide
150 mg/12.5 
mg 
 
once daily
150–300 mg 
irbesartan 
once daily
$3.71/150 mg
$111.30
Losartan
Cozaar
50 mg 
 
once daily
25–100 mg in 
 
1 or 2 doses
$0.81/50 mg
$24.30
Losartan and 
HCTZ
Hyzaar
50 mg/12.5 mg 
once daily
50 mg/12.5 mg
 
–100 mg/
 
25 mg
 
 tablets
 
 once daily
$0.28/50 
mg/12.5 mg/
tablet
$8.40
Olmesartan
Benicar
20 mg 
 
once daily
20–40 mg 
 
once daily
$6.28/20 mg
$188.40
Table 11–8
.
 
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
Cost of 30 
Days 
t
r
eat
-
ment (
a
v
er
-
1
a
dv
erse 
e
ff
ects
Comments
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Olmesartan 
and HCTZ
Benicar HCT
20 mg/12.5 mg 
once daily
20 mg/1
 
2.5 mg–
 
40 mg/25 mg 
once daily
$6.28/20 
mg/12.5 mg
$188.40
and 
Azor
20 mg/5 mg 
once daily
20 mg/5 mg–
 
40 mg/
 
10 mg
$3.03/20 mg/
 
5 mg
$90.90
and amlo
-
dipine and 
HCTZ
Tribenzor
20 mg/5 
mg/12.5 mg 
once daily
20 mg/
 
5 mg/
 
12.5 mg–
 
40 mg/10 
mg/25 mg 
once daily
$4.54/20 mg/
 
5 mg/
 
12.5 mg
$136.20
Telmisartan
Micardis
40 mg once 
daily
20–80 mg 
 
once daily
$4.34/40 mg
$130.20
Telmisartan 
and HCTZ
Micardis HCT
once daily
40 mg/
 
12.5 mg–
 
80 mg/
 
25 mg 
 
once daily
$4.83/
 
40 mg/
 
12.5 mg
$144.90
and 
Twynsta
40 mg/5 mg 
once daily
40 mg/
 
5 mg–
 
80 mg/
 
10 mg 
 
once daily
$5.20/any dose
$156.00
Valsartan
Diovan
80 mg once 
daily
80–320 mg 
once daily
$0.72/160 mg
$21.60
Valsartan and 
HCTZ
Diovan HCT
80 mg/12.5 mg 
once daily
80–320 mg val
-
sartan once 
daily
$4.27/
 
160 mg/
 
12.5 mg
$128.10
(
continued
 
)
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Exforge
160 mg/5 mg 
once daily
160 mg/
 
5 mg–
 
320 mg/
 
10 mg once 
daily
$1.71/
 
160 mg/
 
10 mg
$51.30
Other Combination 
p
r
oducts
Amlodipine 
and valsar
-
tan and 
HCTZ
Exforge HCT
5 mg/160 
mg/12.5 mg 
once daily
10 mg/320 
mg/25 mg 
up to once 
daily
$5.47/160 mg 
valsartan
$164.10
1
Source: 
Red Book
ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide.
 
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
Cost of 30 
Days 
t
r
eat
-
ment (
a
v
er
-
1
a
dv
erse 
e
ff
ects
Comments
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captopril in heart failure and post–myocardial infarction 
left ventricular dysfunction showed trends toward worse 
outcomes in the losartan group. By contrast, valsartan 
seems as effective as ACE inhibitors in these settings. 
Within group heterogeneity of antihypertensive potency 
and duration of action might explain such observations. 
The Losartan Intervention for Endpoints (LIFE) trial in 
nearly 9000 hypertensive patients with electrocardio
-
graphic evidence of left ventricular hypertrophy—comparing 
losartan with the beta-blocker atenolol as initial ther
-
apy—demonstrated a significant reduction in stroke with 
losartan. Of note is that in diabetic patients, death and 
myocardial infarction were also reduced, and there was a 
lower occurrence of new-onset diabetes. In this trial, as in 
the Antihypertensive and Lipid-Lowering Treatment to 
Prevent Heart Attack Trial (ALLHAT), blacks treated 
with renin-angiotensin-aldosterone system (RAAS) 
inhibitors exhibited less blood pressure reduction and 
less benefit with regard to clinical end points. In the 
treatment of hypertension, combination therapy with an 
ACE inhibitor and an ARB is not advised because it 
generally offers no advantage over monotherapy at maxi
-
mum dose with addition of a complementary class where 
Unlike ACE inhibitors, the ARBs rarely cause cough 
and are less likely to be associated with skin rashes or 
angioedema. However, as seen with ACE inhibitors, hyper
-
kalemia can be a problem, and patients with bilateral renal 
artery stenosis may exhibit hypotension and worsened 
kidney function. Olmesartan has been linked to a sprue-
like syndrome, presenting with abdominal pain, weight 
loss, and nausea, which subsides upon drug discontinua
-
tion. There is evidence from an observational study sug
-
gesting that ARBs and ACE inhibitors are less likely to be 
associated with depression than calcium channel blockers 
and beta-blockers.
F. Aldosterone Receptor Antagonists
Spironolactone and eplerenone are natriuretic in sodium-
retaining states, such as heart failure and cirrhosis, but only 
very weakly so in hypertension. These drugs have 
reemerged in the treatment of hypertension, particularly in 
resistant patients and are helpful additions to most other 
antihypertensive medications. Consistent with the increas
-
ingly appreciated importance of aldosterone in essential 
hypertension, the aldosterone receptor blockers are effec
-
tive at lowering blood pressure in all hypertensive patients 
regardless of renin level, and are also effective in blacks. 
Aldosterone plays a central role in target-organ damage, 
including the development of ventricular and vascular 
hypertrophy and renal fibrosis. Aldosterone receptor 
antagonists ameliorate these consequences of hyperten
-
sion, to some extent independently of effects on blood 
pressure. Spironolactone can cause breast pain and gyneco
-
mastia in men through activity at the progesterone recep
-
tor, an effect not seen with the more specific eplerenone. 
Hyperkalemia is a problem with both drugs, chiefly in 
patients with chronic kidney disease. Hyperkalemia is 
more likely if the pretreatment plasma potassium exceeds 
4.5 mmol/L.
G. Calcium Channel Blocking Agents
These agents act by causing peripheral vasodilation but 
with less reflex tachycardia and fluid retention than other 
vasodilators. They are effective as single-drug therapy in 
approximately 60% of patients in all demographic groups 
and all grades of hypertension (Table 11–9). For these rea
-
sons, they may be preferable to beta-blockers and ACE 
inhibitors in blacks and older persons. Verapamil and dil
-
tiazem should be combined cautiously with beta-blockers 
because of their potential for depressing AV conduction 
and sinus node automaticity as well as contractility.
Initial concerns about possible adverse cardiac effects of 
calcium channel blockers have been convincingly allayed

calcium channel blockers have been convincingly allayed 
by several subsequent large studies that have demonstrated 
that calcium channel blockers are equivalent to ACE 
inhibitors and thiazide diuretics in prevention of coronary 
heart disease, major cardiovascular events, cardiovascular 
death, and total mortality. A protective effect against stroke 
with calcium channel blockers is well established, and in 
two trials (ALLHAT and the Systolic Hypertension in 
Europe trial), these agents appeared to be more effective 
than diuretic-based therapy.
The most common side effects of calcium channel 
blockers are headache, peripheral edema, bradycardia, and 
constipation (especially with verapamil in older adults). 
The dihydropyridine agents—nifedipine, nicardipine, isra
-
dipine, felodipine, nisoldipine, and amlodipine—are more 
likely to produce symptoms of vasodilation, such as head
-
ache, flushing, palpitations, and peripheral edema. Edema 
is minimized by coadministration of an ACE inhibitor or 
ARB. Calcium channel blockers have negative inotropic 
effects and should be used cautiously in patients with car
-
diac dysfunction. Amlodipine is the only calcium channel 
blocker with established safety in patients with severe heart 
failure.
H. Alpha-Adrenoceptor Antagonists
Prazosin, terazosin, and doxazosin (Table 11–10) block 
postsynaptic alpha-receptors, relax smooth muscle, and 
reduce blood pressure by lowering peripheral vascular 
resistance. These agents are effective as single-drug therapy 
in some individuals, but tachyphylaxis may appear during 
long-term therapy and side effects are relatively common. 
These include marked hypotension after the first dose 
which, therefore, should be small and given at bedtime. 
Post-dosing palpitations, headache, and nervousness may 
continue to occur during long-term therapy; these symp
-
toms may be less frequent or severe with doxazosin 
because of its more gradual onset of action. Cataractec
-
tomy in patients exposed to alpha-blockers can be compli
-
cated by the floppy iris syndrome, even after discontinuation 
of the drug, so the ophthalmologist should be alerted that 
the patient has been taking the drug prior to surgery.
Unlike beta-blockers and diuretics, alpha-blockers have 
no adverse effect on serum lipid levels—in fact, they 
increase HDL cholesterol while reducing total cholesterol. 
Whether this is beneficial in the long term has not been 
established. In ALLHAT, persons receiving doxazosin as 
initial therapy had a significant increase in heart failure 
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Table 11–9.
 
Antihypertensive drugs: calcium channel blocking agents.
Special 
p
r
operties
Drug
p
r
oprietary 
Name
Dosage
Dosage 
r
ange
t
r
eatment (
a
v
er
-
1
p
eripher
al 
Vasodilation
Cardiac 
a
ut
o
-
maticity and 
Conduction
Contractility
a
dv
erse 
e
ff
ects
Comments
Nondihydropyridine 
a
gen
ts
Diltiazem
Cardizem SR
90 mg 
 
180–360 mg in 
 
2 doses
$283.20 (120 mg 
twice daily)
++
↓↓
↓↓
Edema, headache, 
 
bradycardia, GI 
 
disturbances, dizziness, 
AV block, heart failure, 
urinary frequency.
Also approved for 
angina.
Cardizem CD
180 mg ER 
 
once daily
180–360 mg ER 
 
once daily
$61.50 (240 mg 
once daily)
Cartia XT
180 or 240 mg ER 
once daily
180–480 mg ER 
 
once daily
Dilacor XR
once daily
180–540 mg ER 
 
once daily
$42.90 (240 mg 
Dilt-CD
once daily
 
once daily
Diltia XT
once daily
 
once daily
Taztia XT
120 or 180 mg ER 
once daily
120–540 mg ER 
 
once daily
$53.40 (240 mg 
Tiazac
120 or 240 mg ER 
once daily
 
once daily
Verapamil
Calan
80 mg three 
80–480 mg in 
 
3 divided doses
$35.10 (80 mg 
three times 
daily)
++
↓↓↓
↓↓↓
Same as diltiazem but 
more likely to cause 
constipation and heart 
failure.
angina and 
Calan SR
180 mg ER 
 
once daily
180–480 mg ER
 
 in 1 or 2 doses
$49.20 (240 mg 
Verelan
once daily
240–480 mg ER 
 
once daily
$68.70 (240 mg 
Verelan PM
100 or 200 mg ER 
once daily
100–400 mg ER 
 
once daily
$75.90 (200 mg 
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Dihydropyridines
Amlodip
-
ine
Norvasc
2.5 mg 
 
once daily
2.5–10 mg 
 
once daily
$67.80 (10 mg 
+++
↓
/0
↓
/0
Edema, dizziness, 
 
palpitations, flushing, 
headache, hypotension, 
tachycardia, GI distur
-
bances, urinary 
frequency.
Amlodipine, 
 
nicardipine, 
and nifedipine 
also approved 
for angina.
Amlodip
-
ine and 
atorvas
-
tatin
Caduet
2.5 mg/10 mg 
once daily
10 mg/80 mg 
 
once daily
$281.10 (10 mg/
 
40 mg daily)
+++
↓/
0
↓
/0
Felodipine
Plendil
5 mg ER once 
daily
5–10 mg ER 
 
once daily
$81.60 (10 mg ER 
daily)
+++
↓
/0
↓
/0
Myopathy, hepatotoxicity, 
edema with amlodipine 
and atorvastatin.
Isradipine
DynaCirc
2.5 mg twice 
daily
2.5–5 mg 
 
$120.00 (5 mg 
+++
↓
/0
↓
 
Nicardip
-
ine
Cardene
20 mg three 
20–40 mg 
 
$200.70 (20 mg 
daily)
+++
↓
/0
↓
 
Nifedipine
Adalat CC
30 mg ER once 
daily
30–90 mg ER 
 
once daily
$74.40/60 mg 
 
daily
+++
↓
↓↓
 
Afeditab CR
daily
30–90 mg ER 
 
once daily
$67.20/60 mg 
 
daily
 
Procardia XL
30 or 60 mg ER 
once daily
30–120 mg ER
 
 once daily
$54.90/60 mg 
 
daily
 
Nisoldip
-
ine
Sular
17 mg daily
17–34 mg daily
$251.70 (34 mg 
+++
↓
/0
↓
 
1
Source: 
Red Book
AV, atrioventricular; GI, gastrointestinal.
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 CMDT 2019
Table 11–10.
 
Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators.
Drug
p
r
oprietary 
Names
Initial 
Dosage
Dosage 
r
ange
t
r
eat
-
ment (
a
v
erage Dosage)
1
a
dv
erse 
e
ff
ects
Comments
a
lpha-
a
dr
enoceptor Blockers
Doxazosin
Cardura
Cardura XL
1 mg at 
bedtime
4 mg ER once 
daily
1–16 mg 
 
once daily
4–8 mg ER 
 
once daily
$1.03/4 mg
$6.42/4 mg ER
$30.90 (4 mg once daily)
$192.60 (4 mg ER 
 
Syncope with first dose; postural hypotension, 
dizziness, palpitations, headache, 
 
weakness, drowsiness, sexual dysfunction, 
 
anticholinergic effects, urinary incontinence; 
first-dose effects may be less with doxazosin.
May 
↑
 HDL and 
↓
 LDL choles
-
terol. May provide short-term 
relief of obstructive prostatic 
symptoms. Less effective in 
preventing cardiovascular 
events than diuretics.
Prazosin
Minipress
1 mg at 
bedtime
2–20 mg in 
 
2 or 3 doses
$2.18/5 mg
$130.80 (5 mg 
 
Terazosin
Hytrin
1 mg at 
bedtime
1–20 mg in 
 
1 or 2 doses
$1.60/1, 2, 5, 
 
10 mg
$48.00 (5 mg once daily)
Central Sympatholytics
Clonidine
Catapres
Catapres TTS 
(transdermal 
patch)
0.1 mg twice 
daily
0.1 mg/day 
patch 
weekly
0.2–0.6 mg 
 
in 2 doses
0.1–0.3 mg/day 
patch weekly
$0.21/0.1 mg
$55.77/0.2 mg 
patch
$12.60 (0.1 mg 
 
$223.08 (0.2 mg weekly)
Sedation, dry mouth, sexual dysfunction, head
-
ache, bradyarrhythmias; side effects may be 
less with guanfacine. Contact dermatitis with 
clonidine patch. Methyldopa also causes 
 
hepatitis, hemolytic anemia, fever.
“Rebound” hypertension may 
occur even after gradual 
Clonidine and 
-
done
Clorpres
0.1 mg/15 mg 
one to three 
0.1 mg/15 mg–
 
0.3 mg/15 mg
$2.77/0.1 
mg/15 mg
$166.20/0.1 mg/
 
15 mg twice daily
Guanfacine
Tenex
1 mg 
 
once daily
1–3 mg once daily
$0.87/1 mg
$26.10 (1 mg once daily)
Methyldopa
Aldochlor
250 mg 
 
500–2000 mg
 
in 2 doses
$0.66/500 mg
$39.60 (500 mg twice daily)
Methyldopa should be avoided 
in favor of safer agents.
p
eripher
al Neuronal 
a
n
tagonists
Reserpine
(generic)
0.05 mg 
 
once daily
0.05–0.25 mg 
once daily
$1.19/0.1 mg
$35.70 (0.1 mg once daily)
Depression (less likely at low dosages, ie, 
 
< 0.25 mg), night terrors, nasal stuffiness, 
drowsiness, peptic disease, GI disturbances, 
Direct Vasodilators
Apresoline
25 mg 
 
50–300 mg in 
 
2–4 doses
$0.15/25 mg
$9.00 (25 mg twice daily)
GI disturbances, tachycardia, headache, nasal 
congestion, rash, LE-like syndrome.
May worsen or precipitate 
angina.
Minoxidil
(generic)
5 mg 
 
once daily
10–40 mg 
 
once daily
$1.29/10 mg
$38.70 (10 mg once daily)
Tachycardia, fluid retention, headache, hirsutism, 
pericardial effusion, thrombocytopenia.
Should be used in combination 
with beta-blocker and diuretic.
1
Source: 
Red Book
GI, gastrointestinal; LE, lupus erythematosus.
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hospitalizations and a higher incidence of stroke relative to 
those receiving diuretics, prompting discontinuation of 
this arm of the study. To summarize, alpha-blockers should 
generally not be used as initial agents to treat hyperten
-
sion—except perhaps in men with symptomatic prostatism 
or nightmares linked to posttraumatic stress disorder.
I. Drugs With Central Sympatholytic Action
Methyldopa, clonidine, guanabenz, and guanfacine (Table 
11–10) lower blood pressure by stimulating alpha-adrener
-
gic receptors in the central nervous system, thus reducing 
efferent peripheral sympathetic outflow. These agents are 
effective as single therapy in some patients, but they are 
usually used as second- or third-line agents because of the 
high frequency of drug intolerance, including sedation, 
fatigue, dry mouth, postural hypotension, and erectile dys
-
function. An important concern is rebound hypertension 
following withdrawal. Methyldopa also causes hepatitis 
and hemolytic anemia and should be restricted to individ
-
uals who have already tolerated long-term therapy. There is 
considerable experience with methyldopa in pregnant 
women, and it is still used for this population. Clonidine is 
available in patches, which may have particular value in 
noncompliant patients.
J. Arteriolar Dilators
Hydralazine and minoxidil (Table 11–10) relax vascular 
smooth muscle and produce peripheral vasodilation. 
When given alone, they stimulate reflex tachycardia, 
increase myocardial contractility, and cause headache, pal
-
pitations, and fluid retention. They are usually given in 
combination with diuretics and beta-blockers in resistant 
patients. Hydralazine produces frequent gastrointestinal 
disturbances and may induce a lupus-like syndrome. Min
-
oxidil causes hirsutism and marked fluid retention; this 
very potent agent is reserved for the most refractory of 
cases.
K. Peripheral Sympathetic Inhibitors
These agents are now used infrequently and usually in 
refractory hypertension. Reserpine remains a cost-effective 
antihypertensive agent (Table 11–10). Its reputation for 
inducing mental depression and its other side effects—
sedation, nasal stuffiness, sleep disturbances, and peptic 
ulcers—has made it unpopular, though these problems are 
uncommon at low dosages. Guanethidine and guanadrel 
inhibit catecholamine release from peripheral neurons but 
frequently cause orthostatic hypotension (especially in the 
morning or after exercise), diarrhea, and fluid retention.
 
»
Developing an Antihypertensive Regimen
Historically, data from large placebo-controlled trials sup
-
ported the overall conclusion that antihypertensive therapy 
with diuretics and beta-blockers had a major beneficial 
effect on a broad spectrum of cardiovascular outcomes, 
reducing the incidence of stroke by 30–50% and of heart 
failure by 40–50%, and halting progression to accelerated 
hypertension syndromes. The decreases in fatal and 
nonfatal coronary heart disease and cardiovascular and 
total mortality were less dramatic, ranging from 10% to 
15%. Similar placebo-controlled data pertaining to the 
newer agents are generally lacking, except for stroke reduc
-
tion with the calcium channel blocker nitrendipine in the 
Systolic Hypertension in Europe trial. However, there is 
substantial evidence that ACE inhibitors, and to a lesser 
extent ARBs, reduce adverse cardiovascular outcomes in 
other related populations (eg, patients with diabetic 
nephropathy, heart failure, or postmyocardial infarction 
and individuals at high risk for cardiovascular events). 
Most large clinical trials that have compared outcomes in 
relatively unselected patients have failed to show a differ
-
ence between newer agents—such as ACE inhibitors, cal
-
cium channel blockers, and ARBs—and the older 
diuretic-based regimens with regard to survival, myocar
-
dial infarction, and stroke. Where differences have been

-
-
dial infarction, and stroke. Where differences have been 
observed, they have mostly been attributable to subtle 
asymmetries in blood pressure control rather than to any 
inherent advantages of one agent over another. Recom
-
mendations for initial treatment identify ACE inhibitors, 
ARBs, and calcium channel blockers as valid choices. 
Because of their adverse metabolic profile, initial therapy 
with thiazides might best be restricted to older patients. 
Thiazides are acceptable as first-line therapy in blacks 
because of specific efficacy in this group.
As discussed above, beta-blockers are not ideal first-line 
drugs in the treatment of hypertension without compelling 
indications for their use (such as active coronary artery 
disease and heart failure). Vasodilator beta-blockers (such 
as carvedilol and nebivolol) may produce better outcomes 
than traditional beta-blockers; however, this possibility 
remains a theoretical consideration.
The American Diabetes Association has advocated eve
-
ning dosing of one or more antihypertensive medications 
to restore nocturnal blood pressure dipping. Outcomes 
data to support this proposal are limited. The Spanish 
MAPEC study of such nocturnal antihypertensive dosing 
showed a significant reduction in a range of major cardio
-
vascular events in 2156 participants over 5.6 years. How
-
ever, there are concerns that ischemic optic neuropathy 
may be triggered by profound nocturnal hypotension. 
Thus, larger studies are necessary before this approach can 
be firmly recommended.
For the purpose of devising an optimal treatment regi
-
men, drugs can be divided into two complementary groups 
easily remembered as 
A
 and 
C
 and 
D
. 
A
 refers to drugs that 
interrupt the renin-angiotensin system (
A
CE/ARB/renin 
inhibitor) and 
C
 and 
D
 refer to those that do not (
c
alcium 
channel blockers and thiazide 
d
iuretics). Combinations of 
drugs between these groups are likely to be more potent in 
lowering blood pressure than combinations within a group. 
Drugs that interrupt the renin-angiotensin cascade are 
more effective in young, white persons, in whom renin 
tends to be higher, and drugs 
C
 and 
D
 are more effective in 
older or black persons, in whom renin levels are generally 
lower. Figure 11–3 illustrates guidelines for initiating anti
-
hypertensive therapy established by the United Kingdom’s 
National Institute for Health and Care Excellence (NICE). 
In trials that include patients with systolic hypertension, 
CMDT19_Ch11_p0451-p0482.indd   475

Chapter 11 
476
 CMDT 2019
elevated systolic pressures (greater than 160/100 mm Hg) 
or difficult-to-control hypertension (which is often associ
-
ated with diabetes or kidney dysfunction). In light of 
unwanted metabolic effects, calcium channel blockers 
might be preferable to thiazides in the younger hyperten
-
sive patient requiring a second antihypertensive drug. 
Furthermore, based on the results from the ACCOM
-
PLISH trial, a combination of ACE inhibitor and calcium 
channel blocker may also prove optimal for patients at high 
risk for cardiovascular events. The initial use of low-dose 
combinations allows faster blood pressure reduction with
-
out substantially higher intolerance rates and is likely to be 
better accepted by patients. Data from the ALTITUDE 
study (in patients with type 2 diabetes and chronic kidney 
disease or cardiovascular disease or both), indicate that the 
addition of aliskiren to either ARB or ACE inhibitor was 
associated with worse outcomes and cannot be recom
-
mended, at least in this population. A suggested approach 
to treatment, tailored to patient demographics, is outlined 
in Table 11–11.
In sum, as a prelude to treatment, the patient should be 
informed of common side effects and the need for diligent 
compliance. In patients with mild or stage 1 hypertension 
(less than 160/90 mm Hg) in whom pharmacotherapy is 
indicated, treatment should start with a single agent at a 
low dose. Follow-up visits should usually be at 4- to 6-week 
intervals to allow for full medication effects to be estab
-
lished (especially with diuretics) before further titration or 
adjustment. If, after titration to usual doses, the patient has 
shown a discernible but incomplete response and a good 
tolerance of the initial drug, a second medication should be 
added. See Goals of Treatment, above. As a rule of thumb, 
a blood pressure reduction of 10 mm Hg can be expected 
for each antihypertensive agent added to the regimen and 
titrated to the optimum dose. In those with more severe 
hypertension (stage 2), or with comorbidities (such as dia
-
betes) that are likely to render them resistant to treatment, 
initiation with combination therapy is advised and more 
frequent follow-up is indicated.
Patients who are compliant with their medications and 
who do not respond to conventional combination regi
-
mens should usually be evaluated for secondary hyperten
-
sion before proceeding to more complex regimens.
 
»
Medication Nonadherence
Adherence to antihypertensive treatment is alarmingly 
poor. In one European study of patients’ antihypertensive 
medication compliance, there was a 40% discontinuation 
rate at 1 year after initiation. Only 39% of patients were 
found to be taking their medications continuously over a 
10-year period. Collaborative care, utilizing physicians, 
pharmacists, social workers, and nurses to encourage com
-
pliance has had a variable and often rather modest effect on 
blood pressure control. Adherence is enhanced by patient 
education and by use of home blood pressure measure
-
ment. The choice of antihypertensive medication is impor
-
tant. Better compliance has been reported for patients 
whose medications could be taken once daily or as combi
-
nation pills. Adherence is best with ACE inhibitors and 
ARBs, and worse with beta-blockers and diuretics.
Persons younger than
55 years and not blac
k
Persons aged 55 year
s
or older or black
C
1
A + C
A + C + D
Resistant hypertension
A + C + D + consider alpha-bloc
ke
r or
diuretic
2
 or alpha- or
beta-bloc
ke
r
3
Consider seeking expert advice
A
Step 1
Step 2
Step 3
Step 4
A, ACE inhibitor or ARB; C, calcium-channel blocker;
D, diuretic, thiazide-like.
1
A CCB is prefer
re
d, but consider a thiazide-li
ke
 diuretic if a  CCB is not 
to
lerat
ed or the pe
rs
on has
 edema, 
ev
idence of heart failur
e,
 or a high risk of
 heart failur
e.
2
Consider a low dose of spi
ro
nolactone or higher
 doses of a thiazide-like diuretic.
3

to
lerat
ed or the pe
rs
on has
 edema, 
ev
e,
e.
2
ro
3
Consider an alpha- or beta-bloc
ke
r if fu
rt
her diuretic
  therap
y 
is not 
to
lerat
ed, or is contraindicated or
  inef
fe
cti
ve
. 
 
▲
Figure 11–3.
 
Hypertension treatment guidelines 
from the United Kingdom’s National Institute for Health 
and Care Excellence. 
Guidelines identify angiotensin-
converting enzyme (ACE) inhibitors, angiotensin receptor 
blockers (ARBs), or calcium channel blockers (CCBs) as 
first-line medications and suggest a sequence of escalat
-
ing drug therapy depending on blood pressure response. 
As noted, the choice of the initial agent is influenced by 
patient demographics. In step 4, higher doses of thia
-
zide-type diuretics may be used as long as serum potas
-
sium levels exceed 4.5 mmol/L. (Modified, with 
permission, from the 2013 hypertension guidelines 
 
published by the National Institute for Health and Care 
Excellence. https://www.nice.org.uk/guidance/cg127/
 
evidence/cg127-hypertension-full-guideline3
)
most patients require two or more medications and even 
then a substantial proportion fail to achieve the goal blood 
pressure. In diabetic patients, three or four drugs are usu
-
ally required to reduce systolic blood pressure to less than 
140 mm Hg. In many patients, blood pressure cannot be 
adequately controlled with any combination. As a result, 
debating the appropriate first-line agent is less relevant 
than determining the most appropriate combinations of 
agents. This has led many experts and practitioners to rec
-
ommend the use of fixed-dose combination antihyperten
-
sive agents as first-line therapy in patients with substantially 
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Table 11–11.
 
Choice of antihypertensive agent based on demographic considerations.
1,2
Black, 
a
ll 
a
ges
a
ll O
thers, 
a
ge < 55 
Years
a
ll O
thers, 
a
ge > 55 
Years
First-line
CCB or diuretic
ACE or ARB
3
 or CCB or diuretic
4
5
Second-line
ACE or ARB
3
 or vasodilating 
beta-blocker
6
Vasodilating beta-blocker
6
ACE or ARB or vasodilating 
6
a
lt
ernatives
Alpha-agonist or 
alpha-antagonist
7
Alpha-agonist or alpha-antagonist
7
r
esistant hypertension
Aldosterone receptor blocker
1
Compelling indications may alter the selection of an antihypertensive drug.
2
Start with full dose of one agent, or lower doses of combination therapy. In stage 2 hypertension, consider initiating therapy with a fixed 
dose combination.
3
Women of childbearing age should avoid ACE and ARB or discontinue as soon as pregnancy is diagnosed.
4
The adverse metabolic effects of thiazide diuretics and beta-blockers should be considered in younger patients but may be less important 
in the older patient.
5
For patients with significant kidney dysfunction, use loop diuretic instead of thiazide.
6
There are theoretical advantages in the use of vasodilating beta-blockers such as carvedilol and nebivolol.
7
Alpha-antagonists may precipitate or exacerbate orthostatic hypotension in older adults.
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker.
 
»
Consideration of Gender in Hypertension
Because of the preponderance of male recruitment into 
large-scale clinical trials, the impact of gender on the evalu
-
ation and management of hypertension remains uncertain. 
The limited data that exist suggest a steeper relationship in 
women between 24-hour ambulatory and night time sys
-
tolic blood pressure and the risk of cardiovascular events. 
There are many gender-specific effects on the mechanisms 
and end organ inpact of hypertension. In younger adults, 
men are more likely to be hypertensive than women, a rela
-
tionship that reverses in later life. Regression of LVH in 
response to ACE inhibitors is less pronounced in women. 
Women are more likely to have isolated systolic hyperten
-
sion, probably because they develop more active left ven
-
tricular systolic function and greater vascular stiffness than 
men. As yet however, there are no data to support a differ
-
ent blood pressure target in women.
 
»
Special Considerations in the Treatment of 
Diabetic Hypertensive Patients
Hypertensive patients with diabetes are at particularly high 
risk for cardiovascular events. Data from the ACCORD 
study of diabetic patients demonstrated that most of the 
benefits of blood pressure lowering were seen with a systolic 
target of less than 140 mm Hg. Although there was a reduc
-
tion in stroke risk at a systolic target below 120/70 mm Hg, 
treatment to this lower target was associated with an 
increased
 risk of serious adverse effects. US and Canadian 
guidelines recommend a blood pressure goal of less than 
130/80 mm Hg in diabetic patients. Because of the benefi
-
cial effects of ACE inhibitors in diabetic nephropathy, they 
should be part of the initial treatment regimen. ARBs or 
perhaps renin inhibitors may be substituted in those intol
-
erant of ACE inhibitors. While the ONTARGET study 
showed that combinations of ACE inhibitors and ARBs 
in persons with atherosclerosis or type 2 diabetes with 
end-organ damage appeared to minimize proteinuria, this 
strategy slightly increased the risks of progression to dialy
-
sis and of death; thus, it is not recommended. Most diabetic 
patients require combinations of three to five agents to 
achieve target blood pressure, usually including a diuretic 
and a calcium channel blocker or beta-blocker. In addition 
to rigorous blood pressure control, treatment of persons

to rigorous blood pressure control, treatment of persons 
with diabetes should include aggressive treatment of other 
risk factors.
 
»
Treatment of Hypertension in Chronic 
Hypertension is present in 40% of patients with a GFR of 
60–90 mL/min, and 75% of patients with a GFR less than 
30 mL/min. The rate of progression of chronic kidney 
disease is markedly slowed by treatment of hypertension. 
In the SPRINT trial, the reduction in cardiovascular risk 
associated with lower blood pressure targets was also 
observed in the subgroup with a GFR of less than 60 mL/min. 
However, an effect of 
lower
 blood pressure targets on the 
slowing of chronic kidney disease progression appears to 
be restricted to those with pronounced proteinuria. 
Accordingly, the Kidney Disease Improving Global Out
-
comes (KDIGO) guidelines advocate a target of less than 
130/80 mm Hg in patients with significant proteinuria. 
Guidelines from the ACC/AHA and Hypertension Can
-
ada extend this recommendation to all those with chronic 
kidney disease irrespective of proteinuria. Medications 
that interrupt the renin-angiotensin cascade can slow the 
progression of kidney disease and are preferred for initial 
therapy, especially in those with albuminuria of greater 
than 300 mg/g creatinine. Transition from thiazide to 
loop diuretic is often necessary to control volume expan
-
sion as the eGFR falls below 30 mL/min. Evidence has 
demonstrated that ACE inhibitors remain protective and 
safe in kidney disease associated with significant proteinuria 
and serum creatinine as high as 5 mg/dL (380 mcmol/L). 
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Kidney function and electrolytes should be measured 1 
week after initiating treatment and subsequently moni
-
tored carefully in patients with kidney disease. An 
increase in creatinine of 20–30% is acceptable and 
expected; more exaggerated responses suggest the possi
-
bility of renal artery stenosis or volume contraction. 
Although lower blood pressure levels are associated with 
acute decreases in GFR, this appears not to translate into 
an increased risk of developing end-stage renal disease in 
the long term. Persistence with ACE inhibitor or ARB 
therapy in the face of hyperkalemia is probably not war
-
ranted, since other antihypertensive medications are 
renoprotective as long as goal blood pressures are main
-
tained. However, diuretics can often be helpful in control
-
ling mild hyperkalemia, and there are novel cation 
exchange polymers that sequester potassium in the gut 
that are more effective and better tolerated than sodium 
polystyrene sulfonate.
 
»
Hypertension Management in Blacks
Substantial evidence indicates that blacks are not only more 
likely to become hypertensive and more susceptible to the 
cardiovascular and renal complications of hypertension—
they also respond differently to many antihypertensive 
medications. The REGARDS study illustrates these differ
-
ences. At systolic blood pressures less than 120 mm Hg, 
black and white participants between 45 and 64 years of age 
had equal risk of stroke. For a 10 mm Hg increase in systolic 
blood pressure, the risk of stroke was threefold higher in 
black participants. At the level of stage 1 hypertension, the 
hazard ratio for stroke in black compared to white partici
-
pants between 45 and 64 years of age was 2.35. This 
increased susceptibility may reflect genetic differences in 
the cause of hypertension or the subsequent responses to it, 
differences in occurrence of comorbid conditions such as 
diabetes or obesity, or environmental factors such as diet, 
activity, stress, or access to health care services. In any case, 
as in all persons with hypertension, a multifaceted program 
of education and lifestyle modification is warranted. Early 
introduction of combination therapy has been advocated, 
but there is no clinical trial data to support a lower than 
usual blood pressure goal (less than 140/90 mm Hg) in 
blacks. Because it appears that ACE inhibitors and ARBs—
in the absence of concomitant diuretics—are less effective 
in blacks than in whites, initial therapy should generally be 
a diuretic or a diuretic in combination with a calcium chan
-
nel blocker. However, inhibitors of the renin-angiotensin-
aldosterone system do lower blood pressure in black 
patients, are useful adjuncts to the recommended diuretic 
and calcium channel blockers, and should be used in 
patients with hypertension and compelling indications such 
as heart failure and kidney disease (especially in the pres
-
ence of proteinuria). Black patients have an elevated risk of 
ACE inhibitor–associated angioedema and cough, so ARBs 
would be the preferred choice.
 
»
Treating Hypertension in Older Adults
Several studies in persons over 60 years of age have con
-
firmed that antihypertensive therapy prevents fatal and 
nonfatal myocardial infarction and reduces overall car
-
diovascular mortality. In initiating therapy in older 
patients, pressure should be reduced more gradually with 
a safe intermediate systolic blood pressure goal of 160 
mm Hg. The HYVET study indicated that a reasonable 
ultimate blood pressure goal would be 150/80 mm Hg. 
Updated guidelines suggest that blood pressure goals 
should not be influenced by age alone. An exploratory 
subgroup analysis of the SPRINT study found that people 
older than age 75 years showed benefit at the 120 mm Hg 
systolic treatment target. Importantly, these benefits were 
also evident in patients classified as frail. This more 
aggressive approach was, however, associated with greater

aggressive approach was, however, associated with greater 
risk of falls and worsening kidney function, indicating 
that close monitoring is required in elderly patients 
treated to lower blood pressure goals. The same medica
-
tions are used in older patients, but at 50% lower doses. 
As treatment is initiated, older patients should be care
-
fully monitored for orthostasis, altered cognition, and 
electrolyte disturbances.
 
»
Follow-Up of Patients Receiving 
Hypertension Therapy
Once blood pressure is controlled on a well-tolerated regi
-
men, follow-up visits can be infrequent and laboratory 
testing limited to those appropriate for the patient and the 
medications used. Y early monitoring of blood lipids is rec
-
ommended, and an electrocardiogram could be repeated at 
2- to 4-year intervals depending on whether initial abnor
-
malities are present and on the presence of coronary risk 
factors. Patients who have had excellent blood pressure 
control for several years, especially if they have lost weight 
and initiated favorable lifestyle modifications, might be 
considered for a trial of reduced antihypertensive 
Boal AH et al. Monotherapy with major antihypertensive 
drug classes and risk of hospital admissions for mood dis
-
orders. Hypertension. 2016 Nov;68(5):1132–8. [PMID: 
27733585]
Burnier M. Drug adherence in hypertension. Pharmacol Res. 
2017 Nov;125(Pt B):142–9. [PMID: 28870498]
Gudsoorkar PS et al. Changing concepts in hypertension man
-
agement. J Hum Hypertens. 2017 Dec;31(12):763–7. [PMID: 
28748919]
Malhotra R et al. Association between more intensive vs less 
intensive blood pressure lowering and risk of mortality in 
chronic kidney disease stages 3 to 5: a systematic review and 
meta-analysis. JAMA Intern Med. 2017 Oct 1;177(10):
 
1498–505. [PMID: 28873137]
Tsai WC et al. Association of intensive blood pressure control 
and kidney disease progression in nondiabetic patients with 
chronic kidney disease: a systematic review and meta-analy
-
sis. JAMA Intern Med. 2017 Jun 1;177(6):792–9. [PMID: 
28288249]
Wenger NK et al; American College of Cardiology Cardiovascu
-
lar Disease in Women Committee. Women, hypertension, 
and the systolic blood pressure intervention trial. Am J Med. 
2016 Oct;129(10):1030–6. [PMID: 27427323]
Williams SK et al. Hypertension treatment in blacks: discussion 
of the U.S. clinical practice guidelines. Prog Cardiovasc Dis. 
2016 Nov–Dec;59(3):282–8. [PMID: 27693861]
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RESISTANT HYPERTENSION
Resistant hypertension is defined as the failure to reach 
blood pressure control in patients who are adherent to full 
doses of an appropriate three-drug regimen (including a 
diuretic). Adherence is a major issue: the rate of partial or 
complete noncompliance probably approaches 50% in this 
group of patients; doxazosin, spironolactone, and hydro
-
chlorothiazide were particularly unpopular in one Eastern 
European study based on drug assay. In the approach to 
resistant hypertension, the clinician should first confirm 
compliance and rule out “white coat hypertension, ” ide
-
ally using ambulatory or home-based measurement of 
blood pressure. Exacerbating factors should be considered 
(as outlined above). Finally, identifiable causes of resistant 
hypertension should be sought (Table 11–12). The clini
-
cian should pay particular attention to the type of diuretic 
being used in relation to the patient’s kidney function. 
Aldosterone may play an important role in resistant 
hypertension and aldosterone receptor blockers can be 
very useful. If goal blood pressure cannot be achieved fol
-
lowing completion of these steps, consultation with a 
hypertension specialist should be considered. Procedure-
based approaches to resistant hypertension are being 
developed, but the Symplicity HTN 3 study failed to show 
that renal sympathetic ablation improved blood pressure 
compared to a sham-operated control group.
Braam B et al. Recognition and management of resistant hyper
-
tension. Clin J Am Soc Nephrol. 2017 Mar 7;12(3):524–35. 
[PMID: 27895136]
Kühl C et al. Recent developments and controversies in the treat
-
ment of resistant hypertension. Exp Clin Endocrinol Diabetes. 
2016 Mar;124(3):178–86. [PMID: 27008634]
HYPERTENSIVE URGENCIES & EMERGENCIES
Hypertensive emergencies have become less frequent in 
recent years but still require prompt recognition and 
aggressive but careful management. A spectrum of urgent 
presentations exists, and the appropriate therapeutic 
approach varies accordingly.
Hypertensive urgencies
 are situations in which blood 
pressure must be reduced within a few hours. These include 
patients with asymptomatic severe hypertension (systolic 
blood pressure greater than 220 mm Hg or diastolic pres
-
sure greater than 125 mm Hg that persists after a period of 
observation) and those with optic disk edema, progressive 
target-organ complications, and severe perioperative hyper
-
tension. Elevated blood pressure levels alone—in the 
absence of symptoms or new or progressive target-organ 
damage—rarely require emergency therapy. Parenteral drug 
therapy is not usually required, and partial reduction of 
blood pressure with relief of symptoms is the goal.
Hypertensive emergencies
 require substantial reduc
-
tion of blood pressure within 1 hour to avoid the risk of 
serious morbidity or death. Although blood pressure is usu
-
ally strikingly elevated (diastolic pressure greater than 130 
mm Hg), the correlation between pressure and end-organ 
damage is often poor. 
It is the presence of critical multiple 
end organ injury that determines the seriousness of the emer
-
gency and the approach to treatment.
 Emergencies include 
hypertensive encephalopathy (headache, irritability, confu
-
sion, and altered mental status due to cerebrovascular 
spasm), hypertensive nephropathy (hematuria, proteinuria, 
and acute kidney injury due to arteriolar necrosis and inti
-
mal hyperplasia of the interlobular arteries), intracranial 
hemorrhage, aortic dissection, preeclampsia-eclampsia, 
pulmonary edema, unstable angina, or myocardial infarc
-
tion. Encephalopathy or nephropathy accompanying hyper
-
tensive retinopathy has historically been termed 
malignant 
, but the therapeutic approach is identical to 
that used in other hypertensive emergencies.
Parenteral therapy is indicated in most hypertensive

malignant 
Parenteral therapy is indicated in most hypertensive 
emergencies, especially if encephalopathy is present. The 
initial goal in hypertensive emergencies is to reduce the 
pressure by no more than 25% (within minutes to 1 or 2 
hours) and then toward a level of 160/100 mm Hg within 
2–6 hours. Excessive reductions in pressure may precipitate 
coronary, cerebral, or renal ischemia. To avoid such 
declines, the use of agents that have a predictable, dose-
dependent, transient, and progressive antihypertensive 
effect is preferable (Table 11–13). In that regard, the use of 
sublingual or oral fast-acting nifedipine preparations is 
Acute ischemic stroke is often associated with marked 
elevation of blood pressure, which will usually fall sponta
-
neously. In such cases, antihypertensives should only be 
used if the systolic blood pressure exceeds 180–200 mm Hg, 
and blood pressure should be reduced cautiously by 10–15% 
(Table 11–13). If thrombolytics are to be given, blood 
Table 11–12.
 
Causes of resistant hypertension.
Improper blood pressure measurement
Volume overload and pseudotolerance
 
Ex
cess sodium intake
 
V
olume retention from kidney disease
 
I
nadequate diuretic therapy
Drug-induced or other causes
 
Nonadherence
 
I
nadequate doses
 
I
nappropriate combinations
 
Nonst
eroidal anti-inflammatory drugs; cyclooxygenase-2 
 
inhibitors
 
C
ocaine, amphetamines, other illicit drugs
 
S
ympathomimetics (decongestants, anorectics)
 
Or
al contraceptives
 
A
drenal steroids
 
C
yclosporine and tacrolimus
 
Erythropoietin
 
Lic
orice (including some chewing tobacco)
 
S
elected over-the-counter dietary supplements and medicines
 
(
eg, ephedra, ma huang, bitter orange)
Associated conditions
 
Obesity
 
Ex
cess alcohol intake
Identifiable causes of hypertension (see Table 11–2)
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Table 11–13.
 
Treatment of hypertensive emergency depending on primary site of end-organ damage. 
 
See Table 11–14 for dosages.
t
ype of 
h
ypertensive 
e
mergency
r
ecommended Drug Options and 
Combinations
Drugs to 
a
v
oid
Myocardial ischemia and infarction
Nicardipine plus esmolol
1
Nitroglycerin plus labetalol
Nitroglycerin plus esmolol
1
Hydralazine, diazoxide, minoxidil, nitroprusside
Acute kidney injury
Fenoldopam
Nicardipine
Clevidipine
Aortic dissection
Esmolol plus nicardipine
Esmolol plus clevidipine
Labetalol
Esmolol plus nitroprusside
Hydralazine, diazoxide, minoxidil
Acute pulmonary edema, LV systolic 
Nicardipine plus nitroglycerin
2
 plus a 
loop diuretic
Clevidipine plus nitroglycerin
2
 plus a 
Hydralazine, diazoxide, beta-blockers
Acute pulmonary edema, diastolic dysfunction
Esmolol plus low-dose nitroglycerin 
 
plus a loop diuretic
Labetalol plus low-dose nitroglycerin 
Ischemic stroke (systolic blood pressure 
 
> 180–200 mm Hg)
Labetalol
Nitroprusside, methyldopa, clonidine, 
nitroglycerin
Intracerebral hemorrhage (systolic blood 
 
pressure > 140–160 mm Hg)
Labetalol
Hyperadrenergic states, including cocaine use
Nicardipine plus a benzodiazepine
Clevidipine plus a benzodiazepine
Phentolamine
Labetalol
Preeclampsia, eclampsia
Labetalol
Diuretics, ACE inhibitors
1
Avoid if LV systolic dysfunction.
2
Drug of choice if LV systolic dysfunction is associated with ischemia.
ACE, angiotensin-converting enzyme; LV, left ventricular.
pressure should be maintained at less than 185/110 mm Hg 
during treatment and for 24 hours following treatment.
In hemorrhagic stroke, the aim is to minimize bleeding 
with a target 
mean arterial pressure
 of less than 130 mm Hg. 
Rapidly lowering the blood pressure below a systolic of 140 
mm Hg in acute stroke has been associated with harm and 
is not recommended. In acute subarachnoid hemorrhage, as 
long as the bleeding source remains uncorrected, a compro
-
mise must be struck between preventing further bleeding 
and maintaining cerebral perfusion in the face of cerebral 
vasospasm. In this situation, blood pressure goals depend 
on the patient’s usual blood pressure. In normotensive 
patients, the target should be a systolic blood pressure of 
110–120 mm Hg; in hypertensive patients, blood pressure 
should be treated to 20% below baseline pressure. In the 
treatment of hypertensive emergencies complicated by (or 
precipitated by) central nervous system injury, labetalol or 
nicardipine are good choices, since they are nonsedating 
and do not appear to cause significant increases in cerebral 
blood flow or intracranial pressure in this setting. In hyper
-
tensive emergencies arising from catecholaminergic mecha
-
nisms, such as pheochromocytoma or cocaine use, 
beta-blockers can worsen the hypertension because of 
unopposed peripheral vasoconstriction; nicardipine, clevi
-
dipine, or phentolamine are better choices. Labetalol is use
-
ful in these patients if the heart rate must be controlled. 
Table 11–13 summarizes treatment recommendations in 
hypertensive emergency.
 
»
Pharmacologic Management
A. Parenteral Agents
Sodium nitroprusside is no longer the treatment of choice 
for acute hypertensive problems; in most situations, 
appropriate control of blood pressure is best achieved 
using combinations of nicardipine or clevidipine plus 
labetalol or esmolol
. (Table 11–14 lists drugs, dosages, 
and adverse effects.)
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Table 11–14.
 
Drugs for hypertensive emergencies and urgencies in descending order of preference.
a
gen
t
a
c
tion
Dosage
Onset
Duration
a
dv
erse 
e
ff
ects
Comments
h
e
mergencies
Nicardipine 
(Cardene)
Calcium chan
-
nel blocker
5 mg/h intravenously; may increase by 1–2.5 
mg/h every 15 minutes to 15 mg/h
1–5 minutes
3–6 hours
Hypotension, tachycardia, headache.
May precipitate myocardial ischemia.
Clevidipine 
(Cleviprex)
-
1–2 mg/h intravenously initially; double rate 
every 90 seconds until near goal, then by 
smaller amounts every 5–10 minutes to a 
maximum of 32 mg/h
2–4 minutes
5–15 minutes
Headache, nausea, vomiting.
Lipid emulsion: contraindicated in patients 
with allergy to soy or egg.
Labetalol 
(Trandate)
Beta- and 
alpha-
blocker
20–40 mg intravenously every 10 minutes to 
300 mg; 2 mg/min infusion
5–10 
minutes
3–6 hours
GI, hypotension, bronchospasm, 
 
bradycardia, heart block.
Avoid in acute LV systolic dysfunction, 
asthma. May be continued orally.
Esmolol 
(Brevibloc)
Beta-blocker
Loading dose 500 mcg/kg intravenously over 
 
1 minute; maintenance, 25–200 mcg/kg/min
1–2 minutes
10–30 
minutes
Bradycardia, nausea.
asthma. Weak antihypertensive.
Fenoldopam 
(Corlopam)
Dopamine 
receptor 
agonist
0.1–1.6 mcg/kg/min intravenously
4–5 minutes
< 10 minutes
Reflex tachycardia, hypotension, 
increased intraocular pressure.
May protect kidney function.
Enalaprilat 
(Vasotec)
ACE inhibitor
1.25 mg intravenously every 6 hours
15 minutes
6 hours or 
more
Excessive hypotension.
Additive with diuretics; may be continued 
orally.
Furosemide 
(Lasix)
Diuretic
10–80 mg orally
15 minutes
4 hours
Hypokalemia, hypotension.
Adjunct to vasodilator.
Hydralazine 
(Apresoline)
Vasodilator
5–20 mg intravenously); may repeat after 
 
20 minutes
10–30 
minutes
2–6 hours
Tachycardia, headache, GI.
Avoid in coronary artery disease, dissection. 
Rarely used except in pregnancy.
Nitroglycerin
0.25–5 mcg/kg/min intravenously
2–5 minutes
3–5 minutes
Headache, nausea, hypotension, 
Tolerance may develop. Useful primarily 
with myocardial ischemia.
Nitroprusside 
(Nitropress)
0.25–10 mcg/kg/min intravenously
Seconds
GI, CNS; thiocyanate and cyanide toxic
-
ity, especially with kidney and liver 
dysfunction; hypotension. Coronary 
steal, decreased cerebral blood flow, 
No longer the first-line agent.
h
ypertensive Urgencies
Clonidine 
(Catapres)
Central 
sympatho
-
lytic
0.1–0.2 mg orally initially; then 0.1 mg every 
hour to 0.8 mg orally
30–60 
minutes
6–8 hours
Sedation.
Rebound may occur.
Captopril 
(Capoten)
12.5–25 mg orally
15–30 
minutes
4–6 hours
Nifedipine 
(Adalat, 
Procardia)
-
10 mg orally initially; may be repeated after 
 
30 minutes
15 minutes
2–6 hours
Excessive hypotension, tachycardia, 
headache, angina, myocardial infarc
-
tion, stroke.
Response unpredictable.
ACE, angiotensin-converting enzyme; CNS, central nervous system; GI, gastrointestinal; LV, left ventricular.
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1. Nicardipine—
Intravenous nicardipine is the most 
potent and the longest acting of the parenteral calcium 
channel blockers. As a primarily arterial vasodilator, it has 
the potential to precipitate reflex tachycardia, and for that 
reason it should not be used without a beta-blocker in 
patients with coronary artery disease.
2. Clevidipine—
Intravenous clevidipine is an L-type 
calcium channel blocker with a 1-minute half-life, which 
facilitates swift and tight control of severe hypertension. 
It acts on arterial resistance vessels and is devoid of veno
-
dilatory or cardiodepressant effects.
3. Labetalol—
This combined beta- and alpha-blocking 
agent is the most potent adrenergic blocker for rapid blood 
pressure reduction. Other beta-blockers are far less potent. 
Excessive blood pressure drops are unusual. Experience 
with this agent in hypertensive syndromes associated with 
pregnancy has been favorable.
4. Esmolol—
This rapidly acting beta-blocker is approved 
only for treatment of supraventricular tachycardia, but is 
often used for lowering blood pressure. It is less potent 
than labetalol and should be reserved for patients in whom 
there is particular concern about serious adverse events 
related to beta-blockers.
5. Fenoldopam—
Fenoldopam is a peripheral dopamine-1 
(DA
1
) receptor agonist that causes a dose-dependent 
reduction in arterial pressure without evidence of toler
-
ance, rebound, withdrawal, or deterioration of kidney 
function. In higher dosage ranges, tachycardia may occur. 
This drug is natriuretic, which may simplify volume man
-
agement in acute kidney injury.
6. Enalaprilat—
This is the active form of the oral ACE 
inhibitor enalapril. The onset of action is usually within 
15 minutes, but the peak effect may be delayed for up to 
6 hours. Thus, enalaprilat is used primarily as an adjunc
-
tive agent.
7. Diuretics—
Intravenous loop diuretics can be very help
-
ful when the patient has signs of heart failure or fluid reten
-
tion, but the onset of their hypotensive response is slow, 
making them an adjunct rather than a primary agent for 
hypertensive emergencies. Low dosages should be used 
initially (furosemide, 20 mg, or bumetanide, 0.5 mg). They 
facilitate the response to vasodilators, which often stimulate 
fluid retention.
8. Hydralazine—
Hydralazine can be given intravenously 
or intramuscularly, but its effect is less predictable than that 
of other drugs in this group. It produces reflex tachycardia 
and should not be given without beta-blockers in patients 
with possible coronary disease or aortic dissection. Hydral
-
azine is used primarily in pregnancy and in children, but 
even in these situations, it is not a first-line drug.
9. Nitroglycerin, intravenous—
This agent should be 
reserved for patients with accompanying acute coronary 
ischemic syndromes.
10. Nitroprusside sodium—
This agent is given by con
-
trolled intravenous infusion gradually titrated to the desired 
effect. It lowers the blood pressure within seconds by direct 
arteriolar and venous dilation. Monitoring with an intra-
arterial line avoids hypotension. Nitroprusside—in combi
-
nation with a beta-blocker—is useful in patients with aortic 
dissection.
B. Oral Agents
Patients with less severe acute hypertensive syndromes can 
often be treated with oral therapy. Suitable drugs will reduce 
the blood pressure over a period of hours. In those presenting 
as a consequence of noncompliance, it is usually sufficient to 
restore the patient’s previously established oral regimen.
1. Clonidine—
Clonidine, 0.2 mg orally initially, followed 
by 0.1 mg every hour to a total of 0.8 mg, will usually lower 
blood pressure over a period of several hours. Sedation is 
frequent, and rebound hypertension may occur if the drug 
is stopped.
2. Captopril—
Captopril, 12.5–25 mg orally, will also lower 
blood pressure in 15–30 minutes. The response is variable

blood pressure in 15–30 minutes. The response is variable 
and may be excessive. Captopril is the drug of choice in the 
management of scleroderma hypertensive crisis.
3. Nifedipine—
The effect of fast-acting nifedipine cap
-
sules is unpredictable and may be excessive, resulting in 
hypotension and reflex tachycardia. Because myocardial 
infarction and stroke have been reported in this setting, the 
use of sublingual nifedipine is not advised. Nifedipine 
retard, 20 mg orally, appears to be safe and effective.
C. Subsequent Therapy
When the blood pressure has been brought under control, 
combinations of oral antihypertensive agents can be 
added as parenteral drugs are tapered off over a period of 
2–3 days.
Guiga H et al. Hospital and out-of-hospital mortality in 
 
670 hypertensive emergencies and urgencies. J Clin Hyper
-
tens (Greenwich). 2017 Nov;19(11):1137–42. [PMID: 
28866866]
Ipek E et al. Hypertensive crisis: an update on clinical approach 
and management. Curr Opin Cardiol. 2017 Jul;32(4):397–406. 
[PMID: 28306673]
Muiesan ML et al; Working Group on Hypertension, Prevention, 
Rehabilitation of the Italian Society of Cardiology. An update 
on hypertensive emergencies and urgencies. J Cardiovasc Med 
(Hagerstown). 2015 May;16(5):372–82. [PMID: 25575271]
Suneja M et al. Hypertensive emergency. Med Clin North Am. 
2017 May;101(3):465–78. [PMID: 28372707]
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º
ATHEROSCLEROTIC PERIPHERAL 
 
VASCULAR DISEASE
OCCLUSIVE DISEASE: AORTA & 
 
ILIAC ARTERIES
 
»
Claudication: cramping pain or tiredness in the 
calf, thigh, or hip while walking.
 
»
Diminished femoral pulses.
 
»
Tissue loss (ulceration, gangrene) or rest pain.
 
»
Occlusive atherosclerotic lesions developing in the extrem
-
ities, or peripheral artery disease (PAD), is evidence of a 
systemic atherosclerotic process. The prevalence of PAD is 
30% in patients who are 50 years old, patients who have 
either diabetes mellitus or a history of tobacco use, or in 
patients who are 70 years old without those risk factors. 
Pathologic changes of atherosclerosis may be diffuse, but 
flow-limiting stenoses occur segmentally. In the lower 
extremities, they classically occur in three anatomic seg
-
ments: the aortoiliac segment, femoral-popliteal segment, 
and the infrapopliteal or tibial segment of the arterial 
tree. Lesions in the distal aorta and proximal common iliac 
arteries classically occur in white male smokers aged 
50–60 years. Disease progression may lead to complete 
occlusion of one or both common iliac arteries, which can 
precipitate occlusion of the entire abdominal aorta to 
the level of the renal arteries.
 
»
Approximately two-thirds of patients with PAD are either 
asymptomatic or do not have classic symptoms. Intermit
-
tent claudication, which is pain that occurs from insuffi
-
cient blood flow when there is increased demand from 12
 
Warren J. Gasper, MD 
 
Joseph H. Rapp, MD 
 
Blood Vessel & 
 
Lymphatic Disorders
exercise, is typically described as severe and cramping and 
primarily occurs in the calf muscles. The pain from aor
-
toiliac lesions may extend into the thigh and buttocks and 
erectile dysfunction may occur from bilateral common 
iliac disease. Rarely, patients complain only of weakness in 
the legs when walking, or simply extreme limb fatigue. The 
symptoms are relieved with rest and are reproducible when 
the patient walks again. Femoral pulses are absent or very 
weak as are the distal pulses. Bruits may be heard over the 
aorta, iliac, and femoral arteries.
B. Doppler and Vascular Findings
The ratio of systolic blood pressure detected by Doppler 
examination at the ankle compared with the brachial artery 
(referred to as the ankle-brachial index [ABI]) is reduced to 
below 0.9 (normal ratio is 0.9–1.2); this difference is exag
-
gerated by exercise. Both the dorsalis pedis and the posterior 
tibial arteries are measured and the higher of the two artery 
pressures is used for calculation. Segmental waveforms or 
pulse volume recordings obtained by strain gauge technol
-
ogy through blood pressure cuffs demonstrate blunting of 
the arterial inflow throughout the lower extremity.
C. Imaging
CT angiography (CTA) and magnetic resonance angiogra
-
phy (MRA) can identify the anatomic location of disease. 
Due to overlying bowel, duplex ultrasound has a limited 
role in imaging the aortoiliac segment. Imaging is required 
only when symptoms necessitate intervention, since a 
history and physical examination with vascular testing 
should appropriately identify the involved levels of the 
arterial tree.
 
»
Treatment
A. Medical and Exercise Therapy
The cornerstones of PAD treatment are cardiovascular 
risk factor reduction and a structured exercise program. 
Essential elements include smoking cessation, antiplatelet 
therapy, lipid and blood pressure management, and weight 
loss. Nicotine replacement therapy, bupropion, and vare
-
nicline have established benefits in smoking cessation 
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(see Chapter 1). Antiplatelet agents (such as aspirin, 81 mg 
orally daily) reduce overall cardiovascular morbidity and 
are recommended for all symptomatic patients. All 
patients with PAD should receive high-dose statin 
 
(eg, atorvastastin 80 mg daily if tolerated) to treat hyper
-
cholesterolemia and inflammation. A trial of cilostazol 
100 mg orally twice a day, may improve walking distance 
in approximately two-thirds of patients.
Supervised exercise programs for PAD provide signifi
-
cant improvements in pain, walking distance, and quality 
of life and may be more effective than an endovascular 
treatment alone. A mininum training goal is a walking 
session of 30–45 minutes at least 3 days per week for a 
minimum of 12 weeks. Structured community or home-
based exercise programs as well as alternative exercises 
(cycling, upper-body ergometry) may also be effective.
B. Endovascular Therapy
When the atherosclerotic lesions are focal, they can be 
effectively treated with angioplasty and stenting. This 
approach matches the results of surgery for single stenoses 
but both effectiveness and durability decrease with longer 
or multiple stenoses.
C. Surgical Intervention
A prosthetic aorto-femoral bypass graft that bypasses the 
diseased artery segments is a highly effective and durable 
treatment for this disease. Patients may be treated with a 
graft from the axillary artery to the femoral arteries (axillo-
femoral bypass graft) or with a graft from the contralateral 
femoral artery (femoral-femoral bypass) when iliac disease 
is limited to one side. The operative risk of axillo-femoral 
and femoral-to-femoral bypass grafts is lower because the 
abdominal cavity is not entered and the aorta is not cross-
clamped, but the grafts are less durable.
 
»
The complications of the aorto-femoral bypass are those of 
any major abdominal surgery in a patient population with a 
high prevalence of cardiovascular disease. Mortality is low 
(2–3%), but morbidity is higher and includes a 5–10% rate 
of myocardial infarction. While endovascular approaches 
are safer and the complication rate is 1% to 3%, they are less 
durable with extensive disease.
 
»
Prognosis
Patients with isolated aortoiliac disease may have a further 
reduction in walking distance without intervention, but 
symptoms rarely progress to rest pain or threatened limb 
loss. Life expectancy is limited by their attendant cardiovas
-
cular disease with a mortality rate of 25–40% at 5 years.
Symptomatic relief is generally excellent with supervised 
exercise or after intervention. After aorto-femoral bypass, a 
patency rate of 90% at 5 years is common. Endovascular 
patency rates and symptom relief for patients with short 
stenoses are also good with 20% symptom return at 3 years. 
Recurrence rates following endovascular treatment of 
extensive disease are 30–50%.
 
»
Patients with progressive reduction in walking distance in 
spite of risk factor modification and supervised exercise 
programs and those with limitations that interfere with 
their activities of daily living should be referred for consul
-
tation to a vascular surgeon.
Gerhard-Herman MD et al. 2016 AHA/ACC Guideline on the 
management of patients with lower extremity peripheral 
Guidelines. Circulation. 2017 Mar 21;135(12):e726–79. 
[PMID: 27840333]
Parmenter BJ et al. Exercise training for management of 
peripheral arterial disease: a systemic review and meta-
analysis. Sports Med. 2015 Feb;45(2):231–44. [PMID: 
25230780]
Stoekenbroek RM et al; Incremental Decrease in End Points 
Through Aggressive Lipid Lowering Study Group. High-dose 
atorvastatin is superior to moderate-dose simvastatin in pre
-
venting peripheral arterial disease. Heart. 2015 Mar;101(5):
 
356–62. [PMID: 25595417]
OCCLUSIVE DISEASE: FEMORAL &

-
 
OCCLUSIVE DISEASE: FEMORAL & 
 
POPLITEAL ARTERIES
 
»
Cramping pain or tiredness in the calf with 
exercise.
 
»
Reduced popliteal and pedal pulses.
 
»
Foot pain at rest, relieved by dependency.
 
»
Foot gangrene or ischemic ulcers.
 
»
The superficial femoral artery is the peripheral artery 
most commonly occluded by atherosclerosis. Atheroscle
-
rosis of the femoral-popliteal segment usually occurs 
about a decade after the development of aortoiliac dis
-
ease, has an even gender distribution, and commonly 
affects black and Hispanic patients. The disease fre
-
quently occurs where the superficial femoral artery passes 
through the abductor magnus tendon in the distal thigh 
(Hunter canal). The common femoral artery and the pop
-
liteal artery are less commonly diseased but lesions in 
these vessels are debilitating, resulting in short-distance 
claudication.
 
»
Symptoms of intermittent claudication caused by lesions of 
the common femoral artery, superficial femoral artery, and 
popliteal artery are confined to the calf. Occlusion or ste
-
nosis of the superficial femoral artery at the adductor canal 
when the patient has good collateral vessels from the 
profunda femoris will cause claudication at approximately 
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CMDT 2019
2–4 blocks. However, with concomitant disease of the pro
-
funda femoris or the popliteal artery, much shorter distances 
may trigger symptoms. With short-distance claudication, 
dependent rubor of the foot with blanching on elevation 
may be present. Chronic low blood flow states will also 
cause atrophic changes in the lower leg and foot with loss 
of hair, thinning of the skin and subcutaneous tissues, and 
disuse atrophy of the muscles. With segmental occlusive 
disease of the superficial femoral artery, the common 
femoral pulsation is normal, but the popliteal and pedal 
pulses are reduced.
ABI values less than 0.9 are diagnostic of PAD and levels 
below 0.4 suggest critical limb ischemia. ABI readings 
depend on arterial compression. Since the vessels may be 
calcified in diabetes mellitus, chronic kidney disease, and 
in older adults, ABIs can be misleading. In such patients, 
the toe-brachial index is usually reliable with a value less 
than 0.7 considered diagnostic of PAD. Pulse volume 
recordings with cuffs placed at the high thigh, mid-thigh, 
calf, and ankle will delineate the levels of obstruction with 
reduced pressures and blunted waveforms.
C. Imaging
Duplex ultrasonography, CTA, or MRA all adequately 
show the anatomic location of the obstructive lesions and 
are done only if revascularization is planned.
 
»
Treatment
As with aortoiliac disease, risk factor reduction, medical 
optimization with a high-dose statin, and exercise treat
-
ment are the cornerstone of therapy. Cilostazol may 
improve intermittent claudication symptoms.
B. Surgical Intervention
Intervention is indicated if claudication is progressive, 
incapacitating, or interferes significantly with essential 
daily activities or employment. Intervention is mandatory 
if there is ischemic rest pain or ischemic ulcers threaten 
the foot.
1. Bypass surgery—
The most effective and durable treat
-
ment for lesions of the superficial femoral artery is a femo
-
ral-popliteal bypass with autogenous saphenous vein. 
Synthetic material, usually polytetrafluoroethylene (PTFE), 
can be used, but these grafts do not have the durability of 
vein bypass.
2. Endovascular surgery—
Endovascular techniques such 
as angioplasty and stenting, are often used for lesions of the 
superficial femoral artery. These techniques have lower 
morbidity than bypass surgery but also have lower rates of 
durability.
Endovascular therapy is most effective in patients 
undergoing aggressive risk factor modification in whom 
lesions measure less than 10 cm long. Paclitaxel-eluting 
stents or paclitaxel-coated balloons offer modest improve
-
ment over bare metal stents and noncoated balloons, but 
the success of local drug delivery in peripheral arteries is 
not as robust as in the coronary arteries. The 1-year 
patency rate is 50% for balloon angioplasty, 70% for drug-
coated balloons, and 80% for stents. However, by 3 years 
the patency rates are significantly worse for all three tech
-
niques and reintervention for restenosis is common. In 
general, treating restenosis in stents is more difficult than 
in arteries that have undergone angioplasty.
3. Thromboendarterectomy—
Removal of the atheroscle
-
rotic plaque is limited to the lesions of the common femoral 
and the profunda femoris arteries where bypass grafts and 
endovascular techniques have a more limited role.
 
»
Open surgical procedures of the lower extremities, particu
-
larly long bypasses with vein harvest, have a risk of wound 
infection that is higher than in other areas of the body. 
Wound infection or seroma can occur in as many as 
10–15% of cases. Myocardial infarction rates after open 
surgery are 5–10%, with a 1–4% mortality rate. Complica
-
tion rates of endovascular surgery are 1–5%, making these 
therapies attractive despite their lower durability.
 
»
Prognosis

-
 
»
Prognosis
The prognosis for motivated patients with isolated superfi
-
cial femoral artery disease is excellent, and surgery is not 
recommended for mild or moderate claudication in these 
patients. However, when claudication significantly limits 
daily activity and undermines quality of life as well as over
-
all cardiovascular health, intervention may be warranted. 
All interventions require close postprocedure follow-up 
with repeated ultrasound surveillance so that recurrent 
narrowing can be treated promptly to prevent complete 
occlusion. The reported patency rate of bypass grafts of the 
femoral artery, superficial femoral artery, and popliteal 
artery is 65–70% at 3 years, whereas the patency of angio
-
plasty is less than 50% at 3 years.
Because of the extensive atherosclerotic disease, 
including associated coronary lesions, 5-year mortality 
among patients with lower extremity disease can be as 
high as 50%, particularly with involvement of the infrap
-
opliteal vessels. However, with aggressive risk factor modi
-
fication, substantial improvement in longevity has been 
reported.
 
»
Patients with progressive symptoms, short-distance claudi
-
cation, rest pain, or any ulceration should be referred to a 
peripheral vascular specialist.
Rocha-Singh KJ et al; VIV A Physicians, Inc. Patient-level meta-
analysis of 999 claudicants undergoing primary femoropopli
-
teal nitinol stent implantation. Catheter Cardiovasc Interv. 
2017 Jun 1;89(7):1250–6. [PMID: 28303688]
Vartanian SM et al. Surgical intervention for peripheral arterial 
disease. Circ Res. 2015 Apr 24;116(9):1614–28. [PMID: 
25908732]
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OCCLUSIVE DISEASE: TIBIAL & 
 
PEDAL ARTERIES
 
»
Severe pain of the forefoot that is relieved by 
dependency.
 
»
Pain or numbness of the foot with walking.
 
»
Ulceration or gangrene of the foot or toes.
 
»
Pallor when the foot is elevated.
 
»
Occlusive processes of the tibial arteries of the lower leg 
and pedal arteries in the foot occur primarily in patients 
with diabetes. There often is extensive calcification of the 
artery wall. While claudication is a common initial symp
-
tom of ischemia, it may not be present. The first manifesta
-
tion of ischemia is frequently an ulcer or gangrene rather 
than claudication.
 
»
Unless there are concomitant lesions in the aortoiliac or 
femoral/superficial femoral artery segments, claudication 
may not occur. The gastrocnemius and soleus muscles may 
be supplied from collateral vessels from the popliteal 
artery; therefore, foot ischemia without attendant claudica
-
tion may be the first sign of severe vascular insufficiency 
due to isolated tibial artery disease. The presence of isch
-
emic rest pain or ulcers is termed 
critical limb ischemia
 
and is associated with the highest rate of amputation. Clas
-
sically, ischemic rest pain is confined to the dorsum of the 
foot and is relieved with dependency: the pain does not 
occur with standing, sitting or dangling the leg over the 
edge of the bed. It is severe and burning in character, and 
because it is present only when recumbent, it may awaken 
the patient from sleep. Because of the high incidence of 
neuropathy in these patients, it is important to differentiate 
rest pain from diabetic neuropathic dysesthesia. Leg night 
cramps, which are not a purely ischemic phenomenon, 
cause pain in the leg rather than the foot and should not be 
confused with ischemic rest pain.
On examination, depending on whether associated 
proximal disease is present, there may or may not be femo
-
ral and popliteal pulses, but the pedal pulses will be absent. 
Dependent rubor may be prominent with pallor on eleva
-
tion. The skin of the foot is generally cool, atrophic, and 
hairless.
The ABI may be quite low (in the range of 0.4 or lower). 
ABIs, however, may be falsely elevated when the medial 
layer of the arterial wall of the tibial arteries calcify 
(Mönckeberg medial calcific sclerosis) and are not com
-
pressible. Toe-brachial indexes should be used if noncom
-
pressible ankle arteries are encountered.
C. Imaging
Digital subtraction angiography is the gold standard 
method to delineate the anatomy of the tibial-popliteal seg
-
ment. MRA or CTA is less helpful for detection of lesions 
in this location due to the small vasculature and other 
technical issues related to image resolution.
 
»
Treatment
Good foot care may prevent ulcers, and most diabetic 
patients will do well with a conservative regimen. How
-
ever, if ulcerations appear and there is no significant 
healing within 2–3 weeks, blood flow studies (ankle-
brachial index/toe-brachial index) are indicated. Poor 
blood flow and a foot ulcer or nightly ischemic rest pain 
requires revascularization to avoid a major amputation. 
However, poor blood flow and infrequent rest pain with
-
out ulceration is not an indication for revascularization.
A. Bypass and Endovascular Techniques
Bypass with vein to the distal tibial or pedal arteries is an 
effective therapy to treat rest pain and heal ischemic 
ulcers of the foot. Because the foot often has relative spar
-
ing of vascular disease, these bypasses have had adequate 
patency rates (70% at 3 years). Fortunately, in nearly all 
series, limb preservation rates are much higher than 
patency rates.
Endovascular treatment with plain balloon angioplasty 
is effective for short segment lesions. The technical failure 
and reocclusion rates increase drastically with long seg
-

-
ment disease in multiple tibial arteries. Drug-coated 
balloons or stents have not been successful in the tibial 
vessels.
B. Amputation
Patients with ischemic rest pain and ulcers are at high 
risk for amputation, particularly if revascularization can
-
not be done. Patients with diabetes and PAD have a 4-fold 
risk of critical limb ischemia compared with nondiabetic 
patients with PAD and have a risk of amputation up to 
20-fold when compared to an age-matched population. 
Many patients who have below-the-knee or above-the-
knee amputations due to vascular insufficiency never 
attain independent ambulatory status and often need 
assisted-living facilities. These factors combine to 
demand revascularization whenever possible to preserve 
the limb.
 
»
The complications of intervention are similar to those 
listed for superficial femoral artery disease with evidence 
that the overall cardiovascular risk of intervention increases 
with decreasing ABI. Patients with critical limb ischemia 
require aggressive risk factor modification. Wound infec
-
tion rates after bypass are higher if there is an open wound 
in the foot.
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»
Prognosis
Patients with tibial atherosclerosis have extensive athero
-
sclerotic burden and a high prevalence of diabetes. Their 
prognosis without intervention is poor and complicated by 
the risk of amputation.
 
»
Patients with diabetes and foot ulcers should be referred 
for a formal vascular evaluation. Intervention may not be 
necessary but the severity of the disease will be quantified, 
which has implications for future symptom development. 
Any patient with an ulcer and a diabetic foot infection 
should be evaluated for an emergent operative incision 
and drainage. Broad-spectrum antibiotics should be given 
to cover gram-positive, gram-negative, and anaerobic 
organisms. Centers that have a multidisciplinary limb 
preservation center staffed with vascular surgeons, podia
-
trists, plastic and orthopedic surgeons, prosthetics and 
orthotic specialists, and diabetes specialists should be 
sought.
Mills JL. Lower limb ischaemia in patients with diabetic foot 
ulcers and gangrene: recognition, anatomic patterns and 
revascularization strategies. Diabetes Metab Res Rev. 2016 Jan;
 
32(Suppl 1):239–45. [PMID: 26455728]
Mills JL Sr et al. The Society for Vascular Surgery Lower 
Extremity Threatened Limb Classification System: risk strat
-
ification based on wound, ischemia, and foot infection 
(WIfI). J Vasc Surg. 2014 Jan;59(1):220–34.e1–2. [PMID: 
24126108]
Torpy JM et al. JAMA patient page. Peripheral arterial disease. 
JAMA. 2009 Jan 14;301(2):236. [PMID: 19141772]
ACUTE ARTERIAL OCCLUSION OF A LIMB
 
»
Sudden pain in an extremity with absent extremity 
pulses.
 
»
Usually some neurologic dysfunction with 
numbness, weakness, or complete paralysis.
 
»
Loss of light touch sensation requires revascular
-
ization within 3 hours for limb viability.
 
»
Acute occlusion may be due to an embolus or to thrombo
-
sis of a diseased atherosclerotic segment. Emboli large 
enough to occlude proximal arteries in the lower extremi
-
ties are almost always from the heart. Over 50% of the 
emboli from the heart go to the lower extremities, 20% to 
the cerebrovascular circulation, and the remainder to the 
upper extremities and mesenteric and renal circulation. 
Atrial fibrillation is the most common cause of cardiac 
thrombus formation; other causes are valvular disease or 
thrombus formation on the ventricular surface of a large 
anterior myocardial infarct.
Emboli from arterial sources such as arterial ulcerations 
or calcified excrescences are usually small and go to the 
distal arterial tree (toes).
The typical patient with primary thrombosis has had a 
history of claudication and now has an acute occlusion. If 
the stenosis has developed over time, collateral blood ves
-
sels will develop, and the resulting occlusion may cause 
only minimal increase in symptoms.
 
»
The sudden onset of extremity pain, with loss or reduction 
in pulses, is diagnostic of acute arterial occlusion. This often 
will be accompanied by neurologic dysfunction, such as 
numbness or paralysis in extreme cases. With popliteal 
occlusion, symptoms may affect only the foot. With proxi
-
mal occlusions, the whole leg may be affected. Signs of 
severe arterial ischemia include pallor, coolness of the 
extremity, and mottling. Impaired neurologic function pro
-
gressing to anesthesia accompanied with paralysis suggests a 
poor prognosis.
B. Doppler and Laboratory Findings
There will be little or no flow found with Doppler examina
-
tion of the distal vessels. Imaging, if done, may show an 
abrupt cutoff of contrast with embolic occlusion. Blood 
work may show myoglobin and metabolic acidosis.
C. Imaging
Whenever possible, imaging should be done in the operat
-
ing room because obtaining angiography, MRA, or CTA 
may delay revascularization and jeopardize the viability of

C. Imaging
-
may delay revascularization and jeopardize the viability of 
the extremity. However, in cases with only modest symp
-
toms and where light touch of the extremity is maintained, 
imaging may be helpful in planning the revascularization 
procedure.
 
»
Treatment
Immediate revascularization is required in all cases of 
symptomatic acute arterial thrombosis. 
Evidence of neu
-
rologic injury, including loss of light touch sensation, indi
-
cates that collateral flow is inadequate to maintain limb 
viability and revascularization should be accomplished 
within 3 hours.
 Longer delays carry a significant risk of 
irreversible tissue damage. This risk approaches 100% at 
6 hours.
A. Heparin
As soon as the diagnosis is made, unfractionated hepa
-
rin should be administered (5000–10,000 units) intrave
-
nously, followed by a heparin infusion to maintain the 
activated partial thromboplastin time (aPTT) in the 
therapeutic range (60–85 seconds) (12–18 units/kg/h). 
This helps prevent clot propagation and may also help 
relieve associated vessel spasm. Anticoagulation may 
improve symptoms, but revascularization will still be 
required.
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B. Endovascular Techniques
Catheter-directed chemical thrombolysis into the clot with 
tissue plasminogen activator (TPA) may be done but often 
requires 24 hours or longer to fully lyse the thrombus. This 
approach can be taken only in patients with an intact neuro
-
logic examination who do not have absolute contraindications 
such as bleeding diathesis, gastrointestinal bleeding, intracra
-
nial trauma, or neurosurgery within the past 3 months. A 
sheath is used to advance a TPA-infusing catheter through the 
clot. Heparin is administered systemically to prevent throm
-
bus formation around the sheath. Frequent vascular and 
access site examinations are required during the thrombolytic 
procedure to assess for improved vascular perfusion and to 
guard against the development of a hematoma.
General anesthesia is usually indicated; local anesthesia 
may be used in extremely high-risk patients if the explora
-
tion is to be limited to the common femoral artery. In 
extreme cases, it may be necessary to perform thrombo-
embolectomy from the femoral, popliteal and even the 
pedal vessels to revascularize the limb. The combined use 
of devices that pulverize and aspirate clot and intraopera
-
tive thrombolysis with TPA improves outcomes.
 
»
Complications of revascularization of an acutely ischemic 
limb can include severe metabolic acidosis, hyperkalemia, 
and cardiac arrest. In cases where several hours have elapsed 
but recovery of viable tissue may still be possible, significant 
levels of lactic acid, potassium, and other harmful agents 
may be released into the circulation during revasculariza
-
tion. Administering sodium bicarbonate (150 mEq NaHCO
3
 
in 1 liter of dextrose 5% in water) prior to reestablishing 
arterial flow is required. Surgery in the presence of thrombo
-
lytic agents and heparin carries a high risk of postoperative 
wound hematoma.
 
»
Prognosis
There is a 10–25% risk of amputation with an acute arterial 
embolic occlusion, and a 25% or higher in-hospital mortal
-
ity rate. Prognosis for acute thrombotic occlusion of an 
atherosclerotic segment is generally better because the col
-
lateral flow can maintain extremity viability. The longer-
term survival reflects the overall condition of the patient. 
In high-risk patients, an acute arterial occlusion is associ
-
ated with a dismal prognosis.
OCCLUSIVE CEREBROVASCULAR DISEASE
 
»
Sudden onset of weakness and numbness of an 
extremity or the face, aphasia, dysarthria, or 
unilateral blindness (amaurosis fugax).
 
»
Bruit heard loudest in the mid neck.
 
»
Unlike the other vascular territories, symptoms of ischemic 
cerebrovascular disease are predominantly due to emboli. 
The ischemia is reversible (transient ischemic attacks 
[TIAs]) when collateral flow reestablishes perfusion, but is 
a sign that the risk of additional emboli and permanent 
deficits is high. Most ischemic strokes are due to emboli 
from the heart. One-quarter of all ischemic strokes may be 
due to emboli from an arterial source; approximately 90% 
of these emboli originate from the proximal internal 
carotid artery, an area uniquely prone to the development 
of atherosclerosis. Lesions in the proximal great vessels of 
the aortic arch and the common carotid are less common. 
Intracranial atherosclerotic lesions are uncommon in the 
west but are the most frequent location of cerebrovascular 
disease in Asian populations.
 
»
Generally, the symptoms of a TIA last only a few seconds 
to minutes (but may continue up to 24 hours) while symp
-
toms of a stroke persist beyond 24 hours. The most com
-
mon lesions involve the anterior circulation in the cortex 
with both motor and sensory involvement. Emboli to the 
retinal artery cause unilateral blindness; when this blind
-
ness is transient, it is termed “amaurosis fugax. ” Posterior

-
ness is transient, it is termed “amaurosis fugax. ” Posterior 
circulation symptoms referable to the brainstem, cerebel
-
lum, and visual regions of the brain may be due to athero
-
sclerosis of the vertebral basilar systems and are much less 
common.
Signs of cerebrovascular disease may include carotid 
artery bruits. However, there is poor correlation between 
the degree of stenosis and the presence of the bruit. Fur
-
thermore, the presence of a bruit does not correlate with 
stroke risk. Nonfocal symptoms, such as dizziness and 
unsteadiness, seldom are related to cerebrovascular 
atherosclerosis.
B. Imaging
Duplex ultrasonography is the imaging modality of choice 
with high specificity and sensitivity for detecting and grad
-
ing the degree of stenosis at the carotid bifurcation (see 
Chapter 24).
Excellent depiction of the full anatomy of the cerebro
-
vascular circulation from arch to cranium can be obtained 
with either MRA or CTA. Each of the modalities may have 
false-positive or false-negative findings. Since the decision 
to intervene in cases of carotid stenosis depends on an 
accurate assessment of the degree of stenosis, it is recom
-
mended that at least two modalities be used to confirm the 
degree of stenosis. Diagnostic cerebral angiography is 
reserved for cases where carotid artery stenting (CAS) is to 
be done.
 
»
Treatment
See Chapter 24 for a discussion of the medical manage
-
ment of occlusive cerebrovascular disease.
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A. Asymptomatic Patients
Large studies have shown a 5-year reduction in stroke rate 
from 11.5% to 5.0% with surgical treatment of asymptom
-
atic carotid stenosis that is greater than 60%. Patients with 
asymptomatic carotid stenosis may benefit from carotid 
intervention if their risk for intervention is low and their 
expected survival is longer than 5 years. Recently, it has 
been proposed that aggressive risk factor modification 
including high potency statins may be as valuable as inter
-
vention in these patients; the large NIH-sponsored CREST2 
study is examining this issue.
Mild to moderate disease (30–50% stenosis) indicates 
the need for ongoing monitoring and aggressive risk factor 
modification. Patients with carotid stenosis that suddenly 
worsens are thought to have an unstable plaque and are at 
particularly high risk for embolic stroke.
B. Symptomatic Patients
Large randomized trials have shown that patients with 
TIAs or strokes from which they have completely or nearly 
completely recovered will benefit from carotid interven
-
tion if the ipsilateral carotid artery has a stenosis of more 
than 70% (Figure 12–1), and they are likely to benefit if 
the artery has a stenosis of 50–69%. In these situations, 
carotid endarterectomy (CEA) and CAS have been shown 
to have a durable effect in preventing further events. In 
symptomatic patients, intervention should ideally be 
planned within 2 weeks since delays increase the risk of a 
second event.
 
▲
Figure 12–1.
 
Digital subtraction angiography of a 
high-grade (90%) stenosis of internal carotid artery, 
with ulceration (arrow). 
Dean SM, Satiani B, Abraham WT. 
Color Atlas and Synopsis 
of Vascular Diseases.
 McGraw-Hill, 2014.)
 
»
The most common complication from carotid intervention 
is cranial nerve injury while the most dreaded complica
-
tion is stroke due to embolization of plaque material. The 
American Heart Association’s recommendations for upper 
limits of acceptable combined morbidity and mortality for 
these interventions is 3% for patients with asymptomatic 
carotid stenosis, 5% for those with TIAs, and 7% for 
patients with previous stroke. Results that are not as good 
as these guidelines will jeopardize the therapeutic benefit 
of carotid intervention.
A. Carotid Endarterectomy
In the 2010 CREST study the stroke risk for CEA was 2.3%. 
CEA also carries transient 1–2% risk cranial nerve injury 
(usually the vagus). There is also the risk of postoperative 
neck hematoma, which can cause acute compromise of the 
airway. Coronary artery disease is a comorbidity in most of 
these patients. Myocardial infarction rates after CEA are 
approximately 2–6%.
B. Angioplasty and Stenting
CAS had a stroke risk of 4.1% in the 2010 CREST study; 
patients over 70 years of age as well as women had higher 
stroke rates with CAS than with CEA. However, the risk of 
myocardial infarction was lower with CAS compared to 
CEA (1.1% vs 2.3%). CAS avoids both cranial nerve injury 
and neck hematoma. Nonetheless, emboli are more com
-
mon during carotid angioplasty and stenting in spite of the 
use of embolic protection devices, especially when the 
carotid artery is tortuous and heavily calcified. In cases of 
restenosis after previous carotid intervention, CAS is an 
excellent choice since the risk of embolization is low and 
the risk of cranial nerve injury with surgery is high.
 
»
Prognosis
Twenty-five percent of patients presenting with carotid 
stenosis and a TIA or small stroke will have further brain 
ischemia within 18 months with most of the events occur
-
ring within the first 6 months. Historically, patients with 
asymptomatic carotid stenosis are believed to have an 
annual stroke rate of just over 2% but this may be lower in 
the statin era. Prospective ultrasound screening at least 
annually is recommended in asymptomatic patients with

annually is recommended in asymptomatic patients with 
known carotid stenosis because approximately 10% of 
asymptomatic patients have evidence of plaque progression 
per year which increases stroke risk. Concomitant coro
-
nary artery disease is common and is an important factor 
in these patients both for perioperative risk and long-term 
prognosis. Aggressive risk factor modification should be 
prescribed for patients with cerebrovascular disease regard
-
less of planned intervention.
 
»
Asymptomatic or symptomatic patients with a carotid ste
-
nosis of more than 80% and patients with carotid stenosis 
of less than 80% with symptoms of a TIA or stroke should 
be referred to a vascular specialist for consultation.
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Brott TG et al; CREST Investigators. Long-term results of 
stenting versus endarterectomy for carotid-artery stenosis. 
N Engl J Med. 2016 Mar 17;374(11):1021–31. [PMID: 
26890472]
Jalbert JJ et al. Outcomes after carotid artery stenting in medicare 
beneficiaries, 2005 to 2009. JAMA Neurol. 2015 Mar;72(3):
 
276–86. [PMID: 25580726]
Zaidat OO et al; VISSIT Trial Investigators. Effect of a balloon-
expandable intracranial stent vs medical therapy on risk of 
stroke in patients with symptomatic intracranial stenosis: the 
VISSIT randomized clinical trial. JAMA. 2015 Mar 24–31;
 
313(12):1240–8. [PMID: 25803346]
VISCERAL ARTERY INSUFFICIENCY 
 
(
Intestinal Angina
)
 
»
Severe postprandial abdominal pain.
 
»
Weight loss with a “fear of eating. ”
 
»
Acute mesenteric ischemia:
 severe abdominal pain 
yet minimal findings on physical examination.
 
»
Acute visceral artery insufficiency
 results from either 
embolic occlusion or primary thrombosis of at least one 
major mesenteric vessel. Ischemia can also result from 
nonocclusive mesenteric vascular insufficiency,
 which is 
generally seen in patients with low flow states, such as heart 
failure, or hypotension. A 
chronic syndrome
 occurs when 
there is adequate perfusion for the viscera at rest but isch
-
emia occurs with severe abdominal pain when flow 
demands increase with feeding. Because of the rich collat
-
eral network in the mesentery, generally at least two of the 
three major visceral vessels (celiac, superior mesenteric, 
inferior mesenteric arteries) are affected before symptoms 
develop. 
Ischemic colitis,
 a variant of mesenteric ischemia, 
usually occurs in the distribution of the inferior mesenteric 
artery. The intestinal mucosa is the most sensitive to isch
-
emia and will slough if underperfused. The clinical presen
-
tation is similar to inflammatory bowel disease. Ischemic 
colitis can occur after aortic surgery, particularly aortic 
aneurysm resection or aortofemoral bypass for occlusive 
disease, when there is a sudden reduction in blood flow to 
the inferior mesenteric artery.
 
»
1. Acute intestinal ischemia—
Patients with primary vis
-
ceral arterial thrombosis often give an antecedent history 
consistent with chronic intestinal ischemia. The key find
-
ing with acute intestinal ischemia is severe, steady epigas
-
tric and periumbilical pain with minimal or no findings on 
physical examination of the abdomen because the visceral 
peritoneum is severely ischemic or infarcted and the 
parietal peritoneum is not involved. A high white cell 
count, lactic acidosis, hypotension, and abdominal disten
-
tion may aid in the diagnosis.
2. Chronic intestinal ischemia—
Patients are generally over 
45 years of age and may have evidence of atherosclerosis in 
other vascular beds. Symptoms consist of epigastric or 
periumbilical postprandial pain lasting 1–3 hours. To avoid 
the pain, patients limit food intake and may develop a fear 
of eating. Weight loss is universal.
3. Ischemic colitis—
Characteristic symptoms are left lower 
quadrant pain and tenderness, abdominal cramping, and 
mild diarrhea, which is often bloody.
B. Imaging and Colonoscopy
Contrast-enhanced CT is highly accurate at determining 
the presence of ischemic intestine. In patients with acute or 
chronic intestinal ischemia, a CTA or MRA can demon
-
strate narrowing of the proximal visceral vessels. In acute 
intestinal ischemia from a nonocclusive low flow state, 
angiography is needed to display the typical “pruned tree” 
appearance of the distal visceral vascular bed. Ultrasound 
scanning of the mesenteric vessels may show proximal 
obstructing lesions.
In patients with ischemic colitis, colonoscopy may 
reveal segmental ischemic changes, most often in the rectal 
sigmoid and splenic flexure where collateral circulation 
may be poor.
 
»
Treatment

»
Treatment
A high suspicion of acute intestinal ischemia dictates 
immediate exploration to determine bowel viability. If the 
bowel remains viable, bypass using a prosthetic conduit 
can be done either from the supra-celiac aorta or common 
iliac artery to the celiac and the superior mesentery artery. 
In cases where bowel viability is questionable or bowel 
resection will be required, the bypass can be done with 
autologous vein to avoid the use of prosthetic conduits in a 
potentially contaminated field. Angioplasty and stenting of 
the arteries can be used but does not avoid a surgical evalu
-
ation of bowel viability.
In chronic intestinal ischemia, angioplasty and stenting 
of the proximal vessel may be beneficial depending on the 
anatomy of the stenosis. Should an endovascular solution 
not be available, an aorto-visceral artery bypass is the pre
-
ferred management. The long-term results are highly 
durable. Visceral artery endarterectomy is reserved for 
cases with multiple lesions where bypass would be 
difficult.
The mainstay of treatment of 
ischemic colitis
 is main
-
tenance of blood pressure and perfusion until collateral 
circulation becomes well established. The patient must be 
monitored closely for evidence of perforation, which will 
require resection.
 
»
Prognosis
The combined morbidity and mortality rates are 10–15% 
from surgical intervention in these debilitated patients. 
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However, without intervention both acute and chronic 
intestinal ischemia are uniformly fatal. Adequate collateral 
circulation usually develops in those who have ischemic 
colitis, and the prognosis for this entity is better than 
chronic intestinal ischemia.
 
»
Any patient in whom there is a suspicion of intestinal isch
-
emia should be urgently referred for imaging and possible 
Clair DG et al. Mesenteric ischemia. N Engl J Med. 2016 Mar 10;
 
374(10):959–68. [PMID: 26962730]
Eslami MH et al. Mortality of acute mesenteric ischemia remains 
unchanged despite significant increase in utilization of endo
-
vascular techniques. Vascular. 2016 Feb;24(1):44–52. [PMID: 
25761854]
Zacharias NN et al. Chronic mesenteric ischemia outcome 
analysis and predictors of endovascular failure. J Vasc Surg. 
2016 Jun;63(6):1582–7. [PMID: 27066948]
ACUTE MESENTERIC VEIN OCCLUSION
The hallmarks of acute mesenteric vein occlusion are post
-
prandial pain and evidence of a hypercoagulable state. 
Acute mesenteric vein occlusion presents similarly to the 
arterial occlusive syndromes but is much less common. 
Patients at risk include those with paroxysmal nocturnal 
hemoglobinuria; protein C, protein S, or antithrombin 
deficiencies; or the 
JAK2
 mutation. These lesions are diffi
-
cult to treat surgically, and thrombolysis is the mainstay of 
therapy. Aggressive long-term anticoagulation is required 
for these patients.
 
º
NONATHEROSCLEROTIC VASCULAR 
DISEASE
THROMBOANGIITIS OBLITERANS 
 
(
Buerger Disease
)
 
»
Typically occurs in male cigarette smokers.
 
»
Distal extremities involved with severe ischemia, 
progressing to tissue loss.
 
»
Thrombosis of the superficial veins may occur.
 
»
Amputation will be necessary unless the patient 
stops smoking.
 
»
Buerger disease is a segmental, inflammatory, and throm
-
botic process of the distal-most arteries and occasionally 
veins of the extremities. Pathologic examination reveals 
arteritis in the affected vessels. The cause is not known but 
it is rarely seen in nonsmokers. Arteries most commonly 
affected are the plantar and digital vessels of the foot and 
lower leg. In advanced stages, the fingers and hands may 
become involved. The incidence of Buerger disease has 
decreased dramatically.
 
»
Buerger disease may be initially difficult to differentiate 
from routine peripheral vascular disease, but in most 
cases, the lesions are on the toes and the patient is 
younger than 40 years of age. The observation of super
-
ficial thrombophlebitis may aid the diagnosis. Because 
the distal vessels are usually affected, intermittent claudi
-
cation is not common with Buerger disease, but rest pain, 
particularly pain in the distal most extremity (ie, toes), is 
frequent. This pain often progresses to tissue loss and 
amputation, unless the patient stops smoking. The pro
-
gression of the disease seems to be intermittent with 
acute and dramatic episodes followed by some periods of 
remission.
B. Imaging
MRA or invasive angiography can demonstrate the oblit
-
eration of the distal arterial tree typical of Buerger 
disease.
 
»
In atherosclerotic peripheral vascular disease, the onset of 
tissue ischemia tends to be less dramatic than in Buerger 
disease, and symptoms of proximal arterial involvement, 
such as claudication, predominate.
Symptoms of Raynaud disease may be difficult to 
differentiate from Buerger disease. Repetitive athero
-
emboli may also mimic Buerger disease and may be 
difficult to differentiate. It may be necessary to image 
the proximal arterial tree to rule out sources of arterial 
microemboli.
 
»
Treatment
Smoking cessation is the mainstay of therapy and will halt 
the disease in most cases. As the distal arterial tree is 
occluded, revascularization is not possible. Sympathec
-

»
Treatment
-
tomy is rarely effective.
 
»
Prognosis
If smoking cessation can be achieved, the outlook for 
Buerger disease may be better than in patients with prema
-
ture peripheral vascular disease. If smoking cessation is not 
achieved, then the prognosis is generally poor, with ampu
-
tation of both lower and upper extremities the eventual 
outcome.
Klein-Weigel P et al. Buerger’s disease: providing integrated care. 
J Multidiscip Healthc. 2016 Oct 12;9:511–8. [PMID: 
27785045]
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º
ARTERIAL ANEURYSMS
ABDOMINAL AORTIC ANEURYSM
 
»
Most aortic aneurysms are asymptomatic until 
rupture.
 
»
Abdominal aortic aneurysms measuring 5 cm are 
palpable in 80% of patients.
 
»
Back or abdominal pain with aneurysmal tender
-
ness may precede rupture.
 
»
Rupture is catastrophic; hypotension; excruciating 
abdominal pain that radiates to the back.
 
»
Dilatation of the infrarenal aorta is a normal part of aging. 
The aorta of a healthy young man measures approximately 
2 cm. An aneurysm is considered present when the aortic 
diameter exceeds 3 cm, but aneurysms rarely rupture until 
their diameter exceeds 5 cm. Abdominal aortic aneurysms 
are found in 2% of men over 55 years of age; the male to 
female ratio is 4:1. Ninety percent of abdominal atheroscle
-
rotic aneurysms originate below the renal arteries. The 
aneurysms usually involve the aortic bifurcation and often 
involve the common iliac arteries.
Inflammatory aneurysms are an unusual variant. 
These have an inflammatory peel (similar to the inflam
-
mation seen with retroperitoneal fibrosis) that surrounds 
the aneurysm and encases adjacent retroperitoneal struc
-
tures, such as the duodenum and, occasionally, the 
ureters.
 
»
1. Asymptomatic—
Although 80% of 5-cm infrarenal 
aneurysms are palpable on routine physical examination, 
most aneurysms are discovered on ultrasound or CT imag
-
ing as part of a screening program or during the evaluation 
of unrelated abdominal symptoms.
2. Symptomatic
a. Pain
—
Aneurysmal expansion may be accompanied by 
pain that is mild to severe midabdominal discomfort often 
radiating to the lower back. The pain may be constant or 
intermittent and is exacerbated by even gentle pressure on 
the aneurysm sack. Pain may also accompany inflammatory 
aneurysms. Most aneurysms have a thick layer of thrombus 
lining the aneurysmal sac, but embolization to the lower 
extremities is rarely seen.
b. Rupture
—
The sudden escape of blood into the retro
-
peritoneal space causes severe pain, a palpable abdominal 
mass, and hypotension. Free rupture into the peritoneal 
cavity is a lethal event.
In acute cases of a contained rupture, the hematocrit may 
be normal, since there has been no opportunity for 
hemodilution.
Patients with aneurysms may also have such cardiopul
-
monary diseases as coronary artery disease, carotid dis
-
ease, kidney impairment, and emphysema, which are 
typically seen in elderly men who smoke. Preoperative 
testing may indicate the presence of these comorbid condi
-
tions, which increase the risk of intervention.
C. Imaging
Abdominal ultrasonography is the diagnostic study of 
choice for initial screening for the presence of an aneu
-
rysm. In approximately three-quarters of patients with 
aneurysms, curvilinear calcifications outlining portions of 
the aneurysm wall may be visible on plain films of the 
abdomen or back. CT scans provide a more reliable assess
-
ment of aneurysm diameter and should be done when the 
aneurysm nears the diameter threshold (5.5 cm) for treat
-
ment. Contrast-enhanced CT scans show the arteries above 
and below the aneurysm. The visualization of this vascula
-
ture is essential for planning repair.
Once an aneurysm is identified, routine follow-up with 
ultrasound will determine size and growth rate. The fre
-
quency of imaging depends on aneurysm size ranging 
from every 2 years for aneurysms smaller than 4 cm to 
every 6 months for aneurysms at or approaching 5 cm. 
When an aneurysm measures approximately 5 cm, a CTA 
with contrast should be done to more accurately assess the 
size of the aneurysm and define the anatomy.
 
»
Screening
Data support the use of abdominal ultrasound to screen 
65- to 75-year-old men, but not women, who are current or 
past smokers. Guidelines do not recommend repeated 
screening if the aorta shows no enlargement.

»
Treatment
A. Elective Repair
In general, elective repair is indicated for aortic aneurysms 
larger than 5.5 cm in diameter or aneurysms that have 
undergone rapid expansion (more than 0.5 cm in 
 
6 months). Symptoms such as pain or tenderness may indi
-
cate impending rupture and require urgent repair regard
-
less of the aneurysm’s diameter.
B. Aneurysmal Rupture
A ruptured aneurysm is a lethal event. Approximately half 
the patients exsanguinate prior to reaching a hospital. In the 
remainder, bleeding may be temporarily contained in the 
retroperitoneum (contained rupture), allowing the patient 
to undergo emergent surgery. However, only half of those 
patients will survive. Endovascular repair is available for 
ruptured aneurysm treatment in most major vascular cen
-
ters, with the results offering some improvement over open 
repair for these critically ill patients.
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C. Inflammatory Aneurysm
The presence of periaortic inflammation (inflammatory 
aneurysm) is not an indication for surgical treatment, 
unless there is associated compression of retroperitoneal 
structures, such as the ureter or pain upon palpation of the 
aneurysm. Interestingly, the inflammation that encases an 
inflammatory aneurysm recedes after either endovascular 
or open surgical aneurysm repair.
D. Assessment of Operative Risk
Aneurysms appear to be a variant of systemic athero
-
sclerosis. Patients with aneurysms have a high rate of 
coronary disease. A 2004 trial demonstrated minimal 
value in addressing stable coronary artery disease prior 
to aneurysm resection. However, in patients with sig
-
nificant symptoms of coronary disease, the coronary 
disease should be treated first. Aneurysm resection 
should follow shortly thereafter because there is a 
slightly increased risk of aneurysm rupture after the 
coronary procedures.
E. Open Surgical Resection Versus 
 
Endovascular Repair
In open surgical aneurysm repair, a graft is sutured to 
the non-dilated vessels above and below the aneurysm. 
This involves an abdominal incision, extensive dissec
-
tion, and interruption of aortic blood flow. The mortal
-
ity rate is low (2–5%) in centers that have a high volume 
for this procedure and when it is performed in good-risk 
patients. Older, sicker patients may not tolerate the 
cardiopulmonary stresses of the operation. With endo
-
vascular repair, a stent-graft is used to line the aorta and 
exclude the aneurysm. The stent must be able to seal 
securely against the wall of the aorta above and below 
the aneurysm, thereby excluding blood from flowing 
into the aneurysm sac. The anatomic requirements to 
securely achieve aneurysm exclusion vary according to 
the performance characteristics of the specific stent-
graft device. Most studies have found that endovascular 
aneurysm repair offers patients reduced operative mor
-
bidity and mortality as well as shorter recovery periods. 
Long-term survival is equivalent between the two tech
-
niques. Patients who undergo endovascular repair, how
-
ever, require more repeat interventions and need to 
 
be monitored postoperatively, since there is a 10–15% inci
-
dence of continued aneurysm growth post–endovascular 
repair.
F. Thrombus in an Aneurysm
The presence of thrombus within the aneurysm is not an 
indication for anticoagulation.
 
»
, the most common complica
-
tion, occurs in up to 10% of patients who undergo open 
aneurysm repair. The incidence of myocardial infarc
-
tion is substantially lower with endovascular repair. For 
routine infrarenal aneurysms, renal injury is unusual; 
however, when it does occur, or if the baseline creati
-
nine is elevated, it is a significant complicating factor in 
the postoperative period. Respiratory complications are 
similar to those seen in most major abdominal surgery. 
Gastrointestinal hemorrhage, even years after aortic 
surgeries, suggests the possibility of 
graft enteric fis
-
tula,
 most commonly between the aorta and the distal 
duodenum; the incidence of this complication is higher 
when the initial surgery is performed on an emergency 
basis.
 
»
Prognosis
The mortality rate for an open elective surgical resection 
is 1–5%, and the mortality rate for endovascular therapy 
is 0.5–2%. Of those who survive surgery, approximately 
60% are alive at 5 years; myocardial infarction is the lead
-
ing cause of death. The decision to repair aneurysms in 
high-risk patients is easier with the reduced periopera
-
tive morbidity and mortality of the endovascular 
approach.
Mortality rates of untreated aneurysms vary with aneu
-
rysm diameter. The mortality rate among patients with 
large aneurysms has been defined as follows: 12% annual 
risk of rupture with an aneurysm larger than 6 cm in diam
-

-
-
eter and a 25% annual risk of rupture in aneurysms of more 
than 7 cm diameter. In general, a patient with an aortic 
aneurysm larger than 5.5 cm has a threefold greater chance 
of dying of a consequence of rupture of the aneurysm than 
of dying of the surgical resection.
At present, endovascular aneurysm repair may be less 
definitive than open surgical repair and requires close fol
-
low up with an imaging procedure. Device migration, 
component separation, and graft limb thrombosis or kink
-
ing are common reasons for repeat intervention. With 
complete exclusion of blood from the aneurysm sac, the 
pressure is lowered, which causes the aneurysm to shrink. 
An “endoleak” from the top or bottom seal zones (type 1) 
or through a graft defect (type 3) is associated with a per
-
sistent risk of rupture. Indirect leakage of blood through 
lumbar and inferior mesenteric branches of the aneurysm 
(endoleak, type 2) produces an intermediate picture with 
somewhat reduced pressure in the sac, slow shrinkage, and 
low rupture risk. However, type 2 endoleak warrants close 
observation because aneurysm dilatation and rupture can 
occur.
 
»
•	
Any patient with a 4.5 cm aortic aneurysm or larger 
should be referred for imaging and assessment by a 
vascular specialist.
•	
Urgent referrals should be made if the patient com
-
plains of pain and gentle palpation of the aneurysm 
confirms that it is the source, regardless of the aneu
-
rysmal size.
 
»
Patients with a tender aneurysm to palpation or signs of 
aortic rupture require emergent hospital admission.
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Brahmbhatt R et al. Improved trends in patient survival and 
decreased major complications after emergency ruptured 
abdominal aortic aneurysm repair. J Vasc Surg. 2016 Jan;
 
63(1):39–47. [PMID: 26506941]
Jackson RS et al. Comparison of long-term survival after open vs 
endovascular repair of intact abdominal aortic aneurysm 
among Medicare beneficiaries. JAMA. 2012 Apr 18;
 
307(15):1621–8. [PMID: 22511690]
Kent KC. Clinical practice. Abdominal aortic aneurysms. N Engl 
J Med. 2014 Nov 27;371(22):2101–8. [PMID: 25427112]
Patel RR et al. Endovascular versus open repair of abdominal aortic 
aneurysm in 15-years’ follow-up of the UK endovascular aneu
-
rysm repair trial 1 (EV AR trial 1): a randomised controlled trial. 
Lancet. 2016 Nov 12;388(10058):2366–74. [PMID: 27743617]
THORACIC AORTIC ANEURYSMS
 
»
Widened mediastinum on chest radiograph.
 
»
With rupture, sudden onset of chest pain radiating 
to the back.
 
»
Most thoracic aortic aneurysms are due to atherosclerosis; 
syphilis is a rare cause. Disorders of connective tissue and 
Ehlers-Danlos and Marfan syndromes also are rare causes 
but have important therapeutic implications. Traumatic, 
false aneurysms, caused by partial tearing of the aortic wall 
with deceleration injuries, may occur just beyond the ori
-
gin of the left subclavian artery. Less than 10% of aortic 
aneurysms occur in the thoracic aorta.
 
»
Most thoracic aneurysms are asymptomatic. When symp
-
toms occur, they depend largely on the size and the posi
-
tion of the aneurysm and its rate of growth. Substernal 
back or neck pain may occur. Pressure on the trachea, 
esophagus, or superior vena cava can result in the following 
symptoms and signs: dyspnea, stridor, or brassy cough; 
dysphagia; and edema in the neck and arms as well as dis
-
tended neck veins. Stretching of the left recurrent laryngeal 
nerve causes hoarseness. With aneurysms of the ascending 
aorta, aortic regurgitation may be present due to dilation of 
the aortic valve annulus. Rupture of a thoracic aneurysm is 
catastrophic because bleeding is rarely contained, allowing 
no time for emergent repair.
B. Imaging
The aneurysm may be diagnosed on chest radiograph by 
the calcified outline of the dilated aorta. CT scanning is the 
modality of choice to demonstrate the anatomy and size of 
the aneurysm and to exclude lesions that can mimic aneu
-
rysms, such as neoplasms or substernal goiter. MRI can also 
be useful. Cardiac catheterization and echocardiography 
may be required to describe the relationship of the coronary 
vessels to an aneurysm of the ascending aorta.
 
»
Treatment
Indications for repair depend on the location of dilation, 
rate of growth, associated symptoms, and overall condition 
of the patient. Aneurysms measuring 6 cm or larger may be 
considered for repair. Aneurysms of the descending tho
-
racic aorta are treated routinely by endovascular grafting. 
Repair of arch aneurysms should be undertaken only if 
there is a skilled surgical team with an acceptable record of 
outcomes for these complex procedures. The availability of 
thoracic aortic endograft technique for descending tho
-
racic aneurysms or complex branched endovascular recon
-
structions for aneurysms involving the arch or visceral 
aorta (custom-made grafts with branches to the vessels 
involved in the aneurysm) does not change the indications 
for aneurysm repair. Aneurysms that involve the proximal 
aortic arch or ascending aorta represent particularly chal
-
lenging problems. Open surgery is usually required; how
-
ever, it carries substantial risk of morbidity (including 
stroke, diffuse neurologic injury, and intellectual impair
-
ment) because interruption of arch blood flow is required.
 
»
With the exception of endovascular repair for discrete sac
-
cular aneurysms of the descending thoracic aorta, the mor
-

-
 
»
-
-
bidity and mortality of thoracic repair is higher than for 
infra-renal abdominal aortic aneurysm repair. Paraplegia 
remains a devastating complication. Most large series report 
approximately 4–10% rate of paraplegia following endovas
-
cular repair of thoracic aortic aneurysms. The spinal arterial 
supply is segmental through intercostal branches of the aorta 
with variable degrees of intersegmental connection. There
-
fore, the more extensive the aneurysm, the greater is the risk 
of paraplegia with repair. Prior infrarenal abdominal aortic 
surgery, subclavian or internal iliac artery occlusion, and 
hypotension all increase the paraplegia risk. Involvement of 
the aortic arch also increases the risk of stroke, even when 
the aneurysm does not directly affect the carotid artery.
 
»
Prognosis
Generally, degenerative aneurysms of the thoracic aorta will 
enlarge and require repair to prevent death from rupture. 
Saccular aneurysms, particularly those distal to the left 
subclavian artery and the descending thoracic aorta, have 
good results with endovascular repair. Resection of aneu
-
rysms of the aortic arch requires a skilled surgical team for 
the major technical issues and should be attempted only in 
low-risk patients. Although available at specialty centers, 
branched or fenestrated endovascular grafting technology 
has demonstrated reduced morbidity and mortality.
 
»
Patients with a 6-cm aneurysm who are deemed to have a 
reasonable surgical risk should be considered for repair, 
particularly if the aneurysm involves the descending tho
-
racic aorta.
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»
Any patient with chest or back pain with a known or sus
-
pected thoracic aorta aneurysm must be brought to the 
hospital and undergo urgent imaging studies to rule out 
the aneurysm as a cause of the pain.
Gasper WJ et al. Assessing the anatomic applicability of the mul
-
tibranched endovascular repair of thoracoabdominal aortic 
aneurysm technique. J Vasc Surg. 2013 Jun;57(6):1553–8. 
[PMID: 23395201]
Patterson BO et al. Predicting mid-term all-cause mortality in 
patients undergoing elective endovascular repair of a descending 
thoracic aortic aneurysm. Ann Surg. 2016 Dec;264(6):1162–7. 
[PMID: 26813915]
von Allmen RS et al. Incidence of stroke following thoracic 
endovascular aortic repair for descending aortic aneurysm: a 
systematic review of the literature with meta-analysis. Eur J 
Vasc Endovasc Surg. 2017 Feb;53(2):176–84. [PMID: 
27993454]
PERIPHERAL ARTERY ANEURYSMS
 
»
Widened, prominent pulses.
 
»
Acute leg or foot pain and paresthesias with loss 
of distal pulses.
 
»
High association of popliteal aneurysms with 
abdominal aortic aneurysms.
 
»
Like aortic aneurysms, peripheral artery aneurysms are 
silent until critically symptomatic. However, unlike aortic 
aneurysms, the presenting manifestations are due to 
peripheral embolization and thrombosis. Popliteal artery 
aneurysms account for 70% of peripheral arterial aneu
-
rysms. Popliteal aneurysms may embolize repetitively over 
time and occlude distal arteries. Due to the redundant 
parallel arterial supply to the foot, ischemia does not occur 
until a final embolus occludes flow.
Primary femoral artery aneurysms are much less com
-
mon. However, pseudoaneurysms of the femoral artery 
following arterial punctures for arteriography and cardiac 
catheterization occur with an incidence ranging from 
0.05% to 6% of arterial punctures.
 
»
The patient may be aware of a pulsatile mass when the aneu
-
rysm is in the groin, but popliteal aneurysms are often unde
-
tected by the patient and clinician. Rarely, peripheral 
aneurysms may produce symptoms by compressing the local 
vein or nerve. The first symptom may be due to ischemia of 
acute arterial occlusion. The symptoms range from sudden 
onset pain and paralysis to short-distance claudication that 
slowly lessens as collateral circulation develops. Symptoms 
from recurrent embolization to the leg are often transient, if 
they occur at all. Sudden ischemia may appear in a toe or 
part of the foot, followed by slow resolution, and the true 
diagnosis may be elusive. The onset of recurrent episodes of 
pain in the foot, particularly if accompanied by cyanosis, 
suggests embolization and requires investigation of the heart 
and proximal arterial tree.
Because popliteal pulses are somewhat difficult to pal
-
pate even in normal individuals, a particularly prominent 
or easily felt pulse is suggestive of aneurysm and should be 
investigated by ultrasound. Since popliteal aneurysms are 
bilateral in 60% of cases, the diagnosis of thrombosis of a 
popliteal aneurysm is often aided by the palpation of a 
pulsatile aneurysm in the contralateral popliteal space. 
Approximately 50% of patients with popliteal aneurysms 
have an aneurysmal abdominal aorta.
B. Imaging Studies
Duplex color ultrasound is the most efficient investigation 
to confirm the diagnosis of peripheral aneurysm, measure 
its size and configuration, and demonstrate mural throm
-
bus. MRA or CTA are required to define the aneurysm and 
local arterial anatomy for reconstruction. Arteriography is 
not recommended because mural thrombus reduces the 
apparent diameter of the lumen on angiography. Patients 
with popliteal aneurysms should undergo abdominal ultra
-
sonography to determine whether an abdominal aortic 
aneurysm is also present.
 
»
Treatment

-
 
»
Treatment
To prevent limb loss from thrombosis or embolization, 
surgery is indicated when an aneurysm is associated with 
any peripheral embolization, is larger than 2 cm, or a mural 
thrombus is present. Immediate or urgent surgery is indi
-
cated when acute embolization or thrombosis has caused 
acute ischemia. Bypass is generally performed. Endovascu
-
lar exclusion of the aneurysm can be done but is reserved 
for high-risk patients. Intra-arterial thrombolysis may be 
done in the setting of acute ischemia, if examination (light 
touch) remains intact, suggesting that immediate surgery is 
not imperative. Acute pseudoaneurysms of the femoral 
artery due to arterial punctures can be successfully treated 
using ultrasound-guided compression. Open surgery with 
prosthetic interposition grafting is preferred for primary 
aneurysms of the femoral artery.
 
»
Prognosis
Approximately one-third of untreated patients will require 
an amputation. The long-term patency of bypass grafts for 
femoral and popliteal aneurysms is generally excellent, but 
depends on the adequacy of the outflow tract. Late graft 
occlusion is less common than in similar surgeries for 
occlusive disease.
 
»
In addition to patients with symptoms of ischemia, any 
patient with a peripheral arterial aneurysm measuring 
 
2 cm or with ultrasound evidence of thrombus within the 
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aneurysm should be referred to prevent progression to 
limb-threatening ischemia.
Cervin A et al. Treatment of popliteal aneurysm by open and 
endovascular surgery: a contemporary study of 592 procedures 
in Sweden. Eur J Vasc Endovasc Surg. 2015 Sep;50(3):342–50. 
[PMID: 25911500]
AORTIC DISSECTION
 
»
Sudden searing chest pain with radiation to the 
back, abdomen, or neck in a hypertensive patient.
 
»
 
»
Pulse discrepancy in the extremities.
 
»
Acute aortic regurgitation may develop.
 
»
Aortic dissection occurs when a spontaneous intimal tear 
develops and blood dissects into the media of the aorta. The 
tear probably results from the repetitive torque applied to 
the ascending and proximal descending aorta during the 
cardiac cycle; hypertension is an important component of 
this disease process. 
Type A dissection
 involves the arch 
proximal to the left subclavian artery, and 
type B dissection
 
occurs in the proximal descending thoracic aorta typically 
just beyond the left subclavian artery. Dissections may occur 
in the absence of hypertension but abnormalities of smooth 
muscle, elastic tissue, or collagen are more common in these 
patients. Pregnancy, bicuspid aortic valve, and coarctation 
also are associated with increased risk of dissection.
Blood entering the intimal tear may extend the dissec
-
tion into the abdominal aorta, the lower extremities, the 
carotid arteries or, less commonly, the subclavian arteries. 
Both absolute pressure levels and the pulse pressure are 
important in propagation of dissection. Aortic dissection is 
a true emergency and requires immediate control of blood 
pressure to limit the extent of the dissection. With type A 
dissection, which has the worse prognosis, death may 
occur within hours due to rupture of the dissection into the 
pericardial sac or dissection into the coronary arteries, 
resulting in myocardial infarction. Rupture into the pleural 
cavity is also possible. The intimal/medial flap of the aortic 
wall created by the dissection may occlude major aortic 
branches, resulting in ischemia of the brain, intestines, 
kidney, or extremities.
 
»
Severe persistent chest pain of sudden onset radiating 
down the back or possibly into the anterior chest is charac
-
teristic. Radiation of the pain into the neck may also occur. 
The patient is usually hypertensive. Syncope, hemiplegia, 
or paralysis of the lower extremities may occur. Intestinal 
ischemia or kidney injury may develop. Peripheral pulses 
may be diminished or unequal. A diastolic murmur may 
develop as a result of a dissection in the ascending aorta 
close to the aortic valve, causing valvular regurgitation, 
heart failure, and cardiac tamponade.
B. Electrocardiographic Findings
Left ventricular hypertrophy from long-standing hyperten
-
sion is often present. Acute changes suggesting myocardial 
ischemia do not develop unless dissection involves the 
coronary artery ostium. Classically, inferior wall abnor
-
malities predominate since dissection leads to compromise 
of the right rather than the left coronary artery. In some 
patients, the ECG may be completely normal.
C. Imaging
A multiplanar CT scan is the immediate diagnostic imaging 
modality of choice; clinicians should have a low threshold 
for obtaining a CT scan in any hypertensive patient with 
chest pain and equivocal findings on ECG.
The CT scan should include both the chest and abdo
-
men to fully delineate the extent of the dissected aorta. 
MRI is an excellent imaging modality for chronic dissec
-
tions, but in the acute situation, the longer imaging time 
and the difficulty of monitoring patients in the MRI scan
-
ner make the CT scan preferable. Chest radiographs may 
reveal an abnormal aortic contour or widened superior 
mediastinum. Although transesophageal echocardiogra
-

-
-
phy (TEE) is an excellent diagnostic imaging method, it is 
generally not readily available in the acute setting.
 
»
Aortic dissection is most commonly misdiagnosed as myo
-
cardial infarction or other causes of chest pain such as 
pulmonary embolization. Dissections may occur with 
minimal pain; branch vessel occlusion of the lower extremity 
can mimic arterial embolus.
 
»
Treatment
A. Medical
Aggressive measures to lower blood pressure should 
occur when an aortic dissection is suspected, even before 
the diagnostic studies have been completed. Treatment 
requires a simultaneous reduction of the systolic blood 
pressure to 100–120 mm Hg and pulse pressure. Beta-
blockers have the most desirable effect of reducing the left 
ventricular ejection force that continues to weaken the 
arterial wall and should be first-line therapy. Labetalol, 
both an alpha- and beta-blocker, lowers pulse pressure 
and achieves rapid blood pressure control. Give 20 mg 
over 2 minutes by intravenous injection. Additional doses 
of 40–80 mg intravenously can be given every 10 minutes 
(maximum dose 300 mg) until the desired blood pressure 
has been reached. Alternatively, 2 mg/min may be given 
by intravenous infusion, titrated to desired effect. In 
patients who have asthma, bradycardia, or other condi
-
tions that necessitate the patient’s reaction to beta-blockers 
be tested, esmolol is a reasonable choice because of its 
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short half-life. Give a loading dose of esmolol, 0.5 mg/kg 
intravenously over 1 minute, followed by an infusion of 
0.0025–0.02 mg/kg/min. Titrate the infusion to a goal 
heart rate of 60–70 beats/min. If beta-blockade alone does 
not control the hypertension, nitroprusside may be added 
as follows: 50 mg of nitroprusside in 1000 mL of 5% dex
-
trose and water, infused at a rate of 0.5 mL/min for a 
70-kg person (0.3 mcg/kg/min); the infusion rate is 
increased by 0.5 mL every 5 minutes until adequate con
-
trol of the pressure has been achieved. In patients with 
bronchial asthma, while there are no data supporting the 
use of the calcium channel antagonists, diltiazem and 
verapamil are potential alternatives to treatment with 
beta-blocking drugs. Morphine sulfate is the appropriate 
drug to use for pain relief. Long-term medical care of 
patients should include beta-blockers in their antihyper
-
tensive regimen.
Urgent surgical intervention is required for all type A 
dissections.
 If a skilled cardiovascular team is not avail
-
able, the patient should be transferred to an appropriate 
facility. The procedure involves grafting and replacing 
the diseased portion of the arch and brachiocephalic 
vessels as necessary. Replacement of the aortic valve 
may be required with reattachment of the coronary 
arteries.
Urgent surgery is required for 
type B dissections
 if 
there is aortic branch compromise resulting in malperfu
-
sion of the renal, visceral, or extremity vessels. The imme
-
diate goal of surgical therapy is to restore flow to the 
ischemic tissue, which is most commonly accomplished 
via a bypass. Endovascular stenting of the entry tear at the 
level of the subclavian artery may result in obliteration of 
the false lumen and restore flow into the branch vessel 
from the true lumen. The results, however, are unpredict
-
able and should only be attempted by an experienced 
team. For acute type B dissections without malperfusion, 
evidence shows that long-term aortic-specific survival 
and late aneurysm formation rates are improved with 
early thoracic stent graft repair. Patients with uncompli
-
cated type B dissections whose blood pressure is con
-
trolled and who survive the acute episode without 
complications may have long-term survival without sur
-
gical treatment.
 
»
Prognosis & Follow-Up
The mortality rate for untreated type A dissections is 
approximately 1% per hour for 72 hours and over 90% at 
 
3 months. Mortality is also extremely high for untreated 
type B dissections with malperfusion or rupture. The surgical 
and endovascular therapies for these patients are techni
-
cally demanding and require an experienced team to 
achieve perioperative mortalities of less than 10%. Aneu
-
rysmal enlargement of the residual false lumen may 
develop despite adequate antihypertensive therapy. Y early 
CT scans are required to monitor for aneurysm develop
-
ment. Indications for late aneurysm repair are determined 
by aneurysm size (6 cm or larger), similar to undissected 
thoracic aneurysms.
 
»
All patients with an acute dissection should be hospitalized. 
Any dissection involving the aortic arch (type A) should be 
immediately repaired. Acute type B dissections require 
repair only when there is evidence of rupture or major 
branch occlusion.
Bossone E et al. Acute aortic syndromes: diagnosis and manage
-
ment, an update. Eur Heart J. 2018 Mar 1;39(9):739–49d. [PMID: 
29106452]
Nienaber CA et al. Endovascular repair of type B aortic dissection: 
long-term results of the randomized investigation of stent grafts 
in aortic dissection trial. Circ Cardiovasc Interv. 2013 Aug;
 
6(4):407–16. [PMID: 23922146]
Suzuki T et al. Medical management in type B aortic dissection. 
Ann Cardiothorac Surg. 2014 Jul;3(4):413–7. [PMID: 
25133106]
 
º
VENOUS DISEASES
 
»

25133106]
 
º
 
»
Dilated, tortuous superficial veins in the legs.
 
»
May be asymptomatic or associated with aching 
discomfort or pain.
 
»
Often hereditary.
 
»
Increased frequency after pregnancy.
 
»
Varicose veins develop in the lower extremities. Periods of 
high venous pressure related to prolonged standing or 
heavy lifting are contributing factors, but the highest inci
-
dence occurs in women after pregnancy. Varicosities 
develop in over 20% of all adults.
This combination of progressive venous reflux and 
venous hypertension is the hallmark of chronic venous 
disease. The superficial veins are involved, typically the 
great saphenous vein and its tributaries, but the short 
saphenous vein (posterior lower leg) may also be affected. 
Distention of the vein prevents the valve leaflets from 
coapting, creating incompetence and reflux of blood 
toward the foot. Focal venous dilation and reflux leads to 
increased pressure and distention of the vein segment 
below that valve, which in turn causes progressive failure 
of the next lower valve. Perforating veins that connect the 
deep and superficial systems may become incompetent, 
allowing blood to reflux into the superficial veins from 
the deep system, increasing venous pressure and 
distention.
Secondary varicosities can develop as a result of 
obstructive changes and valve damage in the deep venous 
system following thrombophlebitis, or rarely as a result of 
proximal venous occlusion due to neoplasm or fibrosis. 
Congenital or acquired arteriovenous fistulas or venous 
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malformations are also associated with varicosities and 
should be considered in young patients with varicosities.
 
»
Symptom severity is not correlated with the number and 
size of the varicosities; extensive varicose veins may pro
-
duce no subjective symptoms, whereas minimal varicosi
-
ties may produce many symptoms. Dull, aching heaviness 
or a feeling of fatigue of the legs brought on by periods of 
standing is the most common complaint. Itching from 
venous eczema may occur either above the ankle or 
directly overlying large varicosities.
Dilated, tortuous veins of the thigh and calf are visible 
and palpable when the patient is standing. Longstanding 
varicose veins may progress to chronic venous insuffi
-
ciency with associated ankle edema, brownish skin hyper
-
pigmentation, and chronic skin induration or fibrosis. A 
bruit or thrill is never found with primary varicose veins 
and when found, alerts the clinician to the presence of an 
arteriovenous fistula or malformation.
B. Imaging
The identification of the source of venous reflux that feeds 
the symptomatic veins is necessary for effective surgical 
treatment. Duplex ultrasonography by a technician expe
-
rienced in the diagnosis and localization of venous reflux 
is the test of choice for planning therapy. In most cases, 
reflux will arise from the greater saphenous vein.
 
»
Varicose veins due to primary superficial venous reflux 
should be differentiated from those secondary to previous 
or ongoing obstruction of the deep veins (post-thrombotic 
syndrome). Pain or discomfort secondary to neuropathy 
should be distinguished from symptoms associated with 
coexistent varicose veins. Similarly, vein symptoms should 
be distinguished from pain due to intermittent claudica
-
tion, which occurs after a predictable amount of exercise 
and resolves with rest. In adolescent patients with varicose 
veins, imaging of the deep venous system is obligatory to 
exclude a congenital malformation or atresia of the deep 
veins. Surgical treatment of varicose veins in these patients 
is contraindicated because the varicosities may play a sig
-
nificant role in venous drainage of the limb.
 
»
Superficial thrombophlebitis of varicose veins is uncom
-
mon. The typical presentation is acute localized pain with 
tender, firm veins. The process is usually self-limiting, 
resolving within several weeks. The risk of deep venous 
thrombosis (DVT) or embolization is very low unless the 
thrombophlebitis extends into the great saphenous vein in 
the upper medial thigh. Predisposing conditions include 
pregnancy, local trauma, or prolonged periods of sitting.
In older patients, superficial varicosities may bleed with 
even minor trauma. The amount of bleeding can be alarm
-
ing as the pressure in the varicosity is high.
 
»
Treatment
A. Nonsurgical Measures
Nonsurgical treatment is effective. Elastic graduated compres
-
sion stockings (20–30 mm Hg pressure) reduce the venous 
pressure in the leg and may prevent the progression of disease. 
Good control of symptoms can be achieved when stockings 
are worn daily during waking hours and legs are elevated, 
especially at night. Compression stockings are well-suited for 
elderly patients or patients who do not want surgery.
B. Sclerotherapy
Direct injection of a sclerosing agent induces permanent 
fibrosis and obliteration of the target veins. Chemical irri
-
tants (eg, glycerin) or hypertonic saline are often used for 
small, less-than-4-mm reticular veins or telangiectasias. 
Foam sclerotherapy is used to treat the great saphenous 
vein, varicose veins larger than 4 mm, and perforating 
veins, often with local anesthesia alone. Injection of a cya
-
noacrylate adhesive is also available for treating the great 
saphenous vein. Foam sclerotherapy and cyanoacrylate 
adhesive therapy have similar clinical results as saphenous

-
adhesive therapy have similar clinical results as saphenous 
vein thermal ablation or stripping, although the long-term 
success rate may be lower and systemic embolization 
remains a concern. Complications such as phlebitis, tissue 
necrosis, or infection may occur with any sclerosing agent.
C. Surgical Measures
Treatment with endovenous thermal ablation (with either 
radiofrequency or laser) or, less commonly, with great saphe
-
nous vein stripping is effective for reflux arising from the great 
saphenous vein. Less common sources of reflux include the 
small saphenous vein (for varicosities in the posterior calf) 
and incompetent perforator veins arising directly from the 
deep venous system. Correction of reflux is performed at the 
same time as excision of the symptomatic varicose veins. Phle
-
bectomy without correction of reflux results in a high rate of 
recurrent varicosities, as the uncorrected reflux progressively 
dilates adjacent veins. Concurrent reflux detected by ultraso
-
nography in the deep system is not a contraindication to treat
-
ment of superficial reflux because the majority of deep vein 
dilatation is secondary to volume overload in this setting, 
which will resolve with correction of the superficial reflux.
 
»
Prognosis
Surgical treatment of superficial vein reflux and excision of 
varicose veins provide excellent results. The 5-year success 
rate (as defined as lack of pain and recurrent varicosities) is 
85–90%. Simple excision (phlebectomy) or injection 
sclerotherapy without correction of reflux is associated 
with higher rates of recurrence. Even after adequate treat
-
ment, secondary tissue changes may persist.
 
»
•	
Absolute indications for referral for saphenous ablation 
include thrombophlebitis and bleeding.
•	
Pain and cosmetic concerns are responsible for the 
majority of referrals for ablation.
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Brittenden J et al. A randomized trial comparing treatments for 
varicose veins. N Engl J Med. 2014 Sep 25;371(13):1218–27. 
[PMID: 25251616]
Hamann SAS et al. Editor’s Choice—Five-year results of great 
saphenous vein treatment: a meta-analysis. Eur J Vasc Endo
-
vasc Surg. 2017 Dec;54(6):760–70. [PMID: 29033337]
Hamdan A et al. JAMA patient page. Treatment of varicose 
veins. JAMA. 2013 Mar 27;309(12):1306. [PMID: 23532249]
SUPERFICIAL VENOUS THROMBOPHLEBITIS
 
»
Red, painful induration along a superficial vein, 
usually at the site of a recent intravenous line.
 
»
Marked swelling of the extremity may not occur.
 
»
Short-term venous catheterization of superficial arm 
veins as well as the use of longer-term peripherally 
inserted central catheter (PICC) lines are the most com
-
mon cause of superficial thrombophlebitis. Intravenous 
catheter sites should be observed daily for signs of local 
inflammation and should be removed if a local reaction 
develops in the vein. Serious thrombotic or septic com
-
plications can occur if this policy is not followed; 
 is the most common pathogen. 
Other organisms, including fungi, may also be 
responsible.
Superficial thrombophlebitis may occur spontane
-
ously, often in pregnant or postpartum women or in 
individuals with varicose veins, or it may be associated 
with trauma, as with a blow to the leg or following intra
-
venous therapy with irritating solutions. It also may be a 
manifestation of systemic hypercoagulability secondary 
to abdominal cancer such as carcinoma of the pancreas 
and may be the earliest sign of these conditions. Super
-
ficial thrombophlebitis may be associated with occult 
DVT in about 20% of cases. Pulmonary emboli are 
exceedingly rare and occur from an associated DVT. 
(See Chapters 9 and 14 for discussion on deep venous 
thrombosis.)
 
»
In spontaneous superficial thrombophlebitis, the great 
saphenous vein is most often involved. The patient usu
-
ally experiences a dull pain in the region of the involved 
vein. Local findings consist of induration, redness, and 
tenderness along the course of a vein. The process may be 
localized, or it may involve most of the great saphenous 
vein and its tributaries. The inflammatory reaction gener
-
ally subsides in 1–2 weeks; a firm cord may remain for a 
much longer period. Edema of the extremity is 
uncommon.
Localized redness and induration at the site of a recent 
intravenous line requires urgent attention. Proximal 
extension of the induration and pain with chills and high 
fever suggest septic phlebitis and requires urgent treatment.
 
»
The linear rather than circular nature of the lesion and the 
distribution along the course of a superficial vein serve to 
differentiate superficial phlebitis from cellulitis, erythema 
nodosum, erythema induratum, panniculitis, and fibrosi
-
tis. Lymphangitis and deep thrombophlebitis must also be 
 
»
Treatment
For spontaneous thrombophlebitis if the process is well 
localized and not near the saphenofemoral junction, local 
heat and nonsteroidal anti-inflammatory medications are 
usually effective in limiting the process. If the induration 
is extensive or is progressing toward the saphenofemoral 
junction (leg) or cephalo-axillary junction (arm), ligation 
and division of the vein at the junction of the deep and 
superficial veins is indicated.
Anticoagulation therapy is usually not required for focal 
processes. Prophylactic dose low-molecular-weight heparin 
or fondaparinux is recommended for 5 cm or longer superfi
-
cial thrombophlebitis of the lower limb veins (Table 14–14) 
and full anticoagulation is reserved for disease that is rapidly 
progressing or if there is concern for extension into the deep 
system (Table 14–16).
Septic superficial thrombophlebitis is an intravascular

Septic superficial thrombophlebitis is an intravascular 
abscess and requires urgent treatment with heparin or 
fondaparinux (see Table 14–16) to limit additional throm
-
bus formation as well as removal of the offending catheter 
in catheter-related infections (see Chapter 30). Treat with 
antibiotics (eg, vancomycin, 15 mg/kg intravenously every 
12 hours plus ceftriaxone, 1 g intravenously every 
 
24 hours). If cultures are positive, therapy should be con
-
tinued for 7–10 days or for 4–6 weeks if complicating 
endocarditis cannot be excluded. Surgical excision of the 
involved vein may also be necessary to control the 
 
»
Prognosis
With spontaneous thrombophlebitis, the course is gener
-
ally benign and brief. The prognosis depends on the 
underlying pathologic process. In patients with phlebitis 
secondary to varicose veins, recurrent episodes are likely 
unless correction of the underlying venous reflux and 
excision of varicosities is done. In contrast, the mortality 
from septic thrombophlebitis is 20% or higher and 
requires aggressive treatment. However, if the involvement 
is localized, the mortality is low and prognosis is excellent 
with early treatment.
Scott G et al. Superficial vein thrombosis: a current approach to 
management. Br J Haematol. 2015 Mar;168(5):639–45. 
[PMID: 25521017]
Stevens SM. ACP Journal Club: review: fondaparinux reduces 
VTE and recurrence in superficial thrombophlebitis of the 
leg. Ann Intern Med. 2012 Aug 21;157(4):JC2–4. [PMID: 
22910958]
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CHRONIC VENOUS INSUFFICIENCY
 
»
History of prior DVT or leg injury.
 
»
Edema, (brawny) skin hyperpigmentation, sub
-
cutaneous lipodermosclerosis in the lower leg.
 
»
Large ulcerations at or above the medial ankle are 
common (venous ulcers).
 
»
Chronic venous insufficiency is a severe manifestation of 
venous hypertension. One of the most common etiologies 
is prior deep venous thrombophlebitis (see Chapter 14), 
although about 25% of patients do not have a known his
-
tory of DVT. In these cases, there may be a history of leg 
trauma or surgery; obesity is often a complicating factor. 
Progressive superficial venous reflux is also a common 
cause. Other causes include congenital or neoplastic 
obstruction of the pelvic veins or a congenital or acquired 
arteriovenous fistula.
The basic pathology is caused by valve leaflets that do not 
coapt because they are either thickened and scarred (post-
thrombotic syndrome) or in a dilated vein and are therefore 
functionally inadequate. Proximal venous obstruction due to 
chronic thrombus or scarring compounds the problem. With 
the valves unable to stop venous blood from returning to the 
foot (venous reflux), the leg develops venous hypertension 
and an abnormally high hydrostatic force is transmitted to 
the subcutaneous veins and tissues of the lower leg. The 
resulting edema results in dramatic and deleterious second
-
ary changes. The stigmata of chronic venous insufficiency 
include fibrosis of the subcutaneous tissue and skin, pigmen
-
tation of skin (hemosiderin taken up by the dermal macro
-
phages), and, later, ulceration, which is extremely slow to 
heal. Itching may precipitate the formation of ulceration or 
local wound cellulitis. Dilation of the superficial veins may 
occur, leading to varicosities. Although surgical treatment for 
venous reflux can improve symptoms, controlling edema and 
the secondary skin changes usually require lifelong compres
-
sion therapy.
 
»
Progressive pitting edema of the leg (particularly the lower 
leg) is the primary presenting symptom. Secondary changes 
in the skin and subcutaneous tissues develop over time 
(Figure 12–2). The usual symptoms are itching, a dull dis
-
comfort made worse by periods of standing, and pain if an 
ulceration is present. The skin at the ankle is usually taut 
from swelling, shiny, and a brownish pigmentation (hemo
-
siderin) often develops. If the condition is longstanding, 
the subcutaneous tissues become thick and fibrous. Ulcer
-
ations may occur, usually just above the ankle, on the 
medial or anterior aspect of the leg. Healing results in a 
 
▲
Figure 12–2.
 
Bilateral pretibial edema and erythema 
consistent with stasis dermatitis (sometimes mimicking 
cellulitis) in chronic venous insufficiency. 
permission, from Dean SM, Satiani B, Abraham WT. 
Color Atlas 
and Synopsis of Vascular Diseases.
thin scar on a fibrotic base that often breaks down with 
minor trauma or further bouts of leg swelling. Varicosities 
may appear (Figure 12–3) that are associated with incom
-
petent perforating veins. Cellulitis, which is often difficult 
to distinguish from the hemosiderin pigmentation, may be 
diagnosed by blanching erythema with pain.
B. Imaging
Patients with post-thrombotic syndrome or signs of chronic 
venous insufficiency should undergo duplex ultrasonogra
-
phy to determine whether superficial reflux is present and 
to evaluate the degree of deep reflux and obstruction.
 
»
Patients with heart failure, chronic kidney disease, or decom
-
pensated liver disease may have bilateral edema of the lower 
extremities. Many medications can cause edema (eg, calcium 
channel blockers, nonsteroidal anti-inflammatory agents, 
thiazolidinediones). Swelling from lymphedema involves the

thiazolidinediones). Swelling from lymphedema involves the 
feet and may be unilateral, but varicosities are absent. Edema 
from these causes pits easily and brawny discoloration is rare. 
Lipedema is a disorder of adipose tissue that occurs almost 
exclusively in women, is bilateral and symmetric, and is char
-
acterized by stopping at a distinct line just above the ankles.
Primary varicose veins may be difficult to differentiate 
from the secondary varicosities of post-thrombotic syn
-
drome or venous obstruction.
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▲
Figure 12–3.
 
Varicose veins, manifested as blue, 
subcutaneous, tortuous veins more than 3 mm in 
diameter.
 (Used, with permission, from Dean SM, 
Satiani B, Abraham WT. 
Color Atlas and Synopsis of Vascular 
Diseases.
Other conditions associated with chronic ulcers of the 
leg include neuropathic ulcers usually from diabetes mel
-
litus, arterial insufficiency (often very painful lateral 
ankle ulcers with absent pulses), autoimmune diseases 
(eg, Felty syndrome), sickle cell anemia, erythema indu
-
ratum (bilateral and usually on the posterior aspect of the 
lower part of the leg), and fungal infections.
 
»
Irreversible tissue changes and associated complications 
in the lower legs can be minimized through early and 
aggressive anticoagulation of acute DVT to minimize the 
valve damages and by prescribing compression stockings 
if chronic edema develops after the DVT has resolved. 
Routine treatment of acute iliofemoral DVT with cathe
-
ter-directed thrombolysis or mechanical thrombectomy 
does not reduce post-thrombotic syndrome and chronic 
 
»
Treatment
Fitted, graduated compression stockings (20–30 mm Hg 
pressure or higher) worn from the foot to just below the 
knee during the day and evening are the mainstays of 
treatment and are usually sufficient. When they are not, 
additional measures, such as avoidance of long periods of 
sitting or standing, intermittent elevations of the involved 
leg, and sleeping with the legs kept above the level of the 
heart, may be necessary to control the swelling. Pneu
-
matic compression of the leg, which can pump the fluid 
out of the leg, is used in cases refractory to the above 
measures.
B. Ulceration
As the primary pathology is edema and venous hyperten
-
sion, healing of the ulcer will not occur until the edema is 
controlled and compression is applied. Circumferential 
nonelastic bandages on the lower leg enhance the pumping 
action of the calf muscles on venous blood flow out of the 
calf. A lesion can often be treated on an ambulatory basis 
by means of a semi-rigid gauze boot made with Unna paste 
(Gelocast, Medicopaste) or a multi-layer compression 
dressing (eg, Profore). Initially, the ulcer needs to be 
debrided and the boot changed every 2–3 days to control 
ulcer drainage. As the edema and drainage subside, opti
-
mal healing is achieved when the boot is kept in place for 
5–7 days. The ulcer, tendons, and bony prominences must 
be adequately padded. Alternatively, knee-high graduated 
compression stockings with an absorbent dressing may be 
used, if wound drainage is minimal. Home compression 
therapy with a pneumatic compression device is used in 
refractory cases, but many patients have severe pain with 
the “milking” action of the pump device. Some patients will 
require admission for complete bed rest and leg elevation 
to achieve ulcer healing. After the ulcer has healed, daily 
graduated compression stocking therapy is mandatory to 
prevent ulcer recurrence.
C. Vein Treatment (Reflux or Obstruction)
Treatment of superficial vein reflux (see Varicose Veins 
section, above) has been shown to decrease the recurrence 
rate of venous ulcers. Where there is substantial obstruc
-
tion of the femoral and popliteal deep venous system, 
superficial varicosities supply the venous return and they 
should not be removed.
Using venous stents, treatment of chronic iliac deep 
vein stenosis or obstruction may improve venous ulcer 
healing and reduce the ulcer recurrence rate in severe 
cases.
 
»
Prognosis
Individuals with chronic venous insufficiency often have 
recurrent edema, particularly if they do not consistently 
wear support stockings that have at least 20–30 mm Hg 
compression.
 
»
•	
Patients with significant saphenous reflux should be 
evaluated for ablation.
•	
Patients with ulcers should be monitored by a interdis
-

»
•	
•	
-
ciplinary wound care team so that these challenging 
wounds receive aggressive care.
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Eberhardt RT et al. Chronic venous insufficiency. Circulation. 
2014 Jul 22;130(4):333–46. [PMID: 25047584]
O’Donnell TF Jr et al. Management of venous leg ulcers: clinical 
practice guidelines of the Society for Vascular Surgery and the 
American Venous Forum. J Vasc Surg. 2014 Aug;60
 
(2 Suppl):3S–59S. [PMID: 24974070]
Seager MJ et al. Editor’s Choice—A systematic review of endove
-
nous stenting in chronic venous disease secondary to iliac 
vein obstruction. Eur J Vasc Endovasc Surg. 2016 Jan;51
 
(1):100–20. [PMID: 26464055]
Vedantham S et al; ATTRACT Trial Investigators. Pharmacom
-
echanical catheter-directed thrombolysis for deep-vein 
thrombosis. N Engl J Med. 2017 Dec 7;377(23):2240–52. 
[PMID: 29211671]
SUPERIOR VENA CAVAL OBSTRUCTION
 
»
Swelling of the neck, face, and upper extremities.
 
»
Dilated veins over the upper chest and neck.
 
»
Partial or complete obstruction of the superior vena cava is 
a relatively rare condition that is usually secondary to neo
-
plastic or inflammatory processes in the superior mediasti
-
num. The most frequent causes are (1) neoplasms, such as 
lymphomas, primary malignant mediastinal tumors, or 
carcinoma of the lung with direct extension (over 80%); (2) 
chronic fibrotic mediastinitis, either of unknown origin or 
secondary to tuberculosis, histoplasmosis, pyogenic infec
-
tions, or drugs, especially methysergide; (3) DVT, often by 
extension of the process from the axillary or subclavian 
vein into the innominate vein and vena cava associated 
with catheterization of these veins for dialysis or for hyper
-
alimentation; (4) aneurysm of the aortic arch; and (5) 
 
»
The onset of symptoms is acute or subacute. Symptoms 
include swelling of the neck and face and upper extremi
-
ties. Symptoms are often perceived as congestion and pres
-
ent as headache, dizziness, visual disturbances, stupor, 
syncope, or cough. There is progressive obstruction of the 
venous drainage of the head, neck, and upper extremities. 
The cutaneous veins of the upper chest and lower neck 
become dilated, and flushing of the face and neck develops. 
Brawny edema of the face, neck, and arms occurs later, and 
cyanosis of these areas then appears. Cerebral and laryn
-
geal edema ultimately result in impaired function of the 
brain as well as respiratory insufficiency. Bending over or 
lying down accentuates the symptoms; sitting quietly is 
generally preferred. The manifestations are more severe if 
the obstruction develops rapidly and if the azygos junction 
or the vena cava between that vein and the heart is 
obstructed.
The venous pressure is elevated (often more than 20 cm of 
water) in the arm and is normal in the leg. Since lung can
-
cer is a common cause, bronchoscopy is often performed; 
transbronchial biopsy, however, is relatively contraindi
-
cated because of venous hypertension and the risk of 
bleeding.
C. Imaging
Chest radiographs and a CT scan will define the location 
and often the nature of the obstructive process, and con
-
trast venography or magnetic resonance venography 
(MRV) will map out the extent and degree of the venous 
obstruction and the collateral circulation. Brachial venog
-
raphy or radionuclide scanning following intravenous 
injection of technetium (Tc-99m) pertechnetate demon
-
strates a block to the flow of contrast material into the right 
heart and enlarged collateral veins. These techniques also 
allow estimation of blood flow around the occlusion as well 
as serial evaluation of the response to therapy.
 
»
Treatment
Conservative measures, such as elevation of the head of the 
bed and lifestyle modification to avoid bending over, are 
useful. Balloon angioplasty of the obstructed caval segment 
combined with stent placement provides prompt relief of

combined with stent placement provides prompt relief of 
symptoms and is the procedure of choice for all etiologies. 
Occasionally, anticoagulation is needed, while thromboly
-
sis is rarely needed.
Urgent treatment for neoplasm
 consists of (1) cau
-
tious use of intravenous diuretics and (2) mediastinal 
irradiation, starting within 24 hours, with a treatment 
plan designed to give a high daily dose but a short total 
course of therapy to rapidly shrink the local tumor. 
Intensive combined therapy will palliate the process in up 
to 90% of patients. In patients with a subacute presenta
-
tion, radiation therapy alone usually suffices. Chemo
-
therapy is added if lymphoma or small-cell carcinoma is 
diagnosed.
Long-term outcome is complicated by risk of 
 
re-occlusion from either thrombosis or further growth of 
the neoplasm. Surgical procedures to bypass the obstruc
-
tion are complicated by bleeding relating to high venous 
pressure. In cases where the thrombosis is secondary to an 
indwelling catheter, thrombolysis may be attempted. Clini
-
cal judgment is required since a long-standing clot may be 
fibrotic and the risk of bleeding will outweigh the potential 
benefit.
 
»
Prognosis
The prognosis depends on the nature and degree of obstruc
-
tion and its speed of onset. Slowly developing forms sec
-
ondary to fibrosis may be tolerated for years. A high degree 
of obstruction of rapid onset secondary to cancer is often 
fatal in a few days or weeks because of increased intracra
-
nial pressure and cerebral hemorrhage, but treatment of the 
tumor with radiation and chemotherapeutic drugs may 
result in significant palliation. Balloon angioplasty and 
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stenting provide good relief, but may require re-treatment 
for recurrent symptoms secondary to thrombosis or 
restenosis.
 
»
Referral should occur with any patient with progressive 
head and neck swelling to rule out superior vena cava 
syndrome.
 
»
Any patient with acute edema of the head and neck or any 
patient in whom signs and symptoms of airway compro
-
mise, such as hoarseness or stridor, develop should be 
admitted.
Lepper PM et al. Superior vena cava syndrome in thoracic 
malignancies. Respir Care. 2011 May;56(5):653–66. [PMID: 
21276318]
 
º
DISEASES OF THE LYMPHATIC CHANNELS
LYMPHANGITIS & LYMPHADENITIS
 
»
Red streak from wound or area of cellulitis toward 
regional lymph nodes, which are usually enlarged 
 
»
Chills, fever, and malaise may be present.
 
»
Lymphangitis and lymphadenitis are common manifesta
-
tions of a bacterial infection that is usually caused by 
hemolytic streptococci or 
S aureus
 (or by both organ
-
isms) and becomes invasive, generally from an infected 
wound. The wound may be very small or superficial, or 
an established abscess may be present, feeding bacteria 
into the lymphatics. The involvement of the lymphatics is 
often manifested by a red streak in the skin extending in 
the direction of the regional lymph nodes, which are, in 
turn, generally tender and engorged. Systemic manifesta
-
tions include fever, chills, and malaise. The infection may 
progress rapidly, often in a matter of hours, and may lead 
to septicemia and even death.
 
»
Throbbing pain is usually present in the area of cellulitis at 
the site of bacterial invasion. Malaise, anorexia, sweating, 
chills, and fever of 38–40°C develop rapidly. The red streak, 
when present, may be definite or may be very faint and eas
-
ily missed, especially in dark-skinned patients. It is usually 
tender or indurated in the area of cellulitis. The involved 
regional lymph nodes may be significantly enlarged and are 
usually quite tender. The pulse is often rapid.
Leukocytosis with a left shift is usually present. Blood cul
-
tures may be positive, most often for staphylococcal or 
streptococcal species. Culture and sensitivity studies of the 
wound exudate or pus may be helpful in treatment of the 
more severe or refractory infections but are often difficult 
to interpret because of skin contaminants.
 
»
Lymphangitis may be confused with superficial throm
-
bophlebitis, but the erythema and induration of throm
-
bophlebitis is localized in and around the thrombosed 
vein. Venous thrombosis is not associated with lymphad
-
enitis, and a wound of entrance with secondary cellulitis 
is generally absent.
Cat-scratch fever 
(Bartonella henselae)
 should be con
-
sidered when lymphadenitis is present; the nodes, though 
often very large, are relatively nontender. Exposure to cats is 
common, but the patient may have forgotten about the 
scratch.
It is extremely important to differentiate cellulitis from 
acute streptococcal hemolytic gangrene or necrotizing fasci
-
itis.
 These are deeper infections that may be extensive and 
are potentially lethal. Patients appear more seriously ill; 
there may be redness due to leakage of red cells, creating a 
non-blanching erythema; and subcutaneous crepitus may 
be palpated or auscultated using the diaphragm with light 
pressure over the involved area. Immediate wide debride
-
ment of all involved deep tissues should be done if these 
signs are present.
 
»
Treatment
Prompt treatment should include heat (hot, moist com
-
presses or heating pad), elevation when feasible, and 
immobilization of the infected area. Analgesics may be 
prescribed for pain.
Empiric antibiotic therapy for hemolytic streptococci or 
 
S aureus

S aureus
 (or by both organisms) should always be instituted. 
Cephalosporins or extended-spectrum penicillins are com
-
monly used (eg, cephalexin, 0.5 g orally four times daily for 
7–10 days; see Table 30–6). Trimethoprim-sulfamethoxazole 
(two double-strength tablets orally twice daily for 7–10 
days) should be considered when there is concern that the 
pathogen is methicillin-resistant 
S aureus
 (MRSA) (see Tables 
30–4 and 30–6).
C. Wound Care
Any wound that is the initiating site of lymphangitis should 
be treated aggressively. Any necrotic tissue must be 
debrided and loculated pus drained.
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»
Prognosis
With proper therapy including an antibiotic effective against 
the invading bacteria, control of the infection can usually be 
achieved in a few days. Delayed or inadequate therapy can 
lead to overwhelming infection with septicemia.
 
»
Infections causing lymphangitis should be treated in the 
hospital with intravenous antibiotics. Debridement may be 
required.
LYMPHEDEMA
 
»
Painless persistent edema of one or both lower 
extremities, primarily in young women.
 
»
Pitting edema without ulceration, varicosities, or 
stasis pigmentation.
 
»
There may be episodes of lymphangitis and 
 
»
When lymphedema is due to congenital developmental 
abnormalities consisting of hypoplastic or hyperplastic 
involvement of the proximal or distal lymphatics, it is 
referred to as the 
primary form
. The obstruction may be in 
the pelvic or lumbar lymph channels and nodes when the 
disease is extensive and progressive. The 
secondary form
 of 
lymphedema involves inflammatory or mechanical lym
-
phatic obstruction from trauma, regional lymph node resec
-
tion or irradiation, or extensive involvement of regional 
nodes by malignant disease or filariasis. Lymphedema may 
occur following surgical removal of the lymph nodes in the 
groin or axillae. Secondary dilation of the lymphatics that 
occurs in both forms leads to incompetence of the valve 
system, disrupts the orderly flow along the lymph vessels, 
and results in progressive stasis of a protein-rich fluid. Epi
-
sodes of acute and chronic inflammation may be superim
-
posed, with further stasis and secondary fibrosis.
 
»
Hypertrophy of the limb results, with markedly thickened 
and fibrotic skin and subcutaneous tissue (Figure 12–4) in 
very advanced cases.
Lymphangiography and radioactive isotope studies may 
identify focal defects in lymph flow but are of little value in 
planning therapy. T
2
–weighted MRI has been used to iden
-
tify lymphatics and proximal obstructing masses.
 
»
Treatment
Since there is no effective cure for lymphedema, the treat
-
ment strategies are designed to control the problem and 
allow normal activity and function. Most patients can be 
treated with some of the following measures: (1) The flow 
of lymph out of the extremity can be aided through inter
-
mittent elevation of the extremity, especially during the 
sleeping hours (foot of bed elevated 15–20 degrees, 
achieved by placing pillows beneath the mattress); the 
constant use of graduated elastic compression stockings; 
and massage toward the trunk—either by hand or by 
means of pneumatic pressure devices designed to milk 
edema out of an extremity. Wound care centers special
-
izing in the care of patients with lymphedema may be 
helpful. (2) Secondary cellulitis in the extremity should be 
avoided by means of good hygiene and treatment of any 
trichophytosis of the toes. Once an infection starts, it 
should be treated by periods of elevation and antibiotic 
therapy that covers 
 and 
 
organisms (see Table 30–6). Infections can be a serious 
and recurring problem and are often difficult to control. 
Prophylactic antibiotics have not been shown to be of 
benefit. (3) Intermittent courses of diuretic therapy, espe
-
cially in those with premenstrual or seasonal exacerba
-
tions, are rarely helpful. (4) Amputation is used only for 
the rare complication of lymphangiosarcoma in the 
extremity.
 
»
Prognosis
With aggressive treatment, including pneumatic compres
-
sion devices, good relief of symptoms can be achieved. The 
long-term outlook is dictated by the associated conditions 
and avoidance of recurrent cellulitis.
Finnane A et al. Review of the evidence of lymphedema treat
-
ment effect. Am J Phys Med Rehabil. 2015 Jun;94(6):483–98. 
[PMID: 25741621]
 
▲
Figure 12–4.
 
Lymphedema with a dorsal pedal hump

-
 
▲
 
Lymphedema with a dorsal pedal hump 
and exaggerated skin folds near the ankle. 
Color 
Atlas and Synopsis of Vascular Diseases.
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º
SHOCK
 
»
Hypotension, tachycardia, oliguria, altered mental 
status.
 
»
Peripheral hypoperfusion and impaired oxygen 
delivery.
 
»
Four classifications: hypovolemic, cardiogenic, 
obstructive, or distributive.
 
»
Shock occurs when the rate of arterial blood flow is inad
-
equate to meet tissue metabolic needs. This results in 
regional hypoxia and subsequent lactic acidosis from 
anaerobic metabolism in peripheral tissues as well as 
eventual end-organ damage and failure.
 
»
Table 12–1 outlines common causes and mechanisms asso
-
ciated with each type of shock.
A. Hypovolemic Shock
Hypovolemic shock results from decreased intravascular 
volume secondary to loss of blood or fluids and electro
-
lytes. The etiology may be suggested by the clinical setting 
(eg, trauma) or by signs and symptoms of blood loss (eg, 
gastrointestinal bleeding) or dehydration (eg, vomiting or 
diarrhea). Compensatory vasoconstriction may transiently 
maintain the blood pressure but unreplaced losses of over 
15% of the intravascular volume can result in hypotension 
and progressive tissue hypoxia.
B. Cardiogenic Shock
Cardiogenic shock results from cardiac failure with the 
resultant inability of the heart to maintain adequate tissue 
perfusion. The clinical definition of cardiogenic shock is 
evidence of tissue hypoxia due to decreased cardiac output 
(cardiac index less than 2.2 L/min/m
2
) in the presence of 
adequate intravascular volume. This is most often caused 
by myocardial infarction but can also be due to cardiomy
-
opathy, myocardial contusion, valvular incompetence or 
stenosis, or arrhythmias. See Chapter 10.
C. Obstructive Shock
Cardiac tamponade, tension pneumothorax, and massive 
pulmonary embolism can cause an acute decrease in 
cardiac output resulting in shock. These are medical 
emergencies requiring prompt diagnosis and treatment.
D. Distributive Shock
Distributive or vasodilatory shock has many causes includ
-
ing sepsis, anaphylaxis, systemic inflammatory response 
Table 12–1.
 
Classification of shock by mechanism and 
common causes.
Hypovolemic shock
 
Blood loss
  
T
raumatic hemorrhage
   
Exsanguination
   
Hemoperitoneum
   
F
racture (femur and pelvis)
  
Nontraumatic hemorrhage
   
Gastrointestinal bleed
   
AAA rupture
   
Ectopic pregnancy rupture
 
V
olume loss
  
Burns
  
Sk
in integrity loss (toxic epidermal necrolysis)
  
Vomiting
  
Diarrhea
  
H
yperosmolar states (diabetic ketoacidosis)
  
T
hird spacing (eg, ascites, pancreatitis)
  
Decreased intake
Cardiogenic shock
 
Dysrhythmia
  
Br
adycardias and blocks
  
Tachycardias
 
M
yocardial disease
  
L
eft or right ventricular infarction
  
Dilated cardiomyopathy
 
Mechanical
  
Valvular
   
A
ortic regurgitation from dissection
   
P
apillary muscle rupture from ischemia
   
A
cute valvular rupture from abscess
  
V
entricular aneurysm rupture
  
V
entricular septum rupture
  
F
ree wall ventricle rupture
Obstructive shoc
k
 
T
ension pneumothorax
 
P
ericardial disease
  
Pericardial tamponade
  
H
igh-risk (massive) pulmonary embolism
 
S
evere pulmonary hypertension
 
A
uto PEEP from mechanical ventilation
Distributive shock
 
Anaph
ylactic shock
 
S
 
Neur
ogenic shock
 
Drug-induc
ed vasodilation
 
A
drenal insufficiency
Modified, with permission, from Stone CK, Humphries RL 
 
(editors). 
Current Emergency Diagnosis & Treatment
, 7th ed. 
McGraw-Hill, 2011.
AAA, abdominal aortic aneurysm; PEEP , positive end expiratory 
pressure.
syndrome (SIRS) produced by severe pancreatitis or burns, 
traumatic spinal cord injury, or acute adrenal insufficiency. 
The reduction in systemic vascular resistance results in 
inadequate cardiac output and tissue hypoperfusion despite 
normal circulatory volume.
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1. Septic shock—
Sepsis is the most common cause of 
distributive shock and carries a mortality rate of 20–50%. 
The Society of Critical Care Medicine and the European 
Society of Intensive Care Medicine’s 2016 definition for 
sepsis
 is life-threatening organ dysfunction caused by a 
dysregulated host response to infection. 
Septic shock
 is 
clinically defined as sepsis with fluid-unresponsive hypo
-
tension (systolic blood pressure less than 100 mm Hg), 
serum lactate level higher than 2 mmol/L, and a need for 
vasopressors to keep mean arterial pressure (MAP) above 
65 mm Hg. The most common cause of septic shock in 
hospitalized patients is infection with gram-positive or 
gram-negative organisms, with a growing incidence of 
infection from multidrug-resistant organisms. Sepsis from 
fungal organisms is increasing, but remains less than that 
for bacterial infections. Risk factors for septic shock 
include bacteremia, extremes of age, diabetes, cancer, 
immunosuppression, and history of a recent invasive 
2. Systemic inflammatory response syndrome (SIRS)—
Defined as a systemic response to a nonspecific infectious 
or noninfectious insult—such as from burns, pancreatitis, 
an autoimmune disorder, ischemia, or trauma—the pres
-
ence of two or more of the following clinical criteria help 
establish the diagnosis of SIRS: (1) body temperature 
higher than 38°C (100.4°F) or lower than 36°C (96.8°F), (2) 
heart rate faster than 90 beats per minute, (3) respiratory 
rate more than 20 breaths per minute or hyperventilation 
with an arterial carbon dioxide tension (Pa
co
2
) less than 
32 mm Hg, or (4) abnormal white blood cell count (greater 
than 12,000/mcL or less than 4000/mcL or greater than 
10% immature [band] forms). When a source of infection 
is confirmed, SIRS is categorized as sepsis. The consensus 
group that issued the 2016 definition of sepsis recom
-
mended eliminating the term SIRS. However, this remains 
controversial in the absence of strong evidence to suggest 
that SIRS criteria are an inferior way to identify patients at 
risk for sepsis. Studies on the impact of the new sepsis defi
-
nitions (SEPSIS-3) as a predictive measure of mortality are 
ongoing.
3. Neurogenic shock—
Neurogenic shock is caused by 
traumatic spinal cord injury or effects of an epidural or 
spinal anesthetic. This results in loss of sympathetic tone 
with a reduction in systemic vascular resistance and hypo
-
tension without a compensatory tachycardia. Reflex vagal 
parasympathetic stimulation evoked by pain, gastric dila
-
tion, or fright may simulate neurogenic shock, producing 
hypotension, bradycardia, and syncope.
 
»
 is traditionally defined as a systolic blood pres
-
sure of 90 mm Hg or less or a MAP of less than 60–65 mm 
Hg but must be evaluated relative to the patient’s normal 
blood pressure. A drop in systolic pressure of greater than 
10–20 mm Hg or an increase in pulse of more than 15 beats 
per minute with positional change suggests depleted intra
-
vascular volume. However, blood pressure is often not the 
best indicator of end-organ perfusion because compensatory 
mechanisms, such as increased heart rate, increased cardiac 
contractility, and vasoconstriction can occur to prevent 
hypotension. Patients with hypotension often have cool or 
mottled extremities and weak or thready peripheral pulses. 
Splanchnic vasoconstriction may lead to oliguria, bowel isch
-
emia, and hepatic dysfunction, which can ultimately result in 
multiorgan failure. Mentation may be normal or patients may 
become restless, agitated, confused, lethargic, or comatose as 
a result of inadequate perfusion of the brain.
 is evident when signs of hypoper
-
fusion, such as oliguria, altered mental status, and cool 
extremities, are present. Jugular venous pressure is low, and 
there is a narrow pulse pressure indicative of reduced

-
there is a narrow pulse pressure indicative of reduced 
stroke volume. Rapid replacement of fluids can restore tis
-
sue perfusion. In 
cardiogenic shock,
 there are also signs of 
global hypoperfusion with oliguria, altered mental status, 
and cool extremities. Jugular venous pressure is elevated 
and there may be evidence of pulmonary edema with respi
-
ratory compromise in the setting of left-sided heart failure. 
A transthoracic echocardiogram (TTE) or a transesopha
-
geal echocardiogram (TEE) is an effective diagnostic tool 
to differentiate hypovolemic from cardiogenic shock. In 
hypovolemic shock, the left ventricle will be small because 
of decreased filling, but contractility is often preserved. In 
cardiogenic shock, there is a decrease in left ventricular 
contractility. The left ventricle may appear dilated and full 
because of the inability of the left ventricle to eject a suffi
-
cient stroke volume.
In 
obstructive shock
, the central venous pressure may 
be elevated but the TTE or TEE may show reduced left 
ventricular filling, a pericardial effusion in the case of tam
-
ponade, or thickened pericardium in the case of pericardi
-
tis. Pericardiocentesis or pericardial window for pericardial 
tamponade, chest tube placement for tension pneumotho
-
rax, or catheter-directed thrombolytic therapy for massive 
pulmonary embolism can be life-saving in cases of obstruc
-
tive shock.
In 
distributive shock,
 signs include hyperdynamic 
heart sounds, warm extremities initially, and a wide pulse 
pressure indicative of large stroke volume. The echocardio
-
gram may show a hyperdynamic left ventricle. Fluid resus
-
citation may have little effect on blood pressure, urinary 
output, or mentation. 
 is diagnosed when 
there is clinical evidence of infection in the setting of per
-
sistent hypotension and evidence of organ hypoperfusion, 
such as lactic acidosis, decreased urinary output, or altered 
mental status despite adequate volume resuscitation. 
Neu
-
rogenic shock
 is diagnosed when there is evidence of cen
-
tral nervous system injury and persistent hypotension 
despite adequate volume resuscitation.
B. Laboratory Findings and Imaging
Blood specimens should be evaluated for complete blood 
count, electrolytes, glucose, arterial blood gas determina
-
tions, coagulation parameters, lactate levels, typing and cross-
matching, and bacterial cultures. An electrocardiogram and 
chest radiograph should also be part of the initial assessment. 
A TTE can help assess right- and left-sided filling pressures 
and cardiac output.
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»
Treatment
Treatment depends on prompt diagnosis and an accurate 
appraisal of inciting conditions. Initial management con
-
sists of basic life support with an assessment of the patient’s 
circulation, airway, and breathing. This may entail airway 
intubation and mechanical ventilation. Ventilatory failure 
should be anticipated in patients with severe metabolic 
acidosis due to shock. Mechanical ventilation along with 
sedation can decrease respiratory muscle oxygen demand 
and allow improved oxygen delivery to hypoperfused tis
-
sues. Intravenous access and fluid resuscitation should be 
instituted along with cardiac monitoring and assessment of 
hemodynamic parameters such as blood pressure and 
heart rate. Cardiac monitoring can detect myocardial isch
-
emia or malignant arrhythmias, which can be treated by 
standard advanced cardiac life support (ACLS) protocols.
Unresponsive or minimally responsive patients should 
have their glucose checked immediately and if their glucose 
levels are low, 1 ampule of 50% dextrose intravenously should 
be given. An arterial line should be placed for continuous 
blood pressure measurement, and a Foley catheter should be 
inserted to monitor urinary output.
B. Hemodynamic Measurements
Early consideration is given to placement of a central 
venous catheter (CVC) for infusion of fluids and medica
-
tions and for hemodynamic pressure measurements. A 
CVC can provide measurements of the central venous 
pressure (CVP) and the central venous oxygen saturation 
(ScvO
2
), both of which can be used to manage sepsis and 
septic shock. Pulmonary artery catheters (PACs) allow 
measurement of the pulmonary artery pressure, left-sided 
filling pressure or the pulmonary capillary wedge pressure 
(PCWP), the mixed venous oxygen saturation (SvO
2
) and 
cardiac output. Meta-analyses of multiple studies suggest 
that PACs do not increase overall mortality or length of 
hospital stay but are associated with higher use of inotropes 
and intravenous vasodilators in critically ill patients from 
different patient populations. Thus, the routine use of 
PACs cannot be recommended. However, in complex situ
-
ations, PACs may be useful in distinguishing between car
-
diogenic and septic shock. The attendant risks associated 
with PACs (such as infection, arrhythmias, vein thrombo
-
sis, and pulmonary artery rupture) can be as high as 4–9%; 
therefore, the value of the information they might provide 
must be carefully weighed in each patient. TTE is a nonin
-
vasive alternative to the PAC. TTE can provide information 
about the pulmonary artery pressure and current cardiac 
function, including cardiac output. The ScvO
2
, which is 
obtained through the CVC, can be used as a surrogate for 
the SvO
2
, which is obtained through the PAC. Pulse pres
-
sure variation, as determined by arterial waveform analy
-
sis, or stroke volume variation are much more sensitive 
than CVP as dynamic measures of fluid responsiveness in 
volume resuscitation, but these measurements have only 
been validated in patients who are mechanically ventilated 
with tidal volumes of 8 mL/kg, not triggering the ventilator, 
and in normal sinus rhythm. Point-of-care ultrasound 
measurements of the inferior vena cava (IVC) can suggest 
intravascular volume status and guide fluid replacement. If 
the patient is mechanically ventilated and the IVC dilates 
~15–20% with respirations, they are likely to respond to 
intravenous fluids. If the patient is spontaneously breath
-
ing, they are likely to be fluid-responsive if their IVC is less 
than 2 cm in diameter and collapses by ~50% with each 
breath.
A CVP less than 5 mm Hg suggests hypovolemia, and 
a CVP greater than 18 mm Hg suggests volume overload, 
cardiac failure, tamponade, or pulmonary hypertension. 
A cardiac index lower than 2 L/min/m
2
 indicates a need

2
 indicates a need 
for inotropic support. A cardiac index higher than 4 L/min/m
2
 
in a hypotensive patient is consistent with early septic 
shock. The systemic vascular resistance is low (less than 
800 dynes · s/cm
–5
) in sepsis and neurogenic shock and 
high (greater than 1500 dynes · s/cm
–5
) in hypovolemic 
and cardiogenic shock. Treatment is directed at maintain
-
ing a CVP of 8–12 mm Hg, a MAP of 65 mm Hg or higher, 
a cardiac index of 2–4 L/min/m
2
, and a ScvO
2
 greater 
than 70%.
C. Volume Replacement
Volume replacement is critical in the initial management of 
shock. 
Hemorrhagic shock
 is treated with immediate 
efforts to achieve hemostasis and rapid infusions of blood 
substitutes, such as type-specific or type O negative packed 
red blood cells (PRBCs) or whole blood, which also pro
-
vides extra volume and clotting factors. Each unit of PRBC 
or whole blood is expected to raise the hematocrit by 3%. 
 secondary to dehydration is managed 
with rapid boluses of isotonic crystalloid (0.9% saline or 
lactated Ringer solution) usually in 1-liter increments. 
 in the absence of fluid overload 
requires smaller fluid challenges, usually in increments of 
250 mL. 
 usually requires large volumes of 
fluid for resuscitation (usually more than 2 L) as the associ
-
ated capillary leak releases fluid into the extravascular 
space. Caution must be used with large-volume resuscita
-
tion with unwarmed fluids because this can produce hypo
-
thermia, which can lead to hypothermia-induced 
coagulopathy. Warming of fluids before administration can 
avoid this complication.
Crystalloid solution is the resuscitation fluid of choice 
in most settings: meta-analyses of studies of heterogenous 
critically ill populations demonstrated no benefit of crys
-
talloid over colloid (albumin) fluid resuscitation except in 
cases of traumatic brain injury (TBI), where resuscitation 
with albumin resulted in higher mortality. For trauma 
patients, especially those with TBI, hypertonic saline 
(7.5%) plus dextran has been found to increase survival, 
but current studies suggest that isotonic crystalloid solutions 
perform just as well.
D. Early Goal-Directed Therapy
Compensated shock can occur in the setting of normalized 
hemodynamic parameters with ongoing global tissue 
hypoxia. Traditional endpoints of resuscitation such as 
blood pressure, heart rate, urinary output, mental status, 
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2
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and skin perfusion can therefore be misleading. Following 
set protocols for the treatment of septic shock by adjusting 
the use of fluids, vasopressors, inotropes, and blood trans
-
fusions to meet hemodynamic targets (MAP 65 mm Hg or 
higher, CVP 8–12 mm Hg, ScvO
2
 greater than 70%), 
termed 
early goal-directed therapy (EGDT),
 provided 
significant mortality benefits. Lactate clearance of more 
than 10% can be used as a substitute for ScvO
2
 criteria if 
ScvO
2
 monitoring is not available.
Since its introduction, there have been data to suggest 
that portions of EGDT, such as transfusing to a hematocrit 
of 30% if the ScvO
2
 was less than 70%, may do more harm 
than good. Two large randomized trials published in 2014 
(ProCESS and ARISE) demonstrated no mortality benefit 
from the institution of EGDT, but this may have been due 
to earlier administration of antibiotics, components of 
EGDT becoming part of the “usual care” that clinicians 
deliver, and the effectiveness of education about detecting 
and treating sepsis in a timely fashion. The Surviving Sep
-
sis Campaign’s recommendations for patients with severe 
sepsis or septic shock are to measure lactate level, obtain 
blood cultures prior to administration of broad-spectrum 
antibiotics, and to administer 30 mL/kg crystalloid for 
hypotension or lactate greater than 4 mmol/L within the 
first 3 hours of presentation. Within the first 6 hours, 
administer vasopressors for hypotension not responsive to 
initial fluid resuscitation to maintain MAP 65 mm Hg or 
higher, remeasure lactate if initial level was high, and reas
-
sess volume status and tissue perfusion. A meta-analysis of 
hemodynamic optimization trials suggested that early 
treatment before the development of organ failure results 
in improved survival, and patients who respond well to 
initial efforts demonstrate a survival advantage over 
nonresponders.
E. Medications
1. Vasoactive therapy—
Vasopressors and inotropic 
agents are administered only after adequate fluid resusci
-
tation. Choice of vasoactive therapy depends on the pre
-
sumed etiology of shock as well as cardiac output. If there 
is continued hypotension with evidence of high cardiac 
output after adequate volume resuscitation, then vasopres
-
sor support is needed to improve vasomotor tone. If there 
is evidence of low cardiac output with high filling pres
-
sures, inotropic support is needed to improve 
contractility.
For 
vasodilatory shock
 when increased vasoconstric
-
tion is required to maintain an adequate perfusion pres
-
sure, alpha-adrenergic catecholamine agonists (such as 
norepinephrine and phenylephrine) are generally used. 
Although norepinephrine is both an alpha-adrenergic and 
beta-adrenergic agonist, it preferentially increases MAP 
over cardiac output. The initial dose is 1–2 mcg/min as an 
intravenous infusion, titrated to maintain the mean arterial 
blood pressure at 65 mm Hg or higher. The usual mainte
-
nance dose is 2–4 mcg/min intravenously (maximum dose 
is 30 mcg/min). Patients with refractory shock may require 
dosages of 10–30 mcg/min intravenously. Epinephrine, 
also with both alpha-adrenergic and beta-adrenergic 
effects, may be used in severe shock and during acute 
resuscitation. It is the vasopressor of choice for 
anaphylac
-
tic shock
. For severe shock, give 1 mcg/min as a continu
-
ous intravenous infusion initially and titrate to hemodynamic 
response; the usual dosage range is 1–10 mcg/min 
intravenously.
Dopamine has variable effects according to dosage. At 
low doses (2–5 mcg/kg/min intravenously), stimulation of 
dopaminergic and beta-adrenergic receptors produces 
increased glomerular filtration, heart rate, and contractility. 
At doses of 5–10 mcg/kg/min, beta-1-adrenergic effects pre
-
dominate, resulting in an increase in heart rate and cardiac 
contractility. At higher doses (greater than 10 mcg/kg/min),

-
contractility. At higher doses (greater than 10 mcg/kg/min), 
alpha-adrenergic effects predominate, resulting in periph
-
eral vasoconstriction. The maximum dose is typically 
 
50 mcg/kg/min.
There is no evidence documenting a survival benefit 
from, or the superiority of, a particular vasopressor in 
septic shock
. Norepinephrine is the initial vasopressor 
of choice in septic shock to maintain the MAP at 65 mm Hg 
or higher. Phenylephrine can be used as a first-line agent 
for hyperdynamic septic shock if (1) there is low sys
-
temic venous resistance but high cardiac output, which 
can manifest as hypotension with 
warm
 extremities or 
(2) dysrhythmias or tachycardias prevent the use of 
agents with beta-adrenergic activity. In meta-analyses, 
the use of dopamine as a first-line vasopressor in septic 
shock resulted in an increase in 28-day mortality and a 
higher incidence of arrhythmic events. Dopamine 
should only be used as an alternative to norepinephrine 
in select patients with septic shock, including patients 
with significant bradycardia or low potential for 
Vasopressin (antidiuretic hormone or ADH) is often 
used as an adjunctive therapy to catecholamine vasopres
-
sors in the treatment of 
distributive
 or 
vasodilatory 
shock
. Vasopressin causes peripheral vasoconstriction 
via V1 receptors located on smooth muscle cells and 
attenuation of nitric oxide (NO) synthesis and cGMP , the 
second messenger of NO. The rationale for using low-
dose vasopressin in the management of septic shock 
includes the relative deficiency of vasopressin in late 
shock. Vasopressin also potentiates the effects of cate
-
cholamines on the vasculature and stimulates cortisol 
production. Some studies have reported reduced cate
-
cholamine requirements with vasopressin administra
-
tion. Intravenous infusion of vasopressin at a low dose 
(0.01–0.04 unit/min) may be safe and beneficial in septic 
patients with hypotension refractory to fluid resuscita
-
tion and conventional catecholamine vasopressors. 
Higher doses of vasopressin decrease cardiac output and 
may put patients at greater risk for splanchnic and coro
-
nary artery ischemia. Studies do not favor the use of 
vasopressin as first-line therapy.
There is insufficient evidence to recommend a specific 
vasopressor to use in 
cardiogenic shock
, but expert opin
-
ion suggests that either norepinephrine or dopamine be 
used as a first-line agent. Dobutamine, a predominantly 
beta-adrenergic agonist, increases contractility and 
decreases afterload. It is used for patients with low cardiac 
output and high PCWP but who do not have hypotension. 
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Dobutamine can be added to a vasopressor if there is 
reduced myocardial function (decreased cardiac output 
and elevated PCWP), or if there are signs of hypoperfusion 
despite adequate volume resuscitation and an adequate 
MAP . The initial dose is 0.1–0.5 mcg/kg/min as a continu
-
ous intravenous infusion, which can be titrated every few 
minutes to hemodynamic effect; the usual dosage range is 
2–20 mcg/kg/min intravenously. Tachyphylaxis can occur 
after 48 hours secondary to the down-regulation of beta-
adrenergic receptors. Amrinone and milrinone are phos
-
phodiesterase inhibitors that can be substituted for 
dobutamine. These drugs increase cyclic AMP levels and 
increase cardiac contractility, bypassing the beta-adrenergic 
receptor. Vasodilation is a side effect of both amrinone and 
milrinone.
2. Antibiotics—
Definitive therapy for septic shock includes 
early initiation of empiric broad-spectrum antibiotics after 
appropriate cultures have been obtained and within 1 hour 
of recognition of septic shock. Imaging studies may prove 
useful to attempt localization of sources of infection. Surgi
-
cal management may also be necessary if necrotic tissue or 
loculated infections are present in attempts to control the 
source of infection (see Table 30–5).
Corticosteroids are the treatment of 
choice in patients with shock secondary to adrenal insuf
-
ficiency but studies do not support their use in patients 
with shock from sepsis or other etiologies. Trials where 
either high or low doses of corticosteroids were adminis
-
tered to patients in septic shock did not show improved 
survival; rather, some worse outcomes were observed from 
increased rates of secondary infections, even in patients 
who had relative adrenal insufficiency, defined by a cortisol 
response of 9 mcg/dL or less after one injection of 250 mcg 
of corticotropin.
F. Other Treatment Modalities
Cardiac failure may require use of transcutaneous or trans
-
venous pacing or placement of an intra-arterial balloon 
pump or left ventricular assist device. Emergent revascu
-
larization by percutaneous angioplasty or coronary artery 
bypass surgery appears to improve long-term outcome 
with increased survival compared with initial medical sta
-
bilization for patients with myocardial ischemia leading to 
cardiogenic shock. Urgent hemodialysis or continuous 
venovenous hemofiltration may be indicated for mainte
-
nance of fluid and electrolyte balance during acute kidney 
injury resulting in shock from multiple modalities.
Gamper G et al. Vasopressors for hypotensive shock. Cochrane 
Database Syst Rev. 2016 Feb 15;2:CD003709. [PMID: 
26878401]
Levy MM et al. Surviving Sepsis Campaign: association between 
performance metrics and outcomes in a 7.5-year study. Crit 
Care Med. 2015 Jan;43(1):3–12. [PMID: 25275252]
Mouncey PR et al; ProMISe Trial Investigators. Trial of early, 
goal-directed resuscitation for septic shock. N Engl J Med. 
2015 Apr 2;372(14):1301–11. [PMID: 25776532]
Peake SL et al; ARISE Investigators; ANZICS Clinical Trials 
Group. Goal-directed resuscitation for patients with early 
septic shock. N Engl J Med. 2014 Oct 16;371(16):1496–506. 
[PMID: 25272316]
Raghunathan K et al. What is the ideal crystalloid? Curr Opin 
Crit Care. 2015 Aug;21(4):309–14. [PMID: 26103144]
Seymour CW et al. Septic shock: advances in diagnosis and 
treatment. JAMA. 2015 Aug 18;314(7):708–17. [PMID: 
26284722]
Singer M et al. The third international consensus definitions for 
sepsis and septic shock (Sepsis-3). JAMA. 2016 Feb 23;
 
315(8):801–10. [PMID: 26903338]
Y ealy DM et al; ProCESS Investigators. A randomized trial of 
protocol-based care for early septic shock. N Engl J Med. 
 
2014 May 1;370(18):1683–93. [PMID: 24635773]
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º
ANEMIAS
 
»
General Approach to Anemias
Anemia is present in adults if the hematocrit is below 41% 
(hemoglobin less than 13.6 g/dL [135 g/L]) in males or 
below 36% (hemoglobin less than 12 g/dL [120 g/L]) in 
females. Congenital anemia is suggested by the patient’s 
personal and family history. The most common cause of 
anemia is iron deficiency. Poor diet may result in folic acid 
deficiency and contribute to iron deficiency, but bleeding is 
the most common cause of iron deficiency in adults. Physi
-
cal examination demonstrates pallor. Attention to physical 
signs of primary hematologic diseases (lymphadenopathy; 
hepatosplenomegaly; or bone tenderness, especially in the 
sternum or anterior tibia) is important. Mucosal changes 
such as a smooth tongue suggest megaloblastic anemia.
Anemias are classified according to their pathophysiologic 
basis, ie, whether related to diminished production (relative or 
absolute reticulocytopenia) or to increased production due to 
accelerated loss of red blood cells (reticulocytosis) (Table 13–1), 
and according to red blood cell size (Table 13–2). A reticulo
-
cytosis occurs in one of three pathophysiologic states: acute 
blood loss, recent replacement of a missing erythropoietic 
nutrient, or reduced red blood cell survival (ie, hemolysis). A 
severely microcytic anemia (mean corpuscular volume 
[MCV] less than 70 fL) is due either to iron deficiency or 
thalassemia, while a severely macrocytic anemia (MCV 
greater than 120 fL) is almost always due to either megaloblas
-
tic anemia or to cold agglutinins in blood analyzed at room 
temperature. A bone marrow biopsy is generally needed to 
complete the evaluation of anemia when the laboratory evalu
-
ation fails to reveal an etiology, when there are additional 
cytopenias present, or when an underlying primary or 
secondary bone marrow process is suspected.
IRON DEFICIENCY ANEMIA
 
»
Iron deficiency: serum ferritin is less than 12 ng/mL 
(27 pmol/L) or less than 30 ng/mL (67 pmol/L) if 
also anemic.
 
»
Caused by bleeding unless proved otherwise.
 
»
Responds to iron therapy.
 
»
Iron deficiency is the most common cause of anemia 
worldwide. The causes are listed in Table 13–3. Aside from 
circulating red blood cells, the major location of iron in the 
body is the storage pool as ferritin or as hemosiderin in 
macrophages.
The average American diet contains 10–15 mg of iron 
per day. About 10% of this amount is absorbed in the stom
-
ach, duodenum, and upper jejunum under acidic condi
-
tions. Dietary iron present as heme is efficiently absorbed 
(10–20%) but nonheme iron less so (1–5%), largely because 
of interference by phosphates, tannins, and other food 
constituents. The major iron transporter from the diet 
across the intestinal lumen is ferroportin, which also facili
-
tates the transport of iron to apotransferrin in macro
-
phages for delivery to erythroid cells prepared to synthesize 
hemoglobin. Hepcidin, which is increasingly produced 
during inflammation, negatively regulates iron transport 
by promoting the degradation of ferroportin. Small 
amounts of iron—approximately 1 mg/day—are normally 
lost through exfoliation of skin and mucosal cells.
Menstrual blood loss plays a major role in iron metabolism. 
The average monthly menstrual blood loss is approximately 
 
50 mL but may be five times greater in some individuals. 
Women with heavy menstrual losses must absorb 3–4 mg of 
iron from the diet each day to maintain adequate iron stores, 
which is not commonly achieved. Women with menorrhagia 
of this degree will almost always become iron deficient without 
iron supplementation.
In general, iron metabolism is balanced between 
absorption of 1 mg/day and loss of 1 mg/day. Pregnancy 
and lactation upset the iron balance, since requirements 
increase to 2–5 mg of iron per day. Normal dietary iron 
cannot supply these requirements, and medicinal iron is

cannot supply these requirements, and medicinal iron is 
needed during pregnancy and lactation. Decreased iron 
absorption can also cause iron deficiency, such as in people 
affected by celiac disease (gluten enteropathy), and it also 
commonly occurs after gastric resection or jejunal bypass 
surgery.13
 
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CMDT 2019
Table 13–1.
 
Classification of anemia by red blood cell 
(RBC) pathophysiology.
Decreased RBC production (relative or absolute 
reticulocytopenia)
 
Hemoglobin 
synthesis lesion: iron deficiency, thalassemia, 
 
anemia of chronic disease, hypoerythropoietinemia
 
DNA syn
thesis lesion: megaloblastic anemia, DNA synthesis 
 
inhibitor medications
 
Hema
topoietic stem cell lesion: aplastic anemia, leukemia
 
B
one marrow infiltration: carcinoma, lymphoma, fibrosis, 
 
sarcoidosis, Gaucher disease, others
 
I
mmune-mediated inhibition: aplastic anemia, pure red cell 
 
aplasia
Increased RBC destruction or accelerated RBC loss 
(reticulocytosis)
 
A
cute blood loss
 
Hemoly
sis (intrinsic)
  
M
embrane lesion: hereditary spherocytosis, elliptocytosis
  
lesion: sickle cell, unstable hemoglobin
  
Gly
colysis lesion: pyruvate kinase deficiency
   
O
xidation lesion: glucose-6-phosphate dehydrogenase deficiency
 
Hemoly
sis (extrinsic)
  
I
mmune: warm antibody, cold antibody
   
M
icroangiopathic: thrombotic thrombocytopenic purpura, 
 
h
emolytic-uremic syndrome, mechanical cardiac valve, 
 
par
avalvular leak
 
Infection: 
Clostridium perfringens
, malaria
 
Hypersplenism
Table 13–2.
 
Classification of anemia by mean red 
blood cell volume (MCV).
Microcytic
 
I
ron deficiency
 
Anemia of 
chronic disease
 
L
ead toxicity
 
Zinc deficienc
y
Macrocytic (Megaloblastic)
 
V
itamin B
12
 deficiency
 
F
olate deficiency
 
DNA syn
thesis inhibitors
Macrocytic (Nonmegaloblastic)
 
Aplastic 
anemia
 
Myelodysplasia
 
Liv
er disease
 
Reticulocytosis
 
B
one marrow failure state (eg, aplastic anemia, marrow 
 
infiltrative disorder, etc)
 
C
opper deficiency
Normocytic
 
K
idney disease
 
Non-th
yroid endocrine gland failure
 
C
 
M
ild form of most acquired microcytic or macrocytic etiologies
 
of anemia
Table 13–3.
 
Causes of iron deficiency.
Deficient diet
Decreased absorption
 
A
utoimmune gastritis
 
C
eliac sprue
 
 gastritis
 
Her
editary iron-refractory iron deficiency anemia
 
y
Increased requirements
 
Pregnancy
 
Lactation
Blood loss (chronic)
 
Gastrointestinal
 
Menstrual
 
Blood dona
tion
 
Hemoglobinuria
Iron sequestration
 
P
ulmonary hemosiderosis
Idiopathic
The most important cause of iron deficiency anemia in 
adults is chronic blood loss, especially menstrual and gastro
-
intestinal blood loss. Iron deficiency demands a search for a 
source of gastrointestinal bleeding if other sites of blood loss 
(menorrhagia, other uterine bleeding, and repeated blood 
donations) are excluded. Prolonged aspirin or nonsteroidal 
anti-inflammatory drug use may cause it even without a 
documented structural lesion. Celiac disease, even when 
asymptomatic, can cause iron deficiency through poor 
absorption in the gastrointestinal tract. Zinc deficiency is 
another cause of poor iron absorption. Chronic hemoglo
-
binuria may lead to iron deficiency, but this is uncommon. 
Traumatic hemolysis due to a prosthetic cardiac valve and 
other causes of intravascular hemolysis (eg, paroxysmal 
nocturnal hemoglobinuria) should also be considered. The 
cause of iron deficiency is not found in up to 5% of cases.
Pure iron deficiency might prove refractory to oral iron 
replacement. Refractoriness is defined as a hemoglobin 
increment of less than 1 g/dL (10 g/L) after 4–6 weeks of 
100 mg/day of elemental oral iron. The differential diagno
-
sis in these cases (Table 13–3) includes malabsorption from 
autoimmune gastritis, 
 gastric infection, 
celiac disease, and hereditary iron-refractory iron defi
-
ciency anemia. Iron-refractory iron deficiency anemia is a 
rare autosomal recessive disorder due to mutations in the 
transmembrane serine protease 6 (
TMPRSS6
) gene, which 
normally down-regulates hepcidin. In iron-refractory iron

TMPRSS6
normally down-regulates hepcidin. In iron-refractory iron 
deficiency anemia, hepcidin levels are normal to high and 
ferritin levels are high despite the iron deficiency.
 
»
The primary symptoms of iron deficiency anemia are 
those of the anemia itself (easy fatigability, tachycardia, 
palpitations, and dyspnea on exertion). Severe deficiency 
causes skin and mucosal changes, including a smooth 
tongue, brittle nails, spooning of nails (koilonychia), and 
cheilosis. Dysphagia due to the formation of esophageal 
webs (Plummer-Vinson syndrome) may occur in severe 
iron deficiency. Many iron-deficient patients develop 
pica, craving for specific foods (ice chips, etc) often not 
rich in iron.
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Iron deficiency develops in stages. The first is depletion of 
iron stores without anemia followed by anemia with a nor
-
mal red blood cell size (normal MCV) followed by anemia 
with reduced red blood cell size (low MCV). The reticulo
-
cyte count is low or inappropriately normal. Ferritin is a 
measure of total body iron stores. A ferritin value less than 
12 ng/mL (27 pmol/L) (in the absence of scurvy) is a highly 
reliable indicator of reduced iron stores. Note that the lower 
limit of normal for ferritin generally is below 12 ng/mL 
 
(27 pmol/L) in women due to the fact that the normal ferri
-
tin range is generated by including healthy menstruating 
women who are iron deficient but not anemic. However, 
because serum ferritin levels may rise in response to inflam
-
mation or other stimuli, a normal or elevated ferritin level 
does not exclude a diagnosis of iron deficiency. A ferritin 
level less than 30 ng/mL (67 pmol/L) almost always indicates 
iron deficiency in anyone who is anemic. As iron deficiency 
progresses, serum iron values decline to less than 30 mcg/dL 
(67 pmol/L) and transferrin (the iron transport protein) 
levels rise to compensate, leading to transferrin saturations 
of less than 15%. Low transferrin saturation is also seen in 
anemia of inflammation, so caution in the interpretation of 
this test is warranted. Isolated iron deficiency anemia has a 
low hepcidin level, not yet a clinically available test. As the 
MCV falls (ie, microcytosis), the blood smear shows hypo
-
chromic microcytic cells. With further progression, anisocy
-
tosis (variations in red blood cell size) and poikilocytosis 
(variation in shape of red cells) develop. Severe iron defi
-
ciency will produce a bizarre peripheral blood smear, with 
severely hypochromic cells, target cells, and pencil-shaped 
or cigar-shaped cells. Bone marrow biopsy for evaluation of 
iron stores is rarely performed. If the biopsy is done, it shows 
the absence of iron in erythroid progenitor cells by Prussian 
blue staining. The platelet count is commonly increased, but 
it usually remains under 800,000/mcL (800 × 10
9
/L).
 
»
Other causes of microcytic anemia include anemia of 
chronic disease (specifically, anemia of inflammation), 
thalassemia, lead poisoning, and congenital X-linked sid
-
eroblastic anemia. Anemia of chronic disease is character
-
ized by normal or increased iron stores in bone marrow 
macrophages and a normal or elevated ferritin level; the 
serum iron and transferrin saturation are low, often drasti
-
cally so, and the total iron-binding capacity (TIBC) (the 
blood’s capacity for iron to bind to transferrin) and trans
-
ferrin are either normal or low. Thalassemia produces a 
greater degree of microcytosis for any given level of anemia 
than does iron deficiency and, unlike virtually every other 
cause of anemia, has a normal or elevated (rather than a 
low) red blood cell count as well as a reticulocytosis. In 
thalassemia, red blood cell morphology on the peripheral 
smear resembles severe iron deficiency.
 
»
Treatment
The diagnosis of iron deficiency anemia can be made 
either by the laboratory demonstration of an iron-
deficient state or by evaluating the response to a therapeutic 
trial of iron replacement. Since the anemia itself is rarely 
life-threatening, the most important part of management 
is identification of the cause—especially a source of occult 
blood loss.
A. Oral Iron
Ferrous sulfate, 325 mg once daily on an empty stomach, is 
a standard approach for replenishing iron stores. As oral 
iron stimulates hepcidin production, once daily dosing 
maximizes iron absorption compared to multiple daily 
dosing, and with fewer side effects. Nausea and constipa
-
tion limit compliance with ferrous sulfate. Extended-
release ferrous sulfate with mucoprotease is a well-tolerated 
oral preparation. Taking ferrous sulfate with food reduces

-
oral preparation. Taking ferrous sulfate with food reduces 
side effects but also its absorption. An appropriate response 
is a return of the hematocrit level halfway toward normal 
within 3 weeks with full return to baseline after 2 months. 
Iron therapy should continue for 3–6 months after restora
-
tion of normal hematologic values to replenish iron stores. 
Failure of response to iron therapy is usually due to non
-
compliance, although occasional patients may absorb iron 
poorly, particularly if the stomach is achlorhydric. Such 
patients may benefit from concomitant administration of 
oral ascorbic acid. Other reasons for failure to respond 
include incorrect diagnosis (anemia of chronic disease, 
thalassemia), celiac disease, and ongoing blood loss that 
exceeds the rate of new erythropoiesis. Treatment of 
 
H pylori
 infection, in appropriate cases, can improve oral 
iron absorption.
B. Parenteral Iron
The indications are intolerance of or refractoriness to 
oral iron (including those with iron-refractory iron defi
-
ciency anemia), gastrointestinal disease (usually inflam
-
matory bowel disease) precluding the use of oral iron, 
and continued blood loss that cannot be corrected, such 
as chronic hemodialysis. Historical parenteral iron prep
-
arations, such as high-molecular-weight iron dextran, 
were problematic due to long infusion times (hours), 
polyarthralgia, and hypersensitivity reactions, including 
anaphylaxis. Current parenteral iron preparations coat 
the iron in protective carbohydrate shells or contain low-
molecular-weight iron dextran, are safe and can be 
administered over 15 minutes to 1 hour. Most iron defi
-
cient patients need 1–1.5 g of parenteral iron; this dose 
corrects for the iron deficit and replenishes iron stores 
for the future.
Ferric pyrophosphate citrate (Triferic), which is FDA-
approved, is added to the dialysate to replace the 5–7 mg of 
iron that patients with chronic kidney disease tend to lose 
during each hemodialysis treatment. Ferric pyrophosphate 
citrate delivers sufficient iron to the marrow to maintain 
hemoglobin and not increase iron stores; it may obviate the 
need for intravenous iron in hemodialysis patients.
 
»
Patients should be referred to a hematologist if the suspected 
diagnosis is not confirmed or if they are not responsive to 
oral iron therapy.
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Auerbach M et al. Single-dose intravenous iron for iron defi
-
ciency: a new paradigm. Hematology Am Soc Hematol Educ 
Program. 2016 Dec 2;2016(1):57–66. [PMID: 27913463]
Hempel EV et al. The evidence-based evaluation of iron defi
-
ciency anemia. Med Clin North Am. 2016 Sep;100(5):1065–75. 
[PMID: 27542426]
Moretti D et al. Oral iron supplements increase hepcidin and 
decrease iron absorption from daily or twice-daily doses in 
iron-depleted young women. Blood. 2015 Oct 22;126(17):
 
1981–9. [PMID: 26289639]
ANEMIA OF CHRONIC DISEASE
 
»
Mild or moderate normocytic or microcytic 
anemia.
 
»
Normal or increased ferritin and normal or reduced 
transferrin.
 
»
Underlying chronic disease.
 
»
Many chronic systemic diseases are associated with mild 
or moderate anemia. The anemias of chronic disease are 
characterized according to etiology and pathophysiology. 
First, the 
anemia of inflammation
chronic inflammatory states (such as inflammatory bowel 
disease, rheumatoid arthritis, chronic infections, and 
malignancy) and is mediated through hepcidin (a nega
-
tive regulator of ferroportin) primarily through elevated 
IL-6, resulting in reduced iron uptake in the gut and 
reduced iron transfer from macrophages to erythroid 
progenitor cells in the bone marrow. This is referred to as 
iron-restricted erythropoiesis since the patient is iron 
replete. There is also reduced responsiveness to erythro
-
poietin, the elaboration of hemolysins that shorten red 
blood cell survival, and the production of inflammatory 
cytokines that dampen red cell production. The serum 
iron is low in the anemia of inflammation. Second, the 
anemia of organ failure
 can occur with kidney disease, 
liver failure, and endocrine gland failure. Erythropoietin 
is reduced and the red blood cell mass decreases in 
response to the diminished signal for red blood cell pro
-
duction; the serum iron is normal (except in chronic 
kidney disease where it is low due to the reduced hepcidin 
clearance and subsequent enhanced degradation of ferro
-
portin). Third, the 
anemia of older adults
 is present in up 
to 20% of individuals over age 85 years in whom a thor
-
ough evaluation for an explanation of anemia is negative. 
The anemia is a consequence of (1) a relative resistance to 
red blood cell production in response to erythropoietin, 
(2) a decrease in erythropoietin production relative to the 
nephron mass, (3) a negative erythropoietic influence of 
low levels of chronic inflammatory cytokines in older 
adults, and (4) the presence of various somatic mutations 
in myeloid genes typically associated with myeloid neo
-
plasms. The serum iron is normal.
 
»
The clinical features are those of the causative condition. 
The diagnosis should be suspected in patients with known 
chronic diseases. In cases of significant anemia, coexistent 
iron deficiency or folic acid deficiency should be sus
-
pected. Decreased dietary intake of iron or folic acid is 
common in chronically ill patients, many of whom will also 
have ongoing gastrointestinal blood losses. Patients under
-
going hemodialysis regularly lose both iron and folic acid 
during dialysis.
The hematocrit rarely falls below 60% of baseline (except 
in kidney failure). The MCV is usually normal or slightly 
reduced. Red blood cell morphology is usually normal, 
and the reticulocyte count is mildly decreased or 
normal.
1. Anemia of inflammation—
In the anemia of inflamma
-
tion, serum iron and transferrin values are low, and the 
transferrin saturation may be extremely low, leading to an 
erroneous diagnosis of iron deficiency. In contrast to iron 
deficiency, serum ferritin values should be normal or 
increased. A serum ferritin value less than 30 ng/mL 
 
(67 pmol/L) indicates coexistent iron deficiency. Anemia

(67 pmol/L) indicates coexistent iron deficiency. Anemia 
of inflammation has elevated hepcidin levels; however, no 
clinical test is yet available. A particular challenge is the 
diagnosis of iron deficiency in the setting of the anemia of 
inflammation, in which the serum ferritin can be as high 
as 200 ng/mL (450 pmol/L). The diagnosis is established 
by a bone marrow biopsy with iron stain. Absent iron 
staining indicates iron deficiency, whereas iron localized 
in marrow macrophages indicates pure anemia of inflam
-
mation. However, bone marrow biopsies are rarely done 
for this purpose. Two other tests all support iron defi
-
ciency in the setting of inflammation: a reticulocyte 
hemoglobin concentration of less than 28 pg or a soluble 
serum transferrin receptor (units: mg/L) to log ferritin 
(units: mcg/L) ratio of 1–8 (a ratio of less than 1 is virtu
-
ally diagnostic of pure anemia of chronic disease). A func
-
tional test is hemoglobin response to oral or parenteral 
iron in the setting of inflammation when iron deficiency is 
suspected. A note of caution: certain circumstances of 
iron-restricted erythropoiesis (such as malignancy) will 
partially respond to parenteral iron infusion even when 
the iron stores are replete due to the immediate distribu
-
tion of iron to erythropoietic progenitor cells after the 
infusion.
2. Other anemias of chronic disease—
In the anemias of 
organ failure and of older adults, the iron studies are gener
-
ally normal. The anemia of older persons is a diagnosis of 
exclusion.
 
»
Treatment
In most cases, no treatment of the anemia is necessary and 
the primary management is to address the condition caus
-
ing the anemia of chronic disease. When the anemia is 
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severe or is adversely affecting the quality of life or func
-
tional status, then treatment involves either red blood cell 
transfusions or parenteral recombinant erythropoietin 
(epoetin alfa or darbepoetin). The indications for recom
-
binant erythropoietin are hemoglobin less than 10 g/dL 
and anemia due to rheumatoid arthritis, inflammatory 
bowel disease, hepatitis C, zidovudine therapy in HIV-
infected patients, myelosuppressive chemotherapy of 
solid malignancy (treated with palliative intent only), or 
chronic kidney disease (estimated glomerular filtration 
rate of less than 60 mL/min). The dosing and schedule of 
recombinant erythropoietin are individualized to main
-
tain the hemoglobin between 10 g/dL (100 g/L) and 12 g/dL 
(120 g/L). The use of recombinant erythropoietin is asso
-
ciated with an increased risk of venothromboembolism 
and arterial thrombotic episodes, especially if the hemo
-
globin rises to greater than 12 g/dL (120 g/L). There is 
concern that recombinant erythropoietin is associated 
with reduced survival in patients with malignancy. For 
patients with end-stage renal disease receiving recombi
-
nant erythropoietin who are on hemodialysis, the anemia 
of chronic kidney disease can be more effectively cor
-
rected by adding soluble ferric pyrophosphate to their 
dialysate than by administering intravenous iron 
 
»
Referral to a hematologist is not usually necessary.
Fraenkel PG. Understanding anemia of chronic disease. Hematol
-
ogy Am Soc Hematol Educ Program. 2015;2015:14–8. [PMID: 
26637695]
Gaspar BL et al. Anemia in malignancies: pathogenetic and diag
-
nostic considerations. Hematology. 2015 Jan;20(1):18–25. 
[PMID: 24666207]
Weiss G. Anemia of chronic disorders: new diagnostic tools and new 
treatment strategies. Semin Hematol. 2015 Oct;52(4):313–20. 
[PMID: 26404443]
THE THALASSEMIAS
 
»
Microcytosis disproportionate to the degree of 
anemia.
 
»
Positive family history.
 
»
Lifelong personal history of microcytic anemia.
 
»
Normal or elevated red blood cell count.
 
»
Abnormal red blood cell morphology with micro
-
cytes, hypochromia, acanthocytes, and target cells.
 
»
In beta-thalassemia, elevated levels of hemoglobin 
A
2
 or F.
 
»
The thalassemias are hereditary disorders characterized by 
reduction in the synthesis of globin chains (alpha or beta). 
Table 13–4.
 
Alpha-thalassemia syndromes.
Number of 
Alpha-Globin 
Genes 
t
r
anscribed
Syndrome
h
ematocrit
MCV
4
Normal
Normal
Normal
3
Silent carrier
Normal
Normal
2
Thalassemia 
minor (or trait)
28–40%
60–75 fL
1
Hemoglobin H 
disease
22–32%
60–70 fL
0
Hydrops fetalis
1
< 18%
< 60 fL
1
Die in utero.
MCV, mean corpuscular volume.
Reduced globin chain synthesis causes reduced hemoglo
-
bin synthesis and a hypochromic microcytic anemia 
because of defective hemoglobinization of red blood cells. 
Thalassemias can be considered among the hyperprolifera
-
tive hemolytic anemias, the anemias related to abnormal 
hemoglobin, and the hypoproliferative anemias, since all of 
these factors play a role in pathogenesis. The hallmark 
laboratory features are small (low MCV) and pale (low 
mean corpuscular hemoglobin [MCH]) red blood cells, 
anemia, and a normal to elevated red blood cell count (ie, 
a large number of the small and pale red blood cells are 
being produced). Although patients often exhibit an ele
-
vated reticulocyte count, generally the degree of reticulo
-
cyte output is inadequate to meet the degree of red blood 
cell destruction (hemolysis) occurring in the bone marrow 
and the patients remain anemic.
Normal adult hemoglobin is primarily hemoglobin A, 
which represents approximately 98% of circulating hemo
-
globin. Hemoglobin A is formed from a tetramer of two 
alpha chains and two beta globin chains—and is designated 
alpha2beta2. Two copies of the alpha-globin gene are

-
alpha2beta2. Two copies of the alpha-globin gene are 
located on each chromosome 16, and there is no substitute 
for alpha-globin in the formation of adult hemoglobin. 
One copy of the beta-globin gene resides on each chromo
-
some 11 adjacent to genes encoding the beta-like globins 
delta and gamma (the so-called beta-globin gene cluster 
region). The tetramer of alpha2delta2 forms hemoglobin 
A
2
, which normally comprises 1–3% of adult hemoglobin. 
The tetramer alpha2gamma2 forms hemoglobin F, which is 
the major hemoglobin of fetal life but which comprises less 
than 1% of normal adult hemoglobin.
The thalassemias are described as 
“trait”
 when there 
are laboratory features without significant clinical impact, 
“intermedia”
 when there is an occasional red blood cell 
transfusion requirement or other moderate clinical impact, 
and 
“major”
 when the disorder is life-threatening and the 
patient is transfusion-dependent. Most patients with thal
-
assemia major die of the consequences of iron overload 
from RBC transfusions.
Alpha-thalassemia
 is due primarily to gene deletions 
causing reduced alpha-globin chain synthesis (Table 13–4). 
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Each alpha-globin gene produces one-quarter of the total 
alpha-globin quantity, so there is a predictable proportionate 
decrease in alpha-globin output with each lost alpha-globin 
gene. Since all adult hemoglobins are alpha containing, 
alpha-thalassemia produces no change in the proportions of 
hemoglobins A, A
2
, and F on hemoglobin electrophoresis. In 
severe forms of alpha-thalassemia, excess beta chains may 
form a beta-4 tetramer called hemoglobin H. In the presence 
of reduced alpha chains, the excess beta chains are unstable 
and precipitate, leading to damage of red blood cell mem
-
branes. This leads to both intramedullary (bone marrow) 
and peripheral blood hemolysis.
Beta-thalassemias
 are usually caused by point muta
-
tions rather than deletions (Table 13–5). These mutations 
result in premature chain termination or in problems with 
transcription of RNA and ultimately result in reduced or 
absent beta-globin chain synthesis. The molecular defects 
leading to beta-thalassemia are numerous and heteroge
-
neous. Defects that result in absent beta-globin chain 
expression are termed beta
0
, whereas those causing reduced 
but not absent synthesis are termed beta
+
. In beta
+
 thalas
-
semia, the degree of reduction of beta-globin synthesis is 
consistent within families but is quite variable between 
families. The reduced beta-globin chain synthesis in beta-
thalassemia results in a relative increase in the proportions 
of hemoglobins A
2
 and F compared to hemoglobin A on 
hemoglobin electrophoresis, as the beta-like globins (delta 
and gamma) substitute for the missing beta chains. In the 
presence of reduced beta chains, the excess alpha chains are 
unstable and precipitate, leading to damage of red blood 
cell membranes. This leads to both intramedullary (bone 
marrow) and peripheral blood hemolysis. The bone mar
-
row demonstrates erythroid hyperplasia under the stimuli 
of anemia and ineffective erythropoiesis (intramedullary 
destruction of the developing erythroid cells). In cases of 
severe thalassemia, the marked expansion of the erythroid 
compartment in the bone marrow may cause severe bony 
deformities, osteopenia, and pathologic bone fractures.
 
»
The 
alpha-thalassemia
 syndromes are seen primarily in 
persons from southeast Asia and China, and, less 
Table 13–5.
 
Beta-thalassemia syndromes.
Beta-Globin Genes 
t
r
anscribed
h
b A
h
b A
2
h
b F
t
r
ansfusions
Normal
Homozygous beta
97–99%
1–3%
< 1%
 
Thalassemia minor
Heterozygous beta
0
80–95%
4–8%
1–5%
None
 
+
80–95%
4–8%
1–5%
None
Thalassemia intermedia
+
 (mild)
0–30%
0–10%
6–100%
Thalassemia major
0
0%
4–10%
90–96%
Dependent
+
0–10%
4–10%
90–96%
Dependent
Hb, hemoglobin.
commonly, in blacks and persons of Mediterranean origin 
(Table 13–4). Normally, adults have four copies of the 
alpha-globin chain. When three alpha-globin genes are 
present, the patient is hematologically normal (silent car
-
rier). When two alpha-globin genes are present, the patient 
is said to have alpha-thalassemia trait, a form of thalas
-
semia minor. In alpha-thalassemia-1 trait, the alpha gene 
deletion is heterozygous (alpha –/alpha –) and affects 
mainly those of Asian descent. In alpha-thalassemia-2 trait, 
the alpha gene deletion is homozygous (alpha alpha/– –) 
and affects mainly blacks. These patients are clinically nor
-
mal and have a normal life expectancy and performance 
status, with a mild microcytic anemia. When only one 
alpha globin chain is present (alpha –/– –), the patient has 
hemoglobin H disease (alpha-thalassemia-3). This is a 
chronic hemolytic anemia of variable severity (thalassemia 
minor or intermedia). Physical examination might reveal 
pallor and splenomegaly. Affected individuals usually do 
not need transfusions; however, they may be required dur
-

-
ing transient periods of hemolytic exacerbation caused by 
infection or other stressors or during periods of erythro
-
poietic shutdown caused by certain viruses (“aplastic cri
-
sis”). When all four alpha-globin genes are deleted, no 
normal hemoglobin is produced and the affected fetus is 
stillborn (hydrops fetalis). In hydrops fetalis, the only 
hemoglobin species gamma made is called hemoglobin 
Bart’s (gamma4).
Beta-thalassemia
 primarily affects persons of Mediter
-
ranean origin (Italian, Greek) and to a lesser extent Asians 
and blacks (Table 13–5). Patients homozygous for beta-
thalassemia (beta
0
/beta
0
 or some with beta
+
/beta
+
) have 
thalassemia major (Cooley anemia). Affected children are 
normal at birth but after 6 months, when hemoglobin syn
-
thesis switches from hemoglobin F to hemoglobin A, severe 
anemia develops that requires transfusion. Numerous clini
-
cal problems ensue, including stunted growth, bony defor
-
mities (abnormal facial structure, pathologic bone fractures), 
hepatosplenomegaly, jaundice (due to gallstones, hepatitis-
related cirrhosis, or both), and thrombophilia. The clinical 
course is modified significantly by transfusion therapy, but 
transfusional iron overload (hemosiderosis) results in a 
clinical picture similar to hemochromatosis, with heart fail
-
ure, cardiac arrhythmias, cirrhosis, endocrinopathies, and 
pseudoxanthoma elasticum (calcification and fragmentation 
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of the elastic fibers of the skin, retina, and cardiovascular 
system), usually after more than 100 units of red blood cells 
have been transfused. Iron overloading occurs because the 
human body has no active iron excretory mechanism. 
Before the application of allogeneic stem cell transplantation 
and the development of more effective forms of iron chela
-
tion, death from iron overload usually occurred between the 
ages of  20 and 30 years.
Patients homozygous for a milder form of beta-
+
/beta
+
, but allowing a higher rate of 
beta-globin synthesis) have thalassemia intermedia. These 
patients have chronic hemolytic anemia but do not require 
transfusions except under periods of stress or during aplas
-
tic crises. They also may develop iron overload because of 
periodic transfusion. They survive into adult life but with 
hepatosplenomegaly and bony deformities. Patients het
-
erozygous for beta-thalassemia (beta/beta
0
 or beta/beta
+
) 
have thalassemia minor and a clinically insignificant micro
-
cytic anemia.
Prenatal diagnosis is available, and genetic counseling 
should be offered and the opportunity for prenatal diagnosis 
discussed.
1. Alpha-thalassemia trait—
These patients have mild 
anemia, with hematocrits between 28% and 40%. The 
MCV is strikingly low (60–75 fL) despite the modest 
anemia, and the red blood count is normal or increased. 
The peripheral blood smear shows microcytes, hypo
-
chromia, occasional target cells, and acanthocytes (cells 
with irregularly spaced spiked projections). The reticu
-
locyte count and iron parameters are normal. Hemoglo
-
bin electrophoresis is normal. Alpha-thalassemia trait is 
thus usually diagnosed by exclusion. Genetic testing to 
demonstrate alpha-globin gene deletion is available.
2. Hemoglobin H disease—
These patients have a more 
marked anemia, with hematocrits between 22% and 
32%. The MCV is remarkably low (60–70 fL) and the 
peripheral blood smear is markedly abnormal, with 
hypochromia, microcytosis, target cells, and poikilocy
-
tosis. The reticulocyte count is elevated and the red 
blood cell count is normal or elevated. Hemoglobin 
electrophoresis will show a fast-migrating hemoglobin 
(hemoglobin H), which comprises 10–40% of the hemo
-
globin. A peripheral blood smear can be stained with 
supravital dyes to demonstrate the presence of hemo
-
globin H.
3. Beta-thalassemia minor—
These patients have a modest 
anemia with hematocrit between 28% and 40%. The MCV 
ranges from 55 fL to 75 fL, and the red blood cell count is 
normal or increased. The reticulocyte count is normal or 
slightly elevated. The peripheral blood smear is mildly 
abnormal, with hypochromia, microcytosis, and target 
cells. In contrast to alpha-thalassemia, basophilic stippling 
is present. Hemoglobin electrophoresis shows an elevation 
of hemoglobin A
2
 to 4–8% and occasional elevations of 
hemoglobin F to 1–5%.
4. Beta-thalassemia intermedia—
These patients have 
a modest anemia with hematocrit between 17% and 
33%. The MCV ranges from 55 fL to 75 fL, and the red 
blood cell count is normal or increased. The reticulo
-
cyte count is elevated. The peripheral blood smear is 
abnormal with hypochromia, microcytosis, basophilic 
stippling, and target cells. Hemoglobin electrophoresis 
shows up to 30% hemoglobin A, an elevation of hemo
-
globin A
2
 up to 10%, and elevation of hemoglobin F 
from 6% to 10%.
5. Beta-thalassemia major—
severe anemia, and without transfusion the hematocrit 
may fall to less than 10%. The peripheral blood smear 
is bizarre, showing severe poikilocytosis, hypochromia, 
microcytosis, target cells, basophilic stippling, and 
nucleated red blood cells. Little or no hemoglobin A is 
present. Variable amounts of hemoglobin A
2
 are seen, and 
the predominant hemoglobin present is hemoglobin F.
 
»

2
 
»
Mild forms of thalassemia must be differentiated from iron 
deficiency. Compared to iron deficiency anemia, patients 
with thalassemia have a lower MCV , a normal or elevated 
red blood cell count (rather than low), a more abnormal 
peripheral blood smear at modest levels of anemia, and 
usually a reticulocytosis. Iron studies are normal or the 
transferrin saturation or ferritin (or both) are elevated. 
Severe forms of thalassemia may be confused with other 
hemoglobinopathies. The diagnosis of beta-thalassemia is 
made by the above findings and hemoglobin electrophore
-
sis showing elevated levels of hemoglobins A
2
 and F (pro
-
vided the patient is replete in iron). The diagnosis of 
alpha-thalassemia is made by exclusion since there is no 
change in the proportion of the normal adult hemoglobin 
species or confirmed by alpha gene deletion studies. The 
only other microcytic anemia with a normal or elevated 
red blood cell count is iron deficiency in a patient with 
 
»
Treatment
Patients with mild thalassemia (alpha-thalassemia trait 
or beta-thalassemia minor) require no treatment and 
should be identified so that they will not be subjected to 
repeated evaluations and treatment for iron deficiency. 
Patients with hemoglobin H disease should take folic 
acid supplementation (1 mg/day orally) and avoid 
medicinal iron and oxidative drugs such as sulfonamides. 
Patients with severe thalassemia are maintained on a 
regular transfusion schedule (in part to suppress endog
-
enous erythropoiesis and therefore bone marrow expan
-
sion) and receive folic acid supplementation. Splenectomy 
is performed if hypersplenism causes a marked increase 
in the transfusion requirement or refractory symptoms. 
Patients with regular transfusion requirements should be 
treated with iron chelation (oral or parenteral) in order 
to prevent or delay life-limiting organ damage from iron 
overload.
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Allogeneic stem cell transplantation is the treatment of 
choice for beta-thalassemia major and the only available 
cure. Children who have not yet experienced organ dam
-
age from iron overload do well, with long-term survival in 
more than 80% of cases.
 
»
All patients with severe thalassemia should be referred to 
a hematologist. Any patient with an unexplained micro
-
cytic anemia should be referred to help establish a diag
-
nosis. Patients with thalassemia minor or intermedia 
should be offered genetic counseling because offspring of 
thalassemic couples are at risk for inheriting thalassemia 
major.
Jagannath V A et al. Hematopoietic stem cell transplantation for 
people with B-thalassaemia major. Cochrane Database Syst 
Rev. 2016 Nov 30;11:CD008708. [PMID: 27900772]
King A et al. Evidence-based focused review of the status of hema
-
topoietic stem cell transplantation as treatment of sickle cell 
disease and thalassemia. Blood. 2014 May 15;123(20):3089–94. 
[PMID: 24511087]
Kwiatkowski JL. Current recommendations for chelation for 
transfusion-dependent thalassemia. Ann N Y Acad Sci. 2016 
Mar;1368(1):107–14. [PMID: 27186943]
Makis A et al. 2017 clinical trials update in new treatments of 
B-thalassemia. Am J Hematol. 2016 Nov;91(11):1135–45. 
[PMID: 27502996]
Piel FB et al. The α-thalassemias. N Engl J Med. 2014 Nov 3;
 
371(20):1908–16. [PMID: 25390741]
Rund D. Thalassemia 2016: modern medicine battles an ancient 
disease. Am J Hematol. 2016 Jan;91(1):15–21. [PMID: 
26537527]
VITAMIN B
12
 DEFICIENCY
 
»
Macrocytic anemia.
 
»
Megaloblastic blood smear (macro-ovalocytes 
and hypersegmented neutrophils).
 
»
Low serum vitamin B
12
 level.
 
»
Vitamin B
12
 belongs to the family of cobalamins and 
serves as a cofactor for two important reactions in 
humans. As methylcobalamin, it is a cofactor for methio
-
nine synthetase in the conversion of homocysteine to 
methionine, and as adenosylcobalamin for the conversion 
of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. 
Vitamin B
12
 comes from the diet and is present in all foods 
of animal origin. The daily absorption of vitamin B
12
 is 
 
5 mcg.
The liver contains 2–5 mg of stored vitamin B
12
. Since 
daily utilization is 3–5 mcg, the body usually has sufficient 
stores of vitamin B
12
 so that it takes more than 3 years for 
vitamin B
12
 deficiency to occur if all intake or absorption 
immediately ceases.
Table 13–6.
 
Causes of vitamin B
12
 deficiency.
Dietary deficiency (rare)
Decreased production or absorption of intrinsic factor
 
P
ernicious anemia (autoimmune)
 
Gastrectomy
 infection
Competition for vitamin B
12
 in the gut
 
Blind loop syndr
ome
 
F
ish tapeworm (rare)
Pancreatic insufficiency
Proton pump inhibitors
Decreased ileal absorption of vitamin B
12
 
Sur
gical resection
 
Cr
ohn disease
Transcobalamin II deficiency (rare)
Since vitamin B
12
 is present in foods of animal origin, 
dietary vitamin B
12
 deficiency is extremely rare but is seen 
in vegans—strict vegetarians who avoid all dairy products, 
meat, and fish (Table 13–6). Pernicious anemia is an auto
-
immune illness whereby autoantibodies destroy gastric 
parietal cells (that produce intrinsic factor) and cause atro
-
phic gastritis or bind to and neutralize intrinsic factor, or 
both. Abdominal surgery may lead to vitamin B
12
 defi
-
ciency in several ways. Gastrectomy will eliminate the site 
of intrinsic factor production; blind loop syndrome will 
cause competition for vitamin B
12
 by bacterial overgrowth 
in the lumen of the intestine; and surgical resection of the 
ileum will eliminate the site of vitamin B
12
 absorption. Rare 
causes of vitamin B
12
 deficiency include fish tapeworm 
(
Diphyllobothrium latum
) infection, in which the parasite 
uses luminal vitamin B
12
; pancreatic insufficiency (with 
failure to inactivate competing cobalamin-binding proteins

(
12
failure to inactivate competing cobalamin-binding proteins 
[R-factors]); severe Crohn disease, causing sufficient 
destruction of the ileum to impair vitamin B
12
 absorption; 
and perhaps prolonged use of proton pump inhibitors.
 
»
Vitamin B
12
 deficiency causes a moderate to severe anemia 
of slow onset; patients may have few symptoms relative to 
the degree of anemia. In advanced cases, the anemia may 
be severe, with hematocrits as low as 10–15%, and may be 
accompanied by leukopenia and thrombocytopenia. The 
deficiency also produces changes in mucosal cells, leading 
to glossitis, as well as other vague gastrointestinal distur
-
bances such as anorexia and diarrhea. Vitamin B
12
 defi
-
ciency also leads to a complex neurologic syndrome. 
Peripheral nerves are usually affected first, and patients 
complain initially of paresthesias. As the posterior columns 
of the spinal cord become impaired, patients complain of 
difficulty with balance or proprioception, or both. In more 
advanced cases, cerebral function may be altered as well, and 
on occasion dementia and other neuropsychiatric abnor
-
malities may be present. It is critical to recognize that the 
nonhematologic manifestations of vitamin B
12
 deficiency 
can be manifest despite a completely normal complete blood 
count.
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Patients are usually pale and may be mildly icteric or 
sallow. Typically, later in the disease course, neurologic 
examination may reveal decreased vibration and position 
sense or memory disturbance (or both).
The diagnosis of vitamin B
12
 deficiency is made by finding a 
low serum vitamin B
12
 (cobalamin) level. Whereas the nor
-
mal vitamin B
12
 level is greater than 210 pg/mL (155 pmol/L), 
most patients with overt vitamin B
12
 deficiency have serum 
levels less than 170 pg/mL (126 pmol/L), with symptomatic 
patients usually having levels less than 100 pg/mL (74 pmol/L). 
12
 deficiency in low or low-normal 
values (level of 170–210 pg/mL [126–155 pmol/L]) is best 
confirmed by finding an elevated level of serum methylma
-
lonic acid (greater than 1000 nmol/L) or homocysteine. Of 
note, elevated levels of serum methylmalonic acid can be due 
to kidney disease.
The anemia of vitamin B
12
 deficiency is typically moderate 
to severe with the MCV quite elevated (110–140 fL). However, 
it is possible to have vitamin B
12
 deficiency with a normal 
MCV from coexistent thalassemia or iron deficiency; in other 
cases, the reason is obscure. Patients with neurologic symp
-
toms and signs that suggest possible vitamin B
12
should be evaluated for that deficiency despite a normal MCV 
or the absence of anemia. The peripheral blood smear is 
megaloblastic, defined as red blood cells that appear as macro-
ovalocytes, (although other shape changes are usually present) 
and neutrophils that are hypersegmented (six [or greater]-
lobed neutrophils or mean neutrophil lobe counts greater 
than four). The reticulocyte count is reduced. Because vitamin 
B
12
 deficiency can affect all hematopoietic cell lines, the 
white blood cell count and the platelet count are reduced in 
Other laboratory abnormalities include elevated serum 
lactate dehydrogenase (LD) and a modest increase in indirect 
bilirubin. These two findings are a reflection of intramedullary 
destruction of developing abnormal erythroid cells.
Bone marrow morphology is characteristically abnormal. 
Marked erythroid hyperplasia is present as a response to 
defective red blood cell production (ineffective erythropoie
-
sis). Megaloblastic changes in the erythroid series include 
abnormally large cell size and asynchronous maturation of 
the nucleus and cytoplasm—ie, cytoplasmic maturation con
-
tinues while impaired DNA synthesis causes retarded nuclear 
development. In the myeloid series, giant bands and meta-
myelocytes are characteristically seen.
 
»
Vitamin B
12
 deficiency should be differentiated from folic 
acid deficiency, the other common cause of megaloblastic 
anemia, in which red blood cell folic acid is low while 
vitamin B
12
 levels are normal. The bone marrow findings of 
vitamin B
12
 deficiency are sometimes mistaken for a myelo
-
dysplastic syndrome (MDS) or even acute erythrocytic 
leukemia. The distinction between vitamin B
12
and myelodysplasia is based on the characteristic morphol
-
ogy and the low vitamin B
12
 and elevated methylmalonic 
acid levels.
 
»
Treatment
Initially, patients with vitamin B
12
 deficiency are usually 
treated with parenteral therapy. Intramuscular or subcuta
-
neous injections of 100 mcg of vitamin B
12
 are adequate for 
each dose. Replacement is usually given daily for the first 
week, weekly for the next month, and then monthly for life. 
The vitamin deficiency will recur if patients discontinue 
their therapy. Oral or sublingual methylcobalamin (1 mg/day) 
may be used instead of parenteral therapy once initial 
correction of the deficiency has occurred. Oral or sublin
-
gual replacement is effective, even in pernicious anemia, 
since approximately 1% of the dose is absorbed in the intes
-
tine via passive diffusion in the absence of active transport.

-
-
tine via passive diffusion in the absence of active transport. 
It must be continued indefinitely and serum vitamin B
12
 
levels must be monitored to ensure adequate replacement. 
For patients with neurologic symptoms caused by vitamin 
B
12
 deficiency, long-term parenteral vitamin B
12
 therapy is 
prudent. Because some patients are concurrently folic acid 
deficient from intestinal mucosal atrophy, simultaneous 
folic acid replacement (1 mg daily) is recommended for the 
first several months of vitamin B
12
 replacement.
Patients respond to therapy with an immediate improve
-
ment in their sense of well-being. Hypokalemia may com
-
plicate the first several days of therapy, particularly if the 
anemia is severe. A brisk reticulocytosis occurs in 5–7 days, 
and the hematologic picture normalizes in 2 months. Cen
-
tral nervous system symptoms and signs are reversible if 
they have been present for less than 6 months but are likely 
permanent if present for 6 months or longer. Red blood cell 
transfusions are rarely needed despite the severity of ane
-
mia, but when given, diuretics are also recommended to 
avoid heart failure because this anemia develops slowly and 
the plasma volume is increased at the time of diagnosis.
 
»
Bunn HF. Vitamin B
12
 and pernicious anemia—the dawn of 
molecular medicine. N Engl J Med. 2014 Feb 20;370(8):773–6. 
[PMID: 24552327]
Green R. Vitamin B(12) deficiency from the perspective of a prac
-
ticing hematologist. Blood. 2017 May 11;129(19):2603–11. 
[PMID: 28360040]
Shipton MJ et al. Vitamin B
12
 deficiency—a 21st century 
perspective. Clin Med (Lond). 2015 Apr;15(2):145–50. 
[PMID: 25824066]
FOLIC ACID DEFICIENCY
 
»
 
»
 
»
Reduced folic acid levels in red blood cells or 
serum.
 
»
Normal serum vitamin B
12
 level.
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»
“Folic acid” is the term commonly used for pteroylmono
-
glutamic acid. Folic acid is present in most fruits and vege
-
tables (especially citrus fruits and green leafy vegetables). 
Daily dietary requirements are 50–100 mcg. Total body 
stores of folic acid are approximately 5 mg, enough to supply 
requirements for 2–3 months.
The most common cause of folic acid deficiency is inad
-
equate dietary intake (Table 13–7). Alcoholic or anorectic 
patients, persons who do not eat fresh fruits and vegetables, 
and those who overcook their food are candidates for folic 
acid deficiency. Reduced folic acid absorption is rarely seen, 
since absorption occurs from the entire gastrointestinal 
tract. However, medications such as phenytoin, trimethoprim-
sulfamethoxazole, or sulfasalazine may interfere with its 
absorption. Folic acid absorption is poor in some patients 
with vitamin B
12
 deficiency due to gastrointestinal mucosal 
atrophy. Folic acid requirements are increased in pregnancy, 
hemolytic anemia, and exfoliative skin disease, and in these 
cases the increased requirements (5 to 10 times normal) may 
not be met by a normal diet.
 
»
The clinical features are similar to those of vitamin B
12
 
deficiency. However, isolated folic acid deficiency does not 
result in the neurologic abnormalities of vitamin B
12
 
Megaloblastic anemia is identical to anemia resulting from 
vitamin B
12
 deficiency. A red blood cell folic acid level 
below 150 ng/mL (340 nmol/L) is diagnostic of folic acid 
deficiency. Whether to order a serum or a red blood cell 
folate level remains unsettled since there are few, if any, 
data to support one test over the other. Usually the serum 
vitamin B
12
 level is normal, and it should always be mea
-
sured when folic acid deficiency is suspected. In some 
instances, folic acid deficiency is a consequence of the 
gastrointestinal mucosal megaloblastosis from vitamin B
12
 
Table 13–7.
 
Causes of folic acid deficiency.
Dietary deficiency
 
T
ropical sprue
 
M
edications: phenytoin, sulfasalazine, 
 
trimethoprim-sulfamethoxazole
 
C
oncurrent vitamin B
12
Increased requirement
 
Chr
 
Pregnancy
 
Exf
oliative skin disease
Excess loss: hemodialysis
Inhibition of reduction to active form
 
»
The megaloblastic anemia of folic acid deficiency should be 
differentiated from vitamin B
12
 deficiency by the finding of 
a normal vitamin B
12
 level and a reduced red blood cell (or 
serum) folic acid level. Alcoholic patients, who often have 
nutritional deficiency, may also have anemia of liver dis
-
ease. Pure anemia of liver disease causes a macrocytic ane
-
mia but does not produce megaloblastic morphologic 
changes in the peripheral blood; rather, target cells are pres
-
ent. Hypothyroidism is associated with mild macrocytosis 
and also with pernicious anemia.
 
»
Treatment
Folic acid deficiency is treated with daily oral folic acid 
 
(1 mg). The response is similar to that seen in the treatment 
of vitamin B
12
 deficiency, with rapid improvement and a 
sense of well-being, reticulocytosis in 5–7 days, and total 
correction of hematologic abnormalities within 2 months. 
Large doses of folic acid may produce hematologic responses 
in cases of vitamin B
12
 deficiency, but permit neurologic 
damage to progress; hence, obtaining a serum vitamin B
12
 
level in suspected folic acid deficiency is paramount.
 
»
Farrell CJ et al. Red cell or serum folate: what to do in clinical 
practice. Clin Chem Lab Med. 2013 Mar 1;51(3):555–69. 
[PMID: 23449524]
Green R et al. Megaloblastic anemias: nutritional and other 
causes. Med Clin North Am. 2017 Mar;101(2):297–317. 
[PMID: 28189172]
HEMOLYTIC ANEMIAS

The hemolytic anemias are a group of disorders in which red 
blood cell survival is reduced, either episodically or continu
-
ously. The bone marrow has the ability to increase erythroid 
production up to eightfold in response to reduced red cell 
survival, so anemia will be present only when the ability of 
the bone marrow to compensate is outstripped. This will 
occur when red cell survival is extremely short or when the 
ability of the bone marrow to compensate is impaired.
Hemolytic disorders are generally classified according to 
whether the defect is intrinsic to the red cell or due to some 
external factor (Table 13–8). Intrinsic defects have been 
described in all components of the red blood cell, including 
the membrane, enzyme systems, and hemoglobin; most of 
these disorders are hereditary. Hemolytic anemias due to 
external factors are immune and microangiopathic hemo
-
lytic anemias and infections of red blood cells.
Certain laboratory features are common to all hemolytic 
anemias. Haptoglobin, a normal plasma protein that binds 
and clears free hemoglobin released into plasma, may be 
depressed in hemolytic disorders. However, the haptoglobin 
level is influenced by many factors and is not always a reliable 
indicator of hemolysis, particularly in end-stage liver disease 
(its site of synthesis). When intravascular hemolysis occurs, 
transient hemoglobinemia ensues. Hemoglobin is filtered 
through the renal glomerulus and is usually reabsorbed by 
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tubular cells. Hemoglobinuria will be present only when the 
capacity for reabsorption of hemoglobin by renal tubular cells 
is exceeded. In the absence of hemoglobinuria, evidence for 
prior intravascular hemolysis is the presence of hemosiderin 
in shed renal tubular cells (positive urine hemosiderin). With 
severe intravascular hemolysis, hemoglobinemia and met
-
hemalbuminemia may be present. Hemolysis increases the 
indirect bilirubin, and the total bilirubin may rise to 4 mg/dL 
(68 mcmol/L) or more. Bilirubin levels higher than this may 
indicate some degree of hepatic dysfunction. Serum LD 
levels are strikingly elevated in cases of microangiopathic 
hemolysis (thrombotic thrombocytopenic purpura, 
hemolytic-uremic syndrome) and may be elevated in other 
hemolytic anemias.
PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA
 
»
Episodic hemoglobinuria.
 
»
Thrombosis is common.
 
»
Suspect in confusing cases of hemolytic anemia or 
pancytopenia.
 
»
Flow cytometry demonstrates deficiencies of 
CD55 and CD59.
 
»
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare 
acquired clonal hematopoietic stem cell disorder that 
results in abnormal sensitivity of the red blood cell mem
-
brane to lysis by complement and therefore hemolysis. Free 
hemoglobin is released into the blood that scavenges nitric 
oxide and promotes esophageal spasms, male erectile dys
-
function, kidney damage, and thrombosis. Patients with 
Table 13–8.
 
Classification of hemolytic anemias.
Intrinsic
 
M
embrane defects: hereditary spherocytosis, hereditary
 
 ellipt
ocytosis, paroxysmal nocturnal hemoglobinuria
 
Gly
colytic defects: pyruvate kinase deficiency, severe
 
hypophosphatemia
 
O
xidation vulnerability: glucose-6-phosphate dehydrogenase
 
deficienc
y, methemoglobinemia
 
Hemoglobinopa
thies: sickle cell syndromes, thalassemia,
 
unstable hemoglobins
, methemoglobinemia
Extrinsic
 
I
mmune: autoimmune, lymphoproliferative disease,
 
drug-induced
 
M
icroangiopathic: thrombotic thrombocytopenic purpura,
 
hemolytic-ur
emic syndrome, disseminated intravascular 
coagulation, valve hemolysis, metastatic adenocarcinoma, 
vasculitis, copper overload
 
Plasmodium, Clostridium, Borrelia
 
Burns
significant PNH live about 10–15 years following diagno
-
sis; thrombosis is the primary cause of death.
 
»
Classically, patients report episodic hemoglobinuria result
-
ing in reddish-brown urine. Hemoglobinuria is most often 
noticed in the first morning urine due to the drop in blood 
pH while sleeping (hypoventilation) that facilitates this 
hemolysis. Besides anemia, these patients are prone to 
thrombosis, especially within mesenteric and hepatic veins, 
central nervous system veins (sagittal vein), and skin vessels 
(with formation of painful nodules). As this is a hematopoi
-
etic stem cell disorder, PNH may appear de novo or arise in 
the setting of aplastic anemia or myelodysplasia with pos
-
sible progression to acute myeloid leukemia (AML). It is 
common that patients with idiopathic aplastic anemia have 
a small PNH clone (less than 2%) on blood or bone marrow 
analysis; this should not be considered PNH per se, espe
-
cially in the absence of a reticulocytosis or thrombosis.
Anemia is of variable severity and frequency, so reticulocy
-
tosis may or may not be present at any given time. Abnor
-
malities on the blood smear are nondiagnostic but may 
include macro-ovalocytes and polychromasia. Since the 
episodic hemolysis is mainly intravascular, urine hemosid
-
erin is a useful test. Serum LD is characteristically elevated. 
Iron deficiency is commonly present, related to chronic 
iron loss from hemoglobinuria.
The white blood cell count and platelet count may be 
decreased and are always decreased in the setting of aplastic

decreased and are always decreased in the setting of aplastic 
anemia. The best screening test is flow cytometry of blood 
erythrocytes, granulocytes, or monocytes to demonstrate 
deficiency of CD55 and CD59. The proportion of erythro
-
cytes deficient in these proteins might be low due to the 
ongoing destruction of affected erythrocytes. The FLAER 
assay (fluorescein-labeled proaerolysin) by flow cytometry 
is more sensitive. Bone marrow morphology is variable and 
may show either generalized hypoplasia or erythroid hyper
-
plasia or both. The bone marrow karyotype may be either 
normal or demonstrate a clonal abnormality.
 
»
Treatment
Many patients with PNH have mild disease not requiring 
intervention. In severe cases and in those occurring in the 
setting of myelodysplasia or previous aplastic anemia, alloge
-
neic hematopoietic stem cell transplantation may prove cura
-
tive. In patients with severe hemolysis (usually requiring red 
cell transfusions) or thrombosis (or both), treatment with 
eculizumab is warranted. Eculizumab is a humanized mono
-
clonal antibody against complement protein C5. Binding of 
eculizumab to C5 prevents its cleavage so the membrane 
attack complex cannot assemble. Eculizumab improves qual
-
ity of life and reduces hemolysis, transfusion requirements, 
fatigue, and thrombosis risk. Eculizumab is extremely expen
-
sive and increases the risk of 
Neisseria meningitidis
 infections; 
patients receiving the antibody must undergo meningococcal 
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vaccination (including vaccines for serogroup B) and penicil
-
lin (or equivalent) meningococcal prophylaxis. Iron replace
-
ment is indicated for treatment of iron deficiency when 
present, which may improve the anemia while also causing a 
transient increase in hemolysis. For unclear reasons, cortico
-
steroids are effective in decreasing hemolysis.
 
»
Most patients with PNH should be under the care of a 
hematologist.
Devalet B et al. Pathophysiology, diagnosis, and treatment of par
-
oxysmal nocturnal hemoglobinuria: a review. Eur J Haematol. 
2015 Sep;95(3):190–8. [PMID: 25753400]
GLUCOSE-6-PHOSPHATE DEHYDROGENASE 
DEFICIENCY
 
»
X-linked recessive disorder seen commonly in 
American black men.
 
»
Episodic hemolysis in response to oxidant drugs 
or infection.
 
»
Bite cells and blister cells on the peripheral blood 
smear.
 
»
Reduced levels of glucose-6-phosphate dehydro
-
genase between hemolytic episodes.
 
»
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is 
a hereditary enzyme defect that causes episodic hemolytic 
anemia because of the decreased ability of red blood cells 
to deal with oxidative stresses. G6PD deficiency leads to 
excess oxidized glutathione (hence, inadequate levels of 
reduced glutathione) that forces hemoglobin to denature 
and form precipitants called Heinz bodies. Heinz bodies 
cause red blood cell membrane damage, which leads to 
premature removal of these red blood cells by reticuloen
-
dothelial cells within the spleen (extravascular hemolysis).
Numerous G6PD isoenzymes have been described. The 
usual isoenzyme found in American blacks is designated 
G6PD-A and that found in whites is designated G6PD-B, 
both of which have normal function and stability and there
-
fore no hemolytic anemia. Ten to 15 percent of American 
blacks have the variant G6PD isoenzyme designated A–, in 
which there is both a reduction in normal enzyme activity 
and a reduction in its stability. The A– isoenzyme activity 
declines rapidly as the red blood cell ages past 40 days, a fact 
that explains the clinical findings in this disorder. More 
than 150 G6PD isoenzyme variants have been described, 
including some Mediterranean, Ashkenazi Jewish, and 
Asian variants with very low enzyme activity, episodic 
hemolysis, and exacerbations due to oxidizing substances 
including fava beans. Patients with G6PD deficiency seem 
to be protected from malaria parasitic infection, have less 
coronary artery disease, and possibly have fewer cancers 
and greater longevity.
 
»
G6PD deficiency is an X-linked disorder affecting 10–15% 
of American hemizygous black males and rare female 
homozygotes. Female carriers are rarely affected—only 
when an unusually high percentage of cells producing the 
normal enzyme are X-inactivated.
Patients are usually healthy, without chronic hemolytic 
anemia or splenomegaly. Hemolysis occurs episodically as 
a result of oxidative stress on the red blood cells, generated 
either by infection or exposure to certain medications. 
Medications initiating hemolysis that should be avoided 
include dapsone, methylene blue, phenazopyridine, prima
-
quine, rasburicase, toluidine blue, nitrofurantoin, trime
-
thoprim/sulfamethoxazole, sulfadiazine, and quinolones. 
Other medications, such as chloroquine, quinine, high-
dose aspirin, and isoniazid, have been implicated but are 
less certain as offenders since they are often given during 
infections. Even with continuous use of the offending 
medication, the hemolytic episode is self-limited because 
older red blood cells (with low enzyme activity) are 
removed and replaced with a population of young red 
blood cells (reticulocytes) with adequate functional levels 
of G6PD. Severe G6PD deficiency (as in Mediterranean 
variants) may produce a chronic hemolytic anemia.

Between hemolytic episodes, the blood is normal. During 
episodes of hemolysis, the hemoglobin rarely falls below 
 
8 g/dL (80 g/L), and there is reticulocytosis and increased 
serum indirect bilirubin. The peripheral blood cell smear 
often reveals a small number of “bite” cells—cells that appear 
to have had a bite taken out of their periphery, or “blister” 
cells. This indicates pitting of precipitated membrane hemo
-
globin aggregates by the splenic macrophages. Heinz bodies 
may be demonstrated by staining a peripheral blood smear 
with cresyl violet; they are not visible on the usual Wright-
Giemsa–stained blood smear. Specific enzyme assays for 
G6PD reveal a low level but may be falsely normal if they are 
performed during or shortly after a hemolytic episode during 
the period of reticulocytosis. In these cases, the enzyme assays 
should be repeated weeks after hemolysis has resolved. In 
severe cases of G6PD deficiency, enzyme levels are always low.
 
»
Treatment
No treatment is necessary except to avoid known oxidant 
Luzzatto L et al. Glucose-6-phosphate dehydrogenase deficiency. 
Hematol Oncol Clin North Am. 2016 Apr;30(2):373–93. 
[PMID: 27040960]
Luzzatto L et al. G6PD deficiency: a classic example of pharma
-
cogenetics with on-going clinical implications. Br J Haematol. 
2014 Feb;164(4):469–80. [PMID: 24372186]
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SICKLE CELL ANEMIA & RELATED 
SYNDROMES
 
»
Recurrent pain episodes.
 
»
Positive family history and lifelong history of 
hemolytic anemia.
 
»
Irreversibly sickled cells on peripheral blood 
smear.
 
»
Hemoglobin S is the major hemoglobin seen on 
electrophoresis.
 
»
Sickle cell anemia is an autosomal recessive disorder in 
which an abnormal hemoglobin leads to chronic hemo
-
lytic anemia with numerous clinical consequences. A 
single DNA base change leads to an amino acid substitu
-
tion of valine for glutamine in the sixth position on the 
beta-globin chain. The abnormal beta chain is designated 
beta
s
 and the tetramer of alpha-2beta
s
-2 is designated 
hemoglobin S. Hemoglobin S is unstable and polymerizes 
in the setting of various stressors, including hypoxemia 
and acidosis, leading to the formation of sickled red blood 
cells. Sickled cells result in hemolysis and the release of 
ATP , which is converted to adenosine. Adenosine binds to 
its receptor (A2B) resulting in the production of 
2,3-biphosphoglycerate and the induction of more sick
-
ling and to its binding to receptor (A2A) on natural killer 
cells resulting in pulmonary inflammation. The free 
hemoglobin from hemolysis scavenges nitric oxide caus
-
ing endothelial dysfunction, vascular injury, and pulmo
-
The rate of sickling is influenced by the intracellular 
concentration of hemoglobin S and by the presence of 
other hemoglobins within the cell. Hemoglobin F cannot 
participate in polymer formation, and its presence mark
-
edly retards sickling. Factors that increase sickling are red 
blood cell dehydration and factors that lead to formation of 
deoxyhemoglobin S (eg, acidosis and hypoxemia) either 
systemic or local in tissues. Hemolytic crises may be related 
to splenic sequestration of sickled cells (primarily in child
-
hood before the spleen has been infarcted as a result of 
repeated sickling) or with coexistent disorders such as 
G6PD deficiency.
The beta
S
 gene is carried in 8% of American blacks, and 
1 of 400 American black children will be born with sickle 
cell anemia; prenatal diagnosis is available when sickle cell 
anemia is suspected. Genetic counseling should be made 
available to patients.
 
»
The disorder has its onset during the first year of life, when 
hemoglobin F levels fall as a signal is sent to switch from 
production of gamma-globin to beta-globin. Chronic 
hemolytic anemia produces jaundice, pigment (calcium 
bilirubinate) gallstones, splenomegaly (early in life), and 
poorly healing ulcers over the lower tibia. Life-threatening 
severe anemia can occur during hemolytic or aplastic crises, 
the latter generally associated with viral or other infection 
or by folic acid deficiency causing reduced erythropoiesis, 
or infection caused by immunoincompetence from 
hyposplenism.
Acute painful episodes due to acute vaso-occlusion 
from clusters of sickled red cells may occur spontaneously 
or be provoked by infection, dehydration, or hypoxia. 
Common sites of acute painful episodes include the spine 
and long appendicular and thoracic bones. These episodes 
last hours to days and may produce low-grade fever. Acute 
vaso-occlusion may cause strokes due to sagittal sinus 
venous thrombosis or to bland or hemorrhagic central 
nervous system arterial ischemia and may also cause pria
-
pism. Vaso-occlusive episodes are not associated with 
increased hemolysis.
Repeated episodes of vascular occlusion especially 
affect the heart, lungs, and liver. The acute chest syndrome 
is characterized by acute chest pain, hypoxemia and pul
-
monary infiltrates on a chest radiograph and must be dis
-
tinguished from an infectious pneumonia. Ischemic 
necrosis of bones may occur, rendering the bone suscepti
-
ble to osteomyelitis due to salmonellae and (somewhat less

-
-
ble to osteomyelitis due to salmonellae and (somewhat less 
commonly) staphylococci. Infarction of the papillae of the 
renal medulla causes renal tubular concentrating defects 
and gross hematuria, more often encountered in sickle cell 
trait than in sickle cell anemia. Retinopathy similar to that 
noted in diabetes mellitus is often present and may lead to 
visual impairment. Pulmonary hypertension may develop 
and is associated with a poor prognosis. These patients are 
prone to delayed puberty. An increased incidence of infec
-
tion is related to hyposplenism as well as to defects in the 
alternate complement pathway.
On examination, patients are often chronically ill and 
jaundiced. There is hepatomegaly, but the spleen is not 
palpable in adult life. The heart is enlarged with a hyperdy
-
namic precordium and systolic murmurs and, in some 
cases, a pronounced increase in P2. Nonhealing ulcers of 
the lower leg and retinopathy may be present.
Chronic hemolytic anemia is present. The hematocrit is 
usually 20–30%. The peripheral blood smear is characteris
-
tically abnormal, with irreversibly sickled cells comprising 
5–50% of red cells. Other findings include reticulocytosis 
(10–25%), nucleated red blood cells, and hallmarks of 
hyposplenism such as Howell-Jolly bodies and target cells. 
The white blood cell count is characteristically elevated to 
12,000–15,000/mcL, and reactive thrombocytosis may 
occur. Indirect bilirubin levels are high.
The diagnosis of sickle cell anemia is confirmed by hemo
-
globin electrophoresis (Table 13–9). Hemoglobin S will usually 
comprise 85–98% of hemoglobin. In homozygous S disease, 
no hemoglobin A will be present. Hemoglobin F levels are 
sometimes increased, and high hemoglobin F levels are associ
-
ated with a more benign clinical course. Patients with 
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CMDT 2019
S-beta
+
-thalassemia and SS alpha-thalassemia also have a 
more benign clinical course than sickle cell anemia (SS) 
patients.
 
»
Treatment
When allogeneic hematopoietic stem cell transplantation is 
performed before the onset of significant end-organ dam
-
age, it can cure more than 80% of children with sickle cell 
anemia who have suitable HLA-matched donors. Transplan
-
tation remains investigational in adults. Other therapies 
modulate disease severity: cytotoxic agents, such as hydroxy
-
urea, increase hemoglobin F levels epigenetically. Hydroxy
-
urea (500–750 mg orally daily) reduces the frequency of 
painful crises in patients whose quality of life is disrupted by 
frequent pain crises (three or more per year). Long-term 
follow-up of patients taking hydroxyurea demonstrates it 
improves overall survival and quality of life with little evi
-
dence for secondary malignancy. The use of omega-3 (n-3) 
fatty acid supplementation may reduce vaso-occlusive epi
-
sodes and reduce transfusion needs in patients with sickle 
cell anemia. L-glutamine has been shown to favorably 
modulate sickle pain crises and acute chest syndrome.
Supportive care is the mainstay of treatment for sickle 
cell anemia. Patients are maintained on folic acid supple
-
mentation (1 mg orally daily) and given transfusions for 
aplastic or hemolytic crises. When acute painful episodes 
occur, precipitating factors should be identified and infec
-
tions treated if present. The patient should be kept well 
hydrated, given generous analgesics, and supplied oxygen if 
hypoxic. Pneumococcal vaccination reduces the incidence 
of infections with this pathogen while hydroxyurea and 
L-glutamine reduce hospitalizations for acute pain. 
Angiotensin-converting enzyme inhibitors are recom
-
mended in patients with microalbuminuria.
Exchange transfusions are indicated for the treatment 
of severe acute vaso-occlusive crises, intractable pain cri
-
ses, acute chest syndrome, priapism, and stroke. Long-term 
transfusion therapy has been shown to be effective in 
reducing the risk of recurrent stroke in children. It has 
been recommended that children with SS who are aged 
2–16 years have annual transcranial ultrasounds and, if the 
Doppler velocity is abnormal (200 cm/s or greater), the 
clinician should strongly consider beginning transfusions 
to prevent stroke. Iron chelation is needed for those on 
chronic transfusion therapy.
 
»
Prognosis
Sickle cell anemia becomes a chronic multisystem disease, 
leading to organ failure that may result in death. With 
improved supportive care, average life expectancy is now 
between 40 and 50 years of age.
 
»
Patients with sickle cell anemia should have their care 
coordinated with a hematologist and should be referred to 
a Comprehensive Sickle Cell Center, if one is available.
 
»
Patients should be admitted for management of acute chest 
crises, for aplastic crisis, or for painful episodes that do not 
respond to outpatient care.
King A et al. Evidence-based focused review of the status of 
hematopoietic stem cell transplantation as treatment of sickle 
cell disease and thalassemia. Blood. 2014 May 15;
 
123(20):3089–94. [PMID: 24511087]
McGann PT et al. Hydroxyurea therapy for sickle cell anemia. 
Expert Opin Drug Saf. 2015 Nov;14(11):1749–58. [PMID: 
26366626]
Novelli EM et al. Crises in sickle cell disease. 2016 Apr;
 
149(4):1082–93. [PMID: 26836899]
Y awn BP et al. Management of sickle cell disease: summary of 
the 2014 evidence-based report by expert panel members. 
JAMA. 2014 Sep 10;312(10):1033–48. Erratum in: JAMA. 
2014 Nov 12;312(18):1932. [PMID: 25203083]
SICKLE CELL TRAIT
People with the heterozygous hemoglobin genotype AS 
have sickle cell trait. These persons are hematologically 
normal, with no anemia and normal red blood cells on 
peripheral blood smear. Hemoglobin electrophoresis will 
reveal that approximately 40% of hemoglobin is hemoglo
-

-
bin S (Table 13–9). People with sickle cell trait experience 
more rhabdomyolysis during vigorous exercise but do not 
Table 13–9.
 
Hemoglobin distribution in sickle cell syndromes.
Genotype
Clinical Diagnosis
h
b A
h
b S
h
b A
2
h
b F
AA
Normal
97–99%
0%
1–2%
< 1%
AS
Sickle trait
60%
40%
1–2%
< 1%
AS, alpha-thalassemia
Sickle trait, alpha-thalassemia
70–75%
25–30%
1–2%
< 1%
SS
Sickle cell anemia
0%
86–98%
1–3%
5–15%
SS, alpha-thalassemia (3 genes)
SS alpha-thalassemia, silent
0%
90%
3%
7–9%
SS, alpha-thalassemia (2 genes)
SS alpha-thalassemia, trait
0%
80%
3%
11–21%
S, beta
0
-thalassemia
Sickle beta
0
0%
70–80%
3–5%
10–20%
S, beta
+
+
10–20%
60–75%
3–5%
10–20%
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have increased mortality compared to the general popula
-
tion. They may be at increased risk for venous thromboem
-
bolism. Chronic sickling of red blood cells in the acidotic 
renal medulla results in microscopic and gross hematuria, 
hyposthenuria (poor urine concentrating ability), and pos
-
sibly chronic kidney disease. No treatment is necessary but 
genetic counseling is recommended.
Thoreson CK et al. Sickle cell trait from a metabolic, renal, and 
vascular perspective: linking history, knowledge, and health. J 
Racial Ethn Health Disparities. 2015 Sep;2(3):330–5. [PMID: 
26322267]
SICKLE THALASSEMIA
Patients with homozygous sickle cell anemia and alpha-
thalassemia have less vigorous hemolysis and run higher 
hemoglobins than SS patients due to reduced red blood cell 
sickling related to a lower hemoglobin concentration within 
the red blood cell and higher hemoglobin F levels (Table 13–9). 
The MCV is low, and the red cells are hypochromic.
Patients who are compound heterozygotes for beta
s
 and 
beta-thalassemia are clinically affected with sickle cell syn
-
dromes. Sickle beta
0
-thalassemia is clinically very similar 
to homozygous SS disease. Vaso-occlusive crises may be 
somewhat less severe, and the spleen is not always infarcted. 
The MCV is low, in contrast to the normal MCV of sickle 
cell anemia. Hemoglobin electrophoresis reveals no hemo
-
globin A but will show an increase in hemoglobins A
2
 and 
F (Table 13–9).
+
-thalassemia is a milder disorder than 
homozygous SS disease, with fewer pain episodes but more 
acute chest syndrome than sickle beta
0
-thalassemia. The 
spleen is usually palpable. The hemolytic anemia is less 
severe, and the hematocrit is usually 30–38%, with reticu
-
locytes of 5–10%. Hemoglobin electrophoresis shows the 
presence of some hemoglobin A and elevated hemoglobins 
A
2
 and F (Table 13–9). The MCV is low.
Benites BD et al. Sickle cell/β-thalassemia: Comparison of Sβ(0) 
and Sβ(+) Brazilian patients followed at a single institution. 
Hematology. 2016 Dec;21(10):623–9. [PMID: 27237196]
Marsella M et al. Transfusional iron overload and iron chelation 
therapy in thalassemia major and sickle cell disease. Hematol 
Oncol Clin North Am. 2014 Aug;28(4):703–27. [PMID: 
25064709]
Y acobovich J et al. Thalassemia major and sickle cell disease in 
adolescents and young adults. Acta Haematol. 2014;132
 
(3–4):340–7. [PMID: 25228560]
AUTOIMMUNE HEMOLYTIC ANEMIA
 
»
Acquired hemolytic anemia caused by IgG 
autoantibody.
 
»
Spherocytes and reticulocytosis on peripheral 
blood smear.
 
»
Positive antiglobulin (Coombs) test.
 
»
Autoimmune hemolytic anemia is an acquired disorder in 
which an IgG autoantibody is formed that binds to a red 
blood cell membrane protein and does so most avidly at 
body temperature (ie, a “warm” autoantibody). The anti
-
body is most commonly directed against a basic compo
-
nent of the Rh system present on most human red blood 
cells. When IgG antibodies coat the red blood cell, the Fc 
portion of the antibody is recognized by macrophages 
present in the spleen and other portions of the reticuloen
-
dothelial system. The interaction between splenic macro
-
phages and the antibody-coated red blood cell results in 
removal of red blood cell membrane and the formation of 
a spherocyte due to the decrease in surface-to-volume ratio 
of the surviving red blood cell. These spherocytic cells have 
decreased deformability and are unable to squeeze through 
the 2-mcm fenestrations of splenic sinusoids and become 
trapped in the red pulp of the spleen. When large amounts 
of IgG are present on red blood cells, complement may be 
fixed. Direct complement lysis of cells is rare, but the 
presence of C3b on the surface of red blood cells allows 
Kupffer cells in the liver to participate in the hemolytic 
process via C3b receptors. The destruction of red blood

process via C3b receptors. The destruction of red blood 
cells in the spleen and liver designates this as extravascular 
hemolysis.
Approximately one-half of all cases of autoimmune 
hemolytic anemia are idiopathic. The disorder may also be 
seen in association with systemic lupus erythematosus, 
other rheumatic disorders, chronic lymphocytic leukemia 
(CLL), or lymphomas. It must be distinguished from drug-
induced hemolytic anemia. When penicillin (or other 
medications, especially cefotetan, ceftriaxone, and piper
-
acillin) coats the red blood cell membrane, the autoanti
-
body is directed against the membrane-drug complex. 
Fludarabine, an antineoplastic, causes autoimmune hemo
-
lytic anemia through its immunosuppression; there is 
defective self- versus non–self-immune surveillance per
-
mitting the escape of a B-cell clone, which produces the 
offending autoantibody.
 
»
Autoimmune hemolytic anemia typically produces an ane
-
mia of rapid onset that may be life-threatening. Patients 
complain of fatigue and dyspnea and may present with 
angina pectoris or heart failure. On examination, jaundice 
and splenomegaly are usually present.
The anemia is of variable degree but may be very severe, 
with hematocrit of less than 10%. Reticulocytosis is pres
-
ent, and spherocytes are seen on the peripheral blood 
smear. In cases of severe hemolysis, the stressed bone mar
-
row may also release nucleated red blood cells. As with 
other hemolytic disorders, the serum indirect bilirubin is 
increased and the haptoglobin is low. Approximately 10% 
of patients with autoimmune hemolytic anemia have coin
-
cident immune thrombocytopenia (Evans syndrome).
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The antiglobulin (Coombs) test forms the basis for diag
-
nosis. The Coombs reagent is a rabbit IgM antibody raised 
against human IgG or human complement. The direct anti
-
globulin (Coombs) test (DAT) is performed by mixing the 
patient’s red blood cells with the Coombs reagent and look
-
ing for agglutination, which indicates the presence of anti
-
body or complement or both on the red blood cell surface. 
The indirect antiglobulin (Coombs) test is performed by 
mixing the patient’s serum with a panel of type O red blood 
cells. After incubation of the test serum and panel red blood 
cells, the Coombs reagent is added. Agglutination in this 
system indicates the presence of free antibody (autoantibody 
or alloantibody) in the patient’s serum.
The direct antiglobulin test is positive (for IgG, comple
-
ment, or both) in about 90% of patients with autoimmune 
hemolytic anemia. The indirect antiglobulin test may or 
may not be positive. A positive indirect antiglobulin test 
indicates the presence of a large amount of autoantibody 
that has saturated binding sites in the red blood cell and 
consequently appears in the serum. Because the patient’s 
serum usually contains the autoantibody, it may be difficult 
to obtain a “compatible” cross-match with homologous red 
blood cells for transfusions since the cross-match indicates 
the possible presence (true or false) of a red blood cell 
“alloantibody. ”
 
»
Treatment
Initial treatment consists of prednisone, 1–2 mg/kg/day 
orally in divided doses. Patients with DAT-negative and 
DAT-positive autoimmune hemolysis respond equally well 
to corticosteroids. Transfused red blood cells will survive 
similarly to the patient’s own red blood cells. Because of dif
-
ficulty in performing the cross-match, possible “incompatible” 
blood may need to be given. Decisions regarding transfu
-
sions should be made in consultation with a hematologist 
and a blood bank specialist. Death from cardiovascular 
collapse can occur in the setting of rapid hemolysis. In 
patients with rapid hemolysis, therapeutic plasmapheresis 
should be performed early in management to remove auto
-
antibodies. If prednisone is ineffective or if the disease 
recurs on tapering the dose, splenectomy should be consid
-
ered, which may cure the disorder. Patients with autoim
-
mune hemolytic anemia refractory to prednisone and 
splenectomy may also be treated with a variety of agents. 
Treatment with rituximab, a monoclonal antibody against 
the B cell antigen CD20, is effective in some cases. The sug
-
gested dose is 375 mg/m
2
 intravenously weekly for 4 weeks. 
Rituximab is used in conjunction with corticosteroids as 
initial therapy in some patients with severe disease. Dan
-
azol, 400–800 mg/day orally, is less often effective than in 
immune thrombocytopenia but is well suited for long-term 
use because of its low toxicity profile. Immunosuppressive 
agents, including cyclophosphamide, vincristine, azathio
-
prine, mycophenolate mofetil, alemtuzumab (an anti-CD52 
antibody), or cyclosporine, may also be used. High-dose 
intravenous immune globulin (1 g/kg daily for 2 days) may 
be effective in controlling hemolysis. The benefit is short-
lived (1–3 weeks), and the medication is very expensive. 
The long-term prognosis for patients with this disorder is 
good, especially if there is no other underlying autoimmune 
disorder or lymphoproliferative disorder. Treatment of an 
associated lymphoproliferative disorder will also treat the 
 
»
Patients with autoimmune hemolytic anemia should be 
referred to a hematologist for confirmation of the diagnosis 
and subsequent care.
 
»
Patients should be hospitalized for symptomatic anemia or 
rapidly falling hemoglobin levels.
Bass GF et al. Diagnosis and classification of autoimmune hemo
-
lytic anemia. Autoimmun Rev. 2014 Apr–May;13(4–5):560–4. 
[PMID: 24418298]

-
Dierickx D et al. The role of rituximab in adults with warm anti
-
body autoimmune hemolytic anemia. Blood. 2015 May 21;
 
125(21):3223–9. [PMID: 25827833]
Go RS et al. How I treat autoimmune hemolytic anemia. Blood. 
2017 Jun 1;129(22):2971–9. [PMID: 28360039]
Kalfa TA. Warm antibody autoimmune hemolytic anemia. 
Hematology Am Soc Hematol Educ Program. 2016 Dec 2;
 
2016(1):690–7. [PMID: 27913548]
COLD AGGLUTININ DISEASE
 
»
Increased reticulocytes on peripheral blood smear.
 
»
Antiglobulin (Coombs) test positive only for 
complement.
 
»
Positive cold agglutinin titer.
 
»
Cold agglutinin disease is an acquired hemolytic anemia 
due to an IgM autoantibody (called a “cold agglutinin”) 
usually directed against the I/i antigen on red blood cells. 
These IgM autoantibodies characteristically will react 
poorly with cells at 37°C but avidly at lower temperatures, 
usually at 0–4°C (ie, “cold” autoantibody). Since the blood 
temperature (even in the most peripheral parts of the 
body) rarely goes lower than 20°C, only cold autoantibod
-
ies reactive at relatively higher temperatures will produce 
clinical effects. Hemolysis results indirectly from attach
-
ment of IgM, which in the cooler parts of the circulation 
(fingers, nose, ears) binds and fixes complement. When the 
red blood cell returns to a warmer temperature, the IgM 
antibody dissociates, leaving complement on the cell. 
Complement lysis of red blood cells rarely occurs. Rather, 
C3b, present on the red blood cells, is recognized by 
Kupffer cells (which have receptors for C3b), and red blood 
cell sequestration and destruction in the liver ensues 
(extravascular hemolysis). In some cases, the complement 
membrane attack complex forms, lysing the red blood cells 
(intravascular hemolysis).
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Most cases of chronic cold agglutinin disease are idio
-
pathic. Others occur in association with Waldenström 
macroglobulinemia, lymphoma, or CLL, in which a 
monoclonal IgM paraprotein is produced. Acute postin
-
fectious cold agglutinin disease occurs following myco
-
plasmal pneumonia or viral infection (infectious 
mononucleosis, measles, mumps, or cytomegalovirus 
[CMV] with autoantibody directed against antigen i 
rather than I).
 
»
In chronic cold agglutinin disease, symptoms related to red 
blood cell agglutination occur on exposure to cold, and 
patients may complain of mottled or numb fingers or toes, 
acrocyanosis, episodic low back pain, and dark-colored urine. 
Hemolytic anemia is occasionally severe, but episodic hemo
-
globinuria may occur on exposure to cold. The hemolytic 
anemia in acute postinfectious syndromes is rarely severe.
Mild anemia is present with reticulocytosis and rarely 
spherocytes. The blood smear made at room temperature 
shows agglutinated red blood cells (there is no agglutina
-
tion on a blood smear made at body temperature). The 
direct antiglobulin (Coombs) test will be positive for com
-
plement only. Serum cold agglutinin titer will semi-
quantitate the autoantibody. A monoclonal IgM is often 
found on serum protein electrophoresis and confirmed by 
serum immunoelectrophoresis. There is indirect hyperbili
-
rubinemia and the haptoglobin is low during periods of 
 
»
Treatment
Treatment is largely symptomatic, based on avoiding expo
-
sure to cold. Splenectomy and prednisone are usually inef
-
fective (except when associated with a lymphoproliferative 
disorder) since hemolysis takes place in the liver and blood 
stream. Rituximab is the treatment of choice. The dose is 
375 mg/m
2
 intravenously weekly for 4 weeks. Relapses may 
be effectively re-treated. High-dose intravenous immuno
-
globulin (2 g/kg) may be effective temporarily, but it is 
rarely used because of the high cost and short duration of 
benefit. Patients with severe disease may be treated with 
cytotoxic agents, such as cyclophosphamide, fludarabine, 
or bortezomib, or with immunosuppressive agents, such as 
cyclosporine. As in warm IgG-mediated autoimmune 
hemolysis, it may be difficult to find compatible blood for 
transfusion. Red blood cells should be transfused through 
an in-line blood warmer.
Berentsen S et al. Cold agglutinin-mediated autoimmune hemo
-
lytic anemia. Hematol Oncol Clin North Am. 2015 Jun;
 
29(3):455–71. [PMID: 26043385]
Chapin J et al. The role of complement activation in thrombosis 
and hemolytic anemias. Transfus Apher Sci. 2016 Apr;
 
54(2):191–8. [PMID: 27156108]
Table 13–10.
 
Causes of aplastic anemia.
Autoimmune: idiopathic, systemic lupus erythematosus
Congenital: defects in telomere length maintenance or DNA repair
Chemotherapy, radiotherapy
Toxins: benzene, toluene, insecticides
Medications: chloramphenicol, gold salts, sulfonamides, phenytoin, 
carbamazepine, quinacrine, tolbutamide
Post-viral hepatitis (A, B, C, E, G, non-A through -G)
Non-hepatitis viruses (EBV, parvovirus, CMV, echovirus 3, others)
Pregnancy
Paroxysmal nocturnal hemoglobinuria
EBV, Epstein-Barr virus; CMV, cytomegalovirus.
APLASTIC ANEMIA
 
»
Pancytopenia.
 
»
No abnormal hematopoietic cells seen in blood or 
bone marrow.
 
»
Hypocellular bone marrow.
 
»
Aplastic anemia is a condition of bone marrow failure 
that arises from suppression of, or injury to, the hemato
-
poietic stem cell. The bone marrow becomes hypoplastic, 
fails to produce mature blood cells, and pancytopenia 
develops.
There are a number of causes of aplastic anemia 
(Table 13–10). Direct hematopoietic stem cell injury may 
be caused by radiation, chemotherapy, toxins, or phar
-

develops.
-
macologic agents. Systemic lupus erythematosus may 
rarely cause suppression of the hematopoietic stem cell 
by an IgG autoantibody directed against the hematopoi
-
etic stem cell. However, the most common pathogenesis 
of aplastic anemia appears to be autoimmune suppression 
of hematopoiesis by a T-cell-mediated cellular mechanism, 
so called idiopathic aplastic anemia. In some cases of 
idiopathic aplastic anemia, defects in maintenance of the 
hematopoietic stem cell telomere length (dyskeratosis 
congenita) or in DNA repair pathways (Fanconi anemia) 
have been identified and are likely linked to both the 
initiation of bone marrow failure and the propensity to 
later progress to myelodysplasia, PNH, or AML. Complex 
detrimental immune responses to viruses can also cause 
aplastic anemia.
 
»
Patients come to medical attention because of the conse
-
quences of bone marrow failure. Anemia leads to symptoms 
of weakness and fatigue, neutropenia causes vulnerability to 
bacterial or fungal infections, and thrombocytopenia results 
CMDT19_Ch13_p0510-p0555.indd   526

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in mucosal and skin bleeding. Physical examination may 
reveal signs of pallor, purpura, and petechiae. Other abnor
-
malities such as hepatosplenomegaly, lymphadenopathy, or 
bone tenderness should 
not
 be present, and their presence 
should lead to questioning the diagnosis.
The hallmark of aplastic anemia is pancytopenia. However, 
early in the evolution of aplastic anemia, only one or two 
cell lines may be reduced.
Anemia may be severe and is always associated with 
reticulocytopenia. Red blood cell morphology is unre
-
markable, but there may be mild macrocytosis (increased 
MCV). Neutrophils and platelets are reduced in number, 
and no immature or abnormal forms are seen on the blood 
smear. The bone marrow aspirate and the bone marrow 
biopsy appear hypocellular, with only scant amounts of 
morphologically normal hematopoietic progenitors. The 
prior dictum that the bone marrow karyotype should be 
normal (or germline if normal variant) has evolved and 
some clonal abnormalities or other genetic aberrations 
may be present even in the setting of idiopathic aplastic 
anemia.
 
»
Aplastic anemia must be differentiated from other causes of 
pancytopenia (Table 13–11). Hypocellular forms of myelo
-
dysplasia or acute leukemia may occasionally be confused 
with aplastic anemia. These are differentiated by the presence 
of cellular morphologic abnormalities, increased percentage 
of blasts, or abnormal karyotype in bone marrow cells 
typical of MDS or acute leukemia. Hairy cell leukemia has 
been misdiagnosed as aplastic anemia and should be recog
-
nized by the presence of splenomegaly and by abnormal 
“hairy” lymphoid cells in a hypocellular bone marrow biopsy. 
Pancytopenia with a normocellular bone marrow may be due 
to systemic lupus erythematosus, disseminated infection, 
hypersplenism, nutritional (eg, vitamin B
12
 or folate) defi
-
ciency, or myelodysplasia. Isolated thrombocytopenia may 
Table 13–11.
 
Causes of pancytopenia.
p
rimar
y bone marrow disorders
 
Aplastic 
anemia
 
A
cute leukemia
 
Chr
onic idiopathic myelofibrosis
 
I
nfiltrative disease: lymphoma, myeloma, carcinoma, hairy cell
 
leuk
emia, etc
Non–primary bone marrow disorders
 
H
ypersplenism (with or without portal hypertension)
 
S
ystemic lupus erythematosus
 
I
nfection: tuberculosis, HIV, leishmaniasis, brucellosis, CMV, 
 
par
vovirus B19
 
Nutritional 
deficiency (megaloblastic anemia)
 
C
ytotoxic chemotherapy
 
Ionizing 
radiation
CMV, cytomegalovirus.
occur early as aplastic anemia develops and may be confused 
with immune thrombocytopenia.
 
»
Treatment
Mild cases of aplastic anemia may be treated with support
-
ive care, including erythropoietic (epoetin or darbepoetin) 
or myeloid (filgrastim or sargramostim) growth factors, or 
both. Red blood cell transfusions and platelet transfusions 
are given as necessary, and antibiotics are used to treat 
Severe aplastic anemia is defined by a neutrophil count 
of less than 500/mcL, platelets less than 20,000/mcL, retic
-
ulocytes less than 1%, and bone marrow cellularity less 
than 20%. The treatment of choice for young adults (under 
age 40 years) who have an HLA-matched sibling is alloge
-
neic bone marrow transplantation. Children or young 
adults may also benefit from allogeneic bone marrow 
transplantation using an unrelated donor. Because of the 
increased risks associated with unrelated donor allogeneic 
bone marrow transplantation compared to sibling donors, 
this treatment is usually reserved for patients who have not 
responded to immunosuppressive therapy.
For adults over age 40 years or those without HLA-
matched hematopoietic stem cell donors, the treatment of 
choice for severe aplastic anemia is immunosuppression 
with equine antithymocyte globulin (ATG) plus cyclospo
-
rine. Equine ATG is given in the hospital in conjunction

-
rine. Equine ATG is given in the hospital in conjunction 
with transfusion and antibiotic support. A proven regimen 
is equine ATG 40 mg/kg/day intravenously for 4 days 
in combination with cyclosporine, 6 mg/kg orally twice 
daily. Equine ATG is superior to rabbit ATG, resulting in a 
higher response rate and better survival. ATG should be 
used in combination with corticosteroids (prednisone or 
methylprednisolone 1–2 mg/kg/day orally for 1 week, 
followed by a taper over 2 weeks) to avoid ATG infusion 
reactions and serum sickness. Responses usually occur in 
1–3 months and are usually only partial, but the blood 
counts rise high enough to give patients a safe and transfu
-
sion-free life. The full benefit of immunosuppression is 
generally assessed at 4 months post-equine ATG. Cyclo
-
sporine is maintained at full dose for 6 months and then 
stopped in responding patients. Androgens (such as 
fluoxymesterone 10–20 mg/day orally in divided doses) 
have been widely used in the past, with a low response rate, 
and may be considered in mild cases. The thrombopoietin 
mimetic, eltrombopag, may help increase platelets (and 
also red blood cells and white blood cells) in patients with 
refractory aplastic anemia.
 
»
Patients with severe aplastic anemia have a rapidly fatal ill
-
ness if left untreated. Allogeneic bone marrow transplant 
from an HLA-matched sibling donor produces survival 
rates of over 80% in recipients under 20 years old and of 
about 65–70% in those 20 to 50 years old. Respective sur
-
vival rates drop 10–15% when the donor is HLA-matched 
but unrelated. Equine ATG-cyclosporine immunosuppres
-
sive treatment leads to a response in approximately 70% of 
patients (including those with hepatitis virus–associated 
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aplastic anemia). Up to one-third of patients will relapse 
with aplastic anemia after ATG-based therapy. Clonal 
hematologic disorders, such as PNH, AML, or myelodys
-
plasia, may develop in one-quarter of patients treated with 
immunosuppressive therapy after 10 years of follow-up. 
Factors that predict response to ATG-cyclosporine therapy 
are patient’s age, reticulocyte count, lymphocyte count, and 
age-adjusted telomere length of leukocytes at the time of 
 
»
All patients should be referred to a hematologist.
 
»
Admission is necessary for treatment of neutropenic 
infection, the administration of ATG, or allogeneic bone 
marrow transplantation.
Bacigalupo A et al. Bone marrow transplantation versus immu
-
nosuppressive therapy in patients with acquired severe aplas
-
tic anemia. Int J Hematol. 2016 Aug;104(2):168–74. [PMID: 
27278666]
Lum SH et al. Eltrombopag for the treatment of aplastic anemia: 
current perspectives. Drug Des Devel Ther. 2016 Sep 13;
 
10:2833–43. [PMID: 27695288]
Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. 
Blood. 2016 Jul 21;128(3):337–47. [PMID: 27121470]
 
º
NEU
t
RO
p
ENIA
 
»
Neutrophils less than 1800/mcL (1.8 × 10
9
/L).
 
»
Severe neutropenia if neutrophils below 500/mcL 
(0.5 × 10
9
/L).
 
»
Neutropenia is present when the absolute neutrophil count 
is less than 1800/mcL (1.8 × 10
9
/L), although blacks, 
Asians, and other specific ethnic groups may have normal 
neutrophil counts as low as 1200/mcL (1.2 × 10
9
/L). The 
neutropenic patient is increasingly vulnerable to infection 
by gram-positive and gram-negative bacteria and by fungi. 
The risk of infection is related to the severity of neutrope
-
nia. The risk of serious infection rises sharply with neutro
-
phil counts below 500/mcL (0.5 × 10
9
/L), and a high risk of 
infection within days occurs with neutrophil counts below 
100/mcL (0.1 × 10
9
/L) (“profound neutropenia”). The clas
-
sification of neutropenic syndromes is unsatisfactory as the 
pathophysiology and natural history of different syn
-
dromes overlap. Patients with “chronic benign neutropenia” 
are free of infection despite very low stable neutrophil 
counts; they seem to physiologically respond adequately to 
infections and inflammatory stimuli with an appropriate 
neutrophil release from the bone marrow. In contrast, the 
neutrophil count of patients with cyclic neutropenia peri
-
odically oscillate (usually in 21-day cycles) between normal 
and low, with infections occurring during the nadirs. Con
-
genital neutropenia is lifelong neutropenia punctuated 
with infection.
A variety of bone marrow disorders and nonmarrow 
conditions may cause neutropenia (Table 13–12). All of 
the causes of aplastic anemia (Table 13–10) and pancyto
-
penia (Table 13–11) may cause neutropenia. The new 
onset of an isolated neutropenia is most often due to an 
idiosyncratic reaction to a medication, and agranulocy
-
tosis (complete absence of neutrophils in the peripheral 
blood) is almost always due to a drug reaction. In these 
cases, examination of the bone marrow shows an almost 
complete absence of granulocyte precursors with other 
cell lines undisturbed. Neutropenia in the presence of a 
normal bone marrow may be due to immunologic 
peripheral destruction (autoimmune neutropenia), sep
-
sis, or hypersplenism. The presence in the serum of 
antineutrophil antibodies supports the diagnosis of auto
-
immune neutropenia but does not prove this as the 
pathophysiologic reason for neutropenia. 
Felty syn
-
drome
 is an immune neutropenia associated with sero
-
positive nodular rheumatoid arthritis and splenomegaly. 
Severe neutropenia may be associated with clonal disor
-
ders of T lymphocytes, often with the morphology of 
large granular lymphocytes, referred to as CD3-positive 
T-cell large granular lymphoproliferative disorder. Iso
-

-
-
lated neutropenia is an uncommon presentation of hairy 
cell leukemia or MDS. By its nature, myelosuppressive 
cytotoxic chemotherapy causes neutropenia in a predict
-
able manner.
Table 13–12.
 
Causes of neutropenia.
Bone marrow disorders
 
Congenital
  
Dyskeratosis congenita
  
Fanconi anemia
 
C
yclic neutropenia
 
C
ongenital neutropenia
 
Hair
y cell leukemia
 
Lar
ge granular lymphoproliferative disorder
 
Non–bone marrow disorders
 
M
edications: antiretroviral medications, cephalosporins, 
 
chlorpr
omazine, chlorpropamide, cimetidine, methimazole, 
myelosuppressive cytotoxic chemotherapy, penicillin, 
 
phenytoin, procainamide, rituximab, sulfonamides
 
Aplastic 
anemia
 
B
enign chronic neutropenia
 
P
ure white cell aplasia
 
Sepsis
 
O
ther immune
  
Autoimmune (idiopathic)
  
Felty syndrome
  
S
  
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»
Neutropenia results in stomatitis and in infections due 
to gram-positive or gram-negative aerobic bacteria or 
to fungi such as 
Candida
 or 
. The most com
-
mon infectious syndromes are septicemia, cellulitis, 
pneumonia, and neutropenic fever of unknown origin. 
Fever in neutropenic patients should always be initially 
assumed to be of infectious origin until proven other
-
wise (Chapter 30).
 
»
Treatment
Treatment of neutropenia depends on its cause. Potential 
causative medications should be discontinued. Myeloid 
growth factors (filgrastim or sargramostim or biosimilar 
myeloid growth factors) help facilitate neutrophil recov
-
ery after offending medications are stopped. Chronic 
myeloid growth factor administration (daily or every other 
day) is effective at dampening the neutropenia seen in 
cyclic or congenital neutropenia. When Felty syndrome 
leads to repeated bacterial infections, splenectomy has 
been the treatment of choice, but sustained use of 
myeloid growth factors is effective and provides a non
-
surgical alternative. Patients with autoimmune neutrope
-
nia often respond briefly to immunosuppression with 
corticosteroids and are best managed with intermittent 
doses of myeloid growth factors. The neutropenia associ
-
ated with large granular lymphoproliferative disorder may 
respond to therapy with oral methotrexate, cyclophospha
-
mide, or cyclosporine.
Fevers during neutropenia should be considered as 
infectious until proven otherwise. Febrile neutropenia is a 
life-threatening circumstance. Enteric gram-negative bac
-
teria are of primary concern and often empirically treated 
with fluoroquinolones or third- or fourth-generation 
cephalosporins (see Infections in the Immunocompro
-
mised Patient, Chapter 30). For protracted neutropenia, 
fungal infections are problematic and empiric coverage 
with azoles (fluconazole for yeast and voriconazole, itra
-
conazole, posaconazole, or isavuconazole for molds) or 
echinocandins is recommended. The neutropenia fol
-
lowing myelosuppressive chemotherapy is predictable 
and is partially ameliorated by the use of myeloid growth 
factors. For patients with acute leukemia undergoing 
intense chemotherapy or patients with solid cancer under
-
going high-dose chemotherapy, the prophylactic use of 
antimicrobial agents and myeloid growth factors is 
 
»
Refer to a hematologist if neutrophils are persistently and 
unexplainably less than 1000/mcL (1.0 × 10
9
/L).
 
»
Neutropenia by itself is not an indication for hospitaliza
-
tion. However, most patients with severe neutropenia have 
a serious underlying disease that may require inpatient 
treatment. Most patients with febrile neutropenia require 
hospitalization to treat infection.
Autrel-Moignet A et al. Autoimmune neutropenia. Presse Med. 
2014 Apr;43(4 Pt 2):e105–18. [PMID: 24680423]
Dale DC. How I diagnose and treat neutropenia. Curr Opin 
Hematol. 2016 Jan;23(1):1–4. [PMID: 26554885]
Palmblad J et al. How we diagnose and treat neutropenia in 
adults. Expert Rev Hematol. 2016 May;9(5):479–87. [PMID: 
26778239]
Smith TJ et al. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology Clinical 
Practice guideline update. J Clin Oncol. 2015 Oct 1;33
 
(28):3199–212. [PMID: 26169616]
 
º
LEUKEMIAS & O
th
ER 
 
MYELO
p
ROLIFERA
t
IVE NEO
p
LASMS
Myeloproliferative disorders are due to acquired clonal 
abnormalities of the hematopoietic stem cell. Since the 
stem cell gives rise to myeloid, erythroid, and platelet cells, 
qualitative and quantitative changes are seen in all of these 
cell lines. Classically, the myeloproliferative disorders pro
-
duce characteristic syndromes with well-defined clinical 
and laboratory features (Tables 13–13 and 13–14). How
-
ever, these disorders are grouped together because they 
may evolve from one into another and because hybrid

-
may evolve from one into another and because hybrid 
disorders are commonly seen. All of the myeloproliferative 
disorders may progress to AML.
The Philadelphia chromosome seen in chronic myeloid 
leukemia (CML) was the first recurrent cytogenetic abnor
-
mality to be described in a human malignancy. Since that 
time, there has been tremendous progress in elucidating 
the genetic nature of these disorders, with identification of 
mutations in 
JAK2, MPL, CALR, CSF3R
, and other genes.
Rumi E et al. Diagnosis, risk stratification, and response evaluation 
in classical myeloproliferative neoplasms. Blood. 2017 Feb 9;
 
129(6):680–92. [PMID: 28028026]
Table 13–13.
 
World Health Organization classification 
of myeloproliferative disorders (modified).
Myeloproliferative neoplasms
 
Chr
onic myeloid leukemia, 
BCR-ABL1
–positive
 
Chr
onic neutrophilic leukemia
 
P
olycythemia vera
 
P
rimary myelofibrosis (PMF)
 
Essen
tial thrombocythemia
 
Chr
onic eosinophilic leukemia, not otherwise specified (NOS)
 
M
yeloproliferative neoplasm, unclassifiable
Mastocytosis
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
Myelodysplastic syndromes
Acute myeloid leukemia and related neoplasms
 
A
cute myeloid leukemia with recurrent genetic abnormalities
 
A
cute myeloid leukemia with myelodysplasia-related changes
 
T
herapy-related myeloid neoplasms
 
A
cute myeloid leukemia, NOS
 
M
yeloid sarcoma
 
M
yeloid proliferations related to Down syndrome
Acute leukemias of ambiguous lineage
B lymphoblastic leukemia/lymphoma
T lymphoblastic leukemia/lymphoma
CMDT19_Ch13_p0510-p0555.indd   529

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POLYCYTHEMIA VERA
 
»
JAK2 (V617F)
 mutation.
 
»
Splenomegaly.
 
»
Normal arterial oxygen saturation.
 
»
Usually elevated white blood count and platelet 
count.
 
»
Polycythemia vera is an acquired myeloproliferative disor
-
der that causes overproduction of all three hematopoietic 
cell lines, most prominently the red blood cells. Erythroid 
production is independent of erythropoietin, and the 
serum erythropoietin level is low. A mutation in exon 14 of 
, a signaling molecule, has been demon
-
strated in 95% of cases. Additional 
JAK2
 mutations have 
been identified (exon 12) and suggest that 
JAK2
 is involved 
in the pathogenesis of this disease and is a potential thera
-
peutic target.
True erythrocytosis, with an elevated red blood cell 
mass, should be distinguished from spurious erythrocytosis 
caused by a constricted plasma volume. Primary polycythe
-
mia (polycythemia vera) is a bone marrow disorder charac
-
terized by autonomous overproduction of erythroid cells.
 
»
Headache, dizziness, tinnitus, blurred vision, and fatigue 
are common complaints related to expanded blood volume 
and increased blood viscosity. Generalized pruritus, espe
-
cially following a warm shower or bath, is related to hista
-
mine release from the basophilia. Epistaxis is probably 
related to engorgement of mucosal blood vessels in combi
-
nation with abnormal hemostasis. Sixty percent of patients 
are men, and the median age at presentation is 60 years. 
Polycythemia rarely occurs in persons under age 40 years.
Physical examination reveals plethora and engorged 
retinal veins. The spleen is palpable in 75% of cases but is 
nearly always enlarged when imaged. Thrombosis is the 
most common complication of polycythemia vera and the 
major cause of morbidity and death in this disorder. 
Thrombosis appears to be related both to increased blood 
viscosity and abnormal platelet function. Uncontrolled 
polycythemia leads to a very high incidence of thrombotic 
complications of surgery, and elective surgery should be 
deferred until the condition has been treated. Paradoxi
-
cally, in addition to thrombosis, increased bleeding can 
also occur. There is a high incidence of peptic ulcer 
disease.
According to the WHO 2016 criteria, the hallmark of poly
-
cythemia vera is a hematocrit (at sea level) that exceeds 
49% in males or 48% in females. Red blood cell morphol
-
ogy is normal (Table 13–14). The white blood count is 
usually elevated to 10,000–20,000/mcL and the platelet 
count is variably increased, sometimes to counts exceeding 
1,000,000/mcL. Platelet morphology is usually normal. 
White blood cells are usually normal, but basophilia and 
eosinophilia are frequently present. Erythropoietin levels 
are suppressed and are usually low. The diagnosis should 
be confirmed with 
JAK2
 mutation screening. The absence 
of a mutation in either exon 14 (most common) or 12 should 
lead the clinician to question the diagnosis.
The bone marrow is hypercellular, with panhyperplasia 
of all hematopoietic elements, but bone marrow examina
-
tion is not necessary to establish the diagnosis. Iron stores 
are usually absent from the bone marrow, having been 
transferred to the increased circulating red blood cell mass. 
Iron deficiency may also result from chronic gastrointesti
-
nal blood loss. Bleeding may lower the hematocrit to the 
normal range (or lower), creating diagnostic confusion, 
and may lead to a situation with significant microcytosis 
with a normal hematocrit.
Vitamin B
12
 levels are strikingly elevated because of 
increased levels of transcobalamin III (secreted by white 
blood cells). Overproduction of uric acid may lead to 
hyperuricemia.
Although red blood cell morphology is usually normal 
at presentation, microcytosis, hypochromia, and poikilocy
-

-
tosis may result from iron deficiency following treatment 
by phlebotomy. Progressive hypersplenism may also lead to 
elliptocytosis.
 
»
Spurious polycythemia, in which an elevated hematocrit is 
due to contracted plasma volume rather than increased red 
Table 13–14.
 
Laboratory features of myeloproliferative neoplasms.
White Count
h
ematocrit
p
latelet Count
Red Cell Morphology
N or 
↑
↑↑
N or 
↑
N
Essential thrombocytosis
N or 
↑
N
↑↑
N
Primary myelofibrosis
N or 
↓
 or 
↑
↓
↓
 or N or 
↑
Abn
Chronic myeloid leukemia
↑↑
N or 
↓
N or 
↑
 or 
↓
N
Abn, abnormal; N, normal.
CMDT19_Ch13_p0510-p0555.indd   530

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CMDT 2019
cell mass, may be related to diuretic use or may occur with
-
out obvious cause.
A secondary cause of polycythemia should be suspected if 
splenomegaly is absent and the high hematocrit is not accom
-
panied by increases in other cell lines. Secondary causes of 
polycythemia include hypoxia and smoking; carboxyhemo
-
globin levels may be elevated in smokers (Table 13–15). A 
renal CT scan or sonogram may be considered to look for an 
erythropoietin-secreting cyst or tumor. A positive family his
-
tory should lead to investigation for congenital high-oxygen-
affinity hemoglobin. An absence of a mutation in 
JAK2
 
suggests a different diagnosis. However, 
JAK2
 mutations are 
also commonly found in other myeloproliferative disorders, 
essential thrombocytosis, and myelofibrosis.
Polycythemia vera should be differentiated from other 
myeloproliferative disorders (Table 13–14). Marked eleva
-
tion of the white blood count (above 30,000/mcL) suggests 
CML. Abnormal red blood cell morphology and nucleated 
red blood cells in the peripheral blood are seen in myelofi
-
brosis. Essential thrombocytosis is suggested when the 
platelet count is strikingly elevated.
 
»
Treatment
The treatment of choice is phlebotomy. One unit of blood 
(approximately 500 mL) is removed weekly until the hema
-
tocrit is less than 45%; the hematocrit is maintained at less 
than 45% by repeated phlebotomy as necessary. Patients for 
whom phlebotomy is problematic (because of poor venous 
access or logistical reasons) may be managed primarily with 
hydroxyurea. Because repeated phlebotomy intentionally 
produces iron deficiency, the requirement for phlebotomy 
should gradually decrease. It is important to avoid medicinal 
iron supplementation, as this can thwart the goals of a phle
-
botomy program. A diet low in iron also is not necessary but 
will increase the intervals between phlebotomies. Maintain
-
ing the hematocrit at normal levels has been shown to 
decrease the incidence of thrombotic complications.
Occasionally, myelosuppressive therapy is indicated. 
Indications include a high phlebotomy requirement, 
thrombocytosis, and intractable pruritus. There is evidence 
that reduction of the platelet count to less than 600,000/mcL 
will reduce the risk of thrombotic complications. Hydroxy
-
urea is widely used when myelosuppressive therapy is 
indicated. The usual dose is 500–1500 mg/day orally, 
adjusted to keep platelets less than 500,000/mcL without 
reducing the neutrophil count to less than 2000/mcL. The 
JAK2
 inhibitor ruxolitinib is FDA-approved for patients 
resistant or intolerant to hydroxyurea. In a randomized 
study comparing best available therapy with ruxolitinib, 
Table 13–15.
 
Causes of polycythemia.
Spurious polycythemia
Secondary polycythemia
 
H
ypoxia: cardiac disease, pulmonary disease, high altitude
 
C
arboxyhemoglobin: smoking
 
Er
ythropoietin-secreting tumors, eg, kidney lesions (rare)
 
Abnormal 
hemoglobins (rare)
treatment with ruxolitinib was associated with greater ben
-
efit for both hematocrit control without phlebotomy (60%) 
and splenic volume reduction (38%). Symptom burden 
improved by greater than 50% in 49% of patients. Studies 
of pegylated alfa-2 interferon have demonstrated consider
-
able efficacy, with hematologic responses in greater than 
80%, as well as molecular responses in 20% (as measured 
by 
JAK2
 mutations). Patients in whom molecular responses 
were not achieved had a higher frequency of mutations 
outside the 
JAK2
 pathway and were more likely to acquire 
new mutations during therapy. Side effects were generally 
acceptable and much less significant than with nonpe
-
gylated forms of interferon. A randomized phase 3 trial 
comparing PEG-alpha-2 interferon to hydroxyurea is 
expected to report in 2018. 
Alkylating agents have been 
shown to increase the risk of conversion of this disease to 
acute leukemia and should be avoided.

Low-dose aspirin (75–81 mg/day orally) has been shown 
to reduce the risk of thrombosis without excessive bleeding, 
and should be part of therapy for all patients without contra
-
indications to aspirin. Allopurinol 300 mg orally daily may 
be indicated for hyperuricemia. Antihistamine therapy with 
diphenhydramine or other H
1
-blockers and, rarely, selective 
serotonin reuptake inhibitors are used to manage pruritus.
 
»
Prognosis
Polycythemia is an indolent disease with median survival 
of over 15 years. The major cause of morbidity and mortal
-
ity is arterial thrombosis. Over time, polycythemia vera 
may convert to myelofibrosis or to CML. In approximately 
5% of cases, the disorder progresses to AML, which is usu
-
ally refractory to therapy.
 
»
Patients with polycythemia vera should be referred to a 
 
»
Inpatient care is rarely required.
Barbui T et al. The 2016 revision of WHO classification of myelo
-
proliferative neoplasms: clinical and molecular advances. 
Blood Rev. 2016 Nov;30(6):453–9. [PMID: 27341755]
Lee G et al. The clinical and laboratory evaluation of the 
patient with erythrocytosis. Eur J Intern Med. 2015 Jun;
 
26(5):297–302. [PMID: 25837692]
Stein BL et al. Polycythemia vera: an appraisal of the biology and 
management 10 years after the discovery of 
JAK2 V617F
. J 
Clin Oncol. 2015 Nov 20;33(33):3953–60. [PMID: 26324368]
ESSENTIAL THROMBOCYTOSIS
 
»
Elevated platelet count in absence of other causes.
 
»
Normal red blood cell mass.
 
»
Absence of 
bcr/abl
 gene (Philadelphia 
chromosome).
CMDT19_Ch13_p0510-p0555.indd   531

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»
Essential thrombocytosis is an uncommon myeloprolifera
-
tive disorder of unknown cause in which marked prolifera
-
tion of the megakaryocytes in the bone marrow leads to 
elevation of the platelet count. As with polycythemia vera, 
the finding of a high frequency of mutations of 
JAK2
 and 
others in these patients promises to advance the under
-
standing of this disorder.
 
»
The median age at presentation is 50–60 years, and there is 
a slightly increased incidence in women. The disorder is 
often suspected when an elevated platelet count is found. 
Less frequently, the first sign is thrombosis, which is the 
most common clinical problem. The risk of thrombosis 
rises with age. Venous thromboses may occur in unusual 
sites such as the mesenteric, hepatic, or portal vein. Some 
patients experience erythromelalgia, painful burning of the 
hands accompanied by erythema; this symptom is reliably 
relieved by aspirin. Bleeding, typically mucosal, is less 
common and is related to a concomitant qualitative platelet 
defect. Splenomegaly is present in at least 25% of patients.
An elevated platelet count is the hallmark of this disorder, and 
may be over 2,000,000/mcL (2000 × 10
9
/L) (Table 13–14). 
 
The white blood cell count is often mildly elevated, usually not 
above 30,000/mcL (30 × 10
9
/L), but with some immature 
myeloid forms. The hematocrit is normal. The peripheral 
blood smear reveals large platelets, but giant degranulated 
forms seen in myelofibrosis are not observed. Red blood cell 
morphology is normal.
The bone marrow shows increased numbers of mega
-
karyocytes but no other morphologic abnormalities. The 
peripheral blood should be tested for the 
bcr/abl
 fusion 
gene (Philadelphia chromosome) since it can differentiate 
CML, where it is present, from essential thrombocytosis, 
where it is absent.
 
»
Essential thrombocytosis must be distinguished from sec
-
ondary causes of an elevated platelet count. In reactive 
thrombocytosis, the platelet count seldom exceeds 
1,000,000/mcL (1000 × 10
9
/L). Inflammatory disorders 
such as rheumatoid arthritis and ulcerative colitis cause 
significant elevations of the platelet count, as may chronic 
infection. The thrombocytosis of iron deficiency is 
observed only when anemia is significant. The platelet 
count is temporarily elevated after splenectomy. 
JAK2
 
mutations are found in over 50% of cases. 
MPL and CALR
 
mutations frequently occur in patients with 
JAK2
-negative 
essential thrombocytosis.
Regarding other myeloproliferative disorders, the lack of 
erythrocytosis distinguishes it from polycythemia vera. 
Unlike myelofibrosis, red blood cell morphology is normal, 
nucleated red blood cells are absent, and giant degranulated 
platelets are not seen. In CML, the Philadelphia chromo
-
some (or 
bcr/abl
 by molecular testing) establishes the 
 
»
Treatment
Patients are considered at high risk for thrombosis if they 
are older than 60 years, have a leukocyte count of 11,000/
mcL (11 × 10
9
/L) or higher, or have a previous history of 
thrombosis. They also have a higher risk for bleeding. The 
risk of thrombosis can be reduced by control of the platelet 
count, which should be kept under 500,000/mcL (500 × 10
9
/L). 
The treatment of choice is oral hydroxyurea in a dose of 
500–1000 mg/day. In rare cases in which hydroxyurea is 
not well tolerated because of anemia, low doses of 
anagrelide, 1–2 mg/day orally, may be added. Higher doses 
of anagrelide can be complicated by headache, peripheral 
edema, and heart failure. Pegylated interferon alfa-2 can 
induce significant hematologic responses and can poten
-
tially target the malignant clone in 
CALR
-mutant cases. 
Strict control of coexistent cardiovascular risk factors is 
mandatory for all patients.
Vasomotor symptoms such as erythromelalgia and pares
-

CALR
-
thesias respond rapidly to aspirin, and its long-term low-dose 
use (81 mg/day orally) may reduce the risk of thrombotic 
complications in low-risk patients. In the unusual event of 
severe bleeding, the platelet count can be lowered rapidly with 
plateletpheresis. In cases of marked thrombocytosis (greater 
than or equal to 1,000,000/mcL (1000 × 10
9
/L) or of any evi
-
dence of bleeding, acquired von Willebrand syndrome must 
be excluded before starting low-dose aspirin.
 
»
Essential thrombocytosis is an indolent disorder and allows 
long-term survival. Average survival is longer than 15 years 
from diagnosis, and the survival of patients younger than 
 
50 years does not appear different from matched controls. 
The major source of morbidity—thrombosis—can be 
reduced by appropriate platelet control. Late in the course of 
the disease, the bone marrow may become fibrotic, and 
massive splenomegaly may occur, sometimes with splenic 
infarction. There is a 10–15% risk of progression to myelo
-
fibrosis after 15 years, and a 1–5% risk of transformation to 
acute leukemia over 20 years.
 
»
Patients with essential thrombocytosis should be referred 
to a hematologist.
Aruch D et al. Contemporary approach to essential thrombo
-
cythemia and polycythemia vera. Curr Opin Hematol. 
2016 Mar;23(2):150–60. [PMID: 26717193]
Kreher S et al. Prophylaxis and management of venous thrombo
-
embolism in patients with myeloproliferative neoplasms: 
consensus statement of the Haemostasis Working Party of the 
German Society of Hematology and Oncology (DGHO), the 
Austrian Society of Hematology and Oncology (ÖGHO) and 
Society of Thrombosis and Haemostasis Research (GTH e.V .). 
Ann Hematol. 2014 Dec;93(12):1953–63. [PMID: 25307456]
Rumi E et al. How I treat essential thrombocythemia. Blood. 
2016 Nov 17;128(20):2403–14. [PMID: 27561316]
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CMDT 2019
PRIMARY MYELOFIBROSIS
 
»
Striking splenomegaly.
 
»
Teardrop poikilocytosis on peripheral smear.
 
»
Leukoerythroblastic blood picture; giant abnor
-
mal platelets.
 
»
Initially hypercellular, then hypocellular bone mar
-
row with reticulin or collagen fibrosis.
 
»
Primary myelofibrosis is a myeloproliferative disorder char
-
acterized by clonal hematopoiesis that is often but not always 
JAK2
, 
CALR
, or 
MPL
 mutation; bone mar
-
row fibrosis; anemia; splenomegaly; and a leukoerythroblas
-
tic peripheral blood picture with teardrop poikilocytosis. 
Myelofibrosis can also occur as a secondary process follow
-
ing the other myeloproliferative disorders (eg, polycythemia 
vera, essential thrombocytosis). It is believed that fibrosis 
occurs in response to increased secretion of platelet-derived 
growth factor (PDGF) and possibly other cytokines. In 
response to bone marrow fibrosis, extramedullary hemato
-
poiesis takes place in the liver, spleen, and lymph nodes. In 
these sites, mesenchymal cells responsible for fetal hemato
-
poiesis can be reactivated. According to the 2016 WHO 
classification, “prefibrotic” primary myelofibrosis is distin
-
guished from “overtly fibrotic” primary myelofibrosis; the 
former might mimic essential thrombocytosis in its presen
-
tation and it is prognostically relevant to distinguish the two.
 
»
Primary myelofibrosis develops in adults over age 50 years 
and is usually insidious in onset. Patients most commonly 
present with fatigue due to anemia or abdominal fullness 
related to splenomegaly. Uncommon presentations include 
bleeding and bone pain. On examination, splenomegaly is 
almost invariably present and is commonly massive. The 
liver is enlarged in more than 50% of cases.
Later in the course of the disease, progressive bone 
marrow failure takes place as it becomes increasingly more 
fibrotic. Progressive thrombocytopenia leads to bleeding. 
The spleen continues to enlarge, which leads to early sati
-
ety. Painful episodes of splenic infarction may occur. The 
patient becomes cachectic and may experience severe bone 
pain, especially in the upper legs. Hematopoiesis in the 
liver leads to portal hypertension with ascites, esophageal 
varices, and occasionally transverse myelitis caused by 
myelopoiesis in the epidural space.
Patients are almost invariably anemic at presentation. The 
white blood count is variable—either low, normal, or 
elevated—and may be increased to 50,000/mcL (50 × 10
9
/L). 
The platelet count is variable. The peripheral blood smear 
is dramatic, with significant poikilocytosis and numerous 
teardrop forms in the red cell line. Nucleated red blood 
cells are present and the myeloid series is shifted, with 
immature forms including a small percentage of promy
-
elocytes or myeloblasts. Platelet morphology may be 
bizarre, and giant degranulated platelet forms (mega
-
karyocyte fragments) may be seen. The triad of tear
-
drop poikilocytosis, leukoerythroblastic blood, and 
giant abnormal platelets is highly suggestive of 
myelofibrosis.
The bone marrow usually cannot be aspirated (dry 
tap), though early in the course of the disease it is hyper
-
cellular, with a marked increase in megakaryocytes. 
Fibrosis at this stage is detected by a silver stain demon
-
strating increased reticulin fibers. Later, biopsy reveals 
more severe fibrosis, with eventual replacement of 
hematopoietic precursors by collagen. There is no char
-
acteristic chromosomal abnormality. 
JAK2
 is mutated in 
~65% of cases, and 
MPL
 and 
CALR
 are mutated in the 
majority of the remaining cases; 10% of cases are 
“triple-negative. ”
 
»
A leukoerythroblastic blood picture from other causes may 
be seen in response to severe infection, inflammation, or 
infiltrative bone marrow processes. However, teardrop

»
infiltrative bone marrow processes. However, teardrop 
poikilocytosis and giant abnormal platelet forms will not 
be present. Bone marrow fibrosis may be seen in metastatic 
carcinoma, Hodgkin lymphoma, and hairy cell leukemia. 
These disorders are diagnosed by characteristic morphol
-
ogy of involved tissues.
Of the other myeloproliferative disorders, CML is diag
-
nosed when there is marked leukocytosis, normal red 
blood cell morphology, and the presence of the 
bcr/abl
 
fusion gene. Polycythemia vera is characterized by an ele
-
vated hematocrit. Essential thrombocytosis shows pre
-
dominant platelet count elevations.
 
»
Treatment
Observation with supportive care is a reasonable treat
-
ment strategy for asymptomatic patients with low or inter
-
mediate-1 Dynamic International Prognostic Scoring 
system (DIPSS)-plus risk disease, especially in the absence 
of high-risk mutations. Anemic patients are supported 
with transfusion. Anemia can also be controlled with 
androgens, prednisone, thalidomide, or lenalidomide. 
First-line therapy for myelofibrosis-associated spleno
-
megaly is hydroxyurea 500–1000 mg/day orally, which is 
effective in reducing spleen size by half in approximately 
40% of patients. Both thalidomide and lenalidomide may 
improve splenomegaly and thrombocytopenia in some 
patients. Splenectomy is not routinely performed but is 
indicated for medication-refractory splenic enlargement 
causing recurrent painful episodes, severe thrombocyto
-
penia, or an unacceptable transfusion requirement. Peri
-
operative complications can occur in 28% of patients and 
include infections, abdominal vein thrombosis, and 
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bleeding. Radiation therapy has a role for painful sites of 
extramedullary hematopoiesis, pulmonary hypertension, 
or severe bone pain. Transjugular intrahepatic portosys
-
temic shunt might also be considered to alleviate symp
-
toms of portal hypertension.
Patients with DIPSS-plus high or intermediate-2 risk 
disease, or those patients harboring high-risk mutations 
such as ASXL1 or SRSF2, should be considered for alloge
-
neic stem cell transplant, which is currently the only 
potentially curative treatment modality in this disease. 
Nontransplant candidates may be treated with JAK2 
inhibitors or immunomodulatory agents for symptom 
control. Ruxolitinib, the first 
JAK2
 inhibitor to be FDA 
approved, results in reduction of spleen size and improve
-
ment of constitutional symptoms, but does not induce 
complete clinical or cytogenetic remissions or signifi
-
cantly affect JAK2/CALR/MPL mutant allele burden. 
Moreover, ruxolitinib can exacerbate cytopenias. The 
immunomodulatory medications lenalidomide and 
pomalidomide result in control of anemia in 25% and 
thrombocytopenia in ~58% of cases, without significant 
reduction in splenic size.
 
»
The median survival from time of diagnosis is approxi
-
mately 5 years. Therapies with biologic agents and the 
application of reduced-intensity allogeneic stem cell trans
-
plantation appear to offer the possibility of improving the 
outcome for many patients. End-stage myelofibrosis is 
characterized by generalized asthenia, liver failure, and 
bleeding from thrombocytopenia, with some cases termi
-
nating in AML. The DIPSS-plus incorporates clinical and 
genetic risk variables and is associated with overall sur
-
vival. Most recently, DIPSS-plus-independent adverse 
prognostic relevance has been demonstrated for certain 
mutations including ASXL1 and SRSF2 whereas patients 
with type 1/like CALR mutations, compared to their coun
-
terparts with other driver mutations, displayed signifi
-
cantly better survival.
 
»
Patients in whom myelofibrosis is suspected should be 
referred to a hematologist.
 
»
Admission is not usually necessary.
Bose P et al. Prognosis of primary myelofibrosis in the genomic 
era. Clin Lymphoma Myeloma Leuk. 2016 Aug;16
 
(Suppl):S105–13. [PMID: 27521306]
Devlin R et al. Myelofibrosis: to transplant or not to transplant? 
 
2016(1):543–51. [PMID: 27913527]
Mesa RA et al. Ruxolitinib dose management as a key to long-
term treatment success. Int J Hematol. 2016 Oct;104(4):420–9. 
[PMID: 27567907]
Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-
stratification, and management. Am J Hematol. 2016 Dec;
 
91(12):1262–71. [PMID: 27870387]
CHRONIC MYELOID LEUKEMIA
 
»
Elevated white blood cell count.
 
»
Markedly left-shifted myeloid series but with a low 
percentage of promyelocytes and blasts.
 
»
Presence of 
bcr/abl
 
»
CML is a myeloproliferative disorder characterized by 
overproduction of myeloid cells. These myeloid cells con
-
tinue to differentiate and circulate in increased numbers in 
the peripheral blood.
CML is characterized by a specific chromosomal abnor
-
mality and specific molecular abnormality. The 
Philadelphia 
chromosome
 is a reciprocal translocation between the long 
arms of chromosomes 9 and 22. The portion of 9q that is 
translocated contains 
abl
, a protooncogene that is received 
at a specific site on 22q, the break point cluster (bcr). The 
fusion gene 
bcr/abl
 produces a novel protein that possesses 
tyrosine kinase activity. This disorder is the first recognized 
example of tyrosine kinase “addiction” by cancer cells.
Early CML (“chronic phase”) does not behave like a 
malignant disease. Normal bone marrow function is 
retained, white blood cells differentiate and, despite some

retained, white blood cells differentiate and, despite some 
qualitative abnormalities, the neutrophils combat infection 
normally. However, untreated CML is inherently unstable, 
and without treatment the disease progresses to an acceler
-
ated and then acute blast phase, which is morphologically 
indistinguishable from acute leukemia. Remarkable 
advances in therapy have changed the natural history of 
the disease, and the relentless progression to more 
advanced stages of disease is at least greatly delayed, if not 
eliminated.
 
»
CML is a disorder of middle age (median age at presenta
-
tion is 55 years). Patients usually complain of fatigue, 
night sweats, and low-grade fevers related to the hyper
-
metabolic state caused by overproduction of white blood 
cells. Patients may also complain of abdominal fullness 
related to splenomegaly. In some cases, an elevated white 
blood count is discovered incidentally. Rarely, the patient 
will present with a clinical syndrome related to leukostasis 
with blurred vision, respiratory distress, or priapism. The 
white blood count in these cases is usually greater than 
100,000/mcL (100 × 10
9
/L) but less than 500,000/mcL 
(500 × 10
9
/L). On examination, the spleen is enlarged 
(often markedly so), and sternal tenderness may be pres
-
ent as a sign of marrow overexpansion. In cases discovered 
during routine laboratory monitoring, these findings are 
often absent. Acceleration of the disease is often associated 
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with fever in the absence of infection, bone pain, and 
splenomegaly.
CML is characterized by an elevated white blood cell count; 
the median white blood count at diagnosis is 150,000/mcL 
(150 × 10
9
/L), although in some cases the white blood cell 
count is only modestly increased (Table 13–14). The 
peripheral blood is characteristic. The myeloid series is left 
shifted, with mature forms dominating and with cells usu
-
ally present in proportion to their degree of maturation. 
Blasts are usually less than 5%. Basophilia and eosinophilia 
may be present. At presentation, the patient is usually not 
anemic. Red blood cell morphology is normal, and nucle
-
ated red blood cells are rarely seen. The platelet count may 
be normal or elevated (sometimes to strikingly high levels). 
A bone marrow biopsy is essential to ensure sufficient 
material for a complete karyotype and for morphologic 
evaluation to confirm the phase of disease. The bone mar
-
row is hypercellular, with left-shifted myelopoiesis. Myelo
-
blasts comprise less than 5% of marrow cells. The hallmark 
of the disease is the 
bcr/abl
 gene that is detected by the 
polymerase chain reaction (PCR) test in the peripheral 
blood and bone marrow.
With progression to the accelerated and blast phases, 
progressive anemia and thrombocytopenia occur, and the 
percentage of blasts in the blood and bone marrow 
increases. Blast phase CML is diagnosed when blasts com
-
prise more than 20% of bone marrow cells.
 
»
Early CML must be differentiated from the reactive leuko
-
cytosis associated with infection. In such cases, the white 
blood count is usually less than 50,000/mcL (50 × 10
9
/L), 
splenomegaly is absent, and the 
bcr/abl
 gene is not present.
CML must be distinguished from other myeloprolifera
-
tive disease (Table 13–14). The hematocrit should not be 
elevated, the red blood cell morphology is normal, and 
nucleated red blood cells are rare or absent. Definitive 
diagnosis is made by finding the 
bcr/abl
 gene.
 
»
Treatment
Treatment is usually not emergent even with white blood 
counts over 200,000/mcL (200 × 10
9
/L), since the majority 
of circulating cells are mature myeloid cells that are 
smaller and more deformable than primitive leukemic 
blasts. In the rare instances in which symptoms result 
from extreme hyperleukocytosis (priapism, respiratory 
distress, visual blurring, altered mental status), emergent 
leukapheresis is performed in conjunction with myelosup
-
pressive therapy.
In chronic-phase CML, the goal of therapy is normal
-
ization of the hematologic abnormalities and suppression 
of the malignant 
bcr/abl
-expressing clone. The treatment of 
choice consists of a tyrosine kinase inhibitor (eg, imatinib, 
nilotinib, dasatinib) targeting the aberrantly active 
abl
 
kinase. It is expected that a hematologic complete remis
-
sion, with normalization of blood counts and splenomeg
-
aly will occur within 3 months of treatment initiation. 
Second, a major cytogenetic response should be achieved, 
ideally within 3 months but certainly within 6 months. A 
major cytogenetic response is identified when less than 
35% of metaphases contain the Philadelphia chromosome. 
Lastly, a major molecular response is desired within 
 
12 months and is defined as a 3-log reduction of the 
bcr/abl
 
transcript as measured by quantitative PCR. This roughly 
corresponds to a 
bcr/abl
 ratio (compared to 
abl
) of less 
than 0.01. Patients who achieve this level of molecular 
response have an excellent prognosis, with 100% of them 
remaining progression-free at 8 years. On the other hand, 
patients have a worse prognosis if these targets are not 
achieved, cytogenetic or molecular response is subse
-
quently lost, or new mutations or cytogenetic abnormali
-
ties develop.
Imatinib mesylate was the first tyrosine kinase inhibitor 
to be approved and it results in nearly universal (98%)

-
-
to be approved and it results in nearly universal (98%) 
hematologic control of chronic phase disease at a dose of 
400 mg/day. The rate of a major molecular response with 
imatinib in chronic-phase disease is ~30% at 1 year. The 
second-generation tyrosine kinase inhibitors, nilotinib and 
dasatinib, are also used as front-line therapy and can sig
-
nificantly increase the rate of a major molecular response 
compared to imatinib (71% for nilotinib at 300–400 mg 
twice daily by 2 years, 64% for dasatinib at 100 mg/day by 
2 years) and result in a lower rate of progression to 
advanced-stage disease. However, these agents can also 
salvage 90% of patients who do not respond to treatment 
with imatinib and may therefore be reserved for use in that 
setting. A dual 
bcr/abl
 tyrosine kinase inhibitor, bosutinib, 
is used for patients who are resistant or intolerant to the 
other tyrosine kinase inhibitors. The complete cytogenetic 
response rate to bosutinib is 25% but it is not active against 
the 
T315I
 mutation.
Patients taking tyrosine kinase inhibitors should be 
monitored with a quantitative PCR assay. Those with a 
consistent increase in 
bcr/abl
 transcript or those with a 
suboptimal molecular response as defined above should 
undergo 
abl
 mutation testing and then be switched to an 
alternative tyrosine kinase inhibitor. The 
T315I
 mutation 
in 
abl
 is specifically resistant to therapy with imatinib, 
dasatinib, nilotinib, and bosutinib but appears to be sensi
-
tive to the third-generation agent ponatinib. However, 
ponatinib is associated with a high rate of vascular throm
-
botic complications. Lastly, omacetaxine—a non–tyrosine 
kinase inhibitor therapy approved for patients with CML 
who are resistant to at least two tyrosine kinase inhibitors—
can produce major cytogenetic responses in 18% of 
patients. Patients in whom a good molecular response to 
any of these agents cannot be achieved or in whom diseases 
progresses despite therapy should be considered for alloge
-
neic stem cell transplantation.
Patients with advanced-stage disease (accelerated phase 
or myeloid/lymphoid blast crisis) should be treated with a 
tyrosine kinase inhibitor alone or in combination with 
myelosuppressive chemotherapy. The doses of tyrosine 
kinase inhibitors in that setting are usually higher than 
those appropriate for chronic-phase disease. Since the 
duration of response to tyrosine kinase inhibitors in this 
setting is limited, patients who have accelerated or blast 
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phase disease should ultimately be considered for alloge
-
 
»
Since the introduction of imatinib therapy in 2001, and with 
the development of molecular-targeted agents, more than 
80% of patients remain alive and without disease progres
-
sion at 9 years. Patients with good molecular responses to 
tyrosine kinase inhibitor therapy have an excellent progno
-
sis, with essentially 100% survival at 9 years, and it is likely 
that some fraction of these patients will be cured. Current 
studies suggest that tyrosine kinase inhibitor therapy may 
be safely discontinued after 2 years in patients who achieve 
a sustained major molecular response, with ~50–60% of 
patients remaining in molecular remission at least 1 year.
 
»
All patients with CML should be referred to a hematologist.
 
»
Hospitalization is rarely necessary and should be reserved 
for symptoms of leukostasis at diagnosis or for transforma
-
tion to acute leukemia.
Barrett AJ et al. The role of stem cell transplantation for chronic 
myelogenous leukemia in the 21st century. Blood. 2015 May 21;
 
125(21):3230–5. [PMID: 25852053]
Rosti G et al. Tyrosine kinase inhibitors in chronic myeloid 
leukaemia: which, when, for whom? Nat Rev Clin Oncol. 
2017 Mar;14(3):141–54. [PMID: 27752053]
Steegmann JL et al. European LeukemiaNet recommendations for 
the management and avoidance of adverse events of treatment 
in chronic myeloid leukaemia. Leukemia. 2016 Aug;30(8):
 
1648–71. [PMID: 27121688]
MYELODYSPLASTIC SYNDROMES
 
»
Cytopenias with a hypercellular bone marrow.
 
»
Morphologic abnormalities in one or more hema
-
topoietic cell lines.
 
»
The myelodysplastic syndromes are a group of acquired 
clonal disorders of the hematopoietic stem cell. They are 
characterized by the constellation of cytopenias, a usually 
hypercellular marrow, morphologic dysplasia, and genetic 
abnormalities. The disorders are usually idiopathic but may 
be caused by prior exposure to cytotoxic chemotherapy, 
radiation or both. In addition to cytogenetics, sequencing can 
detect genetic mutations in 80–90% of MDS patients. Impor
-
tantly, acquired clonal mutations identical to those seen in 
MDS can occur in the hematopoietic cells of ~10% of appar
-
ently healthy older individuals, defining the disorder of 
clonal hematopoiesis of indeterminate potential (CHIP).
Myelodysplasia encompasses several heterogeneous 
syndromes. A key distinction is whether there is an 
increase in bone marrow blasts (greater than 5% of marrow 
elements). The category of MDS with excess blasts repre
-
sents a more aggressive form of the disease, often leading 
to AML. Those without excess blasts are characterized by 
the degree of dysplasia, eg, MDS with single lineage dyspla
-
sia and MDS with multilineage dysplasia. The morphologic 
finding of 
“ringed sideroblasts”
 is retained in the 2016 
WHO classification and is used to define a subcategory of 
the lower-risk MDS syndromes. Patients with 
isolated 5q 
loss,
 which is characterized by the cytogenetic finding of 
loss of part of the long arm of chromosome 5, comprise an 
important subgroup of patients with a different natural his
-
tory. Last, patients with a proliferative syndrome including 
sustained peripheral blood monocytosis more than 1000/mcL 
(1.0 × 10
9
/L) are termed 
“chronic myelomonocytic leuke
-
mia” (CMML),
 a disorder that shares features of myelo
-
dysplastic and myeloproliferative disorders. An International 
Prognostic Scoring System (IPSS) classifies patients by 
risk status based on the percentage of bone marrow blasts, 
cytogenetics, and severity of cytopenias. The IPSS is asso
-
ciated with the rate of progression to AML and with 
overall survival, which can range from a median of 6 years 
for the low-risk group to 5 months for the high-risk 
patients.
 
»

-
patients.
 
»
Patients are usually over age 60 years. Many patients are 
asymptomatic when the diagnosis is made because of the 
finding of abnormal blood counts. Fatigue, infection, or 
bleeding related to bone marrow failure are usually the 
presenting symptoms and signs. The course may be indo
-
lent, and the disease may present as a wasting illness with 
fever, weight loss, and general debility. On examination, 
splenomegaly may be present in combination with pallor, 
bleeding, and various signs of infection. Myelodysplastic 
syndromes can also be accompanied by a variety of para
-
neoplastic syndromes prior to or following this diagnosis.
Anemia may be marked with the MCV normal or increased, 
and transfusion support may be required. On the peripheral 
blood smear, macro-ovalocytes may be seen. The white 
blood cell count is usually normal or reduced, and neutro
-
penia is common. The neutrophils may exhibit morpho
-
logic abnormalities, including deficient numbers of granules 
or deficient segmentation of the nucleus, especially a 
bilobed nucleus (Pelger-Huet abnormality). The myeloid 
series may be left shifted, and small numbers of promyelo
-
cytes or blasts may be seen. The platelet count is normal or 
reduced, and hypogranular platelets may be present.
The bone marrow is characteristically hypercellular but 
occasionally may be hypocellular. Erythroid hyperplasia is 
common, and signs of abnormal erythropoiesis include 
megaloblastic features, nuclear budding, or multinucleated 
erythroid precursors. The Prussian blue stain may demon
-
strate ringed sideroblasts. In the marrow, too, the myeloid 
CMDT19_Ch13_p0510-p0555.indd   536

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CMDT 2019
series is often left shifted, with variable increases in blasts. 
Deficient or abnormal granules may be seen. A character
-
istic abnormality is the presence of dwarf megakaryocytes 
with a unilobed nucleus. Genetic abnormalities define 
MDS; there are frequent cytogenetic abnormalities involv
-
ing the long arm of chromosome 5 as well as deletions of 
chromosomes 5 and 7. Some patients with an indolent 
form of the disease have an isolated partial deletion of 
chromosome 5 (MDS with isolated del[5q]). Aside from 
cytogenetic abnormalities, the most commonly mutated 
genes are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, 
RUNX1, U2AF1, TP53, and EZH2.
 
»
Myelodysplastic syndromes should be distinguished from 
megaloblastic anemia, aplastic anemia, myelofibrosis, HIV-
associated cytopenias, and acute or chronic drug effect. In 
subtle cases, cytogenetic evaluation of the bone marrow 
may help distinguish this clonal disorder from other causes 
of cytopenias. As the number of blasts increases in the bone 
marrow, myelodysplasia is arbitrarily separated from AML 
by the presence of less than 20% blasts.
 
»
Treatment
Myelodysplasia is a heterogeneous disease, and the appro
-
priate treatment depends on a number of factors. For 
patients with anemia who have a low serum erythropoietin 
level (500 milliunits/mL or less), erythropoiesis-stimulating 
agents may raise the hematocrit and reduce the red cell 
transfusion requirement in 40%. Addition of intermittent 
granulocyte colony-stimulating factor (G-CSF) therapy may 
augment the erythroid response to epoetin. Unfortunately, 
the patients with the highest transfusion requirements are 
the least likely to respond. Patients who remain dependent 
on red blood cell transfusion and who do not have immedi
-
ately life-threatening disease should receive iron chelation in 
order to prevent serious iron overload; the dose of oral agent 
deferasirox is 20 mg/kg/day. Patients affected primarily with 
severe neutropenia may benefit from the use of myeloid 
growth factors such as filgrastim. Oral thrombopoietin ana
-
logues such as romiplostim and eltrombopag that stimulate 
platelet production by binding the thrombopoietin receptor 
have shown effectiveness in raising the platelet count in 
myelodysplasia. Finally, occasional patients can benefit from 
immunosuppressive therapy including ATG. Predictors of 
response to ATG include age younger than 60 years, absence 
of 5q–, and presence of HLA DR15.
For patients who do not respond to these interventions, 
there are several therapeutic options available. Lenalidomide 
is approved for the treatment of transfusion-dependent 
anemia due to myelodysplasia. It is the treatment of choice 
in patients with MDS with isolated del(5q) with significant 
responses in 70% of patients, and responses typically lasting 
longer than 2 years. In addition, nearly half of these patients 
enter a cytogenetic remission with clearing of the abnormal 
5q– clone. The recommended initial dose is 10 mg/day 
orally. The most common side effects are neutropenia and 
thrombocytopenia, but venous thrombosis occurs and 
warrants prophylaxis with aspirin, 325 mg/day orally. For 
patients with high-risk myelodysplasia, azacitidine is the 
treatment of choice. It can improve both symptoms and 
blood counts and prolong both overall survival and the time 
to conversion to acute leukemia. It is used at a dose of 
 
75 mg/m
2
 daily for 5–7 days every 28 days and up to six 
cycles of therapy may be required to achieve a response. A 
related hypomethylating agent, decitabine, given at 20 mg/m
2
 
daily for 5 days every 28 days can produce similar hemato
-
logic responses but has not demonstrated a benefit in over
-
all survival compared to supportive care alone. Combination 
therapy of azacitidine with either lenalidomide or vorino
-
stat, the histone deacetylase inhibitor, has shown prelimi
-

-
-
-
nary promise in patients with high-risk disease and is being 
tested in a large prospective clinical trial. Allogeneic stem 
cell transplantation is the only curative therapy for myelo
-
dysplasia, but its role is limited by the advanced age of many 
patients and the indolent course of disease in some subsets 
of patients. The optimal use and timing of allogeneic trans
-
plantation are controversial, but the use of reduced-inten
-
sity preparative regimens and alternative donor sources 
(cord blood, haplotype-matched) has expanded the role of 
this therapy. Agents targeting the emerging genetic muta
-
tions in MDS are in development.
 
»
Myelodysplasia is an ultimately fatal disease, and allogeneic 
transplantation is the only curative therapy, with cure rates 
of 30–60% depending primarily on the risk status of the 
disease. Patients most commonly die of infections or bleed
-
ing. Patients with MDS with isolated del(5q) have a favorable 
prognosis, with 5-year survival over 90%. Other patients 
with low-risk disease (with absence of both excess blasts and 
adverse cytogenetics) may also do well, with similar survival. 
Those with excess blasts or CMML have a higher (30–50%) 
risk of developing acute leukemia, and short survival (less 
than 2 years) without allogeneic transplantation.
 
»
All patients with myelodysplasia should be referred to a 
 
»
Hospitalization is needed only for specific complications, 
such as severe infection.
Bulycheva E et al. Myelodysplasia is in the niche: novel concepts 
and emerging therapies. Leukemia. 2015 Feb;29(2):259–68. 
[PMID: 25394715]
de Witte T et al. Allogeneic hematopoietic stem cell transplanta
-
tion for MDS and CMML: recommendations from an inter
-
national expert panel. Blood. 2017 Mar 30;129(13):1753–62. 
[PMID: 28096091]
Kennedy JA et al. Clinical implications of genetic mutations in 
myelodysplastic syndrome. J Clin Oncol. 2017 Mar 20;
 
35(9):968–74. [PMID: 28297619]
Sekeres MA et al. Established and novel agents for myelodysplas
-
tic syndromes. Hematology Am Soc Hematol Educ Program. 
2014 Dec 5;2014(1):82–9. [PMID: 25696839]
Sperling AS et al. The genetics of myelodysplastic syndrome: 
from clonal haematopoiesis to secondary leukaemia. Nat Rev 
Cancer. 2017 Jan;17(1):5–19. [PMID: 27834397]
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ACUTE LEUKEMIA
 
»
Short duration of symptoms, including fatigue, 
fever, and bleeding.
 
»
Cytopenias or pancytopenia.
 
»
Blasts in peripheral blood in 90% of patients.
 
»
More than 20% blasts in the bone marrow.
 
»
Acute leukemia is a malignancy of the hematopoietic 
progenitor cell. These cells proliferate in an uncontrolled 
fashion and replace normal bone marrow elements. 
Most cases arise with no clear cause. However, radiation 
and some toxins (benzene) are leukemogenic. In addi
-
tion, a number of chemotherapeutic agents (especially 
cyclophosphamide, melphalan, other alkylating agents, 
and etoposide) may cause leukemia. The leukemias seen 
after toxin or chemotherapy exposure often develop 
from a myelodysplastic prodrome and are often associ
-
ated with abnormalities in chromosomes 5 and 7. Those 
related to etoposide may have abnormalities in chromo
-
some 11q23 (MLL locus).
Most of the clinical findings in acute leukemia are due 
to replacement of normal bone marrow elements by the 
malignant cells. Less common manifestations result from 
organ infiltration (skin, gastrointestinal tract, meninges). 
Acute leukemia is potentially curable with combination 
chemotherapy.
The myeloblastic subtype, AML, is primarily an adult 
disease with a median age at presentation of 60 years and an 
increasing incidence with advanced age. Acute promyelo
-
cytic leukemia (APL) is characterized by the chromosomal 
translocation t(15;17), which produces the fusion gene 
PML-RAR
-alpha, which interacts with the retinoic acid 
receptor to produce a block in differentiation that can be 
overcome with pharmacologic doses of retinoic acid. The 
lymphoblastic subtype of acute leukemia, ALL, comprises 
80% of the acute leukemias of childhood. The peak inci
-
dence is between 3 and 7 years of age. It is also seen in adults, 
causing approximately 20% of adult acute leukemias.
 
»
Classification of the Leukemias
A. Acute Myeloid Leukemia (AML)
AML is primarily categorized based on recurrent structural 
chromosomal and molecular abnormalities. The cytoge
-
netic abnormalities can be identified on traditional karyo
-
typing or metaphase FISH and the molecular abnormalities 
are identified by either targeted or genome-wide sequenc
-
ing of tumor DNA. Favorable cytogenetics such as t(8;21) 
producing a chimeric RUNX1/RUNX1T1 protein and 
inv(16)(p13;q22) are seen in 15% of cases and are termed 
the “core-binding factor” leukemias. These patients have a 
higher chance of achieving both short- and long-term 
disease control. Unfavorable cytogenetics confer a very 
poor prognosis. These consist of isolated monosomy 5 or 7, 
the presence of two or more other monosomies, or three or 
more separate cytogenetic abnormalities and account for 
25% of the cases. The majority of cases of AML are of inter
-
mediate risk by traditional cytogenetics and have either a 
normal karyotype or chromosomal abnormalities that do 
not confer strong prognostic significance. However, there 
are several recurrent gene mutations with prognostic sig
-
nificance in this subgroup. On the one hand, internal tan
-
dem duplication in the gene 
FLT3
 occurs in ~30% of AML 
and is conditionally associated with a very poor prognosis 
in the setting of 
NPM1
 and 
DNMT3A
 mutation. Other 
mutations conferring a poor prognosis occur in 
TET2, 
ASXL1, MLL
-PTD, 
PHF6,
 and SRSF2. On the other hand, 
a relatively favorable group of patients has been identified 
that lacks 
FLT3-ITD
 mutations and includes mutations of 
nucleophosmin 1 (
NPM1
) and 
IDH1
 or 
IDH2
 or carries 
CEBPA
 biallelic mutations.
B. Acute Promyelocytic Leukemia (APL)
In considering the various types of AML, APL is discussed 
separately because of its unique biologic features and 
response to non-chemotherapy treatments. APL is charac
-
terized by the cytogenetic finding of t(15;17) and the fusion 
gene 
PML-RAR

-
gene 
PML-RAR
-alpha. It is a highly curable form of leuke
-
mia (over 90%) with integration of all-trans-retinoic acid 
(ATRA) and arsenic trioxide (ATO) in induction, consoli
-
dation, and maintenance regimens.
C. Acute Lymphoblastic Leukemia (ALL)
ALL is most usefully classified by immunologic phenotype 
as follows: common, early B lineage, and T cell. Hyperdip
-
loidy (with more than 50 chromosomes), especially of 
chromosomes 4, 10 and 17, and translocation t(12;21) 
(TEL-AML1), is associated with a better prognosis. Unfa
-
vorable cytogenetics are hypodiploidy (less than 44 chro
-
mosomes), the Philadelphia chromosome t(9;22), the 
t(4;11) translocation (which has fusion genes involving the 
MLL
 gene at 11q23), and a complex karyotype with more 
than five chromosomal abnormalities.
D. Mixed Phenotype Acute Leukemias
These leukemias consist of blasts that lack differentiation 
along the lymphoid or myeloid lineage or blasts that 
express both myeloid and lymphoid lineage-specific anti
-
gens. This group is considered very high risk and has a 
poor prognosis. The limited available data suggest that an 
“acute lymphoblastic leukemia–like” regimen followed by 
allogeneic stem cell transplant may be advisable; addition 
of a tyrosine kinase inhibitor in patients with t(9;22) trans
-
location is recommended.
 
»
Most patients have been ill only for days or weeks. Bleeding 
(usually due to thrombocytopenia) occurs in the skin and 
mucosal surfaces, with gingival bleeding, epistaxis, or 
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menorrhagia. Less commonly, widespread bleeding is seen 
in patients with disseminated intravascular coagulation 
(DIC) (in APL and monocytic leukemia). Infection is due 
to neutropenia, with the risk of infection rising as the neu
-
trophil count falls below 500/mcL (0.5 × 10
9
/L). Common 
presentations include cellulitis, pneumonia, and perirectal 
infections; death within a few hours may occur if treatment 
with appropriate antibiotics is delayed. Fungal infections 
are also commonly seen.
Patients may also seek medical attention because of 
gum hypertrophy and bone and joint pain. The most dra
-
matic presentation is hyperleukocytosis, in which a mark
-
edly elevated circulating blast count (total white blood 
count greater than 100,000/mcL) leads to impaired circu
-
lation, presenting as headache, confusion, and dyspnea. 
Such patients require emergent chemotherapy with 
adjunctive leukapheresis as mortality approaches 40% in 
the first 48 hours.
On examination, patients appear pale and have purpura 
and petechiae; signs of infection may not be present. Sto
-
matitis and gum hypertrophy may be seen in patients with 
monocytic leukemia, as may rectal fissures. There is vari
-
able enlargement of the liver, spleen, and lymph nodes. 
Bone tenderness may be present, particularly in the ster
-
num, tibia, and femur.
The hallmark of acute leukemia is the combination of pan
-
cytopenia with circulating blasts. However, blasts may be 
absent from the peripheral smear in as many as 10% of 
cases (“aleukemic leukemia”). The bone marrow is usually 
hypercellular and dominated by blasts. More than 20% 
blasts are required to make a diagnosis of acute leukemia.
Hyperuricemia may be seen. If DIC is present, the 
fibrinogen level will be reduced, the prothrombin time 
prolonged, and fibrin degradation products or fibrin 
D-dimers present. Patients with ALL (especially T cell) 
may have a mediastinal mass visible on chest radiograph. 
Meningeal leukemia will have blasts present in the spinal 
fluid, seen in approximately 5% of cases at diagnosis; it is 
more common in monocytic types of AML and can be seen 
with ALL.
The 
Auer rod,
 an eosinophilic needle-like inclusion in 
the cytoplasm, is pathognomonic of AML and, if seen, 
secures the diagnosis. The phenotype of leukemia cells is 
usually demonstrated by flow cytometry or immunohisto
-
chemistry. AML cells usually express myeloid antigens 
such as CD13 or CD33 and myeloperoxidase. ALL cells of 
B lineage will express CD19, and most cases will express 
CD10, formerly known as the “common ALL antigen. ” ALL 
cells of T lineage will usually not express mature T-cell 
markers, such as CD3, CD4, or CD8, but will express some 
combination of CD2, CD5, and CD7 and will not express 
surface immunoglobulin. Almost all ALL cells express ter
-
minal deoxynucleotidyl transferase (TdT).
 
»
AML must be distinguished from other myeloproliferative 
disorders, CML, and myelodysplastic syndromes. Acute 
leukemia may also resemble a left-shifted bone marrow 
recovering from a previous toxic insult. If the diagnosis is 
in doubt, a bone marrow study should be repeated in sev
-
eral days to see if maturation has taken place. ALL must be 
separated from other lymphoproliferative disease such as 
CLL, lymphomas, and hairy cell leukemia. It may also be 
confused with the atypical lymphocytosis of mononucleo
-
sis and pertussis.
 
»
Treatment
Most patients up to age 60 with acute leukemia are treated 
with the objective of cure. The first step in treatment is to 
obtain complete remission, defined as normal peripheral 
blood with resolution of cytopenias, normal bone marrow 
with no excess blasts, and normal clinical status. The type 
of initial chemotherapy depends on the subtype of 
leukemia.
1. AML—
Most patients with AML are treated with a com
-
bination of an anthracycline (daunorubicin or idarubicin)

leukemia.
1. AML—
-
bination of an anthracycline (daunorubicin or idarubicin) 
plus cytarabine, either alone or in combination with other 
agents. This therapy will produce complete remissions in 
80–90% of patients under age 60 years and in 50–60% of 
older patients (see Table 39–2). Older patients with AML 
who are not candidates for traditional chemotherapy may 
be given 5-azacitidine, decitabine, or clofarabine initially 
with acceptable outcomes. Addition of the bcl2 inhibitor 
venetoclax to these agents shows higher complete remis
-
sion rates in phase 2 studies.
Once a patient has entered remission, post-remission 
therapy should be given with curative intent whenever pos
-
sible. Options include standard chemotherapy and alloge
-
neic stem cell transplantation. The optimal treatment 
strategy depends on the patient’s age and clinical status, 
and the genetic risk factor profile of the leukemia. Patients 
with a favorable genetic profile can be treated with chemo
-
therapy alone or with autologous transplant with cure rates 
of 60–80%. Patients who do not enter remission (primary 
induction failure) or those with high-risk genetics have 
cure rates of less than 10% with chemotherapy alone and 
are referred for allogeneic stem cell transplantation. For 
intermediate-risk patients with AML, cure rates are 
35–40% with chemotherapy and 40–60% with allogeneic 
transplantation. Addition of the FLT3 kinase inhibitor 
midostaurin to the induction, consolidation, and mainte
-
nance therapy of AML patients with 
FLT3
 mutation has 
been shown to prolong event-free and overall survival.
Patients over age 60 have had a poor prognosis, even in 
first remission, when treated with standard chemotherapy 
approaches, and only 10–20% become long-term survivors. 
The use of reduced-intensity allogeneic transplant has 
improved the outcome for such patients, with studies sug
-
gesting that up to 40% of selected patients may be cured.
Once leukemia has recurred after initial chemotherapy, 
the prognosis is poor. For patients in second remission, 
transplantation offers a 20–30% chance of cure. Targeted 
therapies directed at recurrent genetic mutations (
FLT3, 
IDH1/ IDH2
) have shown promising activity in this setting, 
and the IDH2 inhibitor enasidenib was approved by the 
FDA in 2017.
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2. ALL—
Adults with ALL are treated with combination 
chemotherapy, including daunorubicin, vincristine, pred
-
nisone, and asparaginase. This treatment produces com
-
plete remissions in 90% of patients. Those patients with 
Philadelphia chromosome-positive ALL (or 
bcr-abl
-
positive ALL) should have a tyrosine kinase inhibitor, such 
as dasatinib, added to their initial chemotherapy. Remis
-
sion induction therapy for ALL is less myelosuppressive 
than treatment for AML and does not necessarily produce 
marrow aplasia. Patients should also receive central ner
-
vous system prophylaxis so that meningeal sequestration of 
leukemic cells does not develop.
After achieving complete remission, patients may be 
treated with either additional cycles of chemotherapy or 
high-dose chemotherapy and stem cell transplantation. 
Treatment decisions are made based on patient age and 
disease risk factors. Adults younger than 39 years have 
uniformly better outcomes when treated under pediatric 
protocols. Low-risk patients with ALL may be treated with 
chemotherapy alone with a 70% chance of cure. Intermedi
-
ate-risk patients have a 30–50% chance of cure with che
-
motherapy, and high-risk patients are rarely cured with 
chemotherapy alone. High-risk patients with adverse cyto
-
genetics or poor responses to chemotherapy are best 
treated with allogeneic transplantation. Minimal residual 
disease testing early on can also identify high-risk patients 
who will not be cured with chemotherapy alone. For 
patients with relapsed disease, the bispecific antibody 
blinatumomab has shown remarkable response rates as a 
bridge to transplantation and is considered superior to 
salvage chemotherapy options. Tisagenlecleucel is a ther
-
apy utilizing autologous T cells engineered to express an anti-
CD-19 antigen receptor (CART-19) and is FDA-approved for 
the treatment of children and young adults with relapsed/
refractory B-ALL.
 
»
Prognosis
Approximately 70–80% of adults with AML under age 60 
years achieve complete remission and ~50% are cured using 
risk-adapted post-remission therapy. Older adults with 
AML achieve complete remission in up to 50% of instances. 
The cure rates for older patients with AML have been very 
low (approximately 10–20%) even if they achieve remission 
and are able to receive post-remission chemotherapy. 
Reduced-intensity allogeneic transplantation is increasingly 
being utilized in order to improve on these outcomes.
Patients younger than 39 years with ALL have excellent 
outcomes after undergoing chemotherapy followed by risk-
adapted intensification and transplantation (cure rates of 
60–80%). Patients with adverse cytogenetics, poor response 
to chemotherapy, or older age have a much lower chance of 
cure (cure rates of 20–40%).
 
»
 
»
Most patients with acute leukemia will be admitted for 
Döhner H et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert 
panel. Blood. 2017 Jan 26;129(4):424–47. [PMID: 27895058]
Lo-Coco F et al. Current standard treatment of adult acute promy
-
elocytic leukaemia. Br J Haematol. 2016 Mar;172(6):841–54. 
[PMID: 26687281]
Marks DI et al. Management of adults with T-cell lymphoblastic 
leukemia. Blood. 2017 Mar 2;129(9):1134–42. Erratum in: 
Blood. 2017 Apr 13;129(15):2204. [PMID: 28115371]
Rytting ME et al. Acute lymphoblastic leukemia in adolescents 
and young adults. Cancer. 2017 Jul 1;123(13):2398–403. 
[PMID: 28328172]
Sanz MA et al. Emerging strategies for the treatment of older 
patients with acute myeloid leukemia. Ann Hematol. 2016 Oct;
 
95(10):1583–93. [PMID: 27118541]
CHRONIC LYMPHOCYTIC LEUKEMIA
 
»
B-cell lymphocytosis with CD19 expression greater 
than 5000/mcL.
 
»
Coexpression of CD19, CD5 on lymphocytes.
 
»

»
 
»
 
»
CLL is a clonal malignancy of B lymphocytes. The disease 
is usually indolent, with slowly progressive accumulation 
of long-lived small lymphocytes. These cells are immune-
incompetent and respond poorly to antigenic stimulation.
CLL is manifested clinically by immunosuppression, 
bone marrow failure, and organ infiltration with lympho
-
cytes. Immunodeficiency is also related to inadequate 
antibody production by the abnormal B cells. With 
advanced disease, CLL may cause damage by direct tissue 
infiltration.
CLL usually pursues an indolent course, but some sub
-
types behave more aggressively; a variant, prolymphocytic 
leukemia, is more aggressive. The morphology of the latter is 
different, characterized by larger and more immature cells. 
In 5–10% of cases, CLL may be complicated by autoimmune 
hemolytic anemia or autoimmune thrombocytopenia. In 
approximately 5% of cases, while the systemic disease 
remains stable, an isolated lymph node transforms into an 
aggressive large-cell lymphoma (
Richter syndrome
).
 
»
CLL is a disease of older patients, with 90% of cases occur
-
ring after age 50 years and a median age at presentation of 
70 years. Many patients will be incidentally discovered to 
have lymphocytosis. Others present with fatigue or lymph
-
adenopathy. On examination, 80% of patients will have 
diffuse lymphadenopathy and 50% will have enlargement 
of the liver or spleen.
The long-standing Rai classification system remains prog
-
nostically useful: stage 0, lymphocytosis only; stage I, lympho
-
cytosis plus lymphadenopathy; stage II, organomegaly (spleen, 
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liver); stage III, anemia; stage IV , thrombocytopenia. These 
stages can be collapsed into low risk (stages 0–I), intermediate 
risk (stage II), and high risk (stages III–IV).
The hallmark of CLL is isolated lymphocytosis. The white 
blood cell count is usually greater than 20,000/mcL 
 
(20 × 10
9
/L) and may be markedly elevated to several hun
-
dred thousand. Usually 75–98% of the circulating cells are 
lymphocytes. Lymphocytes appear small and mature, with 
condensed nuclear chromatin, and are morphologically 
indistinguishable from normal small lymphocytes, but 
smaller numbers of larger and activated lymphocytes may 
be seen. The hematocrit and platelet count are usually nor
-
mal at presentation. The bone marrow is variably infiltrated 
with small lymphocytes. The immunophenotype of CLL 
demonstrates coexpression of the B lymphocyte lineage 
marker CD19 with the T lymphocyte marker CD5; this 
finding is commonly observed only in CLL and mantle cell 
lymphoma. CLL is distinguished from mantle cell lym
-
phoma by the expression of CD23, low expression of surface 
immunoglobulin and CD20, and the absence of a transloca
-
tion or overexpression of cyclin D1. Patients whose CLL 
cells have mutated forms of the immunoglobulin gene 
(IgVH somatic mutation) have a more indolent form of 
disease; these cells typically express low levels of the surface 
antigen CD38 and do not express the zeta-associated pro
-
tein (ZAP-70). Conversely, patients whose cells have unmu
-
tated IgVH genes and high levels of ZAP-70 expression do 
less well and require treatment sooner. The assessment of 
genomic changes by fluorescence in-situ hybridization 
(FISH) provides important prognostic information. The 
finding of deletion of chromosome 17p (TP53) confers the 
worst prognosis, while deletion of 11q (ATM) confers an 
inferior prognosis to the average genotype, and isolated 
deletion of 13q has a more favorable outcome.
Hypogammaglobulinemia is present in 50% of patients 
and becomes more common with advanced disease. In some, 
a small amount of IgM paraprotein is present in the serum.
 
»
Few syndromes can be confused with CLL. Viral infections 
producing lymphocytosis should be obvious from the pres
-
ence of fever and other clinical findings; however, fever may 
occur in CLL from concomitant bacterial infection. Pertussis 
may cause a particularly high total lymphocyte count. Other 
lymphoproliferative diseases such as Waldenström macro
-
globulinemia, hairy cell leukemia, or lymphoma (especially 
mantle cell) in the leukemic phase are distinguished on the 
basis of the morphology and immunophenotype of circulat
-
ing lymphocytes and bone marrow. Monoclonal B-cell lym
-
phocytosis is a disorder characterized by fewer than 5000/mcL 
B cells and is considered a precursor to B-CLL.
 
»
Treatment
The treatment of CLL is evolving as several active targeted 
agents emerge. Most cases of early indolent CLL require no 
specific therapy, and the standard of care for early-stage 
disease has been observation. Indications for treatment 
include progressive fatigue, symptomatic lymphadenopa
-
thy, anemia, or thrombocytopenia. These patients have 
either symptomatic and progressive Rai stage II disease or 
stage III/IV disease. Initial treatment for patients younger 
than 70 years without significant comorbidities historically 
consisted of chemoimmunotherapy with either FCR 
(fludarabine with cyclophosphamide and rituximab) or BR 
(bendamustine with rituximab). The latter combination is 
better tolerated and associated with fewer adverse events 
but results in a shorter time to progression (see Table 39–3). 
The Bruton tyrosine kinase inhibitor ibrutinib is a well-
tolerated, oral agent given at 420 mg daily; it has shown 
remarkable activity and duration of response in the front-
line setting and is another option for those patients who

line setting and is another option for those patients who 
wish to avoid chemotherapy. Ibrutinib can be associated 
with hypertension, cardiac arrhythmias, rash, and increased 
infections. Caution should be exercised when this agent is 
used in conjunction with CYP3A inhibitors or inducers. In 
addition, there is a potential for serious bleeding when it is 
used in patients taking warfarin.
For older patients or young patients with significant 
comorbidities, chlorambucil, 0.6–1 mg/kg orally, every 2 or 
3 weeks, had been the standard therapy. The monoclonal 
antibody obinutuzumab in combination with chlorambucil 
produces a significant number of responses (75%), includ
-
ing elimination of disease at the molecular level (in 17%), 
and offers another well-tolerated choice in this patient 
population. However, ibrutinib has become the standard of 
care in the United States for these patients, based on its 
tolerability profile.
For patients with relapsed or refractory disease, both 
idelalisib (a PI3 kinase delta inhibitor) and ibrutinib dem
-
onstrate significant activity, even for patients with high-
risk genetics. Both of these agents can be associated with 
marked lymphocytosis due to release of tumor cells from 
the lymph nodes into the peripheral blood. This results in 
a significant early reduction in lymphadenopathy but a 
potentially misleading, more delayed clearance of periph
-
eral blood and bone marrow. Idelalisib, 150 mg orally twice 
a day, is given in combination with rituximab. There are 
risks for colitis, liver injury, and fatal infectious complica
-
tions in patients treated with idelalisib. Patients should be 
given antimicrobial prophylaxis and monitored closely 
while taking idelalisib. In patients with deletion of chromo
-
some 17p, treatment with ibrutinib can result in a sus
-
tained duration of response (85% at 2 years), a breakthrough 
in this disease. The targeted oral bcl2 inhibitor venetoclax 
(slowly titrated up to 400 mg daily) is approved in the 
United States for this specific group of patients with similar 
response rates and a substantial number of minimal resid
-
ual disease (MRD) negative responses. However, it can be 
associated with tumor lysis and neutropenia, and patients 
may require hospitalization for initial therapy.
Associated autoimmune hemolytic anemia or immune 
thrombocytopenia may require treatment with rituximab, 
prednisone, or splenectomy. Fludarabine should be avoided 
in patients with autoimmune hemolytic anemia since it may 
exacerbate it. Rituximab should be used with caution in 
patients with past HBV infection since HBV reactivation, 
fulminant hepatitis, and, rarely, death can occur without 
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anti-HBV agent prophylaxis. Patients with recurrent bacte
-
rial infections and hypogammaglobulinemia benefit from 
prophylactic infusions of gamma globulin (0.4 g/kg/month), 
but this treatment is very expensive and can be justified only 
when these infections are severe. Patients undergoing ther
-
apy with a nucleoside analogue (fludarabine, pentostatin) 
should receive anti-infective prophylaxis for 
Pneumocystis 
jirovecii
 pneumonia, herpes viruses, and invasive fungal 
infections until there is evidence of T-cell recovery.
Allogeneic transplantation offers potentially curative 
treatment for patients with CLL, but it should be used only 
in patients whose disease cannot be controlled by the avail
-
able therapies. Nonmyeloablative allogeneic transplant can 
result in over 40% long-term disease control in CLL at the 
risk of moderate toxicity.
 
»
Prognosis
Therapies have changed the prognosis of CLL. In the past, 
median survival was approximately 6 years, and only 25% of 
patients lived more than 10 years. Patients with stage 0 or 
stage I disease have a median survival of 10–15 years, and 
these patients may be reassured that they can live a normal 
life for many years. Patients with stage III or stage IV dis
-
ease had a median survival of less than 2 years in the past, 
but with current therapies, 2-year survival is now more than 
90% and the long-term outlook appears to be substantially 
changed. For patients with high-risk and resistant forms of 
CLL, there is evidence that allogeneic transplantation can 
overcome risk factors and lead to long-term disease 
control.
 
»
All patients with CLL should be referred to a hematologist.
 
»
Hospitalization is rarely needed.
Hallek M. Chronic lymphocytic leukemia: 2017 update on 
diagnosis, risk stratification, and treatment. Am J Hematol. 
2017 Sep;92(9):946–65. [PMID: 28782884]
Jain N et al. Richter transformation of CLL. Expert Rev Hematol. 
2016 Aug;9(8):793–801. [PMID: 27351634]
Kharfan-Dabaja MA et al. Clinical practice recommendations 
for use of allogeneic hematopoietic cell transplantation in 
chronic lymphocytic leukemia on behalf of the Guidelines 
Committee of the American Society for Blood and Marrow 
Transplantation. Biol Blood Marrow Transplant. 2016 Dec;
 
22(12):2117–25. [PMID: 27660167]
HAIRY CELL LEUKEMIA
 
»
 
»
Splenomegaly, often massive.
 
»
Hairy cells present on blood smear and especially 
in bone marrow biopsy.
 
»
Hairy cell leukemia is a rare malignancy of hematopoietic 
stem cells differentiated as mature B-lymphocytes with 
hairy cytoplasmic projections. The V600E mutation in the 
BRAF
 gene is recognized as the causal genetic event of 
hairy cell leukemia, since it is detectable in almost all cases 
at diagnosis and is present at relapse.
 
»
The disease characteristically presents in middle-aged 
men. The median age at presentation is 55 years, and there 
is a striking 5:1 male predominance. Most patients present 
with gradual onset of fatigue, others complain of symptoms 
related to markedly enlarged spleen, and some come to 
attention because of infection.
Splenomegaly is almost invariably present and may be 
massive. The liver is enlarged in 50% of cases; lymphade
-
nopathy is uncommon.
Hairy cell leukemia is usually an indolent disorder 
whose course is dominated by pancytopenia and recurrent 
infections, including mycobacterial infections.
The hallmark of hairy cell leukemia is pancytopenia. Ane
-
mia is nearly universal, and 75% of patients have thrombo
-
cytopenia and neutropenia. The “hairy cells” are usually 
present in small numbers on the peripheral blood smear 
and have a characteristic appearance with numerous cyto
-
plasmic projections. The bone marrow is usually inaspi
-
rable (dry tap), and the diagnosis is made by characteristic

-
-
rable (dry tap), and the diagnosis is made by characteristic 
morphology on bone marrow biopsy. The hairy cells have 
a characteristic histochemical staining pattern with tar
-
trate-resistant acid phosphatase (TRAP). On immunophe
-
notyping, the cells coexpress the antigens CD11c, CD20, 
CD22, CD25, CD103, and CD123. Pathologic examination 
of the spleen shows marked infiltration of the red pulp with 
hairy cells. This is in contrast to the usual predilection of 
lymphomas to involve the white pulp of the spleen.
 
»
Hairy cell leukemia should be distinguished from other 
-
globulinemia and non-Hodgkin lymphomas. It also may be 
confused with other causes of pancytopenia, including 
hypersplenism due to any cause, aplastic anemia, and par
-
oxysmal nocturnal hemoglobinuria.
 
»
Treatment
Treatment is indicated for symptomatic disease, ie, splenic 
discomfort, recurrent infections, or significant cytopenias. 
The treatment of choice is a nucleoside analog, specifically 
pentostatin or cladribine for a single course, producing a 
complete remission in 70–95% of patients. Treatment is 
associated with infectious complications, and patients 
should be closely monitored. The median duration of 
response is over 8 years and patients who relapse a year or 
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more after initial therapy can be treated again with one of 
these agents. Rituximab can be used in the relapsed setting 
either as a single agent or in combination with a nucleoside 
analog. The BRAF inhibitor vemurafenib exhibits ~100% 
overall response rate in patients with refractory/relapsed 
hairy cell leukemia, with 35–40% complete remissions. The 
median relapse-free survival is ~19 months in patients who 
achieved complete remission and 6 months in those who 
obtained a partial response.
 
»
More than 95% of patients with hairy cell leukemia live longer 
than 10 years.
Grever MR et al. Consensus guidelines for the diagnosis and 
management of patients with classic hairy cell leukemia. 
Blood. 2017 Feb 2;129(5):553–60. [PMID: 27903528]
Pettirossi V et al. 
BRAF
 inhibitors reverse the unique molecular 
signature and phenotype of hairy cell leukemia and exert potent 
anti-leukemic activity. Blood. 2015 Feb 19;125(8):1207–16. 
[PMID: 25480661]
Wierda WG et al. Hairy cell leukemia, version 2.2018, NCCN 
Clinical Practice Guidelines in Oncology. J Natl Compr Canc 
Netw. 2017 Nov;15(11):1414–27. [PMID: 29118233]
 
º
LYM
ph
OMAS
NON-HODGKIN LYMPHOMAS
 
»
Often present with painless lymphadenopathy.
 
»
Diagnosis is made by tissue biopsy.
 
»
The non-Hodgkin lymphomas are a heterogeneous group 
of cancers of lymphocytes usually presenting as enlarged 
lymph nodes. The disorders vary in clinical presentation 
and course from indolent to rapidly progressive.
Molecular biology has provided clues to the pathogenesis 
of these disorders, often a matter of balanced chromosomal 
translocations whereby an oncogene becomes juxtaposed 
next to either an immunoglobulin gene (B-cell lymphoma) 
or the T-cell receptor gene or related gene (T-cell lym
-
phoma). The net result is oncogene overexpression and 
development of lymphoma. The best-studied example is 
Burkitt lymphoma, in which a characteristic cytogenetic 
abnormality of translocation between the long arms of chro
-
mosomes 8 and 14 has been identified. The protooncogene 
c-
myc
 is translocated from its normal position on chromo
-
some 8 to the immunoglobulin heavy chain locus on chro
-
mosome 14. Overexpression of c-
myc
 is related to malignant 
transformation through excess B-cell proliferation. In the 
follicular lymphomas, the t(14;18) translocation is charac
-
teristic and 
bcl-2 is
 overexpressed, resulting in protection 
against apoptosis, the usual mechanism of B-cell death.
Table 13–16.
 
of B-cell neoplasms (most common).
Precursor B-cell lymphoblastic lymphoma
Mature B-cell lymphomas
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Monoclonal B-cell lymphocytosis
Hairy cell leukemia
Plasma cell myeloma
Diffuse large B-cell lymphoma
Primary diffuse large B-cell lymphoma of the CNS
High-grade B-cell lymphoma, with 
MYC
 and 
BCL2
 and/or 
BCL6
 
rearrangements
 
M
ediastinal large B-cell lymphoma
 
F
ollicular lymphoma
 
Small 
lymphocytic lymphoma
 
L
ymphoplasmacytic lymphoma (Waldenström 
 
macroglobulinemia)
 
M
antle cell lymphoma
 
Burk
itt lymphoma
 
M
arginal zone lymphoma
  
MALT type
  
Nodal type
  
Splenic type
Mature T (and NK cell) lymphomas
 
Anaplastic 
large-cell lymphoma
 
Ang
ioimmunoblastic T-cell lymphoma
 
P
eripheral T-cell lymphoma, NOS
 
C
utaneous T-cell lymphoma (Mycosis fungoides, 
 
S
ézary syndrome)
 
Ex
tranodal NK/T-cell lymphoma, nasal type
 
A
dult T-cell leukemia/lymphoma
 
T
-cell large granular lymphocytic leukemia
Hodgkin lymphoma
 
Nodular 
lymphocyte predominant Hodgkin lymphoma
 
Classic Hodgk
in lymphoma
Posttransplant lymphoproliferative disorders
Histiocytic and dendritic cell neoplasms
CNS, central nervous system; MALT, mucosa-associated lymphoid 
tissue; NOS, not otherwise specified.
Classification of the lymphomas is a dynamic area still

Classification of the lymphomas is a dynamic area still 
undergoing evolution. The 2017 grouping (Table 13–16) 
separates diseases based on both clinical and pathologic 
features. Eighty-five percent of non-Hodgkin lymphomas 
are B-cell and 15% are T-cell or NK-cell in origin. Even 
though non-Hodgkin lymphomas represent a diverse 
group of diseases, they are historically divided in two cat
-
egories based on clinical behavior and pathology: the indo
-
lent (low-grade) and the aggressive (intermediate- or 
high-grade).
 
»
Patients with non-Hodgkin lymphomas usually present 
with lymphadenopathy. Involved lymph nodes may be 
present peripherally or centrally (in the retroperitoneum, 
mesentery, and pelvis). The indolent lymphomas are usu
-
ally disseminated at the time of diagnosis, and bone mar
-
row involvement is frequent. Many patients with lymphoma 
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have constitutional symptoms such as fever, drenching 
night sweats, and weight loss of greater than 10% of prior 
body weight (referred to as “B” symptoms).
On examination, lymphadenopathy may be isolated or 
diffuse, and extranodal sites of disease (such as the skin, 
gastrointestinal tract, liver, and bone marrow) may be 
found. Patients with Burkitt lymphoma are noted to have 
abdominal pain or abdominal fullness because of the pre
-
dilection of the disease for the abdomen.
Once a pathologic diagnosis is established, staging is 
done using a whole-body positron emission tomogra
-
phy (PET)/CT scan, a bone marrow biopsy, and, in 
patients with high-grade lymphoma or intermediate-
grade lymphoma with high-risk features, a lumbar 
puncture.
The peripheral blood is usually normal even with extensive 
bone marrow involvement by lymphoma. Circulating lym
-
phoma cells in the blood are not commonly seen.
Bone marrow involvement is manifested as paratra
-
becular monoclonal lymphoid aggregates. In some high-
grade lymphomas, the meninges are involved and 
malignant cells are found with cerebrospinal fluid cytology. 
The serum LD, a useful prognostic marker, is incorporated 
in risk stratification of treatment.
The diagnosis of lymphoma is made by tissue biopsy. 
Needle aspiration may yield evidence for non-Hodgkin 
lymphoma, but a lymph node biopsy (or biopsy of involved 
extranodal tissue) is required for accurate diagnosis and 
classification.
 
»
Treatment
A. Indolent Lymphomas
The most common lymphomas in this group are follicular 
lymphoma, marginal zone lymphomas, and small lympho
-
cytic lymphoma (CLL). The treatment of 
indolent lym
-
phomas
 depends on the stage of disease and the clinical 
status of the patient. A small number of patients have 
limited disease with only one or two contiguous abnormal 
lymph node groups and may be treated with localized 
irradiation with curative intent. However, most patients 
(85%) with indolent lymphoma have disseminated disease 
at the time of diagnosis and are not considered curable. 
Historically, treatment of these patients has not affected 
overall survival; therefore, treatment is offered only when 
symptoms develop or for high tumor bulk. Following each 
treatment response, patients will experience a relapse at 
traditionally shorter intervals. Some patients will have tem
-
porary spontaneous remissions (8%). There are an increas
-
ing number of reasonable treatment options for indolent 
lymphomas, but no consensus exists on the best strategy. 
Treatment with rituximab (375 mg/m
2
 intravenously 
weekly for 4 weeks) is commonly used either alone or in 
combination with chemotherapy and may be the only 
agent to affect overall survival in these disorders. Patients 
should be screened for hepatitis B because rare cases of 
fatal fulminant hepatitis have been described with the use 
of anti-CD20 monoclonal therapies without anti-HBV 
agent prophylaxis. Rituximab is added to chemotherapy 
regimens including bendamustine; cyclophosphamide, 
vincristine, and prednisone (R-CVP); and cyclophospha
-
mide, doxorubicin, vincristine, and prednisone (R-CHOP) 
(see Table 39–3). Radioimmunoconjugates that fuse anti-B 
cell monoclonal antibodies with radioactive nuclides can 
produce higher response rates compared to antibody alone 
but are infrequently used. One such agent (yttrium-90 
ibritumomab tiuxetan) is available in the United States. 
Some patients with clinically aggressive low-grade lym
-
phomas may be appropriate candidates for allogeneic stem 
cell transplantation with curative intent. The role of 
autologous hematopoietic stem cell transplantation 
remains uncertain, but some patients with recurrent dis
-
ease appear to have prolonged remissions without the 
expectation of cure.
Patients with mucosal-associated lymphoid tumors of 
the stomach may be appropriately treated with combina
-
tion antibiotics directed against

-
tion antibiotics directed against 
H pylori
 and with acid 
blockade but require frequent endoscopic monitoring. 
Alternatively, MALT confined to the stomach can also be 
cured with whole-stomach radiotherapy.
B. Aggressive Lymphomas
diffuse large B-cell lymphoma
 are treated 
with curative intent. Most patients are treated with six 
cycles of immunochemotherapy such as R-CHOP (see 
Table 39–3). Involved nodal radiotherapy (INRT) may be 
added for patients with bulky or extranodal disease. 
Patients with diffuse large B-cell lymphoma who relapse 
after initial chemotherapy can still be cured by autolo
-
gous hematopoietic stem cell transplantation if their 
disease remains responsive to chemotherapy. For patients 
who do not respond to second-line chemotherapy, the 
FDA has approved the chimeric antigen receptor T-cell 
therapy axicabtagene ciloleucel, which has a durable 
complete response rate of ~40% but is associated with 
significant systemic cytokine release syndrome and 
neurotoxicity.
A subtype of diffuse large B-cell lymphoma with chro
-
mosomal translocations affecting 
MYC
, such as t(8;14), 
and affecting 
BCL2
, such as t(14;18), is called “double-hit 
lymphoma” and has a very aggressive course. Patients with 
this disease may do better with dose-adjusted R-EPOCH 
therapy. About 25% of patients with diffuse large B-cell 
lymphoma have been identified as “double-protein expres
-
sors” with overexpression of 
MYC
 and 
BCL2
 by immuno
-
histochemistry. While the outcomes with R-CHOP are 
inferior, no definitive alternative treatment recommenda
-
tions can be made at this time.
Mantle cell lymphoma
 is not effectively treated with 
standard immunochemotherapy regimens. Intensive ini
-
tial immunochemotherapy including autologous hemato
-
poietic stem cell transplantation has been shown to 
improve outcomes. Reduced-intensity allogeneic stem cell 
transplantation offers curative potential for selected 
patients. Ibrutinib and acalabrutinib are active in relapsed 
or refractory patients with mantle cell lymphoma. For 
primary central nervous system lymphoma,
 repetitive 
cycles of high-dose intravenous methotrexate with 
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rituximab early in the treatment course produce better 
results than whole-brain radiotherapy and with less cogni
-
tive impairment.
high-grade lymphomas
 (Burkitt or lym
-
phoblastic) require urgent, intense, cyclic chemotherapy in 
the hospital similar to that given for ALL, and they also 
require intrathecal chemotherapy as central nervous sys
-
tem prophylaxis.
peripheral T-cell lymphomas
 usually 
have advanced stage nodal and extranodal disease and 
typically have inferior response rates to therapy compared 
to patients with aggressive B-cell disease. Autologous stem 
cell transplantation is often incorporated in first-line ther
-
apy. The antibody-drug conjugate brentuximab vedotin has 
significant activity in patients with relapsed CD30 positive 
peripheral T-cell lymphomas, such as anaplastic large-cell 
lymphoma.
 
»
Prognosis
The median survival of patients with indolent lymphomas 
is 10–15 years. These diseases ultimately become refractory 
to chemotherapy. This often occurs at the time of histologic 
progression of the disease to a more aggressive form of 
lymphoma.
The International Prognostic Index is widely used to 
categorize patients with aggressive lymphoma into risk 
groups. Factors that confer adverse prognosis are age 
over 60 years, elevated serum LD, stage III or stage IV 
disease, more than one extranodal site of disease, and 
poor performance status. Cure rates range from more 
than 80% for low-risk patients (zero risk factors) to less 
than 50% for high-risk patients (four or more risk 
factors).
For patients who relapse after initial chemotherapy, the 
prognosis depends on whether the lymphoma is still 
responsive to chemotherapy. If the lymphoma remains 
responsive to chemotherapy, autologous hematopoietic 
stem cell transplantation offers a 50% chance of long-term 
lymphoma-free survival.
The treatment of older patients with lymphoma has 
been difficult because of poorer tolerance of aggressive 
chemotherapy. The use of myeloid growth factors and pro
-
phylactic antibiotics to reduce neutropenic complications 
may improve outcomes.
Molecular profiling techniques using gene array tech
-
nology and immunophenotyping have defined subsets of 
lymphomas with different biologic features and prognoses 
are being studied in clinical trials to determine choice of 
therapy.
 
»
All patients with lymphoma should be referred to a hema
-
tologist or an oncologist.
 
»
Admission is necessary only for specific complications of 
lymphoma or its treatment and for the treatment of all 
high-grade lymphomas.
Armitage JO. The aggressive peripheral T-cell lymphomas: 2017. 
Am J Hematol. 2017 Jul;92(7):706–15. [PMID: 28516671]
Campo E et al. Mantle cell lymphoma: evolving management 
strategies. Blood. 2015 Jan 1;125(1):48–55. [PMID: 25499451]
Chiappella A et al. Diffuse large B-cell lymphoma in the elderly: 
standard treatment and new perspectives. Expert Rev Hematol. 
2017 Apr;10(4):289–97. [PMID: 28290728]
Kritharis A et al. Current therapeutic strategies and new treatment 
paradigms for follicular lymphoma. Cancer Treat Res. 
2015;165:197–226. [PMID: 25655611]
Kubuschok B et al. Management of diffuse large B-cell lym
-
phoma (DLBCL). Cancer Treat Res. 2015;165:271–88. 
[PMID: 25655614]
Paydas S. Primary central nervous system lymphoma: essential 
points in diagnosis and management. Med Oncol. 2017 Apr;
 
34(4):61. [PMID: 28315229]
HODGKIN LYMPHOMA
 
»
Often painless lymphadenopathy.
 
»
Constitutional symptoms may or may not be 
present.
 
»
Pathologic diagnosis by lymph node biopsy.
 
»
Hodgkin lymphoma is characterized by lymph node biopsy 
showing Reed-Sternberg cells in an appropriate reactive 
cellular background. The malignant cell is derived from B 
lymphocytes of germinal center origin.
 
»
There is a bimodal age distribution, with one peak in the

»
There is a bimodal age distribution, with one peak in the 
20s and a second over age 50 years. Most patients seek 
medical attention because of a painless mass, commonly in 
the neck. Others may seek medical attention because of 
constitutional symptoms such as fever, weight loss, or 
drenching night sweats, or because of generalized pruritus. 
An unusual symptom of Hodgkin lymphoma is pain in an 
involved lymph node following alcohol ingestion.
An important feature of Hodgkin lymphoma is its ten
-
dency to arise within single lymph node areas and spread 
in an orderly fashion to contiguous areas of lymph nodes. 
Late in the course of the disease, vascular invasion leads to 
widespread hematogenous dissemination.
Hodgkin lymphoma is divided into two subtypes: classic 
Hodgkin (nodular sclerosis, mixed cellularity, lymphocyte 
rich, and lymphocyte depleted) and non-classic Hodgkin 
(nodular lymphocyte predominant). Hodgkin lymphoma 
should be distinguished pathologically from other malig
-
nant lymphomas and may occasionally be confused with 
reactive lymph nodes seen in infectious mononucleosis, 
cat-scratch disease, or drug reactions (eg, phenytoin).
Patients undergo a staging evaluation to determine the 
extent of disease, including serum chemistries, whole-body 
PET/CT scan, and bone marrow biopsy.
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»
Treatment
Chemotherapy is the mainstay of treatment for Hodgkin 
lymphoma and ABVD (doxorubicin, bleomycin, vinblas
-
tine, dacarbazine) remains the standard first-line regimen. 
Even though others such as Stanford V (cyclophospha
-
mide, doxorubicin, vinblastine, vincristine, bleomycin, 
etoposide, prednisone) or escalated BEACOPP (bleomy
-
cin, etoposide, doxorubicin, cyclophosphamide, vincris
-
tine, procarbazine, prednisone) may improve response 
rates and reduce the need for consolidative radiotherapy, 
they are usually associated with increased toxicity and lack 
a definitive overall survival advantage. Low-risk patients 
are those with stage I or II disease without bulky lymph
-
adenopathy or evidence of systemic inflammation. They 
traditionally receive a combination of short-course chemo
-
therapy with INRT or a full course of chemotherapy alone 
(see Table 39–3). High-risk patients are those with stage III 
or IV disease or with stage II disease and a large mediasti
-
nal or other bulky mass. These patients are treated with a 
full course of ABVD for six cycles. Pulmonary toxicity can 
unfortunately occur following either chemotherapy (bleo
-
mycin) or radiation and should be treated aggressively in 
these patients, since it can lead to permanent fibrosis and 
death. A normal interim PET/CT scan after 2–4 cycles of 
chemotherapy can be used to identify patients with an 
excellent progression-free survival who can receive abbrevi
-
ated chemotherapy or forego radiation altogether. Conversely, 
an abnormal interim PET/CT scan is associated with a worse 
prognosis and should prompt early intensification of 
treatment to achieve a complete response (CR).
Classic Hodgkin lymphoma relapsing after initial treat
-
ment is treatable with high-dose chemotherapy and autolo
-
gous hematopoietic stem cell transplantation. This offers a 
35–50% chance of cure when disease is still chemotherapy 
responsive. The antibody-drug conjugate brentuximab 
vedotin has shown impressive activity in patients relapsing 
after autologous stem cell transplantation (overall response 
rate [ORR] of 75%; CR of 34%) and is FDA-approved for 
this indication. It is being studied as front-line therapy, to 
replace the bleomycin in ABVD. Last, immune checkpoint 
inhibition by PD1 blockade with nivolumab or pembroli
-
zumab has shown remarkable activity (ORR of 65%) in 
brentuximab failures.
 
»
Prognosis
All patients should be treated with curative intent. Prognosis 
in advanced stage Hodgkin lymphoma is influenced by 
seven features: stage, age, gender, hemoglobin, albumin, 
white blood cell count, and lymphocyte count. The cure rate 
is 75% if zero to two risk features are present and 55% when 
three or more risk features are present. The prognosis of 
patients with stage IA or IIA disease is excellent, with 
10-year survival rates in excess of 90%. Patients with 
advanced disease (stage III or IV) have 10-year survival rates 
of 50–60%. Poorer results are seen in patients who are older, 
those who have bulky disease, and those with lymphocyte 
depletion or mixed cellularity on histologic examination. 
Non-classic Hodgkin lymphoma (nodular lymphocyte pre
-
dominant) is highly curable with radiotherapy alone for 
early-stage disease; however, for high-stage disease, it is 
characterized by long survival with repetitive relapses after 
 
»
•	
All patients should be sent to an oncologist or 
•	
Secondary referral to a radiation oncologist might be 
 
»
Patients should be admitted for complications of the disease 
or its treatment.
Bachanova V et al. Hodgkin lymphoma in the elderly, pregnant, 
and HIV-infected. Semin Hematol. 2016 Jul;53(3):203–8. 
[PMID: 27496312]
Connors JM. Risk assessment in the management of newly diag
-
nosed classical Hodgkin lymphoma. Blood. 2015 Mar 
12;125(11):1693–702. [PMID: 25575542]

-
Donato EM et al. Immunotherapy for the treatment of Hodgkin 
lymphoma. Expert Rev Hematol. 2017 May;10(5):417–23. 
[PMID: 28359170]
Evens AM et al. The role of FDG-PET in defining prognosis of 
Hodgkin lymphoma for early-stage disease. Blood. 2014 Nov 
27;124(23):3356–64. [PMID: 25428223]
PLASMA CELL MYELOMA
 
»
Bone pain, often in the spine, ribs, or proximal 
long bones.
 
»
Monoclonal immunoglobulin (ie, paraprotein) in 
the serum or urine.
 
»
Clonal plasma cells in the bone marrow or in a tissue 
biopsy, or both.
 
»
Organ damage due to plasma cells (eg, bones, 
kidneys, hypercalcemia, anemia) or other defined 
criteria.
 
»
Plasma cell myeloma (previously called multiple myeloma) 
is a malignancy of hematopoietic stem cells terminally dif
-
ferentiated as plasma cells characterized by infiltration of 
the bone marrow, bone destruction, and paraprotein forma
-
tion. The diagnosis is established when monoclonal plasma 
cells (either kappa or lambda light chain restricted) in the 
bone marrow (any percentage) or as a tumor (plasmacy
-
toma), or both, are associated with end-organ damage (such 
as bone disease [lytic lesions seen on bone radiographs, 
magnetic resonance imaging {MRI}, or PET/CT scan], 
anemia [hemoglobin less than 10 g/dL {100 g/L}], hypercalce
-
mia [calcium greater than 11.5 mg/dL {2.9 mmol/L}], or kid
-
ney injury [creatinine greater than 2 mg/dL {176.8 mcmol/L}]) 
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with or without paraprotein elaboration. Sixty percent or 
more clonal plasma cells in the bone marrow, or a serum 
free kappa to lambda ratio of greater than 100 or less than 
0.01 (both criteria regardless of end-organ damage), are also 
diagnostic of plasma cell myeloma. Smoldering myeloma is 
defined as 10–59% clonal plasma cells in the bone marrow, 
a serum paraprotein level of 3 g/dL (30 g/L) or higher, or 
both, without plasma cell–related end-organ damage.
Malignant plasma cells can form tumors (plasmacyto
-
mas) that may cause spinal cord compression or other soft-
tissue–related problems. Bone disease is common and due 
to excessive osteoclast activation mediated largely by the 
interaction of the receptor activator of NF-kappa-B 
(RANK) with its ligand (RANKL). In plasma cell myeloma, 
osteoprotegerin (a decoy receptor for RANKL) is under
-
produced, thus promoting the binding of RANK with 
RANKL with consequent excessive bone resorption.
The paraproteins (monoclonal immunoglobulins) 
secreted by the malignant plasma cells may cause prob
-
lems in their own right. Very high paraprotein levels 
(either IgG or IgA) may cause hyperviscosity, although 
this is more common with the IgM paraprotein in 
Waldenström macroglobulinemia. The light chain com
-
ponent of the immunoglobulin, when produced in excess, 
often leads to kidney injury (frequently aggravated by 
hypercalcemia or hyperuricemia, or both). Light chain 
components may be deposited in tissues as amyloid, 
resulting in kidney failure with albuminuria and a vast 
array of systemic symptoms.
Myeloma patients are prone to recurrent infections for a 
number of reasons, including neutropenia, the underproduc
-
tion of normal immunoglobulins and the immunosuppres
-
sive effects of chemotherapy. Myeloma patients are especially 
prone to infections with encapsulated organisms such as 
 and 
.
 
»
Myeloma is a disease of older adults (median age 65 years). 
The most common presenting complaints are those related 
to anemia, bone pain, kidney disease, and infection. Bone 
pain is most common in the back, hips, or ribs or may pres
-
ent as a pathologic fracture, especially of the femoral neck 
or vertebrae. Patients may also come to medical attention 
because of spinal cord compression from a plasmacytoma 
or the hyperviscosity syndrome (mucosal bleeding, vertigo, 
nausea, visual disturbances, alterations in mental status, 
hypoxia). Many patients are diagnosed because of labora
-
tory findings of elevated total protein, hypercalcemia, pro
-
teinuria, elevated sedimentation rate, or abnormalities on 
serum protein electrophoresis obtained for symptoms or in 
routine screening studies. A few patients come to medical 
attention because of organ dysfunction due to amyloidosis.
Examination may reveal pallor, bone tenderness, or soft 
tissue masses. Patients may have neurologic signs related to 
neuropathy or spinal cord compression. Fever occurs 
mainly with infection. Acute oliguric or nonoliguric kid
-
ney injury may be present due to hypercalcemia, hyperuri
-
cemia, light chain cast injury, or primary amyloidosis.
Anemia is nearly universal. Red blood cell morphology is 
normal, but rouleaux formation is common and may be 
marked. The absence of rouleaux formation, however, 
excludes neither plasma cell myeloma nor the presence of 
a serum paraprotein. The neutrophil and platelet counts 
are usually normal at presentation. Only rarely will plasma 
cells be visible on peripheral blood smear (plasma cell 
leukemia).
The hallmark of myeloma is the finding of a paraprotein 
on serum or urine protein electrophoresis (PEP) or immu
-
nofixation electrophoresis (IFE). The majority of patients 
will have a monoclonal spike visible in the gamma- or beta-
globulin region of the PEP . The semi-quantification of the

-
globulin region of the PEP . The semi-quantification of the 
paraprotein on the PEP is referred to as the M-protein, and 
IFE will reveal this to be a monoclonal immunoglobulin. 
Approximately 15% of patients will have no demonstrable 
paraprotein in the serum on PEP because their myeloma 
cells produce only light chains and not intact immuno
-
globulin (but sometimes seen on serum IFE), and the light 
chains pass rapidly through the glomerulus into the urine. 
Urine PEP and IFE usually demonstrate the light chain 
paraprotein in this setting. The free light chain assay will 
sometimes demonstrate excess monoclonal light chains in 
serum and urine, and in a small proportion of patients, will 
be the only means to identify and quantify the paraprotein 
being produced. Overall, the paraprotein is IgG (60%), IgA 
(20%), or light chain only (15%) in plasma cell myeloma, 
with the remainder being rare cases of IgD, IgM, or 
biclonal gammopathy. In sporadic cases, no paraprotein is 
present (“nonsecretory myeloma”); these patients have 
particularly aggressive disease.
The bone marrow will be infiltrated by variable num
-
bers of monoclonal plasma cells. The plasma cells may be 
morphologically abnormal often demonstrating multi-
nucleation and vacuolization. The plasma cells will display 
marked skewing of the normal kappa-to-lambda light 
chain ratio, which will indicate their clonality. Many 
benign inflammatory processes can result in bone marrow 
plasmacytosis, but with the absence of clonality and mor
-
phologic atypia.
C. Imaging
Bone radiographs are important in establishing the diagno
-
sis of myeloma. Lytic lesions are most commonly seen in 
the axial skeleton: skull, spine, proximal long bones, and 
ribs. At other times, only generalized osteoporosis is seen. 
The radionuclide bone scan is not useful in detecting bone 
lesions in myeloma, since there is usually no osteoblastic 
component. In the evaluation of patients with known or 
suspected plasma cell myeloma, MRI and PET scans are 
more sensitive to detect bone disease than plain radio
-
graphs and are preferred.
 
»
When a patient is discovered to have a paraprotein, the 
distinction between plasma cell myeloma or another 
lymphoproliferative malignancy with a paraprotein 
(CLL, Waldenström macroglobulinemia, non-Hodgkin 
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lymphoma, primary amyloid, cryoglobulinemia) or 
monoclonal gammopathy of undetermined significance 
(MGUS) must be made. Plasma cell myeloma, smoldering 
plasma cell myeloma, and MGUS must be distinguished 
from reactive (benign) polyclonal hypergammaglobu
-
linemia (which is commonly seen in cirrhosis or chronic 
inflammation).
 
»
Treatment
Patients with low-risk smoldering myeloma are observed. 
Those with high-risk disease are treated with lenalidomide 
(an immunomodulatory agent) and dexamethasone since 
they take longer to progress to symptomatic myeloma and 
live longer than when simply observed. Most patients with 
plasma cell myeloma require treatment at diagnosis 
because of bone pain or other symptoms and complica
-
tions related to the disease. The initial treatment generally 
involves triple therapy: an immunomodulatory agent, 
such as lenalidomide; a proteasome inhibitor, such as 
bortezomib or carfilzomib; and moderate- or high-dose 
dexamethasone. The major side effects of lenalidomide are 
neutropenia and thrombocytopenia, skin rash, venous 
thromboembolism, peripheral neuropathy, and possibly 
birth defects. Bortezomib and carfilzomib have the advan
-
tages of producing rapid responses and of being effective in 
poor-prognosis myeloma. The major side effect of bortezo
-
mib is neuropathy (both peripheral and autonomic), which 
is largely ameliorated when given subcutaneously rather 
than intravenously. Carfilzomib rarely causes neuropathy 
but sometimes causes pulmonary hypertension or cardiac 
systolic dysfunction that is usually reversible. An oral pro
-
teasome inhibitor, ixazomib, is available for relapsed dis
-
ease. Pomalidomide, an immunomodulatory agent, is 
effective as salvage therapy after relapse. Other salvage 
agents include daratumumab (an anti-CD38 monoclonal 
antibody), elotuzumab (an anti-SLAMF7 monoclonal anti
-
body), and panobinostat (a histone deacetylase inhibitor).
After initial therapy, many patients under age 80 years 
are consolidated with autologous hematopoietic stem cell 
transplantation following high-dose melphalan (an alkylat
-
ing chemotherapeutic agent). Autologous stem cell trans
-
plantation prolongs both duration of remission and overall 
survival. Lenalidomide or thalidomide prolong remission 
and survival when given as posttransplant maintenance 
therapy but at the expense of an elevated rate of second 
malignancies. Proteasome inhibitors prolong remis
-
sions in high-risk patients after autologous stem cell 
transplantation.
Localized radiotherapy may be useful for palliation of 
bone pain or for eradicating tumor at the site of pathologic 
fracture. Vertebral collapse with its attendant pain and 
mechanical disturbance can be treated with vertebroplasty 
or kyphoplasty. Hypercalcemia and hyperuricemia should 
be treated aggressively and immobilization and dehydra
-
tion avoided. The bisphosphonates (pamidronate 90 mg or 
zoledronic acid 4 mg intravenously monthly) reduce 
pathologic fractures in patients with bone disease and are 
an important adjunct in this subset of patients. The bisphos
-
phonates are also used to treat myeloma-related hyper
-
calcemia. However, long-term bisphosphonates have been 
associated with a risk of osteonecrosis of the jaw and other 
bony areas, so the use of bisphosphonates is limited to 
1–2 years after definitive initial therapy. Myeloma patients 
with oliguric or anuric kidney disease at diagnosis should 
be treated aggressively with chemotherapy and considered 
for therapeutic plasma exchange (to reduce the paraprotein 
burden) because return of kidney function can commonly 
occur.
 
»
Prognosis
The outlook for patients with myeloma has been steadily 
improving for the past decade. The median survival of 
patients is more than 7 years. Patients with low-stage 
disease who lack high-risk genomic changes respond very 
well to treatment and derive significant benefit from

well to treatment and derive significant benefit from 
autologous hematopoietic stem cell transplantation and 
have survivals approaching a decade. The International 
Staging System for myeloma relies on two factors: beta-
2-microglobulin and albumin. Stage 1 patients have both 
beta-2-microglobulin less than 3.5 mg/L and albumin 
greater than 3.5 g/dL (survival more than 5 years). Stage 3 
is established when beta-2-microglobulin is greater than 
5.5 mg/L (survival less than 2 years). Stage 2 is established 
with values in between stage 1 and 3. Other adverse prog
-
nostic findings are an elevated serum LD or bone marrow 
genetic abnormalities established by FISH involving the 
immunoglobulin heavy chain locus at chromosome 
14q32, multiple copies of the 1q21-23 locus, or 17p chro
-
mosome abnormalities (causing the loss or mutation of 
TP53).
 
»
All patients with plasma cell myeloma should be referred to 
a hematologist or an oncologist.
 
»
Hospitalization is indicated for treatment of acute kidney 
injury, hypercalcemia, or suspicion of spinal cord compres
-
sion, for certain chemotherapy regimens, or for hematopoietic 
stem cell transplantation.
Bailly C et al. PET imaging for initial staging and therapy assess
-
ment in multiple myeloma patients. Int J Mol Sci. 2017 Feb 18;
 
18(2). pii: E445. [PMID: 28218709]
Broijl A et al. An update in treatment options for multiple 
myeloma in nontransplant eligible patients. Expert Opin 
Pharmacother. 2015;16(13):1945–57. [PMID: 26245702]
Dingli D et al. Therapy for relapsed multiple myeloma: guide
-
lines from the Mayo stratification for myeloma and risk-
adapted therapy. Mayo Clin Proc. 2017 Apr;92(4):578–98. 
[PMID: 28291589]
Gavriatopoulou M et al. Emerging treatment approaches for 
myeloma-related bone disease. Expert Rev Hematol. 2017 Mar;
 
10(3):217–28. [PMID: 28092987]
Laubach JP et al. Daratumumab, elotuzumab, and the develop
-
ment of therapeutic monoclonal antibodies in multiple 
myeloma. Clin Pharmacol Ther. 2017 Jan;101(1):81–8. 
[PMID: 27806428]
Moreau P et al. Frontline therapy of multiple myeloma. Blood. 
2015 May 14;125(20):3076–84. [PMID: 25838345]
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MONOCLONAL GAMMOPATHY OF 
UNDETERMINED SIGNIFICANCE
 
»
the serum (less than 3 g/dL [less than 30 g/L]) or 
urine.
 
»
Clonal plasma cells in the bone marrow less than 
10% (if performed).
 
»
No symptoms and no organ damage from the 
paraprotein.
 
»
MGUS is present in 1% of all adults, (3% of those over age 
50 years and more than 5% of those over age 70 years). 
Among all patients with paraproteins, MGUS is far more 
common than plasma cell myeloma. MGUS is defined as 
bone marrow monoclonal plasma cells less than 10% in the 
setting of a paraprotein (serum M-protein less than 3 g/dL 
[30 g/L]) and the absence of plasma cell–related end-organ 
damage. If an excess of serum free light chains (kappa or 
lambda) is established, the kappa to lambda ratio is 100 or 
less or 0.01 or greater. In approximately one-quarter of 
cases, MGUS progresses to overt malignant disease in a 
median of one decade. The transformation of MGUS to 
plasma cell myeloma is approximately 1% per year. Two 
adverse risk factors for progression of MGUS to a plasma 
cell or lymphoid disorder are an abnormal serum kappa to 
lambda free light chain ratio and a serum monoclonal pro
-
tein (M protein) level 1.5 g/dL or greater. Patient with 
MGUS have shortened survival (median 8.1 years vs 
12.4 years for age and sex-matched controls). Twelve 
percent of patients with MGUS will convert to primary 
amyloidosis in a median of 9 years. Plasma cell myeloma, 
smoldering plasma cell myeloma, and MGUS must be dis
-
tinguished from reactive (benign) polyclonal hypergam
-
maglobulinemia (which is commonly seen in cirrhosis or 
chronic inflammation).
 
»
Laboratory Findings
To establish the diagnosis, serum and urine should be 
sent for PEP and IFE to search for a monoclonal protein; 
serum should be sent for free light chain analysis and 
quantitative immunoglobulins. Additional tests include a 
hemoglobin and serum albumin, calcium, and creati
-
nine. If these additional tests are normal (or if abnormal 
is otherwise explained), then a bone marrow biopsy is 
usually deferred provided the serum M-protein is less 
than 3 g/dL (less than 30 g/L). In asymptomatic individu
-
als, a skeletal survey (radiographs) is performed, but if 
there are some bone complaints or a question regarding 
bone disease, MRI or PET/CT imaging is preferred. 
MGUS is diagnosed if patients do not meet the criteria 
for smoldering plasma cell myeloma or plasma cell 
myeloma.
 
»
Treatment
Patients with MGUS are observed without treatment.
Kyle RA et al. Long-term follow up of monoclonal gammopathy of 
undetermined significance. N Engl J Med. 2018 January 18;
 
378(3):241–9. [PMID: 29342381]
van de Donk NW et al. The clinical relevance and management 
of monoclonal gammopathy of undetermined significance 
and related disorders: recommendations from the European 
Myeloma Network. Haematologica. 2014 Jun;99(6):984–96. 
[PMID: 24658815]
Willrich MAV et al. Laboratory testing for monoclonal gam
-
mopathies: focus on monoclonal gammopathy of undeter
-
mined significance and smoldering multiple myeloma. 
Clin Biochem. 2018 Jan;51:38–47. [PMID: 28479151]
WALDENSTRÖM MACROGLOBULINEMIA
 
»
Monoclonal IgM paraprotein.
 
»
Infiltration of bone marrow by plasmacytic 
lymphocytes.
 
»
Absence of lytic bone disease.
 
»
Waldenström macroglobulinemia is a syndrome of IgM 
hypergammaglobulinemia that occurs in the setting of a 
low-grade non-Hodgkin lymphoma characterized by 
 
B cells that are morphologically a hybrid of lymphocytes 
and plasma cells. These cells characteristically secrete the 
IgM paraprotein, and many clinical manifestations of the 
disease are related to this macroglobulin.
 
»
This disease characteristically develops insidiously in

»
This disease characteristically develops insidiously in 
patients in their 60s or 70s. Patients usually present with 
fatigue related to anemia. Hyperviscosity of serum may be 
manifested in a number of ways. Mucosal and gastrointes
-
tinal bleeding is related to engorged blood vessels and 
platelet dysfunction. Other complaints include nausea, 
vertigo, and visual disturbances. Alterations in conscious
-
ness vary from mild lethargy to stupor and coma. The IgM 
paraprotein may also cause symptoms of cold agglutinin 
disease (hemolysis) or chronic demyelinating peripheral 
On examination, there may be hepatosplenomegaly or 
lymphadenopathy. The retinal veins are engorged. Purpura 
may be present. There should be no bone tenderness.
Anemia is nearly universal, and rouleaux formation is 
common, although the red blood cells are agglutinated 
when the blood smear is prepared at room temperature. 
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The anemia is related in part to expansion of the plasma 
volume by 50–100% due to the presence of the paraprotein. 
Other blood counts are usually normal. The abnormal 
plasmacytic lymphocytes may appear in small numbers on 
the peripheral blood smear. The bone marrow is character
-
istically infiltrated by the plasmacytic lymphocytes.
The hallmark of macroglobulinemia is the presence of a 
monoclonal IgM spike seen on serum PEP in the beta-
globulin region. The serum viscosity is usually increased 
above the normal of 1.4–1.8 times that of water. Symptoms 
of hyperviscosity usually develop when the serum viscosity 
is over four times that of water, and marked symptoms usu
-
ally arise when the viscosity is over six times that of water. 
Because paraproteins vary in their physicochemical prop
-
erties, there is no strict correlation between the concentra
-
tion of paraprotein and serum viscosity.
The IgM paraprotein may cause a positive antiglobulin 
(Coombs) test for complement and have cold agglutinin or 
cryoglobulin properties. If macroglobulinemia is suspected 
but the serum PEP shows only hypogammaglobulinemia, 
the test should be repeated while taking special measures 
to maintain the blood at 37°C, since the paraprotein may 
precipitate out at room temperature. Bone radiographs are 
normal, and there is no evidence of kidney injury.
 
»
Waldenström macroglobulinemia is differentiated from 
MGUS by the finding of bone marrow infiltration with 
monoclonal malignant cells. It is distinguished from CLL by 
bone marrow morphology, the absence of CD5 expression 
and the absence of lymphocytosis and from plasma cell 
myeloma by bone marrow morphology, the finding of the 
characteristic IgM paraprotein, and the absence of bone 
disease.
 
»
Treatment
Patients with marked hyperviscosity syndrome (stupor, 
coma, pulmonary edema) should be treated on an emer
-
gency basis with plasmapheresis. On a chronic basis, some 
patients can be managed with periodic plasmapheresis 
alone. As with other indolent malignant lymphoid diseases, 
rituximab (375 mg/m
2
 intravenously weekly for 4–8 weeks) 
has significant activity. However, a word of caution: the IgM 
often rises first after rituximab therapy before it falls. Com
-
bination therapy is recommended for advanced disease (see 
Table 39–3). 
MYD88
 is commonly mutated in Waldenström 
macroglobulinemia, and in patients with relapsed or refrac
-
tory disease, the BTK inhibitor ibrutinib, at a dose of 420 
mg daily, has shown significant activity with a 90% response 
rate and a 73% major response rate that can result in dura
-
ble remissions. Bortezomib, lenalidomide, and bendamus
-
tine have also been shown to have activity in this disease. 
Autologous hematopoietic stem cell transplantation is 
reserved for relapsed or refractory patients.
 
»
Prognosis
Waldenström macroglobulinemia is an indolent disease 
with a median survival rate of 5 years, and 10% of patients 
are alive at 15 years.
 
»
All patients should be referred to a hematologist or an 
oncologist.
 
»
Patients should be admitted for treatment of hyperviscosity 
syndrome.
Castillo JJ et al. Overall survival and competing risks of death in 
patients with Waldenström macroglobulinaemia: an analysis 
of the Surveillance, Epidemiology and End Results database. 
Br J Haematol. 2015 Apr;169(1):81–9. [PMID: 25521528]
Oza A et al. Waldenstrom macroglobulinemia: prognosis and 
management. Blood Cancer J. 2015 Mar 27;5:e296. [PMID: 
25815903]
Treon SP et al. Ibrutinib in previously treated Waldenström’s 
macroglobulinemia. N Engl J Med. 2015 Apr 9;372(15):1430–40. 
[PMID: 25853747]
AMYLOIDOSIS
 
»
Congo red positive amyloid protein on tissue 
biopsy.
 
»
Primary amyloid protein is kappa or lambda 
immunoglobulin light chain.
 
»
Serum or urine (or both) light chain paraprotein.
 
»

biopsy.
 
»
 
»
 
»
Amyloidosis is a rare condition whereby a protein abnor
-
mally deposits in tissue resulting in organ dysfunction. The 
propensity of a protein to be amyloidogenic is a conse
-
quence of disturbed translational or posttranslational pro
-
tein folding and lack of consequential water solubility. The 
input of amyloid protein into tissues far exceeds its output, 
so amyloid build up inexorably proceeds to organ dysfunc
-
tion and ultimately organ failure and premature death.
Amyloidosis is classified according to the type of amy
-
loid protein deposited. The six main categories are 
pri
-
mary
 (immunoglobulin light chain [AL]), 
secondary
 
(serum protein A, produced in inflammatory conditions 
[AA]), 
hereditary
 (mutated transthyretin [TTR]; many 
others), 
senile
 (wild-type TTR; atrial natriuretic peptide; 
others), 
dialysis-related
 (beta-2-microglobulin, not fil
-
tered out by dialysis membranes [Abeta-2M]), and 
LECT2
 
(associated with Latino patients). Amyloidosis is further 
classified as 
localized
 (amyloid deposits only in a single 
tissue type or organ) or, most common, 
systemic
 (wide
-
spread amyloid deposition).
 
»
localized amyloidosis
 have symptoms and 
signs related to the affected single organ, such as hoarseness 
(vocal cords) or proptosis and visual disturbance (orbits). 
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systemic amyloidosis
signs of unexplained medical syndromes, including heart 
failure (infiltrative/restrictive cardiomyopathy), nephrotic 
syndrome, malabsorption and weight loss, hepatic dysfunc
-
tion, autonomic insufficiency, carpal tunnel syndrome (often 
bilateral), and sensorimotor peripheral neuropathy. Other 
symptoms and signs include an enlarged tongue; waxy, rough 
plaques on skin; contusions (including the periorbital areas); 
cough or dyspnea; and disturbed deglutition. These symp
-
toms and signs arise insidiously, and the diagnosis of amyloi
-
dosis is generally made late in the disease process.
The diagnosis of amyloid protein requires a tissue biopsy 
that demonstrates deposition of a pink interstitial sub
-
stance in the tissue with the H&E stain. Amyloid is a triple-
stranded fibril composed of the amyloid protein, amyloid 
protein P , and glycosaminoglycan. The amyloid fibrils form 
beta-pleated sheets as demonstrated by electron micros
-
copy. In primary amyloidosis, the amyloid protein is either 
the kappa or lambda immunoglobulin light chain.
When systemic amyloidosis is suspected, a blind aspira
-
tion of the abdominal fat pad will reveal amyloid two-thirds 
of the time. If the fat pad aspiration is unrevealing, then the 
affected organ needs biopsy. In 90% of patients with pri
-
mary amyloidosis, analysis of the serum and urine will 
reveal a kappa or lambda light chain paraprotein by PEP , 
IFE, or free light chain assay; in the remainder, mass spec
-
troscopy demonstrates light chain in the tissue biopsy. 
Lambda amyloid is more common than kappa amyloid, a 
relative proportion opposite from normal B-cell stoichiom
-
etry. Most patients with primary amyloidosis have a small 
excess of kappa- or lambda-restricted plasma cells in the 
bone marrow (but less than 10%). The bone marrow may 
or may not demonstrate interstitial amyloid deposition or 
amyloid in the blood vessels.
Patients with primary cardiac amyloidosis have an infiltra
-
tive cardiomyopathy with thick ventricular walls on echocar
-
diogram that sometimes shows a unique speckling pattern. 
Paradoxically, QRS voltages are low on ECG. With renal 
amyloid, albuminuria is present, which can be in the nephrotic 
range. Late in renal involvement, kidney function decreases.
 
»
Amyloidosis must be distinguished from MGUS and plasma 
cell myeloma or other malignant lymphoproliferative disor
-
ders with an associated paraprotein. Of note, 12% of patients 
with MGUS will convert to primary amyloidosis in a 
median of 9 years. One-fifth of patients who have primary 
amyloidosis will meet the diagnostic criteria for plasma cell 
myeloma; conversely, 5% of patients with plasma cell 
myeloma will have amyloid deposition of their paraprotein 
at diagnosis.
 
»
Treatment
The treatment approach to primary amyloidosis closely 
resembles that of plasma cell myeloma. Prospective, ran
-
domized trials of plasma cell myeloma chemotherapy 
versus colchicine have demonstrated a survival benefit to 
chemotherapy. The goal is reduction of light chain produc
-
tion and deposition as a means to arrest progressive end-
organ dysfunction. Active agents in primary amyloidosis 
include melphalan, cyclophosphamide, dexamethasone, 
lenalidomide, and bortezomib (see Table 39–3). The anti-
CD38 monoclonal antibody daratumumab may have a role 
in treating this disorder. New antibodies are being developed 
that bind the deposited light chain and facilitate its breakage 
and dissolution. As in plasma cell myeloma, autologous 
hematopoietic stem cell transplantation after high-dose mel
-
phalan is used in patients with reasonable organ function and 
a good performance status. The treatment-related mortality, 
however, is higher in patients with primary amyloidosis than 
in myeloma (6% vs 1%). Some patients will demonstrate end-

organ improvement after therapy. Agents are being devel
-
oped that facilitate amyloid dissolution or correct protein 
folding abnormalities in the amyloid protein.
 
»
Prognosis
Untreated primary amyloidosis is associated with progressive 
end-organ failure and premature death. There is no known 
cure for primary amyloidosis. Although virtually every tissue 
examined at autopsy will contain amyloid, patients with pri
-
mary amyloidosis usually have one or two primary organs 
failing that clinically drive the presentation and prognosis. 
The cardiac biomarkers, B-type natriuretic peptide (BNP), 
n-terminal pro-BNP , and troponins T and I are prognostic in 
this disease regardless of overt clinical cardiac involvement. 
Historically, patients with predominantly cardiac or auto
-
nomic nerve presentations had survivals of 3–9 months, and 
those with carpal tunnel syndrome or nephrosis, 1.5–3 years, 
and those with peripheral neuropathy, 5 years. These survivals 
are roughly doubled with plasma cell myeloma-like treatment. 
In those patients able to undergo autologous hematopoietic 
stem cell transplantation, the median survival approaches 
 
5 years (and approaches 10 years for those achieving a com
-
plete hematologic remission).
 
»
•	
All patients who have primary amyloidosis or in whom 
it is suspected should be referred to a hematologist or 
•	
All patients with hereditary amyloidosis should be 
referred to a hepatologist for consideration of liver 
 
»
•	
Patients with systemic amyloidosis require hospitaliza
-
tion to treat exacerbations of end-organ failure, includ
-
ing for heart, liver, or kidney.
•	
Patients with primary amyloidosis require hospitaliza
-
tion to undergo autologous hematopoietic stem cell 
Gertz MA. Immunoglobulin light chain amyloidosis: 2016 
update on diagnosis, prognosis, and treatment. Am J Hema
-
tol. 2016 Sep;91(9):447–56. [PMID: 27527836]
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Muchtar E et al. Immunoglobulin light-chain amyloidosis: from 
basics to new developments in diagnosis, prognosis and ther
-
apy. Acta Haematol. 2016;135(3):172–90. [PMID: 26771835]
Zumbo G et al. New and developing therapies for AL amyloido
-
sis. Expert Opin Pharmacother. 2017 Feb;18(2):139–49. 
[PMID: 28002971]
 
º
BLOOD 
t
RANSFUSIONS
RED BLOOD CELL TRANSFUSIONS
Red blood cell transfusions are given to raise the hemoglo
-
bin levels in patients with anemia or to replace losses after 
acute bleeding episodes.
 
»
Preparations of Red Cells for Transfusion
Several types of preparations containing red blood cells are 
A. Fresh Whole Blood
The advantage of whole blood for transfusion is the simul
-
taneous presence of red blood cells, plasma, and fresh 
platelets. Fresh whole blood is never absolutely necessary, 
since all the above components are available separately. The 
major indications for use of whole blood are cardiac sur
-
gery or massive hemorrhage when more than 10 units of 
blood is required in a 24-hour period.
B. Packed Red Blood Cells
Packed red cells are the component most commonly used 
to raise the hemoglobin. Each unit has a volume of about 
300 mL, of which approximately 200 mL consists of red 
blood cells. One unit of packed red cells will usually raise 
the hemoglobin by approximately 1 g/dL. Current guide
-
lines recommend a transfusion “trigger” hemoglobin 
threshold of 7–8 g/dL (70–80 g/L) for hospitalized critically 
ill patients, those undergoing cardiothoracic surgery or 
repair of a hip fracture, those with upper gastrointestinal 
bleeding, and those with hematologic malignancy under
-
going chemotherapy or hematopoietic cell transplant.
C. Leukocyte-Poor Blood
Most blood products are leukoreduced in-line during 
acquisition and are thus prospectively leukocyte-poor. 
Leukoreduced blood products reduce the incidence of leu
-
koagglutination reactions, platelet alloimmunization, 
transfusion-related acute lung injury, and CMV exposure.
D. Autologous Packed Red Blood Cells
Patients scheduled for elective surgery may donate blood 
for autologous transfusion. These units may be stored for 
up to 35 days before freezing is necessary.
 
»
Compatibility Testing
Before transfusion, the recipient’s and the donor’s blood are 
typed and cross-matched to avoid hemolytic transfusion 
reactions. Although many antigen systems are present on 
red blood cells, only the ABO and Rh systems are specifi
-
cally tested prior to all transfusions. The A and B antigens 
are the most important, because everyone who lacks one or 
both red cell antigens has IgM isoantibodies (called isoag
-
glutinins) in his or her plasma against the missing antigen(s). 
The isoagglutinins activate complement and can cause 
rapid intravascular lysis of the incompatible red blood cells. 
In emergencies, type O/Rh-negative blood can be given to 
any recipient, but only packed cells should be given to mini
-
mize transfusion of donor plasma containing anti-A and 
anti-B antibodies.
The other important antigen routinely tested for is the 
 
D antigen of the Rh system. Approximately 15% of the 
population lacks this antigen. In patients lacking the anti
-
gen, anti-D antibodies are not naturally present, but the 
antigen is highly immunogenic. A recipient whose red cells 
lack D and who receives D-positive blood may develop anti-
D antibodies that can cause severe lysis of subsequent trans
-
fusions of D-positive red cells or reject a D-positive fetus.
Blood typing includes a cross-match assay of recipient 
serum for unusual alloantibodies directed against donor red 
blood cells by mixing recipient serum with panels of red 
blood cells representing commonly occurring minor red cell 
antigens. The screening is particularly important if the 
recipient has had previous transfusions or pregnancy.
 
»
Hemolytic Transfusion Reactions
The most severe hemolytic transfusion reactions are acute

»
The most severe hemolytic transfusion reactions are acute 
(temporally related to the transfusion), involving incom
-
patible mismatches in the ABO system that are isoaggluti
-
nin-mediated. Most of these cases are due to clerical errors 
and mislabeled specimens. With current compatibility 
testing and double-check clerical systems, the risk of an 
acute hemolytic reaction is 1 in 76,000 transfused units of 
red blood cells. Death from acute hemolytic reaction 
occurs in 1 in 1.8 million transfused units. When hemoly
-
sis occurs, it is rapid and intravascular, releasing free 
hemoglobin into the plasma. The severity of these reac
-
tions depends on the dose of red blood cells given. The 
most severe reactions are those seen in surgical patients 
under anesthesia.
Delayed hemolytic transfusion reactions are caused by 
minor red blood cell antigen discrepancies and are typi
-
cally less severe. The hemolysis usually takes place at a 
slower rate and is mediated by IgG alloantibodies causing 
extravascular red blood cell destruction. These transfusion 
reactions may be delayed for 5–10 days after transfusion. In 
such cases, the recipient has received red blood cells con
-
taining an immunogenic antigen, and in the time since 
transfusion, a new alloantibody has formed. The most 
common antigens involved in such reactions are Duffy, 
Kidd, Kell, and C and E loci of the Rh system. The current 
risk of a delayed hemolytic transfusion reaction is 1 in 6000 
transfused units of red blood cells.
Major acute hemolytic transfusion reactions cause fever and 
chills, with backache and headache. In severe cases, there 
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may be apprehension, dyspnea, hypotension, and cardio
-
vascular collapse. Patients under general anesthesia will not 
manifest such symptoms, and the first indication may be 
tachycardia, generalized bleeding, or oliguria. 
The transfu
-
sion must be stopped immediately
. In severe cases, acute 
DIC, acute kidney injury from tubular necrosis, or both can 
occur. Death occurs in 4% of acute hemolytic reactions due 
to ABO incompatibility. Delayed hemolytic transfusion 
reactions are usually without symptoms or signs.
When an acute hemolytic transfusion episode is suspected, 
the identification of the recipient and of the transfusion 
product bag label should be rechecked. The transfusion 
product bag with its pilot tube must be returned to the 
blood bank, and a fresh sample of the recipient’s blood 
must accompany the bag for retyping and re–cross-matching 
of donor and recipient blood samples. The hemoglobin will 
fail to rise by the expected amount. Coagulation studies may 
reveal evidence of acute kidney injury or acute DIC. The 
plasma-free hemoglobin in the recipient will be elevated 
resulting in hemoglobinuria.
In cases of delayed hemolytic reactions, there will be an 
unexpected drop in hemoglobin and an increase in the 
total and indirect bilirubins. The new offending alloanti
-
body is easily detected in the patient’s serum.
C. Treatment
If an acute hemolytic transfusion reaction is suspected, the 
transfusion should be stopped at once. The patient should 
be vigorously hydrated to prevent acute tubular necrosis. 
Forced diuresis with mannitol may help prevent or mini
-
mize acute kidney injury.
 
»
Leukoagglutinin Reactions
Most transfusion reactions are not hemolytic but represent 
reactions to antigens present on transfused passenger leu
-
kocytes in patients who have been sensitized to leukocyte 
antigens through previous transfusions or pregnancy. 
Transfusion products relatively rich in leukocyte-rich 
plasma, especially platelets, are most likely to cause this. 
Moderate to severe leukoagglutinin reactions occur in 1% 
of red blood cell transfusions and 2% of platelet transfu
-
sions. Most commonly, fever and chills develop in patients 
within 12 hours after transfusion. In severe cases, cough 
and dyspnea may occur and the chest radiograph may 
show transient pulmonary infiltrates. Because no hemoly
-
sis is involved, the hemoglobin rises by the expected 
amount despite the reaction.
Leukoagglutinin reactions may respond to acetamino
-
phen (500–650 mg orally) and diphenhydramine (25 mg 
orally or intravenously); corticosteroids, such as hydrocorti
-
sone (1 mg/kg intravenously), are also of value. Overall, 
leukoagglutination reactions are diminishing through the 
routine use of in-line leukotrapping during blood donation 
(ie, leukoreduced blood). Patients experiencing severe leu
-
koagglutination episodes despite receiving leukoreduced 
blood transfusions should receive leukopoor or washed 
blood products.
 
»
Hypersensitivity Reactions
Urticaria or bronchospasm may develop during or soon 
after a transfusion. These reactions are almost always due to 
exposure to allogeneic plasma proteins rather than to leuko
-
cytes. The risk is low enough that the routine use of antihis
-
tamine premedications has been eliminated before PRBC 
transfusions. A hypersensitivity reaction, including anaphy
-
lactic shock, may develop in patients who are IgA deficient 
because of antibodies to IgA in the patient’s plasma directed 
against the IgA in the transfused blood product. Patients 
with such reactions may require transfusion of washed or 
even frozen red blood cells to avoid future severe reactions.
 
»
Contaminated Blood
Blood products can be contaminated with bacteria. Plate
-
lets are especially prone to bacterial contamination because 
they cannot be refrigerated. Bacterial contamination 
occurs in 1 of every 30,000 red blood cell donations and 1

-
occurs in 1 of every 30,000 red blood cell donations and 1 
of every 5000 platelet donations. Receipt of a blood prod
-
uct contaminated with gram-positive bacteria will cause 
fever and bacteremia, but rarely causes a sepsis syndrome. 
Receipt of a blood product contaminated with gram-
negative bacteria often causes septic shock, acute DIC, and 
acute kidney injury due to the transfused endotoxin and is 
usually fatal. Strategies to reduce bacterial contamination 
include enhanced venipuncture site skin cleansing, divert
-
ing of the first few milliliters of donated blood, use of sin
-
gle-donor blood products (as opposed to pooled-donor 
products), and point-of-care rapid bacterial screening in 
order to discard questionable units. Blood products infused 
with psoralen and then exposed to UV A light will have no 
living organisms in them, but add cost to acquisition of the 
blood product. The current risk of a septic transfusion 
reaction from a culture-negative unit of single-donor plate
-
lets (not psoralen treated) is 1 in 60,000. In any patient who 
may have received contaminated blood, the recipient and 
the donor blood bag should both be cultured, and antibiot
-
ics should be given immediately to the recipient.
 
»
Infectious Diseases Transmitted Through 
Transfusion
Despite the use of only volunteer blood donors and the 
routine screening of blood, transfusion-associated viral 
diseases remain a problem. All blood products (red blood 
cells, platelets, plasma, cryoprecipitate) can transmit viral 
diseases. All blood donors are screened with question
-
naires designed to detect (and therefore reject) donors at 
high risk for transmitting infectious diseases. All blood is 
screened for hepatitis B surface antigen, antibody to hepa
-
titis B core antigen, syphilis, antibodies to HIV1 and HIV2 
and NAT (nucleic acid amplification) for HIV , antibody to 
hepatitis C virus (HCV) and NAT for hepatitis C, antibody 
to human T-cell lymphotropic/leukemia virus (HTLV), 
and NAT for West Nile virus. Zika virus contamination is 
screened for by donor questionnaire but the routine use of 
an FDA-approved detection test has not been uniformally 
adopted to screen donated blood. It is recommended that 
blood donors get screened once for antibodies against 
Trypanosoma cruzi
, the infectious agent that causes Chagas 
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disease (and if negative, no further screening for additional 
blood donations).
With improved screening, the risk of posttransfusion 
hepatitis has steadily decreased after the receipt of screened 
“negative” blood products. The risk of acquiring hepatitis B 
is about 1 in 200,000 transfused units in the United States 
(vs about 1 in 21,000 to 1 in 600 transfused units in Asia). 
The risk of hepatitis C acquisition is 1 in 1.5 to 2 million 
transfused units in the United States. The risk of HIV acqui
-
sition is 1 in 2 million transfused units. Unscreened 
but
 
leukoreduced blood products appear to be equivalent to 
CMV screened-negative blood products in terms of the risk 
of CMV transmission to a CMV-seronegative recipient.
 
»
Transfusion Graft-Versus-Host Disease
Allogeneic passenger lymphocytes within transfused blood 
products will engraft in some recipients and mount an 
alloimmune attack against tissues expressing discrepant 
HLA antigens causing graft-versus-host disease (GVHD). 
The symptoms and signs of transfusion-associated GVHD 
include fever, rash, diarrhea, hepatitis, lymphadenopathy, 
and severe pancytopenia. The outcome is usually fatal. 
Transfusion-associated GVHD occurs most often in recipi
-
ents with immune defects, malignant lymphoproliferative 
disorders, solid tumors being treated with chemotherapy 
or immunotherapy, treatment with immunosuppressive 
medications (especially purine analogs such as fludara
-
bine), or older patients undergoing cardiac surgery. HIV 
infection alone does not increase the risk. The use of leu
-
koreduced blood products is inadequate to prevent trans
-
fusion-associated GVHD. This complication can be 
avoided by irradiating blood products (25 Gy or more) to 
prevent lymphocyte proliferation in blood products given 
to recipients at high risk for transfusion-associated GVHD.
 
»
Transfusion-Related Acute Lung Injury
Transfusion-related acute lung injury (TRALI) occurs in 1 in 
every 5000 transfused units of blood products. It has been 
associated with allogeneic antibodies in the donor plasma 
component that bind to recipient leukocyte antigens, includ
-
ing HLA antigens and other granulocyte- and monocyte-
specific antigens (such as HNA-1a, -1b, -2a, and -3a). In 20% 
of cases, no antileukocyte antibodies are identified raising the 
concern that bioactive lipids or other substances that accu
-
mulate while the blood product is in storage can also mediate 
TRALI in susceptible recipients. TRALI is clinically defined 
as noncardiogenic pulmonary edema after a blood product 
transfusion without other explanation, and transfused surgi
-
cal and critically ill patients seem most susceptible. Ten to 
20% of female blood donors and 1–5% of male blood donors 
have antileukocyte antibodies in their serum. The risk of 
TRALI is reduced through the use of male-only plasma 
donors, when possible. There is no specific treatment for 
TRALI, only supportive care.
PLATELET TRANSFUSIONS
Platelet transfusions are indicated in cases of thrombocyto
-
penia due to decreased platelet production. They are of 
some use in immune thrombocytopenia when active 
bleeding is evident, but the clearance of transfused platelets 
is rapid as they are exposed to the same pathophysiologic 
forces as the recipient’s endogenous platelets. The risk of 
spontaneous bleeding rises when the platelet count falls to 
less than 80,000/mcL (80 × 10
9
/L), and the risk of life-
threatening spontaneous bleeding increases when the 
platelet count is less than 5000/mcL (5 × 10
9
/L). Because of 
this, prophylactic platelet transfusions are often given at 
these very low levels, usually when less than 10,000/mcL 
(10 × 10
9
/L). Platelet transfusions are also given prior to 
invasive procedures or surgery in thrombocytopenic 
patients, and the goal is often to raise the platelet count to 
50,000/mcL (50 × 10
9
/L) or more.
Platelets for transfusion are most commonly derived

9
Platelets for transfusion are most commonly derived 
from single-donor apheresis collections (roughly the 
equivalent to the platelets recovered from six donations of 
whole blood). A single donor unit of platelets should raise 
the platelet count by 50,000 to 60,000 platelets per mcL 
(50–60 × 10
9
/L) in a transfusion-naïve recipient without 
hypersplenism or ongoing platelet consumptive disorder. 
Transfused platelets typically last for 2 or 3 days. Platelet 
transfusion responses may be suboptimal with poor plate
-
let increments and short platelet survival times. This may 
be due to one of several causes, including fever, sepsis, 
hypersplenism, DIC, large body habitus, low platelet dose 
in the transfusion, or platelet alloimmunization (from 
prior transfusions, prior pregnancy or prior organ trans
-
plantation). Many, but not all, alloantibodies causing plate
-
let destruction are directed at HLA antigens. Patients 
requiring long periods of platelet transfusion support 
should be monitored to document adequate responses to 
transfusions so that the most appropriate product can be 
used. If random platelet transfusions prove inadequate, 
then the patient should be cross-matched with potential 
donors who might prove better able to provide adequate 
platelet-transfusion increments and platelet survival. 
Patients requiring ongoing platelet transfusions who 
become alloimmunized may benefit from HLA-matched 
platelets derived from either volunteer donors or family 
members.
TRANSFUSION OF PLASMA COMPONENTS
Fresh frozen plasma (FFP)
 is available in units of 
approximately 200 mL. FFP contains normal levels of all 
coagulation factors (about 1 unit/mL of each factor). FFP 
is used to correct coagulation factor deficiencies and to 
treat thrombotic thrombocytopenia purpura or hemolytic-
uremic syndrome. FFP is also used to correct or prevent 
coagulopathy in trauma patients receiving massive transfu
-
sion of PRBC. A FFP:PRBC ratio of 1:2 or more is associ
-
ated with improved survival in trauma patients receiving 
massive transfusions, regardless of the presence of a 
coagulopathy.
Cryoprecipitate
 is made from fresh plasma by cool
-
ing the plasma to 4°C and collecting the precipitate. One 
unit of cryoprecipitate has a volume of approximately 
15–20 mL and contains approximately 250 mg of fibrino
-
gen and between 80 and 100 units of factor VIII and von 
Willebrand factor. Cryoprecipitate is most commonly 
used to supplement fibrinogen in cases of acquired 
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hypofibrinogenemia (eg, DIC) or in rare instances of 
congenital hypofibrinogenemia. One unit of cryoprecipi
-
tate will raise the fibrinogen level by about 8 mg/dL 
(0.24 mcmol/L). Cryoprecipitate is sometimes used to 
temporarily correct the acquired qualitative platelet dys
-
function associated with kidney disease.
Fasano RM et al. Platelet transfusion goals in oncology patients. 
Hematology Am Soc Hematol Educ Program. 2015;
 
2015:462–70. [PMID: 26637759]
Hoeks MPA et al. Impact of red blood cell transfusion strategies in 
haemato-oncological patients: a systematic review and meta-
analysis. Br J Haematol. 2017 Jul;178(1):137–51. [PMID: 28589623]
Kumar A et al; AABB Platelet Transfusion Guidelines Panel. Plate
-
let transfusion: a systematic review of the clinical evidence. 
Transfusion. 2015 May;55(5):1116–275. [PMID: 25387589]
Marfin AA et al. Granulocyte transfusion therapy. J Intensive 
Care Med. 2015 Feb;30(2):79–88. [PMID: 23920161]
Tariket S et al. Transfusion-related acute lung injury: transfu
-
sion, platelets and biological response modifiers. Expert Rev 
Hematol. 2016 May;9(5):497–508. [PMID: 26855042]
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In evaluating patients for defects of hemostasis, the clini
-
cal context must be considered carefully (Table 14–1). 
Heritable defects are suggested by bleeding that begins in 
infancy or childhood, is recurrent, and occurs at multiple 
anatomic sites, although many other patterns of presenta
-
tion are possible. Acquired disorders of hemostasis more 
typically are associated with bleeding that begins later in 
life and may be relatable to introduction of medications 
(eg, agents that affect platelet activity) or to onset of 
underlying medical conditions (such as kidney disease, 
liver disease, myelodysplasia, aortic stenosis, prosthetic 
aortic valve, myeloproliferative neoplasms), or may be 
idiopathic. Importantly, however, a sufficient hemostatic 
challenge (such as major trauma) may produce excessive 
bleeding even in individuals with completely normal 
hemostasis. A personal history for hemostatic challenges 
(eg, circumcision, trauma, injury during youth sports, 
tooth extractions, motor vehicle accidents, prior surgery, 
and pregnancy and delivery) is critical for evaluating a 
patient for a possible bleeding disorder.
 
º
PLATELET DISORDERS
Selected causes of thrombocytopenia are shown in 
Table 14–2. The age of the patient and presence of comor
-
bid conditions can help direct the diagnostic workup.
The risk of clinically relevant spontaneous bleeding 
(including petechial hemorrhage and bruising) does not 
typically increase appreciably until the platelet count falls 
below 10,000–20,000/mcL, although patients with dys
-
functional platelets may bleed with higher platelet 
counts. Suggested platelet counts to prevent spontaneous 
bleeding or to provide adequate hemostasis around the 
time of invasive procedures are found in Table 14–3. 
However, most medical centers develop their own local 
guidelines to have a consistent approach to such complex 
situations.
DECREASED PLATELET PRODUCTION
1. Bone Marrow Failure
 
»
Bone marrow failure states may be congenital or 
acquired.
 
»
Most congenital marrow failure disorders present 
in childhood.
 
»
Congenital conditions
 that cause thrombocytopenia 
include amegakaryocytic thrombocytopenia, the thrombo
-
cytopenia-absent radius syndrome, and Wiskott-Aldrich 
syndrome; these disorders usually feature isolated throm
-
bocytopenia, whereas patients with Fanconi anemia and 
dyskeratosis congenita typically include cytopenias in 
other blood cell lineages. Mutations in a growing number 
of genes (
FLI1, MYH9, GATA1, ETV6
, among others) that 
cause thrombocytopenia are being identified.
Acquired causes
 of bone marrow failure (see Chapter 13) 
leading to thrombocytopenia include, but are not limited 
to, acquired aplastic anemia, myelodysplastic syndrome 
(MDS), acquired amegakaryocytic thrombocytopenia 
(albeit a rare disorder), alcohol, and drugs. Unlike aplastic 
anemia, MDS is more common among older patients.
 
»
Acquired aplastic anemia typically presents with reduc
-
tions in multiple blood cell lineages, and the CBC reveals 
pancytopenia (anemia, thrombocytopenia, and neutrope
-
nia). A bone marrow biopsy is required for diagnosis 
and  reveals marked hypocellularity. Myelodysplastic syn
-
drome (MDS) also presents as cytopenias and can have 
pancytopenia, but the marrow cellularity is not decreased; 
14
 
Tracy Minichiello, MD 
Disorders of Hemostasis, 
Thrombosis, & 
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DISORDERS OF HEMOSTASIS, THROMBOSIS
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CMDT 2019
the marrow typically demonstrates hypercellularity. The 
presence of macrocytosis, ringed sideroblasts on iron stain
-
ing of the bone marrow aspirate, dysplasia of hematopoietic 
elements, or cytogenetic abnormalities (especially mono
-
somy 5 or 7, and trisomy 8) are more suggestive of MDS.
 
»
Adult patients with acquired amegakaryocytic thrombocy
-
topenia (rare) have isolated thrombocytopenia and reduced 
or absent megakaryocytes in the bone marrow, which 
(along with failure to respond to immunomodulatory regi
-
mens typically administered in immune thrombocytope
-
nia [ITP]) distinguishes them from patients with ITP .
Table 14–1.
 
Evaluation of the bleeding patient.
Necessary Component 
of Evaluation
Diagnostic Correlate
Location
Mucocutaneous (bruises, 
petechiae, gingivae, 
nosebleeds, GI, GU)
Suggests qualitative/quantitative 
platelet defects; vWD
Joints, soft tissue
Suggests disorders of coagulation 
factors
Onset
Infancy/childhood
Suggests heritable condition
Adulthood
Suggests milder heritable condition 
or acquired defect of hemostasis 
(eg, ITP , medication related)
Clinical Context
Postsurgical
Anatomic/surgical defect must be 
ruled out
Pregnancy
vWD, HELLP syndrome, ITP , acquired 
factor VIII inhibitor
Sepsis
May indicate DIC
Exposure to anticoagulants
Rule out excessive anticoagulation
Personal History
1
Absent
Suggests acquired rather than 
 
congenital defect, or anatomic/
surgical defect (if applicable)
Present
Suggests established acquired 
 
defect or congenital disorder
Absent
Suggests acquired defect or no 
defect of hemostasis
Present
May signify hemophilia A or B, 
 
vWD, other heritable bleeding 
 
disorders
1
Includes evaluation of prior spontaneous bleeding, as well as 
excessive bleeding with circumcision, menses, dental extractions, 
trauma, minor procedures (eg, endoscopy, biopsies), and major 
procedures (surgery).
DIC, disseminated intravascular coagulation; GI, gastrointestinal; GU, 
genitourinary; HELLP , hemolysis, elevated liver enzymes, low plate
-
lets; ITP , immune thrombocytopenia; vWD, von Willebrand disease.
Table 14–3.
 
Desired platelet count ranges.
Clinical Scenario
Platelet Count (/mcL)
Prevention of spontaneous 
 
mucocutaneous bleeding
> 10,000–20,000
Insertion of central venous catheters
> 20,000–50,000
1
Administration of therapeutic 
> 30,000–50,000
Minor surgery and selected invasive 
procedures
2
> 50,000–80,000
Major surgery
> 80,000–100,000
1
A platelet target within the higher range of the reference is 
required for tunneled catheters.
2
Such as endoscopy with biopsy.
Table 14–2.
 
Selected causes of thrombocytopenia.
Decreased production of platelets
Congenital bone marrow failure (eg, Fanconi anemia, 
 
Wiskott-Aldrich syndrome; congenital amegakaryocytic 
thrombocytopenia)
Acquired bone marrow failure (eg, aplastic anemia, 
 
myelodysplasia, leukemia)
Exposure to chemotherapy, irradiation
Marrow infiltration (neoplastic, infectious)
Nutritional (deficiency of vitamin B
12
, folate)
Other: HIV infection, alcohol
Increased destruction of platelets
Immune thrombocytopenia (primary)
Immune thrombocytopenia (secondary), including drug-
induced or related to lymphoproliferative disorders (ie, CLL), 
hepatitis C virus, Epstein-Barr virus, or HIV
Heparin-induced thrombocytopenia
Thrombotic microangiopathy
Disseminated intravascular coagulation
Posttransfusion purpura
Neonatal alloimmune thrombocytopenia
Mechanical (aortic valvular dysfunction; extracorporeal bypass)
von Willebrand disease, type 2B
Hemophagocytosis
Increased sequestration of platelets
Hypersplenism (eg, related to cirrhosis, myeloproliferative 
 
disorders, lymphoma)
Other conditions causing thrombocytopenia
Gestational thrombocytopenia
Bernard-Soulier syndrome, gray platelet syndrome, 
 
May-
 
Hegglin anomaly
Pseudothrombocytopenia
CLL, chronic lymphocytic leukemia.

May-
 
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»
Treatment
A. Congenital Conditions
Treatment is varied but may include blood product sup
-
port, blood cell growth factors, androgens and, in some 
cases, allogeneic hematopoietic stem cell transplantation.
B. Acquired Conditions
Patients with severe aplastic anemia are treated with immu
-
nosuppressive therapy or allogeneic hematopoietic stem cell 
transplantation. Allogeneic hematopoietic stem cell trans
-
plantation is the preferred therapy for patients younger 
than age 40 who have an HLA-matched sibling donor (see 
Chapter 13), and immunosuppressive therapy is preferred for 
older patients and those who lack an HLA-matched sibling 
donor. Eltrombopag has been shown to induce multilineage 
responses (some of which are durable after discontinuing the 
medication) in selected patients with severe aplastic anemia 
that is unresponsive to immunosuppressive therapy.
Treatment of thrombocytopenia due to MDS, if clini
-
cally significant bleeding is present or if the risk of bleeding 
is high, is limited to chronic transfusion of platelets in most 
instances (Table 14–3). Immunomodulatory agents such as 
lenalidomide do not produce increases in the platelet count 
in most patients. The thrombopoietin (TPO) receptor ago
-
nists eltrombopag and romiplostim have shown efficacy as 
an adjunct to hypomethylating agents in low-risk MDS in 
clinical trials. However, these agents are often avoided in 
moderate- and high-risk MDS patients due to possibility of 
accelerating leukemic transformation.
Desmond R et al. Eltrombopag in aplastic anemia. Semin Hema
-
tol. 2015 Jan;52(1):31–7. [PMID: 25578417]
Greenberg PL et al. A randomized controlled trial of romiplos
-
tim in patients with low- or intermediate-risk myelodysplastic 
syndrome receiving decitabine. Leuk Lymphoma. 2013 Feb;
 
54(2):321–8. [PMID: 22906162]
Sekeres MA et al. Development and validation of a model to 
predict platelet response to romiplostim in patients with lower-
risk myelodysplastic syndromes. Br J Haematol. 2014 Nov;
 
167(3):337–45. [PMID: 25039607]
Townsley DM et al. Eltrombopag added to standard immuno
-
suppression for aplastic anemia. N Engl J Med. 2017 Apr 20;
 
376(16):1540–50. [PMID: 28423296]
2. Bone Marrow Infiltration
Replacement of the normal bone marrow elements by leu
-
kemic cells, myeloma, lymphoma, or other nonhemato
-
logic tumors, or by infections (such as mycobacterial 
disease or ehrlichiosis) may cause thrombocytopenia; 
however, abnormalities in other blood cell lines are usually 
present. These entities are easily diagnosed after examining 
the bone marrow biopsy and aspirate or determining the 
infecting organism from an aspirate specimen, and they 
often lead to a leukoerythroblastic peripheral blood smear 
(left-shifted myeloid lineage cells, nucleated red blood 
cells, and teardrop-shaped red blood cells). Treatment of 
thrombocytopenia is directed at eradication of the under
-
lying infiltrative disorder, but platelet transfusion may be 
required if clinically significant bleeding is present.
3. Chemotherapy & Irradiation
Chemotherapeutic agents and irradiation may lead to throm
-
bocytopenia by direct toxicity to megakaryocytes, hematopoi
-
etic progenitor cells, or both. The severity and duration of 
chemotherapy-induced depressions in the platelet count are 
determined by the specific regimen used, although the platelet 
count typically resolves more slowly following a chemothera
-
peutic insult than does neutropenia or anemia, especially if 
multiple cycles of treatment have been given. Until recovery 
occurs, patients may be supported with transfused platelets if 
bleeding is present or the risk of bleeding is high (Table 14–3). 
Preliminary studies indicate that platelet growth factors such 
as eltrombopag and romiplostim may help prevent chemo
-
therapy-induced thrombocytopenia and allow patients to 
receive their full chemotherapy doses on schedule.

-
Kuter DJ. Managing thrombocytopenia associated with cancer 
chemotherapy. Oncology (Williston Park). 2015 Apr;29(4):
 
282–94. [PMID: 25952492]
Soff GA et al. Romiplostim for Chemotherapy-Induced Throm
-
bocytopenia (CIT). Results of a phase 2 trial. Blood. 2017;
 
130(Suppl 1):289.
4. Nutritional Deficiencies
Thrombocytopenia, typically in concert with anemia, may 
be observed with a deficiency of folate (that may accompany 
alcoholism) or vitamin B
12
 (concomitant neurologic find
-
ings may be manifest). In addition, thrombocytopenia rarely 
can occur in very severe iron deficiency, but thrombocytosis 
is far more common. Replacing the deficient vitamin or 
mineral results in improvement in the platelet count.
Briani C et al. Cobalamin deficiency: clinical picture and radiologi
-
cal findings. Nutrients. 2013 Nov 15;5(11):4521–39. [PMID: 
24248213]
5. Cyclic Thrombocytopenia
Cyclic thrombocytopenia is a rare disorder that produces 
cyclic oscillations of the platelet count, usually with a periodic
-
ity of 3–6 weeks. The pathophysiologic mechanism responsible 
for the condition is unclear and varies among patients. Severe 
thrombocytopenia and bleeding typically occur at the platelet 
nadir. Oral contraceptive medications, androgens, azathio
-
prine, and thrombopoietic growth factors have been used suc
-
cessfully in the management of cyclic thrombocytopenia.
INCREASED PLATELET DESTRUCTION
1. Immune Thrombocytopenia
 
»
Isolated thrombocytopenia (rule out pseudothrom
-
bocytopenia by review of peripheral smear).
 
»
Assess for any new causative medications and HIV, 
hepatitis B and hepatitis C infections.
 
»
ITP is a diagnosis of exclusion.
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CMDT 2019
 
»
ITP is an autoimmune condition in which pathogenic anti
-
bodies bind platelets, accelerating their clearance from the 
circulation. Many patients with ITP also lack appropriate 
compensatory platelet production, thought, at least in part, 
to reflect the antibody’s effect on megakaryocytopoiesis 
and thrombopoiesis. ITP is primary and idiopathic in most 
adult patients, although it can be associated with connec
-
tive tissue disease (such as systemic lupus erythematosus), 
lymphoproliferative disease (such as lymphoma), medica
-
tions, and infections (such as hepatitis C virus and HIV 
infections). Antiplatelet antibody targets include glycopro
-
teins IIb/IIIa and Ib/IX on the platelet membrane, although 
antibodies are demonstrable in only two-thirds of patients. 
In addition to production of antiplatelet antibodies, HIV 
and hepatitis C virus may lead to thrombocytopenia 
through additional mechanisms (for instance, by direct 
suppression of platelet production [HIV] and cirrhosis-
related decreased TPO production and secondary spleno
-
megaly [hepatitis C virus]).
 
»
Mucocutaneous bleeding may be present, depending on 
the platelet count. Clinically relevant spontaneous bruis
-
ing, nosebleeds, gingival bleeding, or other types of hemor
-
rhage generally do not occur until the platelet count has 
fallen below 10,000–20,000/mcL. Individuals with second
-
ary ITP (such as due to collagen vascular disease, HIV or 
HCV infection, or lymphoproliferative malignancy) may 
have additional disease-specific findings.
Typically, patients have isolated thrombocytopenia. If 
bleeding has occurred, anemia may also be present. Hepati
-
tis B and C viruses and HIV infections should be excluded 
by serologic testing. Bone marrow should be examined in 
patients with unexplained cytopenias in two or more lin
-
eages, in patients older than 40 years with isolated throm
-
bocytopenia, or in those who do not respond to primary 
ITP-specific therapy. A bone marrow biopsy is not neces
-
sary in all cases to make an ITP diagnosis in younger 
patients. Megakaryocyte morphologic abnormalities and 
hypocellularity or hypercellularity are not characteristic of 
ITP , but ITP patients often have increased numbers of bone 
marrow megakaryocytes. If there are clinical findings sug
-
gestive of a lymphoproliferative malignancy, a CT scan 
should be performed. In the absence of such findings, oth
-
erwise asymptomatic patients younger than 40 years with 
unexplained isolated thrombocytopenia of recent onset 
may be considered to have ITP . 
 infec
-
tions can sometimes cause isolated thrombocytopenia.
 
»
Treatment
Individuals with platelet counts less than 20,000–30,000/mcL 
 
or those with significant bleeding should be treated; the 
remainder may be monitored serially for progression, but 
that is a patient-specific decision. The mainstay of initial 
treatment of new-onset primary ITP is a short course 
 
of corticosteroids with or without intravenous immuno
-
globulin (IVIG) or anti-D (WinRho) (Figure 14–1). 
Responses are generally seen within 3–5 days of initiating 
treatment, with responses to IVIG typically seen in 
24–36 hours. Platelet transfusions may be given concomi
-
tantly if active bleeding is present. The addition of the 
monoclonal anti-B cell antibody rituximab to corticoste
-
roids as first-line treatment may improve the initial 
response rate, but it is associated with increased toxicity 
and is not regarded as standard first-line therapy in most 
centers. Short course of high-dose dexamethasone is also 
an option for initial treatment.
Although over two-thirds of patients with ITP respond 
to initial treatment with oral corticosteroids, most relapse 
following reduction of the corticosteroid dose. Patients 
with a persistent platelet count less than 30,000/mcL or

with a persistent platelet count less than 30,000/mcL or 
clinically significant bleeding are appropriate candidates 
for second-line treatments (Figure 14–1). These treatments 
are chosen empirically, bearing in mind potential toxicities 
and the patient’s preference. IVIG or anti-D (WinRho) 
temporarily increases platelet counts (duration, up to 
3  weeks, rarely longer), although serial IVIG or anti-D 
treatment (platelet counts less than 30,000/mcL) may allow 
adult patients to delay or avoid splenectomy. Rituximab 
leads to clinical responses in about 50% of adults with 
corticosteroid-refractory chronic ITP , which decreases to 
about 20% at 5 years. The TPO-mimetics romiplostim 
(administered subcutaneously weekly) and eltrombopag 
(taken orally daily) are approved for use in adult patients 
with chronic ITP who have not responded durably to cor
-
ticosteroids, IVIG, or splenectomy and are typically taken 
indefinitely to maintain the platelet response, and they can 
be used as second-line therapy. Splenectomy has a durable 
response rate of over 50% and may be considered for cases 
of severe thrombocytopenia that fail to respond durably to 
initial treatment or are refractory to second-line agents; 
patients should receive pneumococcal, 
Haemophilus influ
-
enzae
 type b, and meningococcal vaccination at least 
2 weeks before therapeutic splenectomy. If available, lapa
-
roscopic splenectomy is preferred. Additional treatments 
for ITP are found in Figure 14–1.
The goals of management of pregnancy-associated ITP 
are a platelet count of 10,000–30,000/mcL in the first tri
-
mester, greater than 30,000/mcL during the second or third 
trimester, and greater than 50,000/mcL prior to cesarean 
section or vaginal delivery. Moderate-dose oral prednisone 
or intermittent infusions of IVIG are standard. Splenec
-
tomy is reserved for failure to respond to these therapies 
and may be performed in the first or second trimester.
For thrombocytopenia associated with HIV or hepatitis 
C virus, effective treatment of either infection leads to an 
amelioration of thrombocytopenia in most cases; refrac
-
tory thrombocytopenia may be treated with infusion of 
IVIG or anti-D (HIV and hepatitis C virus), splenectomy 
(HIV), or interferon-alpha or eltrombopag (hepatitis C 
virus, including eradication). Treatment with corticoste
-
roids is not recommended in hepatitis C virus infection. 
Occasionally, ITP treatment response is impaired due to 
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H pylori
 infection, so that should be ruled out in the appro
-
priate situation.
 
»
All patients with ITP should be referred to a hematologist 
for evaluation at the time of diagnosis.
 
»
Patients with major hemorrhage or very severe thrombocy
-
topenia associated with bleeding should be admitted and 
monitored in-hospital until the platelet count has stably 
risen to more than 20,000–30,000/mcL and hemodynamic 
stability has been achieved.
Chaturvedi S et al. Splenectomy for immune thrombocytopenia: 
down but not out. Blood. 2018 Mar 15;131(11):1172–82. [PMID: 
29295846]
Gudbrandsdottir S et al. Rituximab and dexamethasone vs dexa
-
methasone monotherapy in newly diagnosed patients with 
primary immune thrombocytopenia. Blood. 2013 Mar 14;
 
121(11):1976–81. [PMID: 23293082]
Kuter DJ et al. TPO concentrations and response to romiplostim. 
Am J Hematol. 2014 Dec;89(12):1155–6. [PMID: 25132329]
Neunert C et al. Severe bleeding events in adults and children with 
primary immune thrombocytopenia: a systematic review. 
 
J Thromb Haemost. 2015 Mar;13(3):457–64. [PMID: 25495497]
2. Thrombotic Microangiopathy
 
»
Microangiopathic hemolytic anemia and throm
-
bocytopenia, in the absence of another plausible 
explanation, are sufficient to diagnose thrombotic 
microangiopathy (TMA).
 
»
Fever, neurologic abnormalities, and kidney dis
-
ease may occur concurrently but are not required 
for diagnosis.
 
»
Kidney dysfunction is more common and more 
severe in hemolytic-uremic syndrome (HUS).
 
»
The TMAs include, but are not limited to, thrombotic 
thrombocytopenic purpura (TTP) and HUS. These disor
-
ders are characterized by thrombocytopenia due to the 
incorporation of platelets into thrombi in the microvascu
-
lature, and microangiopathic hemolytic anemia, which 
results from shearing of erythrocytes in fibrin networks in 
the microcirculation.
Initial
Treatment
Relapsed
or
Persistent ITP
Persistent
or
Worsening ITP
, 1 mg/kg/day orally for
7–10 days followed by rapid taper
or
, 40 mg/day orally
for 4 days every 2 weeks for
4 cycles
IVIG
, 1 g/kg/day
intravenously for 2 days
or
Anti-D
, 75 mcg/kg
intravenously for 1 dose
1
±±
Platelets
,
if bleeding
Note: Consider use of corticosteroids/IVIG to recapture response if clinically
required while initiating second-line therapy.
Rituximab
,
375 mg/m
2
weekly
for 4 weeks
Anti-D
,
75 mcg/kg
serially
as needed
for platelets
< 30,000/mcL
1,2
IVIG
for 2 days
serially as
needed
1,2
Thrombopoietin
receptor agonist:
Romiplostim
, 1 mcg/kg
subcutaneously weekly
initially
or
Eltrombopag
, 50 mg
orally daily initially
3
or
or
or
Splenectomy
(laparoscopic)
Tr
ial of
agent(s)
abo
ve
, 
or
Mycophenolate mofetil
Azathioprine/danazol
Chemotherapy
Clinical trial
Autologous transplantation
1
Use in non-splenectomized, Rh blood type–positive, non-anemic patients only.
2
May need to repeat infusion every 2–6 weeks to maintain platelet response.
3
Recommended starting dose in Asians is 25 mg daily.
 
▲
Figure 14–1.
 
Management of immune thrombocytopenia (ITP), a simplified overview. 
Note:
 All patients with ITP 
need to be managed by a hematologist as the above is a general map and actual management is full of nuanced 
decision-making.
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In idiopathic TTP , autoantibodies against ADAMTS-13 
(a disintegrin and metalloproteinase with thrombospondin 
type 1 repeat, member 13), also known as the von Wille
-
brand factor cleaving protease (vWFCP), lead to accumula
-
tion of ultra-large von Willebrand factor (vWF) multimers. 
The ultra-large multimers bridge and aggregate platelets 
in the absence of hemostatic triggers, which in turn leads 
to the vessel obstruction and various organ dysfunctions 
seen in TTP . In some cases of pregnancy-associated TMA, 
an antibody to ADAMTS-13 is present. In contrast, the 
activity of the ADAMTS-13 in congenital TTP is decreased 
due to a mutation in the gene encoding the molecule. 
 
Classic HUS, called Shiga toxin–mediated HUS, is thought 
to be secondary to toxin-mediated endothelial damage and 
is often contracted through the ingestion of undercooked 
ground beef contaminated with 
 (especially 
types O157:H7 or O145).
Complement-mediated HUS (formerly called atypical 
HUS) is not related to Shiga toxin. Patients with complement-
 
mediated HUS often have genetic defects in proteins that 
regulate complement activity. Damage to endothelial 
cells—such as the damage that occurs in endemic HUS due 
to presence of toxins from 
E coli
 (especially type O157:H7 
or O145) or in the setting of cancer, hematopoietic stem 
cell transplantation, or HIV infection—may also lead to 
TMA. Certain drugs (eg, cyclosporine, quinine, ticlopi
-
dine, clopidogrel, mitomycin C, and bleomycin) have been 
associated with the development of TMA, possibly by pro
-
moting injury to endothelial cells, although inhibitory 
antibodies to ADAMTS-13 have been demonstrated in 
 
»
Microangiopathic hemolytic anemia and thrombocytope
-
nia are presenting signs in all patients with TTP and most 
patients with HUS; in a subset of patients with HUS, the 
platelet count remains in the normal range. Only approxi
-
mately 25% of patients with TMA manifest all components 
of the original pentad of findings (microangiopathic hemo
-
lytic anemia, thrombocytopenia, fever, kidney disease, and 
neurologic system abnormalities) (Table 14–4). Most 
patients (especially children) with HUS have a recent or 
current diarrheal illness, often bloody. Neurologic manifes
-
tations, including headache, somnolence, delirium, sei
-
zures, paresis, and coma, may result from deposition of 
microthrombi in the cerebral vasculature.
Laboratory features of TMA include those associated with 
microangiopathic hemolytic anemia (anemia, elevated lactate 
dehydrogenase [LD], elevated indirect bilirubin, decreased 
haptoglobin, reticulocytosis, schistocytes on the blood smear, 
and a negative direct antiglobulin test); thrombocytopenia; 
elevated creatinine; positive stool culture for 
E coli
 O157:H7 
or stool assays for Shiga toxin; reductions in ADAMTS-13 
activity with the presence (acquired TTP) or absence (inher
-
ited TTP) of ADAMTS-13 inhibitor; and mutations of genes 
encoding complement proteins (complement-mediated HUS; 
specialized laboratory assessment). Routine coagulation stud
-
ies (prothrombin time [PT], activated partial thromboplastin 
Table 14–4.
 
Presentation and management of thrombotic microangiopathies.
TTP
Complement-Mediated HUS
Shiga toxin–Mediated HUS
Patient population
Adult patients
Children (occasionally adults)
Usually children, often following bloody 
diarrhea
Pathogenesis
Acquired auto-antibody to 
ADAMTS-13
Some cases: heritable deficiency 
in function of complement 
regulatory proteins
Bacterial (such as enterotoxogenic 
 
Escherichia coli;
 Shiga toxin)
Typically severe, except in very 
early clinical course
Variable
May be mild/absent in a minority of 
patients
Fever
Typical
Variable
Atypical
Kidney disease
Typical, but may be mild
Typical
Typical
Neurologic 
Variable

Variable
patients
Fever
Typical
Variable
Atypical
Typical
Typical
Variable
Less than half of cases
investigation
Decreased activity of 
ADAMTS-13; inhibitor usually 
identified
Defects in complement regula
-
tory proteins
Typically normal ADAMTS-13 activity
Positive stool culture for 
E coli
 0157:H7 or 
detectable antibody to Shiga toxin
TPE
Hemodialysis for severe renal 
Platelet transfusions contraindi
-
cated unless TPE underway
Immediate TPE in most cases
Supportive care
Eculizumab (selected cases)
Hemodialysis for severe kidney impairment
TPE rarely beneficial (exception: selected 
cases in adults)
ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; HUS, hemolytic-uremic syndrome; 
 
TPE, therapeutic plasma exchange; TTP , thrombotic thrombocytopenic purpura.
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time [aPTT], fibrinogen) are within the normal range in most 
patients with TTP or HUS.
 
»
Treatment
Immediate administration of plasma exchange is essential 
in most cases because the TTP mortality rate is more than 
95% without treatment. With the exception of children or 
adults with endemic diarrhea-associated HUS, who gener
-
ally recover with supportive care only, plasma exchange 
must be initiated as soon as the diagnosis of TMA is sus
-
pected and in all cases of TTP . Plasma exchange usually is 
administered once daily until the platelet count and LD 
have returned to normal for at least 2 days, after which the 
frequency of treatments may be tapered slowly while the 
platelet count and LD are monitored for relapse. In cases of 
insufficient response to once-daily plasma exchange, twice-
daily treatments can be considered. Fresh frozen plasma 
(FFP) may be administered if immediate access to plasma 
exchange is not available or in cases of familial TMA. 
Plate
-
let transfusions are contraindicated
 in the treatment of TMA 
due to reports of worsening TMA, possibly due to propaga
-
tion of platelet-rich microthrombi. In cases of documented 
life-threatening bleeding, however, platelet transfusions 
may be given slowly and after plasma exchange is underway. 
Red blood cell transfusions may be administered in cases of 
clinically significant anemia. Hemodialysis should be con
-
sidered for patients with significant kidney injury.
In cases of TTP relapse following initial treatment, 
plasma exchange should be reinstituted. If ineffective, or in 
cases of primary refractoriness, second-line treatments 
should be considered including rituximab (which has 
shown efficacy when administered preemptively in selected 
cases of relapsing TTP), corticosteroids, IVIG, vincristine, 
cyclophosphamide, and splenectomy. Since idiopathic TTP 
is an autoimmune disorder (antibody inhibitor to 
ADAMTS-13), immunosuppression, often with rituximab, 
is often needed to prevent or reduce relapse events.
Cases of complement-mediated HUS may respond to 
plasma infusion initially; however, once this diagnosis is 
strongly suspected, apheresis is typically stopped and serial 
infusions of the anti-complement C5 antibody eculizumab 
are provided, which have produced sustained remissions in 
some patients. If irreversible kidney disease has occurred, 
hemodialysis or kidney transplantation may be necessary.
 
»
Consultation by a hematologist or transfusion medicine 
specialist familiar with plasma exchange is required at the 
time of presentation. Patients with TMA require ongoing 
care by a hematologist.
 
»
All patients with newly suspected or diagnosed TMA 
should be hospitalized immediately.
George JN et al. Syndromes of thrombotic microangiopathy 
associated with pregnancy. Hematology Am Soc Hematol 
Educ Program. 2015 Dec 5;2015(1):644–8. [PMID: 26637783]
Hie M et al; French Thrombotic Microangiopathies Reference 
Centre. Preemptive rituximab infusions after remission effi
-
ciently prevent relapses in acquired thrombotic thrombocyto
-
penic purpura. Blood. 2014 Jul 10;124(2):204–10. [PMID: 
24869941]
Legendre CM et al. Terminal complement inhibitor eculizumab in 
atypical hemolytic-uremic syndrome. N Engl J Med. 2013 Jun 6;
 
368(23):2169–81. [PMID: 23738544]
Sayani FA et al. How I treat refractory thrombotic thrombocyto
-
penic purpura. Blood. 2015 Jun 18;125(25):3860–7. [PMID: 
25784681]
Scully M et al; International Working Group for Thrombotic 
Thrombocytopenic Purpura. Consensus on the standardiza
-
tion of terminology in thrombotic thrombocytopenic pur
-
pura and related thrombotic microangiopathies. J Thromb 
Haemost. 2017 Feb;15(2):312–22. [PMID: 27868334]
3. Heparin-Induced Thrombocytopenia
 
»
Thrombocytopenia within 5–14 days of exposure 
to heparin.
 
»
Decline in baseline platelet count of 50% or greater.
 
»

»
 
»
 
»
Thrombosis occurs in up to 50% of cases; bleeding 
is uncommon.
 
»
Heparin-induced thrombocytopenia (HIT) is an acquired 
disorder that affects approximately 3% of patients exposed to 
unfractionated heparin and 0.6% of patients exposed to low-
molecular-weight heparin (LMWH). The condition results 
from formation of IgG antibodies to heparin-platelet factor 4 
(PF4) complexes; the antibody:heparin-PF4 complex binds 
to and activates platelets independent of physiologic hemo
-
stasis, which leads to thrombocytopenia and thromboses.
 
»
Patients are usually asymptomatic, and due to the pro-
thrombotic nature of HIT, bleeding usually does not occur. 
Thrombosis (at any venous or arterial site), however, may 
be detected in up to 50% of patients, up to 30 days 
post-diagnosis.
A presumptive diagnosis of HIT is made when new-onset 
thrombocytopenia is detected in a patient (frequently a hospi
-
talized patient) within 5–14 days of exposure to heparin; other 
presentations (eg, rapid-onset HIT) are less common. A 
decline of 50% or more from the baseline platelet count is typi
-
cal. The 4T score (http://www.qxmd.com/calculate-online/
hematology/hit-heparin-induced-thrombocytopenia-
 
probability) is a clinical prediction rule for assessing pretest 
probability for HIT, although low scores have been shown to be 
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more predictive of excluding HIT, than are intermediate or 
high scores of predicting its presence. Once HIT is clinically 
suspected, the clinician must establish the diagnosis by per
-
forming a screening PF4-heparin antibody enzyme-linked 
immunosorbent assay (ELISA). If the PF4-heparin antibody 
ELISA is positive, the diagnosis must be confirmed using a 
functional assay (such as serotonin release assay). The magni
-
tude of a positive ELISA result correlates with the clinical prob
-
ability of HIT, but even high optical density values on the PF4 
may be falsely positive. The confirmatory assay is essential.
 
»
Treatment
Treatment should be initiated as soon as the diagnosis of HIT 
is suspected, before results of laboratory testing are available.
Management of HIT (Table 14–5) involves the immedi
-
ate discontinuation of all forms of heparin. If thrombosis 
has not already been detected, duplex Doppler ultrasound 
of the lower extremities should be performed to rule out 
subclinical deep venous thrombosis (DVT). Despite throm
-
bocytopenia, platelet transfusions are rarely necessary and 
should be avoided. Due to the substantial frequency of 
thrombosis among HIT patients, an alternative anticoagu
-
lant, typically a direct thrombin inhibitor (DTI) such as 
argatroban or bivalirudin should be administered immedi
-
ately while awaiting confirmatory testing. For confirmed 
HIT, the DTI should be continued until the platelet count 
has recovered to at least 100,000/mcL, at which point 
treatment with a vitamin K antagonist (warfarin) may be 
initiated. The DTI should be continued until therapeutic 
anticoagulation with the vitamin K antagonist warfarin has 
been achieved (ie, international normalized ratio [INR] of 
2.0–3.0); the infusion of argatroban must be temporarily 
discontinued before the INR is obtained so that it reflects 
the anticoagulant effect of warfarin alone. There is growing 
use of the subcutaneous indirect anti-Xa inhibitor 
fondaparinux for initial treatment of HIT. In all patients 
with HIT, some form of anticoagulation (warfarin or other) 
should be continued for at least 30 days, due to a persistent 
risk of thrombosis even after the platelet count has recov
-
ered, but in patients in whom thrombosis has been docu
-
mented, anticoagulation should continue for 3–6 months.
Subsequent exposure to heparin should be avoided in all 
patients with a prior history of HIT, if possible. If its use is 
regarded as necessary for a procedure, it should be withheld 
until PF4-heparin antibodies are no longer detectable by 
ELISA (usually as of 100 days following an episode of HIT), 
and exposure should be limited to the shortest time period 
possible. A common example is a cardiac catherterization. The 
heparin is gone before the antibody returns, so HIT is avoided.
 
»
Due to the tremendous thrombotic potential of the disor
-
der and the complexity of use of the DTI, all patients with 
HIT should be evaluated by a hematologist.
 
»
Most patients with HIT are hospitalized at the time of 
detection of thrombocytopenia. Any outpatient in whom 
HIT is suspected should be admitted because the DTIs 
must be administered by continuous intravenous infusion.
Chaudhary RK et al. Emerging therapy options in heparin-
induced thrombocytopenia. Cardiovasc Hematol Agents Med 
Chem. 2014;12(1):50–8. [PMID: 25374012]
McKenzie SE et al. Advances in the pathophysiology and treat
-
ment of heparin-induced thrombocytopenia. Curr Opin 
Hematol. 2014 Sep;21(5):380–7. [PMID: 24992313]
Schindewolf M et al. Use of fondaparinux off-label or approved 
anticoagulants for management of heparin-induced thrombo
-
cytopenia. J Am Coll Cardiol. 2017 Nov 28;70(21):2636–48. 
 
[PMID: 29169470]
Warkentin TE et al. Serological investigation of patients with a 
previous history of heparin-induced thrombocytopenia who

previous history of heparin-induced thrombocytopenia who 
are reexposed to heparin. Blood. 2014 Apr 17;123(16):2485–93. 
 
[PMID: 24516044]
4. Disseminated Intravascular Coagulation
 
»
A frequent cause of thrombocytopenia in hospi
-
talized patients.
 
»
Prolonged PT and aPTT, and low/declining 
fibrinogen.
 
»
Thrombocytopenia.
Table 14–5.
 
Management of suspected or proven HIT.
I.
  
Disc
ontinue all forms of heparin. Send PF4-heparin ELISA (if 
indicated).
II.
  
B
egin treatment with direct thrombin inhibitor.
Agent
Indication
Dosing
Argatroban
Prophylaxis or 
treatment of 
HIT
Continuous intravenous infusion 
of 0.5–1.2 mcg/kg/min, titrate 
to aPTT = 1.5 to 3 × the base
-
line value.
1
 Max infusion rate 
≤ 10 mcg/kg/min.
Bivalirudin
Percutaneous 
coronary 
intervention
2
Bolus of 0.75 mg/kg intrave
-
nously followed by initial con
-
tinuous intravenous infusion 
of 1.75 mg/kg/h. Manufacturer 
indicates monitoring should 
be by ACT.
III.
  
P
erform Doppler ultrasound of lower extremities to rule out 
subclinical thrombosis (if indicated).
IV.
  
F
ollow platelet counts daily until recovery occurs.
V.
  
W
hen platelet count has recovered, transition anticoagulation 
to warfarin; treat for 30 days (HIT) or 3–6 months (HITT).
VI.
  
D
ocument heparin allergy in medical record (confirmed cases).
1
Hepatic insufficiency: initial infusion rate = 0.5 mcg/kg/min.
2
Not approved for HIT/HITT.
ACT, activated clotting time; aPTT, activated partial thromboplastin 
time; ELISA, enzyme-linked immunosorbent assay; HIT, heparin-
induced thrombocytopenia; HITT, heparin-induced thrombocyto
-
penia and thrombosis; PF4, platelet factor 4.
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»
Disseminated intravascular coagulation (DIC) is caused by 
uncontrolled local or systemic activation of coagulation, 
which leads to depletion of coagulation factors and fibrino
-
gen, and often results in thrombocytopenia as platelets are 
activated and consumed.
Numerous disorders that are associated with DIC, 
including sepsis (in which coagulation is activated by pres
-
ence of lipopolysaccharide), cancer, trauma, burns, and 
pregnancy-associated complications (in which tissue factor 
is released). Aortic aneurysm and cavernous hemangiomas 
may promote localized intravascular coagulation, and 
snake bites may result in DIC due to the introduction of 
exogenous toxins.
 
»
Bleeding in DIC usually occurs at multiple sites, such as 
intravenous catheters or incisions, and may be widespread 
(purpura fulminans). Malignancy-related DIC may mani
-
fest principally as thrombosis (Trousseau syndrome).
In early DIC, the platelet count and fibrinogen levels may 
remain within the normal range, albeit reduced from base
-
line levels. There is progressive thrombocytopenia (rarely 
severe), prolongation of the PT, decrease in fibrinogen 
levels, and eventually elevation in the aPTT. D-dimer levels 
typically are elevated due to the activation of coagulation 
and diffuse cross-linking of fibrin. Schistocytes on the 
blood smear, due to shearing of red cells through the 
microvasculature, are present in 10–20% of patients. Labo
-
ratory abnormalities in the HELLP syndrome (hemolysis, 
elevated liver enzymes, low platelets), a severe form of DIC 
with a particularly high mortality rate that occurs in peri
-
partum women, include elevated liver transaminases and 
kidney injury due to gross hemoglobinuria and pigment 
nephropathy. Malignancy-related DIC may feature normal 
platelet counts and coagulation studies, but clinicians often 
see a dropping platelet count and fibrinogen, with a rising 
INR.
 
»
Treatment
The underlying causative disorder must be treated (eg, 
antimicrobials, chemotherapy, surgery, or delivery of con
-
ceptus). If clinically significant bleeding is present, hemo
-
stasis must be achieved (Table 14–6).
Blood products should be administered only if clinically 
significant hemorrhage has occurred or is thought likely to 
occur without intervention (Table 14–6). The goal of plate
-
let therapy for most cases is greater than 20,000/mcL 
 
or greater than 50,000/mcL for serious bleeding, such as 
intracranial bleeding. FFP should be given only to patients 
with a prolonged aPTT and PT and significant bleeding. 
Cryoprecipitate may be given for bleeding or for fibrinogen 
levels less than 80–100 mg/dL. The clinician should correct 
the fibrinogen level with cryoprecipitate prior to giving 
FFP for prolonged PT and aPTT, to see if the fibrinogen 
replacement alone corrects the PT and aPTT. The PT, 
aPTT, fibrinogen, and platelet count should be monitored 
at least every 6–8 hours in acutely ill patients with DIC.
In some cases of refractory bleeding despite replace
-
ment of blood products, administration of low doses of 
heparin can be considered. The clinician must remember 
that DIC is primarily excessive clotting with secondary 
fibrinolysis, and that heparin can interfere with thrombin 
generation, which could then lead to a lessened consump
-
tion of coagulation proteins and platelets. An infusion of 
5 units/kg/h (no bolus) may be used with appropriate clini
-
cal judgement, uptitrated as clinically appropriate. 
Heparin, 
however, is contraindicated if the platelet count cannot be 
maintained at 50,000/mcL or more and in cases of central 
nervous system hemorrhage, gastrointestinal bleeding, pla
-
cental abruption, and any other condition that is likely to 
require imminent surgery
. Fibrinolysis inhibitors may be 
considered in some patients with refractory DIC, but this

-
considered in some patients with refractory DIC, but this 
can promote dangerous clotting and should be undertaken 
with great caution and only in consultation with a 
The treatment of HELLP syndrome must include evac
-
uation of the uterus (eg, delivery of a term or near-term infant 
or removal of retained placental or fetal fragments). Patients 
with Trousseau syndrome require treatment of the underlying 
malignancy and administration of unfractionated heparin or 
subcutaneous therapeutic-dose LMWH as treatment of 
Table 14–6.
 
Management of DIC.
 
  I.
 
Assess f
or underlying cause of DIC and treat.
 
II.
  
Establish baseline pla
telet count, PT, aPTT, D-dimer, 
 
III.
  
Transfuse blood 
products only if 
ongoing bleeding 
or high risk of 
bleeding.
Platelets:
 goal > 20,000/mcL (most 
patients) or > 50,000/mcL (severe 
bleeding, eg, intracranial hemorrhage)
Cryoprecipitate:
 goal fibrinogen level 
> 80–100 mg/dL
Fresh frozen plasma:
 goal PT and aPTT 
< 1.5 × normal
Packed red blood cells:
 goal hemoglobin 
> 8 g/dL or improvement in symptom
-
atic anemia
 
IV.
  
F
ollow platelets, aPTT/PT, fibrinogen every 4–6 hours or as 
clinically indicated.
 
 V.
  
I
f persistent bleeding, consider use of heparin
1
 (initial infusion, 
5–10 units/kg/h); do not administer bolus.
 
VI.
  
F
ollow laboratory parameters every 4–6 hours until DIC 
resolved and underlying condition successfully treated
1
Contraindicated if platelets cannot be maintained at > 50,000/mcL, 
 
in cases of gastrointestinal or central nervous system bleeding, in 
conditions that may require surgical management, or placental 
abruption.
aPTT, activated partial thromboplastin time; DIC, disseminated 
intravascular coagulation; PT, prothrombin time.
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thrombosis, since warfarin typically is ineffective at sec
-
ondary prevention of thromboembolism in the disorder. 
Typically, the heparin or LMWH treatment will gradually 
return the fibrinogen, PT (INR), aPTT, and platelet count 
back to normal, but it can take days. Oral anti-Xa agents or 
oral DTIs can be considered once stabilized with parenteral 
heparin or LMWH.
Immediate initiation of chemotherapy (usually within 
24 hours of diagnosis) is required for patients with acute 
promyelocytic leukemia (APL)–associated DIC, along 
with administration of blood products as clinically 
 
»
•	
Diffuse bleeding that is unresponsive to administration of 
blood products should be evaluated by a hematologist.
•	
All patients with DIC starting treatment with heparin 
or LMWH should be cared for by a hematologist.
 
»
Most patients with DIC are hospitalized when DIC is 
detected.
Feinstein DI. Disseminated intravascular coagulation in patients 
with solid tumors. Oncology (Williston Park). 2015 Feb;
 
29(2):96–102. [PMID: 25683828]
Iba T et al. Anticoagulant therapy for sepsis-associated dissemi
-
nated intravascular coagulation: the view from Japan. J 
Thromb Haemost. 2014 Jul;12(7):1010–9. [PMID: 24801203]
Levi M. Diagnosis and treatment of disseminated intravascular 
coagulation. Int J Lab Hematol. 2014 Jun;36(3):228–36. 
[PMID: 24750668]
Wada H et al. Disseminated intravascular coagulation: testing 
and diagnosis. Clin Chim Acta. 2014 Sep 25;436:130–4. 
[PMID: 24792730]
OTHER CONDITIONS CAUSING 
1. Drug-Induced Thrombocytopenia
The mechanisms underlying drug-induced thrombocyto
-
penia are thought in most cases to be immune, although 
exceptions exist (such as chemotherapy). Table 14–7 
lists medications associated with thrombocytopenia. The 
typical presentation of drug-induced (or drug-related) 
thrombocytopenia is severe thrombocytopenia and muco
-
cutaneous bleeding 7–14 days after exposure to a new 
drug, although a range of presentations is possible. Dis
-
continuation of the offending agent leads to resolution of 
thrombocytopenia within 7–10 days in most cases, but 
recovery kinetics depends on rate of drug clearance, which 
can be affected by liver and kidney function. Patients with 
severe thrombocytopenia should be given platelet trans
-
fusions with (immune cases only) or without IVIG. The 
University of Oklahoma Health Sciences center maintains 
a useful website for drug-induced thrombocytopenia 
(https://www.ouhsc.edu/platelets/).
2. Posttransfusion Purpura
Posttransfusion purpura (PTP) is a rare disorder that fea
-
tures sudden-onset thrombocytopenia in an individual 
who received transfusion of red cells, platelets, or plasma 
within 1 week prior to detection of thrombocytopenia. 
Antibodies against the human platelet antigen Pl
A1
 are 
detected in most individuals with PTP . Patients with PTP 
often are either multiparous women or persons who have 
received transfusions previously. Severe thrombocytopenia 
and bleeding are typical. Initial treatment consists of 
administration of IVIG (1 g/kg/day for 2 days), which 
should be administered as soon as the diagnosis is sus
-
pected. Platelets are not indicated unless severe bleeding is 
present, but if they are to be administered, HLA-matched 
platelets are preferred. A second course or IVIG, plasma 
Table 14–7.
 
Selected medications causing drug-
 
associated thrombocytopenia.
1
Class
Examples
Most agents
Antiplatelet agents
Abciximab
Anagrelide
Eptifibatide
Ticlopidine, tirofiban
Antimicrobial agents
Adefovir, indinavir, ritonavir
Fluconazole
Isoniazid
Linezolid
Penicillins
Rifampin
Sulfa drugs
Vancomycin
Cardiovascular agents
Atorvastatin, simvastatin
Captopril
Digoxin
Hydrochlorothiazide
Gastrointestinal agents
Cimetidine, famotidine, ranitidine
Neuropsychiatric agents
Carbamazepine
Phenytoin

Captopril
Digoxin
Phenytoin
Analgesic agents
Acetaminophen
Diclofenac, ibuprofen, naproxen, 
sulindac
Anticoagulant agents
Heparin
Low-molecular-weight heparin
Immunomodulator agents
Interferon-alpha
Rituximab
Immunosuppressant agents
Other agents
Immunizations
Iodinated contrast dye
1
See also https://www.ouhsc.edu/platelets/.
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exchange, corticosteroids, or splenectomy may be required 
in case of refractoriness. TPO-mimetics are also an option. 
Pl
A1
-negative or washed blood products are preferred for 
subsequent transfusions, but data supporting various treat
-
ment options are limited.
3. von Willebrand Disease Type 2B
von Willebrand disease (vWD) type 2B leads to chronic, 
characteristically mild to moderate thrombocytopenia via 
an abnormal vWF molecule that binds platelets with 
increased affinity, resulting in aggregation and clearance.
4. Platelet Sequestration
At any given time, one-third of the platelet mass is seques
-
tered in the spleen. Splenomegaly, due to a variety of condi
-
tions, may lead to thrombocytopenia of variable severity. 
Whenever possible, treatment of the underlying disorder 
should be pursued, but splenectomy, splenic embolization, 
or splenic irradiation may be considered in selected cases.
5. Pregnancy
Gestational thrombocytopenia is thought to result from 
progressive expansion of the blood volume that typically 
occurs during pregnancy, leading to hemodilution. Cyto
-
penias result, although production of blood cells is normal 
or increased. Platelet counts less than 100,000/mcL, how
-
ever, are observed in less than 10% of pregnant women in 
the third trimester; decreases to less than 70,000/mcL 
should prompt consideration of pregnancy-related ITP as 
well as preeclampsia or a pregnancy-related thrombotic 
microangiopathy.
6. Infection or Sepsis
Both immune- and platelet production–mediated defects 
are possible, and there may be significant overlap with 
concomitant DIC. Regardless, the platelet count typically 
improves with effective antimicrobial treatment or after the 
infection has resolved. In some critically ill patients, a 
defect in immunomodulation may lead to bone marrow 
macrophages (histiocytes) engulfing cellular components 
of the marrow in a process also called hemophagocytosis. 
The phenomenon typically resolves with resolution of the 
infection, but with certain infections (Epstein-Barr virus) 
immunosuppression may be required. Hemophagocytosis 
also may arise in the setting of malignancy, in which case 
the disorder is usually unresponsive to treatment with 
immunosuppression. Sepsis-related thrombocytopenia 
may be due to increased hepatic clearance of platelets 
caused by loss of asialoglycoprotein moieties on the platelet 
surface.
7. Pseudothrombocytopenia
Pseudothrombocytopenia results from EDTA anticoagulant-
 
induced platelet clumping; the phenomenon typically 
disappears when blood is collected in a tube containing 
citrate anticoagulant. Pseudothrombocytopenia diagnosis 
requires review of the peripheral blood smear.
Kasai J et al. Clinical features of gestational thrombocytopenia 
difficult to differentiate from immune thrombocytopenia 
diagnosed during pregnancy. J Obstet Gynaecol Res. 2015 Jan;
 
41(1):44–9. [PMID: 25163390]
Koyama K et al. Time course of immature platelet count and its rela
-
tion to thrombocytopenia and mortality in patients with sepsis. 
PLoS One. 2018 Jan 30;13(1):e0192064. [PMID: 29381746]
Menis M et al. Posttransfusion purpura occurrence and potential 
risk factors among the inpatient US elderly, as recorded in 
large Medicare databases during 2011 through 2012. Transfu
-
sion. 2015 Feb;55(2):284–95. [PMID: 25065878]
QUALITATIVE PLATELET DISORDERS
CONGENITAL DISORDERS OF PLATELET 
FUNCTION
 
»
Usually diagnosed in childhood.
 
»
Family history usually is positive.
 
»
May be diagnosed in adulthood when there is 
excessive bleeding.
 
»
Heritable qualitative platelet disorders are far less common 
than acquired disorders of platelet function and lead to vari
-
ably severe bleeding, often beginning in childhood. Occasion
-
ally, however, disorders of platelet function may go undetected 
until later in life when excessive bleeding occurs following a

-
-
until later in life when excessive bleeding occurs following a 
sufficient hemostatic challenge. Thus, the true incidence of 
hereditary qualitative platelet disorders is unknown.
Bernard-Soulier syndrome (BSS)
 is a rare, autosomal 
recessive bleeding disorder due to reduced or abnormal 
platelet membrane expression of glycoprotein Ib/IX (vWF 
receptor).
Glanzmann thrombasthenia
 results from a qualitative or 
quantitative abnormality in glycoprotein IIb/IIIa receptors on 
the platelet membrane, which are required to bind fibrinogen 
and vWF, both of which bridge platelets during aggregation/
platelet plug formation. Inheritance is autosomal recessive.
Under normal circumstances, activated platelets release 
the contents of platelet granules to reinforce the aggrega
-
tory response. 
Storage pool disease
 includes a spectrum of 
defects in release of alpha or dense (delta) platelet granules, 
or both (alpha-delta storage pool disease).
 
»
In patients with 
Glanzmann thrombasthenia,
 the onset of 
bleeding is usually in infancy or childhood. The degree of 
deficiency in IIb/IIIa may not correlate well with bleeding 
symptoms. Patients with 
storage pool disease
 are affected 
by variable bleeding, ranging from mild and trauma-related 
to spontaneous.
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In 
Bernard-Soulier syndrome,
 there are abnormally large 
platelets (approaching the size of red cells), moderate 
thrombocytopenia, and a prolonged bleeding time. Platelet 
aggregation studies show a marked defect in response to 
ristocetin, whereas aggregation in response to other ago
-
nists is normal; the addition of normal platelets corrects the 
abnormal aggregation. The diagnosis can be confirmed by 
platelet flow cytometry.
In 
 platelet aggregation 
studies show marked impairment of aggregation in 
response to stimulation with various agonists.
 describes defects in the number, 
content, or function of platelet alpha or dense granules, or 
both. The 
gray platelet syndrome
 comprises abnormali
-
ties of platelet alpha granules, thrombocytopenia, and 
marrow fibrosis. The blood smear shows agranular plate
-
lets, and the diagnosis is confirmed with electron 
microscopy.
Albinism-associated storage pool disease
 involves 
defective dense granules in disorders of oculocutaneous albi
-
nism, such as the Hermansky-Pudlak and Chediak-Higashi 
syndromes. Electron microscopy confirms the diagnosis.
Non–albinism-associated storage pool disease
 results 
from quantitative or qualitative defects in dense granules 
and is seen in Ehlers-Danlos and Wiskott-Aldrich syn
-
dromes, among others.
The 
Quebec platelet disorder
 comprises mild throm
-
bocytopenia, an abnormal platelet factor V molecule, and a 
prolonged bleeding time. Patients typically experience 
moderate bleeding. Interestingly, platelet transfusion does 
not ameliorate the bleeding. Patients have a prolonged 
bleeding time. Platelet aggregation studies characteristically 
show platelet dissociation following an initial aggregatory 
response, and electron microscopy confirms the diagnosis.
 
»
Treatment
The mainstay of treatment (including periprocedural pro
-
phylaxis) is transfusion of normal platelets, although des
-
mopressin acetate (DDAVP), antifibrinolytic agents, and 
recombinant human activated factor VII each have a role in 
selected clinical situations.
Andrews RK et al. Bernard-Soulier syndrome: an update. Semin 
Thromb Hemost. 2013 Sep;39(6):656–62. [PMID: 23929303]
Lambert MP . What to do when you suspect an inherited platelet 
disorder. Hematology Am Soc Hematol Educ Program. 
2011;2011:377–83. [PMID: 22160061]
Orsini S et al; European Hematology Association-Scientific 
Working Group (EHA-SWG) on thrombocytopenias and 
platelet function disorders. Bleeding risk of surgery and its 
prevention in patients with inherited platelet disorders. Hae
-
matologica. 2017 Jul;102(7):1192–203. [PMID: 28385783]
ACQUIRED DISORDERS OF 
PLATELET FUNCTION
Platelet dysfunction is more commonly acquired than 
inherited; the widespread use of platelet-altering medica
-
tions accounts for most of the cases of qualitative defects 
(Table 14–8). In cases where platelet function is irreversibly 
altered, platelet inhibition typically recovers within 7–9 days 
 
following discontinuation of the drug. In cases where plate
-
let function is non-irreversibly affected, platelet inhibition 
recovers with clearance of the drug from the system. Trans
-
fusion of platelets may be required if clinically significant 
bleeding is present.
DISORDERS OF COAGULATION
CONGENITAL DISORDERS OF COAGULATION
1. Hemophilia A & B
 
»
Hemophilia A:
 congenital deficiency of coagula
-
tion factor VIII.
 
»
Hemophilia B:
-
tion factor IX.
 
»
Recurrent hemarthroses and arthropathy.
 
»
Risk of development of inhibitory antibodies to 
factor VIII or factor IX.
 
»
In many older patients, infection with HIV or hepa
-
titis C virus from receipt of contaminated blood 
products.
 
»
The frequency of hemophilia A is ~1 per 5000 live male 
births, whereas hemophilia B occurs in ~1 in 25,000 live

products.
 
»
births, whereas hemophilia B occurs in ~1 in 25,000 live 
male births. Inheritance is X-linked recessive, leading to 
affected males and carrier females. There is no race predi
-
lection. Testing is indicated for male infants with a hemo
-
philic pedigree who are asymptomatic or who experience 
excessive bleeding, or for an otherwise asymptomatic ado
-
lescent or adult who experiences unexpected excessive 
bleeding with trauma or invasive procedures.
Inhibitors to factor VIII will develop in approximately 
20–25% of patients with severe hemophilia A, and inhibi
-
tors to factor IX will develop in less than 5% of patients 
with severe hemophilia B.
A substantial proportion of older patients with hemo
-
philia acquired infection with HIV or HCV or both in the 
1980s due to exposure to contaminated factor concentrates 
and blood products.
 
»
Severe hemophilia (factor VIII activity less than 1%) pres
-
ents in infant males or in early childhood with spontaneous 
bleeding into joints, soft tissues, or other locations. Sponta
-
neous bleeding is rare in patients with mild hemophilia (fac
-
tor VIII activity greater than 5%), but bleeding may occur 
with a significant hemostatic challenge (eg, surgery, trauma). 
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Intermediate clinical symptoms are seen in patients with 
moderate hemophilia (factor VIII activity 1–5%). Female 
carriers of hemophilia can have a wide range of factor VIII 
activity, with some manifesting a bleeding disorder.
Significant hemophilic arthropathy is usually avoided 
in patients who have received long-term prophylaxis with 
factor concentrate starting in early childhood, whereas 
joint disease is common in adults who have experienced 
recurrent hemarthroses. Patients tend to have one or two 
‘target’ joints into which they bleed most often.
Inhibitor development to factor VIII or factor IX is 
characterized by bleeding episodes that are resistant to 
treatment with clotting factor VIII or IX concentrate, and 
by new or atypical bleeding.
Hemophilia is diagnosed by demonstration of an isolated 
reproducibly low factor VIII or factor IX activity level, in 
the absence of other conditions. If the aPTT is prolonged, 
it typically corrects upon mixing with normal plasma. A 
variety of mutations, including inversions, large and small 
deletions, insertions, missense mutations, and nonsense 
mutations may be causative. Depending on the level of 
residual factor VIII or factor IX activity and the sensitivity 
of the thromboplastin used in the aPTT coagulation 
reaction, the aPTT may or may not be prolonged (although 
it typically is markedly prolonged in severe hemophilia). 
Hemophilia is classified according to the level of factor 
activity in the plasma. 
Severe hemophilia
 is characterized 
by less than 1% factor activity, 
mild hemophilia
 features 
greater than 5% factor activity, and 
moderate hemophilia
 
features 1–5% factor activity. Female carriers may become 
symptomatic if significant lyonization has occurred favor
-
ing the defective factor VIII or factor IX gene, leading to 
factor VIII or factor IX activity level markedly less than 
50%. Typically, a clinical bleeding diathesis occurs once the 
factor activity is less than 20%, but bleeding can occur in 
trauma, surgery, and delivery if the factor activity is less 
than 50%.
In the presence of an inhibitor to factor VIII or factor IX, 
there is accelerated clearance of and suboptimal or absent 
rise in measured activity of infused factor, and the aPTT 
does not correct on mixing. The Bethesda assay measures 
the potency of the inhibitor.
 
»
Treatment
Plasma-derived or recombinant factor VIII or IX products 
are the mainstay of treatment. The standard of care for 
most individuals with severe hemophilia is primary pro
-
phylaxis: by the age of 4 years, most children with severe 
Table 14–8.
 
Causes of acquired platelet dysfunction.
Cause
Mechanism(s)
Treatment of Bleeding
Drug-Induced
Salicylates (eg, aspirin)
Irreversible inhibition of platelet 
cyclooxygenase
Discontinuation of drug; platelet transfusion
NSAIDs (eg, ibuprofen)
Reversible inhibition of cyclooxygenase
Glycoprotein IIb/IIIa inhibitors (eg, abciximab, 
tirofiban, eptifibatide)
↓
 Binding of fibrinogen to PM IIb/IIIa 
receptor
Thienopyridines (eg, clopidogrel, ticlopidine)
↓
 ADP binding to PM receptor
Dipyridamole
↓
 Intracellular cAMP metabolism
SSRIs (eg, paroxetine, fluoxetine)
↓
 Serotonin in dense granules
Omega-3 fatty acids (eg, DHA, EHA)
Disruption of PM phospholipid
Antibiotics (eg, high-dose penicillin, nafcillin, 
ticarcillin, cephalothin, moxalactam)
Not fully elucidated; PM binding may 
 
interfere with receptor-ligand 
interactions
Alcohol
↓
 TXA2 release
Disease-Related
Uremia
↑
 Nitric oxide; 
↓
 release of granules
DDAVP , high-dose estrogens; platelet 
 
transfusion, dialysis
Myeloproliferative disorder/myelodysplastic 
syndrome
Abnormal PM receptors, signal transduc
-
tion, and/or granule release
Platelet transfusion; myelosuppressive 
 
treatment (myeloproliferative disorder)
Surgical Procedure-Related
Cardiac bypass
Platelet activation in bypass circuit
Platelet transfusion

ADP , adenosine diphosphate; cAMP , cyclic adenosine monophosphate; DDAVP , desmopressin acetate; DHA, docosahexaenoic acid; EHA, 
eicosahexaenoic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; PM, platelet membrane; SSRIs, selective serotonin release inhibitors; 
TXA2, thromboxane A2.
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hemophilia have begun twice- or thrice-weekly infusions 
of factor to prevent the recurrent joint bleeding that oth
-
erwise would characterize the disorder and lead to severe 
musculoskeletal morbidity. In selected cases of nonsevere 
hemophilia, or as an adjunct to prophylaxis in severe 
hemophilia, treatment with factor products is given peri
-
procedurally, prior to high-risk activities (such as sports), 
or as needed for bleeding episodes (Table 14–9). Recombi
-
nant factor VIII and factor IX molecules that are bioengi
-
neered to have an extended half-life may allow for 
extended dosing intervals in patients who are treated 
prophylactically. The decision to switch to a long-acting 
product is patient specific. The long-acting factor IX prod
-
ucts have clear added value in reducing frequency of factor 
injections. This is not so clear with the long-acting factor 
VIII products. Patients with mild hemophilia A may 
respond to as-needed (on demand) intravenous or intra
-
nasal treatment with DDAVP . Antifibrinolytic agents may 
be useful in cases of mucosal bleeding and are commonly 
used adjunctively, such as following dental procedures. 
Gene therapy for hemophilia A and B is now a reality and 
is likely to change the treatment landscape over the next 
decade, transforming patient’s lives and reducing or elimi
-
nating the need for prophylactic infusions of factor IX 
protein.
Factor inhibitors (antibodies that interfere with activity 
or half-life), are a major clinical problem for patients with 
hemophilia. It may be possible to overcome low-titer 
inhibitors (less than 5 Bethesda units [BU]) by giving larger 
doses of factor, whereas treatment of bleeding in the pres
-
ence of a high-titer inhibitor (more than 5 BU) requires 
infusion of an activated prothrombin complex concentrate 
(such as FEIBA [factor eight inhibitor bypassing activity]) 
or recombinant activated factor VII. Inhibitor tolerance 
induction, achieved by giving large doses (50–300 units/kg 
intravenously of factor VIII daily) for 6–18 months, suc
-
ceeds in eradicating the inhibitor in 70% of patients with 
hemophilia A and in 30% of patients with hemophilia B. 
Patients with hemophilia B who receive inhibitor tolerance 
induction, however, are at risk for development of nephrotic 
syndrome and anaphylactic reactions, making eradication 
of their inhibitors less feasible. Additional immunomodu
-
lation may allow for eradication in selected inhibitor toler
-
ance induction–refractory patients. Emicizumab is a novel 
bi-specific antibody that brings factors IX and X together, 
effectively replacing the cofactor function of factor VIII in 
the clotting cascade, offering new hope for patients with 
Antiretroviral treatment is almost universally adminis
-
tered to individuals with HIV infection. Patients with 
Table 14–9.
 
Treatment of bleeding in selected inherited disorders of hemostasis.
Disorder
Subtype
Treatment for Minor 
Bleeding
Treatment for 
Major Bleeding
Comment
Hemophilia A
Mild
DDAVP
1
DDAVP
1
 or factor VIII 
product
Treat for 3–10 days for major bleeding or 
 
following surgery, keeping factor activity 
level 50–80% initially. Adjunctive 
 
aminocaproic acid (EACA) may be useful 
for mucosal bleeding or procedures
 
Moderate or severe
Factor VIII product
Hemophilia B
Mild, moderate, or 
severe
Factor IX product
von Willebrand 
disease
Type 1
DDAVP
DDAVP , vWF product
Type 2
DDAVP ,
1
 vWF product
vWF product
 
Type 3
 
Factor XI 
deficiency
—
FFP or EACA
FFP
Adjunctive EACA should be used for mucosal 
bleeding or procedures
1
Mild hemophilia A and type 2A or 2B vWD patients: therapeutic trial must have previously confirmed an adequate response (ie, elevation 
of factor VIII or vWF activity level into the normal range) and (for type 2B) no exacerbation of thrombocytopenia. DDAVP is not typically

of factor VIII or vWF activity level into the normal range) and (for type 2B) no exacerbation of thrombocytopenia. DDAVP is not typically 
effective for type 2M vWD. A vWF-containing factor VIII concentrate is preferred for treatment of type 2N vWD.
Notes:
DDAVP
 dose is 0.3 mcg/kg intravenously in 50 mL saline over 20 minutes, or nasal spray 300 mcg for weight > 50 kg or 150 mcg for < 50 kg, 
every 12–24 hours, maximum of three doses in a 48-hour period. If more than two doses are used in a 12- to 24-hour period, free water 
restriction and monitoring for hyponatremia is essential.
EACA
 dose is 50 mg/kg orally four times daily for 3–5 days; maximum 24 g/day, useful for mucosal bleeding/dental procedures.
 dose is 50 units/kg intravenously initially followed by 25 units/kg every 8 hours followed by lesser doses at longer 
intervals once hemostasis has been established.
 
dose is 100 units/kg (120 units/kg if using Benefix) intravenously initially followed by 50 units/kg (60 units/kg if using 
Benefix) every 8 hours followed by lesser doses at longer intervals once hemostasis has been established.
vWF-containing factor VIII product
 dose is 60–80 RCoF units/kg intravenously every 12 hours initially followed by lesser doses at longer 
FFP
 is typically administered in 4-unit boluses and may not need to be re-bolused after the initial administration due to the long half-life 
of factor XI.
DDAVP , desmopressin acetate; FFP , fresh frozen plasma; vWF, von Willebrand factor.
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hepatitis C infection should be referred for treatment to 
eradicate the virus.
 
»
All patients with hemophilia should be seen regularly in a 
comprehensive hemophilia treatment center.
 
»
•	
Major invasive procedures because of the need for serial 
infusions of clotting factor concentrate.
•	
Bleeding that is unresponsive to outpatient treatment.
Aledort L et al. Factor VIII therapy for hemophilia A: current 
and future issues. Expert Rev Hematol. 2014 Jun;7(3):373–85. 
[PMID: 24717090]
George LA et al. Hemophilia B gene therapy with a high-
 
specific-activity factor IX variant. N Engl J Med. 2017 Dec 7;
 
377(23):2215–27. [PMID: 29211678]
Manco-Johnson MJ et al; Joint Outcomes Committee of the 
Universal Data Collection, US Hemophilia Treatment Center 
Network. Prophylaxis usage, bleeding rates, and joint out
-
comes of hemophilia, 1999 to 2010: a surveillance project. 
Blood. 2017 Apr 27;129(17):2368–74. [PMID: 28183693]
Mazepa MA et al; US Hemophilia Treatment Center Network. 
Men with severe hemophilia in the United States: birth cohort 
analysis of a large national database. Blood. 2016 Jun 16;
 
127(24):3073–81. [PMID: 26983851]
Oldenburg J et al. Emicizumab prophylaxis in hemophilia A 
with inhibitors. N Engl J Med. 2017 Aug 31;377(9):809–18. 
[PMID: 28691557]
Rangarajan S et al. AAV5-factor VIII gene transfer in severe 
hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519–30. 
[PMID: 29224506]
2. von Willebrand Disease
 
»
The most common inherited bleeding disorder.
 
»
von Willebrand factor binds platelets to subendo
-
thelial surfaces, aggregates platelets, and pro
-
longs the half-life of factor VIII.
 
»
vWF is an unusually large multimeric glycoprotein that 
binds to subendothelial collagen and its platelet receptor, 
glycoprotein Ib, bridging platelets to the subendothelial 
matrix at the site of vascular injury and contributing to 
linking them together in the platelet plug. vWF also has a 
binding site for factor VIII, prolonging factor VIII half-life 
in the circulation.
Between 75% and 80% of patients with vWD have type 1, 
a quantitative abnormality of the vWF molecule that usu
-
ally does not feature an identifiable causal mutation in the 
vWF gene.
Type 2 vWD is seen in 15–20% of patients with vWD. 
In type 2A or 2B vWD, a qualitative defect in the vWF 
molecule is causative. Type 2N and 2M vWD are due to 
defects in vWF that decrease binding to factor VIII or 
to platelets, respectively. Importantly, type 2N vWD clini
-
cally resembles hemophilia A, with the exception of a 
 
family history that shows affected females. Factor VIII 
activity levels are decreased, and vWF activity and antigen 
(Ag) are normal. Type 2M vWD features a normal multi
-
mer pattern. Type 3 vWD is rare, and like type 1, is a quan
-
titative defect, with mutational homozygosity or double 
heterozygosity yielding undetectable levels of vWF and 
severe bleeding in infancy or childhood.
 
»
Patients with type 1 vWD usually have mild or moderate 
platelet-type bleeding (especially involving the integument 
and mucous membranes). Patients with type 2 vWD usu
-
ally have moderate to severe bleeding that presents in 
childhood or adolescence. Patient with type 3 vWD dem
-
onstrate a severe bleeding phenotype.
In type 1 vWD, the vWF activity (ristocetin co-factor 
assay) and the vWF Ag are mildly depressed, whereas the 
vWF multimer pattern is normal (Table 14–10). Labora
-
tory testing of type 2A or 2B vWD typically shows a ratio 
of vWF Ag:vWF activity of approximately 2:1 and a multi
-
mer pattern that lacks the highest molecular weight 
Table 14–10.
 
Laboratory diagnosis of von Willebrand disease.
Type
vWF Activity
vWF Antigen
Factor VIII
RIPA
Multimer Analysis
1
↓
↓
Nl or 
↓
↓
Normal pattern; uniform 
↓
 intensity of bands
2
A
↓↓
↓
↓
↓

Type
RIPA
1
↓
↓
Nl or 
↓
↓
↓
2
A
↓↓
↓
↓
↓
Large and intermediate multimers decreased or absent
B
↓↓
↓
↓
↑
Large multimers decreased or absent
M
↓
↓
↓
↓
↓
N
Nl
Nl
↓↓
Nl
Nl
3
↓↓↓
↓↓↓
↓↓↓
↓↓↓
Multimers absent
Nl, normal; RIPA, ristocetin-induced platelet aggregation; vWF, von Willebrand factor.
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multimers. Thrombocytopenia is common in type 2B 
vWD due to a gain-of-function mutation of the vWF mol
-
ecule, which leads to increased binding to its receptor on 
platelets, resulting in platelet clearance; a ristocetin-
induced platelet aggregation (RIPA) study shows an 
increase in platelet aggregation in response to low concen
-
trations of ristocetin. Except in the more severe forms of 
vWD that feature a significantly decreased factor VIII 
activity, aPTT and PT are normal in patients with vWD.
 
»
Treatment
The treatment of vWD is outlined in Table 14–9. DDAVP 
is useful in the treatment of mild bleeding in most cases of 
type 1 and some cases of type 2 vWD. DDAVP causes 
release of vWF and factor VIII from storage sites, leading 
to increases in vWF and factor VIII twofold to sevenfold 
that of baseline levels. A therapeutic trial to document suf
-
ficient vWF levels posttreatment is strongly recommended. 
Due to tachyphylaxis and the risk of significant hyponatre
-
mia secondary to fluid retention, more than two doses 
should not be given in a 48-hour period. vWF-containing 
factor VIII concentrates or recombinant VWF products are 
used in all other clinical scenarios, and when bleeding is 
not controlled with DDAVP . Cryoprecipitate should not be 
given due to lack of viral inactivation. Antifibrinolytic 
agents (eg, aminocaproic acid or tranexamic acid) may be 
used adjunctively for mucosal bleeding or procedures. 
Pregnant patients with vWD usually do not require treat
-
ment at the time of delivery because of the natural physio
-
logic increase in vWF levels (up to threefold that of 
baseline) that are observed by parturition. However, levels 
need to be confirmed in late pregnancy, and if they are low 
or if excessive bleeding is encountered, vWF products may 
be given. Moreover, patients are at risk for significant 
bleeding 1–2 weeks postpartum when vWF levels fall sec
-
ondary to the fall in estrogen levels.
Abshire TC et al. Prophylaxis in severe forms of von Willebrand’s 
disease: results from the von Willebrand Disease Prophylaxis 
Network (VWD PN). Haemophilia. 2013 Jan;19(1):76–81. 
[PMID: 22823000]
De Jong A et al. Developments in the diagnostic procedures for 
von Willebrand disease. J Thromb Haemost. 2016 Mar;
 
14(3):449–60. [PMID: 26714181]
Kouides PA. Present day management of inherited bleeding 
disorders in pregnancy. Expert Rev Hematol. 2016 Oct;
 
9(10):987–95. [PMID: 27459638]
Lenting PJ et al. von Willebrand factor biosynthesis, secretion, 
and clearance: connecting the far ends. Blood. 2015 Mar 26;
 
125(13):2019–28. [PMID: 25712991]
Neff AT. Current controversies in the diagnosis and management 
of von Willebrand disease. Ther Adv Hematol. 2015 Aug;
 
6(4):209–16. [PMID: 26288715]
3. Factor XI Deficiency
Factor XI deficiency (also called 
hemophilia C
) is inher
-
ited in an autosomal recessive manner, leading to hetero
-
zygous or homozygous defects. It is most prevalent 
among individuals of Ashkenazi Jewish descent. Levels of 
factor XI, while variably reduced, do not correlate well 
with bleeding symptoms. Mild bleeding is most common, 
and surgery or trauma may expose or worsen the bleeding 
tendency. FFP is the mainstay of treatment in locales 
where the plasma-derived factor XI concentrate is not 
available. Administration of adjunctive aminocaproic 
acid or tranexamic acid is regarded as mandatory for 
procedures or bleeding episodes involving the mucosa 
(Table 14–9).
Bolton-Maggs PH. Factor XI deficiency—resolving the enigma? 
Hematology Am Soc Hematol Educ Program. 2009:97–105. 
[PMID: 20008187]
James P et al. Rare bleeding disorders—bleeding assessment 
tools, laboratory aspects and phenotype and therapy of FXI 
deficiency. Haemophilia. 2014 May;20(Suppl 4):71–5. [PMID: 
24762279]
4. Less Common Heritable Disorders 
of Coagulation
Congenital deficiencies of clotting factors II, V , VII, and 
X

24762279]
X
 are rare and typically are inherited in an autosomal 
recessive pattern. A prolongation in the PT (and aPTT for 
factor X, factor V , and factor II deficiency) that corrects 
upon mixing with normal plasma is typical. Definitive 
diagnosis requires testing for specific factor activity. The 
treatment of factor II deficiency is with a prothrombin 
complex concentrate; factor V deficiency is treated with 
infusions of FFP or platelets (which contain factor V in 
alpha granules); factor VII deficiency is treated with 
recombinant human activated factor VII at 15–30 mcg/kg 
every 4–6 hours. Factor X deficiency, previously treated 
with FFP , can now be treated with a FDA-approved 
plasma-derived factor X product (Coagadex).
Deficiency of factor XIII,
 a transglutamase that cross-
links fibrin, characteristically leads to delayed bleeding that 
occurs hours to days after a hemostatic challenge (such as 
surgery or trauma). The condition is usually life-long, and 
spontaneous intracranial hemorrhages as well as recurrent 
pregnancy loss appear to occur with increased frequency in 
these patients compared with other congenital deficiencies. 
Cryoprecipitate or infusion of a plasma-derived factor XIII 
concentrate (appropriate for patients with A-subunit defi
-
ciency only) is the treatment of choice for bleeding or sur
-
gical prophylaxis. Factor XIII deficiency does not cause a 
prolongation of the PT or aPTT.
de Moerloose P et al. Rare coagulation disorders: fibrinogen, 
factor VII and factor XIII. Haemophilia. 2016 Jul;22(Suppl 5):
 
61–5. [PMID: 27405678]
ACQUIRED DISORDERS OF COAGULATION
1. Acquired Antibodies to Factor VIII
Spontaneous antibodies to factor VIII (acquired hemo
-
philia A) occasionally occur in adults without a prior his
-
tory of hemophilia; older adults and patients with 
lymphoproliferative malignancy or connective tissue dis
-
ease and those who are postpartum or postsurgical are at 
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highest risk. The clinical presentation, which should be 
viewed as a medical emergency, typically includes exten
-
sive soft tissue ecchymoses, hematomas, and mucosal 
bleeding, as opposed to hemarthrosis in congenital hemo
-
philia A. The aPTT is typically prolonged and does not 
correct upon mixing; factor VIII activity is found to be low 
and a Bethesda assay reveals the titer of the inhibitor. 
Inhibitors of low titer (less than 5 BU) may often be over
-
come by infusion of high doses of factor VIII concentrates, 
whereas high-titer inhibitors (greater than 5 BU) must be 
treated with serial infusions of activated prothrombin com
-
plex concentrates, recombinant human activated factor VII, 
 
or recombinant porcine factor VIII (hemophilia A patients 
only). Along with establishment of hemostasis by one of 
these measures, immunosuppressive treatment with corti
-
costeroids and oral cyclophosphamide should be insti
-
tuted; treatment with IVIG, rituximab, or plasmapheresis 
can be considered in refractory cases. Unlike in congenital 
factor VIII deficiency, the patient’s bleeding does not cor
-
relate well with the factor VIII activity level, so the clinician 
must be concerned with any elevation of aPTT secondary 
to acquired factor VIII inhibitor. All such patients require 
immediate referral to a hematologist.
Astermark J. FVIII inhibitors: pathogenesis and avoidance. 
Blood. 2015 Mar 26;125(13):2045–51. [PMID: 25712994]
Gibson CJ et al. Clinical problem-solving. A Bruising Loss. N 
Engl J Med. 2016 Jul 7;375(1):76–81. [PMID: 27406351]
Tiede A et al. Prognostic factors for remission of and survival in 
acquired hemophilia A (AHA): results from the GTH-AH 01/2010 
study. Blood. 2015 Feb 12;125(7):1091–7. [PMID: 25525118]
Zeng Y et al. Interventions for treating acute bleeding episodes 
in people with acquired hemophilia A. Cochrane Database 
Syst Rev. 2014 Aug 28;8:CD010761. [PMID: 25165992]
2. Acquired Antibodies to Factor II
Patients with antiphospholipid antibodies occasionally 
have antibody specificity to coagulation factor II (pro
-
thrombin), leading typically to a severe hypoprothrombin
-
emia and bleeding. Mixing studies may or may not reveal 
presence of an inhibitor, as the antibody typically binds a 
non-enzymatically active portion of the molecule that 
leads to accelerated clearance, but characteristically the PT 
is prolonged and levels of factor II are low. FFP should be 
administered for treatment of bleeding. Treatment is 
immunosuppressive.
3. Acquired Antibodies to Factor V
Products containing bovine factor V (such as topical 
thrombin or fibrin glue, frequently used in surgical proce
-
dures) can lead to formation of an anti–factor V antibody 
that cross-reacts with human factor V . Clinicopathologic 
manifestations range from a prolonged PT in an otherwise 
asymptomatic individual to severe bleeding. Mixing stud
-
ies suggest the presence of an inhibitor, and the factor V 
activity level is low. In cases of serious or life-threatening 
bleeding, IVIG or platelet transfusions, or both, should be 
administered, and immunosuppression (as for acquired 
inhibitors to factor VIII) may be offered.
4. Vitamin K Deficiency
Vitamin K deficiency may occur as a result of deficient 
dietary intake of vitamin K (from green leafy vegetables, 
soybeans, and other sources), malabsorption, or decreased 
production by intestinal bacteria (due to treatment with 
chemotherapy or antibiotics). Vitamin K is required for 
normal function of vitamin K epoxide reductase that 
assists in posttranslational gamma-carboxylation of the 
coagulation factors II, VII, IX, and X, which is necessary 
for their activity. Thus, mild to moderate vitamin K defi
-
ciency typically features a prolonged PT (activity of the 
vitamin K–dependent factors is more reflected than in the 
aPTT; aPTT is prolonged if the deficiency is more severe) 
that corrects upon mixing; activity levels of individual clot
-

-
ting factors II, VII, IX, and X typically are low. Importantly, 
a concomitantly low factor V activity level is not indicative 
of isolated vitamin K deficiency, and may indicate an 
underlying defect in liver synthetic function.
For treatment, vitamin K
1
 (phytonadione) may be 
administered via intravenous or oral routes; the subcutane
-
ous route is not recommended due to erratic absorption. 
The oral dose is 5–10 mg/day and absorption is typically 
excellent; at least partial improvement in the PT should be 
observed within 18–24 hours of administration. Intrave
-
nous administration results in even faster normalization of 
a prolonged PT than oral administration; due to descriptions 
of anaphylaxis, parenteral doses should be administered at 
lower doses (1–5 mg/day) and slowly (eg, over 30 minutes) 
with concomitant monitoring. Overreplacement can make 
it difficult to resume warfarin when necessary.
5. Coagulopathy of Liver Disease
Impaired hepatic function due to cirrhosis or other causes 
leads to decreased synthesis of clotting factors, including 
factors II, V , VII, and IX, and fibrinogen, whereas factor VIII 
 
levels may be elevated in spite of depressed levels of other 
coagulation factors. The PT (and with advanced disease, 
the aPTT) is typically prolonged and usually corrects on 
mixing with normal plasma. A normal factor V level, in 
spite of decreases in the activity of factors II, VII, IX, and X, 
 
however, suggests vitamin K deficiency rather than liver 
disease. Qualitative and quantitative deficiencies of fibrin
-
ogen also are prevalent among patients with advanced liver 
disease, typically leading to a prolonged PT, thrombin time, 
and reptilase time.
The coagulopathy of liver disease usually does not 
require hemostatic treatment until bleeding occurs. Infusion 
of FFP may be considered if active bleeding is present and 
the aPTT and PT are markedly prolonged; however, the 
effect is transient and concern for volume overload may 
limit infusions. Patients with bleeding and a fibrinogen level 
consistently below 80–100 mg/dL should receive cryopre
-
cipitate. Liver transplantation, if feasible, results in produc
-
tion of coagulation factors at normal levels. The use of 
recombinant human activated factor VII in patients with 
bleeding varices is controversial, although some patient sub
-
groups may experience benefit. The coagulopathy of liver 
disease can predispose to bleeding or thrombosis, so caution 
and experience are needed for optimal management.
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Bianchini M et al. Coagulopathy in liver diseases: complication 
or therapy? Dig Dis. 2014;32(5):609–14. [PMID: 25034295]
Franchini M et al. Acquired factor V inhibitors: a systematic 
review. J Thromb Thrombolysis. 2011 May;31(4):449–57. 
[PMID: 21052780]
Tripodi A et al. The coagulopathy of chronic liver disease. N 
Engl J Med. 2011 Jul 14;365(2):147–56. [PMID: 21751907]
6. Warfarin Ingestion
See 
 section, below.
7. Disseminated Intravascular Coagulation
The consumptive coagulopathy of DIC is typically initi
-
ated by excessive tissue factor exposure or release and 
results in decreases in clotting factor activity due to con
-
sumption. The result can be bleeding or thrombosis in 
any given patient. The aPTT and PT are characteristically 
prolonged, and platelets and fibrinogen levels are reduced 
from baseline. Dropping fibrinogen can be a tip off 
to DIC.
8. Heparin/Fondaparinux/Direct-Acting Oral 
Anticoagulant Use
See Classes of Anticoagulants, below.
Connolly SJ et al; ANNEXA-4 Investigators. Andexanet alfa for 
acute major bleeding associated with factor Xa inhibitors. N 
Engl J Med. 2016 Sep 22;375(12):1131–41. [PMID: 27573206]
Das A et al. Novel antidotes for target specific oral anticoagu
-
lants. Exp Hematol Oncol. 2015 Sep 15;4:25. [PMID: 
26380149]
Pollack CV Jr et al. Idarucizumab for dabigatran reversal. N Engl 
J Med. 2015 Aug 6;373(6):511–20. [PMID: 26095746]
Siegal DM et al. Andexanet alfa for the reversal of factor Xa 
inhibitor activity. N Engl J Med. 2015 Dec 17;373(25):2413–24. 
 
[PMID: 26559317]
9. Lupus Anticoagulants
Lupus anticoagulants prolong the aPTT by interfering 
with interactions between the clotting cascade and the 
phospholipid surface on which they function, but they do 
not lead to bleeding. In fact, they predispose to thrombo
-
sis. Lupus anticoagulants were so named because of their 
early identification in patients with connective tissue dis
-
ease, although they also occur with increased frequency in 
individuals with underlying infection, inflammation, or 
malignancy, and they also can occur in asymptomatic 
individuals in the general population. A prolongation in 
the aPTT is observed that does not correct completely on 
mixing but that normalizes with excessive phospholipid. 
Specialized testing such as the hexagonal phase phospho
-
lipid neutralization assay, the dilute Russell viper venom 
time, and platelet neutralization assays can confirm the 
presence of a lupus anticoagulant. Rarely, the antibodies 
also interfere with factor II activity (see above), and that 
tiny subset of lupus anticoagulant patients are at risk for 
bleeding.
Adams M. Measurement of lupus anticoagulants: an update on 
quality in laboratory testing. Semin Thromb Hemost. 2013 
Apr;39(3):267–71. [PMID: 23424052]
OTHER CAUSES OF BLEEDING
Occasionally, abnormalities of the vasculature and integu
-
ment may lead to bleeding despite normal hemostasis; 
congenital or acquired disorders may be causative. These 
abnormalities include Ehlers-Danlos syndrome, osteogen
-
esis imperfecta, Osler-Weber-Rendu disease (hereditary 
hemorrhagic telangiectasia), and Marfan syndrome (heri
-
table defects) and integumentary thinning due to pro
-
longed corticosteroid administration or normal aging, 
amyloidosis, vasculitis, and scurvy (acquired defects). The 
bleeding time often is prolonged. If possible, treatment of 
the underlying condition should be pursued, but if this is 
not possible or feasible (ie, congenital syndromes), globally 
hemostatic agents such as DDAVP can be considered for 
treatment of bleeding.
Patients with hereditary hemorrhagic telangiectasia 
should be referred to a hereditary hemorrhagic telangiectasia 
center of excellence (https://curehht.org/understanding-hht/
 
get-support/hht-treatment-centers/). Bevacizumab and 
tranexamic acid have a growing role in the treatment of

tranexamic acid have a growing role in the treatment of 
patients who have hereditary hemorrhagic telangiectasia.
Gaillard S et al; ATERO Study Group. Tranexamic acid for epi
-
staxis in hereditary hemorrhagic telangiectasia patients: a 
European cross-over controlled trial in a rare disease. J Thromb 
Haemost. 2014 Sep;12(9):1494–502. [PMID: 25040799]
Iyer VN et al. Intravenous bevacizumab for refractory hereditary 
hemorrhagic telangiectasia-related epistaxis and gastrointes
-
tinal bleeding. Mayo Clin Proc. 2018 Feb;93(2):155–66. 
[PMID: 29395350]
ANTITHROMBOTIC THERAPY
The currently available anticoagulants include unfraction
-
ated heparin, LMWHs, fondaparinux, vitamin K antago
-
nist (ie, warfarin), and DOACs (ie, dabigatran, rivaroxaban, 
apixaban, edoxaban). (For a discussion of the injectable 
DTIs, see section 
Heparin-Induced Thrombocytopenia
 
above.)
 
»
Classes of Anticoagulants
A. Unfractionated Heparin and LMWHs
Unfractionated heparin is a repeating polymer of sulfated 
glycosaminoglycans that is most commonly derived from 
porcine intestinal tissue, which is rich in heparin-bearing 
mast cells. Only about one-third of the molecules in a given 
preparation of unfractionated heparin contain the crucial 
pentasaccharide sequence that is necessary for binding of 
antithrombin and, through conversion of thrombin from a 
slow inhibitor of coagulation factor activity to a rapid 
inhibitor, exertion of its anticoagulant effect. The pharma
-
cokinetics of unfractionated heparin are poorly predict
-
able, and the degree of anticoagulation is typically 
monitored (by aPTT or anti-Xa level) in patients who are 
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receiving the drug in therapeutic doses. Only a fraction of 
an infused dose of heparin is metabolized by the kidneys, 
however, making it safe to use in most patients with signifi
-
cant kidney disease. Heparin should be discontinued in 
patients who have bleeding and in some cases, protamine 
sulfate should be administered; 1 mg of protamine neutral
-
izes approximately 100 units of heparin sulfate, and the 
maximum dose is 50 mg intravenously.
The LMWHs are produced from chemical depolymeriza
-
tion of unfractionated heparin, resulting in products of lower 
molecular weight (mean molecular weight, 4500–6500d, 
 
depending on the LMWH). Due to less protein and cellular 
binding, the pharmacokinetics of the LMWHs are much 
more predictable than those of unfractionated heparin, 
allowing for fixed weight-based dosing. All LMWHs are 
principally renally cleared and must be avoided or used 
with extreme caution in individuals with creatinine clear
-
ance less than 30 mL/min. A longer half-life permits once- 
or twice-daily subcutaneous dosing, allowing for greater 
convenience and outpatient therapy in selected cases. Most 
patients do not require monitoring, although monitoring 
using the anti-Xa activity level is appropriate for patients 
with moderate kidney disease, those with elevated body 
mass index or low weight, and selected pregnant patients. 
About 30% of the molecules in a dose of LMWH are long 
enough (ie, sufficiently negatively charged) to bind prot
-
amine sulfate, allowing for some neutralization of antico
-
agulant effect. LMWHs are associated with a lower 
frequency of HIT (approximately 0.6%) than unfraction
-
ated heparin.
B. Fondaparinux
Fondaparinux, which is chemically related to LMWHs, is 
a synthetic molecule consisting of the highly active pen
-
tasaccharide sequence. As such, it exerts almost no 
thrombin inhibition and works to indirectly inhibit factor 
Xa through binding to antithrombin. Fondaparinux, like 
the LMWHs, is almost exclusively metabolized by the 
kidneys, and should be avoided in patients with creati
-
nine clearance less than 30 mL/min. Predictable pharma
-
cokinetics allow for weight-based dosing. A particularly 
long half-life (17–21 hours) allows for once-daily subcu
-
taneous dosing, but the absence of necessary charge char
-
acteristics leads to a lack of binding to protamine sulfate; 
therefore, unlike heparin, no effective neutralizing agent 
exists.
C. Vitamin K Antagonist (Warfarin)
The vitamin K antagonist warfarin inhibits the activity of 
the vitamin K–dependent carboxylase that is important 
for the posttranslational modification of coagulation fac
-
tors II, VII, IX, and X. Although warfarin may be taken 
orally, leading to a significant advantage over the heparins 
and heparin derivatives, which must be given parenterally 
or subcutaneously, interindividual differences in response 
to the agent related to nutritional status, comorbid dis
-
eases, concomitant medications, and genetic polymor
-
phisms lead to a poorly predictable anticoagulant response. 
Individuals taking warfarin must undergo periodic 
1
Importantly, because the INR is not standardized for abnormalities of 
factor V and fibrinogen, the INR should be used only in reference to anti
-
coagulation in patients who are receiving warfarin.
monitoring to verify the intensity of the anticoagulant 
effect. The intensity of anticoagulant effect is reported as 
the INR, which corrects for differences in potency of 
 
commercially available thromboplastin used to perform 
the PT.
1
D. Direct-Acting Oral Anticoagulants
Unlike warfarin, the DOACs (1) have a predictable dose 
effect and therefore do not require laboratory monitoring, 
(2) have anticoagulant activity independent of vitamin K 
with no need for dietary stasis, and (3) are renally metabo
-
lized to varying degrees so there are restrictions or dose 
reductions related to reduced kidney function (Table 14–11).

-
reductions related to reduced kidney function (Table 14–11). 
While the DOACs have fewer drug interactions than warfa
-
rin, if DOACs are given with a potentially interacting medi
-
cation, there is no reliable way to measure the impact on 
anticoagulant activity of the concomitant administration. 
There is no reliable way to measure adherence, either. There 
is a paucity of data on the use of DOACs in morbidly obese 
patients (more than 120 kg). Only dabigatran has a reversal 
agent. The provider must carefully consider kidney func
-
tion, weight, concomitant medications, indication for use, 
candidacy for lead-in parenteral therapy (as required for 
acute VTE treatment with edoxaban and dabigatran only) 
and anticipated patient adherence. Providers must be care
-
ful to dose each DOAC properly for the indication, kidney 
function, weight of patient, and for drug interactions. (See 
Table 14–11 for details).
Routine monitoring
 is not recommended for patients 
taking DOACs. However, there are clinical scenarios where 
assessing anticoagulant activity would be helpful, including 
active bleeding, pending urgent surgery, suspected thera
-
peutic failure, or concern for accumulation. There is no 
standardized laboratory assay to measure anticoagulant 
effect of the DOACs. They have varying effects on the PT 
and aPTT. A normal thrombin time excludes the presence 
of clinically relevant dabigatran levels; a normal aPTT 
likely excludes excess drug levels of dabigatran. A negative 
anti-Xa level likely excludes clinically relevant levels of 
rivaroxaban, apixaban, or edoxaban; a normal PT likely 
excludes excess drug levels of rivaroxaban but not apixaban 
or edoxaban. The INR is unreliable for the evaluation of 
factor Xa activity.
Ageno W et al. Oral anticoagulant therapy: Antithrombotic 
Therapy and Prevention of Thrombosis, 9th ed: American 
College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. Chest. 2012 Feb;141(2 Suppl):e44S–88S. [PMID: 
22315269]
Burnett AE et al. Guidance for the practical management of the 
direct oral anticoagulants (DOACs) in VTE treatment. J 
Thromb Thrombolysis. 2016 Jan;41(1):206–32. [PMID: 
26780747]
Cuker A. Laboratory measurement of the non-vitamin K antag
-
onist oral anticoagulants: selecting the optimal assay based on 
drug, assay availability, and clinical indication. J Thromb 
Thrombolysis. 2016 Feb;41(2):241–7. [PMID: 26386967]
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Table 14–11.
 
Direct-acting oral anticoagulants (DOACs) for VTE treatment and prevention.
1
Apixaban
Edoxaban
Betrixaban
Mechanism
Oral direct thrombin inhibitor
Oral direct factor Xa inhibitor
Approved uses
VTE treatment and secondary 
VTE replacement prophylaxis 
following hip replacement
VTE prophylaxis post-hip or knee 
replacement
VTE prophylaxis post-hip or 
knee replacement
VTE treatment and second
-
ary prevention
Prophylaxis of VTE in adults 
hospitalized for acute 
medical illness with mod
-
erate or severe restricted 
mobility and other risk 
factors for VTE
Frequency of dosing
Twice daily for first 21 days of acute 
VTE therapy, then daily
Once daily for DVT prevention
Once daily
Once daily
Food
With or without food
With food (for 15- and 20-mg tablets)
With food
Crushable?
No
Can crush; do not administer via J 
tube
Can crush and administer 
orally or via NG tube
No data
 
Renal clearance
80%
30–60%
25%
50%
15%
Kinetics
t ½ = 12–17 hours; tmax = 
2 hours
t ½ = 5–9 hours; tmax = 3 hours
t ½ = 12 hours; tmax = 
3 hours
t ½ = 10–14 hours; tmax = 
2 hours
t ½ = 19–27 hours; tmax = 
3 hours
Influences INR?
↑
 (or 
→
)
↑↑
 (or 
→
 at low concentrations)
↑
 (or 
→
)
↑
Unknown
Influences aPTT?
↑↑
↑
↑
↑
Unknown
Drug interactions (list not 
comprehensive)
Avoid
 rifampin, St John’s wort, 
and possibly carbamazepine
Caution
 with amiodarone, 
clarithromycin, dronedar
-
one, ketoconazole, quini
-
dine, verapamil. No dosage 
adjustment of dabigatran is 
recommended if CrCl 
 
> 50 mL/min
Reduce dose
 to 75 mg orally 
twice daily if CrCl 
 
30–50 mL/min and 
 
concurrent use of dronedar
-
one or ketoconazole
Avoid
 carbamazepine, conivaptan, 
indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, 
phenytoin, rifampin, ritonavir, St 
John’s wort
Caution
 with the concurrent use of 
combined P-gp inhibitors and/or 
weak or moderate inhibitors of 
CYP3A4 (eg, amiodarone, azithro
-
mycin, diltiazem, dronedarone, 
erythromycin, felodipine, quini
-
dine, ranolazine, verapamil) with 
rivaroxaban, particularly in patients 
with impaired kidney function
Avoid
 carbamazepine, phe
-
nytoin, rifampin, St John’s 
wort
Avoid
 clarithromycin, itra
-
conazole, ketoconazole, 
and ritonavir in patients 
already taking apixaban 
even at a reduced dose of 
Caution
 with clarithromycin, 
itraconazole, ketoconazole, 
and ritonavir
Avoid
 rifampin
 with certain 
P-gp inhibitors. Use has 
not been studied with 
many other P-gp inhibi
-
tors and inducers
Some recommend avoiding 
concomitant use 
altogether
 to 40 mg 
 
orally daily with 
 
concomitant use of P-gp 
inhibitors (eg, amioda
-
rone, 
 
azithromycin, 
 
verapamil, ketoconazole, 
clarithromycin)
(
continued
 
)
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1
Apixaban
Edoxaban
Switching from DOAC to 
warfarin
(per AC Forum Clinical Guidance: 
either approach [ie, stop 
DOAC then
start LMWH and warfarin; or 
overlap warfarin with DOAC] 
can be used for all DOAC to 
warfarin transitions.
If overlapping warfarin and 
DOAC, measure INR just 
before next DOAC dose and 
stop DOAC when INR ≥ 2.0)
Start warfarin and overlap 
with dabigatran;
CrCl C50 mL/min, overlap 
3 days
CrCl 30–50 mL/min, overlap 
2 days
CrCl 15–30 mL/min, overlap 
1 day
Stop DOAC; start warfarin and LMWH 
at time of next scheduled DOAC 
dose and bridge until
INR ≥ 2.0
Stop DOAC; start warfarin 
and LMWH at time of next 
scheduled DOAC dose and 
bridge until
INR ≥ 2.0
For 60-mg dose, reduce dose 
to 30 mg and start 
 
warfarin concomitantly
For 30-mg dose reduce dose 
to 15 mg and start 
 
warfarin concomitantly 
Stop edoxaban when INR 
≥ 2.0
No data available
Warfarin to DOAC
Start when INR < 2.0
Start when INR < 3.0
Start when INR ≤ 2.5
Start when INR < 2.5
Special considerations
Dyspepsia is common and 
starts within first 10 days
GI bleeding risk higher with 
dabigatran vs warfarin
GI bleeding risk higher with rivaroxa
-
ban vs warfarin
Do not use if CrCl ≥ 95 mL/min
 
Management of life-threatening 
bleeding
Idarucizumab 2 doses of 2.5 g 
intravenously no more than 
15 min apart
Activated charcoal, supportive care, 
consider 4-component PCC
Recombinant coagulation factor Xa 
(Andexxa) anticipated wide 
 
availability in 2019
Activated charcoal, support
-
ive care, consider 
 
4-component PCC
Recombinant coagulation 
 
factor Xa (Andexxa) 
 
anticipated wide 
 
-
 
-
 
1
Previously called new (novel) oral anticoagulants and target-specific oral anticoagulants. Consult prescribing information for updated dosing.
aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; GI, gastrointestinal; INR, international normalized ratio; NG, nasogastric; PCC, prothrombin complex concentrate; P-gp, 
P-glycoprotein; VTE, venous thromboembolism.
 
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Garcia DA et al. Parenteral anticoagulants: Antithrombotic 
Guidelines. Chest. 2012 Feb;141(2 Suppl):e24S–43S. Erratum 
in: Chest. 2012 May;141(5):1369. Dosage error in article text. 
[PMID: 22315264]
Heidbuchel H et al. Updated European Heart Rhythm Associa
-
tion Practical Guide on the use of non-vitamin K antagonist 
anticoagulants in patients with non-valvular atrial fibrillation. 
Europace. 2015 Oct;17(10):1467–507. [PMID: 26324838]
Robertson L et al. Oral direct thrombin inhibitors or oral factor 
Xa inhibitors for the treatment of deep vein thrombosis. 
Cochrane Database Syst Rev. 2015 Jun 30;6:CD010956. 
[PMID: 26123214]
Xa inhibitors for the treatment of pulmonary embolism. 
Cochrane Database Syst Rev. 2015 Dec 4;12:CD010957. 
[PMID: 26636644]
Streiff MB et al. Guidance for the treatment of deep vein throm
-
bosis and pulmonary embolism. J Thromb Thrombolysis. 
2016 Jan;41(1):32–67. Erratum in: J Thromb Thrombolysis. 
2016 Apr;41(3):548. [PMID: 26780738]
Witt DM et al. Guidance for the practical management of warfa
-
rin therapy in the treatment of venous thromboembolism. J 
Thromb Thrombolysis. 2016 Jan;41(1):187–205. [PMID: 
26780746]
 
»
Prevention of Venous 
Thromboembolic Disease
The frequency of venous thromboembolic disease (VTE) 
among hospitalized patients ranges widely; up to 20% of 
medical patients and 80% of critical care patients and high-
risk surgical patients have been reported to experience this 
complication, which includes DVT and PE.
Avoidance of fatal PE, which occurs in up to 5% of 
high-risk inpatients as a consequence of hospitalization or 
surgery is a major goal of pharmacologic prophylaxis. 
Tables 14–12 and 14–13 provide risk stratification for 
DVT/VTE among hospitalized surgical and medical inpa
-
tients. Standard pharmacologic prophylactic regimens are 
listed in Table 14–14. Prophylactic strategies should be 
guided by individual risk stratification, with all moderate- 
and high-risk patients receiving pharmacologic prophy
-
laxis, unless contraindicated. Contraindications to VTE 
prophylaxis for hospital inpatients at high risk for VTE are 
listed in Table 14–15. In patients at high risk for VTE with 
absolute contraindications to pharmacologic prophylaxis, 
mechanical devices such as intermittent pneumatic com
-
pression devices should be used, ideally portable devices 
with at least an 18-hour daily wear time.
It is recommended that VTE prophylaxis be used judi
-
ciously in hospitalized medical patients who are not criti
-
cally ill since a comprehensive review of evidence suggested 
harm from bleeding in low-risk patients given low-dose 
heparin and skin necrosis in stroke patients given compres
-
sion stockings. The Padua Risk Score provides clinicians 
with a simple approach to risk stratification in medical 
patients (Table 14–13). The IMPROVE risk score offers 
clinicians another standardized approach to risk assess
-
ment although both scores require further validation. 
Certain high-risk surgical patients should be considered 
for extended-duration prophylaxis of approximately 1 
month, including those undergoing total hip replacement, 
hip fracture repair, and abdominal and pelvic cancer sur
-
gery. If bleeding is present, if the risk of bleeding is high, or 
Table 14–12.
 
Risk stratification for DVT/VTE among 
surgical inpatients.
High risk
Recent major orthopedic surgery/arthroplasty/fracture
Abdominal/pelvic cancer undergoing surgery
Recent spinal cord injury or major trauma within 90 days
More than three of the intermediate risk factors (see below)
Intermediate risk
Not ambulating independently outside of room at least

Not ambulating independently outside of room at least 
twice daily
Active infectious or inflammatory process
Active malignancy
Major surgery (nonorthopedic)
History of VTE
Stroke
Central venous access or PICC line
Prior immobilization (> 72 hours) preoperatively
Obesity (BMI > 30)
Patient age > 50 years
Hormone replacement or oral contraceptive therapy
Hypercoagulable state
Burns
Paresis
HF (systolic dysfunction)
COPD exacerbation
Low risk
Minor procedure and age < 40 years with no additional 
risk factors
Ambulatory with expected length of stay of < 24 hours or 
minor surgery
BMI, body mass index; COPD, chronic obstructive pulmonary dis
-
ease; DVT, deep venous thrombosis, HF, heart failure; PICC, periph
-
erally inserted central catheter; VTE, venous thromboembolism.
Table 14–13.
 
Padua Risk Assessment Model for VTE 
prophylaxis in hospitalized medical patients.
Condition
Points
1
Active cancer, history of VTE, immobility, 
 
laboratory thrombophilia
3 points each
Recent (≤ 1 mo) trauma and/or surgery
2 points each
Age ≥ 70, acute MI or CVA, acute infection, 
rheumatologic disorder, BMI ≥ 30, hor
-
monal therapy
1 point each
1
A score ≥ 4 connotes high risk of VTE in the noncritically ill medi
-
cal patients and pharmacologic prophylaxis is indicated, absent 
absolute contraindications.
BMI, body mass index; CVA, cerebrovascular accident; MI, myocar
-
dial infarction; VTE, venous thromboembolism.
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Table 14–14.
 
Pharmacologic prophylaxis of VTE in selected clinical scenarios.
1
Anticoagulant
Dose
Frequency
Comment
Enoxaparin
40 mg subcutaneously
Once daily
Most medical inpatients and 
critical care patients
—
Surgical patients (moderate 
risk for VTE)
Abdominal/pelvic cancer 
surgery
Consider continuing for 4 weeks total dura
-
tion after abdomino-pelvic cancer surgery
Bariatric surgery
Higher doses may be required
30 mg subcutaneously
Orthopedic surgery
2
Give for at least 10 days. For THR, TKA, or HFS, 
consider continuing up to 1 month after 
surgery in high-risk patients
Major trauma
Not applicable to patients with isolated lower 
extremity trauma
Acute spinal cord injury
—
Dalteparin
2500 units subcutaneously
Once daily
Most medical inpatients
—
Abdominal surgery (moder
-
ate risk for VTE)
Give for 5–10 days
5000 units subcutaneously
Once daily
2
First dose = 2500 units. Give for at least 
10 days. For THR, TKA, or HFS, consider 
 
continuing up to 1 month after surgery in 
high-risk patients
Abdominal surgery (higher-
Medical inpatients
—
Fondaparinux
2.5 mg subcutaneously
Once daily
2
10 mg orally
Once daily
Orthopedic surgery: total hip 
and total knee replacement
Give for 12 days following total knee replace
-
ment; give for 35 days following total hip 
Apixaban
2.5 mg orally
Following hip or knee 
replacement surgery
-
110 mg orally first day, 
then 220 mg
Once daily
Following hip replacement 
surgery
For patients with CrCl > 30 mL/min
Initial single dose of 
160 mg, then 80 mg 
once daily with food
Reduce dose for patients 
with severe renal 
impairment or taking 
P-gp inhibitors
Daily
Adult patients hospitalized 
for an acute medical ill
-
ness with moderately to 
severely restricted mobil
-
ity and other risk factors 
for VTE
Recommended duration of treatment is 
35–42 days
Unfractionated 
heparin
5000 units 
subcutaneously
Three times 
daily
Higher VTE risk with low 
bleeding risk
Includes gynecologic surgery for malignancy 
and urologic surgery, medical patients with 
multiple risk factors for VTE
5000 units 
Hospitalized patients at 
intermediate risk for VTE
Includes gynecologic surgery (moderate risk)
Patients with epidural 
catheters
LMWHs usually avoided due to risk of spinal 
hematoma
Patients with severe kidney 
disease
3
LMWHs contraindicated
(
continued
 
)
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Falck-Ytter Y et al. Prevention of VTE in orthopedic surgery 
patients: Antithrombotic Therapy and Prevention of Throm
-
bosis, 9th ed: American College of Chest Physicians 
 
Evidence-Based Clinical Practice Guidelines. Chest. 2012 
Feb;141(2 Suppl):e278S–325S. [PMID: 22315265]
Gibson CM et al. The IMPROVEDD VTE risk score: incorpora
-
tion of D-Dimer into the IMPROVE score to improve venous 
thromboembolism risk stratification. TH Open. 2017;1:
 
e56–65.
Gould MK et al. Prevention of VTE in nonorthopedic surgical 
patients: Antithrombotic Therapy and Prevention of Thrombosis, 
9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):
 
e227S–77S. Erratum in: Chest. 2012 May;141(5):1369. [PMID: 
22315263]
Hostler DC et al. Validation of the International Medical Preven
-
tion Registry on venous thromboembolism bleeding risk 
score. Chest. 2016 Feb;149(2):372–9. [PMID: 26867833]
Kahn SR et al. Prevention of VTE in nonsurgical patients: Anti
-
thrombotic Therapy and Prevention of Thrombosis, 9th ed: 
American College of Chest Physicians Evidence-Based Clinical 
Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e195S–226S. 
 
[PMID: 2231526]
Sachdeva A et al. Graduated compression stockings for preven
-
tion of deep vein thrombosis. Cochrane Database Syst Rev. 
2014 Dec 17;12:CD001484. [PMID: 25517473]
Stewart DW et al. Aspirin for the prophylaxis of venous throm
-
boembolic events in orthopedic surgery patients: a compari
-
son of the AAOS and ACCP guidelines with review of the 
evidence. Ann Pharmacother. 2013 Jan;47(1):63–74. [PMID: 
23324504]
 
»
Treatment of Venous 
A. Anticoagulant Therapy
Treatment for VTE should be offered to patients with 
objectively confirmed DVT or PE, or to those in whom the 
clinical suspicion is high for the disorder but who have not 
yet undergone diagnostic testing (see Chapter 9). The man
-
agement of VTE primarily involves administration of anti
-
coagulants; the goal is to prevent recurrence, extension and 
embolization of thrombosis and to reduce the risk of post-
thrombotic syndrome. Suggested anticoagulation regimens 
are found in Table 14–16.
if the risk of VTE is high for the inpatient (Table 14–12) 
and therefore combined prophylactic strategies are needed, 
some measure of thromboprophylaxis may be provided 
through use of mechanical devices, including intermittent 
pneumatic compression devices, or graduated compression 
stockings.
An VV et al. Aspirin as thromboprophylaxis in hip and knee 
arthroplasty: a systematic review and meta-analysis. J Arthro
-
plasty. 2016 Nov;31(11):2608–16. [PMID: 27178011]
Buesing KL et al. Deep venous thrombosis and venous thrombo
-
embolism prophylaxis. Surg Clin North Am. 2015 Apr;95(2):
 
285–300. [PMID: 25814107]
Table 14–15.
 
Contraindications to VTE prophylaxis 
for medical or surgical hospital inpatients at high risk 
for VTE.
Absolute contraindications
Acute hemorrhage from wounds or drains or lesions
Intracranial hemorrhage within prior 24 hours
Heparin-induced thrombocytopenia (HIT): consider using 
fondaparinux
Severe trauma to head or spinal cord or extremities
Epidural anesthesia/spinal block within 12 hours of initiation of 
anticoagulation (concurrent use of an epidural catheter and anti
-
coagulation other than low prophylactic doses of unfractionated 
heparin should require review and approval by service who 
 
performed the epidural or spinal procedure, eg, anesthesia/
 
pain service, and in many cases, should be avoided entirely)
Currently receiving warfarin or heparin or LMWH or direct 
thrombin inhibitor for other indications
Relative contraindications
Coagulopathy (INR > 1.5)
Intracranial lesion or neoplasm
Severe thrombocytopenia (platelet count < 50,000/mcL)
Intracranial hemorrhage within past 6 months
Gastrointestinal or genitourinary hemorrhage within past 
6 months

6 months
INR, international normalized ratio; LMWH, low-molecular-weight 
heparin; VTE, venous thromboembolic disease.
Adapted from guidelines used at the Veterans Affairs Medical 
Center, San Francisco, CA.
 
1
Dose
Frequency
Comment
Warfarin
(variable) oral
Once daily
2
Titrate to goal INR = 2.5. Give for at least 
10 days. For high-risk patients undergoing 
THR, TKA, or HFS, consider continuing up 
to 1 month after surgery
Aspirin
variable
Hip and knee replacement
1
All regimens administered subcutaneously, except for warfarin.
2
Includes TKA, THR, and HFS.
3
Defined as creatinine clearance < 30 mL/min.
HFS, hip fracture surgery; LMWH, low-molecular-weight heparin; P-gp, P-glycoprotein; THR, total hip replacement; TKA, total knee arthro
-
plasty; VTE, venous thromboembolic disease.
 
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Table 14–16.
 
Initial anticoagulation for VTE.
1
Dose/Frequency
Comment
DVT, 
Lower 
Extremity
DVT, 
Upper 
Extremity
PE
VTE, With 
Concomi
-
tant Severe 
Kidney 
Disease
2
VTE, 
Cancer-
Related
Unfractionated Heparin
heparin
80 units/kg intravenous bolus, 
then continuous intravenous 
infusion of 18 units/kg/h
×
×
×
×
Bolus may be omitted if risk 
of bleeding is perceived to 
be elevated. Maximum 
bolus, 10,000 units. 
Requires aPTT monitoring. 
Most patients: begin war
-
farin at time of initiation 
of heparin.
330 units/kg subcutaneously × 
1, then 250 units/kg subcuta
-
neously every 12 hours
×
Fixed-dose; no aPTT moni
-
toring required
LMWH and Fondaparinux
3
1 mg/kg subcutaneously every 
12 hours
×
×
×
Most patients: begin warfa
-
rin at time of initiation of 
LMWH
3
200 units/kg subcutaneously 
once daily for first month, 
then 150 units/kg/day
×
×
×
×
Cancer: administer LMWH 
for ≥ 3–6 months; reduce 
dose to 150 units/kg after 
first month of treatment
5–10 mg subcutaneously once 
daily (see Comment)
×
×
×
Use 7.5 mg for body weight 
50–100 kg; 10 mg for 
body weight > 100 kg
Direct-Acting Oral Anticoagulants (DOACs)
15 mg orally twice daily with 
food for 21 days then 20 mg 
orally daily with food
×
×
×
Contraindicated if CrCl 
< 30 mL/min
Apixaban
10 mg orally twice daily for first 
7 days then 5 mg twice daily
×
×
×
< 25 mL/min
Monotherapy without need 
for initial parenteral 
therapy
5–10 days of parenteral antico
-
agulation, then 150 mg orally 
×
×
×
< 15 mL/min
Initial need for parenteral 
therapy
Edoxaban
-
agulation, then 60 mg orally 
once daily; 30 mg once daily 
recommended if CrCl is 
between 15 and 50 mL/min, 
if weight ≤ 60 kg, or if certain 
P-gp inhibitors are present
×
×
×
< 15 mL/min or 
 
> 95 mL/min
therapy
1
Obtain baseline hemoglobin, platelet count, aPTT, PT/INR, creatinine, prior to initiation of anticoagulation.
Anticoagulation is contraindicated in the setting of active bleeding
.
2
3
If body weight < 50 kg, reduce dose and monitor anti-Xa levels.
CrCl, creatinine clearance; DVT, deep venous thrombosis; PE, pulmonary embolism; P-gp, P-glycoprotein; VTE, venous thromboembolic 
disease (includes DVT and PE).
Note: An “×” denotes appropriate use of the anticoagulant.
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B. Selecting Appropriate Anticoagulant Therapy
Most patients with DVT alone may be treated as outpa
-
tients, provided that their risk of bleeding is low, and they 
have good follow-up. Table 14–17 outlines proposed selec
-
tion criteria for outpatient treatment of DVT.
Among patients with PE, risk stratification should be 
done at time of diagnosis to direct treatment and triage. 
Patients with persistent hemodynamic instability are clas
-
sified as high-risk patients (previously referred to as hav
-
ing “massive PE”) and have an early PE-related mortality 
of more than 15%. These patients should be admitted to an 
intensive care unit and generally receive thrombolysis 
(both full-dose and half-dose regimens have been shown 
to be effective) and anticoagulation with intravenous 
heparin. Intermediate-risk patients (previously, “submas
-
sive PE”) have a mortality rate of up to 15% and should be 
admitted to a higher level of inpatient care, with consider
-
ation of thrombolysis on a case-by-case basis. Catheter-
directed techniques, if available, may be an option for 
patients who are poor candidates for systemic thromboly
-
sis. Low-risk patients have a mortality rate less than 3% 
and are candidates for expedited discharge or outpatient 
therapy.
Because both intermediate- and low-risk patients are 
hemodynamically stable, additional assessment is neces
-
sary to differentiate the two. Echocardiography can be used 
to identify patients with right ventricular dysfunction, 
which connotes intermediate risk. An RV/LV ratio less 
than 1.0 on chest CT angiogram has been shown to have 
good negative predictive value for adverse outcome but 
suffers from inter-observer variability. Serum biomarkers 
such as B-type natriuretic peptide and troponin are most 
useful for their negative predictive value, and mainly in 
combination with other predictors. The PE severity index 
(PESI) and simplified PESI clinical risk scores, which do 
not require additional testing, accurately identify patients 
at low risk for 30-day PE-related mortality (Table 14–18) 
and thus potential candidates for expedited discharge or 
outpatient treatment. The PESI48 and sPESI48 scores iden
-
tify a subgroup of patients hospitalized with intermediate-
risk PE who are reclassified as low risk by 48 hours and 
may be appropriate for early discharge.
Selection of an initial anticoagulant should be deter
-
mined by patient characteristics (kidney function, imme
-
diate bleeding risk, weight) and the clinical scenario (eg, 
whether thrombolysis is being considered).
1. Parenteral anticoagulants—
Heparins
—
In patients in whom parenteral anticoagula
-
tion is being considered, LMWHs are more effective than 
unfractionated heparin in the immediate treatment of 
DVT and PE and are preferred as initial treatment because 
of predictable pharmacokinetics, which allow for subcuta
-
neous, once- or twice-daily dosing with no requirement for 
monitoring in most patients. Monitoring of the therapeutic 
effect of LMWH may be indicated in pregnancy, compro
-
mised kidney function, and extremes of weight. Accumula
-
tion of LMWH and increased rates of bleeding have been 
observed among patients with severe kidney disease (cre
-
atinine clearance less than 30 mL/min), leading to a recom
-
mendation to use intravenous unfractionated heparin 
preferentially in these patients. 
If concomitant thrombolysis 
is being considered, unfractionated heparin is indicated
. 
Patients with VTE and a perceived higher risk of bleeding 
(ie, post-surgery) may be better candidates for treatment 
with unfractionated heparin than LMWH given its shorter 
half-life and reversibility. Unfractionated heparin can be 
Table 14–17.
 
Patient selection for outpatient 
 
treatment of DVT.
Patients considered appropriate for outpatient treatment
No clinical signs or symptoms of PE and pain controlled
Motivated and capable of self-administration of injections

Confirmed prescription insurance that covers injectable medica
-
tion or patient can pay out-of-pocket for injectable agents
Capable and willing to comply with frequent follow-up
Initially, patients may need to be seen daily to weekly
Potential contraindications for outpatient treatment
DVT involving inferior vena cava, iliac, common femoral, or 
upper extremity vein (these patients might benefit from 
 
vascular intervention)
Comorbid conditions
Active peptic ulcer disease, GI bleeding in past 14 days, liver 
synthetic dysfunction
Brain metastases, current or recent CNS or spinal cord injury/
surgery in the last 10 days, CVA ≤ 4–6 weeks
Familial bleeding diathesis
Active bleeding from source other than GI
Creatinine clearance < 30 mL/min
Patient weighs < 55 kg (male) or < 45 kg (female)
Recent surgery, spinal or epidural anesthesia in the past 3 days
History of heparin-induced thrombocytopenia
Inability to inject medication at home, reliably follow medica
-
tion schedule, recognize changes in health status, under
-
stand or follow directions
Table 14–18.
 
Simplified Pulmonary Embolism Severity 
Index (PESI).
Points
Age > 80
1
Cancer
1
Chronic cardiopulmonary disease
1
Systolic blood pressure < 100 mm Hg
1
Oxygen saturation ≤ 90%
1
Severity Class
Points
30-Day Mortality
Low risk
0
1%
High risk
≥ 1
10%
Adapted, with permission, from Jiménez D et al; RIETE Investigators. 
Simplification of the pulmonary embolism severity index for prog
-
nostication in patients with acute symptomatic pulmonary embo
-
lism. Arch Intern Med. 2010 Aug 9;170(15):1383–9. Copyright © 
2010 American Medical Association. All rights reserved.
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effectively neutralized with the positively charged prot
-
amine sulfate while protamine may only have partial rever
-
sal effect at best on LMWH. Use of unfractionated heparin 
leads to HIT in approximately 3% of patients, so most 
individuals require serial platelet count determinations 
during the initial 10–14 days of exposure.
Weight-based, fixed-dose daily subcutaneous fondaparinux 
(a synthetic factor Xa inhibitor) may also be used for 
the initial treatment of DVT and PE, with no increase in 
 
bleeding over that observed with LMWH. Its lack of 
reversibility, long half-life, and renal clearance limit its use 
in patients with an increased risk of bleeding or kidney 
disease.
2. Oral anticoagulants—
a. W arfarin
—
If warfarin is chosen as the oral anticoagu
-
lant it will be initiated along with the parenteral anticoagu
-
lant, which is continued until INR is in therapeutic range. 
Most patients require 5 mg of warfarin daily for initial 
treatment, but lower doses (2.5 mg daily) should be consid
-
ered for patients of Asian descent, older adults, and those 
with hyperthyroidism, heart failure, liver disease, recent 
major surgery, malnutrition, certain polymorphisms for 
the 
CYP2C9
 or the 
VKORC1
 genes or who are receiving 
concurrent medications that increase sensitivity to warfa
-
rin. Conversely, individuals of African descent, those with 
larger body mass index or hypothyroidism, and those who 
are receiving medications that increase warfarin metabo
-
lism may require higher initial doses (7.5 mg daily). Daily 
INR results should guide dosing adjustments in the hospi
-
talized patient while at least biweekly INR results guide 
dosing in the outpatient (Table 14–19). Web-based warfa
-
rin dosing calculators that consider these clinical and 
genetic factors are available to help clinicians choose the 
appropriate starting dose (eg, see www.warfarindosing
 
.org). Because an average of 5 days is required to 
 
achieve a steady-state reduction in the activity of vitamin 
K–dependent coagulation factors, the parenteral anticoag
-
ulant should be continued for at least 5 days and until 
the INR is more than 2.0. Meticulous follow-up should be 
arranged for all patients taking warfarin because of the 
bleeding risk that is associated with initiation of therapy. 
Once stabilized, the INR should be checked at an interval 
no longer than every 6 weeks and warfarin dosing should 
be adjusted by guidelines (Table 14–20) since this strategy 
has been shown to improve the time patients spend in the 
therapeutic range and their clinical outcomes. Suprathera
-
peutic INRs should be managed according to evidence-
based guidelines (Table 14–21).
b. Direct-acting oral anticoagulants
—
DOACs 
have a predictable dose effect, few drug-drug interactions, 
rapid onset of action, and freedom from laboratory moni
-
toring (Table 14–11). Dabigatran, rivaroxaban, apixaban, 
and edoxaban are approved for treatment of acute DVT 
and PE. While rivaroxaban and apixaban can be used as 
monotherapy eliminating the need for parenteral therapy, 
patients who will be treated with dabigatran or edoxaban 
must first receive 5–10 days of parenteral anticoagulation 
and then be transitioned to the oral agent. Unlike warfarin, 
parenteral therapies do not require an overlap or “bridge,” 
since these agents are immediately active; the patient first 
receives a course of a parenteral agent, the agent is then 
stopped and the DOAC is started. Compared to warfarin 
and LMWH, the DOACs are all “noninferior” with respect 
to prevention of recurrent VTE; both rivaroxaban and 
apixaban have a lower bleeding risk than warfarin and 
LMWH. Agent selection for acute treatment of VTE 
should be individualized and consider kidney function, 
concomitant medications, ability to use LMWH bridge 
therapy, cost, and adherence.
LMWH is still endorsed as the preferred agent for treat
-
ment of cancer-related VTE according to American Col
-

-
-
lege of Chest Physicians and National Comprehensive 
Cancer Network guidelines. However, these guidelines 
were published prior to the Hokusai trial, which found 
edoxaban to be noninferior to LMWH for treatment of 
cancer-associated VTE. While edoxaban resulted in 
reduced risk of recurrent DVT when compared to daltepa
-
rin, there was an increased risk of major bleeding, mostly 
in patients with gastrointestinal malignancies. Additional 
studies with other DOACs are expected shortly. Clinicians 
must be aware that many chemotherapeutic agents may 
interact with DOACs and their use should be avoided in 
cases of potential interactions because there is no easily 
accessible and reliable way to measure the anticoagulant 
effect of DOACs. Due to lack of safety data, DOACs 
 
should be avoided in patients with severe thrombophilia 
(ie, antiphospholipid antibody syndrome), splanchnic vein 
thrombosis as well as in patients in whom anticoagulation 
fails and thrombosis develops during treatment with 
LMWH or warfarin.
c. Aspirin
—
Low-dose aspirin therapy (81 orally daily) 
should be considered in patients with unprovoked VTE 
who are not candidates for ongoing anticoagulation. Aspi
-
rin, however, is inferior to anticoagulation for risk reduc
-
tion and is not an equivalent alternative.
3. Duration of anticoagulation therapy—
The clinical 
scenario in which the thrombosis occurred is the stron
-
gest predictor of recurrence and, in most cases, guides 
duration of anticoagulation (Table 14–22). In the first 
year after discontinuation of anticoagulation therapy, the 
frequency of recurrent VTE among individuals whose 
thrombosis occurred in the setting of a transient, major, 
reversible risk factor (such as surgery) is approximately 
3% after completing 3 months of anticoagulation, com
-
pared with at least 8% for individuals whose thrombosis 
was unprovoked, and greater than 20% in patients with 
cancer. Patients with provoked VTE are generally treated 
with a minimum of 3 months of anticoagulation, whereas 
unprovoked VTE should prompt consideration of indefi
-
nite anticoagulation provided the patient is not at high 
risk for bleeding. Merely extending duration of anticoag
-
ulation beyond 3 months will not reduce risk of recur
-
rence once anticoagulation is stopped; if anticoagulants 
are stopped after 3, 6, 12, or 18 months in a patient with 
unprovoked VTE the risk of recurrence after cessation 
 
of therapy is similar. Individual risk stratification may 
help identify patients most likely to suffer recurrent 
 
disease and thus most likely to benefit from ongoing 
CMDT19_Ch14_p0556-p0588.indd   582

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CMDT 2019
anticoagulation therapy. Normal D-dimer levels 1 month 
after cessation of anticoagulation are associated with 
lower recurrence risk, although some would argue not 
low enough to consider stopping anticoagulant therapy, 
particularly in men. One risk scoring system uses body 
mass index, age, D-dimer, and post-phlebitic symptoms 
to identify women at lower risk for recurrence after 
unprovoked VTE. The Vienna Prediction Model, a simple 
scoring system based on age, sex, D-dimer, and location 
of thrombosis, can help estimate an individual’s recur
-
rence risk to guide duration of therapy decisions. The 
following facts are important to consider when 
determining duration of therapy: (1) men have a greater 
than twofold higher risk of recurrent VTE compared to 
women, (2) recurrent PE is more likely to develop in 
patients with clinically apparent PE than in those with 
DVT alone and has a case fatality rate of nearly 10%, and 
(3) proximal DVT has a higher recurrence risk than distal 
DVT. Laboratory workup for thrombophilia is not recom
-
mended routinely for determining duration of therapy 
because clinical presentation is a much stronger predictor 
of recurrence risk. The workup may be pursued in 
patients younger than 50 years, with a strong family his
-
tory, with a clot in unusual locations, or with recurrent 
Table 14–19.
 
Warfarin adjustment guidelines.
Measurement Day
INR
Action
For Hospitalized Patients Newly Starting Therapy
Day 1
5 mg (2.5 or 7.5 mg in select populations
1
)
Day 2
< 1.5
Continue dose
≥ 1.5
Decrease or hold dose
2
Day 3
≤ 1.2
Increase dose
2
> 1.2 and < 1.7
≥ 1.7
Decrease dose
2
Day 4 until therapeutic
Daily increase < 0.2 units
2
Daily increase 0.2–0.3 units
Daily increase 0.4–0.6 units
2
Daily increase ≥ 0.7 units
Hold dose
For Outpatients Newly Starting Therapy
Measure PT/INR on Day 1
Baseline
Start treatment with 2–7.5 mg
Measure PT/INR on Day 3–4
< 1.5
Increase weekly dose by 5–25%
1.5–1.9
No dosage change
2.0–2.5
Decrease weekly dose by 25–50%
> 2.5
Decrease weekly dose by 50% or HOLD dose
Measure PT/INR on Day 5–7
< 1.5
Increase weekly dose by 10–25%
1.5–1.9
Increase weekly dose by 0–20%
2.0–3.0
> 3.0
Decrease weekly dose by 10–25% or HOLD dose
Measure PT/INR on Day 8–10
< 1.5
Increase weekly dose by 15–35%
1.5–1.9
Increase weekly dose by 5–20%
2.0–3.0
> 3.0
Measure PT/INR on Day 11–14
< 1.6
1.6–1.9
2.0–3.0
> 3.0
Decrease weekly dose by 5–20% or HOLD dose
1
See text.
2
In general, dosage adjustments should not exceed 2.5 mg or 50%.
Data from Kim YK et al. 
J Thromb Haemost
 2010;8:101–6. From Center for Health Quality, Outcomes, and Economic Research, VA Medical 
Center, Bedford, MA.
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thromboses (Table 14–23). In addition, a workup for 
thrombophilia may be considered in women of childbear
-
ing age in whom results may influence fertility and preg
-
nancy outcomes and management or in those patients in 
whom results will influence duration of therapy. An 
important hypercoagulable state to identify is antiphos
-
pholipid syndrome [APS] because these patients have a 
marked increase in recurrence rates, are at risk for both 
arterial and venous disease, and in general receive bridge 
therapy during any interruption of anticoagulation. Due 
to effects of anticoagulants and acute thrombosis on 
many of the tests, the thrombophilia workup should be 
delayed in most cases until at least 3 months after 
the acute event, if it is indicated at all (Table 14–24). The 
benefit of anticoagulation must be weighed against 
the bleeding risks posed, and the benefit-risk ratio should 
be assessed at the initiation of therapy, at 3 months, and 
then at least annually in any patient receiving prolonged 
anticoagulant therapy. While bleeding risk scores have 
been developed to estimate risk of these complications, 
their performance may not offer any advantage over a 
clinician’s subjective assessment, particularly in older 
individuals. Assessment of bleeding risk is of particular 
importance when identifying candidates for extended 
duration therapy for treatment of unprovoked VTE; it is 
recommended that patients with a high risk of bleeding 
receive a defined course of anticoagulation, rather than 
indefinite therapy, even if the VTE was unprovoked.
Secondary prevention
 (antithrombotic therapy offered 
after the initial 3–6 months of treatment) should be consid
-
ered in patients with VTE that is not majorly provoked and 
is most compelling for those with unprovoked VTE. 
 
Aspirin will provide about a 30% reduction in risk of recur
-
rent VTE compared to placebo, while low-dose DOAC 
therapy (at prophylactic doses) will provide risk reduction 
similar to that achieved with ongoing full-intensity 
anticoagulation.
Agnelli G et al; AMPLIFY-EXT Investigators. Apixaban for 
extended treatment of venous thromboembolism. N Engl J 
Med. 2013 Feb 21;368(8):699–708. [PMID: 23216615]
Brighton TA et al; ASPIRE Investigators. Low-dose aspirin for 
preventing recurrent venous thromboembolism. N Engl J 
Med. 2012 Nov 22;367(21):1979–87. [PMID: 23121403]
direct oral anticoagulants (DOACs) in VTE treatment. J Thromb 
Thrombolysis. 2016 Jan;41(1):206–32. [PMID: 26780747]
-
Kearon C et al. Antithrombotic therapy for VTE disease: Anti
-
Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S–94S. 
 
[PMID: 22315268]
guideline and expert panel report. Chest. 2016 Feb;149(2):315–52. 
 
[PMID: 26867832]
an update. J Am Coll Cardiol. 2016 Mar 1;67(8):976–90. 
[PMID: 26916489]
Konstantinides SV et al; Task Force for the Diagnosis and Man
-
agement of Acute Pulmonary Embolism of the European 
Society of Cardiology (ESC). 2014 ESC guidelines on the 
diagnosis and management of acute pulmonary embolism. 
Eur Heart J. 2014 Nov 14;35(43):3033–69, 3069a–3069k. 
Erratum in: Eur Heart J. 2015 Oct 14;36(39):2666. Eur Heart 
J. 2015 Oct 14;36(39):2642. [PMID: 25173341]
Raskob GE et al; Hokusai VTE Cancer Investigators. Edoxaban for 
the treatment of cancer-associated venous thromboembolism. 
N Engl J Med. 2018 Feb 15;378(7):615–24. [PMID: 29231094]

Smythe MA et al. Guidance for the practical management of the 
heparin anticoagulants in the treatment of venous thrombo
-
embolism. J Thromb Thrombolysis. 2016 Jan;41(1):165–86. 
[PMID: 26780745]
Table 14–20.
 
Warfarin-dosing adjustment guidelines 
for patients receiving long-term therapy, with target 
INR 2–3.
Patient 
 
INR
Weekly Dosing Change
Dose change
Follow-up INR
≤ 1.5
Increase by 10–15%
Within 1 week
1.51–1.79
If falling or low on two or 
more occasions, increase 
weekly dose by 5–10%.
7–14 days
1.80–2.29
Consider not changing the 
dose unless a consistent 
pattern has been 
observed.
7–14 days
2.3–3.0 
 
(in range)
No change in dosage.
28 days (42 days if 
INR in range 
consecutively)
3.01–3.20
observed.
7–14 days
3.21–3.69
Do not hold warfarin. If ris
-
ing or high on two or 
more occasions, decrease 
7–14 days
3.70–4.99
Hold warfarin for 1 day and 
decrease weekly dose by 
5–10%.
Within 1 week, 
sooner if clini
-
cally indicated
5.0–8.99
Hold warfarin. Clinical evalu
-
ation for bleeding. When 
INR is therapeutic, restart 
at lower dose (decrease 
weekly dose by 10–15%). 
Check INR at least weekly 
until stable.
-
cally indicated, 
then weekly 
until stabilized
≥ 9
See Table 14–21
From Center for Health Quality, Outcomes, and Economic Research, 
VA Medical Center, Bedford, MA. Data from Kim YK et al. 
J Thromb 
Haemost
 2010;8:101–6. See also Van Spall HE et al. Variation in 
warfarin dose adjustment practice is responsible for differences in 
the quality of anticoagulation control between centers and coun
-
tries: an analysis of patients receiving warfarin in the randomized 
evaluation of long-term anticoagulation therapy (RE-LY) trial. 
Circulation. 2012 Nov 6:126(19):2309–16. [PMID: 23027801]
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Table 14–21.
 
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Management 
of Supratherapeutic INR.
Clinical Situation
INR
No significant bleed
Above therapeutic 
range but < 5.0
•	
Lower dose or omit dose
•	
Monitor more frequently and resume at lower dose when INR falls within therapeutic 
range (if INR only slightly above range, may not be necessary to decrease dose)
≥ 5.0 but < 9.0
•	
Hold next 1–2 doses
•	
Monitor more frequently and resume therapy at lower dose when INR falls within 
 
therapeutic range
•	
Patients at high risk for bleeding
1
: Hold warfarin and consider giving vitamin K
1
 1–2.5 mg 
orally; check INR in 24–48 h to ensure response to therapy
≥ 9.0
•	
Hold warfarin
•	
Vitamin K
1
 2.5–5 mg orally
•	
Monitor frequently and resume therapy at lower dose when INR within therapeutic range
Serious/life-threatening 
bleed
•	
Hold warfarin and give 10 mg vitamin K by slow intravenous infusion supplemented by 
FFP , PCC, or recombinant factor VIIa (PCC preferred)
1
Patients at higher risk for bleeding include elderly people, conditions that increase the risk of bleeding include kidney disease, hyperten
-
sion, falls, liver disease, and history of gastrointestinal or genitourinary bleeding.
FFP , fresh frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate.
Table 14–22.
 
Duration of treatment of VTE.
Scenario
Suggested Duration of Therapy
Comments
Major transient risk factor (eg, major surgery, 
major trauma, major hospitalization)
3 months
VTE prophylaxis upon future exposure to transient risk 
factors
Cancer-related
≥ 3–6 months or as long as cancer 
active, whichever is longer
LMWH recommended for initial treatment (see 
Table 14–16)
Unprovoked
At least 3 months; consider indefi
-
nite if bleeding risk allows
May individually risk-stratify for recurrence with 
D-dimer, clinical risk scores and clinical presentation
Recurrent unprovoked
Indefinite
Underlying significant thrombophilia (eg, 
antiphospholipid antibody syndrome, anti
-
thrombin deficiency, protein C deficiency, 
protein S deficiency, ≥ two concomitant 
thrombophilic conditions)
To avoid false positives, consider delaying investigation 
for laboratory thrombophilia until 3 months after 
event
LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease.
-
-
rin therapy in the treatment of venous thromboembolism. 
J  Thromb Thrombolysis. 2016 Jan;41(1):187–205. [PMID: 
26780746]
C. Thrombolytic Therapy
Anticoagulation alone is appropriate treatment for most 
patients with PE; however, those with high-risk, massive 
PE, defined as PE with persistent hemodynamic instabil
-
ity, have an in-hospital mortality rate that approaches 30% 
and absent contraindications require immediate throm
-
bolysis in combination with anticoagulation (Table 14–25). 
Systemic thrombolytic therapy has been used in selected 
patients with intermediate-risk, submassive PE, defined as 
PE without hemodynamic instability but with evidence of 
right ventricular compromise and myocardial injury. 
Thrombolysis in this cohort decreases risk of hemody
-
namic compromise but increases the risk of major hemor
-
rhage and stroke. A “safe dose” of tPA (50% or less of the 
standard dose [100 mg] commonly used for the treatment 
of PE) has been evaluated in small trials of both high- and 
intermediate-risk PE showing similar efficacy and a better 
safety profile. The use of thrombolysis in hemodynami
-
cally stable intermediate risk PE patients should be con
-
sidered on a case-by-case basis. The use of catheter-directed 
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-

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Howard LS. Thrombolytic therapy for submassive pulmonary 
embolus? PRO viewpoint. Thorax. 2014 Feb;69(2):103–5. 
[PMID: 23624534]
Meyer G et al; PEITHO Investigators. Fibrinolysis for patients 
with intermediate-risk pulmonary embolism. N Engl J Med. 
2014 Apr 10;370(15):1402–11. [PMID: 24716681]
Sharifi M et al. Moderate pulmonary embolism treated with 
thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 
2013 Jan 15;111(2):273–7. [PMID: 23102885]
-
D. Nonpharmacologic Therapy
1. Graduated compression stockings—
Although use of 
graduated compression stockings with 30–40 mm Hg pres
-
sure at the ankle in patients with DVT on the affected lower 
extremity had been advocated for 1–2 years after diagnosis, 
a randomized placebo-controlled trial failed to show a 
reduction in the postthrombotic syndrome at 6 months. 
Stockings may provide symptomatic relief to selected 
patients with ongoing swelling; however, they are contrain
-
dicated in patients with peripheral vascular disease.
2. Inferior vena caval (IVC) filters—
There is a paucity of 
data to support the use of IVC filters for the prevention of 
PE in any clinical scenario. There are two randomized, 
controlled trials of IVC filters for prevention of PE. In the 
therapy for acute PE may be considered for high-risk or 
intermediate-risk PE when systemic thrombolysis has 
failed or as an alternative to systemic thrombolytic 
therapy.
In patients with large proximal iliofemoral DVT, data 
from randomized controlled trials are conflicting on the 
benefit of catheter-directed thrombolysis in addition to 
treatment with anticoagulation; the CaVenT trial showed 
some reduction in risk of postthrombotic syndrome, but 
the more recent larger ATTRACT trial failed to show 
reduction in postthrombotic syndrome but did find an 
increased risk of major bleeding.
Enden T et al; CaVenT Study Group. Long-term outcome after 
additional catheter-directed thrombolysis versus standard 
treatment for acute iliofemoral deep vein thrombosis (the 
CaVenT study): a randomised controlled trial. Lancet. 2012 Jan 7;
 
379(9810):31–8. [PMID: 22172244]
Table 14–23.
 
Candidates for thrombophilia workup if 
results will influence management.
Patients younger than 50 years
Strong family history of VTE
Clot in unusual locations
Recurrent thromboses
Women of childbearing age
Suspicion for APS
APS, antiphospholipid syndrome; VTE, venous thromboembolism.
Table 14–24.
 
Laboratory evaluation of thrombophilia.
Hypercoagulable State
When to Suspect
Laboratory Workup
Influence of Anticoagulation and Acute 
Antiphospholipid anti
-
body syndrome
Unexplained DVT/PE
CVA/TIA age < 50
Recurrent thrombosis (despite 
anticoagulation)
Thrombosis at an unusual site
Arterial and venous thrombosis
Livedo reticularis, Raynaud phe
-
nomenon, thrombocytopenia, 
recurrent early pregnancy loss
Anti-cardiolipin IgG and/or 
IgM medium or high titer 
(ie, > 40 GPL or MPL, 
 
or > the 99th percentile)
1
Anti-beta-2 glycoprotein I 
IgG and/or IgM medium 
or high titer (> the 99th 
percentile)
1
Lupus anticoagulant
1
Lupus anticoagulant can be falsely positive 
or falsely negative on anticoagulation
Protein C, S, antithrombin 
deficiencies
Thrombosis < 50 years of age 
with family history of VTE
Screen with protein C activ
-
ity, free protein S, protein 
S activity, antithrombin 
activity
Acute thrombosis can result in decreased 
protein C, S and antithrombin activity. 
Warfarin can decrease protein C and S 
activity, heparin can cause decrease 
antithrombin activity. DOACs can 
increase protein C, S, and antithrombin 
activity
Factor V Leiden, pro
-
thrombin gene 
mutation

activity
-
mutation
Thrombosis on OCPs, cerebral 
vein thrombosis, DVT/PE in 
white population
PCR for factor V Leiden or 
prothrombin gene 
mutation
No influence
Hyperhomocysteinemia
Fasting homocysteine
1
Detected on two occasions not less than 12 weeks apart.
CVA/TIA, cerebrovascular accident/transient ischemic attack; DOACs, direct-acting oral anticoagulants; DVT/PE, deep venous thrombosis/
pulmonary embolism; OCPs, oral contraceptives; PCR, polymerase chain reaction; VTE, venous thromboembolism.
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first study, patients with documented DVT received full 
intensity, time-limited anticoagulation with or without 
placement of a permanent IVC filter. Patients with IVC 
filters had a lower rate of nonfatal asymptomatic PE at 
 
12 days but an increased rate of DVT at 2 years. In the 
second study, patients with symptomatic PE and residual 
DVT plus at least one additional risk factor for severity 
received anticoagulation with or without a retrievable IVC 
filter. IVC filter use did not reduce the risk of symptomatic 
recurrent PE at 3 months. Most experts agree with place
-
ment of an IVC filter in patients with acute proximal 
 
DVT and an absolute contraindication to anticoagulation 
despite lack of evidence to support this practice. While IVC 
filters were once commonly used to prevent VTE recur
-
rence in the setting of anticoagulation failure, many experts 
now recommend switching to an alternative agent or 
increasing the intensity of the current anticoagulant regi
-
men instead. The remainder of the indications (submassive/
 
intermediate-risk PE, free-floating iliofemoral DVT, peri
-
operative risk reduction) are controversial. If the contrain
-
dication to anticoagulation is temporary (active bleeding 
with subsequent resolution), placement of a retrievable 
IVC filter may be considered so that the device can be 
removed once anticoagulation has been started and has 
been shown to be tolerated. Rates of IVC filter retrieval are 
very low, often due to a failure to arrange for its removal. 
Thus, if a device is placed, removal should be arranged at 
the time of device placement.
Complications of IVC filters include local thrombosis, 
tilting, migration, fracture, and inability to retrieve the 
device. When considering placement of an IVC filter, it is 
best to consider both short- and long-term complications, 
since devices intended for removal may become perma
-
nent. To improve patient safety, institutions should develop 
systems that guide appropriate patient selection for IVC 
filter placement, tracking, and removal.
Kahn SR et al. Graduated compression stockings to treat acute 
leg pain associated with proximal DVT. A randomised con
-
trolled trial. Thromb Haemost. 2014 Dec 1;112(6):1137–41. 
[PMID: 25183442]
Milovanovic L et al. Procedural and indwelling complications 
with inferior vena cava filters: frequency, etiology, and man
-
agement. Semin Intervent Radiol. 2015 Mar;32(1):34–41. 
[PMID: 25762846]
Mismetti P et al; PREPIC2 Study Group. Effect of a retrievable 
inferior vena cava filter plus anticoagulation vs anticoagula
-
tion alone on risk of recurrent pulmonary embolism: a ran
-
domized clinical trial. JAMA. 2015 Apr 28;313(16):1627–35. 
[PMID: 25919526]
PREPIC Study Group. Eight-year follow-up of patients with 
permanent vena cava filters in the prevention of pulmonary 
embolism: the PREPIC (Prévention du Risque d’Embolie 
Pulmonaire par Interruption Cave) randomized study. Circu
-
lation. 2005 Jul 19;112(3):416–22. [PMID: 16009794]
Sarosiek S et al. Indications, complications, and management of 
inferior vena cava filters: the experience in 952 patients at an 
academic hospital with a level I trauma center. JAMA Intern 
Med. 2013 Apr 8;173(7):513–7. [PMID: 23552968]
 
»
•	
Presence of large iliofemoral VTE, IVC thrombosis, 
portal vein thrombosis, or Budd-Chiari syndrome for 
consideration of catheter-directed thrombolysis.
•	
High-risk PE for urgent embolectomy or catheter-
directed therapies.
•	
Intermediate-risk PE if considering thrombolysis.
•	
History of HIT or prolonged PTT plus renal failure for 
alternative anticoagulation regimens.
Table 14–25.
 
Thrombolytic therapies for pulmonary embolism.
Thrombolytic Agent
Dose
Frequency
Comment
High Risk (Massive Pulmonary Embolism)
Alteplase
100 mg
over 2 hours
Follow with continuous intravenous 
 
infusion of unfractionated heparin

Dose
Frequency
Comment
Alteplase
100 mg
 
infusion of unfractionated heparin 
(see Table 14–16 for dosage)
100 mg
Intravenous bolus × 1
Appropriate for acute management of 
cardiac arrest and suspected pulmo
-
nary embolism
Urokinase
4400 international units/kg
Intravenous bolus × 1 followed 
 
by 4400 international units/kg 
continuous intravenous infu
-
sion for 12 hours
Unfractionated heparin should be 
 
administered concurrently (see 
Table 14–16 for dosage)
Intermediate Risk (Submassive Pulmonary Embolism)
r t-PA
50 mg/2 hours
Continuous infusion over 2 hours
30–50 mg
Alteplase
100 mg
(10-mg intravenous bolus, fol
-
lowed by a 90-mg intravenous 
infusion 2 hours)
rtPA, recombinant tissue plasminogen activator.
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•	
Consideration of IVC filter placement.
•	
Clots in unusual locations (eg, renal, hepatic or cerebral 
vein), or simultaneous arterial and venous thrombosis, 
to assess possibility of a hypercoagulable state.
•	
Recurrent VTE while receiving therapeutic 
 
»
•	
Documented or suspected intermediate- or high-risk 
PE and low-risk PE at high risk for bleeding or poor 
candidate for outpatient treatment.
•	
DVT with poorly controlled pain, high bleeding risk, 
concerns about follow-up.
•	
Large iliofemoral DVT for consideration of 
thrombolysis.
•	
Acute DVT and absolute contraindication to anticoagu
-
lation for IVC filter placement.
•	
Venous thrombosis despite therapeutic anticoagulation.
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º
SYMPTOMS & SIGNS OF 
 
GASTROINTESTINAL DISEASE
DYSPEPSIA
 
»
Predominant epigastric pain.
 
»
May be associated epigastric fullness, nausea, 
heartburn, or vomiting.
 
»
Endoscopy is warranted in all patients age 60 years 
or older and selected younger patients with alarm 
features.
 
»
In all other patients, testing for 
 
is recommended; if positive, antibacterial treat
-
ment is given.
 
»
Patients who are 
H pylori
-negative or do not 
improve after 
H pylori
 eradication should be pre
-
scribed a trial of empiric proton pump inhibitor 
therapy.
 
»
Patients with refractory symptoms should be 
offered a trial of tricyclic antidepressant, a proki
-
netic agent, or psychological therapy.
 
»
Dyspepsia refers to acute, chronic, or recurrent pain or 
discomfort centered in the upper abdomen. A 2017 American 
College of Gastroenterology guideline has further defined 
clinically relevant dyspepsia as predominant epigastric 
pain for at least 1 month. The epigastric pain may be 
associated with other symptoms of heartburn, nausea, 
fullness, or vomiting. Heartburn (retrosternal burning) 
should be distinguished from dyspepsia. When heartburn 
is the dominant complaint, gastroesophageal reflux is 
nearly always present. Dyspepsia occurs in 7% of the adult 
population and accounts for 3% of general medical office 
visits.15
Kenneth R. McQuaid, MD 
Gastrointestinal Disorders
 
»
Etiology
A. Food or Drug Intolerance
Acute, self-limited “indigestion” may be caused by overeat
-
ing, eating too quickly, eating high-fat foods, eating during 
stressful situations, or drinking too much alcohol or coffee. 
Many medications cause dyspepsia, including aspirin, non
-
steroidal anti-inflammatory drugs (NSAIDs), antibiotics 
(metronidazole, macrolides), dabigatran, diabetes drugs 
(metformin, alpha-glucosidase inhibitors, amylin analogs, 
GLP-1 receptor antagonists), antihypertensive medications 
(angiotensin-converting enzyme [ACE] inhibitors, angiotensin-
receptor blockers), cholesterol-lowering agents (niacin, 
fibrates), neuropsychiatric medications (cholinesterase 
inhibitors [donepezil, rivastigmine]), SSRIs (fluoxetine, 
sertraline), serotonin-norepinephrine-reuptake inhibitors 
(venlafaxine, duloxetine), Parkinson drugs (dopamine ago
-
nists, monoamine oxidase [MAO]-B inhibitors), corticoste
-
roids, estrogens, digoxin, iron, and opioids.
B. Functional Dyspepsia
Functional dyspepsia refers to dyspepsia for which no 
organic etiology has been determined by endoscopy or 
other testing. This is the most common cause of 
chronic
 
dyspepsia, accounting for the majority of patients. Symp
-
toms may arise from a complex interaction of increased 
visceral afferent sensitivity, gastric delayed emptying or 
impaired accommodation to food, or psychosocial stress
-
ors. Although benign, these symptoms may be chronic and 
difficult to treat.
C. Luminal Gastrointestinal Tract Dysfunction
Peptic ulcer disease is present in 5–15% of patients with 
dyspepsia. Gastroesophageal reflux disease (GERD) is 
present in up to 20% of patients with dyspepsia, even 
without significant heartburn. Gastric or esophageal can
-
cer is identified in less than 1% but is extremely rare in 
persons under age 60 years with uncomplicated dys
-
pepsia. Other causes include gastroparesis (especially in 
diabetes mellitus) and parasitic infection (
Giardia, Strongy
-
loides, Anisakis
).
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D. 
 Infection
Chronic gastric infection with 
H pylori
 is an important cause 
of peptic ulcer disease, and may cause dyspepsia in a small 
number of patients in the absence of peptic ulcer disease.
E. Pancreatic Disease
Pancreatic carcinoma and chronic pancreatitis may cause 
chronic epigastric pain that is more severe, sometimes 
radiates to the back, and usually is associated with anorexia, 
rapid weight loss, steatorrhea, or jaundice.
F. Biliary Tract Disease
The abrupt onset of epigastric or right upper quadrant pain 
due to cholelithiasis or choledocholithiasis should be read
-
ily distinguished from dyspepsia.
G. Other Conditions
Diabetes mellitus, thyroid disease, chronic kidney disease, 
myocardial ischemia, intra-abdominal malignancy, gastric 
volvulus or paraesophageal hernia, chronic gastric or intes
-
tinal ischemia, and pregnancy are sometimes accompanied 
by acute or chronic epigastric pain or discomfort.
 
»
Given the nonspecific nature of dyspeptic symptoms, the 
history has limited diagnostic utility. It should clarify the 
chronicity, location, and quality of the epigastric pain, and 
its relationship to meals. The pain may be accompanied by 
one or more upper abdominal symptoms including post
-
prandial fullness, heartburn, nausea, or vomiting. Con
-
comitant weight loss, persistent vomiting, constant or 
severe pain, progressive dysphagia, hematemesis, or melena 
warrants endoscopy or abdominal CT imaging. Potentially 
offending medications and excessive alcohol use should be 
identified and discontinued if possible. The patient’s reason 
for seeking care should be determined. Recent changes in 
employment, marital discord, physical and sexual abuse, 
anxiety, depression, and fear of serious disease may all 
contribute to the development and reporting of symptoms. 
Patients with functional dyspepsia often are younger, 
report a variety of abdominal and extragastrointestinal 
complaints, show signs of anxiety or depression, or have a 
history of use of psychotropic medications.
The symptom profile alone does not differentiate 
between functional dyspepsia and organic gastrointestinal 
disorders. Based on the clinical history alone, primary care 
clinicians misdiagnose nearly half of patients with peptic 
ulcers or gastroesophageal reflux.
The physical examination is rarely helpful. Signs of seri
-
ous organic disease such as weight loss, organomegaly, 
abdominal mass, or fecal occult blood are to be further 
evaluated.
In patients younger than age 60 with uncomplicated dys
-
pepsia (in whom gastric cancer is rare), initial noninvasive 
strategies should be pursued. In patients older than age 
60 years, initial laboratory work should include a blood 
count, electrolytes, liver enzymes, calcium, and thyroid 
function tests. The cost-effectiveness of routine laboratory 
studies is uncertain. In most patients younger than age 
60, a noninvasive test for 
H pylori
 (urea breath test, fecal 
antigen test) should be performed first. Although serologic 
tests are inexpensive, performance characteristics are poor 
in low-prevalence populations, whereas breath and fecal 
antigen tests have 95% accuracy. If 
H pylori
 breath test or 
fecal antigen test results are negative in a patient not taking 
NSAIDs, peptic ulcer disease is virtually excluded.
C. Upper Endoscopy
Upper endoscopy is the study of choice to diagnose gastro
-
duodenal ulcers, erosive esophagitis, and upper gastroin
-
testinal malignancy. However, gastroduodenal ulcers and 
erosive esophagitis can be treated empirically with 
H pylori
 
eradication or empiric proton pump inhibitor therapy or 
both. Therefore, upper endoscopy is mainly indicated to 
look for upper gastric or esophageal malignancy in patients 
over age 60 years with new-onset dyspepsia (in whom there 
is increased malignancy risk) and in selected younger

is increased malignancy risk) and in selected younger 
patients with “alarm” features. In patients under age 60, the 
risk of malignancy is less than 1%—even among patients 
with reported “alarm” features. Recent guidelines therefore 
recommend against routine endoscopy for younger 
patients—even those with “alarm” features. However, 
endoscopy should be performed in patients with promi
-
nent “alarm” features, such as progressive weight loss, rap
-
idly progressive dysphagia, severe vomiting, evidence of 
bleeding or anemia, or jaundice. It is also helpful for 
selected patients who are excessively concerned about seri
-
ous underlying disease. For patients born in regions in 
which there is a higher incidence of gastric cancer, such as 
Central or South America, China and Southeast Asia, or 
Africa, an age threshold of 45 years may be more 
Endoscopic evaluation may also be warranted when 
symptoms fail to respond to initial empiric management 
strategies or when frequent symptom relapse occurs after 
discontinuation of empiric therapy.
D. Other Tests
In patients with refractory symptoms or progressive weight 
loss, antibodies for celiac disease or stool testing for ova 
and parasites or 
Giardia
 antigen, fat, or elastase may be 
considered. Abdominal imaging (ultrasonography or CT 
scanning) is performed only when pancreatic, biliary tract, 
vascular disease, or volvulus is suspected. Gastric emptying 
studies may be useful in patients with recurrent nausea and 
vomiting who have not responded to empiric therapies.
 
»
Treatment
Initial empiric treatment is warranted for patients who are 
younger than age 60 years and who lack severe or worri
-
some “alarm” features. All other patients as well as patients 
whose symptoms do not to respond to or relapse after 
empiric treatment should undergo upper endoscopy with 
CMDT19_Ch15_p0589-p0687.indd   590

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591
 
CMDT 2019
subsequent treatment directed at the specific disorder 
identified (eg, peptic ulcer, gastroesophageal reflux, can
-
cer). When endoscopy is performed, gastric biopsies 
should be obtained to test for 
H pylori
 infection. If infec
-
tion is present, antibacterial treatment should be given.
A. Empiric Therapy
H pylori
–negative patients most likely have functional dys
-
pepsia or atypical GERD and can be treated with an antise
-
cretory agent (proton pump inhibitor) for 4 weeks. For 
patients who have symptom relapse after discontinuation 
of the proton pump inhibitor, intermittent or long-term 
proton pump inhibitor therapy may be considered. For 
patients in whom test results are positive for 
H pylori
, anti
-
biotic therapy proves definitive for patients with underly
-
ing peptic ulcers and may improve symptoms in a small 
subset (less than 10%) of infected patients with functional 
dyspepsia. Patients with persistent dyspepsia after 
H pylori
 
eradication can be given a trial of proton pump inhibitor 
therapy.
B. Treatment of Functional Dyspepsia
Patients who have no significant findings on endoscopy 
as well as patients under age 60 who do not respond to 
H pylori
 eradication or empiric proton pump inhibitor 
therapy are presumed to have functional dyspepsia.
1. General measures—
Most patients have mild, intermit
-
tent symptoms that respond to reassurance and lifestyle 
changes. Alcohol and caffeine should be reduced or dis
-
continued. Patients with postprandial symptoms should be 
instructed to consume small, low-fat meals. A food diary, 
in which patients record their food intake, symptoms, and 
daily events, may reveal dietary or psychosocial precipi
-
tants of pain.
2. Anti–
H pylori
 treatment—
Meta-analyses have sug
-
gested that a small number of patients with functional 
dyspepsia (less than 10%) derive benefit from 
H pylori
 
eradication therapy. Therefore, patients with functional 
dyspepsia should be tested and treated for 
H pylori
.
3. Other pharmacologic agents—
Drugs have demon
-
strated limited efficacy in the treatment of functional dys
-
pepsia. One-third of patients derive relief from placebo. 
Antisecretory therapy for 4–8 weeks with proton pump 
inhibitors (omeprazole, esomeprazole, or rabeprazole 20 mg, 
dexlansoprazole or lansoprazole 30 mg, or pantoprazole 
 
40 mg orally daily) may benefit up to 10% of patients. Low 
doses of antidepressants (eg, desipramine or nortriptyline, 
25–50 mg orally at bedtime) benefit some patients, possibly 
by moderating visceral afferent sensitivity. A 2015 multi
-
center controlled trial reported adequate symptom 
improvement in 53% of patients treated with amitriptyline 
(50 mg/day) at 10 weeks compared with placebo (40%) and 
escitalopram (38%), particularly those with upper abdomi
-
nal pain (ulcer-like dyspepsia). Doses should be increased 
slowly to minimize side effects. Metoclopramide (5–10 mg 
three times daily) may improve symptoms, but improve
-
ment does not correlate with the presence or absence of 
gastric emptying delay. In 2009, the FDA issued a black box 
warning that metoclopramide use for more than 3 months 
is associated with a high incidence of tardive dyskinesia 
and should be avoided. Older adults, particularly elderly 
women, are most at risk.
4. Alternative therapies—
Psychotherapy and hypnother
-
apy may be of benefit in selected motivated patients with 
functional dyspepsia. Herbal therapies (peppermint, cara
-
way) may offer benefit with little risk of adverse effects.
Moayyedi PM et al. ACG and CAG Clinical Guideline: manage
-
ment of dyspepsia. Am J Gastroenterol. 2017 Jul;112(7):
 
988–1013. [PMID: 28631728]
Shaukat A et al; ASGE Standards of Practice Committee. The role 
of endoscopy in dyspepsia. Gastrointest Endosc. 2015 Aug;
 
82(2):227–32. [PMID: 26032200]
Talley NJ et al. Effect of amitriptyline and escitalopram on func
-

-
tional dyspepsia: a multicenter, randomized controlled study. 
Gastroenterology. 2015 Aug;149(2):340–9. [PMID: 25921377]
Vakil NB et al. White Paper AGA: functional dyspepsia. Clin 
Gastroenterol Hepatol. 2017 Aug;15(8):1191–4. [PMID: 
28529164]
Nausea is a vague, intensely disagreeable sensation of sick
-
ness or “queasiness” and is distinguished from anorexia. 
Vomiting often follows, as does retching (spasmodic respi
-
ratory and abdominal movements). Vomiting should be 
distinguished from regurgitation, the effortless reflux of 
liquid or food stomach contents; and from rumination, the 
chewing and swallowing of food that is regurgitated voli
-
tionally after meals.
The brainstem vomiting center is composed of a group 
of neuronal areas (area postrema, nucleus tractus solitar
-
ius, and central pattern generator) within the medulla that 
coordinate emesis. It may be stimulated by four different 
sources of afferent input: (1) Afferent vagal fibers from the 
gastrointestinal viscera are rich in serotonin 5-HT
3
 recep
-
tors; these may be stimulated by biliary or gastrointestinal 
distention, mucosal or peritoneal irritation, or infections. 
(2) Fibers of the vestibular system, which have high con
-
centrations of histamine H
1
 and muscarinic cholinergic 
receptors. (3) Higher central nervous system centers 
(amygdala); here, certain sights, smells, or emotional expe
-
riences may induce vomiting. For example, patients receiv
-
ing chemotherapy may start vomiting in anticipation of its 
administration. (4) The chemoreceptor trigger zone, 
located outside the blood-brain barrier in the area pos
-
trema of the medulla, which is rich in opioid, serotonin 
5-HT
3
, neurokinin 1 (NK
1
) and dopamine D
2
 receptors. 
This region may be stimulated by drugs and chemothera
-
peutic agents, toxins, hypoxia, uremia, acidosis, and radia
-
tion therapy. Although the causes of nausea and vomiting 
are many, a simplified list is provided in Table 15–1.
 
»
Acute symptoms without abdominal pain are typically 
caused by food poisoning, infectious gastroenteritis, drugs, 
or systemic illness. Inquiry should be made into recent 
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Table 15–1.
 
Causes of nausea and vomiting.
Visceral afferent stimulation
Mechanical obstruction
 
G
astric outlet obstruction: peptic ulcer disease, malignancy, gastric volvulus
 
Small 
intestinal obstruction: adhesions, hernias, volvulus, Crohn disease, carcinomatosis
Dysmotility
 
G
astroparesis: diabetic, postviral, postvagotomy
 
Small 
intestine: scleroderma, amyloidosis, chronic intestinal pseudo-obstruction, familial myoneuropathies
Peritoneal irritation
 
P
eritonitis: perforated viscus, appendicitis, spontaneous bacterial peritonitis
 
V
iral gastroenteritis: Norwalk agent, rotavirus
 
“F
ood poisoning”: toxins from 
Bacillus cereus, Staphylococcus aureus, Clostridium perfringens
 
A
cute systemic infections
h
epatobiliary or pancreatic disorders
 
Hepa
titis A or B
 
A
cute pancreatitis
 
Cholec
ystitis or choledocholithiasis
Topical gastrointestinal irritants
 
Alc
ohol, NSAIDs, oral antibiotics
Postoperative
Other
 
C
ardiac disease: acute myocardial infarction, heart failure
 
Ur
ologic disease: stones, pyelonephritis
Vestibular disorders
 
Lab
yrinthitis, Ménière syndrome, motion sickness
CNS disorders
Increased intracranial pressure
 
CNS tumors
, subdural or subarachnoid hemorrhage
Migraine
 
M
eningitis, encephalitis
Psychogenic
 
An
ticipatory vomiting, anorexia nervosa and bulimia, psychiatric disorders
Irritation of chemoreceptor 
trigger zone
Antitumor chemotherapy
Medications and drugs
 
Opioids
 
Anticonvulsants
 
An
tiparkinsonism drugs
 
B
eta-blockers, antiarrhythmics, digoxin
 
Nicotine
 
Or
 
Cholinest
erase inhibitors
 
Diabet
es medications (metformin, acarbose, pramlintide, exenatide)
Radiation therapy
 
Diabetic 
ketoacidosis
 
Uremia
 
A
drenocortical crisis
 
P
arathyroid disease
 
Pregnancy
 
P
araneoplastic syndrome
CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs.
changes in medications, diet, other intestinal symptoms, or 
similar illnesses in family members. The acute onset of 
severe pain and vomiting suggests peritoneal irritation, 
acute gastric or intestinal obstruction, or pancreaticobili
-
ary disease. Persistent vomiting suggests pregnancy, gastric 
outlet obstruction, gastroparesis, intestinal dysmotility, 
psychogenic disorders, and central nervous system or sys
-
temic disorders. Vomiting that occurs in the morning 
before breakfast is common with pregnancy, uremia, alco
-
hol intake, and increased intracranial pressure. Vomiting 
immediately after meals strongly suggests bulimia or psy
-
chogenic causes. Vomiting of undigested food one to sev
-
eral hours after meals is characteristic of gastroparesis or a 
gastric outlet obstruction; physical examination may 
reveal a succussion splash. Patients with acute or chronic 
symptoms should be asked about neurologic symptoms 
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(eg, headache, stiff neck, vertigo, and focal paresthesias or 
weakness) that suggest a central nervous system cause.
B. Special Examinations
With vomiting that is severe or protracted, serum electro
-
lytes should be obtained to look for hypokalemia, azote
-
mia, or metabolic alkalosis resulting from loss of gastric 
contents. Flat and upright abdominal radiographs or 
abdominal CT are obtained in patients with severe pain or 
suspicion of mechanical obstruction to look for free intra
-
peritoneal air or dilated loops of small bowel. The cause of 
gastric outlet obstruction is best demonstrated by upper 
endoscopy, and the cause of small intestinal obstruction is 
best demonstrated with abdominal CT imaging. Gastropa
-
resis is confirmed by nuclear scintigraphic studies or 
13
C-octanoic acid breath tests, which show delayed gastric 
emptying and either upper endoscopy or barium upper 
gastrointestinal series showing no evidence of mechanical 
gastric outlet obstruction. Abnormal liver biochemical 
tests or elevated amylase or lipase suggest pancreaticobili
-
ary disease, which may be investigated with an abdominal 
sonogram or CT scan. Central nervous system causes are 
best evaluated with either head CT or MRI.
 
»
Complications include dehydration, hypokalemia, meta
-
bolic alkalosis, aspiration, rupture of the esophagus (Boer
-
haave syndrome), and bleeding secondary to a mucosal 
tear at the gastroesophageal junction (Mallory-Weiss 
syndrome).
 
»
Treatment
Most causes of acute vomiting are mild, self-limited, and 
require no specific treatment. Patients should ingest clear 
liquids (broths, tea, soups, carbonated beverages) and small 
quantities of dry foods (soda crackers). Ginger may be an 
effective nonpharmacologic treatment. For more severe 
acute vomiting, hospitalization may be required. Patients 
unable to eat and losing gastric fluids may become dehy
-
drated, resulting in hypokalemia with metabolic alkalosis. 
Intravenous 0.45% saline solution with 20 mEq/L of potas
-
sium chloride is given in most cases to maintain hydration. 
A nasogastric suction tube for gastric or mechanical small 
bowel obstruction improves patient comfort and permits 
monitoring of fluid loss.
B. Antiemetic Medications
Medications may be given either to prevent or to control 
vomiting. Combinations of drugs from different classes 
may provide better control of symptoms with less toxicity 
in some patients. Table 15–2 outlines common antiemetic 
dosing regimens.
1. Serotonin 5-HT
3
-receptor antagonists—
Ondansetron, 
granisetron, dolasetron, and palonosetron are effective in 
preventing chemotherapy- and radiation-induced emesis 
when initiated prior to treatment. Due to its prolonged 
half-life and internalization of the 5-HT
3
-receptor, palono
-
setron is superior to other 5-HT
3
-receptor antagonists for 
the prevention of acute and delayed chemotherapy-induced 
emesis from moderately or highly emetogenic chemothera
-
peutic regimens. Although 5-HT
3
-receptor antagonists are 
effective as single agents for the prevention of chemotherapy-
induced nausea and vomiting, their efficacy is enhanced 
by combination therapy with a corticosteroid (dexameth
-
asone) and NK
1
-receptor antagonist. Serotonin antago
-
nists increasingly are used for the prevention of 
postoperative nausea and vomiting because of increased 
restrictions on the use of other antiemetic agents (such as 
droperidol).
Corticosteroids (eg, dexamethasone) 
have antiemetic properties, but the basis for these effects is 
unknown. These agents enhance the efficacy of serotonin 
receptor antagonists for preventing acute and delayed nau
-
sea and vomiting in patients receiving moderately to highly 
emetogenic chemotherapy regimens.
3. Neurokinin receptor antagonists—
Aprepitant, fosapre
-
pitant, and rolapitant are highly selective antagonists for 
NK
1

-
NK
1
-receptors in the area postrema. They are used in com
-
bination with corticosteroids and serotonin antagonists for 
the prevention of acute and delayed nausea and vomiting 
with highly emetogenic chemotherapy regimens. Netupitant 
is another oral NK
1
-receptor antagonist that is administered 
in a fixed-dose combination with palonosetron. Combined 
therapy with a neurokinin-1 receptor antagonist prevents 
acute emesis in 80–90% and delayed emesis in more than 
70% of patients treated with highly emetogenic regimens.
4. Dopamine antagonists—
The phenothiazines, butyro
-
phenones, and substituted benzamides (eg, prochlorpera
-
zine, promethazine) have antiemetic properties that are 
due to dopaminergic blockade as well as to their sedative 
effects. High doses of these agents are associated with anti
-
dopaminergic side effects, including extrapyramidal reac
-
tions and depression. With the advent of more effective 
and safer antiemetics, these agents are infrequently used, 
mainly in outpatients with minor, self-limited symptoms. 
The atypical antipsychotic agent olanzapine has potent 
antiemetic properties that may be mediated by blockade of 
both dopamine and serotonin neurotransmitters. In a 
phase 3 randomized controlled trial in which patients who 
received highly emetogenic chemotherapy were already 
being given dexamethasone, an NK
1
-receptor antagonist, 
and a 5-HT
3
 antagonist, olanzapine was superior to pla
-
cebo for the prevention of acute and delayed nausea.
5. Antihistamines and anticholinergics—
These drugs (eg, 
meclizine, dimenhydrinate, transdermal scopolamine) may 
be valuable in the prevention of vomiting arising from stimu
-
lation of the labyrinth, ie, motion sickness, vertigo, and 
migraines. They may induce drowsiness. A combination of 
oral vitamin B
6
 and doxylamine is recommended by the 
American College of Obstetricians and Gynecologists as 
first-line therapy for nausea and vomiting during pregnancy.
6. Cannabinoids—
Marijuana has been used widely as an 
appetite stimulant and antiemetic. Pure Delta
9
-tetrahydro
-
cannabinol (THC) is the major active ingredient in 
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Table 15–2.
 
Common antiemetic dosing regimens.
Dosage
Route
Serotonin 5-
h
T
3
 Antagonists
Ondansetron
Doses vary: 4–8 mg twice daily for postoperative nausea and vomiting
Intravenously, orally
8 mg twice daily for moderately or highly emetogenic chemotherapy
Granisetron
1 mg once daily
Intravenously
1–2 mg once daily
Orally
Dolasetron
12.5 mg postoperatively
100 mg once daily
Orally
Palonosetron
0.25 mg once as a single dose 30 min before start of chemotherapy
0.5 mg once as single dose
Orally
4 mg once pre-induction for prevention of postoperative nausea and 
vomiting
8 mg once daily for chemotherapy
40–100 mg once daily
Intravenously, intramuscularly, orally
Dopamine Receptor Antagonists
Metoclopramide
10–20 mg or 0.5 mg/kg every 6–8 hours
10–20 mg every 6–8 hours
Orally
Prochlorperazine
5–10 mg every 4–6 hours
25 mg suppository every 6 hours
Per rectum
Promethazine
12.5–25 mg every 6–8 hours
25 mg every 6–8 hours
Per rectum
Trimethobenzamide
200 mg every 6–8 hours
Orally
250–300 mg every 6–8 hours
10 mg once daily on days 1–4 for chemotherapy
Neurokinin Receptor Antagonists
1
Aprepitant
125 mg once before chemotherapy; then 80 mg on days 1 and 
 
2 after chemotherapy
Orally
Fosaprepitant
115 mg once 30 minutes before chemotherapy
Rolapitant
180 mg once before chemotherapy
Orally
Netupitant/palonosetron
Netupitant 300 mg / palonosetron 0.50 mg once before chemotherapy
Orally
1
Neurokinin receptor antagonists are used solely for highly emetogenic chemotherapy regimens in combination with 5-HT
3
 antagonists or 
dexamethasone or both.
marijuana and the most psychoactive and is available by 
prescription as dronabinol. In doses of 5–15 mg/m
2
, oral 
dronabinol is effective in treating nausea associated with 
chemotherapy, but it is associated with central nervous 
system side effects in most patients. Some states allow the 
use of medical marijuana with a clinician’s certification. 
Strains of medical marijuana with different proportions of 
various naturally occurring cannabinoids (primarily THC 
and Cannabidiol [CBD]) can be chosen to minimize its 
psychoactive effects.
Hesketh PJ et al. Antiemetics: American Society of Clinical 
Oncology clinical practice guideline update. J Clin Oncol. 
2017 Oct;35(28):3240–61. [PMID: 28759346]
Navari RM et al. Antiemetic prophylaxis for chemotherapy-
induced nausea and vomiting. N Engl J Med. 2016 Apr 7;
 
374(14):1356–67. [PMID: 27050207]
Navari RM et al. Olanzapine for the prevention of chemotherapy-
induced nausea and vomiting. N Engl J Med. 2016 Jul 14;
 
375(2):134–42. [PMID: 27410922]
Tageja N et al. Chemotherapy-induced nausea and vomiting: an 
overview and comparison of three consensus guidelines. 
Postgrad Med J. 2016 Jan;92(1083):34–40. [PMID: 26561590]
HICCUPS (
Singultus
)
Though usually a benign and self-limited annoyance, hic
-
cups may be persistent and a sign of serious underlying 
illness. In patients on mechanical ventilation, hiccups can 
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Table 15–3.
 
Causes of constipation in adults.
Most common
 
I
nadequate fiber or fluid intake
 
P
oor bowel habits
Systemic disease
 
Endocrine: 
hypothyroidism, hyperparathyroidism, diabetes 
 
mellitus
 
M
etabolic: hypokalemia, hypercalcemia, uremia, porphyria
 
Neur
ologic: Parkinson disease, multiple sclerosis, sacral nerve 
 
damage 
(prior pelvic surgery, tumor), paraplegia, autonomic 
 
Opioids
 
Diuretics
 
C
alcium channel blockers
 
Psychotropics
 
C
alcium and iron supplements
 
NSAIDs
 
Clonidine
 
Cholestyramine
Structural abnormalities
 
Anor
ectal: rectal prolapse, rectocele, rectal intussusception, 
 
anor
ectal stricture, anal fissure, solitary rectal ulcer syndrome
 
P
erineal descent
 
C
olonic mass with obstruction: adenocarcinoma
 
C
olonic stricture: radiation, ischemia, diverticulosis
 
H
irschsprung disease
 
Idiopa
thic megarectum
Slow colonic transit
 
Idiopa
thic: isolated to colon
 
Ea
ting disorders
 
Chr
onic intestinal pseudo-obstruction
Pelvic floor dyssynergia
NSAIDs, nonsteroidal anti-inflammatory drugs.
trigger a full respiratory cycle and result in respiratory 
alkalosis.
Causes of benign, self-limited hiccups include gastric 
distention (carbonated beverages, air swallowing, overeat
-
ing), sudden temperature changes (hot then cold liquids, 
hot then cold shower), alcohol ingestion, and states of 
heightened emotion (excitement, stress, laughing). There 
are over 100 causes of recurrent or persistent hiccups due 
to gastrointestinal, central nervous system, cardiovascular, 
and thoracic disorders.
 
»
Evaluation of the patient with persistent hiccups should 
include a detailed neurologic examination, serum creatinine, 
liver chemistry tests, and a chest radiograph. When the cause 
remains unclear, CT or MRI of the head, chest, and abdo
-
men, echocardiography, and upper endoscopy may help.
 
»
Treatment
A number of simple remedies may be helpful in patients 
with acute benign hiccups. (1) Irritation of the nasophar
-
ynx by tongue traction, lifting the uvula with a spoon, 
catheter stimulation of the nasopharynx, or eating 1 tea
-
spoon (tsp) (7 g) of dry granulated sugar. (2) Interruption 
of the respiratory cycle by breath holding, Valsalva maneu
-
ver, sneezing, gasping (fright stimulus), or rebreathing into 
a bag. (3) Stimulation of the vagus by carotid massage. (4) 
Irritation of the diaphragm by holding knees to chest or by 
continuous positive airway pressure during mechanical 
ventilation. (5) Relief of gastric distention by belching or 
insertion of a nasogastric tube.
A number of drugs have been promoted as being useful 
in the treatment of hiccups. Chlorpromazine, 25–50 mg 
orally or intramuscularly, is most commonly used. Other 
agents reported to be effective include anticonvulsants 
(phenytoin, carbamazepine), benzodiazepines (lorazepam, 
diazepam), metoclopramide, baclofen, gabapentin, and 
occasionally general anesthesia.
Bredenoord AJ. Management of belching, hiccups, and aeropha
-
gia. Clin Gastroenterol Hepatol. 2013 Jan;11(1):6–12. [PMID: 
22982101]
Steger M et al. Systemic review: the pathogenesis and pharmaco
-
logical treatment of hiccups. Aliment Pharmacol Ther. 
2015 Nov;42(9):1037–50. [PMID: 26307025]
Constipation occurs in 15% of adults and up to one-third 
of elderly adults and is a common reason for seeking medi
-
cal attention. It is more common in women. Older indi
-
viduals are predisposed due to comorbid medical 
conditions, medications, poor eating habits, decreased 
mobility and, in some cases, inability to sit on a toilet (bed-
bound patients). The first step in evaluating the patient is 
to determine what is meant by “constipation. ” Patients may 
define constipation as infrequent stools (fewer than three 
in a week), hard stools, excessive straining, or a sense of

in a week), hard stools, excessive straining, or a sense of 
incomplete evacuation. Table 15–3 summarizes the many 
causes of constipation, which are discussed below.
 
»
Etiology
A. Primary Constipation
Most patients have constipation that cannot be attributed 
to any structural abnormalities or systemic disease. Some 
of these patients have normal colonic transit time; how
-
ever, a subset have slow colonic transit or defecatory dis
-
orders. Normal colonic transit time is approximately 35 
hours; more than 72 hours is significantly abnormal. Slow 
colonic transit is commonly idiopathic but may be part of 
a generalized gastrointestinal dysmotility syndrome. 
Patients may complain of infrequent bowel movements 
and abdominal bloating. Slow transit is more common in 
women, some of whom have a history of psychosocial 
problems (depression, anxiety, eating disorder, childhood 
trauma) or sexual abuse. Normal defecation requires coor
-
dination between relaxation of the anal sphincter and 
pelvic floor musculature while abdominal pressure is 
increased. Patients with defecatory disorders (also known 
dyssynergic defecation)—women more often than men—
have impaired relaxation or paradoxical contraction of 
the anal sphincter and/or pelvic floor muscles during 
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attempted defecation that impedes the bowel movement. 
This problem may be acquired during childhood or adult
-
hood. Patients may complain of excessive straining, sense 
of incomplete evacuation, or need for digital manipulation. 
Patients with primary complaints of abdominal pain or 
bloating with alterations in bowel habits (constipation, or 
alternating constipation and diarrhea) may have irritable 
bowel syndrome.
B. Secondary Constipation
Constipation may be caused by systemic disorders, medi
-
cations, or obstructing colonic lesions. Systemic disorders 
can cause constipation because of neurologic gut dysfunc
-
tion, myopathies, endocrine disorders, or electrolyte 
abnormalities (eg, hypercalcemia or hypokalemia); medi
-
cation side effects are often responsible (eg, anticholiner
-
gics or opioids). Colonic lesions that obstruct fecal passage, 
such as neoplasms and strictures, are an uncommon cause 
but important in new-onset constipation. Such lesions 
should be excluded in patients older than age 50 years, in 
patients with “alarm” symptoms or signs (hematochezia, 
weight loss, anemia, or positive fecal occult blood tests 
[FOBT] or fecal immunochemical tests [FIT]), and in 
patients with a family history of colon cancer or inflamma
-
tory bowel disease. Defecatory difficulties also can be due 
to a variety of anorectal problems that impede or obstruct 
flow (perineal descent, rectal prolapse, rectocele), some of 
which may require surgery, and Hirschsprung disease 
(usually suggested by lifelong constipation).
 
»
All patients should undergo a history and physical exami
-
nation to distinguish primary from secondary causes of 
constipation. Physical examination should include digital 
rectal examination with assessment for anatomic abnor
-
malities, such as anal stricture, rectocele, rectal prolapse, or 
perineal descent during straining as well as assessment of 
pelvic floor motion during simulated defecation (ie, the 
patient’s ability to “expel the examiner’s finger”). Further 
diagnostic tests should be performed in patients with any 
of the following: age 50 years or older, severe constipation, 
signs of an organic disorders, alarm symptoms (hemato
-
chezia, weight loss, positive FOBT or FIT), or a family 
history of colon cancer or inflammatory bowel disease. 
These tests should include laboratory studies (complete 
blood count; serum electrolytes, calcium, glucose, and 
thyroid-stimulating hormone) and a colonoscopy or flexi
-
ble sigmoidoscopy.
Patients with refractory constipation not responding to 
routine medical management warrant further diagnostic 
studies. Anorectal manometry including a balloon expul
-
sion test should be performed first to evaluate for defeca
-
tory disorders. Inability to expel a balloon (attached to a 
16F Foley catheter) filled with 50 mL of warm water within 
2 minutes while sitting on a toilet is strongly suggestive of 
pelvic floor dyssenergia. Defecography to further assess 
pelvic floor function may be considered in selected 
patients. Subsequent colon transit studies are recom
-
mended only after defecatory disorders have been excluded. 
Colon transit time may be assessed by radiopaque markers, 
scintigraphy, or wireless motility capsule.
 
»
Treatment
A. Chronic Constipation
1. Dietary and lifestyle measures—
Adverse psychosocial 
issues should be identified and addressed. Patients should 
be instructed on normal defecatory function and optimal 
toileting habits, including regular timing, proper position
-
ing, and abdominal pressure. Adequate dietary fluid and 
fiber intake should be emphasized. A trial of fiber supple
-
ments is recommended (Table 15–4). Increased dietary 
fiber may cause distention or flatulence, which often 
diminishes over several days. Response to fiber therapy is 
not immediate, and increases in dosage should be made

not immediate, and increases in dosage should be made 
gradually over 7–10 days. Fiber is most likely to benefit 
patients with normal colonic transit, but it may not benefit 
patients with colonic inertia, defecatory disorders, opioid-
induced constipation, or irritable bowel syndrome; it may 
even exacerbate symptoms in these patients. Regular exer
-
cise is associated with a decreased risk of constipation. 
When possible, discontinue medications that may be caus
-
ing or contributing to constipation. Probiotics are widely 
promoted to patients in direct advertising for treatment of 
constipation. A 2014 meta-analysis of randomized con
-
trolled trials suggests probiotics improve stool frequency 
and consistency; however, more study is needed.
2. Laxatives—
Laxatives may be given on an intermittent 
or chronic basis for constipation that does not respond to 
dietary and lifestyle changes (Table 15–4). There is no evi
-
dence that long-term use of these agents is harmful.
a. 
O
smotic laxatives—
Treatment usually is initiated 
with regular (daily) use of an osmotic laxative. Nonabsorb
-
able osmotic agents increase secretion of water into the 
intestinal lumen, thereby softening stools and promoting 
defecation. Magnesium hydroxide, nondigestible carbohy
-
drates (sorbitol, lactulose), and polyethylene glycol are all 
efficacious and safe for treating acute and chronic cases. 
The dosages are adjusted to achieve soft to semi-liquid 
movements. Magnesium-containing saline laxatives should 
not be given to patients with chronic renal insufficiency. 
Nondigestible carbohydrates may induce bloating, cramps, 
and flatulence. Polyethylene glycol 3350 (Miralax) is a 
component of solutions traditionally used for colonic 
lavage prior to colonoscopy and does not cause flatulence. 
When used in conventional doses, the onset of action of 
these osmotic agents is generally within 24 hours. For more 
rapid treatment of acute constipation, purgative laxatives 
may be used, such as magnesium citrate. Magnesium 
citrate may cause hypermagnesemia.
b
. S
timulant laxatives—
For patients with incomplete 
response to osmotic agents, stimulant laxatives may be pre
-
scribed as needed as a “rescue” agent or on a regular basis 
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Table 15–4.
 
Pharmacologic management of constipation.
Agent
Dosage
Onset of Action
Comments
Fiber laxatives
Bran powder
1–4 tbsp orally twice daily
Days
Inexpensive; may cause gas, flatulence
Psyllium
1 tsp once or twice daily
Days
(Metamucil; Perdiem)
Methylcellulose
Days
(Citrucel) Less gas, flatulence
Calcium polycarbophil
1 or 2 tablets once or twice daily
12–24 hours
(FiberCon) Does not cause gas; pill form
Guargum
1 tbsp once or twice daily
Days
(Benefiber) Non-gritty, tasteless, less gas
Stool surfactants
Docusate sodium
100 mg once or twice daily
12–72 hours
(Colace) Marginal benefit
Mineral oil
15–45 mL once or twice daily
6–8 hours
May cause lipoid pneumonia if aspirated
Osmotic laxatives
Magnesium hydroxide
15–30 mL orally once or twice daily
6–24 hours
(Milk of magnesia; Epsom salts)
Lactulose or 70% sorbitol
15–60 mL orally once daily to three 
6–48 hours
Cramps, bloating, flatulence
Polyethylene glycol 
 
(PEG 3350)
17 g in 8 oz liquid once or twice 
daily
6–24 hours
(Miralax) Less bloating than lactulose, sorbitol
Stimulant laxatives
Bisacodyl
5–20 mg orally as needed
6–8 hours
May cause cramps; avoid daily use if possible
Bisacodyl suppository
10 mg per rectum as needed
1 hour
Cascara
4–8 mL or 2 tablets as needed
8–12 hours
(Nature’s Remedy) May cause cramps; avoid daily use 
if possible
Senna
8.6–17.2 mg orally as needed
8–12 hours
(ExLax; Senekot) May cause cramps; avoid daily use if 
possible
Lubiprostone
24 mcg orally twice daily
12–48 hours
Expensive; may cause nausea. Contraindicated in 
pregnancy
Linaclotide
145 mcg orally once daily
Expensive; contraindicated in pediatric patients
Plecanatide
3 mg once daily
 
Enemas
Tap water
500 mL per rectum
Sodium phosphate 
enema
120 mL per rectum
Commonly used for acute constipation or to induce 
movement prior to medical procedures
Mineral oil enema
100–250 mL per rectum
To soften and lubricate fecal impaction
Agents used for Acute Purgative or to Clean Bowel Prior to Medical Procedures
 
(PEG 3350)
4 L orally administered over 
 
2–4 hours
< 4 hours
(GoLYTELY; CoLYTE; NuLYTE, MoviPrep) Used to 
cleanse bowel before colonoscopy
Magnesium citrate
10 oz orally
3–6 hours
Lemon-flavored
three or four times a week. These agents stimulate fluid 
secretion and colonic contraction, resulting in a bowel 
movement within 6–12 hours after oral ingestion or 15–60 
minutes after rectal administration. Oral agents are usually 
administered once daily at bedtime. Common preparations 
include bisacodyl, senna, and cascara (Table 15–4).
c. 
C
hloride secretory agents—
Several agents stimu
-
late intestinal chloride secretion either through activation 
of chloride channels (lubiprostone) or guanylcyclase C 
(linaclotide and plecanatide), resulting in increased intesti
-
nal fluid and accelerated colonic transit. In multicenter 
controlled trials, patients treated with lubiprostone 24 mcg 
orally twice daily, linaclotide 145 mcg once daily, or ple
-
canatide 3 mg once daily increased the number of bowel 
movements compared with patients treated with placebo. 
Because these agents are expensive, they should be reserved 
for patients who have suboptimal response or side effects 
with less expensive agents.
d. 
O
pioid-receptor antagonists—
Long-term use of 
opioids can cause constipation by inhibiting peristalsis and 
increasing intestinal fluid absorption. Methylnaltrexone 
(450 mg orally once daily), naloxegol (25 mg orally once daily) 
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and naldemedine (0.2 mg orally once daily) are mu-opioid 
receptor antagonists that block peripheral opioid receptors 
(including in the gastrointestinal tract) without affecting 
central analgesia. They are approved for the treatment of 
opioid-induced constipation in patients receiving opioids 
for chronic noncancer pain (see Chapter 5). A subcutane
-
ous formulation of methylnaltrexone also is approved for 
treatment of patients receiving palliative care for advanced 
illness who have not responded to conventional laxative 
regimens.
B. Fecal Impaction
Severe impaction of stool in the rectal vault may result in 
obstruction to further fecal flow, leading to partial or com
-
plete large bowel obstruction. Predisposing factors include 
medications (eg, opioids), severe psychiatric disease, pro
-
longed bed rest, neurogenic disorders of the colon, and spi
-
nal cord disorders. Clinical presentation includes decreased 
appetite, nausea and vomiting, and abdominal pain and dis
-
tention. There may be paradoxical “diarrhea” as liquid stool 
leaks around the impacted feces. Firm feces are palpable on 
digital examination of the rectal vault. Initial treatment is 
directed at relieving the impaction with enemas (saline, min
-
eral oil, or diatrizoate) or digital disruption of the impacted 
fecal material. Long-term care is directed at maintaining soft 
stools and regular bowel movements (as above).
 
»
•	
Patients with refractory constipation for anorectal testing.
•	
Patients with defecatory disorders may benefit from 
biofeedback therapy.
•	
Patients with alarm symptoms or who are over age 50 
should be referred for colonoscopy.
•	
Rarely, surgery (subtotal colectomy) is required for 
patients with severe colonic inertia.
ASGE Standards of Practice Committee; Cash BD et al. The role 
of endoscopy in the management of constipation. Gastroin
-
test Endosc. 2014 Oct;80(4):563–5. [PMID: 25150599]
Brenner DM et al. Chronic constipation. Gastroenterol Clin 
North Am. 2016 Jun;45(2):205–16. [PMID: 27261894]
Hale M et al. Naldemedine versus placebo for opioid-induced 
constipation (COMPOSE-1 and COMPOSE-2): two multi
-
center, phase 3, double-blind, randomized, parallel-group tri
-
als. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):555–64. 
[PMID: 28576452]
Katakami N et al. Randomized phase III and extension studies of 
naldemedine in patients with opioid-induced constipation 
and cancer. J Clin Oncol 2017 Dec 1;35(34):3859–66. [PMID: 
28968171]
Miner PB Jr et al. A randomized phase III clinical trial with 
plecanatide, a uroguanylin analog in patients with chronic 
idiopathic constipation. Am J Gastroenterol. 2017 Apr;
 
112(4):613–21. [PMID: 28169285]
Murphy JA et al. Evidence based review of pharmacotherapy for 
opioid-induced constipation in noncancer pain. Ann Pharma
-
cother. 2018 Apr;52(4):370-9. [PMID: 29092627]
Wald A. Constipation: advances in diagnosis and treatment. 
JAMA. 2016 Jan 12;315(2):185–91. [PMID: 26757467]
Wald A. JAMA patient page. Treating constipation with medica
-
tions. JAMA. 2016 Mar 22–29;315(12):1299. [PMID: 27002462]
GASTROINTESTINAL GAS
 
»
Belching
Belching (eructation) is the involuntary or voluntary 
release of gas from the stomach or esophagus. It occurs 
most frequently after meals, when gastric distention results 
in transient lower esophageal sphincter (LES) relaxation. 
Belching is a normal reflex and does not itself denote gas
-
trointestinal dysfunction. Virtually all stomach gas comes 
from swallowed air. With each swallow, 2–5 mL of air is 
ingested, and excessive amounts may result in distention, 
flatulence, and abdominal pain. This may occur with rapid 
eating, gum chewing, smoking, and the ingestion of car
-
bonated beverages. Evaluation should be restricted to 
patients with other complaints such as dysphagia, heart
-
burn, early satiety, or vomiting.
Chronic excessive belching is almost always caused by

-
Chronic excessive belching is almost always caused by 
supragastric belching (voluntary diaphragmatic contrac
-
tion, followed by upper esophageal relaxation with air 
inflow to the esophagus) or true air swallowing (aerophagia), 
both of which are behavioral disorders that are more common 
in patients with anxiety or psychiatric disorders. These 
patients may benefit from referral to a behavioral or speech 
therapist.
Kessing BF et al. The pathophysiology, diagnosis and treat
-
ment of excessive belching symptoms. Am J Gastroenterol. 
2014 Aug;109(8):1196–203. [PMID: 25001253]
Lang IM. The physiology of eructation. Dysphagia. 2016 Apr;
 
31(2):121–33. [PMID: 26694063]
 
»
Flatus & Bloating
The rate and volume of expulsion of flatus is highly vari
-
able. Healthy adults pass flatus up to 20 times daily and 
excrete up to 750 mL. Flatus is derived from two sources: 
swallowed air (primarily nitrogen) and bacterial fermenta
-
tion of undigested carbohydrate (which produces H
2
, CO
2
, 
and methane). A number of short-chain carbohydrates 
(fermentable oligosaccharides, disaccharides, monosac
-
charides, and polyols or “FODMAPS”) are incompletely 
absorbed in the small intestine and pass into the colon. 
These include lactose (dairy products); fructose (fruits, 
corn syrups, and some sweeteners); polyols (stone-fruits, 
mushrooms, and some sweeteners); and fructans (legumes, 
cruciferous vegetables, pasta, and whole grains). Abnormal 
gas production may be caused by increased ingestion of 
these carbohydrates or, less commonly, by disorders of 
malabsorption. Foul odor may be caused by garlic, onion, 
eggplant, mushrooms, and certain herbs and spices.
Determining abnormal from normal amounts of flatus 
is difficult. Patients with a long-standing history of flatu
-
lence and no other symptoms or signs of malabsorption 
disorders can be treated conservatively. Gum chewing and 
carbonated beverages should be avoided to reduce air swal
-
lowing. Lactose intolerance may be assessed by a 2-week 
trial of a lactose-free diet or by a hydrogen breath test. A 
list of foods containing FODMAPS should be provided. 
Multiple low-FODMAP dietary guides are available; how
-
ever, referral to a knowledgeable dietician may be helpful.
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Table 15–5.
 
Causes of acute infectious diarrhea.
Noninflammatory Diarrhea
Inflammatory Diarrhea
Viral
 
Nor
oviruses, astrovirus, 
adenovirus,
 
Rota
virus, sapovirus
Viral
 
Cytomegalovirus
Protozoal
 
Giardia lamblia
 
Cryptosporidium
 
Cyclospora
Protozoal
 
Entamoeba histolytica
Bacterial
1. Preformed enterotoxin 
production
  
Bacillus cereus
  
2. Enterotoxin production
   
En
terotoxigenic 
 
E coli
 (ETEC)
   
Vibrio cholera, Vibrio 
 
vulnificus
Bacterial
1. Cytotoxin production
   
En
terohemorrhagic 
E coli
 
O157:H5 and O157:H7
 
(EHEC)
  
Vibrio parahaemolyticus
 
2. Mucosal invasion
  
Shigella
  
Campylobacter jejuni
  
Enteroinvasive 
E coli
 (EIEC)
  
Aeromonas
  
Plesiomonas
  
Yersinia enterocolitica
  
Chlamydia
  
Listeria monocytogenes
The nonprescription agent Beano (alpha-d-galactosidase 
enzyme) reduces gas caused by foods containing galacto-
oligosaccharides (legumes, chickpeas, lentils) but not other 
FODMAPS. Activated charcoal may afford relief. Simethi
-
cone is of no proved benefit.
Complaints of chronic abdominal distention or bloat
-
ing are common. Some patients produce excess gas. Others 
have impaired gas propulsion or expulsion, increased 
bowel wall tension, enhanced visceral sensitivity, or altered 
viscero-somatic reflexes leading to abdominal protrusion 
(bloating). Many of these patients have an underlying func
-
tional gastrointestinal disorder such as irritable bowel 
syndrome or functional dyspepsia. Reducing fermentable 
sugars with a FODMAP-restricted diet or reducing 
intake of dietary fat, which delays intestinal gas clearance, 
may be helpful. Constipation should be treated, and exer
-
cise (which accelerates gas propulsion) is recommended. 
Rifaximin, 400 mg twice daily, a nonabsorbable oral antibi
-
otic with high activity against enteric bacteria, has been 
shown to reduce abdominal bloating and flatulence in 
approximately 40% of treated patients compared with 20% 
of controls. Symptom improvement may be attributable to 
suppression of gas-producing colonic bacteria; however, 
relapse commonly occurs within days after stopping the 
antibiotic. Further trials are needed to clarify the role of 
nonabsorbable antibiotics in symptom management. Many 
patients report reduced flatus production with use of pro
-
biotics, although there has been limited controlled study of 
these agents for this purpose. Patients interested in com
-
plementary medical therapies may be offered a trial of 4–8 
ounces daily of Kefir, a commercially available fermented 
milk drink containing multiple probiotics.
Malagelada JR et al. Bloating and abdominal distension: old 
misconceptions and current knowledge. Am J Gastroenterol. 
2017 Aug;112(8):1221–31. [PMID: 28508867]
Nanayakkara WS et al. Efficacy of the low FODMAP diet for 
treating irritable bowel syndrome: the evidence to date. Clin 
Exp Gastroenterol. 2016 Jun 17;9:131–42. [PMID: 27382323]
DIARRHEA
Diarrhea can range in severity from an acute self-limited 
episode to a severe, life-threatening illness. To properly 
evaluate the complaint, the clinician must determine the 
patient’s normal bowel pattern and the nature of the cur
-
rent symptoms.
Approximately 10 L of fluid enter the duodenum 
daily, of which all but 1.5 L are absorbed by the small intes
-
tine. The colon absorbs most of the remaining fluid, with 
less than 200 mL lost in the stool. Although diarrhea 
sometimes is defined as a stool weight of more than 
200–300 g/24 h, quantification of stool weight is necessary 
only in some patients with chronic diarrhea. In most cases, 
the physician’s working definition of diarrhea is increased 
stool frequency (more than three bowel movements per 
day) or liquidity of feces.
The causes of diarrhea are myriad. In clinical practice, it

The causes of diarrhea are myriad. In clinical practice, it 
is helpful to distinguish acute from chronic diarrhea, as the 
evaluation and treatment are entirely different (Tables 15–5 
and 15–6).
1. Acute Diarrhea
 
»
Diarrhea of less than 2 weeks’ duration is most 
commonly caused by invasive or noninvasive 
pathogens and their enterotoxins. 
Acute noninflammatory diarrhea
 
»
Watery, nonbloody.
 
»
Usually mild, self-limited.
 
»
Caused by a virus or noninvasive bacteria.
 
»
Diagnostic evaluation is limited to patients with 
diarrhea that is severe or persists beyond 7 days.
Acute inflammatory diarrhea
 
»
Blood or pus, fever.
 
»
Usually caused by an invasive or toxin-producing 
bacterium.
 
»
Diagnostic evaluation requires routine stool bac
-
terial cultures (including 
E coli
 O157:H5 and 
O157:H7) in all and testing as clinically indicated for 
 toxin, and ova and parasites.
 
»
Etiology & Clinical Findings
Diarrhea acute in onset and persisting for less than 2 weeks 
is most commonly caused by infectious agents, bacterial 
CMDT19_Ch15_p0589-p0687.indd   599

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 1
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600
 CMDT 2019
Table 15–6.
 
Causes of chronic diarrhea.
Osmotic diarrhea
 
CL
UES: Stool volume decreases with fasting; increased stool 
 
osmotic gap
1.
 
M
edications: antacids, lactulose, sorbitol
2
  
Disac
charidase deficiency: lactose intolerance
3.
 
F
actitious diarrhea: magnesium (antacids, laxatives)
Secretory diarrhea
 
CL
UES: Large volume (> 1 L/day); little change with fasting;
 
normal 
stool osmotic gap
1.
  
Hormonally 
mediated: VIPoma, carcinoid, medullary 
carcinoma of thyroid (calcitonin), Zollinger-Ellison 
syndrome (gastrin)
2.
  
F
actitious diarrhea (laxative abuse); phenolphthalein, 
 
cascara, senna
3.
 
V
illous adenoma
4.
  
Bile salt malabsorption 
(idiopathic, ileal resection; 
Crohn ileitis; postcholecystectomy)
5.
 
Inflammatory conditions
 
CL
UES: Fever, hematochezia, abdominal pain
1.
 
Ulc
erative colitis
2.
 
Cr
3.
 
M
icroscopic colitis
4.
 
M
alignancy: lymphoma, adenocarcinoma 
 
(with obstruction and pseudodiarrhea)
5.
 
R
adiation enteritis
 
C
ommon offenders: SSRIs, cholinesterase inhibitors, 
 
NSAIDs
, proton pump inhibitors, angiotensin II receptor 
 
block
ers, metformin, allopurinol
Malabsorption syndromes
 
CL
UES: Weight loss, abnormal laboratory values; fecal fat > 10 g/24h
1.
  
Small bo
wel mucosal disorders: celiac disease, tropical sprue, 
 
Whipple disease, eosinophilic gastroenteritis, small bowel resection 
(short bowel syndrome), Crohn disease
2.
  
L
ymphatic obstruction: lymphoma, carcinoid, infectious (tuberculo
-
sis, MAI), Kaposi sarcoma, sarcoidosis, retroperitoneal fibrosis
3.
 
P
ancreatic disease: chronic pancreatitis, pancreatic carcinoma
4.
  
Bac
terial overgrowth: motility disorders (diabetes, vagotomy), 
 
scleroderma, fistulas, small intestinal diverticula
Motility disorders
 
CL
UES: Systemic disease or prior abdominal surgery
1.
 
P
ostsurgical: vagotomy, partial gastrectomy, blind loop with 
 
bacterial overgrowth
2.
 
S
ystemic disorders: scleroderma, diabetes mellitus, hyperthyroidism
3.
 
I
rritable bowel syndrome
Chronic infections
1.
  
Parasites: 
Giardia lamblia, Entamoeba histolytica, Strongyloidiasis 
 
stercoralis, Capillaria philippinensis
2.
  
AIDS-related: Viral: 
, HIV infection (?); Bacterial: 
 
Clostridium difficile, Mycobacterium avium
 complex; Protozoal: 
 
Microsporidia 
(Enterocytozoon bieneusi), Cryptosporidium, Isospora 
belli
Factitious
 
S
ee Osmotic and Secretory diarrhea above
MAI, 
Mycobacterium avium-intracellulare;
 NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.
toxins (either preformed or produced in the gut), or medi
-
cations. Community outbreaks (including nursing homes, 
schools, cruise ships) suggest a viral etiology or a common 
food source. Similar recent illnesses in family members 
suggest an infectious origin. Ingestion of improperly stored 
or prepared food implicates food poisoning. Pregnant 
women have an increased risk of developing listeriosis. Day 
care attendance or exposure to unpurified water (camping, 
swimming) may result in infection with 
Giardia
 or 
Crypto
-
sporidium
. Large 
 outbreaks have been traced to 
contaminated produce. Recent travel abroad suggests 
“traveler’s diarrhea” (see Chapter 30). Antibiotic adminis
-
tration within the preceding several weeks increases the 
likelihood of 
C difficile
 colitis. Finally, risk factors for HIV 
infection or sexually transmitted diseases should be deter
-
mined. (AIDS-associated diarrhea is discussed in Chapter 31; 
infectious proctitis is discussed later in this chapter under 
Anorectal Infections.) Persons engaging in anal intercourse 
or oral-anal sexual activities are at risk for a variety of 
infections that cause proctitis, including gonorrhea, syphi
-
lis, lymphogranuloma venereum, and herpes simplex.
The nature of the diarrhea helps distinguish among dif
-
ferent infectious causes (Table 15–5).

-
-
A. Noninflammatory Diarrhea
Watery, nonbloody diarrhea associated with periumbilical 
cramps, bloating, nausea, or vomiting suggests a small 
bowel source caused by either a toxin-producing bacterium 
(enterotoxigenic 
E coli
 [ETEC], 
Staphylococcus aureus, 
Bacillus cereus, Clostridium perfringens
) or other agents 
(viruses, 
Giardia
) that disrupt normal absorption and 
secretory process in the small intestine. Prominent vomit
-
ing suggests viral enteritis or 
S aureus
 food poisoning. 
Although typically mild, the diarrhea (which originates in 
the small intestine) can be voluminous and result in dehy
-
dration with hypokalemia and metabolic acidosis (eg, 
cholera). Because tissue invasion does not occur, fecal leu
-
kocytes are not present.
B. Inflammatory Diarrhea
The presence of fever and bloody diarrhea (dysentery) 
indicates colonic tissue damage caused by invasion (shigel
-
losis, salmonellosis, 
 or 
Yersinia
 infection, 
amebiasis) or a toxin (
, Shiga-toxin–producing 
E coli
 [STEC; also known as enterohemorrhagic 
E coli
]). 
Because these organisms predominantly involve the colon, 
the diarrhea is small in volume (less than 1 L/day) and 
associated with left lower quadrant cramps, urgency, and 
tenesmus. Fecal leukocytes or lactoferrin usually are pres
-
ent in infections with invasive organisms. 
E coli
 O157:H7 is 
a Shiga-toxin–producing noninvasive organism most com
-
monly acquired from contaminated meat that has resulted 
in several outbreaks of an acute, often severe hemorrhagic 
colitis. In 2011, an outbreak of severe gastroenteritis in 
CMDT19_Ch15_p0589-p0687.indd   600

601
 
CMDT 2019
Germany, caused by an unusual Shiga-toxin–producing 
strain, 
E coli
 O104:H4, was traced to contaminated sprouts. 
A major complication of STEC is hemolytic-uremic syn
-
drome, which develops in 6–22% of cases. In immunocom
-
promised and HIV-infected patients, cytomegalovirus 
(CMV) can cause intestinal ulceration with watery or 
bloody diarrhea.
Infectious dysentery must be distinguished from acute 
ulcerative colitis, which may also present acutely with fever, 
abdominal pain, and bloody diarrhea. Diarrhea that per
-
sists for more than 14 days is not attributable to bacterial 
pathogens (except for 
) and should be evaluated 
as chronic diarrhea.
 
»
In over 90% of patients with acute noninflammatory diar
-
rhea, the illness is mild and self-limited, responding within 
5 days to simple rehydration therapy or antidiarrheal 
agents; diagnostic investigation is unnecessary except in 
suspected outbreaks or in patients at high risk for spread
-
ing infection to others.
The isolation rate of bacterial pathogens from stool 
cultures in patients with acute noninflammatory diarrhea 
is under 3%. Thus, the goal of initial evaluation is to distin
-
guish patients with mild disease from those with more 
serious illness. If diarrhea worsens or persists for more 
than 7–14 days, stool should be sent for analysis for viral, 
protozoan, and bacterial pathogens.
Prompt medical evaluation is indicated in the following 
situations (Figure 15–1): (1) Signs of inflammatory diar
-
rhea manifested by any of the following: fever (higher than 
38.5°C), WBC 15,000/mcL or more, bloody diarrhea, or 
severe abdominal pain. (2) The passage of six or more 
unformed stools in 24 hours. (3) Profuse watery diarrhea 
and dehydration. (4) Frail older patients or nursing home 
residents. (5) Immunocompromised patients (AIDS, post
-
transplantation). (6) Exposure to antibiotics. (7) Hospital-
acquired diarrhea (onset following at least 3 days of 
hospitalization). (8) Systemic illness.
Physical examination pays note to the patient’s level of 
hydration, mental status, and the presence of abdominal 
tenderness or peritonitis. Peritoneal findings may be pres
-
ent in infection with 
 or STEC. Hospitalization is 
required in patients with severe dehydration, organ failure, 
marked abdominal pain, or altered mental status.
In patients with dysentery (bloody stools), severe illness 
or persistent diarrhea, stool should be sent for microbial 
assessment. At present, stool specimens in most centers are 
sent for microscopy (to assess for fecal white cells and pro
-
tozoa) and bacterial cultures (requiring 48–72 hrs). These 
traditional methods provide a positive diagnosis in 60–75% 
Are the following present?
1.
 Se
ve
re
 illness: T > 38.5°C, abdominal pain,
 b
loody diarrhea, > 6 stools/24 h, deh
yd
ration
2. Immunocompromised patient: AIDS, posttransplantation
3. Elder
ly
 patient (> 70 yrs)
Acute diarrhea (≤ 7 da
ys
)
Ye
s
No
Send stool for following:
1.
 Fecal leukocytes
2. Routine stool culture
3. 
 assa
y,
 if recent hospitalization or antibiotics
4. Ova and parasite testing, if:
a. Diarrhea > 
10
 da
ys
b.
 
Tr
av
el 
to
 endemic region
c. Community 
wa
te
r-borne outbreak
d. HIV infection or men who ha
ve
 sex with men
Consider empiric antibiotic therapy while 
aw
aiting 
cultur
e,
 if:
1.
 Fecal leukocyte positive
2. Bloody diarrhea, 
fev
er, abdominal pain
3. Deh
yd
ration or > 8 stools/24 h
4. Immunocompromised
5. Hospitalization required
Symptomatic therapy
Antidiarrheal agents: loperamide,
   bismuth subsalicylate
Illness resol
ve
s Illness persists for 7–10 
   da
ys
 or wor
sens
&
 
▲
Figure 15–1.
 
Evaluation of acute diarrhea.
CMDT19_Ch15_p0589-p0687.indd   601

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APTER
 1
5
602
 CMDT 2019
of patients with dysenteric diarrhea but not in the majority 
of people with acute diarrhea. For bloody stools, the labo
-
ratory should be directed to perform serotyping for 
Shiga-toxin–producing 
E coli
 (STEC). Special culture 
media are required for 
Yersinia, Vibrio
, and 
Aeromonas
. In 
patients who are hospitalized or who have a history of anti
-
biotic exposure, a stool sample should be tested for 
 
toxin. Increasingly, many centers send stool specimens for 
microbial assessment using molecular techniques that 
screen for a panel of pathogens, including viruses, proto
-
zoa, and bacteria; these tests obviate the need for labor-
intensive microscopy and culturing and yield results within 
2–5 hours.
 
»
Treatment
A. Diet
Most mild diarrhea will not lead to dehydration provided the 
patient takes adequate oral fluids containing carbohydrates 
and electrolytes. Patients find it more comfortable to rest the 
bowel by avoiding high-fiber foods, fats, milk products, caf
-
feine, and alcohol. Frequent feedings of tea, “flat” carbonated 
beverages, and soft, easily digested foods (eg, soups, crackers, 
bananas, applesauce, rice, toast) are encouraged.
B. Rehydration
In more severe diarrhea, dehydration can occur quickly, 
especially in children and frail older adults. Oral rehydra
-
tion with fluids containing glucose, Na
+
, K
+
, Cl
–
, and bicar
-
bonate or citrate is preferred when feasible. A convenient 
mixture is ½ tsp salt (3.5 g), 1 tsp baking soda (2.5 g 
NaHCO
3
), 8 tsp sugar (40 g), and 8 oz orange juice (1.5 g 
KCl), diluted to 1 L with water. Alternatively, oral electro
-
lyte solutions (eg, Pedialyte, Gatorade) are readily available. 
Fluids should be given at rates of 50–200 mL/kg/24 h 
depending on the hydration status. Intravenous fluids (lac
-
tated Ringer injection) are preferred in patients with severe 
dehydration.
C. Antidiarrheal Agents
Antidiarrheal agents may be used safely in patients with 
mild to moderate diarrheal illnesses to improve patient 
comfort. Opioid agents help decrease the stool number 
and liquidity and control fecal urgency. However, they 
should not be used in patients with bloody diarrhea, high 
fever, or systemic toxicity and should be discontinued in 
patients whose diarrhea is worsening despite therapy. With 
these provisos, such drugs provide excellent symptomatic 
relief. Loperamide is preferred, in a dosage of 4 mg orally 
initially, followed by 2 mg after each loose stool (maximum: 
8 mg/24 h).
Bismuth subsalicylate (Pepto-Bismol), two tablets or 
30 mL orally four times daily, reduces symptoms in 
patients with traveler’s diarrhea by virtue of its anti-
inflammatory and antibacterial properties. It also reduces 
vomiting associated with viral enteritis. Anticholinergic 
agents (eg, diphenoxylate with atropine) are contraindicated 
in acute diarrhea because of the rare precipitation of toxic 
megacolon.
D. Antibiotic Therapy
1. Empiric treatment—
Empiric antibiotic treatment of 
patients with acute, community-acquired diarrhea generally 
is not indicated. Even patients with inflammatory diarrhea 
caused by invasive pathogens usually have symptoms that 
will resolve within several days without antimicrobials. In 
centers in which stool microbial testing with rapid molecu
-
lar assays is not available (yielding results within 5 hours), 
empiric treatment may be considered while the stool bacte
-
rial culture is incubating in certain patients: those with 
non–hospital-acquired diarrhea; those with moderate to 
severe fever, tenesmus, or bloody stools; and those with no 
suspicion of infection with STEC. It should also be consid
-
ered in patients who are immunocompromised or who have 
significant dehydration. The oral drugs of choice for empiric 
treatment are the fluoroquinolones (eg, ciprofloxacin 
500 mg, ofloxacin 400 mg, or levofloxacin 500 mg once 
daily) for 1–3 days. Alternatives include trimethoprim-

sulfamethoxazole, 160/800 mg twice daily; or doxycycline, 
100 mg twice daily. Macrolides and penicillins are no longer 
recommended because of widespread microbial resistance to 
these agents. Rifaximin (200 mg three times daily for 3 days) 
and azithromycin (1000 mg single dose or 500 mg daily for 
3 days) are approved for empiric treatment of noninflamma
-
tory traveler’s diarrhea (see Chapter 30).
2. Specific antimicrobial treatment—
Antibiotics are not 
recommended in patients with nontyphoid 
Salmonella, 
, STEC
, Aeromonas
, or 
Yersinia
, except in 
severe disease, because they do not hasten recovery or 
reduce the period of fecal bacterial excretion. The infec
-
tious bacterial diarrheas for which treatment is recom
-
mended are shigellosis, cholera, extraintestinal 
salmonellosis, listeriosis, and 
. The parasitic 
infections for which treatment is indicated are amebiasis, 
giardiasis, cryptosporidiosis, cyclosporiasis, and 
Enterocy
-
tozoon bienusi
 infection. Therapy for traveler’s diarrhea, 
infectious (sexually transmitted) proctitis, and AIDS-
related diarrhea is presented in Chapters 30 and 31.
 
»
•	
Severe dehydration for intravenous fluids, especially if 
vomiting or unable to maintain sufficient oral fluid 
intake.
•	
Bloody diarrhea that is severe or worsening in order to 
distinguish infectious versus noninfectious cause.
•	
Severe abdominal pain, worrisome for toxic colitis, 
inflammatory bowel disease, intestinal ischemia, or 
surgical abdomen.
•	
Signs of severe infection or sepsis (temperature higher 
than 39.5°C, leukocytosis, rash).
•	
Severe or worsening diarrhea in patients who are older 
than 70 years or immunocompromised.
•	
Signs of hemolytic-uremic syndrome (acute kidney 
injury, thrombocytopenia, hemolytic anemia).
Giddings SL et al. Traveler’s diarrhea. Med Clin North Am. 
2016 Mar;100(2):317–30. [PMID: 26900116]
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Riddle MS et al. ACG Clinical Guideline: diagnosis, treatment, 
and prevention of acute diarrheal infections in adults. Am J 
Gastroenterol. 2016 May;111(5):602–22. [PMID: 27068718]
2. Chronic Diarrhea
 
»
Diarrhea present for longer than 4 weeks.
 
»
Before embarking on extensive workup, common 
causes should be excluded, including medica
-
tions, chronic infections, and irritable bowel 
syndrome.
 
»
Etiology
The causes of chronic diarrhea may be grouped into the 
following major pathophysiologic categories: medications, 
osmotic diarrheas, secretory conditions, inflammatory 
conditions, malabsorptive conditions, motility disorders, 
chronic infections, and systemic disorders (Table 15–6).
Numerous medications can cause diarrhea. Common 
offenders include cholinesterase inhibitors, SSRIs, angio
-
tensin II-receptor blockers, proton pump inhibitors, 
NSAIDs, metformin, allopurinol, and orlistat. All medica
-
tions should be carefully reviewed, and discontinuation of 
potential culprits should be considered.
B. Osmotic Diarrheas
As stool leaves the colon, fecal osmolality is equal to the 
serum osmolality, ie, approximately 290 mOsm/kg. Under 
normal circumstances, the major osmoles are Na
+
, K
+
, Cl
–
, 
and HCO
3
–
. The stool osmolality may be estimated by 
multiplying the stool (Na
+
 + K
+
) × 2. The 
 is 
the difference between the 
measured
 osmolality of the stool 
(or serum) and the 
estimated
 stool osmolality and is nor
-
mally less than 50 mOsm/kg. An increased osmotic gap 
(greater than 75 mOsm/kg) implies that the diarrhea is 
caused by ingestion or malabsorption of an osmotically 
active substance. The most common causes are carbohy
-
drate malabsorption (lactose, fructose, sorbitol), laxative 
abuse, and malabsorption syndromes. Osmotic diarrheas 
resolve during fasting. Those caused by malabsorbed car
-
bohydrates are characterized by abdominal distention, 
bloating, and flatulence due to increased colonic gas 
production.
Carbohydrate malabsorption is common and should be 
considered in all patients with chronic, postprandial diar
-
rhea. Patients should be asked about their intake of dairy 
products (lactose), fruits and artificial sweeteners (fructose 
and sorbitol), processed foods and soft drinks (high-
fructose corn syrup), and alcohol. The diagnosis of carbo
-
hydrate malabsorption may be established by an elimination 
trial for 2–3 weeks or by hydrogen breath tests.
Ingestion of magnesium- or phosphate-containing 
compounds (laxatives, antacids) should be considered in 
enigmatic chronic diarrhea. The fat substitute olestra also 
causes diarrhea and cramps in occasional patients.
C. Secretory Conditions
Increased intestinal secretion or decreased absorption 
results in a high-volume watery diarrhea with a normal 
osmotic gap. There is little change in stool output during 
the fasting state, and dehydration and electrolyte imbal
-
ance may develop. Causes include endocrine tumors (stim
-
ulating intestinal or pancreatic secretion), bile salt 
malabsorption (stimulating colonic secretion), and micro
-
scopic colitis. Microscopic colitis is a common cause of 
chronic watery diarrhea in older adults (see Inflammatory 
Bowel Disease, below).
D. Inflammatory Conditions
Diarrhea is present in most patients with inflammatory 
bowel disease (ulcerative colitis, Crohn disease). A variety 
of other symptoms may be present, including abdominal 
pain, fever, weight loss, and hematochezia.
E. Malabsorptive Conditions
The major causes of malabsorption are small mucosal 
intestinal diseases, intestinal resections, lymphatic obstruc
-
tion, small intestinal bacterial overgrowth, and pancreatic 
insufficiency. Its characteristics are weight loss, osmotic 
diarrhea, steatorrhea, and nutritional deficiencies. Signifi
-
cant diarrhea in the absence of weight loss is not likely to

-
cant diarrhea in the absence of weight loss is not likely to 
be due to malabsorption. The physical and laboratory 
abnormalities related to deficiencies of vitamins or miner
-
als are discussed in Chapter 29.
F. Motility Disorders (Including 
 
Irritable Bowel Syndrome)
Irritable bowel syndrome is the most common cause of 
chronic diarrhea in young adults (see Irritable Bowel Syn
-
drome, below). It should be considered in patients with 
lower abdominal pain and altered bowel habits who have 
no other evidence of serious organic disease (weight loss, 
nocturnal diarrhea, anemia, or gastrointestinal bleeding). 
Abnormal intestinal motility secondary to systemic disor
-
ders, radiation enteritis, or surgery may result in diarrhea 
due to rapid transit or to stasis of intestinal contents with 
bacterial overgrowth, resulting in malabsorption.
G. Chronic Infections
Chronic parasitic infections may cause diarrhea through a 
number of mechanisms. Pathogens most commonly 
associated with diarrhea include the protozoans 
Giardia, 
, and 
 as well as the intes
-
tinal nematodes. Strongyloidiasis and capillariasis should 
be excluded in patients from endemic regions, especially in 
the presence of eosinophilia. Bacterial infections with 
 and, uncommonly, 
Aeromonas
 and 
 
may cause chronic diarrhea.
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Immunocompromised patients are susceptible to infec
-
tious organisms that can cause acute or chronic diarrhea 
(see Chapter 31), including Microsporidia, 
, 
CMV , 
Isospora belli, Cyclospora
, and 
 
complex.
H. Systemic Conditions
Chronic systemic conditions, such as thyroid disease, dia
-
betes, and collagen vascular disorders, may cause diarrhea 
through alterations in motility or intestinal absorption.
 
»
The history and physical examination commonly suggest 
the underlying pathophysiology that guides the subsequent 
diagnostic workup (Figure 15–2). The clinician should 
establish whether the diarrhea is continuous or intermit
-
tent, its relationship to meals, and whether it occurs at 
night or during fasting. The stool appearance may suggest 
a malabsorption disorder (greasy or malodorous), inflam
-
matory disorder (containing blood or pus), or a secretory 
process (watery). The presence of abdominal pain suggests 
irritable bowel syndrome or inflammatory bowel disease. 
Medications, diet, and recent psychosocial stressors should 
be reviewed. Physical examination should assess for signs of 
malnutrition, dehydration, and inflammatory bowel 
disease.
Because chronic diarrhea is caused by so many condi
-
tions, the subsequent diagnostic approach is guided by the 
relative suspicion for the underlying cause, and no specific 
algorithm can be followed in all patients. Prior to embark
-
ing on an extensive evaluation, the most common causes of 
chronic diarrhea should be considered, including medica
-
tions, irritable bowel syndrome, and lactose intolerance. 
The presence of nocturnal diarrhea, weight loss, anemia, or 
positive results on FOBT are inconsistent with these disor
-
ders and warrant further evaluation. AIDS-associated diar
-
rhea is discussed in Chapter 31.
A. Initial Diagnostic Tests
1. Routine laboratory tests—
Complete blood count, 
serum electrolytes, liver chemistries, calcium, phosphorus, 
albumin, thyroid-stimulating hormone, vitamin A and D 
levels, INR, erythrocyte sedimentation rate, and C-reactive 
protein should be obtained in most patients. Serologic test
-
ing for celiac disease with an IgA tissue transglutaminase 
CHRONIC DIARRHEA
Exclude:   
1.
 Causes of acute diarrhea
  
2. Lactose intolerance
  
3. Irritable bowel syndrome
  
4. Previous gastric surgery or ileal resection
                 5. Parasitic infections
                 6. Medications
                 7. Systemic disease
Fecal leukocytes and occult blood
Colonoscopy with biopsy
Small bowel imaging with barium, CT, or MR enterography
Abnormal
Cancer
Normal
Stool electrolytes, osmolality,
  weight/24 h, quantitative fat
Increased osmotic gap
Increased fecal fat
Bacterial overgrowth
Normal fecal fat
Lactose intolerance 
Sorbitol, lactulose
Laxative abuse
Normal stool weight
Factitious diarrhea
Increased stool weight
Secretory laxative abuse
(> 1000 g/24 h)
Normal osmotic gap
 
▲
Figure 15–2.
 
Decision diagram for diagnosis of causes of chronic diarrhea.
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(tTG) test may be recommended in the evaluation of most 
patients with chronic diarrhea and all patients with signs of 
malabsorption. Anemia occurs in malabsorption syn
-
dromes (folate, iron deficiency, or vitamin B
12
) as well as 
inflammatory conditions. Hypoalbuminemia is present in 
malabsorption, protein-losing enteropathies, and inflam
-
matory diseases. Hyponatremia and nonanion gap meta
-
bolic acidosis occur in secretory diarrheas. Increased 
erythrocyte sedimentation rate or C-reactive protein sug
-
gests inflammatory bowel disease.
2. Routine stool studies—
Stool sample should be analyzed 
for ova and parasites, electrolytes (to calculate osmotic 
gap), qualitative staining for fat (Sudan stain), occult blood, 
and leukocytes or lactoferrin. Parasitic infections (
Giardia
, 
E histolytica
, 
Cryptosporidia
, and 
) may be diag
-
nosed with stool antigen assays or microscopy with special 
stains. Alternatively, stool molecular diagnostic tests are 
available that screen for a panel of pathogens, providing 
results within 5 hours. As discussed previously, an increased 
osmotic gap suggests an osmotic diarrhea or disorder of 
malabsorption. A positive fecal fat stain suggests a disorder 
of malabsorption. The presence of fecal leukocytes or lac
-
toferrin may suggest inflammatory bowel disease.
3. Endoscopic examination and mucosal biopsy—
Most 
patients with chronic persistent diarrhea undergo colonos
-
copy with mucosal biopsy to exclude inflammatory bowel 
disease (including Crohn disease and ulcerative colitis), 
microscopic colitis, and colonic neoplasia. Upper endos
-
copy with small bowel biopsy is performed when a small 
intestinal malabsorptive disorder is suspected (celiac dis
-
ease, Whipple disease) from abnormal laboratory studies 
or a positive fecal fat stain. It may also be done in patients 
with advanced AIDS to document 
, 
Micro
-
sporidia
, and 
M avium-intracellulare
B. Further Studies
If the cause of diarrhea is still not apparent, further studies 
may be warranted.
1. 24-hour stool collection quantification of total weight 
and fat—
A stool weight of less than 200–300 g/24 h 
excludes diarrhea and suggests a functional disorder such 
as irritable bowel syndrome. A weight greater than 1000–
1500 g suggests a significant secretory process, including 
neuroendocrine tumors. A fecal fat determination in 
excess of 10 g/24 h confirms a malabsorptive disorder. 
Fecal elastase less than 100 mcg/g may be caused by pan
-
creatic insufficiency. (See Celiac Disease and specific tests 
for malabsorption, below.)
2. Other imaging studies—
Calcification on a plain 
abdominal radiograph confirms a diagnosis of chronic 
pancreatitis, although abdominal CT and endoscopic 
ultrasonography are more sensitive for the diagnosis of 
chronic pancreatitis as well as pancreatic cancer. Small 
intestinal imaging with CT or MRI enterography is helpful 
in the diagnosis of Crohn disease, small bowel lymphoma, 
carcinoid, and jejunal diverticula. Neuroendocrine tumors 
may be localized using somatostatin receptor scintigraphy. 
Retention of less than 11% at 7 days of intravenous 
75Se-homotaurocholate on scintigraphy suggests bile salt 
malabsorption.
3. Laboratory tests—
a. 
S
erologic tests for neuroendocrine tumors—
Secretory diarrheas due to neuroendocrine tumors are rare 
but should be considered in patients with chronic, high-
volume watery diarrhea (greater than 1 L/day) with a nor
-
mal osmotic gap that persists during fasting. Measurements 
of the secretagogues of various neuroendocrine tumors 
may be assayed, including serum chromogranin A (pan
-
creatic neuroendocrine tumors), vasoactive intestinal 
peptide (VIP) (VIPoma), calcitonin (medullary thyroid 
carcinoma), gastrin (Zollinger-Ellison syndrome), and 
urinary 5-hydroxyindoleacetic acid (5-HIAA) (carcinoid).
b. 
B
reath test—
The diagnosis of small bowel bacterial

b. 
B
The diagnosis of small bowel bacterial 
overgrowth is suggested by a noninvasive breath tests (glu
-
cose or lactulose); however, a high-rate of false-positive test 
results limits the utility of these tests. A definitive diagnosis 
of bacterial overgrowth is determined by aspirate of small 
intestinal contents for quantitative aerobic and anaerobic 
bacterial culture; however, this procedure is not available at 
most centers.
 
»
Treatment
A number of antidiarrheal agents may be used in certain 
patients with chronic diarrheal conditions and are listed 
below. Opioids are safe in most patients with chronic, sta
-
ble symptoms.
Loperamide:
 4 mg orally initially, then 2 mg after each 
loose stool (maximum: 16 mg/day).
Diphenoxylate with atropine:
 One tablet orally three 
or four times daily as needed.
Codeine 
and
 deodorized tincture of opium:
 Because 
of potential habituation, these drugs are avoided except in 
cases of chronic, intractable diarrhea. Codeine may be 
given in a dosage of 15–60 mg orally every 4 hours; tincture 
of opium, 0.3–1.2 mL orally every 6 hours as needed.
Clonidine:
 Alpha-2-adrenergic agonists inhibit intesti
-
nal electrolyte secretion. Clonidine, 0.1–0.3 mg orally twice 
daily, or a clonidine patch, 0.1–0.2 mg/day, may help in 
some patients with secretory diarrheas, diabetic diarrhea, 
or cryptosporidiosis.
Octreotide:
 This somatostatin analog stimulates intes
-
tinal fluid and electrolyte absorption and inhibits intestinal 
fluid secretion and the release of gastrointestinal peptides. 
It is given for secretory diarrheas due to neuroendocrine 
tumors (VIPomas, carcinoid). Effective doses range from 
50 mcg to 250 mcg subcutaneously three times daily.
Bile salt binders:
 Cholestyramine or colestipol (2–4 g 
once to three times daily) or colesevelam (625 mg, 1–3 
tablets once or twice daily) may be useful in patients with 
bile salt-induced diarrhea, which may be idiopathic or 
secondary to intestinal resection or ileal disease.
Camilleri M et al. Pathophysiology, evaluation, and management 
of chronic watery diarrhea. Gastroenterology. 2017 Feb;
 
152(3):515–32. [PMID: 27773805]
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DuPont HL. Persistent diarrhea: a clinical review. JAMA. 2016 
Jun 28;315(24):2712–23. [PMID: 27357241]
Schiller LR et al. Chronic diarrhea: diagnosis and management. 
Clin Gastroenterol Hepatol. 2017 Feb;15(2):182–93. [PMID: 
27496381]
GASTROINTESTINAL BLEEDING
1. Acute Upper Gastrointestinal Bleeding
 
»
Hematemesis (bright red blood or “coffee grounds”).
 
»
Melena in most cases; hematochezia in massive 
upper gastrointestinal bleeds.
 
»
Volume status to determine severity of blood loss; 
hematocrit is a poor early indicator of blood loss.
 
»
Endoscopy diagnostic and may be therapeutic.
 
»
There are over 250,000 hospitalizations a year in the United 
States for acute upper gastrointestinal bleeding. In the 
United States, the mortality rate for nonvariceal upper gas
-
trointestinal bleeding has declined steadily over the past 
20 years to 2.1% in 2009. Mortality is higher in patients 
who are older than age 60 years and in patients in whom 
bleeding develops during hospitalization. Patients seldom 
die of exsanguination but rather of complications from an 
underlying disease.
The most common presentation of upper gastrointesti
-
nal bleeding is hematemesis or melena. Hematemesis may 
be either bright red blood or brown “coffee grounds” mate
-
rial. Melena develops after as little as 50–100 mL of blood 
loss in the upper gastrointestinal tract, whereas hemato
-
chezia requires a loss of more than 1000 mL. Although 
hematochezia generally suggests a lower bleeding source 
(eg, colonic), severe upper gastrointestinal bleeding may 
present with hematochezia in 10% of cases.
Upper gastrointestinal bleeding is self-limited in 80% of 
patients; urgent medical therapy and endoscopic evalua
-
tion are obligatory in the rest. Patients with bleeding more 
than 48 hours prior to presentation have a low risk of 
recurrent bleeding.
 
»
Etiology
Acute upper gastrointestinal bleeding may originate from a 
number of sources. These are listed in order of their fre
-
quency and discussed in detail below.
A. Peptic Ulcer Disease
Peptic ulcers account for 40% of major upper gastrointesti
-
nal bleeding with an overall mortality rate of less than 5%. 
In North America, the incidence of bleeding from ulcers is 
declining due to eradication of 
H pylori
 and prophylaxis 
with proton pump inhibitors in high-risk patients.
B. Portal Hypertension
Portal hypertension accounts for 10–20% of upper gastro
-
intestinal bleeding. Bleeding usually arises from esopha
-
geal varices and less commonly gastric or duodenal varices 
or portal hypertensive gastropathy. Approximately 25% of 
patients with cirrhosis have medium to large esophageal 
varices, of whom 30% experience acute variceal bleeding 
within a 2-year period. Due to improved care, the hospital 
mortality rate has declined over the past 20 years from 40% 
to 15%. Nevertheless, a mortality rate of 60–80% is expected 
at 1–4 years due to recurrent bleeding or other complica
-
tions of chronic liver disease.
C. Mallory-Weiss Tears
Lacerations of the gastroesophageal junction cause 5–10% 
of cases of upper gastrointestinal bleeding. Many patients 
report a history of heavy alcohol use or retching. Less than 
10% have continued or recurrent bleeding.
D. Vascular Anomalies
Vascular anomalies are found throughout the gastrointesti
-
nal tract and may be the source of chronic or acute gastro
-
intestinal bleeding. They account for 7% of cases of acute 
upper tract bleeding. The most common are 
angioectasias
 
(angiodysplasias) which are 1–10 mm distorted, aberrant 
submucosal vessels caused by chronic, intermittent 
obstruction of submucosal veins. They have a bright red 
stellate appearance and occur throughout the gastrointestinal 
tract but most commonly in the right colon. 
Telangiectasias
 
are small, cherry red lesions caused by dilation of venules 
that may be part of systemic conditions (hereditary hemor
-

-
rhagic telangiectasia, CREST syndrome) or occur sporadi
-
cally. The 
Dieulafoy lesion
 is an aberrant, large-caliber 
submucosal artery, most commonly in the proximal stom
-
ach that causes recurrent, intermittent bleeding.
E. Gastric Neoplasms
Gastric neoplasms result in 1% of upper gastrointestinal 
hemorrhages.
F. Erosive Gastritis
Because this process is superficial, it is a relatively unusual 
cause of severe gastrointestinal bleeding (less than 5% of cases) 
and more commonly results in chronic blood loss. Gastric 
mucosal erosions are due to NSAIDs, alcohol, or severe medi
-
cal or surgical illness (stress-related mucosal disease).
G. Erosive Esophagitis
Severe erosive esophagitis due to chronic gastroesophageal 
reflux may rarely cause significant upper gastrointestinal 
bleeding, especially in patients who are bed bound 
long-term.
H. Others
An aortoenteric fistula complicates 2% of abdominal aortic 
grafts or, rarely, can occur as the initial presentation of a 
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previously untreated aneurysm. Unusual causes of upper 
gastrointestinal bleeding include hemobilia (from hepatic 
tumor, angioma, penetrating trauma), pancreatic malig
-
nancy, and pseudoaneurysm (hemosuccus pancreaticus).
 
»
Initial Evaluation & Treatment
A. Stabilization
The initial step is assessment of the hemodynamic status. A 
systolic blood pressure lower than 100 mm Hg identifies a 
high-risk patient with severe acute bleeding. A heart rate 
over 100 beats/min with a systolic blood pressure over 
100 mm Hg signifies moderate acute blood loss. A normal 
systolic blood pressure and heart rate suggest relatively 
minor hemorrhage. Postural hypotension and tachycardia 
are useful when present but may be due to causes other 
than blood loss. Because the hematocrit may take 24–72 hours 
to equilibrate with the extravascular fluid, it is not a reliable 
indicator of the severity of acute bleeding.
In patients with significant bleeding, two 18-gauge or 
larger intravenous lines should be started prior to further 
diagnostic tests. Blood is sent for complete blood count, 
prothrombin time with international normalized ratio 
(INR), serum creatinine, liver enzymes, and blood typing 
and screening (in anticipation of the possible need for 
transfusion). In patients without hemodynamic compro
-
mise or overt active bleeding, aggressive fluid repletion can 
be delayed until the extent of the bleeding is further clari
-
fied. Patients with evidence of hemodynamic compromise 
are given 0.9% saline or lactated Ringer injection and 
cross-matched for 2–4 units of packed red blood cells. It is 
rarely necessary to administer type-specific or O-negative 
blood. Central venous pressure monitoring is desirable in 
some cases, but line placement should not interfere with 
rapid volume resuscitation.
Placement of a nasogastric tube is not routinely recom
-
mended in clinical guidelines but may be helpful in the ini
-
tial assessment and triage of selected patients with suspected 
active upper tract bleeding. The aspiration of red blood or 
“coffee grounds” confirms an upper gastrointestinal source 
of bleeding, though up to 18% of patients with confirmed 
upper tract sources of bleeding have nonbloody aspirates—
especially when bleeding originates in the duodenum. 
Erythromycin (250 mg) administered intravenously 30 minutes 
prior to upper endoscopy promotes gastric emptying and 
may improve the quality of endoscopic evaluation when 
substantial amounts of blood or clot in the stomach is sus
-
pected. Efforts to stop or slow bleeding by gastric lavage 
with large volumes of fluid are of no benefit and expose the 
patient to an increased risk of aspiration.
B. Blood Replacement
The amount of fluid and blood products required is based 
on assessment of vital signs, evidence of active bleeding 
from nasogastric aspirate, and laboratory tests. Sufficient 
packed red blood cells should be given to maintain a hemo
-
globin of no lower than 7–9 g/dL, based on the patient’s 
hemodynamic status, comorbidities (especially cardiovas
-
cular disease), and presence of continued bleeding. In the 
absence of continued bleeding, the hemoglobin should rise 
approximately 1 g/dL for each unit of transfused packed 
red cells. Transfusion of blood should not be withheld from 
patients with massive active bleeding regardless of the 
hemoglobin value. In patients with severe gastrointestinal 
bleeding, it is desirable to transfuse blood before the hemo
-
globin reaches 7 g/dL to prevent decreases below that level 
occurring from hemodilution with fluid resuscitation. In 
actively bleeding patients, platelets are transfused if the 
platelet count is under 50,000/mcL and considered if there 
is impaired platelet function due to aspirin or clopidogrel 
use (regardless of the platelet count). Uremic patients (who 
also have dysfunctional platelets) with active bleeding are

also have dysfunctional platelets) with active bleeding are 
given three doses of desmopressin (DDAVP), 0.3 mcg/kg 
intravenously, at 12-hour intervals. Fresh frozen plasma is 
administered for actively bleeding patients with a coagu
-
lopathy and an INR greater than 1.8; however, endoscopy 
may be performed safely if the INR is less than 2.5. In the 
face of massive bleeding, administration of four factor pro
-
thrombin complex concentrates is preferred (rather than 
fresh frozen plasma) because it is more rapid and effective 
at correcting the INR and requires a smaller volume. Some 
patients with ongoing, serious gastrointestinal bleeding 
have taken the direct thrombin inhibitor, dabigatran, 
within the previous 12–24 hours; reversal with the intrave
-
nous monoclonal antibody idarucizumab may be consid
-
ered. For patients who have taken direct or indirect factor 
Xa inhibitors, andexanet is a potential future reversal agent 
(not yet FDA approved).
C. Initial Triage
A preliminary assessment of risk based on several clinical 
factors aids in the resuscitation as well as the rational triage 
of the patient. Clinical predictors of increased risk of 
rebleeding and death include age over 60 years, comorbid 
illnesses, systolic blood pressure less than 100 mm Hg, 
pulse greater than 100 beats/min, and bright red blood in 
the nasogastric aspirate or on rectal examination.
1. High risk—
Patients with active bleeding manifested by 
hematemesis or bright red blood on nasogastric aspirate, 
shock, persistent hemodynamic derangement despite fluid 
resuscitation, serious comorbid medical illness, or evi
-
dence of advanced liver disease require admission to an 
intensive care unit (ICU). After adequate resuscitation, 
endoscopy should be performed within 2–24 hours in most 
patients, but may be delayed in selected patients with seri
-
ous comorbidities (eg, acute coronary syndrome) who do 
not have signs of continued bleeding.
2. Low to moderate risk—
All other patients are admitted 
to a step-down unit or medical ward after appropriate sta
-
bilization for further evaluation and treatment. Patients 
without evidence of active bleeding undergo nonemergent 
endoscopy usually within 12–24 hours.
 
»
Subsequent Evaluation & Treatment
Specific treatment of the various causes of upper gastroin
-
testinal bleeding is discussed elsewhere in this chapter. The 
following general comments apply to most patients with 
bleeding.
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The clinician’s impression of the bleeding source is cor
-
rect in only 40% of cases. Signs of chronic liver disease 
implicate bleeding due to portal hypertension, but a differ
-
ent lesion is identified in 25% of patients with cirrhosis. A 
history of dyspepsia, NSAID use, or peptic ulcer disease 
suggests peptic ulcer. Acute bleeding preceded by heavy 
alcohol ingestion or retching suggests a Mallory-Weiss tear, 
though most of these patients have neither.
A. Upper Endoscopy
Virtually all patients with upper tract bleeding should 
undergo upper endoscopy within 24 hours of arriving in 
the emergency department. The benefits of endoscopy in 
this setting are threefold.
1. To identify the source of bleeding—
The appropriate 
acute and long-term medical therapy is determined by the 
cause of bleeding. Patients with portal hypertension will be 
treated differently from those with ulcer disease. If surgery 
or radiologic interventional therapy is required for uncon
-
trolled bleeding, the source of bleeding identified at endos
-
copy will determine the approach.
2. To determine the risk of rebleeding and guide triage—
Patients with a nonbleeding Mallory-Weiss tear, esophagi
-
tis, gastritis, and ulcers that have a clean, white base have a 
very low risk (less than 5%) of rebleeding. Patients with one 
of these findings who are younger than 60 years, without 
hemodynamic instability or transfusion requirement, with
-
out serious coexisting illness, and who have stable social 
support may be discharged from the emergency depart
-
ment or medical ward after endoscopy with outpatient 
follow-up. All others with one of these low-risk lesions 
should be observed on a medical ward for 24–48 hours. 
Patients with ulcers that are actively bleeding or have a vis
-
ible vessel or adherent clot, or who have variceal bleeding 
usually require at least a 3-day hospitalization with closer 
initial observation in an ICU or step-down unit.
3. To render endoscopic therapy—
Hemostasis can be 
achieved in actively bleeding lesions with endoscopic 
modalities such as cautery, injection, or endoclips. About 
90% of bleeding or nonbleeding varices can be effectively 
treated immediately with injection of a sclerosant or appli
-
cation of rubber bands to the varices. Similarly, 90% of 
bleeding ulcers, angiomas, or Mallory-Weiss tears can be 
controlled with either injection of epinephrine, direct cau
-
terization of the vessel by a heater probe or multipolar 
electrocautery probe, or application of an endoclip. Certain 
nonbleeding lesions such as ulcers with visible blood ves
-
sels, and angioectasias are also treated with these therapies. 
Specific endoscopic therapy of varices, peptic ulcers, and 
Mallory-Weiss tears is dealt with elsewhere in this chapter.
B. Acute Pharmacologic Therapies
1. Acid inhibitory therapy—
Intravenous proton pump 
 (esomeprazole or pantoprazole, 80 mg bolus, 
followed by 8 mg/h continuous infusion for 72 hours) 
reduce the risk of rebleeding in patients with peptic ulcers 
with high-risk features (active bleeding, visible vessel, or 
adherent clot) after endoscopic treatment. 
Oral proton 
 (omeprazole, esomeprazole, or pantopra
-
zole 40 mg; lansoprazole or dexlansoprazole 30–60 mg) 
once or twice daily are sufficient for lesions at low-risk for 
rebleeding (eg, esophagitis, gastritis, clean-based ulcers, 
and Mallory-Weiss tears).
Administration of continuous intravenous proton 
pump inhibitor 
before
 endoscopy results in a decreased 
number of ulcers with lesions that require endoscopic 
therapy. It therefore is standard clinical practice at many 
institutions to administer either an intravenous or a high-
dose oral proton pump inhibitor prior to endoscopy in 
patients with significant upper gastrointestinal bleeding. 
Based on the findings during endoscopy, the intravenous 
proton pump inhibitor may be continued or discontinued.
2. Octreotide—

Continuous intravenous infusion of octreo
-
tide (100 mcg bolus, followed by 50–100 mcg/h) reduces 
splanchnic blood flow and portal blood pressures and is 
effective in the initial control of bleeding related to portal 
hypertension. It is administered promptly to all patients 
with active upper gastrointestinal bleeding and evidence of 
liver disease or portal hypertension until the source of 
bleeding can be determined by endoscopy. In countries 
where it is available, terlipressin may be preferred to octreo
-
tide for the treatment of bleeding related to portal hyperten
-
sion because of its sustained reduction of portal and 
variceal pressures and its proven reduction in mortality.
C. Other Treatment
1. Intra-arterial embolization—
Angiographic treatment is 
used in patients with persistent bleeding from ulcers, 
angiomas, or Mallory-Weiss tears who have failed endo
-
scopic therapy and are poor operative risks.
2. Transvenous intrahepatic portosystemic shunts 
(TIPS)—
Placement of a wire stent from the hepatic vein 
through the liver to the portal vein provides effective 
decompression of the portal venous system and control of 
acute variceal bleeding. It is indicated in patients in whom 
endoscopic modalities have failed to control acute variceal 
bleeding.
Abougergi MS et al. The in-hospital mortality rate for upper GI 
hemorrhage has decreased over 2 decades in the United 
States: a nationwide analysis. Gastrointest Endosc. 2015 Apr;
 
81(4):882–8. [PMID: 25484324]
Aisenberg J. The specific direct oral anticoagulant reversal 
agents: their current status and future place in gastroenterol
-
ogy practice. Am J Gastroenterol Suppl. 2016 Jul;3:36–44.
Jairath V et al. Restrictive versus liberal blood transfusion for 
acute upper gastrointestinal bleeding (TRIGGER): a prag
-
matic, open-label, cluster randomized feasibility trial. Lancet. 
2015 Jul 11;386(9989):137–44. [PMID: 25956718]
Kumar NL et al. Initial management and timing of endoscopy in 
nonvariceal upper GI bleeding. Gastrointest Endosc. 2016 Jul;
 
84(1):10–17. [PMID: 26944336]
Laursen SB et al. Relationship between timing of endoscopy and 
mortality in patients with peptic ulcer bleeding: a nationwide 
cohort study. Gastrointest Endosc. 2017 May;85(5):936–44. 
[PMID: 27623102]
Nable JV et al. Gastrointestinal bleeding. Emerg Med Clin North Am. 
2016 May;34(2):309–25. [PMID: 27133246]
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2. Acute Lower Gastrointestinal Bleeding
 
»
Hematochezia usually present.
 
»
Ten percent of cases of hematochezia due to 
upper gastrointestinal source.
 
»
Evaluation with colonoscopy in stable patients.
 
»
Massive active bleeding calls for evaluation with 
sigmoidoscopy, upper endoscopy, angiography, 
or nuclear bleeding scan.
 
»
Lower gastrointestinal bleeding is defined as that arising 
below the ligament of Treitz, ie, the small intestine or 
colon; however, up to 95% of cases arise from the colon. 
The severity of lower gastrointestinal bleeding ranges from 
mild anorectal bleeding to massive, large-volume hemato
-
chezia. Bright red blood that drips into the bowl after a 
bowel movement or is mixed with solid brown stool signi
-
fies mild bleeding, usually from an anorectosigmoid 
source, and can be evaluated in the outpatient setting. In 
patients hospitalized with gastrointestinal bleeding, lower 
tract bleeding is one-third as common as upper gastroin
-
testinal hemorrhage and tends to have a more benign 
course. Patients hospitalized with lower gastrointestinal 
tract bleeding are less likely to present with shock or ortho
-
stasis (less than 20%) or to require transfusions (less than 
40%). Spontaneous cessation of bleeding occurs in over 
75% of cases, and hospital mortality is less than 4%.
 
»
Etiology
The cause of these lesions depends on both the age of the 
patient and the severity of the bleeding. In patients under 
50 years of age, the most common causes are infectious 
colitis, anorectal disease, and inflammatory bowel disease. 
In older patients, significant hematochezia is most often 
seen with diverticulosis, angioectasias, malignancy, or 
ischemia. There is an increased risk of lower gastrointesti
-
nal bleeding in patients taking aspirin, nonaspirin anti
-
platelet agents, and NSAIDs.
A. Diverticulosis
Hemorrhage occurs in 3–5% of all patients with diverticu
-
losis and is the most common cause of major lower tract 
bleeding, accounting for over 50% of cases. Diverticular 
bleeding usually presents as acute, painless, large-volume 
maroon or bright red hematochezia in patients over age 
50 years. More than 95% of cases require less than 4 units 
of blood transfusion. Bleeding subsides spontaneously in 
80% but may recur in up to 25% of patients.
B. Angioectasias
Angioectasias (angiodysplasias) occur throughout the 
upper and lower intestinal tracts and cause painless bleed
-
ing ranging from melena or hematochezia to occult blood 
loss. They are responsible for 5% of cases of lower gastro
-
intestinal bleeding, where they are most often seen in the 
cecum and ascending colon. They are flat, red lesions 
(2–10 mm) with ectatic peripheral vessels radiating from 
a central vessel, and are most common in patients over 
 
70 years and in those with chronic renal failure. Bleeding 
in younger patients more commonly arises from the small 
intestine.
 Ectasias can be identified in up to 6% of persons over 
age 60 years, so the mere presence of ectasias does not 
prove that the lesion is the source of bleeding, since active 
bleeding is seldom seen.
C. Neoplasms
Benign polyps and carcinoma are associated with chronic 
occult blood loss or intermittent anorectal hematochezia. 
Furthermore, they may cause up to 7% of acute lower gas
-
trointestinal hemorrhage. After endoscopic removal of 
colonic polyps, important bleeding may occur up to 2 weeks 
later in 0.3% of patients. In general, prompt colonoscopy is 
recommended to treat postpolypectomy hemorrhage and 
minimize the need for transfusions.
D. Inflammatory Bowel Disease
Patients with inflammatory bowel disease (especially ulcer
-
ative colitis) often have diarrhea with variable amounts of

-
ative colitis) often have diarrhea with variable amounts of 
hematochezia. Bleeding varies from occult blood loss to 
recurrent hematochezia usually mixed with stool. Symp
-
toms of abdominal pain, tenesmus, and urgency are often 
present.
E. Anorectal Disease
Anorectal disease (hemorrhoids, fissures) usually results in 
small amounts of bright red blood noted on the toilet 
paper, streaking of the stool, or dripping into the toilet 
bowl; clinically significant blood loss can sometimes occur. 
Hemorrhoids are the source in 10% of patients admitted 
with lower bleeding. Rectal ulcers may account for up to 
8% of lower bleeding, usually in elderly or debilitated 
patients with constipation.
F. Ischemic Colitis
This condition is seen commonly in older patients, most 
of whom have atherosclerotic disease. Most cases occur 
spontaneously due to transient episodes of nonocclusive 
ischemia. Ischemic colitis may also occur in 5% of 
patients after surgery for ileoaortic or abdominal aortic 
aneurysm. In younger patients, colonic ischemia may 
develop due to vasculitis, coagulation disorders, estrogen 
therapy, and long-distance running. Ischemic colitis 
results in hematochezia or bloody diarrhea associated 
with mild cramps. In most patients, the bleeding is mild 
and self-limited.
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G. Others
Radiation-induced proctitis causes anorectal bleeding that 
may develop months to years after pelvic radiation. Endos
-
copy reveals multiple rectal telangiectasias. Acute infec
-
tious colitis (see Acute Diarrhea, above) commonly causes 
bloody diarrhea. Rare causes of lower tract bleeding 
include vasculitic ischemia, solitary rectal ulcer, NSAID-
induced ulcers in the small bowel or right colon, small 
bowel diverticula, and colonic varices.
 
»
The color of the stool helps distinguish upper from lower 
gastrointestinal bleeding, especially when observed by the 
clinician. Brown stools mixed or streaked with blood pre
-
dict a source in the rectosigmoid or anus. Large volumes of 
bright red blood suggest a colonic source; maroon stools 
imply a lesion in the right colon or small intestine; and 
black stools (melena) predict a source proximal to the liga
-
ment of Treitz. Although 10% of patients admitted with 
self-reported hematochezia have an upper gastrointestinal 
source of bleeding (eg, peptic ulcer), this almost always 
occurs in the setting of massive hemorrhage with hemody
-
namic instability. Painless large-volume bleeding usually 
suggests diverticular bleeding. Bloody diarrhea associated 
with cramping abdominal pain, urgency, or tenesmus is 
characteristic of inflammatory bowel disease, infectious 
colitis, or ischemic colitis.
Important considerations in management include exclu
-
sion of an upper tract source, anoscopy and sigmoidos
-
copy, colonoscopy, nuclear bleeding scans and angiography, 
and small intestine push enteroscopy or capsule imaging.
1. Exclusion of an upper tract source—
A nasogastric tube 
with aspiration should be considered, especially in patients 
with hemodynamic compromise. Aspiration of red blood 
or dark brown (“coffee grounds”) guaiac-positive material 
strongly implicates an upper gastrointestinal source of 
bleeding. Upper endoscopy should be performed in most 
patients presenting with hematochezia and hemodynamic 
instability to exclude an upper gastrointestinal source 
before proceeding with evaluation of the lower gastrointes
-
tinal tract.
2. Anoscopy and sigmoidoscopy—
In otherwise healthy 
patients without anemia under age 45 years with small-
volume bleeding, anoscopy and sigmoidoscopy are per
-
formed to look for evidence of anorectal disease, 
inflammatory bowel disease, or infectious colitis. If a lesion 
is found, no further evaluation is needed immediately unless 
the bleeding persists or is recurrent. In patients over age 
45 years with small-volume hematochezia, the entire colon 
must be evaluated with colonoscopy to exclude tumor.
3. Colonoscopy—
In patients with acute, large-volume 
bleeding requiring hospitalization, colonoscopy is the pre
-
ferred initial study in most cases. The bowel first is purged 
rapidly by administration of a high-volume colonic lavage 
solution, given until the effluent is clear of blood and 
clots (4–8 L of GoLYTELY , CoLYTE, NuLYTE given 
orally or 1 L every 30 minutes over 2–5 hours by nasogas
-
tric tube). For patients with stable vital signs and whose 
lower gastrointestinal bleeding appears to have stopped 
(more than 75% of patients), colonoscopy can be per
-
formed electively within 24 hours of admission after appro
-
priate resuscitation and bowel cleansing. For patients who 
are resuscitated and hemodynamically stable but have signs 
of continued active bleeding during bowel preparation (less 
than 25% of patients), early colonoscopy (within 12–24 hours) 
should be performed. Preferably, this colonoscopy should 
be done within 1–2 hours of completing the bowel purga
-
tive when the bowel discharge is without clots. The proba
-
ble site of bleeding can be identified in 70–85% of patients, 
and a high-risk lesion can be identified and treated in up to 
25%. Early colonoscopy is associated with shorter 
hospitalizations.

-
4. Nuclear bleeding scans and angiography—
In patients 
with massive lower gastrointestinal bleeding manifested by 
continued hemodynamic instability and hematochezia 
despite resuscitative efforts and in patients in whom colo
-
noscopic hemostasis was unsuccessful, urgent radiographic 
imaging is warranted. Technetium-labeled red blood cell 
scanning can detect significant active bleeding and, in some 
cases, can localize the source to the small intestine, right 
colon, or left colon. Because most bleeding is slow or inter
-
mittent, less than half of nuclear studies are diagnostic and 
the accuracy of localization is poor. Increasingly, multide
-
tector CT angiography is used instead of scintigraphy in an 
attempt to localize active bleeding. If scintigraphy or CT 
angiography demonstrates active bleeding, urgent angiog
-
raphy is performed in an attempt to localize the bleeding 
site and make embolization therapy possible. In patients 
with massive lower gastrointestinal bleeding and continued 
hemodynamic instability, urgent angiography may be per
-
formed without first attempting scintigraphy or CT 
5. Small intestine push enteroscopy or capsule imag
-
ing—
Up to 5% of acute episodes of lower gastrointestinal 
bleeding arise from the small intestine, eluding diagnostic 
evaluation with upper endoscopy and colonoscopy. 
Because of the difficulty of examining the small intestine 
and its relative rarity as a source of acute bleeding, evalua
-
tion of the small bowel is not usually pursued in patients 
during the initial episode of acute lower gastrointestinal 
bleeding. However, the small intestine is investigated in 
patients with unexplained recurrent hemorrhage of obscure 
origin.
 
»
Treatment
Initial stabilization, blood replacement, and triage are 
managed in the same manner as described above in Acute 
Upper Gastrointestinal Bleeding. In patients with ongoing 
bleeding, consideration should be given to discontinuation 
of antiplatelet agents and anticoagulants. Compared to 
persons who do not take long-term low-dose aspirin, the 
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incidence of recurrent lower gastrointestinal bleeding 
within 5 years was higher in those who resumed low-dose 
aspirin postdischarge (18.9% vs 6.9%); however, these 
patients had a lower risk of serious cardiovascular events 
(22.8% vs 36.5%) and death (8.2% vs 26.7%).
A. Therapeutic Colonoscopy
High-risk lesions (eg, angioectasia or diverticulum, rectal 
ulcer with active bleeding, or a visible vessel) may be treated 
endoscopically with epinephrine injection, cautery (bipolar 
or heater probe), or application of metallic endoclips or 
bands. In diverticular hemorrhage with high-risk lesions 
identified at colonoscopy, rebleeding occurs in half of 
untreated patients compared with virtually no rebleeding in 
patients treated endoscopically. Radiation proctitis is effec
-
tively treated with applications of cautery therapy to the 
rectal telangiectasias, preferably with an argon plasma 
coagulator.
B. Intra-arterial Embolization
When a bleeding lesion is identified, angiography with 
selective embolization achieves immediate hemostasis in 
more than 95% of patients. Major complications occur in 
5% (mainly ischemic colitis) and rebleeding occurs in up to 
25%.
C. Surgical Treatment
Emergency surgery is required in less than 5% of patients 
with acute lower gastrointestinal bleeding due to the effi
-
cacy of colonoscopic and angiographic therapies. It is 
indicated in patients with ongoing bleeding that requires 
more than 6 units of blood within 24 hours or more than 
10 total units in whom attempts at endoscopic or angio
-
graphic therapy failed. Most such hemorrhages are caused 
by a bleeding diverticulum or angioectasia.
Surgery may also be indicated in patients with two or 
more hospitalizations for diverticular hemorrhage depend
-
ing on the severity of bleeding and the patient’s other 
comorbid conditions.
Aoki T et al. Recurrence and mortality among patients hospital
-
ized for acute lower gastrointestinal bleeding. Clin Gastroen
-
terol Hepatol. 2015 Mar;13(3):488–94. [PMID: 24997327]
Becq A et al. Hemorrhagic angiodysplasia of the digestive tract: 
pathogenesis, diagnosis, and management. Gastrointest 
Endosc. 2017 Nov 86(5):792–806. [PMID: 28554655]
Chan FK et al. Risks of bleeding recurrence and cardiovascular 
events with continued aspirin use after lower gastrointestinal 
hemorrhage. Gastroenterology. 2016 Aug;151(2):271–7. 
[PMID: 27130815]
Gralnek IM et al. Acute lower gastrointestinal bleeding. N Engl J 
Med. 2017 Mar 16;376(11):1054–63. [PMID: 28296600]
Nagata N et al. Safety and effectiveness of early colonoscopy in 
management of acute lower gastrointestinal bleeding on the 
basis of propensity score matching analysis. Clin Gastroen
-
terol Hepatol. 2016 Apr;14(4):558–64. [PMID: 26492844]
3. Small Bowel Bleeding
Bleeding from the small intestine can be overt or occult. 
Overt
 small bowel bleeding manifests as melena, maroon 
stools, or bright red blood per rectum. Up to 5–10% of 
patients admitted to hospitals with clinically overt gastro
-
intestinal bleeding do not have a cause identified on upper 
endoscopy or colonoscopy and are presumed to have a 
small bowel source. In up to one-third of cases, however, a 
source of bleeding has been overlooked in the upper or 
lower tract on prior endoscopic studies. 
Occult
 small bowel 
bleeding refers to bleeding that is manifested by recurrent 
positive FOBTs or FITs or recurrent iron deficiency ane
-
mia, or both in the absence of visible blood loss. Occult 
small bowel bleeding is discussed in the next section.
The likely etiology of overt small bowel bleeding 
depends on the age of the patient. The most common 
causes of small intestinal bleeding in patients younger than 
40 years are neoplasms (stromal tumors, lymphomas, ade
-
nocarcinomas, carcinoids), Crohn disease, celiac disease, 
and Meckel diverticulum. These disorders also occur in 
patients over age 40; however, angioectasias and NSAID-

-
induced ulcers are far more common.
 
»
Evaluation of Small Bowel Bleeding
The evaluation of overt small bowel bleeding depends on 
the age and overall health status of the patient, associated 
symptoms, and severity of the bleeding. Before pursuing 
evaluation of the small intestine, upper endoscopy and 
colonoscopy should be repeated to ascertain that a lesion in 
these regions has not been overlooked. Repeat upper 
endoscopy should be performed with a longer instrument 
(usually a colonoscope) to evaluate the distal duodenum. If 
these studies are unrevealing and the patient is hemody
-
namically stable, capsule endoscopy should be performed 
to evaluate the small intestine. Further management 
depends on the capsule endoscopic findings (most com
-
monly, angioectasias (25%), ulcers (10–25%), and neo
-
plasms (1–10%). Abdominal CT may be considered to 
exclude a hepatic or pancreatic source of bleeding. CT 
enterography may be considered if capsule endoscopy is 
unrevealing, since it is more sensitive for the detection of 
small bowel neoplasms. Laparotomy is warranted if a small 
bowel tumor is identified by capsule endoscopy or radio
-
graphic studies. Most other lesions identified by capsule 
imaging can be further evaluated with enteroscopes that 
use overtubes with balloons to advance the scope through 
most of the small intestine in a forward and retrograde 
direction (balloon-assisted enteroscopy). Neoplasms can 
be biopsied or resected, and angioectasias may be 
cauterized.
For massive or hemodynamically significant acute 
bleeding, urgent angiography is recommended (instead of 
capsule endoscopy) for localization and possible emboli
-
zation of a bleeding vascular abnormality. For hemody
-
namically stable overt bleeding, CT angiography may be 
useful to localize bleeding and guide other interventions 
(enteroscopy or angiography with embolization). A 
nuclear scan for Meckel diverticulum should be obtained 
in patients under age 30. With the advent of capsule imag
-
ing and advanced endoscopic technologies for evaluating 
and treating bleeding lesions in the small intestine, intra
-
operative enteroscopy of the small bowel is seldom 
required.
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4. Occult Gastrointestinal Bleeding
Occult gastrointestinal bleeding refers to bleeding that is 
not apparent to the patient. Chronic gastrointestinal blood 
loss of less than 100 mL/day may cause no appreciable 
change in stool appearance. Thus, occult bleeding in an 
adult is identified by a positive FOBT, FIT, or by iron defi
-
ciency anemia in the absence of visible blood loss. FOBT or 
FIT may be performed in patients with gastrointestinal 
symptoms or as a screening test for colorectal neoplasia 
(see Chapter 39). From 2% to 6% of patients in screening 
programs have a positive FOBT or FIT.
In the United States, 2% of men and 5% of women 
have iron deficiency anemia (serum ferritin less than 
30–45 mcg/L). In premenopausal women, iron deficiency 
anemia is most commonly attributable to menstrual and 
pregnancy-associated iron loss; however, a gastrointestinal 
source of chronic blood loss is present in 10%. Occult 
blood loss may arise from anywhere in the gastrointestinal 
tract. Among men and postmenopausal women, a poten
-
tial gastrointestinal cause of blood loss can be identified in 
the colon in 15–30% and in the upper gastrointestinal tract 
in 35–55%; a malignancy is present in 10%. Iron deficiency 
on rare occasions is caused by malabsorption (especially 
celiac disease) or malnutrition. The most common causes 
of occult bleeding with iron deficiency are (1) neoplasms; 
(2) vascular abnormalities (angioectasias); (3) acid-peptic 
lesions (esophagitis, peptic ulcer disease, erosions in hiatal 
hernia); (4) infections (nematodes, especially hookworm; 
tuberculosis); (5) medications (especially NSAIDs or 
aspirin); and (6) other causes such as inflammatory bowel 
disease.
 
»
Evaluation of Occult Bleeding
Asymptomatic adults with positive FOBTs or FITs that are 
performed for routine colorectal cancer screening should 
undergo colonoscopy (see Chapter 39). All symptomatic 
adults with positive FOBTs or FITs or iron deficiency ane
-
mia should undergo evaluation of the lower and upper 
gastrointestinal tract with colonoscopy and upper endos
-
copy, unless the anemia can be definitively ascribed to a 
nongastrointestinal source (eg, menstruation, blood dona
-
tion, or recent surgery). Patients with iron deficiency ane
-
mia should be evaluated for possible celiac disease with 
either IgA anti-tissue transglutaminase or duodenal biopsy. 
After evaluation of the upper and lower gastrointestinal 
tract with upper endoscopy and colonoscopy, the origin of 
occult bleeding remains unexplained in 30–50% of patients. 
In many of these patients, a source for occult bleeding from 
a small intestine source is suspected.
In patients younger than 60 years with unexplained 
occult bleeding or iron deficiency after upper endoscopy 
and colonoscopy, it is recommended to pursue further 
evaluation of the small intestine for a source of obscure-
occult bleeding in order to exclude a small intestinal neo
-
plasm or inflammatory bowel disease. Patients over age 60 
with obscure-occult bleeding who have a normal initial 
endoscopic evaluation and no other worrisome symptoms 
or signs (eg, abdominal pain, weight loss) most commonly 
have blood loss from small intestine angioectasias, which 
may be clinically unimportant. Therefore, it is reasonable 
to give an empiric trial of iron supplementation and 
observe the patient for evidence of clinically significant 
bleeding. For anemia that responds poorly to iron supple
-
mentation or recurrent or persistent chronic occult gastro
-
intestinal blood loss, further evaluation is pursued for a 
source of obscure-occult bleeding with capsule endoscopy. 
If a small intestine source is identified, push enteroscopy, 
balloon-assisted enteroscopy, abdominal CT, angiography, 
or laparotomy are pursued, as indicated. When possible, 
antiplatelet agents (aspirin, NSAIDs, clopidogrel) should 
be discontinued. Patients with occult bleeding without a

be discontinued. Patients with occult bleeding without a 
bleeding source identified after upper endoscopy, colonos
-
copy, and capsule endoscopy have a low risk of recurrent 
bleeding and usually can be managed with close 
ASGE Standards of Practice Committee; Gurudu SR et al. The 
role of endoscopy in the management of suspected small-
bowel bleeding. Gastrointest Endosc. 2017 Jan;85(1):22–31. 
[PMID: 27374798]
ASGE Technology Committee; Chauhan SS et al. Enteroscopy. 
Gastrointest Endosc. 2015 Dec;82(6):975–90. [PMID: 
26388546]
Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015 
May 7;372(19):1832–43. [PMID: 25946282]
Gerson LB et al. ACG clinical guideline: diagnosis and manage
-
ment of small bowel bleeding. Am J Gastroenterol. 2015 Sep;
 
110(9):1265–87. [PMID: 26303132]
 
º
DISEASES OF T
h
E PERITONEUM
ASSESSMENT OF THE PATIENT WITH ASCITES
 
»
Etiology of Ascites
The term “ascites” denotes the pathologic accumulation of 
fluid in the peritoneal cavity. Healthy men have little or no 
intraperitoneal fluid, but women normally may have up to 
20 mL depending on the phase of the menstrual cycle. The 
causes of ascites may be classified into two broad patho
-
physiologic categories: that which is associated with a 
normal peritoneum and that which occurs due to a dis
-
eased peritoneum (Table 15–7). The most common cause 
of ascites is portal hypertension secondary to chronic liver 
disease, which accounts for over 80% of patients with ascites. 
The management of portal hypertensive ascites is dis
-
cussed in Chapter 16. The most common causes of non
-
portal hypertensive ascites include infections (tuberculous 
peritonitis), intra-abdominal malignancy, inflammatory 
disorders of the peritoneum, and ductal disruptions (chy
-
lous, pancreatic, biliary).
 
»
The history usually is one of increasing abdominal girth, 
with the presence of abdominal pain depending on the 
cause. Because most ascites is secondary to chronic liver 
disease with portal hypertension, patients should be asked 
about risk factors for liver disease, especially alcohol 
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consumption, transfusions, tattoos, injection drug use, a 
history of viral hepatitis or jaundice, and birth in an area 
endemic for hepatitis. A history of cancer or marked 
weight loss arouses suspicion of malignant ascites. Fevers 
may suggest infected peritoneal fluid, including bacterial 
peritonitis (spontaneous or secondary). Patients with 
chronic liver disease and ascites are at greatest risk for 
developing spontaneous bacterial peritonitis. In immi
-
grants, immunocompromised hosts, or severely malnour
-
ished alcoholics, tuberculous peritonitis should be 
Physical examination should emphasize signs of portal 
hypertension and chronic liver disease. Elevated jugular 
venous pressure may suggest right-sided heart failure or 
constrictive pericarditis. A large tender liver is characteris
-
tic of acute alcoholic hepatitis or Budd-Chiari syndrome 
(thrombosis of the hepatic veins). The presence of large 
abdominal wall veins with cephalad flow also suggests por
-
tal hypertension; inferiorly directed flow implies hepatic 
vein obstruction. Signs of chronic liver disease include pal
-
mar erythema, cutaneous spider angiomas, gynecomastia, 
and muscle wasting. Asterixis secondary to hepatic enceph
-
alopathy may be present. Anasarca results from cardiac 
failure or nephrotic syndrome with hypoalbuminemia. 
Finally, firm lymph nodes in the left supraclavicular region 
or umbilicus may suggest intra-abdominal malignancy.
The physical examination is relatively insensitive for 
detecting ascitic fluid. In general, patients must have at least 
1500 mL of fluid to be detected reliably by this method. 
Even the experienced clinician may find it difficult to dis
-
tinguish between obesity and small-volume ascites. Abdom
-
inal ultrasound establishes the presence of fluid.
B. Laboratory Testing
1. Abdominal paracentesis—
Abdominal paracentesis is 
performed as part of the diagnostic evaluation in all 
patients with new onset of ascites to help determine the 
cause. It also is recommended for patients admitted to the 
hospital with cirrhosis and ascites (in whom the prevalence 
of bacterial peritonitis is 10–20%) and when patients with 
known ascites deteriorate clinically (development of fever, 
abdominal pain, rapid worsening of kidney function, or 
worsened hepatic encephalopathy) to exclude bacterial 
peritonitis.
a. 
I
nspection—
Cloudy fluid suggests infection. Milky 
fluid is seen with chylous ascites due to high triglyceride 
levels. Bloody fluid is most commonly attributable to a 
traumatic paracentesis, but up to 20% of cases of malignant 
ascites are bloody.
b. 
R
outine studies—
 
(1) Cell count—
A white blood cell count with differen
-
tial is the most important test. Normal ascitic fluid contains 
less than 500 leukocytes/mcL and less than 250 polymor
-
phonuclear neutrophils (PMNs)/mcL. Any inflammatory 
condition can cause an elevated ascitic white blood cell 
count. A PMN count of greater than 250/mcL (neutrocytic 
ascites) with a percentage of more than 75% of all white 
cells is highly suggestive of bacterial peritonitis, either 
spontaneous primary peritonitis or secondary peritonitis 
(ie, caused by an intra-abdominal source of infection, such 
as a perforated viscus or appendicitis). An elevated white 
count with a predominance of lymphocytes arouses suspi
-
cion of tuberculosis or peritoneal carcinomatosis. 
Table 15–7.
 
Causes of ascites.
Normal Peritoneum
Portal hypertension (SAAG ≥ 1.1 g/dL)
1.
 
h
epatic congestion
1
Tricuspid insufficiency
Budd-Chiari syndrome
Veno-occlusive disease
2.
 
Liver disease
2
Cirrhosis
Alcoholic hepatitis
Fulminant hepatic failure
Massive hepatic metastases
Hepatic fibrosis
Acute fatty liver of pregnancy
3.
 
Portal vein occlusion
h
ypoalbuminemia (SAAG < 1.1 g/dL)
 
Nephr
otic syndrome
 
P
rotein-losing enteropathy
 
S
evere malnutrition with anasarca

3.
 
h
 
Nephr
 
P
 
S
Miscellaneous conditions (SAAG < 1.1 g/dL)
 
Ch
ylous ascites
 
P
ancreatic ascites
 
Bile ascit
es
 
Nephr
ogenic ascites
 
Urine ascit
es
 
M
yxedema (SAAG ≥ 1.1 g/dL)
 
O
varian disease
Diseased Peritoneum (SAAG < 1.1 g/dL)
2
 
Bac
terial peritonitis
 
T
uberculous peritonitis
 
F
ungal peritonitis
 
HIV
-associated peritonitis
Malignant conditions
 
P
eritoneal carcinomatosis
 
P
rimary mesothelioma
 
P
seudomyxoma peritonei
 
M
assive hepatic metastases
 
Hepa
tocellular carcinoma
Other conditions
 
F
amilial Mediterranean fever
 
Vasculitis
 
Gr
anulomatous peritonitis
 
E
osinophilic peritonitis
1
Hepatic congestion is usually associated with SAAG ≥ 1.1 g/dL 
and ascitic fluid total protein > 2.5 g/dL.
2
There may be cases of “mixed ascites” in which portal hyperten
-
sive ascites is complicated by a secondary process such as infection. 
In these cases, the SAAG is ≥ 1.1 g/dL.
SAAG, serum-ascites albumin gradient = serum albumin minus 
ascitic fluid albumin.
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(2) Albumin and total protein—
The serum-ascites 
albumin gradient (SAAG) is the best single test for the clas
-
sification of ascites into portal hypertensive and nonportal 
hypertensive causes (Table 15–7). Calculated by subtract
-
ing the ascitic fluid albumin from the serum albumin, the 
gradient correlates directly with the portal pressure. An 
SAAG of 1.1 g/dL or more suggests underlying portal 
hypertension, while gradients less than 1.1 g/dL implicate 
nonportal hypertensive causes.
The accuracy of the SAAG exceeds 95% in classifying 
ascites. It should be recognized, however, that approxi
-
mately 4% of patients have “mixed ascites, ” ie, underlying 
cirrhosis with portal hypertension complicated by a second 
cause for ascites formation (such as malignancy or tuber
-
culosis). Thus, a high SAAG is indicative of portal hyper
-
tension but does not exclude concomitant malignancy.
The ascitic fluid total protein provides some additional 
clues to the cause. An elevated SAAG and a high protein 
level (greater than 2.5 g/dL) are seen in most cases of 
hepatic congestion secondary to cardiac disease or Budd-
Chiari syndrome. However, an increased ascitic fluid pro
-
tein is also found in up to 20% of cases of uncomplicated 
cirrhosis. Two-thirds of patients with malignant ascites 
have a total protein level more than 2.5 g/dL. 
(3) Culture and Gram stain—
The best technique con
-
sists of the inoculation of aerobic and anaerobic blood 
culture bottles with 5–10 mL of ascitic fluid at the patient’s 
bedside, which increases the sensitivity for detecting bacte
-
rial peritonitis to over 85% in patients with neutrocytic 
ascites (greater than 250 PMNs/mcL), compared with 
approximately 50% sensitivity by conventional agar plate or 
broth cultures.
c. 
O
ptional studies—
Other laboratory tests are of util
-
ity in some specific clinical situations. Glucose and lactate 
dehydrogenase (LD) may be helpful in distinguishing spon
-
taneous from secondary bacterial peritonitis. An elevated 
amylase may suggest pancreatic ascites or a perforation of 
the gastrointestinal tract with leakage of pancreatic secre
-
tions into the ascitic fluid. Perforation of the biliary tree is 
suspected with an ascitic bilirubin concentration that is 
greater than the serum bilirubin. An elevated ascitic creati
-
nine suggests leakage of urine from the bladder or ureters. 
Ascitic fluid cytologic examination is ordered if peritoneal 
carcinomatosis is suspected. Adenosine deaminase may be 
useful for the diagnosis of tuberculous peritonitis.
C. Imaging
Abdominal ultrasound is useful in confirming the presence 
of ascites and in the guidance of paracentesis. Both ultra
-
sound and CT imaging are useful in distinguishing between 
causes of portal and nonportal hypertensive ascites. Dop
-
pler ultrasound and CT can detect Budd-Chiari syndrome. 
In patients with nonportal hypertensive ascites, these stud
-
ies are useful in detecting lymphadenopathy and masses of 
the mesentery and of solid organs such as the liver, ovaries, 
and pancreas. Furthermore, they permit directed percuta
-
neous needle biopsies of these lesions. Ultrasound and CT 
are poor procedures for the detection of peritoneal carci
-
nomatosis; the role of positron emission tomography 
(PET) imaging is unclear.
D. Laparoscopy
Laparoscopy is an important test in the evaluation of some 
patients with nonportal hypertensive ascites (low SAAG) 
or mixed ascites. It permits direct visualization and biopsy 
of the peritoneum, liver, and some intra-abdominal lymph 
nodes. Cases of suspected peritoneal tuberculosis or sus
-
pected malignancy with nondiagnostic CT imaging and 
ascitic fluid cytology are best evaluated by this method.
Gaetano JN et al. The benefit of paracentesis on hospitalized 
adults with cirrhosis and ascites. J Gastroenterol Hepatol. 
2016 May;31(5):1025–30. [PMID: 26642977]
Pericleous M et al. The clinical management of abdominal asci
-

-
tes, spontaneous bacterial peritonitis and hepatorenal syn
-
drome: a review of current guidelines and recommendations. 
Eur J Gastroenterol Hepatol. 2016 Mar;28(3):e10–8. [PMID: 
26671516]
Solà E et al. Management of uninfected and infected ascites in 
cirrhosis. Liver Int. 2016 Jan;36(Suppl 1):109–15. [PMID: 
26725907]
SPONTANEOUS BACTERIAL PERITONITIS
 
»
A history of chronic liver disease and ascites.
 
»
Fever and abdominal pain.
 
»
Peritoneal signs uncommonly encountered on 
 
»
Ascitic fluid neutrophil count greater than 250 
white blood cells/mcL.
 
»
“Spontaneous” bacterial infection of ascitic fluid occurs in 
the absence of an apparent intra-abdominal source of 
infection. It is seen with few exceptions in patients with 
ascites caused by chronic liver disease. Translocation of 
enteric bacteria across the gut wall or mesenteric lymphat
-
ics leads to seeding of the ascitic fluid, as may bacteremia 
from other sites. Approximately 20–30% of cirrhotic 
patients with ascites develop spontaneous peritonitis; how
-
ever, the incidence is greater than 40% in patients with 
ascitic fluid total protein less than 1 g/dL, probably due to 
decreased ascitic fluid opsonic activity.
Virtually all cases of spontaneous bacterial peritonitis 
are caused by a monomicrobial infection. The most com
-
mon pathogens are enteric gram-negative bacteria (
E coli, 
) or gram-positive bacteria (
Strepto
-
coccus pneumoniae
, viridans streptococci, 
Enterococcus
 
species). Anaerobic bacteria are not associated with spon
-
taneous bacterial peritonitis.
 
»
Eighty to 90 percent of patients with spontaneous bacterial 
peritonitis are symptomatic; in many cases the presentation 
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is subtle. Spontaneous bacterial peritonitis may be present 
in 10–20% of patients hospitalized with chronic liver dis
-
ease, sometimes in the absence of any suggestive symptoms 
or signs.
The most common symptoms are fever and abdominal 
pain, present in two-thirds of patients. Spontaneous bacte
-
rial peritonitis may also present with a change in mental 
status due to exacerbation or precipitation of hepatic 
encephalopathy, or sudden worsening of kidney function. 
Physical examination typically demonstrates signs of 
chronic liver disease with ascites. Abdominal tenderness is 
present in less than 50% of patients, and its presence sug
-
gests other processes.
The most important diagnostic test is abdominal paracen
-
tesis. Ascitic fluid should be sent for cell count with dif
-
ferential, and blood culture bottles should be inoculated at 
the bedside; Gram stain and reagent strips are insensitive.
In the proper clinical setting, an ascitic fluid PMN 
count of greater than 250 cells/mcL (neutrocytic ascites) is 
presumptive evidence of bacterial peritonitis. The percent
-
age of PMNs is greater than 50–70% of the ascitic fluid 
white blood cells and commonly approximates 100%. 
Patients with neutrocytic ascites are presumed to be 
infected and should be started—regardless of symptoms—
on antibiotics. Although 10–30% of patients with neutro
-
cytic ascites have negative ascitic bacterial cultures 
(“culture-negative neutrocytic ascites”), it is presumed that 
these patients have bacterial peritonitis and should be 
treated empirically. Occasionally, a positive blood culture 
identifies the organism when ascitic fluid is sterile.
 
»
Spontaneous bacterial peritonitis must be distinguished 
from secondary bacterial peritonitis, in which ascitic fluid 
has become secondarily infected by an intra-abdominal 
infection. Even in the presence of perforation, clinical 
symptoms and signs of peritonitis may be lacking owing to 
the separation of the visceral and parietal peritoneum by 
the ascitic fluid. Causes of secondary bacterial peritonitis 
include appendicitis, diverticulitis, perforated peptic ulcer, 
and perforated gallbladder. Secondary bacterial infection 
accounts for 3% of cases of infected ascitic fluid.
Ascitic fluid total protein, LD, and glucose are useful in 
distinguishing spontaneous bacterial peritonitis from sec
-
ondary infection. Up to two-thirds of patients with sec
-
ondary bacterial peritonitis have at least two of the 
following: decreased glucose level (less than 50 mg/dL), an 
elevated LD level (greater than serum), and total protein 
greater than 1 g/dL. Ascitic neutrophil counts greater than 
10,000/mcL also are suspicious; however, most patients 
with secondary peritonitis have neutrophil counts within 
the range of spontaneous peritonitis. The presence of mul
-
tiple organisms on ascitic fluid Gram stain or culture is 
diagnostic of secondary peritonitis.
If secondary bacterial peritonitis is suspected, abdomi
-
nal CT imaging of the upper and lower gastrointestinal 
tracts should be obtained to look for evidence of an 
intra-abdominal source of infection. If these studies are 
negative and secondary peritonitis still is suspected, repeat 
paracentesis should be performed after 48 hours of antibi
-
otic therapy to confirm that the PMN count is decreasing. 
Secondary bacterial peritonitis should be suspected in 
patients in whom the PMN count is not below the pretreat
-
ment value at 48 hours.
Neutrocytic ascites may also be seen in some patients 
with peritoneal carcinomatosis, pancreatic ascites, or 
tuberculous ascites. In these circumstances, however, 
PMNs account for less than 50% of the ascitic white blood 
cells.
 
»
Up to 70% of patients who survive an episode of spontane
-
ous bacterial peritonitis will have another episode within 
1 year. Oral once-daily prophylactic therapy—with nor
-

cells.
 
»
-
-
floxacin, 400 mg, ciprofloxacin, 250–500 mg, or trime
-
thoprim-sulfamethoxazole, one double-strength tablet—has 
been shown to reduce the rate of recurrent infections to 
less than 20% and is recommended. Prophylaxis should be 
considered also in patients who have not had prior bacte
-
rial peritonitis but are at increased risk of infection due to 
low-protein ascites (total ascitic protein less than 1 g/dL). 
Although improvement in survival in cirrhotic patients 
with ascites treated with prophylactic antibiotics has not 
been shown, decision analytic modeling suggests that in 
patients with prior bacterial peritonitis or low ascitic fluid 
protein, the use of prophylactic antibiotics is a cost-effective 
strategy.
 
»
Treatment
Empiric therapy for spontaneous bacterial peritonitis 
should be initiated with a third-generation cephalosporin 
(such as cefotaxime, 2 g intravenously every 8–12 hours, or 
ceftriaxone, 1–2 g intravenously every 24 hours) or a com
-
bination beta-lactam/beta-lactamase agent (such as ampi
-
cillin/sulbactam, 2 g/1 g intravenously every 6 hours). 
Because of a high risk of nephrotoxicity in patients with 
chronic liver disease, aminoglycosides should not be used. 
A repeat paracentesis is recommended after 48 hours of 
treatment in patients without clinical improvement. If the 
ascitic neutrophil count has not decreased by 25%, antibi
-
otic coverage should be adjusted (guided by culture and 
sensitivity results, if available) and secondary causes of 
peritonitis excluded. Although the optimal duration of 
therapy is unknown, a course of 5–10 days is sufficient in 
most patients, or until the ascites fluid PMN count 
decreases to less than 250 cells/mcL.
Kidney injury develops in up to 40% of patients and is 
a major cause of death. Intravenous albumin increases 
effective arterial circulating volume and renal perfusion, 
decreasing the incidence of kidney injury and mortality. 
Intravenous albumin, 1.5 g/kg on day 1 and 1 g/kg on day 
3, should be administered to patients at high risk for hepa
-
torenal failure (ie, patients with baseline creatinine 
greater than 1 mg/dL, blood urea nitrogen [BUN] more 
than 30 mg/dL, or bilirubin more than 4 mg/dL). Nonselective 
beta-blockers increase the risk of hepatorenal syndrome in 
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patients with bacterial peritonitis and should be discontin
-
ued permanently due to their adverse impact on cardiac 
output and renal perfusion in advanced cirrhosis which is 
associated with decreased long-term survival. Patients with 
suspected secondary bacterial peritonitis should be given 
broad-spectrum coverage for enteric aerobic and anaerobic 
flora with a third-generation cephalosporin and metroni
-
dazole pending identification and definitive (usually surgical) 
treatment of the cause.
 
»
Prognosis
The mortality rate of spontaneous bacterial peritonitis 
exceeds 30%. However, if the disease is recognized and 
treated early, the rate is less than 10%. As the majority of 
patients have underlying severe liver disease, many may die 
of liver failure, hepatorenal syndrome, or bleeding compli
-
cations from portal hypertension. The most effective treat
-
ment for recurrent spontaneous bacterial peritonitis is liver 
transplant.
Fiore M et al. Are third-generation cephalosporins still the 
empirical antibiotic treatment of community-acquired spon
-
taneous bacterial peritonitis? A systematic review and meta-
analysis. Eur J Gastroenterol Hepatol. 2018 Mar;30(3):329–36.  
[PMID: 29303883]
Fiore M et al. Current concepts and future strategies in the anti
-
microbial therapy of emerging Gram-positive spontaneous 
bacterial peritonitis. World J Hepatol. 2017 Oct 28;9(30):1166–75. 
[PMID: 29109849]
Garcia-Tsao G. Current management of the complications of 
cirrhosis and portal hypertension: variceal hemorrhage, ascites, 
and spontaneous bacterial peritonitis. Dig Dis. 2016;34(4):
 
382–6. [PMID: 27170392]
Jamtgaard L et al. Does albumin infusion reduce renal impair
-
ment and mortality in patients with spontaneous bacterial 
peritonitis? Ann Emerg Med. 2016 Apr;67(4):458–9. [PMID: 
26234193]
Pericleous M et al. The clinical management of abdominal ascites, 
spontaneous bacterial peritonitis and hepatorenal syndrome: a 
review of current guidelines and recommendations. Eur J Gas
-
troenterol Hepatol. 2016 Mar;28(3):e10–8. [PMID: 26671516]
Sidhu GS et al. Rifaximin versus norfloxacin for prevention of spon
-
taneous bacterial peritonitis: a systematic review. BMJ Open 
Gastroenterol. 2017 Jul 17;4(1):e000154. [PMID: 28944070]
MALIGNANT ASCITES
Two-thirds of cases of malignant ascites are caused by peri
-
toneal carcinomatosis. The most common tumors causing 
carcinomatosis are primary adenocarcinomas of the ovary, 
uterus, pancreas, stomach, colon, lung, or breast. The 
remaining one-third is due to lymphatic obstruction or 
portal hypertension due to hepatocellular carcinoma or 
diffuse hepatic metastases. Patients present with nonspe
-
cific abdominal discomfort and weight loss associated with 
increased abdominal girth. Nausea or vomiting may be 
caused by partial or complete intestinal obstruction. 
Abdominal CT may be useful to demonstrate the primary 
malignancy or hepatic metastases but seldom confirms the 
diagnosis of peritoneal carcinomatosis. In patients with 
carcinomatosis, paracentesis demonstrates a low serum 
ascites-albumin gradient (less than 1.1 mg/dL), an 
increased total protein (greater than 2.5 g/dL), and an ele
-
vated white cell count (often both neutrophils and mono
-
nuclear cells) but with a lymphocyte predominance. 
Cytology is positive in over 95%, but laparoscopy may be 
required in patients with negative cytology to confirm the 
diagnosis and to exclude tuberculous peritonitis, with 
which it may be confused. Malignant ascites attributable to 
portal hypertension usually is associated with an increased 
serum ascites-albumin gradient (greater than 1.1 g/dL), a 
variable total protein, and negative ascitic cytology. Ascites 
caused by peritoneal carcinomatosis does not respond to 

Patients may be treated with periodic large-volume 
paracentesis for symptomatic relief. Indwelling catheters 
can be left in place for patients approaching the end of life 
who require periodic paracentesis for symptomatic relief. 
Intraperitoneal chemotherapy is sometimes used to shrink 
the tumor, but the overall prognosis is extremely poor, with 
only 10% survival at 6 months. Ovarian cancers represent 
an exception to this rule. With newer treatments consisting 
of surgical debulking and intraperitoneal chemotherapy, 
long-term survival from ovarian cancer is possible.
Bohn KA et al. Repeat large-volume paracentesis versus tun
-
neled peritoneal catheter placement for malignant ascites: a 
cost-minimization study. AJR Am J Roentgenol. 2015 Nov;
 
205(5):1126–34. [PMID: 26496562]
Ha T et al. Symptomatic fluid drainage: tunneled peritoneal and 
pleural catheters. Semin Intervent Radiol. 2017 Dec;34(4):
 
337–42. [PMID: 29249857]
Maeda H et al. Evaluation and treatment of malignant ascites 
secondary to gastric cancer. World J Gastroenterol. 2015 
Oct 21;21(39):10936–47. [PMID: 26494952]
FAMILIAL MEDITERRANEAN FEVER
This is a rare autosomal recessive disorder of unknown 
pathogenesis that almost exclusively affects people of 
Mediterranean ancestry, especially Sephardic Jews, 
 
Armenians, Turks, and Arabs. Patients lack a protease in 
serosal fluids that normally inactivates interleukin-8 and 
the chemotactic complement factor 5A. Symptoms present 
in most patients before the age of 20 years. It is character
-
ized by episodic bouts of acute peritonitis that may be 
associated with serositis involving the joints and pleura. 
Peritoneal attacks are marked by the sudden onset of fever, 
severe abdominal pain, and abdominal tenderness with 
guarding or rebound tenderness. If left untreated, attacks 
resolve within 24–48 hours. Because symptoms resemble 
those of surgical peritonitis, patients may undergo unnec
-
essary exploratory laparotomy. Colchicine, 0.6 mg orally 
two or three times daily, has been shown to decrease the 
frequency and severity of attacks.
Özen S et al. EULAR recommendations for the management of 
familial Mediterranean fever. Ann Rheum Dis. 2016 Apr;
 
75(4):644–51. [PMID: 26802180]
Özen S et al. Familial Mediterranean Fever: recent developments 
in pathogenesis and new recommendations for management. 
Front Immunol. 2017 Mar 23;8:253. [PMID: 28386255]
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CMDT 2019
MESOTHELIOMA
(See Chapter 39.)
 
º
h
E ESOP
h
AGUS
(See Chapter 39 for Esophageal Cancer.)
 
»
Symptoms
Heartburn, dysphagia, and odynophagia almost always 
indicate a primary esophageal disorder.
A. Heartburn
Heartburn (pyrosis) is the feeling of substernal burning, 
often radiating to the neck. Caused by the reflux of acidic 
(or, rarely, alkaline) material into the esophagus, it is highly 
specific for GERD.
B. Dysphagia
Difficulties in swallowing may arise from problems in 
transferring the food bolus from the oropharynx to the 
upper esophagus (oropharyngeal dysphagia) or from 
impaired transport of the bolus through the body of the 
esophagus (esophageal dysphagia). The history usually 
leads to the correct diagnosis.
1. Oropharyngeal dysphagia—
The oropharyngeal phase 
of swallowing is a complex process requiring elevation of 
the tongue, closure of the nasopharynx, relaxation of the 
upper esophageal sphincter, closure of the airway, and pha
-
ryngeal peristalsis. A variety of mechanical and neuromus
-
cular conditions can disrupt this process (Table 15–8). 
Problems with the oral phase of swallowing cause drooling 
or spillage of food from the mouth, inability to chew or 
initiate swallowing, or dry mouth. Pharyngeal dysphagia is 
characterized by an immediate sense of the bolus catching 
in the neck, the need to swallow repeatedly to clear food 
from the pharynx, or coughing or choking during meals. 
There may be associated dysphonia, dysarthria, or other 
neurologic symptoms.
2. Esophageal dysphagia—
Esophageal dysphagia may be 
caused by 
mechanical obstructions
 of the esophagus or by 
motility disorders
 (Table 15–9). Patients with 
mechanical 
obstruction
 experience dysphagia, primarily for solids. 
This is recurrent, predictable, and, if the lesion progresses, 
will worsen as the lumen narrows. Patients with 
motility 
disorders
 have dysphagia for both solids and liquids. It is 
episodic, unpredictable, and can be progressive.
C. Odynophagia
Odynophagia is sharp substernal pain on swallowing that 
may limit oral intake. It usually reflects severe erosive dis
-
ease. It is most commonly associated with infectious 
esophagitis due to 
Candida
, herpesviruses, or CMV , espe
-
cially in immunocompromised patients. It may also be 
caused by corrosive injury due to caustic ingestions and by 
pill-induced ulcers.
 
»
Endoscopy is the study of choice for evaluating persistent 
heartburn, dysphagia, odynophagia, and structural abnor
-
malities detected on barium esophagography. In addition 
to direct visualization, it allows biopsy of mucosal 
Table 15–8.
 
Causes of oropharyngeal dysphagia.
 
Br
ainstem cerebrovascular accident, mass lesion
 
Am
yotrophic lateral sclerosis, multiple sclerosis, pseudobulbar 
 
palsy
, post-polio syndrome, Guillain-Barré syndrome
 
P
arkinson disease, Huntington disease, dementia
 
T
ardive dyskinesia
Muscular and rheumatologic disorders
 
M
yopathies, polymyositis
 
O
culopharyngeal dystrophy
 
Sjög
ren syndrome
Metabolic disorders
 
T
hyrotoxicosis, amyloidosis, Cushing disease, Wilson disease
 
M
edication side effects: anticholinergics, phenothiazines
 
P
olio, diphtheria, botulism, Lyme disease, syphilis, mucositis 
 
(
Candida
, herpes)
Structural disorders
 
Z
enker diverticulum
 
C
ervical osteophytes, cricopharyngeal bar, proximal 
 
esophageal 
webs
 
Or
opharyngeal tumors
 
P
ostsurgical or radiation changes
 
P
ill-induced injury
 
Upper esophageal sphinc
ter dysfunction
Table 15–9.
 
Causes of esophageal dysphagia.
Cause
Clues
Mechanical 
Solid foods worse than liquids
Schatzki ring
Intermittent dysphagia; not progressive
Peptic stricture
Chronic heartburn; progressive 
dysphagia
Esophageal cancer
Progressive dysphagia; age over 
 
50 years
Eosinophilic 
esophagitis
Young adults; small-caliber lumen,

dysphagia
 
50 years
Young adults; small-caliber lumen, 
 
proximal stricture, corrugated rings, 
or white papules
Motility disorder
Solid and liquid foods
Achalasia
Progressive dysphagia
Diffuse esophageal 
spasm
Intermittent; not progressive; may have 
chest pain
Chronic heartburn; Raynaud 
phenomenon
Ineffective esophageal 
motility
Intermittent; not progressive; commonly 
associated with GERD
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 CMDT 2019
abnormalities and of normal mucosa (to evaluate for 
eosinophilic esophagitis) as well as dilation of strictures.
B. Videoesophagography
Oropharyngeal dysphagia is best evaluated with rapid-
sequence videoesophagography.
C. Barium Esophagography
Patients with esophageal dysphagia often are evaluated first 
with a radiographic barium study to differentiate between 
mechanical lesions and motility disorders, providing 
important information about the latter in particular. In 
patients with esophageal dysphagia and a suspected motil
-
ity disorder, barium esophagoscopy should be obtained 
first. In patients in whom there is a high suspicion of a 
mechanical lesion, many clinicians will proceed first to 
endoscopic evaluation because it better identifies mucosa 
lesions (eg, erosions) and permits mucosal biopsy and dila
-
tion. However, barium study is more sensitive for detecting 
subtle esophageal narrowing due to rings, achalasia, and 
proximal esophageal lesions.
D. Esophageal Manometry
Esophageal motility may be assessed using manometric 
techniques. High-resolution manometry with multiple, 
closely spaced sensors is replacing conventional manometry 
in most centers. Manometry is indicated (1) to determine 
the location of the LES to allow precise placement of a con
-
ventional electrode pH probe; (2) to establish the etiology of 
dysphagia in patients in whom a mechanical obstruction 
cannot be found, especially if a diagnosis of achalasia is sus
-
pected by endoscopy or barium study; (3) for the preopera
-
tive assessment of patients being considered for antireflux 
surgery to exclude an alternative diagnosis (eg, achalasia) or 
possibly to assess peristaltic function in the esophageal body. 
High-resolution manometry may be superior to conven
-
tional manometry for distinguishing motility disorders.
E. Esophageal pH Recording and 
 
Impedance Testing
The pH within the esophageal lumen may be monitored 
continuously for 24–48 hours. There are two kinds of sys
-
tems in use: catheter-based and wireless. Traditional sys
-
tems use a long transnasal catheter that is connected 
directly to the recording device. Wireless systems are 
increasingly used; in these systems, a capsule is attached 
directly to the esophageal mucosa under endoscopic visu
-
alization and data are transmitted by radiotelemetry to the 
recording device. The recording provides information 
about the amount of esophageal acid reflux and the tempo
-
ral correlations between symptoms and reflux.
Esophageal pH monitoring devices provide informa
-
tion about the amount of esophageal acid reflux but not 
nonacid reflux. Techniques using combined pH and multi
-
channel intraluminal impedance allow assessment of acid 
and nonacid liquid reflux. They may be useful in evalua
-
tion of patients with atypical reflux symptoms or persistent 
symptoms despite therapy with proton pump inhibitors to 
diagnose hypersensitivity, functional symptoms, and 
symptoms caused by nonacid reflux.
Carlson DA et al. How to effectively use high-resolution esopha
-
geal manometry. Gastroenterology. 2016 Nov;151(5):789–92. 
[PMID: 27693348]
Pugliese D et al. pH impedance vs. traditional pH monitoring in 
clinical practice: an outcome study. J Gastroenterol. 2016 Feb;
 
51(2):130–7. [PMID: 26033511]
Roman S et al. High-resolution manometry improves the diag
-
nosis of esophageal motility disorders in patients with dys
-
phagia: a randomized multicenter study. Am J Gastroenterol. 
2016 Mar;111(3):372–80. [PMID: 26832656]
Xiao Y et al. Tailored therapy for the refractory GERD patients 
by combined multichannel intraluminal impedance-pH 
monitoring. J Gastroenterol Hepatol. 2016 Feb;31(2):350–4. 
[PMID: 26202002]
GASTROESOPHAGEAL REFLUX DISEASE
 
»
Heartburn; may be exacerbated by meals, bend
-
ing, or recumbency.
 
»
Typical uncomplicated cases do not require diag
-
nostic studies.
 
»
Endoscopy demonstrates abnormalities in one-

»
-
 
»
-
 
»
third of patients.
 
»
GERD is a condition that develops when the reflux of 
stomach contents causes troublesome symptoms or com
-
plications. It affects 20% of adults. The two most common 
symptoms are heartburn and regurgitation. However, other 
symptoms of GERD include dyspepsia, dysphagia, belch
-
ing, chest pain, cough, and hoarseness. Although most 
patients have mild disease, esophageal mucosal damage 
(reflux esophagitis) develops in up to one-third and more 
serious complications develop in a few others. Several fac
-
tors may contribute to GERD.
A. Dysfunction of the Gastroesophageal Junction
The antireflux barrier at the gastroesophageal junction 
depends on LES pressure, the intra-abdominal location of 
the sphincter (resulting in a “flap valve” caused by angula
-
tion of the esophageal-gastric junction), and the extrinsic 
compression of the sphincter by the crural diaphragm. In 
most patients with GERD, baseline LES pressures are nor
-
mal (10–35 mm Hg). Most reflux episodes occur during 
transient relaxations of the LES that are triggered by gastric 
distention by a vagovagal reflex. A subset of patients with 
GERD have an incompetent (less than 10 mm Hg) LES that 
results in increased acid reflux, especially when supine or 
when intra-abdominal pressures are increased by lifting or 
bending. A hypotensive sphincter is present in up to 50% 
of patients with severe erosive GERD.
Hiatal hernias are found in one-fourth of patients with 
nonerosive GERD, three-fourths of patients with severe 
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CMDT 2019
erosive esophagitis, and over 90% of patients with Barrett 
esophagus. They are caused by movement of the LES above 
the diaphragm, resulting in dysfunction of the gastro
-
esophageal junction reflux barrier. Hiatal hernias are com
-
mon and may cause no symptoms; however, in patients 
with gastroesophageal reflux, they are associated with 
higher amounts of acid reflux and delayed esophageal acid 
clearance, leading to more severe esophagitis and Barrett 
esophagus. Increased reflux episodes occur during normal 
swallowing-induced relaxation, transient LES relaxations, 
and straining due to reflux of acid from the hiatal hernia 
sac into the esophagus.
Truncal obesity may contribute to GERD, presumably 
due to an increased intra-abdominal pressure, which con
-
tributes to dysfunction of the gastroesophageal junction 
and increased likelihood of hiatal hernia.
B. Irritant Effects of Refluxate
Esophageal mucosal damage is related to the potency of the 
refluxate and the amount of time it is in contact with the 
mucosa. Acidic gastric fluid (pH less than 4.0) is extremely 
caustic to the esophageal mucosa and is the major injurious 
agent in the majority of cases. In some patients, reflux of 
bile or alkaline pancreatic secretions may be contributory.
C. Abnormal Esophageal Clearance
Acid refluxate normally is cleared and neutralized by 
esophageal peristalsis and salivary bicarbonate. One-half of 
patients with severe GERD have diminished clearance due 
to hypotensive peristaltic contractions (less than 30 mm Hg) 
or intermittent failed peristalsis after swallowing. Certain 
medical conditions such as scleroderma are associated with 
diminished peristalsis. Sjögren syndrome, anticholinergic 
medications, and oral radiation therapy may exacerbate 
GERD due to impaired salivation.
D. Delayed Gastric Emptying
Impaired gastric emptying due to gastroparesis or partial 
gastric outlet obstruction potentiates GERD.
 
»
The typical symptom is heartburn. This most often occurs 
30–60 minutes after meals and upon reclining. Patients 
often report relief from taking antacids or baking soda. 
When this symptom is dominant, the diagnosis is estab
-
lished with a high degree of reliability. Many patients, 
however, have less specific dyspeptic symptoms with or 
without heartburn. Overall, a clinical diagnosis of gastro
-
esophageal reflux has a sensitivity and specificity of only 
65%. Severity is not correlated with the degree of tissue 
damage. In fact, some patients with severe esophagitis are 
only mildly symptomatic. Patients may complain of regur
-
gitation—the spontaneous reflux of sour or bitter gastric 
contents into the mouth. Dysphagia occurs in one-third of 
patients and may be due to erosive esophagitis, abnormal 
esophageal peristalsis, or the development of an esophageal 
stricture.
“ Atypical” or “extraesophageal” manifestations of gas
-
troesophageal disease may occur, including asthma, 
chronic cough, chronic laryngitis, sore throat, noncardiac 
chest pain, and sleep disturbances. In the absence of heart
-
burn or regurgitation, atypical symptoms are unlikely to be 
related to gastroesophageal reflux.
Physical examination and laboratory data are normal in 
uncomplicated disease.
Initial diagnostic studies are not warranted for patients 
with typical GERD symptoms suggesting uncomplicated 
reflux disease. Patients with typical symptoms of heartburn 
and regurgitation should be treated empirically with a 
twice-daily H
2
-receptor antagonist or a once daily proton 
pump inhibitor for 4–8 weeks. Symptomatic response to 
empiric treatment (while clinically desirable) has only a 
78% sensitivity and 54% specificity for GERD. Therefore, 
further investigation is required in patients with symptoms 
that persist despite empiric acid inhibitory therapy to iden
-
tify complications of reflux disease and to diagnose other

-
tify complications of reflux disease and to diagnose other 
conditions, particularly in patients with “alarm features” 
(troublesome dysphagia, odynophagia, weight loss, iron 
deficiency anemia).
1. Upper endoscopy—
Upper endoscopy is excellent for 
documenting the type and extent of tissue damage in gas
-
troesophageal reflux; for detecting other gastroesophageal 
lesions that may mimic GERD; and for detecting GERD 
complications, including esophageal stricture, Barrett 
metaplasia, and esophageal adenocarcinoma. In the 
absence of prior antisecretory therapy, up to one-third of 
patients with GERD have visible mucosal damage (known 
as reflux esophagitis), characterized by single or multiple 
erosions or ulcers in the distal esophagus at the squamoco
-
lumnar junction. In patients treated with a proton pump 
inhibitor prior to endoscopy, preexisting reflux esophagitis 
may be partially or completely healed. The Los Angeles 
(LA) classification grades reflux esophagitis on a scale of A 
(one or more isolated mucosal breaks 5 mm or less that do 
not extend between the tops of two mucosal folds) to D 
(one or more mucosal breaks that involve at least 75% of 
the esophageal circumference).
2. Barium esophagography—
This study should not be 
performed to diagnose GERD. In patients with severe dys
-
phagia, it is sometimes obtained prior to endoscopy to 
identify a stricture.
3. Esophageal pH or combined esophageal pH-imped
ance 
testing—
Esophageal pH monitoring measures the amount 
of esophageal acid reflux, whereas combined pH-imped
-
ance testing measures both acidic and nonacidic reflux. 
Both tests may also be useful to establish whether there is a 
temporal relationship between reflux events and symp
-
toms. They are the most accurate studies for documenting 
gastroesophageal reflux but are unnecessary in most 
patients who have typical symptoms and satisfactory 
response to empiric antisecretory therapy. They are indi
-
cated in patients with typical symptoms who have unsatis
-
factory response to empiric therapy, patients with atypical 
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or extraesophageal symptoms, and patients who are being 
considered for antireflux surgery.
 
»
Symptoms of GERD may be similar to those of other dis
-
eases such as angina pectoris, esophageal motility disor
-
ders, dyspepsia, peptic ulcer, or functional disorders. 
Reflux erosive esophagitis may be confused with pill-
induced damage, eosinophilic esophagitis, or infections 
(CMV , herpes, 
Candida
).
 
»
A. Barrett Esophagus
This is a condition in which the squamous epithelium of 
the esophagus is replaced by metaplastic columnar epithe
-
lium containing goblet and columnar cells (specialized 
intestinal metaplasia). Present in up to 15% of patients with 
chronic reflux, Barrett esophagus is believed to arise from 
chronic reflux-induced injury to the esophageal squamous 
epithelium; however, it is also increased in patients with 
truncal obesity independent of GERD. Barrett esophagus is 
suspected at endoscopy from the presence of orange, gas
-
tric type epithelium that extends upward more than 1 cm 
from the gastroesophageal junction into the distal tubular 
esophagus in a tongue-like or circumferential fashion. 
Biopsies obtained at endoscopy confirm the diagnosis. 
Three types of columnar epithelium may be identified: 
gastric cardiac, gastric fundic, and specialized intestinal 
metaplasia. There is agreement that the latter carries an 
increased risk of dysplasia; however, some authorities 
believe that gastric cardiac mucosa also raises risk.
Barrett esophagus does not provoke specific symptoms 
but gastroesophageal reflux does. Most patients have a long 
history of reflux symptoms, such as heartburn and regurgi
-
tation. Barrett esophagus should be treated with long-term 
proton pump inhibitors once or twice daily to control 
reflux symptoms. Although these medications do not 
appear to cause regression of Barrett esophagus, they may 
reduce the risk of cancer. Paradoxically, one-third of 
patients report minimal or no symptoms of GERD, sug
-
gesting decreased acid sensitivity of Barrett epithelium. 
Indeed, over 90% of individuals with Barrett esophagus in 
the general population do not seek medical attention.
The most serious complication of Barrett esophagus is 
esophageal adenocarcinoma. It is believed that most 
adenocarcinomas of the esophagus and many such 
tumors of the gastric cardia arise from dysplastic epithe
-
lium in Barrett esophagus. The incidence of adenocarci
-
noma in patients with Barrett esophagus has been 
estimated at 0.2–0.5% per year. Although this still is an 
11-fold increased risk compared with patients without Bar
-
rett esophagus, adenocarcinoma of the esophagus remains 
a relatively uncommon malignancy in the United States 
(7000 cases/year). Given the large number of adults with 
chronic GERD relative to the small number in whom 
adenocarcinoma develops, a 2016 clinical guideline recom
-
mended against endoscopic screening for Barrett esopha
-
gus in adults with GERD except in men with two or more 
risk factors for adenocarcinoma (aged older than 50 years, 
truncal obesity, white race, current or prior history of 
smoking, family history of Barrett esophagus or esophageal 
adenocarcinoma) and in selected women with multiple 
In patients known to have nondysplastic Barrett esopha
-
gus, surveillance endoscopy every 3–5 years is recom
-
mended to look for low- or high-grade dysplasia or 
adenocarcinoma. However, given the relatively low risk of 
progression to cancer in patients with nondysplastic Barrett 
esophagus (0.2–0.5%/year), the risks and benefits of surveil
-
lance should be discussed with patients. During endoscopy, 
biopsies are obtained from nodular or irregular mucosa 
(which have an increased risk of high-grade dysplasia or 
cancer) as well as randomly from the esophagus every 1–2 cm. 
The finding of dysplasia should be confirmed by a second,

The finding of dysplasia should be confirmed by a second, 
expert pathologist. The risk of progression to adenocarci
-
noma is 0.7% per year for patients with low-grade dysplasia 
and 7% per year for high-grade dysplasia. Approximately 
13% of patients with high-grade dysplasia may harbor an 
unrecognized invasive esophageal cancer. Therefore, a repeat 
endoscopy by an endoscopist with expertise in advanced 
resection and ablation techniques is recommended.
On repeat endoscopy, all nodules should be removed 
with mucosal snare resection or dissection techniques to 
assess for the presence and depth of cancer; random biop
-
sies should again be obtained. The subsequent manage
-
ment of patients with intramucosal cancer or high-grade 
dysplasia has rapidly evolved. Until recently, esophagec
-
tomy was recommended for patients deemed to have a low 
operative risk; however, this procedure is associated with 
high morbidity and mortality rates (40% and 1–5%, respec
-
tively). Therefore, endoscopic therapy is now standard care 
for all patients with low- or high-grade dysplasia and 
patients with well-differentiated intramucosal cancer (Tis 
and T1a) without lymphatic or vascular invasion. Of the 
patients who have cancer confined to the mucosa, less than 
2% have recurrence of cancer or high-grade dysplasia after 
snare resection. Following resection, ablation of any 
remaining Barrett mucosa—including flat (nonnodular) 
high-grade dysplasia—is performed with radiofrequency 
wave electrocautery or cryotherapy. Current guidelines 
also recommend that patients with flat 
low-grade
 dysplasia 
(confirmed by a second expert pathologist) also be consid
-
ered for ablation, reserving annual endoscopic surveillance 
to patients with increased comorbidities and reduced life-
expectancy. The efficacy of endoscopic ablation therapies 
in patients with Barrett dysplasia is supported by several 
studies. When high-dose proton pump inhibitors are 
administered to normalize intraesophageal pH, radiofre
-
quency wave ablation electrocautery eradication of Barrett 
columnar epithelium is followed by complete healing with 
normal squamous epithelium in greater than 78% of 
patients and elimination of dysplasia in 91%.
Endoscopic ablation techniques have a risk of complica
-
tions (bleeding, perforation, strictures). Therefore, endo
-
scopic eradication therapy currently is not recommended 
for patients with nondysplastic Barrett esophagus for 
whom the risk of developing esophageal cancer is low and 
treatment does not appear to be cost-effective.
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B. Peptic Stricture
Stricture formation occurs in about 5% of patients with 
esophagitis. It is manifested by the gradual development of 
solid food dysphagia progressive over months to years. 
Often there is a reduction in heartburn because the stric
-
ture acts as a barrier to reflux. Most strictures are located at 
the gastroesophageal junction. Endoscopy with biopsy is 
mandatory in all cases to differentiate peptic stricture from 
stricture by esophageal carcinoma. Active erosive esopha
-
gitis is often present. Up to 90% of symptomatic patients 
are effectively treated with dilation with graduated polyvi
-
nyl catheters passed over a wire placed at the time of 
endoscopy or fluoroscopically, or balloons passed fluoro
-
scopically or through an endoscope. Dilation is continued 
over one to several sessions. A luminal diameter of 13–17 mm 
is usually sufficient to relieve dysphagia. Long-term ther
-
apy with a proton pump inhibitor is required to decrease 
the likelihood of stricture recurrence. Some patients 
require intermittent dilation to maintain luminal patency, 
but operative management for strictures that do not respond 
to dilation is seldom required. Refractory strictures may 
benefit from endoscopic injection of triamcinolone into 
the stricture.
 
»
Treatment
A. Medical Treatment
The goal of treatment is to provide symptomatic relief, to 
heal esophagitis (if present), and to prevent complications. 
In the majority of patients with uncomplicated disease, 
empiric treatment is initiated based on a compatible his
-
tory without the need for further confirmatory studies. 
Patients not responding and those with suspected compli
-
cations undergo further evaluation with upper endoscopy 
or esophageal manometry and pH recording.
1. Mild, intermittent symptoms—
Patients with mild or 
intermittent symptoms that do not impact adversely on 
quality of life may benefit from lifestyle modifications with 
medical interventions taken as needed. Patients may find 
that eating smaller meals and elimination of acidic foods 
(citrus, tomatoes, coffee, spicy foods), foods that precipi
-
tate reflux (fatty foods, chocolate, peppermint, alcohol), 
and cigarettes may reduce symptoms. Weight loss should 
be recommended for patients who are overweight or have 
had recent weight gain. All patients should be advised to 
avoid lying down within 3 hours after meals (the period of 
greatest reflux). Patients with nocturnal symptoms should 
also elevate the head of the bed on 6-inch blocks or a foam 
wedge to reduce reflux and enhance esophageal clearance.
Patients with infrequent heartburn (less than once 
weekly) may be treated on demand with antacids or oral 
H
2
-receptor antagonists. Antacids provide rapid relief of 
heartburn; however, their duration of action is less than 
2 hours. Many are available over the counter. Those con
-
taining magnesium should not be used for patients with 
kidney disease, and patients with acute or chronic kidney 
disease should be cautioned appropriately.
All oral H
2
-receptor antagonists are available in over-
the-counter formulations: cimetidine 200 mg, ranitidine 
and nizatidine 75 mg, famotidine 10 mg—all of which are 
half of the typical prescription strength. When taken for 
active heartburn, these agents have a delay in onset of at 
least 30 minutes. However, once these agents take effect, 
they provide heartburn relief for up to 8 hours. When 
taken before meals known to provoke heartburn, these 
agents reduce the symptom.
2. Troublesome symptoms—
a. 
I
nitial therapy—
Patients with troublesome reflux 
symptoms and patients with known complications of 
GERD should be treated with a once-daily oral proton 
pump inhibitor (omeprazole or rabeprazole, 20 mg; 
omeprazole, 40 mg with sodium bicarbonate; lansoprazole, 
30 mg; dexlansoprazole, 60 mg; esomeprazole or panto
-
prazole, 40 mg) taken 30 minutes before breakfast for

-
prazole, 40 mg) taken 30 minutes before breakfast for 
4–8 weeks. Because there appears to be little difference 
between these agents in efficacy or side effect profiles, the 
choice of agent is determined by cost. Oral omeprazole, 
20 mg, and lansoprazole, 15 mg, are available as over-
the-counter formulations. Once-daily proton pump inhibi
-
tors achieve adequate control of heartburn in 80–90% of 
patients, complete heartburn resolution in over 50%, and 
healing of erosive esophagitis (when present) in over 80%. 
Because of their superior efficacy and ease of use, proton 
pump inhibitors are preferred to H
2
-receptor antagonists 
for the treatment of acute and chronic GERD. Approxi
-
mately 10–20% of patients do not achieve symptom relief 
with a once-daily dose within 2–4 weeks and require a 
twice-daily proton pump inhibitor (taken 30 minutes 
before breakfast and dinner).
b. 
L
ong-term therapy—
In those who achieve good 
symptomatic relief with a course of empiric once-daily 
proton pump inhibitor, therapy may be discontinued after 
8–12 weeks. Most patients (over 80%) will experience 
relapse of GERD symptoms, usually within 3 months. 
Patients whose symptoms relapse may be treated with 
either continuous proton pump inhibitor therapy, intermit
-
tent 2- to 4-week courses, or “on demand” therapy (ie, drug 
taken until symptoms abate) depending on symptom fre
-
quency and patient preference. Alternatively, twice daily 
H
2
-receptor antagonists may be used to control symptoms 
in patients without erosive esophagitis. Patients who 
require twice-daily proton pump inhibitor therapy for ini
-
tial symptom control and patients with complications of 
GERD, including severe erosive esophagitis, Barrett esoph
-
agus, or peptic stricture, should be maintained on long-
term therapy with a once- or twice-daily proton pump 
inhibitor titrated to the lowest effective dose to achieve 
satisfactory symptom control.
Side effects of proton pump inhibitors are uncommon. 
Headache, diarrhea, and abdominal pain may occur with 
any of the agents but generally resolve when another for
-
mulation is tried. Potential risks of long-term use of proton 
pump inhibitors include an increased risk of infectious 
gastroenteritis (including 
), iron and vitamin B
12
 
deficiency, hypomagnesemia, pneumonia, hip fractures 
(possibly due to impaired calcium absorption), and fundic 
gland polyps (which appear to be of no clinical signifi
-
cance). Recent observational studies report a slight increase 
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in acute and chronic kidney disease (due to interstitial 
nephritis) and dementia; however, causality has not been 
established. Long-term proton pump inhibitor therapy 
should be prescribed to patients with appropriate indica
-
tions and at the lowest effective dose.
3. Extraesophageal reflux manifestations—
Establishing 
a causal relationship between gastroesophageal reflux and 
extraesophageal symptoms (eg, asthma, hoarseness, cough, 
sleep disturbances) is difficult. Gastroesophageal reflux 
seldom is the sole cause of extraesophageal disorders but 
may be a contributory factor. Although ambulatory esoph
-
ageal pH testing can document the presence of increased 
acid esophageal reflux, it does not prove a causative con
-
nection. Current guidelines recommend that a trial of a 
twice-daily proton pump inhibitor be administered for 2–3 
months in patients with suspected extraesophageal GERD 
syndromes who also have typical GERD symptoms. 
Improvement of extraesophageal symptoms suggests but 
does not prove that acid reflux is the causative factor. 
Esophageal impedance-pH testing or oropharyngeal pH 
testing may be performed in patients whose extraesopha
-
geal symptoms persist after 3 months of proton pump 
inhibitor therapy and may be considered before proton 
pump inhibitor therapy in patients without typical GERD 
symptoms in whom other causes of extraesophageal symp
-
toms have been excluded.
4. Unresponsive disease—
Approximately 5% do not 
respond to twice-daily proton pump inhibitors or a change 
to a different proton pump inhibitor. These patients should 
undergo endoscopy for detection of severe, inadequately 
treated reflux esophagitis and for other gastroesophageal 
lesions (including eosinophilic esophagitis) that may 
mimic GERD. Truly refractory esophagitis may be caused 
by gastrinoma with gastric acid hypersecretion (Zollinger-
Ellison syndrome), pill-induced esophagitis, resistance to 
proton pump inhibitors, and medical noncompliance. 
Patients without endoscopically visible esophagitis should 
undergo ambulatory impedance-pH monitoring while tak
-
ing a twice-daily proton pump inhibitor to determine 
whether the symptoms are correlated with acid or nonacid 
reflux episodes. The pH study is performed on therapy if 
the suspicion for GERD is high (to determine whether 
therapy has adequately suppressed acid esophageal reflux) 
and off therapy if the suspicion for GERD is low (to deter
-
mine whether the patient has reflux disease). Combined 
esophageal pH monitoring with impedance monitoring is 
preferred over pH testing alone because of its ability to 
detect both acid and nonacid reflux events. Approximately 
60% of patients with unresponsive symptoms do not have 
increased reflux and may be presumed to have a functional 
disorder. Treatment with a low-dose tricyclic antidepres
-
sant (eg, imipramine or nortriptyline 25 mg at bedtime) 
B. Surgical Treatment
Surgical fundoplication affords good to excellent relief of 
symptoms and healing of esophagitis in over 85% of prop
-
erly selected patients and can be performed laparoscopically 
with low complication rates in most instances. Although 
patient satisfaction is high, typical reflux symptoms recur in 
10–30% of patients. Furthermore, new symptoms of dys
-
phagia, bloating, increased flatulence, dyspepsia, or diar
-
rhea develop in over 30% of patients. In 2011, results from a 
randomized trial comparing laparoscopic fundoplication 
with prolonged medical therapy (esomeprazole 40 mg/day) 
for chronic GERD were reported. After 5 years, adequate 
GERD symptom control (symptom remission) was similar, 
occurring in 85–92% of patients; however, patients who had 
undergone fundoplication had increased dysphagia, bloat
-
ing, and flatulence. In 2012, the FDA approved a novel, 
minimally invasive magnetic artificial sphincter for the 
treatment of GERD. The device is made up of a flexible,

-
treatment of GERD. The device is made up of a flexible, 
elastic string of titanium beads (wrapped around a magnetic 
core) that is placed laparoscopically below the diaphragm at 
the gastroesophageal junction. A 2016 follow-up study of 85 
persons who underwent placement of this device because of 
incomplete symptom relief of chronic GERD with proton 
pump inhibitors reported that proton pump inhibitor use 
decreased from 100% pre-placement to 15% at 5 years and 
regurgitation decreased from 57% to 1.2%. There were no 
device migrations, malfunctions, or erosions. The rate of 
laparoscopic device removal for persistent dysphagia was 
3–7%. Given the excellent safety and efficacy data demon
-
strated with this device to date, it should be considered as an 
alternative to fundoplication surgery.
Surgical treatment is not recommended for patients 
who are well controlled with medical therapies but should 
be considered for (1) otherwise healthy, carefully selected 
patients with extraesophageal manifestations of reflux, as 
these symptoms often require high doses of proton pump 
inhibitors and may be more effectively controlled with 
antireflux surgery; (2) those with severe reflux disease who 
are unwilling to accept lifelong medical therapy due to its 
expense, inconvenience, or theoretical risks; and (3) 
patients with large hiatal hernias and persistent regurgita
-
tion despite proton pump inhibitor therapy. Gastric bypass 
(rather than fundoplication) should be considered for 
obese patients with GERD.
 
»
•	
Patients with typical GERD whose symptoms do not 
resolve with empiric management with a twice-daily 
proton pump inhibitor.
•	
Patients with suspected extraesophageal GERD symp
-
toms that do not resolve with 3 months of twice-daily 
proton pump inhibitor therapy.
•	
Patients with significant dysphagia or other alarm 
symptoms for upper endoscopy.
•	
Patients with Barrett esophagus for endoscopic 
surveillance.
•	
Patients who have Barrett esophagus with dysplasia or 
early mucosal cancer.
•	
Surgical fundoplication is considered.
Adler DG et al. Endoscopic management of esophageal stric
-
tures. Gastrointest Endosc. 2017 Jul;86(1):35–43. [PMID: 
28288841]
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Desai M et al. Efficacy and safety outcomes of multimodal endo
-
scopic eradication therapy in Barrett’s esophagus-related 
neoplasia: a systematic review and pooled analysis. Gastroin
-
test Endosc. 2017 Mar;85(3):482–95. [PMID: 27670227]
Duits LC et al. Patients with Barrett’s esophagus and confirmed 
persistent low-grade dysplasia are at increased risk for pro
-
gression to neoplasia. Gastroenterology. 2017 Apr;152(5):
 
993–1001. [PMID: 28012849]
Eluri S et al. Barrett’s esophagus: diagnosis and management. 
Gastrointest Endosc. 2017 May;85(5):889–903. [PMID: 
28109913]
Hatlebakk JG et al; LOTUS Study Group. Gastroesophageal acid 
reflux control 5 years after antireflux surgery, compared with 
long-term esomeprazole therapy. Clin Gastroenterol Hepatol. 
2016 May;14(5):678–85. [PMID: 26226096]
Limsrivilai J et al. Imipramine for treatment of esophageal 
hypersensitivity and functional heartburn: a randomized, 
placebo-controlled trial. Am J Gastroenterol. 2016 Feb;
 
111(2):217–24. [PMID: 26753892]
Qumseya BJ et al. Adverse events after radiofrequency ablation 
in patients with Barrett’s esophagus: a systematic review and 
meta-analysis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):
 
1086–95. [PMID: 27068041]
Repici A et al. Natural history and management of refractory 
benign esophageal strictures. Gastrointest Endosc. 2016 Aug;
 
84(2):222–8. [PMID: 26828759]
Vaezi MF et al. Complications of proton pump inhibitor therapy. 
Gastroenterology. 2017 Jul;153(1):35–48. [PMID: 28528705]
Vaezi MF et al. White paper AGA: optimal strategies to define 
and diagnose gastroesophageal reflux disease. Clin Gastroen
-
terol Hepatol. 2017 Aug;15(8):1162–72. [PMID: 28344064]
INFECTIOUS ESOPHAGITIS
 
»
Immunosuppressed patient.
 
»
Odynophagia, dysphagia, and chest pain.
 
»
Endoscopy with biopsy establishes diagnosis.
 
»
Infectious esophagitis occurs most commonly in immuno
-
suppressed patients. Patients with AIDS, solid organ trans
-
plants, leukemia, lymphoma, and those receiving 
immunosuppressive drugs are at particular risk for oppor
-
tunistic infections. 
, herpes simplex, and 
CMV are the most common pathogens. 
Candida
 infection 
may occur also in patients who have uncontrolled diabetes 
and those being treated with systemic corticosteroids, 
radiation therapy, or systemic antibiotic therapy. Herpes 
simplex can affect normal hosts, in which case the infec
-
tion is generally self-limited.
 
»
The most common symptoms are odynophagia and dys
-
phagia. Substernal chest pain occurs in some patients. 
Patients with candidal esophagitis are sometimes asymp
-
tomatic. Oral thrush is present in only 75% of patients with 
candidal esophagitis and 25–50% of patients with viral 
esophagitis and is therefore an unreliable indicator of the 
cause of esophageal infection. Patients with esophageal 
CMV infection may have infection at other sites such as the 
colon and retina. Oral ulcers (herpes labialis) are often 
associated with herpes simplex esophagitis.
Treatment may be empiric. For diagnostic certainty, endos
-
copy with biopsy and brushings (for microbiologic and 
histopathologic analysis) is preferred because of its high 
diagnostic accuracy. The endoscopic signs of candidal 
esophagitis are diffuse, linear, yellow-white plaques adher
-
ent to the mucosa. CMV esophagitis is characterized by 
one to several large, shallow, superficial ulcerations. Herpes 
esophagitis results in multiple small, deep ulcerations.
 
»
Treatment
A. Candidal Esophagitis
Systemic therapy is required for esophageal candidiasis. An 
empiric trial of antifungal therapy is often administered 
without performing diagnostic endoscopy. Initial therapy 
is generally with fluconazole, 400 mg on day 1, then 200–
400 mg/day orally for 14–21 days. Patients not responding

400 mg/day orally for 14–21 days. Patients not responding 
to empiric therapy within 3–5 days should undergo endos
-
copy with brushings, biopsy, and culture to distinguish 
resistant fungal infection from other infections (eg, CMV , 
herpes). Esophageal candidiasis not responding to flucon
-
azole therapy may be treated with itraconazole suspension 
(not capsules), 200 mg/day orally, or voriconazole, 200 mg 
orally twice daily. Refractory infection may be treated 
intravenously with caspofungin, 50 mg daily.
B. Cytomegalovirus Esophagitis
In patients with HIV infection, immune restoration with 
antiretroviral therapy is the most effective means of con
-
trolling CMV disease. Initial therapy is with ganciclovir, 
 
5 mg/kg intravenously every 12 hours for 3–6 weeks. Neu
-
tropenia is a frequent dose-limiting side effect. Once reso
-
lution of symptoms occurs, it may be possible to complete 
the course of therapy with oral valganciclovir, 900 mg once 
daily. Patients who either do not respond to or cannot 
tolerate ganciclovir are treated acutely with foscarnet, 
 
90 mg/kg intravenously every 12 hours for 3–6 weeks. The 
principal toxicity is acute kidney injury, hypocalcemia, and 
hypomagnesemia.
C. Herpetic Esophagitis
Immunocompetent patients may be treated symptomati
-
cally and generally do not require specific antiviral therapy. 
Immunosuppressed patients may be treated with oral acy
-
clovir, 400 mg orally five times daily, or 250 mg/m
2
 intrave
-
nously every 8–12 hours, usually for 14–21 days. Oral 
famciclovir, 500 mg orally three times daily, or valacyclovir, 
1 g twice daily, are also effective but more expensive than 
generic acyclovir. Nonresponders require therapy with fos
-
carnet, 40 mg/kg intravenously every 8 hours for 21 days.
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»
Prognosis
Most patients with infectious esophagitis can be effectively 
treated with complete symptom resolution. Depending on 
the patient’s underlying immunodeficiency, relapse of 
symptoms off therapy can raise difficulties. Long-term 
suppressive therapy is sometimes required.
Daniell HW . Acid suppressing therapy as a risk factor for 
Can
-
dida
 esophagitis. Dis Esophagus. 2016 Jul;29(5):479–83. 
[PMID: 25833302]
O’Rourke A. Infective oesophagitis: epidemiology, cause, diag
-
nosis and treatment options. Curr Opin Otolaryngol Head 
Neck Surg. 2015 Dec;23(6):459–63. [PMID: 26371605]
PILL-INDUCED ESOPHAGITIS
A number of different medications may injure the esopha
-
gus, presumably through direct, prolonged mucosal con
-
tact or mechanisms that disrupt mucosal integrity. The 
most commonly implicated are the NSAIDs, potassium 
chloride pills, quinidine, zalcitabine, zidovudine, alendro
-
nate and risedronate, emepronium bromide, iron, vitamin 
C, and antibiotics (doxycycline, tetracycline, clindamycin, 
trimethoprim-sulfamethoxazole). Because injury is most 
likely to occur if pills are swallowed without water or while 
supine, hospitalized or bed-bound patients are at greater 
risk. Symptoms include severe retrosternal chest pain, 
odynophagia, and dysphagia, often beginning several 
hours after taking a pill. These may occur suddenly and 
persist for days. Some patients (especially older patients) 
have relatively little pain, presenting with dysphagia. 
Endoscopy may reveal one to several discrete ulcers that 
may be shallow or deep. Chronic injury may result in 
severe esophagitis with stricture, hemorrhage, or perfora
-
tion. Healing occurs rapidly when the offending agent is 
eliminated. To prevent pill-induced damage, patients 
should take pills with 4 oz of water and remain upright for 
30 minutes after ingestion. Known offending agents 
should not be given to patients with esophageal dysmotil
-
ity, dysphagia, or strictures.
Kim SH et al. Clinical and endoscopic characteristics of drug-
induced esophagitis. World J Gastroenterol. 2014 Aug 21;
 
20(31):10994–9. [PMID: 25152603]
BENIGN ESOPHAGEAL LESIONS
1. Mallory-Weiss Syndrome 
 
(Mucosal Laceration of Gastroesophageal 
Junction)
 
»
Hematemesis; usually self-limited.
 
»
Prior history of vomiting, retching in 50%.
 
»
Endoscopy establishes diagnosis.
 
»
Mallory-Weiss syndrome is characterized by a nonpene
-
trating mucosal tear at the gastroesophageal junction that 
is hypothesized to arise from events that suddenly raise 
transabdominal pressure, such as lifting, retching, or vom
-
iting. Alcoholism is a strong predisposing factor. Mallory-
Weiss tears are responsible for approximately 5% of cases of 
upper gastrointestinal bleeding.
 
»
Patients usually present with hematemesis with or without 
melena. A history of retching, vomiting, or straining is 
obtained in about 50% of cases.
As with other causes of upper gastrointestinal hemorrhage, 
upper endoscopy should be performed after the patient has 
been appropriately resuscitated. The diagnosis is established 
by identification of a 0.5- to 4-cm linear mucosal tear usu
-
ally located either at the gastroesophageal junction or, more 
commonly, just below the junction in the gastric mucosa.
 
»
At endoscopy, other potential causes of upper gastrointes
-
tinal hemorrhage are found in over 35% of patients with 
Mallory-Weiss tears, including peptic ulcer disease, erosive 
gastritis, arteriovenous malformations, and esophageal 
varices. Patients with underlying portal hypertension are at 
higher risk for continued or recurrent bleeding.
 
»
Treatment
Patients are initially treated as needed with fluid resuscita
-
tion and blood transfusions. Most patients stop bleeding 
spontaneously and require no therapy. Endoscopic hemo
-

»
Treatment
-
-
static therapy is employed in patients who have continuing 
active bleeding. Injection with epinephrine (1:10,000), 
cautery with a bipolar or heater probe coagulation device, 
or mechanical compression of the artery by application of 
an endoclip or band is effective in 90–95% of cases. Angio
-
graphic arterial embolization or operative intervention is 
required in patients who fail endoscopic therapy.
Brown JD. Hiccups: an unappreciated cause of the Mallory-
Weiss syndrome. Am J Med. 2015 Dec;128(12):e19–20. 
[PMID: 26232752]
Nojkov B et al. Distinctive aspects of peptic ulcer disease, Dieu
-
lafoy’s lesion, and Mallory-Weiss syndrome in patients with 
advanced alcoholic liver disease or cirrhosis. World J Gastro
-
enterol. 2016 Jan 7;22(1):446–66. [PMID: 26755890]
2. Eosinophilic Esophagitis
 
»
Eosinophilia of the esophagus may be caused by eosino
-
philic esophagitis and GERD (and, rarely, celiac disease, 
Crohn disease, and pemphigus).
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Eosinophilic esophagitis is a disorder in which food or 
environmental antigens are thought to stimulate an inflam
-
matory response. Initially recognized in children, it is 
increasingly identified in young or middle-aged adults 
(estimated incidence 57/100,000), predominantly men 
(75%). A history of allergies or atopic conditions (asthma, 
eczema, hay fever) is present in over half of patients.
 
»
Most adults have a long history of dysphagia for solid-foods 
or an episode of food impaction. Heartburn may be present. 
Children may have abdominal pain, vomiting, chest pain, or 
failure to thrive. On laboratory tests, a few have eosinophilia 
or elevated IgE levels. Barium swallow studies may demon
-
strate a small-caliber esophagus; focal or long, tapered stric
-
tures; or multiple concentric rings. However, endoscopy 
with esophageal biopsy and histologic evaluation is required 
to establish the diagnosis. Endoscopic appearances include 
e
dema, concentric 
r
ings (“trachealization”), 
e
xudates (white 
plaques), 
f
urrows (vertical lines), and 
s
trictures (EREFS); 
however, the esophagus is grossly normal in up to 10% of 
patients. Multiple biopsies (at least 2–4) from the proximal 
and distal esophagus should be obtained to demonstrate 
multiple (greater than 15/high-powered field) eosinophils in 
the mucosa. Most children have other coexisting atopic 
disorders. Skin testing for food allergies may be helpful to 
identify causative factors, especially in children.
 
»
Treatment
All patients first should be given an empiric trial of a pro
-
ton pump inhibitor orally twice daily for 2 months fol
-
lowed by repeat endoscopy and mucosal biopsy. Up to 50% 
of symptomatic patients with increased esophageal eosino
-
phils have clinical and histologic improvement with proton 
pump inhibitor treatment. It is hypothesized that esopha
-
geal acid exposure may contribute to antigen-mediated 
eosinophilic inflammation. Proton pump inhibitor therapy 
should be discontinued in patients with persistent symp
-
toms and inflammation.
In patients with continued symptoms, optimal treat
-
ment is uncertain. Referral to an allergist for evaluation of 
coexisting atopic disorders and for testing for food and 
environmental allergens may be considered, but studies 
suggest limited predictive value in adults. Empiric elimina
-
tion of suspected dietary allergens leads to clinical, endo
-
scopic and histologic improvement in 50–70% of adults. 
The most common allergenic foods are dairy, eggs, wheat, 
and soy followed by peanuts and shellfish. With progres
-
sive reintroduction of each food group, the trigger food 
group may be identified in up to 85% of patients. Topical 
corticosteroids lead to symptom resolution in 70% of 
adults. Either budesonide suspension, 1 mg, or powdered 
fluticasone, 1 mg (from foil-lined inhaler diskus), is admin
-
istered twice daily for 2–4 weeks. Symptomatic relapse is 
common after discontinuation of therapy and may require 
maintenance therapy at reduced doses of 0.25 mg twice 
daily. Graduated dilation of strictures should be conducted 
in patients with dysphagia and strictures or narrow-caliber 
esophagus but should be performed cautiously because 
there is an increased risk of perforation and postprocedural 
chest pain.
Dougherty M et al. Esophageal dilation with either bougie or 
balloon technique as treatment for eosinophilic esophagitis: a 
systematic review. Gastrointest Endosc. 2017 Oct;86(4):
 
581–91. [PMID: 28461094]
Greuter T et al. Long-term treatment of eosinophilic esophagitis 
with swallowed topical corticosteroids: development and 
evaluation of a therapeutic concept. Am J Gastroenterol. 2017 
Oct;112(10):1527–35. [PMID: 28719593]
Hirano I. How I approach the management of eosinophilic 
esophagitis in adults. Am J Gastroenterol. 2017 Feb;112(2):
 
197–9. [PMID: 27845336]
Lucendo AJ et al. Efficacy of proton pump inhibitor drugs for

Lucendo AJ et al. Efficacy of proton pump inhibitor drugs for 
inducing clinical and histologic remission in patients with 
symptomatic esophageal eosinophilia: a systematic review 
and meta-analysis. Clin Gastroenterol Hepatol. 2016 Jan;
 
14(1):13–22. [PMID: 26247167]
3. Esophageal Webs & Rings
Esophageal webs are thin, diaphragm-like membranes of 
squamous mucosa that typically occur in the mid or upper 
esophagus and may be multiple. They may be congenital 
but also occur with eosinophilic esophagitis, graft-versus-
host disease, pemphigoid, epidermolysis bullosa, pemphi
-
gus vulgaris, and, rarely, in association with iron deficiency 
anemia (Plummer-Vinson syndrome). Esophageal 
“Schatzki” rings are smooth, circumferential, thin (less 
than 4 mm in thickness) mucosal structures located in the 
distal esophagus at the squamocolumnar junction. Their 
pathogenesis is controversial. They are associated in nearly 
all cases with a hiatal hernia, and reflux symptoms are 
common, suggesting that acid gastroesophageal reflux may 
be contributory in many cases. Most webs and rings are 
over 20 mm in diameter and are asymptomatic. Solid food 
dysphagia most often occurs with rings less than 13 mm in 
diameter. Characteristically, dysphagia is intermittent and 
not progressive. Large poorly chewed food boluses such as 
beefsteak are most likely to cause symptoms. Obstructing 
boluses may pass by drinking extra liquids or after regurgi
-
tation. In some cases, an impacted bolus must be extracted 
endoscopically. Esophageal webs and rings are best visual
-
ized using a barium esophagogram with full esophageal 
distention. Endoscopy is less sensitive than barium 
esophagography.
The majority of symptomatic patients with a single ring 
or web can be effectively treated with the passage of bougie 
dilators to disrupt the lesion or endoscopic electrosurgical 
incision of the ring. A single dilation may suffice, but repeat 
dilations are required in many patients. Patients who have 
heartburn or who require repeated dilation should receive 
long-term acid suppressive therapy with a proton pump 
inhibitor.
Jouhourian C et al. Abdominal compression during endoscopy 
(the Bolster technique) demonstrates hidden Schatzki rings 
(with videos). Gastrointest Endosc. 2016 May;83(5):1024–6. 
[PMID: 26548850]
Novak SH et al. Effective treatment of symptomatic lower 
esophageal (Schatzki) rings with acid suppression therapy: 
confirmed on barium esophagography. AJR Am J Roentgenol. 
2015 Dec;205(6):1182–7. [PMID: 26587923]
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4. Zenker Diverticulum
Zenker diverticulum is a protrusion of pharyngeal mucosa 
that develops at the pharyngoesophageal junction between 
the inferior pharyngeal constrictor and the cricopharyn
-
geus. The cause is believed to be loss of elasticity of the 
upper esophageal sphincter, resulting in restricted opening 
during swallowing. Symptoms of dysphagia and regurgita
-
tion tend to develop insidiously over years in older, pre
-
dominantly male patients. Initial symptoms include vague 
oropharyngeal dysphagia with coughing or throat discom
-
fort. As the diverticulum enlarges and retains food, patients 
may note halitosis, spontaneous regurgitation of undi
-
gested food, nocturnal choking, gurgling in the throat, or a 
protrusion in the neck. Complications include aspiration 
pneumonia, bronchiectasis, and lung abscess. The diagno
-
sis is best established by a videoesophagography.
Symptomatic patients require upper esophageal myot
-
omy. Minimally invasive intraluminal approaches have 
been developed in which the septum between the esopha
-
gus and diverticulum is incised using a rigid or flexible 
endoscope or a diverticuloscope. Significant improvement 
occurs in over 90% of patients. Small asymptomatic diver
-
ticula may be observed.
Bonavina L et al. Long-term outcome and quality of life after 
transoral stapling for Zenker diverticulum. World J Gastroen
-
terol. 2015 Jan 28;21(4):1167–72. [PMID: 25632189]
Ishaq S et al. Flexible endoscopic treatment for Zenker’s diver
-
ticulum: a systematic review and meta-analysis. Gastrointest 
Endosc. 2016 Jun;83(6):1076–89. [PMID: 26802196]
Johnson CM et al. Zenker diverticulum—which surgical 
approach is superior? JAMA Otolaryngol Head Neck Surg. 
2016 Apr;142(4):401–3. [PMID: 26914440]
5. Esophageal Varices
 
»
Develop secondary to portal hypertension.
 
»
Found in 50% of patients with cirrhosis.
 
»
One-third of patients with varices develop upper 
gastrointestinal bleeding.
 
»
Diagnosis established by upper endoscopy.
 
»
Esophageal varices are dilated submucosal veins that develop 
in patients with underlying portal hypertension and may 
result in serious upper gastrointestinal bleeding. The causes 
of portal hypertension are discussed in Chapter 16. Under 
normal circumstances, there is a 2–6 mm Hg pressure gradi
-
ent between the portal vein and the inferior vena cava. When 
the gradient exceeds 10–12 mm Hg, significant portal hyper
-
tension exists. Esophageal varices are the most common 
cause of important gastrointestinal bleeding due to portal 
hypertension, though gastric varices and, rarely, intestinal 
varices may also bleed. Bleeding from esophageal varices 
most commonly occurs in the distal 5 cm of the esophagus.
The most common cause of portal hypertension is cir
-
rhosis. Approximately 50% of patients with cirrhosis have 
esophageal varices. Bleeding from varices occurs in 30% of 
patients with esophageal varices. In the absence of any 
treatment, variceal bleeding spontaneously stops in about 
50% of patients. Patients surviving this bleeding episode 
have a 60% chance of recurrent variceal bleeding, usually 
within the first 6 weeks. With current therapies, the in-
hospital mortality rate associated with bleeding esophageal 
varices is 15%.
A number of factors have been identified that may por
-
tend an increased risk of bleeding from esophageal varices. 
The most important are (1) the size of the varices; (2) the 
presence at endoscopy of red wale markings (longitudinal 
dilated venules on the varix surface); (3) the severity of 
liver disease (as assessed by Child scoring); and (4) active 
alcohol abuse—patients with cirrhosis who continue to 
drink have an extremely high risk of bleeding.
 
»
Patients with bleeding esophageal varices present with 
symptoms and signs of acute gastrointestinal hemorrhage.

»
symptoms and signs of acute gastrointestinal hemorrhage. 
(See Acute Upper Gastrointestinal Bleeding, above.) In 
some cases, there may be preceding retching or dyspepsia 
attributable to alcoholic gastritis or withdrawal. Varices per 
se do not cause symptoms of dyspepsia, dysphagia, or 
retching. Variceal bleeding usually is severe, resulting in 
hypovolemia manifested by postural vital signs or shock. 
Twenty percent of patients with chronic liver disease in 
whom bleeding develops have a nonvariceal source of 
bleeding.
These are identical to those listed above in the section on 
acute upper gastrointestinal tract bleeding.
 
»
Initial Management
A. Acute Resuscitation
The initial management of patients with acute upper gas
-
trointestinal bleeding is also discussed in the section on 
Acute Upper Gastrointestinal Bleeding. Variceal hemorrhage 
is life-threatening; rapid assessment and resuscitation with 
fluids or blood products are essential. Overtransfusion 
should be avoided as it leads to increased central and portal 
venous pressures, increasing the risk of rebleeding. Many 
patients with bleeding esophageal varices have coagulopa
-
thy due to underlying cirrhosis; fresh frozen plasma 
(20 mL/kg loading dose, then 10 mg/kg every 6 hours) or 
platelets should be administered to patients with INRs 
greater than 1.8–2.0 or with platelet counts less than 
50,000/mcL in the presence of active bleeding. Recombi
-
nant factor VIIa has not demonstrated efficacy in con
-
trolled studies and is not recommended. The role of 
prothrombin complex concentrates requires further study. 
Patients with advanced liver disease are at high risk for 
poor outcome regardless of the bleeding source and should 
be transferred to an ICU.
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B. Pharmacologic Therapy
1. Antibiotic prophylaxis—
Cirrhotic patients admitted 
with upper gastrointestinal bleeding have a greater than 
50% chance of developing a severe bacterial infection dur
-
ing hospitalization—such as bacterial peritonitis, pneumo
-
nia, or urinary tract infection. Most infections are caused 
by gram-negative organisms of gut origin. Prophylactic 
administration of oral or intravenous fluoroquinolones (eg, 
norfloxacin, 400 mg orally twice daily) or intravenous 
third-generation cephalosporins (eg, ceftriaxone, 1 g/day) 
for 5–7 days reduces the risk of serious infection to 10–20% 
as well as hospital mortality, especially in patients with 
Child-Pugh class C cirrhosis. Because of a rising incidence 
of infections caused by gram-positive organisms as well as 
fluoroquinolone-resistant organisms, intravenous third-
generation cephalosporins may be preferred.
2. Vasoactive drugs—
Somatostatin and octreotide infu
-
sions reduce portal pressures in ways that are poorly under
-
stood. Somatostatin (250 mcg/h)—not available in the 
United States—or octreotide (50 mcg intravenous bolus fol
-
lowed by 50 mcg/h) reduces splanchnic and hepatic blood 
flow and portal pressures in cirrhotic patients. Both agents 
appear to provide acute control of variceal bleeding in up to 
80% of patients although neither has been shown to reduce 
mortality. Data about the absolute efficacy of both are con
-
flicting, but they may be comparable in efficacy to endo
-
scopic therapy. Combined treatment with octreotide or 
somatostatin infusion and endoscopic therapy (band liga
-
tion or sclerotherapy) is superior to either modality alone in 
controlling acute bleeding and early rebleeding, and it may 
improve survival. In patients with advanced liver disease and 
upper gastrointestinal hemorrhage, it is reasonable to initiate 
therapy with octreotide or somatostatin on admission and 
continue for 3–5 days if varices are confirmed by endoscopy. 
If bleeding is determined by endoscopy not to be secondary 
to portal hypertension, the infusion can be discontinued.
Terlipressin, 1–2 mg intravenous every 4 hours (not 
available in the United States), is a synthetic vasopressin 
analog that causes a significant and sustained reduction in 
portal and variceal pressures while preserving renal perfu
-
sion. Where available, terlipressin may be preferred to 
somatostatin or octreotide. Terlipressin is contraindicated 
in patients with significant coronary, cerebral, or periph
-
eral vascular disease.
3. Vitamin K—
In cirrhotic patients with an abnormal pro
-
thrombin time, vitamin K (10 mg) should be administered 
4. Lactulose—
Encephalopathy may complicate an episode 
of gastrointestinal bleeding in patients with severe liver 
disease. In patients with encephalopathy, lactulose 
should be administered in a dosage of 30 mL orally 
every 1–2 hours until evacuation occurs then reduced to 
15–45 mL/h every 8–12 hours as needed to promote two or 
three bowel movements daily. (See Chapter 16.)
C. Emergent Endoscopy
Emergent endoscopy is performed after the patient’s 
hemodynamic status has been appropriately stabilized 
(usually within 2–12 hours). In patients with active bleed
-
ing, endotracheal intubation is commonly performed to 
protect against aspiration during endoscopy. An endo
-
scopic examination is performed to exclude other or asso
-
ciated causes of upper gastrointestinal bleeding such as 
Mallory-Weiss tears, peptic ulcer disease, and portal 
hypertensive gastropathy. In many patients, variceal bleed
-
ing has stopped spontaneously by the time of endoscopy, 
and the diagnosis of variceal bleeding is made presump
-
tively. Immediate endoscopic treatment of the varices gen
-
erally is performed with banding. In clinical practice, 
sclerotherapy seldom is used. These techniques arrest 
active bleeding in 80–90% of patients and reduce the

-
active bleeding in 80–90% of patients and reduce the 
chance of in-hospital recurrent bleeding to about 20%.
If banding is chosen, repeat sessions are scheduled at 
intervals of 2–4 weeks until the varices are obliterated or 
reduced to a small size. Banding achieves lower rates of 
rebleeding, complications, and death than sclerotherapy and 
should be considered the endoscopic treatment of choice.
D. Balloon Tube Tamponade
Mechanical tamponade with specially designed nasogastric 
tubes containing large gastric and esophageal balloons 
(Minnesota or Sengstaken-Blakemore tubes) provides ini
-
tial control of active variceal hemorrhage in 60–90% of 
patients; rebleeding occurs in 50%. Given its high rate of 
complications, mechanical tamponade is used as a tempo
-
rizing measure only in patients with bleeding that cannot 
be controlled with pharmacologic or endoscopic tech
-
niques until more definitive decompressive therapy (eg, 
TIPS) can be provided.
E. Portal Decompressive Procedures
In the 10–20% of patients with variceal bleeding that can
-
not be controlled with pharmacologic or endoscopic ther
-
apy, emergency portal decompression may be considered.
1. Transvenous intrahepatic portosystemic shunts 
(TIPS)
—
Over a wire that is passed through a catheter 
inserted in the jugular vein, an expandable wire mesh stent 
(8–12 mm in diameter) is passed through the liver paren
-
chyma, creating a portosystemic shunt from the portal vein 
to the hepatic vein. TIPS can control acute hemorrhage in 
over 90% of patients actively bleeding from gastric or 
esophageal varices. However, when TIPS is performed in 
the actively bleeding patient, the mortality approaches 
40%, especially in patients requiring ventilatory support or 
blood pressure support and patients with renal insuffi
-
ciency, bilirubin greater than 3 mg/dL, or encephalopathy. 
Therefore, TIPS should be considered in the 10–20% of 
patients with acute variceal bleeding that cannot be con
-
trolled with pharmacologic and endoscopic therapy, but it 
may not be warranted in patients with a particularly poor 
2. Emergency portosystemic shunt surgery—
Emergency 
portosystemic shunt surgery is associated with a 40–60% 
mortality rate. At centers where TIPS is available, that pro
-
cedure has become the preferred means of providing emer
-
gency portal decompression.
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»
Prevention of Rebleeding
Once the initial bleeding episode has been controlled, 
therapy is warranted to reduce the high risk (60%) of 
rebleeding.
A. Combination Beta-Blockers and Variceal Band 
Ligation
Nonselective beta-adrenergic blockers (propranolol, 
nadolol) reduce the risk of rebleeding from esophageal 
varices to about 40%. Likewise, long-term treatment with 
band ligation reduces the incidence of rebleeding to about 
30%. In most patients, two to six treatment sessions 
(performed at 2- to 4-week intervals) are needed to eradicate 
the varices.
Meta-analyses of randomized controlled trials suggest 
that a 
combination
 of band ligation plus beta-blockers is 
superior to either variceal band ligation alone (RR 0.68) or 
beta-blockers alone (RR 0.71). Therefore, combination 
therapy is recommended for patients without contraindica
-
tions to beta-blockers. Recommended starting doses of 
beta-blockers are propranolol (20 mg orally twice daily), 
long-acting propranolol (60 mg orally once daily), or nado
-
lol (20–40 mg orally once daily), with gradual increases in 
the dosage every 1–2 weeks until the heart rate falls by 25% 
or reaches 55–60 beats/min, provided the systolic blood 
pressure remains above 90 mm Hg and the patient has no 
side effects. The average dosage of long-acting propranolol 
is 120 mg once daily and for nadolol, 80 mg once daily. 
One-third of patients with cirrhosis are intolerant of beta-
blockers, experiencing fatigue or hypotension. Drug 
administration at bedtime may reduce the frequency and 
severity of side effects.
B. Transvenous Intrahepatic Portosystemic Shunt
TIPS has resulted in a significant reduction in recurrent 
bleeding compared with endoscopic sclerotherapy or band 
ligation—either alone or in combination with beta-blocker 
therapy. At 1 year, rebleeding rates in patients treated with 
TIPS versus various endoscopic therapies average 20% and 
40%, respectively. However, TIPS was also associated with 
a higher incidence of encephalopathy (35% vs 15%) and 
did not result in a decrease in mortality. Another limita
-
tion of TIPS is that stenosis and thrombosis of the stents 
occur in the majority of patients over time with a conse
-
quent risk of rebleeding. Therefore, periodic monitoring 
with Doppler ultrasonography or hepatic venography is 
required. Stent patency usually can be maintained by bal
-
loon angioplasty or additional stent placement. Given 
these problems, TIPS should be reserved for patients who 
have recurrent (two or more) episodes of variceal bleeding 
that have failed endoscopic or pharmacologic therapies. 
TIPS is also useful in patients with recurrent bleeding from 
gastric varices or portal hypertensive gastropathy (for 
which endoscopic therapies cannot be used). TIPS is like
-
wise considered in patients who are noncompliant with 
other therapies or who live in remote locations (without 
access to emergency care).
C. Surgical Portosystemic Shunts
Shunt surgery has a significantly lower rate of rebleeding 
compared with endoscopic therapy but also a higher inci
-
dence of encephalopathy. With the advent and widespread 
adoption of TIPS, surgical shunts are seldom performed.
D. Liver Transplantation
Candidacy for orthotopic liver transplantation should be 
assessed in all patients with chronic liver disease and bleed
-
ing due to portal hypertension. Transplant candidates 
should be treated with band ligation or TIPS to control 
bleeding pretransplant.
 
»
Prevention of First Episodes 
 
of Variceal Bleeding
Among patients with varices that have not previously bled, 
bleeding occurs in 12% of patients each year, with a lifetime 
risk of 30%. Because of the high mortality rate associated 
with variceal hemorrhage, prevention of the initial bleeding 
episode is desirable. Therefore, patients with cirrhosis 
should undergo diagnostic endoscopy or capsule endoscopy 
to determine whether varices are present. Varices are pres
-

-
ent in 40% of patients with Child-Pugh class A cirrhosis and 
in 85% with Child-Pugh class C cirrhosis. In patients with
-
out varices on screening endoscopy, a repeat endoscopy is 
recommended in 3 years, since varices develop in 8% of 
patients per year. Patients with varices have a higher risk of 
bleeding if they have varices larger than 5 mm, varices with 
red wale markings, or Child-Pugh class B or C cirrhosis. The 
risk of bleeding in patients with varices smaller than 5 mm 
is 5% per year and with large varices is 15–20% per year. 
Patients with small varices without red wale marks and 
compensated (Child-Pugh class A) cirrhosis have a low-risk 
of bleeding; hence, prophylaxis is unnecessary, but endos
-
copy should be repeated in 1–2 years to reassess size.
Nonselective beta-adrenergic blockers are recom
-
mended to reduce the risk of first variceal hemorrhage in 
patients with medium/large varices and patients with small 
varices who either have variceal red wale marks or advanced 
cirrhosis (Child-Pugh class B or C). (See Combination 
Beta-Blockers and Variceal Band Ligation, above.) Band 
ligation is not recommended for small varices due to tech
-
nical difficulties in band application. Prophylactic band 
ligation may be preferred over beta-blockers for patients at 
higher risk for bleeding, especially patients with medium/
large varices with red wale markings or with advanced cir
-
rhosis (Child-Pugh class B or C) as well as patients with 
contraindications to or intolerance of beta-blockers.
 
»
•	
All patients with upper gastrointestinal bleeding and 
suspected varices should be evaluated by a physician 
skilled in therapeutic endoscopy.
•	
Patients being considered for TIPS procedures or liver 
•	
Patients with cirrhosis for endoscopic evaluation for 
varices.
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»
All patients with acute upper gastrointestinal bleeding and 
suspected cirrhosis should be admitted to an ICU.
Albillos A et al; Baveno Cooperation. Stratifying risk in the pre
-
vention of recurrent variceal hemorrhage: results of an indi
-
vidual patient meta-analysis. Hepatology. 2017 Oct;66(4):
 
1219–31. [PMID: 28543862]
ASGE Standards of Practice Committee; Hwang JH et al. The 
role of endoscopy in the management of variceal hemorrhage. 
Gastrointest Endosc. 2014 Aug;80(2):221–7. [PMID: 
25034836]
Brunner F et al. Prevention and treatment of variceal haemor
-
rhage in 2017. Liver Int. 2017 Jan;37(Suppl 1):104–15. [PMID: 
28052623]
Cárdenas A et al. Endoscopic hemostasis in acute esophageal 
variceal bleeding. Gastroenterol Clin North Am. 2014 Dec;
 
43(4):795–806. [PMID: 25440926]
Moon AM et al. Use of antibiotics among patients with cirrhosis 
and upper gastrointestinal bleeding is associated with reduced 
mortality. Clin Gastroenterol Hepatol. 2016 Nov;14(11):
 
1629–37. [PMID: 27311621]
Tandon P et al. Risk of bacterial infection in patients with cir
-
rhosis and acute variceal hemorrhage, based on Child-Pugh 
class and effects of antibiotics. Clin Gastroenterol Hepatol. 
2015 Jun;13(6):1189–96. [PMID: 25460564]
ESOPHAGEAL MOTILITY DISORDERS
1. Achalasia
 
»
Gradual, progressive dysphagia for solids and 
liquids.
 
»
Regurgitation of undigested food.
 
»
Barium esophagogram with “bird’s beak” distal 
esophagus.
 
»
Esophageal manometry confirms diagnosis.
 
»
Achalasia is an idiopathic motility disorder characterized 
by loss of peristalsis in the distal two-thirds (smooth mus
-
cle) of the esophagus and impaired relaxation of the LES. 
There appears to be denervation of the esophagus resulting 
primarily from loss of nitric oxide–producing inhibitory 
neurons in the myenteric plexus. The cause of the neuronal 
degeneration is unknown.
 
»
There is a steady increase in the incidence of achalasia 
with age; however, it can be seen in individuals as young 
as 25 years. Patients complain of the gradual onset of dys
-
phagia for solid foods and, in the majority, of liquids also. 
Symptoms at presentation may have persisted for months to 
years. Substernal discomfort or fullness may be noted after 
eating. Many patients eat more slowly and adopt specific 
maneuvers such as lifting the neck or throwing the shoul
-
ders back to enhance esophageal emptying. Regurgitation 
of undigested food is common and may occur during 
meals or up to several hours later. Nocturnal regurgitation 
can provoke coughing or aspiration. Up to 50% of patients 
report substernal chest pain that is unrelated to meals or 
exercise and may last up to hours. Weight loss is common. 
Physical examination is unhelpful.
B. Imaging
Chest radiographs may show an air-fluid level in the 
enlarged, fluid-filled esophagus. Barium esophagography 
discloses characteristic findings, including esophageal dila
-
tion, loss of esophageal peristalsis, poor esophageal empty
-
ing, and a smooth, symmetric “bird’s beak” tapering of the 
distal esophagus. Without treatment, the esophagus may 
become markedly dilated (“sigmoid esophagus”).
C. Special Examinations
After esophagography, endoscopy is always performed to 
evaluate the distal esophagus and gastroesophageal junc
-
tion to exclude a distal stricture or a submucosal infiltrat
-
ing carcinoma. The diagnosis is confirmed by esophageal 
manometry. The manometric features are complete 
absence of normal peristalsis and incomplete lower esoph
-
ageal sphincteric relaxation with swallowing. Using high-
resolution esophageal topographic tracings, three achalasia 
subtypes are recognized. Type III is a spastic variant with 
less favorable treatment outcomes (66%) than types I 
(81%) or II (96%).
 
»

»
Chagas disease is associated with esophageal dysfunction 
that is indistinguishable from idiopathic achalasia and 
should be considered in patients from endemic regions 
(Central and South America); it is becoming more com
-
mon in the southern United States. Primary or metastatic 
tumors can invade the gastroesophageal junction, resulting 
in a picture resembling that of achalasia, called “pseudo
-
achalasia. ” Endoscopic ultrasonography and chest CT may 
be required to examine the distal esophagus in suspicious 
cases.
 
»
Treatment
A. Botulinum Toxin Injection
Endoscopically guided injection of botulinum toxin directly 
into the LES results in a marked reduction in LES pressure 
with initial improvement in symptoms in 65–85% of 
patients. However, symptom relapse occurs in over 50% 
of patients within 6–9 months and in all patients within 
2 years. Because it is inferior to pneumatic dilation therapy 
and surgery in producing sustained symptomatic relief, this 
therapy is most appropriate for patients with comorbidities 
who are poor candidates for more invasive procedures.
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B. Pneumatic Dilation
Up to 90% of patients derive good to excellent relief of 
dysphagia after one to three sessions of pneumatic dilation 
of the LES. Dilation is less effective in patients who are 
younger than age 45, have the type III variant, or have a 
dilated esophagus. Symptoms recur following pneumatic 
dilation in up to 35% within 10 years but usually respond 
to repeated dilation. Perforations occur in less than 3% of 
dilations and may require operative repair. The success of 
laparoscopic myotomy is not compromised by prior pneu
-
matic dilation.
C. Surgery
A modified Heller cardiomyotomy of the LES and cardia 
results in good to excellent symptomatic improvement in 
over 90% of patients. Because gastroesophageal reflux 
develops in up to 20% of patients after myotomy, most 
surgeons also perform an antireflux procedure (fundopli
-
cation), and all patients are prescribed a once-daily proton 
pump inhibitor. Myotomy is performed with a laparo
-
scopic approach and is preferred to the open surgical 
approach. Symptoms recur following cardiomyotomy in 
greater than 25% of cases within 10 years but usually 
respond to pneumatic dilation. A 2015 systematic review of 
nine randomized controlled trials reported treatment effi
-
cacy in 70–90% of patients treated with pneumatic dilation 
and 88–95% with laparoscopic myotomy. This was con
-
firmed in a 2016 multicenter randomized trial, which 
found similar improvement with pneumatic dilation and 
Heller myotomy at 1 year. Thus, in experienced hands, the 
initial efficacies of pneumatic dilation and laparoscopic 
myotomy are nearly equivalent. Pneumatic dilation may be 
less effective in men younger than 45 years, so surgical 
myotomy may be preferred for them. Surgical myotomy 
may also be preferred for patients with the type III variant. 
Complete esophagectomy or percutaneous gastrostomy is 
required in 2–5% of patients in whom massive dilation of 
the esophagus (megaesophagus) develops despite dilation 
or myotomy. In megaesophagus, dysphagia, food retention, 
and regurgitation may decrease nutrition and quality of life 
and increase risk of aspiration.
D. Per Oral Endoscopic Myotomy (POEM)
Since 2011, selected, highly experienced centers in Southeast 
Asia and in the United States have reported excellent 
results with a less invasive endoscopic procedure in which 
an endoscope is inserted into the patient’s mouth and 
passed into the upper esophagus. After a small incision is 
made in the esophageal mucosa, the endoscope dissects 
through the submucosal space to the lower esophageal 
sphincter, where the circular muscle fibers of the cardia 
and distal esophagus are incised. In multiple uncontrolled 
studies involving thousands of patients, success rates of 
over 90% are reported, including patients with type III 
achalasia. Because a fundoplication is not performed, long-
term antisecretory therapy for gastroesophageal reflux 
with a proton pump inhibitor is required in many patients. 
In expert centers, POEM may be the preferred treatment 
modality for type III achalasia (where a longer myotomy of 
the distal esophagus is indicated) and an appropriate 
option in patients with type I and II achalasia who do not 
wish to have laparoscopic surgery.
Chrystoja CC et al. Achalasia-specific quality of life after pneu
-
matic dilation or laparoscopic Heller myotomy with partial 
fundoplication: a multicenter, randomized controlled trial. 
Am J Gastroenterol. 2016 Nov;111(11):1536–45. [PMID: 
27619832]
Haito-Chavez Y et al. Comprehensive analysis of adverse events 
associated with per oral endoscopic myotomy in 1826 
patients: an international multicenter study. Am J Gastroen
-
terol. 2017 Aug;112(8):1267–76. [PMID: 28534521]
Kahrilas PJ et al. Clinical practice update: the use of per-oral 
endoscopic myotomy in achalasia: expert review and best 
practice advice from the AGA Institute. Gastroenterology.

practice advice from the AGA Institute. Gastroenterology. 
2017 Nov;153(5):1205–11. [PMID: 28989059]
Ngamruengphong S et al. Long-term outcomes of per-oral endo
-
scopic myotomy in patients with achalasia with a minimum 
follow-up of 2 years: an international multicenter study. Gas
-
trointest Endosc. 2017 May;85(5):927–33. [PMID: 27663714]
Pannala R et al. ASGE Technology Status Evaluation Report: 
Per-oral myotomy (with video). Gastrointest Endosc. 
2016 Jun;83(6):1051–60. [PMID: 27033144]
2. Other Primary Esophageal Motility Disorders
 
»
Abnormalities in esophageal motility may cause dysphagia 
or chest pain. Dysphagia for liquids as well as solids tends 
to be intermittent and nonprogressive. Periods of normal 
swallowing may alternate with periods of dysphagia, which 
usually is mild though bothersome—rarely severe enough 
to result in significant alterations in lifestyle or weight loss. 
Dysphagia may be provoked by stress, large boluses of 
food, or hot or cold liquids. Some patients may experience 
anterior chest pain that may be confused with angina pec
-
toris but usually is nonexertional. The pain generally is 
unrelated to eating. (See Chest Pain of Undetermined 
Origin, below.)
The evaluation of suspected esophageal motility disorders 
includes barium esophagography, upper endoscopy, and, in 
some cases, esophageal manometry. Barium esophagogra
-
phy is useful to exclude mechanical obstruction and to 
evaluate esophageal motility. The presence of simultaneous 
contractions (spasm), disordered peristalsis, or failed peri
-
stalsis supports a diagnosis of esophageal dysmotility. 
Upper endoscopy also is performed to exclude a mechani
-
cal obstruction (as a cause of dysphagia) and to look for 
evidence of erosive reflux esophagitis (a common cause of 
chest pain) or eosinophilic esophagitis (confirmed by 
esophageal biopsy). Manometry is not routinely used for 
mild to moderate symptoms because the findings seldom 
influence further medical management, but it may be use
-
ful in patients with persistent, disabling dysphagia to 
exclude achalasia and to look for other disorders of 
esophageal motility. These include diffuse esophageal 
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spasm, hypercontractile esophagus, esophagogastric junc
-
tion outflow obstruction, and findings of ineffective esoph
-
ageal peristalsis (failed or weak esophageal peristalsis). The 
further evaluation of noncardiac chest pain is discussed 
below.
 
»
Treatment
For patients with mild symptoms of dysphagia, therapy is 
directed at symptom reduction and reassurance. Patients 
should be instructed to eat more slowly and take smaller 
bites of food. In some cases, a warm liquid at the start of a 
meal may facilitate swallowing. Because unrecognized gas
-
troesophageal reflux may cause dysphagia, a trial of a pro
-
ton pump inhibitor (esomeprazole 40 mg, lansoprazole 
30 mg) orally twice daily should be administered for 
4–8 weeks. Treatment of patients with severe dysphagia is 
empiric. Suspected spastic disorders may be treated with 
isosorbide (10–20 mg four times daily) or nitroglycerin 
(0.4 mg sublingually as needed) and nifedipine (10 mg) or 
diltiazem (60–90 mg) 30–45 minutes before meals; their 
efficacy is unproved. For unclear reasons, esophageal dila
-
tion provides symptomatic relief in some cases.
Carlson DA et al. Diagnosis of esophageal motility disorders: 
esophageal pressure topography vs. conventional line tracing. 
Am J Gastroenterol. 2015 Jul;110(7):967–77. [PMID: 
26032151]
Khan MA et al. Is POEM the answer for management of spastic 
esophageal disorders? A systematic review and meta-analysis. 
Dig Dis Sci. 2017 Jan;62(1):35–44. [PMID: 27858325]
Rohof WOA et al. Chicago Classification of esophageal motility 
disorders: lessons learned. Curr Gastroenterol Rep. 2017 Aug;
 
19(8):37. [PMID: 28730503]
CHEST PAIN OF UNDETERMINED ORIGIN
One-third of patients with chest pain undergo negative 
cardiac evaluation. Patients with recurrent noncardiac chest 
pain thus pose a difficult clinical problem. Because coro
-
nary artery disease is common and can present atypically, it 
must be excluded prior to evaluation for other causes.
Causes of noncardiac chest pain may include the 
following.
A. Chest Wall and Thoracic Spine Disease
These are easily diagnosed by history and physical 
B. Gastroesophageal Reflux
Up to 50% of patients have increased amounts of gastro
-
esophageal acid reflux or a correlation between acid reflux 
episodes and chest pain demonstrated on esophageal pH 
testing. An empiric 4-week trial of acid-suppressive ther
-
apy with a high-dose proton pump inhibitor is recom
-
mended (eg, omeprazole or rabeprazole, 40 mg orally twice 
daily; lansoprazole, 30–60 mg orally twice daily; or esome
-
prazole or pantoprazole, 40 mg orally twice daily), espe
-
cially in patients with reflux symptoms. In patients with 
persistent symptoms, ambulatory esophageal pH or 
impedance and pH study may be useful to exclude defini
-
tively a relationship between acid and nonacid reflux epi
-
sodes and chest pain events.
C. Esophageal Dysmotility
Esophageal motility abnormalities such as diffuse esopha
-
geal spasm or hypercontractile swallow (“jackhammer 
esophagus”) are uncommon causes of noncardiac chest 
pain. In patients with chest pain and dysphagia, a barium 
swallow radiograph should be obtained to look for evi
-
dence of achalasia or diffuse esophageal spasm. Esophageal 
manometry is not routinely performed because of low 
specificity and the unlikelihood of finding a clinically sig
-
nificant disorder, but it may be recommended in patients 
with frequent symptoms.
D. Heightened Visceral Sensitivity
Some patients with noncardiac chest pain report pain in 
response to a variety of minor noxious stimuli such as 
physiologically normal amounts of acid reflux, inflation of 
balloons within the esophageal lumen, injection of intrave
-
nous edrophonium (a cholinergic stimulus), or intracardiac 
catheter manipulation. Low doses of oral antidepressants 
such as trazodone 50 mg or imipramine 10–50 mg reduce 
chest pain symptoms and are thought to reduce visceral

chest pain symptoms and are thought to reduce visceral 
afferent awareness. In a 2010 controlled crossover trial, 
over 50% of patients treated with venlafaxine, 75 mg once 
daily at bedtime, achieved symptomatic improvement com
-
pared with only 4% treated with placebo.
E. Psychological Disorders
A significant number of patients have underlying depres
-
sion, anxiety, and panic disorder. Patients reporting dys
-
pnea, sweating, tachycardia, suffocation, or fear of dying 
should be evaluated for panic disorder.
Bowers SP . Esophageal motility disorders. Surg Clin North Am. 
2015 Jun;95(3):467–82. [PMID: 25965124]
Coss-Adame E et al. Treatment of esophageal (noncardiac) chest 
pain: an expert review. Clin Gastroenterol Hepatol. 2014 
Aug;12(8):1224–45. [PMID: 23994670]
 
º
h
E STOMAC
h
 
& 
DUODENUM
(See Chapter 39 for Gastric Cancers.)
GASTRITIS & GASTROPATHY
The term “gastropathy” should be used to denote condi
-
tions in which there is epithelial or endothelial damage 
without inflammation, and “gastritis” should be used to 
denote conditions in which there is histologic evidence of 
inflammation. In clinical practice, the term “gastritis” is 
commonly applied to three categories: (1) erosive and 
hemorrhagic “gastritis” (gastropathy); (2) nonerosive, non
-
specific (histologic) gastritis; and (3) specific types of gas
-
tritis, characterized by distinctive histologic and endoscopic 
features diagnostic of specific disorders.
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1. Erosive & 
h
emorrhagic “Gastritis” 
(Gastropathy)
 
»
Most commonly seen in alcoholic or critically ill 
patients, or patients taking NSAIDs.
 
»
Often asymptomatic; may cause epigastric pain, 
nausea, and vomiting.
 
»
May cause hematemesis; usually insignificant 
bleeding.
 
»
The most common causes of erosive gastropathy are medi
-
cations (especially NSAIDs), alcohol, stress due to severe 
medical or surgical illness, and portal hypertension (“por
-
tal gastropathy”). Major risk factors for stress gastritis 
include mechanical ventilation, coagulopathy, trauma, 
burns, shock, sepsis, central nervous system injury, liver 
failure, kidney disease, and multiorgan failure. The use of 
enteral nutrition reduces the risk of stress-related bleeding. 
Uncommon causes of erosive gastropathy include isch
-
emia, caustic ingestion, and radiation. Erosive and hemor
-
rhagic gastropathy typically are diagnosed at endoscopy, 
often being performed because of dyspepsia or upper gas
-
trointestinal bleeding. Endoscopic findings include subepi
-
thelial hemorrhages, petechiae, and erosions. These lesions 
are superficial, vary in size and number, and may be focal 
or diffuse. There usually is no significant inflammation on 
histologic examination.
 
»
Erosive gastropathy is usually asymptomatic. Symptoms, 
when they occur, include anorexia, epigastric pain, nausea, 
and vomiting. There is poor correlation between symp
-
toms and the number or severity of endoscopic abnormali
-
ties. The most common clinical manifestation of erosive 
gastritis is upper gastrointestinal bleeding, which presents 
as hematemesis, “coffee grounds” emesis, or bloody aspi
-
rate in a patient receiving nasogastric suction, or as melena. 
Because erosive gastritis is superficial, hemodynamically 
significant bleeding is rare.
The laboratory findings are nonspecific. The hematocrit is 
low if significant bleeding has occurred; iron deficiency 
may be found.
Upper endoscopy is the most sensitive method of diagno
-
sis. Although bleeding from gastritis is usually insignifi
-
cant, it cannot be distinguished on clinical grounds from 
more serious lesions such as peptic ulcers or esophageal 
varices. Hence, endoscopy is generally performed within 
24 hours in patients with upper gastrointestinal bleeding to 
identify the source. An upper gastrointestinal series is 
sometimes obtained in lieu of endoscopy in patients with 
hemodynamically insignificant upper gastrointestinal 
bleeds to exclude serious lesions but is insensitive for the 
detection of gastritis.
 
»
Epigastric pain may be due to peptic ulcer, gastroesopha
-
geal reflux, gastric cancer, biliary tract disease, food poi
-
soning, viral gastroenteritis, and functional dyspepsia. 
With severe pain, one should consider a perforated or 
penetrating ulcer, pancreatic disease, esophageal rupture, 
ruptured aortic aneurysm, gastric volvulus, gastrointestinal 
ischemia, and myocardial ischemia. Causes of upper gas
-
trointestinal bleeding include peptic ulcer disease, esopha
-
geal varices, Mallory-Weiss tear, and angioectasias.
 
»
Specific Causes & Treatment
A. Stress Gastritis
1. Prophylaxis—
Stress-related mucosal erosions and sub
-
epithelial hemorrhages may develop within 72 hours in 
critically ill patients. Clinically overt bleeding occurs in 6% 
of ICU patients, but clinically important bleeding in less 
than 1.5%. Bleeding is associated with a higher mortality 
rate but is seldom the cause of death. Two of the most 
important risk factors for bleeding are coagulopathy (plate
-
lets less than 50,000/mcL or INR greater than 1.5) and 
respiratory failure with the need for mechanical ventilation 
for over 48 hours. When these two risk factors are absent, 
the risk of significant bleeding is only 0.1%. Other risk fac
-

-
tors include traumatic brain injury, severe burns, sepsis, 
vasopressor therapy, corticosteroid therapy, and prior his
-
tory of peptic ulcer disease and gastrointestinal bleeding. 
Early enteral tube feeding may decrease the risk of signifi
-
cant bleeding.
Prophylaxis should be routinely administered to criti
-
cally ill patients with risk factors for significant bleeding 
upon admission. Prophylactic suppression of gastric acid 
with intravenous H
2
-receptor antagonists or proton pump 
inhibitors (oral or intravenous) has been shown to reduce 
the incidence of clinically overt and significant bleeding 
but may increase the risk of nosocomial pneumonia. A 
2016 meta-analysis of 19 randomized trials found that oral 
and intravenous proton pump inhibitors were superior to 
H
2
-receptor antagonists in reducing the risk of overt bleed
-
ing (RR 0.48) and clinically important bleeding (RR 0.36) 
but did not affect the risk of pneumonia, length of ICU 
stay, or mortality.
The optimal, cost-effective prophylactic regimen 
remains uncertain, hence clinical practices vary. For 
patients with nasoenteric tubes, immediate-release 
omeprazole (40 mg at 1 and 6 hours on day 1; then 40 mg 
once daily beginning on day 2) may be preferred because of 
lower cost and ease of administration. For patients requir
-
ing intravenous administration, continuous intravenous 
infusions of H
2
-receptor antagonists provide adequate 
control of intragastric pH in most patients in the following 
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doses over 24 hours: cimetidine (900–1200 mg), ranitidine 
(150 mg), or famotidine (20 mg). Alternatively, intrave
-
nous proton pump inhibitors, although more expensive, 
may be preferred due to superior efficacy. The optimal 
dosing of intravenous proton pump inhibitors is uncertain; 
however, in clinical trials pantoprazole doses ranging from 
40 mg to 80 mg and administered every 8–24 hours appear 
equally effective.
2. Treatment—
Once bleeding occurs, patients should 
receive continuous infusions of a proton pump inhibitor 
(esomeprazole or pantoprazole, 80 mg intravenous bolus, 
followed by 8 mg/h continuous infusion) as well as sucral
-
fate suspension, 1 g orally every 4 to 6 hours. Endoscopy 
should be performed in patients with clinically significant 
bleeding to look for treatable causes, especially stress-
related peptic ulcers with active bleeding or visible vessels. 
When bleeding arises from diffuse gastritis, endoscopic 
hemostasis techniques are not helpful.
B. NSAID Gastritis
Of patients receiving NSAIDs in clinical trials, 25–50% 
have gastritis and 10–20% have ulcers at endoscopy; how
-
ever, symptoms of significant dyspepsia develop in about 
5%. NSAIDs that are more selective for the cyclooxygenase 
(COX)-2 enzyme (“coxibs”), such as celecoxib, etodolac, 
and meloxicam, decrease the incidence of endoscopically 
visible ulcers by approximately 75% and significant ulcer 
complications by up to 50% compared with nonselective 
NSAIDs (nsNSAIDs). However, a twofold increase in the 
incidence in cardiovascular complications (myocardial 
infarction, cerebrovascular infarction, and death) in 
patients taking coxibs compared with placebo led to the 
withdrawal of two highly selective coxibs (rofecoxib and 
valdecoxib) from the market by the manufacturers. Cele
-
coxib and all currently available nsNSAIDs (with notable 
exception of aspirin and possibly naproxen) are associated 
with increased risk of cardiovascular complications and 
therefore should be used with caution in patients with car
-
diovascular risk factors.
In population surveys, the rate of dyspepsia is increased 
1.5- to 2-fold with nsNSAID and coxib use. However, dys
-
peptic symptoms correlate poorly with significant mucosal 
abnormalities or the development of adverse clinical events 
(ulcer bleeding or perforation). Given the frequency of 
dyspeptic symptoms in patients taking NSAIDs, it is nei
-
ther feasible nor desirable to investigate all such cases. 
Patients with alarm symptoms or signs, such as severe pain, 
weight loss, vomiting, gastrointestinal bleeding, or anemia, 
should undergo diagnostic upper endoscopy. For other 
patients, symptoms may improve with discontinuation of 
the agent, reduction to the lowest effective dose, or admin
-
istration with meals. Proton pump inhibitors have demon
-
strated efficacy in controlled trials for the treatment of 
NSAID-related dyspepsia and superiority to H
2
-receptor 
antagonists for healing of NSAID-related ulcers even in the 
setting of continued NSAID use. Therefore, an empiric 
2- to 4-week trial of an oral proton pump inhibitor 
(omeprazole, rabeprazole, or esomeprazole 20–40 mg/day; 
lansoprazole or dexlansoprazole, 30 mg/day; pantoprazole, 
40 mg/day) is recommended for patients with NSAID-
related dyspepsia, especially those in whom continued 
NSAID treatment is required. If symptoms do not improve, 
diagnostic upper endoscopy should be conducted.
C. Alcoholic Gastritis
Excessive alcohol consumption may lead to dyspepsia, 
nausea, emesis, and minor hematemesis—a condition 
sometimes labeled “alcoholic gastritis. ” However, it is not 
proven that alcohol alone actually causes significant erosive 
gastritis. Therapy with H
2
-receptor antagonists, proton 
pump inhibitors, or sucralfate for 2–4 weeks often is 
empirically prescribed.
D. Portal Hypertensive Gastropathy
Portal hypertension commonly results in gastric mucosal

Portal hypertension commonly results in gastric mucosal 
and submucosal congestion of capillaries and venules, which 
is correlated with the severity of the portal hypertension and 
underlying liver disease. Usually asymptomatic, it may cause 
chronic gastrointestinal bleeding in 10% of patients and, less 
commonly, clinically significant bleeding with hematemesis. 
Treatment with propranolol or nadolol reduces the inci
-
dence of recurrent acute bleeding by lowering portal pres
-
sures. Patients who fail propranolol therapy may be 
successfully treated with portal decompressive procedures 
(see section above on treatment of esophageal varices).
Alshamsi F et al. Efficacy and safety of proton pump inhibitors 
for stress ulcer prophylaxis in critically ill patients: a system
-
atic review and meta-analysis of randomized trials. Crit Care. 
2016 May 4;20(1):120. [PMID: 27142116]
Bardou M et al. Stress-related mucosal disease in the critically ill 
patient. Nat Rev Gastroenterol Hepatol. 2015 Feb;12(2):
 
98–107. [PMID: 25560847]
Buendgens L et al. Prevention of stress-related ulcer bleeding at 
the intensive care unit: risks and benefits of stress ulcer pro
-
phylaxis. World J Crit Care Med. 2016 Feb 4;5(1):57–64. 
[PMID: 26855894]
2. Nonerosive, Nonspecific Gastritis
The diagnosis of nonerosive gastritis is based on histologic 
assessment of mucosal biopsies. Endoscopic findings are 
normal in many cases and do not reliably predict the pres
-
ence of histologic inflammation. The main types of noner
-
osive gastritis are those due to 
H pylori
 infection, those 
associated with pernicious anemia, and eosinophilic gastri
-
tis. (See Specific Types of Gastritis below.)
A. 
 Gastritis
H pylori
 is a spiral gram-negative rod that resides beneath 
the gastric mucous layer adjacent to gastric epithelial cells. 
Although not invasive, it causes gastric mucosal inflamma
-
tion with PMNs and lymphocytes. The mechanisms of 
injury and inflammation may in part be related to the 
products of two genes, 
vacA
 and 
cagA.
In developed countries, the prevalence of 
H pylori
 is 
rapidly declining. In the United States, the prevalence rises 
from less than 10% in non-immigrants under age 30 years to 
over 50% in those over age 60 years. The prevalence is 
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higher in non-whites and immigrants from developing 
countries and is correlated inversely with socioeconomic 
status. Transmission is from person to person, mainly dur
-
ing infancy and childhood; however, the mode of transmis
-
sion is unknown.
Acute infection with 
H pylori
 may cause a transient 
clinical illness characterized by nausea and abdominal pain 
that may last for several days and is associated with acute 
histologic gastritis with PMNs. After these symptoms 
resolve, the majority progress to chronic infection with 
chronic, diffuse mucosal inflammation (gastritis) charac
-
terized by PMNs and lymphocytes. Although chronic 
H pylori
 
infection with gastritis is present in 30–50% of the popula
-
tion, most persons are asymptomatic and suffer no sequelae. 
Three gastritis phenotypes occur which determine clinical 
outcomes. Most infected people have a mild, diffuse gastri
-
tis that does not disrupt acid secretion and seldom causes 
clinically important outcomes. About 15% of infected peo
-
ple have inflammation that predominates in the gastric 
antrum but spares the gastric body (where acid is secreted). 
People with this phenotype tend to have increased gastrin; 
increased acid production; and increased risk of developing 
peptic ulcers, especially duodenal ulcers. An even smaller 
subset of infected adults has inflammation that predomi
-
nates in the gastric body. Over time, this may lead to 
destruction of acid-secreting glands with resultant mucosal 
atrophy, decreased acid secretion, and intestinal metaplasia. 
This phenotype is associated with an increased risk of gas
-
tric ulcers and gastric cancer. Long-term treatment with 
proton pump inhibitors can potentiate the development of 
H pylori
–associated atrophic gastritis. Chronic 
H pylori
 
gastritis leads to the development of duodenal or gastric 
ulcers in up to 10%, gastric cancer in 0.1–3%, and low-
grade B cell gastric lymphoma (mucosa-associated lym
-
phoid tissue lymphoma; MALToma) in less than 0.01%.
Eradication of 
H pylori
 may be achieved with antibiot
-
ics in over 85% of patients and leads to resolution of the 
chronic gastritis (see section on Peptic Ulcer Disease). 
Testing for 
H pylori
 is indicated for patients with either 
active or a past history of documented peptic ulcer disease, 
gastric MALToma, and a personal or family history of gas
-
tric carcinoma. Testing and empiric treatment is cost-
effective in young patients (less than 60 years of age) 
 
with uncomplicated dyspepsia prior to further medical 
evaluation. Testing for and treating 
H pylori
 in patients 
with functional dyspepsia is generally recommended (see 
Dyspepsia, above). In addition, testing for (and, if positive, 
treating) 
H pylori
 infection is recommended in patients 
taking low-dose aspirin or NSAIDs long-term to reduce 
the risk of ulcer-related bleeding. Some groups recom
-
mend population-based screening of all asymptomatic 
persons in regions in which there is a high prevalence of 
H pylori
 and gastric cancer (such as Japan, Korea, and 
China) to reduce the incidence of gastric cancer. Population-
based screening of asymptomatic individuals is not recom
-
mended in western countries, in which the incidence of 
gastric cancer is low, but should be considered in immi
-
grants from high-prevalence regions.
1. Noninvasive testing for 
H pylori
—
Although serologic 
tests are easily obtained and widely available, clinical 
guidelines no longer endorse their use for testing for 
H pylori
 infection because they are less accurate than other 
noninvasive tests that measure active infection. Laboratory-
based quantitative serologic ELISA tests have an overall 
accuracy of only 80%. In comparison, the fecal antigen 
immunoassay and [
13
C] urea breath test have excellent 
sensitivity and specificity (greater than 95%) at a cost of 
less than $60. Although more expensive and cumbersome

13
less than $60. Although more expensive and cumbersome 
to perform, these tests of active infection are more cost-
effective in most clinical settings because they reduce 
unnecessary treatment for patients without active 
Recent proton pump inhibitors or antibiotics signifi
-
cantly reduce the sensitivity of urea breath tests and fecal 
antigen assays (but not serologic tests). Prior to testing, 
proton pump inhibitors should be discontinued for 7–14 days 
and antibiotics for at least 28 days.
2. Endoscopic testing for 
H pylori
—
Endoscopy is not 
indicated to diagnose 
H pylori
 infection in most circum
-
stances. However, when it is performed for another rea
-
son, gastric biopsy specimens can be obtained for detection 
of 
H pylori
 and tested for active infection by urease pro
-
duction. This simple, inexpensive ($10) test has excellent 
sensitivity (90%) and specificity (95%). In patients with 
active upper gastrointestinal bleeding or patients recently 
taking proton pump inhibitors or antibiotics, histologic 
assessment for 
H pylori
 is preferred. Histologic assessment 
of biopsies from the gastric antrum and body is more 
definitive but more expensive ($150–$250) than a rapid 
urease test. Histologic assessment is also indicated in 
patients with suspected MALTomas and, possibly, in 
patients with suspected infection whose rapid urease test 
is negative. However, serologic testing is the most cost-
effective means of confirming 
H pylori
 infection in 
patients with a negative rapid urease test.
Chey WD et al. ACG Clinical Guideline: treatment of 
Helico
-
bacter pylori
. Am J Gastroenterol. 2017 Feb;112(2):212–39. 
[PMID: 28071659]
B. Pernicious Anemia Gastritis
Pernicious anemia gastritis is a rare autoimmune disorder 
involving the fundic glands with resultant achlorhydria, 
decreased intrinsic factor secretion, and vitamin B
12
 malab
-
sorption. Of patients with B
12
 deficiency, a small number 
have pernicious anemia. Most patients have malabsorption 
secondary to chronic 
H pylori
 infection that results in atro
-
phic gastritis, small intestine bacterial overgrowth, or 
dietary insufficiency. Fundic histology in pernicious ane
-
mia is characterized by severe gland atrophy and intestinal 
metaplasia caused by autoimmune destruction of the gas
-
tric fundic mucosa. Anti-intrinsic factor antibodies are 
present in 70% of patients. Achlorhydria leads to pro
-
nounced hypergastrinemia (greater than 1000 pg/mL) due 
to loss of acid inhibition of gastrin G cells. Hypergastrin
-
emia may induce hyperplasia of gastric enterochromaffin-
like cells that may lead to the development of small, 
multicentric carcinoid tumors in 5% of patients. Metastatic 
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spread is uncommon in lesions smaller than 2 cm. The risk 
of gastric adenocarcinoma is increased threefold, with a 
prevalence of 1–3%. Endoscopy with biopsy is indicated in 
patients with pernicious anemia at the time of diagnosis. 
Patients with extensive atrophy and metaplasia involving 
the antrum and body, dysplasia or small carcinoids require 
periodic endoscopic surveillance. Pernicious anemia is 
discussed in detail in Chapter 13.
Minalyan A et al. Autoimmune atrophic gastritis: current per
-
spectives. Clin Exp Gastroenterol. 2017 Feb 7;10:19–27. 
[PMID: 28223833]
Rojas Hernandez CM et al. Advances in mechanisms, diagnosis, 
and treatment of pernicious anemia. Discov Med. 2015 Mar;
 
19(104):159–68. [PMID: 25828519]
Rusak E et al. Anti-parietal cell antibodies—diagnostic signifi
-
cance. Adv Med Sci. 2016 Jan 13;61(2):175–9. [PMID: 
26918709]
12
 deficiency—a 21st century per
-
spective. Clin Med (Lond). 2015 Apr;15(2):145–50. [PMID: 
25824066]
3. Specific Types of Gastritis
 
»
Acute bacterial infection of the gastric submucosa and mus
-
cularis with a variety of aerobic or anaerobic organisms 
produces a rare, rapidly progressive, life-threatening condi
-
tion known as phlegmonous or necrotizing gastritis, which 
requires broad-spectrum antibiotic therapy and, in many 
cases, emergency gastric resection. Viral infection with 
CMV is seen in patients with AIDS and after bone marrow 
or solid organ transplantation. Endoscopic findings include 
thickened gastric folds and ulcerations. Fungal infection 
with mucormycosis and 
Candida
 may occur in immuno
-
compromised and diabetic patients. Larvae of 
Anisakis 
marina
 ingested in raw fish or sushi may become embedded 
in the gastric mucosa, producing severe abdominal pain. 
Pain persists for several days until the larvae die. Endoscopic 
removal of the larvae provides rapid symptomatic relief.
PEPTIC ULCER DISEASE
 
»
History of dyspepsia present in 80–90% of patients 
with variable relationship to meals.
 
»
Ulcer symptoms characterized by rhythmicity and 
periodicity.
 
»
Ulcer complications present without antecedent 
symptoms in 10–20% of patients.
 
»
Most NSAID-induced ulcers are asymptomatic.
 
»
Upper endoscopy with gastric biopsy for 
H pylori
 is 
the diagnostic procedure of choice in most 
patients.
 
»
Gastric ulcer biopsy or documentation of complete 
healing necessary to exclude gastric malignancy.
 
»
Peptic ulcer is a break in the gastric or duodenal mucosa 
that arises when the normal mucosal defensive factors are 
impaired or are overwhelmed by aggressive luminal factors 
such as acid and pepsin. By definition, ulcers extend 
through the muscularis mucosae and are usually over 5 mm 
in diameter. In the United States, there are about 
500,000 new cases per year of peptic ulcer and 4 million 
ulcer recurrences; the lifetime prevalence of ulcers in the 
adult population is approximately 10%. Ulcers occur 
either in the duodenum, where over 95% are in the bulb or 
pyloric channel, or in the stomach, where benign ulcers 
are located most commonly in the antrum (60%) or at the 
junction of the antrum and body on the lesser curvature 
(25%).
Although ulcers can occur in any age group, duodenal 
ulcers most commonly occur in patients between the ages 
of 30 and 55 years, whereas gastric ulcers are more com
-
mon in patients between the ages of 55 and 70 years. The 
incidence of duodenal ulcer disease has been declining 
dramatically for the past 30 years (due to the eradication of 
H pylori
), but the incidence of gastric ulcers has not been 
declining (due to the widespread use of NSAIDs and low-
dose aspirin).
 
»
Etiology
There are two major causes of peptic ulcer disease: NSAIDs 
and chronic 
H pylori
 infection. Evidence of 
H pylori
 infec
-
tion or NSAID ingestion should be sought in all patients

»
Etiology
H pylori
H pylori
 infec
-
tion or NSAID ingestion should be sought in all patients 
with peptic ulcer. Alcohol, dietary factors, and stress do not 
appear to cause ulcer disease. Less than 5–10% of ulcers are 
caused by other conditions, including acid hypersecretory 
states (such as Zollinger-Ellison syndrome or systemic 
mastocytosis), CMV (especially in transplant recipients), 
Crohn disease, lymphoma, medications (eg, alendronate), 
chronic medical illness (cirrhosis or chronic kidney dis
-
ease), or are idiopathic. NSAID-induced and 
H pylori
-
associated ulcers will be presented in this section; 
Zollinger-Ellison syndrome will be discussed subsequently.
A. 
H pylori
–Associated Ulcers
H pylori
 infection with associated gastritis and, in some 
cases, duodenitis appears to be a necessary cofactor for the 
majority of duodenal and gastric ulcers not associated with 
NSAIDs. Ulcer disease will develop in an estimated 10% of 
infected patients. The prevalence of 
H pylori
duodenal ulcer patients is 70–90%. The association with 
gastric ulcers is lower, but 
H pylori
 is found in most 
patients in whom NSAIDs cannot be implicated.
The natural history of 
H pylori
–associated peptic ulcer 
disease is well defined. In the absence of specific antibiotic 
treatment to eradicate the organism, 85% of patients will 
have an endoscopically visible recurrence within 1 year. 
Half of these will be symptomatic. After successful eradica
-
tion of 
H pylori
 with antibiotics, ulcer recurrence rates are 
reduced dramatically to 5–20% at 1 year. Most of these 
ulcer recurrences are due to NSAID use or, rarely, reinfec
-
tion with 
H pylori.
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B. NSAID-Induced Ulcers
There is a 10–20% prevalence of gastric ulcers and a 2–5% 
prevalence of duodenal ulcers in long-term NSAID users. 
Approximately 2–5%/year of long-term NSAID users will 
have an ulcer that causes clinically significant dyspepsia or 
a serious complication. The incidence of serious gastroin
-
testinal complications (hospitalization, bleeding, perfora
-
tion) is 0.2–1.9%/year. Meta-analyses of clinical trials 
detected an increased risk of upper gastrointestinal bleeding 
in patients taking low-dose aspirin (1 of 1000), coxibs (2 of 
1000), and nsNSAIDs (4–6 of 1000). The risk of NSAID 
complications is greater within the first 3 months of therapy 
and in patients who are older than 60 years; who have a 
prior history of ulcer disease; or who take NSAIDs in com
-
bination with aspirin, corticosteroids, or anticoagulants.
Traditional nsNSAIDs inhibit prostaglandins through 
reversible inhibition of both COX-1 and COX-2 enzymes. 
Aspirin causes irreversible inhibition of COX-1 and COX-2 
as well as of platelet aggregation. Coxibs (or selective 
NSAIDs) preferentially inhibit COX-2—the principal 
enzyme involved in prostaglandin production at sites of 
inflammation—while providing relative sparing of COX-1, 
the principal enzyme involved with mucosal cytoprotec
-
tion in the stomach and duodenum. Celecoxib is the only 
coxib currently available in the United States, although 
other older NSAIDs (etodolac, meloxicam) may have simi
-
lar COX-2/COX-1 selectivity.
Coxibs decrease the incidence of endoscopically visible 
ulcers by approximately 75% compared with nsNSAIDs. Of 
greater clinical importance, the risk of significant clinical 
events (obstruction, perforation, bleeding) is reduced by 
up to 50% in patients taking coxibs versus nsNSAIDs. 
However, a twofold increase in the incidence in cardiovas
-
cular complications (myocardial infarction, cerebrovascu
-
lar infarction, and death) has been detected in patients 
taking coxibs compared with placebo, prompting the vol
-
untary withdrawal of two highly selective coxibs (rofecoxib 
and valdecoxib) from the market by the manufacturers. A 
review by an FDA panel suggested that all NSAIDs (other 
than aspirin and, possibly, naproxen) may be associated 
with an increased risk of cardiovascular complications, but 
concluded that celecoxib, which has less COX-2 selectivity 
than rofecoxib and valdecoxib, does not have higher risk 
than other nsNSAIDs when used in currently recom
-
mended doses (200 mg/day). In 2016, a large, randomized, 
noninferiority trial comparing ibuprofen, naproxen, and 
celecoxib in arthritis patients with increased cardiovascu
-
lar risk found no difference in cardiovascular safety 
between the three drugs over 3 years. However, celecoxib 
was associated with significantly fewer serious gastrointes
-
tinal events than both naproxen (hazard ratio 0.71) and 
ibuprofen (hazard ratio 0.65).
Use of even low-dose aspirin (81–325 mg/day) leads to 
a twofold increased risk of gastrointestinal bleeding com
-
plications. In randomized controlled trials, the absolute 
annual increase of gastrointestinal bleeding attributable to 
low-dose aspirin is only 0.12% higher than with placebo 
therapy. However, in population studies, gastrointestinal 
bleeding occurs in 1.2% of patients each year. Patients with 
a prior history of peptic ulcers or gastrointestinal bleeding 
have a markedly increased risk of complications on low-
dose aspirin. It should be noted that low-dose aspirin in 
combination with NSAIDs or coxibs increases the risk of 
ulcer complications by up to tenfold compared with 
NSAIDs or low-dose aspirin alone. Dual antiplatelet ther
-
apy with aspirin and a thienopyridine (eg, clopidogrel) 
incurs a twofold to threefold increased risk of bleeding 
compared with aspirin alone.
H pylori
 infection increases the risk of ulcer disease and 
complications over threefold in patients taking NSAIDs or

H pylori
complications over threefold in patients taking NSAIDs or 
low-dose aspirin. It is hypothesized that NSAID initiation 
may potentiate or aggravate ulcer disease in susceptible 
infected individuals.
 
»
Epigastric pain (dyspepsia), the hallmark of peptic ulcer 
disease, is present in 80–90% of patients. However, this 
complaint is not sensitive or specific enough to serve as a 
reliable diagnostic criterion for peptic ulcer disease. The 
clinical history cannot accurately distinguish duodenal 
from gastric ulcers. Less than 25% of patients with dyspep
-
sia have ulcer disease at endoscopy. Twenty percent of 
patients with ulcer complications such as bleeding have no 
antecedent symptoms (“silent ulcers”). Nearly 60% of 
patients with NSAID-related ulcer complications do not 
have prior symptoms.
Pain is typically well localized to the epigastrium and 
not severe. It is described as gnawing, dull, aching, or 
“hunger-like. ” Approximately 50% of patients report relief 
of pain with food or antacids (especially those with duode
-
nal ulcers) and a recurrence of pain 2–4 hours later. How
-
ever, many patients deny any relationship to meals or report 
worsening of pain. Two-thirds of duodenal ulcers and one-
third of gastric ulcers cause nocturnal pain that awakens the 
patient. A change from a patient’s typical rhythmic discom
-
fort to constant or radiating pain may reflect ulcer penetra
-
tion or perforation. Most patients have symptomatic periods 
lasting up to several weeks with intervals of months to years 
in which they are pain free (periodicity).
Nausea and anorexia may occur with gastric ulcers. 
Significant vomiting and weight loss are unusual with 
uncomplicated ulcer disease and suggest gastric outlet 
obstruction or gastric malignancy.
The physical examination is often normal in uncompli
-
cated peptic ulcer disease. Mild, localized epigastric ten
-
derness to deep palpation may be present. FOBT or FIT is 
positive in one-third of patients.
Laboratory tests are normal in uncomplicated peptic ulcer 
disease but are ordered to exclude ulcer complications or 
confounding disease entities. Anemia may occur with acute 
blood loss from a bleeding ulcer or less commonly from 
chronic blood loss. Leukocytosis suggests ulcer penetration 
or perforation. An elevated serum amylase in a patient with 
severe epigastric pain suggests ulcer penetration into the 
pancreas. A fasting serum gastrin level to screen for 
Zollinger-Ellison syndrome is obtained in some patients.
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C. Endoscopy
Upper endoscopy is the procedure of choice for the diagnosis 
of duodenal and gastric ulcers. Duodenal ulcers are virtually 
never malignant and do not require biopsy. Three to 5 per
-
cent of benign-appearing gastric ulcers prove to be malig
-
nant. Hence, biopsies of the ulcer margin are almost always 
performed. Provided that the gastric ulcer appears benign to 
the endoscopist and adequate biopsy specimens reveal no 
evidence of cancer, dysplasia, or atypia, the patient may be 
monitored without further endoscopy. If these conditions are 
not fulfilled, follow-up endoscopy should be performed 
12 weeks after the start of therapy to document complete 
healing; nonhealing ulcers are suspicious for malignancy.
D. Imaging
Barium upper gastrointestinal series is no longer recom
-
mended because it is less sensitive for detection of ulcers 
and less accurate for distinguishing benign from malignant 
ulcers than upper endoscopy. Abdominal CT imaging is 
obtained in patients with suspected complications of peptic 
ulcer disease (perforation, penetration, or obstruction).
E. Testing for 
H pylori
In patients in whom an ulcer is diagnosed by endoscopy, 
gastric mucosal biopsies should be obtained both for a rapid 
urease test and for histologic examination. The specimens 
for histology are discarded if the urease test is positive.
Noninvasive assessment for 
H pylori
 with fecal antigen 
assay or urea breath testing may be done in patients with a 
history of peptic ulcer disease to diagnose active infection 
or in patients following its treatment to confirm successful 
eradication. Both tests have a sensitivity and specificity of 
95%. Proton pump inhibitors may cause false-negative urea 
breath tests and fecal antigen tests and should be withheld 
for at least 14 days before testing. Because of its lower sen
-
sitivity (85%) and specificity (79%), serologic testing 
should not be performed unless fecal antigen testing or 
urea breath testing is unavailable.
 
»
Peptic ulcer disease must be distinguished from other causes 
of epigastric distress (dyspepsia). Over 50% of patients with 
dyspepsia have no obvious organic explanation for their 
symptoms and are classified as having functional dyspepsia 
(see sections above on Dyspepsia and Functional Dyspep
-
sia). Atypical gastroesophageal reflux may be manifested by 
epigastric symptoms. Biliary tract disease is characterized by 
discrete, intermittent episodes of pain that should not be 
confused with other causes of dyspepsia. Severe epigastric 
pain is atypical for peptic ulcer disease unless complicated by 
a perforation or penetration. Other causes include acute 
pancreatitis, acute cholecystitis or choledocholithiasis, 
esophageal rupture, gastric volvulus, gastric or intestinal 
ischemia, and ruptured aortic aneurysm.
 
»
Pharmacologic Agents
The pharmacology and use of several agents that enhance 
the healing of peptic ulcers is briefly discussed here. They 
may be divided into three categories: (1) acid-antisecretory 
agents, (2) mucosal protective agents, and (3) agents that 
promote healing through eradication of 
H pylori.
A. Acid-Antisecretory Agents
1. Proton pump inhibitors—
Proton pump inhibitors cova
-
lently bind the acid-secreting enzyme H
+
-K
+
-ATPase, or 
“proton pump, ” permanently inactivating it. Restoration of 
acid secretion requires synthesis of new pumps, which have 
a half-life of 18 hours. Thus, although these agents have a 
serum half-life of less than 60 minutes, their duration of 
action exceeds 24 hours.
There are six oral proton pump inhibitors currently 
available: omeprazole, rabeprazole, esomeprazole, lanso
-
prazole, dexlansoprazole, and pantoprazole. The available 
oral agents inhibit over 90% of 24-hour acid secretion, 
compared with under 65% for H
2
-receptor antagonists in 
standard dosages. Despite minor differences in their phar
-

2
-
macology, they are equally efficacious in the treatment of 
peptic ulcer disease. Treatment with oral proton pump 
inhibitors results in over 90% healing of duodenal ulcers 
after 4 weeks and 90% of gastric ulcers after 8 weeks when 
given once daily (30 minutes before breakfast) at the fol
-
lowing recommended doses: omeprazole, 20–40 mg; 
esomeprazole, 40 mg; rabeprazole, 20 mg; lansoprazole, 30 
mg; dexlansoprazole, 30–60 mg; pantoprazole, 40 mg. 
Compared with H
2
-receptor antagonists, proton pump 
inhibitors provide faster pain relief and more rapid ulcer 
healing.
The proton pump inhibitors are remarkably safe for 
short-term therapy. Long-term use may lead to mild 
decreases in vitamin B
12
, iron, magnesium, and calcium 
absorption. Observational studies suggest increased risks 
of enteric infections, including 
 and bacterial 
gastroenteritis; pneumonia; and an increased risk of hip 
fracture (a 1.4-fold increase). Recent observational studies 
also report small increased risks of acute and chronic kid
-
ney disease (due to interstitial nephritis) and dementia; 
however, causality has not been demonstrated. Nonethe
-
less, long-term proton pump inhibitor therapy should be 
prescribed only for patients with appropriate indications. 
Serum gastrin levels rise significantly in 3% of patients 
receiving long-term therapy but return to normal limits 
within 2 weeks after discontinuation.
2. H
2
Although H
2
-receptor antag
-
onists are effective in the treatment of peptic ulcer disease, 
proton pump inhibitors are now the preferred agents 
because of their ease of use and superior efficacy. Four 
H
2
-receptor antagonists are available: cimetidine, raniti
-
dine, famotidine, and nizatidine. For uncomplicated peptic 
ulcers, H
2
-receptor antagonists may be administered once 
daily at bedtime as follows: ranitidine and nizatidine 300 mg, 
famotidine 40 mg, and cimetidine 800 mg. Duodenal and 
gastric ulcer healing rates of 85–90% are obtained within 
6 weeks and 8 weeks, respectively.
B. Agents Enhancing Mucosal Defenses
Bismuth sucralfate, misoprostol, and antacids all have been 
shown to promote ulcer healing through the enhancement 
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of mucosal defensive mechanisms. Given the greater effi
-
cacy and safety of antisecretory agents and better compli
-
ance of patients, these agents are no longer used as first-line 
therapy for active ulcers in most clinical settings.
C. 
H pylori
 Eradication Therapy
H pylori
 has proved difficult. Combination 
regimens that use two or three antibiotics with a proton 
pump inhibitor or bismuth are required to achieve ade
-
quate rates of eradication and to reduce the number of 
failures due to antibiotic resistance. In the United States, up 
to 50% of strains are resistant to metronidazole and 
10–20% are resistant to clarithromycin. Recommended 
regimens are listed in Table 15–10. Ideally, the optimal 
regimen would be determined by antibiotic susceptibility 
testing. However, this requires endoscopic biopsy, and few 
laboratories are equipped for 
H pylori
 cultures. Thus, in 
most clinical settings, therapy is chosen empirically. Until 
recently, in the United States a 14-day course of so-called 
triple therapy with a proton pump inhibitor, clarithromy
-
cin, and either amoxicillin or metronidazole (if penicillin 
allergic) was recommended as first-line therapy. However, 
a 2016 updated guideline from the Toronto Consensus 
Table 15–10.
 
Treatment options for peptic ulcer disease.
Active 
–associated ulcer
1.
 
T
reat with anti–
H pylori
 regimen for 14 days. Treatment options:
Standard Bismuth Quadruple Therapy
•  Proton
 
pump
 
inhibit
or
 
or
ally
 
t
wice
 
daily
1,2
•  Bismuth
 
subsalic
ylate
 
262
 
mg
 
t
wo
 
tablets
 
or
ally
 
f
our
 
times
 
daily
 
or
 
bismuth
 
subcitr
ate
 
120–400
 
mg
 
or
ally
 
f
our
 
times
 
daily
•  Tetracycline
 
500
 
mg
 
or
ally
 
f
our
 
times
 
daily
•  Metronidazole
 
500
 
mg
 
thr
ee
 
times
 
daily
OR
•  Proton
 
pump
 
inhibit
or
 
or
ally
 
t
wice
 
daily
1
•  Bismuth
 
subcitr
ate
 
potassium
 
140
 
mg/metr
onidazole
 
125
 
mg/t
etracycline
 
125
 
mg
 
[P
ylera]
 
thr
ee
 
capsules
 
or
ally
 
f
our
 
times
 
daily)
3
Standard Nonbismuth Quadruple Therapy
•  Proton
 
pump
 
inhibit
or
 
or
ally
 
t
wice
 
daily
•  Amoxicillin
 
1000
 
mg
 
t
wice
 
daily
 
500
 
mg
 
t
wice
 
daily
•  Clarithromycin
 
500
 
mg
 
t
wice
 
daily
Standard Triple Therapy
 (No longer recommended except in locales where clarithromycin resistance is < 15%)
•  Proton
 
pump
 
inhibit
or
 
t
wice
 
daily
 
500
 
mg
 
t
wice
 
daily
 
1
 
g
 
or
ally
 
t
wice
 
daily
 
(
or,
 
if
 
penicillin
 
aller
gic,
 
metr
onidazole
 
500
 
mg
 
or
ally
 
t
wice
 
daily)
2.
  
A
fter completion of course of 
H pylori
 eradication therapy, continue treatment with proton pump inhibitor
1
 once daily for 4–6 weeks 
 
if ulcer is large (> 1 cm) or complicated.
3.
  
C
onfirm successful eradication of 
H pylori
 with urea breath test, fecal antigen test, or endoscopy with biopsy at least 4 weeks after 
completion of antibiotic treatment and 1–2 weeks after completion of proton pump inhibitor treatment.
Active ulcer not attributable to 
H pylori
1.
 
C
onsider other causes: NSAIDs, Zollinger-Ellison syndrome, gastric malignancy. Treatment options:
•  Proton
 
pump
 
inhibit
ors:
1
Uncomplicated duodenal ulcer: treat for 4 weeks
Uncomplicated gastric ulcer: treat for 8 weeks
•  H
2
-receptor antagonists:
Uncomplicated duodenal ulcer: cimetidine 800 mg, ranitidine or nizatidine 300 mg, famotidine 40 mg, orally once daily at bedtime 
for 6 weeks
Uncomplicated gastric ulcer: cimetidine 400 mg, ranitidine or nizatidine 150 mg, famotidine 20 mg, orally twice daily for 8 weeks
Complicated ulcers: proton pump inhibitors
1
 are the preferred drugs
Prevention of ulcer relapse
1.
  
NSAID
-induced ulcer: prophylactic therapy for high-risk patients (prior ulcer disease or ulcer complications, use of corticosteroids or 
anticoagulants, age > 60 years, serious comorbid illnesses). Treatment options:
•  Proton

•  Proton
 
pump
 
inhibit
or
 
onc
e
 
daily
•  Celecoxib
 
(
contraindicated
 
in
 
pa
tients
 
with
 
incr
eased
 
risk
 
of
 
car
diovascular
 
disease)
•  Misoprostol
 
200
 
mcg
 
or
ally
 
4
 
times
 
daily
2.
  
L
ong-term “maintenance” therapy indicated in patients with recurrent ulcers who either are 
H pylori
–negative or who have failed 
attempts at eradication therapy: once-daily oral proton pump inhibitor
1
1
Oral proton pump inhibitors: omeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, dexlansoprazole 30–60 mg, pantoprazole 40 mg, 
esomeprazole 40 mg. Proton pump inhibitors are administered 30 minutes before meals.
2
Preferred regimen in regions with high clarithromycin resistance or in patients who have previously received a macrolide antibiotic or are 
penicillin allergic. Effective against metronidazole-resistant organisms.
3
Pylera is an FDA-approved formulation containing bismuth subcitrate 140 mg/tetracycline 125 mg/metronidazole 125 mg per capsule.
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CMDT 2019
group and 2017 guideline from the American College of 
Gastroenterology recommended that triple therapy no 
longer be used (due to increasing clarithromycin resis
-
tance) except in areas with known low-level clarithromy
-
cin resistance (less than 15%). In most settings, empiric 
treatment with a 14-day bismuth-based or a nonbismuth-
based regimen of so-called quadruple therapy is now rec
-
ommended as first-line therapy. Both achieve a greater 
than 85% eradication rate. The bismuth-based quadruple 
therapy regimen consists of bismuth, tetracycline, a pro
-
ton pump inhibitor, and metronidazole or tinidazole 
(Table 15–10). It is effective even for metronidazole-
 
resistant strains. Nonbismuth-based quadruple therapy 
consists of a proton pump inhibitor, amoxicillin, metroni
-
dazole, and clarithromycin; it is effective even for clarithro
-
mycin-resistant strains.
 
»
Medical Treatment
Patients should be encouraged to eat balanced meals at 
regular intervals. There is no justification for bland or 
restrictive diets. Moderate alcohol intake is not harmful. 
Smoking retards the rate of ulcer healing and increases the 
frequency of recurrences and should be prohibited.
A. Treatment of 
H pylori
1. Treatment of active ulcer—
The goals of treatment of 
active 
H pylori
–associated ulcers are to relieve dyspeptic 
symptoms, to promote ulcer healing, and to eradicate 
H pylori
 infection. Uncomplicated 
H pylori
–associated 
ulcers should be treated for 14 days with one of the proton 
pump inhibitor–based 
H pylori
 eradication regimens listed 
in Table 15–10. At that point, no further antisecretory 
therapy is needed, provided the ulcer was small (less than 
1 cm) and dyspeptic symptoms have resolved. For patients 
with large or complicated ulcers, an antisecretory agent 
should be continued for an additional 2–4 weeks (duode
-
nal ulcer) or 4–6 weeks (gastric ulcer) after completion of 
the antibiotic regimen to ensure complete ulcer healing. A 
once-daily oral proton pump inhibitor (as listed in Table 
15–10) is recommended. Confirmation of 
H pylori
 eradica
-
tion is recommended for all patients more than 4 weeks 
after completion of antibiotic therapy and more than 2 
weeks after discontinuation of the proton pump inhibitor 
either with noninvasive tests (urea breath test, fecal antigen 
test) or endoscopy with biopsy for histology.
2. Therapy to prevent recurrence—
Successful eradication 
reduces ulcer recurrences to less than 20% after 1–2 years. 
The most common cause of recurrence after antibiotic 
therapy is failure to achieve successful eradication. Once 
cure has been achieved, reinfection rates are less than 0.5% 
per year. Although 
H pylori
 eradication has reduced the 
need for long-term maintenance antisecretory therapy to 
prevent ulcer recurrences, there remains a subset of 
patients who require long-term therapy with a proton 
pump inhibitor once daily. This subset includes patients 
with 
H pylori
–positive ulcers who have not responded to 
repeated attempts at eradication therapy, patients with a 
history of 
H pylori
–positive ulcers who have recurrent 
ulcers despite successful eradication, and patients with 
idiopathic ulcers (ie, 
H pylori
–negative and not taking 
NSAIDs). In all patients with recurrent ulcers, NSAID 
usage (unintentional or surreptitious) and hypersecretory 
states (including gastrinoma) should be excluded.
B. Treatment of NSAID-Induced Ulcers
1. Treatment of active ulcers—
In patients with NSAID-
induced ulcers, the offending agent should be discontinued 
whenever possible. Both gastric and duodenal ulcers 
respond rapidly to therapy with H
2
-receptor antagonists or 
proton pump inhibitors (Table 15–10) once NSAIDs are 
eliminated. All patients with NSAID-associated ulcers 
should undergo testing for 
H pylori
 infection. Antibiotic 
eradication therapy should be given if 
H pylori
 tests are 
positive.

H pylori
H pylori
 tests are 
positive.
2. Prevention of NSAID-induced ulcers—
Clinicians 
should carefully weigh the benefits of NSAID therapy with 
the risks of cardiovascular and gastrointestinal complica
-
tions. Both coxibs and nsNSAIDs may increase the risk of 
cardiovascular complications. Ulcer complications occur 
in up to 2% of all nsNSAID-treated patients per year, but 
in up to 10–20% per year of patients with multiple risk 
factors. These include age over 60 years, history of ulcer 
disease or complications, concurrent use of antiplatelet 
therapy (low-dose aspirin or clopidogrel, or both), con
-
current therapy with anticoagulants or corticosteroids, 
and serious underlying medical illness. After considering 
the patient’s risk of cardiovascular and gastrointestinal 
complications due to NSAID use, the clinician can 
decide what type of NSAID (nsNSAID vs coxib) is 
appropriate and what strategies should be used to reduce 
the risk of such complications. To minimize cardiovas
-
cular and gastrointestinal risks, all NSAIDs should be used 
at the lowest effective dose and for the shortest time 
a. 
T
est for and treat 
h
 
pylori
 infection—
All patients 
with a known history of peptic ulcer disease who are 
treated with NSAIDs or antiplatelet agents (aspirin, clopi
-
dogrel) should be tested for 
H pylori
 infection and treated, 
if positive. Although 
H pylori
 eradication may decrease the 
risk of NSAID-related complications, co-therapy with a 
proton pump inhibitor is still required in high-risk patients.
b. 
P
roton pump inhibitor—
Treatment with an oral 
proton pump inhibitor given once daily (rabeprazole 20 mg, 
omeprazole 20–40 mg, lansoprazole 30 mg, dexlansopra
-
zole 30–60 mg, or pantoprazole or esomeprazole 40 mg) is 
effective in the prevention of NSAID-induced gastric and 
duodenal ulcers and is approved by the FDA for this indi
-
cation. Among high-risk patients taking nsNSAIDs or 
coxibs, the incidence of endoscopically visible gastric and 
duodenal ulcers after 6 months of therapy in patients 
treated with esomeprazole 20–40 mg/day was 5%, com
-
pared with 17% who were given placebo. Nonetheless, 
proton pump inhibitors are not fully protective in high-risk 
patients in preventing NSAID-related complications. In 
prospective, controlled trials of patients with a prior his
-
tory of NSAID-related ulcer complications, the incidence 
of recurrent bleeding was almost 5% after 6 months in 
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patients taking nsNSAIDs and a proton pump inhibitor. In 
-
tory of ulcer complications related to low-dose aspirin, the 
incidence of recurrent ulcer bleeding in patients taking 
low-dose aspirin alone was approximately 15% per year 
compared with 0–2% per year in patients taking low-dose 
aspirin and proton pump inhibitor and 9–14% per year in 
patients taking clopidogrel. Thus, proton pump inhibitors 
are highly effective in preventing complications related to 
low-dose aspirin, even in high-risk patients. Enteric coat
-
ing of aspirin may reduce direct topical damage to the 
stomach but does not reduce complications.
c. 
R
ecommendations to reduce risk of ulcer 
com
plications from nsnsaids and coxibs—
For 
patients with a low-risk of cardiovascular disease who have 
no risk factors for gastrointestinal complications, an nsN
-
SAID alone may be given. For patients with one or two 
gastrointestinal risk factors, a coxib alone or an nsNSAID 
with a proton pump inhibitor once daily should be given to 
reduce the risk of gastrointestinal complications. NSAIDs 
should be avoided if possible in patients with multiple risk 
factors; if required, however, combination therapy with a 
coxib or a partially COX-2 selective nsNSAID (etodolac, 
meloxicam) and a proton pump inhibitor once daily is 
For patients with an increased risk of cardiovascular 
complications, it is preferable to avoid NSAIDs, if possible. 
Almost all patients with increased cardiovascular risk also 
will be taking antiplatelet therapy with low-dose aspirin or 
clopidogrel, or both. Because combination therapy with an 
nsNSAID and antiplatelet therapy increases the risks of 
gastrointestinal complications, these patients should all 
receive cotherapy with a proton pump inhibitor once daily 
or misoprostol.
d. 
R
ecommendations to reduce risk of ulcer com
-
plications with use of antiplatelet agents—
The 
risk of significant gastrointestinal complications in persons 
taking low-dose aspirin (81–325 mg/day) or clopidogrel, or 
both, for cardiovascular prophylaxis is 0.5%/year. Aspirin, 
81 mg/day, is recommended in most patients because it has 
a lower risk of gastrointestinal complications but equiva
-
lent cardiovascular protection compared with higher aspi
-
rin doses. Complications are increased with combinations 
of aspirin and clopidogrel or aspirin and anticoagulants. 
Clopidogrel does not cause gastrointestinal ulcers or ero
-
sions. However, its antiplatelet activity may promote bleed
-
ing from erosions or ulcers caused by low-dose aspirin or 
H pylori
. Patients with dyspepsia or prior ulcer disease 
should be tested for 
H pylori
 infection and treated, if posi
-
tive. Patients younger than 60–70 years who have no other 
risk factors for gastrointestinal complications may be 
treated with low-dose aspirin or dual antiplatelet therapy 
without a proton pump inhibitor. Virtually all other 
patients who require low-dose aspirin or aspirin plus anti
-
coagulant therapy should receive a proton pump inhibitor 
once daily.
At the present time, the optimal management of patients 
who require dual antiplatelet therapy with clopidogrel and 
aspirin is uncertain. Clopidogrel is a prodrug that is 
activated by the cytochrome P450 CYP2C19 enzyme. All 
proton pump inhibitors inhibit CYP2C19 to varying 
degrees, with omeprazole having the highest and pantopra
-
zole the least level of inhibition. In vitro and in vivo platelet 
aggregation studies demonstrate that proton pump inhibi
-
tors (especially omeprazole) may attenuate the antiplatelet 
effects of clopidogrel, although the clinical importance of 
this interaction is uncertain. The FDA has issued a warning 
that patients should avoid using clopidogrel with omepra
-
zole and esomeprazole. A 2010 expert consensus panel 
concluded that once daily treatment with an oral proton

-
concluded that once daily treatment with an oral proton 
pump inhibitor (pantoprazole 40 mg; rabeprazole 20 mg; 
lansoprazole or dexlansoprazole 30 mg) may be recom
-
mended for patients who have an increased risk of upper 
gastrointestinal bleeding (prior history of peptic ulcer dis
-
ease or gastrointestinal bleeding; concomitant NSAIDs). 
For patients with a lower risk of gastrointestinal bleeding, 
the risks and benefits of proton pump inhibitors must be 
weighed. Pending further recommendations, an acceptable 
alternative is to treat with an oral H
2
-receptor antagonist 
(famotidine 20 mg, ranitidine 150 mg, nizatidine 150 mg) 
twice daily; however, proton pump inhibitors are more 
effective in preventing upper gastrointestinal bleeding. 
Cimetidine is a CYP2C19 inhibitor and should not be used. 
An alternative strategy is ticagrelor, an antiplatelet agent 
approved for use with low-dose aspirin in the treatment of 
acute coronary syndrome. Like clopidogrel, ticagrelor 
blocks the platelet ADP p2y12 receptor; however, it does 
not require hepatic activation, it does not interact with the 
CYP2C19 enzyme, and its efficacy is not diminished by 
proton pump inhibitors.
C. Refractory Ulcers
Ulcers that are truly refractory to medical therapy are now 
uncommon. Less than 5% of ulcers are unhealed after 
8 weeks of once daily therapy with proton pump inhibitors, 
and almost all benign ulcers heal with twice daily therapy. 
Thus, noncompliance is the most common cause of ulcer 
nonhealing. NSAID and aspirin use, sometimes surrepti
-
tious, are commonly implicated in refractory ulcers and 
must be stopped. 
H pylori
 infection should be sought and 
the infection treated, if present, in all refractory ulcer 
patients. Single or multiple linear gastric ulcers may occur 
in large hiatal hernias where the stomach slides back and 
forth through the diaphragmatic hiatus (“Cameron 
lesions”), which may be a cause of iron deficiency anemia. 
Other causes of nonhealing ulcers include acid hypersecre
-
tion (Zollinger-Ellison syndrome), unrecognized malig
-
nancy (adenocarcinoma or lymphoma), medications 
causing gastrointestinal ulceration (eg, iron or bisphospho
-
nates), Crohn disease, and unusual infections (
H heilmanii
, 
CMV , mucormycosis). Fasting serum gastrin levels should 
be obtained to exclude gastrinoma with acid hypersecre
-
tion (Zollinger-Ellison syndrome). Repeat ulcer biopsies 
are mandatory after 2–3 months of therapy in all non
-
healed ulcers to look for malignancy or infection. Patients 
with persistent nonhealing ulcers are referred for surgical 
therapy after exclusion of NSAID use and persistent 
H pylori
 
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Helicobacter 
pylori
 infection. Am J Gastroenterol. 2017 Feb;112(2):212–39. 
Fallone CA et al. The Toronto Consensus for the treatment of 
 infection in adults. Gastroenterology. 2016 
Jul;151(1):51–69. [PMID: 27102658]
Klatte DCF et al. Association between proton pump inhibitor 
use and risk of progression of chronic kidney disease. Gastro
-
enterology. 2017 Sep;153(3):702–10. [PMID: 28583827]
Laine L. NSAID-associated gastrointestinal bleeding: assessing 
the role of concomitant medications. Gastroenterology. 
2014 Oct;147(4):730–3. [PMID: 25167988]
Lazarus B et al. Proton pump inhibitor use and the risk of 
chronic kidney disease. JAMA Intern Med. 2016 Feb;
 
176(2):238–46. [PMID: 26752337]
Lochhead P et al. Association between proton pump inhibitor 
use and cognitive function in women. Gastroenterology. 2017 
Oct;153(4):971–9. [PMID: 28728964]
Nissen SE et al; PRECISION Trial Investigators. Cardiovascular 
safety of celecoxib, naproxen, or ibuprofen for arthritis. N 
Engl J Med. 2016 Dec 29;375(26):2519–29. [PMID: 27959716]
COMPLICATIONS OF PEPTIC ULCER DISEASE
1. Gastrointestinal 
h
emorrhage
 
»
“Coffee grounds” emesis, hematemesis, melena, or 
hematochezia.
 
»
Emergent upper endoscopy is diagnostic and 
therapeutic.
 
»
Approximately 50% of all episodes of upper gastrointesti
-
nal bleeding are due to peptic ulcer. Clinically significant 
bleeding occurs in 10% of ulcer patients. About 80% of 
patients stop bleeding spontaneously and generally have an 
uneventful recovery; the remaining 20% have more severe 
bleeding. The overall mortality rate for ulcer bleeding is 
7%, but it is higher in older patients, in patients with 
comorbid medical problems, and in patients with hospital-
associated bleeding. Mortality is also higher in patients 
who present with persistent hypotension or shock, bright 
red blood in the vomitus or nasogastric lavage fluid, or 
severe coagulopathy.
 
»
Up to 20% of patients have no antecedent symptoms of 
pain; this is particularly true of patients receiving NSAIDs. 
Common presenting signs include melena and hemateme
-
sis. Massive upper gastrointestinal bleeding or rapid gas
-
trointestinal transit may result in hematochezia rather than 
melena; this may be misinterpreted as signifying a lower 
tract bleeding source. Nasogastric lavage that demonstrates 
“coffee grounds” or bright red blood confirms an upper 
tract source. Recovered nasogastric lavage fluid that is 
negative for blood does not exclude active bleeding from a 
duodenal ulcer.
The hematocrit may fall as a result of bleeding or expan
-
sion of the intravascular volume with intravenous fluids. 
The BUN may rise as a result of absorption of blood nitro
-
gen from the small intestine and prerenal azotemia.
 
»
Treatment
The assessment and initial management of upper gastroin
-
testinal tract bleeding are discussed above. Specific issues 
pertaining to peptic ulcer bleeding are described below.
A. Medical Therapy
1. Antisecretory agents—
inhibitors should be administered for 3 days in patients 
with ulcers whose endoscopic appearance suggests a high 
risk of rebleeding after endoscopic therapy. Intravenous 
proton pump inhibitors have been associated with a reduc
-
tion in rebleeding, transfusions, the need for further endo
-
scopic therapy, and surgery in the subset of patients with 
high-risk ulcers, ie, an ulcer with active bleeding, visible 
vessel, or adherent clot. After initial successful endoscopic 
treatment of ulcer hemorrhage, intravenous esomeprazole, 
pantoprazole, or omeprazole (80 mg bolus injection, fol
-

-
lowed by 8 mg/h continuous infusion for 72 hours) reduces 
the rebleeding rate from approximately 20% to less than 
10%; however, intravenous omeprazole is not available in 
the United States.
High-dose oral proton pump inhibitors (omeprazole 40 
mg twice daily) also appear to be effective in reducing 
rebleeding but have not been compared with the intrave
-
nous regimen. Intravenous H
2
-receptor antagonists have 
not been demonstrated to be of any benefit in the treat
-
ment of acute ulcer bleeding.
2. Long-term prevention of rebleeding—
Recurrent ulcer 
bleeding develops within 3 years in one-third of patients if 
no specific therapy is given. In patients with bleeding 
ulcers who are 
H pylori
–positive, successful eradication 
effectively prevents recurrent ulcer bleeding in almost all 
cases. It is therefore recommended that all patients with 
bleeding ulcers be tested for 
H pylori
 infection and treated 
if positive. Four to 8 weeks after completion of antibiotic 
therapy, a urea breath or fecal antigen test for 
H pylori
 
should be administered or endoscopy performed with 
biopsy and histology for confirmation of successful eradi
-
cation. In patients in whom 
H pylori
 persists or the small 
subset of patients whose ulcers are not associated with 
NSAIDs or 
H pylori
, long-term acid suppression with a 
once-daily proton pump inhibitor should be prescribed to 
reduce the likelihood of recurrence of bleeding.
B. Endoscopy
Endoscopy is the preferred diagnostic procedure in almost 
all cases of upper gastrointestinal bleeding because of its 
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high diagnostic accuracy, its ability to predict the likeli
-
hood of recurrent bleeding, and its availability for thera
-
peutic intervention in high-risk lesions. Endoscopy should 
be performed within 24 hours in most cases. In cases of 
severe active bleeding, endoscopy is performed as soon as 
patients have been appropriately resuscitated and are 
hemodynamically stable.
On the basis of clinical and endoscopic criteria, it is pos
-
sible to predict which patients are at a higher risk of 
rebleeding and therefore to make more rational use of hos
-
pital resources. Nonbleeding ulcers under 2 cm in size with 
a base that is clean have a less than 5% chance of rebleeding. 
Most young (under age 60 years), otherwise healthy patients 
with clean-based ulcers may be safely discharged from the 
emergency department or hospital after endoscopy. Ulcers 
that have a flat red or black spot have a less than 10% chance 
of significant rebleeding. Patients who are hemodynami
-
cally stable with these findings should be admitted to a 
hospital ward for 24–72 hours and may begin immediate 
oral feedings and antiulcer (or anti–
H pylori
) medication.
By contrast, the risk of rebleeding or continued bleeding 
in ulcers with a nonbleeding visible vessel is 50%, and with 
active bleeding it is 80–90%. Endoscopic therapy with ther
-
mocoagulation (bipolar or heater probes) or application of 
endoscopic clips (akin to a staple) is the standard of care for 
such lesions because it reduces the risk of rebleeding, the 
number of transfusions, and the need for subsequent sur
-
gery. The optimal treatment of ulcers with a dense clot that 
adheres despite vigorous washing is controversial; removal 
of the clot followed by endoscopic treatment of an underly
-
ing vessel may be considered in selected high-risk patients. 
For actively bleeding ulcers, a combination of epinephrine 
injection followed by thermocoagulation or clip application 
commonly is used. These techniques achieve successful 
hemostasis of actively bleeding lesions in 90% of patients. 
After endoscopic therapy followed by an intravenous pro
-
ton pump inhibitor, significant rebleeding occurs in less 
than 10%, of which over 70% can be managed successfully 
with repeat endoscopic treatment. After endoscopic 
treatment, patients should remain hospitalized for at least 
72 hours, when the risk of rebleeding falls to below 3%.
Patients with recurrent bleeding or bleeding that cannot be 
controlled by endoscopic techniques should be evaluated 
by a surgeon. However, less than 5% of patients treated 
with hemostatic therapy require surgery for continued or 
recurrent bleeding. Overall surgical mortality for emer
-
gency ulcer bleeding is less than 6%. The prognosis is 
poorer for patients over age 60 years, those with serious 
underlying medical illnesses or chronic kidney disease, and 
those who require more than 10 units of blood transfusion. 
Percutaneous arterial embolization is an alternative to sur
-
gery for patients in whom endoscopic therapy has failed.
2. Ulcer Perforation
Perforations develop in less than 5% of ulcer patients, usu
-
ally from ulcers on the anterior wall of the stomach or 
duodenum. Perforation results in a chemical peritonitis 
that causes sudden, severe generalized abdominal pain that 
prompts most patients to seek immediate attention. Elderly 
or debilitated patients and those receiving long-term corti
-
costeroid therapy may experience minimal initial symp
-
toms, presenting late with bacterial peritonitis, sepsis, and 
shock. On physical examination, patients appear ill, with a 
rigid, quiet abdomen and rebound tenderness. Hypoten
-
sion develops later after bacterial peritonitis has developed. 
If hypotension is present early with the onset of pain, other 
abdominal emergencies should be considered such as a 
ruptured aortic aneurysm, mesenteric infarction, or acute

ruptured aortic aneurysm, mesenteric infarction, or acute 
pancreatitis. Leukocytosis is almost always present. A 
mildly elevated serum amylase (less than twice normal) is 
sometimes seen with ulcer perforation. Abdominal CT 
usually establishes the diagnosis without need for further 
studies. The absence of free air may lead to a misdiagnosis 
of pancreatitis, cholecystitis, or appendicitis.
Laparoscopic perforation closure can be performed in 
many centers, significantly reducing operative morbidity 
compared with open laparotomy.
3. Gastric Outlet Obstruction
Gastric outlet obstruction occurs in less than 2% of 
patients with ulcer disease and is due to edema or cicatri
-
cial narrowing of the pylorus or duodenal bulb. With the 
advent of potent antisecretory therapy with proton pump 
inhibitors and the eradication of 
H pylori
, obstruction now 
is less commonly caused by peptic ulcers than by gastric 
neoplasms or extrinsic duodenal obstruction by intra-
abdominal neoplasms. The most common symptoms are 
early satiety, vomiting, and weight loss. Later, vomiting 
may develop that typically occurs one to several hours after 
eating and consists of partially digested food contents. 
Patients may develop dehydration, metabolic alkalosis, and 
hypokalemia. On physical examination, a succussion 
splash may be heard in the epigastrium. In most cases, 
nasogastric aspiration will result in evacuation of a large 
amount (greater than 200 mL) of foul-smelling fluid, which 
establishes the diagnosis. Patients are treated initially with 
intravenous isotonic saline and KCl to correct fluid and 
electrolyte disorders, an intravenous proton pump inhibi
-
tor, and nasogastric decompression of the stomach. Upper 
endoscopy is performed after 24–72 hours to define the 
nature of the obstruction and to exclude gastric neoplasm.
Beales I. Recent advances in the management of peptic ulcer 
bleeding. F1000Res. 2017 Sep 27;6:1763. [PMID: 29043071]
Graham DY . Upper gastrointestinal bleeding due to a peptic 
ulcer. N Engl J Med. 2016 Sep 22;375(12):1197–8. [PMID: 
27653583]
Laine L. Clinical practice. Upper gastrointestinal bleeding due to 
a peptic ulcer. N Engl J Med. 2016 Jun 16;374(24):2367–76. 
[PMID: 27305194]
Nykänen T et al. Bleeding gastric and duodenal ulcers: case-
control study comparing angioembolization and surgery. 
Scand J Gastroenterol. 2017 May;52(5):523–30. [PMID: 
28270041]
Shimomura A et al. New predictive model for acute gastrointes
-
tinal bleeding in patients taking oral anticoagulants: a cohort 
study. J Gastroenterol Hepatol. 2018 Jan;33(1):164–71. 
[PMID: 28544091]
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ZOLLINGER-ELLISON SYNDROME 
(
Gastrinoma
)
 
»
Peptic ulcer disease; may be severe and atypical.
 
»
Gastric acid hypersecretion.
 
»
Diarrhea common, relieved by nasogastric 
suction.
 
»
Most cases are sporadic; 25% with multiple endo
-
crine neoplasia type 1 (MEN 1).
 
»
Zollinger-Ellison syndrome is caused by gastrin-secreting 
gut neuroendocrine tumors (gastrinomas), which result in 
hypergastrinemia and acid hypersecretion. Less than 1% of 
peptic ulcer disease is caused by gastrinomas. Primary gas
-
trinomas may arise in the pancreas (25%), duodenal wall 
(45%), or lymph nodes (5–15%), and in other locations or 
of unknown primary (20%). Approximately 80% arise 
within the “gastrinoma triangle” bounded by the porta 
hepatis, the neck of the pancreas, and the third portion of 
the duodenum. Most gastrinomas are solitary or multifocal 
nodules that are potentially resectable. Approximately 25% 
of patients have small multicentric gastrinomas associated 
with MEN 1 that are more difficult to resect. Over two-
thirds of gastrinomas are malignant, and one-third have 
already metastasized to the liver at initial presentation.
 
»
Over 90% of patients with Zollinger-Ellison syndrome 
develop peptic ulcers. In most cases, the symptoms are 
indistinguishable from other causes of peptic ulcer disease 
and therefore the syndrome may go undetected for years. 
Ulcers usually are solitary and located in the duodenal 
bulb, but they may be multiple or occur more distally in the 
duodenum. Isolated gastric ulcers do not occur. Gastro
-
esophageal reflux symptoms occur often. Diarrhea occurs 
in one-third of patients, in some cases in the absence of 
peptic symptoms. Gastric acid hypersecretion can cause 
direct intestinal mucosal injury and pancreatic enzyme 
inactivation, resulting in diarrhea, steatorrhea, and weight 
loss; nasogastric aspiration of stomach acid stops the diar
-
rhea. Screening for Zollinger-Ellison syndrome with fast
-
ing gastrin levels should be obtained in patients with ulcers 
that are refractory to standard therapies, giant ulcers 
(larger than 2 cm), ulcers located distal to the duodenal 
bulb, multiple duodenal ulcers, frequent ulcer recurrences, 
ulcers associated with diarrhea, ulcers occurring after ulcer 
surgery, and patients with ulcer complications. Ulcer 
patients with hypercalcemia or family histories of ulcers 
(suggesting MEN 1) should also be screened. Finally, 
patients with peptic ulcers who are 
H pylori
–negative and 
who are not taking NSAIDs should be screened.
The most sensitive and specific method for identifying 
Zollinger-Ellison syndrome is demonstration of an increased 
fasting serum gastrin concentration (greater than 150 pg/
mL [150 ng/L]). If possible, levels should be obtained with 
patients not taking H
2
-receptor antagonists for 24 hours or 
proton pump inhibitors for 6 days; however, withdrawal of 
the proton pump inhibitor may be accompanied by massive 
gastric hypersecretion with serious consequences and 
should be closely monitored. The median gastrin level is 
500–700 pg/mL (500–700 ng/L), and 60% of patients have 
levels less than 1000 pg/mL (1000 ng/L). Hypochlorhydria 
with increased gastric pH is a much more common cause of 
hypergastrinemia than is gastrinoma. Therefore, a measure
-
ment of gastric pH (and, where available, gastric secretory 
studies) is performed in patients with fasting hypergastrin
-
emia. Most patients have a basal acid output of over 15 mEq/h. 
A gastric pH of greater than 3.0 implies hypochlorhydria 
and excludes gastrinoma. In a patient with a serum gastrin 
level of greater than 1000 pg/mL (1000 ng/L) and acid 
hypersecretion, the diagnosis of Zollinger-Ellison syndrome 
is established. With lower gastrin levels (150–1000 pg/mL 
[150–1000 ng/L]) and acid secretion, a secretin stimulation

[150–1000 ng/L]) and acid secretion, a secretin stimulation 
test may be performed to distinguish Zollinger-Ellison syn
-
drome from other causes of hypergastrinemia. Intravenous 
secretin (2 units/kg) produces a rise in serum gastrin of over 
200 pg/mL (200 ng/L) within 2–30 minutes in 85% of 
patients with gastrinoma. An elevated serum calcium sug
-
gests hyperparathyroidism and MEN 1 syndrome. In all 
patients with Zollinger-Ellison syndrome, a serum parathy
-
roid hormone (PTH), prolactin, luteinizing hormone-
follicle-stimulating hormone (LH-FSH), and growth 
hormone (GH) level should be obtained to exclude MEN 1.
C. Imaging
Imaging studies are obtained in an attempt to determine 
whether there is metastatic disease and, if not, to identify 
the site of the primary tumor. CT and MRI scans are com
-
monly obtained first to look for large hepatic metastases 
and primary lesions, but they have low sensitivity for small 
lesions. Gastrinomas express somatostatin receptors that 
bind radiolabeled octreotide. Somatostatin receptor scin
-
tigraphy (SRS) with single photon emission computed 
tomography (SPECT) allows total body imaging for detec
-
tion of primary gastrinomas in the pancreas and lymph 
nodes, primary gastrinomas in unusual locations, and 
metastatic gastrinomas (liver and bone). The 80% sensitiv
-
ity for tumor detection of SRS exceeds all other imaging 
studies combined. If SRS is positive for tumor localization, 
further imaging studies are not necessary. In patients with 
negative SRS, endoscopic ultrasonography (EUS) may be 
useful to detect small gastrinomas in the duodenal wall, 
pancreas, or peripancreatic lymph nodes. With a combina
-
tion of SRS and EUS, more than 90% of primary gastrino
-
mas can be localized preoperatively.
 
»
Gastrinomas are one of several gut neuroendocrine tumors 
that have similar histopathologic features and arise either 
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Table 15–11.
 
Clinical manifestations and laboratory findings in malabsorption of various nutrients.
Manifestations
Malabsorbed Nutrients
Steatorrhea (bulky, light-colored stools)
Increased fecal fat; decreased serum cholesterol; 
decreased serum carotene, vitamin A, vitamin D
Triglycerides, fatty acids, phospholipids, 
cholesterol. Fat-soluble vitamins: A, D, E, K
Diarrhea (increased fecal water)
Increased stool volume and weight; increased 
 
fecal fat; increased stool osmolality gap
Fats, carbohydrates
Weight loss; muscle wasting
Increased fecal fat; decreased carbohydrate 
(D-xylose) absorption
Fat, protein, carbohydrates
Microcytic anemia
Low serum iron
Iron
Macrocytic anemia
Decreased serum vitamin B
12
 or red blood cell 
folate
Vitamin B
12
 or folic acid
Paresthesia; tetany; positive Trousseau 
and Chvostek signs
Decreased serum calcium or magnesium
Calcium, vitamin D, magnesium
Bone pain; pathologic fractures; 
 
skeletal deformities
Osteopenia on radiograph; osteoporosis (adults); 
osteomalacia (children)
Calcium, vitamin D
Bleeding tendency (ecchymoses, 
epistaxis)
Prolonged prothrombin time or INR
Vitamin K
Edema
Decreased serum total protein and albumin; 
increased fecal loss of alpha-1-antitrypsin
Protein
Milk intolerance (cramps, bloating, 
diarrhea)
Abnormal lactose tolerance test
Lactose
INR, international normalized ratio.
from the gut or pancreas. These include carcinoid, insuli
-
noma, VIPoma, glucagonoma, and somatostatinoma. 
These tumors usually are differentiated by the gut peptides 
that they secrete; however, poorly differentiated neuroen
-
docrine tumors may not secrete any hormones. Patients 
may present with symptoms caused by tumor metastases 
(jaundice, hepatomegaly) rather than functional symp
-
toms. Once a diagnosis of a neuroendocrine tumor is 
established from the liver biopsy, the specific type of tumor 
can subsequently be determined. Both carcinoid and gas
-
trinoma tumors may be detected incidentally during 
endoscopy after biopsy of a submucosal nodule and must 
be distinguished by subsequent studies.
Hypergastrinemia due to gastrinoma must be distin
-
guished from other causes of hypergastrinemia. Atrophic 
gastritis with decreased acid secretion is detected by gastric 
secretory analysis. Other conditions associated with hyper
-
gastrinemia (eg, gastric outlet obstruction, vagotomy, 
chronic kidney disease) are associated with a negative secre
-
tin stimulation test.
 
»
Treatment
A. Metastatic Disease
The most important predictor of survival is the presence of 
hepatic metastases. In patients with multiple hepatic 
metastases, initial therapy should be directed at controlling 
hypersecretion. Oral proton pump inhibitors (omeprazole, 
esomeprazole, rabeprazole, pantoprazole, or lansoprazole) 
are given at a dose of 40–120 mg/day, titrated to achieve a 
basal acid output of less than 10 mEq/h. At this level, there 
is complete symptomatic relief and ulcer healing. Owing to 
the slow growth of these tumors, 30% of patients with 
hepatic metastases have a survival of 10 years.
B. Localized Disease
Cure can be achieved only if the gastrinoma can be resected 
before hepatic metastatic spread has occurred. Lymph node 
metastases do not adversely affect prognosis. Laparotomy 
should be considered in all patients in whom preoperative 
studies fail to demonstrate hepatic or other distant metastases. 
A combination of preoperative studies, duodenotomy with 
careful duodenal inspection, and intraoperative palpation 
and sonography allows successful localization and resection 
in the majority of cases. The 15-year survival of patients who 
do not have liver metastases at initial presentation is over 
95%. Surgery usually is not recommended in patients with 
MEN 1 due to the presence of multifocal tumors and long-
term survival in the absence of surgery in most patients.
De Angelis C et al. Diagnosis and management of Zollinger-

De Angelis C et al. Diagnosis and management of Zollinger- 
 
Ellison syndrome in 2017. Minerva Endocrinol. 2017 Sep 25. 
[Epub ahead of print] [PMID: 28949124] 
Epelboym I et al. Zollinger-Ellison syndrome: classical consider
-
ations and current controversies. Oncologist. 2014 Jan;
 
19(1):44–50. [PMID: 24319020]
Singh Ospina N et al. Assessing for multiple endocrine neoplasia 
type 1 in patients evaluated for Zollinger-Ellison Syndrome—
clues to a safer diagnostic process. Am J Med. 2017 May;
 
130(5):603–5. [PMID: 28011308]
 
º
h
E SMALL INTESTINE
MALABSORPTION
The term “malabsorption” denotes disorders in which there 
is a disruption of digestion and nutrient absorption. The 
clinical and laboratory manifestations of malabsorption 
are summarized in Table 15–11.
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Avitzur Y et al. Enteral approaches in malabsorption. Best Pract 
Res Clin Gastroenterol. 2016 Apr;30(2):295–307. [PMID: 
27086892]
Wanten GJ. Parenteral approaches in malabsorption: home 
parenteral nutrition. Best Pract Res Clin Gastroenterol. 
2016 Apr;30(2):309–18. [PMID: 27086893]
1. Celiac Disease
 
»
Typical symptoms
: weight loss, chronic diarrhea, 
abdominal distention, growth retardation.
 
»
Atypical symptoms
: dermatitis herpetiformis, iron 
deficiency anemia, osteoporosis.
 
»
Abnormal serologic test results.
 
»
Abnormal small bowel biopsy.
 
»
Clinical improvement on gluten-free diet.
 
»
Celiac disease (also called sprue, celiac sprue, and gluten 
enteropathy) is a permanent dietary disorder caused by an 
immunologic response to gluten, a storage protein found in 
certain grains, that results in diffuse damage to the proxi
-
mal small intestinal mucosa with malabsorption of nutri
-
ents. Although symptoms may manifest between 6 months 
and 24 months of age after the introduction of weaning 
foods, the majority of cases present in childhood or adult
-
hood. Population screening with serologic tests suggests 
that the disease is present in 1:100 whites of Northern 
European ancestry, in whom a clinical diagnosis of celiac 
disease is made in only 10%, suggesting that most cases are 
undiagnosed or asymptomatic. Celiac disease develops 
only in people with the HLA-DQ2 (95%) or -DQ8 (5%) 
class II molecules, which are present in 40% of the popula
-
tion. Although the precise pathogenesis is unclear, celiac 
disease arises in a small subset of genetically susceptible 
(-DQ2 or -DQ8) individuals when dietary gluten stimu
-
lates an inappropriate immunologic response.
 
»
The most important step in diagnosing celiac disease is to 
consider the diagnosis. Symptoms are present for more 
than 10 years in most adults before the correct diagnosis 
is established. Because of its protean manifestations, 
celiac disease is grossly underdiagnosed in the adult 
population.
The gastrointestinal symptoms and signs of celiac disease 
depend on the length of small intestine involved and the 
patient’s age when the disease presents. “Classic” symptoms 
of malabsorption, including diarrhea, steatorrhea, weight 
loss, abdominal distention, weakness, muscle wasting, or 
growth retardation, more commonly present in infants 
(younger than 2 years). Older children and adults are less 
likely to manifest signs of serious malabsorption. They may 
report chronic diarrhea, dyspepsia, or flatulence due to 
colonic bacterial digestion of malabsorbed nutrients, but 
the severity of weight loss is variable. Many adults have 
minimal or no gastrointestinal symptoms but present with 
extraintestinal “atypical” manifestations, including fatigue, 
depression, iron deficiency anemia, osteoporosis, short 
stature, delayed puberty, amenorrhea, or reduced fertility. 
Approximately 40% of patients with positive serologic tests 
consistent with disease have no symptoms of disease; the 
natural history of these patients with “silent” disease is 
unclear.
Physical examination may be normal in mild cases or 
may reveal signs of malabsorption such as loss of muscle 
mass or subcutaneous fat, pallor due to anemia, easy bruis
-
ing due to vitamin K deficiency, hyperkeratosis due to 
vitamin A deficiency, bone pain due to osteomalacia, or 
neurologic signs (peripheral neuropathy, ataxia) due to 
vitamin B
12
 or vitamin E deficiency (Table 15–11). Abdom
-
inal examination may reveal distention with hyperactive 
bowel sounds.
Dermatitis herpetiformis
 is regarded as a cutaneous 
variant of celiac disease. It is a characteristic skin rash con
-
sisting of pruritic papulovesicles over the extensor surfaces 
of the extremities and over the trunk, scalp, and neck. 
Dermatitis herpetiformis occurs in less than 10% of

-
Dermatitis herpetiformis occurs in less than 10% of 
patients with celiac disease; however, almost all patients 
who present with dermatitis herpetiformis have evidence 
of celiac disease on intestinal mucosal biopsy, though it 
may not be clinically evident.
1. Routine la
bor
atory tests—
Depending on the severity 
of illness and the extent of intestinal involvement, non
-
specific laboratory abnormalities may be present that 
may raise the suspicion of malabsorption and celiac dis
-
ease (Table 15–11). Limited proximal involvement may 
result only in microcytic anemia due to iron deficiency. 
Up to 5% of adults with iron deficiency not due to gastro
-
intestinal blood loss have undiagnosed celiac disease. 
Megaloblastic anemia may be due to folate or vitamin B
12
 
deficiency (due to terminal ileal involvement or associated 
autoimmune gastritis). Low serum calcium or elevated 
alkaline phosphatase may reflect impaired calcium or 
vitamin D absorption with osteomalacia or osteoporosis. 
Dual-energy x-ray densitometry scanning is recommended 
for all patients with sprue to screen for osteoporosis. Eleva
-
tions of prothrombin time, or decreased vitamin A or D 
levels reflect impaired fat-soluble vitamin absorption. A 
low serum albumin may reflect small intestine protein loss 
or poor nutrition. Other deficiencies may include zinc and 
vitamin B
6
. Mild elevations of aminotransferases are found 
in up to 40%.
2. Serologic tests—
Serologic tests should be performed in 
all patients in whom there is a suspicion of celiac disease. 
The recommended test is the IgA tissue transglutaminase 
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(IgA tTG) antibody, which has a 98% sensitivity and 98% 
specificity for the diagnosis of celiac disease. Antigliadin 
antibodies are not recommended because of their lower 
sensitivity and specificity. IgA antiendomysial antibodies 
are no longer recommended due to the lack of standardiza
-
tion among laboratories. An IgA level should be obtained 
in patients with a negative IgA tTG antibody when celiac 
disease is strongly suspected because up to 3% of patients 
with celiac disease have IgA deficiency. In patients with 
IgA deficiency, tests that measures IgG antibodies to tissue 
transglutaminase (IgG tTG) or to deamidated gliadin 
peptides (anti-DGP) have excellent sensitivity and specific
-
ity. Levels of all antibodies become undetectable after 
3–24 months of dietary gluten withdrawal and may be 
used to monitor dietary compliance, especially in patients 
whose symptoms fail to resolve after institution of a gluten-
free diet.
C. Mucosal Biopsy
Endoscopic mucosal biopsy of the proximal duodenum 
(bulb) and distal duodenum is the standard method for 
confirmation of the diagnosis in patients with a positive 
serologic test for celiac disease. Mucosal biopsy should also 
be pursued in patients with negative serologies when symp
-
toms and laboratory studies are strongly suggestive of celiac 
disease. At endoscopy, atrophy or scalloping of the duode
-
nal folds may be observed. Histology reveals abnormalities 
ranging from intraepithelial lymphocytosis alone to exten
-
sive infiltration of the lamina propria with lymphocytes and 
plasma cells with hypertrophy of the intestinal crypts and 
blunting or complete loss of intestinal villi. An adequate 
normal biopsy excludes the diagnosis. Partial or complete 
reversion of these abnormalities occurs within 3–24 months 
after a patient is placed on a gluten-free diet, but symptom 
resolution remains incomplete in 30% of patients. If a 
patient with a compatible biopsy demonstrates prompt 
clinical improvement on a gluten-free diet and a decrease in 
serologic markers, a repeat biopsy is unnecessary.
 
»
Many patients with chronic diarrhea or flatulence are erro
-
neously diagnosed as having irritable bowel syndrome. 
Celiac sprue must be distinguished from other causes of 
malabsorption, as outlined above. Severe panmalabsorp
-
tion of multiple nutrients is almost always caused by muco
-
sal disease. The histologic appearance of celiac sprue may 
resemble other mucosal diseases such as tropical sprue, 
bacterial overgrowth, cow’s milk intolerance, viral gastro
-
enteritis, eosinophilic gastroenteritis, and mucosal damage 
caused by acid hypersecretion associated with gastrinoma. 
Documentation of clinical response to gluten withdrawal 
therefore is essential to the diagnosis.
Some patients complain of symptoms after gluten 
ingestion but do not have serologic or histologic evidence 
of celiac disease. The frequency and cause of this entity is 
debated. A large 2013 study found that symptoms improved 
in gluten-sensitive patients when placed on a FODMAP-
restricted diet and worsened to similar degrees when chal
-
lenged in a double-blind crossover trial with gluten or 
whey proteins. These data suggest that nonceliac gluten 
sensitivity may not be a true entity and that the symptom 
improvement reported by patients with gluten restriction 
may be due to broader FODMAP elimination.
 
»
Treatment
Removal of all gluten from the diet is essential to therapy—
all wheat, rye, and barley must be eliminated. Although 
oats appear to be safe for many patients, commercial prod
-
ucts may be contaminated with wheat or barley during 
processing. Because of the pervasive use of gluten products 
in manufactured foods and additives, in medications, and 
by restaurants, it is imperative that patients and their fami
-
lies confer with a knowledgeable dietitian to comply satis
-
factorily with this lifelong diet. Several excellent dietary

-
-
factorily with this lifelong diet. Several excellent dietary 
guides and patient support groups are available. Most 
patients with celiac disease also have lactose intolerance 
either temporarily or permanently and should avoid dairy 
products until the intestinal symptoms have improved on 
the gluten-free diet. Dietary supplements (folate, iron, zinc, 
calcium, and vitamins A, B
6
, B
12
, D, and E) should be pro
-
vided in the initial stages of therapy but usually are not 
required long-term with a gluten-free diet. Patients with 
confirmed osteoporosis may require long-term calcium, 
vitamin D, and bisphosphonate therapy.
Improvement in symptoms should be evident within a 
few weeks on the gluten-free diet. The most common rea
-
son for treatment failure is incomplete removal of gluten. 
Intentional or unintentional rechallenge with gluten may 
trigger acute severe diarrhea with dehydration, electrolyte 
imbalance, and may require TPN and intravenous or oral 
corticosteroids (prednisone 40 mg or budesonide 9 mg) for 
2 or more weeks as a gluten-free diet is reinitiated.
 
»
Prognosis & Complications
If appropriately diagnosed and treated, patients with celiac 
disease have an excellent prognosis. Celiac disease may be 
associated with other autoimmune disorders, including 
Addison disease, Graves disease, type 1 diabetes mellitus, 
myasthenia gravis, scleroderma, Sjögren syndrome, atro
-
phic gastritis, and pancreatic insufficiency. In some 
patients, celiac disease may evolve and become refractory 
to the gluten-free diet. The most common cause is inten
-
tional or unintentional dietary noncompliance, which may 
be suggested by positive serologic tests. Celiac disease that 
is truly refractory to gluten withdrawal occurs in less than 
5% and generally carries a poor prognosis. There are two 
types of refractory disease, which are distinguished by their 
intraepithelial lymphocyte phenotype. This diagnosis 
should be considered in patients previously responsive to 
the gluten-free diet in whom new weight loss, abdominal 
pain, and malabsorption develop.
Celiac Disease Foundation, 20350 Ventura Blvd, Suite #240, 
Woodland Hills, CA 91364. https://celiac.org
Elli L et al. Use of enteroscopy for the detection of malignant and 
premalignant lesions of the small bowel in complicated celiac 
disease: a meta-analysis. Gastrointest Endosc. 2017 Aug;
 
86(2):264–73. [PMID: 28433612]
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Kelly CP et al. Advances in diagnosis and management of celiac 
disease. Gastroenterology. 2015 May;148(6):1175–86. [PMID: 
25662623]
Leonard MM et al. Celiac disease and nonceliac gluten sensitiv
-
ity: a review. JAMA. 2017 Aug 15;318:647–56. [PMID: 
28810029]
Oxentenko AS et al. Celiac disease: ten things that every gastro
-
enterologist should know. Clin Gastroenterol Hepatol. 2015 
Aug;13(8):1396–404. [PMID: 25051511]
2. Whipple Disease
 
»
Multisystem disease.
 
»
Fever, lymphadenopathy, arthralgias.
 
»
Weight loss, malabsorption, chronic diarrhea.
 
»
Duodenal biopsy with periodic acid-Schiff 
(PAS)-positive macrophages with characteristic 
bacillus.
 
»
Whipple disease is a rare multisystem illness caused by 
infection with the bacillus 
Tropheryma whipplei.
 It may 
occur at any age but most commonly affects white men in 
the fourth to sixth decades. The source of infection is 
unknown, but no cases of human-to-human spread have 
been documented.
 
»
The clinical manifestations are protean; however, the 
most common are arthralgias, diarrhea, abdominal pain, 
and weight loss. Arthralgias or a migratory, nondeform
-
ing arthritis occurs in 80% and is typically the first symp
-
tom experienced. Gastrointestinal symptoms occur in 
approximately 75% of cases. They include abdominal 
pain, diarrhea, and some degree of malabsorption with 
distention, flatulence, and steatorrhea. Weight loss is the 
most common presenting symptom—seen in almost all 
patients. Loss of protein due to intestinal or lymphatic 
involvement may result in protein-losing enteropathy 
with hypoalbuminemia and edema. In the absence of 
gastrointestinal symptoms, the diagnosis often is delayed 
for several years. Intermittent low-grade fever occurs in 
over 50% of cases.
Physical examination may reveal hypotension (a late 
finding), low-grade fever, and evidence of malabsorption 
(see Table 15–11). Lymphadenopathy is present in 50%. 
Heart murmurs due to valvular involvement may be evi
-
dent. Peripheral joints may be enlarged or warm, and 
peripheral edema may be present. Neurologic findings are 
cited above. Hyperpigmentation on sun-exposed areas is 
evident in up to 40%.
If significant malabsorption is present, patients may have 
laboratory abnormalities as outlined in Table 15–11. There 
may be steatorrhea.
C. Histologic Evaluation
The diagnosis of Whipple disease is established in 90% of 
cases by endoscopic biopsy of the duodenum with histo
-
logic evaluation, which demonstrates infiltration of the 
lamina propria with PAS-positive macrophages that con
-
tain gram-positive bacilli (which are not acid-fast) and 
dilation of the lacteals. The remainder of cases are diag
-
nosed by 
T whipplei
–specific polymerase chain reaction 
(PCR) or immunohistochemistry of duodenal biopsies or 
extraintestinal fluids (cerebrospinal, synovial) or tissue 
(lymph nodes, synovium, endocardium). The sensitivity of 
PCR is 97% and the specificity 100%. Because asymptom
-
atic central nervous system infection occurs in 40% of 
patients, examination of the cerebrospinal fluid by PCR for 
T whipplei
 should be performed routinely.
 
»
Whipple disease should be considered in patients who 
present with signs of malabsorption, fever of unknown 
origin, lymphadenopathy, seronegative arthritis, culture-
negative endocarditis, or multisystem disease. Small bowel 
biopsy readily distinguishes Whipple disease from other 
mucosal malabsorptive disorders, such as celiac sprue.
 
»
Treatment
Antibiotic therapy results in a dramatic clinical improvement 
within several weeks, even in some patients with neurologic 
involvement. The optimal regimen is unknown. Complete 
clinical response usually is evident within 1–3 months; how
-
ever, relapse may occur in up to one-third of patients after

-
ever, relapse may occur in up to one-third of patients after 
discontinuation of treatment. Therefore, prolonged treat
-
ment for at least 1 year is required. Drugs that cross the 
blood-brain barrier are preferred. A randomized controlled 
trial in 40 patients with 3–10 years’ follow-up demonstrated 
100% remission with either ceftriaxone 1 g intravenously 
twice daily or meropenem 1 g intravenously three times 
daily for 2 weeks, followed by trimethoprim-sulfamethoxa
-
zole 160/800 mg twice daily for 12 months. After treatment, 
repeat duodenal biopsies for histologic analysis and cere
-
brospinal fluid PCR should be obtained every 6 months for 
at least 1 year. The absence of PAS-positive material predicts 
a low likelihood of clinical relapse.
 
»
Prognosis
If untreated, the disease is fatal. Because some neurologic 
signs may be permanent, the goal of treatment is to prevent 
this progression. Patients must be followed closely after 
treatment for signs of symptom recurrence.
Biagi F et al. What is the best therapy for Whipple’s disease? Our 
point of view. Scand J Gastroenterol. 2017 Apr;52(4):465–6. 
[PMID: 27924649]
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Günther U et al. Gastrointestinal diagnosis of classical Whipple 
disease: clinical, endoscopic, and histopathologic features in 
191 patients. Medicine (Baltimore). 2015 Apr;94(15):e714. 
[PMID: 25881849]
Marth T. Whipple’s disease. Acta Clin Belg. 2016 Dec;71(6):373–8. 
[PMID: 27884091]
Marth T et al. 
Tropheryma whipplei
 infection and Whipple’s 
disease. Lancet Infect Dis. 2016 Mar;16(3):e13–22. [PMID: 
26856775]
3. Bacterial Overgrowth
 
»
Symptoms of distention, flatulence, diarrhea, and 
 
»
Increased qualitative or quantitative fecal fat.
 
»
Advanced cases associated with deficiencies of 
iron or vitamins A, D, and B
12
.
 
»
Diagnosis suggested by breath tests using glu
-
cose, lactulose, or 
14
C-xylose as substrates.
 
»
Diagnosis confirmed by jejunal aspiration with 
quantitative bacterial cultures.
 
»
The small intestine normally contains a small number of 
bacteria. Bacterial overgrowth in the small intestine of 
whatever cause may result in malabsorption via a number 
of mechanisms. Bacterial deconjugation of bile salts may 
lead to inadequate micelle formation, resulting in decreased 
fat absorption with steatorrhea and malabsorption of fat-
soluble vitamins (A, D). Microbial uptake of specific nutri
-
ents reduces absorption of vitamin B
12
 and carbohydrates. 
Bacterial proliferation also causes direct damage to intesti
-
nal epithelial cells and the brush border, further impairing 
absorption of proteins, carbohydrates, and minerals. Pas
-
sage of the malabsorbed bile acids and carbohydrates into 
the colon leads to an osmotic and secretory diarrhea and 
increased flatulence.
Causes of bacterial overgrowth include (1) gastric 
achlorhydria (including proton pump inhibitor therapy); 
(2) anatomic abnormalities of the small intestine with 
stagnation (afferent limb of Billroth II gastrojejunos
-
tomy, resection of ileocecal valve, small intestine diver
-
ticula, obstruction, blind loop); (3) small intestine 
motility disorders (vagotomy, scleroderma, diabetic 
enteropathy, chronic intestinal pseudo-obstruction); (4) 
gastrocolic or coloenteric fistula (Crohn disease, malig
-
nancy, surgical resection); and (5) miscellaneous disor
-
ders. Bacterial overgrowth is an important cause of 
malabsorption in older patients, perhaps because of 
decreased gastric acidity or impaired intestinal motility. 
It may also be present in a subset of patients with irrita
-
ble bowel syndrome.
 
»
Many patients with bacterial overgrowth are asymptomatic. 
Symptoms are nonspecific and include flatulence, weight 
loss, abdominal pain, diarrhea, and sometimes steatorrhea. 
Severe cases may result in clinically significant vitamin and 
mineral deficiencies, including fat-soluble vitamins A or D, 
vitamin B
12
, and iron (Table 15–11). Qualitative or quantita
-
tive fecal fat assessment typically is abnormal. Bacterial 
overgrowth should be considered in any patient with diar
-
rhea, flatulence, weight loss, or macrocytic anemia, espe
-
cially if the patient has a predisposing cause (such as prior 
gastrointestinal surgery). A stool collection should be 
obtained to corroborate the presence of steatorrhea. 
Vitamins A, D, B
12
, and serum iron should be measured. A 
specific diagnosis can be established firmly only by an aspi
-
rate and culture of proximal jejunal secretion that demon
-
strates over 10
5
 organisms/mL. However, this is an invasive 
and laborious test that requires careful collection and cultur
-
ing techniques and therefore is not available in many clinical 
settings. Noninvasive breath tests are easier to perform and 
reported to have a sensitivity of 60–90% and a specificity of 
85% compared with jejunal cultures. However, some studies 
confirm a high rate (up to 50%) of false-positive breath test 
results due to misinterpretation of bacterial fermentation.

results due to misinterpretation of bacterial fermentation. 
Breath hydrogen and methane tests with glucose or lactulose 
as substrates are commonly done because of their ease of 
use. A small bowel study (CT or MR enterography, barium 
radiography) may be obtained to look for mechanical factors 
predisposing to intestinal stasis.
Owing to the lack of an optimal test for bacterial over
-
growth, many clinicians use an empiric antibiotic trial as a 
diagnostic and therapeutic maneuver in patients with pre
-
disposing conditions for bacterial overgrowth in whom 
unexplained diarrhea or steatorrhea develops.
 
»
Treatment
Where possible, the anatomic defect that has potentiated 
bacterial overgrowth should be corrected. Otherwise, 
treatment as follows for 1–2 weeks with oral broad-
spectrum antibiotics effective against enteric aerobes and 
anaerobes usually leads to dramatic improvement: twice-
daily ciprofloxacin 500 mg, norfloxacin 400 mg, or amoxi
-
cillin clavulanate 875 mg, or a combination of metronidazole 
250 mg three times daily plus either trimethoprim-
sulfamethoxazole (one double-strength tablet) twice daily 
or cephalexin 250 mg four times daily. Rifaximin 400 mg 
three times daily is a nonabsorbable antibiotic that also 
appears to be effective but has fewer side effects than the 
other systemically absorbed antibiotics.
In patients in whom symptoms recur off antibiotics, 
cyclic therapy (eg, 1 week out of 4) may be sufficient. Con
-
tinuous antibiotics should be avoided, if possible, to avoid 
development of bacterial antibiotic resistance.
Gatta L et al. Systematic review with meta-analysis: rifaximin is 
effective and safe for the treatment of small intestine bacterial 
overgrowth. Aliment Pharmacol Ther. 2017 Mar;45(5):
 
604–16. [PMID: 28078798]
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Krajicek EJ et al. Small intestinal bacterial overgrowth: a primary 
care review. Mayo Clin Proc. 2016 Dec;91(12):1828–33. 
[PMID: 27916156]
Lin EC et al. Scintigraphy demonstrates high rate of false-posi
-
tive results from glucose breath tests for small bacterial over
-
growth. Clin Gastroenterol Hepatol. 2016 Feb;14(2):203–8. 
[PMID: 26241509]
Rezaie A et al. Hydrogen and methane-based breath testing in 
gastrointestinal disorders: the North American consensus. Am 
J Gastroenterol. 2017 May;112(5):775–84. [PMID: 28323273]
4. Short Bowel Syndrome
Short bowel syndrome is the malabsorptive condition that 
arises secondary to removal of significant segments of the 
small intestine. The most common causes in adults are 
Crohn disease, mesenteric infarction, radiation enteritis, 
volvulus, tumor resection, and trauma. The type and 
degree of malabsorption depend on the length and site of 
the resection and the degree of adaptation of the remaining 
bowel.
 
»
Terminal Ileal Resection
Resection of the terminal ileum results in malabsorption of 
bile salts and vitamin B
12
, which are normally absorbed in 
this region. Patients with low serum vitamin B
12
 levels or 
resection of over 50 cm of ileum require monthly subcuta
-
neous or intramuscular vitamin B
12
 injections. In patients 
with less than 100 cm of ileal resection, bile salt malabsorp
-
tion stimulates fluid secretion from the colon, resulting in 
watery diarrhea. This may be treated with bile salt-binding 
resins (colestipol or cholestyramine, 2–4 g orally three 
times daily with meals or colesevelam, 625 mg, 1–3 tablets 
twice daily). Resection of over 100 cm of ileum leads to a 
reduction in the bile salt pool that results in steatorrhea 
and malabsorption of fat-soluble vitamins. Treatment is 
with a low-fat diet and vitamins supplemented with 
medium-chain triglycerides, which do not require micellar 
solubilization. Unabsorbed fatty acids bind with calcium, 
reducing its absorption and enhancing the absorption of 
oxalate. Oxalate kidney stones may develop. Calcium sup
-
plements should be administered to bind oxalate and 
increase serum calcium. Cholesterol gallstones due to 
decreased bile salts are common also. In patients with 
resection of the ileocolonic valve, bacterial overgrowth 
may occur in the small intestine, further complicating mal
-
absorption (as outlined above).
 
»
Extensive Small Bowel Resection
Resection of up to 40–50% of the total length of small 
intestine usually is well tolerated. A more massive resection 
may result in “short bowel syndrome, ” characterized by 
weight loss and diarrhea due to nutrient, water, and elec
-
trolyte malabsorption. If the colon is preserved, 100 cm of 
proximal jejunum may be sufficient to maintain adequate 
oral nutrition with a low-fat, high–complex carbohydrate 
diet, though fluid and electrolyte losses may still be signifi
-
cant. In patients in whom the colon has been removed, at 
least 200 cm of proximal jejunum is typically required to 
maintain oral nutrition. Antidiarrheal agents (loperamide, 
2–4 mg orally three times daily) slow transit and reduce 
diarrheal volume. Octreotide reduces intestinal transit 
time and fluid and electrolyte secretion. Gastric hyperse
-
cretion initially complicates intestinal resection and should 
be treated with proton pump inhibitors.
Patients with less than 100–200 cm of proximal jeju
-
num remaining almost always require parenteral nutrition. 
Teduglutide is a glucagon-like peptide-2 analogue that 
stimulates small bowel growth and absorption and is FDA 
approved for the treatment of short bowel syndrome. In 
clinical trials, it resulted in a reduced need for parenteral 
nutrition. Small intestine transplantation has reported 
5-year graft survival rates of 40%. Currently, it is per
-
formed chiefly in patients in whom serious problems 
develop due to parenteral nutrition.

-
Iyer KR et al. Independence from parenteral nutrition and intra
-
venous fluid support during treatment with teduglutide 
among patients with intestinal failure associated with short 
bowel syndrome. JPEN J Parenter Enteral Nutr. 2017 Aug;
 
41(6):946–51. [PMID: 27875291]
Jeppesen PB et al. Factors associated with response to teduglu
-
tide in patients with short-bowel syndrome and intestinal 
failure. Gastroenterology.  2018 Mar;154(4):874–85.  [PMID: 
29174926]
Parrish CR et al. Managing the adult patient with short bowel 
syndrome. Gastroenterol Hepatol (N Y). 2017 Oct;13(10):
 
600–8. [PMID: 29230136]
5. Lactase Deficiency
 
»
Diarrhea, bloating, flatulence, and abdominal pain 
after ingestion of milk-containing products.
 
»
Diagnosis supported by symptomatic improve
-
ment on lactose-free diet.
 
»
Diagnosis confirmed by hydrogen breath test.
 
»
Lactase is a brush border enzyme that hydrolyzes the disac
-
charide lactose into glucose and galactose. The concentration 
of lactase enzyme levels is high at birth but declines steadily 
in most people of non-European ancestry during childhood 
and adolescence and into adulthood. As many as 90% of 
Asian Americans, 70% of African Americans, 95% of Native 
Americans, 50% of Mexican Americans, and 60% of Jewish 
Americans are lactose intolerant compared with less than 
25% of white adults. Lactase deficiency may also arise sec
-
ondary to other gastrointestinal disorders that affect the 
proximal small intestinal mucosa. These include Crohn dis
-
ease, celiac disease, viral gastroenteritis, giardiasis, short 
bowel syndrome, and malnutrition. Malabsorbed lactose is 
fermented by intestinal bacteria, producing gas and organic 
acids. The nonmetabolized lactose and organic acids result in 
an increased stool osmotic load with an obligatory fluid loss.
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»
Patients have great variability in clinical symptoms, 
depending both on the severity of lactase deficiency and 
the amount of lactose ingested. Because of the nonspecific 
nature of these symptoms, there is a tendency for both 
lactose-intolerant and lactose-tolerant individuals to mis
-
takenly attribute a variety of abdominal symptoms to lac
-
tose intolerance. Most patients with lactose intolerance can 
drink at least one 8-oz serving of milk daily (12 g of lac
-
tose) without symptoms, though rare patients have almost 
complete intolerance. With mild to moderate amounts of 
lactose malabsorption, patients may experience bloating, 
abdominal cramps, and flatulence. With higher lactose 
ingestions, an osmotic diarrhea will result. Isolated lactase 
deficiency does not result in other signs of malabsorption 
or weight loss. If these findings are present, other gastroin
-
testinal disorders should be pursued. Diarrheal specimens 
reveal an increased osmotic gap and a pH of less than 6.0.
The most widely available test for the diagnosis of lactase 
deficiency is the hydrogen breath test. After ingestion of 
50 g of lactose, a rise in breath hydrogen of more than 
20 ppm within 90 minutes is a positive test, indicative of 
bacterial carbohydrate metabolism. In clinical practice, 
many clinicians prescribe an empiric trial of a lactose-free 
diet for 2 weeks. Resolution of symptoms (bloating, flatu
-
lence, diarrhea) is suggestive of lactase deficiency (though 
a placebo response cannot be excluded) and may be con
-
firmed, if necessary, with a breath hydrogen study.
 
»
The symptoms of late-onset lactose intolerance are nonspe
-
cific and may mimic a number of gastrointestinal disorders, 
such as inflammatory bowel disease, mucosal malabsorp
-
tive disorders, irritable bowel syndrome, and pancreatic 
insufficiency. Furthermore, lactase deficiency frequently 
develops secondary to other gastrointestinal disorders (as 
listed above). Concomitant lactase deficiency should always 
be considered in these gastrointestinal disorders.
 
»
Treatment
The goal of treatment in patients with isolated lactase defi
-
ciency is achieving patient comfort. Patients usually find 
their “threshold” of intake at which symptoms will occur. 
Foods that are high in lactose include milk (12 g/cup), ice 
cream (9 g/cup), and cottage cheese (8 g/cup). Aged 
cheeses have a lower lactose content (0.5 g/oz). Unpasteur
-
ized yogurt contains bacteria that produce lactase and is 
generally well tolerated.
By spreading dairy product intake throughout the day 
in quantities of less than 12 g of lactose (one cup of milk), 
most patients can take dairy products without symptoms 
and do not require lactase supplements. Most food markets 
provide milk that has been pretreated with lactase, render
-
ing it 70–100% lactose free. Lactase enzyme replacement is 
commercially available as nonprescription formulations 
(Lactaid, Lactrase, Dairy Ease). Caplets or drops of lactase 
may be taken with milk products, improving lactose 
absorption and eliminating symptoms. The number of 
caplets ingested depends on the degree of lactose intoler
-
ance. Patients who choose to restrict or eliminate milk 
products may have increased risk of osteoporosis. Calcium 
supplementation (calcium carbonate 500 mg orally two to 
three times daily) is recommended for susceptible patients.
Bayless TM et al. Lactase non-persistence and lactose intoler
-
ance. Curr Gastroenterol Rep. 2017 May;19(5):23. [PMID: 
28421381]
Deng Y et al. Lactose intolerance in adults: biological mecha
-
nism and dietary management. Nutrients. 2015 Sep;
 
7(9):8020–35. [PMID: 26393648]
INTESTINAL MOTILITY DISORDERS
1. Acute Paralytic Ileus
 
»
Precipitating factors: surgery, peritonitis, electro
-
lyte abnormalities, medications, severe medical 
illness.
 
»

»
-
illness.
 
»
Nausea, vomiting, obstipation, distention.
 
»
Minimal abdominal tenderness; decreased bowel 
sounds.
 
»
Plain abdominal radiography with gas and fluid 
distention in small and large bowel.
 
»
Ileus is a condition in which there is neurogenic failure or 
loss of peristalsis in the intestine in the absence of any 
mechanical obstruction. It is commonly seen in hospital
-
ized patients as a result of (1) intra-abdominal processes 
such as recent gastrointestinal or abdominal surgery or 
peritoneal irritation (peritonitis, pancreatitis, ruptured 
viscus, hemorrhage); (2) severe medical illness such as 
pneumonia, respiratory failure requiring intubation, sepsis 
or severe infections, uremia, diabetic ketoacidosis, and 
electrolyte abnormalities (hypokalemia, hypercalcemia, 
hypomagnesemia, hypophosphatemia); and (3) medica
-
tions that affect intestinal motility (opioids, anticholiner
-
gics, phenothiazines). Following surgery, small intestinal 
motility usually normalizes first (often within hours), fol
-
lowed by the stomach (24–48 hours), and the colon (48–72 
hours). Postoperative ileus is reduced by the use of patient-
controlled or epidural analgesia and avoidance of intrave
-
nous opioids as well as early ambulation, gum chewing, 
and initiation of a clear liquid diet.
 
»
Patients who are conscious report mild diffuse, continuous 
abdominal discomfort with nausea and vomiting. 
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Generalized abdominal distention is present with minimal 
abdominal tenderness but no signs of peritoneal irritation 
(unless due to the primary disease). Bowel sounds are 
diminished to absent.
The laboratory abnormalities are attributable to the under
-
lying condition. Serum electrolytes (sodium, potassium), 
magnesium, phosphorus, and calcium, should be obtained 
to exclude abnormalities as contributing factors.
C. Imaging
Plain film radiography of the abdomen demonstrates dis
-
tended gas-filled loops of the small and large intestine. 
Air-fluid levels may be seen. Under some circumstances, it 
may be difficult to distinguish ileus from partial small 
bowel obstruction. A CT scan may be useful in such 
instances to exclude mechanical obstruction, especially in 
postoperative patients.
 
»
Ileus must be distinguished from mechanical obstruction 
of the small bowel or proximal colon. Pain from small 
bowel mechanical obstruction is usually intermittent, 
cramping, and associated initially with profuse vomiting. 
Acute gastroenteritis, acute appendicitis, and acute pancre
-
atitis may all present with ileus.
 
»
Treatment
The primary medical or surgical illness that has precipi
-
tated adynamic ileus should be treated. Most cases of ileus 
respond to restriction of oral intake with gradual liberaliza
-
tion of diet as bowel function returns. Severe or prolonged 
ileus requires nasogastric suction and parenteral adminis
-
tration of fluids and electrolytes. Alvimopan is a peripher
-
ally acting mu-opioid receptor antagonist with limited 
absorption or systemic activity that reverses opioid-
induced inhibition of intestinal motility. In five random
-
ized controlled trials in postoperative patients, it reduced 
the time to first flatus, bowel movement, solid meal, 
and hospital discharge compared with placebo. Alvimo
-
pan, 12 mg orally twice daily (available only through a 
restricted program for short-term use—no more than 
15 doses), may be considered in patients undergoing par
-
tial large or small bowel resection when postoperative 
opioid therapy is anticipated.
Doorly MG et al. Pathogenesis and clinical and economic conse
-
quences of paralytic ileus. Surg Clin North Am. 2012 Apr;
 
92(2):259–72. [PMID: 22414412]
Güngördük K et al. Effects of coffee consumption on gut recovery 
after surgery of gynecological cancer patients: a randomized 
controlled trial. Am J Obstet Gynecol. 2017 Feb;216(2):145.
e1–145. [PMID: 27780709]
Sultan S et al. Alvimopan for recovery of bowel function after 
radical cystectomy. Cochrane Database Syst Rev. 2017 May 2;
 
5:CD012111. [PMID: 28462518]
Taylor RW . Gut motility issues in critical illness. Crit Care Clin. 
2016 Apr;32(2):191–201. [PMID: 27016161]
2. Acute Colonic Pseudo-obstruction 
 
(Ogilvie Syndrome)
 
»
Severe abdominal distention.
 
»
Arises in postoperative state or with severe medi
-
cal illness.
 
»
May be precipitated by electrolyte imbalances, 
 
»
Absent to mild abdominal pain; minimal 
tenderness.
 
»
Massive dilation of cecum or right colon.
 
»
Spontaneous massive dilation of the cecum and proximal 
colon may occur in a number of different settings in hospi
-
talized patients. Progressive cecal dilation may lead to 
spontaneous perforation with dire consequences. The risk 
of perforation correlates poorly with absolute cecal size and 
duration of colonic distention. Early detection and man
-
agement are important to reduce morbidity and mortality. 
Colonic pseudo-obstruction is most commonly detected in 
postsurgical patients (mean 3–5 days), after trauma, and in 
medical patients with respiratory failure, metabolic imbal
-
ance, malignancy, myocardial infarction, heart failure, 
pancreatitis, or a recent neurologic event (stroke, subarach
-
noid hemorrhage, trauma). Liberal use of opioids or anticho
-

-
-
-
linergic agents may precipitate colonic pseudo-obstruction 
in susceptible patients. It may also occur as a manifestation 
of colonic ischemia.
 
»
Many patients are on ventilatory support or are unable to 
report symptoms due to altered mental status. Abdominal 
distention is frequently noted by the clinician as the first 
sign, often leading to a plain film radiograph that demon
-
strates colonic dilation. Some patients are asymptomatic, 
although most report constant but mild abdominal pain. 
Nausea and vomiting may be present. Bowel movements 
may be absent, but up to 40% of patients continue to pass 
flatus or stool. Abdominal tenderness with some degree of 
guarding or rebound tenderness may be detected; however, 
signs of peritonitis are absent unless perforation has 
occurred. Bowel sounds may be normal or decreased.
Laboratory findings reflect the underlying medical or sur
-
gical problems. Serum sodium, potassium, magnesium, 
phosphorus, and calcium should be obtained to exclude 
abnormalities as contributing factors. Significant fever or 
leukocytosis raises concern for colonic ischemia or 
perforation.
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C. Imaging
Radiographs demonstrate colonic dilation, usually con
-
fined to the cecum and proximal colon. The upper limit of 
normal for cecal size is 9 cm. A cecal diameter greater than 
10–12 cm is associated with an increased risk of colonic 
perforation. Varying amounts of small intestinal dilation 
and air-fluid levels due to adynamic ileus may be seen. 
Because the dilated appearance of the colon may raise con
-
cern that there is a distal colonic mechanical obstruction 
due to malignancy, volvulus, or fecal impaction, a CT scan 
or water-soluble (diatrizoate meglumine) enema may 
sometimes be performed.
 
»
Colonic pseudo-obstruction should be distinguished from 
distal colonic mechanical obstruction (as above) and toxic 
megacolon, which is acute dilation of the colon due to 
inflammation (inflammatory bowel disease) or infection 
(
–associated colitis, CMV). Patients with toxic 
megacolon manifest fever; dehydration; significant abdom
-
inal pain; leukocytosis; and diarrhea, which is often bloody.
 
»
Treatment
Conservative treatment is the appropriate first step for 
patients with no or minimal abdominal tenderness, no 
fever, no leukocytosis, and a cecal diameter smaller than 
12 cm. The underlying illness is treated appropriately. A 
nasogastric tube and a rectal tube should be placed. 
Patients should be ambulated or periodically rolled from 
side to side and to the knee-chest position in an effort to 
promote expulsion of colonic gas. All drugs that reduce 
intestinal motility, such as opioids, anticholinergics, and 
calcium channel blockers, should be discontinued if pos
-
sible. Enemas may be administered judiciously if large 
amounts of stool are evident on radiography. Oral laxatives 
are not helpful and may cause perforation, pain, or electro
-
lyte abnormalities.
Conservative treatment is successful in over 80% of 
cases within 1–2 days. Patients must be watched for signs 
of worsening distention or abdominal tenderness. Cecal 
size should be assessed by abdominal radiographs every 
12 hours. Intervention should be considered in patients 
with any of the following: (1) no improvement or clinical 
deterioration after 24–48 hours of conservative therapy; (2) 
cecal dilation greater than 10 cm for a prolonged period 
(more than 3–4 days); (3) patients with cecal dilation 
greater than 12 cm. Neostigmine injection should be given 
unless contraindicated. A single dose (2 mg intravenously) 
results in rapid (within 30 minutes) colonic decompression 
in 75–90% of patients. Cardiac monitoring during neostig
-
mine infusion is indicated for possible bradycardia that 
may require atropine administration. Colonoscopic 
decompression is indicated in patients who fail to respond 
to neostigmine. Colonic decompression with aspiration of 
air or placement of a decompression tube is successful in 
70% of patients. However, the procedure is technically dif
-
ficult in an unprepared bowel and has been associated with 
perforations in the distended colon. Dilation recurs in up 
to 50% of patients. In patients in whom colonoscopy is 
unsuccessful, a tube cecostomy can be created through a 
small laparotomy or with percutaneous radiologically 
guided placement.
 
»
Prognosis
In most cases, the prognosis is related to the underlying 
illness. The risk of perforation or ischemia is increased 
with cecal diameter more than 12 cm and when distention 
has been present for more than 6 days. With aggressive 
therapy, the development of perforation is unusual.
Ross SW et al. Acute colonic pseudo-obstruction: defining the 
epidemiology, treatment, and adverse outcomes of Ogilvie’s 
syndrome. Am Surg. 2016 Feb;82(2):102–11. [PMID: 
26874130]
Wells CI et al. Acute colonic pseudo-obstruction: a systematic 
review of aetiology and mechanisms. World J Gastroenterol. 
2017 Aug 14;23(30):5634–44. [PMID: 28852322]
3. Chronic Intestinal Pseudo-obstruction & 
Gastroparesis

Gastroparesis and chronic intestinal pseudo-obstruction 
are chronic conditions characterized by intermittent, wax
-
ing and waning symptoms and signs of gastric or intestinal 
obstruction in the absence of any mechanical lesions to 
account for the findings. They are caused by a heteroge
-
neous group of endocrine disorders (diabetes mellitus, 
hypothyroidism, cortisol deficiency), postsurgical condi
-
tions (vagotomy, partial gastric resection, fundoplication, 
gastric bypass, Whipple procedure), neurologic conditions 
(Parkinson disease, muscular and myotonic dystrophy, 
autonomic dysfunction, multiple sclerosis, postpolio syn
-
drome, porphyria), rheumatologic syndromes (progressive 
systemic sclerosis), infections (postviral, Chagas disease), 
amyloidosis, paraneoplastic syndromes, medications, and 
eating disorders (anorexia); a cause may not always be 
identified.
 
»
Gastric involvement leads to chronic or intermittent symp
-
toms of gastroparesis with postprandial fullness (early 
satiety), nausea, and vomiting (1–3 hours after meals). 
Patients with predominantly small bowel involvement may 
have abdominal distention, vomiting, diarrhea, and vary
-
ing degrees of malnutrition. Abdominal pain is not com
-
mon and should prompt investigation for structural causes 
of obstruction. Bacterial overgrowth in the stagnant intes
-
tine may result in malabsorption. Colonic involvement 
may result in constipation or alternating diarrhea and 
B. Imaging
Plain film radiography may demonstrate dilation of the 
esophagus, stomach, small intestine, or colon resembling 
ileus or mechanical obstruction. Mechanical obstruction 
of the stomach, small intestine, or colon is much more 
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common than gastroparesis or intestinal pseudo-obstruc
-
tion and must be excluded with endoscopy or CT or bar
-
ium enterography, especially in patients with prior surgery, 
recent onset of symptoms, or abdominal pain. In cases of 
unclear origin, studies based on the clinical picture are 
obtained to exclude underlying systemic disease. Gastric 
scintigraphy with a low-fat solid meal is the optimal 
means for assessing gastric emptying. Gastric retention of 
60% after 2 hours or more than 10% after 4 hours is abnor
-
mal. Recently, the FDA approved both a wireless motility 
capsule and a nonradioactive, 13-C labeled blue-green 
algae (
Spirulina platensis
) to assess gastric emptying time. 
Small bowel manometry is useful for distinguishing vis
-
ceral from myopathic disorders and for excluding cases of 
mechanical obstruction that are otherwise difficult to 
diagnose by endoscopy or radiographic studies.
 
»
Treatment
There is no specific therapy for gastroparesis or pseudo-
obstruction. Acute exacerbations are treated with nasogas
-
tric suction and intravenous fluids. Long-term treatment is 
directed at maintaining nutrition. Patients should eat small, 
frequent meals that are low in fiber, milk, gas-forming 
foods, and fat. Foods that are well tolerated include tea, 
ginger ale, soup, white rice, potatoes and sweet potatoes, 
fish, gluten-free foods, and applesauce. Some patients may 
require liquid enteral supplements. Agents that reduce gas
-
trointestinal motility (opioids, anticholinergics) should be 
avoided. In diabetic patients, glucose levels should be main
-
tained below 200 mg/dL, as hyperglycemia may slow gastric 
emptying even in the absence of diabetic neuropathy, and 
amylin and GLP-1 analogs (exenatide or pramlintide) 
should be discontinued. Metoclopramide (5–20 mg orally 
or 5–10 mg intravenously or subcutaneously four times 
daily) and erythromycin (50–125 mg orally three times 
daily) before meals are each of benefit in treatment of gas
-
troparesis but not small bowel dysmotility. Since the use of 
metoclopramide for more than 3 months is associated with 
a less than 1% risk of tardive dyskinesia, patients are advised 
to discontinue the medication if neuromuscular side effects, 
particularly involuntary movements, develop. Older 
patients are at greatest risk. Gastric electrical stimulation 
with internally implanted neurostimulators has shown 
reduction in nausea and vomiting in small studies and one 
controlled trial in some patients with severe gastroparesis 
(especially those with diabetes mellitus); however, the 
mechanism of action is uncertain as improvement is not 
correlated with changes in gastric emptying. Many patients 
with gastroparesis have pylorospasm and antral hypomotility. 
Uncontrolled studies report symptom improvement with 
modalities that reduce intrapyloric pressure, including bot
-
ulinum toxin injection, laparoscopic myotomy, and endo
-
scopic myotomy. Bacterial overgrowth should be treated 
with intermittent antibiotics. Patients with predominant 
small bowel distention may require a venting gastrostomy 
to relieve distress. Some patients may require placement of 
a jejunostomy for long-term enteral nutrition. Patients 
unable to maintain adequate enteral nutrition require TPN 
or small bowel transplantation. Difficult cases should be 
referred to centers with expertise in this area.
Bharucha AE et al. Relationship between glycemic control and 
gastric emptying in poorly controlled type 2 diabetes. Clin 
Gastroenterol Hepatol. 2015 Mar;13(3):466–76. [PMID: 
25041866]
Camilleri M. Novel diet, drugs, and gastric interventions for 
gastroparesis. Clin Gastroenterol Hepatol. 2016 Aug;
 
14(6):1072–80. [PMID: 26762845]
Camilleri M et al. POEMs for gastroparesis. Gastrointest Endosc. 
2017 Jan;85(1):129–31. [PMID: 27986106]
Lembo A et al. Relamorelin reduces vomiting frequency and

Lembo A et al. Relamorelin reduces vomiting frequency and 
severity and accelerates gastric emptying in adults with dia
-
betic gastroparesis. Gastroenterology. 2016 Jul;151(1):87–96. 
[PMID: 27055601]
APPENDICITIS
 
»
Early:
 periumbilical pain; 
later:
 right lower quad
-
rant pain and tenderness.
 
»
Anorexia, nausea and vomiting, obstipation.
 
»
Tenderness or localized rigidity at McBurney point.
 
»
Low-grade fever and leukocytosis.
 
»
Appendicitis is the most common abdominal surgical 
emergency, affecting approximately 10% of the population. 
It occurs most commonly between the ages of 10 and 
30 years. It is initiated by obstruction of the appendix by a 
fecalith, inflammation, foreign body, or neoplasm. 
Obstruction leads to increased intraluminal pressure, 
venous congestion, infection, and thrombosis of intramu
-
ral vessels. If untreated, gangrene and perforation develop 
within 36 hours.
 
»
Appendicitis usually begins with vague, often colicky peri
-
umbilical or epigastric pain. Within 12 hours the pain 
shifts to the right lower quadrant, manifested as a steady 
ache that is worsened by walking or coughing. Almost all 
patients have nausea with one or two episodes of vomiting. 
Protracted vomiting or vomiting that begins before the 
onset of pain suggests another diagnosis. A sense of consti
-
pation is typical, and some patients administer cathartics in 
an effort to relieve their symptoms—though some report 
diarrhea. Low-grade fever (below 38°C) is typical; high 
fever or rigors suggest another diagnosis or appendiceal 
On physical examination, localized tenderness with 
guarding in the right lower quadrant can be elicited with 
gentle palpation with one finger. When asked to cough, 
patients may be able to precisely localize the painful area, a 
sign of peritoneal irritation. Light percussion may also 
elicit pain. Although rebound tenderness is also present, it 
is unnecessary to elicit this finding if the above signs are 
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present. The psoas sign (pain on passive extension of the 
right hip) and the obturator sign (pain with passive flexion 
and internal rotation of the right hip) are indicative of 
adjacent inflammation and strongly suggestive of 
B. Atypical Presentations of Appendicitis
Owing to the variable location of the appendix, there are a 
number of “atypical” presentations. Because the retrocecal 
appendix does not touch the anterior abdominal wall, the 
pain remains less intense and poorly localized; abdominal 
tenderness is minimal and may be elicited in the right 
flank. The psoas sign may be positive. With pelvic appen
-
dicitis, there is pain in the lower abdomen, often on the left, 
with an urge to urinate or defecate. Abdominal tenderness 
is absent, but tenderness is evident on pelvic or rectal 
examination; the obturator sign may be present. In elderly 
patients, the diagnosis of appendicitis is often delayed 
because patients present with minimal, vague symptoms 
and mild abdominal tenderness. Appendicitis in preg
-
nancy may present with pain in the right lower quadrant, 
periumbilical area, or right subcostal area owing to dis
-
placement of the appendix by the uterus.
Moderate leukocytosis (10,000–20,000/mcL) with neutro
-
philia is common. Microscopic hematuria and pyuria are 
present in 25% of patients.
D. Imaging
Both abdominal ultrasound and CT scanning are useful in 
diagnosing appendicitis as well as excluding other diseases 
presenting with similar symptoms, including adnexal dis
-
ease in younger women. However, CT scanning appears to 
be more accurate (sensitivity 94%, specificity 95%, positive 
likelihood ratio 13.3, negative likelihood ratio 0.09). 
Abdominal CT scanning is also useful in cases of suspected 
appendiceal perforation to diagnose a periappendiceal 
abscess. In patients in whom there is a clinically high sus
-
picion of appendicitis, some surgeons feel that preoperative 
diagnostic imaging is unnecessary. However, studies sug
-
gest that even in this group, imaging studies suggest an 
alternative diagnosis in up to 15%.
 
»
Given its frequency and myriad presentations, appendicitis 
should be considered in the differential diagnosis of all 
patients with abdominal pain. It is difficult to reliably diag
-
nose the disease in some cases. A several-hour period of 
close observation with reassessment usually clarifies the 
diagnosis. Absence of the classic migration of pain (from 
the epigastrium to the right lower abdomen), right lower 
quadrant pain, fever, or guarding makes appendicitis less 
likely. Ten to 20 percent of patients with suspected appen
-
dicitis have either a negative examination at laparotomy or 
an alternative surgical diagnosis. The widespread use of 
ultrasonography and CT has reduced the number of 
incorrect diagnoses to less than 2%. Still, in some cases 
diagnostic laparotomy or laparoscopy is required. The 
most common causes of diagnostic confusion are gastroen
-
teritis and gynecologic disorders. Viral gastroenteritis 
presents with nausea, vomiting, low-grade fever, and diar
-
rhea and can be difficult to distinguish from appendicitis. 
The onset of vomiting before pain makes appendicitis less 
likely. As a rule, the pain of gastroenteritis is more general
-
ized and the tenderness less well localized. Acute salpingi
-
tis or tubo-ovarian abscess should be considered in young, 
sexually active women with fever and bilateral abdominal 
or pelvic tenderness. A twisted ovarian cyst may also cause 
sudden severe pain. The sudden onset of lower abdominal 
pain in the middle of the menstrual cycle suggests mittel
-
schmerz. Sudden severe abdominal pain with diffuse pelvic 
tenderness and shock suggests a ruptured ectopic preg
-
nancy. A positive pregnancy test and pelvic ultrasonogra
-
phy are diagnostic. Retrocecal or retroileal appendicitis

-
-
phy are diagnostic. Retrocecal or retroileal appendicitis 
(often associated with pyuria or hematuria) may be con
-
fused with ureteral colic or pyelonephritis. Other condi
-
tions that may resemble appendicitis are diverticulitis, 
Meckel diverticulitis, carcinoid of the appendix, perforated 
colonic cancer, Crohn ileitis, perforated peptic ulcer, chole
-
cystitis, and mesenteric adenitis. It is virtually impossible 
to distinguish appendicitis from Meckel diverticulitis, but 
both require surgical treatment.
 
»
Perforation occurs in 20% of patients and should be sus
-
pected in patients with pain persisting for over 36 hours, 
high fever, diffuse abdominal tenderness or peritoneal 
findings, a palpable abdominal mass, or marked leukocyto
-
sis. Localized perforation results in a contained abscess, 
usually in the pelvis. A free perforation leads to suppura
-
tive peritonitis with toxicity. Septic thrombophlebitis (pyle
-
phlebitis) of the portal venous system is rare and suggested 
by high fever, chills, bacteremia, and jaundice.
 
»
Treatment
The treatment of early, uncomplicated appendicitis is surgi
-
cal appendectomy in most patients. When possible, a lapa
-
roscopic approach is preferred to open laparotomy. Prior to 
surgery, patients should be given broad-spectrum antibiot
-
ics with gram-negative and anaerobic coverage to reduce 
the incidence of postoperative infections. Recommended 
preoperative intravenous regimens include cefoxitin or 
cefotetan 1–2 g every 8 hours; ampicillin-sulfabactam 3 g 
every 6 hours; or ertapenem 1 g as a single dose. Up to 
80–90% of patients with uncomplicated appendicitis treated 
with antibiotics alone for 7 days have resolution of symp
-
toms and signs. Therefore, conservative management with 
antibiotics alone may be considered in patients with a non
-
perforated appendicitis with surgical contraindications or 
with a strong preference to avoid surgery; however, appen
-
dectomy generally still is recommended in most patients to 
prevent recurrent appendicitis (20–35% within 1 year).
Emergency appendectomy is required in patients with 
perforated appendicitis with generalized peritonitis. The 
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CMDT 2019
optimal treatment of stable patients with perforated appen
-
dicitis and a contained abscess is controversial. Surgery in 
this setting can be difficult. Many recommend percutane
-
ous CT-guided drainage of the abscess with intravenous 
fluids and antibiotics to allow the inflammation to subside. 
An interval appendectomy may be performed after 6 weeks 
to prevent recurrent appendicitis.
 
»
Prognosis
The mortality rate from uncomplicated appendicitis is 
extremely low. Even with perforated appendicitis, the mor
-
tality rate in most groups is only 0.2%, though it approaches 
15% in older adults.
Darwazeh G et al. A systematic review of perforated appendicitis 
and phlegmon: interval appendectomy or wait-and-see? Am 
Surg. 2016 Jan;82(1):11–5. [PMID: 26802841]
Flum DR. Clinical practice. Acute appendicitis—appendectomy 
or the “antibiotics first” strategy. N Engl J Med. 2015 May 14;
 
372(20):1937–43. Erratum in: N Engl J Med. 2015 Jun 4;
 
372(23):2274. [PMID: 25970051]
Salminen P et al. Antibiotic therapy vs appendectomy for treat
-
ment of uncomplicated acute appendicitis: the APPAC ran
-
domized clinical trial. JAMA. 2015 Jun 16;313(23):2340–8. 
[PMID: 26080338]
INTESTINAL TUBERCULOSIS
Intestinal tuberculosis is common in underdeveloped 
countries but rare in the United States except in immigrant 
groups or in patients with untreated AIDS. It is caused by 
both 
 and 
M bovis.
 Active pul
-
monary disease is present in less than 50% of patients. The 
most frequent site of involvement is the ileocecal region; 
however, any region of the gastrointestinal tract may be 
involved. Patients may be without symptoms or complain 
of chronic abdominal pain, obstructive symptoms, weight 
loss, and diarrhea. An abdominal mass may be palpable. 
Complications include intestinal obstruction, hemorrhage, 
and fistula formation. The purified protein derivative 
(PPD) skin test may be negative, especially in patients with 
weight loss or AIDS. Abdominal CT may show thickening 
of the cecum and ileocecal valve and massive lymphade
-
nopathy. Colonoscopy may demonstrate an ulcerated mass, 
multiple ulcers with steep edges and adjacent small sessile 
polyps, small ulcers or erosions, or small diverticula, most 
commonly in the ileocecal region. The differential diagno
-
sis includes Crohn disease, carcinoma, lymphoma, and 
intestinal amebiasis. The diagnosis is established by either 
endoscopic or surgical biopsy revealing acid-fast bacilli, 
caseating granuloma, or positive cultures from the organism. 
Detection of tubercle bacilli in biopsy specimens by PCR is 
now the most sensitive means of diagnosis.
Treatment with standard antituberculous regimens 
(Tables 9–13 and 9–14) is effective.
Gan H et al. An analysis of the clinical, endoscopic, and patho
-
logic features of intestinal tuberculosis. J Clin Gastroenterol. 
2016 Jul;50(6):470–5. [PMID: 26974755]
Limsrivilai J et al. Meta-analytic Bayesian model for differentiat
-
ing intestinal tuberculosis from Crohn’s disease. Am J Gastro
-
enterol. 2017 Mar;112(3):415–27. [PMID: 28045023]
Y ajnik V et al. Case Records of the Massachusetts General Hos
-
pital. Case 7-2016. An 80-year-old man with weight loss, 
abdominal pain, diarrhea, and an ileocecal mass. N Engl J 
Med. 2016 Mar 10;374(10):970–9. [PMID: 26962732]
PROTEIN-LOSING ENTEROPATHY
Protein-losing enteropathy comprises a number of condi
-
tions that result in excessive loss of serum proteins into the 
gastrointestinal tract.
Hypoalbuminemia is the sine qua non of protein-losing 
enteropathy. However, a number of other serum proteins 
such as alpha-1-antitrypsin also are lost from the gut epi
-
thelium. In protein-losing enteropathy caused by lym
-
phatic obstruction, loss of lymphatic fluid commonly 
results in lymphocytopenia (less than 1000/mcL), hypo
-
globulinemia, and hypocholesterolemia.
In most cases, protein-losing enteropathy is recognized

-
In most cases, protein-losing enteropathy is recognized 
as a sequela of a known gastrointestinal disorder. In patients 
in whom the cause is unclear, evaluation is indicated and is 
guided by the clinical suspicion. Protein-losing enteropathy 
must be distinguished from other causes of hypoalbumin
-
emia, which include liver disease and nephrotic syndrome, 
and from heart failure. Protein-losing enteropathy is con
-
firmed by determining the gut alpha-1-antitrypsin clearance 
(24-hour volume of feces × stool concentration of alpha-
1-antitrypsin ÷ serum alpha-1-antitrypsin concentration). 
A clearance of more than 27 mL/24 h is abnormal.
Laboratory evaluation of protein-losing enteropathy 
includes serum protein electrophoresis, lymphocyte count, 
and serum cholesterol to look for evidence of lymphatic 
obstruction. Serum ANA and C3 levels are useful to screen 
for autoimmune disorders. Stool samples should be exam
-
ined for ova and parasites. Evidence of malabsorption is 
evaluated by means of a stool qualitative fecal fat determi
-
nation. Intestinal imaging is performed with small bowel 
enteroscopy biopsy, CT enterography, or wireless capsule 
endoscopy of the small intestine. Colonic diseases are 
excluded with colonoscopy. A CT scan of the abdomen is 
performed to look for evidence of neoplasms or lymphatic 
obstruction. Rarely, lymphangiography is helpful. In some 
situations, laparotomy with full-thickness intestinal biopsy 
is required to establish a diagnosis.
Treatment is directed at the underlying cause.
Kochi S et al. Gastrointestinal: endoscopic findings of collagenous 
gastroenterocolitis with protein-losing enteropathy. J Gastro
-
enterol Hepatol. 2015 Jun;30(6):967. [PMID: 25916480]
Levitt DG et al. Protein losing enteropathy: comprehensive 
review of the mechanistic association with clinical and sub
-
clinical disease states. Clin Exp Gastroenterol. 2017 Jul 17;
 
10:147–68. [PMID: 28761367]
 
º
h
E COLON & RECTUM
(See Chapter 39 for Colorectal Cancer.)
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IRRITABLE BOWEL SYNDROME
 
»
Chronic functional disorder characterized by 
abdominal pain with alterations in bowel habits.
 
»
Symptoms usually begin in late teens to early 
twenties.
 
»
Limited evaluation to exclude organic causes of 
symptoms.
 
»
Irritable bowel syndrome can be defined as an idiopathic 
clinical entity characterized by chronic (more than 6 months) 
abdominal pain that occurs in association with altered bowel 
habits. These symptoms may be continuous or intermittent. 
The 2016 Rome IV consensus definition of irritable bowel 
syndrome is abdominal pain that has two of the following 
three features: (1) related to defecation, (2) associated with a 
change in frequency of stool, or (3) associated with a change 
in form (appearance) of stool. Symptoms of abdominal pain 
should be present on average at least 1 day per week. Other 
symptoms supporting the diagnosis include abnormal stool 
frequency; abnormal stool form (lumpy or hard; loose or 
watery); abnormal stool passage (straining, urgency, or feel
-
ing of incomplete evacuation); and abdominal bloating or a 
feeling of abdominal distention.
Patients may have other somatic or psychological com
-
plaints such as dyspepsia, heartburn, chest pain, head
-
aches, fatigue, myalgias, urologic dysfunction, gynecologic 
symptoms, anxiety, or depression.
The disorder is a common problem presenting to both 
gastroenterologists and primary care physicians. Up to 10% 
of the adult population have symptoms compatible with 
the diagnosis, but most never seek medical attention. 
Approximately two-thirds of patients with irritable bowel 
syndrome are women.
 
»
A number of pathophysiologic mechanisms have been 
identified and may have varying importance in different 
individuals.
A. Abnormal Motility
A variety of abnormal myoelectrical and motor abnormali
-
ties have been identified in the colon and small intestine. In 
some cases, these are temporally correlated with episodes 
of abdominal pain or emotional stress. Differences between 
patients with constipation-predominant (slow intestinal 
transit) and diarrhea-predominant (rapid intestinal transit) 
syndromes are reported.
B. Visceral Hypersensitivity
Patients often have a lower visceral pain threshold, report
-
ing abdominal pain at lower volumes of colonic gas 
insufflation or colonic balloon inflation than controls. 
Many patients complain of bloating and distention, which 
may be due to a number of different factors including 
increased visceral sensitivity, increased gas production, 
impaired gas transit through the intestine, or impaired 
rectal expulsion. Many patients report rectal urgency 
despite small rectal volumes of stool.
C. Intestinal Inflammation
The intestinal epithelium and immune system interact with 
the intra-intestinal microbiome, which is made up of an 
estimated 30,000 different microbial species. It is postu
-
lated that dietary factors, medications (antibiotics), or 
infections may increase intestinal permeability, leading to 
intestinal inflammation that may contribute to alterations 
in intestinal motility or visceral hypersensitivity. Increased 
inflammatory cells have been found in the mucosa, submu
-
cosa, and muscularis of some patients with irritable bowel 
syndrome, but their importance is unclear.
Symptoms compatible with irritable bowel syndrome 
develop within 1 year in over 10% of patients after an epi
-
sode of bacterial gastroenteritis compared with less than 
2% of controls. Women and patients with antibiotic expo
-
sure or psychological stress at the onset of gastroenteritis 
appear to be at increased risk for developing “postinfectious” 
irritable bowel syndrome.
Alterations in the intestinal microbiome composition 
may cause increased postprandial gas as well as bloating 
and distention due to degradation of undigested, ferment
-
able carbohydrates in the small intestine or colon. An

-
able carbohydrates in the small intestine or colon. An 
increase in breath hydrogen or methane excretion after 
lactulose ingestion has been reported in 65% of patients 
with irritable bowel syndrome, believed by some investiga
-
tors to indicate small intestinal bacterial overgrowth. How
-
ever, many investigators dispute these findings because 
overgrowth was confirmed in only 4% of patients using 
jejunal aspiration and bacterial culture.
D. Psychosocial Abnormalities
More than 50% of patients with irritable bowel who seek 
medical attention have underlying depression, anxiety, or 
somatization. Psychological abnormalities may influence 
how the patient perceives or reacts to illness and minor 
visceral sensations. Chronic stress may alter intestinal 
motility or modulate pathways that affect central and spi
-
nal processing of visceral afferent sensation.
 
»
Irritable bowel is a chronic condition. Symptoms usually 
begin in the late teens to twenties. Symptoms should be 
present for at least 6 months before the diagnosis can be 
considered. The diagnosis is established in the presence of 
compatible symptoms and the judicious use of tests to 
exclude organic disease.
Abdominal pain usually is intermittent, crampy, and in 
the lower abdominal region. As previously stated, pain 
typically is associated with a change in stool frequency or 
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form and may be improved or worsened by defecation. It 
does not usually occur at night or interfere with sleep. 
Patients with irritable bowel syndrome may be classified 
into one of four categories based on the predominant stool 
habits and stool form: irritable bowel syndrome with diar
-
rhea, irritable bowel syndrome with constipation, irritable 
bowel syndrome with mixed constipation and diarrhea, or 
irritable bowel syndrome that is not subtyped. It is impor
-
tant to clarify what the patient means by these complaints. 
Patients with irritable bowel and constipation report infre
-
quent bowel movements (less than three per week), hard or 
lumpy stools, or straining. Patients with irritable bowel 
syndrome with diarrhea refer to loose or watery stools, 
frequent stools (more than three per day), urgency, or fecal 
incontinence. Many patients report that they have a firm 
stool in the morning followed by progressively looser 
movements. Complaints of visible distention and bloating 
are common, though these are not always clinically 
evident.
The patient should be asked about “alarm symptoms” 
that suggest a diagnosis other than irritable bowel syn
-
drome and warrant further investigation. The acute onset 
of symptoms raises the likelihood of organic disease, espe
-
cially in patients older than 40–50 years. Nocturnal diar
-
rhea, severe constipation or diarrhea, hematochezia, weight 
loss, and fever are incompatible with a diagnosis of irritable 
bowel syndrome and warrant investigation for underlying 
disease. Patients who have a family history of cancer, 
inflammatory bowel disease, or celiac disease should 
undergo additional evaluation.
A physical examination should be performed to look 
for evidence of organic disease and to allay the patient’s 
anxieties. The physical examination usually is normal. 
Abdominal tenderness, especially in the lower abdomen, is 
common but not pronounced. A digital rectal examination 
should be performed in patients with constipation to 
screen for paradoxical anal squeezing during attempted 
straining that may suggest pelvic floor dyssenergia. A pel
-
vic examination is recommended for postmenopausal 
women with recent onset constipation and lower abdomi
-
nal pain to screen for gynecologic malignancy.
B. Laboratory Findings and Special Examinations
In patients whose symptoms fulfill the diagnostic criteria 
for irritable bowel syndrome and who have no other alarm 
symptoms, evidence-based consensus guidelines do not 
support further diagnostic testing, as the likelihood of seri
-
ous organic diseases does not appear to be increased. 
Although the vague nature of symptoms and patient anxiety 
may prompt clinicians to consider a variety of diagnostic 
studies, overtesting should be avoided. A 2013 study of 
primary care patients aged 30–50 years with suspected irri
-
table bowel found that, patients randomized to a strategy of 
extensive testing prior to diagnosis had higher health care 
costs but similar symptoms and satisfaction at 1 year as 
patients randomized to a strategy of minimal testing but a 
positive clinical diagnosis. The use of routine blood tests 
(complete blood count, chemistry panel, serum albumin, 
thyroid function tests, erythrocyte sedimentation rate) is 
unnecessary in most patients. In selected patients with 
diarrhea, serum C-reactive protein and fecal calprotectin 
level should be considered to screen for inflammatory 
bowel disease and serologic testing for celiac disease should 
be performed. Stool specimen examinations for ova and 
parasites should be obtained in patients with increased like
-
lihood of infection (eg, day care workers, campers, foreign 
travelers). Routine sigmoidoscopy or colonoscopy is not 
recommended in young patients with symptoms of irritable 
bowel syndrome without alarm symptoms, but should be 
considered in patients who do not improve with conserva
-

-
tive management. In all patients aged 50 years or older who 
have not had a previous evaluation, colonoscopy should be 
obtained to exclude malignancy. When colonoscopy is per
-
formed, random mucosal biopsies should be obtained to 
look for evidence of microscopic colitis (which may have 
similar symptoms). Routine testing for bacterial overgrowth 
with hydrogen breath tests are not recommended.
 
»
A number of disorders may present with similar symp
-
toms. Examples include colonic neoplasia, inflammatory 
bowel disease (ulcerative colitis, Crohn disease, micro
-
scopic colitis), hyperthyroidism or hypothyroidism, para
-
sites, malabsorption (especially celiac disease, bacterial 
overgrowth, lactase deficiency), causes of chronic secretory 
diarrhea (carcinoid), and gynecologic disorders (endome
-
triosis, ovarian cancer). Psychiatric disorders such as 
depression, panic disorder, and anxiety must be considered 
as well. Women with refractory symptoms have an 
increased incidence of prior sexual and physical abuse. 
These diagnoses should be excluded in patients with pre
-
sumed irritable bowel syndrome who do not improve 
within 2–4 weeks of empiric treatment or in whom subse
-
quent alarm symptoms develop.
 
»
Treatment
As with other functional disorders, the most important 
interventions the clinician can offer are reassurance, edu
-
cation, and support. This includes identifying and respond
-
ing to the patient’s concerns, careful explanation of the 
pathophysiology and natural history of the disorder, setting 
realistic treatment goals, and involving the patient in the 
treatment process. Because irritable bowel symptoms are 
chronic, the patient’s reasons for seeking consultation at 
this time should be determined. These may include major 
life events or recent psychosocial stressors, dietary or 
medication changes, concerns about serious underlying 
disease, or reduced quality of life and impairment of daily 
activities. In discussing with the patient the importance of 
the mind-gut interaction, it may be helpful to explain that 
alterations in visceral motility and sensitivity may be exac
-
erbated by environmental, social, or psychological factors 
such as foods, medications, hormones, and stress. Symp
-
toms such as pain, bloating, and altered bowel habits may 
lead to anxiety and distress, which in turn may further 
exacerbate bowel disturbances due to disordered commu
-
nication between the gut and the central nervous system. 
Fears that the symptoms will progress, require surgery, or 
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degenerate into serious illness should be allayed. The 
patient should understand that irritable bowel syndrome is 
a chronic disorder characterized by periods of exacerba
-
tion and quiescence. The emphasis should be shifted from 
finding the cause of the symptoms to finding a way to cope 
with them. Moderate exercise is beneficial. Clinicians must 
resist the temptation to chase chronic complaints with new 
or repeated diagnostic studies.
B. Dietary Therapy
Patients commonly report dietary intolerances. Proposed 
mechanisms for dietary intolerance include food allergy, 
hypersensitivity, effects of gut hormones, changes in bacte
-
rial flora, increased bacterial gas production (arising in the 
small or large intestine), and direct chemical irritation. 
Fatty foods, alcohol, caffeine, spicy foods, and grains are 
poorly tolerated by many patients with irritable bowel syn
-
drome. In patients with diarrhea, bloating, and flatulence, 
lactose intolerance should be excluded with a hydrogen 
breath test or a trial of a lactose-free diet. A host of poorly 
absorbed, fermentable, monosaccharides and short-chain 
carbohydrates (“FODMAPS”) may exacerbate bloating, 
flatulence, and diarrhea in some patients. These include six 
food groups: fructose (corn syrups, apples, pears, honey, 
watermelon, raisins), lactose, fructans (garlic, onions, 
leeks, asparagus, artichokes), wheat-based products 
(breads, pasta, cereals, cakes), sorbitol (stone fruits), and 
raffinose (legumes, lentils, brussel sprouts, soybeans, 
cabbage). Dietary restriction of these fermentable carbohy
-
drates for 2–4 weeks may improve symptoms (especially 
abdominal pain and bloating in 50–65% of patients. 
Responders should gradually reintroduce different FOD
-
MAPS to identify food triggers.
A high-fiber diet and fiber supplements appears to be of 
little value in patients with irritable bowel syndrome. Many 
patients report little change in bowel frequency but 
increased gas and distention.
C. Pharmacologic Measures
More than two-thirds of patients with irritable bowel syn
-
drome have mild symptoms that respond readily to educa
-
tion, reassurance, and dietary interventions. Drug therapy 
should be reserved for patients with moderate to severe 
symptoms that do not respond to conservative measures. 
These agents should be viewed as being adjunctive rather 
than curative. Given the wide spectrum of symptoms, no 
single agent is expected to provide relief in all or even most 
patients. Nevertheless, therapy targeted at the specific 
dominant symptom (pain, constipation, or diarrhea) may 
be beneficial.
1. Antispasmodic agents—
Anticholinergic agents are 
used by some practitioners for treatment of acute episodes 
of pain or bloating despite a lack of well-designed trials 
demonstrating efficacy. Available agents include hyoscya
-
mine, 0.125 mg orally (or sublingually as needed) or sus
-
tained-release, 0.037 mg or 0.75 mg orally twice daily; 
dicyclomine, 10–20 mg orally; or methscopolamine 2.5–5 mg 
orally before meals and at bedtime. Anticholinergic side 
effects are common, including urinary retention, constipa
-
tion, tachycardia, and dry mouth. Hence, these agents 
should be used with caution in older patients and in 
patients with constipation. Peppermint oil formulations 
(which relax smooth muscle) may be helpful.
2. Antidiarrheal agents—
Loperamide (2 mg orally three 
or four times daily) is effective for the treatment of patients 
with diarrhea, reducing stool frequency, liquidity, and 
urgency. It may best be used “prophylactically” in situa
-
tions in which diarrhea is anticipated (such as stressful 
situations) or would be inconvenient (social engagements). 
Increased intracolonic bile acids due to alterations in 
enterohepatic circulation may contribute to diarrhea in a 
subset of patients with diarrhea. An empiric trial of bile 
salt-binding agents (cholestyramine 2–4 g with meals; cole
-

-
sevelam, 625 mg, 1–3 tablets twice daily) may be consid
-
ered. Eluxadoline (75–100 mg twice daily) is an opioid 
antagonist that was approved by the FDA in 2016 for 
treatment of irritable bowel with diarrhea. In phase III 
trials, eluxadoline decreased abdominal pain and 
improved stool consistency in approximately 25% of 
patients versus 16–19% with placebo; however, sphincter 
of Oddi dysfunction and pancreatitis developed in a small 
percentage (0.5%) of patients. Given its minimal efficacy, 
adverse side effect profile, and unproven benefit versus 
loperamide, further study is needed before its use can be 
3. Anticonstipation agents—
Treatment with oral osmotic 
laxatives polyethylene glycol 3350 (Miralax, 17–34 g/day) 
may increase stool frequency, improve stool consistency, 
and reduce straining. Lactulose or sorbitol produces 
increased flatus and distention, which are poorly tolerated 
in patients with irritable bowel syndrome and should be 
avoided. Lubiprostone (8 mcg orally twice daily) and lina
-
clotide (290 mcg orally once daily) are newer agents 
approved for treatment of irritable bowel syndrome with 
constipation. Through different mechanisms, both stimu
-
late increased intestinal chloride and fluid secretion, result
-
ing in accelerated colonic transit. In clinical trials, 
lubiprostone led to global symptom improvement in 18% 
of patients compared with 10% of patients who received 
placebo. Trials of linaclotide included similar patient popu
-
lations but measured different primary end points. Higher 
combined response rates (defined as greater than 30% 
reduction in abdominal pain and more than three sponta
-
neous bowel movements per week, including an increase of 
one or more from baseline) were found in 12.5% of lina
-
clotide-treated patients compared with 4% of placebo-
treated patients. Patients with intractable constipation 
should undergo further assessment for slow colonic transit 
and pelvic floor dysfunction (see Constipation, above).
4. Psychotropic agents—
Patients with predominant 
symptoms of pain or bloating may benefit from low doses 
of tricyclic antidepressants, which are believed to have 
effects on motility, visceral sensitivity, and central pain 
perception that are independent of their psychotropic 
effects. Because of their anticholinergic effects, these agents 
may be more useful in patients with diarrhea-predominant 
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CMDT 2019
than constipation-predominant symptoms. Oral nortripty
-
line, desipramine, or imipramine, may be started at a low 
dosage of 10 mg at bedtime and increased gradually to 
50–150 mg as tolerated. Response rates do not correlate 
with dosage, and many patients respond to doses of 50 mg 
or less daily. Side effects are common, and lack of efficacy 
with one agent does not preclude benefit from another. 
Improvement should be evident within 4 weeks. The oral 
serotonin reuptake inhibitors (sertraline, 25–100 mg daily; 
citalopram 10–20 mg; paroxetine 20–50 mg daily; or fluox
-
etine, 10–40 mg daily) may lead to improvement in overall 
sense of well-being, but have little impact on abdominal 
pain or bowel symptoms. Anxiolytics should not be used 
chronically in irritable bowel syndrome because of their 
habituation potential. Patients with major depression or 
anxiety disorders should be identified and treated with 
therapeutic doses of appropriate agents.
5. Serotonin receptor antagonists—
Serotonin is an 
important mediator of gastrointestinal motility and sensa
-
tion. In patients with irritable bowel syndrome with diar
-
rhea, 5-HT
3
 antagonists may reduce diarrhea and improve 
overall symptoms through central and peripheral mecha
-
nisms. Alosetron is a 5-HT
3
 antagonist that is FDA-
approved for the treatment of women with severe irritable 
bowel syndrome with predominant diarrhea. Unfortu
-
nately, due to cases of severe constipation and a small 
(1:1000) but significant risk of ischemic colitis, alosetron is 
restricted to women with severe irritable bowel syndrome 
with diarrhea who have not responded to conventional 
therapies and who have been educated about the relative 
risks and benefits of the agent. It should not be used in 
patients with constipation. A randomized crossover trial of 
another 5-HT
3
 antagonist, ondansetron 4–8 mg three times 
daily, showed overall superior symptom improvement, 
including stool frequency, consistency, and urgency. At this 
time, 5-HT
3
 antagonists may be considered after careful 
discussion of the risks and benefits in carefully selected 
patients with severe diarrhea-predominant irritable bowel 
syndrome.
6. Nonabsorbable antibiotics—
Rifaximin may be consid
-
ered in patients with refractory symptoms, especially bloat
-
ing. A 2012 meta-analysis identified a 9.9% greater 
improvement in bloating compared with placebo, a modest 
gain that is similar to other less expensive therapies. Symp
-
tom improvement may be attributable to suppression of 
bacteria in either the small intestine or colon, resulting in 
decreased bacterial carbohydrate fermentation, diarrhea, 
and bloating.
7. Probiotics—
Meta-analyses of small controlled clinical 
trials report improved symptoms in some patients treated 
with one probiotic, 
Bifidobacterium infantis
, but not with 
another probiotic, 
Lactobacillus salivarius
, or placebo. It is 
hypothesized that alterations in gut flora may reduce 
symptoms through suppression of inflammation or reduc
-
tion of bacterial gas production, resulting in reduced dis
-
tention, flatus, and visceral sensitivity. Such therapy is 
attractive because it is safe, well tolerated, and inexpensive. 
Although promising, further study is needed to define the 
efficacy and optimal formulations of probiotic therapy. The 
probiotics VSL#3 (1 packet twice daily) or 
Bifidobacterium 
infantis
 (1 tablet twice daily) have shown modest benefit in 
small studies.
D. Psychological Therapies
Cognitive-behavioral therapies, relaxation techniques, and 
hypnotherapy appear to be beneficial in some patients. 
Patients with underlying psychological abnormalities may 
benefit from evaluation by a psychiatrist or psychologist. 
Patients with severe disability should be referred to a pain 
treatment center.
 
»
Prognosis
The majority of patients with irritable bowel syndrome learn 
to cope with their symptoms and lead productive lives.

»
Prognosis
Chey WD. Food: the main course to wellness and illness in 
patients with irritable bowel syndrome. Am J Gastroenterol. 
2016 Mar;111(3):366–71. [PMID: 26856749]
Chey WD et al. JAMA patient page. Irritable bowel syndrome. 
JAMA. 2015 Mar 3;313(9):982. [PMID: 25734751]
Eswaran S et al. A diet low in fermentable oligo-, di-, and mono
-
saccharides and polyols improves quality of life and reduces 
activity impairment in patients with irritable bowel syndrome 
and diarrhea. Clin Gastroenterol Hepatol. 2017 Dec;
 
15(12):1890–9. [PMID: 28668539]
Ford AC et al. Irritable bowel syndrome. N Engl J Med. 2017 
Jun 29;376(26):2566–78. [PMID: 28657875]
Klem F et al. Prevalence, risk factors, and outcomes of irritable 
bowel syndrome after infectious enteritis: a systematic review 
and meta-analysis. Gastroenterology. 2017 Apr;152(5):1042–
54. [PMID: 28069350]
Lembo A et al. Repeat treatment with rifaximin is safe and effec
-
tive in patients with diarrhea-predominant irritable bowel 
syndrome. Gastroenterology. 2016 Dec;151(6):1113–21. 
[PMID: 27528177]
Lembo AJ et al. Eluxadoline for irritable bowel syndrome with 
diarrhea. N Engl J Med. 2016 (Jan);374(3):242–53. [PMID: 
26789872]
Mearin F et al. Bowel disorders. Gastroenterology. 2016 Feb 18. 
[Epub ahead of print] [PMID: 27144627]
Staudacher HM et al. A diet low in FODMAPs reduces symp
-
toms in patients with irritable bowel syndrome and a probi
-
otic restores 
Bifidobacterium
 species: a randomized controlled 
trial. Gastroenterology. 2017 Oct;153(4):936–47. [PMID: 
28625832]
ANTIBIOTIC-ASSOCIATED COLITIS
 
»
Most cases of antibiotic-associated diarrhea are 
not attributable to 
 and are usually mild 
 
»
Symptoms of antibiotic-associated colitis vary 
from mild to fulminant; almost all colitis is attribut
-
able to 
.
 
»
Diagnosis in most cases established by stool assay.
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»
Antibiotic-associated diarrhea is a common clinical occur
-
rence. Characteristically, the diarrhea occurs during the 
period of antibiotic exposure, is dose related, and resolves 
spontaneously after discontinuation of the antibiotic. In 
most cases, this diarrhea is mild, self-limited, and does not 
require any specific laboratory evaluation or treatment. 
Stool examination usually reveals no fecal leukocytes, and 
stool cultures reveal no pathogens. Although 
 is 
identified in the stool of 15–25% of cases of antibiotic-
associated diarrhea, it is also identified in 5–10% of 
patients treated with antibiotics who do not have diarrhea. 
Most cases of antibiotic-associated diarrhea are due to 
changes in colonic bacterial fermentation of carbohydrates 
and are not due to 
C difficile.
Antibiotic-associated colitis
 is a significant clinical 
problem almost always caused by 
 infection that 
colonizes the colon and releases two toxins: TcdA and 
TcdB. This anaerobic bacterium is acquired by fecal-oral 
transmission of spores that colonize the colon of 3% of 
healthy adults and 8% of hospitalized patients. 
 
colitis is the major cause of diarrhea in patients hospital
-
ized for more than 3 days, affecting up to 15 of every 1000 
patients and increasing mean hospital stay costs as much 
as $30,000. In the United States, there are an estimated 
453,000 cases per year with 29,000 associated deaths. 
Found throughout hospitals in patient rooms and bath
-
rooms
, C difficile
 is readily transmitted from patient to 
patient by hospital personnel. Fastidious hand washing 
and use of disposable gloves are helpful in minimizing 
transmission and reducing infections in hospitalized 
patients. In hospitalized patients, 
 colitis occurs 
in approximately 20% of those who are colonized at 
admission and 3.5% of those not colonized. In both hospi
-
tal-associated and community infections, most episodes of 
colitis occur in people who have received antibiotics that 
disrupt the normal bowel flora and thus allow the spores 
to germinate and the bacterium to flourish. Although 
almost all antibiotics have been implicated, colitis most 
commonly develops after use of ampicillin, clindamycin, 
third-generation cephalosporins, and fluoroquinolones. A 
2017 meta-analysis of 19 clinical studies suggested that 
prophylactic administration of probiotics to hospitalized 
patients within 48 hours of antibiotic initiation reduces 
the risk of 
 infection by more than 50%. Symp
-
toms usually begin during or shortly after antibiotic ther
-
apy but may be delayed for up to 8 weeks. All patients with 
acute diarrhea should be asked about recent antibiotic 
exposure. Patients who are elderly; debilitated; immuno
-
compromised; receiving multiple antibiotics or prolonged 
(more than 10 days) antibiotic therapy; receiving enteral 
tube feedings, proton pump inhibitors, or chemotherapy; 
or who have inflammatory bowel disease have a higher 
risk of acquiring 
 and developing 
–
associated diarrhea.
A more virulent strain of 
 (NAP1) that con
-
tains an 18-base pair deletion of the TcdC inhibitory gene 
results in higher toxin A and B production. This hyper
-
virulent strain is more prevalent among hospital-associated 
infections (31%) than community-acquired infections 
(19%) and has been associated with outbreaks of severe 
disease with up to 7% mortality.
 
»
Most patients report mild to moderate greenish, foul-
smelling watery diarrhea 5–15 times per day with lower 
abdominal cramps. Physical examination is normal or 
reveals mild left lower quadrant tenderness. The stools may 
have mucus but seldom gross blood. In most patients, coli
-
tis is most severe in the distal colon and rectum. Over half 
of hospitalized patients diagnosed with 
 colitis

-
 colitis 
have a white blood count greater than 15,000/mcL, and 
C 
difficile
 should be considered in all hospitalized patients 
with unexplained leukocytosis.
Severe or fulminant disease occurs in 10–15% of 
patients. It is characterized by fever; hemodynamic insta
-
bility; and abdominal distention, pain, and tenderness. 
Most patients have profuse diarrhea (up to 30 stools/day); 
however, diarrhea may be absent or appear to be improving 
in patients with fulminant disease or ileus. Laboratory data 
suggestive of severe disease include a white blood count 
greater than 30,000/mcL, serum albumin less than 2.5 g/dL 
(due to protein-losing enteropathy), elevated serum lactate, 
or rising serum creatinine.
1. Stool studies—
Pathogenic strains of 
 produce 
two toxins: toxin TcdA is an enterotoxin and toxin TcdB is 
a cytotoxin. Rapid enzyme immunoassays (EIAs) for toxins 
TcdA and TcdB have a 75–90% sensitivity with a single 
stool specimen; sensitivity increases to 90–95% with two 
specimens; however, these have now been supplanted in 
many laboratories by nucleic acid amplification tests (eg, 
PCR assays) that amplify the toxin TcdB gene. PCR assays 
are superior to EIA tests due to their high sensitivity (97%) 
as well as their ability to detect the NAP1 hypervirulent 
strain. Some laboratories first perform an assay for gluta
-
mate dehydrogenase (a common 
 antigen), which 
has a high sensitivity and negative predictive value (greater 
than 95%). A negative glutamate dehydrogenase assay 
effectively excludes infection, while a positive assay 
requires confirmation with PCR or EIA to determine 
whether the strain that is present is toxin producing.
2. Flexible sigmoidoscopy—
Flexible sigmoidoscopy is not 
needed in patients who have typical symptoms and a posi
-
tive stool toxin assay. It may clarify the diagnosis in 
patients with positive 
 toxin assays who have 
atypical symptoms or who have persistent diarrhea despite 
appropriate therapy. In patients with mild to moderate 
symptoms, there may be no abnormalities or only patchy 
or diffuse, nonspecific colitis indistinguishable from other 
causes. In patients with severe illness, true 
pseudomem
-
branous colitis
 is seen.
3. Imaging studies—
Abdominal radiographs or noncon
-
trast abdominal CT scans are obtained in patients with 
severe or fulminant symptoms to look for evidence of 
colonic dilation and wall thickening. Abdominal CT also is 
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useful in the evaluation of hospitalized patients with 
abdominal pain or ileus without significant diarrhea, in 
whom the presence of colonic wall thickening suggests 
unsuspected 
 colitis. CT scanning is also useful in 
the detection of possible perforation.
 
»
In the hospitalized patient in whom acute diarrhea develops 
after admission, the differential diagnosis includes simple 
antibiotic-associated diarrhea (not related to 
), 
enteral feedings, medications, and ischemic colitis. Other 
infectious causes are unusual in hospitalized patients in 
whom diarrhea develops more than 72 hours after admis
-
sion, and it is not cost-effective to obtain stool cultures 
unless tests for 
 are negative. Rarely, other organ
-
isms (staphylococci, 
) have been 
associated with pseudomembranous colitis. 
Klebsiella oxy
-
toca
 may cause a distinct form of antibiotic-associated 
hemorrhagic colitis that is segmental (usually in the right 
or transverse colon); spares the rectum; and is more com
-
mon in younger, healthier outpatients.
 
»
Severe colitis may progress quickly to fulminant disease, 
resulting in hemodynamic instability, respiratory failure, 
metabolic acidosis, megacolon (more than 7-cm diameter), 
perforation, and death. Chronic untreated colitis may 
result in weight loss and protein-losing enteropathy.
 
»
Treatment
A. Immediate Treatment
If possible, antibiotic therapy should be discontinued and 
therapy with metronidazole, vancomycin, or fidaxomicin 
(a poorly absorbable macrolide antibiotic) should be initi
-
ated. For patients with mild disease, oral metronidazole 
(500 mg orally three times daily), vancomycin (125 mg 
orally four times daily), or fidaxomicin, (200 mg orally two 
times daily) are equally effective for initial treatment. Van
-
comycin and fidaxomicin are significantly more expensive 
than metronidazole. At present, metronidazole remains the 
preferred first-line therapy in patients with mild disease, 
except in patients who are intolerant of metronidazole, 
patients with inflammatory bowel disease, pregnant 
women, and children, although vancomycin is increasingly 
used due to its superior efficacy against the NAP1 strain 
and the decreased cost of its generic version. The duration 
of initial therapy is usually 10–14 days. Symptomatic 
improvement occurs in most patients within 72 hours.
For patients with severe disease, characterized by a 
white blood cell count greater than 15,000/mcL, serum 
albumin less than 3 g/dL, or a rise in serum creatinine to 
more than 1.5 times baseline, vancomycin, 125 mg orally 
four times daily, is the preferred agent because it achieves 
significantly higher response rates (97%) than metronida
-
zole (76%). In patients with severe, complicated disease, 
characterized by fever higher than 38.5°C, hypotension, 
mental status changes, ileus, megacolon, or WBC greater 
than 30,000/mcL, intravenous metronidazole, 500 mg 
every 6 hours, should be given—supplemented by vanco
-
mycin (500 mg four times daily administered by nasoen
-
teric tube) and, in some cases, vancomycin enemas (500 mg 
in 100 mL every 6 hours). Intravenous vancomycin does 
not penetrate the bowel and should not be used. The effi
-
cacy of fidaxomicin for severe or fulminant disease requires 
further investigation. Early surgical consultation is recom
-
mended for all patients with severe or fulminant disease. 
Total abdominal colectomy or loop ileostomy with colonic 
lavage may be required in patients with toxic megacolon, 
perforation, sepsis, or hemorrhage.
Bezlotoxumab is a monoclonal antibody to 
 
toxin B. It was approved by the FDA in 2016 for patients 
with 
 infection who are receiving antimicrobial 
and are deemed at high risk for disease recurrence. In two

with 
and are deemed at high risk for disease recurrence. In two 
phase III randomized controlled trials, patients given one 
intravenous infusion of bezlotoxumab had a lower risk of 
disease relapse within 12 weeks (16%) than patients given 
placebo (26%). In light of this modest clinical benefit, 
bezlotoxumab should be considered only in patients at 
high risk for disease recurrence, including patients who are 
immunocompromised, have inflammatory bowel disease, 
are undergoing dialysis, require continued antimicrobial 
therapy for ongoing infection, or have had prior 
 
B. Treatment of Relapse
Up to 25% of patients have a relapse of diarrhea from 
 
 within 1 or 2 weeks after stopping initial therapy. 
This may be due to reinfection or failure to eradicate the 
organism. The optimal treatment regimen for recurrent 
relapses is evolving. The first episode of recurrent infection 
usually responds promptly to a second course of the same 
regimen used for the initial episode. Some patients, how
-
ever, have further relapses that can be difficult to treat. For 
patients with two relapses, a 7-week tapering regimen of 
vancomycin is recommended: 125 mg orally four times 
daily for 14 days; twice daily for 7 days; once daily for 
7 days; every other day for 7 days; and every third day for 
2–8 weeks. Fidaxomicin may be appropriate for patients 
with recurrent 
 infection or as initial therapy in 
patients believed to be at higher risk for recurrent disease. 
Patients treated with fidaxomicin have lower recurrence 
rates (15%) of non-NAP1 
 strains than patients 
treated with vancomycin (25%).
For patients with three or more relapses, updated 2013 
guidelines recommend consideration of an installation of a 
suspension of fecal bacteria from a healthy donor (“fecal 
microbiota transplant”). Until 2017, “fecal transplantation” 
was performed by installation into the terminal ileum or 
proximal colon (by colonoscopy) or into the duodenum 
and jejunum (by nasoenteric tube). Multiple case series 
reported disease remission after a single treatment in over 
90% of patients with recurrent 
 infection, and in 
a 2013 randomized study, duodenal infusion of donor feces 
led to resolution of 
 diarrhea in 94%, which was 
dramatically higher than vancomycin treatment (31%). In 
2017, a freeze-dried capsule fecal formulation became 
commercially available. In a multicenter, randomized 
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APTER
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controlled trial of 116 patients with recurrent 
 
infection, the proportion of patients without recurrent 
infection after 12 weeks was noninferior in patients treated 
with fecal transplantation administered by oral capsules 
versus colonoscopy-infusion (96.2% in both groups). Due 
to its efficacy and relative safety and ease of administration, 
fecal transplantation by oral capsule administration has 
become the preferred mode of fecal administration in most 
patients.
Bagdasarian N et al. Diagnosis and treatment of 
Clostridium 
difficile
 in adults: a systematic review. JAMA. 2015 Jan 27;
 
313(4):398–408. [PMID: 25626036]
Gupta A et al. JAMA patient page. Fecal microbiota transplanta
-
tion. JAMA. 2017 Jul 4;318(1):102. [PMID: 28672320]
Kao D et al. Effect of oral capsule- vs colonoscopy-delivered fecal 
microbiota transplantation on recurrent 
 
infection: a randomized clinical trial. JAMA. 2017 Nov 28;
 
318(20):1985–93. [PMID: 29183074]
Kelly CR et al. Update on fecal microbiota transplantation 2015: 
indications, methodologies, mechanisms, and outlook. Gas
-
troenterology. 2015 Jul;149(1):223–37. [PMID: 25982290]
Leffler DA et al. 
 infection. N Engl J Med. 
2015 Apr 16;372(16):1539–48. [PMID: 25875259]
Lessa FC et al. Burden of 
 infection in the 
United States. N Engl J Med. 2015 Feb 26;372(9):825–34. 
[PMID: 25714160]
Shen NT et al. Timely use of probiotics in hospitalized adults 
prevents 
 infection: a systematic review 
with meta-regression analysis. Gastroenterology. 2017 Jun;
 
152(8):1889–900. [PMID: 28192108]
Wilcox MH et al; MODIFY I and MODIFY II Investigators. 
Bezlotoxumab for prevention of recurrent 
 
infection. N Engl J Med. 2017 Jan 26;376(4):305–17. [PMID: 
28121498]
INFLAMMATORY BOWEL DISEASE
The term “inflammatory bowel disease” includes ulcerative 
colitis and Crohn disease. In the United States, there are 
approximately 1.6 million people with inflammatory bowel 
disease with adjusted annual incidences of 12.2 
cases/100,000 and 10.7 cases/100,000 person-years for 
ulcerative colitis and Crohn disease, respectively. Ulcer
-
ative colitis is a chronic, recurrent disease characterized by 
diffuse mucosal inflammation involving only the colon. 
Ulcerative colitis invariably involves the rectum and may 
extend proximally in a continuous fashion to involve part 
or all of the colon. Crohn disease is a chronic, recurrent 
disease characterized by patchy transmural inflammation 
involving any segment of the gastrointestinal tract from the 
mouth to the anus.
Crohn disease and ulcerative colitis may be associated 
in 50% of patients with a number of extraintestinal mani
-
festations, including oral ulcers, oligoarticular or polyar
-
ticular nondeforming peripheral arthritis, spondylitis or 
sacroiliitis, episcleritis or uveitis, erythema nodosum, 
pyoderma gangrenosum, hepatitis and sclerosing cholangi
-
tis, and thromboembolic events.
 
»
Pharmacologic Therapy
Although ulcerative colitis and Crohn disease appear to be 
distinct entities, the same pharmacologic agents are used to 
treat both. Despite extensive research, there are still no 
specific therapies for these diseases. The mainstays of 
therapy are 5-aminosalicylic acid derivatives, corticoste
-
roids, immunomodulating agents (such as mercaptopurine 
or azathioprine and methotrexate), and biologic agents.
A. 5-Aminosalicylic Acid (5-ASA)
5-ASA is a topically active agent that has a variety of anti-
inflammatory effects. It is used in the active treatment of 
ulcerative colitis and Crohn disease and during disease 
inactivity to maintain remission. It is readily absorbed 
from the small intestine but demonstrates minimal colonic 
absorption. A number of oral and topical compounds have 
been designed to target delivery of 5-ASA to the colon or

been designed to target delivery of 5-ASA to the colon or 
small intestine while minimizing absorption. Commonly 
used formulations of 5-ASA are sulfasalazine, mesalamine, 
and azo compounds. Side effects of these compounds are 
uncommon but include nausea, rash, diarrhea, pancreati
-
tis, and acute interstitial nephritis.
1. Oral mesalamine agents—
These 5-ASA agents are 
coated in various pH-sensitive resins (Asacol, Apriso, and 
Lialda) or packaged in timed-release capsules (Pentasa). 
Pentasa releases 5-ASA slowly throughout the small intes
-
tine and colon. Asacol, Apriso, and Lialda tablets dissolve 
at pH 6.0–7.0, releasing 5-ASA in the terminal small bowel 
and proximal colon. Lialda has a multi-matrix system that 
gradually releases 5-ASA throughout the colon.
2. Azo compounds—
Sulfasalazine, balsalazide and olsala
-
zine contain 5-ASA linked by an azo bond that requires 
cleavage by colonic bacterial azoreductases to release 
5-ASA. Absorption of these drugs from the small intestine 
is negligible. After release within the colon, the 5-ASA 
works topically and is largely unabsorbed.
Sulfasalazine contains 5-ASA linked to a sulfapyridine 
moiety. It is unclear whether the sulfapyridine group has 
any anti-inflammatory effects. One gram of sulfasalazine 
contains 400 mg of 5-ASA. The sulfapyridine group, how
-
ever, is absorbed and may cause side effects in 15–30% of 
patients—much higher than with other 5-ASA compounds. 
Dose-related side effects include nausea, headaches, leuko
-
penia, oligospermia, and impaired folate metabolism. 
Allergic and idiosyncratic side effects are fever, rash, hemo
-
lytic anemia, neutropenia, worsened colitis, hepatitis, pan
-
creatitis, and pneumonitis. Because of its side effects, 
sulfasalazine is less frequently used than other 5-ASA 
agents. It should always be administered in conjunction 
with folate. Eighty percent of patients intolerant of sul
-
fasalazine can tolerate mesalamine.
3. Topical mesalamine—
5-ASA is provided in the form of 
suppositories (Canasa; 1000 mg) and enemas (Rowasa; 
4 g/60 mL). These formulations can deliver much higher 
concentrations of 5-ASA to the distal colon than oral com
-
pounds. Side effects are uncommon.
B. Corticosteroids
A variety of intravenous, oral, and topical corticosteroid 
formulations have been used in inflammatory bowel dis
-
ease. They have utility in the short-term treatment of 
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moderate to severe disease. However, long-term use is 
associated with serious, potentially irreversible side effects 
and is to be avoided. The agents, route of administration, 
duration of use, and tapering regimens used are based 
more on personal bias and experience than on data from 
rigorous clinical trials. The most commonly used intrave
-
nous formulations have been hydrocortisone or methyl
-
prednisolone, which are given by continuous infusion or 
every 6 hours. Oral formulations are prednisone or meth
-
ylprednisolone. Adverse events commonly occur during 
short-term systemic corticosteroid therapy, including 
mood changes, insomnia, dyspepsia, weight gain, edema, 
elevated serum glucose levels, acne, and moon facies. Side 
effects of long-term use include osteoporosis, osteonecrosis 
of the femoral head, myopathy, cataracts, and susceptibility 
to infections. Calcium and vitamin D supplementation 
should be administered to all patients receiving long-term 
corticosteroid therapy. Bone densitometry should be con
-
sidered in patients with inflammatory bowel disease with 
other risk factors for osteoporosis and in all patients with a 
lifetime use of corticosteroids for 3 months or more. 
Budesonide is an oral corticosteroid with high topical anti-
inflammatory activity but low systemic activity due to high 
first-pass hepatic metabolism. An enteric-coated formula
-
tion is available (Entocort) that targets delivery to the ter
-
minal ileum and proximal colon. An enteric coated, 
multi-matrix, delayed-release formulation is available 
(Uceris) that releases budesonide throughout the colon. 
Budesonide produces less suppression of the hypotha
-
lamic-pituitary-adrenal axis and fewer steroid-related side 
effects than hydrocortisone or prednisone. Topical prepa
-
rations are provided as hydrocortisone suppositories 
(100 mg), foam (90 mg), enemas (100 mg), and as 
budesonide foam (2 mg).
C. Immunomodulating Drugs: Mercaptopurine, 
Azathioprine, or Methotrexate
Mercaptopurine and azathioprine are thiopurine drugs 
that are used in many patients with moderate to severe 
Crohn disease and ulcerative colitis either alone or in com
-
bination with anti-TNF agents. Thiopurines are used alone 
in patients who are corticosteroid-dependent in an attempt 
to reduce or withdraw corticosteroids and in patients in 
remission to reduce the risk of disease recurrence. Thiopu
-
rines are used in combination with biologic agents (espe
-
cially anti-TNF agents) to reduce antibody formation 
against the biologic agent and to increase the likelihood of 
clinical remission through increased anti-TNF drug levels 
and possible synergistic effects. Azathioprine is converted 
in vivo to mercaptopurine. It is believed that the active 
metabolite of mercaptopurine is 6-thioguanine. Side effects 
of mercaptopurine and azathioprine, including allergic 
reactions (fever, rash, or arthralgias) and nonallergic reac
-
tions (nausea, vomiting, pancreatitis, hepatotoxicity, bone 
marrow suppression, infections), occur in 15% of patients. 
Thiopurines are associated with up to a 2.5-fold increased 
risk of non-Hodgkin lymphomas (0.5/1000 patient-years). 
The risk rises after 1–2 years of exposure and is higher in 
men younger than age 30 years and patients older than age 
50 years. Thiopurines also are associated with a risk of 
human papillomavirus (HPV)–related cervical dysplasia; 
and with an increased risk of non-melanoma skin cancer. 
Y ounger patients also are at risk for severe primary 
Epstein-Barr virus (EBV) infection, if not previously 
exposed.
Three competing enzymes are involved in the metabo
-
lism of mercaptopurine to its active (6-thioguanine) and 
inactive but potentially toxic metabolites (6-MMP). About 
1 person in 300 has a homozygous mutation of one of the 
enzymes that metabolizes thiopurine methyltransferase 
(TPMT), placing them at risk for profound immunosup
-

-
pression; 1 person in 9 is heterozygous for TPMT, resulting 
in intermediate enzyme activity. Measurement of TPMT 
functional activity is recommended prior to initiation of 
therapy. Treatment should be withheld in patients with 
absent TPMT activity. The most effective dose of mercap
-
topurine is 1–1.5 mg/kg. For azathioprine, it is 2–3 mg/kg 
daily. For patients with normal TPMT activity, both drugs 
may be initiated at the weight-calculated dose. A complete 
blood count should be obtained weekly for 4 weeks, 
biweekly for 4 weeks, and then every 1–3 months for the 
duration of therapy. Liver biochemical tests should be mea
-
sured periodically. Some clinicians prefer gradual dose 
escalation, especially for patients with intermediate TPMT 
activity or for whom TPMT measurement is not available; 
both drugs may be started at 25 mg/day and increased by 
25 mg every 1–2 weeks while monitoring for myelosup
-
pression until the target dose is reached. If the white blood 
count falls below 4000/mcL or the platelet count falls below 
100,000/mcL, the medication should be held for at least 
1 week before reducing the daily dose by 25–50 mg. Mea
-
surement of thiopurine metabolites (6-TG and 6-MMP) is 
of unproved value in most patients but is recommended in 
patients who have not responded to standard, weight-
based dosing or in whom adverse effects develop.
Methotrexate is used in the treatment of patients with 
inflammatory bowel disease, especially in combination with 
biologic agents to prevent immunogenicity. Methotrexate is 
an analog of dihydrofolic acid. Although at high doses it 
interferes with cell proliferation through inhibition of 
nucleic acid metabolism, at low doses it has anti-inflamma
-
tory properties, including inhibition of expression of tumor 
necrosis factor (TNF) in monocytes and macrophages. 
Methotrexate may be given subcutaneously or orally. Side 
effects of methotrexate include nausea, vomiting, stomati
-
tis, infections, bone marrow suppression, hepatic fibrosis, 
and life-threatening pneumonitis. A complete blood cell 
count and liver chemistries should be monitored every 1–3 
months. Folate supplementation (1 mg/day) should be 
administered. Because methotrexate is teratogenic, it should 
be discontinued in men and women at least 6 months 
before conception and during pregnancy.
D. Biologic Therapies
Although the etiology of inflammatory bowel disorders is 
uncertain, it appears that an abnormal response of the 
mucosal innate immune system to luminal bacteria may 
trigger inflammation, which is perpetuated by dysregula
-
tion of cellular immunity. A number of biologic therapies 
are available or in clinical testing that more narrowly target 
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various components of the immune system. Biologic agents 
are highly effective for patients with moderate to severe 
disease and when administered early in the disease course 
may improve the natural history of disease. The potential 
benefits of these agents, however, must be carefully weighed 
with their high cost and risk of serious and potentially life-
threatening side effects.
1. Anti-TNF therapies—
TNF is one of the key proinflam
-
matory cytokines in the T
H
1 response. TNF exists in two 
biologically active forms: a soluble form (sTNF), which is 
enzymatically cleaved from its cell surface, and a mem
-
brane-bound precursor (tmTNF). When either form binds 
to the TNF-receptors on effector cells, they initiate a vari
-
ety of signaling pathways that lead to inflammatory gene 
activation. Four monoclonal antibodies to TNF currently 
are available for the treatment of inflammatory bowel dis
-
ease: infliximab, adalimumab, golimumab, and certoli
-
zumab. All four agents bind and neutralize soluble as well 
as membrane-bound TNF on macrophages and activated 
T lymphocytes, thereby preventing TNF stimulation of 
effector cells.
Infliximab is a chimeric (75% human/25% mouse) IgG
1
 
antibody that is administered by intravenous infusion. A 
three-dose regimen of 5 mg/kg administered at 0, 2, and 
6 weeks is recommended for acute induction, followed by 
infusions every 8 weeks for maintenance therapy. Acute 
infusion reactions occur in 5–10% of infusions but occur 
less commonly in patients receiving regularly scheduled 
infusions or concomitant immunomodulators (ie, azathio
-
prine or methotrexate). Most reactions are mild or moder
-
ate (nausea; headache; dizziness; urticaria; diaphoresis; or 
mild cardiopulmonary symptoms that include chest tight
-
ness, dyspnea, or palpitations) and can be treated by slow
-
ing the infusion rate and administering acetaminophen and 
diphenhydramine. Severe reactions (hypotension, severe 
shortness of breath, rigors, severe chest discomfort) occur 
in less than 1% and may require oxygen, diphenhydramine, 
hydrocortisone, and epinephrine. Delayed serum sickness-
like reactions occur in 1%. With repeated, intermittent 
intravenous injections, antibodies to infliximab develop in 
up to 40% of patients, which are associated with a shortened 
duration or loss of response and increased risk of acute or 
delayed infusion reactions. Giving infliximab in a regularly 
scheduled maintenance therapy (eg, every 8 weeks), con
-
comitant use of infliximab with other immunomodulating 
agents (azathioprine, mercaptopurine, or methotrexate), or 
preinfusion treatment with corticosteroids (intravenous 
hydrocortisone 200 mg) significantly reduces the develop
-
ment of antibodies to approximately 10%.
Adalimumab and golimumab are fully human IgG
1
 
antibodies that are administered by subcutaneous injec
-
tion. For adalimumab, a dose of 160 mg at week 0 and 
80 mg at week 2 is recommended for acute induction, fol
-
lowed by maintenance therapy with 40 mg subcutaneously 
every other week. For golimumab, a dose of 200 mg at week 
0 and 100 mg at week 2 is recommended for acute induc
-
tion, followed by maintenance therapy with 100 mg subcu
-
taneously every 4 weeks.
Certolizumab is a fusion compound in which the 
Fab1 portion of a chimeric (95% human/5% mouse) 
TNF-antibody is bound to polyethylene glycol in order to 
prolong the drug half-life. A dose of 400 mg at weeks 0, 2, 
and 4 is recommended for acute induction, followed by 
maintenance therapy with 400 mg subcutaneously every 4 
weeks. Injection site reactions (burning, pain, redness, itch
-
ing) are relatively common but are usually minor and 
self-limited.
Acute and delayed hypersensitivity reactions are rare 
with subcutaneous anti-TNF therapies. Antibodies to 
adalimumab or golimumab develop in 5% of patients and 
to certolizumab in 10%, which may lead to shortened dura
-
tion or loss of response to the drug.

-
Serious infections with anti-TNF therapies may occur 
in 2–5% of patients, including sepsis, pneumonia, abscess, 
and cellulitis; however, controlled studies suggest the 
increased risk may be attributable to increased severity of 
disease and concomitant use of corticosteroids. Patients 
treated with anti-TNF therapies are at increased risk for the 
development of opportunistic infections with intracellular 
bacterial pathogens including tuberculosis, mycoses (can
-
didiasis, histoplasmosis, coccidioidomycosis, nocardiosis), 
and listeriosis, and with reactivation of viral infections, 
including hepatitis B, herpes simplex, varicella zoster, and 
EBV . Prior to use of these agents, patients should be 
screened for latent tuberculosis with PPD testing and a 
chest radiograph. Antinuclear and anti-DNA antibodies 
occur in a large percentage of patients; however, the devel
-
opment of drug-induced lupus is rare. All agents may cause 
severe hepatic reactions leading to acute hepatic failure; 
liver biochemical tests should be monitored routinely dur
-
ing therapy. Anti-TNF therapies increase the risk of non-
melanoma skin cancer, hence annual dermatologic 
examinations are recommended. The risk of non-Hodgkin 
lymphoma is increased approximately 2.4-fold (0.4/1000 
person-years) in patients taking anti-TNF monotherapy; 
however, the risk is much higher in patients receiving a 
combination of anti-TNF and a thiopurine (6.1-fold 
increase; 0.95/1000 person-years). Rare cases of optic neu
-
ritis and demyelinating diseases, including multiple sclero
-
sis have been reported. Anti-TNF therapies may worsen 
heart failure in patients with cardiac disease.
In patients with active inflammatory bowel disease, 
monitoring of anti-TNF trough levels and any anti-drug 
antibodies can help guide therapy, especially in patients 
who have poor clinical response or who have lost clinical 
response. At present, recommended trough concentrations 
are, for infliximab greater than 5 mcg/mL and for adalim
-
umab, greater than 7.5 mcg/mL. Patients with high titers of 
anti-drug antibodies should be switched to a different anti-
TNF agent. Anti-TNF therapy is considered to have failed 
when patients have a poor response despite adequate 
anti-TNF trough concentrations; another class of drugs 
should be tried.
2. Anti-integrins—
Anti-integrins decrease the trafficking 
of circulating leukocytes through the vasculature, reducing 
chronic inflammation. Vedolizumab is an anti-integrin that 
blocks the alpha
4
beta
7
 heterodimer, selectively blocking gut, 
but not brain, lymphocyte trafficking. Vedolizumab is FDA 
approved for patients with moderately active ulcerative 
colitis or Crohn disease who have an inadequate response to 
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CMDT 2019
or intolerance of anti-TNF agents. Induction therapy is 
given as a 300-mg intravenous dose at weeks 0, 2, and 6. 
This is followed by maintenance therapy of 300 mg intrave
-
nously every 4–8 weeks. Thus far, vedolizumab does not 
appear to be associated with an increased risk of serious 
infections or malignancy. Infusion reactions are uncom
-
mon. Antibodies develop in 5%, which may interfere with 
drug efficacy. Natalizumab is another anti-integrin com
-
pound that targets the alpha
4
 integrin, thereby blocking 
trafficking to both the gut and brain. However, natalizumab 
may cause a reactivation of JC polyoma virus, leading to an 
increased incidence of progressive multifocal leukoen
-
cephalopathy (PML). To date, there are no cases of PML 
associated with vedolizumab, likely due to its greater selec
-
tivity for gut lymphocytes. With the advent of vedolizumab, 
natalizumab is now rarely used for inflammatory bowel 
disease.
3. Anti-IL
-12/23 antibody—
Ustekinumab is a human IgG
1
 
monoclonal antibody that binds the p40 subunit of IL-12 
and IL-23, interfering with their receptor binding on T cells, 
NK cells, and antigen presenting cells. Ustekinumab was 
FDA approved in 2016 for the treatment of patients with 
moderate to severe Crohn disease (not ulcerative colitis) 
who have not responded to or are intolerant of conven
-
tional therapies. Induction therapy is given as a single, 
weight-based intravenous dose (approximately 5–7 mg/kg), 
followed by 90 mg every 8 weeks by subcutaneous injec
-
tion. In extensive experience with its use in the treatment 
of psoriasis and clinical trial experience in treatment of 
Crohn disease, there has been no demonstrated increase in 
severe infections or malignancy, and other serious events 
are rare. Antibodies to ustekinumab develop in less than 
5% of patients but their impact on treatment efficacy is 
uncertain.
Bonovas S et al. Biologic therapies and risk of infection and 
malignancy in patients with inflammatory bowel disease: a 
systematic review and network meta-analysis. Clin Gastroen
-
terol Hepatol. 2016 Oct;14(10):1385–97. [PMID: 27189910]
Farraye F et al. ACG Clinical Guideline: preventive care in 
inflammatory bowel disease. Am J Gastroenterol. 2017 Feb;
 
112(2):241–58. [PMID: 28071656]
Feuerstein JD et al. American Gastroenterological Association 
Institute guidelines on therapeutic drug monitoring in 
inflammatory bowel disease. Gastroenterology. 2017 Sep;
 
153(3):827–34. [PMID: 28780013]
Herfarth HH et al. Use of methotrexate in the treatment of 
inflammatory bowel diseases. Inflamm Bowel Dis. 2016 Jan;
 
22(1):224–33. [PMID: 26457382]
Lemaitre M et al. Association between use of thiopurines or 
tumor necrosis factor antagonists alone or in combination 
and risk of lymphoma in patients with inflammatory bowel 
disease. JAMA. 2017 Nov 7;318(17):1679–86. [PMID: 
29114832]
Papamichael K et al. Improved long-term outcomes of patients 
with inflammatory bowel disease receiving proactive com
-
pared with reactive monitoring of serum concentrations of 
infliximab. Clin Gastroenterol Hepatol. 2017 Oct;15(10):1580–8. 
[PMID: 28365486]
Regueiro MD et al. Established management paradigms in IBD: 
treatment targets and therapeutic tools. Am J Gastroenterol 
Suppl. 2016;3:8–16.
Rosen DJ et al. The evolving role of thiopurines for inflamma
-
tory bowel disease. Inflamm Bowel Dis. 2016 Jan;22(1):
 
234–40. [PMID: 26355469]
Shivashankar R et al. Incidence and prevalence of Crohn’s dis
-
ease and ulcerative colitis in Olmsted County, Minnesota 
from 1970 through 2010. Clin Gastroenterol Hepatol. 
2017 Jun;15(6):857–63. [PMID: 27856364]
Willet N et al. Association between low trough levels of vedoli
-
zumab during induction therapy for inflammatory bowel 
diseases and need for additional doses within 6 months. Clin 
Gastroenterol Hepatol. 2017 Nov;15(11):1750–57. [PMID: 
27890854]
 
»
Social Support for Patients

27890854]
 
»
Inflammatory bowel disease is a lifelong illness that can 
have profound emotional and social impacts on the indi
-
vidual. Patients should be encouraged to become involved 
in the Crohn’s and Colitis Foundation of America (CCFA). 
National headquarters may be contacted at 733 Third 
Avenue, Suite 510, New Y ork, NY 10017; phone 800-932-
2423. Internet address: www.ccfa.org.
1. Crohn Disease
 
»
Insidious onset.
 
»
Intermittent bouts of low-grade fever, diarrhea, 
and right lower quadrant pain.
 
»
Right lower quadrant mass and tenderness.
 
»
Perianal disease with abscess, fistulas.
 
»
Radiographic or endoscopic evidence of ulcer
-
ation, stricturing, or fistulas of the small intestine 
or colon.
 
»
One-third of cases of Crohn disease involve the small 
bowel only, most commonly the terminal ileum (ileitis). 
Half of all cases involve the small bowel and colon, most 
often the terminal ileum and adjacent proximal ascending 
colon (ileocolitis). In 20% of cases, the colon alone is 
affected. One-third of patients have associated perianal 
disease (fistulas, fissures, abscesses). Less than 5% of patients 
have symptomatic involvement of the upper intestinal 
tract. Unlike ulcerative colitis, Crohn disease is a transmu
-
ral process that can result in mucosal inflammation and 
ulceration, stricturing, fistula development, and abscess 
formation. Cigarette smoking is strongly associated with 
the development of Crohn disease, resistance to medical 
therapy, and early disease relapse.
 
»
Because of the variable location of involvement and sever
-
ity of inflammation, Crohn disease may present with a 
variety of symptoms and signs. In eliciting the history, the 
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clinician should take particular note of fevers, the patient’s 
general sense of well-being, weight loss, the presence of 
abdominal pain, the number of liquid bowel movements 
per day, and prior surgical resections. Physical examination 
should focus on the patient’s temperature, weight, and 
nutritional status, the presence of abdominal tenderness or 
mass, rectal examination, and extraintestinal manifesta
-
tions. Most commonly, there is one or a combination of the 
following clinical constellations.
1. Chronic inflammatory disease—
This is the most com
-
mon presentation and is often seen in patients with ileitis 
or ileocolitis. Patients report malaise, weight loss, and loss 
of energy. In patients with ileitis or ileocolitis, there may be 
diarrhea, which is usually nonbloody and often intermit
-
tent. In patients with colitis involving the rectum or left 
colon, there may be bloody diarrhea and fecal urgency, 
which may mimic the symptoms of ulcerative colitis. 
Cramping or steady right lower quadrant or periumbilical 
pain is common. Physical examination reveals focal ten
-
derness, usually in the right lower quadrant. A palpable, 
tender mass that represents thickened or matted loops of 
inflamed intestine may be present in the lower abdomen.
2. Intestinal obstruction—
Narrowing of the small bowel 
may occur as a result of inflammation, spasm, or fibrotic 
stenosis. Patients report postprandial bloating, cramping 
pains, and loud borborygmi. This may occur in patients 
with active inflammatory symptoms (as above) or later in 
the disease from chronic fibrosis without other systemic 
symptoms or signs of inflammation.
3. Penetrating disease and fistulae—
Sinus tracts that 
penetrate through the bowel, where they may be contained 
or form fistulas to adjacent structures, develop in a subset 
of patients. Penetration through the bowel can result in an 
intra-abdominal or retroperitoneal phlegmon or abscess 
manifested by fevers, chills, a tender abdominal mass, and 
leukocytosis. Fistulas between the small intestine and 
colon commonly are asymptomatic, but can result in diar
-
rhea, weight loss, bacterial overgrowth, and malnutrition. 
Fistulas to the bladder produce recurrent infections. Fistu
-
las to the vagina result in malodorous drainage and prob
-
lems with personal hygiene. Fistulas to the skin usually 
occur at the site of surgical scars.
4. Perianal disease—
One-third of patients with either 
large or small bowel involvement develop perianal disease 
manifested by large painful skin tags, anal fissures, perianal 
abscesses, and fistulas.
5. Extraintestinal manifestations—
Extraintestinal mani
-
festations may be seen with both Crohn disease and ulcer
-
ative colitis. These include arthralgias, arthritis, iritis or 
uveitis, pyoderma gangrenosum, or erythema nodosum. 
Oral aphthous lesions are common. There is an increased 
prevalence of gallstones due to malabsorption of bile salts 
from the terminal ileum. Nephrolithiasis with urate or 
calcium oxalate stones may occur.
Laboratory values may reflect inflammatory activity or 
nutritional complications of disease. A complete blood 
count and serum albumin should be obtained in all patients. 
Anemia may reflect chronic inflammation, mucosal blood 
loss, iron deficiency, or vitamin B
12
 malabsorption second
-
ary to terminal ileal inflammation or resection. Leukocyto
-
sis may reflect inflammation or abscess formation or may 
be secondary to corticosteroid therapy. Hypoalbuminemia 
may be due to intestinal protein loss (protein-losing enter
-
opathy), malabsorption, bacterial overgrowth, or chronic 
inflammation. The sedimentation rate or C-reactive protein 
level is elevated in many patients during active inflamma
-
tion; however, one-third have a normal C-reactive protein 
level. Fecal calprotectin is an excellent noninvasive test. 
Elevated levels are correlated with active inflammation as

-
Elevated levels are correlated with active inflammation as 
demonstrated by ileocolonoscopy or radiologic CT or MR 
enterography. Stool specimens are sent for examination by 
culture for routine pathogens, microscopy for ova and para
-
sites, and conventional or rapid PCR diagnostic assessment 
for 
 toxin.
C. Special Diagnostic Studies
In most patients, the initial diagnosis of Crohn disease is 
based on a compatible clinical picture with supporting 
endoscopic, pathologic, and radiographic findings. Colo
-
noscopy usually is performed first to evaluate the colon 
and terminal ileum and to obtain mucosal biopsies. Typi
-
cal endoscopic findings include aphthoid, linear or stellate 
ulcers, strictures, and segmental involvement with areas of 
normal-appearing mucosa adjacent to inflamed mucosa. 
In 10% of cases, it may be difficult to distinguish ulcerative 
colitis from Crohn disease. Granulomas on biopsy are 
present in less than 25% of patients but are highly sugges
-
tive of Crohn disease. CT or MR enterography is obtained 
in patients with suspected small bowel involvement. Sug
-
gestive findings include ulcerations, strictures, and fistu
-
las; in addition, CT or MR enterography may identify 
bowel wall thickening and vascularity, mucosal enhance
-
ment, and fat stranding. MR enterography, where avail
-
able, may be preferred due its lack of radiation exposure. 
Capsule imaging may help establish a diagnosis when clini
-
cal suspicion for small bowel involvement is high but 
radiographs are normal or nondiagnostic. Barium upper 
gastrointestinal series with small bowel follow through 
should no longer be performed except where CT or MR 
enterography is unavailable.
 
»
A. Abscess
The presence of a tender abdominal mass with fever and 
leukocytosis suggests an abscess. Emergent CT of the abdo
-
men is necessary to confirm the diagnosis. Patients should 
be given broad-spectrum antibiotics. Percutaneous drain
-
age or surgery is usually required.
B. Obstruction
Small bowel obstruction may develop secondary to active 
inflammation or chronic fibrotic stricturing and is often 
acutely precipitated by dietary indiscretion. Patients should 
be given intravenous fluids with nasogastric suction. 
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Systemic corticosteroids are indicated in patients with 
symptoms or signs of active inflammation but are unhelpful 
in patients with inactive, fixed disease. Patients unimproved 
on medical management require surgical resection of the 
stenotic area or stricturoplasty.
C. Abdominal and Rectovaginal Fistulas
Many fistulas are asymptomatic and require no specific 
therapy. Most symptomatic fistulas eventually require surgi
-
cal therapy; however, medical therapy is effective in a subset 
of patients and is usually tried first in outpatients who oth
-
erwise are stable. Large abscesses associated with fistulas 
require percutaneous or surgical drainage. After percutane
-
ous drainage, long-term antibiotics are administered in 
order to reduce recurrent infections until the fistula is 
closed or surgically resected. Fistulas may close temporarily 
in response to TPN or oral elemental diets but recur when 
oral feedings are resumed. Anti-TNF agents may promote 
closure in up to 60% within 10 weeks; however, relapse 
occurs in over one-half of patients within 1 year despite 
continued therapy. Surgical therapy is required for symp
-
tomatic fistulas that do not respond to medical therapy. 
Fistulas that arise above (proximal to) areas of intestinal 
stricturing commonly require surgical treatment.
D. Perianal Disease
Patients with fissures, fistulas, and skin tags commonly 
have perianal discomfort. Successful treatment of active 
intestinal disease also may improve perianal disease. Spe
-
cific treatment of perianal disease can be difficult and is 
best approached jointly with a surgeon with an expertise in 
colorectal disorders. Pelvic MRI is the best noninvasive 
study for evaluating perianal fistulas. Patients should be 
instructed on proper perianal skin care, including gentle 
wiping with a premoistened pad (baby wipes) followed by 
drying with a cool hair dryer, daily cleansing with sitz baths 
or a water wash, and use of perianal cotton balls or pads to 
absorb drainage. Oral antibiotics (metronidazole, 250 mg 
three times daily, or ciprofloxacin, 500 mg twice daily) may 
promote symptom improvement or healing in patients 
with fissures or uncomplicated fistulas; however, recurrent 
symptoms are common. Refractory fissures may benefit 
from mesalamine suppositories or topical 0.1% tacrolimus 
ointment. Immunomodulators or anti-TNF agents or both 
promote short-term symptomatic improvement from anal 
fistulas in two-thirds of patients and complete closure in up 
to one-half of patients; however, less than one-third main
-
tain symptomatic remission during long-term mainte
-
nance treatment.
Anorectal abscesses should be suspected in patients 
with severe, constant perianal pain, or perianal pain in 
association with fever. Superficial abscesses are evident on 
perianal examination, but deep perirectal abscesses may be 
detected by digital examination or pelvic CT scan. Depend
-
ing on the abscess location, surgical drainage may be 
achieved by incision, or catheter or seton placement. Sur
-
gery should be considered for patients with severe, refrac
-
tory symptoms but is best approached after medical 
therapy of the Crohn disease has been optimized.
E. Carcinoma
Patients with colonic Crohn disease are at increased risk 
for developing colon carcinoma; hence, annual screening 
colonoscopy to detect dysplasia or cancer is recommended 
for patients with a history of 8 or more years of Crohn 
colitis. Patients with Crohn disease have an increased risk 
of lymphoma and of small bowel adenocarcinoma; how
-
ever, both are rare.
F. Hemorrhage
Unlike ulcerative colitis, severe hemorrhage is unusual in 
Crohn disease.
G. Malabsorption
Malabsorption may arise after extensive surgical resections 
of the small intestine and from bacterial overgrowth in 
patients with enterocolonic fistulas, strictures, and stasis 
resulting in bacterial overgrowth.
 
»

»
Chronic cramping abdominal pain and diarrhea are typical 
of both irritable bowel syndrome and Crohn disease, but 
radiographic examinations are normal in the former. 
Celiac disease may cause diarrhea with malabsorption. 
Acute fever and right lower quadrant pain may resemble 
appendicitis or 
 enteritis. Intestinal 
lymphoma causes fever, pain, weight loss, and abnormal 
small bowel radiographs that may mimic Crohn disease. 
Patients with undiagnosed AIDS may present with fever 
and diarrhea. Segmental colitis may be caused by tubercu
-
losis, 
E histolytica, Chlamydia
, or ischemic colitis. 
 
or CMV infection may develop in patients with inflamma
-
tory bowel disease, mimicking disease recurrence. In 
patients from tuberculosis-endemic countries, it can be 
extremely difficult to distinguish active intestinal tubercu
-
losis from Crohn disease, even with biopsies and PCR 
analyses. Diverticulitis or appendicitis with abscess forma
-
tion may be difficult to distinguish acutely from Crohn 
disease. NSAIDs may exacerbate inflammatory bowel dis
-
ease and may also cause NSAID-induced colitis character
-
ized by small bowel or colonic ulcers, erosion, or strictures 
that tend to be most severe in the terminal ileum and right 
colon.
 
»
Treatment of Active Disease
Crohn disease is a chronic lifelong illness characterized by 
exacerbations and periods of remission. As no specific 
therapy exists, current treatment is directed toward symp
-
tomatic improvement and control of the disease process, in 
order to improve quality of life and reduce disease progres
-
sion and complications. Although sustained clinical remis
-
sion should be the therapeutic goal, this cannot be achieved 
in all patients. Choice of therapies depends on the disease 
location and severity, patient age and comorbidities, and 
patient preference. Early introduction of biologic therapy 
should be considered strongly in patients with risk factors 
for aggressive disease, including young age, perianal 
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disease, stricturing disease, or need for corticosteroids. All 
patients with Crohn disease should be counseled to discon
-
tinue cigarettes.
A. Nutrition
1. Diet—
Patients should eat a well-balanced diet with as 
few restrictions as possible. Eating smaller but more fre
-
quent meals may be helpful. Patients with diarrhea should 
be encouraged to drink fluids to avoid dehydration. Many 
patients report that certain foods worsen symptoms, espe
-
cially fried or greasy foods. Because lactose intolerance is 
common, a trial off dairy products is warranted if flatu
-
lence or diarrhea is a prominent complaint. Patients with 
obstructive symptoms should be placed on a low-roughage 
diet, ie, no raw fruits or vegetables, popcorn, nuts, etc. 
Resection of more than 100 cm of terminal ileum results in 
fat malabsorption for which a low-fat diet is recom
-
mended. Parenteral vitamin B
12
 (1000 mcg subcutaneously 
per month) and oral vitamin D supplementation com
-
monly is needed for patients with previous ileal resection 
or extensive terminal ileal disease.
2. Enteral therapy—
Supplemental enteral therapy via 
nasogastric tube may be required for children and adoles
-
cents with poor intake and growth retardation.
3. Total parenteral nutrition—
TPN is used short term in 
patients with active disease and progressive weight loss or 
those awaiting surgery who have malnutrition but cannot 
tolerate enteral feedings because of high-grade obstruction, 
high-output fistulas, severe diarrhea, or abdominal pain. It 
is required long term in a small subset of patients with 
extensive intestinal resections resulting in short bowel syn
-
drome with malnutrition.
B. Symptomatic Medications
There are several potential mechanisms by which diarrhea 
may occur in Crohn disease in addition to active Crohn 
disease. A rational empiric treatment approach often yields 
therapeutic improvement that may obviate the need for 
corticosteroids or immunosuppressive agents. Involvement 
of the terminal ileum with Crohn disease or prior ileal 
resection may lead to reduced absorption of bile acids that 
may induce secretory diarrhea from the colon. This diar
-
rhea commonly responds to cholestyramine 2–4 g, 
colestipol 5 g, or colesevelam 625 mg one to two times 
daily before meals to bind the malabsorbed bile salts. 
Patients with extensive ileal disease (requiring more than 
100 cm of ileal resection) have such severe bile salt malab
-
sorption that steatorrhea may arise. Such patients may 
benefit from a low-fat diet; bile salt-binding agents will 
exacerbate the diarrhea and should not be given. Patients 
with Crohn disease are at risk for the development of small 
intestinal bacterial overgrowth due to enteral fistulas, ileal 
resection, and impaired motility and may benefit from a 
course of broad-spectrum antibiotics (see Bacterial Over
-
growth, above). Other causes of diarrhea include lactase 
deficiency and short bowel syndrome (described in other 
sections). Use of oral antidiarrheal agents may provide benefit 
in some patients. Loperamide (2–4 mg), diphenoxylate with 
atropine (one tablet), or tincture of opium (5–15 drops) 
may be given as needed up to four times daily. Because of 
the risk of toxic megacolon, these drugs should not be used 
in patients with active severe colitis.
C. Specific Drug Therapy
1. 5-Aminosalicylic acid agents—
Mesalamine has long 
been used as initial therapy for the treatment of mild to 
moderately active colonic and ileocolonic Crohn disease. 
However, meta-analyses of published and unpublished trial 
data suggest that mesalamine is of no value in either the 
treatment of active Crohn disease or the maintenance of 
remission. Current treatment guidelines recommend 
against its use for Crohn disease.
Antibiotics also are widely used by clini
-
cians for the treatment of active luminal Crohn disease, 
although meta-analyses of controlled trials suggest that

-
although meta-analyses of controlled trials suggest that 
they have little or no efficacy. It is hypothesized that antibi
-
otics may reduce inflammation through alteration of gut 
flora, reduction of bacterial overgrowth, or treatment of 
microperforations. Oral metronidazole (10 mg/kg/day) or 
ciprofloxacin (500 mg twice daily), or rifaximin (800 mg 
twice daily) are commonly administered for 6–12 weeks.
Approximately one-half of patients 
with Crohn disease require corticosteroids at some time in 
their illness. Corticosteroids dramatically suppress the acute 
clinical symptoms or signs in most patients with both small 
and large bowel disease; however, they do not alter the 
underlying disease. An ileal-release budesonide preparation 
(Entocort), 9 mg once daily for 8–16 weeks, induces remis
-
sion in 50–70% of patients with mild to moderate Crohn 
disease involving the terminal ileum or ascending colon. 
After initial treatment, budesonide is tapered over 2–4 weeks 
in 3 mg increments. In some patients, low-dose budesonide 
(6 mg/day) may be used for up to 1 year to maintain remis
-
sion. Budesonide is superior to mesalamine but somewhat 
less effective than prednisone. However, because budesonide 
has markedly reduced acute and chronic steroid-related 
adverse effects, including smaller reductions of bone min
-
eral density, it is preferred to other systemic corticosteroids 
for the treatment of mild to moderate Crohn disease involv
-
ing the terminal ileum or ascending colon.
Prednisone or methylprednisolone, 40–60 mg/day, is 
generally administered to patients with Crohn disease that 
is severe, that involves the distal colon or proximal small 
intestine, or that has failed treatment with budesonide. 
Remission or significant improvement occurs in greater 
than 80% of patients after 8–16 weeks of therapy. After 
improvement at 2 weeks, tapering proceeds at 5 mg/wk 
until a dosage of 20 mg/day is being given. Thereafter, slow 
tapering by 2.5 mg/wk is recommended. Approximately 
20% of patients cannot be completely withdrawn from cor
-
ticosteroids without experiencing a symptomatic flare-up. 
Furthermore, more than 50% of patients who achieve initial 
remission on corticosteroids will experience a relapse 
within 1 year. Use of long-term low corticosteroid doses 
(2.5–10 mg/day) should be avoided because of associated 
complications. Patients requiring long-term corticosteroid 
treatment should be given immunomodulatory drugs or 
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biologic therapies or both in an effort to wean them from 
Patients with persisting symptoms despite oral cortico
-
steroids or those with high fever, persistent vomiting, evi
-
dence of intestinal obstruction, severe weight loss, severe 
abdominal tenderness, or suspicion of an abscess should be 
hospitalized. In patients with a tender, palpable inflamma
-
tory abdominal mass, CT scan of the abdomen should be 
obtained prior to administering corticosteroids to rule out 
an abscess. If no abscess is identified, parenteral corticoste
-
roids should be administered (as described for ulcerative 
colitis below).
4. Azathioprine, mercaptopurine, or methotrexate—
The 
three main indications for immunomodulators in Crohn 
disease are (1) after induction therapy with corticosteroids 
to allow their withdrawal (particularly in patients who are 
corticosteroid-dependent) and to maintain remission; (2) 
for the induction of remission, in combination with anti-
TNF therapy, in patients with moderate to severe active 
Crohn disease (discussed in next section); (3) in combina
-
tion with biologic agents to reduce the likelihood of neu
-
tralizing antibody formation. In the United States, 
mercaptopurine or azathioprine are more commonly used 
than methotrexate. Immunomodulators are used in up to 
60% of patients with Crohn disease for maintenance after 
induction of remission with corticosteroids. Although the 
magnitude of benefit is debated, meta-analysis of con
-
trolled trials suggest that patients treated with thiopurines 
are 2.3 times as likely to maintain remission as patients 
treated with placebo, reducing the 3-year relapse rate from 
more than 60% to less than 25%. Methotrexate (25 mg 
subcutaneously weekly for 12 weeks, followed by 12.5–15 mg 
once weekly) is used in patients who are unresponsive 
to, or intolerant of, mercaptopurine or azathioprine. 
Because oral absorption may be erratic, parenteral admin
-
istration of methotrexate is preferred. Immunomodulators 
do not appear to be effective at inducing remission. Two 
2013 randomized controlled trials in patients with newly 
diagnosed Crohn disease (treated with or without cortico
-
steroids) found equivalent corticosteroid-free remissions 
rates in patients treated with thiopurines or placebo. A 
2013 AGA guideline has recommended against the use of 
thiopurine monotherapy to induce remission.
5. Anti-TNF therapies—
Infliximab, adalimumab, and cer
-
tolizumab are used to induce and maintain remission in 
patients with moderate to severe Crohn disease, including 
fistulizing disease. These agents are also used to treat 
extraintestinal manifestations of Crohn disease (except 
optic neuritis).
a. 
A
cute
 induction therapy—
Anti-TNF therapies are 
recommended as the preferred first-line agents to induce 
remission in patients with moderate to severe Crohn dis
-
ease, either as monotherapy or in combination with thio
-
purines. Currently, there are two major controversies 
about the use of anti-TNF agents: (1) whether anti-TNF 
agents should be reserved as second-line therapy in patients 
with moderate to severe Crohn disease who have not 
responded to prior therapy with corticosteroids and immu
-
nomodulators (“step-up” therapy) or whether they should be 
used early in the course of illness with the goal of inducing 
early remission and altering the natural history of the dis
-
ease; (2) whether an anti-TNF agent should be used alone 
or in combination with an immunomodulator (azathio
-
prine, mercaptopurine, or methotrexate) to enhance remis
-
sion and reduce the development of antibodies to the 
anti-TNF agent. The best data support the use of anti-TNF 
agents early in the course of disease and suggest that 
“step-up therapy” (corticosteroids, followed by azathio
-
prine, followed by infliximab) is obsolete, especially in 
patients with moderate to severe disease. Data in support

-
patients with moderate to severe disease. Data in support 
of use of early combination therapy come from a large 2010 
trial (SONIC) that compared three treatment arms: combi
-
nation therapy with infliximab and azathioprine versus 
infliximab alone or azathioprine alone in patients with 
moderate to severe Crohn disease who had not previously 
been treated with immunomodulators or anti-TNF agents. 
After 6 months, clinical remission (57%) and mucosal 
healing (44%) was significantly higher with combination 
therapy than with either agent alone. Combination therapy 
with anti-TNF and azathioprine beyond 1 year may not be 
appropriate in men younger than 30 years of age in whom 
there is a higher risk of hepatosplenic T-cell lymphoma and 
in adults older than 50–60 years in whom there is a higher 
risk of lymphoma and infectious complications. Anti-TNF 
serum trough levels should be obtained after induction 
therapy to optimize drug dosing. Low trough levels are 
associated with a decreased likelihood of remission and 
increased risk of developing anti-drug antibodies.
The doses for acute induction therapy are described 
above. Up to two-thirds of patients have significant clinical 
improvement during acute induction therapy.
b. 
M
aintenance therapy—
After initial clinical response, 
symptom relapse occurs in more than 80% of patients 
within 1 year in the absence of further maintenance ther
-
apy. Therefore, scheduled maintenance therapy is usually 
recommended (infliximab, 5 mg/kg infusion every 8 weeks; 
adalimumab, 40 mg subcutaneous injection every 2 weeks; 
certolizumab, 400 mg subcutaneous injection every 4 weeks). 
With long-term maintenance therapy, approximately two-
thirds have continued clinical response and up to one-half 
have complete symptom remission. Loss of efficacy is due 
to low anti-TNF levels, the development of antibodies to 
the anti-TNF agent, or inflammation that is unresponsive 
to anti-TNF therapy. Serum anti-TNF trough levels and 
drug antibody levels may guide subsequent therapy in 
patients who have lost response. Patients with antibodies 
to the anti-TNF agent should be switched to another 
anti-TNF agent. Patients with low serum anti-TNF trough 
levels and absent drug antibodies should receive 
increased anti-TNF dosing (infliximab 10 mg/kg; adalim
-
umab 80 mg) or decreased dosing intervals (infliximab 
every 6 weeks; adalimumab every week). Patients with 
inadequate response despite adequate anti-TNF trough 
levels should be changed to an alternative biologic agent, 
such as vedolizumab or ustekinumab. Concomitant ther
-
apy with anti-TNF agents and immunomodulating agents 
(azathioprine, mercaptopurine, or methotrexate) reduces 
the risk of development of antibodies to the anti-TNF 
agent but may increase the risk of complications 
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(non-Hodgkin lymphoma and opportunistic infections). 
For this reason, consideration should be given to stopping 
or reducing the dose of the immunomodulating agent after 
6–12 months in patients who are in remission.
6. Anti-integrins—
Anti-integrins may offer a therapeutic 
option for patients who do not respond to, or who lose 
response to, anti-TNF agents.
Vedolizumab
 is used primarily in patients with moder
-
ate to severe Crohn disease in whom anti-TNF therapy has 
failed or is not tolerated. The full clinical effects of vedoli
-
zumab may take 14 weeks to be apparent. A 2014 phase III 
trial studying patients with Crohn disease showed that 
when response was lost or side effects developed to one 
anti-TNF therapy, switching to vedolizumab (300 mg 
intravenously at weeks 0 and 2) resulted in clinical remis
-
sion in 26.6% of patients at week 10 compared to 12.1% of 
patients treated with placebo. In another phase III trial, 
among patients demonstrating initial clinical improvement 
with vedolizumab induction therapy, 39% of patients 
treated with long-term vedolizumab (300 mg every 8 weeks) 
were in remission at 1 year compared with 21.6% of 
patients given placebo.
7. Anti-IL12/IL-23 antibody—
In 2016, 
ustekinumab
 was 
approved by the FDA for treatment of patients with moder
-
ate to severe Crohn disease who had not responded to or 
were intolerant of conventional therapies. In a phase III trial 
involving 741 patients with Crohn disease in whom anti-
TNF therapy failed, clinical response was seen in 34% of 
patients 6 weeks after a single-dose of intravenous 
ustekinumab compared to 21.5% with placebo. In a second 
phase III trial composed of patients in whom conventional 
therapy with immunomodulators or corticosteroids (but not 
anti-TNF) had failed, clinical improvement occurred in 55% 
compared to 28.7% with placebo. Among patients from both 
induction trials who were enrolled in a chronic maintenance 
trial (ustekinumab versus placebo subcutaneously every 
8 weeks), 53% of those given ustekinumab were in clinical 
remission at week 44 versus 36% given the placebo.
 
»
Indications for Surgery
Over 50% of patients will require at least one surgical pro
-
cedure. The main indications for surgery are intractability 
to medical therapy, intra-abdominal abscess, massive 
bleeding, symptomatic refractory internal or perianal fistu
-
las, and intestinal obstruction. Patients with chronic 
obstructive symptoms due to a short segment of ileal ste
-
nosis are best treated with resection or stricturoplasty 
(rather than long-term medical therapy), which promotes 
rapid return of well-being and elimination of corticoste
-
roids. After surgery, endoscopic evidence of recurrence 
occurs in 60% within 1 year. Endoscopic recurrence pre
-
cedes clinical recurrence by months to years; clinical recur
-
rence occurs in 20% of patients within 1 year and 80% 
within 10–15 years. Therapy with metronidazole, 250 mg 
three times daily for 3 months, or long-term therapy with 
immunomodulators (mercaptopurine or azathioprine) has 
only been modestly effective in preventing clinical and 
endoscopic recurrence after ileocolic resection. In a 2016 
controlled trial of 297 patients undergoing ileocolonic 
resection, endoscopic recurrence occurred in 30% of 
patients treated with infliximab every 8 weeks compared 
with 60% treated with placebo. It may be reasonable to 
initiate empiric infliximab postoperatively for patients at 
high risk for disease recurrence and to perform endoscopy 
in low-risk patients 6 months after surgery in order to 
identify patients with early endoscopic recurrence who 
may benefit from anti-TNF therapy.
 
»
Prognosis
With proper medical and surgical treatment, the majority 
of patients are able to cope with this chronic disease and its 
complications and lead productive lives. Few patients die as 
a direct consequence of the disease.
 
»
•

»
•	
For expertise in endoscopic procedures or capsule 
endoscopy.
•	
For follow-up of any patient requiring hospitalization.
•	
Patients with moderate to severe disease for whom 
therapy with immunomodulators or biologic agents is 
being considered.
•	
When surgery may be necessary.
 
»
•	
An intestinal obstruction is suspected.
•	
An intra-abdominal or perirectal abscess is suspected.
•	
A serious infectious complication is suspected, espe
-
cially in patients who are immunocompromised due to 
concomitant use of corticosteroids, immunomodula
-
tors, or anti-TNF agents.
•	
Patients with severe symptoms of diarrhea, dehydra
-
tion, weight loss, or abdominal pain.
•	
Patients with severe or persisting symptoms despite 
treatment with corticosteroids.
Cheifetz A. JAMA patient page. Crohn disease. JAMA. 2014 Oct 
22–29;312(16):1708. [PMID: 25335164]
Cohen BL et al. Update on anti-tumor necrosis factor agents and 
other new drugs for inflammatory bowel disease. BMJ. 2017 
Jun 19;357:j2505. [PMID: 28630047]
Danese S et al. Early intervention in Crohn’s disease: towards 
disease modification trials. Gut. 2017 Dec;66(12):2179–87. 
[PMID: 28874419]
Dulai PS et al. The real-world effectiveness and safety of vedoli
-
zumab for moderate-severe Crohn’s disease: results from the 
US VICTORY consortium. Am J Gastroenterol. 2016 Aug;
 
111(8):1147–55. [PMID: 27296941]
Feagan BG et al; UNITI–IM-UNITI Study Group. Ustekinumab 
as induction and maintenance therapy for Crohn’s disease. N 
Engl J Med. 2016 Nov 17;375(20):1946–60. [PMID: 27959607]
Jones JL et al. Effects of concomitant immunomodulator therapy 
on efficacy and safety of anti-tumor necrosis factor therapy 
for Crohn’s disease: a meta-analysis of placebo-controlled tri
-
als. Clin Gastroenterol Hepatol. 2015 Dec;13(13):2233–40. 
[PMID: 26142167]
Regueiro M et al; PREVENT Study Group. Infliximab reduces 
endoscopic, but not clinical, recurrence of Crohn’s disease 
after ileocolonic resection. Gastroenterology. 2016 Jun;
 
150(7):1568–78. [PMID: 26946343]
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Vande Casteele N et al. Trough concentrations of infliximab 
guide dosing for patients with inflammatory bowel disease. 
Gastroenterology. 2015 Jun;148(7):1320–9. [PMID: 25724455]
2. Ulcerative Colitis
 
»
Bloody diarrhea.
 
»
Lower abdominal cramps and fecal urgency.
 
»
Anemia, low serum albumin.
 
»
Negative stool cultures.
 
»
Sigmoidoscopy is the key to diagnosis.
 
»
Ulcerative colitis is an idiopathic inflammatory condition 
that involves the mucosal surface of the colon, resulting in 
diffuse friability and erosions with bleeding. Approxi
-
mately one-fourth of patients have disease confined to the 
rectosigmoid region (proctosigmoiditis); one-half have 
disease that extends to the splenic flexure (left-sided colitis); 
and one-fourth have disease that extends more proximally 
(extensive colitis). In patients with distal colitis, the disease 
progresses with time to more extensive involvement in 
25–50%. There is some correlation between disease extent 
and symptom severity. In most patients, the disease is char
-
acterized by periods of symptomatic flare-ups and remis
-
sions. Ulcerative colitis is more common in nonsmokers 
and former smokers. Disease severity may be lower in 
active smokers and may worsen in patients who stop smok
-
ing. Appendectomy before the age of 20 years for acute 
appendicitis is associated with a reduced risk of developing 
ulcerative colitis.
 
»
The clinical profile in ulcerative colitis is highly variable. 
Bloody diarrhea is the hallmark. On the basis of several 
clinical and laboratory parameters, it is clinically useful to 
classify patients as having mild, moderate, or severe disease 
(Table 15–12). Patients should be asked about stool fre
-
quency, the presence and amount of rectal bleeding, 
cramps, abdominal pain, fecal urgency, and tenesmus. 
Physical examination should focus on the patient’s volume 
status as determined by orthostatic blood pressure and 
pulse measurements and by nutritional status. On abdomi
-
nal examination, the clinician should look for tenderness 
and evidence of peritoneal inflammation. Red blood may 
be present on digital rectal examination.
1. Mild to moderate disease—
Patients with mild disease 
have a gradual onset of infrequent diarrhea (less than four 
movements per day) with intermittent rectal bleeding and 
mucus. Stools may be formed or loose in consistency. 
Because of rectal inflammation, there is fecal urgency and 
tenesmus. Left lower quadrant cramps relieved by defeca
-
tion are common, but there is no significant abdominal 
tenderness. Patients with moderate disease have more 
severe diarrhea with frequent bleeding. Abdominal pain 
and tenderness may be present but are not severe. There 
may be mild fever, anemia, and hypoalbuminemia.
2. Severe disease—
Patients with severe disease have more 
than six bloody bowel movements per day, resulting in 
severe anemia, hypovolemia, and impaired nutrition with 
hypoalbuminemia. Abdominal pain and tenderness are 
present. “Fulminant colitis” is a subset of severe disease 
characterized by rapidly worsening symptoms with signs of 
toxicity.
The degree of abnormality of the hematocrit, sedimenta
-
tion rate, and serum albumin reflects disease severity 
(Table 15–12).
In acute colitis, the diagnosis is readily established by sig
-
moidoscopy. The mucosal appearance is characterized by 
edema, friability, mucopus, and erosions. Colonoscopy 
should not be performed in patients with fulminant disease 
because of the risk of perforation. After patients have dem
-
onstrated improvement on therapy, colonoscopy is per
-
formed to determine the extent of disease.
D. Imaging
Plain abdominal radiographs are obtained in patients with 
severe colitis to look for significant colonic dilation. Bar
-

-
D. Imaging
-
ium enemas are of little utility in the evaluation of acute 
ulcerative colitis and may precipitate toxic megacolon in 
patients with severe disease.
 
»
The initial presentation of ulcerative colitis is indistin
-
guishable from other causes of colitis, clinically as well as 
endoscopically. Thus, the diagnosis of idiopathic ulcerative 
Table 15–12.
 
Ulcerative colitis: assessment of disease 
activity.
Mild
Moderate
Severe
Stool frequency 
(per day)
< 4
4–6
> 6 (mostly 
bloody)
Pulse (beats/min)
< 90
90–100
> 100
Hematocrit (%)
Normal
30–40
< 30
Weight loss (%)
None
1–10
> 10
Temperature (°F)
Normal
99–100
> 100
ESR (mm/h)
< 20
20–30
> 30
Albumin (g/dL)
Normal
3–3.5
< 3
ESR, erythrocyte sedimentation rate.
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colitis is reached after excluding other known causes of 
colitis. Infectious colitis should be excluded by sending 
stool specimens for routine bacterial cultures (to exclude 
Salmonella, Shigella
, and 
, as well as specific 
assays for 
E coli
 O157), ova and parasites (to exclude ame
-
biasis), and stool toxin assay for 
 Mucosal biopsy 
can distinguish amebic colitis from ulcerative colitis. CMV 
colitis occurs in immunocompromised patients, including 
patients receiving prolonged corticosteroid therapy, and is 
diagnosed on mucosal biopsy. Gonorrhea, chlamydial 
infection, herpes, and syphilis are considerations in sexu
-
ally active patients with proctitis. In elderly patients with 
cardiovascular disease, ischemic colitis may involve the 
rectosigmoid. A history of radiation to the pelvic region 
can result in proctitis months to years later. Crohn disease 
involving the colon but not the small intestine may be con
-
fused with ulcerative colitis. In 10% of patients, a distinc
-
tion between Crohn disease and ulcerative colitis may not 
be possible.
 
»
Treatment
There are two main treatment objectives: (1) to terminate 
the acute, symptomatic attack and (2) to prevent recur
-
rence of attacks. The treatment of acute ulcerative colitis 
depends on the extent of colonic involvement and the 
severity of illness. Patients with systemic signs of inflam
-
mation (ie, anemia, low serum albumin, elevated C-reactive 
protein or erythrocyte sedimentation rate levels) and deep 
ulcerations with extensive disease on colonoscopy are at 
increased risk for hospitalization or surgery, and early 
aggressive therapy with corticosteroids, immunomodula
-
tors, or biologic agents is warranted.
Patients with mild to moderate disease should eat a 
regular diet but limit their intake of caffeine and gas-
 
producing vegetables. Antidiarrheal agents should not be 
given in the acute phase of illness but are safe and helpful 
in patients with mild chronic symptoms. Oral loperamide 
(2 mg) or diphenoxylate with atropine (one tablet) may be 
given up to four times daily. Such remedies are particularly 
useful at nighttime and when taken prophylactically for 
occasions when patients may not have reliable access to 
toilet facilities.
A. Mild to Moderate Distal Colitis
Patients with disease confined to the rectum or rectosig
-
moid region generally have mild to moderate but distress
-
ing symptoms. Patients may be treated with topical 
mesalamine, topical corticosteroids, or oral aminosalicy
-
lates (5-ASA) according to patient preference and cost 
considerations. Topical mesalamine is the drug of choice 
and is superior to topical corticosteroids and 5-ASA. Mesa
-
lamine is administered as a suppository, 1000 mg once 
daily at bedtime for proctitis, and as an enema, 4 g at bed
-
time for proctosigmoiditis, for 4–8 weeks, with 75% of 
patients improving. Patients who either decline or are 
unable to manage topical therapy may be treated with oral 
5-ASA, as discussed below. Topical corticosteroids are a 
less expensive alternative to mesalamine but are also less 
effective. Hydrocortisone enema or foam (80–100 mg) or 
budesonide foam are prescribed for proctitis or proctosig
-
moiditis. Systemic effects from short-term use are very 
slight. For patients with distal disease who do not improve 
with topical or oral mesalamine therapy, the following 
options may be considered: (1) a combination of a topical 
agent with an oral 5-ASA agent is more effective than 
either drug alone; (2) combination topical therapy with a 
5-ASA suppository or enema at bedtime and a corticoste
-
roid enema or foam in the morning; or (3) a combination 
of oral 5-ASA agent, topical 5-ASA agent, and a topical 
corticosteroid. Patients with distal colitis who are refrac
-
tory to all of these therapies or who have severe disease 
may require treatment with oral prednisone 40–60 mg/day

-
may require treatment with oral prednisone 40–60 mg/day 
or infliximab, as described below.
Most patients with proctitis or proctosigmoiditis who 
achieve complete remission with oral or rectal 5-ASA 
should continue indefinitely on the same therapy to reduce 
the likelihood of symptomatic relapse. Maintenance treat
-
ment with 5-ASA reduces the 12-month relapse rate from 
75% to less than 40%. Some patients, however, may prefer 
intermittent therapy for symptomatic relapse. Topical cor
-
ticosteroids are ineffective for maintaining remission of 
distal colitis.
B. Mild to Moderate Colitis
1. 5-ASA agents—
Disease extending above the sigmoid 
colon is best treated with oral 5-ASA agents (mesalamine, 
balsalazide), which result in symptomatic improvement in 
50–75% of patients. The optimal dose for induction of 
remission of mild disease is 2.4 g once daily and for moder
-
ate disease is 2.4–4.8 g once daily. Most patients improve 
within 4–8 weeks. These agents achieve clinical improve
-
ment in 50–70% of patients and remission in 20–30%. Oral 
sulfasalazine (1.5–2 g twice daily) is comparable in efficacy 
to mesalamine, but it is uncommonly used due to its asso
-
ciated side effects.
Patients with mild to moderate dis
-
ease who do not improve within 4–8 weeks of 5-ASA 
therapy should have corticosteroid therapy added. Predni
-
sone and methylprednisolone are most commonly used. 
Depending on the severity of illness, the initial oral dose of 
prednisone is 40–60 mg daily. Rapid improvement is 
observed in most cases within 2 weeks. Thereafter, tapering 
of prednisone should proceed by 5–10 mg/wk. After taper
-
ing to 20 mg/day, slower tapering (2.5 mg/week) is some
-
times required. Complete tapering without symptomatic 
flare-ups is possible in the majority of patients. Delayed-
release budesonide (Uceris) 9 mg ER orally once daily has 
shown modest benefit in mild to moderate colitis, achiev
-
ing remission in 17.5% of patients after 8 weeks compared 
with 12.5% with placebo. In view of its low incidence of 
corticosteroid-associated side effects, it may be considered 
in patients with mild colitis for whom other systemic cor
-
ticosteroids are deemed high risk.
3. Imm
unomodulating agents—
Approximately 30% of 
patients either do not respond to corticosteroids or have 
symptomatic flares during attempts at corticosteroid 
tapering and develop steroid dependency. Patients with 
steroid dependency may be treated with thiopurines 
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(mercaptopurine or azathioprine), although rigorous con
-
trolled trials are lacking and their absolute benefit appears 
to be modest compared with other alternatives (anti-TNF 
or vedolizumab). In a large 2016 randomized controlled 
study, subcutaneous methotrexate was not superior to pla
-
cebo for induction of corticosteroid-free remission.
The anti-TNF agents infliximab, adalimumab, and goli
-
mumab are approved in the United States for the treatment 
of patients with moderate to severe ulcerative colitis who 
have had an inadequate response to conventional therapies 
(oral corticosteroids, mercaptopurine or azathioprine, and 
mesalamine). Following a three-dose induction regimen of 
infliximab 5 mg/kg administered at 0, 2, and 6 weeks, clini
-
cal response occurs in 65%. In two, large, controlled studies 
of patients with active moderate to severe colitis, initial 
induction therapy was followed by infliximab maintenance 
infusions (5 mg/kg) administered every 8 weeks for 
30–54 weeks. At the end of the study (30 or 54 weeks), 35% 
were in clinical remission (and 21% were in corticosteroid-
free remission), a modest but impressive response in 
patients with more refractory disease. By comparison, 
phase III trials of adalimumab and golimumab reported 
clinical response rates of 50–59% and remission rates of 
16–21% after 8 weeks. Although the response and remission 
rates appear lower with adalimumab and golimumab than 
infliximab, differences in study design and patient popula
-
tions limit comparisons. Importantly, 40% of patients in the 
adalimumab trials were previously treated with other anti-
TNF agents, in whom lower response rates were noted. 
When initiating anti-TNF therapy, it should be combined in 
most patients with an immunomodulator (azathioprine, 
mercaptopurine, or methotrexate) for at least the first year. 
Combination therapy increases the likelihood of disease 
remission and reduces the development of antibodies that 
may result in secondary loss of response to anti-TNF thera
-
pies. After initiating anti-TNF therapy, serum trough levels 
and anti-drug antibody titers should be obtained at least 
once in order to optimize drug dosing.
4. Anti-integrin therapy—
Vedolizumab, a monoclonal 
antibody directed against the alpha
4
beta
7
 heterodimer, is 
FDA-approved for the treatment of moderate to severe 
ulcerative colitis in patients who have not responded to, lost 
response to, or been intolerant of other therapies. In a phase 
III clinical trial of patients with moderate to severe ulcer
-
ative colitis, vedolizumab induction (300 mg intravenously 
at 0, 2, and 6 weeks) led to clinical improvement in 47.1% of 
patients compared with 25.5% who were given placebo. 
Among patients who demonstrated initial clinical improve
-
ment, 41.8% of those given long-term maintenance 
treatment with vedolizumab (300 mg intravenous every 
 
8 weeks) were in clinical remission at 1 year compared with 
15.9% of those given placebo. At present, vedolizumab is 
recommended for treatment of acute cases and mainte
-
nance therapy in patients with moderate to severe ulcerative 
colitis who have not responded to or have lost response to 
anti-TNF therapy or immunomodulator therapy, or both.
5. Probiotics—
VSL#3 (two packets twice daily), a probiotic 
compound containing eight different nonpathogenic strains 
of lactobacilli, bifidobacteria, and streptococci, has 
demonstrated significant benefit versus placebo in the 
treatment of mild to moderate ulcerative colitis in two ran
-
domized, controlled multicenter trials. Although its efficacy 
relative to other agents is unclear, it may be considered as an 
adjunctive therapy for mild to moderate disease.
C. Severe and Fulminant Colitis
About 15% of patients with ulcerative colitis have a more 
severe course. Of these, a small subset has a fulminant 
course with rapid progression of symptoms over 1–2 weeks

course with rapid progression of symptoms over 1–2 weeks 
and signs of severe toxicity. These patients appear quite ill, 
with fever, prominent hypovolemia, hemorrhage requiring 
transfusion, and abdominal distention with tenderness. 
Toxic megacolon develops in less than 2% of cases of ulcer
-
ative colitis. It is characterized by colonic dilation of more 
than 6 cm on plain films with signs of toxicity.
Discontinue all oral intake for 
24–48 hours or until the patient demonstrates clinical 
improvement. TPN is indicated only in patients with poor 
nutritional status or if feedings cannot be reinstituted 
within 7–10 days. All opioid or anticholinergic agents 
should be discontinued. Restore circulating volume with 
fluids, correct electrolyte abnormalities, and consider 
transfusion for significant anemia (hematocrit less than 
25–28%). A plain abdominal radiograph or CT scan should 
be ordered on admission to look for evidence of colonic 
dilation. Send stools for assessment of bacterial pathogens, 
 and parasites, either by conventional bacterial 
culture, 
 toxin assay, and for ova and parasite 
examinations or by rapid, multiplex PCR assay. CMV 
superinfection should be considered in patients receiving 
long-term immunosuppressive therapy who are unrespon
-
sive to corticosteroid therapy. Due to a high risk of venous 
thromboembolic 
(VTE) 
disease, 
VTE 
prophylaxis should 
be administered to all hospitalized patients with inflamma
-
tory bowel disease. Surgical consultation should be sought 
for all patients with severe disease.
Patients with fulminant disease are at higher risk for 
perforation or toxic megacolon and must be monitored 
closely. Abdominal examinations should be repeated to look 
for evidence of worsening distention or pain. Broad-spectrum 
antibiotics should be administered to cover anaerobes and 
gram-negative bacteria. In addition to the therapies outlined 
above, nasogastric suction should be initiated. Patients 
should be instructed to roll from side to side and onto the 
abdomen in an effort to decompress the distended colon. 
Serial abdominal plain films should be obtained to look for 
worsening dilation or signs of ischemia. Patients with fulmi
-
nant disease or toxic megacolon who worsen or do not 
improve within 48–72 hours should undergo surgery to 
prevent perforation. If the operation is performed before 
perforation, the mortality rate should be low.
2. Corticosteroid therapy—
Methylprednisolone, 
48–64 mg, or hydrocortisone, 300 mg, is administered 
intravenously in four divided doses or by continuous infu
-
sion over 24 hours. Higher or “pulse” doses are of no ben
-
efit. Hydrocortisone enemas (100 mg) may also be 
administered twice daily for treatment of urgency or tenes
-
mus. Approximately 50–75% of patients achieve remission 
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with systemic corticosteroids within 7–10 days. Once 
symptomatic improvement has occurred, oral fluids are 
reinstituted. If fluids are well tolerated, intravenous corti
-
costeroids are discontinued and the patient is started on 
oral prednisone (as described for moderate disease). 
Patients without significant improvement within 3–5 days 
of intravenous corticosteroid therapy should be referred 
for surgery or considered for anti-TNF therapies or 
cyclosporine.
3. Anti-TNF therapies—
Infusion of infliximab, 5 mg/kg, 
has been shown in controlled and uncontrolled studies to 
be effective in treating severe colitis in patients who did 
not improve within 4–7 days of intravenous corticosteroid 
therapy. In a controlled study of patients hospitalized for 
ulcerative colitis, colectomy was required within 3 months in 
69% who received placebo therapy, compared with 47% 
who received infliximab. Thus, infliximab therapy should 
be considered in patients with severe ulcerative colitis who 
have not improved with intravenous corticosteroid ther
-
apy. Recent studies have demonstrated more rapid clear
-
ance of infliximab in patients with severe ulcerative 
colitis. Uncontrolled trials have found lower colectomy 
rates in patients administered higher doses of infliximab 
(three infusions of 5–10 mg/kg within 2–3 weeks) than 
with conventional dosing (5 mg/kg at 0, 2, and 6 weeks).
4. Cyclosporine—
Intravenous cyclosporine (2–4 mg/kg/
day as a continuous infusion) benefits 60–75% of patients 
with severe colitis who have not improved after 7–10 days 
of corticosteroids, but it is associated with significant toxic
-
ity (nephrotoxicity, seizures, infection, hypertension). Up 
to two-thirds of responders may be maintained in remis
-
sion with a combination of oral cyclosporine for 3 months 
and long-term therapy with mercaptopurine or azathio
-
prine. A 2011 randomized study of patients with severe 
colitis refractory to intravenous corticosteroids found 
similar response rates (85%) with cyclosporine and inflix
-
imab therapy.
5. Surgical therapy—
Patients with severe disease who do 
not improve after corticosteroid, infliximab, or cyclospo
-
rine therapy are unlikely to respond to further medical 
therapy, and surgery is recommended.
 
»
Risk of Colon Cancer
In patients with ulcerative colitis with disease proximal to 
the rectum and in patients with Crohn colitis, there is an 
increased risk of developing colon carcinoma. Although 
older meta-analyses from referral centers reported a high 
risk (8% after 20 years), more recent systematic reviews of 
population-based studies report a 2.4-fold increased risk 
(1.4% after a mean of 14 years follow up). Retrospective 
studies suggest that the risk of colon cancer may be 
reduced in patients treated with long-term 5-ASA therapy. 
Ingestion of folic acid, 1 mg/day, also is associated with a 
decreased risk of cancer development. Colonoscopies are 
recommended every 1–2 years in patients with colitis, 
beginning 8 years after diagnosis. Several prospective 
studies demonstrate that dye spraying with methylene 
blue or indigo carmine (“chromoendoscopy”) enhances 
the detection of subtle mucosal lesions, thereby signifi
-
cantly increasing the detection of dysplasia compared with 
standard colonoscopy. At colonoscopy, all polypoid and 
nonpolypoid lesions should be resected, when possible, 
and biopsies obtained of endoscopically unresectable 
lesions.
 
»
Surgery in Ulcerative Colitis
Surgery is required in 25% of patients. Severe hemorrhage, 
perforation, and documented carcinoma are absolute indi
-
cations for surgery. Surgery is indicated also in patients 
with fulminant colitis or toxic megacolon that does not 
improve within 48–72 hours, in patients with invisible flat 
dysplasia or non-endoscopically resectable dysplastic 
lesions on surveillance colonoscopy, and in patients with 
refractory disease requiring long-term corticosteroids to 
control symptoms.

Although total proctocolectomy (with placement of an 
ileostomy) provides complete cure of the disease, most 
patients seek to avoid it out of concern for the impact it 
may have on their bowel function, their self-image, and 
their social interactions. After complete colectomy, patients 
may have a standard ileostomy with an external appliance, 
a continent ileostomy, or an internal ileal pouch that is 
anastomosed to the anal canal (ileal pouch–anal anastomo
-
sis). The latter maintains intestinal continuity, thereby 
obviating an ostomy. Under optimal circumstances, 
patients have five to seven loose bowel movements per day 
without incontinence. Endoscopic or histologic inflamma
-
tion in the ileal pouch (“pouchitis”) develops in over 40% 
of patients, resulting in increased stool frequency, fecal 
urgency, cramping, and bleeding, but usually resolves with 
a 2-week course of oral metronidazole (250–500 mg three 
times daily) or ciprofloxacin (500 mg twice daily). Patients 
with frequently relapsing pouchitis may need continuous 
antibiotics. Probiotics containing nonpathogenic strains of 
lactobacilli, bifidobacteria, and streptococci (VSL#3) are 
effective in the maintenance of remission in patients with 
recurrent pouchitis.
 
»
Prognosis
Ulcerative colitis is a lifelong disease characterized by exac
-
erbations and remissions. For most patients, the disease is 
readily controlled by medical therapy without need for 
surgery. The majority never require hospitalization. A sub
-
set of patients with more severe disease will require sur
-
gery, which results in complete cure of the disease. Properly 
managed, most patients with ulcerative colitis lead close to 
normal productive lives.
 
»
•	
Colonoscopy: for evaluation of activity and extent 
 
of active disease and for surveillance for neoplasia 
 
in patients with quiescent disease for more than 
 
8–10 years.
•	
•	
When surgical colectomy is indicated.
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»
•	
Patients with severe disease manifested by frequent 
bloody stools, anemia, weight loss, and fever.
•	
Patients with fulminant disease manifested by rapid 
progression of symptoms, worsening abdominal pain, 
distention, high fever, tachycardia.
•	
Patients with moderate to severe symptoms that do not 
respond to oral corticosteroids and require a trial of 
bowel rest and intravenous corticosteroids.
Beaugerie L et al. Cancers complicating inflammatory bowel 
disease. N Engl J Med. 2015 Apr 9;372(15):1441–52. [PMID: 
25853748]
Bitton A et al; Canadian Association of Gastroenterology Severe 
Ulcerative Colitis Consensus Group. Treatment of hospital
-
ized adult patients with severe ulcerative colitis: Toronto 
consensus statements. Am J Gastroenterol. 2012 
Feb;107(2):179–94. [PMID: 22108451]
Bollegala N et al. Increased postoperative mortality and compli
-
cations among elderly patients with inflammatory bowel dis
-
eases: an analysis of the National Surgical Quality 
Improvement Program Cohort. Clin Gastroenterol Hepatol. 
2016 Sep;14(9):1274–81. [PMID: 26656299]
Brandse JF et al. Pharmacokinetic features and presence of anti
-
drug antibodies associate with response to infliximab induc
-
tion therapy in patients with moderate to severe ulcerative 
colitis. Clin Gastroenterol Hepatol. 2016 Feb;14(2):251–8. 
[PMID: 26545802]
Bressler B et al. Clinical practice guidelines for the medical man
-
agement of nonhospitalized ulcerative colitis: the Toronto 
consensus. Gastroenterology. 2015 May;148(5):1035–58. 
[PMID: 25747596]
Carbonnel F et al. Methotrexate is not superior to placebo for 
inducing steroid-free remission, but induces steroid-free 
clinical remission in a larger proportion of patients with 
ulcerative colitis. Gastroenterology. 2016 Feb;150(2):380–8. 
[PMID: 26632520]
Hindryckx P et al. Review article: dose optimisation of inflix
-
imab for acute severe ulcerative colitis. Aliment Pharmacol 
Ther. 2017 Mar;45(5):617–30. [PMID: 28074618]
Kaltenbach T et al. Endoscopy in inflammatory bowel disease: 
advances in dysplasia detection and management. Gastroin
-
test Endosc. 2017 Dec;86(6):962–71. [PMID: 28987547]
Laine L et al. SCENIC international consensus statement on 
surveillance and management of dysplasia in inflammatory 
bowel disease. Gastrointest Endosc. 2015 Mar;81(3):489–501. 
[PMID: 25708752]
Nguyen GC et al; IBD in Pregnancy Consensus Group; Canadian 
Association of Gastroenterology. The Toronto Consensus 
Statements for the management of inflammatory bowel disease 
in pregnancy. Gastroenterology. 2016 Mar;150(3):734–57. 
[PMID: 26688268]
Sandborn WJ et al. Budesonide foam induces remission in 
patients with mild to moderate ulcerative proctitis and ulcer
-
ative proctosigmoiditis. Gastroenterology. 2015 Apr;
 
148(4):740–50. [PMID: 25644096]
Shah SC et al. Mucosal healing is associated with improved long-
term outcomes of patients with ulcerative colitis: a systematic 
review and meta-analysis. Clin Gastroenterol Hepatol. 2016 
Sep;14(9):1245–56. [PMID: 26829025]
3. Microscopic Colitis
Microscopic colitis is an idiopathic condition that is found 
in up to 15% of patients who have chronic or intermittent 
watery diarrhea with normal-appearing mucosa at endos
-
copy. There are two major subtypes—lymphocytic colitis 
and collagenous colitis. In both, histologic evaluation of 
mucosal biopsies reveals chronic inflammation (lympho
-
cytes, plasma cells) in the lamina propria and increased 
intraepithelial lymphocytes. 
Collagenous colitis
 is further 
characterized by the presence of a thickened band (greater 
than 10 mcm) of subepithelial collagen. Both forms occur 
more commonly in women, especially in the fifth to sixth 
decades. Symptoms tend to be chronic or recurrent but may 
remit in most patients after several years. A more severe 
illness characterized by abdominal pain, fatigue, dehydra
-

-
tion, and weight loss may develop in a subset of patients. 
The cause of 
microscopic colitis
 usually is unknown. Sev
-
eral medications have been implicated as etiologic agents, 
including NSAIDs, proton pump inhibitors, low-dose aspi
-
rin, selective serotonin reuptake inhibitors, ACE inhibitors, 
and beta-blockers. Diarrhea usually abates within 30 days of 
stopping the offending medication. Celiac disease may be 
present in 2–9% of patients and should be excluded with 
serologic testing (anti-tissue transglutaminase IgA). Treat
-
ment is largely empiric since there are few well-designed, 
controlled treatment trials. Antidiarrheal therapy with lop
-
eramide is the first-line treatment, providing symptom 
improvement in up to 70%. For patients who do not 
respond to loperamide, bismuth subsalicylate (three 262-
mg tablets three times daily) leads to complete response 
in up to 50% patients in some series. The next option 
is delayed-release budesonide (Entocort), 9 mg/day for 
6–8 weeks. Budesonide has been shown in three prospec
-
tive controlled studies to induce clinical remission in 
greater than 80% of patients; however, relapse occurs in 
most patients after stopping therapy. Remission is main
-
tained in 75% of patients treated long-term with low doses 
of budesonide. In clinical practice, budesonide is tapered to 
the lowest effective dose for suppressing symptoms (3 mg 
every other day to 6 mg daily). For patients who do not 
respond to budesonide, uncontrolled studies report that 
treatment with bile-salt binding agents (cholestyramine, 
colestipol) or 5-ASAs (sulfasalazine, mesalamine) may be 
effective in some patients. Less than 3% of patients have 
refractory or severe symptoms, which may be treated with 
immunosuppressive agents (azathioprine or methotrexate) 
or anti-TNF agents (infliximab, adalimumab).
Masclee GM et al. Increased risk of microscopic colitis with use 
of proton pump inhibitors and non-steroidal anti-inflamma
-
tory drugs. Am J Gastroenterol. 2015 May;110(5):749–59. 
[PMID: 25916221]
Pardi DS. Diagnosis and management of microscopic colitis. Am 
J Gastroenterol. 2017 Jan;112(1):78–85. [PMID: 27897155]
Tong J et al. Incidence, prevalence, and temporal trends of micro
-
scopic colitis: a systematic review and meta-analysis. Am J 
Gastroenterol. 2015 Feb;110(2):265–76. [PMID: 25623658]
DIVERTICULAR DISEASE OF THE COLON
Colonic diverticulosis increases with age, ranging from 5% 
in those under age 40, to 30% at age 60, to more than 50% 
over age 80 years in Western societies. Most are asymptom
-
atic, discovered incidentally at endoscopy or on barium 
enema. Complications occur in less than 5%, including 
gastrointestinal bleeding and diverticulitis.
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Colonic diverticula may vary in size from a few milli
-
meters to several centimeters and in number from one to 
several dozen. Almost all patients with diverticulosis have 
involvement in the sigmoid and descending colon; how
-
ever, only 15% have proximal colonic disease.
For over 40 years, it has been believed that diverticulo
-
sis arises after many years of a diet deficient in fiber. Recent 
epidemiologic studies challenge this theory, finding no 
association between the prevalence of asymptomatic diver
-
ticulosis and low dietary fiber intake or constipation. Thus, 
the etiology of diverticulosis is uncertain. The extent to 
which abnormal motility and hereditary factors contribute 
to diverticular disease is unknown. Patients with abnormal 
connective tissue are also disposed to development of 
diverticulosis, including Ehlers-Danlos syndrome, Marfan 
syndrome, and scleroderma.
1. Uncomplicated Diverticulosis
More than 90% of patients with diverticulosis have uncom
-
plicated disease and no specific symptoms. In most, diver
-
ticulosis is an incidental finding detected during 
colonoscopic examination or barium enema examination. 
Some patients have nonspecific complaints of chronic con
-
stipation, abdominal pain, or fluctuating bowel habits. It is 
unclear whether these symptoms are due to alterations in 
the colonic motility, visceral hypersensitivity, gut microbi
-
ota, or low-grade inflammation. Physical examination is 
usually normal but may reveal mild left lower quadrant 
tenderness with a thickened, palpable sigmoid and 
descending colon. Screening laboratory studies should be 
normal in uncomplicated diverticulosis.
There is no reason to perform imaging studies for the 
purpose of diagnosing asymptomatic, uncomplicated dis
-
ease. Diverticula are well seen on barium enema, colonos
-
copy and CT imaging. Involved segments of colon may also 
be narrowed and deformed.
Patients in whom diverticulosis is discovered, especially 
patients with symptoms or a history of complicated disease 
should be treated with a high-fiber diet or fiber supple
-
ments (bran powder, 1–2 tbsp twice daily; psyllium or 
methylcellulose) (see section on constipation).
Peery AF et al. Distribution and characteristics of colonic diver
-
ticula in a United States screening population. Clin Gastroen
-
terol Hepatol. 2016 Jul;14(7):980–5. [PMID: 26872402]
2. Diverticulitis
 
»
Acute abdominal pain and fever.
 
»
Left lower abdominal tenderness and mass.
 
»
Leukocytosis.
 
»
Diverticulitis is defined as macroscopic inflammation of a 
diverticulum that may reflect a spectrum from inflamma
-
tion alone, to microperforation with localized paracolic 
inflammation, to macroperforation with either abscess or 
generalized peritonitis. Thus, there is a range from mild to 
severe disease. Most patients with localized inflammation 
or infection report mild to moderate aching abdominal 
pain, usually in the left lower quadrant. Constipation or 
loose stools may be present. Nausea and vomiting are fre
-
quent. In many cases, symptoms are so mild that the 
patient may not seek medical attention until several days 
after onset. Physical findings include a low-grade fever, left 
lower quadrant tenderness, and a palpable mass. Stool 
occult blood is common, but hematochezia is rare. Leuko
-
cytosis is mild to moderate. Patients with free perforation 
present with a more dramatic picture of generalized 
abdominal pain and peritoneal signs.
B. Imaging
In patients with mild symptoms and a presumptive diag
-
nosis of diverticulitis, empiric medical therapy is started 
without further imaging in the acute phase. Patients who 
respond to acute medical management should undergo 
complete colonic evaluation with colonoscopy or radio
-
logic imaging (CT colonography or barium enema) after 
resolution of clinical symptoms to corroborate the diag
-

-
-
nosis or exclude other disorders such as colonic neo
-
plasms. In patients who do not improve rapidly after 
2–4 days of empiric therapy and in those with severe 
disease, CT scan of the abdomen is obtained to look for 
evidence of diverticulitis and determine its severity, and 
to exclude other disorders that may cause lower abdomi
-
nal pain. The presence of colonic diverticula and wall 
thickening, pericolic fat infiltration, abscess formation, 
or extraluminal air or contrast suggests diverticulitis. 
Endoscopy and colonography are contraindicated during 
the initial stages of an acute attack because of the risk of 
free perforation.
 
»
Diverticulitis must be distinguished from other causes of 
lower abdominal pain, including perforated colonic car
-
cinoma, Crohn disease, appendicitis, ischemic colitis, 
 
–associated colitis, and gynecologic disorders 
(ectopic pregnancy, ovarian cyst or torsion) by abdominal 
CT scan, pelvic ultrasonography, or radiographic studies of 
the distal colon that use water-soluble contrast enemas.
 
»
Two 2017 prospective cohort studies reported a lower risk 
of diverticulitis in men consuming diets high in fruits, 
vegetables, and whole grains than diets high in red meat 
and refined grains.
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»
Chronic inflammation or an untreated abscess may lead to 
fistula formation that may involve the bladder, ureter, 
vagina, uterus, bowel, and abdominal wall. Acute or 
chronic inflammation may result in stricturing of the colon 
with partial or complete obstruction.
 
»
Treatment
A. Medical Management
Most patients can be managed with conservative measures. 
Patients with mild symptoms and no peritoneal signs may 
be managed initially as outpatients on a clear liquid diet. 
Although broad-spectrum oral antibiotics with anaerobic 
activity commonly are prescribed, large clinical trials con
-
firm that antibiotics are not beneficial in uncomplicated 
disease. A 2015 American Gastroenterological Association 
guideline suggests that antibiotics should be used selectively 
for uncomplicated disease. Reasonable regimens include 
amoxicillin and clavulanate potassium (875 mg/125 mg) 
twice daily; or metronidazole, 500 mg three times daily; plus 
either ciprofloxacin, 500 mg twice daily, or trimethoprim-
sulfamethoxazole, 160/800 mg twice daily orally, for 
7–10 days or until the patient is afebrile for 3–5 days. 
Symptomatic improvement usually occurs within 3 days, at 
which time the diet may be advanced. Once the acute epi
-
sode has resolved, a high-fiber diet is often recommended. 
Patients with increasing pain, fever, or inability to tolerate 
oral fluids require hospitalization. Patients with severe 
diverticulitis (high fevers, leukocytosis, or peritoneal signs) 
and patients who are elderly or immunosuppressed or who 
have serious comorbid disease require hospitalization 
acutely. Patients should be given nothing by mouth and 
should receive intravenous fluids. If ileus is present, a naso
-
gastric tube should be placed. Intravenous antibiotics should 
be given to cover anaerobic and gram-negative bacteria. 
Single-agent therapy with either a second-generation cepha
-
losporin (eg, cefoxitin), piperacillin-tazobactam, or ticarcillin 
clavulanate appears to be as effective as combination therapy 
(eg, metronidazole or clindamycin plus an aminoglycoside 
or third-generation cephalosporin [eg, ceftazidime, cefo
-
taxime]). Symptomatic improvement should be evident 
within 2–3 days. Intravenous antibiotics should be continued 
for 5–7 days, before changing to oral antibiotics.
B. Surgical Management
Surgical consultation and repeat abdominal CT imaging 
should be obtained on all patients with severe disease or 
those who do not improve after 72 hours of medical man
-
agement. Patients with a localized abdominal abscess 4 cm 
in size or larger are usually treated urgently with a percuta
-
neous catheter drain placed by an interventional radiologist. 
This permits control of the infection and resolution of the 
immediate infectious inflammatory process. In this man
-
ner, a subsequent elective one-stage surgical operation can 
be performed (if deemed necessary) in which the diseased 
segment of colon is removed and primary colonic 
anastomosis performed. After recovery, the decision to 
perform elective surgery depends on the patient’s age, 
comorbid disease, and frequency and severity of attacks. 
Patients with chronic disease resulting in fistulas or colonic 
obstruction will require elective surgical resection.
Indications for emergent surgical management include 
generalized peritonitis, large undrainable abscesses, and 
clinical deterioration despite medical management and 
percutaneous drainage. Surgery may be performed in one- 
or two-stage operations depending on the patient’s nutri
-
tional status, severity of illness, and extent of intra-abdominal 
peritonitis and abscess formation.
 
»
Prognosis
Diverticulitis recurs in 15–30% of patients treated with 
medical management over 10–20 years. However, less than 
5% have more than two recurrences. Recurrent mild attacks 
may warrant elective surgical resection in selected patients,

may warrant elective surgical resection in selected patients, 
especially those who have multiple attacks or those in 
whom chronic symptoms develop. Diverticulosis is not 
associated with an increased risk of colorectal cancer. None
-
theless, colorectal cancer may cause symptoms that may be 
confused with diverticulitis. Therefore, colonoscopy is rec
-
ommended in patients over age 50 who have not undergone 
appropriate screening and should be considered in other 
high-risk patients, especially those with suspicious radio
-
logic imaging, diverticulitis with complications or pro
-
tracted symptoms, or family history of colorectal cancer.
 
»
•	
Failure to improve within 72 hours of medical 
management. 
•	
Presence of significant peridiverticular abscesses (4 cm 
or larger) requiring possible percutaneous or surgical 
drainage.
•	
Generalized peritonitis or sepsis.
•	
Recurrent attacks.
•	
Chronic complications, including colonic strictures or 
fistulas.
 
»
•	
Severe pain or inability to tolerate oral intake.
•	
Signs of sepsis or peritonitis.
•	
CT scan showing signs of complicated disease (abscess, 
perforation, obstruction).
•	
Failure to improve with outpatient management.
•	
Immunocompromised or frail, elderly patient.
Andeweg CS et al. A Markov decision model to guide treatment 
of recurrent colonic diverticulitis. Clin Gastroenterol Hepatol. 
2016 Jan;14(1):87–95. [PMID: 25766651]
Andeweg CS et al. Patient-reported outcomes after conservative 
or surgical management of recurrent and chronic complaints 
of diverticulitis: systematic review and meta-analysis. Clin 
Gastroenterol Hepatol. 2016 Feb;14(2):183–90. [PMID: 
26305068]
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Deery SE et al. Management of diverticulitis in 2017. J Gastroin
-
test Surg. 2017 Oct;21(10):1732–41. [PMID: 28547631]
Liu PH et al. Adherence to a healthy lifestyle is associated with a 
lower risk of diverticulitis among men. Am J Gastroenterol. 
2017 Dec;112(12):1868–76. [PMID: 29112202]
Stollman N et al. American Gastroenterological Association 
Institute Guideline on the management of acute diverticulitis. 
Gastroenterology. 2015 Dec;149(7):1944–9. [PMID: 26453777]
Strate L et al. Western dietary pattern increases, and prudent 
dietary pattern decreases, risk of incident diverticulitis in a 
prospective cohort study. Gastroenterology. 2017 Apr;
 
152(5):1023–30. [PMID: 28065788]
3. Diverticular Bleeding
Half of all cases of acute lower gastrointestinal bleeding 
are attributable to diverticulosis. For a full discussion, see 
the section on Acute Lower Gastrointestinal Bleeding, 
above.
POLYPS OF THE COLON
Polyps are discrete mass lesions that protrude into the 
intestinal lumen. Although most commonly sporadic, 
they may be inherited as part of a familial polyposis syn
-
drome. Polyps may be divided into four major pathologic 
groups: mucosal adenomatous polyps (tubular, tubulovil
-
lous, and villous), mucosal serrated polyps (hyperplastic, 
sessile serrated polyps, and traditional serrated ade
-
noma), mucosal nonneoplastic polyps (juvenile polyps, 
hamartomas, inflammatory polyps), and submucosal 
lesions (lipomas, lymphoid aggregates, carcinoids, pneu
-
matosis cystoides intestinalis). Of polyps removed at 
colonoscopy, over 70% are adenomatous; most of the 
remainder are serrated. Adenomatous polyps and ser
-
rated polyps have significant clinical implications and will 
be considered further below.
NONFAMILIAL ADENOMATOUS 
 
& SERRATED POLYPS
Adenomas and serrated polyps may be non-polypoid 
(flat, slightly elevated, or depressed), sessile, or peduncu
-
lated (containing a stalk). They are present in 30% of 
adults over 50 years of age. Their significance is that over 
95% of cases of adenocarcinoma of the colon are believed 
to arise from these lesions. It is proposed that there is a 
polyp 
→
 carcinoma sequence whereby nonfamilial 
colorectal cancer develops through a continuous process 
from normal mucosa to adenomatous or serrated polyp to 
carcinoma. The majority of cancers arise in adenomas 
after inactivation of the 
APC
 gene leads to chromosomal 
instability and inactivation or loss of other tumor sup
-
pressor genes. By contrast, cancers arising in the serrated 
pathway appear to have either 
Kras
 (traditional serrated 
adenomas) mutations or 
BRAF
 oncogene activation (ses
-
sile serrated adenomas) with methylation of CpG-rich 
promoter regions that leads to inactivation of tumor sup
-
pressor genes or mismatch repair genes (
MLH1
) with 
microsatellite instability.
Most adenomas are smaller than 1 cm and have a low 
risk of becoming malignant; less than 5% of these enlarge 
with time. Adenomas and serrated polyps are classified as 
“advanced” if they are 1 cm or larger, or contain villous 
features or high-grade dysplasia. Advanced lesions are 
believed to have a higher risk of harboring or progressing 
to malignancy. It has been estimated from longitudinal 
studies that it takes an average of 5 years for a medium-
sized polyp to develop from normal-appearing mucosa and 
10 years for a gross cancer to arise. The prevalence of 
advanced adenomas is 6% and colorectal cancer 0.3%.
Most sessile serrated polyps and traditional serrated 
adenomas are believed to arise from hyperplastic polyps. It 
is believed that sessile serrated polyps and traditional ser
-
rated adenomas harbor an increased risk of colorectal 
cancer similar or greater to that of adenomas. Many 
pathologists cannot reliably distinguish between hyper
-
plastic polyps and sessile serrated polyps. Hyperplastic 
polyps smaller than 5 mm located in the rectosigmoid

-
polyps smaller than 5 mm located in the rectosigmoid 
region are of no consequence, except that they cannot reli
-
ably be distinguished from adenomatous lesions other than 
by biopsy. Hyperplastic polyps located in the proximal 
colon (ie, proximal to the splenic flexure) are associated 
with an increased risk of neoplasia, particularly those 
larger than 1 cm.
 
»
Most patients with adenomatous and serrated polyps are 
completely asymptomatic. Chronic occult blood loss may 
lead to iron deficiency anemia. Large polyps may ulcerate, 
resulting in intermittent hematochezia.
B. Fecal Occult Blood or Multitarget DNA Tests
FOBT, FIT, and fecal DNA tests are available as part of 
colorectal cancer screening programs (see Chapter 39). FIT 
is a fecal immunochemical test for hemoglobin with a sin
-
gle specimen having a sensitivity of approximately 80% for 
colorectal cancer and 20–30% for advanced adenomas but 
a much lower sensitivity for serrated lesions. FIT is more 
sensitive than guaiac-based tests for the detection of 
colorectal cancer and advanced adenomas. In 2014, a test 
combining a fecal DNA test with a fecal immunochemical 
test for stool hemoglobin (under the proprietary name 
“Cologuard”) was approved by the FDA. In a prospective 
comparative trial conducted in persons at average risk for 
colorectal cancer undergoing colonoscopy, the sensitivity 
for colorectal cancer for Cologuard was 92.3% compared to 
73.8% for FIT and the sensitivity for large (greater than 
1 cm) adenomas or serrated polyps for Cologuard was 
42.4% compared to 23.8% for FIT.
C. Radiologic Tests
Polyps can be identified by means of barium enema exami
-
nations or CT colonography. Both studies require bowel 
cleansing with laxatives before the study and insertion of a 
rectal catheter for air insufflation during the study. CT 
colonography (“virtual colonoscopy”) uses data from heli
-
cal CT imaging with computer-enabled luminal image 
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reconstruction to generate two-dimensional and three-
dimensional images of the colon. Using optimal imaging 
software with multidetector helical CT scanners, several 
studies report a sensitivity of 90% or more for the detection 
of polyps larger than 10 mm in size. However, the accuracy 
for detection of polyps 5–9 mm in size is significantly lower 
(sensitivity 50%). A small proportion of these diminutive 
polyps harbor advanced histology (up to 1.2%) or carci
-
noma (less than 1%). Abdominal CT imaging also results 
in a radiation exposure that may lead to a small risk of 
cancer. Barium enema is no longer recommended due to its 
poor diagnostic accuracy.
D. Endoscopic Tests
Colonoscopy allows evaluation of the entire colon and is 
the best means of detecting and removing adenomatous 
and serrated polyps. It should be performed in all patients 
who have positive FOBT, FIT, or fecal DNA tests or iron 
deficiency anemia (see Occult Gastrointestinal Bleeding 
above), as the prevalence of colonic neoplasms is increased 
in these patients. Colonoscopy should also be performed 
in patients with polyps detected on radiologic imaging 
studies (CT colonography or barium enema) or adenomas 
detected on flexible sigmoidoscopy to remove these polyps 
and to fully evaluate the entire colon. The newest genera
-
tion of capsule endoscopy of the colon has an 86% sensi
-
tivity and 88% specificity for detection of adenomas 
greater than 6 mm compared with colonoscopy, but only 
29% sensitivity and 33% specificity for sessile serrated 
polyps. The bowel preparation required for the colon cap
-
sule study is more extensive than for colonoscopy and 
10–30% of studies may be inadequate due to poor bowel 
preparation or failure to excrete the capsule. At this time, 
colonoscopy remains the best test in most patients to 
detect colorectal polyps. However, capsule endoscopy may 
be considered in patients who are unsuitable or unwilling 
to undergo colonoscopy or who have an incomplete 
colonoscopy.
 
»
Treatment
A. Colonoscopic Polypectomy
Most adenomatous and serrated polyps are amenable to 
colonoscopic removal with biopsy forceps or snare cautery. 
Sessile polyps larger than 2–3 cm may be removed by snare 
cautery using a variety of techniques (eg, piecemeal or 
saline-lift assisted mucosal resection) or may require surgi
-
cal resection. Patients with large sessile polyps removed in 
piecemeal fashion should undergo repeated colonoscopy in 
2–6 months to verify complete polyp removal. Complica
-
tions after colonoscopic polypectomy include perforation 
in 0.2% and clinically significant bleeding in 0.3–1% of 
patients.
B. Postpolypectomy Surveillance
Adenomas and serrated polyps can be found in 30–40% 
of patients when another colonoscopy is performed 
within 3–5 years after the initial examination and polyp 
removal. Periodic colonoscopic surveillance is therefore 
recommended to detect these “metachronous” lesions, 
which either may be new or may have been overlooked 
during the initial examination. Most of these polyps are 
small, without high-risk features and of little immediate 
clinical significance. The probability of detecting advanced 
neoplasms at surveillance colonoscopy depends on the 
number, size, and histologic features of the polyps removed 
on initial (index) colonoscopy. Patients with 1–2 tubular 
adenomas smaller than 1 cm (without villous features or 
high-grade dysplasia) should have their next colonoscopy 
in 5–10 years. Patients with 3–10 adenomas, an adenoma 
larger than 1 cm, or an adenoma with villous features or 
high-grade dysplasia should have their next colonoscopy at 
3 years. Patients with more than 10 adenomas should have 
a repeat colonoscopy at 1–2 years and may be considered 
for evaluation for a familial polyposis syndrome. Surveil
-
lance colonoscopy at 5 years is appropriate for patients with 
small (less than 1 cm) serrated polyps without cytologic

-
small (less than 1 cm) serrated polyps without cytologic 
dysplasia; surveillance colonoscopy at 3 years should be 
considered for serrated polyps larger than 1 cm and those 
with cytologic atypia. No surveillance is recommended for 
patients with small, typical hyperplastic polyps located in 
the distal colon and rectum.
Lieberman D et al. Management of diminutive colon polyps 
based on endoluminal imaging. Clin Gastroenterol Hepatol. 
2015 Nov;13(11):1860–6. [PMID: 26192139]
Payne SR et al. Endoscopic detection of proximal serrated lesions 
and pathologic identification of sessile serrated adenomas/
polyps vary on the basis of center. Clin Gastroenterol Hepatol. 
2014 Jul;12(7):1119–26. [PMID: 24333512]
Rex DK et al. The colonoscopist’s guide to the vocabulary of 
colorectal neoplasia: histology, morphology, and manage
-
ment. Gastrointest Endosc. 2017 Aug;86(2):253–63. [PMID: 
28396276]
Robertson DJ et al. Recommendations on fecal immunochemi
-
cal testing to screen for colorectal neoplasia: a consensus 
statement by the US Multi-Society Task Force on colorectal 
cancer. Gastrointest Endosc. 2017 Jan;85(1):2–21. [PMID: 
27769516]
Spada C et al. Accuracy of first- and second-generation colon 
capsules in endoscopic detection of colorectal polyps: a sys
-
tematic review and meta-analysis. Clin Gastroenterol Hepatol. 
2016 Nov;14(11):1533–43. [PMID: 27165469]
HEREDITARY COLORECTAL CANCER & 
POLYPOSIS SYNDROMES
Up to 4% of all colorectal cancers are caused by germline 
genetic mutations that impose on carriers a high lifetime 
risk of developing colorectal cancer (see Chapter 39). 
Because the diagnosis of these disorders has important 
implications for treatment of affected members and for 
screening of family members, it is important to consider 
these disorders in patients with a family history of colorec
-
tal cancer that has affected more than one family member, 
those with a personal or family history of colorectal cancer 
developing at an early age (50 years or younger), those with 
a personal or family history of multiple polyps (more than 
20), and those with a personal or family history of multiple 
extracolonic malignancies.
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1. Familial Adenomatous Polyposis
 
»
Inherited condition characterized by early devel
-
opment of hundreds to thousands of colonic 
adenomatous polyps and even one or more ade
-
nocarcinoma (s).
 
»
Variety of extracolonic manifestations, including 
duodenal adenomas, desmoid tumors, and 
osteomas.
 
»
Attenuated variant with fewer than 500 (average 25) 
colonic adenomas.
 
»
Genetic testing confirms mutation of 
APC
 gene 
(90%) or 
MUTYH
 gene (8%).
 
»
Prophylactic colectomy recommended to pre
-
vent otherwise inevitable colorectal cancer 
(adenocarcinoma).
 
»
Familial adenomatous polyposis (FAP) is a syndrome 
affecting 1:10,000 people and accounts for approximately 
0.5% of colorectal cancer. The classic form of FAP is char
-
acterized by the development of hundreds to thousands of 
colonic adenomatous polyps and a variety of extracolonic 
manifestations. Of patients with classic FAP , approximately 
90% have a mutation in the 
APC
 gene that is inherited in 
an autosomal dominant fashion and 8% have mutations in 
the 
MUTYH
 gene that are inherited in an autosomal reces
-
sive fashion. FAP arises de novo in 15% of patients in the 
absence of genetic mutations in the parents. An attenuated 
variant of FAP also has been recognized in which an aver
-
age of only 25 polyps (range of 1–500) develop.
 
»
Colorectal polyps develop by a mean age of 15 years and 
cancer at 40 years. Unless prophylactic colectomy is per
-
formed, colorectal cancer is inevitable by age 50 years. In 
attenuated FAP , the mean age for development of cancer is 
about 56 years.
Adenomatous polyps of the duodenum and periampul
-
lary area develop in over 90% of patients, resulting in a 
5–8% lifetime risk of adenocarcinoma. Adenomas occur 
less frequently in the gastric antrum and small bowel and, 
in those locations, have a lower risk of malignant transfor
-
mation. Gastric fundus gland polyps occur in over 50% but 
have an extremely low (0.6%) malignant potential.
A variety of other benign extraintestinal manifestations, 
including soft tissue tumors of the skin, desmoid tumors, 
osteomas, and congenital hypertrophy of the retinal pig
-
ment, develop in some patients with FAP . These extraint
-
estinal manifestations vary among families, depending in 
part on the type or site of mutation in the 
APC
 gene. 
Desmoid tumors are locally invasive fibromas, most com
-
monly intra-abdominal, that may cause bowel obstruction, 
ischemia, or hemorrhage. They occur in 15% of patients 
and are the second leading cause of death in FAP . Malig
-
nancies of the central nervous system (Turcot syndrome) 
and tumors of the thyroid and liver (hepatoblastomas) may 
also develop in patients with FAP .
B. Genetic Testing
Genetic counseling and testing should be offered to patients 
found to have multiple adenomatous polyps at endoscopy 
and to first-degree family members of patients with FAP . 
Genetic testing is best performed by sequencing the 
APC
 
gene to identify disease-associated mutations followed by 
MUTYH
 mutational assessment in patients with no 
detectable 
APC
 mutations. 
APC
 gene mutations are identi
-
fied in 80% of patients with more than 1000, and 56% with 
100–1000 polyps (ie, the classic phenotype of FAP). Recent 
guidelines also recommend that genetic testing be consid
-
ered in individuals with as few as 10 adenomas to exclude 
a diagnosis of attenuated disease. 
APC
 or 
MUTYH
 muta
-
tions are found in 10% and 7%, respectively, of patients 
with 20–100 adenomas and 5% and 4%, respectively, of 
those with 10–19 adenomas.
 
»
Treatment
Once the diagnosis has been established, complete procto
-
colectomy with ileoanal anastomosis or colectomy with 
ileorectal anastomosis is recommended, usually before age 
20 years. Ileorectal anastomosis affords superior bowel 
function but has a 5% risk of development of rectal cancer,

function but has a 5% risk of development of rectal cancer, 
and for that reason frequent sigmoidoscopy with fulgura
-
tion of polyps is required. Upper endoscopic evaluation of 
the stomach, duodenum, and periampullary area should be 
performed every 1–3 years to look for adenomas or carci
-
noma. Periampullary adenomas larger than 2 cm require 
surgical resection. Sulindac and celecoxib have been shown 
to decrease the number and size of polyps in the rectal 
stump but not the duodenum.
Buecher B. Colorectal adenomatous polyposis syndromes: 
genetic determinism, clinical presentation and recommenda
-
tions for care. Bull Cancer. 2016 Feb;103(2):199–209. [PMID: 
26805944]
Kanth P et al. Hereditary colorectal polyposis and cancer syn
-
dromes: a primer on diagnosis and management. Am J Gas
-
troenterol. 2017 Oct;112(10):1509–25. [PMID: 28786406]
Stoffel EM et al. Familial colorectal cancer, beyond Lynch syn
-
drome. Clin Gastroenterol Hepatol. 2014 Jul;12(7):1059–68. 
[PMID: 23962553]
2. 
h
amartomatous Polyposis Syndromes
Hamartomatous polyposis syndromes are rare and account 
for less than 0.1% of colorectal cancers.
Peutz-Jeghers syndrome
condition characterized by hamartomatous polyps through
-
out the gastrointestinal tract (most notably in the small 
intestine) as well as mucocutaneous pigmented macules on 
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the lips, buccal mucosa, and skin. The hamartomas may 
become large, leading to bleeding, intussusception, or 
obstruction. Although hamartomas are not malignant, gas
-
trointestinal malignancies (stomach, small bowel, and 
colon) develop in 40–60%, breast cancer in 30–50%, as well 
as a host of other malignancies of nonintestinal organs 
(gonads, pancreas). The defect has been localized to the 
serine threonine kinase 11 gene, and genetic testing is 
Familial juvenile polyposis
 is also autosomal domi
-
nant and is characterized by multiple (more than ten) 
juvenile hamartomatous polyps located most commonly in 
the colon. There is an increased risk (up to 50%) of adeno
-
carcinoma due to synchronous adenomatous polyps or 
mixed hamartomatous-adenomatous polyps. Genetic 
defects have been identified to loci on 18q and 10q 
(
MADH4
 and 
BMPR1A)
. Genetic testing is available.
PTEN multiple hamartoma syndrome (Cowden dis
-
ease)
 is characterized by hamartomatous polyps and 
lipomas throughout the gastrointestinal tract, trichilem
-
momas, and cerebellar lesions. An increased rate of 
malignancy is demonstrated in the thyroid, breast, and 
urogenital tract.
Jelsig AM et al. Disease pattern in Danish patients with Peutz-
Jeghers syndrome. Int J Colorectal Dis. 2016 May;31(5):
 
997–1004. [PMID: 26979979]
-
Syngal S et al; American College of Gastroenterology. ACG clini
-
cal guideline: genetic testing and management of hereditary 
gastrointestinal cancer syndromes. Am J Gastroenterol. 
 
2015 Feb;110(2):223–62. [PMID: 25645574]
3. Lynch Syndrome
 
»
Autosomal dominant inherited condition.
 
»
Caused by mutations in a gene that detects and 
repairs DNA base-pair mismatches, resulting in 
DNA microsatellite instability and inactivation of 
tumor suppressor genes.
 
»
Increased lifetime risk of colorectal cancer (22–
75%), endometrial cancer (30–60%), and other 
cancers that may develop at young age.
 
»
Evaluation warranted in patients with personal 
history of early-onset colorectal cancer or family 
history of colorectal, endometrial, or other Lynch 
syndrome–related cancers at young age or in mul
-
tiple members.
 
»
Diagnosis suspected by tumor tissue immunohis
-
tochemical staining for mismatch repair proteins 
or testing for microsatellite instability.
 
»
Diagnosis confirmed by genetic testing.
 
»
Lynch syndrome (also known as hereditary nonpolyposis 
colon cancer [HNPCC]) is an autosomal dominant condi
-
tion in which there is a markedly increased risk of develop
-
ing colorectal cancer as well as a host of other cancers, 
including endometrial, ovarian, renal or bladder, hepatobi
-
liary, gastric, and small intestinal cancers. It is estimated to 
account for up to 3% of all colorectal cancers. Affected 
individuals have a 22–75% lifetime risk of developing 
colorectal carcinoma and a 30–60% lifetime risk of endo
-
metrial cancer, depending on the affected gene. Unlike 
individuals with familial adenomatous polyposis, patients 
with Lynch syndrome develop only a few adenomas, which 
may be flat and more often contain villous features or high-
grade dysplasia. In contrast to the traditional polyp 
→
 
cancer progression (which may take over 10 years), these 
polyps are believed to undergo rapid transformation over 
1–2 years from normal tissue 
→
 adenoma 
→
 cancer. Colon 
and endometrial cancer tend to develop at an earlier age 
than sporadic, nonhereditary cancers (mean age 45–50 years). 
Compared with patients with sporadic tumors of similar 
pathologic stage, those with Lynch syndrome tumors have 
improved survival. Synchronous or metachronous cancers 
occur within 10 years in up to 45% of patients.
Lynch syndrome is caused by a defect in one of several

Lynch syndrome is caused by a defect in one of several 
genes that are important in the detection and repair of 
DNA base-pair mismatches: 
MLH1, MSH2, MSH6, 
and
 
PMS2.
 Germline mutations in 
MLH1
 and 
MSH2
 account 
for almost 90% of the known mutations in families with 
Lynch syndrome. Mutations in any of these mismatch 
repair genes result in a characteristic phenotypic DNA 
abnormality known as microsatellite instability.
 
»
A thorough family cancer history is essential to identify 
families that may be affected by the Lynch syndrome so 
that appropriate genetic and colonoscopic screening can be 
offered. Owing to the limitations of genetic testing and the 
medical, psychological, and social implications that such 
testing may have, families should be evaluated first by a 
genetic counselor and give informed consent before genetic 
testing is performed.
Patients whose families meet any of the revised 
“Bethesda criteria” have an increased likelihood of harbor
-
ing a germline mutation in one of the mismatch repair 
genes and should be considered for genetic testing. The 
“Bethesda criteria” are (1) colorectal cancer under age 50; 
(2) synchronous or metachronous colorectal or Lynch syn
-
drome–associated tumor regardless of age (endometrial, 
stomach, ovary, pancreas, ureter and renal pelvis, biliary 
tract, brain); (3) colorectal cancer with one or more first-
degree relatives with colorectal or Lynch syndrome–related 
cancer, with one of the cancers occurring before age 50; (4) 
colorectal cancer with two or more second-degree relatives 
with colorectal or Lynch syndrome–related cancer, regard
-
less of age; (5) tumors with infiltrating lymphocytes, muci
-
nous/signet ring differentiation, or medullary growth 
pattern in patients younger than 60 years.
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The Bethesda criteria identify approximately 70% of 
mutation-positive Lynch syndrome families but overlook 
30%. For this reason, the 2014 U.S. Multi-Society Task 
Force consensus guidelines  recommend that 
all
 colorectal 
cancers should undergo testing for Lynch syndrome with 
either immunohistochemistry or microsatellite instability. 
Universal testing has the greatest sensitivity for the diagno
-
sis of Lynch syndrome and is cost-effective. Individuals 
whose tumors have normal immunohistochemical staining 
or do not have microsatellite instability are unlikely to have 
germline mutations in mismatch repair genes, do not 
require further genetic testing, and do not require intensive 
cancer surveillance. Up to 15% of sporadic (noninherited) 
tumors have microsatellite instability or absent 
MLH1
 
staining due to somatic (noninherited) methylation of the 
MLH1
 gene promoter and somatic 
BRAF
 mutations, which 
must be excluded before further genetic testing is consid
-
ered. Germline testing for gene mutations is positive in 
more than 90% of individuals whose tumors show absent 
histochemical staining of one of the mismatch repair genes 
or high level of microsatellite instability without a 
BRAF
 
mutation. Germline testing is also warranted in families 
with a strong history consistent with Lynch syndrome 
when tumors from affected members are unavailable for 
assessment. If a mutation is detected in a patient with can
-
cer in one of the known mismatch genes, genetic testing of 
other first-degree family members is indicated.
 
»
Screening & Treatment
If genetic testing documents a Lynch syndrome gene muta
-
tion, affected relatives should be screened with colonos
-
copy every 1–2 years beginning at age 25 (or at age 5 years 
younger than the age at diagnosis of the youngest affected 
family member). If cancer is found, subtotal colectomy 
with ileorectal anastomosis (followed by annual surveil
-
lance of the rectal stump) should be performed. Women 
should undergo screening for endometrial and ovarian 
cancer beginning at age 30–35 years with pelvic examina
-
tion, transvaginal ultrasound, and endometrial sampling. 
Prophylactic hysterectomy and oophorectomy is recom
-
mended to women at age 40 or once they have finished 
childbearing. Screening for gastric cancer with upper 
endoscopy should be considered every 2–3 years beginning 
at age 30–35 years.
Dubé C et al. Risk of advanced adenoma, colorectal cancer, and 
colorectal cancer mortality in people with low-risk adenomas 
at baseline colonoscopy: a systematic review and meta-analysis. 
Am J Gastroenterol. 2017 Dec;112(12):1790–801. [PMID: 
29087393]
Durno C et al. Recommendations on surveillance and manage
-
ment of biallelic mismatch repair deficiency (BMMRD) syn
-
drome: a consensus statement by the US Multi-Society Task 
Force on Colorectal Cancer. Gastroenterology. 2017 May;
 
152(6):1605–14. [PMID: 28363489]
Rubenstein JH et al. American Gastroenterological Association 
Institute Guideline on the diagnosis and management of 
Lynch syndrome. Gastroenterology. 2015 Sep;149(3):777–82. 
[PMID: 26226577]
Samadder NJ et al. Cancer risk in families fulfilling the Amster
-
dam criteria for Lynch syndrome. JAMA Oncol. 2017 Dec 1;
 
3(12):1697–701. [PMID: 28772302]
Syngal S et al. ACG clinical guideline: genetic testing and man
-
agement of hereditary gastrointestinal cancer syndromes. Am 
J Gastroenterol. 2015 Feb;110(2):223–62. [PMID: 25645574]
Tiwari AK et al. Lynch syndrome in the 21st century: clinical 
perspectives. QJM. 2016 Mar;109(3):151–8. [PMID: 26224055]
 
º
ANORECTAL DISEASES
(See Chapter 39 for Carcinoma of the Anus.)
 
»
Bright red blood per rectum.
 
»
Protrusion, discomfort.
 
»
Characteristic findings on external anal inspection 
and anoscopic examination.
 
»
Internal hemorrhoids are subepithelial vascular cushions

»
 
»
 
»
Internal hemorrhoids are subepithelial vascular cushions 
consisting of connective tissue, smooth muscle fibers, and 
arteriovenous communications between terminal branches 
of the superior rectal artery and rectal veins. They are a 
normal anatomic entity, occurring in all adults, that con
-
tribute to normal anal pressures and ensure a water-tight 
closure of the anal canal. They commonly occur in three 
primary locations—right anterior, right posterior, and left 
lateral. External hemorrhoids arise from the inferior hem
-
orrhoidal veins located below the dentate line and are 
covered with squamous epithelium of the anal canal or 
perianal region.
Hemorrhoids may become symptomatic as a result of 
activities that increase venous pressure, resulting in disten
-
tion and engorgement. Straining at stool, constipation, 
prolonged sitting, pregnancy, obesity, and low-fiber diets 
all may contribute. With time, redundancy and enlarge
-
ment of the venous cushions may develop and result in 
bleeding or protrusion.
 
»
Patients often attribute a variety of perianal complaints to 
“hemorrhoids. ” However, the principal problems attribut
-
able to internal hemorrhoids are bleeding, prolapse, and 
mucoid discharge. Bleeding is manifested by bright red 
blood that may range from streaks of blood visible on toilet 
paper or stool to bright red blood that drips into the toilet 
bowl after a bowel movement. Uncommonly, bleeding is 
severe and prolonged enough to result in anemia. Initially, 
internal hemorrhoids are confined to the anal canal (stage 
I). Over time, the internal hemorrhoids may gradually 
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enlarge and protrude from the anal opening. At first, this 
mucosal prolapse occurs during straining and reduces 
spontaneously (stage II). With progression over time, the 
prolapsed hemorrhoids may require manual reduction 
after bowel movements (stage III) or may remain chroni
-
cally protruding (stage IV). Chronically prolapsed hemor
-
rhoids may result in a sense of fullness or discomfort and 
mucoid discharge, resulting in irritation of perianal skin 
and soiling of underclothes. Pain is unusual with internal 
hemorrhoids, occurring only when there is extensive 
inflammation and thrombosis of irreducible tissue or with 
thrombosis of an external hemorrhoid.
B. Examination
External hemorrhoids are readily visible on perianal 
inspection. Nonprolapsed internal hemorrhoids are not 
visible but may protrude through the anus with gentle 
straining while the clinician spreads the buttocks. Pro
-
lapsed hemorrhoids are visible as protuberant purple nod
-
ules covered by mucosa. The perianal region should also be 
examined for other signs of disease such as fistulas, fis
-
sures, skin tags, condyloma, anal cancer, or dermatitis. On 
digital examination, uncomplicated internal hemorrhoids 
are neither palpable nor painful. Anoscopic evaluation, 
best performed in the prone jackknife position, provides 
optimal visualization of internal hemorrhoids.
 
»
Small volume rectal bleeding may be caused by an anal fis
-
sure or fistula, neoplasms of the distal colon or rectum, 
ulcerative colitis or Crohn colitis, infectious proctitis, or 
rectal ulcers. Rectal prolapse, in which a full thickness of 
rectum protrudes concentrically from the anus, is readily 
distinguished from mucosal hemorrhoidal prolapse. Proc
-
tosigmoidoscopy or colonoscopy should be performed in 
all patients with hematochezia to exclude disease in the 
rectum or sigmoid colon that could be misinterpreted in 
the presence of hemorrhoidal bleeding.
 
»
Treatment
A. Conservative Measures
Most patients with early (stage I and stage II) disease can 
be managed with conservative treatment. To decrease 
straining with defecation, patients should be given instruc
-
tions for a high-fiber diet and told to increase fluid intake 
with meals. Dietary fiber may be supplemented with bran 
powder (1–2 tbsp twice daily added to food or in 8 oz of 
liquid) or with commercial bulk laxatives (eg, Benefiber, 
Metamucil, Citrucel). Suppositories and rectal ointments 
have no demonstrated utility in the management of mild 
disease. Mucoid discharge may be treated effectively by the 
local application of a cotton ball tucked next to the anal 
opening after bowel movements.
B. Medical Treatment
Patients with stage I, stage II, and stage III hemorrhoids 
and recurrent bleeding despite conservative measures may 
be treated without anesthesia with injection sclerotherapy, 
rubber band ligation, or application of electrocoagulation 
(bipolar cautery or infrared photocoagulation). The choice 
of therapy is dictated by operator preference, but rubber 
band ligation is preferred due to its ease of use and high 
rate of efficacy. Major complications occur in less than 2%, 
including pelvic sepsis, pelvic abscess, urinary retention, 
and bleeding. Recurrence is common unless patients alter 
their dietary habits. Edematous, prolapsed (stage IV) inter
-
nal hemorrhoids, may be treated acutely with topical 
creams, foams, or suppositories containing various combi
-
nations of emollients, topical anesthetics, (eg, pramoxine, 
dibucaine), vasoconstrictors (eg, phenylephrine), astrin
-
gents (witch hazel) and corticosteroids. Common prepara
-
tions include Preparation H (several formulations), Anusol 
HC, Proctofoam, Nupercainal, Tucks, and Doloproct (not 
available in the United States).
Surgical excision (hemorrhoidectomy) is reserved for less 
than 5–10% of patients with chronic severe bleeding due to

than 5–10% of patients with chronic severe bleeding due to 
stage III or stage IV hemorrhoids or patients with acute 
thrombosed stage IV hemorrhoids with necrosis. Compli
-
cations of surgical hemorrhoidectomy include postopera
-
tive pain (which may persist for 2–4 weeks) and impaired 
 
»
Thrombosed External Hemorrhoid
Thrombosis of the external hemorrhoidal plexus results in 
a perianal hematoma. It most commonly occurs in other
-
wise healthy young adults and may be precipitated by 
coughing, heavy lifting, or straining at stool. The condition 
is characterized by the relatively acute onset of an exqui
-
sitely painful, tense and bluish perianal nodule covered 
with skin that may be up to several centimeters in size. Pain 
is most severe within the first few hours but gradually eases 
over 2–3 days as edema subsides. Symptoms may be 
relieved with warm sitz baths, analgesics, and ointments. 
If the patient is evaluated in the first 24–48 hours, removal 
of the clot may hasten symptomatic relief. With the patient 
in the lateral position, the skin around and over the lump 
is injected subcutaneously with 1% lidocaine using a tuber
-
culin syringe with a 30-gauge needle. An ellipse of skin is 
then excised and the clot evacuated. A dry gauze dressing 
is applied for 12–24 hours, and daily sitz baths are then 
begun.
 
»
•	
Stage I, II, or III: When conservative measures fail and 
expertise in medical procedures is needed (injection, 
banding, thermocoagulation).
•	
Stage IV: When surgical excision is required.
Jacobs D. Clinical practice. Hemorrhoids. N Engl J Med. 2014 
Sep 4;371(10):944–51. [PMID: 25184866]
Sugerman DT. JAMA patient page. Hemorrhoids. JAMA. 2014 
Dec 24–31;312(24):2698. [PMID: 25536271]
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Tupe CL et al. Anorectal complaints in the emergency depart
-
ment. Emerg Med Clin North Am. 2016 May;34(2):251–70. 
[PMID: 27133243]
ANORECTAL INFECTIONS
A number of organisms can cause inflammation of the 
anal and rectal mucosa. Proctitis is characterized by ano
-
rectal discomfort, tenesmus, constipation, and mucus or 
bloody discharge. Most cases of proctitis are sexually 
transmitted, especially by anal-receptive intercourse. 
Infectious proctitis must be distinguished from noninfec
-
tious causes of anorectal symptoms, including anal fis
-
sures or fistulae, perirectal abscesses, anorectal carcinomas, 
and inflammatory bowel disease (ulcerative colitis or 
Crohn disease).
 
»
Etiology & Management
Several organisms may cause infectious proctitis.
A. 
Gonorrhea may cause itching, burning, tenesmus, and a 
mucopurulent discharge, although many anorectal infec
-
tions are asymptomatic. Rectal swab specimens should be 
taken during anoscopy for culture; Gram staining is unreli
-
able. Cultures should also be taken from the pharynx and 
urethra in men and from the pharynx and cervix in 
women. Complications of untreated infections include 
strictures, fissures, fistulas, and perirectal abscesses. (For 
treatment, see Chapter 33.)
B. 
Anal syphilis may be asymptomatic or may lead to perianal 
pain and discharge. With primary syphilis, the chancre 
may be at the anal margin or within the anal canal and may 
mimic a fissure, fistula, or ulcer. Proctitis or inguinal 
lymphadenopathy may be present. With secondary syphi
-
lis, condylomata lata (pale-brown, flat verrucous lesions) 
may be seen, with secretion of foul-smelling mucus. 
Although the diagnosis may be established with dark-field 
microscopy or fluorescent antibody testing of scrapings 
from the chancre or condylomas, this requires proper 
equipment and trained personnel. The VDRL or RPR test 
is positive in 75% of primary cases and in 99% of secondary 
cases. (For treatment, see Chapter 34.)
C. 
Chlamydial infection may cause proctitis similar to gonor
-
rheal proctitis; however, some infections are asymptomatic. 
It also may cause lymphogranuloma venereum, character
-
ized by proctocolitis with fever and bloody diarrhea, 
painful perianal ulcerations, anorectal strictures and 
fistulas, and inguinal adenopathy (buboes). Previously 
rare in developed countries, an increasing number of cases 
have been identified among men who have sex with 
men. The diagnosis is established by serology, culture, or 
PCR-based testing of rectal discharge or rectal biopsy. Rec
-
ommended treatment is doxycycline 100 mg orally twice 
daily for 21 days.
D. Herpes simplex type 2
Herpes simplex type 2 virus is a common cause of anorectal 
infection. Symptoms occur 4–21 days after exposure and 
include severe pain, itching, constipation, tenesmus, urinary 
retention, and radicular pain from involvement of lumbar or 
sacral nerve roots. Small vesicles or ulcers may be seen in the 
perianal area or anal canal. Sigmoidoscopy is not usually 
necessary but may reveal vesicular or ulcerative lesions in the 
distal rectum. Diagnosis is established by viral culture, PCR, 
or antigen detection assays of vesicular fluid. Symptoms 
resolve within 2 weeks, but viral shedding may continue for 
several weeks. Patients may remain asymptomatic with or 
without viral shedding or may have recurrent mild relapses. 
Treatment of acute infection for 7–10 days with acyclovir, 
400 mg, or famciclovir, 250 mg orally three times daily, or 
valacyclovir, 1 g twice daily, has been shown to reduce the 
duration of symptoms and viral shedding. Patients with 
AIDS and recurrent relapses may benefit from long-term 
suppressive therapy (see Chapter 31).
E. 
Condylomata acuminata
Condylomata acuminata (warts) are a significant cause of 
anorectal symptoms. Caused by the HPV , they may occur on

E. 
anorectal symptoms. Caused by the HPV , they may occur on 
the perianal area, in the anal canal, or on the genitals. Perianal 
or anal warts are seen in up to 25% of men who have sex 
with men. HIV-positive individuals with condylomas have 
a higher relapse rate after therapy and a higher rate of pro
-
gression to high-grade dysplasia or anal cancer. The warts 
are located on the perianal skin and extend within the anal 
canal up to 2 cm above the dentate line. Patients may have 
no symptoms or may report itching, bleeding, and pain. 
The warts may be small and flat or verrucous, or may form 
a confluent mass that may obscure the anal opening. Warts 
must be distinguished from condyloma lata (secondary 
syphilis) or anal cancer. Biopsies should be obtained from 
large or suspicious lesions. Treatment can be difficult. Sex
-
ual partners should also be examined and treated. The 
treatment of anogenital warts is discussed in Chapter 30. 
HPV vaccines have demonstrated efficacy in preventing 
anogenital warts and routine vaccination is now recom
-
mended for all children and adults 9–26 years old (see 
Chapters 1 and 30). Vaccination also should be considered 
in all men who have sex with men. HIV-positive individuals 
with condylomas who have detectable serum HIV RNA 
levels should have anoscopic surveillance for anal cancer 
every 3–6 months.
Stoner BP et al. Lymphogranuloma venereum 2015: clinical 
presentation, diagnosis, and treatment. Clin Infect Dis. 2015 
Dec 15;61(Suppl 8):S865–73. [PMID: 26602624]
Workowski KA et al; Centers for Disease Control and Prevention 
(CDC). Sexually transmitted diseases treatment guidelines, 
2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1–137. 
Erratum in: MMWR Recomm Rep. 2015 Aug 28;64(33):924. 
[PMID: 26042815]
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FECAL INCONTINENCE
There are five general requirements for bowel continence: 
(1) solid or semisolid stool (even healthy young adults have 
difficulty maintaining continence with liquid rectal con
-
tents); (2) a distensible rectal reservoir (as sigmoid contents 
empty into the rectum, the vault must expand to accommo
-
date); (3) a sensation of rectal fullness (if the patient cannot 
sense this, overflow may occur before the patient can take 
appropriate action); (4) intact pelvic nerves and muscles; 
and (5) the ability to reach a toilet in a timely fashion.
 
»
Minor Incontinence
Many patients complain of inability to control flatus or 
slight soilage of undergarments that tends to occur after 
bowel movements or with straining or coughing. This may 
be due to local anal problems such as prolapsed hemor
-
rhoids that make it difficult to form a tight anal seal or iso
-
lated weakness of the internal anal sphincter, especially if 
stools are somewhat loose. Patients should be treated with 
fiber supplements to provide greater stool bulk. Coffee and 
other caffeinated beverages should be eliminated. The peri
-
anal skin should be cleansed with moist, lanolin-coated 
tissue (baby wipes) to reduce excoriation and infection. 
After wiping, loose application of a cotton ball near the anal 
opening may absorb small amounts of fecal leakage. Pro
-
lapsing hemorrhoids may be treated with band ligation or 
surgical hemorrhoidectomy. Control of flatus and seepage 
may be improved by Kegel perineal exercises. Conditions 
such as ulcerative proctitis that cause tenesmus and urgency, 
chronic diarrheal conditions, and irritable bowel syndrome 
may result in difficulty in maintaining complete continence, 
especially if a toilet is not readily available. Loperamide may 
be helpful to reduce urge incontinence in patients with 
loose stools and may be taken in anticipation of situations 
in which a toilet may not be readily available. Older patients 
may require more time or assistance to reach a toilet, which 
may lead to incontinence. Scheduled toileting and the avail
-
ability of a bedside commode are helpful. Elderly patients 
with chronic constipation may develop stool impaction 
leading to “overflow” incontinence.
 
»
Major Incontinence
Complete uncontrolled loss of stool reflects a significant 
problem with central perception or neuromuscular func
-
tion. Incontinence that occurs without awareness suggests 
a loss of central awareness (eg, dementia, cerebrovascular 
accident, multiple sclerosis) or peripheral nerve injury (eg, 
spinal cord injury, cauda equina syndrome, pudendal 
nerve damage due to obstetric trauma or pelvic floor pro
-
lapse, aging, or diabetes mellitus). Incontinence that occurs 
despite awareness and active efforts to retain stool suggests 
sphincteric damage, which may be caused by traumatic 
childbirth (especially forceps delivery), episiotomy, pro
-
lapse, prior anal surgery, and physical trauma.
Physical examination should include careful inspection 
of the perianal area for hemorrhoids, rectal prolapse, fis
-
sures, fistulas, and either gaping or a keyhole defect of the 
anal sphincter (indicating severe sphincteric injury or 
neurologic disorder). The perianal skin should be stimu
-
lated to confirm an intact anocutaneous reflex. Digital 
examination during relaxation gives valuable information 
about resting tone (due mainly to the internal sphincter) 
and contraction of the external sphincter and pelvic floor 
during squeezing. It also excludes fecal impaction. Anos
-
copy is required to evaluate for hemorrhoids, fissures, and 
fistulas. Proctosigmoidoscopy is useful to exclude rectal 
carcinoma or proctitis. Anal ultrasonography or pelvic 
MRI is the most reliable test for definition of anatomic 
defects in the external and internal anal sphincters. Anal 
manometry may also be useful to define the severity of

manometry may also be useful to define the severity of 
weakness, to assess sensation, and to predict response to 
biofeedback training. In special circumstances, surface 
electromyography is useful to document sphincteric dener
-
vation and proctography to document perineal descent or 
rectal intussusception.
Patients who are incontinent only of loose or liquid 
stools are treated with bulking agents and antidiarrheal 
drugs (eg, loperamide, 2 mg before meals and prophylacti
-
cally before social engagements, shopping trips, etc). 
Patients with incontinence of solid stool benefit from 
scheduled toilet use after glycerin suppositories or tap 
water enemas. Biofeedback training with anal sphincteric 
strengthening (Kegel) exercises (alternating 5-second 
squeeze and 10-second rest for 10 minutes twice daily) may 
be helpful in motivated patients to lower the threshold for 
awareness of rectal filling—or to improve anal sphincter 
squeeze function—or both. In 2012, the FDA approved two 
interventions for fecal incontinence. The first is a sterile gel 
(containing dextranomer and sodium hyaluronate) for 
submucosal injection into the proximal anal canal for the 
treatment of anal incontinence for patients who have not 
responded to conservative therapies, such as fiber supple
-
ments and antidiarrheal agents. This treatment is hypoth
-
esized to reduce incontinence episodes by bulking and 
narrowing the anal canal. In clinical trials, more than one-
half of treated patients reported a greater than 50% reduc
-
tion in the number of fecal incontinence episodes. The 
second is a sacral nerve stimulation device. In uncontrolled 
trials in selected patients, 83% of patients were improved 
with sacral stimulation. Inserts also are available that can 
be placed in the anus or vagina to enhance continence. 
Operative management is seldom needed, but should be 
considered in patients with major incontinence due to 
prior injury to the anal sphincter who have not responded 
to medical therapy.
 
»
•	
Conservative measures fail.
•	
Anorectal tests are deemed necessary (manometry, 
ultrasonography, electromyography).
•	
A surgically correctable lesion is suspected.
Bharucha AE et al. Epidemiology, pathophysiology, and classifi
-
cation of fecal incontinence: state of the science summary for 
the National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK) workshop. Am J Gastroenterol. 2015 Jan;
 
110(1):127–36. [PMID: 25533002]
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Forte ML et al. Systematic review of surgical treatments for fecal 
incontinence. Dis Colon Rectum. 2016 May;59(5):443–69. 
[PMID: 27050607]
Freeman A et al. Fecal incontinence and pelvic floor dysfunction 
in women: a review. Gastroenterol Clin North Am. 2016 Jun;
 
45(2):217–37. [PMID: 27261895]
Markland AD et al. Anal intercourse and fecal incontinence: 
evidence from the 2009–2010 National Health and Nutrition 
Examination Survey. Am J Gastroenterol. 2016 Feb;
 
111(2):269–74. [PMID: 26753893]
Menees SB. My approach to fecal incontinence: it’s all about 
consistency (stool, that is). Am J Gastroenterol. 2017 Jul;
 
112(7):977–80. [PMID: 28631727]
Whitehead WE et al. Treatment of fecal incontinence: state of the 
science summary for the National Institute of Diabetes and 
Digestive and Kidney Diseases workshop. Am J Gastroenterol. 
2015 Jan;110(1):138–46. [PMID: 25331348]
OTHER ANAL CONDITIONS
 
»
Anal Fissures
Anal fissures are linear or rocket-shaped ulcers that are 
usually less than 5 mm in length. Most fissures are believed 
to arise from trauma to the anal canal during defecation, 
perhaps caused by straining, constipation, or high internal 
sphincter tone. They occur most commonly in the poste
-
rior midline, but 10% occur anteriorly. Fissures that occur 
off the midline should raise suspicion for Crohn disease, 
HIV/AIDS, tuberculosis, syphilis, or anal carcinoma. 
Patients complain of severe, tearing pain during defecation 
followed by throbbing discomfort that may lead to consti
-
pation due to fear of recurrent pain. There may be mild 
associated hematochezia, with blood on the stool or toilet 
paper. Anal fissures are confirmed by visual inspection of 
the anal verge while gently separating the buttocks. Acute 
fissures look like cracks in the epithelium. Chronic fissures 
result in fibrosis and the development of a skin tag at the 
outermost edge (sentinel pile). Digital and anoscopic 
examinations may cause severe pain and may not be pos
-
sible. Medical management is directed at promoting effort
-
less, painless bowel movements. Fiber supplements and sitz 
baths should be prescribed. Topical anesthetics (5% lido
-
caine; 2.5% lidocaine plus 2.5% prilocaine) may provide 
temporary relief. Healing occurs within 2 months in up to 
45% of patients with conservative management. Chronic 
fissures may be treated with topical 0.2–0.4% nitroglycerin 
or diltiazem 2% ointment (1 cm of ointment) applied twice 
daily just inside the anus with the tip of a finger for 4–8 
weeks or injection of botulinum toxin (20 units) into the 
internal anal sphincter. All of these treatments result in 
healing in 50–80% of patients with chronic anal fissure, but 
headaches occur in up to 40% of patients treated with 
nitroglycerin. Fissures recur in up to 40% of patients after 
treatment. Chronic or recurrent fissures benefit from lat
-
eral internal sphincterotomy; however, minor incontinence 
may complicate this procedure.
Barnes TG et al. Fissurectomy combined with high-dose botuli
-
num toxin is a safe and effective treatment for chronic anal fis
-
sure and a promising alternative to surgical sphincterotomy. Dis 
Colon Rectum. 2015 Oct;58(10):967–73. [PMID: 26347969]
Beaty JS et al. Anal fissure. Clin Colon Rectal Surg. 2016 Mar;
 
29(1):30–7. [PMID: 26929749]
Liang J et al. Lateral internal sphincterotomy for surgically recur
-
rent chronic anal fissure. Am J Surg. 2015 Oct;210(4):715–9. 
[PMID: 26231724]
Lin JX et al. Optimal dosing of botulinum toxin for treatment of 
chronic anal fissure: a systematic review and meta-analysis. 
Dis Colon Rectum. 2016 Sep;59(9):886–94. [PMID: 27505118]
Sugerman DT. JAMA patient page. Anal fissure. JAMA. 2014 
Mar 19;311(11):1171. [PMID: 24643618]
 
»
Perianal Abscess & Fistula
The anal glands located at the base of the anal crypts at the 
dentate line may become infected, leading to abscess for
-
mation. Other causes of abscess include anal fissure and

-
mation. Other causes of abscess include anal fissure and 
Crohn disease. Abscesses may extend upward or down
-
ward through the intersphincteric plane. Symptoms of 
perianal abscess are throbbing, continuous perianal pain. 
Erythema, fluctuance, and swelling may be found in the 
perianal region on external examination or in the ischio
-
rectal fossa on digital rectal examination. Perianal abscesses 
are treated with local incision and drainage, while ischio
-
rectal abscesses require drainage in the operating room. 
After drainage of an abscess, most patients are found to 
have a fistula in ano.
Fistula in ano most often arises in an anal crypt and is 
usually preceded by an anal abscess. In patients with fistu
-
las that connect to the rectum, other disorders such as 
Crohn disease, lymphogranuloma venereum, rectal tuber
-
culosis, and cancer should be considered. Fistulas are asso
-
ciated with purulent discharge that may lead to itching, 
tenderness, and pain. The treatment of Crohn-related fis
-
tula is discussed elsewhere in this chapter. Treatment of 
simple idiopathic fistula in ano is by surgical incision or 
excision under anesthesia. Care must be taken to preserve 
the anal sphincters. Surgical fistulotomy for treatment of 
complex (high, transphincteric) anal fissures carries a high 
risk of incontinence. Techniques for healing the fistula 
while preserving the sphincter include an endoanal 
advancement flap over the internal opening and insertion 
of a bioprosthetic plug into the fistula opening.
Lange EO et al. Ligation of intersphincteric fistula tract: a 
sphincter-sparing option for complex fistula-in-ano. J Gastro
-
intest Surg. 2016 Feb;20(2):439–44. [PMID: 26394877]
Ratto C et al. Fistulotomy or fistulectomy and primary sphinc
-
teroplasty for anal fistula (FIPS): a systematic review. Tech 
Coloproctol. 2015 Jul;19(7):391–400. [PMID: 26062740]
Vogel JD et al. Clinical practice guideline for the management of 
anorectal abscess, fistula-in-ano, and rectovaginal fistula. Dis 
Colon Rectum. 2016 Dec;59(12):1117–33. [PMID: 27824697]
 
»
Perianal Pruritus
Perianal pruritus is characterized by perianal itching and 
discomfort. It may be caused by poor anal hygiene asso
-
ciated with fistulas, fissures, prolapsed hemorrhoids, 
skin tags, and minor incontinence. Conversely, overzeal
-
ous cleansing with soaps may contribute to local irritation 
or contact dermatitis. Contact dermatitis, atopic dermati
-
tis, bacterial infections (
 or 
), 
parasites (pinworms, scabies), candidal infection (especially 
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in diabetics), sexually transmitted disease (condylomata 
acuminata, herpes, syphilis, molluscum contagiosum), and 
other skin conditions (psoriasis, Paget disease, lichen scle
-
rosis) must be excluded. In patients with idiopathic peri
-
anal pruritus, examination may reveal erythema, 
excoriations, or lichenified, eczematous skin. Education is 
vital to successful therapy. Spicy foods, coffee, chocolate, 
and tomatoes may cause irritation and should be elimi
-
nated. After bowel movements, the perianal area should be 
cleansed with nonscented wipes premoistened with lanolin 
followed by gentle drying. A piece of cotton ball should be 
tucked next to the anal opening to absorb perspiration or 
fecal seepage. Anal ointments and lotions may exacerbate 
the condition and should be avoided. A short course of 
high-potency topical corticosteroid may be tried, although 
efficacy has not been demonstrated. Diluted capsaicin 
cream (0.006%) led to symptomatic relief in 75% of 
patients in a double-blind crossover study.
 
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16
 
JAUNDICE & EVALUATION OF ABNORMAL 
LIVER BIOCHEMICAL TESTS
 
»
Jaundice results from accumulation of bilirubin 
in body tissues; the cause may be hepatic or 
nonhepatic.
 
»
Hyperbilirubinemia may be due to abnormalities 
in the formation, transport, metabolism, or excretion 
of bilirubin.
 
»
Persistent mild elevations of the aminotransferase 
levels are common in clinical practice and caused 
most often by nonalcoholic fatty liver disease.
 
»
Evaluation of obstructive jaundice begins with 
ultrasonography and is usually followed by 
cholangiography.
 
»
Jaundice (icterus) results from the accumulation of bilirubin—
a product of heme metabolism—in body tissues. Hyperbili
-
rubinemia may be due to abnormalities in the formation, 
transport, metabolism, or excretion of bilirubin. Total serum 
bilirubin is normally 0.2–1.2 mg/dL (3.42–20.52 mcmol/L). 
Mean levels are higher in men than women, higher in whites 
and Hispanics than blacks, and correlate with an increased 
risk of symptomatic gallstone disease and inversely with the 
risk of stroke, respiratory disease, cardiovascular disease, 
and mortality, presumably because of an antioxidant effect. 
Jaundice may not be recognizable until serum bilirubin lev
-
els are about 3 mg/dL (51.3 mcmol/L).
Jaundice may be caused by predominantly unconjugated 
or conjugated bilirubin in the serum (Table 16–1). Unconju
-
gated hyperbilirubinemia may result from overproduction 
of bilirubin because of hemolysis; impaired hepatic uptake of 
bilirubin due to certain drugs; or impaired conjugation of 
bilirubin by glucuronide, as in Gilbert syndrome, due to 
mild decreases in uridine diphosphate (UDP) glucuronyl 
transferase, or Crigler-Najjar syndrome, caused by moderate 
decreases or absence of UDP glucuronyl transferase. Hemolysis 
alone rarely elevates the serum bilirubin level to more than 
 
7 mg/dL (119.7 mcmol/L). Predominantly conjugated 
hyperbilirubinemia may result from impaired excretion of 
bilirubin from the liver due to hepatocellular disease, drugs, 
sepsis, or hereditary hepatocanalicular transport defects 
(such as Dubin-Johnson syndrome, progressive familial 
intrahepatic cholestasis syndromes, and intrahepatic cho
-
lestasis of pregnancy) or from extrahepatic biliary obstruc
-
tion. Features of some hyperbilirubinemic syndromes are 
summarized in Table 16–2. The term “cholestasis” denotes 
retention of bile in the liver, and the term “cholestatic 
jaundice” is often used when conjugated hyperbilirubinemia 
results from impaired bile flow. Mediators of pruritus due to 
cholestasis have been identified to be lysophosphatidic acid 
and autotaxin, the enzyme that forms lysophosphatidic acid.
 
»
A. Unconjugated Hyperbilirubinemia
Stool and urine color are normal, and there is mild jaundice 
and indirect (unconjugated) hyperbilirubinemia with no 
bilirubin in the urine. Splenomegaly occurs in all hemolytic 
disorders except in sickle cell disease.
B. Conjugated Hyperbilirubinemia
1. Hereditary cholestatic syndromes or intrahepatic 
cholestasis—
The patient may be asymptomatic; cholesta
-
sis is often accompanied by pruritus, light-colored stools, 
and jaundice.
2. Hepatocellular disease—
Malaise, anorexia, low-grade 
fever, and right upper quadrant discomfort are frequent. 
Dark urine, jaundice, and, in women, amenorrhea occur. 
An enlarged tender liver, spider telangiectasias, palmar 
erythema, ascites, gynecomastia, sparse body hair, fetor 
hepaticus, and asterixis may be present, depending on the 
cause, severity, and chronicity of liver dysfunction.
C. Biliary Obstruction
There may be right upper quadrant pain, weight loss 
 
(suggesting carcinoma), jaundice, pruritus, dark urine, 
and light-colored stools. Symptoms and signs may be 
Liver, Biliary Tract, & 
Pancreas Disorders
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Table 16–1.
 
Classification of jaundice.
Type of Hyperbilirubinemia
Location and Cause
Unconjugated hyperbilirubinemia 
(predominantly indirect 
bilirubin)
Increased bilirubin production (eg, hemolytic anemias, hemolytic reactions, hematoma, pulmonary infarction)
Impaired bilirubin uptake and storage (eg, posthepatitis hyperbilirubinemia, Gilbert syndrome, Crigler-Najjar 
syndrome, drug reactions)
Conjugated hyperbilirubinemia 
(predominantly direct 
Hereditary Cholestatic Syndromes
 (see also Table 16–2)
Faulty excretion of bilirubin conjugates (eg, Dubin-Johnson syndrome, Rotor syndrome) or mutation in 
genes coding for bile salt transport proteins (eg, progressive familial intrahepatic cholestasis syndromes, 
benign recurrent intrahepatic cholestasis, and some cases of intrahepatic cholestasis of pregnancy)
Hepatocellular Dysfunction
Biliary epithelial and hepatocyte damage (eg, hepatitis, hepatic cirrhosis)
Intrahepatic cholestasis (eg, certain drugs, biliary cirrhosis, sepsis, postoperative jaundice)
Hepatocellular damage or intrahepatic cholestasis resulting from miscellaneous causes (eg, spirochetal infections, 
infectious mononucleosis, cholangitis, sarcoidosis, lymphomas, hyperthyroidism, industrial toxins)
Biliary Obstruction
Choledocholithiasis, biliary atresia, carcinoma of biliary duct, sclerosing cholangitis, choledochal cyst, 
external pressure on bile duct, pancreatitis, pancreatic neoplasms
Table 16–2.
 
Hyperbilirubinemic disorders.
Nature of Defect
Type of 
Hyperbilirubinemia
Clinical and Pathologic Characteristics
Gilbert 
 
syndrome
1
Reduced activity  of 
uridine  diphos
-
phate glucuronyl 
transferase
Unconjugated 
 
(indirect) bilirubin
Benign, asymptomatic hereditary jaundice. Hyperbilirubinemia increased 
by 24- to 36-hour fast. No treatment required. Associated with 
reduced mortality from cardiovascular disease.
Dubin-Johnson 
syndrome
2
Reduced excretory 
function of 
hepatocytes
Conjugated (direct) 
bilirubin
Benign, asymptomatic hereditary jaundice. Gallbladder does not visualize 
on oral cholecystography. Liver darkly pigmented on gross examination. 
Biopsy shows centrilobular brown pigment. Prognosis excellent.
Rotor 
 
syndrome
3
Reduced hepatic 
reuptake of bili
-
rubin conjugates
bilirubin
Similar to Dubin-Johnson syndrome, but liver is not pigmented and the 
gallbladder is visualized on oral cholecystography. Prognosis excellent.
Recurrent or 
 
progressive 
 
intrahepatic 
cholestasis
4
Cholestasis, often on 
a familial basis
Predominantly 
 
conjugated (direct) 
bilirubin
Episodic attacks of or progressive jaundice, itching, and malaise. Onset in 
early life and may persist for a lifetime. Alkaline phosphatase 
increased. Cholestasis found on liver biopsy. (Biopsy may be normal 
during remission.) Prognosis is generally excellent for “benign” 
recurrent intrahepatic cholestasis but may not be for familial forms.
Intrahepatic 
 
cholestasis of 
pregnancy
5
Cholestasis
 
bilirubin
Benign cholestatic jaundice, usually occurring in the third trimester of 
pregnancy. Itching, gastrointestinal symptoms, and abnormal liver 
excretory function tests. Cholestasis noted on liver biopsy. Prognosis 
excellent, but recurrence with subsequent pregnancies or use of oral 
contraceptives is characteristic.
1
Gilbert syndrome generally results from the addition of extra dinucleotide(s) TA sequences to the TATA promoter of the conjugating 
enzyme 
UGT1A1
.
2
Dubin-Johnson syndrome is caused by a mutation in the 
ABCC2
 gene coding for organic anion transporter multidrug resistance 
protein  2 in bile canaliculi on chromosome 10q24.
3
Rotor syndrome is caused by mutations in the genes coding for organic anion transporting polypeptides OATP1B1 and OATP1B3 on 
chromosome 12p.
4
Mutations in genes that control hepatocellular transport systems that are involved in the formation of bile and inherited as autosomal

4
Mutations in genes that control hepatocellular transport systems that are involved in the formation of bile and inherited as autosomal 
recessive traits are on chromosomes 18q21–22, 2q24, 7q21, and others in families with progressive familial intrahepatic cholestasis. Gene 
mutations on chromosome 18q21–22 alter a P-type ATPase expressed in the small intestine and liver and other tissues on chromosome 
2q24 alter the bile acid export pump and also cause benign recurrent intrahepatic cholestasis. Less common causes of progressive familial 
intrahepatic cholestasis are mutations in genes that encode TJP2, FXR, and MY05B.
5
Mutations in genes (especially 
ABCB4
 and 
ABCB11
) that encode biliary canalicular transporters account for many cases of intrahepatic 
cholestasis of pregnancy.
LIVER, BILIARY TRACT, & PANCREAS DISORDERS
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intermittent if caused by a stone, carcinoma of the ampulla, 
or cholangiocarcinoma. Pain may be absent early in pan
-
creatic cancer. Occult blood in the stools suggests cancer 
of the ampulla. A palpable gallbladder (Courvoisier sign) 
is characteristic, but neither specific nor sensitive, of a 
pancreatic head tumor. Fever and chills are more common 
in benign obstruction with associated cholangitis.
 
»
(See Tables 16–3 and 16–4.)
A. Laboratory Findings
Elevated serum alanine and aspartate aminotransferase 
(ALT and AST) levels reflect hepatocellular injury. Normal 
reference values for ALT and AST are lower than generally 
reported when persons with risk factors for fatty liver are 
excluded. The upper limit of normal for ALT is 29–33 units/L 
in men and 19–25 units/L in women. Levels decrease with 
age and correlate with body mass index and mortality from 
liver disease and inversely with caffeine consumption and 
physical activity. There is controversy about whether an 
elevated ALT level is associated with a low or high vitamin 
D level and with mortality from coronary artery disease, 
cancer, diabetes mellitus, and all causes. Truncal fat and 
early-onset paternal obesity are risk factors for increased 
ALT levels. Levels are mildly elevated in more than 25% of 
persons with untreated celiac disease and in type 1 diabetic 
patients with so-called glycogenic hepatopathy and often rise 
transiently in healthy persons who begin taking 4 g of acet
-
aminophen per day or experience rapid weight gain on a 
fast-food diet. Levels may rise strikingly but transiently in 
patients with acute biliary obstruction from choledocholi
-
thiasis. Nonalcoholic fatty liver disease is by far the most 
common cause of mildly to moderately elevated amino
-
transferase levels. Elevated ALT and AST levels, often 
greater than 1000 units/L (20 mckat/L), are the hallmark 
of hepatocellular necrosis or inflammation. Elevated alka
-
line phosphatase levels are seen in cholestasis or infiltrative 
Table 16–3.
 
Liver biochemical tests: normal values and changes in hepatocellular and obstructive jaundice.
Tests
Normal Values
Hepatocellular Jaundice
Obstructive Jaundice
Bilirubin
1
 
Direct
 
Indirect
0.1–0.3 mg/dL (1.71–5.13 mcmol/L)
0.2–0.7 mg/dL (3.42–11.97 mcmol/L)
Increased
Increased
Increased
Increased
Urine bilirubin
None
Increased
Increased
3.5–5.5 g/dL (35–55 g/L)
Decreased
Generally unchanged
Alkaline phosphatase
30–115 units/L (0.6–2.3 mkat/L)
Mildly increased (+)
Markedly increased (++++)
Prothrombin time
INR of 1.0–1.4. After vitamin K, 
 
10% decrease in 24 hours
Prolonged if damage is severe; does 
not respond to parenteral 
 
vitamin K
Prolonged if obstruction is 
marked; generally responds to 
parenteral vitamin K
ALT, AST
ALT, ≤ 30 units/L (0.6 mkat/L) (men), 
 
≤ 19 units/L (0.38 mkat/L) (women); 
AST, 5–40 units/L (0.1–0.8 mkat/L)
Increased, as in viral hepatitis
Minimally increased
1
Measured by the van den Bergh reaction, which overestimates direct bilirubin in normal persons.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.
Table 16–4.
 
Causes of serum aminotransferase 
elevations.
1
Mild 
e
levations 
 
(5 × normal)
Severe 
e
levations 
 
(> 15 × normal)
Hepatic: 
a
LT-predominant
 
Chr
onic hepatitis B, C, and D
 
A
cute viral hepatitis (A-E, EBV, CMV)
 
Steatosis/steatohepatitis
 
Hemochromatosis
 
Medications/toxins
 
A
utoimmune hepatitis
 
Alpha-1-antitrypsin 
 
(alpha-1-an
tiprotease) deficiency
 
W
ilson disease
 
C
eliac disease
 
Gly
cogenic hepatopathy
Hepatic: 
a
ST-predominant
 
Alc
ohol-related liver injury 
 
(
AST:ALT > 2:1)
 
Cirrhosis
Nonhepatic
 
S
trenuous exercise
 
Hemolysis
 
Myopathy
 
T
hyroid disease
 
Macro-AST
Acute viral hepatitis 
 
(A–E, herpes)
Ischemic hepatitis
Autoimmune hepatitis
Wilson disease
Acute bile duct 
Acute Budd-Chiari 
syndrome

T
 
Macro-AST
 
syndrome
Hepatic artery ligation
1
Almost any liver disease can cause moderate aminotransferase 
elevations (5–15 × normal).
ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
CMV, cytomegalovirus; EBV, Epstein-Barr virus.
Adapted, with permission, from Green RM et al. AGA technical 
review on the evaluation of liver chemistry tests. Gastroenterology. 
2002 Oct;123(4):1367–84. Copyright © Elsevier.
liver disease (such as tumor, granulomas, or amyloidosis). 
Isolated alkaline phosphatase elevations of hepatic rather 
than bone, intestinal, or placental origin are confirmed by 
concomitant elevation of gamma-glutamyl transpeptidase 
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CMDT 2019
or 5
′
-nucleotidase levels. Serum gamma-glutamyl trans
-
peptidase levels appear to correlate with the risk of mortal
-
ity and disability in the general population. The differential 
diagnosis of any liver test elevation always includes toxicity 
caused by drugs, herbal and dietary supplements, and 
toxins.
B. Imaging
Demonstration of dilated bile ducts by ultrasonography 
or CT indicates biliary obstruction (90–95% sensitivity). 
Ultrasonography, CT, and MRI may also demonstrate 
hepatomegaly, intrahepatic tumors, and portal hyperten
-
sion. Use of color Doppler ultrasonography or contrast 
agents that produce microbubbles increases the sensitiv
-
ity of transcutaneous ultrasonography for detecting small 
neoplasms. MRI is the most accurate technique for iden
-
tifying isolated liver lesions such as hemangiomas, focal 
nodular hyperplasia, or focal fatty infiltration and for 
detecting hepatic iron overload. The most sensitive tech
-
niques for detection of individual small hepatic metasta
-
ses in patients eligible for resection are multiphasic 
helical or multislice CT; CT arterial portography, in 
which imaging follows intravenous contrast infusion via a 
catheter placed in the superior mesenteric artery; MRI 
with use of gadolinium or ferumoxides as contrast agents; 
and intraoperative ultrasonography. Dynamic gadolinium-
enhanced MRI and MRI following administration of 
superparamagnetic iron oxide show promise in visualiz
-
ing hepatic fibrosis. Because of its much lower cost, ultra
-
sonography is preferable to CT (~six times more 
expensive) or MRI (~seven times more expensive) as a 
screening test. Positron emission tomography (PET) can 
be used to detect small pancreatic tumors and metastases. 
Ultrasonography can detect gallstones with a sensitivity 
of 95%.
Magnetic resonance cholangiopancreatography (MRCP) 
is a sensitive, noninvasive method of detecting bile duct 
stones, strictures, and dilatation; however, it is less reliable 
than endoscopic retrograde cholangiopancreatography 
(ERCP) for distinguishing malignant from benign stric
-
tures. ERCP requires a skilled endoscopist and may be 
used to demonstrate pancreatic or ampullary causes of 
jaundice, carry out sphincterotomy and stone extraction, 
insert a stent through an obstructing lesion, or facilitate 
direct cholangiopancreatoscopy. Complications of ERCP 
include pancreatitis (5% or less) and, less commonly, 
cholangitis, bleeding, or duodenal perforation after 
sphincterotomy. Risk factors for post-ERCP pancreatitis 
include female sex, pregnancy, prior post-ERCP pancreatitis, 
suspected sphincter of Oddi dysfunction, and a difficult 
or failed cannulation. Percutaneous transhepatic cholan
-
giography (PTC) is an alternative approach to evaluating 
the anatomy of the biliary tract. Serious complications of 
PTC occur in 3% and include fever, bacteremia, bile 
peritonitis, and intraperitoneal hemorrhage. Endoscopic 
ultrasonography (EUS) is the most sensitive test for 
detecting small lesions of the ampulla or pancreatic head 
and for detecting portal vein invasion by pancreatic 
cancer. It is also accurate for detecting or excluding bile 
duct stones.
C. Liver Biopsy
Percutaneous liver biopsy is considered the definitive 
study for determining the cause and histologic severity of 
hepatocellular dysfunction or infiltrative liver disease, 
although it is subject to sampling error and subjective 
interpretation. In patients with suspected metastatic dis
-
ease or a hepatic mass, it is performed under ultrasound or 
CT guidance. A transjugular route can be used in patients 
with coagulopathy or ascites. The risk of bleeding after a 
percutaneous liver biopsy is approximately 0.6% and is 
increased in persons with a platelet count of 60,000/mcL 
(60 × 10
9
/mcL) or less. The risk of death is up to 0.1%. 
Panels of blood tests (eg, FibroSure, NAFLD fibrosis score,

(60 × 10
9
Panels of blood tests (eg, FibroSure, NAFLD fibrosis score, 
Enhanced liver fibrosis score) and ultrasound (vibration-
controlled transient, shear wave, or acoustic radiation force 
impulse) elastography or magnetic resonance elastography 
to measure liver stiffness are used for estimating the stage 
of liver fibrosis and degree of portal hypertension without 
the need for liver biopsy; they are most accurate for excluding 
advanced fibrosis.
 
»
Patients with jaundice should be referred for diagnostic 
 
»
Patients with liver failure should be hospitalized.
ASGE Standards of Practice Committee et al. Adverse events asso
-
ciated with ERCP . Gastrointest Endosc. 2017 Jan;85(1):32–47. 
[PMID: 27546389]
Kasarala G et al. Standard liver tests. Clin Liver Dis. 2016 Jul;
 
8(1):13–8.
Kwo PY et al. ACG Clinical Guideline: evaluation of abnormal 
liver chemistries. Am J Gastroenterol. 2017 Jan;112(1):18–35. 
[PMID: 27995906]
Lim JK et al. American Gastroenterological Association Institute 
guideline on the role of elastography in the evaluation of liver 
fibrosis. Gastroenterology. 2017 May;152(6):1536–43. [PMID: 
28442119]
Tapper EB et al. Use of liver imaging and biopsy in clinical practice. 
N Engl J Med. 2017 Aug 24;377(8):756–68. [PMID: 28834467]
 
º
DIS
ea
S
e
S OF TH
e
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er
See Chapter 39 for Hepatocellular Carcinoma.
ACUTE HEPATITIS A
 
»
Prodrome of anorexia, nausea, vomiting, malaise, 
aversion to smoking.
 
»
Fever, enlarged and tender liver, jaundice.
 
»
Normal to low white cell count; markedly elevated 
aminotransferases.
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»
Hepatitis can be caused by viruses, including the five 
hepatotropic viruses—A, B, C, D, and E—and many drugs 
and toxic agents; the clinical manifestations may be similar 
regardless of cause. Hepatitis A virus (HAV) is a 27-nm 
RNA hepatovirus (in the picornavirus family) that causes 
epidemics or sporadic cases of hepatitis. HAV infection is 
hyperendemic in developing countries. The virus is trans
-
mitted by the fecal-oral route, and its spread is favored by 
crowding and poor sanitation. Since introduction of the 
HAV vaccine in the United States in 1995, the incidence 
rate of HAV infection has declined from as much as 14 to 
0.4 per 100,000 population, with a corresponding decline 
in the mortality rate from 0.1 to 0.02 death per 100,000 
population and an increase in the mean age of death. In the 
United States, international travel has emerged as the lead
-
ing risk factor, accounting for over 40% of cases, with 
another 18% of cases attributable to exposure to an inter
-
national traveler. Common source outbreaks may still 
result from contaminated water or food, including inade
-
quately cooked shellfish. In 2017, an outbreak in California, 
Michigan, and Utah affected a large number of homeless 
persons and resulted in many deaths. In addition, HAV 
infection has been described as a reemerging food-borne 
public health threat in Europe. Outbreaks among people 
who inject drugs or who are unvaccinated residents in 
institutions and cases among international adoptees and 
their contacts also have been reported.
The incubation period averages 30 days. HAV is 
excreted in feces for up to 2 weeks before clinical illness 
but rarely after the first week of illness. The mortality rate 
for hepatitis A is low, and fulminant hepatitis A is uncom
-
mon except for rare instances in which it occurs in a 
patient with concomitant chronic hepatitis C. There is no 
chronic carrier state. In the United States, about 30% of 
the population have serologic evidence of previous HAV 
 
»
Figure 16–1 shows the typical course of acute hepatitis A. 
Clinical illness is more severe in adults than in children, in 
whom it is usually asymptomatic. The onset may be abrupt 
or insidious, with malaise, myalgia, arthralgia, easy fatiga
-
bility, upper respiratory symptoms, and anorexia. A dis
-
taste for smoking, paralleling anorexia, may occur early. 
Nausea and vomiting are frequent, and diarrhea or consti
-
pation may occur. Fever is generally present but is low-
grade except in occasional cases in which systemic toxicity 
may occur. Defervescence and a fall in pulse rate often 
coincide with the onset of jaundice.
Abdominal pain is usually mild and constant in the 
right upper quadrant or epigastrium, often aggravated by 
jarring or exertion, and rarely may be severe enough to 
simulate cholecystitis. Jaundice occurs after 5–10 days but 
may appear at the same time as the initial symptoms. In 
many patients, jaundice never develops. With the onset of 
jaundice, prodromal symptoms often worsen, followed by 
progressive clinical improvement. Stools may be acholic 
Titer
0
4
8
Fecal
HAV
Jaundice
Symptoms
↑
 ALT
HAV in serum
12
16
20
Weeks after exposure
IgM
anti-HAV
IgG
anti-HAV
 
▲
Figure 16–1.
 
The typical course of acute type A 
hepatitis. (HAV, hepatitis A virus; anti-HAV, antibody to 
hepatitis A virus; ALT, alanine aminotransferase.) 
(
Reprinted, with permission, from Koff RS. Acute viral 
hepatitis. In: Friedman LS, Keeffe EB [editors]. 
Handbook 
of Liver Disease
, 3rd ed. Philadelphia: Saunders Elsevier, 
2012. Copyright © Elsevier.)
during this phase. Hepatomegaly—rarely marked—is present 
in over half of cases. Liver tenderness is usually present. 
Splenomegaly is reported in 15% of patients, and soft, 
enlarged lymph nodes—especially in the cervical or epitroch
-
lear areas—may be noted.

-
The acute illness usually subsides over 2–3 weeks with 
complete clinical and laboratory recovery by 9 weeks. In 
some cases, clinical, biochemical, and serologic recovery 
may be followed by one or two relapses, but recovery is the 
rule. Acute cholecystitis occasionally complicates the 
course of acute hepatitis A. Other occasional extrahepatic 
complications include acute kidney injury, arthritis, vascu
-
litis, acute pancreatitis, and a variety of neurologic 
manifestations.
The white blood cell count is normal to low, especially in 
the preicteric phase. Large atypical lymphocytes may 
occasionally be seen. Mild proteinuria is common, and 
bilirubinuria often precedes the appearance of jaundice. 
Strikingly elevated ALT or AST levels occur early, fol
-
lowed by elevations of bilirubin and alkaline phospha
-
tase; in a minority of patients, the latter persist after 
aminotransferase levels have normalized. Cholestasis is 
occasionally marked. Antibody to hepatitis A (anti-HAV) 
appears early in the course of the illness (Figure 16–1). 
Both IgM and IgG anti-HAV are detectable in serum 
soon after the onset. Peak titers of IgM anti-HAV occur 
during the first week of clinical disease and usually 
disappear within 3–6 months. Detection of IgM anti-HAV 
is an excellent test for diagnosing acute hepatitis A but is 
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not recommended for the evaluation of asymptomatic 
persons with persistently elevated serum aminotransfer
-
ase levels because false-positive results occur. False-
negative results have been described in a patient receiving 
rituximab for rheumatoid arthritis. Titers of IgG anti-
HAV rise after 1 month of the disease and may persist for 
years. IgG anti-HAV (in the absence of IgM anti-HAV) 
indicates previous exposure to HAV , noninfectivity, and 
immunity.
 
»
The differential diagnosis includes other viruses that cause 
hepatitis, particularly hepatitis B and C, and diseases such 
as infectious mononucleosis, cytomegalovirus infection, 
herpes simplex virus infection, Middle East respiratory 
syndrome, and infections caused by many other viruses, 
including influenza and Ebola virus; spirochetal diseases 
such as leptospirosis and secondary syphilis; brucellosis; 
rickettsial diseases such as Q fever; drug-induced liver 
injury; and ischemic hepatitis (shock liver). Occasionally, 
autoimmune hepatitis may have an acute onset mimicking 
acute viral hepatitis. Rarely, metastatic cancer of the liver, 
lymphoma, or leukemia may present as a hepatitis-like 
picture.
The prodromal phase of viral hepatitis must be distin
-
guished from other infectious disease such as influenza, 
upper respiratory infections, and the prodromal stages of 
the exanthematous diseases. Cholestasis may mimic 
obstructive jaundice.
 
»
Strict isolation of patients is not necessary, but hand 
washing after bowel movements is required. Unvacci
-
nated persons who are exposed to HAV are advised to 
receive postexposure prophylaxis with a single dose of 
HAV vaccine or immune globulin (0.02 mL/kg) as soon as 
possible. The vaccine is preferred in healthy persons aged 
1 year to 40 years, whereas immune globulin is preferred 
in those who are younger than 1 year or older than 
 
40 years, are immunocompromised, or have chronic liver 
disease.
Vaccination with one of two effective inactivated 
hepatitis A vaccines available in the United States pro
-
vides long-term immunity and is recommended for 
persons living in or traveling to endemic areas (includ
-
ing military personnel), patients with chronic liver dis
-
ease upon diagnosis after prescreening for immunity 
(although the cost-effectiveness of vaccinating all 
patients with concomitant chronic hepatitis C has been 
questioned), persons with clotting-factor disorders who 
are treated with concentrates, men who have sex with 
men, animal handlers, illicit drug users, sewage workers, 
food handlers, close personal contacts of international 
adoptees, and children and caregivers in day-care cen
-
ters and institutions. For healthy travelers, a single dose 
of vaccine at any time before departure can provide 
adequate protection. Routine vaccination is advised for 
all children in states with an incidence of hepatitis A at 
least twice the national average and has been approved 
by the Advisory Committee on Immunization Practices 
of the Centers for Disease Control and Prevention 
(CDC) for use in all children between ages 1 and 2 in the 
United States. HAV vaccine is also effective in the pre
-
vention of secondary spread to household contacts of 
primary cases. The recommended dose for adults is 1 mL 
(1440 ELISA units) of Havrix (GlaxoSmithKline) or 
 
1 mL (50 units) of Vaqta (Merck) intramuscularly, fol
-
lowed by a booster dose at 6–18 months. A combined 
hepatitis A and B vaccine (Twinrix, GlaxoSmithKline) is 
available. HIV infection impairs the response to the 
HAV vaccine, especially in persons with a CD4 count 
less than 200/mcL.
 
»
Treatment
Bed rest is recommended only if symptoms are marked. If 
nausea and vomiting are pronounced or if oral intake 
 
is substantially decreased, intravenous 10% glucose is 
Dietary management consists of palatable meals as tol
-

-
erated, without overfeeding; breakfast is usually tolerated 
best. Strenuous physical exertion, alcohol, and hepatotoxic 
agents should be avoided. Small doses of oxazepam are safe 
because metabolism is not hepatic; morphine sulfate 
should be avoided.
Corticosteroids have no benefit in patients with viral 
hepatitis, including those with fulminant disease.
 
»
Prognosis
In most patients, clinical recovery is generally complete 
within 3 months. Laboratory evidence of liver dysfunction 
may persist for a longer period, but most patients recover 
completely. Hepatitis A does not cause chronic liver dis
-
ease, although it may persist for up to 1 year, and clinical 
and biochemical relapses may occur before full recovery. 
The mortality rate is less than 1.0%, with a higher rate in 
older adults than in younger persons.
 
»
•	
Encephalopathy is present.
•	
INR greater than 1.6.
•	
The patient is unable to maintain hydration.
Centers for Disease Control and Prevention (CDC). 2017—
Outbreaks of hepatitis A in multiple states among people who 
are homeless and people who use drugs. https://www.cdc.gov/
hepatitis/outbreaks/2017March-hepatitisA.htm
Linder KA et al. JAMA patient page. Hepatitis A. JAMA. 
2017 Dec 19;318(23):2393. [PMID: 29094153]
Mohsen W et al. Hepatitis A to E: what’s new? Intern Med J. 
2017 Apr;47(4):380–9. [PMID: 28401719]
Murphy TV et al. Progress toward eliminating hepatitis A dis
-
ease in the United States. MMWR Suppl. 2016 Feb 12;
 
65(1):29–41. [PMID: 26916458]
Spradling PR et al. Persistence of seropositivity among persons 
vaccinated for hepatitis A during infancy by maternal antibody 
status: 15-year follow-up. Hepatology. 2016 Mar;63(3):703–11. 
[PMID: 26637987]
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ACUTE HEPATITIS B
 
»
 
»
 
»
Normal to low white blood cell count; markedly 
elevated aminotransferases early in the course.
 
»
Liver biopsy shows hepatocellular necrosis and 
mononuclear infiltrate but is rarely indicated.
 
»
Hepatitis B virus (HBV) is a 42-nm hepadnavirus with a 
partially double-stranded DNA genome, inner core protein 
(hepatitis B core antigen, HBcAg), and outer surface coat 
(hepatitis B surface antigen, HBsAg). There are eight dif
-
ferent genotypes (A–H), which may influence the course of 
infection and responsiveness to antiviral therapy. HBV is 
usually transmitted by inoculation of infected blood or 
blood products or by sexual contact and is present in saliva, 
semen, and vaginal secretions. HBsAg-positive mothers 
may transmit HBV at delivery; the risk of chronic infection 
in the infant is as high as 90%.
Since 1990, the incidence of HBV infection in the 
United States has decreased from 8.5 to 1.5 cases per 
100,000 population. The prevalence is 0.27% in persons 
aged 6 or over. Because of universal vaccination since 1992, 
exposure to HBV is now very low among persons aged 18 
or younger. HBV is prevalent in men who have sex with 
men and in people who inject drugs (about 7% of HIV-
infected persons are coinfected with HBV), but the greatest 
number of cases result from heterosexual transmission. 
Other groups at risk include patients and staff at hemodi
-
alysis centers, physicians, dentists, nurses, and personnel 
working in clinical and pathology laboratories and blood 
banks. Half of all patients with acute hepatitis B in the 
United States have previously been incarcerated or treated 
for a sexually transmitted disease. The risk of HBV infec
-
tion from a blood transfusion in the United States is no 
higher than 1 in 350,000 units transfused. Screening for 
HBV infection is recommended for high-risk groups by the 
US Preventive Services Task Force.
The incubation period of hepatitis B is 6 weeks to 
 
6 months (average 12–14 weeks). The onset of hepatitis B is 
more insidious and the aminotransferase levels are higher 
on average than in HAV infection. Fulminant hepatitis 
occurs in less than 1%, with a mortality rate of up to 60%. 
Following acute hepatitis B, HBV infection persists in 1–2% 
of immunocompetent adults, but in a higher percentage of 
children and immunocompromised adults. There are as many 
as 2.2 million persons (including an estimated 1.32 million 
foreign-born persons from endemic areas) with chronic 
hepatitis B in the United States and 248 million worldwide. 
Compared with the general population, the prevalence 
of chronic HBV infection is increased 2- to 3-fold in 
non-Hispanic blacks and 10-fold in Asians. Persons with 
chronic hepatitis B, particularly when HBV infection is 
acquired early in life and viral replication persists, are at 
substantial risk for cirrhosis and hepatocellular carcinoma 
(up to 25–40%); men are at greater risk than women.
 
»
The clinical picture of viral hepatitis is extremely variable, 
ranging from asymptomatic infection without jaundice to 
a fulminating disease and death in a few days. Figure 16–2 
shows the typical course of acute HBV infection. The onset 
may be abrupt or insidious, and the clinical features are 
similar to those for acute hepatitis A. Serum sickness may 
be seen early in acute hepatitis B. Fever is generally present 
and is low-grade. Defervescence and a fall in pulse rate 
often coincide with the onset of jaundice. Infection caused 
by HBV may be associated with glomerulonephritis and 
polyarteritis nodosa.
complete clinical and laboratory recovery by 16 weeks. In 
5–10% of cases, the course may be more protracted, but

5–10% of cases, the course may be more protracted, but 
less than 1% will have a fulminant course. Hepatitis B may 
become chronic.
The laboratory features are similar to those for acute 
hepatitis A, although serum aminotransferase levels are 
higher on average in acute hepatitis B, and marked cho
-
lestasis is not a feature. Marked prolongation of the 
prothrombin time in severe hepatitis correlates with 
increased mortality.
Titer
0
4
8
HBsAg
Jaundice
Symptoms
↑
 ALT
Anti-HBe
HBeA
g
HBV DNA
12
16
18
20
24
28
32
36
40
52
IgG
anti-HBc
Anti-
HBs
IgM
anti-HBc
 
▲
Figure 16–2.
 
The typical course of acute type B 
 
hepatitis. (anti-HBs, antibody to HBsAg; HBeAg, hepatitis 
Be antigen; HBsAg, hepatitis B surface antigen; anti-HBe, 
antibody to HBeAg; anti-HBc, antibody to hepatitis B core 
antigen; ALT, alanine aminotransferase.) 
(Reprinted, with 
permission, from Koff RS. Acute viral hepatitis. In: Friedman 
LS, Keeffe EB [editors]. 
Handbook of Liver Disease
, 3rd ed. 
Philadelphia: Saunders Elsevier, 2012. Copyright © Elsevier.)
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There are several antigens and antibodies as well as 
HBV DNA that relate to HBV infection and that are useful 
in diagnosis. Interpretation of common serologic patterns 
is shown in Table 16–5.
1. HBsAg—
The appearance of HBsAg in serum is the first 
evidence of infection, appearing before biochemical evi
-
dence of liver disease, and persisting throughout the clinical 
illness. Persistence of HBsAg more than 6 months after the 
acute illness signifies chronic hepatitis B.
2. Anti-HBs—
Specific antibody to HBsAg (anti-HBs) 
appears in most individuals after clearance of HBsAg 
and after successful vaccination against hepatitis B. Dis
-
appearance of HBsAg and the appearance of anti-HBs 
signal recovery from HBV infection, noninfectivity, and 
immunity.
3. Anti-HBc—
IgM anti-HBc appears shortly after HBsAg is 
detected. (HBcAg alone does not appear in serum.) In the 
setting of acute hepatitis, IgM anti-HBc indicates a diagno
-
sis of acute hepatitis B, and it fills the serologic gap in rare 
patients who have cleared HBsAg but do not yet have 
detectable anti-HBs. IgM anti-HBc can persist for 3–6 months, 
and sometimes longer. IgM anti-HBc may also reappear 
during flares of previously inactive chronic hepatitis B. IgG 
anti-HBc also appears during acute hepatitis B but persists 
indefinitely, whether the patient recovers (with the appear
-
ance of anti-HBs in serum) or chronic hepatitis B develops 
(with persistence of HBsAg). In asymptomatic blood 
donors, an isolated anti-HBc with no other positive HBV 
serologic results may represent a falsely positive result or 
latent infection in which HBV DNA is detectable in serum 
only by polymerase chain reaction (PCR) testing.
4. HBeAg—
HBeAg is a secretory form of HBcAg that 
appears in serum during the incubation period shortly 
after the detection of HBsAg. HBeAg indicates viral repli
-
cation and infectivity. Persistence of HBeAg beyond 
 
3 months indicates an increased likelihood of chronic 
hepatitis B. Its disappearance is often followed by the 
appearance of anti-HBe, generally signifying diminished 
viral replication and decreased infectivity.
5. HBV DNA—
The presence of HBV DNA in serum gener
-
ally parallels the presence of HBeAg, although HBV DNA 
is a more sensitive and precise marker of viral replication 
and infectivity. In some patients with chronic hepatitis B, 
HBV DNA is present at high levels without HBeAg in 
serum because of development of a mutation in the core 
promoter or precore region of the gene that codes HBcAg; 
these mutations prevent synthesis of HBeAg in infected 
hepatocytes. When additional mutations in the core gene 
are also present, the severity of HBV infection is enhanced 
and the risk of cirrhosis is increased.
 
»
The differential diagnosis includes hepatitis A and the 
same disorders listed for the differential diagnosis of acute 
hepatitis A. In addition, coinfection with HDV must be 
 
»
Strict isolation of patients is not necessary. Thorough hand 
washing by medical staff who may contact contaminated 
utensils, bedding, or clothing is essential. Medical staff 
should handle disposable needles carefully and not recap 
them. Screening of donated blood for HBsAg, anti-HBc, and 
anti-HCV has reduced the risk of transfusion-associated 
hepatitis markedly. All pregnant women should undergo 
testing for HBsAg. HBV-infected persons should practice 
safe sex. Although cesarean section, in combination with 
immunoprophylaxis of the neonate, reduces the risk of peri
-
natal transmission of HBV infection when the mother’s 
serum HBV DNA level is 200,000 international units/mL or 
higher (or the mother’s serum HBsAg level is above 4–4.5 log
10
 
international units/mL), it is preferable to initiate antiviral 
treatment of the mother in the third trimester (see Chronic 
Hepatitis B & Chronic Hepatitis D). HBV-infected health

10
 
Hepatitis B & Chronic Hepatitis D). HBV-infected health 
care workers are not precluded from practicing medicine or 
dentistry if they follow CDC guidelines.
Hepatitis B immune globulin (HBIG) may be protective—
or may attenuate the severity of illness—if given within 
 
7 days after exposure (adult dose is 0.06 mL/kg body 
Table 16–5.
 
Common serologic patterns in hepatitis B virus infection and their interpretation.
HBs
a
g
a
n
ti-HBs
a
n
ti-HBc
HBe
a
g
a
n
ti-HBe
Interpretation
+
–
IgM
+
–
Acute hepatitis B
+
–
IgG
1
+
–
Chronic hepatitis B with active viral replication
+
–
IgG
–
+
Inactive HBV carrier state (low HBV DNA level) or HBeAg-negative chronic 
hepatitis B with active viral replication (high HBV DNA level)
+
+
IgG
+ or –
+ or –
Chronic hepatitis B with heterotypic anti-HBs (about 10% of cases)
–
–
IgM
+ or –
–
–
+
IgG
–
+ or –
Recovery from hepatitis B (immunity)
–
+
–
–
–
Vaccination (immunity)
–
–
IgG
–
–
False-positive; less commonly, infection in remote past
1
Low levels of IgM anti-HBc may also be detected.
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weight) followed by initiation of the HBV vaccine series. 
This approach is recommended for unvaccinated persons 
exposed to HBsAg-contaminated material via mucous 
membranes or through breaks in the skin and for individu
-
als who have had sexual contact with a person with HBV 
infection (irrespective of the presence or absence of HBeAg 
in the source). HBIG is also indicated for newborn infants 
of HBsAg-positive mothers, followed by initiation of the 
vaccine series.
The CDC recommends HBV vaccination of all infants 
and children in the United States and all adults who are at 
risk for hepatitis B (including persons under age 60 with 
diabetes mellitus) or who request vaccination. Over 90% of 
recipients of the vaccine mount protective antibody to 
hepatitis B; immunocompromised persons, including 
patients receiving dialysis (especially those with diabetes 
mellitus), respond poorly (see Table 30–7). Reduced 
response to the vaccine may have a genetic basis in some 
cases and has also been associated with age over 40 years 
and celiac disease. The standard regimen for adults is 
10–20 mcg (depending on the formulation) repeated again 
at 1 and 6 months, but alternative schedules have been 
approved, including accelerated schedules of 0, 1, 2, and 
12 months and of 0, 7, and 21 days plus 12 months. For 
greatest reliability of absorption, the deltoid muscle is the 
preferred site of innoculation. Vaccine formulations free of 
the mercury-containing preservative thimerosal are given 
to infants under 6 months of age. A new vaccine, Hepislav-B, 
which uses a novel immune system–stimulating ingredient, 
was approved by the FDA for adults in 2017. Immunization 
requires only two injections, and Hepislav-B appears to be 
more effective than previous HBV vaccines. When docu
-
mentation of seroconversion is considered desirable, 
postimmunization anti-HBs titers may be checked. Protec
-
tion appears to be excellent even if the titer wanes—at least 
for 20 years—and booster reimmunization is not routinely 
recommended but is advised for immunocompromised 
persons in whom anti-HBs titers fall below 10 milli-
international units/mL. For vaccine nonresponders, three 
additional vaccine doses may elicit seroprotective anti-HBs 
levels in 30–50% of persons. Doubling of the standard dose 
may also be effective. Universal vaccination of neonates in 
countries endemic for HBV has reduced the incidence of 
hepatocellular carcinoma. Incomplete immunization is the 
most important predictor of liver disease among vaccinees.
 
»
Treatment
Treatment of acute hepatitis B is the same as that for acute 
hepatitis A. Encephalopathy or severe coagulopathy indi
-
cates acute liver failure, and hospitalization at a liver trans
-
plant center is mandatory. Antiviral therapy is generally 
unnecessary in patients with acute hepatitis B but is usually 
prescribed in cases of fulminant hepatitis B as well as in 
spontaneous reactivation of chronic hepatitis B presenting 
as acute-on-chronic liver failure (see Acute Liver Failure).
 
»
Prognosis
In most patients, clinical recovery is complete in 3–6 months. 
Laboratory evidence of liver dysfunction may persist for a 
longer period, but most patients recover completely. The 
mortality rate for acute hepatitis B is 0.1–1% but is higher 
with superimposed hepatitis D.
Chronic hepatitis, characterized by elevated amino
-
transferase levels for more than 3–6 months, develops in 
1–2% of immunocompetent adults with acute hepatitis B, 
but in as many as 90% of infected neonates and infants and 
a substantial proportion of immunocompromised adults. 
Ultimately, cirrhosis develops in up to 40% of those with 
chronic hepatitis B; the risk of cirrhosis is even higher in 
HBV-infected patients coinfected with hepatitis C or HIV . 
Patients with cirrhosis are at risk for hepatocellular carci
-
noma at a rate of 3–5% per year. Even in the absence of

-
noma at a rate of 3–5% per year. Even in the absence of 
cirrhosis, patients with chronic hepatitis B—particularly 
those with active viral replication—are at increased risk for 
hepatocellular carcinoma.
 
»
Refer patients with acute hepatitis who require liver biopsy 
 
»
•	
•	
•	
Abara WE et al. Hepatitis B vaccination, screening, and linkage 
to care: best practice advice from the American College of 
Physicians and the Centers for Disease Control and Preven
-
tion. Ann Intern Med. 2017 Dec 5;167(11):794–804. [PMID: 
29159414]
European Association for the Study of the Liver. EASL 2017 
Clinical Practice Guidelines on the management of hepatitis B 
virus infection. J Hepatol. 2017 Aug;67(2):370–98. [PMID: 
28427875]
Roberts H et al. Prevalence of chronic hepatitis B virus (HBV) 
infection in U.S. households: National Health and Nutrition 
Examination Survey (NHANES), 1988–2012. Hepatology. 
2016 Feb;63(2):388–97. [PMID: 26251317]
Visvanathan K et al. Managing HBV in pregnancy. Prevention, 
prophylaxis, treatment and follow-up: position paper produced 
by Australian, UK and New Zealand key opinion leaders. Gut. 
2016 Feb;65(2):340–50. [PMID: 26475631]
ACUTE HEPATITIS C & OTHER CAUSES OF 
ACUTE VIRAL HEPATITIS
Viruses other than HAV and HBV that can cause hepatitis 
are hepatitis C virus (HCV), hepatitis D virus (HDV) 
(delta agent), and hepatitis E virus (HEV) (an enterically 
transmitted hepatitis seen in epidemic form in Asia, 
the Middle East, and North Africa). Human pegivirus 
(formerly hepatitis G virus [HGV]) rarely, if ever, causes 
frank hepatitis. A related virus has been named human 
hepegivirus-1. A DNA virus designated the TT virus 
(TTV) has been identified in up to 7.5% of blood donors 
and found to be transmitted readily by blood transfu
-
sions, but an association between this virus and liver 
disease has not been established. A related virus known as 
SEN-V has been found in 2% of US blood donors, is 
transmitted by transfusion, and may account for some 
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cases of transfusion-associated non-ABCDE hepatitis. In 
immunocompromised and rare immunocompetent per
-
sons, cytomegalovirus, Epstein-Barr virus, and herpes 
simplex virus should be considered in the differential 
diagnosis of hepatitis. Middle East respiratory syndrome 
(MERS), severe acute respiratory syndrome (SARS), 
Ebola virus infection, and influenza may be associated 
with marked serum aminotransferase elevations. Uniden
-
tified pathogens account for a small percentage of cases of 
acute viral hepatitis.
1. Hepatitis C
HCV is a single-stranded RNA virus (hepacivirus) with 
properties similar to those of flaviviruses. Seven major 
genotypes of HCV have been identified. In the past, HCV 
was responsible for over 90% of cases of posttransfusion 
hepatitis, yet only 4% of cases of hepatitis C were attribut
-
able to blood transfusions. Over 50% of cases are trans
-
mitted by injection drug use, and both reinfection and 
superinfection of HCV are common in people who 
actively inject drugs. Body piercing, tattoos, and hemodi
-
alysis are risk factors. The risk of sexual and maternal–
neonatal transmission is low and may be greatest in a 
subset of patients with high circulating levels of HCV 
RNA. Having multiple sexual partners may increase the 
risk of HCV infection, and HIV coinfection, unprotected 
receptive anal intercourse with ejaculation, and sex while 
high on methamphetamine increase the risk of HCV 
transmission in men who have sex with men. Transmis
-
sion via breastfeeding has not been documented. An 
outbreak of hepatitis C in patients with immune deficien
-
cies has occurred in some recipients of intravenous 
immune globulin. Hospital- and outpatient facility–
acquired transmission has occurred via multidose vials of 
saline used to flush Portacaths; through reuse of dispos
-
able syringes; through drug “diversion” and tampering 
with injectable opioids by an infected health care worker; 
through contamination of shared saline, radiopharma
-
ceutical, and sclerosant vials; via inadequately disinfected 
endoscopy equipment; and between hospitalized patients 
on a liver unit. In the developing world, unsafe medical 
practices lead to a substantial number of cases of HCV 
infection. Covert transmission during bloody fisticuffs 
has even been reported, and incarceration in prison is a 
risk factor, with a frequency of 26% in the United States. 
In many patients, the source of infection is unknown. 
Coinfection with HCV is found in at least 30% of HIV-
infected persons. HIV infection leads to an increased risk 
of acute liver failure and more rapid progression of 
chronic hepatitis C to cirrhosis; in addition, HCV 
increases the hepatotoxicity of antiretroviral therapy. The 
number of cases of chronic HCV infections in the United 
States is reported to have decreased from 3.2 million in 
2001 to 2.3 million in 2013, although estimates of at least 
4.6 million exposed and 3.5 million currently infected 
have also been reported. The incidence of new cases of 
acute, symptomatic hepatitis C declined from 1992 to 
2005, but an increase was observed in persons aged 15 to 
24 after 2002, as a result of injection drug use. An increase 
has also been observed in women of reproductive age.
 
»
Figure 16–3 shows the typical course of HCV infection. 
The incubation period for hepatitis C averages 6–7 weeks, 
and clinical illness is often mild, usually asymptomatic, 
and characterized by waxing and waning aminotransferase 
elevations and a high rate (greater than 80%) of chronic 
hepatitis. Spontaneous clearance of HCV following acute 
infection is more common (64%) in persons with the CC 
genotype of the 
IFNL3
 (
IL28B
) gene than in those with 
the CT or TT genotype (24% and 6%, respectively). In 
persons with the CC genotype, jaundice is more likely

IFNL3
 (
IL28B
persons with the CC genotype, jaundice is more likely 
to develop during the course of acute hepatitis C. In pregnant 
patients with chronic hepatitis C, serum aminotransfer
-
ase levels frequently normalize despite persistence of 
viremia, only to increase again after delivery.
Diagnosis of hepatitis C is based on an enzyme immunoassay 
(EIA) that detects antibodies to HCV . Anti-HCV is not 
protective, and in patients with acute or chronic hepatitis, 
its presence in serum generally signifies that HCV is the 
cause. Limitations of the EIA include moderate sensitivity 
(false-negatives) for the diagnosis of acute hepatitis C early 
in the course and low specificity (false-positives) in some 
persons with elevated gamma-globulin levels. In these situ
-
ations, a diagnosis of hepatitis C may be confirmed by using 
an assay for HCV RNA. Occasional persons are found to 
have anti-HCV in serum, without HCV RNA in serum, 
suggesting recovery from HCV infection in the past.
 
»
HCV is a pathogenic factor in mixed cryoglobulinemia and 
membranoproliferative glomerulonephritis and may be 
Symptoms
Jaundice
HCV RNA (PCR)
01
23
45
61
23
45
6
Y ears
Months
Anti-HCV
ALT
Time after exposure
 
▲
Figure 16–3.
 
The typical course of acute and 
chronic hepatitis C. 
(ALT, alanine aminotransferase; Anti-
HCV, antibody to hepatitis C virus by enzyme immunoassay; 
HCV RNA [PCR], hepatitis C viral RNA by polymerase chain 
reaction.)
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related to lichen planus, autoimmune thyroiditis, lymphocytic 
sialadenitis, idiopathic pulmonary fibrosis, sporadic por
-
phyria cutanea tarda, and monoclonal gammopathies. 
HCV infection confers a 20–30% or more increased risk of 
non-Hodgkin lymphoma, and chronic HCV infection 
(especially genotype 1) is associated with an increased risk 
of end-stage renal disease. Hepatic steatosis is a particular 
feature of infection with HCV genotype 3 and may also 
occur in patients infected with other HCV genotypes who 
have risk factors for fatty liver. On the other hand, chronic 
HCV infection is associated with a decrease in serum 
cholesterol and low-density lipoprotein levels.
 
»
Testing donated blood for HCV has helped reduce the risk 
of transfusion-associated hepatitis C from 10% in 1990 to 
about 1 case per 2 million units in 2011. Birth cohort 
screening of persons born between 1945 and 1965 (“baby 
boomers”) for HCV infection has been recommended by 
the CDC and the US Preventive Services Task Force and 
could identify over 900,000 new cases. Universal one-time 
testing has been suggested as an alternative approach. 
HCV-infected persons should practice safe sex, but there is 
little evidence that HCV is spread easily by sexual contact 
or perinatally, and no specific preventive measures are 
recommended for persons in a monogamous relationship 
or for pregnant women. Vaccination against HAV (after 
prescreening for prior immunity) and HBV is recom
-
mended for patients with chronic hepatitis C, just as 
vaccination against HAV is recommended for patients with 
chronic hepatitis B.
 
»
Treatment
In the past, treatment of patients with acute hepatitis C 
with a peginterferon-based regimen for 6–24 weeks was 
shown to appreciably decrease the risk of chronic hepatitis. 
Because 20% of patients with acute hepatitis C, particularly 
those who are symptomatic, clear the virus without such 
treatment, reserving treatment for patients in whom serum 
HCV RNA levels failed to clear after 3 months was advised. 
Oral direct-acting agents have supplanted interferon-based 
therapy (see Chronic Viral Hepatitis), and a 6-week 
course of ledipasvir and sofosbuvir has been shown to 
prevent chronic hepatitis in patients with acute geno
-
type-1 hepatitis C.
 
»
Prognosis
longer period. The overall mortality rate is less than 1%, but 
the rate is reportedly higher in older people. Fulminant 
hepatitis C is rare in the United States.
Chronic hepatitis, which progresses very slowly in 
many cases, develops in as many as 85% of all persons with 
acute hepatitis C. Ultimately, cirrhosis develops in up to 
30% of those with chronic hepatitis C; the risk of cirrhosis 
and hepatic decompensation is higher in patients coin
-
fected with both HCV and HBV or HIV . Patients with 
cirrhosis are at risk for hepatocellular carcinoma at a rate of 
3–5% per year. Long-term morbidity and mortality in 
patients with chronic hepatitis C is lower in black than in 
white patients and lowest in those infected with HCV 
genotype 2 and highest in those with HCV genotype 3.
2. Hepatitis D (Delta 
a
gen
t)
HDV is a defective RNA virus that causes hepatitis only in 
association with HBV infection and specifically only in the 
presence of HBsAg; it is cleared when the latter is cleared.
HDV may coinfect with HBV or may superinfect a 
person with chronic hepatitis B, usually by percutaneous 
exposure. When acute hepatitis D is coincident with acute 
HBV infection, the infection is generally similar in severity 
to acute hepatitis B alone. In chronic hepatitis B, superin
-
fection by HDV appears to carry a worse short-term prog
-
nosis, often resulting in fulminant hepatitis or severe 
chronic hepatitis that progresses rapidly to cirrhosis.
New cases of hepatitis D are now infrequent in the

-
New cases of hepatitis D are now infrequent in the 
United States primarily because of the control of HBV 
infection (although rates of testing HBV carriers for HDV 
are inappropriately low), and cases seen today are usually 
from cohorts infected years ago who survived the initial 
impact of hepatitis D and now have cirrhosis. These 
patients are at risk for decompensation and have a three
-
fold increased risk of hepatocellular carcinoma. New cases 
are seen primarily in immigrants from endemic areas, 
including Africa, central Asia, Eastern Europe, and the 
Amazon region of Brazil. More than 15 million people are 
infected worldwide. The diagnosis of hepatitis D is made 
by detection of antibody to hepatitis D antigen (anti-HDV) 
and, where available, hepatitis D antigen (HDAg) or HDV 
RNA in serum.
3. Hepatitis 
e
HEV is a 27- to 34-nm RNA hepevirus (in the Hepeviridae 
family) that is a major cause of acute hepatitis throughout 
Central and Southeast Asia, the Middle East, and North 
Africa, where it is responsible for waterborne hepatitis 
outbreaks. It is uncommon in the United States (although 
up to 20% of the population have antibodies to the virus) 
but should be considered in patients with acute hepatitis 
after a trip to an endemic area. In rare cases, hepatitis E can 
be mistaken for drug-induced liver injury. In industrialized 
countries, it may be spread by swine, and having a pet in 
the home and consuming undercooked organ meats or 
infected cow’s milk are risk factors. The risk appears to be 
increased in patients undergoing hemodialysis. Illness 
generally is self-limited (no carrier state), but instances of 
chronic hepatitis with rapid progression to cirrhosis 
attributed to HEV have been reported in transplant recipi
-
ents (particularly when tacrolimus rather than cyclosporine 
is used as the main immunosuppressant) and, rarely, in 
persons with HIV infection, preexisting liver disease, or 
cancer undergoing chemotherapy. The diagnosis of acute 
hepatitis E is made most readily by testing for IgM anti-HEV 
in serum, although available tests may not be reliable. 
Reported extrahepatic manifestations include arthritis; pan
-
creatitis; monoclonal gammopathy; thrombocytopenia; a 
variety of neurologic complications, including Guillain-Barré 
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syndrome and peripheral neuropathy; and hemophago
-
cytic lymphohistiocytosis. In endemic regions, the mortality 
rate is high (15–25%) in pregnant women and correlates 
with high levels of HEV RNA in serum and gene mutations 
that lead to reduced expression of progesterone receptors. 
The risk of hepatic decompensation is increased in patients 
with underlying chronic liver disease. A 3-month course of 
treatment with oral ribavirin has been reported to induce 
sustained clearance of HEV RNA from the serum in 78% of 
patients. Improved public hygiene reduces the risk of HEV 
infection in endemic areas. Recombinant vaccines against 
HEV have shown promise in clinical trials, and one (Hecolin) 
is approved in China.
Deterding K et al. Ledipasvir plus sofosbuvir fixed-dose combina
-
tion for 6 weeks in patients with acute hepatitis C virus 
genotype 1 monoinfection (HepNet Acute HCV IV): an open-
label, single-arm, phase 2 study. Lancet Infect Dis. 2017 Feb;
 
17 (2):215–22. [PMID: 28029529]
Donnelly MC et al. Review article: hepatitis E—a concise review 
of virology, epidemiology, clinical presentation and therapy. 
Aliment Pharmacol Ther. 2017 Jul;46(2):126–41. [PMID: 
28449246]
Friedman LS et al. Case Records of the Massachusetts General 
Hospital: Case 36-2016: a 50-year-old man with acute liver 
injury. N Engl J Med. 2016 Nov 24;375(21):2082–92. [PMID: 
27959737]
Ly KN et al. Hepatitis C virus infection among reproductive-aged 
women and children in the United States, 2006 to 2014. Ann 
Intern Med. 2017 Jun 6;166(11):775–82. [PMID: 28492929]
ACUTE LIVER FAILURE
 
»
May be fulminant or subfulminant; both forms 
carry a poor prognosis.
 
»
Acetaminophen and idiosyncratic drug reactions 
are the most common causes.
 
»
Acute liver failure may be fulminant or subfulminant. 
Fulminant hepatic failure is characterized by the develop
-
ment of hepatic encephalopathy within 8 weeks after the 
onset of acute liver injury. Coagulopathy (international 
normalized ratio [INR] 1.5 or higher) is invariably present. 
Subfulminant hepatic failure occurs when these findings 
appear between 8 weeks and 6 months after the onset of acute 
liver injury and carries an equally poor prognosis. Acute-
on-chronic liver failure refers to acute deterioration in liver 
function in a person with preexisting chronic liver disease.
An estimated 1600 cases of acute liver failure occur each 
year in the United States. Acetaminophen toxicity is the 
most common cause, accounting for at least 45% of cases. 
Suicide attempts account for 44% of cases of acetaminophen-
induced hepatic failure, and unintentional overdoses (“ther
-
apeutic misadventures”), which are often a result of a 
decrease in the threshold toxic dose because of chronic 
alcohol use or fasting and have been reported after weight 
loss surgery, account for at least 48%. Other causes include 
idiosyncratic drug reactions (the second most common 
cause, with antituberculosis drugs, antiepileptics, and antibi
-
otics implicated most commonly), viral hepatitis, poisonous 
mushrooms (
Amanita phalloides
), shock, hyperthermia, 
Budd-Chiari syndrome, malignancy (most commonly lym
-
phomas), Wilson disease, Reye syndrome, fatty liver of 
pregnancy and other disorders of fatty acid oxidation, auto
-
immune hepatitis, parvovirus B19 infection and, rarely, 
grand mal seizures. The risk of acute liver failure is increased 
in patients with diabetes mellitus, and outcome is worsened 
by obesity. Herbal and dietary supplements are thought to be 
contributory to acute liver failure in a substantial portion of 
cases, regardless of cause, and may be associated with lower 
rates of transplant-free survival. Acute-on-chronic liver fail
-
ure is often precipitated by a bacterial infection or an alcohol 
binge and alcoholic hepatitis.

-
Viral hepatitis now accounts for only 12% of all cases of 
acute liver failure. The decline of viral hepatitis as the prin
-
cipal cause of acute liver failure is due to universal vaccina
-
tion of infants and children against hepatitis B and the 
availability of the hepatitis A vaccine. Acute liver failure may 
occur after reactivation of hepatitis B in carriers who receive 
immunosuppressive therapy. In endemic areas, hepatitis E is 
an important cause of acute liver failure, particularly in preg
-
nant women. Hepatitis C is a rare cause of acute liver failure 
in the United States, but acute hepatitis A or B superimposed 
on chronic hepatitis C may cause acute liver failure.
 
»
Gastrointestinal symptoms, systemic inflammatory 
response, renal dysfunction, and hemorrhagic phenomena 
are common. Adrenal insufficiency and subclinical myo
-
cardial injury manifesting as an elevated serum troponin I 
level often complicate acute liver failure. Jaundice may be 
absent or minimal early, but laboratory tests show severe 
hepatocellular damage. In acetaminophen toxicity, serum 
aminotransferase elevations are often towering (greater 
than 5000 units/L). In acute liver failure due to microve
-
sicular steatosis (eg, fatty liver of pregnancy), serum 
aminotransferase elevations may be modest (less than 
300 units/L). Over 10% of patients have an elevated serum 
amylase level at least three times the upper limit of normal, 
often as a result of renal dysfunction. The blood ammonia 
level is typically elevated and correlates (along with the 
Model for End-Stage Liver Disease [MELD] score) with the 
development of encephalopathy and intracranial hyperten
-
sion. Intracranial hypertension rarely develops when the 
blood ammonia level is less than 75 mcmol/L and is invariable 
when it is greater than 200 mcmol/L. The severity of extra
-
hepatic organ dysfunction (as assessed by the Sequential 
Organ Failure Assessment [SOFA]) also correlates with the 
likelihood of intracranial hypertension. Acute kidney injury 
frequently complicates acute-on-chronic liver failure.
 
»
Treatment
The treatment of acute liver failure is directed toward achiev
-
ing metabolic and hemodynamic stability. Intravascular 
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volume should be preserved, but large-volume infusions of 
hypotonic fluids should be avoided. Norepinephrine is the 
preferred vasopressor. Hypoglycemia should be prevented. 
Intermittent renal replacement therapy may be required. To 
preserve muscle mass and immune function, enteral admin
-
istration of protein, 1–1.5 g/kg/day, is advised, with careful 
monitoring of the ammonia level. Cerebral edema and sepsis 
are the leading causes of death. Prophylactic antibiotic therapy 
decreases the risk of infection, observed in up to 90%, but has 
no effect on survival and is not routinely recommended. 
Microbiological screening cultures should be obtained for 
patients admitted to hospital. For suspected sepsis, broad 
coverage is indicated. Despite a high rate of adrenal insuffi
-
ciency, corticosteroids do not reduce mortality and may 
lower overall survival in patients with a high MELD score, 
though they may reduce vasopressor requirements. Stress 
gastropathy prophylaxis with an H
2
-receptor blocker or pro
-
ton pump inhibitor is recommended. Administration of 
acetylcysteine (140 mg/kg orally followed by 70 mg/kg orally 
every 4 hours for an additional 17 doses or 150 mg/kg in 
 
5% dextrose intravenously over 15 minutes followed by 
50 mg/kg over 4 hours and then 100 mg/kg over 16 hours) is 
indicated for acetaminophen toxicity up to 72 hours after 
ingestion. For massive acetaminophen overdoses, treatment 
with intravenous acetylcysteine may need to be extended in 
duration until the serum aminotransferase levels are declin
-
ing and serum acetaminophen levels are undetectable. Treat
-
ment with acetylcysteine improves cerebral blood flow and 
oxygenation as well as transplant-free survival in patients 
with stage 1 or 2 encephalopathy due to fulminant hepatic 
failure of any cause. (Acetylcysteine treatment can prolong 
the prothrombin time, leading to the erroneous assumption 
that liver failure is worsening; it can also cause nausea, vomiting, 
and an anaphylactoid reaction [especially in persons with a 
history of asthma].) Penicillin G (300,000 to 1 million units/kg/
day) or silibinin (silymarin or milk thistle), which is not 
licensed in the United States, is administered to patients with 
mushroom poisoning. Nucleoside analogs are recommended 
for patients with fulminant hepatitis B (see Chronic Viral 
Hepatitis), and intravenous acyclovir has shown benefit in 
those with herpes simplex virus hepatitis. Plasmapheresis 
combined with D-penicillamine has been used in fulminant 
Wilson disease. Subclinical seizure activity is common in 
patients with acute liver failure, but the value of prophylactic 
phenytoin is uncertain.
Early transfer to a liver transplantation center is essen
-
tial. The head of the patient’s bed should be elevated to 
 
30 degrees, and patients with stage 3 or 4 encephalopathy 
should be intubated. Extradural sensors may be placed in 
patients at high risk for intracranial hypertension. to moni
-
tor intracranial pressure for impending cerebral edema 
with the goal of maintaining the intracranial pressure 
below 20 mm Hg and the cerebral perfusion pressure above 
70 mm Hg. Recombinant activated factor VIIa may be admin
-
istered to reduce the risk of bleeding associated with intra
-
cranial pressure monitoring. Lactulose is generally avoided. 
Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by 
intravenous infusion over 10 minutes, may decrease cerebral 
edema but should be used with caution in patients with 
advanced chronic kidney disease. Intravenously administered 
hypertonic saline to induce hypernatremia (serum sodium 
concentration of 145–155 mEq/L [145–155 mmol/L]) also may 
reduce intracranial hypertension. Hypothermia to a tem
-
perature of 32–34°C may reduce intracranial pressure 
when other measures have failed and may improve survival 
long enough to permit liver transplantation, although a 
controlled trial showed no benefit and some authorities

controlled trial showed no benefit and some authorities 
recommend a target core temperature of 35–36°C. The 
value of hyperventilation and intravenous prostaglandin E
1
 
is uncertain. A short-acting barbiturate, propofol, or intra
-
venous boluses of indomethacin, 25 mg, is considered for 
refractory intracranial hypertension.
 
»
Prognosis
With earlier recognition of acute liver failure, the fre
-
quency of cerebral edema has declined, and overall survival 
has improved steadily since the 1970s and is now as high 
as 75%. However, the survival rate in fulminant hepatic 
failure with severe encephalopathy is as low as 20%, 
except for acetaminophen hepatotoxicity, in which the 
transplant-free survival is 65% and no more than 8% of 
patients undergo liver transplantation. For patients with 
fulminant hepatic failure of other causes, the outlook is 
poor in patients younger than 10 and older than 40 years of 
age and in those with an idiosyncratic drug reaction but 
appears to be improved when acetylcysteine is adminis
-
tered to patients with stage 1 or 2 encephalopathy. Sponta
-
neous recovery is less likely for hepatitis B than for 
hepatitis A. Other adverse prognostic factors are a serum 
bilirubin level greater than 18 mg/dL (307.8 mcmol/L), 
INR higher than 6.5, onset of encephalopathy more than 7 
days after the onset of jaundice, and a low factor V level 
(less than 20% of normal). For acetaminophen-induced 
fulminant hepatic failure, indicators of a poor outcome are 
acidosis (pH < 7.3), INR greater than 6.5, and azotemia 
(serum creatinine 3.4 mg/dL [283.22 mcmol/L] or 
higher), whereas a rising serum alpha-fetoprotein level pre
-
dicts a favorable outcome. An elevated blood lactate level 
(greater than 3.5 mEq/L [3.5 mmol/L]), elevated blood 
ammonia level (greater than 211 mcg/dL [124 mcmol/L]), 
and possibly hyperphosphatemia (greater than 3.7 mg/dL 
[1.2 mmol/L]) also predict poor survival. One study has 
shown that patients with persistent elevation of the arterial 
ammonia level (211 mcg/dL [122 mcmol/L] or higher) for 
3 days have greater rates of complications and mortality 
than those with decreasing ammonia levels. The develop
-
ment of thrombocytopenia in the first week is associated 
with the development of multiorgan system failure and a 
poor outcome. A number of prognostic indices have been 
proposed: the “BiLE” score, based on the serum bilirubin, 
serum lactate, and etiology; the Acute Liver Failure Early 
Dynamic (ALFED) model, based on the arterial ammonia 
level, serum bilirubin, INR, and hepatic encephalopathy; 
and the Acute Liver Failure Study Group (ALFSG) index, 
based on coma grade, INR, serum bilirubin and phospho
-
rous levels, and serum levels of M30, a cleavage product of 
cytokeratin-18 caspase. The likelihood of transplant-free 
survival on admission has been reported to be predicted by 
a regression model that incorporates the grade of hepatic 
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encephalopathy, etiology, vasopressor use, and log trans
-
formations of the serum bilirubin and INR. Emergency 
liver transplantation is considered for patients with stage 2 
to stage 3 encephalopathy or a MELD score of 30.5 or 
higher (see Cirrhosis) and is associated with a 70% sur
-
vival rate at 5 years. For mushroom poisoning, liver trans
-
plantation should be considered when the interval between 
ingestion and the onset of diarrhea is less than 
 
8 hours or the INR is 6.0 or higher, even in the absence of 
encephalopathy. Acute-on-chronic liver failure has a poor 
prognosis, particularly when associated with kidney dys
-
function. Some patients may be candidates for liver 
 
»
All patients with acute liver failure should be hospitalized.
European Association for the Study of the Liver et al. EASL 
Clinical Practical Guidelines on the management of acute 
(fulminant) liver failure. J Hepatol. 2017 May;66(5):1047–81. 
[PMID: 28417882]
Flamm SL et al. American Gastroenterological Association 
Institute guidelines for the diagnosis and management of 
acute liver failure. Gastroenterology. 2017 Feb;152(3):644–7. 
[PMID: 28056348]
Hernaez R et al. Acute-on-chronic liver failure: an update. Gut. 
2017 Mar;66(3):541–53. [PMID: 28053053]
Herrine SK et al. American Gastroenterological Association 
Institute technical review on initial testing and management 
of acute liver disease. Gastroenterology. 2017 Feb;152(3):
 
648–64. [PMID: 28061338]
Putignano A et al. New concepts in acute-on-chronic liver failure: 
implications for liver transplantation. Liver Transpl. 2017 Feb;
 
23(2):234–43. [PMID: 27750389]
CHRONIC VIRAL HEPATITIS
 
»
Defined by chronic infection (HBV, HCV, HDV) for 
longer than 3–6 months.
 
»
Diagnosis is usually made by antibody tests and 
viral nucleic acid in serum.
 
»
Chronic hepatitis is defined as chronic necroinflammation of 
the liver of more than 3–6 months’ duration, demonstrated 
by persistently elevated serum aminotransferase levels or 
characteristic histologic findings. In many cases, the diagno
-
sis of chronic hepatitis may be made on initial presentation. 
The causes of chronic hepatitis include HBV , HCV , and HDV 
as well as autoimmune hepatitis; alcoholic and nonalcoholic 
steatohepatitis; certain medications, such as isoniazid and 
nitrofurantoin; Wilson disease; alpha-1-antiprotease defi
-
ciency; and, rarely, celiac disease. Mortality from chronic 
HBV and HCV infection has been rising in the United States, 
and HCV has surpassed HIV as a cause of death. Chronic 
hepatitis is categorized on the basis of etiology; the grade of 
portal, periportal, and lobular inflammation (minimal, mild, 
moderate, or severe); and the stage of fibrosis (none, mild, 
moderate, severe, cirrhosis). In the absence of advanced 
cirrhosis, patients are often asymptomatic or have mild non
-
specific symptoms.
1. Chronic Hepatitis B & Chronic Hepatitis D
 
»
Clinical Findings & Diagnosis
Chronic hepatitis B afflicts 248 million people worldwide 
(2 billion overall have been infected; endemic areas include 
Asia and sub-Saharan Africa) and up to 2.2 million (pre
-
dominantly males) in the United States. It may be noted as 
a continuum of acute hepatitis B or diagnosed because of 
repeated detection of HBsAg in serum, often with elevated 
aminotransferase levels.
Four phases of HBV infection are recognized: immune 
tolerant phase, immune clearance phase, inactive HBsAg 
carrier state, and reactivated chronic hepatitis B phase. In 
the 
immune tolerant phase,
 HBeAg and HBV DNA are 
present in serum and are indicative of active viral replica
-
tion, and serum aminotransferase levels are normal, with 
little necroinflammation in the liver. This phase is common 
in infants and young children whose immature immune 
system fails to mount an immune response to HBV . Per

-
sons in the immune tolerant phase and those who acquire 
HBV infection later in life may enter an 
immune clearance 
phase,
 in which aminotransferase levels are elevated and 
necroinflammation is present in the liver, with a risk of 
progression to cirrhosis (at a rate of 2–5.5% per year) and 
of hepatocellular carcinoma (at a rate of more than 2% per year 
in those with cirrhosis); low-level IgM anti-HBc is present 
in serum in about 70%.
Patients enter the 
inactive HBsAg carrier state
 when 
biochemical improvement follows immune clearance. This 
improvement coincides with disappearance of HBeAg and 
reduced HBV DNA levels (less than 10
5
 copies/mL, or less 
than 20,000 international units/mL) in serum, appearance 
of anti-HBe, and integration of the HBV genome into 
the host genome in infected hepatocytes. Patients in this 
phase are at a low risk for cirrhosis (if it has not already 
developed) and hepatocellular carcinoma, and those with 
persistently normal serum aminotransferase levels infre
-
quently have histologically significant liver disease, especially 
if the HBsAg level is low.
The 
reactivated chronic hepatitis B phase
 may result 
from infection by a pre-core mutant of HBV or spontane
-
ous mutation of the pre-core or core promoter region of the 
HBV genome during the course of chronic hepatitis caused 
by wild-type HBV . So-called HBeAg-negative chronic 
hepatitis B accounts for less than 10% of cases of chronic 
hepatitis B in the United States, up to 50% in southeast 
Asia, and up to 90% in Mediterranean countries, reflecting 
in part differences in the frequencies of HBV genotypes. In 
reactivated chronic hepatitis B, there is a rise in serum 
HBV DNA levels and possible progression to cirrhosis 
(at a rate of 8–10% per year), particularly when additional 
mutations in the core gene of HBV are present. Risk factors 
for reactivation include male sex and HBV genotype C as 
well as immunosuppression. Treatment of HCV infection 
with direct-acting antiviral agents has been reported to 
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lead to instances of HBV reactivation. In patients with 
either HBeAg-positive or HBeAg-negative chronic hepatitis 
B, the risk of cirrhosis and of hepatocellular carcinoma 
correlates with the serum HBV DNA level. Other risk 
factors include advanced age, male sex, alcohol use, cigarette 
smoking, HBV genotype C, and coinfection with HCV or 
HDV . HIV coinfection is also associated with an increased 
frequency of cirrhosis when the CD4 count is low.
Acute 
hepatitis D
 infection superimposed on chronic 
HBV infection may result in severe chronic hepatitis, which 
may progress rapidly to cirrhosis and may be fatal. Patients 
with long-standing chronic hepatitis D and B often have 
inactive cirrhosis and are at risk for decompensation and 
hepatocellular carcinoma. The diagnosis is confirmed by 
detection of anti-HDV or HDAg (or HDV RNA) in serum.
 
»
Treatment
Patients with active viral replication (HBeAg and HBV 
DNA [10
5
 copies/mL or more, or 20,000 international 
units/mL or more] in serum and elevated aminotransferase 
levels) may be treated with a nucleoside or nucleotide analog 
or with pegylated interferon. Nucleoside and nucleotide 
analogs are preferred because they are better tolerated and 
can be taken orally. For patients who are HBeAg-negative, 
the threshold for treatment is a serum HBV DNA level of 
10
4
 copies/mL or more, or 2000 international units/mL or 
more. If the threshold HBV DNA level for treatment is met 
but the serum ALT level is normal, treatment may still be 
considered in patients over age 35–40 if liver biopsy dem
-
onstrates a fibrosis stage of 2 of 4 (moderate) or higher. 
Therapy is aimed at reducing and maintaining the serum 
HBV DNA level to the lowest possible levels, thereby leading 
to normalization of the ALT level and histologic improvement. 
An additional goal in HBeAg-positive patients is serocon
-
version to anti-HBe, and some responders eventually clear 
HBsAg. Although nucleoside and nucleotide analogs gen
-
erally have been discontinued 6–12 months after HBeAg-
to-anti-HBe seroconversion, some patients (especially 
Asian patients) serorevert to HBeAg after discontinuation, 
have a rise in HBV DNA levels and recurrence of hepatitis 
activity, and require long-term therapy, which also is 
required when seroconversion does not occur. HBeAg-
negative patients with chronic hepatitis B also generally 
require long-term therapy because relapse is frequent when 
therapy is stopped.
The available nucleoside and nucleotide analogs—
entecavir, tenofovir, lamivudine, adefovir, and telbivudine—
differ in efficacy and rates of resistance; however, in 
HBeAg-positive patients, they all achieve an HBeAg-to-anti-
HBe seroconversion rate of about 20% at 1 year, with 
higher rates after more prolonged therapy. The preferred 
first-line oral agents are entecavir and tenofovir. Entecavir 
is rarely associated with resistance unless a patient is 
already resistant to lamivudine. The daily dose is 0.5 mg 
orally for patients not resistant to lamivudine and 1 mg for 
patients who previously became resistant to lamivudine. 
Suppression of HBV DNA in serum occurs in nearly all 
treated patients, and histologic improvement is observed in 
70% of patients. Entecavir has been reported to cause lactic 
acidosis when used in patients with decompensated 
cirrhosis. Tenofovir disoproxil fumarate, 300 mg orally 
daily, is equally effective and is used as a first-line agent or 
when resistance to a nucleoside analog has developed. Like 
entecavir, tenofovir has a low rate of resistance when used 
as initial therapy. Long-term use may lead to an elevated 
serum creatinine level and reduced serum phosphate level 
(Fanconi-like syndrome) that is reversible with discontinu
-
ation of the drug. Tenofovir alafenamide, 25 mg orally 
daily, is an alternative formulation of tenofovir that was 
approved by the FDA in 2016 and that may be associated

-
approved by the FDA in 2016 and that may be associated 
with a lower rate of renal and bone toxicity than tenofovir 
disoproxil fumarate.
The first available nucleoside analog was lamivudine, 
100 mg orally daily. By the end of 1 year of therapy with 
lamivudine, however, 15–30% of responders experience a 
relapse (and occasionally frank decompensation). The rate 
of resistance reaches 70% by 5 years of therapy, and the drug 
is no longer considered first-line therapy in the United 
States but may be used in countries in which cost is a 
deciding factor. Adefovir dipivoxil has activity against 
wild-type and lamivudine-resistant HBV but is the least 
potent of the oral antiviral agents for HBV . The standard 
dose is 10 mg orally once a day for at least 1 year. As with 
lamivudine, only a small number of patients achieve sus
-
tained suppression of HBV replication with adefovir, and 
long-term suppressive therapy is often required. Resistance 
to adefovir occurs in up to 29% of patients treated for 
 
5 years. Patients with underlying kidney dysfunction are at 
risk for nephrotoxicity from adefovir. Telbivudine, given in 
a daily dose of 600 mg orally, is more potent than either 
lamivudine or adefovir. Resistance to this drug may 
develop, however, particularly in patients who are resistant 
to lamivudine, and elevated creatine kinase levels are com
-
mon in patients treated with telbivudine. Strategies using 
multiple drugs have generally not proved advantageous. 
Other antiviral agents are under study.
The development of resistance occasionally results in 
hepatic decompensation. Resistance is most likely to 
develop to lamivudine and may develop to adefovir and 
telbivudine, but these drugs are no longer used as first-line 
agents in the United States. Sequential addition of a second 
antiviral agent is usually effective after resistance to the 
first agent has developed. Combined use of peginterferon 
and a nucleoside or nucleotide analog has not been shown 
convincingly to have a substantial advantage over the use of 
either type of drug alone. Nucleoside and nucleotide ana
-
logs are well tolerated even in patients with decompensated 
cirrhosis (for whom the treatment threshold may be an 
HBV DNA level less than 10
4
 copies/mL and therapy 
should be continued indefinitely) and may be effective in 
patients with rapidly progressive hepatitis B (“fibrosing 
cholestatic hepatitis”) following organ transplantation.
Nucleoside analogs are also recommended for inactive 
HBV carriers (and those positive only for anti-HBc) prior 
to the initiation of immunosuppressive therapy (including 
rituximab or anti-tumor necrosis factor antibody therapy) 
or cancer chemotherapy to prevent reactivation; entecavir 
has been shown to be more effective than lamivudine. In 
patients infected with both HBV and HIV , antiretroviral 
therapy, including two drugs active against both viruses 
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(eg, tenofovir plus lamivudine or emtricitabine), has been 
recommended when treatment of HIV infection is indicated. 
Telbivudine and tenofovir are classified as pregnancy 
category B drugs, and lamivudine, a category C drug, 
has been shown to be safe in pregnant women with HIV 
infection. Antiviral therapy has been recommended, 
beginning in the third trimester, when the mother’s 
serum HBV DNA level is 200,000 international units/mL 
or higher to reduce levels at the time of delivery.
Peginterferon alfa-2a is still an alternative to the oral 
agents in selected cases. A dose of 180 mcg subcutaneously 
once weekly for 48 weeks leads to sustained normalization of 
aminotransferase levels, disappearance of HBeAg and HBV 
DNA from serum, and appearance of anti-HBe in up to 40% 
of treated patients and results in improved survival. A 
response is most likely in patients with a low baseline HBV 
DNA level and high aminotransferase levels and is more 
likely in those who are infected with HBV genotype A than 
with other genotypes (especially genotype D). Moreover, 
many complete responders eventually clear HBsAg and 
develop anti-HBs in serum, and are thus cured. Relapses are 
uncommon in complete responders who seroconvert from 
HBeAg to anti-HBe. Peginterferon may be considered in 
order to avoid long-term therapy with an oral agent, as in 
young women who may want to become pregnant in the 
future. Patients with HBeAg-negative chronic hepatitis B 
have a response rate of 60% after 48 weeks of therapy with 
peginterferon, but the response may not be durable once 
peginterferon is stopped. The response to peginterferon is 
poor in patients with HIV coinfection.
In 
chronic hepatitis D
, peginterferon alfa-2b (1.5 mcg/
kg/wk for 48 weeks) may lead to normalization of serum 
aminotransferase levels, histologic improvement, and elimi
-
nation of HDV RNA from serum in 20–50% of patients, but 
relapse may occur and tolerance is poor. Nucleoside and 
nucleotide analogs are generally not effective in treating 
chronic hepatitis D.
 
»
Prognosis
The course of chronic hepatitis B is variable. The sequelae 
of chronic hepatitis secondary to hepatitis B include cirrhosis, 
liver failure, and hepatocellular carcinoma. The 5-year 
mortality rate is 0–2% in those without cirrhosis, 14–20% 
in those with compensated cirrhosis, and 70–86% follow
-
ing decompensation. The risk of cirrhosis and hepatocel
-
lular carcinoma correlates with serum HBV DNA levels, 
and a focus of therapy is to suppress HBV DNA levels 
below 300 copies/mL (60 international units/mL). In 
patients with cirrhosis, even low levels of HBV DNA in 
serum increase the risk of hepatocellular carcinoma com
-
pared with undetectable levels. HBV genotype C is associ
-
ated with a higher risk of cirrhosis and hepatocellular 
carcinoma than other genotypes. Antiviral treatment 
improves the prognosis in responders, prevents (or leads to 
regression of) cirrhosis, and decreases the frequency of 
liver-related complications (although the risk of hepatocel
-
lular carcinoma does not become as low as that in inactive 
HBV carriers and hepatocellular carcinoma may even 
occur after clearance of HBsAg). A risk score (PAGE-B) 
based on a patient’s age, sex, and platelet count has been 
reported to predict the 5-year risk of hepatocellular carcinoma 
in white patients taking entecavir or tenofovir.
2. Chronic Hepatitis C
 
»
Chronic hepatitis C develops in up to 85% of patients with 
acute hepatitis C. It is clinically indistinguishable from 
chronic hepatitis due to other causes and may be the most 
common. Worldwide, 170 million people are infected with 
HCV , with 1.8% of the US population infected. Peak preva
-
lence in the United States (about 4%) is in persons born 
between 1945 and 1964. In approximately 40% of cases, 
serum aminotransferase levels are persistently normal. The

-
serum aminotransferase levels are persistently normal. The 
diagnosis is confirmed by detection of anti-HCV by EIA. 
In rare cases of suspected chronic hepatitis C but a negative 
EIA, HCV RNA is detected by PCR testing. Progression to 
cirrhosis occurs in 20% of affected patients after 20 years, 
with an increased risk in men, those who drink more than 
50 g of alcohol daily, and those who acquire HCV infection 
after age 40 years. The rate of fibrosis progression acceler
-
ates after age 50. African Americans have a higher rate of 
chronic hepatitis C but lower rates of fibrosis progression 
and response to therapy than whites. Immunosuppressed 
persons—including patients with hypogammaglobu
-
linemia or HIV infection with a low CD4 count or those 
receiving immunosuppressants—appear to progress more 
rapidly to cirrhosis than immunocompetent persons with 
chronic hepatitis C. Tobacco and cannabis smoking and 
hepatic steatosis also appear to promote progression of 
fibrosis, but coffee consumption appears to slow progres
-
sion. Persons with chronic hepatitis C and persistently 
normal serum aminotransferase levels usually have mild 
chronic hepatitis with slow or absent progression to cirrhosis; 
however, cirrhosis is present in 10% of these patients. Serum 
fibrosis testing (eg, FibroSure) or ultrasound elastography 
may be used to identify the absence of fibrosis or presence of 
cirrhosis.
 
»
Treatment
The introduction of direct-acting and host-targeting anti
-
viral agents has rapidly expanded the therapeutic arma
-
mentarium against HCV (Table 16–6). Standard therapy 
for HCV infection from the late 1990s to the early 2010s 
was a combination of peginterferon plus ribavirin, and 
ribavirin continues to be used in some all-oral regimens. 
Sustained virologic response rates (negative HCV RNA in 
serum at 24 weeks after completion of therapy) for 
peginterferon plus ribavirin were 45% in patients with 
HCV genotype 1 infection and 70–80% in those with geno
-
type 2 or 3 infection. Higher rates of response were 
achieved in persons infected with HCV genotype 1 when a 
first-generation direct-acting antiviral agent—boceprevir 
or telaprevir (agents no longer available in the United 
States), nonstructural (NS) 3/4A serine protease inhibi
-
tors—was added to peginterferon plus ribavirin. Sustained 
response rates were as high as 75% for HCV genotype 1 
with a standard three-drug regimen. With the addition of 
the protease inhibitor, the treatment duration for HCV 
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Table 16–6.
 
Direct-acting antiviral agents for HCV infection (in alphabetic order within class).
1
a
gen
t
Genotype(s)
Dose
2
Comment
NS3/4
a
 Protease Inhibitors
Glecaprevir
1–6
300 mg orally once daily
Used in combination with pibrentasvir
3
 with or without ribavirin
Grazoprevir
1 and 4
100 mg orally once daily
Used in combination with elbasvir
4
Paritaprevir
1 and 4
150 mg orally once daily
Used in combination with ombitasvir and dasabuvir; ritonavir (100 mg) 
boosted;
5
 for genotype 1b with cirrhosis and genotype 1a, used with 
ribavirin. Used in combination with ombitasvir, ritonavir boosting, and 
ribavirin for genotype 4
6
Simeprevir
1 and 4
Used in combination with pegylated interferon and ribavirin or with 
sofosbuvir
Voxilaprevir
1–6
Used in combination with sofosbuvir and velpatasvir
7
NS5
a
Daclatasvir
8
1–6
60 mg orally once daily
Used in combination with sofosbuvir (genotypes 1–6, with or without 
 
ribavirin depending on presence of cirrhosis) or with pegylated interferon 
and ribavirin (genotype 4) or with asunaprevir (not available in the 
 
Elbasvir
1–6
50 mg orally once daily
Used in combination with grazoprevir
Ledipasvir
1, 4–6
90 mg orally once daily
Used in combination with sofosbuvir
9
Ombitasvir
1 and 4
25 mg orally once daily
Used in combination with paritaprevir (ritonavir boosted) with or without 
dasabuvir and with or without ribavirin as per paritaprevir above
Pibrentasvir
1–6
120 mg orally once daily
Used in combination with glecaprevir with or without ribavirin
Velpatasvir
1–6
10
, may be used with sofosbuvir and 
voxilaprevir
NS5B Nucleos(t)ide Polymerase Inhibitor
Sofosbuvir
1–6
400 mg orally once daily
Used in combination with pegylated interferon and ribavirin (all 
 
genotypes) or with ribavirin alone (genotypes 2 and 3) or with simeprevir 
(genotypes 1 and 4) or with daclatasvir (all genotypes) or with ledipasvir 
(genotypes 1, 3, and 4) or with velpatasvir (all genotypes) or with 
velpatasvir and voxilaprevir (all genotypes)
NS5B Non-Nucleos(t)ide Polymerase Inhibitor
Dasabuvir
1 and 4
250 mg orally twice daily
Used in combination with paritaprevir (ritonavir boosted) and ombitasvir 
with or without ribavirin as per paritaprevir above
1
Regimens approved by the FDA as of early 2018; additional drugs are under study.
2
The preferred regimen and duration of treatment may vary depending on HCV genotype, presence or absence of cirrhosis, or nonresponse 
to prior therapy for HCV infection. In selected cases, testing for resistance-associated substitutions may be considered.
3
 Marketed as Mavyret (AbbVie).
4
Marketed as Zepatier (Merck) for HCV genotypes 1 and 4 infection.
5
Marketed as Viekira Pak and Viekira XR (AbbVie).
6
Marketed as Technivie (AbbVie).
7
 Marketed as Vosevi (Gilead Sciences).
8
Approved by the FDA for use with sofosbuvir in HCV genotypes 1 and 3 infection.
9
Marketed as Harvoni (Gilead Sciences).
10
Marketed as Epclusa (Gilead Sciences).
genotype 1 infection could be shortened to 24 weeks, 
depending on the rapidity of clearance of HCV RNA from 
serum—so-called response-guided therapy.
Treatment with peginterferon-based therapy was asso
-
ciated with frequent, often distressing, side effects, and 
discontinuation rates were as high as 15–30%. Peginterferon 
alfa is contraindicated in pregnant or breastfeeding women 
and those with decompensated cirrhosis, profound cytope
-
nias, severe psychiatric disorders, autoimmune diseases, or 
an inability to self-administer or comply with treatment. 
Men and women taking ribavirin must practice strict con
-
traception until 6 months after the conclusion of therapy 
because of its teratogenic effects in animals. Ribavirin 
should be used with caution in persons over 65 years of age 
and in others in whom hemolysis could pose a risk of 
angina or stroke.

The definition of clearance of HCV RNA requires use 
of a sensitive real-time reverse transcriptase-PCR assay to 
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monitor HCV RNA during treatment (the lower limit of 
quantification should be 25 international units/mL or less, 
and the limit of detection should be 10–15 international 
units/mL). After the introduction of all-oral regimens, the 
criterion for a sustained virologic response was shortened 
from 24 weeks to 12 weeks following the completion of 
Several types of direct-acting antiviral agents have been 
developed (Table 16–6). HCV protease inhibitors (“…previrs”) 
generally have high antiviral potency but differ with respect to 
the development of resistance (although resistance-associated 
substitutions in the HCV genome tend not to persist after 
therapy with these agents is stopped). Some of the compounds 
show better response rates in HCV genotype 1b than in 
genotype 1a infection.
HCV polymerase inhibitors (“…buvirs”) are categorized 
as nucleoside or nucleotide analog and non-nucleoside poly
-
merase inhibitors. Nucleos(t)ide analogs are active against 
all HCV genotypes and have a high barrier to resistance. 
Non-nucleos(t)ide polymerase inhibitors are the weakest 
class of compounds against HCV because of a low barrier to 
resistance. Drugs in this class are generally more active 
against HCV genotype 1b than HCV genotype 1a. They have 
been developed to be used only in combination with the other 
direct-acting antiviral agents, mainly protease inhibitors and 
NS5A inhibitors. The first approved HCV NS5B nucleotide 
polymerase inhibitor was sofosbuvir in 2013.
Sofosbuvir was initially approved for use in combina
-
tion with peginterferon and ribavirin in patients with HCV 
genotype 1 infection and with ribavirin alone in patients 
with HCV genotype 2 or 3 infection (see Table 16–6). Most 
patients with HCV genotype 2 or 3 infection, including 
those with HIV coinfection, are cured with 12 or 24 weeks 
of therapy, respectively. HCV genotype 2 responds much 
better to interferon-free sofosbuvir-based therapy than 
HCV genotype 3, but the sustained virologic response is 
20–30% lower in patients with cirrhosis and the combina
-
tion of sofosbuvir and ribavirin has been reported to cause 
lactic acidosis in some patients with advanced cirrhosis. 
Importantly, no sofosbuvir-resistant variants have been 
selected during therapy. The combination of sofosbuvir 
and simeprevir was found to be effective in HCV genotype 1 
infection and was approved by the FDA in 2014; the 
approval was extended to HCV genotypes 4, 5, and 6 in 
2015. Sofosbuvir was also approved to be used in combination 
with ledipasvir.
The combination of paritaprevir (an NS3/4A protease 
inhibitor), boosted by ritonavir, plus ombitasvir (an NS5A 
inhibitor) and dasabuvir (an NS5B non-nucleoside poly
-
merase inhibitor) is effective in HCV genotype-1 treatment-
naive patients and prior nonresponders to interferon-based 
therapy, with or without cirrhosis, and was approved by the 
FDA in 2014. The same combination without dasabuvir was 
FDA approved in 2015 for HCV genotype 4 infection. 
Instances of hepatotoxicity have been reported with these 
regimens in patients with advanced cirrhosis. Daclatasvir in 
combination with sofosbuvir has proven effective in 
genotypes 1-, 2-, and 3-infected patients, including those 
coinfected with HIV , and was approved by the FDA in 
2015 for HCV genotype 3 infection.
NS5A inhibitors (“…asvirs”) are characterized by high 
antiviral potency at picomolar doses. The cross-genotype 
efficacy of these agents varies. Ledipasvir was the first NS5A 
inhibitor approved by the FDA in 2014 (see Table 16–6). 
Ledipasvir has potent activity against genotypes 1, 4, 5, and 
6 HCV and has been formulated in combination with 
sofosbuvir. The combination is highly effective in both 
treatment-naive and treatment-experienced patients, even 
those with cirrhosis and is given in a fixed dose of ledipasvir

those with cirrhosis and is given in a fixed dose of ledipasvir 
90 mg and sofosbuvir 400 mg once daily for 12 weeks in 
HCV genotype 1–infected treatment-naive patients and 
treatment-experienced patients without cirrhosis and for 
24 weeks in treatment-experienced patients with cirrhosis. 
In treatment-naive patients without cirrhosis, the duration 
of treatment can be shortened to 8 weeks if the baseline 
HCV RNA level is less than 6 million international units/
mL. Sustained virologic response rates are well above 90%, 
including in patients coinfected with HIV , and this regimen 
has emerged as a first-line therapy for HCV genotype 1. The 
combination of ledipasvir, sofosbuvir, and ribavirin 
achieves high rates of sustained virologic response in 
patients with HCV genotype 3 as well as in patients with 
HCV genotype 1 or 4 and advanced cirrhosis. Side effects 
are mild and include fatigue and headache. Concomitant 
use of a proton pump inhibitor, particularly twice-daily 
dosing in patients with cirrhosis, may reduce the effec
-
tiveness of the combination of ledipasvir and sofosbuvir. 
Re-treatment of occasional nonresponders or relapsers 
with resistance-associated substitutions that persist for 
years with an alternative regimen that may include sofos
-
buvir is often effective.
Since 2016, the FDA has approved other highly effective 
combinations: 100 mg of grazoprevir (an NS3/4A protease 
inhibitor) plus 50 mg/day of elbasvir (an NS5A inhibitor) 
for HCV genotypes 1 and 4; 300 mg of glecaprevir (an 
NS3/4A protease inhibitor) plus 120 mg/day of pibrentas
-
vir (an NS5A inhibitor) for genotypes 1–6 (pangenotypic); 
and another pangenotypic regimen, sofosbuvir and velpa
-
tasvir, with the addition of ribavirin in patients with 
cirrhosis, and with the addition of voxilaprevir (an NS3A/N4 
protease inhibitor) as “rescue” therapy in patients with 
nonresponse or relapse following initial treatment with 
various regimens. Other “rescue” regimens are under 
study, including grazoprevir, ruzasvir (an NS5A inhibitor), 
and uprifosbuvir (an NS5B polymerase nucleotide inhibi
-
tor), with or without ribavirin, for patients who have not 
responded to NS5A-containing therapy. Where available, 
testing for resistance-associated substitutions may be help
-
ful before re-treatment. Use of any regimen containing a 
protease inhibitor is contraindicated in patients with 
decompensated cirrhosis, and pretreatment testing for 
resistance-associated substitutions is recommended.
Despite the efficacy of the new regimens, their cost has 
been high (although declining), and insurance coverage has 
often been a barrier to their use. Additional factors to con
-
sider in the selection of a regimen are the presence of 
cirrhosis or kidney dysfunction, prior treatment, and 
potential drug interactions. For some regimens, an 8-week 
course of treatment may be effective in selected cases. Other 
agents that have been studied include NS3/4A protease 
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inhibitors (eg, danoprevir, faldaprevir); polymerase inhibitors 
(eg, mericitabine); virus entry, assembly, and secretion 
inhibitors; microRNA-122 antisense oligonucleotides (eg, 
miravirsen); cyclophilin A inhibitors (eg, alisporivir); inter
-
feron lambda-3; and therapeutic vaccines. HCV genotype 1 
is now easy to cure with oral direct-acting agents, with 
expected sustained virologic response rates well above 90%, 
and virtually all HCV genotype 2 infection is curable with 
all-oral regimens. HCV genotype 3 infection, particularly in 
association with cirrhosis, has been the most challenging to 
treat, but the newest regimens have increased the likelihood 
of cure. Interferon is now rarely required, and the need for 
ribavirin is decreasing.
Antiviral therapy has been shown to be beneficial 
in the treatment of cryoglobulinemia associated with 
chronic hepatitis C; an acute flare of cryoglobulinemia 
may first require treatment with rituximab, cyclophosphamide 
plus methylprednisolone, or plasma exchange. As noted 
above, patients with HCV and HIV coinfection have been 
shown to respond well to treatment of HCV infection. 
Moreover, in persons coinfected with HCV and HIV , 
long-term liver disease–related mortality increases as 
HIV infection–related mortality is reduced by antiretroviral 
therapy. Occasional instances of reactivation of HBV 
infection, as well as herpesvirus, have occurred with 
direct-acting antiviral agents for HCV infection, and all 
candidates should be prescreened for HBV infection, with 
the initiation of antiviral prophylactic therapy in those 
who are HBsAg positive when treatment of HCV infection 
is begun.
 
»
Prognosis
Chronic hepatitis C is an indolent, often subclinical disease 
that may lead to cirrhosis and hepatocellular carcinoma 
after decades. The overall mortality rate in patients with 
transfusion-associated hepatitis C may be no different 
from that of an age-matched control population. Never
-
theless, mortality or transplantation rates clearly rise to 
5% per year once cirrhosis develops, and mortality from 
cirrhosis and hepatocellular carcinoma due to hepatitis C 
is still rising. A risk score combining age, sex, platelet 
count, and AST-to-ALT ratio has been proposed. There is 
some evidence that HCV genotype 1b is associated with a 
higher risk of hepatocellular carcinoma than other geno
-
types. Antiviral therapy has a beneficial effect on mortal
-
ity and quality of life, is cost-effective, appears to retard 
and even reverse fibrosis, and reduces (but does not 
eliminate) the risk of decompensated cirrhosis and 
hepatocellular carcinoma in responders with advanced 
fibrosis. Even patients who achieve a sustained virologic 
response remain at an increased risk for mortality com
-
pared with the general population. The risk of mortality 
from drug addiction is higher than that for liver disease 
in patients with chronic hepatitis C. HCV infection 
appears to be associated with increased cardiovascular 
mortality, especially in persons with diabetes mellitus and 
hypertension. Statin use has been reported to be associ
-
ated with improved virologic response to antiviral therapy 
and decreased progression of liver fibrosis and frequency 
of hepatocellular carcinoma.
 
»
•	
For liver biopsy.
•	
For antiviral therapy.
 
»
For complications of decompensated cirrhosis.
Bourlière M et al; POLARIS-1 and POLARIS-4 Investigators. 
Sofosbuvir, velpatasvir, and voxilaprevir for previously treated 
HCV infection. N Engl J Med. 2017 Jun 1;376(22):2134–46. 
[PMID: 28564569]
European Association for the Study of the Liver. EASL recom
-
mendations on treatment of hepatitis C 2016. J Hepatol. 
2017 Jan;66(1):153–94. [PMID: 27667367]
Falade-Nwulia O et al. Oral direct-acting agent therapy for 
hepatitis C virus infection: a systematic review. Ann Intern Med. 
2017 May 2;166(9):637–48. [PMID: 28319996]

Jacobson IM et al. American Gastroenterological Association 
Institute clinical practice update—expert review: care of 
patients who have achieved a sustained virologic response 
after antiviral therapy for chronic hepatitis C infection. 
Gastroenterology. 2017 May;152(6):1578–87. [PMID: 28344022]
Terrault NA et al. AASLD guidelines for treatment of chronic 
hepatitis B. Hepatology. 2016 Jan;63(1):261–83. [PMID: 
26566064]
Wranke A et al. Antiviral treatment and liver-related complica
-
tions in hepatitis delta. Hepatology. 2017 Feb;65(2):414–25. 
[PMID: 27770553]
AUTOIMMUNE HEPATITIS
 
»
Usually young to middle-aged women.
 
»
Chronic hepatitis with high serum globulins and 
characteristic liver histology.
 
»
Positive antinuclear antibody (ANA) and/or smooth 
muscle antibody in most cases in the United 
States.
 
»
Responds to corticosteroids.
 
»
Although autoimmune hepatitis is usually seen in young 
women, it can occur in either sex at any age. The incidence, 
which has been rising, and prevalence are estimated to be 
8.5 and 107 per million population, respectively.
 
»
The onset is usually insidious, but about 20% of cases present 
with acute (occasionally fulminant) hepatitis and some cases 
follow a viral illness (such as hepatitis A, Epstein-Barr infection, 
or measles) or exposure to a drug or toxin (such as nitro
-
furantoin, minocycline, hydralazine, methyldopa, or inflix
-
imab). Exacerbations may occur postpartum. Amenorrhea 
may be a presenting feature, and the frequency of depression 
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appears to be increased. Thirty-four percent of patients, and 
particularly elderly patients, are asymptomatic. Typically, 
examination reveals a healthy-appearing young woman with 
multiple spider telangiectasias, cutaneous striae, acne, hir
-
sutism, and hepatomegaly. Extrahepatic features include 
arthritis, Sjögren syndrome, thyroiditis, nephritis, ulcerative 
colitis, and Coombs-positive hemolytic anemia. Patients, 
especially elderly patients, with autoimmune hepatitis are 
at increased risk for cirrhosis, which, in turn, increases 
the risk of hepatocellular carcinoma (at a rate of about 
1% per year).
Serum aminotransferase levels may be greater than 
1000 units/L, and the total bilirubin is usually increased. 
Autoimmune hepatitis has been classified as type 1 or type 
2, although the clinical features and response to treatment 
are similar between the two types. In type I (classic) auto
-
immune hepatitis, ANA or smooth muscle antibodies 
(either or both) are usually detected in serum. Serum 
gamma-globulin levels are typically elevated (up to 5–6 g/dL 
[0.05–0.06 g/L]); in such patients, the EIA for antibody to 
HCV may be falsely positive. Other antibodies, including 
atypical perinuclear antineutrophil cytoplasmic antibodies 
(pANCA) and antibodies to histones, F-actin, and alpha-
actinin may be found. Antibodies to soluble liver antigen 
(anti-SLA) characterize a variant of type I that is marked by 
severe disease, a high relapse rate after treatment, and 
absence of the usual antibodies (ANA and smooth muscle 
antibodies). Type II, seen more often in girls under age 14 
in Europe, is characterized by circulating antibodies to 
liver-kidney microsome type 1 (anti-LKM1) without 
smooth muscle antibodies or ANA. In some cases, anti
-
bodies to liver cytosol type 1, are detected. Type II autoim
-
mune hepatitis can be seen in patients with autoimmune 
polyglandular syndrome type 1. Concurrent primary biliary 
cholangitis (PBC; formerly primary biliary cirrhosis) or 
primary sclerosing cholangitis (“overlap syndrome”) has 
been recognized in 7–13% and 6–11% of patients with 
autoimmune hepatitis, respectively. Liver biopsy is indi
-
cated to help establish the diagnosis (interface hepatitis is 
the hallmark), evaluate disease severity, and determine the 
need for treatment.
Simplified diagnostic criteria based on the detection of 
autoantibodies (1 point for a titer of > 1:40 or 2 points for 
a titer of > 1:80), elevated IgG levels (1 point for IgG level 
≥ upper limit of normal or 2 points for level ≥ 1.1 times 
upper limit of normal), and characteristic histologic fea
-
tures (1 or 2 points depending on how typical the features 
are) and exclusion of viral hepatitis (2 points) can be useful 
for diagnosis; a score of 6 indicates probable and a score of 
7 indicates definite autoimmune hepatitis with a high 
degree of specificity but moderate sensitivity. Diagnostic 
criteria for an overlap of autoimmune hepatitis and PBC 
(“Paris criteria”) have been proposed.
 
»
Treatment
Prednisone with or without azathioprine improves symp
-
toms; decreases the serum bilirubin, aminotransferase, and 
gamma-globulin levels; and reduces hepatic inflammation. 
Symptomatic patients with aminotransferase levels ele
-
vated 10-fold (or 5-fold if the serum globulins are elevated 
at least 2-fold) are optimal candidates for therapy, and 
asymptomatic patients with modest enzyme elevations 
may be considered for therapy depending on the clinical 
circumstances and histologic severity; however, asymp
-
tomatic patients usually remain asymptomatic, have either 
mild hepatitis or inactive cirrhosis on liver biopsy speci
-
mens, and have a good long-term prognosis without 
therapy.
Prednisone is given initially in a dose of 30 mg orally 
daily with azathioprine, 50 mg orally daily, which is gener
-

-
therapy.
-
ally well tolerated and permits the use of lower corticoste
-
roid doses than a regimen beginning with prednisone 
 
60 mg orally daily alone. Intravenous corticosteroids or 
prednisone, 60 mg orally daily, is recommended for patients 
with acute severe autoimmune hepatitis. Budesonide, 3 mg 
orally two or three daily, may be at least as effective as 
prednisone in noncirrhotic autoimmune hepatitis and 
associated with fewer side effects. Whether patients should 
undergo testing for the genotype or level of thiopurine 
methyltransferase prior to treatment with azathioprine to 
predict toxicity is debated. Blood counts are monitored 
weekly for the first 2 months of therapy and monthly there
-
after because of the small risk of bone marrow suppression. 
The dose of prednisone is lowered from 30 mg/day after 
 
1 week to 20 mg/day and again after 2 or 3 weeks to 15 mg/day. 
Treatment is response guided, and ultimately, a mainte
-
nance dose of 10 mg/day should be achieved. While symp
-
tomatic improvement is often prompt, biochemical 
improvement is more gradual, with normalization of 
serum aminotransferase levels after an average of 
 
22 months. Histologic resolution of inflammation lags 
biochemical remission by 3–6 months, and repeat liver 
biopsy is recommended at least 3 months after the amino
-
transferase levels have normalized. Failure of aminotransferase 
levels to return to normal invariably predicts lack of histologic 
The response rate to therapy with prednisone and 
azathioprine is 80%, with remission in 65% by 3 years. 
Older patients and those with HLA genotype 
DRB1
*
04
 are 
more likely to respond than younger patients and those 
with HLA 
DRB1
*
03
, hyperbilirubinemia, or a high MELD 
score (12 or higher, see Cirrhosis). Fibrosis may reverse 
with therapy and rarely progresses after apparent biochem
-
ical and histologic remission. Once complete remission is 
achieved, therapy may be withdrawn, but the subsequent 
relapse rate is 90% by 3 years. Relapses may again be 
treated in the same manner as the initial episode, with the 
same remission rate. After successful treatment of a relapse, 
the patient may continue taking azathioprine (up to 2 mg/kg) 
or the lowest dose of prednisone with or without azathio
-
prine (50 mg/day) needed to maintain aminotransferase 
levels as close to normal as possible; another attempt at 
withdrawing therapy may be considered in patients 
remaining in remission long term (eg, 4 years or longer). 
During pregnancy, flares can be treated with prednisone, 
and maintenance azathioprine does not have to be 
discontinued.
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Nonresponders to corticosteroids and azathioprine 
(failure of serum aminotransferase levels to decrease by 
50% after 6 months) may be considered for a trial of cyclo
-
sporine, tacrolimus, sirolimus, everolimus, methotrexate, 
rituximab, or infliximab. Mycophenolate mofetil, 1 g twice 
daily, is an effective alternative to azathioprine in patients 
who cannot tolerate it but is less effective in nonresponders 
to azathioprine. Occasionally, 6-mercaptopurine may be 
tolerated in patients who do not tolerate azathioprine. 
Bone density should be monitored—particularly in patients 
receiving maintenance corticosteroid therapy—and 
measures undertaken to prevent or treat osteoporosis 
(see Chapter 26). Liver transplantation may be required for 
treatment failures and patients with a fulminant presenta
-
tion, but the outcome may be worse than that for PBC 
because of an increased rate of infectious complications. As 
immunosuppression is reduced, the disease has been rec
-
ognized to recur in up to 70% of transplanted livers at 
 
5 years (and rarely to develop de novo); sirolimus can be 
effective in such cases.
Overall long-term mortality of patients with autoim
-
mune hepatitis appears to be twofold higher than that of 
the general population despite response to immunosup
-
pressive therapy. Factors that predict the need for liver 
transplantation or that predict liver-related death include 
the following: (1) age 20 years or younger or older than 
 
60 years at presentation, (2) low serum albumin level at 
diagnosis, (3) cirrhosis at diagnosis, (4) the presence of 
anti-SLA, and (5) incomplete normalization of the serum 
ALT level after 6 months of treatment.
 
»
•	
•	
For immunosuppressive therapy.
 
»
•	
Hepatic encephalopathy.
•	
de Boer YS et al. Features of autoimmune hepatitis in patients 
with drug-induced liver injury. Clin Gastroenterol Hepatol. 
2017 Jan;15(1):103–12. [PMID: 27311619]
Liberal R et al. Expert clinical management of autoimmune hepatitis 
in the real world. Aliment Pharmacol Ther. 2017 Mar;45(5):
 
723–32. [PMID: 28004405]
Tansel A et al. Incidence and determinants of hepatocellular carci
-
noma in autoimmune hepatitis: a systematic review and meta-
analysis. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1207–17. 
[PMID: 28215616]
ALCOHOLIC LIVER DISEASE
 
»
Chronic alcohol intake usually exceeds 80 g/day in 
men and 30–40 g/day in women with alcoholic 
hepatitis or cirrhosis.
 
»
Fatty liver is often asymptomatic.
 
»
Fever, right upper quadrant pain, tender hepato
-
megaly, and jaundice characterize alcoholic hepatitis, 
but the patient may be asymptomatic.
 
»
AST is usually elevated but usually not above 
300 units/L (6 mckat/L); AST is greater than ALT, 
usually by a factor of 2 or more.
 
»
Alcoholic hepatitis is often reversible but it is the 
most common precursor of cirrhosis in the United 
States.
 
»
Excessive alcohol intake can lead to fatty liver, hepatitis, 
and cirrhosis. Alcoholic hepatitis is characterized by acute 
or chronic inflammation and parenchymal necrosis of the 
liver induced by alcohol. Alcoholic hepatitis is often a 
reversible disease but the most common precursor of 
cirrhosis in the United States. It is associated with four to 
five times the number of hospitalizations and deaths as 
hepatitis C, which is the second most common cause of 
The frequency of alcoholic cirrhosis is estimated to be 
10–15% among persons who consume over 50 g of alcohol 
(4 oz of 100-proof whiskey, 15 oz of wine, or four 12-oz 
cans of beer) daily for over 10 years (although the risk of 
cirrhosis may be lower for wine than for a comparable 
intake of beer or spirits). The risk of cirrhosis is lower (5%) 
in the absence of other cofactors such as chronic viral 
hepatitis and obesity. Genetic factors may also account for

hepatitis and obesity. Genetic factors may also account for 
differences in susceptibility to and severity of liver disease. 
Women appear to be more susceptible than men, in part 
because of lower gastric mucosal alcohol dehydrogenase 
levels.
 
»
The clinical presentation of alcoholic liver disease can vary 
from asymptomatic hepatomegaly to a rapidly fatal acute ill
-
ness or end-stage cirrhosis. A recent period of heavy drinking, 
complaints of anorexia and nausea, and the demonstration of 
hepatomegaly and jaundice strongly suggest the diagnosis. 
Abdominal pain and tenderness, splenomegaly, ascites, fever, 
and encephalopathy may be present. Infection, including 
invasive aspergillosis, is common in patients with severe 
In patients with steatosis, mild liver enzyme elevations may 
be the only laboratory abnormality. Anemia (usually macro
-
cytic) may be present. Leukocytosis with a shift to the left is 
common in patients with severe alcoholic hepatitis. Leuko
-
penia is occasionally seen and resolves after cessation of 
drinking. About 10% of patients have thrombocytopenia 
related to a direct toxic effect of alcohol on megakaryocyte 
production or to hypersplenism.
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AST is usually elevated but infrequently above 300 units/L 
(6 mckat/L). AST is greater than ALT, usually by a factor of 
 
2 or more. Serum alkaline phosphatase is generally elevated, 
but seldom more than three times the normal value. Serum 
bilirubin is increased in 60–90% of patients with alcoholic 
Serum bilirubin levels greater than 10 mg/dL (171 mcmol/L) 
and marked prolongation of the prothrombin time (6 sec
-
onds or more above control) indicate severe alcoholic 
hepatitis with a mortality rate as high as 50%. The serum 
albumin is depressed, and the gamma-globulin level is 
elevated in 50–75% of individuals, even in the absence of 
cirrhosis. Increased transferrin saturation, hepatic iron 
stores, and sideroblastic anemia are found in many alcoholic 
patients. Folic acid deficiency may coexist.
C. Imaging
Imaging studies can detect moderate to severe hepatic 
steatosis reliably but not inflammation or fibrosis. Ultraso
-
nography helps exclude biliary obstruction and identifies 
subclinical ascites. CT with intravenous contrast or MRI 
may be indicated in selected cases to evaluate patients for 
collateral vessels, space-occupying lesions of the liver, or 
concomitant disease of the pancreas.
D. Liver Biopsy
Liver biopsy, if done, demonstrates macrovesicular fat and, 
in patients with alcoholic hepatitis, polymorphonuclear 
infiltration with hepatic necrosis, Mallory (or Mallory-
Denk) bodies (alcoholic hyaline), and perivenular and 
perisinusoidal fibrosis. Micronodular cirrhosis may be 
present as well. The findings are identical to those of non
-
alcoholic steatohepatitis.
 
»
Alcoholic hepatitis may be closely mimicked by chole
-
cystitis and cholelithiasis and by drug toxicity. Other 
causes of hepatitis or chronic liver disease may be 
excluded by serologic or biochemical testing, imaging 
studies, or liver biopsy. A formula based on the AST/ALT 
ratio, body mass index, mean corpuscular volume, and sex 
has been reported to reliably distinguish alcoholic liver 
disease from nonalcoholic fatty liver disease (NAFLD).
 
»
Treatment
Abstinence from alcohol is essential. Naltrexone, acampro
-
sate, or baclofen may be considered in combination with 
counseling to reduce the likelihood of recidivism. Fatty liver 
is quickly reversible with abstinence. Every effort should be 
made to provide sufficient amounts of carbohydrates and 
calories in anorectic patients to reduce endogenous protein 
catabolism, promote gluconeogenesis, and prevent hypo
-
glycemia. Nutritional support (30–40 [and no less than 
21.5] kcal/kg with 1.0–1.5 g/kg as protein) improves liver 
disease, but not necessarily survival, in patients with malnu
-
trition. Intensive enteral nutrition is difficult to implement, 
however. The administration of micronutrients, particularly 
folic acid, thiamine, and zinc, is indicated, especially when 
deficiencies are noted; glucose administration increases 
the thiamine requirement and can precipitate Wernicke-
Korsakoff syndrome if thiamine is not coadministered. 
Nephrotoxic drugs should be avoided in patients with 
severe alcoholic hepatitis.
B. Pharmacologic Measures
Methylprednisolone, 32 mg/day orally, or the equivalent, 
for 1 month, may reduce short-term (1-month but not 
6-month) mortality in patients with alcoholic hepatitis and 
encephalopathy or a Maddrey discriminant function index 
(defined by the patient’s prothrombin time minus the con
-
trol prothrombin time times 4.6 plus the total bilirubin 
in mg/dL) of 32 or more, or a MELD score of 18 or more 
(see Cirrhosis). Concomitant gastrointestinal bleeding or 
infection may not preclude treatment with corticosteroids 
if otherwise indicated, but treatment with prednisolone 
increases the risk of serious infections during and after 
treatment is completed. Prophylactic antibiotic therapy is

treatment is completed. Prophylactic antibiotic therapy is 
under study. The combination of corticosteroids and 
N-acetylcysteine has been reported to further improve 
1-month but not 6-month survival and reduce the risk of 
hepatorenal syndrome and infections; the combination 
may be superior to corticosteroids alone, but more data are 
needed.
Pentoxifylline, 400 mg orally three times daily for 
 
4 weeks decreases the risk of hepatorenal syndrome. It may 
be less effective in reducing short-term mortality than 
corticosteroids, but is often used when corticosteroids are 
contraindicated. The addition of pentoxifylline to predniso
-
lone does not appear to improve survival but may reduce 
the frequency of hepatorenal syndrome compared with 
prednisolone alone.
 
»
Prognosis
A. Short-Term
The overall mortality rate is 34% (20% within 1 month) 
without corticosteroid therapy. Individuals in whom the 
prothrombin time prohibits liver biopsy have a 42% mor
-
tality rate at 1 year. Other unfavorable prognostic factors 
are older age, a serum bilirubin greater than 10 mg/dL 
(171 mcmol/L), hepatic encephalopathy, coagulopathy, 
azotemia, leukocytosis, sepsis and other infections, system
-
atic inflammatory response syndrome (which is associated 
with multiorgan failure), lack of response to corticosteroid 
therapy, and possibly a paucity of steatosis on a liver biopsy 
specimen and reversal of portal blood flow by Doppler 
ultrasonography. Concomitant gastrointestinal bleeding 
does not appear to worsen survival. Failure of the serum 
bilirubin level to decline after 7 days of treatment with 
corticosteroids predicts nonresponse and poor long-term 
survival, as does the Lille model (which includes age, 
serum creatinine, serum albumin, prothrombin time [or 
INR], serum bilirubin on admission, and serum bilirubin 
on day 7). The MELD score used for cirrhosis and the Glasgow 
alcoholic hepatitis score (based on age, white blood cell 
count, blood urea nitrogen, prothrombin time ratio, and 
bilirubin level) also correlate with mortality from alcoholic 
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hepatitis and have higher specificities than the discrimi
-
nant function and Lille score. A scoring system based on 
age, serum bilirubin, INR, and serum creatinine (ABIC) 
has been proposed, and at least one study has shown that 
the development of acute kidney injury is the most accu
-
rate predictor of 90-day mortality. The combination of 
the MELD score and Lille model has also been reported 
to be the best predictor of short-term mortality among 
the scoring systems. Histologic features associated with 
90-day mortality include the degree of fibrosis and 
neutrophil infiltration, presence of metamitochondria, and 
bilirubinostasis.
B. Long-Term
Overall mortality from alcoholic liver disease has declined 
slightly in the United States since 1980. Nevertheless, the 
3-year mortality rate of persons who recover from acute 
alcoholic hepatitis is 10 times greater than that of control 
individuals of comparable age; the 5-year mortality rate is 
as high as 85%. Histologically severe disease is associated 
with continued excessive mortality rates after 3 years, 
whereas the death rate is not increased after the same 
period in those whose liver biopsies show only mild alco
-
holic hepatitis. Complications of portal hypertension 
(ascites, variceal bleeding, hepatorenal syndrome), coag
-
ulopathy, and severe jaundice following recovery from 
acute alcoholic hepatitis also suggest a poor long-term 
The most important long-term prognostic factor is 
continued excessive drinking. The risk of alcoholic cirrhosis 
is greater in women than in men, associated with obesity, 
cigarette smoking, chronic hepatitis C, and low vitamin D 
levels; the risk is inversely associated with coffee drinking. 
Alcoholic cirrhosis is a risk factor for hepatocellular carci
-
noma, and the risk is highest in carriers of the 
C282Y
 
mutation for hemochromatosis or those with increased 
hepatic iron. A 6-month period of abstinence is generally 
required before liver transplantation is considered, 
although this requirement has been questioned and early 
liver transplantation has been performed in selected 
patients with alcoholic hepatitis, with good outcomes. 
Optimal candidates have adequate social support, do not 
smoke, have no psychosis or personality disorder, are 
adherent to therapy, and have regular appointments with a 
psychiatrist or psychologist who specializes in addiction 
treatment. Patients with alcoholic liver disease are at higher 
risk for posttransplant malignancy than those with other 
types of liver disease because of alcohol and tobacco use.
 
»
Refer patients with alcoholic hepatitis who require liver 
 
»
•	
•	
•	
Total bilirubin 10 mg/dL or more.
•	
Inability to maintain hydration.
Dunne PDJ et al. Review article: recent insights into clinical 
decision-making in severe alcoholic hepatitis. Aliment Pharmacol 
Ther. 2017 Aug;46(3):274–81. [PMID: 28543549]
Lee YS et al. Treatment of severe alcoholic hepatitis with cortico
-
steroid, pentoxifylline, or dual therapy: a systematic review and 
meta-analysis. J Clin Gastroenterol. 2017 Apr;51(4):364–77. 
[PMID: 27636406]
Mitchell MC et al. Medical management of severe alcoholic 
hepatitis: expert review from the Clinical Practice Updates 
Committee of the AGA Institute. Clin Gastroenterol Hepatol. 
2017 Jan;15(1):5–12. [PMID: 27979049]
Vergis N et al. In patients with severe alcoholic hepatitis, pred
-
nisolone increases susceptibility to infection and infection-
related mortality, and is associated with high circulating levels 
of bacterial DNA. Gastroenterology. 2017 Apr;152(5):1068–77. 
[PMID: 28043903]
DRUG- & TOXIN-INDUCED LIVER INJURY
 
»
Drug-induced liver injury can mimic viral hepatitis, 
biliary tract obstruction, or other types of liver 
disease.
 
»
Clinicians must inquire about the use of many

»
disease.
 
»
Clinicians must inquire about the use of many 
widely used therapeutic agents, including over-
the-counter “natural” and herbal and dietary 
supplements, in any patient with liver disease.
 
»
Many therapeutic agents may cause drug-induced liver 
injury, and up to 10% of patients with drug-induced liver 
injury die or undergo liver transplantation within 6 months 
of onset. The medications most commonly implicated are 
nonsteroidal anti-inflammatory drugs and antibiotics 
because of their widespread use. In any patient with liver 
disease, the clinician must inquire carefully about the use 
of potentially hepatotoxic drugs or exposure to hepatotoxins, 
including over-the-counter herbal and dietary supple
-
ments. In some cases, coadministration of a second agent 
may increase the toxicity of the first (eg, isoniazid and 
rifampin, acetaminophen and alcohol). The diagnosis 
often depends on exclusion of other causes of liver disease; 
various biomarkers are under study. A relationship between 
increased serum ALT levels in premarketing clinical trials 
and postmarketing reports of hepatotoxicity has been iden
-
tified. Except for drugs used to treat tuberculosis and HIV 
infection and possibly azithromycin, the risk of hepatotox
-
icity is not increased in patients with preexisting cirrhosis, 
but hepatotoxicity may be more severe and the outcome 
worse when it does occur. Older persons may be at higher 
risk for hepatotoxicity from certain agents, such as 
amoxicillin-clavulanic acid, isoniazid, and nitrofurantoin, 
and more likely to have persistent and cholestatic, rather 
than hepatocellular, injury compared with younger per
-
sons. Drug toxicity may be categorized on the basis of 
pathogenesis or predominant histologic appearance. 
biliary tract obstruction, or other types of liver disease. 
 
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The development of jaundice in a patient with serum amino
-
transferase levels at least three times the upper limit of 
normal predicts a mortality rate of at least 10%. A useful 
resource is the website https://livertox.nlm.nih.gov/.
 
»
Categorization by Pathogenesis
A. Direct Hepatotoxicity
Liver toxicity caused by this group of drugs is characterized 
by dose-related severity, a latent period following exposure, 
and susceptibility in all individuals. Examples include 
acetaminophen (toxicity is enhanced by fasting and chronic 
alcohol use because of depletion of glutathione and induc
-
tion of cytochrome P450 2E1, possibly reduced by statins, 
fibrates, and nonsteroidal anti-inflammatory drugs, and 
treated with acetylcysteine), alcohol, 
 
mushrooms, carbon tetrachloride, chloroform, heavy met
-
als, mercaptopurine, niacin, plant alkaloids, phosphorus, 
pyrazinamide, tetracyclines, tipranavir, valproic acid, and 
vitamin A.
B. Idiosyncratic Reactions
Except for acetaminophen, most severe hepatotoxicity is 
idiosyncratic. Reactions of this type are (1) sporadic, 
(2) not related to dose above a general threshold of 
 
100 mg/day, and (3) occasionally associated with features 
suggesting an allergic reaction, such as fever and eosino
-
philia (including drug rash with eosinophilia and systemic 
symptoms [DRESS] syndrome), which may be associated 
with a favorable outcome. In many instances, the drug is 
lipophilic, and toxicity results directly from a reactive 
metabolite that is produced only in certain individuals on 
a genetic basis. Illness tends to be more severe in blacks 
than in whites. Drug-induced liver injury may be observed 
only during post-marketing surveillance and not during 
preclinical trials. Examples include abacavir, amiodarone, 
aspirin, carbamazepine, chloramphenicol, dapsone, 
diclofenac, disulfiram, duloxetine, ezetimibe, flavocoxid 
(a “medical food”), fluoroquinolones (levofloxacin and 
moxifloxacin, in particular), flutamide, halothane, isoniazid, 
ketoconazole, lamotrigine, methyldopa, natalizumab, 
nevirapine, oxacillin, phenytoin, pyrazinamide, quinidine, 
rivaroxaban, streptomycin, temolozomide, thiazolidinediones, 
tolvaptan, and perhaps tacrine. Statins, like all cholesterol-
lowering agents, may cause serum aminotransferase 
elevations but rarely cause true hepatitis, and even more 
rarely cause acute liver failure, and are no longer consid
-
ered contraindicated in patients with liver disease. Most 
acute idiosyncratic drug-induced liver injury is reversible 
with discontinuation of the offending agent. Risk factors 
for chronicity (longer than 1 year) are older age, dyslipidemia, 
and severe acute injury.
 
»
Categorization by Histopathology
A. Cholestasis
1. Noninflammatory—
Drug-induced cholestasis results 
from inhibition or genetic deficiency of various hepatobiliary 
transporter systems. The following drugs cause cholestasis: 
anabolic steroids containing an alkyl or ethinyl group at 
carbon 17, azathioprine, cetirizine, cyclosporine, diclofe
-
nac, estrogens, febuxostat, indinavir (increased risk of 
indirect hyperbilirubinemia in patients with Gilbert syn
-
drome), mercaptopurine, methyltestosterone, tamoxifen, 
temozolomide, and ticlopidine.
2. Inflammatory—
The following drugs cause inflamma
-
tion of portal areas with bile duct injury (cholangitis [and, 
in some cases, bile duct loss]), often with allergic features 
such as eosinophilia: amoxicillin-clavulanic acid (among 
the most common causes of drug-induced liver injury), 
azathioprine, azithromycin, captopril, celecoxib, cephalospo
-
rins, chlorothiazide, chlorpromazine, chlorpropamide, eryth
-
romycin, mercaptopurine, penicillamine, prochlorperazine, 
semisynthetic penicillins (eg, cloxacillin), sulfadiazine, and 
temozolomide. Ketamine abuse may cause secondary biliary

-
temozolomide. Ketamine abuse may cause secondary biliary 
cirrhosis. Cholestatic and mixed cholestatic-hepatocellular 
toxicity is more likely than pure hepatocellular toxicity to lead 
to chronic liver disease.
B. Acute or Chronic Hepatitis
Medications that may result in acute or chronic hepatitis that 
is histologically and in some cases clinically similar to auto
-
immune hepatitis include minocycline and nitrofurantoin, 
most commonly, as well as aspirin, isoniazid (increased risk 
in HBV and HCV carriers), methyldopa, nonsteroidal anti-
inflammatory drugs, propylthiouracil, terbinafine, tumor 
necrosis factor inhibitors, and varenicline. Histologic features 
that favor a drug cause include portal tract neutrophils and 
hepatocellular cholestasis. Hepatitis also can occur in patients 
taking cocaine, diclofenac, dimethyl fumarate, efavirenz, 
imatinib mesylate, ipilimumab and other checkpoint inhibi
-
tors (including nivolumab), methylenedioxymethamphet
-
amine (MDMA; Ecstasy), nafazodone (has a black box 
warning for a potential to cause liver failure), nevirapine (like 
other protease inhibitors, increased risk in HBV and HCV 
carriers), pioglitazone, ritonavir (greater rate than other pro
-
tease inhibitors), rosiglitazone, saquinavir, sulfonamides, 
telithromycin, and zafirlukast, as well as a variety of alternative 
remedies (eg, black cohosh, chaparral, germander, green tea 
extract, Herbalife products, Hydroxycut, jin bu huan, kava, 
saw palmetto, skullcap, and other traditional Chinese 
herbal preparations), in addition to dietary supplements (eg, 
1, 3-dimethylamylamine in OxyELITE Pro, a weight-loss 
supplement withdrawn from the US market).
C. Other Reactions
1. Fatty liver
a. Macrovesicular
—
This type of liver injury may be pro
-
duced by alcohol, amiodarone, corticosteroids, irinotecan, 
methotrexate, tamoxifen, vinyl chloride (in exposed workers), 
zalcitabine, and possibly oxaliplatin.
b. Microvesicular
—
Often resulting from mitochondrial 
injury, this condition is associated with didanosine, stavudine, 
tetracyclines, valproic acid, and zidovudine.
2. Granulomas—
Allopurinol, phenytoin, pyrazinamide, 
quinidine, quinine, and vemurafenib can lead to granulomas 
and, in some cases, granulomatous hepatitis.
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3. Fibrosis and cirrhosis—
Methotrexate and vitamin A are 
associated with fibrosis and cirrhosis.
4. Sinusoidal obstruction syndrome (veno-occlusive 
disease)—
This disorder may result from treatment with 
antineoplastic agents (eg, pre–bone marrow transplant, 
busulfan, gemtuzumab ozogamicin, oxaliplatin), and 
pyrrolizidine alkaloids (eg, Comfrey).
5. Peliosis hepatis (blood-filled cavities)—
Peliosis hepatis 
may be caused by anabolic steroids and oral contraceptive 
steroids as well as azathioprine and mercaptopurine, which 
may also cause nodular regenerative hyperplasia.
6. Neoplasms—
Neoplasms may result from therapy with 
oral contraceptive steroids, including estrogens (hepatic 
adenoma but not focal nodular hyperplasia) and vinyl 
chloride (angiosarcoma).
 
»
Refer patients with drug- and toxin-induced hepatitis who 
require liver biopsy for diagnosis.
 
»
Bonkovsky HL et al; U.S. Drug Induced Liver Injury Network 
Investigators. Clinical presentations and outcomes of bile duct 
loss caused by drugs and herbal and dietary supplements. 
Hepatology. 2017 Apr;65(4):1267–77. [PMID: 27981596]
Hunt CM et al. Drug rechallenge following drug-induced liver 
injury. Hepatology. 2017 Aug;66(2):646–54. [PMID: 28295448]
Kullak-Ublick GA et al. Drug-induced liver injury: recent advances 
in diagnosis and risk assessment. Gut. 2017 Jun;66(6):1154–64. 
[PMID: 28341748]
Navarro VJ et al. Liver injury from herbal and dietary supple
-
ments. Hepatology. 2017 Jan;65(1):363–73. [PMID: 27677775]
Rustgi VK (editor). Drug hepatotoxicity. Clin Liver Dis. 2017; 
21(1):1–214. [Full issue]
NONALCOHOLIC FATTY LIVER DISEASE
 
»
Often asymptomatic.
 
»
Elevated aminotransferase levels, hepatomegaly, 
or steatosis on ultrasonography.
 
»
Predominantly macrovesicular steatosis with or 
without inflammation and fibrosis on liver biopsy.
 
»
Nonalcoholic fatty liver disease (NAFLD) is estimated to 
affect 20–45% of the US population and is increasing in 
prevalence, including in adolescents and young adults. The 
principal causes of NAFLD are obesity (present in 40% or 
more of affected patients), diabetes mellitus (in 20% or 
more), and hypertriglyceridemia (in 20% or more) in asso
-
ciation with insulin resistance as part of the metabolic 
syndrome. The risk of NAFLD in persons with metabolic 
syndrome is 4 to 11 times higher than that of persons with
-
out insulin resistance. Nonobese persons (more frequently 
Asians) account for 3–30% of persons with NAFLD and 
have metabolic profiles characteristic of insulin resistance. 
Other causes of fatty liver include corticosteroids, amioda
-
rone, diltiazem, tamoxifen, irinotecan, oxaliplatin, antiret
-
roviral therapy, toxins (vinyl chloride, carbon tetrachloride, 
yellow phosphorus), endocrinopathies such as Cushing 
syndrome and hypopituitarism, polycystic ovary syn
-
drome, hypothyroidism, hypobetalipoproteinemia and 
other metabolic disorders, obstructive sleep apnea (with 
chronic intermittent hypoxia), excessive dietary fructose 
consumption, starvation and refeeding syndrome, and 
total parenteral nutrition. Gut dysbiosis and genetic factors 
play a role, and may account in part for an increased risk in 
Hispanics. The risk of NAFLD is increased in persons with 
psoriasis and appears to correlate with the activity of 
psoriasis. Soft drink consumption and cholecystectomy 
have been reported to be associated with NAFLD. Physical 
activity protects against the development of NAFLD.
In addition to macrovesicular steatosis, histologic fea
-
tures may include focal infiltration by polymorphonuclear 
neutrophils and Mallory hyalin, a picture indistinguishable 
from that of alcoholic hepatitis and referred to as nonalco
-
holic steatohepatitis (NASH), which affects 3–5% of the US 
population. In patients with NAFLD, older age, obesity,

-
population. In patients with NAFLD, older age, obesity, 
and diabetes mellitus are risk factors for advanced hepatic 
fibrosis and cirrhosis, whereas coffee consumption reduces 
the risk. In women, synthetic hormone use (oral contra
-
ceptives and hormone replacement therapy) increases the 
histologic severity of NASH. Cirrhosis caused by NASH 
appears to be uncommon in African Americans. Persons 
with NAFLD are at increased risk for cardiovascular dis
-
ease, chronic kidney disease, and colorectal cancer.
Microvesicular steatosis is seen with Reye syndrome, 
didanosine or stavudine toxicity, valproic acid toxicity, 
high-dose tetracycline, or acute fatty liver of pregnancy and 
may result in acute liver failure. Women in whom fatty liver 
of pregnancy develops often have a defect in fatty acid 
oxidation due to reduced long-chain 3-hydroxyacyl-CoA 
dehydrogenase activity.
 
»
Most patients with NAFLD are asymptomatic or have mild 
right upper quadrant discomfort. Hepatomegaly is present 
in up to 75% of patients, but stigmata of chronic liver dis
-
ease are uncommon. Rare instances of subacute liver fail
-
ure caused by previously unrecognized NASH have been 
described. Signs of portal hypertension generally signify 
advanced liver fibrosis or cirrhosis, but occasionally occur 
in patients with mild or no fibrosis and severe steatosis.
Laboratory studies may show mildly elevated aminotrans
-
ferase and alkaline phosphatase levels; however, laboratory 
values may be normal in up to 80% of persons with hepatic 
steatosis. In contrast to alcoholic liver disease, the ratio of 
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ALT to AST is almost always greater than 1 in NAFLD, but 
it decreases, often to less than 1, as advanced fibrosis and 
cirrhosis develop. Antinuclear or smooth muscle antibodies 
and an elevated serum ferritin level may each be detected 
in one-fourth of patients with NASH. Elevated serum fer
-
ritin levels may signify so-called dysmetabolic iron over
-
load syndrome and mildly increased body iron stores, 
which may play a causal role in insulin resistance and 
oxidative stress in hepatocytes and correlate with advanced 
fibrosis; the frequency of mutations in the 
HFE
 gene for 
hemochromatosis is not increased in patients with NAFLD. 
Iron deficiency is also common and associated with female 
sex, obesity, increased waist circumference, diabetes melli
-
tus, and black or Native American race.
C. Imaging
Macrovascular steatosis may be demonstrated on ultraso
-
nography, CT, or MRI. However, imaging does not distin
-
guish steatosis from steatohepatitis or detect fibrosis.
Percutaneous liver biopsy is diagnostic and is the standard 
approach to assessing the degree of inflammation and 
fibrosis. The risks of the procedure must be balanced 
against the impact of the added information on manage
-
ment decisions and assessment of prognosis. Liver biopsy 
is generally not recommended in asymptomatic persons 
with unsuspected hepatic steatosis detected on imaging but 
normal liver biochemistry test results. The histologic spec
-
trum of NAFLD includes fatty liver, isolated portal fibrosis, 
steatohepatitis, and cirrhosis. A risk score for predicting 
advanced fibrosis, known as BARD, is based on body mass 
index more than 28, AST/ALT ratio 0.8 or more, and 
diabetes mellitus; it has a 96% negative predictive value (ie, 
a low score reliably excludes advanced fibrosis). Another 
risk score for advanced fibrosis, the NAFLD Fibrosis 
Score (http://nafldscore.com) based on age, hyperglycemia, 
body mass index, platelet count, albumin, and AST/ALT 
ratio, has a positive predictive value of over 80% and 
identifies patients at increased risk for liver-related compli
-
cations and death. A clinical scoring system to predict the 
likelihood of NASH in morbidly obese persons includes 
six predictive factors: hypertension, type 2 diabetes 
mellitus, sleep apnea, AST greater than 27 units/L (0.54 mckat/L), 
ALT greater than 27 units/L (0.54 mckat/L), and non-
black race.
 
»
Treatment
Treatment consists of lifestyle changes to remove or modify 
the offending factors. Weight loss, dietary fat restriction, 
and even moderate exercise (through reduction of abdomi
-
nal obesity) often lead to improvement in liver biochemical 
tests and steatosis in obese patients with NAFLD. A Medi
-
terranean diet can reduce liver fat without weight loss and 
is often recommended. Loss of 3–5% of body weight 
appears necessary to improve steatosis, but loss of at least 
10% may be needed to improve necroinflammation and 
fibrosis. Exercise may reduce liver fat with minimal or no 
weight loss and no reduction in ALT levels. Resistance 
training and aerobic exercise are equally effective in reduc
-
ing hepatic fat content in patients with NAFLD and type 2 
diabetes mellitus. Various drugs are under study. Vitamin E 
800 international units/day (to reduce oxidative stress) 
appears to be of benefit in patients with NASH who do not 
have diabetes mellitus; there is concern that vitamin E may 
increase the risk of prostate cancer in men. Thiazolidinediones 
reverse insulin resistance and, in most relevant studies, 
have improved both serum aminotransferase levels and 
histologic features of steatohepatitis but lead to weight 
gain. Metformin, which reduces insulin resistance, 
improves abnormal liver chemistries but may not reliably 
improve liver histology. Pentoxifylline improves liver bio
-
chemical test levels but is associated with a high rate of

-
chemical test levels but is associated with a high rate of 
side effects, particularly nausea. Ursodeoxycholic acid, 
12–15 mg/kg/day, has not consistently resulted in bio
-
chemical and histologic improvement in patients with 
NASH but may be effective when given in combination 
with vitamin E. Hepatic steatosis due to total parenteral 
nutrition may be ameliorated—and perhaps prevented—
with supplemental choline. Other approaches under study 
include obeticholic acid, a semisynthetic bile acid analog 
that has been approved for the treatment of primary biliary 
cholangitis as well as orlistat, an inhibitor of gastrointesti
-
nal lipases; recombinant human leptin; liraglutide, a gluca
-
gon-like protein-1-analog that promotes insulin secretion; 
L-carnitine, which regulates the turnover of fatty acids in 
phospholipid membranes; omega-3 fatty acids, which alter 
hepatic gene expression to favor fatty acid oxidation over 
lipogenesis; probucol, a lipid-lowering agent; elafibranor, 
an agonist of the peroxisome proliferator-activated receptor-
alpha and -delta; losartan, an angiotensin antagonist; selec
-
tive caspase inhibitors; and iron depletion therapy. Statins 
are not contraindicated in persons with NAFLD and may 
protect against histologic progression in some patients. 
Bariatric surgery may be considered in patients with a 
body mass index greater than 35 and leads to histologic 
regression of NASH in most patients. Liver transplantation 
is indicated in appropriate candidates with advanced cir
-
rhosis caused by NASH, now the third most common (and 
most rapidly increasing) indication for liver transplantation 
in the United States. Liver transplantation for NASH with 
advanced cirrhosis may be associated with increased mortality 
from cardiovascular disease and sepsis compared with liver 
transplantation for other indications.
 
»
Prognosis
Fatty liver often has a benign course and is readily revers
-
ible with discontinuation of alcohol (or no more than one 
glass of wine per day, which may actually reduce the fre
-
quency of NASH in persons with NAFLD), or treatment of 
other underlying conditions; if untreated, fibrosis pro
-
gresses at an average rate of 1 stage every 14 years, with a 
subset of 20% of patients progressing more rapidly. In 
patients with NAFLD, the likelihood of NASH is increased 
by the following factors: obesity, older age, non–African 
American ethnicity, female sex, diabetes mellitus, hyper
-
tension, higher ALT or AST level, higher AST/ALT ratio, 
low platelet count, elevated fasting C-peptide level, and a 
high ultrasound steatosis score. NASH may be associated 
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with hepatic fibrosis in 40% of cases with progression at a 
rate of 1 stage every 7 years; cirrhosis develops in 9–25%; 
and decompensated cirrhosis occurs in 30–50% of cirrhotic 
patients over 10 years. The course may be more aggressive 
in diabetic persons than in nondiabetic persons. Mortality 
is increased in patients with NAFLD, correlates with fibro
-
sis stage, and is more likely to be the result of malignancy 
and cardiovascular disease than liver disease. Risk factors 
for mortality are older age, male sex, white race, smoking, 
higher body mass index, hypertension, diabetes mellitus, 
and cirrhosis. Steatosis is a cofactor for the progression of 
fibrosis in patients with other causes of chronic liver dis
-
ease, such as hepatitis C. Hepatocellular carcinoma is a 
complication of cirrhosis caused by NASH, as it is for other 
causes of cirrhosis, and has been reported even in the 
absence of cirrhosis. NASH accounts for a substantial per
-
centage of cases labeled as cryptogenic cirrhosis and can 
recur following liver transplantation. Central obesity is an 
independent risk factor for death from cirrhosis of any 
cause.
 
»
Refer patients with NAFLD who require liver biopsy for 
Ajmera VH et al. Is moderate alcohol use in nonalcoholic fatty 
liver disease good or bad? A critical review. Hepatology. 
2017 Jun;65(6):2090–9. [PMID: 28100008]
Diehl AM et al. Cause, pathogenesis, and treatment of nonalcoholic 
steatohepatitis. N Engl J Med. 2017 Nov 23;377(21):2063–72. 
[PMID: 29166236]
Klebanoff MJ et al. Bariatric surgery for nonalcoholic steatohepa
-
titis: a clinical and cost-effectiveness analysis. Hepatology. 
 
2017 Apr;65(4):1156–64. [PMID: 27880977]
Romero-Gómez M et al. Treatment of NAFLD with diet, physical 
activity and exercise. J Hepatol. 2017 Oct;67(4):829–46. [PMID: 
28545937]
Y ang JD et al; Nonalcoholic Steatohepatitis Clinical Research 
Network. Patient sex, reproductive status, and synthetic hor
-
mone use associate with histologic severity of nonalcoholic 
steatohepatitis. Clin Gastroenterol Hepatol. 2017 Jan; 15(1):
 
127–31. [PMID: 27523635]
CIRRHOSIS
 
»
End result of injury that leads to both fibrosis and 
regenerative nodules.
 
»
May be reversible if cause is removed.
 
»
The clinical features result from hepatic cell 
dysfunction, portosystemic shunting, and portal 
 
»
Cirrhosis, the eighth leading cause of death in the United 
States with a prevalence rate of 0.27%, is the end result of 
hepatocellular injury that leads to both fibrosis and 
regenerative nodules throughout the liver. Hospitalization 
rates for cirrhosis and portal hypertension are rising in the 
United States. Causes include chronic viral hepatitis; 
alcohol; drug toxicity; autoimmune and metabolic liver 
diseases, including NAFLD; and miscellaneous disorders. 
Celiac disease appears to be associated with an increased 
risk of cirrhosis. Many patients have more than one risk 
factor (eg, chronic hepatitis and alcohol use). Mexican 
Americans and African Americans have a higher fre
-
quency of cirrhosis than whites because of a higher rate of 
risk factors. In persons at increased risk for liver injury 
(eg, heavy alcohol use, obesity, iron overload), higher cof
-
fee and tea consumption and statin use reduce the risk of 
cirrhosis. The risk of hospitalization or death due to cirrhosis 
has been reported to correlate with protein and cholesterol 
consumption and with hyperuricemia and inversely with 
carbohydrate consumption.
Clinically, cirrhosis is considered to progress through 
three stages that correlate with the thickness of fibrous 
septa: compensated, compensated with varices, and decom
-
pensated (ascites, variceal bleeding, encephalopathy, or 
jaundice).
 
»
The clinical features of cirrhosis result from hepatocyte

-
 
»
The clinical features of cirrhosis result from hepatocyte 
dysfunction, portosystemic shunting, and portal hyperten
-
sion. Patients may have no symptoms for long periods. The 
onset of symptoms may be insidious or, less often, abrupt. 
Fatigue, disturbed sleep, muscle cramps, and weight loss 
are common. In advanced cirrhosis, anorexia is usually 
present and may be extreme, with associated nausea and 
occasional vomiting, as well as reduced muscle strength 
and exercise capacity. Abdominal pain may be present and 
is related either to hepatic enlargement and stretching of 
Glisson capsule or to the presence of ascites. Menstrual 
abnormalities (usually amenorrhea), erectile dysfunction, 
loss of libido, sterility, and gynecomastia may occur. 
Hematemesis is the presenting symptom in 15–25%. The 
risk of falls is increased in hospitalized patients with 
cirrhosis who are taking psychoactive medications.
Skin manifestations consist of spider telangiectasias 
(invariably on the upper half of the body), palmar erythema 
(mottled redness of the thenar and hypothenar eminences), 
and Dupuytren contractures. Evidence of vitamin deficien
-
cies (glossitis and cheilosis) is common. Weight loss, wast
-
ing (due to sarcopenia), and the appearance of chronic 
illness are present. Jaundice—usually not an initial sign—is 
mild at first, increasing in severity during the later stages of 
the disease. In 70% of cases, the liver is enlarged, palpable, 
and firm if not hard and has a sharp or nodular edge; the left 
lobe may predominate. Splenomegaly is present in 35–50% 
of cases and is associated with an increased risk of compli
-
cations of portal hypertension. The superficial veins of the 
abdomen and thorax are dilated, reflecting the intrahepatic 
obstruction to portal blood flow, as do rectal varices. The 
abdominal wall veins fill from below when compressed. 
Ascites, pleural effusions, peripheral edema, and ecchymo
-
ses are late findings. Encephalopathy, characterized by 
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day-night reversal, asterixis, tremor, dysarthria, delirium, 
drowsiness and, ultimately coma also occurs late in the 
course except when precipitated by an acute hepatocellular 
insult or an episode of gastrointestinal bleeding or infection. 
Fever is present in up to 35% of patients and usually reflects 
associated alcoholic hepatitis, spontaneous bacterial perito
-
nitis, or another intercurrent infection.
Laboratory abnormalities are either absent or minimal in 
early or compensated cirrhosis. Anemia, a frequent finding, 
is often macrocytic; causes include suppression of erythro
-
poiesis by alcohol as well as folate deficiency, hemolysis, 
hypersplenism, and occult or overt blood loss from the gas
-
trointestinal tract. The white blood cell count may be low, 
reflecting hypersplenism, or high, suggesting infection. 
Thrombocytopenia, the most common cytopenia in cirrhotic 
patients, is secondary to alcoholic marrow suppression, sep
-
sis, folate deficiency, or splenic sequestration. Prolongation of 
the prothrombin time may result from reduced levels of clot
-
ting factors (except factor VIII). However, bleeding risk cor
-
relates poorly with the prothrombin time because of 
concomitant abnormalities of fibrinolysis, and among hospi
-
talized patients under age 45, cirrhosis is associated with an 
increased risk of venous thromboembolism.
Blood chemistries reflect hepatocellular injury and dys
-
function, manifested by modest elevations of AST and 
alkaline phosphatase and progressive elevation of the 
bilirubin. Serum albumin decreases as the disease pro
-
gresses; gamma-globulin levels are increased and may be as 
high as in autoimmune hepatitis. The risk of diabetes 
mellitus is increased in patients with cirrhosis, particularly 
when associated with HCV infection, alcoholism, hemo
-
chromatosis, or NAFLD. Vitamin D deficiency has been 
reported in as many as 91% of patients with cirrhosis. 
Patients with alcoholic cirrhosis may have elevated serum 
cardiac troponin I and B-type natriuretic peptide (BNP) 
levels. In cirrhosis of all causes, the following are common: 
(1) blunted cardiac inotropic and chronotropic responses 
to exercise, stress, and drugs, (2) prolongation of the QT 
interval in the setting of a hyperkinetic circulation, and (3) 
systolic and diastolic ventricular dysfunction in the absence 
of other known causes of cardiac disease (“cirrhotic cardio
-
myopathy”); however, overt heart failure is rare in the 
absence of alcoholism. Relative adrenal insufficiency 
appears to be common in patients with advanced cirrhosis, 
even in the absence of sepsis, and may relate in part to 
reduced synthesis of cholesterol and increased levels of 
proinflammatory cytokines.
C. Imaging
Ultrasonography is helpful for assessing liver size and 
detecting ascites or hepatic nodules, including small 
hepatocellular carcinomas. Together with a Doppler 
study, it may establish patency of the splenic, portal, and 
hepatic veins. Hepatic nodules are characterized further 
by contrast-enhanced CT or MRI. Nodules suspicious for 
malignancy may be biopsied under ultrasound or CT 
guidance.
Liver biopsy may show inactive cirrhosis (fibrosis with 
regenerative nodules) with no specific features to suggest 
the underlying cause. Alternatively, there may be addi
-
tional features of alcoholic liver disease, chronic hepatitis, 
NASH, or other specific causes of cirrhosis. Liver biopsy 
may be performed by laparoscopy or, in patients with 
coagulopathy and ascites, by a transjugular approach. 
Combinations of routine blood tests (eg, AST, platelet 
count), including the FibroSure test, serum markers of 
hepatic fibrosis (eg, hyaluronic acid, amino-terminal pro
-
peptide of type III collagen, tissue inhibitor of matrix 
metalloproteinase 1), and ultrasound or magnetic reso
-

-
-
nance elastography are potential alternatives to liver biopsy 
for the diagnosis or exclusion of cirrhosis. In persons with 
chronic hepatitis C, for example, a low FibroSure or elas
-
tography score reliably excludes advanced fibrosis, a high 
score reliably predicts advanced fibrosis, and intermediate 
scores are inconclusive.
E. Other Tests
Esophagogastroduodenoscopy confirms the presence of 
varices and detects specific causes of bleeding in the 
esophagus, stomach, and proximal duodenum. In selected 
cases, wedged hepatic vein pressure measurement may 
establish the presence and cause of portal hypertension.
 
»
The most common causes of cirrhosis are alcohol, chronic 
hepatitis C infection, NAFLD, and hepatitis B infection. 
Hemochromatosis is the most commonly identified genetic 
disorder that causes cirrhosis. Other diseases associated 
with cirrhosis include Wilson disease, alpha-1-antitrypsin 
(alpha-1-antiprotease) deficiency, and celiac disease. PBC 
occurs more frequently in women than men. Secondary 
biliary cirrhosis may result from chronic biliary obstruc
-
tion due to a stone, stricture, or neoplasm. Heart failure 
and constrictive pericarditis may lead to hepatic fibrosis 
(“cardiac cirrhosis”) complicated by ascites. Hereditary 
hemorrhagic telangiectasia can lead to portal hypertension 
because of portosystemic shunting and nodular transfor
-
mation of the liver as well as high-output heart failure. 
Many cases of cirrhosis are “cryptogenic, ” in which unrec
-
ognized NAFLD may play a role.
 
»
Upper gastrointestinal tract bleeding may occur from vari
-
ces, portal hypertensive gastropathy, or gastroduodenal 
ulcer (see Chapter 15). Varices may also result from portal 
vein thrombosis, which may complicate cirrhosis. Liver 
failure may be precicpitated by alcoholism, surgery, and 
infection. Hepatic Kupffer cell (reticuloendothelial) dys
-
function and decreased opsonic activity lead to an increased 
risk of systemic infection (which may be increased further 
by the use of proton pump inhibitors), and which increase 
mortality fourfold. These infections include nosocomial 
infections, which may be classified as spontaneous blood
-
stream infections, urinary tract infections, pulmonary 
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infections, spontaneous bacterial peritonitis, 
difficile
 infection, and intervention-related infections. 
These nosocomial infections are increasingly caused by 
multidrug-resistant bacteria. Osteoporosis occurs in 
12–55% of patients with cirrhosis. The risk of hepatocellular 
carcinoma is increased greatly in persons with cirrhosis 
(see Chapter 39). Varices, ascites, and encephalopathy may 
arise when there is clinically significant portal hyperten
-
sion (hepatic venous pressure gradient greater than 
 
10 mm Hg).
 
»
Treatment
Most important is abstinence from alcohol. The diet 
should be palatable, with adequate calories (20–40 kcal/kg 
body weight per day depending on the patient’s body mass 
index and the presence or absence of malnutrition) and 
protein (1–1.5 g/kg/day depending on the presence or 
absence of malnutrition) and, if there is fluid retention, 
sodium restriction. In the presence of hepatic encepha
-
lopathy, protein intake should be reduced to no less than 
60–80 g/day. Vitamin supplementation is desirable. Muscle 
cramps may be helped by L-carnitine, 300 mg orally four 
times a day. Patients with cirrhosis should receive the HAV , 
HBV , and pneumococcal vaccines and a yearly influenza 
vaccine. Liver transplantation in appropriate candidates is 
curative. Care coordination and palliative care, when 
appropriate, have been shown to improve outcomes and 
reduce readmission rates.
B. Treatment of Complications
1. Ascites and edema—
Diagnostic paracentesis is indi
-
cated for patients who have new ascites or who have been 
hospitalized for a complication of cirrhosis; it reduces 
mortality, especially if performed within 12 hours of 
admission. Serious complications of paracentesis, includ
-
ing bleeding, infection, or bowel perforation, occur in 1.6% 
of procedures and are associated with therapeutic (vs diag
-
nostic) paracentesis and possibly with Child-Pugh class C, 
a platelet count less than 50,000/mcL (50 × 10
9
/L), and 
alcoholic cirrhosis. In patients with coagulopathy, however, 
pre-paracentesis prophylactic transfusions do not appear 
to be necessary. In addition to a cell count and culture, the 
ascitic albumin level should be determined: a serum-ascites 
albumin gradient (serum albumin minus ascitic fluid albu
-
min) greater than or equal to 1.1 suggests portal hyper
-
tension. An elevated ascitic adenosine deaminase level is 
suggestive of tuberculous peritonitis. Occasionally, cirrhotic 
ascites is chylous (rich in triglycerides); other causes of 
chylous ascites are malignancy, tuberculosis, and recent 
abdominal surgery or trauma.
In individuals with ascites, the urinary sodium concen
-
tration is often less than 10 mEq/L (10 mmol/L). Free water 
excretion is also impaired in cirrhosis, and hyponatremia 
may develop.
In all patients with cirrhotic ascites, dietary sodium 
intake may initially be restricted to 2000 mg/day; the intake 
of sodium may be liberalized slightly after diuresis ensues. 
Nonsteroidal anti-inflammatory drugs are contraindicated, 
and angiotensin-converting enzyme inhibitors and 
angiotensin II antagonists should be avoided. In some 
patients, ascites diminishes promptly with bed rest and 
dietary sodium restriction alone. Fluid intake is often 
restricted (to 800–1000 mL/day) in patients with hypo
-
natremia. Treatment of severe hyponatremia (serum 
sodium less than 125 mEq/L [125 mmol/L]) with vaso
-
pressin receptor antagonists (eg, intravenous conivaptan, 
20 mg daily) can be considered but such treatment is 
expensive, causes thirst, and does not improve survival; 
oral tolvaptan is contraindicated in patients with liver 
disease because of potential hepatotoxicity.
a. Diuretics—
Spironolactone, generally in combination 
with furosemide, should be used in patients who do not 
respond to salt restriction alone. The dose of spironolactone 
is initially 100 mg orally daily and may be increased by

is initially 100 mg orally daily and may be increased by 
 
100 mg every 3–5 days (up to a maximal conventional daily 
dose of 400 mg/day, although higher doses have been used) 
until diuresis is achieved, typically preceded by a rise in the 
urinary sodium concentration. A “spot” urine sodium con
-
centration that exceeds the potassium concentration cor
-
relates with a 24-hour sodium excretion greater than 
 
78 mmol/day, which predicts diuresis in patients adherent 
to a salt-restricted diet. Monitoring for hyperkalemia is 
important. In patients who cannot tolerate spironolactone 
because of side effects, such as painful gynecomastia, 
amiloride (another potassium-sparing diuretic) may be 
used in a starting dose of 5–10 mg orally daily. Diuresis is 
augmented by the addition of a loop diuretic such as furo
-
semide. This potent diuretic, however, will maintain its 
effect even with a falling glomerular filtration rate, with 
resulting prerenal azotemia. The dose of oral furosemide 
ranges from 40 mg/day to 160 mg/day, and blood pressure, 
urinary output, mental status, and serum electrolytes 
(especially potassium) should be monitored in patients 
taking the drug. The goal of weight loss in the ascitic 
patient without associated peripheral edema should be no 
more than 1–1.5 lb/day (0.5–0.7 kg/day).
b. Large-volume paracentesis—
In patients with mas
-
sive ascites and respiratory compromise, ascites refractory 
to diuretics (“diuretic resistant”), or intolerable diuretic 
side effects (“diuretic intractable”), large-volume paracente
-
sis (more than 5 L) is effective. Intravenous albumin con
-
comitantly at a dosage of 6–8 g/L of ascites fluid removed 
protects the intravascular volume and may prevent post
-
paracentesis circulatory dysfunction, although the useful
-
ness of this practice is debated and the use of albumin is 
expensive. Large-volume paracentesis can be repeated 
daily until ascites is largely resolved and may decrease 
the need for hospitalization. If possible, diuretics should 
be continued in the hope of preventing recurrent 
ascites.
c. Transjugular intrahepatic portosystemic 
shunt (tips
)
—
TIPS is an effective treatment of variceal 
bleeding refractory to standard therapy (eg, endoscopic 
band ligation) and has shown benefit in the treatment of 
severe refractory ascites. The technique involves insertion 
of an expandable metal stent between a branch of the 
hepatic vein and the portal vein over a catheter inserted via 
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the internal jugular vein. Increased renal sodium excretion 
and control of ascites refractory to diuretics can be achieved 
in about 75% of selected cases. The success rate is lower in 
patients with underlying chronic kidney disease. TIPS 
appears to be the treatment of choice for refractory hepatic 
hydrothorax (translocation of ascites across the diaphragm 
to the pleural space); video-assisted thoracoscopy with 
pleurodesis using talc may be effective when TIPS is con
-
traindicated. Complications of TIPS include hepatic 
encephalopathy in 20–30% of cases, infection, shunt steno
-
sis in up to 60% of cases, and shunt occlusion in up to 30% 
of cases when bare stents are used; polytetrafluoroethylene-
covered stents are associated with long-term patency rates 
of 80–90%. Long-term patency often requires periodic 
shunt revisions. In most cases, patency can be maintained 
by balloon dilation, local thrombolysis, or placement of an 
additional stent. TIPS is particularly useful in patients who 
require short-term control of variceal bleeding or ascites 
until liver transplantation can be performed. In patients 
with refractory ascites, TIPS results in lower rates of 
ascites recurrence and hepatorenal syndrome but a higher 
rate of hepatic encephalopathy than occurs with repeated 
large-volume paracentesis; a benefit in survival has been 
demonstrated in one study and a meta-analysis. Chronic 
kidney disease, diastolic cardiac dysfunction, refractory 
encephalopathy, and hyperbilirubinemia (greater than 
 
5 mg/dL [85.5 mcmol/L]) are associated with mortality 
after TIPS.
2. Spontaneous bacterial peritonitis—
Spontaneous bacterial 
peritonitis is heralded by abdominal pain, increasing 
ascites, fever, and progressive encephalopathy in a patient 
with cirrhotic ascites; symptoms are typically mild. (Analo
-
gously, spontaneous bacterial empyema may complicate 
hepatic hydrothorax and is managed similarly.) Risk fac
-
tors in cirrhotic patients with ascites include gastroesopha
-
geal variceal bleeding and possibly use of a proton pump 
inhibitor. Paracentesis reveals an ascitic fluid with, most 
commonly, a total white cell count of up to 500 cells/mcL 
with a high polymorphonuclear (PMN) cell count (250/mcL 
or more) and a protein concentration of 1 g/dL (10 g/L) or 
less, corresponding to decreased ascitic opsonic activity. 
Cultures of ascites give the highest yield—80–90% positive—
using specialized culture bottles inoculated at the bedside. 
Common isolates are 
 and 
 
spp. Gram-positive cocci are the most common isolates in 
patients who have undergone an invasive procedure such 
as central venous line placement, and the frequency of 
enterococcal isolates is increasing. Anaerobes are uncom
-
mon. Pending culture results, if there are 250 or more 
PMNs/mcL or symptoms or signs of infection, intravenous 
antibiotic therapy should be initiated with cefotaxime, 2 g 
every 8–12 hours for at least 5 days. Alternative choices 
include ceftriaxone, amoxicillin-clavulanic acid, and levo
-
floxacin (in patients not receiving fluoroquinolone prophy
-
laxis). Oral ofloxacin, 400 mg twice daily for 7 days, or, 
in a patient not already taking a fluoroquinolone for 
prophylaxis against bacterial peritonitis, a 2-day course 
of intravenous ciprofloxacin, 200 mg twice daily, fol
-
lowed by oral ciprofloxacin, 500 mg twice daily for 
 
5 days, may be effective alternative regimens in selected 
patients. A carbapenem has been recommended for 
patients with hospital-acquired spontaneous bacterial peri
-
tonitis, which is increasingly caused by multidrug-resistant 
organisms. Supplemental administration of intravenous 
albumin (which may have anti-inflammatory effects in addi
-
tion to expanding plasma volume) prevents further renal 
impairment and reduces mortality, particularly in patients

-
impairment and reduces mortality, particularly in patients 
with a serum creatinine greater than 1 mg/dL (83.3 mcmol/L), 
blood urea nitrogen greater than 30 mg/dL (10.8 mmol/L), 
or total bilirubin greater than 4 mg/dL (68.4 mcmol/L). 
Response to therapy can be documented, if necessary, by a 
decrease in the PMN count of at least 50% on repeat para
-
centesis 48 hours after initiation of therapy. The overall 
mortality rate is high—up to 30% during hospitalization 
and up to 70% by 1 year. Mortality may be predicted by the 
22/11 model: MELD score greater than 22 and peripheral 
white blood cell count higher than 11,000/mcL (11 ×10
9
/L). 
Another model predictive of mortality includes the blood 
urea nitrogen, white blood cell count, Child-Pugh score, 
and mean arterial pressure. Patients with cirrhosis and 
septic shock have a high frequency of relative adrenal 
insufficiency, which if present requires administration of 
hydrocortisone.
In survivors of bacterial peritonitis, the risk of recurrent 
peritonitis may be decreased by long-term ciprofloxacin 
(eg, 500 mg orally once per day) or norfloxacin (400 mg 
orally daily; no longer available in the United States) or 
trimethoprim-sulfamethoxazole (eg, one double-strength 
tablet once per day). In cases of recurrent peritonitis, the 
causative organism is often resistant to fluoroquinolones 
and may become multidrug resistant in some cases. In 
high-risk cirrhotic patients without prior peritonitis (eg, 
those with an ascitic protein less than 1.5 g/dL and serum 
bilirubin greater than 3 mg/dL (51.3 mcmol/L), serum 
creatinine greater than 1.2 mg/dL (99.96 mcmol/L), blood 
urea nitrogen 25 mg/dL or more (9 mmol/L or more), or 
sodium 130 mEq/L or less [130 mmol/L or less]), the risk 
of peritonitis, hepatorenal syndrome, and mortality for at 
least 1 year may be reduced by prophylactic trimethoprim-
sulfamethoxazole, one double-strength tablet once per day, 
ciprofloxacin, 500 mg once per day, or norfloxacin, 400 mg 
orally once a day (though not in the United States). In 
patients hospitalized for acute variceal bleeding, intrave
-
nous ceftriaxone (1 g per day), followed by oral trimethoprim-
sulfamethoxazole (one double-strength tablet once per 
day) or ciprofloxacin (500 mg every 12 hours), for a total of 
7 days, reduces the risk of bacterial peritonitis. Nonantibiotic 
prophylactic strategies, including probiotics, bile acids, and 
statins, are under study.
3. Hepatorenal syndrome—
Hepatorenal syndrome occurs 
in up to 10% of patients with advanced cirrhosis and ascites. 
It is characterized by (1) azotemia (increase in serum 
creatinine level of greater than 0.3 mg/dL [26.5 mcmol/L]) 
within 48 hours or increase by 50% or more from baseline 
within the previous 7 days in the absence of current or 
recent nephrotoxic drug use, (2) macroscopic signs of 
structural kidney injury, (3) shock, and (4) failure of kidney 
function to improve following 2 days of diuretic with
-
drawal and volume expansion with albumin, 1 g/kg up to a 
maximum of 100 g/day. Oliguria, hyponatremia, and a low 
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urinary sodium concentration are typical features. Hepatorenal 
syndrome is diagnosed only when other causes of acute 
kidney injury (including prerenal azotemia and acute 
tubular necrosis) have been excluded. Hepatorenal 
syndrome-acute kidney injury (formerly type 1 hepatore
-
nal syndrome) is typically associated with at least doubling 
of the serum creatinine to a level greater than 2.5 mg/dL 
(208.25 mcmol/L) or by halving of the creatinine clearance 
to less than 20 mL/min (0.34 mL/s/1.73 m
2
 BSA) in less 
than 2 weeks. Hepatorenal-chronic kidney disease (formerly 
type 2 hepatorenal syndrome) is more slowly progressive 
and chronic. An acute decrease in cardiac output is often 
the precipitating event. In addition to discontinuation of 
diuretics, clinical improvement and an increase in short-
term survival may follow intravenous infusion of albumin 
in combination with one of the following vasoconstrictor 
regimens for 7–14 days: oral midodrine plus octreotide, 
subcutaneously or intravenously; intravenous terlipressin 
(not yet available in the United States but the preferred 
agent where available); or intravenous norepinephrine. 
Oral midodrine, 7.5 mg three times daily, added to diuret
-
ics, increases the blood pressure and has also been reported 
to convert refractory ascites to diuretic-sensitive ascites. 
Prolongation of survival has been associated with use of 
MARS, a modified dialysis method that selectively removes 
albumin-bound substances. Improvement and sometimes 
normalization of kidney function may also follow place
-
ment of a TIPS; survival after 1 year is reported to be pre
-
dicted by the combination of a serum bilirubin level less 
than 3 mg/dL (50 mcmol/L) and a platelet count greater 
than 75,000/mcL (75 ×10
9
/L). Continuous venovenous 
hemofiltration and hemodialysis are of uncertain value in 
hepatorenal syndrome. Liver transplantation is the ulti
-
mate treatment of choice, but many patients die before a 
donor liver can be obtained. Mortality correlates with the 
MELD score and presence of a systemic inflammatory 
response. Hepatorenal syndrome-acute kidney injury is 
often irreversible in patients with a systemic infection. The 
3-month probability of survival in cirrhotic patients with 
hepatorenal syndrome (15%) is lower than that for renal 
failure associated with infections (31%), hypovolemia (46%), 
and parenchymal kidney disease (73%).
4. Hepatic encephalopathy—
Hepatic encephalopathy is a 
state of disordered central nervous system function result
-
ing from failure of the liver to detoxify noxious agents of 
gut origin because of hepatocellular dysfunction and por
-
tosystemic shunting. The clinical spectrum ranges from 
day-night reversal and mild intellectual impairment to 
coma. Patients with covert (formerly minimal) hepatic 
encephalopathy have no recognizable clinical symptoms 
but demonstrate mild cognitive, psychomotor, and atten
-
tion deficits on standardized psychometric tests and an 
increased rate of traffic accidents. The stages of overt 
encephalopathy are (1) mild confusion, (2) drowsiness, 
(3) stupor, and (4) coma. A revised staging system known 
as SONIC (
s
pectrum 
o
f 
n
eurocognitive 
i
mpairment in 
c
irrhosis) encompasses absent, covert, and stages 2 to 
 
4 encephalopathy. Ammonia is the most readily identified 
and measurable toxin but is not solely responsible for the 
disturbed mental status. Bleeding into the intestinal tract 
may significantly increase the amount of protein in the 
bowel and precipitate encephalopathy. Other precipitants 
include constipation, alkalosis, and potassium deficiency 
induced by diuretics, opioids, hypnotics, and sedatives; 
medications containing ammonium or amino compounds; 
paracentesis with consequent hypovolemia; hepatic or sys
-
temic infection; and portosystemic shunts (including 
TIPS). The diagnosis is based primarily on detection of

-
TIPS). The diagnosis is based primarily on detection of 
characteristic symptoms and signs, including asterixis. A 
smartphone app called EncephalApp using the “Stroop 
test” (asking the patient to name the color of a written word 
rather than the word itself, even when the word is the name 
of a different color) has proved useful for detecting covert 
hepatic encephalopathy. The role of neuroimaging studies 
(eg, cerebral PET, magnetic resonance spectroscopy) in the 
diagnosis of hepatic encephalopathy is evolving.
Protein is withheld during acute episodes if the patient 
cannot eat. When the patient resumes oral intake, protein 
intake should be 60–80 g/day as tolerated; vegetable protein is 
better tolerated than meat protein. Gastrointestinal bleeding 
should be controlled and blood purged from the gastrointestinal 
tract. This can be accomplished with 120 mL of magnesium 
citrate by mouth or nasogastric tube every 3–4 hours until 
the stool is free of gross blood or by administration of lactu
-
lose. The value of treating patients with covert hepatic 
encephalopathy is uncertain; probiotic agents may have 
some benefit.
Lactulose, a nonabsorbable synthetic disaccharide 
syrup, is digested by bacteria in the colon to short-chain 
fatty acids, resulting in acidification of colon contents. This 
acidification favors the formation of ammonium ion in the 
NH
4
+
 
↔
 NH
3
 + H
+
 equation; NH
4
+
 is not absorbable, 
whereas NH
3
 is absorbable and thought to be neurotoxic. 
Lactulose also leads to a change in bowel flora so that fewer 
ammonia-forming organisms are present. When given 
orally, the initial dose of lactulose for acute hepatic enceph
-
alopathy is 30 mL three or four times daily. The dose 
should then be titrated so that the patient produces 2–3 soft 
stools per day. When given rectally because the patient is 
unable to take medicines orally, the dose is 200 g/300 mL a 
solution of lactulose in saline or sorbitol as a retention enema 
for 30–60 minutes; it may be repeated every 4–6 hours. Bowel 
cleansing with a polyethylene glycol colonoscopy preparation 
is also effective in patients with acute overt hepatic encepha
-
lopathy and may be preferable. Continued use of lactulose 
after an episode of acute encephalopathy reduces the fre
-
quency of recurrences.
The ammonia-producing intestinal flora may also be 
controlled with an oral antibiotic. The nonabsorbable agent 
rifaximin, 550 mg orally twice daily, is preferred and has 
been shown as well to maintain remission of and reduce 
the risk of rehospitalization for hepatic encephalopathy 
over a 24-month period, with or without the concomitant 
use of lactulose. Metronidazole, 250 mg orally three times 
daily, has also shown benefit. Patients who do not respond 
to lactulose alone may improve with a course of an antibi
-
otic added to treatment with lactulose.
Opioids and sedatives metabolized or excreted by the 
liver should be avoided. If agitation is marked, oxazepam, 
10–30 mg, which is not metabolized by the liver, may be 
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given cautiously by mouth or by nasogastric tube. Zinc 
deficiency should be corrected, if present, with oral zinc 
sulfate, 600 mg/day in divided doses. Sodium benzoate, 5 g 
orally twice daily, ornithine aspartate, 9 g orally three times 
daily, and L-acyl-carnitine (an essential factor in the mito
-
chrondrial transport of long-chain fatty acids), 4 g orally 
daily, may lower blood ammonia levels, but there is less 
experience with these drugs than with lactulose. Flumazenil 
is effective in about 30% of patients with severe hepatic 
encephalopathy, but the drug is short-acting and intrave
-
nous administration is required. Use of special dietary 
supplements enriched with branched-chain amino acids is 
usually unnecessary except in occasional patients who are 
intolerant of standard protein supplements.
5. Coagulopathy—
Hypoprothrombinemia caused by 
malnutrition and vitamin K deficiency may be treated with 
vitamin K (eg, phytonadione, 5 mg orally or intravenously 
daily); however, this treatment is ineffective when synthesis 
of coagulation factors is impaired because of hepatic 
disease. In such cases, correcting the prolonged prothrom
-
bin time requires large volumes of fresh frozen plasma (see 
Chapter 14). Because the effect is transient, plasma infu
-
sions are not indicated except for active bleeding or before 
an invasive procedure, and even then, their value has been 
questioned because of concomitant alterations in anti-
hemostatic factors and because bleeding risk does not cor
-
relate with the INR. Recombinant activated factor VIIa 
may be an alternative but is expensive and poses a 1–2% 
risk of thrombotic complications. In fact, bleeding risk in 
critically ill patients with cirrhosis has been shown to cor
-
relate with bleeding on hospital admission, a platelet count 
less than 30,000/mcL (30 × 10
9
/L), a fibrinogen level less 
than 60 mg/dL (1.764 mcmol/L), and an activated partial 
thromboplastin time greater than 100 seconds. Eltrombopag 
reduces the need for platelet transfusions in patients with 
cirrhosis and a platelet count less than 50,000/mcL 
 
(50 × 10
9
/L) who undergo invasive procedures, but 
eltrombopag is associated with an increased risk of portal 
vein thrombosis and arterial thromboembolism.
6. Hemorrhage from esophageal varices—
See Chapter 15.
7. Hepatopulmonary syndrome and portopulmonary 
hypertension—
Shortness of breath in patients with 
cirrhosis may result from pulmonary restriction and atel
-
ectasis caused by massive ascites or hepatic hydrothorax. 
The hepatopulmonary syndrome—the triad of chronic 
liver disease, an increased alveolar-arterial gradient while 
the patient is breathing room air, and intrapulmonary vas
-
cular dilatations or arteriovenous communications that 
result in a right-to-left intrapulmonary shunt—occurs in 
5–32% of patients with cirrhosis. Patients often have 
greater dyspnea (platypnea) and arterial deoxygenation 
(orthodeoxia) in the upright than in the recumbent posi
-
tion. The diagnosis should be suspected in a cirrhotic 
patient with a pulse oximetry level of 96% or less.
Contrast-enhanced echocardiography is a sensitive 
screening test for detecting pulmonary vascular dilatations, 
whereas macroaggregated albumin lung perfusion scanning 
is more specific and may be used to confirm the diagnosis. 
High-resolution CT may be useful for detecting dilated 
pulmonary vessels that may be amenable to embolization in 
patients with severe hypoxemia (PO
2
 less than 60 mm Hg 
[7.8 kPa]) who respond poorly to supplemental oxygen.
Medical therapy has been disappointing; experimen
-
tally, intravenous methylene blue, oral garlic powder, oral 
norfloxacin, and mycophenolate mofetil may improve 
oxygenation by inhibiting nitric oxide-induced vasodilata
-
tion and angiogenesis, and pentoxifylline may prevent 
hepatopulmonary syndrome by inhibiting production of

-
hepatopulmonary syndrome by inhibiting production of 
tumor necrosis factor. Long-term oxygen therapy is recom
-
mended for severely hypoxemic patients. The syndrome 
may reverse with liver transplantation, although postoper
-
ative morbidity and mortality from severe hypoxemic 
respiratory failure are increased in patients with a preop
-
erative arterial PO
2
 less than 44 mm Hg (5.9 kPa) or with 
substantial intrapulmonary shunting. TIPS may provide 
palliation in patients with hepatopulmonary syndrome 
awaiting transplantation.
Portopulmonary hypertension occurs in 0.7% of patients 
with cirrhosis. Female sex and autoimmune hepatitis have 
been reported to be risk factors, and large spontaneous por
-
tosystemic shunts are present in many affected patients and 
are associated with a lack of response to treatment. In cases 
confirmed by right-sided heart catheterization, treatment 
with the prostaglandin epoprostenol, the endothelin-
receptor antagonists bosentan or ambrisentan, or the 
 
phosphodiesterase-5 inhibitors sildenafil or tadalafil may 
reduce pulmonary hypertension and thereby facilitate liver 
transplantation; beta-blockers worsen exercise capacity and 
are contraindicated, and calcium channel blockers should 
be used with caution because they may worsen portal 
hypertension. Liver transplantation is contraindicated in 
patients with moderate to severe pulmonary hypertension 
(mean pulmonary pressure greater than 35 mm Hg).
C. Liver Transplantation
Liver transplantation is indicated in selected cases of irre
-
versible, progressive chronic liver disease, acute liver failure, 
and certain metabolic diseases in which the metabolic defect 
is in the liver. Absolute contraindications include malig
-
nancy (except relatively small hepatocellular carcinomas in a 
cirrhotic liver—see Chapter 39), advanced cardiopulmonary 
disease (except hepatopulmonary syndrome), and sepsis. 
Relative contraindications include age over 70 years, morbid 
obesity, portal and mesenteric vein thrombosis, active alco
-
hol or drug abuse, severe malnutrition, and lack of patient 
understanding. With the emergence of effective antiretrovi
-
ral therapy for HIV disease, a major cause of mortality in 
these patients has shifted to liver disease caused by HCV and 
HBV infection; experience to date suggests that the outcome 
of liver transplantation is comparable to that for non–HIV-
infected liver transplant recipients. Patients with alcoholism 
should be abstinent for 6 months. Liver transplantation 
should be considered in patients with worsening functional 
status, rising bilirubin, decreasing albumin, worsening coag
-
ulopathy, refractory ascites, recurrent variceal bleeding, 
or worsening encephalopathy; prioritization is based on the 
MELD score. Treatment of HCV infection should be 
deferred until after transplantation in patients in whom the 
MELD score is greater than 25. Combined liver-kidney 
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transplantation is indicated in patients with associated 
kidney failure presumed to be irreversible. The major 
impediment to more widespread use of liver transplantation 
is a shortage of donor organs. Adult living donor liver trans
-
plantation is an option for some patients, and extended-
criteria donors are used. Five-year survival rates over 80% 
are now reported. Hepatocellular carcinoma, hepatitis B and 
C, and some cases of Budd-Chiari syndrome and autoimmune 
liver disease may recur in the transplanted liver. The inci
-
dence of recurrence of hepatitis B can be reduced by preop
-
erative and postoperative treatment with a nucleoside or 
nucleotide analog and perioperative administration of 
HBIG, and hepatitis C can be treated with direct-acting 
antiviral agents. Immunosuppression is achieved with com
-
binations of cyclosporine, tacrolimus, sirolimus, corticoste
-
roids, azathioprine, and mycophenolate mofetil and may be 
complicated by infections, advanced chronic kidney disease, 
neurologic disorders, and drug toxicity, as well as graft 
rejection, vascular occlusion, or bile leaks. Patients taking 
these drugs are at risk for obesity, diabetes mellitus, and 
hyperlipidemia.
 
»
Prognosis
The risk of death from compensated cirrhosis is 4.7 times 
that of the risk in the general population, and the risk from 
decompensated cirrhosis is 9.7 times higher. Use of statins 
appears to decrease the risk of decompensation in patients 
with compensated cirrhosis. Prognostic scoring systems for 
cirrhosis include the Child-Pugh score and MELD score 
(Table 16–7). The MELD (or MELD-Na) score, which 
incorporates the serum bilirubin, creatinine, and sodium 
levels and the INR, is also a measure of mortality risk in 
patients with end-stage liver disease and is particularly use
-
ful for predicting short- and intermediate-term survival and 
complications of cirrhosis (eg, bacterial peritonitis) as well 
as determining allocation priorities for donor livers. Addi
-
tional (MELD-exception) points are given for patients with 
conditions such as hepatopulmonary syndrome and 
hepatocellular carcinoma that may benefit from liver trans
-
plantation. A MELD score of 17 or more is required for liver 
transplant listing. In patients with a relatively low MELD 
score (less than 21) and a low priority for liver transplanta
-
tion, an elevated hepatic venous pressure gradient, persis
-
tent ascites, hepatic encephalopathy, and a low health-related 
quality of life are additional independent predictors of 
mortality, and further modifications of the MELD score are 
under consideration. Only 50% of patients with severe 
hepatic dysfunction (serum albumin less than 3 g/dL [30 g/L], 
bilirubin greater than 3 mg/dL [51.3 mcmol/L], ascites, 
encephalopathy, cachexia, and upper gastrointestinal bleed
-
ing) survive 6 months without transplantation. The risk of 
death in this subgroup of patients with advanced cirrhosis 
is associated with muscle wasting, age 65 years or older, 
mean arterial pressure 82 mm Hg or less, renal failure, cog
-
nitive dysfunction, ventilatory insufficiency, prothrombin 
time 16 seconds or longer, delayed and suboptimal treat
-
ment of sepsis, and second infections. For cirrhotic patients 
admitted to an intensive care unit, the Royal Free Hospital 
score, consisting of the serum bilirubin, INR, serum lactate, 
alveolar-arterial oxygen gradient, and blood urea nitrogen, 
Table 16–7.
 
Child-Pugh and Model for End-Stage Liver 
Disease (MELD) scoring systems for staging cirrhosis.
Child-Pugh Scoring System
Parameter
Numerical Score
1
2
3
Ascites
None
Slight
Moderate to 
severe
Encephalopathy
None
Slight to 
moderate
severe
Bilirubin, mg/dL 
(mcmol/L)
< 2.0 
 
(34.2)
2–3 
(34.2–51.3)
> 3.0 
 
(51.3)
Albumin, g/dL (g/L)
> 3.5 
 
(35)
2.8–3.5 
(28–35)
< 2.8 
 
(28)
Prothrombin time 
(seconds 
increased)
1–3
4–6
> 6.0
Total Numerical Score and Corresponding 
 
Child-Pugh Class
Score

> 3.0 
 
(51.3)
> 3.5 
 
(35)
2.8–3.5 
(28–35)
< 2.8 
 
(28)
(seconds 
1–3
4–6
> 6.0
 
Score
Class
5–6
A
7–9
B
10–15
C
M
e
LD Scoring System
Original MELD = 11.2 log
e
 (INR) + 3.78 log
e
 (bilirubin [mg/dL]) + 9.57 
log
e
 (creatinine [mg/dL]) + 6.43. (Range 6–40); in 2016, the serum 
sodium was added as a component (referred to as the MELDNa 
score): MELDNa = MELD + (140 – Na) × (1 – 0.025 × MELD).
has been reported to predict mortality. Renal failure 
increases mortality up to sevenfold in patients with cirrho
-
sis. Obesity and diabetes mellitus appear to be risk factors 
for clinical deterioration and cirrhosis-related mortality, as 
is continued alcohol use in patients with alcoholic cirrhosis. 
The use of beta-blockers for portal hypertension is benefi
-
cial early in the course but become ineffective and may be 
associated with reduced survival in patients with refractory 
ascites, spontaneous bacterial peritonitis, sepsis, or severe 
alcoholic hepatitis because of their negative effect on car
-
diac compensatory reserve. In general, beta-blockers should 
be discontinued when the systolic blood pressure is less 
than 90 mm Hg, the serum sodium level is less than 
 
130 mEq/L, or acute kidney injury has developed, although 
results of some studies have challenged these guidelines. 
Patients with cirrhosis are at risk for the development of 
hepatocellular carcinoma, with rates of 3–5% per year for 
alcoholic and viral hepatitis-related cirrhosis. Liver trans
-
plantation has markedly improved the outlook for patients 
with cirrhosis who are candidates and are referred for eval
-
uation early in the course. Patients with compensated 
cirrhosis are given additional priority for liver transplanta
-
tion if they are found to have a lesion larger than 2 cm in 
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diameter consistent with hepatocellular carcinoma. In-
hospital mortality from cirrhosis declined from 9.1% 
in 2002 to 5.4% in 2010 and that from variceal bleeding in 
patients with cirrhosis declined from over 40% in 1980 to 
15% in 2000. Patients hospitalized with cirrhosis and an 
infection are at high risk for subsequent infections, par
-
ticularly if they are older, taking a proton pump inhibitor, 
or receiving antibiotic prophylaxis for spontaneous bacterial 
 
»
•	
•	
When the MELD score is 14 or higher.
•	
For upper endoscopy to screen for gastroesophageal 
varices.
 
»
•	
Gastrointestinal bleeding.
•	
Stage 3–4 hepatic encephalopathy.
•	
Worsening kidney function.
•	
Severe hyponatremia.
•	
Serious infection.
•	
Profound hypoxia.
Firpi RJ (editor). Liver transplantation. Clin Liver Dis. 2017; 
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Gifford FJ et al. Systematic review with meta-analysis: vasoactive 
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Kim RG et al. Statin use and risk of cirrhosis and related complica
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tions in patients with chronic liver diseases: a systematic review 
and meta-analysis. Clin Gastroenterol Hepatol. 2017 Oct;
 
15(10):1521–30. [PMID: 28479502]
Patel YA et al. Evaluation of new-onset ascites. JAMA. 2016 Jul 19;
 
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Reiberger T et al. Beta adrenergic blockade and decompensated 
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[PMID: 28245324]
Tandon P et al. A practical approach to nutritional screening and 
assessment in cirrhosis. Hepatology. 2017 Mar;65(3):1044–57. 
[PMID: 28027577]
PRIMARY BILIARY CHOLANGITIS
 
»
Occurs in middle-aged women.
 
»
 
»
Elevation of alkaline phosphatase, positive antimi
-
tochondrial antibodies, elevated IgM, increased 
 
»
Characteristic liver biopsy.
 
»
In later stages, can present with fatigue, jaundice, 
features of cirrhosis, xanthelasma, xanthoma, 
steatorrhea.
 
»
Primary biliary cholangitis (PBC) is a chronic disease of 
the liver characterized by autoimmune destruction of small 
intrahepatic bile ducts and cholestasis. The designation 
“primary biliary cholangitis” has replaced “primary biliary 
cirrhosis” because many patients do not have cirrhosis. The 
disease is insidious in onset, occurs usually in women aged 
40–60 years, and is often detected by the chance finding of 
elevated alkaline phosphatase levels. Estimated incidence 
and prevalence rates in the United States are 4.5 and 65.4 per 
100,000, respectively, in women, and 0.7 and 12.1 per 
100,000, respectively, in men. These rates may be increas
-
ing. The frequency of the disease among first-degree rela
-
tives of affected persons is 1.3–6%, and the concordance 
rate in identical twins is high. PBC is associated with HLA 
DRB1*08
 and 
DQB1
. The disease may be associated with 
Sjögren syndrome, autoimmune thyroid disease, Raynaud 
syndrome, scleroderma, hypothyroidism, and celiac disease. 
Novosphingobium aromaticivorans
 or 
Chla
-
 may trigger or cause PBC. A 
history of urinary tract infections (caused by 
E coli
 or 
Lactobacillus delbrueckii
) and smoking, and possibly use of 
hormone replacement therapy and hair dye, are risk 
factors, and clustering of cases in time and space argues for 
a causative role of environmental agents.
 
»
Many patients are asymptomatic for years. The onset of 
clinical illness is insidious and is heralded by fatigue 
(excessive daytime somnolence) and pruritus. With pro
-
gression, physical examination reveals hepatosplenomeg
-

-
-
aly. Xanthomatous lesions may occur in the skin and 
tendons and around the eyelids. Jaundice, steatorrhea, and 
signs of portal hypertension are late findings, although 
occasional patients have esophageal varices despite an early 
histologic stage. Autonomic dysfunction, including ortho
-
static hypotension and associated fatigue and cognitive 
dysfunction, appear to be common. The risk of low bone 
density, osteoporosis, and fractures is increased in patients 
with PBC (who tend to be older women) possibly due in 
part to polymorphisms of the vitamin D receptor.
Blood counts are normal early in the disease. Liver biochemical 
tests reflect cholestasis with elevation of alkaline phosphatase, 
cholesterol (especially high-density lipoproteins), and, in later 
stages, bilirubin. Antimitochondrial antibodies are present in 
95% of patients, and serum IgM levels are elevated.
 
»
Diagnosis
The diagnosis of PBC is based on the detection of choles
-
tatic liver chemistries (often initially an isolated elevation 
of the alkaline phosphatase) and antimitochondrial anti
-
bodies in serum. Liver biopsy is not necessary for diagnosis 
unless antimitochondrial antibodies are absent but permits 
histologic staging: I, portal inflammation with granulo
-
mas; II, bile duct proliferation, periportal inflammation; III, 
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interlobular fibrous septa; and IV , cirrhosis. Estimation of 
histologic stage by an “enhanced liver fibrosis (ELF) assay, ” 
which incorporates serum levels of hyaluronic acid, tissue 
inhibitor of metalloproteinase-1, and procollagen III ami
-
nopeptide, has shown promise.
 
»
The disease must be differentiated from chronic biliary 
tract obstruction (stone or stricture), carcinoma of the bile 
ducts, primary sclerosing cholangitis, sarcoidosis, choles
-
tatic drug toxicity (eg, chlorpromazine), and in some cases 
chronic hepatitis. Patients with a clinical and histologic 
picture of PBC but no antimitochondrial antibodies are 
said to have antimitochondrial antibody-negative PBC 
(previously termed “autoimmune cholangitis”), which has 
been associated with lower serum IgM levels and a greater 
frequency of smooth muscle antibodies and ANA. Many 
such patients are found to have antimitochondrial antibod
-
ies by immunoblot against recombinant proteins (rather 
than standard immunofluorescence). Some patients have 
overlapping features of PBC and autoimmune hepatitis.
 
»
Treatment
Cholestyramine (4 g) in water or juice three times daily 
may be beneficial for pruritus; colestipol and colesevelam 
may be better tolerated but have not been shown to reduce 
pruritus. Rifampin, 150–300 mg orally twice daily, is incon
-
sistently beneficial. Opioid antagonists (eg, naloxone, 
 
0.2 mcg/kg/min by intravenous infusion, or naltrexone, 
starting at 12.5 mg/day by mouth) show promise in the 
treatment of pruritus but may cause opioid withdrawal 
symptoms. The 5-hydroxytryptamine (5-HT
3
) serotonin 
receptor antagonist ondansetron, 4 mg orally three times a 
day as needed, and the selective serotonin reuptake inhibi
-
tor sertraline, 75–100 mg/day orally, may also provide 
some benefit. For refractory pruritus, plasmapheresis or 
extracorporeal albumin dialysis may be needed. Modafinil, 
100–200 mg/day orally, may improve daytime somnolence 
but is poorly tolerated. Deficiencies of vitamins A, D, and 
K may occur if steatorrhea is present and are aggravated 
when cholestyramine is administered.
Ursodeoxycholic acid (13–15 mg/kg/day in one or two 
doses) is the preferred medical treatment for PBC. It has 
been shown to slow the progression of disease (particularly 
in early-stage disease), stabilize histology, improve long-
term survival, reduce the risk of developing esophageal 
varices, and delay (and possibly prevent) the need for liver 
transplantation, even in the absence of liver biochemical 
improvement. Complete normalization of liver biochemi
-
cal tests occurs in 20% of treated patients within 2 years 
and 40% within 5 years, and survival is similar to that of 
healthy controls when the drug is given to patients with 
stage 1 or 2 PBC. Response rates have been reported to be 
lower in men than women (72% vs 80%) and higher in 
women diagnosed after age 70 than before age 30 (90% vs 
50%). Ursodeoxycholic acid has also been reported to 
reduce the risk of recurrent colorectal adenomas in patients 
with PBC. Side effects include weight gain and rarely loose 
stools. The drug can be continued during pregnancy.
Obeticholic acid, a farsenoid-X receptor agonist, was 
approved by the FDA in 2016 for the treatment of PBC in 
patients with an incomplete response or intolerance to 
ursodeoxycholic acid. Obeticholic acid is begun in a dose 
of 5 mg orally daily and increased to 10 mg daily if neces
-
sary, based on the decline in serum alkaline phosphatase 
and bilirubin levels. In patients with Child-Pugh class B or 
C cirrhosis, the initial dose is 5 mg weekly. The principal 
side effect is pruritus. Given the expensesiveness of the 
drug, it may not be cost-effective.
Colchicine (0.6 mg orally twice daily) and methotrexate 
(15 mg/wk orally) have had some reported benefit in 
improving symptoms and serum levels of alkaline phos
-

-
phatase and bilirubin. Methotrexate may also improve liver 
histology in some patients, but overall response rates have 
been disappointing. For patients with advanced disease, 
liver transplantation is the treatment of choice.
 
»
Prognosis
Without liver transplantation, survival averages 7–10 years 
once symptoms develop but has improved for younger 
women since the introduction of ursodeoxycholic acid. 
Progression to liver failure and portal hypertension may be 
accelerated by smoking. Patients with early-stage disease in 
whom the alkaline phosphatase and AST are less than 
1.5 times normal and bilirubin is 1 mg/dL (17.1 mcmol/L) 
or less after 1 year of therapy with ursodeoxycholic acid 
(Paris II criteria) are at low long-term risk for cirrhosis and 
have a life expectancy similar to that of the healthy popula
-
tion. Pregnancy is well tolerated in younger patients. In 
advanced disease, an adverse prognosis is indicated by a 
high Mayo risk score that includes older age, high serum 
bilirubin, edema, low serum albumin, and prolonged pro
-
thrombin time as well as by variceal hemorrhage. Other 
prognostic models include the Globe index, which is based 
on age, serum bilirubin, serum albumin, serum alkaline 
phosphatase, and platelet count and, in treated patients, the 
UK-PBC score, which is based on the baseline serum albu
-
min and platelet count and the serum bilirubin, amino
-
transferases, and alkaline phosphatase after 12 months of 
ursodeoxycholic acid. A prediction tool for varices has 
been proposed based on the serum albumin, serum alka
-
line phosphatase, platelet count, and splenomegaly. Fatigue 
is associated with an increased risk of cardiac mortality and 
may not be reversed by liver transplantation. Among 
asymptomatic patients, at least one-third will become 
symptomatic within 15 years. The risk of hepatocellular 
carcinoma appears to be increased in patients with PBC; 
risk factors include older age, male sex, prior blood trans
-
fusions, advanced histologic stage, signs of cirrhosis or 
portal hypertension, and a biochemical nonresponse to 
ursodeoxycholic acid. Liver transplantation for advanced 
PBC is associated with a 1-year survival rate of 85–90%. 
The disease recurs in the graft in 20% of patients by 3 years, 
but this does not seem to affect survival.
 
»
•	
•	
For liver transplant evaluation.
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•	
•	
•	
•	
•	
European Association for the Study of the Liver. EASL Clinical 
Practice Guidelines: the diagnosis and management of patients 
with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):
 
145–72. [PMID: 28427765]
Levy C (editor). Advances in cholestatic liver diseases. Clin Liver 
Dis. 2016;20(1):1–203. [Full issue]
Nevens F et al; POISE Study Group. A placebo-controlled trial of 
obeticholic acid in primary biliary cholangitis. N Engl J Med. 
2016 Aug 18;375(7):631–43. [PMID: 27532829]
Samur S et al. Long-term clinical impact and cost-effectiveness of 
obeticholic acid for the treatment of primary biliary cholangitis. 
Hepatology. 2017 Mar;65(3):920–8. [PMID: 27906472]
HEMOCHROMATOSIS
 
»
Usually suspected because of a family history or 
an elevated iron saturation or serum ferritin.
 
»
Most patients are asymptomatic; the disease is 
rarely recognized clinically before the fifth decade.
 
»
Hepatic abnormalities and cirrhosis, heart failure, 
hypogonadism, and arthritis.
 
»
HFE
 gene mutation (usually 
C282Y/C282Y
) is found 
in most cases.
 
»
Hemochromatosis is an autosomal recessive disease caused in 
most cases by a mutation in the 
HFE
 gene on chromosome 6. 
The HFE protein is thought to play an important role in the 
process by which duodenal crypt cells sense body iron 
stores, and a mutation of the gene leads to increased iron 
absorption from the duodenum. A decrease in the synthe
-
sis or expression of hepcidin, the principal iron regulatory 
hormone, is thought to be a key pathogenic factor in all 
forms of hemochromatosis. About 85% of persons with 
well-established hemochromatosis are homozygous for the 
C282Y
 mutation (type 1a hemochromatosis). The fre
-
quency of the gene mutation averages 7% in Northern 
European and North American white populations, result
-
ing in a 0.5% frequency of homozygotes (of whom 38–50% 
will develop biochemical evidence of iron overload but 
only 28% of men and 1% of women will develop clinical 
symptoms). Polymorphisms in modifier genes have been 
shown to lead to a high iron phenotype. The 
HFE
 gene 
mutation and hemochromatosis are uncommon in blacks 
and Asian American populations. A second genetic muta
-
tion (
H63D
) may contribute to the development of iron 
overload in a small percentage (1.5%) of persons who are 
compound heterozygotes for 
C282Y
 and 
H63D
 (type 1b); 
iron overload–related disease develops in few patients 
(particularly those who have a comorbidity such as diabe
-
tes mellitus and fatty liver). A juvenile-onset variant that is 
characterized by severe iron overload, cardiac dysfunction, 
hypogonadotropic hypogonadism, and a high mortality 
rate is usually linked to a mutation of a gene on chromosome 
1q designated 
HJV
 that produces a protein called hemojuv
-
elin (type 2a) or, rarely, to a mutation in the 
HAMP
 gene on 
chromosome 19 that encodes hepcidin (type 2b). Rare 
instances of hemochromatosis result from mutations in the 
genes that encode transferrin receptor 2 (
TFR2
) (type 3) and 
ferroportin (
SLC11A3
) (type 4).
Hemochromatosis is characterized by increased accu
-
mulation of iron as hemosiderin in the liver, pancreas, 
heart, adrenals, testes, pituitary, and kidneys. Cirrhosis is 
more likely to develop in affected persons who drink alco
-
hol excessively or have obesity-related hepatic steatosis 
than in those who do not. Eventually, hepatic and pancre
-
atic insufficiency, heart failure, and hypogonadism may 
develop; overall mortality is increased slightly. Heterozy
-
gotes do not develop cirrhosis in the absence of associated 
disorders such as viral hepatitis or NAFLD.
 
»

-
 
»
The onset of clinical disease is usually after age 50 years—
earlier in men than in women; however, because of wide
-
spread liver biochemical testing and iron screening, the 
diagnosis is usually made long before symptoms develop. 
Early symptoms are nonspecific (eg, fatigue, arthralgia). 
Later clinical manifestations include arthropathy (and ulti
-
mately the need for joint replacement surgery in some 
cases), hepatomegaly and evidence of hepatic dysfunction, 
skin pigmentation (combination of slate-gray due to iron 
and brown due to melanin, sometimes resulting in a 
bronze color), cardiac enlargement with or without heart 
failure or conduction defects, diabetes mellitus with its 
complications, and erectile dysfunction in men. Population 
studies have shown an increased prevalence of liver disease 
but not of diabetes mellitus, arthritis, or heart disease in 
C282Y
 homozygotes. In patients in whom cirrhosis 
develops, bleeding from esophageal varices may occur, 
and there is a 15–20% frequency of hepatocellular carcinoma. 
Affected patients are at increased risk of infection with 
Vibrio vulnificus, Listeria monocytogenes, Yersinia entero
-
colitica
, and other siderophilic organisms. The risk of 
porphyria cutanea tarda is increased in persons with the 
C282Y
 or 
H63D
 mutation, and 
C282Y
 homozygotes have 
twice the risk of colorectal and breast cancer than persons 
without the 
C282Y
 variant.
Laboratory findings include mildly abnormal liver tests 
(AST, alkaline phosphatase), an elevated plasma iron with 
greater than 45% transferrin saturation, and an elevated 
serum ferritin (although a normal iron saturation or a nor
-
mal ferritin does not exclude the diagnosis). Affected men 
are more likely than affected women to have an elevated 
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ferritin level. Testing for 
HFE
 mutations is indicated in any 
patient with evidence of iron overload. Interestingly, in 
persons with an elevated serum ferritin, the likelihood of 
detecting 
C282Y
 homozygosity decreases with increasing 
ALT and AST levels, which are likely to reflect hepatic 
inflammation and secondary iron overload.
C. Imaging
MRI and CT may show changes consistent with iron over
-
load of the liver, and MRI can quantitate hepatic iron stores 
and help assess the degree of hepatic fibrosis.
In patients who are homozygous for 
C282Y
, liver biopsy is 
often indicated to determine whether cirrhosis is present. 
Biopsy can be deferred, however, in patients in whom the 
serum ferritin level is less than 1000 mcg/L, serum AST 
level is normal, and hepatomegaly is absent; the likelihood 
of cirrhosis is low in these persons. The combination of a 
serum ferritin level of 1000 mcg/L or more and a serum 
hyaluronic acid level of 46.5 mcg/L or more has been 
reported to identify all patients with cirrhosis, with a high 
specificity. Risk factors for advanced fibrosis include male 
sex, excess alcohol consumption, and diabetes mellitus. 
Liver biopsy is also indicated when iron overload is sus
-
pected even though the patient is neither homozygous for 
C282Y
 nor a 
C282Y/H63D
 compound heterozygote. In 
patients with hemochromatosis, the liver biopsy character
-
istically shows extensive iron deposition in hepatocytes 
and in bile ducts, and the hepatic iron index—hepatic iron 
content per gram of liver converted to micromoles and 
divided by the patient’s age—is generally higher than 1.9. 
Only 5% of patients with hereditary hemochromatosis 
identified by screening in a primary care setting have 
 
»
Screening
Iron studies and 
HFE
 testing are recommended for all first-
degree family members of a proband; children of an 
affected person (
C282Y
 homozygote) need to be screened 
only if the patient’s spouse carries the 
C282Y
 or 
H63D
 
mutation. General population screening for hemochroma
-
tosis is not recommended because the clinical penetrance 
of 
C282Y
 homozygosity and morbidity and mortality from 
hemochromatosis are low. Patients with otherwise unex
-
plained chronic liver disease, chondrocalcinosis, erectile 
dysfunction, and type 1 diabetes mellitus (especially late-
onset) should be screened for iron overload.
 
»
Treatment
Affected patients are advised to avoid foods rich in iron 
(such as red meat), alcohol, vitamin C, raw shellfish, and 
supplemental iron. Weekly phlebotomies of 1 or 2 units 
(250–500 mL) of blood (each containing about 250 mg of 
iron) is indicated in all symptomatic patients, those with a 
serum ferritin level of at least 1000 mcg/L, and those with 
an increased fasting iron saturation and should be contin
-
ued for up to 2–3 years to achieve depletion of iron stores. 
The hematocrit and serum iron values should be monitored. 
When iron store depletion is achieved (iron saturation less 
than 50% and serum ferritin level 50–100 mcg/L), 
phlebotomies (every 2–4 months) to maintain serum fer
-
ritin levels between 50 mcg/L and 100 mcg/L are continued, 
although compliance has been reported to decrease with 
time. Administration of a proton pump inhibitor, which 
reduces intestinal iron absorption, decreases the maintenance 
phlebotomy volume requirement. In 
C282Y
 homozygous 
women, a body mass index greater than 28 is associated with 
a lower phlebotomy requirement, possibly because hepcidin 
levels are increased by overweight. Complications of 
hemochromatosis—arthropathy, diabetes mellitus, heart 
disease, portal hypertension, and hypopituitarism—also 
require treatment.
The chelating agent deferoxamine is indicated for 
patients with hemochromatosis and anemia or in those 
with secondary iron overload due to thalassemia who can
-
not tolerate phlebotomies. The drug is administered intra
-

-
-
venously or subcutaneously in a dose of 20–40 mg/kg/day 
infused over 24 hours and can mobilize 30 mg of iron per 
day; however, treatment is painful and time-consuming. 
Two oral chelators, deferasirox, 20 mg/kg once daily, and 
deferiprone, 25 mg/kg three times daily, have been 
approved for treatment of iron overload due to blood 
transfusions and may be appropriate in persons with 
hemochromatosis who cannot tolerate phlebotomy; how
-
ever, these agents have a number of side effects and drug-
drug interactions.
The course of hemochromatosis is favorably altered by 
phlebotomy therapy. Hepatic fibrosis may regress, and in 
precirrhotic patients, cirrhosis may be prevented. Cardiac 
conduction defects and insulin requirements improve with 
treatment. More severe joint symptoms are associated with 
persistent increases in the transferrin saturation, even if the 
serum ferritin level is maintained below 50 mcg/L. In 
patients with cirrhosis, varices may reverse, and the risk of 
variceal bleeding declines, although the risk of hepatocel
-
lular carcinoma persists. In those with an initial serum 
ferritin level greater than 1000 mcg/L (2247 pmol/L), the 
risk of death is fivefold greater than in those with a serum 
ferritin of 1000 mcg/L (2247 pmol/L) or less. In treated 
patients, only those with a serum ferritin greater than 
2000 mcg/L (4494 pmol/L) have increased mortality, 
mainly related to liver disease. Since 1997, posttransplant 
survival rates have been excellent. Following liver trans
-
plantation, serum iron studies and hepcidin levels are 
normal, and phlebotomy is not required.
 
»
•	
•	
For initiation of therapy.
Bardou-Jacquet E et al. Worse outcomes of patients with HFE 
hemochromatosis with persistent increases in transferrin 
saturation during maintenance therapy. Clin Gastroenterol 
Hepatol. 2017 Oct;15(10):1620–7. [PMID: 28111337]
Powell LW et al. Haemochromatosis. Lancet. 2016 Aug 13;388
 
(10045):706–16. [PMID: 26975792]
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Vanclooster A et al. Proton pump inhibitors decrease phlebotomy 
need in HFE hemochromatosis: double-blind randomized 
placebo-controlled trial. Gastroenterology. 2017 Sep;153(3):
 
678–80. [PMID: 28624580]
WILSON DISEASE
 
»
Rare autosomal recessive disorder that usually 
occurs in persons under age 40.
 
»
Excessive deposition of copper in the liver and 
brain.
 
»
Serum ceruloplasmin, the plasma copper-carrying 
protein, is low.
 
»
Urinary excretion of copper and hepatic copper 
concentration are high.
 
»
Wilson disease (hepatolenticular degeneration) is a rare 
autosomal recessive disorder that usually occurs in persons 
under age 40 (mean age of onset is between 12 and 23 years 
of age). The worldwide prevalence is about 30 per million 
population. The condition is characterized by excessive 
deposition of copper in the liver and brain. The genetic 
defect, localized to chromosome 13 (
ATP7B
), has been 
shown to affect a copper-transporting adenosine triphos
-
phatase in the liver and leads to copper accumulation in 
the liver and oxidative damage of hepatic mitochondria. 
Most patients are compound heterozygotes (ie, carry two 
different mutations). Over 500 mutations in the Wilson 
disease gene have been identified. The 
H1069Q
 mutation 
accounts for 37–63% of disease alleles in populations of 
Northern European descent. The major physiologic aber
-
ration in Wilson disease is excessive absorption of copper 
from the small intestine and decreased excretion of copper 
by the liver, resulting in increased tissue deposition, espe
-
cially in the liver, brain, cornea, and kidney.
 
»
Wilson disease tends to present as liver disease in adoles
-
cents and neuropsychiatric disease in young adults, but 
there is great variability, and onset of symptoms after age 
40 is more common than previously thought. The diagno
-
sis should always be considered in any child or young adult 
with hepatitis, splenomegaly with hypersplenism, Coombs-
negative hemolytic anemia, portal hypertension, and neu
-
rologic or psychiatric abnormalities. Wilson disease should 
also be considered in persons under 40 years of age with 
chronic or fulminant hepatitis.
Hepatic involvement may range from elevated liver 
biochemical tests (although the alkaline phosphatase may 
be low) to cirrhosis and portal hypertension. In patients 
with acute liver failure (seen much more often in females 
than males), the diagnosis of Wilson disease is suggested 
by an alkaline phosphatase (in units/L)-to-total bilirubin 
(in mg/dL) ratio less than 4 and an AST-to-ALT ratio 
greater than 2.2. The neurologic manifestations of Wilson 
disease are related to basal ganglia dysfunction and include 
an akinetic-rigid syndrome similar to parkinsonism, 
pseudosclerosis with tremor, ataxia, and a dystonic 
syndrome. Dysarthria, dysphagia, incoordination, and 
spasticity are common. Migraines, insomnia, and seizures 
have been reported. Psychiatric features include behavioral 
and personality changes and emotional lability and may 
precede characteristic neurologic features. The risk of 
depression is increased. The pathognomonic sign of the 
condition is the brownish or gray-green Kayser-Fleischer 
ring, which represents fine pigmented granular deposits in 
Descemet membrane in the cornea (Figure 16–4). The ring 
is usually most marked at the superior and inferior poles of 
the cornea. It is sometimes seen with the naked eye and is 
readily detected by slit-lamp examination. It may be 
absent in patients with hepatic manifestations only but is 
usually present in those with neuropsychiatric disease. 
Renal calculi, aminoaciduria, renal tubular acidosis, 
hypoparathyroidism, infertility, hemolytic anemia, and 
subcutaneous lipomas may occur.
 
»
Diagnosis
The diagnosis can be challenging, even with the use of

»
Diagnosis
The diagnosis can be challenging, even with the use of 
scoring systems (eg, the Leipzig criteria), and is generally 
based on demonstration of increased urinary copper excre
-
tion (greater than 40 mcg/24 h and usually greater than 
100 mcg/24 h) or low serum ceruloplasmin levels (less 
than 14 mg/dL [140 mg/L]; less than 5 mg/dL [50 mg/L] is 
diagnostic), and elevated hepatic copper concentration 
(greater than 210–250 mcg/g of dry liver) as well as Kay
-
ser-Fleischer rings, neurologic symptoms, and Coombs-
negative hemolytic anemia. However, increased urinary 
copper and a low serum ceruloplasmin level (by a stan
-
dard immunologic assay) are neither completely sensitive 
nor specific for Wilson disease, although an enzymatic 
assay for ceruloplasmin appears to be more accurate. 
 
▲
Figure 16–4.
 
Brownish Kayser-Fleischer ring at the 
rim of the cornea in a patient with Wilson disease. 
 
(Used, with permission, from Marc Solioz, University of 
Berne in Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H, 
 McGraw-Hill, 
2009.)
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The ratio of exchangeable copper to total copper in serum 
has been reported to improve diagnostic accuracy. In 
equivocal cases (when the serum ceruloplasmin level is 
normal), the diagnosis may require demonstration of a 
rise in urinary copper after a penicillamine challenge, 
although the test has been validated only in children and 
is rarely used now. Liver biopsy may show acute or 
chronic hepatitis or cirrhosis. MRI of the brain may show 
evidence of increased basal ganglia, brainstem, and cerebel
-
lar copper even early in the course of the disease. If available, 
molecular analysis of 
ATP7B
 mutations can be diagnostic.
 
»
Treatment
Early treatment to remove excess copper before it can 
produce hepatic or neurologic damage is essential. Early in 
treatment, restriction of dietary copper (shellfish, organ 
foods, nuts, mushrooms, and chocolate) may be of value. 
Oral penicillamine (0.75–2 g/day in divided doses taken 
 
1 h before or 2 h after food) has been the drug of choice 
and enhances urinary excretion of chelated copper. Oral 
pyridoxine, 50 mg per week, is added because penicillamine 
is an antimetabolite of this vitamin. If penicillamine treat
-
ment cannot be tolerated because of gastrointestinal 
intolerance, hypersensitivity, autoimmune reactions, neph
-
rotoxicity, or bone marrow toxicity, consider the use of 
trientine, 250–500 mg three times a day, a chelating agent 
as effective as penicillamine but with a lower rate of 
adverse effects. Trientine is increasingly used as a first-line 
agent, although its cost has become exorbitant. Oral zinc 
acetate or zinc gluconate, 50 mg three times a day, inter
-
feres with intestinal absorption of copper, promotes fecal 
copper excretion, and has been used as first-line therapy in 
presymptomatic or pregnant patients and those with 
neurologic disease and as maintenance therapy after 
decoppering with a chelating agent, but adverse gastroin
-
testinal effects often lead to discontinuation and its 
long-term efficacy and safety (including a risk of hepa
-
totoxicity) have been questioned. Ammonium tetrathio
-
molybdate, which complexes copper in the intestinal 
tract, has shown promise as initial therapy for neuro
-
logic Wilson disease.
Treatment should continue indefinitely. The doses of 
penicillamine and trientine should be reduced during 
pregnancy. Supplemental vitamin E, an antioxidant, has 
been recommended but not rigorously studied. Once the 
serum nonceruloplasmin copper level is within the normal 
range (50–150 mcg/L), the dose of chelating agent can be 
reduced to the minimum necessary for maintaining that 
level. The prognosis is good in patients who are effectively 
treated before liver or brain damage has occurred, but 
long-term survival is reduced in patients with cirrhosis at 
diagnosis (84% after 20 years). Liver transplantation is 
indicated for fulminant hepatitis (often after plasma 
exchange or dialysis with MARS as a stabilizing measure), 
end-stage cirrhosis (with excellent outcomes), and, in 
selected cases, intractable neurologic disease, although 
survival is lower when liver transplantation is undertaken 
for neurologic disease than for liver disease. All first-
degree relatives, especially siblings, require screening with 
serum ceruloplasmin, liver biochemical tests, and slit-lamp 
examination or, if the causative mutation is known, with 
mutation analysis.
 
»
All patients with Wilson disease should be referred for 
 
»
•	
Acute liver failure.
•	
•	
•	
•	
•	
Lv T et al. Recent advance in the molecular genetics of Wilson 
disease and hereditary hemochromatosis. Eur J Med Genet. 
2016 Oct;59(10):532–9. [PMID: 27592149]
Olson KR et al. Case 2-2017. An 18-year-old woman with acute

Olson KR et al. Case 2-2017. An 18-year-old woman with acute 
liver failure. N Engl J Med. 2017 Jan 19;376(3):268–78. 
[PMID: 28099829]
Schilsky ML. Wilson disease: diagnosis, treatment, and follow-
up. Clin Liver Dis. 2017 Nov;21(4):755–67. [PMID: 28987261]
HEPATIC VEIN OBSTRUCTION 
 
(
Budd-Chiari Syndrome
)
 
»
Right upper quadrant pain and tenderness.
 
»
Ascites.
 
»
Imaging studies show occlusion/absence of flow 
in the hepatic vein(s) or inferior vena cava.
 
»
Clinical picture is similar in sinusoidal obstruction 
syndrome but major hepatic veins are patent.
 
»
Factors that predispose patients to hepatic vein obstruction, 
or Budd-Chiari syndrome, including hereditary and 
acquired hypercoagulable states, can be identified in 75% of 
affected patients; multiple disorders are found in up to 45%. 
Up to 50% of cases are associated with polycythemia vera or 
other myeloproliferative neoplasms (which entail a 1% risk 
of Budd-Chiari syndrome). These cases are often associated 
with a specific mutation (V617F) in the gene that codes for 
JAK2 tyrosine kinase and may otherwise be subclinical. 
Other predispositions to thrombosis (eg, activated protein C 
resistance [factor V Leiden mutation] [25% of cases], protein C 
or S or antithrombin deficiency, hyperprothrombinemia 
[factor II G20210A mutation] [rarely], the methylenetetra
-
hydrofolate reductase TT677 mutation, antiphospholipid 
antibodies) may be identified in other cases. Hepatic vein 
obstruction may be associated with caval webs, right-sided 
heart failure or constrictive pericarditis, neoplasms that 
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cause hepatic vein occlusion, paroxysmal nocturnal hemo
-
globinuria, Behçet syndrome, blunt abdominal trauma, use 
of oral contraceptives, and pregnancy. Some cytotoxic agents 
and pyrrolizidine alkaloids (Comfrey or “bush teas”) may 
cause sinusoidal obstruction syndrome (previously known 
as veno-occlusive disease because the terminal venules are 
often occluded), which mimics Budd-Chiari syndrome 
clinically. Sinusoidal obstruction syndrome may occur in 
patients who have undergone hematopoietic stem cell trans
-
plantation, particularly those with pretransplant serum 
aminotransferase elevations or fever during cytoreductive 
therapy with cyclophosphamide, azathioprine, carmustine, 
busulfan, etoposide, or gemtuzumab ozogamicin or those 
receiving high-dose cytoreductive therapy or high-dose total 
body irradiation. In India, China, and South Africa, Budd-
Chiari syndrome is associated with a poor standard of living 
and often the result of occlusion of the hepatic portion of 
the inferior vena cava, presumably due to prior thrombosis. 
The clinical presentation is mild but the course is frequently 
complicated by hepatocellular carcinoma.
 
»
The presentation is most commonly subacute but may be 
fulminant, acute, or chronic. Clinical manifestations gener
-
ally include tender, painful hepatic enlargement, jaundice, 
splenomegaly, and ascites. With chronic disease, bleeding 
varices and hepatic encephalopathy may be evident; 
hepatopulmonary syndrome may occur.
B. Imaging
Hepatic imaging studies may show a prominent caudate lobe, 
since its venous drainage may be occluded. The screening test 
of choice is contrast-enhanced, color, or pulsed-Doppler 
ultrasonography, which has a sensitivity of 85% for detecting 
evidence of hepatic venous or inferior vena caval thrombosis. 
MRI with spin-echo and gradient-echo sequences and intra
-
venous gadolinium injection allows visualization of the 
obstructed veins and collateral vessels. Direct venography 
can delineate caval webs and occluded hepatic veins (“spider-
web” pattern) most precisely.
Percutaneous or transjugular liver biopsy in Budd-Chiari 
syndrome may be considered when the results of noninvasive 
imaging are inconclusive and frequently shows characteristic 
centrilobular congestion and fibrosis and often multiple large 
regenerative nodules. Liver biopsy is often contraindicated in 
sinusoidal obstruction syndrome because of thrombocytope
-
nia, and the diagnosis is based on clinical findings.
 
»
Treatment
Ascites should be treated with salt and fluid restriction and 
diuretics. Treatable causes of Budd-Chiari syndrome 
should be sought. Prompt recognition and treatment of an 
underlying hematologic disorder may avoid the need for 
surgery; however, the optimal anticoagulation regimen is 
uncertain, and anticoagulation is associated with a high 
risk of bleeding, particularly in patients with portal hyper
-
tension and those undergoing invasive procedures. Low-
molecular-weight heparins are preferred over unfractionated 
heparin because of a high rate of heparin-induced throm
-
bocytopenia with the latter. Infusion of a thrombolytic 
agent into recently occluded veins has been attempted with 
success. Defibrotide, an adenosine receptor agonist that 
increases endogenous tissue plasminogen activator levels, 
has been approved by the FDA for the prevention and 
treatment of sinusoidal obstruction syndrome. The drug is 
given as an intravenous infusion every 6 hours for a mini
-
mum of 21 days. Serious adverse effects include hypoten
-
sion and hemorrhage; the drug is expensive and has no 
benefit in severe sinusoidal obstruction syndrome. TIPS 
placement may be attempted in patients with Budd-Chiari 
syndrome and persistent hepatic congestion or failed 
thrombolytic therapy and possibly in those with sinusoidal

thrombolytic therapy and possibly in those with sinusoidal 
obstruction syndrome. Late TIPS dysfunction is less fre
-
quent with the use of polytetrafluoroethylene-covered 
stents than uncovered stents. TIPS is now preferred over 
surgical decompression (side-to-side portacaval, mesoca
-
val, or mesoatrial shunt), which, in contrast to TIPS, has 
generally not been proven to improve long-term survival. 
Older age, a higher serum bilirubin level, and a greater INR 
predict a poor outcome with TIPS. Balloon angioplasty, in 
some cases with placement of an intravascular metallic 
stent, is preferred in patients with an inferior vena caval 
web and is being performed increasingly in patients with a 
short segment of thrombosis in the hepatic vein. Liver 
transplantation can be considered in patients with acute liver 
failure, cirrhosis with hepatocellular dysfunction, and failure 
of a portosystemic shunt, and outcomes have improved with 
the advent of patient selection based on the MELD score. 
Patients with Budd-Chiari syndrome often require lifelong 
anticoagulation and treatment of the underlying myelopro
-
liferative disease; antiplatelet therapy with aspirin and 
hydroxyurea has been suggested as an alternative to warfarin 
in patients with a myeloproliferative disorder. For all patients 
with Budd-Chiari syndrome, a poor outcome has been 
reported to correlate with Child-Pugh class C and a lack of 
response to interventional therapy of any kind.
 
»
Prognosis
The overall 5-year survival rate is 50–90% with treatment 
(but less than 10% without intervention). Adverse prognostic 
factors in patients with Budd-Chiari syndrome are older 
age, high Child-Pugh score, ascites, encephalopathy, elevated 
total bilirubin, prolonged prothrombin time, elevated 
serum creatinine, concomitant portal vein thrombosis, and 
histologic features of acute liver disease superimposed on 
chronic liver injury. The 3-month mortality may be pre
-
dicted by the Rotterdam score, which is based on encepha
-
lopathy, ascites, prothrombin time, and bilirubin. A serum 
ALT level at least fivefold above the upper limit of normal 
on presentation indicates hepatic ischemia and also pre
-
dicts a poor outcome, particularly when the ALT level 
decreases slowly. The risk of hepatocellular carcinoma is 
increased; risk factors include cirrhosis, combined hepatic 
vein and inferior vena cava obstruction, and a long-segment 
inferior vena cava block.
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»
All patients with hepatic vein obstruction should be 
hospitalized.
European Association for the Study of the Liver. EASL clinical 
practice guidelines: vascular diseases of the liver. J Hepatol. 
2016 Jan;64(1):179–202. [PMID: 26516032]
Lin M et al. Liver cirrhosis caused by chronic Budd-Chiari syn
-
drome. Medicine (Baltimore). 2017 Aug;96(34):e7425. 
[PMID: 28834866]
Parekh J et al. Budd-Chiari syndrome causing acute liver failure: a 
multicenter case series. Liver Transpl. 2017 Feb;23(2):135–42. 
[PMID: 27656864]
THE LIVER IN HEART FAILURE
, also called 
ischemic hepatopathy, 
hypoxic hepatitis, shock liver
, or 
acute cardiogenic liver 
injury
 may affect 2.5 of every 100 patients admitted to an 
intensive care unit and results from an acute fall in cardiac 
output due to acute myocardial infarction, arrhythmia, or 
septic or hemorrhagic shock, usually in a patient with pas
-
sive congestion of the liver. Clinical hypotension may be 
absent (or unwitnessed). In some cases, the precipitating 
event is arterial hypoxemia due to respiratory failure, sleep 
apnea, severe anemia, heat stroke, carbon monoxide poi
-
soning, cocaine use, or bacterial endocarditis. More than 
one precipitant is common. Statin therapy prior to admis
-
sion may protect against ischemic hepatitis. 
The hallmark of ischemic hepatitis  is a rapid and strik
-
ing elevation of serum aminotransferase levels (often 
greater than 5000 units/L); an early rapid rise in the serum 
lactate dehydrogenase (LD) level (with an ALT-to-LD ratio 
less than 1.5) is also typical. Elevations of serum alkaline 
phosphatase and bilirubin are usually mild, but jaundice is 
associated with worse outcomes. The prothrombin time may 
be prolonged, and encephalopathy or hepatopulmonary 
syndrome may develop. The mortality rate due to the 
underlying disease is high (particularly in patients 
receiving vasopressor therapy or with septic shock, acute 
kidney disease, or coagulopathy), but in patients who recover, 
the aminotransferase levels return to normal quickly, usually 
within 1 week—in contrast to viral hepatitis.
passive congestion of the liver
 (“nutmeg 
liver”) due to right-sided heart failure, the serum bilirubin 
level may be elevated, occasionally as high as 40 mg/dL 
(684 mcmol/L), due in part to hypoxia of perivenular 
hepatocytes, and its level is a predictor of mortality and 
morbidity. Serum alkaline phosphatase levels are normal or 
slightly elevated, and, in the absence of superimposed isch
-
emia, aminotransferase levels are only mildly elevated. 
Hepatojugular reflux is present, and with tricuspid regurgi
-
tation the liver may be pulsatile. Ascites may be out of pro
-
portion to peripheral edema, with a high serum 
ascites-albumin gradient (greater than or equal to 1.1) and 
an ascitic fluid protein level of more than 2.5 g/dL (25 g/L). 
A markedly elevated serum N-terminal-proBNP or BNP 
level (greater than 364 pg/mL [364 ng/L]) has been reported 
to distinguish ascites due to heart failure from ascites due to 
cirrhosis in the absence of renal insufficiency. In severe 
cases, signs of encephalopathy may develop. Mortality is 
generally attributable to the underlying heart disease but 
has also been reported to correlate with a noninvasive mea
-
sure of liver stiffness.
Hilscher M et al. Congestive hepatopathy. Clin Liver Dis. 
2016;8(3):68–71.
Sato Y et al. Liver stiffness assessed by Fibrosis-4 index pre
-
dicts mortality in patients with heart failure. Open Heart. 
2017 Apr 28;4(1):e000598. [PMID: 28674631]
Wells ML et al. Congestive hepatopathy. Abdom Radiol (NY). 
2017 Nov 17. [Epub ahead of print] [PMID: 29147765]
NONCIRRHOTIC PORTAL HYPERTENSION
 
»
Splenomegaly or upper gastrointestinal bleeding 
from esophageal or gastric varices in patients 
without liver disease.
 
»
Portal vein thrombosis complicating cirrhosis.
 
»

»
 
»
 
»
Causes of noncirrhotic portal hypertension include extra
-
hepatic portal vein obstruction (portal vein thrombosis 
often with cavernous transformation [portal cavernoma]), 
splenic vein obstruction (presenting as gastric varices with
-
out esophageal varices), schistosomiasis, nodular regenera
-
tive hyperplasia, and arterial-portal vein fistula. Idiopathic 
noncirrhotic portal hypertension is common in India and 
has been attributed to chronic infections, exposure to 
medications or toxins, prothrombotic disorders, immuno
-
logic disorders, and genetic disorders that result in oblitera
-
tive vascular lesions in the liver. It is rare in Western 
countries, where increased mortality is attributable to 
associated disorders and older age. Portal vein thrombosis 
may occur in 10–25% of patients with cirrhosis, is associ
-
ated with the severity of the liver disease, and may be asso
-
ciated with hepatocellular carcinoma but not with increased 
mortality. Other risk factors are oral contraceptive use, 
pregnancy, chronic inflammatory diseases (including pan
-
creatitis), injury to the portal venous system (including 
surgery), other malignancies, and treatment of thrombocy
-
topenia with eltrombopag. Portal vein thrombosis may be 
classified as type 1, involving the main portal vein; type 2, 
involving one (2a) or both (2b) branches of the portal vein; 
or type 3, involving the trunk and branches of the portal 
vein. Additional descriptors are occlusive or nonocculsive; 
recent or chronic; extent (eg, into the mesenteric vein); and 
nature of any underlying liver disease. Splenic vein throm
-
bosis may complicate pancreatitis or pancreatic cancer. Pyle
-
phlebitis (septic thrombophlebitis of the portal vein) may 
complicate intra-abdominal inflammatory disorders such 
as appendicitis or diverticulitis, particularly when anaero
-
bic organisms (especially 
 species) are involved. 
Nodular regenerative hyperplasia results from altered 
hepatic perfusion and can be associated with collagen vascu
-
lar diseases; myeloproliferative disorders; and drugs, 
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including azathioprine, 5-fluorouracil, and oxaliplatin. In 
patients infected with HIV , long-term use of didanosine 
and use of a combination of didanosine and stavudine have 
been reported to account for some cases of noncirrhotic por
-
tal hypertension often due to nodular regenerative hyperplasia; 
genetic factors may play a role. The term “obliterative portal 
venopathy” is used to describe primary occlusion of intrahe
-
patic portal veins in the absence of cirrhosis, inflammation, 
or hepatic neoplasia.
 
»
Acute portal vein thrombosis usually causes abdominal 
pain. Aside from splenomegaly, the physical findings are 
not remarkable, although hepatic decompensation can 
follow severe gastrointestinal bleeding or a concurrent 
hepatic disorder, and intestinal infarction may occur when 
portal vein thrombosis is associated with mesenteric 
venous thrombosis. Ascites may occur in 25% of persons 
with noncirrhotic portal hypertension. Covert hepatic 
encephalopathy is reported to be common in patients with 
noncirrhotic portal vein thrombosis.
Liver biochemical test levels are usually normal, but there 
may be findings of hypersplenism. An underlying hyper
-
coagulable state is found in many patients with portal 
vein thrombosis; this includes myeloproliferative neo
-
plasms (often associated with a specific mutation [V617F] 
in the gene coding for JAK2 tyrosine kinase, which is 
found in 24% of cases of portal vein thrombosis), mutation 
G20210A of prothrombin, factor V Leiden mutation, 
protein C and S deficiency, antiphospholipid syndrome, 
mutation TT677 of methylenetetrahydrofolate reductase, 
elevated factor VIII levels, hyperhomocysteinemia, and a 
mutation in the gene that codes for thrombin-activatable 
fibrinolysis inhibitor. It is possible, however, that in many 
cases evidence of hypercoagulability is a secondary phe
-
nomenon due to portosystemic shunting and reduced 
hepatic blood flow.
C. Imaging
Color Doppler ultrasonography and contrast-enhanced CT 
are usually the initial diagnostic tests for portal vein 
thrombosis. Magnetic resonance angiography (MRA) of the 
portal system is generally confirmatory. EUS may be helpful 
in some cases. In patients with jaundice, magnetic resonance 
cholangiography may demonstrate compression of the bile 
duct by a large portal cavernoma (portal biliopathy), a find
-
ing that may be more common in patients with an underlying 
hypercoagulable state than in those without one. In patients 
with pylephlebitis, CT may demonstrate an intra-abdominal 
source of infection, thrombosis or gas in the portal venous 
system, and a hepatic abscess.
D. Other Studies
Endoscopy shows esophageal or gastric varices. Needle biopsy 
of the liver may be indicated to diagnose schistosomiasis, 
nodular regenerative hyperplasia, and noncirrhotic portal 
fibrosis and may demonstrate sinusoidal dilatation.
 
»
Treatment
If splenic vein thrombosis is the cause of variceal bleeding, 
splenectomy is curative. For other causes of noncirrhotic 
portal hypertension, band ligation followed by beta-blockers 
to reduce portal pressure is initiated for variceal bleeding, 
and portosystemic shunting (including TIPS) is reserved 
for failures of endoscopic therapy; rarely, progressive liver 
dysfunction requires liver transplantation. Anticoagulation, 
particularly with low-molecular-weight heparin or throm
-
bolytic therapy, may be indicated for isolated acute portal 
vein thrombosis (and leads to at least partial recanaliza
-
tion in up to 75% of cases when started within 6 months 
of thrombosis) and possibly for acute splenic vein throm
-
bosis; an oral anticoagulant is continued long-term if a 
hypercoagulable disorder is identified or if an acute por
-
tal vein thrombosis extends into the mesenteric veins. 
The use of enoxaparin to prevent portal vein thrombosis

-
The use of enoxaparin to prevent portal vein thrombosis 
and hepatic decompensation in patients with cirrhosis 
has shown promise.
 
»
All patients with noncirrhotic portal hypertension should 
be referred.
Loffredo L et al. Effects of anticoagulants in patients with 
cirrhosis and portal vein thrombosis: a systematic review and 
meta-analysis. Gastroenterology. 2017 Aug;153(2):480–7. 
[PMID: 28479379]
Loudin M et al. Portal vein thrombosis in cirrhosis. J Clin 
Gastroenterol. 2017 Aug;51(7):579–85. [PMID: 28489645]
Sarin SK et al. Toward a comprehensive new classification of portal 
vein thrombosis in patients with cirrhosis. Gastroenterology. 
2016 Oct;151(4):574–7. [PMID: 27575821]
PYOGENIC HEPATIC ABSCESS
 
»
Fever, right upper quadrant pain, jaundice.
 
»
Often in setting of biliary disease, but up to 40% 
are “cryptogenic” in origin.
 
»
Detected by imaging studies.
 
»
The incidence of liver abscess is 3.6 per 100,000 population 
in the United States and has increased since the 1990s. 
The liver can be invaded by bacteria via (1) the bile duct 
(acute “suppurative” [formerly ascending] cholangitis); 
(2) the portal vein (pylephlebitis); (3) the hepatic artery, 
secondary to bacteremia; (4) direct extension from an 
infectious process; and (5) traumatic implantation of bacteria 
through the abdominal wall. Risk factors for liver abscess 
include older age and male sex. Predisposing conditions 
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and factors include presence of malignancy, diabetes mel
-
litus, inflammatory bowel disease, and cirrhosis; necessity 
for liver transplantation; and use of proton pump inhibi
-
tors. Statin use may reduce the risk of pyogenic liver 
abscess. Pyogenic liver abscess has been observed to be 
associated with a subsequent increased risk of gastrointes
-
tinal malignancy and hepatocellular carcinoma.
Acute cholangitis resulting from biliary obstruction due 
to a stone, stricture, or neoplasm is the most common 
identifiable cause of hepatic abscess in the United States. In 
10% of cases, liver abscess is secondary to appendicitis or 
diverticulitis. At least 40% of abscesses have no demon
-
strable cause and are classified as cryptogenic; a dental 
source is identified in some cases. The most frequently 
encountered organisms are 
E coli, Klebsiella pneumoniae, 
Proteus vulgaris, Enterobacter aerogenes
, and multiple 
microaerophilic and anaerobic species (eg, 
Streptococcus 
anginosus
 [also known as 
S milleri
]). Liver abscess caused 
by virulent strains of 
 may be associated 
with thrombophlebitis of the portal or hepatic veins and 
hematogenously spread septic ocular or central nervous 
system complications. 
 is usually the 
causative organism in patients with chronic granulomatous 
disease. Uncommon causative organisms include 
Salmo
-
nella, Haemophilus, Yersinia
, and 
Listeria
. Hepatic candidiasis, 
tuberculosis, and actinomycosis are seen in immunocom
-
promised patients and those with hematologic malignancies. 
Rarely, hepatocellular carcinoma can present as a pyogenic 
abscess because of tumor necrosis, biliary obstruction, and 
superimposed bacterial infection (see Chapter 39). The 
possibility of an amebic liver abscess must always be 
considered (see Chapter 35).
 
»
The presentation is often insidious. Fever is almost always 
present and may antedate other symptoms or signs. Pain 
may be a prominent complaint and is localized to the right 
upper quadrant or epigastric area. Jaundice, tenderness in 
the right upper abdomen, and either steady or spiking fever 
are the chief physical findings. The risk of acute kidney 
injury is increased.
Laboratory examination reveals leukocytosis with a shift to 
the left. Liver biochemical tests are nonspecifically abnormal. 
Blood cultures are positive in 50–100% of cases.
C. Imaging
Chest radiographs usually reveal elevation of the dia
-
phragm if the abscess is in the right lobe of the liver. Ultra
-
sonography, CT, or MRI may reveal the presence of 
intrahepatic lesions. On MRI, characteristic findings 
include high signal intensity on T2-weighted images and 
rim enhancement. The characteristic CT appearance of 
hepatic candidiasis, usually seen in the setting of systemic 
candidiasis, is that of multiple “bull’s-eyes, ” but imaging 
studies may be negative in neutropenic patients.
 
»
Treatment
Treatment should consist of antimicrobial agents (generally 
a third-generation cephalosporin such as cefoperazone 
 
1–2 g intravenously every 12 hours and metronidazole 
 
500 mg intravenously every 6 hours) that are effective 
against coliform organisms and anaerobes. Antibiotics are 
administered for 2–3 weeks, and sometimes up to 6 weeks. 
If the abscess is at least 5 cm in diameter or the response to 
antibiotic therapy is not rapid, intermittent needle aspira
-
tion, percutaneous or EUS-guided catheter drainage or 
stent placement or, if necessary, surgical (eg, laparoscopic) 
drainage should be done. Other suggested indications for 
abscess drainage are patient age of at least 55 years, symp
-
tom duration of at least 7 days, and involvement of two 
lobes of the liver. The underlying source (eg, biliary disease, 
dental infection) should be identified and treated. The 
mortality rate is still substantial (at least 5% in most studies)

mortality rate is still substantial (at least 5% in most studies) 
and is highest in patients with underlying biliary malig
-
nancy or severe multiorgan dysfunction. Other risk factors 
for mortality include older age, cirrhosis, chronic kidney 
disease, and other cancers. Hepatic candidiasis often 
responds to intravenous amphotericin B (total dose of 
2–9 g). Fungal abscesses are associated with mortality rates 
of up to 50% and are treated with intravenous amphotericin 
B and drainage.
 
»
Nearly all patients with pyogenic hepatic abscess should be 
Haider SJ et al. Liver abscesses: factors that influence outcome of 
percutaneous drainage. AJR Am J Roentgenol. 2017 Jul;
 
209(1):205–13. [PMID: 28504550]
Liao KF et al. Statin use correlates with reduced risk of pyogenic 
liver abscess: a population-based case-control study. Basic 
Clin Pharmacol Toxicol. 2017 Aug;121(2):144–49. [PMID: 
28273396]
Rismiller K et al. Pyogenic liver abscesses: a contemporary 
analysis of management strategies at a tertiary institution. 
HPB (Oxford). 2017 Oct;19(10):889–93. [PMID: 28693978]
BENIGN LIVER NEOPLASMS
Benign neoplasms of the liver must be distinguished from 
hepatocellular carcinoma, intrahepatic cholangiocarcinoma, 
and metastases (see Chapter 39). The most common benign 
neoplasm of the liver is the 
cavernous hemangioma,
 often 
an incidental finding on ultrasonography or CT. This lesion 
may enlarge in women who take hormonal therapy and 
must be differentiated from other space-occupying intrahe
-
patic lesions, usually by contrast-enhanced MRI, CT, or 
ultrasonography. Rarely, fine-needle biopsy is necessary to 
differentiate these lesions and does not appear to carry an 
increased risk of bleeding. Surgical resection of cavernous 
hemangiomas is infrequently necessary but may be required 
for abdominal pain or rapid enlargement, to exclude malig
-
nancy, or to treat Kasabach-Merritt syndrome (consumptive 
coagulopathy complicating a hemangioma).
In addition to rare instances of sinusoidal dilatation and 
peliosis hepatis, two distinct benign lesions with characteristic 
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clinical, radiologic, and histopathologic features have been 
described in women taking oral contraceptives—focal nodular 
hyperplasia and hepatocellular adenoma. 
Focal nodular 
hyperplasia
 occurs at all ages and in both sexes and is prob
-
ably not caused by the oral contraceptives. It is often asymp
-
tomatic and appears as a hypervascular mass, often with a 
central hypodense “stellate” scar on contrast-enhanced ultra
-
sonography, CT, or MRI. Microscopically, focal nodular 
hyperplasia consists of hyperplastic units of hepatocytes that 
stain positively for glutamine synthetase with a central stellate 
scar containing proliferating bile ducts. It is not a true neo
-
plasm but a proliferation of hepatocytes in response to altered 
blood flow. Focal nodular hyperplasia may also occur in 
patients with cirrhosis, with exposure to certain drugs such as 
azathioprine, and in antiphospholipid syndrome. The preva
-
lence of hepatic hemangiomas is increased in patients with 
focal nodular hyperplasia.
Hepatocellular adenoma
 occurs most commonly in 
women in the third and fourth decades of life and is usually 
caused by oral contraceptives; acute abdominal pain may 
occur if the tumor undergoes necrosis or hemorrhage. The 
tumor may be associated with mutations in (1) the gene cod
-
ing for hepatocyte nuclear factor 1 alpha (
HNF1alpha
) in 
40–50% of cases (characterized by steatosis and a low risk of 
malignant transformation, although in men concomitant 
metabolic syndrome appears to increase the risk of malignant 
transformation); (2) the gene coding for beta-catenin (charac
-
terized by a high rate of malignant transformation) in 15–25% 
of cases; or (3) genes resulting in activation of the IL6/JAK/STAT 
pathway, with the designation of inflammatory adenoma 
(previously termed “telangiectatic focal nodular hyperplasia”), 
which is associated with a high body mass index and serum 
biomarkers of inflammation (such as C-reactive protein and 
serum amyloid A) in 35–45% of cases. Unclassified adenomas 
account for less than 7% of tumors. Rare instances of multiple 
hepatocellular adenomas in association with maturity-onset 
diabetes of the young occur in families with a germline muta
-
tion in 
HNF1alpha.
 Hepatocellular adenomas (inflammatory 
or unclassified adenomas) also occur in patients with 
glycogen storage disease and familial adenomatous polyposis. 
The tumor is hypovascular. Grossly, the cut surface appears 
structureless. As seen microscopically, the hepatocellular 
adenoma consists of sheets of hepatocytes without portal 
tracts or central veins.
Cystic neoplasms of the liver, such as cystadenoma 
and cystadenocarcinoma, must be distinguished from 
simple and echinococcal cysts, von Meyenburg complexes 
(hamartomas), and polycystic liver disease.
 
»
The only physical finding in focal nodular hyperplasia or 
hepatocellular adenoma is a palpable abdominal mass in a 
minority of cases. Liver function is usually normal. Contrast-
enhanced ultrasonography, arterial phase helical CT, and 
especially multiphase dynamic MRI with contrast can distin
-
guish an adenoma from focal nodular hyperplasia in 80–90% 
of cases and may suggest a specific subtype of adenoma (eg, 
homogeneous fat pattern in 
HNF1alpha
-mutated adenomas 
and marked and persistent arterial enhancement in inflam
-
matory adenomas).
 
»
Treatment
While oral contraceptives should not necessarily be discon
-
tinued in women who have focal nodular hyperplasia, 
affected women who continue taking oral contraceptives 
should undergo annual ultrasonography for 2–3 years to 
ensure that the lesion is not enlarging. The prognosis is 
excellent. Hepatocellular adenoma may undergo bleeding, 
necrosis, and rupture, often after hormone therapy, in the 
third trimester of pregnancy, or in men in whom the rate of 
malignant transformation is high. Resection is advised in all

malignant transformation is high. Resection is advised in all 
affected men and in women in whom the tumor causes 
symptoms or is 5 cm or greater in diameter, even in the 
absence of symptoms. If an adenoma is less than 5 cm in size, 
resection is also recommended if a beta-catenin gene muta
-
tion is present in a biopsy sample. In selected cases, laparo
-
scopic resection or percutaneous radiofrequency ablation 
may be feasible. Rarely, liver transplantation is required. 
Regression of benign hepatic tumors may follow cessation of 
oral contraceptives. Transarterial embolization is the initial 
treatment for adenomas complicated by hemorrhage.
 
»
•	
Diagnostic uncertainty.
•	
For surgery.
 
»
•	
Severe pain.
•	
Rupture.
European Association for the Study of the Liver (EASL). EASL 
clinical practice guidelines on the management of benign 
liver tumours. J Hepatol. 2016 Aug;65(2):386–98. [PMID: 
27085809]
Nault JC et al. Molecular classification of hepatocellular ade
-
noma in clinical practice. J Hepatol. 2017 Nov;67(5):1074–83. 
[PMID: 28733222]
Sinclair M et al. Regression of hepatocellular adenomas and systemic 
inflammatory syndrome after cessation of estrogen therapy. 
Hepatology. 2017 Sep;66(3):989–91. [PMID: 28295483]
van Rosmalen BV et al. Systematic review of transarterial embo
-
lization for hepatocellular adenomas. Br J Surg. 2017 Jun;
 
104(7):823–35. [PMID: 28518415]
 
º
DIS
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See Chapter 39 for Carcinoma of the Biliary Tract.
CHOLELITHIASIS (
Gallstones
)
 
»
 
»
Classic biliary pain (“episodic gallbladder pain”) 
characterized by infrequent episodes of steady 
severe pain in epigastrium or right upper quadrant 
with radiation to right scapula.
 
»
Detected on ultrasonography.
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»
Gallstones are more common in women than in men and 
increase in incidence in both sexes and all races with age. 
In the United States, the prevalence of gallstones is 8.6% in 
women and 5.5% in men. The highest rates are, in persons 
over age 60 and rates are higher in Mexican Americans 
than in non-Hispanic whites and African Americans. 
Gallstone disease is associated with increased overall mor
-
tality, cardiovascular mortality, and cancer mortality. 
Although cholesterol gallstones are less common in black 
people, cholelithiasis attributable to hemolysis occurs in 
over a third of individuals with sickle cell disease. Native 
Americans of both the Northern and Southern Hemi
-
spheres have a high rate of cholesterol cholelithiasis, prob
-
ably because of a predisposition resulting from “thrifty” 
(
LITH
) genes that promote efficient calorie utilization and 
fat storage. As many as 75% of Pima and other American 
Indian women over 25 years of age have cholelithiasis. 
Other genetic mutations that predispose persons to gall
-
stones have been identified. Obesity is a risk factor for 
gallstones, especially in women. Rapid weight loss, as 
occurs after bariatric surgery, also increases the risk of 
symptomatic gallstone formation. Diabetes mellitus, glu
-
cose intolerance, and insulin resistance are risk factors for 
gallstones, and a high intake of carbohydrate and high 
dietary glycemic load increase the risk of cholecystectomy in 
women. Hypertriglyceridemia may promote gallstone for
-
mation by impairing gallbladder motility. The prevalence 
of gallbladder disease is increased in men (but not women) 
with cirrhosis and hepatitis C virus infection. Moreover, 
cholecystectomy has been reported to be associated with 
an increased risk of NAFLD and cirrhosis, possibly because 
gallstones and liver disease share risk factors. 
The incidence of gallstones is high in individuals with 
Crohn disease; approximately one-third of those with 
inflammatory involvement of the terminal ileum have gall
-
stones due to disruption of bile salt resorption that results 
in decreased solubility of the bile. Drugs such as clofibrate, 
octreotide, and ceftriaxone can cause gallstones. Prolonged 
fasting (over 5–10 days) can lead to formation of biliary 
“sludge” (microlithiasis), which usually resolves with 
refeeding but can lead to gallstones or biliary symptoms. 
Pregnancy, particularly in obese women and those with 
insulin resistance, is associated with an increased risk of 
gallstones and of symptomatic gallbladder disease. Hor
-
mone replacement therapy appears to increase the risk of 
gallbladder disease and need for cholecystectomy; the risk 
is lower with transdermal than oral therapy. Gallstones 
detected by population screening have been reported to be 
associated with an increased risk of right-sided colon 
cancers. 
A low-carbohydrate diet and a Mediterranean 
diet as well as physical activity and cardiorespiratory fit
-
ness may help prevent gallstones. Consumption of caffein
-
ated coffee appears to protect against gallstones in women, 
and a high intake of magnesium and of polyunsaturated 
and monounsaturated fats reduces the risk of gallstones in 
men. A diet high in fiber and rich in fruits and vegetables, 
and statin use reduce the risk of cholecystectomy, par
-
ticularly in women. Aspirin and other nonsteroidal anti-
inflammatory drugs may protect against gallstones.
Gallstones are classified according to their predomi
-
nant chemical composition as cholesterol or calcium 
bilirubinate stones. The latter comprise less than 20% of 
the gallstones found in patients in the United States or 
Europe but 30–40% of gallstones found in patients in 
Japan.
 
»
Table 16–8 lists the clinical and laboratory features of sev
-
eral diseases of the biliary tract as well as their treatment. 
Cholelithiasis is frequently asymptomatic and is discovered

-
Cholelithiasis is frequently asymptomatic and is discovered 
in the course of a routine radiographic study, surgery, or 
autopsy. Symptoms (biliary [or “episodic gallbladder”] 
pain) develop in 10–25% of patients (1–4% annually), and 
acute cholecystitis develops in 20% of these symptomatic 
persons over time. Risk factors for the development of 
symptoms or complications include female sex; young age; 
awareness of having gallstones; and large, multiple, and 
older stones. Occasionally, small intestinal obstruction due 
to “gallstone ileus” (or Bouveret syndrome when the 
obstructing stone is in the pylorus or duodenum) presents 
as the initial manifestation of cholelithiasis.
 
»
Treatment
Nonsteroidal anti-inflammatory drugs (eg, diclofenac 
50–75 mg intramuscularly) can be used to relieve biliary 
pain. Laparoscopic cholecystectomy is the treatment of 
choice for symptomatic gallbladder disease. Pain relief after 
cholecystectomy is most likely in patients with episodic 
pain (generally once a month or less), pain lasting 30 minutes 
to 24 hours, pain in the evening or at night, and the onset 
of symptoms 1 year or less before presentation. Patients 
may go home within 1 day of the procedure and return to 
work within days (instead of weeks for those undergoing 
open cholecystectomy). The procedure is often performed 
on an outpatient basis and is suitable for most patients, 
including those with acute cholecystitis. Conversion to a 
conventional open cholecystectomy may be necessary in 
2–8% of cases (higher for acute cholecystitis than for 
uncomplicated cholelithiasis). Bile duct injuries occur in 
0.1% of cases done by experienced surgeons, and the over
-
all complication rate is 11% and correlates with the 
patient’s comorbidities, duration of surgery, and emer
-
gency admissions for gallbladder disease prior to cholecys
-
tectomy. There is generally no need for prophylactic 
cholecystectomy in an asymptomatic person unless the 
gallbladder is calcified, gallstones are 3 cm or greater in 
diameter, or the patient is a Native American or a candidate 
for bariatric surgery or cardiac transplantation. Cholecys
-
tectomy may increase the risk of esophageal, proximal 
small intestinal, and colonic adenocarcinomas because of 
increased duodenogastric reflux and changes in intestinal 
exposure to bile. In pregnant patients, a conservative 
approach to biliary pain is advised, but for patients with 
repeated attacks of biliary pain or acute cholecystitis, 
cholecystectomy can be performed—even by the laparoscopic 
route—preferably in the second trimester. Enterolithotomy 
alone is considered adequate treatment in most patients 
with gallstone ileus. Cholecystectomy via natural orifice 
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Table 16–8.
 
Diseases of the biliary tract.
Clinical Features
Laboratory Features
Diagnosis
Treatment
Asymptomatic 
gallstones
Normal
None
Symptomatic 
Biliary pain
Normal
Laparoscopic 
cholecystectomy
Cholesterolosis of 
gallbladder
Usually asymptomatic
Normal
Oral cholecystography
None
Adenomyomatosis
May cause biliary pain
Normal
Laparoscopic cholecystec
-
tomy if symptomatic
Porcelain gallbladder
Usually asymptomatic, high risk 
of gallbladder cancer
Normal
Radiograph or CT
Acute cholecystitis
Epigastric or right upper 
 
quadrant pain, nausea, 
 
vomiting, fever, Murphy sign
Leukocytosis
Ultrasonography, HIDA 
scan
Antibiotics, laparoscopic 
Chronic cholecystitis
Biliary pain, constant epigastric 
or right upper quadrant pain, 
nausea
Normal
Ultrasonography (stones), 
oral cholecystography 
(nonfunctioning 
gallbladder)
Choledocholithiasis
Asymptomatic or biliary pain, 
jaundice, fever; gallstone 
pancreatitis
Cholestatic liver 
 
biochemical tests; 
 
leukocytosis and 
positive blood cul
-
tures in cholangitis; 
elevated amylase 
and lipase in 
Ultrasonography (dilated 
ducts), EUS, MRCP , 
ERCP
Endoscopic sphincterot
-
omy and stone 
 
extraction; antibiotics 
for cholangitis
ERCP , endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; HIDA, hepatic iminodiacetic acid; MRCP , 
magnetic resonance cholangiopancreatography.
translumenal endoscopic surgery (NOTES) has been per
-
formed on a limited basis.
Ursodeoxycholic acid is a bile salt that when given 
orally for up to 2 years dissolves some cholesterol stones 
and may be considered in occasional, selected patients 
who refuse cholecystectomy. The dose is 8–13 mg/kg in 
divided doses daily. It is most effective in patients with a 
functioning gallbladder, as determined by gallbladder 
visualization on oral cholecystography, and multiple 
small “floating” gallstones (representing not more than 
15% of patients with gallstones). In half of patients, gall
-
stones recur within 5 years after treatment is stopped. 
Ursodeoxycholic acid, 500–600 mg daily, and diets higher 
in fat reduce the risk of gallstone formation with rapid 
weight loss. Lithotripsy in combination with bile salt 
therapy for single radiolucent stones smaller than 20 mm 
in diameter was an option in the past but is no longer 
generally used in the United States.
 
»
Patients should be referred when they require surgery.
Barré A et al. Diet and risk of cholecystectomy: a prospective 
study based on the French E3N cohort. Am J Gastroenterol. 
2017 Sep;112(9):1448–56. [PMID: 28741614]
clinical practice guidelines on the prevention, diagnosis and 
treatment of gallstones. J Hepatol. 2016 Jul;65(1):146–81. 
[PMID: 27085810]
Shabanzadeh DM et al. Association between screen-detected gall
-
stone disease and cancer in a cohort study. Gastroenterology. 
2017 Jun;152(8):1965–74. [PMID: 28238770]
ACUTE CHOLECYSTITIS
 
»
Steady, severe pain and tenderness in the right 
hypochondrium or epigastrium.
 
»
Nausea and vomiting.
 
»
Fever and leukocytosis.
 
»
Cholecystitis is associated with gallstones in over 90% of 
cases. It occurs when a stone becomes impacted in the cystic 
duct and inflammation develops behind the obstruction. 
Acalculous cholecystitis should be considered when unex
-
plained fever or right upper quadrant pain occurs within 
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2–4 weeks of major surgery or in a critically ill patient who 
has had no oral intake for a prolonged period; multiorgan 
failure is often present. Acute cholecystitis may be caused by 
infectious agents (eg, cytomegalovirus, cryptosporidiosis, 
microsporidiosis) in patients with AIDS or by vasculitis 
(eg, polyarteritis nodosa, Henoch-Schönlein purpura).
 
»
The acute attack is often precipitated by a large or fatty 
meal and is characterized by the sudden appearance of 
steady pain localized to the epigastrium or right hypochon
-
drium, which may gradually subside over a period of 
12–18 hours. Vomiting occurs in about 75% of patients and 
in half of instances affords variable relief. Fever is typical. 
Right upper quadrant abdominal tenderness (often with a 
Murphy sign, or inhibition of inspiration by pain on palpation 
of the right upper quadrant) is almost always present and is 
usually associated with muscle guarding and rebound 
tenderness (Table 16–8). A palpable gallbladder is present 
in about 15% of cases. Jaundice is present in about 25% of 
cases and, when persistent or severe, suggests the possibility 
of choledocholithiasis.
The white blood cell count is usually high (12,000–15,000/mcL 
[12–15 ×10
9
/L]). Total serum bilirubin values of 1–4 mg/dL 
(17.1–68.4 mcmol/L) may be seen even in the absence of bile 
duct obstruction. Serum aminotransferase and alkaline 
phosphatase levels are often elevated—the former as high 
as 300 units/mL, and even higher when associated with 
acute cholangitis. Serum amylase may also be moderately 
elevated.
C. Imaging
Plain films of the abdomen may show radiopaque gallstones 
in 15% of cases. 
99m
Tc hepatobiliary imaging (using imino
-
diacetic acid compounds), also known as the hepatic 
iminodiacetic acid (HIDA) scan, is useful in demonstrating 
an obstructed cystic duct, which is the cause of acute 
cholecystitis in most patients. This test is reliable if the 
bilirubin is under 5 mg/dL (85.5 mcmol/L) (98% sensitivity 
and 81% specificity for acute cholecystitis). False-positive 
results can occur with prolonged fasting, liver disease, and 
chronic cholecystitis, and the specificity can be improved 
by intravenous administration of morphine, which induces 
spasm of the sphincter of Oddi. Right upper quadrant 
abdominal ultrasonography, which is often performed 
first, may show gallstones but is not as sensitive for acute 
cholecystitis (67% sensitivity, 82% specificity); findings 
suggestive of acute cholecystitis are gallbladder wall thick
-
ening, pericholecystic fluid, and a sonographic Murphy 
sign. CT may show complications of acute cholecystitis, 
such as perforation or gangrene.
 
»
The disorders most likely to be confused with acute 
cholecystitis are perforated peptic ulcer, acute pancreatitis, 
appendicitis in a high-lying appendix, perforated colonic 
carcinoma or diverticulum of the hepatic flexure, liver 
abscess, hepatitis, pneumonia with pleurisy on the right 
side, and myocardial ischemia. Definite localization of pain 
and tenderness in the right upper quadrant, with radiation 
around to the infrascapular area, strongly favors the diag
-
nosis of acute cholecystitis. True cholecystitis without 
stones suggests acalculous cholecystitis.
 
»
A. Gangrene of the Gallbladder
Continuation or progression of right upper quadrant 
abdominal pain, tenderness, muscle guarding, fever, and 
leukocytosis after 24–48 hours suggests severe inflammation 
and possible gangrene of the gallbladder, resulting from 
ischemia due to splanchnic vasoconstriction and intravascu
-
lar coagulation. Necrosis may occasionally develop without 
specific signs in the obese, diabetic, elderly, or immunosup
-
pressed patient. Gangrene may lead to gallbladder perfora
-
tion, usually with formation of a pericholecystic abscess, and

-
-
tion, usually with formation of a pericholecystic abscess, and 
rarely to generalized peritonitis. Other serious acute compli
-
cations include emphysematous cholecystitis (secondary 
infection with a gas-forming organism) and empyema.
B. Chronic Cholecystitis and Other Complications
Chronic cholecystitis results from repeated episodes of 
acute cholecystitis or chronic irritation of the gallbladder 
wall by stones and is characterized pathologically by vary
-
ing degrees of chronic inflammation of the gallbladder. 
Calculi are usually present. In about 4–5% of cases, the villi 
of the gallbladder undergo polypoid enlargement due to 
deposition of cholesterol that may be visible to the naked 
eye (“strawberry gallbladder, ” cholesterolosis). In other 
instances, hyperplasia of all or part of the gallbladder wall 
may be so marked as to give the appearance of a myoma 
(adenomyomatosis). Hydrops of the gallbladder results 
when acute cholecystitis subsides but cystic duct obstruc
-
tion persists, producing distention of the gallbladder with a 
clear mucoid fluid. Occasionally, a stone in the neck of the 
gallbladder may compress the common hepatic duct and 
cause jaundice (Mirizzi syndrome). Xanthogranulomatous 
cholecystitis is a rare, aggressive variant of chronic 
cholecystitis characterized by grayish-yellow nodules or 
streaks, representing lipid-laden macrophages, in the wall 
of the gallbladder and often presents with acute jaundice.
Cholelithiasis with chronic cholecystitis may be associ
-
ated with acute exacerbations of gallbladder inflammation, 
bile duct stone, fistulization to the bowel, pancreatitis and, 
rarely, carcinoma of the gallbladder. Calcified (porcelain) 
gallbladder is associated with gallbladder carcinoma and is 
generally an indication for cholecystectomy; the risk of 
gallbladder cancer may be higher when calcification is 
mucosal rather than intramural.
 
»
Treatment
Acute cholecystitis usually subsides on a conservative 
regimen, including withholding oral feedings, intrave
-
nous alimentation, analgesics, and intravenous antibiotics 
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(generally a second- or third-generation cephalosporin 
such as ceftriaxone 1 g intravenously every 24 hours, with 
the addition of metronidazole, 500 mg intravenously 
every 6 hours), although the need for antibiotics has been 
questioned in patients undergoing immediate cholecystectomy. 
In severe cases, a fluoroquinolone such as ciprofloxacin, 
250 mg intravenously every 12 hours, plus metronidazole 
may be given. Morphine or meperidine may be adminis
-
tered for pain. Because of the high risk of recurrent 
attacks (up to 10% by 1 month and over 20% by 1 year), 
cholecystectomy—generally laparoscopically—should be 
performed within 24 hours of admission to the hospital 
for acute cholecystitis. Compared with delayed surgery, 
surgery within 24 hours is associated with a shorter 
length of stay, lower costs, and greater patient satisfaction. 
If nonsurgical treatment has been elected, the patient 
(especially if diabetic or elderly) should be watched care
-
fully for recurrent symptoms, evidence of gangrene of the 
gallbladder, or cholangitis. In high-risk patients, ultra
-
sound-guided aspiration of the gallbladder, if feasible, 
percutaneous or EUS-guided cholecystostomy, or endo
-
scopic insertion of a stent or nasobiliary drain into the 
gallbladder may postpone or even avoid the need for 
surgery. Immediate cholecystectomy is mandatory when 
there is evidence of gangrene or perforation.
Surgical treatment of chronic cholecystitis is the same 
as for acute cholecystitis. If indicated, cholangiography can 
be performed during laparoscopic cholecystectomy. 
Choledocholithiasis can also be excluded by either 
preoperative or postoperative MRCP or ERCP .
 
»
Prognosis
The overall mortality rate of cholecystectomy is less than 
0.2%, but hepatobiliary tract surgery is a more formida
-
ble procedure in older patients, in whom mortality rates 
are higher; mortality rates are also higher in persons 
with diabetes mellitus and cirrhosis. A technically suc
-
cessful surgical procedure in an appropriately selected 
patient is generally followed by complete resolution of 
symptoms.
 
»
All patients with acute cholecystitis should be hospitalized.
Dollhopf M et al. EUS-guided gallbladder drainage in patients 
with acute cholecystitis and high surgical risk using an 
electrocautery-enhanced lumen-apposing metal stent 
device. Gastrointest Endosc. 2017 Oct;86(4):636–43. 
[PMID: 28259594]
Drachman DE et al. Case 27-2017. A 32-year-old man with acute 
chest pain. N Engl J Med. 2017 Aug 31;377(9):874–82. 
[PMID: 28854089]
Irani S et al. Similar efficacies of endoscopic ultrasound gallblad
-
der drainage with a lumen-apposing metal stent versus 
 
percutaneous transhepatic gallbladder drainage for acute 
 
cholecystitis. Clin Gastroenterol Hepatol. 2017 May;15(5): 
738–45. [PMID: 28043931]
Khan MA et al. Efficacy and safety of endoscopic gallbladder 
drainage in acute cholecystitis: is it better than percutaneous 
gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):
 
76–87. [PMID: 27343412]
PRE- & POSTCHOLECYSTECTOMY 
SYNDROMES
1. Precholecystectomy
In a small group of patients (mostly women) with bili
-
ary pain, conventional radiographic studies of the 
upper gastrointestinal tract and gallbladder—including 
cholangiography—are unremarkable. Emptying of the 
gallbladder may be markedly reduced on gallbladder 
scintigraphy following injection of cholecystokinin; 
cholecystectomy may be curative in such cases. Histologic 
examination of the resected gallbladder may show chronic 
cholecystitis or microlithiasis. An additional diagnostic 
consideration is sphincter of Oddi dysfunction.
2. Postcholecystectomy
Following cholecystectomy, some patients complain of 
continuing symptoms, ie, right upper quadrant pain, 
flatulence, and fatty food intolerance. The persistence of 
symptoms in this group of patients suggests the possibil
-

-
ity of an incorrect diagnosis prior to cholecystectomy, 
eg, esophagitis, pancreatitis, radiculopathy, or functional 
bowel disease. Choledocholithiasis or bile duct stricture 
should be ruled out. Pain may also be associated with 
dilatation of the cystic duct remnant, neuroma formation 
in the ductal wall, foreign body granuloma, anterior cuta
-
neous nerve entrapment syndrome, or traction on the bile 
duct by a long cystic duct.
The clinical presentation of right upper quadrant pain, 
chills, fever, or jaundice suggests biliary tract disease. EUS 
is recommended to demonstrate or exclude a stone or 
stricture. Biliary pain associated with elevated liver bio
-
chemical tests or a dilated bile duct in the absence of an 
obstructing lesion suggests sphincter of Oddi dysfunction. 
Biliary manometry may be useful for documenting ele
-
vated baseline sphincter of Oddi pressures typical of 
sphincter dysfunction when biliary pain is associated with 
elevated liver biochemical tests (twofold) or a dilated bile 
duct (greater than 10 mm) (“sphincter disorder, ” formerly 
type II sphincter of Oddi dysfunction), but is not necessary 
when both are present (“sphincter stenosis, ” formerly type I 
sphincter of Oddi dysfunction) and is associated with a 
high risk of pancreatitis. In the absence of either elevated 
liver biochemical tests or a dilated bile duct (“functional 
pain, ” formerly type III sphincter of Oddi dysfunction), a 
nonbiliary source of symptoms should be suspected, and 
biliary sphincterotomy does not benefit this group. 
(Analogous criteria have been developed for pancreatic 
sphincter dysfunction.) Biliary scintigraphy after intrave
-
nous administration of morphine and MRCP following 
intravenous administration of secretin have been studied 
as screening tests for sphincter dysfunction. Endoscopic 
sphincterotomy is most likely to relieve symptoms in 
patients with a sphincter disorder or stenosis, although 
many patients continue to have some pain. In some cases, 
treatment with a calcium channel blocker, long-acting 
nitrate, phosphodiesterase inhibitor (eg, vardenafil), 
duloxetine, or tricyclic antidepressants or possibly injec
-
tion of the sphincter with botulinum toxin may be 
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beneficial. The rate of psychosocial comorbidity with 
sphincter of Oddi dysfunction does not appear to differ 
from that of the general population. In refractory cases, 
surgical sphincteroplasty or removal of the cystic duct 
remnant may be considered.
 
»
Patients with sphincter of Oddi dysfunction should be 
referred for diagnostic procedures.
Cotton PB et al. The EPISOD study: long-term outcomes. 
 
Gastrointest Endosc. 2018 Jan;87(1):205–10. [PMID: 28455162]
Y ang D et al. Cost effective therapy for sphincter of Oddi dysfunction. 
Clin Gastroenterol Hepatol. 2018 Mar;16(3):328–30. [PMID: 
28711688]
CHOLEDOCHOLITHIASIS & CHOLANGITIS
 
»
Often a history of biliary pain, which may be 
accompanied by jaundice.
 
»
Occasional patients present with painless jaundice.
 
»
 
»
Cholangitis should be suspected with fever followed 
by hypothermia and gram-negative shock, jaundice, 
and leukocytosis.
 
»
Stones in bile duct most reliably detected by ERCP 
or EUS.
 
»
About 15% of patients with gallstones have choledocho
-
lithiasis (bile duct stones). The percentage rises with 
age, and the frequency in elderly people with gallstones 
may be as high as 50%. Bile duct stones usually originate 
in the gallbladder but may also form spontaneously in 
the bile duct after cholecystectomy. The risk is increased 
twofold in persons with a juxtapapillary duodenal 
diverticulum. Symptoms and possible cholangitis result 
if there is obstruction.
 
»
A history of biliary pain or jaundice may be obtained. Biliary 
pain results from rapid increases in bile duct pressure due 
to obstructed bile flow. The features that suggest the pres
-
ence of a bile duct stone are (1) frequently recurring attacks 
of right upper abdominal pain that is severe and persists 
for hours, (2) chills and fever associated with severe pain, 
and (3) a history of jaundice associated with episodes of 
abdominal pain (Table 16–8). The combination of pain, 
fever (and chills), and jaundice represents 
Charcot triad
 
and denotes the classic picture of acute cholangitis. The 
addition of altered mental status and hypotension 
(
Reynolds pentad
) signifies acute suppurative cholangitis 
and is an endoscopic emergency. According to the Tokyo 
guidelines (2006), the diagnosis of acute cholangitis is 
established by the presence of either (1) the Charcot triad 
or (2) two elements of the Charcot triad plus laboratory 
evidence of an inflammatory response (eg, elevated white 
blood cell count, C-reactive protein), elevated liver 
biochemical test levels, and imaging evidence of biliary 
dilatation or a cause of obstruction.
Hepatomegaly may be present in calculous biliary 
obstruction, and tenderness is usually present in the right 
upper quadrant and epigastrium. Bile duct obstruction 
lasting more than 30 days results in liver damage leading to 
cirrhosis. Hepatic failure with portal hypertension occurs 
in untreated cases. In a population-based study from 
Denmark, acute cholangitis was reported to be a marker of 
occult gastrointestinal cancer.
Acute obstruction of the bile duct typically produces a 
transient albeit striking increase in serum aminotransfer
-
ase levels (often greater than 1000 units/L [20 mckat/L]). 
Bilirubinuria and elevation of the serum bilirubin are 
present if the bile duct remains obstructed; levels com
-
monly fluctuate. Serum alkaline phosphatase levels rise 
more slowly. Not uncommonly, serum amylase elevations 
are present because of secondary pancreatitis. When 
extrahepatic obstruction persists for more than a few 
weeks, differentiation of obstruction from chronic chole
-
static liver disease becomes more difficult. Leukocytosis 
is present in patients with acute cholangitis. Prolongation 
of the prothrombin time can result from the obstructed

-
of the prothrombin time can result from the obstructed 
flow of bile to the intestine. In contrast to hepatocellular 
dysfunction, hypoprothrombinemia due to obstructive 
jaundice will respond to intravenous vitamin K, 10 mg, or 
water-soluble oral vitamin K (phytonadione, 5 mg) within 
24–36 hours.
C. Imaging
Ultrasonography and CT may demonstrate dilated bile 
ducts, and radionuclide imaging may show impaired bile 
flow. EUS, helical CT, and magnetic resonance cholangiog
-
raphy are accurate in demonstrating bile duct stones and 
may be used in patients thought to be at intermediate risk 
for choledocholithiasis (age older than 55 years, cholecystitis, 
bile duct diameter greater than 6 mm on ultrasonography, 
serum bilirubin 1.8–4 mg/dL [30.78–68.4 mcmol/L], ele
-
vated serum liver enzymes, or pancreatitis). A decision 
analysis has suggested that magnetic resonance cholangi
-
ography is preferable when the risk of bile duct stones is 
low (less than 40%), and EUS is preferable when the risk is 
intermediate (40–91%). ERCP (occasionally with intra
-
ductal ultrasonography) or percutaneous transhepatic 
cholangiography (PTC) provides the most direct and 
accurate means of determining the cause, location, and 
extent of obstruction, but in patients at intermediate risk 
of choledocholithiasis, initial cholecystectomy with 
intraoperative cholangiography results in a shorter 
length of hospital stay, fewer bile duct investigations, and 
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no increase in morbidity. If the likelihood that obstruction 
is caused by a stone is high (bile duct stone seen on ultra
-
sonography, serum bilirubin greater than 4 mg/dL [68.4 
mcmol/L], or acute cholangitis), ERCP with sphincterot
-
omy and stone extraction or stent placement is the proce
-
dure of choice; meticulous technique is required to avoid 
causing acute cholangitis. Because the sensitivity of these 
criteria for choledocholithiasis is only 80%, it is not unrea
-
sonable for magnetic resonance cholangiography or EUS to 
be done before ERCP .
 
»
The most common cause of obstructive jaundice is a bile 
duct stone. Next in frequency are neoplasms of the 
pancreas, ampulla of Vater, or bile duct or an obstructed 
stent placed previously for decompression of an obstruct
-
ing tumor. Extrinsic compression of the bile duct may 
result from metastatic carcinoma (usually from the gastro
-
intestinal tract or breast) involving porta hepatis lymph 
nodes or, rarely, from a large duodenal diverticulum. 
Gallbladder cancer extending into the bile duct often pres
-
ents as obstructive jaundice. Chronic cholestatic liver 
diseases (PBC, sclerosing cholangitis, drug-induced) must 
be considered. Hepatocellular jaundice can usually be 
differentiated by the history, clinical findings, and liver 
biochemical tests, but liver biopsy is necessary on occasion. 
Recurrent pyogenic cholangitis should be considered in 
persons from Asia (and occasionally elsewhere) with 
intrahepatic biliary stones (particularly in the left ductal 
system) and recurrent cholangitis.
 
»
Treatment
In general, bile duct stones, even small ones, should be 
removed, even in an asymptomatic patient. A bile duct 
stone in a patient with cholelithiasis or cholecystitis is usu
-
ally treated by endoscopic sphincterotomy and stone 
extraction followed by laparoscopic cholecystectomy 
within 72 hours in patients with cholecystitis and within 
 
2 weeks in those without cholecystitis. In select cases, lapa
-
roscopic cholecystectomy and ERCP can be performed in a 
single session. An alternative approach, which is also asso
-
ciated with a shorter duration of hospitalization in patients 
at intermediate risk for choledocholithiasis, is laparoscopic 
cholecystectomy and bile duct exploration. For patients 
older than 70 years or poor-risk patients with cholelithiasis 
and choledocholithiasis, cholecystectomy may be deferred 
after endoscopic sphincterotomy because the risk of subse
-
quent cholecystitis is low (although the risk of subsequent 
complications is lower when cholecystectomy is per
-
formed). ERCP with sphincterotomy, generally within 
 
48 hours, should be performed before cholecystectomy in 
patients with gallstones and cholangitis, jaundice (serum 
total bilirubin greater than 4 mg/dL [68.4 mcmol/L]), 
 
a dilated bile duct (greater than 6 mm), or stones in the bile 
duct seen on ultrasonography or CT. (Stones may ulti
-
mately recur in up to 12% of patients, particularly in older 
patients, when the bile duct diameter is 15 mm or greater, 
or when brown pigment stones are found at the time of 
the initial sphincterotomy.) Endoscopic balloon dilation of 
the sphincter of Oddi is not associated with a higher rate of 
pancreatitis than endoscopic sphincterotomy if adequate 
dilation for more than 1 min is carried out and may be 
associated with a lower rate of stone recurrence. This pro
-
cedure is generally reserved for patients with coagulopathy 
because the risk of bleeding is lower with balloon dilation 
than with sphincterotomy. EUS-guided biliary drainage 
and PTC with drainage are second-line approaches if 
ERCP fails or is not possible. In patients with biliary 
pancreatitis that resolves rapidly, the stone usually passes 
into the intestine, and ERCP prior to cholecystectomy is 
not necessary if intraoperative cholangiography is planned.

Choledocholithiasis discovered at laparoscopic cholecys
-
tectomy may be managed via laparoscopic or, if necessary, 
open bile duct exploration or by postoperative endoscopic 
sphincterotomy. Operative findings of choledocholithiasis 
are palpable stones in the bile duct, dilatation or thickening 
of the wall of the bile duct, or stones in the gallbladder small 
enough to pass through the cystic duct. Laparoscopic intra
-
operative cholangiography (or intraoperative ultrasonogra
-
phy) should be done at the time of cholecystectomy in 
patients with liver enzyme elevations but a bile duct diameter 
of less than 5 mm; if a ductal stone is found, the duct should 
be explored. In the post-cholecystectomy patient with 
choledocholithiasis, endoscopic sphincterotomy with stone 
extraction is preferable to transabdominal surgery. Litho
-
tripsy (endoscopic or external), peroral cholangioscopy 
(choledoscopy), or biliary stenting may be a therapeutic 
consideration for large stones. For the patient with a T 
tube and bile duct stone, the stone may be extracted via the 
T tube.
Postoperative antibiotics are not administered routinely 
after biliary tract surgery. Cultures of the bile are always 
taken at operation. If biliary tract infection was present 
preoperatively or is apparent at operation, ampicillin-
sulbactam (3 g intravenously every 6 hours) or piperacillin-
tazobactam (3.375 or 4.5 g intravenously every 6 hours) or 
a third-generation cephalosporin (eg, ceftriaxone, 1 g 
intravenously every 24 hours) is administered postopera
-
tively until the results of sensitivity tests on culture 
specimens are available. A T-tube cholangiogram should 
be done before the tube is removed, usually about 3 weeks 
after surgery. A small amount of bile frequently leaks from 
the tube site for a few days.
Urgent ERCP with sphincterotomy and stone extrac
-
tion is generally indicated for choledocholithiasis com
-
plicated by acute cholangitis and is preferred to surgery. 
Before ERCP , liver function should be evaluated thor
-
oughly. The prothrombin time should be restored to 
normal by intravenous administration of vitamin K. For 
mild-to-moderately severe community-acquired acute 
cholangitis, ciprofloxacin (400 mg intravenously every 
12 hours), penetrates well into bile and is effective treat
-
ment, with metronidazole (500 mg intravenously every 
6–8 hours) for anaerobic coverage. An alternative regi
-
men is ampicillin-sulbactam (3 g intravenously every 
 
6 hours). Regimens for patients with severe or hospital-
acquired acute cholangitis, and those potentially infected 
with an antibiotic-resistant pathogen. include intrave
-
nous piperacillin-tazobactam, 3.375 or 4 g every 6 hours 
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or a carbopenem such as meropenem (1 g intravenously 
every 8 hours). Aminoglycosides (eg, gentamicin 5–7 mg/kg 
intravenously every 24 hours) may be added in cases of 
severe sepsis or septic shock but should not be given for 
more than a few days because the risk of aminoglycoside 
nephrotoxicity is increased in patients with cholestasis. 
Regimens that include drugs active against anaerobes are 
required when a biliary-enteric communication is present. 
Emergent decompression of the bile duct (within 12 hours), 
generally by ERCP , is required for patients who are septic 
or fail to improve on antibiotics within 12–24 hours. 
Medical therapy alone is most likely to fail in patients 
with tachycardia, a serum albumin less than 3 g/dL 
 
(30 g/L), marked hyperbilirubinemia, a high serum ALT 
level, a high white blood cell count, and a prothrombin 
time greater than 14 seconds on admission. If sphincter
-
otomy cannot be performed, the bile duct can be decom
-
pressed by a biliary stent or nasobiliary catheter. Once 
decompression is achieved, antibiotics are generally 
continued for at least another 3 days. Elective cholecys
-
tectomy can be undertaken after resolution of cholangitis, 
unless the patient remains unfit for surgery. Mortality 
from acute cholangitis has been reported to correlate 
with a high total bilirubin level, prolonged partial throm
-
boplastin time, presence of a liver abscess, and unsuccessful 
ERCP .
 
»
All symptomatic patients with choledocholithiasis should 
 
»
All patients with acute cholangitis should be hospitalized.
Elmunzer BJ et al. The impact of cholecystectomy after endo
-
scopic sphincterotomy for complicated gallstone disease. Am 
J Gastroenterol. 2017 Oct;112(10):1596–602. [PMID: 
28809384]
Huang RJ et al. Practice patterns for cholecystectomy after endoscopic 
retrograde cholangiopancreatography for patients with choledo
-
cholithiasis. Gastroenterology. 2017 Sep;153(3): 762–71. [PMID: 
28583822]
Liao WC et al. International consensus recommendations for 
difficult biliary access. Gastrointest Endosc. 2017 Feb;85 (2):
 
295–304. [PMID: 27720741]
Sharaiha RZ et al. Efficacy and safety of EUS-guided biliary 
drainage in comparison with percutaneous biliary drainage 
when ERCP fails: a systematic review and meta-analysis. 
Gastrointest Endosc. 2017 May;85(5):904–14. [PMID: 
28063840]
Williams E et al. Updated guideline on the management of com
-
mon bile duct stones (CBDS). Gut. 2017 May;66(5):765–82. 
[PMID: 28122906]
BILIARY STRICTURE
Benign biliary strictures are the result of surgical (including 
liver transplantation) anastomosis or injury in about 95% of 
cases. The remainder of cases are caused by blunt external 
injury to the abdomen, pancreatitis, IgG
4
-related disease, 
erosion of the duct by a gallstone, or prior endoscopic 
sphincterotomy.
Signs of injury to the duct may or may not be recog
-
nized in the immediate postoperative period. If complete 
occlusion has occurred, jaundice will develop rapidly; 
more often, however, a tear has been made accidentally in 
the duct, and the earliest manifestation of injury may be 
excessive or prolonged loss of bile from the surgical drains. 
Bile leakage resulting in a bile collection (biloma) may 
predispose to localized infection, which in turn accentuates 
scar formation and the ultimate development of a fibrous 
Cholangitis is the most common complication of stric
-
ture. Typically, the patient experiences episodes of pain, 
fever, chills, and jaundice within a few weeks to months 
after cholecystectomy. Physical findings may include 
jaundice during an acute attack of cholangitis and right 
upper quadrant abdominal tenderness. Serum alkaline 
phosphatase is usually elevated. Hyperbilirubinemia is 
variable, fluctuating during exacerbations and usually 
remaining in the range of 5–10 mg/dL (85.5–171 mcmol/L).

remaining in the range of 5–10 mg/dL (85.5–171 mcmol/L). 
Blood cultures may be positive during an acute episode of 
cholangitis. Secondary biliary cirrhosis will inevitably 
develop if a stricture is not treated.
MRCP or multidetector CT is valuable in demonstrat
-
ing the stricture and outlining the anatomy. ERCP is the 
first-line interventional approach and permits biopsy and 
cytologic specimens to exclude malignancy (in conjunc
-
tion with EUS-guided fine-needle aspiration, an even more 
sensitive test for distal bile duct malignancy), sphincterot
-
omy to allow closure of a bile leak, and dilation (often 
repeated) and stent placement, thereby avoiding surgical 
repair in some cases. When ERCP is unsuccessful, dilation 
of a stricture may be accomplished by PTC or under EUS 
guidance. Placement of multiple plastic stents appears to be 
more effective than placement of a single stent. The use of 
covered metal stents, which are more easily removed endo
-
scopically than uncovered metal stents, as well as bioab
-
sorbable stents, is an alternative to use of plastic stents and 
requires fewer ERCPs to achieve stricture resolution. 
Uncovered metal stents, which often cannot be removed 
endoscopically, are generally avoided in benign strictures 
unless life expectancy is less than 2 years. Strictures related 
to chronic pancreatitis are more difficult than postsurgical 
strictures to treat endoscopically and may be best man
-
aged with a temporary covered metal stent. Following liver 
transplantation, endoscopic management is more success
-
ful for anastomotic than for nonanastomotic strictures. 
Results for nonanastomotic strictures may be improved 
with repeated dilations or the use of multiple plastic stents. 
Biliary strictures after live liver donor liver transplanta
-
tion, particularly in patients with a late-onset (after 24 
weeks) stricture or with intrahepatic biliary dilatation, 
are also challenging and require aggressive endoscopic 
therapy; in addition, the risk of post-ERCP pancreatitis 
appears to be increased. When malignancy cannot be 
excluded with certainty, additional endoscopic diagnostic 
approaches may be considered—if available—including 
intraductal ultrasonography, peroral cholangioscopy, and 
confocal laser endomicroscopy. Differentiation from 
cholangiocarcinoma may ultimately require surgical explo
-
ration in 20% of cases. Operative treatment of a stricture 
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frequently necessitates performance of an end-to-end 
ductal repair, choledochojejunostomy, or hepaticojeju
-
nostomy to reestablish bile flow into the intestine.
 
»
All patients with biliary stricture should be referred.
 
»
Patients with acute cholangitis should be hospitalized.
Bowlus CL et al. Evaluation of indeterminate biliary strictures. 
Nat Rev Gastroenterol Hepatol. 2016 Jan;13(1):28–37. [PMID: 
26526122]
Coté GA et al. Effect of covered metallic stents compared with 
plastic stents on benign biliary stricture resolution: a random
-
ized clinical trial. JAMA. 2016 Mar 22–29;315(12):1250–7. 
[PMID: 27002446]
Hu B et al. Asia-Pacific consensus guidelines for endoscopic 
management of benign biliary strictures. Gastrointest Endosc. 
2017 Jul;86(1):44–58. [PMID: 28283322]
PRIMARY SCLEROSING CHOLANGITIS
 
»
Most common in men aged 20–50 years.
 
»
Often associated with ulcerative colitis.
 
»
Progressive jaundice, itching, and other features 
of cholestasis.
 
»
Diagnosis based on characteristic cholangiographic 
findings.
 
»
At least 10% risk of cholangiocarcinoma.
 
»
Primary sclerosing cholangitis is an uncommon disease 
thought to result from an increased immune response to 
intestinal endotoxins and characterized by diffuse inflam
-
mation of the biliary tract leading to fibrosis and strictures 
of the biliary system. From 60% to 70% of affected persons 
are male, usually 20–50 years of age (median age 41). There 
is an incidence of nearly 3.3 per 100,000 in Asian Ameri
-
cans, 2.8 per 100,000 in Hispanic Americans, and 2.1 per 
100,000 in African Americans, and an intermediate inci
-
dence in whites (and increasing) and a prevalence of 21 per 
100,000 men and 6 per 100,000 women in the United 
States. Primary sclerosing cholangitis is closely associated 
with inflammatory bowel disease (more commonly ulcer
-
ative colitis than Crohn colitis), which is present in approx
-
imately two-thirds of patients with primary sclerosing 
cholangitis; however, clinically significant sclerosing 
cholangitis develops in only 1–4% of patients with ulcerative 
colitis. The association with inflammatory bowel disease 
has suggested a role for intestinal microbial dysbiosis in the 
pathogenesis of primary sclerosing cholangitis. Smoking is 
associated with a decreased risk of primary sclerosing 
cholangitis in patients who also have inflammatory bowel 
disease. Coffee consumption is also associated with a 
decreased risk of primary sclerosing cholangitis. Women 
with primary sclerosing cholangitis may be more likely to 
have recurrent urinary tract infections and less likely to use 
hormone replacement therapy than healthy controls. Asso
-
ciations with cardiovascular disease and diabetes mellitus 
have been reported. Primary sclerosing cholangitis is asso
-
ciated with the histocompatibility antigens HLA-B8 and 
-DR3 or -DR4, and first-degree relatives of patients with 
primary sclerosing cholangitis have a fourfold increased 
risk of primary sclerosing cholangitis and a threefold 
increased risk of ulcerative colitis. A subset of patients with 
primary sclerosing cholangitis have increased serum IgG
4
 
levels and distinct HLA associations (with a poorer prog
-
nosis) but do not meet criteria for IgG
4
-related disease-
associated cholangitis. The diagnosis of primary sclerosing 
cholangitis may be difficult to make after biliary surgery.
 
»
Primary sclerosing cholangitis presents as progressive 
obstructive jaundice, frequently associated with fatigue, 
pruritus, anorexia, and indigestion. Patients may be diag
-
nosed in the presymptomatic phase because of an elevated 
alkaline phosphatase level or a subclinical phase based on 
abnormalities on magnetic resonance cholangiography 
despite normal liver enzyme levels. Complications of

despite normal liver enzyme levels. Complications of 
chronic cholestasis, such as osteoporosis and malabsorp
-
tion of fat-soluble vitamins, may occur late in the course. 
Risk factors for osteoporosis include older age, lower body 
mass index, and longer duration of inflammatory bowel 
disease. Esophageal varices on initial endoscopy are most 
likely in patients with a higher Mayo risk score based on 
age, bilirubin, albumin, and AST and a higher AST/ALT 
ratio, and new varices are likely to develop in those with a 
lower platelet count and higher bilirubin at 2 years. In 
patients with primary sclerosing cholangitis, ulcerative 
colitis is frequently characterized by rectal sparing and 
backwash ileitis.
B. Diagnostic Findings
The diagnosis of primary sclerosing cholangitis is generally 
made by MRCP , the sensitivity of which approaches that of 
ERCP . Characteristic cholangiographic findings are seg
-
mental fibrosis of bile ducts with saccular dilatations 
between strictures. Biliary obstruction by a stone or tumor 
should be excluded. Liver biopsy is not necessary for diag
-
nosis when cholangiographic findings are characteristic. 
The disease may be confined to small intrahepatic bile 
ducts in about 15% of cases, in which case MRCP and 
ERCP are normal and the diagnosis is suggested by liver 
biopsy findings. These patients have a longer survival than 
patients with involvement of the large ducts and do not 
appear to be at increased risk for cholangiocarcinoma 
unless large-duct sclerosing cholangitis develops (which 
occurs in about 20% over 7–10 years). Liver biopsy may 
show characteristic periductal fibrosis (“onion-skinning”) 
and allows staging, which is based on the degree of fibrosis 
and which correlates with liver stiffness as measured by 
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ultrasound elastography. Perinuclear ANCA (directed 
against myeloid-specific tubulin-beta isotype 5) as well as 
antinuclear, anticardiolipin, antithyroperoxidase, and anti-
Saccharomyces cerevisiae
 antibodies and rheumatoid factor 
are frequently detected in serum. Occasional patients have 
clinical and histologic features of both sclerosing cholangi
-
tis and autoimmune hepatitis. Cholangitis in IgG
4
-related 
disease may be difficult to distinguish from primary scle
-
rosing cholangitis and even cholangiocarcinoma, is associ
-
ated with autoimmune pancreatitis (see Chronic 
Pancreatitis), and is responsive to corticosteroids. Primary 
sclerosing cholangitis must also be distinguished from idio
-
pathic adulthood ductopenia (a rare disorder that affects 
young to middle-aged adults who manifest cholestasis result
-
ing from loss of interlobular and septal bile ducts yet who 
have a normal cholangiogram. It is caused in some cases by 
a mutation in the canalicular phospholipid transporter 
gene 
ABCB4
). Primary sclerosing cholangitis must also be 
distinguished  from other cholangiopathies (including PBC; 
cystic fibrosis; eosinophilic cholangitis; AIDS cholangiopa
-
thy; histiocytosis X; allograft rejection; graft-versus-host 
disease; ischemic cholangiopathy [often with biliary “casts, ” a 
rapid progression to cirrhosis, and a poor outcome] caused 
by hepatic artery thrombosis, shock, respiratory failure, or 
drugs; intra-arterial chemotherapy; and sarcoidosis).
 
»
Cholangiocarcinoma may complicate the course of pri
-
mary sclerosing cholangitis in up to 20% of cases (1.2% per 
year) and may be difficult to diagnose by cytologic exami
-
nation or biopsy because of false-negative results. A serum 
CA 19-9 level above 100 units/mL is suggestive but not 
diagnostic of cholangiocarcinoma. Annual right-upper-
quadrant ultrasonography or MRI with MRCP and serum 
CA 19-9 testing (a level of 20 is the threshold for further 
investigation) are recommended for surveillance, with 
ERCP and biliary cytology if the results are suggestive of 
malignancy. PET and peroral cholangioscopy may play 
roles in the early detection of cholangiocarcinoma. Patients 
with ulcerative colitis and primary sclerosing cholangitis 
are at high risk (tenfold higher than ulcerative colitis 
patients without primary sclerosing cholangitis) for 
colorectal neoplasia. The risks of gallstones, cholecystitis, 
gallbladder polyps, and gallbladder carcinoma appear to be 
increased in patients with primary sclerosing cholangitis.
 
»
Treatment
Episodes of acute bacterial cholangitis may be treated with 
ciprofloxacin (750 mg twice daily orally or intravenously). 
Ursodeoxycholic acid in standard doses (10–15 mg/kg/day 
orally) may improve liver biochemical test results but does 
not appear to alter the natural history. However, withdrawal 
of ursodeoxycholic acid may result in worsening of liver 
biochemical test levels and increased pruritus, and ursode
-
oxycholic acid in intermediate doses (17–23 mg/kg/day) has 
been reported to be beneficial. High-dose ursodeoxycholic 
acid (25–30 mg/kg/day) has been shown not to reduce chol
-
angiographic progression and liver fibrosis, nor to improve 
survival or prevent cholangiocarcinoma, and has been 
shown to increase the risk of death and need for liver trans
-
plantation in patients with a normal serum bilirubin level 
and an early histologic stage. Other approaches such as 
antibiotics (vancomycin, metronidazole, minocycline, 
azithromycin), obeticholic acid (a farsenoid-X receptor ago
-
nist), 24-norursodeoxycholic acid, budesonide, anti-tumor 
necrosis factor antibodies, simtuzumab (a monoclonal 
antibody to lysyl oxidase, an enzyme that functions as a 
profibrotic protein), cenicriviroc (a dual chemokine recep
-
tor [CCR] 5 and CCR2 antagonist), cyclosporine, tacroli
-
mus, other antifibrotic agents, mitomycin C, and fecal

-
-
mus, other antifibrotic agents, mitomycin C, and fecal 
microbial transplantation are under study. Careful endo
-
scopic evaluation of the biliary tract may permit balloon 
dilation of localized strictures, and repeated dilation of a 
dominant stricture may improve survival, although such 
patients have reduced survival compared with patients who 
do not have a dominant stricture. Short-term (2–3 weeks) 
placement of a stent in a major stricture also may relieve 
symptoms and improve biochemical abnormalities, with 
sustained improvement after the stent is removed; how
-
ever, long-term stenting may increase the rate of complica
-
tions such as cholangitis and is not recommended. 
Cholecystectomy is indicated in patients with primary 
sclerosing cholangitis and a gallbladder polyp greater than 
8 mm in diameter. In patients without cirrhosis, surgical 
resection of a dominant bile duct stricture may lead to 
longer survival than endoscopic therapy by decreasing the 
subsequent risk of cholangiocarcinoma. When feasible, 
extensive surgical resection of cholangiocarcinoma com
-
plicating primary sclerosing cholangitis may result in 
5-year survival rates of greater than 50%. In patients with 
ulcerative colitis, primary sclerosing cholangitis is an inde
-
pendent risk factor for the development of colorectal dys
-
plasia and cancer (especially in the right colon), and strict 
adherence to a colonoscopic surveillance program (yearly 
for those with ulcerative colitis and every 5 years for those 
without ulcerative colitis) is recommended. Whether treat
-
ment with ursodeoxycholic acid reduces the risk of colorec
-
tal dysplasia and carcinoma in patients with ulcerative 
colitis and primary sclerosing cholangitis is still uncertain. 
For patients with cirrhosis and clinical decompensation, 
liver transplantation is the treatment of choice; primary 
sclerosing cholangitis recurs in the graft in 30% of cases, 
with a possible reduction in the risk of recurrence when 
colectomy has been performed for ulcerative colitis before 
 
»
Prognosis
Survival of patients with primary sclerosing cholangitis 
averages 9–17 years, and up to 21 years in population-based 
studies. Adverse prognostic markers are older age, 
hepatosplenomegaly, higher serum bilirubin and AST 
levels, lower albumin levels, a history of variceal bleeding, a 
dominant bile duct stricture, and extrahepatic duct changes. 
Variceal bleeding is also a risk factor for cholangiocarci
-
noma. Patients in whom serum alkaline phosphatase levels 
decline by 40% or more (spontaneously, with ursodeoxycholic 
acid therapy, or after treatment of a dominant stricture) have 
longer transplant-free survival times than those in whom the 
alkaline phosphatase does not decline. Moreover, improvement 
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in the serum alkaline phosphatase to less than 1.5 times the 
upper limit of normal is associated with a reduced risk of 
cholangiocarcinoma. The risk of progression can be pre
-
dicted by three findings on MRI and MRCP: a cirrhotic 
appearance to the liver, portal hypertension, and enlarged 
perihepatic lymph nodes. Transplant-free survival can also 
be predicted by serum levels of markers of liver fibrosis—
hyaluronic acid, tissue inhibitor of metalloproteinase-1, and 
propeptide of type III procollagen. Reduced quality of life is 
associated with older age, large-duct disease, and systemic 
symptoms. Although maternal primary sclerosing 
cholangitis is associated with preterm birth and cesarean 
section delivery, the risk of congenital malformations is not 
increased. Interestingly, patients with milder ulcerative 
colitis tend to have more severe primary cholangitis and a 
higher rate of liver transplantation. Actuarial survival rates 
with liver transplantation are as high as 72% at 5 years, but 
rates are much lower once cholangiocarcinoma has devel
-
oped. Following transplantation, patients have an increased 
risk of nonanastomotic biliary strictures and—in those with 
ulcerative colitis—colon cancer, and the disease recurs in 
25%. The retransplantation rate is higher than that for PBC. 
Those patients who are unable to undergo liver transplanta
-
tion will ultimately require high-quality palliative care 
(see Chapter 5).
European Society of Gastrointestinal Endoscopy; European 
Association for the Study of the Liver. Role of endoscopy in 
primary sclerosing cholangitis: European Society of Gastro
-
intestinal Endoscopy (ESGE) and European Association for 
the Study of the Liver (EASL) clinical guideline. J Hepatol. 
2017 Jun;66(6):1265–81. [PMID: 28427764]
Fickert P et al. norUrsodeoxycholic acid improves cholestasis in 
primary sclerosing cholangitis. J Hepatol. 2017 Sep;67(3):
 
549–58. [PMID: 28529147]
Lazaridis KN et al. Primary sclerosing cholangitis. N Engl J Med. 
2016 Sep 22;375(12):1161–70. [PMID: 27653566]
Schramm C et al. Recommendations on the use of magnetic 
resonance imaging in PSC-A position statement from the 
International PSC Study Group. Hepatology. 2017 Nov;
 
66(5):1675–88. [PMID: 28555945]
 
º
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See Chapter 39 for Carcinoma of the Pancreas and 
Periampullary Area.
ACUTE PANCREATITIS
 
»
Abrupt onset of deep epigastric pain, often with 
radiation to the back.
 
»
History of previous episodes, often related to alcohol 
intake.
 
»
Nausea, vomiting, sweating, weakness.
 
»
Abdominal tenderness and distention and fever.
 
»
Leukocytosis, elevated serum amylase, elevated 
serum lipase.
The annual incidence of acute pancreatitis ranges from 
13 to 45 per 100,000 population and has increased since 
1990. Most cases of acute pancreatitis are related to biliary 
tract disease (a passed gallstone, usually 5 mm or less in 
diameter) or heavy alcohol intake. The exact pathogenesis 
is not known but may include edema or obstruction of the 
ampulla of Vater, reflux of bile into pancreatic ducts, and 
direct injury of pancreatic acinar cells by prematurely 
activated pancreatic enzymes. Among the numerous other 
causes or associations are hypercalcemia, hyperlipidemias 
(chylomicronemia, hypertriglyceridemia, or both), abdom
-
inal trauma (including surgery), drugs (including aza
-
thioprine, mercaptopurine, asparaginase, pentamidine, 
didanosine, valproic acid, tetracyclines, dapsone, isoniazid, 
metronidazole, estrogen and tamoxifen [by raising serum 
triglycerides], sulfonamides, mesalamine, celecoxib, sulin
-
dac, leflunomide, thiazides, simvastatin, fenofibrate, enala
-
pril, methyldopa, procainamide, sitagliptin, exenatide, 
possibly corticosteroids, and others), vasculitis, infections 
(eg, mumps, cytomegalovirus, HEV , 
M avium intracellulare

-
 
complex), peritoneal dialysis, cardiopulmonary bypass, 
single- or double-balloon enteroscopy, and ERCP . In 
patients with pancreas divisum, a congenital anomaly in 
which the dorsal and ventral pancreatic ducts fail to fuse, 
acute pancreatitis may result from stenosis of the minor 
papilla with obstruction to flow from the accessory pancre
-
atic duct, although concomitant genetic mutations, particu
-
larly in the cystic fibrosis transmembrane conductance 
regulator (
CFTR
) gene, may actually account for acute pan
-
creatitis in these patients. Genetic mutations also predispose 
to chronic pancreatitis, particularly in persons younger than 
30 years of age if no other cause is evident and a family his
-
tory of pancreatic disease is present. Acute pancreatitis may 
also result from the anomalous union of the pancreaticobili
-
ary duct. Rarely, acute pancreatitis may be the presenting 
manifestation of a pancreatic or ampullary neoplasm. Celiac 
disease appears to be associated with an increased risk of 
acute and chronic pancreatitis. Apparently “idiopathic” 
acute pancreatitis is often caused by occult biliary microli
-
thiasis but unlikely to be caused by sphincter of Oddi dys
-
function involving the pancreatic duct. Between 15% and 
25% of cases are truly idiopathic. Smoking, high dietary 
glycemic load, and abdominal adiposity increase the risk of 
pancreatitis, and older age and obesity increase the risk of 
a severe course; vegetable consumption, dietary fiber, and 
use of statins may reduce the risk of pancreatitis, and coffee 
drinking may reduce the risk of nonbiliary pancreatitis.
 
»
Epigastric abdominal pain, generally abrupt in onset, is 
steady, boring, and severe and often made worse by walk
-
ing and lying supine and better by sitting and leaning for
-
ward. The pain usually radiates into the back but may 
radiate to the right or left. Nausea and vomiting are usually 
present. Weakness, sweating, and anxiety are noted in 
severe attacks. There may be a history of alcohol intake or 
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a heavy meal immediately preceding the attack or a history 
of milder similar episodes or biliary pain in the past.
The upper abdomen is tender, most often without guard
-
ing, rigidity, or rebound. The abdomen may be distended, 
and bowel sounds may be absent with associated ileus. Fever 
of 38.4–39°C, tachycardia, hypotension (even shock), pallor, 
and cool clammy skin are present in severe cases. Mild jaun
-
dice may be seen. Occasionally, an upper abdominal mass 
due to the inflamed pancreas or a pseudocyst may be 
palpated. Acute kidney injury (usually prerenal azotemia) 
may occur early in the course of acute pancreatitis.
Serum amylase and lipase are elevated—usually more than 
three times the upper limit of normal—within 24 hours in 
90% of cases; their return to normal is variable depending 
on the severity of disease. Lipase remains elevated longer 
than amylase and is slightly more accurate for the diagnosis 
of acute pancreatitis. Leukocytosis (10,000–30,000/mcL), 
proteinuria, granular casts, glycosuria (10–20% of cases), 
hyperglycemia, and elevated serum bilirubin may be pres
-
ent. Blood urea nitrogen and serum alkaline phosphatase 
may be elevated and coagulation tests abnormal. An ele
-
vated serum creatinine level (greater than 1.8 mg/dL 
[149.94 mcmol/L]) at 48 hours is associated with the devel
-
opment of pancreatic necrosis. In patients with clear evi
-
dence of acute pancreatitis, a serum ALT level of more than 
150 units/L (3 mkat/L) suggests biliary pancreatitis. A 
decrease in serum calcium may reflect saponification and 
correlates with severity of the disease. Levels lower than 
7 mg/dL (1.75 mmol/L) (when serum albumin is normal) 
are associated with tetany and an unfavorable prognosis. 
Patients with acute pancreatitis caused by hypertriglyceri
-
demia generally have fasting triglyceride levels above 1000 
mg/dL (10 mmol/L) and often have other risk factors for 
pancreatitis; in some cases, the serum amylase is not elevated 
substantially because of an inhibitor in the serum of patients 
with marked hypertriglyceridemia that interferes with mea
-
surement of serum amylase. An early rise in the hematocrit 
value above 44% suggests hemoconcentration and predicts 
pancreatic necrosis. An elevated C-reactive protein concen
-
tration (greater than 150 mg/L [1500 mg/L]) at 48 hours 
suggests severe disease.
Other diagnostic tests that offer the possibility of simplicity, 
rapidity, ease of use, and low cost—including urinary 
trypsinogen-2, trypsinogen activation peptide, and carboxy
-
peptidase B—are not widely available. In patients in whom 
ascites or a left pleural effusion develops, fluid amylase content 
is high. Electrocardiography may show ST–T wave changes.
C. Assessment of Severity
In addition to the individual laboratory parameters noted 
above, the severity of acute alcoholic pancreatitis can be 
assessed using several scoring systems (none of which has 
been shown to have high prognostic accuracy), including 
the 
Ranson criteria
 (Table 16–9). The 
Sequential Organ 
Failure Assessment
 (
SOFA
) score or 
modified Marshall 
scoring system
 can be used to assess injury to other 
organs, and the 
Acute Physiology and Chronic Health 
Table 16–9.
 
Ranson criteria for assessing the severity 
of acute pancreatitis.
Three or more of the following predict a severe course complicated 
by pancreatic necrosis with a sensitivity of 60–80%
 
A
ge over 55 years
 
W
hite blood cell count > 16 × 10
3
/mcL (> 16 × 10
9
/L)
 
Blood gluc
ose > 200 mg/dL (> 11 mmol/L)
 
S
erum lactic dehydrogenase > 350 units/L (> 7 mkat/L)
 
Aspar
tate aminotransferase > 250 units/L (> 5 mkat/L)
Development of the following in the first 48 hours indicates a 
worsening prognosis
 
Hema
tocrit drop of more than 10 percentage points
 
Blood ur
ea nitrogen rise > 5 mg/dL (> 1.8 mmol/L)
 
Ar
terial Po
2
 of < 60 mm Hg (< 7.8 kPa)
 
S
erum calcium of < 8 mg/dL (< 0.2 mmol/L)

Hema
 
Blood ur
 
Ar
terial Po
2
 
S
 
Base deficit 
over 4 mEq/L
 
Estima
ted fluid sequestration of > 6 L
Mortality rates correlate with the number of criteria present
1
Number of Criteria
Mortality 
r
a
te
0–2
1%
3–4
16%
5–6
40%
7–8
100%
1
An APACHE II score ≥ 8 also correlates with mortality.
 (
AP ACHE II
) score is another tool for assess
-
ing severity. A simple 5-point clinical scoring system (the 
Bedside Index for Severity in Acute Pancreatitis,
 or 
BISAP
) based on blood urea nitrogen above 25 mg/dL 
 
(9 mmol/L), impaired mental status, systemic inflamma
-
tory response syndrome, age older than 60 years, and 
pleural effusion during the first 24 hours (before the 
onset of organ failure) identifies patients at increased risk 
for mortality. More simply, the presence of a systemic 
inflammatory response alone and an elevated blood urea 
nitrogen level on admission as well as a rise in blood urea 
nitrogen within the first 24 hours of hospitalization are 
independently associated with increased mortality; the 
greater the rise in blood urea nitrogen after admission, 
the greater the mortality rate. A model based on the 
change in serum amylase in the first 2 days after admis
-
sion and the body mass index has been proposed. An 
early rise in serum levels of neutrophil gelatinase-associated 
lipocalin has also been proposed as a marker of severe 
acute pancreatitis. The absence of rebound abdominal 
tenderness or guarding, a normal hematocrit value, and a 
normal serum creatinine level (the “
harmless acute pan
-
creatitis score
, ” or 
HAPS
) predicts a nonsevere course 
with 98% accuracy. The 
revised Atlanta classification
 of 
the severity of acute pancreatitis uses the following three 
categories: (1) 
mild
 disease is the absence of organ failure 
and local ([peri]pancreatic necrosis or fluid collections) 
or systemic complications; (2) 
moderate
 disease is the 
presence of transient (under 48 hours) organ failure or 
local or systemic complications, or both; and (3) 
severe
 
disease is the presence of persistent (48 hours or more) 
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organ failure. A similar 
“determinant-based” classifica
-
tion
 also includes a category of 
critical
 acute pancreatitis 
characterized by both persistent organ failure and infected 
peripancreatic necrosis. A dynamic assessment instru
-
ment, the 
pancreatitis activity scoring system (P ASS)
, has 
been proposed and includes five components: organ fail
-
ure, systemic inflammatory response syndrome, abdomi
-
nal pain, opioid requirement, and intolerance of oral 
intake.
D. Imaging
Plain radiographs of the abdomen may show gallstones 
(if calcified), a “sentinel loop” (a segment of air-filled small 
intestine most commonly in the left upper quadrant), the 
“colon cutoff sign”—a gas-filled segment of transverse 
colon abruptly ending at the area of pancreatic inflamma
-
tion—or focal linear atelectasis of the lower lobe of the 
lungs with or without pleural effusion. Ultrasonography is 
often not helpful in diagnosing acute pancreatitis because 
of intervening bowel gas but may identify gallstones in the 
gallbladder. Unenhanced CT is useful for demonstrating an 
enlarged pancreas when the diagnosis of pancreatitis is 
uncertain, differentiating pancreatitis from other possible 
intra-abdominal catastrophes, and providing an initial 
assessment of prognosis but is often unnecessary early in 
the course (Table 16–10). Rapid-bolus intravenous con
-
trast-enhanced CT following aggressive volume resuscita
-
tion is of particular value after the first 3 days of severe 
acute pancreatitis for identifying areas of necrotizing pan
-
creatitis and assessing the degree of necrosis (although the 
use of intravenous contrast may increase the risk of com
-
plications of pancreatitis and of acute kidney injury and 
should be avoided when the serum creatinine level is above 
1.5 mg/dL [124.95 mcmol/L].) MRI appears to be a suitable 
alternative to CT. Perfusion CT on day 3 demonstrating 
areas of ischemia in the pancreas has been reported to 
predict the development of pancreatic necrosis. The pres
-
ence of a fluid collection in the pancreas correlates with an 
increased mortality rate. CT-guided needle aspiration of 
areas of necrotizing pancreatitis after the third day may 
disclose infection, usually by enteric organisms, which 
typically requires debridement. The presence of gas bub
-
bles on CT implies infection by gas-forming organisms. 
EUS is useful in identifying occult biliary disease (eg, small 
stones, sludge, microlithiasis), which is present in a major
-
ity of patients with apparently idiopathic acute pancreatitis, 
and is indicated in persons over age 40 to exclude malig
-
nancy. ERCP is generally not indicated after a first attack of 
acute pancreatitis unless there is associated cholangitis or 
jaundice or a bile duct stone is known to be present, but 
EUS or MRCP should be considered, especially after 
repeated attacks of idiopathic acute pancreatitis. Following 
a single attack of idiopathic acute pancreatitis, a negative 
EUS examination predicts a low risk of relapse. In select 
cases, aspiration of bile for crystal analysis may confirm the 
suspicion of microlithiasis, and manometry of the pancre
-
atic duct sphincter may detect sphincter of Oddi dysfunc
-
tion as a cause of recurrent pancreatitis.
 
»
Acute pancreatitis must be differentiated from an acutely 
perforated duodenal ulcer, acute cholecystitis, acute intes
-
tinal obstruction, leaking aortic aneurysm, renal colic, and 
acute mesenteric ischemia. Serum amylase may also be 
elevated in proximal intestinal obstruction, gastroenteritis, 
mumps not involving the pancreas (salivary amylase), and 
ectopic pregnancy and after administration of opioids and 
abdominal surgery. Serum lipase may also be elevated in 
many of these conditions.
 
»
Intravascular volume depletion secondary to leakage of fluids

»
Intravascular volume depletion secondary to leakage of fluids 
in the pancreatic bed and ileus with fluid-filled loops of 
bowel may result in prerenal azotemia and even acute tubular 
necrosis without overt shock. This sequence usually occurs 
within 24 hours of the onset of acute pancreatitis and lasts 
8–9 days. Some patients require renal replacement therapy.
According to the revised Atlanta classification, fluid 
collections and necrosis may be acute (within the first 
 
4 weeks) or chronic (after 4 weeks) and sterile or infected. 
Chronic collections, including pseudocysts and walled-off 
Table 16–10.
 
Severity index for acute pancreatitis.
CT Grade
Points
Pancreatic 
Necrosis
Additional 
Points
Severity 
Index
1
Mortality 
r
at
e
2
A Normal pancreas
0
0%
0
0
0%
B Pancreatic enlargement
1
0%
0
1
0%
C Pancreatic inflammation and/or peripancreatic fat
2
< 30%
2
4
< 3%
D Single acute peripancreatic fluid collection
3
30–50%
4
7
6%
E Two or more acute peripancreatic fluid collections or retro
-
peritoneal air
4
> 50%
6
10
> 17%
1
Severity Index = CT Grade 
Points
 + Pancreatic Necrosis 
Additional Points
.
2
Based on the Severity Index.
Adapted with permission from Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology. 2002 
Jun;223(3):603–13.
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necrosis, are characterized by encapsulation. Sterile or 
infected necrotizing pancreatitis may complicate the course 
of 5–10% of cases and accounts for most of the deaths. The 
risk of infection does not correlate with the extent of necro
-
sis. Pancreatic necrosis is often associated with fever, leu
-
kocytosis, and, in some cases, shock and is associated with 
organ failure (eg, gastrointestinal bleeding, respiratory 
failure, acute kidney injury) in 50% of cases. Because 
infected pancreatic necrosis is often an indication for 
debridement, fine-needle aspiration of necrotic tissue 
under CT guidance should be performed (if necessary, 
repeatedly) for Gram stain and culture.
A serious complication of acute pancreatitis is acute 
respiratory distress syndrome (ARDS); cardiac dysfunction 
may be superimposed. It usually occurs 3–7 days after the 
onset of pancreatitis in patients who have required large 
volumes of fluid and colloid to maintain blood pressure and 
urinary output. Most patients with ARDS require intuba
-
tion, mechanical ventilation, and supplemental oxygen.
Pancreatic abscess (also referred to as infected or sup
-
purative pseudocyst) is a suppurative process characterized 
by rising fever, leukocytosis, and localized tenderness and 
an epigastric mass usually 6 or more weeks into the course 
of acute pancreatitis. The abscess may be associated with a 
left-sided pleural effusion or an enlarging spleen secondary 
to splenic vein thrombosis. In contrast to infected necrosis, 
the mortality rate is low following drainage.
Pseudocysts, encapsulated fluid collections with high 
amylase content, commonly appear in pancreatitis when 
CT is used to monitor the evolution of an acute attack. 
Pseudocysts that are smaller than 6 cm in diameter often 
resolve spontaneously. They most commonly are within or 
adjacent to the pancreas, but can present almost anywhere 
(eg, mediastinal, retrorectal) by extension along anatomic 
planes. Multiple pseudocysts are seen in 14% of cases. 
Pseudocysts may become secondarily infected, necessitat
-
ing drainage as for an abscess. Pancreatic ascites may pres
-
ent after recovery from acute pancreatitis as a gradual 
increase in abdominal girth and persistent elevation of the 
serum amylase level in the absence of frank abdominal 
pain. Marked elevations in ascitic protein (greater than 3 g/dL) 
and amylase (greater than 1000 units/L [20 mkat/L]) con
-
centrations are typical. The condition results from disrup
-
tion of the pancreatic duct or drainage of a pseudocyst into 
the peritoneal cavity.
Rare complications of acute pancreatitis include 
hemorrhage caused by erosion of a blood vessel to form a 
pseudoaneurysm and colonic necrosis. Portosplenomesen
-
teric venous thrombosis frequently develops in patients 
with necrotizing acute pancreatitis but rarely leads to com
-
plications. Chronic pancreatitis develops in about 10% of 
cases. Permanent diabetes mellitus and exocrine pancreatic 
insufficiency occur uncommonly after a single acute 
episode.
 
»
Treatment
A. Treatment of Acute Disease
1. Mild disease—
In most patients, acute pancreatitis is a 
mild disease (“nonsevere acute pancreatitis”) that subsides 
spontaneously within several days. The pancreas is “rested” 
by a regimen of withholding food and liquids by mouth, 
bed rest, and, in patients with moderately severe pain or 
ileus and abdominal distention or vomiting, nasogastric 
suction. Early fluid resuscitation (one-third of the total 
72-hour fluid volume administered within 24 hours of 
presentation, 250–500 mL/h initially) may reduce the fre
-
quency of systemic inflammatory response syndrome and 
organ failure in this group of patients
. Lactated
 Ringer 
solution may be preferable to normal saline; however, 
overly aggressive fluid resuscitation may lead to morbidity 
as well. Pain is controlled with meperidine, up to 100–150 mg 
intramuscularly every 3–4 hours as necessary. In those

intramuscularly every 3–4 hours as necessary. In those 
with severe liver or kidney dysfunction, the dose may need 
to be reduced. Morphine had been thought to cause 
sphincter of Oddi spasm but is now considered an accept
-
able alternative and, given the potential side effects of 
meperidine, may even be preferable. Oral intake of fluid 
and foods can be resumed when the patient is largely free 
of pain and has bowel sounds (even if the serum amylase is 
still elevated). Clear liquids are given first (this step may be 
skipped in patients with mild acute pancreatitis), followed 
by gradual advancement to a low-fat diet, guided by the 
patient’s tolerance and by the absence of pain. Pain may 
recur on refeeding in 20% of patients. Following recovery 
from acute biliary pancreatitis, laparoscopic cholecystec
-
tomy is generally performed, preferably during the same 
hospital admission, and is associated with a reduced rate of 
recurrent gallstone-related complications compared with 
delayed cholecystectomy. In selected cases endoscopic 
sphincterotomy alone may be done. In patients with recur
-
rent pancreatitis associated with pancreas divisum, inser
-
tion of a stent in the minor papilla (or minor papilla 
sphincterotomy) may reduce the frequency of subsequent 
attacks, although complications of such therapy are 
frequent. In patients with recurrent acute pancreatitis 
attributed to pancreatic sphincter of Oddi dysfunction, 
biliary sphincterotomy alone is as effective as combined 
biliary and pancreatic sphincterotomy in reducing the 
frequency of recurrent acute pancreatitis, but chronic pan
-
creatitis may still develop in treated patients. Hypertri
-
glyceridemia with acute pancreatitis has been treated with 
combinations of insulin, heparin, apheresis, and hemofil
-
tration, but the benefit of these approaches has not been 
proven.
In more severe pancreatitis—par
-
ticularly necrotizing pancreatitis—there may be consider
-
able leakage of fluids, necessitating large amounts of 
intravenous fluids (eg, 500–1000 mL/h for several hours, 
then 250–300 mL/h) to maintain intravascular volume. 
Risk factors for high levels of fluid sequestration include 
younger age, alcohol etiology, higher hematocrit value, 
higher serum glucose, and systemic inflammatory response 
syndrome in the first 48 hours of hospital admission. 
Hemodynamic monitoring in an intensive care unit is 
required, and the importance of aggressive intravenous 
hydration targeted to result in adequate urinary output, 
stabilization of blood pressure and heart rate, restoration of 
central venous pressure, and a modest decrease in hematocrit 
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value cannot be overemphasized. Calcium gluconate must 
be given intravenously if there is evidence of hypocalcemia 
with tetany. Infusions of fresh frozen plasma or serum 
albumin may be necessary in patients with coagulopathy or 
hypoalbuminemia. With colloid solutions, the risk of 
ARDS may be increased. If shock persists after adequate 
volume replacement (including packed red cells), pressors 
may be required. For the patient requiring a large volume 
of parenteral fluids, central venous pressure and blood 
gases should be monitored at regular intervals. Enteral 
nutrition via a nasojejunal or possibly nasogastric feeding 
tube is preferable to parenteral nutrition in patients who 
will otherwise be without oral nutrition for at least 7–10 days 
and reduces the risk of multiorgan failure and mortality 
when started within 48 hours of admission, but may not be 
tolerated in some patients with an ileus and does not 
reduce the rates of infection and death compared with the 
introduction of an oral diet after 72 hours. Parenteral nutri
-
tion (including lipids) should be considered in patients 
who have severe pancreatitis and ileus; glutamine supple
-
mentation appears to reduce the risk of infectious compli
-
cations and mortality. The routine use of antibiotics to 
prevent conversion of sterile necrotizing pancreatitis to 
infected necrosis is of no benefit and generally is not indi
-
cated in patients with less than 30% pancreatic necrosis. 
Imipenem (500 mg intravenously every 6 hours) and pos
-
sibly cefuroxime (1.5 g intravenously three times daily, 
then 250 mg orally twice daily) administered for no more 
than 14 days to patients with sterile necrotizing pancreati
-
tis has been reported in some studies to reduce the risk of 
pancreatic infection and mortality, but in general, prophy
-
lactic antibiotics are not recommended; meropenem and 
the combination of ciprofloxacin and metronidazole do 
not appear to reduce the frequency of infected necrosis, 
multiorgan failure, or mortality. When infected necrotizing 
pancreatitis is confirmed, imipenem or meropenem should 
be continued. Drug-resistant organisms are increasingly 
prevalent. In occasional cases, a fungal infection is found, 
and appropriate antifungal therapy should be prescribed. 
The role of intravenous somatostatin in severe acute 
pancreatitis is uncertain, and octreotide is thought to have 
no benefit. A small study has suggested benefit from pent
-
oxifylline. To date, probiotic agents have not been shown to 
reduce infectious complications of severe pancreatitis and 
may increase mortality. Nonsteroidal anti-inflammatory 
drugs (eg, indomethacin administered rectally) and 
aggressive hydration with lactated Ringer solution have 
been reported to reduce the frequency and severity of 
post-ERCP pancreatitis in persons at high risk, and rec
-
tal indomethacin is widely used, but studies of the benefit 
of indomethacin in unselected patients have yielded con
-
flicting results. Placement of a stent across the pancreatic 
duct or orifice has been shown to reduce the risk of post-
ERCP pancreatitis by 60–80% and is a common practice 
but has not been compared directly with rectal 
indomethacin.
B. Treatment of Complications and Follow-Up
A surgeon should be consulted in all cases of severe acute 
pancreatitis. If the diagnosis is in doubt and investigation 
indicates a strong possibility of a serious surgically correct
-
able lesion (eg, perforated peptic ulcer), exploratory lapa
-
rotomy is indicated. When acute pancreatitis is found 
unexpectedly, it is usually wise to close without intervention. 
If the pancreatitis appears mild and cholelithiasis or microli
-
thiasis is present, cholecystectomy or cholecystostomy may 
be justified. When severe pancreatitis results from choledo
-
cholithiasis and jaundice (serum total bilirubin above 5 mg/dL

-
-
cholithiasis and jaundice (serum total bilirubin above 5 mg/dL 
[85.5 mcmol/L]) or cholangitis is present, ERCP with 
endoscopic sphincterotomy and stone extraction is indi
-
cated. MRCP may be useful in selecting patients for 
therapeutic ERCP . Endoscopic sphincterotomy does not 
appear to improve the outcome of severe pancreatitis in 
the absence of cholangitis or jaundice.
Necrosectomy may improve survival in patients with 
necrotizing pancreatitis and clinical deterioration with 
multiorgan failure or lack of resolution by 4 weeks and is 
often indicated for infected necrosis, although a select 
group of relatively stable patients with infected pancreatic 
necrosis may be managed with antibiotics alone. The goal 
is to debride necrotic pancreas and surrounding tissue and 
establish adequate drainage. Outcomes are best if necrosec
-
tomy is delayed until the necrosis has organized, usually 
about 4 weeks after disease onset. A “step-up” approach in 
which nonsurgical drainage of walled-off pancreatic necro
-
sis under radiologic guidance with subsequent open surgi
-
cal necrosectomy if necessary has been shown to reduce 
mortality and resource utilization in select patients with 
necrotizing pancreatitis and confirmed or suspected sec
-
ondary infection. Endoscopic (transgastric or transduodenal) 
drainage combined with percutaneous drainage and, in 
some cases, laparoscopic guidance are additional options, 
depending on local expertise. Treatment is labor intensive, 
and multiple procedures are often required. Peritoneal 
lavage has not been shown to improve survival in severe 
acute pancreatitis, in part because the risk of late septic 
complications is not reduced.
The development of a pancreatic abscess is an indication 
for prompt percutaneous or surgical drainage. Chronic 
pseudocysts require endoscopic, percutaneous catheter, or 
surgical drainage when infected or associated with persisting 
pain, pancreatitis, or bile duct obstruction. For pancreatic 
infections, imipenem, 500 mg every 8 hours intravenously, is 
a good choice of antibiotic because it achieves bactericidal 
levels in pancreatic tissue for most causative organisms. 
Pancreatic duct leaks and fistulas may require endoscopic or 
surgical therapy.
 
»
Prognosis
Mortality rates for acute pancreatitis have declined from at 
least 10% to around 5% since the 1980s, but the mortality 
rate for severe acute pancreatitis (more than three Ranson 
criteria; see Table 16–9) remains at least 20%, with rates of 
10% and 25% in those with sterile and infected necrosis, 
respectively. Severe acute pancreatitis is predicted by fea
-
tures of the systemic inflammatory response on admission; 
a persistent systemic inflammatory response is associated 
with a mortality rate of 25% and a transient response with 
a mortality rate of 8%. Half of the deaths occur within the 
first 2 weeks, usually from multiorgan failure. Multiorgan 
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failure is associated with a mortality rate of at least 30%, 
and if it persists beyond the first 48 hours, the mortality 
rate is over 50%. Later deaths occur because of complica
-
tions of infected necrosis. The risk of death doubles when 
both organ failure and infected necrosis are present. More
-
over, hospital-acquired infections increase the mortality of 
acute pancreatitis, independent of severity. Readmission to 
the hospital for acute pancreatitis within 30 days may be 
predicted by a scoring system based on five factors during 
the index admission: eating less than a solid diet at dis
-
charge; nausea, vomiting, or diarrhea at discharge; pancre
-
atic necrosis; use of antibiotics at discharge; and pain at 
discharge. Male sex, an alcohol etiology, and severe acute 
disease are risk factors. Recurrences are common (24%) in 
alcoholic pancreatitis, particularly in those who smoke 
(40%), but can be reduced by repeated, regularly sched
-
uled interventions to eliminate alcohol consumption and 
smoking after discharge from the hospital. A severe ini
-
tial attack also increases the risk of recurrence. The risk 
of chronic pancreatitis following an episode of acute 
alcoholic pancreatitis is 8% in 5 years, 13% in 10 years, 
and 16% in 20 years, and the risk of diabetes mellitus is 
increased more than twofold over 5 years. Overall, 
chronic pancreatitis develops in 36% of patients with 
recurrent acute pancreatitis; alcohol use and smoking 
are principal risk factors.
 
»
Nearly all patients with acute pancreatitis should be 
Forsmark CE et al. Acute pancreatitis. N Engl J Med. 2016 Nov 17;
 
375(20):1972–81. [PMID: 27959604]
Inamdar S et al. Rectal indomethacin is protective against post-
ERCP pancreatitis in high-risk patients but not average-risk 
patients: a systematic review and meta-analysis. Gastrointest 
Endosc. 2017 Jan;85(1):67–75. [PMID: 27612923]
Setiawan VW et al. Dietary factors reduce risk of acute pancreati
-
tis in a large multiethnic cohort. Clin Gastroenterol Hepatol. 
2017 Feb;15(2):257–65. [PMID: 27609706]
Vaughn VM et al. Early versus delayed feeding in patients with 
acute pancreatitis: a systematic review. Ann Intern Med. 
2017 Jun 20;166(12):883–92. [PMID: 28505667]
Wu BU et al. Dynamic measurement of disease activity in 
acute pancreatitis: the pancreatitis activity scoring system. 
Am J Gastroenterol. 2017 Jul;112(7):1144–52. [PMID: 
28462914]
CHRONIC PANCREATITIS
 
»
Chronic or intermittent epigastric pain, steatorrhea, 
weight loss, abnormal pancreatic imaging.
 
»
A mnemonic for the predisposing factors of 
chronic pancreatitis is TIGAR-O: toxic-metabolic, 
idiopathic, genetic, autoimmune, recurrent and 
severe acute pancreatitis, or obstructive.
 
»
Chronic pancreatitis occurs most often in patients with 
alcoholism (45–80% of all cases). The risk of chronic pan
-
creatitis increases with the duration and amount of alcohol 
consumed, but pancreatitis develops in only 5–10% of 
heavy drinkers. Tobacco smoking is a risk factor for idio
-
pathic chronic pancreatitis and has been reported to accel
-
erate progression of alcoholic chronic pancreatitis. About 
2% of patients with hyperparathyroidism develop pancre
-
atitis. In tropical Africa and Asia, tropical pancreatitis, 
related in part to malnutrition, is the most common cause 
of chronic pancreatitis. A stricture, stone, or tumor 
obstructing the pancreas can lead to obstructive chronic 
pancreatitis. Autoimmune pancreatitis is associated with 
hypergammaglobulinemia (IgG
4
 in particular), often with 
autoantibodies and other autoimmune diseases, and is 
responsive to corticosteroids. Affected persons are at 
increased risk for various cancers. Type 1 autoimmune 
pancreatitis (or simply “autoimmune pancreatitis”) is a 
multisystem disease characterized by lymphoplasmacytic 
sclerosing pancreatitis on biopsy, associated bile duct stric

-
tures, retroperitoneal fibrosis, renal and salivary gland 
lesions, and a high rate of relapse after treatment. It is the 
pancreatic manifestation of IgG
4
-related disease. Type 2 
(“idiopathic duct-centric chronic pancreatitis”) affects the 
pancreas alone and is characterized by duct-centric pan
-
creatitis on biopsy, lack of systemic IgG
4
 involvement, an 
association with inflammatory bowel disease in 25% of 
cases, often a tumor-like mass, and a low rate of relapse 
after treatment. Between 10% and 30% of cases of chronic 
pancreatitis are idiopathic, with either early onset (median 
age 23) or late onset (median age 62). Genetic factors may 
predispose to chronic pancreatitis in some of these cases 
and include mutations of the cystic fibrosis transmem
-
brane conductance regulator (
CFTR
) gene, the pancreatic 
secretory trypsin inhibitory gene (
PSTI
, serine protease 
inhibitor, 
SPINK1
), and possibly the gene for uridine 
5
′
-diphosphate glucuronosyltransferase. Mutation of the cat
-
ionic trypsinogen gene on chromosome 7 (serine protease 1, 
PRSS1
) is associated with hereditary pancreatitis, transmitted 
as an autosomal dominant trait with variable penetrance. 
A useful mnemonic for the predisposing factors to chronic 
pancreatitis is TIGAR-O: toxic-metabolic, idiopathic, genetic, 
autoimmune, recurrent and severe acute pancreatitis, or 
obstructive.
The pathogenesis of chronic pancreatitis may be 
explained by the SAPE (
s
entinel 
a
cute 
p
ancreatitis 
e
vent) 
hypothesis by which the first (sentinel) acute pancreatitis 
event initiates an inflammatory process that results in 
injury and later fibrosis (“necrosis-fibrosis”). In many 
cases, chronic pancreatitis is a self-perpetuating disease 
characterized by chronic pain or recurrent episodes of 
acute pancreatitis and ultimately by pancreatic exocrine or 
endocrine insufficiency (sooner in alcoholic pancreatitis 
than in other types). After many years, chronic pain may 
resolve spontaneously or as a result of surgery tailored to 
the cause of pain. Over 80% of adults develop diabetes 
mellitus within 25 years after the clinical onset of chronic 
pancreatitis.
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Persistent or recurrent episodes of epigastric and left upper 
quadrant pain are typical. The pain results in part from 
impaired inhibitory pain modulation by the central nervous 
system. Anorexia, nausea, vomiting, constipation, flatulence, 
and weight loss are common. During attacks, tenderness over 
the pancreas, mild muscle guarding, and ileus may be noted. 
Attacks may last only a few hours or as long as 2 weeks; pain 
may eventually be almost continuous. Steatorrhea (as indi
-
cated by bulky, foul, fatty stools) may occur late in the course.
Serum amylase and lipase may be elevated during acute 
attacks; however, normal values do not exclude the diagno
-
sis. Serum alkaline phosphatase and bilirubin may be ele
-
vated owing to compression of the bile duct. Glycosuria may 
be present. Excess fecal fat may be demonstrated on chemi
-
cal analysis of the stool. Pancreatic insufficiency generally is 
confirmed by response to therapy with pancreatic enzyme 
supplements; the secretin stimulation test can be used if 
available (and has a high negative predictive factor for ruling 
out early acute chronic pancreatitis), as can detection of 
decreased fecal chymotrypsin or elastase levels, although the 
latter tests lack sensitivity and specificity. Vitamin B
12
 malab
-
sorption is detectable in about 40% of patients, but clinical 
deficiency of vitamin B
12
 and fat-soluble vitamins is rare. 
Accurate diagnostic tests are available for the major tryp
-
sinogen gene mutations, but because of uncertainty about 
the mechanisms linking heterozygous 
CFTR
 and 
PSTI
 muta
-
tions with pancreatitis, genetic testing for mutations in these 
two genes is not currently recommended. Elevated IgG
4
 
levels, ANA, and antibodies to lactoferrin and carbonic 
anhydrase II are often found in patients with autoimmune 
pancreatitis (especially type 1). Pancreatic biopsy, if neces
-
sary, shows a lymphoplasmacytic inflammatory infiltrate 
with characteristic IgG
4
 immunostaining, which is also 
found in biopsy specimens of the major papilla, bile duct, 
and salivary glands, in type 1 autoimmune pancreatitis.
C. Imaging
Plain films show calcifications due to pancreaticolithiasis in 
30% of affected patients. CT may show calcifications not 
seen on plain films as well as ductal dilatation and heteroge
-
neity or atrophy of the gland. Occasionally, the findings raise 
suspicion of pancreatic cancer (“tumefactive chronic pancre
-
atitis”). ERCP is the most sensitive imaging study for chronic 
pancreatitis and may show dilated ducts, intraductal stones, 
strictures, or pseudocyst but is infrequently used for diagno
-
sis alone; moreover, the results may be normal in patients 
with so-called minimal change pancreatitis. MRCP (includ
-
ing secretin-enhanced MRCP) and EUS (with pancreatic 
tissue sampling) are less invasive alternatives to ERCP . Endo
-
scopic ultrasonographic (“Rosemont”) criteria for the diag
-
nosis of chronic pancreatitis include hyperechoic foci with 
shadowing indicative of calculi in the main pancreatic duct 
and lobularity with honeycombing of the pancreatic paren
-
chyma. Characteristic imaging features of autoimmune 
pancreatitis include diffuse enlargement of the pancreas, a 
peripheral rim of hypoattenuation, and irregular narrowing 
of the main pancreatic duct. In the United States, the diag
-
nosis of autoimmune pancreatitis is based on the HISORt 
criteria: 
h
istology, 
i
maging, 
s
erology, other 
o
rgan involvement, 
and 
r
esponse to corticosteroid 
t
herapy.
 
»
Opioid addiction is common. Other frequent complica
-
tions include often brittle diabetes mellitus, pancreatic 
pseudocyst or abscess, cholestatic liver enzymes with or 
without jaundice, bile duct stricture, steatorrhea, malnutri
-
tion, osteoporosis, and peptic ulcer. Pancreatic cancer

-
tion, osteoporosis, and peptic ulcer. Pancreatic cancer 
develops in 4% of patients after 20 years; the risk may relate 
to tobacco and alcohol use. In patients with hereditary 
pancreatitis, the risk of pancreatic cancer rises after age 
 
50 years and reaches 19% by age 70 years (see Chapter 39).
 
»
Treatment
A. Medical Measures
A low-fat diet should be prescribed. Alcohol is forbidden 
because it frequently precipitates attacks. Opioids should be 
avoided if possible. Preferred agents for pain are acetamino
-
phen, nonsteroidal anti-inflammatory drugs, and tramadol, 
along with pain-modifying agents such as tricyclic antidepres
-
sants, selective serotonin reuptake inhibitors, and gabapentin 
or pregabalin. Steatorrhea is treated with pancreatic supple
-
ments that are selected on the basis of their high lipase activity 
(Table 16–11). A total dose of at least 40,000 units of lipase in 
capsules is given with each meal. Doses of 90,000 units or more 
of lipase per meal may be required in some cases. The tablets 
should be taken at the start of, during, and at the end of a meal. 
Concurrent administration of an H
2
-receptor antagonist (eg, 
ranitidine, 150 mg orally twice daily), a proton pump inhibitor 
(eg, omeprazole, 20–60 mg orally daily), or sodium bicarbon
-
ate, 650 mg orally before and after meals, decreases the inacti
-
vation of lipase by acid and may thereby further decrease 
steatorrhea. In selected cases of alcoholic pancreatitis and in 
cystic fibrosis, enteric-coated microencapsulated preparations 
may offer an advantage; however, in patients with cystic fibro
-
sis, high-dose pancreatic enzyme therapy has been associated 
with strictures of the ascending colon. Pain secondary to idio
-
pathic chronic pancreatitis may be alleviated in some cases by 
the use of pancreatic enzymes (not enteric-coated) or octreo
-
tide, 200 mcg subcutaneously three times daily. Associated 
diabetes mellitus should be treated (see Chapter 27). Auto
-
immune pancreatitis is treated with prednisone 40 mg/day 
orally for 1–2 months, followed by a taper of 5 mg every 
2–4 weeks. Nonresponse or relapse occurs in 45% of type 1 
cases (particularly in those with concomitant IgG
4
-associated 
cholangitis); rituximab is an effective induction and main
-
tenance agent, and azathioprine or long-term low-dose 
corticosteroid use appears to reduce the risk of relapse.
B. Endoscopic and Surgical Treatment
Endoscopic therapy or surgery may be indicated in chronic 
pancreatitis to treat underlying biliary tract disease, ensure 
free flow of bile into the duodenum, drain persistent pseu
-
docysts, treat other complications, eliminate obstruction of 
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Table 16–11.
 
FDA-approved pancreatic enzyme 
 
(pancrelipase) preparations.
Product
e
nzyme Content/Unit Dose, USP Units
Lipase
a
m
ylase
Protease
Immediate-
r
elease Capsules
Nonenteric-coated
Viokace 10,440
10,440
39,150
39,150
Viokace 20,880
20,880
78,300
78,300
Delayed-
r
Enteric-coated minimicrospheres
Creon 3000
3000
15,000
9500
Creon 6000
6000
30,000
19,000
Creon 12,000
12,000
60,000
38,000
Creon 24,000
24,000
120,000
76,000
Creon 36,000
36,000
180,000
114,000
Enteric-coated minitablets
Ultresa 13,800
13,800
27,600
27,600
Ultresa 20,700
20,700
46,000
41,400
Ultresa 23,000
23,000
46,000
41,400
Enteric-coated beads
Zenpep 3000
3000
16,000
10,000
Zenpep 5000
5000
27,000
17,000
Zenpep 10,000
10,000
55,000
34,000
Zenpep 15,000
15,000
82,000
51,000
Zenpep 20,000
20,000
109,000
68,000
Zenpep 25,000
25,000
136,000
85,000
Enteric-coated microtablets
Pancreaze 4200
4200
17,500
10,000
Pancreaze 10,500
10,500
43,750
25,000
Pancreaze 16,800
16,800
70,000
40,000
Pancreaze 21,000
21,000
61,000
37,000
Bicarbonate-buffered enteric-coated microspheres
Peptyze 8000
8000
30,250
28,750
Peptyze 16,000
16,000
60,500
57,500
FDA, US Food and Drug Administration; USP , US Pharmacopeia.
the pancreatic duct, attempt to relieve pain, or exclude 
pancreatic cancer. Liver fibrosis may regress after biliary 
drainage. Distal bile duct obstruction may be relieved by 
endoscopic placement of multiple bile duct stents. When 
obstruction of the duodenal end of the pancreatic duct can 
be demonstrated by ERCP , dilation of or placement of a 
stent in the duct and pancreatic duct stone lithotripsy or 
surgical resection of the tail of the pancreas with implanta
-
tion of the distal end of the duct by pancreaticojejunos
-
tomy may be performed. Endoscopic therapy is successful 
in about 50% of cases. In patients who do not respond to 
endoscopic therapy, surgery is successful in about 50%. 
When the pancreatic duct is diffusely dilated, anastomosis 
between the duct after it is split longitudinally and a 
defunctionalized limb of jejunum (modified Puestow pro
-
cedure), in some cases combined with resection of the head 
of the pancreas (Beger or Frey procedure), is associated 
with relief of pain in 80% of cases. In advanced cases, sub
-
total or total pancreatectomy may be considered as a last 
resort, but has variable efficacy and causes pancreatic 
insufficiency and diabetes mellitus. Perioperative adminis
-
tration of somatostatin or octreotide may reduce the risk of 
postoperative pancreatic fistulas. Endoscopic or surgical 
(including laparoscopic) drainage is indicated for symptom
-
atic pseudocysts and, in many cases, those over 6 cm in diam
-
eter. EUS may facilitate selection of an optimal site for 
endoscopic drainage. Pancreatic ascites or pancreaticopleural 
fistulas due to a disrupted pancreatic duct can be managed 
by endoscopic placement of a stent across the disrupted 
duct. Pancreatic sphincterotomy or fragmentation of stones 
in the pancreatic duct by lithotripsy and endoscopic 
removal of stones from the duct may relieve pain in selected 
patients. For patients with chronic pain and nondilated 
ducts, a percutaneous celiac plexus nerve block may be con
-
sidered under either CT or EUS guidance, with pain relief 
(albeit often short-lived) in approximately 50% of patients. A 
single session of radiation therapy to the pancreas has been 
reported to relieve otherwise refractory pain.
 
»
Prognosis
Chronic pancreatitis often leads to disability and reduced 
life expectancy; pancreatic cancer is the main cause of 
death. The prognosis is best in patients with recurrent 
acute pancreatitis caused by a remediable condition, such 
as cholelithiasis, choledocholithiasis, stenosis of the sphinc
-
ter of Oddi, or hyperparathyroidism, and in those with 
autoimmune pancreatitis. Medical management of hyper
-
lipidemia, if present, may also prevent recurrent attacks of

-
-
lipidemia, if present, may also prevent recurrent attacks of 
pancreatitis. A chronic pancreatitis diagnosis score based 
on pain, hemoglobin A
1c
 level, C-reactive protein level, 
body mass index, and platelet count has been shown to 
correlate with hospital admissions and number of hospital 
days. In alcoholic pancreatitis, pain relief is most likely 
when a dilated pancreatic duct can be decompressed. In 
patients with disease not amenable to decompressive sur
-
gery, addiction to opioids is a frequent outcome of treat
-
ment. A poorer quality of life is associated with constant 
pain rather than intermittent pain, pain-related disability 
or unemployment, current smoking, and comorbidities.
 
»
All patients with chronic pancreatitis should be referred for 
diagnostic and therapeutic procedures.
 
»
•	
•	
New jaundice.
•	
New fever.
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Beyer G et al. Development and validation of a chronic pancreatitis 
prognosis score in 2 independent cohorts. Gastroenterology. 
2017 Dec;153(6):1544–54. [PMID: 28918191]
de la Iglesia-García D et al. Efficacy of pancreatic enzyme 
replacement therapy in chronic pancreatitis: systematic review 
and meta-analysis. Gut. 2017 Aug;66(8):1354–5. [PMID: 
27941156]
Kirkegård J et al. Chronic pancreatitis and pancreatic cancer risk: 
a systematic review and meta-analysis. Am J Gastroenterol. 
2017 Sep;112(9):1366–72. [PMID: 28762376]
Machicado JD et al. Quality of life in chronic pancreatitis is deter
-
mined by constant pain, disability/unemployment, current 
smoking, and associated co-morbidities. Am J Gastroenterol. 
2017 Apr;112(4):633–42. [PMID: 28244497]
Majumder S et al. Chronic pancreatitis. Lancet. 2016 May 7;
 
387(10031):1957–66. [PMID: 26948434]
Masamune A et al; Research Committee of Intractable Pancreas 
Diseases in Japan. Randomised controlled trial of long-term 
maintenance corticosteroid therapy in patients with autoimmune 
pancreatitis. Gut. 2017 Mar;66(3):487–94. [PMID: 27543430]
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º
BENIGN BREAST DISORDERS
FIBROCYSTIC CONDITION
 
»
Painful breast masses; often multiple and bilateral.
 
»
Rapid fluctuation in mass size is common.
 
»
Pain often worsens during premenstrual phase of 
cycle.
 
»
Most common age is 30–50. Rare in postmeno
-
pausal women not receiving hormonal replacement.
 
»
Fibrocystic condition is the most frequent lesion of the 
breast. Although commonly referred to as “fibrocystic 
disease, ” it does not, in fact, represent a pathologic or ana
-
tomic disorder. It is common in women 30–50 years of age 
but rare in postmenopausal women who are not taking 
hormonal replacement. Estrogen is considered a causative 
factor. There may be an increased risk in women who 
drink alcohol, especially women between 18 and 22 years 
of age.
The microscopic findings of fibrocystic condition 
include cysts (gross and microscopic), papillomatosis, 
adenosis, fibrosis, and ductal epithelial hyperplasia. 
Although fibrocystic condition has generally been consid
-
ered to increase the risk of subsequent breast cancer, only 
the variants with a component of epithelial proliferation 
(especially with atypia), papillomatosis, or increased breast 
density on mammogram represent true risk factors.
 
»
Fibrocystic condition may produce an asymptomatic mass 
in the breast that is discovered by accident, but pain or 
tenderness often calls attention to it. Discomfort often 17
Armando E. Giuliano, MD, FACS, FRCSEd, 
 
occurs or worsens during the premenstrual phase of the 
cycle, at which time the cysts tend to enlarge. Fluctuations 
in size and rapid appearance or disappearance of a breast 
mass are common with this condition as are multiple or 
bilateral masses and serous nipple discharge. Patients will 
give a history of a transient lump in the breast or cyclic 
breast pain.
Mammography and ultrasonography should be used to 
evaluate a mass in a patient with fibrocystic condition. 
Ultrasonography alone may be used in women under 
30 years of age. Because a mass due to fibrocystic condition 
is difficult to distinguish from carcinoma on the basis of 
clinical findings, suspicious lesions should be biopsied. 
Core needle biopsy, rather than fine-needle aspiration 
(FNA), is the preferable technique. Excisional biopsy is 
rarely necessary but should be done for lesions with atypia 
or where imaging and biopsy results are discordant. Surgery 
should be conservative, since the primary objective is to 
exclude cancer. Occasionally, FNA cytology will suffice. 
Simple mastectomy or extensive removal of breast tissue is 
rarely, if ever, indicated for fibrocystic condition.
 
»
Pain, fluctuation in size, and multiplicity of lesions are the 
features most helpful in differentiating fibrocystic condi
-
tion from carcinoma. If a dominant mass is present, the 
diagnosis of cancer should be assumed until disproven by 
biopsy. Mammography may be helpful, but the breast tissue 
in young women is usually too radiodense to permit a 
worthwhile study. Sonography is useful in differentiating a 
cystic mass from a solid mass, especially in women with 
dense breasts. Final diagnosis, however, depends on analy
-
sis of a biopsy specimen.
 
»
Treatment
When the diagnosis of fibrocystic condition has been 
established by previous biopsy or is likely because the his
-
tory is classic, aspiration of a discrete mass suggestive of a 
cyst is indicated to alleviate pain and, more importantly, to 
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confirm the cystic nature of the mass. The patient is reex
-
amined at intervals thereafter. If no fluid is obtained by 
aspiration, if fluid is bloody, if a mass persists after aspira
-
tion, or if at any time during follow-up a persistent or 
recurrent mass is noted, biopsy should be performed.
Breast pain associated with generalized fibrocystic con
-
dition is best treated by avoiding trauma and by wearing a 
good supportive brassiere during the night and day. 
Hormone therapy is not advisable because it does not cure 
the condition and has undesirable side effects. Danazol 
(100–200 mg orally twice daily), a synthetic androgen, is 
the only treatment approved by the US Food and Drug 
Administration (FDA) for patients with severe pain. This 
treatment suppresses pituitary gonadotropins, but andro
-
genic effects (acne, edema, hirsutism) usually make this 
treatment intolerable; in practice, it is rarely used. Simi
-
larly, tamoxifen reduces some symptoms of fibrocystic 
condition, but because of its side effects, it is not useful for 
young women unless it is given to reduce the risk of cancer. 
Postmenopausal women receiving hormone replacement 
therapy may stop or change doses of hormones to reduce 
pain. Oil of evening primrose, a natural form of gamolenic 
acid, has been shown to decrease pain in 44–58% of users. 
The dosage of gamolenic acid is six capsules of 500 mg 
orally twice daily. Studies have also demonstrated a low-fat 
diet or decreasing dietary fat intake may reduce the painful 
symptoms associated with fibrocystic condition. Topical 
treatments such as nonsteroidal anti-inflammatory drugs 
are rarely of value.
The role of caffeine consumption in the development 
and treatment of fibrocystic condition is controversial. 
Some studies suggest that eliminating caffeine from the 
diet is associated with improvement while other studies 
refute the benefit entirely. Many patients are aware of these 
studies and report relief of symptoms after giving up coffee, 
tea, and chocolate. Similarly, many women find vitamin E 
(400 international units daily) helpful; however, these 
observations remain anecdotal.
 
»
Prognosis
Exacerbations of pain, tenderness, and cyst formation may 
occur at any time until menopause, when symptoms usu
-
ally subside, except in patients receiving hormonal replace
-
ment. The patient should be advised to examine her own 
breasts regularly just after menstruation and to inform her 
clinician if a mass appears. The risk of breast cancer devel
-
oping in women with fibrocystic condition with a prolif
-
erative or atypical epithelial hyperplasia or papillomatosis 
is higher than that of the general population. These women 
should be monitored carefully with physical examinations 
and imaging studies.
Chetlen AL et al. Mastalgia: imaging work-up appropriateness. 
Acad Radiol. 2017 Mar;24:345–9. [PMID: 27916596]
Genç A et al. The effects of exercise on mastalgia. Phys 
Sportsmed. 2017 Feb;45(1):17–21. [PMID: 27776458]
Groen JW et al. Cyclic and non-cyclic breast pain: a systematic 
review on pain reduction, side effects, and quality of life 
for various treatments. Eur J Obstet Gynecol Reprod Biol. 
 
2017 Dec;219:74–93. [PMID: 29059585]
Neal L et al. Diagnosis and management of benign, atypical, and 
indeterminate breast lesions detected on core needle biopsy. 
Mayo Clin Proc. 2014 Apr;89(4):536–47. [PMID: 24684875]
FIBROADENOMA OF THE BREAST
This common benign neoplasm occurs most frequently in 
young women, usually within 20 years after puberty. It is 
somewhat more frequent and tends to occur at an earlier 
age in black women. Multiple tumors are found in 10–15% 
of patients.
The typical 
fibroadenoma
 is a round or ovoid, rubbery, 
discrete, relatively movable, nontender mass 1–5 cm in 
diameter. It is usually discovered accidentally. Clinical 
diagnosis in young patients is generally not difficult. In

diagnosis in young patients is generally not difficult. In 
women over 30 years, fibrocystic condition of the breast 
and carcinoma of the breast must be considered. Cysts can 
be identified by aspiration or ultrasonography. Fibroadenoma 
does not normally occur after menopause but may 
 
occasionally develop after administration of hormones.
No treatment is usually necessary if the diagnosis can 
be made by core needle biopsy. Excision with pathologic 
examination of the specimen is performed if the diagnosis 
is uncertain or the lesion grows significantly. Cryoablation, 
or freezing of the fibroadenoma, appears to be a safe pro
-
cedure if the lesion is a biopsy-proven fibroadenoma prior 
to ablation. Cryoablation is not appropriate for all fibroad
-
enomas because some are too large to freeze or the diagnosis 
may not be certain. There is no obvious advantage to cryo
-
ablation of a histologically proven fibroadenoma except 
that some patients may feel relief that a mass is gone. 
However, at times a mass of scar or fat necrosis replaces the 
mass of the fibroadenoma. Reassurance seems preferable. It 
is usually not possible to distinguish a large fibroadenoma 
from a phyllodes tumor on the basis of needle biopsy 
results or imaging alone and histology is usually required. 
Presumed fibroadenomas larger than 3–4 cm should be 
excised to rule out phyllodes tumors.
Phyllodes tumor
 is a fibroadenoma-like tumor with 
cellular stroma that grows rapidly. It may reach a large size 
and, if inadequately excised, will recur locally. The lesion 
can be benign or malignant. If benign, phyllodes tumor is 
treated by local excision. The treatment of malignant 
phyllodes tumor is more controversial, but complete 
removal of the tumor with a margin of normal tissue avoids 
recurrence. Because these tumors may be large, total mas
-
tectomy is sometimes necessary. Lymph node dissection is 
not performed, since the sarcomatous portion of the tumor 
metastasizes to the lungs and not the lymph nodes.
Co M et al. Mammary phyllodes tumour: a 15-year multicentre 
clinical review. J Clin Pathol. 2017 Nov 16. [Epub ahead of 
print] [PMID: 29146885]
Hubbard JL et al. Criteria for excision of suspected fibroadenomas 
of the breast. Am J Surg. 2015 Feb;209(2):297–301. [PMID: 
25682095]
Koh VCY et al. Size and heterologous elements predict metastases 
in malignant phyllodes tumours of the breast. Virchows Arch. 
2017 Nov 10. [Epub ahead of print] [PMID: 29127495]
Krings G et al. Fibroepithelial lesions; the WHO spectrum. Semin 
Diagn Pathol. 2017 Sep;34(5):438–52. [PMID: 28688536]
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Table 17–1.
 
Characteristics of nipple discharge in the 
nonpregnant, nonlactating woman.
Finding
Significance
Serous
Most likely benign FCC, ie, duct ectasia
Bloody
More likely neoplastic–papilloma, 
carcinoma
Associated mass
More likely neoplastic
Unilateral
Either neoplastic or non-neoplastic
Bilateral
Most likely non-neoplastic
Single duct
Multiple ducts
More likely FCC
Milky
Endocrine disorders, medications
Spontaneous
Produced by pressure 
at single site
Related to menses
Premenopausal
Taking hormones
FCC, fibrocystic condition.
NIPPLE DISCHARGE
In order of decreasing frequency, the following are the 
most common causes of nipple discharge in the nonlactat
-
ing breast: duct ectasia, intraductal papilloma, and carci
-
noma. The important characteristics of the discharge and 
some other factors to be evaluated by history and physical 
examination are listed in Table 17–1.
Spontaneous, unilateral, serous or serosanguineous 
discharge from a single duct is usually caused by an 
ectatic duct or an intraductal papilloma or, rarely, by an 
intraductal cancer. A mass may not be palpable. The 
involved duct may be identified by pressure at different 
sites around the nipple at the margin of the areola. Bloody 
discharge is suggestive of cancer but is more often caused 
by a benign papilloma in the duct. Cytologic examination 
may identify malignant cells, but negative findings do not 
rule out cancer, which is more likely in women over age 
50 years. In any case, the involved bloody duct—and a 
mass if present—should be excised. A ductogram (a mam
-
mogram of a duct after radiopaque dye has been injected), 
like cytology, is of limited value since excision of the 
suspicious ductal system is indicated regardless of find
-
ings. Ductoscopy, evaluation of the ductal system with a 
small scope inserted through the nipple, has been attempted 
but is not effective management.
In premenopausal women, spontaneous multiple duct 
discharge, unilateral or bilateral, most noticeable just 
before menstruation, is often due to fibrocystic condition. 
Discharge may be green or brownish. Papillomatosis and 
ductal ectasia are usually detected only by biopsy. If a mass 
is present, it should be removed.
A milky discharge from multiple ducts in the nonlactat
-
ing breast may occur from hyperprolactinemia. Serum 
prolactin levels should be obtained to search for a pituitary 
tumor. Thyroid-stimulating hormone (TSH) helps exclude 
causative hypothyroidism. Numerous antipsychotic drugs 
and other drugs may also cause a milky discharge that 
ceases on discontinuance of the medication.
Oral contraceptive agents or estrogen replacement 
therapy may cause clear, serous, or milky discharge from a 
single duct, but multiple duct discharge is more common. 
In the premenopausal woman, the discharge is more evi
-
dent just before menstruation and disappears on stopping 
the medication. If it does not stop, is from a single duct, 
and is copious, exploration should be performed since this 
may be a sign of cancer.
A purulent discharge may originate in a subareolar 
abscess and require removal of the abscess and the related 
lactiferous sinus.
When localization is not possible, no mass is palpable, 
and the discharge is nonbloody, the patient should be 
reexamined every 3 or 4 months for a year, and a mam
-
mogram and an ultrasound should be performed. Although 
most discharge is from a benign process, patients may find 
it annoying or disconcerting. To eliminate the discharge, 
proximal duct excision can be performed both for treatment 
and diagnosis.
Castellano I et al. The impact of malignant nipple discharge 
cytology (NDc) in surgical management of breast cancer

cytology (NDc) in surgical management of breast cancer 
patients. PLoS One. 2017 Aug 14;12(8):e0182073. [PMID: 
28806416]
Morgan HS. Primary care management of the female patient 
presenting with nipple discharge. Nurse Pract. 2015 Mar 12;
 
40(3):1–6. [PMID: 25679138]
Patel BK et al. Management of nipple discharge and the associ
-
ated imaging findings. Am J Med. 2015 Apr;128(4):353–60. 
[PMID: 25447625]
FAT NECROSIS
Fat necrosis is a rare lesion of the breast but is of clinical 
importance because it produces a mass (often accompanied 
by skin or nipple retraction) that is usually indistinguishable 
from carcinoma even with imaging studies. Fat necrosis is 
commonly seen after fat injections to augment breast size or 
fill defects after breast surgery. Trauma is presumed to be 
the cause, though only about 50% of patients give a history 
of injury. Ecchymosis is occasionally present. If untreated, 
the mass gradually disappears. The safest course is to obtain 
a biopsy. Core needle biopsy is often adequate, but fre
-
quently the entire mass must be excised to exclude carci
-
noma. Fat necrosis is common after segmental resection, 
radiation therapy, or flap reconstruction after mastectomy.
Kerridge WD et al. Fat necrosis of the breast: a pictorial review 
of the mammographic, ultrasound, CT, and MRI findings 
with histopathologic correlation. Radiol Res Pract. 2015;
 
2015:613139. [PMID: 25861475]
Mirzabeigi MN et al. Treating breast conservation therapy 
defects with brava and fat grafting: technique, outcomes, and 
safety profile. Plast Reconstr Surg. 2017 Sep;140(3):372e–81e. 
[PMID: 28841599]
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BREAST ABSCESS
During nursing, an area of redness, tenderness, and indu
-
ration may develop in the breast. The organism most com
-
monly found in these abscesses is 
 
(see Puerperal Mastitis, Chapter 19).
Infection in the nonlactating breast is rare. A subareolar 
abscess may develop in young or middle-aged women who 
are not lactating. These infections tend to recur after inci
-
sion and drainage unless the area is explored during a 
quiescent interval, with excision of the involved lactiferous 
duct or ducts at the base of the nipple. In the nonlactating 
breast, inflammatory carcinoma must always be consid
-
ered. Thus, incision and biopsy of any indurated tissue with 
a small piece of erythematous skin is indicated when sus
-
pected abscess or cellulitis in the nonlactating breast does 
not resolve promptly with antibiotics. Often needle or 
catheter drainage is adequate to treat an abscess, but surgi
-
cal incision and drainage may be necessary.
Barron AU et al. Do acute-care surgeons follow best practices for 
breast abscess management? A single-institution analysis of 
325 consecutive cases. J Surg Res. 2017 Aug;216:169–71. 
[PMID: 28807202]
Saboo A et al. Trends in non-lactation breast abscesses in a 
tertiary hospital setting. ANZ J Surg. 2017 Oct 18. [Epub 
ahead of print] [PMID: 29045009]
Taffurelli M et al. Recurrent periductal mastitis: surgical treatment. 
Surgery. 2016 Dec;160(6):1689–92. [PMID: 27616631]
DISORDERS OF THE AUGMENTED BREAST
At least 4 million American women have had breast 
implants. Breast augmentation is performed by placing 
implants under the pectoralis muscle or, less desirably, in 
the subcutaneous tissue of the breast. Most implants are 
made of an outer silicone shell filled with a silicone gel, 
saline, or some combination of the two. Capsule contrac
-
tion or scarring around the implant develops in about 
15–25% of patients, leading to a firmness and distortion of 
the breast that can be painful. Some require removal of the 
implant and surrounding capsule.
Implant rupture may occur in as many as 5–10% of 
women, and bleeding of gel through the capsule is noted 
even more commonly. Although silicone gel may be an 
immunologic stimulant, there is no increase in autoimmune 
disorders in patients with such implants. The FDA has 
advised symptomatic women with ruptured silicone 
implants to discuss possible surgical removal with their 
clinicians. However, women who are asymptomatic and 
have no evidence of rupture of a silicone gel prosthesis 
should probably not undergo removal of the implant. 
Women with symptoms of autoimmune illnesses often 
undergo removal, but no benefit has been shown.
Studies have failed to show any association between 
implants and an increased incidence of breast cancer. How
-
ever, breast cancer may develop in a patient with an aug
-
mentation prosthesis, as it does in women without them. 
Detection in patients with implants may be more difficult 
because mammography is less able to detect early lesions. 
Mammography is better if the implant is subpectoral rather 
than subcutaneous. Prostheses should be placed retro
-
pectorally after mastectomy to facilitate detection of a 
local recurrence of cancer, which is usually cutaneous or 
subcutaneous and is easily detected by palpation. Rarely 
lymphoma of the breast with silicone implants has been 
reported.
If a cancer develops in a patient with implants, it should 
be treated in the same manner as in women without 
implants. Such women should be offered the option of 
mastectomy or breast-conserving therapy, which may 
require removal or replacement of the implant. Radiother
-
apy of the augmented breast often results in marked capsu
-
lar contracture. Adjuvant treatments should be given for 
the same indications as for women who have no implants.
Balk EM et al. Long-term health outcomes in women with silicone

-
Balk EM et al. Long-term health outcomes in women with silicone 
gel breast implants: a systematic review. Ann Intern Med. 
2016 Feb 2;164(3):164–75. [PMID: 26550776]
Clemens MW et al. NCCN consensus guidelines for the diagno
-
sis and management of breast implant-associated anaplastic 
large cell lymphoma. Aesthet Surg J. 2017 Mar 1;37(3):285–9. 
[PMID: 28184418]
Doren EL et al. U.S. epidemiology of breast implant-associated 
anaplastic large cell lymphoma. Plast Reconstr Surg. 
2017 May;139(5):1042–50. [PMID: 28157769]
Elston JB et al. Complications and recurrence in implant-sparing 
oncologic breast surgery. Ann Plast Surg. 2017 Jun;
 
78(6S Suppl 5):S269–74. [PMID: 28328633]
 
º
CARCINOMA OF T
h
E FEMALE BREAST
 
»
Risk factors: Age, delayed childbearing, family his
-
tory of breast cancer or genetic mutations (
BRCA1
, 
BRCA2
), and personal history of breast cancer or 
some types of proliferative conditions.
 
»
Early findings:
 Single, nontender, firm to hard 
mass with ill-defined margins; mammographic 
abnormalities and no palpable mass.
 
»
Later findings:
 Skin or nipple retraction; axillary 
lymphadenopathy; breast enlargement, erythema, 
edema, pain; fixation of mass to skin or chest wall.
 
»
Incidence & Risk Factors
Breast cancer will develop in one of eight American women. 
Next to skin cancer, breast cancer is the most common cancer 
in women; it is second only to lung cancer as a cause of 
death. In 2017, there were approximately 255,180 new cases 
and 41,070 deaths from breast cancer in the United States. 
Worldwide, breast cancer is diagnosed in approximately 
1.7 million women, and about 521,900 die of breast cancer 
each year, with the highest rates of diagnosis in Western 
Europe and North America and lowest rates in Africa and 
Asia. The highest rates of death are in black women in the 
United States and the lowest rates are in Korean women.
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Table 17–2.
 
Factors associated with increased risk of 
breast cancer.
Race
White
Age
Older
Family history
Breast cancer in parent, sibling, or child 
(especially bilateral or premenopausal)
Genetics
BRCA1
, 
BRCA2
, or other unknown 
mutations
Previous medical 
history
Endometrial cancer
Proliferative forms of fibrocystic disease
Cancer in other breast
Menstrual history
Early menarche (under age 12)
Late menopause (after age 50)
Reproductive history
Nulliparous or late first pregnancy
The most significant risk factor for the development of 
breast cancer is age. A woman’s risk of breast cancer rises 
rapidly until her early 60s, peaks in her 70s, and then 
declines. A significant family history of breast or ovarian 
cancer may also indicate a high risk of developing breast 
cancer. Germline mutations in the 
BRCA
 family of tumor 
suppressor genes accounts for approximately 5–10% of 
breast cancer diagnoses and tend to cluster in certain ethnic 
groups, including women of Ashkenazi Jewish descent. 
Women with a mutation in the 
BRCA1
 gene, located on 
chromosome 17, have an estimated 85% chance of develop
-
ing breast cancer in their lifetime. Other genes associated 
with an increased risk of breast and other cancers include 
BRCA2
 (associated with a gene on chromosome 13); 
ataxia-telangiectasia mutation; and mutation of the tumor 
suppressor gene 
p53
. Other mutations have been identified 
that increase the risk of breast cancer but have significantly 
lower risk than 
BRCA
 mutations. If a woman has a compel
-
ling family history (such as breast cancer diagnosed in two 
first-degree relatives, especially if diagnosed younger than 
age 50; ovarian cancer; male breast cancer; or a first-degree 
relative with bilateral breast cancer), genetic testing may be 
appropriate. In general, it is best for a woman who has a 
strong family history to meet with a genetics counselor to 
undergo a risk assessment and decide whether genetic test
-
ing is indicated.
Even when genetic testing fails to reveal a predisposing 
genetic mutation, women with a strong family history of 
breast cancer are at higher risk for development of breast 
cancer. Compared with a woman with no affected family 
members, a woman who has one first-degree relative with 
breast cancer has double the risk of developing breast 
cancer and a woman with two first-degree relatives with 
breast cancer has triple the risk of developing breast cancer. 
The risk is further increased for a woman whose affected 
family member was premenopausal at the time of diagnosis 
or had bilateral breast cancer. Lifestyle and reproductive 
factors also contribute to risk of breast cancer. Nulliparous 
women and women whose first full-term pregnancy 
occurred after the age of 30 have an elevated risk. Early 
menarche (under age 12) and late natural menopause (after 
age 55) are associated with an increase in risk, especially for 
hormone receptor–positive breast cancer. Combined oral 
contraceptive pills also appear to increase the risk of breast 
cancer, with longer use associated with higher risk. Several 
studies show that concomitant administration of progester
-
one and estrogen to postmenopausal women may increase 
the incidence of breast cancer, compared with the use of 
estrogen alone or with no hormone replacement treatment. 
Alcohol consumption, high dietary intake of fat, and lack of 
exercise may also increase the risk of breast cancer. Fibro
-
cystic breast condition, when accompanied by proliferative 
changes, papillomatosis, or atypical epithelial hyperplasia, 
and increased breast density on mammogram are also asso
-
ciated with an increased incidence. A woman who had 
cancer in one breast is at increased risk for cancer develop
-
ing in the other breast. In these women, a contralateral 
cancer develops at rate of 1% or 2% per year. Women with 
cancer of the uterine corpus have a risk of breast cancer

-
cancer of the uterine corpus have a risk of breast cancer 
significantly higher than that of the general population, and 
women with breast cancer have a comparably increased risk 
of endometrial cancer. Socioeconomic and racial factors 
have also been associated with breast cancer risk. Breast 
cancer tends to be diagnosed more frequently in women of 
higher socioeconomic status.
Women at greater than average risk for developing 
breast cancer (Table 17–2) should be identified by their 
clinicians and monitored carefully. Several risk assessment 
models have been validated (most extensively the Gail 2 
model) to evaluate a woman’s risk of developing cancer. 
Those with an exceptional family history should be coun
-
seled about the option of genetic testing. Some of these 
high-risk women may consider prophylactic mastectomy, 
oophorectomy, tamoxifen, or an aromatase inhibitor.
Women with genetic mutations in whom breast cancer 
develops may be treated in the same way as women who do 
not have mutations (ie, lumpectomy), though there is an 
increased risk of ipsilateral and contralateral breast cancer 
after lumpectomy for these women. One study showed that 
of patients with a diagnosis of breast cancer who were 
found to be carriers of a 
BRCA
 mutation, approximately 
50% chose to undergo bilateral mastectomy.
Brouckaert O et al. Reproductive profiles and risk of breast cancer 
subtypes: a multi-center case-only study. Breast Cancer Res. 
2017 Nov 7;19(1):119. [PMID: 29116004]
Day FR et al. Genomic analyses identify hundreds of variants 
associated with age at menarche and support a role for 
puberty timing in cancer risk. 2017 Jun;49(6):834–41. [PMID: 
28436984]
Ginsburg O et al. The global burden of women’s cancers: a grand 
challenge in global health. Lancet. 2017 Feb 25;389(10071):
 
847–60. [PMID: 27814965]
Hardefeldt PJ et al. Physical activity and weight loss reduce the 
risk of breast cancer: a meta-analysis of 139 prospective and 
retrospective studies. Clin Breast Cancer. 2017 Oct 17. [Epub 
ahead of print] [PMID: 29223719]
Ma H et al. Reproductive factors and the risk of triple-negative 
breast cancer in white women and African-American women: 
a pooled analysis. Breast Cancer Res. 2017 Jan 13;19(1):6. 
[PMID: 28086982]
Michailidou K et al. Association analysis identifies 65 new breast 
cancer risk loci. Nature. 2017 Nov 2;551(7678):92–4. [PMID: 
29059683]
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Mørch LS et al. Contemporary hormonal contraception and 
the risk of breast cancer. N Engl J Med. 2017 Dec 7;377(23):
 
2228–39. [PMID: 29211679]
Sefton P . JAMA patient page. Testing for 
BRCA1/2
JAMA. 2017 Nov 28;318(20):2054. [PMID: 29183078]
Siegel RL et al. Cancer statistics, 2017. CA Cancer J Clin. 
2017 Jan;67(1):7–30. [PMID: 28055103]
 
»
Several clinical trials have evaluated the use of selective 
estrogen receptor modulators (SERMs), including tamoxifen 
and raloxifene, for prevention of breast cancer in women 
with no personal history of breast cancer but at high risk 
for developing the disease. A meta-analysis of nine of these 
studies including 83,399 women with a median follow-up 
of 65 months demonstrated a 38% reduction in breast can
-
cer incidence (hazard ratio [HR], 0.62; 95% CI, 0.56, 0.69) 
with a 10-year cumulative incidence of 6.3% in control 
groups and 4.2% in SERM-treated groups. An increased 
risk of endometrial cancer, cataracts and venous thrombo
-
embolic events but a reduced risk of vertebral fractures was 
seen in SERM groups. While SERMs have been shown to 
be effective at reducing the risk of breast cancer, the use of 
this intervention by women has been relatively low, possi
-
bly due to the perceived risks and side effects of therapy. A 
cost-effectiveness study based on a meta-analysis of four 
randomized prevention trials showed that tamoxifen saves 
costs and improves life expectancy when higher risk (Gail 
5-year risk at least 1.66%) women under the age of 55 years 
were treated.
Similar to SERMs, aromatase inhibitors (AIs), such as 
exemestane and anastrozole, have shown success in pre
-
venting breast cancer with a lower risk of uterine cancer 
and thromboembolic events, although bone loss is a sig
-
nificant side effect of this treatment.
Cuzick J. Preventive therapy for cancer. Lancet Oncol. 2017 
Aug;18(8):e472–82. [PMID: 28759386]
Cuzick J et al; IBIS-II investigators. Anastrozole for prevention 
of breast cancer in high-risk postmenopausal women (IBIS-
II): an international, double-blind, randomised placebo-
controlled trial. Lancet. 2014 Mar 22;383(9922):1041–8. 
[PMID: 24333009]
Cuzick J et al; SERM Chemoprevention of Breast Cancer Over
-
view Group. Selective oestrogen receptor modulators in pre
-
vention of breast cancer: an updated meta-analysis of individual 
participant data. Lancet. 2013 May 25;381(9880):1827–34. 
[PMID: 23639488]
 
»
Early Detection of Breast Cancer
A. Screening Programs
Screening detects breast cancer before it has spread to the 
lymph nodes in about 80% of the women evaluated. This 
increases the chance of survival to about 85% at 5 years.
Substantial evidence supports the use of routine screen
-
ing mammography; however, recommendations relating to 
timing and frequency vary by different agencies and coun
-
tries. About one-third of the abnormalities detected on 
screening mammograms will be found to be malignant 
when biopsy is performed. The probability of cancer on a 
screening mammogram is directly related to the Breast 
Imaging Reporting and Data System (BIRADS) assess
-
ment, and workup should be performed based on this clas
-
sification. The sensitivity of mammography varies from 
approximately 60% to 90%. This sensitivity depends on 
several factors, including patient age, breast density, tumor 
size, tumor histology (lobular versus ductal), location, and 
mammographic appearance. In young women with dense 
breasts, mammography is less sensitive than in older 
women with fatty breasts, in whom mammography can 
detect at least 90% of malignancies. Smaller tumors, par
-
ticularly those without calcifications, are more difficult to 
detect, especially in dense breasts. The lack of sensitivity 
and the low incidence of breast cancer in young women 
have led to questions concerning the value of mammography 
for screening in women 40–50 years of age. The specificity

for screening in women 40–50 years of age. The specificity 
of mammography in women under 50 years varies from 
about 30% to 40% for nonpalpable mammographic abnor
-
malities to 85% to 90% for clinically evident malignancies. 
Guidelines from at least six separate organizations exist in 
the United States and each differs slightly, making it some
-
what complex for clinicians and patients to navigate. While 
the American College of Radiology, American Medical 
Association, and National Comprehensive Cancer Net
-
work (NCCN) recommend starting mammography screen
-
ing at age 40, the US Preventive Services Task Force 
(USPSTF) recommends starting screening at age 50. Most 
guidelines recommend annual screening; however, the 
American Cancer Society recommends decreasing the 
frequency of screening to every 1–2 years starting at age 
55 years and the USPSTF recommends routine mammog
-
raphy be done no more than every 2 years beginning at age 
50 years. It is generally agreed that mammography should 
continue until life expectancy is shorter than 7–10 years, 
although the USPSTF recommends stopping screening 
after age 74 years regardless of life expectancy. Thus, clini
-
cians should have an informed discussion with patients 
about screening mammography regarding its potential 
risks (eg, false positives, overdiagnosis) and benefits 
(eg, early diagnosis), taking into consideration a patient’s 
individual risk factors.
B. Imaging
1. Mammography—
Mammography is the most reliable 
means of detecting breast cancer before a mass can be pal
-
pated. Most slowly growing cancers can be identified by 
mammography at least 2 years before reaching a size 
detectable by palpation.
Indications for mammography
 are as follows: (1) screen
-
ing at regular intervals asymptomatic women at risk for 
developing breast cancer; (2) evaluating each breast when 
a diagnosis of potentially curable breast cancer has been 
made, and at regular intervals thereafter; (3) evaluating a 
questionable or ill-defined breast mass or other suspicious 
change in the breast; (4) searching for an occult breast 
cancer in women with metastatic disease in axillary nodes 
or elsewhere from an unknown primary; (5) screening 
women prior to cosmetic operations or prior to biopsy of 
a mass, to examine for an unsuspected cancer; (6) moni
-
toring women with breast cancer who have been treated 
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with breast-conserving surgery and radiation; and (7) moni
-
toring the contralateral breast in women with breast cancer 
treated with mastectomy.
Film screen mammography delivers less than 0.4 mSv 
to the mid breast per view which is slightly more than that 
delivered by a routine chest film (0.1 mSv). Although full-
field digital mammography provides an easier method to 
maintain and review mammograms and may improve 
image quality, it has not been proven to improve overall 
cancer detection and is less economical. It may offer 
screening benefits to women younger than age 50 years and 
to women with dense breasts. While computer-assisted 
detection may increase the sensitivity of mammography, 
it has not been shown to improve mortality rates. Tomo
-
synthesis creates tomographic “slices” of the breast volume 
with a single acquisition. This technique may improve the 
sensitivity of mammogram especially in patients with 
dense breast tissue and reduces the number of callbacks but 
has not yet been shown in prospective studies to improve 
long-term patient outcomes.
Calcifications are the most easily recognized mammo
-
graphic abnormality. The most common findings associ
-
ated with carcinoma of the breast are clustered pleomorphic 
microcalcifications. Such calcifications are usually at least 
five to eight in number, aggregated in one part of the breast 
and differing from each other in size and shape, often 
including branched or V- or Y-shaped configurations. 
There may be an associated mammographic mass density 
or, at times, only a mass density with no calcifications. Such 
a density usually has irregular or ill-defined borders and 
may lead to architectural distortion within the breast, but 
may be subtle and difficult to detect.
Patients with a dominant or suspicious mass on exami
-
nation must undergo biopsy despite mammographic find
-
ings. The mammogram should be obtained prior to biopsy 
so that other suspicious areas can be noted and the contra
-
lateral breast can be evaluated. Mammography is never a 
substitute for biopsy because it may not reveal clinical 
cancer, especially in a very dense breast.
Communication and documentation among the patient, 
the referring clinician, and the interpreting physician are 
critical for high-quality screening and diagnostic mam
-
mography. The patient should be told about 
how
 she will 
receive timely results of her mammogram; that mammog
-
raphy does not “rule out” cancer; and that she may receive 
a correlative examination such as ultrasound at the mammog
-
raphy facility if referred for a suspicious lesion. She should 
also be aware of the technique and need for breast com
-
pression and that this may be uncomfortable. The mam
-
mography facility should be informed in writing by the 
clinician of abnormal physical examination findings. The 
Agency for Health Care Policy and Research (AHCPR) 
Clinical Practice Guidelines strongly recommend that all 
mammography reports be communicated in writing to the 
patient and referring clinician. Legislation has been passed 
in a number of US states that requires imaging facilities to 
report to patients the density of their breasts. This may 
prompt women with dense breasts to discuss with their 
clinician whether or not additional screening options 
would be appropriate in addition to mammogram.
2. Other imaging—
MRI and ultrasound may be useful 
screening modalities in women who are at high risk for 
breast cancer but not for the general population. The sen
-
sitivity of MRI is much higher than mammography; how
-
ever, the specificity is significantly lower and this results in 
multiple unnecessary biopsies. The increased sensitivity 
despite decreased specificity may be considered a reason
-
able trade-off for those at increased risk for developing 
breast cancer but not for normal-risk population. The 
National Comprehensive Cancer Network guidelines

-
National Comprehensive Cancer Network guidelines 
recommend MRI in addition to screening mammography 
for high-risk women, including those with 
BRCA1/2
 muta
-
tions, those who have a lifetime risk of breast cancer of 
greater than 20%, and those with a personal history of 
LCIS. Women who received radiation therapy to the chest 
in their teens or twenties are also known to be at high risk 
for developing breast cancer and screening MRI may be 
considered in addition to mammography. MRI is useful in 
women with breast implants to determine the character of 
a lesion present in the breast and to search for implant 
rupture and at times is helpful in patients with prior 
lumpectomy and radiation.
C. Clinical Breast Examination and 
 
Self-Examination
Breast self-examination has not been shown to improve 
survival. Because of the lack of strong evidence demon
-
strating value, the American Cancer Society no longer 
recommends monthly breast self-examination. While 
breast self-examination is not a recommended practice, 
patients should recognize and report any breast changes to 
their clinicians as it remains an important facet of proactive 
care.
Myers ER et al. Benefits and harms of breast cancer screening: a 
systematic review. JAMA. 2015 Oct 20;314(15):1615–34. 
[PMID: 26501537]
Oeffinger KC et al. Breast cancer screening for women at average 
risk: 2015 guideline update from the American Cancer Society. 
JAMA. 2015 Oct 20;314(15):1599–614. [PMID: 26501536]
Onega T et al. Breast cancer screening in an era of personalized 
regimens: a conceptual model and National Cancer Institute 
initiative for risk-based and preference-based approaches at a 
population level. Cancer. 2014 Oct 1;120(19):2955–64. 
[PMID: 24830599]
Pace LE et al. A systematic assessment of benefits and risks to 
guide breast cancer screening decisions. JAMA. 2014 Apr 2;
 
311(13):1327–35. [PMID: 24691608]
Welch HG et al. Breast-cancer tumor size, overdiagnosis, and 
mammography screening effectiveness. N Engl J Med. 
2016 Oct 13;375(15):1438–47. [PMID: 27732805]
 
»
Clinical Findings Associated With Early 
Detection of Breast Cancer
The presenting complaint in about 70% of patients with 
breast cancer is a lump (usually painless) in the breast. 
About 90% of these breast masses are discovered by the 
patient. Less frequent symptoms are breast pain; nipple 
discharge; erosion, retraction, enlargement, or itching of 
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15
%
5%
60%
15
%
5%
 
▲
Figure 17–1.
 
Frequency of breast carcinoma at 
 
various anatomic sites.
 
▲
Figure 17–2.
 
Skin dimpling 
from Armando E. Giuliano, MD.)
 
▲
Figure 17–3.
 
Palpation of axillary region for 
enlarged lymph nodes.
 
▲
Figure 17–4.
 
Paget disease. 
the nipple; and redness, generalized hardness, enlarge
-
ment, or shrinking of the breast. Rarely, an axillary mass or 
swelling of the arm may be the first symptom. Back or bone 
pain, jaundice, or weight loss may be the result of systemic 
metastases, but these symptoms are rarely seen on initial 
presentation.
The relative frequency of carcinoma in various ana
-
tomic sites in the breast is shown in Figure 17–1.
Inspection of the breast is the first step in physical 
examination and should be carried out with the patient 
sitting, arms at her sides and then overhead. Abnormal 
variations in breast size and contour, minimal nipple 
retraction, and slight edema, redness, or retraction of 
the skin can be identified (Figure 17–2). Asymmetry of the 
breasts and retraction or dimpling of the skin can often be 
accentuated by having the patient raise her arms overhead 
or press her hands on her hips to contract the pectoralis 
muscles. Axillary and supraclavicular areas should be thor
-
oughly palpated for enlarged nodes with the patient sitting 
(Figure 17–3). Palpation of the breast for masses or other 
changes should be performed with the patient both seated 
and supine with the arm abducted. Palpation with a rotary 
motion of the examiner’s fingers as well as a horizontal 
stripping motion has been recommended.
Breast cancer usually consists of a nontender, firm or 
hard mass with poorly delineated margins (caused by local 
infiltration). Very small (1–2 mm) erosions of the nipple 
epithelium may be the only manifestation of Paget disease 
of the breast (Figure 17–4). Watery, serous, or bloody dis
-
charge from the nipple is an occasional early sign but is 
more often associated with benign disease.
A lesion smaller than 1 cm in diameter may be difficult 
or impossible for the examiner to feel but may be 
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discovered by the patient. She should always be asked to 
demonstrate the location of the mass; if the clinician fails to 
confirm the patient’s suspicions and imaging studies are 
normal, the examination should be repeated in 2–3 months, 
preferably 1–2 weeks after the onset of menses. During the 
premenstrual phase of the cycle, increased innocuous 
nodularity may suggest neoplasm or may obscure an 
underlying lesion. If there is any question regarding the 
nature of an abnormality under these circumstances, the 
patient should be asked to return after her menses.
Metastases tend to involve regional lymph nodes, which 
may be palpable. One or two movable, nontender, not par
-
ticularly firm axillary lymph nodes 5 mm or less in 
diameter are frequently present and are generally of no 
significance. Firm or hard nodes larger than 1 cm are typical 
of metastases. Axillary nodes that are matted or fixed to 
skin or deep structures indicate advanced disease (at least 
stage III). On the other hand, if the examiner thinks that 
the axillary nodes are involved, that impression will be 
borne out by histologic section in about 85% of cases. The 
incidence of positive axillary nodes increases with the 
size of the primary tumor. Noninvasive cancers (in situ) do 
not metastasize. Metastases are present in about 30% of 
patients with clinically negative nodes.
In most cases, no nodes are palpable in the supracla
-
vicular fossa. Firm or hard nodes of any size in this location 
or just beneath the clavicle should be biopsied. Ipsilateral 
supraclavicular or infraclavicular nodes containing cancer 
indicate that the tumor is in an advanced stage (stage III 
or IV). Edema of the ipsilateral arm, commonly caused by 
metastatic infiltration of regional lymphatics, is also a sign 
of advanced cancer.
Liver or bone metastases may be associated with elevation 
of serum alkaline phosphatase. Hypercalcemia is an occa
-
sional important finding in advanced cancer of the breast. 
Serum tumor markers such as carcinoembryonic antigen 
(CEA) and CA 15-3 or CA 27-29 are not recommended for 
diagnosis of early lesions or for routine surveillance for 
recurrence after a breast cancer diagnosis.
C. Imaging
1. For lesions felt only by the patient—
Ultrasound is 
often valuable and mammography essential when an area 
is felt by the patient to be abnormal but the clinician feels 
no mass. MRI should not be used to rule out cancer 
because MRI has a false-negative rate of about 3–5%. 
Although lower than mammography, this false-negative 
rate cannot permit safe elimination of the possibility of 
cancer. False-negative results are more likely seen in infil
-
trating lobular carcinomas and DCIS than invasive ductal 
2. For metastatic lesions—
For patients with suspicious 
symptoms or signs (bone pain, abdominal symptoms, ele
-
vated liver biochemical tests) or locally advanced disease 
(clinically abnormal lymph nodes or large primary tumors), 
staging scans are indicated prior to surgery or systemic 
therapy. Chest imaging with CT or radiographs may be 
done to evaluate for pulmonary metastases. Abdominal 
imaging with CT or ultrasound may be obtained to evalu
-
ate for liver metastases. Bone scans using 
99m
Tc-labeled 
phosphates or phosphonates are more sensitive than skel
-
etal radiographs in detecting metastatic breast cancer. Bone 
scanning has not proved to be of clinical value as a routine 
preoperative test in the absence of symptoms, physical 
findings, or abnormal alkaline phosphatase or calcium 
levels. The frequency of abnormal findings on bone scan 
parallels the status of the axillary lymph nodes on patho
-
logic examination. Positron emission tomography (PET) 
scanning alone or combined with CT (PET-CT) may also 
be used for detecting soft tissue or visceral metastases in 
patients with symptoms or signs of metastatic disease.
D. Diagnostic Tests
1. Biopsy—

1. Biopsy—
The diagnosis of breast cancer depends ulti
-
mately on examination of tissue or cells removed by biopsy. 
Treatment should never be undertaken without an 
unequivocal histologic or cytologic diagnosis of cancer. 
The safest course is biopsy examination of all suspicious 
lesions found on physical examination or mammogra
-
phy, or both.
 About 60% of lesions clinically thought to be 
cancer prove on biopsy to be benign, while about 30% of 
clinically benign lesions are found to be malignant. These 
findings demonstrate the fallibility of clinical judgment 
and the necessity for biopsy.
All breast masses require a histologic diagnosis by 
biopsy with one probable exception: a nonsuspicious, pre
-
sumably fibrocystic mass, in a premenopausal woman. 
Rather, these masses can be observed through one or two 
menstrual cycles. However, if the mass is not cystic and 
does not completely resolve during this time, it must be 
biopsied. Figures 17–5 and 17–6 present algorithms for 
management of breast masses in premenopausal and post
-
menopausal patients.
The simplest biopsy method is needle biopsy, either by 
aspiration of tumor cells (FNA cytology) or by obtaining a 
small core of tissue with a hollow needle (core needle 
biopsy).
Large-needle (core) biopsy
 removes a core of tissue 
with a large cutting needle and is 
the diagnostic procedure 
of choice
 for both palpable and image-detected abnormali
-
ties. Handheld biopsy devices make large-core needle 
(14-gauge) biopsy of a palpable mass easy and cost effective 
in the office with local anesthesia. As in the case of any 
needle biopsy, the main problem is sampling error due to 
improper positioning of the needle, giving rise to a false-
negative test result. This is extremely unusual with image-
guided biopsies. Core biopsy allows the tumor to be tested 
for the expression of biological markers, such as estrogen 
receptor (ER), progesterone receptor (PR) and 
HER2
.
FNA cytology
 is a technique whereby cells are aspirated 
with a small needle and examined cytologically. This tech
-
nique can be performed easily with virtually no morbidity 
and is much less expensive than excisional or open biopsy. 
The main disadvantages are that it requires a pathologist 
skilled in the cytologic diagnosis of breast cancer and it is 
subject to sampling problems, particularly because deep 
lesions may be missed. Furthermore, noninvasive cancers 
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Solitary mass
Dominant mass
Multiple nodules
Not clinically
malignant
Mammogram;
ultrasound
No abnormalit
y,
 or solid
mass but not suggestive
of malignancy
Appears
malignant
Co
re
 needle biopsy
1
or 
re
ex
amine after next
menses or 1–4 months
Resolution
Pe
rsistence
Excision
Routine
follow-up
Clinically
malignant
Mammogra
m
Co
re
 needle
biopsy
1
Co
re
 needle
biopsy
1
Pr
eoperative
ev
aluation and 
counseling
Definitive
procedure
1
Lesions that are atypical but not malignant should be 
ex
cised.
Cy
stic
Aspirate
Nonbloody fluid
Completely
resol
ve
s
Re
ex
amine
No recurrence
Recurrence
Excision
Routine
follow-up
 
▲
Figure 17–5.
 
Evaluation of breast masses in premenopausal women. 
(Adapted, with permission, from Chang S, 
Haigh PI, Giuliano AE. Breast disease. In: Berek JS, Hacker NF [editors], 
Practical Gynecologic Oncology, 
4th ed, Philadelphia: 
Lippincott Williams & Wilkins, 2004.)
usually cannot be distinguished from invasive cancers and 
immunohistochemical tests to determine expression of 
hormone receptors and the amplification of the 
HER2
 
oncogene cannot be reliably performed on FNA biopsies. 
The incidence of false-positive diagnoses is extremely low, 
perhaps 1–2%. The false-negative rate is as high as 10%. 
Most experienced clinicians would not leave a suspicious 
dominant mass in the breast even when FNA cytology is 
negative unless the clinical diagnosis, breast imaging 
studies, and cytologic studies were all in agreement, such as 
a fibrocystic lesion or fibroadenoma. 
Given the stated limi
-
tations, FNA is not the modality of choice for sampling an 
abnormal breast mass.
Open biopsy
 under local anesthesia as a separate proce
-
dure prior to deciding upon definitive treatment has become 
less common with the increased use of core needle biopsy. 
Needle biopsy, when positive, offers a more rapid approach 
with less expense and morbidity, but when nondiagnostic it 
must be followed by open biopsy. It generally consists of an 
excisional biopsy, which is done through an incision with 
the intent to remove the entire abnormality, not simply a 
sample. As an alternative in highly suspicious circum
-
stances, the diagnosis may be made on a frozen section of 
tissue obtained by open biopsy under general anesthesia. If 
the frozen section is positive, the surgeon can proceed 
immediately with the definitive operation. This one-step 
method is rarely used today except when a cytologic study 
has suggested cancer but is not diagnostic and there is a high 
clinical suspicion of malignancy in a patient well prepared 
for the diagnosis of cancer and its treatment options.
In general, the two-step approach—outpatient large-
needle core biopsy followed by definitive operation at a 
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later date—is preferred in the diagnosis and treatment of 
breast cancer because patients can be given time to adjust 
to the diagnosis of cancer, can consider alternative forms of 
therapy, and can seek a second opinion if they wish. There 
is no adverse effect on the cancer from the few weeks’ delay 
of the two-step procedure.
2. Biopsy with ultrasound guidance—
Ultrasonography is 
performed primarily to differentiate cystic from solid 
lesions but may show signs suggestive of carcinoma. Ultra
-
sonography may show an irregular mass within a cyst in the 
rare case of intracystic carcinoma. If a tumor is palpable and 
feels like a cyst, an 18-gauge needle can be used to aspirate 
the fluid and make the diagnosis of cyst. If a cyst is aspirated 
and the fluid is nonbloody, it does not have to be examined 
cytologically. If the mass does not recur, no further diagnos
-
tic test is necessary. Nonpalpable mammographic densities 
that appear benign should be investigated with ultrasound 
to determine whether the lesion is cystic or solid. These 
may even be needle biopsied with ultrasound guidance.
3. Biopsy with mammographic guidance (“stereotactic 
biopsy”)—
When a suspicious abnormality is identified by 
mammography alone and cannot be palpated by the clini
-
cian, the lesion should be biopsied under mammographic 
guidance. In the 
computerized stereotactic guided core 
needle
 technique, a biopsy needle is inserted into the 
lesion with mammographic guidance, and a core of tissue 
for histologic examination can then be examined. Vacuum 
assistance increases the amount of tissue obtained and 
improves diagnosis.
Mammographic localization biopsy
 is performed by 
obtaining a mammogram in two perpendicular views and 
placing a needle or hook-wire near the abnormality so that 
the surgeon can use the metal needle or wire as a guide 
during operation to locate the lesion. After mammography 
confirms the position of the needle in relation to the lesion, 
an incision is made and the subcutaneous tissue is dis
-
sected until the needle is identified. Often, the abnormality 
cannot even be palpated through the incision—as is the 
case with microcalcifications—and thus it is essential to 
obtain a mammogram of the specimen to document that 
the lesion was excised. At that time, a second marker nee
-
dle can further localize the lesion for the pathologist. 
Stereotactic core needle biopsies have proved equivalent to 
mammographic localization biopsies. Core biopsy is prefer
-
able to mammographic localization for accessible lesions 
since an operation can be avoided. A metal clip should be 
placed after any image-guided core biopsy to facilitate find
-
ing the site of the lesion if subsequent treatment is 
4. Other imaging modalities—
Other modalities of breast 
imaging have been investigated for diagnostic purposes. 
Automated breast ultrasonography is useful in distinguish
-
ing cystic from solid lesions but should be used only as a 
supplement to physical examination and mammography. 
MRI is highly sensitive but not specific and should not be 
used for screening except in highly selective cases. For 
example, MRI is useful in differentiating scar from recur
-
rence postlumpectomy and may be valuable to screen high-
risk women (eg, women with 
BRCA
 mutations). It may also 
be of value to examine for multicentricity when there is a 
known primary cancer; to examine the contralateral breast 
in women with cancer; to examine the extent of cancer, 
especially lobular carcinomas; or to determine the response 
to neoadjuvant chemotherapy. Moreover, MRI-detected 
suspicious findings that are not seen on mammogram or 
ultrasound may be biopsied under MRI-guidance. PET 
scanning does not appear useful in evaluating the breast 
itself but is useful to examine for distant metastases.
5. Cytology—
Cytologic examination of nipple discharge or 
cyst fluid may be helpful on rare occasions. As a rule,

cyst fluid may be helpful on rare occasions. As a rule, 
mammography (or ductography) and breast biopsy are 
required when nipple discharge or cyst fluid is bloody or 
cytologically questionable.
 
»
The lesions to be considered most often in the differential 
diagnosis of breast cancer are the following, in descending 
order of frequency: fibrocystic condition of the breast, 
fibroadenoma, intraductal papilloma, lipoma, and fat 
necrosis.
 
»
Staging
The American Joint Committee on Cancer and the Inter
-
national Union Against Cancer have a joint TNM (tumor, 
regional lymph nodes, distant metastases) staging system 
for breast cancer.
 
»
Pathologic Types
Numerous pathologic subtypes of breast cancer can be 
identified histologically (Table 17–3).
Palpable mass
Mammograph
y
Co
re
1
Co
re
 needle
biopsy
1
Definitive procedure
Pr
eoperative 
ev
aluation
and counseling
malignant
malignant
1
Lesions that are atypical but not malignant
  should 
ex
cised.
 
▲
Figure 17–6.
 
Evaluation of breast masses in 
 
postmenopausal women. 
(Adapted, with permission, 
from Chang S, Haigh PI, Giuliano AE. Breast disease. In: 
Berek JS, Hacker NF [editors], 
Practical Gynecologic Oncology
, 
4th ed, Philadelphia: Lippincott Williams & Wilkins, 2004.)
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Table 17–3.
 
Histologic types of breast cancer.
Type
Frequency of Occurrence
Infiltrating ductal (not 
 
otherwise specified)
80–90%
 
Medullary
5–8%
 
C
olloid (mucinous)
2–4%
 
Tubular
1–2%
 
Papillary
1–2%
Invasive lobular
6–8%
Noninvasive
4–6%
 
Intraductal
2–3%
 
L
obular in situ
2–3%
Rare cancers
< 1%
 
Juv
enile (secretory)
 
A
denoid cystic
 
Epidermoid
 
Sudoriferous
Except for the in situ cancers, the histologic subtypes 
have only a slight bearing on prognosis when outcomes 
are compared after accurate staging. The noninvasive 
cancers by definition are confined by the basement mem
-
brane of the ducts and lack the ability to spread. Histologic 
parameters for invasive cancers, including lymphovascular 
invasion and tumor grade, have been shown to be of prog
-
nostic value. Immunohistochemical analysis for expression 
of hormone receptors and for overexpression of HER2 
in the primary tumor offers prognostic and therapeutic 
information.
 
»
Special Clinical Forms of Breast Cancer
A. Paget Carcinoma
Paget carcinoma is not common (about 1% of all breast 
cancers). Over 85% of cases are associated with an underly
-
ing invasive or noninvasive cancer, usually a well differenti
-
ated infiltrating ductal carcinoma or a DCIS. The ducts of 
the nipple epithelium are infiltrated, but gross nipple 
changes are often minimal, and a tumor mass may not be 
palpable.
Because the nipple changes appear innocuous, the diag
-
nosis is frequently missed. The first symptom is often itch
-
ing or burning of the nipple, with superficial erosion or 
ulceration. These are often diagnosed and treated as der
-
matitis or bacterial infection, leading to delay or failure in 
detection. The diagnosis is established by biopsy of the area 
of erosion. When the lesion consists of nipple changes only, 
the incidence of axillary metastases is less than 5%, and the 
prognosis is excellent. When a breast mass is also present, 
the incidence of axillary metastases rises, with an associ
-
ated marked decrease in prospects for cure by surgical or 
other treatment.
B. Inflammatory Carcinoma
This is the most malignant form of breast cancer and con
-
stitutes less than 3% of all cases. The clinical findings con
-
sist of a rapidly growing, sometimes painful mass that 
enlarges the breast. The overlying skin becomes erythematous, 
edematous, and warm. Often there is no distinct mass, 
since the tumor infiltrates the involved breast diffusely. The 
inflammatory changes, often mistaken for an infection, are 
caused by carcinomatous invasion of the subdermal lym
-
phatics, with resulting edema and hyperemia. If the clini
-
cian suspects infection but the lesion does not respond 
rapidly (1–2 weeks) to antibiotics, biopsy should be per
-
formed. The diagnosis should be made when the redness 
involves more than one-third of the skin over the breast 
and biopsy shows infiltrating carcinoma with invasion of 
the subdermal lymphatics. Metastases tend to occur early 
and widely, and for this reason inflammatory carcinoma is 
rarely curable. Radiation, hormone therapy (if hormone 
receptor positive), anti-HER2 therapy (if HER2 overex
-
pressing or amplified), and chemotherapy are the measures 
most likely to be of value initially rather than operation. 
Mastectomy is indicated when chemotherapy and radia
-
tion have resulted in clinical remission with no evidence of 
distant metastases. In these cases, residual disease in the 
breast may be eradicated.
 
»
Breast Cancer Occurring During 
 
Pregnancy or Lactation
Breast cancer complicates up to one in 3000 pregnancies. 
The diagnosis is frequently delayed, because physiologic 
changes in the breast may obscure the lesion and screening 
mammography is not done in young or pregnant women. 
Data are insufficient to determine whether interruption of 
pregnancy improves the prognosis of patients who are 
identified to have potentially curable breast cancer and

identified to have potentially curable breast cancer and 
who receive definitive treatment during pregnancy. Theo
-
retically, the high levels of estrogen produced by the pla
-
centa as the pregnancy progresses could be detrimental to 
the patient with occult metastases of hormone-sensitive 
breast cancer. The decision whether or not to terminate the 
pregnancy must be made on an individual basis, taking 
into account the patient’s clinical stage of the cancer and 
overall prognosis, the gestational age of the fetus, the 
potential for premature ovarian failure in the future with 
systemic therapy, and the patient’s wishes.
It is important for primary care and reproductive 
specialists to aggressively work up any breast abnormality 
discovered in a pregnant woman. Pregnancy (or lactation) 
is not a contraindication to operation or treatment, and 
therapy should be based on the stage of the disease as in 
the nonpregnant (or nonlactating) woman. Women with 
early-stage gestational breast cancer who choose to con
-
tinue their pregnancy should undergo surgery to remove the 
tumor and systemic therapy if indicated. Retrospective 
reviews of patients treated with anthracycline-containing 
regimens for gestational cancers (including leukemia and 
lymphomas) have established the relative safety of these 
regimens during pregnancy for both the patient and the 
fetus. Taxane-based and trastuzumab-based regimens 
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have not been evaluated extensively, however. Radiation 
therapy should be delayed until after delivery. Overall sur
-
vival rates have improved, since cancers are now diagnosed 
in pregnant women earlier than in the past and treatment 
has improved.
 
»
Bilateral Breast Cancer
Bilateral breast cancer occurs in less than 5% of cases, but 
there is as high as a 20–25% incidence of later occurrence 
of cancer in the second breast. Bilaterality occurs more 
often in familial breast cancer, in women under age 50 years, 
and when the tumor in the primary breast is lobular. The 
incidence of second breast cancers increases directly with 
the length of time the patient is alive after her first cancer—
about 1–2% per year.
In patients with breast cancer, mammography should 
be performed before primary treatment and at regular 
intervals thereafter, to search for occult cancer in the oppo
-
site breast or conserved ipsilateral breast.
 
»
Noninvasive Cancer
Noninvasive cancer can occur within the ducts (DCIS) or 
lobules (LCIS). DCIS tends to be unilateral and most often 
progresses to invasive cancer if untreated. In approximately 
40–60% of women who have DCIS treated with biopsy 
alone, invasive cancer develops within the same breast. 
LCIS is generally agreed to be a marker of an increased risk 
of breast cancer rather than a direct precursor of breast 
cancer itself. The probability of breast cancer (DCIS or 
invasive in either breast) in a woman in whom LCIS has 
been diagnosed is estimated to be 1% per year. If LCIS is 
detected on core needle biopsy, an excisional biopsy with
-
out lymph node sampling should be performed to rule out 
DCIS or invasive cancer since these are found in 10–20% of 
patients. The incidence of LCIS is rising, likely due to 
increased use of screening mammography. In addition, the 
rate of mastectomy after the diagnosis of LCIS is increasing 
in spite of the fact that mastectomy is only recommended 
in those patients who otherwise have an increased risk of 
breast cancer through family history, genetic mutation, or 
past exposure to thoracic radiation. Pleomorphic LCIS 
may behave more like DCIS and may be associated with 
invasive carcinoma. For this reason, pleomorphic LCIS 
should be surgically removed with clear margins.
The treatment of intraductal lesions is controversial. 
DCIS can be treated by wide excision with or without 
radiation therapy or with total mastectomy. Conservative 
management is advised in patients with small lesions ame
-
nable to lumpectomy. Patients in whom LCIS is diagnosed 
or who have received lumpectomy for DCIS may discuss 
chemoprevention (with hormonal blockade therapy) with 
their clinician, which is effective in reducing the risk of 
invasive breast cancer in DCIS that has been completely 
excised by breast-conserving surgery and in LCIS. Axillary 
metastases from in situ cancers should not occur unless 
there is an occult invasive cancer. Because one cannot per
-
form a sentinel lymph node biopsy after mastectomy, one 
might consider performing a sentinel node biopsy in a 
patient undergoing mastectomy for DCIS in case an inva
-
sive component is discovered.
Hartman EK et al. The prognosis of women diagnosed with 
breast cancer before, during and after pregnancy: a meta-
analysis. Breast Cancer Res Treat. 2016 Nov;160(2):347–60. 
[PMID: 27683280]
Portschy PR et al. Trends in incidence and management of lobu
-
lar carcinoma in situ: a population-based analysis. Ann Surg 
Oncol. 2013 Oct;20(10):3240–6. [PMID: 23846782]
Vapiwala N et al. No impact of breast magnetic resonance imag
-
ing on 15-year outcomes in patients with ductal carcinoma in 
situ or early-stage invasive breast cancer managed with breast 
conservation therapy. Cancer. 2017 Apr 15;123(8):1324–32. 
[PMID: 27984658]
 
»
Biomarkers & Gene Expression Profiling
Determining the ER, PR, and HER2 status of the tumor at

»
Determining the ER, PR, and HER2 status of the tumor at 
the time of diagnosis of early breast cancer and, if possible, 
at the time of recurrence is critical, both to gauge a patient’s 
prognosis and to determine the best treatment regimen. In 
addition to ER status and PR status, the rate at which 
tumor divides (assessed by an immunohistochemical stain 
for Ki67) and the grade and differentiation of the cells are 
also important prognostic factors. These markers may be 
obtained on core biopsy or surgical specimens, but not reli
-
ably on FNA cytology. Patients whose tumors are hormone 
receptor-positive tend to have a more indolent disease 
course than those whose tumors are receptor-negative. 
Moreover, treatment with an anti-hormonal agent is an 
essential component of therapy for hormone-receptor 
positive breast cancer at any stage. While up to 60% of 
patients with metastatic breast cancer will respond to hor
-
monal manipulation if their tumors are ER-positive, less 
than 5% of patients with metastatic, ER-negative tumors 
will respond.
Another key element in determining treatment and 
prognosis is the amount of the 
HER2
 oncogene present in 
the cancer. HER2 overexpression (HER2-oncogene–positive 
breast cancer) is generally more aggressive than breast 
cancer with normal HER2 expression (HER2-negative 
breast cancer). Individually these biomarkers are predictive 
and thus provide insight to guide appropriate therapy. 
Moreover, when combined they provide useful informa
-
tion regarding risk of recurrence and prognosis. In general, 
tumors that lack expression of HER2, ER, and PR (“triple 
negative”) have a higher risk of recurrence and metastases 
and are associated with a worse survival compared with 
other types. Neither endocrine therapy nor HER2-targeted 
agents are useful for this type of breast cancer, leaving 
chemotherapy as the only treatment option. In contrast, 
patients with early stage, hormone receptor–positive breast 
cancer may not benefit from the addition of chemotherapy 
to hormonally targeted treatments. Several molecular tests 
have been developed to assess risk of recurrence and to 
predict which patients are most likely to benefit from 
chemotherapy. Oncotype DX (Genomic Health) evaluates 
the expression of 21 genes relating to ER, PR, HER2, and 
proliferation in a tumor specimen and categorizes a patient’s 
risk of recurrence (recurrence score) as high, intermediate, 
or low risk. This test is primarily indicated for ER-positive, 
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lymph node-negative tumors but at least one study has 
shown that it may also have value in node-positive tumors. 
Mammaprint (Agendia) is an FDA-approved 70-gene 
signature assay that is available for evaluating prognosis. 
This test classifies patients into good and poor prognostic 
groups to predict clinical outcome and may be used on 
patients with hormone receptor positive or negative breast 
cancer. American Society of Clinical Oncology (ASCO) 
guidelines indicate this assay may be best used to help 
determine whether chemotherapy may be safely withheld 
in patients with hormone receptor–negative, HER2-negative, 
node-positive breast cancer at high clinical risk. ASCO 
does not recommend using this assay in hormone receptor–
negative or HER2-positive breast cancer.
Barcenas CH et al. Outcomes in patients with early-stage breast 
cancer who underwent a 21-gene expression assay. Cancer. 
2017 Jul 1;123(13):2422–31. [PMID: 28199747]
Cardoso F et al; MINDACT Investigators. 70-Gene signature as 
an aid to treatment decisions in early-stage breast cancer. 
N Engl J Med. 2016 Aug 25;375(8):717–29. [PMID: 27557300]
Esserman LJ et al. Use of molecular tools to identify patients 
with indolent breast cancers with ultralow risk over 2 decades. 
JAMA Oncol. 2017 Nov 1;3(11):1503–10. [PMID: 28662222]
Gluz O et al. West German Study Group Phase III PlanB Trial: 
first prospective outcome data for the 21-gene recurrence 
score assay and concordance of prognostic markers by central 
and local pathology assessment. J Clin Oncol. 2016 Jul 10;
 
34(20):2341–9. [PMID: 26926676]
Krop I et al. Use of biomarkers to guide decisions on adjuvant 
systemic therapy for women with early-stage invasive breast 
cancer: American Society of Clinical Oncology clinical prac
-
tice guideline focused update. J Clin Oncol. 2017 Aug 20;
 
35(24):2838–47. [PMID: 28692382]
Mamounas EP et al. 21-gene recurrence score and locoregional 
recurrence in node-positive/ER-positive breast cancer treated 
with chemo-endocrine therapy. J Natl Cancer Inst. 2017 
 
Jan 25;109(4). pii: djw259. [PMID: 28122895]
Sparano JA et al. Prospective validation of a 21-gene expression 
assay in breast cancer. N Engl J Med. 2015 Nov 19;
 
373(21):2005–14. [PMID: 26412349]
Tsai M et al. Association of 70-gene signature assay findings with 
physicians’ treatment guidance for patients with early breast 
cancer classified as intermediate risk by the 21-gene assay. 
JAMA Oncol. 2017 Oct 26:e173470. [PMID: 29075751]
Wolff AC et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of 
Clinical Oncology/College of American Pathologists clinical 
practice guideline update. J Clin Oncol. 2013 Nov 1;
 
31(31):3997–4013. [PMID: 24101045]
 
»
Curative Treatment
Not all breast cancer is systemic at the time of diagnosis 
and a pessimistic attitude concerning the management of 
breast cancer is unwarranted. Most patients with early 
breast cancer can be cured. Treatment with a curative 
intent is advised for clinical stage I, II, and III disease 
(see Table 39–2). Patients with locally advanced (T3, T4) 
and even inflammatory tumors may be cured with multi
-
modality therapy, but metastatic disease will be diagnosed 
in most patients and at that point, palliation becomes the 
goal of therapy. Treatment with palliative intent is appro
-
priate for all patients with stage IV disease and for patients 
with unresectable local cancers.
A. Choice and Timing of Primary Therapy
The extent of disease and its biologic aggressiveness are the 
principal determinants of the outcome of primary therapy. 
Clinical and pathologic staging help in assessing extent of 
disease, but each is to some extent imprecise. Other factors 
such as tumor grade, hormone receptor assays, and 
HER2
 
oncogene amplification are of prognostic value and are key 
to determining systemic therapy, but are not as relevant in

HER2
 
to determining systemic therapy, but are not as relevant in 
determining the type of local therapy.
Controversy has surrounded the choice of primary 
therapy of stage I, II, and III breast carcinoma. Currently, 
the standard of care for stage I, stage II, and most stage III 
cancer is surgical resection followed by adjuvant radiation 
or systemic therapy, or both, when indicated. Neoadjuvant 
therapy has become popular since large tumors may be 
shrunk by chemotherapy prior to surgery, making some 
patients who require mastectomy candidates for lumpec
-
tomy. It is important for patients to understand all of the 
surgical options, including reconstructive options, prior to 
having surgery. Patients with large primary tumors, inflam
-
matory cancer, or palpably enlarged lymph nodes should 
have staging scans performed to rule out distant metastatic 
disease prior to definitive surgery. In general, adjuvant 
systemic therapy is started when the breast has adequately 
healed, usually within 4–8 weeks after surgery. While no 
prospective studies have defined the appropriate timing of 
adjuvant chemotherapy, a single institution study of over 
6800 patients suggests that systemic therapy should be 
started within 60 days of surgery, especially in women with 
stage II or III breast cancer, triple-negative breast cancer or 
HER2-positive disease.
B. Surgical Resection
1. Breast-conserving therapy—
Multiple, large, random
-
ized studies including the Milan and NSABP trials show 
that disease-free and overall survival rates are similar for 
patients with stage I and stage II breast cancer treated with 
partial mastectomy (breast-conserving lumpectomy or 
“breast conservation”) plus axillary dissection followed by 
radiation therapy and for those treated by modified radical 
mastectomy (total mastectomy plus axillary dissection).
Tumor size is a major consideration in determining the 
feasibility of breast conservation. The NSABP lumpectomy 
trial randomized patients with tumors as large as 4 cm. To 
achieve an acceptable cosmetic result, the patient must have 
a breast of sufficient size to enable excision of a 4-cm tumor 
without considerable deformity. Therefore, large tumor size 
is only a relative contraindication. Subareolar tumors, also 
difficult to excise without deformity, are not contraindica
-
tions to breast conservation. Clinically detectable multifo
-
cality is a relative contraindication to breast-conserving 
surgery, as is fixation to the chest wall or skin or involvement 
of the nipple or overlying skin. The patient—not the surgeon—
should be the judge of what is cosmetically acceptable. Given 
the relatively high risk of poor outcome after radiation, 
concomitant scleroderma is a contraindication to breast-
conserving surgery. A history of prior therapeutic radiation 
to the ipsilateral breast or chest wall (or both) is also gener
-
ally a contraindication for breast conservation.
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Axillary dissection is primarily used to properly stage 
cancer and plan radiation and systemic therapy. Intraop
-
erative lymphatic mapping and sentinel node biopsy iden
-
tify lymph nodes most likely to harbor metastases if 
present (Figure 17–7). Sentinel node biopsy is a reasonable 
alternative to axillary dissection in patients without clinical 
evidence of axillary lymph node metastases. If sentinel 
node biopsy reveals no evidence of axillary metastases, it is 
highly likely that the remaining lymph nodes are free of 
disease and axillary dissection may be omitted. An impor
-
tant study from the American College of Surgeons 
Oncology Group randomized women with sentinel node 
metastases to undergo completion of axillary dissection or 
to receive no further axillary treatment after lumpectomy; 
no difference in survival was found, showing that axillary 
dissection is not necessary for selected patients with node 
involvement who are treated with lumpectomy, whole 
breast irradiation, and adjuvant systemic therapy. Omis
-
sion of axillary dissection is accepted at many major cancer 
institutions.
Breast-conserving surgery with radiation is the pre
-
ferred form of treatment for patients with early-stage breast 
cancer. Despite the numerous randomized trials showing 
no survival benefit of mastectomy over breast-conserving 
partial mastectomy and irradiation, breast-conserving sur
-
gery still appears to be underutilized.
2. Mastectomy—
Modified radical mastectomy was the 
standard therapy for most patients with early-stage breast 
cancer. This operation removes the entire breast, overly
-
ing skin, nipple, and areolar complex usually with under
-
lying pectoralis fascia with the axillary lymph nodes in 
continuity. The major advantage of modified radical 
mastectomy is that radiation therapy may not be neces
-
sary, although radiation may be used when lymph nodes 
are involved with cancer or when the primary tumor is 
5 cm or larger. The disadvantage of mastectomy is the 
cosmetic and psychological impact associated with breast 
loss. Radical mastectomy, which removes the underlying 
pectoralis muscle, should be performed rarely, if at all. 
Axillary node dissection is not indicated for noninvasive 
cancers because nodal metastases are rarely present. Skin-
sparing and nipple-sparing mastectomy is available but is 
not appropriate for all patients. Breast reconstruction, 
immediate or delayed, should be discussed with patients 
who choose or require mastectomy. Patients should have 
an interview with a reconstructive plastic surgeon to dis
-
cuss options prior to making a decision regarding recon
-
struction. Time is well spent preoperatively in educating 
the patient and family about these matters.
C. Radiotherapy
Radiotherapy after partial mastectomy consists of 5–7 weeks 
of five daily fractions to a total dose of 5000–6000 cGy. 
Most radiation oncologists use a boost dose to the cancer 
location. Shorter fractionation schedules may be reason
-
able for women over the age of 50 with early stage, lymph 
node–negative breast cancer. Accelerated partial breast 
irradiation, in which only the portion of the breast from 
which the tumor was resected is irradiated for 1–2 weeks, 
appears effective in achieving local control for selected 
patients; however, the results of prospective randomized 
trials, such as the NSABP B-39/RTOG 0413, are awaited. In 
women over the age of 70 with small (less than 2 cm), 
lymph node–negative, hormone receptor–positive cancers, 
radiation therapy may be avoided. The recurrence rates 
after intraoperative radiation, while low, appear signifi
-
cantly higher than postoperative whole breast radiation 
therapy. However, in all of these situations, a balanced 
discussion with a radiation oncologist to weigh the risks 
and benefits of each approach is warranted.
Current studies suggest that radiotherapy after mastec
-

-
tomy may improve recurrence rates and survival in younger 
patients and those with tumors 5 cm or larger or positive 
D. Adjuvant Systemic Therapy
The goal of systemic therapy, including hormone-modulating 
drugs (endocrine therapy), cytotoxic chemotherapy, and 
HER2-targeted agents such as trastuzumab, is to kill cancer 
cells that have escaped the breast and axillary lymph nodes 
as micrometastases before they become macrometastases 
(ie, stage IV cancer). Systemic therapy improves survival 
and is advocated for most patients with curable breast 
cancer. In practice, most medical oncologists are currently 
using adjuvant chemotherapy for patients with either 
node-positive or higher-risk (eg, hormone receptor-negative 
or HER2-positive) node-negative breast cancer and using 
endocrine therapy for all hormone receptor–positive inva
-
sive breast cancer unless contraindicated. Prognostic fac
-
tors other than nodal status that are used to determine the 
patient’s risks of recurrence are tumor size, ER and PR 
status, nuclear grade, histologic type, proliferative rate, 
oncogene expression (Table 17–4), and patient’s age and 
menopausal status. In general, systemic chemotherapy 
decreases the chance of recurrence by about 30%, hor
-
monal modulation decreases the relative risk of recurrence 
by 40–50% (for hormone receptor–positive cancer), and 
HER2-targeted therapy decreases the relative risk of recur
-
rence by up to 40% (for HER2-positive cancer). Systemic 
chemotherapy is usually given sequentially, rather than con
-
currently with radiation. In terms of sequencing, typically 
 
▲
Figure 17–7.
 
Sentinel node. 
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Table 17–4.
 
Prognostic factors in node-negative breast 
cancer.
p
r
ognostic Factors
Increased 
Decreased 
Size
1
T3, T2
T1, T0
Hormone receptors (ER, PR)
Negative
Positive
Histologic grade
High
Low
S phase fraction
> 5%
< 5%
Lymphatic or vascular invasion
Present
Absent
HER2
 oncogene amplification
High
Low
Epidermal growth factor receptor
High
Low
High Oncotype DX Recurrence 
Score or other genomic 
 
prognostic assays
High score
Low score
1
See eTable 17–1 on 
 for TNM staging for breast cancer.
chemotherapy is given before radiation and endocrine 
therapy is started concurrent with or after radiation 
therapy.
The long-term advantage of systemic therapy is well 
established. All patients with invasive hormone receptor–
positive tumors should consider the use of hormone-
modulating therapy. Most patients with HER2-positive 
tumors should receive trastuzumab-containing chemo
-
therapy regimens. In general, adjuvant systemic chemo
-
therapy should not be given to women who have small 
node-negative breast cancers with favorable histologic 
findings and tumor biomarkers. The ability to predict more 
accurately which patients with HER2-negative, hormone 
receptor–positive, lymph node–negative tumors should 
receive chemotherapy is improving with the advent of 
prognostic tools, such as Oncotype DX and Mamma-print. 
These tests are undergoing prospective evaluation in two 
clinical trials (TAILORx and MINDACT).
1. Chemotherapy—
The Early Breast Cancer Trialists’ Col
-
laborative Group (EBCTCG) meta-analysis involving over 
28,000 women enrolled in 60 trials of adjuvant polychemo
-
therapy versus no chemotherapy demonstrated a signifi
-
cant beneficial impact of chemotherapy on clinical outcome 
in non–stage IV breast cancer. This study showed that 
adjuvant chemotherapy reduces the risk of recurrence and 
breast cancer–specific mortality in all women and also 
showed that women under the age of 50 derive the greatest 
benefit.
a. Anthracycline- and cyclophosphamide-
 
con
taining regimens—
On the basis of the superiority 
of anthracycline-containing regimens in metastatic breast 
cancer, both doxorubicin and epirubicin have been studied 
extensively in the adjuvant setting. Studies comparing 
Adriamycin (doxorubicin) and cyclophosphamide (AC) or 
epirubicin and cyclophosphamide (EC) to cyclophosphamide-
methotrexate-5-fluorouracil (CMF) have shown that treat
-
ments with anthracycline-containing regimens are at least 
as effective as treatment with CMF. The EBCTCG analysis 
including over 14,000 patients enrolled in trials comparing 
anthracycline-based regimens to CMF, showed a small but 
statistically significant improved disease-free and overall 
survival with the use of anthracycline-based regimens. It 
should be noted, however, that most of these studies 
included a mixed population of patients with HER2-positive 
and HER2-negative breast cancer and were performed 
before the introduction of trastuzumab. Retrospective 
analyses of a number of these studies suggest that anthra
-
cyclines may be primarily effective in tumors with HER2 
overexpression or alteration in the expression of topoisom
-
erase IIa (the target of anthracyclines and close to the 
HER2
 gene). Given this, for HER2-negative, node-negative 
breast cancer, four cycles of AC or six cycles of CMF are 
probably equally effective.
b. Taxanes—
When taxanes (paclitaxel and docetaxel) 
emerged in the 1990s, multiple trials were conducted to 
evaluate their use in combination with anthracycline-based 
regimens. The majority of these trials showed an improve
-
ment in disease-free survival and at least one showed an 
improvement in overall survival with the taxane-based 
regimen. A meta-analysis of taxane versus non-taxane 
anthracycline-based regimen trials showed an improve
-
ment in disease-free and overall survival for the taxane-
based regimens. Several regimens have been reported

-
based regimens. Several regimens have been reported 
including AC followed by paclitaxel (AC-P) or docetaxel 
(Taxotere) (AC-T), docetaxel concurrent with AC (TAC), 
5-fluorouracil-epirubicine-cyclophosphamide (FEC)-
docetaxel and FEC-paclitaxel.
The US Oncology trial 9735 compared four cycles of AC 
with four cycles of docetaxel (Taxotere) and cyclophospha
-
mide (TC). With a median of 7 years’ follow-up, this study 
showed a statistically significantly improved disease-free 
survival and overall survival in the patients who received 
TC. Subsequently, substudy results from the phase III 
MINDACT trial were presented in which 1301 patients 
with operable tumors were randomized 1:1 to standard 
anthracycline/cyclophosphamide-based therapy (with tax
-
ane in the 30% of patients with node-positive disease) or 
docetaxel plus capecitabine (DC). The 5-year disease-free 
survival was similar for the anthracycline arm (88.8%) and 
DC arm (90.7%) (
P
 = 0.263) and 5-year overall survival was 
also similar (96.2% anthracycline vs 96.3% DC, 
P
 = 0.722).
The three Anthracyclines in early Breast Cancer (ABC) 
(USOR 06-090, NSABP B-46, NSABP B-49) trials (total 
 
N = 4242) each compared the TC regimen to anthracycline/
taxane-based chemotherapy regimens (TaxAC) in HER2-
negative early-stage breast cancer. An interim joint analysis 
showed that the invasive disease-free survival at 4 years 
was improved by 2.5% with the addition of an anthracycline 
(
P
 = 0.04) but that the benefit of an anthracycline was pri
-
marily seen in triple-negative disease (HR 1.42, 95% CI 
1.04, 1.94). No survival difference was observed at the time 
of interim reporting. In contrast, the West German Study 
Group phase III PlanB study compared six cycles of adju
-
vant TC to four cycles of EC followed by four cycles of 
docetaxel (EC-D) in 2449 patients with intermediate to high 
risk, HER2-negative breast cancer. Dose reductions were 
higher in the anthracycline arm (19.7% vs 6.6%, 
P
 < 0.001) 
and grade 3/4 toxicities were consistently and significantly 
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higher in the anthracycline arm. TC demonstrated nonin
-
feriority to EC-D with a 5-year disease-free survival of 
90% for each arm (HR TC vs. EC-D = 0.996; 95% CI 
[0.77–1.29]). In contrast to the ABC study, subset analysis 
indicated a similar disease-free survival in each treatment 
arm regardless of recurrence score, nodal status, Ki67 reac
-
tivity, grade, or triple-negative subtype. A Danish phase III 
study was conducted to compare six cycles of TC to six 
cycles of EC-D in 2012 high-risk patients with 
TOP2A
 
normal breast cancer. The 5-year disease-free survival was 
87.9% for EC-D vs 88.3% for DC (HR, 1.00; 
P
 = 1.00). 
While it is generally agreed that taxanes should be used for 
most patients receiving chemotherapy for early breast can
-
cer, data relating to the benefits of anthracyclines are con
-
flicting, thus a balanced discussion regarding the potential 
risks versus benefits of the addition of anthracyclines is 
c. Duratio
n of chemotherapy—
The overall duration 
of adjuvant chemotherapy still remains uncertain. How
-
ever, based on the meta-analysis performed in the Oxford 
Overview (EBCTCG), the current recommendation is 
for 3–6 months of the commonly used regimens. Although 
it is clear that dose intensity to a specific threshold is 
essential, there is no evidence to support the long-term 
survival benefit of high-dose chemotherapy with stem cell 
support.
d. Chemotherapy side effects—
Chemotherapy side 
effects, which are discussed in Chapter 39, are generally 
well controlled.
2. Targeted therapy—
Targeted therapy refers to agents 
that are directed specifically against a protein or molecule 
expressed uniquely on tumor cells or in the tumor 
microenvironment.
a. 
HER2
 overexpression
—
Approximately 20% of breast 
cancers are characterized by amplification of the 
HER2
 
oncogene leading to overexpression of the HER2 oncoprotein. 
The poor prognosis associated with HER2 overexpression 
has been drastically improved with the development of 
HER2-targeted therapy. Trastuzumab (Herceptin [H]), a 
monoclonal antibody that binds to HER2, has proved 
effective in combination with chemotherapy in patients 
with HER2-overexpressing metastatic and early breast 
cancer. In the adjuvant setting, the first and most com
-
monly studied chemotherapy backbone used with trastu
-
zumab is AC-T. Subsequently, the BCIRG006 study showed 
similar efficacy for AC-TH and a nonanthracycline-
containing regimen, TCH (docetaxel, carboplatin, trastu
-
zumab). Both were significantly better than AC-T in terms 
of disease-free and overall survival and TCH had a lower 
risk of cardiac and bone marrow (leukemia/myelodyspla
-
sia) toxicity. Both AC-TH and TCH are FDA-approved for 
nonmetastatic, HER2-positive breast cancer. In these regi
-
mens, trastuzumab is given with chemotherapy and then 
continues beyond the course of chemotherapy to com
-
plete a full year. Neoadjuvant chemotherapy plus dual 
HER2
-targeted therapy with trastuzumab and pertu
-
zumab (also a HER2-targeted monoclonal antibody that 
prevents dimerization of HER2 with HER3 and has been 
shown to be synergistic in combination with trastuzumab) 
is a standard of care option available to patients with non
-
metastatic HER2-positive breast cancer (see Neoadjuvant 
Therapy). The phase III randomized placebo-controlled 
adjuvant “ APHINITY” study, reported in 2017, evaluated 
1 year of adjuvant pertuzumab in combination with trastu
-
zumab and showed a small but statistically significant red
-
ucation in recurrence of disease with pertuzumab (7.1% vs 
8.7%, HR, 0.81; 
P
 = 0.045). The improved disease-free 
survival is most pronounced in patients with node-positive 
disease. Neratinib, an orally bioavailable dual HER1 
(EGFR), HER2 tyrosine kinase inhibitor, is FDA-approved 
as adjuvant therapy. The phase III placebo-controlled 
EXTENET study demonstrated that neratinib improves

EXTENET study demonstrated that neratinib improves 
invasive disease-free survival when given for 1 year after 
completion of a year of standard adjuvant trastuzumab-
based therapy (median follow-up 5.2 years, stratified HR 
0.73, 95% CI 0.57, 0.92, 
P
 = 0.0083). Neratinib is associated 
with gastrointestinal toxicity, most notably moderate to 
severe diarrhea in approximately 40% of patients who did 
not use antidiarrheal prophylaxis. Measures to mitigate this 
side effect are being evaluated in a clinical trial.
Retrospective studies have shown that even small 
(stage T1a,b) HER2-positive tumors have a worse progno
-
sis compared with same-sized 
HER2
-negative tumors and 
may thus be appropriate for trastuzumab-based regimens. 
The NSABP B43 study is ongoing to evaluate whether the 
addition of trastuzumab to radiation therapy is warranted 
for DCIS.
Cardiomyopathy develops in a small but significant 
percentage (0.4–4%) of patients who receive trastuzumab-
based regimens. For this reason, anthracyclines and trastu
-
zumab are rarely given concurrently and cardiac function 
is monitored periodically throughout therapy.
b. Endocrine therapy—
Adjuvant hormone modulation 
therapy is highly effective in decreasing relative risk of 
recurrence by 40–50% and mortality by 25% in women 
with hormone receptor–positive tumors regardless of 
menopausal status.
(1) Tamoxifen—
The traditional regimen had been 5 years 
of the estrogen-receptor antagonist/agonist tamoxifen until 
the 2012 reporting of the Adjuvant Tamoxifen Longer 
Against Shorter (ATLAS) trial in which 5 versus 10 years of 
adjuvant tamoxifen were compared. In this study, disease-
free and overall survival were significantly improved in 
women who received 10 years of tamoxifen, particularly 
after year 10. Though these results are impressive, the clini
-
cal application of long-term tamoxifen use must be dis
-
cussed with patients individually, taking into consideration 
risks of tamoxifen (such as secondary uterine cancers, 
venous thromboembolic events, and side effects that 
impact quality of life). The addition of ovarian suppression 
to tamoxifen has been shown to significantly improve 
8-year disease-free survival (83.2% vs 78.9%) compared to 
tamoxifen alone in the randomized Suppression of Ovarian 
Function Trial [SOFT] study, though the benefits appeared 
to be seen primarily in chemotherapy-treated patients with 
higher risk disease. 
(2) Aromatase inhibitors—
AIs, including anastrozole, 
letrozole, and exemestane, reduce estrogen production and 
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are also effective in the adjuvant setting for postmeno
-
pausal women. AIs should not be used in a patient with 
functioning (premenopausal) ovaries since they do not 
block ovarian production of estrogen. At least seven large 
randomized trials enrolling more than 24,000 postmeno
-
pausal patients with hormone receptor–positive nonmeta
-
static breast cancer have compared the use of AIs with 
tamoxifen or placebo as adjuvant therapy. All of these stud
-
ies have shown small but statistically significant improve
-
ments in disease-free survival (absolute benefits of 2–6%) 
with the use of AIs. In addition, AIs have been shown to 
reduce the risk of contralateral breast cancers and to have 
fewer associated serious side effects (such as endometrial 
cancers and thromboembolic events) than tamoxifen. 
However, they are associated with accelerated bone loss 
and an increased risk of fractures as well as a musculoskel
-
etal syndrome characterized by arthralgias or myalgias (or 
both) in the majority of patients. The American Society of 
Clinical Oncology and the NCCN have recommended that 
postmenopausal
 women with hormone receptor–positive 
breast cancer be offered an AI either initially or after 
tamoxifen therapy. HER2 status should not affect the use or 
choice of hormone therapy. A combined analysis of the 
SOFT and Tamoxifen and Exemestane Trial (TEXT) stud
-
ies showed for the first time that exemestane plus ovarian 
suppression with triptorelin was associated with a reduced 
risk of relapse compared to tamoxifen plus ovarian sup
-
pression, making this a viable adjuvant therapy option for 
premenopausal
 women with high-risk ER-positive breast 
cancers.
3. Bisphosphonates—
Multiple randomized studies have 
evaluated the use of adjuvant bisphosphonates in addition 
to standard local and systemic therapy for early-stage 
breast cancer and have shown, in addition to improvement 
in bone density, a consistent reduction in the risk of meta
-
static recurrence in postmenopausal patients. A meta-
analysis evaluating more than 18,000 women with 
early-stage breast cancer treated with bisphosphonates or 
placebo showed that bisphosphonates reduce the risk of 
cancer recurrence (especially in bone) and improve breast 
cancer–specific survival primarily in postmenopausal 
women. Side effects associated with bisphosphonate 
therapy include bone pain, fever, osteonecrosis of the jaw 
(rare, less than 1%), esophagitis or ulcers (for oral bisphos
-
phonates), and kidney injury. Although the FDA has not 
yet approved the adjuvant use of bisphosphonates to reduce 
the risk of breast cancer recurrence, the 2017 jointly pub
-
lished guidelines of the Cancer Care Ontario and 
American Society of Clinical Oncology recommend that 
bisphosphonate use (zoledronic acid or clodronate) be 
considered in the adjuvant therapy plan for postmeno
-
pausal breast cancer patients. In addition, denosumab 
(another bone stabilizing drug), which is an antibody 
directed against receptor activator of nuclear factor 
kappa B ligand (RANK-B), is being investigated for its 
impact on breast cancer recurrence rates.
4. Adjuvant therapy in older women—
Data relating to the 
optimal use of adjuvant systemic treatment for women over 
the age of 65 are limited. Results from the EBCTCG 
overview indicate that while adjuvant chemotherapy yields 
a smaller benefit for older women compared with younger 
women, it still improves clinical outcomes. Moreover, indi
-
vidual studies do show that older women with higher risk 
disease derive benefits from chemotherapy. One study 
compared the use of oral chemotherapy (capecitabine) to 
standard chemotherapy in older women and concluded 
that standard chemotherapy is preferred. Another study 
(USO TC vs AC) showed that women over the age of 65 
derive similar benefits from the taxane-based regimen as 
women who are younger. The benefits of endocrine

women who are younger. The benefits of endocrine 
therapy for hormone receptor–positive disease appear to 
be independent of age. In general, decisions relating to the 
use of systemic therapy should take into account a patient’s 
comorbidities and physiological age, more so than chrono
-
logic age.
E. Neoadjuvant Therapy
The use of systemic therapy prior to resection of the pri
-
mary tumor (neoadjuvant) is a standard option that in 
many cases should be discussed with patients prior to sur
-
gery. This enables the assessment of in vivo sensitivity of 
the tumor to the selected systemic therapy. Patients with 
hormone receptor–negative, triple-negative, or HER2-
positive breast cancer are more likely to have a pathologic 
complete response (meaning no residual invasive cancer at 
the time of surgery) to neoadjuvant chemotherapy than 
those with hormone receptor–positive breast cancer. A 
complete pathologic response at the time of surgery, espe
-
cially in hormone receptor–negative tumors, is associated 
with improvement in event-free and overall survival. Neo
-
adjuvant chemotherapy also increases the chance of breast 
conservation by shrinking the primary tumor in women 
who would otherwise need mastectomy for local control. 
Survival after neoadjuvant chemotherapy is similar to that 
seen with postoperative adjuvant chemotherapy.
1. HER2-positive breast cancer—
Dual targeting of HER2 
with two monoclonal antibodies, trastuzumab and per
-
tuzumab, showed positive results in two clinical trials in 
the neoadjuvant setting, the TRYPHAENA and the 
NEOSPHERE studies.
Based on these clinical trials, three regimens are FDA-
approved in the 
HER2
-positive neoadjuvant setting: 
docetaxel [T], cyclophosphamide [C], trastuzumab [H], 
and pertuzumab [P] (TCHP) for six cycles; 5-fluorouracil, 
epirubicin, cyclophosphamide [FEC] for 3 cycles followed 
by THP for 3 cycles; or THP for 4 cycles (followed by three 
cycles of postoperative FEC). The National Comprehensive 
Cancer Network guidelines list pertuzumab plus trastuzumab 
as an appropriate adjuvant therapy to be given concur
-
rently with chemotherapy if pertuzumab was not given in 
the neoadjuvant setting. After completing chemotherapy 
(and surgery, if chemotherapy is given in the neoadjuvant 
setting), all patients should continue to receive trastu
-
zumab to complete a full year. Dual HER2-targeted therapy 
without standard cytotoxic chemotherapy has been evalu
-
ated in the neoadjuvant setting as well. The phase III 
KRISTINE study evaluated the antibody drug conjugate, 
trastuzumab emtansine (T-DM1, Kadcyla) in combination 
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with pertuzumab compared to standard TCHP treatment. 
While the T-DM1/P arm was well tolerated and yielded a 
pathological complete response in 44% of patients, TCHP 
performed significantly better with a pathological com
-
plete response rate 56%. Thus, the use of T-DM1 in the 
neoadjuvant setting outside of a clinical trial is not 
2. Hormone receptor–positive, 
HER2
-negative breast 
cancer—
Patients with hormone receptor–positive breast 
cancer have a lower chance of achieving a pathologic com
-
plete response with neoadjuvant therapy than those 
patients with triple-negative or 
HER2
-positive breast 
cancers. Studies are ongoing to evaluate hormonally tar
-
geted regimens in the neoadjuvant setting. Outside of the 
clinical trial setting, the use of neoadjuvant hormonal 
therapy is generally restricted to postmenopausal patients 
who are unable or unwilling to tolerate chemotherapy.
3. Triple-negative breast cancer—
No targeted therapy has 
been identified for patients with breast cancer that is lack
-
ing in 
HER2
 amplification or hormone receptor expres
-
sion. Neoadjuvant chemotherapy leads to pathologic 
complete response in up to 40–50% of patients with triple-
negative breast cancer. Patients who achieve a pathologic 
complete response seem to have a similar prognosis to 
other breast cancer subtypes with pathologic complete 
response. However, those patients with residual disease 
at the time of surgery have a poor prognosis. Based on 
the theory that triple-negative breast cancers may be more 
vulnerable to DNA-damaging agents, several studies are 
evaluating whether the addition of platinum salts to a neo
-
adjuvant chemotherapy regimen is beneficial in this dis
-
ease subtype. A randomized phase II trial (GeparSixto) 
randomly assigned 595 patients with triple-negative or 
HER2
-positive breast cancer to weekly paclitaxel plus 
weekly liposomal doxorubicin (18 weeks) alone or with 
weekly carboplatin. Patients with triple-negative disease 
also received bevacizumab. Those patients with triple-
negative disease who received carboplatin had a pathologic 
complete response rate of 53.2% compared to those who 
did not receive carboplatin (36.9%; 
P
 = 0.005). The 3-year 
disease-free survival (DFS) data were presented in 2015; 
the addition of carboplatin improved disease-free survival 
from 76.1% to 85.8% (HR 0.56, 95% CI (0.33, 0.96), 
P
 = 0.0350) 
Similarly designed phase II studies including the Cancer 
Leukemia Group (CALGB) 40603 and the Adjuvant 
Dynamic Marker-Adjusted Personalized Therapy 
(ADAPT) triple-negative trial showed improved pathologi
-
cal complete response rates with platinum-based neoadju
-
vant therapy. Other studies are ongoing to evaluate the 
pathologic complete response rates and long-term out
-
comes associated with incorporating platinums into stan
-
dard chemotherapy regimens.
4. Timing of sentinel lymph node biopsy in neoadjuvant 
setting—
There is considerable concern about the timing 
of sentinel lymph node biopsy, since the chemotherapy 
may affect cancer present in the lymph nodes. Several stud
-
ies have shown that sentinel node biopsy can be done after 
neoadjuvant therapy. However, a large multicenter study, 
ACOSOG 1071, demonstrated a false-negative rate of 
10.7%, well above the false-negative rate outside the neoad
-
juvant setting (less than 1–5%). Some physicians recom
-
mend performing sentinel lymph node biopsy before 
administering the chemotherapy in order to avoid a false-
negative result and to aid in planning subsequent radiation 
therapy. Others prefer to perform sentinel lymph node 
biopsy after neoadjuvant therapy to avoid a second opera
-
tion and assess post-chemotherapy nodal status. If a com
-
plete dissection is desired, this can be performed at the 
time of the definitive breast surgery. The SENTINA trial 
showed similarly poor results for sentinel node biopsy after

-
showed similarly poor results for sentinel node biopsy after 
neoadjuvant therapy. No study has evaluated the impact of 
no axillary treatment for node-positive patients who 
become node-negative after neoadjuvant therapy.
Important questions remaining to be answered are the 
timing and duration of adjuvant and neoadjuvant chemo
-
therapy, which chemotherapeutic agents should be applied 
for which subgroups of patients, the use of combinations of 
hormonal therapy and chemotherapy as well as possibly 
targeted therapy, and the value of prognostic factors other 
than hormone receptors in predicting response to therapy.
 
»
Palliative Treatment
Palliative treatments are those to manage symptoms, 
improve quality of life, and even prolong survival, without 
the expectation of achieving cure. In the United States, it is 
uncommon to have distant metastases at the time of diagno
-
sis (de novo metastases). However, most patients who have a 
breast cancer recurrence after initial local and adjuvant 
therapy have metastatic rather than local (in breast) disease. 
Breast cancer most commonly metastasizes to the liver, 
lungs and bone, causing symptoms such as fatigue, change in 
appetite, abdominal pain, cough, dyspnea, or bone pain. 
Headaches, imbalance, vision changes, vertigo, and other 
neurologic symptoms may be signs of brain metastases. 
Triple-negative (ER-, PR-, HER2-negative) and HER2-positive 
tumors have a higher rate of brain metastases than hormone 
receptor–positive, HER2-negative tumors.
A. Radiotherapy and Bisphosphonates
Palliative radiotherapy may be advised for primary treat
-
ment of locally advanced cancers with distant metastases to 
control ulceration, pain, and other manifestations in the 
breast and regional nodes. Irradiation of the breast and 
chest wall and the axillary, internal mammary, and 
supraclavicular nodes should be undertaken in an attempt 
to cure locally advanced and inoperable lesions when there 
is no evidence of distant metastases. A small number of 
patients in this group are cured in spite of extensive breast 
and regional node involvement.
Palliative irradiation is of value also in the treatment of 
certain bone or soft-tissue metastases to control pain or 
avoid fracture. Radiotherapy is especially useful in the 
treatment of isolated bony metastases, chest wall recur
-
rences, brain metastases and sometimes, in lieu of the 
preferred option of orthopedic surgery for acute spinal 
cord compression.
In addition to radiotherapy, bisphosphonate therapy has 
shown excellent results in delaying and reducing skeletal 
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events in women with bony metastases. Pamidronate and 
zoledronic acid are FDA-approved intravenous bisphospho
-
nates given for bone metastases or hypercalcemia of malig
-
nancy from breast cancer. Denosumab, a fully human 
monoclonal antibody that targets RANK-ligand, is FDA-
approved for the treatment of bone metastases from breast 
cancer, with data showing that it reduced the time to first 
skeletal-related event (eg, pathologic fracture) compared to 
zoledronic acid.
Caution should be exercised when combining radiation 
therapy with chemotherapy because toxicity of either or 
both may be augmented by their concurrent administra
-
tion. In general, only one type of therapy should be given 
at a time unless it is necessary to irradiate a destructive 
lesion of weight-bearing bone while the patient is receiving 
chemotherapy. Systemic therapy should be changed only if 
the disease is clearly progressing. This is especially difficult 
to determine for patients with destructive bone metastases, 
since changes in the status of these lesions are difficult to 
determine radiographically.
B. Targeted Therapy
1. Hormonally based therapy for metastatic disease—
The following therapies have all been shown to be effective 
in hormone receptor–positive metastatic breast cancer: 
administration of drugs that block or downregulate estro
-
gen receptors (such as tamoxifen or fulvestrant, respec
-
tively) or drugs that block the synthesis of hormones (such 
as AIs); ablation of the ovaries, adrenals, or pituitary; and 
the administration of hormones (eg, estrogens, androgens, 
progestins); see Table 17–5. Because only 5–10% of women 
with ER-negative tumors respond, they should not receive 
endocrine therapy. Women within 1 year of their last men
-
strual period are arbitrarily considered to be premeno
-
pausal and should have surgical (bilateral oophorectomy) 
or chemical ovarian ablation (using a gonadotropin-releasing 
hormone [GnRH] analog such as leuprolide [Lupron], 
goserelin [Zoladex] or tritorelin). Premenopausal women 
who have had chemical or surgical ovarian ablation are 
then eligible to receive the same hormonally targeted 
therapies that are available to postmenopausal women. 
Current guidelines indicate that sequential hormonal 
therapy is the preferred treatment for hormone receptor–
positive metastatic breast cancer except in the rare case 
when disease is immediately threatening visceral organs.
a. First-line treatment options 
(1) Hormonally targeted agents—
Single agent hormon
-
ally targeted therapy options include fulvestrant (500 mg 
intramuscularly day 1, 15, then every month), tamoxifen 
(20 mg orally daily), or an AI (anastrozole, letrozole, or 
exemestane). The average time to progression associated 
with single agent first-line tamoxifen is 5–8 months and 
with AI is approximately 8–12 months. The side effect 
profile of AIs differs from tamoxifen. The main side effects 
of tamoxifen are nausea, skin rash, and hot flushes. Rarely, 
tamoxifen induces hypercalcemia in patients with bony 
metastases. Tamoxifen also increases the risk of venous 
thromboembolic events and uterine hyperplasia and cancer. 
The main side effects of AIs include hot flushes, vaginal 
dryness, and joint stiffness; however, osteoporosis and 
bone fractures are significantly higher than with tamoxifen. 
Results from the phase III FALCON study (comparing 
Table 17–5.
 
Hormonal agents commonly used for management of metastatic breast cancer.
Drug
Action
Dose, Route, Frequency
Major Side Effects
Tamoxifen citrate 
(Nolvadex)
SERM
20 mg orally daily
Hot flushes, uterine bleeding, thrombophlebitis, 
rash
Toremifene citrate 
(Fareston)
SERM
60 mg orally daily
Hot flushes, sweating, nausea, vaginal discharge, 
dry eyes, dizziness
Fulvestrant (Faslodex)
Steroidal estrogen 
receptor antagonist
500 mg intramuscularly days 1, 
15, 29 and then monthly
Gastrointestinal upset, headache, back pain, hot

Gastrointestinal upset, headache, back pain, hot 
flushes, pharyngitis, injection site pain
Goserelin (Zoladex)
Synthetic luteinizing 
hormone releasing 
analog
3.6 mg subcutaneously monthly
Arthralgias, blood pressure changes, hot flushes, 
headaches, vaginal dryness, bone loss
Leuprolid (Lupron)
analog
3.75 or 7.5 mg subcutaneously 
monthly
Megestrol acetate 
(Megace)
Progestin
40 mg orally four times daily
Fluid retention; venous thromboembolic events; 
rarely used except in very late stage, treatment 
refractory disease
Anastrozole (Arimidex)
AI
1 mg orally daily
Hot flushes, skin rashes, nausea and vomiting, bone 
loss
Exemestane (Aromasin)
AI
25 mg orally daily
Hot flushes, increased arthralgia/arthritis, myalgia, 
bone loss
Letrozole (Femara)
AI
2.5 mg orally daily
Hot flushes, arthralgia/arthritis, myalgia, bone loss
AI, aromatase inhibitor; SERM, selective estrogen receptor modulator.
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first-line treatment with the pure estrogen antagonist ful
-
vestrant to anastrozole) confirmed that the use of first-line 
fulvestrant improves progression-free survival by almost 
3 months (HR 0.79, 95% CI (0.637, 0.999), 
P
 = 0.0486) with 
the largest treatment effect observed in patients without 
visceral disease. Overall survival data are needed. 
(2) Hormonally targeted therapy plus cyclin dependent 
kinase inhibition—
Hormonally driven breast cancer may 
be particularly sensitive to inhibition of cell cycle regula
-
tory proteins, called cyclin dependent kinases (CDK). A 
phase III randomized, placebo-controlled study 
(PALOMA-2) of letrozole plus an oral CDK 4/6 inhibitor 
(palbociclib) for the first-line treatment of postmenopausal 
women with hormone receptor–positive advanced breast 
cancer demonstrated a striking and highly significant 
10-month improvement in progression-free survival associ
-
ated with the use of palbociclib. Another CDK4/6 inhibitor, 
ribociclib, was also evaluated in a phase III trial (MONA
-
LEESA-2) in the same disease setting and demonstrated a 
similar improvement in progression-free survival when 
added to letrozole. These studies both demonstrated a 
median progression-free survival of over 2 years; the lon
-
gest reported progression-free survival reported in meta
-
static ER-positive breast cancer to date, leading many to 
consider the use of a CDK4/6 inhibitor plus AI the gold 
standard treatment in the first-line setting. Both agents are 
FDA-approved in the first-line setting in combination with 
an AI. Overall survival results are not yet mature. In gen
-
eral, palbociclib and ribociclib are well tolerated. However, 
they are associated with grade 3/4 neutropenia; thus, moni
-
toring patients closely is required. Febrile neutropenia and 
infections are rare and use of growth factors is not required; 
however, the CDK4/6 inhibitors are given for 3 consecutive 
weeks, stopping for 1 week to allow white cell count to 
recover. Abemaciclib, a third CDK4/6 inhibitor, which is 
given continuously (28-day cycles), has been evaluated in 
the phase III MONARCH-3 study and has reported a simi
-
lar improvement in median progression-free survival when 
added to either anastrozole or letrozole.
b. Treatment options when disease progresses 
after hormonal-based therapy 
(1) Secondary or tertiary hormonal therapy—
Patients 
who have disease progression following first-line hormonal 
therapy may be offered a different form of endocrine 
therapy. For example, if a patient has been treated with an 
AI as first-line therapy, fulvestrant or tamoxifen should be 
considered at the time of disease progression as second-
line therapy. 
(2) Fulvestrant plus CDK4/6 inhibitor—
All three 
CDK4/6 inhibitors have also been evaluated in phase III 
trials (PALOMA-3, MONALEESA-3, MONARCH-2) in 
patients whose disease has progressed on prior endocrine 
therapy and all have shown a significant improvement in 
median progression-free survival with the addition of 
CDK4/6 inhibitor to fulvestrant compared to placebo plus 
fulvestrant. Currently, palbociclib (125 mg orally daily) and 
abemaciclib (150 mg orally twice daily) are both FDA 
approved in combination with fulvestrant for this indica
-
tion. Abemaciclib is also FDA-approved as a single agent 
(200 mg orally twice daily) for patients with advanced ER-
positive breast cancer who have received prior endocrine 
therapy and chemotherapy. It should be noted that there is 
no evidence to date that use of a CDK4/6 inhibitor benefits 
patients whose disease has progressed despite therapy with 
a CDK4/6 inhibitor. Thus, at this time, use of any CDK4/6 
inhibitor after disease progression on a CDK4/6 inhibitor 
is not appropriate outside of a clinical trial. 
(3) Everolimus plus endocrine therapy—
Everolimus 
(Afinitor) is an oral inhibitor of the mammalian target of 
rapamycin (MTOR)—a protein whose activation has been

rapamycin (MTOR)—a protein whose activation has been 
associated with the development of endocrine resistance. A 
phase III, placebo-controlled trial (BOLERO-2) evaluated 
the AI exemestane with or without everolimus in 724 
patients with AI-resistant, hormone receptor–positive met
-
astatic breast cancer and found that patients treated with 
everolimus had a significantly improved progression-free 
survival (7.8 months vs 3.2 months; HR, 0.45; 95% CI, 
0.38–0.54; 
P
 < 0.0001) but no significant difference in over
-
all survival. Everolimus has also been evaluated in combi
-
nation with fulvestrant and shown to have similar 
improvements in progression-free survival compared to 
single agent fulvestrant.
2. HER2-targeted agents—
For patients with 
HER2
-
positive tumors, trastuzumab plus chemotherapy signifi
-
cantly improves clinical outcomes, including survival 
compared to chemotherapy alone. 
Pertuzumab
 is an FDA-
approved monoclonal antibody that targets the extracellu
-
lar domain of 
HER2
 at a different epitope than targeted by 
trastuzumab and inhibits receptor dimerization. A phase 
III placebo-controlled randomized study (CLEOPATRA) 
showed that patients treated with the combination of 
pertuzumab, trastuzumab, and docetaxel had a signifi
-
cantly longer progression-free survival (18.5 months vs 
12.4 months; HR, 0.62; 95% CI, 0.51–0.75; 
P
 < 0.001) com
-
pared with those treated with docetaxel and trastuzumab. 
Longer follow-up revealed a significant overall survival 
benefit associated with pertuzumab as well.
Lapatinib
, an oral targeted drug that inhibits the intra
-
cellular tyrosine kinases of the epidermal growth factor 
and 
HER2
 receptors, is FDA-approved for the treatment of 
trastuzumab-resistant 
HER2
-positive metastatic breast 
cancer in combination with capecitabine, thus, a com
-
pletely oral regimen. The combination of trastuzumab plus 
lapatinib has been shown to be more effective than lapa
-
tinib alone for trastuzumab-resistant metastatic breast 
cancer. Moreover, several trials have shown a significant 
clinical benefit for continuing 
HER2
-targeted agents 
beyond progression. 
T-DM1 ado-trastuzumab emtansine
 
(
Kadcyla
) is an FDA-approved novel antibody drug conju
-
gate in which trastuzumab is stably linked to a derivative of 
maytansine, enabling targeted delivery of the cytotoxic 
chemotherapy to 
HER2
-overexpressing cells. T-DM1 is 
associated with an improved progression-free and overall 
survival compared to lapatinib plus capecitabine in patients 
with 
HER2
-positive, trastuzumab-pretreated advanced dis
-
ease (EMILIA). Several other drugs targeting 
HER2
 and its 
associated signaling pathways are in development, includ
-
ing tucatinib (ONT-380), DS-8201, margetuximab, pyro
-
tinib, and 
HER2
-targeted vaccines.
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CMDT 2019
3. Targeting “triple-negative” breast cancer—
Breast cancers 
lacking expression of the hormone receptors ER, PR, and 
HER2
 have been amenable only to therapy with cytotoxic 
chemotherapy. This type of “triple-negative” breast cancer, 
while heterogeneous, generally behaves aggressively and is 
associated with a poor prognosis. Newer classes of targeted 
agents are being evaluated specifically for triple-negative 
breast cancer, although most have failed to demonstrate 
improved outcomes. A phase II placebo-controlled random
-
ized trial (LOTUS) demonstrated a significantly improved 
progression-free survival (6.2 mos vs 4.9 mos, stratified HR 
0.60, 
P
 = 0.037) by adding the oral AKT inhibitor ipatasertib 
to first-line paclitaxel. These results need to be confirmed in 
a larger phase III study but are the first promising results of 
an AKT inhibitor for triple-negative breast cancer. Early 
phase clinical trials show promise for immune checkpoint 
inhibitors (such as monoclonal antibodies that target PDL-1 
or PD-1) and androgen receptor inhibitors. Research in this 
area is rapidly expanding with multiple clinical trials of 
molecularly targeted agents ongoing.
4. Targeting 
PARP
 in 
BRCA1
/2
 mutation-associated breast 
cancer—
Poly (adenosine diphosphate-ribose) polymerase 
(PARP) is an enzyme important in single-strand DNA 
repair. Patients who carry germline mutations in 
BRCA1
 or 
BRCA2
 have tumors with deficient double-strand DNA 
repair mechanisms. Experts have theorized that inhibiting 
PARP selectively kills 
BRCA1/2
 mutated cancers. A 
phase III clinical trial (OlympiAD) that compared olaparib 
(an oral PARP inhibitor) to treatment of physician’s choice 
(single-agent chemotherapy) demonstrated a significantly 
improved progression-free survival (7.0 mos vs 4.2 mos, 
HR 0.58; 
P
 < 0.001), an improved response rate, and a 
lower rate of adverse events than standard therapy. Tala
-
zoparib, a second PARP inhibitor, has also been shown to 
improve outcomes similarly in the phase III EMBRACA 
study. Olaparib is the only PARP inhibitor that is FDA-
approved for 
BRCA-
mutated breast cancer.
C. Palliative Chemotherapy
Cytotoxic drugs should be considered for the treatment of 
metastatic breast cancer (1) if life- or organ-threatening 
visceral metastases are present (especially brain, liver, or 
lymphangitic pulmonary), (2) if hormonal treatment is 
unsuccessful or the disease has progressed after an initial 
response to hormonal manipulation, or (3) if the tumor is 
ER-negative or HER2-positive. Prior adjuvant chemother
-
apy does not seem to alter response rates in patients who 
relapse. A number of chemotherapy drugs (including 
vinorelbine, paclitaxel, docetaxel, gemcitabine, ixabepilone, 
carboplatin, cisplatin, capecitabine, albumin-bound pacli
-
taxel, eribulin, and liposomal doxorubicin) may be used as 
single agents with first-line objective response rates rang
-
ing from 30% to 50%.
Combination chemotherapy yields statistically signifi
-
cantly higher response rates and progression-free survival 
rates, but has not been conclusively shown to improve overall 
survival rates compared with sequential single-agent therapy. 
Combinations that have been tested in phase III studies and 
have proven efficacy compared with single-agent therapy 
include capecitabine/docetaxel, gemcitabine/paclitaxel, and 
capecitabine/ixabepilone (see Tables 39–3 and 39–13). 
Various other combinations of drugs have been tested in 
phase II studies, and a number of clinical trials are ongoing 
to identify effective combinations. Patients should be 
encouraged to participate in clinical trials given the number 
of promising targeted therapies in development. It is gener
-
ally appropriate to treat willing patients with multiple 
sequential lines of therapy as long as they tolerate the treat
-
ment and as long as their performance status is good (eg, at

-
-
ment and as long as their performance status is good (eg, at 
least ambulatory and able to care for self, up out of bed 
more than 50% of waking hours).
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»
Prognosis
Stage of breast cancer is the most reliable indicator of 
prognosis (Table 17–6). Axillary lymph node status is the 
best-analyzed prognostic factor and correlates with sur
-
vival at all tumor sizes. When cancer is localized to the 
breast with no evidence of regional spread after pathologic 
examination, the clinical cure rate with most accepted 
methods of therapy is 75% to more than 90%. In fact, 
patients with small mammographically detected biologi
-
cally favorable tumors and no evidence of axillary spread 
have a 5-year survival rate greater than 95%. When the 
axillary lymph nodes are involved with tumor, the survival 
rate drops to 50–70% at 5 years and probably around 
25–40% at 10 years. The use of biologic markers, such as 
ER, PR, grade, and HER2, helps identify high-risk tumor 
types as well as direct treatment used (see Biomarkers & 
Gene Expression Profiling). Tumors with marked aneu
-
ploidy have a poor prognosis (see Table 17–4). Gene analy
-
sis studies can predict disease-free survival for some 
subsets of patients.
Five-year statistics do not accurately reflect the final 
outcome of therapy. The mortality rate of breast cancer 
patients exceeds that of age-matched normal controls for 
nearly 20 years. Thereafter, the mortality rates are equal, 
though deaths that occur among breast cancer patients are 
often directly the result of tumor.
In general, breast cancer appears to be somewhat more 
aggressive and associated with worse outcomes in younger 
than in older women, and this may be related to the fact 
that fewer younger women have ER-positive tumors. 
 
Disparities in treatment outcome for different racial and 
ethnic backgrounds have been reported by several studies. 
These differences appear to be not only due to different 
socioeconomic factors (and a resulting difference in access 
Table 17–6.
 
Approximate survival of patients with 
breast cancer by TNM stage.
TNM Stage
5 Years
10 Years
0
95%
90%
I
85%
70%
IIA
70%
50%
IIB
60%
40%
IIIA
55%
30%
IIIB
30%
20%
IV
5–10%
2%
All
65%
30%
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to healthcare) but also due to differences in the subtype of 
breast cancer diagnosed.
For those patients whose disease progresses despite treat
-
ment, studies suggest supportive group therapy may improve 
survival. As they approach the end of life, such patients will 
require meticulous palliative care (see Chapter 5).
DeSantis CE et al. Breast cancer statistics, 2017, racial disparity 
in mortality by state. CA Cancer J Clin. 2017 Nov;67(6):
 
439–448. [PMID: 28972651]
Miller JW et al. Disparities in breast cancer survival in the 
United States (2001–2009): findings from the CONCORD-2 
study. Cancer. 2017 Dec 15;(123 Suppl 24):5100–18. [PMID: 
29205311]
Warner et al. Racial and ethnic differences in breast cancer sur
-
vival: mediating effect of tumor characteristics and sociode
-
mographic and treatment factors. J Clin Oncol. 2015 Jul 10;
 
33(20):2254–61. [PMID: 25964252]
 
»
Follow-Up Care
After primary therapy, patients with breast cancer should 
be monitored long term in order to detect recurrences and 
to observe the opposite breast for a second primary carci
-
noma. Local and distant recurrences occur most frequently 
within the first 2–5 years. During the first 2 years, most 
patients should be examined every 6 months, then annu
-
ally thereafter. Special attention is paid to the contralateral 
breast because a new primary breast malignancy will 
develop in 20–25% of patients. In some cases, metastases 
are dormant for long periods and may appear 15 years or 
longer after removal of the primary tumor. Although stud
-
ies have failed to show an adverse effect of hormonal 
replacement in disease-free patients, it is rarely used after 
breast cancer treatment, particularly if the tumor was hor
-
mone receptor–positive. Even pregnancy has not been 
associated with shortened survival of patients rendered 
disease free—yet many oncologists are reluctant to advise a 
young patient with breast cancer that it is safe to become 
pregnant. The use of estrogen replacement for conditions 
such as osteoporosis, vaginal dryness and hot flushes may 
be considered for a woman with a history of breast cancer 
after discussion of the benefits and risks; however, it is not 
routinely recommended, especially given the availability of 
nonhormonal agents for these conditions (such as bisphos
-
phonates and denosumab for osteoporosis).
A. Local Recurrence
The incidence of local recurrence correlates with tumor 
size, the presence and number of involved axillary nodes, 
the histologic type of tumor, the presence of skin edema 
or skin and fascia fixation with the primary tumor, and 
the type of definitive surgery and local irradiation. Local 
recurrence on the chest wall after total mastectomy and 
axillary dissection develops in as many as 8% of patients. 
When the axillary nodes are not involved, the local 
recurrence rate is less than 5%, but the rate is as high as 
25% when they are heavily involved. A similar difference 
in local recurrence rate was noted between small and 
large tumors. Factors such as multifocal cancer, in situ 
tumors, positive resection margins, chemotherapy, and 
radiotherapy have an effect on local recurrence in patients 
treated with breast-conserving surgery. Adjuvant systemic 
therapy greatly decreases the rate of local recurrence.
Chest wall recurrences usually appear within the first 
several years but may occur as late as 15 or more years after 
mastectomy. All suspicious nodules and skin lesions should 
be biopsied. Local excision or localized radiotherapy may 
be feasible if an isolated nodule is present. If lesions are 
multiple or accompanied by evidence of regional involve
-
ment in the internal mammary or supraclavicular nodes, 
the disease is best managed by radiation treatment of the 
entire chest wall including the parasternal, supraclavicular, 
and axillary areas and usually by systemic therapy.
Local recurrence after mastectomy usually signals the

Local recurrence after mastectomy usually signals the 
presence of widespread disease and is an indication for 
studies to search for evidence of metastases. Distant metas
-
tases will develop within a few years in most patients with 
locally recurrent tumor after mastectomy. When there is no 
evidence of metastases beyond the chest wall and regional 
nodes, irradiation for cure after complete local excision 
should be attempted. After partial mastectomy, local recur
-
rence does not have as serious a prognostic significance as 
after mastectomy. However, those patients in whom a 
recurrence develops have a worse prognosis than those 
who do not. It is speculated that the ability of a cancer to 
recur locally after radiotherapy is a sign of aggressiveness 
and resistance to therapy. Completion of the mastectomy 
should be done for local recurrence after partial mastec
-
tomy; some of these patients will survive for prolonged 
periods, especially if the breast recurrence is DCIS or 
occurs more than 5 years after initial treatment. Systemic 
chemotherapy or hormonal treatment should be used for 
women in whom disseminated disease develops or those in 
whom local recurrence occurs.
B. Breast Cancer Survivorship Issues
Given that most women with non-metastatic breast cancer 
will be cured, a significant number of women face survi
-
vorship issues stemming from either the diagnosis or the 
treatment of the breast cancer. These challenges include 
psychological struggles, upper extremity lymphedema, 
weight management problems, cardiovascular issues, bone 
loss, postmenopausal side effects, and fatigue. One ran
-
domized study reported that survivors who received psy
-
chological intervention from the time of diagnosis had a 
lower risk of recurrence and breast cancer–related mortality. 
A randomized study in older, overweight cancer survivors 
showed that diet and exercise reduced the rate of self-
reported functional decline compared with no interven
-
tion. Cognitive dysfunction (also called “chemo brain”) is a 
commonly reported symptom experienced by women who 
have undergone systemic treatment for early breast 
cancer.
1. Edema of the arm—
Significant edema of the arm occurs 
in about 10–30% of patients after axillary dissection with 
or without mastectomy. It occurs more commonly in obese 
women, in women who had radiotherapy, and in women 
who had postoperative infection. Partial mastectomy with 
radiation to the axillary lymph nodes is followed by 
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chronic edema of the arm in 10–20% of patients. Sentinel 
lymph node dissection has proved to be an accurate form 
of axillary staging without the side effects of edema or 
infection. Judicious use of radiotherapy, with treatment 
fields carefully planned to spare the axilla as much as pos
-
sible, can greatly diminish the incidence of edema, which 
will occur in only 5% of patients if no radiotherapy is given 
to the axilla after a partial mastectomy and lymph node 
Late or secondary edema of the arm may develop years 
after treatment, as a result of axillary recurrence or infec
-
tion in the hand or arm, with obliteration of lymphatic 
channels. When edema develops, a careful examination 
of the axilla for recurrence or infection is performed. Infec
-
tion in the arm or hand on the dissected side should be 
treated with antibiotics, rest, and elevation. If there is no 
sign of recurrence or infection, the swollen extremity 
should be treated with rest and elevation. A mild diuretic 
may be helpful. If there is no improvement, a compressor 
pump or manual compression decreases the swelling, and 
the patient is then fitted with an elastic glove or sleeve. 
Most patients are not bothered enough by mild edema to 
wear an uncomfortable glove or sleeve and will treat them
-
selves with elevation or manual compression alone. Rarely, 
edema may be severe enough to interfere with use of the 
limb. A prospective randomized study has shown that 
twice weekly progressive weight lifting improves lymph
-
edema symptoms and exacerbations and improves extrem
-
ity strength.
2. Breast reconstruction—
Breast reconstruction is usually 
feasible after total or modified radical mastectomy. Recon
-
struction should be discussed with patients prior to mas
-
tectomy, because it offers an important psychological focal 
point for recovery. Reconstruction is not an obstacle to the 
diagnosis of recurrent cancer. The most common breast 
reconstruction has been implantation of a silicone gel or 
saline prosthesis in the subpectoral plane between the pec
-
toralis minor and pectoralis major muscles. Alternatively, 
autologous tissue can be used for reconstruction.
Autologous tissue flaps have the advantage of not feel
-
ing like a foreign body to the patient. The most popular 
autologous technique currently is reconstruction using 
abdominal tissue flaps. This includes the deep inferior 
epigastric perforator (DIEP) flap and the more traditional 
transrectus abdominis muscle (TRAM) flap. A latissimus 
dorsi flap can be swung from the back but offers less vol
-
ume than the TRAM flap and thus often requires supple
-
mentation with an implant. Reconstruction may be 
performed immediately (at the time of initial mastectomy) 
or may be delayed until later, usually when the patient has 
completed adjuvant therapy. When considering recon
-
structive options, concomitant illnesses should be consid
-
ered, since the ability of an autologous flap to survive 
depends on medical comorbidities. In addition, the need 
for radiotherapy may affect the choice of reconstruction as 
radiation may increase fibrosis around an implant or 
decrease the volume of a flap.
3. Risks of pregnancy—
Clinicians are often asked to 
advise patients regarding the potential risk of future 
pregnancy after definitive treatment for early-stage breast 
cancer. To date, no adverse effect of pregnancy on survival 
of women who have had breast cancer has been demon
-
strated. When counseling patients, oncologists must take 
into consideration the patients’ overall prognosis, age, 
comorbidities, and life goals.
In patients with inoperable or metastatic cancer 
(stage IV disease), induced abortion may be advisable 
because of the possible adverse effects of hormonal 
treatment, radiotherapy, or chemotherapy upon the fetus 
in addition to the expectant mother’s poor prognosis.
Asdourian MS et al. Association between precautionary behav
-

-
iors and breast cancer-related lymphedema in patients under
-
going bilateral surgery. J Clin Oncol. 2017 Dec 
10;35(35):3934–41. [PMID: 28976793]
Berger AM et al. Cancer-related fatigue: implications for breast 
cancer survivors. Cancer. 2012 Apr 15;118(8 Suppl):2261–9. 
[PMID: 22488700]
Hermelink K. Acute and late onset cognitive dysfunction associ
-
ated with chemotherapy in women with breast cancer. 
Cancer. 2011 Mar 1;117(5):1103. [PMID: 20960507]
Hummel SB et al. Efficacy of internet-based cognitive behavioral 
therapy in improving sexual functioning of breast cancer 
survivors: results of a randomized controlled trial. J Clin 
Oncol. 2017 Apr 20;35(12):1328–40. [PMID: 28240966]
Janelsins MC et al. Cognitive complaints in survivors of breast 
cancer after chemotherapy compared with age-matched con
-
trols: an analysis from a nationwide, multicenter, prospective 
longitudinal study. J Clin Oncol. 2017 Feb 10;35(5):506–14. 
[PMID: 28029304]
Thong MS et al. Population-based cancer registries for quality-
of-life research: a work-in-progress resource for survivorship 
studies? Cancer. 2013 Jun 1;119(Suppl 11):2109–23. [PMID: 
23695923]
 
º
h
E MALE BREAST
 
»
A painless lump beneath the areola in a man usu
-
ally over 50 years of age.
 
»
Nipple discharge, retraction, or ulceration may be 
present.
 
»
Generally poorer prognosis than in women.
 
»
Breast cancer in men is a rare disease; the incidence is only 
about 1% of all breast cancer diagnoses. The average age at 
occurrence is about 70 years and there may be an increased 
incidence of breast cancer in men with prostate cancer. As 
in women, hormonal influences are probably related to the 
development of male breast cancer. There is a high inci
-
dence of both breast cancer and gynecomastia in Bantu 
men, theoretically owing to failure of estrogen inactivation 
by associated liver disease. It is important to note that first-
degree relatives of men with breast cancer are considered to 
be at high risk. This risk should be taken into account 
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when discussing options with the patient and family. In 
addition, 
BRCA2
 mutations are common in men with 
breast cancer. Men with breast cancer, especially with a his
-
tory of prostate cancer, should receive genetic counseling. 
The prognosis, even in stage I cases, is worse in men than 
in women.
 
»
A painless lump, occasionally associated with nipple dis
-
charge, retraction, erosion, or ulceration, is the primary 
complaint. Examination usually shows a hard, ill-defined, 
nontender mass beneath the nipple or areola. Gynecomas
-
tia not uncommonly precedes or accompanies breast can
-
cer in men. Nipple discharge is an uncommon presentation 
for breast cancer in men but is an ominous finding associ
-
ated with carcinoma in nearly 75% of cases.
Breast cancer staging is the same in men as in women. 
Gynecomastia and metastatic cancer from another site (eg, 
prostate) must be considered in the differential diagnosis. 
Benign tumors are rare, and biopsy should be performed 
on all males with a defined breast mass.
 
»
Treatment
Treatment consists of modified radical mastectomy in 
operable patients, who should be chosen by the same crite
-
ria as women with the disease. Breast conserving therapy is 
rarely performed. Irradiation is the first step in treating 
localized metastases in the skin, lymph nodes, or skeleton 
that are causing symptoms. Examination of the cancer for 
hormone receptors and 
HER2
 overexpression is of value in 
determining adjuvant therapy. Over 95% of men have ER-
positive tumors and less than 10% have overexpression of 
HER2
. Androgen receptor is also commonly overexpressed 
in male breast cancer. Adjuvant systemic therapy and 
radiation are used for the same indications as in breast 
cancer in women.
Because breast cancer in men is frequently a dissemi
-
nated disease, endocrine therapy is of considerable impor
-
tance in its management. Tamoxifen is the main drug for 
management of advanced breast cancer in men. Tamoxifen 
(20 mg orally daily) should be the initial treatment. There 
is little data regarding the use of AIs in men. Castration in 
advanced breast cancer is a successful measure and more 
beneficial than the same procedure in women but is rarely 
used. Objective evidence of regression may be seen in 
60–70% of men with endocrine therapy for metastatic dis
-
ease—approximately twice the proportion in women. Bone 
is the most frequent site of metastases from breast cancer 
in men (as in women), and endocrine therapy relieves bone 
pain in most patients so treated. The longer the interval 
between mastectomy and recurrence, the longer the remis
-
sion following treatment is likely. Corticosteroid therapy 
alone has been considered to be efficacious but probably 
has no value when compared with major endocrine 
ablation.
Chemotherapy should be administered for the same 
indications and using the same dosage schedules as for 
women with metastatic disease or for adjuvant treatment.
 
»
Prognosis
A large population based, international study reported 
that after adjustment for prognostic features (age, stage, 
treatment), men have a significantly improved relative 
survival from breast cancer compared to women. For 
node-positive disease, 5-year survival is approximately 
69%, and for node-negative disease, it is 88%. A practice-
patterns database study reported that based on NCCN 
guidelines, only 59% of patients received the recom
-
mended chemotherapy, 82% received the recommended 
hormonal therapy, and 71% received the recommended 
post-mastectomy radiation, indicating a relatively low 
adherence to NCCN guidelines for men.
For those patients whose disease progresses despite 
treatment, meticulous efforts at palliative care are essential 
Colfry AJ III. Miscellaneous syndromes and their management: 
occult breast cancer, breast cancer in pregnancy, male 
breast cancer, surgery in stage IV disease. Surg Clin North

breast cancer, surgery in stage IV disease. Surg Clin North 
Am. 2013 Apr;93(2):519–31. [PMID: 23464700]
Ruddy KJ et al. Male breast cancer: risk factors, biology, diagno
-
sis, treatment, and survivorship. Ann Oncol. 2013 Jun;
 
24(6):1434–43. [PMID: 23425944]
Sousa B et al. An update on male breast cancer and future direc
-
tions for research and treatment. Eur J Pharmacol. 2013 Oct 
5;717(1–3):71–83. [PMID: 23545364]
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18
PREMENOPAUSAL ABNORMAL UTERINE 
BLEEDING
 
»
Accurate diagnosis of abnormal uterine bleeding 
(AUB) depends on appropriate categorization and 
 
»
Pregnancy should always be ruled out as a cause 
of AUB in reproductive age women.
 
»
The evaluation of AUB depends on the age and 
risk factors of the patient.
 
»
Normal menstrual bleeding lasts an average of 5 days 
(range, 2–7 days), with a mean blood loss of 40 mL per 
cycle. 
 is defined as blood loss of over 80 mL 
per cycle and frequently produces anemia. 
 is 
defined as bleeding between periods. 
Polymenorrhea
 is 
defined as bleeding that occurs more often than every 
21  days, and 
oligomenorrhea
 is defined as bleeding that 
occurs less frequently than every 35 days.
The International Federation of Gynecology and 
Obstetrics (FIGO) introduced the current classification 
system for abnormal uterine bleeding, and it was then 
endorsed by the American College of Obstetrics and Gyne
-
cology. The new classification system does not use the term 
“dysfunctional uterine bleeding. ” Instead, it uses the term 
“abnormal uterine bleeding” (AUB)
 and pairs it with 
descriptive terms denoting the bleeding pattern (ie, 
heavy
, 
light
 and 
menstrual
, 
intermenstrual
) and etiology (the 
acronym 
P ALM-COEIN
 standing for 
P
olyp, 
A
denomyosis, 
L
eiomyoma, 
M
alignancy and hyperplasia, 
C
oagulopathy, 
 
O
vulatory dysfunction, 
E
ndometrial, 
I
atrogenic, and 
N
ot 
yet classified). In adolescents, AUB often occurs as a result 
of persistent 
anovulation
 due to the immaturity of the 
hypothalamic-pituitary-ovarian axis and represents nor
-
mal physiology. Once regular menses has been established 
during adolescence, 
ovulatory dysfunction
 AUB (AUB-O) 
accounts for most cases. AUB in women aged 19–39 years 
is often a result of pregnancy, structural lesions, anovula
-
tory cycles, use of hormonal contraception, or endometrial 
hyperplasia.
 
»
The diagnosis depends on the following: (1) A history of 
the duration and amount of flow, associated pain, and rela
-
tionship to the last menstrual period (LMP), with the pres
-
ence of blood clots or the degree of inconvenience caused 
by the bleeding serving as useful indicators; (2) a history of 
pertinent illnesses, such as recent systemic infections, 
other significant physical or emotional stressors, such as 
thyroid disease or weight change; (3) a history of medica
-
tions (such as warfarin, heparin, or exogenous hormones) 
or herbal remedies that might cause AUB (such as ginkgo, 
motherwort and ginseng); (4) a history of coagulation dis
-
orders in the patient or family members; (5) a complete 
physical examination to evaluate for excessive weight and 
signs of polycystic ovary syndrome (PCOS), thyroid dis
-
ease, insulin resistance, or bleeding disorder; and (6) a 
pelvic examination to rule out vulvar, vaginal, or cervical 
lesions, pregnancy, uterine myomas, adnexal masses, ade
-
nomyosis, or infection.
B. Laboratory Studies
A complete blood count, pregnancy test, and thyroid tests 
should be done. For adolescents with heavy menstrual 
bleeding and adults with a positive screening history, 
coagulation studies should be considered, since up to 18% 
of women with severe menorrhagia have an underlying 
coagulopathy. Vaginal or urine samples should be obtained 
for polymerase chain reaction (PCR) or culture to rule out 
Chlamydia
 infection. If indicated, cervical cytology should 
also be obtained.
C. Imaging
Transvaginal ultrasound is useful to diagnose intrauterine 
or ectopic pregnancy or adnexal or uterine masses and to 
evaluate endometrial thickness. Sonohysterography or 
Jason Woo, MD, MPH, FACOG
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hysteroscopy may be used to diagnose endometrial polyps 
or subserous myomas. MRI is not a primary imaging 
modality for AUB but can more definitively diagnose sub
-
mucous myomas and adenomyosis.
D. Cervical Biopsy and Endometrial Sampling
The purpose of endometrial sampling is to determine if 
hyperplasia or carcinoma is present. Sampling methods 
and other gynecologic diagnostic procedures are described 
in Table 18–1. Polyps, endometrial hyperplasia and, occa
-
sionally, submucous myomas are identified on endometrial 
biopsy. Endometrial sampling should be performed in 
patients with AUB who are older than 45 years, or in 
younger patients with a history of unopposed estrogen 
exposure or failed medical management and persistent 
AUB
.
 If the Papanicolaou smear abnormality requires it, or 
a gross cervical lesion is seen, colposcopic-directed biop
-
sies and endocervical curettage are usually indicated.
 
»
Treatment
Treatment for premenopausal patients with AUB depends 
on the etiology of the bleeding, determined by history, 
physical examination, laboratory findings, imaging, and 
endometrial sampling. Patients with AUB secondary to 
submucosal myomas, infection, early abortion, thrombo
-
philias, or pelvic neoplasms may require definitive therapy. 
A large proportion of premenopausal patients, however, 
have ovulatory dysfunction AUB (AUB-O).
AUB-O can be treated hormonally. Progestins, which 
limit and stabilize endometrial growth, are generally effec
-
tive. For patients with irregular or light bleeding, medroxy
-
progesterone acetate, 10 mg/day orally, or norethindrone 
acetate, 5 mg/day orally, should be given for 10 days, fol
-
lowing which withdrawal bleeding will occur. If successful, 
the treatment can be repeated for several cycles, starting 
medication on day 15 of subsequent cycles, or it can be 
reinstituted if amenorrhea or dysfunctional bleeding 
recurs. Nonsteroidal anti-inflammatory drugs (NSAIDs), 
such as naproxen or mefenamic acid, in the usual anti-
inflammatory doses, will also often reduce blood loss in 
menorrhagia—even that associated with a copper intra
-
uterine device (IUD). Women who are experiencing 
heavier bleeding can be given a taper of any of the combi
-
nation oral contraceptives (with 30–35 mcg of estrogen 
estradiol) to control the bleeding. There are several com
-
monly used contraceptive dosing regimens, including four 
times daily for 1 or 2 days followed by two pills daily 
through day 5 and then one pill daily through day 20; after 
withdrawal bleeding occurs, pills are taken in the usual 
dosage for three cycles. In cases of intractable heavy bleed
-
ing, a gonadotropin-releasing hormone (GnRH) agonist 
such as depot leuprolide, 3.75 mg intramuscularly monthly, 
can be used for up to 6 months to create a temporary ces
-
sation of menstruation by ovarian suppression. These 
therapies require 2–4 weeks to down-regulate the pituitary 
and stop bleeding and will not stop bleeding acutely. In 
cases of heavy bleeding requiring hospitalization, intrave
-
nous conjugated estrogens, 25 mg every 4 hours for three 
or four doses, can be used, followed by oral conjugated 
estrogens, 2.5 mg daily, or ethinyl estradiol, 20 mcg orally 
daily, for 3 weeks, with the addition of medroxyprogester
-
one acetate, 10 mg orally daily for the last 10 days of treat
-
ment, or a combination oral contraceptive daily for 3 weeks. 
This will thicken the endometrium and control the 
bleeding.
If the abnormal bleeding is not controlled by hormonal 
treatment, hysteroscopy with tissue sampling or saline infu
-
sion sonohysterography is used to evaluate for structural 
lesions (such as polyps, submucous myomas) or neoplasms 
(such as endometrial cancer). In the absence of specific 
pathology, bleeding unresponsive to medical therapy may be 
treated with endometrial ablation, levonorgestrel-releasing 
IUD (LNG-IUD), or hysterectomy. While hysterectomy 
Table 18–1.

Common gynecologic diagnostic 
Colposcopy
Visualization of cervical, vaginal, or vulvar epithelium under 
5–50 × magnification with and without dilute acetic acid 
to identify abnormal areas requiring biopsy. An office 
Dilation & curettage (D&C)
Dilation of the cervix and curettage of the entire endometrial 
cavity, using a metal curette or suction cannula and often 
using forceps for the removal of endometrial polyps. Can 
usually be done in the office under local anesthesia or in the 
operating room under sedation or general anesthesia. D&C is 
often combined with hysteroscopy for improved sensitivity.
Blind sampling of the endometrium by means of a curette or 
small aspiration device without cervical dilation. Diagnostic 
accuracy similar to D&C. An office procedure performed with 
or without local anesthesia.
Endocervical curettage
Removal of endocervical epithelium with a small curette for 
diagnosis of cervical dysplasia and cancer. An office proce
-
dure performed with or without local anesthesia.
Hysterosalpingography
Injection of radiopaque dye through the cervix to visualize the 
uterine cavity and oviducts. Mainly used in investigation of 
infertility, to identify a space-occupying lesion, or to confirm 
fallopian tube inserts (Essure
®
) sterilization.
Hysteroscopy
Visual examination of the uterine cavity with a small fiberoptic 
endoscope passed through the cervix. Curettage, endome
-
trial ablation, biopsies of lesions, and excision of myomas or 
polyps can be performed concurrently. Can be done in the 
office under local anesthesia or in the operating room under 
sedation or general anesthesia. Greater sensitivity for diag
-
nosis of uterine pathology than D&C.
Visualization of the abdominal and pelvic cavity through a 
small fiberoptic endoscope passed through a subumbilical 
incision. Permits diagnosis, tubal sterilization, and treatment 
of many conditions previously requiring laparotomy. General 
anesthesia is used.
Saline infusion sonohysterography
Introduction of saline solution into endometrial cavity with a 
catheter to visualize submucous myomas or endometrial 
 
polyps by transvaginal ultrasound. May be performed in the 
office with oral or local analgesia, or both.
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was used commonly in the past for bleeding unresponsive 
to medical therapy, the low risk of complications and the 
good short-term results of both endometrial ablation and 
LNG-IUD make them attractive alternatives to hysterec
-
tomy. Endometrial ablation may be performed through the 
hysteroscope with laser photocoagulation or electrocau
-
tery. Nonhysteroscopic techniques include balloon thermal 
ablation, cryoablation, free-fluid thermal ablation, impe
-
dence bipolar radiofrequency ablation, and microwave 
ablation. The latter methods are well-adapted to outpatient 
therapy under local anesthesia.
The LNG-IUD markedly reduces menstrual blood loss 
and may be a good alternative to other therapies. A risk-
benefit review concluded the LNG-IUD is equally effective 
as surgical procedures in improving quality of life and is 
consistently a cost-effective option across a variety of coun
-
tries and settings.
 
»
•	
If bleeding is not controlled with first-line therapy.
•	
If expertise is needed for a surgical procedure.
 
»
If bleeding is uncontrollable with first-line therapy or the 
patient is not hemodynamically stable.
American College of Obstetricians and Gynecologists. ACOG 
Committee Opinion No. 557: Management of acute abnormal 
uterine bleeding in nonpregnant reproductive-aged women. 
Obstet Gynecol. 2013 Apr;121(4):891–6. [PMID: 23635706]
American College of Obstetricians and Gynecologists. Practice 
Bulletin No. 128: Diagnosis of abnormal uterine bleeding in 
reproductive aged women. Obstet Gynecol. 2012 Jul;120(1):
 
197–206. [PMID: 22914421]
Bradley LD et al. The medical management of abnormal uterine 
bleeding in reproductive-aged women. Am J Obstet Gynecol. 
2016 Jan;214(1):31–44. [PMID: 26254516]
Dueholm M et al. Structured imaging technique in the gyneco
-
logic office for the diagnosis of abnormal uterine bleeding. 
Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:23–43. 
[PMID: 27818130]
Wise MR et al. Body mass index trumps age in decision for 
endometrial biopsy: cohort study of symptomatic premeno
-
pausal women. Am J Obstet Gynecol. 2016 Nov;215(5):598.
e1–598. [PMID: 27287687]
POSTMENOPAUSAL VAGINAL BLEEDING
 
»
Vaginal bleeding that occurs 6 months or more 
following cessation of menstrual cycle.
 
»
Postmenopausal bleeding of any amount always 
should be evaluated.
 
»
Transvaginal ultrasound measurement of the 
endometrium is an important tool in evaluating 
the etiology of postmenopausal bleeding.
 
»
The most common causes are endometrial atrophy, endo
-
metrial proliferation or hyperplasia, endometrial or cervi
-
cal cancer, and administration of estrogens without or with 
added progestin. Other causes include atrophic vaginitis, 
trauma, endometrial polyps, friction ulcers of the cervix 
associated with prolapse of the uterus, and blood 
dyscrasias.
 
»
Diagnosis
The vulva and vagina should be inspected for areas of 
bleeding, ulcers, or neoplasms. Cervical cytology should be 
obtained, if indicated. Transvaginal sonography should be 
used to measure endometrial thickness. An endometrial 
stripe measurement of 4 mm or less indicates a low likeli
-
hood of hyperplasia or endometrial cancer. If the endome
-
trial thickness is greater than 4 mm or there is a 
heterogeneous appearance to the endometrium, endome
-
trial sampling is indicated. Sonohysterography may be 
helpful in determining if the endometrial thickening is 
diffuse or focal. If the thickening is global, endometrial 
biopsy or D&C is appropriate. If focal, guided sampling 
with hysteroscopy should be done.
 
»
Treatment
Simple endometrial hyperplasia calls for cyclic or continu
-
ous progestin therapy (medroxyprogesterone acetate, 
10  mg/day orally, or norethindrone acetate, 5 mg/day 
orally) for 21 or 30 days of each month for 3 months. 
The  use of a levonorgestrel intrauterine system is also a

The  use of a levonorgestrel intrauterine system is also a 
treatment option. Repeat sampling should be performed if 
symptoms recur. If endometrial hyperplasia with atypia or 
if carcinoma of the endometrium is found, hysterectomy is 
 
»
•	
Expertise in performing ultrasonography is required.
•	
Endometrial hyperplasia with atypia is present.
•	
Hysteroscopy is indicated.
Seckin B et al. Diagnostic value of sonography for detecting 
endometrial pathologies in postmenopausal women with and 
without bleeding. J Clin Ultrasound. 2016 Jul 8;44(6):339–46. 
[PMID: 26857098]
Turnbull HL et al. Investigating vaginal bleeding in postmeno
-
pausal women found to have an endometrial thickness of 
equal to or greater than 10 mm on ultrasonography. Arch 
Gynecol Obstet. 2017 Feb;295(2):445–50. [PMID: 27909879]
PREMENSTRUAL SYNDROME 
 
(Premenstrual Tension)
 
»
The 
premenstrual syndrome (PMS)
 is a recurrent, variable 
cluster of troublesome physical and emotional symptoms 
that develop during the 5 days before the onset of menses 
and subside within 4 days after menstruation occurs. PMS 
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intermittently affects about 40% of all premenopausal 
women, primarily those 25–40 years of age. In about 5–8% 
of affected women, the syndrome may be severe. Although 
not every woman experiences all the symptoms or signs at 
one time, many describe bloating, breast pain, ankle swell
-
ing, a sense of increased weight, skin disorders, irritability, 
aggressiveness, depression, inability to concentrate, libido 
change, lethargy, and food cravings. When emotional or 
mood symptoms predominate, along with physical symp
-
toms, and there is a clear functional impairment with work 
or personal relationships, the term 
“premenstrual dys
-
phoric disorder” (PMDD)
 may be applied. The pathogen
-
esis of PMS/PMDD is still uncertain, and current treatment 
methods are mainly empiric. The clinician should provide 
support for both the patient’s emotional and physical dis
-
tress. This includes the following:
1.
 
Careful evaluation of the patient, with understanding, 
explanation, and reassurance.
2.
 
Advice to the patient to keep a daily diary of all symp
-
toms for 2–3 months, such as the Daily Record of 
Severity of Problems, to evaluate the timing and charac
-
teristics of her symptoms. If her symptoms occur 
throughout the month rather than in the 2 weeks before 
menses, she may have depression or other mental 
health problems instead of or in addition to PMS.
 
»
Treatment
For mild to moderate symptoms, a program of aerobic 
exercise; reduction of caffeine, salt, and alcohol intake; an 
increase in dietary calcium (to 1200 mg/day), vitamin D, or 
magnesium, and complex carbohydrates in the diet; and 
use of alternative therapies such as acupuncture and herbal 
treatments may be helpful, although these interventions 
remain unproven.
Medications that prevent ovulation, such as hormonal 
contraceptives, may lessen physical symptoms. These 
include continuous combined oral contraceptive pill or vagi
-
nal ring use; depot medroxyprogesterone acetate (DMPA), 
150 mg intramuscularly every 3 months; etonogestrel sub
-
dermal (Nexplanon) progestin implant, every 3 years; high-
dose progestin (eg, medroxyprogesterone acetate, 20–30 mg 
orally daily); or GnRH agonist with “add-back” therapy (eg, 
conjugated equine estrogen, 0.625 mg orally daily with 
medroxyprogesterone acetate, 2.5–5 mg orally daily).
When mood disorders predominate, several serotonin 
reuptake inhibitors have been shown to be effective in 
relieving tension, irritability, and dysphoria with few side 
effects. First-line medication therapy includes serotonergic 
antidepressants (citalopram, escitalopram, fluoxetine, ser
-
traline, venlafaxine) either daily or only on symptom days. 
There are few data to support the use of calcium, 
 
v
itamin D, 
and vitamin B
6
 supplementation. There is insufficient evi
-
dence to support cognitive behavioral therapy.
Green-top Guideline No. 48. Management of premenstrual syn
-
drome. BJOG. 2017 Feb;124(3):e73–105. [PMID: 27900828]
Hofmeister S et al. Premenstrual syndrome and premenstrual 
dysphoric disorder. Am Fam Physician. 2016 Aug 1;94(3):236–40. 
 
[PMID: 27479626]
Kelderhouse K et al. A review of treatment and management 
modalities for premenstrual dysphoric disorder. Nurs Wom
-
ens Health. 2013 Aug–Sep;17(4):294–305. [PMID: 23957795]
Naheed B et al. Non-contraceptive oestrogen-containing prepa
-
rations for controlling symptoms of premenstrual syndrome. 
Cochrane Database Syst Rev. 2017 Mar 3;3:CD010503. 
[PMID: 28257559]
Y onkers KA et al. Premenstrual disorders. Am J Obstet Gynecol. 
2018 Jan;218(1):68–74. [PMID: 28571724]
1. 
p
rimar
y Dysmenorrhea
Primary dysmenorrhea is menstrual pain associated with 
menstrual cycles in the absence of pathologic findings. 
Pain usually begins within 1–2 years after the menarche 
and may become progressively more severe. The frequency 
of cases increases up to age 20 and then decreases with

of cases increases up to age 20 and then decreases with 
both increasing age and parity. Fifty to 75% of women are 
affected by dysmenorrhea at some time and 5–6% have 
incapacitating pain.
 
»
Primary dysmenorrhea is low, midline, wave-like, cramp
-
ing pelvic pain often radiating to the back or inner thighs. 
Cramps may last for 1 or more days and may be associated 
with nausea, diarrhea, headache, and flushing. The pain is 
produced by uterine vasoconstriction, anoxia, and sus
-
tained contractions mediated by prostaglandins. The pelvic 
examination is normal between menses; examination dur
-
ing menses may produce discomfort, but there are no 
pathologic findings.
 
»
Treatment
NSAIDs (ibuprofen, ketoprofen, mefenamic acid, 
naproxen) and the cyclooxygenase (COX)-2 inhibitor cele
-
coxib are generally helpful. The medication should be 
started 1–2 days before expected menses. Symptoms can be 
suppressed with use of combined oral contraceptives, 
DMPA, etonogestrel subdermal (Nexplanon), or the LNG-
IUD. Continuous use of oral contraceptives can be used to 
suppress menstruation completely and prevent dysmenor
-
rhea. For women who do not wish to use hormonal contra
-
ception, other therapies that have shown at least some 
benefit include local heat; thiamine, 100 mg/day orally; 
vitamin E, 200 units/day orally from 2 days prior to and for 
the first 3 days of menses; and high-frequency transcutane
-
ous electrical nerve stimulation.
2. Other Categories of 
p
elvic 
p
ain
Unlike primary dysmenorrhea, other causes of pelvic pain 
may or may not be associated with the menstrual cycle but 
are more likely to be associated with pelvic pathology. Con
-
ditions such as endometriosis, adenomyosis, fibroids, pel
-
vic inflammatory disease (PID), or other anatomic 
abnormalities of the pelvic organs, including the bowel or 
bladder, may present with symptoms during the menstrual 
cycle or with a more chronic nature.
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»
The history and physical examination may suggest endo
-
metriosis, adenomyosis, or fibroids. Other causes include 
PID, submucous myoma(s), IUD use, cervical stenosis with 
obstruction, or blind uterine horn (rare). Careful review of 
associated bowel or bladder symptoms should be done to 
exclude another pelvic organ source.
 
»
Diagnosis
Pelvic imaging is useful for diagnosing the presence of uter
-
ine fibroids or other anomalies. Adenomyosis (the presence 
of islands of endometrial tissue in the myometrium) may be 
detected with ultrasound or MRI. Cervical stenosis may 
result from procedures done to the cervix, such as loop 
electrosurgical excision procedure (LEEP) or from an 
induced abortion. Such stenosis can create crampy pain at 
the time of expected menses with obstruction of blood flow. 
Laparoscopy may be used to diagnose endometriosis or 
other pelvic abnormalities not visualized by imaging.
 
»
Treatment
Combined estrogen and progestin and progestin-only 
hormonal contraceptives are first-line therapies in allevi
-
ating the symptoms of dysmenorrhea. Periodic use of 
analgesics, including the NSAIDs given for primary dys
-
menorrhea, may be beneficial, particularly in endometrio
-
sis. GnRH agonists are also an effective treatment of 
endometriosis, although their long-term use may be lim
-
ited by cost or side effects. Adenomyosis may respond to 
the levonorgestrel-releasing intrauterine system, uterine 
artery embolization, or hormonal approaches used to treat 
endometriosis, but hysterectomy remains the definitive 
treatment of choice for women for whom childbearing is 
not a consideration. Cervical stenosis is easily cured by 
passing a sound into the uterine cavity after administering 
a paracervical block.
B. Surgical Measures
If disability is marked or prolonged, laparoscopy or explor
-
atory laparotomy is usually warranted. Definitive surgery 
depends on the degree of disability and the findings at 
operation. Uterine fibroids may be removed or treated by 
uterine artery embolization. Hysterectomy may be done if 
other treatments have not worked but is usually a last resort.
 
»
•	
Standard therapy fails to relieve pain.
•	
Suspicion of pelvic pathology, such as endometriosis, 
leiomyomas, or adenomyosis.
Ayorinde AA et al. Chronic pelvic pain in women of reproduc
-
tive and post-reproductive age: a population-based study. Eur 
J Pain. 2017 Mar;21(3):445–55. [PMID: 27634190]
Carey ET et al. Pharmacological management of chronic pelvic pain 
in women. Drugs. 2017 Mar;77(3):285–301. [PMID: 28074359]
Iacovides S et al. What we know about primary dysmenorrhea 
today: a critical review. Hum Reprod Update. 2015 Nov–Dec;
 
21(6):762–78. [PMID: 26346058]
Morotti M et al. Mechanisms of pain in endometriosis. Eur J 
Obstet Gynecol Reprod Biol. 2017 Feb;209:8–13. [PMID: 
27522645]
Radzinsky VE et al. Treatment strategies for pelvic pain associ
-
ated with adenomyosis. Gynecol Endocrinol. 2016 Oct;
 
32(Suppl 2):19–22. [PMID: 27759444]
Y osef A et al. Multifactorial contributors to the severity of chronic 
pelvic pain in women. Am J Obstet Gynecol. 2016 Dec;
 
215(6):760.e1–760. [PMID: 27443813]
VAGINITIS
 
»
Vaginal irritation.
 
»
Pruritus.
 
»
Abnormal or malodorous discharge.
 
»
Inflammation and infection of the vagina are common 
gynecologic complaints, resulting from a variety of patho
-
gens, allergic reactions to vaginal contraceptives or other 
products, vaginal atrophy, or friction during coitus. The 
normal vaginal pH is 4.5 or less, and 
Lactobacillus
 is the 
predominant organism. Normal secretions during the 
middle of the cycle, or during pregnancy, can be confused 
with vaginitis by concerned women.
 
»
When the patient complains of vaginal irritation, pain, or 
unusual or malodorous discharge, a history should be

»
unusual or malodorous discharge, a history should be 
taken, noting the onset of the LMP; recent sexual activity; 
use of contraceptives, tampons, or douches; recent 
changes in medications or use of antibiotics; and the pres
-
ence of vaginal burning, pain, pruritus, or unusually 
profuse or malodorous discharge. The physical examina
-
tion should include careful inspection of the vulva and 
speculum examination of the vagina and cervix. A vagi
-
nal, cervical, or urine sample can be obtained for detec
-
tion of gonococcus and 
Chlamydia,
 if clinically indicated. 
A specimen of vaginal discharge is examined under the 
microscope in a drop of 0.9% saline solution to look for 
trichomonads or clue cells and in a drop of 10% potas
-
sium hydroxide to search for 
Candida
. The vaginal pH 
should be tested; it is frequently greater than 4.5 in infec
-
tions due to trichomonads and bacterial vaginosis. A 
bimanual examination to look for evidence of pelvic 
infection, namely cervical motion or adnexal tenderness, 
should follow. Point-of-care testing is available for all 
three main organisms that cause vaginitis and can be used 
if microscopy is not available or for confirmatory testing 
of microscopy.
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A. Vulvovaginal Candidiasis
Pregnancy, diabetes, and use of broad-spectrum antibiotics 
or corticosteroids predispose patients to 
Candida
 infec
-
tions. Heat, moisture, and occlusive clothing also contrib
-
ute to the risk. Pruritus, vulvovaginal erythema, and a 
white curd-like discharge that is not malodorous are found 
(Figure 18–1). Microscopic examination with 10% potas
-
sium hydroxide reveals hyphae and spores. A swab for 
cultures with Nickerson medium or for PCR testing may be 
performed if 
Candida
 is suspected but not demonstrated.
B. 
 Vaginitis
This sexually transmitted protozoal flagellate infects the 
vagina, Skene ducts, and lower urinary tract in women and 
the lower genitourinary tract in men. Pruritus and a mal
-
odorous frothy, yellow-green discharge occur, along with 
diffuse vaginal erythema and red macular lesions on the 
cervix in severe cases (“
strawberry cervix
, ” Figure 18–2). 
Motile organisms with flagella are seen by microscopic 
examination of a wet mount with saline solution.
C. Bacterial Vaginosis
This condition is a polymicrobial disease that is 
not
 sexu
-
ally transmitted. An overgrowth of 
Gardnerella
 and other 
anaerobes is often associated with increased malodorous 
discharge without obvious vulvitis or vaginitis. The dis
-
charge is grayish and sometimes frothy, with a pH of 
 
5.0–5.5. An amine-like (“fishy”) odor is present if a drop of 
discharge is alkalinized with 10% potassium hydroxide. 
 
On wet mount in saline, epithelial cells are covered with 
bacteria to such an extent that cell borders are obscured 
(
clue cells
,
 Figure 18–3). Vaginal cultures are generally not 
useful in diagnosis; however, PCR testing is available.
 
»
Treatment
A variety of topical and oral regimens are available to treat 
vulvovaginal candidiasis. Women with uncomplicated vulvo
-
vaginal candidiasis will usually respond to a 1- to 3-day regi
-
men of a topical azole or a one-time dose of oral fluconazole. 
Women with complicated infection (including four or more 
episodes in 1 year [
recurrent
 vulvovaginal candidiasis], severe 
signs and symptoms, non-albicans species, uncontrolled dia
-
betes, HIV infection, corticosteroid treatment, or pregnancy) 
should receive 7–14 days of a topical regimen or two doses of 
oral fluconazole 3 days apart. In recurrent non-albicans 
 
▲
Figure 18–1.
 
Cervical candidiasis. 
(Public Health 
 
▲
Figure 18–2.
 
Strawberry cervix in 
Trichomonas 
 
vaginalis
 infection, with inflammation and punctate 
hemorrhages. 
Usatine, MD.)
 
▲
Figure 18–3.
 
Clue cells seen in bacterial vaginosis 
due to 
Gardnerella vaginalis.
 
(Reproduced, with permis
-
sion, from Richard P . Usatine, MD.)
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infections, 600 mg of boric acid in a gelatin capsule intravagi
-
nally once daily for 2 weeks is approximately 70% effective. If 
recurrence occurs, referral to a gynecologist or an infectious 
disease specialist is indicated.
1. Single-dose regimens—
Effective single-dose regimens 
include miconazole (1200-mg vaginal suppository), tio
-
conazole (6.5% cream, 5 g vaginally), sustained-release 
butoconazole (2% cream, 5 g vaginally), or fluconazole 
(150-mg oral tablet).
2. Three-day regimens—
Effective 3-day regimens include 
butoconazole (2% cream, 5 g vaginally once daily), clotrim
-
azole (2% cream, 5 g vaginally once daily), terconazole 
(0.8% cream, 5 g, or 80-mg vaginal suppository once daily), 
or miconazole (200-mg vaginal suppository once daily).
3. Seven-day regimens—
The following regimens are 
given once daily: clotrimazole (1% cream), miconazole (2% 
cream, 5 g, or 100-mg vaginal suppository), or terconazole 
(0.4% cream, 5 g).
4. Fourteen-day regimen—
An effective 14-day regimen is 
nystatin (100,000-unit vaginal tablet once daily).
5. Recurrent vulvovaginal candidiasis (maintenance 
therapy)—
Clotrimazole (500-mg vaginal suppository 
once weekly or 200 mg cream twice weekly) or fluconazole 
(100, 150, or 200 mg orally once weekly) are effective regi
-
mens for maintenance therapy for up to 6 months.
B. 
Trichomonas vaginalis 
Vaginitis
Treatment of both partners simultaneously is recom
-
mended; metronidazole or tinidazole, 2 g orally as a single 
dose or 500 mg orally twice a day for 7 days, is usually used.
In the case of treatment failure with metronidazole in 
the absence of reexposure, the patient should be re-treated 
with metronidazole, 500 mg orally twice a day for 7 days, 
or tinidazole, 2 g orally as a single dose. If treatment failure 
occurs again, give metronidazole or tinidazole, 2 g orally 
once daily for 5 days. If this is not effective in eradicating 
the organisms, metronidazole and tinidazole susceptibility 
testing can be arranged with the Centers for Disease Con
-
trol and Prevention (CDC) at 404-718-4141 or at http://
www.cdc.gov/std. Women infected with 
T vaginalis
 are at 
increased risk for concurrent infection with other sexually 
transmitted diseases and should be offered comprehensive 
STD testing.
The recommended regimens are metronidazole (500 mg 
orally, twice daily for 7 days), clindamycin vaginal cream 
(2%, 5 g, once daily for 7 days), or metronidazole gel 
(0.75%, 5 g, twice daily for 5 days). Alternative regimens 
include clindamycin (300 mg orally twice daily for 7 days), 
clindamycin ovules (100 g intravaginally at bedtime for 
3  days), tinidazole (2 g orally once daily for 3 days), or 
tinidazole (1 g orally once daily for 7 days).
The CDC offers a helpful training module to clinicians 
to review current recommendations for treatment of 
 
vaginitis (www2a.cdc.gov/stdtraining/self-study/vaginitis/
default.htm).
CONDYLOMA ACUMINATA
Warty growths on the vulva, perianal area, vaginal walls, or 
cervix are caused by various types of the human papilloma
-
virus (HPV). Pregnancy and immunosuppression favor 
growth. Ninety percent of genital warts are caused by HPV 
6 and 11. With increasing use of a quadrivalent HPV vac
-
cine in the United States, the prevalence of HPV types 6, 
11, 16 and 18 decreased from 11.5% in 2003–2006 to 4.3% 
in 2009–2012 among girls aged 14–19 years, and from 
18.5% to 12.1% in women aged 20–24 years. Vulvar lesions 
may be obviously wart-like or may be diagnosed only after 
application of 4% acetic acid (vinegar) and colposcopy, 
when they appear whitish, with prominent papillae. Vagi
-
nal lesions may show diffuse hypertrophy or a cobblestone 
appearance.
Recommended treatments for vulvar warts include 
podophyllum resin 10–25% in tincture of benzoin (do not 
use during pregnancy or on bleeding lesions) or 80–90% 
trichloroacetic or bichloroacetic acid, carefully applied to

trichloroacetic or bichloroacetic acid, carefully applied to 
avoid the surrounding skin. The pain of bichloroacetic or 
trichloroacetic acid application can be lessened by a 
sodium bicarbonate paste applied immediately after treat
-
ment. Podophyllum resin must be washed off after 
 
2–4 hours. Freezing with liquid nitrogen or a cryoprobe 
and electrocautery are also effective. Patient-applied regi
-
mens, useful when the entire lesion is accessible to the 
patient, include podofilox 0.5% solution or gel, imiquimod 
5% cream, or sinecatechins 15% ointment. Vaginal warts 
may be treated with cryotherapy with liquid nitrogen or 
trichloroacetic acid. Extensive warts may require treatment 
with CO
2
 laser, electrocautery, or excision under local or 
general anesthesia.
Dunne EF et al. Reduction in human papillomavirus vaccine 
type prevalence among young women screened for cervical 
cancer in an integrated US healthcare delivery system in 2007 
and 2012–2013. J Infect Dis. 2015 Dec 15;212(12):1970–5. 
[PMID: 26123561]
Park IU et al. Human papillomavirus and genital warts: a review 
of the evidence for the 2015 Centers for Disease Control and 
Prevention Sexually Transmitted Diseases Treatment Guide
-
lines. Clin Infect Dis. 2015 Dec 15;61(Suppl 8):S849–55. 
[PMID: 26602622]
Workowski KA et al; Centers for Disease Control and Preven
-
tion. Sexually transmitted diseases treatment guidelines, 
[PMID: 26042815] https://www.cdc.gov/mmwr/preview/
mmwrhtml/rr6403a1.htm
CERVICAL POLYPS
Cervical polyps commonly occur after menarche and are 
occasionally noted in postmenopausal women. The cause 
is not known, but inflammation may play an etiologic role. 
The principal symptoms are discharge and abnormal vagi
-
nal bleeding. However, abnormal bleeding should not be 
ascribed to a cervical polyp without sampling the endocer
-
vix and endometrium. The polyps are visible in the cervical 
os on speculum examination.
Cervical polyps must be differentiated from polypoid 
neoplastic disease of the endometrium, small submucous 
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pedunculated myomas, large nabothian cysts, and endo
-
metrial polyps. Cervical polyps rarely contain dysplasia 
(0.5%) or malignant (0.5%) foci. Asymptomatic polyps in 
women under age 45 may be left untreated.
 
»
Treatment
Cervical polyps can generally be removed in the office by 
avulsion with uterine packing forceps or ring forceps.
BARTHOLIN DUCT CYSTS & ABSCESSES
Trauma or infection may involve the Bartholin duct, caus
-
ing obstruction of the gland. Drainage of secretions is 
prevented, leading to pain, swelling, and abscess formation 
(Figure 18–4). The infection usually resolves and pain dis
-
appears, but stenosis of the duct outlet with distention 
often persists. Reinfection causes recurrent tenderness and 
further enlargement of the duct.
The principal symptoms are periodic painful swelling 
on either side of the introitus and dyspareunia. A fluctuant 
swelling 1–4 cm in diameter lateral to either labium minus 
is a sign of occlusion of Bartholin duct. Tenderness is evi
-
dence of active infection.
Pus or secretions from the gland should be cultured for 
Chlamydia
 and other pathogens and treated accordingly 
(see Chapter 33); frequent warm soaks may be helpful. If 
an abscess develops, aspiration or incision and drainage 
are the simplest forms of therapy, but the problem may 
recur. Marsupialization (in the absence of an abscess), 
incision, and drainage with the insertion of an indwelling 
Word catheter, or laser treatment will establish a new duct 
opening. Antibiotics are unnecessary unless cellulitis 
is present. In women under 40 years of age, asymptomatic 
cysts do not require therapy; in women over age 40, biopsy 
or removal are recommended to rule out vulvar 
 
»
Surgical therapy (marsupialization) is indicated.
CERVICAL INTRAEPITHELIAL NEOPLASIA 
(CIN) (
Dysplasia of the Cervix)
 
»
The presumptive diagnosis is made by an abnor
-
mal Papanicolaou smear of an asymptomatic 
woman with no grossly visible cervical changes.
 
»
Diagnose by colposcopically directed biopsy.
 
»
The squamocolumnar junction of the cervix is an area of 
active squamous cell proliferation. In childhood, this junc
-
tion is located on the exposed vaginal portion of the cervix. 
At puberty, because of hormonal influence and possibly 
because of changes in the vaginal pH, the squamous mar
-
gin begins to encroach on the single-layered, mucus-
secreting epithelium, creating an area of metaplasia 
(
transformation zone
). Infection with HPV (see Preven
-
tion, below) may lead to cellular abnormalities, which over 
a period of time develop into squamous cell dysplasia or 
cancer. There are varying degrees of dysplasia (Table 18–2), 
defined by the degree of cellular atypia; all atypia must be 
observed and treated if persistent or worsening.
 
»
There are no specific symptoms or signs of CIN. The pre
-
sumptive diagnosis is made by cytologic screening of an 
asymptomatic population with no grossly visible cervical 
changes. All visible abnormal cervical lesions should be 
biopsied (Figure 18–5).
 
▲
Figure 18–4.
 
Right-sided Bartholin cyst (abscess). 
The Bartholin gland is located in the lower two-thirds of 
the introitus. 
(From Susan Lindsley, Public Health Image 
Library, CDC.)
Table 18–2.
 
Classification systems for Papanicolaou 
smears.
Numerical
Dysplasia
CIN
Bethesda 
System
1
Benign
Benign
Normal
2
Benign with 
inflammation
Normal, 
ASC-US
3
Mild dysplasia
CIN I
Low-grade 
SIL
3
Moderate 
dysplasia
CIN II
High-grade 
SIL
3
Severe dysplasia
CIN III
4
Carcinoma in 
situ
5
Invasive cancer
Invasive 
cancer
ASC-US, atypical squamous cells of undetermined significance; 
CIN, cervical intraepithelial neoplasia; SIL, squamous intraepithelial 
lesion.
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»
Screening & Diagnosis
A. Cytologic Examination (Papanicolaou Smear)
In immunocompetent women, cervical cancer screening 
should begin at age 21. The recommendation to start 
screening at age 21 years regardless of the age of onset of 
sexual intercourse is based on the very low incidence of 
cancer in younger women and the potential for adverse 
effects associated with treatment of young women with 
abnormal cytology screening results. In contrast to the 
high rate of infection with HPV in sexually active adoles
-
cents, invasive cervical cancer is very rare in women 
younger than age 21 years. The US Preventive Services 
Task Force (USPSTF) recommends screening for cervical 
cancer in women aged 21 to 65 years with cytology (Papa
-
nicolaou smear) every 3 years or, for women aged 30 to 
65  years, screening with a combination of cytology and 
against screening for cervical cancer with HPV testing, 
alone or in combination with cytology, in women younger 
than age 30 years. The USPSTF also recommends against 
cervical cancer screening for women older than age 
 
65 years who have had adequate prior screening and are 
not otherwise at high risk for cervical cancer. Online 
guidelines are available for the management of abnormal 
Papanicolaou smears (https://www.imedicalapps.
com/2013/04/cervical-cancer-screening-medical-app-
asccp-obgyn-physicians/ and https://www.uspreventi
-
veservicestaskforce.org/Page/Document/draft-
 
recommendation-statement/cervical-cancer-screening2). 
Screening may be done with either 
 
liq
uid-based or con
-
ventional cytology. Women with risk factors that place 
them at higher risk for CIN may require more frequent 
screening. These risk factors include HIV infection, immu
-
nosuppression, exposure to diethylstilbesterol in utero, and 
previous treatment for CIN 2, CIN 3, or cervical cancer.
Cytology is performed by collecting exfoliated cells 
from the transformation zone of the cervix with a brush, 
broom, or spatula, and transferring the cells to a vial of 
liquid preservative that is processed in the laboratory to 
produce a slide for interpretation—the liquid-based 
 
technique—or to a slide and fixed using the conventional 
technique. Performance of conventional cervical cytology 
is less commonly used because it requires avoidance of 
contaminating blood, discharge, and lubricant.
Cytologic reports from the laboratory may describe 
findings in one of several ways (see Table 18–2). The 
Bethesda System uses the terminology “atypical squamous 
cells of unknown significance” (
ASC-US
) and “squamous 
intraepithelial lesions, ” either low-grade (
LSIL
) or high-
grade (
HSIL
). Cytopathologists consider a Papanicolaou 
smear to be a medical consultation and will recommend 
further diagnostic procedures, treatment for infection, and 
comments on factors preventing adequate evaluation of the 
specimen.
Although cervical cancer screening with HPV co-testing 
is only recommended in women age 30 and older, HPV 
DNA testing is used as an adjunct in cervical cancer 
screening as a triage test to stratify risk in women age 
21 years and older with a cytologic diagnosis of ASC-US 
and in postmenopausal women with a cytologic diagnosis 
of ASC-US or LSIL. HPV testing should not be used in 
females younger than age 21 years; if inadvertently per
-
formed, a positive result should not influence 
B. Colposcopy
Women with ASC-US and a negative HPV screening may 
be followed up in 1 year for a repeat Pap smear and HPV 
co-testing. If the HPV screen is positive, colposcopy is 
indicated. If HPV screening is unavailable, repeat cytology 
may be done at 12 months. All patients with SIL or atypical 
glandular cells should undergo colposcopy. Viewing the 
cervix with 10–20 × magnification allows for assessment of 
the size and margins of an abnormal transformation zone

the size and margins of an abnormal transformation zone 
and determination of extension into the endocervical 
canal. The application of 3–5% acetic acid (vinegar) dis
-
solves mucus, and the acid’s desiccating action sharpens 
the contrast between normal and actively proliferating 
squamous epithelium. Abnormal changes include white 
patches and vascular atypia, which indicate areas of great
-
est cellular activity.
C. Biopsy
Colposcopically directed punch biopsy and endocervical 
curettage are office procedures. Data from both cervical 
biopsy and endocervical curettage are important in decid
-
ing on treatment.
 
»
Cervical infection with the HPV is associated with a high 
percentage of all cervical dysplasias and cancers. There are 
over 70 recognized HPV subtypes. Types 6 and 11 tend to 
cause genital warts and mild dysplasia and rarely progress 
to cervical cancer; types 16, 18, 31, and others cause 
higher-grade dysplasia. The quadrivalent HPV 6/11/16/18 
L1 virus-like-particle vaccine (known as Gardasil) also 
provides protection against genital warts caused by HPV 
 
▲
Figure 18–5.
 
Erosion of the cervix due to cervical 
intraepithelial neoplasia (CIN), a precursor lesion to 
 
cervical cancer. 
(Public Health Image Library, CDC.)
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types 6 and 11. Vaccination can prevent cervical, vaginal, 
and vulvar cancers and low-grade and precancerous 
lesions caused by HPV types 16 and 18. Gardasil is recom
-
mended for females and males aged 9 to 26. Both vaccines 
provide partial protection against several other HPV types 
that cause approximately 30% of cervical cancers. 
 
Gardasil-9 expands protection to HPV types 31, 33, 45, 52, 
and 58 to cover the strains causing up to 90% of cervical 
cancers; in addition, it has been proven to protect against 
anal cancer and anal intraepithelial neoplasia caused by 
these strains. The use of HPV vaccination in the United 
States continues to increase but varies by state. In 2015, 
63% of girls and 50% of boys aged 13–17 received one or 
more doses of the HPV vaccine; however, these percent
-
ages are still below the target goal of 80% adherence by 
2020 set by the CDC. Because complete coverage of all 
carcinogenic HPV types is not provided by either vaccine, 
all women need to have regular cytologic screening as 
outlined above. In addition to vaccination, preventive 
measures include limiting the number of sexual partners 
and thus exposure to HPV , using a diaphragm or condom 
for coitus, and smoking cessation and avoiding exposure 
to secondhand smoke.
 
»
Treatment
Treatment varies depending on the degree and extent of 
CIN. Biopsies should precede treatment, except in cases of 
HSIL where it may be appropriate to proceed directly to a 
LEEP .
A. Cryosurgery
The use of freezing (cryosurgery) is effective for noninva
-
sive small lesions visible on the cervix without endocervi
-
cal extension.
B. CO
2
 Laser
This well-controlled method minimizes tissue destruc
-
tion. It is colposcopically directed and requires special 
training. It may be used with large visible lesions. In cur
-
rent practice, it involves the vaporization of the transfor
-
mation zone on the cervix and the distal 5–7 mm of 
endocervical canal.
C. Loop Excision
When the CIN is clearly visible in its entirety, a wire loop 
can be used for excisional biopsy. This office procedure, 
called 
LEEP (loop electrosurgical excision procedure)
, 
done with local anesthesia is quick and uncomplicated. 
Cutting and hemostasis are achieved with a low-voltage 
electrosurgical machine.
D. Conization of the Cervix
Conization is surgical removal of the entire transformation 
zone and endocervical canal. It should be reserved for cases 
of severe dysplasia (CIN III) or cancer in situ, particularly 
those with endocervical extension. The procedure can be 
performed with the scalpel, the CO
2
 laser, the needle elec
-
trode, or by large-loop excision.
 
»
Follow-Up
Because recurrence is possible—especially in the first 2 years 
after treatment—and because the false-negative rate of a sin
-
gle cervical cytologic test is 20%, close follow-up after colpos
-
copy and biopsy is imperative. For CIN II or III, cytologic 
examination or cytology and colposcopy should be repeated 
at 12-month intervals for up to 2 years. If CIN II or III is 
identified at the margins of an endocervical curettage proce
-
dure, however, repeat cytology with endocervical curettage is 
recommended at 4–6 months. For CIN I, cytology should be 
performed at 12 months or HPV DNA testing can be done at 
12 months. If testing is normal, routine cytologic screening 
can be resumed unless there is a discrepancy between the 
cytology and the endocervical curettage pathology (eg, a Pap 
test showing HSIL and negative endocervical curettage 
pathology), in which case cytology and HPV DNA co-testing 
at 12 and 14 months, a diagnostic excisional procedure, and 
a review of the cytology and pathology findings is indicated.
The American Society for Colposcopy and Cervical 
Pathology Guidelines for cervical cancer screening and 
management of abnormal Papanicolaou smears are available 
online for free or for purchase as an online application

online for free or for purchase as an online application 
(https://www.imedicalapps.com/2013/04/cervical-cancer-
 
screening-medical-app-asccp-obgyn-physicians/).
 
»
•	
Patients with CIN II/III should be referred to an expe
-
rienced colposcopist.
•	
Patients requiring conization biopsy should be referred 
to a gynecologist.
Bulletin No. 168: Cervical cancer screening and prevention. 
Obstet Gynecol. 2016 Oct;128(4):e111–30. [PMID: 27661651]
Harper DM et al. HPV vaccines—a review of the first decade. 
Gynecol Oncol. 2017 Jul;146(1):196–204. [PMID: 28442134]
Joura EA et al. A 9-valent HPV vaccine against infection and 
intraepithelial neoplasia in women. N Engl J Med. 2015 Feb 19;
 
372(8):711–23. [PMID: 25693011]
Smith RA et al. Cancer screening in the United States, 2017: a 
review of current American Cancer Society guidelines and cur
-
rent issues in cancer screening. CA Cancer J Clin. 2017 Mar;
 
67(2):100–21. [PMID: 28170086]
CARCINOMA OF THE CERVIX
 
»
Increased risk in women who smoke and those 
with HIV or high-risk HPV types.
 
»
Gross lesions should be evaluated by colposcopi
-
cally directed biopsies and not cytology alone.
 
»
Cervical cancer is the third most common cancer in the 
world and the leading cause of cancer death among women 
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in developing countries. It is considered a sexually trans
-
mitted disease as both squamous cell and adenocarcinoma 
of the cervix are secondary to infection with HPV , primar
-
ily types 16 and 18. Women infected with HIV are at an 
increased risk for high-risk HPV infection and CIN. Smok
-
ing and possibly dietary factors such as decreased circulat
-
ing vitamin A appear to be cofactors. Squamous cell 
carcinoma (SCC) accounts for approximately 80% of cervi
-
cal cancers, while adenocarcinoma accounts for 15% and 
adenosquamous carcinoma for 3–5%; neuroendocrine or 
small cell carcinomas are rare.
SCC appears first in the intraepithelial layers (the pre
-
invasive stage, or carcinoma in situ). Preinvasive cancer 
(CIN III) is a common diagnosis in women 25–40 years of 
age. Two to 10 years are required for carcinoma to pene
-
trate the basement membrane and become invasive. While 
cervical cancer mortality has declined steadily in the 
United States due to high rates of screening and improved 
treatment, the rate of decline has slowed in recent years. In 
general, black women experienced much higher incidence 
and mortality than white women. The 5-year survival rate 
ranges from 63% for stage II cervical cancer to less than 
20% for stage IV .
 
»
The most common signs are metrorrhagia, postcoital spot
-
ting, and cervical ulceration. Bladder and rectal dysfunc
-
tion or fistulas and pain are late symptoms.
B. Cervical Biopsy and Endocervical Curettage 
or Conization
These procedures are necessary steps after a positive Papa
-
nicolaou smear to determine the extent and depth of inva
-
sion of the cancer. Even if the smear is positive, treatment 
with additional surgery or radiation is never justified until 
definitive diagnosis has been established through biopsy.
C. “Staging” or Estimate of Gross Spread of Cancer 
of the Cervix
Staging of invasive cervical cancer is achieved by clinical 
evaluation, usually conducted under anesthesia. Further 
examinations, such as ultrasonography, CT, MRI, lym
-
phangiography, laparoscopy, and fine-needle aspiration, 
are valuable for treatment planning.
 
»
Metastases to regional lymph nodes occur with increasing 
frequency from stage I to stage IV . Paracervical extension 
occurs in all directions from the cervix. The ureters may 
become obstructed lateral to the cervix, causing hydroure
-
ter and hydronephrosis and consequently impaired kidney 
function. Almost two-thirds of patients with untreated 
carcinoma of the cervix die of uremia when ureteral 
obstruction is bilateral. Pain in the back, in the distribution 
of the lumbosacral plexus, is often indicative of neurologic 
involvement. Gross edema of the legs may be indicative of 
vascular and lymphatic stasis due to tumor. Vaginal fistulas 
to the rectum and urinary tract are severe late complica
-
tions. Hemorrhage is the cause of death in 10–20% of 
patients with extensive invasive carcinoma.
 
»
Vaccination with the recombinant 4- or 9-valent HPV vac
-
cines (Gardasil) can prevent cervical cancer by targeting the 
HPV types that pose the greatest risk as well as protect 
against low-grade and precancerous lesions caused by other 
HPV types (see Cervical Intraepithelial Neoplasia).
 
»
Treatment
A. Emergency Measures
Vaginal hemorrhage originates from gross ulceration and 
cavitation in later stage cervical carcinoma. Ligation and 
suturing of the cervix are usually not feasible, but emergent 
vaginal packing, cautery, tranexamic acid, and irradiation 
are helpful to stop bleeding temporarily. Ligation, resec
-
tion, or embolization of the uterine or hypogastric arteries 
may be lifesaving when other measures fail.
1. Carcinoma in situ (stage 0)—
In women for whom child
-
bearing is not a consideration, total hysterectomy is the 
definitive treatment. In women who wish to retain the uterus,

-
definitive treatment. In women who wish to retain the uterus, 
acceptable alternatives include cryosurgery, laser surgery, 
LEEP , or cervical conization. Close follow-up with Papanico
-
laou smears every 3 months for 1 year and every 6 months for 
another year is necessary after cryotherapy or laser.
2. Invasive carcinoma—
Microinvasive carcinoma (stage 
IA1) is treated with simple, extrafascial hysterectomy. 
Stages IA2, IB1, and IIA cancers may be treated with either 
radical hysterectomy with concomitant radiation and che
-
motherapy or with radiation plus chemotherapy alone. 
Women with stage IB1 may be candidates for fertility-
sparing surgery that includes radical trachelectomy and 
lymph node dissection with preservation of the uterus and 
ovaries. Stages IB2, IIB, III, and IV cancers are treated with 
radiation therapy plus concurrent chemotherapy.
 
»
Prognosis
The overall 5-year relative survival rate for carcinoma of 
the cervix is 68% in white women and 55% in black women 
in the United States. Survival rates are inversely propor
-
tionate to the stage of cancer: stage 0, 99–100%; stage IA, 
more than 95%; stage IB–IIA, 80–90%; stage IIB, 65%; 
stage III, 40%; and stage IV , less than 20%.
 
»
All patients with invasive cervical carcinoma (stage 1A or 
higher) should be referred to a gynecologic oncologist.
American Cancer Society. Survival rates for cervical cancer, by 
stage. https://www.cancer.org/cancer/cervical-cancer/detection-
 
diagnosis-staging/survival.html
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Eleje GU et al. Palliative interventions for controlling vaginal 
bleeding in advanced cervical cancer. Cochrane Database Syst 
Rev. 2015 May 1;(5):CD011000. [PMID: 25932968]
Li H et al. Advances in diagnosis and treatment of metastatic 
cervical cancer. J Gynecol Oncol. 2016 Jul;27(4):e43. [PMID: 
27171673]
Tsikouras P et al. Cervical cancer: screening, diagnosis and stag
-
ing. J BUON. 2016 Mar–Apr;21(2):320–5. [PMID: 27273940]
Vegunta S et al. Screening women at high risk for cervical can
-
cer: special groups of women who require more frequent 
screening. Mayo Clin Proc. 2017 Aug;92(8):1272–7. [PMID: 
28778260]
Verma J et al. New strategies for multimodality therapy in treating 
locally advanced cervix cancer. Semin Radiat Oncol. 2016 Oct;
 
26(4):344–8. [PMID: 27619255]
LEIOMYOMA OF THE UTERUS 
 
(
Fibroid Tumor
)
 
»
Irregular enlargement of the uterus (may be 
asymptomatic).
 
»
Heavy or irregular vaginal bleeding, dysmenorrhea.
 
»
Pelvic pain and pressure.
 
»
Uterine leiomyoma is the most common benign neoplasm 
of the female genital tract. It is a discrete, round, firm, 
often multiple uterine tumor composed of smooth muscle 
and connective tissue. The most convenient classification 
is by anatomic location: (1) intramural, (2) submucous, (3) 
subserous, (4) intraligamentous, (5) parasitic (ie, deriving 
its blood supply from an organ to which it becomes 
attached), and (6) cervical. Submucous myomas may 
become pedunculated and descend through the cervix 
into the vagina.
 
»
In nonpregnant women, myomas are frequently asymp
-
tomatic. The two most common symptoms of uterine 
leiomyomas for which women seek treatment are AUB 
and pelvic pain or pressure. Occasionally, degeneration 
occurs, causing intense pain. The risk of miscarriage is 
increased if the myoma significantly distorts the uterine 
cavity and interferes with implantation. Fibroids rarely 
cause infertility by leading to bilateral tubal blockage; they 
more commonly cause miscarriage and pregnancy com
-
plications such as preterm labor, preterm delivery, and 
malpresentation.
Iron deficiency anemia may result from blood loss.
C. Imaging
Ultrasonography will confirm the presence of uterine myomas 
and can be used sequentially to monitor growth. When mul
-
tiple subserous or pedunculated myomas are being followed, 
ultrasonography is important to exclude ovarian masses. MRI 
can delineate intramural and submucous myomas accurately 
and is necessary prior to uterine artery embolization to assess 
blood flow to the fibroids. Hysterography or hysteroscopy can 
also confirm cervical or submucous myomas.
 
»
Irregular myomatous enlargement of the uterus must be 
differentiated from the similar, but symmetric enlargement 
that may occur with pregnancy or adenomyosis. Subserous 
myomas must be distinguished from ovarian tumors. Leio
-
myosarcoma is an unusual tumor occurring in 0.5% of 
women operated on for symptomatic myoma. It is very rare 
under the age of 40 and increases in incidence thereafter.
 
»
Treatment
Emergency surgery may be required for acute torsion of a 
pedunculated myoma. If the patient is markedly anemic as a 
result of long, heavy menstrual periods, preoperative treat
-
ment with DMPA, 150 mg intramuscularly every 3 months, 
or use of a GnRH agonist, such as depot leuprolide, 3.75 mg 
intramuscularly monthly, will slow or stop bleeding, and 
medical treatment of anemia can be given prior to surgery. 
Levonorgestrel-containing IUDs have also been used to 
decrease the bleeding associated with fibroids; however, IUD 
placement can be more technically challenging in patients 
with fibroids. The only emergency indication for myomec
-
tomy during pregnancy is torsion of a pedunculated fibroid.

-
Women who have small asymptomatic myomas can be 
managed expectantly and evaluated annually. In patients 
wishing to defer surgical management, nonhormonal ther
-
apies (such as NSAIDs and tranexamic acid) have been 
shown to decrease menstrual blood loss. Hormonal thera
-
pies such as GnRH agonists and selective progesterone 
receptor modulators (SPRMs), such as low-dose mifepris
-
tone (5–10 mg/day) have been shown to reduce myoma 
volume, uterine size, and menstrual blood loss. Surgical 
intervention is based on the patient’s symptoms and desire 
for future fertility. Uterine size alone is not an indication 
for surgery. Cervical myomas larger than 3–4 cm in diam
-
eter or pedunculated myomas that protrude through the 
cervix can cause bleeding, infection, degeneration, pain, or 
urinary retention and often require removal. Submucous 
myomas can be removed by hysteroscopic resection.
Because the risk of surgical complications increases 
with the increasing size of the myoma, preoperative reduc
-
tion of myoma size is sometimes desirable prior to hyster
-
ectomy. GnRH analogs such as depot leuprolide, 3.75 mg 
intramuscularly monthly, can be used preoperatively for 
3- to 4-month periods to induce reversible hypogonadism, 
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to temporarily reduce the size of myomas, and reduce sur
-
rounding vascularity.
A variety of surgical measures are available for the treat
-
ment of myomas: myomectomy (hysteroscopic, laparo
-
scopic, or abdominal) and hysterectomy (vaginal, 
laparoscopy-assisted vaginal, laparoscopic, abdominal, or 
robotic). Myomectomy is the treatment of choice for 
women who wish to preserve fertility. Uterine artery 
embolization is a minimally invasive treatment for uterine 
fibroids. In uterine artery embolization, the goal is to block 
the blood vessels supplying the fibroids, causing them to 
shrink. Magnetic resonance–guided high-intensity focused 
ultrasound, myolysis/radiofrequency ablation, and laparo
-
scopic or vaginal occlusion of uterine vessels are newer 
interventions, with a smaller body of evidence.
 
»
Prognosis
Surgical therapy is curative. In women desiring future fertil
-
ity, myomectomy can be offered, but patients should be 
counseled that recurrence is common, postoperative pelvic 
adhesions may impact fertility, and cesarean delivery may be 
necessary secondary to interruption of the myometrium.
 
»
Refer to a gynecologist for treatment of symptomatic 
leiomyomata.
 
»
For acute abdomen associated with an infarcted leiomyoma 
or hemorrhage not controlled by outpatient measures.
Kashani BN et al. Role of medical management for uterine leiomyo
-
mas. Best Pract Res Clin Obstet Gynaecol. 2016 Jul;34:85–103. 
[PMID: 26796059]
Laughlin-Tommaso SK. Alternatives to hysterectomy: manage
-
ment of uterine fibroids. Obstet Gynecol Clin North Am. 
2016 Sep;43(3):397–413. [PMID: 27521875]
Murji A et al. Selective progesterone receptor modulators 
(SPRMs) for uterine fibroids. Cochrane Database Syst Rev. 
2017 Apr 26;4:CD010770. [PMID: 28444736]
Ordulu Z. Fibroids: genotype and phenotype. Clin Obstet Gyne
-
col. 2016 Mar;59(1):25–9. [PMID: 26710305]
Wise LA et al. Epidemiology of uterine fibroids: from menarche 
to menopause. Clin Obstet Gynecol. 2016 Mar;59(1):2–24. 
[PMID: 26744813]
CARCINOMA OF THE ENDOMETRIUM
 
»
Abnormal bleeding is the presenting sign in 90% 
of cases.
 
»
Papanicolaou smear is frequently negative.
 
»
After a negative pregnancy test, endometrial tis
-
sue is required to confirm the diagnosis.
 
»
Adenocarcinoma of the endometrium is the second most 
common cancer of the female genital tract. It occurs most 
often in women 50–70 years of age. Obesity, nulliparity, 
diabetes, and polycystic ovaries with prolonged anovula
-
tion, unopposed estrogen therapy, and the extended use of 
tamoxifen for the treatment of breast cancer are also risk 
factors. Women with a family history of colon cancer 
(hereditary nonpolyposis colorectal cancer, Lynch syn
-
drome) are at significantly increased risk, with a lifetime 
incidence as high as 30%.
Abnormal bleeding is the presenting sign in 90% of 
cases. Any postmenopausal bleeding requires investiga
-
tion. Pain generally occurs late in the disease, with metas
-
tases or infection.
Papanicolaou smears of the cervix occasionally show 
atypical endometrial cells but are an insensitive diagnostic 
tool. Endocervical and endometrial sampling is the only 
reliable means of diagnosis. Simultaneous hysteroscopy 
can be a valuable addition in order to localize polyps or 
other lesions within the uterine cavity. Vaginal ultrasonog
-
raphy may be used to determine the thickness of the endo
-
metrium as an indication of hypertrophy and possible 
neoplastic change. The finding of a thin endometrial lining 
on ultrasound is clinically reassuring in cases where very 
little tissue is obtainable through endometrial biopsy.
Pathologic assessment is important in differentiating 
hyperplasias, which often can be treated with cyclic oral 
progestins.
 
»
Prompt endometrial sampling for patients who report

»
Prompt endometrial sampling for patients who report 
abnormal menstrual bleeding or postmenopausal uterine 
bleeding will reveal many incipient as well as clinical cases 
of endometrial cancer. Y ounger women with chronic 
anovulation are at risk for endometrial hyperplasia and 
subsequent endometrial cancer; they can significantly 
reduce the risk of hyperplasia with the use of oral contra
-
ceptives or cyclic progestin therapy.
 
»
Staging
Staging and prognosis are based on surgical and pathologic 
evaluation only. Examination under anesthesia, endome
-
trial and endocervical sampling, chest radiography, intra
-
venous urography, cystoscopy, sigmoidoscopy, transvaginal 
sonography, and MRI will help determine the extent of the 
disease and its appropriate treatment.
 
»
Treatment
Treatment consists of total hysterectomy and bilateral 
 
salpingo-oophorectomy. Peritoneal washings for cytologic 
examination are routinely taken and lymph node sampling 
may be done. If invasion deep into the myometrium has 
occurred or if sampled lymph nodes are positive for tumor, 
postoperative irradiation is indicated. Patients with stage III 
endometrial cancer are generally treated with surgery fol
-
lowed by chemotherapy and/or radiation therapy. A review 
by the Society of Gynecologic Oncology Clinical Practice 
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Committee concluded “the use of adjuvant chemotherapy 
to treat stage I or II endometrial carcinoma is not sup
-
ported by the available evidence. ” Palliation of advanced or 
metastatic endometrial adenocarcinoma may be accom
-
plished with large doses of progestins, eg, medroxyproges
-
terone, 400 mg weekly intramuscularly, or megestrol 
acetate, 80–160 mg daily orally.
 
»
Prognosis
With early diagnosis and treatment, the overall 5-year sur
-
vival is 80–85%. With stage I disease, the depth of myome
-
trial invasion is the strongest predictor of survival, with a 
98% 5-year survival with less than 66% depth of invasion 
and 78% survival with 66% or more invasion.
 
»
All patients with endometrial carcinoma should be referred 
to a gynecologic oncologist.
American College of Obstetricians and Gynecologists. Commit
-
tee Opinion No. 631: Endometrial intraepithelial neoplasia. 
Obstet Gynecol. 2015 May;125(5):1272–8. [PMID: 25932867]
Holloway RW et al. Sentinel lymph node mapping and staging in 
endometrial cancer: a Society of Gynecologic Oncology lit
-
erature review with consensus recommendations. Gynecol 
Oncol. 2017 Aug;146(2):405–15. [PMID: 28566221]
McAlpine JN et al. Endometrial cancer: not your grandmother’s 
cancer. Cancer. 2016 Sep 15;122(18):2787–98. [PMID: 
27308732]
SGO Clinical Practice Endometrial Cancer Working Group; 
Burke WM et al; Society of Gynecologic Oncology Clinical 
Practice Committee. Endometrial cancer: a review and current 
management strategies: part II. Gynecol Oncol. 2014 Aug;
 
134(2):393–402. [PMID: 24929052]
CARCINOMA OF THE VULVA
 
»
History of genital warts.
 
»
History of prolonged vulvar irritation, with pruri
-
tus, local discomfort, or slight bloody discharge.
 
»
Early lesions may suggest or include non-neoplastic 
epithelial disorders.
 
»
Late lesions appear as a mass, an exophytic growth, 
or a firm, ulcerated area in the vulva.
 
»
Biopsy is necessary for diagnosis.
 
»
The majority of cancers of the vulva are squamous lesions 
that classically have occurred in women over 50 years of 
age. Several subtypes (particularly 16, 18, and 31) of HPV 
have been identified in some but not all vulvar cancers. 
About 70–90% of vulvar intraepithelial neoplasia (VIN) 
and 40–60% of vulvar cancers are HPV associated. As with 
squamous cell lesions of the cervix, a grading system of 
VIN from mild dysplasia to carcinoma in situ is used.
 
»
Benign vulvar disorders that must be excluded in the diag
-
nosis of carcinoma of the vulva include chronic granulo
-
matous lesions (eg, lymphogranuloma venereum, syphilis), 
condylomas, hidradenoma, or neurofibroma. Lichen scle
-
rosus and other associated leukoplakic changes in the skin 
should be biopsied. The likelihood that a superimposed 
vulvar cancer will develop in a woman with a non-neoplastic 
 
epithelial disorder (vulvar dystrophy) is 1–5%.
 
»
Diagnosis
Biopsy is essential for the diagnosis of VIN and vulvar 
cancer and should be performed with any localized atypi
-
cal vulvar lesion, including white patches. Multiple skin-
punch specimens can be taken in the office under local 
anesthesia, with care to include tissue from the edges of 
each lesion sampled. Colposcopy of vulva, vagina, and 
cervix can help in identifying areas for biopsy and in plan
-
ning further treatment.
 
»
Staging
Vulvar cancer generally spreads by direct extension into 
the vagina, urethra, perineum, and anus, with discontinu
-
ous spread into the inguinal and femoral lymph nodes. CT 
or MRI of the pelvis or abdomen is generally not required 
except in advanced cases for planning therapeutic options.
 
»
Treatment
Early diagnosis and treatment of irritative or other predis
-
posing causes, such as lichen sclerosis and VIN, should be 
pursued. A 7:3 combination of betamethasone and crota
-

-
-
miton is particularly effective for itching. After an initial 
response, fluorinated steroids should be replaced with 
hydrocortisone because of their skin atrophying effect. For 
lichen sclerosus, recommended treatment is clobetasol 
propionate cream 0.05% twice daily for 2–3 weeks, then 
once daily until symptoms resolve. Application one to three 
times a week can be used for long-term maintenance 
therapy.
High-grade VIN may be treated with a variety of approaches 
including topical chemotherapy, laser ablation, wide local 
excision, skinning vulvectomy, and simple vulvectomy. 
Small, invasive basal cell carcinoma of the vulva should be 
excised with a wide margin. If the VIN is extensive or mul
-
ticentric, laser therapy or superficial surgical removal of 
vulvar skin may be required. In this way, the clitoris and 
uninvolved portions of the vulva may be spared.
Invasive carcinoma confined to the vulva without evi
-
dence of spread to adjacent organs or to the regional lymph 
nodes is treated with wide local excision and inguinal 
lymphadenectomy or wide local excision alone if invasion 
CMDT19_Ch18_p0776-p0810.indd   789

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is less than 1 mm. To avoid the morbidity of inguinal 
lymphadenectomy, some guidelines recommend sentinel 
lymph node sampling for women with early-stage vulvar 
cancer. Patients with more advanced disease may receive 
preoperative radiation, chemotherapy, or both.
 
»
Prognosis
Basal cell vulvar carcinomas very seldom metastasize, and 
carcinoma in situ by definition has not metastasized. With 
adequate excision, the prognosis for both lesions is excel
-
lent. Patients with invasive vulvar SCC 2 cm in diameter or 
less, without inguinal lymph node metastases, have an 
85–90% 5-year survival rate. If the lesion is larger than 
2  cm and lymph node involvement is present, the likeli
-
hood of 5-year survival is approximately 40%.
 
»
All patients with invasive vulvar carcinoma should be 
referred to a gynecologic oncologist.
Alkatout I et al. Vulvar cancer: epidemiology, clinical presentation, 
and management options. Int J Womens Health. 2015 Mar 20;
 
7:305–13. [PMID: 25848321]
-
tee Opinion No. 675 Summary: Management of vulvar 
intraepithelial neoplasia. Obstet Gynecol. 2016 Oct;
 
128(4):937–8. [PMID: 27661648]
Rajaram S et al. Management of vulvar cancer. Rev Recent Clin 
Trials. 2015;10(4):282–8. [PMID: 26411953]
ENDOMETRIOSIS
 
»
Dysmenorrhea.
 
»
Dyspareunia.
 
»
Increased frequency among infertile women.
 
»
Abnormal uterine bleeding.
 
»
Endometriosis is an aberrant growth of endometrium out
-
side the uterus, particularly in the dependent parts of the 
pelvis and in the ovaries, whose principal manifestations 
are chronic pain and infertility. While retrograde men
-
struation is the most widely accepted cause, its pathogen
-
esis and natural course are not fully understood. The 
overall prevalence in the United States is 6–10% and is 
four- to fivefold greater among infertile women. Endome
-
triosis is associated with an increased risk of coronary 
 
»
The clinical manifestations of endometriosis are variable 
and unpredictable in both presentation and course. Dys
-
menorrhea, chronic pelvic pain, and dyspareunia, are 
among the well-recognized manifestations. A significant 
number of women with endometriosis, however, remain 
asymptomatic and most women with endometriosis have a 
normal pelvic examination. However, in some women, 
pelvic examination can disclose tender nodules in the cul-
de-sac or rectovaginal septum, uterine retroversion with 
decreased uterine mobility, cervical motion tenderness, or 
an adnexal mass or tenderness.
Endometriosis must be distinguished from PID, ovar
-
ian neoplasms, and uterine myomas. Bowel invasion by 
endometrial tissue may produce blood in the stool that 
must be distinguished from bowel neoplasm.
Imaging is of limited value and is useful only in the 
presence of a pelvic or adnexal mass. Transvaginal ultra
-
sonography is the imaging modality of choice to detect 
the presence of deeply penetrating endometriosis of the 
rectum or rectovaginal septum, while MRI should be 
reserved for equivocal cases of rectovaginal or bladder 
endometriosis. Ultimately, a definitive diagnosis of endo
-
metriosis is made only by histology of lesions removed at 
surgery.
 
»
Treatment
Although there is no conclusive evidence that NSAIDs 
improve pain associated with endometriosis, these agents 
are reasonable options in appropriately selected patients. 
Medical treatment, using a variety of hormonal therapies, 
is effective in the amelioration of pain associated with 
endometriosis. However, there is no evidence that any of 
these agents increase the likelihood of pregnancy. Their 
preoperative use is of questionable value in reducing the 
difficulty of surgery. Most of these regimens are designed 
to inhibit ovulation over 4–9 months and lower hormone

to inhibit ovulation over 4–9 months and lower hormone 
levels, thus preventing cyclic stimulation of endometriotic 
implants and inducing atrophy. The optimum duration of 
therapy is not clear, and the relative merits in terms of side 
effects and long-term risks and benefits show insignificant 
differences when compared with each other and, in mild 
cases, with placebo. Commonly used medical regimens 
include the following:
1.
 
Low-dose
 
oral contraceptives
 can be given cyclically 
or continuously; prolonged suppression of ovulation 
often inhibits further stimulation of residual endome
-
triosis, especially if taken after one of the therapies 
mentioned here. Any of the combination oral contra
-
ceptives, the contraceptive patch, or vaginal ring may be 
used continuously for 6–12 months. Breakthrough 
bleeding can be treated with conjugated estrogens, 
1.25 mg orally daily for 1 week, or estradiol, 2 mg daily 
orally for 1 week.
2.
 
Progestins,
 specifically oral norethindrone acetate and 
subcutaneous DMPA, have been approved by the FDA 
for treatment of endometriosis-associated pain.
3.
 
Intrauterine progestin,
 with the levonorgestrel intra
-
uterine system has also been shown to be effective in 
reducing endometriosis-associated pelvic pain, and it is 
recommended before surgery.
CMDT19_Ch18_p0776-p0810.indd   790

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CMDT 2019
4.
 
GnRH agonists
 are highly effective in reducing the 
pain syndromes associated with endometriosis. 
However, they are not superior to other methods such 
as combined oral contraceptives as first-line therapy. 
The GnRH analogs (such as long-acting injectable leu
-
prolide acetate, 3.75 mg intramuscularly monthly, used 
for 6 months) suppresses ovulation. Side effects of vaso
-
motor symptoms and bone demineralization may be 
relieved by “add-back” therapy, such as conjugated 
equine estrogen, 0.625 mg, or norethindrone, 5 mg 
orally daily.
5.
 
Danazol
 is an androgenic medication that has been 
used for the treatment of endometriosis-associated 
pain. It should be used for 4–6 months in the lowest 
dose necessary to suppress menstruation, usually 
 
200–400 mg orally twice daily. However, danazol has a 
high incidence of androgenic side effects that are more 
severe than other medications available, including 
decreased breast size, weight gain, acne, and hirsutism.
6.
 
Aromatase inhibitors
 (such as anastrozole or letrozole) 
in combination with conventional therapy have been 
evaluated with positive results in premenopausal 
women with endometriosis-associated pain and pain 
recurrence.
Surgical treatment of endometriosis—particularly exten
-
sive disease—is effective both in reducing pain and in 
promoting fertility. Laparoscopic ablation of endometrial 
implants significantly reduces pain. Ablation of implants 
and, if necessary, removal of ovarian endometriomas 
enhance fertility, although subsequent pregnancy rates are 
inversely related to the severity of disease. Women with 
disabling pain for whom childbearing is not a consider
-
ation can be treated definitively with total abdominal hys
-
terectomy and bilateral salpingo-oophorectomy. In 
premenopausal women, hormone replacement then may 
be used to relieve vasomotor symptoms. However, hor
-
mone replacement may lead to a recurrence of endome
-
triosis and associated pain.
 
»
Prognosis
There is little systematic research regarding either the pro
-
gression of the disease or the prediction of clinical out
-
comes. The prognosis for reproductive function in early or 
moderately advanced endometriosis appears to be good 
with conservative therapy. Hysterectomy, with bilateral 
salpingo-oophorectomy, often is regarded as definitive 
therapy for the treatment of endometriosis associated with 
intractable pelvic pain, adnexal masses, or multiple previ
-
ous ineffective conservative surgical procedures. However, 
symptoms may recur even after hysterectomy and 
oophorectomy.
 
»
Refer to a gynecologist for laparoscopic diagnosis or 
 
»
Rarely necessary except for acute abdomen associated with 
ruptured or bleeding endometrioma.
Abu Hashim H. Potential role of aromatase inhibitors in the 
treatment of endometriosis. Int J Womens Health. 2014 Jul 21;
 
6:671–80. [PMID: 25092998]
Practice Bulletin No. 114: Management of endometriosis. 
Obstet Gynecol. 2010 July:116(1):223–36. [Reaffirmed 2017] 
[PMID: 20567196]
-
tee Opinion No. 663: Aromatase inhibitors in gynecologic 
practice. Obstet Gynecol. 2016 Jun;127(6):e170–4. [PMID: 
27214191]
Brown J et al. Nonsteroidal anti-inflammatory drugs for pain in 
women with endometriosis. Cochrane Database Syst Rev. 
2017 Jan 23;1:CD004753. [PMID: 28114727]
Casper RF. Progestin-only pills may be a better first-line treat
-
ment for endometriosis than combined estrogen-progestin 
contraceptive pills. Fertil Steril. 2017 Mar;107(3):533–6. 
[PMID: 28162779]
Fu J et al. Progesterone receptor modulators for endometriosis. 
Cochrane Database Syst Rev. 2017 Jul 25;7:CD009881. 
[PMID: 28742263]
Singh SS et al. Surgery for endometriosis: beyond medical thera
-
pies. Fertil Steril. 2017 Mar;107(3):549–54. [PMID: 28189295]

-
Tafi E et al. Advances in pharmacotherapy for treating endome
-
triosis. Expert Opin Pharmacother. 2015 Nov;16(16):2465–83. 
 
[PMID: 26569155]
Taylor HS et al. Treatment of endometriosis-associated pain with 
elagolix, an oral GnRH antagonist. N Engl J Med. 2017 Jul 6;
 
377(1):28–40. [PMID: 28525302]
PELVIC ORGAN PROLAPSE
 
»
Cystocele, rectocele, and enterocele are vaginal hernias 
commonly seen in multiparous women. 
Cystocele
 is a 
hernia of the bladder wall into the vagina, causing a soft 
anterior fullness. Cystocele may be accompanied by 
 
urethrocele,
 which is not a hernia but a sagging of the 
urethra following its detachment from the pubic symphysis 
during childbirth. 
Rectocele
 is a herniation of the terminal 
rectum into the posterior vagina, causing a collapsible 
pouch-like fullness. 
Enterocele
 is a vaginal vault hernia 
containing small intestine, usually in the posterior vagina 
and resulting from a deepening of the pouch of Douglas. 
Two or all three types of hernia may occur in combination. 
Risk factors may include vaginal birth, genetic predisposi
-
tion, advancing age, prior pelvic surgery, connective tissue 
disorders, and increased intra-abdominal pressure associ
-
ated with obesity or straining associated with chronic 
constipation or coughing.
 
»
Symptoms of pelvic organ prolapse may include sensation 
of a bulge or protrusion in the vagina, urinary or fecal 
incontinence, constipation, a sense of incomplete bladder 
emptying, and dyspareunia. The cause of pelvic organ 
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prolapse, including prolapse of the uterus, vaginal apex, and 
anterior or posterior vaginal walls, is likely multifactorial.
 
»
Treatment
The type of therapy depends on the extent of prolapse and 
the patient’s age and her desire for menstruation, preg
-
nancy, and coitus.
Supportive measures include a high-fiber diet and laxatives 
to improve constipation. Weight reduction in obese 
patients and limitation of straining and lifting are helpful. 
Pelvic muscle training (Kegel exercises) is a simple, nonin
-
vasive intervention that may improve pelvic function that 
has clearly demonstrated benefit for women with urinary 
or fecal symptoms, especially incontinence. Pessaries may 
reduce cystocele, rectocele, or enterocele and are helpful in 
women who do not wish to undergo surgery or are poor 
surgical candidates.
The most common surgical procedure is vaginal or abdom
-
inal hysterectomy with additional attention to restoring 
apical support after the uterus is removed, including sus
-
pension by either uterosacral or sacrospinous fixation vagi
-
nally or abdominal sacral colpopexy. Since stress 
incontinence is common after vault suspension procedures, 
an anti-incontinence procedure should be considered. 
While the use of various surgical mesh materials with these 
procedures increased substantially since 2000, several safety 
advisories recommend a more cautious use of mesh materi
-
als. In 2016, the FDA issued orders that reclassify the use of 
mesh as a high-risk device requiring submission of a pre
-
market approval application within 30 months to address 
these safety concerns. If the patient desires pregnancy, the 
same procedures for vaginal suspension can be performed 
without hysterectomy, though limited data on pregnancy 
outcomes or prolapse outcomes are available. For elderly 
women who do not desire coitus, colpocleisis, the partial 
obliteration of the vagina, is surgically simple and effective. 
Uterine suspension with sacrospinous cervicocolpopexy 
may be an effective approach in older women who wish to 
avoid hysterectomy but preserve coital function.
 
»
•	
Refer to urogynecologist or gynecologist for inconti
-
nence evaluation.
•	
Refer if nonsurgical therapy is ineffective.
-
tee on Practice Bulletins—Gynecology and the American 
Urogynecologic Society. Practice Bulletin No. 176: Pelvic 
Organ Prolapse. Obstet Gynecol. 2017 Apr;129(4):e56–72. 
[PMID: 28333818]
Barber MD. Pelvic organ prolapse. BMJ. 2016 Jul 20;354:i3853. 
[PMID: 27439423]
Iglesia CB et al. Pelvic organ prolapse. Am Fam Physician. 
 
2017 Aug 1;96(3):179–85. [PMID: 28762694]
PELVIC INFLAMMATORY DISEASE 
 
(Salpingitis, Endometritis)
 
»
Uterine, adnexal, or cervical motion tenderness.
 
»
Abnormal discharge from the vagina or cervix.
 
»
Absence of a competing diagnosis.
 
»
Pelvic inflammatory disease (PID) is a polymicrobial infection 
of the upper genital tract associated with the sexually transmit
-
ted organisms 
 and 
Chlamydia trachoma
-
tis
 as well as endogenous organisms, including anaerobes, 
 
, enteric gram-negative rods, and 
streptococci. It is most common in young, nulliparous, sexu
-
ally active women with multiple partners and is a leading cause 
of infertility and ectopic pregnancy. The use of barrier meth
-
ods of contraception may provide significant protection.
 
»
Patients with PID may have lower abdominal pain, chills and 
fever, menstrual disturbances, purulent cervical discharge, 
and cervical and adnexal tenderness. Right upper quadrant 
pain (
Fitz-Hugh and Curtis syndrome
) may indicate an 
associated perihepatitis. However, diagnosis of PID is com
-
plicated by the fact that many women may have subtle or

pain (
-
plicated by the fact that many women may have subtle or 
mild symptoms that are not readily recognized as PID, such 
as postcoital bleeding, urinary frequency, or low back pain.
B. Minimum Diagnostic Criteria
Women with cervical motion, uterine, or adnexal tender
-
ness should be considered to have PID and be treated with 
antibiotics unless there is a competing diagnosis such as 
ectopic pregnancy or appendicitis.
C. Additional Criteria
No single historical, physical, or laboratory finding is 
definitive for acute PID. The following criteria may be used 
to enhance the specificity of the diagnosis: (1) oral tem
-
perature higher than 38.3°C, (2) abnormal cervical or vagi
-
nal discharge with white cells on saline microscopy (greater 
than 1 leukocyte per epithelial cell), (3) elevated erythro
-
cyte sedimentation rate, (4) elevated C-reactive protein, 
and (5) laboratory documentation of cervical infection 
with 
N gonorrhoeae
 or 
C trachomatis
. Endocervical culture 
should be performed routinely, but treatment should not 
be delayed while awaiting results.
 
»
Appendicitis, ectopic pregnancy, septic abortion, hemor
-
rhagic or ruptured ovarian cysts or tumors, torsion of an 
CMDT19_Ch18_p0776-p0810.indd   792

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CMDT 2019
ovarian cyst, degeneration of a myoma, and acute enteritis 
must be considered. PID is more likely to occur when there 
is a history of PID, recent sexual contact, recent onset of 
menses, recent insertion of an IUD, or if the partner has a 
sexually transmitted disease. Acute PID is highly unlikely 
when recent (within 60 days) intercourse has not taken 
place. A sensitive serum pregnancy test should be obtained 
to rule out ectopic pregnancy. Pelvic and vaginal ultraso
-
nography is helpful in the differential diagnosis of ectopic 
pregnancy of over 6 weeks and to rule out tubo-ovarian 
abscess. Laparoscopy is often used to diagnose PID, and it 
is imperative if the diagnosis is not certain or if the patient 
has not responded to antibiotic therapy after 48 hours. The 
appendix should be visualized at laparoscopy to rule out 
appendicitis. Cultures obtained at the time of laparoscopy 
are often specific and helpful.
 
»
Treatment
A. Antibiotics
Early treatment with appropriate antibiotics effective 
against 
, 
, and the endogenous 
organisms listed above is essential to prevent long-term 
sequelae. The sexual partner should be examined and 
treated appropriately. Most women with mild to moderate 
disease can be treated successfully as an outpatient. The 
recommended outpatient regimen is a single dose of 
cefoxitin, 2 g intramuscularly, with probenecid, 1 g orally, 
plus doxycycline 100 mg orally twice a day for 14 days, or 
ceftriaxone 250 mg intramuscularly plus doxycycline, 100 mg 
 
orally twice daily, for 14 days. Metronidazole 500 mg orally 
twice daily for 14 days may also be added to either of these 
two regimens and will also treat bacterial vaginosis that is 
frequently associated with PID. For patients with severe 
disease or those who meet the other criteria for hospitaliza
-
tion, there are two recommended regimens. One regimen 
includes either cefotetan, 2 g intravenously every 12 hours, 
or cefoxitin, 2 g intravenously every 6 hours, plus doxycy
-
cline 100 mg orally or intravenously every 12 hours. The 
other recommended regimen is clindamycin, 900 mg intra
-
venously every 8 hours, plus gentamicin, a loading dose of 
2 mg/kg intravenously or intramuscularly followed by a 
maintenance dose of 1.5 mg/kg every 8 hours (or as a single 
daily dose, 3–5 mg/kg). These regimens should be contin
-
ued for a minimum of 24 hours after the patient shows 
significant clinical improvement. Then, an oral regimen 
should be given for a total course of antibiotics of 14 days 
with either doxycycline, 100 mg orally twice a day, or 
clindamycin, 450 mg orally four times a day. If a tubo-
ovarian abscess is present, clindamycin or metronidazole 
should be used with doxycycline to complete the 14-day 
treatment for better anaerobic coverage.
Tubo-ovarian abscesses may require surgical excision or 
transcutaneous or transvaginal aspiration. Unless rupture is 
suspected, institute high-dose antibiotic therapy in the hos
-
pital, and monitor therapy with ultrasound. In 70% of cases, 
antibiotics are effective; in 30%, there is inadequate response 
in 48–72 hours, and surgical intervention is required. 
 
Unilateral adnexectomy is acceptable for unilateral 
 
abscess. Hysterectomy and bilateral salpingo-oophorectomy 
 
may be necessary for overwhelming infection or in cases of 
chronic disease with intractable pelvic pain.
 
»
Prognosis
In spite of treatment, long-term sequelae, including 
repeated episodes of infection, chronic pelvic pain, dyspa
-
reunia, ectopic pregnancy, or infertility, develop in one-
fourth of women with acute disease. The risk of infertility 
increases with repeated episodes of salpingitis: it is esti
-
mated at 10% after the first episode, 25% after a second 
episode, and 50% after a third episode.
 
»
The following patients with acute PID should be admitted 
for intravenous antibiotic therapy:
•

»
•	
The patient has a tubo-ovarian abscess (direct inpatient 
observation for at least 24 hours before switching to 
outpatient parenteral therapy).
•	
The patient is pregnant.
•	
The patient is unable to follow or tolerate an outpatient 
regimen.
•	
The patient has not responded clinically to outpatient 
therapy within 72 hours.
•	
The patient has severe illness, nausea and vomiting, or 
high fever.
•	
Another surgical emergency, such as appendicitis, can
-
not be ruled out.
Bugg CW et al. Pelvic inflammatory disease: diagnosis and treat
-
ment in the emergency department. Emerg Med Pract. 
 
2016 Dec;18(12):1–24. [PMID: 27879197]
Das BB et al. Pelvic inflammatory disease: improving awareness, 
prevention, and treatment. Infect Drug Resist. 2016 Aug 19;
 
9:191–7. [PMID: 27578991]
OVARIAN CANCER & OVARIAN TUMORS
 
»
Symptoms include vague gastrointestinal discom
-
fort, pelvic pressure, or pain.
 
»
Many cases of early-stage cancer are asymptomatic.
 
»
Pelvic examination and ultrasound are mainstays 
of diagnosis.
 
»
Ovarian tumors are common. Most are benign, but malig
-
nant ovarian tumors are the leading cause of death from 
reproductive tract cancer. The wide range of types and 
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patterns of ovarian tumors is due to the complexity of ovar
-
ian embryology and differences in tissues of origin.
In women with no family history of ovarian cancer, the 
lifetime risk is 1.6%, whereas a woman with one affected 
first-degree relative has a 5% lifetime risk. Ultrasound or 
tumor marker screening for women with one or no affected 
first-degree relatives have not been shown to reduce mor
-
tality from ovarian cancer, and the risks associated with 
unnecessary prophylactic surgical procedures outweigh the 
benefits in low-risk women. With two or more affected 
first-degree relatives, the risk is 7%. Approximately 3% of 
women with two or more affected first-degree relatives will 
have a 
hereditary ovarian cancer syndrome
 with a life
-
time risk of 40%. Women with a 
BRCA1
 gene mutation 
have a 45% lifetime risk of ovarian cancer and those with a 
BRCA2
 mutation, a 25% risk. Consideration should be 
given to screening with transvaginal sonography and 
serum CA 125 testing, starting at age 30–35 years for 
women with 
BRCA 1
 or age 35–40 for women with 
BRCA2
 
or 5–10 years earlier than the earliest age that ovarian can
-
cer was first diagnosed in any family member. Of note, this 
screening regimen has not been shown to reduce mortality; 
thus, prophylactic oophorectomy should be considered at 
conclusion of childbearing.
 
»
Most women with both benign and malignant ovarian 
neoplasms are either asymptomatic or experience only 
mild nonspecific gastrointestinal symptoms or pelvic pres
-
sure. Women with advanced malignant disease may expe
-
rience abdominal pain and bloating, and a palpable 
abdominal mass with ascites is often present.
Serum CA 125 is elevated in 80% of women with epithelial 
ovarian cancer overall but in only 50% of women with early 
disease. CA 125 may be elevated in premenopausal women 
with benign disease (such as endometriosis), minimizing 
its usefulness in ovarian cancer screening. In premeno
-
pausal women with ovarian masses, other tumor markers 
(such as human chorionic gonadotropin [hCG], lactate 
dehydrogenase, or alpha fetoprotein) may be indicators of 
the tumor type.
C. Imaging
Transvaginal sonography is useful for screening high-risk 
women but has inadequate sensitivity for screening low-
risk women. Ultrasound is helpful in differentiating ovar
-
ian masses that are benign and likely to resolve 
spontaneously from those with malignant potential. Color 
Doppler imaging may further enhance the specificity of 
ultrasound diagnosis.
 
»
Once an ovarian mass has been detected, it must be catego
-
rized as functional, benign neoplastic, or potentially malig
-
nant. Predictive factors include age, size of the mass, 
ultrasound configuration, serum CA 125 level, the pres
-
ence of symptoms, and whether the mass is unilateral or 
bilateral. Simple cysts up to 5 cm in diameter are almost 
universally benign in both premenopausal and postmeno
-
pausal patients. Most will resolve spontaneously and may 
be monitored without intervention. If the mass is larger or 
unchanged on repeat pelvic examination and transvaginal 
sonography, surgical evaluation is warranted.
Laparoscopic or robotic approaches may be used for 
oophorectomy and staging in early-stage ovarian cancer 
when an ovarian mass is small. In these cases, malignancy 
is often not diagnosed prior to the surgery. Data (retro
-
spective) comparing open with laparoscopic approaches to 
ovarian cancer staging are limited. Laparotomy is generally 
preferred for staging and debulking if malignancy is sus
-
pected from findings on transvaginal ultrasound with 
morphologic scoring, color Doppler assessment of vascular 
quality, and CA 125 level.
 
»
Treatment
If a malignant ovarian mass is suspected, surgical evalua
-
tion should be performed by a gynecologic oncologist. For

»
Treatment
-
tion should be performed by a gynecologic oncologist. For 
benign neoplasms, tumor removal or unilateral oophorec
-
tomy is usually performed. For ovarian cancer in an early 
stage, the standard therapy is complete surgical staging 
followed by hysterectomy and bilateral salpingo-
 
oophorectomy with omentectomy and selective lymphad
-
enectomy. With more advanced disease, aggressive 
removal of all visible tumor improves survival. Except for 
women with low-grade ovarian cancer in an early stage, 
postoperative chemotherapy is indicated (see Table 39–3). 
Several chemotherapy regimens are effective, such as the 
combination of cisplatin or carboplatin with paclitaxel, 
with clinical response rates of up to 60–70% (see Table 
39–13).
 
»
Prognosis
Advanced disease is diagnosed in approximately 75% of 
women with ovarian cancer. The overall 5-year survival is 
approximately 17% with distant metastases, 36% with local 
spread, and 89% with early disease.
 
»
If a malignant mass is suspected, surgical evaluation should 
be performed by a gynecologic oncologist.
-
tee Opinion No. 634: Hereditary cancer syndromes and risk 
assessment. Obstet Gynecol. 2015 Jun;125(6):1538–43. 
[PMID: 26000542]
-
tee Opinion No. 716: The role of the obstetrician-gynecologist 
in the early detection of epithelial ovarian cancer in women at 
average risk. Obstet Gynecol. 2017 Sep;130(3):e146–9. 
[PMID: 28832487]
Arie S. Routine testing for women with ovarian cancer. BMJ. 
2014 Feb 26;348:g1200. [PMID: 24574473]
Centers for Disease Control and Prevention. Ovarian cancer 
screening. 2017 Feb 9. https://www.cdc.gov/cancer/ovarian/
basic_info/screening.htm
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Girolimetti G et al. 
BRCA
-associated ovarian cancer: from 
molecular genetics to risk management. Biomed Res Int. 
2014;2014:787143. [PMID: 25136623]
Minig L et al. Robotic surgery in women with ovarian cancer: 
surgical technique and evidence of clinical outcomes. J 
Minim Invasive Gynecol. 2016 Mar–Apr;23(3):309–16. 
[PMID: 26538410]
POLYCYSTIC OVARY SYNDROME
 
»
Clinical or biochemical evidence of hyper
-
androgenism.
 
»
Oligoovulation or anovulation.
 
»
Polycystic ovaries on ultrasonography.
 
»
Polycystic ovary syndrome (PCOS)
 is a common endocrine 
disorder of unknown etiology affecting 5–10% of reproduc
-
tive age women. PCOS is characterized by chronic anovula
-
tion, polycystic ovaries, and hyperandrogenism. It is associated 
with hirsutism and obesity as well as an increased risk of dia
-
betes mellitus, cardiovascular disease, and metabolic syn
-
drome. Unrecognized or untreated PCOS is a risk factor for 
cardiovascular disease. The Rotterdam Criteria identify 
androgen production,
 
ovulatory dysfunction,
 and 
polycys
-
tic ovaries
 as the key diagnostic features of the disorder in 
adult women; the emerging consensus is that at least two of 
these features must be present for diagnosis. The classification 
system has been endorsed by the National Institutes of Health.
 
»
PCOS often presents as a menstrual disorder (ranging 
from amenorrhea to menorrhagia) and infertility. Skin 
disorders due to peripheral androgen excess, including 
hirsutism and acne, are common. Patients may also show 
signs of insulin resistance and hyperinsulinemia, and these 
women are at increased risk for early-onset type 2 diabetes 
and metabolic syndrome. Patients who do become preg
-
nant are at increased risk for perinatal complications, such 
as gestational diabetes and preeclampsia. In addition, they 
have an increased long-term risk of endometrial cancer 
secondary to unopposed estrogen secretion.
 
»
Anovulation in the reproductive years may also be due to 
(1) premature ovarian failure (high FSH and LH levels); 
 
(2) rapid weight loss, extreme physical exertion (normal 
FSH and LH levels for age), or obesity; (3) discontinuation of 
hormonal contraceptives (anovulation for 6 months or more 
occasionally occurs); (4) pituitary adenoma with elevated 
prolactin (galactorrhea may or may not be present); and 
(5) hyperthyroidism or hypothyroidism. To rule out other 
etiologies in women with suspected PCOS, serum FSH, LH, 
prolactin, and TSH should be checked. Because of the high 
risk of insulin resistance and dyslipidemia, all women with 
suspected PCOS should have a hemoglobin A
1C
 and fasting 
glucose along with a lipid and lipoprotein profile. Women 
with clinical evidence of androgen excess should have total 
testosterone and sex hormone–binding globulin or free 
(bioavailable) testosterone, and 17-hydroxyprogesterone 
measured. Women with stigmata of Cushing syndrome 
should have a 24-hour urinary free-cortisol or a low-dose 
dexamethasone suppression test. Congenital adrenal hyper
-
plasia and androgen-secreting adrenal tumors also tend to 
have high circulating androgen levels and anovulation with 
polycystic ovaries; these disorders must also be ruled out in 
women with presumed PCOS.
 
»
Treatment
In obese patients with PCOS, weight reduction and exer
-
cise are often effective in reversing the metabolic effects 
and in inducing ovulation. For those women who do not 
respond to weight loss and exercise, metformin therapy 
may be helpful. Metformin is beneficial for metabolic or 
glucose abnormalities, and it can improve menstrual func
-
tion. Metformin has little or no benefit in the treatment of 
hirsutism, acne, or infertility. Contraceptive counseling 
should be offered to prevent unplanned pregnancy in case 
of a return of ovulatory cycles. For women who are seeking

of a return of ovulatory cycles. For women who are seeking 
pregnancy and remain anovulatory, clomiphene or other 
medications can be used for ovarian stimulation (see sec
-
tion on Infertility below). Clomiphene is the first-line 
therapy for infertility. If induction of ovulation fails, treat
-
ment with gonadotropins, but at low dose to lower the risk 
of ovarian hyperstimulation syndrome, may be successful. 
Second-line therapies such as use of aromatase inhibitors 
or laparoscopic “ovarian drilling” are of unproved benefit. 
Women with PCOS are at greater risk than normal women 
for twin gestation with ovarian stimulation.
If the patient does not desire pregnancy and does not 
want or is not a candidate for contraception, then medroxy
-
progesterone acetate, 10 mg/day orally for the first 10 days 
of every 1–3 months, should be given to ensure regular 
shedding of the endometrium and thus avoid endometrial 
hyperplasia. If contraception is desired, combination con
-
traceptives (pill, ring, or patch) can be used; this is also 
useful in controlling hirsutism, for which treatment must 
be continued for 6–12 months before results are seen. The 
levonorgestrel-containing IUD is another option to mini
-
mize uterine bleeding and protect against endometrial 
hyperplasia, but unlike the combined estrogen-progestin 
contraceptives, the IUD does not help control hirsutism.
Spironolactone is useful for hirsutism in doses of 25 mg 
three or four times daily. Flutamide, 125–250 mg orally 
daily, and finasteride, 5 mg orally daily, are also effective for 
treating hirsutism. Because these three agents are poten
-
tially teratogenic, they should be used only in conjunction 
with secure contraception. Topical eflornithine cream 
applied to affected facial areas twice daily for 6 months may 
be helpful in the majority of women. Hirsutism may also be 
managed with depilatory creams, electrolysis, and laser 
therapy. The combination of laser therapy and topical eflo
-
rnithine may be particularly effective.
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Weight loss, exercise, and treatment of unresolved meta
-
bolic derangements are important in preventing cardiovas
-
cular disease. Women with PCOS should be managed 
aggressively and should have regular monitoring of lipid 
profiles and glucose. In adolescent patients with PCOS, 
hormonal contraceptives and metformin are treatment options.
 
»
•	
If expertise in diagnosis is needed.
•	
If patient is infertile.
Bednarska S et al. The pathogenesis and treatment of polycystic 
ovary syndrome: what’s new? Adv Clin Exp Med. 2017 Mar–Apr;
 
26(2):359–67. [PMID: 28791858]
McCartney CR et al. Clinical practice: polycystic ovary syndrome. 
N Engl J Med. 2016 Jul 7;375(1):54–64. [PMID: 27406348]
FEMALE SEXUAL DYSFUNCTION
 
»
Female sexual dysfunction is a common problem. Depend
-
ing on the questions asked, surveys have shown that from 
35% to 98% of women report sexual concerns. Questions 
related to sexual functioning should be asked as part of the 
routine medical history. Three helpful questions to broach 
the topic are “ Are you currently involved in a sexual rela
-
tionship?, ” “With men, women, or both?, ” and “Do you 
have any sexual concerns or any pain with sex?” If the 
woman is not involved in a sexual relationship, she should 
be asked if there are any concerns that are contributing to 
a lack of sexual behavior. If a history of sexual dysfunction 
is elicited, a complete history of factors that may affect 
sexual function should be taken. These factors include her 
reproductive history (including pregnancies and mode of 
delivery) as well as history of infertility, sexually transmit
-
ted diseases, rape or sexual violence, gynecologic or uro
-
logic disorders, endocrine abnormalities (such as diabetes 
mellitus or thyroid disease), neurologic problems, cardio
-
vascular disease, psychiatric disease, and current prescrip
-
tion and over-the-counter medication use. A detailed 
history of the specific sexual dysfunction should be elic
-
ited, and a gynecologic examination should focus on find
-
ings that may contribute to sexual complaints.
 
»
Etiology
A. Disorders of Sexual Desire
Sexual desire in women is a complex and poorly under
-
stood phenomenon. Emotion is a key factor in sexual 
desire. Anger toward a partner, fear or anxiety related to 
previous sexual encounters, or history of sexual abuse vio
-
lence may contribute. Physical factors such as chronic ill
-
ness, fatigue, depression, and specific medical disorders 
(such as diabetes mellitus, thyroid disease, or adrenal insuf
-
ficiency) may contribute to a lack of desire. Menopause and 
attitudes toward aging may play a role. In addition, sexual 
desire may be influenced by other sexual dysfunction, such 
as arousal disorders, dyspareunia, or anorgasmia.
B. Sexual Arousal Disorders
Sexual arousal disorders may be both subjective and objec
-
tive. Sexual stimulation normally leads to genital vasocon
-
gestion and lubrication. Some women may have a 
physiologic response to sexual stimuli, but may not subjec
-
tively feel aroused because of factors such as distractions; 
negative expectations; anxiety; fatigue; depression; or med
-
ications, such as selective serotonin reuptake inhibitors 
(SSRIs) or oral contraceptives. Other women may lack both 
a subjective and physiologic response to sexual stimuli 
related to vaginal atrophy.
C. Orgasmic Disorders
In spite of subjective and physiologic arousal, women may 
experience a marked delay in orgasm, diminished sensa
-
tion of an orgasm, or anorgasmia. The etiology is complex 
and typically multifactorial, but the disorder is usually 
amenable to treatment.
D. Sexual Pain Disorders
Dyspareunia and vaginismus are two subcategories of sex
-
ual pain disorders.
 is defined as recurrent or persistent genital 
pain associated with sexual intercourse that is not caused 
exclusively by lack of lubrication or by vaginismus and

-
exclusively by lack of lubrication or by vaginismus and 
causes marked distress or interpersonal difficulty. 
Vulvo
-
dynia
 is the most frequent cause of dyspareunia in premeno
-
pausal women. It is characterized by a sensation of burning 
along with other symptoms, including pain, itching, sting
-
ing, irritation, and rawness. The discomfort may be constant 
or intermittent, focal or diffuse, and experienced as either 
deep or superficial. There are generally no physical findings 
except minimal erythema that may be associated in a subset 
of patients with vulvodynia, those with vulvar vestibulitis. 
Vulvar vestibulitis
 is normally asymptomatic but pain is 
associated with touching or pressure on the vestibule, such 
as with vaginal entry or insertion of a tampon. Pain occur
-
ring with deep thrusting during coitus is usually due to acute 
or chronic infection of the cervix, uterus, or adnexa; endo
-
metriosis; adnexal tumors; or adhesions resulting from prior 
pelvic disease or operation.
Vaginismus
 is defined as recurrent or persistent invol
-
untary spasm of the musculature of the outer third of the 
vagina that interferes with sexual intercourse, resulting 
from fear, pain, sexual violence, or a negative attitude 
toward sex, often learned in childhood, and causing 
marked distress or interpersonal difficulty. Other medical 
causes of sexual pain may include vulvovaginitis; vulvar 
disease, including lichen planus, lichen sclerosus, and 
lichen simplex chronicus; pelvic disease, such as endome
-
triosis or chronic PID; or vaginal atrophy.
 
»
Treatment
In the absence of specific medical disorders, arousal or 
orgasmic disorders or dyspareunia, the focus of therapy is 
psychological. Cognitive behavioral therapy, sexual 
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therapy, and couples therapy may all play a role. Success 
with pharmacologic therapy, particularly the use of dopa
-
mine agonists or testosterone with estrogen, has been 
reported, but data from large long-term clinical trials are 
lacking.
As with disorders of sexual desire, arousal disorders may 
respond to psychological therapy. The phosphodiesterase 
inhibitors used in men do not appear to benefit the major
-
ity of women with sexual arousal disorders. However, there 
is some evidence to suggest a role for sildenafil in women 
with sexual dysfunction due to multiple sclerosis, type 1 
diabetes mellitus, spinal cord injury, and antidepressant 
medications if other established approaches fail. Flibanse
-
rin (Addyi), an antidepressant, was approved by the FDA 
in August 2015 as an effective treatment of hypoactive 
sexual desire disorder in premenopausal women; however, 
it must be used long term to be effective and has significant 
risks that require specific certifications of providers 
 
and pharmacies for dispensation to patients in the 
 
United States. While this medication remains available, it is 
not commonly prescribed.
For many women, counseling or sex therapy may be ade
-
quate treatment. There is an FDA-approved vacuum device 
that increases clitoral blood flow and may improve the 
likelihood of orgasm.
Specific medical disorders, such as endometriosis, vulvo
-
vaginitis, or vaginal atrophy, should be treated as outlined 
in other sections of this chapter. Lichen planus and lichen 
simplex chronicus are addressed in Chapter 6. Lichen scle
-
rosus, a thinning and whitening of the vulvar epithelium, is 
treated with clobetasol propionate 0.05% ointment, applied 
twice daily for 2–3 months.
Vaginismus may be treated initially with sexual coun
-
seling and education on anatomy and sexual functioning. 
The patient can be instructed in self-dilation, using a lubri
-
cated finger or dilators of graduated sizes. Before coitus 
(with adequate lubrication) is attempted, the patient—and 
then her partner—should be able to easily and painlessly 
introduce two fingers into the vagina. Penetration should 
never be forced, and the woman should always be the one 
to control the depth of insertion during dilation or inter
-
course. Injection of botulinum toxin has been used suc
-
cessfully in refractory cases.
Since the cause of vulvodynia is unknown, management 
is difficult. Few treatment approaches have been subjected 
to methodologically rigorous trials. A variety of topical 
agents have been tried, although only topical anesthetics 
(eg, estrogen cream and a compounded mixture of topical 
amitriptyline 2% and baclofen 2% in a water washable 
base) have been useful in relieving vulvodynia. Useful oral 
medications include tricyclic antidepressants, such as ami
-
triptyline in gradually increasing doses from 10 mg/day to 
75–100 mg/day; various SSRIs; and anticonvulsants, such 
as gabapentin, starting at 300 mg three times daily and 
increasing to 1200 mg three times daily. Biofeedback and 
physical therapy, with a physical therapist experienced with 
the treatment of vulvar pain, have been shown to be help
-
ful. Surgery—usually consisting of vestibulectomy—has 
been useful for women with introital dyspareunia. See also 
Chapter e6.
 
»
•	
When symptoms or concerns persist despite first-line 
therapy.
•	
For expertise in surgical procedures.
-
tee Opinion No 706: Sexual health. Obstet Gynecol. 2017 Jul;
 
130(1):e42–7. [PMID: 28644338]
Dawson ML et al. The evaluation and management of female 
sexual dysfunction. J Fam Pract. 2017 Dec;66(12):722–8. 
[PMID: 29202143]
Goldstein I et al. Hypoactive sexual desire disorder: Interna
-
tional Society for the Study of Women’s Sexual Health 
 
(ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc.

-
 
(ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc. 
2017 Jan;92(1):114–28. [PMID: 27916394]
Jin J. JAMA patient page. Flibanserin for treating low sexual 
desire in women. JAMA. 2015 Sep 22–29;314(12):1312. 
[PMID: 26393863]
Nappi RE et al. Advances in pharmacotherapy for treating female 
sexual dysfunction. Expert Opin Pharmacother. 2015 Apr;
 
16(6):875–87. [PMID: 25732267]
Stenson AL. Vulvodynia: diagnosis and management. Obstet 
Gynecol Clin North Am. 2017 Sep;44(3):493–508. [PMID: 
28778645]
Zhou ES et al. Hormonal changes and sexual dysfunction. Med 
Clin North Am. 2017 Nov;101(6):1135–50. [PMID: 28992859]
INFERTILITY
A couple is said to be infertile if pregnancy does not result 
after 1 year of normal sexual activity without contracep
-
tives. About 25% of couples experience infertility at some 
point in their reproductive lives; the incidence of infertility 
increases with age, with a decline in fertility beginning in 
the early 30s and accelerating in the late 30s. The male 
partner contributes to about 40% of cases of infertility, and 
a combination of factors is common. The most recent data 
from the CDC National Survey of Family Growth noted 
that 12% of women in the United States aged 15–44 have 
impaired fecundity.
A. Initial Testing
During the initial interview, the clinician can present an 
overview of infertility and discuss an evaluation and man
-
agement plan. Private consultations with each partner 
separately are then conducted, allowing appraisal of psy
-
chosexual adjustment without embarrassment or criticism. 
Pertinent details (eg, sexually transmitted disease or prior 
pregnancies) must be obtained. The ill effects of cigarettes, 
alcohol, and other recreational drugs on male fertility 
should be discussed. Prescription medications that impair 
male potency and factors that may lead to scrotal hyper
-
thermia, such as tight underwear or frequent use of saunas 
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or hot tubs, should be discussed. The gynecologic history 
should include the menstrual pattern, the use and types of 
contraceptives, libido, sexual practices, frequency and suc
-
cess of coitus, and correlation of intercourse with time of 
ovulation. Family history includes repeated spontaneous 
abortions. The American Society for Reproductive Medi
-
cine provides patient information on the infertility evalua
-
tion and treatment (www.reproductivefacts.org/topics/
topics-index/infertility/).
General physical and genital examinations are per
-
formed on the female partner. Basic laboratory studies 
include complete blood count, urinalysis, cervical culture 
for 
 rubella antibody determination, and thy
-
roid function tests. If the woman has regular menses with 
minimal symptoms, the likelihood of ovulatory cycles is very 
high. A luteal phase serum progesterone above 3 ng/mL 
 
establishes ovulation. Couples should be advised that 
coitus resulting in conception occurs during the 6-day 
window around the day of ovulation. Ovulation predictor 
kits have largely replaced basal body temperatures for pre
-
dicting ovulation, but temperature charting is a natural and 
inexpensive way to identify most fertile days. Basal body 
temperature charts cannot predict ovulation; they can only 
retrospectively confirm ovulation occurred.
A semen analysis to rule out a male factor for infertility 
should be completed. Men must abstain from sexual activ
-
ity for at least 3 days before the semen is obtained. A clean, 
dry, wide-mouthed bottle for collection is preferred. Semen 
should be examined within 1–2 hours after collection. 
Semen is considered normal with the following minimum 
values: volume, 2.0 mL; concentration, 20 million sperm 
per milliliter; motility, 50% or more forward progression, 
25% or more rapid progression; and normal forms, 30%. If 
the sperm count is abnormal, further evaluation includes 
physical examination of the male partner and a search for 
exposure to environmental and workplace toxins, alcohol 
or drug use.
B. Further Testing
1.
 
Gross deficiencies of sperm (number, motility, or 
appearance) require repeat analysis. 
Intracytoplasmic 
sperm injection (ICSI)
 is the treatment option avail
-
able for sperm deficiencies except for azoospermia 
(absence of sperm). ICSI requires the female partner to 
undergo 
in vitro fertilization (IVF)
.
2.
 
A screening pelvic ultrasound and hysterosalpingogra
-
phy to identify uterine cavity or tubal anomalies should 
be performed. Hysterosalpingography using an oil dye 
is performed within 3 days following the menstrual 
period if structural abnormalities are suspected. This 
radiographic study will demonstrate uterine abnormali
-
ties (septa, polyps, submucous myomas) and tubal 
obstruction. Oil-based (versus water-soluble) contrast 
media may improve pregnancy rates, but reports of 
complications using oil-based media resulted in a 
decrease in its usage. Women who have had prior pelvic 
inflammation should receive doxycycline, 100 mg orally 
twice daily, beginning immediately before and for 
 
7 days after the radiographic study. IVF is recommended 
as the primary treatment option for tubal disease. 
Surgery can be considered in women with mild tubal 
disease, but no rigorous research has evaluated surgical 
outcomes compared to IVF or expectant management.
3.
 
Absent or infrequent ovulation requires additional lab
-
oratory evaluation. Elevated FSH and LH levels and low 
estradiol levels indicate ovarian insufficiency. Elevated 
LH levels in the presence of normal FSH levels may 
indicate the presence of polycystic ovaries. Elevation of 
blood prolactin (PRL) levels suggests a pituitary ade
-
noma. In women over age 35, 
ovarian reserve
 should 
be assessed. A markedly elevated FSH (greater than 
15–20 international units/L) on day 3 of the menstrual 
cycle suggests inadequate ovarian reserve. Although

 should 
cycle suggests inadequate ovarian reserve. Although 
less widely used clinically, a Clomiphene Citrate 
Challenge Test, with measurement of FSH on day 10 
after administration of clomiphene from days 5–9, can 
help confirm a diagnosis of diminished ovarian reserve. 
The number of antral follicles during the early follicular 
phase of the cycle can provide useful information about 
ovarian reserve and can confirm serum testing. 
Antimullerian hormone can be used as part of the 
assessment of ovarian reserve. Unlike FSH, it can be 
measured at any time during the menstrual cycle and is 
less likely to be affected by hormones.
4.
 
If all the above testing is normal, 
unexplained infertility
 
is diagnosed. In approximately 25% of women whose 
basic evaluation is normal, the first-line therapy is 
 
usually controlled ovarian hyperstimulation (usually 
clomiphene citrate) and intrauterine insemination. IVF 
may be recommended as second-line therapy.
 
»
Treatment
Fertility may be restored by treatment of endocrine abnor
-
malities, particularly hypothyroidism or hyperthyroidism. 
Women who are anovulatory as a result of low body weight 
or exercise may become ovulatory when they gain weight 
or decrease their exercise levels.
Excision of ovarian tumors or ovarian foci of endometrio
-
sis can improve fertility. Microsurgical relief of tubal 
obstruction due to salpingitis or tubal ligation will reestab
-
lish fertility in a significant number of cases, although with 
severe disease or proximal obstruction, IVF is preferable. 
Peritubal adhesions or endometriotic implants often can be 
treated via laparoscopy.
In a male with a varicocele, sperm characteristics may 
be improved following surgical treatment. For men who 
have sperm production but obstructive azoospermia, 
transepidermal sperm aspiration or microsurgical epidermal 
sperm aspiration has been successful.
C. Induction of Ovulation
1. Clomiphene citrate—
Clomiphene citrate stimulates 
gonadotropin release, especially FSH. It acts as a selective 
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estrogen receptor modulator, similar to tamoxifen and 
raloxifene, and binds to the estrogen receptor. The body 
perceives a low level of estrogen, decreasing the negative 
feedback on the hypothalamus, and there is an increased 
release of FSH and LH. When FSH and LH are present in 
the appropriate amounts and timing, ovulation occurs.
After a normal menstrual period or induction of with
-
drawal bleeding with progestin, 50 mg of clomiphene 
orally daily for 5 days, typically on days 3–7 of the cycle, 
should be given. If ovulation does not occur, the dosage is 
increased to 100 mg daily for 5 days. If ovulation still does 
not occur, the course is repeated with 150 mg daily and 
then 200 mg daily for 5 days. The maximum dosage is 
200 mg. Ovulation and appropriate timing of intercourse 
can be facilitated with the addition of chorionic gonadotro
-
pin, 10,000 units intramuscularly. Monitoring of the folli
-
cles by transvaginal ultrasound usually is necessary to 
appropriately time the hCG injection. The rate of ovulation 
following this treatment is 90% in the absence of other 
infertility factors. The pregnancy rate is high. Twinning 
occurs in 5% of these patients, and three or more fetuses 
are found in rare instances (less than 0.5% of cases). Preg
-
nancy is most likely to occur within the first three ovula
-
tory cycles, and unlikely to occur after cycle six. In 
addition, several studies have suggested a twofold to three
-
fold increased risk of ovarian cancer with the use of clomi
-
phene for more than 1 year, so treatment with clomiphene 
is usually limited to a maximum of six cycles.
In the presence of increased androgen production 
(DHEA-S greater than 200 mcg/dL), the addition of dexa
-
methasone, 0.5 mg orally, or prednisone, 5 mg orally, at 
bedtime, improves the response to clomiphene in selected 
patients. Dexamethasone should be discontinued after 
pregnancy is confirmed.
2. Letrozole—
The aromatase inhibitor, letrozole, appears 
to be at least as effective as clomiphene for ovulation induc
-
tion in women with PCOS. There is a reduced risk of mul
-
tiple pregnancy, a lack of antiestrogenic effects, and a 
reduced need for ultrasound monitoring. The dose is 
5–7.5 mg daily, starting on day 3 of the menstrual cycle. In 
women who have a history of estrogen dependent tumors, 
such as breast cancer, letrozole is preferred as the estrogen 
levels with this medication are much lower.
3. Carbergoline or bromocriptine—
Carbergoline or bro
-
mocriptine is used only if PRL levels are elevated and there 
is no withdrawal bleeding following progesterone adminis
-
tration (otherwise, clomiphene is used). The initial dosage 
is 2.5 mg orally once daily, increased to two or three times 
daily in increments of 1.25 mg. The medication is discon
-
tinued once pregnancy has occurred. Cabergoline causes 
fewer adverse effects than bromocriptine. However, it is 
much more expensive. Cabergoline is often used in patients 
who cannot tolerate the adverse effects of bromocriptine or 
in those who do not respond to bromocriptine.
4. Human menopausal gonadotropins (hMG) or 
 
recombinant FSH—
hMG or recombinant FSH is indicated 
in cases of hypogonadotropism and most other types of 
anovulation resistant to clomiphene treatment. Because of 
the complexities, laboratory tests, and expense associated 
with this treatment, these patients should be referred to an 
infertility specialist.
D. Treatment of Endometriosis
See above.
E. Artificial Insemination in Azoospermia
If azoospermia is present, artificial insemination by a 
donor usually results in pregnancy, assuming female func
-
tion is normal. The use of frozen sperm provides the 
opportunity for screening for sexually transmitted diseases, 
including HIV infection.
F. Assisted Reproductive Technology (ART)
Couples who have not responded to traditional infertility 
treatments, including those with tubal disease, severe

treatments, including those with tubal disease, severe 
endometriosis, oligospermia, and immunologic or unex
-
plained infertility, may benefit from IVF. Gamete intrafal
-
lopian transfer and zygote intrafallopian transfer are rarely 
performed, although they may be an option in a few 
selected patients. These techniques are complex and 
require a highly organized team of specialists. All of the 
procedures involve ovarian stimulation to produce multi
-
ple oocytes, oocyte retrieval by transvaginal sonography–
guided needle aspiration, and handling of the oocytes 
outside the body. With IVF, the eggs are fertilized in vitro 
and the embryos transferred to the uterus. ICSI allows 
fertilization with a single sperm. While originally intended 
for couples with male factor infertility, it is now used in 
two-thirds of all IVF procedures in the United States.
The chance of a multiple gestation pregnancy (ie, twins, 
triplets) is increased in all assisted reproductive proce
-
dures, increasing the risk of preterm delivery and other 
pregnancy complications. To minimize this risk, most 
infertility specialists recommend transferring only one 
embryo in appropriately selected patients with a favorable 
prognosis. In women with prior failed IVF cycles who are 
over the age of 40 who have poor embryo quality, up to 4 
embryos may be transferred. In the event of a multiple 
gestation pregnancy, a couple may consider selective reduc
-
tion to avoid the medical issues generally related to multi
-
ple births. This issue should be discussed with the couple 
before
 embryo transfer.
 
»
Prognosis
The prognosis for conception and normal pregnancy is 
good if minor (even multiple) disorders can be identified 
and treated; it is poor if the causes of infertility are severe, 
untreatable, or of prolonged duration (over 3 years).
It is important to remember that in the absence of iden
-
tifiable causes of infertility, 60% of couples will achieve a 
pregnancy within 3 years. Couples with unexplained infer
-
tility who do not achieve pregnancy within 3 years may be 
offered ovulation induction or assisted reproductive tech
-
nology. Women over the age of 35 should be offered a more 
aggressive approach, with consideration of ART within 
3–6 months of not achieving pregnancy with more conser
-
vative approaches. Also, offering appropriately timed 
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information about adoption is considered part of a com
-
plete infertility regimen.
 
»
Refer to reproductive endocrinologist if ART is indicated, 
or surgery is required.
Chua SJ et al. Surgery for tubal infertility. Cochrane Database 
Syst Rev. 2017 Jan 23;1:CD006415. [PMID: 28112384]
Hanson B et al. Female infertility, infertility-associated diagnoses, 
and comorbidities: a review. J Assist Reprod Genet. 2017 Feb;
 
34(2):167–77. [PMID: 27817040]
Legro RS et al; Eunice Kennedy Shriver NICHD Reproductive 
Medicine Network. Letrozole or clomiphene for infertility in 
the polycystic ovary syndrome. N Engl J Med. 2014 Oct 9;
 
371(15):1463–4. [PMID: 25295506]
CONTRACEPTION
Unintended pregnancies are a worldwide problem but dis
-
proportionately impact developing countries. Studies esti
-
mate that 40% of the 213 million pregnancies that occurred 
in 2012 were unintended. Globally, 50% ended in abortion, 
13% ended in miscarriage, and 38% resulted in an 
unplanned birth. It is important for primary care providers 
to educate their patients about the benefits of contracep
-
tion and to provide options that are appropriate and desir
-
able for the patient.
1. Oral Contraceptives
A. Combined Oral Contraceptives
1. Efficacy and methods of use—
Combined oral contra
-
ceptives have a perfect use failure rate of 0.3% and a typical 
use failure rate of 8%. Their primary mode of action is 
suppression of ovulation. The pills can be initially started 
on the first day of the menstrual cycle, the first Sunday 
after the onset of the cycle or on any day of the cycle. If 
started on any day other than the first day of the cycle, a 
backup method should be used. If an active pill is missed at 
any time, and no intercourse occurred in the past 5 days, 
two pills should be taken immediately and a backup 
method should be used for 7 days. If intercourse occurred 
in the previous 5 days, emergency contraception should be 
used immediately, and the pills restarted the following day. 
A backup method should be used for 5 days.
2. Benefits of oral contraceptives—
Noncontraceptive 
benefits of oral contraceptives include lighter menses and 
improvement of dysmenorrhea symptoms, decreased risk 
of ovarian and endometrial cancer, and improvement in 
acne. Functional ovarian cysts are less likely with oral con
-
traceptive use. The frequency of developing myomas is 
lower in patients who have taken oral contraceptives for 
longer than 4 years. There is also a beneficial effect on bone 
mass.
3. Selection of an oral contraceptive—
Any of the combi
-
nation oral contraceptives containing 35 mcg or less of 
ethinyl estradiol or 3 mg of estradiol valerate are suitable 
for most women. There is some variation in potency of the 
various progestins in the pills, but there are essentially no 
clinically significant differences for most women among 
the progestins in the low-dose pills. The available evidence 
is insufficient to determine whether triphasic oral contra
-
ceptives differ from monophasic oral contraceptives in 
effectiveness, bleeding patterns or discontinuation rates. 
Therefore, monophasic pills are recommended as a first 
choice for women starting oral contraceptive use. Women 
who have acne or hirsutism may benefit from treatment 
with desogestrel, drospirenone, or norgestimate, since they 
are the least androgenic. A combination regimen with 84 
active and 7 inert pills that results in only four withdrawal 
bleeds per year is available. There is also a combination 
regimen that is taken continuously with withdrawal bleed. 
At the end of one years’ use, 58% of the women had amen
-
orrhea, and nearly 80% reported no bleeding requiring 
sanitary protection. Studies have not shown any significant 
risk from long-term amenorrhea in patients taking con
-
tinuous oral contraceptives. The low-dose oral contracep
-
tives commonly used in the United States are listed in 
Table 18–3.
4. Drug interactions—

-
-
Several medications interact with 
oral contraceptives to decrease their efficacy by causing 
induction of microsomal enzymes in the liver, or by other 
mechanisms. Some commonly prescribed medications in 
this category are phenytoin, phenobarbital (and other bar
-
biturates), primidone, topiramate, carbamazepine, and 
rifampin and St. John’s Wort. Women taking these medica
-
tions should use another means of contraception for maxi
-
mum safety.
Antiretroviral medications, specifically ritonavir-
boosted protease inhibitors, may significantly decrease the 
efficacy of combined oral contraceptives. Non-nucleoside 
reverse transcriptase inhibitors have smaller effects on oral 
contraceptive efficacy.
5. Contraindications and adverse effects—
Oral contra
-
ceptives have been associated with many adverse effects; 
they are contraindicated with some conditions and should 
be used with caution in others (Table 18–4).
a. Myocardial infarction—
The risk of heart attack is 
higher with use of oral contraceptives, particularly with 
pills containing 50 mcg of estrogen or more. Cigarette 
smoking, obesity, hypertension, diabetes, or hypercholes
-
terolemia increases the risk. Y oung nonsmoking women 
have minimal increased risk. Smokers over age 35 and 
women with other cardiovascular risk factors should use 
other non-estrogen–containing methods of birth control.
b. Thromboembolic disease
—
An increased rate of 
venous thromboembolism is found in oral contraceptive 
users, especially if the dose of estrogen is 50 mcg or more. 
While the overall risk is very low (5–6 per 100,000 woman-
years compared to 50–300 per 100,000 pregnancies), sev
-
eral studies have reported a twofold increased risk in 
women using oral contraceptives containing the progestins 
gestodene (not available in the United States), drospire
-
none, or desogestrel compared with women using oral 
contraceptives with levonorgestrel and norethindrone. 
Women in whom thrombophlebitis develops should stop 
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Table 18–3.
 
Commonly used low-dose oral contraceptives (listed within each group in order of increasing estrogen dose).
Name
p
r
ogestin
Estrogen (Ethinyl Estradiol)
Cost per Month
1
Combination
Alesse
2,3
0.1 mg levonorgestrel
20 mcg
$37.80
Loestrin 1/20
2
1 mg norethindrone acetate
20 mcg
$30.90
Mircette
2
0.15 mg desogestrel
20 mcg
$64.20
Yaz
2
3 mg drospirenone
20 mcg
$75.90
Loestrin 1.5/30
2
1.5 mg norethindrone acetate
30 mcg
$36.90
LoOvral
2
0.3 mg norgestrel
30 mcg
$32.70
Levlen
2
0.15 mg levonorgestrel
30 mcg
$33.12
Ortho-Cept
2
 Desogen
2
30 mcg
$36.90
Yasmin
2
30 mcg
$82.20
Brevicon
2
 Modicon
2
0.5 mg norethindrone
35 mcg
$34.50
Demulen 1/35
2
1 mg ethynodiol diacetate
35 mcg
$32.10
Ortho-Novum 1/35
2
1 mg norethindrone
35 mcg
$42.00
Ortho-Cyclen
2
0.25 mg norgestimate
35 mcg
$34.50
Ovcon 35
2
0.4 mg norethindrone
35 mcg
$48.00
Combination: Extended-Cycle
LoSeasonique (91-day cycle)
2
0.10 mg levonorgestrel (days 1–84)/0 mg 
 
levonorgestrel (days 85–91)
20 mcg (84 days)/10 mcg 
(7 days)
$88.50
Amethyst (28-day pack)
90 mcg levonorgestrel
20 mcg
$59.40
Seasonique (91-day cycle)
2
0.15 mg levonorgestrel (days 1–84)/0 mg 
 
30 mcg (84 days)/10 mcg 
(7 days)
$127.20
t
riphasic
Estrostep
2
1 mg norethindrone acetate (days 1–5)
1 mg norethindrone acetate (days 6–12)
1 mg norethindrone acetate (days 13–21)
20 mcg
30 mcg
35 mcg
$61.20
Cyclessa
2
0.1 mg desogestrel (days 1–7)
0.125 mg desogestrel (days 8–14)
0.15 mg desogestrel (days 15–21)
25 mcg
$36.00
Ortho-Tri-Cyclen Lo
0.18 norgestimate (days 1–7)
0.21 norgestimate (days 8–14)
0.25 norgestimate (days 15–21)
25 mcg
$34.80
Triphasil
2,3
0.05 mg levonorgestrel (days 1–6)
0.075 mg levonorgestrel (days 7–11)
0.125 mg levonorgestrel (days 12–21)
30 mcg
40 mcg
30 mcg
$27.50
Ortho-Novum 7/7/7
2,3
0.5 mg norethindrone (days 1–7)
0.75 mg norethindrone (days 8–14)
1 mg norethindrone (days 15–21)
35 mcg
$34.50
Ortho-Tri-Cyclen
2,3
0.18 mg norgestimate (days 1–7)
0.215 mg norgestimate (days 8–14)
0.25 mg norgestimate (days 15–21)
35 mcg
$42.00
Tri-Norinyl
2,3
1 mg norethindrone (days 8–16)
0.5 mg norethindrone (days 17–21)
35 mcg
$42.00
p
r
ogestin-Only Minipill
Ortho Micronor
2,3
0.35 mg norethindrone to be taken continuously
None
$39.60
1
Red Book
Analytics Information, http://www.micromedexsolutions.com, accessed April 10, 2018. AWP may not accurately represent the actual 
 
pharmacy cost because wide contractual variations exist among institutions.
2
Generic equivalent available.
3
Multiple other brands available.
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using this method, as should those at increased risk for 
thrombophlebitis because of surgery, fracture, serious 
injury, hypercoagulable condition, or immobilization. 
Women with a known thrombophilia should not use 
estrogen-containing contraceptives.
c. Cerebrovascular disease
—
Overall, a small increased 
risk of hemorrhagic stroke and subarachnoid hemorrhage 
and a somewhat greater increased risk of thrombotic stroke 
have been found; smoking, hypertension, and age over 
 
35 years are associated with increased risk. Women should 
stop using estrogen-containing contraceptives if such warn
-
ing symptoms as severe headache, blurred or lost vision, or 
other transient neurologic disorders develop.
d. Carcinoma
—
There is no increased risk of breast can
-
cer in women aged 35–64 who are current or former users 
of oral contraceptives. Women with a family history of 
breast cancer or women who started oral contraceptive use 
at a young age are not at increased risk. Combination oral 
contraceptives reduce the risk of endometrial carcinoma by 
40% after 2 years of use and 60% after 4 or more years of 
use. The risk of ovarian cancer is reduced by 30% with pill 
use for less than 4 years, by 60% with use for 5–11 years, 
and by 80% after 12 or more years. Oral contraceptives 
have been associated with the development of benign 
hepatocellular adenomas and peliosis hepatis (blood-filled 
cavities) (but not focal nodular hyperplasia or hepatocel
-
lular carcinoma); hepatocellular adenomas may rarely 
cause rupture of the liver, hemorrhage, and death. The risk 
of hepatocellular adenoma increases with higher dosage, 
longer duration of use, and older age.
e. Hypertension
—
Oral contraceptives may cause hyper
-
tension in some women; the risk is increased with longer 
duration of use and older age. Women in whom hyperten
-
sion develops while using oral contraceptives should use 
other non-estrogen–containing contraceptive methods. 
However, with regular blood pressure monitoring, non
-
smoking women with well-controlled mild hypertension 
may use oral contraceptives.
f. Headache
—
Migraine or other vascular headaches may 
occur or worsen with pill use. If severe or frequent head
-
aches develop while using this method, it should be discon
-
tinued. Women with migraine headaches 
with an aura
 
should not use oral contraceptives.
g. Lactation
—
Combined oral contraceptives can impair 
the quantity and quality of breast milk. While it is prefera
-
ble to avoid the use of combination oral contraceptives 
during lactation, the effects on milk quality are small and 
are not associated with developmental abnormalities in 
infants. Combination oral contraceptives should be started 
no earlier than 6 weeks postpartum to allow for establish
-
ment of lactation. Progestin-only pills, levonorgestrel 
implants, and DMPA are alternatives with no adverse 
effects on milk quality.
h. Other disorders
—
Depression may occur or be wors
-
ened with oral contraceptive use. Fluid retention may 
occur. Patients who had cholestatic jaundice during preg
-
nancy may develop it while taking birth control pills.
i. Obesity
—
Obese and overweight women have generally 
been excluded from oral contraceptive trials until recently, 
and some studies have suggested that oral contraceptives 
are less effective in overweight women. In addition, obesity 
is a risk factor for thromboembolic complications. It is 
important that obese women are not denied effective con
-
traception as a result of concerns about complications or 
efficacy of oral contraceptives. Alternatives, including 
progestin only injections, implants, or intrauterine devices, 
should be considered as first options instead of oral 
contraceptives.
6. Minor side effects—
Nausea and dizziness may occur in 
the first few months of pill use. A weight gain of 2–5 lb 
(0.9–2.25 kg) commonly occurs. Spotting or breakthrough

(0.9–2.25 kg) commonly occurs. Spotting or breakthrough 
bleeding between menstrual periods may occur, especially 
if a pill is skipped or taken late; this may be helped by 
switching to a pill of slightly greater potency (see section 3, 
above). Missed menstrual periods may occur, especially 
with low-dose pills. A pregnancy test should be performed 
if pills have been skipped or if two or more expected men
-
strual periods are missed. Fatigue and decreased libido can 
occur. Chloasma may occur, as in pregnancy, and is 
increased by exposure to sunlight.
B. Progestin Minipill
A formulation contain
-
ing 0.35 mg of norethindrone is available in the 
 
United States. The efficacy is similar to that of combined 
oral contraceptives but is highly dependent on consistent 
use (eg, taking the pill within the same 3-hour window 
Table 18–4.
 
Contraindications to use of oral 
a
bsolut
e contraindications
Pregnancy
Thrombophlebitis or thromboembolic disorders (past or 
present)
Stroke or coronary artery disease (past or present)
Cancer of the breast (known or suspected)
Undiagnosed abnormal vaginal bleeding
Estrogen-dependent cancer (known or suspected)
Hepatocellular adenoma (past or present)
Uncontrolled hypertension
Diabetes mellitus with vascular disease
Age over 35 and smoking > 15 cigarettes daily
Known thrombophilia
Migraine with aura
Active hepatitis
Surgery or orthopedic injury requiring prolonged 
immobilization
Migraine without aura
Heart or kidney disease
Gallbladder disease
Cholestasis during pregnancy
Sickle cell disease (S/S or S/C type)
Lactation
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every day). The minipill is believed to prevent conception 
by causing thickening of the cervical mucus to make it 
hostile to sperm, alteration of ovum transport (which may 
account for the slightly higher rate of ectopic pregnancy 
with these pills), and inhibition of implantation. Ovulation 
is inhibited inconsistently with this method. The minipill is 
begun on the first day of a menstrual cycle and then taken 
continuously for as long as contraception is desired; there 
is no “placebo week. ”
2. Advantages—
The low dose of progestin and absence of 
estrogen make the minipill safe during lactation; it may 
increase the flow of milk. It is often tried by women who 
want minimal doses of hormones and by patients who are 
over age 35. They lack the cardiovascular side effects of 
combination pills. The minipill can be safely used by 
women with sickle cell disease (S/S or S/C).
3. Complications and contraindications—
Minipill users 
often have bleeding irregularities (eg, prolonged flow, spot
-
ting, or amenorrhea); such patients may need regular 
pregnancy tests. Ectopic pregnancies are more frequent, 
and complaints of abdominal pain should be investigated 
with this in mind. Many of the absolute contraindications 
and relative contraindications listed in Table 18–4 apply to 
the minipill; however, the contraceptive benefit of the 
minipill may outweigh the risks for patients who smoke, 
who are over age 35, or who have such conditions as super
-
ficial deep venous thrombosis or known thromboembolic 
disorders or diabetes with vascular disease. Minor side 
effects of combination oral contraceptives such as weight 
gain and mild headache may also occur with the minipill.
Curtis KM et al. U.S. medical eligibility criteria for contraceptive 
use, 2016. MMWR Recomm Rep. 2016 Jul 29;65(3):1–103. 
[PMID: 27467196]
Curtis KM et al. U.S. selected practice recommendations for 
contraceptive use, 2016 MMWR Recomm Rep. 2016 Jul 29;
 
65(4):1–66. [PMID: 27467319]
Edelman A et al. Continuous or extended cycle vs. cyclic use of 
combined hormonal contraceptives for contraception. 
Cochrane Database Syst Rev. 2014 Jul 29;7:CD004695. 
[PMID: 25072731]
Golobof A et al. The current status of oral contraceptives: prog
-
ress and recent innovations. Semin Reprod Med. 2016 May;
 
34(3):145–51. [PMID: 26960906]
Jin J. JAMA patient page. Oral contraceptives. JAMA. 2014 Jan 15;
 
311(3):321. [PMID: 24430333]
2. Contraceptive Injections & Implants 
 
(Long-
a
c
ting 
p
r
ogestins)
The injectable progestin 
DM PA
 is approved for contracep
-
tive use in the United States. There has been extensive 
worldwide experience with this method over the past 3 
decades. The medication is given as a deep intramuscular 
injection of 150 mg every 3 months and has a contraceptive 
efficacy of 99.7%. Common side effects include irregular 
bleeding, amenorrhea, weight gain, and headache. It is asso
-
ciated with bone mineral loss that is reversible after discon
-
tinuation of the method. Users commonly have irregular 
bleeding initially and subsequently develop amenorrhea. 
Ovulation may be delayed after the discontinuation. Con
-
traindications are similar to those for the minipill.
A single-rod, subdermal progestin implant, etonoges
-
trel subdermal (
Nexplanon)
, is approved for use in the 
United States. Nexplanon is a 40-mm by 2-mm rod con
-
taining 68 mg of the progestin etonogestrel that is inserted 
in the inner aspect of the nondominant arm and remains 
effective for 3 years. Hormone levels drop rapidly after 
removal, and there is no delay in the return of fertility. In 
clinical trials, the pregnancy rate was 0.0% with 3 years of 
use. The side effect profile is similar to minipills, and 
DMPA. Irregular bleeding has been the most common 
reason for discontinuation. Both the American College of 
Obstetricians and Gynecologists and the American Acad
-
emy of Pediatrics have recommended that adolescents

-
emy of Pediatrics have recommended that adolescents 
should be encouraged to consider long-acting reversible 
contraception methods. In a large prospective study, a 75% 
reduction in unintended pregnancy was demonstrated 
with the use of long-acting reversible contraception.
-
tee Opinion No. 672: Clinical challenges of long-acting 
reversible contraceptive methods. Obstet Gynecol. 2016 Sep;
 
128(3):e69–77. [PMID: 27548557]
Hubacher D et al. Long-acting reversible contraceptive accept
-
ability and unintended pregnancy among women presenting 
for short-acting methods: a randomized patient preference 
trial. Am J Obstet Gynecol. 2017 Feb;216(2):101–9. [PMID: 
27662799]
Raymond EG et al. Effects of depot medroxyprogesterone ace
-
tate injection timing on medical abortion efficacy and repeat 
pregnancy: a randomized controlled trial. Obstet Gynecol. 
2016 Oct;128(4):739–45. [PMID: 27607859]
Raymond EG et al. Effect of immediate compared with delayed 
insertion of etonogestrel implants on medical abortion effi
-
cacy and repeat pregnancy: a randomized controlled trial. 
Obstet Gynecol. 2016 Feb;127(2):306–12. [PMID: 26942358]
Sothornwit J et al. Immediate versus delayed postpartum inser
-
tion of contraceptive implant for contraception. Cochrane 
Database Syst Rev. 2017 Apr 22;4:CD011913. [PMID: 
28432791]
Turok DK et al. New developments in long-acting reversible 
contraception: the promise of intrauterine devices and 
implants to improve family planning services. Fertil Steril. 
2016 Nov;106(6):1273–81. [PMID: 27717553]
3. Other Hormonal Methods
A 
transdermal contraceptive
 
patch
 containing norelge
-
stromin (150 mcg) and ethinyl estradiol (20 mcg) and 
measuring 20 cm
2
 is available. The patch is applied to the 
lower abdomen, upper torso, or buttock once a week for 3 
consecutive weeks, followed by 1 week without the patch. It 
appears that the average steady-state concentration of 
ethinyl
 
 es
tradiol with the patch is approximately 60% 
higher than with a 35-mcg pill. However, there is currently 
no evidence for an increased incidence of estrogen-related 
side effects. The mechanism of action, side effects, and 
efficacy are similar to those associated with oral contracep
-
tives, although compliance may be better. However, discon
-
tinuation for side effects is more frequent.
A 
contraceptive vaginal ring
 that releases 120 mcg of 
etonogestrel and 15 mcg of ethinyl estradiol daily is 
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available. The ring is soft and flexible and is placed in the 
upper vagina for 3 weeks, removed, and replaced 1 week 
later, or can be removed and replaced after 4 weeks for 
continuous cycling, similar to oral contraceptives. The 
efficacy, mechanism of action, and systemic side effects are 
similar to those associated with oral contraceptives. Ring 
users may experience an increased incidence of vaginal 
4. Intrauterine Devices
In the United States, the following devices are available: 
the levonorgestrel-releasing 
Mirena, Liletta,
 and 
Skyla
 
IUDs and the copper-bearing 
TCu380A.
 The mechanism 
of action of the copper IUD is thought to involve either 
spermicidal or inhibitory effects on sperm capacitation 
and transport. The levonorgestrel-containing IUDs also 
cause thickening of cervical mucus, prevent endometrial 
thickening, and can inhibit ovulation. IUDs are not 
abortifacients.
Skyla and Liletta are FDA approved for 3 years, Mirena 
for 5 years, and the TCu380A for 10 years. The hormone-
containing IUDs have the advantage of reducing cramping 
and menstrual flow.
The IUD is an excellent contraceptive method for most 
women. The devices are highly effective, with failure rates 
similar to those achieved with surgical sterilization. 
 
Nulliparity is not a contraindication to IUD use. Adoles
-
cents are also candidates for IUD use. Women who are not 
in mutually monogamous relationships should use con
-
doms for protection from sexually transmitted diseases. 
Levonorgestrel-containing IUDs may have a protective 
effect against upper tract infection similar to that of the 
oral contraceptives.
A. Insertion
Insertion can be performed during or after the menses, at 
midcycle to prevent implantation, or later in the cycle if the 
patient has not become pregnant. There is growing evi
-
dence to suggest that IUDs can be safely inserted in the 
immediate postabortal and postpartum periods.
Both types of IUDs (levonorgestrel-releasing and cop
-
per bearing) may be inserted up to 48 hours after vaginal 
delivery, or prior to closure of the uterus at the time of 
cesarean section. Insertion immediately following abortion 
is acceptable if there is no sepsis and if follow-up insertion 
a month later will not be possible; otherwise, it is wise to 
wait until 4 weeks’ postabortion. Misoprostol and NSAIDs 
given as premedications may help insertions in nulliparous 
patients or when insertion is not performed during 
menses.
B. Contraindications and Complications
Contraindications to use of IUDs are outlined in Table 18–5.
1. Pregnancy—
A copper-containing IUD can be inserted 
within 5 days following a single episode of unprotected 
midcycle coitus as a 
postcoital contraceptive
. An IUD 
should not be inserted into a pregnant uterus. If pregnancy 
occurs as an IUD failure, there is a greater chance of 
spontaneous abortion if the IUD is left in situ (50%) than 
if it is removed (25%). Spontaneous abortion with an IUD 
in place is associated with a high risk of severe sepsis, and 
death can occur rapidly. Women using an IUD who 
become pregnant should have the IUD removed if the 
string is visible. It can be removed at the time of abortion if 
this is desired. If the string is not visible and the patient 
wants to continue the pregnancy, she should be informed 
of the serious risk of sepsis and, occasionally, death with 
such pregnancies. She should be informed that any flu-like 
symptoms such as fever, myalgia, headache, or nausea war
-
rant immediate medical attention for possible septic 
abortion.
Since the ratio of ectopic to intrauterine pregnancies is 
increased among IUD users, clinicians should search for 
adnexal masses in early pregnancy and should always 
check the products of conception for placental tissue fol
-
lowing abortion.
2. Pelvic infection—
There is an increased risk of pelvic 
infection during the first month following insertion; how
-

-
-
ever, prophylactic antibiotics given at the time of inser
-
tion do not appear to decrease this risk. The subsequent 
risk of pelvic infection appears to be primarily related to 
the risk of acquiring sexually transmitted infections. 
Infertility rates do not appear to be increased among 
women who have previously used the currently available 
IUDs. At the time of insertion, women with an increased 
risk of sexually transmitted diseases should be screened 
for gonorrhea and 
Chlamydia.
 Women with a history of 
recent or recurrent pelvic infection are not good candi
-
dates for IUD use.
3. Menorrhagia or severe dysmenorrhea—
The copper 
IUD can cause heavier menstrual periods, bleeding 
between periods, and more cramping, so it is generally not 
suitable for women who already suffer from these prob
-
lems. Alternatively, the hormone-releasing IUD Mirena 
has been approved by the FDA to treat heavy menstrual 
bleeding. NSAIDs are also helpful in decreasing bleeding 
and pain in IUD users.
4. Complete or partial expulsion—
Spontaneous expulsion 
of the IUD occurs in 10–20% of cases during the first year 
Table 18–5.
 
Contraindications to IUD use.
a
bsolut
Pregnancy
Acute or subacute pelvic inflammatory disease or purulent 
cervicitis
Significant anatomic abnormality of uterus
Unexplained uterine bleeding
Active liver disease (Mirena only)
Relative contraindication
s
History of pelvic inflammatory disease since the last pregnancy
Lack of available follow-up care
Menorrhagia or severe dysmenorrhea (copper IUD)
Cervical or uterine neoplasia
IUD, intrauterine device.
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of use. Any IUD should be removed if the body of the 
device can be seen or felt in the cervical os.
5. Missing IUD strings—
If the transcervical tail cannot be 
seen, this may signify unnoticed expulsion, perforation of 
the uterus with abdominal migration of the IUD, or simply 
retraction of the string into the cervical canal or uterus 
owing to movement of the IUD or uterine growth with 
pregnancy. Once pregnancy is ruled out, a cervical specu
-
lum may be used to visualize the IUD string in the cervical 
canal. If not visualized, one should probe for the IUD with 
a sterile sound or forceps designed for IUD removal after 
administering a paracervical block. If the IUD cannot be 
detected, pelvic ultrasound will demonstrate the IUD if it 
is in the uterus. Alternatively, obtain anteroposterior and 
lateral radiographs of the pelvis with another IUD or a 
sound in the uterus as a marker to confirm an extrauterine 
IUD. If the IUD is in the abdominal cavity, it should gener
-
ally be removed by laparoscopy or laparotomy. Perforations 
of the uterus are less likely if insertion is performed slowly, 
with meticulous care taken to follow directions applicable 
to each type of IUD.
-
tee Opinion No. 670: Immediate postpartum long-acting 
reversible contraception. Obstet Gynecol. 2016 Aug;
 
128(2):e32–7. [PMID: 27454734]
Lopez LM et al. Immediate postpartum insertion of intrauterine 
device for contraception. Cochrane Database Syst Rev. 
 
2015 Jun 26;6:CD003036. [PMID: 26115018]
Moniz MH et al. Inpatient postpartum long-acting reversible 
contraception and sterilization in the United States, 
 
2008–2013. Obstet Gynecol. 2017 Jun;129(6):1078–85. 
[PMID: 28486357]
Okusanya BO et al. Immediate postabortal insertion of intra
-
uterine devices. Cochrane Database Syst Rev. 2014 Jul 28;7:
 
CD001777. [PMID: 25101364]
5. Diaphragm & Cervical Cap
The 
diaphragm (with contraceptive jelly)
 is a safe and 
effective contraceptive method with features that make it 
acceptable to some women and not others. Failure rates 
range from 6% to 16%, depending on the motivation of the 
woman and the care with which the diaphragm is used. 
The advantages of this method are that it has no systemic 
side effects and gives significant protection against pelvic 
infection and cervical dysplasia as well as pregnancy. The 
disadvantages are that it must be inserted near the time of 
coitus and that pressure from the rim predisposes some 
women to cystitis after intercourse.
The 
cervical cap (with contraceptive jelly)
 is similar to 
the diaphragm but fits snugly over the cervix only (the 
diaphragm stretches from behind the cervix to behind the 
pubic symphysis). The cervical cap is more difficult to 
insert and remove than the diaphragm. The main advan
-
tages are that it can be used by women who cannot be fitted 
for a diaphragm because of a relaxed anterior vaginal wall 
or by women who have discomfort or develop repeated 
bladder infections with the diaphragm. However, failure 
rates are 9% (perfect use) and 16% (typical use) in nullipa
-
rous women and 26% (perfect use) and 32% (typical use) 
in parous women.
Because of the small risk of toxic shock syndrome, a 
cervical cap or diaphragm should not be left in the vagina 
for over 12–18 hours, nor should these devices be used 
during the menstrual period.
6. Contraceptive Foam, Cream, Film, Sponge, 
Jelly, & Suppository
These products are available without prescription, are easy 
to use, and have typical failure rates of 10–22%. All contain 
the spermicide nonoxynol-9, which also has some viru
-
cidal and bactericidal activity. Nonoxynol-9 does not 
appear to adversely affect the vaginal colonization of 
hydrogen peroxide–producing lactobacilli. The FDA 
requires products containing nonoxynol-9 to include a 
warning that the products do not protect against HIV or

warning that the products do not protect against HIV or 
other sexually transmitted diseases and that use of these 
products can irritate the vagina and rectum and may 
increase the risk of getting the AIDS virus from an infected 
partner. Low-risk women using a nonoxynol-9 product, 
with coital activity two to three times per week, are not at 
increased risk for epithelial disruption, compared with 
couples using condoms alone.
7. Condom
The male condom of latex, polyurethane or animal mem
-
brane affords protection against pregnancy—equivalent to 
that of a diaphragm and spermicidal jelly; latex and poly
-
urethane (but not animal membrane) condoms also offer 
protection against many sexually transmitted diseases, 
including HIV . When a spermicide, such as vaginal foam, 
is used with the condom, the failure rate (approximately 
2% with perfect use and 15% with typical use) approaches 
that of oral contraceptives. The disadvantages of condoms 
are dulling of sensation and spillage of semen due to tear
-
ing, slipping, or leakage with detumescence of the penis.
Two female condoms, one made of polyurethane and 
the other of synthetic nitrile, are available in the United 
States. The reported failure rates range from 5% to 21%; the 
efficacy is comparable to that of the diaphragm. These are 
the only female-controlled method that offers significant 
protection from both pregnancy and sexually transmitted 
diseases.
8. Contraception Based on 
a
w
areness of 
Fertile 
p
eriods
These methods are most effective when the couple restricts 
intercourse to the post-ovular phase of the cycle or uses a 
barrier method at other times. Well-instructed, motivated 
couples may be able to achieve low pregnancy rates with 
fertility awareness methods. However, properly done ran
-
domized clinical trials comparing the efficacy of most of 
these methods with other contraceptive methods do not 
exist.
9. Emergency Contraception
If unprotected intercourse occurs in midcycle and if the 
woman is certain she has not inadvertently become preg
-
nant earlier in the cycle, the following regimens are 
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effective in preventing implantation. These methods 
should be started as soon as possible and within 120 hours 
after unprotected coitus. (1) Levonorgestrel, 1.5 mg orally 
as a single dose (available in the United States prepackaged 
as Plan B and available over-the-counter for women aged 
17 years and older), has a 1% failure rate when taken within 
72 hours. It remains efficacious up to 120 hours after inter
-
course, though less so compared with earlier use. (2) If the 
levonorgestrel regimen is not available, a combination oral 
contraceptive containing ethinyl estradiol and levonorg
-
estrel given twice in 12 hours may be used. At least 
 
20 brands of pills may be used in this way. For specific dos
-
ages and instructions for each pill brand, consult “not-
 
2-late” at http://ec.princeton.edu/. Used within 72 hours, 
the failure rate of these regimens is approximately 3%, but 
antinausea medication is often necessary. (3) Ulipristal, 
 
30 mg orally as a single dose, has been shown to be more 
effective than levonorgestrel, especially when used between 
72 and 120 hours, particularly among overweight women. 
It is available by prescription in the United States and West
-
ern Europe. (4) IUD insertion within 5 days after one epi
-
sode of unprotected midcycle coitus will also prevent 
pregnancy; copper-bearing IUDs have been tested and 
used for many years for this purpose. All victims of sexual 
violence should be offered emergency contraception.
Information on clinics or individual clinicians provid
-
ing emergency contraception in the United States may be 
obtained by calling 1-888-668-2528.
-
tee Opinion No. 707: Access to emergency contraception. 
Obstet Gynecol. 2017 Jul;130(1):e48–52. [PMID: 28644339]
Bulletin No. 152: Emergency contraception. Obstet Gynecol. 
2015 Sep;126(3):e1–11. [PMID: 26287787]
Fok WK et al. Update on emergency contraception. Curr Opin 
Obstet Gynecol. 2016 Dec;28(6):522–9. [PMID: 27676405]
10. 
a
bor
tion
Since the legalization of abortion in the United States in 
1973, the related maternal mortality rate has fallen mark
-
edly, because illegal and self-induced abortions have been 
replaced by safer medical procedures. Abortions in the first 
trimester of pregnancy are performed by vacuum aspira
-
tion under local anesthesia or with medical regimens. Dila
-
tion and evacuation, a variation of vacuum aspiration is 
generally used in the second trimester. Techniques utilizing 
intra-amniotic instillation of hypertonic saline solution or 
various prostaglandins regimens, along with medical or 
osmotic dilators are occasionally used after 18 weeks. Sev
-
eral medical abortion regimens utilizing mifepristone and 
multiple doses of misoprostol have been reported as being 
effective in the second trimester. Overall, legal abortion in 
the United States has a mortality rate of less than 1:100,000. 
Rates of morbidity and mortality rise with length of gesta
-
tion. In the United States, more than 60% of abortions are 
performed before 9 weeks, and more than 90% are per
-
formed before 13 weeks’ gestation; only 1.2% are per
-
formed after 20 weeks. If abortion is chosen, every effort 
should be made to encourage the patient to seek an early 
procedure. In the United States, while numerous state laws 
limiting access to abortion and a federal law banning a 
rarely used variation of dilation and evacuation have been 
enacted, abortion remains legal and available until 
 
fetal viability, between 24 and 28 weeks’ gestation, under 
 
Roe v. Wade
.
Complications resulting from abortion include retained 
products of conception (often associated with infection 
and heavy bleeding), uterine perforation, and unrecog
-
nized ectopic pregnancy. Immediate analysis of the 
removed tissue for placenta can exclude or corroborate the

-
removed tissue for placenta can exclude or corroborate the 
diagnosis of ectopic pregnancy. Women who have fever, 
bleeding, or abdominal pain after abortion should be 
examined; use of broad-spectrum antibiotics and reaspira
-
tion of the uterus are frequently necessary. Hospitalization 
is advisable if acute salpingitis requires intravenous admin
-
istration of antibiotics. Complications following illegal 
abortion often need emergency care for hemorrhage, septic 
shock, or uterine perforation.
Prophylactic antibiotics are indicated for surgical abor
-
tion; for example, a one-dose regimen of doxycycline, 
 
200 mg orally can be given 1 hour before the procedure. 
Many clinics prescribe tetracycline, 500 mg orally four 
times daily for 5 days after the procedure, as presumptive 
treatment for 
 Rh immune globulin should be 
given to all Rh-negative women following abortion. 
 
Contraception should be thoroughly discussed and contra
-
ceptive supplies or pills provided at the time of abortion. 
There is growing evidence to support the safety and effi
-
cacy of immediate postabortal insertion of IUDs.
Mifepristone (RU 486) is approved by the FDA as an 
oral abortifacient at a dose of 600 mg on day 1, followed by 
400 mcg orally of misoprostol on day 3. This combination 
is 95% successful in terminating pregnancies of up to 
9 weeks’ duration with minimum complications. A more 
commonly used, evidence-based regimen is mifepristone, 
200 mg orally on day 1, followed by misoprostol, 800 mcg 
vaginally either immediately or within 6–8 hours. 
Although not approved by the FDA for this indication, a 
combination of intramuscular methotrexate, 50 mg/m
2
 of 
body surface area, followed 3–7 days later by vaginal miso
-
prostol, 800 mcg, is 98% successful in terminating preg
-
nancy at 8 weeks or less. Minor side effects, such as 
nausea, vomiting, and diarrhea, are common with these 
regimens. There is a 5–10% incidence of hemorrhage or 
incomplete abortion requiring curettage. Medical abor
-
tion is generally considered as safe as surgical abortion in 
the first trimester but is associated with a lower success 
rate (requiring surgical abortion). Overall, the risk of uter
-
ine infection is lower with medical than with surgical 
abortion.
Nissi R et al. Mifepristone and misoprostol is safe and effective 
method in the second-trimester pregnancy termination. Arch 
Gynecol Obstet. 2016 Nov;294(6):1243–7. [PMID: 27522599]
11. Sterilization
In the United States, sterilization is the most popular method 
of birth control for couples who want no more children. 
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Although sterilization is reversible in some instances, 
reversal surgery in both men and women is costly, compli
-
cated, and not always successful. Therefore, patients should 
be counseled carefully before sterilization and should view 
the procedure as permanent.
Male sterilization by vasectomy is a safe, simple proce
-
dure in which the vas deferens is severed and sealed 
through a scrotal incision under local anesthesia. Long-
term follow-up studies on vasectomized men show no 
excess risk of cardiovascular disease. Despite past contro
-
versy, there is no definite association of vasectomy with 
prostate cancer.
Female sterilization procedures include laparoscopic 
bipolar electrocoagulation, salpingectomy, or plastic ring 
application on the uterine tubes, minilaparotomy with 
tubal resection, or hysteroscopic transcervical sterilization. 
The advantages of laparoscopy are minimal postoperative 
pain, small incisions, and rapid recovery. The advantages of 
minilaparotomy are that it can be performed with standard 
surgical instruments under local or general anesthesia. 
However, there is more postoperative pain and a longer 
recovery period. The cumulative 10-year failure rate for all 
methods combined is 1.85%, varying from 0.75% for post
-
partum partial salpingectomy and laparoscopic unipolar 
coagulation to 3.65% for spring clips; this fact should be 
discussed with women preoperatively. Some studies have 
found an increased risk of menstrual irregularities as a 
long-term complication of tubal ligation, but findings in 
different studies have been inconsistent. A method of trans
-
cervical sterilization, Essure

, can be performed as an 
outpatient procedure. Essure

 involves the placement of an 
expanding microcoil of titanium into the proximal uterine 
tube under hysteroscopic guidance. The efficacy rate at 
1  year is 99.8%. Tubal occlusion should be confirmed at 
3 months with a hysterosalpingogram.
 
»
Refer to experienced clinicians for etonogestrel subdermal 
(Nexplanon) or other subcutaneous insertion, IUD inser
-
tion, tubal occlusion or ligation, vasectomy, or therapeutic 
abortion.
contraceptive use, 2016. MMWR Recomm Rep. 2016 Jul 29;
 
Danis RB et al. Postpartum permanent sterilization: could bilat
-
eral salpingectomy replace bilateral tubal ligation? J Minim 
Invasive Gynecol. 2016 Sep–Oct;23(6):928–32. [PMID: 
27234430]
Dhruva SS et al. Revisiting Essure—toward safe and effective 
sterilization. N Engl J Med. 2015 Oct 8;373(15):e17. [PMID: 
26397951]
Nutt M et al. Vasectomy and prostate cancer risk: a historical syn
-
opsis of undulating false causality. Res Rep Urol. 2016 Jul 18;
 
8:85–93. [PMID: 27486569]
Patil E et al. Update on permanent contraception options for 
women. Curr Opin Obstet Gynecol. 2015 Dec;27(6):465–70. 
[PMID: 26406934]
SEXUAL VIOLENCE
 
»
The legal definition of rape varies by state and 
geographic location. The term “sexual violence” is 
used by the CDC and will be used in this discus
-
sion. It can be committed by a stranger, but more 
commonly by an assailant known to the victim, 
including a current or former partner or spouse (a 
form of intimate partner violence [IPV]).
 
»
All victims of sexual violence should be offered 
emergency contraception, and counseled that 
this method does not induce abortion.
 
»
The large number of individuals affected, the 
enormous health care costs, and the need for a 
multidisciplinary approach make sexual violence 
and IPV important health care issues.
 
»
Knowledge of state laws and collection of evi
-
dence requirements are essential for clinicians 
evaluating possible victims of sexual violence, 
including IPV.
 
»

»
-
 
»
Rape, or sexual assault, is legally defined in different ways 
in various jurisdictions. Clinicians and emergency depart
-
ment personnel who deal with victims of sexual violence 
should be familiar with the laws pertaining to sexual 
assault in their own state. From a medical and psychologi
-
cal viewpoint, it is essential that persons treating victims of 
sexual violence recognize the nonconsensual and violent 
nature of the crime. About 95% of reported victims of 
sexual violence are women. Each year in the United States, 
4.8 million incidents of physical or sexual assault are 
reported by women. Penetration may be vaginal, anal, or 
oral and may be by the penis, hand, or a foreign object. The 
absence of genital injury does not imply consent by the 
victim. The assailant may be unknown to the victim or, 
more frequently, may be an acquaintance or even the 
spouse.
“Unlawful sexual intercourse, ” or statutory rape, is 
intercourse with a female before the age of majority even 
with her consent.
Health care providers can have a significant impact in 
increasing the reporting of sexual violence and in identify
-
ing resources for the victims. The International Rescue 
Committee has developed a multimedia training tool to 
encourage competent, compassionate, and confidential 
clinical care for sexual violence survivors in low-resource 
settings. They studied this intervention in over 100 health
-
care providers, and found knowledge and confidence in 
clinical care for sexual violence survivors increased from 
49% to 62% (
P
 < 0.001) and 58% to 73% (
P
 < 0.001), 
respectively, following training. There was also a docu
-
mented increase in eligible survivors receiving emergency 
contraception from 50% to 82% (
P
 < 0.01), HIV 
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postexposure prophylaxis from 42% to 92% (
P
 < 0.001), 
and sexually transmitted infection prophylaxis and treat
-
ment from 45% to 96% (
P
 < 0.01). This training encourages 
providers to offer care in the areas of pregnancy and sexu
-
ally transmitted infection prevention as well as assistance 
for psychological trauma.
Because sexual violence is a personal crisis, each patient 
will react differently, but anxiety disorders and posttrau
-
matic stress disorder (PTSD) are common sequelae. The 
rape trauma syndrome
 comprises two principal phases. (1) 
Immediate or acute: Shaking, sobbing, and restless activity 
may last from a few days to a few weeks. The patient may 
experience anger, guilt, or shame or may repress these emo
-
tions. Reactions vary depending on the victim’s personality 
and the circumstances of the attack. (2) Late or chronic: 
Problems related to the attack may develop weeks or 
months later. The lifestyle and work patterns of the indi
-
vidual may change. Sleep disorders or phobias often 
develop. Loss of self-esteem can lead to suicide, albeit rarely.
Clinicians and emergency department personnel who 
deal with victims of sexual violence should work with com
-
munity rape crisis centers or other sources of ongoing 
psychological support and counseling.
 
»
General Office Procedures
The clinician who first sees the alleged victim of sexual 
violence should be empathetic and prepared with appro
-
priate evidence collection and treatment materials. Stan
-
dardized information and training, such as the program 
created by the International Rescue Committee, can be a 
helpful resource to the providers caring for these patients. 
Many emergency departments have a protocol for sexual 
violence victims and personnel who are trained in inter
-
viewing and examining victims of sexual violence.
 
»
Treatment
1.
 
Give analgesics or sedatives if indicated. Administer teta
-
nus toxoid if deep lacerations contain soil or dirt particles.
2.
 
Give ceftriaxone, 125 mg intramuscularly, to prevent 
gonorrhea. In addition, give metronidazole, 2 g as a 
single dose, and azithromycin 1 g orally or doxycycline, 
100 mg orally twice daily for 7 days to treat chlamydial 
infection. Incubating syphilis will probably be pre
-
vented by these medications, but the VDRL test should 
be repeated 6 weeks after the assault.
3.
 
Prevent pregnancy by using one of the methods dis
-
cussed under Emergency Contraception.
4.
 
Vaccinate against hepatitis B. Consider HIV prophy
-
laxis (see Chapter 31).
5.
 
Because women who are sexually assaulted are at 
increased risk for long-term psychological sequelae, 
such as PTSD and anxiety disorders, it is critical that 
the patient and her family and friends have a source of 
ongoing counseling and psychological support.
 
»
All women who seek care for sexual assault should be 
referred to a facility that has expertise in the management 
of victims of sexual violence and is capable of performing 
expert forensic examination, if requested.
American College of Obstetricians and Gynecologists. Committee 
Opinion No. 592: Sexual assault. Obstet Gynecol. 2014 Apr;
 
123(4):905–9. [PMID: 24785635]
Vrees RA. Evaluation and management of female victims of 
sexual assault. Obstet Gynecol Surv. 2017 Jan;72(1):39–53. 
[PMID: 28134394]
MENOPAUSAL SYNDROME
 
»
Menopause is a retrospective diagnosis after 
12 months of amenorrhea.
 
»
Approximately 80% of women will experience hot 
flushes and night sweats.
 
»
Elevated follicle-stimulating hormone (FSH) and 
low estradiol can help confirm the diagnosis.
 
»
The term “menopause” denotes the final cessation of men
-
struation, either as a normal part of aging or as the result of 
surgical removal of both ovaries. In a broader sense, as the 
term is commonly used, it denotes a 1- to 3-year period 
during which a woman adjusts to a diminishing and then

during which a woman adjusts to a diminishing and then 
absent menstrual flow and the physiologic changes that 
may be associated with lowered estrogen levels—hot 
flushes, night sweats, and vaginal dryness.
The average age at menopause in Western societies is 
51 years. Premature menopause is defined as ovarian fail
-
ure and menstrual cessation before age 40; this often has a 
genetic or autoimmune basis. Surgical menopause due to 
bilateral oophorectomy is common and can cause more 
severe symptoms owing to the sudden rapid drop in sex 
hormone levels.
There is no objective evidence that cessation of ovarian 
function is associated with severe emotional disturbance or 
personality changes. However, mood changes toward 
depression and anxiety can occur at this time. Disruption 
of sleep patterns associated with the menopause can affect 
mood and concentration and cause fatigue. Furthermore, 
the time of menopause often coincides with other major 
life changes, such as departure of children from the home, 
a midlife identity crisis, or divorce.
 
»
1. Cessation of menstruation—
Menstrual cycles generally 
become irregular as menopause approaches. Anovular 
cycles occur more often, with irregular cycle length and 
occasional menorrhagia. Menstrual flow usually dimin
-
ishes in amount owing to decreased estrogen secretion, 
resulting in less abundant endometrial growth. Finally, 
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cycles become longer, with missed periods or episodes of 
spotting only. When no bleeding has occurred for 1 year, 
the menopausal transition can be said to have occurred. 
Any bleeding after 6 months of the cessation of menses 
warrants investigation by endometrial curettage or aspira
-
tion to rule out endometrial cancer.
2. Hot flushes—
Hot flushes (feelings of intense heat over 
the trunk and face, with flushing of the skin and sweating) 
occur in over 80% of women as a result of the decrease in 
ovarian hormones. Hot flushes can begin before the cessa
-
tion of menses. Menopausal vasomotor symptoms last 
longer than previously thought, and there are ethnic differ
-
ences in the duration of symptoms. Vasomotor symptoms 
were found to last more than 7 years in more than 50% of 
the women. African-American women reported the longest 
duration of vasomotor symptoms. The etiology of hot 
flushes is unknown. Occurring at night, they often cause 
sweating and insomnia and result in fatigue on the following 
day.
3. Vaginal atrophy—
With decreased estrogen secretion, 
thinning of the vaginal mucosa and decreased vaginal 
lubrication occur and may lead to dyspareunia. The introi
-
tus decreases in diameter. Pelvic examination reveals pale, 
smooth vaginal mucosa and a small cervix and uterus. The 
ovaries are not normally palpable after the menopause. 
Continued sexual activity will help prevent vaginal 
atrophy.
4. Osteoporosis—
Osteoporosis may occur as a late sequela of 
menopause. The US Preventive Services Task Force recom
-
mends screening for osteoporosis beginning at age 65. A sum
-
mary that is currently being updated can be found at https://
www.uspreventiveservicestaskforce.org/Page/Document/
draft-recommendation-statement/osteoporosis-screening1.
Serum FSH, LH, and estradiol levels are of little diagnostic 
value because of unpredictable variability during the 
menopausal transition but can provide confirmation if the 
FSH is elevated and the estradiol is low. Vaginal cytologic 
examination will show a low estrogen effect with predomi
-
nantly parabasal cells, indicating lack of epithelial matura
-
tion due to hypoestrogenism.
 
»
Treatment
A. Natural Menopause
Education and support from health providers, midlife dis
-
cussion groups, and reading material will help most 
women having difficulty adjusting to the menopause. 
Physiologic symptoms can be treated with both hormonal 
or nonhormonal therapies. Hormonal replacement therapy 
has been shown to be effective in treating perimenopausal 
and menopausal symptoms but is not effective in preven
-
tion of chronic conditions such as coronary heart disease.
1. Vasomotor symptoms—
For women with mild symp
-
toms, lifestyle modification, such as increased hydration, 
decreased caffeine consumption, tobacco cessation, and 
dressing in layers are first-line therapies to be undertaken 
before consideration of other nonhormonal or hormonal 
medical treatments. For women with moderate to severe 
vasomotor symptoms, hormone replacement estrogen or 
estrogen/progestin regimens are the most effective 
approach to symptom relief. Conjugated estrogens, 0.3 mg, 
0.45 mg, or 0.625 mg; 17-beta-estradiol, 0.5 or 1 mg; or 
estrone sulfate, 0.625 mg can be given once daily orally; or 
estradiol can be given transdermally as skin patches that 
are changed once or twice weekly and secrete 0.05–0.1 mg 
of hormone daily. Unless the patient has undergone hyster
-
ectomy, a combination regimen of an estrogen with a pro
-
gestin such as medroxyprogesterone, 1.5 or 2.5 mg, or 
norethindrone, 0.1, 0.25, or 0.5 mg, should be used to pre
-
vent endometrial hyperplasia or cancer. There is also a 
patch available containing estradiol and the progestin 
levonorgestrel. Oral hormones can be given in several dif
-
fering regimens. Give estrogen on days 1–25 of each calen
-
dar month, with 5–10 mg of oral medroxyprogesterone

-
-
dar month, with 5–10 mg of oral medroxyprogesterone 
acetate added on days 14–25. Withhold hormones from 
day 26 until the end of the month, when the endometrium 
will be shed, producing a light, generally painless monthly 
period. Alternatively, give the estrogen along with a proges
-
tin daily, without stopping. This regimen causes some 
 
initial bleeding or spotting, but within a few months it 
produces an atrophic endometrium that will not bleed. If 
the patient has had a hysterectomy, a progestin need not be 
used.
Postmenopausal women generally should not use com
-
bination progestin-estrogen therapy for more than 3 or 
4  years (see discussion below). Women who cannot find 
relief with alternative approaches may wish to consider 
continuing use of combination therapy after a thorough 
discussion of the risks and benefits. Alternatives to hor
-
mone therapy for vasomotor symptoms include SSRIs such 
as paroxetine, 12.5 mg or 25 mg/day orally, or venlafaxine, 
75 mg/day orally. Gabapentin, an antiseizure medication, is 
also effective at 900 mg/day orally. Clonidine given orally 
or transdermally, 100–150 mcg daily, may also reduce the 
frequency of hot flushes, but its use is limited by side 
effects, including dry mouth, drowsiness, and hypotension. 
There is some evidence that soy isoflavones may be effec
-
tive in treating menopausal symptoms. Other compounds 
including red clover and black cohosh have not been 
shown to be effective. Because little is known about adverse 
effects, particularly with long-term use, dietary supple
-
ments should be used with caution.
2. Vaginal atrophy—
A vaginal ring containing 2 mg of 
estradiol can be left in place for 3 months and is suitable for 
long-term use. Although serum estrogen level increases 
associated with vaginal rings are lower than other routes of 
administration, it is recommended that the ring be used 
with caution. ACOG suggests that vaginal estrogen is an 
option for urogenital symptoms even in breast cancer sur
-
vivors. Short-term use of estrogen vaginal cream will 
relieve symptoms of atrophy, but because of variable 
absorption, therapy with either the vaginal ring or systemic 
hormone replacement is preferable. A low-dose estradiol 
tablet (10 mcg) is available and is inserted in the vagina 
daily for 2 weeks and then twice a week for long-term use. 
Testosterone propionate 1–2%, 0.5–1 g, in a vanishing 
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cream base used in the same manner is also effective if 
estrogen is contraindicated. A bland lubricant such as 
unscented cold cream or water-soluble gel can be helpful at 
the time of coitus.
3. Osteoporosis—
(See also discussion in Chapter 26.) 
Women should ingest at least 800 mg of calcium daily 
throughout life. Nonfat or low-fat milk products, calcium-
fortified orange juice, green leafy vegetables, corn tortillas, 
and canned sardines or salmon consumed with the bones 
are good dietary sources. Vitamin D, at least 800 interna
-
tional units/day from food, sunlight, or supplements, is 
necessary to enhance calcium absorption and maintain 
bone mass. A daily program of energetic walking and exer
-
cise to strengthen the arms and upper body helps maintain 
bone mass. Screening bone densitometry is recommended 
for women beginning at age 65 (see Chapter 1). Women 
most at risk for osteoporotic fractures should consider 
bisphosphonates, raloxifene, or hormone replacement 
therapy. This includes white and Asian women, especially 
if they have a family history of osteoporosis, are thin, short, 
cigarette smokers, have a history of hyperthyroidism, use 
corticosteroid medications long term, or are physically 
inactive.
B. Risks of Hormone Therapy
Double-blind, randomized, controlled trials have shown no 
overall cardiovascular benefit with estrogen-progestin 
replacement therapy in a group of postmenopausal women 
with or without established coronary disease. Both in the 
Women’s Health Initiative (WHI) trial and the Heart and 
Estrogen/Progestin Replacement Study (HERS), the overall 
health risks (increased risk of coronary heart events; strokes; 
thromboembolic disease; gallstones; and breast cancer, 
including an increased risk of mortality from breast cancer) 
exceeded the benefits from the long-term use of combina
-
tion estrogen and progesterone. An ancillary study of the 
WHI study showed that not only did estrogen-progestin 
hormone replacement therapy not benefit cognitive func
-
tion, but there was a small increased risk of cognitive 
decline in that group compared with women in the placebo 
group. The unopposed estrogen arm of the WHI trial dem
-
onstrated a decrease in the risk of hip fracture, a small but 
not significant decrease in breast cancer, but an increased 
risk of stroke and no evidence of protection from coronary 
heart disease. The study also showed a small increase in the 
combined risk of mild cognitive impairment and dementia 
with estrogen use compared with placebo, similar to the 
estrogen-progestin arm. Women who have been receiving 
long-term estrogen-progestin hormone replacement ther
-
apy, even in the absence of complications, should be 
encouraged to stop, especially if they do not have meno
-
pausal symptoms. However, the risks appear to be lower in 
women starting therapy at the time of menopause and 
higher in previously untreated women starting therapy 
long after menopause. Therapy should be individualized as 
the risk-benefit profile varies with age and individual risk 
factors. (See also discussions of estrogen and progestin 
replacement therapy in Chapter 26.)
C. Surgical Menopause
The abrupt hormonal decrease resulting from oophorec
-
tomy generally results in severe vasomotor symptoms and 
rapid onset of dyspareunia and osteoporosis unless treated. 
If not contraindicated, estrogen replacement is generally 
started immediately after surgery. Conjugated estrogens 
1.25 mg orally, estrone sulfate 1.25 mg orally, or estradiol 
2 mg orally is given for 25 days of each month. After age 
45–50 years, this dose can be tapered to 0.625 mg of conju
-
gated estrogens or equivalent.
-
tee Opinion No. 659: The use of vaginal estrogen in women 
with a history of estrogen-dependent breast cancer. Obstet 
Gynecol. 2016 Mar;127(3):e93–6. [PMID: 26901334]

-
Avis NE et al; Study of Women’s Health Across the Nation. Dura
-
tion of menopausal vasomotor symptoms over the meno
-
pause transition. JAMA Intern Med. 2015 Apr;175(4):531–9. 
[PMID: 25686030]
Gartlehner G et al. Hormone therapy for the primary prevention 
of chronic conditions in postmenopausal women: evidence 
report and systematic review for the US Preventive Services 
Task Force. JAMA. 2017 Dec 12;318(22):2234–49. [PMID: 
29234813]
LeFevre ML. Screening for vitamin D deficiency in adults: U.S. 
Preventive Services Task Force Recommendation Statement. 
Ann Intern Med. 2015 Jan 20;162(2):133–40. [PMID: 
25419853]
Lumsden MA et al. Diagnosis and management of menopause: 
The National Institute of Health Care and Excellence (NICE) 
guideline. JAMA Intern Med. 2016 Aug 1;176(8):1205–6. 
[PMID: 27322881]
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DIAGNOSIS OF PREGNANCY
It is advantageous to diagnose pregnancy as promptly as 
possible when a sexually active woman misses a menstrual 
period or has symptoms suggestive of pregnancy. Prenatal 
care can begin early for a desired pregnancy, and poten
-
tially harmful medications and activities such as drug and 
alcohol use, smoking, and occupational chemical exposure can 
be halted. In the event of an unwanted pregnancy, coun
-
seling about adoption or termination of the pregnancy can 
be provided at an early stage.
 
»
Pregnancy Tests
All urine or blood pregnancy tests rely on the detection of 
human chorionic gonadotropin (hCG) produced by the 
placenta. Levels increase shortly after implantation, 
approximately double every 48 hours (this rise can range 
from 30% to 100% in normal pregnancies), reach a peak at 
50–75 days, and fall to lower levels in the second and third 
trimesters. Pregnancy tests are performed on serum or 
urine and are accurate at the time of the missed period or 
shortly after it.
Compared with intrauterine pregnancies, 
ectopic preg
-
nancies
 may show lower levels of hCG that plateau or fall in 
serial determinations. Quantitative assays of hCG repeated 
at 48-hour intervals are used in the diagnosis of ectopic 
pregnancy as well as in cases of molar pregnancy, threat
-
ened abortion, and missed abortion. Comparison of hCG 
levels between laboratories may be misleading in a given 
patient because different international standards may pro
-
duce results that vary by as much as twofold. hCG levels can 
also be problematic because they require a series of mea
-
surements. Progesterone levels, however, remain relatively 
stable in the first trimester. A single measurement of pro
-
gesterone is the best indicator of whether a pregnancy is 
viable, although there is a broad indeterminate zone. 
 
A value less than 5 ng/mL (16 nmol/L) predicts pregnancy 
failure while a value greater than 25 ng/mL (80 nmoL/L) 
indicates a pregnancy will be successful. There is uncer
-
tainty when the value is between these two points. Combin
-
ing several serum biomarkers (beta hCG and progesterone) 
may provide a better prediction of pregnancy viability. 
Pregnancy of unknown location
 is a term used to describe 
a situation where a woman has a positive pregnancy test, 
but the location and viability of the pregnancy is not known 
because it is not seen on transvaginal ultrasound.
Senapati S et al. Biomarkers for ectopic pregnancy and pregnancy 
of unknown location. Fertil Steril. 2013 Mar 15;99(4):1107–16. 
[PMID: 23290746]
 
»
Manifestations of Pregnancy
The following symptoms and signs are usually due to preg
-
nancy, but none are diagnostic. A record of the time and 
frequency of coitus is helpful for diagnosing and dating a 
Amenorrhea, nausea and vomiting, breast tenderness and 
tingling, urinary frequency and urgency, “quickening” (per
-
ception of first movement noted at about the 18th week), 
weight gain.
B. Signs (in Weeks From Last Menstrual Period)
Breast changes (enlargement, vascular engorgement, colos
-
trum) start to occur very early in pregnancy and continue 
until the postpartum period. Cyanosis of the vagina and 
cervical portio and softening of the cervix occur in about 
the 7th week. Softening of the cervicouterine junction 
takes place in the 8th week, and generalized enlargement 
and diffuse softening of the corpus occurs after the 
 
8th week. When a woman’s abdomen will start to enlarge 
depends on her body habitus but typically starts in the 
16th week.
The uterine fundus is palpable above the pubic symphy
-
sis by 12–15 weeks from the last menstrual period and 
reaches the umbilicus by 20–22 weeks. Fetal heart tones 
can be heard by Doppler at 10–12 weeks of gestation.
 
»
The nonpregnant uterus enlarged by myomas can be con
-
fused with the gravid uterus, but it is usually very firm and

»
-
fused with the gravid uterus, but it is usually very firm and 
irregular. An ovarian tumor may be found midline, displac
-
ing the nonpregnant uterus to the side or posteriorly. 19
 
 Scott W. Roberts, MD 
Obstetrics & Obstetric 
Disorders
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Ultrasonography and a pregnancy test will provide accurate 
diagnosis in these circumstances.
ESSENTIALS OF PRENATAL CARE
The first prenatal visit should occur as early as possible after 
the diagnosis of pregnancy and should include the following: 
history, physical examination, advice to the patient, and 
appropriate tests and procedures.
 
»
History
The patient’s age, ethnic background, and occupation 
should be obtained. The onset of the last menstrual period 
and its normality, possible conception dates, bleeding after 
the last menstruation, medical history, all prior pregnancies 
(duration, outcome, and complications), and symptoms of 
present pregnancy should be documented. The patient’s 
nutritional habits should be discussed with her, as well as 
any use of caffeine, tobacco, alcohol, or drugs (Table 19–1). 
Whether there is any family history of congenital anomalies 
and heritable diseases, a personal history of childhood vari
-
cella, prior sexually transmitted diseases (STDs), or risk factors 
for HIV infection should be determined. The woman should 
be screened for domestic violence. She should also be asked 
about recent travel to determine the possibility of exposure 
to the Zika virus.
 
»
Physical Examination
Height, weight, and blood pressure should be measured, 
and a general physical examination should be done, 
including a breast examination. Abdominal and pelvic 
examination should include the following: (1) estimate of 
Table 19–1.
 
Common drugs that are teratogenic or 
fetotoxic.
1
ACE inhibitors
Alcohol
Androgens
Angiotensin-II receptor blockers
Antiepileptics (phenytoin, 
 
valproic acid, 
carbamazepine)
Diazoxide
Diethylstilbestrol
Disulfiram
Ergotamine
Estrogens
Griseofulvin
Isotretinoin
Lithium
Misoprostol
NSAIDs (third trimester)
Opioids (prolonged use)
Radioiodine (antithyroid)
Reserpine
Ribavirin
Sulfonamides (second and third 
trimesters)
Tetracycline (third trimester)
Thalidomide
Warfarin and other coumarin 
anticoagulants
1
Many other drugs are also contraindicated during pregnancy. 
Evaluate any drug for its need versus its potential adverse effects. 
Further information can be obtained from the manufacturer or 
from any of several teratogenic registries around the country.
ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal 
anti-inflammatory drugs; SSRIs, selective serotonin reuptake 
uterine size or measure of fundal height; (2) evaluation of 
bony pelvis for symmetry and adequacy; (3) evaluation 
of cervix for structural anatomy, infection, effacement, 
dilation; (4) detection of fetal heart tones by Doppler 
device after 10 weeks.
 
»
Laboratory Tests
See Tests & Procedures, below.
 
»
Advice to Patients
A. Prenatal Visits
Prenatal care should begin early and maintain a schedule of 
regular prenatal visits: 4–28 weeks, every 4 weeks; 28–36 weeks, 
every 2 weeks; 36 weeks on, weekly.
B. Diet
The patient should be counseled to eat a balanced diet con
-
taining the major food groups. See Nutrition in Pregnancy, 
below.
1.
 
Prenatal vitamins with 30–60 mg of elemental iron and 
0.4 mg of folic acid should be prescribed. Supplements 
that are not specified for pregnant women should be 
avoided as they may contain dangerous amounts of 
certain vitamins.
2.
 
Caffeine intake should be decreased to 0–1 cup of 
coffee, tea, or caffeinated cola daily.
3.
 
The patient should be advised to avoid eating raw or 
rare meat as well as fish known to contain elevated 
levels of mercury.
4.
 
Patients should be encouraged to eat fresh fruits and 
vegetables (washed before eating).
C. Medications
Only medications prescribed or authorized by the obstetric 
provider should be taken.
D. Alcohol and Other Drugs
Patients should be encouraged to abstain from alcohol, 
tobacco, and all recreational (“street”) drugs. No safe level 
of alcohol intake has been established for pregnancy. Fetal

of alcohol intake has been established for pregnancy. Fetal 
effects are manifest in the 
fetal alcohol syndrome
, which 
includes growth restriction; facial, skeletal, and cardiac 
abnormalities; and serious central nervous system dys
-
function. These effects are thought to result from direct 
toxicity of ethanol as well as of its metabolites such as 
acetaldehyde.
Cigarette smoking results in fetal exposure to carbon 
monoxide and nicotine, and this is thought to eventuate in 
a number of adverse pregnancy outcomes. An increased 
risk of placental abruption (abruptio placentae), placenta 
previa, and premature rupture of the membranes is docu
-
mented among women who smoke. Preterm delivery, low 
birth weight, and ectopic pregnancy are also more likely 
among smokers. Women who smoke should quit smoking 
or at least reduce the number of cigarettes smoked per day 
to as few as possible. Clinicians should ask all pregnant 
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women about their smoking history and offer smoking 
cessation counseling during pregnancy, since women are 
more motivated to change at this time. Pregnant women 
should also avoid exposure to environmental smoke 
(“passive smoking”), smokeless tobacco, and e-cigarettes 
(see Tables 1–4, 1–5). Pharmacotherapy for smoking cessation 
has been used with mixed results. Studies of buproprion 
and nicotine replacement systems are inadequate to prop
-
erly weigh risks and benefits, and prolonged cessation from 
smoking has not been proven.
Sometimes compounding the above effects on preg
-
nancy outcome are the independent adverse effects of illicit 
drugs. Cocaine use in pregnancy is associated with an 
increased risk of premature rupture of membranes, preterm 
delivery, placental abruption, intrauterine growth restric
-
tion, neurobehavioral deficits, and sudden infant death 
syndrome. Similar adverse pregnancy effects are associated 
with amphetamine use, perhaps reflecting the vasoconstric
-
tive potential of both amphetamines and cocaine. Adverse 
effects associated with opioid use include intrauterine 
growth restriction, prematurity, and fetal death.
E. Radiographs and Noxious Exposures
Radiographs should be avoided unless essential and 
approved by a clinician. Abdominal shielding should be 
used whenever possible. The patient should be told to 
inform her other health care providers that she is pregnant. 
Chemical or radiation hazards should be avoided as should 
excessive heat in hot tubs or saunas. Patients should be told 
to avoid handling cat feces or cat litter and to wear gloves 
when gardening to avoid infection with toxoplasmosis.
F. Rest and Activity
The patient should be encouraged to obtain adequate rest 
each day. She should abstain from strenuous physical work 
or activities, particularly when heavy lifting or weight bear
-
ing is required. Regular exercise can be continued at a mild 
to moderate level; however, exhausting or hazardous exer
-
cises or new athletic training programs should be avoided 
during pregnancy. Exercises that require a great deal of 
balance should also be done with caution.
G. Birth Classes
The patient should be encouraged to enroll in a childbirth 
preparation class with a family member, if possible, well 
before her due date.
 
»
Tests & Procedures
A. Each Visit
Weight, blood pressure, fundal height, and fetal heart rate 
are measured, and a urine specimen is obtained and tested 
for protein and glucose. Any concerns the patient may have 
about pregnancy, health, and nutrition should be addressed.
B. 6–12 Weeks
Confirm uterine size and growth by pelvic examination. 
Document fetal heart tones (audible at 10–12 weeks of 
gestation by Doppler). Urinalysis; culture of a clean-voided 
midstream urine sample; random blood glucose; complete 
blood count (CBC) with red cell indices; serologic test for 
syphilis, rubella antibody titer; varicella immunity; blood 
group; Rh type; antibody screening for anti-Rh
o
(D), hepa
-
titis B surface antigen (HBsAg), and HIV should be per
-
formed. Women at increased risk for infection should 
be tested for 
 and 
Neisseria gon
-
orrhoeae
. Women who are at least 21 years old should 
undergo cervical cancer screening. All women of African 
origin should have sickle cell screening. Women of 
African, Asian, or Mediterranean ancestry with anemia or 
low mean corpuscular volume (MCV) values should have 
hemoglobin electrophoresis performed to identify abnor
-
mal hemoglobins (Hb S, C, F, alpha-thalassemia, beta-
thalassemia). Tuberculosis testing is indicated for high-risk 
populations. Blood screening for Tay-Sachs, Canavan 
disease, and familial dysautonomia is offered to couples 
who are of Eastern and Central European Jewish (Ashkenazi) 
descent. Couples of French Canadian or Cajun ancestry 
should also be screened as possible Tay-Sachs carriers.

should also be screened as possible Tay-Sachs carriers. 
Screening for cystic fibrosis and spinal muscular atrophy is 
offered to all pregnant women. Hepatitis C antibody 
screening should be offered to pregnant women who are at 
high risk for infection. Fetal aneuploidy screening is avail
-
able in the first and second trimester and should be offered 
to all women, ideally before 20 weeks’ gestation. Noninva
-
sive first trimester screening for Down syndrome includes 
ultrasonographic nuchal translucency and serum levels of 
PAPP-A (pregnancy-associated plasma protein A) and the 
free beta subunit of hCG. For pregnancies at high risk for 
aneuploidy, noninvasive testing with cell free fetal DNA 
from maternal plasma can be performed. It screens rou
-
tinely only for the common trisomies (13, 18, and 21). 
Screening for other conditions may be available upon 
request at certain laboratories. If indicated and requested 
by the patient, chorionic villus sampling can be performed 
during this period (11–13 weeks).
C. 16–20 Weeks
The “quad screen” and amniocentesis are performed as 
indicated and requested by the patient during this time. 
First and second trimester tests have similar detection 
rates. When first and second trimester screening for Down 
syndrome are combined (integrated screening), the detec
-
tion rates are even higher. Fetal ultrasound examination to 
determine pregnancy dating and evaluate fetal anatomy is 
also done. An earlier examination provides the most accu
-
rate dating, and a later examination demonstrates fetal 
anatomy in greatest detail. The best compromise is at 
18–20 weeks of gestation. Cervical length measurement 
(greater than 2.5 cm is normal) is not performed univer
-
sally in all practices, but is used by some clinicians to iden
-
tify women at risk for preterm birth.
D. 24 Weeks to Delivery
The patient should be instructed about the symptoms and 
signs of preterm labor and rupture of membranes. Ultrasound 
examination is performed as indicated. Typically, fetal size 
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and growth are evaluated when fundal height is 3 cm less 
than or more than expected for gestational age. In multi-
fetal pregnancies, ultrasound should be performed every 
2–6 weeks to evaluate for discordant growth.
E. 24–28 Weeks
Screening for gestational diabetes is performed using a 50-g 
glucose load (Glucola) and a 1-hour post-Glucola blood 
glucose determination. Abnormal values (greater than or 
equal to 140 mg/dL or 7.8 mmol/L) should be followed up 
with a 3-hour glucose tolerance test (see Table 19–4).
F. 28 Weeks
If initial antibody screen for anti-Rh
o
(D) is negative, repeat 
antibody testing for Rh-negative patients is performed, but 
the result is not required before Rh
o
(D) immune globulin 
is administered.
G. 28–32 Weeks
A CBC is done to evaluate for anemia of pregnancy. Screen
-
ing for syphilis and HIV is also performed at this time. 
Providers should familiarize themselves with the laws in 
their state since testing requirements vary.
H. 28 Weeks to Delivery
Fetal position and presentation are determined. The patient 
is asked about symptoms or signs of preterm labor or rup
-
ture of membranes at each visit. Maternal perception of fetal 
movement should be assessed at each visit. Antepartum fetal 
testing in the form of nonstress tests and biophysical profiles 
can be performed as medically indicated.
I. 36 Weeks to Delivery
Repeat syphilis and HIV testing (depending on state laws) 
and tests for 
 and 
 should be 
performed in at-risk patients. The indicators of onset of 
labor, admission to the hospital, management of labor and 
delivery, and options for analgesia and anesthesia should 
be discussed with the patient. Weekly cervical examina
-
tions are not necessary unless indicated to assess a specific 
clinical situation. Patients should not be delivered prior to 
39 completed weeks without a clinical indication.
The CDC recommends universal prenatal culture-based 
screening for group B streptococcal colonization in preg
-
nancy. A single standard culture of the distal vagina and 
anorectum is collected at 35–37 weeks. No prophylaxis is 
needed if the screening culture is negative. Patients whose 
cultures are positive receive intrapartum penicillin prophy
-
laxis during labor. Except when group B streptococci are 
found in urine, asymptomatic colonization is not to be 
treated before labor. Patients who have had a previous 
infant with invasive group B streptococcal disease or who 
have group B streptococcal bacteriuria during this preg
-
nancy should receive intrapartum prophylaxis regardless, so 
rectovaginal cultures are not needed. Patients whose cul
-
tures at 35–37 weeks were not done or whose results are not 
known should receive prophylaxis if they have a risk factor 
for early-onset neonatal disease, including intrapartum 
temperature 38°C or higher, membrane rupture more than 
18 hours, or delivery before 37 weeks’ gestation.
The routine recommended regimen for prophylaxis 
for group B streptococcal colonization is penicillin G, 
 
5 million units intravenously as a loading dose and then 
2.5–3 million units intravenously every 4 hours until delivery. 
In penicillin-allergic patients not at high risk for anaphy
-
laxis, 2 g of cefazolin can be given intravenously as an initial 
dose and then 1 g intravenously every 8 hours until delivery. 
In patients at high risk for anaphylaxis, vancomycin 1 g 
intravenously every 12 hours until delivery is used or, after 
confirmed susceptibility testing of group B streptococcal 
isolate to both clindamycin and erythromycin, clindamycin 
900 mg intravenously every 8 hours until delivery.
J. 41 Weeks
The patient should have a cervical examination to deter
-
mine the probability of successful induction of labor. 
Induction is undertaken if the cervix is favorable (gener
-
ally, cervix 2 cm or more dilated, 50% or more effaced, 
vertex at –1 station, soft cervix, and midposition); if unfa
-

-
-
vorable, antepartum fetal testing is begun. Induction is 
performed at 42 weeks’ gestation regardless of the cervical 
examination findings; some providers elect induction at 
 
41 weeks regardless of the cervical examination findings.
NUTRITION IN PREGNANCY
Nutrition in pregnancy can affect maternal health and 
infant size and well-being. Pregnant women should have 
nutrition counseling early in prenatal care and access to 
supplementary food programs if necessary. Counseling 
should stress abstention from alcohol, smoking, and recre
-
ational drugs. Caffeine and artificial sweeteners should be 
used only in small amounts.
Recommendations regarding weight gain in pregnancy 
should be based on maternal body mass index (BMI) pre
-
conceptionally or at the first prenatal visit. According to 
the National Academy of Medicine guidelines, total weight 
gain should be 25–35 lbs (11.3–15.9 kg) for normal weight 
women (BMI of 18.5–24.9) and 15–25 lbs (6.8–11.3 kg) for 
overweight women. For obese women (BMI of 30 or 
greater), weight gain should be limited to 11–20 lbs 
(5.0–9.1 kg). Excessive maternal weight gain has been asso
-
ciated with increased birth weight as well as postpartum 
retention of weight. Not gaining weight in pregnancy, con
-
versely, has been associated with low birth weight. Nutri
-
tion counseling must be tailored to the individual patient.
The increased calcium needs of pregnancy (1200 mg/
day) can be met with milk, milk products, green vegetables, 
soybean products, corn tortillas, and calcium carbonate 
supplements.
The increased need for iron and folic acid should be met 
with foods as well as vitamin and mineral supplements. 
(See Anemia section.) Megavitamins should not be taken in 
pregnancy, as they may result in fetal malformation or dis
-
turbed metabolism. However, a balanced prenatal supple
-
ment containing 30–60 mg of elemental iron, 0.4 mg of 
folate, and the recommended daily allowances of various 
vitamins and minerals is widely used in the United States 
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and is probably beneficial to many women with marginal 
diets. There is evidence that periconceptional folic acid 
supplements can decrease the risk of neural tube defects in 
the fetus. For this reason, the United States Public Health 
Service recommends the consumption of 0.4 mg of folic 
acid per day for all pregnant and reproductive age women. 
Women with a prior pregnancy complicated by neural tube 
defect may require higher supplemental doses as deter
-
mined by their providers.
Committee Opinion No. 548: Weight gain during pregnancy. 
Obstet Gynecol. 2013 Jan;121(1):210–2. [Reaffirmed 2015] 
[PMID: 23262962]
Haider BA et al. Multiple-micronutrient supplementation for 
women during pregnancy. Cochrane Database Syst Rev. 
 
2015 Nov 1;(11):CD004905. [PMID: 26522344]
PREVENTION OF RHESUS 
ALLOIMMUNIZATION
The antibody anti-Rh
o
(D) causes severe hemolytic disease 
of the newborn. About 15% of whites and much lower 
proportions of blacks and Asians are Rh
o
(D)–negative. If 
an Rh
o
(D)–negative woman carries an Rh
o
(D)–positive 
fetus, antibodies against Rh
o
(D) may develop in the mother 
when fetal red cells enter her circulation during small feto
-
maternal bleeding episodes in the early third trimester or 
during delivery, abortion, ectopic pregnancy, placental 
abruption, or other instances of antepartum bleeding. This 
antibody, once produced, remains in the woman’s circula
-
tion and poses the threat of hemolytic disease for subse
-
quent Rh-positive fetuses.
Passive immunization against hemolytic disease of the 
newborn is achieved with Rh
o
(D) immune globulin, a 
purified concentrate of antibodies against Rh
o
(D) antigen. 
The Rh
o
(D) immune globulin (one vial of 300 mcg intra
-
muscularly) is given to the mother within 72 hours after 
delivery (or spontaneous or induced abortion or ectopic 
pregnancy). The antibodies in the immune globulin 
destroy fetal Rh-positive cells so that the mother will not 
produce anti-Rh
o
(D). During her next Rh-positive gesta
-
tion, erythroblastosis will be prevented. An additional 
safety measure is the routine administration of the immune 
globulin at the 28th week of pregnancy. The passive anti
-
body titer that results is too low to significantly affect an 
Rh-positive fetus. The maternal clearance of the globulin is 
slow enough that protection will continue for 12 weeks. 
Once a woman is alloimmunized, Rh
o
(D) immune globu
-
lin is no longer helpful and should not be given.
LACTATION
Breastfeeding should be encouraged by education through
-
out pregnancy and the puerperium. Mothers should be told 
the benefits of breastfeeding, including infant immunity, 
emotional satisfaction, mother-infant bonding, and eco
-
nomic savings. The period of amenorrhea associated with 
frequent and consistent breastfeeding provides some 
(although not reliable) birth control until menstruation 
begins at 6–12 months postpartum or the intensity of 
breastfeeding diminishes. Even a brief period of nursing is 
beneficial. Transfer of immunoglobulins, macrophages, and 
lymphocytes in colostrum and breast milk immunoprotects 
the infant against many systemic and enteric infections. The 
intestinal flora of breastfed infants inhibit the growth of 
pathogens. Breastfed infants have fewer bacterial and viral 
infections, fewer gastrointestinal tract infections, and fewer 
allergy problems than bottle-fed infants. Furthermore, they 
are less apt to be obese as children and adults.
Frequent breastfeeding on an infant-demand schedule 
enhances milk flow and successful breastfeeding. Mothers 
breastfeeding for the first time need help and encourage
-
ment from providers, nurses, and other nursing mothers. 
Milk supply can be increased by increased suckling and 
increased rest.
Nursing mothers should have a fluid intake of over 3 L/day.

-
Nursing mothers should have a fluid intake of over 3 L/day. 
The United States RDA calls for 21 g of extra protein (over the 
44 g/day baseline for an adult woman) and 550 extra kcal/day 
in the first 6 months of nursing. Calcium intake should be 
1200 mg/day. Continuation of a prenatal vitamin and mineral 
supplement is wise. Strict vegetarians who eschew both milk 
and eggs should always take vitamin B
12
 supplements during 
pregnancy and lactation.
1. 
e
ff
ects of Drugs in a Nursing Mother
Drugs taken by a nursing mother may accumulate in milk 
and be transmitted to the infant (Table 19–2). The amount 
of drug entering the milk depends on the drug’s lipid solu
-
bility, mechanism of transport, and degree of ionization.
2. Suppression of Lactation
The simplest and safest method of suppressing lactation 
after it has started is to gradually transfer the baby to a 
bottle or a cup over a 3-week period. Milk supply will 
decrease with decreased demand, and minimal discomfort 
ensues. If nursing must be stopped abruptly, the mother 
should avoid nipple stimulation, refrain from expressing 
milk, and use a snug brassiere. Ice packs and analgesics can 
be helpful. This same technique can be used in cases where 
suppression is desired before nursing has begun. Engorgement 
will gradually recede over a 2- to 3-day period. Hormonal 
suppression of lactation is no longer practiced.
Denne SC. Neonatal nutrition. Pediatr Clin North Am. 2015 Apr;
 
62(2):427–38. [PMID: 25836706]
TRAVEL & IMMUNIZATIONS DURING 
PREGNANCY
During an otherwise normal low-risk pregnancy, travel can 
be planned most safely up to the 32nd week. Commercial 
flying in pressurized cabins does not pose a threat to the 
fetus. An aisle seat will allow frequent walks. Adequate fluids 
should be taken during the flight. Travelling to endemic 
areas of yellow fever (Africa or Latin America) or of Zika 
virus (Latin America) is not advisable; since Zika virus can 
be sexually transmitted, partner travel should also be dis
-
cussed (see Chapter 32). Similarly, it is inadvisable to travel 
to areas of Africa or Asia where chloroquine-resistant 
falciparum malaria is a hazard, since complications of malaria 
are more common in pregnancy.
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Ideally, all immunizations should precede pregnancy. 
Live virus products are contraindicated during pregnancy 
(measles, rubella, yellow fever, and smallpox)
. Inactivated 
polio vaccine should be given subcutaneously instead of 
the oral live-attenuated vaccine. The varicella vaccine 
should be given 1–3 months before becoming pregnant. 
Vaccines against pneumococcal pneumonia, meningococcal 
meningitis, and hepatitis A can be used as indicated. Preg
-
nant women who are considered to be at high-risk for 
hepatitis B and who have not been previously vaccinated 
should be vaccinated during pregnancy.
The CDC lists pregnant women as a high-risk group for 
influenza. Annual influenza vaccination is indicated in all 
women who are pregnant or will be pregnant during the “flu 
season. ” It can be given in the first trimester. The CDC also 
recommends that every pregnant woman receive a dose of 
Tdap during each pregnancy irrespective of her prior vacci
-
nation history. The optimal timing for such Tdap administra
-
tion is between 27 and 36 weeks of gestation, in order to 
maximize the antibody response of the pregnant woman 
against pertussis and the passive antibody transfer to the 
infant. For any woman who was not previously vaccinated 
with Tdap and for whom the vaccine was not given during 
her pregnancy, Tdap should be administered immediately 
postpartum. Further, any teenagers or adults not previously 
vaccinated who will have close contact with the infant should 
also receive it, ideally 2 weeks before exposure to the child. 
This vaccination strategy is referred to as “cocooning, ” and its 
purpose is to protect the infant aged younger than 12 months 
who is at particularly high risk for lethal pertussis.
Hepatitis A vaccine contains formalin-inactivated virus 
and can be given in pregnancy when needed. Pooled immune 
globulin to prevent hepatitis A is safe and does not carry risk 
of HIV transmission. Chloroquine can be used for malaria 
prophylaxis in pregnancy, and proguanil is also safe.
Water should be purified by boiling, since iodine purifica
-
tion may provide more iodine than is safe during pregnancy.
Prophylactic antibiotics or bismuth subsalicylate should 
not be used during pregnancy to prevent diarrhea. Oral rehy
-
dration and treatment of bacterial diarrhea with erythromycin 
or ampicillin if necessary is preferred.
Centers for Disease Control and Prevention (CDC). Updated 
recommendations for use of tetanus toxoid, reduced diphtheria 
toxoid and acellular pertussis vaccine (Tdap) in pregnant 
women—Advisory Committee on Immunization Practices 
(ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2013 Feb 22; 
62(7):131–5. [PMID: 23425962]
 
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S
VOMITING OF PREGNANCY & HYPEREMESIS 
GRAVIDARUM
 
»
Morning or evening nausea and vomiting.
 
»
Persistent vomiting severe enough to result in weight 
loss, dehydration, starvation ketosis, hypochloremic 
alkalosis, hypokalemia.
 
»
May have transient elevation of liver enzymes.
Table 19–2.
 
Drugs and substances that require a careful assessment of risk before they are prescribed for 
 
breastfeeding women.
1
Category of Drug
Specific Drug
Concern
Unknown effects. Captopril or enalapril is preferred if an ACE inhibitor is needed.
Alkylating agents
Neonatal neutropenia. No breastfeeding.
Analgesics
Codeine, oxycodone
Cause CNS depression. Unpredictable metabolism.
Ciprofloxacin
Association with adverse effects on fetal cartilage and bone. Must weigh risks versus benefits.
Tetracyclines
Concern for bone growth and dental staining.
Antiepileptics
Valproic acid
Long-term effects are unknown. Although levels in milk are low, it is teratogenic, so it should 
be avoided if possible.
Fluoxetine

Present in breast milk in higher levels than other SSRIs. Watch for adverse effects like an infant’s 
fussiness and crying.
Antihistamines
Diphenhydramine
Present in very small quantities in milk; sources are conflicting with regard to its safety.
Atenolol
Has been associated with hypotension and bradycardia in the infant. Metoprolol and propranolol 
are preferred.
Mood stabilizers
Lithium
Circulating levels in the neonate are variable. Follow infant’s serum creatinine and blood urea 
nitrogen levels and thyroid function tests.
1
The above list is not all-inclusive. For additional information, see the below reference from which this information is adapted or the online 
drug and lactation database, Lactmed, at http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.
ACE, angiotensin-converting enzyme; CNS, central nervous system; SSRIs, selective serotonin reuptake inhibitors.
Data from Rowe H et al. Maternal medication, drug use, and breastfeeding. Pediatr Clin North Am. 2013 Feb;60(1):275–94.
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»
Appears related to high or rising serum hCG.
 
»
More common with multi-fetal pregnancies or 
hydatidiform mole.
 
»
Nausea and vomiting begin soon after the first missed 
period and cease by the fifth month of gestation. Up to 
three-fourths of women complain of nausea and vomiting 
during early pregnancy, with the vast majority noting 
nausea throughout the day. This problem exerts no adverse 
effects on the pregnancy and does not presage other 
Persistent, severe vomiting during pregnancy—
hyperemesis gravidarum—can be disabling and require 
hospitalization. Hyperthyroidism can be associated with 
hyperemesis gravidarum, so it is advisable to determine 
thyroid-stimulating hormone (TSH) and free thyroxine 
(FT
4
) values in these patients. Of note, these patients will 
not have a goiter.
 
»
Treatment
A. Mild Nausea and Vomiting of Pregnancy
In most instances, only reassurance and dietary advice are 
required. Because of possible teratogenicity, drugs used 
during the first half of pregnancy should be restricted to 
those of major importance to life and health. Vitamin B
6
 
(pyridoxine), 50–100 mg/day orally, is nontoxic and may 
be helpful in some patients. Pyridoxine alone or in combi
-
nation with doxylamine (10 mg doxylamine succinate and 
10 mg pyridoxine hydrochloride, two tablets at bedtime) 
is first-line pharmacotherapy. Antiemetics, antihistamines, 
and antispasmodics are generally unnecessary to treat nausea 
of pregnancy.
B. Hyperemesis Gravidarum
With more severe nausea and vomiting, it may become 
necessary to hospitalize the patient. In this case, a private 
room with limited activity is preferred. It is recom
-
mended to give nothing by mouth until the patient is 
improving, and maintain hydration and electrolyte bal
-
ance by giving appropriate parenteral fluids and vitamin 
supplements as indicated. Antiemetics such as prometha
-
zine (25 mg orally, rectally, or intravenously every 
4–6 hours), metoclopramide (10 mg orally or intrave
-
nously every 6 hours), or ondansetron (4–8 mg orally or 
intravenously every 8 hours) should be started. Ondanse
-
tron has been associated in some studies with congenital 
anomalies. Data are limited, but the risks and benefits of 
treatment should be addressed with the patient. Anti
-
emetics will likely need to be given intravenously initially. 
Rarely, total parenteral nutrition may become necessary 
but only if enteral feedings cannot be done. As soon as 
possible, the patient should be placed on a dry diet con
-
sisting of six small feedings daily. Antiemetics may be 
continued orally as needed. After in-patient stabilization, 
the patient can be maintained at home even if she requires 
intravenous fluids in addition to her oral intake. There are 
conflicting studies regarding the use of corticosteroids for 
the control of hyperemesis gravidarum, and it has also 
been associated with fetal anomalies. Therefore, this 
treatment should be withheld before 10 weeks’ gestation 
and until more accepted treatments have been exhausted.
 
»
•	
Patient does not respond to first-line outpatient 
•	
There is concern for other pathology (ie, hydatidiform 
mole).
 
»
•	
Patient is unable to tolerate any food or water.
•	
Condition precludes the patient from ingesting necessary 
•	
Weight loss.
•	
Presence of a hydatidiform mole.
American College of Obstetricians and Gynecologists. 
ACOG Practice Bulletin No. 153: Nausea and vomiting of 
pregnancy. Obstet Gynecol. 2015 Sep;126(3):e12–24. 
[PMID: 26287788]
SPONTANEOUS ABORTION
 
»
Intrauterine pregnancy at less than 20 weeks.
 
»
Low or falling levels of hCG.
 
»
Bleeding, midline cramping pain.
 
»
Open cervical os.
 
»
Complete or partial expulsion of products of 
conception.
 
»

»
 
»
 
»
 
»
 
»
About three-fourths of spontaneous abortions occur before 
the 16th week; of these, three-fourths occur before the 
8th week. Almost 20% of all clinically recognized pregnancies 
terminate in spontaneous abortion.
More than 60% of spontaneous abortions result from 
chromosomal defects due to maternal or paternal 
 
factors; about 15% appear to be associated with maternal 
trauma, infections, dietary deficiencies, diabetes mellitus, 
hypothyroidism, the lupus anticoagulant-anticardiolipin-
antiphospholipid antibody syndrome, or anatomic malfor
-
mations. There is no reliable evidence that abortion may be 
induced by psychic stimuli such as severe fright, grief, 
anger, or anxiety. In about one-fourth of cases, the cause of 
abortion cannot be determined. There is no evidence that 
video display terminals or associated electromagnetic fields 
are related to an increased risk of spontaneous abortion.
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It is important to distinguish women with a history of 
incompetent cervix from those with more typical early 
abortion. Characteristically, incompetent cervix presents as 
“silent” cervical dilation (ie, with minimal uterine contrac
-
tions) in the second trimester. When the cervix reaches 
 
4 cm or more, active uterine contractions or rupture of the 
membranes may occur secondary to the degree of cervical 
dilation. This does not change the primary diagnosis. 
Factors that predispose to incompetent cervix are a history 
of incompetent cervix with a previous pregnancy, cervical 
conization or surgery, cervical injury, diethylstilbestrol 
(DES) exposure, and anatomic abnormalities of the cervix. 
Prior to pregnancy or during the first trimester, there are 
no methods for determining whether the cervix will even
-
tually be incompetent. After 14–16 weeks, ultrasound may 
be used to evaluate the internal anatomy of the lower 
uterine segment and cervix for the funneling and shortening 
abnormalities consistent with cervical incompetence.
 
»
1. Threatened abortion—
Bleeding or cramping occurs, 
but the pregnancy continues. The cervix is not dilated.
2. Inevitable abortion—
The cervix is dilated and the mem
-
branes may be ruptured, but passage of the products of 
conception has not yet occurred. Bleeding and cramping 
persist, and passage of the products of conception is consid
-
ered inevitable.
3. Complete abortion—
Products of conception are com
-
pletely expelled. Pain ceases, but spotting may persist. Cervical 
os is closed.
4. Incomplete abortion—
The cervix is dilated. Some por
-
tion of the products of conception remains in the uterus. 
Only mild cramps are reported, but bleeding is persistent 
and often excessive.
5. Missed abortion—
The pregnancy has ceased to develop, 
but the conceptus has not been expelled. Symptoms of 
pregnancy disappear. There may be a brownish vaginal 
discharge but no active bleeding. Pain does not develop. 
The cervix is semifirm and slightly patulous; the uterus 
becomes smaller and irregularly softened; the adnexa are 
normal.
Pregnancy tests show low or falling levels of hCG. A CBC 
should be obtained if bleeding is heavy. Determine Rh type, 
and give Rh
o
(D) immune globulin if Rh-negative. All tissue 
recovered should be assessed by a pathologist and may be 
sent for genetic analysis in selected cases.
C. Ultrasonographic Findings
The gestational sac can be identified at 5–6 weeks from the 
last menstruation, a fetal pole at 6 weeks, and fetal cardiac 
activity at 6–7 weeks by transvaginal ultrasound. Serial 
observations are often required to evaluate changes in size 
of the embryo. Diagnostic criteria of early pregnancy loss 
are a crown-rump length of 7 mm or more and no heartbeat 
or a mean sac diameter of 25 mm or more and no embryo.
 
»
The bleeding that occurs in abortion of a uterine pregnancy 
must be differentiated from the abnormal bleeding of an 
ectopic pregnancy and anovulatory bleeding in a nonpreg
-
nant woman. The passage of hydropic villi in the bloody 
discharge is diagnostic of hydatidiform mole.
 
»
Treatment
Bed rest for 24–48 hours fol
-
lowed by gradual resumption of usual activities has been 
offered in the past. Studies do not support that this strategy 
is beneficial. Abstinence from sexual activity has also been 
suggested without proven benefit. Data are lacking to sup
-
port the administration of progestins to all women with a 
threatened abortion. If during the patient’s evaluation, an 
infection is diagnosed (ie, urinary tract infection), it should 
2. Missed abortion—
This calls for counseling regarding 
the fate of the pregnancy and planning for its elective ter
-
mination at a time chosen by the patient and clinician. 
Management can be medical or surgical. Each has risks and

-
Management can be medical or surgical. Each has risks and 
benefits. Medically induced first-trimester termination 
with prostaglandins (ie, misoprostol given vaginally or 
orally in a dose of 200–800 mcg) is safe, effective, less inva
-
sive, and more private than surgical intervention; however, 
if it is unsuccessful or if there is excessive bleeding, a surgi
-
cal procedure (dilation and curettage) may still be needed. 
Patients must be counseled about the different therapeutic 
options.
1. Incomplete or inevitable abortion—
Prompt removal of 
any products of conception remaining within the uterus is 
required to stop bleeding and prevent infection. Analgesia 
and a paracervical block are useful, followed by uterine 
exploration with ovum forceps or uterine aspiration. 
Regional anesthesia may be required.
2. Cerclage and restriction of activities—
A cerclage is the 
treatment of choice for incompetent cervix, but a viable 
intrauterine pregnancy should be confirmed prior to place
-
ment of the cerclage.
A variety of suture materials including a 5-mm Mersilene 
tape or No. 2 nonabsorbable monofilament suture can be 
used to create a purse-string type of stitch around the cervix, 
using either the McDonald or Shirodkar method. Cerclage 
should be undertaken with caution when there is advanced 
cervical dilation or when the membranes are prolapsed 
into the vagina. 
Rupture of the membranes and infection are 
specific contraindications to cerclage
. Cervical cultures for 
N gonorrhoeae, C trachomatis
, and group B streptococci 
should be obtained before elective placement of a cerclage. 
 and 
 should be treated before 
placement.
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•	
Patient with history of two second-trimester losses.
•	
Vaginal bleeding in a pregnant patient that resembles 
menstruation in a nonpregnant woman.
•	
Patient with an open cervical os.
•	
No signs of uterine growth in serial examinations of a 
pregnant patient.
•	
Leakage of amniotic fluid.
 
»
•	
•	
Heavy vaginal bleeding.
•	
Practice Bulletin No. 142: Cerclage for the management of 
cervical insufficiency. Obstet Gynecol. 2014 Feb; 123(2 Pt 1):
 
372–9. [Reaffirmed 2016] [PMID: 24451674]
Practice Bulletin No. 150: Early pregnancy loss. Obstet Gynecol. 
2015 May;125(5):1258–67. [Reaffirmed 2017] [PMID: 
25932865]
RECURRENT ABORTION
According to the American Society of Reproductive 
Medicine, recurrent pregnancy loss is defined as the loss of 
two or more previable (less than 24 weeks’ gestation or 
500 g) pregnancies in succession. Recurrent abortion 
affects about 1–5% of couples. Abnormalities related to 
recurrent abortion can be identified in approximately 
50% of these couples. If a woman has lost three previous 
pregnancies without identifiable cause, she still has at least 
a 55% chance of carrying a fetus to viability.
Recurrent abortion is a clinical rather than pathologic 
diagnosis. The clinical findings are similar to those 
observed in other types of abortion. It is appropriate to 
begin a medical evaluation in a woman who has had two 
first-trimester losses.
 
»
Treatment
A. Preconception Therapy
Preconception therapy is aimed at detection of maternal 
or paternal defects that may contribute to abortion. A 
thorough history and examination is essential. A random 
blood glucose test and thyroid function studies (including 
thyroid antibodies) can be done if history indicates a pos
-
sible predisposition to diabetes mellitus or thyroid disease. 
Detection of lupus anticoagulant and other hemostatic 
abnormalities (proteins S and C and antithrombin defi
-
ciency, hyperhomocysteinemia, anticardiolipin antibody, 
factor V Leiden mutations) and an antinuclear antibody 
test may be indicated. Hysteroscopy, saline infusion sono
-
gram, or hysterography can be used to exclude submucosal 
myomas and congenital anomalies of the uterus. In 
women with recurrent losses, resection of a uterine sep
-
tum, if present, has been recommended. Chromosomal 
(karyotype) analysis of both partners can be done to 
rule out balanced translocations (found in 3–4% of 
infertile couples), but karyotyping is expensive and may 
not be helpful.
Many therapies have been tried to prevent recurrent 
pregnancy loss from immunologic causes. Low-molecular-
weight heparin (LMWH), aspirin, intravenous immuno
-
globulin, and corticosteroids have all been used but the 
definitive treatment has not yet been determined (see 
Antiphospholipid Syndrome, below). Prophylactic dose 
heparin and low-dose aspirin have been recommended for 
women with antiphospholipid antibodies and recurrent 
pregnancy loss.
B. Postconception Therapy
The patient should be provided early prenatal care and 
scheduled frequent office visits. Empiric sex steroid 
hormone therapy is complicated and should be done by an 
expert if undertaken.
 
»
Prognosis
The prognosis is excellent if the cause of abortion can be 
corrected or treated.
Shahine L et al. Recurrent pregnancy loss: evaluation and treat
-
ment. Obstet Gynecol Clin North Am. 2015 Mar;42(1):117–34. 
[PMID: 25681844]
ECTOPIC PREGNANCY
 
»
Amenorrhea or irregular bleeding and spotting.
 
»
Pelvic pain, usually adnexal.
 
»
Adnexal mass by clinical examination or ultrasound.
 
»
Failure of serum beta-hCG to double every 
 
48 hours.
 
»
No intrauterine pregnancy on transvaginal 
ultrasound with serum beta-hCG greater than 
2000 milli-units/mL.
 
»

»
 
48 hours.
 
»
 
»
Ectopic implantation occurs in approximately 2% of first 
trimester pregnancies. About 98% of ectopic pregnancies 
are tubal. Other sites of ectopic implantation are the 
peritoneum or abdominal viscera, the ovary, and the cer
-
vix. Any condition that prevents or retards migration of the 
fertilized ovum to the uterus can predispose to an ectopic 
pregnancy, including a history of infertility, pelvic inflam
-
matory disease, ruptured appendix, and prior tubal 
surgery. Combined intrauterine and extrauterine preg
-
nancy (heterotopic) may occur rarely. In the United States, 
undiagnosed or undetected ectopic pregnancy is one of the 
most common causes of maternal death during the first 
trimester.
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»
Severe lower quadrant pain occurs in almost every case. It 
is sudden in onset, stabbing, intermittent, and does not 
radiate. Backache may be present during attacks. Shock 
occurs in about 10%, often after pelvic examination. At 
least two-thirds of patients give a history of abnormal men
-
struation; many have been infertile.
Blood may leak from the tubal ampulla over a period 
of days, and considerable blood may accumulate in the 
peritoneum. Slight but persistent vaginal spotting is usually 
reported, and a pelvic mass may be palpated. Abdominal 
distention and mild paralytic ileus are often present.
The CBC may show anemia and slight leukocytosis. Quan
-
titative serum pregnancy tests will show levels generally 
lower than expected for normal pregnancies of the same 
duration. If beta-hCG levels are followed over a few days, 
there may be a slow rise or a plateau rather than the near 
doubling every 2 days associated with normal early intrauter
-
ine pregnancy or the falling levels that occur with spontaneous 
abortion. A progesterone level can also be measured to assess 
the viability of the pregnancy.
C. Imaging
Ultrasonography can reliably demonstrate a gestational sac 
5–6 weeks from the last menstruation and a fetal pole at 
 
6 weeks if located in the uterus. An empty uterine cavity 
raises a strong suspicion of extrauterine pregnancy, which 
can occasionally be revealed by transvaginal ultrasound. 
Specified levels of serum beta-hCG have been reliably cor
-
related with ultrasound findings of an intrauterine preg
-
nancy. For example, a beta-hCG level of 6500 milli-units/mL 
with an empty uterine cavity by transabdominal ultra
-
sound is highly suspicious for an ectopic pregnancy. Simi
-
larly, a beta-hCG value of 2000 milli-units/mL or more can 
be indicative of an ectopic pregnancy if no products of 
conception are detected within the uterine cavity by 
transvaginal ultrasound. Serum beta-hCG values can vary 
by laboratory.
Laparoscopy is the surgical procedure of choice both to 
confirm an ectopic pregnancy and in most cases to permit 
removal of the ectopic pregnancy without the need for 
exploratory laparotomy.
Ectopic pregnancy should be suspected when postabor
-
tal tissue examination fails to reveal chorionic villi. Steps 
must be taken for immediate diagnosis, including prompt 
microscopic tissue examination, ultrasonography, and 
serial beta-hCG titers every 48 hours.
 
»
Clinical and laboratory findings suggestive or diagnostic of 
pregnancy will distinguish ectopic pregnancy from many 
acute abdominal illnesses such as acute appendicitis, acute 
pelvic inflammatory disease, ruptured corpus luteum cyst 
or ovarian follicle, and urinary calculi. Uterine enlarge
-
ment with clinical findings similar to those found in ecto
-
pic pregnancy is also characteristic of an aborting uterine 
pregnancy or hydatidiform mole.
 
»
Treatment
Patients must be warned about the complications of an 
ectopic pregnancy and monitored closely. In a stable 
patient with normal liver and renal function tests, metho
-
trexate (50 mg/m
2
) intramuscularly—given as single or 
multiple doses—is acceptable medical therapy for early 
ectopic pregnancy. Favorable criteria are that the preg
-
nancy should be less than 3.5 cm in largest dimension and 
unruptured, with no active bleeding and no fetal heart 
tones. Several small studies have not found an increased 
risk of fetal malformations or pregnancy losses in women 
who conceive within 6 months of methotrexate therapy.
When a patient with an ectopic pregnancy is unsta
-
ble or when surgical therapy is planned, the patient is 
hospitalized. Blood is typed and cross-matched. The 
goal is to diagnose and operate before there is frank 
rupture of the tube and intra-abdominal hemorrhage. 
The use of methotrexate in an unstable patient is abso
-

-
lutely contraindicated.
Surgical treatment is definitive. In most patients, diag
-
nostic laparoscopy is the initial surgical procedure per
-
formed. Depending on the size of the ectopic pregnancy 
and whether or not it has ruptured, salpingostomy with 
removal of the ectopic pregnancy or a partial or complete 
salpingectomy can usually be performed. Clinical condi
-
tions permitting, patency of the contralateral tube can be 
established by injection of indigo carmine into the uterine 
cavity and flow through the contralateral tube confirmed 
visually by the surgeon; iron therapy for anemia may be 
necessary during convalescence. Rh
o
(300 mcg) should be given to Rh-negative patients.
 
»
Prognosis
Repeat tubal pregnancy occurs in about 10% of cases. This 
should not be regarded as a contraindication to future preg
-
nancy, but the patient requires careful observation and early 
ultrasound confirmation of an intrauterine pregnancy.
 
»
•	
Severe abdominal pain.
•	
Palpation of an adnexal mass on pelvic examination.
•	
Abdominal pain and vaginal bleeding in a pregnant 
patient.
 
»
Presence of symptoms or signs of a ruptured ectopic 
Brady PC. New evidence to guide ectopic pregnancy diagnosis 
and management. Obstet Gynecol Surv. 2017 Oct; 72 (10):
 
618–25. [PMID: 29059454]
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Capmas P et al. Treatment of ectopic pregnancies in 2014: new 
answers to some old questions. Fertil Steril. 2014 Mar;101(3):
 
615–20. [PMID: 24559615]
GESTATIONAL TROPHOBLASTIC 
 
DISEASE (H
ydatidiform Mole & 
Choriocarcinoma
)
h
ydatidiform Mole
 
»
Amenorrhea.
 
»
Irregular uterine bleeding.
 
»
Serum beta-hCG greater than 40,000 milli-units/mL.
 
»
Passage of grapelike clusters of enlarged edematous 
villi per vagina.
 
»
Uterine Ultrasound shows characteristic hetero
-
geneous echogenic image and no fetus or 
placenta.
 
»
Cytogenetic composition is 46, XX (85%), of paternal 
origin.
 
»
Persistence of detectable beta-hCG after mole 
evacuation.
 
»
Gestational trophoblastic disease is a spectrum of disorders 
that includes hydatidiform mole (partial and complete), 
invasive mole (local extension into the uterus or vagina), 
choriocarcinoma (malignancy often complicated by distant 
metastases), and placental site trophoblastic tumor. Com
-
plete moles show no evidence of a fetus on ultrasonogra
-
phy. The majority are 46, XX, with all chromosomes of 
paternal origin. Partial moles generally show evidence of 
an embryo or gestational sac; are triploid, slower-growing, 
and less symptomatic; and often present clinically as a 
missed abortion. Partial moles tend to follow a benign 
course, while complete moles have a greater tendency to 
become choriocarcinoma.
In North America, the frequency of gestational tropho
-
blastic disease is 1:1500 pregnancies. The highest rates occur 
in Asians. Risk factors include prior spontaneous abortion, a 
history of mole, and age younger than 21 or older than 
 
35. Approximately 10% of women require further treatment 
after evacuation of the mole; choriocarcinoma develops in 
2–3% of women.
 
»
Uterine bleeding, beginning at 6–16 weeks, is observed in 
most instances. In some cases, the uterus is larger than 
would be expected in a normal pregnancy of the same 
duration. Excessive nausea and vomiting may occur. 
Bilaterally enlarged cystic ovaries are sometimes palpable. 
They are the result of ovarian hyperstimulation due to 
excess beta-hCG.
Preeclampsia-eclampsia may develop during the second 
trimester of an untreated molar pregnancy, but this is 
unusual because most are diagnosed early.
Choriocarcinoma may be manifested by continued or 
recurrent uterine bleeding after evacuation of a mole or 
following delivery, abortion, or ectopic pregnancy. The 
presence of an ulcerative vaginal tumor, pelvic mass, or 
distant metastases may be the presenting manifestation.
Hydatidiform moles are generally characterized by high 
serum beta-hCG values, which can range from high nor
-
mal to the millions. Levels are higher with complete moles 
than with partial moles. Serum beta-hCG values, if 
extremely high, can assist in making the diagnosis, but they 
are more helpful in managing response to treatment. 
Hematocrit, creatinine, blood type, liver biochemical tests, 
and thyroid function tests should also be measured. High 
beta-hCG levels can cause the release of thyroid hormone, 
and rarely, symptoms of hyperthyroidism. Patients with 
hyperthyroidism may require beta-blocker therapy until 
the mole has been evacuated.
C. Imaging
The preoperative diagnosis of hydatidiform mole is con
-
firmed by ultrasound. Placental vesicles can be easily 
seen on transvaginal ultrasound. A preoperative chest 
film is indicated to rule out pulmonary metastases of the 
trophoblast.
 
»
Treatment
A. Specific (Surgical) Measures
The uterus should be emptied as soon as the diagnosis of 
hydatidiform mole is established, preferably by suction 
curettage. Ovarian cysts should not be resected nor ovaries 
removed; spontaneous regression of theca lutein cysts will 
occur with elimination of the mole. The products of con
-

-
ception removed from the uterus should be sent to a 
pathologist for review. In patients who have completed 
their childbearing, hysterectomy is an acceptable alterna
-
tive. Hysterectomy does not preclude the need for follow-
up of beta-hCG levels.
B. Follow-Up Measures
Weekly quantitative beta-hCG level measurements are ini
-
tially required. Following successful surgical evacuation, 
moles show a progressive decline in beta-hCG. After three 
negative weekly tests (less than 5 milli-units/mL), the 
interval may be increased to every 1 month for an addi
-
tional 6 months. The purpose of this follow-up is to iden
-
tify persistent nonmetastatic and metastatic disease, 
including choriocarcinoma, which is more likely to occur if 
the initial beta-hCG is high and the uterus is large. If levels 
plateau or begin to rise, the patient should be evaluated by 
repeat laboratory tests, chest film, and dilatation and 
CMDT19_Ch19_p0811-p0839.indd   821

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 CMDT 2019
curettage (D&C) before the initiation of chemotherapy. 
Effective contraception (preferably birth control pills) 
should be prescribed to avoid the hazard and confusion of 
elevated beta-hCG from a new pregnancy. The beta-hCG 
levels should be negative for 6 months before pregnancy is 
attempted again. Because the risk of recurrence of a molar 
pregnancy is 1%, an ultrasound should be performed in the 
first trimester of the pregnancy following a mole to ensure 
that the pregnancy is normal. In addition, a beta-hCG level 
should then be checked 6 weeks’ postpartum (after the 
subsequent normal pregnancy) to ensure there is no persis
-
tent trophoblastic tissue, and the placenta should be exam
-
ined by a pathologist.
C. Antitumor Chemotherapy
If malignant tissue is discovered at surgery or during the 
follow-up examination, chemotherapy is indicated. For 
low-risk patients with a good prognosis, methotrexate is 
considered first-line therapy followed by dactinomycin 
(see Table 39–3). Patients with high-risk disease should be 
referred to a cancer center, where multiple-agent chemo
-
therapy probably will be given.
 
»
Prognosis
Five-year survival after courses of chemotherapy, even 
when metastases have been demonstrated, can be expected 
in at least 85% of cases of choriocarcinoma.
 
»
•	
Uterine size exceeds that anticipated for gestational age.
•	
Vaginal bleeding similar to menstruation.
•	
Pregnant patient with a history of a molar pregnancy.
 
»
•	
Confirmed molar pregnancy by ultrasound and labora
-
tory studies.
•	
Heavy vaginal bleeding in a pregnant patient under 
Brown J et al. 15 years of progress in gestational trophoblastic 
disease: scoring, standardization, and salvage. Gynecol Oncol. 
2017 Jan;144(1):200–7. [PMID: 27743739]
 
º
OBS
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IC COM
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LIC
a
t
IONS OF 
the
 
S
e
COND & 
th
I
r
D 
tr
IM
e
S
ter
S
PREECLAMPSIA-ECLAMPSIA
p
r
eeclampsia
 
»
Blood pressure of 140 mm Hg or higher systolic or 
90 mm Hg or higher diastolic after 20 weeks of 
 
»
Proteinuria of 0.3 g or more in 24 hours.
 
»
When hypertension is present with severe features 
of preeclampsia, seizure prophylaxis could be 
beneficial.
p
r
eeclampsia with Severe Features
 
»
Blood pressure of 160 mm Hg or higher systolic or 
110 mm Hg or higher diastolic.
 
»
Progressive kidney injury.
 
»
 
»
Hemolysis, elevated liver enzymes, low platelets 
(HELLP).
 
»
Pulmonary edema.
 
»
Vision changes or headache.
e
clampsia
 
»
Seizures in a patient with evidence of preeclampsia.
 
»
Preeclampsia is defined as the presence of newly elevated 
blood pressure and proteinuria during pregnancy. Eclampsia 
is diagnosed when seizures develop in a patient with evi
-
dence of preeclampsia. Historically, the presence of three 
elements was required for the diagnosis of preeclampsia: 
hypertension, proteinuria, and edema. Edema was diffi
-
cult to objectively quantify and is no longer a required 
element. In addition, proteinuria may not always be 
present.
Preeclampsia-eclampsia can occur any time after 
 
20 weeks of gestation and up to 6 weeks’ postpartum. It 
is a disease unique to pregnancy, with the only cure being 
delivery of the fetus and placenta. Preeclampsia develops 
in approximately 7% of pregnant women in the United 
States; of those, eclampsia will develop in 5% (0.04% of 
pregnant women). Primiparas are most frequently 
affected; however, the incidence of preeclampsia-eclampsia 
is increased with multi-fetal pregnancies, chronic hyper
-
tension, diabetes mellitus, kidney disease, collagen-vascular 
and autoimmune disorders, and gestational  trophoblastic 
disease. Uncontrolled eclampsia is a significant cause of 
maternal death.
 
»
Clinically, the severity of preeclampsia-eclampsia can be 
measured with reference to the six major sites in which it

»
measured with reference to the six major sites in which it 
exerts its effects: the central nervous system, the kidneys, 
the liver, the hematologic system, the vascular system, and 
the fetal-placental unit. By evaluating each of these areas 
for the presence of mild to severe preeclampsia, the degree 
of involvement can be assessed, and an appropriate man
-
agement plan can be formulated that balances the severity 
of disease and gestational age (Table 19–3).
A. Preeclampsia
1. Without severe features—
Patients usually have few 
complaints, and the diastolic blood pressure is less than 
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110 mm Hg. Edema may be present. The platelet count is 
over 100,000/mcL, antepartum fetal testing is reassuring 
(see Tests & Procedures, above), central nervous system 
irritability is minimal, epigastric pain is not present, and 
liver enzymes are not elevated.
2. With severe features—
Symptoms are more dramatic 
and persistent. Patients may complain of headache and 
changes in vision. The blood pressure is often above 
160/110 mm Hg. Thrombocytopenia (platelet count less 
than 100,000/mcL) may be present and progress to dis
-
seminated intravascular coagulation. Severe epigastric pain 
may be present from hepatic subcapsular hemorrhage with 
significant stretch or rupture of the liver capsule. HELLP 
syndrome (hemolysis, elevated liver enzymes, low platelets) 
is an advanced form of severe preeclampsia.
B. Eclampsia
The occurrence of seizures defines eclampsia. It is a mani
-
festation of severe central nervous system involvement. 
Other findings of preeclampsia are observed.
 
»
Preeclampsia-eclampsia can mimic and be confused 
with many other diseases, including chronic hyperten
-
sion, chronic kidney disease, primary seizure disorders, 
gallbladder and pancreatic disease, immune thrombocy
-
topenia, thrombotic thrombocytopenic purpura, and 
hemolytic-uremic syndrome. It must always be consid
-
ered in any pregnant woman beyond 20 weeks of gesta
-
tion with consistent signs and symptoms. Although it is 
most common in the third trimester, it can occur earlier, 
especially in women with comorbid conditions like 
hypertension, kidney disease, and systemic lupus erythe
-
matosus. It is particularly difficult to diagnose when a 
preexisting disease such as hypertension is present.
 
»
Treatment
Based on evidence and expert consensus, the American 
College of Obstetricians and Gynecologists (ACOG) sup
-
ports considering the use of low-dose aspirin (81 mg orally 
daily) initiated between 12 weeks’ and 28 weeks’ gestation 
for women at increased risk for preclampsia; risk factors 
include a history of preeclampsia, multifetal gestation, 
chronic hypertension, diabetes mellitus, kidney disease, or 
autoimmune diseases (such as systemic lupus erythematosus 
or antiphospholipid syndrome). In clinical studies, diuret
-
ics, dietary restriction or enhancement, sodium restriction, 
and vitamin-mineral supplements (eg, calcium or vitamin 
C and E) have not been confirmed to be useful. The only 
cure is delivery of the fetus at a time as favorable as possible 
for its survival.
Early recognition is the key to treatment. This requires careful 
attention to the details of prenatal care—especially subtle 
Table 19–3.
 
Indicators of mild to moderate versus severe preeclampsia-eclampsia.
Site
Indicator
Mild to Moderate
Severe
Central nervous system
Symptoms and signs
Hyperreflexia
Seizures
Scotomas
Headache
Clonus
Irritability
Kidney
0.3–5 g/24 h
> 5 g/24 h or catheterized urine with 4+ protein
Urinary output
> 30 mL/h
< 30 mL/h
Liver
AST, ALT, LD
Normal liver enzymes
Elevated liver enzymes
Epigastric pain
Ruptured liver
Hematologic
Platelets
< 100,000/mcL
Hemoglobin
Normal
Low, normal, or elevated
Vascular
Blood pressure
< 160/110 mm Hg
> 160/110 mm Hg
Retina
Arteriolar spasm
Fetal-placental unit
Growth restriction
Absent
Present
Oligohydramnios
Absent
Present
Fetal distress
Absent
Present
ALT, alanine aminotransferase; AST, aspartate aminotransferase; LD, lactate dehydrogenase.
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changes in blood pressure and weight. The objectives are to 
prolong pregnancy if possible to allow fetal lung maturity 
while preventing progression to severe disease and eclampsia. 
The critical factors are the gestational age of the fetus, fetal 
pulmonary maturity, and the severity of maternal disease. 
Preeclampsia-eclampsia at term is managed by delivery. Prior 
to term, severe preeclampsia-eclampsia requires delivery with 
very few exceptions. Epigastric pain, seizures, severe range 
blood pressures, thrombocytopenia, and visual disturbances 
are strong indications for delivery of the fetus. Marked 
proteinuria alone can be managed more conservatively.
1. Home management—
Home management may be 
attempted for patients with preeclampsia without severe 
features and a stable home situation. This requires assis
-
tance at home, rapid access to the hospital, a reliable 
patient, and the ability to obtain frequent blood pressure 
readings. A home health nurse can often provide frequent 
home visits and assessments.
2. Hospital care—
Hospitalization is required for women 
with preeclampsia with severe features or those with unre
-
liable home situations. Regular assessments of blood pres
-
sure, urine protein, and fetal heart tones and activity are 
required. A CBC with platelet count, electrolyte panel, and 
liver enzymes should be checked regularly, with frequency 
dependent on severity. A 24-hour urine collection for total 
protein and creatinine clearance should be obtained on 
admission and repeated as indicated. Magnesium sulfate is 
not used until the diagnosis of severe preeclampsia is made 
and delivery planned (see Eclampsia, below).
Fetal evaluation should be obtained as part of the 
workup. If the patient is being admitted to the hospital, 
fetal testing should be performed on the same day to assess 
fetal wellbeing. This may be done by fetal heart rate testing 
with nonstress testing or by biophysical profile. A regular 
schedule of fetal surveillance must then be followed. Daily 
fetal kick counts can be recorded by the patient herself. If 
the fetus is less than 34 weeks’ gestation, corticosteroids 
(betamethasone 12 mg intramuscularly every 24 h for two 
doses, or dexamethasone 6 mg intramuscularly every 12 h 
for four doses) can be administered to the mother. 
How
-
ever, when a woman is clearly suffering from unstable severe 
preeclampsia, delivery should not be delayed for fetal lung 
maturation or administration of corticosteroids
.
The method of delivery is determined by the maternal 
and fetal status. A vaginal delivery is preferred because it 
has less blood loss than a cesarean section and requires less 
coagulation factors. Cesarean section is reserved for the 
usual fetal indications. For mild preeclampsia, delivery 
should take place at term.
1. Emergency care—
If the patient is convulsing, she is 
turned on her side to prevent aspiration and to improve 
blood flow to the placenta. The seizure may be stopped by 
giving an intravenous bolus of either magnesium sulfate, 
4–6 g, or lorazepam, 2–4 mg over 4 minutes or until the 
seizure stops. Magnesium sulfate is the preferred agent, and 
alternatives should be used only if magnesium sulfate is 
unavailable. A continuous intravenous infusion of magnesium 
sulfate is then started at a rate of 2–3 g/h unless the patient is 
known to have significantly reduced kidney function. 
Magnesium blood levels are then checked every 4–6 hours 
and the infusion rate adjusted to maintain a therapeutic 
blood level (4–7 mEq/L). Urinary output is checked hourly 
and the patient assessed for signs of possible magnesium 
toxicity such as loss of deep tendon reflexes or decrease in 
respiratory rate and depth, which can be reversed with 
calcium gluconate, 1 g intravenously over 2 minutes.
2. General care—
In patients who have preeclampsia with 
severe features, magnesium sulfate should be given intra
-

-
venously, 4- to 6-g load over 15–20 minutes followed by 
2–3 g/h maintenance, for seizure prophylaxis. The occur
-
rence of eclampsia necessitates delivery once the patient 
is stabilized. It is important, however, that assessment of 
the status of the patient and fetus take place first. Con
-
tinuous fetal monitoring must be performed and mater
-
nal blood typed and cross-matched quickly. A urinary 
catheter is inserted to monitor urinary output, and a CBC 
with platelets, electrolytes, creatinine, and liver enzymes 
are obtained. If hypertension is present with systolic val
-
ues of 160 mm Hg or higher or diastolic values 110 mm 
Hg or higher, antihypertensive medications should be 
administered to reduce the blood pressure to 140–150/
 
90–100 mm Hg. Lower blood pressures than this may 
induce placental insufficiency through reduced perfusion. 
Hydralazine given in 5- to 10-mg increments intrave
-
nously every 20 minutes is frequently used to lower blood 
pressure. Labetalol, 10–20 mg intravenously, every 20 minutes 
as needed, can also be used.
3. Delivery—
Delivery is mandated once eclampsia has 
occurred. Vaginal delivery is preferred. The rapidity with 
which delivery must be achieved depends on the fetal and 
maternal status following the seizure and the availability of 
laboratory data on the patient. Oxytocin, given intrave
-
nously and titrated to a dose that results in adequate con
-
tractions, may be used to induce or augment labor. 
Oxytocin should only be administered by a clinician spe
-
cifically trained in its use. Regional analgesia or general 
anesthesia is acceptable. Cesarean section is used for the 
usual obstetric indications.
4. Postpartum—
Magnesium sulfate infusion (2–3 g/h) 
should be continued for 24 hours postpartum. Late-onset 
preeclampsia-eclampsia can occur during the postpartum 
period. It is usually manifested by either hypertension or 
seizures. Treatment is the same as prior to delivery—ie, 
with hydralazine and magnesium sulfate.
 
»
•	
New onset of hypertension and proteinuria in a preg
-
nant patient more than 20 weeks’ gestation.
•	
New onset of seizure activity in a pregnant patient.
 
»
•	
Symptoms of preeclampsia with severe features in a 
pregnant patient with elevated blood pressure above 
baseline.
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•	
Evaluation for preeclampsia when severe features of the 
disease are suspected.
•	
Evaluation for preeclampsia in a patient with an unsta
-
ble home environment.
•	
Evidence of eclampsia.
Hypertension in pregnancy. Report of the American Col
-
lege of Obstetricians and Gynecologists’ Task Force on 
Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;
 
122(5):1122–31. [PMID: 24150027]
Mol BW et al. Pre-eclampsia. Lancet. 2016 Mar 5;387(10022):
 
999–1011. [PMID: 26342729]
American College of Obstetrics and Gynecologists. Committee 
Opinion No. 692: Emergent therapy for acute-onset, severe 
hypertension during pregnancy and the postpartum period. 
Obstet Gynecol. 2017 Apr;129(4):e90–5. [PMID: 28333820]
Practice Advisory on low-dose aspirin and prevention of 
preeclampsia, 2016. https://www.acog.org/Clinical-Guidance-
and-Publications/Practice-Advisories/Practice-Advisory-Low-
 
Dose-Aspirin-and-Prevention-of-Preeclampsia-Updated-
PRETERM LABOR
 
»
Preterm regular uterine contractions approximately 
5 minutes apart.
 
»
Cervical dilatation, effacement, or both.
 
»
Preterm birth is defined as delivery prior to 37 weeks’ gesta
-
tion, and spontaneous preterm labor with or without prema
-
ture rupture of the fetal membranes is responsible for at least 
two-thirds of all preterm births. Prematurity is the largest 
single contributor to infant mortality, and survivors are at 
risk for a myriad of short- and long-term complications. 
Rates of infant death and long-term neurologic impairment 
are inversely related to gestational age at birth. The cusp of 
viability in contemporary practice is 23–25 weeks’ gestation, 
and infants born prior to 23 weeks rarely survive. About 
two-thirds of the preterm births occur between 34 weeks 
and 36 weeks and 6 days (termed 
late preterm birth
), and 
good outcomes are expected at these gestational ages. 
Importantly, however, even these late preterm infants are at 
significantly increased risk for both morbidity and mortality 
when compared to those infants born at term.
Major risk factors for spontaneous preterm labor 
include a past history of preterm birth and a short cervical 
length as measured by transvaginal ultrasound. Patients 
with one or both of these risk factors have largely been the 
focus of recent intervention trials aiming to prevent 
preterm birth. Other known risk factors are many but 
include black race, multi-fetal pregnancies, intrauterine 
infection, substance abuse, smoking, periodontal disease, 
and socioeconomic deprivation.
 
»
In women with regular uterine contractions and cervical 
change, the diagnosis of preterm labor is straightforward. 
However, symptoms such as pelvic pressure, cramping, or 
vaginal discharge may be the first complaints in high-risk 
patients who later develop preterm labor. Because these 
complaints may be vague and irregular uterine contrac
-
tions are common, distinguishing which patients merit 
further evaluation can be problematic. In some cases, this 
distinction can be facilitated by the use of fetal fibronectin 
measurement in cervicovaginal specimens. This test is 
most useful when it is negative (less than 50 ng/mL), since 
the negative predictive value for delivery within 7–14 days 
is 93–97%. A negative test, therefore, usually means the 
patient can be reassured and discharged home. Because of 
its low sensitivity, however, fetal fibronectin is not recom
-
mended as a screening test in asymptomatic women.
 
»
Treatment
Patients must be educated to identify symptoms associated 
with preterm labor to avoid unnecessary delay in their 
evaluation. In patients who are believed to be at increased 
risk for preterm delivery, conventional recommendations

risk for preterm delivery, conventional recommendations 
are for limited activity and bed rest. Randomized trials, 
however, have failed to demonstrate improved outcomes in 
women placed on activity restriction. Paradoxically, such 
recommendations may place a woman at an 
increased
 risk 
to deliver preterm. Women with preterm labor at the 
threshold of viability present unique ethical and obstetric 
challenges and are best managed in consultation with 
maternal-fetal medicine and neonatology specialists. The 
families in such situations should be actively and continu
-
ally engaged about decisions regarding the aggressiveness 
of resuscitative efforts.
In pregnancies between 23 and 34 weeks’ gestation where 
preterm birth is anticipated, a single short course of corti
-
costeroids should be administered to promote fetal lung 
maturity. Such therapy has been demonstrated to reduce 
the frequency of respiratory distress syndrome, intracra
-
nial hemorrhage, and even death in preterm infants. 
Betamethasone, 12 mg intramuscularly repeated once 
24 hours later, or dexamethasone, 6 mg intramuscularly 
repeated every 12 hours for four doses, both cross the pla
-
centa and are the preferred treatments in this setting. A 
single repeat course of antenatal corticosteroids should be 
considered in women who are at risk for preterm delivery 
within the next 7 days, and whose prior dose of antenatal 
corticosteroids was administered more than 14 days previ
-
ously. Rescue course corticosteroids could be provided as 
early as 7 days from the prior dose, if indicated by the 
clinical scenario. Administration of betamethasone may be 
considered in pregnant women between 34 0/7 and 36 6/7 
weeks of gestation at imminent risk for preterm birth 
within 7 days, and who have not received a previous course 
of antenatal corticosteroids.
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Although antibiotics have not been proven to forestall 
delivery, women in preterm labor should receive antimi
-
crobial prophylaxis against group B streptococcus.
C. Tocolytic Agents
Numerous tocolytic pharmacologic agents have been given 
in an attempt to forestall preterm birth, although none are 
completely effective, and there is no evidence that such 
therapy directly improves neonatal outcomes. Administer
-
ing tocolytic agents, however, remains a reasonable 
approach to the initial management of preterm labor and 
may provide sufficient prolongation of pregnancy to 
administer a course of corticosteroids and (if appropriate) 
transport the patient to a facility better equipped to care for 
premature infants. Maintenance therapy (continuation of 
treatment beyond 48 hours) is not effective at preventing 
preterm birth and is not recommended. Likewise, despite 
the finding that preterm labor is associated with intrauter
-
ine infection in certain cases, there is no evidence that 
antibiotics forestall delivery in women with preterm labor 
and intact membranes.
Magnesium sulfate
 is commonly used (but no longer 
recommended as a first-line agent) for tocolysis, and there 
is evidence that it may also be protective against cerebral 
palsy in infants from 24 weeks’ to 32 weeks’ gestation when 
given at time of birth. Magnesium sulfate is given intrave
-
nously as a 4- to 6-g bolus followed by a continuous infu
-
sion of 2 g/h. Magnesium levels are not typically checked 
but should be monitored if there is any concern for toxicity. 
Magnesium sulfate is entirely cleared by the kidney and 
must, therefore, be used with caution in women with any 
degree of kidney disease.
Beta-adrenergic drugs such as 
terbutaline
 can be given 
as an intravenous infusion starting at 2.5 mcg/min or as a 
subcutaneous injection starting at 250 mcg given every 
 
30 minutes. Oral terbutaline is not recommended because 
of the lack of proven efficacy and concerns about maternal 
safety. Serious maternal side effects have been reported 
with the use of terbutaline and include tachycardia, pulmo
-
nary edema, arrhythmias, metabolic derangements (such 
as hyperglycemia and hypokalemia), and even death. Pulmo
-
nary edema occurs with increased frequency with con
-
comitant administration of corticosteroids, large volume 
intravenous fluid infusion, maternal sepsis, or prolonged 
tocolysis. Because of these safety concerns, the US Food 
and Drug Administration warns that terbutaline be admin
-
istered exclusively in a hospital setting and discontinued 
after 48–72 hours of treatment.
, 20 mg orally every 6 hours, and 
indometha
-
cin
, 50 mg orally once then 25 mg orally every 6 hours up 
to 48 hours, have also been used with limited success. Nife
-
dipine should not be given in conjunction with magnesium 
sulfate.
Before attempts are made to prevent preterm delivery 
with tocolytic agents, the patient should be assessed for 
conditions in which delivery would be indicated. Severe 
preeclampsia, lethal fetal anomalies, placental abruption, 
and intrauterine infection are all examples of indications 
for preterm delivery. In such cases, attempts to forestall 
delivery would be inappropriate.
 
»
Preterm Birth Prevention
Strategies aimed at preventing preterm birth in high-risk 
women—principally those with a history of preterm birth 
or a shortened cervix (or both)—have focused on the 
administration of progesterone or progesterone com
-
pounds and the use of cervical cerclage. Prospective ran
-
domized controlled trials have demonstrated reductions in 
rates of preterm birth in high-risk women with singleton 
pregnancies who received progesterone supplementation, 
although the optimal preparation, dose, and route of 
administration (intramuscular injection versus vaginal 
suppository) are unclear. Although the issue has not been 
settled, there is also some evidence that progesterone

settled, there is also some evidence that progesterone 
therapy may decrease rates of preterm birth in nulliparous 
women who are found to have a shortened cervix as mea
-
sured by transvaginal ultrasound. ACOG does not recom
-
mend universal transvaginal cervical length screening but 
acknowledges that this strategy may be considered.
There is also evidence that women with a previous 
spontaneous preterm birth and a shortened cervix (less 
than 25 mm before 24 weeks’ gestation) may benefit from 
placement of a cervical cerclage. Incidentally detected 
short cervical length in the second trimester in the absence 
of a prior singleton preterm birth is not diagnostic of 
cervical insufficiency, and cerclage is not indicated in 
this setting. In twin and triplet gestations, however, neither 
progesterone administration nor cervical cerclage place
-
ment has been effective at prolonging pregnancy, and these 
therapies are not recommended in women with multi-fetal 
pregnancies.
 
»
•	
Symptoms of increased pelvic pressure or cramping in 
high-risk patients.
•	
Regular uterine contractions.
•	
Rupture of membranes.
•	
Vaginal bleeding.
 
»
•	
Cervical dilation of 2 cm or more prior to 34 weeks’ 
•	
Contractions that cause cervical change.
•	
Practice Bulletin No. 130: Prediction and prevention of 
preterm birth. Obstet Gynecol. 2012 Oct;120(4):964–73. 
[Reaffirmed 2016] [PMID: 22996126]
cervical insufficiency. Obstet Gynecol. 2014 Feb;123(2 Pt 1):
 
Practice Bulletin No. 171: Management of preterm labor. 
Obstet Gynecol. 2016 Oct;128:e155–64. [PMID: 27661654]
-
tee Opinion No. 713: Antenatal corticosteroid therapy for 
fetal maturation. Obstet Gynecol. 2017 Aug;130(2):e102–9. 
[PMID: 28742678]
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Iams JD. Clinical practice. Prevention of preterm parturition. 
 
N Engl J Med. 2014 Jan 16;370(3):254–61. [PMID: 24428470]
Obstetric Care Consensus No. 3: Periviable birth. Obstet Gynecol. 
2015 Nov;126(5):e82–94. [PMID: 26488525]
THIRD-TRIMESTER BLEEDING
Five to 10 percent of women have vaginal bleeding in late 
pregnancy. The clinician must distinguish between placental 
causes (placenta previa, placental abruption, vasa previa) 
and nonplacental causes (labor, infection, disorders of the 
lower genital tract, systemic disease). The approach to bleed
-
ing in late pregnancy depends on the underlying cause, the 
gestational age at presentation, the degree of blood loss, and 
the overall status of the mother and her fetus.
 
»
Treatment
The patient should initially be observed closely with con
-
tinuous fetal monitoring to assess for fetal distress. A com
-
plete blood count with platelets and a prothrombin time 
(INR) should be obtained and repeated serially if the bleed
-
ing continues. If hemorrhage is significant or if there is 
evidence of acute hypovolemia, the need for transfusion 
should be anticipated and an appropriate volume of red 
cells prepared with cross-matching. Ultrasound examina
-
tion should be performed to determine placental location. 
Digital pelvic examinations are done only after ultrasound 
examination has ruled out placenta previa. Administration 
of anti-D immune globulin may be required for women 
who are Rh negative.
B. Placenta Previa
Placenta previa occurs when the placenta implants over the 
internal cervical os. Risk factors for this condition include 
previous cesarean delivery, increasing maternal age, multi
-
parity, and smoking. If the diagnosis is initially made in the 
first or second trimester, the ultrasound should be repeated 
in the third trimester. Persistence of placenta previa at this 
point is an indication for cesarean as the route of delivery. 
Painless vaginal bleeding is the characteristic symptom 
in placenta previa and can range from light spotting to 
profuse hemorrhage. Hospitalization for extended evalua
-
tion is the appropriate initial management approach. For 
pregnancies that have reached 37 weeks’ gestation or beyond 
with continued bleeding, cesarean delivery is generally 
indicated. Pregnancies at 36 weeks or earlier are candidates 
for expectant management provided the bleeding is not 
prodigious, and a subset of these women can be discharged 
if the bleeding and contractions completely subside.
C. Morbidly Adherent Placenta
Morbidly adherent placenta is a general term describing an 
abnormally adherent placenta that has invaded into the 
uterus. The condition can be further classified depending 
on whether the depth of invasion is limited to the endome
-
trium (
accreta
), extends into the myometrium (
increta
), or 
invades beyond the uterine serosa (
percreta
). The most 
important risk factor for a morbidly adherent placenta is a 
prior uterine scar—typically from one or more prior cesar
-
ean deliveries. The focus of invasion usually involves the 
scar itself, and 
placenta previa
 is commonly associated with 
morbid adherence. Of serious concern for the field of 
obstetrics, the incidence of these syndromes has increased 
dramatically over the last 50 years commensurate with the 
increasing cesarean delivery rate.
After delivery of the infant, the morbidly adherent 
placenta does not separate normally, and the bleeding 
that results can be torrential. Emergency hysterectomy is 
usually required to stop the hemorrhage, and transfusion 
requirements are often massive. Because of the consider
-
able increase in both maternal morbidity and mortality 
associated with this condition, careful preoperative plan
-
ning is imperative when the diagnosis is suspected ante
-
natally. Ultrasound findings such as intraplacental 
lacunae, bridging vessels into the bladder, and loss of the

-
-
lacunae, bridging vessels into the bladder, and loss of the 
retroplacental clear space suggest placental invasion in 
women who have placenta previa. 
Importantly, however, 
even if ultrasound findings are subtle, an abnormally 
adherent placenta should be suspected in any patient with 
one or more prior cesarean deliveries and an anterior pla
-
centa previa
. Ideally, delivery planning should involve a 
multidisciplinary team, and the surgery should take place 
at an institution with appropriate personnel and a blood 
bank equipped to handle patients requiring massive 
transfusion. It has been demonstrated that a systematic 
approach to management with a multidisciplinary team 
improves patient outcomes. Evidence-based recommen
-
dations regarding delivery timing are lacking, but the goal 
is to have a planned, late-preterm cesarean delivery. As 
such, delivery at 34–36 weeks in a stable patient seems a 
reasonable approach.
D. Placental Abruption
Placental abruption is the premature separation of the pla
-
centa from its implantation site before delivery. Hyperten
-
sion is a known risk factor for abruption. Other risk factors 
include multiparity, cocaine use, smoking, previous abrup
-
tion, and thrombophilias. Classic symptoms are vaginal 
bleeding, uterine tenderness, and frequent contractions, 
but the clinical presentation is highly variable. There is 
often concealed hemorrhage when the placenta abrupts, 
which causes increased pressure in the intervillous space. 
Excess amounts of thromboplastin escape into the mater
-
nal circulation and defibrination occurs. Profound coagu
-
lopathy and acute hypovolemia from blood loss can occur 
and are more likely with an abruption severe enough to kill 
the fetus. Ultrasound may be helpful to exclude placenta 
previa, but failure to identify a retroplacental clot does not 
exclude abruption. In most cases, abruption is an indica
-
tion for immediate cesarean delivery because of the high 
risk of fetal death.
-
tee Opinion No. 529: Placenta accreta. Obstet Gynecol. 
2012 Jul;120(1):207–11. [Reaffirmed 2015] [PMID: 22914422]
Bulletin No. 183: Postpartum hemorrhage. Obstet Gynecol. 
2017 Oct;130(4):e168–86. [PMID: 28937571]
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Shamshirsaz AA et al. Maternal morbidity in patients with mor
-
bidly adherent placenta treated with and without a standardized 
multidisciplinary approach. Am J Obstet Gynecol. 2015 Feb;
 
212(2):218.e1–9. [PMID: 25173187]
Silver RM. Abnormal placentation: placenta previa, vasa previa, 
and placenta accreta. Obstet Gynecol. 2015 Sep;126(3):654–68. 
[PMID: 26244528]
 
º
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IC COM
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LIC
a
t
IONS OF 
the
 
per
I
part
UM 
per
IOD
PUERPERAL MASTITIS
Postpartum mastitis occurs sporadically in nursing mothers, 
usually with symptom onset after discharge from the 
hospital (see also Chapter 17). 
 is 
usually the causative agent. Women nursing for the first 
time and those with difficulty breastfeeding appear to be at 
greatest risk. Rarely, inflammatory carcinoma of the breast 
can be mistaken for puerperal mastitis. Unfortunately, 
strategies aimed at preventing mastitis in breastfeeding 
women have been unsuccessful.
Mastitis frequently begins within 3 months after delivery 
and may start with an engorged breast and a sore or fissured 
nipple. Cellulitis is typically unilateral with the affected area of 
breast being red, tender, and warm. Fever and chills are com
-
mon complaints as well. Treatment consists of antibiotics 
effective against penicillin-resistant staphylococci (dicloxacil
-
lin 500 mg orally every 6 hours or a cephalosporin for 
10–14 days) and regular emptying of the breast by nursing or 
by using a mechanical suction device. Although nursing of the 
infected breast is safe for the infant, local inflammation of the 
nipple may complicate latching. Failure to respond to usual 
antibiotics within 3 days may represent an organizing abscess 
or infection with a resistant organism. When the causative 
organism is methicillin-resistant 
S aureus
 (MRSA), the risk 
for abscess formation is increased when compared with infec
-
tion caused by nonresistant staphylococcal species. If an 
abscess is suspected, ultrasound of the breast can help confirm 
the diagnosis. In these cases, aspiration or surgical evacuation 
is usually required. Changing antibiotics based on culture 
sensitivity (to vancomycin or trimethoprim-sulfamethoxazole, 
for example) is useful, especially if the clinical course is not 
improving appropriately.
Dixon JM. Breast infection. BMJ. 2013 Dec 16;347:f3291. [PMID: 
24344239]
Sheffield JS. Methicillin-resistant 
 in 
obstetrics. Am J Perinatol. 2013 Feb;30(2):125–9. [PMID: 
23292915]
CHORIOAMNIONITIS & METRITIS
 
»
Fever not attributable to another source.
 
»
Uterine tenderness.
 
»
Tachycardia in the mother, fetus, or both.
 
»
Pelvic infections are relatively common problems encoun
-
tered during the peripartum period. Chorioamnionitis is 
an infection of the amnion and chorion (fetal parts), usu
-
ally occurring during labor. Uterine infection after delivery 
is often called endometritis or endomyometritis, but the 
term “metritis” is probably most accurate to emphasize that 
the infection extends throughout the uterine tissue. These 
infections are polymicrobial and are most commonly 
attributed to urogenital pathogens. The single most impor
-
tant risk factor for puerperal infection is cesarean delivery, 
which increases the risk from 5- to 20-fold. Other recog
-
nized risk factors include prolonged labor, use of internal 
monitors, nulliparity, multiple pelvic examinations, pro
-
longed rupture of membranes, and lower genital tract 
infections. Although maternal complications such as dys
-
functional labor and postpartum hemorrhage are increased 
with clinical chorioamnionitis, the principal reason to ini
-
tiate treatment is to prevent morbidity in the offspring. 
Neonatal complications such as sepsis, pneumonia, intra
-
ventricular hemorrhage, and cerebral palsy are increased 
in the setting of chorioamnionitis. Intrapartum initiation

-
in the setting of chorioamnionitis. Intrapartum initiation 
of antibiotics, however, significantly reduces neonatal 
morbidity.
 
»
Puerperal infections are diagnosed principally by the pres
-
ence of fever (38°C or higher) in the absence of any other 
source and one or more of the following signs: maternal or 
fetal tachycardia (or both), and uterine tenderness. Foul-
smelling lochia may be present, but is an insensitive marker 
of infection as many women without infection also expe
-
rience an unpleasant odor. Likewise, some life-threaten
-
ing infections such as necrotizing fasciitis are typically 
odorless. Cultures are typically not done because of the 
polymicrobial nature of the infection.
 
»
Treatment
Treatment is empiric with broad-spectrum antibiotics that 
will cover gram-positive and gram-negative organisms if 
still pregnant and gram-negative organisms and anaerobes 
if postpartum. A common regimen for chorioamnionitis is 
ampicillin, 2 g intravenously every 6 hours, and genta
-
micin, 2 mg/kg intravenous load then 1.5 mg/kg intrave
-
nously every 8 hours. A common regimen for metritis is 
gentamicin, 2 mg/kg intravenous load then 1.5 mg/kg 
intravenously every 8 hours, and clindamycin, 900 mg 
intravenously every 8 hours. Antibiotics are stopped in the 
mother when she has been afebrile for 24 hours. No oral 
antibiotics are subsequently needed. Patients with metritis 
who do not respond in the first 24–48 hours may have 
enterococcus and require additional gram-positive cover
-
age (such as ampicillin) to the regimen.
Higgins RD et al; Chorioamnionitis Workshop Participants. 
Evaluation and management of women and newborns with a 
maternal diagnosis of chorioamnionitis: summary of a work
-
shop. Obstet Gynecol. 2016 Mar;127(3):426–36. [PMID: 
26855098]
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Mackeen AD et al. Antibiotic regimens for postpartum endome
-
tritis. Cochrane Database Syst Rev. 2015 Feb 2;(2):CD001067. 
[PMID: 25922861]
 
º
M
e
DIC
a
L CONDI
t
IONS COM
p
LIC
a
t
ING 
pre
GN
a
NCY
ANEMIA
Normal pregnancy is characterized by an increase in 
maternal plasma volume of about 50% and an increase in 
red cell volume of about 25%. Because of these changes, the 
mean hemoglobin and hematocrit values are lower than in 
the nonpregnant state. Anemia in pregnancy is considered 
when the hemoglobin measurement is below 11 g/dL. By 
far, the most common causes are iron deficiency and acute 
blood loss anemia, the latter usually occurring in the peri
-
partum period. Symptoms such as fatigue and dyspnea that 
would otherwise suggest the presence of anemia in non
-
pregnant women are common in pregnant women; there
-
fore, periodic measurement of hematocrits in pregnancy is 
essential so that anemia can be identified and treated. In 
addition to its impact on maternal health, untoward preg
-
nancy outcomes such as low birthweight and preterm 
delivery have been associated with second- and third-
trimester anemia.
A. Iron Deficiency Anemia
The increased requirement for iron over the course of 
pregnancy is appreciable in order to support fetal growth 
and expansion of maternal blood volume. Dietary intake of 
iron is generally insufficient to meet this demand, and it is 
recommended that all pregnant women receive about 
 
30 mg of elemental iron per day in the second and third 
trimesters. Oral iron therapy is commonly associated with 
gastrointestinal side effects, such as nausea and constipa
-
tion, and these symptoms often contribute to noncompli
-
ance. If supplementation is inadequate, however, anemia 
often becomes evident by the third trimester of pregnancy. 
Because iron deficiency is by far the most common cause 
of anemia in pregnancy, treatment is usually empiric and 
consists of 60–100 mg of elemental iron per day and a diet 
containing iron-rich foods. Iron studies can confirm the 
diagnosis if necessary (see Chapter 13), and further evalu
-
ation should be considered in patients who do not respond 
to oral iron. Intermittent iron supplementation (eg, every 
other day) has been associated with fewer side effects and 
may be reasonable for women who cannot tolerate daily 
therapy.
B. Folic Acid Deficiency Anemia
Megaloblastic anemia in pregnancy is almost always caused 
by folic acid deficiency, since vitamin B
12
 deficiency is 
extremely uncommon in the childbearing years. Folate 
deficiency is usually caused by inadequate dietary intake of 
fresh leafy vegetables, legumes, and animal proteins.
The diagnosis is made by finding macrocytic red cells 
and hypersegmented neutrophils on a blood smear (see 
Chapter 13). However, blood smears in pregnancy may be 
difficult to interpret, since they frequently show iron defi
-
ciency changes as well. With established folate deficiency, a 
supplemental dose of 1 mg/day and a diet with increased 
folic acid is generally sufficient to correct the anemia.
C. Sickle Cell Anemia
Women with sickle cell anemia are subject to serious com
-
plications in pregnancy. The anemia becomes more severe, 
and acute pain crises often occur more frequently. When 
compared with women who do not have hemoglobinopa
-
thies, women with hemoglobin SS are at increased risk for 
infections (especially pulmonary and urinary tract), 
thromboembolic events, pregnancy-related hypertension, 
transfusion, cesarean delivery, preterm birth, and fetal 
growth restriction. There also continues to be an increased 
rate of maternal mortality, despite an increased recognition 
of the high-risk nature of these pregnancies. Intensive 
medical treatment may improve the outcomes for both 
mother and fetus. Prophylactically transfusing packed red 
cells to lower the level of hemoglobin S and elevate the level

cells to lower the level of hemoglobin S and elevate the level 
of hemoglobin A is a controversial practice without clear 
benefit. Most women with sickle cell disease will not 
require iron supplementation, but folate requirements can 
be appreciable due to red cell turnover from hemolysis.
D. Other Anemias
Although many of the inherited or acquired causes of 
anemia are relatively rare in women of childbearing age, 
they can be encountered in pregnancy. The implications 
for the mother and her offspring vary widely depending on 
the etiology of anemia. For example, mild microcytic ane
-
mia may be caused by iron deficiency, but it could also 
represent anemia of chronic disease as a result of previ
-
ously undiagnosed malignancy. As such, women who have 
anemia caused by a disorder besides a nutritional defi
-
ciency are best managed in conjunction with a maternal 
fetal medicine specialist and a hematologist. Additionally, 
women who have an inherited form of anemia (hemoglo
-
binopathies and thalassemia syndromes, for example) 
should be offered genetic counseling; prenatal diagnosis, if 
available, should be discussed if the parents wish to know 
whether the fetus is affected.
Practice Bulletin No. 95: Anemia in pregnancy. Obstet 
Gynecol. 2008 Jul;112(1):201–7. [Reaffirmed 2015] [PMID: 
18591330]
Boulet SL et al. Sickle cell disease in pregnancy: maternal com
-
plications in a Medicaid-enrolled population. Matern Child 
Health J. 2013 Feb;17(2):200–7. [PMID: 23315242]
Kumar KJ et al. Maternal anemia in various trimesters and its 
effect on newborn weight and maturity: an observational 
study. Int J Prev Med. 2013 Feb;4(2):193–9. [PMID: 23543625]
ANTIPHOSPHOLIPID SYNDROME
(See also Chapter 20.)
The antiphospholipid syndrome (APS) is characterized 
by the presence of specific autoantibodies in association with 
certain clinical conditions, most notably arterial and venous 
thrombosis and adverse pregnancy outcomes. Clinically, the 
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diagnosis can be suspected after any of the following out
-
comes: an episode of thrombosis, three or more unexplained 
consecutive spontaneous abortions prior to 10 weeks’ gesta
-
tion, one or more unexplained deaths of a morphologically 
normal fetus after 10 weeks’ gestation, or a preterm delivery 
at less than 34 weeks due to preeclampsia or placental insuf
-
ficiency. In addition to these clinical features, laboratory 
criteria include the identification of at least one of the fol
-
lowing three antiphospholipid antibodies: (1) the lupus 
anticoagulant, (2) anticardiolipin antibodies, or (3) anti-beta-
2-glycoprotein I antibodies. The lupus anticoagulant cannot 
be directly assayed, but it is tested for in several different 
phospholipid-dependent clotting tests and is interpreted as 
either present or absent. Anticardiolipin antibodies may be 
detected with enzyme-linked immunosorbent assay (ELISA) 
testing but should be considered diagnostic only when the 
IgG or IgM isotypes are present in medium to high titer 
 
(40 GPL or MPL, respectively). Likewise, anti-beta-
2-glycoprotein I antibodies are detected with ELISA, but 
should only be considered positive when they are present in 
a titer that is greater than 99th percentile for a normal 
population. The diagnosis of APS requires two positive 
antiphospholipid antibody test results at least 12 weeks apart 
since transient positive results can occur.
The optimal treatment for APS in pregnancy is unclear 
but generally involves administration of a heparin com
-
pound and low-dose aspirin (81 mg). Although anticoagu
-
lation is particularly prudent in women with a history of 
thrombosis, there is also evidence that this management 
reduces the risk for spontaneous abortion in women with 
recurrent pregnancy loss from APS. It is not clear whether 
continuation of therapy beyond the first trimester decreases 
the risk for stillbirth or placental dysfunction; however, 
treatment is typically continued through pregnancy and 
the early postpartum period for thromboprophylaxis. 
LMWH is also commonly used for this indication; how
-
ever, it is not clear that LMWH has the same effect on 
reducing the risk of recurrent abortion as unfractionated 
heparin. Either prophylactic or therapeutic dosing strate
-
gies may be appropriate depending on the patient’s history 
and clinical risk factors. The use of corticosteroids and 
intravenous immunoglobulin is of unclear benefit in these 
patients, and neither treatment is recommended.
American College of Obstetricians and Gynecologists. No. 132: 
Antiphospholipid syndrome. Obstet Gynecol. 2012 Dec;
 
120(6):1514–21. [Reaffirmed 2015] [PMID: 23168789]
de Jesus GR et al. 14th International Congress on Antiphospholipid 
Antibodies Task Force report on obstetric antiphospholipid 
syndrome. Autoimmun Rev. 2014 Aug;13(8):795–813. [PMID: 
24650941]
THYROID DISEASE
Thyroid disease is relatively common in pregnancy, and in 
their overt states, both hypothyroidism and hyperthyroid
-
ism have been consistently associated with adverse preg
-
nancy outcomes. Fortunately, these risks are mitigated by 
adequate treatment. It is essential to understand the gesta
-
tional age-specific effects that pregnancy has on thyroid 
function tests, since these biochemical markers are required 
to make the diagnosis of thyroid dysfunction. Failure to 
recognize these physiologic alterations can result in mis
-
classification or misdiagnosis. Women who have a history 
of a thyroid disorder or symptoms that suggest thyroid 
dysfunction should be screened with thyroid function 
tests. Screening asymptomatic pregnant women, however, 
is of unproven benefit and is not currently recommended.
Overt hypothyroidism
 is defined by an elevated serum 
TSH level with a depressed FT
4
 level. The condition in 
pregnancy has consistently been associated with an increase 
in complications such as spontaneous abortion, preterm

4
in complications such as spontaneous abortion, preterm 
birth, preeclampsia, placental abruption, and impaired 
neuropsychological development in the offspring. The 
most common etiology is Hashimoto (autoimmune) 
thyroiditis. Many of the symptoms of hypothyroidism 
mimic those of normal pregnancy, making its clinical iden
-
tification difficult. Initial treatment is empiric with oral 
levothyroxine started at 75–100 mcg/day. Thyroid function 
tests can be repeated at 4–6 weeks and the dose adjusted as 
necessary with the goal of normalizing the TSH level (pref
-
erably to a trimester-specific gestational reference range). 
An increase in the dose of levothyroxine may be required 
in the second and third trimesters.
Subclinical hypothyroidism
 is defined as an increased 
serum TSH with a normal FT
4
 level. Although some stud
-
ies have found associations with untoward pregnancy out
-
comes such as miscarriage, preterm birth, and preeclampsia, 
others have failed to confirm these findings. There is cur
-
rently no evidence, however, that identification and treat
-
ment of subclinical hypothyroidism will prevent any of 
these outcomes. Early observational studies also suggested 
that cognitive function was impaired in offspring of 
women with untreated subclinical hypothyroidism. Data 
from an NIH-sponsored Maternal-Fetal Medicine Units 
Network randomized, controlled trial, however, demon
-
strated no improvement in cognitive function of 5-year-
olds born to women screened and treated for subclinical 
hypothyroidism. For these reasons, the American College 
of Obstetricians and Gynecologists and the American 
Association of Clinical Endocrinologists recommend 
against universal screening for thyroid disease in 
Overt hyperthyroidism
, defined as excessive produc
-
tion of thyroxine with a depressed (usually undetectable) 
serum TSH level, is also associated with increased risks in 
pregnancy. Spontaneous abortion, preterm birth, pre
-
eclampsia, and maternal heart failure occur with increased 
frequency with untreated thyrotoxicosis. Thyroid storm, 
although rare, can be a life-threatening complication. 
Medical treatment of thyrotoxicosis is usually accom
-
plished with the antithyroid drugs propylthiouracil or 
methimazole. Although teratogenicity has not been clearly 
established, in utero exposure to methimazole has been 
associated with aplasia cutis and choanal and esophageal 
atresia in the offspring of pregnancies so treated. Propyl
-
thiouracil is not believed to be teratogenic, but it has been 
associated with the rare complications of hepatotoxicity 
and agranulocytosis. Recommendations by the American 
Thyroid Association are to treat with propylthiouracil in 
the first trimester and convert to methimazole for the 
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remainder of the pregnancy. The therapeutic target for the 
FT
4
 level is the upper limit of the normal reference range. 
The TSH levels generally stay suppressed even with ade
-
quate treatment. A beta-blocker can be used for such 
symptoms as palpitations or tremors. Fetal hypothyroidism 
or hyperthyroidism is uncommon but can occur with 
maternal Graves disease, which is the most common cause 
of hyperthyroidism in pregnancy. Radioiodine ablation is 
absolutely contraindicated in pregnancy because it may 
destroy the fetal thyroid as well.
Transient autoimmune thyroiditis
 can occur in the 
postpartum period and is evident within the first year after 
delivery. The first phase, occurring up to 4 months post
-
partum, is a hyperthyroid state. Over the next few months, 
there is a transition to a hypothyroid state, which may 
require treatment with levothyroxine. Spontaneous resolu
-
tion to a euthyroid state within the first year is the expected 
course; however, some women remain hypothyroid beyond 
this time (see Chapter 26).
Bulletin No. 148: Thyroid disease in pregnancy. Obstet 
Gynecol. 2015 Apr;125(4):996–1005. [Reaffirmed 2017] 
[PMID: 25798985]
Casey BM et al; Eunice Kennedy Shriver National Institute of 
Child Health and Human Development Maternal–Fetal 
Medicine Units Network. Treatment of subclinical hypothy
-
roidism or hypothyroxinemia in pregnancy. N Engl J Med. 
2017 Mar 2;376(9):815–25. [PMID: 28249134]
DIABETES MELLITUS
Normal pregnancy can be characterized as a state of 
increased insulin resistance that helps ensure a steady 
stream of glucose delivery to the developing fetus. Thus, 
both mild fasting hypoglycemia and postprandial hyper
-
glycemia are physiologic. These metabolic changes are felt 
to be hormonally mediated with likely contributions from 
human placental lactogen, estrogen, and progesterone.
A. Gestational Diabetes Mellitus
Gestational diabetes mellitus is abnormal glucose tolerance 
in pregnancy and is generally believed to be an exaggeration 
of the pregnancy-induced physiologic changes in carbohy
-
drate metabolism. Alternatively, pregnancy may unmask an 
underlying propensity for glucose intolerance, which will be 
evident in the nonpregnant state at some future time if not 
in the immediate postpartum period. Indeed, at least 50% of 
women with gestational diabetes are diagnosed with overt 
diabetes at some point in their lifetime. During the preg
-
nancy, the principal concern in women identified to have 
gestational diabetes is excessive fetal growth, which can 
result in increased maternal and perinatal morbidity. Shoul
-
der dystocia occurs more frequently in infants of diabetic 
mothers because of fetal overgrowth and increased fat 
deposition on the shoulders. Cesarean delivery and 
preeclampsia are also significantly increased in women 
with diabetes, both gestational and overt.
All asymptomatic pregnant women should undergo 
laboratory screening for gestational diabetes after 24 weeks’ 
gestation. The diagnostic thresholds for glucose tolerance 
Table 19–4.
 
Screening and diagnostic criteria for 
 
gestational diabetes mellitus.
Screening for gestational diabetes mellitus
1.
  
50-
g oral glucose load, administered between 24 and 28 weeks, 
without regard to time of day or time of last meal.
2.
 
V
enous plasma glucose measured 1 hour later.
3.
  
V
alue of 140 mg/dL (7.8 mmol/L) or above in venous plasma 
indicates the need for a diagnostic glucose tolerance test.
Diagnosis of gestational diabetes mellitus
1.
  
100-
g oral glucose load, administered in the morning after 
 
overnight fast lasting at least 8 hours but not more than 
 
14 hours, and following at least 3 days of unrestricted diet 
 
(> 150 g carbohydrate) and physical activity.
2.
  
V
enous plasma glucose is measured fasting and at 1, 2, and

2.
  
V
 
3 hours. Subject should remain seated and should not 
 
smoke throughout the test.
3.
  
T
he diagnosis of gestational diabetes is made when two or 
more of the following venous plasma concentrations are met 
or exceeded: fasting, 95 mg/dL (5.3 mmol/L); 1 hour, 180 mg/dL 
(10 mmol/L); 2 hours, 155 mg/dL (8.6 mmol/L); 3 hours, 
 
140 mg/dL (7.8 mmol/L).
tests in pregnancy are not universally agreed upon, and 
importantly, adverse pregnancy outcomes appear to occur 
along a continuum of glucose intolerance even if the diag
-
nosis of gestational diabetes is not formally assigned. A 
two-stage testing strategy is recommended by the American 
College of Obstetricians and Gynecologists, starting with 
a 50-g screening test offered to all pregnant women at 
24–28 weeks’ gestation. If this test is abnormal, the diagnos
-
tic test is a 100-g oral glucose tolerance test (Table 19–4).
Women in whom gestational diabetes is diagnosed 
should undergo nutrition counseling, and medications are 
typically initiated for those with persistent fasting hyper
-
glycemia. Insulin has historically been considered the 
standard medication used to achieve glycemic control. 
Oral hypoglycemic agents, principally glyburide and met
-
formin, have been evaluated in short-term clinical trials 
and appear to achieve similar degrees of glycemic control 
to insulin without increasing maternal or neonatal morbid
-
ity. These medications, however, have not been approved 
by the US Food and Drug Administration for this indica
-
tion, and the long-term safety of oral agents has not been 
adequately studied in the women so treated or in their 
offspring. The current standard of care, nonetheless, is that 
either insulin or oral agents are appropriate first-line ther
-
apy. Insulin regimens commonly include multiple daily 
injections of a split dose mix of intermediate-acting and 
short-acting agents. Regular and NPH insulins, as well as 
insulin lispro and aspart, do not cross the placenta. Once 
therapy is initiated, blood glucose surveillance is important 
to assess for adequacy of glycemic control. Capillary blood 
glucose levels should be checked four times per day, once 
fasting and three times after meals. Euglycemia is consid
-
ered to be 60–90 mg/dL (3.3–5.0 mmol/L) while fasting 
and less than 120 mg/dL (6.7 mmol/L) 2 hours postprandi
-
ally. Intensive therapy with dietary modifications or insulin 
therapy, or both, has been demonstrated to decrease rates 
of macrosomia, shoulder dystocia, and preeclampsia. 
Because of the increased prevalence of overt diabetes in 
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women identified to have gestational diabetes, they should 
be screened at 6–12 weeks’ postpartum with a fasting 
plasma glucose test or a 2-hour oral glucose tolerance test 
(75-g glucose load).
B. Overt Diabetes Mellitus
Overt diabetes is diabetes mellitus that antedates the 
pregnancy. As in gestational diabetes, fetal overgrowth 
from inadequately controlled hyperglycemia remains a 
significant concern because of the increased maternal 
and perinatal morbidity that accompany macrosomia. 
Women with overt diabetes are subject to a number of 
other complications as well. Spontaneous abortions and 
third trimester stillbirths occur with increased fre
-
quency in these women. There is also at least a twofold 
to threefold increased risk for fetal malformations, as 
hyperglycemia during organogenesis is teratogenic. The 
most common malformations in offspring of diabetic 
women are cardiac, skeletal, and neural tube defects. For 
the mother, the likelihood of infections and pregnancy-
related hypertension is increased.
Preconception counseling and evaluation in a diabetic 
woman is ideal to maximize the pregnancy outcomes. This 
provides an opportunity to optimize glycemic control and 
evaluate for evidence of end-organ damage. The initial 
evaluation of diabetic women should include a complete 
chemistry panel, HbA
1c
 determination, 24-hour urine col
-
lection for total protein and creatinine clearance, fundu
-
scopic examination, and an ECG. Hypertension is common 
and may require treatment. Optimally, euglycemia should 
be established before conception and maintained during 
pregnancy with daily home glucose monitoring by the 
patient. There is an inverse relationship between glycemic 
control and the occurrence of fetal malformations, and 
women whose periconceptional glycosylated hemoglobin 
levels are at or near normal levels have rates of malforma
-
tions that approach baseline. A well-planned dietary 
program is a key component, with an intake of 1800–
2200 kcal/day divided into three meals and three snacks. 
Insulin is given subcutaneously in a split-dose regimen as 
described above for women with gestational diabetes. 
The use of continuous insulin pump therapy may be help
-
ful for some patients.
Throughout the pregnancy, diabetic women should 
be seen every 2–3 weeks and more frequently depending 
on the clinical condition. Adjustments in the insulin regi
-
men may be necessary as the pregnancy progresses to 
maintain optimal glycemic control. A specialized ultra
-
sound is often performed around 20 weeks to screen for 
fetal malformations. Symptoms and signs of infections 
should be evaluated and promptly treated. In the third 
trimester, fetal surveillance is indicated, and women with 
diabetes should receive serial antenatal testing (usually in 
the form of a nonstress test or biophysical profile). The 
timing of delivery is dictated by the quality of diabetic 
control, the presence or absence of medical complications, 
and fetal status. The goal is to reach 39 weeks (38 completed 
weeks) and then proceed with delivery. Confirmation of 
lung maturity may be appropriate if preterm delivery is 
contemplated.
Bulletin No. 60. Pregestational diabetes mellitus. Obstet 
Gynecol. 2005 Mar;105(3):675–85. [Reaffirmed 2016] 
[PMID: 15738045]
Bulletin No. 180: Gestational diabetes mellitus. Obstet 
Gynecol. 2017 Jul;130(1):e17–37. [PMID: 28644336]
Moyer V A et al. Screening for gestational diabetes mellitus: U.S. 
Preventive Services Task Force recommendation statement. 
Ann Intern Med. 2014 Mar 18;160(6):414–20. [PMID: 
24424622]
CHRONIC HYPERTENSION
Chronic hypertension is estimated to complicate up to 5% 
of pregnancies. To establish this diagnosis, hypertension 
should antedate the pregnancy or be evident before 
 
20 weeks’ gestation to differentiate it from pregnancy-

related hypertension. This distinction can be problematic 
when the initial presentation is after 20 weeks, but chronic 
hypertension is confirmed if the blood pressure remains 
elevated beyond 12 weeks’ postpartum. Risk factors for 
chronic hypertension include older maternal age, African- 
American race, and obesity. While essential hypertension 
is by far the most common cause, secondary causes should 
be sought when clinically indicated.
Women with chronic hypertension are at increased risk 
for adverse maternal and perinatal outcomes. Superim
-
posed preeclampsia develops in up to 20% of women with 
mild hypertension, but the risk increases up to 50% when 
there is severe baseline hypertension (160/110 mm Hg or 
higher) and may be even higher when there is evidence of 
end-organ damage. When preeclampsia is superimposed 
on chronic hypertension, there is a tendency for it to occur 
at an earlier gestational age, be more severe, and impair 
fetal growth. Women with chronic hypertension are also at 
increased risk for placental abruption, cesarean delivery, 
preterm birth, and perinatal mortality.
Ideally, women with chronic hypertension should 
undergo a preconceptional evaluation to detect end-organ 
damage, assess the need for antihypertensive therapy, and 
discontinue teratogenic medications. The specific tests 
ordered may vary depending on the severity of the hyper
-
tensive disorder, but an evaluation of kidney and cardiac 
function (eg, 24-hour urine protein and maternal echocar
-
diogram if mother takes medications) is appropriate.
If the woman is not known to have chronic hyperten
-
sion, then initiation of antihypertensive therapy in preg
-
nant women is indicated only if the blood pressure is 
sustained at or above 160/105 mm Hg or if there is evi
-
dence of end-organ damage. Treatment of hypertension 
has not been demonstrated to improve pregnancy out
-
comes, but it is indicated in women with significant hyper
-
tension for long-term maternal cardiovascular health. 
Although methyldopa has the longest record of safety in 
pregnancy, nifedipine and labetalol are also acceptable, and 
these three agents are recommended above all others when 
initiating therapy in pregnancy. Care must be taken not to 
excessively reduce the blood pressure, as this may decrease 
uteroplacental perfusion. The goal is a modest reduction in 
blood pressure and avoidance of severe hypertension.
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If a woman with mild chronic hypertension is stable on 
a medical regimen when she becomes pregnant, it is usu
-
ally appropriate to continue this therapy, although the 
benefits of doing so are not well established. Angiotensin-
converting enzyme (ACE) inhibitors and angiotensin 
receptor blockers, however, are contraindicated in all tri
-
mesters of pregnancy. These medications are teratogenic in 
the first trimester and cause fetal hypocalvaria and acute 
kidney injury in the second and third trimesters.
When there is sustained severe hypertension despite 
multiple medications or significant end-organ damage from 
hypertensive disease, pregnancy is not likely to be tolerated 
well. In these situations, therapeutic abortion may be appro
-
priate. If the pregnancy is continued, the woman must be 
counseled that the maternal and perinatal risks are appre
-
ciable, and complications such as superimposed preeclamp
-
sia and fetal growth restriction should be anticipated.
Abalos E et al. Antihypertensive drug therapy for mild to moder
-
ate hypertension during pregnancy. Cochrane Database Syst 
Rev. 2014 Feb 6;2:CD002252. [PMID: 24504933]
American College of Obstetricians and Gynecologists; Task 
Force on Hypertension in Pregnancy. Hypertension in preg
-
nancy. Obstet Gynecol. 2013 Nov;122(5):1122–31. [PMID: 
24150027]
Bramham K et al. Chronic hypertension and pregnancy outcomes: 
systematic review and meta-analysis. BMJ. 2014 Apr 15;348:g2301. 
[PMID: 24735917]
Normal pregnancy physiology is characterized by cardio
-
vascular adaptations in the mother. Cardiac output increases 
markedly as a result of both augmented stroke volume and 
an increase in the resting heart rate, and the maternal blood 
volume expands by up to 50%. These changes may not be 
tolerated well in women with functional or structural 
abnormalities of the heart. Thus, although only a small 
number of pregnancies are complicated by cardiac disease, 
these contribute disproportionately to overall rates of 
maternal morbidity and mortality. Most cardiac disease in 
women of childbearing age in the United States is caused by 
congenital heart disease. Ischemic heart disease, however, is 
being seen more commonly in pregnant women due to 
increasing rates of comorbid conditions, such as diabetes 
mellitus, hypertension, and obesity.
For practical purposes, the best single measurement of 
cardiopulmonary status is defined by the New Y ork Heart 
Association Functional Classification. Most pregnant 
women with cardiac disease have class I or II functional 
disability, and although good outcomes are generally 
anticipated in this group, complications such as preeclamp
-
sia, preterm birth, and low birth weight appear to occur 
with increased frequency. Women with more severe dis
-
ability (class III or IV) are rare in contemporary obstetrics; 
however, the maternal mortality is markedly increased in 
this setting and is usually the result of heart failure. Because 
of these risks, therapeutic abortion for maternal health 
should be considered in women who are severely disabled 
from cardiac disease. Specific conditions that have been 
associated with a particularly high risk for maternal death 
include Eisenmenger syndrome, primary pulmonary 
hypertension, Marfan syndrome with aortic root dilata
-
tion, and severe aortic or mitral stenosis. In general, these 
conditions should be considered contraindications to 
The importance of preconceptional counseling for 
women with heart disease cannot be overstated. A thor
-
ough evaluation prior to pregnancy provides an opportu
-
nity for comprehensive risk assessment and detailed 
planning. Once pregnant, women with cardiac disease are 
best treated by a team of practitioners with experience in 
caring for such patients. Heart failure is the most common 
cardiovascular complication associated with heart disease

cardiovascular complication associated with heart disease 
in pregnancy, and adverse maternal and fetal outcomes 
are increased when heart failure occurs. Symptoms of 
volume overload should therefore be evaluated and treated 
promptly. Labor management depends on the underlying 
cardiac lesion and the degree of disability. Cesarean deliv
-
ery is generally reserved for obstetric indications but may 
be appropriate for women in whom Valsalva maneuvers are 
contraindicated. The early postpartum period is a critical 
time for fluid management. Patients who are predisposed 
to heart failure should be monitored closely during the 
puerperium.
Infective endocarditis prophylaxis is not recommended 
for a vaginal or cesarean delivery in the absence of infec
-
tion, except in the very small subset of patients at highest 
risk for adverse outcomes from endocarditis. The women 
at highest risk include those with cyanotic heart disease, 
prosthetic valves, or both. If infection is present, such as 
chorioamnionitis, the underlying infection should be 
treated with the usual regimen and additional agents are 
not needed specifically for endocarditis prophylaxis. 
Prophylaxis, if required, should be given intravenously 
(see Table 33–5).
Bulletin No. 120: Use of prophylactic antibiotics in labor and 
delivery. Obstet Gynecol. 2011 Jun;117(6):1472–83. [PMID: 
21606770]
Brickner ME. Cardiovascular management in pregnancy: 
congenital heart disease. Circulation. 2014 Jul 15;130(3):273–82. 
Ruys TP et al. Heart failure in pregnant women with cardiac 
disease: data from the ROPAC. Heart. 2014 Feb;100(3):231–8. 
[PMID: 24293523]
ASTHMA
(See also Chapter 9.)
Asthma is one of the most common medical conditions 
encountered in pregnancy. Women with mild to moderate 
asthma can generally expect excellent pregnancy out
-
comes, but severe or poorly controlled asthma has been 
associated with a number of pregnancy complications, 
including preterm birth, small-for-gestational-age infants, 
and preeclampsia. The effects of pregnancy on asthma are 
likely minimal as asthma severity in the pregnancy has 
been reported to be similar to its severity during the year 
preceding the pregnancy. Strategies for treatment are simi
-
lar to those in nonpregnant women. Patients should be 
educated about symptom management and avoidance of 
asthma triggers. Baseline pulmonary function tests can 
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provide an objective assessment of lung function and may 
help the patient with self-monitoring of her asthma sever
-
ity using a peak flow meter. As in nonpregnant women, 
treatment algorithms generally follow a stepwise approach, 
and commonly used medications, particularly those for 
mild to moderate asthma symptoms, are generally consid
-
ered safe in pregnancy. Concerns about teratogenicity and 
medication effects on the fetus should be thoroughly dis
-
cussed with the patient to decrease noncompliance rates. 
Inhaled beta-2-agonists are indicated for all asthma 
patients, and low to moderate dose inhaled corticosteroids 
are added for persistent symptoms when a rescue inhaler 
alone is inadequate. Systemic corticosteroid administration 
is reserved for severe exacerbations but should not be 
withheld, if indicated, irrespective of gestational age. The 
primary goals of management in pregnancy include mini
-
mizing symptoms and avoiding hypoxic episodes to the 
fetus. Prostaglandin F2a and ergonovine—medications 
frequently used to treat postpartum uterine atony—should 
be avoided because they can precipitate bronchospasm in 
women with asthma.
Bulletin No. 90: Asthma in pregnancy. Obstet Gynecol. 2008 Feb;
 
111 (2 Pt 1):457–64. [Reaffirmed 2014] [PMID: 18238988]
Gregersen TL et al. Safety of bronchodilators and corticosteroids 
for asthma during pregnancy: what we know and what we 
need to do better. J Asthma Allergy. 2013 Nov 15;6:117–25. 
[PMID: 24259987]
McCallister JW . Asthma in pregnancy: management strate
-
gies. Curr Opin Pulm Med. 2013 Jan;19(1):13–7. [PMID: 
23154712]
SEIZURE DISORDERS
Epilepsy is one of the most common serious neurologic 
disorders in pregnant women. Many of the commonly used 
antiepileptic drugs are known human teratogens. There
-
fore, the principal objectives in managing pregnancy in 
epileptic women are achieving adequate control of seizures 
while minimizing exposure to medications that can cause 
congenital malformations. Certain women who are con
-
templating pregnancy and have been seizure-free for 
2–5 years may be considered candidates for discontinua
-
tion of antiseizure medication prior to pregnancy. For 
those who continue to require treatment, however, therapy 
with one medication is preferred. Selecting a regimen 
should be based on the type of seizure disorder and the 
risks associated with each medication. Valproic acid should 
not be considered first-line therapy because it has consis
-
tently been associated with higher rates of fetal malforma
-
tions than most other commonly used antiepileptic drugs, 
and it may be associated with impaired neurocognitive 
development in the offspring. Phenytoin and carbamaze
-
pine both have established patterns of associated fetal 
malformations. Concerns about teratogenicity have 
prompted increasing use of the newer antiepileptic drugs 
such as lamotrigine, topiramate, oxcarbazepine, and leveti
-
racetam. Although the safety of these medications in preg
-
nancy continues to be evaluated, experiences from ongoing 
registries and large, population-based studies suggest that 
in utero exposure to the newer antiepileptic drugs in the 
first trimester of pregnancy carries a lower risk of major 
malformations than older medications. Lamotrigine and 
levetiracetam appear to be the least teratogenic. Although 
it is recommended that pregnant women with epilepsy be 
given supplemental folic acid, it is unclear if supplemental 
folate decreases rates of fetal malformations in women tak
-
ing anticonvulsant therapy.
Patel SI et al. Management of epilepsy during pregnancy: an update. 
Ther Adv Neurol Disord. 2016 Mar;9(2):118–29. [PMID: 
27006699]
Shallcross R et al; Liverpool and Manchester Neurodevelopment 
Group; UK Epilepsy and Pregnancy Register. In utero exposure 
to levetiracetam vs valproate: development and language at

27006699]
to levetiracetam vs valproate: development and language at 
 
3 years of age. Neurology. 2014 Jan 21;82(3):213–21. [PMID: 
24401687]
 
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INF
e
C
t
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URINARY TRACT INFECTION
The urinary tract is especially vulnerable to infections dur
-
ing pregnancy because the altered secretions of steroid sex 
hormones and the pressure exerted by the gravid uterus on 
the ureters and bladder cause hypotonia and congestion 
and predispose to urinary stasis. Labor and delivery and 
urinary retention postpartum also may initiate or aggra
-
vate infection. 
 is the offending organism in 
over two-thirds of cases.
From 2% to 8% of pregnant women have asymptomatic 
bacteriuria, which some believe to be associated with an 
increased risk of preterm birth. It is estimated that pyelone
-
phritis will develop in 20–40% of these women if untreated.
An evaluation for asymptomatic bacteriuria at the first 
prenatal visit is recommended for all pregnant women. If a 
urine culture is positive, treatment should be initiated. 
Nitrofurantoin (100 mg orally twice daily), ampicillin 
(250 mg orally four times daily), and cephalexin (250 mg 
orally four times daily) are acceptable medications for 
4–7 days. Sulfonamides should be avoided in the third tri
-
mester because they may interfere with bilirubin binding 
and thus impose a risk of neonatal hyperbilirubinemia and 
kernicterus. Fluoroquinolones are also contraindicated 
because of their potential teratogenic effects on fetal carti
-
lage and bone. Patients with recurrent bacteriuria should 
receive suppressive medication (once daily dosing of an 
appropriate antibiotic) for the remainder of the pregnancy. 
Acute pyelonephritis requires hospitalization for intravenous 
administration of antibiotics and crystalloids until the patient 
is afebrile; this is followed by a full course of oral antibiotics.
Glaser AP et al. Urinary tract infection and bacteriuria in preg
-
nancy. Urol Clin North Am. 2015 Nov;42(4):547–60. [PMID: 
26475951]
GROUP B STREPTOCOCCAL INFECTION
Group B streptococci frequently colonize the lower 
female genital tract, with an asymptomatic carriage rate 
in pregnancy of 10–30%. This rate depends on maternal 
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age, gravidity, and geographic variation. Vaginal carriage 
is asymptomatic and intermittent, with spontaneous 
clearing in approximately 30% and recolonization in 
about 10% of women. Adverse perinatal outcomes associ
-
ated with group B streptococcal colonization include 
urinary tract infection, intrauterine infection, premature 
rupture of membranes, preterm delivery, and postpartum 
metritis.
Women with postpartum metritis due to infection with 
group B streptococci, especially after cesarean section, 
develop fever, tachycardia, and abdominal pain, usually 
within 24 hours after delivery. Approximately 35% of these 
women are bacteremic.
Group B streptococcal infection is a common cause of 
neonatal sepsis. Transmission rates are high, yet the rate of 
neonatal sepsis is surprisingly low at less than 1:1000 live 
births. Unfortunately, the mortality rate associated with 
early-onset disease can be as high as 20–30% in premature 
infants. In contrast, it is approximately 2–3% in those at 
term. Moreover, these infections can contribute markedly 
to chronic morbidity, including mental retardation and 
neurologic disabilities. Late-onset disease develops through 
contact with hospital nursery personnel. Up to 45% of 
these health care workers can carry the bacteria on their 
skin and transmit the infection to newborns.
CDC recommendations for screening and prophy
-
laxis for group B streptococcal colonization are set forth 
above (see Essentials of Prenatal Care: Tests and 
Procedures).
Ohlsson A et al. Intrapartum antibiotics for known maternal 
group B streptococcal colonization. Cochrane Database Syst 
Rev. 2014 Jun 10;6:CD007467. [PMID: 24915629]
Verani JR et al; Division of Bacterial Diseases, National Center 
for Immunization and Respiratory Diseases, Centers for 
Disease Control and Prevention (CDC). Prevention of perinatal 
group B streptococcal disease—revised guidelines from CDC, 
2010. MMWR Recomm Rep. 2010 Nov 19;59(RR-10):1–36. 
[PMID: 21088663]
VARICELLA
Commonly known as chickenpox, varicella-zoster virus 
(VZV) infection has a fairly benign course when incurred 
during childhood but may result in serious illness in adults, 
particularly during pregnancy. Infection results in lifelong 
immunity. Approximately 95% of women born in the 
United States have VZV antibodies by the time they reach 
reproductive age. The incidence of VZV infection during 
pregnancy has been reported as up to 7:10,000.
 
»
The incubation period for this infection is 10–20 days. 
 
A primary infection follows and is characterized by a flu-
like syndrome with malaise, fever, and development of a 
pruritic maculopapular rash on the trunk, which becomes 
vesicular and then crusts. Pregnant women are prone to the 
development of VZV pneumonia, often a fulminant infec
-
tion sometimes requiring respiratory support. After pri
-
mary infection, the virus becomes latent, ascending to 
dorsal root ganglia. Subsequent reactivation can occur as 
zoster, often under circumstances of immunocompromise, 
although this is rare during pregnancy.
Two types of fetal infection have been documented. 
The first is congenital VZV syndrome, which typically 
occurs in 0.4–2% of fetuses exposed to primary VZV 
infection during the first trimester. Anomalies include 
limb and digit abnormalities, microphthalmos, and 
microcephaly.
Infection during the second and third trimesters is less 
threatening. Maternal IgG crosses the placenta, protecting 
the fetus. The only infants at risk for severe infection 
are those born after maternal viremia but before develop
-
ment of maternal protective antibody. Maternal infection 
manifesting 5 days before or up to 2 days after delivery is 
the time period believed to be most hazardous for trans
-
mission to the fetus.
Diagnosis is commonly made on clinical grounds. Labora
-

-
-
tory verification is made by ELISA, fluorescent antibody, 
and hemagglutination inhibition antibody techniques. 
Serum obtained by cordocentesis may be tested for VZV 
IgM to document fetal infection.
 
»
Treatment
Varicella-zoster immune globulin (VZIG) has been shown 
to prevent or modify the symptoms of infection in exposed 
persons. Treatment success depends on identification of 
susceptible women at or just following exposure. Exposed 
women with a questionable or negative history of chicken
-
pox should be checked for antibody, since the overwhelm
-
ing majority will have been previously exposed. If the 
antibody is negative, VZIG (625 units intramuscularly) 
should ideally be given within 96 hours of exposure for 
greatest efficacy, but the CDC reports it can be given for up 
to 10 days. There are no known adverse effects of VZIG 
administration during pregnancy, although the incubation 
period for disease can be lengthened. Infants born to 
women in whom symptoms develop in the period from 
 
5 days before delivery to 2 days after delivery should also 
receive VZIG (125 units).
Pregnant women with varicella may benefit from treat
-
ment with oral acyclovir if started within 24 hours of rash 
onset. Treatment has been shown to improve maternal 
symptoms but does not prevent congenital varicella. 
Infected pregnant women should be closely observed and 
hospitalized at the earliest signs of pulmonary involve
-
ment. Intravenous acyclovir (10 mg/kg intravenously every 
8 hours) is recommended in the treatment of VZV 
pneumonia.
Practice Bulletin No. 151: Cytomegalovirus, parvovirus B19, 
varicella zoster, and toxoplasmosis in pregnancy. Obstet 
Gynecol. 2015 Jun;125(6):1510–25. [PMID: 26000539]
recommendations for use of VariZIG—United States, 2013. 
MMWR Morb Mortal Wkly Rep. 2013 July 19;62(28):574–6. 
[PMID: 23863705]
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TUBERCULOSIS
The diagnosis of tuberculosis in pregnancy is made by his
-
tory taking, physical examination, and testing, with special 
attention to women in high-risk groups. Women at high risk 
include those who are from endemic areas, those infected 
with HIV , drug users, health care workers, and close contacts 
of people with tuberculosis. Chest radiographs should not be 
obtained as a routine screening measure in pregnancy but 
should be used only in patients with a positive test or with 
suggestive findings in the history and physical examination. 
Abdominal shielding must be used if a chest radiograph is 
obtained. Both tuberculin skin testing and interferon gamma 
release assays are acceptable tests in pregnancy.
Decisions on treatment depend on whether the patient 
has active disease or is at high risk for progression to active 
disease. Pregnant women with latent disease not at high 
risk for disease progression can receive treatment postpar
-
tum, which does not preclude breastfeeding. The concen
-
tration of medication in breast milk is neither toxic nor 
adequate for treatment of the newborn. Treatment is 
with isoniazid and ethambutol or isoniazid and rifampin 
(see Chapters 9 and 33). Because isoniazid therapy may 
result in vitamin B
6
 deficiency, a supplement of 50 mg/day 
6
 should be given simultaneously. There is 
concern that isoniazid, particularly in pregnant women, 
can cause hepatitis. Liver biochemical tests should be per
-
formed regularly in pregnant women who receive treat
-
ment. Streptomycin, ethionamide, and most other 
antituberculous drugs should be avoided in pregnancy. If 
adequately treated, tuberculosis in pregnancy has an excellent 
susceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63 (7):
 
HIV/AIDS DURING PREGNANCY
Asymptomatic HIV infection is associated with a normal 
pregnancy rate and no increased risk of adverse pregnancy 
outcomes. There is no evidence that pregnancy causes 
AIDS progression.
Previously, two-thirds of HIV-positive neonates acquired 
their infection close to, or during, the time of delivery. Rou
-
tine HIV screening in pregnancy, including the use of rapid 
HIV tests in Labor and Delivery units, and the use of anti
-
retroviral drugs has markedly reduced this transmission 
risk to approximately 2%. In an HIV-positive pregnant 
woman, a CD4 count, plasma RNA level, and resistance 
testing (if virus is detectable, and the patient has not already 
had this) should be obtained at the first prenatal visit. Treat
-
ment should not be delayed while waiting for the results of 
resistance testing. Prior or current antiretroviral use should 
be reviewed. A woman already taking and tolerating an 
acceptable antiretroviral regimen does not have to discon
-
tinue it in the first trimester. Patients should also be 
tested for hepatitis C, tuberculosis, toxoplasmosis, and 
cytomegalovirus.
Women not taking medication should be offered combi
-
nation antiretroviral therapy (commonly a dual nucleoside 
reverse transcriptase inhibitor combination and a ritonavir-
boosted protease inhibitor) after counseling regarding the 
potential impact of therapy on both mother and fetus. Anti
-
retroviral therapy should be offered regardless of viral load 
and CD4 count. Whether to start in the first or second tri
-
mester should be determined on a case-by-case basis, but it 
should be started as early as reasonably possible. It can be 
started in the first trimester after explanation of risks and 
benefits, provided the mother is not experiencing nausea 
and vomiting. The majority of drugs used to treat HIV/
AIDS have thus far proven to be safe in pregnancy with an 
acceptable risk/benefit ratio. Efavirenz has been linked with

acceptable risk/benefit ratio. Efavirenz has been linked with 
a small increase in anomalies (myelomeningocele) and 
should not be used in the first trimester of pregnancy. How
-
ever, efavirenz does not need to be discontinued if a virologi
-
caly suppressed patient becomes pregnant while taking it. 
Standard of care also includes administration of intravenous 
zidovudine prior to cesarean delivery and during the surgery 
in women whose viral load near delivery is greater than or 
equal to 1000 copies/mL or unknown. Antiretroviral therapy 
on the patient’s usual schedule should be continued in labor. 
Intravenous zidovudine is not required for antiretroviral 
therapy-compliant women with a suppressed viral load.
The use of prophylactic elective cesarean section at 
 
38 weeks (before the onset of labor or rupture of the mem
-
branes) to prevent vertical transmission of HIV infection 
from mother to fetus has been shown to further reduce the 
transmission rate. In patients with a viral load of less than 
1000 copies/mL, there may be no additional benefit of 
cesarean delivery, and those women can be offered a vagi
-
nal delivery. Amniotomy should not be performed in the 
setting of viremia unless there is a clear obstetric indica
-
tion. Amniotomy has not been associated with an increased 
risk of perinatal transmission when the mother is receiving 
antiretroviral therapy and virologically suppressed. Inter
-
nal monitors, particularly the fetal scalp electrode, should 
be avoided. Methergine (used for postpartum hemorrhage) 
should be avoided in patients receiving certain regimens. 
HIV-infected women should be advised not to breastfeed 
their infants.
The Public Health Task Force provides guidelines for 
the management of HIV/AIDS in pregnancy that are regu
-
larly updated and available at http://www.aidsinfo.nih.gov. 
In addition, there is the National Perinatal HIV Hotline, 
which provides free consultation regarding perinatal HIV 
care (1-888-448-8765).
Panel on Treatment of HIV-Infected Pregnant Women and Pre
-
vention of Perinatal Transmission. Recommendations for use 
of antiretroviral drugs in pregnant HIV-1 infected women 
for maternal health and interventions to reduce perinatal 
HIV transmission in the United States. 2017 Nov 14. https://
aidsinfo.nih.gov/ContentFiles/lvguidelines/PerinatalGL.pdf
MATERNAL HEPATITIS B & C CARRIER STATE
There are an estimated 350 million chronic carriers of 
hepatitis B virus
 worldwide (see also Chapter 1). In the 
United States, 1.4 million people are infected, with the 
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highest rate among Asian Americans. All pregnant women 
should be screened for HBsAg. Transmission of the virus to 
the baby after delivery is likely if both surface antigen and 
e antigen are positive. Vertical transmission can be blocked 
by the immediate postdelivery administration to the new
-
born of hepatitis B immunoglobulin and hepatitis B 
vaccine intramuscularly. The vaccine dose is repeated at 
 
1 and 6 months of age. Third trimester administration of 
tenofovir disoproxil fumarate (first line), lamivudine, or 
telbivudine to women with a viral load of greater than 
10
6
–10
8
 copies/mL has been shown to reduce vertical 
transmission particularly if the viral load is less than 10
6
 
copies/mL at delivery. This therapy appears safe in preg
-
nancy although long-term follow-up data are lacking. 
Pregnant women with chronic hepatitis B should have liver 
biochemical tests and viral load testing during the preg
-
nancy. Hepatitis B infection is not a contraindication to 
breastfeeding, and antiviral therapy if given does not need 
to be continued postpartum.
Hepatitis C virus
 infection is the most common 
chronic blood-borne infection in the United States. The 
average rate of hepatitis C virus (HCV) infection among 
infants born to HCV-positive, HIV-negative women is 
5–6%. However, the average infection rate increases to 
10–11% when mothers are coinfected with HCV and HIV . 
The principal factor associated with transmission is the 
presence of HCV RNA in the mother at the time of birth. 
Treatment is not recommended in pregnancy. Interferon 
and ribavirin have been considered contraindicated. 
Ledipasvir/sofosbuvir (Harvoni) has been shown to be safe 
in animal studies, but there are no human studies on safety 
or efficacy at reducing vertical transmission.
Pan CQ et al; China Study Group for the Mother-to-Child 
Transmission of Hepatitis B. Tenofovir to prevent hepatitis B 
transmission in mothers with high viral load. N Engl J Med. 
2016 Jun 16;374(24):2324–34. [PMID: 27305192]
Society for Maternal-Fetal Medicine (SMFM). Hepatitis C in 
pregnancy: screening, treatment, and management. Am J 
Obstet Gynecol. 2017 Nov;217(5):B2–12. [PMID: 28782502]
HERPES GENITALIS
Infection of the lower genital tract by herpes simplex virus 
type 2 (HSV-2) (see also Chapter 6) is a common STD with 
potentially serious consequences to pregnant women and 
their newborn infants. Although up to 20% of women in an 
obstetric practice may have antibodies to HSV-2, a history 
of the infection is unreliable and the incidence of neonatal 
infection is low (10–60/100,000 live births). Most infected 
neonates are born to women with no history, symptoms, or 
signs of infection.
Women who have had 
primary
 herpes infection late in 
pregnancy are at high risk for shedding virus at delivery. 
Some experts suggest use of prophylactic acyclovir, 400 mg 
orally three times daily, to decrease the likelihood of active 
lesions at the time of labor and delivery.
Women with a history of 
recurrent
 genital herpes have 
a lower neonatal attack rate than women infected during 
the pregnancy, but they should still be monitored with 
clinical observation and culture of any suspicious lesions. 
Since asymptomatic viral shedding is not predictable by 
antepartum cultures, current recommendations do not 
include routine cultures in individuals with a history of 
herpes without active disease. However, when labor begins, 
vulvar and cervical inspection should be performed. Cesar
-
ean delivery is indicated at the time of labor if there are 
prodromal symptoms or active genital lesions.
For treatment, see Chapter 32. The use of acyclovir in 
pregnancy is acceptable, and prophylaxis starting at 
 
36 weeks’ gestation has been shown to decrease the number 
of cesarean sections performed for active disease.
Stephenson-Famy A et al. Herpes simplex virus infection during

Stephenson-Famy A et al. Herpes simplex virus infection during 
pregnancy. Obstet Gynecol Clin North Am. 2014 Dec;41(4):
 
601–14. [PMID: 25454993]
SYPHILIS, GONORRHEA, & 
 
CHLAMYDIA TRACHOMATIS
 INFECTION
These STDs have significant consequences for mother and 
child (see also Chapters 33 and 34). Untreated syphilis in 
pregnancy can cause late abortion, stillbirth, transplacental 
infection, and congenital syphilis. Gonorrhea can produce 
large-joint arthritis by hematogenous spread as well as 
ophthalmia neonatorum. Maternal chlamydial infections 
are largely asymptomatic but are manifested in the new
-
born by inclusion conjunctivitis and, at age 2–4 months, by 
pneumonia. The diagnosis of each can be reliably made by 
appropriate laboratory tests. All women should be tested 
for syphilis and 
 as part of their routine pre
-
natal care. Repeat testing is dependent on risk factors, 
prevalence, and state laws. A pregnant patient treated for 
 should have a test of cure 3–4 weeks later 
and then 3 months after that because of high reinfection 
rates. Women at risk should be tested for gonorrhea. The 
sexual partners of women with STDs should be identified 
and treated also if possible; the local health department can 
assist with this process.
 
º
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Complications involving the gastrointestinal tract, liver, 
and gallbladder are common in pregnancy. Nausea and 
vomiting in the first trimester affect the majority of preg
-
nant women to some degree (see Obstetric Complications 
of the First & Second Trimesters). Nausea and vomiting in 
the last half of pregnancy, however, are never normal; a 
thorough evaluation of such complaints is mandatory. 
Some of these conditions are incidental to pregnancy 
(eg, appendicitis), while others are related to the gravid 
state and tend to resolve with delivery (eg, acute fatty liver 
of pregnancy). Importantly, the myriad anatomic and 
physiologic changes associated with normal pregnancy 
must be considered when assessing for a disease state. 
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Likewise, interpretation of laboratory studies must take 
into account the pregnancy-associated changes in hepatic 
protein production.
For conditions in which surgery is clinically indicated, 
operative intervention should never be withheld based solely 
on the fact that a woman is pregnant. While purely elective 
surgery is avoided during pregnancy, women who undergo 
surgical procedures for an urgent or emergent indication 
during pregnancy do not appear to be at increased risk for 
adverse outcomes. Obstetric complications, when they 
occur, are more likely to be associated with the underlying 
maternal illness. Recommendations have held that the opti
-
mal time for semi-elective surgery is the second trimester to 
avoid exposure to anesthesia in the first trimester and the 
enlarged uterus in the third. Importantly, however, there is 
no convincing evidence that general anesthesia induces 
malformations or increases the risk for abortion.
CHOLELITHIASIS & CHOLECYSTITIS
Cholelithiasis is common in pregnancy as physiologic 
changes such as increased cholesterol production and 
incomplete gallbladder emptying predispose to gallstone 
formation. The diagnosis is usually suspected based on clas
-
sic symptoms of nausea, vomiting, and right upper quadrant 
pain, usually after meals, and is confirmed with right upper 
quadrant ultrasound. Symptomatic cholelithiasis without 
cholecystitis is usually managed conservatively, but recur
-
rent symptoms are common. Cholecystitis results from 
obstruction of the cystic duct and often is accompanied by 
bacterial infection. Medical management with antibiotics is 
reasonable in selected cases, but definitive treatment with 
cholecystectomy will help prevent complications such as 
gallbladder perforation and pancreatitis. Cholecystectomy 
has successfully been performed in all trimesters of preg
-
nancy and should not be withheld based on the stage of 
pregnancy if clinically indicated. Laparoscopy is preferred in 
the first half of pregnancy, but becomes more technically 
challenging in the last trimester due to the enlarged uterus 
and cephalad displacement of abdominal contents.
Obstruction of the common bile duct, which can lead to 
cholangitis, is an indication for surgical removal of gallstones 
and establishment of biliary drainage. Increasingly, endo
-
scopic retrograde cholangiopancreatography (ERCP) with 
or without sphincterotomy is being performed in this situa
-
tion. Pregnant women can safely undergo ERCP provided 
that precautions are taken to minimize fetal exposure to 
radiation. There does, however, appear to be a slightly higher 
rate of post-procedure pancreatitis in pregnant women who 
undergo ERCP . Magnetic resonance cholangiopancreatogra
-
phy (MRCP) can also be of use in patients with suspected 
common bile duct obstruction. This study is particularly 
useful for those women in whom the etiology of common 
duct dilatation is unclear on ultrasound. MRCP can provide 
detailed evaluation of the entire biliary system and the 
pancreas while avoiding ionizing radiation.
Fine S et al. Continued evidence for safety of endoscopic retrograde 
cholangiopancreatography during pregnancy. World J 
 
Gastrointest Endosc. 2014 Aug 16;6(8):352–8. [PMID: 25132918]
ACUTE FATTY LIVER OF PREGNANCY
Acute fatty liver of pregnancy, a disorder limited to the 
gravid state, occurs in the third trimester of pregnancy and 
causes acute hepatic failure. With improved recognition 
and immediate delivery, the maternal mortality rate in 
contemporary reports is about 4%. The disorder is usually 
seen after the 35th week of gestation and is more common 
in primigravidas and those with twins. The incidence is 
about 1:10,000 deliveries.
The etiology of acute fatty liver of pregnancy is likely 
poor placental mitochondrial function. Many cases may be 
due to a homozygous fetal deficiency of long-chain acyl 
coenzyme A dehydrogenase (LCHAD).
 
»

»
Pathologic findings are unique to the disorder, with fatty 
engorgement of hepatocytes. Clinical onset is gradual, 
with nausea and vomiting being the most common pre
-
senting symptoms. Varying degrees of flu-like symptoms 
are also typical. Eventually, symptoms progress to those of 
fulminant hepatic failure: jaundice, encephalopathy, dis
-
seminated intravascular coagulation, and death. On exam
-
ination, the patient shows signs of hepatic failure.
Laboratory findings include marked elevation of alka
-
line phosphatase but only moderate elevations of alanine 
aminotransferase (ALT) and aspartate aminotransferase 
(AST). Hypocholesterolemia and hypofibrinogenemia are 
typical, and hypoglycemia can be extreme. Coagulopathy is 
also frequently seen with depressed procoagulant protein 
production. Kidney function should be assessed for 
hepatorenal syndrome. The white blood cell count is 
elevated, and the platelet count is depressed.
 
»
The differential diagnosis is that of fulminant hepatitis. 
Liver aminotransferases for fulminant hepatitis are higher 
(greater than 1000 units/mL) than those for acute fatty 
liver of pregnancy (usually 500–1000 units/mL). Pre
-
eclampsia may involve the liver but typically does not cause 
jaundice; the elevations in liver biochemical tests in patients 
with preeclampsia usually do not reach the levels seen in 
patients with acute fatty liver of pregnancy.
 
»
Treatment
Diagnosis of acute fatty liver of pregnancy mandates imme
-
diate delivery. Intensive supportive care with ICU-level 
observation is essential and typically includes administra
-
tion of blood products and glucose as well as correction of 
acidemia. Vaginal delivery is preferred. Resolution of 
encephalopathy and laboratory derangements occurs over 
days with supportive care, and recovery is usually com
-
plete. Rare cases of liver transplantation have been 
reported.
Nelson DB et al. Acute fatty liver of pregnancy: clinical outcomes 
and expected duration of recovery. Am J Obstet Gynecol. 
2013 Nov;209(5):456.e1–7. [PMID: 23860212]
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INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Intrahepatic cholestasis of pregnancy is characterized by 
incomplete clearance of bile acids in genetically suscepti
-
ble women. The principal symptom is pruritus, which can 
be generalized but tends to have a predilection for the 
palms and soles. Presentation is typically in the third 
trimester, and women with multi-fetal pregnancies are at 
increased risk. The finding of an elevated serum bile acid 
level, ideally performed in the fasting state, confirms 
the diagnosis. Associated laboratory derangements 
include modest elevations in hepatic transaminase levels 
and mild hyperbilirubinemia. Although rare, the biliru
-
bin level may be sufficiently elevated to result in clinical 
jaundice. The symptoms and laboratory abnormalities 
resolve quickly after delivery but can recur in subse
-
quent pregnancies or with exposure to combination oral 
Ursodeoxycholic acid (8–10 mg/kg/day) is the treat
-
ment of choice and results in decreased pruritus in most 
women.
Adverse fetal outcomes, particularly preterm birth, 
nonreassuring fetal status, meconium-stained amniotic 
fluid, and stillbirth, have consistently been reported in 
women with cholestasis of pregnancy. The risk for 
adverse perinatal outcomes appears to correlate with dis
-
ease severity as measured by the degree of bile acid eleva
-
tion, and women with fasting bile acids greater than 
 
40 mcmol/L have been reported to be at greatest risk. 
Because of the risks associated with cholestasis of preg
-
nancy, many clinicians recommend antenatal testing in 
the third trimester and elective early delivery in attempt 
to avoid stillbirth. Evidence-based recommendations 
regarding such management practices, however, are not 
currently available.
Geenes V et al. Association of severe intrahepatic cholestasis of 
pregnancy with adverse pregnancy outcomes: a prospective 
population-based case-control study. Hepatology. 2014 Apr;
 
59(4):1482–91. [PMID: 23857305]
Williamson C et al. Intrahepatic cholestasis of pregnancy. Obstet 
Gynecol. 2014 Jul;124(1):120–33. [PMID: 24901263]
Appendicitis occurs in about 1 of 1500 pregnancies. The 
diagnosis is more difficult to make clinically in pregnant 
women where the appendix is displaced cephalad from 
McBurney point. Furthermore, nausea, vomiting, and mild 
leukocytosis occur in normal pregnancy, so with or with
-
out these findings, any complaint of right-sided pain 
should raise suspicion. Imaging can help confirm the diag
-
nosis if clinical findings are equivocal. Abdominal 
sonography is a reasonable initial imaging choice, but 
nonvisualization of the appendix is common in pregnancy. 
CT scanning is more sensitive than ultrasound, and with 
proper shielding, the radiation exposure to the fetus is 
minimized. MRI is also used to evaluate for appendicitis in 
pregnant women and is a reasonable alternative to CT 
scanning. Unfortunately, the diagnosis of appendicitis is 
not made until the appendix has ruptured in at least 20% of 
obstetric patients. Peritonitis in these cases can lead to 
preterm labor or abortion. With early diagnosis and 
appendectomy, the prognosis is good for mother and baby.
Cheng HT et al. Laparoscopic appendectomy versus open 
appendectomy in pregnancy: a population-based analysis of 
maternal outcome. Surg Endosc. 2015 Jun;29(6):1394–9. 
[PMID: 25171885]
Dewhurst C et al. MRI evaluation of acute appendicitis in pregnancy. 
J Magn Reson Imaging. 2013 Mar;37(3):566–75. [PMID: 
23423797]
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20
 
º
RHEUMATOLOGIC DISORDERS
 
»
Diagnosis & Evaluation
A. Examination of the Patient
Two helpful clinical clues for diagnosing arthritis are the 
joint pattern
 and 
the presence or absence of extra-articular 
 The joint pattern is defined by the answers 
to three questions: (1) Is inflammation present? (2) How 
many joints are involved? and (3) What joints are affected? 
Joint inflammation manifests as warmth, swelling, and 
morning stiffness of at least 30 minutes’ duration. Overlying 
erythema occurs with the intense inflammation of crystal-
induced and septic arthritis. Both the number of affected 
joints and the specific sites of involvement affect the differ
-
ential diagnosis (Table 20–1). Some diseases—gout, for 
example—are characteristically monarticular, whereas other 
diseases, such as rheumatoid arthritis, are usually polyarticular. 
The location of joint involvement can also be distinctive. 
Only two diseases frequently cause prominent involvement 
of the distal interphalangeal (DIP) joint: osteoarthritis and 
psoriatic arthritis. Extra-articular manifestations such as 
fever (eg, gout, Still disease, endocarditis), rash (eg, systemic 
lupus erythematosus [SLE], psoriatic arthritis, Still disease), 
nodules (eg, rheumatoid arthritis, gout), or neuropathy 
(eg, polyarteritis nodosa, granulomatosis with polyangiitis 
narrow the differential diagnosis further.
B. Arthrocentesis and Examination of Joint Fluid
If the diagnosis is uncertain, synovial fluid should be exam
-
ined whenever possible (Table 20–2). Most large joints are 
easily aspirated, and contraindications to arthrocentesis are 
few. The aspirating needle should never be passed through 
an overlying cellulitis or psoriatic plaque because of the risk of 
introducing infection. For patients who are receiving direct-
acting oral anticoagulants or long-term anticoagulation 
therapy with warfarin, joints can be aspirated with a small-
gauge needle (eg, 22F); the international normalized ratio 
(INR) should be less than 3.0 for patients taking warfarin.
1. Types of studies
a
. Gross examination
—
Clarity is an approximate guide 
to the degree of inflammation. Noninflammatory fluid is 
David B. Hellmann, MD, MACP 
 
John B. Imboden Jr., MD 
Rheumatologic, 
Immunologic, & Allergic 
Disorders
transparent, mild inflammation produces translucent fluid, 
and purulent effusions are opaque. Bleeding disorders, 
trauma, and traumatic taps are the most common causes of 
bloody effusions.
b. Cell count
—
The synovial fluid white cell count dis
-
criminates between noninflammatory (less than 2000 white 
cells/mcL [2.0 × 10
9
/L]), inflammatory (2000–75,000 white 
9
/L–75.0 × 10
9
/L]), and purulent (greater 
than 100,000 white cells/mcL [100 × 10
9
/L]) joint effusions. 
Synovial fluid glucose and protein levels add little 
information and should not be ordered.
c. Microscopic examination
—
Compensated polarized 
light microscopy identifies and distinguishes monosodium 
urate (gout, negatively birefringent) and calcium pyrophos
-
phate (pseudogout, positive birefringent) crystals. Gram stain 
has specificity but limited sensitivity (50%) for septic arthritis.
d. Culture
—
Bacterial cultures as well as special studies for 
gonococci, tubercle bacilli, or fungi are ordered as appropriate.
2. Interpretation—
Synovial fluid analysis is diagnostic in 
infectious or microcrystalline arthritis. Although the 
severity of inflammation in synovial fluid can overlap 
among various conditions, the synovial fluid white cell 
count is a helpful guide to diagnosis (Table 20–3).
 
º
DEGENERATIVE & CRYSTAL-INDUCED 
ARTHRITIS
DEGENERATIVE JOINT DISEASE 
(
)
 
»
A degenerative disorder with minimal articular 
inflammation.
 
»
No systemic symptoms.
 
»
Pain relieved by rest; morning stiffness brief.
 
»
Radiographic findings: narrowed joint space, osteo
-

»
 
»
 
»
 
»
-
phytes, increased density of subchondral bone, 
bony cysts.
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841
 
CMDT 2019
Table 20–1.
 
Diagnostic value of the joint pattern.
Characteristic
Status
Representative 
Disease
Present
Absent
Rheumatoid arthritis, 
systemic lupus 
 
erythematosus, gout
Number of 
involved joints
Monarticular
Oligoarticular 
 
(2–4 joints)
Polyarticular 
 
(≥ 5 joints)
Gout, trauma, septic 
arthritis, Lyme disease, 
osteoarthritis
Reactive arthritis, psoriatic 
arthritis, inflammatory 
bowel disease
Site of joint 
involvement
Distal 
interphalangeal
Metacarpophalan
-
geal, wrists
First metatarsal 
phalangeal
Osteoarthritis, psoriatic 
arthritis (not rheu
-
matoid arthritis)
systemic lupus ery
-
thematosus, calcium 
pyrophosphate depo
-
sition disease (not 
osteoarthritis)
Gout, osteoarthritis
Table 20–2.
 
Examination of joint fluid.
Measure
(Normal)
Group I 
(Noninflammatory)
Group II 
(Inflammatory)
Group III (Purulent)
Volume (mL) (knee)
< 3.5
Often > 3.5
Often > 3.5
Often > 3.5
Clarity
Transparent
Translucent to opaque
Opaque
Color
Clear
Yellow
Yellow to opalescent
Yellow to green
WBC (per mcL)
< 200
< 2000
2000–75,000
1
> 100,000
2
Polymorphonuclear 
leukocytes
< 25%
< 25%
50% or more
75% or more
Culture
Negative
Negative
Negative
Usually positive
2
1
Gout, rheumatoid arthritis, and other inflammatory conditions occasionally have synovial fluid WBC counts > 75,000/mcL but rarely 
 
> 100,000/mcL.
2
Most purulent effusions are due to septic arthritis. Septic arthritis, however, can present with group II synovial fluid, particularly if infection 
is caused by organisms of low virulence (eg, 
) or if antibiotic therapy has been started.
WBC, white blood cell count.
 
»
Osteoarthritis, the most common form of joint disease, is 
chiefly a disease of aging. Ninety percent of all people have 
radiographic features of osteoarthritis in weight-bearing 
joints by age 40. Symptomatic disease also increases with 
age. Sex is also a risk factor; osteoarthritis develops in 
women more frequently than in men.
This arthropathy is characterized by degeneration of 
cartilage and by hypertrophy of bone at the articular 
margins. Inflammation is usually minimal. Hereditary and 
mechanical factors may be involved in the pathogenesis.
Obesity is a risk factor for osteoarthritis of the knee, 
hand, and probably of the hip. Recreational running does 
not increase the incidence of osteoarthritis, but participation 
in competitive contact sports does. Jobs requiring frequent 
bending and carrying increase the risk of knee osteoarthritis 
(see Chapter 41).
 
»
Degenerative joint disease is divided into two types: (1) 
primary, which most commonly affects some or all of the 
following: the DIP and the proximal interphalangeal (PIP) 
joints of the fingers, the carpometacarpal joint of the 
thumb, the hip, the knee, the metatarsophalangeal (MTP) 
joint of the big toe, and the cervical and lumbar spine; and 
(2) secondary, which may occur in any joint as a sequela to 
articular injury resulting from either intra-articular (includ
-
ing rheumatoid arthritis) or extra-articular causes. The 
injury may be acute, as in a fracture; or chronic, as that due 
to occupational overuse of a joint or metabolic disease (eg, 
hyperparathyroidism, hemochromatosis, ochronosis).
The onset is insidious. Initially, there is articular stiffness, 
seldom lasting more than 15 minutes; this develops later into 
pain on motion of the affected joint and is made worse by 
activity or weight bearing and relieved by rest. Flexion con
-
tracture or varus deformity of the knee is not unusual, and 
bony enlargements of the DIP (Heberden nodes) and PIP 
(Bouchard nodes) are occasionally prominent (Figure 20–1). 
There is no ankylosis, but limitation of motion of the affected

There is no ankylosis, but limitation of motion of the affected 
joint or joints is common. Crepitus may often be felt over the 
knee. Joint effusion and other articular signs of inflammation 
are mild. There are no systemic manifestations.
Osteoarthritis does not cause elevation of the erythrocyte 
sedimentation rate (ESR) or other laboratory signs of 
inflammation. Synovial fluid is noninflammatory.
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C. Imaging
Radiographs may reveal narrowing of the joint space; 
osteophyte formation and lipping of marginal bone; and 
thickened, dense subchondral bone. Bone cysts may also 
 
»
Because articular inflammation is minimal and systemic 
manifestations are absent, degenerative joint disease 
should seldom be confused with other arthritides. The 
distribution of joint involvement in the hands also helps 
distinguish osteoarthritis from rheumatoid arthritis. 
Osteoarthritis chiefly affects the DIP and PIP joints 
and spares the wrist and metacarpophalangeal (MCP) 
joints; rheumatoid arthritis involves the wrists and MCP 
joints and spares the DIP joints. Furthermore, the joint 
enlargement is bony-hard and cool in osteoarthritis but 
Table 20–3.
 
Differential diagnosis by joint fluid groups.
Group I (Noninflammatory) 
 
(< 2000 white cells/mcL)
Group II (Inflammatory) 
(2000–75,000 white cells/mcL)
Group III (Purulent) 
 
(> 100,000 white cells/mcL)
Hemorrhagic
Degenerative joint disease
Trauma
1
Osteochondritis dissecans
Osteochondromatosis
Neuropathic arthropathy
1
Subsiding or early inflammation
Hypertrophic osteoarthropathy
2
Pigmented villonodular synovitis
1
Acute crystal-induced synovitis 
(gout and pseudogout)
Reactive arthritis
Ankylosing spondylitis
2
Pyogenic bacterial infections
Hemophilia or other hemorrhagic 
diathesis
Trauma with or without fracture
Synovioma
Hemangioma and other benign 
neoplasms
1
May be hemorrhagic.
2
Noninflammatory or inflammatory group.
Reproduced, with permission, from Rodnan GP (editor). Primer on the rheumatic diseases, 7th ed. JAMA. 1973;224(Suppl):662. 
 
Copyright © 1973 American Medical Association. All rights reserved.
spongy and warm in rheumatoid arthritis. Skeletal symp
-
toms due to degenerative changes in joints—especially in 
the spine—may cause coexistent metastatic neoplasia, 
osteoporosis, plasma cell myeloma, or other bone disease 
to be overlooked.
 
»
Weight reduction reduces the risk of developing symptom
-
atic knee osteoarthritis. Correcting leg length discrepancy 
of greater than 1 cm with shoe modification may prevent 
knee osteoarthritis from developing in the shorter leg. 
Maintaining normal vitamin D levels may reduce the 
occurrence and progression of osteoarthritis, in addition to 
being important for bone health.
 
»
Treatment
Patients with osteoarthritis of the hand may benefit from 
assistive devices and instruction on techniques for joint pro
-
tection; splinting is beneficial for those with symptomatic 
osteoarthritis of the first carpometacarpal joint. Patients with 
mild to moderate osteoarthritis of the knee or hip should 
participate in a regular exercise program (eg, a supervised 
walking program, hydrotherapy classes) and, if overweight, 
should lose weight. The use of assistive devices (eg, a cane on 
the contralateral side) can improve functional status.
B. Medical Management
1. Acetaminophen—
Patients with mild osteoarthritis may 
benefit from acetaminophen (2.6–4 g/day orally). Growing 
awareness of the danger of hepatotoxicity from high doses 
of acetaminophen and clearer appreciation that its impact 
on pain is frequently neglible, acetaminophen is no longer 
recommended as first-line treatment for osteoarthritis of 
the hip or knee.
2. Topical therapies—
Topical nonsteroidal anti-inflamma
-
tory drugs (NSAIDs) (eg, 4 g of diclofenac gel 1% applied 
to the affected joint four times daily) appear more effective 
 
▲
Figure 20–1.
 
Osteoarthritis in an older woman with 
Heberden nodes at the distal interphalangeal joints. 
There is some swelling beginning at the proximal inter
-
phalangeal joints creating Bouchard nodes. 
permission, from Richard P . Usatine, MD.)
CMDT19_Ch20_p0840-p0897.indd   842

843
 
CMDT 2019
than placebo for knee and hand osteoarthritis and have 
lower rates of systemic side effects than with oral NSAIDs. 
Few studies have compared the efficacy of oral and topical 
NSAIDs. Because of their attractive safety profile, topical 
NSAIDs should be considered early in the treatment of 
patients with mild osteoarthritis affecting a few joints, 
especially of the hand or knee.
Topical capsaicin may be of benefit for osteoarthritis of 
the hand or the knee.
3. Oral NSAIDs—
NSAIDs (see Table 5–7) are more effec
-
tive than acetaminophen for osteoarthritis but have 
greater toxicity. NSAIDs inhibit cyclooxygenase (COX), 
the enzyme that converts arachidonic acid to prostaglan
-
dins. Prostaglandins play important roles in promoting 
inflammation, but they also help maintain homeostasis in 
several organs—especially the stomach, where prostaglandin E 
serves as a local hormone responsible for gastric mucosal 
cytoprotection. COX exists in two isomers—COX-1, which 
is expressed continuously in many cells and is responsible 
for the homeostatic effects of prostaglandins, and COX-2, 
which is induced by cytokines and expressed in inflamma
-
tory tissues. Most NSAIDs inhibit both isomers. Celecoxib 
is the only selective COX-2 inhibitor currently available in 
Gastrointestinal toxicity, such as gastric ulceration, per
-
foration, and gastrointestinal hemorrhage, are the most 
common serious side effects of NSAIDs. NSAIDs can also 
affect the lower intestinal tract, causing perforation or 
aggravating inflammatory bowel disease. The overall rate 
of bleeding with NSAID use in the general population is 
low (1:6000 users or less) but is increased by the risk factors 
of long-term use, higher NSAID dose, concomitant corti
-
costeroids or anticoagulants, the presence of rheumatoid 
arthritis, history of peptic ulcer disease or alcoholism, and 
age over 70. 
Proton pump inhibitors (eg, omeprazole 20 mg 
orally daily) reduce the incidence of serious gastrointestinal 
toxicity and should be used for patients with risk factors for 
NSAID-induced gastrointestinal toxicity.
 Patients who have 
recently recovered from an NSAID-induced bleeding 
gastric ulcer appear to be at high risk for rebleeding (about 
5% in 6 months) when an NSAID is reintroduced, even if 
prophylactic measures (such as proton pump inhibitors) 
are used. Compared with nonselective NSAIDs, celecoxib 
may be less likely in some circumstances to cause upper 
gastrointestinal tract adverse events.
All of the NSAIDs, including aspirin and celecoxib, can 
produce renal toxicity, including interstitial nephritis, 
nephrotic syndrome, prerenal azotemia, and aggravation of 
hypertension. Hyperkalemia due to hyporeninemic hypoal
-
dosteronism is seen rarely. The risk of renal toxicity is low 
but is increased by the following risk factors: age older than 
60 years, history of kidney disease, heart failure, ascites, and 
diuretic use.
All NSAIDs, except the nonacetylated salicylates and the 
COX-2 inhibitor celecoxib, interfere with platelet function 
and prolong bleeding time. Aspirin irreversibly inhibits 
platelet function, so the bleeding time effect resolves only as 
new platelets are made. In contrast, the effect of nonselec
-
tive NSAIDs on platelet function is reversible and resolves 
as the drug is cleared. Concomitant administration of a 
nonselective NSAID can interfere with the ability of aspirin 
to acetylate platelets and thus may interfere with the cardio
-
protective effects of low-dose aspirin. 
The FDA has warned 
that all NSAIDs can increase the risk of myocardial infarction 
and stroke in patients with or without risk factors for heart 
disease or known heart disease.
 While the cardiovascular 
risk is related to the dose and duration of treatment, stroke 
and myocardial infarction can occur within the first week of 
treatment. Cardiovascular risks associated with naproxen,

treatment. Cardiovascular risks associated with naproxen, 
ibuprofen, and moderate dose celecoxib (200 mg orally 
daily) are comparable.
Chondroitin sulfate and glucosamine, alone or in com
-
bination, are no better than placebo in reducing pain in 
patients with knee or hip osteoarthritis.
4. Intra-articular injections—
Many patients with moder
-
ately severe osteoarthritis of the knee who do not respond 
to NSAIDs receive intra-articular injections of corticoste
-
roids, hyaluronate, or platelet-rich plasma. Although each 
of these can temporarily reduce pain, none has convinc
-
ingly produced long-term benefits in reducing pain or 
preserving function. For example, a 2-year controlled trial 
demonstrated that injecting the knee with triamcinolone 
every 6 months was no more effective than injecting saline 
in reducing knee pain. The American College of Rheuma
-
tology does not recommend corticosteroid injections for 
osteoarthritis of the hand.
Total hip and knee replacements provide excellent symp
-
tomatic and functional improvement when involvement of 
that joint severely restricts walking or causes pain at rest, 
particularly at night. Arthroscopic surgery for knee osteo
-
arthritis is ineffective.
 
»
Prognosis
Symptoms may be quite severe and limit activity consider
-
ably (especially with involvement of the hips, knees, and 
cervical spine).
 
»
Refer patients to an orthopedic surgeon when recalcitrant 
symptoms or functional impairment, or both, warrant con
-
sideration of joint replacement surgery of the hip or knee.
Bennell KL et al. Platelet-rich plasma for the management of hip 
and knee osteoarthritis. Curr Rheumatol Rep. 2017 May;
 
19(5):24. [PMID: 28386761]
da Costa BR et al. Effectiveness of non-steroidal anti-inflammatory 
drugs for the treatment of pain in knee and hip osteoarthritis: a 
network meta-analysis. Lancet. 2016 May 21;387(10033):
 
2093–105. [PMID: 26997557]
McAlindon TE et al. Effect of intra-articular triamcinolone vs 
saline on knee cartilage volume and pain in patients with 
knee osteoarthritis: a randomized clinical trial. JAMA. 2017 
May 16;317(19):1967–75. [PMID: 28510679]
Nissen SE et al; PRECISION Trial Investigators. Cardiovascu
-
lar safety of celecoxib, naproxen, or ibuprofen for arthritis. 
N Engl J Med. 2016 Dec 29;375(26):2519–29. [PMID: 
27959716]
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CRYSTAL DEPOSITION ARTHRITIS
1. Gouty Arthritis
 
»
Acute, monarticular arthritis, often of the first MTP 
joint; recurrence is common.
 
»
Polyarticular involvement more common in 
patients with longstanding disease.
 
»
Identification of urate crystals in joint fluid or 
tophi is diagnostic.
 
»
Dramatic therapeutic response to NSAIDs.
 
»
With chronicity, urate deposits in subcutaneous 
tissue, bone, cartilage, joints, and other tissues.
 
»
Gout is a metabolic disease of a heterogeneous nature, 
often familial, associated with abnormal deposits of urate 
in tissues and characterized initially by a recurring acute 
arthritis, usually monarticular, and later by chronic 
deforming arthritis. Urate deposition occurs when serum 
uric acid is supersaturated (ie, at levels greater than 6.8 mg/dL 
[404.5 mcmol/L]). Hyperuricemia is due to overproduc
-
tion or underexcretion of uric acid—sometimes both. The 
disease is especially common in Pacific islanders, eg, Filipi
-
nos and Samoans. Primary gout has a heritable component, 
and genome-wide surveys have linked risk of gout to sev
-
eral genes whose products regulate urate handling by the 
kidney. Secondary gout, which may have a heritable com
-
ponent, is related to acquired causes of hyperuricemia, eg, 
medication use (especially diuretics, low-dose aspirin, 
cyclosporine, and niacin), myeloproliferative disorders, 
plasma cell myeloma, hemoglobinopathies, chronic kidney 
disease, hypothyroidism, psoriasis, sarcoidosis, and lead 
poisoning (Table 20–4). Alcohol ingestion promotes hyper
-
uricemia by increasing urate production and decreasing 
the renal excretion of uric acid. Finally, hospitalized 
patients frequently suffer attacks of gout because of changes 
in diet, fluid intake, or medications that lead either to rapid 
reductions or increases in the serum urate level.
About 90% of patients with primary gout are men, usu
-
ally over 30 years of age. In women, the onset is typically 
postmenopausal. The characteristic lesion is the tophus, a 
nodular deposit of monosodium urate monohydrate crys
-
tals with an associated foreign body reaction. Tophi are 
found in cartilage, subcutaneous and periarticular tissues, 
tendon, bone, the kidneys, and elsewhere. Urates have been 
demonstrated in the synovial tissues (and fluid) during 
acute arthritis; indeed, the acute inflammation of gout is 
believed to be initiated by the ingestion of uncoated urate 
crystals by monocytes and synoviocytes. The precise rela
-
tionship of hyperuricemia to gouty arthritis is still obscure, 
since chronic hyperuricemia is found in people who never 
develop gout or uric acid stones. Rapid fluctuations in 
serum urate levels, either increasing or decreasing, are 
Table 20–4.
 
Origin of hyperuricemia.
Primary hyperuricemia
A. Increased production of purine
1. Idiopathic
2. Specific enzyme defects (eg, Lesch-Nyhan syndrome, glycogen 
storage diseases)
B. Decreased renal clearance of uric acid (idiopathic)
Secondary hyperuricemia
A. Increased catabolism and turnover of purine
1. Myeloproliferative disorders
2. Lymphoproliferative disorders
3. Carcinoma and sarcoma (disseminated)
4. Chronic hemolytic anemias
5. Cytotoxic drugs
6. Psoriasis
B. Decreased renal clearance of uric acid
1. Intrinsic kidney disease
2. Functional impairment of tubular transport
a. Drug-induced (eg, thiazides, low-dose aspirin)
b. Hyperlacticacidemia (eg, lactic acidosis, alcoholism)
c. Hyperketoacidemia (eg, diabetic ketoacidosis, starvation)
d. Diabetes insipidus (vasopressin-resistant)
e. Bartter syndrome
Modified, with permission, from Rodnan GP . Gout and other 
 
crystalline forms of arthritis. Postgrad Med. 1975 Oct;58(5):6–14.
important factors in precipitating acute gout. The mecha
-
nism of the late, chronic stage of gouty arthritis is better 
understood. This is characterized pathologically by topha
-

-
-
ceous invasion of the articular and periarticular tissues, 
with structural derangement and secondary degeneration 
(osteoarthritis).
Uric acid kidney stones are present in 5–10% of patients 
with gouty arthritis. Hyperuricemia correlates highly with 
the likelihood of developing stones, with the risk of stone 
formation reaching 50% in patients with a serum urate 
level greater than 13 mg/dL. Chronic urate nephropathy is 
caused by the deposition of monosodium urate crystals in 
the renal medulla and pyramids. Although progressive 
chronic kidney disease occurs in a substantial percentage 
of patients with chronic gout, the role of hyperuricemia in 
causing this outcome is controversial, because many 
patients with gout have numerous confounding risk factors 
for chronic kidney disease (eg, hypertension, alcohol use, 
lead exposure, and other risk factors for vascular disease).
 
»
Acute gouty arthritis is sudden in onset and frequently 
nocturnal. It may develop without apparent precipitating 
cause or may follow rapid increases or decreases in serum 
urate levels. Common precipitants are alcohol excess (par
-
ticularly beer), changes in medications that affect urate 
metabolism, and, in the hospitalized patient, fasting 
before medical procedures. The MTP joint of the great toe 
is the most susceptible joint (“podagra”), although others, 
especially those of the feet, ankles, and knees, are com
-
monly affected. Gouty attacks may develop in periarticular 
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soft tissues such as the arch of the foot. Hips and shoulders 
are rarely affected. More than one joint may occasionally be 
affected during the same attack; in such cases, the distribu
-
tion of the arthritis is usually asymmetric. As the attack 
progresses, the pain becomes intense. The involved joints 
are swollen and exquisitely tender and the overlying skin 
tense, warm, and dusky red. Fever is common and may 
reach 39°C. Local desquamation and pruritus during 
recovery from the acute arthritis are characteristic of gout 
but are not always present. Tophi may be found in the 
external ears, feet, olecranon and prepatellar bursae, and 
hands (Figure 20–2). They usually develop years after the 
initial attack of gout.
Asymptomatic periods of months or years commonly 
follow the initial acute attack. After years of recurrent 
severe monoarthritis attacks of the lower extremities and 
untreated hyperuricemia, gout can evolve into a chronic, 
deforming polyarthritis of upper and lower extremities that 
mimics rheumatoid arthritis.
Although serial measurements of the serum uric acid 
detect hyperuricemia in 95% of patients, a single uric acid 
determination during an acute flare of gout is normal in up 
to 25% of cases. A normal serum uric acid level, therefore, 
does not exclude gout, especially in patients taking urate-
lowering drugs. During an acute attack, the peripheral 
blood white cell count is frequently elevated. Identification 
of sodium urate crystals in joint fluid or material aspirated 
from a tophus establishes the diagnosis. The crystals, 
which may be extracellular or found within neutrophils, 
are needle-like and negatively birefringent when examined 
by polarized light microscopy.
C. Imaging
Early in the disease, radiographs show no changes. Later, 
punched-out erosions with an overhanging rim of cortical 
bone (“rat bite”) develop. When these are adjacent to a soft 
 
▲
Figure 20–2.
 
Typical inflammatory changes of gout 
at first MTP joint (podagra). 
 2nd ed. 
tissue tophus, they are diagnostic of gout. Ultrasonography 
is increasingly used to confirm the diagnosis of gout. Tophi 
that are too small to appreciate on physical examination 
and smaller deposits of urate crystals can freqently be 
imaged by ultrasonography.
 
»
Acute gout is often confused with cellulitis. Bacteriologic 
studies usually exclude acute pyogenic arthritis. Pseudogout 
is distinguished by the identification of calcium pyrophos
-
phate crystals (positive birefringence) in the joint fluid, 
usually normal serum uric acid, and the radiographic 
appearance of chondrocalcinosis.
Chronic tophaceous arthritis may resemble chronic 
rheumatoid arthritis; gout is suggested by an earlier history 
of monoarthritis and is established by the demonstration of 
urate crystals in a suspected tophus. Likewise, hips and 
shoulders are generally spared in tophaceous gout. Biopsy 
may be necessary to distinguish tophi from rheumatoid 
nodules. Chronic lead intoxication may result in attacks of 
gouty arthritis (saturnine gout).
 
»
Treatment
A. Asymptomatic Hyperuricemia
Asymptomatic hyperuricemia should not be treated; uric 
acid–lowering drugs should not be instituted until arthritis, 
renal calculi, or tophi become apparent.
B. Acute Attack
Treatment of the acute attack focuses on reducing inflam
-
mation, not lowering serum uric acid. Indeed, sudden 
reduction of serum uric acid often precipitates further 
episodes of gouty arthritis.
1. NSAIDs—
Oral NSAIDs in full dose (eg, naproxen 500 mg 
twice daily or indomethacin 25–50 mg every 8 hours; see 
Table 5–7) are effective treatment for acute gout and should 
be continued until the symptoms have resolved (usually

be continued until the symptoms have resolved (usually 
5–10 days). Contraindications include active peptic ulcer 
disease, impaired kidney function, and a history of allergic 
reaction to NSAIDs.
2. Colchicine—
Oral colchicine is an appropriate treatment 
option for acute gout, provided the duration of the attack is 
less than 36 hours. For acute gout, colchicine should be 
administered orally as follows: a loading dose of 1.2 mg 
followed by a dose of 0.6 mg 1 hour later and then dosing for 
prophylaxis (0.6 mg once or twice daily) beginning 12 hours 
later. Patients who are already taking prophylactic doses of 
colchicine and have an acute flare of gout may receive the 
full loading dose (1.2 mg) followed by 0.6 mg 1 hour later 
(before resuming the usual 0.6 mg once or twice daily) pro
-
vided they have not received this regimen within the preced
-
ing 14 days (in which case, NSAIDs or corticosteroids should 
be used). The use of oral colchicine during the intercritical 
period to prevent gout attacks is discussed below.
Corticosteroids often give dramatic 
symptomatic relief in acute episodes of gout and will con
-
trol most attacks. They are most useful in patients with 
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contraindications to the use of NSAIDs. Corticosteroids 
may be given intravenously (eg, methylprednisolone, 
40 mg/day) or orally (eg, prednisone, 40–60 mg/day). 
These corticosteroids can be given at the suggested dose for 
5–10 days and then simply discontinued or given at the 
suggested initial dose for 2–5 days and then tapered over 
7–10 days. If the patient’s gout is monarticular or oligoar
-
ticular, intra-articular administration of the corticosteroid 
(eg, triamcinolone, 10–40 mg depending on the size of the 
joint) is very effective. Because gouty and septic arthritis 
can coexist, albeit rarely, joint aspiration and Gram stain 
with culture of synovial fluid should be performed when 
intra-articular corticosteroids are given.
4. Interleukin-1 inhibitors—
Anakinra (an interleukin-1 
receptor antagonist), canakinumab (a monoclonal anti
-
body against interleukin-1 beta), and rilonacept (a chimera 
composed of IgG constant domains and the extracellular 
components of the interleukin-1 receptor) have efficacy for 
the management of acute gout, but these drugs have not 
been approved by the US Food and Drug Administration 
(FDA) for this indication.
C. Management Between Attacks
Treatment during symptom-free periods is intended to 
minimize urate deposition in tissues, which causes chronic 
tophaceous arthritis, and to reduce the frequency and 
severity of recurrences. Potentially reversible causes of 
hyperuricemia are a high-purine diet, obesity, alcohol con
-
sumption, and use of certain medications. Patients with a 
single episode of gout who have normal kidney function 
and are willing to lose weight and stop drinking alcohol are 
at low risk for another attack and may not require long-
term medical therapy. In contrast, individuals with mild 
chronic kidney disease or with a history of multiple attacks 
of gout are likely to benefit from pharmacologic treatment. 
In general, the higher the uric acid level and the more fre
-
quent the attacks, the more likely that long-term medical 
therapy will be beneficial. All patients with tophaceous 
gout should receive urate-lowering therapy.
1. Diet—
Excessive alcohol consumption can precipitate 
attacks and should be avoided. Beer consumption appears 
to confer a higher risk of gout than does whiskey or wine. 
Although dietary purines usually contribute only 1 mg/dL 
to the serum uric acid level, moderation in eating foods 
with high purine content is advisable (Table 20–5). Patients 
should avoid organ meats and beverages sweetened with 
high fructose corn syrup. A high liquid intake and, more 
importantly, a daily urinary output of 2 L or more will aid 
urate excretion and minimize urate precipitation in the 
urinary tract.
2. Avoidance of hyperuricemic medications—
Thiazide 
and loop diuretics inhibit renal excretion of uric acid and, 
if possible, should be avoided in patients with gout. Simi
-
larly, niacin can raise serum uric acid levels and should be 
discontinued if there are therapeutic alternatives. Low 
doses of aspirin also aggravate hyperuricemia but, in gen
-
eral, should be continued due to their overriding benefits 
in cardiovascular prophylaxis.
Table 20–5.
 
The purine content of foods.
1
Low-purine foods
 
Refined c
ereals and cereal products, cornflakes, white bread,
 
pasta, flour
, arrowroot, sago, tapioca, cakes
 
M
ilk, milk products, and eggs
 
Sugar
, sweets, and gelatin
 
Butt
er, polyunsaturated margarine, and all other fats
 
F
ruit, nuts, and peanut butter
 
L
ettuce, tomatoes, and green vegetables (except those 
 
list
ed below)
 
Cr
eam soups made with low-purine vegetables but without
 
mea
t or meat stock
 
W
ater, fruit juice, cordials, and carbonated drinks
High-purine foods
 
All mea
ts, including organ meats, and seafood
 
M
eat extracts and gravies
 
Y
east and yeast extracts, beer, and other alcoholic beverages
 
B
eans, peas, lentils, oatmeal, spinach, asparagus, cauliflower,
 
and mushr
ooms
1

M
 
Y
 
B
 
and mushr
ooms
1
The purine content of a food reflects its nucleoprotein content 
and turnover. Foods containing many nuclei (eg, liver) have many 
purines, as do rapidly growing foods such as asparagus. The con
-
sumption of large amounts of a food containing a small concentra
-
tion of purines may provide a greater purine load than consumption 
of a small amount of a food containing a large concentration of 
purines.
Reproduced, with permission, from Emmerson BT. The manage
-
ment of gout. N Engl J Med. 1996 Feb 15;334(7):445–51. Copyright 
© 1996 Massachusetts Medical Society. Reprinted with permission 
from Massachusetts Medical Society.
3. Colchicine prophylaxis—
There are two indications for 
daily colchicine administration. First, colchicine can be 
used to prevent future attacks for the individual who has 
mild hyperuricemia and only occasional attacks of gouty 
arthritis. Second, colchicine can be used when urate-lowering 
therapy is started, to suppress attacks precipitated by 
abrupt changes in the serum uric acid level. For either 
indication, the usual dose is 0.6 mg either once or twice a 
day. Colchicine is renally cleared. Patients who have coex
-
isting moderate chronic kidney disease should take colchi
-
cine only once a day or once every other day in order to 
avoid peripheral neuromyopathy and other complications 
of colchicine toxicity.
4. Reduction of serum uric acid—
Indications for a urate-
lowering therapy in a person with gout include frequent 
acute arthritis (two or more episodes per year), tophaceous 
deposits, or chronic kidney disease (stage 2 or worse). If 
instituted, the minimum goal of urate-lowering therapy is 
to maintain the serum uric acid at or below 6 mg/dL or 
357 mcmol/L (ie, below the level at which serum is super
-
saturated with uric acid, thereby allowing urate crystals to 
solubilize); in some cases, control of gout may require lower
-
ing serum uric acid to less than 5 mg/dL or 297.4 mcmol/L. 
Lowering serum uric acid levels is not of benefit for the 
treatment of an acute gout flare.
Three classes of agents may be used to lower the serum 
uric acid—xanthine oxidase inhibitors (allopurinol or 
febuxostat), uricosuric agents, and uricase (pegloticase).
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a. Xanthine oxidase inhibitors
—
Allopurinol and 
febuxostat are the preferred first-line agents for lowering 
urate. They reduce plasma uric acid levels by blocking the 
final enzymatic steps in the production of uric acid. Allo
-
purinol and febuxostat should not be used together, but 
they can be tried sequentially if the initial agent fails to 
lower serum uric acid to the target level or if it is not toler
-
ated. The most frequent adverse effect with either medica
-
tion is the precipitation of an acute gouty attack; thus, 
patients generally should be receiving prophylactic doses of 
colchicine.
Hypersensitivity to allopurinol occurs in 2% of cases, 
usually within the first few months of therapy, and it can be 
life-threatening. The most common initial sign of hyper
-
sensitivity is a pruritic rash that may progress to toxic epi
-
dermal necrolysis, particularly if allopurinol is continued; 
vasculitis and hepatitis are other manifestations. Patients 
should be instructed to stop allopurinol immediately if a 
rash develops. Chronic kidney disease and concomitant 
thiazide therapy are risk factors. There is a strong associa
-
tion between allopurinol hypersensitivity and HLA-
B
*
5801, which is a prevalent allele in certain East Asian 
populations. Current recommendations are to screen for 
HLA-B
*
5801 prior to initiating allopurinol in Koreans 
with stage 3 or worse chronic kidney disease, and in all 
persons of Han Chinese and Thai descent.
The initial daily dose of allopurinol is 100 mg/day orally 
(50 mg/day for those with stage 4 or worse chronic kidney 
disease); the dose of allopurinol should be titrated upward 
every 2–5 weeks to achieve the target serum uric acid level 
(either less than or equal to 6.0 mg/dL [357 mcmol/L] for 
men or less than or equal to 5.0 mg/dL [297.4 mcmol/L] for 
women). Successful treatment usually requires a dose of at 
least 300 mg of allopurinol daily. The maximum daily dose 
is 800 mg.
Allopurinol interacts with other drugs. The combined 
use of allopurinol and ampicillin causes a drug rash in 20% 
of patients. Allopurinol can increase the half-life of pro
-
benecid, while probenecid increases the excretion of allo
-
purinol. Thus, a patient taking both drugs may need to use 
slightly higher than usual doses of allopurinol and lower 
doses of probenecid.
Febuxostat does not cause the hypersensitivity reactions 
seen with allopurinol and can be given without dose 
adjustment to patients with mild to moderate kidney 
disease. However, abnormal liver tests may develop in 
2–3% of patients taking febuxostat. In addition, one clinical 
study showed that febuxostat was associated with a slightly 
higher rate of fatal and nonfatal cardiovascular events than 
allopurinol (0.97 vs 0.58 per 100 patient-year). The initial 
dose of febuxostat is 40 mg/day orally. If the target serum 
uric acid is not reached, the dose of febuxostat can be 
increased to 80 mg/day and then to the maximum dose of 
120 mg/day.
B. Uricosuric drugs
—
Uricosuric drugs lower serum 
uric acid levels by blocking the tubular reabsorption of 
filtered urate, thereby increasing uric acid excretion by 
the kidney. Probenecid (0.5 g/day orally) and lesinurad 
(200 mg/day orally) are the uricosurics of choice in the 
United States, and are typically reserved for patients who 
cannot achieve a serum uric acid of less than or equal to 
 
6.0 mg/dL with allopurinol or febuxostat alone. Lesinurad 
carries a FDA black box warning that acute kidney injury 
can occur with treatment, especially when lesinurad is used 
as monotherapy; it is contraindicated in patients with a 
creatinine clearance of less than 45 mL/min. Probenecid 
can be added to a xanthine oxidase inhibitor or used as 
monotherapy. Probenecid should not be used in patients 
with a creatinine clearance of less than 50 mL/min due to 
limited efficacy; contraindications include a history of

limited efficacy; contraindications include a history of 
nephrolithiasis (uric acid or calcium stones) and evidence 
of overproduction of uric acid (ie, greater than 800 mg of 
uric acid in a 24-hour urine collection). To reduce the 
development of uric acid stones (which occur in up to 
11%), patients should be advised to increase their fluid 
intake and clinicians should consider prescribing an alka
-
linizing agent (eg, potassium citrate, 30–80 mEq/day 
orally) to maintain a urinary pH > 6.0.
c. Uricase
—
 Pegloticase, a recombinant uricase that must 
be administered intravenously (8 mg every 2 weeks), is 
indicated for the rare patient with refractory chronic 
tophaceous gout. Pegloticase carries an FDA black box 
warning, which advises administering the drug only in 
health care settings and by health care professionals pre
-
pared to manage anaphylactic and other serious infusion 
reactions.
D. Chronic Tophaceous Arthritis
With rigorous medical compliance, allopurinol, febuxostat, 
or pegloticase shrinks tophi and in time can lead to their 
disappearance. Resorption of extensive tophi requires 
maintaining a serum uric acid below 6 mg/dL. Surgical 
excision of large tophi offers mechanical improvement in 
selected deformities.
E. Gout in the Transplant Patient
Hyperuricemia and gout commonly develop in many 
transplant patients because they have decreased kidney 
function and require drugs that inhibit uric acid excretion 
(especially cyclosporine and diuretics). Treating acute gout 
in these patients is challenging. Often the best approach for 
monarticular gout—after excluding infection—is injecting 
corticosteroids into the joint. For polyarticular gout, 
increasing the dose of systemic corticosteroid may be the 
only alternative. Since transplant patients often have mul
-
tiple attacks of gout, long-term relief requires lowering the 
serum uric acid with allopurinol or febuxostat. (Kidney 
dysfunction seen in many transplant patients makes urico
-
suric agents ineffective.) Both allopurinol and febuxostat 
inhibit the metabolism of azathioprine and should be 
avoided in patients who must take azathioprine.
 
»
Prognosis
Without treatment, the acute attack may last from a few 
days to several weeks. The intervals between acute attacks 
vary up to years, but the asymptomatic periods often 
become shorter if the disease progresses. Chronic gouty 
arthritis occurs after repeated attacks of acute gout, but 
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only after inadequate treatment. The younger the patient at 
the onset of disease, the greater the tendency to a progres
-
sive course. Destructive arthropathy is rarely seen in 
patients whose first attack is after age 50.
Patients with gout are anecdotally thought to have an 
increased incidence of hypertension, kidney disease (eg, 
nephrosclerosis, interstitial nephritis, pyelonephritis), dia
-
betes mellitus, hypertriglyceridemia, and atherosclerosis.
Bardin T et al. Lesinurad in combination with allopurinol: a 
randomised, double-blind, placebo-controlled study in 
patients with gout with inadequate response to standard of 
care (the multinational CLEAR 2 study). Ann Rheum Dis. 
2017 May;76(5):811–20. [PMID: 27821644]
Dalbeth N et al. Gout. Lancet. 2016 Oct 22;388(10055):2039–52. 
[PMID: 27112094]
Qaseem A et al. Management of acute and recurrent gout: a 
-
sicians. Ann Intern Med. 2017 Jan 3;166(1):58–68. [PMID: 
27802508]
van Durme CM et al. Nonsteroidal anti-inflammatory drugs for 
treatment of acute gout. JAMA. 2015 Jun 9;313(22):2276–7. 
[PMID: 26057289]
2. Calcium Pyrophosphate Deposition
Calcium pyrophosphate deposition (CPPD) in fibrocartilage 
and hyaline cartilage (chondrocalcinosis) can cause an acute 
crystal-induced arthritis (“pseudogout”), a degenerative 
arthropathy, and a chronic inflammatory polyarthritis 
(“pseudorheumatoid arthritis”). CPPD also can be an 
asymptomatic condition detected as incidental chondrocal
-
cinosis on radiographs. The prevalence of CPPD increases 
with age. Hyperparathyroidism, hemochromatosis, and 
hypomagnesemia confer risk of CPPD, but most cases have 
no associated condition.
Pseudogout is most often seen in persons aged 60 or 
older, is characterized by acute, recurrent and rarely 
chronic arthritis involving large joints (most commonly 
the knees and the wrists) and is almost always accompa
-
nied by radiographic chondrocalcinosis of the affected 
joints. The crowned dens syndrome, caused by pseudogout 
of the atlantoaxial junction associated with “crown-like” 
calcifications around the dens, manifests with severe neck 
pain, rigidity, and high fever that can mimic meningitis or 
polymyalgia rheumatica. Pseudogout, like gout, frequently 
develops 24–48 hours after major surgery. Identification of 
calcium pyrophosphate crystals in joint aspirates is diag
-
nostic. NSAIDs are helpful in the treatment of acute epi
-
sodes. Colchicine, 0.6 mg orally once or twice daily, is more 
effective for prophylaxis than for acute attacks. Aspiration 
of the inflamed joint and intra-articular injection of triam
-
cinolone, 10–40 mg, depending on the size of the joint, are 
also of value in resistant cases.
The degenerative arthropathy associated with CPPD 
can involve joints not usually affected by osteoarthritis (eg, 
glenohumeral joint, wrist, patellofemoral compartment of 
the knee). The “pseudorheumatoid arthritis” of CPPD 
affects the metacarpophalangeal joints and wrists. In both 
conditions, radiographs demonstrate chondrocalcinosis 
and degenerative changes such as asymmetric joint space 
narrowing and osteophyte formation.
Kleiber Balderrama C et al. Calcium pyrophosphate deposition 
disease and associated medical co-morbidities: a national 
cross-sectional study of US veterans. Arthritis Care Res 
(Hoboken). 2017 Sep;69(9):1400–6. [PMID: 27898996]
Rheinboldt M et al. Musculoskeletal ultrasonography in the 
diagnosis of acute crystalline synovitis. Emerg Radiol. 2016 Dec;
 
23(6):623–32. [PMID: 27439716]
 
º
AUTOIMMUNE DISEASES
RHEUMATOID ARTHRITIS
 
»
Usually insidious onset with morning stiffness and 
joint pain.
 
»
Symmetric polyarthritis with predilection for small 
joints of the hands and feet; deformities common 
with progressive disease.
 
»
Radiographic findings:
 juxta-articular osteoporosis, 
joint erosions, and joint space narrowing.
 
»

»
 
»
Rheumatoid factor and antibodies to cyclic citrul
-
linated peptides (anti-CCP) are present in 70–80%.
 
»
Extra-articular manifestations:
 subcutaneous 
nodules, interstitial lung disease, pleural effusion, 
pericarditis, splenomegaly with leukopenia, and 
vasculitis.
 
»
Rheumatoid arthritis is a chronic systemic inflammatory 
disease whose major manifestation is synovitis of multiple 
joints. It has a prevalence of 1% and is more common in 
women than men (female:male ratio of 3:1). Rheumatoid 
arthritis can begin at any age, but the peak onset is in the 
fourth or fifth decade for women and the sixth to eighth 
decades for men. The cause is not known. Susceptibility to 
rheumatoid arthritis is genetically determined with mul
-
tiple genes contributing. Inheritance of HLA DRB1 alleles 
encoding a distinctive five-amino-acid sequence known as 
the “shared epitope” is the best characterized genetic risk 
factor. Untreated, rheumatoid arthritis causes joint 
destruction with consequent disability and shortens life 
expectancy. Early, aggressive treatment is the standard 
of care.
The pathologic findings in the joint include chronic 
synovitis with formation of a pannus, which erodes carti
-
lage, bone, ligaments, and tendons. Effusion and other 
manifestations of inflammation are common.
 
»
1. Joint symptoms—
The clinical manifestations of rheu
-
matoid disease are highly variable, but joint symptoms usu
-
ally predominate. Although acute presentations may occur, 
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the onset of articular signs of inflammation is usually insidi
-
ous, with prodromal symptoms of vague periarticular pain 
or stiffness. Symmetric swelling of multiple joints with 
tenderness and pain is characteristic. Monarticular disease 
is occasionally seen initially. Stiffness persisting for longer 
than 30 minutes (and usually many hours) is prominent in 
the morning. Stiffness may recur after daytime inactivity 
and be much more severe after strenuous activity. Although 
any diarthrodial joint may be affected, PIP joints of the 
fingers, MCP joints (Figure 20–3), wrists, knees, ankles, and 
MTP joints are most often involved. Synovial cysts and 
rupture of tendons may occur. Entrapment syndromes are 
common—particularly of the median nerve at the carpal 
tunnel of the wrist. Rheumatoid arthritis can affect the neck 
but spares the other components of the spine and does not 
involve the sacroiliac joints. In advanced disease, atlanto
-
axial (C1–C2) subluxation can lead to myelopathy.
2. Rheumatoid nodules—
Twenty percent of patients have 
subcutaneous rheumatoid nodules, most commonly situ
-
ated over bony prominences but also observed in the 
bursae and tendon sheaths (Figure 20–4). Nodules are 
occasionally seen in the lungs, the sclerae, and other tis
-
sues. Nodules correlate with the presence of rheumatoid 
factor in serum (“seropositivity”), as do most other extra-
articular manifestations.
3. Ocular symptoms—
Dryness of the eyes, mouth, and 
other mucous membranes is found especially in advanced 
disease (see Sjögren syndrome). Other ocular manifesta
-
tions include episcleritis, scleritis, scleromalacia due to 
scleral nodules, and peripheral ulcerative keratitis.
4. Other symptoms—
Interstitial lung disease is not uncom
-
mon (estimates of prevalence vary widely according to 
method of detection) and manifests clinically as cough and 
progressive dyspnea. Pericarditis and pleural disease, when 
present, are usually silent clinically. Patients with active 
 
▲
Figure 20–3.
 
Rheumatoid arthritis with ulnar deviation 
at the metacarpophalangeal (MCP) joints.
 (Used, with 
 
▲
Figure 20–4.
 
Rheumatoid nodules over the extensor 
surface of the forearm. 
 2nd ed. 
joint disease often have palmar erythema. Occasionally, a 
small vessel vasculitis develops and manifests as tiny hem
-
orrhagic infarcts in the nail folds or finger pulps. Necrotiz
-
ing arteritis is well reported but rare. A small subset of 
patients with rheumatoid arthritis have Felty syndrome, the 
occurrence of splenomegaly and neutropenia, usually in the 
setting of severe, destructive arthritis. Felty syndrome must 
be distinguished from large granular lymphoproliferative 
disorder, with which it shares many features.
Anti-CCP antibodies and rheumatoid factor, an IgM anti
-
body directed against the Fc region of IgG, are present in 
70–80% of patients with established rheumatoid arthritis. 
Rheumatoid factor has a sensitivity of only 50% in early 
disease. Anti-CCP antibodies are the most specific blood 
test for rheumatoid arthritis (specificity ~95%). Rheuma
-
toid factor can occur in other autoimmune disease and in 
chronic infections, including hepatitis C, syphilis, subacute 
bacterial endocarditis, and tuberculosis. The prevalence of 
rheumatoid factor positivity also rises with age in healthy 
individuals. Approximately 20% of rheumatoid patients 
have antinuclear antibodies.
The ESR and levels of C-reactive protein are typically 
elevated in proportion to disease activity. A moderate hypo
-
chromic normocytic anemia of chronic disease is common. 
The white cell count is normal or slightly elevated, but leu
-

-
-
kopenia may occur, often in the presence of splenomegaly 
(eg, Felty syndrome). The platelet count is often elevated, 
roughly in proportion to the severity of overall joint inflam
-
mation. Initial joint fluid examination confirms the inflam
-
matory nature of the arthritis (see Table 20–2).
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Arthrocentesis is needed to diagnose superimposed 
septic arthritis, which is a common complication of rheu
-
matoid arthritis and should be considered whenever a 
patient with rheumatoid arthritis has one joint inflamed 
out of proportion to the rest.
C. Imaging
Of all the laboratory tests, radiographic changes are the 
most specific for rheumatoid arthritis. Radiographs 
obtained during the first 6 months of symptoms, however, 
are usually normal. The earliest changes occur in the hands 
or feet and consist of soft tissue swelling and juxta-articular 
demineralization. Later, diagnostic changes of uniform 
joint space narrowing and erosions develop. The erosions 
are often first evident at the ulnar styloid and at the juxta-
articular margin, where the bony surface is not protected 
by cartilage. Characteristic changes also occur in the cervi
-
cal spine, with C1–2 subluxation, but these changes usually 
take many years to develop. Although both MRI and ultra
-
sonography are more sensitive than radiographs in detect
-
ing bony and soft tissue changes in rheumatoid arthritis, 
their value in early diagnosis relative to that of plain 
radiographs has not been established.
 
»
The differentiation of rheumatoid arthritis from other 
joint conditions and immune-mediated disorders can be 
difficult. In contrast to rheumatoid arthritis, osteoarthri
-
tis spares the wrist and the MCP joints. Osteoarthritis is 
not associated with constitutional manifestations, and the 
joint pain is characteristically relieved by rest, unlike the 
morning stiffness of rheumatoid arthritis. Signs of articu
-
lar inflammation, prominent in rheumatoid arthritis, are 
usually minimal in degenerative joint disease. CPPD dis
-
ease can cause a degenerative arthropathy of the MCPs 
and wrists; radiographs are usually diagnostic. Although 
gouty arthritis is almost always intermittent and monar
-
ticular in the early years, it may evolve with time into a 
chronic polyarticular process that mimics rheumatoid 
arthritis. Gouty tophi can resemble rheumatoid nodules 
but are not associated with rheumatoid factor, whose 
sensitivity for rheumatoid nodules approaches 100%. The 
early history of intermittent monoarthritis and the pres
-
ence of synovial urate crystals are distinctive features of 
gout. Spondyloarthropathies, particularly earlier in their 
course, can be a source of diagnostic uncertainty; predi
-
lection for lower extremities and involvement of the spine 
and sacroiliac joints point to the correct diagnosis. 
Chronic Lyme arthritis typically involves only one joint, 
most commonly the knee, and is associated with positive 
serologic tests (see Chapter 34). Acute viral infections, 
most notably with Chikungunya virus and parvovirus 
B19, can cause a polyarthritis that mimics early-onset 
rheumatoid arthritis. However, fever is common, the 
arthritis usually resolves within weeks, and serologic 
studies confirm recent infection. Chronic infection with 
hepatitis C can cause a chronic nonerosive polyarthritis 
associated with rheumatoid factor; tests for anti-CCP 
antibodies are negative.
Malar rash, photosensitivity, discoid skin lesions, alopecia, 
high titer antibodies to double-stranded DNA, glomerulo
-
nephritis, and central nervous system abnormalities point 
to the diagnosis of SLE. Polymyalgia rheumatica occasion
-
ally causes polyarthralgias in patients over age 50, but these 
patients remain rheumatoid factor–negative and have 
chiefly proximal muscle pain and stiffness, centered on the 
shoulder and hip girdles. Joint pain that can be confused 
with rheumatoid arthritis presents in a substantial minor
-
ity of patients with granulomatosis with polyangiitis. This 
diagnostic error can be avoided by recognizing that, in 
contrast to rheumatoid arthritis, the arthritis of granulo
-
matosis with polyangiitis preferentially involves large joints

-
matosis with polyangiitis preferentially involves large joints 
(eg, hips, ankles, wrists) and usually spares the small joints 
of the hand. Rheumatic fever is characterized by the migra
-
tory nature of the arthritis, an elevated antistreptolysin 
titer, and a more dramatic and prompt response to aspirin; 
carditis and erythema marginatum may occur in adults, 
but chorea and subcutaneous nodules virtually never do. 
Finally, a variety of cancers produce paraneoplastic syn
-
dromes, including polyarthritis. One form is hypertrophic 
pulmonary osteoarthropathy most often produced by lung 
and gastrointestinal carcinomas, characterized by a 
rheumatoid-like arthritis associated with clubbing, perios
-
teal new bone formation, and a negative rheumatoid factor. 
Diffuse swelling of the hands with palmar fasciitis occurs 
in a variety of cancers, especially ovarian carcinoma.
 
»
Treatment
The primary objectives in treating rheumatoid arthritis are 
reduction of inflammation and pain, preservation of func
-
tion, and prevention of deformity. Success requires early, 
effective pharmacologic intervention. Disease-modifying 
antirheumatic drugs (DMARDs) should be started as soon 
as the diagnosis of rheumatoid disease is certain and then 
adjusted with the aim of suppressing disease activity. 
NSAIDs provide some symptomatic relief in rheumatoid 
arthritis but do not prevent erosions or alter disease pro
-
gression. They are not appropriate for monotherapy and 
should only be used in conjunction with DMARDs, if at all. 
The American College of Rheumatology recommends 
using standardized assessments, such as the Disease Activity 
Score 28 Joints (DAS28) or the Clinical Disease Activity 
Index, to gauge therapeutic responses, with the target of 
mild disease activity or remission by these measures. In 
advanced disease, surgical intervention may help improve 
function of damaged joints and to relieve pain.
A. Corticosteroids
Low-dose corticosteroids (eg, oral prednisone 5–10 mg 
daily) produce a prompt anti-inflammatory effect and slow 
the rate of articular erosion. These often are used as a 
“bridge” to reduce disease activity until the slower acting 
DMARDs take effect or as adjunctive therapy for active 
disease that persists despite treatment with DMARDs. No 
more than 10 mg of prednisone or equivalent per day is 
appropriate for articular disease. Many patients do reason
-
ably well on 5–7.5 mg daily. (The use of 1-mg tablets, to 
facilitate doses of less than 5 mg/day, is encouraged.) 
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Higher doses are used to manage serious extra-articular 
manifestations (eg, pericarditis, necrotizing scleritis). 
When the corticosteroids are to be discontinued, they 
should be tapered gradually on a planned schedule appro
-
priate to the duration of treatment. All patients receiving 
long-term corticosteroid therapy should take measures to 
prevent osteoporosis (Table 26–16).
Intra-articular corticosteroids may be helpful if one or 
two joints are the chief source of difficulty. Intra-articular 
triamcinolone, 10–40 mg depending on the size of the joint 
to be injected, may be given for symptomatic relief but not 
more than four times a year.
B. DMARDs
1. Synthetic DMARDs—
a. Methotrexate
—
Methotrexate is usually the initial 
synthetic DMARD of choice for patients with rheumatoid 
arthritis. It is generally well tolerated and often produces a 
beneficial effect in 2–6 weeks. The usual initial dose is 
7.5 mg of methotrexate orally once weekly. If the patient 
has tolerated methotrexate but has not responded in 1 month, 
the dose can be increased to 15 mg orally once per week. 
The maximal dose is usually 20–25 mg/wk. The most 
frequent side effects are gastric irritation and stomatitis. 
Cytopenia, most commonly leukopenia or thrombocyto
-
penia but rarely pancytopenia, due to bone marrow sup
-
pression, is another important potential problem. The risk 
of developing pancytopenia is much higher in patients whose 
serum creatinine is greater than 2 mg/dL (176.8 mcmol/L). 
Hepatotoxicity with fibrosis and cirrhosis is an important 
toxic effect that correlates with cumulative dose and is 
uncommon with appropriate monitoring of liver biochem
-
ical tests. Methotrexate is contraindicated in a patient with 
any form of chronic hepatitis, in pregnant women, and in 
any patient with significant kidney dysfunction (estimated 
glomerular filtration rate less than 30 mL/min). Heavy 
alcohol use increases the hepatotoxicity, so patients should 
be advised to drink alcohol in extreme moderation, if at all. 
Diabetes mellitus, obesity, and kidney disease also increase 
the risk of hepatotoxicity. Liver biochemical tests should be 
monitored at least every 12 weeks, along with a complete 
blood count. The dose of methotrexate should be reduced 
if aminotransferase levels are elevated, and the drug should 
be discontinued if abnormalities persist despite dosage 
reduction. Gastric irritation, stomatitis, cytopenias, and 
hepatotoxicity are reduced by prescribing either daily folate 
(1 mg orally) or weekly leucovorin calcium (2.5–5 mg 
taken orally 24 hours after the dose of methotrexate). 
Hypersensitivity to methotrexate can cause an acute or 
subacute interstitial pneumonitis that can be life-threaten
-
ing but which usually responds to cessation of the drug and 
institution of corticosteroids. Because methotrexate is tera
-
togenic, women of childbearing age as well as men must 
use effective contraception while taking the medication. 
Methotrexate is associated with an increased risk of B-cell 
lymphomas, some of which resolve following the discon
-
tinuation of the medication. The combination of metho
-
trexate and other folate antagonists, such as 
trimethoprim-sulfamethoxazole, should be used cautiously 
since pancytopenia can result. Amoxicillin can decrease 
renal clearance of methotrexate, leading to toxicity. Pro
-
benecid also increases methotrexate drug levels and toxic
-
ity and should be avoided.
b. Sulfasalazine
—
This drug is a second-line agent for 
rheumatoid arthritis. It is usually introduced at a dosage 
of 0.5 g orally twice daily and then increased each week 
by 0.5 g until the patient improves or the daily dose 
reaches 3 g. Side effects, particularly neutropenia and 
thrombocytopenia, occur in 10–25% and are serious in 
2–5%. Sulfasalazine also causes hemolysis in patients 
with glucose-6-phosphate dehydrogenase (G6PD) defi
-

-
ciency, so a G6PD level should be checked before initiat
-
ing sulfasalazine. Patients with aspirin sensitivity should 
not be given sulfasalazine. Patients taking sulfasalazine 
should have complete blood counts monitored every 
2–4 weeks for the first 3 months, then every 3 months.
c. Leflunomide
—
Leflunomide, a pyrimidine synthesis 
inhibitor, is FDA-approved for treatment of rheumatoid 
arthritis and is administered as a single oral daily dose of 
 
20 mg. The most frequent side effects are diarrhea, rash, 
reversible alopecia, and hepatotoxicity. Some patients expe
-
rience dramatic unexplained weight loss. The drug is car
-
cinogenic, teratogenic, and has a half-life of 2 weeks. Thus, 
it is contraindicated in premenopausal women who wish 
to bear children or in men who wish to father children.
d. Antimalarials
—
Hydroxychloroquine sulfate is the 
antimalarial agent most often used against rheumatoid 
arthritis. Monotherapy with hydroxychloroquine should be 
reserved for patients with mild disease because only a small 
percentage will respond and in some of those cases only 
after 3–6 months of therapy. Hydroxychloroquine is often 
used in combination with other conventional DMARDs, 
particularly methotrexate and sulfasalazine. The advantage 
of hydroxychloroquine is its comparatively low toxicity, 
especially at a dosage of 200–400 mg/day orally (not to 
exceed 5 mg/kg/day). The prevalence of the most impor
-
tant reaction, pigmentary retinitis causing visual loss, is a 
function of duration of therapy, occurring in less than 2% 
of patients (dosed properly) during the first 10 years of use, 
but rising to 20% after 20 years of treatment. Ophthalmo
-
logic examinations every 12 months are required. Other 
reactions include neuropathies and myopathies of both 
skeletal and cardiac muscle, which usually improve when 
the drug is withdrawn.
e. Tofacitinib
—
Tofacitinib, an inhibitor of Janus kinase 
3, is used to manage severe rheumatoid arthritis that is 
refractory to methotrexate. While it appears to be superior 
to methotrexate as initial monotherapy for rheumatoid 
arthritis, it has greater toxicity. Tofacitinib can be used 
either as monotherapy or in combination with methotrex
-
ate. It is administered orally in a dose of 5 mg or 10 mg 
twice daily. Patients should be screened and treated for 
latent tuberculosis prior to receiving the drug.
2. Biologic DMARDs—
a. Tumor necrosis factor inhibitors
—
Inhibitors of 
tumor necrosis factor (TNF)—a pro-inflammatory 
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cytokine—are frequently added to the treatment of patients 
who have not responded adequately to methotrexate and 
are increasingly used as initial therapy in combination with 
methotrexate for patients with poor prognostic factors.
Five inhibitors are in use: etanercept, infliximab, adali
-
mumab, golimumab, and certolizumab pegol. Etanercept, a 
soluble recombinant TNF receptor:Fc fusion protein, is 
usually administered at a dosage of 50 mg subcutaneously 
once per week. Infliximab, a chimeric monoclonal anti
-
body, is administered at a dosage of 3–10 mg/kg intrave
-
nously; infusions are repeated after 2, 6, 10, and 14 weeks 
and then are administered every 8 weeks. Adalimumab, a 
human monoclonal antibody that binds to TNF, is given at 
a dosage of 40 mg subcutaneously every other week. The 
dose for golimumab, a human anti-TNF monoclonal anti
-
body, is 50 mg subcutaneously once monthly. Certoli
-
zumab pegol is a PEGylated Fab fragment of an anti-TNF 
monoclonal antibody; the dose is 200–400 mg subcutane
-
ously every 2 to 4 weeks. Each drug produces substantial 
improvement in more than 60% of patients. Each is usually 
very well tolerated. Minor irritation at injection sites is the 
most common side effect of etanercept and adalimumab. 
Rarely, nonrecurrent leukopenia develops in patients. TNF 
plays a physiologic role in combating many types of infection; 
TNF inhibitors have been associated with a several-fold 
increased risk of serious bacterial infections and a striking 
increase in granulomatous infections, particularly reactiva
-
tion of tuberculosis. Screening for latent tuberculosis (see 
Chapter 9) is mandatory before the initiation of TNF 
blockers. It is prudent to suspend TNF blockers when a 
fever or other manifestations of a clinically important 
infection develops in a patient. Demyelinating neurologic 
complications that resemble multiple sclerosis have been 
reported rarely in patients taking etanercept, but the true 
magnitude of this risk—likely quite small—has not been 
determined with precision. While there are conflicting data 
with respect to increased risk of malignancy, there is an 
FDA safety alert about case reports of malignancies, 
including leukemias, in patients treated with TNF inhibi
-
tors. Infliximab was associated with increased morbidity in 
a heart failure trial, therefore, TNF inhibitors should be 
used with extreme caution in patients with heart failure. 
Infliximab can rarely cause anaphylaxis and induce anti-
DNA antibodies (but rarely clinically evident SLE).
b. Abatacept
—
Abatacept, a recombinant protein made 
by fusing a fragment of the Fc domain of human IgG with 
the extracellular domain of a T-cell inhibitory receptor 
(CTLA4), blocks T-cell costimulation and produces clini
-
cally meaningful responses in approximately 50% of indi
-
viduals whose disease is active despite the combination of 
methotrexate and a TNF inhibitor.
c. Rituximab
—
Rituximab, a humanized mouse mono
-
clonal antibody that depletes B cells, can be used in combi
-
nation with methotrexate for patients whose disease has 
been refractory to treatment with a TNF inhibitor.
d. Tocilizumab
—
Tocilizumab is a monoclonal antibody 
that blocks the receptor for IL-6, an inflammatory cytokine 
involved in the pathogenesis of rheumatoid arthritis. It is 
used most often in combination with methotrexate for 
patients whose disease has been refractory to treatment 
with a TNF inhibitor.
3. Combination DMARDs—
As a general rule, DMARDs 
have greater efficacy when administered in combination 
than when used individually. The most commonly used 
combination is methotrexate with one of the TNF inhibi
-
tors, which is more effective than methotrexate alone. Still, 
most patients who require DMARD therapy are given 
methotrexate monotherapy initially because methotrexate 
alone usually works and is less expensive and less toxic 
than combination therapy. The combination of methotrex
-

-
ate, sulfasalazine, and hydroxychloroquine is also effective 
and is not inferior to the combination of methotrexate plus 
etanercept for those who have not responded to metho
-
trexate monotherapy.
 
»
After months or years, deformities may occur; the most 
common are ulnar deviation of the fingers, boutonnière 
deformity (hyperextension of the DIP joint with flexion of 
the PIP joint), “swan-neck” deformity (flexion of the DIP 
joint with extension of the PIP joint), valgus deformity of 
the knee, and volar subluxation of the MTP joints. The 
excess mortality associated with rheumatoid arthritis is 
largely due to cardiovascular disease that is unexplained by 
traditional risk factors and that appears to be a result of 
deleterious effects of chronic systemic inflammation on the 
vascular system.
 
»
Early referral to a rheumatologist is essential for appropri
-
ate diagnosis and the timely introduction of effective 
therapy.
Goodman SM et al. 2017 American College of Rheumatology/
American Association of Hip and Knee Surgeons guideline 
for the perioperative management of antirheumatic medica
-
tion in patients with rheumatic diseases undergoing elective 
total hip or total knee arthroplasty. Arthritis Rheumatol. 
2017 Aug;69(8):1538–51. [PMID: 28620948]
Singh JA et al. Risk of serious infection in biological treatment of 
patients with rheumatoid arthritis: a systematic review and 
meta-analysis. Lancet. 2015 Jul 18;386(9990):258–65. [PMID: 
25975452]
Singh JA et al. Biologics or tofacitinib for people with rheumatoid 
arthritis naive to methotrexate: a systematic review and net
-
work meta-analysis. Cochrane Database Syst Rev. 2017 May 8;
 
5:CD012657. [PMID: 28481462]
ADULT STILL DISEASE
Still disease is a systemic form of juvenile chronic arthritis 
in which high spiking fevers are much more prominent, 
especially at the outset, than arthritis. This syndrome also 
occurs in adults. Most adults are in their 20s or 30s; onset 
after age 60 is rare. The fever is dramatic, often with daily 
spikes to 40°C, associated with sweats and chills, and then 
plunging to normal or several degrees below normal in 
the absence of antipyretics. Many patients initially com
-
plain of sore throat. An evanescent salmon-colored non
-
pruritic rash, chiefly on the chest and abdomen, is a 
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characteristic feature. The rash can easily be missed since 
it often appears only with the fever spike. Many patients 
also have lymphadenopathy and pericardial effusions. 
Joint symptoms are mild or absent in the beginning, but a 
destructive arthritis, especially of the wrists, may develop 
months later. Anemia and leukocytosis, with white blood 
counts sometimes exceeding 40,000/mcL, are the rule. 
Serum ferritin levels are often strikingly elevated (greater than 
3000 mg/mL or 6741 pmol/L). The diagnosis of adult Still 
disease is strongly suggested by the quotidian fever pat
-
tern, sore throat, and the classic rash but requires exclu
-
sion of other causes of fever. About half of the patients 
respond to NSAIDs, and half require prednisone, some
-
times in doses greater than 60 mg/day orally. Targeting 
IL-1 with anakinra or canakinumab or IL-6 with tocili
-
zumab can be effective for patients with refractory disease. 
The course of adult Still disease can be monophasic, 
intermittent, or chronic. Macrophage activation syndrome 
is a life-threatening complication of adult Still disease and 
manifests as fever; splenomegaly; cytopenias; hypertri
-
glyceridemia; hypofibrinogenemia; marked elevation of 
serum ferritin; elevated soluble CD25; depressed natural 
killer cell activity; and hemophagocytosis in bone marrow, 
spleen, and lymph nodes.
Castañeda S et al. Adult-onset Still’s disease: advances in the 
treatment. Best Pract Res Clin Rheumatol. 2016 Apr;
 
30(2):222–38. [PMID: 27886796]
SYSTEMIC LUPUS ERYTHEMATOSUS
 
»
Occurs mainly in young women.
 
»
Rash over areas exposed to sunlight.
 
»
Joint symptoms in 90% of patients.
 
»
Anemia, leukopenia, thrombocytopenia.
 
»
Glomerulonephritis, central nervous system disease, 
and complications of antiphospholipid antibodies 
are major sources of disease morbidity.
 
»
Serologic findings:
 antinuclear antibodies (100%), 
anti–double-stranded DNA antibodies (approxi
-
mately two-thirds), and low serum complement 
levels (particularly during disease flares).
 
»
SLE is an inflammatory autoimmune disorder character
-
ized by autoantibodies to nuclear antigens. It can affect 
multiple organ systems. Many of its clinical manifesta
-
tions are secondary to the trapping of antigen-antibody 
complexes in capillaries of visceral structures or to 
autoantibody-mediated destruction of host cells (eg, 
thrombocytopenia). The clinical course is marked by 
spontaneous remission and relapses. The severity may 
vary from a mild episodic disorder to a rapidly fulmi
-
nant, life-threatening illness.
Table 20–6.
 
Criteria for the classification of SLE. 
 
(A patient is classified as having SLE if any 4 or more 
 
of 11 criteria are met.)
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Kidney disease
a. > 0.5 g/day proteinuria, or
b. ≥ 3+ dipstick proteinuria, or
c. Cellular casts
8. Neurologic disease
a. Seizures, or
b. Psychosis (without other cause)
9. Hematologic disorders
a. Hemolytic anemia, or Leukopenia (< 4000/mcL), or
b. Lymphopenia (< 1500/mcL), or
c. Thrombocytopenia (< 100,000/mcL)
10. Immunologic abnormalities
a. Antibody to native DNA, or
b. Antibody to Sm, or
c. Antibodies to antiphospholipid antibodies based on (1) IgG 
or IgM anticardiolipin antibodies, (2) lupus anticoagulant, or 
(3) false-positive serologic test for syphilis
11. Positive ANA
ANA, antinuclear antibody; SLE, systemic lupus erythematosus.
Modified and reproduced, with permission, from Tan EM et al. The 
1982 revised criteria for the classification of systemic lupus erythe
-
matosus. 
Arthritis Rheum
. 1982 Nov;25(11):1271-7, and data from 
Hochberg MC. Updating the American College of Rheumatology 
revised criteria for the classification of systemic lupus erythematosus. 
. 1997 Sep;40(9):1725.

The incidence of SLE is influenced by many factors, 
including sex, race, and genetic inheritance. About 85% of 
patients are women. Sex hormones appear to play some 
role; most cases develop after menarche and before meno
-
pause. Among older individuals, the sex distribution is 
more equal. Race is also a factor, as SLE occurs in 1:1000 
white women but in 1:250 black women. Familial occur
-
rence of SLE has been repeatedly documented, and the 
disorder is concordant in 25–70% of identical twins. If a 
mother has SLE, her daughters’ risks of developing the 
disease are 1:40 and her sons’ risks are 1:250. Aggregation 
of serologic abnormalities (positive antinuclear antibody) 
is seen in asymptomatic family members, and the preva
-
lence of other rheumatic diseases is increased among close 
relatives of patients. The importance of specific genes in 
SLE is emphasized by the high frequency of certain HLA 
haplotypes, especially DR2 and DR3, and null complement 
alleles.
The diagnosis of SLE should be suspected in patients 
having a multisystem disease with a positive test for 
antinuclear antibodies. It is imperative to ascertain that 
the condition has not been induced by a drug (see Drug-
Induced Lupus below).
The diagnosis of SLE can be made with reasonable prob
-
ability if 4 of the 11 criteria set forth in Table 20–6 are met. 
These criteria, developed as guidelines for the inclusion of 
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patients in research studies, do not supplant clinical judg
-
ment in the diagnosis of SLE.
 
»
The systemic features include fever, anorexia, malaise, and 
weight loss. Most patients have skin lesions at some time; 
the characteristic “butterfly” (malar) rash affects less than 
half of patients. Other cutaneous manifestations are pan
-
niculitis (lupus profundus), discoid lupus, typical fingertip 
lesions, periungual erythema, nail fold infarcts, and splin
-
ter hemorrhages. Alopecia is common. Mucous membrane 
lesions tend to occur during periods of exacerbation. Rayn
-
aud phenomenon, present in about 20% of patients, often 
antedates other features of the disease.
Joint symptoms, with or without active synovitis, occur in 
over 90% of patients and are often the earliest manifestation. 
The arthritis can lead to reversible swan-neck deformities, 
but erosive changes are almost never noted on radiographs. 
Subcutaneous nodules are rare.
Ocular manifestations include conjunctivitis, photo
-
phobia, transient or permanent monocular blindness, and 
blurring of vision. Cotton-wool spots on the retina (cytoid 
bodies) represent degeneration of nerve fibers due to 
occlusion of retinal blood vessels.
Pleurisy, pleural effusion, bronchopneumonia, and pneu
-
monitis are frequent. Restrictive lung disease can develop. 
Alveolar hemorrhage is uncommon but life-threatening. 
Interstitial lung disease is rare.
The pericardium is affected in the majority of patients. 
Heart failure may result from myocarditis and hypertension. 
Cardiac arrhythmias are common. Atypical verrucous endo
-
carditis of Libman-Sacks is usually clinically silent but 
occasionally can produce acute or chronic valvular 
regurgitation—most commonly mitral regurgitation.
Table 20–7.
 
Frequency (%) of autoantibodies in rheumatic diseases.
1
ANA
Anti-
Native 
DNA
Rheumatoid 
Factor
Anti-
Sm
Anti-
SS-A
Anti-
SS-B
Anti-
SCL-70
Anti-
 
Centromere
Anti-
Jo-1
ANCA
30–60
0–5
70
0
0–5
0–2
0
0
0
0
Systemic lupus 
95–100
60
20
10–25
15–20
5–20
0
0
0
0–1
Sjögren syndrome
95
0
75
0
65
65
0
0
0
0
Diffuse scleroderma
>95
0
30
0
0
0
33
1
0
0
Limited scleroderma 
(CREST syndrome)
>95
0
30
0
0
0
20
50
0
0
Polymyositis/
dermatomyositis
80
0
33
0
0
0
0
0
20–30
0
Granulomatosis with 
polyangiitis
0–15
0
50
0
0
0
0
0
0
93–96
1
1
Frequency for generalized, active disease.
ANA, antinuclear antibodies; Anti-Sm, anti-Smith antibody; anti-SCL-70, anti-scleroderma antibody; ANCA, antineutrophil cytoplasmic 
antibody; CREST, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia.
Mesenteric vasculitis occasionally occurs in SLE and 
may closely resemble polyarteritis nodosa, including the 
presence of aneurysms in medium-sized blood vessels. 
Abdominal pain (particularly postprandial), ileus, peritonitis, 
and perforation may result.
Neurologic complications of SLE include psychosis, cogni
-
tive impairment, seizures, peripheral and cranial neuropathies, 
transverse myelitis, and strokes. Severe depression and psycho
-
sis are sometimes exacerbated by the administration of large 
doses of corticosteroids.
Several forms of glomerulonephritis may occur, includ
-
ing mesangial, focal proliferative, diffuse proliferative, and 
membranous (see Chapter 22). Some patients may also have 
interstitial nephritis. With appropriate therapy, the survival 
rate even for patients with serious chronic kidney disease 
(proliferative glomerulonephritis) is favorable, albeit a sub
-
stantial portion of patients with severe lupus nephritis still 
eventually require renal replacement therapy.
(Tables 20–7 and 20–8.) SLE is characterized by the produc
-
tion of many different autoantibodies. Antinuclear antibody 
tests based on immunofluorescence assays using HEp-2 cells 
(a human cell line) as a source of nuclei are nearly 100% sensi
-

-
-
tive for SLE but not specific—ie, they are positive in low titer 
in up to 20% of healthy adults and also in many patients with 
nonlupus conditions such as rheumatoid arthritis, autoim
-
mune thyroid disease, scleroderma, and Sjögren syndrome. 
False-negative results can occur with tests for antinuclear 
antibodies based on multiplex assays that use specific nuclear 
antigens rather than cell lines. Therefore, SLE should not be 
excluded on the basis of a negative multiplex assay for anti
-
nuclear antibodies. Antibodies to double-stranded DNA and 
to Sm are specific for SLE but not sensitive, since they are 
present in only 60% and 30% of patients, respectively. 
Depressed serum complement—a finding suggestive of 
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disease activity—often returns toward normal in remission. 
Anti–double-stranded DNA antibody levels also correlate 
with disease activity in some patients; anti-Sm levels do not.
Three types of antiphospholipid antibodies occur 
(Table 20–8). The first is anti-cardiolipin antibodies (which 
includes antibodies that cause the biologic false-positive 
tests for syphilis); the second is the lupus anticoagulant, 
which despite its name is a risk factor for venous and arte
-
rial thrombosis and for miscarriage. The lupus anticoagu
-
lant often causes prolongation of the activated partial 
thromboplastin time, and its presence is confirmed by an 
abnormal phospholipid-dependent clotting test, such as 
the Russell viper venom time (RVVT), that corrects with 
the addition of excess phospholipid but not normal plasma. 
Antibodies to beta-2-glycoprotein 1 is the third type of 
antiphospholipid antibody. Abnormality of urinary sedi
-
ment is almost always found in association with kidney 
lesions. Showers of red blood cells, with or without casts, 
and proteinuria (varying from mild to nephrotic range) are 
frequent during exacerbation of the disease.
 
»
Differential diagnosis includes drug-induced lupus, rheu
-
matoid arthritis, systemic vasculitis, scleroderma, primary 
antiphospholipid syndrome, inflammatory myopathies, 
viral hepatitis, sarcoidosis, and acute drug reactions.
 
»
Treatment
Since the various manifestations of SLE affect prognosis 
differently and since SLE activity often waxes and wanes, 
Table 20–8.
 
Frequency (%) of laboratory abnormalities 
in systemic lupus erythematosus.
Anemia
60%
Leukopenia
45%
30%
Antiphospholipid antibodies
 
An
ti-cardiolipin antibody
25%
 
L
upus anticoagulant
7%
 
An
ti-beta-2-glycoprotein 1
25%
Direct Coombs-positive
30%
30%
Hematuria
30%
Hypocomplementemia
60%
ANA
95–100%
Anti-native DNA
50%
Anti-Sm
20%
ANA, antinuclear antibody; Anti-Sm, anti-Smith antibody.
Modified and reproduced, with permission, from Hochberg MC 
 
et al. Systemic lupus erythematosus: a review of clinicolaboratory 
features and immunologic matches in 150 patients with emphasis 
on demographic subsets. Medicine (Baltimore). 1985 Sep; 64(5): 
285–95.
drug therapy—both the choice of agents and the intensity 
of their use—must be tailored to match disease severity. 
Patients should be cautioned against sun exposure and 
should apply a protective lotion to the skin while out of 
doors. Skin lesions often respond to the local administra
-
tion of corticosteroids. Minor joint symptoms can usually 
be alleviated by rest and NSAIDs.
Antimalarials (hydroxychloroquine) may be helpful in 
treating lupus rashes or joint symptoms and appear to 
reduce the incidence of severe disease flares. The dose of 
hydroxychloroquine is 200 or 400 mg/day orally and should 
not exceed 5 mg/kg/day; annual monitoring for retinal 
changes is recommended. Drug-induced neuropathy and 
myopathy may be erroneously ascribed to the underlying 
disease.
Corticosteroids are required for the control of certain 
complications. (Systemic corticosteroids are not usually 
given for minor arthritis, skin rash, leukopenia, or the ane
-
mia associated with chronic disease.) Glomerulonephritis, 
hemolytic anemia, pericarditis or myocarditis, alveolar 
hemorrhage, central nervous system involvement, and 
thrombotic thrombocytopenic purpura all require cortico
-
steroid treatment and often other interventions as well. 
Forty to 60 mg of oral prednisone is often needed initially; 
however, the lowest dose of corticosteroid that controls the 
condition should be used (Table 26–16). Central nervous 
system lupus may require higher doses of corticosteroids 
than are usually given; however, corticosteroid psychosis 
may mimic lupus cerebritis, in which case reduced doses 
are appropriate. Immunosuppressive agents such as cyclo
-

-
phosphamide, mycophenolate mofetil, and azathioprine 
are used in cases resistant to corticosteroids. Treatment of 
severe lupus nephritis includes an induction phase and a 
maintenance phase. Cyclophosphamide, which improves 
renal survival but not patient survival, has been used for 
many years as the standard treatment for both phases of 
lupus nephritis. Cyclophosphamide can be administered 
according to the National Institutes of Health regimen 
(3–6 monthly intravenous pulses [0.5–1 g/m
2
] for induc
-
tion followed by maintenance infusions every 3 months) or 
the Euro-Lupus regimen (500 mg intravenously every 
 
2 weeks for 6 doses followed by maintenance with azathio
-
prine). Mycophenolate mofetil appears to be an equally 
effective alternative treatment to cyclophosphamide for 
many patients with lupus nephritis. Very close follow-up is 
needed to watch for potential side effects when immuno
-
suppressants are given; these agents should be adminis
-
tered by clinicians experienced in their use. When 
cyclophosphamide is required, gonadotropin-releasing hor
-
mone analogs can be given to protect a woman against the 
risk of premature ovarian failure. Belimumab, a monoclonal 
antibody that inhibits the activity of a B-cell growth factor, 
is FDA approved for treating antibody-positive SLE 
patients with active disease who have not responded to 
standard therapies (eg, NSAIDs, antimalarials, or immu
-
nosuppressive therapies); it is not recommended for lupus 
nephritis or for use in conjunction with cyclophospha
-
mide. Rituximab is usually reserved for life-threatening or 
organ-threatening manifestations that have failed conven
-
tional therapies.
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»
Ten-year survival rates exceeding 85% are routine. In most 
patients, the illness pursues a relapsing and remitting course. 
Prednisone, often needed in doses of 40 mg/day orally or 
more during severe flares, can usually be tapered to low 
doses (5–10 mg/day) when the disease is inactive. However, 
there are some in whom the disease pursues a virulent 
course, leading to serious impairment of vital structures 
such as lungs, heart, brain, or kidneys, and the disease may 
lead to death. With improved control of lupus activity and 
with increasing use of corticosteroids and immunosuppres
-
sive drugs, the mortality and morbidity patterns in lupus 
have changed. Mortality in SLE shows a bimodal pattern. In 
the early years after diagnosis, infections—especially with 
opportunistic organisms—are the leading cause of death, 
followed by active SLE, chiefly due to kidney or central ner
-
vous system disease. In later years, accelerated atherosclero
-
sis, linked to chronic inflammation, becomes a major cause 
of death. Indeed, the incidence of myocardial infarction is 
five times higher in persons with SLE than in the general 
population. Therefore, it is especially important for SLE 
patients to avoid smoking and to minimize other conven
-
tional risk factors for atherosclerosis (eg, hypercholesterol
-
emia, hypertension, obesity, and inactivity). Patients with 
SLE should receive influenza vaccination every year and 
pneumococcal vaccination every 5 years. Since SLE patients 
have a higher risk of developing malignancy (especially lym
-
phoma, lung cancer, and cervical cancer), preventive cancer 
screening recommendations should be followed assiduously. 
With more patients living longer, it has become evident that 
avascular necrosis of bone, affecting most commonly the 
hips and knees, is responsible for substantial morbidity. 
Nonetheless, the outlook for most patients with SLE is 
increasingly favorable.
 
»
•	
Appropriate diagnosis and management of SLE requires 
the active participation of a rheumatologist.
•	
The severity of organ involvement dictates referral to 
other subspecialists, such as nephrologists and 
pulmonologists.
 
»
•	
Rapidly progressive glomerulonephritis, pulmonary 
hemorrhage, transverse myelitis, and other severe 
organ-threatening manifestations of lupus usually 
require in-patient assessment and management.
•	
Severe infections, particularly in the setting of immu
-
nosuppressant therapy, should prompt admission.
Andreoli L et al. EULAR recommendations for women’s health 
and the management of family planning, assisted reproduc
-
tion, pregnancy and menopause in patients with systemic 
lupus erythematosus and/or antiphospholipid syndrome. 
Ann Rheum Dis. 2017 Mar;76(3):476–85. [PMID: 27457513]
Ospina FE et al. Distinguishing infections vs flares in patients 
with systemic lupus erythematosus. Rheumatology (Oxford). 
2017 Apr 1;56(Suppl 1):i46–54. [PMID: 27744359]
Pisetsky DS. Antinuclear antibody testing—misunderstood or 
misbegotten? Nat Rev Rheumatol. 2017 Aug;13(8):495–502. 
[PMID: 28541299]
Thong B et al. Systemic lupus erythematosus diagnosis and man
-
agement. Rheumatology (Oxford). 2017 Apr 1;56(Suppl 1):
 
i3–13. [PMID: 28013206]
DRUG-INDUCED LUPUS
Drug-induced lupus shares several clinical and serologic 
features with SLE but is due to ongoing exposure to a drug 
and resolves when the offending drug is discontinued. In 
contrast to SLE, the sex ratio is nearly equal. As a general 
rule, drug-induced lupus presents with fever, arthralgia, 
myalgia, and serositis but not renal involvement, neurologic 
symptoms, or other features of SLE. Serologic testing 
reveals elevated titers of antinuclear antibodies in all 
patients, but antibodies to DNA, Sm, RNP , SS-A, and SS-B 
are rare. Antibodies to histones are common but also are 
seen in SLE and thus do not distinguish drug-induced lupus

seen in SLE and thus do not distinguish drug-induced lupus 
from SLE. Complement levels are usually normal. There are 
definite associations between the development of drug-
induced lupus and the use of hydralazine, isoniazid, and 
minocycline as well as several medications no longer com
-
monly prescribed (procainamide, quinidine, methyldopa, 
chlorpromazine). The list of drugs implicated as possible 
causes of drug-induced lupus in observational studies and 
case reports is extensive. The incidence of drug-induced 
lupus in patients taking hydralazine for a year or longer is as 
high as 5–8%; for most other medications, the risk is con
-
siderably lower (less than 1%). TNF inhibitors can induce 
antibodies to DNA, but the incidence of lupus-like syndromes 
on these medications is low (0.5–1%).
Pérez-De-Lis M et al. Autoimmune diseases induced by biological 
agents. A review of 12,731 cases (BIOGEAS Registry). Expert 
Opin Drug Saf. 2017 Nov;16(11):1255–71. [PMID: 28854831]
 
»
Hypercoagulability; recurrent arterial or venous 
thromboses.
 
»
Thrombocytopenia is common.
 
»
Recurrent fetal loss.
 
»
Recurrent events are common; lifetime anticoagu
-
lation with warfarin is recommended.
 
»
Primary antiphospholipid syndrome (APS) is diagnosed in 
patients who have venous or arterial occlusions or preg
-
nancy complications (ie, three or more first-trimester 
miscarriages, unexplained fetal death and premature birth 
before 34 weeks of gestation attributable to severe pre
-
eclampsia, eclampsia or placental insufficiency) in the 
presence of persistent (12 weeks or longer), high-titer, 
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diagnostic antiphospholipid antibodies but no other fea
-
tures of SLE (see Chapter 19). Diagnostic antiphospholipid 
antibodies are IgG or IgM anticardiolipin, or IgG or IgM 
antibodies to beta-2-glycoprotein 1, and lupus anticoagu
-
lant. In less than 1% of patients with antiphospholipid 
antibodies, a potentially devastating syndrome known as 
the “catastrophic antiphospholipid syndrome” occurs, lead
-
ing to diffuse thromboses, thrombotic microangiopathy, 
and multiorgan system failure.
 
»
Patients are often asymptomatic until suffering a throm
-
botic complication of this syndrome or a pregnancy loss. 
Thrombotic events may occur in either the arterial or 
venous circulations. Thus, deep venous thromboses, pul
-
monary emboli, and cerebrovascular accidents are typical 
clinical events among patients with the APS. In case-
control studies, 3.1% of patients in the general population 
who experienced a venous thrombotic event (in the 
absence of cancer) tested positive for the lupus anticoagu
-
lant (versus 0.9% of controls, yielding an odds ratio of 3.6). 
For women younger than 50 years in whom stroke devel
-
oped, the odds ratio for having the lupus anticoagulant is 
43.1. Budd-Chiari syndrome, cerebral sinus vein throm
-
bosis, myocardial or digital infarctions, hemorrhagic 
infarction of the adrenal glands (due to adrenal vein 
thrombosis), and other thrombotic events also occur. A 
variety of other symptoms and signs are often attributed to 
the APS, including thrombocytopenia, mental status 
changes, livedo reticularis, skin ulcers, microangiopathic 
nephropathy, and cardiac valvular dysfunction—typically 
mitral regurgitation due to Libman-Sacks endocarditis. 
Livedo reticularis is strongly associated with the subset of 
patients with APS in whom arterial ischemic events 
develop. Pregnancy losses that are associated with APS 
include unexplained fetal death after the first trimester, 
one or more premature births before 34 weeks because of 
eclampsia or preeclampsia, or three or more unexplained 
miscarriages during the first trimester.
As noted in the discussion of SLE, three types of antiphos
-
pholipid antibody are associated with this syndrome: (1) 
anti-cardiolipin antibodies, (2) antibodies to beta-2 glyco
-
protein, and (3) a “lupus anticoagulant” that prolongs cer
-
tain phospholipid-dependent coagulation tests (see below). 
Antibodies to cardiolipin and to beta-2 glycoprotein are 
typically measured with enzyme immunoassays. Anti-
cardiolipin antibodies can produce a biologic false-positive 
test for syphilis (ie, a positive rapid plasma reagin but nega
-
tive specific anti-treponemal assay). In general, IgG anti-
cardiolipin antibodies are believed to be more pathologic 
than IgM. Presence of the lupus anticoagulant is a stronger 
risk factor for thrombosis or pregnancy loss than is the 
presence of antibodies to either beta-2-glycoprotein I or 
anticardiolipin. A clue to the presence of a lupus anticoagu
-
lant, which may occur in individuals who do not have 
SLE, may be detected by a prolongation of the partial 
thromboplastin time (which, paradoxically, is associated 
with a thrombotic tendency rather than a bleeding risk). 
Testing for the lupus anticoagulant involves phospholipid-
dependent functional assays of coagulation, such as the 
Russell viper venom time (RVVT). In the presence of a 
lupus anticoagulant, the RVVT is prolonged and does not 
correct with mixing studies but does with the addition of 
excess phospholipid.
 
»
The exclusion of other autoimmune disorders, particularly 
those in the SLE spectrum, is essential because such disor
-
ders may be associated with additional complications 
requiring alternative treatments. Other genetic or acquired 
conditions associated with hypercoagulability such as pro
-

-
-
tein C, protein S, or antithrombin deficiency and factor V 
Leiden should be excluded. Catastrophic APS has a broad 
differential, including sepsis, pulmonary-renal syndromes, 
systemic vasculitis, disseminated intravascular coagula
-
tion, and thrombotic thrombocytopenic purpura.
 
»
Treatment
Patients should be given warfarin to maintain an INR of 
2.0–3.0. The efficacy and safety of direct-acting oral antico
-
agulants for the antiphospholipid syndrome have not been 
established. Patients who have recurrent thrombotic events 
on this level of anticoagulation may require higher INRs 
(greater than 3.0), but the bleeding risk increases substan
-
tially with this degree of anticoagulation. Guidelines indicate 
that patients with APS should be treated with anticoagula
-
tion for life. Because of the teratogenic effects of warfarin, 
subcutaneous heparin and low-dose aspirin (81 mg) is the 
usual approach to prevent pregnancy complications in 
women with APS (see Chapter 19). In patients with cata
-
strophic APS, a three-pronged approach is taken in the acute 
setting: intravenous heparin, high doses of corticosteroids, 
and either intravenous immune globulin or plasmapheresis.
Arachchillage DRJ et al. Pathogenesis and management of antiphos
-
pholipid syndrome. Br J Haematol. 2017 Jul;178(2):181–95. 
[PMID: 28339096]
Sciascia S et al. Diagnosing antiphospholipid syndrome: ‘extra-
criteria’ manifestations and technical advances. Nat Rev 
Rheumatol. 2017 Sep;13(9):548–60. [PMID: 28769114]
RAYNAUD PHENOMENON
 
»
Paroxysmal bilateral digital pallor and cyanosis 
followed by rubor.
 
»
Precipitated by cold or emotional stress; relieved 
by warmth.
 
»
Primary form:
 benign course; usually affects young 
women.
 
»
Secondary form:
 can cause digital ulceration or 
gangrene.
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»
Raynaud phenomenon (RP) is a syndrome of paroxysmal 
digital ischemia, most commonly caused by an exaggerated 
response of digital arterioles to cold or emotional stress. 
The initial phase of RP , mediated by excessive vasocon
-
striction, consists of well-demarcated digital pallor or cya
-
nosis; the subsequent (recovery) phase of RP , caused by 
vasodilation, leads to intense hyperemia and rubor. 
Although RP chiefly affects fingers, it can also affect toes 
and other acral areas such as the nose and ears. RP is clas
-
sified as primary (idiopathic or Raynaud disease) or sec
-
ondary. Nearly one-third of the population reports being 
“sensitive to the cold” but does not experience the parox
-
ysms of digital pallor, cyanosis, and erythema characteris
-
tic of RP . Primary RP occurs in 2–6% of adults, is especially 
common in young women, and poses more of a nuisance 
than a threat to good health. In contrast, secondary RP is 
less common, is chiefly associated with rheumatic diseases 
(especially scleroderma), and is frequently severe enough 
to cause digital ulceration or gangrene.
 
»
In early attacks of RP , only one or two fingertips may be 
affected; as it progresses, all fingers down to the distal palm 
may be involved. The thumbs are rarely affected. During 
recovery there may be intense rubor, throbbing, paresthe
-
sia, pain, and slight swelling. Attacks usually terminate 
spontaneously or upon returning to a warm room or put
-
ting the extremity in warm water. The patient is usually 
asymptomatic between attacks. Sensory changes that often 
accompany vasomotor manifestations include numbness, 
stiffness, diminished sensation, and aching pain.
Primary RP appears first between ages 15 and 30, almost 
always in women. It tends to be mildly progressive and, 
unlike secondary RP (which may be unilateral and may 
involve only one or two fingers), symmetric involvement of 
the fingers of both hands is the rule. Spasm becomes more 
frequent and prolonged. Unlike secondary RP , primary RP 
does not cause digital pitting, ulceration, or gangrene.
Nailfold capillary abnormalities are among the earliest 
clues that a person has secondary rather than primary RP . 
The nailfold capillary pattern can be visualized by placing a 
drop of grade B immersion oil at the patient’s cuticle and 
then viewing the area with an ophthalmoscope set to 
20–40 diopters. Dilation or dropout of the capillary loops 
indicates the patient has a secondary form of RP , most com
-
monly scleroderma (Table 20–9). While highly specific for 
secondary RP , nailfold capillary changes have a low sensitiv
-
ity. Digital pitting or ulceration or other abnormal physical 
findings (eg, skin tightening, loss of extremity pulse, rash, 
swollen joints) can also provide evidence of secondary RP .
Primary RP must be differentiated from the numerous 
causes of secondary RP (Table 20–9). The history and 
examination may suggest the diagnosis of scleroderma, 
SLE, and mixed connective tissue disease; RP is often the 
first manifestation of limited scleroderma (CREST syn
-
drome). The diagnosis of many of these rheumatic dis
-
eases can be confirmed with specific serologic tests (see 
Table 20–7).
Table 20–9.
 
Causes of secondary Raynaud phenomenon.
Rheumatic diseases
 
S
 
Dermatomyositis/polymyositis
 
Sjög
 
V
asculitis (polyarteritis nodosa, Takayasu disease, Buerger disease)
Neurovascular compression and occupational
 
C
arpal tunnel syndrome
 
T
horacic outlet obstruction
 
V
ibration injury
 
S
erotonin agonists (sumatriptan)
 
S
ympathomimetic drugs (decongestants)
 
Chemother
apy (bleomycin, vinblastine)
 
Caffeine
 
Nicotine
Hematologic disorders
 
Cryoglobulinemia
 
P
 
Paraproteinemia
 
C
old agglutinins
Endocrine disorders
 
Miscellaneous

Caffeine
 
Nicotine
 
P
 
C
 
Atherosclerosis
 
Embolic 
disease
 
Migraine
 
Exposur
e to epoxy resins
 
S
equela of frostbite
RP may occur in patients with the thoracic outlet syn
-
dromes. In these disorders, involvement is generally uni
-
lateral, and symptoms referable to brachial plexus 
compression tend to dominate the clinical picture. Carpal 
tunnel syndrome should also be considered, and nerve 
conduction tests are appropriate in selected cases.
 
»
The differentiation from Buerger disease (thromboangiitis 
obliterans) is usually not difficult, since thromboangiitis 
obliterans is generally a disease of men, particularly smok
-
ers; peripheral pulses are often diminished or absent; and, 
when RP occurs in association with thromboangiitis oblit
-
erans, it is usually in only one or two digits.
In acrocyanosis, cyanosis of the hands is permanent and 
diffuse; the sharp and paroxysmal line of demarcation with 
pallor does not occur with acrocyanosis. Frostbite may lead 
to chronic RP .
RP may be mimicked by type I cryoglobulinemia, in 
which a monoclonal antibody cryoprecipitates in the cooler 
distal circulation. Type I cryoglobulinemia is usually associ
-
ated with plasma cell myeloma or with lymphoproliferative 
Erythromelalgia can mimic the rubor phase of RP; 
exacerbation by heat and relief with cold readily distin
-
guish erythromelalgia from RP .
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»
Treatment
Patients should wear gloves or mittens whenever outside 
in temperatures that precipitate attacks. Keeping the body 
warm is also a cornerstone of initial therapy. Wearing 
warm shirts, coats, and hats will help prevent the exagger
-
ated vasospasm that causes RP and that is not prevented 
by warming only the hands. The hands should be pro
-
tected from injury at all times; wounds heal slowly, and 
infections are consequently hard to control. Softening and 
lubricating lotion to control the fissured dry skin should 
be applied to the hands frequently. Smoking should be 
stopped and sympathomimetic drugs (eg, decongestants, 
diet pills, and amphetamines) should be avoided. For 
most patients with primary RP , general measures alone 
are sufficient to control symptoms. Medical or surgical 
therapy should be considered in patients who have severe 
symptoms or are experiencing tissue injury from digital 
ischemia.
Calcium channel blockers are first-line therapy for RP . 
Calcium channel blockers produce a modest benefit and 
are more effective in primary RP than secondary RP . 
Slow release nifedipine (30–180 mg/day orally), amlo
-
dipine (5–20 mg/day orally), felodipine, isradipine, or 
nisoldipine are popular and more effective than vera
-
pamil, nicardipine, and diltiazem. Other medications 
that are sometimes effective in treating RP include 
angiotensin-converting enzyme inhibitors, sympatho
-
lytic agents (eg, prazosin), topical nitrates, phosphodies
-
terase inhibitors (eg, sildenafil, tadalafil, and vardenafil), 
selective serotonin reuptake inhibitors (fluoxetine), 
endothelin-receptor inhibitors (ie, bosentan), statins, 
parenteral prostaglandins (prostaglandin E
1
), and oral 
prostaglandins (misoprostol).
Sympathectomy may be indicated when attacks have 
become frequent and severe, when they interfere with work 
and well-being, and particularly when trophic changes 
have developed and medical measures have failed. Cervical 
sympathectomy is modestly effective for primary but 
not secondary RP . Digital sympathectomy may improve 
secondary RP .
 
»
Prognosis
Primary RP is benign and largely a nuisance for affected 
individuals who are exposed to cold winters or excessive air 
conditioning. The prognosis of secondary RP depends on 
the severity of the underlying disease. Unfortunately, 
severe pain from ulceration and gangrene is not rare with 
scleroderma, especially the CREST variant.
 
»
Appropriate management of patients with secondary RP 
often requires consultation with a rheumatologist.
 
»
Patients with severe digital ischemia as evidenced by 
demarcation should be admitted for intensive therapy.
Mueller M et al. Relation of nailfold capillaries and autoanti
-
bodies to mortality in patients with Raynaud phenomenon. 
Circulation. 2016 Feb 2;133(5):509–17. [PMID: 26733605]
SCLERODERMA (
Systemic Sclerosis
)
 
»
Limited disease
 (80% of patients): skin thickening 
confined to face, neck, and distal extremities.
 
»
Diffuse disease
 (20%): widespread thickening of 
skin, including truncal involvement, with areas of 
increased pigmentation and depigmentation.
 
»
Raynaud phenomenon and antinuclear antibodies 
are present in virtually all patients.
 
»
Systemic features:
 gastroesophageal reflux, gas
-
trointestinal hypomotility, pulmonary fibrosis, 
pulmonary hypertension, renal involvement.
 
»
Scleroderma (systemic sclerosis) is a rare chronic disorder 
characterized by diffuse fibrosis of the skin and internal 
organs. Symptoms usually appear in the third to fifth 
decades, and women are affected two to three times as 
frequently as men.
Two forms of scleroderma are generally recognized: lim
-
ited (80% of patients) and diffuse (20%). In limited sclero
-
derma, which is also known as the CREST syndrome

-
-
derma, which is also known as the CREST syndrome 
(representing calcinosis cutis, Raynaud phenomenon, esopha
-
geal motility disorder, sclerodactyly, and telangiectasia), the 
hardening of the skin (scleroderma) is limited to the face and 
hands. In contrast, in diffuse scleroderma, the skin changes 
also involve the trunk and proximal extremities. Tendon fric
-
tion rubs over the forearms and shins occur uniquely (but not 
universally) in diffuse scleroderma. In general, patients with 
limited scleroderma have better outcomes than those with 
diffuse disease, largely because kidney disease or interstitial 
lung disease rarely develops in patients with limited disease. 
Cardiac disease is also more characteristic of diffuse sclero
-
derma. Patients with limited disease, however, are more sus
-
ceptible to digital ischemia, leading to finger loss, and to 
life-threatening pulmonary hypertension. Small and large 
bowel hypomotility, which may occur in either form of sclero
-
derma, can cause constipation alternating with diarrhea, 
malabsorption due to bacterial overgrowth, pseudoobstruc
-
tion, and severe bowel distention with rupture.
 
»
Raynaud phenomenon is usually the initial manifestation 
and can precede other signs and symptoms by years in 
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cases of limited scleroderma. Polyarthralgia, weight loss, 
and malaise are common early features of diffuse sclero
-
derma but are infrequent in limited scleroderma. Cutane
-
ous disease usually, but not always, develops before visceral 
involvement and can manifest initially as non-pitting sub
-
cutaneous edema associated with pruritus. With time the 
skin becomes thickened and hidebound, with loss of nor
-
mal folds. Telangiectasia, pigmentation, and depigmenta
-
tion are characteristic. Ulceration about the fingertips and 
subcutaneous calcification are seen. Dysphagia and symp
-
toms of reflux due to esophageal dysfunction are common 
and result from abnormalities in motility and later from 
fibrosis. Fibrosis and atrophy of the gastrointestinal tract 
cause hypomotility. Large-mouthed diverticuli occur in the 
jejunum, ileum, and colon. Diffuse pulmonary fibrosis and 
pulmonary vascular disease are reflected in restrictive lung 
physiology and low diffusing capacities. Cardiac abnor
-
malities include pericarditis, heart block, myocardial 
fibrosis, and right heart failure secondary to pulmonary 
hypertension. Scleroderma renal crisis, resulting from 
intimal proliferation of smaller renal arteries and usually 
associated with hypertension, is a marker for a poor out
-
come even though many cases can be treated effectively 
with angiotensin-converting enzyme inhibitors.
Mild anemia is often present. In scleroderma renal crisis, 
the peripheral blood smear shows findings consistent with 
a microangiopathic hemolytic anemia (due to mechanical 
damage to red cells from diseased small vessels). Elevation 
of the ESR is unusual. Proteinuria appears in association 
with renal involvement. Antinuclear antibody tests are 
nearly always positive, frequently in high titers (Table 20–7). 
The scleroderma antibody (anti-SCL-70), directed against 
topoisomerase III, is found in one-third of patients with 
diffuse systemic sclerosis and in 20% of those with CREST 
syndrome. Although present in only a small number of 
patients with diffuse scleroderma, anti-SCL-70 antibodies 
may portend a poor prognosis, with a high likelihood of 
serious internal organ involvement (eg, interstitial lung 
disease). Anticentromere antibodies are seen in 50% of 
those with CREST syndrome and in 1% of individuals 
with diffuse scleroderma (Table 20–7). Anticentromere 
antibodies are highly specific for limited scleroderma, but 
they also occur occasionally in overlap syndromes. Anti-
RNA polymerase III antibodies develop in 10–20% of 
scleroderma patients overall and correlate with the devel
-
opment of diffuse skin disease and renal hypertensive 
crisis.
 
»
Early in its course, scleroderma can cause diagnostic con
-
fusion with other causes of Raynaud phenomenon, partic
-
ularly SLE, mixed connective tissue disease, and the 
inflammatory myopathies. Eosinophilic fasciitis is a rare 
disorder presenting with skin hardening that resemble dif
-
fuse scleroderma. The inflammatory abnormalities, how
-
ever, are limited to the fascia rather than the dermis and 
epidermis. Moreover, patients with eosinophilic fasciitis 
are distinguished from those with scleroderma by the pres
-
ence of peripheral blood eosinophilia, the absence of Rayn
-
aud phenomenon, the good response to prednisone, and an 
association (in some cases) with paraproteinemias. Diffuse 
skin thickening and visceral involvement are features of 
scleromyxedema; the presence of a paraprotein, the absence 
of Raynaud phenomenon, and distinct skin histology point 
to scleromyxedema. Diabetic cheiropathy typically devel
-
ops in longstanding, poorly controlled diabetes mellitus 
and can mimic sclerodactyly. Nephrogenic fibrosing der
-
mopathy produces thickening and hardening of the skin of 
the trunk and extremities in patients with chronic kidney 
disease; exposure to gadolinium may play a pathogenic

-
disease; exposure to gadolinium may play a pathogenic 
role. Morphea and linear scleroderma cause scleroderma
-
tous changes limited to circumscribed areas of the skin and 
usually have excellent outcomes.
 
»
Treatment
Treatment of scleroderma is symptomatic and supportive 
and focuses on the organ systems involved. There is no effec
-
tive therapy for the underlying disease process. However, 
interventions for management of specific organ manifesta
-
tions of this disease have improved substantially. First-line 
therapy for moderately severe Raynaud syndrome is a 
calcium channel blocker, eg, long-acting nifedipine, 
30–120 mg/day orally. Poor responders can be treated with 
a PDE-5 inhibitor, eg, sildenafil 50 mg orally twice daily. 
Severe Raynaud syndrome can be treated with intravenous 
iloprost. Patients with esophageal disease should take medi
-
cations in liquid or crushed form. Esophageal reflux can be 
reduced and the risk of scarring diminished by avoidance of 
late-night meals and by the use of proton pump inhibitors 
(eg, omeprazole, 20–40 mg/day orally), which achieve near-
complete inhibition of gastric acid production and are 
remarkably effective for refractory esophagitis. Patients with 
delayed gastric emptying maintain their weight better if they 
eat small, frequent meals and remain upright for at least 
 
2 hours after eating. Malabsorption due to bacterial over
-
growth responds to antibiotics, eg, tetracycline, 500 mg four 
times orally daily, often prescribed cyclically. The hyperten
-
sive crises associated with scleroderma renal crisis must be 
treated early and aggressively (in the hospital) with angio
-
tensin-converting enzyme inhibitors, eg, captopril, initiated 
at 25 mg orally every 6 hours and titrated up as tolerated to 
a maximum of 100 mg every 6 hours. Apart from the patient 
with myositis, prednisone has little or no role in the treat
-
ment of scleroderma; doses higher than 15 mg/day have 
been associated with scleroderma renal crisis. Cyclophos
-
phamide improves dyspnea and pulmonary function tests 
modestly in patients with severe interstitial lung disease; this 
highly toxic drug should only be administered by physicians 
familiar with its use. In patients with early diffuse sclero
-
derma, methotrexate has been used in the treatment of skin 
disease, arthritis, and myositis. The usual initial dose is 
7.5 mg of methotrexate orally once weekly. If the patient has 
tolerated methotrexate but has not responded in 1 month, 
the dose can be increased to 15 mg orally once per week. The 
maximal dose is usually 20–25 mg/wk. Mycophenolate 
mofetil, 1 g twice daily, stabilized lung function in small, 
uncontrolled studies of patients with interstitial lung disease. 
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Bosentan, an endothelin receptor antagonist, improves exer
-
cise capacity and cardiopulmonary hemodynamics in 
patients with pulmonary hypertension and helps prevent 
digital ulceration. Sildenafil, prostaglandins (delivered by 
continuous intravenous infusion or intermittent inhalation), 
or riociguat may also be useful in treating pulmonary hyper
-
tension. At an experimental level, immunoablative therapy 
with or without stem cell rescue has achieved promising 
results for some patients with severe, rapidly progressive dif
-
fuse scleroderma.
The 9-year survival rate in scleroderma averages 
approximately 40%. The prognosis tends to be worse in 
those with diffuse scleroderma, in blacks, in men, and in 
older patients. Lung disease—in the form of pulmonary 
fibrosis or pulmonary arterial hypertension—is the num
-
ber one cause of mortality. Death from advanced heart 
failure or chronic kidney disease is also common. Those 
persons in whom severe internal organ involvement does 
not develop in the first 3 years have a substantially better 
prognosis, with 72% surviving at least 9 years. Breast and 
lung cancer may be more common in patients with sclero
-
derma. Studies conducted in a small number of patients 
with simultaneous onset of cancer and scleroderma have 
demonstrated that the scleroderma developed as a conse
-
quence of an immune response directed at the cancer.
 
»
•	
Appropriate management of scleroderma requires 
frequent consultations with a rheumatologist.
•	
Severity of organ involvement dictates referral to other 
subspecialists, such as pulmonologists, gastroenterologists, 
or nephrologists.
Gelber AC et al. Race and association with disease manifesta
-
tions and mortality in scleroderma: a 20-year experience at 
the Johns Hopkins Scleroderma Center and review of the lit
-
erature. Medicine (Baltimore). 2013 Jul;92(4):191–205. 
[PMID: 23793108]
Hughes M et al. Digital ulcers in systemic sclerosis. Rheumatol
-
ogy (Oxford). 2017 Jan;56(1):14–25. [PMID: 27094599]
Kowal-Bielecka O et al; EUSTAR Coauthors. Update of EULAR 
recommendations for the treatment of systemic sclerosis. 
Ann Rheum Dis. 2017 Aug;76(8):1327–39. [PMID: 27941129]
Woodworth TG et al. Scleroderma renal crisis and renal 
involvement in systemic sclerosis. Nat Rev Nephrol. 2016 Nov;
 
12(11):678–91. [PMID: 27641135]
IDIOPATHIC INFLAMMATORY MYOPATHIES 
(Polymyositis & Dermatomyositis)
 
»
Bilateral proximal muscle weakness.
 
»
 characteristic cutaneous mani
-
festations (Gottron papules, heliotrope rash); 
increased risk of malignancy.
 
»
Elevated creatine kinase, myositis-specific antibodies, 
diagnostic muscle biopsy.
 
»
Inclusion body myositis:
 can mimic polymyositis 
but is less responsive to treatment.
 
»
Polymyositis and dermatomyositis are systemic disorders of 
unknown cause whose principal manifestation is muscle 
weakness. Although their clinical presentations (aside from 
the presence of certain skin findings in dermatomyositis, 
some of which are pathognomonic) and treatments are simi
-
lar, the two diseases are pathologically quite distinct. They 
affect persons of any age group, but the peak incidence is in 
the fifth and sixth decades of life. Women are affected twice 
as commonly as men, and the diseases (particularly poly
-
myositis) also occur more often among blacks than whites. 
There is an increased risk of malignancy in adult patients 
with dermatomyositis. Indeed, up to one patient in four with 
dermatomyositis has an occult malignancy. Malignancies 
may be evident at the time of presentation with the muscle 
disease but may not be detected until months afterward in 
some cases. The malignancies most commonly associated 
with dermatomyositis in descending order of frequency are 
ovarian, lung, pancreatic, stomach, colorectal, and non-

Hodgkin lymphoma. Patients may have skin disease without 
overt muscle involvement, a condition termed dermatomyo
-
sitis sine myositis; these patients can have aggressive intersti
-
tial lung disease. Myositis may also be associated with other 
connective tissue diseases, especially scleroderma, systemic 
lupus erythematosus, mixed connective tissue disease, and 
Sjögren syndrome.
 
»
 may begin abruptly, but the usual presenta
-
tion is one of progressive muscle weakness over weeks to 
months. The weakness chiefly involves proximal muscle 
groups of the upper and lower extremities as well as the 
neck. Leg weakness (eg, difficulty in rising from a chair or 
climbing stairs) typically precedes arm symptoms. In con
-
trast to myasthenia gravis, polymyositis and dermatomyosi
-
tis do not cause facial or ocular muscle weakness. Pain and 
tenderness of affected muscles occur in one-fourth of cases, 
but these are rarely the chief complaints. About one-fourth 
of patients have dysphagia. In contrast to scleroderma, 
which affects the smooth muscle of the lower esophagus 
and can cause a “sticking” sensation below the sternum, 
polymyositis or dermatomyositis involves the striated mus
-
cles of the upper pharynx and can make initiation of swal
-
lowing difficult. Muscle atrophy and contractures occur as 
late complications of advanced disease. Clinically signifi
-
cant myocarditis is uncommon even though there is often 
creatine kinase-MB elevation. Patients who are bed-bound 
from myositis should be screened for respiratory muscle 
weakness that can be severe enough to cause CO
2
 retention 
and can progress to require mechanical ventilation.
The characteristic rash of 
 is dusky red 
and may appear in a malar distribution mimicking the classic 
rash of SLE. Facial erythema beyond the malar distribution is 
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also characteristic of dermatomyositis. Erythema also occurs 
over other areas of the face, neck, shoulders, and upper chest 
and back (“shawl sign”). Periorbital edema and a purplish 
(heliotrope) suffusion over the eyelids are typical signs 
(Figure 20–5). Coloration of the heliotrope and other rashes 
of dermatomyositis can be affected by skin tone. In blacks, 
the rashes may appear more hyperpigmented than erythema
-
tous or violaceous. Periungual erythema, dilations of nailfold 
capillaries, Gottron papules (raised violaceous lesions overly
-
ing the dorsa of DIP , PIP , and MCP joints) and Gottron sign 
(erythematous rash on the extensors surfaces of the fingers, 
elbows, and knees) are highly suggestive. Scalp involvement 
by dermatomyositis may mimic psoriasis. Infrequently, the 
cutaneous findings of this disease precede the muscle inflam
-
mation by weeks or months. Diagnosing polymyositis in 
patients over age 70 years can be difficult because weakness 
may be overlooked or attributed erroneously to idiopathic 
frailty. A subset of patients with polymyositis and dermato
-
myositis develop the 
“antisynthetase syndrome, ”
 a group of 
findings including inflammatory nonerosive arthritis, fever, 
Raynaud phenomenon, “mechanic’s hands” (hyperkeratosis 
along the radial and palmar aspects of the fingers), interstitial 
lung disease, and often severe muscle disease associated with 
certain autoantibodies (eg, anti-Jo-1 antibodies).
Measurement of serum levels of muscle enzymes, especially 
creatine kinase and aldolase, is most useful in diagnosis and 
in assessment of disease activity. Polymyositis can be misdi
-
agnosed as hepatitis because of elevations in alanine amino
-
transferase (ALT) and aspartate aminotransferase (AST) 
levels. Anemia is uncommon. The ESR and C-reactive pro
-
tein are often normal and are not reliable indicators of dis
-
ease activity. Rheumatoid factor is found in a minority of 
patients. Antinuclear antibodies are present in many 
patients, especially those who have an associated connective 
tissue disease. A number of autoantibodies are seen exclu
-
sively in patients with myositis and are associated with dis
-
tinctive clinical features (Table 20–10). The most common 
 
▲
Figure 20–5.
 
Bilateral heliotrope rash, which is a 
pathognomonic sign of dermatomyositis. 
myositis-specific antibody, anti-Jo-1 antibody, is seen in the 
subset of patients who have antisynthetase syndrome. The 
other myositis-specific autoantibodies are anti-Mi-2, associ
-
ated with dermatomyositis; anti-SRP (anti-signal recogni
-
tion particle), associated with rapidly progressive, severe 
polymyositis, and dysphagia; and anti-155/140, strongly 
associated with dermatomyositis with malignancy (malig
-
nancy in 71% with versus 11% without this antibody). Chest 
radiographs are usually normal unless there is associated 
interstitial lung disease. Electromyographic abnormalities 
can point toward a myopathic, rather than a neurogenic, 
cause of weakness. MRI can detect early and patchy muscle 
involvement, can guide biopsies, and often is more useful 
than electromyography. The search for an occult malignancy 
should begin with a history and physical examination, sup
-
plemented with a complete blood count, comprehensive 
biochemical panel, serum protein electrophoresis, and uri
-
nalysis, and should include age- and risk-appropriate cancer 
screening tests. Given the especially strong association of 
ovarian carcinoma and dermatomyositis, transvaginal ultra
-
sonography, CT scanning, and CA-125 levels may be useful 
in women. No matter how extensive the initial screening, 
some malignancies will not become evident for months after 
the initial presentation.
C. Muscle Biopsy

Biopsy of clinically involved muscle is the only specific diag
-
nostic test. The pathology findings in polymyositis and der
-
matomyositis are distinct. Although both include lymphoid 
inflammatory infiltrates, the findings in dermatomyositis 
are localized to perivascular regions and there is evidence of 
Table 20–10.
 
Myositis-specific antibodies.
Antibody
Clinical Association
Anti-Jo-1 and other antisynthe
-
tase antibodies
Polymyositis or dermatomyosi
-
tis with interstitial lung dis
-
ease, arthritis, mechanic’s 
hands
Anti-Mi-2
Dermatomyositis with rash 
more than myositis
Anti-MDA5 (anti-CADM 140)
Dermatomyositis with rapidly 
progressive lung disease, 
cutaneous ulcers
Anti-155/140
Cancer-associated myositis
Anti-140
Juvenile dermatomyositis
Anti-SAE
Cancer-associated dermatomyo
-
sitis, dermatomyositis with 
rapidly progressive lung 
disease
Anti-signal recognition particle
Severe, acute necrotizing 
myopathy
Anti-HMG CoA reductase
Necrotizing myopathy related 
 
to statin use
Adapted, with permission, from Imboden JB, Hellmann DB, Stone 
JH (editors): 
Current Diagnosis & Treatment Rheumatology
, 3rd ed. 
McGraw-Hill, 2013.
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humoral and complement-mediated destruction of micro
-
vasculature associated with the muscle. In addition to its 
vascular orientation, the inflammatory infiltrate in dermato
-
myositis centers on the interfascicular septa and is located 
around, rather than in, muscle fascicles. A pathologic 
hallmark of dermatomyositis is perifascicular atrophy. In 
contrast, the pathology of polymyositis characteristically 
includes endomysial infiltration of the inflammatory 
infiltrate. However, false-negative biopsies sometimes occur 
in both disorders because of the sometimes patchy distribu
-
tion of pathologic abnormalities.
 
»
Muscle inflammation may occur as a component of SLE, 
scleroderma, Sjögren syndrome, and overlap syndromes. In 
those cases, associated findings usually permit the precise 
diagnosis of the primary condition.
Inclusion body myositis, because of its tendency to 
mimic polymyositis, is a common cause of “treatment-
resistant polymyositis. ” In contrast to the epidemiologic fea
-
tures of polymyositis, however, the typical inclusion body 
myositis patient is white, male, and over the age of 50. The 
onset of inclusion body myositis is more insidious than that 
of polymyositis or dermatomyositis (eg, occurring over years 
rather than months), and asymmetric distal motor weakness 
is common in inclusion body myositis. Creatine kinase levels 
in inclusion body myositis are often minimally elevated and 
are normal in 25%. Electromyography may show a mixed 
picture of myopathic and neurogenic abnormalities. Muscle 
biopsy shows characteristic intracellular vacuoles by light 
microscopy and either tubular or filamentous inclusions in 
the nucleus or cytoplasm by electron microscopy. Inclusion 
body myositis is less likely to respond to therapy.
Hypothyroidism is a common cause of proximal muscle 
weakness associated with elevations of serum creatine 
kinase. Hyperthyroidism and Cushing disease may both be 
associated with proximal muscle weakness with normal 
levels of creatine kinase. Patients with polymyalgia rheu
-
matica are over the age of 50 and—in contrast to patients 
with polymyositis—have pain but no objective weakness; 
creatine kinase levels are normal. Disorders of the peripheral 
and central nervous systems (eg, chronic inflammatory poly
-
neuropathy, multiple sclerosis, myasthenia gravis, Lambert-
Eaton disease, and amyotrophic lateral sclerosis) can produce 
weakness but are distinguished by characteristic symptoms 
and neurologic signs and often by distinctive electromyo
-
graphic abnormalities. A number of systemic vasculitides 
(polyarteritis nodosa, microscopic polyangiitis, eosinophilic 
granulomatosis with polyangiitis [formerly called Churg-
Strauss syndrome], granulomatosis with polyangiitis, and 
mixed cryoglobulinemia) can produce profound weakness 
through vasculitic neuropathy. The muscle weakness associ
-
ated with these disorders, however, is typically distal and 
asymmetric, at least in the early stages.
Limb-girdle muscular dystrophy can present in early 
adulthood with a clinical picture that mimics polymyositis: 
proximal muscle weakness, elevations in serum levels of 
creatine kinase, and inflammatory changes on muscle 
biopsy. Failure to respond to treatment for polymyositis or 
the presence of atypical clinical features such as scapular 
winging or weakness of ankle plantar flexors should prompt 
genetic testing for limb-girdle muscular dystrophy.
Many drugs, including corticosteroids, alcohol, clofi
-
brate, penicillamine, tryptophan, and hydroxychloro
-
quine, can produce proximal muscle weakness. Long-term 
use of colchicine at doses as low as 0.6 mg twice a day in 
patients with moderate chronic kidney disease can pro
-
duce a mixed neuropathy-myopathy that mimics poly
-
myositis. The weakness and muscle enzyme elevation 
reverse with cessation of the drug. Polymyositis can occur

-
-
reverse with cessation of the drug. Polymyositis can occur 
as a complication of HIV or HTLV-1 infection and with 
zidovudine therapy as well.
HMG-CoA reductase inhibitors can cause myopathy 
and rhabdomyolysis. Although only about 0.1% of patients 
taking a statin drug alone develop myopathy, concomitant 
administration of other drugs (especially gemfibrozil, 
cyclosporine, niacin, macrolide antibiotics, azole antifun
-
gals, and protease inhibitors) increases the risk. Statin use 
has also been linked to the development of an autoim
-
mune-mediated necrotizing myositis, which persists after 
the statin has been discontinued and is associated with 
autoantibodies to HMG-CoA reductase.
Immune check point inhibitors, which are increasingly 
used to treat advanced staged cancers, can cause rheumatic 
and musculoskeletal symptoms including myalgia.
 
»
Treatment
Most patients respond to corticosteroids. Often a daily dose 
of 40–60 mg or more of oral prednisone is required initially. 
The dose is then adjusted downward while monitoring mus
-
cle strength and serum levels of muscle enzymes. Long-term 
use of corticosteroids is often needed, and the disease may 
recur or reemerge when they are withdrawn. Patients with an 
associated neoplasm have a poor prognosis, although remis
-
sion may follow treatment of the tumor; corticosteroids may 
or may not be effective in these patients. In patients resistant 
or intolerant to corticosteroids, therapy with methotrexate or 
azathioprine may be helpful. Intravenous immune globulin is 
effective for dermatomyositis resistant to prednisone. Myco
-
phenolate mofetil (1–1.5 g orally twice daily) may be useful 
as a steroid-sparing agent. Rituximab is effective in some 
patients with inflammatory myositis unresponsive to 
prednisone. Since the rash of dermatomyositis is often 
photosensitive, patients should limit sun exposure. Hydroxy
-
chloroquine (200–400 mg/day orally not to exceed 5 mg/kg) 
can also help ameliorate the skin disease.
 
»
•	
All patients with myositis should be referred to a rheuma
-
tologist or neurologist.
•	
Severe lung disease may require consultation with a 
pulmonologist.
 
»
•	
Signs of rhabdomyolysis.
•	
New onset of dysphagia.
•	
Respiratory insufficiency with hypoxia or carbon diox
-
ide retention.
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Cappelli LC et al. Rheumatic and musculoskeletal immune-
related adverse events due to immune checkpoint inhibitors: 
a systematic review of the literature. Arthritis Care Res 
(Hoboken). 2017 Nov;69(11):1751–63. [PMID: 27998041]
Fujimoto M et al. Recent advances in dermatomyositis-specific 
autoantibodies. Curr Opin Rheumatol. 2016 Nov;28 (6):
 
636–44. [PMID: 27533321]
Hozumi H et al. Comprehensive assessment of myositis-specific 
autoantibodies in polymyositis/dermatomyositis-associated 
interstitial lung disease. Respir Med. 2016 Dec;121:91–9. 
[PMID: 27888997]
Lundberg IE et al. 2017 European League Against Rheumatism/
American College of Rheumatology classification criteria for 
adult and juvenile idiopathic inflammatory myopathies and 
their major subgroups. Ann Rheum Dis. 2017 Dec;76 (12):
 
1955–64. [PMID: 29079590]
Milone M. Diagnosis and management of immune-mediated 
myopathies. Mayo Clin Proc. 2017 May;92(5):826–37. 
[PMID: 28473041]
Moghadam-Kia S et al. Anti-melanoma differentiation-associated 
gene 5 is associated with rapidly progressive lung disease and 
poor survival in US patients with amyopathic and myopathic 
dermatomyositis. Arthritis Care Res (Hoboken). 2016 May;
 
68(5):689–94. [PMID: 26414240]
MIXED CONNECTIVE TISSUE DISEASE & 
OVERLAP SYNDROMES
Many patients with symptoms and signs compatible with a 
connective tissue disease have features consistent with 
more than one type of rheumatic disease. Special attention 
has been drawn to antinuclear antibody–positive patients 
who have overlapping features of SLE, scleroderma, and 
inflammatory myopathy together with autoantibodies to 
ribonuclear protein (RNP). Some consider these patients to 
have a distinct entity (“mixed connective tissue disease”), 
and others view this as a subset of SLE characterized by a 
higher prevalence of Raynaud phenomenon, polyarthritis, 
myositis, and pulmonary hypertension and a lower inci
-
dence of renal involvement. Other patients have features of 
more than one connective tissue disease (eg, rheumatoid 
arthritis and SLE, SLE and scleroderma) in the absence of 
anti-RNP antibodies and are referred to as having an “over
-
lap syndrome. ” Treatments are guided more by the distri
-
bution and severity of patients’ organ system involvement 
than by therapies specific to these overlap syndromes.
Kawano-Dourado L et al. Pulmonary involvement in long-term 
mixed connective tissue disease: functional trends and image 
findings after 10 years. Clin Exp Rheumatol. 2015 Mar–Apr;
 
33(2):234–40. [PMID: 25896472]
SJÖGREN SYNDROME
 
»
Women (average age 50 years) are 90% of patients.
 
»
Dryness of eyes and dry mouth (sicca components) 
are the most common features; they occur alone or 
with rheumatoid arthritis or other connective 
 
tissue disease.
 
»
Rheumatoid factor and antinuclear antibodies are 
common.
 
»
Increased incidence of lymphoma.
 
»
Sjögren syndrome is a systemic autoimmune disorder 
whose clinical presentation is usually dominated by dry
-
ness of the eyes and mouth due to immune-mediated dys
-
function of the lacrimal and salivary glands. The disorder 
is predominantly seen in women, with a ratio of 9:1; most 
cases develop between the ages of 40 and 60 years. Sjögren 
syndrome can occur in isolation (“primary” Sjögren syn
-
drome) or in association with another rheumatic disease. 
Sjögren syndrome is most frequently associated with rheu
-
matoid arthritis but also occurs with SLE, primary biliary 
cholangitis, scleroderma, polymyositis, Hashimoto thyroiditis, 
polyarteritis, and interstitial pulmonary fibrosis.
 
»
Keratoconjunctivitis sicca results from inadequate tear pro
-
duction caused by lymphocyte and plasma cell infiltration 
of the lacrimal glands. Ocular symptoms are usually mild. 
Burning, itching, and the sensation of having a foreign body

-
Burning, itching, and the sensation of having a foreign body 
or a grain of sand in the eye occur commonly. For some 
patients, the initial manifestation is the inability to tolerate 
wearing contact lenses. Many patients with more severe 
ocular dryness notice ropy secretions across their eyes, 
especially in the morning. Photophobia may signal corneal 
ulceration resulting from severe dryness. For most patients, 
symptoms of dryness of the mouth (xerostomia) dominate 
those of dry eyes. Patients frequently complain of a “cotton 
mouth” sensation and difficulty swallowing foods, espe
-
cially dry foods like crackers, unless they are washed down 
with liquids. The persistent oral dryness causes most 
patients to carry water bottles or other liquid dispensers 
from which they sip constantly. A few patients have such 
severe xerostomia that they have difficulty speaking. Persis
-
tent xerostomia results often in rampant dental caries; car
-
ies at the gum line strongly suggest Sjögren syndrome. 
Some patients are most troubled by loss of taste and smell. 
Parotid enlargement, which may be chronic or relapsing, 
develops in one-third of patients. Desiccation may involve 
the nose, throat, larynx, bronchi, vagina, and skin.
Systemic manifestations include dysphagia, small vessel 
vasculitis, pleuritis, obstructive airways disease and inter
-
stitial lung disease (in the absence of smoking), neuropsy
-
chiatric dysfunction (most commonly peripheral 
neuropathies), and pancreatitis; they may be related to the 
associated diseases noted above. Renal tubular acidosis 
(type I, distal) occurs in 20% of patients. Chronic intersti
-
tial nephritis, which may result in impaired kidney function, 
may be seen.
Laboratory findings include mild anemia, leukopenia, 
and eosinophilia. Polyclonal hypergammaglobulinemia, 
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rheumatoid factor positivity (70%), and antinuclear 
antibodies (95%) are all common findings. Antibodies 
against SS-A and SS-B (also called Ro and La, respec
-
tively) are often present in primary Sjögren syndrome 
and tend to correlate with the presence of extra-glandu
-
lar manifestations (Table 20–7). Thyroid-associated 
autoimmunity is a common finding among patients with 
Useful ocular diagnostic tests include the Schirmer test, 
which measures the quantity of tears secreted. Lip biopsy, a 
simple procedure, reveals characteristic lymphoid foci in 
accessory salivary glands. Biopsy of the parotid gland 
should be reserved for patients with atypical presentations 
such as unilateral gland enlargement that suggest a neo
-
plastic process.
 
»
Isolated complaints of dry mouth are most commonly due 
to medication side effects. Chronic hepatitis C can cause 
sicca symptoms and rheumatoid factor positivity. Minor 
salivary gland biopsies reveal lymphocytic infiltrates but 
not to the extent of Sjögren syndrome, and tests for anti-
SS-A and anti-SS-B are negative. Involvement of the lacri
-
mal or salivary glands, or both in sarcoidosis can mimic 
Sjögren syndrome; biopsies reveal noncaseating granulo
-
mas. Rarely, amyloid deposits in the lacrimal and salivary 
glands produce sicca symptoms. IgG
4
-related systemic 
disease (characterized by high serum IgG
4
 levels and infil
-
tration of tissues with IgG
4
+
 plasma cells) can result in 
lacrimal and salivary gland enlargement that mimics 
 
»
Treatment of sicca symptoms is symptomatic and support
-
ive. Artificial tears applied frequently will relieve ocular 
symptoms and avert further desiccation. Topical ocular 
0.05% cyclosporine also improves ocular symptoms and 
signs of dryness. The mouth should be kept well lubricated. 
Sipping water frequently or using sugar-free gums and 
hard candies usually relieves dry mouth symptoms. Pilo
-
carpine (5 mg orally four times daily) and the acetylcholine 
derivative cevimeline (30 mg orally three times daily) may 
improve xerostomia symptoms. Atropinic drugs and 
decongestants decrease salivary secretions and should be 
avoided. A program of oral hygiene, including fluoride 
treatment, is essential in order to preserve dentition. If 
there is an associated rheumatic disease, its systemic treat
-
ment is not altered by the presence of Sjögren syndrome.
Although Sjögren syndrome may compromise patients’ 
quality of life significantly, the disease is usually consistent 
with a normal life span. Poor prognoses are influenced 
mainly by the presence of systemic features associated with 
underlying disorders, the development in some patients of 
lymphocytic vasculitis, the occurrence of a painful periph
-
eral neuropathy, and the complication (in a minority of 
patients) of lymphoma. Severe systemic inflammatory 
manifestations are treated with prednisone or various 
immunosuppressive medications. The patients at greatest 
risk for developing lymphoma are those with severe 
exocrine dysfunction, marked parotid gland enlargement, 
splenomegaly, vasculitis, peripheral neuropathy, anemia, 
and mixed monoclonal cryoglobulinemia (3–10% of the 
total Sjögren population).
 
»
•	
Presence of systemic symptoms or signs.
•	
Ocular dryness not responsive to artificial tears.
 
»
Presence of severe systemic signs such as vasculitis unre
-
sponsive to outpatient management.
Saraux A et al. Treatment of primary Sjögren syndrome. Nat Rev 
Rheumatol. 2016 Aug;12(8):456–71. [PMID: 27411907]
Verstappen GM et al. The value of rituximab treatment in 
primary Sjögren’s syndrome. Clin Immunol. 2017 Sep;
 
182:62–71. [PMID: 28478105]
I
g
G
4
-RELATED DISEASE
 
»
Predominantly affects men (75% of patients); 
average age older than 50 years.
 
»

I
g
G
4
 
»
 
»
Protean manifestations caused by lymphoplasma
-
cytic infiltrates in any organ or tissue, especially 
the pancreas, lacrimal glands, biliary tract, and 
retroperitoneum.
 
»
Subacute onset; fever, constitutional symptoms 
rare.
 
»
Diagnostic histopathology.
 
»
IgG
4
-related disease is a systemic disorder of unknown 
cause marked by highly characteristic fibroinflammatory 
changes that can affect virtually any organ. Elevations of 
serum IgG
4
 levels occur often but are not diagnostic. The 
disorder chiefly affects men over the age of 50 years.
 
»
IgG
4
-related disease has been compared with sarcoidosis: 
both disorders can affect any organ of the body, can be 
localized or generalized, demonstrate the same distinctive 
histopathology at all sites of involvement, produce protean 
manifestations depending on location and extent of 
involvement, and cause disease that ranges in severity 
from asymptomatic to organ- or life-threatening. The 
inflammatory infiltration in IgG
4
-related disease fre
-
quently produces tumefactive masses that can be found 
during physical examination or on imaging. Some of the 
common presenting manifestations include enlargement 
of submandibular glands, proptosis from periorbital 
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infiltration, retroperitoneal fibrosis, mediastinal fibrosis, 
inflammatory aortic aneurysm, and pancreatic mass with 
autoimmune pancreatitis. IgG
4
-related disease can also 
affect the thyroid, kidney, meninges, pituitary, sinuses, 
lung, prostate, breast, and bone. Most symptomatic 
patients with IgG
4
-related disease present subacutely; 
fever and constitutional symptoms are usually absent. 
Nearly half of the patients with IgG
4
-related disease also 
have allergic disorders such as sinusitis or asthma.
The infiltrating lesions in IgG
4
-related disease often pro
-
duce tumors or fibrotic changes that are evident on CT or 
MRI imaging. However, the cornerstone of diagnosis is the 
histopathology. The key pathological findings are a dense 
lymphoplasmacytic infiltrate rich in IgG
4
 plasma cells, 
storiform (matted and irregularly whorled) fibrosis, and 
obliterative phlebitis. Serum IgG
4
 levels are usually, but not 
invariably, elevated so this finding cannot be used as the 
sole diagnostic criterion.
 
»
IgG
4
-related disease can mimic many disorders including 
sarcoidosis, Sjögren syndrome (lacrimal gland enlarge
-
ment), pancreatic cancer (pancreatic mass), and granulo
-
matosis with polyangiitis (proptosis). Some cases of 
retroperitoneal fibrosis and mediastinal fibrosis are caused 
by IgG
4
-related disease. Lymphoma can mimic some of the 
histopathologic features of IgG
4
-related disease.
 
»
Patients who are asymptomatic and have no organ-
threatening disease can be monitored carefully. Spontane
-
ous resolution can occur. The optimal therapy for symptomatic 
patients has not been defined, but initial therapy is usually 
oral prednisone 0.6 mg/kg/day, tapered over weeks or 
months depending on response. Patients who do not 
respond to prednisone or respond only to sustained high 
doses of prednisone can be treated with rituximab, myco
-
phenolate mofetil, or azathioprine. The degree of fibrosis in 
affected organs determines the patient’s responsiveness to 
 
»
•	
•	
Symptoms or signs not responsive to prednisone.
 
»
Presence of severe systemic signs unresponsive to outpa
-
tient management.
Ebbo M et al. Long-term efficacy and safety of rituximab in 
IgG4-related disease: data from a French nationwide study of 
thirty-three patients. PLoS One. 2017 Sep 15;12(9):e0183844. 
[PMID: 28915275]
Kamisawa et al. IgG
4
-related disease. Lancet. 2015 Apr 11;
 
385(9976):1460–71. [PMID: 25481618]
RHABDOMYOLYSIS
 
»
Associated with crush injuries to muscle, immobility, 
drug toxicities, and hypothermia.
 
»
Usually markedly elevated muscle enzymes.
 
»
Rhabdomyolysis is a syndrome of acute necrosis of skeletal 
muscle associated with myoglobinuria and markedly ele
-
vated creatine kinase levels. Acute tubular necrosis is a 
common complication of rhabdomyolysis and is due to the 
toxic effects of filtering excessive quantities of myoglobin 
in the setting of hypovolemia (See Acute Tubular Necrosis 
in Chapter 22). Many patients in whom rhabdomyolysis 
develops are volume-contracted and, therefore, oliguric 
renal failure is encountered routinely. Compartment 
syndrome, disseminated intravascular coagulation, and 
cardiac arrhythmias are serious but less common compli
-
cations of rhabdomyolysis.
Rhabdomyolysis is a common complication of severe 
crush injuries to muscle. Cocaine use and alcohol intoxica
-
tion, particularly in the setting of prolonged immobility 
and exposure hypothermia, are leading causes of admis
-
sions due to rhabdomyolysis on the medical services of 
inner-city hospitals. Use of statins is another important 
cause of rhabdomyolysis. The presence of compromised 
kidney and liver function, diabetes mellitus, and hypothy
-
roidism as well as concomitant use of other medications

-
roidism as well as concomitant use of other medications 
increase the risk of rhabdomyolysis in patients taking 
statins. The cytochrome P450 liver enzymes metabolize all 
statins except for pravastatin and rosuvastatin. Drugs that 
block the action of cytochrome P450 include protease 
inhibitors, erythromycin, itraconazole, clarithromycin, dil
-
tiazem, and verapamil. Use of these drugs concomitantly 
with the statins (but not pravastatin or rosuvastatin) can 
increase the risk of development of rhabdomyolysis. The 
likelihood of rhabdomyolysis also increases when statins 
are used with niacin and fibric acids (gemfibrozil, clofi
-
brate, and fenofibrate). Rhabdomyolysis is an uncommon 
complication of polymyositis, dermatomyositis, and the 
myopathy of hypothyroidism, despite the high levels of 
creatine kinase often seen in these conditions.
Often there is little evidence for muscle injury on clini
-
cal assessment of the patients with rhabdomyolysis—
specifically, myalgias and weakness are usually absent. The 
first clue to muscle necrosis in such individuals may be a 
urinary dipstick testing positive for “blood” (actually myo
-
globin) in the absence of red cells in the sediment. This 
myoglobinuria results in a false-positive reading for hemo
-
globin. Urine tests for myoglobin are insensitive, however, 
positive in only 25% of patients with rhabdomyolysis. Such 
an abnormality should prompt determination of the serum 
creatine kinase level, which invariably is elevated (usually 
markedly so). Other commonly encountered laboratory 
abnormalities in rhabdomyolysis include elevated serum 
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levels of AST, ALT, and lactate dehydrogenase (due to 
release of these enzymes from skeletal muscle), hyperkale
-
mia, and hypocalcemia. The massive acute elevations of 
muscle enzymes peak quickly and usually resolve within 
days once the inciting injury has been removed.
 
»
Treatment
Vigorous fluid resuscitation (eg, 4–6 L/day but often more in 
the setting of severe crush injuries) is indicated. Urine alka
-
linization (to minimize precipitation of myoglobin within 
tubules) have been recommended as measures to reduce 
kidney injury, but definitive evidence for the efficacy of these 
measures is lacking. Myopathic complications of statins usu
-
ally resolve within several weeks of discontinuing the drug.
Cervellin G et al. Non-traumatic rhabdomyolysis: background, 
laboratory features, and acute clinical management. Clin 
Biochem. 2017 Aug;50(12):656–62. [PMID: 28235546]
Panzio N et al. Molecular mechanisms and novel therapeutic 
approaches to rhabdomyolysis-induced acute kidney injury. 
Kidney Blood Press Res. 2015;40(5):520–32. [PMID: 
26512883]
 
º
VASCULITIS SYNDROMES
“Vasculitis” is a heterogeneous group of disorders charac
-
terized by inflammation within the walls of affected blood 
vessels. The major forms of primary systemic vasculitis are 
listed in Table 20–11. The first consideration in classifying 
cases of vasculitis is the size of the major vessels involved: 
large, medium, or small. The presence of the clinical signs 
and symptoms shown in Table 20–12 helps distinguish 
among these three groups. After determining the size of 
Table 20–11.
 
Classification scheme of primary vasculi
-
tides according to size of predominant blood vessels 
involved.
Predominantly large-vessel vasculitides
 
T
akayasu arteritis
 
Gian
t cell arteritis (temporal arteritis)
 
B
ehçet disease
1
Predominantly medium-vessel vasculitides
 
P
olyarteritis nodosa
 
Buer
ger disease
 
P
rimary angiitis of the central nervous system
Predominantly small-vessel vasculitides
 
I
mmune-complex mediated
 
C
utaneous leukocytoclastic angiitis 
 
(“
hypersensitivity vasculitis”)
 
Henoch-S
chönlein purpura
 
Essen
tial cryoglobulinemia
2
 
“
ANCA-associated” disorders
3
  
Gr
anulomatosis with polyangiitis
2
  
Microscopic polyangiitis
2
  
E
osinophilic granulomatosis with polyangiitis
2
1
May involve small-, medium-, and large-sized blood vessels.
2
Frequent overlap of small- and medium-sized blood vessel 
involvement.
3
Not all forms of these disorders are always associated with ANCA.
ANCA, antineutrophil cytoplasmic antibodies.
the major vessels involved, other issues that contribute to 
the classification include the following:
•	
Does the process involve arteries, veins, or both?
•	
What are the patient’s demographic characteristics (age, 
sex, ethnicity, smoking status)?
•	
Which organs are involved?
•	
Is there hypocomplementemia or other evidence of 
immune complex deposition?
•	
Is there granulomatous inflammation on tissue biopsy?
•	
Are antineutrophil cytoplasmic antibodies (ANCA) 
present?
In addition to the disorders considered to be primary vas
-
culitides, there are also multiple forms of vasculitis that are 
associated with other known underlying conditions. These 
“secondary” forms of vasculitis occur in the setting of chronic 
infections (eg, hepatitis B or C, subacute bacterial endocardi
-
tis), connective tissue disorders, inflammatory bowel disease, 
malignancies, and reactions to medications. Only the major 
primary forms of vasculitis are discussed here.
Grau RG. Drug-induced vasculitis: new insights and a changing 
lineup of suspects. Curr Rheumatol Rep. 2015 Dec;17(12):71. 
[PMID: 26503355]
Gwathmey KG et al. Vasculitic neuropathies. Lancet Neurol. 
2014 Jan;13(1):67–82. [PMID: 24331794]
POLYMYALGIA RHEUMATICA & 
 
GIANT CELL ARTERITIS
 
»
Age over 50 years.
 
»
Markedly elevated ESR.
 
»

»
 
»
 
»
 pain and stiffness in 
shoulders and hips lasting for several weeks with
-
out other explanation.
Table 20–12.
 
Typical clinical manifestations of large-, 
medium-, and small-vessel involvement by vasculitis.
Large
Medium
Small
Constitutional symptoms: fever, weight loss, malaise, arthralgias/
arthritis
Limb claudication
Asymmetric blood 
pressures
Absence of pulses
Bruits
Aortic dilation
Cutaneous 
nodules
Ulcers
Livedo reticularis
Digital gangrene
Mononeuritis 
multiplex
Microaneurysms
Purpura
Vesiculobullous lesions
Urticaria
Glomerulonephritis
Alveolar hemorrhage
Cutaneous extravascu
-
lar necrotizing 
Splinter hemorrhages
Uveitis
Episcleritis
Scleritis
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»
Giant cell arteritis:
 headache, jaw claudication, 
 
polymyalgia rheumatica, visual abnormalities.
 
»
Polymyalgia rheumatica and giant cell arteritis probably 
represent a spectrum of one disease: Both affect the same 
population (patients over the age of 50), and the incidence 
of the disease increases with each decade of life. Both show 
preference for the same HLA haplotypes, and show similar 
patterns of cytokines in blood and arteries. Giant cell arte
-
ritis is a systemic panarteritis affecting medium-sized and 
large vessels. Giant cell arteritis is also called temporal 
arteritis because the temporal artery is frequently involved, 
as are other extracranial branches of the carotid artery. 
Polymyalgia rheumatica and giant cell arteritis also fre
-
quently coexist. The important differences between the 
two conditions are that polymyalgia rheumatica alone does 
not cause blindness and responds to low-dose (10–20 mg/day 
orally) prednisone therapy, whereas giant cell arteritis can 
cause blindness and large artery complications and requires 
high-dose (40–60 mg/day) prednisone.
 
»
A. Polymyalgia Rheumatica
Polymyalgia rheumatica is a clinical diagnosis based on 
pain and stiffness of the shoulder and pelvic girdle areas, 
frequently in association with fever, malaise, and weight 
loss. In approximately two-thirds of cases, polymyalgia 
occurs in the absence of giant cell arteritis. Because of the 
stiffness and pain in the shoulders, hips, and lower back, 
patients have trouble combing their hair, putting on a coat, 
or rising from a chair. In contrast to polymyositis and poly
-
arteritis nodosa, polymyalgia rheumatica does not cause 
muscular weakness either through primary muscle inflam
-
mation or secondary to nerve infarction. A few patients 
have joint swelling, particularly of the knees, wrists, and 
sternoclavicular joints.
B. Giant Cell Arteritis
The mean age at onset is approximately 79 years. About 
50% of patients with giant cell arteritis also have polymyal
-
gia rheumatica. While the cause of giant cell arteritis is 
unknown, varicella-zoster antigen is found in nearly 75% 
of the temporal arteries of affected patients (compared to 
22% of controls). The classic symptoms suggesting that a 
patient has arteritis are headache, scalp tenderness, visual 
symptoms (particularly amaurosis fugax or diplopia), jaw 
claudication, or throat pain. Of these symptoms, jaw clau
-
dication has the highest positive predictive value. The 
temporal artery is usually normal on physical examination 
but may be nodular, enlarged, tender, or pulseless. Blindness 
usually results from the syndrome of anterior ischemic 
optic neuropathy, caused by occlusive arteritis of the poste
-
rior ciliary branch of the ophthalmic artery. The ischemic 
optic neuropathy of giant cell arteritis may produce no 
funduscopic findings for the first 24–48 hours after the 
onset of blindness.
Asymmetry of pulses in the arms, a murmur of aortic 
regurgitation, or bruits heard near the clavicle resulting 
from subclavian artery stenoses identify patients in whom 
giant cell arteritis has affected the aorta or its major 
branches. Clinically evident large vessel involvement—
characterized chiefly by aneurysm of the thoracic aorta or 
stenosis of the subclavian, vertebral, carotid, and basilar 
arteries—occurs in approximately 25% of patients with 
giant cell arteritis, sometimes years after the diagnosis. 
Subclinical large artery disease is the rule: positron emis
-
sion tomography scans reveal inflammation in the aorta 
and its major branches in nearly 85% of untreated patients. 
Forty percent of patients with giant cell arteritis have non
-
classic symptoms at presentation, including large artery 
involvement causing chiefly aortic regurgitation or arm 
claudication, respiratory tract problems (most frequently 
dry cough), mononeuritis multiplex (most frequently with

dry cough), mononeuritis multiplex (most frequently with 
painful paralysis of a shoulder), or fever of unknown 
origin. Giant cell arteritis accounts for 15% of all cases of 
fever of unknown origin in patients over the age of 65. The 
fever can be as high as 40°C and is frequently associated 
with rigors and sweats. In contrast to patients with infection, 
patients with giant cell arteritis and fever usually have nor
-
mal white blood cell counts (before prednisone is started). 
Thus, in an older patient with fever of unknown origin, 
marked elevations of acute phase reactants, and a normal 
white blood count, giant cell arteritis must be considered 
even in the absence of specific features such as headache or 
jaw claudication. In some cases, instead of having the well-
known symptom of jaw claudication, patients complain of 
vague pain affecting other locations, including the tongue, 
nose, or ears. Indeed, unexplained head or neck pain in an 
older patient may signal the presence of giant cell arteritis.
1. Polymyalgia rheumatica—
Anemia and elevated acute 
phase reactants (often markedly elevated ESRs, for exam
-
ple) are present in the most cases, but cases of polymyalgia 
rheumatica occurring with normal acute phase reactants 
are well documented.
2. Giant cell arteritis—
Nearly 90% of patients with giant cell 
arteritis have ESRs higher than 50 mm/h. The ESR in this 
disorder is often more than 100 mm/h, but cases in which the 
ESR is lower or even normal do occur. In one series, 5% of 
patients with biopsy-proven giant cell arteritis had ESRs below 
40 mm/h. Although the C-reactive protein is slightly more 
sensitive, patients with biopsy-proven giant cell arteritis with 
normal C-reactive proteins have also been described. Most 
patients also have a mild normochromic, normocytic anemia 
and thrombocytosis. The alkaline phosphatase (liver source) 
is elevated in 20% of patients with giant cell arteritis.
 
»
The differential diagnosis of malaise, anemia, and striking 
acute phase reactant elevations includes rheumatic diseases 
(such as rheumatoid arthritis, other systemic vasculitides, 
plasma cell myeloma, and other malignant disorders) and 
chronic infections (such as bacterial endocarditis and 
osteomyelitis).
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»
Treatment
Patients with isolated polymyalgia rheumatica (ie, those 
not having “above the neck” symptoms of headache, jaw 
claudication, scalp tenderness, or visual symptoms) are 
treated with prednisone, 10–20 mg/day orally. If the 
patient does not experience a dramatic improvement 
within 72 hours, the diagnosis should be revisited. Usually 
after 2–4 weeks of treatment, slow tapering of the predni
-
sone can be attempted. Most patients require some dose of 
prednisone for a minimum of approximately 1 year; 
 
6 months is too short in most cases. Disease flares are 
common (50% or more) as prednisone is tapered. The 
addition of weekly methotrexate may increase the chance 
of successfully tapering prednisone in some patients.
The urgency of early diagnosis and treatment in giant cell 
arteritis relates to the prevention of blindness. Once blind
-
ness develops, it is usually permanent. Therefore, when a 
patient has symptoms and findings suggestive of temporal 
arteritis, therapy with prednisone (60 mg/day orally) should 
be initiated immediately and a temporal artery biopsy per
-
formed promptly thereafter. For patients who seek medical 
attention for visual loss, intravenous pulse methylpredniso
-
lone (eg, 1 g daily for 3 days) has been advocated; unfortu
-
nately, few patients recover vision no matter what the initial 
treatment. Retrospective studies suggest that low-dose 
aspirin (~81 mg/day orally) may reduce the chance of visual 
loss or stroke in patients with giant cell arteritis and should 
be added to prednisone in the initial treatment. Although it 
is prudent to obtain a temporal artery biopsy as soon as 
possible after instituting treatment, diagnostic findings of 
giant cell arteritis may still be present 2 weeks (or even 
considerably longer) after starting corticosteroids. Typi
-
cally, a positive biopsy shows inflammatory infiltrate in the 
media and adventitia with lymphocytes, histiocytes, plasma 
cells, and giant cells. An adequate biopsy specimen is essen
-
tial (at least 2 cm in length is ideal), because the disease may 
be segmental. Unilateral temporal artery biopsies are posi
-
tive in approximately 80–85% of patients, but bilateral 
biopsies add incrementally to the yield (10–15% in some 
studies, less in others). Imaging with ultrasonography, MRI, 
or CT angiography can sometimes obviate the need for 
temporal artery biopsy. Temporal artery biopsy is abnormal 
in only 50% of patients with large artery disease (eg, arm 
claudication and unequal upper extremity blood pressures). 
In these patients, magnetic resonance angiography or CT angi
-
ography will establish the diagnosis by demonstrating long 
stretches of narrowing of the subclavian and axillary arteries. 
Prednisone should be continued in a dosage of 60 mg/day 
orally for about 1 month before tapering. When only the 
symptoms of polymyalgia rheumatica are present, temporal 
artery biopsy is not necessary.
After 1 month of high-dose prednisone, almost all 
patients will have a normal ESR. When tapering and 
adjusting the dosage of prednisone, the ESR (or C-reactive 
protein) is a useful but not absolute guide to disease activity. 
A common error is treating the ESR rather than the 
patient. The ESR often rises slightly as the prednisone is 
tapered, even as the disease remains quiescent. Because 
elderly individuals often have baseline ESRs that are above 
the normal range, mild ESR elevations should not be an 
occasion for renewed treatment with prednisone in patients 
who are asymptomatic. The many side effects of prolonged 
prednisone use, including weight gain, osteoporosis, diabetes, 
hypertension, and proximal muscle weakness, have 
prompted searches for treatments that could reduce pred
-
nisone use. Tocilizumab, an inhibitor of the IL-6 receptor, 
appears to be such a treatment: clinical trials demonstrate

-
appears to be such a treatment: clinical trials demonstrate 
that patients treated initially with both tocilizumab and 
prednisone can taper off of prednisone more rapidly and 
successfully than patients treated with prednisone alone. 
Methotrexate has been less promising; it was modestly 
effective in one double-blind, placebo-controlled treatment 
trial but ineffective in another. Anti-TNF therapies do not 
work in giant cell arteritis. Thoracic aortic aneurysms 
occur 17 times more frequently in patients with giant cell 
arteritis than in normal individuals and can result in aortic 
regurgitation, dissection, or rupture. The aneurysms can 
develop at any time but typically occur 7 years after the 
diagnosis of giant cell arteritis is made.
Stone JH et al. Trial of tocilizumab in giant-cell arteritis. N Engl 
J Med. 2017 Jul 27;377(4):317–28. [PMID: 28745999]
TAKAYASU ARTERITIS
Takayasu arteritis is a granulomatous vasculitis of the aorta 
and its major branches. Rare in North America but more 
prevalent in the Far East, it primarily affects women and 
typically has its onset in early adulthood. Takayasu arteritis 
can present with nonspecific constitutional symptoms of 
malaise, fever, and weight loss or with manifestations of 
vascular inflammation and damage: diminished pulses, 
unequal blood pressures in the arms, carotidynia (tender
-
ness over the carotid arteries), bruits over carotids and 
subclavian arteries, retinopathy, limb claudication, and 
hypertension). There are no specific laboratory abnormali
-
ties; the ESR and the C-reactive protein level are elevated in 
most cases. The diagnosis is established by imaging studies, 
usually MRI, which can detect inflammatory thickening of 
the walls of affected vessels, or CT angiography, which can 
provide images of the stenoses, occlusions, and dilations 
characteristic of arteritis. Corticosteroids (eg, oral predni
-
sone, 1 mg/kg for 1 month, followed by a taper over several 
months to 10 mg daily) are the mainstays of treatment. The 
addition of methotrexate, azathioprine, or mycophenolate 
mofetil to prednisone may be more effective than the pred
-
nisone alone. Case series suggest that biologic therapy with 
either inhibitors of TNF (eg, infliximab) or the IL-6 recep
-
tor (tocilizumab) may be effective for patients refractory to 
prednisone. Takayasu arteritis has a chronic relapsing and 
remitting course that requires ongoing monitoring and 
adjustment of therapy.
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Comarmond C et al; French Takayasu Network. Long-term out
-
comes and prognostic factors of complications in Takayasu 
arteritis: a multicenter study of 318 patients. Circulation. 2017 
Sep 19;136(12):1114–22. [PMID: 28701469]
Mekinian A et al; French Takayasu Network. Efficacy of biolog
-
ical-targeted treatments in Takayasu arteritis: multicenter, 
retrospective study of 49 patients. Circulation. 2015 Nov 3;
 
132(18):1693–700. [PMID: 26354797]
POLYARTERITIS NODOSA
 
»
Medium-sized arteries are affected.
 
»
Clinical findings depend on the arteries involved; 
lungs are spared.
 
»
Common features include fever, abdominal pain, 
extremity pain, livedo reticularis, mononeuritis mul
-
tiplex, anemia, and elevated acute phase reactants 
(ESR or C-reactive protein or both).
 
»
Kidney involvement causes renin-mediated 
 
»
Associated with hepatitis B (10% of cases).
 
»
Polyarteritis nodosa is a necrotizing arteritis of medium-
sized vessels that has a predilection for involving the skin, 
peripheral nerves, mesenteric vessels (including renal 
arteries), heart, and brain but spares the lungs. Polyarteritis 
nodosa is relatively rare, with a prevalence of about 30 per 
1 million people. Approximately 10% of cases of polyarteri
-
tis nodosa are caused by hepatitis B. Most cases of hepatitis 
B–associated disease occur within 6 months of hepatitis B 
infection. Mutations in the gene for adenosine deaminase 
 
2 have been identified in early-onset familial polyarteritis.
 
»
The clinical onset is usually insidious, with fever, malaise, 
weight loss, and other symptoms developing over weeks to 
months. Pain in the extremities is often a prominent early 
feature caused by arthralgia, myalgia (particularly affecting 
the calves), or neuropathy. The combination of mononeu
-
ritis multiplex (with the most common finding being foot-
drop) and features of a systemic illness is one of the earliest 
specific clues to the presence of an underlying vasculitis. 
Polyarteritis nodosa is among the forms of vasculitis most 
commonly associated with vasculitic neuropathy.
In polyarteritis nodosa, the typical skin findings—
livedo reticularis, subcutaneous nodules, and skin ulcers—
reflect the involvement of deeper, medium-sized blood 
vessels. Digital gangrene is not an unusual occurrence. The 
most common cutaneous presentation is lower extremity 
ulcerations, usually occurring near the malleoli. Involve
-
ment of the renal arteries leads to a renin-mediated hyper
-
tension (much less characteristic of vasculitides involving 
smaller blood vessels). For unclear reasons, classic polyar
-
teritis nodosa seldom (if ever) involves the lung, with the 
occasional exception of the bronchial arteries.
Abdominal pain—particularly diffuse periumbilical 
pain precipitated by eating—is common but often difficult 
to attribute to mesenteric vasculitis in the early stages. 
Nausea and vomiting are common symptoms. Infarction 
compromises the function of major viscera and may lead to 
acalculous cholecystitis or appendicitis. Some patients 
present dramatically with an acute abdomen caused by 
mesenteric vasculitis and gut perforation or with hypoten
-
sion resulting from rupture of a microaneurysm in the 
liver, kidney, or bowel.
Subclinical cardiac involvement is common in polyar
-
teritis nodosa, and overt cardiac dysfunction occasionally 
occurs (eg, myocardial infarction secondary to coronary 
vasculitis, or myocarditis).
Most patients with polyarteritis nodosa have a slight ane
-
mia, and leukocytosis is common. Acute-phase reactants 
are often (but not always) strikingly elevated. A major chal
-
lenge in making the diagnosis of polyarteritis nodosa, 
however, is the absence of a disease-specific serologic test 
(eg, an autoantibody). Patients with classic polyarteritis

-
(eg, an autoantibody). Patients with classic polyarteritis 
nodosa are ANCA-negative but may have low titers of 
rheumatoid factor or antinuclear antibodies, both of which 
are nonspecific findings. Appropriate tests for active hepa
-
titis B infection (HBsAg, HBeAg, hepatitis B viral load) 
should be performed.
C. Biopsy and Angiography
The diagnosis of polyarteritis nodosa requires confirma
-
tion with either a tissue biopsy or an angiogram. Biopsies 
of symptomatic sites such as skin (from the edge of an ulcer 
or the center of a nodule), nerve, or muscle have sensitivi
-
ties of approximately 70%. The least invasive tests should 
usually be obtained first, but biopsy of an involved organ is 
essential. If performed by experienced clinicians, tissue 
biopsies normally have high benefit-risk ratios because of 
the importance of establishing the diagnosis. Patients in 
whom polyarteritis nodosa is suspected—eg, on the basis 
of mesenteric ischemia or new-onset hypertension occur
-
ring in the setting of a systemic illness—may be diagnosed 
by the angiographic finding of aneurysmal dilations in the 
renal, mesenteric, or hepatic arteries. Angiography must be 
performed cautiously in patients with baseline kidney 
disease.
 
»
Treatment
For polyarteritis nodosa, corticosteroids in high doses (up 
to 60 mg of oral prednisone daily) may control fever and 
constitutional symptoms and heal vascular lesions. Pulse 
methylprednisolone (eg, 1 g intravenously daily for 3 days) 
may be necessary for patients who are critically ill at presen
-
tation. The addition of cyclophosphamide lowers the risk of 
disease-related death and morbidity among patients who 
have severe disease. Methotrexate or azathioprine are used 
to maintain remissions induced by cyclophosphamide. For 
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patients with polyarteritis nodosa associated with hepatitis B, 
the preferred treatment regimen is a short course of predni
-
sone accompanied by anti-HBV therapy and plasmaphere
-
sis (three times a week for up to 6 weeks). Inhibitors of TNF 
are first-line therapy for the polyarteritis associated with 
deficiency of adenosine deaminase 2.
 
»
Prognosis
Without treatment, the 5-year survival rate in this disorder 
is poor—on the order of 10%. With appropriate therapy, 
remissions are possible in many cases and the 5-year sur
-
vival rate has improved to 60–90%. Poor prognostic factors 
are chronic kidney disease with serum creatinine greater 
than 1.6 mg/dL (141 mcmol/L), proteinuria greater than 
 
1 g/day, gastrointestinal ischemia, central nervous system 
disease, and cardiac involvement. In the absence of any of 
these five factors, 5-year survival is nearly 90%. Survival at 
5 years drops to 75% with one poor prognostic factor pres
-
ent and to about 50% with two or more factors. Substantial 
morbidity and even death may result from adverse effects of 
cyclophosphamide and corticosteroids (Table 26–16). Con
-
sequently, these therapies require careful monitoring and 
expert management. In contrast to many other forms of 
systemic vasculitis, disease relapses in polyarteritis follow
-
ing the successful induction of remission are the exception 
rather than the rule, occurring in only about 20% of cases.
Hashem H et al. Deficiency of adenosine deaminase 2 (DADA2), 
an inherited cause of polyarteritis nodosa and a mimic of 
other systemic rheumatologic disorders. Curr Rheumatol Rep. 
2017 Oct 5;19(11):70. [PMID: 28983775]
Ozen S. The changing face of polyarteritis nodosa and necrotizing 
vasculitis. Nat Rev Rheumatol. 2017 Jun;13(6):381–6. [PMID: 
28490787]
GRANULOMATOSIS WITH POLYANGIITIS 
(Formerly Wegener Granulomatosis)
 
»
Classic triad of upper and lower respiratory tract 
disease and glomerulonephritis.
 
»
Suspect if upper respiratory tract symptoms (eg, 
nasal congestion, sinusitis) are refractory to usual 
 
»
Tissue biopsy usually necessary for diagnosis.
 
»
ANCAs (90% of patients), usually directed against 
proteinase-3 (less commonly against myeloper
-
oxidase present in severe, active disease).
 
»
Kidney disease often rapidly progressive without 
 
»
Granulomatosis with polyangiitis, which has an estimated 
incidence of approximately 12 cases per million individuals 
per year, is the prototype of diseases associated with 
 
▲
Figure 20–6.
 
Scleritis in a patient with granulomatosis 
with polyangiitis.
 (Used, with permission, from Everett 
Allen, MD in Usatine RP , Smith MA, Mayeaux EJ Jr, Chumley H. 
 2nd ed. McGraw-Hill, 
2013.)
antineutrophil cytoplasmic antibodies (ANCA). Other 
“ ANCA-associated vasculitides” include microscopic poly
-
angiitis and eosinophilic granulomatosis with polyangiitis. 
Granulomatosis with polyangiitis is characterized in its full 
expression by vasculitis of small arteries, arterioles, and 
capillaries, necrotizing granulomatous lesions of both 
upper and lower respiratory tract, glomerulonephritis, and 
other organ manifestations. Without treatment, general
-
ized disease is invariably fatal, with most patients surviving 
less than 1 year after diagnosis. It occurs most commonly 
in the fourth and fifth decades of life and affects men and 
women with equal frequency.
 
»
The disorder usually develops over 4–12 months. Upper 
respiratory tract symptoms develop in 90% of patients and 
lower respiratory tract symptoms develop in 60% of 
patients; some patients may have both upper and lower 
respiratory tract symptoms. Upper respiratory tract symp
-
toms can include nasal congestion, sinusitis, otitis media, 
mastoiditis, inflammation of the gums, or stridor due to

-
mastoiditis, inflammation of the gums, or stridor due to 
subglottic stenosis. Since many of these symptoms are 
common, the underlying disease is not often suspected 
until the patient develops systemic symptoms or the origi
-
nal problem is refractory to treatment. The lungs are 
affected initially in 40% and eventually in 80%, with symp
-
toms including cough, dyspnea, and hemoptysis. Other 
early symptoms can include a migratory oligoarthritis with 
a predilection for large joints; a variety of symptoms related 
to ocular disease (unilateral proptosis from orbital pseudo
-
tumor; red eye from scleritis [Figure 20–6], episcleritis, 
anterior uveitis, or peripheral ulcerative keratitis); purpura 
or other skin lesions; and dysesthesia due to neuropathy. 
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Renal involvement, which develops in three-fourths of the 
cases, may be subclinical until kidney disease is advanced. 
Fever, malaise, and weight loss are common.
Physical examination can be remarkable for congestion, 
crusting, ulceration, bleeding, and even perforation of the 
nasal septum. Destruction of the nasal cartilage with “sad
-
dle nose” deformity occurs late. Otitis media, proptosis, 
scleritis, episcleritis, and conjunctivitis are other common 
findings. Newly acquired hypertension, a frequent feature 
of polyarteritis nodosa, is rare in granulomatosis with poly
-
angiitis. Venous thrombotic events (eg, deep venous throm
-
bosis and pulmonary embolism) are a common occurrence 
in granulomatosis with polyangiitis, at least in part because 
of the tendency of the disease to involve veins as well as 
arteries. Although limited forms of granulomatosis with 
polyangiitis have been described in which the kidney is 
spared initially, kidney disease will develop in the majority 
of untreated patients.
1. Serum tests and urinalysis—
Most patients have slight 
anemia, mild leukocytosis, and elevated acute-phase reac
-
tants. If there is kidney involvement, there is proteinuria 
and the urinary sediment contains red cells, with or with
-
out white cells, and often has red cell casts.
Serum tests for ANCA help in the diagnosis of granulo
-
matosis with polyangiitis and related forms of vasculitis 
(Table 20–7). Several different types of ANCA are recog
-
nized, but the two subtypes relevant to systemic vasculitis 
are those directed against proteinase-3 (PR3) and myelo
-
peroxidase (MPO). Antibodies to these two antigens are 
termed “PR3-ANCA ” and “MPO-ANCA, ” respectively. The 
cytoplasmic pattern of immunofluorescence (c-ANCA) 
caused by PR3-ANCA has a high specificity (more than 
90%) for either granulomatosis with polyangiitis or a 
closely related disease, microscopic polyangiitis (or, less 
commonly, eosinophilic granulomatosis with polyangiitis). 
In the setting of active disease, particularly cases in which 
the disease is severe and generalized to multiple organ 
systems, the sensitivity of PR3-ANCA is greater than 95%. 
A substantial percentage of patients with “limited” granu
-
lomatosis with polyangiitis—disease that does not pose an 
immediate threat to life and is often confined to the respi
-
ratory tract—are ANCA-negative. Furthermore, ANCA 
levels correlate erratically with disease activity, and changes 
in titer should not dictate changes in therapy in the absence 
of supporting clinical data. The perinuclear (p-ANCA) 
pattern, caused by MPO-ANCA, is more likely to occur in 
microscopic polyangiitis or eosinophilic granulomatosis 
with polyangiitis but may also be found in granulomatosis 
with polyangiitis. Approximately 10–25% of patients with 
classic granulomatosis with polyangiitis have MPO-ANCA. 
All positive immunofluorescence assays for ANCA should 
be confirmed by enzyme immunoassays for the specific 
autoantibodies directed against PR3 or MPO.
2. Histologic findings—
Although ANCA testing may be 
helpful when used properly, there remains the need in most 
cases for confirmation of the diagnosis by tissue biopsy. 
Histologic features of granulomatosis with polyangiitis 
include vasculitis, granulomatous inflammation, geo
-
graphic necrosis, and acute and chronic inflammation. The 
full range of pathologic changes is usually evident only on 
thoracoscopic lung biopsy; granulomas, observed only 
rarely in kidney biopsy specimens, are found much more 
commonly on lung biopsy specimens. Nasal biopsies 
often do not show vasculitis but may show chronic inflam
-
mation and other changes which, interpreted by an experi
-
enced pathologist, can serve as convincing evidence of the 
diagnosis. Kidney biopsy discloses a segmental necrotizing 
glomerulonephritis with multiple crescents; this is charac
-

-
-
teristic but not diagnostic. Pathologists characterize the 
kidney lesion of granulomatosis with polyangiitis (and 
other forms of “ ANCA-associated vasculitis”) as a pauci-
immune glomerulonephritis because of the relative 
absence (compared with immune complex–mediated 
disorders) of IgG, IgM, IgA, and complement proteins 
within glomeruli.
C. Imaging
Chest CT is more sensitive than chest radiography; lesions 
include infiltrates, nodules, masses, and cavities. Pleural 
effusions are uncommon. Often the radiographs prompt 
concern about lung cancer. Hilar adenopathy large enough 
to be evident on chest film is unusual in granulomatosis 
with polyangiitis; if present, sarcoidosis, tumor, or infec
-
tion is more likely. Other common radiographic abnor
-
malities include extensive sinusitis and even bony sinus 
erosions.
 
»
In most patients with granulomatosis with polyangiitis, 
refractory sinusitis or otitis media is initially suspected. 
When upper respiratory tract inflammation persists and is 
accompanied by additional systemic inflammatory signs 
(eg, red eye from scleritis, joint pain, and swelling), the 
diagnosis of granulomatosis with polyangiitis should be 
considered. Initial complaints of joint pain can lead to a 
misdiagnosis of rheumatoid arthritis. Arriving at the cor
-
rect diagnosis is aided by awareness that rheumatoid 
arthritis typically involves small joints of the hand, whereas 
granulomatosis with polyangiitis favors large joints, such as 
the hip, knee, elbow, and shoulder. Lung cancer may be the 
first diagnostic consideration for some middle-aged 
patients in whom cough, hemoptysis, and lung masses are 
presenting symptoms and signs; typically, evidence of glo
-
merulonephritis, a positive ANCA or, ultimately, the lung 
biopsy findings will point to the proper diagnosis. Granu
-
lomatosis with polyangiitis shares with SLE, anti–glomerular 
basement membrane disease, and microscopic polyangiitis 
the ability to cause an acute pulmonary-renal syndrome. 
Approximately 10–25% of patients with classic granulo
-
matosis with polyangiitis have MPO-ANCA. Owing to 
involvement of the same types of blood vessels, similar 
patterns of organ involvement, and the possibility of failing 
to identify granulomatous pathology on tissue biopsies 
because of sampling error, granulomatosis with polyangi
-
itis is often difficult to differentiate from microscopic 
polyangiitis. The crucial distinctions between the 
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two disorders are the tendencies for granulomatosis with 
polyangiitis to involve the upper respiratory tract (includ
-
ing the ears) and to cause granulomatous inflammation. 
Cocaine use can cause destruction of midline tissues—the 
nose and palate—that mimics granulomatosis with polyan
-
giitis. Indeed, distinguishing between the two conditions 
can be challenging because patients with cocaine-mediated 
midline destructive disease frequently have positive tests 
for PR-3-ANCA and lesional biopsies that demonstrate 
vasculitis. In contrast to granulomatosis with polyangiitis, 
cocaine-mediated midline destructive disease does not 
cause pulmonary or renal disease. IgG
4
-related disease may 
mimic some of the manifestations of granulomatosis with 
polyangiitis.
 
»
Treatment
Early treatment is crucial in preventing the devastating 
end-organ complications of this disease, and often in 
preserving life. While granulomatosis with polyangiitis 
may involve the sinuses or lung for months, once pro
-
teinuria or hematuria develops, progression to advanced 
chronic kidney disease can be rapid (over several 
weeks). Current practice divides treatment into 2 phases: 
induction of remission and maintenance of remission. 
Choice of induction therapy is dictated by whether the 
patient has mild disease (ie, no significant kidney dys
-
function or immediately life-threatening disease) or 
severe disease (ie, life- or organ-threatening disease 
such as rapidly progressive glomerulonephritis or pul
-
monary hemorrhage).
A. Induction of Remission
For patients with severe disease, the treatment options 
for inducing remission are corticosteroids and either 
rituximab or cyclophosphamide.
1. Rituximab plus prednisone—
One option for induc
-
tion therapy is rituximab, a B-cell depleting antibody. 
Rituximab is FDA approved in combination with cortico
-
steroids (prednisone 1 mg/kg orally daily) for the treat
-
ment of granulomatosis with polyangiitis and microscopic 
polyangiitis. Studies demonstrate that rituximab is not 
less effective than cyclophosphamide for remission-
induction in these conditions. Indeed, post-hoc analysis 
of one clinical trial demonstrated that rituximab is more 
effective than cyclophosphamide for treating relapses of 
granulomatosis with polyangiitis and microscopic 
2. Cyclophosphamide and prednisone—
Remissions can 
be induced in more than 90% of patients treated with 
prednisone (1 mg/kg daily) plus cyclophosphamide (2 mg/
kg/day orally with adjustments required for acute or 
chronic kidney disease and patients over age 70). Cyclo
-
phosphamide is best given daily by mouth; intermittent 
high-dose intravenous cyclophosphamide is less effective. 
To minimize toxicity, patients are treated with cyclophos
-
phamide for only 3–6 months; once remission is achieved, 
the patient is switched to a maintenance regimen more 
likely to be tolerated well.
Both rituximab and cyclophosphamide increase the 
risk of developing life-threatening opportunistic infections 
(including progressive multifocal leukoencephalopathy 
[PML]). 
Whenever cyclophosphamide or rituximab is used
, 
Pneumocystis jirovecii 
prophylaxis with single-strength oral 
trimethoprim-sulfamethoxazole daily is essential
.
B. Maintenance of Remission
There are three options for maintaining remission in 
patients with normal or near normal kidney function after 
rituximab or cyclophosphamide induction: azathioprine 
(up to 2 mg/kg/day orally), methotrexate (20–25 mg/wk 
administered either orally or intramuscularly), or ritux
-
imab (500 mg administered intravenously when remission 
is achieved, repeated in 14 days, then repeated every 
 
6 months three more times). Methotrexate should not be 
used in patients with kidney dysfunction. One random
-
ized, controlled trial comparing rituximab and azathio
-
prine for maintenance of remission showed that the risk of

-
-
prine for maintenance of remission showed that the risk of 
relapse over 28 months was 5% with rituximab and 29% 
with azathioprine. Before the institution of azathioprine, 
patients should be tested (through a commercially avail
-
able blood test) for deficiencies in the level of thiopurine 
methyltransferase, an enzyme essential to the metabolism 
of azathioprine.
Because of its superior side-effect profile, methotrexate 
is viewed as an appropriate substitute for cyclophospha
-
mide or rituximab for initial and maintenance treatment in 
patients who have mild disease and normal kidney 
function.
Puéchal X et al; French Vasculitis Study Group. Long-term 
outcomes among participants in the wegent trial of remis
-
sion-maintenance therapy for granulomatosis with polyangi
-
itis (Wegener’s) or microscopic polyangiitis. Arthritis 
Rheumatol. 2016 Mar;68(3):690–701. [PMID: 26473755]
Singer O et al. Update on maintenance therapy for granulomato
-
sis with polyangiitis and microscopic polyangiitis. Curr Opin 
Rheumatol. 2017 May;29(3):248–53. [PMID: 28306595]
Unizony S et al; RAVE-ITN Research Group. Clinical outcomes 
of treatment of anti-neutrophil cytoplasmic antibody 
(ANCA)-associated vasculitis based on ANCA type. Ann 
Rheum Dis. 2016 Jun;75(6):1166–9. [PMID: 26621483]
MICROSCOPIC POLYANGIITIS
 
»
Necrotizing vasculitis of small- and medium-sized 
arteries and veins.
 
»
Most common cause of pulmonary-renal syn
-
drome: diffuse alveolar hemorrhage and 
glomerulonephritis.
 
»
ANCA in 75% of cases, usually anti-myeloperoxi
-
dase antibodies (MPO-ANCA) that cause a p-ANCA 
pattern on immunofluorescence testing. ANCA 
directed against proteinase-3 (PR3-ANCA) can also 
be observed.
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»
Microscopic polyangiitis is a pauci-immune nongranulo
-
matous necrotizing vasculitis that (1) affects small blood 
vessels (capillaries, venules, or arterioles), (2) often causes 
glomerulonephritis and pulmonary capillaritis, and (3) is 
often associated with ANCA on immunofluorescence test
-
ing (directed against MPO, a constituent of neutrophil 
granules). Because microscopic polyangiitis may involve 
medium-sized as well as small blood vessels and because it 
tends to affect capillaries within the lungs and kidneys, its 
spectrum overlaps those of both polyarteritis nodosa and 
granulomatosis with polyangiitis.
In rare instances, medications, particularly propylthioura
-
cil, hydralazine, allopurinol, penicillamine, minocycline, and 
sulfasalazine, induce a systemic vasculitis associated with high 
titers of p-ANCA and features of microscopic polyangiitis.
 
»
A wide variety of findings suggesting vasculitis of small 
blood vessels may develop in microscopic polyangiitis. 
These include “palpable” (or “raised”) purpura and other 
signs of cutaneous vasculitis (ulcers, splinter hemorrhages, 
vesiculobullous lesions).
Microscopic polyangiitis is the most common cause of 
pulmonary-renal syndromes, being several times more 
common than anti–glomerular basement membrane disease. 
Interstitial lung fibrosis that mimics usual interstitial pneu
-
monitis is the presenting condition. Pulmonary hemor
-
rhage may occur. The pathologic findings in the lung are 
typically those of capillaritis.
Vasculitic neuropathy (mononeuritis multiplex) is also 
common in microscopic polyangiitis.
Three-fourths of patients with microscopic polyangiitis are 
ANCA-positive. Elevated acute-phase reactants are also 
typical of active disease. Microscopic hematuria, protein
-
uria, and red blood cell casts in the urine may occur. The 
kidney lesion is a segmental, necrotizing glomerulonephri
-
tis, often with localized intravascular coagulation and the 
observation of intraglomerular thrombi upon renal biopsy.
 
»
Distinguishing this disease from granulomatosis with poly
-
angiitis may be challenging in some cases. Microscopic 
polyangiitis is not associated with the chronic destructive 
upper respiratory tract disease often found in granuloma
-
tosis with polyangiitis. Moreover, as noted, a critical differ
-
ence between the two diseases is the absence of 
granulomatous inflammation in microscopic polyangiitis. 
Because their treatments may differ, microscopic polyangi
-
itis must also be differentiated from polyarteritis nodosa.
 
»
Treatment
Microscopic polyangiitis is usually treated in the same 
way as granulomatosis with polyangiitis: patients with 
severe disease, typically involving pulmonary hemor
-
rhage and glomerulonephritis, require urgent induction 
treatment with corticosteroids and either cyclophospha
-
mide or rituximab. If cyclophosphamide is chosen, it may 
be administered either in an oral daily regimen or via 
intermittent (usually monthly) intravenous pulses; fol
-
lowing induction of remission, cyclophosphamide may be 
replaced with azathioprine, rituximab, or methotrexate 
(provided the patient has normal kidney function). In 
cases of drug-induced MPO-ANCA–associated vasculitis, 
the offending medication should be discontinued; signifi
-
cant organ involvement (eg, pulmonary hemorrhage, 
glomerulonephritis) requires immunosuppressive 
therapy.
 
»
Prognosis
The key to effecting good outcomes is early diagnosis. 
Compared with patients who have granulomatosis with 
polyangiitis, those who have microscopic polyangiitis are 
more likely to have significant fibrosis on renal biopsy 
because of later diagnosis. The likelihood of disease recur
-
rence following remission in microscopic polyangiitis is 
about 33%.
Bossuyt X et al. Position paper: Revised 2017 international con
-

-
about 33%.
-
sensus on testing of ANCAs in granulomatosis with polyan
-
giitis and microscopic polyangiitis. Nat Rev Rheumatol. 
2017 Nov;13(11):683–92. [PMID: 28905856]
BuBui VL et al. Clinical significance of a positive antineutrophil 
cytoplasmic antibody (ANCA) test. JAMA. 2016 Sep 6;316 (9):
 
984–5. [PMID: 27599333]
Cartin-Ceba R et al. Diffuse alveolar hemorrhage secondary to 
antineutrophil cytoplasmic antibody-associated vasculitis: 
predictors of respiratory failure and clinical outcomes. Arthritis 
Rheumatol. 2016 Jun;68(6):1467–76. [PMID: 26713723]
LEVAMISOLE-ASSOCIATED PURPURA
Exposure to levamisole, a prevalent adulterant of illicit 
cocaine in North America, can induce a distinctive clinical 
syndrome of retiform purpura and cutaneous necrosis 
affecting the extremities, ears, and skin overlying the zygo
-
matic arch. Biopsies reveal widespread thrombosis of small 
cutaneous vessels with varying degrees of vasculitis. The 
syndrome is associated with the lupus anticoagulant, IgM 
antibodies to cardiolipin, and very high titers of p-ANCAs 
(due to autoantibodies to elastase, lactoferrin, cathepsin-G, 
and other neutrophil components rather than to myeloper
-
oxidase alone). There is no consensus on treatment of 
levamisole-induced purpura, but early lesions can resolve 
with abstinence. Use of levamisole-adulterated cocaine also 
has been linked to neutropenia, agranulocytosis, and 
pauci-immune glomerulonephritis.
Carmona-Rivera C et al. A role for muscarinic receptors in neu
-
trophil extracellular trap formation and levamisole-induced 
autoimmunity. JCI Insight. 2017 Feb 9;2(3):e89780. [PMID: 
28194438]
Cascio MJ et al. Cocaine/levamisole-associated autoimmune 
syndrome: a disease of neutrophil-mediated autoimmu
-
nity. Curr Opin Hematol. 2018 Jan;25(1):29–36. [PMID: 
29211697]
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CRYOGLOBULINEMIA
Cryoglobulinemia can be associated with an immune-
complex mediated, small-vessel vasculitis. Chronic infec
-
tion with hepatitis C is the most common underlying 
condition; cryoglobulinemic vasculitis also can occur with 
other chronic infections (such as subacute bacterial endo
-
carditis, osteomyelitis, HIV , and hepatitis B), with connec
-
tive tissues diseases (especially Sjögren syndrome), and 
with lympho-proliferative disorders. The cryoglobulins 
associated with vasculitis are cold-precipitable immune 
complexes consisting of rheumatoid factor and IgG (rheu
-
matoid factor is an autoantibody to the constant region of 
IgG). The rheumatoid factor component can be monoclo
-
nal (type II cryoglobulins) or polyclonal (type III cryo
-
globulins). (Type I cryoglobulins are cryoprecipitable 
monoclonal proteins that lack rheumatoid factor activity; 
these cause cold-induced hyperviscosity syndromes, not 
vasculitis, and are associated with B-cell lymphoproliferative 
diseases.)
 
»
Cryoglobulinemic vasculitis typically manifests as recur
-
rent palpable purpura and peripheral neuropathy. A prolif
-
erative glomerulonephritis can develop and can manifest as 
rapidly progressive glomerulonephritis. Abnormal liver 
biochemical tests, abdominal pain, digital gangrene, and 
pulmonary disease may also occur. The diagnosis is based 
on a compatible clinical picture and a positive serum test 
for cryoglobulins. The presence of a disproportionately low 
C4 level can be a diagnostic clue to the presence of 
cryoglobulinemia.
 
»
Treatment
Antiviral regimens that do not include interferon are first-
line therapy for hepatitis C–associated cryoglobulinemic 
vasculitis that is neither life- nor organ-threatening. 
Patients with severe cryoglobulinemic vasculitis (eg, exten
-
sive digital gangrene, extensive neuropathy, and rapidly 
progressive glomerulonephritis) and hepatitis C should 
receive immunosuppressive therapy with corticosteroids 
and either rituximab or cyclophosphamide as well as 
interferon-free antiviral therapy; plasma exchange may 
provide additional benefit in selected cases.
Desbois AC et al. Cryoglobulinemia vasculitis: how to handle. 
Curr Opin Rheumatol. 2017 Jul;29(4):343–7. [PMID: 
28368978]
Sise ME et al. Treatment of hepatitis C virus-associated mixed 
cryoglobulinemia with direct-acting antiviral agents. 
Hepatology. 2016 Feb;63(2):408–17. [PMID: 26474537]
HENOCH-SCHÖNLEIN PURPURA
Henoch-Schönlein purpura, the most common systemic 
vasculitis in children, occurs in adults as well. Typical fea
-
tures are palpable purpura, arthritis, and hematuria. 
Abdominal pain occurs less frequently in adults than in 
children. Pathologic features include leukocytoclastic vas
-
culitis with IgA deposition. The cause is not known.
The purpuric skin lesions are typically located on the 
lower extremities but may also be seen on the hands, arms, 
trunk, and buttocks. Joint symptoms are present in the 
majority of patients, the knees and ankles being most com
-
monly involved. Abdominal pain secondary to vasculitis of 
the intestinal tract is often associated with gastrointestinal 
bleeding. Hematuria signals the presence of a renal lesion 
that is usually reversible, although it occasionally may 
progress to chronic kidney disease. Children tend to have 
more frequent and more serious gastrointestinal vasculitis, 
whereas adults more often suffer from chronic kidney dis
-
ease. Biopsy of the kidney reveals segmental glomerulone
-
phritis with crescents and mesangial deposition of IgA.
Chronic courses with persistent or intermittent skin 
disease are more likely to occur in adults than in children. 
The value of corticosteroids has been controversial. In chil
-
dren, prednisone (1–2 mg/kg/day orally) does not decrease 
the frequency of proteinuria 1 year after onset of disease.

-
the frequency of proteinuria 1 year after onset of disease. 
Severe disease is often treated with aggressive immunosup
-
pressive agents, such as mycophenolate mofetil, but there is 
no consensus as to the efficacy of this approach or the 
optimal therapeutic regimen.
Heineke MH et al. New insights in the pathogenesis of immuno
-
globulin A vasculitis (Henoch-Schönlein purpura). Autoimmun 
Rev. 2017 Dec;16(12):1246–53. [PMID: 29037908]
Hong S et al. Late-onset IgA vasculitis in adult patients exhibits 
distinct clinical characteristics and outcomes. Clin Exp 
Rheumatol. 2016 May–Jun;34(3 Suppl 97):S77–83. [PMID: 
26842218]
RELAPSING POLYCHONDRITIS
This disease is characterized by inflammatory destructive 
lesions of cartilaginous structures, principally the ears, 
nose, trachea, and larynx. Nearly 40% of cases are associ
-
ated with another disease, especially either other immuno
-
logic disorders (such as SLE, rheumatoid arthritis, or 
Hashimoto thyroiditis) or cancers (such as plasma cell 
myeloma) or hematologic disorders (such as myelodys
-
plastic syndrome). The disease, which is usually episodic, 
affects males and females equally. The cartilage is painful, 
swollen, and tender during an attack and subsequently 
becomes atrophic, resulting in permanent deformity. 
Biopsy of the involved cartilage shows inflammation and 
chondrolysis. Laryngotracheal and broncial chondritis can 
lead to life-threatening airway narrowing and collapse. 
Noncartilaginous manifestations of the disease include 
fever, episcleritis, uveitis, deafness, aortic regurgitation, 
and rarely glomerulonephritis. In 85% of patients, a 
migratory, asymmetric, and seronegative arthropathy 
occurs, affecting both large and small joints and the costo
-
chondral junctions. Diagnosing this uncommon disease is 
especially difficult since the signs of cartilage inflamma
-
tion (such as red ears or nasal pain) may be more subtle 
than the fever, arthritis, rash, or other systemic 
Prednisone, 0.5–1 mg/kg/day orally, is often effective. 
Dapsone (100–200 mg/day orally) or methotrexate (7.5–20 mg 
orally per week) may also have efficacy, sparing the need for 
long-term high-dose corticosteroid treatment. Involvement 
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of the tracheobronchial tree may respond to inhibitors 
of TNF.
Kingdon J et al. Relapsing polychondritis: a clinical review for 
rheumatologists. Rheumatology (Oxford). 2017 Nov 6. [Epub 
ahead of print] [PMID: 29126262]
BEHÇET SYNDROME
 
»
Recurrent, painful oral and genital aphthous 
ulcers.
 
»
Erythema nodosum–like lesions; follicular rash; 
and the pathergy phenomenon.
 
»
Anterior or posterior uveitis. Posterior uveitis may 
be asymptomatic until significant damage to the 
retina has occurred.
 
»
Neurologic lesions can mimic multiple sclerosis.
 
»
Named after the Turkish dermatologist who first described 
it, Behçet disease is of unknown cause and most commonly 
occurs in persons of Asian, Turkish, or Middle Eastern 
background. The protean manifestations are believed to 
result from vasculitis that may involve all types of blood 
vessels: small, medium, and large, on both the arterial and 
venous side of the circulation.
 
»
The hallmark of Behçet disease is painful aphthous ulcer
-
ations in the mouth. These lesions, which usually are mul
-
tiple, may be found on the tongue, gums, and inner 
surfaces of the oral cavity. Genital lesions, similar in 
appearance, are also common but do not occur in all 
patients. Other cutaneous lesions of Behçet disease include 
tender, erythematous, papular lesions that resemble ery
-
thema nodosum. (On biopsy, however, many of these 
lesions are shown to be secondary to vasculitis rather than 
septal panniculitis.) These erythema nodosum–like lesions 
have a tendency to ulcerate, a major difference between the 
lesions of Behçet disease and the erythema nodosum seen 
in cases of sarcoidosis and inflammatory bowel disease. An 
erythematous follicular rash that occurs frequently on the 
upper extremities may be a subtle feature of the disease. 
The 
pathergy phenomenon
 is frequently underappreci
-
ated (unless the patient is asked); in this phenomenon, 
sterile pustules develop at sites where needles have been 
inserted into the skin (eg, for phlebotomy) in some 
patients.
A nonerosive arthritis occurs in about two-thirds of 
patients, most commonly affecting the knees and ankles. 
Eye involvement may be one of the most devastating com
-
plications of Behçet disease. Posterior uveitis, in essence a 
retinal venulitis, may lead to the insidious destruction of 
large areas of the retina before the patient becomes aware 
of visual problems. Anterior uveitis, associated with the 
triad of photophobia, blurred vision, and a red eye, is 
intensely symptomatic. This complication may lead to a 
hypopyon, the accumulation of pus in the anterior chamber. 
If not treated properly with mydriatic agents to dilate the 
pupil and corticosteroid eyedrops to diminish inflamma
-
tion, the anterior uveitis may lead to synechial formation 
between the iris and lens, resulting in permanent pupillary 
distortion.
Central nervous system involvement is another cause of 
major potential morbidity. The central nervous system 
lesions may mimic multiple sclerosis radiologically. Find
-
ings include sterile meningitis (recurrent meningeal head
-
aches associated with a lymphocytic pleocytosis), cranial 
nerve palsies, seizures, encephalitis, mental disturbances, 
and spinal cord lesions. Aphthous ulcerations of the ileum 
and cecum and other forms of gastrointestinal involvement 
develop in approximately a quarter of patients. Large vessel 
vasculitis can lead to pulmonary artery aneurysms and life-
threatening pulmonary hemorrhage. Finally, patients have 
a hypercoagulable tendency that may lead to complicated 
venous thrombotic events, particularly multiple deep 
venous thrombosis, pulmonary emboli, cerebral sinus 
thrombosis, and other problems associated with clotting.
The clinical course may be chronic but is often charac
-
terized by remissions and exacerbations.

-
There are no pathognomonic laboratory features of Behçet 
disease. Although acute-phase reactants are often elevated, 
there is no autoantibody or other assay that is distinctive. 
No markers of hypercoagulability specific to Behçet have 
been identified.
 
»
Treatment
Both colchicine (0.6 mg once to three times daily orally) 
and thalidomide (100 mg/day orally) help ameliorate the 
mucocutaneous findings. Apremilast, a selective phospho
-
diesterase-4 inhibitor, is effective for the treatment of the 
oral ulcers. Corticosteroids (1 mg/kg/day of oral predni
-
sone) are a mainstay of initial therapy for severe disease 
manifestations. Azathioprine (2 mg/kg/day orally) may be 
an effective steroid-sparing agent. Infliximab, cyclosporine, 
or cyclophosphamide is indicated for severe ocular and 
central nervous system complications of Behçet disease.
Bulur I et al. Behçet disease: new aspects. Clin Dermatol. 2017 
Sep–Oct;35(5):421–34. [PMID: 28916023]
PRIMARY ANGIITIS OF THE CENTRAL 
NERVOUS SYSTEM
Primary angiitis of the central nervous system is a syndrome 
with several possible causes that produces small- and medium-
sized vasculitis limited to the brain and spinal cord. Biopsy-
proved cases have predominated in men who have a history of 
weeks to months of headaches, encephalopathy, and 
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multifocal strokes. Systemic symptoms and signs are absent, 
and routine laboratory tests, including ESR and C-reactive 
protein, are usually normal. MRI of the brain is almost always 
abnormal, and the spinal fluid often reveals a mild lymphocy
-
tosis and a modest increase in protein level. Angiograms clas
-
sically reveal a “string of beads” pattern produced by 
alternating segments of arterial narrowing and dilation. How
-
ever, neither the MRI nor the angiogram appearance is spe
-
cific for vasculitis. Indeed, in one study, none of the patients 
who had biopsy-proved central nervous system vasculitis had 
an angiogram showing “the string of beads, ” and none of the 
patients with the classic angiographic findings had a positive 
brain biopsy for vasculitis. Review of many studies suggests 
that the sensitivity of angiography varies greatly (from 40% to 
90%) and the specificity is only approximately 30%. Many 
conditions, including vasospasm, can produce the same 
angiographic pattern as vasculitis. Definitive diagnosis 
requires a compatible clinical picture; exclusion of infection 
(including subacute bacterial endocarditis), neoplasm, or 
metabolic disorder or drug exposure (eg, cocaine) that can 
mimic primary angiitis of the central nervous system; and a 
positive brain biopsy. In contrast to biopsy-proved cases, 
patients with angiographically defined central nervous system 
vasculopathy are chiefly women who have had an abrupt 
onset of headaches and stroke (often in the absence of enceph
-
alopathy) with normal spinal fluid findings. Many patients 
who fit this clinical profile may have reversible cerebral vaso
-
constriction rather than true vasculitis. Such cases may best be 
treated with calcium channel blockers (such as nimodipine or 
verapamil) and possibly a short course of corticosteroids. 
Biopsy-proved cases usually improve with prednisone therapy 
and often require cyclophosphamide. Treatment response 
correlates with the size of arteries involved: vasculitis of small 
cortical and leptomeningeal vessels is associated with a better 
response and outcome than vasculitis of larger arteries. Cases 
of central nervous system vasculitis associated with cerebral 
amyloid angiopathy often respond well to corticosteroids, 
albeit the long-term natural history remains poorly defined.
Mandal J et al. Primary angiitis of the central nervous system. 
Rheum Dis Clin North Am. 2017 Nov;43(4):503–18. [PMID: 
29061238]
Salvarani C et al. Management of primary and secondary central 
nervous system vasculitis. Curr Opin Rheumatol. 2016 Jan;
 
28(1):21–8. [PMID: 26599380]
LIVEDO RETICULARIS & LIVEDO RACEMOSA
Livedo reticularis produces a mottled, purplish discolor
-
ation of the skin with reticulated cyanotic areas surround
-
ing paler central cores. This distinctive “fishnet” pattern is 
caused by spasm or obstruction of perpendicular arteri
-
oles, combined with pooling of blood in surrounding 
venous plexuses. Idiopathic livedo reticularis is a benign 
condition that worsens with cold exposure, improves with 
warming, and primarily affects the extremities. Apart from 
cosmetic concerns, it is usually asymptomatic. Systemic 
symptoms or the development of cutaneous ulcerations 
point to the presence of an underlying disease.
Secondary livedo reticularis, now more properly known as 
livedo racemosa, occurs in association with a variety of 
diseases that cause vascular obstruction or inflammation. 
Livedo racemosa resembles idiopathic livedo reticularis but 
has a wider distribution (often found on trunk and buttocks as 
well as extremities) and its lesions are more irregular, broken, 
and circular. Of particular importance is the link with antiphos
-
pholipid antibody syndrome. Livedo racemosa is the present
-
ing manifestation of 25% of patients with antiphospholipid 
antibody syndrome and is strongly associated with the sub
-

-
-
-
group that has arterial thromboses, including those with Sned
-
don syndrome (livedo reticularis and cerebrovascular events). 
Other underlying causes of livedo racemosa include the vascu
-
litides (particularly polyarteritis nodosa), cholesterol emboli 
syndrome, thrombocythemia, cryoglobulinemia, cold aggluti
-
nin disease, primary hyperoxaluria (due to vascular deposits of 
calcium oxalate), and disseminated intravascular coagulation.
Sajjan VV et al. Livedo reticularis: a review of the literature. 
Indian Dermatol Online J. 2015 Sep–Oct;6(5):315–21. 
[PMID: 26500860]
 
º
SERONEGATIVE 
SPONDYLOARTHROPATHIES
The seronegative spondyloarthropathies are ankylosing 
spondylitis, psoriatic arthritis, reactive arthritis, the arthritis 
associated with inflammatory bowel disease, and undiffer
-
entiated spondyloarthropathy. These disorders are noted for 
male predominance, onset usually before age 40, inflamma
-
tory arthritis of the spine and sacroiliac joints, asymmetric 
oligoarthritis of large peripheral joints, enthesopathy 
(inflammation of where ligaments, tendons, and joint cap
-
sule insert into bone), uveitis in a significant minority, the 
absence of autoantibodies in the serum, and a striking asso
-
ciation with HLA-B27. HLA-B27 is positive in up to 90% of 
patients with ankylosing spondylitis and 75% with reactive 
arthritis. HLA-B27 also occurs in 50% of the psoriatic and 
inflammatory bowel disease patients who have sacroiliitis. 
Patients with only peripheral arthritis in these latter two 
syndromes do not show an increase in HLA-B27.
ANKYLOSING SPONDYLITIS
 
»
Chronic low backache in young adults, generally 
worst in the morning.
 
»
Progressive limitation of back motion and of chest 
expansion.
 
»
Transient (50%) or persistent (25%) peripheral 
arthritis.
 
»
Anterior uveitis in 20–25%.
 
»
Diagnostic radiographic changes in sacroiliac joints.
 
»
Negative serologic tests for rheumatoid factor and 
anti-CCP antibodies.
 
»
HLA-B27 testing is most helpful when there is an 
intermediate probability of disease.
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»
Ankylosing spondylitis is a chronic inflammatory disease 
of the joints of the axial skeleton, manifested clinically by 
pain and progressive stiffening of the spine. The age at 
onset is usually in the late teens or early 20s. The incidence 
is greater in males than in females, and symptoms are more 
prominent in men, with ascending involvement of the 
spine more likely to occur.
 
»
The onset is usually gradual, with intermittent bouts of 
back pain that may radiate into the buttocks. The back pain 
is worse in the morning and usually associated with stiff
-
ness that lasts hours. The pain and stiffness improve with 
activity, in contrast to back pain due to mechanical causes 
and degenerative disease, which improves with rest and 
worsens with activity. As the disease advances, symptoms 
progress in a cephalad direction, and back motion becomes 
limited, with the normal lumbar curve flattened and the 
thoracic curvature exaggerated. Chest expansion is often 
limited as a consequence of costovertebral joint involve
-
ment. In advanced cases, the entire spine becomes fused, 
allowing no motion in any direction. Transient acute 
arthritis of the peripheral joints occurs in about 50% of 
cases, and permanent changes in the peripheral joints—
most commonly the hips, shoulders, and knees—are seen 
in about 25%. Enthesopathy, a hallmark of the spondyloar
-
thropathies, can manifest as swelling of the Achilles tendon 
at its insertion, plantar fasciitis (producing heel pain), or 
“sausage” swelling of a finger or toe (less common in anky
-
losing spondylitis than in psoriatic arthritis).
Anterior uveitis is associated in as many as 25% of cases 
and may be a presenting feature. Spondylitic heart disease, 
characterized chiefly by atrioventricular conduction 
defects and aortic regurgitation occurs in 3–5% of patients 
with longstanding severe disease. Constitutional symptoms 
similar to those of rheumatoid arthritis are absent in most 
patients.
The ESR is elevated in 85% of cases, but serologic tests for 
rheumatoid factor and anti-CCP antibodies are negative. 
Anemia of chronic disease may be present but is often 
mild. HLA-B27 is found in 90% of white patients and 50% 
of black patients with ankylosing spondylitis. Because this 
antigen occurs in 8% of the healthy white population and 
2% of healthy blacks, it is not a specific diagnostic test.
C. Imaging
The earliest radiographic changes are usually in the sacro
-
iliac joints. In the first 2 years of the disease process, the 
sacroiliac changes may be detectable only by MRI. Indeed, 
patients who have symptoms and findings of ankylosing 
spondylitis and sacroiliitis evident by MRI but not by con
-
ventional radiographs are classified as having nonradio
-
graphic axial spondyloarthritis. Later, erosion and sclerosis 
of these joints often become evident on plain radiographs; 
the sacroiliitis of ankylosing spondylitis is bilateral and 
symmetric. Inflammation where the annulus fibrosus 
attaches to the vertebral bodies initially causes sclerosis 
(“the shiny corner sign”) and then characteristic squaring 
of the vertebral bodies. The term “bamboo spine” describes 
the late radiographic appearance of the spinal column in 
which the vertebral bodies are fused by vertically oriented, 
bridging syndesmophytes formed by the ossification of the 
annulus fibrosus and calcification of the anterior and lat
-
eral spinal ligaments. Fusion of the posterior facet joints of 
the spine is also common.
Additional radiographic findings include periosteal 
new bone formation on the iliac crest, ischial tuberosities 
and calcanei, and alterations of the pubic symphysis and 
sternomanubrial joint similar to those of the sacroiliacs. 
Radiologic changes in peripheral joints, when present, tend 
to be asymmetric and lack the demineralization and ero
-

-
sions seen in rheumatoid arthritis.
 
»
Low back pain due to mechanical causes, disk disease, and 
degenerative arthritis is very common. Onset of back pain 
prior to age 30 and an “inflammatory” quality of the back 
pain (ie, morning stiffness and pain that improve with 
activity) should raise the possibility of ankylosing spondy
-
litis. In contrast to ankylosing spondylitis, rheumatoid 
arthritis predominantly affects multiple, small, peripheral 
joints of the hands and feet. Rheumatoid arthritis spares 
the sacroiliac joints and only affects the cervical compo
-
nent of the spine. Bilateral sacroiliitis indistinguishable 
from ankylosing spondylitis is seen with the spondylitis 
associated with inflammatory bowel disease. Sacroiliitis 
associated with reactive arthritis and psoriasis, on the other 
hand, is often asymmetric or even unilateral. Osteitis con
-
densans ilii (sclerosis on the iliac side of the sacroiliac 
joint) is an asymptomatic, postpartum radiographic find
-
ing that is occasionally mistaken for sacroiliitis. Diffuse 
idiopathic skeletal hyperostosis (DISH) causes exuberant 
osteophytes (“enthesophytes”) of the spine that occasion
-
ally are difficult to distinguish from the syndesmophytes of 
ankylosing spondylitis. The enthesophytes of DISH are 
thicker and more anterior than the syndesmophytes of 
ankylosing spondylitis, and the sacroiliac joints are normal 
in DISH.
 
»
Treatment
NSAIDs remain first-line treatment of ankylosing spondy
-
litis and may slow radiographic progression of spinal dis
-
ease. TNF inhibitors have established efficacy for 
NSAID-resistant axial disease; responses are often substan
-
tial and durable. Etanercept (50 mg subcutaneously once a 
week), adalimumab (40 mg subcutaneously every other 
week), infliximab (5 mg/kg every other month by intrave
-
nous infusion), golimumab (50 mg subcutaneously once a 
month), or certolizumab (200 mg subcutaneously every 
other week) is reasonable for patients whose symptoms are 
refractory to NSAIDs. Secukinumab, an inhibitor of the 
proinflammatory cytokine IL-17A, is also highly effective 
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in the treatment of ankylosing spondylitis. Corticosteroids 
have minimal impact on the arthritis—particularly the 
spondylitis—of ankylosing spondylitis and can worsen 
osteopenia. All patients should be referred to a physical 
therapist for instruction in postural exercises.
 
»
Prognosis
Almost all patients have persistent symptoms over decades; 
rare individuals experience long-term remissions. The sever
-
ity of disease varies greatly, with about 10% of patients having 
work disability after 10 years. Developing hip disease within 
the first 2 years of disease onset presages a worse prognosis. 
TNF inhibitors provide symptomatic relief and improve 
quality of life for many patients with ankylosing spondylitis.
Marzo-Ortega H et al; Measure 2 Study Group. Secukinumab 
and sustained improvement in signs and symptoms of patients 
with active ankylosing spondylitis through two years: results 
from a phase iii study. Arthritis Care Res (Hoboken). 2017 Jul;
 
69(7):1020–9. [PMID: 28235249]
Taurog JD et al. Ankylosing spondylitis and axial spondyloar
-
thritis. N Engl J Med. 2016 Jun 30;374(26):2563–74. [PMID: 
27355535]
Ward MM et al. American College of Rheumatology/Spondylitis 
Association of America/Spondyloarthritis Research and 
Treatment Network 2015 recommendations for the treatment 
of ankylosing spondylitis and nonradiographic axial spondy
-
loarthritis. Arthritis Rheumatol. 2016 Feb;68(2):282–98. 
[PMID: 26401991]
PSORIATIC ARTHRITIS
 
»
Psoriasis precedes arthritis in 80% of cases.
 
»
Arthritis:
 usually asymmetric, with “sausage” 
appearance of fingers and toes; polyarthritis that 
resembles rheumatoid arthritis also occurs.
 
»
Sacroiliac joint involvement common.
 
»
 osteolysis; pencil-in-cup 
deformity; relative lack of osteoporosis; bony 
ankylosis; asymmetric sacroiliitis and atypical 
syndesmophytes.
 
»
Although psoriasis usually precedes the onset of arthritis, 
arthritis precedes (by up to 2 years) or occurs simultane
-
ously with the skin disease in approximately 20% of cases.
 
»
The patterns or subsets of psoriatic arthritis include the 
following:
1.
 
A symmetric polyarthritis that resembles rheumatoid 
arthritis. Usually, fewer joints are involved than in rheu
-
matoid arthritis.
2.
 
An oligoarticular form that may lead to considerable 
destruction of the affected joints.
3.
 
A pattern of disease in which the DIP joints are primar
-
ily affected. Early, this may be monarticular, and often 
the joint involvement is asymmetric. Pitting of the nails 
and onycholysis frequently accompany DIP involve
-
ment.
4.
 
A severe deforming arthritis (arthritis mutilans) in 
which osteolysis is marked.
5.
 
A spondylitic form in which sacroiliitis and spinal 
involvement predominate; 50% of these patients are 
HLA-B27-positive.
Arthritis is at least five times more common in patients 
with severe skin disease than in those with only mild skin 
findings. Occasionally, however, patients may have a single 
patch of psoriasis (typically hidden in the scalp, gluteal cleft, 
or umbilicus) and are unaware of its presence. Thus, a 
detailed search for cutaneous lesions is essential in patients 
with arthritis of new onset. Also, the psoriatic lesions may 
have cleared when arthritis appears—in such cases, the his
-
tory is most useful in diagnosing previously unexplained 
cases of mono- or oligoarthritis. Nail pitting is sometimes a 
clue. “Sausage” swelling of one or more digits is a common 
manifestation of enthesopathy in psoriatic arthritis.
Laboratory studies show an elevation of the ESR; rheuma
-
toid factor and anti-CCP antibodies are not present. Uric 
acid levels may be high, reflecting the active turnover of 
skin affected by psoriasis. There is a correlation between

-
skin affected by psoriasis. There is a correlation between 
the extent of psoriatic involvement and the level of uric 
acid, but gout is no more common than in patients with
-
out psoriasis. Desquamation of the skin may also reduce 
iron stores.
C. Imaging
Radiographic findings are most helpful in distinguishing 
the disease from other forms of arthritis. There are mar
-
ginal erosions of bone and irregular destruction of joint 
and bone, which, in the phalanx, may give the appearance 
of a sharpened pencil. Fluffy periosteal new bone may be 
marked, especially at the insertion of muscles and liga
-
ments into bone. Such changes will also be seen along the 
shafts of metacarpals, metatarsals, and phalanges. Psoriatic 
spondylitis causes asymmetric sacroiliitis and syndesmo
-
phytes, which are coarser than those seen in ankylosing 
spondylitis. In psoriatic arthritis as in ankylosing spondyli
-
tis, MRI is more sensitive in detecting axial abnormalities 
than plain radiographs, especially in the first few years of 
disease onset. Ultrasonography and MRI are more sensitive 
than conventional radiographs in detecting peripheral 
arthritis, enthesitis, and dactylitis.
 
»
Treatment
NSAIDs are usually sufficient for mild cases. For patients 
with peripheral arthritis, methotrexate (7.5–20 mg orally 
once a week) is generally considered the drug of choice for 
patients who have not responded to NSAIDs; methotrexate 
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is not effective for axial arthritis. Methotrexate can improve 
both the cutaneous and arthritic manifestations. For 
patients with axial disease or peripheral arthritis that is 
refractory to methotrexate, treatment with a TNF inhibitor 
(at doses similar to the treatment of ankylosing spondyli
-
tis) is usually effective for both arthritis and psoriatic skin 
disease. Patients who do not respond to TNF inhibitors can 
be treated with ustekinumab, a monoclonal antibody that 
inhibits IL-12 and IL-23, or secukinumab, which inhibits 
IL-17. Apremilast, an oral phosphodiesterase-4 inhibitor, is 
an option for patients who cannot use, or choose not to 
use, biologic agents. Corticosteroids are less effective in 
psoriatic arthritis than in other forms of inflammatory 
arthritis and may precipitate pustular psoriasis during 
tapers. Successful treatment directed at the skin lesions 
alone (eg, by PUV A therapy) occasionally is accompanied 
by an improvement in peripheral articular symptoms.
Naik GS et al. Th17 inhibitors in active psoriatic arthritis: a sys
-
tematic review and meta-analysis of randomized controlled 
clinical trials. Dermatology. 2017;233(5):366–77. [PMID: 
29258093]
Schemoul J et al. Treatment strategies for psoriatic arthritis. Joint 
Bone Spine. 2017 Nov 16. [Epub ahead of print] [PMID: 
29155104]
REACTIVE ARTHRITIS 
 
(
Formerly Reiter Syndrome)
 
»
Oligoarthritis, conjunctivitis, urethritis, and mouth 
ulcers most common features.
 
»
Usually follows dysentery or a sexually transmitted 
 
»
HLA-B27–positive in 50–80% of patients.
 
»
Reactive arthritis is precipitated by antecedent gastrointes
-
tinal and genitourinary infections and manifests as an 
asymmetric sterile oligoarthritis, typically of the lower 
extremities. It is frequently associated with enthesitis. 
Extra-articular manifestations are common and include 
urethritis, conjunctivitis, uveitis, and mucocutaneous 
lesions. Reactive arthritis occurs most commonly in young 
men and is associated with HLA-B27 in 80% of white 
patients and 50–60% of blacks.
 
»
Most cases of reactive arthritis develop within 1–4 weeks 
after either a gastrointestinal infection (usually with 
Shigella, Salmonella, Yersinia, or Campylobacter
) or a sexu
-
ally transmitted infection (with 
 or 
perhaps 
Ureaplasma urealyticum
). Whether the inciting 
infection is sexually transmitted or dysenteric does not affect 
the subsequent manifestations but does influence the gen
-
der ratio: The ratio is 1:1 after enteric infections but 9:1 
with male predominance after sexually transmitted infec
-
tions. Synovial fluid from affected joints is culture-negative. 
A clinically indistinguishable syndrome can occur without 
an apparent antecedent infection, suggesting that subclinical 
infection can precipitate reactive arthritis or that there are 
other, as yet unrecognized, triggers.
The arthritis is most commonly asymmetric and fre
-
quently involves the large weight-bearing joints (chiefly the 
knee and ankle); sacroiliitis or ankylosing spondylitis is 
observed in at least 20% of patients, especially after fre
-
quent recurrences. Systemic symptoms including fever and 
weight loss are common at the onset of disease. The muco
-
cutaneous lesions may include balanitis (Figure 20–7), 
stomatitis, and keratoderma blennorrhagicum, indistin
-
guishable from pustular psoriasis. Involvement of the fin
-
gernails in reactive arthritis also mimics psoriatic changes. 
When present, conjunctivitis is mild and occurs early in 
the disease course. Anterior uveitis, which can develop at 
any time in HLA-B27-positive patients, is a more clinically 
significant ocular complication. Carditis and aortic regur
-
gitation may occur. While most signs of the disease disap
-
pear within days or weeks, the arthritis may persist for

-
-
pear within days or weeks, the arthritis may persist for 
several months or become chronic. Recurrences involving 
any combination of the clinical manifestations are com
-
mon and are sometimes followed by permanent sequelae, 
especially in the joints (eg, articular destruction).
B. Imaging
Radiographic signs of permanent or progressive joint disease 
may be seen in the sacroiliac as well as the peripheral joints.
 
»
Gonococcal arthritis can initially mimic reactive arthritis, 
but the marked improvement after 24–48 hours of antibiotic 
administration and the culture results distinguish the two 
disorders. Rheumatoid arthritis, ankylosing spondylitis, and 
 
▲
Figure 20–7.
 
Circinate balanitis due to reactive 
arthritis (Reiter syndrome). 
(From Susan Lindsley, Dr. M. F. 
Rein, Public Health Image Library, CDC.)
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psoriatic arthritis must also be considered. By causing simi
-
lar oral, ocular, and joint lesions, Behçet disease may also 
mimic reactive arthritis. The oral lesions of reactive arthritis, 
however, are typically painless, in contrast to those of Behçet 
disease. HIV is not more common in sexually active men 
with reactive arthritis.
 
»
Treatment
NSAIDs have been the mainstay of therapy. Antibiotics 
given at the time of a nongonococcal sexually transmitted 
infection reduce the chance that the individual will develop 
this disorder. For chronic reactive arthritis associated with 
chlamydial infection, combination antibiotics taken for 6 
months are more effective than placebo. Patients who do 
not respond to NSAIDs may respond to sulfasalazine, 1000 
mg orally twice daily, or to methotrexate, 7.5–20 mg orally 
per week. For those patients with recent-onset disease that 
is refractory to NSAIDs and these DMARDs, anti-TNF 
agents, which are effective in the other spondyloarthropa
-
thies, may be effective.
Courcoul A et al. A bicentre retrospective study of features and 
outcomes of patients with reactive arthritis. Joint Bone Spine. 
2018 Mar;85(2):201–5. [PMID: 28238883]
ARTHRITIS & INFLAMMATORY 
 
INTESTINAL DISEASES
One-fifth of patients with 
inflammatory bowel disease
 have 
arthritis, which complicates Crohn disease somewhat more 
frequently than it does ulcerative colitis. In both diseases, two 
distinct forms of arthritis occur. The first is peripheral 
arthritis—usually a nondeforming asymmetric oligoarthritis 
of large joints—in which the activity of the joint disease paral
-
lels that of the bowel disease. The arthritis usually begins 
months to years after the bowel disease, but occasionally the 
joint symptoms develop earlier and may be prominent enough 
to cause the patient to overlook intestinal symptoms. The 
second form of arthritis is a spondylitis that is indistinguish
-
able by symptoms or radiographs from ankylosing spondylitis 
and follows a course independent of the bowel disease. About 
50% of these patients are HLA-B27 positive.
Controlling the intestinal inflammation usually elimi
-
nates the peripheral arthritis. NSAIDs can be effective when 
the arthritis is mild but must be used cautiously since they 
can exacerbate inflammatory bowel disease. TNF inhibitors 
are attractive therapies because they are effective both for 
the bowel and for the joints. Range-of-motion exercises as 
prescribed for ankylosing spondylitis can be helpful.
About two-thirds of patients with 
Whipple disease
 experi
-
ence arthralgia or arthritis, most often an episodic, large-joint 
polyarthritis. The arthritis usually precedes the gastrointesti
-
nal manifestations by years and often resolves as the diarrhea 
develops. Thus, Whipple disease should be considered in 
the differential diagnosis of unexplained episodic arthritis.
Malaty HM et al. Characterization and prevalence of spondylo
-
arthritis and peripheral arthritis among patients with inflam
-
matory bowel disease. Clin Exp Gastroenterol. 2017 Sep 27;
 
10:259–63. [PMID: 29026327]
 
º
INFECTIOUS ARTHRITIS
1
NONGONOCOCCAL ACUTE BACTERIAL 
(
Septic
) ARTHRITIS
 
»
Acute onset of inflammatory monarticular arthritis, 
most often in large weight-bearing joints and 
wrists.
1
 
»
Common risk factors include previous joint damage 
and injection drug use.
 
»
Infection with causative organism commonly 
found elsewhere in body.
 
»
Joint effusions are usually large, with white blood 
cell counts commonly over 50,000/mcL.
1
 
»
Nongonococcal acute bacterial arthritis is most often due 
to hematogenous seeding of the joint; direct inoculation 
from penetrating trauma is rare.
1
 The key risk factors are 
bacteremia (eg, injection drug use, endocarditis, infection 
at other sites), damaged joints (eg, rheumatoid arthritis),

1
at other sites), damaged joints (eg, rheumatoid arthritis), 
prosthetic joints, compromised immunity (eg, advanced 
age, diabetes mellitus, advanced chronic kidney disease, 
alcoholism, cirrhosis, and immunosuppressive therapy), 
and loss of skin integrity (eg, cutaneous ulcer or psoriasis). 
 is the most common cause of non
-
gonococcal septic arthritis, accounting for about 50% of all 
cases. Methicillin-resistant 
S aureus
 (MRSA) and group B 
streptococcus have become increasing frequent and impor
-
tant causes of septic arthritis. Gram-negative septic arthri
-
tis causes about 10% of cases and is especially common in 
injection drug users and in immunocompromised persons. 
 and 
 are the most 
common gram-negative isolates in adults. Pathologic 
changes include varying degrees of acute inflammation, 
with synovitis, effusion, abscess formation in synovial or 
subchondral tissues, and, if treatment is not adequate, 
articular destruction.
 
»
The onset is usually acute, with pain, swelling, and heat of 
the affected joint worsening over hours. The knee is most 
frequently involved; other commonly affected sites are the 
hip, wrist, shoulder, and ankle. Unusual sites, such as the 
sternoclavicular or sacroiliac joint, can be involved in 
injection drug users. Chills and fever are common but are 
absent in up to 20% of patients. Infection of the hip usually 
does not produce apparent swelling but results in groin 
pain greatly aggravated by walking. More than one joint is 
1
Lyme disease is discussed in Chapter 34.   
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involved in 15% of cases of septic arthritis; risk factors for 
multiple joint involvement include rheumatoid arthritis, 
associated endocarditis, and infection with group B 
Synovial fluid analysis is critical for diagnosis. The leukocyte 
count of the synovial fluid is always inflammatory (greater 
than 2000/mcL), usually exceeds 50,000/mcL, and often is 
more than 100,000/mcL, with 90% or more polymorphonu
-
clear cells (Table 20–2). Gram stain of the synovial fluid is posi
-
tive in 75% of staphylococcal infections and in 50% of 
gram-negative infections. Synovial fluid cultures are positive in 
70–90% of cases; administration of antibiotics prior to arthro
-
centesis reduces the likelihood of a positive culture result. 
Blood cultures are positive in approximately 50% of patients.
C. Imaging
Imaging tests generally add little to the diagnosis of septic 
arthritis. Indeed, other than demonstrating joint effusion, 
radiographs are usually normal early in the disease; however, 
evidence of demineralization may develop within days of 
onset. MRI and CT are more sensitive in detecting fluid in 
joints that are not accessible to physical examination (eg, the 
hip). Bony erosions and narrowing of the joint space 
followed by osteomyelitis and periostitis may be seen within 
2 weeks.
D. Prosthetic Joint Infection
The clinical and laboratory manifestations of prosthetic 
joint infection is influenced by whether the infection is early 
(less than 3 months after surgery), delayed (3–12 months 
after surgery), or late (more than 12 months after surgery). 
Early infections present with acute redness and swelling and 
are usually caused by 
S aureus
 and gram-negative organ
-
isms. Delayed infections often present with subtle manifes
-
tations: pain is common but only 50% of patients will have 
fever. Less virulent organisms, such as coagulase-negative 
staphylococcus, 
Propionibacterium acnes
, and enterococci, 
are most common causes of delayed infections. Late infec
-
tions present with acute pain, swelling and fever, are often 
caused by hematogenous seeding of 
S aureus
, gram-negative 
bacilli, and hemolytic streptococci.
 
»
Gout and pseudogout can cause acute, very inflammatory 
monarticular arthritis and high-grade fever; the failure to 
find crystals on synovial fluid analysis excludes these diag
-
noses. A well-recognized but uncommon initial presenta
-
tion of rheumatoid arthritis is an acute inflammatory 
monoarthritis (“pseudoseptic”). The most common articu
-
lar manifestation of chronic Lyme disease is inflammatory 
monoarthritis of the knee, which yields synovial fluid that 
is Gram stain and culture negative. Acute rheumatic fever 
commonly involves several joints; Still disease may mimic 
septic arthritis, but laboratory evidence of infection is 
absent. Pyogenic arthritis may be superimposed on other 
types of joint disease, notably rheumatoid arthritis. Indeed, 
septic arthritis must be excluded by joint fluid examination 
in any patient with rheumatoid arthritis who has a joint 
strikingly more inflamed than the other joints.
 
»
There is no evidence that patients with prosthetic joints 
undergoing procedures should receive antibiotic prophy
-
laxis to prevent joint infection unless the patient has a 
prosthetic heart valve or the procedure requires antibiot
-
ics to prevent a surgical site infection. However, the topic 
remains controversial. The American Academy of Ortho
-
pedic Surgeons advocates prescribing antibiotic prophy
-
laxis for any patient with a prosthetic joint replacement 
undergoing a procedure that can cause bacteremia.
 
»
Treatment
The effective treatment of septic arthritis requires appro
-
priate antibiotic therapy together with drainage of the 
infected joint. Hospitalization is always necessary. If the 
likely causative organism cannot be determined clinically

-
likely causative organism cannot be determined clinically 
or from the synovial fluid Gram stain, treatment should be 
started with broad-spectrum antibiotic coverage effective 
against staphylococci, streptococci, and gram-negative 
organisms. The recommendation for initial treatment is to 
give vancomycin (1 g intravenously every 12 hours, 
adjusted for age, weight, and renal function) plus a third-
generation cephalosporin: ceftriaxone, 1–2 g intravenously 
daily (or every 12 hours if concomitant meningitis or 
endocarditis is suspected); or cefotaxime, 1–2 g intrave
-
nously every 8 hours; or ceftazidime, 1–2 g intravenously 
every 8 hours. Antibiotic therapy should be adjusted when 
culture results become available; the duration of antibiotic 
therapy is usually 4–6 weeks.
Early orthopedic consultation is essential. Effective 
drainage is usually achieved through early arthroscopic 
lavage and debridement together with drain placement. 
Open surgical drainage should be performed when conser
-
vative treatment fails, when there is concomitant osteomy
-
elitis requiring debridement, or when the involved joint (eg, 
hip, shoulder, sacroiliac joint) cannot be drained by more 
conservative means. Immobilization with a splint and eleva
-
tion are used at the onset of treatment. Early active motion 
exercises within the limits of tolerance will hasten recovery. 
Options for treating prosthetic joint infections depend, in 
part, on the timing of the infection and include chronic sup
-
pression, debridement without removal of the prosthesis, or 
one- or two-stage exchange of the prosthesis.
 
»
Prognosis
The outcome of septic arthritis depends largely on the ante
-
cedent health of the patient, the causative organism (eg, 
 
S aureus
 bacterial arthritis is associated with a poor func
-
tional outcome in about 40% of cases), and the promptness 
of treatment. Five to 10 percent of patients with an infected 
joint die of respiratory complications of sepsis. The mortal
-
ity rate is 30% for patients with polyarticular sepsis. Bony 
ankylosis and articular destruction commonly also occur if 
treatment is delayed or inadequate.
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Kapadia BH et al. Periprosthetic joint infection. Lancet. 2016 
Jan 23;387(10016):386–94. [PMID: 26135702]
Salar O et al. Septic arthritis in the era of immunosuppressive 
treatments. Ann R Coll Surg Engl. 2014 Mar;96(2):e11–2. 
[PMID: 24780657]
Wang DA et al. Septic arthritis in immunocompetent and immu
-
nosuppressed hosts. Best Pract Res Clin Rheumatol. 2015 Apr;
 
29(2):275–89. [PMID: 26362744]
GONOCOCCAL ARTHRITIS
 
»
Prodromal migratory polyarthralgias.
 
»
Tenosynovitis is the most common sign.
 
»
Purulent monoarthritis in 50%.
 
»
Characteristic skin lesions.
 
»
Most common in young women during menses or 
 
»
Symptoms of urethritis frequently absent.
 
»
Dramatic response to antibiotics.
 
»
In contrast to nongonococcal bacterial arthritis, gonococ
-
cal arthritis usually occurs in otherwise healthy individu
-
als. Host factors, however, influence the expression of the 
disease: gonococcal arthritis is two to three times more 
common in women than in men, is especially common 
during menses and pregnancy, and is rare after age 40. 
Gonococcal arthritis is also common in men who have sex 
with men, whose high incidence of asymptomatic gono
-
coccal pharyngitis and proctitis predisposes them to dis
-
seminated gonococcal infection. Recurrent disseminated 
gonococcal infection should prompt testing of the patient’s 
CH50 level to evaluate for a congenital deficiency of a ter
-
minal complement component (C5, C6, C7, or C8).
 
»
One to 4 days of migratory polyarthralgias involving the wrist, 
knee, ankle, or elbow are common at the outset. Thereafter, 
two patterns emerge. The first pattern is characterized by 
tenosynovitis that most often affects wrists, fingers, ankles, or 
toes and is seen in 60% of patients. The second pattern is 
purulent monoarthritis that most frequently involves the 
knee, wrist, ankle, or elbow and is seen in 40% of patients. Less 
than half of patients have fever, and less than one-fourth have 
any genitourinary symptoms. Most patients will have asymp
-
tomatic but highly characteristic skin lesions that usually 
consist of 2 to 10 small necrotic pustules distributed over the 
extremities, especially the palms and soles.
The peripheral blood leukocyte count averages about 
10,000 cells/mcL and is elevated in less than one-third of 
patients. The synovial fluid white blood cell count usually 
ranges from 30,000 to 60,000 cells/mcL. The synovial fluid 
Gram stain is positive in one-fourth of cases and culture in 
less than half. Positive blood cultures are uncommon. Ure
-
thral, throat, cervical, and rectal cultures should be done in 
all patients, since they are often positive in the absence of 
local symptoms. Urinary nucleic acid amplification tests 
have excellent sensitivity and specificity for the detection of 
 in genitourinary sites.
C. Imaging
Radiographs are usually normal or show only soft tissue 
swelling.
 
»
Reactive arthritis can produce acute monoarthritis, urethritis, 
and fever in a young person but is distinguished by negative 
cultures and failure to respond to antibiotics. Lyme disease 
involving the knee is less acute, does not show positive 
cultures, and may be preceded by known tick exposure and 
characteristic rash. The synovial fluid analysis will exclude 
gout, pseudogout, and nongonococcal bacterial arthritis. 
Rheumatic fever and sarcoidosis can produce migratory 
tenosynovitis but have other distinguishing features. Infective 
endocarditis with septic arthritis can mimic disseminated 
gonococcal infection. Meningococcemia occasionally pres
-
ents with a clinical picture that resembles disseminated 
gonococcal infection; blood cultures establish the correct 
diagnosis. Early hepatitis B infection is associated with

-
diagnosis. Early hepatitis B infection is associated with 
circulating immune complexes that can cause a rash and 
polyarthralgias. In contrast to disseminated gonococcal 
infection, the rash in hepatitis B is urticarial.
 
»
Treatment
In most cases, patients in whom gonococcal arthritis is 
suspected should be admitted to the hospital to confirm the 
diagnosis, to exclude endocarditis, and to start treatment. 
The recommendation for initial treatment is to give azithro
-
mycin (1 g orally as a single dose) and a third-generation 
cephalosporin: ceftriaxone, 1 g intravenously daily (or every 
12 hours if concomitant meningitis or endocarditis is 
suspected); or cefotaxime, 1 g intravenously every 8 hours; 
or ceftizoxime, 1 g intravenously every 8 hours. Azithromycin 
enhances eradication of gonorrhea and covers potential 
coinfection with 
Chlamydia
. Because of the increasing 
prevalence of resistant strains of gonococci, step-down 
treatment from parenteral to oral antibiotics is no longer 
recommended in the absence of culture results document
-
ing sensitivity to the antibiotic being selected. Otherwise, 
once improvement has been achieved for 24–48 hours, 
patients must receive ceftriaxone 250 mg intramuscularly 
every 24 hours to complete a 7–14 day course.
 
»
Prognosis
Generally, gonococcal arthritis responds dramatically in 
24–48 hours after initiation of antibiotics, and drainage of 
the infected joint(s) is required infrequently. Complete 
recovery is the rule.
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Sena Corrales G et al. Gonococcal arthritis in human immuno
-
deficiency virus-infected patients. Review of the literature. 
Reumatol Clin. 2017 Jan–Feb;13(1):39–41. [PMID: 26826910]
RHEUMATIC MANIFESTATIONS OF 
 
HIV INFECTION
Infection with HIV has been associated with various rheu
-
matic disorders, most commonly arthralgias and arthritis. 
HIV painful articular syndrome causes severe arthralgias 
in an oligoarticular, asymmetric pattern that resolve within 
24 hours; the joint examination is normal. HIV-associated 
arthritis is an asymmetric oligoarticular process with 
objective findings of arthritis and a self-limited course that 
ranges from weeks to months. Psoriatic arthritis and reac
-
tive arthritis occur in HIV-infected individuals and can be 
severe. These spondyloarthropathies can respond to 
NSAIDs, though many cases are unresponsive. Along with 
antiretroviral therapies, immunosuppressive medications 
can be used if necessary in HIV-infected patients, though 
with caution. Muscle weakness associated with an elevated 
creatine kinase can be due to nucleoside reverse transcrip
-
tase inhibitor-associated myopathy or HIV-associated 
myopathy; the clinical presentations of each resemble idio
-
pathic polymyositis but the muscle biopsies show minimal 
inflammation. Less commonly, an inflammatory myositis 
indistinguishable from idiopathic polymyositis occurs. 
Other rheumatic manifestations of HIV include diffuse 
infiltrative lymphocytosis syndrome (with parotid gland 
enlargement) and various forms of vasculitis. The use of 
antiretroviral therapy has been associated with a marked 
decreased frequency of painful articular syndromes, psori
-
atric arthritis, spondyloarthropathy, and diffuse infiltrative 
lymphocytosis syndrome, and an increased frequency of 
the immune reconstitution inflammatory syndrome (IRIS) 
and osteoporosis.
Adizie T et al. Inflammatory arthritis in HIV positive patients: a 
practical guide. BMC Infect Dis. 2016 Mar 1;16:100. [PMID: 
26932524]
Mehsen-Cêtre N et al. Osteoarticular manifestations associated 
with HIV infection. Joint Bone Spine. 2017 Jan;84(1):29–33. 
[PMID: 27238195]
VIRAL ARTHRITIS
Arthralgias occur frequently in the course of acute infec
-
tions with many viruses, but frank arthritis is uncommon 
with the notable exceptions of acute parvovirus B19 infec
-
tion and Chikungunya fever. Parvovirus B19 causes an 
acute polyarthritis in 50–60% of adult cases (infected chil
-
dren develop the febrile exanthem known as “slapped 
cheek fever”). The arthritis can mimic rheumatoid arthritis 
but is almost always self-limited and resolves within several 
weeks. The diagnosis is established by the presence of IgM 
antibodies specific for parvovirus B19. Chikungunya fever 
is an arthropod-borne viral infection that is endemic to 
West Africa but has spread to multiple locations including 
the Indian Ocean islands, the Caribbean and Central and 
Latin America. Clinical manifestations include high fever, 
rash, and incapacitating bone pain. Acute polyarthralgia 
and polyarthritis are common and can persist for months 
or years.
Self-limited polyarthritis is common in acute hepatitis 
B infection and typically occurs before the onset of jaun
-
dice. Urticaria or other types of skin rash may be present. 
Indeed, the clinical picture resembles that of serum sick
-
ness. Serum transaminase levels are elevated, and tests for 
hepatitis B surface antigen are positive. Serum comple
-
ment levels are often low during active arthritis and 
become normal after remission of arthritis. The incidence 
of hepatitis B–associated polyarthritis has fallen substan
-
tially with the introduction of hepatitis B vaccination. 
Effective vaccination programs in the United States have 
eliminated acute rubella infections, formerly a common 
cause of virally induced polyarthritis. Changes in the 
rubella vaccine (an attenuated live vaccine) have greatly

rubella vaccine (an attenuated live vaccine) have greatly 
reduced the incidence of rubella vaccine–induced polyar
-
thritis as well.
Chronic infection with hepatitis C is associated with 
chronic polyarthralgia in up to 20% of cases and with 
chronic polyarthritis in 3–5%. Both can mimic rheumatoid 
arthritis, and the presence of rheumatoid factor in most 
hepatitis C–infected individuals leads to further diagnostic 
confusion. Indeed, hepatitis C–associated arthritis is fre
-
quently misdiagnosed as rheumatoid arthritis. Distin
-
guishing hepatitis C–associated arthritis/arthralgias from 
the co-occurrence of hepatitis C and rheumatoid arthritis 
can be difficult. Rheumatoid arthritis always causes objec
-
tive arthritis (not just arthralgias) and can be erosive 
(hepatitis C–associated arthritis is nonerosive). The pres
-
ence of anti-CCP antibodies points to the diagnosis of 
rheumatoid arthritis.
Hua C et al. Chikungunya virus-associated disease. Curr Rheu
-
matol Rep. 2017 Oct 5;19(11):69. [PMID: 28983760]
 
º
INFECTIONS OF BONES
ACUTE PYOGENIC OSTEOMYELITIS
 
»
Fever associated with pain and tenderness of 
involved bone.
 
»
Diagnosis usually requires culture of bone biopsy.
 
»
Elevated ESR and C-reactive protein.
 
»
Radiographs early in the course are typically 
negative.
 
»
Osteomyelitis is a serious infection that is often difficult to 
diagnose and treat. Infection of bone occurs as a conse
-
quence of (1) hematogenous dissemination of bacteria, (2) 
invasion from a contiguous focus of infection, and (3) skin 
breakdown in the setting of vascular insufficiency.
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»
1. Hematogenous osteomyelitis—
Osteomyelitis resulting 
from bacteremia is a disease associated with sickle cell dis
-
ease, injection drug users, diabetes mellitus, or older adults. 
Patients with this form of osteomyelitis often present with 
sudden onset of high fever, chills, and pain and tenderness of 
the involved bone. The site of osteomyelitis and the causative 
organism depend on the host. Among patients with hemo
-
globinopathies such as sickle cell anemia, osteomyelitis is 
caused most often by salmonellae; 
S aureus
 is the second 
most common cause. Osteomyelitis in injection drug users 
develops most commonly in the spine. Although in this set
-
ting 
S aureus
 is most common, gram-negative infections, 
especially 
 and 
Serratia
 species, are also fre
-
quent pathogens. Rapid progression to epidural abscess 
causing fever, pain, and sensory and motor loss is not 
uncommon. In older patients with hematogenous osteomy
-
elitis, the most common sites are the thoracic and lumbar 
vertebral bodies. Risk factors for these patients include dia
-
betes, intravenous catheters, and indwelling urinary catheters. 
These patients often have more subtle presentations, with 
low-grade fever and gradually increasing bone pain.
2. Osteomyelitis from a contiguous focus of infection—
Prosthetic joint replacement, pressure injury (formerly 
called pressure ulcer), neurosurgery, and trauma most fre
-
quently cause soft tissue infections that can spread to bone. 
S aureus
 and 
Staphylococcus epidermidis
 are the most com
-
mon organisms. Polymicrobial infections, rare in hematog
-
enously spread osteomyelitis, are more common in 
osteomyelitis due to contiguous spread. Localized signs of 
inflammation are usually evident, but high fever and other 
signs of toxicity are usually absent. Septic arthritis and cel
-
lulitis can also spread to contiguous bone.
3. Osteomyelitis associated with vascular insufficiency—
Patients with diabetes mellitus and vascular insufficiency 
are susceptible to developing a very challenging form of 
osteomyelitis. The foot and ankle are the most commonly 
affected sites. Infection originates from an ulcer or other 
break in the skin that is usually still present when the 
patient presents but may appear disarmingly unimpressive. 
Bone pain is often absent or muted by the associated neu
-
ropathy. Fever is also commonly absent. Two of the best 
bedside clues that the patient has osteomyelitis are the abil
-
ity to easily advance a sterile probe through a skin ulcer to 
bone and an ulcer area larger than 2 cm
2
.
B. Imaging and Laboratory Findings
The ESR and serum C-reactive protein are almost always 
elevated and can be useful parameters to follow during the 
course of therapy.
The plain film is the most readily available imaging 
procedure to establish the diagnosis of osteomyelitis, but it 
can be falsely negative initially. Early radiographic findings 
may include soft tissue swelling, loss of tissue planes, and 
periarticular demineralization of bone. About 2 weeks after 
onset of symptoms, erosion of bone and alteration of can
-
cellous bone appear, followed by periostitis.
MRI, CT, and nuclear medicine bone scanning are 
more sensitive than conventional radiography. MRI is the 
most sensitive and is particularly helpful in demonstrating 
the extent of soft tissue involvement. Radionuclide bone 
scanning is most valuable when osteomyelitis is suspected 
but no site is obvious. Nuclear medicine studies may also 
detect multifocal sites of infection. Ultrasound is useful in 
diagnosing the presence of effusions within joints and 
extra-articular soft tissue fluid collections but not in 
detecting bone infections.
Identifying the offending organism is a crucial step in 
selection of antibiotic therapy. Bone biopsy for culture is

selection of antibiotic therapy. Bone biopsy for culture is 
required except in those with hematogenous osteomyelitis, 
who have positive blood cultures. Cultures from overlying 
ulcers, wounds, or fistulas are unreliable.
 
»
Acute hematogenous osteomyelitis should be distinguished 
from suppurative arthritis, rheumatic fever, and cellulitis. 
More subacute forms must be differentiated from tubercu
-
losis or mycotic infections of bone and Ewing sarcoma or, 
in the case of vertebral osteomyelitis, from metastatic can
-
cer. When osteomyelitis involves the vertebrae, it com
-
monly traverses the disk—a finding not observed in cancer. 
Charcot arthropathy of the foot or ankle can mimic osteo
-
myelitis, particularly in patients with diabetes but does not 
cause an elevated ESR or serum C-reactive protein.
 
»
Inadequate treatment of bone infections results in chronic
-
ity of infection, and this possibility is increased by delaying 
diagnosis and treatment. Extension to adjacent bone or 
joints may complicate acute osteomyelitis. Recurrence of 
bone infections often results in anemia of chronic disease, a 
markedly elevated ESR, weight loss, weakness and, rarely, 
amyloidosis or nephrotic syndrome. Pseudoepithelioma
-
tous hyperplasia, squamous cell carcinoma, or fibrosarcoma 
may occasionally arise in persistently infected tissues.
 
»
Treatment
Most patients require both debridement of necrotic bone 
and prolonged administration of antibiotics. Patients with 
vertebral body osteomyelitis and epidural abscess may 
require urgent neurosurgical decompression. Depending 
on the site and extent of debridement, surgical procedures 
to stabilize, fill in, cover, or revascularize may be needed. 
Oral therapy with quinolones (eg, ciprofloxacin, 750 mg 
twice daily) for 6–8 weeks has been shown to be as effective 
as standard parenteral antibiotic therapy for chronic osteo
-
myelitis with susceptible organisms. When treating osteo
-
myelitis caused by 
S aureus
, quinolones are usually 
combined with rifampin, 300 mg orally twice daily.
 
»
Prognosis
If sterility of the lesion is achieved within 2–4 days, a good 
result can be expected in most cases if there is no compro
-
mise of the patient’s immune system. However, progression 
of the disease to a chronic form may occur. It is especially 
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common in the lower extremities and in patients in whom 
circulation is impaired (eg, diabetics).
Kwon JW et al. Pyogenic vertebral osteomyelitis: clinical features, 
diagnosis, and treatment. Korean J Spine. 2017 Jun;14(2):
 
27–34. [PMID: 28704905]
Peters EJ et al; International Working Group on the Diabetic 
Foot. Interventions in the management of infection in the 
foot in diabetes: a systematic review. Diabetes Metab Res Rev. 
2016 Jan;32(Suppl 1):145–53. [PMID: 26344844]
 
º
TUBERCULOSIS OF BONES & JOINTS
SPINAL TUBERCULOSIS 
(Pott Disease)
 
»
Seen primarily in immigrants from developing 
countries or immunocompromised patients.
 
»
Back pain and gibbus deformity.
 
»
Radiographic evidence of vertebral involvement.
 
»
Evidence of 
 in aspirate 
or biopsies of spinal lesions.
 
»
In the developing world, children primarily bear the bur
-
den of musculoskeletal tuberculosis. In the United States, 
however, musculoskeletal infection is more often seen in 
adult immigrants from countries where tuberculosis is 
prevalent, or it develops in the setting of immunosuppres
-
sion (eg, HIV infection, therapy with TNF inhibitors). 
Spinal tuberculosis (Pott disease) accounts for about 50% 
of musculoskeletal infection due to 
 (see 
Chapter 9). Seeding of the vertebrae may occur through 
hematogenous spread from the respiratory tract at the time 
of primary infection, with clinical disease developing years 
later as a consequence of reactivation, or through lymphat
-
ics from infected foci in the pleura or kidneys. The thoracic 
and lumbar vertebrae are the most common sites of spinal 
involvement; vertebral infection is associated with paraver
-
tebral cold abscesses in 75% of cases.
 
»
Patients complain of back pain, often present for months 
and sometimes associated with radicular pain and lower 
extremity weakness. Constitutional symptoms are usually 
absent, and less than 20% have active pulmonary disease. 
Destruction of the anterior aspect of the vertebral body can 
produce the characteristic gibbus deformity.
Most patients have a positive reaction to purified protein 
derivative (PPD) or a positive interferon-gamma release 
assay. Cultures of paravertebral abscesses and biopsies of 
vertebral lesions are positive in up to 70–90%. Biopsies 
reveal characteristic caseating granulomas in most cases. 
Isolation of 
 from an extraspinal site is 
sufficient to establish the diagnosis in the proper clinical 
setting.
C. Imaging
Radiographs can reveal lytic and sclerotic lesions and bony 
destruction of vertebrae but are normal early in the disease 
course. CT scanning can demonstrate paraspinal soft tissue 
extensions of the infection; MRI is the imaging technique 
of choice to detect compression of the spinal cord or cauda 
equina.
 
»
Spinal tuberculosis must be differentiated from subacute 
and chronic spinal infections due to pyogenic organisms, 
Brucella
, and fungi as well as from malignancy.
 
»
Paraplegia due to compression of the spinal cord or cauda 
equina is the most serious complication of spinal 
 
»
Treatment
Antimicrobial therapy should be administered for 6–9 months, 
usually in the form of isoniazid, rifampin, pyrazinamide, and 
ethambutol for 2 months followed by isoniazid and rifampin 
for an additional 4–7 months (see also Chapter 9). Medical 
management alone is often sufficient. Surgical interven
-
tion, however, may be indicated when there is neurologic 
compromise or severe spinal instability.
Batirel A et al. The course of spinal tuberculosis (Pott disease): 
results of the multinational, multicentre Backbone-2 study. 
Clin Microbiol Infect. 2015 Nov;21(11):1008.e9–18. [PMID: 
26232534]
Hu HT et al. Vertebral column decortication for the manage
-

26232534]
-
ment of sharp angular spinal deformity in Pott disease: case 
report. Medicine (Baltimore). 2017 Nov;96(45):e8592. 
[PMID: 29137084]
TUBERCULOUS ARTHRITIS
Infection of peripheral joints by 
 usually 
presents as a monoarticular arthritis lasting for weeks to 
months (or longer), but less often, it can have an acute 
presentation that mimics septic arthritis. Any joint can be 
involved; the hip and knee are most commonly affected. 
Constitutional symptoms and fever are present in only a 
small number of cases. Tuberculosis also can cause a 
chronic tenosynovitis of the hand and wrist. Joint destruc
-
tion occurs far more slowly than in septic arthritis due to 
pyogenic organisms. Synovial fluid is inflammatory but not 
to the degree seen in pyogenic infections, with synovial 
white cell counts in the range of 10,000–20,000 cells/mcL. 
Smears of synovial fluid are positive for acid-fast bacilli in 
a minority of cases; synovial fluid cultures, however, are 
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positive in 80% of cases. Because culture results may take 
weeks, the diagnostic procedure of choice usually is syno
-
vial biopsy, which yields characteristic pathologic findings 
and positive cultures in greater than 90%. Antimicrobial 
therapy is the mainstay of treatment. Rarely, a reactive, 
sterile polyarthritis associated with erythema nodosum 
(Poncet disease) develops in patients with active pulmo
-
nary or extrapulmonary tuberculosis.
Rueda JC et al. Clinical features of Poncet’s disease. From the 
description of 198 cases found in the literature. Clin Rheumatol. 
2013 Jul;32(7):929–35. [PMID: 23624588]
 
º
ARTHRITIS IN SARCOIDOSIS
The frequency of arthritis among patients with sarcoidosis 
is variously reported between 10% and 35%. It is usually 
acute in onset, but articular symptoms may appear insidi
-
ously and often antedate other manifestations of the dis
-
ease. Knees and ankles are most commonly involved, but 
any joint may be affected. Distribution of joint involvement 
is usually polyarticular and symmetric. The arthritis is 
commonly self-limited, resolving after several weeks or 
months and rarely resulting in chronic arthritis, joint 
destruction, or significant deformity. Sarcoid arthropathy 
is often associated with erythema nodosum, but the diag
-
nosis is contingent on the demonstration of other extra-
articular manifestations of sarcoidosis and, notably, biopsy 
evidence of noncaseating granulomas. Despite the clinical 
appearance of an inflammatory arthritis, synovial fluid 
often is noninflammatory (ie, less than 2000 leukocytes/mcL). 
In chronic arthritis, radiographs show typical changes in 
the bones of the extremities with intact cortex and cystic 
changes.
Treatment of arthritis in sarcoidosis is usually symp
-
tomatic and supportive. Colchicine may be of value. 
Patients with severe and progressive joint disease may 
respond to corticosteroids or to TNF inhibitors.
Ungprasert P et al. Clinical characteristics of sarcoid arthropa
-
thy: a population-based study. Arthritis Care Res (Hoboken). 
2016 May;68(5):695–9. [PMID: 26415117]
 
º
MISCELLANEOUS RHEUMATOLOGIC 
DISORDERS
THORACIC OUTLET SYNDROMES
Thoracic outlet syndromes result from compression of the 
neurovascular structures supplying the upper extremity. 
Symptoms and signs arise from intermittent or continu
-
ous pressure on elements of the brachial plexus (more 
than 90% of cases) or the subclavian or axillary vessels 
(veins or arteries) by a variety of anatomic structures of 
the shoulder girdle region. The neurovascular bundle can 
be compressed between the anterior or middle scalene 
muscles and a normal first thoracic rib or a cervical rib. 
Most commonly thoracic outlet syndromes are caused by 
scarred scalene neck muscle secondary to neck trauma or 
sagging of the shoulder girdle resulting from aging, 
obesity, or pendulous breasts. Faulty posture, occupation, 
or thoracic muscle hypertrophy from physical activity 
(eg, weight-lifting, baseball pitching) may be other pre
-
disposing factors.
Thoracic outlet syndromes present in most patients 
with some combination of four symptoms involving the 
upper extremity: pain, numbness, weakness, and swelling. 
The predominant symptoms depend on whether the com
-
pression chiefly affects neural or vascular structures. The 
onset of symptoms is usually gradual but can be sudden. 
Some patients spontaneously notice aggravation of symp
-
toms with specific positioning of the arm. Pain radiates 
from the point of compression to the base of the neck, the 
axilla, the shoulder girdle region, arm, forearm, and hand. 
Paresthesias are common and distributed to the volar 
aspect of the fourth and fifth digits. Sensory symptoms 
may be aggravated at night or by prolonged use of the 
extremities. Weakness and muscle atrophy are the princi
-
pal motor abnormalities. Vascular symptoms consist of

-
pal motor abnormalities. Vascular symptoms consist of 
arterial ischemia characterized by pallor of the fingers on 
elevation of the extremity, sensitivity to cold and, rarely, 
gangrene of the digits or venous obstruction marked by 
edema, cyanosis, and engorgement.
The symptoms of thoracic outlet syndromes can be 
provoked within 60 seconds over 90% of the time by having 
a patient elevate the arms in a “stick-em-up” position (ie, 
abducted 90 degrees in external rotation). Reflexes are usu
-
ally not altered. Obliteration of the radial pulse with certain 
maneuvers of the arm or neck, once considered a highly 
sensitive sign of thoracic outlet obstruction, does not occur 
Chest radiography will identify patients with cervical 
rib (although most patients with cervical ribs are asymp
-
tomatic). MRI with the arms held in different positions is 
useful in identifying sites of impaired blood flow. Intra-
arterial or venous obstruction is confirmed by angiogra
-
phy. Determination of conduction velocities of the ulnar 
and other peripheral nerves of the upper extremity may 
help localize the site of their compression.
Thoracic outlet syndrome must be differentiated from 
osteoarthritis of the cervical spine, tumors of the superior 
pulmonary sulcus, cervical spinal cord, or nerve roots, and 
periarthritis of the shoulder.
Treatment is directed toward relief of compression of 
the neurovascular bundle. Greater than 95% of patients can 
be treated successfully with conservative therapy consist
-
ing of physical therapy and avoiding postures or activities 
that compress the neurovascular bundle. Some women will 
benefit from a support bra. Operative treatment, required 
by less than 5% of patients, is more likely to relieve the 
neurologic rather than the vascular component that causes 
symptoms.
Buller LT et al. Thoracic outlet syndrome: current concepts, 
imaging features, and therapeutic strategies. Am J Orthop 
(Belle Mead NJ). 2015 Aug;44(8):376–82. [PMID: 26251937]
Povlsen B et al. Treatment for thoracic outlet syndrome. 
Cochrane Database Syst Rev. 2014 Nov 26;11:CD007218. 
[PMID: 25427003]
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FIBROMYALGIA
 
»
Most frequent in women aged 20–50.
 
»
Chronic widespread musculoskeletal pain syndrome 
with multiple tender points.
 
»
Fatigue, headaches, numbness common.
 
»
Objective signs of inflammation absent; laboratory 
studies normal.
 
»
Fibromyalgia is a common syndrome, affecting 3–10% of 
the general population. It shares many features with the 
chronic fatigue syndrome, namely, an increased fre
-
quency among women aged 20–50, absence of objective 
findings, and absence of diagnostic laboratory test 
results. While many of the clinical features of the two 
conditions overlap, musculoskeletal pain predominates 
in fibromyalgia whereas lassitude dominates the chronic 
fatigue syndrome.
The cause is unknown, but aberrant perception of pain
-
ful stimuli, sleep disorders, depression, and viral infections 
have all been proposed. Fibromyalgia can be a complica
-
tion of hypothyroidism, rheumatoid arthritis or, in men, 
sleep apnea.
 
»
The patient complains of chronic aching pain and stiffness, 
frequently involving the entire body but with prominence 
of pain around the neck, shoulders, low back, and hips. 
Fatigue, sleep disorders, subjective numbness, chronic 
headaches, and irritable bowel symptoms are common. 
Even minor exertion aggravates pain and increases fatigue. 
Physical examination is normal except for “trigger points” 
of pain produced by palpation of various areas such as the 
trapezius, the medial fat pad of the knee, and the lateral 
epicondyle of the elbow.
 
»
Fibromyalgia is a diagnosis of exclusion. A detailed history 
and repeated physical examination can obviate the need for 
extensive laboratory testing. Rheumatoid arthritis and SLE 
present with objective physical findings or abnormalities 
on routine testing. Thyroid function tests are useful, since 
hypothyroidism can produce a secondary fibromyalgia 
syndrome. Polymyositis produces weakness rather than 
pain. The diagnosis of fibromyalgia probably should be 
made hesitantly in a patient over age 50 and should never 
be invoked to explain fever, weight loss, or any other objec
-
tive signs. Polymyalgia rheumatica produces shoulder and 
pelvic girdle pain, is associated with anemia and an ele
-
vated ESR, and occurs after age 50. Hypophosphatemic 
states, such as oncogenic osteomalacia, can cause musculo
-
skeletal pain unassociated with physical findings. In 
contrast to fibromyalgia, oncogenic osteomalacia usually 
produces pain in only a few areas and is associated with a 
low serum phosphate level.
 
»
Treatment
A multidisciplinary approach is most effective. Patient 
education is essential. Patients can be comforted that they 
have a diagnosable syndrome treatable by specific though 
imperfect therapies and that the course is not progressive. 
Cognitive behavioral therapy, including programs that 
emphasize mindfulness meditation, is often helpful. There 
is modest efficacy of amitriptyline, fluoxetine, duloxetine, 
milnacipran, chlorpromazine, cyclobenzaprine, pregaba
-
lin, or gabapentin. Amitriptyline is initiated at a dosage of 
10 mg orally at bedtime and gradually increased to 40–50 mg 
depending on efficacy and toxicity. Less than 50% of the 
patients experience a sustained improvement. Exercise 
programs are also beneficial. NSAIDs are generally ineffec
-
tive. Tramadol and acetaminophen combinations have 
ameliorated symptoms modestly in short-term trials. Opi
-
oids and corticosteroids are ineffective and should not be 
used to treat fibromyalgia. Acupuncture is also ineffective.
 
»
Prognosis
All patients have chronic symptoms. With treatment, how
-
ever, many do eventually resume increased activities. Pro
-
gressive or objective findings do not develop.
Clauw DJ. Fibromyalgia and related conditions. Mayo Clin Proc. 
2015 May;90(5):680–92. [PMID: 25939940]

-
Lichtenstein A et al. The complexities of fibromyalgia and its 
comorbidities. Curr Opin Rheumatol. 2018 Jan;30(1):94–100. 
[PMID: 29040155]
Sugerman DT. JAMA patient page. Fibromyalgia. JAMA. 2014 
Apr 16;311(15):1577. [PMID: 24737379]
COMPLEX REGIONAL PAIN SYNDROME
Complex regional pain syndrome (formerly called reflex 
sympathetic dystrophy) is a rare disorder of the extremities 
characterized by autonomic and vasomotor instability. The 
cardinal symptoms and signs are pain localized to an arm or 
leg, swelling of the involved extremity, disturbances of color 
and temperature in the affected limb, dystrophic changes in 
the overlying skin and nails, and limited range of motion. 
Strikingly, the findings are not limited to the distribution of 
a single peripheral nerve. Most cases are preceded by sur
-
gery or direct physical trauma, often of a relatively minor 
nature, to the soft tissues, bone, or nerve. Early mobilization 
after injury or surgery reduces the likelihood of developing 
the syndrome. Any extremity can be involved, but the syn
-
drome most commonly occurs in the hand and is associated 
with ipsilateral restriction of shoulder motion (“shoulder-
hand” syndrome). This syndrome proceeds through phases: 
pain, swelling, and skin color and temperature changes 
develop early and, if untreated, lead to atrophy and dystrophy. 
The swelling in complex regional pain syndrome is dif
-
fuse (“catcher’s mitt hand”) and not restricted to joints. 
Pain is often burning in quality, intense, and often 
greatly worsened by minimal stimuli such as light touch. 
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The shoulder-hand variant of this disorder sometimes com
-
plicates myocardial infarction or injuries to the neck or 
shoulder. Complex regional pain syndrome may occur after 
a knee injury or after arthroscopic knee surgery. There are 
no systemic symptoms. In the early phases of the syndrome, 
bone scans are sensitive, showing diffuse increased uptake 
in the affected extremity. Radiographs eventually reveal 
severe generalized osteopenia. In the posttraumatic variant, 
this is known as Sudeck atrophy. Symptoms and findings 
are bilateral in some. This syndrome should be differenti
-
ated from other cervicobrachial pain syndromes, rheuma
-
toid arthritis, thoracic outlet obstruction, and scleroderma, 
among others.
Early treatment offers the best prognosis for recovery. 
For mild cases, NSAIDs (eg, naproxen 250–500 mg twice 
daily orally) can be effective. For more severe cases associ
-
ated with edema, prednisone, 30–60 mg/day orally for 
 
2 weeks and then tapered over 2 weeks, can be effective. 
Pain management is important and facilitates physical 
therapy, which plays a critical role in efforts to restore func
-
tion. Some patients will also benefit from antidepressant 
agents (eg, nortriptyline initiated at a dosage of 10 mg 
orally at bedtime and gradually increased to 40–75 mg at 
bedtime) or from anticonvulsants (eg, gabapentin 300 mg 
three times daily orally). Bisphosphonates, calcitonin, 
regional nerve blocks, and dorsal-column stimulation have 
also been reported to be helpful. Patients who have 
restricted shoulder motion may benefit from the treatment 
described for scapulohumeral periarthritis. The prognosis 
partly depends on the stage in which the lesions are 
encountered and the extent and severity of associated 
organic disease.
Petersen PB et al. Risk factors for post-treatment complex 
regional pain syndrome (CRPS): an analysis of 647 cases of 
CRPS from the Danish Patient Compensation Association. 
Pain Pract. 2018 Mar;18(3):341–9. [PMID: 28691184]
Tajerian M et al. New concepts in complex regional pain syn
-
drome. Hand Clin. 2016 Feb;32(1):41–9. [PMID: 26611388]
RHEUMATOLOGIC MANIFESTATIONS 
 
OF CANCER
Rheumatologic syndromes may be the presenting manifes
-
tations for a variety of cancers (see eTable 39–1). Dermato
-
myositis in adults, for example, is often associated with 
cancer. Hypertrophic pulmonary osteoarthropathy, which 
is characterized by the triad of polyarthritis, new onset of 
clubbing, and periosteal new bone formation, is associated 
with both malignant diseases (eg, lung and intrathoracic 
cancers) and nonmalignant ones (eg, cyanotic heart dis
-
ease, cirrhosis, and lung abscess). Cancer-associated poly
-
arthritis is rare, has both oligoarticular and polyarticular 
forms, and should be considered when “seronegative rheu
-
matoid arthritis” develops abruptly in an elderly patient. 
Palmar fasciitis manifests as bilateral palmar swelling with 
finger contractures and may be the first indication of 
cancer, particularly ovarian carcinoma. Remitting sero
-
negative synovitis with non-pitting edema (“RS3PE”) pres
-
ents with a symmetric small-joint polyarthritis associated 
with non-pitting edema of the hands; it can be idiopathic 
or associated with malignancy. Palpable purpura due to 
leukocytoclastic vasculitis may be the presenting complaint 
in myeloproliferative disorders. Hairy cell leukemia can be 
associated with medium-sized vessel vasculitis such as 
polyarteritis nodosa. Acute leukemia can produce joint 
pains that are disproportionately severe in comparison to 
the minimal swelling and heat that are present. Leukemic 
arthritis complicates approximately 5% of cases. Rheu
-
matic manifestations of myelodysplastic syndromes include 
cutaneous vasculitis, lupus-like syndromes, neuropathy, 
and episodic intense arthritis. Erythromelalgia, a painful 
warmth and redness of the extremities that (unlike Raynaud)

warmth and redness of the extremities that (unlike Raynaud) 
improves with cold exposure or with elevation of the 
extremity, is often associated with myeloproliferative dis
-
eases, particularly essential thrombocythemia.
Durieux V et al. Autoimmune paraneoplastic syndromes associ
-
ated to lung cancer: a systematic review of the literature. Lung 
Cancer. 2017 Apr;106:102–9. [PMID: 28285683]
NEUROGENIC ARTHROPATHY 
 
(Charcot Joint)
Neurogenic arthropathy is joint destruction resulting from 
loss or diminution of proprioception, pain, and tempera
-
ture perception. Although initially described in the knees 
of patients with tabes dorsalis, it is more frequently seen in 
association with diabetic neuropathy (foot and ankle) or 
syringomyelia (shoulder). As normal muscle tone and pro
-
tective reflexes are lost, secondary degenerative joint dis
-
ease ensues, resulting in an enlarged, boggy, relatively 
painless joint with extensive cartilage erosion, osteophyte 
formation, and multiple loose joint bodies. Radiographs 
can reveal striking osteolysis that mimics osteomyelitis or 
dramatic destruction of the joint with subluxation, frag
-
mentation of bone, and bony sclerosis.
Treatment is directed toward the primary disease; 
mechanical devices are used to assist in weight bearing and 
prevention of further trauma. In some instances, amputa
-
tion becomes unavoidable.
Shazadeh Safavi P et al. A systematic review of current surgical 
interventions for Charcot neuroarthropathy of the midfoot. J 
Foot Ankle Surg. 2017 Nov–Dec;56(6):1249–52. [PMID: 
28778632]
PALINDROMIC RHEUMATISM
Palindromic rheumatism is a disease of unknown cause 
characterized by frequent recurring attacks (at irregular 
intervals) of acutely inflamed joints. Periarticular pain with 
swelling and transient subcutaneous nodules may also 
occur. The attacks cease within several hours to several 
days. The knee and finger joints are most commonly 
affected, but any peripheral joint may be involved. Systemic 
manifestations other than fever do not occur. Although 
hundreds of attacks may take place over a period of years, 
there is no permanent articular damage. Laboratory find
-
ings are usually normal. Palindromic rheumatism must be 
distinguished from acute gouty arthritis and an atypical 
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acute onset of rheumatoid arthritis. In some patients, pal
-
indromic rheumatism is a prodrome of rheumatoid 
Symptomatic treatment with NSAIDs is usually all that 
is required during the attacks. Hydroxychloroquine may be 
of value in preventing recurrences.
OSTEONECROSIS 
 
(Avascular Necrosis of Bone)
Osteonecrosis is a complication of corticosteroid use, alco
-
holism, trauma, SLE, pancreatitis, gout, sickle cell disease, 
dysbaric syndromes (eg, “the bends”), knee menisectomy, 
and infiltrative diseases (eg, Gaucher disease). The most 
commonly affected sites are the proximal and distal femoral 
heads, leading to hip or knee pain. Other commonly 
affected sites include the ankle, shoulder, and elbow. Osteo
-
necrosis of the jaw has been associated with use of bisphos
-
phonate therapy, usually when the bisphosphonate is used 
for treating metastatic cancer or plasma cell myeloma rather 
than osteoporosis. Initially, radiographs are often normal; 
MRI, CT scan, and bone scan are all more sensitive tech
-
niques. Treatment involves avoidance of weight bearing on 
the affected joint for at least several weeks. The value of 
surgical core decompression is controversial. For osteone
-
crosis of the hip, a variety of procedures designed to pre
-
serve the femoral head have been developed for early 
disease, including vascularized and nonvascularized bone 
grafting procedures. These procedures are most effective in 
avoiding or forestalling the need for total hip arthroplasty in 
young patients who do not have advanced disease. Without 
a successful intervention of this nature, the natural history 
of avascular necrosis is usually progression of the bony 
infarction to cortical collapse, resulting in significant joint 
dysfunction. Total hip replacement is the usual outcome for 
all patients who are candidates for that procedure.
Chughtai M et al. An evidence-based guide to the treatment of 
osteonecrosis of the femoral head. Bone Joint J. 2017 Oct;
 
99-B(10):1267–79. [PMID: 28963146]
Ruggiero SL. Diagnosis and staging of medication-related osteo
-
necrosis of the jaw. Oral Maxillofac Surg Clin North Am. 
2015 Nov;27(4):479–87. [PMID: 26293329]
 
º
ALLERGIC & IMMUNOLOGIC DISORDERS
N. Franklin Adkinson Jr., MD
Allergy is an immunologically mediated hypersensitivity 
reaction to a foreign antigen manifested by tissue inflamma
-
tion and organ dysfunction. The clinical expression of aller
-
gic disease depends on prior immunologic responsiveness, 
antigen exposure, and genetically influenced host factors 
such as atopy. Atopic patients have a genetically aggregated 
predisposition to a limited number of disorders: allergic rhi
-
nitis (Chapter 8), allergic asthma (Chapter 9), atopic derma
-
titis (Chapter 6), and IgE-mediated food allergies. Although 
these disorders tend to aggregate in families designated as 
“atopic, ” each of these disorders can occur in individuals 
without personal or familial history of an atopic diathesis. In 
addition, many mast cell and IgE-dependent disorders (eg, 
many drug and chemical sensitivities, eosinophilic disorders, 
mast cell stability syndromes, chronic urticaria) occur equally 
frequently in atopic and nonatopic persons.
The timing of the onset of clinical allergic syndromes 
after exposure to a suspected allergen serves as a useful 
clinical marker on which to base diagnosis and treatment. 
Reactions will usually be either 
immediate
 (generally 
occurring within 60 minutes after initial exposure), or 
delayed
, appearing after many hours to days or weeks of 
antigen exposure.
IMMEDIATE HYPERSENSITIVITY
IgE antibodies occupy receptor sites on mast cells. Within 
minutes after exposure to the allergen, a multivalent antigen 
links adjacent IgE molecules, activating and degranulating 
mast cells. Clinical manifestations can be explained by the 
effects of released mediators on target end organs. Both

effects of released mediators on target end organs. Both 
preformed and newly generated mediators cause vasodila
-
tion and permeability changes, visceral smooth muscle 
contraction, mucous secretory gland stimulation, vascular 
permeability, and tissue inflammation. Arachidonic acid 
metabolites, cytokines, and other mediators (such as che
-
moattractants) induce a late-phase inflammatory response 
that appears several hours later in affected tissues when 
antigen exposure is continuous (eg, pollen) or chronic.
1. Anaphylaxis
 
»
Anaphylaxis is the most serious and potentially life-
threatening manifestation of mast cell and basophil media
-
tor release. Anaphylaxis is defined clinically under the 
following circumstances: (1) an allergen exposure followed 
by the acute onset of illness involving skin or mucosal tis
-
sue and either respiratory compromise or hypotension 
(systolic blood pressure less than 90 mm Hg or 30% less 
than known baseline); (2) a likely allergen exposure followed 
by the acute onset of two or more of the following conditions: 
skin or mucosal tissue involvement, respiratory compromise, 
hypotension, and persistent gastrointestinal symptoms; or (3) 
a known allergen exposure followed by hypotension.
IgE-dependent anaphylaxis is usually an acute syn
-
drome initiated by a new allergen exposure after a prior 
silent exposure has sensitized the patient with IgE antibodies. 
Thus, anaphylaxis (or systemic allergic reactions which do 
not meet the definition of anaphylaxis) cannot occur on 
first-time exposure to allergens like drugs, insect venoms, 
latex, and foods. In contrast, other syndromes of anaphy
-
laxis (sometimes called “anaphylactoid”), such as reactions 
to radiocontrast media and most NSAID and opioid reac
-
tions, is pseudoallergic without known immunologic 
mechanisms and can occur with first-time exposure.
 
»
Symptoms and signs typically occur within 30 minutes of 
initial exposure but may appear up to several hours later. 
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These include (in order of frequency) (1) skin manifesta
-
tions, typically urticaria but also flushing, blotchy rashes, 
and pruritus; (2) respiratory distress, including wheezing, 
stridor, bronchospasm, and airway angioedema; (3) gastro
-
intestinal symptoms, including cramping, emesis, and diar
-
rhea (especially in food allergy); and (4) hypotension, often 
manifested as lightheadedness, dizziness, or syncope. The 
condition is potentially fatal, especially if untreated, and 
can affect both nonatopic and atopic persons.
Identification of anaphylaxis is clinical as the need for 
treatment is urgent. Elevated serum levels of mast cell 
mediators, such as tryptase and histamine, may be detected 
shortly after a reaction providing support to the diagnosis. 
Referral to an allergy specialist is standard because of con
-
cern for a future reaction and need for appropriate inter
-
ventions and education. Specific IgE serum or skin testing 
may be performed to suspected allergens. Skin testing, 
which is usually more sensitive, optimally occurs 4–6 weeks 
after a severe reaction to avoid falsely negative testing 
during a post-reaction “refractory” period. The positive 
predictive value of these tests is highly dependent on a 
suggestive temporal relationship to putative allergen 
exposure.
 
»
Treatment
Early administration of intramuscular epinephrine at the 
onset of suspected anaphylaxis is the cornerstone of 
therapy. Supportive measures, such as oxygen, intrave
-
nous fluids and, if required, airway management are also 
appropriate. Adjunctive pharmacologic therapies include 
antihistamines, bronchodilators, and corticosteroids. 
Self-administered epinephrine at the earliest signs of 
recurrence can be life-sparing, whereas antihistamines 
and corticosteroids have limited value in reversing ana
-
phylactic syndromes.
 
»
Patients with new or unexplained onset of anaphylaxis 
should be evaluated by an allergist.
Lieberman P et al. Anaphylaxis—a practice parameter update 
2015. Ann Allergy Asthma Immunol. 2015 Nov;115(5):
 
341–84. [PMID: 26505932]
Muraro A et al; EAACI Food Allergy and Anaphylaxis Guide
-
lines Group. Anaphylaxis: guidelines from the European 
Academy of Allergy and Clinical Immunology. Allergy. 2014 
Aug;69(8):1026–45. [PMID: 24909803]
Williams KW et al. Anaphylaxis and urticaria. Immunol Allergy 
Clin North Am. 2015 Feb;35(1):199–219. [PMID: 25459585]
2. Food Allergy
Immediate allergic reactions within 2 hours of ingestion of 
foods are much less common among adults than children. 
Most acute systemic food allergy is caused by proteins in 
milk, egg, wheat, soy, fish, shellfish, peanuts, and tree nuts. 
Milk and egg allergies in atopic children are often out
-
grown by adulthood. Shellfish, peanuts, and tree nuts are 
the most common causes of food anaphylaxis in adults. 
Diagnosis of food allergy relies on a combination of his
-
tory, skin tests, and specific IgE tests. There is no role for 
specific IgG testing for evaluating food hypersensitivity. 
Because of frequent false-positive IgE tests, especially 
among atopic patients, oral food challenge remains the 
gold standard for diagnosis. However, this procedure 
should only be conducted by an experienced provider in a 
well-equipped setting. Management involves strict avoid
-
ance of the culprit food and guaranteed access to self-
administered epinephrine.
Other IgE-mediated food reactions include oral allergy 
syndrome and hypersensitivity to alpha-gal (galactose-
alpha-1,3-galactose). Oral allergy syndrome, also known as 
pollen-associated food allergy syndrome, is the result of 
cross-reactivity between food and pollen proteins. Affected 
individuals have known seasonal pollen allergies (most 
commonly tree pollens) and experience itching of the oral 
mucosa upon ingestion of certain raw fruits and vegetables.

mucosa upon ingestion of certain raw fruits and vegetables. 
In contrast to systemic food allergy, symptoms are limited 
to the oropharynx and usually do not involve other organ 
systems or progress to anaphylaxis.
Alpha-gal (galactose-alpha-1,3-galactose) is a carbohy
-
drate found in red mammalian meats, including beef, pork 
and lamb but not in human tissues. Sensitization to this 
epitope has been linked to tick bites, so nonatopic indi
-
viduals are at risk. In contrast to conventional systemic 
food allergy, the reaction to red meat typically occurs 4–6 hours 
after ingestion.
Kattan JD et al. Optimizing the diagnosis of food allergy. Immu
-
nol Allergy Clin North Am. 2015 Feb;35(1):61–76. [PMID: 
25459577]
Muraro A et al. EAACI food allergy and anaphylaxis guidelines: 
diagnosis and management of food allergy. Allergy. 2014 
Aug;69(8):1008–25. [PMID: 24909706]
3. Drug Allergy
Skin testing for immediate allergy to drugs is reliable for 
high molecular weight proteins (eg, cytokines, antisera, 
enzymes) but often not as reliable for low-molecular-weight 
compounds (eg, most drugs), which must bind to larger 
proteins (as haptens) to become immunogenic. With the 
exception of beta-lactam antibiotics like penicillins and 
some intraoperative drugs, in vivo skin testing for low-
molecular-weight drugs is largely unvalidated, and interpre
-
table only if the test is positive at a nonirritating 
concentration. Testing for IgE-mediated allergy to penicil
-
lin is available because the immunochemistry has been 
delineated and appropriate skin testing reagents are avail
-
able. Skin testing with the major and minor metabolic 
determinants of penicillin has a very high (more than 98%) 
negative predictive value. Referral of individuals who relate 
histories of acute penicillin reactions to an allergist for skin 
testing is worthwhile because more than 90% have negative 
testing, indicating loss of allergic sensitization. Such patients 
may then safely receive penicillins and related antibiotics.
Chiriac AM et al. Drug allergy diagnosis. Immunol Allergy Clin 
North Am. 2014 Aug;34(3):461–7. [PMID: 25017672]
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Kelso JM. Drug and vaccine allergy. Immunol Allergy Clin 
North Am. 2015 Feb;35(1):221–30. [PMID: 25459586]
Mirakian R et al; Standards of Care Committee of the British 
Society for Allergy and Clinical Immunology. Management of 
allergy to penicillins and other beta-lactams. Clin Exp Allergy. 
2015 Feb;45(2):300–27. [PMID: 25623506]
4. Venom Allergy
The most common insects causing systemic allergic reac
-
tions include honeybees, vespids (yellow jackets, hornets, 
wasps), and fire ants. Systemic reactions often occur after 
several unremarkable stinging events and can develop at any 
age. Patients at highest risk for a severe reaction are those 
who have had a history of recent and severe reactions. The 
risk of a systemic reaction appears to decline over time since 
the last sting. If a systemic allergy is suspected, referral to an 
allergist for testing and, if appropriate, initiation of venom 
immunotherapy, is recommended. In the interim, making 
self-administrated epinephrine available is indicated for 
those with continuing exposure.
5. Pseudoallergic Reactions
Pseudoallergic reactions (Table 20–13) resemble immedi
-
ate hypersensitivity reactions but are not mediated by 
allergen-IgE interaction. Examples include radiocontrast 
reactions, opioid reactions (direct mast cell activation), and 
“red man syndrome” from rapid infusion of vancomycin. 
Patients with mast cell disorders may be more prone to 
these reactions due to more easily triggered mast cell 
degranulation. In contrast to IgE-mediated reactions, these 
can often be prevented by prophylactic medical regimens.
 
»
Radiocontrast Media Reactions
Reactions to radiocontrast media are not IgE antibody–
mediated, yet they are clinically similar to anaphylaxis and 
can be life-threatening. If a patient has had an anaphylac
-
toid reaction to conventional radiocontrast media, the risk 
for a second reaction upon reexposure may be as high as 
30%. Patients with a history of atopy are at increased risk.
Management includes use of low-osmolality contrast 
preparations and prophylactic administration of prednisone 
(50 mg orally every 6 hours beginning 13 hours before the 
procedure) and diphenhydramine (25–50 mg orally, intra
-
muscularly or intravenously 60 minutes before the proce
-
dure). The use of lower-osmolality radiocontrast media in 
combination with the pretreatment regimen decreases the 
incidence of recurrent reactions to less than 1%.
Red Man Syndrome
Like radiocontrast media reactions, the “red man syn
-
drome” (Table 20–13) is not IgE mediated and results in 
anaphylactoid symptoms, especially flushing, pruritus, and 
erythema of the upper body. First described as a vancomy
-
cin infusion reaction, it is related to the rate of drug admin
-
istration resulting in direct activation of mast cells. 
Management includes administration of an antihistamine 
such as diphenhydramine, 25–50 mg intravenously or 
intramuscularly, and reinitiation of the vancomycin infu
-
sion at no more than half the former rate. In patients who 
have previously experienced a vancomycin infusion reac
-
tion, premedication with an H
1
-antagonist (eg, diphen
-
hydramine) and H
2
-antagonist (eg, cimetidine) is 
recommended 1 hour prior to the infusion. Although rare, 
IgE sensitization to vancomycin does occur and should be 
suspected in patients who have received multiple courses of 
the drug. Skin testing is helpful because vancomycin, as a 
“complete allergen, ” can elicit positive skin tests. Desensiti
-
zation to vancomycin is possible for patients with positive 
skin tests and no acceptable alternative antibiotic.
Davis PL. Anaphylactoid reactions to the nonvascular adminis
-
tration of water-soluble iodinated contrast media. AJR Am J 
Roentgenol. 2015 Jun;204(6):1140–5. [PMID: 26001221]
6. Aspirin (NSAID) Exacerbated 
 
Respiratory Disease
Although aspirin (NSAID) hypersensitivity is a feature of

Although aspirin (NSAID) hypersensitivity is a feature of 
this condition, the reaction is a result of aberrant arachidonic 
acid metabolism, rather than a product of an IgE-activated 
process. The inhibition of cyclooxygenase-1 (COX-1) by 
these anti-inflammatory drugs results in the overproduction 
of cysteinyl leukotrienes and increased expression of leu
-
kotriene receptors, leading to increased airway responsive
-
ness, bronchospasm, rhinorrhea, and nasal congestion. 
Reactions outside of the respiratory system can also occur, 
including ocular, cutaneous, and gastric symptoms.
In addition to aspirin or NSAID sensitivity, patients with 
aspirin exacerbated respiratory disease typically have a 
chronic rhinosinusitis with nasal polyps and asthma, a syn
-
drome referred to as “Samter triad” or “triad asthma. ” Diag
-
nosis is largely based on history and clinical findings. If 
required, a positive aspirin challenge can demonstrate the 
NSAID hypersensitivity, the presence of which may suggest 
increased responsiveness to treatments such as nasal polypec
-
tomy and aspirin desensitization. Patients who require daily 
aspirin or NSAID treatment can be desensitized to permit 
such treatment. Desensitization and long-term aspirin 
therapy have also been shown to reduce the need for nasal 
polypectomy and asthma therapy. Referral to an allergy spe
-
cialist is appropriate for consideration of such desensitization.
Morales DR et al. Safety risks for patients with aspirin-exacerbated 
respiratory disease after acute exposure to selective nonsteroidal 
anti-inflammatory drugs and COX-2 inhibitors: meta-analysis 
of controlled clinical trials. J Allergy Clin Immunol. 2014 Jul;
 
134(1):40–5. [PMID: 24388008]
Saff RR et al. Management of patients with nonaspirin-
exacerbated respiratory disease aspirin hypersensitivity reac
-
tions. Allergy Asthma Proc. 2015 Jan–Feb;36(1):34–9. [PMID: 
25562554]
Simon RA et al. Update on aspirin desensitization for chronic 
rhinosinusitis with polyps in aspirin-exacerbated respiratory 
disease (AERD). Curr Allergy Asthma Rep. 2015 Mar;
 
15(3):508. [PMID: 25663486]
ALLERGY TESTING
To maximize the positive predictive value of allergy testing, a 
positive test result must be correlated with the history. 
Patients selected for testing include those with moderate to 
severe disease, those who are potential candidates for allergen 
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Table 20–13.
 
Uncommon allergic and pseudoallergic conditions.
Disease
Symptoms and Signs
Diagnostic Findings
1
Treatment
Allergic bronchopulmo
-
nary aspergillosis
Immunologic response to 
pulmonary fungal 
colonization
Often underlying moderate to severe 
 
allergic asthma and/or cystic fibrosis, with 
wheezing, cough productive of thick 
brown sputum, fever, weight loss, fatigue
Elevated serum total IgE (> 1000 ng/mL); SPT 
positive to
 
;
 
positive
 
precipitins
, eosinophilia (off corticosteroids) 
(total eosinophils > 1000 cells/mcL), pulmonary 
infiltrates, central bronchiectasis
Oral corticosteroids, antifungal 
 
(azole) agent
Hereditary angioedema
Quantitative or functional C1 
esterase inhibitor defi
-
ciency, resulting in 
increased serum bradyki
-
nin levels
Unpredictable swelling of face, lips, tongue, 
hands, feet; no urticaria; gastrointestinal 
tract swelling causing severe abdominal 
pain
Decreased C1 esterase inhibitor serum level 
 
and/or function
, decreased serum C4 level
Prophylactic treatment: Danazol, 
tranexamic acid
Acute treatment: C1 esterase inhibitor 
product, kallikrein inhibitor, bradykinin 
B
2
-receptor antagonist
Hypereosinophilic 
syndromes
Leukoproliferative disorder 
characterized by overpro
-
duction of eosinophils
Symptoms related to eosinophilic infiltration 
of organs: angioedema, urticaria, pruritic 
papules, chronic cough, splenomegaly, 
heart failure
Eosinophilia (eosinophils > 1500 cells/mcL)
, 
 
elevated serum vitamin B
12
 level, elevated serum 
tryptase level, anemia, PDGFRA gene mutation
Corticosteroids, tyrosine kinase inhibitors
Mast cell hyperplasia
Pruritus, flushing, nausea, vomiting, diarrhea, 
abdominal pain, hypotension
Dense bone marrow mast cell infiltrate (≥ 15/hpf) 
on biopsy, elevated serum tryptase level 
 
(> 20 ng/mL)
, atypical mast cell morphology, 
cKIT
 mutation
Antihistamine, cromolyn, epinephrine, 
chemotherapy directed at underlying 
mast cell hyperplasia
“Red man syndrome” 
(acute infusion 
reaction)
Direct activation of mast 
cells by vancomycin 
 
(opioids and other drugs)
Flushing, pruritus, and erythema, especially 
of the upper body, during intravenous 
infusion of drug
Clinical history and physical examination, no role 
for laboratory testing
Antihistamine pretreatment 1 hour prior 
to subsequent vancomycin (or opioid 
and other causative drug) infusions, 
decreased rate of infusion
Serum sickness (and 
serum sickness-like 
syndromes)
Mediated by circulating 
immune complexes
Fever, pruritic urticarial or maculopapular 
rash, lymphadenopathy, arthralgias, 
arthritis, nephritis
Increased ESR, leukocytosis
, possible low serum 
C3 and C4 levels
Self-limited illness: NSAIDs, 
antihistamines
Severe illness: Corticosteroids, plasma 
exchange
1
Key diagnostic findings in bold.
cKIT
, stem cell factor receptor or CD117; ESR, erythrocyte sedimentation rate; NSAID, nonsteroidal anti-inflammatory drug; PDGFRA, platelet-derived growth factor receptor alpha; SPT, skin prick test.
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immunotherapy, and those with strong predisposing factors 
for atopic diatheses, eg, a strong family history of atopy or 
ongoing exposure to potential sources of allergen. Since the 
development of rhinitis precedes the presentation of asthma 
in over half of cases, early intervention may decrease the risk 
of more severe clinical illness. The type of immune response 
must be consistent with the nature of the disease. For exam
-
ple, IgE antibody causes allergic rhinitis but not allergic con
-
tact dermatitis. IgE antibodies are detected by in vivo (skin 
tests) or in vitro methods.
Adkinson NF Jr et al. Clinical history-driven diagnosis of allergic 
diseases: utilizing in vitro IgE testing. J Allergy Clin Immunol 
Pract. 2015 Nov–Dec:3(6):871–6. [PMID: 26553614]
DELAYED HYPERSENSITIVITY
According to the Gell and Coombs classification, type IV 
delayed hypersensitivity is mediated by activated T cells, 
which accumulate in areas of antigen deposition. A com
-
mon example is allergic contact dermatitis, which develops 
when a low-molecular-weight sensitizing substance serves 
as a hapten for dermal proteins, becoming a complete 
antigen. Sensitized T cells release cytokines, activating 
macrophages and promoting subsequent dermal inflam
-
mation; this typically occurs 48–72 hours after contact. 
Another common expression of delayed hypersensitivity is 
drug allergy that occurs after a similar process and that 
often results in maculopapular or morbilliform exanthems. 
T-cell–mediated hypersensitivity is now understood to 
involve both Th1 and Th2 cells. In addition, subsequent 
inflammation and tissue damage occurs via various effec
-
tor cell types, including monocytes, eosinophils, and 
neutrophils.
1. Drug Exanthems
The clinical manifestation of these reactions is vast 
(Chapter 6), ranging from the commonly observed morbil
-
liform rash to skin sloughing observed in Stevens-Johnson 
syndrome and toxic epidermal necrolysis. Given the range 
of cutaneous findings, the differential diagnosis is broad 
and includes miliaria, lichen planus, folliculitis, pityriasis 
rosea, tinea corporis, and mycosis fungoides. Physical 
examination of rash characteristics, dermatologic consulta
-
tion, and biopsy findings can help narrow the differential. 
While a whole spectrum of drugs can result in exanthems, 
there are no commercially available laboratory or other 
diagnostic tests to reliably identify the culprit drug.
Management consists mainly of immediate cessation of 
suspected medications and monitoring for symptom reso
-
lution. Systemic corticosteroids may be indicated for exten
-
sive dermatitis or other organ involvement.
Martin SF. New concepts in cutaneous allergy. Contact Dermatitis. 
2015 Jan;72(1):2–10. [PMID: 25348820]
Naisbitt DJ et al. In vitro diagnosis of delayed-type drug hyper
-
sensitivity: mechanistic aspects and unmet needs. Immunol 
Allergy Clin North Am. 2014 Aug;34(3):691–705. [PMID: 
25017686]
Pavlos R et al. T cell-mediated hypersensitivity reactions to 
drugs. Annu Rev Med. 2015;66:439–54. [PMID: 25386935]
2. Drug-Induced Hypersensitivity Syndrome 
(Drug Reaction With Eosinophilia & Systemic 
Symptoms)
 
»
Potentially life-threatening, systemic drug-induced hyper
-
sensitivity reactions most commonly occur with exposure to 
anticonvulsants and sulfonamides, although many other 
classes of drugs, including other antimicrobials and antide
-
pressants, have been implicated. The onset of symptoms 
typically occurs 2–6 weeks after drug initiation. As suggested 
by its alternative name, drug reaction with eosinophilia and 
systemic symptoms (DRESS), it typically includes eosino
-
philia and/or lymphocytosis and systemic symptoms such as 
fever and lymph node enlargement, along with the rash. The 
exact pathogenesis of DRESS is not well elucidated but may 
include deficient drug metabolism due to genetic mutations

include deficient drug metabolism due to genetic mutations 
in specific detoxification enzymes; reactivation of herpesvi
-
ruses including HHV-6, HHV-7, cytomegalovirus, and 
Epstein-Barr virus; and a genetic predisposition based on 
the presence of specific HLA haplotypes.
 
»
HLA Haplotypes & Risk of Delayed-Onset 
Drug Hypersensitivity Syndromes
Activated cytotoxic CD8 T lymphocytes play a key role in the 
pathogenesis of serious, drug-induced adverse cutaneous 
reactions, such as toxic epidermal necrolysis. There are strik
-
ing, medication-specific associations between inheritance of 
particular HLA-B alleles and risk of these hypersensitivity 
reactions in defined populations. Most notably, B
*
57:01 con
-
fers risk for reactions to abacavir; B
*
15:02, for carbamazepine; 
B
*
58:01, for allopurinol; and B
*
13:01, for dapsone. The most 
likely mechanism is a direct interaction between the drug and 
the antigen-binding cleft of the HLA-B molecule, such that 
many “self ” antigens subsequently bound by the HLA-B mol
-
ecule are perceived as “foreign, ” eliciting massive CD8 T-cell 
activation. Current FDA recommendations call for testing for 
the relevant HLA-B allele prior to initiating therapy with aba
-
cavir in all patients and with carbamazepine in Asian patients. 
The American College of Rheumatology recommends such 
testing before starting allopurinol therapy in patients of 
Korean descent, especially those with kidney disease, and Han 
Chinese and individuals of Thai extraction. Pretreatment 
HLA testing for other drugs or in other populations may not 
be useful at the present time due to low prevalence of the 
implicated isotypes.
 
»
Drug-induced hypersensitivity syndrome often begins with 
pruritus and fever, but cutaneous manifestations generally 
follow soon thereafter, most commonly an erythematous 
morbilliform rash. Although the entire skin surface can be 
involved, the face, trunk, and upper and lower extremities 
are commonly affected. The most common systemic find
-
ings involve the lymphatic (lymphadenopathy), hematologic 
and hepatic systems, although renal, pulmonary and cardiac 
involvement is also documented.
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Laboratory abnormalities include leukocytosis with eosin
-
ophilia (greater than 1.5 × 10
9
/L) and atypical lymphocyto
-
sis; elevated hepatic transaminases (more than 2 times 
upper limits of normal) and alkaline phosphatase, and 
increased serum creatinine, pyuria, and proteinuria, which 
may indicate the development of interstitial nephritis. The 
most common skin biopsy findings are a dense, perivascu
-
lar lymphocytic infiltrate in the papillary dermis with 
eosinophils and dermal edema.
 
»
Treatment
Management consists of cessation of the causative medi
-
cation and initiation of systemic corticosteroids. A dose 
of 1.0 mg/kg of oral prednisone is recommended as a 
starting dose, followed by a gradual taper occurring over 
3–6 months after laboratory normalization and stabiliza
-
tion. Additional supportive therapies may include anti
-
pyretics for fever, topical steroids for skin lesions, or fluid 
and electrolyte replacement in the case of more severe 
exfoliative dermatitis.
Table 20–14.
 
Selected immunodeficiency syndromes.
Disease
Clinical Presentation
Diagnosis
1
Treatment
Common variable 
immunodeficiency
Most common symptomatic primary 
Recurrent sinopulmonary infections, par
-
asitic (especially 
) gas
-
trointestinal infections, autoimmune 
diseases, and increased risk of 
Poor antibody response to immu
-
nizations, low serum IgG, low 
serum IgA and/or IgM; exclu
-
sion of secondary causes of 
hypogammaglobulinemia
Subcutaneous or intravenous 
immunoglobulins
Prophylactic antibiotics
Selective IgA deficiency
Most prevalent primary immunodeficiency; 
most cases asymptomatic; recurrent 
sinopulmonary infections; atopic disor
-
ders, rheumatoid arthritis and systemic 
lupus erythematosus common; rarely, 
anaphylaxis to transfusion of blood or 
blood products
Undetectable serum IgA levels 
 
(< 7 mg/dL)
, normal serum IgG 
and IgM levels
Early use of antibiotics for bacte
-
rial infections; monitor for 
progression into common 
variable immunodeficiency
Adult T-cell deficiencies
Opportunistic infections (similar to HIV); 
eg CMV, EBV, other herpes viruses, 
mycobacteria, and fungi (
Candida, 
Cryptococcus, Pneumocystis
)
Exclude HIV infection; obtain 
CD4 and CD8 T-cell counts, 
and in vitro T-cell function
Antibiotics; some patients are 
candidates for bone marrow 
transplantation
Complement disorders
“Early” complement component deficien
-
cies: autoimmune diseases
“Late” complement component 
 
(C5–C8) deficiencies: recurrent menin
-
gococcal or gonococcal infections
Screen with CH50 and AH50. 
Obtain individual serum com
-
plement levels if abnormal
Prompt administration of 
antibiotics
Granulocyte disorders
Recurrent invasive skin and soft tissue 
infections, abscesses requiring incision 
and drainage
Common organisms are 
S aureus
, gram-
negative bacilli, 
Nocardia, Aspergillus
CBC with differential to evaluate 
neutrophil count
Dihydrorhodamine assay to 
evaluate neutrophil oxidative 
burst
Antibiotic prophylaxis; interferon 
in patients with chronic gran
-
ulomatous disease
1
Modified, with permission, from Ashar B, Miller R, Sisson S (editors): Johns Hopkins Internal Medicine Board Review Certification and 
Recertification, 5th ed. © Elsevier, 2015.
review. J Immunol Res. 2014;2014:565320. [PMID: 24901010]
Husain Z et al. DRESS syndrome: Part I. Clinical perspectives. J Am 
Acad Dermatol. 2013 May;68(5):693.e1–14. [PMID: 23602182]
Husain Z et al. DRESS syndrome: Part II. Management and 
therapeutics. J Am Acad Dermatol. 2013 May;68(5):709.e1–9. 
[PMID: 23602183]
Schwartz RA et al. Toxic epidermal necrolysis. Part I. Introduc
-

-
tion, history, classification, clinical diagnosis, systemic mani
-
festations, etiology, and immunopathogenesis. J Am Acad 
Dermatol. 2013 Aug;69(2):173.e1–13. [PMID: 23866878]
PRIMARY IMMUNODEFICIENCY DISORDERS 
IN ADULTS
Primary immunologic deficiency diseases are estimated to 
affect 1 in 4000 individuals; many are genetically determined 
and present in childhood. Nonetheless, several important 
immunodeficiency disorders present in adulthood, most 
notably the antibody deficiency syndromes: selective IgA 
deficiency, common variable immunodeficiency, and 
specific (functional) antibody deficiency (Table 20–14). 
 
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Antibody deficiency predisposes patients to recurrent infec
-
tions, particularly of the respiratory tract, including refractory 
chronic rhinosinusitis, bronchitis, pneumonia, and bronchi
-
ectasis. Patients are most susceptible to infections with 
encapsulated bacteria (eg, 
Haemophilus influenzae, Strepto
-
coccus pneumoniae, Neisseria meningitides
). However, any 
part of the innate or adaptive immune system can be defective 
and results in infections with different spectra of organisms.
1. Selective Immunoglobulin A Deficiency
Selective IgA deficiency is the most common primary immu
-
nodeficiency disorder and is characterized by undetectable 
serum IgA levels (lower than 7 mg/dL) with normal levels of 
IgG and IgM; its prevalence is about 1 in 500 individuals 
(Table 20–14). Most affected individuals are asymptomatic. A 
minority of patients have recurrent infections such as sinus
-
itis, otitis, and bronchitis. Selective IgA deficiency can be 
associated with atopic diseases and autoimmune disorders, 
including Graves disease, SLE, juvenile rheumatoid arthritis, 
type 1 diabetes mellitus, and celiac disease.
Some individuals with undetectable levels of serum IgA 
may have high titers of anti-IgA antibodies and are at risk 
for anaphylactic reactions to IgA following exposure to it 
through infusions of plasma (or blood transfusions). Treat
-
ment with commercial immune globulin is not indicated 
and may very rarely result in anaphylactic reactions.
 
»
•	
Refer patients with anaphylaxis following infusions of 
plasma (or blood transfusions) to an immunologist for 
further evaluation of possible IgA deficiency.
•	
Refer patients with low serum IgA and recurrent sinopul
-
monary infections, celiac disease, giardiasis, or a family 
history of immunodeficiency to an immunologist.
Bonilla FA et al. Practice parameter for the diagnosis and man
-
agement of primary immunodeficiency. J Allergy Clin Immu
-
nol. 2015 Nov;136(5):1186–205. [PMID: 26371839]
Singh K et al. IgA deficiency and autoimmunity. Autoimmun 
Rev. 2014 Feb;13(2):163–77. [PMID: 24157629]
Wang N et al. IgA deficiency: what is new? Curr Opin Allergy 
Clin Immunol. 2012 Dec;12(6):602–8. [PMID: 23026772]
2. Common Variable Immunodeficiency
 
»
Frequent sinopulmonary infections secondary to 
humoral immune deficiency.
 
»
Low serum immunoglobulin levels and deficient 
functional antibody responses.
 
»
Primary defect may be with B cells or T cells.
 
»
The most common symptomatic primary immunodefi
-
ciency disorder is common variable immunodeficiency, a 
heterogeneous immunodeficiency disorder clinically char
-
acterized by an increased incidence of recurrent infections, 
autoimmune phenomena, and neoplastic diseases. The 
onset is generally in early adulthood but it can occur at any 
age. The prevalence of common variable immunodefi
-
ciency is about 1 in 25,000 in the United States. Most cases 
are sporadic; about 10–20% are familial.
 
»
Increased susceptibility to infections, especially with 
encapsulated organisms, is the hallmark of the disease. 
Virtually all patients suffer from recurrent sinusitis; bron
-
chitis, otitis, pharyngitis, and pneumonia are common 
infections. Infections may be prolonged or associated with 
unusual complications such as meningitis or sepsis.
Gastrointestinal infections and dysfunction are com
-
monly associated with common variable immunodefi
-
ciency, and a sprue-like syndrome, with diarrhea, 
steatorrhea, malabsorption, protein-losing enteropathy, 
and hepatosplenomegaly, may develop in patients. Para
-
doxically, there is an increased incidence of autoimmune 
disease (20%), although patients may not display the usual 
serologic markers. Autoimmune cytopenias are most 
common, but autoimmune endocrinopathies, seronega
-
tive rheumatic disease, and gastrointestinal disorders

-
tive rheumatic disease, and gastrointestinal disorders 
are also commonly seen. Lymph nodes may be enlarged in 
these patients, yet biopsies show marked reduction in 
plasma cells. Noncaseating granulomas are frequently 
found in the spleen, liver, lungs, or skin. There is an 
increased propensity for the development of B-cell neo
-
plasms (50- to 400-fold increased risk of lymphoma), 
and gastric carcinomas. Chronic lung disease is one of the 
most common complications of common variable 
immunodeficiency.
Assess serum quantitative immunoglobulin levels. All 
patients have a reduced serum IgG level, either serum IgM 
or IgA or both are reduced as well. Demonstration of func
-
tional or quantitative defects in antibody production is 
essential and is typically performed by checking antibody 
response to polysaccharide (Pneumovax) and protein 
antigens (such as tetanus and diphtheria). The diagnosis is 
made in patients who have reduced serum immunoglobu
-
lins and poor antibody response to vaccines, after exclu
-
sion of secondary causes (eg, proteinuria, protein-losing 
enteropathy, drug effects such as rituximab, antiepileptics, 
chronic lymphocytic leukemia, lymphoma, and plasma 
cell myeloma).
The causes of hypogammaglobulinemia in patients 
with common variable immunodeficiency include intrinsic 
B-cell defects that prevent terminal maturation into anti
-
body-secreting plasma cells. The absolute B-cell count in 
the peripheral blood in most patients, despite the underly
-
ing cellular defect, is normal. A subset of these patients has 
concomitant T-cell immunodeficiency with increased 
numbers of activated CD8 cells, splenomegaly, and 
decreased delayed-type hypersensitivity.
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»
Treatment
Patients with common variable immunodeficiency should 
be treated aggressively with antibiotics at the first sign of 
infection. Since antibody deficiency predisposes patients to 
high-risk pyogenic infections, antibiotic coverage should 
be sure to cover encapsulated bacteria. Infections with 
other microorganisms also can develop, including viruses, 
parasites, and extracellular gram-positive or gram-negative 
bacteria (such as 
S aureus
 or 
). Mainstay of 
preventive therapy is with subcutaneous or intravenous 
immunoglobulin replacement therapy, typically provided 
every 1–4 weeks, with a typical monthly dose of 300–
600 mg/kg. Subcutaneous injections of IgG offer the con
-
venience of self-administration at home and lower 
incidence of adverse effects. Adjustment of dosage or of the 
infusion interval is made on the basis of clinical responses 
and steady-state serum IgG levels. Such therapy is essential 
for decreasing the incidence of potentially life-threatening 
infections, increasing quality of life, and reducing the 
progression of lung disease.
 
»
•	
Refer patients with low serum immunoglobulins and 
history of recurrent or unusual infections, autoimmune 
disease, or family history of immunodeficiency.
•	
The presence of bronchiectasis without a known under
-
lying cause such as cystic fibrosis should raise the sus
-
picion of a primary immunodeficiency; even when 
serum immunoglobulins are normal, the patient can 
have a specific antibody deficiency that would warrant 
further evaluation.
3. Specific (Functional) Antibody Deficiency
Specific antibody deficiency is characterized by decreased or 
absent IgG antibody response to vaccines in the setting of 
normal or mildly decreased serum immunoglobulin levels. 
The clinical spectrum can range from mild to severe with 
features very similar to common variable immunodeficiency.
Gathmann B et al; European Society for Immunodeficiencies 
Registry Working Party. Clinical picture and treatment of 2212 
patients with common variable immunodeficiency. J Allergy 
Clin Immunol. 2014 Jul;134(1):116–26. [PMID: 24582312]
Jolles S. The variable in common variable immunodeficiency: a 
disease of complex phenotypes. J Allergy Clin Immunol 
Pract. 2013 Nov–Dec;1(6):545–56. [PMID: 24565700]
Kashani S et al. Clinical characteristics of adults with chronic rhino
-
sinusitis and specific antibody deficiency. J Allergy Clin Immu
-
nol Pract. 2015 Mar–Apr:3(2):236–42. [PMID: 25609325]
Wall LA et al. Specific antibody deficiencies. Immunol Allergy 
Clin North Am. 2015 Nov;35(4):659–70. [PMID: 26454312]
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ASSESSMENT OF THE PATIENT
The diagnosis and treatment of fluid and electrolyte disor
-
ders are based on (1) careful history, (2) physical examina
-
tion and assessment of total body water and its distribution, 
(3) serum electrolyte concentrations, (4) urine electrolyte 
concentrations, and (5) serum osmolality. The pathophysi
-
ology of electrolyte disorders is rooted in basic principles 
of  total body water and its distribution across fluid 
compartments.
A. Body Water and Fluid Distribution
Total body water is different in men than in women, and it 
decreases with aging (Table 21–1). Approximately 50–60% 
of total body weight is water; two-thirds (40% of body 
weight) is intracellular, while one-third (20% of body 
weight) is extracellular. One-fourth of extracellular fluid 
(5% of body weight) is intravascular. Water may be lost 
from either or both compartments (intracellular and extra
-
cellular). Changes in total body water content are best 
evaluated by documenting changes in body weight. Effec
-
tive circulating volume may be assessed by physical exami
-
nation (eg, blood pressure, pulse, jugular venous 
distention). Quantitative measurements of effective circu
-
lating volume and intravascular volume may be invasive 
(ie, central venous pressure or pulmonary wedge pressure) 
or noninvasive (ie, inferior vena cava diameter and right 
atrial pressure by echocardiography) but still require care
-
ful interpretation.
B. Serum Electrolytes
The cause of electrolyte disorders may be determined 
by  reviewing the history, underlying diseases, and 
C. Evaluation of Urine
The urine concentration of an electrolyte is helpful to 
determine whether the kidney is appropriately (or inap
-
propriately) excreting or retaining the electrolyte in 
response to high or low serum levels. A 24-hour urine col
-
lection for daily electrolyte excretion is the gold standard 
for renal electrolyte handling, but it is slow and onerous. 
A more convenient method is the fractional excretion (Fe) of 
an electrolyte X (Fe
x
) calculated from a spot urine sample:
=×
F(
%)
/uni00A0
Urin
eX
/Serum
X
Urin
eC
r/Seru
mC
r
100
E
x
A low fractional excretion indicates renal reabsorption 
(high avidity or electrolyte retention), while a high frac
-
tional excretion indicates renal wasting (low avidity or 
electrolyte excretion). Thus, the fractional excretion helps 
the clinician determine whether the kidney’s response is 
appropriate for a specific electrolyte disorder.
D. Serum Osmolality
Solute concentration is measured by osmolality in milli
-
moles per kilogram. Osmolarity is measured in millimoles 
of solute per liter of solution. At physiologic solute concen
-
trations (normally 285–295 mmol/kg), the two measure
-
ments are clinically interchangeable. Tonicity refers to 
osmolytes that are impermeable to cell membranes. Differ
-
ences in osmolyte concentration across cell membranes 
lead to osmosis and fluid shifts, stimulation of thirst, and 
secretion of antidiuretic hormone (ADH). Substances that 
easily permeate cell membranes (eg, urea, ethanol) are 
ineffective osmoles that do not cause fluid shifts across 
fluid compartments.
Serum osmolality can be estimated using the following 
formula:
=
++
+
Osmolality
2(Na mEq/L)
Gl
uc
os
em
g/dL
18
BU
Nm
g/dL
2.
8
(1 mOsm/L of glucose equals 180 mg/L or 18 mg/dL and 
1 mOsm/L of urea nitrogen equals 28 mg/L or 2.8 mg/dL.) 
 
Sodium is the major extracellular cation; doubling the 
serum sodium in the formula for estimated osmolality 
accounts for counterbalancing anions. A discrepancy 
between measured and estimated osmolality of greater 
than 10 mmol/kg suggests an osmolal gap, which is the 
presence of unmeasured osmoles such as ethanol, metha
-
nol, isopropanol, and ethylene glycol (see Table 38–5).21
Electrolyte & Acid-Base 
Disorders
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DISORDERS OF SODIUM CONCENTRATION
 
»
Volume status and serum osmolality are essential 
to determine etiology.
 
»
Hyponatremia usually reflects excess water 
 
retention relative to sodium rather than sodium 
 
deficiency. The sodium concentration is not a 
measure of total body sodium.
 
»
Hypotonic fluids commonly cause hyponatremia 
in hospitalized patients.
 
»
Defined as a serum sodium concentration less than 
 
135 mEq/L (135 mmol/L), hyponatremia is the most com
-
mon electrolyte abnormality in hospitalized patients. The 
clinician should be wary about hyponatremia since mis
-
management can result in neurologic catastrophes from 
cerebral osmotic demyelination. Indeed, iatrogenic com
-
plications from aggressive or inappropriate therapy can be 
more harmful than hyponatremia itself.
A common misconception is that the sodium con
-
centration is a reflection of total body sodium or total 
body water. In fact, total body water and sodium can be 
low, normal, or high in hyponatremia since the kidney 
independently regulates sodium and water homeostasis. 
Most cases of hyponatremia reflect water imbalance and 
abnormal water handling, not sodium imbalance, indicat
-
ing the primary role of ADH in the pathophysiology of 
hyponatremia.
 
 A di
agnostic algorithm using serum osmo
-
lality and volume status separates the causes of hyponatre
-
mia into therapeutically useful categories (Figure 21–1).
 
»
Etiology
A. Isotonic and Hypertonic Hyponatremia
Serum osmolality identifies isotonic and hypertonic hypo
-
natremia, although these cases can often be identified by 
careful history or previous laboratory tests.
Table 21–1.
 
Total body water (as percentage of body 
weight) in relation to age and sex.
Age
Male
Female
18–40
60%
50%
41–60
60–50%
50–40%
Over 60
50%
40%
HYPON
AT
REMIA
Serum osmolality
  
1.
 Hyperproteinemia
  2. Hyperlipidemia (chylomicrons, 
      trig
ly
cerides
, ra
rely
 cholesterol)
Low
(< 280 mOsm/kg)
Normal
(280–295 mOsm/kg)
High
(> 295 mOsm/kg)
  
1.
 Hype
rgly
cemia
  2. Mannitol, sorbitol,
      glycerol, maltose
  3. Radiocontrast agents
Hypo
to
nic
hyponatremia
Volume status
Euvolemic
Hypervolemic
Hyp
ov
olemic
U
Na
+ 
< 
10
 mEq/L
Extrar
enal salt loss
  
1.
 Deh
yd
ratio
n
  2. Diarrhea
  3.
 V
omiting
U
Na
+ 
> 20 mEq/L
Renal salt loss
  
1.
 Diuretics
  2.
 A
CE inhibitors
  3. Nephropathies
  4. Mineralocorticoid
      def
iciency
  5. 
Ce
re
bral sodium-
      wasting 
sy
ndrome
1.
 SIADH
2. Postoperative hyponatremia
3. Hypot
hy
ro
idism
4. P
syc
hogenic po
ly
dipsia
5. Beer potomania
6. Idiosyncratic drug 
re
action (thiazide
    diuretics, 
AC
E inhibitors)
7.
 Endurance 
exe
rc
ise
8. 
Adre
nocorticotropin deficiency
Edematous states
  
1.
 Heart failure
  2. Liver disease
  3. Nephrotic syndrome 
      (rare)
  4. 
Ad
vanced kidney 
      disease
Isotonic
Hyper
to
nic
hy
ponatremia
 
▲
Figure 21–1.
 
Evaluation of hyponatremia using serum osmolality and extracellular fluid volume status. ACE, 
angiotensin-converting enzyme; SIADH, syndrome of inappropriate antidiuretic hormone.
 
from Narins RG et al. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med. 1982 
Mar;72(3):496–520. Copyright © Elsevier.)
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Pseudohyponatremia does not occur with hyperpro
-
teinemia or lipemia if the serum sodium is measured with 
an ion-specific electrode in a direct assay of an undiluted 
serum specimen.
Hypertonic hyponatremia occurs with hyperglycemia 
and mannitol administration for increased intracranial 
pressure. Glucose and mannitol osmotically pull intracel
-
lular water into the extracellular space. The translocation 
of water lowers the serum sodium concentration. Translo
-
cational hyponatremia is not pseudohyponatremia or an 
artifact of sodium measurement. There is some contro
-
versy about a correction factor for the serum sodium in the 
presence of hyperglycemia. Many guidelines recommend a 
single correction factor, whereby the serum sodium con
-
centration decreases by 1.6 mEq/L (or 1.6 mmol/L) for 
every 100 mg/dL (5.56 mmol/L) rise in plasma glucose 
above normal. A higher correction factor of 2.4 mEq/L (or 
2.4 mmol/L) per 100 mg/dL (5.56 mmol), however, tends 
to correlate more closely with observed sodium levels.
B. Hypotonic Hyponatremia
Most cases of hyponatremia are hypotonic, highlighting 
sodium’s role as the predominant extracellular osmole. The 
next step is classifying hypotonic cases by the patient’s 
 
1. Hypovolemic hypotonic hyponatremia—
Hypovolemic 
hyponatremia occurs with renal or extrarenal volume loss 
and hypotonic fluid replacement (Figure 21–1). Total body 
sodium and total body water are decreased. To maintain 
intravascular volume, the pituitary increases ADH secre
-
tion, causing free water retention from hypotonic fluid 
replacement. The body sacrifices serum osmolality to pre
-
serve intravascular volume. In short, losses of water and 
salt are replaced by water alone. Without ongoing hypo
-
tonic fluid intake, the renal or extrarenal volume loss 
would produce hypovolemic hypernatremia.
Cerebral salt wasting is a distinct and rare subset of hypo
-
volemic hyponatremia seen in patients with intracranial 
disease (eg, infections, cerebrovascular accidents, tumors, 
and neurosurgery). Clinical features include refractory 
hypovolemia and hypotension, often requiring continuous 
infusion of isotonic or hypertonic saline and ICU monitor
-
ing. The exact pathophysiology is unclear but includes renal 
sodium wasting possibly through B-type natriuretic peptide, 
ADH release, and decreased aldosterone secretion.
2. Euvolemic hypotonic hyponatremia—
Euvolemic hypo
-
natremia has the broadest differential diagnosis. Most causes 
are mediated directly or indirectly through ADH, including 
hypothyroidism, adrenal insufficiency, medications, and the 
syndrome of inappropriate ADH (SIADH). The exceptions 
are primary polydipsia, beer potomania, and reset osmostat.
a. Hormonal abnormalities
—
Hypothyroidism and 
adrenal insufficiency can cause hyponatremia. Exactly how 
hypothyroidism induces hyponatremia is unclear but may 
be related to ADH. Adrenal insufficiency may be associ
-
ated with the hyperkalemia and metabolic acidosis of 
hypoaldosteronism. Cortisol provides feedback inhibition 
for ADH release.
b. Thiazide diuretics and other medications
—
Thiazides induce hyponatremia typically in older female 
patients within days of initiating therapy. The mechanism 
appears to be a combination of mild diuretic-induced 
 
volume contraction, ADH effect, and intact urinary con
-
centrating ability resulting in water retention and hypona
-
tremia. Loop diuretics do not cause hyponatremia as 
frequently because of disrupted medullary concentrating 
gradient and impaired urine concentration.
Nonsteroidal anti-inflammatory drugs (NSAIDs) 
increase ADH by inhibiting prostaglandin formation. 
Prostaglandins and selective serotonin reuptake inhibitors 
(eg, fluoxetine, paroxetine, and citalopram) can cause 
hyponatremia, especially in geriatric patients. Enhanced 
secretion or action of ADH may result from increased 
serotonergic tone. Angiotensin-converting enzyme (ACE)

serotonergic tone. Angiotensin-converting enzyme (ACE) 
inhibitors do not block the conversion of angiotensin I to 
angiotensin II in the brain. Angiotensin II stimulates thirst 
and ADH secretion. Hyponatremia during amiodarone 
loading has been reported; it usually improves with dose 
reduction.
Use of 3,4-methylenedioxymethamphetamine (MDMA, 
also known as Ecstasy) can lead to hyponatremia and 
severe neurologic symptoms, including seizures, cerebral 
edema, and brainstem herniation. MDMA and its metabo
-
lites increase ADH release from the hypothalamus. Pri
-
mary polydipsia may contribute to hyponatremia since 
MDMA users typically increase fluid intake to prevent 
hyperthermia.
c. Nausea, pain, surgery, and medical procedures
—
Nausea and pain are potent stimulators of ADH release. 
Severe hyponatremia can develop after elective surgery in 
healthy patients, especially premenopausal women. Hypo
-
tonic fluids in the setting of elevated ADH levels can pro
-
duce severe, life-threatening hyponatremia. Medical 
procedures such as colonoscopy have also been associated 
with hyponatremia.
d. HIV infection
—
Hyponatremia occurs in up to 50% of 
hospitalized HIV-infected patients and 20% of ambulatory 
HIV-infected patients. The differential diagnosis is broad: 
medication effect, adrenal insufficiency, hypoaldosteron
-
ism, central nervous system or pulmonary disease, SIADH, 
malignancy, and volume depletion.
e. Exercise-associated hyponatremia
—
Hyponatremia 
 
after exercise, especially endurance events such as triath
-
lons and marathons, may be caused by a combination of 
excessive hypotonic fluid intake and continued ADH 
secretion. Reperfusion of the exercise-induced ischemic 
splanchnic bed causes delayed absorption of excessive 
quantities of hypotonic fluid ingested during exercise. Sus
-
tained elevation of ADH prevents water excretion in this 
setting. Current guidelines suggest that endurance athletes 
drink water according to thirst rather than according to 
specified hourly rates of fluid intake. Specific universal 
recommendations for fluid replacement rates are not pos
-
sible given the variability of sweat production, renal water 
excretion, and environmental conditions. Electrolyte-
 
containing sport drinks do not protect against hyponatremia 
since they are markedly hypotonic relative to serum.
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f. Syndrome of inappropriate antidiuretic hor
-
mone secretion
—
Under normal circumstances, hypovo
-
lemia and hyperosmolality stimulate ADH secretion. ADH 
release is inappropriate without these physiologic cues. 
Normal regulation of ADH release occurs from both the 
central nervous system and the chest via baroreceptors and 
neural input. The major causes of SIADH (Table 21–2) are 
disorders affecting the central nervous system (structural, 
metabolic, psychiatric, or pharmacologic processes) or the 
lungs (infectious, mechanical, oncologic). Medications 
commonly cause SIADH by increasing ADH or its action. 
Some carcinomas, especially small cell lung carcinoma, can 
autonomously secrete ADH.
g. Psychogenic polydipsia and beer potomania
—
Marked free water intake (generally greater than 10 L/day) 
may produce hyponatremia. Euvolemia is maintained 
through renal excretion of sodium. Urine sodium is there
-
fore generally elevated (greater than 20 mEq/L), and ADH 
levels are appropriately suppressed. As the increased free 
water is excreted, the urine osmolality approaches the 
minimum of 50 mOsm/kg (or 50 mmol/kg). Polydipsia 
occurs in psychiatric patients. Psychiatric medications may 
interfere with water excretion or increase thirst through 
anticholinergic side effects, further increasing water intake. 
The hyponatremia of beer potomania occurs in patients 
who consume large amounts of beer. Free water excretion 
is decreased because of decreased solute consumption and 
production; muscle wasting and malnutrition are contrib
-
uting factors. Without enough solute, these patients have 
decreased free water excretory capacity even if they maxi
-
mally dilute the urine.
h. Reset osmostat
—
Reset osmostat is a rare cause of 
hyponatremia characterized by appropriate ADH regula
-
tion in response to water deprivation and fluid challenges. 
Patients with reset osmostat regulate serum sodium and 
serum osmolality around a lower set point, concentrating 
or diluting urine in response to hyperosmolality and hypo-
osmolality. The mild hypo-osmolality of pregnancy is a 
form of reset osmostat.
3. Hypervolemic hypotonic hyponatremia—
Hypervol
-
emic hyponatremia occurs in the edematous states of cir
-
rhosis, heart failure, nephrotic syndrome, and advanced 
kidney disease (Figure 21–1). In cirrhosis and heart failure, 
effective circulating volume is decreased due to peripheral 
vasodilation or decreased cardiac output. Increased renin-
angiotensin-aldosterone system activity and ADH secre
-
tion result in water retention. Note the pathophysiologic 
similarity to hypovolemic hyponatremia—the body sacri
-
fices osmolality in an attempt to restore effective circulat
-
ing volume.
The pathophysiology of hyponatremia in nephrotic 
syndrome is not completely understood, but the primary 
disturbance may be renal sodium retention, resulting in 
overfilling of the intravascular space and secondary edema 
formation as fluid enters the interstitial space. Previously, it 
was thought that the decreased oncotic pressure of hypoal
-
buminemia caused fluid shifts from the intravascular space 
to the interstitial compartment. Intravascular underfilling 
led to secondary renal sodium retention. However, patients 
receiving therapy for glomerular disease and nephrotic 
syndrome often have edema resolution prior to normaliza
-
tion of the serum albumin.
Patients with advanced kidney disease typically have 
sodium retention and decreased free water excretory 
capacity, resulting in hypervolemic hyponatremia.
Table 21–2.
 
Causes of syndrome of inappropriate ADH 
secretion (SIADH).
Central nervous system disorders
Brain tumor
Encephalitis
Head trauma
Psychosis, acute
Stroke
p
ulmonar
y lesions
Aspergillosis
Bacterial pneumonia
Neoplasms
Positive pressure ventilation
Adenocarcinoma of colon

Stroke
p
ulmonar
y lesions
Neoplasms
Bronchogenic carcinoma
Leukemia
Lymphoma
Prostatic carcinoma
Renal cell carcinoma
Thymoma
Drugs
Increase ADH production
Antidepressants: tricyclics, SSRIs, monoamine oxidase 
Antineoplastics: cyclophosphamide, vincristine
Clofibrate
Methylenedioxymethamphetamine (MDMA; Ecstasy)
Neuroleptics: haloperidol, fluphenazine, trifluoperazine 
 
thioridazine, thiothixene
Potentiate ADH action
Chlorpropamide, tolbutamide
NSAIDs
Somatostatin and analogs
Others
Acute intermittent porphyria
AIDS
Pain, postoperative, stress
Pregnancy (physiologic)
ADH, antidiuretic hormone; NSAIDs, nonsteroidal anti-inflammatory 
drugs; SSRIs, selective serotonin reuptake inhibitors.
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»
Whether hyponatremia is symptomatic depends on its sever
-
ity and acuity. Chronic disease can be severe (sodium con
-
centration less than 110 mEq/L), yet remarkably asymptomatic 
because the brain has adapted by decreasing its tonicity over 
weeks to months. Acute disease that has developed over 
hours to days can be severely symptomatic with relatively 
modest hyponatremia. Mild hyponatremia (sodium concen
-
trations of 130–135 mEq/L) is usually asymptomatic.
Mild symptoms of nausea and malaise progress to 
headache, lethargy, and disorientation as the sodium 
concentration drops. The most serious symptoms are 
respiratory arrest, seizure, coma, permanent brain dam
-
age, brainstem herniation, and death. Premenopausal 
women are much more likely than menopausal women 
to die or suffer permanent brain injury from hypona
-
tremic encephalopathy, suggesting a hormonal role in the 
pathophysiology.
Evaluation starts with a careful history for new medica
-
tions, changes in fluid intake (polydipsia, anorexia, intrave
-
nous fluid rates and composition), fluid output (nausea 
and vomiting, diarrhea, ostomy output, polyuria, oliguria, 
insensible losses). The physical examination should help 
categorize the patient’s volume status into hypovolemia, 
euvolemia, or hypervolemia.
Laboratory assessment should include serum electrolytes, 
creatinine, and osmolality as well as urine sodium. The 
etiology of most cases of hyponatremia will be apparent 
from the history, physical, and basic laboratory tests. Addi
-
tional tests of thyroid and adrenal function will occasion
-
ally be necessary.
SIADH is a clinical diagnosis characterized by (1) hypo
-
natremia; (2) decreased osmolality (less than 280 mOsm/kg 
 
[280 mmol/kg]); (3) absence of heart, kidney, or liver disease; 
(4) normal thyroid and adrenal function (see Chapter 26); 
 
and (5) urine sodium usually over 20 mEq/L. In clinical 
practice, ADH levels are not measured. Patients with 
SIADH may have low blood urea nitrogen (BUN) (less 
than 10 mg/dL [3.6 mmol/L]) and hypouricemia (less than 
4 mg/dL [238 mcmol/L]), which are not only dilutional but 
result from increased urea and uric acid clearances in 
response to the volume-expanded state. Azotemia may 
reflect volume contraction, ruling out SIADH, which is 
seen in euvolemic patients.
 
»
The most serious complication of hyponatremia is iatro
-
genic cerebral osmotic demyelination from overly rapid 
sodium correction. Also called central pontine myelinoly
-
sis, cerebral osmotic demyelination may occur outside the 
brainstem. Demyelination may occur days after sodium 
correction or initial neurologic recovery from hyponatre
-
mia. Hypoxic episodes during hyponatremia may contrib
-
ute to demyelination. The neurologic effects are generally 
catastrophic and irreversible.
 
»
Treatment
Regardless of the etiology of hyponatremia and the patient’s 
volume status, restriction of free water and hypotonic fluid 
intake is the initial step in hyponatremia management 
since excessive free water intake will exacerbate hyponatre
-
mia. Free water clearance by the kidneys must exceed free 
water intake for the serum sodium concentration to rise. 
Free water intake should generally be less than 1–1.5 L/day, 
although more severe free water restriction may be neces
-
sary in patients with minimal free water clearance, and 
hypertonic saline may be necessary in patients with nega
-
tive free water clearance.
Hypovolemic
 patients require adequate fluid resuscita
-
tion from isotonic fluids (either normal saline or lactated 
Ringer solution) to suppress the hypovolemic stimulus for 
ADH release. Patients with cerebral salt wasting may 
require hypertonic saline to prevent circulatory collapse; 
some may respond to fludrocortisone. 
 
patients may require loop diuretics or dialysis, or both, to

patients may require loop diuretics or dialysis, or both, to 
correct increased total body water and sodium. 
Euvolemic
 
patients may respond to free water restriction alone.
Pseudohyponatremia from hypertriglyceridemia or 
hyperproteinemia requires no therapy except confirmation 
with the clinical laboratory. Translocational hyponatremia 
from glucose or mannitol can be managed with glucose 
correction or mannitol discontinuation (if possible). No 
specific therapy is necessary in patients with reset osmostat 
since they successfully regulate their serum sodium with 
fluid challenges and water deprivation.
Symptomatic and severe hyponatremia
 generally 
require hospitalization for careful monitoring of fluid bal
-
ance and weights, treatment, and frequent sodium checks. 
Inciting medications should be discontinued if possible.
Guidelines provide consensus recommendations for the 
optimal rate of sodium correction in symptomatic hypona
-
tremic patients. First, a relatively small increase of 4–6 mEq/L 
 
in the serum sodium may be all that is necessary to reverse 
the neurologic manifestations of symptomatic hyponatre
-
mia. Second, acute hyponatremia (eg, exercise-associated 
hyponatremia) with severe neurologic manifestations can be 
reversed rapidly with 100 mL of 3% hypertonic saline infused 
over 10 minutes (repeated twice as necessary). Third, correc
-
tion rates for chronic hyponatremia are low (6 mEq/L 
 
per 24 hours in patients at high risk for demyelination). 
Fourth, chronic hyponatremic patients at high risk for 
demyelination who are corrected too rapidly are candidates 
for treatment with a combination of DDAVP and intrave
-
nous dextrose 5% to relower the serum sodium. In severely 
symptomatic patients, the clinician should calculate the 
sodium deficit and deliver 3% hypertonic saline. The sodium 
deficit can be calculated by the following formula:
Sodium deficit = 
 
T
otal body water (TBW)
 
× (Desired serum Na – Actual serum Na)
where TBW is typically 50% of total mass in women and 
55% of total mass in men (Table 21–1). For example, a 
nonedematous, severely symptomatic 70 kg woman with a 
serum sodium of 124 mEq/L should have her serum 
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sodium corrected to approximately 130 mEq/L in the first 
24 hours. Her sodium deficit is calculated as:
Sodium deficit 
 
= 70 kg × 0.5 × (130 mE
q/L – 124 mEq/L)
 
= 210 mEq
3% hypertonic saline has a sodium concentration of 
 
513 mEq/1000 mL. The delivery rate for hypertonic saline 
can be calculated as:
Delivery rate 
 
= S
odium deficit/(513 mEq/1000 mL)/
 
24 hours
 
= 210 mEq / (513 mEq/1000 mL)/24 hours
 
= 17 mL/hour
In general, the 3% hypertonic saline infusion rate 
should be approximately 0.25 mL/kg body weight/h and 
should not exceed 0.5 mL/kg body weight/h; higher rates 
may represent a mathematical error or overly aggressive 
sodium correction. Hypertonic saline in hypervolemic 
patients can be hazardous, resulting in worsening volume 
overload, pulmonary edema, and ascites.
For patients who cannot adequately restrict free water 
or have an inadequate response to conservative measures, 
demeclocycline (300–600 mg orally twice daily) inhibits 
the effect of ADH on the distal tubule. Onset of action may 
require 1 week, and urinary concentrating ability may be 
permanently impaired, resulting in nephrogenic diabetes 
insipidus (DI) and even hypernatremia. Cirrhosis may 
increase the nephrotoxicity of demeclocycline.
Vasopressin 2 (V
2
) receptors mediate the diuretic effect 
of ADH, and V
2
 receptor antagonists are recommended for 
use in hospitalized patients with euvolemic SIADH or 
hyponatremic patients with heart failure. V
2
-receptor 
antagonists can be considered for patients who are unable to 
maintain a serum sodium above 120 mEq/L despite ade
-
quate resuscitation for hypovolemia, hypertonic saline 
therapy, or both. Tolvaptan (oral) and conivaptan (intrave
-
nous) are selective V
2
-receptor antagonists and available in 
the United States. The starting dose of tolvaptan is 15 mg 
orally daily; it can be increased to 30 mg daily and 60 mg 
daily at 24 hour intervals if hyponatremia persists or if the 
increase in sodium concentration is less than 4–6 mEq/L 
over the preceding 24 hours. Tolvaptan is contraindicated in 
patients with liver disease, including cirrhosis, and should 
not be used for longer than 30 days due to the potential for 
liver toxicity. Conivaptan is given as an intravenous loading 
dose of 20 mg delivered over 30 minutes, then as 20 mg 
continuously over 24 hours. Subsequent infusions may be 
administered every 1–3 days at 20–40 mg/day by continu
-
ous infusion. The standard free water restriction for hypo
-
natremic patients should be lifted for patients receiving V
2
 
antagonists since the aquaresis can result in excessive 
sodium correction in a fluid-restricted patient. Frequent 
monitoring of the serum sodium is necessary.
 
»
•	
Nephrology or endocrinology consultation should be 
considered in severe, symptomatic, refractory, or com
-
plicated cases of hyponatremia.
•	
Aggressive therapies with hypertonic saline, demeclo
-
cycline, V
2
 antagonists, or dialysis mandate specialist 
consultation.
•	
Consultation may be necessary with severe liver or heart 
disease.
 
»
Hospital admission is necessary for symptomatic patients 
or those requiring aggressive therapies for close monitor
-
ing and frequent laboratory testing.
Henry DA. In the clinic: hyponatremia. Ann Intern Med. 2015 
Aug 4;163(3):ITC1–19. [PMID: 26237763]
Hoorn EJ et al. Diagnosis and treatment of hyponatremia: com
-
pilation of the guidelines. J Am Soc Nephrol. 2017 May;28(5):
 
1340–9. [PMID: 28174217]
Sterns RH. Treatment of severe hyponatremia. Clin J Am Soc 
Nephrol. 2018 Apr 6;13(4):641–9. [PMID: 29295830]
 
»
Increased thirst and water intake are the main 
defense against hypernatremia.
 
»
Urine osmolality helps differentiate renal from 
nonrenal water loss.
 
»
Hypernatremia is defined as a sodium concentration greater

»
 
»
Hypernatremia is defined as a sodium concentration greater 
than 145 mEq/L. All patients with hypernatremia have 
hyperosmolality, unlike hyponatremic patients who can have 
a low, normal, or high serum osmolality. The hypernatremic 
patient is typically hypovolemic due to free water losses, 
although hypervolemia is frequently seen, often as an iatro
-
genic complication in hospitalized patients with impaired 
access to free water. Rarely, excessive sodium intake may 
cause hypernatremia. Hypernatremia in primary aldosteron
-
ism is mild and usually does not cause symptoms.
An intact thirst mechanism and access to water are the 
primary defense against hypernatremia. The hypothalamus 
can sense minimal changes in serum osmolality, triggering 
the thirst mechanism and increased water intake. Thus, 
whatever the underlying disorder (eg, dehydration, 
encephalopathy, lactulose or mannitol therapy, central and 
nephrogenic DI), excess water loss can cause hypernatre
-
mia only when adequate water intake is not possible.
 
»
When the patient is dehydrated, orthostatic hypotension and 
oliguria are typical findings. Because water shifts from the 
cells to the intravascular space to protect volume status, these 
symptoms may be delayed. Lethargy, irritability, and weakness 
are early signs. Hyperthermia, delirium, seizures, and coma 
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may be seen with severe hypernatremia (ie, sodium greater 
than 158 mEq/L). Symptoms in older adults may not be spe
-
cific; a recent change in consciousness is associated with a 
poor prognosis. Osmotic cerebral demyelination is an uncom
-
mon but reported consequence of severe hypernatremia.
1. Urine osmolality greater than 400 mOsm/kg—
Renal 
water-conserving ability is functioning.
a. Nonrenal los
ses
—
Hypernatremia will develop if 
water intake falls behind hypotonic fluid losses from exces
-
sive sweating, the respiratory tract, or bowel movements. 
Lactulose causes an osmotic diarrhea with loss of free water.
b. Renal losses
—
While severe hyperglycemia can cause 
translocational hyponatremia, progressive volume deple
-
tion from glucosuria can result in hypernatremia. Osmotic 
diuresis can occur with the use of mannitol or urea.
2
. Urine osmolality less than 250 mOsm/kg—
Hypernatre
-
mia with a dilute urine (osmolality less than 250 mOsm/kg) 
 
is characteristic of DI. Central DI results from inadequate 
ADH release. Nephrogenic DI results from renal insensi
-
tivity to ADH; common causes include lithium, demeclo
-
cycline, relief of urinary obstruction, interstitial nephritis, 
hypercalcemia, and hypokalemia.
 
»
Treatment
Treatment of hypernatremia includes correcting the cause of 
the fluid loss, replacing water, and replacing electrolytes (as 
needed). In response to increases in plasma osmolality, brain 
cells synthesize idiogenic osmoles, which are solutes that cause 
intracellular fluid shifts. Osmole production begins 4–6 hours 
after dehydration and takes several days to reach steady state. If 
hypernatremia is rapidly corrected, the osmotic imbalance 
may cause cerebral edema and potentially severe neurologic 
impairment. Fluids should be administered over a 48-hour 
period, aiming for serum sodium correction of approximately 
1 mEq/L/h (1 mmol/L/h). There is no consensus about the 
optimal rates of sodium correction in hypernatremia.
A. Choice of Type of Fluid for Replacement
1. Hypernatremia with hypovolemia—
patients should receive isotonic 0.9% normal saline to 
restore euvolemia and to treat hyperosmolality because 
normal saline (308 mOsm/kg or 308 mmol/kg) is hypo-
osmolar compared with the hyperosmolar plasma. After 
adequate volume resuscitation with normal saline, 0.45% 
saline or 5% dextrose (or both) can be used to replace any 
remaining free water deficit. Milder volume deficits may be 
treated with 0.45% saline and 5% dextrose.
2. Hypernatremia with euvolemia—
Water ingestion or 
intravenous 5% dextrose will result in the excretion of 
excess sodium in the urine. If the glomerular filtration rate 
(GFR) is decreased, diuretics will increase urinary sodium 
excretion but may impair renal concentrating ability, 
increasing the quantity of water that needs to be replaced.
3. Hypernatremia with hypervolemia—
Treatment 
includes 5% dextrose solution to reduce hyperosmolality. 
Loop diuretics may be necessary to promote natriuresis 
and lower total body sodium. In severe rare cases with 
kidney disease, hemodialysis may be necessary to correct 
the excess total body sodium and water.
B. Calculation of Water Deficit
Fluid replacement should include the free water deficit and 
additional maintenance fluid to replace ongoing and antic
-
ipated fluid losses.
1. Acute hypernatremia—
In acute dehydration without 
much solute loss, free water loss is similar to the weight 
loss. Initially, a 5% dextrose solution may be used. As cor
-
rection of water deficit progresses, therapy should continue 
with 0.45% saline with dextrose.
2. Chronic hypernatremia—
The water deficit is calculated 
to restore normal sodium concentration, typically 140 
mEq/L. Total body water (TBW) (Table 21–1) correlates 
with muscle mass and therefore decreases with advancing 
age, cachexia, and dehydration and is lower in women than

age, cachexia, and dehydration and is lower in women than 
in men. Current TBW equals 40–60% current body weight. 
(See Table 21–1.)
to/uni00A0b
er
ep
l
a
ce
d
Volu
me
(i
nL
)
/uni00A0C
u
rrent
TB
W/uni00A0
/uni00A0
[N
a]
/uni00A0
140
140
=×
−
+
 
»
Patients with refractory or unexplained hypernatremia 
should be referred for subspecialist consultation.
 
»
•	
Patients with symptomatic hypernatremia require hos
-
pitalization for evaluation and treatment.
•	
Significant comorbidities or concomitant acute illnesses, 
especially if contributing to hypernatremia, may neces
-
sitate hospitalization.
Liamis G et al. Evaluation and treatment of hypernatremia: a prac
-
tical guide for physicians. Postgrad Med. 2016;128(3):299–306. 
 
[PMID: 26813151]
Morley JE. Dehydration, hypernatremia, and hyponatremia. 
Clin Geriatr Med. 2015 Aug;31(3):389–99. [PMID: 26195098]
Muhsin SA et al. Diagnosis and treatment of hypernatremia. Best 
Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):189–203. 
 
[PMID: 27156758]
Tsipotis E et al. Hospital-associated hypernatremia spectrum 
and clinical outcomes in an unselected cohort. Am J Med. 
2018 Jan;131(1):72–82. [PMID: 28860033]
 
º
h
Y
p
EROSMOLAR DISORDERS & 
OSMOLAR GA
p
S
HYPEROSMOLALITY WITH TRANSIENT OR NO 
SIGNIFICANT SHIFT IN WATER
Urea and alcohol readily cross cell membranes and can pro
-
duce hyperosmolality. Urea is an ineffective osmole with lit
-
tle effect on osmotic water movement across cell 
 
m
embranes. 
 
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Alcohol quickly equilibrates between the intracellular and 
extracellular compartments, adding 22 mOsm/L for every 
100 mg/dL (or 21.7 mmol/L) of ethanol. Ethanol ingestion 
should be considered in any case of stupor or coma with an 
elevated osmol gap (measured osmolality
 
–
 
c
alculated 
osmolality greater than 10 mOsm/kg [10 mmol/kg]). 
Other toxic alcohols such as methanol and ethylene glycol 
cause an osmol gap and a metabolic acidosis with an 
increased anion gap (see Chapter 38). The combination of 
an increased anion gap metabolic acidosis and an osmol 
gap exceeding 10 mOsm/kg (or 10 mmol/kg) is not specific 
for toxic alcohol ingestion and may occur with alcoholic 
ketoacidosis or lactic acidosis (see Metabolic Acidosis).
Wiener SW . Toxicologic acid-base disorders. Emerg Med Clin 
North Am. 2014 Feb;32(1):149–65. [PMID: 24275173]
HYPEROSMOLALITY ASSOCIATED WITH 
SIGNIFICANT SHIFTS IN WATER
Increased concentrations of solutes that do not readily 
enter cells cause a shift of water from intracellular to extra
-
cellular. Hyperosmolality of effective osmoles (such as 
sodium and glucose) causes symptoms, primarily neuro
-
logic. The severity of symptoms depends on the degree of 
hyperosmolality and rapidity of development. In acute 
hyperosmolality, somnolence and confusion can appear 
when the osmolality exceeds 320–330 mOsm/kg (320–330 
mmol/kg); coma, respiratory arrest, and death can result 
when osmolality exceeds 340–350 mOsm/kg (340–350 
mmol/kg).
Kraut JA et al. Approach to the evaluation of a patient with an 
increased serum osmolal gap and high-anion-gap metabolic aci
-
dosis. Am J Kidney Dis. 2011 Sep;58(3):480–4. [PMID: 21794966]
 
º
DISORDERS OF 
p
OTASSIUM 
CONCENTRATION
 
»
Serum potassium level less than 3.5 mEq/L 
(3.5 mmol/L).
 
»
Severe hypokalemia may induce arrhythmias and 
rhabdomyolysis.
 
»
Transtubular potassium concentration gradient 
(TTKG) can distinguish renal from nonrenal loss of 
potassium.
 
»
Hypokalemia can result from insufficient dietary potas
-
sium intake, intracellular shifting of potassium from the 
extracellular space, extrarenal potassium loss, or renal 
potassium loss (Table 21–3). Cellular uptake of potassium 
is increased by insulin and beta-adrenergic stimulation 
and blocked by alpha-adrenergic stimulation. Aldosterone 
is an important regulator of total body potassium, increas
-
ing potassium secretion in the distal renal tubule. The 
most common cause of hypokalemia, especially in devel
-
oping countries, is gastrointestinal loss from infectious 
diarrhea. The potassium concentration in intestinal 
 
secretion is ten times higher (80 mEq/L) than in gastric 
secretions. Hypokalemia in the presence of acidosis sug
-
gests profound potassium depletion and requires urgent 
treatment. Self-limited hypokalemia occurs in 50–60% of 
trauma patients, perhaps related to enhanced release of 
epinephrine.
Hypokalemia induced by beta-2-adrenergic agonists 
and diuretics may substantially increase the risk of arrhyth
-
mias. Hypokalemia increases the likelihood of digitalis 
toxicity. Numerous genetic mutations affect fluid and elec
-
trolyte metabolism, including disorders of potassium 
metabolism (Table 21–4).
Magnesium is an important cofactor for potassium 
uptake and maintenance of intracellular potassium levels. 
Loop diuretics (eg, furosemide) cause substantial renal 
potassium and magnesium losses. Magnesium depletion 
should be considered in refractory hypokalemia.
Table 21–3.
 
Causes of hypokalemia.
Decreased potassium intake
p
otassium shif
t into the cell
Alkalosis
Barium intoxication
Beta-adrenergic agonists
Increased postprandial secretion of insulin
Periodic paralysis (hypokalemic)
Trauma (via beta-adrenergic stimulation)
Renal potassium loss
Increased aldosterone (mineralocorticoid) effects
Primary hyperaldosteronism

Secondary aldosteronism (dehydration, heart failure)
Bartter syndrome, Gitelman syndrome
Cushing syndrome, ectopic ACTH-producing tumor
Congenital abnormality of steroid metabolism (eg, adreno
-
genital syndrome, 17-alpha-hydroxylase defect, apparent 
mineralocorticoid excess, 11-beta-hydroxylase deficiency)
Licorice (European)
Renin-producing tumor
Renovascular hypertension, malignant hypertension
Increased flow to distal nephron
Diuretics (furosemide, thiazides)
Salt-losing nephropathy, polyuria
Hypomagnesemia
Unreabsorbable anion
Bicarbonaturia
Carbenicillin, penicillin
Hippurate from toluene use or glue sniffing
Renal tubular acidosis (type I or II)
Extrarenal potassium loss
Vomiting, diarrhea, laxative abuse
Villous adenoma, Zollinger-Ellison syndrome
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»
Muscular weakness, fatigue, and muscle cramps are fre
-
quent complaints in mild to moderate hypokalemia. Gas
-
trointestinal smooth muscle involvement may result in 
constipation or ileus. Flaccid paralysis, hyporeflexia, 
hypercapnia, tetany, and rhabdomyolysis may be seen with 
severe hypokalemia (less than 2.5 mEq/L). The presence 
 
of hypertension may be a clue to the diagnosis of hypoka
-
lemia from aldosterone or mineralocorticoid excess 
 
(Table 21–4). Renal manifestations include nephrogenic DI 
and interstitial nephritis.
Urinary potassium concentration is low (less than 
20 mEq/L) as a result of extrarenal loss (eg, diarrhea, vom
-
iting) and inappropriately high (greater than 40 mEq/L) 
with renal loss (eg, mineralocorticoid excess, Bartter syn
-
drome, Liddle syndrome) (Table 21–3).
The transtubular [K
+
] gradient (TTKG) is a simple and 
rapid evaluation of net potassium secretion. TTKG is cal
-
culated as follows:
TTK
G
Urine/uni00A0
K/
Plasma
K
Urin
eO
sm/Plasm
aO
sm
/uni00A0
=
++
Hypokalemia with a TTKG more than 4 suggests renal 
potassium loss with increased distal K
+
 secretion. In such 
cases, plasma renin and aldosterone levels are helpful in 
differential diagnosis. The presence of nonabsorbed anions, 
such as bicarbonate, increases the TTKG.
C. Electrocardiogram
The electrocardiogram (ECG) may show decreased 
amplitude and broadening of T waves, prominent U 
waves, 
 
p
remature ventricular contractions, and depressed 
ST segments.
 
»
Treatment
Oral potassium supplementation is the safest and easiest 
treatment for mild to moderate deficiency. Dietary potas
-
sium is almost entirely coupled to phosphate—rather than 
chloride—and is therefore not effective in correcting 
potassium loss associated with chloride depletion from 
diuretics or vomiting. In the setting of abnormal kidney 
function and mild to moderate diuretic dosage, 
 
20 mEq/day of oral potassium is generally sufficient to 
prevent hypokalemia, but 40–100 mEq/day over a period 
of days to weeks is needed to treat hypokalemia and fully 
replete potassium stores.
Intravenous potassium is indicated for patients with 
severe hypokalemia and for those who cannot take oral 
supplementation. For severe deficiency, potassium may be 
given through a peripheral intravenous line in a concentra
-
tion up to 40 mEq/L and at rates up to 10 mEq/h. Concen
-
trations of up to 20 mEq/h may be given through a central 
venous catheter. Continuous ECG monitoring is indicated, 
and the serum potassium level should be checked every 
Table 21–4.
 
Genetic disorders associated with 
 
electrolyte metabolism disturbances.
Disease
Site of Mutation
p
otassium
Hypokalemic periodic 
paralysis
Dihydropyridine-sensitive 
 
skeletal muscle voltage-
 
gated calcium channel
Bartter syndrome
Na
+
-K
+
-2Cl
–
 cotransporter, K
+
 
channel (ROMK), or Cl
–
 channel 
of thick ascending limb of 
Henle (hypofunction), barttin
Gitelman syndrome
Thiazide-sensitive 
Na
+
-Cl
–
 cotransporter
Beta or gamma subunit of 
amiloride-sensitive Na
+
 
channel (hyperfunction)
Apparent 
 
mineralocorticoid 
excess
11-beta-hydroxysteroid 
 
dehydrogenase (failure to 
 
inactivate cortisol)
Glucocorticoid-
 
remediable 
hyperaldosteronism
Regulatory sequence of 
 
controls aldosterone 
synthase inappropriately
Hyperkalemic periodic 
paralysis
Alpha subunit of calcium 
 
channel
Pseudohypoaldoste
-
ronism type I
+
 
channel (hypofunction)
Pseudohypoaldosteron
-
ism type II 
 
(
Gordon 
syndrome)
WNK2, WNK4
Calcium
Familial hypocalciuric 
hypercalcemia
Ca
2+
-sensing protein 
(hypofunction)
Familial hypocalcemia
Ca
2+
(hyperfunction)
p
hosphate
Hypophosphatemic rickets
PEX
 gene, FGF23
Magnesium
Hypomagnesemia- 
 
hypercalciuria 
 
syndrome
Paracellin-1
Water

Ca
2+
p
hosphate
PEX
Magnesium
 
syndrome
Water
Nephrogenic diabetes 
insipidus
V
2
 receptor (Type 1), 
 
aquaporin-2
Acid-base
Proximal RTA
Na
+
 HCO
3
–
Distal RTA
Cl
–
 HCO
3
–
 exchanger, H
+
-ATPase
Proximal and distal RTA
Carbonic anhydrase II
FGF23, fibroblast growth factor 23; RTA, renal tubular acidosis; 
 
V
2
, vasopressin.
CMDT19_Ch21_p0898-p0925.indd   906

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CMDT 2019
3–6 hours. Avoid glucose-containing fluid to prevent fur
-
ther shifts of potassium into the cells. Magnesium defi
-
ciency should be corrected, particularly in refractory 
 
»
Patients with unexplained hypokalemia, refractory hypo
-
kalemia, or suggestive alternative diagnoses (eg, aldoste
-
ronism or hypokalemic periodic paralysis) should be 
referred for endocrinology or nephrology consultation.
 
»
Patients with symptomatic or severe hypokalemia, espe
-
cially with cardiac manifestations, require cardiac monitor
-
ing, potassium supplementation, and frequent laboratory 
testing.
Gumz ML et al. An integrated view of potassium homeostasis. N 
Engl J Med. 2015 Jul 2;373(1):60–72. Erratum in: N Engl J 
Med. 2015 Sep 24;373(13):1281. [PMID: 26132942]
Palmer BF et al. Physiology and pathophysiology of potassium 
homeostasis. Adv Physiol Educ. 2016 Dec;40(4):480–90. 
[PMID: 27756725]
Wu KL et al. Identification of the causes for chronic hypokale
-
mia: importance of urinary sodium and chloride excretion. 
Am J Med. 2017 Jul;130(7):846–55. [PMID: 28213045]
 
»
Serum potassium level greater than 5.0 mEq/L 
 
(5.0 mmol/L).
 
»
Hyperkalemia may develop in patients taking ACE 
inhibitors, angiotensin-receptor blockers, potas
-
sium-sparing diuretics, or their combination, even 
with no or only mild kidney dysfunction.
 
»
The ECG may be normal despite life-threatening 
 
»
Measurement of plasma potassium level differen
-
tiates potassium leak from blood cells from truly 
elevated serum potassium.
 
»
Rule out extracellular potassium shift from the 
cells in acidosis and assess renal potassium 
 
»
Hyperkalemia usually occurs in patients with advanced 
kidney disease but can also develop with normal kidney 
function (Table 21–5). Acidosis causes intracellular potas
-
sium to shift extracellularly. Serum potassium concentra
-
tion rises about 0.7 mEq/L for every decrease of 0.1 pH 
unit during acidosis. Fist clenching during venipuncture 
may raise the potassium concentration by 1–2 mEq/L by 
causing acidosis and potassium shift from cells. In the 
absence of acidosis, serum potassium concentration rises 
about 1 mEq/L when there is a total body potassium excess 
of 1–4 mEq/kg. However, the higher the serum potassium 
concentration, the smaller the excess necessary to raise the 
potassium levels further.
Mineralocorticoid deficiency from Addison disease or 
chronic kidney disease (CKD) is another cause of hyperka
-
lemia with decreased renal excretion of potassium. Miner
-
alocorticoid resistance due to genetic disorders, interstitial 
kidney disease, or urinary tract obstruction also leads to 
ACE inhibitors or angiotensin-receptor blockers 
(ARBs) may cause hyperkalemia. The concomitant use of 
spironolactone, eplerenone, or beta-blockers further 
increases the risk of hyperkalemia. Thiazide or loop diuret
-
ics and sodium bicarbonate may minimize hyperkalemia. 
Persistent mild hyperkalemia in the absence of ACE inhibi
-
tor or ARB therapy is usually due to type IV renal tubular 
acidosis (RTA). Heparin inhibits aldosterone production in 
the adrenal glands, causing hyperkalemia.
Table 21–5.
 
Causes of hyperkalemia.
Spurious/
p
seudoh
yperkalemia
Leakage from erythrocytes when separation of serum from clot 
is delayed (plasma K
+
 normal)
Marked thrombocytosis or leukocytosis with release of 
 
intracellular K
+
 (plasma K
+
 normal)
Repeated fist clenching during phlebotomy, with release of K
+
 
from forearm muscles
Specimen drawn from arm with intravenous K
+
 infusion
Decreased K
+
 excretion
Kidney disease, acute and chronic
Renal secretory defects (may or may not have reduced kidney 
function): kidney transplant, interstitial nephritis, systemic 
lupus erythematosus, sickle cell disease, amyloidosis, 
obstructive nephropathy

Hypoaldosteronism
 
A
ddison disease 
 
T
ype IV renal tubular acidosis 
 
Heparin
Drugs that inhibit potassium excretion: spironolactone, 
 
eplerenone, drospirenone, NSAIDs, ACE inhibitors, 
 
angiotensin II receptor blockers, triamterene, amiloride, 
 
trimethoprim, pentamidine, cyclosporine, tacrolimus
Shift of K
+
 from within the cell
Massive release of intracellular K
+
 in burns, rhabdomyolysis, 
 
hemolysis, severe infection, internal bleeding, vigorous exercise
Metabolic acidosis (in the case of organic acid accumulation—
eg, lactic acidosis—a shift of K
+
 does not occur since organic 
acid can easily move across the cell membrane)
Hypertonicity (solvent drag)
Insulin deficiency (metabolic acidosis may not be apparent)
Hyperkalemic periodic paralysis
Drugs: succinylcholine, arginine, digitalis toxicity, 
 
beta-
 
adrenergic antagonists
Alpha-adrenergic stimulation?
Excessive intake of K
+
Especially in patients taking medications that decrease 
 
potassium secretion (see above)
 
anti-inflammatory drugs.
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Trimethoprim is structurally similar to amiloride and 
triamterene, and all three drugs inhibit renal potassium 
excretion through suppression of sodium channels in the 
distal nephron.
Cyclosporine and tacrolimus can induce hyperkalemia 
in organ transplant recipients, especially kidney trans
-
plant patients, partly due to suppression of the basolateral 
Na
+
–K
+
-ATPase in principal cells. Hyperkalemia is com
-
monly seen in HIV patients and has been attributed to 
impaired renal excretion of potassium due to pentamidine 
or trimethoprim-sulfamethoxazole or to hyporeninemic 
hypoaldosteronism.
 
»
Hyperkalemia impairs neuromuscular transmission, caus
-
ing muscle weakness, flaccid paralysis, and ileus. Electro
-
cardiography is not a sensitive method for detecting 
hyperkalemia, since nearly half of patients with a serum 
potassium level greater than 6.5 mEq/L will not manifest 
ECG changes. ECG changes in hyperkalemia include bra
-
dycardia, PR interval prolongation, peaked T waves, QRS 
widening, and biphasic QRS–T complexes. Conduction 
disturbances, such as bundle branch block and atrioven
-
tricular block, may occur. Ventricular fibrillation and 
 
cardiac arrest are terminal events.
 
»
Inhibitors of the renin-angiotensin-aldosterone axis (ie, 
ACE inhibitors, ARBs, and spironolactone) and potas
-
sium-sparing diuretics (eplerenone, triamterene) should be 
used cautiously in patients with heart failure, liver failure, 
and kidney disease. Laboratory monitoring should be per
-
formed within 1 week of drug initiation or dosage increase.
 
»
Treatment
The diagnosis should be confirmed by repeat laboratory 
testing to rule out spurious hyperkalemia, especially in the 
absence of medications that cause hyperkalemia or in 
patients without kidney disease or a previous history of 
hyperkalemia. Plasma potassium concentration can be 
measured to avoid spurious hyperkalemia due to potas
-
sium leakage out of red cells, white cells, and platelets. 
Kidney dysfunction should be ruled out at the initial 
assessment.
Treatment consists of withholding exogenous potas
-
sium, identifying the cause, reviewing the patient’s medica
-
tions and dietary potassium intake, and correcting the 
hyperkalemia. Emergent treatment is indicated when 
 
cardiac toxicity, muscle paralysis, or severe hyperkalemia 
(potassium greater than 6.5 mEq/L) is present, even in the 
absence of ECG changes. Insulin, bicarbonate, and beta-
agonists shift potassium intracellularly within minutes of 
administration (Table 21–6). Intravenous calcium may be 
given to antagonize the cell membrane effects of potas
-
sium, but its use should be restricted to life-threatening 
hyperkalemia in patients taking digitalis because hypercal
-
cemia may cause digitalis toxicity. Hemodialysis may be 
required to remove potassium in patients with acute or 
chronic kidney injury. Patiromer binds potassium in the 
intestine and is FDA-approved for the treatment of chronic 
hyperkalemia in patients with CKD who take at least one 
drug that inhibits the renin-angiotensin-aldosterone sys
-
tem. Patiromer may decrease the absorption of orally 
administered drugs. Another potassium binder sodium 
zirconium cyclosilicate has been studied for chronic hyper
-
kalemia treatment but has not received FDA approval. 
Neither agent has been studied in acute hyperkalemia or in 
patients with end-stage renal disease. Sodium polystyrene 
has been widely used for decades although its efficacy and 
safety have been questioned. It may not increase potassium 
excretion above laxatives alone and has been associated 
with colonic necrosis, both with and without sorbitol coad
-
ministration. The FDA has recommended that sodium 
polystyrene should not be administered in sorbitol, but the 
mixture remains commonly available. Its use should be 
restricted to patients with life-threatening hyperkalemia

restricted to patients with life-threatening hyperkalemia 
when dialysis is not available and other therapies (eg, 
diuretics) have failed. Sodium polystyrene is contraindi
-
cated in patients with risk factors for colonic necrosis, such 
as bowel obstruction, ileus, and postoperative state.
 
»
•	
Patients with hyperkalemia from kidney disease and 
reduced renal potassium excretion should see a 
•	
Transplant patients may need adjustment of their 
immunosuppression regimen by transplant specialists.
 
»
Patients with severe hyperkalemia greater than 6 mEq/L, 
any degree of hyperkalemia associated with ECG changes, 
or concomitant illness (eg, tumor lysis, rhabdomyolysis, 
metabolic acidosis) should be sent to the emergency 
department for immediate treatment.
Kovesdy CP et al. Potassium homeostasis in health and disease: 
a scientific workshop cosponsored by the National Kidney 
Foundation and the American Society of Hypertension. J Am 
Soc Hypertens. 2017 Dec;11(12):783–800. [PMID: 29030153]
Kovesdy CP . Updates in hyperkalemia: outcomes and therapeutic 
strategies. Rev Endocr Metab Disord. 2017 Mar;18(1):41–7. 
 
[PMID: 27600582]
Montford JR et al. How dangerous is hyperkalemia? J Am Soc 
Nephrol. 2017 Nov;28(11):3155–65. [PMID: 28778861]
 
º
DISORDERS OF CALCIUM 
The normal total plasma (or serum) calcium concentration 
is 8.5–10.5 mg/dL (or 2.1–2.6 mmol/L). Ionized calcium 
(normal: 4.6–5.3 mg/dL [or 1.15–1.32 mmol/L]) is physi
-
ologically active and necessary for muscle contraction and 
nerve function.
The calcium-sensing receptor, a transmembrane pro
-
tein that detects the extracellular calcium concentration, is 
in the parathyroid gland and the kidney. Functional defects 
in this protein are associated with diseases of abnormal 
calcium metabolism such as familial hypocalcemia and 
familial hypocalciuric hypercalcemia (Table 21–4).
CMDT19_Ch21_p0898-p0925.indd   908

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Table 21–6.
 
Treatment of hyperkalemia.
Immediate
Modality
Mechanism of 
Action
Onset
Duration
p
r
escription
K
+
 Removed From Body
Calcium
Antagonizes cardiac 
conduction 
0–5 minutes
1 hour
Calcium gluconate 10%, 5–30 mL 
intravenously; or calcium chlo
-
ride 5%, 5–30 mL intravenously
None
Bicarbonate
Distributes K
+
 into 
cells
15–30 minutes
1–2 hours
NaHCO
3
, 50–100 mEq 
Note:
 Sodium bicarbonate may 
not be effective in end-stage 
kidney disease patients; dialysis 
is more expedient and effective. 
Some patients may not tolerate 
the additional sodium load of 
bicarbonate therapy.
None
Insulin
+
 into 
cells
15–60 minutes
4–6 hours
Regular insulin, 5–10 units intra
-
venously, plus glucose 50%, 
25 g intravenously
None
Albuterol
+
 into 
cells
2–4 hours
Nebulized albuterol, 10–20 mg in 
4 mL normal saline, inhaled 
over 10 minutes
Note:
 Much higher doses are nec
-
essary for hyperkalemia therapy 
(10–20 mg) than for airway 
 
disease (2.5 mg).
None
Urgent
Modality
Action
p
r
K
+
Loop diuretic
Renal K
+
 excretion
0.5–2 hours
Furosemide, 40–160 mg 
Note:
 Diuretics may not be effec
-
tive in patients with acute and 
chronic kidney diseases.
Variable
Sodium 
 
polystyrene 
sulfonate (eg, 
Kayexalate)
Ion-exchange resin 
binds K
+
1–3 hours
Oral: 15–60 g in 20% sorbitol 
 
(60–240 mL)
Rectal: 30–60 g in 20% sorbitol
Note:
 Resins with sorbitol may 
cause bowel necrosis and intes
-
tinal perforation, especially in 
patients with abnormal bowel 
function.
0.5–1 mEq/g resin
Hemodialysis
1
Extracorporeal K
+
 
removal
1–8 hours
Dialysate [K
+
] 0–1 mEq/L
Note:
 A fast and effective therapy 
for hyperkalemia, hemodialysis 
can be delayed by vascular 
access placement and equip
-
ment and/or staffing availabil
-
ity. Serum K can be rapidly 
corrected within minutes, but 
post-dialysis rebound can 
occur.
25–50 mEq/h
Note:
 Serum K can be 
 
rapidly and effectively 
corrected within min
-
utes; post-dialysis 
rebound can occur. 
Hemodialysis can be 
delayed by vascular 
access placement and 
equipment and/or 
staffing availability.
Peritoneal 
dialysis
Peritoneal K
+
 
removal
1–4 hours
Frequent exchanges
200–300 mEq
1
Can be both acute immediate and urgent treatment of hyperkalemia.
Modified and reproduced, with permission, from Cogan MG. 
Fluid and Electrolytes: Physiology and Pathophysiology
. McGraw-Hill, 1991.
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»
Often mistaken as a neurologic disorder.
 
»
Decreased serum parathyroid hormone (PTH), 
vitamin D, or magnesium levels.
 
»
Despite a low total serum calcium, calcium metab
-
olism is likely normal if ionized calcium level is 
normal.
 
»
The most common cause of low total serum calcium is 
hypoalbuminemia. When serum albumin concentration 
is  lower than 4 g/dL (40 g/L), serum Ca
2+
 concentration is 
reduced by 0.8–1 mg/dL (0.20–0.25 mmol/L) for every 1 g/dL 
 
(10 g/L) of albumin.
The most accurate measurement of serum calcium is 
the ionized calcium concentration. True hypocalcemia 
(decreased ionized calcium) implies insufficient action of 
PTH or active vitamin D. Important causes of hypocalce
-
mia are listed in Table 21–7.
The most common cause of hypocalcemia is advanced 
CKD, in which decreased production of active vitamin D
3
 
(1,25 dihydroxyvitamin D
3
) and hyperphosphatemia both 
play a role (see Chapter 22). Some cases of primary hypo
-
parathyroidism are due to mutations of the calcium-
 
sensing receptor in which inappropriate suppression of 
PTH release leads to hypocalcemia (see Chapter 26). Mag
-
nesium depletion reduces both PTH release and tissue 
responsiveness to PTH, causing hypocalcemia. Hypocalce
-
mia in pancreatitis is a marker of severe disease. Elderly 
hospitalized patients with hypocalcemia and hypophospha
-
temia, with or without an elevated PTH level, are likely 
vitamin D deficient.
 
»
Hypocalcemia increases excitation of nerve and muscle 
cells, primarily affecting the neuromuscular and cardiovas
-
cular systems. Spasm of skeletal muscle causes cramps and 
tetany. Laryngospasm with stridor can obstruct the airway. 
Convulsions, perioral and peripheral paresthesias, and 
abdominal pain can develop. Classic physical findings 
include Chvostek sign (contraction of the facial muscle in 
response to tapping the facial nerve) and Trousseau sign 
(carpal spasm occurring with occlusion of the brachial 
artery by a blood pressure cuff). QT prolongation predis
-
poses to ventricular arrhythmias. In chronic hypoparathy
-
roidism, cataracts and calcification of basal ganglia may 
appear (see Chapter 26).
Serum calcium concentration is low (less than 8.5 mg/dL 
[2.1 mmol/L]). In true hypocalcemia, the ionized serum 
calcium concentration is also low (less than 4.6 mg/dL 
[1.15 mmol/L]). Serum phosphate is usually elevated in 
hypoparathyroidism or in advanced CKD, whereas it is 
suppressed in early CKD or vitamin D deficiency.
Serum magnesium concentration is commonly low. In 
respiratory alkalosis, total serum calcium is normal but 
ionized calcium is low. The ECG shows a prolonged QT 
interval.
 
»
Treatment
1
A. Severe, Symptomatic Hypocalcemia
In the presence of tetany, arrhythmias, or seizures, intrave
-
nous calcium gluconate is indicated.
1
 Because of the short 
duration of action, continuous calcium infusion is usually 
required. Ten to 15 milligrams of calcium per kilogram 
body weight, or six to eight 10-mL vials of 10% calcium 
gluconate (558–744 mg of calcium), is added to 1 L of 
D
5
W and infused over 4–6 hours. By monitoring the 
serum calcium level frequently (every 4–6 hours), the 
infusion rate is adjusted to maintain the serum calcium 
level at 7–8.5 mg/dL.
B. Asymptomatic Hypocalcemia
Oral calcium (1–2 g) and vitamin D preparations, includ
-
ing active vitamin D sterols, are used. Calcium carbonate 
 
is well tolerated and less expensive than many other cal
-
cium tablets. A check of urinary calcium excretion is 
Table 21–7.
 
Causes of hypocalcemia.
Decreased intake or absorption
Malabsorption
Small bowel bypass, short bowel
Vitamin D deficit (decreased absorption, decreased production 
of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D)
Increased loss
Diuretic therapy
Endocrine disease

Hypoparathyroidism (genetic, acquired; including 
 
hypomagnesemia and hypermagnesemia)
Post-parathyroidectomy (hungry bone syndrome)
Pseudohypoparathyroidism
Calcitonin secretion with medullary carcinoma of the thyroid
Associated diseases
Rhabdomyolysis
p
hysiologic causes
Decreased serum albumin
1
Decreased end-organ response to vitamin D
Hyperphosphatemia
Aminoglycoside antibiotics, plicamycin, loop diuretics, foscarnet
1
Ionized calcium concentration is normal.
1
See also Chapter 26 for discussion of the treatment of hypoparathyroidism.
CMDT19_Ch21_p0898-p0925.indd   910

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recommended after the initiation of therapy because 
hypercalciuria (urine calcium excretion greater than 
300 mg or 7.5 mmol per day) or urine calcium:creatinine 
ratio greater than 0.3 may impair kidney function in these 
patients. The low serum calcium associated with hypoalbu
-
minemia does not require replacement therapy. If serum 
Mg
2+
 is low, therapy must include magnesium replacement, 
which by itself will usually correct hypocalcemia.
 
»
Patients with complicated hypocalcemia from hypopara
-
thyroidism, familial hypocalcemia, or CKD require referral 
to an endocrinologist or nephrologist.
 
»
Patients with tetany, arrhythmias, seizures, or other symp
-
toms of hypocalcemia require immediate therapy.
Aberegg SK. Ionized calcium in the ICU: should it be measured 
and corrected? Chest. 2016 Mar;149(3):846–55. [PMID: 
26836894]
Rosner MH. Hypocalcemia in a patient with cancer. Clin J Am 
Soc Nephrol. 2017 Apr 3;12(4):696–9. [PMID: 28274993]
Schafer AL et al. Hypocalcemia: diagnosis and treatment. In: 
 
De Groot LJ et al, editors. Endotext. 2016 Jan 3. [PMID: 
25905251]
 
»
Most common causes: primary hyperparathyroid
-
ism and malignancy-associated hypercalcemia.
 
»
Hypercalciuria usually precedes hypercalcemia.
 
»
Asymptomatic, mild hypercalcemia (above 
10.5 mg/dL [2.6 mmol/L]) is usually due to primary 
hyperparathyroidism; symptomatic, severe hyper
-
calcemia (above 14 mg/dL [3.5 mmol/L]) is due to 
hypercalcemia of malignancy.
 
»
Important causes of hypercalcemia are listed in Table 21–8. 
Primary hyperparathyroidism and malignancy account for 
90% of cases. Primary hyperparathyroidism is the most 
common cause of hypercalcemia (usually mild) in ambula
-
tory patients. Chronic hypercalcemia (over 6 months) or 
some manifestation such as nephrolithiasis also suggests a 
benign cause. Tumor production of PTH-related proteins 
(PTHrP) is the most common paraneoplastic endocrine 
syndrome, accounting for most cases of hypercalcemia in 
inpatients. The neoplasm is clinically apparent in nearly all 
cases when the hypercalcemia is detected, and the progno
-
sis is poor. Granulomatous diseases, such as sarcoidosis 
and tuberculosis, cause hypercalcemia via overproduction 
of active vitamin D
3
 (1,25 dihydroxyvitamin D
3
).
Milk-alkali syndrome has had a resurgence due to 
 
calcium ingestion for prevention of osteoporosis. Heavy 
calcium carbonate intake causes hypercalcemic acute kid
-
ney injury, likely from renal vasoconstriction. The 
decreased GFR impairs bicarbonate excretion, while hyper
-
calcemia stimulates proton secretion and bicarbonate 
reabsorption. Metabolic alkalosis decreases calcium excre
-
tion, maintaining hypercalcemia.
Hypercalcemia causes nephrogenic DI through activa
-
tion of calcium-sensing receptors in collecting ducts, 
which reduces ADH-induced water permeability. Volume 
depletion further worsens hypercalcemia.
 
»
The history and physical examination should focus on the 
duration of hypercalcemia and evidence for a neoplasm. 
Hypercalcemia may affect gastrointestinal, kidney, and 
neurologic function. Mild hypercalcemia is often asymp
-
tomatic. Symptoms usually occur if the serum calcium is 
higher than 12 mg/dL (3 mmol/L) and tend to be more 
severe if hypercalcemia develops acutely. Symptoms 
include constipation and polyuria, except in hypocalciuric 
hypercalcemia, in which polyuria is absent. Other symp
-
toms include nausea, vomiting, anorexia, peptic ulcer dis
-
ease, renal colic, and hematuria from nephrolithiasis. 
Polyuria from hypercalciuria-induced nephrogenic DI can 
result in volume depletion and acute kidney injury. Neuro
-
logic manifestations range from mild drowsiness to weak
-
ness, depression, lethargy, stupor, and coma in severe 
Table 21–8.
 
Causes of hypercalcemia.

-
-
 
Increased intake or absorption
Milk-alkali syndrome
Vitamin D or vitamin A excess
Primary hyperparathyroidism
Secondary or tertiary hyperparathyroidism (usually associated 
with hypocalcemia)
Adrenal insufficiency
Neoplastic diseases
Tumors producing PTH-related proteins (ovary, kidney, lung)
Plasma cell myeloma (elaboration of osteoclast-activating 
factor)
Lymphoma (occasionally from production of calcitriol)
Miscellaneous causes
Thiazide diuretics
Granulomatous diseases (production of calcitriol)
Paget disease of bone
Hypophosphatasia
Immobilization
Familial hypocalciuric hypercalcemia
Complications of kidney transplantation
Lithium intake
PTH, parathyroid hormone.
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hypercalcemia. Ventricular ectopy and idioventricular 
rhythm occur and can be accentuated by digitalis.
The ionized calcium exceeds 1.32 mmol/L. A high serum 
chloride concentration and a low serum phosphate con
-
centration in a ratio greater than 33:1 (or greater than 
102 if SI units are utilized) suggests primary hyperpara
-
thyroidism where PTH decreases proximal tubular phos
-
phate reabsorption. A low serum chloride concentration 
with a high serum bicarbonate concentration, along with 
elevated BUN and creatinine, suggests milk-alkali syn
-
drome. Severe hypercalcemia (greater than 15 mg/dL 
[3.75 mmol/L]) generally occurs in malignancy. More 
than 300 mg (7.5 mmol) per day of urinary calcium 
excretion suggests hypercalciuria; less than 100 mg 
 
(2.5 mmol) per day suggests hypocalciuria. Hypercalciuric 
patients—such as those with malignancy or those receiv
-
ing oral active vitamin D therapy—may easily develop 
hypercalcemia in case of volume depletion. Serum phos
-
phate may or may not be low, depending on the cause. 
Hypocalciuric hypercalcemia occurs in milk-alkali syn
-
drome, thiazide diuretic use, and familial hypocalciuric 
hypercalcemia.
The chest radiograph may reveal malignancy or granu
-
lomatous disease. The ECG can show a shortened QT 
interval. Measurements of PTH and PTHrP help distin
-
guish between hyperparathyroidism (elevated PTH) and 
malignancy-associated hypercalcemia (suppressed PTH, 
elevated PTHrP).
 
»
Treatment
Until the primary cause can be identified and treated, renal 
excretion of calcium is promoted through aggressive 
hydration and forced calciuresis. The tendency in hypercal
-
cemia is hypovolemia from nephrogenic DI. In dehydrated 
patients with normal cardiac and kidney function, 0.45% 
saline or 0.9% saline can be given rapidly (250–500 mL/h). 
 
A meta-analysis questioned the efficacy and safety profile 
of intravenous furosemide for hypercalcemia. Thiazides 
can worsen hypercalcemia.
Bisphosphonates are the treatment of choice for hyper
-
calcemia of malignancy. Although they are safe, effective, 
and normalize calcium in more than 70% of patients, 
bisphosphonates may require up to 48–72 hours before 
reaching full therapeutic effect. Calcitonin may be helpful 
in the short-term until bisphosphonates reach therapeutic 
levels. In emergency cases, dialysis with low calcium dialy
-
sate may be needed. Denosumab, a monoclonal antibody 
against RANKL inhibits osteoclasts, reducing bone resorp
-
tion and serum calcium levels; this medication is FDA-
approved for malignancy-associated hypercalcemia 
refractory to bisphosphonate therapy. The calcimimetic 
agent cinacalcet suppresses PTH secretion and decreases 
serum calcium concentration; it has been recommended 
for use in patients with symptomatic or severe primary 
hyperparathyroidism who are unable to undergo parathy
-
roidectomy and patients with inoperable parathyroid carci
-
noma. (See Chapters 26 and 39.)
Typically, if dialysis patients do not receive proper sup
-
plementation of calcium and active vitamin D, hypocalce
-
mia and hyperphosphatemia develop. On the other hand, 
hypercalcemia can sometimes develop, particularly in the 
setting of severe secondary hyperparathyroidism, charac
-
terized by high PTH levels and subsequent release of cal
-
cium from bone. Therapy may include intravenous vitamin 
D, which further increases the serum calcium concentra
-
tion. Another type of hypercalcemia occurs when PTH 
levels are low. Bone turnover is decreased, which results in 
a low buffering capacity for calcium. When calcium is 
administered in calcium-containing phosphate binders or 
dialysate, or when vitamin D is administered, hypercalce
-
mia results. Hypercalcemia in dialysis patients usually 
occurs in the presence of hyperphosphatemia, and meta
-
static calcification may occur. Malignancy should be con
-
sidered as a cause of the hypercalcemia.
 
»
•

-
-
 
»
•	
Patients may require referral to an oncologist or endo
-
crinologist depending on the cause of hypercalcemia.
•	
Patients with granulomatous diseases (eg, tuberculosis 
and other chronic infections, granulomatosis with poly
-
angiitis, sarcoidosis) may require assistance from 
 
infectious disease specialists, rheumatologists, or 
 
»
•	
Patients with symptomatic or severe hypercalcemia 
require immediate treatment.
•	
Unexplained hypercalcemia with associated conditions, 
such as acute kidney injury or suspected malignancy, 
may require urgent treatment and expedited evaluation.
Ahmad S et al. Hypercalcemic crisis: a clinical review. Am J Med. 
2015 Mar;128(3):239–45. [PMID: 25447624]
Bazari H et al. Case records of the Massachusetts General Hos
-
pital. Case 24-2016. A 66-year-old man with malaise, weak
-
ness, and hypercalcemia. N Engl J Med. 2016 Aug 11;375(6):
 
567–74. [PMID: 27509105]
Minisola S et al. The diagnosis and management of hypercalcae
-
mia. BMJ. 2015 Jun 2;350:h2723. [PMID: 26037642]
Tebben PJ et al. Vitamin D-mediated hypercalcemia: mecha
-
nisms, diagnosis, and treatment. Endocr Rev. 2016 Oct;37(5):
 
521–47. [PMID: 27588937]
Thosani S et al. Denosumab: a new agent in the management of 
hypercalcemia of malignancy. Future Oncol. 2015;11(21):
 
2865–71. [PMID: 26403973]
 
º
ph
OS
ph
ORUS 
Plasma phosphorus is mainly inorganic phosphate and 
represents a small fraction (less than 0.2%) of total body 
phosphate. Important determinants of plasma inorganic 
phosphate are renal excretion, intestinal absorption, and 
shift between the intracellular and extracellular spaces. The 
kidney is the most important regulator of the serum phos
-
phate level. PTH decreases reabsorption of phosphate in 
CMDT19_Ch21_p0898-p0925.indd   912

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CMDT 2019
the proximal tubule while 1,25-dihydroxyvitamin D
3
 
increases reabsorption. Renal proximal tubular reabsorp
-
tion of phosphate is decreased by volume expansion, corti
-
costeroids, and proximal tubular dysfunction (as in 
Fanconi syndrome). Fibroblast growth factor 23 (FGF23) is 
a potent phosphaturic hormone. Intestinal absorption of 
phosphate is facilitated by active vitamin D. PTH stimu
-
lates phosphate release from bone and renal phosphate 
excretion; primary hyperparathyroidism can lead to hypo
-
phosphatemia and depletion of bone phosphate stores. By 
contrast, growth hormone augments proximal tubular 
reabsorption of phosphate. Cellular phosphate uptake is 
stimulated by various factors and conditions, including 
alkalemia, insulin, epinephrine, feeding, hungry bone syn
-
drome, and accelerated cell proliferation.
Phosphorus metabolism and homeostasis are inti
-
mately related to calcium metabolism. See sections on 
metabolic bone disease in Chapter 26.
HYPOPHOSPHATEMIA
 
»
Severe hypophosphatemia may cause tissue 
hypoxia and rhabdomyolysis.
 
»
Renal loss of phosphate can be diagnosed by 
 
calculating the fractional excretion of phosphate 
(F
E
PO
4
).
 
»
PTH and FGF23 are the major factors that increase 
urine phosphate.
 
»
The leading causes of hypophosphatemia are listed in 
Table 21–9. Hypophosphatemia may occur in the presence 
of normal phosphate stores. Serious depletion of body 
phosphate stores may exist with low, normal, or high 
serum phosphate concentrations.
Serum phosphate levels decrease transiently after food 
intake, thus fasting samples are recommended for accu
-
racy. 
Moderate hypophosphatemia
 (1.0–2.4 mg/dL 
 
[0.32–0.79 mmol/L]) occurs commonly in hospitalized 
patients and may not reflect decreased phosphate stores.
In 
severe hypophosphatemia
 (less than 1 mg/dL [0.32 
mmol/L]), the affinity of hemoglobin for oxygen increases 
through a decrease in the erythrocyte 2,3-biphosphoglyc
-
erate concentration, impairing tissue oxygenation and cell 
metabolism and resulting in muscle weakness or even 
rhabdomyolysis. Severe hypophosphatemia is common 
and multifactorial in alcoholic patients. In acute alcohol 
withdrawal, increased plasma insulin and epinephrine 
along with respiratory alkalosis promote intracellular shift 
of phosphate. Vomiting, diarrhea, and poor dietary intake 
contribute to hypophosphatemia. Chronic alcohol use 
results in a decrease in the renal threshold of phosphate 
excretion. This renal tubular dysfunction reverses after a 
month of abstinence. Patients with chronic obstructive 
pulmonary disease and asthma commonly have hypophos
-
phatemia, attributed to xanthine derivatives causing shifts 
of phosphate intracellularly and the phosphaturic effects of 
beta-adrenergic agonists, loop diuretics, xanthine deriva
-
tives, and corticosteroids. Refeeding or glucose administra
-
tion to phosphate-depleted patients may cause fatal 
hypophosphatemia.
 
»
Acute, severe hypophosphatemia (less than 1.0 mg/dL 
[0.32 mmol/L]) can lead to rhabdomyolysis, paresthesias, 
and encephalopathy (irritability, confusion, dysarthria, 
seizures, and coma). Respiratory failure or failure to wean 
from mechanical ventilation may occur as a result of dia
-
phragmatic weakness. Arrhythmias and heart failure are 
uncommon but serious manifestations. Hematologic man
-
ifestations include acute hemolytic anemia from 
Table 21–9.
 
Causes of hypophosphatemia.
Diminished supply or absorption
Starvation
Parenteral alimentation with inadequate phosphate content
Malabsorption syndrome, small bowel bypass
Absorption blocked by oral antacids with aluminum or 
magnesium
Vitamin D–deficient and vitamin D–resistant osteomalacia
I
ncreased loss
Phosphaturic drugs: theophylline, diuretics, bronchodilators, 
Hyperparathyroidism (primary or secondary)

I
Renal tubular defects with excessive phosphaturia (congenital, 
Fanconi syndrome induced by monoclonal gammopathy, 
heavy metal poisoning), alcoholism
Hypokalemic nephropathy
Inadequately controlled diabetes mellitus
Phosphatonins of oncogenic osteomalacia (eg, FGF23 
production)
Intracellular shift of phosphorus
Administration of glucose
Anabolic steroids, estrogen, oral contraceptives, beta-
 
adrenergic agonists, xanthine derivatives
Hungry bone syndrome
Respiratory alkalosis
Salicylate poisoning
Electrolyte abnormalities
Metabolic alkalosis
Abnormal losses followed by inadequate repletion
Diabetes mellitus with acidosis, particularly during aggressive 
therapy
Recovery from starvation or prolonged catabolic state
Chronic alcoholism, particularly during restoration of nutrition; 
associated with hypomagnesemia
Recovery from severe burns
FGF23, fibroblast growth factor 23.
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erythrocyte fragility, platelet dysfunction with petechial 
hemorrhages, and impaired chemotaxis of leukocytes 
(leading to increased susceptibility to gram-negative 
sepsis).
Chronic severe depletion may cause anorexia, pain in 
muscles and bones, and fractures.
Urine phosphate excretion is a useful clue in the evaluation 
of hypophosphatemia. The normal renal response to hypo
-
phosphatemia is decreased urinary phosphate excretion to 
less than 100 mg/day, and a fractional excretion of phos
-
phate (F
E
PO
4
) less than 5%. The main factors regulating 
F
E
PO
4
 are PTH and phosphate intake. Increased PTH or 
phosphate intake decreases F
E
PO
4
 (ie, more phosphate is 
excreted into the urine).
Measurement of plasma PTH or PTHrP levels may be 
helpful. The clinical utility of serum FGF levels is undeter
-
mined except in uncommon diseases.
Other clinical features may be suggestive of hypophos
-
phatemia, such as hemolytic anemia and rhabdomyolysis. 
Fanconi syndrome may present with any combination of 
uricosuria, aminoaciduria, normoglycemic glucosuria, 
normal anion gap metabolic acidosis, and phosphaturia. In 
chronic hypophosphatemia, radiographs and bone biopsies 
show changes resembling osteomalacia.
 
»
Treatment
Hypophosphatemia can be prevented by including phos
-
phate in repletion and maintenance fluids. A rapid 
decline in calcium levels can occur with parenteral 
administration of phosphate; oral replacement of phos
-
phate is preferable. Moderate hypophosphatemia (1.0–2.5 
mg/dL [or 0.32–0.79 mmol/L]) is usually asymptomatic 
and does not require treatment. The hypophosphatemia 
in patients with diabetic ketoacidosis (DKA) will usually 
correct with normal dietary intake. Chronic hypophos
-
phatemia can be treated with oral phosphate repletion. 
Mixtures of sodium and potassium phosphate salts may 
be given to provide 0.5–1 g (16–32 mmol) of phosphate 
per day. For severe, symptomatic hypophosphatemia (less 
than 1 mg/dL [0.32 mmol/L]), an infusion should provide 
279–310 mg/12 h (or 9–10 mmol/12 h) until the serum 
phosphorus exceeds 1 mg/dL and the patient can be 
switched to oral therapy. The infusion rate should be 
decreased if hypotension occurs. Monitoring of plasma 
phosphate, calcium, and potassium every 6 hours is nec
-
essary because the response to phosphate supplementa
-
tion is not predictable. Magnesium deficiency often 
coexists and should be treated.
Contraindications to phosphate replacement include 
hypoparathyroidism, advanced CKD, tissue damage and 
necrosis, and hypercalcemia. When an associated hyper
-
glycemia is treated, phosphate accompanies glucose into 
cells, and hypophosphatemia may ensue.
 
»
•	
Patients with refractory hypophosphatemia with 
increased urinary phosphate excretion may require 
evaluation by an endocrinologist (eg, for hyperparathy
-
roidism and vitamin D disorders) or a nephrologist (eg, 
for renal tubular defects).
•	
Patients with decreased gastrointestinal absorption may 
require referral to a gastroenterologist.
 
»
Patients with severe or refractory hypophosphatemia will 
require intravenous phosphate.
Kraft MD. Phosphorus and calcium: a review for the adult nutri
-
tion support clinician. Nutr Clin Pract. 2015 Feb;30(1):21–33. 
Erratum in: Nutr Clin Pract. 2015 Jun;30(3):450. [PMID: 
25550328]
Manghat P et al. Phosphate homeostasis and disorders. Ann Clin 
Biochem. 2014 Nov;51(Pt 6):631–56. [PMID: 24585932]
HYPERPHOSPHATEMIA
 
»
Advanced CKD is the most common cause.
 
»
Hyperphosphatemia in the presence of hypercalce
-
mia imposes a high risk of metastatic calcification.
 
»
Advanced CKD with decreased urinary excretion of phos
-
phate is the most common cause of hyperphosphatemia. 
Other causes are listed in Table 21–10.
 
»
The clinical manifestations are those of the underlying

-
 
»
The clinical manifestations are those of the underlying 
disorder or associated condition.
In addition to elevated phosphate, blood chemistry abnor
-
malities are those of the underlying disease.
 
»
Treatment
Treatment is directed at the underlying cause. Exogenous 
sources of phosphate, including enteral or parenteral nutri
-
tion and medications, should be reduced or eliminated. 
Dietary phosphate absorption can be reduced by oral phos
-
phate binders, such as calcium carbonate, calcium acetate, 
sevelamer carbonate, lanthanum carbonate, and aluminum 
hydroxide. Sevelamer, lanthanum, and aluminum may be 
used in patients with hypercalcemia, although aluminum 
use should be limited to a few days because of the risk of 
aluminum accumulation and neurotoxicity. In acute 
 
k
idney 
injury and advanced CKD, dialysis will reduce serum 
phosphate.
CMDT19_Ch21_p0898-p0925.indd   914

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CMDT 2019
 
»
Patients with acute severe hyperphosphatemia require hos
-
pitalization for emergent therapy, possibly including dialy
-
sis. Concomitant illnesses, such as acute kidney injury or 
cell lysis, may necessitate admission.
Criscuolo M et al. Tumor lysis syndrome: review of pathogene
-
sis, risk factors and management of a medical emergency. 
Expert Rev Hematol. 2016;9(2):197–208. [PMID: 26629730]
Felsenfeld AJ et al. Pathophysiology of calcium, phosphorus, and 
magnesium dysregulation in chronic kidney disease. Semin 
Dial. 2015 Nov–Dec;28(6):564–77. [PMID: 26303319]
Ketteler M et al. Treating hyperphosphatemia—current and 
advancing drugs. Expert Opin Pharmacother. 2016 Oct;17(14):
 
1873–9. [PMID: 27643443]
Leaf DE et al. A physiologic-based approach to the evaluation of 
a patient with hyperphosphatemia. Am J Kidney Dis. 2013 Feb;
 
61(2):330–6. [PMID: 22938849]
 
º
DISORDERS OF MAGNESIUM 
Normal plasma magnesium concentration is 1.8–3.0 mg/dL 
 
(or 0.75–1.25 mmol/L), with about one-third bound to 
protein and two-thirds existing as free cation. Magne
-
sium excretion is via the kidney. Magnesium’s physio
-
logic effects on the nervous system resemble those of 
calcium.
Altered magnesium concentration usually provokes 
 
an associated alteration of Ca
2+
. Both hypomagnesemia 
and hypermagnesemia can decrease PTH secretion or 
action. Severe hypermagnesemia (greater than 5 mg/dL 
[2.1 mmol/L]) suppresses PTH secretion with consequent 
hypocalcemia; this disorder is typically seen only in 
patients receiving magnesium therapy for preeclampsia. 
Severe hypomagnesemia causes PTH resistance in end 
organs and eventually decreased PTH secretion in severe 
cases.
HYPOMAGNESEMIA
 
»
Serum concentration of magnesium may be 
 
normal even in the presence of magnesium 
 
depletion. Check urinary magnesium excretion if 
renal magnesium wasting is suspected.
 
»
Causes neurologic symptoms and arrhythmias.
 
»
Impairs release of PTH.
 
»
Causes of hypomagnesemia are listed in Table 21–11. 
 
Normomagnesemia does not exclude magnesium deple
-
tion because only 1% of total body magnesium is in the 
extracellular fluid (ECF). Hypomagnesemia and hypokale
-
mia share many etiologies, including diuretics, diarrhea, 
alcoholism, aminoglycosides, and amphotericin. Renal 
potassium wasting also occurs from hypomagnesemia, and 
is refractory to potassium replacement until magnesium is 
repleted. Hypomagnesemia also suppresses PTH release 
and causes end-organ resistance to PTH and low 
1,25-
 
dihydroxyvitamin D
3
 levels. The resultant hypocalce
-
mia is refractory to calcium replacement until the magne
-
sium is normalized. Molecular mechanisms of magnesium 
Table 21–10.
 
Causes of hyperphosphatemia.
Massive load of phosphate into the extracellular fluid
Exogenous sources
Hypervitaminosis D
Laxatives or enemas containing phosphate
Intravenous phosphate supplement
Endogenous sources
Rhabdomyolysis (especially if chronic kidney disease 
coexists)
Cell lysis by chemotherapy of malignancy, particularly 
 
lymphoproliferative diseases
Metabolic acidosis (lactic acidosis, ketoacidosis)
Respiratory acidosis (phosphate incorporation into cells is 
disturbed)
Decreased excretion into urine
p
seudoh
yperphosphatemia
Hemolysis in vitro
Table 21–11.
 
Causes of hypomagnesemia.
Diminished absorption or intake
Malabsorption, chronic diarrhea, laxative abuse
Prolonged gastrointestinal suction
Small bowel bypass
Total parenteral alimentation with inadequate Mg
2+
 content
Increased renal loss
Diuretic therapy (loop diuretics, thiazide diuretics)
Hyperaldosteronism, Gitelman syndrome
Hyperparathyroidism, hyperthyroidism

2+
 content
Volume expansion
Tubulointerstitial diseases
Transplant kidney
Drugs (aminoglycoside, cetuximab, cisplatin, amphotericin B, 
pentamidine)
Others
Pregnancy
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wasting have been revealed in some hereditary disorders. 
There is an FDA warning about hypomagnesemia for 
patients taking proton pump inhibitors. The presumed 
mechanism is decreased intestinal magnesium absorption, 
but it is not clear why this complication develops in only a 
small fraction of patients taking these medications.
 
»
Common symptoms are those of hypokalemia and hypo
-
calcemia, with weakness and muscle cramps. Marked neu
-
romuscular and central nervous system hyperirritability 
may produce tremors, athetoid movements, jerking, nys
-
tagmus, Babinski response, confusion, and disorientation. 
Cardiovascular manifestations include hypertension, 
tachycardia, and ventricular arrhythmias.
Urinary excretion of magnesium exceeding 10–30 mg/day 
or a fractional excretion greater than 2% indicates renal 
magnesium wasting. Hypocalcemia and hypokalemia are 
often present. The ECG may show prolonged QT interval, 
due to lengthening of the ST segment. PTH secretion is 
often suppressed (see Hypocalcemia).
 
»
Treatment
Magnesium oxide, 250–500 mg orally once or twice daily, 
is useful for treating chronic hypomagnesemia. Symp
-
tomatic hypomagnesemia requires intravenous magne
-
sium sulfate 1–2 g over 5–60 minutes mixed in either 
dextrose 5% or 0.9% normal saline. Torsades de pointes in 
the setting of hypomagnesemia can be treated with 1–2 g 
of magnesium sulfate in 10 mL of dextrose 5% solution 
pushed intravenously over 15 minutes. Severe, non–life-
threatening deficiency can be treated at a rate to 1–2 g/h 
over 3–6 hours. Magnesium sulfate may also be given 
intramuscularly in a dosage of 200–800 mg/day 
 
(8–33 mmol/day) in four divided doses. Serum levels 
must be monitored daily and dosage adjusted to keep the 
concentration from rising above 3 mg/dL (1.23 mmol/L). 
Tendon reflexes may be checked for hyporeflexia of 
hypermagnesemia. K
+
 and Ca
2+
 replacement may be 
required, but patients with hypokalemia and hypocalce
-
mia of hypomagnesemia do not recover without magne
-
sium supplementation.
Patients with normal kidney function can excrete excess 
magnesium; hypermagnesemia should not develop with 
replacement dosages. In patients with CKD, magnesium 
replacement should be done cautiously to avoid hypermag
-
nesemia. Reduced doses (50–75% dose reduction) and more 
frequent monitoring (at least twice daily) are indicated.
Cheungpasitporn W et al. Dysmagnesemia in hospitalized 
patients: prevalence and prognostic importance. Mayo Clin 
Proc. 2015 Aug;90(8):1001–10. [PMID: 26250725]
Gommers LM et al. Hypomagnesemia in type 2 diabetes: a 
vicious circle? Diabetes. 2016 Jan;65(1):3–13. [PMID: 
26696633]
HYPERMAGNESEMIA
 
»
Often associated with advanced CKD and chronic 
intake of magnesium-containing drugs.
 
»
Hypermagnesemia is almost always the result of advanced 
CKD and impaired magnesium excretion. Antacids and 
laxatives are underrecognized sources of magnesium. Preg
-
nant patients may have severe hypermagnesemia from 
intravenous magnesium for preeclampsia and eclampsia. 
Magnesium replacement should be done cautiously in 
patients with CKD; dose reductions up to 75% may be 
necessary to avoid hypermagnesemia.
 
»
Muscle weakness, decreased deep tendon reflexes, mental 
obtundation, and confusion are characteristic manifesta
-
tions. Weakness, flaccid paralysis, ileus, urinary retention, 
and hypotension are noted. Serious findings include respi
-
ratory muscle paralysis and cardiac arrest.
Serum Mg
2+
 is elevated. In the common setting of CKD, 
BUN, creatinine, potassium, phosphate, and uric acid may 
all be elevated. Serum Ca
2+
 is often low. The ECG may 
show increased PR interval, broadened QRS complexes, 
and peaked T waves, probably related to associated 
 
»
Treatment

2+
 
»
Treatment
Exogenous sources of magnesium should be discontinued. 
Calcium antagonizes Mg
2+
 and may be given intravenously 
as calcium chloride, 500 mg or more at a rate of 100 mg 
 
(4.1 mmol) per minute. Hemodialysis or peritoneal dialysis 
may be necessary to remove magnesium, particularly with 
severe kidney disease.
Long-term use of magnesium hydroxide and magne
-
sium sulfate should be avoided in patients with advanced 
stages of CKD.
Broman M et al. Analysis of hypo- and hypermagnesemia in an 
intensive care unit cohort. Acta Anaesthesiol Scand. 2018 
May;62(5):648–57. [PMID: 29341068]
Chang WT et al. Calcium, magnesium, and phosphate abnor
-
malities in the emergency department. Emerg Med Clin 
North Am. 2014 May;32(2):349–66. [PMID: 24766937]
Haider DG et al. Hypermagnesemia is a strong independent risk 
factor for mortality in critically ill patients: results from a 
cross-sectional study. Eur J Intern Med. 2015 Sep;26(7):504–7. 
 
[PMID: 26049918]
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(P
co
2
 greater than 40 mm Hg) or metabolic (HCO
3
–
 less 
than 24 mEq/L). If the pH is > 7.40, the primary process is 
alkalosis, either respiratory (P
co
2
 less than 40 mm Hg) or 
metabolic (HCO
3
–
 greater than 24 mEq/L). One respira
-
tory or metabolic disorder with its appropriate compensa
-
tory response is a simple acid-base disorder.
MIXED ACID-BASE DISORDERS
Two or three simultaneous disorders can be present in a 
mixed acid-base disorder, but there can never be two pri
-
mary respiratory disorders. Uncovering a mixed acid-base 
disorder is clinically important, and requires a methodical 
approach to acid-base analysis (see box Step-by-Step Analy
-
sis of Acid-Base Status). Once the primary disturbance has 
been determined, the clinician should assess whether the 
compensatory response is appropriate (Table 21–12). An 
inadequate or an exaggerated response indicates the pres
-
ence of another primary acid-base disturbance.
The anion gap should always be calculated for two rea
-
sons. First, it is possible to have an abnormal anion gap 
even if the sodium, chloride, and bicarbonate concentra
-
tions are normal. Second, an anion gap larger than 
20 mEq/L suggests a primary metabolic acid-base distur
-
bance regardless of the pH or serum bicarbonate level 
 
º
ACID–BASE DISORDERS
Assessment of a patient’s acid-base status requires mea
-
surement of arterial pH, P
co
2
, and plasma bicarbonate 
(HCO
3
–
). Blood gas analyzers directly measure pH and 
P
co
2
. The HCO
3
–
 value is calculated from the Henderson–
Hasselbalch equation:
pH
6.
1/uni00A0
/uni00A0l
og
/uni00A0
HC
O
0.03
/uni00A0/uni00A0
PC
O
3
2
=+
×
−
The total venous CO
2
 measurement is a more direct 
determination of HCO
3
–
. Because of the dissociation char
-
acteristics of carbonic acid (H
2
CO
3
) at body pH, dissolved 
CO
2
 is almost exclusively in the form of HCO
3
–
, and for 
clinical purposes the total carbon dioxide content is equiv
-
alent (± 3 mEq/L) to the HCO
3
–
 concentration:
+↔
↔+
+−
3
HH
CO
/uni00A0H
CO
/uni00A0C
O/uni00A0
HO
23
22
Venous blood gases can provide useful information for 
acid-base assessment since the arteriovenous differences in 
pH and P
co
2
 are small and relatively constant. Venous blood 
pH is usually 0.03–0.04 units lower than arterial blood pH, 
and venous blood P
co
2
 is 7 or 8 mm Hg higher than arterial 
blood P
co
2
. Calculated HCO
3
–
 concentration in venous 
blood is at most 2 mEq/L higher than arterial blood HCO
3
–
. 
Arterial and venous blood gases will not be equivalent during 
a cardiopulmonary arrest; arterial samples should be obtained 
for the most accurate measurements of pH and P
co
2
.
TY
p
ES OF ACID–BASE DISORDERS
There are two types of acid-base disorders: acidosis and 
alkalosis. These disorders can be either metabolic 
(decreased or increased HCO
3
–
) or respiratory (decreased 
or increased P
co
2
). Primary respiratory disorders affect 
blood acidity by changes in P
co
2
, and primary metabolic 
disorders are disturbances in HCO
3
–
 concentration. A pri
-
mary disturbance is usually accompanied by a compensa
-
tory response, but the compensation does not fully correct 
the pH disturbance of the primary disorder. If the pH is 
 
< 7.40, the primary process is acidosis, either respiratory 
STEP-BY-STEP ANALYSIS OF ACID-BASE 
STATUS
Step 1:
  
Determ
ine the
 primary (or main) disorder—
whether it is metabolic or respiratory—
from blood pH, HCO
3
–
, and P
co
2
 values.
Step 2:
  
D
etermine the presence of mixed acid-base 
disorders by calculating the range of com
-
pensatory responses (see Table 21–12).
Step 3
:
  
C
alculate the anion gap (see Table 21–13).
Step 4:
  
C
alculate the corrected HCO
3
–
 concentration 
if the anion gap is increased (see above).
Step 5:
  
Examine the pa
tient to determine whether 
the clinical signs are compatible with the 
acid-base analysis.
Table 21–12.

3
–
Step 5:
  
Primary acid-base disorders and expected compensation.
Disorder
p
rimar
y Defect
Compensatory Response
Magnitude of Compensation
Respiratory acidosis
Acute
↑
 PCO
2
↑
 HCO
3
–
↑
 HCO
3
–
 1 mEq/L per 10 mm Hg 
↑
 PCO
2
Chronic
↑
 PCO
2
↑
 HCO
3
–
↑
 HCO
3
–
 3.5 mEq/L per 10 mm Hg 
↑
 PCO
2
Acute
↓
 PCO
2
↓
 HCO
3
–
↓
 HCO
3
–
 2 mEq/L per 10 mm Hg 
↓
 PCO
2
Chronic
↓
 PCO
2
↓
 HCO
3
–
↓
 HCO
3
–
 5 mEq/L per 10 mm Hg 
↓
 PCO
2
Metabolic acidosis
↓
 HCO
3
–
↓
 PCO
2
↓
 PCO
2
 1.3 mm Hg per 1 mEq/L 
↓
 HCO
3
–
↑
 HCO
3
–
↑
 PCO
2
↑
 PCO
2
 0.7 mm Hg per 1 mEq/L 
↑
 HCO
3
–
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because a markedly abnormal anion gap is never a com
-
pensatory response to a respiratory disorder. In patients 
with an increased anion gap metabolic acidosis, clinicians 
should calculate the corrected bicarbonate. In increased 
anion gap acidoses, there should be a mole for mole 
decrease in HCO
3
–
 as the anion gap increases. A corrected 
HCO
3
–
 value higher or lower than normal (24 mEq/L) 
indicates the concomitant presence of metabolic alkalosis 
or normal anion gap metabolic acidosis, respectively.
Filippatos T et al. Acid-base and electrolyte disorders associated 
with the use of antidiabetic drugs. Expert Opin Drug Saf. 
2017 Oct;16(10):1121–32. [PMID: 28748724]
Gomez H et al. Understanding acid base disorders. Crit Care 
Clin. 2015 Oct;31(4):849–60. [PMID: 26410149]
Hamm LL et al. Acid-base homeostasis. Clin J Am Soc Nephrol. 
2015 Dec 7;10(12):2232–42. [PMID: 26597304]
Scheiner B et al. Acid-base disorders in liver disease. J Hepatol. 
2017 Nov;67(5):1062–73. [PMID: 28684104]
Seifter JL. Integration of acid-base and electrolyte disorders. N 
Engl J Med. 2014 Nov 6;371(19):1821–31. [PMID: 25372090]
METABOLIC ACIDOSIS
 
»
Decreased HCO
3
–
 with acidemia.
 
»
Classified into increased anion gap acidosis and 
normal anion gap acidosis.
 
»
Lactic acidosis, ketoacidosis, and toxins produce 
metabolic acidoses with the largest anion gaps.
 
»
Normal anion gap acidosis is mainly caused by 
gastrointestinal HCO
3
–
 loss or RTA. Urinary anion 
gap may help distinguish between these causes.
 
»
The hallmark of metabolic acidosis is decreased HCO
3
–
. 
Metabolic acidoses are classified by the anion gap, usually 
normal or increased (Table 21–13). The anion gap is the 
difference between readily measured anions and cations.
In plasma,
+=
++
=−
+
+
+
−−
−−
/uni00A0[Na
]
Un
me
asured
(H
CO Cl
)
Un
me
asured
c
ations
anions
Anio
ng
ap
Na
(H
CO Cl
)
3
3
Major unmeasured cations are calcium (2 mEq/L), 
magnesium (2 mEq/L), gamma-globulins, and potassium 
(4 mEq/L). Major unmeasured anions are albumin 
(2  mEq/L per g/dL), phosphate (2 mEq/L), sulfate 
(1 mEq/L), lactate (1–2 mEq/L), and other organic anions 
(3–4 mEq/L). Traditionally, the normal anion gap has been 
12 ± 4 mEq/L. With current auto-analyzers, the reference 
range may be lower (6 ± 1 mEq/L), primarily from an 
increase in Cl
–
 values. Despite its usefulness, the anion gap 
can be misleading. Non–acid-base disorders may cause 
errors in anion gap interpretation; these disorders include 
hypoalbuminemia, hypernatremia, or hyponatremia; anti
-
biotics (eg, carbenicillin is an unmeasured anion; poly
-
myxin is an unmeasured cation) may also cause errors in 
anion gap interpretation. Although not usually associated 
with metabolic acidosis, a decreased anion gap can occur 
because of a reduction in unmeasured anions or an 
increase in unmeasured cations. In hypoalbuminemia, a 
2 mEq/L decrease in anion gap will occur for every 1 g/dL 
decline in serum albumin.
INCREASED ANION GAP ACIDOSIS 
 
(Increased Unmeasured Anions)
Normochloremic metabolic acidosis generally results from 
addition of organic acids such as lactate, acetoacetate, beta-
hydroxybutyrate, and exogenous toxins. Other anions such 
as isocitrate, alpha-ketoglutarate, malate, and D-lactate may 
contribute to the anion gap of lactic acidosis, DKA, and 
acidosis of unknown etiology. Uremia causes an increased 
anion gap metabolic acidosis from unexcreted organic 
acids and anions.
Table 21–13.
 
Anion gap in metabolic acidosis.
1
Decreased (< 6 mEq)
Hypoalbuminemia (decreased unmeasured anion)
Plasma cell dyscrasias
Monoclonal protein (cationic paraprotein accompanied by 
chloride and bicarbonate)
Bromide intoxication
I
ncreased (> 12 mEq)
Metabolic anion
Diabetic ketoacidosis
Alcoholic ketoacidosis
Lactic acidosis

I
Chronic kidney disease (advanced stages) (PO
4
 
3–
, SO
4
 
2–
)
Metabolic alkalosis (increased number of negative charges 
on protein)
5-oxoproline acidosis from acetaminophen toxicity
Drug or chemical anion
Salicylate intoxication
Sodium carbenicillin therapy
Methanol (formic acid)
Ethylene glycol (oxalic acid)
Normal (6–12 mEq)
Loss of HCO
3
Diarrhea
Recovery from diabetic ketoacidosis
Pancreatic fluid loss, ileostomy (unadapted)
Chloride retention
Renal tubular acidosis
Ileal loop bladder
Administration of HCl equivalent or NH
4
Cl
Arginine and lysine in parenteral nutrition
1
Reference ranges for anion gap may vary based on differing 
 
laboratory methods.
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A. Lactic Acidosis
Lactic acidosis is a common cause of metabolic acidosis, 
producing an elevated anion gap and decreased serum pH 
when present without other acid-base disturbances. Lac
-
tate is formed from pyruvate in anaerobic glycolysis. Nor
-
mally, lactate levels remain low (1 mEq/L) because of 
metabolism of lactate principally by the liver through glu
-
coneogenesis or oxidation via the Krebs cycle.
In lactic acidosis, lactate levels are at least 4–5 mEq/L 
but commonly 10–30 mEq/L. There are two basic types of 
lactic acidosis.
Type A (hypoxic) lactic acidosis
 is more common, 
resulting from decreased tissue perfusion; cardiogenic, 
septic, or hemorrhagic shock; and carbon monoxide or 
cyanide poisoning. These conditions increase peripheral 
lactic acid production and decrease hepatic metabolism of 
lactate as liver perfusion declines.
Type B lactic acidosis
 may be due to metabolic causes 
(eg, diabetes, ketoacidosis, liver disease, kidney disease, 
infection, leukemia, or lymphoma) or toxins (eg, ethanol, 
methanol, salicylates, isoniazid, or metformin). Propylene 
glycol can cause lactic acidosis from decreased liver metab
-
olism; it is used as a vehicle for intravenous drugs, such as 
nitroglycerin, etomidate, and diazepam. Parenteral nutri
-
tion without thiamine causes severe refractory lactic acido
-
sis from deranged pyruvate metabolism. Patients with 
short bowel syndrome may develop 
D
-lactic acidosis with 
encephalopathy due to carbohydrate malabsorption and 
subsequent fermentation by colonic bacteria. Nucleoside 
analog reverse transcriptase inhibitors can cause type B 
lactic acidosis due to mitochondrial toxicity.
Idiopathic lactic acidosis, usually in debilitated patients, 
has an extremely high mortality rate. (For treatment of 
lactic acidosis, see below and Chapter 27.)
B. Diabetic Ketoacidosis (DKA)
DKA is characterized by hyperglycemia and metabolic 
acidosis with an increased anion gap:
HB
NaHC
O/uni00A0
CO
/uni00A0N
aB
/uni00A0H
O
32
2
++
↔+
+
+−
where B
–
 is beta-hydroxybutyrate or acetoacetate, the 
ketones responsible for the increased anion gap. The anion 
gap should be calculated from the measured serum electro
-
lytes; correction of the serum sodium for the dilutional 
effect of hyperglycemia will exaggerate the anion gap. Dia
-
betics with ketoacidosis may have lactic acidosis from tis
-
sue hypoperfusion and increased anaerobic metabolism.
During the recovery phase of DKA, a hyperchloremic 
non-anion gap acidosis can develop because saline resusci
-
tation results in chloride retention, restoration of GFR, and 
ketoaciduria. Ketone salts (NaB) are formed as bicarbonate 
is consumed:
HB 
+
 NaHCO
3
 
→ 
NaB 
+
 H
2
CO
3
The kidney reabsorbs ketone anions poorly but can 
compensate for the loss of anions by increasing the reab
-
sorption of Cl
–
.
Patients with DKA and normal kidney function may 
have marked ketonuria and severe metabolic acidosis but 
only a mildly increased anion gap. Thus, the size of the 
anion gap correlates poorly with the severity of the DKA; 
the urinary loss of Na
+
 or K
+
 salts of beta-hydroxybutyrate 
will lower the anion gap without altering the H
+
 excretion 
or the severity of the acidosis. Urine dipsticks for ketones 
test primarily for acetoacetate and, to a lesser degree, ace
-
tone but not the predominant ketoacid, beta-hydroxybu
-
tyrate. Dipstick tests for ketones may become more positive 
even as the patient improves due to the metabolism of 
beta-hydroxybutyrate. Thus, the patient’s clinical status 
and pH are better markers of improvement than the anion 
gap or ketone levels.
C. Alcoholic Ketoacidosis
Chronically malnourished patients who consume large 
quantities of alcohol daily may develop alcoholic ketoaci
-
dosis. Most of these patients have mixed acid-base disor
-
ders (10% have a triple acid-base disorder). Although 
decreased HCO
3
–
 is usual, 50% of the patients may have

-
-
3
–
 is usual, 50% of the patients may have 
normal or alkalemic pH. Three types of metabolic acidosis 
are seen in alcoholic ketoacidosis: (1) Ketoacidosis is due to 
beta-hydroxybutyrate and acetoacetate excess. (2) Lactic 
acidosis: Alcohol metabolism increases the NADH:NAD 
ratio, causing increased production and decreased utiliza
-
tion of lactate. Accompanying thiamine deficiency, which 
inhibits pyruvate carboxylase, further enhances lactic acid 
production in many cases. Moderate to severe elevations of 
lactate (greater than 6 mmol/L) are seen with concomitant 
disorders such as sepsis, pancreatitis, or hypoglycemia. 
 
(3) Hyperchloremic acidosis from bicarbonate loss in the 
urine is associated with ketonuria (see above). Metabolic 
alkalosis occurs from volume contraction and vomiting. 
Respiratory alkalosis results from alcohol withdrawal, pain, 
or associated disorders such as sepsis or liver disease. 
 
Half of the patients have hypoglycemia or hyperglycemia. 
When serum glucose levels are greater than 250 mg/dL 
(13.88 mmol/L), the distinction from DKA is difficult. 
 
The absence of a diabetic history and normoglycemia after 
initial therapy support the diagnosis of alcoholic 
ketoacidosis.
D. Toxins
(See also Chapter 38.) Multiple toxins and drugs increase 
the anion gap by increasing endogenous acid production. 
Common examples include methanol (metabolized to for
-
mic acid), ethylene glycol (glycolic and oxalic acid), and 
salicylates (salicylic acid and lactic acid). The latter can 
cause a mixed disorder of metabolic acidosis with respira
-
tory alkalosis. In toluene poisoning, the metabolite hippu
-
rate is rapidly excreted by the kidney and may present as a 
normal anion gap acidosis. Isopropanol, which is metabo
-
lized to acetone, increases the osmolar gap, but not the 
anion gap.
E. Uremic Acidosis
As the GFR drops below 15–30 mL/min, the kidneys are 
increasingly unable to synthesize NH
3
. The reduced 
 
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 CMDT 2019
excretion of H
+
 and organic acids (eg, phosphate and sul
-
fate) as NH
4
Cl results in an increased anion gap metabolic 
acidosis.
NORMAL ANION GAP ACIDOSIS
The two major causes are gastrointestinal HCO
3
–
 loss and 
defects in renal acidification (renal tubular acidosis) 
(Table  21–14). The urinary anion gap can differentiate 
between these causes.
A. Gastrointestinal HCO
3
–
 Loss
The gastrointestinal tract secretes bicarbonate at multiple 
sites. Small bowel and pancreatic secretions contain large 
amounts of HCO
3
–
; massive diarrhea or pancreatic drain
-
age can result in HCO
3
–
 loss. Hyperchloremia occurs 
because the ileum and colon secrete HCO
3
–
 in exchange for 
Cl
–
 by countertransport. The resultant volume contraction 
causes increased Cl
–
 retention by the kidney in the setting 
of decreased HCO
3
–
. Patients with ureterosigmoidostomies 
can develop hyperchloremic metabolic acidosis because 
the colon secretes HCO
3
–
 in the urine in exchange for Cl
–
.
B. Renal Tubular Acidosis (RTA)
Hyperchloremic acidosis with a normal anion gap and 
normal (or near normal) GFR, and in the absence of diar
-
rhea, defines RTA. The defect is either inability to excrete 
H
+
 (inadequate generation of new HCO
3
–
) or inadequate 
reabsorption of HCO
3
–
. Three major types can be differen
-
tiated by the clinical setting, urinary pH, urinary anion 
gap, and serum K
+
 level. The pathophysiologic mecha
-
nisms of RTA have been elucidated by identifying the 
responsible molecules and gene mutations.
1. Classic distal RTA (type I)—
This disorder is characterized 
by selective deficiency in H
+
 secretion in alpha intercalated 
cells in the collecting tubule. Despite acidosis, urinary pH 
cannot be acidified and is above 5.5, which retards the 
binding of H
+
 to phosphate (H
+
 + HPO
4
 
2–
 
→
 H
2
PO
4
) and 
inhibits titratable acid excretion. Furthermore, urinary 
excretion of NH
4
 
+
Cl
–
 is decreased, and the urinary anion 
gap is positive. Enhanced K
+
 excretion occurs probably 
because there is less competition from H
+
 in the distal neph
-
ron transport system. Furthermore, hyperaldosteronism 
occurs in response to renal salt wasting, which will increase 
potassium excretion. Nephrocalcinosis and nephrolithiasis 
are often seen in patients with distal RTA since chronic aci
-
dosis decreases tubular calcium reabsorption. Hypercalci
-
uria, alkaline urine, and lowered level of urinary citrate cause 
calcium phosphate stones and nephrocalcinosis. Distal RTA 
develops as a consequence of paraproteinemias, 
 
a
utoimmune 
disease, and drugs and toxins such as amphotericin.
2. Proximal RTA (type II)—
Proximal RTA is due to a selec
-
tive defect in the proximal tubule’s ability to reabsorb fil
-
tered HCO
3
–
. Carbonic anhydrase inhibitors (acetazolamide) 
can cause proximal RTA. About 90% of filtered HCO
3
–
 is 
absorbed by the proximal tubule. A proximal defect in 
HCO
3
–
 reabsorption will overwhelm the distal tubule’s lim
-
ited capacity to reabsorb HCO
3
–
, resulting in bicarbonaturia 
and metabolic acidosis. Distal delivery of HCO
3
–
 declines as 
the plasma HCO
3
–
 level decreases. When the plasma HCO
3
–
 
level drops to 15–18 mEq/L, the distal nephron can reab
-
sorb the diminished filtered load of HCO
3
–
. Bicarbonaturia 
resolves, and the urinary pH can be acidic. Thiazide-
induced volume contraction can be used to enhance proxi
-
mal HCO
3
–
 reabsorption, leading to the decrease in distal 
HCO
3
–
 delivery and improvement of bicarbonaturia and 
renal acidification. The increased delivery of HCO
3
–
 to the 
distal nephron increases K
+
 secretion, and hypokalemia 
results if a patient is loaded with excess HCO
3
–
 and K
+
 is not 
adequately supplemented. Proximal RTA can exist with 
other proximal reabsorption defects, such as Fanconi syn
-
drome, resulting in glucosuria, aminoaciduria, phosphatu
-
ria, and uricosuria. Causes include plasma cell myeloma

-
-
ria, and uricosuria. Causes include plasma cell myeloma 
(formerly called multiple myeloma) and nephrotoxic drugs.
Table 21–14.
 
Hyperchloremic, normal anion gap metabolic acidoses.
Renal Defect
Serum 
[K
+
]
Distal 
h
+
 Secretion
Urinary 
Anion 
Gap
Treatment
Urine p
h
Titratable 
Acid
Gastrointestinal 
HCO
3
–
 loss
None
↓
< 5.5
↑↑
Negative
Na
+
, K
+
, and HCO
3
–
 as required
 
  I.
 
Classic distal
Distal H
+
 secretion
↓
> 5.5
↓
Positive
NaHCO
3
 (1–3 mEq/kg/day)
 
 II.
 
P
roximal
Proximal HCO
3
–
 
reabsorption
↓
Variable
Usually > 5.5
Normal
Positive
NaHCO
3
 or KHCO
3
 (10–15 mEq/
kg/day), thiazide
 
IV
.
  
Hyporeninemic 
hypoaldosteronism
Distal Na
+
 reabsorp
-
tion, K
+
 secretion, 
and H
+
 secretion
↑
Variable
↓
Positive
Fludrocortisone (0.1–0.5 mg/day), 
dietary K
+
 restriction, furose
-
mide (40–160 mg/day), 
NaHCO
3
Fluid and Electrolytes: Physiology and Pathophysiology.
 McGraw-Hill, 1991.
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3. Hyporeninemic hypoaldosteronemic RTA (type IV)—
Type IV is the most common RTA in clinical practice. The 
defect is aldosterone deficiency or antagonism, which 
impairs distal nephron Na
+
 reabsorption and K
+
 and H
+
 
excretion. Renal salt wasting and hyperkalemia are fre
-
quently present. Common causes are diabetic nephropathy, 
tubulointerstitial renal diseases, hypertensive nephroscler
-
osis, and AIDS. In patients with these disorders, drugs, 
such as ACE inhibitors, ARBs, spironolactone, and 
NSAIDs, can exacerbate the hyperkalemia.
C. Dilutional Acidosis
Rapid dilution of plasma volume by 0.9% NaCl may cause 
hyperchloremic acidosis.
D. Recovery from DKA
See Increased Anion Gap Acidosis (Increased Unmeasured 
Anions).
E. Posthypocapnia
In prolonged respiratory alkalosis, HCO
3
–
 decreases and Cl
–
 
increases from decreased renal NH
4
 
+
Cl
–
 excretion. If the 
respiratory alkalosis is corrected quickly, HCO
3
–
 will remain 
low until the kidneys can generate new HCO
3
–
, which gener
-
ally takes several days. In the meantime, the increased P
co
2
 
with low HCO
3
–
 causes metabolic acidosis.
F. Hyperalimentation
Hyperalimentation fluids may contain amino acid solu
-
tions that acidify when metabolized, such as arginine 
hydrochloride and lysine hydrochloride.
 
»
Assessment of Hyperchloremic Metabolic 
Acidosis by Urinary Anion Gap
Increased renal NH
4
 
+
Cl
–
 excretion to enhance H
+
 removal 
is the normal physiologic response to metabolic acidosis. 
The daily urinary excretion of NH
4
Cl can be increased 
from 30 mEq to 200 mEq in response to acidosis.
The urinary anion gap (Na
+
 + K
+
 – Cl
–
) reflects the abil
-
ity of the kidney to excrete NH
4
Cl. The urinary anion gap 
differentiates between gastrointestinal and renal causes of 
hyperchloremic acidosis. If the cause is gastrointestinal 
HCO
3
–
 loss (diarrhea), renal acidification remains normal 
and NH
4
Cl excretion increases, and the urinary anion gap 
is negative. If the cause is distal RTA, the urinary anion gap 
is positive, since the basic lesion in the disorder is the inabil
-
ity of the kidney to excrete H
+
 as NH
4
Cl. In proximal (type 
II) RTA, the kidney has defective HCO
3
–
 reabsorption, lead
-
ing to increased HCO
3
–
 excretion rather than decreased 
NH
4
Cl excretion; the urinary anion gap is often negative.
Urinary pH may not readily differentiate between the 
two causes. Despite acidosis, if volume depletion from 
diarrhea causes inadequate Na
+
 delivery to the distal neph
-
ron and therefore decreased exchange with H
+
, urinary pH 
may not be lower than 5.3. In the presence of this relatively 
high urinary pH, however, H
+
 excretion continues due to 
buffering of NH
3
 to NH
4
+
, since the p
K
 of this reaction is 
as high as 9.1. Potassium depletion, which can accompany 
diarrhea (and surreptitious laxative abuse), may also impair 
renal acidification. Thus, when volume depletion is pres
-
ent, the urinary anion gap is a better measure of ability to 
acidify the urine than urinary pH.
When large amounts of other anions are present in the 
urine, the urinary anion gap may not be reliable. In such a 
situation, NH
4
+
 excretion can be estimated using the uri
-
nary osmolar gap where urine concentrations and osmolal
-
ity are in mmol/L.
NH
4
+
 excretion (mmol/L) 
=
 0.5 
×
 Urinary osmolar gap 
 
=
 0.5 [U Osm – 2(U Na
+
 + U K
+
) + U urea + U glucose]
 
»
Symptoms of metabolic acidosis are mainly those of the under
-
lying disorder. Compensatory hyperventilation is an important 
clinical sign and may be misinterpreted as a primary respira
-
tory disorder; Kussmaul breathing (deep, regular, sighing res
-
pirations) may be seen with severe metabolic acidosis.
Blood pH, serum HCO
3
–
, and P
co
2
 are decreased. Anion 
gap may be normal (hyperchloremic) or increased (nor
-

-
3
–
, and P
co
2
-
mochloremic). Hyperkalemia may be seen.
 
»
Treatment
A. Increased Anion Gap Acidosis
Treatment is aimed at the underlying disorder, such as insu
-
lin and fluid therapy for diabetes and appropriate volume 
resuscitation to restore tissue perfusion. The metabolism of 
lactate will produce HCO
3
–
 and increase pH. Supplemental 
HCO
3
–
 is indicated for treatment of hyperkalemia (see 
Table 21–6) and some forms of normal anion gap acidosis 
but has been controversial for treatment of increased anion 
gap metabolic acidosis with respect to efficacy and safety. 
Large amounts of HCO
3
–
 may have deleterious effects, 
including hypernatremia, hyperosmolality, volume over
-
load, and worsening of intracellular acidosis.
In addition, alkali administration stimulates phospho
-
fructokinase activity, thus exacerbating lactic acidosis via 
enhanced lactate production. Ketogenesis is also aug
-
mented by alkali therapy.
In salicylate intoxication, alkali therapy must be started 
to decrease central nervous system damage unless blood 
pH is already alkalinized by respiratory alkalosis, since an 
increased pH converts salicylate to more impermeable sali
-
cylic acid. In alcoholic ketoacidosis, thiamine should be 
given with glucose to avoid Wernicke encephalopathy. The 
bicarbonate deficit can be calculated as follows:
HCO
3
–
 deficit 
=
 0.5 
×
 body weight in kg 
×
 (24 – HCO
3
–
)
Half of the calculated deficit should be administered 
within the first 3–4 hours to avoid overcorrection and vol
-
ume overload. In methanol intoxication, inhibition of 
alcohol dehydrogenase by fomepizole is standard care. 
Ethanol had previously been used as a competitive sub
-
strate for alcohol dehydrogenase, which metabolizes to 
formaldehyde.
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B. Normal Anion Gap Acidosis
Treatment of RTA is mainly achieved by administration of 
alkali (either as bicarbonate or citrate) to correct metabolic 
abnormalities and prevent nephrocalcinosis and CKD.
Large amounts of oral alkali (10–15 mEq/kg/day) 
(Table  21–14) may be required to treat proximal RTA 
because most of the alkali is excreted into the urine, which 
exacerbates hypokalemia. Thus, a mixture of sodium and 
potassium salts is preferred. Thiazides may reduce the amount 
of alkali required, but hypokalemia may develop. Treatment of 
type 1 distal RTA requires less alkali (1–3 mEq/kg/day) than 
proximal RTA. Potassium supplementation may be necessary.
For type IV RTA, dietary potassium restriction may be 
necessary and potassium-retaining drugs should be with
-
drawn. Fludrocortisone may be effective in cases with 
hypoaldosteronism, but should be used with care, prefera
-
bly in combination with loop diuretics. In some cases, oral 
alkali supplementation (1–3 mEq/kg/day) may be required.
 
»
Most clinicians will refer patients with renal tubular acidoses 
to a nephrologist for evaluation and possible alkali therapy.
 
»
Patients will require emergency department evaluation or 
hospital admission depending on the severity of the acido
-
sis and underlying conditions.
Fayfman M et al. Management of hyperglycemic crises: diabetic 
ketoacidosis and hyperglycemic hyperosmolar state. Med Clin 
North Am. 2017 May;101(3):587–606. [PMID: 28372715]
Lalau JD et al. Metformin-associated lactic acidosis (MALA): mov
-
ing towards a new paradigm. Diabetes Obes Metab. 2017 Nov;
 
19(11):1502–12. [PMID: 28417525]
Table 21–15.
 
Metabolic alkalosis.
Saline-Responsive (U
Cl
 < 20 mEq/L)
Saline-Unresponsive (U
Cl
 > 40 mEq/L)
Excessive body bicarbonate content
Renal alkalosis
Poorly reabsorbable anion therapy: carbenicillin, 
 
penicillin, sulfate, phosphate
Posthypercapnia
Gastrointestinal alkalosis
Loss of HCl from vomiting or nasogastric suction
Intestinal alkalosis: chloride diarrhea
NaHCO
3
 (baking soda)
Sodium citrate, lactate, gluconate, acetate
Transfusions
Antacids
Normal body bicarbonate content
“Contraction alkalosis”
Normotensive
Bartter syndrome (renal salt wasting and secondary 
hyperaldosteronism)
Severe potassium depletion
Refeeding alkalosis
Hypercalcemia and hypoparathyroidism
Hypertensive
Endogenous mineralocorticoids
Hyperreninism
Adrenal enzyme (11-beta-hydroxylase and 17-alpha-hydroxylase) 
Exogenous alkali
Exogenous mineralocorticoids
Licorice
Modified and reproduced, with permission, from Narins RG et al. Diagnostic strategies in disorders of fluid, electrolyte and acid-base 
 
homeostasis. Am J Med. 1982 Mar;72(3):496–520. Copyright © Elsevier.
Palmer BF et al. Electrolyte and acid-base disturbances in 
patients with diabetes mellitus. N Engl J Med. 2015 Aug 6;
 
373(6):548–59. [PMID: 26244308]
Seheult J et al. Lactic acidosis: an update. Clin Chem Lab Med. 
2017 Mar 1;55(3):322–33. [PMID: 27522622]
Sharma S et al. Comprehensive clinical approach to renal tubular 
acidosis. Clin Exp Nephrol. 2015 Aug;19(4):556–61. [PMID: 
25951806]
Suetrong B et al. Lactic acidosis in sepsis: it’s not all anaerobic: 
implications for diagnosis and management. Chest. 2016 Jan;
 
149(1):252–61. [PMID: 26378980]
METABOLIC ALKALOSIS
 
»
High HCO
3
–
 with alkalemia.
 
»
Evaluate effective circulating volume by physical 
 
»
Urinary chloride concentration differentiates saline-
responsive alkalosis from saline-unresponsive 
 
»
Metabolic alkalosis is characterized by high HCO
3
–
. Abnor
-
malities that generate HCO
3
–
 are called “initiation factors, ” 
whereas abnormalities that promote renal conservation of 
HCO
3
–
 are called “maintenance factors. ” Thus, metabolic alka
-

-
3
–
HCO
3
–
-
losis may remain even after the initiation factors have resolved.
The causes of metabolic alkalosis are classified into two 
groups based on “saline responsiveness” using the urine Cl
–
 as 
a marker for volume status (Table 21–15). Saline-responsive 
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CMDT 2019
metabolic alkalosis is a sign of extracellular volume con
-
traction, and saline-unresponsive alkalosis implies exces
-
sive total body bicarbonate with either euvolemia or 
hypervolemia. The compensatory increase in P
co
2
 rarely 
exceeds 55 mm Hg; higher P
co
2
 values imply a superim
-
posed primary respiratory acidosis.
A. Saline-Responsive Metabolic Alkalosis
Much more common than saline-unresponsive alkalosis, 
saline-responsive alkalosis is characterized by normotensive 
extracellular volume contraction and hypokalemia. Hypoten
-
sion and orthostasis may be seen. In vomiting or nasogastric 
suction, loss of acid (HCl) initiates the alkalosis, but volume 
contraction from Cl
–
 loss maintains the alkalosis because the 
kidney avidly reabsorbs Na
+
 to restore the ECF. Increased 
sodium reabsorption necessitates increased HCO
3
–
 reabsorp
-
tion proximally, and the urinary pH remains acidic despite 
alkalemia (paradoxical aciduria). Renal Cl
–
 reabsorption is 
high, and urine Cl
–
 is low (less than 20 mEq/L). In alkalosis, 
bicarbonaturia may force Na
+
 excretion as the accompanying 
cation even if volume depletion is present. Therefore, urine 
Cl
–
 is preferred to urine Na
+
 as a measure of extracellular 
volume. Diuretics may limit the utility of urine chloride by 
increasing urine chloride and sodium excretion, even in the 
setting of volume contraction.
Metabolic alkalosis is generally associated with hypo
-
kalemia due to the direct effect of alkalosis on renal potas
-
sium excretion and secondary hyperaldosteronism from 
volume depletion. Hypokalemia exacerbates the metabolic 
alkalosis by increasing bicarbonate reabsorption in the 
proximal tubule and hydrogen ion secretion in the distal 
tubule. Administration of KCl will correct the disorder.
1. Contraction alkalosis—
Diuretics decrease extracellular 
volume from urinary loss of NaCl and water. The plasma 
HCO
3
–
 concentration increases because the extracellular fluid 
volume contracts around a stable total body bicarbonate. 
Contraction alkalosis is the opposite of dilutional acidosis.
2. Posthypercapnia alkalosis—
In chronic respiratory aci
-
dosis, the kidney decreases bicarbonate excretion, increas
-
ing plasma HCO
3
–
 concentration (see Table 21–12). 
Hypercapnia directly affects the proximal tubule to 
decrease NaCl reabsorption, which can cause extracellular 
volume depletion. If P
co
2
 is rapidly corrected, metabolic 
alkalosis will exist until the kidney excretes the retained 
bicarbonate. Many patients with chronic respiratory acido
-
sis receive diuretics, which further exacerbates the meta
-
bolic alkalosis.
B. Saline-Unresponsive Alkalosis
1. Hyperaldosteronism—
Primary hyperaldosteronism 
causes extracellular volume expansion and hypertension by 
increasing distal sodium reabsorption. Aldosterone increases 
H
+
 and K
+
 excretion, producing metabolic alkalosis and 
hypokalemia. In an attempt to decrease extracellular volume, 
high levels of NaCl are excreted resulting in a high urine Cl
–
 
(greater than 20 mEq/L). Therapy with NaCl will only 
increase volume expansion and hypertension and will not 
treat the underlying problem of mineralocorticoid excess.
2. Alkali administration with decreased GFR—
The nor
-
mal kidney has a substantial capacity for bicarbonate 
excretion, protecting against metabolic alkalosis even with 
large HCO
3
–
 intake. However, urinary excretion of bicar
-
bonate is inadequate in CKD. If large amounts of HCO
3
–
 
are consumed, as with intensive antacid therapy, metabolic 
alkalosis will occur. Lactate, citrate, and gluconate can also 
cause metabolic alkalosis because they are metabolized to 
bicarbonate. In milk-alkali syndrome, sustained heavy 
ingestion of absorbable antacids and milk causes hypercal
-
cemic kidney injury and metabolic alkalosis. Volume con
-
traction from renal hypercalcemic effects exacerbates the 
 
»

-
-
 
»
There are no characteristic symptoms or signs. Orthostatic 
hypotension may be encountered. Concomitant hypokale
-
mia may cause weakness and hyporeflexia. Tetany and 
neuromuscular irritability occur rarely.
The arterial blood pH and bicarbonate are elevated. With 
respiratory compensation, the arterial P
co
2
 is increased. 
Serum potassium and chloride are decreased. There may 
be an increased anion gap. The urine chloride can differen
-
tiate between saline-responsive (less than 25 mEq/L) and 
unresponsive (greater than 40 mEq/L) causes.
 
»
Treatment
Mild alkalosis is generally well tolerated. Severe or symp
-
tomatic alkalosis (pH > 7.60) requires urgent treatment.
Therapy for saline-responsive metabolic alkalosis is correc
-
tion of the extracellular volume deficit with isotonic saline. 
Diuretics should be discontinued. H
2
-blockers or proton 
pump inhibitors may be helpful in patients with alkalosis 
from nasogastric suctioning. If pulmonary or cardiovascu
-
lar disease prohibits adequate resuscitation, acetazolamide 
will increase renal bicarbonate excretion. Hypokalemia 
may develop because bicarbonate excretion may induce 
kaliuresis. Severe cases, especially those with reduced 
 
kidney function, may require dialysis with low-bicarbonate 
dialysate.
B. Saline-Unresponsive Metabolic Alkalosis
Therapy for saline-unresponsive metabolic alkalosis 
includes surgical removal of a mineralocorticoid-produc
-
ing tumor and blockage of aldosterone effect with an ACE 
inhibitor or with spironolactone (see Chapter 26). Meta
-
bolic alkalosis in primary aldosteronism can be treated 
only with potassium repletion.
Feldman M et al. Respiratory compensation to a primary meta
-
bolic alkalosis in humans. Clin Nephrol. 2012 Nov;78(5):365–9. 
 
[PMID: 22854166]
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RESPIRATORY ALKALOSIS
Respiratory alkalosis occurs when hyperventilation reduces 
the P
co
2
, increasing serum pH. The most common cause 
of respiratory alkalosis is hyperventilation syndrome 
(Table  21–16), but bacterial septicemia and cirrhosis are 
other common causes. In pregnancy, progesterone stimu
-
lates the respiratory center, producing an average P
co
2
 of 
30 mm Hg and respiratory alkalosis. Symptoms of acute 
respiratory alkalosis are related to decreased cerebral blood 
flow induced by the disorder.
Determination of appropriate metabolic compensation 
may reveal an associated metabolic disorder (see Mixed 
Acid-Base Disorders).
As in respiratory acidosis, the metabolic compensation 
is greater if the respiratory alkalosis is chronic (see 
Table  21–12). Although serum HCO
3
–
 is frequently less 
than 15 mEq/L in metabolic acidosis, such a low level in 
respiratory alkalosis is unusual and may represent a con
-
comitant primary metabolic acidosis.
 
»
In acute cases (hyperventilation), there is light-headedness, 
anxiety, perioral numbness, and paresthesias. Tetany 
Peixoto AJ et al. Treatment of severe metabolic alkalosis in a 
patient with congestive heart failure. Am J Kidney Dis. 2013 May;
 
61(5):822–7. [PMID: 23481366]
Soifer JT et al. Approach to metabolic alkalosis. Emerg Med Clin 
North Am. 2014 May;32(2):453–63. [PMID: 24766943]
Yi JH et al. Metabolic alkalosis from unsuspected ingestion: use 
of urine pH and anion gap. Am J Kidney Dis. 2012 Apr;59(4):
 
577–81. [PMID: 22265393]
RESPIRATORY ACIDOSIS (
Hypercapnia
)
Respiratory acidosis results from hypoventilation and sub
-
sequent hypercapnia. Pulmonary and extrapulmonary 
disorders can cause hypoventilation.
Acute respiratory failure is associated with severe aci
-
dosis and only a small increase in the plasma bicarbonate. 
After 6–12 hours, the primary increase in P
co
2
 evokes a 
renal compensation to excrete more acid and to generate 
more HCO
3
–
; complete metabolic compensation by the 
kidney takes several days.
Chronic respiratory acidosis is generally seen in patients 
with underlying lung disease, such as chronic obstructive 
pulmonary disease. Renal excretion of acid as NH
4
Cl results 
in hypochloremia. When chronic respiratory acidosis is cor
-
rected suddenly, posthypercapnic metabolic alkalosis ensues 
until the kidneys excrete the excess bicarbonate over 2–3 days.
 
»
With acute onset, somnolence, confusion, mental status 
changes, asterixis, and myoclonus may develop. Severe 
hypercapnia increases cerebral blood flow, cerebrospinal 
fluid pressure, and intracranial pressure; papilledema and 
pseudotumor cerebri may be seen.
Arterial pH is low and P
co
2
 is increased. Serum HCO
3
–
 is 
elevated but does not fully correct the pH. If the disorder is 
chronic, hypochloremia is seen. Respiratory etiologies of 
respiratory acidosis usually have a wide A-a gradient; a 
relatively normal A-a gradient suggests a nonpulmonary 
(eg, central) etiology.
 
»
Treatment
If opioid overdose is a possible diagnosis or there is no 
other obvious cause for hypoventilation, the clinician 
should consider a diagnostic and therapeutic trial of intra
-
venous naloxone (see Chapter 38). In all forms of respira
-
tory acidosis, treatment is directed at the underlying 
disorder to improve ventilation.
Bruno CM et al. Acid-base disorders in patients with chronic 
obstructive pulmonary disease: a pathophysiological review. J 
Biomed Biotechnol. 2012;2012:915150. [PMID: 22500110]
Chebbo A et al. Hypoventilation syndromes. Med Clin North 
Am. 2011 Nov;95(6):1189–202. [PMID: 22032434]
Schwartzstein RM et al. Rising PaCO
2
 in the ICU: using a physi
-
ologic approach to avoid cognitive biases. Chest. 2011 Dec;
 
140(6):1638–42. [PMID: 22147823]
Table 21–16.
 
Causes of respiratory alkalosis.
h
ypoxia

2
-
 
h
ypoxia
Decreased inspired oxygen tension
High altitude
Ventilation/perfusion inequality
Severe anemia
CNS-mediated disorders
Voluntary hyperventilation
Anxiety-hyperventilation syndrome
Neurologic disease
Cerebrovascular accident (infarction, hemorrhage)
Infection
Trauma
Tumor
Pharmacologic and hormonal stimulation
Nicotine
Xanthines
Pregnancy (progesterone)
Hepatic failure
Gram-negative septicemia
Recovery from metabolic acidosis
Heat exposure
p
ulmonar
y disease
Pneumonia
Mechanical overventilation
Adapted, with permission, from Gennari FJ. Respiratory acidosis 
and alkalosis. In: 
Maxwell and Kleeman’s Clinical Disorders of Fluid 
and Electrolyte Metabolism,
 5th ed. Narins RG (editor). McGraw-Hill, 
1994.
CMDT19_Ch21_p0898-p0925.indd   924

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CMDT 2019
occurs from a low ionized calcium, since severe alkalosis 
increases calcium binding to albumin.
Arterial blood pH is elevated, and P
co
2
 is low. Serum 
bicarbonate is decreased in chronic respiratory alkalosis.
 
»
Treatment
Treatment is directed toward the underlying cause. In acute 
hyperventilation syndrome from anxiety, the traditional 
treatment of breathing into a paper bag should be discour
-
aged because it does not correct P
co
2
 and may decrease 
P
o
2
. Reassurance may be sufficient for the anxious patient, 
but sedation may be necessary if the process persists. 
Hyperventilation is usually self-limited since muscle weak
-
ness caused by the respiratory alkalemia will suppress 
ventilation. Rapid correction of chronic respiratory alkalo
-
sis may result in metabolic acidosis as P
co
2
 is increased 
with a previous compensatory decrease in HCO
3
–
. The 
severity of hypocapnia in critically ill patients has been 
associated with adverse outcomes.
Batlle D et al. Metabolic acidosis or respiratory alkalosis? Evalu
-
ation of a low plasma bicarbonate using the urine anion gap. 
Am J Kidney Dis. 2017 Sep;70(3):440–4. [PMID: 28599903]
Palmer BF. Evaluation and treatment of respiratory alkalosis. 
Am J Kidney Dis. 2012 Nov;60(5):834–8. [PMID: 22871240]
 
º
FLUID MANAGEMENT
Daily parenteral maintenance fluids and electrolytes for an 
average adult of 70 kg would include at least 2 L of water in 
the form of 0.45% saline with 20 mEq/L of potassium 
chloride. Patients with hypoglycemia, starvation ketosis, or 
ketoacidosis being treated with insulin may require 5% 
dextrose-containing solutions. Guidelines for gastrointesti
-
nal fluid losses are shown in Table 21–17.
Weight loss or gain is the best indication of water bal
-
ance. Insensible water loss should be considered in febrile 
patients. Water loss increases by 100–150 mL/day for each 
degree of body temperature over 37°C.
In patients requiring maintenance and possibly replace
-
ment of fluid and electrolytes by parenteral infusion, the 
total daily ration should be administered continuously over 
24 hours to ensure optimal utilization.
If intravenous fluids are the only source of water, elec
-
trolytes, and calories for longer than a week, parenteral 
nutrition containing amino acids, lipids, trace metals, and 
vitamins may be indicated. (See Chapter 29.)
The ideal resuscitation fluid composition and dose are 
not established, and there is little evidence that one type of 
fluid (crystalloid, colloid, or semisynthetic colloid) is supe
-
rior to or safer than another. Excessive fluid resuscitation 
and maintenance are complications in hospitalized patients, 
especially those with critical illness or acute kidney injury, 
and have been associated with worsened outcomes such as 
prolonged mechanical ventilation, dependence on dialysis, 
and longer hospitalization with increased mortality.
Bentzer P et al. Will this hemodynamically unstable patient 
respond to a bolus of intravenous fluids? JAMA. 2016 Sep 27;
 
316(12):1298–309. [PMID: 27673307]
Moritz ML et al. Maintenance intravenous fluids in acutely ill 
patients. N Engl J Med. 2015 Oct;373(14):1350–60. [PMID: 
26422725]
Schindler AW et al. Evidence-based fluid management in the 
ICU. Curr Opin Anaesthesiol. 2016 Apr;29(2):158–65. 
[PMID: 26784351]
Table 21–17.
 
Replacement guidelines for sweat and gastrointestinal fluid losses.
Average Electrolyte Composition
Replacement Guidelines per Liter Lost
Na
+
 
(mEq/L)
K
+
 
(mEq/L)
Cl
–
 
(mEq/L)
h
CO
3
–
 
(mEq/L)
0.9% 
Saline 
(mL)
0.45% 
Saline 
(mL)
D
5
W 
(mL)
KCl 
(mEq/L)
7.5% Na
h
CO
3
 
(45 mEq 
 
h
CO
3
–
/amp)
Sweat
30–50
5
50
500
500
5
Gastric secretions
20
10
10
300
700
20
Pancreatic juice
130
5
35
115
400
600
5
2 amps
Bile
145
5
100
25
600
400
5
0.5 amp
Duodenal fluid
60
15
100
10
1000
15
0.25 amp
Ileal fluid
100
10
60
60
600
400
10
1 amp
Colonic diarrhea
140
1
10
85
60
1000
10
1 amp

130
5
35
115
400
600
5
2 amps
Bile
145
5
100
25
600
400
5
0.5 amp
60
15
100
10
1000
15
0.25 amp
100
10
60
60
600
400
10
1 amp
140
1
10
85
60
1000
10
1 amp
1
In the absence of diarrhea, colonic fluid Na
+
 levels are low (40 mEq/L).
CMDT19_Ch21_p0898-p0925.indd   925

926
 CMDT 2019
22
 
Although some patients with kidney disease experience 
evidence of their disease such as hypertension, edema, 
nausea, or hematuria that may lead to its discovery, kidney 
disease is often discovered incidentally during a routine 
medical evaluation. The initial approach to kidney disease 
is to assess the cause and severity of renal abnormalities. In 
all cases, this evaluation includes (1) estimation of disease 
duration, (2) careful examination of the urine, and (3) 
assessment of the glomerular filtration rate (GFR). The 
history and physical examination, though equally impor
-
tant, are variable among renal syndromes—thus, specific 
symptoms and signs are discussed under each disease entity.
 
º
ASSESSMENT OF KIDNEY DISEASE
 
»
Disease Duration
Kidney disease can be acute or chronic. Acute kidney 
injury (AKI) is worsening of kidney function over hours to 
days, resulting in retention of waste products (such as urea 
nitrogen) and creatinine in the blood. Retention of these 
substances is called azotemia. Chronic kidney disease 
(CKD) is the abnormal loss of kidney function over 
months to years. Differentiating between AKI and CKD is 
important for diagnosis and treatment, and certain clues 
may help distinguish the two. For instance, oliguria is only 
observed in AKI, whereas anemia (from low kidney eryth
-
ropoietin production) suggests CKD. Additionally, small 
kidney size on ultrasound or other imaging is more consis
-
tent with CKD, whereas normal to large kidney size can be 
seen with both acute and chronic disease.
 
»
Examination of the urine can provide important clues to 
underlying kidney disease. A urine specimen should be 
collected in midstream or by bladder catheterization and 
examined within 1 hour after collection to avoid destruction 
of formed elements. Urinalysis includes a dipstick examina
-
tion followed by microscopy if the dipstick has positive find
-
ings. The dipstick examination measures urinary pH, 
specific gravity, protein, hemoglobin, glucose, ketones, 
bilirubin, nitrites, and leukocyte esterase. Microscopy of 
centrifuged urinary sediment permits examination of 
formed elements—crystals, cells, casts, and infectious 
organisms. A bland (normal) sediment is common, espe
-
cially in CKD and acute nonparenchymal disorders, such 
as limited effective blood flow to the kidney or urinary 
obstruction. Urinary casts form when urine flow is slow, 
leading to precipitation of Tamm-Horsfall mucoprotein in 
the renal tubule; if there are many red or white blood cells 
in the urine, cellular casts may form. The presence of pro
-
tein on dipstick examination strongly suggests underlying 
glomerular disease. If the glomerular basement membrane 
(GBM) is damaged (eg, by inflammation), red blood cells 
may leak into the urinary space and appear “dysmorphic” 
(also called “acanthocytes”). Thus, proteinuria, hematuria 
with acanthocytes, and red blood cells casts are highly sug
-
gestive of glomerulonephritis. Heavy proteinuria and lipi
-
duria are consistent with nephrotic syndrome. Pigmented 
granular casts (also termed “muddy brown casts”) and 
renal tubular epithelial cells alone or in casts are hallmarks 
of acute tubular necrosis (ATN). White blood cells (includ
-
ing neutrophils and eosinophils), white blood cell casts 
(Table 22–1), and proteinuria of varying degree can be seen 
with pyelonephritis and interstitial nephritis; Wright and 
Hansel stains can detect eosinophiluria. Pyuria alone can 
indicate a urinary tract infection. Proteinuria and hematuria 
are discussed more thoroughly below.
A. Proteinuria
Proteinuria is defined as excessive protein excretion in the 
urine, generally greater than 150 mg/24 h in adults. Pro
-
teinuria more than 1–2 g/day is usually a sign of underly
-
ing glomerular kidney disease, whereas proteinuria less 
than 1 g/day can be due to multiple causes along the 
nephron segment, as listed below. Proteinuria can be

-
nephron segment, as listed below. Proteinuria can be 
accompanied by other clinical abnormalities—elevated 
blood urea nitrogen (BUN) and serum creatinine levels, 
abnormal urine sediment, or evidence of systemic illness 
(eg, fever, rash, vasculitis).
There are several reasons proteinuria may develop: (1) 
Functional proteinuria
 is a benign process stemming from 
stressors such as acute illness, exercise, and “orthostatic pro
-
teinuria. ” The latter condition, generally found in people 
under 30 years of age, usually causes protein excretion less 
 
Tyler Woodell, MD 
CMDT19_Ch22_p0926-p0965.indd   926
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927
 
CMDT 2019
than 1 g/day. The orthostatic nature of the proteinuria is 
confirmed by measuring an 8-hour overnight supine uri
-
nary protein excretion, which should be less than 50 mg. (2) 
Overload proteinuria
 can result from overproduction of 
circulating, filterable plasma proteins (monoclonal gam
-
mopathies), such as Bence Jones proteins associated with 
plasma cell myeloma (formerly multiple myeloma). Protein 
electrophoresis from the serum or urine will exhibit a dis
-
crete protein peak. Other examples of overload proteinuria 
include myoglobinuria in rhabdomyolysis and hemoglobin
-
uria in hemolysis. (3) 
Glomerular proteinuria
 results from 
effacement of epithelial cell foot processes and altered 
glomerular permeability with an increased filtration fraction 
of normal plasma proteins, as in diabetic nephropathy. Pro
-
tein electrophoresis will have a pattern exhibiting a large 
albumin spike indicative of the increased permeability of 
albumin across the damaged GBM. (4) 
Tubular proteinuria
 
occurs as a result of faulty reabsorption of normally filtered 
proteins in the proximal tubule, such as beta-2-microglobulin 
and immunoglobulin light chains. Causes may include ATN, 
toxic injury (lead, aminoglycosides and certain antiretrovirals), 
drug-induced interstitial nephritis, and hereditary meta
-
bolic disorders (Wilson disease and Fanconi syndrome).
Evaluation of proteinuria by urinary dipstick primarily 
detects albumin, overlooking the positively charged immu
-
noglobulin light chains. The light chains can be detected by 
the addition of sulfosalicylic acid to the urine specimen. 
Precipitation without dipstick detection of albumin indicates 
the presence of these paraproteins.
The next step is estimation of daily urinary protein 
excretion, which can be done by a random urine sample or 
a timed urine collection (typically over 24 hours). Collec
-
tion of a random urine sample is far simpler, and the ratio 
of urinary protein-to-creatinine concentration ([U
protein
]/
[U
creatinine
]) correlates with a 24-hour urinary protein col
-
lection (less than 0.2 is normal and corresponds to excre
-
tion of less than 200 mg/24 h). In a 24-hour urine 
collection, proteinuria more than 150 mg is abnormal and 
greater than 3.5 g is consistent with nephrotic range protein
-
uria. One benefit of a random urinary protein-to-creatinine 
Table 22–1.
 
Significance of specific urinary casts.
Type
Hyaline casts
Concentrated urine, febrile disease, after 
strenuous exercise, during diuretic therapy 
(not indicative of kidney disease)
Red cell casts
White cell casts
Pyelonephritis, interstitial nephritis 
 
(indicative of infection or inflammation)
Renal tubular cell 
casts
Acute tubular necrosis, interstitial nephritis
Coarse, granular 
casts
Nonspecific; can represent acute tubular 
necrosis
Broad, waxy casts
Chronic kidney disease (indicative of stasis 
in enlarged collecting tubules)
ratio is the minimization of error from overcollection or 
undercollection of urine in the 24-hour specimen. If a 
patient has abnormal proteinuria, a kidney biopsy may be 
indicated, particularly if accompanied by AKI. The clinical 
sequelae of proteinuria are discussed in the section on 
Nephrotic Spectrum Glomerular Diseases.
B. Hematuria
Hematuria is clinically significant if there are more than 
three red cells per high-power field on at least two occasions. 
It is usually detected incidentally by the urine dipstick 
examination or clinically following an episode of macro
-
scopic hematuria. The diagnosis must be confirmed via 
microscopic examination, as false-positive dipstick tests can 
be caused by myoglobin, oxidizing agents, beets and rhu
-
barb, hydrochloric acid, and bacteria. Transient hematuria is 
common, but it is less often of clinical significance in patients 
younger than 40 years due to lower concern for malignancy.
Hematuria may be due to renal or extrarenal causes.

Hematuria may be due to renal or extrarenal causes. 
Most worrisome are urologic malignancies (see Chapter 39). 
Extrarenal causes are addressed in Chapter 23. Renal 
causes account for approximately 10% of cases and are best 
considered anatomically as glomerular or extraglomerular. 
Glomerular causes include immunoglobulin A (IgA) 
nephropathy, thin GBM disease, membranoproliferative 
glomerulonephritis (MPGN), other hereditary glomerular 
diseases (eg, Alport syndrome), and systemic nephritic 
syndromes. The most common extraglomerular sources 
include cysts, calculi, interstitial nephritis, and renal neo
-
plasia. Currently, due to insufficient evidence, the United 
States Preventive Services Task Force gives no recommen
-
dation to screen for hematuria to test for bladder cancer in 
asymptomatic adults.
 
»
Estimation of GFR
The GFR provides a useful measure of kidney function at 
the level of the glomerulus. Patients with kidney disease 
can have a decreased GFR from any process that causes loss 
of nephron (and thus glomerular) mass. However, they can 
also have a normal or increased GFR, either from hyperfil
-
tration at the glomerulus or disease at a different segment 
of the nephron, interstitium, or vascular supply. The GFR 
measures the amount of plasma ultrafiltered across the 
glomerular capillaries and reflects the ability of the kidneys 
to filter fluids and various substances. Daily GFR in normal 
individuals is variable, with a range of 150–250 L/24 h or 
100–120 mL/min/1.73 m
2
 of body surface area. GFR can be 
estimated by determining the renal clearance of plasma 
substances that are not bound to plasma proteins, are freely 
filterable across the glomerulus and are neither secreted 
nor reabsorbed along the renal tubules. The formula used 
to determine the renal clearance of a substance is:
=
×
C
UV
P
where C is the clearance, U and P are the respective urine 
and plasma concentrations of the substance (mg/dL), and 
V
.
 is the urine flow rate (mL/min). In clinical practice, the 
CMDT19_Ch22_p0926-p0965.indd   927

Ch
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p
TE
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 CMDT 2019
clearance rate of endogenous creatinine (termed 
clearance
) is the primary way to estimate GFR. Creatinine 
is a product of muscle metabolism produced at a relatively 
constant rate and cleared by renal excretion. It is freely 
filtered by the glomerulus and not reabsorbed by the renal 
tubules. With stable kidney function, creatinine produc
-
tion and excretion are equal; thus, plasma creatinine con
-
centrations remain constant. However, creatinine is not a 
perfect indicator of GFR for the following reasons: (1) a 
small amount is normally eliminated by tubular secretion, 
and the fraction secreted progressively increases as GFR 
declines (overestimating GFR); (2) with severe kidney 
failure, gut microorganisms degrade creatinine; (3) dietary 
meat intake and muscle mass affect plasma creatinine levels; 
(4) commonly used drugs such as aspirin, cimetidine, pro
-
benecid, and trimethoprim reduce tubular secretion of 
creatinine, increasing the plasma creatinine concentration 
and falsely suggesting kidney dysfunction; and (5) the 
accuracy of the measurement necessitates a stable plasma 
creatinine concentration over a 24-hour period, so when 
values are changing during the development of and recov
-
ery from AKI, the creatinine clearance is unhelpful. Of 
note, the creatinine clearance is the traditional estimating 
equation used to determine drug dosing in patients with 
kidney disease.
One way to measure creatinine clearance is to perform 
a timed urine collection and determine the plasma creati
-
nine level midway through the collection. An incomplete 
or prolonged urine collection is a common source of error. 
A method of estimating the completeness of the collection 
is to calculate a 24-hour creatinine excretion; the amount 
should be constant:
U
c
 
r
 × V
.
    
= 15–20 mg/kg for healthy young women
U
c
 
r
 × V
.
    
= 
 
20–25 mg/k
g for healthy young men
The creatinine clearance (C
cr
) is approximately 100 mL/
min/1.73 m
2
 in healthy young women and 120 mL/min/ 
1.73 m
2
 in healthy young men. The creatinine clearance 
declines by an average of 0.8 mL/min/yr after age 40 years 
as part of the aging process, but this is variable, with 35% 
of subjects in one study having no decline in kidney func
-
tion over 10 years.
The Kidney Disease Improving Global Outcomes work
-
group recommends that estimated glomerular filtration 
rate (eGFR) in adults be calculated using serum creatinine. 
They recommend using the 2009 CKD-Epidemiology 
(EPI) Collaboration creatinine equation. An alternative 
creatinine-based GFR estimating equation is acceptable if 
it improves accuracy over the CKD-EPI equation. Several 
web-based calculators will calculate the eGFR (eg, www
 
.nephron.com).
Cystatin C
 is another endogenous marker of GFR 
that is filtered freely at the glomerulus, produced at a 
relatively constant rate, and less dependent on muscle 
mass. It is reabsorbed and partially metabolized in the 
renal tubular epithelial cells. Adding the measurement of 
cystatin C to serum creatinine can improve the accuracy 
of the eGFR. A large meta-analysis showed that cystatin 
C alone or in combination with serum creatinine is a 
stronger predictor of important clinical events, such as 
end-stage renal disease (ESRD) or death, than serum 
creatinine alone. Use of cystatin C improves classifica
-
tion of kidney disease and prediction of outcomes among 
at-risk individuals.
Creatinine clearance (C
cr
) can also be estimated using 
the Modification of Diet in Renal Disease (MDRD) Study 
equation, which incorporates serum creatinine, age, sex, 
and race to estimate GFR. However, multiple studies across 
many populations show that the CKD-EPI equation is 
more accurate. It is important to note that another formula, 
the Cockcroft and Gault formula, is still commonly used to 
determine drug dosing, but it was developed before the 
standardization of creatinine assays currently in use today

standardization of creatinine assays currently in use today 
and, thus, its use is not recommended.
BUN is another index used in assessing kidney func
-
tion. It is synthesized mainly in the liver and is the end 
product of protein catabolism. Urea is freely filtered by the 
glomerulus, but about 30–70% is reabsorbed in the renal 
tubules. Unlike creatinine clearance, which overestimates 
GFR, urea clearance underestimates GFR. Urea reabsorp
-
tion in the kidney decreases in volume repleted patients 
and increases (in conjunction with increased sodium reab
-
sorption) in volume depleted patients (who, therefore, have 
an increased BUN). A normal BUN:creatinine ratio is 
approximately 10:1, although this can vary between indi
-
viduals. With volume depletion, the ratio can increase to 
20:1 or higher. Other causes of increased BUN include 
increased catabolism (gastrointestinal [GI] bleeding, cell 
lysis, and corticosteroid usage), increased dietary protein, 
and decreased renal perfusion prompting increased sodium 
(and therefore BUN) reabsorption (eg, heart failure, renal 
artery stenosis) (Table 22–2). Reduced BUN levels are seen 
in liver disease and in the syndrome of inappropriate 
antidiuretic hormone (SIADH).
As patients approach end-stage renal disease (ESRD), a 
more accurate measure of GFR than creatinine clearance is 
the average of the creatinine and urea clearances. The cre
-
atinine clearance overestimates GFR, as mentioned above, 
while the urea clearance underestimates GFR. Therefore, 
an average of the two more accurately approximates the 
true GFR.
Table 22–2.
 
Conditions affecting BUN independently 
of GFR.
Increased BUN
 
Reduc
ed effective circulating blood volume (prerenal azotemia)
 
C
atabolic states (gastrointestinal bleeding, corticosteroid use)
 
H
igh-protein diets
 
Tetracycline
Decreased BUN
 
Liv
er disease
 
Sick
le cell anemia
 
SIADH
BUN, blood urea nitrogen; GFR, glomerular filtration rate; SIADH, 
syndrome of inappropriate antidiuretic hormone.
CMDT19_Ch22_p0926-p0965.indd   928

929
 
CMDT 2019
KIDNEY BIOPSY
Indications for percutaneous needle biopsy include (1) unex
-
plained AKI or CKD; (2) unexplained proteinuria and hema
-
turia; (3) previously identified and treated lesions to guide 
future therapy; (4) systemic diseases associated with kidney 
dysfunction, such as systemic lupus erythematosus (SLE), 
anti-GBM disease (Goodpasture syndrome), and granuloma
-
tosis with polyangiitis, to confirm the extent of renal involve
-
ment and to guide management; and (5) suspected kidney 
transplant rejection, to differentiate it from other causes of 
AKI. If a patient is unwilling to accept therapy based on 
biopsy findings, the risk of biopsy may outweigh its benefit. 
Relative contraindications include a solitary or ectopic kid
-
ney (exception: transplant allografts), horseshoe kidney, 
ESRD, congenital anomalies, and multiple cysts. Absolute 
contraindications include an uncorrected bleeding disorder, 
severe uncontrolled hypertension, renal infection, renal 
neoplasm, hydronephrosis, or an uncooperative patient.
Prior to a kidney biopsy, patients should not use medi
-
cations that prolong clotting times, and blood pressure 
should be less than 160/90 mm Hg. Blood work should 
include hemoglobin concentration, platelet count, pro
-
thrombin time, and partial thromboplastin time. After 
biopsy, hematuria occurs in nearly all patients, although 
less than 10% will have macroscopic hematuria. Patients 
should remain supine for 4–6 hours postbiopsy and should 
be closely monitored when the hemoglobin is more than 
1 g/dL lower than baseline by 6 hours postbiopsy.
Percutaneous kidney biopsies are generally safe. The 
major risk is bleeding, which may occur up to 72 hours post 
biopsy. More than half of patients will have at least a small 
hematoma; approximately 1% of patients will experience 
significant bleeding requiring a blood transfusion. Antico
-
agulation therapy should be held for 5–7 days postbiopsy if 
possible. The risks of nephrectomy and mortality are about 
0.06–0.08%. When a percutaneous needle biopsy is techni
-
cally not feasible and kidney tissue is deemed clinically essen
-
tial, a closed biopsy via interventional radiologic techniques 
or open biopsy under general anesthesia can be performed.
Becker GJ et al. Advances in urine microscopy. Am J Kidney Dis. 
2016 Jun;67(6):954–64. [PMID: 26806004]
Hogan JJ et al. The native kidney biopsy: update and evidence 
for best practice. Clin J Am Soc Nephrol. 2016 Feb;11:354–62. 
[PMID: 26339068]
Levey AS et al. Assessment of glomerular filtration rate in health 
and disease: a state of the art review. Clin Pharmacol Ther. 
2017 Sep;102(3):405–19. [PMID: 28474735]
O'Neill WC. Renal relevant radiology: use of ultrasound in kidney 
disease and nephrology procedures. Clin J Am Soc Nephrol. 
2014 Feb;9(2):373–81. [PMID: 24458082]
 
º
ACUTE KIDNEY INJU
r
Y
 
»
Rapid increase in serum creatinine.
 
»
Oliguria may be present.
 
»
Symptoms and signs depend on cause.
 
»
AKI is defined as an absolute increase in serum creatinine 
by 0.3 mg/dL or more within 48 hours or a relative 
increase of greater than or equal to 1.5 times baseline that 
is known or presumed to have occurred within 7 days. AKI 
is characterized as oliguric if urine production is less than 
400–500 mL/day or less than 20 mL/h. Clinically, AKI is 
characterized by an inability to maintain acid-base, fluid, 
and electrolyte balance and to excrete nitrogenous wastes. 
The three stages of AKI defined by the 2012 Kidney Dis
-
ease Improving Global Outcomes Clinical Practice Guide
-
lines for Acute Kidney Injury are based on the elevation in 
serum creatinine or decline in urinary output, both of 
which correlate with prognosis. 
Stage 1
 is a 1.0- to 1.5-fold 
increase in serum creatinine or a decline in urinary output 
to less than 0.5 mL/kg/h over 6–12 hours; 
stage 2
 is a

Stage 1
stage 2
 is a 
2.0- to 2.9-fold increase in serum creatinine or decline in 
urinary output to less than 0.5 mL/kg/h over 12 hours or 
longer; 
stage 3
 is a 3-fold or greater increase in serum 
creatinine, an increase in serum creatinine to greater than 
or equal to 4 mg/dL, a decline in urinary output to less 
than 0.3 mL/kg/h for 24 hours or longer, anuria for 
 
12 hours or longer, or initiation of renal replacement 
therapy. In the absence of functioning kidneys, serum 
creatinine concentration will typically increase by 1–1.5 mg/dL 
daily, although with certain conditions, such as rhabdomy
-
olysis, serum creatinine can increase more rapidly. On 
average, 5% of hospital admissions and 30% of intensive 
care unit (ICU) admissions carry a diagnosis of AKI, and 
it will develop in 25% of hospitalized patients. Patients 
with AKI of any type are at higher risk for all-cause mor
-
tality according to prospective cohort studies, even if renal 
recovery is substantial. The rates of AKI in the hospital 
setting have increased steadily since the 1980s and are 
continuing to rise.
 
»
Although many patients will not experience any symptoms 
or exhibit any signs of AKI, the buildup of waste products 
can sometimes cause nonspecific symptoms and signs col
-
lectively termed 
uremia.
 Additionally, patients may experi
-
ence symptoms and signs of the underlying disease process 
causing their AKI (eg, SLE). Uremia can cause nausea, 
vomiting, malaise, and altered sensorium. Hypertension 
can occur, and fluid homeostasis is often impaired. Hypo
-
volemia can cause states of low blood flow to the kidneys, 
sometimes termed “prerenal” states, whereas hypervolemia 
can result from intrinsic or “postrenal” disease. Pericardial 
effusions can occur with uremia and may result in cardiac 
tamponade; a pericardial friction rub can be present, sig
-
naling pericarditis. Arrhythmias can occur, especially with 
hyperkalemia. The lung examination may reveal rales in 
the presence of hypervolemia. AKI can cause nonspecific 
diffuse abdominal pain and ileus as well as platelet dys
-
function; bleeding and clotting disorders are more com
-
mon in these patients. The neurologic examination 
sometimes reveals encephalopathic changes with asterixis 
and confusion; seizures may ensue in significant AKI.
CMDT19_Ch22_p0926-p0965.indd   929

Ch
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 CMDT 2019
Elevated BUN and serum creatinine levels are present, 
though these elevations do not distinguish AKI from 
CKD. Anion gap and non-gap metabolic acidosis (due to 
decreased clearance of organic and nonorganic acids) are 
often noted. Hyperkalemia can occur from impaired renal 
potassium excretion or from extracellular shifting of 
potassium into the blood as a result of metabolic acidosis. 
With hyperkalemia, the ECG can reveal peaked T waves, 
PR prolongation, and QRS widening. A long QT segment 
can occur with hypocalcemia. Hyperphosphatemia occurs 
when phosphorus cannot be secreted by damaged tubules 
either with or without increased cell catabolism. Anemia 
can occur as a result of decreased erythropoietin produc
-
tion over weeks, and associated platelet dysfunction is 
typical.
 
»
Classification & Etiology
AKI can be divided into three categories: prerenal causes 
(kidney hypoperfusion leading to lower GFR), intrinsic 
kidney disease, and postrenal causes (obstructive uropathy 
or other obstruction to outflow). Identifying the cause is 
the first step toward treating the patient (Table 22–3).
A. Prerenal Causes
Prerenal causes are the most common etiology of AKI, 
accounting for 40–80% of cases, depending on the popula
-
tion studied. Prerenal azotemia is due to renal hypoperfu
-
sion, which is an appropriate physiologic change. If reversed 
quickly with restoration of renal blood flow (eg, fluid resus
-
citation), renal parenchymal damage often does not occur. 
If hypoperfusion persists, ischemia can lead to intrinsic 
kidney injury.
Decreased renal perfusion can occur in several ways, 
such as a decrease in intravascular volume, a change in 
vascular resistance, or low cardiac output. Causes of 
volume depletion include hemorrhage (eg, from trauma), 
GI losses, dehydration, excessive diuresis, and extravas
-
cular space sequestration (eg, pancreatitis, burns, and 
peritonitis).
Changes in vascular resistance can occur systemically 
with sepsis, anaphylaxis, anesthesia, and afterload-reducing 
drugs. Blockade of the renin-angiotensin-aldosterone 
system, such as with angiotensin-converting enzyme 
(ACE) inhibitors, limits efferent renal arteriolar constric
-
tion out of proportion to afferent arteriolar constriction; 
GFR will decrease with these medications. Nonsteroidal 
anti-inflammatory drugs (NSAIDs) minimize afferent 
arteriolar vasodilation by inhibiting prostaglandin-mediated 
signals. Thus, in cirrhosis and heart failure, when prosta
-
glandins are recruited to increase renal blood flow, NSAIDs 
will have particularly deleterious effects. Epinephrine, 
norepinephrine, high-dose dopamine, anesthetic agents, 
and calcineurin inhibitors also can cause renal vasocon
-
striction. Renal artery stenosis causes increased resistance 
and decreased renal perfusion.
Low cardiac output is a state of low effective renal arterial 
blood flow. This occurs in states of cardiogenic shock, heart 
failure, pulmonary embolism, and pericardial tamponade. 
Arrhythmias and valvular disorders can also reduce cardiac 
output. In the intensive care setting, positive pressure venti
-
lation will decrease venous return and, in effect, cardiac 
output.
When GFR falls acutely, it is important to determine 
whether AKI is due to prerenal or intrinsic renal causes. 
The history and physical examination are important, and 
urinalysis may be helpful in distinguishing between these 
causes. In prerenal causes of AKI, the BUN:creatinine ratio 
Table 22–3.
 
Classification and differential diagnosis of acute kidney injury.
p
r
erenal 
Azotemia
p
ostr
enal 
Azotemia
Intrinsic 
r
enal Disease
Acute Tubular 
Necrosis
Acute Glomerulonephritis
Acute Interstitial 
Nephritis
Etiology
Poor renal 
perfusion
Obstruction of the 
urinary tract
Ischemia, 
nephrotoxins
Immune complex-mediated, 
pauci-immune, anti-GBM 
related, monoclonal 
 
immunoglobulin–
 
mediated, 
 
C3 glomerulopathy

perfusion
Ischemia, 
 
mediated, 
 
Allergic reaction; drug 
reaction; infection, 
collagen vascular 
disease
Serum BUN:Cr ratio
> 20:1
> 20:1
< 20:1
> 20:1
< 20:1
U
Na
 (mEq/L)
< 20
Variable
> 20
< 20
Variable
F
E
Na
 (%)
< 1
Variable
> 1 (when oliguric)
< 1
< 1; > 1
Urine osmolality 
(mOsm/kg)
> 500
< 400
250–300
Variable
Variable
Urinary sediment
Benign or 
hyaline 
casts
Normal or red cells, 
white cells, or 
crystals
Granular (muddy 
brown) casts, renal 
tubular casts
Red cells, dysmorphic red 
cells and red cell casts
White cells, white cell 
casts, with or with
-
out eosinophils
BUN:Cr, blood urea nitrogen:creatinine ratio; F
E
Na
, fractional excretion of sodium; GBM, glomerular basement membrane; U
Na
, urinary 
concentration of sodium.
CMDT19_Ch22_p0926-p0965.indd   930

931
 
CMDT 2019
often exceeds 20:1 due to increased urea reabsorption. In 
an oliguric patient, another useful index is the fractional 
excretion of sodium (F
E
Na
). With decreased GFR, the 
kidney will reabsorb salt and water avidly if there is no 
intrinsic tubular dysfunction. Thus, patients with prerenal 
causes of AKI should have a low fractional excretion per
-
cent of sodium (less than 1%). Oliguric patients with 
intrinsic kidney dysfunction typically have a high frac
-
tional excretion of sodium (greater than 1–2%). The F
E
Na
 
is calculated as follows: F
E
Na
 = clearance of Na
+
/GFR = 
 
clearance of Na
+
/C
cr
:
=×
F
Ur
in
e/
Se
ru
m
Ur
in
e/
Se
ru
m
100%
E
Na
Na
Na
cr
cr
The equation was specifically created and validated to 
assess the difference between 
oliguric
 ATN and prerenal 
states. Renal sodium handling is more accurately assessed 
by the F
E
Na
 in oliguric states than in nonoliguric states 
because the F
E
Na
 could be relatively low in nonoliguric 
ATN if sodium intake and excretion are relatively low. Of 
note, diuretics act by increasing sodium excretion and so if 
the F
E
Na
 is high within 12–24 hours after diuretic adminis
-
tration, the cause of AKI cannot be accurately assessed. In 
contrast, a low F
E
Na
 
despite
 receiving diuretics offers strong 
evidence of prerenal states in oliguric patients. AKI due to 
glomerulonephritis may result in a low F
E
Na
 if tubular 
function is intact.
Treatment of prerenal AKI depends entirely on the 
causes, but achievement of euvolemia, attention to serum 
electrolytes, and avoidance of nephrotoxic drugs are bench
-
marks of therapy. This involves careful assessment of volume 
status, cardiac function, diet, and drug usage.
B. Postrenal Causes
Postrenal causes of AKI are the least common, accounting 
for approximately 5–10% of cases, but are important to 
detect because of their reversibility. Postrenal azotemia 
occurs when urinary flow from both kidneys, or a single 
functioning kidney, is obstructed. Occasionally, postrenal 
uropathies can occur when a single kidney is obstructed if 
the contralateral kidney cannot compensate for the loss in 
function, (eg, in a patient with advanced CKD). Obstruc
-
tion leads to elevated intraluminal pressure and resultant 
kidney parenchymal damage, with marked effects on renal 
blood flow and tubular function and a decrease in GFR.
Postrenal causes of AKI include urethral obstruction, 
bladder dysfunction or obstruction, and obstruction of 
both ureters or renal pelvises. In men, benign prostatic 
hyperplasia is the most common cause. Patients taking 
anticholinergic drugs are at risk for urinary retention. 
Obstruction can also be caused by bladder, prostate, and 
cervical cancers; retroperitoneal fibrosis; and neurogenic 
bladder. Less common causes are blood clots, bilateral ure
-
teral stones, urethral stones or strictures, and bilateral 
papillary necrosis.
Patients may be anuric or polyuric and may experience 
lower abdominal pain. Polyuria can occur in the setting of 
partial obstruction with resultant tubular dysfunction and 
an inability to appropriately reabsorb salt and water loads. 
Obstruction can be constant or intermittent and partial or 
complete. On examination, the patient may have an 
enlarged prostate, distended bladder, or mass detected on 
pelvic examination.
Laboratory examination may initially reveal high urine 
osmolality, low urine sodium, high BUN:creatinine ratio, 
and low F
E
Na
 (as tubular function may not be compro
-
mised initially). These indices are similar to a prerenal 
picture because extensive intrinsic renal damage has not 
yet occurred. After several days, however, the urine sodium 
increases as the kidneys fail and are unable to concentrate 
the urine—thus, isosthenuria is present. The urine sedi
-
ment is generally bland.
Patients with AKI and suspected postrenal insults 
should undergo bladder catheterization and ultrasonogra
-

-
-
phy to assess for hydroureter and hydronephrosis. After 
reversal of the underlying process, these patients often 
undergo a postobstructive diuresis, and care should be 
taken to avoid volume depletion. Rarely, obstruction is not 
diagnosed by ultrasonography. For example, patients with 
retroperitoneal fibrosis from tumor or radiation may not 
show dilation of the urinary tract. If suspicion persists, a 
CT scan or MRI (without gadolinium, which can cause 
nephrogenic systemic sclerosis if given to patients with 
eGFR less than 30 mL/min/1.73 m
2
) can establish the diag
-
nosis. Prompt treatment of obstruction within days by 
catheters, stents, or other surgical procedures can result in 
partial or complete reversal of the acute process.
C. Intrinsic Acute Kidney Injury
Intrinsic renal disorders account for up to 50% of all cases 
of AKI referred to a nephrologist. Intrinsic dysfunction is 
considered after prerenal and postrenal causes have been 
excluded. The potential sites of injury are the tubules, 
interstitium, vasculature, and glomeruli.
 
»
•	
If a patient has signs of AKI that have not reversed over 
1–2 weeks without uremia, the patient can usually be 
referred to a nephrologist rather than admitted.
•	
If a patient has signs of persistent urinary tract obstruc
-
tion, the patient should be referred to a urologist.
 
»
The patient should be admitted if there is sudden loss of 
kidney function resulting in abnormalities that cannot be 
handled expeditiously in an outpatient setting (eg, hyper
-
kalemia, volume overload, uremia) or other requirements 
for acute intervention, such as emergent urologic intervention 
or dialysis.
Okusa MD et al. Reading between the (guide)lines—the KDIGO 
practice guideline on acute kidney injury in the individual 
patient. Kidney Int. 2014 Jan;85(1):39–48. [PMID: 24067436]
Ostermann M et al. Acute kidney injury 2016: diagnosis and 
diagnostic workup. Crit Care. 2016 Sep 27;20(1):299–312. 
[PMID: 27670788]
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Thomas ME et al. The definition of acute kidney injury and its 
use in practice. Kidney Int. 2015 Jan;87(1):62–73. [PMID: 
25317932]
ACUTE TUBULAR NECROSIS
 
»
AKI.
 
»
Ischemic or toxic insult or underlying sepsis.
 
»
Urine sediment with pigmented granular casts and 
renal tubular epithelial cells is pathognomonic but 
not essential.
 
»
AKI due to tubular damage is termed “acute tubular necrosis” 
and accounts for approximately 85% of intrinsic AKI. The 
two major causes of ATN are ischemia and nephrotoxin 
exposure. Ischemic AKI is characterized not only by inade
-
quate GFR but also by renal blood flow that is inadequate to 
maintain parenchymal cellular perfusion. Renal tubular 
damage with low effective arterial blood flow to the kidney 
can result in tubular necrosis and apoptosis. This occurs in 
the setting of prolonged hypotension or hypoxemia, such as 
volume depletion or shock. Underlying sepsis can also be an 
independent risk factor for ATN. Major surgical procedures 
can involve prolonged periods of hypoperfusion, which are 
exacerbated by vasodilating anesthetic agents.
A. Exogenous Nephrotoxins
 cause some degree of ATN in up to 25% 
of hospitalized patients receiving therapeutic levels of the 
drugs. Nonoliguric kidney injury typically occurs after 
5–10 days of exposure. Predisposing factors include under
-
lying kidney damage, volume depletion, and advanced age. 
Aminoglycosides can remain in renal tissue for up to a 
month, so renal recovery may be delayed after stopping the 
medication. Monitoring of peak and trough levels is 
important, but trough levels are more helpful in predicting 
renal toxicity. Gentamicin and tobramycin are equally 
nephrotoxic; streptomycin is the least nephrotoxic of the 
aminoglycosides, likely due to the number of cationic 
amino side chains present on each molecule.
Amphotericin B
 is typically nephrotoxic after a dose of 
2–3 g. This causes a type I (distal) renal tubular acidosis 
with severe vasoconstriction and distal tubular damage, 
which can lead to hypokalemia and nephrogenic diabetes 
, intravenous 
acyclovir
, and several 
cephalosporins
 have also been known to cause or be asso
-
ciated with ATN.
Radiographic contrast media
 may be directly nephro
-
toxic. Contrast nephropathy is the third leading cause of 
incident AKI in hospitalized patients and is thought to 
result from the synergistic combination of direct renal 
tubular epithelial cell toxicity and renal medullary ischemia. 
Predisposing factors include advanced age; preexisting 
kidney disease (serum creatinine greater than 2 mg/dL); 
volume depletion; diabetic nephropathy; heart failure; 
plasma cell myeloma; repeated doses of contrast; and recent 
exposure to other nephrotoxic agents, including NSAIDs 
and ACE inhibitors. The combination of preexisting diabe
-
tes mellitus and kidney dysfunction poses the greatest risk 
(15–50%) for contrast nephropathy. Lower volumes of con
-
trast with lower osmolality are recommended in high-risk 
patients. Toxicity usually occurs within 24–48 hours after 
the radiocontrast study. Nonionic contrast media may be 
less toxic, but this has not been well proven. Prevention of 
contrast nephropathy is the goal when using these agents. 
The mainstay of therapy is 500–1000 mL of intravenous 
0.9% saline over 10–12 hours both before and after the con
-
trast administration—cautiously in patients with preexist
-
ing cardiac dysfunction. Isotonic intravenous volume 
repletion is superior to hypotonic intravenous solutions, 
and both are superior to oral solutions in small studies. 
Other nephrotoxic agents should be avoided during the day 
before and after dye administration. Neither mannitol nor 
furosemide offers benefit over 0.9% (normal) saline admin
-
istration. In fact, furosemide may lead to increased rates of 
kidney dysfunction in this setting. 
N-

-
N-
acetylcysteine, a thiol-
containing antioxidant with little toxicity whose mecha
-
nism of action is unclear, has been proposed to decrease the 
incidence of contrast nephropathy when given before and 
after the contrast agent. Investigators have shown conflict
-
ing results when using sodium bicarbonate (154 mEq/L, 
intravenously at 3 mL/kg/h for 1 hour before the procedure, 
then 1 mL/kg/h for 6 hours after the procedure) over a more 
conventional regimen of normal saline as the isotonic vol
-
ume expander. However, after years of clinical equipoise, 
the largest randomized controlled trial (5177 patients) com
-
paring normal saline versus sodium bicarbonate and 
N
-acetylcysteine versus placebo in preventing AKI was 
completed in 2017. The primary outcome was a composite 
of death, need for dialysis, or persistent increase in serum 
creatinine of at least 50% from baseline at 90 days. The 
trial, a 2-by-2 factorial design, was stopped early during 
prespecified interim analysis when no benefit was demon
-
strated with either sodium bicarbonate or 
N
-acetylcysteine 
compared to normal saline or placebo, respectively.
 toxicity is usually dose dependent. It 
causes distal tubular dysfunction (a type 4 renal tubular 
acidosis) and severe vasoconstriction. Regular blood level 
monitoring is important to prevent both acute and chronic 
nephrotoxicity. In patients who are taking cyclosporine to 
prevent kidney allograft rejection, kidney biopsy is often 
necessary to distinguish transplant rejection from cyclo
-
sporine toxicity. Kidney function usually improves after 
reducing the dose or stopping the drug.
Other exogenous nephrotoxins include antineoplastics, 
such as cisplatin and organic solvents, and heavy metals 
such as mercury, cadmium, and arsenic. Exogenous neph
-
rotoxins more commonly cause damage than endogenous 
nephrotoxins.
B. Endogenous Nephrotoxins
Endogenous nephrotoxins include heme-containing products, 
uric acid, and paraproteins. 
Myoglobinuria
 as a consequence 
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of rhabdomyolysis leads to ATN. Necrotic muscle releases 
large amounts of myoglobin, which is freely filtered across 
the glomerulus. The myoglobin is reabsorbed by the renal 
tubules, and direct damage can occur. Distal tubular obstruc
-
tion from pigmented casts and intrarenal vasoconstriction 
can also cause damage. This type of kidney injury occurs in 
the setting of crush injury, or muscle necrosis from prolonged 
unconsciousness, seizures, cocaine, and alcohol abuse. Dehy
-
dration and acidosis predispose to the development of 
myoglobinuric AKI. Patients may complain of muscle pain 
and often have signs of muscle injury. Rhabdomyolysis of 
clinical importance commonly occurs with a serum cre
-
atine kinase (CK) greater than 20,000–50,000 international 
units/L; one study showed that 58% of patients with AKI 
from rhabdomyolysis had CK levels greater than 16,000 
international units/L, while only 11% of patients without 
kidney injury had CK values greater than 16,000 interna
-
tional units/L. The globin moiety of myoglobin will cause 
the urine dipstick to read falsely positive for hemoglobin: 
the urine appears dark brown, but no red cells are present. 
With lysis of muscle cells, patients also become hyperka
-
lemic, hyperphosphatemic, and hyperuricemic. Hypocalcemia 
may ensue due to phosphorus and calcium precipitation. 
The mainstay of treatment is volume repletion with normal 
saline. Adjunctive treatments with mannitol and alkalini
-
zation of the urine have not been proven to change out
-
comes in human trials. As the patient recovers, calcium 
can move back from tissues to plasma, so early exogenous 
calcium administration for hypocalcemia is not recom
-
mended unless the patient is symptomatic or the level 
becomes exceedingly low in an unconscious patient; cal
-
cium repletion can result in hypercalcemia later in the 
course of the illness.
 can cause a similar form of ATN. Massive 
intravascular hemolysis is seen in transfusion reactions and 
in certain hemolytic anemias. Reversal of the underlying 
disorder and hydration are the mainstays of treatment.
Hyperuricemia
 can occur in the setting of rapid cell 
turnover and lysis. Chemotherapy for germ cell neoplasms 
and leukemia and lymphoma are the primary causes. Spon
-
taneous tumor lysis syndrome is a less common cause. AKI 
occurs with intratubular deposition of uric acid crystals; 
serum uric acid levels are often greater than 15–20 mg/dL and 
urine uric acid levels are typically greater than 600 mg/24 h. 
A urine uric acid to urine creatinine ratio greater than 
1.0 identifies individuals at risk for AKI. Allopurinol or 
rasburicase can be used prophylactically, and rasburicase 
with or without dialysis is often used for treatment in diag
-
nosed cases.
Bence Jones proteinuria
 seen in conjunction with 
plasma cell myeloma can cause direct tubular toxicity and 
tubular obstruction. Other renal complications from plasma 
cell myeloma include hypercalcemia and renal tubular dys
-
function, including proximal renal tubular acidosis (see 
Plasma Cell Myeloma below).
 
»
See Acute Kidney Injury.
Hyperkalemia and hyperphosphatemia are commonly 
present. The BUN:creatinine ratio is usually less than 20:1 
because tubular function is not intact, as described in the 
general section on AKI (Table 22–3). Urinary output can 
be oliguric or nonoliguric, with oliguria portending a 
worse prognosis. Urine sodium concentration and the F
E
Na
 
are typically elevated, indicative of tubular dysfunction. 
Urinalysis may show evidence of acute tubular damage; the 
presence of two or more muddy brown casts or renal tubu
-
lar epithelial cells are strongly predictive of ATN but have a 
low negative predictive value (see Table 22–1).
 
»
Treatment
Treatment of ATN is aimed at hastening recovery and 
avoiding complications. Preventive measures should be

»
Treatment
avoiding complications. Preventive measures should be 
taken to avoid volume overload and hyperkalemia. A pro
-
spective randomized controlled trial did not show a benefit 
from loop diuretics on either recovery from AKI or death. 
Widespread use of diuretics in critically ill patients with 
AKI should be encouraged only when otherwise clinically 
indicated (eg, in states of volume overload). Disabling side 
effects of supranormal dosing include hearing loss and 
cerebellar dysfunction. This is mainly due to peak furose
-
mide levels and can be minimized by the use of a continu
-
ous furosemide infusion. A starting dose of 0.1–0.3 mg/kg/h 
is appropriate, increasing to a maximum of 0.5–1 mg/kg/h, 
as needed; a bolus of 1–1.5 mg/kg should be administered 
with each dose escalation. Thiazide diuretics can be used to 
augment urinary output; metolazone (2.5–5 mg orally 
every 12–24 hours) or chlorothiazide (250–500 mg intrave
-
nously every 8–12 hours) are reasonable choices. Metola
-
zone is less expensive than intravenous chlorothiazide and 
has reasonable bioavailability. Short-term effects of loop 
diuretics include activation of the renin-angiotensin sys
-
tem. A 2012 randomized controlled trial did not show a 
benefit on mortality from plasma ultrafiltration compared 
to intravenous diuretics in patients with decompensated 
heart failure. Thus, ultrafiltration should generally be 
reserved for ICU patients with AKI in need of volume 
removal who are nonresponsive to diuretics, with the rec
-
ognition that this has not ultimately improved survival in 
this patient population. Nutritional support should meet 
daily needs while preventing excessive catabolism. Dietary 
protein restriction of 0.6 g/kg/day helps prevent metabolic 
acidosis. Hypocalcemia and hyperphosphatemia can be 
improved with dietary modification and phosphate-binding 
agents taken with meals three times daily; examples 
include aluminum hydroxide (500 mg orally) over the 
short term, and calcium carbonate (500–1500 mg orally), 
calcium acetate (667 mg, two or three tablets), sevelamer 
carbonate (800–1600 mg orally), and lanthanum carbonate 
(1000 mg orally) over longer periods. Hypocalcemia should 
not be treated in patients with rhabdomyolysis unless they 
are symptomatic. Hypermagnesemia can occur because of 
reduced magnesium excretion by the renal tubules, so 
magnesium-containing antacids and laxatives should be 
avoided in these patients. Dosages of all medications must 
be adjusted for drugs eliminated by the kidney.
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Indications for dialysis in AKI from ATN or other 
intrinsic disorders include life-threatening electrolyte dis
-
turbances (such as hyperkalemia), volume overload unre
-
sponsive to diuresis, refractory acidosis, and uremic 
complications (eg, encephalopathy, pericarditis, and sei
-
zures). In gravely ill patients, less severe but worsening 
abnormalities may also be indications for dialytic support. 
Two large randomized controlled trials showed that an 
intensive dialysis dose was not superior to a more conven
-
tional dose. Further, two 2016 randomized controlled trials 
comparing early versus delayed initiation of dialysis for 
AKI showed conflicting results.
 
»
The clinical course of ATN is often divided into three 
phases: initial injury, maintenance, and recovery. The main
-
tenance phase is expressed as either oliguric (urinary output 
less than 500 mL/day) or nonoliguric. Nonoliguric ATN has 
a better outcome. Conversion from oliguric to nonoliguric 
states with the use of diuretics has not been shown to 
change prognosis. While dopamine has sometimes been 
used for this purpose, numerous studies have shown that its 
use in this setting is not beneficial. Average duration of the 
maintenance phase is 1–3 weeks, but some cases may last 
several months. Cellular repair and removal of tubular 
debris occur during this period. The recovery phase can be 
heralded by diuresis. This can be due to inability of recover
-
ing renal tubules to reabsorb salt and water appropriately, 
and a solute diuresis from elevated BUN levels. GFR begins 
to rise; BUN and serum creatinine fall.
The mortality rate associated with AKI is 20–50% in 
hospitalized settings, and up to 70% for those in the ICU 
requiring dialysis with additional comorbid illnesses, both 
of which are actually slightly improved according to retro
-
spective cohort studies conducted within the past decade. 
Increased mortality is associated with advanced age, severe 
underlying disease, and multisystem organ failure. Leading 
causes of death are infections, fluid and electrolyte distur
-
bances, and worsening of underlying disease.
 
»
•	
Nephrology referral improves outcomes in AKI.
•	
For fluid, electrolyte, and acid-base abnormalities that 
are recalcitrant to interventions.
 
»
A patient with symptoms or signs of AKI that require 
immediate intervention, such as administration of intrave
-
nous fluids, or dialytic therapy, or that require a team 
approach that cannot be coordinated as an outpatient.
Gaudry S et al; AKIKI Study Group. Initiation strategies for 
renal-replacement therapy in the intensive care unit. N Engl J 
Med. 2016 Jul 14;375(2):122–33. [PMID: 27181456]
Weisbord SD et al; PRESERVE Trial Group. Outcomes after 
angiography with sodium bicarbonate and acetylcysteine.
 
 N Engl J Med. 2018 Feb 15;378(7):603–14. [PMID: 29130810]
Zarbock A et al. Effect of early vs delayed initiation of renal 
replacement therapy on mortality in critically ill patients with 
acute kidney injury: the ELAIN randomized clinical trial. 
JAMA. 2016 May 24–31;315(20):2190–9. [PMID: 27209269]
INTERSTITIAL NEPHRITIS
 
»
Fever.
 
»
Transient maculopapular rash.
 
»
Acute or chronic kidney injury.
 
»
Pyuria (including eosinophiluria), white blood cell 
casts, and hematuria.
 
»
Acute interstitial nephritis accounts for 10–15% of cases of 
intrinsic renal failure. An interstitial inflammatory response 
with edema and possible tubular cell damage is the typical 
pathologic finding.
Although drugs account for over 70% of cases, acute inter
-
stitial nephritis also occurs in infectious diseases or immuno
-
logic disorders or as idiopathic conditions. The most common 
drugs implicated are penicillins and cephalosporins, sulfon
-

-
-
-
amides and sulfonamide-containing diuretics, NSAIDs, 
proton pump inhibitors, rifampin, phenytoin, and allopuri
-
nol. Infectious causes include streptococcal infections, 
leptospirosis, cytomegalovirus, histoplasmosis, and Rocky 
Mountain spotted fever. Immunologic entities are more 
commonly associated with glomerulonephritis, but SLE, 
Sjögren syndrome, sarcoidosis, and cryoglobulinemia can 
cause interstitial nephritis.
 
»
Clinical features can include fever (more than 80% of 
cases), rash (25–50%), arthralgias, and peripheral blood 
eosinophilia (80%). The classic triad of fever, rash, and 
arthralgias is present in only 10–15% of cases. The urine 
often contains white cells (95%), red cells, and white cell 
casts. Proteinuria can be a feature, particularly in NSAID-
induced interstitial nephritis, but is usually modest (less 
than 2 g/24 h). Eosinophiluria is neither very sensitive nor 
specific but can be detected by Wright or Hansel stain.
 
»
Acute interstitial nephritis often carries a good prognosis, 
with recovery occurring over weeks to months. Urgent 
dialytic therapy may be necessary in up to one-third of all 
referred patients before resolution but patients rarely prog
-
ress to ESRD. Those with prolonged courses of oliguria and 
advanced age have a worse prognosis. Treatment consists 
of supportive measures and removal of the inciting agent. 
If kidney injury persists after these steps, a short course of 
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corticosteroids can be considered, although the data to 
support use of corticosteroids are not substantial and their 
efficacy may depend on the time that has elapsed between 
onset of AKI and their initiation. Short-term, high-dose 
methylprednisolone (0.5–1 g/day intravenously for 1–4 
days) or prednisone (60 mg/day orally for 1–2 weeks) fol
-
lowed by a prednisone taper can be used in these more 
severe cases of drug-induced interstitial nephritis.
GLOMERULONEPHRITIS
 
»
Hematuria, mild proteinuria.
 
»
Non-dysmorphic or dysmorphic red cells.
 
»
Red cell casts pathognomonic but not required for 
 
»
Dependent edema and hypertension.
 
»
AKI.
 
»
Acute glomerulonephritis is a relatively uncommon cause 
of AKI, accounting for about 5% of cases. Pathologically, 
inflammatory glomerular lesions are seen. These include 
mesangioproliferative, focal and diffuse proliferative, and 
crescentic lesions. The larger the percentage of glomeruli 
involved and the more severe the lesion, the more likely it 
is that the patient will have a poor clinical outcome.
Acute glomerulonephritis is classified according to patho
-
genic type, which can be aided by serologic analysis. Markers 
include anti-GBM antibodies, antineutrophil cytoplasmic 
antibodies (ANCAs), and other immune markers of disease.
Immune complex deposition
 usually occurs when 
moderate antigen excess over antibody production occurs. 
Complexes formed with marked antigen excess tend to 
remain in the circulation. Antibody excess with large anti
-
gen–antibody aggregates usually results in phagocytosis 
and clearance of the precipitates by the mononuclear 
phagocytic system in the liver and spleen. Causes include 
IgA nephropathy, infection-related glomerulonephritis, 
lupus nephritis, and cryoglobulinemic glomerulonephritis 
(often associated with hepatitis C virus [HCV]).
Anti-GBM–associated acute glomerulonephritis
 is 
either confined to the kidney or associated with pulmonary 
hemorrhage. The latter is termed “Goodpasture syn
-
drome. ” Injury is related to autoantibodies against type IV 
collagen in the GBM rather than to immune complex 
deposition.
Pauci-immune acute glomerulonephritis
 is a form of 
small-vessel vasculitis associated with ANCAs, causing 
kidney diseases without direct immune complex deposi
-
tion or antibody binding. Tissue injury is believed to be 
due to cell-mediated immune processes. An example is 
granulomatosis with polyangiitis, a systemic necrotizing 
vasculitis of small arteries and veins associated with intra
-
vascular and extravascular granuloma formation. In 
addition to glomerulonephritis, these patients can have 
upper airway, pulmonary, and skin manifestations of dis
-
ease. Cytoplasmic ANCA (c-ANCA) is the common pat
-
tern. Microscopic polyangiitis is another pauci-immune 
vasculitis causing acute glomerulonephritis, which is more 
commonly associated with perinuclear staining (p-ANCA). 
ANCA-associated and anti-GBM-associated acute glomer
-
ulonephritides can evolve to crescentic glomerulonephritis 
and often have poor outcomes unless treatment is started 
early. Both are described more fully below.
Monoclonal immunoglobulin–mediated glomerulone
-
phritis
 is characterized by the deposition of a monoclonal 
immunoglobulin in glomeruli or tubular basement mem
-
brane or both. It is detected on immunofluorescent or immu
-
nohistochemical staining of kidney biopsies as monotypic 
immunoglobulin deposits. Serum protein electrophoresis and 
serum free light chains are useful diagnostic tests to perform 
when monoclonal immunoglobulin–mediated glomerulone
-
phritis is suspected or confirmed. While many cases will 
occur in the setting of a monoclonal gammopathy, this is not 
always the case.
 results from predominant C3 depo
-
sition in the glomeruli with or without minimal deposition

-
sition in the glomeruli with or without minimal deposition 
of immunoglobulins. It is also identified by immunofluores
-
cence or immunohistochemistry. The pathogenesis of C3 
glomerulonephropathy stems from abnormalities in regula
-
tion of the alternative pathway of complement. While check
-
ing the serum C3 level may be helpful, normal levels do not 
rule out C3 glomerulopathy.
Other vascular causes
 of acute glomerulonephritis 
include hypertensive emergencies and the thrombotic 
microangiopathies such as hemolytic-uremic syndrome and 
thrombotic thrombocytopenic purpura (see Chapter 14).
 
»
Patients with acute glomerulonephritis are often hyperten
-
sive and edematous with an abnormal urinary sediment. 
The edema is found first in body parts with low tissue 
tension, such as the periorbital and scrotal regions.
Serum creatinine can rise over days to months, depending 
on the rapidity of the underlying process. The BUN:creatinine 
ratio is not a reliable marker of kidney function and is more 
reflective of the patient’s underlying volume status. Dipstick 
and microscopic evaluation will reveal evidence of hematu
-
ria and typically mild proteinuria (usually less than 3 g/day); 
there may be cellular elements such as dysmorphic red cells, 
red cell casts, and white cells. Red cell casts are specific for 
glomerulonephritis, and a detailed search is warranted. 
Either spot urinary protein-creatinine ratios or 24-hour 
urine collections can quantify protein excretion; the latter 
can quantify creatinine clearance when renal function is 
stable. However, in cases of rapidly changing serum creati
-
nine values, the urinary creatinine clearance is an unreliable 
marker of GFR. The F
E
Na
 is usually low unless the renal 
tubulointerstitial space is affected, and renal dysfunction is 
marked (see Table 22–3).
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Additional tests include serum complement levels (C3, 
C4, CH50) that may be low in immune complex glomerulo
-
nephritis aside from IgA nephropathy or C3 glomerulopathy 
and normal in pauci-immune, anti-GBM–related, and 
monoclonal immunoglobulin–mediated glomerulonephrit
-
ides. Other tests include ASO titers, anti-GBM antibody 
levels, ANCAs, antinuclear antibody titers, cryoglobulins, 
hepatitis serologies, serum protein electrophoresis and 
serum free light chains, blood cultures, and renal ultra
-
sound. With few exceptions, however, a kidney biopsy is 
ultimately necessary to confirm the diagnosis, irrespective of 
laboratory data.
 
»
Treatment
Depending on the nature and severity of disease, treatment 
might include high-dose corticosteroids, rituximab, and 
cytotoxic agents (such as cyclophosphamide). Plasma 
exchange can be used in Goodpasture syndrome and pauci-
immune glomerulonephritis as a temporizing measure until 
chemotherapy can take effect. Treatment and prognosis for 
specific diseases are discussed more fully below.
Perazella MA. Diagnosing drug-induced AIN in the hospital
-
ized patient: a challenge for the clinician. Clin Nephrol. 
2014 Jun;81(6):381–8. [PMID: 24691017]
Sethi S et al. Mayo Clinic/Renal Pathology Society consensus 
report on pathologic classification, diagnosis, and reporting of 
GN. J Am Soc Nephrol. 2016 May;27(5):1278–87. [PMID: 
26567243]
CARDIORENAL SYNDROME
 
»
Cardiac dysfunction:
 acute or chronic heart failure, 
ischemic injury or arrhythmias.
 
»
Kidney disease:
 acute or chronic, depending on 
the type of cardiorenal syndrome.
 
»
Cardiorenal syndrome is a pathophysiologic disorder of the 
heart and kidneys wherein the acute or chronic deteriora
-
tion of one organ results in the acute or chronic deteriora
-
tion of the other. This syndrome is classified into five types 
as a matter of convention, though achieving euvolemia is 
the overarching therapeutic goal regardless of type.
Type 1 consists of AKI stemming from acute cardiac 
disease. Type 2 is CKD due to chronic cardiac disease. Type 
3 is acute cardiac disease as a result of AKI. Type 4 is 
chronic cardiac decompensation from CKD. Type 5 con
-
sists of heart and kidney dysfunction due to other acute or 
chronic systemic disorders (such as sepsis). Identifying and 
defining this common syndrome may assist in the future 
with treatments to improve its morbidity and mortality. 
Although novel agents are being examined for future thera
-
pies, the mainstay of treatment is to address the primary 
underlying cardiac or renal dysfunction.
Braam B et al. Cardiorenal syndrome—current understanding 
and future perspectives. Nat Rev Nephrol. 2014 Jan;10 (1):
 
48–55. [PMID: 24247284]
 
º
C
hr
ONIC KIDNEY DISEASE
 
»
Decline in the GFR over months to years.
 
»
Persistent proteinuria or abnormal renal morphology 
 
»
Hypertension in most cases.
 
»
Symptoms and signs of uremia when nearing end-
stage disease.
 
»
Bilateral small or echogenic kidneys on ultrasound 
in advanced disease.
 
»
CKD affects at least 10% of Americans. Many may be 
unaware of the condition because they remain asymptom
-
atic until the disease is near end stage. The National Kidney 
Foundation’s staging system helps clinicians formulate prac
-
tice plans (Table 22–4). Over 70% of cases of late-stage CKD 
(stage 5 CKD and ESRD) in the United States are due to 
diabetes mellitus or hypertension/vascular disease. Glomer
-
ulonephritis, cystic diseases, chronic tubulointerstitial dis
-
eases, and other urologic diseases account for the remainder 
(Table 22–5). Genetic polymorphisms of the 
APOL-1
 gene 
have been shown to be associated with an increased risk of 
the development of CKD in persons of African descent.
CKD usually leads to a progressive decline in kidney

APOL-1
 gene 
CKD usually leads to a progressive decline in kidney 
function even if the inciting cause can be identified and 
treated or removed. Destruction of nephrons leads to com
-
pensatory hypertrophy and supranormal GFR of the 
remaining nephrons in order to maintain overall homeo
-
stasis. As a result, the serum creatinine may remain rela
-
tively normal even in the face of significant loss of renal 
mass and is, therefore, a relatively insensitive marker for 
renal damage and scarring. In addition, compensatory 
hyperfiltration leads to overwork injury in the remaining 
nephrons, which in turn causes progressive glomerular 
sclerosis and interstitial fibrosis. Angiotensin receptor 
blockers (ARBs) and ACE inhibitors can help reduce hyper
-
filtration injury and are particularly helpful in slowing the 
progression of proteinuric CKD.
While CKD is an independent risk factor for cardiovas
-
cular disease (CVD), proteinuric CKD confers the highest 
risk. Most patients with stage 3 CKD die of underlying 
CVD prior to progression to ESRD.
 
»
In the early stages, CKD is asymptomatic. Symptoms develop 
slowly with the progressive decline in GFR, are nonspecific, 
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Table 22–4.
 
Stages of chronic kidney disease: a clinical action plan.
1,2
Stage
3
Description
GF
r
 (mL/min/1.73 m
2
)
Action
1
Kidney damage with normal or 
↑↑
 GFR
≥ 90
Diagnosis and treatment of underlying etiology if possible. 
Treatment of comorbid conditions. Estimate progression, 
work to slow progression. Cardiovascular disease risk 
2
Kidney damage with mildly 
↓
 GFR
60–89
3a
Mildly-moderately 
↓
 GFR
45–59
As above, and evaluating and treating complications. 
3b
Moderately-severely 
↓
 GFR
30–44
4
Severely 
↓
 GFR
15–29
Preparation for end-stage renal disease.
5
End-stage renal disease
< 15 (or dialysis)
Dialysis, transplant, or palliative care.
1
Based on National Kidney Foundation, KDOQI, and KDIGO Chronic Kidney Disease Guidelines.
2
Chronic kidney disease is defined as either kidney damage or GFR < 60 mL/min/1.73 m
2
 for 3 or more months. Kidney damage is defined 
as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
3
At all stages, persistent albuminuria confers added risk for chronic kidney disease progression and cardiovascular disease in the following 
gradations: < 30 mg/day = lowest added risk, 30–300 mg/day = mildly increased risk, > 300–1000 mg/day moderately increased risk, 
 
> 1000 mg/day = severely increased risk.
GFR, glomerular filtration rate.
Modified and reproduced, with permission, from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2013 Jan;3(1) (Suppl):1–150.
Table 22–5.
 
Major causes of chronic kidney disease.
Glomerular Diseases
p
rimar
y glomerular diseases
 
F
ocal segmental glomerulosclerosis
 
M
embranoproliferative glomerulonephritis
 
IgA nephr
opathy
 
M
embranous nephropathy
 
Alpor
t syndrome (hereditary nephritis)
Secondary glomerular diseases
 
Diabetic 
nephropathy
 
Renal am
yloidosis
 
P
ostinfectious glomerulonephritis
 
HIV
-associated nephropathy
 
C
ollagen-vascular diseases (eg, SLE)
 
HC
V-associated membranoproliferative glomerulonephritis
Tubulointerstitial Nephritis
 
Drug h
ypersensitivity
 
Hea
vy metals
 
Analgesic 
 
Reflux/chr
onic pyelonephritis
 
Sick
le cell nephropathy
 
Cystic Diseases
 
P
olycystic kidney disease
 
M
edullary cystic disease
Obstructive Nephropathies
 
P
rostatic disease
 
Retr
operitoneal fibrosis/tumor
 
Vascular Diseases
 
H
ypertensive nephrosclerosis
 
Renal ar
tery stenosis
HCV, hepatitis C virus; SLE, systemic lupus erythematosus.
and do not manifest until kidney disease is far advanced 
(GFR less than 5–10 mL/min/1.73 m
2
). At this point, the 
accumulation of metabolic waste products, or uremic toxins, 
results in the uremic syndrome. General symptoms of ure
-
mia may include fatigue and weakness; anorexia, nausea, 
vomiting, and a metallic taste in the mouth are also com
-
mon. Patients or family members may report irritability, 
memory impairment, insomnia, restless legs, paresthesias, 
and twitching. Generalized pruritus (without rash) may 
occur. Decreased libido and menstrual irregularities are 
common. Pericarditis, a rare complication of CKD, may 
present with pleuritic chest pain. Drug toxicity can develop 
as renal clearance worsens; in particular, as insulin is renally 
cleared, hypoglycemia may develop and can be life-threatening 
in patients if doses are not appropriately reduced.
The most common physical finding in CKD is hyper
-
tension—due in part to impaired sodium excretion. It is 
often present in early stages of CKD and tends to worsen 
with CKD progression. In later stages of CKD, sodium 
retention may lead to typical physical signs of volume over
-
load. Uremic signs are seen with a profound decrease in 
GFR (less than 5–10 mL/min/1.73 m
2
) and may include a 
generally sallow and ill appearance, halitosis (uremic

-
2
generally sallow and ill appearance, halitosis (uremic 
fetor), and the uremic encepholopathic signs of decreased 
mental status, asterixis, myoclonus, and possibly seizures.
Symptoms and signs of uremia warrant immediate 
hospital admission and nephrology consultation for initia
-
tion of dialysis. The uremic syndrome improves or resolves 
with dialytic therapy.
In any patient with kidney disease, it is important to 
identify and correct all possibly reversible insults or exacer
-
bating factors (Table 22–6). Urinary tract infections, obstruc
-
tion, hypovolemia, hypotension, nephrotoxins (such as 
NSAIDs, aminoglycosides, or proton pump inhibitors), 
severe or emergent hypertension, and heart failure should be 
excluded.
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CKD is usually defined by an abnormal GFR persisting for 
at least 3 months. Persistent proteinuria or abnormalities 
on renal imaging (eg, polycystic kidneys) are also diagnos
-
tic of CKD, even when eGFR is normal. It is helpful to plot 
the inverse of serum creatinine (1/S
Cr
) or eGFR (if reported 
by the laboratory) versus time. If three or more prior mea
-
surements are available, the time to ESRD can be roughly 
estimated (Figure 22–1). If the slope of the line acutely 
declines, new and potentially reversible renal insults should 
be excluded as outlined above. Anemia, hyperphosphate
-
mia, hypocalcemia, hyperkalemia, and metabolic acidosis 
are common complications of advanced CKD. The urinary 
sediment may show broad waxy casts as a result of dilated, 
hypertrophic nephrons. Proteinuria may be present. If so, 
it should be quantified as described above. Quantification 
of urinary protein is important for several reasons. First, it 
helps narrow the differential diagnosis of the etiology of 
the CKD (Table 22–5); for example, glomerular diseases 
tend to present with protein excretion of more than 1 g/day. 
Second, the presence of proteinuria is associated with more 
rapid progression of CKD and with increased risk of car
-
diovascular mortality.
C. Imaging
The finding of small, echogenic kidneys bilaterally (less 
than 9–10 cm) by ultrasonography suggests the chronic 
parenchymal scarring of advanced CKD. Large kidneys can 
be seen with adult polycystic kidney disease, diabetic 
nephropathy, HIV-associated nephropathy, plasma cell 
myeloma, amyloidosis, and obstructive uropathy.
 
»
The complications of CKD tend to occur at relatively 
predictable stages of disease as noted in Figure 22–2.
Table 22–6.
 
Reversible causes of kidney injury.
r
eversible Factors
Diagnostic Clues
Infection
Urine culture and sensitivity 
tests
Obstruction
Bladder catheterization, then 
renal ultrasound
Extracellular fluid volume 
 
depletion or significant hypo
-
tension relative to baseline
Blood pressure and pulse, 
including orthostatic pulse
Hypokalemia, hypercalcemia, 
and hyperuricemia (usually 
>15 mg/dL)
Serum electrolytes, calcium, 
phosphate, uric acid
Nephrotoxic agents
Drug history
Severe/urgent hypertension
Blood pressure, chest 
radiograph
Physical examination, chest 
•
•
•
1
2
3
1.
0
0.9
0.7
0.5
0.3
0.1
1
23
4
56
78
91
0
1/S
cr
Time (years)
1
 V
alue of serum creatinine level = 1 .0 mg/dL
2
 V
alue of serum creatinine level = 2.0 mg/dL
3
 V
alue of serum creatinine level = 5.0 mg/dL
 
▲
Figure 22–1.
 
Decline in kidney function (expressed 
as the reciprocal of serum creatinine as shown here, or 
as estimated glomerular filtration rate [eGFR]) plotted 
against time to end-stage renal disease (ESRD). The 
solid line indicates the linear decline in kidney function 
over time. The dotted line indicates the approximate 
time to ESRD.
A. Cardiovascular Complications
Patients with CKD experience greater morbidity and mor
-
tality from CVD in comparison to the general population. 
Roughly 80% of patients with CKD die, primarily of CVD, 
before reaching the need for dialysis. Of those undergoing 
dialysis, 45% will die of a cardiovascular cause. The precise 
biologic mechanisms for this enhanced mortality are 
unclear but may have to do with the uremic milieu includ
-
ing abnormal phosphorus and calcium homeostasis, 
increased burden of oxidative stress, increased vascular 
reactivity, increased left ventricular hypertrophy, and 
underlying coexistent comorbidities such as hypertension 
and diabetes mellitus.
1. Hypertension—
Hypertension is the most common com
-
plication of CKD; it tends to be progressive and salt-sensitive. 
Hyperreninemic states and exogenous erythropoietin admin
-
istration can also exacerbate hypertension.
As with other patient populations, control of hyperten
-
sion should focus on both nonpharmacologic therapy (eg,

-
-
sion should focus on both nonpharmacologic therapy (eg, 
diet, exercise, weight loss, treatment of obstructive sleep 
apnea) and pharmacologic therapy. CKD results in dis
-
turbed sodium homeostasis such that the ability of the 
kidney to adjust to variations in sodium and water intake 
becomes limited as GFR declines. A low salt diet (2 g/day) 
is often essential to control blood pressure and help avoid 
overt volume overload. Diuretics are nearly always needed 
to help control hypertension (see Table 11–6); thiazides 
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work well in early CKD, but in those with a GFR less than 
30 mL/min/1.73 m
2
, loop diuretics are more effective. 
However, volume contraction as a result of very low 
sodium intake (especially with intercurrent illness) or 
over-diuresis in the presence of impaired sodium homeo
-
stasis can result in AKI. Initial drug therapy for proteinuric 
patients should include ACE inhibitors or ARBs (see 
Table 11–8). When an ACE inhibitor or an ARB is initiated 
or uptitrated, patients must have serum creatinine and 
potassium checked within 7–14 days. Hyperkalemia or a 
rise in serum creatinine greater than 30% from baseline 
mandates reduction or cessation of the drug. An ACE 
inhibitor and ARB should not be used in combination. 
Hypertension in CKD can be difficult to control and addi
-
tional agents from other classes are often needed. Current 
guidelines differ with respect to blood pressure goals in 
CKD; those from the Joint National Commission suggest a 
blood pressure goal of less than 140/90 mm Hg, while 
the American Heart Association advocates for less than 
130/80 mm Hg. Additionally, patients with CKD may be at 
risk for renal hypoperfusion and AKI with overtreatment 
of hypertension. Thus, many experts agree that more stud
-
ies are needed in this patient population, and that it is 
prudent to continue with an individualized approach to 
blood pressure control.
2. Coronary artery disease—
Patients with CKD are at 
higher risk for death from CVD than the general popula
-
tion. Traditional modifiable risk factors for CVD, such as 
hypertension, tobacco use, and hyperlipidemia, should be 
aggressively treated in patients with CKD. Uremic vascular 
calcification involving disordered phosphorus homeostasis 
and other mediators may also be a cardiovascular risk 
factor in these patients.
3. Heart failure—
The complications of CKD result in 
increased cardiac workload 
due to hypertension
, volume 
overload, and anemia. Patients with CKD may also have 
accelerated rates of atherosclerosis and vascular calcifica
-
tion resulting in vessel stiffness. All of these factors con
-
tribute to left ventricular hypertrophy and heart failure 
with preserved ejection fraction, which is common in 
CKD. Over time, heart failure with decreased ejection frac
-
tion may also develop. Diuretic therapy, in addition to 
prudent fluid and salt restriction, is usually necessary. 
Thiazides may be adequate therapy for most patients 
through CKD stage 3, but loop diuretics are usually needed 
when the GFR is less than 30 mL/min/1.73 m
2
; higher 
doses may be needed as kidney function declines. Digoxin 
is excreted by the kidney, and its toxicity is exacerbated in 
the presence of electrolyte disturbances, which are com
-
mon in CKD. ACE inhibitors and ARBs can be used for 
patients with advanced CKD with close monitoring of 
blood pressure as well as for hyperkalemia and worsening 
kidney function.
4. Pericarditis—
Pericarditis rarely develops in uremic 
patients; typical findings include pleuritic chest pain and a 
friction rub. Development of a significant effusion may 
result in pulsus paradoxus, an enlarged cardiac silhouette 
on chest radiograph, and low QRS voltage and electrical 
alternans on ECG. The effusion is generally hemorrhagic, 
and anticoagulants should be avoided if this diagnosis is 
suspected. Cardiac tamponade can occur; therefore, uremic 
pericarditis is a mandatory indication for hospitalization and 
initiation of hemodialysis.
B. Disorders of Mineral Metabolism
The metabolic bone disease of CKD refers to the complex 
disturbances of calcium and phosphorus metabolism, 
parathyroid hormone (PTH), active vitamin D, and fibro
-
blast growth factor-23 (FGF-23) homeostasis (see Chapter 
21 and Figure 22–3). A typical pattern seen as early as CKD 
stage 3 is hyperphosphatemia, hypocalcemia, and hypovi
-
taminosis D, resulting in secondary hyperparathyroidism.

-
taminosis D, resulting in secondary hyperparathyroidism. 
These abnormalities can contribute to vascular calcifica
-
tion and may be responsible in part for the accelerated 
CVD and excess mortality seen in the CKD population. 
Epidemiologic studies in humans show an association 
between elevated phosphorus levels and increased risk of 
cardiovascular mortality in early CKD through ESRD. 
↑
 
PTH
Glomerular filtration rate (mL/min)
↑
 
Phosphorus
HTN
Anemia
Acidosis, hyperkalemia
Uremic syndrome
CKD stage
54
32
02
04
06
08
0 100
 
▲
Figure 22–2.
 
Complications of chronic kidney disease (CKD) by stage and glomerular filtration rate (GFR). Complications 
arising from CKD tend to occur at the stages depicted, although there is considerable variability noted in clinical practice. 
HTN, hypertension; PTH, parathyroid hormone. 
(Adapted, with permission, from William Bennett, MD.)
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As yet, there are no intervention trials suggesting the best 
course of treatment in these patients; control of mineral 
and PTH levels per current guidelines is discussed below.
Bone disease, or 
renal osteodystrophy,
 in advanced 
CKD is common and there are several types of lesions. 
Renal osteodystrophy can be diagnosed only by bone 
biopsy, which is rarely done. The most common bone dis
-
ease, 
osteitis fibrosa cystica,
 is a result of secondary 
hyperparathyroidism and the osteoclast-stimulating effects 
of PTH. This is a high-turnover disease with bone resorp
-
tion and subperiosteal lesions; it can result in bone pain 
and proximal muscle weakness. 
Adynamic bone disease,
 
or low-bone turnover, is becoming more common; it may 
result iatrogenically from suppression of PTH or via spon
-
taneously low PTH production. 
-
ized by lack of bone mineralization. In the past, osteomalacia 
was associated with aluminum toxicity—either as a result 
of chronic ingestion of prescribed aluminum-containing 
phosphorus binders or from high levels of aluminum in 
impure dialysate water. Currently, osteomalacia is more likely 
to result from hypovitaminosis D; there is also theoretical risk 
of osteomalacia associated with use of bisphosphonates in 
advanced CKD.
All of the above entities increase the risk of fractures. 
Aluminum exposure should be avoided. In addition, treat
-
ment may involve correction of calcium, phosphorus, and 
25-OH vitamin D levels toward normal values, and miti
-
gation of hyperparathyroidism. Understanding the inter
-
play between these abnormalities can help target therapy 
(Figure 22–3). Declining GFR leads to phosphorus reten
-
tion. This results in hypocalcemia as phosphorus com
-
plexes with calcium, deposits in soft tissues, and stimulates 
PTH. Loss of renal mass and low 25-OH vitamin D levels 
often seen in CKD patients result in low 1,25(OH) vitamin 
D production by the kidney. Because 1,25(OH) vitamin D 
is a suppressor of PTH production, hypovitaminosis D also 
leads to secondary hyperparathyroidism.
The first step in treatment of metabolic bone disease is 
control of hyperphosphatemia. This involves dietary 
phosphorus restriction initially (see section on dietary 
management), followed by the administration of oral 
phosphorus binders if targets are not achieved. Oral 
↓
GFR
↓
25(OH) 
Vitamin 
D
↑
PTH
↓
Calcium
↑
↓
1,25(OH) Vitamin 
D
 
▲
Figure 22–3.
 
Mineral abnormalities of chronic kidney 
disease (CKD). Decline in glomerular filtration rate (GFR) 
and loss of renal mass lead directly to increased serum 
phosphorus and hypovitaminosis D. Both of these 
abnormalities result in hypocalcemia and hyperparathy
-
roidism. Many CKD patients also have nutritional 25(OH) 
vitamin D deficiency. PTH, parathyroid hormone.
phosphorus binders block absorption of dietary phospho
-
rus in the gut and are given thrice daily with meals. These 
should be titrated toward achieving a normal serum 
phosphorus level. Calcium-containing binders (calcium 
carbonate, 650 mg/tablet, or calcium acetate, 667 mg/capsule, 
used at doses of one to three pills per meal) are relatively 
inexpensive but may contribute to positive calcium bal
-
ance and vascular calcification; overt hypercalcemia may 
also occur. Thus, current guidelines suggest limiting their 
use in favor of the non-calcium–containing binders 
sevelamer carbonate (800–3200 mg/meal) and lanthanum 
carbonate (500–1000 mg/meal). Aluminum hydroxide is 
a highly effective phosphorus binder but can cause osteo
-
malacia and neurologic complications when used long-
term. It can be used in the acute setting for severe 
hyperphosphatemia or for short periods (eg, 3 weeks) in 
CKD patients.
Once serum phosphorus levels are controlled, active 
vitamin D (1,25[OH] vitamin D, or calcitriol) or active 
vitamin D analogs are recommended to treat secondary

vitamin D analogs are recommended to treat secondary 
hyperparathyroidism in advanced CKD and ESRD. Serum 
25-OH vitamin D levels should be measured and brought 
to normal (see Chapter 26) prior to considering adminis
-
tration of active vitamin D. Active vitamin D (calcitriol) 
increases serum calcium and phosphorus levels; both need 
to be monitored closely during calcitriol therapy, and its 
dose should be decreased if hypercalcemia or hyperphos
-
phatemia occurs. Typical calcitriol dosing is 0.25 or 0.5 mcg 
orally daily or every other day. Cinacalcet targets the 
calcium-sensing receptors of the parathyroid gland and 
suppresses PTH production. Cinacalcet, 30–90 mg orally 
once a day, can be used if elevated serum phosphorus or 
calcium levels prohibit the use of vitamin D analogs; cina
-
calcet can cause serious hypocalcemia, and patients should 
be closely monitored for this complication. Optimal PTH 
levels in CKD are not known, but because skeletal resis
-
tance to PTH develops with uremia, relatively high levels 
are targeted in advanced CKD to avoid adynamic bone 
disease. Expert guidelines generally suggest goal PTH 
levels near or just above the upper limit of normal for mod
-
erate CKD, and at least twofold and up to ninefold the 
upper limit of normal for ESRD.
C. Hematologic Complications
1. Anemia—
The anemia of CKD is primarily due to decreased 
erythropoietin production, which often becomes clinically 
significant during stage 3 CKD. Many patients are iron 
deficient as well due to impaired GI iron absorption.
Erythropoiesis-stimulating agents (ESAs, eg, recombi
-
nant erythropoietin [epoetin] and darbepoetin) are used to 
treat the anemia of CKD if other treatable causes are 
excluded. There is likely no benefit of starting an ESA 
before Hgb values are less than 9 g/dL. The starting dose of 
epoetin is 50 units/kg (3000–4000 units/dose) once or 
twice a week, and darbepoetin is started at 0.45 mcg/kg and 
can be administered every 2–4 weeks. These agents can be 
given intravenously (eg, to the hemodialysis patient) or 
subcutaneously (to both the predialysis or dialysis patient); 
subcutaneous dosing of erythropoietin is roughly 30% 
more effective than intravenous dosing. ESAs should be 
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titrated to an Hgb of 10–11 g/dL for optimal safety; studies 
show that targeting a higher Hgb increases the risk of 
stroke and possibly other cardiovascular events. When 
titrating doses, Hgb levels should rise no more than 1 g/dL 
every 3–4 weeks. Hypertension is a complication of treat
-
ment with ESAs in about 20% of patients. The dosage may 
require adjustment, or antihypertensive drugs may need to 
be given.
Iron stores must be adequate to ensure response to 
ESAs. Hepcidin, a molecule that blocks GI iron absorption 
and mobilization of iron from body stores, tends to be high 
in CKD. Therefore, traditional measures of iron stores are 
measured in CKD patients but are targeted to higher goals; 
in CKD, a serum ferritin below 100–200 ng/mL or iron 
saturation less than 20% is suggestive of iron deficiency. 
Iron stores should be repleted with oral or parenteral iron 
prior to the initiation of an ESA. Iron therapy should prob
-
ably be withheld if the serum ferritin is greater than 500–
800 ng/mL, even if the iron saturation is less than 20%. 
Oral therapy with ferrous sulfate, gluconate, or fumarate, 
325 mg once to three times daily, is the initial therapy in 
pre-ESRD CKD. For those who do not respond due to poor 
GI absorption or lack of tolerance, intravenous iron (eg, 
iron sucrose) may be necessary.
The preliminary investigation of anemia in any CKD 
patient should also include assessment of thyroid function 
tests, and serum vitamin B
12
 testing prior to initiating 
therapy with an ESA.
2. Coagulopathy—
The bleeding diathesis that may occur in 
advanced stage CKD is mainly due to platelet dysfunction, 
but severe anemia may also contribute.
Treatment is required only in patients who are symptom
-
atic. Raising the Hgb to 9–10 g/dL in anemic patients can 
reduce risk of bleeding via improved clot formation. Desmo
-
pressin (25 mcg intravenously every 8–12 hours for two 
doses) is a short-lived but effective treatment for platelet 
dysfunction and it is often used in preparation for surgery. 
Conjugated estrogens, 2.5–5 mg orally for 5–7 days, may 
have an effect for several weeks but are seldom used. Dialysis 
improves the bleeding time.
D. Hyperkalemia
Potassium balance generally remains intact in CKD until 
stages 4–5. However, hyperkalemia may occur at earlier 
stages when certain conditions are present, such as type 
 
4 renal tubular acidosis (seen in patients with diabetes mel
-
litus), high potassium diets, or medications that decrease 
renal potassium secretion (amiloride, triamterene, spirono
-
lactone, eplerenone, NSAIDs, ACE inhibitors, ARBs) or 
block cellular potassium uptake (beta-blockers). Other 
causes include acidemic states and any type of cellular 
destruction causing release of intracellular contents, such 
as hemolysis and rhabdomyolysis.
Treatment of acute hyperkalemia is discussed in 
Chapter 21 (see Table 21–6). Cardiac monitoring is indi
-
cated for any ECG changes seen with hyperkalemia or a 
serum potassium level greater than 6.0–6.5 mEq/L or 
mmol/L. Chronic hyperkalemia is best treated with 
dietary potassium restriction (2 g/day) and minimization 
or elimination of any medications that may impair renal 
potassium excretion, as noted above. Loop diuretics may 
also be administered for their kaliuretic effect as long as 
the patient is not volume-depleted.
E. Acid-Base Disorders
Damaged kidneys are unable to excrete the 1 mEq/kg/day 
of acid generated by metabolism of dietary animal proteins 
in the typical Western diet. The resultant metabolic acido
-
sis is primarily due to decreased GFR; proximal or distal 
tubular defects may contribute to or worsen the acidosis. 
Excess hydrogen ions are buffered by bone; the consequent 
leaching of calcium and phosphorus from the bone con
-
tributes to the metabolic bone disease described above and 
to growth retardation in children with CKD. Chronic aci
-

-
-
dosis can also result in muscle protein catabolism, and may 
accelerate progression of CKD. The serum bicarbonate 
level should be normalized. Reduction in the intake of 
dietary animal protein and the administration of oral 
sodium bicarbonate (in doses of 0.5–1.0 mEq/kg/day 
divided twice daily and titrated as needed) may achieve this 
goal. Citrate salts increase the absorption of dietary alumi
-
num and should be avoided in CKD.
F. Neurologic Complications
Uremic encephalopathy, resulting from the aggregation 
of uremic toxins, does not occur until GFR falls below 
5–10 mL/min/1.73 m
2
. Symptoms begin with difficulty 
in concentrating and can progress to lethargy, confusion, 
seizure, and coma. Physical findings may include altered 
mental status, weakness, and asterixis. These findings 
improve with dialysis.
Other neurologic complications, which can manifest with 
advanced CKD include peripheral neuropathies (stocking-
glove or isolated mononeuropathies), erectile dysfunction, 
autonomic dysfunction, and restless leg syndrome. These 
may not improve with dialysis therapy.
G. Endocrine Disorders
There is risk of hypoglycemia in treated diabetic patients 
with advanced CKD due to decreased renal elimination of 
insulin. Doses of oral hypoglycemics and insulin may need 
reduction. The risk of lactic acidosis with metformin is due 
to both dose and eGFR; it should be discontinued when 
eGFR is less than 30 mL/min/1.73 m
2
. Whether to discon
-
tinue metformin when the eGFR is between 30 mL/min 
and 60 mL/min is controversial.
Decreased libido and erectile dysfunction are common 
in advanced CKD. Men have decreased testosterone levels; 
women are often anovulatory. Women with serum creati
-
nine less than 1.4 mg/dL are not at increased risk for poor 
outcomes in pregnancy; however, those with serum creati
-
nine greater than 1.4 mg/dL may experience faster progres
-
sion of CKD with pregnancy. Fetal survival is not 
compromised, however, unless CKD is advanced. Despite a 
high degree of infertility in patients with ESRD, pregnancy 
can occur in this setting; however, fetal mortality 
approaches 50%, and babies who survive are often prema
-
ture. In female patients with ESRD, renal transplantation 
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with a well-functioning allograft affords the best chances 
for a successful pregnancy.
 
»
Treatment
A. Slowing Progression
Treatment of the underlying cause of CKD is vital. Control 
of diabetes should be aggressive in early CKD; risk of hypo
-
glycemia increases in advanced CKD, and glycemic targets 
may need to be relaxed to avoid this dangerous complica
-
tion. Blood pressure control is vital to slow progression of 
all forms of CKD; agents that block the renin-angiotensin-
aldosterone system are particularly important in proteinuric 
disease (see section on hypertension regarding blood pres
-
sure goals). Several small studies suggest a possible benefit of 
oral bicarbonate therapy in slowing CKD progression when 
acidemia is present; there is also theoretic value in lowering 
uric acid levels in those with concomitant hyperuricemia, 
but clinical data are lacking. Obese patients should be 
encouraged to lose weight. Management of traditional 
cardiovascular risk factors should also be emphasized.
B. Dietary Management
Patients with CKD should be evaluated by a renal nutritionist. 
Patient-specific recommendations should be made concern
-
ing protein, salt, water, potassium, and phosphorus intake to 
help manage CKD progression and complications.
1. Protein restriction—
Reduced intake of animal protein 
to 0.6-0.8 g/kg/day may retard CKD progression and is 
likely not harmful in the otherwise well-nourished patient; 
it is not advisable in those with cachexia or low serum 
albumin in the absence of the nephrotic syndrome.
2. Salt and water restriction—
In advanced CKD, the kid
-
ney is unable to adapt to large changes in sodium intake. 
Intake of greater than 3–4 g/day can lead to hypertension 
and hypervolemia, whereas intake of less than 1 g/day can 
lead to volume depletion and hypotension. A goal of 
 
2 g/day of sodium is reasonable for most patients. Daily 
fluid restriction to 2 L may be needed if volume overload is 
present.
3. Potassium restriction—
Restriction is needed once the 
GFR has fallen below 10–20 mL/min/1.73 m
2
, or earlier if 
the patient is hyperkalemic. Patients should receive detailed 
lists describing potassium content of foods and should 
limit their intake to less than 50–60 mEq/day (2 g/day). An 
aggressive bowel regimen should be instituted for patients 
with hyperkalemia (more than two bowel movements 
daily), since a higher percentage of potassium is excreted 
through the gastrointestinal tract as GFR declines.
4. Phosphorus restriction—
Updated guidelines suggest low
-
ering elevated serum phosphorus levels toward normal in all 
stages of CKD. Dietary phosphate restriction to 800–
1000 mg/day is the first step. Processed foods and cola bever
-
ages are often preserved with highly bioavailable phosphorus 
and should be avoided. Foods rich in phosphorus such as 
eggs, dairy products, nuts, beans, and meat may also need to 
be limited, although care must be taken to avoid protein 
malnutrition. When GFR is less than 20–30 mL/min/1.73 m
2
, 
dietary restriction is rarely sufficient to reach target levels, 
and phosphorus binders are usually required.
C. Medication Management
Many drugs are excreted by the kidney; dosages should be 
adjusted for GFR. Insulin doses may need to be decreased 
as noted above. Magnesium-containing medications, such 
as laxatives or antacids, and phosphorus-containing medi
-
cines, (eg, cathartics) should be avoided. Active morphine 
metabolites can accumulate in advanced CKD; this problem 
is not encountered with other opioid agents. Drugs with 
potential nephrotoxicity (NSAIDs, intravenous contrast, as 
well as others noted in the Acute Kidney Injury section) 
D. Treatment of ESRD
When GFR declines to 5–10 mL/min/1.73 m
2
, renal 
replacement therapy (hemodialysis, peritoneal dialysis, or 
kidney transplantation) is required to sustain life. Patient 
education is important in understanding which mode of

2
, renal 
education is important in understanding which mode of 
therapy is most suitable, as is timely preparation for treat
-
ment; therefore, referral to a nephrologist should take place 
in late stage 3 CKD, or when the GFR is declining rapidly. 
Such referral has been shown to improve mortality. Prepa
-
ration for ESRD treatment requires a team approach with 
the involvement of dieticians, social workers, primary care 
clinicians, and nephrologists. For very elderly patients, or 
those with multiple debilitating or life-limiting comorbidi
-
ties, dialysis therapy may not meaningfully prolong life, 
and the option of palliative care should be discussed with 
the patient and family. Conversely, for patients who are 
otherwise relatively healthy, evaluation for possible kidney 
transplantation should be considered prior to initiation of 
dialysis.
1. Dialysis—
Dialysis initiation should be considered when 
GFR is 10 mL/min/1.73 m
2
. Studies suggest that the well-
selected patient without overt uremic symptoms may wait 
to initiate dialysis until GFR is closer to 7 mL/min/1.73 m
2
. 
Other indications for dialysis, which may occur when GFR 
is 10–15 mL/min/1.73 m
2
 include (1) uremic symptoms, 
(2) fluid overload unresponsive to diuresis, and (3) refrac
-
tory hyperkalemia.
a. Hemodialysis
—
Vascular access for hemodialysis can 
be accomplished by an arteriovenous fistula (the preferred 
method) or prosthetic graft; creation of dialysis access 
should be considered well before dialysis initiation. An 
indwelling catheter is used when there is no useable vascu
-
lar access. Because catheters confer a high risk of blood
-
stream infection, they should be considered a temporary 
measure. Native fistulas typically last longer than pros
-
thetic grafts but require a longer time after surgical con
-
struction for maturation (6–8 weeks for a fistula versus 
 
2 weeks for a graft). Infection, thrombosis, and aneurysm 
formation are complications seen more often in grafts than 
fistulas. 
 species are the most common cause 
of soft tissue infections and bacteremia.
Treatment at a hemodialysis center occurs three times a 
week. Sessions last 3–5 hours depending on patient size 
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and type of dialysis access. Home hemodialysis is often 
performed more frequently (3–6 days per week for shorter 
sessions) and requires a trained helper. Results of trials 
comparing quotidian modalities (nocturnal and frequent 
home hemodialysis) to conventional in-center dialysis have 
not thus far shown significant mortality differences, but 
there may be improvements in blood pressure control, 
mineral metabolism, and quality of life.
b. Peritoneal dialysis
—
With peritoneal dialysis, the 
peritoneal membrane is the “dialyzer. ” Dialysate is instilled 
into the peritoneal cavity through an indwelling catheter; 
water and solutes move across the capillary bed that lies 
between the visceral and parietal layers of the membrane into 
the dialysate during a “dwell. ” After equilibration, the dialysate 
is drained, and fresh dialysate is instilled—this is an “exchange. ”
The most common complication of peritoneal dialysis is 
peritonitis. Peritonitis may present with nausea and vomit
-
ing, abdominal pain, diarrhea or constipation, and fever. The 
normally clear dialysate becomes cloudy; and a diagnostic 
peritoneal fluid cell count greater than 100 white blood cells/
mcL with a differential of greater than 50% polymorphonu
-
clear neutrophils is present. 
 is the 
most common infecting organism, but streptococci and 
gram-negative species are also common.
2. Kidney transplantation—
Many patients with ESRD are 
otherwise healthy enough to be suitable for transplantation, 
although standard criteria for recipient selection are lacking 
between transplant centers. Two-thirds of kidney allografts 
come from deceased donors, with the remainder from liv
-
ing related or unrelated donors. Over 100,000 patients are 
on the waiting list for a deceased donor transplant in the 
United States; the average wait is 2–6 years, depending on 
geographic location and recipient blood type.
The 1- and 5-year kidney graft survival rates are approx
-
imately 95% and 80%, respectively, for living donor trans
-
plants and 89% and 66%, respectively, for deceased donor 
transplants.
3. Medical management of ESRD—
As noted above, some 
patients are not candidates for kidney transplantation and 
may not benefit from dialysis. Very elderly persons may die 
soon after dialysis initiation; those who do not may none
-
theless rapidly lose functional status in the first year of treat
-
ment. The decision to initiate dialysis in patients with 
limited life expectancy should be weighed against possible 
deterioration in quality of life. For patients with ESRD who 
elect not to undergo dialysis or who withdraw from dialysis, 
progressive uremia with gradual suppression of sensorium 
results in a painless death within days to months. Hyperka
-
lemia may intervene with a fatal cardiac dysrythmia. 
Diuretics, volume restriction, and opioids, as described in 
Chapter 5, may help decrease the symptoms of volume 
overload. Involvement of a palliative care team is essential.
 
»
Prognosis in ESRD
Compared with kidney transplant recipients and age-
matched controls, mortality is higher for patients undergoing 
dialysis. There is likely little difference in survival for well-
matched peritoneal versus hemodialysis patients.
Survival rates on dialysis depend on the underlying 
disease process. Five-year Kaplan-Meier survival rates vary 
from 37% for patients with diabetes to 54% for patients 
with glomerulonephritis. Overall 5-year survival is cur
-
rently estimated at 40%. Patients undergoing dialysis have 
an average life-expectancy of 3–5 years, but survival for as 
long as 25 years may be achieved depending on comorbidi
-
ties. The most common cause of death is cardiac disease 
(more than 50%). Other causes include infection, cerebro
-
vascular disease, and malignancy. Diabetes, advanced age, 
a low serum albumin, lower socioeconomic status, and 
inadequate dialysis are all significant predictors of mortal
-

-
-
ity; high fibroblast growth factor (FGF)-23 levels are a 
novel marker for mortality in ESRD.
 
»
•	
A patient with stage 3–5 CKD should be referred to a 
nephrologist for management in conjunction with the 
primary care provider.
•	
A patient with other forms of CKD such as those with 
proteinuria greater than 1 g/day or polycystic kidney 
disease should be referred to a nephrologist at earlier 
stages.
 
»
•	
Admission should be considered for patients with 
decompensation of problems related to CKD, such as 
worsening of acid-base status, electrolyte abnormalities, 
and volume overload that cannot be appropriately treated 
in the outpatient setting.
•	
Admission is appropriate when a patient needs to start 
dialysis and is not stable for its outpatient initiation.
Farrington K et al. Clinical Practice Guideline on management of 
older patients with chronic kidney disease stage 3b or higher 
(eGFR<45 mL/min/1.73 m
2
): a summary document from the 
European Renal Best Practice Group. Nephrol Dial Transplant. 
2017 Jan 1;32(1):9–16. [PMID: 28391313]
Kalantar-Zadeh K et al. Nutritional management of chronic 
kidney disease. N Engl J Med. 2017 Nov 2;377(18):1765–76. 
[PMID: 29091561]
Kraut JA et al. Retarding progression of chronic kidney disease: use 
of modalities that counter acid retention. Curr Opin Nephrol 
Hypertens. 2018 Mar;27(2):94–101. [PMID: 29140821]
Ponticelli C et al. Drug management in the elderly adult with 
chronic kidney disease: a review for the primary care physi
-
cian. Mayo Clin Proc. 2015 May;90(5):633–45. [PMID: 
25771152]
Vassalotti JA et al; National Kidney Foundation Kidney Disease 
Outcomes Quality Initiative. Practical approach to detection 
and management of chronic kidney disease for the primary 
care clinician. Am J Med. 2016 Feb;129(2):153–62. [PMID: 
26391748]
Webster AC et al. Chronic kidney disease. Lancet. 2017 Mar 25;
 
389(10075):1238–52. [PMID: 27887750]
Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
APhA/ASH/ASPC/NMA/PCNA Guideline for the preven
-
tion, detection, evaluation, and management of high blood 
pressure in adults: executive summary: a report of the Ameri
-
can College of Cardiology/American Heart Association Task 
Force on Clinical Practice Guidelines. Hypertension. 2017 
Nov 13. [Epub ahead of print] [PMID: 29133354]
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Zoccali C et al; European Renal and Cardiovascular Medicine 
(EURECA-m) Working Group of the European Renal Asso
-
ciation—European Dialysis Transplantation Association 
(ERA-EDTA). The systemic nature of CKD. Nat Rev Nephrol. 
2017 Jun;13(6):344–58. [PMID: 28435157]
RENAL ARTERY STENOSIS
 
»
Produced by atherosclerotic occlusive disease 
(80–90% of patients) or fibromuscular dysplasia 
(10–15%).
 
»
Hypertension.
 
»
AKI in patients starting ACE inhibitor therapy if 
stenosis is bilateral.
 
»
Atherosclerotic ischemic renal disease accounts for most 
cases of renal artery stenosis. Fibromuscular dysplasia is a 
less common cause of renal artery stenosis. Approximately 
5% of Americans with hypertension suffer from renal 
artery stenosis. It occurs most commonly in those over 
 
45 years of age with a history of atherosclerotic disease. 
Other risk factors include CKD, diabetes mellitus, tobacco 
use, and hypertension.
 
»
Patients with atherosclerotic ischemic renal disease may 
have refractory hypertension, new-onset hypertension (in 
an older patient), pulmonary edema with poorly controlled 
blood pressure, and AKI upon starting an ACE inhibitor. 
In addition to hypertension, physical examination may 
reveal an audible abdominal bruit on the affected side. 
Fibromuscular dysplasia primarily affects young women. 
Unexplained hypertension in a woman younger than 40 years 
is a reason to screen for this disorder.
BUN and serum creatinine may be elevated if there is signifi
-
cant renal ischemia. Patients with bilateral renal artery ste
-
nosis may have hypokalemia, a finding that reflects activation 
of the renin-angiotensin-aldosterone system in response to 
reduced blood flow (a “prerenal” state).
C. Imaging
Abdominal ultrasound can reveal either asymmetric kidney 
size if one renal artery is affected more than the other or 
small hyperechoic kidneys if both are affected.
Three prevailing methods used for screening are Doppler 
ultrasonography, CT angiography, and magnetic resonance 
angiography (MRA). According to the American College of 
Cardiology/American Heart Association guidelines, one of 
these should be undertaken if a corrective procedure would 
be performed when a positive test result is found. 
Doppler 
 is highly sensitive and specific (85% and 
92% respectively in a meta-analysis of 88 studies) and rela
-
tively inexpensive. However, this method is extremely 
operator and patient dependent.
CT angiography
 consists of intravenous digital sub
-
traction angiography with arteriography. A noninvasive 
procedure, it uses a spiral (helical) CT scan with intrave
-
nous contrast injection. The sensitivities from various 
studies range from 77% to 98%, with specificities in the 
range of 90–94%.
MRA
 is an excellent but expensive way to screen for 
renal artery stenosis, particularly in those with atheroscle
-
rotic disease. Sensitivity is 77–100%, although one flawed 
study showed a sensitivity of only 62%. Specificity ranges 
from 71% to 96%. Turbulent blood flow can cause false-
positive results. The imaging agent for MRA (gadolinium) 
has been associated with nephrogenic systemic fibrosis, 
which occurs primarily in patients with a GFR of less than 
15 mL/min/1.73 m
2
, and rarely in patients with a GFR of 
15–29 mL/min/1.73 m
2
. This fibrosis has also occurred in 
those with AKI and kidney transplants.
 is the gold standard for diagnosis 
but it is more invasive than the three screening tests dis
-
cussed above. Thus, it is performed after a positive 
screening test. CO
2
 subtraction angiography can be used 
in place of dye when the risk of dye nephropathy exists—
eg, in diabetic patients with kidney injury. Lesions are 
most commonly found in the proximal third or ostial 
region of the renal artery. The risk of atheroembolic phe
-

-
nomena after angiography ranges from 5% to 10%. Fibro
-
muscular dysplasia has a characteristic “beads-on-a-string” 
appearance on angiography.
 
»
Treatment
Treatment of atherosclerotic ischemic renal disease is 
controversial. Options include medical management, 
angioplasty with or without stenting, and surgical bypass. 
Two large randomized trials showed that vascular inter
-
vention is no better than optimal medical management in 
typical patients with renal artery stenosis. Angioplasty 
might reduce the number of antihypertensive medications 
but does not significantly change the progression of kidney 
dysfunction in comparison to patients medically managed. 
Stenting produces significantly better angioplastic results. 
However, with medical management blood pressure and 
serum creatinine are similar at 6 months compared with 
both angioplasty and stents. Angioplasty is equally as effec
-
tive as, and safer than, surgical revision.
Treatment of fibromuscular dysplasia with percutane
-
ous transluminal angioplasty is often curative, which is in 
stark contrast to treatments for atherosclerotic disease.
Cooper CJ et al; CORAL Investigators. Stenting and medical 
therapy for atherosclerotic renal-artery stenosis. N Engl J 
Med. 2014 Jan 2;370(1):13–22. [PMID: 24245566]
Gupta R et al. Renal artery stenosis: new findings from the 
CORAL trial. Curr Cardiol Rep. 2017 Sep;19(9):75. [PMID: 
28752274]
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º
GLOME
r
ULA
r
 DISEASES
Abnormalities of glomerular function can be caused by 
damage to the major components of the glomerulus: the 
epithelium (podocytes), basement membrane, capillary 
endothelium, or mesangium. The damage may be caused 
by overwork injury, as in CKD; by an inflammatory pro
-
cess, such as SLE; by a podocyte protein mutation, as in 
hereditary focal segmental glomerulosclerosis (FSGS); or a 
deposition disease, as in diabetes or amyloidosis. A specific 
histologic pattern of glomerular injury results from this 
damage and can be seen on kidney biopsy.
 
»
Clinically, a glomerular disease can be classified as being in 
one of two spectra—either in the nephritic spectrum or the 
nephrotic spectrum (Figure 22–4). At the “least severe” end 
of the 
nephritic spectrum
, the findings of 
asymptomatic 
glomerular hematuria
 (ie, dysmorphic red blood cells with 
or without some proteinuria [<1 g/day]) are characteristic. 
The nephritic 
syndrome
, comprising glomerular hematuria, 
subnephrotic proteinuria (less than 3 g/day), edema, and 
elevated creatinine, falls in the mid-portion of the spec
-
trum. The 
rapidly progressive glomerulonephridities 
(RPGNs)
, with systemic symptoms, are at the “most severe” 
and clinically urgent end of the nephritic spectrum. The 
glomerular hematuria 
 
Nephritic
syndrome
Nephritic Spectrum
Nephrotic Spectrum
Microscopic or
macroscopic
hematuria
with or without
proteinuria  (<1 g/d)
with proteinuria 
of 1–3 g/d,
hematuria, RBC
casts, edema, and
with proteinuria of
1–3 g/d, hematuria,
RBC casts, and
systemic symptoms
Proteinuria of
300 mg/d–10 g/d
and bland urine
Proteinuria  of 
> 3 g/d
 
           plus
hypoalbuminemia,
edema,
hyperlipidemia,
and possible oval
fat bodies in urine
proteinuria
Nephrotic
syndrome
Chronic
glomerular
disease
Chronic kidney
disease with or
without
hematuria,
proteinuria,
hypertension,
late-stage
glomerulo-
nephritis,
burned-out
disease
Rapidly progressive
glomerulonephritis
 
▲
Figure 22–4.
 
Glomerular diseases present within one of the clinical spectra shown; the exact presentation is 
determined by the severity of the underlying disease and the pattern of injury. Nephritic diseases are characterized 
by the presence of an active urine sediment with glomerular hematuria and often with proteinuria. Nephrotic 
spectrum diseases are proteinuric with bland urine sediments (no cells or cellular casts). All glomerular diseases may 
progress to a chronic, scarred state. 
(Adapted, with permission, from Megan Troxell, MD, PhD.)
nephrotic spectrum
 is comprised of diseases that present 
primarily with proteinuria of at least 0.5–1 g/day and a 
bland urine sediment (no cells or cellular casts). At the 
more severe end of the nephrotic spectrum is the 
nephrotic
 syndrome,
 consisting of nephrotic-range pro
-
teinuria (>3 g/day), hypoalbuminemia, edema, hyperlipid
-
emia, and urinary oval fat bodies. Differentiating between 
a clinical presentation within the 
nephritic
 spectrum versus 
the 
nephrotic
 spectrum is important because it helps nar
-
row the differential diagnosis of the underlying glomerular 
disease (Tables 22–7 and 22–8).
Glomerular diseases can also be classified according to 
whether they cause only renal abnormalities (primary 
renal disease) or whether the renal abnormalities result 
from a systemic disease (secondary renal disease).
Further evaluation prior to kidney biopsy may include 
serologic testing for systemic diseases that can result in 
glomerular damage (Figure 22–5).
Caliskan Y et al. Novel biomarkers in glomerular disease. 
 
Adv Chronic Kidney Dis. 2014 Mar;21(2):205–16. [PMID: 
24602470]
Couser WG et al. The etiology of glomerulonephritis: roles of infec
-
tion and autoimmunity. Kidney Int. 2014 Nov;86(5):905–14. 
[PMID: 24621918]
Floege J et al. Primary glomerulonephritides. Lancet. 2016

-
Floege J et al. Primary glomerulonephritides. Lancet. 2016 
May 14;387(10032):2036–48. [PMID: 26921911]
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Table 22–7.
 
Classification and findings in glomerulonephritis: nephritic spectrum presentations.
Typical 
p
r
esentation
Association/Notes
Serology
Postinfectious 
Children: abrupt onset of nephritic 
 
syndrome and acute kidney injury 
 
but can present anywhere in 
 
Streptococci, other bacterial 
 
infections (eg, staphylococci, 
endocarditis, shunt infections)
Rising ASO titers, low 
 
complement levels
IgA nephropathy (Berger 
disease) and Henoch-
Schönlein purpura, 
 
systemic IgA vasculitis
Classically: gross hematuria with 
 
respiratory tract infection; can 
 
present anywhere in nephritic 
 
spectrum; Henoch-Schönlein 
 
purpura with vasculitic rash and 
 
gastrointestinal hemorrhage
Abnormal IgA glycosylation in both 
primary (familial predisposition) 
and secondary disease (associated 
with cirrhosis, HIV, celiac disease)
Henoch-Schönlein purpura in 
 
children after an inciting infection
No serologic tests helpful; 
complement levels are 
normal
Pauci-immune 
 
(granulomatosis with 
polyangiitis, eosinophilic 
granulomatosis with 
polyangiitis [formerly 
Churg-Strauss], 
 
polyarteritis, idiopathic 
crescentic 
glomerulonephritis)
Classically as crescentic or RPGN, but 
can present anywhere in nephritic 
spectrum; may have respiratory 
 
tract/sinus symptoms in 
 
See Figure 22–5
ANCAs: MPO or PR3 titers 
high; complement levels 
normal
Anti-GBM glomerulone
-
phritis; Goodpasture 
syndrome
spectrum; with pulmonary hemor
-
rhage in Goodpasture syndrome
May develop as a result of respiratory 
irritant exposure (chemicals or 
tobacco use)
Anti-GBM antibody titers 
 
high; complement 
 
levels normal
Cryoglobulin-associated 
Often acute nephritic syndrome; often 
with systemic vasculitis including 
 
rash and arthritis
Most commonly associated with 
chronic hepatitis C; may occur with 
other chronic infections or some 
connective tissue diseases
Cryoglobulins positive; 
 
rheumatoid factor may 
 
be elevated; complement 
levels low
MPGN
Classically presents with acute
 
nephritic syndrome, but can see 
nephrotic syndrome features in 
addition
Most patients are < 30 years old
Type I/immune complex most common
Type II (dense deposit disease) and 
C3 glomerulonephritis
Low complement levels, 
 
may have findings of 
underlying infection or 
paraproteinemia
Hepatitis C infection
Anywhere in nephritic spectrum
Can cause MPGN pattern of injury or 
cryoglobulinemic glomerulone
-
phritis; membranous nephropathy 
pattern of injury uncommon
Low complement levels; 
 
positive hepatitis C
 
serology; rheumatoid 
 
factor may be elevated
Anywhere in nephritic spectrum, 
depending on pattern/severity of 
injury
Treatment depends on clinical course 
and International Society of Nephrol
-
ogy and Renal Pathology Society 
(ISN/RPS) classification on biopsy
High ANA and anti-double-
stranded DNA titers; low 
ANA, antinuclear antibodies; ANCAs: antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; MPGN, membrano
-
proliferative glomerulonephritis; MPO, myeloperoxidase; PR3, proteinase 3; RPGN, rapidly progressive glomerulonephritis.
NEPHRITIC SPECTRUM GLOMERULAR 
DISEASES
 
»
Asymptomatic glomerular hematuria
 
–Hematuria with dysmorphic RBCs
–Proteinuria < 1 g/day
 
»
Nephritic syndrome
 in more severe cases
–
 
Glomerular 
hematuria (and RBC casts if glomeru
-
lar bleeding is heavy)
–Proteinuria of 1-3 g/day
–Hypertension
–Edema
–Rising creatinine over days to months.
 
»
Rapidly progressive glomerulonephritis in most 
severe cases
–AKI with rising creatinine over days to months
–Glomerular hematuria (and RBC casts)
–Proteinuria of 1–3 g/day
–Systemic symptoms
–Hypertension and edema uncommon
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CMDT 2019
Table 22–8.
 
Classification and findings in glomerulonephritis: nephrotic spectrum presentations.
Disease
Typical 
p
r
Minimal change disease 
 
(nil disease; lipoid nephrosis)
Child with sudden onset of full nephrotic 
syndrome
Children: associated with allergy or viral infection
Adults: associated with Hodgkin disease, NSAIDs
Membranous nephropathy
Anywhere in nephrotic spectrum, but 
nephrotic syndrome not uncommon; 
particular predisposition to 
 
hypercoagulable state
Primary (idiopathic) may be associated with antibodies to PLA
2
R
Secondary may be associated with non-Hodgkin lymphoma, 
 
carcinoma (gastrointestinal, renal, bronchogenic, thyroid), 
gold therapy, penicillamine, SLE, chronic hepatitis B or 
 
C infection
Focal and segmental 
glomerulosclerosis
Anywhere in nephrotic spectrum; 
 
children with congenital disease 
 
have nephrotic syndrome
Children: congenital disease with podocyte gene mutation,
 
or in spectrum of disease with minimal change disease
Adults: associated with heroin abuse, HIV infection, reflux 
nephropathy, obesity, pamidronate, podocyte protein 
 
mutations, 
APOL1
 mutations
Anywhere in nephrotic spectrum
AL: plasma cell dyscrasia with Ig light chain overproduction 
and deposition; check SPEP and UPEP
AA: serum amyloid protein A overproduction and 
 
deposition in response to chronic inflammatory disease 
 
(rheumatoid arthritis, inflammatory bowel disease, 
chronic infection)
Diabetic nephropathy
High GFR (hyperfiltration) 
→
 
microalbuminuria 
→
 frank 
 
proteinuria 
→
 decline in GFR
Diabetes diagnosis precedes diagnosis of nephropathy by 
years
HIV-associated nephropathy
Heavy proteinuria, often nephrotic 
 
syndrome, progresses to ESRD 
 
relatively quickly
Usually seen in antiviral treatment-naïve patients 
 
(rare in antiretroviral therapy era), predilection for 
 
those of African descent (
APOL1
 mutations)
Membranoproliferative 
glomerulonephropathy
Can present with nephrotic syndrome, but 
usually with nephritic features as well 
(glomerular hematuria)
See Table 22–7
ESRD, end-stage renal disease; GFR, glomerular filtration rate; NSAIDs, nonsteroidal anti-inflammatory drugs; PLA
2
R, phospholipase A
2
 receptor; 
SLE, systemic lupus erythematosus; SPEP/UPEP: serum and urine protein electrophoresis.
 
»
“Glomerulonephritis” is a term given to those diseases that 
present in the nephritic spectrum and usually signifies an 
inflammatory process causing renal dysfunction. It can be 
acute, developing over days to weeks, with or without reso
-
lution, or may be more chronic and indolent with progres
-
sive scarring. As noted above, diseases that cause a nephritic 
spectrum presentation may present with glomerular hema
-
turia and proteinuria, with nephritic syndrome, or with 
RPGN (Figure 22–4). The presentation depends on the 
severity of the underlying inflammation and the pattern of 
injury caused by the disease process.
 
»
If the nephritic syndrome is present, the acute decrease in 
GFR leads to sodium retention. This is clinically mani
-
fested by edema, first seen in regions of low tissue pressure 
such as the periorbital and scrotal areas, and by hyperten
-
sion. Heavy glomerular bleeding from inflammation 
may result in gross hematuria (smoky or cola-colored 
urine).
1. Serologic testing—
Serologic tests, including complement 
levels, antinuclear antibodies, cryoglobulins, hepatitis serol
-
ogies, ANCAs, anti-GBM antibodies, and antistreptolysin O 
(ASO) titers (Figure 22–5) based on the history and physical 
examination help narrow the differential diagnosis of the 
nephritic spectrum disorder.
2. Urinalysis—
The urine dipstick is positive for protein and 
blood. Urinary microscopy reveals red blood cells that are 
misshapen or dysmorphic from traversing a damaged glo
-

-
merular filtration barrier. Red blood cell casts are seen with 
heavy glomerular bleeding and tubular stasis. When quanti
-
fied, proteinuria is usually subnephrotic (less than 3 g/day).
3. Biopsy—
Kidney biopsy should be considered if there are no 
contraindications (eg, bleeding disorders, thrombocytopenia, 
uncontrolled hypertension). Important morphologic informa
-
tion is gleaned from light, electron, and immunofluorescent 
 
»
Treatment
General measures for all include treatment of hypertension 
and of fluid overload if present. Antiproteinuric therapy with 
CMDT19_Ch22_p0926-p0965.indd   947

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+
+
+
(GN)
Serologic ana
ly
sis
Anti-glomerular basement
membrane (GBM) antibodies
Anti-GBM GN
Antineutr
ophil cyt
oplasmic
antibodies (ANCA)
No lung
hemorrhage
Anti-GBM
GN
Lung
Goodpasture
syndrome
Immune complex
disease mar
kers
Immune complex GN
IgA
IgA
Antipathogen
Postinfectious
or peri-
infectious GN
Cryoglobulins
Cryoglobulinemic
GN
Antinuclear
Lupus GN
Complement
activation
MPGN
ANCA GN
Sy
stemic 
necrotizing 
vasculitis
Microscopic
po
ly
angiitis
Respiratory 
Granulomatosis
with
po
ly
angiitis
Asthma
and
eosinophilia
No extra-
renal
disease
AN
CA-
associated
crescentic GN
granulomatosis 
with polyangiitis
1
1
Formerly Churg-Strauss syndrome.
 
▲
Figure 22–5.
 
Serologic analysis of patients with glomerulonephritis. MPGN, membranoproliferative glomerulonephritis. (
Modified, with permission, from Greenberg A 
et al. 
Primer on Kidney Diseases
. Academic Press, 1994; and Jennette JC, Falk RJ. Diagnosis and management of glomerulonephritis and vasculitis presenting as acute renal failure. 
Med Clin North Am. 1990;74(4):893–908. © Elsevier.)
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an ACE inhibitor or ARB should be considered for those 
without AKI. For those with profound AKI, dialysis may be 
needed. The inflammatory glomerular injury may require 
immunosuppressive agents (see specific diseases discussed 
below).
 
»
Any patient in whom a glomerulonephritis is suspected 
should be referred to a nephrologist.
 
»
Any suspicion of acute nephritic syndrome or RPGN war
-
rants consideration of immediate hospitalization.
Kazi SN et al. Work-up of hematuria. Prim Care. 2014 Dec;
 
41(4):737–48. [PMID: 25439531]
Thurman JM. Many drugs for many targets: novel treatments 
for complement-mediated glomerular disease. Nephrol Dial 
Transplant. 2017 Jan 1;32(Suppl 1):i57–64. [PMID: 28391332]
1. Infection-
r
elated and 
p
ostinf
ectious 
 
»
Proteinuria.
 
»
Glomerular hematuria.
 
»
Symptoms 1–3 weeks after some infections (often 
pharyngitis or impetigo) or during course of other 
infections (eg, pneumonia or endocarditis).
 
»
Postinfectious glomerulonephritis is most often due to 
infection with nephritogenic group A beta-hemolytic strep
-
tococcal infections (pharyngitis or impetigo). It can occur 
sporadically or in clusters and during epidemics. with onset 
up to 1–3 weeks after infection (average 7–10 days).
Other infections have been associated with glomerulone
-
phritis including bacteremic states (especially with 
S aureus
), 
bacterial pneumonias, deep-seated abscesses, gram-negative 
infections, infective endocarditis, and shunt infections; viral, 
fungal, and parasitic causes of glomerulonephritis include 
hepatitis B or C, HIV , cytomegalovirus infection, infectious 
mononucleosis, coccidioidomycosis, malaria, mycobacteria, 
syphilis, and toxoplasmosis. These entities result in glomer
-
ular injury during active infection, and are better termed 
“infection-related glomerulonephritis” rather than “postin
-
fectious glomerulonephritis. ”
 
»
Disease presentation can vary widely across the nephritic 
spectrum from asymptomatic glomerular hematuria (espe
-
cially in epidemic cases) with minimal change in kidney 
function, to nephritic syndrome with hypertension, edema, 
and perhaps gross glomerular hematuria (smokey-colored 
urine); the most severe cases may result in oliguric AKI 
requiring dialysis.
Serum complement levels are low; in postinfectious glo
-
merulonephritis due to group A streptococcal infection, 
anti-streptolysin O (ASO) titers can be high unless the 
immune response has been blunted with previous antibi
-
otic treatment. Glomerular hematuria and subnephrotic 
proteinuria are present. Kidney biopsy shows a diffuse 
proliferative pattern of injury on light microscopy. Immu
-
nofluorescence demonstrates granular deposition of IgG 
and C3 in the mesangium and along the capillary basement 
membrane. Electron microscopy shows large, dense subepi
-
thelial deposits or “humps. ”
 
»
Treatment
The underlying infection should be identified and treated 
appropriately; otherwise, treatment for postinfectious glo
-
merulonephritis is supportive. Antihypertensives, salt 
restriction, and diuretics should be used if needed. Corti
-
costeroids have not been shown to improve outcomes but 
have been tried in severe cases. Prognosis depends on the 
severity of the glomerular injury and age of the patient. 
Children are more likely to fully recover; adults are more 
prone to the development of severe disease (RPGN with 
crescent formation) and CKD.
Glassock RJ et al. 
-related glomerulonephritis and 
poststreptococcal glomerulonephritis: why defining “post” is 
important in understanding and treating infection-related 
glomerulonephritis. Am J Kidney Dis. 2015 Jun;65(6):826–32. 
[PMID: 25890425]
Wang SY et al. Clinical, pathological, and prognostic characteristics of

Wang SY et al. Clinical, pathological, and prognostic characteristics of 
glomerulonephritis related to staphylococcal infection. Medicine 
(Baltimore). 2016 Apr;95(15):e3386. [PMID: 27082609]
2. IgA Nephropathy
 
»
Proteinuria: minimal to nephrotic range.
 
»
Glomerular hematuria: microscopic is common; 
macroscopic (gross) after infection.
 
»
Positive IgA staining on kidney biopsy.
 
»
IgA nephropathy (Berger disease) is a primary renal dis
-
ease of IgA deposition in the glomerular mesangium. The 
inciting cause is unknown but is likely due to deficient 
O-linked glycosylation of IgA subclass 1 molecules. IgA 
nephropathy can be a primary (renal-limited) disease, or it 
can be secondary to hepatic cirrhosis, celiac disease, and 
infections such as HIV and cytomegalovirus. Susceptibility 
to IgA nephropathy seems to be inheritable.
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IgA nephropathy is the most common primary glo
-
merular disease worldwide, particularly in Asia. It is most 
commonly seen in children and young adults, with males 
affected two to three times more commonly than females.
 
»
An episode of gross hematuria is the most common pre
-
senting symptom. Frequently, this is associated with a 
mucosal viral infection such as an upper respiratory infec
-
tion. The urine becomes red or smokey-colored 1–2 days 
after illness onset—a so-called synpharyngitic presentation 
in contradistinction to the latent period seen in postinfec
-
tious glomerulonephritis. IgA nephropathy can present 
anywhere along the nephritic spectrum from asymptom
-
atic microscopic hematuria to RPGN. Rarely, nephrotic 
syndrome can be present as well.
There are no serologic tests that aid in this diagnosis; 
serum IgA subclass 1 testing may be a possibility in the 
future. Serum complements are normal. The typical pat
-
tern of injury seen on kidney biopsy is a focal glomerulo
-
nephritis with mesangial proliferation; immunofluorescence 
demonstrates diffuse mesangial IgA and C3 deposits.
 
»
Treatment
The disease course of primary IgA nephropathy varies 
widely among patients; treatment approach needs to be tai
-
lored to risk for progression. Patients with low risk for 
progression (no hypertension, normal GFR, minimal pro
-
teinuria) can be monitored annually. Patients at higher risk 
(proteinuria greater than 1.0 g/day, decreased GFR, or 
hypertension or any combination of these three conditions) 
should be treated with an ACE inhibitor or ARB. Therapy 
should be titrated to reduce proteinuria to less than 1 g/day 
and to control blood pressure in the range of 125/75 mm Hg 
to 130/80 mm Hg. Addition of corticosteroids (eg, methyl
-
prednisolone, 1 g/day intravenously for 3 days during 
months 1, 3, and 5, plus prednisone in a dosage of 0.5 mg/kg 
orally every other day for 6 months) in patients with GFR 
greater than 50 mL/min/1.73 m
2
 and persistent proteinuria 
greater than 1 g/day has been shown to reduce proteinuria, 
but there seems to be little durable effect and risk of infec
-
tion and hyperglycemia is significant. Azathioprine and 
mycophenolate mofetil have also been used in patients at 
high risk for progression, but studies with these agents are 
small and their use is not routinely recommended. For the 
rare patient with IgA neuropathy and a rapidly progressive 
clinical course with crescent formation on biopsy, cyclo
-
phosphamide and corticosteroid therapy should be consid
-
ered (see section on ANCA-associated vasculitis below). 
Kidney transplantation is an excellent option for patients 
with ESRD, but recurrent disease has been documented in 
30% of patients 5–10 years posttransplant. Fortunately, 
recurrent disease rarely leads to failure of the allograft.
 
»
Prognosis
Approximately one-third of patients experience spontane
-
ous clinical remission. Progression to ESRD occurs in 
20–40% of patients. The remaining patients have chronic 
microscopic hematuria and a stable serum creatinine. The 
most unfavorable prognostic indicator is proteinuria 
greater than 1 g/day; other unfavorable prognostic indica
-
tors include hypertension, tubulointerstitial fibrosis, glo
-
merulosclerosis, or glomerular crescents on biopsy, and 
abnormal GFR on presentation.
Lv J et al; TESTING Study Group. Effect of oral methylpredniso
-
lone on clinical outcomes in patients with IgA nephropathy: 
the TESTING randomized clinical trial. JAMA. 2017 Aug 1;
 
318(5):432–42. [PMID: 28763548]
Rauen T et al; STOP-IgAN Investigators. Intensive supportive care 
plus immunosuppression in IgA nephropathy. N Engl J Med. 
2015 Dec 3;373(23):2225–36. [PMID: 26630142]
Rodrigues JC et al. IgA nephropathy. Clin J Am Soc Nephrol. 
2017 Apr 3;12(4):677–86. [PMID: 28159829]
3. 
h
enoch-Schönlein 
p
urpur
a
Henoch-Schönlein purpura is a systemic small-vessel leu
-

3. 
h
p
urpur
a
-
kocytoclastic vasculitis associated with IgA subclass 1 
deposition in vessel walls. It is most common in children 
and is often associated with an inciting infection, such as 
group A streptococcus or other exposure. There is a male 
predominance. It classically presents with palpable pur
-
pura in the lower extremities and buttock area; arthralgias; 
and abdominal symptoms, such as nausea, colic, and 
melena. A decrease in GFR is common with a nephritic 
presentation. The renal lesions can be identical to those 
found in IgA nephropathy, and the underlying pathophysi
-
ology appears to be similar. Most patients with microscopic 
hematuria and minimal proteinuria recover fully over sev
-
eral weeks. Progressive CKD and possibly ESRD are more 
likely to develop in those with the nephrotic syndrome and 
the presence of both nephritic and nephrotic syndrome 
features poses the worst renal prognosis. Histologic classi
-
fication of the lesions in children may also provide prog
-
nostic information. Although several treatment regimens 
of various immunosuppressive agents have been clinically 
tested, none have been definitively proven to alter the 
course of severe Henoch-Schönlein purpura nephritis. 
Rituximab treatment and plasma exchange have been suc
-
cessful for severe disease according to several case reports, 
but clinical trials are lacking. Rapidly progressive disease 
with crescent formation on biopsy may be treated as in 
ANCA-associated vasculitis (see section below).
Further details about Henoch-Schönlein purpura are 
provided in Chapter 20.
Audemard-Verger A et al. IgA vasculitis (Henoch-Shönlein 
purpura) in adults: diagnostic and therapeutic aspects. Autoimmun 
Rev. 2015 Jul;14(7):579–85. [PMID: 25688001]
Fenoglio R et al. Rituximab therapy for IgA-vasculitis with 
nephritis: a case series and review of the literature. Immunol 
Res. 2017 Feb;65(1):186–192. [PMID: 27449502]
Hahn D et al. Interventions for preventing and treating kidney 
disease in Henoch-Schönlein Purpura (HSP). Cochrane Data
-
base Syst Rev. 2015 Aug 7;8:CD005128. [PMID: 26258874]
4. 
p
auci-I
mmune Glomerulonephritis 
 
(ANCA-Associated)
Pauci-immune necrotizing glomerulonephritis is caused by 
the following systemic ANCA-associated small-vessel vas
-
culitides: granulomatosis with polyangiitis, microscopic 
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polyangiitis, and eosinophilic granulomatosis with polyangiitis 
(formerly Churg-Strauss disease; see Chapter 20). ANCA-
associated glomerulonephritis can also present as a primary 
renal lesion without systemic involvement; this is termed “idio
-
pathic crescentic glomerulonephritis. ” The pathogenesis of 
these entities appears to involve cytokine-primed neutrophils 
presenting cytoplasmic antigens on their surfaces (proteinase 3 
and myeloperoxidase). Circulating ANCAs then bind to these 
antigens and activate a neutrophil respiratory burst with con
-
sequent vascular damage; primed neutrophils also appear to 
activate the alternative complement pathway. Putative environ
-
mental exposures that may encite the initial response include 
S 
aureus
 and silica. Immunofluorescence of kidney biopsy speci
-
mens demonstrates lack of immunoglobulin or complement 
deposition, hence the term “pauci-immune. ” Renal involve
-
ment classically presents as an RPGN, but more indolent pre
-
sentations can be seen as well.
 
»
Symptoms of a systemic inflammatory disease, including 
fever, malaise, and weight loss may be present and usually 
precede initial presentation by several months. In addition to 
hematuria and proteinuria from glomerular inflammation, 
some patients exhibit purpura from dermal capillary involve
-
ment and mononeuritis multiplex from nerve arteriolar 
involvement. Ninety percent of patients with granulomatosis 
with polyangiitis have upper (especially sinus) or lower respi
-
ratory tract symptoms with nodular lesions that can cavitate 
and bleed. Hemoptysis is a concerning sign and usually war
-
rants hospitalization and aggressive immunosuppression.
Serologically, ANCA subtype analysis is done to determine 
whether antiproteinase-3 antibodies (PR3-ANCA) or anti
-
myeloperoxidase antibodies (MPO-ANCA) are present. 
Most patients with granulomatosis with polyangiitis are 
PR3 positive; the remainder are MPO positive or, more 
rarely, do not demonstrate circulating ANCA. Microscopic 
angiitis is generally associated with MPO ANCA. Renal 
biopsy demonstrates necrotizing lesions and crescents on 
light microscopy; immunofluorescence is negative for 
immune complex deposition.
 
»
Treatment
Treatment should be instituted early if aggressive disease is 
present. Induction therapy of high-dose corticosteroids 
(methylprednisolone, 1–2 g/day intravenously for 3 days, 
followed by prednisone, 1 mg/kg orally for 1 month, with a 
slow taper over the next 6 months) and cytotoxic agents 
(cyclophosphamide, 0.5–1 g/m
2
 intravenously per month 
or 1.5–2 mg/kg orally for 3–6 months) is followed by long-
term azathioprine or mycophenolate mofetil. Rituximab 
has been shown to be noninferior to cyclophosphamide for 
induction and is also used in refractory or relapsing cases 
and as an alternative to azathioprine for maintenance of 
remission. Plasma exchange has been used in conjunction 
with induction therapy in particularly severe cases; 
however, its efficacy is controversial and a large trial to test 
this therapy is currently underway. Patients receiving 
cyclophosphamide should receive prophylaxis for 
Pneumo
-
cystis jirovecii
, such as trimethoprim-sulfamethoxazole 
double-strength orally 3 days per week.
 
»
Prognosis
Without treatment, prognosis is extremely poor. However, 
with aggressive treatment, complete remission can be 
achieved in about 75% of patients. Prognosis depends on 
the extent of renal involvement before treatment is started 
and may be worse in those with PR3-associated disease. 
ANCA titers may be monitored to follow treatment efficacy; 
rising titers may herald relapse.
Chen M et al. Complement in ANCA-associated vasculitis: 
mechanisms and implications for management. Nat Rev 
Nephrol. 2017 Jun;13(6):359–67. [PMID: 28316335]
Jeannette JC et al. ANCA glomerulonephritis and vasculitis. Clin J

Jeannette JC et al. ANCA glomerulonephritis and vasculitis. Clin J 
Am Soc Nephrol. 2017 Oct 6;12(10):1680–91. [PMID: 28842398]
Y ates M et al. EULAR/ERA-EDTA recommendations for the 
management of ANCA-associated vasculitis. Ann Rheum 
Dis. 2016 Sep;75(9):1583–94. [PMID: 27338776]
5. Anti-Glomerular Basement Membrane 
Glomerulonephritis & Goodpasture Syndrome
Goodpasture syndrome is defined by the clinical constella
-
tion of glomerulonephritis and pulmonary hemorrhage; 
injury to both the kidneys and the lungs is mediated by anti
-
bodies to epitopes in the GBM (Figure 22–5). Up to one-third 
of patients with anti-GBM glomerulonephritis have no evi
-
dence of concomitant lung injury (anti-GBM disease). Anti-
GBM–associated glomerulonephritis accounts for 10–20% of 
patients with acute RPGN. The incidence peaks in the second 
and third decades of life during which time males are pre
-
dominantly affected and lung involvement is more common, 
and again in the sixth and seventh decades with less male sex 
predominance. Lung involvement has been associated with 
pulmonary infection, tobacco use, and hydrocarbon solvent 
exposure; HLA-DR2 and -B7 antigens may predispose as well.
 
»
The onset of disease may be preceded by an upper respira
-
tory tract infection; hemoptysis, dyspnea, and possible 
respiratory failure may ensue. Other findings are consistent 
with an RPGN, although some cases may present with 
much milder forms of the nephritic spectrum of disease 
(eg, glomerular hematuria and proteinuria with minimal 
renal dysfunction).
Chest radiographs may demonstrate pulmonary infiltrates 
if pulmonary hemorrhage is present. Serum complement 
levels are normal. Circulating anti-GBM antibodies are 
present in over 90% of patients. A small percentage of 
patients also have elevated ANCA titers; these patients 
should be treated with plasma exchange as for anti-GBM 
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disease. Kidney biopsy typically shows crescent formation 
on light microscopy, with linear IgG staining along the 
GBM on immunofluorescence.
 
»
Treatment
Treatment is a combination of plasma exchange therapy 
daily for up to 2 weeks to remove circulating antibodies, 
and administration of corticosteroids and cyclophospha
-
mide to prevent formation of new antibodies and control 
the inflammatory response. Rituximab has been used in a 
small number of patients with refractory disease. Patients 
with oliguric AKI or who require dialysis upon presenta
-
tion have a poor prognosis. Anti-GBM antibody titers 
should decrease as the clinical course improves.
Henderson SR et al. Diagnostic and management challenges in 
Goodpasture’s (anti-glomerular basement membrane) disease. 
Nephrol Dial Transplant. 2018 Feb 1;33(2):196–202 [PMID: 
28459999]
McAdoo SP et al. Anti-glomerular basement membrane disease. 
Clin J Am Soc Nephrol. 2017 Jul 7;12(7):1162–72. [PMID: 
28515156]
van Daalen EE et al. Predicting outcome in patients with anti-
GBM glomerulonephritis. Clin J Am Soc Nephrol. 2018 Jan 6;
 
13(1):63–72. [PMID: 29162595]
6. Cryoglobulin-Associated Glomerulonephritis
Essential (mixed) cryoglobulinemia is a vasculitis associated 
with cold-precipitable immunoglobulins (cryoglobulins). 
The most common underlying etiology is HCV infection; in 
these cases, there is clonal expansion of B lymphocytes, 
which produce IgM rheumatoid factor. Rheumatoid factor, 
HCV antigen and polyclonal anti-HCV IgG form complexes 
that deposit in vessels and incite inflammation. Other overt 
or occult infections (eg, viral, bacterial, and fungal) as well 
as some connective tissue diseases can also be causative.
Patients exhibit purpuric and necrotizing skin lesions in 
dependent areas, arthralgias, fever, and hepatosplenomegaly. 
Serum complement levels are depressed. Rheumatoid fac
-
tor is often elevated when cryoglobulins are present. Kidney 
biopsy may show several different patterns of injury; there 
may be crescent formation, glomerular capillary thrombi, 
or MPGN (see below). Treatment consists of aggressively 
targeting the causative infection. Pulse corticosteroids, 
plasma exchange, rituximab, and cytotoxic agents have been 
used when there is little risk of exacerbating the underlying 
infection or when no infection is present. See also section 
Hepatitis C Virus–Associated Renal Disease.
De Vita S et al. A randomized controlled trial of rituximab for 
the treatment of severe cryoglobulinemic vasculitis. Arthritis 
Rheum. 2012 Mar;64(3):843–53. [PMID: 22147661]
Zaidan M et al; CryoVas Study Group. Spectrum and prognosis 
of noninfectious renal mixed cryoglobulinemic GN. J Am Soc 
Nephrol. 2016 Apr;27(4):1213–24. [PMID: 26260165]
7. Membranoproliferative Glomerulonephritis 
& C3 Glomerulopathies
MPGN is a relatively rare pattern of glomerular injury that 
can be caused by a wide range of identifiable etiologies or 
can be idiopathic. Clinically, it can present anywhere along 
the nephritic spectrum from asymptomatic glomerular 
hematuria to acute nephritic syndrome with bouts of gross 
hematuria to RPGN; nephrotic syndrome can also be seen. 
Traditionally, MPGN has been classified into several histo
-
pathologic subtypes; this classification is now in evolution. 
Type I is relatively more common and can be idiopathic 
(especially in children and young adults) or secondary to 
chronic infection (most commonly HCV), a paraprotein
-
emia, or an underlying autoimmune disease such as lupus. 
The pathogenesis is likely a chronic antigenemia leading to 
classical complement pathway activation with immune com
-
plex deposition; however, it is now recognized that some 
cases may result from alternative complement pathway dys
-
regulation. Type II MPGN is caused by several inherited or 
acquired abnormalities in the alternative complement path
-
way. Both types result in low circulating C3 complement;

-
-
way. Both types result in low circulating C3 complement; 
immune complex type I also has low C4. Light microscopy 
of both types shows varying degrees of mesangial hyper
-
cellularity, endocapillary proliferation and capillary wall 
remodeling resulting in double contours of the GBM (“tram 
track” appearance). Immunofluorescence and electron 
microscopy provide distinguishing information. Type II 
MPGN reveals C3 deposition without immunoglobulin 
staining on immunofluorescence, and electron microscopy 
demonstrates thick ribbon-like electron dense deposits 
along the GBM; thus, type II disease is also known as “dense 
deposit disease. ” Conversely, type I MPGN has scattered 
subendothelial and subepithelial deposits on electron 
microscopy. When there is immunoglobulin and C3 staining 
on immunofluorescence in type I MPGN, it is also called 
immune complex MPGN (more common type); when a type 
I case demonstrates only C3 staining on immunofluores
-
cence, it is now termed “C3 glomerulonephritis” (C3 GN). 
Together, dense deposit disease (type II) and C3 GN are now 
termed “C3 glomerulopathies”; both result from inherited or 
acquired alternative complement dysregulation/activation.
Treatment of type I immune complex MPGN should be 
directed at any underlying cause. Treatment of idiopathic 
immune complex disease is controversial and controlled 
trial data are lacking. For those with mild disease, ACE 
inhibitors and ARBs should be used. For severe disease, a 
combination of oral cyclophosphamide or mycophenolate 
mofetil plus corticosteroids could be considered; rituximab 
is also sometimes used. Those with RPGN and crescents on 
biopsy may be treated the same as those with ANCA-
associated disease provided secondary causes have been 
ruled out. Despite therapy, most will progress to ESRD. 
Treatment for the C3 glomerulopathies is in evolution as 
novel therapies to target the dysregulated alternative com
-
plement cascade are being explored; small, uncontrolled 
series suggest a possible benefit of eculizumab. Less favor
-
able prognostic findings include type II/dense deposit dis
-
ease, early decline in GFR, hypertension, and persistent 
nephrotic syndrome. All types of MPGN recur with high 
frequency after renal transplantation; however, type II recurs 
more commonly. Plasma exchange has been used with 
mixed results to treat posttransplant recurrence of MPGN.
Ito N et al. C3 glomerulopathy and current dilemmas. Clin Exp 
Nephrol. 2017 Aug;21(4):541–51. [PMID: 27878657]
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Lionaki S et al. Understanding the complement-mediated glomeru
-
lar diseases: focus on membranoproliferative glomerulonephritis 
and C3 glomerulopathies. APMIS. 2016 Sep;124(9):725–35. 
[PMID: 27356907]
Riedl M et al. C3 glomerulopathy. Pediatr Nephrol. 2017 Jan;
 
32(1):43–57. [PMID: 27056062]
8. 
h
epatitis C Virus–Associated Kidney Disease
Kidney disease can occur in the setting of HCV infection. 
The three patterns of kidney injury associated with HCV 
are secondary MPGN (most common), cryoglobulinemic 
glomerulonephritis, and membranous nephropathy. The 
clinical presentation is dictated by the underlying pattern 
of injury. Many patients have elevated serum transami
-
nases and an elevated rheumatoid factor. Hypocomple
-
mentemia is very common, with C4 typically more reduced 
than C3; complement levels and rheumatoid factor tend to 
be normal if there is a membranous pattern of injury.
 
»
Treatment
Viral suppression or eradication is the cornerstone of treat
-
ment of HCV–associated kidney disease; IFN-alpha–based 
therapy has been supplanted by direct-acting antivirals. 
Ribavirin may cause hemolysis in those with significant 
kidney impairment and is relatively contraindicated in that 
population. Therapy with rituximab and possibly cortico
-
steroids and plasmapheresis should be initiated in patients 
with severe vasculitis prior to the initiation of antiviral 
therapy. Small, uncontrolled series suggested safety and 
efficacy of direct-acting antivirals in those with markedly 
impaired GFR or ESRD; however, there are several case 
reports of AKI associated with the use of some direct-acting 
antiviral agents (see Chapter 16).
Carrier P et al. Anti-hepatitis C virus drugs and kidney. World J 
Hepatol. 2016 Nov 18;8(32):1343–53. [PMID: 27917261]
Kupin WL. Viral-associated GN: hepatitis C and HIV . Clin J Am 
Soc Nephrol. 2017 Aug 7;12(8):1337–42. [PMID: 27797895]
Park H et al. Chronic hepatitis C virus (HCV) increases the risk 
of chronic kidney disease (CKD) while effective HCV treat
-
ment decreases the incidence of CKD. Hepatology. 2017 Sep 5. 
[Epub ahead of print] [PMID: 28873225]
Patel YA et al. Treatment of HCV in renal disease: subtle man
-
agement considerations in the era of direct-acting antivirals. 
Curr Hepatol Rep. 2016 Dec;15(4):285–90. [PMID: 28584732]
9. Systemic Lupus Erythematosus
Renal involvement in SLE is very common; estimates range 
from 35% to 90%, with higher estimates encompassing 
subclinical disease. Rates of lupus nephritis are highest in 
nonwhites. The pathogenesis may be dysregulated cellular 
apoptosis resulting in autoantibodies against nucleosomes; 
antibody/nucleosome complexes then bind to components 
of the glomerulus to form immune complex glomerular 
disease. See Chapter 20 for further discussion of SLE.
The term “lupus nephritis” encompasses many possible 
patterns of renal injury—most cases present within the 
nephritic spectrum (class I–IV). Nonglomerular syndromes 
include tubulointerstitial nephritis and vasculitis. All patients 
with SLE should have routine urinalyses to monitor for the 
appearance of hematuria or proteinuria. If urinary abnor
-
malities are detected, kidney biopsy is often performed. The 
2003 International Society of Nephrology and Renal Pathol
-
ogy Society (ISN/RPS) classification of renal glomerular 
lesions is class I, minimal mesangial nephritis; class II, 
mesangial proliferative nephritis; class III, focal (less than 
50% of glomeruli affected with capillary involvement) pro
-
liferative nephritis; class IV , diffuse (greater than 50% of 
glomeruli affected with capillary involvement) proliferative 
nephritis; class V , membranous nephropathy; and class VI, 
advanced sclerosis without residual disease activity. Classes 
III and IV , the most severe forms of lupus nephritis, are 
further classified as active or chronic, and global or segmen
-
tal, which confers additional prognostic value.
 
»
Treatment

-
 
»
Treatment
class I
 and 
class II lesions
 generally 
require no treatment; corticosteroids or calcineurin inhibi
-
tors should be considered for those with class II lesions 
with nephrotic-range proteinuria. Transformation of these 
types to a more active lesion may occur and is usually 
accompanied by an increase in lupus serologic activity (eg, 
rising titers of anti–double-stranded DNA antibodies and 
falling C3 and C4 levels) and increasing proteinuria or fall
-
ing GFR. Repeat biopsy in such patients is recommended. 
Some experts recommend hydroxychloroquine treatment 
in all patients with lupus nephritis, regardless of histologi
-
cal class. Patients with extensive 
class III lesions
 and all 
class IV lesions
 should receive aggressive immunosup
-
pressive therapy. The features signifying the poorest prog
-
nosis in patients with class III or IV lesions include 
elevated serum creatinine, lower complement levels, male 
sex, presence of antiphospholipid antibodies, nephrotic-
range proteinuria, African descent (possibly in association 
with 
APOL1
 risk alleles), and poor response to therapy. 
Immunosuppressive therapy for class V lupus nephritis is 
indicated if superimposed proliferative lesions exist. Class 
VI lesions should not be treated.
class III
 or 
IV lupus nephritis
 consists of 
induction therapy, followed by maintenance treatment. All 
induction therapy includes corticosteroids (eg, methyl
-
prednisolone 1 g intravenously daily for 3 days followed by 
prednisone, 1 mg/kg orally daily with subsequent taper 
over 6–12 months) in combination with either cyclophos
-
phamide or mycophenolate mofetil. Data suggest that 
blacks and Hispanics respond more favorably to mycophe
-
nolate mofetil rather than cyclophosphamide; in addition, 
mycophenolate mofetil has a more favorable side-effect 
profile than cyclophosphamide and should be favored 
when preservation of fertility is a consideration. Mycophe
-
nolate mofetil induction is typically given at 2–3 g/day, 
then tapered to 1–2 g/day for maintenance. Cyclophospha
-
mide induction regimens vary but usually involve monthly 
intravenous pulse doses (500–1000 mg/m
2
) for 6 months. 
Induction is followed by daily oral mycophenolate mofetil 
or azathioprine maintenance therapy; mycophenolate 
mofetil may be superior to azathioprine maintenance and 
causes few adverse effects. Maintenance with calcineurin 
inhibitors may also be considered, but the relapse rate is 
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high upon discontinuation of these agents. With standard 
therapy, remission rates with induction vary from 80% 
for partial remission to 50–60% for full remission; it may 
take more than 6 months to see these effects. Relapse is 
common and rates of disease flare are higher in those 
who do not experience complete remission; similarly, 
progression to ESRD is more common in those who 
relapse more frequently, or in whom no remission has been 
achieved. Studies to assess safety and efficacy of newer 
biologic immunomodulatory drugs for lupus nephritis are 
ongoing.
The normalization of various laboratory tests (double-
stranded DNA antibodies, serum C3, C4, CH
50
 levels) can 
be useful in monitoring treatment. Urinary protein levels 
and sediment activity are also helpful markers. Patients with 
SLE who undergo dialysis have a favorable prospect for 
long-term survival; interestingly, systemic lupus symptoms 
may become quiescent with the development of ESRD. 
Patients with SLE undergoing kidney transplants can have 
recurrent renal disease, although rates are relatively low.
Almaani S et al. Update on lupus nephritis. Clin J Am Soc 
Nephrol. 2017 May 8;12(5):825–35. [PMID: 27821390]
Chavarot N et al; Groupe Coopératif sur le Lupus Rénal. Rituximab 
alone as induction therapy for membranous lupus nephritis: 
a multicenter retrospective study. Medicine (Baltimore). 
2017 Jul;96(27):e7429. [PMID: 28682905]
Palmer SC et al. Induction and maintenance immunosuppression 
treatment of proliferative lupus nephritis: a network meta-
analysis of randomized trials. Am J Kidney Dis. 2017 Sep;
 
70(3):324–36. [PMID: 28233655]
Ponticelli C et al. Hydroxychloroquine in systemic lupus erythe
-
matosus (SLE). Expert Opin Drug Saf. 2017 Mar;16(3):411–9. 
[PMID: 27927040]
Zampeli E et al. A comprehensive evaluation for the treatment of 
lupus nephritis. J Autoimmun. 2017 Mar;78:1–10. [PMID: 
28082046]
NEPHROTIC SPECTRUM GLOMERULAR 
DISEASES
 
»
Bland urine sediment (few if any cells or cellular 
casts).
 
»
Nephrotic syndrome is characterized by the 
–Heavy proteinuria (urine protein excretion greater
 
than 3 g per 24 hours).
–Hypoalbuminemia (albumin less than 3 g/dL).
–Peripheral edema.
–Hyperlipidemia.
–Oval fat bodies may be seen in the urine.
 
»
In American adults, the most common cause of nephrotic 
spectrum glomerular disease is diabetes mellitus. Other 
causes of this presentation include minimal change disease, 
FSGS, membranous nephropathy, and amyloidosis. Any of 
these entities can present on the less severe end of the spec
-
trum with a bland urinalysis and proteinuria, or with the 
most severe presentation of the nephrotic syndrome. Serum 
creatinine may or may not be abnormal at the time of pre
-
sentation, depending on the severity and acuity of the 
disease.
 
»
Patients with subnephrotic range proteinuria do not mani
-
fest symptoms of the kidney disease. In those with the 
nephrotic syndrome, peripheral edema is present and is 
most likely due to sodium retention and, at albumin levels 
less than 2 g/dL (20 g/L), arterial underfilling from low 
plasma oncotic pressure. Edema may present in dependent 
regions, such as the lower extremities, or it may become 
generalized and include periorbital edema. Dyspnea due to 
pulmonary edema, pleural effusions, and diaphragmatic 
compromise with ascites can occur.
Proteinuria occurs as a result of effacement 
of podocytes (foot processes) and an alteration of the nega
-
tive charge of the GBM. The urinary dipstick is a good 
screening test for proteinuria; however, it detects only 
albumin. The addition of sulfosalicylic acid to the urine 
causes total protein to precipitate, allowing for the possible 
discovery of paraproteins (and albumin). A spot urine pro
-

-
tein to urine creatinine ratio gives a reasonable approxima
-
tion of grams of protein excreted per day; a 24-hour urine 
sample for protein excretion is rarely needed.
Microscopically, the urinary sediment has relatively few 
cellular elements or casts. However, if marked hyperlipid
-
emia is present, urinary oval fat bodies may be seen. They 
appear as “grape clusters” under light microscopy and 
“Maltese crosses” under polarized light.
2. Blood chemistries—
The nephrotic syndrome results in 
hypoalbuminemia (less than 3 g/dL [30 g/L]) and hypopro
-
teinemia (less than 6 g/dL [60 g/L]). Hyperlipidemia occurs 
in over 50% of patients with early nephrotic syndrome, and 
becomes more frequent and worsens in degree as the sever
-
ity of the nephrotic syndrome increases. A fall in oncotic 
pressure triggers increased hepatic production of lipids 
(cholesterol and apolipoprotein B). There is also decreased 
clearance of very low-density lipoproteins, causing hyper
-
triglyceridemia. Patients may also have an elevated eryth
-
rocyte sedimentation rate as a result of alterations in some 
plasma components such as increased levels of fibrinogen. 
Patients may become deficient in vitamin D, zinc, and cop
-
per from loss of binding proteins in the urine.
Laboratory testing to determine the underlying cause 
may include complement levels, serum and urine protein 
electrophoresis, antinuclear antibodies, and serologic tests 
for viral hepatitides.
3. Kidney biopsy—
Kidney biopsy is often performed in 
adults with new-onset idiopathic nephrotic syndrome if a 
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CMDT 2019
primary renal disease that may require immunosuppressive 
therapy is suspected. Chronically and significantly decreased 
GFR indicates irreversible kidney disease mitigating the 
usefulness of kidney biopsy. In the setting of long-standing 
diabetes mellitus type 1 or 2, proteinuric renal disease is 
rarely biopsied unless atypical features (such as significant 
glomerular hematuria or cellular casts) are also present, or if 
there is other reason to suspect an additional renal lesion.
 
»
Treatment
A. Protein Loss
In those with subnephrotic proteinuria or mild nephrotic 
syndrome, dietary protein restriction may be helpful in 
slowing progression of renal disease (see CKD section). In 
those with proteinuria greater than 10 g/day, protein mal
-
nutrition may occur and daily protein intake should 
replace daily urinary protein losses.
In both diabetic and nondiabetic patients, therapy that is 
aimed at reducing proteinuria may also reduce progression of 
renal disease. ACE inhibitors and ARBs lower urine protein 
excretion by reducing glomerular capillary pressure; they 
also have antifibrotic effects. These agents can be used in 
patients with reduced GFR as long as significant hyperkale
-
mia (potassium greater than 5.2–5.5 mEq/L or mmol/L) does 
not occur and serum creatinine rises less than 30%; patients 
should be monitored closely to avoid AKI and hyperkalemia. 
Combination therapy of an ARB and an ACE inhibitor is not 
recommended because of the risk of AKI and hyperkalemia.
B. Edema
Dietary salt restriction is essential for managing edema; 
most patients also require diuretic therapy. Both thiazide 
and loop diuretics are highly protein bound; therefore, 
with hypoalbuminemia and decreased GFR, diuretic deliv
-
ery to the kidney is reduced, and patients often require 
larger doses. A combination of loop and thiazide diuretics 
can potentiate the diuretic effect and may be needed for 
patients with refractory fluid retention.
C. Hyperlipidemia
Hypercholesterolemia and hypertriglyceridemia occur as 
noted above. Dietary modification and exercise should be 
advocated; however, effective lipid-lowering usually also 
requires pharmacologic treatment (see Chapter 28). There 
is significant risk of rhabdomyolysis in patients with CKD 
who take gemfibrozil in combination with statins; combin
-
ing fenofibrate or niacin with a statin may be safer.
D. Hypercoagulable State
Patients with serum albumin less than 2 g/dL (20 g/L) can 
become hypercoagulable. Nephrotic patients have urinary 
losses of antithrombin, protein C, and protein S and 
increased platelet activation. Patients are prone to renal 
vein thrombosis, pulmonary embolus, and other venous 
thromboemboli, particularly with membranous nephropa
-
thy. Anticoagulation therapy with warfarin is warranted for 
at least 3–6 months in patients with evidence of thrombosis 
in any location. Patients with renal vein thrombosis, 
pulmonary embolus, or recurrent thromboemboli require 
indefinite anticoagulation. After an initial clotting event, 
ongoing nephrotic syndrome poses a risk of thrombosis 
recurrence, and continued anticoagulation should be con
-
sidered until resolution of the nephrotic syndrome.
 
»
Any patient with the nephrotic syndrome should be 
referred immediately to a nephrologist for volume and 
blood pressure management, assessment for kidney biopsy, 
and treatment of the underlying disease. Proteinuria of 
more than 1 g/day without the nephrotic syndrome also 
merits nephrology referral, though with less urgency.
 
»
Patients with edema refractory to outpatient therapy or 
rapidly worsening kidney function that may require inpa
-
tient interventions should be admitted.
Agrawal S et al. Dyslipidaemia in nephrotic syndrome: mecha
-
nisms and treatment. Nat Rev Nephrol. 2018 Jan;14(1):57–70. 
[PMID: 29176657]
Bierzynska A et al. Recent advances in understanding and treat
-

-
-
ing nephrotic syndrome. F1000Res. 2017 Feb 9;6:121. [PMID: 
28232870]
Fried LF et al; V A NEPHRON-D Investigators. Combined angio
-
tensin inhibition for the treatment of diabetic nephropathy. N 
Engl J Med. 2013 Nov 14;369(20):892–903. [PMID: 24206457]
McCloskey O et al. Diagnosis and management of nephrotic 
syndrome. Practitioner. 2017 Feb;261(1801):11–5. [PMID: 
29020719]
Rankin AJ et al. Venous thromboembolism in primary nephrotic 
syndrome—is the risk high enough to justify prophylactic anti
-
coagulation? Nephron. 2017;135(1):39–45. [PMID: 27669572]
Snyder S et al. Workup for proteinuria. Prim Care. 2014 Dec;
 
41(4):719–35. [PMID: 25439530]
 
º
NE
phr
OTIC S
p
ECT
r
UM DISEASE 
 
IN 
pr
IMA
r
Y
 
r
ENAL DISO
r
DE
r
S
MINIMAL CHANGE DISEASE
 
»
Nephrotic-range proteinuria.
 
»
Kidney biopsy shows no changes on light 
 
»
Characteristic foot-process effacement on electron 
 
»
Minimal change disease is the most common cause of pro
-
teinuric renal disease in children, accounting for about 
80% of cases. It often remits upon treatment with a course 
of corticosteroids. Indeed, children with nephrotic syn
-
drome are often treated for minimal change disease 
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empirically without a biopsy diagnosis. Biopsy should be 
considered for children with nephrotic syndrome who 
exhibit unusual features (such as signs of other systemic 
illness), who are steroid-resistant, or who relapse upon 
withdrawal of corticosteroid therapy. Minimal change dis
-
ease is less common in adults, accounting for 20–25% of 
cases of primary nephrotic syndrome in those over age 
 
40 years. This entity can be idiopathic but also occurs fol
-
lowing viral upper respiratory infections (especially in 
children), in association with neoplasms such as Hodgkin 
disease, with drugs (lithium), and with hypersensitivity 
reactions (especially to NSAIDs and bee stings).
 
»
Patients present with nephrotic syndrome, which confers 
susceptibility to infection, tendency toward thromboem
-
bolic events, severe hyperlipidemia, and possibly protein 
malnutrition. Minimal change disease can cause AKI due 
to renal tubular damage and interstitial edema.
B. Laboratory and Histologic Findings
There is no helpful serologic testing. Glomeruli usually appear 
normal on light microscopy and immunofluorescence. On 
electron microscopy, there is a characteristic effacement of 
podocyte foot processes. Mesangial cell proliferation may be 
seen in a subgroup of patients; this finding is associated with 
more hematuria and hypertension and poor response to 
standard corticosteroid treatment.
 
»
Treatment
Treatment is with prednisone, 60 mg/m
2
/day orally; remis
-
sion in steroid-responsive minimal change disease generally 
occurs within 4–8 weeks. Adults often require longer courses 
of therapy than children, requiring up to 16 weeks to achieve 
a response. Treatment should be continued for several weeks 
after complete remission of proteinuria, and dosing tapers 
should be individualized. A significant number of patients 
will relapse and require repeated corticosteroid treatment. 
Patients with frequent relapses or corticosteroid resistance 
may require cyclophosphamide, a calcineurin inhibitor 
(tacrolimus, cyclosporine), or rituximab to induce subse
-
quent remissions. Progression to ESRD is rare. Complica
-
tions most often arise from prolonged corticosteroid use.
Li X et al. Tacrolimus monotherapy after intravenous methylpred
-
nisolone in adults with minimal change nephrotic syndrome. J 
Am Soc Nephrol. 2017 Apr;28(4):1286–95. [PMID: 27807213]
Ravani P et al. Clinical trials in minimal change disease. Nephrol 
Dial Transplant. 2017 Jan 1;32(Suppl 1):i7–13. [PMID: 28391333]
Vivarelli M et al. Minimal change disease. Clin J Am Soc Nephrol. 
2017 Feb 7;12(2):332–45. [PMID: 27940460]
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
 
»
This relatively common renal pattern of injury results 
from damage to podocytes; such damage may be a 
primary/renal-limited disorder or may be secondary to 
another underlying disease state. Primary causes fall into 
three categories: (1) heritable abnormalities in any one of 
several podocyte proteins, or to underlying type 4 colla
-
gen mutations; (2) polymorphisms in the 
APOL1
 gene in 
those of African descent; or (3) increased levels of a cir
-
culating permeability factor. Secondary causes include 
renal overwork injury, obesity, hypertension, chronic 
urinary reflux, HIV infection, or analgesic or bisphos
-
phonate exposure. Genetic testing in primary cases is 
becoming more common, especially in the pediatric 
 
»
Proteinuria is present in patients with FSGS. In FSGS 
caused by a primary renal disease, 80% of children and 
50% of adults have overt nephrotic syndrome; however, 
when it develops due to a secondary cause, frank nephrotic 
syndrome is uncommon. Decreased GFR is present in 
25–50% of those with FSGS at time of diagnosis. ESRD 
typically develops in patients with FSGS and nephrotic 
syndrome in 6–8 years.
Diagnosis requires kidney biopsy; there is no helpful

Diagnosis requires kidney biopsy; there is no helpful 
serologic test. Light microscopy shows sclerosis of segments 
of some, but not all, glomeruli. On immunofluorescence, 
IgM and C3 are seen in the sclerotic lesions, although it is 
presumed that these immune components are simply 
trapped in the sclerotic glomeruli and not pathogenetic. As 
in minimal change disease, electron microscopy shows 
fusion of epithelial foot processes.
 
»
Treatment
Treatment for all forms of FSGS should include diuretics 
for edema, ACE inhibitors or ARBs to control proteinuria 
and hypertension, and statins or niacin for hyperlipidemia. 
Immunosuppression therapy (oral prednisone, 1 mg/kg/day 
for 4–16 weeks followed by a slow taper) is reserved for 
nephrotic primary FSGS cases presumed to be due to a cir
-
culating permeability factor; in those with steroid-resistance 
or intolerance, calcineurin inhibitors and mycophenolate 
mofetil can be considered. Kidney transplantation in this 
subgroup of FSGS patients is complicated by a relatively 
high relapse rate and risk of graft loss. Plasma exchange 
therapy, and possibly rituximab, just prior to the transplant 
surgery and with early signs of relapse, appear to be benefi
-
cial. Those with 
APOL1
-associated and nonhereditary 
primary renal disease may not benefit from immunosup
-
pression, although robust clinical trials are lacking. Patients 
with secondary FSGS do not benefit from immunosup
-
pressive therapy; treatment should be directed at the 
inciting cause.
Maas RJ et al. Minimal change disease and idiopathic FSGS: 
manifestations of the same disease. Nat Rev Nephrol. 
2016 Dec;12(12):768–76. [PMID: 27748392]
Rosenberg AZ et al. Focal segmental glomerulosclerosis. Clin J 
Am Soc Nephrol. 2017 Mar 7;12(3):502–17. [PMID: 
28242845]
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MEMBRANOUS NEPHROPATHY
 
»
Varying degrees of proteinuria, may have nephrotic 
syndrome.
 
»
Associated with coagulopathy, eg, renal vein throm
-
bosis, if nephrotic syndrome present.
 
»
“Spike and dome” pattern on kidney biopsy from 
subepithelial deposits.
 
»
Secondary causes notably include hepatitis B virus 
and carcinomas.
 
»
Membranous nephropathy is the most common cause of 
primary nephrotic syndrome in adults and often presents 
in the fifth and sixth decades. It is an immune-mediated 
disease characterized by immune complex deposition in 
the subepithelial portion of glomerular capillary walls. 
The antigen in the primary form of the disease appears to 
be a phospholipase A
2
 receptor (PLA
2
R) on the podocyte 
in 70–80% of patients. Secondary disease is associated 
with underlying carcinomas (some of these cases may 
involve autoimmunity to podocyte-expressed thrombos
-
pondin type-1 domain-containing 7A [THSD7A]); infec
-
tions, such as hepatitis B and C, endocarditis, and syphilis; 
autoimmune disease, such as SLE, mixed connective tissue 
disease, and thyroiditis; and certain drugs, such as NSAIDs 
and captopril. The course of disease is variable, with about 
50% of patients progressing to ESRD over 3–10 years. 
Poorer outcome is associated with concomitant tubuloint
-
erstitial fibrosis, male sex, elevated serum creatinine, 
hypertension, and proteinuria greater than 10 g/day.
Patients with membranous nephropathy and nephrotic 
syndrome have a higher risk of hypercoagulable state than 
those with nephrosis from other etiologies; there is a par
-
ticular predisposition to renal vein thrombosis in these 
patients.
 
»
Patients may be asymptomatic or may have edema or 
frothy urine. Venous thrombosis, such as an unprovoked 
deep venous thrombosis may be an initial sign. There may 
be symptoms or signs of an underlying infection or neo
-
plasm (especially lung, stomach, breast, and colon cancers) 
in secondary membranous nephropathy.
Hypoalbuminemia and hyperlipidemia are characteristic 
laboratory findings in the nephrotic syndrome. Evaluation 
for secondary causes including serologic testing for SLE, 
syphilis, viral hepatidites, and age- and risk-appropriate 
cancer screening should be performed. Serum evaluation 
for circulating PLA
2
R antibodies to assess for idiopathic 
membranous nephropathy is possible; additionally, titers 
can be followed during treatment. Renal biopsy findings 
include increased capillary wall thickness without inflam
-
matory changes or cellular proliferation; when stained with 
silver methenamine, a “spike and dome” pattern results 
from projections of excess GBM between the subepithelial 
deposits. Immunofluorescence shows IgG and C3 staining 
along capillary loops. Electron microscopy shows a discon
-
tinuous pattern of dense deposits along the subepithelial 
surface of the basement membrane.
 
»
Treatment
Underlying causes must be excluded prior to consideration 
of treatment. Idiopathic/primary disease treatment 
depends on the risk of renal disease progression. Roughly 
30% of patients present with subnephrotic proteinuria (less 
than 3 g/day) and most have a good prognosis with conser
-
vative management, including antiproteinuric therapy with 
ACE inhibitor or ARB if blood pressure is greater than 
125/75 mm Hg. Spontaneous remission may develop even 
in those with heavy proteinuria (about 30% of cases). Thus, 
use of immunosuppressive agents should be limited to 
those at highest risk for progression and with salvageable 
renal function. Patients with nephrotic syndrome despite 6 
months of conservative management and serum creatinine 
less than 3.0 mg/dL (265 mcmol/L) may elect therapy with 
rituximab or with corticosteroids and cyclophosphamide 
for 6 months. Calcineurin inhibitors with or without corti
-

-
costeroids may be considered as well. Remission may take 
up to 6 months. Patients with primary membranous 
nephropathy are excellent candidates for transplant.
Cattran D et al. Membranous nephropathy: thinking through 
the therapeutic options. Nephrol Dial Transplant. 2017 Jan 1;
 
32(Suppl 1):i22–9. [PMID: 28391348]
Couser WG. Primary membranous nephropathy. Clin J Am Soc 
Nephrol. 2017 Jun 7;12(6):983–97. Erratum in: Clin J Am 
Soc Nephrol. 2017 Sep 7;12 (9):1528. [PMID: 28550082]
Hofstra JM et al. Should aspirin be used for primary preven
-
tion of thrombotic events in patients with membranous 
nephropathy? Kidney Int. 2016 May;89(5):981–3. [PMID: 
27083274]
 
º
NE
phr
OTIC S
p
ECT
r
UM DISEASE F
r
OM 
SYSTEMIC DISO
r
DE
r
S
DIABETIC NEPHROPATHY
 
»
Prior evidence of diabetes mellitus, typically over 
10 years.
 
»
Albuminuria usually precedes decline in GFR.
 
»
Other end-organ damage, such as retinopathy, is 
common.
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»
Diabetic nephropathy is the most common cause of ESRD in 
the United States. Type 1 diabetes mellitus carries a 30–40% 
risk of nephropathy after 20 years, whereas type 2 has a 
15–20% risk after 20 years. ESRD is much more likely to 
develop in persons with type 1 diabetes mellitus, in part due 
to fewer comorbidities and deaths before ESRD ensues. With 
the current epidemic of obesity and type 2 diabetes mellitus, 
rates of diabetic nephropathy are projected to continue to 
increase. Patients at higher risk include males, African 
Americans, Native Americans, and those with a positive 
family history. Mortality rates are higher for diabetics with 
kidney disease compared to those without CKD.
 
»
Diabetic nephropathy develops about 10 years after the 
onset of diabetes mellitus. It may be present at the time 
type 2 diabetes mellitus is diagnosed. The first stage of 
classic diabetic nephropathy is hyperfiltration with an 
increase in GFR, followed by the development of microal
-
buminuria (30–300 mg/day). With progression, albumin
-
uria increases to greater than 300 mg/day and can be 
detected on a urine dipstick as overt proteinuria; the GFR 
subsequently declines over time. Y early screening for 
microalbuminuria is recommended for all diabetic 
patients to detect disease at its earliest stage; however, 
diabetic nephropathy can, less commonly present as non
-
proteinuric CKD.
The most common lesion in diabetic nephropathy is 
diffuse glomerulosclerosis, but nodular glomerulosclerosis 
(Kimmelstiel-Wilson nodules) is pathognomonic. The 
kidneys are usually enlarged. Kidney biopsy is not 
required in most patients, though, unless atypical find
-
ings are present, such as sudden onset of proteinuria, 
nephritic spectrum features (see above), massive protein
-
uria (greater than 10 g/day), urinary cellular casts, or 
rapid decline in GFR.
Patients with diabetes are prone to other renal diseases. 
These include papillary necrosis, chronic interstitial 
nephritis, and type 4 (hyporeninemic hypoaldosterone
-
mic) renal tubular acidosis. Patients are more susceptible to 
AKI from many insults, including intravenous contrast 
material and concomitant use of an ACE inhibitor or ARB 
with NSAID.
 
»
Treatment
With the onset of microalbuminuria, aggressive treatment 
is necessary. Strict glycemic control should be emphasized 
early in diabetic nephropathy, with recognition of risk of 
hypoglycemia as CKD becomes advanced (see CKD 
section). Recommended blood pressure goals should be 
tailored to the individual patient: based on the ACCORD 
trial, those with microalbuminuria (30–300 mg/day) and 
preserved GFR and those with significant CVD likely 
derive little benefit from blood pressure lowering much below 
140/90 mm Hg, although recent guidelines from the American 
Heart Association advocate treatment to 130/80 mm Hg or 
less. Those with overt proteinuria (especially when more than 
1 g/day) benefit from a goal of less than 130/80 mm Hg. 
ACE inhibitors and ARBs in those with microalbuminuria 
lower the rate of progression to overt proteinuria and slow 
progression to ESRD by reducing intraglomerular pressure 
and via antifibrotic effects; these agents are not absolutely 
indicated in diabetics without albuminuria. Diabetic 
patients, especially with advanced CKD, are at relatively 
high risk for AKI and hyperkalemia with inhibition of the 
renin-angiotensin system, so monitoring for hyperkalemia 
or a decline in GFR more than 30% with the initiation or 
uptitration of this therapy is required, with dose reduction 
or discontinuation of therapy if these complications are 
encountered. Combination ARB and ACE inhibitor ther
-
apy is not recommended due to lack of efficacy and 
increased adverse events of hyperkalemia and AKI. Newer 
antidiabetic agents, including canagliflozin and empa
-
gliflozin (SGLT inhibitors), linagliptin (DPP-4 inhibitor),

-
gliflozin (SGLT inhibitors), linagliptin (DPP-4 inhibitor), 
and liraglutide (GLP-1 receptor antagonist), show early 
promise in slowing the progression of diabetic nephropa
-
thy, but more experience with these agents is needed. 
Treatment of other cardiovascular risk factors and obesity 
is crucial. Many with diabetes have multiple comorbid 
conditions; therefore, in patients undergoing dialysis who 
progress to ESRD, mortality over the first 5 years is high. 
Patients who are relatively healthy, however, benefit from 
renal transplantation.
Alicic RZ et al. Diabetic kidney disease: challenges, progress, and 
possibilities. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):
 
2032–45. [PMID: 28522654]
Doshi SM et al. Diagnosis and management of type 2 diabetic 
kidney disease. Clin J Am Soc Nephrol. 2017 Aug 7;12(8):
 
1366–73. [PMID: 28280116]
Mann JFE et al; LEADER Steering Committee and Investigators. 
Liraglutide and renal outcomes in type 2 diabetes. N Engl J 
Med. 2017 Aug 31;377(9):839–48. [PMID: 28854085]
Ruospo M et al. Glucose targets for preventing diabetic kidney 
disease and its progression. Cochrane Database Syst Rev. 
2017 Jun 8;6:CD010137. [PMID: 28594069]
HIV-ASSOCIATED NEPHROPATHY
HIV-associated nephropathy usually presents with 
nephrotic syndrome and declining GFR in patients with 
active HIV infection. Most patients are of African descent, 
likely due to the association of 
APOL1
 polymorphisms with 
increased risk for HIV-associated nephropathy. HIV-associ
-
ated nephropathy is usually associated with low CD4 counts 
and AIDS, but it can also be the initial presentation of HIV 
disease. Patients with HIV are at risk for kidney disease 
other than HIV-associated nephropathy, such as toxicity 
from antiretroviral medications such as tenofovir, vascular 
disease, and diabetes, or an immune complex–mediated 
glomerular disease (HIV-immune complex disease).
Classic HIV-associated nephropathy results in an FSGS 
pattern of injury with glomerular collapse; severe tubuloin
-
terstitial damage may also be present.
HIV-associated nephropathy is becoming less common 
in the era of HIV screening and more effective antiretrovi
-
ral therapy. Small, uncontrolled studies have shown that 
antiretroviral therapy slows progression of disease. ACE 
inhibitors or ARBs can be used to control blood pressure 
and proteinuria. Corticosteroid treatment may be considered 
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for those with significant inflammation on biopsy; caution 
should be exercised when administering these drugs to 
immunocompromised individuals. Patients who progress 
to ESRD and are otherwise healthy are good candidates for 
kidney transplantation.
Cohen SD et al. Kidney diseases associated with human immuno
-
deficiency virus infection. N Engl J Med. 2017 Dec 14; 377
 
(24):2363–74. [PMID: 29236630]
Jotwani V et al. Kidney disease in HIV: moving beyond HIV-
associated nephropathy. J Am Soc Nephrol. 2017 Nov;28(11):
 
3142–54. [PMID: 28784698]
Nobakht E et al. HIV-associated immune complex kidney 
disease. Nat Rev Nephrol. 2016 May;12(5):291–300. [PMID: 
26782145]
RENAL AMYLOIDOSIS
Amyloidosis is caused by tissue deposition of an abnor
-
mally folded protein (amyloid). Several different proteins 
can form amyloid fibrils. Primary amyloidosis, or AL 
amyloidosis, is the most common form and is due to a 
plasma cell dyscrasia causing overproduction and deposi
-
tion of monoclonal Ig light chains (see Chapter 13). 
Secondary, or AA, amyloidosis results from a chronic 
inflammatory disease such as rheumatoid arthritis, inflam
-
matory bowel disease, or chronic infection; in these cases, 
there is deposition of an acute phase reactant, serum amy
-
loid A protein.
Proteinuria, decreased GFR, and nephrotic syndrome 
are presenting symptoms and signs of renal involvement in 
amyloidosis; evidence of other organ involvement is com
-
mon. Serum and urine protein electrophoresis should be 
done as screening tests; if a monoclonal spike is found on 
either, serum free light chains should be quantified by 
immunoelectrophoresis. Amyloid-affected kidneys are 
often larger than 10 cm. Pathologically, glomeruli are filled 
with amorphous deposits that show green birefringence 
with Congo red staining.
AL amyloidosis progresses to ESRD in an average of 
2–3 years. Five-year overall survival is less than 20%, with 
death occurring from ESRD and heart disease. Standard 
treatment is a combination of melphalan, corticosteroids, 
and the proteosome inhibitor bortezomib. A greater than 
90% reduction in the level of serum free light chains cor
-
relates with improved renal outcomes. Melphalan and 
stem cell transplantation are associated with a high (45%) 
mortality rate, but can induce remission in 80% of survi
-
vors; however, few patients are eligible for this treatment. 
In AA amyloidosis, remission can occur if the underlying 
disease is treated. Renal transplantation is an option.
Jelinek T et al. Immunomodulatory drugs in AL amyloidosis. Crit 
Rev Oncol Hematol. 2016 Mar;99:249–60. [PMID: 26806146]
Li T et al. Utility of abdominal skin plus subcutaneous fat and 
rectal mucosal biopsy in the diagnosis of AL amyloidosis with 
renal involvement. PLoS One. 2017 Sep 19;12(9):e0185078. 
[PMID: 28926601]
Małyszko J et al. Amyloidosis: a cancer-derived paraproteinemia 
and kidney involvement. Adv Med Sci. 2017 Mar;62(1):31–8. 
[PMID: 28153807]
Table 22–9.
 
Causes of acute tubulointerstitial nephritis 
(abbreviated list).
Drug 
r
eactions
 
B
eta-lactam antibiotics: methicillin, penicillin, ampicillin,
 
Trimethoprim-sulfamethoxazole
 
Rifampin
Nonsteroidal anti-inflammatory drugs
Diuretics
 
Thiazides
 
Cimetidine
 
Phenytoin
 
P
roton pump inhibitors
Systemic Infections
Bacteria
 
Corynebacterium diphtheriae
 
Viruses
 
Epstein-Barr
Others
 
Rickettsia rickettsii
 
Leptospira icterohaemorrhagiae
 
Toxoplasma
Tubulointerstitial nephritis-uveitis (TIN–U)
 
º
TUBULOINTE
r
STITIAL DISEASES
Tubulointerstitial disease may be acute or chronic. Acute 
disease is most commonly associated with medications, 
infectious agents, and systemic rheumatologic disorders.

r
infectious agents, and systemic rheumatologic disorders. 
Interstitial edema, infiltration with polymorphonuclear neu
-
trophils, and tubular cell necrosis can be seen. (See Acute 
Kidney Injury, above, and Table 22–9.) Chronic disease is 
associated with insults from an acute factor or progressive 
insults without any obvious acute cause. Interstitial fibrosis 
and tubular atrophy are present, with a mononuclear cell 
predominance. The chronic disorders are described below.
CHRONIC TUBULOINTERSTITIAL DISEASES
 
»
Kidney size is small and contracted.
 
»
Decreased urinary concentrating ability.
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»
Hyperchloremic metabolic acidosis.
 
»
Reduced GFR.
 
»
The most common cause of 
chronic
 tubulointerstitial disease 
is 
obstructive uropathy
, which may result from prolonged 
or recurrent obstruction. The major causes are prostate dis
-
ease in men; ureteral calculus in a single functioning kidney; 
bilateral ureteral calculi; carcinoma of the cervix, colon, or 
bladder; and retroperitoneal tumors or fibrosis.
Reflux nephropathy from 
vesicoureteral reflux
 is pri
-
marily a disorder of childhood and occurs when urine 
passes retrograde from the bladder to the kidneys during 
voiding. It is the second most common cause of chronic 
tubulointerstitial disease. It occurs as a result of an incom
-
petent vesicoureteral sphincter. Urine can extravasate into 
the interstitium, triggering an inflammatory response that 
leads to fibrosis over time. The inflammatory response is 
due to either bacteria or normal urinary components.
Analgesic nephropathy
 is most commonly seen in 
patients who ingest large quantities of pain medication. 
The drugs of concern are phenacetin, paracetamol, aspirin 
and other NSAIDs; acetaminophen is a possible but less 
certain culprit. Ingestion of at least 1 g/day for 3 years of 
these analgesics is considered necessary for kidney dys
-
function to develop, and most patients grossly underesti
-
mate their analgesic use. This disorder occurs most 
frequently in individuals who are using analgesics for 
chronic headaches, muscular pains, and arthritis; female 
sex, older age, and malnutrition are risk factors for analge
-
sic nephropathy. Tubulointerstitial inflammation and pap
-
illary necrosis are seen on pathologic examination. 
Papillary tip and inner medullary concentrations of some 
analgesics are tenfold higher than in the renal cortex. 
Phenacetin—once a common cause of this disorder and 
now rarely available—is metabolized in the papillae by the 
prostaglandin hydroperoxidase pathway to reactive inter
-
mediates that bind covalently to interstitial cell macromol
-
ecules, causing necrosis. Aspirin and other NSAIDs can 
cause damage by their metabolism to active intermediates 
which can result in cell necrosis. These drugs also decrease 
medullary blood flow (via inhibition of prostaglandin syn
-
thesis) and decrease glutathione levels, which are necessary 
for detoxification.
Environmental exposure to 
heavy metals
—such as 
lead, cadmium, mercury, and bismuth—is seen infre
-
quently now in the United States but can cause tubuloin
-
terstitial disease. Individuals at risk for lead-induced 
tubulointerstitial disease are those with occupational 
exposure (eg, welders who work with lead-based paint) 
and drinkers of alcohol distilled in automobile radiators 
(“moonshine” whiskey users). Lead is filtered by the 
glomerulus and is transported across the proximal convo
-
luted tubules, where it accumulates and causes cell dam
-
age. Fibrosed arterioles and cortical scarring also lead to 
damaged kidneys. The proximal tubular dysfunction 
from cadmium exposure can cause hypercalciuria and 
nephrolithiasis.
A form of chronic tubulointerstial disease dispropor
-
tionately affecting male agricultural workers in Central 
America is increasingly recognized as an important cause 
of ESRD. While the exact pathophysiology is still unknown, 
the term 
Mesoamerican nephropathy
 is applied to reflect 
the geographic region in which this disease occurs. Affected 
individuals tend to be 30–50 years of age without diabetes, 
hypertension, or other causes of kidney disease who work 
under hot conditions, particularly in sugar cane or cotton 
fields, and thus are susceptible to dehydration.
 
»
A. General Findings
Polyuria is common because tubular damage leads to 
inability to concentrate the urine. Volume depletion can 
also occur as a result of a salt-wasting defect in some 
Patients can become hyperkalemic both because the

Patients can become hyperkalemic both because the 
GFR is lower and the distal tubules become aldosterone 
resistant. A hyperchloremic renal tubular acidosis is char
-
acteristic from a type 1 or type 4 renal tubular acidosis. 
Less commonly, a proximal (type 2) renal tubular acidosis 
is seen due to direct proximal tubular damage. The cause of 
the renal tubular acidosis is threefold: (1) reduced ammo
-
nia production, (2) inability to acidify the distal tubules, 
and (3) proximal tubular bicarbonate wasting. The urinaly
-
sis is nonspecific, as opposed to that seen in acute intersti
-
tial nephritis; a few cells may be seen, and broad waxy casts 
are often present. Proteinuria is typically less than 2 g/day 
(owing to inability of the proximal tubule to reabsorb freely 
filterable proteins).
B. Specific Findings
1. Obstructive uropathy—
In partial obstruction, patients 
can exhibit polyuria (possibly due to vasopressin insensitiv
-
ity and poor ability to concentrate the urine) or oliguria (due 
to decreased GFR). Azotemia and hypertension (due to 
increased renin-angiotensin production) are usually pres
-
ent. Abdominal, rectal, and genitourinary examinations 
may be helpful. Urinalysis can show hematuria, pyuria, and 
bacteriuria but is often bland. Abdominal ultrasound may 
detect mass lesions, hydroureter, and hydronephrosis. CT 
scanning and MRI provide more detailed information and 
can be considered if clinical suspicion remains despite a 
normal ultrasound.
2. Vesicoureteral reflux—
Vesicoureteral reflux is typically 
diagnosed in young children with a history of recurrent 
urinary tract infections; it can also develop after kidney 
transplantation. This entity can be detected before birth via 
screening fetal ultrasonography or after birth via voiding 
cystourethrography. Less commonly, this entity is not diag
-
nosed until adolescence or young adulthood when patients 
present with hypertension and substantial proteinuria, 
unusual in most tubular diseases. At this point, renal ultra
-
sound or IVP can show renal scarring and hydronephrosis. 
IVP is relatively contraindicated in patients with kidney 
dysfunction who are at higher risk for contrast nephropathy. 
On kidney biopsy, FSGS can be seen in those with kidney 
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damage. Although most damage occurs before age 5 years, 
progressive renal deterioration to ESRD continues as a result 
of early insults.
3. Analgesics—
Patients can exhibit hematuria, mild pro
-
teinuria, polyuria (from tubular damage), anemia (from GI 
bleeding or erythropoietin deficiency), and sterile pyuria. 
Sloughed papillae can be found in the urine when papillary 
necrosis occurs. An IVP may be helpful for detecting 
these—contrast will fill the area of the sloughed papillae, 
leaving a “ring shadow” sign at the papillary tip. However, 
IVP is rarely used in patients with significant kidney dys
-
function, given the need for dye and associated AKI risk.
4. Heavy metals—
Proximal tubular damage from lead 
exposure can cause decreased secretion of uric acid, result
-
ing in hyperuricemia and saturnine gout. Patients com
-
monly are hypertensive. Diagnosis is most reliably performed 
with a calcium disodium edetate (EDTA) chelation test. 
Urine excretion of greater than 600 mg of lead in 24 hours 
following 1 g of EDTA indicates excessive lead exposure. The 
proximal tubular dysfunction from cadmium can cause 
hypercalciuria and nephrolithiasis.
5. Mesoamerican nephropathy—
In addition to low-grade 
proteinuria, hyperuricemia and hypokalemia are consis
-
tently (but not universally) identified among affected indi
-
viduals. On kidney biopsy, chronic tubulointerstitial injury 
may be accompanied by areas of glomerular ischemia 
despite very mild vascular changes.
 
»
Treatment
Treatment depends first on identifying the disorder 
responsible for kidney dysfunction. The degree of intersti
-
tial fibrosis that has developed can help predict recovery 
of kidney function. Once there is evidence of paren
-
chymal loss (small shrunken kidneys or interstitial fibrosis 
on biopsy), little can prevent the progression to ESRD. 
Treatment is then directed at medical management. Tubu
-
lar dysfunction may require potassium and phosphorus 
restriction and sodium, calcium, or bicarbonate 
If hydronephrosis is present, the obstruction should be 
promptly relieved. Prolonged obstruction leads to further 
tubular damage—particularly in the distal nephron—
which may be irreversible despite relief of obstruction. 
Neither surgical correction of reflux nor medical therapy 
with antibiotics can prevent deterioration toward ESRD 
once renal scarring has occurred.
Patients in whom lead nephropathy is suspected should 
continue chelation therapy with EDTA if there is no evi
-
dence of irreversible renal damage (eg, renal scarring or 
small kidneys). Continued exposure should be avoided.
Treatment of analgesic nephropathy requires withdrawal 
of all analgesics. Stabilization or improvement of renal func
-
tion may occur if significant interstitial fibrosis is not present. 
Ensuring volume repletion during exposure to analgesics 
may also have some beneficial effects.
Patients with Mesoamerican nephropathy should be 
counseled to remain adequately hydrated and, if possible, 
minimize heat exposure. NSAIDs should be avoided due to 
their hemodynamic effects (reduced renal blood flow and 
glomerular filtration), which may exacerbate renal injury 
in states of volume depletion and hot climates.
 
»
•	
Patients with stage 3–5 CKD should be referred to a 
nephrologist when tubulointerstitial diseases are sus
-
pected. Other select cases of stage 1–2 CKD should also 
•	
Patients with urologic abnormalities should be referred 
to a urologist.
Correa-Rotter R et al. CKD of unknown origin in Central 
America: the case for a Mesoamerican nephropathy. Am J 
Kidney Dis. 2014 Mar;63(3):506–20. [PMID: 24412050]
Perazella MA. Clinical approach to diagnosing acute and chronic 
tubulointerstitial disease. Adv Chronic Kidney Dis. 2017 Mar;
 
24(2):57–63. [PMID: 28284380]
 
º
CYSTIC DISEASES OF T
h
E KIDNEY
Renal cysts are epithelium-lined cavities filled with fluid or

º
h
E KIDNEY
Renal cysts are epithelium-lined cavities filled with fluid or 
semisolid material that develop primarily from renal tubu
-
lar elements. One or more simple cysts are found in 50% of 
individuals over the age of 50 years. They are rarely symp
-
tomatic and have little clinical significance. In contrast, 
generalized cystic diseases are associated with cysts scat
-
tered throughout the cortex and medulla of both kidneys 
and can progress to ESRD (Table 22–10).
SIMPLE OR SOLITARY CYSTS
Simple cysts account for 65–70% of all renal masses. They 
are generally found at the outer cortex and contain fluid 
that is consistent with an ultrafiltrate of plasma. Most are 
found incidentally on ultrasonographic examination. Sim
-
ple cysts are typically asymptomatic but can become 
infected.
The major diagnostic objective with simple cysts is to 
differentiate them from malignancy, abscess, or polycystic 
kidney disease. Renal cystic disease can develop in dialysis 
patients and has the potential to progress to malignancy. 
Ultrasound and CT scanning are the recommended proce
-
dures for evaluating these masses. Simple cysts must meet 
three sonographic criteria to be considered benign: (1) echo 
free, (2) sharply demarcated mass with smooth walls, and 
(3) an enhanced back wall (indicating good transmission 
through the cyst). Complex cysts can have thick walls, cal
-
cifications, solid components, and mixed echogenicity. On 
CT scan, the simple cyst should have a smooth thin wall 
that is sharply demarcated. It should not enhance with con
-
trast media. A renal cell carcinoma will enhance but typi
-
cally is of lower density than the rest of the parenchyma. 
Arteriography can also be used to evaluate a mass preopera
-
tively. A renal cell carcinoma is hypervascular in 80%, 
hypovascular in 15%, and avascular in 5% of cases.
If a cyst is benign, periodic reevaluation is the standard 
of care. If the lesion is not consistent with a simple cyst, 
urologic consultation and possible surgical exploration is 
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Cramer MT et al. Cystic kidney disease: a primer. Adv Chronic 
Kidney Dis. 2015 Jul;22(4):297–305. [PMID: 26088074]
AUTOSOMAL DOMINANT POLYCYSTIC 
 
»
Multiple cysts in both kidneys; total number of 
cysts depends on patient age.
 
»
Combination of hypertension and abdominal 
mass suggestive of disease.
 
»
Autosomal dominant inheritance pattern chromo
-
somal abnormalities present in some patients.
 
»
Family history and large, palpable kidneys are 
compelling but not necessary.
 
»
Polycystic kidney disease is among the most common heredi
-
tary diseases in the United States, affecting 500,000 individu
-
als, or 1 in 800 live births. ESRD develops by age 60 years in 
50% of patients. The disease has variable penetrance but 
accounts for 10% of dialysis patients in the United States. At 
least two genes account for this disorder: 
ADPKD1
 on the 
short arm of chromosome 16 (85–90% of patients) and 
ADPKD2
 on chromosome 4 (10–15%). Patients with the 
PKD2
 mutation have slower progression of disease and lon
-
ger life expectancy than those with 
PKD1
. Other sporadic 
cases without these mutations are also recognized.
 
»
Abdominal or flank pain and microscopic or gross hema
-
turia are present in most patients. A history of urinary tract 
Table 22–10.
 
Clinical features of renal cystic disease.
Simple 
r
enal 
Cysts
Acquired 
r
enal 
Cysts
Autosomal Dominant 
p
oly
cystic Kidney Disease
Medullary Sponge 
Kidney
Medullary Cystic 
Kidney
Prevalence
Common
Dialysis patients
1:1000
1:5000
Rare
Inheritance
None
None
Autosomal dominant
None
Age at onset
…
…
20–40
40–60
Adulthood
Kidney size
Normal
Small
Large
Normal
Small
Cyst location
Cortex and 
 
medulla
Cortex and 
 
medulla
Cortex and medulla
Collecting ducts
Corticomedullary 
junction
Hematuria
Common
Rare
Rare
None
Variable
Common
None
None
Associated 
complications
None
Adenocarcinoma in 
cysts
Urinary tract infections, 
 
renal calculi, cerebral 
aneurysms 10–15%, 
hepatic cysts 40–60%
Renal calculi, urinary 
tract infections
Polyuria, salt wasting
Kidney failure
Never
Always
Frequently
Never
Always
infections and nephrolithiasis is common. A family history 
is present in 75% of cases, and more than 50% of patients 
have hypertension that may precede clinical manifestations 
of the disease. Patients have large kidneys that may be pal
-
pable on abdominal examination. The combination of 
hypertension and an abdominal mass should suggest the 
disease. Forty to 50 percent have concurrent hepatic cysts; 
pancreatic and splenic cysts may occur. Hemoglobin tends 
to be maintained as a result of erythropoietin production 
by the cysts. The urinalysis may show hematuria and mild 
proteinuria. In patients with a confirmed family history of 
PKD1
, ultrasonography confirms the diagnosis—two or 
more cysts in patients under age 30 years (sensitivity of 
88.5%), two or more cysts in each kidney in patients aged 
30–59 years (sensitivity of 100%), and four or more cysts in 
each kidney in patients aged 60 years or older are diagnos
-
tic for autosomal dominant polycystic kidney disease. 
Importantly, these criteria do 
not
 apply to individuals with
-
out a known family history; patients without a known fam
-
ily history of polycystic kidney disease require additional 
diagnostic evaluation including CT scanning, which 
reveals numerous cysts in cases of polycystic kidney dis
-
ease (Figure 22–6). In some cases, genetic testing for 
ADPKD1
 and 
ADPKD2
 mutations may be required.
 
»
Complications & Treatment
A. Pain
Abdominal or flank pain is caused by infection, bleeding into 
cysts, and nephrolithiasis. Bed rest and analgesics are recom
-
mended. Cyst decompression can help with chronic pain.
Gross hematuria is most commonly due to rupture of a cyst

-
Gross hematuria is most commonly due to rupture of a cyst 
into the renal pelvis, but it can also be caused by a kidney 
stone or urinary tract infection. Hematuria typically resolves 
within 7 days with bed rest and hydration. Recurrent 
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bleeding should suggest the possibility of underlying renal 
cell carcinoma, particularly in men over age 50 years.
C. Renal Infection
An infected renal cyst should be suspected in patients who 
have flank pain, fever, and leukocytosis. Blood cultures 
may be positive, and urinalysis may be normal because the 
cyst does not communicate directly with the urinary tract. 
CT scans can be helpful because an infected cyst may have 
an increased wall thickness. Bacterial cyst infections are 
difficult to treat. Antibiotics with cystic penetration (eg, 
fluoroquinolones or trimethoprim-sulfamethoxazole) should 
be used. Treatment may require 2 weeks of parenteral therapy 
followed by long-term oral therapy.
D. Nephrolithiasis
Up to 20% of patients have kidney stones, primarily calcium 
oxalate. Hydration (2–3 L/day) is recommended.
E. Hypertension
Fifty percent of patients have hypertension at time of presen
-
tation, and it will develop in most patients during the course 
of the disease. Cyst-induced ischemia appears to cause acti
-
vation of the renin-angiotensin system, and cyst decompres
-
sion can lower blood pressure temporarily. Hypertension 
should be treated; a randomized controlled trial comparing 
aggressive control (blood pressures 95–110/60–75 mm Hg) 
to usual care (blood pressures 120–130/70–80 mm Hg) 
showed that aggressive control slowed the increase of kidney 
volume but not the decline in GFR.
F. Cerebral Aneurysms
About 10–15% of these patients have arterial aneurysms in 
the circle of Willis. Screening arteriography is not 
 
▲
Figure 22–6.
 
Polycystic kidney disease. CT scan 
showing bilateral polycystic kidneys in a 43-year-old 
woman who presented with newly diagnosed hyper
-
tension and microscopic hematuria. 
-
sion, from Michael Freckleton, MD in Usatine RP , Smith MA, 
 
Medicine
recommended unless the patient has a family history of 
aneurysms, is employed in a high-risk profession (such as 
airline pilot), or is undergoing elective surgery with a high 
risk of developing moderate to severe perioperative 
G. Other Complications
Vascular problems include mitral valve prolapse in up to 
25% of patients, aortic aneurysms, and aortic valve abnor
-
malities. Colonic diverticula are more common in patients 
with polycystic kidneys.
 
»
Prognosis
Vasopressin receptor antagonists decrease the rate of 
change in total kidney volume and eGFR decline; however, 
they have not been approved by the US Food and Drug 
Administration and are thus infrequently used. Other 
agents such as octreotide, sirolimus, and tyrosine kinase 
inhibitors decrease the rate of cyst growth but not the 
decline in kidney function. Avoidance of caffeine may pre
-
vent cyst formation due to effects on G-coupled proteins. 
Treatment of hypertension and a low-protein diet may slow 
the progression of disease, although this is not well proven.
Chapman AB et al; Conference Participants. Autosomal-
dominant polycystic kidney disease (ADPKD): executive 
summary from a Kidney Disease: Improving Global Out
-
comes (KDIGO) Controversies Conference. Kidney Int. 
2015 Jul; 88 (1):17–27. [PMID: 25786098]
Tesar V et al. Bosutinib versus placebo for autosomal dominant 
polycystic kidney disease. J Am Soc Nephrol. 2017 Nov;
 
28(11):3404–13. [PMID: 28838955]
MEDULLARY SPONGE KIDNEY
This disease is a relatively common and benign disorder 
that is present at birth and not usually diagnosed until the 
fourth or fifth decade. It can be caused by autosomal domi
-
nant mutations in the 
MCKD1
 or 
MCKD2
 genes on chro
-
mosomes 1 and 16, respectively. Kidneys have a marked 
irregular enlargement of the medullary and interpapillary 
collecting ducts. This is associated with medullary cysts 
that are diffuse, giving a “Swiss cheese” appearance in these 
regions.
 
»

regions.
 
»
Medullary sponge kidney presents with gross or microscopic 
hematuria, recurrent urinary tract infections, or nephroli
-
thiasis. Common abnormalities are a decreased urinary 
concentrating ability and nephrocalcinosis; less common is 
incomplete type I distal renal tubular acidosis. The diagnosis 
can be made by CT, which shows cystic dilatation of the 
distal collecting tubules, a striated appearance in this area, 
and calcifications in the renal collecting system.
 
»
Treatment
There is no known therapy. Adequate fluid intake (2 L/day) 
helps prevent stone formation. If hypercalciuria is present, 
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thiazide diuretics are recommended because they decrease 
calcium excretion. Alkali therapy is recommended if renal 
tubular acidosis is present.
 
»
Prognosis
Renal function is well maintained unless there are com
-
plications from recurrent urinary tract infections and 
Meola M et al. Clinical scenarios in chronic kidney disease: 
cystic renal diseases. Contrib Nephrol. 2016;188:120–30. 
[PMID: 27169740]
Sun H et al. Safety and efficacy of minimally invasive percutane
-
ous nephrolithotomy in the treatment of patients with medul
-
lary sponge kidney. Urolithiasis. 2016 Oct;44(5):421–6. 
[PMID: 26671346]
 
º
MULTISYSTEM DISEASES WIT
h
 V
A
r
IABLE 
KIDNEY INVOLVEMENT
Plasma cell myeloma is a malignancy of plasma cells (see 
Chapter 13) that can cause a variety of renal disorders. 
“Myeloma kidney” is the most common kidney disease in 
plasma cell myeloma and occurs when light chain immu
-
noglobulins (Bence Jones protein) present in the urine 
cause renal toxicity and tubular obstruction by precipitat
-
ing in the distal tubules. The earliest tubular damage results 
in Fanconi syndrome (a type 2 proximal renal tubular aci
-
dosis). Proteinuria in myeloma kidney is exclusively tubular; 
hence, urine dipstick findings are minimal since glomeru
-
lar proteinuria and hematuria are not present. Hypercalcemia 
and hyperuricemia are frequently seen. Glomerular amy
-
loidosis can develop in patients with plasma cell myeloma; 
in these patients, dipstick protein determinations are posi
-
tive due to glomerular epithelial cell foot process efface
-
ment and albumin “spilling” into the Bowman capsule with 
resultant albuminuria; hematuria may or may not be pres
-
ent. Other conditions resulting in kidney dysfunction 
include plasma cell infiltration of the renal parenchyma 
and a hyperviscosity syndrome compromising renal blood 
flow. Therapy for AKI attributed to plasma cell myeloma 
includes correction of hypercalcemia, volume repletion, 
and chemotherapy for the underlying malignancy. Plasma
-
pheresis has been proposed to reduce the burden of circu
-
lating monoclonal proteins, but results have been equivocal 
and its use is controversial.
Dimopoulos MA et al. International Myeloma Working Group 
recommendations for the diagnosis and management of 
myeloma-related renal impairement. J Clin Oncol. 2016 May1;
 
34(13):1544–57. [PMID: 26976420]
Finkel KW et al. Paraprotein-related kidney disease: evaluation 
and treatment of myeloma cast nephropathy. Clin J Am Soc 
Nephrol. 2016 Dec 7;11(12):2273–9. [PMID: 27526708]
Rosner MH et al. Paraprotein-related kidney disease: diagnosing 
and treating monoclonal gammopathy of renal significance. 
Clin J Am Soc Nephrol. 2016 Dec 7;11(12):2280–7. [PMID: 
27526705]
SICKLE CELL DISEASE
Kidney dysfunction associated with sickle cell disease is 
most commonly due to sickling of red blood cells in the 
renal medulla because of low oxygen tension and hyperto
-
nicity. Congestion and stasis lead to hemorrhage, intersti
-
tial inflammation, and papillary infarcts with resultant 
necrosis. Clinically, hematuria is common. Damage to 
renal capillaries also leads to diminished concentrating 
ability. Isosthenuria (urine osmolality equal to that of 
serum) is routine, and patients can easily become dehy
-
drated. These abnormalities are also encountered in 
patients with sickle cell trait. Sickle cell glomerulopathy is 
less common but will inexorably progress to ESRD. Its 
primary clinical manifestation is proteinuria. Optimal 
treatment requires adequate hydration and control of the 
sickle cell disease.
Ataga KI et al. The glomerulopathy of sickle cell disease. Am J 
Hematol. 2014 Sep;89(9):907–14. [PMID: 24840607]
Naik RP et al. Sickle cell trait and the risk of ESRD in blacks. 
 
J Am Soc Nephrol. 2017 Jul;28(7):2180–7. [PMID: 28280138]
Nath KA et al. Sickle cell disease: renal manifestations and

Nath KA et al. Sickle cell disease: renal manifestations and 
mechanisms. Nat Rev Nephrol. 2015 Mar;11(3):161–71. 
[PMID: 25668001]
The classic renal manifestation of tuberculosis is the pres
-
ence of microscopic pyuria with a sterile urine culture—or 
“sterile pyuria. ” More often, other bacteria are also present. 
Microscopic hematuria is often present with pyuria. Urine 
cultures are the gold standard for diagnosis. Three to six 
first morning midstream specimens should be performed 
to improve sensitivity. Papillary necrosis and cavitation of 
the renal parenchyma occur less frequently, as do ureteral 
strictures and calcifications. Adequate drug therapy can 
result in resolution of renal involvement.
Figueiredo AA et al. Urogenital tuberculosis. Microbiol Spectr. 
2017 Jan;5(1). [PMID: 28087922]
GOUT & THE KIDNEY
The kidney is the primary organ for excretion of uric acid. 
Patients with proximal tubular dysfunction have decreased 
excretion of uric acid and are more prone to gouty arthritis 
attacks. Depending on the pH and uric acid concentration, 
deposition can occur in the tubules, the interstitium, or the 
urinary tract. The more alkaline pH of the interstitium 
causes urate salt deposition, whereas the acidic environ
-
ment of the tubules and urinary tract causes uric acid 
crystal deposition at high concentrations.
Three disorders are commonly seen: (1) uric acid neph
-
rolithiasis, (2) acute uric acid nephropathy, and (3) chronic 
urate nephropathy. Kidney dysfunction with uric acid 
nephrolithiasis stems from obstructive physiology. Acute 
uric acid nephropathy presents similarly to acute tubuloin
-
terstitial nephritis with direct toxicity from uric acid crys
-
tals. Chronic urate nephropathy is caused by deposition of 
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urate crystals in the alkaline medium of the interstitium; 
this can lead to fibrosis and atrophy. Epidemiologically, 
hyperuricemia and gout have been associated with worsen
-
ing cardiovascular outcomes.
Treatment between gouty attacks involves avoidance of 
food and drugs causing hyperuricemia (see Chapter 20), 
aggressive hydration, and pharmacotherapy aimed at 
reducing serum uric acid levels (such as with allopurinol 
and febuxostat). The three disorders mentioned above are 
seen in both “overproducers” and “underexcretors” of uric 
acid. The latter situation may seem counterintuitive; how
-
ever, these patients have hyperacidic urine, which explains 
the deposition of relatively insoluble uric acid crystals. For 
those with uric acid nephrolithiasis, fluid intake should 
exceed 3 L/day, and use of a urinary alkalinizing agent can 
Singh JA et al. Comparative effectiveness of allopurinol versus 
febuxostat for preventing incident renal disease in older 
adults: an analysis of Medicare claims data. Ann Rheum Dis. 
2017 Oct;76(10):1669–78. [PMID: 28584186]
Vargas-Santos AB et al. Management of gout and hyperuricemia 
in CKD. Am J Kidney Dis. 2017 Sep;70(3):422–39. [PMID: 
28456346]
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23
 
HEMATURIA
 
»
Both gross and microscopic hematuria require 
 
»
The upper urinary tract should be imaged, and 
cystoscopy should be performed if there is hema
-
turia in the absence of infection.
 
»
An 
upper tract source
 (kidneys and ureters) can be identi
-
fied in 10% of patients with gross or microscopic hematuria. 
For upper tract sources, stone disease accounts for 40%, 
medical kidney disease (medullary sponge kidney, glomer
-
ulonephritis, papillary necrosis) for 20%, renal cell carci
-
noma for 10%, and urothelial cell carcinoma of the ureter or 
renal pelvis for 5%. Medication ingestion and associated 
medical problems may provide diagnostic clues. Analgesic 
use (papillary necrosis), cyclophosphamide (chemical cysti
-
tis), antibiotics (interstitial nephritis), diabetes mellitus, 
sickle cell trait or disease (papillary necrosis), a history of 
stone disease, or malignancy should all be investigated. The 
lower tract source
 of gross hematuria (in the absence of 
infection) is most commonly from urothelial carcinoma 
of the bladder. Microscopic hematuria in the male is most 
commonly from benign prostatic hyperplasia. The presence 
of hematuria in patients receiving antiplatelet or antico
-
agulation therapy cannot be presumed to be due to the 
medication; a complete evaluation is warranted consisting 
of upper tract imaging, cystoscopy, and urine cytology (see 
Chapter 39 for Bladder Cancer, Cancers of the Ureter & 
Renal Pelvis, Renal Cell Carcinoma, and Other Primary 
Tumors of the Kidney).
 
»
If gross hematuria occurs, a description of the timing (initial, 
terminal, total) may provide a clue to the localization of 
disease. Associated symptoms (ie, renal colic, irritative 
voiding symptoms, constitutional symptoms) should be 
investigated. Physical examination should emphasize signs 
of systemic disease (fever, rash, lymphadenopathy, abdomi
-
nal or pelvic masses) as well as signs of medical kidney 
disease (hypertension, volume overload). Urologic evalua
-
tion may demonstrate an enlarged prostate, flank mass, or 
urethral disease.
Initial laboratory investigations include a urinalysis and 
urine culture. Proteinuria and casts suggest renal origin. 
Irritative voiding symptoms, bacteriuria, and a positive 
urine culture in the female suggest urinary tract infection, 
but follow-up urinalysis is important after treatment to 
ensure resolution of the hematuria. An estimate of the kidney 
function should be obtained, since intrinsic kidney disease 
has implications for further evaluation and management of 
patients with hematuria. Urine cytology, or other urinary-
based markers, is not routinely recommended in the evalu
-
ation of asymptomatic microscopic hematuria.
C. Imaging
The upper tract should be imaged using abdominal and 
pelvic CT scanning without and with contrast to identify 
neoplasms of the kidney or ureter as well as benign condi
-
tions such as urolithiasis, obstructive uropathy, papillary 
necrosis, medullary sponge kidney, or polycystic kidney 
disease. The role of ultrasonographic evaluation of the 
urinary tract for hematuria is unclear. Although it may 
provide adequate information for the kidney, its sensitivity 
in detecting ureteral disease is lower.
D. Cystoscopy
Cystoscopy can be used to assess for bladder or urethral 
neoplasm, benign prostatic enlargement, and radiation or 
chemical cystitis; it is indicated for patients with gross 
hematuria and those over age 35 years with asymptomatic 
microscopic hematuria. For gross hematuria, cystoscopy is 
ideally performed while the patient is actively bleeding to 
allow better localization (ie, lateralize to one side of the 
upper tracts, bladder, or urethra).
Maxwell V. Meng, MD, FACS 
 
Thomas J. Walsh, MD, MS 
 
Thomas D. Chi, MD 
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»
Follow-Up
In patients with negative evaluations, repeat evaluations may 
be warranted to avoid a missed malignancy; however, the 
ideal frequency of such evaluations is not defined. Urinary 
cytology can be obtained after initial negative evaluation or 
in persons with risk factors (irritative voiding symptoms, 
tobacco use, chemical exposures), and cystoscopy and upper 
tract imaging may be repeated 1 year after an initial negative 
 
»
In the absence of infection or other benign etiology, hema
-
turia (either gross or microscopic) requires evaluation.
Daher Ede F et al. Renal tuberculosis in the modern era. Am J 
Trop Med Hyg. 2013 Jan;88(1):54–64. [PMID: 23303798]
Davis R et al. Diagnosis, evaluation and follow-up of asymptom
-
atic microhematuria (AMH) in adults: AUA guideline. J Urol. 
2012 Dec;188(6 Suppl):2473–81. [PMID: 23098784]
Halpern JA et al. Cost-effectiveness of common diagnostic 
approaches for evaluation of asymptomatic microscopic hema
-
turia. JAMA Intern Med. 2017 Jun 1;177(6):800–7. [PMID: 
28418451]
Kaag MG et al. Clinical guidelines: clearing murky water—a 
guideline-based approach to haematuria. Nat Rev Urol. 
2016 May;13(5):243–4. [PMID: 27071454]
Kiragu D et al. Evaluation of patients with asymptomatic micro
-
hematuria. JAMA. 2015 Nov 3;314(17):1865–6. [PMID: 
26529165]
Nielsen M et al. Hematuria as a marker of occult urinary tract 
cancer: advice for high-value care from the American College 
of Physicians. Ann Intern Med. 2016 Apr 5;164(7):488–97. 
[PMID: 26810935]
Sountoulides P et al. Non-visible asymptomatic haematuria: a 
review of the guidelines from the urologist’s perspective. 
Expert Rev Anticancer Ther. 2017 Mar;17(3):203–16. [PMID: 
28116915]
GENITOURINARY TRACT INFECTIONS
Urinary tract infections are among the most common enti
-
ties encountered in medical practice. In acute infections, a 
single pathogen is usually found, whereas two or more 
pathogens are often seen in chronic infections. Coliform 
bacteria are responsible for most non-nosocomial, uncom
-
plicated urinary tract infections, with 
 being 
the most common. Such infections typically are sensitive to 
a wide variety of orally administered antibiotics and 
respond quickly. Nosocomial infections often are due to 
more resistant pathogens and may require parenteral anti
-
biotics. Renal infections are of particular concern because 
if they are inadequately treated, loss of kidney function 
may result. Previously, a colony count greater than 10
5
/mL 
was considered the criterion for urinary tract infection. 
However, it is now recognized that up to 50% of women 
with symptomatic infections have lower counts. In addi
-
tion, the presence of pyuria correlates poorly with the 
diagnosis of urinary tract infection, and thus urinalysis 
alone is not adequate for diagnosis. With respect to treat
-
ment, soft tissue infections (pyelonephritis, prostatitis) 
require therapy for 1–2 weeks, while mucosal infections 
(cystitis) require only 1–3 days of therapy.
1. Acute Cystitis
 
»
Irritative voiding symptoms.
 
»
Patient usually afebrile.
 
»
Positive urine culture; blood cultures may also be 
positive.
 
»
Acute cystitis is an infection of the bladder most com
-
monly due to the coliform bacteria (especially 
E coli
) and 
occasionally gram-positive bacteria (enterococci). The 
route of infection is typically ascending from the urethra. 
Viral cystitis due to adenovirus is sometimes seen in chil
-
dren but is rare in adults. Uncomplicated cystitis in men is 
rare and implies a pathologic process such as infected stones, 
prostatitis, or chronic urinary retention requiring further 
investigation.
 
»
Irritative voiding symptoms (frequency, urgency, dysuria) 
and suprapubic discomfort are common. Women may 
experience gross hematuria, and symptoms may often

experience gross hematuria, and symptoms may often 
appear following sexual intercourse. Physical examination 
may elicit suprapubic tenderness, but examination is often 
unremarkable. Systemic toxicity is absent.
Urinalysis shows pyuria, bacteriuria, and varying degrees of 
hematuria. The degree of pyuria and bacteriuria does not 
necessarily correlate with the severity of symptoms. Urine 
culture is positive for the offending organism, but colony 
counts exceeding 10
5
/mL are not required for the diagnosis.
C. Imaging
Because uncomplicated cystitis is rare in men, elucidation of 
the underlying problem with appropriate investigations, 
such as abdominal ultrasonography or cystoscopy (or both), 
is warranted. Follow-up imaging using CT scanning is 
warranted if pyelonephritis, recurrent infections, or ana
-
tomic abnormalities are suspected.
 
»
In women, infectious processes such as vulvovaginitis and 
pelvic inflammatory disease can usually be distinguished 
by pelvic examination and urinalysis. In men, urethritis 
and prostatitis may be distinguished by physical examination 
(urethral discharge or prostatic tenderness).
Noninfectious causes of cystitis-like symptoms include 
pelvic irradiation, chemotherapy (cyclophosphamide), 
bladder carcinoma, interstitial cystitis, voiding dysfunction 
disorders, and psychosomatic disorders.
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»
Women who have more than three episodes of cystitis per 
year are considered candidates for prophylactic antibiotic 
therapy to prevent recurrence after treatment of urinary 
tract infection. Prior to institution of therapy, a thorough 
urologic evaluation is warranted to exclude any anatomic 
abnormality (eg, stones, reflux, fistula). The three most 
commonly used oral agents for prophylaxis are trime
-
thoprim-sulfamethoxazole (40 mg/200 mg), nitrofurantoin 
(100 mg), and cephalexin (250 mg). Single dosing at 
bedtime or at the time of intercourse is the recommended 
schedule.
The risk of acquiring a catheter-associated urinary 
tract infection in hospitalized patients can be minimized 
by using indwelling catheters only when necessary, 
implementing systems to ensure removal of catheters 
when no longer needed, using antimicrobial catheters in 
high-risk patients, using external collection devices 
 
in select men, identifying significant postvoid residuals by 
ultrasound, maintaining proper insertion techniques, and 
utilizing alternatives such as intermittent catheterization.
 
»
Treatment
Uncomplicated cystitis in women can be treated with short-
term antimicrobial therapy, which consists of single-dose 
therapy or 1–9 days of therapy. Cephalexin, nitrofurantoin, 
and trimethoprim-sulfamethoxazole are the medications of 
choice for uncomplicated cystitis (Table 23–1). The US 
Food and Drug Administration (FDA) advises restricting 
fluoroquinolone use for uncomplicated infections, includ
-
ing uncomplicated urinary tract infections. Local patterns 
of bacterial resistance should be consulted to identify best 
Table 23–1.
 
Empiric therapy for urinary tract infections (antibiotics listed in alphabetical order within each diagnostic 
category).
Diagnosis
Antibiotic
Route
Duration
Cost per Duration Noted
1
Acute pyelonephritis
Ampicillin, 1 g every 6 hours, and gentamicin, 
 
1 mg/kg every 8 hours
Intravenous
14 days
$377.00 not including 
 
intravenous supplies
Ciprofloxacin, 750 mg every 12 hours
2
Oral
7–14 days
$76.00–152.00
Levofloxacin, 750 mg daily
Oral
5 days
$123.00
Trimethoprim-sulfamethoxazole, 160/800 mg 
every 12 hours
3
Oral
10–14 days
$10.00–14.00
Chronic pyelonephritis
Same as for acute pyelonephritis
3–6 months
Acute cystitis
Cephalexin, 250–500 mg every 6 hours
Oral
1–3 days
$14.50/3 days (500 mg)
Ciprofloxacin, 250–500 mg every 12 hours
4
Oral
1–3 days
$30.00/3 days (500 mg)
4
Oral
5 days
$123.00
Nitrofurantoin (macrocrystals), 100 mg every 
12 hours
Oral
5–7 days
$45.00
Norfloxacin, 400 mg every 12 hours
4
Oral
1–3 days
 
Trimethoprim-sulfamethoxazole, 160/800 mg, 
2
Oral
3 days
$1.00/day
Acute bacterial prostatitis
21 days
Chronic bacterial 
Oral
1–3 months
$296.00/1 month (500 mg)
Oral
28 days
$689.10
2
Oral
1–3 months
$30.00/1 month
Acute epididymitis
 
S
exually transmitted
Ceftriaxone, 250 mg as single dose, 
plus
Doxycycline, 100 mg every 12 hours
Intramuscular
Oral
Once
10 days
$0.90/250 mg
$52.40
 
Non-se
xually transmitted
Same as for chronic bacterial prostatitis
Oral
3 weeks
1
Average wholesale price, (AWP , for AB-rated generic when available) for quantity listed. Source: 
Red Book
2
Increasing resistance noted.
3
Increasing resistance noted (up to 20%).
4
FDA advises restricting fluoroquinolone use for some uncomplicated infections, including uncomplicated urinary tract infections.
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treatment options. Some antibiotics may be ineffective 
because of the emergence of resistant organisms. A review 
of the literature proposed that acute uncomplicated cystitis 
in women can be diagnosed without office evaluation or 
urine culture, and that appropriate first-line therapies 
include trimethoprim-sulfamethoxazole (160/800 mg twice 
daily for 3 days), nitrofurantoin (100 mg twice daily for 5–7 
days), and fosfomycin trometamol (3 g single dose). In 
men, uncomplicated urinary tract infection is rare; thus, the 
duration of antibiotic therapy depends on the underlying 
etiology. Hot sitz baths or urinary analgesics (phenazopyri
-
dine, 200 mg orally three times daily) may provide symp
-
tomatic relief.
 
»
Prognosis
Infections typically respond rapidly to therapy, and 
failure to respond suggests resistance to the selected 
medication or anatomic abnormalities requiring further 
 
»
•	
Suspicion or radiographic evidence of anatomic 
abnormality.
•	
Evidence of urolithiasis.
•	
Recurrent cystitis due to bacterial persistence.
Bader MS et al. An update on the management of urinary tract 
infections in the era of antimicrobial resistance. Postgrad 
Med. 2017 Mar;129(2):242–58. [PMID: 27712137]
infection in the outpatient setting: a review. JAMA. 2014 
Oct 22–29;312(16):1677–84. [PMID: 25335150]
Mody L et al. JAMA patient page. Urinary tract infections in 
older women. JAMA. 2014 Feb 26;311(8):874. [PMID: 
24570259]
U.S. Food & Drug Administration. FDA Drug Safety Communi
-
cation: FDA updates warnings for oral and injectable fluoro
-
quinolone antibiotics due to disabling side effects. 2016 Jul 26. 
http://www.fda.gov/Drugs/DrugSafety/ucm511530.htm
2. Acute 
p
y
elonephritis
 
»
Fever.
 
»
Flank pain.
 
»
 
»
Positive urine culture.
 
»
Acute pyelonephritis is an infectious inflammatory disease 
involving the kidney parenchyma and renal pelvis. Gram-
negative bacteria are the most common causative agents 
including 
E coli, Proteus, Klebsiella, Enterobacter
, and 
. Gram-positive bacteria are less commonly 
seen but include 
Enterococcus faecalis
 and 
aureus
. The infection usually ascends from the lower 
urinary tract—with the exception of 
S aureus
, which usually 
is spread by a hematogenous route.
 
»
Symptoms include fever, flank pain, shaking chills, and 
irritative voiding symptoms (urgency, frequency, dysuria). 
Associated nausea and vomiting, and diarrhea are com
-
mon. Signs include fever and tachycardia. Costovertebral 
angle tenderness is usually pronounced.
Complete blood cell count shows leukocytosis and a left 
shift. Urinalysis shows pyuria, bacteriuria, and varying 
degrees of hematuria. White cell casts may be seen. Urine 
culture demonstrates heavy growth of the offending organism, 
and blood culture may also be positive.
C. Imaging
In complicated pyelonephritis, renal ultrasound may show 
hydronephrosis from a stone or other source of obstruction.
 
»
The differential diagnosis includes acute cystitis or a lower 
urinary source. Acute intra-abdominal disease such as 
appendicitis, cholecystitis, pancreatitis, or diverticulitis must 
be distinguished from pyelonephritis. A normal urinalysis is 
usually seen in gastrointestinal disorders; however, on occa
-
sion, inflammation from adjacent bowel (appendicitis or 
diverticulitis) may result in hematuria or sterile pyuria. 
Abnormal liver biochemical tests or elevated amylase levels 
may assist in the differentiation. Lower-lobe pneumonia is 
distinguishable by the abnormal chest radiograph.

In males, the main differential diagnosis for acute 
pyelonephritis also includes acute epididymitis and acute 
prostatitis. Physical examination and the location of the 
pain should permit this distinction.
 
»
Sepsis with shock can occur with acute pyelonephritis. In 
diabetic patients, emphysematous pyelonephritis resulting 
from gas-producing organisms may be life-threatening if not 
adequately treated. Healthy adults usually recover complete 
kidney function, yet if coexistent kidney disease is present, 
scarring or chronic pyelonephritis may result. Inadequate 
therapy could result in abscess formation.
 
»
Treatment
Urine and blood cultures are obtained to identify the caus
-
ative agent and to determine antimicrobial sensitivity. In the 
inpatient setting, intravenous ampicillin and an aminogly
-
coside are initiated prior to obtaining sensitivity results 
(Table 23–1). In the outpatient setting, empiric therapy may 
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be initiated (Table 23–1). Antibiotics are adjusted according 
to sensitivities. Fevers may persist for up to 72 hours even 
with appropriate antibiotics; failure to respond within 
 
48 hours warrants imaging (CT or ultrasound) to exclude 
complicating factors that may require intervention. Cathe
-
ter drainage may be necessary in the face of urinary reten
-
tion and nephrostomy drainage if there is ureteral 
obstruction. In inpatients, intravenous antibiotics are con
-
tinued for 24 hours after the fever resolves, and oral antibi
-
otics are then given to complete a 14-day course of therapy. 
However, a shorter 7-day course may be just as effective 
with fewer side effects, such as mucosal candidiasis. Follow-
up urine cultures are mandatory following the completion 
of treatment. Randomized trial data suggest that ceftolo
-
zane-tazobactam may yield better response rates compared 
to high-dose levofloxacin in the treatment of complicated 
lower urinary tract infection and pyelonephritis.
 
»
Prognosis
With prompt diagnosis and appropriate treatment, acute 
pyelonephritis carries a good prognosis. Complicating 
factors, underlying kidney disease, and increasing patient 
age may lead to a less favorable outcome.
 
»
•	
Evidence of complicating factors (urolithiasis, 
obstruction).
•	
Absence of clinical improvement in 48 hours.
 
»
•	
Severe infections or complicating factors, evidence of 
sepsis or need for parenteral antibiotics.
•	
Need for radiographic imaging or drainage of urinary 
Talan DA et al; EMERGEncy ID Net Study Group. Fluoroquino
-
lone-resistant and extended-spectrum β-lactamase-producing 
 infections in patients with pyelonephritis, United 
States. Emerg Infect Dis. 2016 Sep;22(9). [PMID: 27532362]
Wagenlehner FM et al. Ceftolozane-tazobactam compared with 
levofloxacin in the treatment of complicated urinary-tract 
infections, including pyelonephritis: a randomised, double-
blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015 May 16;
 
385(9981):1949–56. [PMID: 25931244]
Y oon YK et al. Role of piperacillin/tazobactam as a carbapenem-
sparing antibiotic for treatment of acute pyelonephritis due to 
extended-spectrum β-lactamase-producing 
. Int J 
Antimicrob Agents. 2017 Apr;49(4):410–15. [PMID: 28263710]
3. Acute Bacterial 
p
r
ostatitis
 
»
Fever.
 
»
 
»
Perineal or suprapubic pain; exquisite tenderness 
common on rectal examination.
 
»
 
»
Acute bacterial prostatitis is usually caused by gram-
negative rods, especially 
E coli
 and 
 species 
and less commonly by gram-positive organisms (eg, 
enterococci). The most likely routes of infection include 
ascent up the urethra and reflux of infected urine into the 
prostatic ducts. Lymphatic and hematogenous routes are 
probably rare.
 
»
Perineal, sacral, or suprapubic pain, fever, and irritative void
-
ing complaints are common. Varying degrees of obstructive 
symptoms may occur as the acutely inflamed prostate swells, 
which may lead to urinary retention. High fevers and a warm 
and often exquisitely tender prostate are detected on exami
-
nation. Care should be taken to perform a gentle rectal 
examination, since vigorous manipulations may result in 
septicemia. Prostatic massage is contraindicated.
Complete blood count shows leukocytosis and a left shift. 
Urinalysis shows pyuria, bacteriuria, and varying degrees 
of hematuria. Urine cultures will demonstrate the offend
-
ing pathogen (Table 23–2).
 
»
Acute pyelonephritis or acute epididymitis should be dis
-

-
 
»
-
tinguishable by the location of pain as well as by physical 
examination. Acute diverticulitis is occasionally confused 
with acute prostatitis; however, the history and urinalysis 
should permit clear distinction. Urinary retention from 
benign or malignant prostatic enlargement is distinguish
-
able by initial or follow-up rectal examination.
 
»
Treatment
Hospitalization may be required, and parenteral antibiotics 
(ampicillin and aminoglycoside) should be initiated until 
organism sensitivities are available (Table 23–1). After the 
patient is afebrile for 24–48 hours, oral antibiotics (eg, qui
-
nolones if organism is sensitive) are used to complete 
 
4–6 weeks of therapy. If urinary retention develops, a per
-
cutaneous suprapubic tube is required as urethral catheter
-
ization is contraindicated. Follow-up urine culture and 
examination of prostatic secretions should be performed 
after the completion of therapy to ensure eradication.
 
»
Prognosis
With effective treatment, chronic bacterial prostatitis is 
rare.
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»
•	
Evidence of urinary retention.
•	
Evidence of chronic prostatitis.
 
»
•	
Signs of sepsis.
•	
Need for surgical drainage of bladder or prostatic abscess.
Campeggi A et al. Acute bacterial prostatitis after transrectal 
ultrasound-guided prostate biopsy: epidemiological, bacteria 
and treatment patterns from a 4-year prospective study. Int J 
Urol. 2014 Feb;21(2):152–5. [PMID: 23906113]
Coker TJ et al. Acute bacterial prostatitis: diagnosis and manage
-
ment. Am Fam Physician. 2016 Jan;93(2):114–20. [PMID: 
26926407]
Gill BC. Bacterial prostatitis. Curr Opin Infect Dis. 2016 Feb; 
29 (1):86–91. [PMID: 26555038]
Khan FU et al. Comprehensive overview of prostatitis. Biomed 
Pharmacother. 2017 Aug 12;94:1064–76. [PMID: 28813783]
26863357]
4. Chronic Bacterial 
p
r
ostatitis
 
»
 
»
Perineal or suprapubic discomfort, often dull and 
poorly localized.
 
»
Positive expressed prostatic secretions and culture.
 
»
Although chronic bacterial prostatitis may evolve from 
acute bacterial prostatitis, many men have no history of 
acute infection. Gram-negative rods are the most common 
etiologic agents, but only one gram-positive organism 
(
) is associated with chronic infection. Routes 
of infection are the same as discussed for acute infection.
 
»
Clinical manifestations are variable. Some patients are 
asymptomatic, but most have varying degrees of irritative 
voiding symptoms. Low back and perineal pain are not 
uncommon. Many patients report a history of urinary tract 
infections. Physical examination is often unremarkable, 
although the prostate may feel normal, boggy, or indurated.
Urinalysis is normal unless a secondary cystitis is present. 
Expressed prostatic secretions demonstrate increased num
-
bers of leukocytes (greater than 10 per high-power field), 
especially lipid-laden macrophages. However, this finding 
is consistent with inflammation and is not diagnostic of 
bacterial prostatitis (Table 23–2). Leukocyte and bacterial 
counts from expressed prostatic secretions do not correlate 
with severity of symptoms. Culture of the secretions or the 
postprostatic massage urine specimen is necessary to make 
C. Imaging
Imaging tests are not necessary, although pelvic radiographs 
or transrectal ultrasound may demonstrate prostatic calculi.
 
»
Chronic urethritis may mimic chronic prostatitis, though 
cultures of the fractionated urine may localize the source of 
infection to the initial specimen, which would come from 
the urethra. Cystitis may be secondary to prostatitis, but 
urine samples after prostatic massage may localize the 
infection to the prostate. Anal disease may share some of 
the symptoms of prostatitis, but physical examination 
should distinguish between the two.
 
»
Treatment
Few antimicrobial agents attain therapeutic intraprostatic 
levels in the absence of acute inflammation. Trimethoprim 
does diffuse into the prostate, and trimethoprim-sulfamethox
-
azole is associated with the best cure rates (Table 23–1). 
However, increasing resistance to this antibiotic (up to 20%) 
has been noted. Other effective agents include quinolones, 
cephalexin, erythromycin, and carbenicillin. The optimal 
duration of therapy remains controversial, ranging from 6 to 
12 weeks. Symptomatic relief may be provided by anti-inflam
-
matory agents (indomethacin, ibuprofen) and hot sitz baths.
 
»
Prognosis
Chronic bacterial prostatitis is difficult to cure, but its 
symptoms and tendency to cause recurrent urinary 
Table 23–2.
 
Clinical characteristics of prostatitis and prostatodynia syndromes.
Findings
Acute Bacterial 
p
r
ostatitis

Findings
p
r
ostatitis
Chronic Bacterial 
p
r
ostatitis
Nonbacterial 
p
r
ostatitis
p
r
ostatodynia
Fever
+
–
–
–
+
–
–
–
Expressed prostate secretions
+
+
–
Bacterial culture
+
+
–
–
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tract infections can be controlled by suppressive antibi
-
otic therapy.
 
»
•	
Persistent symptoms.
•	
Consideration of enrollment in clinical trials.
Holt JD et al. Common questions about chronic prostatitis. Am 
Fam Physician. 2016 Feb 15;93(4):290–6. [PMID: 26926816]
Perletti G et al. Antimicrobial therapy for chronic bacterial pros
-
tatitis. Cochrane Database Syst Rev. 2013 Aug 12;8:CD009071. 
[PMID: 23934982]
26863357]
5. Nonbacterial 
p
r
ostatitis
 
»
 
»
Perineal or suprapubic discomfort, similar to that 
of chronic bacterial prostatitis.
 
»
Positive expressed prostatic secretions, but nega
-
tive culture.
 
»
Nonbacterial prostatitis is the most common of the prosta
-
titis syndromes, and its cause is unknown. Speculation 
implicates chlamydiae, mycoplasmas, ureaplasmas, and 
viruses, but no substantial proof exists. In some cases, non
-
bacterial prostatitis may represent a noninfectious inflam
-
matory or autoimmune disorder. Because the cause of 
nonbacterial prostatitis remains unknown, the diagnosis is 
usually one of exclusion.
 
»
The clinical presentation is identical to that of chronic bacte
-
rial prostatitis; however, no history of urinary tract infections 
is present. The National Institutes of Health Chronic Prosta
-
titis Symptom Index (NIH-CPSI) (www.prostatitisclinic
 
.com/graphics/questionnaire2.pdf) has been validated to 
quantify symptoms of chronic nonbacterial prostatitis 
or chronic pelvic pain syndrome.
Increased numbers of leukocytes are seen on expressed 
prostatic secretions, but all cultures are negative.
 
»
The major distinction is from chronic bacterial prostatitis. 
The absence of a history of urinary tract infection and of 
positive cultures makes the distinction (Table 23–2). In 
older men with irritative voiding symptoms and negative 
cultures, bladder cancer must be excluded. Urinary cyto
-
logic examination and cystoscopy are warranted.
 
»
Treatment
Because of the uncertainty regarding the etiology of non
-
bacterial prostatitis, a trial of antimicrobial therapy 
directed against 
Ureaplasma, Mycoplasma
, or 
Chlamydia
 
is warranted. Erythromycin (250 mg orally four times 
daily) can be initiated for 14 days; it should be continued 
for 3–6 weeks only if a favorable clinical response ensues. 
Some symptomatic relief may be obtained with nonsteroi
-
dal anti-inflammatory agents or sitz baths. Dietary 
restrictions are not necessary unless the patient relates a 
history of symptom exacerbation by certain substances 
such as alcohol, caffeine, or particular foods.
 
»
Prognosis
Annoying, recurrent symptoms are common, but serious 
sequelae have not been identified.
Fam Physician. 2016 Feb;93(4):290–6. [PMID: 26926816]
Magistro G et al. Contemporary management of chronic 
prostatitis/chronic pelvic pain syndrome. Eur Urol. 2016 Feb;
 
69(2):286–97. [PMID: 26411805]
Polackwich AS et al. Chronic prostatitis/chronic pelvic pain 
syndrome: a review of evaluation and therapy. Prostate Cancer 
Prostatic Dis. 2016 Jun;19(2):132–8. [PMID: 26951713]
Sandhu J et al. Recent advances in managing chronic prostatitis/
chronic pelvic pain syndrome. F1000Res. 2017 Sep 25;6. [PMID: 
29034074]
6. 
p
r
Prostatodynia is a noninflammatory disorder that affects 
young and middle-aged men and has variable causes, 
including voiding dysfunction and pelvic floor muscula
-
ture dysfunction. The term “prostatodynia” is a misnomer, 
since the prostate is actually normal.
 
»

-
 
»
Symptoms are the same as those seen with chronic prosta
-
titis, yet there is no history of urinary tract infection. Addi
-
tional symptoms may include hesitancy and interruption 
of flow. Patients may relate a lifelong history of voiding 
difficulty. Physical examination is unremarkable, but 
increased anal sphincter tone and periprostatic tenderness 
may be observed.
Urinalysis is normal. Expressed prostatic secretions show 
normal numbers of leukocytes (Table 23–2). Urodynamic 
testing may show signs of dysfunctional voiding (detrusor 
contraction without urethral relaxation, high urethral pres
-
sures, spasms of the urinary sphincter) and is indicated in 
patients who do not respond to empiric treatment.
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»
Normal urinalysis will distinguish it from acute and 
chronic bacterial prostatitis. Examination of expressed 
prostatic secretions will distinguish nonbacterial prostatitis 
from other etiologies of prostatodynia (Table 23–2).
 
»
Treatment
Bladder neck and urethral spasms can be treated by alpha-
blocking agents (terazosin, 1–10 mg orally once a day, or 
doxazosin, 1–8 mg orally once a day). Pelvic floor muscle 
dysfunction may respond to diazepam and biofeedback 
techniques. Sitz baths may provide some symptomatic 
relief.
 
»
Prognosis
Prognosis is variable depending on the specific cause.
Magistro G et al. Contemporary management of chronic prostatitis/
chronic pelvic pain syndrome. Eur Urol. 2016 Feb;69(2):286–97. 
[PMID: 26411805]
29034074]
7. Acute Epididymitis
 
»
Fever.
 
»
 
»
Painful enlargement of epididymis.
 
»
Most cases of acute epididymitis are infectious and can be 
divided into one of two categories that have different age 
distributions and etiologic agents. 
Sexually transmitted 
forms
 typically occur in men under age 40 years, are asso
-
ciated with urethritis, and result from 
Chlamydia tracho
-
matis
 or 
. 
Non-sexually transmitted 
forms
 typically occur in older men, are associated with 
urinary tract infections and prostatitis, and are caused by 
gram-negative rods. The route of infection is probably via 
the urethra to the ejaculatory duct and then down the vas 
deferens to the epididymis. Amiodarone has been associated 
with self-limited epididymitis, which is a dose-dependent 
phenomenon.
 
»
Symptoms may follow acute physical strain (heavy lifting), 
trauma, or sexual activity. Associated symptoms of urethritis 
(pain at the tip of the penis and urethral discharge) or cystitis 
(irritative voiding symptoms) may occur. Pain develops in the 
scrotum and may radiate along the spermatic cord or to the 
flank. Fever and scrotal swelling are usually apparent. Early in 
the course, the epididymis may be distinguishable from the 
testis; however, later the two may appear as one enlarged, ten
-
der mass. The prostate may be tender on rectal examination.
Complete blood count shows leukocytosis and a left shift. In 
the sexually transmitted variety, Gram staining of a smear 
of urethral discharge may be diagnostic of gram-negative 
intracellular diplococci 
(N gonorrhoeae)
. White cells without 
visible organisms on urethral smear represent nongonococcal 
urethritis, and 
 is the most likely pathogen. In 
the non-sexually transmitted variety, urinalysis shows 
pyuria, bacteriuria, and varying degrees of hematuria. Urine 
cultures will demonstrate the offending pathogen.
C. Imaging
Scrotal ultrasound may aid in the diagnosis if examination 
is difficult because of the presence of a large hydrocele or 
because questions exist regarding the diagnosis.
 
»
Tumors generally cause painless enlargement of the testis. 
Urinalysis is negative, and examination reveals a normal 
epididymis. Scrotal ultrasound is helpful to define the 
pathology. Testicular torsion usually occurs in prepubertal 
males but is occasionally seen in young adults. Acute onset 
of symptoms and a negative urinalysis favor testicular tor
-
sion or torsion of one of the testicular or epididymal 
appendages. Prehn sign (elevation of the scrotum above the 
pubic symphysis improves pain from epididymitis) may be 
helpful but is not reliable.
 
»
Treatment

»
Treatment
Bed rest with scrotal elevation is important in the acute 
phase. Treatment is directed toward the identified 
pathogen (Table 23–1). The sexually transmitted variety 
is treated with 10–21 days of antibiotics, and the sexual 
partner must be treated as well. Non-sexually transmit
-
ted forms are treated for 21–28 days with appropriate 
antibiotics, at which time evaluation of the urinary tract is 
warranted to identify underlying disease.
 
»
Prognosis
Prompt treatment usually results in a favorable outcome. 
Delayed or inadequate treatment may result in epididymo-
orchitis, decreased fertility, or abscess formation.
 
»
•	
Persistent symptoms and infection despite antibiotic 
therapy.
•	
Signs of sepsis or abscess formation.
McConaghy JR et al. Epididymitis: an overview. Am Fam 
Physician. 2016 Nov 1;94(9):723–6. [PMID: 27929243]
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INTERSTITIAL CYSTITIS
 
»
Pain with a full bladder or urinary urgency.
 
»
Submucosal petechiae or ulcers on cystoscopic 
 
»
Diagnosis of exclusion.
 
»
Interstitial cystitis (painful bladder syndrome) is character
-
ized by pain with bladder filling that is relieved by empty
-
ing and is often associated with urgency and frequency. 
This is a diagnosis of exclusion, and patients must have a 
negative urine culture and cytology and no other obvious 
cause such as radiation cystitis, chemical cystitis (cyclo
-
phosphamide), vaginitis, urethral diverticulum, or genital 
herpes. Up to 40% of patients referred to urologists for 
interstitial cystitis may actually be found to have a different 
diagnosis after careful evaluation.
Population-based studies have demonstrated a prevalence 
of between 18 and 40 per 100,000 people. Both sexes are 
involved, but most patients are women, with a mean age of 
 
40 years at onset. Patients with interstitial cystitis are more 
likely to report bladder problems in childhood, and there 
appears to be a higher prevalence of these in women. Up to 50% 
of patients may experience spontaneous remission of symp
-
toms, with a mean duration of 8 months without treatment.
The etiology of interstitial cystitis is unknown, and 
it is most likely not a single disease but rather several 
diseases with similar symptoms. Associated diseases 
include severe allergies, irritable bowel syndrome, or 
inflammatory bowel disease. Theories regarding the 
cause of interstitial cystitis include increased epithelial 
permeability, neurogenic causes (sensory nervous system 
abnormalities), and autoimmunity.
 
»
Pain with bladder filling that is relieved with urination or 
urgency, frequency, and nocturia are the most common 
symptoms. Patients should be asked about exposure to 
pelvic radiation or treatment with cyclophosphamide. 
Examination should exclude genital herpes, vaginitis, or a 
urethral diverticulum.
Urinalysis, urine culture, and urinary cytologies are 
obtained to examine for infectious causes and bladder 
malignancy. Urodynamic testing assesses bladder sensation 
and compliance and excludes detrusor instability.
C. Cystoscopy
The bladder is distended with fluid (hydrodistention) to 
detect glomerulations (submucosal hemorrhage), which may 
or may not be present. Biopsy should be performed to exclude 
other causes such as carcinoma, eosinophilic cystitis, and 
tuberculous cystitis. The presence of submucosal mast cells is 
not
 needed to make the diagnosis of interstitial cystitis.
 
»
Exposures to radiation or cyclophosphamide are discovered 
by the history. Bacterial cystitis, genital herpes, or vaginitis 
can be excluded by urinalysis, culture, and physical exami
-
nation. A urethral diverticulum may be suspected if palpa
-
tion of the urethra demonstrates an indurated mass that 
results in the expression of pus from the urethral meatus. 
Urethral carcinoma presents as a firm mass on palpation.
 
»
Treatment
There is no cure for interstitial cystitis, but most patients 
achieve symptomatic relief from one of several approaches, 
including hydrodistention, which is usually done as part of 
the diagnostic evaluation. Approximately 20–30% of 
patients notice symptomatic improvement following this 
maneuver. Also of importance is the measurement of bladder 
capacity during hydrodistention, since patients with very 
small bladder capacities (less than 200 mL) are unlikely to 
respond to medical therapy.
Amitriptyline (10–75 mg/day orally) is often used as 
first-line medical therapy in patients with interstitial cysti
-
tis. Both central and peripheral mechanisms may contrib
-
ute to its activity. Nifedipine (30–60 mg/day orally) and 
other calcium channel blockers have also demonstrated

-
-
other calcium channel blockers have also demonstrated 
some activity in patients with interstitial cystitis. Pentosan 
polysulfate sodium (Elmiron) is an oral synthetic sulfated 
polysaccharide that helps restore integrity to the epithe
-
lium of the bladder in a subset of patients and has been 
evaluated in a placebo-controlled trial. Other options 
include intravesical instillation of dimethyl sulfoxide 
(DMSO) and heparin. Intravesical bacillus Calmette-
Guérin (BCG) is not beneficial.
Further treatment modalities include transcutaneous 
electric nerve stimulation (TENS) and acupuncture. Surgical 
therapy for interstitial cystitis should be considered only as 
a last resort and may require cystourethrectomy with urinary 
diversion.
 
»
Persistent and bothersome symptoms in the absence of 
identifiable cause.
Cox A et al. CUA guideline: diagnosis and treatment of interstitial 
cystitis/bladder pain syndrome. Can Urol Assoc J. 2016 May–Jun;
 
10(5-6):E136–55. [PMID: 27790294]
Hanno PM et al; American Urological Association. Diagnosis 
and treatment of interstitial cystitis/bladder pain syndrome: 
AUA guideline amendment. J Urol. 2015 May;193(5):1545–53. 
[PMID: 25623737]
Patanaik SS et al. Etiology, pathophysiology and biomarkers of 
interstitial cystitis/painful bladder syndrome. Arch Gynecol 
Obstet. 2017 Jun;295(6):1341–59. [PMID: 28391486]
Zhang W et al. Intravesical treatment of interstitial cystitis/painful 
bladder syndrome: a network meta-analysis. Int Urogynecol J. 
2017 Apr;28(4):515–25. [PMID: 27614759]
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URINARY STONE DISEASE
 
»
Severe flank pain.
 
»
 
»
Identification on noncontrast CT or ultrasonography.
 
»
Urinary stone disease is exceeded in frequency as a urinary 
tract disorder only by infections and prostatic disease and 
is estimated to afflict 240,000–720,000 Americans per year. 
While men are more frequently affected by urolithiasis 
than women, with a ratio of 2.5:1, the incidence in women 
is increasing. Initial presentation predominates between 
the third and fifth decade.
Urinary calculi are polycrystalline aggregates composed of 
varying amounts of crystalloid and a small amount of organic 
matrix. Stone formation requires saturated urine that is 
dependent on pH, ionic strength, solute concentration, and 
complexation. There are five major types of urinary stones: 
calcium oxalate
, 
calcium phosphate
, 
struvite
 (magnesium 
ammonium phosphate), 
uric acid
, and 
cystine.
 The most 
common types are composed of calcium (85%), and for that 
reason most urinary stones are radiopaque on plain abdomi
-
nal radiographs. Uric acid stones frequently are composed of 
a combination of uric acid and calcium oxalate and thus are 
frequently radiopaque, though pure uric acid stones are radio
-
lucent. Cystine stones frequently have a smooth-edged 
ground-glass appearance and are radiolucent.
Geographic factors contribute to the development of 
stones. High humidity and elevated temperatures appear to 
be contributing factors, and the incidence of symptomatic 
ureteral stones is greatest in such areas during hot summer 
months. Higher incidence rates of stones have also been 
associated with sedentary lifestyle, hypertension, carotid 
calcification, and cardiovascular disease.
High protein and salt intake as well as inadequate 
hydration appear to be the most important dietary factors 
in the development of urinary stones.
Genetic factors may contribute to urinary stone forma
-
tion. While approximately 50% of calcium-based stones are 
thought to have a heritable component, other stone types are 
better characterized genetically. For example, cystinuria is an 
autosomal recessive disorder. Homozygous individuals have 
markedly increased excretion of cystine and frequently have 
numerous recurrent episodes of urinary stones. Distal renal 
tubular acidosis may be transmitted as a hereditary trait, and 
urolithiasis occurs in up to 75% of affected patients.
 
»
Obstructing urinary stones usually present with acute, unre
-
mitting, and severe colic. Pain most often occurs suddenly 
and may awaken patients from sleep. It is typically localized 
to the flank and may be associated with nausea and vomit
-
ing. In sharp contrast to patients with an acute abdomen, 
patients with kidney stones are constantly moving trying to 
find a comfortable position. The pain may occur episodi
-
cally and may radiate anteriorly over the abdomen. As the 
stone progresses down the ureter, the pain may be referred 
into the ipsilateral groin. If the stone becomes lodged at the 
uretero-vesicular junction, patients will complain of marked 
urinary urgency and frequency and in men, pain may radi
-
ate to the tip of the penis. After the stone passes into the 
bladder, there typically is minimal pain with passage through 
the urethra. Stone size does not correlate with the severity of 
the symptoms.
Regardless of symptom severity, urinalysis usually reveals 
microscopic or gross hematuria (~90%). However, the 
absence of microhematuria does not exclude urinary 
stones. Urinary pH is a valuable clue to the cause of the 
possible stone. Normal urinary pH is 5.8–6.2, and persis
-
tent urinary pH < 5.5 is suggestive of uric acid stones. In 
contrast, a persistent urinary pH > 7.2 is suggestive of a 
struvite (infection-related) stone and pH > 7.5, a calcium

-
struvite (infection-related) stone and pH > 7.5, a calcium 
phosphate stone. Patients with calcium oxalate–based 
stones typically have a urinary pH between 5.5 and 6.8.
C. Metabolic Evaluation
Stone analysis on recovered stones can facilitate counseling 
for prevention of recurrence. Patients with uncomplicated 
first-time stones should undergo dietary counseling as 
outlined below and can be offered an optional complete 
metabolic evaluation.
General dietary counseling includes encouraging 
patients to change their diet to reduce sodium intake, to 
reduce their non-dairy animal protein intake during indi
-
vidual meals, and to ingest adequate fluid to achieve a 
voided volume of 2.5 L/day of urine. Detailed medical and 
dietary history, serum chemistries, and urinalysis should 
be obtained for all patients with newly diagnosed nephro
-
lithiasis. A 24-hour urine collection to determine urinary 
volume, pH, calcium, uric acid, oxalate, phosphate, sodium, 
and citrate excretion is recommended for interested 
patients with their first stone, patients who have recurrent 
stones, or patients at high risk for recurrence. Results are 
used to tailor medical management to individual patient 
needs. In addition, serum parathyroid hormone (PTH) 
should be checked for patients with suspected hyperpara
-
thyroidism and serum uric acid, for suspected gout.
D. Imaging
A plain abdominal radiograph (kidney, ureter, and bladder 
[KUB]) and renal ultrasound examination will diagnose up 
to 80% of stones. Since more than 60% of patients with acute 
renal colic will have a stone in the distal 4 cm of the ureter, 
attention should be directed to that region when examining 
radiographs and ultrasonographic studies. Spiral CT is the 
most accurate imaging modality in evaluating flank pain 
given its increased sensitivity and specificity over other tests; 
however, ultrasonography (which is devoid of ionizing 
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radiation) is a safe and effective alternative for evaluating 
renal colic that can be used in the emergency department 
with good accuracy. If CT scan is used, it should be obtained 
in the prone position to help differentiate distal ureterove
-
sicular stones from those that have already passed into the 
urinary bladder. A “low-dose” imaging protocol should be 
used when available and repeated CT scans should be mini
-
mized due to the substantial cumulative radiation exposure 
patients with recurrent stones can face. Stone density can be 
estimated with Hounsfield units (HU) on CT scans to help 
determine stone type. All stones whether radiopaque or 
radiolucent on plain abdominal radiographs will be visible 
on noncontrast CT except the rare protease inhibitor 
calculus (classically, with indinavir).
 
»
Medical Treatment & Prevention
To reduce the recurrence rate of urinary stones, dietary 
modification is important. Metabolic evaluation often identi
-
fies a modifiable risk factor that can further reduce stone 
recurrence rates. If no medical treatment is provided, stones 
will generally recur in 50% of patients within 5 years. Some 
stone types (eg, uric acid, cystine) are more prone to rapid 
recurrence than others. An increased fluid intake is of great
-
est importance in reducing stone recurrence. Increasing fluid 
intake to ensure a voided volume of 2.5 L/day is recom
-
mended (normal average voided volume is 1.6 L/day). 
Medical therapy is initiated based on metabolic evaluation 
findings. Routine follow-up every 6–8 months will help encour
-
age medical compliance and permit adjustments in medical 
therapy based on repeat metabolic studies.
A. Diet
Sodium intake
 should be restricted to keep urinary 
sodium levels less than 150 mEq/day. Increased sodium 
intake will increase renal sodium and calcium excretion, 
increase urinary monosodium urates (that can act as a 
nidus for stone growth), increase the relative saturation of 
calcium phosphate, and decrease urinary citrate excretion. 
All of these factors encourage stone growth. 
Animal protein 
intake
 should be spread out through the day, not all con
-
sumed during any individual meal, and is best limited to 
 
1 g/kg/day. An increased protein load during an individual 
meal can also increase calcium, oxalate, and uric acid 
excretion and decrease urinary citrate excretion.
Excessive intake of oxalate and purines can increase the 
incidence of stones in predisposed individuals. 
Dietary 
calcium or calcium supplements should not be routinely 
decreased
 since a decreased calcium intake only benefits 
the small percentage of calcium stone formers who have 
dietary-dependent hypercalciuria. In fact, decreased calcium 
consumption has been found to increase stone recurrence in 
many patients.
B. Calcium Nephrolithiasis
1. Hypercalciuric—
Hypercalciuric calcium nephrolithiasis 
(greater than 250 mg/24 h; greater than 4 mg/kg/24 h) can 
be caused by absorptive, resorptive, and renal disorders. 
Thiazide diuretics should be offered to patients with high 
urinary calcium and recurrent calcium stones.
Absorptive hypercalciuria
 is secondary to increased 
absorption of calcium at the level of the small bowel, pre
-
dominantly in the jejunum, and can be further subdivided 
into types I, II, and III.
Type I
 
absorptive hypercalciuria
 is independent of 
calcium intake. There is increased urinary calcium on a 
regular or even a calcium-restricted diet. Thiazide diuretics 
can be used to decrease renal calcium excretion and result 
in increased bone density of approximately 1% per year. 
Thiazides have limited long-term utility (less than 5 years) 
since they may lose their hypocalciuric effect with continued 
therapy.
Type II
 
 is diet-dependent 
and fortunately rare. Decreasing calcium intake by 50% 
(approximately 400 mg/day) will decrease the hypercalci
-
uria to normal values (150–200 mg/24 h). There is no spe
-

is diet-dependent 
-
-
cific medical therapy.
Type III
 
 is secondary to a 
renal phosphate leak. This results in increased vitamin D 
synthesis and secondarily increased small bowel absorp
-
tion of calcium. This can be readily reversed by orthophos
-
phates (250 mg orally three to four times per day), 
presently available without need for a prescription. Ortho
-
phosphates do not change intestinal absorption but rather 
inhibit vitamin D synthesis.
Resorptive hypercalciuria
 is secondary to hyperparathy
-
roidism. Hypercalcemia, hypophosphatemia, hypercalciuria, 
and an elevated serum PTH value are present. Appropriate 
surgical resection of the parathyroid adenoma cures the 
disease, although recurrent urinary stones can still occur in 
10% of patients after parathyroidectomy. Medical management 
invariably fails.
Renal hypercalciuria
 occurs when the renal tubules are 
unable to efficiently reabsorb filtered calcium, and hyper
-
calciuria results. Spilling calcium in the urine results in 
secondary hyperparathyroidism. Serum calcium typically 
is normal. Thiazides are an effective long-term therapy in 
patients with this disorder.
2. Hyperuricosuric—
Hyperuricosuric calcium nephroli
-
thiasis is secondary to dietary purine excess or endoge
-
nous uric acid metabolic defects. Dietary purine restriction 
can reduce hyperuricosuria in 85% of cases. Patients with 
hyperuricosuria, normocalciuria, and recurrent calcium 
oxalate stones can be successfully treated with allopurinol. 
In contrast to uric acid nephrolithiasis, patients with 
hyperuricosuric calcium stones typically maintain a uri
-
nary pH > 5.5.
3. Hyperoxaluric—
Hyperoxaluric calcium nephrolithiasis 
(greater than 40 mg oxalate/24 h urine) is usually due to 
primary intestinal disorders. Patients often have a history of 
chronic diarrhea frequently associated with inflammatory 
bowel disease. In these situations, increased bowel fat or bile 
(or both) combine with intraluminal calcium to form a 
soap-like product. Calcium is therefore unavailable to bind 
to oxalate in the gut, which is then freely and rapidly 
absorbed. A small increase in oxalate absorption will sig
-
nificantly increase stone formation. If the diarrhea or steat
-
orrhea cannot be effectively curtailed, oral calcium should 
be taken with meals, either by ingesting dairy products or 
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taking calcium carbonate supplements (250–500 mg). This 
helps to bind dietary oxalate in the gut and oxalate move
-
ment into the kidneys. Excess ascorbic acid (greater than 
 
2 g/day) will substantially increase urinary oxalate levels. 
Patients with significant dietary ingestion of oxalate-rich 
foods can reduce their oxalate intake, but this should not be 
routinely recommended. Rare enzymatic liver defects can 
lead to primary hyperoxaluria that is routinely fatal without 
a combined liver and kidney transplantation.
4. Hypocitraturic—
Hypocitraturic calcium nephrolithiasis 
may be secondary to chronic diarrhea, type I (distal) renal 
tubular acidosis, chronic hydrochlorothiazide treatment, 
or in any condition that results in a metabolic acidosis. The 
metabolic acidosis enhances citrate transport into the 
proximal tubular cells where it is consumed by the citric 
acid cycle in their mitochondria, resulting in hypocitratu
-
ria (less than 450 mg/24h). Hypocitraturia is frequently 
associated with calcium stone formation. Urinary citrate 
binds to calcium in solution, thereby decreasing available 
calcium for precipitation and subsequent stone formation. 
Potassium citrate supplements (eg, Urocit-K™) are usually 
effective treatment in these situations. Urinary citrate is 
decreased in acidosis and is increased during alkalosis. The 
potassium will supplement the frequently associated hypo
-
kalemic states, and citrate will help correct the acidosis. A 
typical dose is 60 mEq total daily intake, divided either into 
three times daily as tablets or twice daily as the crystal 
formulations dissolved in water (it is also available as a 
solution). Alternatively, oral lemonade has been shown to 
increase urinary citrate by about 150 mg/24h.
C. Uric Acid Calculi
Urinary pH is consistently less than 5.5 in persons who 
form pure uric acid stones. Increasing the urinary pH to 
greater than 6.2 dramatically increases uric acid solubility, 
can effectively dissolve large calculi at a rate of 1 cm per 
month, and effectively prevents future uric acid stone 
formation. Urinary alkalinization with potassium citrate or 
an equivalent agent is the key to stone dissolution and 
prophylaxis. The target should be a urinary pH greater 
than 6.2 and less than 7.5 (to avoid calcium phosphate 
precipitation). Other precipitating factors include hyper
-
uricemia, myeloproliferative disorders, malignancy with 
increased uric acid production, abrupt and dramatic weight 
loss, and uricosuric medications. If hyperuricemia is pres
-
ent in addition to hyperuricosuria, allopurinol (300 mg/day 
orally) may be given for stone prevention. Although pure 
uric acid stones are relatively radiolucent, most have some 
calcium components and can be visualized on plain 
abdominal radiographs.
D. Struvite Calculi
Struvite stones are radiodense magnesium-ammonium-
phosphate stones. They are most common in women with 
recurrent urinary tract infections with urease-producing 
organisms, including 
Proteus, Pseudomonas, Providencia
 
and, less commonly, 
Klebsiella, Staphylococcus
, and 
 (but not 
E coli)
. They rarely present as ureteral 
stones with colic without prior upper tract endourologic 
intervention. Frequently, a struvite stone is discovered as a 
large staghorn calculus forming a cast of the renal collect
-
ing system. Urinary pH is high, routinely above 7.2. Struvite 
stones are relatively soft and amenable to percutaneous 
removal. Appropriate perioperative antibiotics are required. 
They can recur rapidly, and efforts should be taken to 
render the patient stone-free.
E. Cystine Calculi
Cystine stones are a result of abnormal excretion of cystine. 
These stones are particularly difficult to manage medically. 
Prevention is centered around marked increased fluid 
intake during the day and evening to achieve a urinary 
volume of 3–4 L/day, urinary alkalinization with a urinary

volume of 3–4 L/day, urinary alkalinization with a urinary 
pH greater than 7.0 (monitored with Nitrazine pH paper), 
and disulfide inhibitors such as tiopronin (alpha-
 
mercaptoproprionylglycine) or penicillamine. There are 
no known inhibitors of cystine calculi.
 
»
Medical Expulsion & Surgical Treatment
In the acute setting, forced intravenous fluids will not push 
stones down the ureter. Forced diuresis can be counterpro
-
ductive and exacerbate pain; instead, a euvolemic state 
should be achieved. Signs of infection, including associated 
fever, tachycardia, or elevated white blood cell count may 
indicate a urinary tract infection behind the obstructing 
stone. Any obstructing stone with associated infection is a 
medical emergency requiring urology consultation and 
prompt drainage by a ureteral stent or a percutaneous neph
-
rostomy tube. Antibiotics alone are inadequate and only 
used as an adjunct to urinary drainage of the obstruction.
A. Ureteral Stones
Impediment to urine flow by ureteral stones usually occurs 
at three sites: the ureteropelvic junction, the crossing of the 
ureter over the iliac artery, or the ureterovesicular junction. 
Stones smaller than 5–6 mm in diameter on a plain 
abdominal radiograph usually pass spontaneously. Medical 
expulsive therapy with alpha-blockers (such as tamsulosin, 
0.4 mg orally once daily) in combination with a nonsteroi
-
dal anti-inflammatory agent (such as ibuprofen 600 mg 
orally three times per day), with or without a short course 
of a low-dose oral corticosteroid (such as prednisone 
 
10 mg orally daily for 3–5 days) may increase the rate of 
spontaneous stone passage and appears to be most effective 
for distal stones. Medical expulsive therapy with appropri
-
ate pain medications and imaging follow-up is appropriate 
for a few weeks. If the stone fails to pass within 4 weeks, the 
patient has fever, intolerable pain or persistent nausea or 
vomiting, or the patient must return to work or anticipates 
travel, then surgical intervention is indicated.
Stones in the mid and distal ureter that require surgical 
removal are best managed with ureteroscopic stone extrac
-
tion, though in situ extracorporeal shock wave lithotripsy 
(SWL) can be offered as second-line therapy. Ureteroscopic 
stone extraction involves placement of a small endoscope 
through the urethra and into the ureter. Under direct vision, 
basket extraction or stone laser fragmentation followed by 
extraction is performed.
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In situ SWL utilizes an external energy source focused 
on the stone with the aid of fluoroscopy or ultrasonography. 
SWL can be performed under anesthesia as an outpatient 
procedure with the goal of stone fragmentation. Most stone 
fragments then pass uneventfully within 2 weeks. Occa
-
sionally, stone fragments will obstruct the ureter after 
SWL. Conservative management will usually result in 
spontaneous resolution with eventual passage of the stone 
fragments. Fragments that have not passed within 6 weeks 
are unlikely to do so without intervention.
Proximal ureteral stones—those above the superior 
margin of the sacroiliac joint—as well as intrarenal stones 
can be treated with SWL or ureteroscopy. Decreased SWL 
success rates are associated with lower pole and distal stone 
location, as well as larger stone burden. After cases of SWL 
failure, ureteroscopic extraction will be required.
B. Renal Calculi
Patients with renal calculi but without pain, urinary tract 
infection, or obstruction may not warrant surgical treatment. 
If surveillance is elected, they should be monitored with serial 
abdominal radiographs or renal ultrasonographic examina
-
tions every 3–12 months. If calculi are growing or become 
symptomatic, intervention should be undertaken. Renal 
calculi smaller than 2 cm in diameter are best treated with 
SWL or ureteroscopic extraction, though a size criteria of 
 
1 cm should be used for stones in the lower pole. Calculi of 
larger diameter, located in the inferior calices, and staghorn 
stones (large branched stones occupying at least two renal 
calices) are best treated via percutaneous nephrolithotomy. 
Percutaneous nephrolithotomy is performed by inserting a 
needle into the appropriate renal calyx and dilating a tract 
large enough to allow a nephroscope to pass directly into the 
kidney. In this fashion, larger and more complex renal stones 
can be inspected, fragmented, and removed. In patients who 
are not appropriate candidates for SWL or whose stones do 
not fragment and pass following SWL, ureteroscopic, or 
percutaneous stone removal, laparoscopic, open, or robotic-
assisted stone removal may be considered. Perioperative anti
-
biotic coverage should be given for any stone procedure, 
ideally based on preoperative urine culture.
 
»
•	
Evidence of urinary obstruction.
•	
Urinary stone with associated flank pain.
•	
Anatomic abnormalities or solitary kidney.
•	
Concomitant pyelonephritis or recurrent infection.
 
»
•	
Intractable nausea and vomiting or pain.
•	
Obstructing stone with signs of infection.
Assimos D et al. Surgical management of stones: American Uro
-
logical Association/Endourological Society Guideline, Part I. 
J Urol. 2016 Oct;196(4):1153–60. [PMID: 27238616]
Gambaro G et al. Metabolic diagnosis and medical prevention of 
calcium nephrolithiasis and its systemic manifestations: a con
-
sensus statement. J Nephrol. 2016 Dec;29(6):715–34. [PMID: 
27456839]
Pearle MS et al. Medical management of kidney stones: AUA 
guideline. J Urol. 2014 Aug;192(2):316–24. [PMID: 24857648]
Pickard R et al. Medical expulsive therapy in adults with ureteric 
colic: a multicentre, randomised, placebo-controlled trial. 
Lancet. 2015 Jul 25;386(9991):341–9. [PMID: 25998582]
Rodgers AL. Physicochemical mechanisms of stone formation. 
Urolithiasis. 2017 Feb;45(1):27–32. [PMID: 27928586]
Smith-Bindman R et al. Ultrasonography versus computed 
tomography for suspected nephrolithiasis. N Engl J Med. 
2014 Sep 18;371(12):1100–10. [PMID: 25229916]
Song L et al. 24-hour urine calcium in the evaluation and man
-
agement of nephrolithiasis. JAMA. 2017 Aug 1;318(5):474–5. 
[PMID: 28763529]
Taguchi K et al. Genetic risk factors for idiopathic urolithiasis: a 
systemic review of the literature and causal network analysis. 
Eur Urol Focus. 2017 Feb;3(1):72–81. [PMID: 28720371]
MALE ERECTILE DYSFUNCTION &
 
SEXUAL DYSFUNCTION
 
»

»
Erectile dysfunction can have organic and psycho
-
genic etiologies, and the two frequently overlap.
 
»
Organic erectile dysfunction may be an early sign 
of cardiovascular disease and requires evaluation.
 
»
Peyronie disease is a common, benign fibrotic 
disorder of the penis that causes pain, penile 
deformity, and sexual dysfunction.
 
»
Erectile dysfunction is the consistent inability to attain or 
maintain a sufficiently rigid penile erection for sexual per
-
formance. More than half of men aged 40–70 years have 
erectile dysfunction and its incidence is age-related. Nor
-
mal male erection is a neurovascular event relying on an 
intact autonomic and somatic nerve supply to the penis, 
arterial blood flow supplied by the paired cavernosal arter
-
ies, and smooth and striated musculature of the corpora 
cavernosa and pelvic floor. Erection is caused and main
-
tained by an increase in arterial flow, active relaxation of 
the smooth muscle within the sinusoids of the corpora 
cavernosa, and an increase in venous resistance. Contrac
-
tion of the ischiocavernosus muscle results in further rigid
-
ity of the penis with intracavernosal pressures exceeding 
systolic blood pressure. Nitric oxide is a key neurotrans
-
mitter that initiates and sustains erections; however, other 
molecules contribute, including acetylcholine, prostaglandins, 
and vasoactive intestinal peptide.
Male sexual dysfunction may be manifested in a variety of 
ways, and patient history is critical to the proper classification 
and treatment. A 
loss of libido
 may indicate androgen defi
-
ciency. 
Loss of erections
 may result from arterial, venous, 
neurogenic, hormonal, or psychogenic causes. Concurrent 
medical problems may damage one or more of the mecha
-
nisms. The most common cause of erectile dysfunction is a 
decrease in arterial flow resultant from progressive vascular 
disease. Endothelial dysfunction results from the decreased 
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bioavailability of nitric oxide with subsequent impairment of 
arterial vasodilation. Erectile dysfunction may be an early 
manifestation of endothelial dysfunction, which precedes 
more severe atherosclerotic cardiovascular disease. Many 
medications, especially antihypertensive, antidepressant, and 
opioid agents, are associated with erectile dysfunction.
Peyronie disease
 is a fibrotic disorder of the tunica 
albuginea of the penis resulting in varying degrees of penile 
pain, curvature, or deformity. Peyronie disease develops in 
approximately 5–10% of men and is more common with 
increased age. While 10% of men improve spontaneously, 
50% will stabilize and the remainder will progress if left 
untreated. Penile deformity can impair normal sexual func
-
tion and impact self-esteem.
Priapism
 is the occurrence of penile erection lasting 
longer than 4 hours resulting in ischemic injury of the cor
-
pora cavernosa from venous congestion and cessation of 
arterial inflow (low flow or “ischemic” priapism). Ischemic 
priapism may be caused by red blood cell dyscrasias, drug 
use, and any of the treatments for erectile dysfunction. Isch
-
emic priapism is a medical emergency requiring immediate 
medical or surgical intervention to avoid irreversible penile 
damage.
Anejaculation
 is the loss of seminal emission and may 
result from androgen deficiency by decreasing prostate and 
seminal vesicle secretions, or by sympathetic denervation as 
a result of spinal cord injury, diabetes mellitus or pelvic or 
retroperitoneal surgery or radiation. 
Retrograde ejacula
-
tion
 may occur as a result of mechanical disruption of the 
bladder neck, due to congenital abnormalities, transure
-
thral resection of the prostate, pelvic radiation, sympathetic 
denervation, or treatment with alpha-blockers. 
Premature 
ejaculation
 is the distressful, recurrent ejaculation with 
minimal stimulation before a person desires. Primary 
premature ejaculation may be treated with behavioral 
modification, sexual health counseling, local anesthetic 
agents, and systemic medications. Secondary premature 
ejaculation is due to erectile dysfunction and responds to 
treatment of the underlying disorder.
 
»
Erectile dysfunction should be distinguished from prob
-
lems with penile deformity, libido, orgasm, and ejaculation. 
The severity, intermittency, and timing of erectile dysfunc
-
tion should be noted. Lifestyle factors should be inquired 
about, including sexual orientation, and quality of relation
-
ship with the partner. The history should include inquiries 
about dyslipidemia, hypertension, depression, neurologic 
disease, diabetes mellitus, chronic kidney disease, endo
-
crine disorders, and cardiac or peripheral vascular disease. 
Pelvic trauma, surgery, or irradiation increases a man’s 
likelihood of erectile dysfunction. Histories of prostate 
cancer treatment or Peyronie disease (penile scarring or 
plaque formation) should be elicited. The ability to attain 
but not maintain an erection may be the first sign of endo
-
thelial dysfunction and further cardiovascular risk stratifi
-
cation should be considered. Medication use should be 
reviewed. Special attention should be given to the use of 
nitrate-containing medications. Alcohol, tobacco, mari
-
juana, and other recreational drug use are associated with 
an increased risk of sexual dysfunction. The use of pornog
-
raphy to maintain sexual arousal should be elicited.
During the physical examination, vital signs, body 
habitus (obesity), and secondary sexual characteristics 
should be assessed. Basic cardiovascular and neurologic 
examinations should be performed. The genitalia should 
be examined, noting the stretched length of the penis, the 
presence of Peyronie disease and any abnormalities in size 
or consistency of either testicle.
Laboratory evaluation should be performed in select cases

Laboratory evaluation should be performed in select cases 
based on patient history and examination. Possible testing 
includes a lipid profile, glucose, and testosterone. Patients 
with abnormalities of testosterone may require further 
evaluation with measurement of free testosterone and 
luteinizing hormone (LH) to distinguish hypothalamic-
pituitary dysfunction from primary testicular failure.
 
»
Treatment
Treatment of men suffering from sexual dysfunction 
should be patient centered and goal oriented. Lifestyle 
modification and reduction of cardiovascular risk factors 
are important components to any treatment plan. This 
should potentially include smoking cessation; reduction of 
alcohol intake; diet; exercise; and treatment of diabetes, 
dyslipidemia, and hypertension. Men who have a psycho
-
genic component to their erectile dysfunction or who are 
experiencing emotional distress will benefit from sexual 
health therapy or counseling.
A. Hormonal Replacement
Testosterone replacement therapy may be offered to men 
with hypogonadism who have undergone complete endo
-
crinologic evaluation and in whom there is no evidence 
of prostate cancer or other contraindication to treatment 
(eg, erythrocytosis). Men being considered for testosterone 
replacement therapy should be made aware of the possible 
increased cardiovascular risk and should seek immediate 
medical attention if they experience symptoms of a myo
-
cardial infarction or stroke during therapy. Restoration of 
normal testosterone levels may improve sexual quality of 
life in some men. (See also the Male Hypogonadism section 
in Chapter 26.)
B. Vasoactive Therapy
1. Oral agents—
Sildenafil, vardenafil, tadalafil, and ava
-
nafil inhibit phosphodiesterase type 5 (PDE-5), prevent
-
ing the degradation of cGMP , thereby enhancing inflow 
of blood into the erect penis. These medications are simi
-
larly effective, but patients who do not respond to one 
PDE-5 inhibitor may respond to one of the other agents. 
The medications can have variable durations of activity 
and side effects. Each medication should be initiated at 
the lowest dose and titrated to achieve the desired effect. 
There is no impact on libido, and priapism is exceedingly rare. 
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When taken with nitrate medications, there may be exag
-
gerated cardiac preload reduction and hypotension; 
therefore, these medications are contraindicated in 
patients taking nitroglycerin or nitrates. All patients 
being evaluated for acute chest pain should be asked if 
they are taking a PDE-5 inhibitor before administering 
nitroglycerin and close monitoring of blood pressure is 
warranted if there is concern regarding medication 
overlap.
The combination of PDE-5 inhibitors and alpha-receptor 
blockers (which may be prescribed for lower urinary tract 
symptoms) may cause a larger reduction in systemic blood 
pressure than when PDE-5 inhibitors are used alone. How
-
ever, these two classes of medication may be safely used in 
combination if they are initiated and titrated in a stepwise 
fashion.
2. Urethral injectable or suppository medications—
Injection of prostaglandin E
2
 into the penis is an acceptable 
form of treatment for many men with erectile dysfunction. 
Injections are performed using a tuberculin-type syringe or 
a metered-dose injection device. The base and lateral 
aspect of the penis is used as the injection site to avoid 
injury to the superficial blood and nerve supply located 
dorsally. Complications are rare and include priapism, 
penile pain, bruising, dizziness, fibrosis, and infection. 
Prostaglandin E
2
 (alprostadil urethral) can also be deliv
-
ered via an intraurethral suppository albeit with less effec
-
tiveness. Prostaglandin E
2
 is often compounded with 
papaverine, phentolamine, or atropine in order to increase 
effectiveness. Patients using such compounded agents 
should be cautioned about the increased risk of priapism 
and variability of drug effect due to differences in 
compounding.
Priapism requires immediate medical attention to pre
-
vent ischemia and fibrosis of the cavernosal tissues. Initial 
treatment is aspiration of blood from the penis and the 
injection of sympathomimetic drugs (epinephrine or 
phenylephrine); if these maneuvers are not successful, 
surgical arteriovenous shunts should be performed to 
restore blood flow to the penis.
C. Vacuum Erection Device
The vacuum erection device creates negative pressure 
around the penis, drawing blood into the corpora caver
-
nosa. Once tumescence is achieved, an elastic constriction 
band is placed around the penile base to prevent loss of 
erection. Such devices are effective in many cases, but may 
cause penile discomfort leading to a high rate of disuse. 
Serious complications are rare.
D. Penile Prosthetic Surgery
Penile prostheses are implanted directly into the paired 
corpora cavernosa and may be semi-rigid (malleable) or 
inflatable (self-contained hydraulic device). Inflatable 
devices are more commonly used, since they result in a 
more natural appearance and function given that they 
emulate the tumescence and detumescence of the normal 
erection. Complications of surgery are rare but include 
mechanical failure, infection, and injury to adjacent ana
-
tomic structures. For men who elect this treatment, 
personal and partner satisfaction rates are very high due to 
enhanced spontaneity and reliability of erections.
E. Medical and Surgical Therapy for 
 
Peyronie Disease
Collagenase clostridium histolyticum is the only FDA-
approved medication for the treatment of Peyronie disease. 
Collagenase is administered to the central portion of the 
penile plaque by needle injection causing enzymatic sever
-
ing of disordered collagen fibers and subsequent improve
-
ment of penile curvature. No oral therapies for Peyronie 
disease are approved by the FDA; however, off-label use of 
multiple vasodilatory, anti-inflammatory, and antioxidant 
medications is common. Surgical treatment is an alterna
-
tive for men with compromised sexual function due to 
severe curvature or lesions causing penile instability. The 
choice of corrective procedure should be tailored to each

-
choice of corrective procedure should be tailored to each 
patient after a detailed evaluation of disease severity and 
sexual function.
 
»
•	
Patients with inadequate response to oral medications, 
who are unable to tolerate side effects or who are dis
-
satisfied with their current treatment.
•	
Patients with Peyronie disease or other penile 
deformity.
•	
Patients with a history of pelvic or perineal trauma, 
surgery, or radiation.
•	
Ischemic priapism is a medical emergency and requires 
immediate referral to a urologist or the emergency 
department for intervention to allow restoration of 
penile blood perfusion.
Gabrielson AT et al. Collagenase 
Clostridium histolyticum
 in the 
treatment of urologic disease: current and future impact. Sex 
Med Rev. 2018 Jan;6(1):143–56. [PMID: 28454897]
Kouidrat Y et al. High prevalence of erectile dysfunction in dia
-
betes: a systematic review and meta-analysis of 145 studies. 
Diabet Med. 2017 Sep;34(9):1185–92. [PMID: 28722225]
Rizk PJ et al. Testosterone therapy improves erectile function 
and libido in hypogonadal men. Curr Opin Urol. 2017 Nov;
 
27(6):511–5. [PMID: 28816715]
MALE INFERTILITY
 
»
The male partner contributes to 50% of infertility 
cases.
 
»
Causes include decreased or absent sperm produc
-
tion or function, or obstruction of the male genital 
tract.
 
»
Abnormal semen quality may indicate poor health 
or increased risk of certain health conditions.
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»
Infertility is the inability of a couple to conceive a child after 
1 year of sexual intercourse without contraceptive use. It 
affects 15–20% of US couples and 50% of cases result from 
male factors. The evaluation of both partners is critical for 
treatment success. Following a detailed history and physical 
examination, a semen analysis should be performed at least 
twice, on two separate occasions (Figure 23–1). Because 
spermatogenesis requires approximately 75 days, it is 
important to review health events and gonadotoxic expo
-
sures from the preceding 3 months. Male infertility is asso
-
ciated with a higher risk of testicular germ cell cancer and 
with a higher rate of medical comorbidity. These men 
should be counseled and screened appropriately and taught 
testicular self-examination.
 
»
The history should include prior testicular insults (torsion, 
cryptorchidism, trauma), infections (mumps orchitis, 
epididymitis, sexually transmitted infections), environmental 
factors (excessive heat, radiation, chemotherapy, prolonged 
pesticide exposure), medications (testosterone, finasteride, 
cimetidine, selective serotonin reuptake inhibitors, and 
spironolactone may affect spermatogenesis; phenytoin may 
lower FSH; sulfasalazine and nitrofurantoin affect sperm 
motility; tamsulosin causes retrograde ejaculation), and 
other drugs (alcohol, tobacco, marijuana). Sexual function, 
frequency and timing of intercourse, use of lubricants, and 
each partner’s previous fertility are important. The past medi
-
cal or surgical history may reveal chronic disease, including, 
obesity, cardiovascular, thyroid, or liver disease (decreased 
spermatogenesis); diabetes mellitus (decreased spermatogen
-
esis, retrograde or anejaculation); or radical pelvic or retro
-
peritoneal surgery (absent seminal emission secondary to 
sympathetic nerve injury).
Physical examination should assess features of hypogo
-
nadism: underdeveloped sexual characteristics, dimin
-
ished male pattern hair distribution (axillary, body, facial, 
pubic), body habitus, gynecomastia, and obesity. Testicular 
size should be noted (normal size approximately 4.5 × 2.5 cm, 
volume 18 mL). 
Varicoceles
 are abnormally dilated and 
Male evaluation
Female evaluation
/uni00A0
Abnormal
/uni00A0
/uni00A0
Normal
/uni00A0
Azoospermia
Advanced/uni00A0sperm
function/uni00A0testing
History
Physical/uni00A0examination
Semen/uni00A0analysis/uni00A0×/uni00A02
Address/uni00A0modifiable/uni00A0factors,
eliminate/uni00A0gonadotoxins or
exogenous/uni00A0androgens
Complete,/uni00A0simultaneous
evaluation
Hormonal
Correct
gonadotropin
Low volume
Oligozoospermia,
asthenozoospermia,
teratozoospermia
Post-ejaculate
urinalysis/uni00A0(for
presence/uni00A0of/uni00A0sperm)
Correct/uni00A0reversible
factors/uni00A0such/uni00A0as
gonadotoxin
exposure/uni00A0or/uni00A0varicocele
Testicular biopsy,
FNA,/uni00A0or/uni00A0sperm
retrieval/uni00A0
Couple-based/uni00A0treatment/uni00A0approach:/uni00A0correct/uni00A0specific/uni00A0etiologies,/uni00A0consider/uni00A0Assisted Reproductive Technology,
sperm/uni00A0donation,/uni00A0or/uni00A0adoption/uni00A0
 
▲
Figure 23–1.
 
Couple-based approach to evaluation and treatment of male factor infertility. FNA, fine-needle 
aspiration.
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refluxing veins of the pampiniform plexus that can be iden
-
tified in the standing position by gentle palpation of the 
spermatic cord and, on occasion, may only be appreciated 
with the Valsalva maneuver. The vas deferens, epididymis, 
and prostate should be palpated (absence of all or part of 
the vas deferens may indicate the presence of a cystic fibro
-
sis variant, congenital bilateral or unilateral absence of the 
vas deferens).
Semen analysis should be performed after 3 to 5 days of 
ejaculatory abstinence. The specimen should be analyzed 
within 1 hour after collection. Abnormal sperm concen
-
trations are less than 15 million/mL 
(oligozoospermia
 is 
the presence of less than 15 million sperm/mL in the 
ejaculate; 
azoospermia
 is the complete absence of sperm). 
Normal semen volumes range between 1.5 mL and 5 mL 
(volumes less than 1.5 mL may be due to retrograde 
ejaculation, ejaculatory duct obstruction, congenital 
bilateral absence of the vasa deferentia, or androgen 
insufficiency). Normal sperm motility and morphology 
demonstrate greater than 45% motile cells and greater 
than 3% normal morphology. Abnormal motility may 
result from varicocele, antisperm antibodies, infection, 
abnormalities of the sperm flagella, or partial ejaculatory 
duct obstruction. Abnormal morphology may result from 
a varicocele, infection, or exposure to gonadotoxins (eg, 
tobacco smoke).
Endocrine evaluation is warranted if sperm concentra
-
tion is below 10 million sperm/mL or if the history and 
physical examination suggest an endocrinologic origin. Ini
-
tial testing should include serum testosterone and FSH. 
Specific abnormalities in these hormones should prompt 
additional testing, including serum LH, prolactin, and estra
-
diol levels. Elevated FSH and LH levels and low testosterone 
levels (
hypergonadotropic
 or 
primary hypogonadism
) are 
associated with primary testicular failure. Low FSH and LH 
associated with low testosterone (
hypogonadotropic
 or 
secondary hypogonadism
) may be of hypothalamic or 
pituitary origin. Elevation of serum prolactin may indicate 
the presence of prolactinoma. Elevation of estradiol may 
impair normal gonadotropin production and impact normal 
spermatogenesis.
C. Genetic Testing
Men with sperm concentrations less than 10 million/mL 
should consider testing for Y chromosome microdeletions 
and karyotypic abnormalities. Gene deletions from the long 
arm of the Y chromosome may cause azoospermia or oligo
-
zoospermia with age-related decline in spermatogenesis 
that is transmissible to male offspring. Karyotyping may 
reveal Klinefelter syndrome. Partial or complete absence of 
the vas deferens should prompt testing for gene mutations 
associated with cystic fibrosis.
D. Imaging
Scrotal ultrasound can aid in characterizing the testes and 
may detect a subclinical varicocele. Men with low ejaculate 
volume and no evidence of retrograde ejaculation should 
undergo transrectal ultrasound to evaluate the prostate and 
seminal vesicles. MRI of the sella turcica should be performed 
in men with elevated prolactin or hypogonadotropic hypogo
-
nadism to evaluate the anterior pituitary gland. MRI of the 
pelvis and scrotum should be considered in men for whom 
the testes cannot be identified in the scrotum by physical 
examination or ultrasound. Men with unilateral absence of 
the vas deferens should have abdominal ultrasound or CT to 
exclude absence of the ipsilateral kidney.
E. Special Tests
Patients with low-volume ejaculate should have post-
ejaculation urine samples centrifuged and analyzed for 
sperm to evaluate for retrograde ejaculation. In cases of 
disproportionately low motility, sperm vitality should 
be assessed. Round cells in concentrations greater than 
 
1 million/mL should prompt special staining to determine 
the presence of leukocytes.
 
»
Treatment
Education about intercourse timing in relation to the

»
Treatment
Education about intercourse timing in relation to the 
woman’s ovulatory cycle as well as the avoidance of sper
-
micidal lubricants should be discussed. In cases of 
gonadotoxic exposure or medication-related factors, the 
offending agent should be removed whenever feasible. 
Patients with active genitourinary tract infections 
should be treated with appropriate antibiotics. Healthy 
lifestyle habits, including diet, exercise, and avoidance of 
gonadotoxins (tobacco, excessive alcohol, and marijuana) 
should be reinforced.
B. Varicocele
Varicocelectomy is performed to stop retrograde blood 
flow in abnormal spermatic cord veins. Surgical ligation, 
which is accomplished via a subinguinal incision with the 
aid of a surgical microscope and Doppler ultrasound, is the 
gold standard approach given its high success and low 
complication rates. Percutaneous venographic emboliza
-
tion of varicoceles is feasible but incurs both radiation and 
intravenous contrast exposure.
C. Endocrine Therapy
Hypogonadotropic hypogonadism may be treated with 
human chorionic gonadotropin (2000 international units 
intramuscularly three times a week) once primary pituitary 
disease has been excluded or treated. If sperm concentra
-
tion fails to rise after 12 months, recombinant FSH therapy 
should be initiated (150 international units subcutaneously 
three times a week).
D. Ejaculatory Dysfunction Therapy
Patients with retrograde ejaculation may benefit from alpha-
adrenergic agonists (pseudoephedrine, 60 mg orally three 
times a day) or imipramine (25 mg orally three times a day). 
Medical failures may require the collection of post-ejaculation 
urine for intrauterine insemination. Anejaculation can be 
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treated with vibratory stimulation or electroejaculation in 
select cases.
E. Ductal Obstruction
Obstruction of the ejaculatory ducts may be corrected by 
transurethral resection of the ducts in the prostatic urethra. 
If obstruction of the vas deferens or epididymis is suspected, 
the level of obstruction must be determined via vasography 
or direct surgical inspection prior to surgical reconstruction, 
with the exception of prior vasectomy. Obstruction of the 
vas deferens is best managed by microsurgical vasovasos
-
tomy or vasoepididymostomy.
F. Assisted Reproductive Techniques
Intrauterine insemination, in vitro fertilization, and intra
-
cytoplasmic sperm injection are alternatives for patients in 
whom other means of treating reduced sperm concentra
-
tion, motility, or functionality have failed. Intrauterine 
insemination should be performed only when adequate 
numbers of motile sperm are noted on an ejaculate sample. 
With the use of intracytoplasmic sperm injection, some 
men with azoospermia may still initiate a pregnancy by 
surgical retrieval of sperm from the testicle, epididymis, or 
vas deferens.
 
»
•	
Couples with infertility or who are concerned about 
their fertility potential.
•	
Men with known genital insults, genetic diagnoses, or 
syndromes that preclude natural fertility.
•	
Reproductive-aged men with newly diagnosed cancer 
or other disease that may require cytotoxic therapies 
with interest in fertility preservation.
Avellino G et al. Common urologic diseases in older men and 
their treatment: how they impact fertility. Fertil Steril. 
2017 Feb;107(2):305–11. [PMID: 28073432]
Duthie EA et al. A conceptual framework for patient-centered 
fertility treatment. Reprod Health. 2017 Sep 7;14(1):114. 
[PMID: 28882134]
Eisenberg ML et al. Relationship between semen production and 
medical comorbidity. Fertil Steril. 2015 Jan;103(1):66–71. 
[PMID: 25497466]
Kashanian JA et al. JAMA patient page. Male infertility. JAMA. 
2015 May 5;313(17):1770. [PMID: 25942742]
Ostrowski KA et al. Infertility with testicular cancer. Urol Clin 
North Am. 2015 Aug;42(3):409–20. [PMID: 26216827]
Semet M et al. The impact of drugs on male fertility: a review. 
Andrology. 2017 Jul;5(4):640–63. [PMID: 28622464]
BENIGN PROSTATIC HYPERPLASIA
 
»
Obstructive or irritative voiding symptoms.
 
»
May have enlarged prostate on rectal examination.
 
»
Absence of urinary tract infection, neurologic 
disorder, stricture disease, prostatic or bladder 
 
»
Benign prostatic hyperplasia is the most common benign 
tumor in men, and its incidence is age related. The preva
-
lence of histologic benign prostatic hyperplasia in 
autopsy studies rises from approximately 20% in men 
aged 41–50 years, to 50% in men aged 51–60, and to over 
90% in men over 80 years of age. Although clinical evi
-
dence of disease occurs less commonly, symptoms of 
prostatic obstruction are also age related. At age 55 years, 
approximately 25% of men report obstructive voiding 
symptoms. At age 75 years, 50% of men report a decrease 
in the force and caliber of the urinary stream.
Risk factors for the development of benign prostatic 
hyperplasia are poorly understood. Some studies have 
suggested a genetic predisposition and some have noted 
racial differences. Approximately 50% of men under age 
 
60 years who undergo surgery for benign prostatic hyper
-
plasia may have a heritable form of the disease. This form 
is most likely an autosomal dominant trait, and first-degree 
male relatives of such patients carry an increased relative 
risk of approximately fourfold.
 
»
The symptoms of benign prostatic hyperplasia can be 
divided into obstructive and irritative complaints. 
Obstructive symptoms
 include hesitancy, decreased force 
and caliber of the stream, sensation of incomplete bladder

and caliber of the stream, sensation of incomplete bladder 
emptying, double voiding (urinating a second time within 
2 hours), straining to urinate, and postvoid dribbling. 
Irritative symptoms
 include urgency, frequency, and 
nocturia.
The American Urological Association (AUA) symptom 
index (Table 23–3) is perhaps the single most important 
tool used in the evaluation of patients with this disorder 
and should be calculated for all patients before starting 
therapy. The answers to seven questions quantitate the 
severity of obstructive or irritative complaints on a scale of 
0–5. Thus, the score can range from 0 to 35, in increasing 
severity of symptoms.
A detailed history focusing on the urinary tract should 
be obtained to exclude other possible causes of symptoms 
such as prostate cancer or disorders unrelated to the pros
-
tate such as urinary tract infection, neurogenic bladder, or 
urethral stricture.
B. Signs
A physical examination, digital rectal examination 
(DRE), and a focused neurologic examination should be 
performed on all patients. The size and consistency of 
the prostate should be noted, but prostate size does not 
correlate with the severity of symptoms or the degree of 
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obstruction. Benign prostatic hyperplasia usually results 
in a smooth, firm, elastic enlargement of the prostate. 
Induration, if detected, must alert the clinician to the 
possibility of cancer, and further evaluation is needed 
(ie, prostate-specific antigen [PSA] testing, transrectal 
ultrasound, and biopsy). Examination of the lower 
abdomen should be performed to assess for a distended 
bladder.
Urinalysis should be performed to exclude infection or 
hematuria. Clinicians should consider obtaining a serum 
PSA test, particularly in patients whose life expectancy is 
longer than 10 years. PSA certainly increases the ability to 
detect prostate cancer over DRE alone; however, because 
there is much overlap between levels seen in benign pros
-
tatic hyperplasia and prostate cancer, its use remains con
-
troversial (see Chapter 39).
D. Imaging
Upper tract imaging (CT or renal ultrasound) is recom
-
mended only in the presence of concomitant urinary tract 
disease or complications from benign prostatic hyperplasia 
(ie, hematuria, urinary tract infection, chronic kidney 
disease, history of stone disease). As included in the 
Choosing Wisely (ABIM Foundation) initiative, neither 
creatinine nor imaging should be routinely ordered for 
patients with benign prostatic hyperplasia.
E. Cystoscopy
Cystoscopy is not recommended to determine the need for 
treatment but may assist in determining the surgical 
approach in patients opting for invasive therapy.
F. Additional Tests
Cystometrograms and urodynamic profiles should be 
reserved for patients with suspected neurologic disease or 
those who have failed prostate surgery. Flow rates, postvoid 
residual urine determination, and pressure-flow studies are 
considered optional.
 
»
A history of prior urethral instrumentation, urethritis, or 
trauma should be elucidated to exclude urethral stricture 
or bladder neck contracture. Hematuria and pain are 
commonly associated with bladder stones. Carcinoma of 
the prostate may be detected by abnormalities on the DRE 
or an elevated PSA (see Chapter 39). A urinary tract 
infection can mimic the irritative symptoms of benign 
prostatic hyperplasia and can be readily identified by 
urinalysis and culture; however, a urinary tract infection 
can also be a complication of benign prostatic hyperplasia. 
Carcinoma of the bladder, especially carcinoma in situ, 
may also present with irritative voiding complaints; how
-
ever, urinalysis usually shows evidence of hematuria (see 
Chapter 39). Patients with a neurogenic bladder may also 
Table 23–3.
 
American Urological Association symptom index for benign prostatic hyperplasia.
1
Questions to Be Answered
Not at 
All
Less 
t
han 
One 
t
ime 
in Five
Less 
t
han 
h
alf the 
t
ime
About 
h
alf the 
t
ime
More 
t
han 
h
alf 
the 
t
ime
Almost 
Always
1.
  
O
ver the past month, how often have you had a 
 
sensation of not emptying your bladder completely 
after you finish urinating?
0
1
2
3
4
5
2.
  
O
ver the past month, how often have you had to
 
urinate again less than 2 hours after you finished 
urinating?
0
1
2
3
4
5
3.
  
O
ver the past month, how often have you found you 
stopped and started again several times when you 
urinated?
0
1
2
3
4
5
4.
  
O
ver the past month, how often have you found it 
 
difficult to postpone urination?
0
1
2
3
4
5
5.
  
O
ver the past month, how often have you had a weak 
urinary stream?
0
1
2
3
4
5
6.
  
O
ver the past month, how often have you had to push 
or strain to begin urination?
0
1
2
3
4
5
7.
  
O
ver the past month, how many times did you most 
typically get up to urinate from the time you went to 
bed at night until the time you got up in the morning?
0
1
2
3
4
5
1
Sum of seven circled numbers equals the symptom score. See text for explanation.
Reproduced, with permission, from Barry MJ et al. The American Urological Association symptom index for benign prostatic hyperplasia.

Reproduced, with permission, from Barry MJ et al. The American Urological Association symptom index for benign prostatic hyperplasia. 
 
J Urol. 1992 Nov;148(5):1549–57.
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have many of the same symptoms and signs as those with 
benign prostatic hyperplasia; however, a history of neuro
-
logic disease, stroke, diabetes mellitus, or back injury may 
be obtained, and diminished perineal or lower extremity 
sensation or alterations in rectal sphincter tone or the 
bulbocavernosus reflex might be observed on examina
-
tion. Simultaneous alterations in bowel function (consti
-
pation) might also suggest the possibility of a neurologic 
disorder.
 
»
Treatment
Clinical practice guidelines exist for the evaluation and 
treatment of patients with benign prostatic hyperplasia 
(Figure 23–2). Following evaluation as outlined above, 
patients should be offered various forms of therapy for 
benign prostatic hyperplasia. Patients are advised to con
-
sult with their primary care clinicians and make an educated 
decision on the basis of the relative efficacy and side 
effects of the treatment options (Table 23–4).
Patients with mild symptoms (AUA scores 0–7) should 
be managed by watchful waiting only. Medical therapy 
is appropriate for many others. Absolute surgical indica
-
tions include refractory urinary retention (failing at least 
one attempt at catheter removal), large bladder divertic
-
ula, or any of the following sequelae of benign prostatic 
hyperplasia: recurrent urinary tract infection, recurrent 
gross hematuria, bladder stones, or chronic kidney 
disease.
A. Watchful Waiting
The risk of progression or complications is uncertain. 
However, in men with symptomatic disease, it is clear 
that progression is not inevitable and that some men 
undergo spontaneous improvement or resolution of their 
symptoms.
Retrospective studies on the natural history of benign 
prostatic hyperplasia are inherently subject to bias, relating 
in part to patient selection and also to the type and extent 
of follow-up. Very few prospective studies addressing the 
natural history have been reported. One small series dem
-
onstrated that approximately 10% of symptomatic men 
may progress to urinary retention while 50% of patients 
 
Pr
esence of
 
Refractory 
re
tention
Any of the following, clear
ly
 secondary 
to
 BPH:
  • R
ecurrent urinary tract infection
  • R
ecurrent or persist
ent gr
oss hematuria
  • Bladder st
ones
  • Kidne
y disease
          
• Hist
ory
• Ph
ysical 
ex
amination and DRE
• Ur
ina
ly
sis
• Cr
eatinine
• PS
A (optional)
Quantitative symptom assessment
Mild
Moderate 
to
 se
ve
re
Offer treatment alternatives
Watchful
waiting
Open surgery:
TUIP
, 
TURP
,
TUNA, HoLEP
,
etc.
Medical
therapy
Option f
or cy
stourethroscop
y or sonograph
y
if important in planning operative approach
Sur
gery
Optional diagnostic tests
based on clinician and patient preference
• Flo
w ra
te
• R
esidual urine
• 
Pr
essure 
flow
Ye
s
C
ompatible
with obstruction?
No
Non-BPH pr
oblems
identified and treated
 Initial 
ev
aluation
1
3
45
6
7
8
9
2
 
▲
Figure 23–2.
 
Benign prostatic hyperplasia decision diagram. 
BPH, benign prostatic hyperplasia; DRE, digital rectal 
examination; HoLEP , Holmium laser enucleation of the prostate; PSA, prostate-specific antigen; TUIP , transurethral incision 
of the prostate; TUNA, transurethral needle ablation; TURP , transurethral resection of the prostate.
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demonstrate marked improvement or resolution of symp
-
toms. A large randomized study compared finasteride with 
placebo in men with moderate to severely symptomatic 
disease and enlarged prostates on DRE. Patients in the 
placebo arm demonstrated a 7% risk of developing urinary 
retention over 4 years.
Men with moderate or severe symptoms can also be 
observed if they so choose. The optimal interval for 
follow-up is not defined, nor are the specific end points 
for intervention.
B. Medical Therapy
1. Alpha-blockers—
Alpha-blockers can be classified 
according to their receptor selectivity as well as their 
half-life (Table 23–5).
Table 23–4.
 
Summary of benign prostatic hyperplasia treatment outcomes.
1
Outcome
t
UI
p
Open 
Surgery
t
UR
p
Watchful 
Waiting
Alpha-
Blockers
2
Chance for improvement
1
78–83%
94–99.8%
75–96%
31–55%
59–86%
54–78%
Degree of symptom improvement 
 
(% reduction in symptom score)
73%
79%
85%
Unknown
51%
31%
Morbidity and complications
1
2.2–33.3%
7–42.7%
5.2–30.7%
1–5%
2.9–43.3%
13.6–8.8%
Death within 30–90 days
1
0.2–1.5%
1–4.6%
0.5–3.3%
0.8%
0.8%
0.8%
Total incontinence
1
0.1–1.1%
0.3–0.7%
0.7–1.4%
2%
2%
2%
Need for operative treatment for surgical 
1
1.3–2.7%
0.6–14.1%
0.7–10.1%
0
0
0
Erectile dysfunction
1
3.9–24.5%
4.7–39.2%
3.3–34.8%
3%
3%
2.5–5.3%
Retrograde ejaculation
6–55%
36–95%
25–99%
0
4–11%
0
Loss of work in days
7–21
21–28
7–21
1
3.5
1.5
Hospital stay in days
1–3
5–10
3–5
0
0
0
1
90% confidence interval.
2
Most of the data reviewed for finasteride are derived from three trials that have required an enlarged prostate for entry. The chance of 
improvement in men with symptoms yet minimally enlarged prostates may be much less, as noted from the VA Cooperative Trial.
TUIP , transurethral incision of the prostate; TURP , transurethral resection of the prostate.
Table 23–5.
 
Alpha-blockade for benign prostatic 
Agent
Action
Oral Dose
Alfuzosin
Alpha-1a-blockade
10 mg daily
Doxazosin
Alpha-1-blockade
1–8 mg daily
Prazosin
1–5 mg twice daily
Terazosin
1–10 mg daily
Silodosin
4 or 8 mg daily
Tamsulosin
0.4 or 0.8 mg daily
Tadalafil
Phosphodiesterase type 
5 inhibitor
5 mg daily
Prazosin is effective; however, it requires dose titration 
and twice daily dosing. Typical side effects include ortho
-
static hypotension, dizziness, tiredness, retrograde ejacu
-
lation, rhinitis, and headache.
Long-acting alpha-blockers allow for once-a-day dosing, 
but dose titration is still necessary because side effects 
similar to those seen with prazosin may occur. Terazosin 
improves symptoms and in numerous studies is superior to 
placebo or finasteride. Terazosin is started at a dosage of 
 
1 mg orally daily for 3 days, increased to 2 mg orally daily 
for 11 days, then 5 mg orally daily. Additional dose escala
-
tion to 10 mg orally daily can be performed if necessary. 
Doxazosin is started at a dosage of 1 mg orally daily for 
 
7 days, increased to 2 mg orally daily for 7 days, then 4 mg 
orally daily. Additional dose escalation to 8 mg orally daily 
can be performed if necessary.
Alpha-1a-receptors are localized to the prostate and 
bladder neck. Selective blockade of these receptors results 
in fewer systemic side effects than alpha-blocker therapy 
(orthostatic hypotension, dizziness, tiredness, rhinitis, and 
headache), thus obviating the need for dose titration. The 
typical dose of tamsulosin is 0.4 mg orally daily taken 
 
30 minutes after a meal. Alfuzosin is a long-acting alpha-
1a-blocker; its dose is 10 mg orally once daily with food 
and does not require titration. Several randomized, dou
-
ble-blind, placebo-controlled trials have been performed 
comparing terazosin, doxazosin, tamsulosin, and alfuzosin 
with placebo. All agents have demonstrated safety and effi
-
cacy. Floppy iris syndrome, a complication of cataract sur
-

-
-
gery, can occur in patients taking alpha-blockers and 
alpha-1a-blockers.
2. 5-alpha-reductase inhibitors—
Finasteride is a 5-alpha-
reductase inhibitor that blocks the conversion of 
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testosterone to dihydrotestosterone. This medication 
impacts upon the epithelial component of the prostate, 
resulting in reduction in size of the gland and improve
-
ment in symptoms. Six months of therapy is required for 
maximum effects on prostate size (20% reduction) and 
symptomatic improvement.
Several randomized, double-blind, placebo-controlled 
trials have been performed comparing finasteride with 
placebo. Efficacy, safety, and durability are well estab
-
lished. However, symptomatic improvement is seen only 
in men with enlarged prostates (greater than 40 mL by 
ultrasonographic examination). Side effects include 
decreased libido, decrease in volume of ejaculate, and 
erectile dysfunction. Serum PSA is reduced by approxi
-
mately 50% in patients receiving finasteride therapy. 
Therefore, in order to compare with pre-finasteride levels, 
the serum PSA of a patient taking finasteride should be 
doubled.
A report suggests that finasteride therapy may 
decrease the incidence of urinary retention and the need 
for operative treatment in men with enlarged prostates 
and moderate to severe symptoms. The larger the pros
-
tate over 40 mL, the greater the relative-risk reduction. 
However, optimal identification of appropriate patients 
for prophylactic therapy remains to be determined. 
Dutasteride is a dual 5-alpha-reductase inhibitor that 
appears to be similar to finasteride in its effectiveness; its 
dose is 0.5 mg orally daily.
Both finasteride and dutasteride have been shown to be 
effective chemopreventive agents for prostate cancer in 
large, randomized clinical trials. The 25% risk reduction 
was observed in men with both low and high risk for pros
-
tate cancer. However, despite the strength of the evidence 
for 5-alpha-reductase inhibitors in reducing the risk of 
prostate cancer, an FDA advisory committee recommended 
against labeling these agents for prostate cancer chemopre
-
vention, citing the potential increased risk of high-grade 
tumors in these studies (1.8% vs 1.0% for finasteride and 
1% vs 0.5% for dutasteride), isolated risk reduction in low-
grade tumors, and inability to apply the findings to the general 
population. Moreover, the FDA has included the increased 
risk of being diagnosed with high-grade prostate cancer in the 
labels of all 5-alpha-reductase inhibitors.
3. Phosphodiesterase-5 inhibitor—
Tadalafil is approved 
by the FDA to treat the signs and symptoms of benign pros
-
tatic hyperplasia; it is also approved for use in men with 
both urinary symptoms and erectile dysfunction. The data 
from two randomized, double-blind, placebo-controlled 
trials demonstrated significant improvements in standard
-
ized measurements of urinary function between 2 and 
 
4 weeks after initiating treatment at 5 mg once daily, with 
minimal adverse effects.
4. Combination therapy—
The Medical Therapy of Pros
-
tatic Symptoms (MTOPS) trial was a large, randomized, 
placebo-controlled trial comparing finasteride, doxazosin, 
the combination of the two, and placebo in 3047 men 
observed for a mean of 4.5 years. Long-term combination 
therapy with doxazosin and finasteride was safe and 
reduced the risk of overall clinical progression of benign 
prostatic hyperplasia significantly more than did treatment 
with either medication alone. Combination therapy and 
finasteride alone reduced the long-term risk of acute 
urinary retention and the need for invasive therapy. Com
-
bination therapy had the risks of additional side effects and 
the cost of two medications.
5. Phytotherapy—
Phytotherapy is the use of plants or 
plant extracts for medicinal purposes. Several plant extracts 
have been popularized, including the saw palmetto berry, 
the bark of 
Pygeum africanum
, the roots of 
Echinacea pur
-
purea
 and 
Hypoxis rooperi
, pollen extract, and the leaves of 
the trembling poplar. However, a prospective, randomized,

the bark of 
-
purea
 and 
the trembling poplar. However, a prospective, randomized, 
double-blind, placebo-controlled trial revealed no improve
-
ment in symptoms, urinary flow rate, or quality of life for 
men with benign prostatic hyperplasia with saw palmetto 
treatment compared with placebo.
C. Conventional Surgical Therapy
1. Transurethral resection of the prostate (TURP)—
Ninety-five percent of simple prostatectomies can be 
performed endoscopically (TURP). Most of these proce
-
dures are performed under a spinal anesthetic and require 
a 1- to 2-day hospital stay. Symptom scores and flow rate 
improvement are superior following TURP relative to any 
minimally invasive therapy; however, the length of the 
hospital stay is greater. Much controversy revolves around 
possible higher rates of morbidity and mortality associated 
with TURP in comparison with open surgery, but the 
higher rates observed in one study probably related to 
more significant comorbidities in the TURP patients com
-
pared with the patients who received open surgical treat
-
ment. Several other studies could not confirm the difference 
in mortality when controlling for age and comorbidities. 
The risks of TURP include retrograde ejaculation (75%), 
erectile dysfunction (5–10%), and urinary incontinence 
(less than 1%). Potential complications include (1) bleed
-
ing; (2) urethral stricture or bladder neck contracture; 
(3) perforation of the prostate capsule with extravasation; 
and (4) transurethral resection syndrome, a hypervolemic, 
hyponatremic state resulting from absorption of the hypo
-
tonic irrigating solution. Clinical manifestations of the 
syndrome include nausea, vomiting, confusion, hyperten
-
sion, bradycardia, and visual disturbances. The risk of trans
-
urethral resection syndrome increases with resection times 
over 90 minutes. Treatment includes diuresis and, in severe 
cases, hypertonic saline administration (see Hyponatremia, 
Chapter 21).
2. Transurethral incision of the prostate (TUIP)—
Men 
with moderate to severe symptoms and small prostates 
often have posterior commissure hyperplasia or an “ele
-
vated bladder neck. ” These patients will often benefit from 
incision of the prostate. The procedure is more rapid and 
less morbid than TURP . Outcomes in well-selected patients 
are comparable, though a lower rate of retrograde ejaculation 
has been reported (25%).
3. Open simple prostatectomy—
When the prostate is too 
large to remove endoscopically, open enucleation is neces
-
sary. What size is “too large” depends upon the surgeon’s 
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experience with TURP . Glands over 100 g are usually consid
-
ered for open enucleation. In addition to size, other relative 
indications for open prostatectomy include concomitant 
bladder diverticulum or bladder stone and whether dorsal 
lithotomy positioning is or is not possible.
Open prostatectomies can be performed with either a 
suprapubic or retropubic approach. Simple suprapubic 
prostatectomy is performed transvesically and is the opera
-
tion of choice if there is concomitant bladder pathology. 
After the prostatic adenoma is removed, both a urethral 
and a suprapubic catheter are inserted prior to closure. In 
simple retropubic prostatectomy, the bladder is not entered 
but rather a transverse incision is made in the surgical 
capsule of the prostate and the adenoma is enucleated as 
described above; only a urethral catheter is needed at the 
end of the case. These operations can also be performed via 
robotic-assisted laparoscopic techniques although long-term 
results are lacking.
D. Minimally Invasive Therapy
1. Laser therapy—
Several coagulation necrosis techniques 
have been utilized. Transurethral laser-induced prostatec
-
tomy (TULIP) is performed under transrectal ultrasound 
guidance. The instrument is placed in the urethra and 
transrectal ultrasound is used to direct the device as it is 
slowly pulled from the bladder neck to the apex. The depth 
of treatment is monitored with ultrasound.
Most urologists prefer to use visually directed laser 
techniques. Visual coagulative necrosis is performed under 
cystoscopic control, and the laser fiber is pulled through 
the prostate at several designated areas depending on the 
size and configuration of the gland. Coagulative techniques 
do not create an immediate visual defect in the prostatic 
urethra—tissue is sloughed over the course of several 
weeks up to 3 months following the procedure.
Visual contact ablative techniques take longer in the 
operating room because the laser fiber is placed in direct 
contact with the prostate tissue, which is vaporized. Photo
-
vaporization of the prostate (PVP), an alternative laser 
technique, uses a high-power KTP laser. An immediate 
defect is obtained in the prostatic urethra, similar to that 
seen during TURP .
Interstitial laser therapy places laser fibers directly into 
the prostate, usually under cystoscopic control. Irritative 
voiding symptoms may be less in these patients as the ure
-
thral mucosa is spared and prostate tissue is resorbed by 
the body rather than sloughed.
Holmium laser enucleation of the prostate (HoLEP) 
is a technique of enucleating the adenomatous lobes 
intact and morcellating the tissue within the bladder. 
Advantages of HoLEP compared with other methods 
include ability to treat all prostate sizes, low re-treatment 
rates, few complications, and shorter duration of 
Advantages to laser surgery include minimal blood loss, 
rarity of transurethral resection syndrome, ability to treat 
patients during anticoagulant therapy, and outpatient sur
-
gery. Disadvantages are the lack of tissue for pathologic 
examination, longer postoperative catheterization time, 
more frequent irritative voiding complaints, and expense 
of laser fibers and generators.
Large multicenter, randomized studies with long-term 
follow-up are needed to compare laser prostate surgery 
with TURP and other forms of minimally invasive 
surgery.
2. Transurethral needle ablation of the prostate (TUNA)—
This procedure uses a specially designed urethral catheter 
that is passed into the urethra. Interstitial radiofrequency 
needles are then deployed from the tip of the catheter, 
piercing the mucosa of the prostatic urethra. Radiofre
-
quencies are then used to heat the tissue, resulting in 
coagulative necrosis. Subjective and objective improve
-
ment in voiding occurs. In randomized trials comparing 
TUNA to TURP , similar improvement was seen when

-
TUNA to TURP , similar improvement was seen when 
comparing life scores, peak urinary flow rates, and post
-
void residual urine. Bladder neck and median lobe enlarge
-
ment are not well treated by TUNA. A technique was 
approved by the FDA in 2015 which delivers the radiofre
-
quency energy through water vapor.
3. Transurethral electrovaporization of the prostate—
This technique uses the standard resectoscope. High cur
-
rent densities result in heat vaporization of tissue, creating 
a cavity in the prostatic urethra. This procedure usually 
takes longer than a standard TURP . Long-term comparative 
data are needed.
4. Hyperthermia—
Microwave hyperthermia is most com
-
monly delivered with a transurethral catheter. Some 
devices cool the urethral mucosa to decrease the risk of 
injury. However, if temperatures do not go above 45°C, 
cooling is unnecessary. Symptom score and flow rate 
improvement are obtained, but (as with laser surgery) large 
randomized studies with long-term follow-up are needed 
to assess durability and cost-effectiveness.
5. Implant to open prostatic urethra—
A minimally 
invasive, FDA-approved implant can be used to retract 
the enlarged lobes of the prostate in symptomatic men 
50 years and older with an enlarged prostate. Data from 
trials suggest that the technique improved symptoms 
and voiding flow while having minimal impact on 
ejaculation.
 
»
•	
Progression to urinary retention.
•	
Patient dissatisfaction with medical therapy.
•	
Need for surgical intervention or further evaluation 
(cystoscopy).
Barry MJ et al; Measurement Committee of the American Uro
-
logical Association. The American Urological Association 
symptom index for benign prostatic hyperplasia. J Urol. 
2017 Feb;197(2S):S189–97. [PMID: 28012747]
Homma Y et al. Clinical guidelines for male lower urinary 
tract symptoms and benign prostatic hyperplasia. Int J Urol. 
2017 Oct;24(10):716–29. [PMID: 28748576]
Huang W et al. Risk factors for bladder calculi in patients 
with benign prostatic hyperplasia. Medicine (Baltimore). 
2017 Aug;96(32):e7728. [PMID: 28796057]
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Kim EH et al. Management of benign prostatic hyperplasia. 
Annu Rev Med. 2016;67:137–51. [PMID: 26331999]
McVary KT et al. Three-year outcomes of the prospective, random
-
ized controlled Rezüm System study: convective radiofrequency 
thermal therapy for treatment of lower urinary tract symptoms 
due to benign prostatic hyperplasia. Urology. 2018 Jan;111:1–9. 
[PMID: 29122620]
Primiceri G et al. Bladder neck contracture after endoscopic surgery 
for benign prostatic obstruction: incidence, treatment, and out
-
comes. Curr Urol Rep. 2017 Aug 9;18(10):79. [PMID: 28795367]
Singapore Urological Association Male Lower Urinary Tract 
Symptoms/Benign Prostatic Hyperplasia Guidelines Commit
-
tee 2015. Singapore Urological Association clinical guidelines 
for male lower urinary tract symptoms/benign prostatic 
hyperplasia. Singapore Med J. 2017 Aug;58(8):473–80. [PMID: 
28848988]
Thomas D et al. Emerging drugs for the treatment of benign 
prostatic hyperplasia. Expert Opin Emerg Drugs. 2017 Sep;
 
22(3):201–12. [PMID: 28829208]
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HEADACHE
Headache is such a common complaint and can occur for 
so many different reasons that its proper evaluation may 
be difficult. New, severe, or acute headaches are more 
likely than chronic headaches to relate to an intracranial 
disorder; the approach to such headaches is discussed 
in Chapter 2. 
Chronic headaches
 may be primary or 
 
secondary to another disorder. Common 
primary
 head
-
ache syndromes include migraine, tension-type headache, 
and cluster headache. Important 
secondary
 causes to 
consider include intracranial lesions, head injury, cervical 
spondylosis, dental or ocular disease, temporomandibular 
joint dysfunction, sinusitis, hypertension, depression, and 
a wide variety of general medical disorders. Although 
underlying structural lesions are not present in most 
patients presenting with headache, it is nevertheless impor
-
tant to bear this possibility in mind. About one-third of 
patients with brain tumors, for example, present with a 
primary complaint of headache.
1. Migraine
 
»
Headache, usually pulsatile, lasting 4–72 hours.
 
»
Pain is typically, but not always, unilateral.
 
»
Nausea, vomiting, photophobia, and phonophobia 
are common accompaniments.
 
»
Pain is aggravated with routine physical activity.
 
»
An aura of transient neurologic symptoms 
 
(commonly visual) may precede head pain.
 
»
Commonly, head pain occurs with no aura.
 
»
The pathophysiology of migraine probably relates to neu
-
ronal dysfunction in the trigeminal system resulting in 
release of vasoactive neuropeptides such as calcitonin 
gene-related peptide leading to neurogenic inflammation, 
sensitization, and headache. Migraine aura is hypothesized 
to result from cortical spreading depression, a wave of neu
-
ronal and glial depolarization that moves slowly across the 
cerebral cortex corresponding to the clinical symptoms 
(ie, occipital cortex and visual aura). Migraine often exhib
-
its a complex, polygenic pattern of inheritance. Sometimes, 
an autosomal dominant inheritance pattern is apparent, as 
in 
familial hemiplegic migraine
 
(FHM),
 in which attacks 
of lateralized weakness represent the aura.
 
»
Typical migrainous headache is a lateralized throbbing 
headache that occurs episodically following its onset in 
adolescence or early adult life. In many cases, the head
-
aches do not conform to this pattern, although their associ
-
ated features and response to antimigrainous preparations 
nevertheless suggest a similar basis. In this broader sense, 
migrainous headaches may be lateralized or generalized, 
may be dull or throbbing, and are sometimes associated 
with anorexia, nausea, vomiting, photophobia, phonopho
-
bia, osmophobia, cognitive impairment, and blurring of 
vision. They usually build up gradually and last several 
hours or longer. Focal disturbances of neurologic function 
(
migraine aura
) may precede or accompany the head
-
aches. Visual disturbances occur commonly and may con
-
sist of field defects (
scotoma
); of luminous visual 
hallucinations such as stars, sparks, unformed light flashes 
(
photopsia
), geometric patterns, or zigzags of light; or of 
some combination of field defects and luminous hallucina
-
tions (
scintillating scotomas
). Other focal disturbances 
such as aphasia or numbness, paresthesias, clumsiness, 
dysarthria, dysequilibrium, or weakness in a circumscribed 
distribution may also occur.
In rare instances, the neurologic or somatic disturbance 
accompanying typical migrainous headaches becomes the 
sole manifestation of an attack (“
migraine equivalent
”). 
Very rarely, the patient may be left with a permanent neu
-
rologic deficit following a migrainous attack, and migraine 
with aura may be a risk factor for stroke.
Patients often give a family history of migraine. Attacks 
may be triggered by emotional or physical stress, lack or

may be triggered by emotional or physical stress, lack or 
excess of sleep, missed meals, specific foods (eg, chocolate), 24
Nervous System Disorders
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CMDT 2019
alcoholic beverages, bright lights, loud noise, menstrua
-
tion, or use of oral contraceptives.
An uncommon variant is 
basilar artery migraine,
 in 
which blindness or visual disturbances throughout both 
visual fields are initially accompanied or followed by dysar
-
thria, dysequilibrium, tinnitus, and perioral and distal 
paresthesias and are sometimes followed by transient loss 
or impairment of consciousness or by a confusional state. 
This, in turn, is followed by a throbbing (usually occipital) 
headache, often with nausea and vomiting.
In 
ophthalmoplegic migraine,
 lateralized pain—often 
about the eye—is accompanied by nausea, vomiting, and 
diplopia due to transient external ophthalmoplegia. The 
ophthalmoplegia is due to third nerve palsy, sometimes 
with accompanying sixth nerve involvement, and may out
-
last the orbital pain by several days or even weeks. The 
ophthalmic division of the fifth nerve has also been 
affected in some patients. Ophthalmoplegic migraine is 
rare and a diagnosis of exclusion; more common causes of 
a painful ophthalmoplegia are internal carotid artery aneu
-
rysms and diabetes.
 
»
Treatment
Management of migraine consists of avoidance of any pre
-
cipitating factors, together with prophylactic or symptom
-
atic pharmacologic treatment if necessary.
A. Symptomatic Therapy
During acute attacks, rest in a quiet, darkened room may 
be helpful until symptoms subside. A simple analgesic (eg, 
aspirin, acetaminophen, ibuprofen, or naproxen) taken 
immediately often provides relief, but prescription medica
-
tion is sometimes necessary. 
To prevent medication overuse, 
use of simple analgesics should be limited to 15 days or less 
per month, and combination analgesics should be limited to 
no more than 10 days per month
.
1. Ergotamines—
Cafergot, a combination of ergotamine 
tartrate (1 mg) and caffeine (100 mg), is often particularly 
helpful; one or two tablets are taken at the onset of head
-
ache or warning symptoms, followed by one tablet every 
30 minutes, if necessary, up to six tablets per attack and no 
more than 10 days per month. Cafergot given rectally (one-
half to one suppository containing 2 mg of ergotamine) or 
dihydroergotamine mesylate (0.5–1 mg intravenously or 
1–2 mg subcutaneously or intramuscularly) may be useful 
when vomiting precludes use of oral medications. Ergota
-
mine-containing preparations should be avoided during 
pregnancy, in patients with cardiovascular disease or its 
risk factors, and in patients taking potent CYP 3A4 
2. Triptans—
The triptans are 5-HT
1
 receptor agonists that 
inhibit release of vasoactive neuropeptides. Sumatriptan is 
a rapidly effective agent for aborting attacks when given 
subcutaneously by an autoinjection device (4–6 mg once 
subcutaneously, may repeat once after 2 hours if needed; 
maximum dose 12 mg/24 h). Nasal and oral preparations 
are available but may be less effective due to slower absorp
-
tion. Zolmitriptan is available in oral and nasal 
formulations. The dose is 5 mg orally or in one nostril 
once; this may be repeated once after 2 hours. The maxi
-
mum dose for both formulations is 10 mg/24 h. Other 
triptans are available, including rizatriptan (5–10 mg orally 
at onset, may repeat every 2 hours twice [maximum dose 
30 mg/24 h]); naratriptan (1–2.5 mg orally at onset, may 
repeat once after 4 hours [maximum dose 5 mg/24 h]); 
almotriptan (6.25–12.5 mg orally at onset, may repeat dose 
once after 2 hours [maximum dose 25 mg/24 h]); frovatrip
-
tan (2.5 mg orally at onset, may repeat after 2 hours once 
[maximum dose 7.5 mg/24]); and eletriptan (20–40 mg 
orally at onset; may repeat after 2 hours once [maximum 
dose 80 mg/24 h]). Eletriptan is useful for immediate 
therapy and frovatriptan, which has a longer half-life, may 
be worthwhile for patients with prolonged attacks or 
attacks provoked by menstrual periods. Patients often

attacks provoked by menstrual periods. Patients often 
experience greater benefit when the triptan is combined 
with naproxen (500 mg orally).
Triptans may cause nausea and vomiting. They should 
probably be avoided in women who are pregnant, and in 
patients with hemiplegic or basilar migraine, a history of 
stroke or transient ischemic attack (TIA), or uncontrolled 
hypertension. In patients whose hypertension is controlled, 
triptans are commonly used safely although caution is 
advised. Triptans are contraindicated in patients with coro
-
nary or peripheral vascular disease and Prinzmetal angina.
3. Other agents—
Prochlorperazine is effective and may be 
administered rectally (25 mg suppository), intravenously 
or intramuscularly (5–10 mg), or orally (5–10 mg). Intrave
-
nous metoclopramide (10–20 mg) or chlorpromazine 
(25–50 mg) is also particularly useful in the emergency 
department setting. Various butalbital-containing combi
-
nation oral analgesics risk overuse and dependence and 
should only be used as a last resort. Opioid analgesics 
should be avoided because of high rates of rebound head
-
ache and the tendency to develop medication overuse 
headache.
4. Neuromodulation—
Transcranial magnetic stimulation 
was effective in aborting migraine with aura in one sham-
controlled trial; a handheld device is approved in the 
United States and Europe but is costly.
B. Preventive Therapy
Preventive treatment may be necessary if migraine head
-
aches occur more frequently than two or three times a 
month or significant disability is associated with attacks. 
Avoidance of triggers and maintenance of homeostasis 
with regular sleep, meals, and hydration should not be 
neglected; a headache diary may be useful to identify trig
-
gers. Some more common agents used for prophylaxis are 
listed in Table 24–1. The medication chosen first will vary 
with the individual patient, depending on factors such as 
comorbid obesity, depression, anxiety, hypertension, and 
patient preference. Several medications may have to be 
tried in turn before headaches are brought under control. 
Once a medication has been found to help, it should be 
continued for several months. If the patient remains head
-
ache-free, the dose may be tapered and the medication 
eventually withdrawn. Acupuncture is as effective as 
CMDT19_Ch24_p0990-p1062.indd   991

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TER
 2
4
992
 CMDT 2019
prophylactic pharmacologic treatment, and botulinum 
toxin type A reduces headache frequency in chronic 
migraine (at least 15 days per month with headaches last
-
ing 4 hours per day or longer). Some neurostimulation 
techniques look promising, including transcranical direct 
current stimulation, vagal and other cranial nerve stimula
-
tors, and implantable occipital nerve stimulation, but criti
-
cal appraisal is necessary. Blockade of calcitonin 
gene-related peptide signaling by a receptor antagonist or 
monoclonal antibody looks promising.
2. Tension-Type 
h
eadache
This is the most common type of primary headache disor
-
der. Patients frequently complain of pericranial tenderness, 
poor concentration, and other nonspecific symptoms, in 
addition to constant daily headaches that are often vise-like 
or tight in quality but not pulsatile. Headaches may be 
exacerbated by emotional stress, fatigue, noise, or glare. 
The headaches are usually generalized, may be most 
intense about the neck or back of the head, and are not 
associated with focal neurologic symptoms. There is diag
-
nostic overlap with migraine.
The therapeutic approach is similar to that in migraine, 
except that triptans are not indicated. Treatment of comor
-
bid anxiety or depression is important. Behavioral thera
-
pies that may be effective include biofeedback and 
relaxation training.
3. Cluster 
h
eadache
Cluster headache affects predominantly middle-aged men. 
The pathophysiology is unclear but may relate to activation 
of cells in the ipsilateral hypothalamus, triggering the tri
-
geminal autonomic vascular system. There is often no fam
-
ily history of headache or migraine. Episodes of severe 
unilateral periorbital pain occur daily for several weeks and 
are often accompanied by one or more of the following: 
ipsilateral nasal congestion, rhinorrhea, lacrimation, red
-
ness of the eye, and Horner syndrome (ptosis, pupillary 
meiosis, and facial anhidrosis or hypohidrosis). During 
attacks, patients are often restless and agitated. Episodes 
typically occur at night, awaken the patient, and last 
between 15 minutes and 3 hours. Spontaneous remission 
then occurs, and the patient remains well for weeks or 
months before another bout of closely spaced attacks. 
Table 24–1.
 
Pharmacologic prophylaxis of migraine (listed in alphabetical order within classes).
Usual 
a
dult O
ral Daily Dose
Selected Side Effects and Comments
a
n
tiepileptic
1
100 mg (divided twice daily)
Somnolence, nausea, dyspepsia, irritability, dizziness, ataxia, nystagmus, diplopia, 
glaucoma, renal calculi, weight loss, hypohidrosis, hyperthermia.
2,3
500–1000 mg (divided 
twice daily)
Nausea, vomiting, diarrhea, drowsiness, alopecia, weight gain, hepatotoxicity, 
thrombocytopenia, tremor, pancreatitis.
Cardiovascular
3
8–32 mg once daily
Dizziness, cough, diarrhea, fatigue.
Dry mouth, somnolence, dizziness, constipation, erectile dysfunction.
4
80–240 mg (divided twice to 
four times daily)
Fatigue, dizziness, hypotension, bradycardia, depression, insomnia, nausea, 
 
vomiting, constipation.
Verapamil
5
120–240 mg (divided three 
times daily)
Headache, hypotension, flushing, edema, constipation. May aggravate 
 
atrioventricular nodal heart block and heart failure.
a
n
tidepressant
6
7
10–150 mg at bedtime
Sedation, dry mouth, constipation, weight gain, blurred vision, edema, 
 
hypotension, urinary retention.
37.5–150 mg extended 
release once daily
Nausea, somnolence, dry mouth, dizziness, diaphoresis, sexual dysfunction, 
 
anxiety, weight loss.
Other
Acupuncture
 
More rapid pain relief and fewer side effects than pharmacologic treatment.
Botulinum toxin A
Intramuscular injection
Injection site reaction, hypersensitivity, muscle weakness.
Riboflavin
400 mg once daily
Yellow-orange discoloration of urine
1

1
Gabapentin and possibly other antiepileptics have also been used successfully.
2
Avoid during pregnancy.
3
Not FDA-approved for this indication.
4
Other beta-adrenergic antagonists such as atenolol, metoprolol, nadolol, and timolol are similarly effective.
5
Other calcium channel antagonists (eg, nimodipine, nicardipine, and diltiazem) may also help.
6
Depression is commonly comorbid with migraine disorder and may warrant separate treatment.
7
Other tricyclic antidepressants (eg, nortriptyline and imipramine) may help similarly.
CMDT19_Ch24_p0990-p1062.indd   992

993
 
CMDT 2019
Bouts may last for 4 to 8 weeks and may occur up to several 
times per year. During a bout, many patients report alcohol 
triggers an attack; others report that stress, glare, or inges
-
tion of specific foods occasionally precipitates attacks. In 
occasional patients, remission does not occur. This variant 
has been referred to as 
chronic cluster headache
. In long
-
standing cases, Horner syndrome may persist between 
attacks.
Cluster headache is one of the 
trigeminal autonomic 
cephalgias
, which include hemicrania continua, paroxys
-
mal hemicranias, and short-lasting neuralgiform head
-
ache attacks with conjunctival injection and tearing. 
Similar to cluster headache, the other trigeminal auto
-
nomic cephalgias consist of unilateral periorbital pain 
associated with ipsilateral autonomic symptoms; they are 
distinguished from cluster headache by different attack 
duration and frequency and their exquisite responsiveness 
to indomethacin.
Treatment of an individual attack with oral medications 
is generally unsatisfactory, but subcutaneous (6 mg dose) 
or intranasal (20 mg/spray) sumatriptan or inhalation of 
100% oxygen (12–15 L/min for 15 minutes via a non-
rebreather mask) may be effective. Zolmitriptan (5- and 
10-mg nasal spray) is also effective. Dihydroergotamine 
(0.5–1 mg intramuscularly or intravenously) or viscous 
lidocaine (1 mg of 4–6% solution intranasally) is some
-
times effective.
Various prophylactic agents include oral medications 
such as lithium carbonate (start at 300 mg daily, titrating 
according to serum levels and treatment response up to a 
typical total daily dose of 900–1200 mg, divided three or 
four times), verapamil (start at 240 mg daily, increase by 
80 mg every 2 weeks to 960 mg daily, with routine ECG to 
monitor the PR interval), topiramate (100–400 mg daily), 
and civamide (not available in the United States). As there 
is often a delay before these medications are effective, tran
-
sitional therapy is often used. Prednisone (60 mg daily for 
5 days followed by gradual withdrawal over 7–10 days) is 
effective in 70–80% of patients, and suboccipital cortico
-
steroid injection about the greater occipital nerve is effec
-
tive in 75%. Ergotamine tartrate can be given as rectal 
suppositories (0.5–1 mg at night or twice daily), by mouth 
(2 mg daily), or by subcutaneous injection (0.25 mg three 
times daily for 5 days per week). As in migraine, limited 
evidence suggests that electrical stimulation of the occipital 
nerve by an implantable device may be helpful, especially 
in chronic cluster headache.
4. 
p
osttr
aumatic 
h
eadache
A variety of nonspecific symptoms may follow closed head 
injury, regardless of whether consciousness is lost (see 
Head Injury). Headache is often a conspicuous feature. It 
usually appears within a day or so following injury, may 
worsen over the ensuing weeks, and then gradually sub
-
sides. It is usually a constant dull ache, with superimposed 
throbbing that may be localized, lateralized, or generalized. 
Headaches are sometimes accompanied by nausea, vomit
-
ing, or scintillating scotomas and often respond to simple 
analgesics; severe headaches may necessitate preventive 
treatment as outlined for migraine.
5. 
p
rimar
y Cough 
h
eadache
Severe head pain may be produced by coughing (and by 
straining, sneezing, and laughing) but, fortunately, usually 
lasts for only a few minutes or less. Intracranial lesions, 
usually in the posterior fossa (eg, Arnold-Chiari malforma
-
tion), are present in about 10% of cases, and brain tumors 
or other space-occupying lesions may present in this way. 
Accordingly, CT scanning or MRI should be undertaken in 
all patients.
The disorder is usually self-limited, although it may 
persist for several years. For unknown reasons, symptoms 
sometimes clear completely after lumbar puncture. Indo
-
methacin (75–150 mg daily orally) may provide relief.

-
methacin (75–150 mg daily orally) may provide relief. 
Similar activity-triggered headache syndromes include 
primary exertional headache and primary headache asso
-
ciated with sexual activity.
6. 
h
eadache Due to Giant Cell (Temporal 
or Cranial) 
a
r
teritis
This topic is discussed in Chapter 20.
7. 
h
eadache Due to Intracranial Mass Lesions
Intracranial mass lesions of all types may cause headache 
owing to displacement of vascular structures and other 
pain-sensitive tissues. While pain and location are nonspe
-
cific, headache may be worse upon lying down, awaken the 
patient at night, or peak in the morning after overnight 
recumbency. The key feature prompting brain imaging is a 
new or worsening headache in middle or later life. Other 
features suggesting an intracranial lesion include signs or 
symptoms of infection or malignancy such as fever, night 
sweats, and weight loss; immunocompromise; or history of 
malignancy. Signs of focal or diffuse cerebral dysfunction 
or of increased intracranial pressure (eg, papilledema) also 
necessitate investigation.
8. Medication Overuse (
a
nalgesic Rebound) 
h
eadache
In approximately half of all patients with chronic daily 
headaches, medication overuse is responsible. Patients 
have chronic pain or severe headache unresponsive 
to  medication (typically defined as no effect after having 
been used regularly for more than 3 months). Ergotamines, 
triptans, medications containing butalbital, and opioids 
cause medication overuse headache when taken on more 
than 10 days per month; acetaminophen, acetylsalicylic 
acid, and nonsteroidal anti-inflammatory drugs may also 
be offenders if taken on more than 15 days per month. 
Early initiation of a migraine preventive therapy permits 
withdrawal of analgesics and eventual relief of headache.
9. 
h
eadache Due to Other Neurologic Causes
Cerebrovascular disease may be associated with headache, 
but the mechanism is unclear. Headache may occur with 
internal carotid artery occlusion or carotid dissection and 
after carotid endarterectomy. Acute severe headache 
accompanies subarachnoid hemorrhage and meningeal 
infections; accompanying signs of impairment of 
CMDT19_Ch24_p0990-p1062.indd   993

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4
994
 CMDT 2019
consciousness and sign of meningeal irritation indicate the 
need for further investigations. Headaches are also a fea
-
ture of pseudotumor cerebri (idiopathic intracranial 
hypertension).
Dull or throbbing headache is a frequent sequela of 
lumbar puncture and may last for several days. It is aggra
-
vated by the erect posture and alleviated by recumbency. 
The mechanism is unclear, but the headache is commonly 
attributed to leakage of cerebrospinal fluid through the 
dural puncture site. Its incidence may be reduced if an 
atraumatic needle (instead of a beveled, cutting needle) is 
used for the lumbar puncture.
 
»
•	
Thunderclap onset.
•	
Increasing headache unresponsive to simple measures.
•	
History of trauma, hypertension, fever, visual changes.
•	
Presence of neurologic signs or of scalp tenderness.
 
»
Suspected subarachnoid hemorrhage or structural intra
-
cranial lesion.
Chiang CC et al. Treatment of medication-overuse headache: a 
systematic review. Cephalalgia. 2016 Apr;36(4):371–86. 
[PMID: 26122645]
Puledda F et al. An update on migraine: current understanding 
and future directions. J Neurol. 2017 Sep;264(9):2031–9. 
[PMID: 28321564]
FACIAL PAIN
1. Trigeminal Neuralgia
 
»
Brief episodes of stabbing facial pain.
 
»
Pain is in the territory of the second and third divi
-
sion of the trigeminal nerve.
 
»
Pain exacerbated by touch.
 
»
Trigeminal neuralgia (“tic douloureux”) is most common 
in middle and later life. It affects women more frequently 
than men. Pain may be due to an anomalous artery or vein 
impinging on the trigeminal nerve.
 
»
Momentary episodes of sudden lancinating facial pain 
commonly arise near one side of the mouth and shoot 
toward the ear, eye, or nostril on that side. The pain may 
be triggered by such factors as touch, movement, drafts, 
and eating. In order to lessen the likelihood of triggering 
further attacks, many patients try to hold the face still 
while talking. Spontaneous remissions for several months 
or longer may occur. As the disorder progresses, however, 
the episodes of pain become more frequent, remissions 
become shorter and less common, and a dull ache may 
persist between the episodes of stabbing pain. Symptoms 
remain confined to the distribution of the trigeminal 
nerve (usually the second or third division) on one 
side only.
 
»
The characteristic features of the pain in trigeminal neural
-
gia usually distinguish it from other causes of facial pain. 
Neurologic examination shows no abnormality except in a 
few patients in whom trigeminal neuralgia is symptomatic 
of some underlying lesion, such as multiple sclerosis or a 
brainstem neoplasm, in which case the finding will depend 
on the nature and site of the lesion. Multiple sclerosis must 
be suspected in a patient younger than 40 years in whom 
trigeminal neuralgia is the presenting symptom, even if 
there are no other neurologic signs. Bilateral symptoms 
should also prompt further investigation. Brain MRI need 
only be obtained when a secondary cause is suspected; it is 
usually normal in classic trigeminal neuralgia.
 
»
Treatment
The medications most helpful for treatment are oxcarbaze
-
pine (although not approved by the FDA for this indica
-
tion) or carbamazepine, with monitoring by serial blood 
counts and liver biochemical tests. If these medications are 
ineffective or cannot be tolerated, phenytoin should be 
tried. (Doses and side effects of these medications are 
shown in Table 24–2). Baclofen (10–20 mg orally three or 
four times daily), topiramate (50 mg orally twice daily), or 
lamotrigine (400 mg orally daily) may also be helpful, 
either alone or in combination with one of these other 
agents. Gabapentin may also relieve pain, especially in 
patients who do not respond to conventional medical

patients who do not respond to conventional medical 
therapy and those with multiple sclerosis. Depending on 
response and tolerance, up to 3600 mg daily orally is given 
in divided doses.
For neuralgia refractory to medical treatment, several 
surgical treatment options are available that provide initial 
pain relief in at least 80% of patients. Microvascular surgi
-
cal decompression with separation of the anomalous vessel 
(usually not visible on CT scans, MRI, or arteriograms) 
from the nerve root produces long-term relief of symptoms 
in roughly 75% of patients. Three less invasive techniques 
are based on destruction of nociceptive trigeminal nerve 
fibers, which causes sensory loss in addition to symptom 
relief in half of patients: (1) radiofrequency rhizotomy 
produces long-term pain relief in 60% of patients, (2) per
-
cutaneous balloon compression of the trigeminal ganglion 
in 67%, and (3) stereotactic radiosurgery to the trigeminal 
nerve root in 45%. In elderly patients with a limited life 
expectancy, radiofrequency rhizotomy and stereotactic 
radiosurgery are sometimes preferred because both can be 
performed without general anesthesia and have few com
-
plications. Surgical exploration is inappropriate in patients 
CMDT19_Ch24_p0990-p1062.indd   994

995
 
CMDT 2019
Table 24–2.
 
Medication treatment for seizures in adults (in alphabetical order within classes).
Usual 
a
dult 
Daily Oral 
Dose
Minimum 
No. of 
Daily 
Doses
Time to 
Steady-
State Drug 
Levels
Optimal Drug 
Level and 
Monitoring
1
Selected Side Effects and 
 
Idiosyncratic Reactions
Generalized or Focal Seizures
Brivaracetam
2,5
50–100 mg
2
1–2 days
CBC, liver 
 
biochemical
 
tests
Somnolence, fatigue, ataxia, vertigo, psychosis, 
leukopenia, hypersensitivity (bronchospasm 
and angioedema)
2
400–1600 mg 
(immediate 
or extended 
release)
2
3–4 days
4–8 mcg/mL
CBC, liver 
 
biochemical tests, 
BUN/Cr
Nystagmus, dysarthria, diplopia, ataxia, drowsi
-
ness, nausea, blood dyscrasias, hepatotoxicity, 
hyponatremia, Stevens-Johnson syndrome.
3
May exacerbate myoclonic seizures.
Clobazam
4
10–40 mg
2
7–10 days
Lethargy and somnolence, ataxia, insomnia, 
 
dysarthria, aggression, constipation, fever, 
Stevens-Johnson syndrome.
Clorazepate
5
22.5–90 mg
2
10 days
Sedation, dizziness, confusion, ataxia, 
 
depression, dependency/abuse.
Eslicarbazepine
2,5
400–1200 mg 
daily
1
4 days
Serum sodium and 
chloride; liver 
 
biochemical tests
As for carbamazepine.
Ezogabine
5
300–1200 mg
3
2–3 days
ECG to assess QT 
interval
Dizziness, somnolence, confusion, vertigo, 
 
nausea, ataxia, psychiatric disturbances, 
 
prolonged QT interval, retinal abnormalities.
6
Felbamate
2,4,5,7
1200–3600 mg
3
4–5 days
CBC and reticulo
-
cytes, liver bio
-
chemical tests
Anorexia, nausea, vomiting, headache, insomnia, 
weight loss, dizziness, hepatotoxicity, fatal 
aplastic anemia; reserved for refractory epilepsy.
5
900–3600 mg
3
1 day
Sedation, fatigue, ataxia, nystagmus, weight loss.
Lacosamide
2,5
100–400 mg
2
3 days
ECG if known cardiac 
 
problems or severe 
cardiac disease
Vertigo, diplopia, nausea, headache, fatigue, 
ataxia, tremor, anaphylactoid reactions, 
PR prolongation, cardiac dysrhythmia, 
suicidality.
Lamotrigine
4,5,8,9
100–500 mg
2
4–5 days
Sedation, skin rash, visual disturbances, 
 
dyspepsia, ataxia.
Levetiracetam
5,8,10
1000–3000 mg
2
2 days
Somnolence, ataxia, headache, behavioral 
changes.
Oxcarbazepine
2,5
900–1800 mg
2
2–3 days
Serum sodium
Perampanel
2,5,8
4–12 mg
1
3 weeks
Dizziness, somnolence, irritability, weight gain, 
falls, ataxia, dysarthria, blurred vision.
Phenobarbital
2,11
100–200 mg
1
14–21 days
10–40 mcg/mL
CBC, liver biochemi
-
cal tests, BUN/Cr
Drowsiness, nystagmus, ataxia, skin rashes, 
learning difficulties, hyperactivity.
Phenytoin
2,11
200–400 mg
1
5–10 days
CBC, liver biochemical 
tests, folate
Nystagmus, ataxia, dysarthria, sedation, confusion, 
gingival hyperplasia, hirsutism, megaloblastic 
anemia, blood dyscrasias, skin rashes, fever, 
 
systemic lupus erythematosus, lymphadenopa
-
thy, peripheral neuropathy, dyskinesias.
5
150–300 mg
2
2–4 days
Somnolence, dizziness, poor concentration, 
weight gain, thrombocytopenia, skin rashes, 
anaphylactoid reactions.
Primidone
2,11
750–1500 mg
3
4–7 days
5–12 mcg/mL
CBC
Sedation, nystagmus, ataxia, vertigo, nausea, 
skin rashes, megaloblastic anemia, irritability.
Rufinamide
4
800–3200 mg 
daily
2
2 days
Somnolence, headache, dizziness, suicidality, 
Stevens-Johnson syndrome, leukopenia, 
shortened QT interval, nausea, vomiting.
(
continued
 
)
CMDT19_Ch24_p0990-p1062.indd   995

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996
 CMDT 2019
 
Usual 
a
dult 
Daily Oral 
Dose
Minimum 
No. of 
Daily 
Doses
Time to 
Steady-
State Drug 
Levels
Level and 
1
 
Tiagabine
5
32–56 mg
2
2 days
Somnolence, anxiety, dizziness, poor 
 
concentration, tremor, diarrhea.
2,4,5,8,11
200–400 mg
2
4 days
Serum bicarbonate, 
BUN/Cr in elderly 
patients
Somnolence, nausea, dyspepsia, irritability, 
 
dizziness
, 
ataxia, nystagmus, diplopia, glaucoma, renal cal
-
culi, weight loss, hypohidrosis, hyperthermia.
2,5,12,13
1500–2000 mg
2–3
2–4 days
50–100 mcg/mL
-
cal tests
Nausea, vomiting, diarrhea, drowsiness, alopecia, 
weight gain, hepatotoxicity, thrombocytope
-
nia, tremor, pancreatitis. 
Teratogenic; avoid in 
women of childbearing age.
5,14
3000 mg
2
2 days
Somnolence, anorexia, nausea, vomiting, 
 
agitation, hostility, confusion, suicidality, 
 
neutropenia, Stevens-Johnson syndrome, 
 
permanent visual field loss.
6
5
200–600 mg
1
14 days
BUN/Cr, serum 
bicarbonate
Somnolence, ataxia, anorexia, nausea, vomiting, 
rash, confusion, renal calculi. Do not use in 
patients with sulfonamide allergy.
a
bsenc
e Seizures
Clonazepam
4,10,12,15,16
0.04–0.2 mg/kg
2
7–10 days
20–80 ng/mL
-
cal tests
Drowsiness, ataxia, irritability, behavioral 
changes, exacerbation of tonic-clonic seizures.
Ethosuximide
12
500–1500 mg
2
5–10 days
40–100 mcg/mL
tests, urinalysis
Nausea, vomiting, anorexia, headache, lethargy, 
unsteadiness, blood dyscrasias, systemic lupus 
erythematosus, urticaria, pruritus.
2,5,12,13
2–3
2–4 days
See above
-
nia, tremor, pancreatitis.
Myoclonic Seizures
2
7–10 days
See above
2,5,12,13
2–3
2–4 days
See above
-
5,8,10
2
2 days
Somnolence, ataxia, headache, behavioral changes.
BUN, blood urea nitrogen; CBC, complete blood count; Cr, creatinine; ECG, electrocardiogram. Note that many factors influence optimal 
dose of these drugs including age, tolerance, and concomitant medication.
1
Patients starting treatment with any antiepileptic drug should be monitored for new or worsening depression or suicidal thoughts, 
 
especially during the first weeks of therapy. Baseline measurement of creatinine clearance is advisable in renally metabolized drugs.
2
Approved as monotherapy for focal-onset seizures.
3
Carriers of the HLA-B*1502 allele are at higher risk for Stevens-Johnson syndrome. Patients of Asian ancestry should be tested for this allele 
prior to initiation of therapy.
4
Approved as adjunctive therapy for Lennox-Gastaut syndrome.
5
Approved as adjunctive therapy for focal-onset seizures.
6
Regular ophthalmologic examination is recommended.
7
Not to be used as a first-line drug; when used, blood counts should be performed regularly (every 2–4 weeks). Should be used only in 
selected patients because of risk of aplastic anemia and hepatic failure. It is advisable to obtain written informed consent before use.
8
Approved as adjunctive therapy for primary generalized tonic-clonic seizures.
9
Approved as monotherapy (after conversion from another drug) in focal-onset seizures.
10
Approved as adjunctive therapy for myoclonic seizures.
11
Approved as initial monotherapy for primary generalized tonic-clonic seizures.
12
Approved as monotherapy and adjunctive therapy for absence seizures.
13

11
12
13
Approved as adjunctive therapy for patients with multiple seizure types including absence seizures.
14
Approved as monotherapy for infantile spasms.
15
Approved as monotherapy for Lennox-Gastaut syndrome.
16
Approved as monotherapy for myoclonic seizures.
 
CMDT19_Ch24_p0990-p1062.indd   996

997
 
CMDT 2019
with trigeminal neuralgia due to multiple sclerosis, but the 
less invasive techniques are sometimes helpful.
Donnet A et al. French guidelines for diagnosis and treatment of 
classical trigeminal neuralgia (French Headache Society and 
French Neurosurgical Society). Rev Neurol (Paris). 2017 
Mar;173(3):131–51. [PMID: 28314515]
2. 
a
t
ypical Facial 
p
ain
Facial pain without the typical features of trigeminal neu
-
ralgia is generally a constant, often burning pain that may 
have a restricted distribution at its onset but soon spreads 
to the rest of the face on the affected side and sometimes 
involves the other side, the neck, or the back of the head as 
well. The disorder is especially common in middle-aged 
women, many of them depressed, but it is not clear 
whether depression is the cause of or a reaction to the pain. 
Simple analgesics should be given a trial, as should tricyclic 
antidepressants, carbamazepine, oxcarbazepine, and phe
-
nytoin; the response is often disappointing. Opioid analge
-
sics pose a danger of addiction in patients with this 
disorder. Attempts at surgical treatment are not indicated.
3. Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia is an uncommon disorder in 
which pain similar in quality to that in trigeminal neuralgia 
occurs in the throat, about the tonsillar fossa, and sometimes 
deep in the ear and at the back of the tongue. The pain may 
be precipitated by swallowing, chewing, talking, or yawning 
and is sometimes accompanied by syncope. In most 
instances, no underlying structural abnormality is present; 
multiple sclerosis is sometimes responsible. Oxcarbazepine 
and carbamazepine are the treatments of choice and should 
be tried before any surgical procedures are considered. 
Microvascular decompression is often effective and is gener
-
ally preferred over destructive surgical procedures such as 
partial rhizotomy in medically refractory cases.
4. 
p
ostherpetic Neur
algia
Postherpetic neuralgia develops in about 15% of patients 
who have herpes zoster (shingles). This complication 
seems especially likely to occur in elderly or immunocom
-
promised persons, when the rash is severe, and when the 
first division of the trigeminal nerve is affected. It also 
relates to the duration of the rash before medical consulta
-
tion. A history of shingles and the presence of cutaneous 
scarring resulting from shingles aid in the diagnosis. Severe 
pain with shingles correlates with the intensity of posther
-
petic symptoms.
Acyclovir (800 mg five times daily) or valacyclovir 
(1000 mg three times daily), when given within 72 hours of 
rash onset, reduces the incidence of postherpetic neuralgia 
by almost half; systemic corticosteroids do 
not
 help (see 
Chapter 6). Management of the established complication is 
with simple analgesics. If they fail to help, a trial of a tricy
-
clic antidepressant (eg, amitriptyline or nortriptyline, up to 
100–150 mg daily orally) is often effective. Other patients 
respond to gabapentin (up to 3600 mg daily orally) or 
pregabalin (up to 600 mg/daily orally). A combination of 
gabapentin and morphine taken orally may provide better 
analgesia at lower doses of each agent than either taken 
alone. Subcutaneous injection of botulinum toxin A into 
the affected region produced sustained pain relief in 87% of 
patients in a small placebo-controlled trial. Topical applica
-
tion of capsaicin cream (eg, Zostrix, 0.025%) may be help
-
ful, as may topical lidocaine (5%). The administration of 
recombinant zoster vaccine
 to patients over the age of 
50 years is important in reducing the likelihood of herpes 
zoster and reducing the severity of postherpetic neuralgia 
should a reactivation occur.
Johnson RW et al. Clinical practice. Postherpetic neuralgia. N Engl 
J Med. 2014 Oct 16;371(16):1526–33. [PMID: 25317872]
5. Facial 
p
ain D
ue to Other Causes
Facial pain may be caused by temporomandibular joint dys
-

5. Facial 
p
ain D
-
function in patients with malocclusion, abnormal bite, or 
faulty dentures. There may be tenderness of the masticatory 
muscles, and sometimes pain begins at the onset of chewing. 
This pattern differs from that of jaw (masticatory) claudica
-
tion, a symptom of giant cell arteritis, in which pain develops 
progressively with mastication. Treatment of the underlying 
joint dysfunction relieves symptoms.
A relationship of facial pain to chewing or temperature 
changes may suggest a dental disturbance. The cause is 
sometimes not obvious, and diagnosis requires careful 
dental examination and radiographs. Sinusitis and ear 
infections causing facial pain are usually recognized by a 
history of respiratory tract infection, fever and, in some 
instances, nasal or aural discharge. There may be localized 
tenderness. Radiologic evidence of sinus infection or mas
-
toiditis is confirmatory.
Glaucoma is an important ocular cause of facial pain, 
usually localized to the periorbital region.
On occasion, pain in the jaw may be the principal mani
-
festation of angina pectoris. Precipitation by exertion and 
radiation to more typical areas suggests a cardiac origin.
 
»
•	
Worsening pain unresponsive to simple measures.
•	
Continuing pain of uncertain cause.
•	
For consideration of surgical treatment (trigeminal or 
glossopharyngeal neuralgia).
EPILEPSY
 
»
Recurrent unprovoked seizures.
 
»
Characteristic electroencephalographic changes 
accompany seizures.
 
»
Mental status abnormalities or focal neurologic 
symptoms may persist for hours postictally.
CMDT19_Ch24_p0990-p1062.indd   997

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998
 CMDT 2019
 
»
The term “epilepsy” denotes any disorder characterized by 
recurrent 
unprovoked
 seizures. A seizure is a transient dis
-
turbance of cerebral function due to an abnormal paroxys
-
mal neuronal discharge in the brain. Epilepsy is relatively 
common, affecting approximately 0.5% of the population 
in the United States.
Patients with recurrent seizures provoked by a readily 
reversible cause, such as withdrawal from alcohol or drugs, 
hypoglycemia, hyperglycemia, or uremia, are not consid
-
ered to have epilepsy.
 
»
Classification of Epilepsy
According to the International League Against Epilepsy 
classification system, recurrent seizures should be classi
-
fied first by seizure type, second by epilepsy type, and 
third, if possible, by epilepsy syndrome. The etiology of 
recurrent seizures should be sought at each stage of classi
-
fication (see Etiology of Epilepsy).
A. Seizure Types
The International League Against Epilepsy distinguishes 
seizures affecting only part of the brain (focal seizures) 
from those that are generalized.
1. Focal onset seizures—
The initial clinical and electroen
-
cephalographic manifestations of focal (partial) seizures 
indicate that only a restricted part of one cerebral hemi
-
sphere has been activated. The ictal manifestations depend 
on the area of the brain involved. Focal seizures are classi
-
fied by motor or nonmotor onset as well as by whether 
awareness is impaired.
a. Motor versus nonmotor onset
—
Seizures with 
motor onset may be 
clonic, tonic, atonic, myoclonic,
 or 
hyperkinetic,
 or may manifest as 
automatisms
 or 
epileptic
 
spasms
. The most commonly observed focal motor sei
-
zures consist of clonic jerking or automatisms. Nonmotor 
seizures may be manifested by sensory symptoms (eg, 
paresthesias or tingling, gustatory, olfactory, visual or audi
-
tory sensations), behavior arrest, cognitive symptoms (eg, 
speech arrest, déjà vu, jamais vu), emotional symptoms (eg, 
fear), or autonomic symptoms or signs (eg, abnormal epi
-
gastric sensations, sweating, flushing, pupillary dilation). 
Focal sensory and motor seizures may spread (or “march”) 
to different parts of the limb or body depending on their 
cortical representation and were previously called “simple 
partial” seizures.
b. Aware versus impaired awareness
—
Awareness is 
defined as knowledge of self and environment, and of 
events occurring during a seizure. Impaired awareness may 
be preceded, accompanied, or followed by the various 
motor and nonmotor symptoms mentioned above. Such 
seizures were previously called “complex partial” seizures.
c. Focal to bilateral tonic-clonic
—
Focal seizures 
sometimes involve loss of awareness and evolve to bilateral 
tonic-clonic seizures, in a process previously called 
secondary 
generalization
.
2. Generalized onset seizures—
Generalized seizures are 
thought to originate in or rapidly spread to involve bilateral 
cortical networks. In some cases, the distinction between 
focal and generalized onset can only be made by electroen
-
cephalogram (EEG). Generalized seizures are classified 
into those with motor or nonmotor features. Awareness is 
typically lost with generalized seizures but may be retained 
partially in the briefest absence attacks and some myo
-
clonic seizures.
a. Nonmotor (absence) seizures
—
These are charac
-
terized by impairment of consciousness, sometimes with 
mild clonic, tonic, myoclonic, or atonic components (ie, 
reduction or loss of postural tone), autonomic components 
(eg, enuresis), or accompanying automatisms. Onset and 
termination of attacks are abrupt. If attacks occur during 
conversation, the patient may miss a few words or may 
break off in midsentence for a few seconds. The impair
-
ment of external awareness is so brief that the patient is 
unaware of it. 
Absence (“petit mal”) seizures
 almost always 
begin in childhood and frequently cease by the age of

-
begin in childhood and frequently cease by the age of 
20 years or are then replaced by other forms of generalized 
seizure. Electroencephalographically, such attacks are asso
-
ciated with bursts of bilaterally synchronous and symmet
-
ric 3-Hz spike-wave activity. A normal background in the 
electroencephalogram and normal or above-normal intel
-
ligence imply a good prognosis for the ultimate cessation of 
these seizures. 
Atypical absence seizures
 may demonstrate 
more marked changes in tone, or attacks may have a more 
gradual onset and termination than in typical absence sei
-
zures. They commonly occur in patients with multiple 
seizure types, may be accompanied by developmental delay 
or mental retardation, and are associated with slower 
spike-wave discharges than those in typical absence attacks.
b. Motor seizures
—
Types of generalized motor seizures 
include 
tonic-clonic, clonic, tonic, myoclonic, myoclonic-
 
tonic-clonic, myoclonic-atonic, atonic,
 and 
epileptic 
spasms.
 During tonic-clonic seizures there is sudden loss 
of consciousness, the patient becomes rigid and falls to the 
ground, and respiration is arrested. This tonic phase, which 
usually lasts for under 1 minute, is followed by a clonic 
phase in which there is jerking of the body musculature 
that may last for 2 or 3 minutes and is then followed by a 
stage of flaccid coma. During the seizure, the tongue or lips 
may be bitten, urinary or fecal incontinence may occur, 
and the patient may be injured. Immediately after the sei
-
zure, the patient may recover consciousness, drift into 
sleep, have a further convulsion without recovery of con
-
sciousness between the attacks 
(status epilepticus),
 or 
after recovering consciousness have a further convulsion 
(serial seizures).
 In other cases, patients may behave in an 
abnormal fashion in the immediate postictal period, with
-
out subsequent awareness or memory of events 
(postepi
-
leptic automatism).
 Headache, disorientation, confusion, 
drowsiness, nausea, soreness of the muscles, or some com
-
bination of these symptoms commonly occurs postictally. 
Myoclonic seizures consist of single or multiple myoclonic 
jerks. Atonic seizures consist of very brief (less than 2 sec
-
onds) loss of muscle tone and often result in falls 
(epileptic 
drop attacks)
. Epileptic spasms are sudden flexion or 
CMDT19_Ch24_p0990-p1062.indd   998

999
 
CMDT 2019
extension of truncal muscles; these seizures usually mani
-
fest during infancy.
3. Unknown onset seizures—
In some circumstances, sei
-
zures cannot be classified because of incomplete informa
-
tion or because they do not fit into any category. Generally, 
with additional information from the history or from 
video-EEG telemetry, the seizure onset can be correctly 
classified.
B. Epilepsy Types
The International League Against Epilepsy classifies epi
-
lepsy by the seizure type. Thus, epilepsy may be 
focal
, 
generalized,
 or 
combined generalized and focal.
 The EEG 
may be helpful in facilitating classification.
C. Epilepsy Syndromes
Epilepsy syndromes are defined by constellations of seizure 
types, EEG findings, and imaging features, and often also 
depend on age at onset and comorbidities. Not every 
patient with epilepsy can be given a syndromic diagnosis. 
Several well-known epilepsy syndromes exist but are 
beyond the scope of this chapter.
 
»
Etiology of Epilepsy
In parallel to classifying the seizure type, epilepsy type, and 
epilepsy syndrome (if applicable), the cause of the patient’s 
seizures should be sought. The International League 
Against Epilepsy lists six broad etiologic categories; some
-
times a patient’s seizures have more than one etiology.
A. Structural Etiology
1. Pediatric age groups—
Congenital abnormalities and 
perinatal injuries may result in seizures presenting in 
infancy or childhood.
2. Mesial temporal sclerosis—
Hippocampal sclerosis is a 
recognized cause of focal and secondarily generalized sei
-
zures of uncertain etiology.
3. Trauma—
Trauma is an important cause of seizures at 
any age, but especially in young adults. Posttraumatic epi
-
lepsy is more likely to develop if the dura mater was pene
-
trated and generally becomes manifest within 2 years 
following the injury. However, seizures developing in the 
first week after head injury do not necessarily imply that 
future attacks will occur. There is no evidence that prophy
-
lactic anticonvulsant 
 treatment reduces the 
incidence of posttraumatic epilepsy.
4. Tumors and other space-occupying lesions—
 
Neoplasms may lead to seizures at any age, but they are an 
especially important cause of seizures in middle and later 
life, when the incidence of neoplastic disease increases. 
Seizures are commonly the initial symptoms of the tumor 
and often are focal in character. They are most likely to 
occur with structural lesions involving the frontal, parietal, 
or temporal regions. Tumors must be excluded by imaging 
studies (MRI preferred over CT) in all patients with onset 
of seizures after 20 years of age, focal seizures or signs, or a 
progressive seizure disorder.
5. Vascular diseases—
Stroke and other vascular diseases 
become increasingly frequent causes of seizures with 
advancing age and are the most common cause of seizures 
with onset at age 60 years or older.
6. Degenerative disorders—
Alzheimer disease and other 
degenerative disorders are a cause of seizures in later life.
B. Genetic Etiology
This category encompasses a broad range of disorders, for 
which the age at onset ranges from the neonatal period to 
adolescence or even later in life. Monogenic disorders tend 
to exhibit an autosomal dominant pattern of inheritance, 
and where the mutation is known, the responsible gene 
often encodes a neuronal ion channel. A genetic etiology 
may also underpin certain epilepsies with a metabolic or 
structural basis.
C. Infectious Etiology
Infectious diseases must be considered in all age groups as 
potentially reversible causes of seizures. Seizures may 
occur with an acute infective or inflammatory illness, such 
as bacterial meningitis or herpes encephalitis, or in patients 
with more longstanding or chronic disorders, such as neu
-
rosyphilis or cerebral cysticercosis. In patients with AIDS, 
seizures may result from central nervous system toxoplas
-

-
-
mosis, cryptococcal meningitis, secondary viral encephali
-
tis, or other infective complications. Seizures are a common 
sequela of supratentorial brain abscess, developing most 
frequently in the first year after treatment.
D. Metabolic Etiology
Inborn errors of metabolism and other inherited condi
-
tions may cause epilepsy as one of their manifestations (eg, 
pyridoxine deficiency, mitochondrial disease); these disor
-
ders typically present during childhood.
E. Immune Etiology
Autoimmune diseases such as systemic lupus erythemato
-
sus and autoimmune limbic encephalitis may cause epi
-
lepsy; often the epilepsy can be cured with immunotherapy 
and lifelong antiepileptic medication treatment is not 
F. Unknown Etiology
In many cases, the cause of epilepsy cannot be determined.
 
»
Nonspecific changes such as headache, mood alterations, 
lethargy, and myoclonic jerking alert some patients to an 
impending seizure hours before it occurs. These prodromal 
symptoms are distinct from the aura; the aura that may 
precede a generalized seizure by a few seconds or minutes 
is itself a part of the seizure indicating focal onset from a 
restricted part of the brain.
In most patients, seizures occur unpredictably at any 
time and without any relationship to posture or ongoing 
CMDT19_Ch24_p0990-p1062.indd   999

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1000
 CMDT 2019
activities. Occasionally, however, they occur at a particular 
time (eg, during sleep) or in relation to external precipi
-
tants such as lack of sleep, missed meals, emotional stress, 
menstruation, alcohol ingestion (or alcohol withdrawal), 
or use of certain recreational drugs. Fever and nonspecific 
infections may also precipitate seizures in epileptic 
patients. In a few patients, seizures are provoked by spe
-
cific stimuli such as flashing lights or a flickering televi
-
sion set 
(photosensitive epilepsy),
 music, or reading.
Clinical examination between seizures shows no abnor
-
mality in patients with idiopathic epilepsy, but in the 
immediate postictal period, extensor plantar responses 
may be seen. The presence of lateralized or focal signs 
postictally suggests that seizures may have a focal origin. In 
patients with symptomatic epilepsy, the findings on exami
-
nation will reflect the underlying cause.
B. Laboratory and Other Studies
Initial investigations after a first seizure should include 
complete blood count, serum glucose, electrolytes, creati
-
nine, calcium, magnesium, and liver biochemical tests to 
exclude various causes of provoked seizures and to provide 
a baseline for subsequent monitoring of long-term effects 
of treatment. Routine laboratory investigations are not 
usually necessary after recurrent seizures in patients with 
known epilepsy. A lumbar puncture may be necessary 
when any sign of infection is present or in the evaluation of 
new-onset seizures in the acute setting.
C. Imaging
MRI is indicated for patients with focal neurologic symp
-
toms or signs, focal seizures, or electroencephalographic 
findings of a focal disturbance. It should also be performed 
in patients with clinical evidence of a progressive disorder 
and in those with new onset of seizures after the age of 
20  years because of the possibility of an underlying neo
-
plasm. CT is generally less sensitive than MRI in detecting 
small structural brain abnormalities but may be used when 
MRI is contraindicated or unavailable.
Electroencephalography may support the clinical diag
-
nosis of epilepsy (by demonstrating paroxysmal abnor
-
malities containing spikes or sharp waves), provide a guide 
to prognosis, and help classify the seizure disorder. Classi
-
fication of the disorder is important for determining the 
most appropriate anticonvulsant medication with which to 
start treatment. For example, absence and focal seizures 
with impaired awareness may be difficult to distinguish 
clinically, but the electroencephalographic findings and 
treatment of choice differ in these two conditions. Finally, 
by localizing the epileptogenic source, the electroencepha
-
lographic findings are important in evaluating candidates 
for surgical treatment.
 
»
The distinction between the various disorders likely to be 
confused with generalized seizures is usually made on the 
basis of the history. The importance of obtaining an eye
-
witness account of the attacks cannot be overemphasized.
A. Differential Diagnosis of Focal Seizures
1. TIAs—
These are distinguished from seizures by their 
longer duration, lack of spread, and negative (eg, weakness 
or numbness) rather than positive (eg, convulsive jerking 
or paresthesias) symptoms. Level of consciousness, which 
is unaltered, does not distinguish them.
2. Migraine aura—
Migraine aura may produce positive or 
negative symptoms, tends to spread slowly from one part of 
the body to another (over minutes rather than seconds), 
and is usually longer in duration (minutes to hours). It is 
usually, but not always, followed by a typical migraine 
headache.
3. Panic attacks—
These may be hard to distinguish from 
focal seizures unless there is evidence of an anxiety disor
-
der between attacks and the attacks have a clear relation
-
ship to external circumstances.
4. Rage attacks—
These are situational and lead to goal-

-
-
directed aggressive behavior.
B. Differential Diagnosis of Generalized Seizures
1. Syncope—
Syncopal episodes usually occur in relation 
to postural change, emotional stress, instrumentation, 
pain, or straining. They are typically preceded by pallor, 
sweating, nausea, and malaise and lead to loss of con
-
sciousness accompanied by flaccidity; recovery occurs 
rapidly with recumbency, and there is no postictal head
-
ache or confusion. In some instances, however, motor 
accompaniments and urinary incontinence may simulate a 
seizure.
2. Cardiac disease—
Cerebral hypoperfusion due to a dis
-
turbance of cardiac rhythm should be suspected in patients 
with known cardiac or vascular disease or in elderly 
patients who present with episodic loss of consciousness. 
Prodromal symptoms are typically absent. Cardiac rhythm 
monitoring may be necessary to establish the diagnosis; 
external event recorders or implantable loop recorders may 
be valuable if the disturbances of consciousness are rare. 
A relationship of attacks to physical activity and the finding 
of a systolic murmur are suggestive of aortic stenosis.
3. Brainstem ischemia—
Loss of consciousness is preceded 
or accompanied by other brainstem signs. Basilar artery 
migraine and vertebrobasilar vascular disease are discussed 
elsewhere in this chapter.
4. Psychogenic nonepileptic seizure (PNES)—
Simulating 
an epileptic seizure, a PNES may occur due to a conversion 
disorder or malingering. Many patients also have epileptic 
seizures or a family history of epilepsy. A history of child
-
hood physical or sexual abuse is common. Although a 
PNES tends to occur at times of emotional stress, this may 
also be the case with epileptic seizures.
Clinically, the attacks superficially resemble tonic-
clonic seizures, but there may be obvious preparation 
before a PNES. Moreover, there is usually no tonic phase; 
instead, there may be an asynchronous thrashing of the 
limbs and the attack rarely leads to injury. Eyes are often 
forcibly closed during PNES, unlike epileptic seizures, in 
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which they are typically open. Consciousness may be nor
-
mal or “lost, ” but in the latter context the occurrence of 
goal-directed behavior or of shouting, swearing, etc, indi
-
cates that it is feigned. Postictally, there are no changes in 
behavior or neurologic findings.
Often, clinical observation is insufficient to discrimi
-
nate epileptic from nonepileptic seizures and 
video elec
-
troencephalographic monitoring
 is required. Elevation 
of serum prolactin level to at least twice the upper limit of 
normal can be seen between 10 and 20 minutes after a 
seizure or syncopal event but not after a PNES. However, 
the test has limited clinical utility because levels are nor
-
mal after an epileptic seizure in roughly half of patients 
and a baseline prolactin must be drawn 6 hours after the 
attack.
 
»
Treatment
For patients with epilepsy, medication is prescribed with 
the goal of preventing further attacks and is usually contin
-
ued until there have been no seizures for at least 2 years. 
Epileptic patients should be advised to avoid situations that 
could be dangerous or life-threatening if further seizures 
should occur. Legislation may require clinicians to report 
to the state authorities any patients with seizures or other 
episodic disturbances of consciousness; driving cessation 
for 6 months or as legislated is appropriate following an 
unprovoked seizure.
1. Choice of medication—
Medication selection depends 
on seizure type (Table 24–2). The dose of the selected 
anticonvulsant is gradually increased until seizures are 
controlled or side effects prevent further increases. If sei
-
zures continue despite treatment at the maximal tolerated 
dose, a second medication is added and the dose increased 
depending on tolerance; the first medication is then 
gradually withdrawn. In most patients with seizures of a 
single type, satisfactory control can be achieved with a 
single anticonvulsant. Treatment with two medications 
may further reduce seizure frequency or severity but usu
-
ally only at the cost of greater toxicity. Treatment with 
more than two medications is almost always unhelpful 
unless the patient is having seizures of different types. 
Other factors to consider in selecting an anticonvulsant 
include likely side effects, teratogenicity, interactions with 
other medications and oral contraceptives, and route of 
metabolism.
All antiepileptics are potentially teratogenic, although 
the teratogenicity of the newer antiseizure medications is 
less clear. Nevertheless, antiepileptic medication must be 
given to pregnant women with epilepsy to prevent seizures, 
which can pose serious risk to the fetus from trauma, 
hypoxia, or other factors.
2. Monitoring—
Individual differences in drug metabo
-
lism cause a given dose of a medication to produce differ
-
ent blood concentrations in different patients, and this 
will affect the therapeutic response. In general, the dose 
of an antiepileptic agent is increased depending on the 
clinical response regardless of the serum drug level. 
When a dose is achieved that either controls seizures or is 
the maximum tolerated, then a steady-state trough drug 
level may be obtained for future reference; rechecking this 
level may be appropriate during pregnancy, if a break
-
through seizure occurs, a dose change occurs, or another 
(potentially interacting) medication is added to the regi
-
men. A laboratory’s therapeutic range for a medication is 
only a guide; many patients achieve good seizure control 
with no adverse effect at serum levels that exceed the 
stipulated range, and in these cases no dose adjustment is 
needed. The most common cause of a lower concentra
-
tion of medication than expected for the prescribed dose 
is suboptimal patient adherence. Adherence can be 
improved by limiting to a minimum the number of daily 
doses. Recurrent seizures or status epilepticus may result

doses. Recurrent seizures or status epilepticus may result 
if medications are taken erratically, and in some circum
-
stances nonadherent patients may be better off without 
any medication. All anticonvulsants have side effects, and 
many require baseline and regular laboratory monitoring 
(Table 24–2).
3. Discontinuance of medication—
Only when adult 
patients have been seizure-free for 2 years should with
-
drawal of medication be considered. Unfortunately, there is 
no way of predicting which patients can be managed suc
-
cessfully without treatment, although seizure recurrence is 
more likely in patients who initially did not respond to 
therapy, those with seizures having focal features or of 
multiple types, and those with continuing electroencepha
-
lographic abnormalities. Dose reduction should be gradual 
(over weeks or months), and medications should be with
-
drawn one at a time. If seizures recur, treatment is reinsti
-
tuted with the previously effective regimen.
4. Surgical treatment—
Patients with seizures refractory to 
two or more medications may be candidates for operative 
treatment. Surgical resection is most efficacious when 
there is a single well-defined seizure focus, particularly in 
the temporal lobe. Among well-chosen patients, up to 70% 
remain seizure-free after extended follow-up. Deep brain 
or cortical stimulation for medically refractory focal-onset 
seizures may be of benefit in medically refractory patients.
5. Vagal nerve stimulation—
Treatment by chronic vagal 
nerve stimulation for adults and adolescents with medi
-
cally refractory focal seizures is approved in the United 
States and provides an alternative approach for patients 
who are not optimal candidates for surgical treatment. The 
mechanism of therapeutic action is unknown. Adverse 
effects consist mainly of transient hoarseness during stim
-
ulus delivery.
B. Special Circumstances
1. Solitary seizures—
In patients who have had only one 
seizure or a flurry of seizures over a brief period of several 
hours, investigation as outlined earlier should exclude an 
underlying cause requiring specific treatment. An electroen
-
cephalogram should be obtained, preferably within 24 hours 
 
after the seizure. Prophylactic anticonvulsant treatment is 
generally not required unless further attacks occur or 
investigations reveal underlying pathology. The risk of 
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seizure recurrence varies in different series between about 
30% and 70%, with higher risk of recurrence in patients 
with structural brain lesions or abnormalities on electroen
-
cephalogram. Epilepsy should 
not
 be diagnosed on the 
basis of a solitary seizure. If seizures occur in the context of 
transient, nonrecurrent systemic disorders such as hypona
-
tremia or hypoglycemia, the diagnosis of epilepsy is inac
-
curate, and long-term prophylactic anticonvulsant 
treatment is unnecessary.
2. Alcohol withdrawal seizures—
The characteristic alco
-
hol withdrawal seizure pattern is one or more generalized 
tonic-clonic seizures that may occur within 48 hours or so 
of withdrawal from alcohol after a period of high or pro
-
longed intake. If the seizures have consistently focal fea
-
tures, the possibility of an associated structural abnormality, 
often traumatic in origin, must be considered. Treatment 
with anticonvulsants is generally not required for alcohol 
withdrawal seizures, since they are self-limited. Benzodiaz
-
epines are effective and safe for preventing further seizures 
(see Chapter 25). Status epilepticus may complicate alcohol 
withdrawal and is managed along conventional lines. Fur
-
ther attacks will not occur if the patient abstains from 
alcohol.
3. Tonic-clonic status epilepticus—
Poor adherence to the 
anticonvulsant regimen is the most common cause; how
-
ever, any disorder that can cause a single seizure may be 
responsible. The mortality rate may be as high as 20%, and 
among survivors the incidence of neurologic and cognitive 
sequelae is high. The prognosis relates to the underlying 
cause as well as the length of time between onset of status 
epilepticus and the start of effective treatment.
Status epilepticus is a medical emergency.
 Initial man
-
agement includes maintenance of the airway and 50% 
dextrose (25–50 mL) intravenously in case hypoglycemia is 
responsible. If seizures continue, an intravenous bolus of 
lorazepam, 4 mg, is given at a rate of 2 mg/min and 
repeated once after 10 minutes if necessary; alternatively, 
10 mg of midazolam is given intramuscularly, and again 
after 10 minutes if necessary. Diazepam can also be given 
rectally as a gel (0.2 mg/kg). These measures are usually 
effective in halting seizures for a brief period. Respiratory 
depression and hypotension may complicate the treatment 
and are treated as in other circumstances, including intuba
-
tion and mechanical ventilation and admission to an inten
-
sive care unit.
Regardless of the response to lorazepam or midazolam, 
fosphenytoin or phenytoin should be administered intrave
-
nously to initiate long-term seizure control. Fosphenytoin 
(18–20 mg phenytoin equivalents [PE]/kg) is rapidly and 
completely converted to phenytoin following intravenous 
administration and is preferred because it is less likely to 
cause reactions at the infusion site, can be given with all 
common intravenous solutions, and may be administered 
at a faster rate (150 mg PE/min). When fosphenytoin is not 
available, phenytoin (18–20 mg/kg) is given intravenously 
at a rate of 50 mg/min. Phenytoin is best injected directly 
but can also be given in saline; it precipitates, however, 
 
if injected into glucose-containing solutions. Because 
arrhythmias may develop during rapid administration of 
fosphenytoin or phenytoin, electrocardiographic monitor
-
ing is prudent. Hypotension may occur, especially if diaz
-
epam has also been given.
If seizures continue, phenobarbital is then given in a 
loading dose of 10–20 mg/kg intravenously by slow or 
intermittent injection (50 mg/min). Respiratory depression 
and hypotension are especially common with this therapy. 
Alternatively or additionally, intravenous valproate is used 
for status epilepticus (loading dose 20–40 mg/kg over 
15 min); although valproate is not approved by the FDA for 
this indication, it has been used with success.

If these measures fail, general anesthesia with ven
-
tilatory assistance may be required; some experts rec
-
ommend proceeding directly to general anesthesia if 
convulsions do not cease after the initial 18–20 PE/kg 
fosphenytoin load. Intravenous midazolam may provide 
control of refractory status epilepticus; the suggested 
loading dose is 0.2 mg/kg, followed by 0.05–0.2 mg/kg/h. 
Propofol (1–2 mg/kg as an intravenous bolus, followed by 
infusion at 2–15 mg/kg/h depending on response) may 
also be used, as may pentobarbital (15 mg/kg intrave
-
nously, followed by 0.5–4 mg/kg/h).
After status epilepticus is controlled, an oral medication 
program for the long-term management of seizures is 
started, and investigations into the cause of the disorder are 
pursued.
4. Nonconvulsive status epilepticus—
In some cases, sta
-
tus epilepticus presents not with convulsions, but with a 
fluctuating abnormal mental status, confusion, impaired 
responsiveness, and automatism. Electroencephalography 
establishes the diagnosis. The treatment approach outlined 
above applies to any type of status epilepticus, although 
intravenous anesthesia is usually not necessary. The prog
-
nosis is a reflection of the underlying cause rather than of 
continuing seizures.
 
»
•	
Behavioral episodes of uncertain nature.
•	
Seizures are difficult to control with monotherapy.
•	
There is a progressive neurologic disorder.
 
»
•	
Status epilepticus.
•	
Frequent seizures requiring rapid medication titration 
and electroencephalographic monitoring.
•	
For inpatient monitoring when PNES is suspected.
Betjemann JP et al. Status epilepticus in adults. Lancet Neurol. 
2015 Jun;14(6):615–24. [PMID: 25908090]
Fisher RS et al. Operational classification of seizure types by the 
International League Against Epilepsy: position paper of the 
ILAE commission for classification and terminology. Epilepsia. 
 
2017 Apr;58(4):522–30. [PMID: 28276060]
Gavvala JR et al. JAMA patient page. Epilepsy. JAMA. 2016 Dec 27;
 
316(24):2686. [PMID: 28027369]
Scheffer IE et al. ILAE classification of the epilepsies: position 
paper of the ILAE commission for classification and termi
-
nology. Epilepsia. 2017 Apr;58(4):512–21. [PMID: 28276062]
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DYSAUTONOMIA
 
»
Postural hypotension or abnormal heart rate 
regulation.
 
»
Abnormalities of sweating, intestinal motility, 
 
sexual function, or sphincter control.
 
»
Syncope may occur.
 
»
Symptoms occur in isolation or any combination.
 
»
Dysautonomia may occur as a result of pathological pro
-
cesses in the central or peripheral nervous system. It is 
manifested by a variety of symptoms related to abnormali
-
ties of blood pressure regulation, thermoregulatory sweat
-
ing, gastrointestinal function, sphincter control, sexual 
function, respiration, and ocular function. The differential 
diagnosis depends on the time course of autonomic dys
-
function and whether dysautonomia is an isolated symp
-
tom or associated with central or peripheral neurologic 
symptoms and signs.
A. Causes in the Central Nervous System
Disease at certain sites, regardless of its nature, may lead to 
dysautonomic symptoms. Postural hypotension, which is 
usually the most troublesome and disabling symptom, may 
result from spinal cord transection and other myelopathies 
(eg, due to tumor or syringomyelia) above the T6 level or 
from brainstem lesions such as syringobulbia and posterior 
fossa tumors. Sphincter or sexual disturbances may result 
from cord lesions at any level. Certain primary degenera
-
tive disorders are responsible for dysautonomia occurring 
in isolation 
(pure autonomic failure)
 or in association 
with more widespread abnormalities 
(multisystem atrophy)
 
that may include parkinsonism, pyramidal symptoms, and 
cerebellar deficits. Postural hypotension is also a prominent 
symptom of idiopathic Parkinson disease and dementia 
with Lewy bodies.
B. Causes in the Peripheral Nervous System
A pure autonomic neuropathy may occur acutely or sub
-
acutely after a viral infection or as a paraneoplastic disor
-
der related usually to small cell lung cancer, particularly in 
association with certain antibodies, such as anti-Hu or 
those directed at neuronal nicotinic ganglionic acetylcho
-
line receptors. Dysautonomia is often conspicuous in 
patients with Guillain-Barré syndrome, manifesting with 
marked hypotension or hypertension or cardiac arrhyth
-
mias that may have a fatal outcome. It may also occur with 
diabetic, uremic, amyloidotic, and various other metabolic 
or toxic neuropathies; in association with leprosy or 
 
Chagas disease; and as a feature of certain hereditary neu
-
ropathies with autosomal dominant or recessive inheri
-
tance or an X-linked pattern. Autonomic symptoms are 
prominent in the crises of hepatic porphyria. Patients with 
botulism or the Lambert-Eaton myasthenic syndrome may 
have constipation, urinary retention, and a sicca syndrome 
as a result of impaired cholinergic function.
 
»
Dysautonomic symptoms include syncope, postural hypo
-
tension, paroxysmal hypertension, persistent tachycardia 
without other cause, facial flushing, hypohidrosis or hyper
-
hidrosis, vomiting, constipation, diarrhea, dysphagia, 
abdominal distention, disturbances of micturition or defe
-
cation, erectile dysfunction, apneic episodes, and declining 
night vision. In syncope, prodromal malaise, nausea, head
-
ache, diaphoresis, pallor, visual disturbance, loss of postural 
tone, and a sense of weakness and impending loss of con
-
sciousness are followed by actual loss of consciousness. It is 
usually accompanied by hypotension and bradycardia and 
may occur in response to emotional stress, postural hypo
-
tension, vigorous exercise in a hot environment, obstructed 
venous return to the heart, acute pain or its anticipation, 
fluid loss, and a variety of other circumstances. Although 
the patient is usually flaccid, some motor activity is not 
uncommon, and urinary (and rarely fecal) incontinence 
may also occur, thereby simulating a seizure. Recovery is

may also occur, thereby simulating a seizure. Recovery is 
rapid once the patient becomes recumbent, but headache, 
nausea, and fatigue are common postictally.
B. Evaluation of the Patient
The extent and severity of autonomic dysfunction should 
be determined, and the presence of associated neurologic 
symptoms and signs ascertained. Bedside testing of auto
-
nomic function includes examination of pupillary reactiv
-
ity, examination of the skin for areas of excessive or 
reduced sweating and of the hands and feet for color or 
temperature changes, as well as assessment of blood pres
-
sure and heart rate in the supine position and 2 minutes 
after standing. With dysautonomia, postural hypotension 
is not accompanied by a compensatory rise in heart rate. 
Specialized tests include the cardiovascular response to the 
Valsalva maneuver and deep respiration, tilt-table testing, 
the thermoregulatory sweat test, the quantitative sudomo
-
tor axon reflex test, and the quantitative direct and indirect 
axon reflex test. Tests of gastrointestinal motility and uro
-
dynamics may be helpful when symptoms of dysmotility, 
incontinence, or urinary retention are present.
The neurologic examination should focus on detecting 
signs of parkinsonism, cerebellar dysfunction, disorders of 
neuromuscular transmission, and peripheral neuropathy. 
All patients should be tested for vitamin B
12
 deficiency and 
diabetes. Patients with acute or subacute isolated dysautono
-
mia should undergo testing for ganglionic acetylcholine 
receptor, anti-Hu, voltage-gated potassium channel com
-
plex, and voltage-gated calcium channel antibodies. For 
those with evidence of peripheral neuropathy, nerve con
-
duction studies; electromyography; and testing for HIV , 
amyloidosis, Sjögren syndrome, and Fabry disease is indi
-
cated. If there is evidence of central pathology, imaging stud
-
ies will exclude a treatable structural cause. If the neurologic 
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 CMDT 2019
examination is normal, reversible, nonneurologic causes of 
symptoms must be considered. Isolated postural hypoten
-
sion and syncope may relate to a reduced cardiac output, 
paroxysmal cardiac dysrhythmias, volume depletion, vari
-
ous medications, and endocrine and metabolic disorders 
such as Addison disease, hypothyroidism or hyperthyroid
-
ism, pheochromocytoma, and carcinoid syndrome.
 
»
Treatment
The most disabling symptoms are usually postural hypo
-
tension and syncope. Abrupt postural change, prolonged 
recumbency, and other precipitants should be avoided. 
Medications associated with postural hypotension should 
be discontinued or reduced in dose. Treatment may include 
wearing waist-high elastic hosiery, salt supplementation, 
sleeping in a semierect position (which minimizes the 
natriuresis and diuresis that occur during recumbency), 
and fludrocortisone (0.1–0.5 mg orally daily). Vasocon
-
strictor agents may be helpful and include midodrine 
(2.5–10 mg orally three times daily), droxidopa (100–600 mg 
 
orally three times daily), and ephedrine (15–30 mg orally 
three times daily). Other agents that have been used occa
-
sionally or experimentally are dihydroergotamine, yohim
-
bine, pyridostigmine, and clonidine; refractory cases may 
respond to erythropoietin (epoetin alfa) or desmopressin. 
Patients must be monitored for recumbent hypertension. 
Postprandial hypotension is helped by caffeine. There is no 
satisfactory treatment for disturbances of sweating, but an 
air-conditioned environment is helpful in avoiding extreme 
swings in body temperature.
 
»
•	
When the diagnosis is uncertain.
•	
When symptoms persist despite conventional treatment.
Benarroch EE. The clinical approach to autonomic failure in neu
-
rological disorders. Nat Rev Neurol. 2014 Jul;10(7):396–407. 
 
[PMID: 24866874]
Iodice V et al. Autonomic neuropathies. Continuum (Minneap 
Minn). 2014 Oct;20(5):1373–97. [PMID: 25299288]
 
»
Focal neurologic deficit of acute onset.
 
»
Clinical deficit resolves completely within 
24 hours.
 
»
Risk factors for vascular disease often present.
 
»
Transient ischemic attacks (TIAs) are characterized by 
focal ischemic cerebral neurologic deficits that last for less 
than 24 hours (usually less than 1–2 hours). About 30% of 
patients with stroke have a history of TIAs and 5–10% of 
patients with TIAs will have a stroke within 90 days. The 
natural history of attacks is variable. Some patients will 
have a major stroke after only a few attacks, whereas others 
may have frequent attacks for weeks or months without 
having a stroke. The risk of stroke is high in the first 
3 months after an attack, particularly in the first month and 
especially within the first 48 hours. The stroke risk is 
greater in patients older than 60 years, in patients with 
diabetes, or after TIAs that last longer than 10 minutes and 
with symptoms or signs of weakness, speech impairment, 
or gait disturbance. In general, carotid ischemic attacks are 
more liable than vertebrobasilar ischemic attacks to be fol
-
lowed by stroke.
Urgent intervention in TIA patients reduces rates of 
subsequent stroke, and the condition should be treated 
with a similar sense of urgency as unstable angina.
 
»
Etiology
An important cause of transient cerebral ischemia is embo
-
lization. In many patients with these attacks, a source is 
readily apparent in the heart or a major extracranial artery 
to the head, and emboli sometimes are visible in the retinal 
arteries. An embolic phenomenon explains why separate 
attacks may affect different parts of the territory supplied 
by the same major vessel. Cardiac causes of embolic isch
-
emic attacks include atrial fibrillation, heart failure, infec
-
tive and nonbacterial thrombotic endocarditis, atrial 
myxoma, and mural thrombi complicating myocardial

-
-
myxoma, and mural thrombi complicating myocardial 
infarction. Atrial septal defects and patent foramen ovale 
may permit venous thromboemboli to reach the brain 
(paradoxical emboli). An ulcerated plaque on a major 
artery to the brain may serve as a source of emboli. In the 
anterior circulation, atherosclerotic changes occur most 
commonly in the region of the carotid bifurcation extracra
-
nially; these changes may cause a bruit. Atherosclerosis 
also affects the vertebrobasilar system and the major intra
-
cranial vessels including the middle and anterior cerebral 
arteries.
Less common abnormalities of blood vessels that may 
cause TIAs include fibromuscular dysplasia, which affects 
particularly the cervical internal carotid artery; atheroscle
-
rosis of the aortic arch; inflammatory arterial disorders 
such as giant cell arteritis, polyarteritis, and granulomatous 
angiitis; and meningovascular syphilis. Critical stenosis of 
a major extracranial or intracranial artery may cause TIA, 
especially in the setting of hypotension.
Hematologic causes of TIA include polycythemia, sickle 
cell disease, hyperviscosity syndromes, and the antiphos
-
pholipid antibody syndrome. Severe anemia may also lead 
to transient focal neurologic deficits in patients with preex
-
isting cerebral arterial disease.
The 
subclavian steal syndrome
 may lead to transient 
vertebrobasilar ischemia. Symptoms develop when there is 
localized stenosis or occlusion of one subclavian artery 
proximal to the source of the vertebral artery, so that blood 
is “stolen” from the vertebral artery to supply the arm. A 
bruit in the supraclavicular fossa, unequal radial pulses, 
and a difference of 20 mm Hg or more between the systolic 
blood pressures in the arms should suggest the diagnosis in 
patients with vertebrobasilar TIAs.
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CMDT 2019
 
»
The symptoms of TIAs vary markedly among patients; 
however, the symptoms in a given individual tend to be 
constant in type. Onset is abrupt and without warning, and 
recovery usually occurs rapidly, often within a few minutes. 
The specific symptoms depend on the arterial distribution 
affected, as outlined in the subsequent section on stroke. 
Of note, TIA 
rarely
 causes of loss of consciousness or acute 
confusion but is often erroneously blamed for such 
symptoms.
B. Imaging
CT or MRI scan is indicated within 24 hours of symptom 
onset, in part to exclude the possibility of a small cerebral 
hemorrhage or a cerebral tumor masquerading as a TIA. 
MRI with diffusion-weighted sequences is particularly 
sensitive for revealing acute or subacute infarction, which 
is seen in up to one-third of cases despite resolution of 
clinical symptoms and indicates a high risk of subsequent 
stroke. Noninvasive imaging of the cervical vasculature 
should also be performed; carotid duplex ultrasonography 
is useful for detecting significant stenosis of the internal 
carotid artery, and MR or CT angiography permits broader 
visualization of cervical and intracranial vasculature.
C. Laboratory and Other Studies
Clinical and laboratory evaluation must include assess
-
ment for hypertension, heart disease, hematologic disor
-
ders, diabetes mellitus, hyperlipidemia, and peripheral 
vascular disease. It should include complete blood count, 
fasting blood glucose and serum cholesterol determina
-
tions and may include serologic tests for syphilis and HIV 
infection. An ECG should be obtained. Echocardiography 
with agitated saline contrast is performed if a cardioem
-
bolic source is likely, and blood cultures are obtained if 
endocarditis is suspected. Cardiac rhythm monitoring is 
indicated to detect paroxysmal atrial fibrillation and, if the 
cause of the TIA remains elusive, extended cardiac event 
monitoring may detect paroxysmal atrial fibrillation in up 
to 20% of patients.
 
»
Focal seizures usually cause abnormal motor or sensory 
phenomena such as clonic limb movements, paresthesias, 
or tingling, rather than weakness or loss of feeling. Symp
-
toms generally spread (“march”) up the limb and may lead 
to a generalized tonic-clonic seizure.
Classic migraine is easily recognized by the visual pre
-
monitory symptoms, followed by nausea, headache, and 
photophobia, but less typical cases may be hard to distin
-
guish. Patients with migraine are typically younger, com
-
monly have a history of episodes since adolescence and 
report that other family members have a similar disorder.
Focal neurologic deficits may occur during periods of 
hypoglycemia in diabetic patients receiving insulin or oral 
hypoglycemic agent therapy.
 
»
Treatment
Medical treatment is aimed at preventing further attacks and 
stroke. Treat diabetes mellitus, hematologic disorders, and 
hypertension, preferably with an angiotensin-converting 
 
enzyme inhibitor or angiotensin receptor blocker. A statin 
should be started regardless of the current low-density 
lipoprotein level (LDL), although this practice is only sup
-
ported by randomized trial data in patients with an LDL 
greater than 100 mg/dL. Cigarette smoking should be 
stopped, and cardiac sources of embolization should be 
treated appropriately. Weight reduction and regular physi
-
cal activity should be encouraged when appropriate. An 
antiplatelet or anticoagulant should be started as soon as 
imaging has established the absence of hemorrhage.
1. Hospitalization—
Hospitalization should be considered 
for patients seen within a week of the attack, when they are 
at increased risk for early recurrence. One commonly used 
method to assess recurrence risk is the 
ABCD
2
 score; 
points are assigned for each of the following criteria: age

ABCD
2
 score; 
points are assigned for each of the following criteria: age 
60 years or older (1 point), blood pressure 140/90 mm Hg 
or higher (1 point), clinical symptoms of focal weakness 
 
(2 points) or speech impairment without weakness (1 point), 
duration 60 minutes or longer (2 points) or 10–59 minutes 
(1 point), or diabetes mellitus (1 point). An ABCD
2
 score 
of 4 or more points has been suggested as a threshold for 
hospital admission. The 
ABCD
2
I
 (with an additional 
3 points for any abnormal diffusion-weighted MRI finding 
or any infarct [new or old] on noncontrast CT) has been 
proposed as a better predictor of subsequent stroke risk. 
Admission is also advisable for patients with crescendo 
attacks, symptomatic carotid stenosis, or a known cardiac 
source of emboli or hypercoagulable state; such hospital
-
ization facilitates early intervention for any recurrence and 
rapid institution of secondary prevention measures.
2. Anticoagulation—
The chief indication for anticoagula
-
tion after TIA is atrial fibrillation.
 Patients with metal heart 
valves, left ventricular thrombus, and the antiphospholipid 
antibody syndrome should also receive anticoagulation 
therapy. Treatment is with warfarin (target INR 2.0–3.0); 
bridging warfarin with heparin is not necessary, but some 
experts advocate treatment with aspirin until the INR 
becomes therapeutic. For long-term anticoagulation in the 
setting of atrial fibrillation, dabigatran (150 mg orally twice 
daily), rivaroxaban (20 mg orally daily), and apixaban 
(2.5–5 mg orally twice daily) are options; these are usually 
not started in the acute setting due to limited experience 
and lack of reversal agents for the latter two. Combination 
antiplatelet-anticoagulation therapy is only indicated in 
patients with mechanical heart valves or those with a sepa
-
rate indication for antiplatelet therapy such as a cardiac 
stent. A randomized trial of patients with heart failure 
(without atrial fibrillation) and an ejection fraction under 
35% failed to show a benefit of warfarin over aspirin.
3. Antiplatelet therapy—
All patients in whom anticoagu
-
lation is not indicated should be treated with antiplatelet 
therapy to reduce the frequency of TIAs and the incidence of 
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stroke.
 Aspirin (81 mg daily orally), aspirin combined with 
extended-release dipyridamole (200 mg twice daily orally), 
or clopidogrel (75 mg daily orally) all have similar efficacy. 
Cilostazol (100 mg twice daily) had similar efficacy as 
aspirin at stroke prevention in an Asian population with 
less risk of hemorrhage. Combining clopidogrel with aspi
-
rin for the long term increases the risk of hemorrhagic 
complications and is not recommended. However, short-
term combination antiplatelet therapy may be beneficial. 
A large Chinese trial showed that when treatment was 
initiated within 24 hours after the TIA, a single loading 
dose of clopidogrel (300 mg) followed by 75 mg/day for 
90 days plus aspirin (75 mg daily for the first 21 days) was 
more effective at reducing 90-day stroke risk than aspirin 
alone. An international trial using a similar protocol is 
ongoing.
B. Surgical or Endovascular Measures
1. Carotid revascularization—
When arteriography reveals 
a surgically accessible high-grade stenosis (70–99% in 
luminal diameter) on the side appropriate to carotid isch
-
emic attacks, operative treatment (
carotid endarterectomy
) 
 
or 
endovascular intervention
 reduces the risk of ipsilat
-
eral carotid stroke, especially when TIAs are of recent onset 
(less than 1 month) and when the perioperative morbidity 
and mortality risk is estimated to be less than 6%. Endovas
-
cular therapy carries a slightly higher procedural stroke 
risk than endarterectomy in patients older than 70 years 
and is generally reserved for younger patients whose neck 
anatomy is unfavorable for surgery. Patients with symp
-
tomatic carotid stenosis of 50–69% derive moderate benefit 
from intervention, but surgery is not indicated for mild 
stenosis (less than 50%).
2. Closure of patent foramen ovale—
Carefully selected 
patients with patent foramen ovale (PFO) and right-to-left 
shunt benefit from PFO closure 
and
 antiplatelet therapy. 
Patients should be considered for PFO closure if they are 
between 18 and 60 years old; have had a cryptogenic stroke 
or TIA; and do not have uncontrolled diabetes, hyperten
-
sion, or a specific indication for long-term anticoagulation. 
A cryptogenic stroke does not have an identified mecha
-
nism, such as large artery atherosclerosis (greater than or 
equal to 30–50% stenosis of the intracranial or cervical 
arteries or a plaque greater than or equal to 4mm thick in 
the aortic arch), known cardioembolic source (eg, atrial 
fibrillation), small vessel arteriolosclerosis (eg, lacunar 
stroke smaller than 1.5 cm in diameter), hypercoagulable 
state, or dissection. Patients with moderate to large inter
-
atrial shunts or associated atrial septal aneurysms appear to 
benefit most from PFO closure.
 
»
All patients should be referred for urgent investigation and 
treatment to prevent stroke.
 
»
If seen within a week of a TIA, patients should be consid
-
ered for admission when they have an ABCD
2
 score of 
4 points or more, when outpatient evaluation is impracti
-
cal, or when there are multiple attacks, carotid stenosis of 
greater than 70%, or other concern for early recurrence or 
stroke.
Kernan WN et al. Guidelines for the prevention of stroke in 
patients with stroke and transient ischemic attack: a guideline for 
healthcare professionals from the American Heart Association/
 
American Stroke Association. Stroke. 2014 Jul;45(7):2160–236. 
 
[PMID: 24788967]
Sposato LA et al. Diagnosis of atrial fibrillation after stroke and 
transient ischaemic attack: a systematic review and meta-
analysis. Lancet Neurol. 2015 Apr;14(4):377–87. [PMID: 
25748102]
STROKE
 
»
Sudden onset of neurologic deficit of cerebrovas
-
cular origin.
 
»
Patient often has hypertension, diabetes mellitus, 
tobacco use, atrial fibrillation, or atherosclerosis.
 
»
Distinctive neurologic signs reflect the region of 
the brain involved.
 
»

»
 
»
 
»
In the United States, stroke is the fifth leading cause of 
death and a leading cause of disability, despite a general 
decline in the incidence of stroke in the last 30 years. The 
precise reasons for this decline are uncertain, but increased 
awareness of risk factors (hypertension, diabetes mellitus, 
hyperlipidemia, cigarette smoking, cardiac disease, HIV 
infection, recreational drug abuse, heavy alcohol consump
-
tion, family history of stroke) and improved prophylactic 
measures and surveillance of those at increased risk have 
been contributory.
Strokes are subdivided pathologically into infarcts and 
hemorrhages. The distinction may be difficult clinically; 
CT scanning is essential to clarify the pathologic basis 
(Table 24–3).
1. Lacunar Infarction
Lacunar infarcts are small lesions (usually less than 
1.5 cm in diameter) that occur in the distribution of short 
penetrating arterioles in the basal ganglia, pons, cerebel
-
lum, internal capsule, thalamus and, less commonly, the 
deep cerebral white matter (Table 24–3). Lacunar infarcts 
are associated with poorly controlled hypertension or 
diabetes and have been found in several clinical syn
-
dromes, including contralateral pure motor hemiparesis 
or pure hemisensory deficit, ipsilateral ataxia with hemi
-
paresis, and dysarthria with clumsiness of the hand. The 
neurologic deficit may progress over 24–36 hours before 
stabilizing.
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Early mortality and risk of stroke recurrence is higher 
for patients with nonlacunar than lacunar infarcts. The 
prognosis for recovery from the deficit produced by a lacu
-
nar infarct is usually good, with partial or complete resolu
-
tion occurring over the following 4–6 weeks in many 
instances. Treatment is as described for TIA and cerebral 
infarction.
2. Cerebral Infarction
Thrombotic or embolic occlusion of a major vessel leads to 
cerebral infarction. Causes are identical to the disorders 
predisposing to TIAs. The resulting deficit depends on the 
particular vessel involved and the extent of any collateral 
circulation. Cerebral ischemia leads to release of excitatory 
Table 24–3.
 
Features of the major stroke subtypes.
Stroke Type and 
Subtype
Diagnosis
Treatment
Ischemic Stroke
Lacunar infarct
Small (< 1.5 cm) lesions in the 
basal ganglia, pons, cerebel
-
lum, or internal capsule; less 
often in deep cerebral white 
matter; prognosis generally 
good; clinical features depend 
on location, but may worsen 
over first 24–36 hours.
MRI with diffusion-weighted 
sequences usually defines the area 
of infarction; CT is insensitive 
acutely but can be used to exclude 
Antiplatelet; control risk factors (hyper
-
tension, tobacco use, hypercholesterol
-
emia, and diabetes mellitus).
Carotid circulation 
See text—signs vary depending 
on occluded vessel.
Noncontrast CT to exclude hemor
-
rhage but findings may be normal 
during first 6–24 hours of an isch
-
emic stroke; diffusion-weighted 
MRI is gold standard for identifying 
acute stroke; electrocardiography, 
carotid duplex studies, echocar
-
diography, blood glucose, com
-
plete blood count, and tests for 
hyperlipidemia are indicated; 
Holter and extended monitoring in 
selected instances; CTA, MRA, or 
conventional angiography in 
selected cases; tests for hypercoag
-
ulable states in selected cases.
0–3 hours in United States: intravenous 
thrombolytics (approved in Europe for 
up to 4.5 hours).
0–6 hours: endovascular mechanical 
embolectomy.
6–24 hours: endovascular mechanical 
embolectomy in select cases.
Secondary prevention: antiplatelet agent 
is first-line therapy; anticoagulation 
without heparin bridge for cardioem
-
bolic strokes due to atrial fibrillation 
and other select cases when no contra
-
indications exist; control risk factors as 
above.
Vertebrobasilar 
occlusion
See text—signs vary based on 
location of occluded vessel.
As for carotid circulation obstruction.
h
emorrhagic Stroke
Spontaneous 
 
intracerebral 
Commonly associated with 
hypertension; also with bleed
-
ing disorders, amyloid 
angiopathy.
Hypertensive hemorrhage is 
located commonly in the basal 
ganglia, pons, thalamus, cere
-
bellum, and less commonly 
the cerebral white matter.
Noncontrast CT is superior to MRI for 
detecting bleeds of < 48 hours 
duration; laboratory tests to iden
-
tify bleeding disorder: angiography 
may be indicated to exclude aneu
-
rysm or AVM in younger patients 
without hypertension. Do 
not
 per
-
form lumbar puncture.
Lower systolic blood pressure to 140 mm 
Hg; cerebellar bleeds or hematomas 
with gross mass effect may require 
urgent surgical evacuation.
AVM: surgical resection indicated to pre
-
vent further bleeding; other modalities 
to treat nonoperable AVMs available at 
specialized centers.
Subarachnoid 
Present with sudden onset of 
worst headache of life, may 
lead rapidly to loss of con
-
sciousness; signs of meningeal 
irritation often present; etiol
-
ogy usually aneurysm or AVM, 
but 20% have no source 
CT to confirm diagnosis, but may be 
normal in rare instances; if CT neg
-
ative and suspicion high, perform 
lumbar puncture to look for red 
blood cells or xanthochromia; angi
-
ography to determine source of 
bleed in candidates for treatment.
Lower systolic blood pressure to

-
Lower systolic blood pressure to 
< 140 mm Hg immediately.
Aneurysm: prevent further bleeding by 
clipping aneurysm or coil embolization; 
nimodipine helps prevent vasospasm; 
once aneurysm has been obliterated 
intravenous fluids and induced hyper
-
tension to prevent vasospasm; angio
-
plasty may also reverse symptomatic 
vasospasm.
AVM: as above.
AVMs, arteriovenous malformations; CTA, computed tomography angiography; MRA, magnetic resonance angiography.
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and other neuropeptides that may augment calcium flux 
into neurons, thereby leading to cell death and increasing 
the neurologic deficit.
 
»
Onset is usually abrupt, and there may then be very little 
progression except that due to brain swelling. Clinical 
evaluation should always include examination of the heart 
for murmurs and rhythm irregularities. Auscultating over 
the carotid or subclavian vessels may reveal a bruit but is 
not sensitive enough to substitute for vascular imaging.
1. Obstruction of carotid circulation—
Occlusion of the 
 distal to its junction with the ante
-
rior communicating artery causes weakness and cortical 
sensory loss in the contralateral leg and sometimes mild 
weakness of the arm, especially proximally. There may be a 
contralateral grasp reflex, paratonic rigidity, abulia (lack of 
initiative) or frank confusion. Urinary incontinence is not 
uncommon, particularly if behavioral disturbances are 
conspicuous. Bilateral anterior cerebral infarction is espe
-
cially likely to cause marked behavioral changes and 
memory disturbances. Unilateral anterior cerebral artery 
occlusion proximal to the junction with the anterior com
-
municating artery is generally well tolerated because of the 
collateral supply from the other side.
Middle cerebral artery
 occlusion leads to contralateral 
hemiplegia, hemisensory loss, and homonymous hemianopia 
(ie, bilaterally symmetric loss of vision in half of the visual 
fields), with the eyes deviated to the side of the lesion. If the 
dominant hemisphere is involved, global aphasia is also pres
-
ent. It may be impossible to distinguish this clinically from 
occlusion of the internal carotid artery. With occlusion of 
either of these arteries, there may also be considerable swell
-
ing of the hemisphere during the first 72 hours. For example, 
an infarct involving one cerebral hemisphere may lead to 
such swelling that the function of the other hemisphere or the 
rostral brainstem is disturbed and coma results. Occlusions 
of different branches of the middle cerebral artery cause more 
limited findings. For example, involvement of the superior 
division in the dominant hemisphere leads to a predomi
-
nantly expressive (Broca) aphasia and to contralateral paraly
-
sis and loss of sensations in the arm, the face and, to a lesser 
extent, the leg. Inferior branch occlusion in the dominant 
hemisphere produces a receptive (Wernicke) aphasia and a 
homonymous visual field defect. With involvement of the 
nondominant hemisphere, speech and comprehension are 
preserved, but there may be a left hemispatial neglect syn
-
drome or constructional and visuospatial deficits.
ophthalmic or central retinal artery
 
leads to sudden painless visual loss with retinal pallor and 
a macular cherry red spot on fundoscopic examination. 
Sudden, transient vision loss in one eye (
amaurosis fugax
) 
is a TIA in this arterial territory. Patients with a cilioretinal 
artery (approximately 25%) may have macular sparing due 
to collateral blood supply.
2. Obstruction of vertebrobasilar circulation—
Occlusion 
of the 
 may lead to a thalamic 
syndrome in which contralateral hemisensory disturbance 
occurs, followed by the development of spontaneous pain 
and hyperpathia. There is often a macular-sparing hom
-
onymous hemianopia and sometimes a mild, usually tem
-
porary, hemiparesis. Depending on the site of the lesion 
and the collateral circulation, the severity of these deficits 
varies and other deficits may also occur, including involun
-
tary movements and alexia. Occlusion of the main artery 
beyond the origin of its penetrating branches may lead 
solely to a macular-sparing hemianopia.
Vertebral artery occlusion
 below the origin of the 
anterior spinal and posterior inferior cerebellar arteries

anterior spinal and posterior inferior cerebellar arteries 
may be clinically silent because the circulation is main
-
tained by the other vertebral artery. If the remaining verte
-
bral artery is congenitally small or severely atherosclerotic, 
however, a deficit similar to that of basilar artery occlusion 
is seen unless there is good collateral circulation from the 
anterior circulation through the circle of Willis. An 
obstruction of the 
posterior inferior cerebellar artery
 or 
an obstruction of the vertebral artery just before it branches 
to this vessel leads to the lateral medullary syndrome, char
-
acterized by vertigo and nystagmus (vestibular nucleus), 
ipsilateral spinothalamic sensory loss involving the face 
(trigeminal nucleus and tract), dysphagia (nucleus ambig
-
uus), limb ataxia (inferior cerebellar peduncle), and Horner 
syndrome (descending sympathetic fibers), combined with 
contralateral spinothalamic sensory loss involving the 
limbs.
Occlusion of 
both
 
vertebral arteries
 or the 
basilar 
artery
 leads to coma with pinpoint pupils, flaccid quadri
-
plegia and sensory loss, and variable cranial nerve abnor
-
malities. With partial basilar artery occlusion, there may be 
diplopia, visual loss, vertigo, dysarthria, ataxia, weakness 
or sensory disturbances in some or all of the limbs, and 
discrete cranial nerve palsies. In patients with hemiplegia 
of pontine origin, the eyes are often deviated to the para
-
lyzed side, whereas in patients with a hemispheric lesion, 
the eyes commonly deviate from the hemiplegic side. 
When the small paramedian arteries arising from the basi
-
lar artery are occluded, contralateral hemiplegia and sen
-
sory deficit occur in association with an ipsilateral cranial 
nerve palsy at the level of the lesion.
Occlusion of any of the major 
cerebellar arteries
 pro
-
duces vertigo, nausea, vomiting, nystagmus, and ipsilateral 
limb ataxia. Contralateral spinothalamic sensory loss in the 
limbs may also be present. Deafness due to cochlear infarc
-
tion may follow occlusion of the anterior inferior cerebellar 
artery, which may also cause ipsilateral facial spinotha
-
lamic sensory loss and weakness. Massive cerebellar infarc
-
tion may lead to obstructive hydrocephalus, coma, tonsillar 
herniation, and death.
B. Imaging
A CT scan of the head (without contrast) should be per
-
formed immediately, before the administration of aspirin 
or other antithrombotic agents, to 
exclude cerebral hemor
-
rhage
 (Table 24–3). CT is relatively insensitive to acute 
ischemic stroke within the first 6–12 hours, and subse
-
quent MRI with diffusion-weighted sequences helps define 
the distribution and extent of infarction as well as exclude 
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tumor or other differential considerations. CT angiography 
of the head and neck should be performed to identify large 
vessel occlusions amenable to endovascular therapy in 
patients presenting within 6 hours of stroke onset, and 
should be considered in those presenting between 6 and 
24 hours, together with CT perfusion studies. Regardless of 
timing of presentation, imaging of the cervical vasculature 
is indicated as part of a search to identify the source of 
the stroke. In patients with a PFO and otherwise crypto
-
genic stroke, the intracranial vasculature must be imaged 
to rule out large vessel atherosclerosis before PFO closure 
can be considered.
Investigations should include a complete blood count, 
blood glucose determination, and fasting lipid panel. Sero
-
logic tests for syphilis and HIV infection may be included 
depending on the circumstances. Screening for antiphos
-
pholipid antibodies (lupus anticoagulants, anticardiolipin, 
and anti-beta2-glycoprotein antibodies); the factor V 
Leiden mutation; abnormalities of protein C, protein S, or 
antithrombin; or a prothrombin gene mutation is indicated 
only if a hypercoagulable disorder is suspected (eg, a young 
patient without apparent risk factors for stroke) or needs to 
be ruled out if PFO closure is under consideration. While 
elevated serum homocysteine is a risk factor for stroke, 
lowering homocysteine levels with vitamin supplementa
-
tion has not been shown to decrease stroke risk, and there
-
fore, routinely checking homocysteine is 
not
 recommended. 
Electrocardiography or continuous cardiac monitoring for 
at least 24 hours will help exclude a recent myocardial 
infarction or a cardiac arrhythmia that might be serving as 
a source of embolization. While atrial fibrillation will be 
discovered in approximately 10% of patients with ischemic 
stroke during their hospitalization, it is estimated that an 
arrhythmia will be found in an additional 10% with con
-
tinuous cardiac event monitoring after discharge; this test
-
ing is indicated in cases where atrial fibrillation is suspected 
(eg, nonlacunar stroke and left atrial enlargement on echo
-
cardiography or lack of intracranial or carotid atheroscle
-
rosis) but has not been demonstrated. Echocardiography 
(with agitated saline contrast) should be performed in 
cases of nonlacunar stroke to exclude valvular disease, left-
to-right shunting, and cardiac thrombus. Blood cultures 
should be performed if endocarditis is suspected but are 
not required routinely. Examination of the cerebrospinal 
fluid is not always necessary but may be helpful if cerebral 
vasculitis or another inflammatory or infectious cause of 
stroke is suspected, but it should be delayed until after CT 
or MRI to exclude any risk for herniation due to mass 
effect.
 
»
Treatment
Management is divided into acute and chronic phases, the 
first aimed at minimizing disability and the second aimed 
at preventing recurrent stroke. The most important initial 
determination is 
the time at which the patient was last nor
-
mal
; this is considered the time of stroke onset. If patients 
receive medical attention within 6 hours of stroke onset, 
a CT and CT angiogram should be performed to rule out 
hemorrhage and to identify large vessel occlusions.
Intravenous thrombolytic therapy with recombinant 
tissue plasminogen activator (rtPA; 0.9 mg/kg to a maxi
-
mum of 90 mg, with 10% given as a bolus over 1 minute 
and the remainder over 1 hour) improves the chance of 
recovery without significant disability at 90 days from 26% 
to 39% if given within 3 hours from stroke onset; it is still 
effective up to 4.5 hours from stroke onset. Treatment 
should be initiated as soon as possible; outcome is directly 
related to the time from stroke onset to treatment. Intrave
-
nous thrombolysis is approved in Europe for use up to

-
nous thrombolysis is approved in Europe for use up to 
4.5 hours from stroke onset but only for up to 3 hours in 
the United States, although off-label use during the 3- to 
4.5-hour window is standard.
The risk of rtPA is hemorrhage; when given beyond 
4.5 hours, the risk of intracerebral hemorrhage outweighs any 
benefit. Contraindications to rtPA include the following: 
(1) significant head trauma or prior stroke in the previous 
3 months, (2) symptoms suggestive of subarachnoid hem
-
orrhage, (3) recent arterial puncture at a noncompressible 
site, (4) previous intracranial hemorrhage, (5) intracranial 
neoplasm or arteriovenous malformation, (6) recent intra
-
cranial or intraspinal surgery, (7) active internal bleeding 
or bleeding diathesis (eg, platelets less than 100,000/mcL, 
recent use of heparin with an elevated aPTT, INR greater 
than 1.7, current use of direct thrombin or factor Xa inhibi
-
tors), (8) glucose less than 50 mg/dL (2.7 mmol/L), (9) large 
cerebral infarction on CT, and (10) systolic pressure greater 
than 185 mm Hg or diastolic pressure greater than 110 mm 
Hg. The blood pressure should be lowered immediately to 
less than 185/110 mm Hg with intravenous labetalol or 
nicardipine to enable rtPA administration. Additional rela
-
tive contraindications include minor stroke, seizure at 
stroke onset, pregnancy, major surgery within previous 
14  days, gastrointestinal or urinary tract hemorrhage 
within previous 21 days, and myocardial infarction within 
previous 3 months.
Several randomized trials have demonstrated an 
increased likelihood of achieving functional independence 
with the use of endovascular mechanical embolectomy by 
stent retrievers as an adjunct to intravenous rtPA. Only 
patients with large vessel occlusion (about 20% of patients 
with acute ischemic stroke) are eligible for embolectomy, 
which must be performed within 6 hours of stroke onset. 
An exception to this time restriction may exist in patients 
with severe clinical deficits and relatively small infarct vol
-
umes (as indicated by diffusion-weighted MRI or perfu
-
sion CT), indicating a large ischemic penumbra amenable 
to salvage with reperfusion. A randomized trial investigat
-
ing embolectomy in such patients achieved functional 
independence in 49% of those treated between 6 and 
24  hours of stroke onset compared to 13% of untreated 
patients.
Early management of a completed stroke otherwise 
requires general supportive measures. Management in a 
stroke care unit has been shown to improve outcomes, 
likely due to early rehabilitation and prevention of medical 
complications. During the acute stage, there may be 
marked brain swelling and edema, with symptoms and 
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signs of increasing intracranial pressure, an increasing 
neurologic deficit, or herniation syndrome. Elevated intra
-
cranial pressure is managed by head elevation and osmotic 
agents such as mannitol. Maintenance of an adequate cere
-
bral perfusion pressure helps prevent further ischemia. 
Early decompressive hemicraniectomy (within 48 hours of 
stroke onset) for malignant middle cerebral artery infarc
-
tions reduces mortality and improves functional outcome. 
Attempts to lower the blood pressure of hypertensive 
patients during the acute phase (ie, within 72 hours) of a 
stroke should generally be 
avoided
 unless the purpose is to 
enable the safe administration of rtPA, as there is loss of 
cerebral autoregulation, and lowering the blood pressure 
may further compromise ischemic areas. However, if the 
systolic pressure exceeds 220 mm Hg, it can be lowered 
using intravenous labetalol or nicardipine with continuous 
monitoring to 170–200 mm Hg and then, after 72 hours, it 
can be reduced further to less than 140/90 mm Hg. Blood 
pressure augmentation is usually not necessary in patients 
with relative hypotension but maintenance of intravenous 
hydration is important.
Prophylactic and medical measures are discussed in 
the section on TIAs and should guide management. Once 
hemorrhage has been excluded by CT, aspirin (325 mg 
orally daily) is started immediately unless the patient 
received thrombolysis, in which case aspirin is initiated 
after a follow-up CT has ruled out thrombolytic-
 
associated hemorrhage at 24 hours. Anticoagulant medi
-
cations are started when indicated, as discussed in the 
section on TIAs. There is generally 
no advantage
 in delay, 
and the common fear of causing hemorrhage into a previ
-
ously infarcted area is misplaced, since there is a far 
greater risk of further embolism to the cerebral circulation 
if treatment is withheld.
Physical therapy has an important role in the manage
-
ment of patients with impaired motor function. Passive 
movements at an early stage will help prevent contractures. 
As cooperation increases and some recovery begins, active 
movements will improve strength and coordination. In all 
cases, early mobilization and active rehabilitation are 
important. Occupational therapy may improve morale and 
motor skills, while speech therapy may help expressive 
aphasia or dysarthria. Because of the risk for dysphagia 
following stroke, access to food and drink is typically 
restricted until an appropriate swallowing evaluation; the 
head of the bed should be kept elevated to prevent aspira
-
tion. Urinary catheters should not be placed and, if placed, 
removed within 24–48 hours.
 
»
Prognosis
The prognosis for survival after cerebral infarction is better 
than after cerebral or subarachnoid hemorrhage. Patients 
receiving treatment with rtPA are at least 30% more likely 
to have minimal or no disability at 3 months than those not 
treated by this means. Those treated with mechanical 
embolectomy are also at least 30% more likely to achieve 
functional independence. Loss of consciousness after a 
cerebral infarct implies a poorer prognosis than otherwise. 
The extent of the infarct governs the potential for rehabili
-
tation. Patients who have had a cerebral infarct are at risk 
for additional strokes and for myocardial infarcts. The 
prophylactic measures discussed earlier reduce this risk. 
Antiplatelet therapy (same treatment guidelines as for TIA) 
reduces the recurrence rate by 30% among patients without 
a cardiac cause for the stroke who are not candidates for 
carotid endarterectomy. Nevertheless, the cumulative risk 
of recurrence of noncardioembolic stroke is still 3–7% 
annually.
 
»
All patients should be referred.
 
»
All patients should be hospitalized, preferably in a stroke 
care unit.
Jüttler E et al; DESTINY II Investigators. Hemicraniectomy in

»
care unit.
Jüttler E et al; DESTINY II Investigators. Hemicraniectomy in 
older patients with extensive middle-cerebral-artery stroke. 
 
N Engl J Med. 2014 Mar 20;370(12):1091–100. [PMID: 24645942]
Muth CC. JAMA patient page. Recovery after stroke. JAMA. 
2016 Dec13;316(22):2440. [PMID: 27959997]
Nogueira RG et al; DAWN Trial Investigators. Thrombectomy 6 to 
24 hours after stroke with a mismatch between deficit and infarct. 
N Engl J Med. 2018 Jan 4;378(1):11–21. [PMID: 29129157]
Powers WJ et al. 2018 Guidelines for the early management of 
patients with acute ischemic stroke: a guideline for healthcare 
professionals from the American Heart Association/American 
 
Stroke Association. Stroke. 2018 Mar;49(3):e46–e110. [PMID: 
29367334]
3. Intracerebral 
h
emorrhage
Spontaneous, nontraumatic intracerebral hemorrhage in 
patients with no angiographic evidence of an associated 
vascular anomaly (eg, aneurysm or angioma) is usually due 
to hypertension. The pathologic basis for hemorrhage is 
probably the presence of microaneurysms that develop on 
perforating vessels in hypertensive patients. Hypertensive 
intracerebral hemorrhage occurs most frequently in the 
basal ganglia, pons, thalamus, cerebellum and less com
-
monly in the cerebral white matter. Hemorrhage may 
extend into the ventricular system or subarachnoid space, 
and signs of meningeal irritation are then found. In older 
adults, cerebral amyloid angiopathy is another important 
and frequent cause of hemorrhage, which is usually lobar 
in distribution, sometimes recurrent, and associated with a 
better immediate prognosis than hypertensive hemor
-
rhage. Arteriovenous malformations are an important 
cause of intracerebral hemorrhage in younger patients.
Other causes of nontraumatic intracerebral hemor
-
rhage include hematologic and bleeding disorders (eg, 
leukemia, thrombocytopenia, hemophilia, or disseminated 
intravascular coagulation), anticoagulant therapy, liver 
disease, high alcohol intake, cocaine and methamphet
-
amine abuse, and primary or secondary brain tumors. 
There is also an association with advancing age and male 
sex. Bleeding is primarily into the subarachnoid space 
when it occurs from an intracranial aneurysm, but it may 
be partly intraparenchymal as well. Hemorrhage can also 
occur into arterial and venous cerebral infarcts.
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»
With hemorrhage into the cerebral hemisphere, conscious
-
ness is initially lost or impaired in about one-half of 
patients. Vomiting occurs very frequently at the onset of 
bleeding, and headache is sometimes present. Focal symp
-
toms and signs then develop, depending on the site of the 
hemorrhage. With hypertensive hemorrhage, there is gen
-
erally a rapidly evolving neurologic deficit with hemiplegia 
or hemiparesis. A hemisensory disturbance is also present 
with more deeply placed lesions. With lesions of the puta
-
men, loss of conjugate lateral gaze may be conspicuous. 
With thalamic hemorrhage, there may be a loss of upward 
gaze, downward or skew deviation of the eyes, lateral gaze 
palsies, and pupillary inequalities.
Cerebellar hemorrhage may present with sudden onset 
of nausea and vomiting, dysequilibrium, ataxia of gait, 
limbs, or trunk; headache; and loss of consciousness that 
may terminate fatally within 48 hours. Pontine hemorrhage 
causes some combination of lateral conjugate gaze palsies 
to the side of the lesion; small reactive pupils; contralateral 
hemiplegia; peripheral facial weakness; and periodic respi
-
ration. These signs may be bilateral with larger pontine 
hemorrhage, and the patient may become locked in, with 
quadriplegia and preserved consciousness.
B. Imaging
CT scanning (without contrast) is important not only in 
confirming that hemorrhage has occurred but also in 
determining the size and site of the hematoma. MRI is 
equally sensitive when magnetic susceptibility weighted 
sequences (eg, gradient echo) are used. If the patient’s con
-
dition permits further intervention, CT angiography, MR 
angiography, or cerebral angiography may be undertaken 
to determine whether an aneurysm or arteriovenous mal
-
formation is present. In patients under age 55 with lobar 
hemorrhage and no history of hypertension, a contrast-
enhanced MRI may indicate a nonhypertensive cause such 
as an underyling neoplasm.
A complete blood count, platelet count, prothrombin and 
partial thromboplastin times, liver biochemical tests, and 
kidney function tests may reveal a predisposing cause for 
the hemorrhage. Lumbar puncture is contraindicated 
because it may precipitate a herniation syndrome in 
patients with a large hematoma, and CT scanning is supe
-
rior in detecting intracerebral hemorrhage.
 
»
Treatment
Patients should be admitted to an intensive care unit for 
observation and supportive care. The systolic blood pres
-
sure should be lowered to 140 mm Hg with intravenous 
labetalol or nicardipine, although randomized trials target
-
ing systolic blood pressures of less than 140 mm Hg and 
less than 180 mm Hg have not shown a difference in out
-
comes. Thrombocytopenia should be treated with platelet 
transfusion; the specific threshold for treatment and the 
goal platelet count after transfusion vary with patient char
-
acteristics and provider experience. Coagulopathies should 
be reversed using fresh frozen plasma, prothrombin com
-
plex concentrates, vitamin K, or specific reversal agents 
(eg, protamine for heparin, idarucizumab for dabigatran). 
Hemostatic therapy with recombinant activated factor VII 
in patients without underlying coagulopathy has not 
improved survival or functional outcome. Intracranial 
pressure may require monitoring and osmotic therapy. 
Ventricular drainage may be required in patients with 
intraventricular hemorrhage and acute hydrocephalus. 
Decompression may be helpful when a superficial hema
-
toma in cerebral white matter is exerting a mass effect and 
causing incipient herniation. In patients with cerebellar 
hemorrhage, prompt surgical evacuation of the hematoma is 
appropriate, because spontaneous unpredictable deteriora
-
tion may otherwise lead to a fatal outcome and because 
operative treatment may lead to complete resolution of the

-
operative treatment may lead to complete resolution of the 
clinical deficit. The treatment of underlying structural 
lesions or bleeding disorders depends on their nature. There 
is no specific treatment for cerebral amyloid angiopathy.
 
»
 
»
All patients should be hospitalized.
Hemphill JC III et al. Guidelines for the management of sponta
-
neous intracerebral hemorrhage: a guideline for healthcare 
professionals from the American Heart Association/Ameri
-
can Stroke Association. Stroke. 2015 Jul;46(7):2032–60. 
[PMID: 26022637]
Qureshi AI et al; ATACH-2 Trial Investigators and the Neuro
-
logical Emergency Treatment Trials Network. Intensive 
blood-pressure lowering in patients with acute cerebral hem
-
orrhage. N Engl J Med. 2016 Sep 15;375(11):1033–43. [PMID: 
27276234]
4. Spontaneous Subarachnoid 
h
emorrhage
 
»
Sudden severe headache.
 
»
Signs of meningeal irritation usually present.
 
»
Obtundation is common.
 
»
Focal deficits frequently absent.
 
»
Between 5% and 10% of strokes are due to subarachnoid 
hemorrhage. Trauma is the most common cause of sub
-
arachnoid hemorrhage, the prognosis of which depends on 
the severity of the head injury. Spontaneous (nontrau
-
matic) subarachnoid hemorrhage frequently results from 
the rupture of an arterial saccular (“berry”) aneurysm or 
from an arteriovenous malformation.
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»
Subarachnoid hemorrhage has a characteristic clinical pic
-
ture. Its onset is with sudden (“thunderclap”) headache of a 
severity never experienced previously by the patient. This 
may be followed by nausea and vomiting and by a loss or 
impairment of consciousness that can either be transient or 
progress inexorably to deepening coma and death. If con
-
sciousness is regained, the patient is often confused and 
irritable and may show other symptoms of an altered men
-
tal status. Neurologic examination generally reveals nuchal 
rigidity and other signs of meningeal irritation, except in 
deeply comatose patients.
Most aneurysms are asymptomatic until they rupture, 
but they may cause a focal neurologic deficit by compress
-
ing adjacent structures. Occasional patients with aneu
-
rysms have headaches, sometimes accompanied by nausea 
and neck stiffness, a few hours or days before massive 
subarachnoid hemorrhage occurs. This has been attributed 
to “warning leaks” of a small amount of blood from the 
aneurysm.
A higher risk of subarachnoid hemorrhage is associated 
with older age, female sex, nonwhite ethnicity, hyperten
-
sion, tobacco smoking, high alcohol consumption (exceed
-
ing 150 g per week), previous symptoms, posterior 
circulation aneurysms, and larger aneurysms. Focal neuro
-
logic signs are usually absent but, when present, may relate 
either to a focal intracerebral hematoma (from arteriove
-
nous malformations) or to ischemia in the territory of the 
vessel with a ruptured aneurysm.
B. Imaging
A CT scan (preferably with CT angiography) should be 
performed immediately to confirm that hemorrhage has 
occurred and to search for clues regarding its source. It is 
preferable to MRI because it is faster and more sensitive in 
detecting hemorrhage in the first 24 hours. CT findings 
sometimes are normal in patients with suspected hemor
-
rhage, and the cerebrospinal fluid must then be examined 
for the presence of blood or xanthochromia before the pos
-
sibility of subarachnoid hemorrhage is discounted.
Cerebral arteriography is undertaken to determine the 
source of bleeding. In general, bilateral carotid and verte
-
bral arteriography are necessary because aneurysms are 
often multiple, while arteriovenous malformations may be 
supplied from several sources. The procedure allows an 
interventional radiologist to treat an underlying aneurysm 
or arteriovenous malformation by various techniques. If 
arteriograms show no abnormality, the examination should 
be repeated after 2 weeks because vasospasm or thrombus 
may have prevented detection of an aneurysm or other 
vascular anomaly during the initial study. CT or MR angi
-
ography may also be revealing but is less sensitive than 
conventional arteriography.
The cerebrospinal fluid demonstrates an elevated red blood 
cell count. Subarachnoid hemorrhage can be differentiated 
from a traumatic lumbar puncture by the lack of clearing of 
red blood cells from the first and fourth tube of cerebrospi
-
nal fluid or by the presence of xanthochromia, which 
occurs due to lysis of red blood cells and takes at least 
2 hours to develop. The absolute red blood cell count is also 
helpful: in the absence of xanthochromia, a count of less 
than 2000 RBC × 10
6
/L is very unlikely to be due to sub
-
arachnoid hemorrhage. Electrocardiographic evidence of 
arrhythmias or myocardial ischemia has been well 
described and probably relates to excessive sympathetic 
activity. Peripheral leukocytosis and transient glycosuria 
are also common findings.
 
»
Treatment
All patients should be hospitalized and seen by a neurolo
-
gist. The measures outlined below in the section on stupor 
and coma are applied to comatose patients. Conscious 
patients are confined to bed, advised against any exertion 
or straining, treated symptomatically for headache and

or straining, treated symptomatically for headache and 
anxiety, and given laxatives or stool softeners. The systolic 
blood pressure should be lowered to 140 mm Hg until the 
aneurysm is secured. Seizure prophylaxis is not necessary 
unless a convulsion has occurred (see Table 24–2). Patients 
are generally hospitalized for at least 14 days to monitor, 
prevent, and treat vasospasm.
The major aim of treatment is to prevent further hem
-
orrhage. The risk of further hemorrhage from a ruptured 
aneurysm is greatest within a few days of the first hemor
-
rhage; approximately 20% of patients will have further 
bleeding within 2 weeks and 40% within 6 months. Defini
-
tive treatment, ideally within 2 days of the hemorrhage, 
requires surgical clipping of the aneurysm or endovascular 
treatment by coil embolization; the latter is sometimes 
feasible even for inoperable aneurysms and has a lower 
morbidity than surgery.
 
»
Spontaneous subarachnoid hemorrhage may result in severe 
complications, so monitoring is necessary, usually in an inten
-
sive care unit. Hemiplegia or other focal deficit sometimes 
may follow aneurysmal bleeding after a delay of 2–14  days 
due to focal arterial spasm. The etiology of 
vasospasm
 is 
uncertain and likely multifactorial, and it sometimes leads 
to significant cerebral ischemia or infarction and may 
further aggravate any existing increase in intracranial 
pressure. Transcranial Doppler ultrasound may be used 
to screen noninvasively for vasospasm, but conventional 
arteriography is required to document and treat vasospasm 
when the clinical suspicion is high. Nimodipine has been 
shown to reduce the incidence of ischemic deficits from 
arterial spasm; a dose of 60 mg every 4 hours orally for 
21 days is given prophylactically to all patients. After surgi
-
cal obliteration of all aneurysms, symptomatic vasospasm 
may also be treated by intravascular volume expansion and 
induced hypertension; transluminal balloon angioplasty of 
involved intracranial vessels is also helpful.
Acute 
hydrocephalus
, which sometimes occurs due to 
cerebrospinal fluid outflow disruption by the subarachnoid 
blood, should be suspected if the patient deteriorates 
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clinically; a repeat CT scan should be obtained. Acute 
hydrocephalus frequently causes intracranial hypertension 
severe enough to require temporary, and less commonly 
prolonged or permanent, intraventricular cerebrospinal 
fluid shunting. 
Renal salt-wasting
 is another complication 
of subarachnoid hemorrhage that may develop abruptly 
during the first several days of hospitalization. The result
-
ing hyponatremia and cerebral edema may exacerbate 
intracranial hypertension and may require carefully titrated 
treatment with oral sodium chloride or intravenous hyper
-
osmotic sodium solution. Daily measurement of the serum 
sodium level allows for the early detection of this complica
-
tion. Hypopituitarism may occur as a late complication of 
Blok KM et al. CT within 6 hours of headache onset to rule out 
subarachnoid hemorrhage in nonacademic hospitals. 
 
N
eurology. 
2015 May 12;84(19):1927–32. [PMID: 25862794]
Perry JJ et al. Differentiation between traumatic tap and aneu
-
rysmal subarachnoid hemorrhage: prospective cohort study. 
BMJ. 2015 Feb 18;350:h568. [PMID: 25694274]
Perry JJ et al. Validation of the Ottowa subarachnoid hemorrhage 
rule in patients with acute headache. CMAJ. 2017 Nov 13;
 
189(45):E1379–85. [PMID: 29133539]
5. Intracranial 
a
neur
ysm
 
»
Subarachnoid hemorrhage or focal deficit.
 
»
Abnormal imaging studies.
 
»
Saccular aneurysms (“berry” aneurysms) tend to occur at 
arterial bifurcations, are frequently multiple (20% of cases), 
and are usually asymptomatic. They may be associated with 
polycystic kidney disease and coarctation of the aorta. Risk 
factors for aneurysm formation include smoking, hyperten
-
sion, and hypercholesterolemia. Most aneurysms are located 
on the anterior part of the circle of Willis—
 
p
articularly on 
the anterior or posterior communicating arteries, at the 
bifurcation of the middle cerebral artery, and at the bifurca
-
tion of the internal carotid artery. Mycotic aneurysms result
-
ing from septic embolism occur in more distal vessels and 
often at the cortical surface. The most significant complica
-
tion of intracranial aneurysms is a subarachnoid hemor
-
rhage, which is discussed in the preceding section.
 
»
Aneurysms may cause a focal neurologic deficit by com
-
pressing adjacent structures. However, most are asymp
-
tomatic or produce only nonspecific symptoms until they 
rupture, at which time subarachnoid hemorrhage results. 
Its manifestations, complications, and management were 
outlined in the preceding section.
B. Imaging
Definitive evaluation is by angiography (bilateral carotid and 
vertebral studies), which generally indicates the size and site 
of the lesion, sometimes reveals multiple aneurysms, and 
may show arterial spasm if rupture has occurred. Visualiza
-
tion by CT or MR angiography is not usually adequate if 
operative treatment is under consideration because lesions 
may be multiple and small lesions are sometimes missed.
 
»
Treatment
The major aim of treatment is to prevent hemorrhage. 
Management of ruptured aneurysms was described in the 
section on subarachnoid hemorrhage. Symptomatic but 
unruptured aneurysms merit prompt treatment, either 
surgically or by endovascular techniques, whereas small 
asymptomatic ones discovered incidentally are often moni
-
tored arteriographically and corrected only if they increase 
in size to over 10 mm.
 
»
 
»
•	
All patients with a subarachnoid hemorrhage.
•	
All patients for detailed imaging.
•	
All patients undergoing surgical or endovascular 
Brown RD Jr et al. Unruptured intracranial aneurysms: epidemi
-
ology, natural history, management options, and familial 
screening. Lancet Neurol. 2014 Apr;13(4):393–404. [PMID: 
24646873]

-
24646873]
Greving JP et al. Development of the PHASES score for predic
-
tion of risk of rupture of intracranial aneurysms: a pooled 
analysis of six prospective cohort studies. Lancet Neurol. 2014 
Jan;13(1):59–66. [PMID: 24290159]
6. 
a
r
teriovenous Malformations
 
»
Sudden onset of subarachnoid and intracerebral 
 
»
 
»
Signs of meningeal irritation in patients present
-
ing with subarachnoid hemorrhage.
 
»
Seizures or focal deficits may occur.
 
»
Arteriovenous malformations are congenital vascular malfor
-
mations that result from a localized maldevelopment of part 
of the primitive vascular plexus and consist of abnormal arte
-
riovenous communications without intervening capillaries. 
 
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They vary in size, ranging from massive lesions that are fed 
by multiple vessels and involve a large part of the brain to 
lesions so small that they are hard to identify at arteriogra
-
phy, surgery, or autopsy. In approximately 10% of cases, 
there is an associated arterial aneurysm, while 1–2% of 
patients presenting with aneurysms have associated arterio
-
venous malformations. Clinical presentation may relate to 
hemorrhage from the malformation or an associated aneu
-
rysm or may relate to cerebral ischemia due to diversion of 
blood by the anomalous arteriovenous shunt or due to 
venous stagnation. Regional maldevelopment of the brain, 
compression or distortion of adjacent cerebral tissue by 
enlarged anomalous vessels, and progressive gliosis due to 
mechanical and ischemic factors may also be contributory. 
In addition, communicating or obstructive hydrocephalus 
may occur and lead to symptoms.
 
»
Most cerebral arteriovenous malformations are supratento
-
rial, usually lying in the territory of the middle cerebral artery. 
Up to 70% bleed at some point in their natural history, most 
commonly before the patient reaches the age of 40 years. 
 
This tendency to bleed is unrelated to the lesion site or to the 
patient’s sex, but small arteriovenous malformations are more 
likely to bleed than large ones. Arteriovenous malformations 
that have bled once are more likely to bleed again.
Initial symptoms consist of hemorrhage in 30–60% of cases, 
recurrent seizures in 20–40%, headache in 5–25%, and miscel
-
laneous complaints (including focal deficits) in 10–15%. Hem
-
orrhage is commonly intracerebral as well as into the 
subarachnoid space, and is fatal in about 10% of cases. Seizures 
are more likely with frontal or parietal arteriovenous malfor
-
mations. Headaches are especially likely when the external 
carotid arteries are involved in the malformation. These some
-
times simulate migraine, but more commonly are nonspecific 
in character, with nothing about them to suggest an underlying 
structural lesion. Brainstem and cerebellar arteriovenous mal
-
formations may cause obstructive hydrocephalus.
In patients presenting with subarachnoid hemorrhage, 
examination may reveal an abnormal mental status and 
signs of meningeal irritation. Additional findings may help 
localize the lesion and sometimes indicate that intracranial 
pressure is increased. A cranial bruit always suggests the 
possibility of a cerebral arteriovenous malformation, but 
bruits may also be found with aneurysms, meningiomas, 
acquired arteriovenous fistulas, and arteriovenous malfor
-
mations involving the scalp, calvarium, or orbit. Bruits are 
best heard over the ipsilateral eye or mastoid region and are 
of some help in lateralization but of no help in localization. 
Absence of a bruit does not exclude the possibility of arte
-
riovenous malformation.
B. Imaging
In patients with suspected hemorrhage, CT scanning indi
-
cates whether subarachnoid or intracerebral bleeding has 
recently occurred, helps localize its source, and may reveal 
the arteriovenous malformation. When intracranial 
hemorrhage is confirmed but the source of hemorrhage is 
not evident on the CT scan, arteriography is necessary to 
exclude aneurysm or arteriovenous malformation. MR and 
CT angiography are not sensitive enough for this purpose. 
Even if the findings on CT scan suggest arteriovenous mal
-
formation, arteriography is required to establish the nature 
of the lesion with certainty and to determine its anatomic 
features so that treatment can be planned. The examination 
must generally include bilateral opacification of the inter
-
nal and external carotid arteries and the vertebral arteries.
In patients presenting without hemorrhage, CT scan or 
MRI usually reveals the underlying abnormality, and MRI 
frequently also shows evidence of old or recent hemor
-

-
rhage that may have been asymptomatic. The nature and 
detailed anatomy of any focal lesion identified by these 
means are delineated by angiography, especially if opera
-
tive treatment is under consideration.
 
»
Treatment
Surgical treatment to prevent further hemorrhage is justi
-
fied in patients with arteriovenous malformations that 
have bled, provided that the lesion is accessible and the 
patient has a reasonable life expectancy. Surgical treatment 
is also appropriate if intracranial pressure is increased and 
to prevent further progression of a focal neurologic deficit. 
In patients presenting solely with seizures, anticonvulsant 
treatment is usually sufficient (Table 24–2), and operative 
treatment is unnecessary unless seizures cannot be con
-
trolled medically.
Definitive operative treatment consists of excision of the 
arteriovenous malformation if it is surgically accessible. 
Arteriovenous malformations that are inoperable because of 
their location are sometimes treated solely by embolization; 
although the risk of hemorrhage is not reduced, neurologic 
deficits may be stabilized or even reversed by this procedure. 
Two other techniques for the treatment of intracerebral arte
-
riovenous malformations are injection of a vascular occlu
-
sive polymer through a flow-guided microcatheter and 
permanent occlusion of feeding vessels by positioning 
detachable balloon catheters in the desired sites and then 
inflating them with quickly solidifying contrast material. 
Stereotactic radiosurgery is also useful in the management 
of inoperable cerebral arteriovenous malformations.
 
»
 
»
•	
All patients with a subarachnoid or cerebral hemorrhage.
•	
•	
Mohr JP et al; international ARUBA investigators. Medical man
-
agement with or without interventional therapy for unruptured 
brain arteriovenous malformations (ARUBA): a multicentre, 
non-blinded, randomised trial. Lancet. 2014 Feb 15;383(9917):
 
614–21. [PMID: 24268105]
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7. Intracranial Venous Thrombosis
Intracranial venous thrombosis may occur in association 
with intracranial or maxillofacial infections, hypercoagu
-
lable states, polycythemia, sickle cell disease, cyanotic 
congenital heart disease and in pregnancy or during the 
puerperium. Genetic factors are also important. The disor
-
der is characterized by headache, focal or generalized con
-
vulsions, drowsiness, confusion, increased intracranial 
pressure, and focal neurologic deficits—and sometimes by 
evidence of meningeal irritation. The diagnosis is con
-
firmed by CT or MR venography or angiography.
Treatment includes anticonvulsants if seizures have 
occurred (Table 24–2) and—if necessary—measures to 
reduce intracranial pressure. Anticoagulation with dose-
adjusted intravenous heparin or weight-adjusted subcuta
-
neous low-molecular-weight heparin, followed by oral 
warfarin anticoagulation for 6 months reduces morbidity 
and mortality of venous sinus thrombosis. Concomitant 
intracranial hemorrhage related to the venous thrombosis 
does not contraindicate heparin therapy. In cases refrac
-
tory to heparin, endovascular techniques including cathe
-
ter-directed thrombolytic therapy (urokinase) and 
thrombectomy are sometimes helpful but may increase the 
risk for major hemorrhage.
 
»
 
»
8. Spinal Cord Vascular Diseases
 
»
Sudden onset of back or limb pain and neurologic 
deficit in limbs.
 
»
Motor, sensory, or reflex changes in limbs depend
-
ing on level of lesion.
 
»
Imaging studies distinguish between infarct and 
hematoma.
 
»
Infarction of the Spinal Cord
Infarction of the spinal cord is rare. It typically occurs in 
the territory of the anterior spinal artery because this ves
-
sel, which supplies the anterior two-thirds of the cord, is 
itself supplied by only a limited number of feeders. Infarc
-
tion usually results from interrupted flow in one or more of 
these feeders, eg, with aortic dissection, aortic aneurysm, 
aortography, polyarteritis, severe hypotension, or after 
surgical repair of the thoracic or abdominal aorta. The 
paired posterior spinal arteries, by contrast, are supplied by 
numerous arteries at different levels of the cord. Spinal 
cord hypoperfusion may lead to a central cord syndrome 
with distal weakness of lower motor neuron type and loss 
of pain and temperature appreciation, with preserved pos
-
terior column function.
Since the anterior spinal artery receives numerous feed
-
ers in the cervical region, infarcts almost always occur 
caudally. Clinical presentation is characterized by acute 
onset of flaccid, areflexive paraplegia that evolves after a 
few days or weeks into a spastic paraplegia with extensor 
plantar responses. There is an accompanying dissociated 
sensory loss, with impairment of appreciation of pain and 
temperature but preservation of sensations of vibration and 
joint position.
The risk of spinal cord infarction in the setting of 
abdominal aortic surgery and thoracic endovascular repair 
may be reduced by intraoperative cerebrospinal fluid 
drainage through a catheter placed in the lumbar subarach
-
noid space to reduce intraspinal pressure. If signs of infarc
-
tion are noted after surgery, blood pressure augmentation 
for 24–48 hours in addition to lumbar drainage has been 
noted anecdotally to improve outcomes. Treatment is oth
-
erwise symptomatic.
 
»
Epidural or Subdural Hemorrhage
Epidural or subdural hemorrhage may lead to sudden 
severe back pain followed by an acute compressive myelop
-
athy necessitating urgent spinal MRI or myelography and 
surgical evacuation. It may occur in patients with bleeding 
disorders or those who are taking anticoagulants, some
-
times following trauma or lumbar puncture. Epidural 
hemorrhage may also be related to a vascular malformation 
or tumor deposit.
 
»

-
 
»
Spinal Dural Arteriovenous Fistulae
Spinal dural arteriovenous fistulae are congenital lesions 
that present with spinal subarachnoid hemorrhage or 
myeloradiculopathy. Since most of these malformations are 
located in the thoracolumbar region, they lead to motor 
and sensory disturbances in the legs and to sphincter dis
-
orders. Pain in the legs or back is often severe. Examination 
reveals an upper, lower, or mixed motor deficit in the legs; 
sensory deficits are also present and are usually extensive, 
although occasionally they are confined to a radicular dis
-
tribution. Cervical spinal dural arteriovenous fistulae lead 
also to symptoms and signs in the arms. Spinal MRI may 
not detect the spinal dural arteriovenous fistula although 
most cases show either T2 hyperintensity in the cord or 
perimedullary flow voids. Myelography (performed with 
the patient prone and supine) may detect serpiginous fill
-
ing defects due to enlarged vessels. Selective spinal arteri
-
ography is required to confirm the diagnosis and plan 
treatment. Most lesions are extramedullary, are posterior to 
the cord (lying either intradurally or extradurally), and can 
easily be treated by ligation of feeding vessels and excision 
of the fistulous anomaly or by embolization procedures. 
Delay in treatment may lead to increased and irreversible 
disability or to death from recurrent subarachnoid 
 
»
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»
Rabinstein AA. Vascular myelopathies. Continuum (Minneap 
Minn). 2015 Feb;21(1 Spinal Cord Disorders):67–83. [PMID: 
25651218]
INTRACRANIAL & SPINAL MASS LESIONS
1. 
p
rimar
y Intracranial Tumors
 
»
Generalized or focal disturbance of cerebral func
-
tion, or both.
 
»
Increased intracranial pressure in some patients.
 
»
Neuroradiologic evidence of space-occupying 
lesion.
 
»
Roughly one-third of all primary intracranial neoplasms 
(Table 24–4) are meningiomas, one-quarter are gliomas, 
and the remainder are pituitary adenomas (see Chapter 26), 
neurofibromas, and other tumors. Certain tumors, espe
-
cially neurofibromas, hemangioblastomas, and retinoblas
-
tomas, may have a familial basis, and congenital factors 
bear on the development of craniopharyngiomas. Tumors 
may occur at any age, but certain gliomas show particular 
age predilections.
 
»
Intracranial tumors typically present with headache, sei
-
zures, or focal neurologic deficits. New headaches or symp
-
toms of elevated intracranial pressure, such as headaches 
awaking a patient at night or worsening with Valsalva 
maneuver, cough, or recumbency, are suggestive of brain 
tumor. Intracranial tumors may also lead to a generalized 
disturbance of cerebral function with personality changes, 
intellectual decline, emotional lability, nausea, and malaise.
1. Frontal lobe lesions—
Tumors of the frontal lobe often 
lead to progressive intellectual decline, slowing of mental 
activity, personality changes, and contralateral grasp 
reflexes. They may lead to expressive aphasia if the poste
-
rior part of the left inferior frontal gyrus is involved. Anos
-
mia may also occur as a consequence of pressure on the 
olfactory nerve. Precentral lesions may cause focal motor 
seizures or contralateral pyramidal deficits.
2. Temporal lobe lesions—
Tumors of the uncinate region 
may be manifested by seizures with olfactory or gustatory 
hallucinations, motor phenomena such as licking or 
smacking of the lips, and some impairment of external 
awareness without actual loss of consciousness. Temporal 
lobe lesions also lead to depersonalization, emotional 
changes, behavioral disturbances, sensations of déjà vu or 
jamais vu, micropsia or macropsia (objects appear smaller 
or larger than they are), visual field defects (crossed upper 
quadrantanopia), and auditory illusions or hallucinations. 
Left-sided lesions may lead to dysnomia and receptive 
aphasia, while right-sided involvement sometimes disturbs 
the perception of musical notes and melodies.
3. Parietal lobe lesions—
Tumors in this location charac
-
teristically cause contralateral disturbances of sensation and 
may cause sensory seizures, sensory loss or inattention, or 
some combination of these symptoms. The sensory loss is 
cortical in type and involves postural sensibility and tactile 
discrimination, so that the appreciation of shape, size, 
weight, and texture is impaired. Objects placed in the hand 
may not be recognized (astereognosis). Extensive parietal 
lobe lesions may produce contralateral hyperpathia and 
spontaneous pain (thalamic syndrome). Involvement of the 
optic radiation leads to a contralateral homonymous field 
defect that sometimes consists solely of lower quadran
-
tanopia. Lesions of the left angular gyrus cause Gerstmann 
syndrome (a combination of alexia, agraphia, acalculia, 
right-left confusion, and finger agnosia), whereas involve
-
ment of the left submarginal gyrus causes ideational apraxia. 
Anosognosia (the denial, neglect, or rejection of a paralyzed 
limb) is seen in patients with lesions of the nondominant 
(right) hemisphere. Constructional apraxia and dressing 
apraxia may also occur with right-sided lesions.
4. Occipital lobe lesions—
Tumors of the occipital lobe

Tumors of the occipital lobe 
characteristically produce contralateral homonymous 
hemianopia or a partial field defect. With left-sided or 
bilateral lesions, there may be visual agnosia both for 
objects and for colors, while irritative lesions on either side 
can cause unformed visual hallucinations. Bilateral occipi
-
tal lobe involvement causes cortical blindness in which 
there is preservation of pupillary responses to light and 
lack of awareness of the defect by the patient. There may 
also be loss of color perception, prosopagnosia (inability to 
identify a familiar face), simultagnosia (inability to inte
-
grate and interpret a composite scene as opposed to its 
individual elements), and Balint syndrome (failure to turn 
the eyes to a particular point in space, despite preservation 
of spontaneous and reflex eye movements). The denial of 
blindness or a field defect constitutes Anton syndrome.
5. Brainstem and cerebellar lesions—
Brainstem lesions 
lead to cranial nerve palsies, ataxia, incoordination, nystag
-
mus, and pyramidal and sensory deficits in the limbs on 
one or both sides. Intrinsic brainstem tumors, such as glio
-
mas, tend to produce an increase in intracranial pressure 
only late in their course. Cerebellar tumors produce 
marked ataxia of the trunk if the vermis cerebelli is 
involved and ipsilateral appendicular deficits (ataxia, inco
-
ordination and hypotonia of the limbs) if the cerebellar 
hemispheres are affected.
6. Herniation syndromes—
If the pressure is increased in a 
particular cranial compartment, brain tissue may herniate 
into a compartment with lower pressure. The most familiar 
syndrome is herniation of the temporal lobe uncus through 
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Table 24–4.
 
Primary intracranial tumors (listed by major histology grouping and by incidence within each group).
Tumor
Treatment and 
p
r
ognosis
Tumors of 
M
eninges
Originates from the dura mater or arachnoid; compresses 
rather than invades adjacent neural structures. Increas
-
ingly common with advancing age. Tumor size varies 
greatly. Symptoms vary with tumor site—eg, unilateral 
proptosis (sphenoidal ridge); anosmia and optic nerve 
compression (olfactory groove). Tumor is usually benign 
and readily detected by CT scanning; may lead to 
 
calcification and bone erosion visible on plain radio
-
graphs of skull.
Treatment is surgical. Tumor may recur if removal is 
incomplete.
Tumors of 
N
euroepithelial 
O
rigin
Glioblastoma 
multiforme
Presents commonly with nonspecific complaints and 
increased intracranial pressure. As it grows, focal deficits 
develop.
Course is rapidly progressive, with poor prognosis 
(< 20% survival at 2 years). Total surgical 
removal is usually not possible. Radiation ther
-
apy and chemotherapy may prolong survival.
Astrocytoma
Presentation similar to glioblastoma multiforme but course 
more protracted, often over several years. Cerebellar 
astrocytoma may have a more benign course.
Prognosis is variable. By the time of diagnosis, total 
excision is usually impossible; tumor may be 
radiosensitive and chemotherapy may also be 
helpful. In cerebellar astrocytoma, total surgical 
removal is often possible.
Ependymoma
Glioma arising from the ependyma of a ventricle, especially 
the fourth ventricle; leads to early signs of increased 
intracranial pressure. Arises also from central canal 
of cord.
Tumor is best treated surgically if possible. Radia
-
tion therapy may be used for residual tumor.
Oligodendroglioma
Slow-growing. Usually arises in cerebral hemisphere in 
adults. Calcification may be visible on skull radiograph.
Treatment is surgical and usually successful. Radia
-
tion and chemotherapy may be used if tumor 
has malignant features.
Brainstem glioma
Presents during childhood with cranial nerve palsies and 
then with long tract signs in the limbs. Signs of increased 
intracranial pressure occur late.
Tumor is inoperable; treatment is by irradiation 
and shunt for increased intracranial pressure.
Neuronal and mixed 
neuronal-glial 
tumors
Slow-growing; usually arise in cerebral hemispheres; often 
associated with seizures. Some are benign (eg, dysem
-
bryoblastic neuroepithelial tumors) and some have malig
-
nant potential (eg, ganglioglioma).
Resection is not always necessary for benign 
tumors unless seizures are medically refractory, 
but is indicated for those with malignant 
Medulloblastoma
Seen most frequently in children. Generally arises from roof 
of fourth ventricle and leads to increased intracranial 
pressure accompanied by brainstem and cerebellar signs. 
May seed subarachnoid space.
Treatment consists of surgery combined with radi
-
ation therapy and chemotherapy; 5-year survival 
exceeds 70%.
Pineal tumor
Presents with increased intracranial pressure, sometimes 
associated with impaired upward gaze (Parinaud syn
-
drome) and other deficits indicative of midbrain lesion.
Ventricular decompression by shunting is followed 
by surgical approach to tumor; irradiation is 
indicated if tumor is malignant. Prognosis 
depends on histopathologic findings and extent 
of tumor.
T
umors of the 
S
ellar 
R
egion
Pituitary adenoma
Functioning adenomas present with symptoms of hormone 
secretion; non-functioning adenomas present with 
 
symptoms of local mass effect (eg, bitemporal 
 
hemianopsia, hypopituitarism) or are found incidentally.
Prolactin-secreting adenomas are treated with bro
-
mocriptine or cabergoline. Others are surgically 
resected. Pituitary hormone replacement may 
be required.
Craniopharyngioma
Originates from remnants of Rathke pouch above the sella,

-
Originates from remnants of Rathke pouch above the sella, 
depressing the optic chiasm. May present at any age but 
usually in childhood, with endocrine dysfunction and 
bitemporal visual field defects.
Treatment is surgical, but total removal may not be 
possible. Radiation may be used for residual 
tumor.
(
continued
 
)
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the tentorial hiatus, which causes compression of the third 
cranial nerve, midbrain, and posterior cerebral artery. The 
earliest sign of this is ipsilateral pupillary dilation, followed 
by stupor, coma, decerebrate posturing, and respiratory 
arrest. Another important herniation syndrome consists of 
displacement of the cerebellar tonsils through the foramen 
magnum, which causes medullary compression leading to 
apnea, circulatory collapse, and death.
7. False localizing signs—
Tumors may lead to neurologic 
signs other than by direct compression or infiltration, 
thereby leading to errors of clinical localization. These false 
localizing signs include third or sixth nerve palsy and bilat
-
eral extensor plantar responses produced by herniation 
syndromes, and an extensor plantar response occurring 
ipsilateral to a hemispheric tumor as a result of compression 
of the opposite cerebral peduncle against the tentorium.
B. Imaging
MRI with gadolinium enhancement is the preferred method 
to detect the lesion and to define its location, shape, and 
size; the extent to which normal anatomy is distorted; and 
the degree of any associated cerebral edema or mass effect. 
CT scanning with radiocontrast enhancement could be 
performed; however, it is less helpful than MRI for small 
lesions or tumors in the posterior fossa. The characteristic 
appearance of meningiomas on MRI or CT scanning is 
virtually diagnostic, ie, a lesion in a typical site (parasagittal 
and sylvian regions, olfactory groove, sphenoidal ridge, 
tuberculum sellae) that appears as a homogeneous area of 
increased density in noncontrast scans and enhances uni
-
formly with contrast. Additional MRI sequences that may 
be helpful in differentiating gliomas from other intracranial 
pathology include perfusion imaging, magnetic resonance 
spectroscopy, and diffusion-weighted imaging, although 
none are specific enough to obviate the need for tissue 
sampling. Arteriography is largely reserved for presurgical 
embolization of highly vascular tumors. In patients with 
normal hormone levels and an intrasellar mass, angiogra
-
phy is sometimes necessary to distinguish with confidence 
between a pituitary adenoma and an arterial aneurysm.
When glial neoplasms are suspected, biopsy is necessary for 
definitive histologic diagnosis and molecular analysis. The 
World Health Organization classifies glial tumors by both 
histology and genetic characteristics. Lumbar puncture is 
rarely necessary; the findings are seldom diagnostic, and the 
procedure carries the risk of causing a herniation syndrome.
 
»
Treatment
Treatment depends on the type and site of the tumor 
(Table 24–4) and the condition of the patient. Some benign 
tumors, especially meningiomas discovered incidentally 
during brain imaging for another purpose, may be moni
-
tored with serial annual imaging. For symptomatic tumors, 
complete surgical removal may be possible if the tumor is 
extra-axial (eg, meningioma, acoustic neuroma) or is not 
in a critical or inaccessible region of the brain (eg, cerebel
-
lar hemangioblastoma). Surgery also permits the diagnosis 
to be verified and may be beneficial in reducing intracra
-
nial pressure and relieving symptoms even if the neoplasm 
cannot be completely removed. Clinical deficits are some
-
times due in part to obstructive hydrocephalus, in which 
case simple surgical shunting procedures often produce 
dramatic benefit. In patients with malignant gliomas, sur
-
vival correlates to the extent of initial resection. Radiation 
therapy increases median survival rates regardless of any 
preceding surgery, and its combination with chemotherapy 
Tumors of 
C
ranial and 
S
pinal 
N
erves
Acoustic neurinoma 
(also referred to as 
acoustic neuroma)
Ipsilateral hearing loss is most common initial symptom. 
Subsequent symptoms may include tinnitus, headache, 
vertigo, facial weakness or numbness, and long tract

vertigo, facial weakness or numbness, and long tract 
signs. (May be familial and bilateral when related to 
 
neurofibromatosis.) Most sensitive screening tests are 
MRI and brainstem auditory evoked potential.
Treatment is excision by translabyrinthine surgery, 
craniectomy, or a combined approach. Outcome 
is usually good.
Lymphomas
Primary cerebral 
lymphoma
Associated with AIDS and other immunodeficient states. 
Presentation may be with focal deficits or with distur
-
bances of cognition and consciousness. May be indistin
-
guishable from cerebral toxoplasmosis.
Treatment is high-dose methotrexate and cortico
-
steroids followed by radiation therapy. Prognosis 
depends on CD4 count at diagnosis.
Unclassified
Cerebellar 
hemangioblastoma
Presents with dysequilibrium, ataxia of trunk or limbs, and 
signs of increased intracranial pressure. Sometimes famil
-
ial. May be associated with retinal and spinal vascular 
lesions, polycythemia, and renal cell carcinoma.
Treatment is surgical. Radiation is used for residual 
tumor.
 
Primary intracranial tumors (listed by major histology grouping and by incidence within each 
 
group). (continued)
Tumor
p
r
ognosis
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provides additional benefit. Indications for irradiation in 
the treatment of patients with other primary intracranial 
neoplasms depend on tumor type and accessibility and the 
feasibility of complete surgical removal. Temozolomide is a 
commonly used oral and intravenous chemotherapeutic 
for gliomas, and the use of monoclonal antibodies like 
bevacizumab as a component of therapy may be helpful 
(see Table 39–2). Corticosteroids help reduce cerebral 
edema and are usually started before surgery. Herniation is 
treated with intravenous dexamethasone (10–20 mg as a 
bolus, followed by 4 mg every 6 hours) and intravenous 
mannitol (20% solution given in a dose of 1.5 g/kg over 
about 30 minutes). Anticonvulsants are also commonly 
administered in standard doses (see Table  24–2), but are 
not indicated for prophylaxis in patients who have no his
-
tory of seizures. Long-term neurocognitive deficits may 
complicate radiation therapy. For those patients whose 
disease deteriorates despite treatment, a palliative care 
focus is important (see Chapter 5).
 
»
 
»
•	
All patients with increased intracranial pressure.
•	
All patients requiring biopsy, surgical treatment, or 
shunting procedures.
Louis DN et al. The 2016 World Health Organization classifica
-
tion of tumors of the central nervous system: a summary. Acta 
Neuropathol. 2016 Jun;131(6):803–20. [PMID: 27157931]
Oberheim Bush NA et al. Treatment strategies for low-grade 
glioma in adults. J Oncol Pract. 2016 Dec;12(12):1235–41. 
[PMID: 27943684]
Ostrom QT et al. CBTRUS Statistical Report: Primary brain and 
other central nervous system tumors diagnosed in the United 
States in 2009–2013. Neuro Oncol. 2016 Oct 1;18(Suppl 5):
 
v1–75. [PMID: 28475809]
2. Metastatic Intracranial Tumors
A. Cerebral Metastases
Metastatic brain tumors present in the same way as other 
cerebral neoplasms, ie, with increased intracranial pres
-
sure, with focal or diffuse disturbance of cerebral function, 
or with both of these manifestations. Indeed, in patients 
with a single cerebral lesion, the metastatic nature of the 
lesion may become evident only on histopathologic exami
-
nation. In other patients, there is evidence of widespread 
metastatic disease, or an isolated cerebral metastasis devel
-
ops during treatment of the primary neoplasm.
The most common source of intracranial metastasis is 
carcinoma of the lung; other primary sites are the breast, 
kidney, skin (melanoma), and gastrointestinal tract. Most 
cerebral metastases are located supratentorially. Laboratory 
and radiologic studies used to evaluate patients with 
metastases are those described for primary neoplasms. 
They include MRI and CT scanning performed both with 
and without contrast material. Lumbar puncture is 
necessary only in patients with suspected carcinomatous 
meningitis. In patients with verified cerebral metastasis 
from an unknown primary, investigation is guided by 
symptoms and signs. In women, mammography is indi
-
cated; in men under 50, germ cell origin is sought.
In patients with only a single, surgically accessible cere
-
bral metastasis who are otherwise well (ie, a high level of 
functioning and little or no evidence of extracranial dis
-
ease), it may be possible to remove the lesion and then treat 
with irradiation; the latter may also be selected as the sole 
treatment. In patients with multiple metastases or wide
-
spread systemic disease, the prognosis is poor; stereotactic 
radiosurgery, whole-brain radiotherapy, or both, may help 
in some instances, but in others treatment is palliative only.
Ba JL et al. Current and emerging treatments for brain metasta
-
ses. Oncology (Williston Park). 2015 Apr;29(4):250–7. 
[PMID: 25952487]
B. Leptomeningeal Metastases 
(Carcinomatous Meningitis)
The neoplasms metastasizing most commonly to the lepto
-
meninges are carcinoma of the breast and lung, lympho
-

-
-
mas, and leukemia (see Chapter 39). Leptomeningeal 
metastases lead to multifocal neurologic deficits, which 
may be associated with infiltration of cranial and spinal 
nerve roots, direct invasion of the brain or spinal cord, 
obstructive or communicating hydrocephalus, or some 
combination of these factors.
The diagnosis is confirmed by examination of the cere
-
brospinal fluid. Findings may include elevated cerebrospi
-
nal fluid pressure, pleocytosis, increased protein 
concentration, and decreased glucose concentration. Cyto
-
logic studies may indicate that malignant cells are present; 
if not, lumbar puncture should be repeated at least twice to 
obtain further samples for analysis.
CT scans showing contrast enhancement in the basal 
cisterns or showing hydrocephalus without any evidence of 
a mass lesion support the diagnosis. Gadolinium-enhanced 
MRI frequently shows enhancing foci in the leptomeninges. 
Myelography may show deposits on multiple nerve roots.
Treatment is by irradiation to symptomatic areas, com
-
bined with intrathecal chemotherapy in select patients. The 
long-term prognosis is poor—only about 10% of patients 
survive for 1 year—and palliative care is therefore impor
-
tant (see Chapter 5).
Passarin MG et al. Leptomeningeal metastasis from solid tumors: 
a diagnostic and therapeutic challenge. Neurol Sci. 2015 Jan;
 
36(1):117–23. [PMID: 25022241]
3. Intracranial Mass Lesions in 
a
IDS 
p
a
tients
Primary cerebral lymphoma
 is a common complication 
in patients with AIDS. This leads to disturbances in cogni
-
tion or consciousness, focal motor or sensory deficits, 
aphasia, seizures, and cranial neuropathies. Similar clinical 
disturbances may result from 
cerebral toxoplasmosis
, 
which is also a common complication in patients with 
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AIDS (see Chapters 31 and 35). Neither CT nor MRI find
-
ings distinguish these two disorders, serologic tests for 
toxoplasmosis are unreliable in AIDS patients, and 
although the finding of Epstein-Barr virus DNA in the 
spinal fluid by polymerase chain reaction suggests lym
-
phoma, it is not specific enough to initiate treatment. 
Accordingly, for neurologically stable patients, a trial of 
treatment for toxoplasmosis with pyrimethamine and sul
-
fadiazine is recommended for 3 weeks (see Table 31–5); the 
imaging studies are then repeated, and if any lesion has 
improved, the regimen is continued indefinitely. If any 
lesion does not improve, cerebral biopsy is necessary. Pri
-
mary cerebral lymphoma in AIDS patients is treated with 
corticosteroids, high-dose methotrexate, and antiretroviral 
therapy. Rituximab may be used in some patients. Whole-
brain irradiation may not be necessary.
Cryptococcal meningitis
 is a common opportunistic 
infection in AIDS patients. Clinically, it may resemble cere
-
bral toxoplasmosis or lymphoma, but cranial CT scans are 
usually normal (see Chapter 36).
4. 
p
rimar
y & Metastatic Spinal Tumors
Approximately 10% of spinal tumors are intramedullary. 
Ependymoma is the most common type of intramedullary 
tumor; the remainder are other types of glioma. Extramed
-
ullary tumors may be extradural or intradural in location. 
Among the primary extramedullary tumors, neurofibro
-
mas and meningiomas are relatively common, benign, and 
may be intradural or extradural. Carcinomatous metasta
-
ses, lymphomatous or leukemic deposits, and myeloma are 
usually extradural; in the case of metastases, the prostate, 
breast, lung, and kidney are common primary sites.
Tumors may lead to spinal cord dysfunction by direct 
compression, by ischemia secondary to arterial or venous 
obstruction and, in the case of intramedullary lesions, by 
invasive infiltration.
 
»
Symptoms usually develop insidiously. Pain is often con
-
spicuous with extradural lesions; is characteristically aggra
-
vated by coughing or straining; may be radicular, localized 
to the back, or felt diffusely in an extremity; and may be 
accompanied by motor deficits, paresthesias, or numbness, 
especially in the legs. Bladder, bowel, and sexual dysfunction 
may occur. When sphincter disturbances occur, they are 
usually particularly disabling. Pain, however, often precedes 
specific neurologic symptoms from epidural metastases.
Examination may reveal localized spinal tenderness. A 
segmental lower motor neuron deficit or dermatomal sen
-
sory changes (or both) are sometimes found at the level of 
the lesion, while an upper motor neuron deficit and sen
-
sory disturbance are found below it.
B. Imaging
MRI with contrast or CT myelography is used to identify 
and localize the lesion. The combination of known tumor 
elsewhere in the body, back pain, and either abnormal 
plain films of the spine or neurologic signs of cord com
-
pression is an indication to perform this on an urgent basis.
The cerebrospinal fluid is often xanthochromic and con
-
tains a greatly increased protein concentration with normal 
cell content and glucose concentration.
 
»
Treatment
Intramedullary tumors are treated by decompression and 
surgical excision (when feasible) and by irradiation. The 
prognosis depends on the cause and severity of cord com
-
pression before it is relieved.
Treatment of epidural spinal metastases consists of sur
-
gical decompression, radiation, or both. Dexamethasone is 
also given in a high dosage (eg, 10–96 mg once intrave
-
nously, followed by 4–25 mg four times daily for 3 days 
orally or intravenously, followed by rapid tapering of the 
dosage, depending on initial dose and response) to reduce 
cord swelling and relieve pain. Radiation alone is often all 
that is required in patients with radiosensitive tumors.

that is required in patients with radiosensitive tumors. 
Surgical decompression is reserved for patients with 
tumors that are unresponsive to irradiation or who have 
previously been irradiated, for those with spinal instability, 
and for patients in whom there is some uncertainty about 
the diagnosis. The long-term outlook is poor, but radiation 
treatment may at least delay the onset of major disability.
Chamberlain MC. Neoplastic myelopathies. Continuum (Minneap 
Minn). 2015 Feb;21(1 Spinal Cord Disorders):132–45. [PMID: 
25651222]
5. Brain 
a
bsc
ess
 
»
Signs of expanding intracranial mass.
 
»
Signs of primary infection or congenital heart 
 
disease are sometimes present.
 
»
Fever may be absent.
 
»
Brain abscess presents as an intracranial space-occupying 
lesion and arises as a sequela of disease of the ear or nose, 
may be a complication of infection elsewhere in the body, 
or may result from infection introduced intracranially by 
trauma or surgical procedures. The most common infec
-
tive organisms are streptococci, staphylococci, and anaer
-
obes; mixed infections also occur.
 
»
Headache, drowsiness, inattention, confusion, and seizures 
are early symptoms, followed by signs of increasing 
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intracranial pressure and then a focal neurologic deficit. 
There may be little or no systemic evidence of infection.
B. Imaging and Other Investigations
A CT scan of the head characteristically shows an area of 
contrast enhancement surrounding a low-density core. 
Similar abnormalities may be found in patients with meta
-
static neoplasms. MRI findings often permit earlier recog
-
nition of focal cerebritis or an abscess. Stereotactic needle 
aspiration may enable a specific etiologic organism to be 
identified. Examination of the cerebrospinal fluid does not 
help in diagnosis and may precipitate a herniation syn
-
drome. Peripheral leukocytosis is sometimes present.
 
»
Treatment
Treatment consists of intravenous antibiotics, combined 
with surgical drainage (aspiration or excision) if necessary 
to reduce the mass effect, or sometimes to establish the 
diagnosis. Abscesses smaller than 2 cm can often be cured 
medically. Broad-spectrum antibiotics, selected based on 
risk factors and likely organisms, are used if the infecting 
organism is unknown (see Chapter 33). An initial empiric 
multi-antibiotic regimen typically includes ceftriaxone (2 g 
intravenously every 12 hours), metronidazole (15 mg/kg 
intravenous loading dose, followed by 7.5 mg/kg intrave
-
nously every 6 hours), and vancomycin (1 g intravenously 
every 12 hours). The regimen is altered once culture and 
sensitivity data are available. Antimicrobial treatment is 
usually continued parenterally for 6–8 weeks and is fol
-
lowed by oral treatment for certain infections, such as 
nocardiosis, actinomycosis, fungal infections, and tubercu
-
losis. The patient should be monitored by serial CT scans 
or MRI every 2 weeks and at deterioration. Dexametha
-
sone (4–25 mg four times daily intravenously or orally, 
depending on severity, followed by tapering of dose, 
depending on response) may reduce any associated edema, 
but intravenous mannitol is sometimes required.
Brouwer MC et al. Brain abscess. N Engl J Med. 2014 Jul 31;
 
371(5):447–56. [PMID: 25075836]
NONMETASTATIC NEUROLOGIC 
COMPLICATIONS OF MALIGNANT DISEASE
A variety of nonmetastatic neurologic complications of 
malignant disease can be recognized. Metabolic encepha
-
lopathy due to electrolyte abnormalities, infections, drug 
overdose, or the failure of some vital organ may be reflected 
by drowsiness, lethargy, restlessness, insomnia, agitation, 
confusion, stupor, or coma. The mental changes are usually 
associated with tremor, asterixis, and multifocal myoclonus. 
The electroencephalogram is generally diffusely slowed. 
Laboratory studies are necessary to detect the cause of the 
encephalopathy, which must then be treated appropriately.
Immune suppression resulting from either the malignant 
disease or its treatment (eg, by chemotherapy) predisposes 
patients to brain abscess, progressive multifocal leukoen
-
cephalopathy, meningitis, herpes zoster infection, and other 
opportunistic infectious diseases. Moreover, an overt or 
occult cerebrospinal fluid fistula, as occurs with some 
tumors, may also increase the risk of infection. MRI or CT 
scanning aids in the early recognition of a brain abscess, but 
metastatic brain tumors may have a similar appearance. 
Examination of the cerebrospinal fluid is essential in the 
evaluation of patients with meningitis and encephalitis but is 
of no help in the diagnosis of brain abscess.
Cerebrovascular disorders that cause neurologic compli
-
cations in patients with systemic cancer include nonbacterial 
thrombotic endocarditis and septic embolization. Cerebral, 
subarachnoid, or subdural hemorrhages may occur in 
patients with myelogenous leukemia and may be found in 
association with metastatic tumors, especially melanoma. 
Spinal subdural hemorrhage sometimes occurs after lumbar 
puncture in patients with marked thrombocytopenia.
Disseminated intravascular coagulation occurs most

Disseminated intravascular coagulation occurs most 
commonly in patients with acute promyelocytic leukemia or 
with some adenocarcinomas and is characterized by a fluctu
-
ating encephalopathy, often with associated seizures, that 
frequently progresses to coma or death. There may be few 
accompanying neurologic signs. Venous sinus thrombosis, 
which usually presents with convulsions and headaches, may 
also occur in patients with leukemia or lymphoma. Examina
-
tion commonly reveals papilledema and focal or diffuse 
neurologic signs. Anticonvulsants, anticoagulants, and medi
-
cations to lower the intracranial pressure may be of value.
Autoimmune paraneoplastic disorders occur when the 
immune system reacts against neuronal antigens expressed 
by tumor cells. The clinical manifestations depend on the 
autoantibody. Symptoms may precede those due to the 
neoplasm itself. Several distinct syndromes are common, 
including paraneoplastic cerebellar degeneration, limbic 
encephalitis, encephalomyelitis, anti-NMDA receptor-
associated encephalitis, opsoclonus/myoclonus, sensory 
neuronopathy, retinopathy, and dermatomyositis.
Paraneoplastic cerebellar degeneration
 occurs most 
commonly in association with carcinoma of the lung, but 
also in breast and gynecologic cancers and Hodgkin lym
-
phoma. Typically, there is a pancerebellar syndrome caus
-
ing dysarthria, nystagmus, and ataxia of the trunk and 
limbs. The disorder is associated with anti-Y o, -Tr, 
-voltage-gated calcium channel (VGCC), and Zic antibod
-
ies. Treatment is of the underlying malignant disease. 
Limbic encephalitis
, characterized by impaired recent 
memory, disturbed affect, hallucinations, and seizures, 
occurs in some patients with tumors of the lungs, breast, 
thymus, and germ cells. Associated antibodies include anti-
Hu, -Ma2, -CV2/CRMP5, -voltage-gated potassium chan
-
nel (VGKC), -leucine rich glioma inactivated 1 (LGI1), 
-contactin associated protein-like 2 (Caspr2), -dipeptidyl-
peptidase-like protein-6 (DPPX), -AMPA receptor, -GABA
A
 
receptor, and -GABA
B
 receptor. Anti-DPPX encephalitis is 
typically preceded by a severe and prolonged diarrheal 
prodrome. A more generalized 
encephalomyelitis
 occurs 
with anti-Hu, -CV2/CRMP5, -Ma2, and -amphiphysin anti
-
bodies in the context of a similar spectrum of tumors. 
Anti-
NMDA receptor-associated encephalitis
 causes a 
characteristic syndrome of severe psychiatric symptoms, dys
-
kinesias, dysautonomia, and hypoventilation, and is frequently 
associated with ovarian teratoma. 
Opsoclonus/myoclonus
, 
 
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a syndrome of involuntary, erratic, and conjugate saccadic 
eye movements and myoclonic movements of the limbs, 
occurs in patients with lung, breast, and gynecologic 
tumors, often without an identifiable antibody. 
Sensory 
neuronopathy
, typically caused by anti-Hu antibodies in 
small cell lung cancer or other carcinomas, manifests itself 
with asymmetric, multifocal sensory nerve root deficits 
leading to pain, numbness, sensory ataxia, and sometimes 
hearing loss. Both a 
sensorimotor
 and a 
purely sensory 
polyneuropathy
 have been associated with circulating 
anti-MAG or anti-Hu antibodies. The sensorimotor poly
-
neuropathy may be mild and occur in the course of known 
malignant disease, or it may have an acute or subacute 
onset, lead to severe disability, and occur before there is any 
clinical evidence of the cancer, occasionally following a 
remitting course. An 
autonomic neuropathy
 may also 
occur as a paraneoplastic disorder related to the presence 
of anti-Hu antibodies or to antibodies against ganglionic 
acetylcholine receptors (anti-nAChR). Paraneoplastic 
reti
-
nopathy
 occurs due to antirecoverin or antibipolar cell 
antibodies associated with small cell lung cancer or mela
-
noma. 
Dermatomyositis
 (see Chapter 20) or the 
Lambert-
Eaton myasthenic syndrome
 (discussed below) may be 
seen in patients with underlying carcinoma. Identification 
of an antibody is not always possible in a suspected autoim
-
mune paraneoplastic condition, and a search for an under
-
lying neoplasm should be undertaken. Treatment of the 
neoplasm offers the best hope for stabilization or improve
-
ment of the neurologic symptoms, which often are not 
completely reversible. Specific treatment of the antibody-
mediated symptoms by intravenous immunoglobulin 
(IVIG) administration, plasmapheresis, corticosteroids, or 
other immunosuppressive regimens is frequently attempted 
despite limited evidence of efficacy. 
Encephalitides
 involv
-
ing antibodies directed against neuronal cell surface anti
-
gens, such as VGKC, LGI1, Caspr2, AMPA, NMDA, 
GABA
B and A
 receptors, and DPPX can occur either as 
paraneoplastic phenomena or in isolation, and typically 
respond well to immunotherapy.
Höftberger R et al. Update on neurological paraneoplastic syn
-
dromes. Curr Opin Oncol. 2015 Nov;27(6):489–95. [PMID: 
26335665]
Linnoila J et al. Autoantibody-associated central nervous system 
neurologic disorders. Semin Neurol. 2016 Aug;36(4):382–96. 
[PMID: 27643908]
PSEUDOTUMOR CEREBRI 
 
(
Idiopathic Intracranial Hypertension
)
 
»
Headache, worse on straining.
 
»
Visual obscurations or diplopia may occur.
 
»
Examination reveals papilledema.
 
»
Abducens palsy is commonly present.
 
»
There are many causes of pseudotumor cerebri. Thrombo
-
sis of the transverse venous sinus as a complication of otitis 
media or chronic mastoiditis is one cause, and sagittal 
sinus thrombosis may lead to a clinically similar picture. 
Other causes include chronic pulmonary disease, systemic 
lupus erythematosus, uremia, endocrine disturbances such 
as hypoparathyroidism, hypothyroidism, or Addison dis
-
ease, vitamin A toxicity, and the use of tetracycline or oral 
contraceptives. Cases have also followed withdrawal of 
corticosteroids after long-term use. In most instances, 
however, no specific cause can be found, and the disorder 
remits spontaneously after several months. This idiopathic 
variety—known as idiopathic intracranial hypertension—
occurs most commonly among overweight women aged 
20–44. In all cases, screening for a space-occupying lesion 
of the brain is important.
 
»
Symptoms consist of headache, diplopia, and other visual 
disturbances due to papilledema and abducens nerve dys
-
function. Pulse-synchronous tinnitus may also occur. 
Examination reveals papilledema and some enlargement of

-
Examination reveals papilledema and some enlargement of 
the blind spots, but patients otherwise look well.
B. Imaging
Investigations reveal no evidence of a space-occupying 
lesion. CT or MRI shows small or normal ventricles and an 
empty sella turcica. MR venography is important in screen
-
ing for thrombosis of the intracranial venous sinuses. In 
some cases, stenosis of one or more of the venous sinuses 
will be observed.
Lumbar puncture confirms the presence of intracranial 
hypertension, but the cerebrospinal fluid is normal. Labo
-
ratory studies help exclude some of the other causes men
-
tioned earlier.
 
»
Treatment
Untreated intracranial hypertension sometimes leads to 
secondary optic atrophy and permanent visual loss. 
Acetazolamide (250–500 mg orally three times daily, 
increasing slowly to a maintenance dose of up to 4000 mg 
daily, divided two to four times daily) reduces formation 
of cerebrospinal fluid. Like acetazolamide, the antiepi
-
leptic medication topiramate (Table 24–2) is a carbonic 
anhydrase inhibitor and was shown to be similarly effec
-
tive in an open label study; topiramate has the added 
benefit of causing weight loss. Furosemide (20–40 mg 
daily) may be helpful as adjunct therapy. Corticosteroids 
(eg, prednisone 60–80 mg daily) are sometimes pre
-
scribed, but side effects and the risk of relapse on with
-
drawal have discouraged their use. Obese patients should 
be advised to lose weight. Repeated lumbar puncture to 
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CMDT 2019
lower the intracranial pressure by removal of cerebrospi
-
nal fluid is effective as a temporizing measure, but phar
-
macologic approaches to treatment provide better 
long-term relief. Treatment is monitored by checking 
visual acuity and visual fields, funduscopic appearance, 
and pressure of the cerebrospinal fluid. The disorder may 
worsen after a period of stability, indicating the need for 
long-term follow-up.
If medical treatment fails to control the intracranial 
pressure, surgical placement of a lumboperitoneal or ven
-
triculoperitoneal shunt or optic nerve sheath fenestration 
should be undertaken to preserve vision. Venous sinus 
stenting is under study as a therapy for dural venous sinus 
stenosis.
In addition to the above measures, any specific cause of 
intracranial hypertension requires appropriate treatment. 
Thus, hormone therapy should be initiated if there is an 
underlying endocrine disturbance. Discontinuing the use of 
tetracycline, oral contraceptives, or vitamin A will allow for 
resolution of intracranial hypertension due to these agents. 
If corticosteroid withdrawal is responsible, the medication 
should be reintroduced and then tapered more gradually.
 
»
 
»
All patients with worsening vision requiring shunt place
-
ment or optic nerve sheath fenestration should be 
NORDIC Idiopathic Intracranial Hypertension Study Group 
Writing Committee et al. Effect of acetazolamide on visual 
function in patients with idiopathic intracranial hypertension 
and mild visual loss: the idiopathic intracranial hypertension 
treatment trial. JAMA. 2014 Apr 23–30;311(16):1641–51. 
[PMID: 24756514]
SELECTED NEUROCUTANEOUS DISEASES
Because the nervous system develops from the epithelial 
layer of the embryo, a number of congenital diseases 
include both neurologic and cutaneous manifestations. 
Among these disorders, three are discussed below, and von 
Hippel-Lindau disease is discussed in Chapter 26.
1. Tuberous Sclerosis
Tuberous sclerosis may occur sporadically or on a familial 
basis with autosomal dominant inheritance. Neurologic 
presentation is with seizures and progressive psychomotor 
retardation beginning in early childhood. The cutaneous 
abnormality 
adenoma sebaceum
 becomes manifest usu
-
ally between 5 and 10 years of age and typically consists of 
reddened nodules on the face (cheeks, nasolabial folds, 
sides of the nose, and chin) and sometimes on the forehead 
and neck. Other typical cutaneous lesions include subun
-
gual fibromas, shagreen patches (leathery plaques of sub
-
epidermal fibrosis, situated usually on the trunk), and 
leaf-shaped hypopigmented spots. Associated abnormali
-
ties include retinal lesions and tumors, benign rhabdomyo
-
mas of the heart, lung cysts, benign tumors in the viscera, 
and bone cysts.
The disease is slowly progressive and leads to increasing 
mental deterioration. There is no specific treatment, but 
anticonvulsants may help in controlling seizures.
2. Neurofibromatosis
Neurofibromatosis may occur either sporadically or on a 
familial basis with autosomal dominant inheritance. Two 
distinct forms are recognized: 
Type 1 (Recklinghausen 
disease)
 is characterized by multiple hyperpigmented mac
-
ules, Lisch nodules, and neurofibromas, and results from 
mutations in the 
NF1
 gene on chromosome 17. 
Type 2
 is 
characterized by bilateral eighth nerve tumors, often 
accompanied by other intracranial or intraspinal tumors, 
and is associated with mutations in the 
NF2
 (merlin) gene 
on chromosome 22.
Neurologic presentation is usually with symptoms and 
signs of tumor. Multiple neurofibromas characteristically 
are present and may involve spinal or cranial nerves, 
especially the eighth nerve. Examination of the superfi
-
cial cutaneous nerves usually reveals palpable mobile 
nodules. In some cases, there is marked overgrowth of

-
nodules. In some cases, there is marked overgrowth of 
subcutaneous tissues (plexiform neuromas), sometimes 
with an underlying bony abnormality. Associated cutane
-
ous lesions include axillary freckling and patches of cuta
-
neous pigmentation (café au lait spots). Malignant 
degeneration of neurofibromas occasionally occurs and 
may lead to peripheral sarcomas. Meningiomas, gliomas 
(especially optic nerve gliomas), bone cysts, pheochro
-
mocytomas, scoliosis, and obstructive hydrocephalus 
may also occur.
3. Sturge-Weber Syndrome
Sturge-Weber syndrome consists of a congenital, usually 
unilateral, cutaneous capillary angioma involving the 
upper face, leptomeningeal angiomatosis and, in many 
patients, choroidal angioma. It has no sex predilection and 
usually occurs sporadically. The cutaneous angioma some
-
times has a more extensive distribution over the head and 
neck and is often quite disfiguring, especially if there is 
associated overgrowth of connective tissue. Focal or gener
-
alized seizures are the usual neurologic presentation and 
may commence at any age. There may be contralateral 
homonymous hemianopia, hemiparesis and hemisensory 
disturbance, ipsilateral glaucoma, and mental subnormal
-
ity. Skull radiographs taken after the first 2 years of life 
usually reveal gyriform (“tramline”) intracranial calcifica
-
tion, especially in the parieto-occipital region, due to min
-
eral deposition in the cortex beneath the intracranial 
angioma.
Treatment is aimed at controlling seizures pharmaco
-
logically (Table 24–2), but surgical treatment may be nec
-
essary. Ophthalmologic advice should be sought concerning 
the management of choroidal angioma and of increased 
intraocular pressure.
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MOVEMENT DISORDERS
1. Essential (Familial) Tremor
 
»
Postural tremor of hands, head, or voice.
 
»
Family history common.
 
»
May improve temporarily with alcohol.
 
»
No abnormal findings other than tremor.
 
»
The cause of essential tremor is uncertain, but it is some
-
times inherited in an autosomal dominant manner.
 
»
Tremor may begin at any age and is enhanced by emotional 
stress. The tremor usually involves one or both hands, the 
head, or the hands and head, while the legs tend to be 
spared. The tremor is not present at rest, but emerges with 
action. Examination reveals no other abnormalities. Inges
-
tion of a small quantity of alcohol commonly provides 
remarkable but short-lived relief by an unknown 
mechanism.
Although the tremor may become more conspicuous 
with time, it generally leads to little disability. Occasionally, 
it interferes with manual skills and leads to impairment of 
handwriting. Speech may also be affected if the laryngeal 
muscles are involved.
 
»
Treatment
Treatment is often unnecessary. When it is required 
because of disability, propranolol (60–240 mg daily orally) 
may be helpful. Long-term therapy is typical; however, 
intermittent therapy is sometimes useful in patients 
whose tremor becomes exacerbated in specific predict
-
able situations. Primidone may be helpful when pro
-
pranolol is ineffective, but patients with essential tremor 
are often very sensitive to it. Therefore, the starting dose 
is 50 mg daily orally, and the daily dose is increased by 
50 mg every 2 weeks depending on the patient’s response; 
a maintenance dose of 125 mg three times daily orally is 
commonly effective. Occasional patients do not respond 
to these measures but are helped by alprazolam (up to 
3 mg daily orally in divided doses), topiramate (titrated 
up to a dose of 400 mg daily orally in divided doses over 
about 8 weeks), or gabapentin (1800 mg daily orally in 
divided doses). Botulinum toxin A may reduce tremor, 
but adverse effects include dose-dependent weakness of 
the injected muscles.
Disabling tremor unresponsive to medical treatment 
may be helped by high-frequency thalamic stimulation on 
one or both sides, according to the laterality of symptoms. 
Focused transcranial ultrasound thalamotomy using MRI 
guidance is also effective.
 
»
•	
When refractory to first-line treatment with proprano
-
lol or primidone.
•	
When additional neurologic signs are present 
(ie, parkinsonism).
 
»
Patients requiring surgical treatment (deep brain stimula
-
tor placement) should be hospitalized.
Elias WJ et al. A randomized trial of focused ultrasound thala
-
motomy for essential tremor. N Engl J Med. 2016 Aug 25;
 
375(8):730–9. [PMID: 27557301]
Schneider SA et al. Medical and surgical treatment of tremors. 
Neurol Clin. 2015 Feb;33(1):57–75. [PMID: 25432723]
2. 
p
ark
inson Disease
 
»
Any combination of tremor, rigidity, bradykinesia, 
and progressive postural instability (“parkinsonism”).
 
»
Cognitive impairment is sometimes prominent.
 
»
Parkinsonism is a relatively common disorder that occurs 
in all ethnic groups, with an approximately equal sex distri
-
bution. The most common variety, idiopathic Parkinson 
disease, begins most often between 45 and 65 years of age 
and is a progressive disease.
 
»
Etiology
Parkinsonism may rarely occur on a familial basis, and the 
parkinsonian phenotype may result from mutations of 
several different genes. Postencephalitic parkinsonism is 
becoming increasingly rare. Exposure to certain toxins (eg, 
manganese dust, carbon disulfide) and severe carbon mon
-
oxide poisoning may lead to parkinsonism. Reversible 
parkinsonism may develop in patients receiving neurolep
-
tic medications (see Chapter 25), reserpine, or metoclo
-
pramide. Only rarely is hemiparkinsonism the presenting

-
-
pramide. Only rarely is hemiparkinsonism the presenting 
feature of a progressive space-occupying lesion.
In idiopathic Parkinson disease, dopamine depletion 
due to degeneration of the dopaminergic nigrostriatal sys
-
tem leads to an imbalance of dopamine and acetylcholine, 
which are neurotransmitters normally present in the cor
-
pus striatum. Treatment of the motor disturbance is 
directed at redressing this imbalance by blocking the effect 
of acetylcholine with anticholinergic medications or by the 
administration of levodopa, the precursor of dopamine. 
Prior use of ibuprofen is associated with a 
decreased
 risk of 
developing Parkinson disease; age, family history, male sex, 
ongoing herbicide/pesticide exposure, and significant prior 
head trauma are risk factors.
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CMDT 2019
 
»
Tremor, rigidity, bradykinesia, and postural instability are 
the cardinal motor features of parkinsonism and may be 
present in any combination. Nonmotor manifestations 
include affective disorders (depression, anxiety, and 
apathy), cognitive changes, fatigue, sleep disorders, anos
-
mia, autonomic disturbances, sensory complaints or pain, 
and seborrheic dermatitis. The tremor of about four to six 
cycles per second is most conspicuous at rest, is enhanced 
by emotional stress, and is often less severe during volun
-
tary activity. Although it may ultimately be present in all 
limbs, the tremor is commonly confined to one limb or to 
the limbs on one side for months or years before it becomes 
more generalized. In some patients, tremor is absent.
Rigidity (an increase in resistance to passive move
-
ment) is responsible for the characteristically flexed pos
-
ture seen in many patients, but the most disabling 
symptoms of parkinsonism are due to bradykinesia, mani
-
fested as a slowness of voluntary movement and a reduc
-
tion in automatic movements such as swinging of the arms 
while walking. Curiously, however, effective voluntary 
activity may briefly be regained during an emergency (eg, 
the patient is able to leap aside to avoid an oncoming motor 
vehicle).
Clinical diagnosis of the well-developed syndrome is 
usually simple. The patient has a relatively immobile face 
with widened palpebral fissures, infrequent blinking, and a 
fixity of facial expression. Seborrhea of the scalp and face is 
common. There is often mild blepharoclonus, and a tremor 
may be present about the mouth and lips. Repetitive tap
-
ping (about twice per second) over the bridge of the nose 
produces a sustained blink response (Myerson sign). Other 
findings may include saliva drooling from the mouth, per
-
haps due to impairment of swallowing; soft and poorly 
modulated voice; a variable rest tremor and rigidity in 
some or all of the limbs; slowness of voluntary movements; 
impairment of fine or rapidly alternating movements; and 
micrographia. There is typically no muscle weakness (pro
-
vided that sufficient time is allowed for power to be devel
-
oped) and no alteration in the tendon reflexes or plantar 
responses. It is difficult for the patient to arise from a sit
-
ting position and begin walking. The gait itself is character
-
ized by small shuffling steps and a loss of the normal 
automatic arm swing; there may be unsteadiness on turn
-
ing, difficulty in stopping, and a tendency to fall. The 
serum urate level may be a prognostic indicator in men—
the rate of progression declines as the urate level increases.
 
»
Diagnostic problems may occur in mild cases, especially if 
tremor is minimal or absent. For example, mild hypokine
-
sia or slight tremor is commonly attributed to old age. 
Depression, with its associated expressionless face, poorly 
modulated voice, and reduction in voluntary activity, can 
be difficult to distinguish from mild parkinsonism, espe
-
cially since the two disorders may coexist. The family his
-
tory, the character of the tremor, and lack of other 
neurologic signs should distinguish essential tremor from 
parkinsonism. 
 can be distinguished by its 
early age at onset, the presence of other abnormal move
-
ments, Kayser-Fleischer rings, and chronic hepatitis, and 
by increased concentrations of copper in the tissues. 
 
Huntington disease
 presenting with rigidity and bradyki
-
nesia may be mistaken for parkinsonism unless the family 
history and accompanying dementia are recognized. In 
multisystem atrophy
 (previously called the 
Shy-Drager 
syndrome
), autonomic insufficiency (leading to postural 
hypotension, anhidrosis, disturbances of sphincter control, 
erectile dysfunction, etc) may be accompanied by parkin
-
sonism, pyramidal deficits, lower motor neuron signs, or 
cerebellar dysfunction. In

-
cerebellar dysfunction. In 
progressive supranuclear palsy
, 
bradykinesia and rigidity are accompanied by a supranu
-
clear disorder of eye movements, pseudobulbar palsy, 
pseudo-emotional lability (pseudobulbar affect), and axial 
dystonia. 
Creutzfeldt-Jakob disease
 may be accompanied 
by features of parkinsonism, but progression is rapid, 
dementia is usual, myoclonic jerking is common, ataxia 
and pyramidal signs may be conspicuous, and the MRI and 
electroencephalographic findings are usually characteris
-
tic. In 
corticobasal degeneration
, asymmetric parkinson
-
ism is accompanied by conspicuous signs of cortical 
dysfunction (eg, apraxia, sensory inattention, dementia, 
aphasia).
 
»
Treatment
Treatment is symptomatic. There is great interest in devel
-
oping disease-modifying therapies, but trials of several 
putative neuroprotective agents have shown no benefit. 
Trials of various gene therapies have shown limited or no 
benefit.
Medication is not required early in the course of Parkinson 
disease, but the nature of the disorder and the availability 
of medical treatment for use when necessary should be 
discussed with the patient.
1. Amantadine—
Patients with mild symptoms but no dis
-
ability may be helped by amantadine. This medication 
improves all of the clinical features of parkinsonism, but its 
mode of action is unclear. Side effects include restlessness, 
confusion, depression, skin rashes, edema, nausea, consti
-
pation, anorexia, postural hypotension, and disturbances 
of cardiac rhythm. However, these are relatively uncom
-
mon with the usual dose (100 mg twice daily orally). It also 
ameliorates dyskinesias resulting from chronic levodopa 
therapy.
2. Levodopa—
Levodopa, which is converted in the body 
to dopamine, improves all of the major features of parkin
-
sonism, including bradykinesia, but does not stop progres
-
sion of the disorder. The most common early side effects of 
levodopa are nausea, vomiting, and hypotension, but car
-
diac arrhythmias may also occur. Dyskinesias, restlessness, 
confusion, and other behavioral changes tend to occur 
somewhat later and become more common with time. 
Levodopa-induced 
dyskinesias
 may take any conceivable 
form, including chorea, athetosis, dystonia, tremor, tics, 
and myoclonus. An even later complication is the 
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1026
 CMDT 2019
wearing off effect
 or the 
on-off phenomenon,
 in which 
abrupt but transient fluctuations in the severity of parkin
-
sonism occur unpredictably but frequently during the day. 
The “off ” period of marked bradykinesia has been shown 
to relate in some instances to falling plasma levels of 
levodopa. During the “on” phase, dyskinesias are often 
conspicuous but mobility is increased. However, such 
response fluctuations may relate to advancing disease 
rather than to levodopa therapy itself.
Carbidopa, which inhibits the enzyme responsible for 
the breakdown of levodopa to dopamine, does not cross 
the blood-brain barrier. When levodopa is given in combi
-
nation with carbidopa, the extracerebral breakdown of 
levodopa is diminished. This reduces the amount of 
levodopa required daily for beneficial effects, and it lowers 
the incidence of nausea, vomiting, hypotension, and car
-
diac irregularities. Such a combination does not prevent 
the development of response fluctuations and the inci
-
dence of other side effects (dyskinesias or psychiatric com
-
plications) may actually be increased.
Sinemet, a commercially available preparation that con
-
tains carbidopa and levodopa in a fixed ratio (1:10 or 1:4), 
is generally used. Treatment is started with a small dose—
eg, one tablet of Sinemet 25/100 (containing 25 mg of car
-
bidopa and 100 mg of levodopa) three times daily—and 
gradually increased depending on the response. Sinemet 
CR is a controlled-release formulation (containing 25 or 
50 mg of carbidopa and 100 or 200 mg of levodopa). It is 
mainly useful when taken at bedtime to lessen motor dis
-
ability upon awakening. A formulation of carbidopa/
levodopa (Rytary) containing both immediate- and 
delayed-release beads provides a smoother response in 
patients with fluctuations. The commercially available 
combination of levodopa with both carbidopa and entaca
-
pone (Stalevo) may also be helpful in this context and is 
discussed in the following section on COMT inhibitors. 
Response fluctuations are also reduced by keeping the daily 
intake of 
protein
 at the recommended minimum and tak
-
ing the main protein meal as the last meal of the day. A 
continuous infusion of a carbidopa-levodopa enteral sus
-
pension through a percutaneous gastrojejunostomy tube 
by a portable infusion pump reduces “off ” time in patients 
with advanced Parkinson disease.
The dyskinesias and behavioral side effects of levodopa 
are dose-related, but reduction in dose may eliminate any 
therapeutic benefit. Levodopa-induced dyskinesias may 
also respond to amantadine.
Levodopa therapy is contraindicated in patients with 
psychotic illness or narrow-angle glaucoma. It should not 
be given to patients taking monoamine oxidase A inhibi
-
tors or within 2 weeks of their withdrawal, because hyper
-
tensive crises may result.
3. Dopamine agonists—
Dopamine agonists, such as 
pramipexole and ropinirole, act directly on dopamine 
receptors, and their use in parkinsonism is associated with 
a lower incidence of the response fluctuations and dyskine
-
sias that occur with long-term levodopa therapy. They are 
effective in both early and advanced stages of Parkinson 
disease. They are often given either before the introduction 
of levodopa or with a low dose of Sinemet 25/100 
(carbidopa 25 mg and levodopa 100 mg, one tablet three 
times daily) when dopaminergic therapy is first intro
-
duced; the dose of Sinemet is kept constant, while the dose 
of the agonist is gradually increased.
Pramipexole is started at a dosage of 0.125 mg three 
times daily orally, and the dose is built up gradually to 
between 0.5 and 1.5 mg three times daily. Ropinirole is 
begun at 0.25 mg three times daily orally and gradually 
increased; most patients require between 2 and 8 mg three 
times daily for benefit. Extended-release, once-daily for
-
mulations of pramipexole and ropinirole have similar effi
-

-
-
cacy and tolerability as the immediate release versions. 
Rotigotine is a dopamine agonist absorbed transdermally 
from a skin patch; it is started at 2 mg once daily and 
increased weekly by 2 mg daily until achieving an optimal 
response, up to a maximum of 8 mg daily. Adverse effects 
of these various agonists include fatigue, somnolence, nau
-
sea, peripheral edema, dyskinesias, confusion, and postural 
hypotension. Less commonly, an irresistible urge to sleep 
may occur, sometimes in inappropriate and hazardous 
circumstances. Impulse control disorders involving gam
-
bling, shopping, or sexual activity also occur. Local skin 
reactions may occur with the rotigotine patch.
4. Selective monoamine oxidase inhibitors—
Rasagiline, 
a selective monoamine oxidase B inhibitor, has a clear 
symptomatic benefit in some patients at a daily oral dose of 
1 mg, taken in the morning; it may also be used for adjunc
-
tive therapy in patients with response fluctuations to 
levodopa. Selegiline (5 mg orally with breakfast and lunch) 
or safinamide (50 mg orally daily, increased to 100 mg daily 
after 14 days) are also approved as adjunctive treatments. 
By inhibiting the metabolic breakdown of dopamine, these 
medications may improve fluctuations or declining 
response to levodopa.
Studies have suggested (but failed to show conclusively) 
that rasagiline may slow the progression of Parkinson dis
-
ease, and it appears to delay the need for other symptom
-
atic therapies. For these reasons, rasagiline is often started 
early, particularly for patients who are young or have mild 
disease. However, the FDA has rejected an expansion of 
rasagiline’s indication to include disease modification.
5. COMT inhibitors—
Catecholamine-
O
-methyltransferase 
(COMT) inhibitors reduce the metabolism of levodopa to 
3-
O
-methyldopa and thereby alter the plasma pharmacoki
-
netics of levodopa, leading to more sustained plasma levels 
and more constant dopaminergic stimulation of the brain. 
Treatment with entacapone or tolcapone results in reduced 
response fluctuations, with a greater period of responsive
-
ness to administered levodopa. Tolcapone is given in a 
dosage of 100 mg or 200 mg three times daily orally, and 
entacapone is given as 200 mg with each dose of Sinemet. 
The dose of Sinemet taken concurrently may have to be 
reduced by up to one-third to avoid side effects. Diarrhea 
is sometimes troublesome. Because rare cases of fulminant 
hepatic failure have followed its use, tolcapone should be 
avoided in patients with preexisting liver disease. Serial 
liver biochemical tests should be performed at 2-week 
intervals for the first year and at longer intervals thereafter 
in patients receiving the medication—as recommended by 
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CMDT 2019
the manufacturer. Hepatotoxicity has not been reported 
with entacapone, which is therefore the preferred agent, 
and serial liver biochemical tests are not required.
Stalevo is the commercial preparation of levodopa com
-
bined with both carbidopa and entacapone. It is best used 
in patients already stabilized on equivalent doses of carbi
-
dopa/levodopa and entacapone. It is priced at or below the 
price of the individual ingredients (ie, carbidopa/levodopa 
and entacapone) and has the added convenience of requir
-
ing fewer tablets to be taken daily. It is available in three 
strengths: Stalevo 50 (12.5 mg of carbidopa, 50 mg of 
levodopa, and 200 mg of entacapone), Stalevo 100 (25 mg 
of carbidopa, 100 mg of levodopa, and 200 mg of entaca
-
pone), and Stalevo 150 (37.5 mg of carbidopa, 150 mg of 
levodopa, and 200 mg of entacapone).
6. Anticholinergic medications—
Anticholinergics are 
more helpful in alleviating tremor and rigidity than brady
-
kinesia. Treatment is started with a small dose and gradu
-
ally increased until benefit occurs or side effects limit 
further increments. If treatment is ineffective, the medica
-
tion is gradually withdrawn and another preparation then 
tried. However, these medications are often poorly toler
-
ated, especially in older adults.
7. Antipsychotics—
Confusion and psychotic symptoms 
may occur as a side effect of dopaminergic therapy or as a 
part of the underlying illness. They often respond to the 
atypical antipsychotic agents clozapine and quetiapine, 
which have few extrapyramidal side effects and do not 
block the effects of dopaminergic medication. Clozapine 
may rarely cause marrow suppression, and weekly blood 
counts are therefore necessary for patients taking it. The 
patient is started on 6.25 mg at bedtime and the dosage 
increased to 25–100 mg/day as needed. In low doses, it may 
also improve iatrogenic dyskinesias. Typical antipsychotic 
agents and the second-generation antipsychotic agents ris
-
peridone and olanzapine may cause 
worsening
 of motor 
symptoms and should be avoided. Pimavanserin (34 mg 
once daily), a serotonin(2A) agonist, is also effective in 
treating the psychosis of Parkinson disease.
B. General Measures
Physical therapy or speech therapy helps many patients. 
Cognitive impairment and psychiatric symptoms may be 
helped by a cholinesterase inhibitor, such as rivastigmine 
(3–12 mg orally daily or 4.6 or 9.5 mg/24 hours transder
-
mally daily). The quality of life can often be improved by 
the provision of simple aids to daily living, eg, rails or ban
-
isters placed strategically about the home, special table 
cutlery with large handles, nonslip rubber table mats, and 
devices to amplify the voice.
C. Brain Stimulation
High-frequency stimulation of the subthalamic nuclei or 
globus pallidus internus may benefit many of the motor 
features of the disease but does not affect its natural history. 
Electrical stimulation of the brain has the advantage over 
ablative thalamotomy and pallidotomy procedures of being 
reversible and of causing minimal or no damage to the 
brain, and is therefore the preferred surgical approach to 
treatment. It is reserved for patients without cognitive 
impairment or psychiatric disorder who have a good 
response to levodopa, but in whom dyskinesias or response 
fluctuations are problematic. It frequently takes 3–6 months 
after surgery to adjust stimulator programming and to 
achieve optimal results. Side effects include depression, 
apathy, impulsivity, executive dysfunction, and decreased 
verbal fluency in a subset of patients.
D. Gene Therapy
Injections of adeno-associated viruses encoding various 
human genes have been made into the subthalamic nucleus 
or putamen in various clinical trials. These approaches may 
be useful in the future but remain experimental as of 2017.
 
»
 
»

»
 
»
Patients requiring surgical treatment should be admitted.
Connolly BS et al. Pharmacological treatment of Parkinson dis
-
ease: a review. JAMA. 2014 Apr 23–30;311(16):1670–83. 
[PMID: 24756517]
National Institute for Health and Care Excellence (2017) Parkin
-
son’s disease in adults. NICE Guideline (NG71). 2017 July. 
https://www.nice.org.uk/guidance/ng71
3. 
h
untington Disease
 
»
Gradual onset and progression of chorea and 
dementia or behavioral change.
 
»
Family history of the disorder.
 
»
Responsible gene identified on chromosome 4.
 
»
Huntington disease is characterized by chorea and demen
-
tia. It is inherited in an autosomal dominant manner and 
occurs throughout the world, in all ethnic groups, with a 
prevalence rate of about 5 per 100,000. There is an 
expanded and unstable CAG trinucleotide repeat in the 
huntingtin gene at 4p16.3; longer repeat lengths corre
-
spond to an earlier age of onset and faster disease 
progression.
 
»
Clinical onset is usually between 30 and 50 years of age. 
The disease is progressive and usually leads to a fatal out
-
come within 15–20 years. The initial symptoms may 
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consist of either abnormal movements or intellectual 
changes, but ultimately both occur. The earliest mental 
changes are often behavioral, with irritability, moodiness, 
antisocial behavior, or a psychiatric disturbance, but a 
more obvious dementia subsequently develops. The dyski
-
nesia may initially be no more than an apparent fidgetiness 
or restlessness, but eventually choreiform movements and 
some dystonic posturing occur. A parkinsonian syndrome 
with progressive rigidity and akinesia (rather than chorea) 
sometimes occurs in association with dementia, especially 
in cases with childhood onset. The diagnosis is established 
with a widely available genetic test, although such testing 
should be pursued under the guidance of a licensed genetic 
counselor.
B. Imaging
CT scanning or MRI usually demonstrates cerebral atrophy 
and atrophy of the caudate nucleus in established cases. 
Positron emission tomography (PET) has shown reduced 
striatal metabolic rate.
 
»
Chorea developing with no family history of choreoatheto
-
sis should not be attributed to Huntington disease, at least 
not until other causes of chorea have been excluded clini
-
cally and by appropriate laboratory studies. Nongenetic 
causes of chorea include stroke, systemic lupus erythema
-
tosus and antiphospholipid antibody syndrome, paraneo
-
plastic syndromes, infection with HIV , and various 
medications. In younger patients, self-limiting Sydenham 
chorea develops after group A streptococcal infections on 
rare occasions. If a patient presents solely with progressive 
intellectual failure, it may not be possible to distinguish 
Huntington disease from other causes of dementia unless 
there is a characteristic family history or a dyskinesia 
develops.
Huntington disease–like (HDL) disorders
 resemble 
Huntington disease but are caused by other genetic muta
-
tions. A clinically similar autosomal dominant disorder 
(dentatorubral-pallidoluysian atrophy),
 manifested by 
chorea, dementia, ataxia, and myoclonic epilepsy, is 
uncommon except in persons of Japanese ancestry. Treat
-
ment is as for Huntington disease.
 
»
Treatment
There is no cure for Huntington disease; progression can
-
not be halted; and treatment is purely symptomatic. The 
reported biochemical changes suggest a relative underac
-
tivity of neurons containing GABA and acetylcholine or a 
relative overactivity of dopaminergic neurons. Tetrabena
-
zine, a medication that interferes with the vesicular storage 
of biogenic amines, is widely used to treat the dyskinesia. 
The starting dose is 12.5 mg twice or three times daily 
orally, increasing by 12.5 mg every 5 days depending on 
response and tolerance; the usual maintenance dose is 
25  mg three times daily. Side effects include depression, 
postural hypotension, drowsiness, and parkinsonian fea
-
tures; tetrabenazine should not be given within 14 days of 
taking monoamine oxidase inhibitors and is not indicated 
for the treatment of levodopa-induced dyskinesias. Reser
-
pine is similar in depleting central monoamines but has 
more peripheral effects and a worse side-effect profile, 
making its use problematic in Huntington disease; if uti
-
lized, the dose is built up gradually to between 2 mg and 
5  mg orally daily, depending on the response. Deutetra
-
benazine is also effective in reducing chorea in Huntington 
disease, but direct comparisons with tetrabenazine are 
lacking. The starting dose is 6 mg once daily orally, 
increased to 6 mg twice daily after 1 week and by 6-mg 
increments weekly thereafter, to a maximum of 24 mg 
twice daily. Treatment with medications blocking dopa
-
mine receptors, such as phenothiazines or haloperidol, 
may control the dyskinesia and any behavioral distur
-
bances. Haloperidol treatment is usually begun with a dose 
of 1 mg once or twice daily orally, which is then increased 
every 3 or 4 days depending on the response; alternatively,

-
every 3 or 4 days depending on the response; alternatively, 
atypical antipsychotic agents such as quetiapine (increasing 
from 25 mg daily orally up to 100 mg twice daily orally as 
tolerated) may be tried. Amantadine in a dose of 200 mg to 
400 mg daily orally is sometimes helpful for chorea. Deep 
brain stimulation has been used successfully to treat chorea 
in a small number of patients. Behavioral disturbances may 
respond to clozapine. Attempts to compensate for the rela
-
tive GABA deficiency by enhancing central GABA activity 
or to compensate for the relative cholinergic underactivity 
by giving choline chloride have not been therapeutically 
helpful.
Offspring should be offered genetic counseling. Genetic 
testing permits presymptomatic detection and definitive 
diagnosis of the disease.
 
»
Huntington Study Group. Effect of deutetrabenazine on chorea 
among patients with Huntington disease: a randomized clini
-
cal trial. JAMA. 2016 Jul 5;316(1):40–50. [PMID: 27380342]
4. Idiopathic Torsion Dystonia
 
»
Dystonic movements and postures.
 
»
Normal birth and developmental history. No other 
 
»
Investigations (including CT scan or MRI) reveal no 
cause of dystonia.
 
»
Idiopathic torsion dystonia may occur sporadically or on a 
hereditary basis, with autosomal dominant, autosomal 
recessive, and X-linked recessive modes of transmission. 
Symptoms may begin in childhood or later and persist 
throughout life.
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»
The disorder is characterized by the onset of abnormal 
movements and postures in a patient with a normal birth 
and developmental history, no relevant past medical ill
-
ness, and no other neurologic signs. Investigations (includ
-
ing CT scan) reveal no cause for the abnormal movements. 
Dystonic movements of the head and neck may take the 
form of torticollis, blepharospasm, facial grimacing, or 
forced opening or closing of the mouth. The limbs may 
also adopt abnormal but characteristic postures. The age at 
onset influences both the clinical findings and the progno
-
sis. With onset in childhood, there is usually a family his
-
tory of the disorder, symptoms commonly commence in 
the legs, and progression is likely until there is severe dis
-
ability from generalized dystonia. In contrast, when onset 
is later, a positive family history is unlikely, initial symp
-
toms are often in the arms or axial structures, and severe 
disability does not usually occur, although generalized 
dystonia may ultimately develop in some patients. If all 
cases are considered together, about one-third of patients 
eventually become so severely disabled that they are con
-
fined to chair or bed, while another one-third are affected 
only mildly.
 
»
Perinatal anoxia, birth trauma, and kernicterus are com
-
mon causes of dystonia, but abnormal movements usually 
then develop before the age of 5, the early development of 
the patient is usually abnormal, and a history of seizures is 
not unusual. Moreover, examination may reveal signs of 
mental retardation or pyramidal deficit in addition to the 
movement disorder. Dystonic posturing may also occur in 
Wilson disease, Huntington disease, or parkinsonism; as a 
sequela of encephalitis lethargica or previous neuroleptic 
drug therapy; and in certain other disorders. In these cases, 
diagnosis is based on the history and accompanying clini
-
cal manifestations.
 
»
Treatment
Idiopathic torsion dystonia usually responds poorly to 
medications. Levodopa, diazepam, baclofen, carbamaze
-
pine, amantadine, or anticholinergic medication such as 
trihexyphenidyl or benztropine (in high dosage) is occa
-
sionally helpful; if not, a trial of treatment with tetra
-
benazine, phenothiazines, or haloperidol may be 
worthwhile. In each case, the dose has to be individual
-
ized, depending on response and tolerance. However, the 
doses of these latter medications that are required for 
benefit lead usually to mild parkinsonism. Pallidal deep 
brain stimulation is helpful for medically refractory dys
-
tonia and has a lower morbidity than stereotactic thala
-
motomy, which is sometimes helpful in patients with 
predominantly unilateral limb dystonia. Potential 
adverse events of deep brain stimulation include cerebral 
infection or hemorrhage, broken leads, affective changes, 
and dysarthria.
A distinct variety of dominantly inherited dystonia, 
caused by a mutation in the gene for GTP cyclohydrolase I 
on chromosome 14q, is remarkably responsive to levodopa; 
therefore, a levodopa trial is warranted in all patients.
 
»
 
»
Fox MD et al. Brain stimulation for torsion dystonia. JAMA 
Neurol. 2015 Jun;72(6):713–9. [PMID: 25894231]
5. Focal Torsion Dystonia
A number of the dystonic manifestations that occur in 
idiopathic torsion dystonia may also occur as isolated phe
-
nomena. They are best regarded as focal dystonias that 
either occur as formes frustes of idiopathic torsion dysto
-
nia in patients with a positive family history or represent a 
focal manifestation of the adult-onset form of that disorder 
when there is no family history. Medical treatment is gen
-
erally unsatisfactory. A trial of the medications used in 
idiopathic torsion dystonia is worthwhile, however, since a

-
idiopathic torsion dystonia is worthwhile, however, since a 
few patients do show some response. In addition, with 
restricted dystonias such as blepharospasm or torticollis, 
local injection of botulinum A toxin into the overactive 
muscles may produce worthwhile benefit for several weeks 
or months and can be repeated as needed.
Both blepharospasm and oromandibular dystonia may 
occur as an isolated focal dystonia. The former is charac
-
terized by spontaneous involuntary forced closure of the 
eyelids for a variable interval. Oromandibular dystonia is 
manifested by involuntary contraction of the muscles 
about the mouth causing, for example, involuntary open
-
ing or closing of the mouth, roving or protruding tongue 
movements, and retraction of the platysma. Cervical dysto
-
nia (spasmodic torticollis), usually with onset between 
25 and 50 years of age, is characterized by a tendency for 
the neck to twist to one side. This initially occurs episodi
-
cally, but eventually the neck is held to the side. Some 
patients have a sensory trick (“geste antagoniste”) that 
lessens the dystonic posture, eg, touching the side of the 
face. Spontaneous resolution may occur in the first year or 
so. The disorder is otherwise usually lifelong. Local injec
-
tion of botulinum A toxin provides benefit in most cases. 
Deep brain stimulation of the globus pallidus interna is an 
option if medical treatment and botulinum toxin injection 
are unsuccessful.
Writer’s cramp is characterized by dystonic posturing of 
the hand and forearm when the hand is used for writing 
and sometimes when it is used for other tasks, eg, playing 
the piano or using a screwdriver or eating utensils. Medica
-
tion treatment is usually unrewarding, and patients are 
often best advised to learn to use the other hand for activi
-
ties requiring manual dexterity. Injections of botulinum A 
toxin are helpful in some instances.
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6. Myoclonus
Occasional myoclonic jerks may occur in anyone, espe
-
cially when drifting into sleep. General or multifocal myoc
-
lonus is common in patients with idiopathic epilepsy and is 
especially prominent in certain hereditary disorders char
-
acterized by seizures and progressive intellectual decline, 
such as the lipid storage diseases. It is also a feature of 
subacute sclerosing panencephalitis and Creutzfeldt-Jakob 
disease. Generalized myoclonic jerking may accompany 
uremic and other metabolic encephalopathies, result from 
therapy with levodopa or tricyclic antidepressants, occur in 
alcohol or drug withdrawal states, or follow anoxic brain 
damage. It also occurs on a hereditary or sporadic basis as 
an isolated phenomenon in otherwise healthy subjects.
Segmental myoclonus is a rare manifestation of a focal 
spinal cord lesion. It may also be the clinical expression of 
epilepsia partialis continua
, a disorder in which a repeti
-
tive focal epileptic discharge arises in the contralateral 
sensorimotor cortex, sometimes from an underlying struc
-
tural lesion. An electroencephalogram is often helpful in 
clarifying the epileptic nature of the disorder, and CT or 
MRI scan may reveal the causal lesion.
Myoclonus may respond to certain anticonvulsant 
medications, especially valproic acid or levetiracetam, or to 
one of the benzodiazepines, particularly clonazepam (see 
Table 24–2). It may also respond to piracetam (up to 16.8 g 
daily; not available in the United States). Myoclonus fol
-
lowing anoxic brain damage is often responsive to oxitrip
-
tan (5-hydroxytryptophan), the precursor of serotonin, 
and sometimes to clonazepam. Oxitriptan is given in 
gradually increasing doses up to 1–1.5 mg daily. In patients 
with segmental myoclonus, a localized lesion should be 
searched for and treated appropriately.
Mills K et al. An update and review of the treatment of myoclo
-
nus. Curr Neurol Neurosci Rep. 2015 Jan;15(1):512. [PMID: 
25398378]
7. Wilson Disease
In this metabolic disorder, abnormal movement and posture 
may occur with or without coexisting signs of liver involve
-
ment. Psychiatric and neuropsychological manifestations are 
common. Wilson disease is discussed in Chapter 16.
8. Drug-Induced 
a
bnormal Mo
vements
Phenothiazines, butyrophenones, and metoclopramide may 
produce a wide variety of abnormal movements, including 
parkinsonism, akathisia (ie, motor restlessness), acute dys
-
tonia, chorea, and tardive dyskinesias or dystonia; several of 
these are also produced by aripiprazole. These complica
-
tions are discussed in Chapter 25. Chorea may also develop 
in patients receiving levodopa, bromocriptine, anticholiner
-
gic medications, phenytoin, carbamazepine, lithium, 
amphetamines, or oral contraceptives, and it resolves with 
withdrawal of the offending substance. Similarly, dystonia 
may be produced by levodopa, bromocriptine, lithium, or 
carbamazepine; and parkinsonism by reserpine and tetra
-
benazine. Postural tremor may occur with a variety of 
medications, including epinephrine, isoproterenol, amioda
-
rone, theophylline, caffeine, lithium, thyroid hormone, tri
-
cyclic antidepressants, and valproic acid.
9. Restless Legs Syndrome
This common disorder, affecting 1–5% of people, may 
occur as a primary (idiopathic) disorder or in relation to 
Parkinson disease, pregnancy, iron deficiency anemia, or 
peripheral neuropathy (especially uremic or diabetic). It 
may have a hereditary basis, and several genetic loci have 
been associated with the disorder. Restlessness and curious 
sensory disturbances lead to an irresistible urge to move 
the limbs, especially during periods of relaxation; move
-
ment of the limbs provides relief. The urge occurs exclu
-
sively in the evening and at night or is worse at night than 
during the day. Most patients also have periodic limb 
movements of sleep and one-third have periodic limb

-
movements of sleep and one-third have periodic limb 
movements during relaxed wakefulness; both consist of 
brief involuntary flexion at the ankle, knee, and hip. Dis
-
turbed nocturnal sleep and excessive daytime somnolence 
may result. Ferritin levels should always be measured; 
treatment with oral iron sulfate in patients with levels less 
than or equal to 75 mcg/L (13.4 mcmol/L) should be 
attempted prior to initiation of other pharmacotherapies. 
Therapy is with nonergot dopamine agonists, such as 
pramipexole (0.125–0.5 mg orally once daily), ropinirole 
(0.25–4 mg orally once daily 2 to 3 hours before bedtime), 
or rotigotine (1–3 mg/24h transdermal patch once daily) or 
with gabapentin enacarbil (300–1200 mg orally each eve
-
ning). Gabapentin (starting with 300 mg orally daily, 
increasing to approximately 1800 mg daily depending on 
response and tolerance) and pregabalin (150–300 mg orally 
divided twice to three times daily) are related medications 
that improve symptoms. Levodopa is helpful but may 
 
lead to an augmentation of symptoms, so that its use is gen
-
erally reserved for those who do not respond to other mea
-
sures. Extended-release oxycodone-naloxone (2.5–5 mg to 
 
5–10 mg orally twice daily) is useful in patients with severe 
symptoms or those who are refractory to first-line 
Winkelman JW et al. Practice guideline summary: treatment of 
restless legs syndrome in adults: report of the Guideline 
Development, Dissemination, and Implementation Subcom
-
mittee of the American Academy of Neurology. Neurology. 
2016 Dec 13;87(24):2585–93. [PMID: 27856776]
10. Gilles de la Tourette Syndrome
 
»
Multiple motor and phonic tics.
 
»
Symptoms begin before age 18 years.
 
»
Tics occur frequently for at least 1 year.
 
»
Tics vary in number, frequency, and nature 
over time.
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»
Simple tics occur transiently in up to 25% of children, 
remit within weeks to months, and do not require treat
-
ment. Tourette syndrome is a more complex disorder, with 
diagnostic criteria as defined above. Motor tics are the 
initial manifestation in 80% of cases and most commonly 
involve the face, whereas in the remaining 20%, the initial 
symptoms are phonic tics; ultimately a combination of dif
-
ferent motor and phonic tics develop in all patients. Tics 
are preceded by an urge that is relieved upon performance 
of the movement or vocalization; they can be temporarily 
suppressed but eventually the urge becomes overwhelm
-
ing. These are noted first in childhood, generally between 
the ages of 2 and 15. Motor tics occur especially about the 
face, head, and shoulders (eg, sniffing, blinking, frowning, 
shoulder shrugging, head thrusting, etc). Phonic tics com
-
monly consist of grunts, barks, hisses, throat-clearing, 
coughs, etc, but sometimes also of verbal utterances includ
-
ing coprolalia (obscene speech). There may also be echola
-
lia (repetition of the speech of others), echopraxia 
(imitation of others’ movements), and palilalia (repetition 
of words or phrases). Some tics may be self-mutilating in 
nature, such as nail-biting, hair-pulling, or biting of the lips 
or tongue. The disorder is chronic, but the course may be 
punctuated by relapses and remissions. Obsessive-compulsive 
disorder (OCD) and attention deficit hyperactivity disor
-
der (ADHD) are commonly associated and may be more 
disabling than the tics themselves. A family history is 
sometimes obtained.
Examination usually reveals no abnormalities other 
than the tics. In addition to OCD, psychiatric disturbances 
may occur because of the associated cosmetic and social 
embarrassment. The diagnosis of the disorder is often 
delayed for years, the tics being interpreted as psychiatric 
illness or some other form of abnormal movement. Patients 
are thus often subjected to unnecessary treatment before 
the disorder is recognized. The tic-like character of the 
abnormal movements and the absence of other neurologic 
signs should differentiate this disorder from other move
-
ment disorders presenting in childhood. Wilson disease, 
however, can simulate the condition and should be excluded.
 
»
Treatment
Treatment is symptomatic and may need to be continued 
indefinitely. Habit reversal training or other forms of 
behavioral therapy can be effective alone or in combination 
with pharmacotherapy. Alpha-adrenergic agonists, such as 
clonidine (start 0.05 mg orally at bedtime, titrating to 
 
0.3–0.4 mg orally daily, divided three to four times per day) 
or guanfacine (start 0.5 mg orally at bedtime, titrating to a 
maximum of 3–4 mg orally daily, divided twice daily) are 
first-line therapies because of a favorable side-effect profile 
compared with typical antipsychotics, which are the only 
FDA-approved therapies for the disorder. They also have 
the advantage of improving the symptoms of concomitant 
ADHD. Many specialists favor the use of tetrabenazine. 
The atypical antipsychotic risperidone (1–6 mg daily 
orally) is more effective than placebo in controlling tics and 
more effective than pimozide in improving symptoms of 
comorbid OCD and may be tried before the typical anti
-
psychotic agents. When a typical antipsychotic is required 
in cases of severe tics, haloperidol is generally regarded as 
the drug of choice. It is started in a low dose (0.25 mg daily 
orally) that is gradually increased (by 0.25 mg every 4 or 
5 days) until there is maximum benefit with a minimum of 
side effects or until side effects limit further increments. 
A total daily oral dose of between 2 mg and 8 mg is usually 
optimal, but higher doses are sometimes necessary. Flu
-
phenazine (1–15 mg orally daily) or pimozide (1–10 mg 
orally daily) are alternatives. Typical antipsychotics can

-
orally daily) are alternatives. Typical antipsychotics can 
cause significant weight gain and carry a risk of tardive 
dyskinesias and other long-term, potentially irreversible 
motor side effects. Small randomized trials or observa
-
tional studies have reported benefit from topiramate, nico
-
tine, tetrahydrocannabinol, and clonazepam.
Injection of botulinum toxin type A at the site of the 
most distressing tics is sometimes worthwhile and has 
fewer side effects than systemic antipsychotic therapy. 
Bilateral high-frequency deep brain stimulation at various 
sites has been helpful in some, otherwise intractable, cases.
 
»
 
»
Patients undergoing surgical (deep brain stimulation) 
treatment should be admitted.
Schrock LE et al; Tourette Syndrome Association International 
Deep Brain Stimulation (DBS) Database and Registry Study 
Group. Tourette syndrome deep brain stimulation: a review 
and updated recommendations. Mov Disord. 2015 Apr;30(4):
 
448–71. [PMID: 25476818]
Serajee FJ et al. Advances in Tourette syndrome: diagnoses and 
treatment. Pediatr Clin North Am. 2015 Jun;62(3):687–701. 
[PMID: 26022170]
DEMENTIA
 
»
Progressive intellectual decline.
 
»
Not due to delirium or psychiatric disease.
 
»
Age is the main risk factor, followed by family 
 
history and vascular disease risk factors.
 
»
Dementia is a progressive decline in intellectual function 
that is severe enough to compromise social or occupational 
functioning. 
Mild cognitive impairment
 describes a 
decline that has not resulted in a change in the level of 
function. Although a few patients identify a precipitating 
event, most experience an insidious onset and gradual 
progression of symptoms.
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Dementia typically begins after age 60, and the preva
-
lence doubles approximately every 5 years thereafter; in 
persons aged 85 and older, around half have dementia. In 
most, the cause of dementia is acquired, either as a spo
-
radic primary neurodegenerative disease or as the result of 
another disorder, such as stroke (Table 24–5). Other risk 
factors for dementia include family history, diabetes melli
-
tus, cigarette smoking, hypertension, obesity, a history of 
significant head injury, and hearing loss. Vitamin D defi
-
ciency and chronic sleep deprivation may also increase the 
risk of dementia. Dementia is more prevalent among 
women, but this may be accounted for by their longer life 
expectancy. Physical activity seems to be protective; educa
-
tion, ongoing intellectual stimulation, and social engage
-
ment may also be protective, perhaps by promoting 
cognitive reserve
, an improved capacity to compensate for 
insidious neurodegeneration.
Dementia is distinct from delirium and psychiatric 
disease. 
Delirium
 is an acute confusional state that often 
occurs in response to an identifiable trigger, such as drug 
or alcohol intoxication or withdrawal (eg, Wernicke 
encephalopathy, described below), medication side effects 
(especially medications with anticholinergic properties, 
antihistamines, benzodiazepines, sleeping aids, opioids, 
neuroleptics, corticosteroids, and other sedative or psycho
-
tropic agents), infection (consider occult urinary tract 
infection or pneumonia in elderly patients), metabolic 
disturbance (including an electrolyte abnormality; hypo
-
glycemia or hyperglycemia; or a nutritional, endocrine, 
renal, or hepatic disorder), sleep deprivation, or other 
neurologic disease (seizure, including a postictal state, or 
stroke). Delirium typically involves 
fluctuating
 levels of 
arousal, including drowsiness or agitation, and it improves 
after removal or treatment of the precipitating factor. 
Patients with dementia are especially susceptible to epi
-
sodes of delirium, but recognition of dementia is not pos
-
sible until delirium lifts. For this reason, dementia is 
typically diagnosed in outpatients who are otherwise medi
-
cally stable, rather than in acutely ill patients in the 
hospital.
Psychiatric disease
 sometimes leads to complaints of 
impaired cognition (
pseudodementia
). Impaired attention 
Table 24–5.
 
Common causes of age-related dementia.
Disorder
p
a
thology
Alzheimer 
disease
Plaques containing beta-amyloid 
peptide, and neurofibrillary tan
-
gles containing tau protein, occur 
throughout the neocortex
•	
Most common age-related neurodegenerative disease; incidence doubles 
every 5 years after age 60
•	
Short-term memory impairment is early and prominent in most cases
•	
Variable deficits of executive function, visuospatial function, and language
Vascular 
dementia
Multifocal ischemic change
•	
Stepwise or progressive accumulation of cognitive deficits in association with 
repeated strokes
•	
Symptoms depend on localization of strokes
Dementia with 
Lewy bodies
Histologically indistinguishable from 
Parkinson disease: alpha-
 
synuclein-containing Lewy bodies 
occur in the brainstem, midbrain, 
olfactory bulb, and neocortex. 
Alzheimer pathology may coexist.
•	
Cognitive dysfunction, with prominent visuospatial and executive deficits
•	
Psychiatric disturbance, with anxiety, visual hallucinations, and fluctuating 
delirium
•	
Parkinsonian motor deficits with or after other features
•	
Cholinesterase inhibitors lessen delirium; poor tolerance of neuroleptics and 
dopaminergics
Frontotemporal 
dementia 
(FTD)
Neuropathology is variable and 
defined by the protein found in 
intraneuronal aggregates. Tau pro
-
tein, TAR DNA-binding protein 43 
(TDP-43), or fused-in-sarcoma 
(FUS) protein account for most 
cases.
•	
Peak incidence in the sixth decade; approximately equal to Alzheimer disease

-
cases.
•	
Peak incidence in the sixth decade; approximately equal to Alzheimer disease 
as a cause of dementia in patients under 60 years old
•	
Familial cases result from mutations in genes for tau, progranulin, or others
Behavioral variant FTD
•	
Deficits in empathy, social comportment, insight, abstract thought, and 
 
executive function
•	
Behavior is disinhibited, impulsive, and ritualistic, with prominent apathy and 
increased interest in sex or sweet/fatty foods
•	
Relative preservation of memory
•	
Focal right frontal atrophy
•	
Association with amyotrophic lateral sclerosis
Semantic variant primary progressive aphasia
•	
Deficits in word-finding, single-word comprehension, object and category 
knowledge, and face recognition
•	
Behaviors may be similar to behavioral variant FTD
•	
Focal, asymmetric temporal pole atrophy
Nonfluent/agrammatic variant primary progressive aphasia
•	
Speech is effortful with dysarthria, phonemic errors, sound distortions, and 
poor grammar
•	
Focal extrapyramidal signs and apraxia of the right arm and leg are common; 
overlaps with corticobasal degeneration
•	
Focal left frontal atrophy
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is usually to blame, and in some patients with depression or 
anxiety, poor focus and concentration may even be a pri
-
mary complaint. The symptoms should improve with 
appropriate psychiatric treatment. Mood disorders are 
commonly seen in patients with neurodegenerative disease 
and in some cases are an early symptom. There is some 
evidence that a persistent, untreated mood disorder may 
predispose to the development of an age-related dementia, 
and psychiatric symptoms can clearly exacerbate cognitive 
impairment in patients who already have dementia; there
-
fore, suspicion of dementia should not distract from appro
-
priate screening for and treatment of depression or 
anxiety.
 
»
Symptoms and signs of the common causes of dementia are 
detailed in Table 24–5. Clinicians should be aware that a 
patient’s insight into a cognitive change may be vague or 
absent, and collateral history is essential to a proper evalu
-
ation. As patients age, primary care clinicians should 
inquire periodically about the presence of any cognitive 
symptoms.
Symptoms depend on the area of the brain affected. 
Short-term memory loss
, involving the repeating of ques
-
tions or stories and a diminished ability to recall the details 
of recent conversations or events, frequently results from 
pathologic changes in the hippocampus. 
Word-finding 
difficulty
 often involves difficulty recalling the names of 
people, places, or objects, with low-frequency words 
affected first, eventually resulting in speech laden with 
pronouns and circumlocutions. This problem is thought to 
arise from pathology at the temporoparietal junction of the 
left hemisphere. Problems with articulation, fluency, com
-
prehension, or word meaning are anatomically distinct and 
less common. 
Visuospatial dysfunction
 may result in 
poor navigation and getting lost in familiar places, impaired 
recognition of previously familiar faces and buildings, or 
trouble discerning an object against a background. The 
right parietal lobe is one of the brain areas implicated in 
such symptoms. 
Executive dysfunction
 may manifest by 
easy distractibility, impulsivity, mental inflexibility, con
-
crete thought, slowed processing speed, poor planning and 
organization, or impaired judgment. Localization may vary 
and could include the frontal lobes or subcortical areas like 
the basal ganglia or cerebral white matter. 
Apathy
 or indif
-
ference, separate from depression, is common and may 
have a similar anatomy as executive dysfunction. 
Apraxia
, 
or the loss of learned motor behaviors, may result from 
dysfunction of the frontal or parietal lobes, especially the 
left parietal lobe.
The time of symptom onset must be established, but 
subtle, early symptoms are often apparent only in retro
-
spect. Another event, such as an illness or hospitalization, 
may lead to new recognition of existing symptoms. Symp
-
toms often accumulate over time, and the nature of the 
earliest symptom is most helpful in forming the differential 
diagnosis. The history should establish risk factors for 
dementia, including family history, other chronic illnesses, 
and vascular disease risk factors. Finally, it is important to 
document the patient’s current capacity to perform basic 
and instrumental activities of daily living (see Chapter 4) 
and to note the extent of decline from the premorbid level 
of function. Indeed, it is this functional assessment that 
defines the presence and severity of dementia.
The physical examination is important to identify any 
occult medical illness. In addition, eye movement abnor
-
malities, parkinsonism, or other motor abnormalities may 
help identify an underlying neurologic condition. The 
workup should prioritize the exclusion of conditions that 
are reversible or require separate therapy. Screening for 
depression is necessary, along with imaging and laboratory

depression is necessary, along with imaging and laboratory 
workup, as indicated below.
B. Neuropsychological Assessment
Brief quantification of cognitive impairment is indicated in 
a patient complaining of cognitive symptoms. The Folstein 
Mini Mental State Exam (MMSE), Montreal Cognitive 
Assessment (MoCA), Mini-Cog, and other similar tests are 
brief, objective, and widely used but have important limita
-
tions: they are insensitive to mild cognitive impairment, 
they may be biased negatively by the presence of language 
or attention problems, and they do not correlate with func
-
tional capacity.
A
 
neuropsychiatric
 
 by a trained neuropsy
-
chologist or psychometrician may be appropriate. The goal 
of such testing is to enhance localization by defining the 
cognitive domains that are impaired as well as to quantify 
the degree of impairment. There is no standard battery of 
tests, but a variety of metrics is commonly used to assess 
the symptom types highlighted above. Assessments are 
most accurate when a patient is well rested, comfortable, 
and otherwise medically stable.
C. Imaging
Brain imaging with MRI or CT without contrast is indicated 
in any patient with a new, progressive cognitive complaint. 
The goal is to exclude occult cerebrovascular disease, 
tumor, or other identifiable structural abnormality, rather 
than to provide positive evidence of a neurodegenerative 
disease. Global or focal brain atrophy may be worse than 
expected for age and could suggest a particular neurode
-
generative process, but such findings are rarely specific.
Positron-emission tomography (PET) with fluorode
-
oxyglucose (FDG) does not confirm or exclude any specific 
cause of dementia but may be useful as an element of the 
workup in specific clinical circumstances, such as discrimi
-
nating between Alzheimer disease and frontotemporal 
dementia in a patient with some symptoms of each. PET 
imaging with a radiolabeled ligand for beta-amyloid, one of 
the pathologic proteins in Alzheimer disease, is highly 
sensitive to amyloid pathology and may provide positive 
evidence for Alzheimer disease in a patient with cognitive 
decline. However, after age 60 or 70, amyloid plaques can 
accumulate in the absence of cognitive impairment; thus, 
the specificity of a positive amyloid scan diminishes with 
age. Single photon-emission computed tomography offers 
similar information as FDG-PET but is less sensitive. 
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PET  imaging with radiolabeled ligands for tau, a patho
-
genic protein in Alzheimer disease, progressive supranu
-
clear palsy, and some forms of frontotemporal dementia, 
also may help refine premortem diagnostic accuracy.
Serum levels of vitamin B
12
, free T
4
, and thyroid-stimulat
-
ing hormone should be measured for any patient with 
cognitive symptoms. A serum rapid plasma reagin (RPR) 
and testing for HIV should be considered. Other testing 
should be driven by clinical suspicion, and often includes a 
complete blood count, serum electrolytes, glucose, and 
lipid profile.
Although the presence of one or two ApoE epsilon-4 
alleles indicates an increased risk of Alzheimer disease and 
ApoE genotyping is clinically available, it is of limited clini
-
cal utility. Finding an ApoE epsilon-4 allele in a young 
patient with dementia might raise the index of suspicion 
for Alzheimer disease, but obtaining a genotype in an 
elderly patient is unlikely to be helpful, and doing so in an 
asymptomatic patient as a marker of risk for Alzheimer 
disease is inappropriate until a preventive therapy becomes 
available. Spinal fluid protein measurements are also avail
-
able; levels of beta-amyloid decrease and tau protein 
increase in Alzheimer disease, but this testing shares some 
of the same concerns as amyloid PET imaging.
 
»
In elderly patients with gradually progressive cognitive 
symptoms and no other complaint or sign, a neurodegen
-
erative disease is likely (Table 24–5). Decline beginning 
before age 60, rapid progression, fluctuating course, unin
-
tended weight loss, systemic complaints, or other unex
-
plained symptoms or signs raise suspicion for a process 
other than a neurodegenerative disease. In this case, the 
differential is broad and includes infection or inflamma
-
tory disease (consider a lumbar puncture to screen for cells 
or antibodies in the spinal fluid), neoplasm or a paraneo
-
plastic condition, endocrine or metabolic disease, drugs or 
toxins, or other conditions. 
Normal pressure hydrocepha
-
lus
 is a difficult diagnosis to establish. Symptoms include 
gait apraxia (sometimes described as a “magnetic” gait, as 
if the feet are stuck to the floor), urinary incontinence, and 
dementia. CT scanning or MRI of the brain reveals ven
-
tricles that are enlarged in obvious disproportion to sulcal 
widening and overall brain atrophy.
 
»
Treatment
A. Nonpharmacologic Approaches
Aerobic exercise
 (45 minutes most days of the week) and 
frequent mental stimulation
 may reduce the rate of func
-
tional decline and decrease the demented patient’s caregiv
-
ing needs, and these interventions may reduce the risk of 
dementia in normal individuals. The most efficacious 
manner of mental stimulation is a matter of debate: main
-
taining as active a role in the family and community as 
practically possible is most likely to be of benefit, empha
-
sizing activities at which the patient feels confident. 
Patients with neurodegenerative diseases have a limited 
capacity to regain lost skills; for instance, memory drills in 
a patient with Alzheimer disease are more likely to lead to 
frustration than benefit and studies show that computer
-
ized cognitive training does 
not
 improve cognition or func
-
tion in demented patients. Vitamin E (1000 international 
units twice daily) appears to reduce the rate of functional 
decline in patients with Alzheimer disease, but does not 
affect cognition or prevent the development of Alzheimer 
disease in patients with mild cognitive impairment.
B. Cognitive Symptoms
Cholinesterase inhibitors
 are first-line therapy for 
Alzheimer disease and dementia with Lewy bodies 
(Table  24–5). They provide modest, symptomatic treat
-
ment for cognitive dysfunction and may prolong the capac
-
ity for independence but do not prevent disease progression. 
Commonly used medications include donepezil (start at

-
-
Commonly used medications include donepezil (start at 
5  mg orally daily for 4 weeks, then increase to 10 mg daily; 
a 23 mg daily dose is approved for moderate to severe 
Alzheimer disease, although its very modest additional 
efficacy over the 10 mg dose is overshadowed by an 
increased risk of side effects); rivastigmine (start at 1.5 mg 
orally twice daily, then increasing every 2 weeks by 1.5 mg 
twice daily to a goal of 3–6 mg twice daily; or 4.6, 9.5, or 
13.3 mg/24 hours transdermally daily); and galantamine 
(start at 4 mg orally twice daily, then increasing every 
4  weeks by 4 mg twice daily to a goal of 8–12 mg twice 
daily; a once-daily extended-release formulation is also 
available). Cholinesterase inhibitors are 
not
 given for fron
-
totemporal dementia because they may worsen behavioral 
symptoms. Nausea and diarrhea are common side effects; 
syncope and cardiac dysrhythmia are uncommon but more 
serious. An ECG is often obtained before and after starting 
therapy, particularly in a patient with cardiac disease or a 
history of syncope.
Memantine (start at 5 mg orally daily, then increase by 
5 mg per week up to a target of 10 mg twice daily) is 
approved for the treatment of moderate to severe Alzheimer 
disease. In frontotemporal dementia, memantine is ineffec
-
tive and may worsen cognition. There is some evidence 
that memantine may improve cognition and behavior 
among patients with dementia with Lewy bodies.
Disease-modifying medications are not yet available for 
Alzheimer disease. Aducanumab, an antibody directed 
against aggregated beta-amyloid, showed promise in a 
phase II trial; phase III trials are ongoing.
C. Mood and Behavioral Disturbances
Selective serotonin reuptake inhibitors
 are generally safe 
and well tolerated in elderly, cognitively impaired patients, 
and they may be efficacious for the treatment of depres
-
sion, anxiety, or agitation. There is evidence to support the 
use of citalopram (10–30 mg orally daily) for agitation; side 
effects include QTc prolongation and worsened cognition 
at the highest dose. Paroxetine should be avoided because 
it has anticholinergic effects; avoid all tricyclic antidepres
-
sants for the same reason. Other antidepressant agents, 
such as buproprion or venlafaxine, may be tried.
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CMDT 2019
Insomnia is common, and trazodone (25–50 mg orally at 
bedtime as needed) can be safe and effective. Over-the-
counter antihistamine hypnotics must be avoided, along with 
benzodiazepines, because of their tendency to worsen cogni
-
tion and precipitate delirium. Other prescription hypnotics 
such as zolpidem may result in similar adverse reactions.
For agitation, impulsivity, and other behaviors that 
interfere with safe caregiving, causes of delirium (detailed 
above) should first be considered. When no reversible trig
-
ger is identified, treatment should be approached in a 
staged manner. Behavioral interventions, such as reorien
-
tation and distraction from anxiety-provoking stimuli, are 
first-line. Ensure that the patient is kept active during the 
day with both physical exercise and mentally stimulating 
activities, and that there is adequate sleep at night. Reassess 
the level of caregiving, and consider increasing the time 
spent directly with an attendant. Next, ensure that appro
-
priate pharmacologic treatment of cognition and mood is 
optimized. Finally, as a last resort, when other measures 
prove insufficient and the patient’s behaviors raise safety 
concerns, consider pharmacologic therapy. Citalopram or 
low doses of an atypical antipsychotic medication such as 
quetiapine (start 25 mg orally daily as needed, increasing to 
two to three times daily as needed) can be tried; even 
though atypical agents cause extrapyramidal side effects 
less frequently than typical antipsychotics, they should be 
used with particular caution in a patient at risk for falls, 
especially if parkinsonian signs are already present. Regu
-
larly scheduled dosing of antipsychotics is not recom
-
mended, and if implemented should be reassessed on a 
frequent basis (eg, weekly), with attempts to taper off as 
tolerated. There is an FDA black box warning against the 
use of all antipsychotic medications in elderly demented 
patients because of an increased risk of death; the reason 
for the increased mortality is unclear. The combination of 
dextromethorphan and quinidine (up to 30/10 mg orally 
twice daily) has shown promise in early clinical trials.
 
»
Special Circumstances
A. Rapidly Progressive Dementia
When dementia develops quickly, with obvious decline 
over a few weeks to a few months, the syndrome may be 
classified as a 
rapidly progressive dementia.
 The differ
-
ential diagnosis for typical dementias is still relevant, but 
additional etiologies must be considered, including prion 
disease; infections; toxins; neoplasms; and autoimmune 
and inflammatory diseases, including corticosteroid-
responsive (Hashimoto) encephalopathy and antibody-
mediated paraneoplastic syndromes. Workup should begin 
with brain MRI with contrast and diffusion-weighted imag
-
ing, routine laboratory studies (serum vitamin B
12
, free T
4
, 
and thyroid-stimulating hormone levels), serum RPR, HIV 
antibody, Lyme serology, rheumatologic tests (erythrocyte 
sedimentation rate, C-reactive protein, and antinuclear 
antibody), anti-thyroglobulin and anti-
 
t
hyroperoxidase 
antibody levels, paraneoplastic autoimmune antibodies 
(see Nonmetastatic Neurologic Complications of Malig
-
nant Disease, above), and cerebrospinal fluid studies (cell 
count and differential; protein and glucose levels; protein 
electrophoresis for oligoclonal bands; IgG index [spinal-
fluid-to-serum gamma-globulin level] ratio; and VDRL). 
Depending on the clinical context, it may be necessary to 
exclude Wilson disease (24-hour urine copper level), heavy 
metal intoxication (24-hour urine heavy metal panel), and 
infectious encephalitis (cerebrospinal fluid polymerase 
chain reaction for Whipple disease, herpes simplex virus, 
cytomegalovirus, varicella-zoster virus, and other viruses).
 is a relatively common cause 
of rapidly progressive dementia (see Chapter 32). Family

of rapidly progressive dementia (see Chapter 32). Family 
history is important since mutations in 
PRNP
, the gene for 
the prion protein, account for around 15% of cases. Diffu
-
sion-weighted MRI is the most helpful diagnostic tool, 
classically revealing cortical ribboning (a gyral pattern of 
hyperintensity) as well as restricted diffusion in the caudate 
and anterior putamen. An electroencephalogram often 
shows periodic complexes. Reflecting the high rate of neu
-
ronal death, cerebrospinal fluid levels of the intraneuronal 
proteins tau, 14-3-3, and neuron-specific enolase are often 
elevated, although this finding is neither sensitive nor 
 
specific. Real time quaking induced conversion (RT-
QuIC), in which patient cerebrospinal fluid is mixed with 
recombinant prion protein and aggregation of prion 
 
protein is detected, shows promise as a sensitive and spe
-
cific diagnostic test.
B. Driving and Dementia
It is recommended that any patient with mild dementia or 
worse should discontinue driving. Most states have laws 
regulating driving among cognitively impaired individuals, 
and many require the clinician to report the patient’s diag
-
nosis to the public health department or department of 
motor vehicles. There is 
no
 evidence that driving classes 
help patients with neurodegenerative diseases.
 
»
All patients with new, unexplained cognitive decline should 
 
»
Admission to the hospital should be avoided in patients 
with dementia due to increased risk of developing hospital-
acquired delirium.
Apostolova LG. Alzheimer disease. Continuum (Minneap 
Minn). 2016 Apr;22(2 Dementia):419–34. [PMID: 27042902]
Farina N et al. Vitamin E for Alzheimer’s dementia and mild cog
-
nitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;
 
4:CD002854. [PMID: 28418065]
Geschwind MD. Rapidly progressive dementia. Continuum 
(Minneap Minn). 2016 Apr;22(2 Dementia):510–37. [PMID: 
27042906]
Guure CB et al. Impact of physical activity on cognitive decline, 
dementia, and its subtypes: meta-analysis of prospective studies. 
Biomed Res Int. 2017;2017:9016924. [PMID: 28271072]
Livingston G et al. Dementia prevention, intervention, and care. 
Lancet. 2017 Dec 16;390(10113):2673–734. [PMID: 28735855]
Sevigny J et al. The antibody aducanumab reduces Aβ plaques in 
Alzheimer’s disease. Nature. 2016 Sep 1;537(7618):50–6. 
[PMID: 27582220]
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MULTIPLE SCLEROSIS
 
»
Episodic neurologic symptoms.
 
»
Patient usually under 55 years of age at onset.
 
»
Single pathologic lesion cannot explain clinical 
findings.
 
»
Multiple foci best visualized by MRI.
 
»
This common neurologic disorder, which probably has an 
autoimmune basis, has its greatest incidence in young 
adults. Epidemiologic studies indicate that multiple sclero
-
sis is much more common in persons of western European 
lineage who live in temperate zones. No population with a 
high risk for multiple sclerosis exists between latitudes 
 
40° N and 40° S. A genetic susceptibility to the disease is 
 
present. Pathologically, focal—often perivenular—areas of 
demyelination with reactive gliosis are found scattered in 
the white matter of the brain and spinal cord and in the 
optic nerves. Axonal damage also occurs.
 
»
The common initial presentation is weakness, numbness, 
tingling, or unsteadiness in a limb; spastic paraparesis; 
retrobulbar optic neuritis; diplopia; dysequilibrium; or a 
sphincter disturbance such as urinary urgency or hesi
-
tancy. Symptoms may disappear after a few days or weeks, 
although examination often reveals a residual deficit.
Several forms of the disease are recognized. In most 
patients, there is an interval of months or years after the 
initial episode before new symptoms develop or the original 
ones recur 
(relapsing-remitting disease)
. Eventually, how
-
ever, relapses and usually incomplete remissions lead to 
increasing disability, with weakness, spasticity, and ataxia of 
the limbs, impaired vision, and urinary incontinence. The 
findings on examination at this stage commonly include 
optic atrophy; nystagmus; dysarthria; and pyramidal, sen
-
sory, or cerebellar deficits in some or all of the limbs. In 
some of these patients, the clinical course changes so that a 
steady deterioration occurs, unrelated to acute relapses 
(secondary progressive disease)
. Less commonly, symp
-
toms are steadily progressive from their onset, and disability 
develops at a relatively early stage 
(primary progressive 
disease)
. The diagnosis cannot be made with confidence 
unless the total clinical picture indicates involvement of dif
-
ferent parts of the central nervous system at different times. 
Fatigue is common in all forms of the disease.
A number of factors (eg, infection) may precipitate or 
trigger exacerbations. Relapses are reduced in pregnancy 
but are more likely during the 2 or 3 months following 
pregnancy, possibly because of the increased demands and 
stresses that occur in the postpartum period.
B. Imaging
MRI of the brain and cervical cord has a major role in 
excluding other causes of neurologic dysfunction and in 
demonstrating the presence of multiple lesions. In 
T1-weighted images, hypointense “black holes” probably 
represent areas of permanent axonal damage. Gadolinium-
enhanced T1-weighted images may highlight areas of 
active inflammation with breakdown of the blood-brain 
barrier, which helps identify newer lesions. T2-weighted 
images provide information about disease burden or total 
number of lesions, which typically appear as areas of high 
signal intensity. CT scans are less helpful than MRI.
In patients with myelopathy alone and no clinical or 
laboratory evidence of more widespread disease, MRI or 
myelography is necessary to exclude a congenital 
or  acquired surgically treatable lesion. In patients with 
mixed pyramidal and cerebellar deficits in the limbs, the 
foramen magnum region must be visualized to exclude 
the  possibility of Arnold-Chiari malformation, in which 
parts of the cerebellum and lower brainstem are displaced 
into the cervical canal.
A definitive diagnosis can never be based solely on the 
laboratory findings. If there is clinical evidence of only a

laboratory findings. If there is clinical evidence of only a 
single lesion in the central nervous system, multiple sclero
-
sis cannot properly be diagnosed unless it can be shown 
that other regions are affected subclinically. Visual, brain
-
stem auditory, and somatosensory evoked potentials are 
helpful in this regard, but other disorders may also be 
characterized by multifocal electrophysiologic abnormali
-
ties reflecting disease of central white matter. Certain 
infections (eg, HIV , Lyme disease, syphilis), connective 
tissue diseases (eg, systemic lupus erythematosus, Sjögren 
syndrome), sarcoidosis, metabolic disorders (eg, vitamin 
B
12
 deficiency), and lymphoma may therefore require 
There may be mild lymphocytosis or a slightly increased 
protein concentration in the cerebrospinal fluid, especially 
soon after an acute relapse. Elevated IgG in cerebrospinal 
fluid and discrete bands of IgG (oligoclonal bands) are 
present in many patients. The presence of such bands is not 
specific, however, since they have been found in a variety 
of inflammatory neurologic disorders and occasionally in 
patients with vascular or neoplastic disorders of the ner
-
vous system.
Vitamin D deficiency may be associated with an 
increased risk of developing multiple sclerosis; whether 
supplementation prevents the disease or disease progres
-
sion is under study.
Multiple sclerosis should not be diagnosed unless there is 
evidence that two or more different regions of the central 
white matter (
dissemination in space
) have been affected at 
different times (
dissemination in time
); the most widely 
used diagnostic algorithm is the 2010 revision to the 
McDonald criteria. The diagnosis may be made in a patient 
with two or more typical attacks and objective evidence on 
CMDT19_Ch24_p0990-p1062.indd   1036

1037
 
CMDT 2019
clinical examination of two lesions (eg, optic disk atrophy 
and pyramidal weakness). To fulfill the criterion of dis
-
semination in space in a patient with two clinical attacks 
but objective clinical evidence of only one lesion, MRI 
should demonstrate at least one lesion in at least two of 
four typical sites (periventricular, juxtacortical, infratento
-
rial, or spinal); alternatively, an additional attack localized 
to a different site suffices. To fulfill the criterion of dissemi
-
nation in time in a patient with only one attack, the simul
-
taneous presence of asymptomatic gadolinium-enhancing 
and nonenhancing lesions at any time (including at initial 
examination) suffices; alternatively, await a new lesion on 
follow-up MRI or a second attack. Primary progressive 
disease requires at least a year of progression, plus two of 
three of the following: at least one typical brain lesion, at 
least two spinal lesions, or oligoclonal banding in the cere
-
brospinal fluid.
In patients with a single clinical event who do not sat
-
isfy criteria for multiple sclerosis, a diagnosis of a 
clinically 
isolated syndrome (CIS)
 is made. Such patients are at risk 
for developing multiple sclerosis and are sometimes offered 
beta-interferon or glatiramer acetate therapy, which may 
delay progression to clinically definite disease. Follow-up 
MRI should be considered 6–12 months later to assess for 
the presence of any new lesion.
 
»
Treatment
At least partial recovery from acute exacerbations can rea
-
sonably be expected, but further relapses may occur with
-
out warning. Some disability is likely to result eventually, 
but about half of all patients are without significant dis
-
ability even 10 years after onset of symptoms. Current 
treatments are chiefly aimed at preventing relapses, thereby 
reducing the accumulation of disability.
Recovery from acute relapses may be hastened by treat
-
ment with corticosteroids, but the extent of recovery is 
unchanged. Intravenous therapy is often given first—
 
typically methylprednisolone 1 g daily for 3 days—followed 
by oral prednisone at 60–80 mg daily for 1 week with a taper 
over the ensuing 2–3 weeks, but randomized trials show 
similar efficacy whether the initial high dose is given orally 
or intravenously. Long-term treatment with corticosteroids 
provides no benefit and does not prevent further relapses. 
Transient exacerbation of symptoms relating to intercurrent 
infection or heat requires no added treatment.
In patients with relapsing disease, numerous medica
-
tions have well-established efficacy at reducing the 
fre
-
quency of attacks
 (Table 24–6). The initial agent is chosen 
after considering medication tolerance and risks, patient 
preference, and disease severity. Glatiramer acetate or an 
interferon is often used initially due to favorable side effect 
profiles and availability, although the efficacy of early treat
-
ment with higher intensity therapy is being explored. In 
general, the medications most effective in reducing relapses 
have stronger immunomodulatory effects and more, albeit 
rare, serious adverse effects. Prescription of these agents 
should be managed by a specialist.
Ocrelizumab is the only medication effective in slowing 
disability progression in primary progressive multiple scle
-
rosis and is approved for this indication by the FDA.
For patients with severe or secondary progressive dis
-
ease, limited evidence supports immunosuppressive ther
-
apy with rituximab, cyclophosphamide, azathioprine, 
methotrexate, or mitoxantrone. Plasmapheresis is some
-
times helpful in patients with severe relapses unresponsive 
to corticosteroids.
Symptomatic therapy for spasticity, neurogenic bladder, 
or fatigue may be required. Fatigue is especially common 
in multiple sclerosis, and modafinil (200 mg orally every 
morning) is an effective and FDA-approved therapy for

morning) is an effective and FDA-approved therapy for 
this indication. Dalfampridine (an extended-release for
-
mulation of 4-aminopyridine administered as 10 mg orally 
twice daily) is efficacious at improving timed gait in mul
-
tiple sclerosis. Depression and even suicidality can occur in 
multiple sclerosis and may worsen with interferon beta-1a 
therapy; screening and conventional treatment of such 
symptoms are appropriate.
 
»
All patients, but especially those with progressive disease 
despite standard therapy, should be referred.
 
»
•	
Patients requiring plasma exchange for severe relapses 
unresponsive to corticosteroids.
•	
During severe relapses.
•	
Patients unable to manage at home.
Filippini G et al. Treatment with disease-modifying drugs for peo
-
ple with a first clinical attack suggestive of multiple sclerosis. 
 
Cochrane Database Syst Rev. 2017 Apr 25;4:CD012200. 
[PMID: 28440858]
Hauser SL et al; OPERA I and OPERA II Clinical Investigators. 
Ocrelizumab versus interferon beta-1a in relapsing multiple 
sclerosis. N Engl J Med. 2017 Jan 19;376(3):221–34. [PMID: 
28002679]
Montalban X et al; ORATORIO Clinical Investigators. Ocrelizumab 
versus placebo in primary progressive multiple sclerosis. N Engl 
J Med. 2017 Jan 19;376(3):209–20. [PMID: 28002688]
NEUROMYELITIS OPTICA
This disorder is characterized by optic neuritis and acute 
myelitis with MRI changes that extend over at least three 
segments of the spinal cord. An isolated myelitis or optic 
neuritis may also occur. Previously known as 
Devic disease
 
and once regarded as a variant of multiple sclerosis, neu
-
romyelitis optica is associated with a specific antibody 
marker (NMO-IgG) targeting the water channel aqua
-
porin-4 in 80% of cases, and with antibodies to myelin 
oligodendrocyte glycoprotein (MOG-IgG) in approxi
-
mately 33% of NMO-IgG seronegative patients. MRI of 
the brain typically does not show widespread white matter 
involvement, but such changes do not exclude the diag
-
nosis. Treatment is by long-term immunosuppression. 
First-line therapy is with rituximab (two 1 g intravenous 
infusions spaced by 2 weeks, or four weekly infusions of 
375 mg/m
2
; re-dosing may occur every 6 months or when 
CD19/20-positive or CD27-positive lymphocytes become 
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detectable), mycophenolate mofetil (500–1500 mg orally 
twice daily, titrated until the absolute lymphocyte count 
falls below 1500/mcL), or with azathioprine (2.5–3 mg/kg 
orally). Acute relapses are treated with corticosteroids at 
doses similar to those outlined for multiple sclerosis and 
with plasma exchange for severe relapses unresponsive to 
Nikoo Z et al. Comparison of the efficacy of azathioprine and 
rituximab in neuromyelitis optica spectrum disorder: a ran
-
domized clinical trial. J Neurol. 2017 Sep;264(9):2003–9. 
[PMID: 28831548]
Wingerchuk DM et al; International Panel for NMO Diagnosis. 
International consensus diagnostic criteria for neuromyelitis 
optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177–89. 
 
[PMID: 26092914]
VITAMIN E DEFICIENCY
Vitamin E deficiency may produce a disorder somewhat 
similar to Friedreich ataxia. There is spinocerebellar degen
-
eration involving particularly the posterior columns of the 
spinal cord and leading to limb ataxia, sensory loss, absent 
tendon reflexes, slurring of speech and, in some cases, pig
-
mentary retinal degeneration. The disorder may occur as a 
consequence of malabsorption or on a hereditary basis (eg, 
abetalipoproteinemia).
The term “spasticity” is commonly used for an upper 
motor neuron deficit, but it properly refers to a velocity-
dependent increase in resistance to passive movement that 
Table 24–6.
 
Treatment of multiple sclerosis (in alphabetical order within categories).
1
Dose
a
cut
e Episode, Including Relapse
2
160 mg orally daily for 3–5 days
1 g intravenously or orally daily for 3–5 days
Relapse 
p
r
evention, First-Line Treatment
Dimethyl fumarate (Tecfidera)
240 mg orally twice daily
Fingolimod (Gilenya)
0.5 mg orally daily
Glatiramer acetate (Copaxone)
20 mg subcutaneously daily
Interferon β-1a (Rebif)
44 mcg subcutaneously three times per week
Interferon β-1a (Avonex)
30 mcg intramuscularly once per week
Interferon β-1b (Betaseron, Extavia)
0.25 mg subcutaneously on alternate days
Ocrelizumab (Ocrevus)
300 mg intravenously on day 1 and day 15, followed by 600 mg every 
6 months
Teriflunomide (Aubagio)
14 mg orally daily
Relapse 
p
r
evention for Disease 
a
c
tivity Despite Use of First-Line Treatment
Alemtuzumab (Lemtrada)
12 mg intravenously daily for 5 days; 3-day course given 1 year later
Mitoxantrone
12 mg/m
2
 intravenously every 3 months; maximum lifetime dose, 140 mg/m
2
Natalizumab (Tysabri)
300 mg intravenously monthly
6 months
h
igh D
isease 
a
c
tivity (Typically With Multiple Gadolinium-Enhancing Lesions on MRI)
6 months
1
Several of these agents require special monitoring or pretreatment; some should be avoided during pregnancy. Readers should refer to 
the manufacturer’s guidelines.
2
For corticosteroid-refractory relapses, plasmapheresis may be used.
Reproduced, with permission from Aminoff MJ et al. 
Clinical Neurology
, 9th ed, McGraw-Hill Education, 2015.
CMDT19_Ch24_p0990-p1062.indd   1038

1039
 
CMDT 2019
affects different muscles to a different extent, is not uni
-
form in degree throughout the range of a particular move
-
ment, and is commonly associated with other features of 
pyramidal deficit. It is often a major complication of stroke, 
cerebral or spinal injury, static perinatal encephalopathy, 
and multiple sclerosis.
Physical therapy with appropriate stretching programs 
is important during rehabilitation after the development of 
an upper motor neuron lesion and in subsequent manage
-
ment of the patient. The aim is to prevent joint and muscle 
contractures
 and perhaps to modulate spasticity.
Medication management is important also, but treat
-
ment may increase functional disability when increased 
extensor tone is providing additional support for patients 
with weak legs. Dantrolene weakens muscle contraction 
by interfering with the role of calcium. It is best avoided 
in patients with poor respiratory function or severe myo
-
cardial disease. Treatment is begun with 25 mg once daily, 
increased by 25 mg every 3 days, depending on tolerance, to 
a maximum of 100 mg four times daily. Side effects include 
diarrhea, nausea, weakness, hepatic dysfunction (that may 
rarely be fatal, especially in women older than 35), drowsi
-
ness, light-headedness, and hallucinations.
Baclofen is an effective medication for treating spastic
-
ity of spinal origin and painful flexor (or extensor) spasms. 
The maximum recommended daily oral dose is 80 mg; 
treatment is started with a dose of 5 or 10 mg twice daily 
orally and then built up gradually. Side effects include 
gastrointestinal disturbances, lassitude, fatigue, sedation, 
unsteadiness, confusion, and hallucinations. Diazepam 
may modify spasticity by its action on spinal interneurons 
and perhaps also by influencing supraspinal centers, but 
effective doses often cause intolerable drowsiness and 
vary with different patients. Tizanidine, a centrally acting 
alpha-2-adrenergic agonist, is as effective as these other 
agents and is probably better tolerated. The daily dose is 
built up gradually, usually to 8 mg taken three times daily. 
Side effects include sedation, lassitude, hypotension, and 
dryness of the mouth. Cannabinoids are also effective in 
reducing spasticity, but are associated with side effects, 
including dizziness, drowsiness, and fatigue.
Intramuscular injection of botulinum toxin has been 
used to relax targeted muscles.
In patients with severe spasticity that is unresponsive to 
other therapies and is associated with marked disability, 
intrathecal injection of phenol or alcohol may be helpful. 
Surgical options include implantation of an intrathecal 
baclofen pump, rhizotomy, or neurectomy. Severe contrac
-
tures may be treated by surgical tendon release.
Spasticity may be exacerbated by decubitus ulcers, uri
-
nary or other infections, and nociceptive stimuli.
Nair KP et al. The management of spasticity in adults. BMJ. 2014 
Aug 5;349:g4737. [PMID: 25096594]
MYELOPATHIES IN AIDS
A variety of myelopathies may occur in patients with 
AIDS. These are discussed in Chapter 31.
MYELOPATHY OF HUMAN T-CELL LEUKEMIA 
VIRUS INFECTION
Human T-cell leukemia virus (HTLV-1), a human retrovi
-
rus, is transmitted by breastfeeding, sexual contact, blood 
transfusion, and contaminated needles. Most patients are 
asymptomatic, but after a variable latent period (which 
may be as long as several years) a myelopathy develops in 
some instances. The MRI, electrophysiologic, and cerebro
-
spinal fluid findings are similar to those of multiple sclero
-
sis, but HTLV-1 antibodies are present in serum and spinal 
fluid. There is no specific treatment, but intravenous or 
oral corticosteroids may help in the initial inflammatory 
phase of the disease. Prophylactic measures are important. 
Needles or syringes should not be shared; infected patients 
should not breastfeed their infants or donate blood, semen,

should not breastfeed their infants or donate blood, semen, 
or other tissue. Infected patients should use condoms to 
prevent sexual transmission.
SUBACUTE COMBINED DEGENERATION OF 
THE SPINAL CORD
Subacute combined degeneration of the spinal cord is due 
to 
vitamin B
12
, such as occurs in pernicious 
anemia. It is characterized by myelopathy with spasticity, 
weakness, proprioceptive loss, and numbness due to 
degeneration of the corticospinal tracts and posterior col
-
umns. Polyneuropathy, mental changes, or optic neuropa
-
thy also develop in some patients. Megaloblastic anemia 
may also occur, but this does not parallel the neurologic 
disorder, and the former may be obscured if folic acid sup
-
plements have been taken. Treatment is with vitamin B
12
. 
 
For pernicious anemia, a convenient therapeutic regimen 
is 1000 mcg cyanocobalamin intramuscularly daily for 1 
week, then weekly for 1 month, and then monthly for the 
remainder of the patient’s life. Oral cyanocobalamin 
replacement is not advised for pernicious anemia when 
neurologic symptoms are present. A similar syndrome is 
caused by recreational abuse of inhaled nitrous oxide due 
to its interference with vitamin B
12
 metabolism. Copper 
deficiency, caused by malabsorption or excess zinc inges
-
tion, may also be responsible.
WERNICKE ENCEPHALOPATHY & 
KORSAKOFF SYNDROME
Wernicke encephalopathy
 is characterized by confusion, 
ataxia, and nystagmus leading to ophthalmoplegia (lateral 
rectus muscle weakness, conjugate gaze palsies); peripheral 
neuropathy may also be present. It is due to thiamine defi
-
ciency and in the United States occurs most commonly in 
patients with alcoholism. It may also occur in patients with 
AIDS or hyperemesis gravidarum, and after bariatric sur
-
gery. In suspected cases, thiamine (100 mg) is given intra
-
venously immediately and then intramuscularly on a daily 
basis until a satisfactory diet can be ensured after which the 
same dose is given orally. Some guidelines recommend 
initial doses of 200–500 mg intravenously three times daily 
for the first 5–7 days of treatment. Intravenous glucose 
given 
before
 thiamine may precipitate the syndrome or 
worsen the symptoms. The diagnosis is confirmed by the 
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response in 1 or 2 days to treatment, which must not be 
delayed while awaiting laboratory confirmation of thia
-
mine deficiency from a blood sample obtained prior to 
thiamine administration. 
Korsakoff syndrome
 occurs in 
more severe cases; it includes anterograde and retrograde 
amnesia and sometimes confabulation, and may not be 
recognized until after the initial delirium has lifted.
Arts NJ et al. Korsakoff ’s syndrome: a critical review. Neuropsy
-
chiatr Dis Treat. 2017 Nov 27;13:2875–90. [PMID: 29225466]
STUPOR & COMA
 
»
Level of consciousness is depressed.
 
»
Stuporous patients respond only to repeated 
 
vigorous stimuli.
 
»
Comatose patients are unarousable and 
unresponsive.
 
»
The patient who is stuporous is unresponsive except when 
subjected to repeated vigorous stimuli, while the comatose 
patient is unarousable and unable to respond to external 
events or inner needs, although reflex movements and 
posturing may be present.
Coma is a major complication of serious central ner
-
vous system disorders. It can result from seizures, hypo
-
thermia, metabolic disturbances, or structural lesions 
causing bilateral cerebral hemispheric dysfunction or a 
disturbance of the brainstem reticular activating system. 
A  mass lesion involving one cerebral hemisphere may 
cause coma by compression of the brainstem.
 
»
Assessment & Emergency Measures
The diagnostic workup of the comatose patient must pro
-
ceed concomitantly with management. Supportive therapy 
for respiration or blood pressure is initiated; in hypother
-
mia, all vital signs may be absent and all such patients 
should be rewarmed before the prognosis is assessed.
The patient can be positioned on one side with the neck 
partly extended, dentures removed, and secretions cleared 
by suction; if necessary, the patency of the airways is main
-
tained with an oropharyngeal airway. Blood is drawn for 
serum glucose, electrolyte, and calcium levels; arterial 
blood gases; liver biochemical and kidney function tests; 
and toxicologic studies as indicated. Dextrose 50% (25 g), 
naloxone (0.4–1.2 mg), and thiamine (100 mg) are given 
intravenously without delay.
Further details are then obtained from attendants of the 
patient’s medical history, the circumstances surrounding 
the onset of coma, and the time course of subsequent 
events. Abrupt onset of coma suggests subarachnoid hem
-
orrhage, brainstem stroke, or intracerebral hemorrhage, 
whereas a slower onset and progression occur with other 
structural or mass lesions. Urgent noncontrast CT scan
-
ning of the head is appropriate if it can be obtained directly 
from the emergency department, in order to identify intra
-
cranial hemorrhage, brain herniation, or other structural 
lesion that may require immediate neurosurgical interven
-
tion. A metabolic cause is likely with a preceding intoxi
-
cated state or agitated delirium. On examination, attention 
is paid to the behavioral response to painful stimuli, the 
pupils and their response to light, the response to touching 
the cornea with a wisp of sterile gauze, position of the eyes 
and their movement in response to passive movement of 
the head and ice-water caloric stimulation, and the respira
-
tory pattern.
A. Response to Painful Stimuli
Purposeful limb withdrawal from painful stimuli implies 
that sensory pathways from and motor pathways to the 
stimulated limb are functionally intact. Unilateral absence 
of responses despite application of stimuli to both sides of 
the body in turn implies a corticospinal lesion; bilateral 
absence of responsiveness suggests brainstem involvement, 
bilateral pyramidal tract lesions, or psychogenic unrespon
-
siveness. Decorticate (flexor) posturing may occur with 
lesions of the internal capsule and rostral cerebral peduncle 
and decerebrate (extensor) posturing with dysfunction or 
destruction of the midbrain and rostral pons. Decerebrate

destruction of the midbrain and rostral pons. Decerebrate 
posturing occurs in the arms accompanied by flaccidity or 
slight flexor responses in the legs in patients with extensive 
brainstem damage extending down to the pons at the tri
-
geminal level.
B. Ocular Findings
1. Pupils—
Hypothalamic disease processes may lead to 
unilateral Horner syndrome, while bilateral diencephalic 
involvement or destructive pontine lesions may lead to 
small but reactive pupils. Ipsilateral pupillary dilation with 
no direct or consensual response to light occurs with com
-
pression of the third cranial nerve, eg, with uncal hernia
-
tion. The pupils are slightly smaller than normal but 
responsive to light in many metabolic encephalopathies; 
however, they may be fixed and dilated following overdos
-
age with atropine or scopolamine, and pinpoint (but 
responsive) with opioids.
2. Corneal reflex—
Touching the cornea with a wisp of 
sterile gauze or cotton should elicit a blink reflex. The affer
-
ent limb of the arc is mediated by the fifth cranial nerve; 
the efferent limb by the seventh nerve. A unilateral absent 
corneal reflex implies damage to the ipsilateral pons or a 
trigeminal deficit. Bilateral loss can be seen with large pon
-
tine lesions or in deep pharmacologic coma.
3. Eye movements—
Conjugate deviation of the eyes to the 
side suggests the presence of an ipsilateral hemispheric 
lesion, a contralateral pontine lesion, or ongoing seizures 
from the contralateral hemisphere. A mesencephalic lesion 
leads to downward conjugate deviation. Dysconjugate ocu
-
lar deviation in coma implies a structural brainstem lesion 
unless there was preexisting strabismus.
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CMDT 2019
The oculomotor responses to passive head turning and to 
caloric stimulation relate to each other and provide comple
-
mentary information. In response to brisk rotation of the 
head from side to side and to flexion and extension of the 
head, normally conscious patients with open eyes do not 
exhibit contraversive conjugate eye deviation (
oculocephalic 
reflex
) unless there is voluntary visual fixation or bilateral 
frontal pathology. With cortical depression in lightly coma
-
tose patients, a brisk oculocephalic reflex is seen. With brain
-
stem lesions, this oculocephalic reflex becomes impaired or 
lost, depending on the site of the lesion.
The 
oculovestibular reflex
 is tested by caloric stimula
-
tion using irrigation with ice water. In normal subjects, jerk 
nystagmus is elicited for about 2 or 3 minutes, with the 
slow component toward the irrigated ear. In unconscious 
patients with an intact brainstem, the fast component of 
the nystagmus disappears, so that the eyes tonically deviate 
toward the irrigated side for 2–3 minutes before returning 
to their original position. With impairment of brainstem 
function, the response becomes abnormal and finally dis
-
appears. In metabolic coma, oculocephalic and oculoves
-
tibular reflex responses are preserved, at least initially.
C. Respiratory Patterns
Diseases causing coma may lead to respiratory abnormali
-
ties. 
Cheyne-Stokes respiration
 (in which episodes of 
deep breathing alternate with periods of apnea) may occur 
with bihemispheric or diencephalic disease or in metabolic 
disorders. 
Central neurogenic hyperventilation
 occurs 
with lesions of the brainstem tegmentum; 
apneustic 
breathing
 (in which there are prominent end-inspiratory 
pauses) suggests damage at the pontine level (eg, due to 
basilar artery occlusion); and 
atactic breathing
 (a com
-
pletely irregular pattern of breathing with deep and shallow 
breaths occurring randomly) is associated with lesions of 
the lower pontine tegmentum and medulla.
1. Stupor & Coma Due to Structural Lesions
Supratentorial mass lesions
 tend to affect brain function 
in a systematic way. There may initially be signs of hemi
-
spheric dysfunction, such as hemiparesis. As coma devel
-
ops and deepens, cerebral function becomes progressively 
disturbed, producing a predictable progression of neuro
-
logic signs that suggest rostrocaudal deterioration.
Thus, as a supratentorial mass lesion begins to impair 
the diencephalon, the patient becomes drowsy, then stu
-
porous, and finally comatose. There may be Cheyne-Stokes 
respiration; small but reactive pupils or an ipsilateral third 
nerve palsy due to uncal herniation; normal oculocephalic 
responses with side-to-side head movements but some
-
times an impairment of reflex upward gaze with brisk 
flexion of the head; tonic ipsilateral deviation of the eyes in 
response to vestibular stimulation with cold water; and 
initially a positive response to pain but subsequently only 
decorticate posturing. With further progression, midbrain 
failure occurs. Motor dysfunction progresses from decorti
-
cate to bilateral decerebrate posturing in response to pain
-
ful stimuli; Cheyne-Stokes respiration is gradually replaced 
by sustained central hyperventilation; the pupils become 
middle-sized and fixed; and the oculocephalic and oculo
-
vestibular reflex responses become impaired, abnormal, or 
lost. As the pons and then the medulla fail, the pupils 
remain unresponsive; oculovestibular responses are unob
-
tainable; respiration is rapid and shallow; and painful 
stimuli may lead only to flexor responses in the legs. 
Finally, respiration becomes irregular and stops, the pupils 
often then dilating widely.
In contrast, a 
subtentorial (ie, brainstem) lesion
 may 
lead to an early, sometimes abrupt disturbance of con
-
sciousness without any orderly rostrocaudal progression of 
neurologic signs. Compressive lesions of the brainstem,

may 
-
neurologic signs. Compressive lesions of the brainstem, 
especially cerebellar hemorrhage, may be clinically indis
-
tinguishable from intraparenchymal processes.
A structural lesion is suspected if the findings suggest 
focality. In such circumstances, a CT scan should be per
-
formed before, or instead of, a lumbar puncture in order to 
avoid any risk of cerebral herniation. Further management 
is of the causal lesion and is considered separately under 
the individual disorders.
2. Stupor & Coma Due to Metabolic 
Disturbances
Patients with a metabolic cause of coma generally have 
signs of patchy, diffuse, and symmetric neurologic involve
-
ment that cannot be explained by loss of function at any 
single level or in a sequential manner, although focal or 
lateralized deficits may occur in hypoglycemia. Pupillary 
reactivity is usually preserved. Comatose patients with 
meningitis, encephalitis, or subarachnoid hemorrhage may 
also exhibit little in the way of focal neurologic signs, how
-
ever, and clinical evidence of meningeal irritation is some
-
times very subtle in comatose patients. Examination of the 
cerebrospinal fluid in such patients is essential to establish 
the correct diagnosis.
In patients with coma due to cerebral ischemia and 
hypoxia, the absence of pupillary light reflexes 24 hours 
after return of spontaneous circulation indicates that there 
is little chance of regaining independence; absent corneal 
reflexes or absent or extensor motor responses at 72 hours 
also indicate a grim prognosis. Physical findings are less 
reliable predictors of outcome among those treated with 
therapeutic hypothermia, although absent corneal or 
pupillary light reflexes at 72 hours likely indicate a poor 
Treatment of metabolic encephalopathy is of the under
-
lying disturbance and is considered in other chapters. If the 
cause of the encephalopathy is obscure, all medications 
except essential ones may have to be withdrawn in case 
they are responsible for the altered mental status.
3. Brain Death
Brain death occurs when there is complete and irreversible 
cessation of all brain function; although the organs can be 
maintained with mechanical ventilation for the purposes of 
donation, in most countries the diagnosis of brain death is 
equivalent to a declaration of death. To diagnose brain 
death, the cause of coma must be established, compatible 
with a known cause of brain death, and irreversible. 
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 CMDT 2019
Reversible coma simulating brain death may be seen with 
hypothermia (temperature lower than 32°C) and overdos
-
age with central nervous system depressant drugs, and 
these conditions must be excluded by warming the patient 
and allowing enough time for all sedating medications to 
be metabolized (ie, at least five half-lives) or by measuring 
serum levels. Severe blood pressure, electrolyte, acid-base, 
and endocrine derangements cannot be present.
Finally, a neurologic examination must demonstrate 
that the patient is comatose (ie, no eye opening and no 
response to central or peripheral pain); has lost all brain
-
stem reflex responses, including the pupillary, corneal, 
oculovestibular, oculocephalic, oropharyngeal, and cough 
reflexes; and has no respiratory drive. The response to pain 
should be absent or only consist of spinal reflex move
-
ments; decerebrate or decorticate posturing is not consis
-
tent with brain death. Absence of respiratory drive is 
demonstrated with an 
apnea test
 (absence of spontaneous 
respiratory activity at a P
ACO
2
 of at least 60 mm Hg or 
after a rise of 20 mm Hg from baseline).
Certain ancillary tests may assist the determination of 
brain death if an apnea test cannot be performed but are 
not essential. These include an isoelectric electroencepha
-
logram, when the recording is made according to the rec
-
ommendations of the American Clinical Neurophysiology 
Society, and demonstration of an absent cerebral circula
-
tion by intravenous radioisotope cerebral angiography or 
by four-vessel contrast cerebral angiography.
4. 
p
ersist
ent Vegetative State
Patients with severe bilateral hemispheric disease may 
show some improvement from an initially comatose state, 
so that, after a variable interval, they appear to be awake 
but lie motionless and without evidence of awareness or 
higher mental activity. This is called a “persistent” vegeta
-
tive state once it has lasted over 4 weeks and has also been 
variously referred to as akinetic mutism, apallic state, or 
coma vigil. Recovery is exceedingly rare among patients in 
a vegetative state from a medical cause (eg, anoxic brain 
injury) for more than 3 months and from a traumatic brain 
injury for more than 12 months.
5. Minimally Conscious State
In this state, patients exhibit inconsistent evidence of con
-
sciousness. There is some degree of functional recovery of 
behaviors suggesting self- or environmental awareness, 
such as basic verbalization or context-appropriate gestures, 
emotional responses (eg, smiling) to emotional but not 
neutral stimuli, or purposive responses to environmental 
stimuli (eg, a finger movement or eye blink apparently to 
command). Further improvement is manifest by the resto
-
ration of communication with the patient. The minimally 
conscious state may be temporary or permanent. Little 
information is available about its natural history or long-
term outlook, which reflects the underlying cause. The 
likelihood of useful functional recovery diminishes with 
time; after 12 months, patients are likely to remain severely 
disabled and without a reliable means of communication. 
Prognostication is difficult.
6. Locked-In Syndrome (De-efferented State)
Acute destructive lesions (eg, infarction, hemorrhage, 
demyelination, encephalitis) involving the ventral pons 
and sparing the tegmentum may lead to a mute, quadripa
-
retic but conscious state in which the patient is capable of 
blinking and voluntary eye movement in the vertical plane, 
with preserved pupillary responses to light. Such a patient 
can mistakenly be regarded as comatose. Clinicians should 
recognize that “locked-in” individuals are fully aware of 
their surroundings. The prognosis is usually poor, but 
recovery has occasionally been reported in some cases, 
including resumption of independent daily life. A similar 
condition may occur with severe Guillain-Barré syndrome 
and has a better prognosis.

Citerio G et al. Brain death: the European perspective. Semin 
Neurol. 2015 Apr;35(2):139–44. [PMID: 25839722]
Edlow JA et al. Diagnosis of reversible causes of coma. Lancet. 
2014 Dec 6;384(9959):2064–76. [PMID: 24767707]
Giacino JT et al. Disorders of consciousness after acquired brain 
injury: the state of the science. Nat Rev Neurol. 2014 Feb;
 
10(2):99–114. [PMID: 24468878]
Wijdicks EF. Determining brain death. Continuum (Minneap 
Minn). 2015 Oct;21(5 Neurocritical Care):1411–24. [PMID: 
26426238]
HEAD INJURY
Trauma is the most common cause of death in young peo
-
ple, and head injury accounts for almost half of these 
trauma-related deaths. Head injury severity ranges from 
concussion
 to 
severe traumatic brain injury (TBI).
 Con
-
cussion is broadly defined as an alteration in mental status 
caused by trauma with or without loss of consciousness. 
The term concussion is often used synonymously with 
mild TBI. Grades of TBI are traditionally defined by the 
Glasgow Coma Scale (GCS) measured 30 minutes after 
injury (Table 24–7).
Table 24–7.
 
Glasgow Coma Scale.
1
p
oin
ts
Eye 
Opening
Verbal Response
Motor 
Response
1
None
None
None
2
To pain
Vocal but not verbal
Extension
3
To voice
Verbal but not 
conversational
Flexion
4
Conversational but 
disoriented
Withdraws from 
pain
5
—
Oriented
Localizes pain
6
—
—
Obeys commands
1
GCS score indicating severity of traumatic brain injury (TBI): 
mild
, 
13–15; 
moderate
, 9–12; 
severe
, ≤ 8.
Reproduced, with permission, from Aminoff MJ et al. 
, 
9th ed, McGraw-Hill Education, 2015; Data from Teasdale G, 
 
Jennett B. Assessment of coma and impaired consciousness. 
A
 
practical scale. 
Lancet
. 1974;304:81-84.
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CMDT 2019
Head trauma may cause cerebral injury through a vari
-
ety of mechanisms (Table 24–8). Central to management is 
determination of which patients need head imaging and 
observation. Of particular concern is identification of 
patients with epidural and subdural hematoma, who may 
present with normal neurologic findings shortly after 
injury (lucid interval) but rapidly deteriorate thereafter, 
and in whom surgical intervention is life-saving.
 
»
Common symptoms of concussion that develop acutely 
include headache, nausea, vomiting, confusion, disorienta
-
tion, dizziness, and imbalance. A period of amnesia 
encompassing the traumatic event and a variable period of 
time leading up to the trauma is typical. Loss of conscious
-
ness may occur. Additional symptoms of photophobia, 
phonophobia, difficulty concentrating, irritability, and 
sleep and mood disturbances may develop over the follow
-
ing hours to days. Examination is usually normal, although 
orientation and attention, short-term memory, and reac
-
tion time may be impaired. Persistent or progressive 
decline in the level of consciousness after the initial injury, 
or focal neurologic findings, suggests the need for urgent 
imaging and neurosurgical consultation.
Patients should also be examined for signs of scalp lacera
-
tions, facial and skull fracture, and neck injury. The clinical 
signs of basilar skull fracture include bruising about the 
orbit (raccoon sign), blood in the external auditory meatus 
(Battle sign), and leakage of cerebrospinal fluid (which can 
be identified by its glucose or beta-2-transferrin content) 
from the ear or nose. Cranial nerve palsies (involving espe
-
cially the first, second, third, fourth, fifth, seventh, and 
eighth nerves in any combination) may also occur. The 
head and neck should be immobilized until imaging can be 
Current recommendations are that head CT be performed 
in patients with concussion and any of the following: GCS 
score less than 15; focal neurologic deficit; seizure; coagu
-
lopathy; aged 65 or older; skull fracture; persistent headache 
or vomiting; retrograde amnesia exceeding 30 minutes; 
intoxication; or soft tissue injury of the head or neck. Oth
-
erwise, patients can be sent home as long as a responsible 
caregiver can check the patient at hourly intervals for the 
next 24 hours. Patients requiring imaging should be admit
-
ted unless the head CT is normal, the GCS score is 15, there 
have been no seizures, there is no predisposition to bleed
-
ing, and they can be monitored by a caregiver at home.
Because injury to the spine may have accompanied 
head trauma, cervical spine radiographs (three views) or 
CT should always be obtained in comatose patients and in 
patients with severe neck pain or a deficit possibly related 
to cord compression.
Table 24–8.
 
Acute cerebral sequelae of head injury.
Sequelae
p
a
thology
Concussion
A transient, trauma-induced alteration in mental status 
that may or may not involve loss of consciousness. 
Symptoms and signs include headache, nausea, dis
-
orientation, irritability, amnesia, clumsiness, visual 
disturbances, and focal neurologic deficit.
Unknown; likely mild diffuse axonal injury and excitotoxic 
neuronal injury.
Cerebral contusion may occur.
Cerebral contusion 
or laceration
Loss of consciousness longer than with concussion. 
Focal neurologic deficits are often present. May lead 
to death or severe residual neurologic deficit.
Bruising on side of impact (coup injury) or contralaterally 
(contrecoup injury).
Vasogenic edema, multiple petechial hemorrhages, and 
mass effect. May have subarachnoid bleeding. Herniation 
may occur in severe cases. Cerebral laceration specifically 
involves tearing of the cerebral tissue and pia-arachnoid 
overlying a contusion.
Acute epidural 

Headache, confusion, somnolence, seizures, and focal 
deficits occur several hours after injury (lucid inter
-
val) and lead to coma, respiratory depression, and 
death unless treated by surgical evacuation.
Tear in meningeal artery, vein, or dural sinus, leading to 
hematoma visible on CT scan.
Acute subdural 
Similar to epidural hemorrhage, but interval before 
onset of symptoms is longer. Neurosurgical consulta
-
tion for consideration of evacuation.
Hematoma from tear in veins from cortex to superior sagit
-
tal sinus or from cerebral laceration, visible on CT scan.
Cerebral 
Generally develops immediately after injury. Clinically 
resembles hypertensive hemorrhage. Surgery to 
relieve mass effect is sometimes necessary.
Hematoma, visible on CT scan.
Diffuse axonal 
 
injury
Persistent loss of consciousness, coma, or persistent 
vegetative state resulting from severe rotational 
shearing forces or deceleration.
Imaging may be normal or may show tiny, scattered white 
matter hemorrhages. Histology reveals torn axons.
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»
Treatment
Head injury can often be prevented by helmets, seatbelts, 
and other protective equipment.
After intracranial bleeding has been excluded clinically 
or by head CT, treatment of mild TBI is aimed at promot
-
ing resolution of postconcussive symptoms and preventing 
recurrent injury, which increases the risk of chronic neu
-
robehavioral impairment and delays recovery. Rarely, a 
recurrent concussion while a patient is still symptomatic 
from a first concussion may lead to fatal cerebral edema 
(
second impact syndrome
). These observations form the 
basis of the recommendation that patients at risk for recur
-
rent concussion (eg, athletes) be held out of the risky activ
-
ity until their concussive symptoms have fully resolved.
In patients hospitalized with moderate or severe TBI, 
management often requires a multidisciplinary approach 
due to multiple concomitant injuries. Elevated intracranial 
pressure can result from diffuse axonal injury or a hema
-
toma requiring surgical evacuation, or from a variety of 
medical causes. Decompressive craniectomy may reduce 
otherwise refractory intracranial hypertension but does 
not improve neurologic outcome. Hypothermia is associ
-
ated with worsened functional outcomes.
Because bridging veins between the brain and venous 
sinuses become more vulnerable to shear injury as the 
brain atrophies, a subdural hematoma may develop days or 
weeks following head injury in elderly patients or even 
occur spontaneously. Clinical presentation can be subtle, 
often with mental changes such as slowness, drowsiness, 
headache, confusion, or memory disturbance. Focal neuro
-
logic deficits such as hemiparesis or hemisensory distur
-
bance are less common. Surgical intervention is indicated 
if the hematoma is 10 mm or more in thickness or there is 
a midline shift of 5 mm ore more; if there is a decline in 
GCS score of 2 or more from injury to hospital admission; 
or if one or both pupils are fixed and dilated.
Scalp lacerations and depressed skull fractures should 
be treated surgically as appropriate. Simple skull frac
-
tures require no specific treatment. If there is any leakage 
of cerebrospinal fluid, conservative treatment, with eleva
-
tion of the head, restriction of fluids, and administration 
of acetazolamide (250 mg orally four times daily), is often 
helpful; if the leak continues for more than a few days, lum
-
bar subarachnoid drainage may be necessary. 
 
A
ntibiotics 
are given if infection occurs, based on culture and sensitiv
-
ity studies; vaccination against pneumococcus is recom
-
mended (see Table 30–7). Only very occasional patients 
require intracranial repair of the dural defect because of 
persistence of the leak or recurrent meningitis.
 
»
Prognosis
Moderate and severe TBI may result in permanent cogni
-
tive and motor impairment depending on the severity and 
location of the initial injury. Initial GCS and head CT find
-
ings have prognostic value. Among patients with a GCS 
score of 8 or less at presentation, mortality approaches 30% 
and only one-third of survivors regain functional indepen
-
dence. Cognitive impairment tends to affect frontal and 
temporal lobe function, causing deficits in attention, 
memory, judgment, and executive function. Behavioral 
dysregulation, depression, and disinhibition can impair 
social functioning. Anosmia, presumably due to shearing 
of fibers from the nasal epithelium, is common.
Epilepsy can develop after TBI, especially with more 
severe injury. Among patients with severe TBI (typically 
loss of consciousness for at least 12–24 hours, intracranial 
hematoma, depressed skull fracture, or cerebral contusion), 
phenytoin or levetiracetam is typically given for 7 days to 
reduce the incidence of early posttraumatic seizures; this is 
done exclusively to minimize acute complications resulting 
from such seizures and does not prevent the development 
of posttraumatic epilepsy.

Among patients with mild TBI, symptoms of concus
-
sion resolve in most patients by 1 month and in the vast 
majority by 3 months. Prolonged postconcussive symp
-
toms are uncommon, persisting at 1 year in 10–15% of 
patients. Risk factors for prolonged postconcussive symp
-
toms included active litigation regarding the injury; 
repeated concussions; and GCS score of 13 or less at pre
-
sentation. Headaches often have migrainous features and 
may respond to tricyclic antidepressants or beta-blockers 
(Table 24–1). Opioids should be avoided to minimize the 
risk of medication overuse headache. Mood symptoms 
may respond to antidepressants, anxiolytics, and cognitive 
behavioral therapy.
There appears to be an association between head 
trauma and the later development of neurodegenerative 
disease, such as Alzheimer disease, Parkinson disease, or 
amyotrophic lateral sclerosis (ALS). Normal pressure 
hydrocephalus may also occur. Repetitive, mild head 
injury, such as that which occures in athletes or military 
personnel, can lead to 
chronic traumatic encephalopathy
, 
a distinct pathologic entity associated with mood and cog
-
nitive changes and characterized by the abnormal aggrega
-
tion of tau or other proteins either focally or globally in the 
cerebral cortex. Whether chronic traumatic encephalopa
-
thy is a static response to recurrent head injury or a pro
-
gressive neurodegenerative disease is not known, but the 
severity of neuropathology appears to correlate to lifetime 
exposure to repetitive head injury.
 
»
•	
Patients with focal neurologic deficits, altered con
-
sciousness, or skull fracture.
•	
Patients with late complications of head injury, eg, post
-
traumatic seizure disorder or normal pressure 
hydrocephalus.
 
»
•	
Patients with concussion and GCS score less than 15, 
predisposition to bleeding, seizure, or no responsible 
caregiver at home.
•	
Patients with abnormal head CT.
Levin HS et al. Diagnosis, prognosis, and clinical management of 
mild traumatic brain injury. Lancet Neurol. 2015 May;
 
14(5):506–17. [PMID: 25801547]
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Mez J et al. Clinicopathological evaluation of chronic traumatic 
encephalopathy in players of American football. JAMA. 2017 
Jul 25;318(4):360–70. [PMID: 28742910]
Thompson K et al. Pharmacological treatment for preventing 
epilepsy following traumatic brain injury. Cochrane Database 
Syst Rev. 2015 Aug 10;(8):CD009900. [PMID: 26259048]
SPINAL TRAUMA
 
»
History of preceding trauma.
 
»
Development of acute neurologic deficit.
 
»
Signs of myelopathy on examination.
 
»
While spinal cord damage may result from whiplash injury, 
severe injury usually relates to fracture-dislocation causing 
compression or angular deformity of the cord either cervi
-
cally or in the lower thoracic and upper lumbar regions. 
Extreme hypotension following injury may also lead to 
cord infarction.
 
»
Total cord transection results in immediate flaccid paralysis 
and loss of sensation below the level of the lesion. Reflex 
activity is lost for a variable period, and there is urinary and 
fecal retention. As reflex function returns over the following 
days and weeks, spastic paraplegia or quadriplegia develops, 
with hyperreflexia and extensor plantar responses, but a flac
-
cid atrophic (lower motor neuron) paralysis may be found 
depending on the segments of the cord that are affected. The 
bladder and bowels also regain some reflex function, permit
-
ting urine and feces to be expelled at intervals. As spasticity 
increases, flexor or extensor spasms (or both) of the legs 
become troublesome, especially if the patient develops bed 
sores or a urinary tract infection. Paraplegia with the legs in 
flexion or extension may eventually result.
With lesser degrees of injury, patients may be left with 
mild limb weakness, distal sensory disturbance, or both. 
Sphincter function may also be impaired, urinary urgency 
and urge incontinence being especially common. More 
particularly, a unilateral cord lesion leads to an ipsilateral 
motor disturbance with accompanying impairment of pro
-
prioception and contralateral loss of pain and temperature 
appreciation below the lesion (
Brown-Séquard syndrome
). 
 
A central cord syndrome may lead to a lower motor neuron 
deficit and loss of pain and temperature appreciation, with 
sparing of posterior column functions. A radicular deficit 
may occur at the level of the injury—or, if the cauda equina 
is involved, there may be evidence of disturbed function in 
several lumbosacral roots.
 
»
Treatment
Treatment of the injury consists of immobilization and—if 
there is cord compression—early decompressive 
laminectomy and fusion (within 24 hours). Early treatment 
with high doses of corticosteroids (eg, methylprednisolone, 
30  mg/kg by intravenous bolus, followed by 5.4 mg/kg/h 
for 23 hours) may improve neurologic recovery if com
-
menced within 8 hours after injury, although the evidence 
is limited and some neurosurgical guidelines do not rec
-
ommend their use. Anatomic realignment of the spinal 
cord by traction and other orthopedic procedures is 
important. Subsequent care of the residual neurologic 
 
deficit—paraplegia or quadriplegia—requires treatment of 
spasticity and care of the skin, bladder, and bowels.
 
»
All patients with focal neurologic deficits should be referred.
 
»
•	
Patients with neurologic deficits.
•	
Patients with spinal cord injury, compression, or acute 
epidural or subdural hematoma.
•	
Patients with vertebral fracture-dislocation likely to 
compress the cord.
Stein DM et al. Management of acute spinal cord injury. Continuum 
(Minneap Minn). 2015 Feb;21(1 Spinal Cord Disorders):159–87. 
[PMID: 25651224]
SYRINGOMYELIA
Destruction or degeneration of gray and white matter 
adjacent to the central canal of the cervical spinal cord 
leads to cavitation and accumulation of fluid within the 
spinal cord. The precise pathogenesis is unclear, but many

spinal cord. The precise pathogenesis is unclear, but many 
cases are associated with 
Arnold-Chiari malformation,
 
in which there is displacement of the cerebellar tonsils, 
medulla, and fourth ventricle into the spinal canal, some
-
times with accompanying meningomyelocele. In such cir
-
cumstances, the cord cavity connects with and may merely 
represent a dilated central canal. In other cases, the cause 
of cavitation is less clear. There is a characteristic clinical 
picture, with segmental atrophy, areflexia and loss of pain 
and temperature appreciation in a “cape” distribution, 
owing to the destruction of fibers crossing in front of the 
central canal in the mid-cervical spinal cord. Thoracic 
kyphoscoliosis is usually present. With progression, 
involvement of the long motor and sensory tracts occurs 
as well, so that a pyramidal and sensory deficit develops in 
the legs. Upward extension of the cavitation (syringobul
-
bia) leads to dysfunction of the lower brainstem and thus 
to bulbar palsy, nystagmus, and sensory impairment over 
one or both sides of the face.
Syringomyelia, ie, cord cavitation, may also occur in 
association with an intramedullary tumor or following 
severe cord injury, and the cavity then does not communi
-
cate with the central canal.
In patients with Arnold-Chiari malformation, CT scans 
reveal a small posterior fossa and enlargement of the fora
-
men magnum, along with other associated skeletal abnor
-
malities at the base of the skull and upper cervical spine. 
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MRI reveals the syrinx as well as the characteristic findings 
of the Arnold-Chiari malformation, including the caudal 
displacement of the fourth ventricle and herniation of the 
cerebellar tonsils through the foramen magnum. Focal 
cord enlargement is found at myelography or by MRI in 
patients with cavitation related to past injury or intramed
-
ullary neoplasms.
Treatment of Arnold-Chiari malformation with associ
-
ated syringomyelia is by suboccipital craniectomy and 
upper cervical laminectomy, with the aim of decompressing 
the malformation at the foramen magnum. The cord cavity 
should be drained and, if necessary, an outlet for the fourth 
ventricle can be made. In cavitation associated with intra
-
medullary tumor, treatment is surgical, but radiation ther
-
apy may be necessary if complete removal is not possible. 
Posttraumatic syringomyelia is also treated surgically if it 
leads to increasing neurologic deficits or to intolerable pain.
DEGENERATIVE MOTOR NEURON DISEASES
 
»
Weakness.
 
»
No sensory loss or sphincter disturbance.
 
»
Progressive course.
 
»
No identifiable underlying cause other than 
genetic basis in familial cases.
 
»
This group of degenerative disorders is characterized clini
-
cally by weakness and variable wasting of affected muscles, 
without accompanying sensory changes.
Motor neuron disease in adults generally commences 
between 30 and 60 years of age. There is degeneration of 
the anterior horn cells in the spinal cord, the motor nuclei 
of the lower cranial nerves, and the corticospinal and cor
-
ticobulbar pathways. The disorder is usually sporadic, but 
familial cases may occur and several genetic mutations or 
loci have been identified. Cigarette smoking may be one 
risk factor.
 
»
Five varieties have been distinguished on clinical grounds.
A. Progressive Bulbar Palsy
Bulbar involvement predominates owing to disease processes 
affecting primarily the motor nuclei of the cranial nerves.
B. Pseudobulbar Palsy
Bulbar involvement predominates in this variety also, but it 
is due to bilateral corticobulbar disease and thus reflects 
upper motor neuron dysfunction. There may be a “pseudo-
bulbar affect, ” with uncontrollable episodes of laughing or 
crying to stimuli that would not normally have elicited 
such marked reactions.
C. Progressive Spinal Muscular Atrophy
This is characterized primarily by a lower motor neuron 
deficit in the limbs due to degeneration of the anterior 
horn cells in the spinal cord.
D. Primary Lateral Sclerosis
There is a purely upper motor neuron deficit in the limbs.
E. Amyotrophic Lateral Sclerosis
A mixed upper and lower motor neuron deficit is found 
in the limbs. This disorder is sometimes associated with 
cognitive decline (in a pattern consistent with frontotem
-
poral dementia), a pseudobulbar affect, or parkinsonism. 
Approximately 10% of ALS cases are familial and have been 
associated with mutations at several different genetic loci, 
including a hexanucleotide repeat on chromosome 9 that 
also associates with frontotemporal dementia.
 
»
The spinal muscular atrophies (SMAs) are inherited syn
-
dromes caused most often by mutations of the survival 
motor neuron 1 (
SMN1
) gene on chromosome 5. Different 
mutations result in more or less severe disruptions of the 
protein, resulting in an age of onset that ranges from 
infancy (SMA type I; Werdnig-Hoffmann disease), to early 
(type II) or late childhood (type III; Kugelberg-Welander 
syndrome), to adulthood (type IV). X-linked bulbospinal 
neuronopathy (Kennedy syndrome) is associated with an 
expanded trinucleotide repeat sequence on the androgen 
receptor gene and carries a more benign prognosis than 
other forms of motor neuron disease.
There are reports of juvenile SMA due to hexosamini
-
dase deficiency. Pure motor syndromes resembling motor

-
dase deficiency. Pure motor syndromes resembling motor 
neuron disease may also occur in association with mono
-
clonal gammopathy or multifocal motor neuropathies with 
conduction block. A motor neuronopathy may also develop 
in Hodgkin disease and has a relatively benign prognosis. 
Infective anterior horn cell diseases (polio virus or West 
Nile virus infection) can generally be distinguished by the 
acute onset and monophasic course of the illness, as dis
-
cussed in Chapter 32.
 
»
Difficulty in swallowing, chewing, coughing, breathing, and 
talking (dysarthria) occur with bulbar involvement. In pro
-
gressive bulbar palsy, there is drooping of the palate; a 
depressed gag reflex; pooling of saliva in the pharynx; a weak 
cough; and a wasted, fasciculating tongue. In pseudobulbar 
palsy, the tongue is contracted and spastic and cannot be 
moved rapidly from side to side. Limb involvement is charac
-
terized by motor disturbances (weakness, stiffness, wasting, 
fasciculations) reflecting lower or upper motor neuron dys
-
function; there are no objective changes on sensory examina
-
tion, although there may be vague sensory complaints. The 
sphincters are generally spared. Cognitive changes or pseu
-
dobulbar affect may be present. The disorder is progressive, 
and ALS is usually fatal within 3–5 years; death usually results 
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CMDT 2019
from pulmonary infections. Patients with bulbar involvement 
generally have the poorest prognosis, while patients with 
primary lateral sclerosis often have a longer survival despite 
profound quadriparesis and spasticity.
Electromyography may show signs of acute and chronic par
-
tial denervation with reinnervation. In patients with sus
-
pected ALS, the diagnosis should not be made with 
confidence unless such changes are found in at least three 
spinal regions (cervical, thoracic, lumbosacral) or two spinal 
regions and the bulbar musculature. Motor conduction 
velocity is usually normal but may be slightly reduced, and 
sensory conduction studies are also normal. Biopsy of a 
wasted muscle shows the histologic changes of denervation 
and is not necessary for diagnosis. The serum creatine kinase 
may be slightly elevated but never reaches the extremely high 
values seen in some of the muscular dystrophies. The cere
-
brospinal fluid is normal. To diagnose SMA, molecular 
genetic testing for pathogenic variants of SMN1 is available. 
There are abnormal findings on rectal biopsy and reduced 
hexosaminidase A in serum and leukocytes in patients with 
juvenile SMA due to hexosaminidase deficiency.
 
»
Treatment
Riluzole, 50 mg orally twice daily, which reduces the pre
-
synaptic release of glutamate, increased short-term sur
-
vival in ALS in randomized trials. Edaravone, a free radical 
scavenger, slows disease progression in patients with mild 
disease. It is administered in monthly cycles as a 60 mg 
intravenous infusion on days 1–14 in the first month and 
days 1–10 in the subsequent months.
Noninvasive ventilation at least 4 hours per day in 
patients with a maximal inspiratory pressure less than 
60 cm H
2
O may prolong survival in ALS. Symptomatic and 
supportive measures to treat spasticity (discussed earlier), 
drooling, and dysphagia, prevent contractures, and pre
-
serve mobility are important. Drooling is treated with over-
the-counter decongestants, anticholinergic medications 
(such as trihexyphenidyl, amitriptyline, or atropine), botu
-
linum toxin injections into the salivary glands, or use of a 
portable suction machine. Physical and occupational ther
-
apy are helpful throughout the disease course. Combina
-
tion dextromethorphan/quinidine (20 mg/10 mg, one 
tablet orally once or twice daily) may relieve symptoms of 
pseudobulbar affect. A semiliquid diet or gastrostomy tube 
feeding may be needed if dysphagia is severe; it is advisable 
to perform the procedure before the forced vital capacity 
falls below 50% of predicted to minimize the risk of com
-
plications. Tracheostomy is sometimes performed if respi
-
ratory muscles are severely affected; however, in the 
terminal stages of these disorders, realistic expectations 
and advance care planning should be discussed. Informa
-
tion on palliative care is provided in Chapter 5.
Treatment of spinal muscular atrophy takes advantage of 
the fact that the SMN protein is also encoded by a second 
gene, 
SMN2,
 that usually does not translate functional pro
-
tein due to aberrant splicing. Nusinersen is an antisense 
oligonucleotide that modulates premessenger RNA splicing 
of the 
SMN2
 gene and results in increased production of 
the full length protein. Intrathecal administration resulted 
in achievement of motor milestones and prolonged sur
-
vival in infants with type 1 SMA; it may also be effective in 
children with later-onset disease. Gene therapy with intra
-
venous delivery of an intact 
SMN1
 gene using a viral vector 
also shows promise.
 
»
All patients (to exclude other treatable causes of symptoms 
and signs) should be referred.
 
»
Patients may need to be admitted for initiation or titration 
of noninvasive ventilation, or for periods of increased 
requirement of noninvasive ventilator support during pul
-
monary infections.

-
Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of 
edaravone in well defined patients with amyotrophic lateral 
sclerosis: a randomized, double-blind, placebo-controlled 
trial. Lancet Neurol. 2017 Jul;16(7):505–12. [PMID: 28522181]
Finkel RS et al; ENDEAR Study Group. Nusinersen versus sham 
control in infantile-onset spinal muscular atrophy. N Engl J 
Med. 2017 Nov 2;377(18):1723–32. [PMID: 29091570]
Mendell JR et al. Single-dose gene-replacement therapy for spinal 
muscular atrophy. N Engl J Med. 2017 Nov 2;377(18):1713–22. 
[PMID: 29091557]
 
º
p
ERI
ph
ER
a
L NEURO
pa
T
h
IES
Peripheral neuropathies can be categorized on the basis of the 
structure primarily affected. The predominant pathologic 
feature may be 
axonal degeneration
 (
axonal or neuronal 
neuropathies
) or 
paranodal or segmental demyelination.
 
The distinction may be possible on the basis of neurophysi
-
ologic findings. Motor and sensory conduction velocity can 
be measured in accessible segments of peripheral nerves. In 
axonal neuropathies, conduction velocity is normal or 
reduced only mildly and needle electromyography provides 
evidence of denervation in affected muscles. In demyelinat
-
ing neuropathies, conduction may be slowed considerably in 
affected fibers, and in more severe cases, conduction is 
blocked completely, without accompanying electromyo
-
graphic signs of denervation.
POLYNEUROPATHIES & 
MONONEURITIS MULTIPLEX
 
»
Weakness, sensory disturbances, or both in the 
 
»
Pain is common.
 
»
Depressed or absent tendon reflexes.
 
»
May be family history of neuropathy.
 
»
May be history of systemic illness or toxic exposure.
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»
Diffuse 
polyneuropathies
 lead to a symmetric sensory, 
motor, or mixed deficit, often most marked distally. They 
include the hereditary, metabolic, and toxic disorders; idio
-
pathic inflammatory polyneuropathy (
Guillain-Barré 
 
syndrome
); and the peripheral neuropathies that may 
occur as a nonmetastatic complication of malignant dis
-
eases. Involvement of motor fibers leads to flaccid weakness 
that is most marked distally; dysfunction of sensory fibers 
causes impaired sensory perception. Tendon reflexes are 
depressed or absent. Paresthesias, pain, and muscle tender
-
ness may also occur. Multiple mononeuropathies (
mono
-
neuropathy multiplex
) suggest a patchy multifocal disease 
process such as vasculopathy (eg, diabetes, arteritis), an 
infiltrative process (eg, leprosy, sarcoidosis), radiation dam
-
age, or an immunologic disorder (eg, brachial plexopathy).
 
»
The cause of polyneuropathy or mononeuritis multiplex is 
suggested by the history, mode of onset, and predominant 
clinical manifestations. Laboratory workup includes a com
-
plete blood count, serum protein electrophoresis with reflex 
to immunofixation or immunotyping, determination of 
plasma urea and electrolytes, liver biochemical tests, thy
-
roid function tests, vitamin B
12
 level, tests for rheumatoid 
factor and antinuclear antibody, HBsAg determination, a 
serologic test for syphilis, fasting blood glucose level and 
hemoglobin A
1c
, urinary heavy metal levels, cerebrospinal 
fluid examination, and chest radiography. These tests 
should be ordered selectively, as guided by symptoms and 
signs. Measurement of nerve conduction velocity can con
-
firm the peripheral nerve origin of symptoms and provides 
a means of following clinical changes, as well as indicate the 
likely disease process (ie, axonal or demyelinating neuropa
-
thy). Cutaneous nerve biopsy may help establish a precise 
diagnosis (eg, polyarteritis, amyloidosis). In about half of 
cases, no specific cause can be established; of these, slightly 
less than half are subsequently found to be familial.
 
»
Treatment
Treatment is of the underlying cause, when feasible, and is 
discussed below under the individual disorders. Physical 
therapy helps prevent contractures, and splints can main
-
tain a weak extremity in a position of useful function. 
Anesthetic extremities must be protected from injury. To 
guard against burns, patients should check the temperature 
of water and hot surfaces with a portion of skin having 
normal sensation, measure water temperature with a ther
-
mometer, and use cold water for washing or lower the 
temperature setting of their hot-water heaters. Shoes 
should be examined frequently during the day for grit or 
foreign objects in order to prevent pressure lesions.
Patients with polyneuropathies or mononeuritis multi
-
plex are subject to additional nerve injury at pressure 
points and should therefore avoid such behavior as leaning 
on elbows or sitting with crossed legs for lengthy periods.
Neuropathic, burning pain may respond to simple anal
-
gesics, such as aspirin or nonsteroidal anti-inflammatory 
agents, and to gabapentin (300 mg orally three times daily, 
titrated up to a maximum of 1200 mg orally three times 
daily as necessary) or pregabalin (50–100 mg orally three 
times daily). Duloxetine (60 mg orally once or twice daily), 
venlafaxine (start 37.5 mg orally twice daily, and titrate up 
to 75 mg orally two to three times daily), or tricyclic anti
-
depressants (eg, amitriptyline 10–150 mg orally at bedtime 
daily) may be helpful, especially in painful diabetic neu
-
ropathy. Medical cannabis may provide some relief, but 
long-term safety data are lacking. The use of a frame or 
cradle to reduce contact with bedclothes may be helpful. 
Many patients experience episodic stabbing pains, which 
may respond to gabapentin, pregabalin, carbamazepine

may respond to gabapentin, pregabalin, carbamazepine 
(start 100 mg orally twice daily, and titrate up to 400 mg 
orally twice daily), or tricyclic antidepressants. Opioids 
may be necessary for severe hyperpathia or pain induced 
by minimal stimuli, but their use should be avoided as 
much as possible.
Symptoms of 
autonomic dysfunction
 are occasionally 
troublesome. Treatment of postural hypotension is dis
-
cussed earlier in this chapter. Erectile dysfunction can be 
treated with phosphodiesterase inhibitors; a flaccid neuro
-
pathic bladder may respond to parasympathomimetic 
medications such as bethanechol chloride, 10–50 mg three 
or four times daily.
Callaghan BC et al. Distal symmetric polyneuropathy: a review. 
JAMA. 2015 Nov 24;314(20):2172–81. [PMID: 26599185]
Watson JC et al. Peripheral neuropathy: a practical approach to 
diagnosis and symptom management. Mayo Clin Proc. 2015 Jul;
 
90(7):940–51. [PMID: 26141332]
1. Inherited Neuropathies
A. Charcot-Marie-Tooth Disease (HMSN Type I, II)
There are several distinct varieties of Charcot-Marie-Tooth 
disease, usually with an autosomal dominant mode of 
inheritance, but occasional cases occur on a sporadic, reces
-
sive, or X-linked basis. Clinical presentation may be with 
foot deformities or gait disturbances in childhood or early 
adult life. Slow progression leads to the typical features of 
polyneuropathy, with distal weakness and wasting that 
begin in the legs, a variable amount of distal sensory loss, 
and depressed or absent tendon reflexes. Tremor is a con
-
spicuous feature in some instances. Hereditary motor and 
sensory neuropathy (HMSN) type I is characterized by 
demyelination on electrodiagnostic studies and is usually 
caused by mutations in the peripheral myelin protein 22 or 
myelin protein zero gene. In HMSN type II, electrodiagnos
-
tic studies show axonal loss rather than demyelination; one-
third of cases are due to mutations in the gene mitofusin 2.
A similar disorder may occur in patients with progres
-
sive distal spinal muscular atrophies, but there is no sen
-
sory loss; electrophysiologic investigation reveals that 
motor conduction velocity is normal or only slightly 
reduced, and nerve action potentials are normal.
B. Dejerine-Sottas Disease (HMSN Type III)
The disorder may occur on a sporadic, autosomal domi
-
nant or, less commonly, autosomal recessive basis. Onset in 
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infancy or childhood leads to a progressive motor and 
sensory polyneuropathy with weakness, ataxia, sensory 
loss, and depressed or absent tendon reflexes. The periph
-
eral nerves may be palpably enlarged and are characterized 
pathologically by segmental demyelination, Schwann cell 
hyperplasia, and thin myelin sheaths. Electrophysiologi
-
cally, there is a slowing of conduction, and sensory action 
potentials may be unrecordable.
C. Friedreich Ataxia
This disorder, 
the only known
 
autosomal recessive trinucle
-
otide repeat disease, 
is caused by expansion of a poly-GAA 
locus in the gene for frataxin on chromosome 9, leading to 
symptoms in childhood or early adult life. The gait becomes 
ataxic, the hands become clumsy, and other signs of cere
-
bellar dysfunction develop accompanied by weakness of 
the legs and extensor plantar responses. Involvement of 
peripheral sensory fibers leads to sensory disturbances in 
the limbs and depressed tendon reflexes. There is bilateral 
pes cavus. Pathologically, there is a marked loss of cells in 
the posterior root ganglia and degeneration of peripheral 
sensory fibers. In the central nervous system, changes are 
conspicuous in the posterior and lateral columns of the 
cord. Electrophysiologically, conduction velocity in motor 
fibers is normal or only mildly reduced, but sensory action 
potentials are small or absent. Cardiac disease is the most 
common cause of death.
In the differential diagnosis for Friedreich ataxia are 
other spinocerebellar ataxias, a growing group of at least 
30 inherited disorders, each involving a different identified 
gene. These heterogeneous disorders, which frequently 
(but not exclusively) exhibit an autosomal dominant inher
-
itance pattern and poly-CAG expansion of the affected 
gene, typically cause cerebellar ataxia and varying combi
-
nations of other symptoms (such as peripheral neuropathy, 
ophthalmoparesis, dysarthria, and pyramidal and extrapy
-
ramidal signs).
D. Refsum Disease (HMSN Type IV)
This autosomal recessive disorder is due to a disturbance in 
phytanic acid metabolism. Pigmentary retinal degenera
-
tion is accompanied by progressive sensorimotor polyneu
-
ropathy and cerebellar signs. Auditory dysfunction, 
cardiomyopathy, and cutaneous manifestations may also 
occur. Motor and sensory conduction velocities are 
reduced, often markedly, and there may be electromyo
-
graphic evidence of denervation in affected muscles. 
Dietary restriction of phytanic acid and its precursors may 
be helpful therapeutically. Plasmapheresis to reduce stored 
phytanic acid may help at the initiation of treatment.
E. Porphyria
Peripheral nerve involvement may occur during acute attacks 
in both variegate porphyria and acute intermittent porphyria. 
Motor symptoms usually occur first, and weakness is often 
most marked proximally and in the upper limbs rather than 
the lower. Sensory symptoms and signs may be proximal or 
distal in distribution. Autonomic involvement is sometimes 
pronounced. The electrophysiologic findings are in keeping 
with the results of neuropathologic studies suggesting that 
the neuropathy is axonal in type (see Chapter 40).
2. Neuropathies 
a
ssociated with Systemic & 
Metabolic Disorders
A. Diabetes Mellitus
In this disorder, involvement of the peripheral nervous 
system may lead to symmetric sensory or mixed polyneu
-
ropathy, asymmetric motor radiculoneuropathy or 
 
plexopathy (diabetic amyotrophy), thoracoabdominal 
radiculopathy, autonomic neuropathy, or isolated lesions of 
individual nerves. These may occur singly or in any com
-
bination and are discussed in Chapter 27.
B. Uremia
Uremia may lead to a symmetric sensorimotor polyneu
-
ropathy that tends to affect the lower limbs more than the 
upper limbs and is more marked distally than proximally 
(see Chapter 22). The diagnosis can be confirmed electro
-
physiologically, for motor and sensory conduction velocity

-
physiologically, for motor and sensory conduction velocity 
is moderately reduced. The neuropathy improves both 
clinically and electrophysiologically with kidney transplan
-
tation and to a lesser extent with chronic dialysis.
C. Alcoholism and Nutritional Deficiency
Many patients with alcoholism have an axonal distal sen
-
sorimotor polyneuropathy that is frequently accompanied 
by painful cramps, muscle tenderness, and painful pares
-
thesias and is often more marked in the legs than in the 
arms. Symptoms of autonomic dysfunction may also be 
conspicuous. Motor and sensory conduction velocity may 
be slightly reduced, even in subclinical cases, but gross 
slowing of conduction is uncommon. Treatment is similar 
to diabetic polyneuropathy but also includes abstinence 
from alcohol. A similar distal sensorimotor polyneu
-
ropathy is a well-recognized feature of beriberi (thiamine 
deficiency). In vitamin B
12
 deficiency, distal sensory poly
-
neuropathy may develop but is usually overshadowed by 
central nervous system manifestations (eg, myelopathy, 
optic neuropathy, or intellectual changes).
D. Paraproteinemias
A symmetric sensorimotor polyneuropathy that is gradual 
in onset, progressive in course, and often accompanied by 
pain and dysesthesias in the limbs may occur in patients 
(especially men) with 
plasma cell myeloma
 (formerly 
mul
-
tiple myeloma
). The neuropathy is of the axonal type in 
classic lytic myeloma, but segmental demyelination (pri
-
mary or secondary) and axonal loss may occur in sclerotic 
myeloma and lead to predominantly motor clinical mani
-
festations. Both demyelinating and axonal neuropathies 
are also observed in patients with paraproteinemias with
-
out myeloma. A small fraction will develop myeloma if 
serially followed. The demyelinating neuropathy in these 
patients may be due to the monoclonal proteins reacting 
to a component of the nerve myelin. The neuropathy of 
classic plasma cell myeloma is poorly responsive to 
 
therapy. The polyneuropathy of benign monoclonal 
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gammopathy may respond to immunosuppressant medi
-
cations and plasmapheresis.
Polyneuropathy may also occur in association with 
monoclonal gammopathy of unknown significance, mac
-
roglobulinemia, and cryoglobulinemia and sometimes 
responds to plasmapheresis. Many patients with an IgM 
M-protein will have antibodies to myelin-associated glyco
-
protein (MAG); these patients may respond to treatment 
with rituximab. Entrapment neuropathy, such as carpal 
tunnel syndrome, is more common than polyneuropathy 
in patients with (nonhereditary) generalized amyloidosis. 
With polyneuropathy due to amyloidosis, sensory and 
autonomic symptoms are especially conspicuous, whereas 
distal wasting and weakness occur later; there is no specific 
3. Neuropathies 
a
ssociated with Infectious & 
Inflammatory Diseases
A. Leprosy
Leprosy is an important cause of peripheral neuropathy 
in certain parts of the world. Sensory disturbances are 
mainly due to involvement of intracutaneous nerves. In 
tuberculoid leprosy, they develop at the same time and in 
the same distribution as the skin lesion, but may be more 
extensive if nerve trunks lying beneath the lesion are also 
involved. In lepromatous leprosy, there is more extensive 
sensory loss, and this develops earlier and to a greater 
extent in the coolest regions of the body, such as the dor
-
sal surfaces of the hands and feet, where the bacilli prolif
-
erate most actively. Motor deficits result from involvement 
of superficial nerves where their temperature is lowest, 
eg, the ulnar nerve in the region proximal to the olecra
-
non groove, the median nerve as it emerges from beneath 
the forearm flexor muscle to run toward the carpal tun
-
nel, the peroneal nerve at the head of the fibula, and the 
posterior tibial nerve in the lower part of the leg; patchy 
facial muscular weakness may also occur owing to 
involvement of the superficial branches of the seventh 
cranial nerve.
Motor disturbances in leprosy are suggestive of multiple 
mononeuropathy, whereas sensory changes resemble those 
of distal polyneuropathy. Examination, however, relates 
the  distribution of sensory deficits to the temperature of 
the tissues; in the legs, for example, sparing frequently 
occurs between the toes and in the popliteal fossae, where 
the temperature is higher. Treatment is with antileprotic 
agents (see Chapter 33).
B. AIDS
A variety of neuropathies occur in HIV-infected patients 
(see Chapter 31).
C. Lyme Borreliosis
The neurologic manifestations of Lyme disease include 
meningitis, meningoencephalitis, polyradiculoneuropathy, 
mononeuropathy multiplex, and cranial neuropathy. Sero
-
logic tests establish the underlying disorder. Lyme disease 
and its treatment are discussed in depth in Chapter 34.
D. Sarcoidosis
Cranial nerve palsies (especially facial palsy), multiple 
mononeuropathy and, less commonly, symmetric polyneu
-
ropathy may all occur, the latter sometimes preferentially 
affecting either motor or sensory fibers. Improvement may 
occur with use of corticosteroids.
E. Polyarteritis
Involvement of the vasa nervorum by the vasculitic process 
may result in infarction of the nerve. Clinically, one encounters 
an asymmetric sensorimotor polyneuropathy (mononeuritis 
multiplex) that pursues a waxing and waning course. Cortico
-
steroids and cytotoxic agents—especially cyclophosphamide—
may be of benefit in severe cases (Chapter 20).
F. Rheumatoid Arthritis
Compressive or entrapment neuropathies, ischemic neu
-
ropathies, mild distal sensory polyneuropathy, and severe 
progressive sensorimotor polyneuropathy can occur in 
4. Neuropathy 
a
ssociated with Critical Illness
Patients in intensive care units with sepsis and multiorgan 
failure sometimes develop polyneuropathies. This may be 
manifested initially by unexpected difficulty in weaning 
patients from a mechanical ventilator and in more advanced

patients from a mechanical ventilator and in more advanced 
cases by wasting and weakness of the extremities and loss of 
tendon reflexes. Sensory abnormalities are relatively incon
-
spicuous. The neuropathy is axonal in type. Its pathogenesis is 
obscure, and treatment is supportive. The prognosis is good 
provided patients recover from the underlying critical illness.
5. Toxic Neuropathies
Axonal polyneuropathy may follow exposure to industrial 
agents or pesticides such as acrylamide, organophosphorus 
compounds, hexacarbon solvents, methyl bromide, and car
-
bon disulfide; metals such as arsenic, thallium, mercury, and 
lead; and medications such as phenytoin, amiodarone, per
-
hexiline, isoniazid, nitrofurantoin, vincristine, and pyridox
-
ine in high doses. Detailed occupational, environmental, 
and medical histories and recognition of clusters of cases are 
important in suggesting the diagnosis. Treatment is by pre
-
venting further exposure to the causal agent. Isoniazid neu
-
ropathy is prevented by pyridoxine supplementation.
Diphtheritic neuropathy results from a neurotoxin 
released by the causative organism and is common in many 
areas. Palatal weakness may develop 2–4 weeks after infec
-
tion of the throat, and infection of the skin may similarly 
be followed by focal weakness of neighboring muscles. 
Disturbances of accommodation may occur about 
4–5 weeks after infection and distal sensorimotor demye
-
linating polyneuropathy after 1–3 months.
6. Neuropathies 
a
ssociated with 
Malignant Diseases
A variety of neuropathies have been associated with non
-
metastatic complications of malignancy and were discussed 
earlier.
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7. 
a
cut
e Idiopathic 
p
olyneur
opathy 
 
(Guillain-Barré Syndrome)
 
»
Acute or subacute progressive polyradiculo-
 
»
Weakness is more severe than sensory 
disturbances.
 
»
Acute dysautonomia may be life-threatening.
 
»
This acute or subacute polyradiculoneuropathy sometimes 
follows infective illness, inoculations, or surgical procedures. 
There is an association with preceding 
 
enteritis. The disorder probably has an immunologic basis, 
but the precise mechanism is unclear.
 
»
The main complaint is of weakness that varies widely in 
severity in different patients and often has a proximal 
emphasis and symmetric distribution. It usually begins in 
the legs, spreading to a variable extent but frequently 
involving the arms and often one or both sides of the face. 
The muscles of respiration or deglutition may also be 
affected. Sensory symptoms are usually less conspicuous 
than motor ones, but distal paresthesias and dysesthesias 
are common, and neuropathic or radicular pain is present 
in many patients. Autonomic disturbances are also com
-
mon, may be severe, and are sometimes life-threatening; 
they include tachycardia, cardiac irregularities, hypoten
-
sion or hypertension, facial flushing, abnormalities of 
sweating, pulmonary dysfunction, and impaired sphincter 
control. The axonal subtypes of the syndrome (
acute 
motor axonal neuropathy [AMAN]
 and 
acute motor and 
sensory axonal neuropathy [AMSAN]
) are caused by 
antibodies to gangliosides on the axon membrane. The 
Miller Fisher syndrome,
 another subtype, is characterized 
by the clinical triad of ophthalmoplegia, ataxia, and are
-
flexia, and is associated with anti-GQ1b antibodies.
The cerebrospinal fluid characteristically contains a high 
protein concentration with a normal cell count, but these 
changes may take up to 2 weeks to develop; white blood cell 
counts greater than 50 cells/mcL should prompt consider
-
ation of alternative diagnoses. Electrophysiologic studies 
may reveal marked abnormalities, which do not necessarily 
parallel the clinical disorder in their temporal course.
 
»
When the diagnosis is made, the history and appropriate 
laboratory studies should exclude the possibility of 
porphyric, diphtheritic, or toxic (heavy metal, hexacarbon, 
organophosphate) neuropathies, and of HIV infection. The 
temporal course excludes other peripheral neuropathies. 
Poliomyelitis, botulism, and tick paralysis must also be 
considered as they cause weakness of acute onset. The 
presence of pyramidal signs, a markedly asymmetric motor 
deficit, a sharp sensory level, or early sphincter involve
-
ment should suggest a focal cord lesion.
 
»
Treatment
Treatment with 
prednisone is ineffective
 and may prolong 
recovery time. Plasmapheresis is of value; it is best per
-
formed within the first few days of illness and is particularly 
useful for clinically severe or rapidly progressive cases or 
those with ventilatory impairment. IVIG (400 mg/kg/day 
for 5 days) is equally helpful. Patients should be admitted 
to intensive care units if their forced vital capacity is declin
-
ing, and intubation is considered if the forced vital capac
-
ity reaches 15 mL/kg, the maximum inspiratory pressure 
reaches –30 mm Hg, or dyspnea becomes evident. Declin
-
ing oxygen saturation is a late indicator of neuromuscular 
respiratory failure. Respiratory toilet and chest physical 
therapy help prevent atelectasis. Marked hypotension may 
respond to volume replacement or pressor agents. Throm
-
boprophylaxis is important.
 
»
Prognosis
Most patients eventually make a good recovery, but this 
may take many months, and about 20% of patients are left 
with persisting disability. Approximately 3% of patients 
with acute idiopathic polyneuropathy have one or more

with acute idiopathic polyneuropathy have one or more 
clinically similar relapses, sometimes several years after the 
initial illness.
 
»
 
»
All patients should be hospitalized until their condition is 
stable and there is no respiratory compromise.
Hughes RA et al. Intravenous immunoglobulin for Guillain-
Barré syndrome. Cochrane Database Syst Rev. 2014 Sep 19;
 
9:CD002063. [PMID: 25238327]
van den Berg B et al. Guillain-Barré syndrome: pathogenesis, 
diagnosis, treatment and prognosis. Nat Rev Neurol. 2014 Aug;
 
10(8):469–82. [PMID: 25023340]
8. Chronic Inflammatory 
p
olyneur
opathy
Chronic inflammatory demyelinating polyneuropathy, an 
acquired immunologically mediated disorder, is clinically 
similar to Guillain-Barré syndrome except that it has a 
relapsing or steadily progressive course over months or 
years and that autonomic dysfunction is generally less 
common. It may present as an exclusively motor disorder 
or with a mixed sensorimotor disturbance. In the relapsing 
form, partial recovery may occur after some relapses, but in 
other instances there is no recovery between exacerbations. 
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Although remission may occur spontaneously with time, 
the disorder frequently follows a progressive downhill 
course leading to severe functional disability.
Electrodiagnostic studies show marked slowing of 
motor and sensory conduction, and focal conduction 
block. Signs of partial denervation may also be present 
owing to secondary axonal degeneration. Nerve biopsy 
may show chronic perivascular inflammatory infiltrates in 
the endoneurium and epineurium, without accompanying 
evidence of vasculitis. However, a normal nerve biopsy 
result or the presence of nonspecific abnormalities does 
not exclude the diagnosis.
Corticosteroids may arrest or reverse the downhill 
course. Treatment is usually begun with prednisone, 60–80 mg 
 
orally daily, continued for 2–3 months or until a definite 
response has occurred. If no response has occurred despite 
3 months of treatment, a higher dose may be tried. In 
responsive cases, the dose is gradually tapered, but most 
patients become corticosteroid-dependent, often requiring 
prednisone, 20 mg daily on alternate days, on a long-term 
basis. IVIG can be used in place of, or in addition to corti
-
costeroids and is best used as the initial treatment in pure 
motor syndromes. When both IVIG and corticosteroids 
are ineffective, plasma exchange may be worthwhile. Con
-
sistent with the notion that the condition is antibody medi
-
ated, rituximab has shown promise. Immunosuppressant 
or immunomodulatory medications (such as azathioprine) 
may be added when the response to other measures is 
unsatisfactory or to enable maintenance doses of cortico
-
steroids to be lowered. Symptomatic treatment is also 
important.
Mahdi-Rogers M et al. Immunomodulatory treatment other 
than corticosteroids, immunoglobulin and plasma exchange 
for chronic inflammatory demyelinating polyneuropathy. 
Cochrane Database Syst Rev. 2017 May 8;5:CD003280. 
[PMID: 28481421]
MONONEUROPATHIES
 
»
Focal motor or sensory deficit.
 
»
Deficit is in territory of an individual peripheral 
nerve.
An individual nerve may be injured along its course or may 
be compressed, angulated, or stretched by neighboring 
anatomic structures, especially at a point where it passes 
through a narrow space (
entrapment neuropathy
). The 
relative contributions of mechanical factors and ischemia to 
the local damage are not clear. With involvement of a sen
-
sory or mixed nerve, pain is commonly felt distal to the 
lesion. Symptoms never develop with some entrapment 
neuropathies, resolve rapidly and spontaneously in others, 
and become progressively more disabling and distressing in 
yet other cases. The precise neurologic deficit depends on 
the nerve involved. Percussion of the nerve at the site of the 
lesion may lead to paresthesias in its distal distribution.
Entrapment neuropathy may be the sole manifestation 
of subclinical polyneuropathy, and this must be borne in 
mind and excluded by nerve conduction studies. Such 
studies are also indispensable for the localization of the 
focal lesion.
In patients with acute compression neuropathy such as 
may occur in intoxicated individuals (
Saturday night 
palsy
), no treatment is necessary. Complete recovery gen
-
erally occurs, usually within 2 months, presumably because 
the underlying pathology is demyelination. However, axo
-
nal degeneration can occur in severe cases, and recovery 
then takes longer and may never be complete.
In chronic compressive or entrapment neuropathies, 
avoidance of aggravating factors and correction of any 
underlying systemic conditions are important. Local infil
-
tration of the region about the nerve with corticosteroids 
may be of value; in addition, surgical decompression may 
help if there is a progressively increasing neurologic deficit 
or if electrodiagnostic studies show evidence of partial 
denervation in weak muscles.
Peripheral nerve tumors are uncommon, except in neu
-

-
rofibromatosis type 1, but also give rise to mononeuropa
-
thy. This may be distinguishable from entrapment 
neuropathy only by noting the presence of a mass along the 
course of the nerve and by demonstrating the precise site of 
the lesion with appropriate electrophysiologic studies. 
Treatment of symptomatic lesions is by surgical removal if 
possible.
1. Carpal Tunnel Syndrome
See Chapter 41.
2. 
p
r
onator Teres or 
a
n
terior 
Interosseous Syndrome
The median nerve gives off its motor branch, the anterior 
interosseous nerve, below the elbow as it descends between 
the two heads of the pronator teres muscle. A lesion of 
either nerve may occur in this region, sometimes after 
trauma or owing to compression from, for example, a 
fibrous band. With anterior interosseous nerve involve
-
ment, there is no sensory loss, and weakness is confined to 
the pronator quadratus, flexor pollicis longus, and the 
flexor digitorum profundus to the second and third digits. 
Weakness is more widespread and sensory changes occur 
in an appropriate distribution when the median nerve itself 
is affected. The prognosis is variable. If improvement 
does not occur spontaneously, decompressive surgery may 
be helpful.
3. Ulnar Nerve Lesions
Ulnar nerve lesions are likely to occur in the elbow 
region as the nerve runs behind the medial epicondyle 
and descends into the cubital tunnel. In the condylar 
groove, the ulnar nerve is exposed to pressure or trauma. 
Moreover, any increase in the carrying angle of the elbow, 
whether congenital, degenerative, or traumatic, may cause 
excessive stretching of the nerve when the elbow is flexed. 
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Ulnar nerve lesions may also result from thickening or 
distortion of the anatomic structures forming the cubital 
tunnel, and the resulting symptoms may also be aggra
-
vated by flexion of the elbow, because the tunnel is then 
narrowed by tightening of its roof or inward bulging of its 
floor. A severe lesion at either site causes sensory changes 
in the fifth and medial half of the fourth digits and along 
the medial border of the hand. There is weakness of the 
ulnar-innervated muscles in the forearm and hand. With a 
cubital tunnel lesion, however, there may be relative spar
-
ing of the flexor carpi ulnaris muscle. Electrophysiologic 
evaluation using nerve stimulation techniques allows 
more precise localization of the lesion.
Initial treatment consists of avoiding pressure on the 
medial elbow (eg, avoid resting the elbows on arm rests; 
pad the elbow during sleep) and preventing prolonged 
elbow flexion, especially at night. Splints are available to 
keep the elbow from flexing beyond 45 to 90 degrees. If 
conservative measures are unsuccessful in relieving symp
-
toms and preventing further progression, surgical treat
-
ment may be necessary. This consists of nerve transposition 
if the lesion is in the condylar groove, or a release proce
-
dure if it is in the cubital tunnel.
Ulnar nerve lesions may also develop at the wrist or in 
the palm of the hand, usually owing to repetitive trauma or 
to compression from ganglia or benign tumors. They can 
be subdivided depending on their presumed site. Com
-
pressive lesions are treated surgically. If repetitive mechani
-
cal trauma is responsible, this is avoided by occupational 
adjustment or job retraining.
Caliandro P et al. Treatment for ulnar neuropathy at the elbow. 
Cochrane Database Syst Rev. 2016 Nov 15;11:CD006839. 
[PMID: 27845501]
4. Radial Nerve Lesions
The radial nerve is particularly liable to compression or 
injury in the axilla (eg, by crutches or by pressure when the 
arm hangs over the back of a chair). This leads to weakness 
or paralysis of all the muscles supplied by the nerve, 
including the triceps. Sensory changes may also occur but 
are often surprisingly inconspicuous, being marked only in 
a small area on the back of the hand between the thumb 
and index finger. Injuries to the radial nerve in the spiral 
groove occur characteristically during deep sleep, as in 
intoxicated individuals, and there is then sparing of the 
triceps muscle, which is supplied more proximally. The 
nerve may also be injured at or above the elbow; its purely 
motor posterior interosseous branch, supplying the exten
-
sors of the wrist and fingers, may be involved immediately 
below the elbow, but then there is sparing of the extensor 
carpi radialis longus, so that the wrist can still be extended. 
The superficial radial nerve may be compressed by hand
-
cuffs or a tight watch strap.
5. Femoral Neuropathy
The clinical features of femoral nerve palsy consist of 
weakness and wasting of the quadriceps muscle, with sen
-
sory impairment over the anteromedian aspect of the thigh 
and sometimes also of the leg to the medial malleolus, and 
a depressed or absent knee jerk. Isolated femoral neuropa
-
thy may occur in patients with diabetes or from compres
-
sion by retroperitoneal neoplasms or hematomas (eg, 
expanding aortic aneurysm). Femoral neuropathy may also 
result from pressure from the inguinal ligament when the 
thighs are markedly flexed and abducted, as in the lithot
-
omy position.
6. Meralgia 
p
ar
esthetica
The 
lateral femoral cutaneous nerve,
 a sensory nerve 
arising from the L2 and L3 roots, may be compressed or 
stretched in obese or diabetic patients and during pregnancy. 
The nerve usually runs under the outer portion of the ingui
-
nal ligament to reach the thigh, but the ligament sometimes 
splits to enclose it. Hyperextension of the hip or increased 
lumbar lordosis—such as occurs during pregnancy—leads

-
lumbar lordosis—such as occurs during pregnancy—leads 
to nerve compression by the posterior fascicle of the liga
-
ment. However, entrapment of the nerve at any point along 
its course may cause similar symptoms, and several other 
anatomic variations predispose the nerve to damage when 
it is stretched. Pain, paresthesia, or numbness occurs about 
the outer aspect of the thigh, usually unilaterally, and is 
sometimes relieved by sitting. The pain stops at the knee, 
unlike the pain from lower lumbar sciatica that radiates 
to the foot. Examination shows no abnormalities except in 
severe cases when cutaneous sensation is impaired in the 
affected area. Symptoms are usually mild and commonly 
settle spontaneously. Hydrocortisone injections medial to 
the anterosuperior iliac spine often relieve symptoms tem
-
porarily, while nerve decompression by transposition may 
provide more lasting relief.
7. Sciatic & Common 
p
er
oneal (Fibular) 
Nerve 
p
alsies
Misplaced deep intramuscular injections are probably 
still the most common cause of sciatic nerve palsy. 
Trauma to the buttock, hip, or thigh may also be respon
-
sible. The resulting clinical deficit depends on whether 
the whole nerve has been affected or only certain fibers. 
In general, the peroneal (fibular) fibers of the sciatic 
nerve are more susceptible to damage than those destined 
for the tibial nerve. A sciatic nerve lesion may therefore 
be difficult to distinguish from peroneal (fibular) neu
-
ropathy unless there is electromyographic evidence of 
involvement of the short head of the biceps femoris 
muscle. The common peroneal (fibular) nerve itself may 
be compressed or injured in the region of the head and 
neck of the fibula, eg, by sitting with crossed legs or wear
-
ing high boots. There is weakness of dorsiflexion and 
eversion of the foot, accompanied by numbness or 
blunted sensation of the anterolateral aspect of the calf 
and dorsum of the foot.
8. Tarsal Tunnel Syndrome
The tibial nerve, the other branch of the sciatic, supplies 
several muscles in the lower extremity, gives origin to the 
sural nerve, and then continues as the posterior tibial nerve 
to supply the plantar flexors of the foot and toes. It passes 
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through the tarsal tunnel behind and below the medial 
malleolus, giving off calcaneal branches and the medial 
and lateral plantar nerves that supply small muscles of the 
foot and the skin on the plantar aspect of the foot and toes. 
Compression of the posterior tibial nerve or its branches 
between the bony floor and ligamentous roof of the tarsal 
tunnel leads to pain, paresthesias, and numbness over the 
bottom of the foot, especially at night, with sparing of the 
heel. Muscle weakness may be hard to recognize clinically. 
Compressive lesions of the individual plantar nerves may 
also occur more distally, with clinical features similar to 
those of the tarsal tunnel syndrome. Treatment is surgical 
decompression.
 
»
•	
If there is uncertainty about the diagnosis.
•	
Symptoms or signs are progressing despite treatment.
BELL PALSY
 
»
Sudden onset of lower motor neuron facial palsy.
 
»
Hyperacusis or impaired taste may occur.
 
»
No other neurologic abnormalities.
 
»
Bell palsy is an idiopathic facial paresis of lower motor 
neuron type that has been attributed to an inflammatory 
reaction involving the facial nerve near the stylomastoid 
foramen or in the bony facial canal. In some instances, this 
may be due to reactivation of herpes simplex or varicella 
zoster virus infection in the geniculate ganglion. The disor
-
der is more common in pregnant women and in persons 
with diabetes mellitus.
 
»
The facial paresis (Figure 24–1) generally comes on 
abruptly, but it may worsen over the following day or so. 
Pain about the ear precedes or accompanies the weakness 
in many cases but usually lasts for only a few days. The face 
itself feels stiff and pulled to one side. There may be ipsilat
-
eral restriction of eye closure and difficulty with eating and 
fine facial movements. A disturbance of taste is common, 
owing to involvement of chorda tympani fibers, and hyper
-
acusis due to involvement of fibers to the stapedius occurs 
occasionally. In cases due to herpes zoster infection, vesi
-
cles may be observed in the external ear canal.
 
»
Lower motor neuron facial palsy can be differentiated from 
stroke by clinical examination. A stroke or other central 
lesion will not cause hyperacusis or disturbance of taste, 
generally spares the forehead, and is accompanied by other 
focal deficits. An isolated facial palsy may occur in patients 
with HIV seropositivity, sarcoidosis, Lyme disease 
 
(Figure  24–1; also see Chapter 34) or with any process 
causing an inflammatory reaction in the subarachnoid 
space, such as meningitis. Whenever facial palsies occur 
bilaterally, or a facial palsy occurs in conjunction with 
other neurologic deficits, MRI brain imaging should be 
undertaken and other investigations considered.
 
»
Treatment
Approximately 60% of cases of Bell palsy recover com
-
pletely without treatment, presumably because the lesion is 
so mild that it leads merely to conduction block. Treatment 
with corticosteroids (prednisone 60 mg orally daily for 
5  days followed by a 5-day taper, or prednisolone 25 mg 
orally twice daily for 10 days) increases the chance of a 
complete recovery at 9–12 months by 12–15%. Treatment 
with acyclovir or valacyclovir is only indicated when there 
is evidence of herpetic vesicles in the external ear canal. 
 
It is helpful to protect the eye with lubricating drops 
 
(or lubricating ointment at night) and a patch if eye closure 
is not possible. There is no evidence that surgical proce
-
dures to decompress the facial nerve are of benefit. Physical 
therapy may improve facial function.
Schwartz SR et al. Reconciling the clinical practice guidelines on 
Bell’s palsy from the AAO-HNSF and the AAN. Neurology. 
2014 May 27;82(21):1927–9. [PMID: 24793182]
 
▲
Figure 24–1.
 
Facial palsy caused by an infection 
with 
 (Lyme disease).

▲
 
with 
CMDT19_Ch24_p0990-p1062.indd   1054

1055
 
CMDT 2019
DISCOGENIC NECK PAIN
 
»
Neck pain, sometimes radiating to arms.
 
»
Restricted neck movements.
 
»
Motor, sensory, or reflex changes in arms with root 
 
»
Neurologic deficit in legs, gait disorder, or sphinc
-
ter disturbance with cord involvement.
 
»
A variety of congenital abnormalities may involve the cervi
-
cal spine and lead to neck pain; these include hemiverte
-
brae, fused vertebrae, basilar impression, and instability of 
the atlantoaxial joint. Traumatic, degenerative, infective, 
and neoplastic disorders may also lead to pain in the neck. 
When rheumatoid arthritis involves the spine, it tends to 
affect especially the cervical region, leading to pain, stiff
-
ness, and reduced mobility; displacement of vertebrae or 
atlantoaxial subluxation may lead to cord compression that 
can be life-threatening if not treated by fixation. Further 
details are given in Chapter 41 (including a discussion on 
low back pain), and discussion here is restricted to disk 
disease.
1. 
a
cut
e Cervical Disk 
p
r
otrusion
Acute cervical disk protrusion leads to pain in the neck and 
radicular pain in the arm, exacerbated by head movement. 
With lateral herniation of the disk, motor, sensory, or reflex 
changes may be found in a radicular (usually C6 or C7) 
distribution on the affected side (Figure 24–2); with more 
centrally directed herniations, the spinal cord may also be 
involved, leading to spastic paraparesis and sensory distur
-
bances in the legs, sometimes accompanied by impaired 
sphincter function. The diagnosis is confirmed by MRI or 
CT myelography. In mild cases, the prognosis is good and 
complete recovery occurs in a majority of patients with 
conservative therapy. Evidence does not support any spe
-
cific intervention, and some combination of bed rest, activ
-
ity restriction, immobilization of the neck in a collar for 
several weeks, and physical therapy is generally prescribed. 
If these measures are unsuccessful or the patient has a sig
-
nificant neurologic deficit, surgical removal of the protrud
-
ing disk may be necessary.
2. Cervical Spondylosis
Cervical spondylosis results from chronic cervical disk 
degeneration, with herniation of disk material, secondary 
calcification, and associated osteophytic outgrowths. One 
or more of the cervical nerve roots may be compressed, 
stretched, or angulated; and myelopathy may also develop 
as a result of compression, vascular insufficiency, or 
recurrent minor trauma to the cord. Patients present with 
neck pain and restricted head movement, occipital 
headaches, radicular pain and other sensory disturbances 
in the arms, weakness of the arms or legs, or some com
-
bination of these symptoms. Examination generally 
reveals that lateral flexion and rotation of the neck are 
limited. A segmental pattern of weakness or dermatomal 
sensory loss (or both) may be found unilaterally or bilat
-
erally in the upper limbs, and tendon reflexes mediated by 
the affected root or roots are depressed. The C5 and C6 
nerve roots are most commonly involved, and examina
-
tion frequently then reveals weakness of muscles supplied 
by these roots (eg, deltoids, supraspinatus and infraspina
-
tus, biceps, brachioradialis), pain or sensory loss about 
the shoulder and outer border of the arm and forearm, 
and depressed biceps and brachioradialis reflexes. Spastic 
paraparesis may also be present if there is an associated 
myelopathy, sometimes accompanied by urinary urgency, 
incontinence, or posterior column or spinothalamic sen
-
sory deficits in the legs.
Plain radiographs of the cervical spine show osteophyte 
formation, narrowing of disk spaces, and encroachment on 
the intervertebral foramina, but such changes are common 
in middle-aged persons and may be unrelated to the pre
-
senting complaint. CT or MRI helps confirm the diagnosis

-
senting complaint. CT or MRI helps confirm the diagnosis 
and exclude other structural causes of the myelopathy.
Restriction of neck movements by a cervical collar may 
relieve pain. Local injection of anesthetics or corticoste
-
roids, for instance by a pain management specialist, may be 
of benefit. Operative treatment may be necessary to prevent 
further progression if there is a significant neurologic defi
-
cit; bowel or bladder symptoms; or if root pain is severe, 
persistent, and unresponsive to conservative measures.
 
»
•	
Pain unresponsive to simple measures.
•	
•	
Patients in whom surgical treatment is under 
consideration.
 
»
•	
Patients with progressive or significant neurologic 
deficit.
•	
Patients with sphincter involvement (from cord 
compression).
•	
Patients requiring surgical treatment.
Corey DL et al. Cervical radiculopathy. Med Clin North Am. 
2014 Jul;98(4):791–9. [PMID: 24994052]
BR
a
C
h
I
a
L & LUMB
a
R 
p
LEXUS LESIONS
1. Brachial 
p
lexus Neuropathy
Brachial plexus neuropathy may be idiopathic, sometimes 
occurring in relationship to a number of different nonspe
-
cific illnesses or factors. In other instances, brachial plexus 
lesions follow trauma or result from congenital anomalies, 
neoplastic involvement, or injury by various physical 
CMDT19_Ch24_p0990-p1062.indd   1055

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agents. In rare instances, the disorder occurs on a familial 
basis.
Idiopathic brachial plexus neuropathy (
neuralgic 
 
amyotrophy
) characteristically begins with severe pain 
about the shoulder, followed within a few days by weak
-
ness, reflex changes, and sensory disturbances involving 
especially the C5 and C6 segments but affecting any nerve 
in the brachial plexus. Symptoms and signs are usually 
unilateral but may be bilateral. Wasting of affected muscles 
is sometimes profound. The disorder relates to disturbed 
function of cervical roots or part of the brachial plexus, but 
its precise cause is unknown. Recovery occurs over the 
ensuing months but may be incomplete. Treatment is 
purely symptomatic.
= Iliohypogast
ri
c
= Ilioinguinal
= Genitofemoral
   Dorsal ner
ve
 of penis
   
Pe
rineal ner
ve
 of penis
Pe
ripheral ner
ve
Ner
ve
 root
Tr
igeminal
(Cranial ner
ve
 V)
Anterior cutaneous ner
ve
 of neck
Supraclavicular ner
ve
s
Axillary ner
ve
Medial cutaneous ner
ve
 of arm 
Lateral cutaneous ner
ve
 of arm
  (branch of radial nerve) 
ve
 of 
fo
rearm 
ve
 of 
fo
rearm 
Radial
Median
Ulnar
Lateral femoral cutaneous
Obturator
Anterior 
fe
moral cutaneous
ve
 of calf
Saphenous
Superficial peroneal
Sural
Lateral and medial plantar 
Deep peroneal 
Ophthalmic branch (V1)
Maxillary branch (V2)
Mandibular branch (V3)
*
*
†
†
X
X
Lateral thoracic rami
P
o
s
t
.
 
M
i
d
.
 
A
n
t
.
 
Anterior thoracic rami
C3
C4
C5
T2
T3
T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L1
L2
L3
L4 L5
S1
T2
T1
C8
C6
C6
C7
 
▲
Figure 24–2.
 
Cutaneous innervation. The segmental or radicular (root) distribution is shown on the left side of 
the body and the peripheral nerve distribution on the right side. Segmental maps show differences depending on 
how they were constructed (single root stimulation or section; local anesthetic 
 
injec
tion into single dorsal root 
 
ganglia). 
(Adapted, with permission, from Aminoff MJ, Greenberg DA, Simon RP . 
 
Clinical
 
Neurology
, 
9th ed. McGraw-Hill 
 
Education, 2015.)
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CMDT 2019
2. Cervical Rib Syndrome
Compression of the C8 and T1 roots or the lower trunk of 
the brachial plexus by a cervical rib or band arising from 
the seventh cervical vertebra leads to weakness and wasting 
of intrinsic hand muscles, especially those in the thenar 
eminence, accompanied by pain and numbness in the 
medial two fingers and the ulnar border of the hand and 
forearm. Electromyography, nerve conduction studies, and 
somatosensory evoked potential studies may help confirm 
the diagnosis. MRI may be especially helpful in revealing 
the underlying compressive structure. Plain radiographs or 
CT scanning sometimes shows the cervical rib or a large 
transverse process of the seventh cervical vertebra, but 
normal findings do not exclude the possibility of a cervical 
band. Treatment of the disorder is by surgical excision of 
the rib or band.
3. Lumbosacral 
p
lexus Lesions
A lumbosacral plexus lesion may develop in association 
with diseases such as diabetes, cancer, or bleeding 
 
▲
 
Pe
ri
pheral ner
ve
Posterior rami of cervical ner
ve
s
Supraclavicular
Axillary 
ve
 of 
fo
re
arm 
Lateral cutaneous ne
rv
e of 
fo
re
arm 
Lateral 
fe
Obturator
An
te
ri
or f
emoral cutaneous
Posterior 
fe
rv
e of calf
Saphenous
Calcaneal
Lateral plantar 
Medial plantar 
Great occipital
Lesser occipita
l
Great auricular
Po
sterior cutaneous ner
ve
 of 
fo
re
arm
ve
 of arm 
rv
e of arm 
Po
ve
 of arm
Median
Po
ster
ior lumbar rami
Po
ster
ior sacral rami
= Iliohypogastric
X
X
Ner
ve
 root
Radial
Ulnar
Sura
l
T2
T2
T1
T3
C2
C3
C4
T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
C8
C6
C7
S1
L5
L5
S3
L
3
S4
S5
L4
S2
Po
ster
ior thoracic rami
C5
C6
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disorders or in relation to injury. It occasionally occurs as 
an isolated phenomenon similar to idiopathic brachial 
plexopathy, and pain and weakness then tend to be more 
conspicuous than sensory symptoms. The distribution of 
symptoms and signs depends on the level and pattern of 
neurologic involvement.
Van Eijk JJ et al. Neuralgic amyotrophy: an update on diagnosis, 
pathophysiology, and treatment. Muscle Nerve. 2016 Mar;
 
53(3):337–50. [PMID: 26662794]
 
º
DISORDERS OF NEUROMUSCUL
a
R 
TR
a
NSMISSION
1. Myasthenia Gravis
 
»
Fluctuating weakness of commonly used voluntary 
muscles, producing symptoms such as diplopia, 
ptosis, and difficulty in swallowing.
 
»
Activity increases weakness of affected muscles.
 
»
Short-acting anticholinesterases transiently improve 
the weakness.
 
»
Myasthenia gravis occurs at all ages, sometimes in associa
-
tion with a thymic tumor or thyrotoxicosis, as well as in 
rheumatoid arthritis and lupus erythematosus. It is most 
common in young women with HLA-DR3; if thymoma is 
associated, older men are more commonly affected. Onset 
is usually insidious, but the disorder is sometimes 
unmasked by a coincidental infection that leads to exacer
-
bation of symptoms. Exacerbations may also occur before 
the menstrual period and during or shortly after preg
-
nancy. Symptoms are due to a variable degree of block of 
neuromuscular transmission caused by autoantibodies 
binding to acetylcholine receptors; these are found in most 
patients with the disease and have a primary role in reduc
-
ing the number of functioning acetylcholine receptors. 
Additionally, cellular immune activity against the receptor 
is found.
 
»
Patients present with ptosis, diplopia, difficulty in chewing 
or swallowing, respiratory difficulties, limb weakness, or 
some combination of these problems. Weakness may 
remain localized to a few muscle groups or may become 
generalized. The external ocular muscles and certain other 
cranial muscles, including the masticatory, facial, and pha
-
ryngeal muscles, are especially likely to be affected, and the 
respiratory and limb muscles may also be involved. Symp
-
toms often fluctuate in intensity during the day, and this 
diurnal variation is superimposed on a tendency to 
longer-term spontaneous relapses and remissions that may 
last for weeks. Nevertheless, the disorder follows a slowly 
progressive course and may have a fatal outcome owing to 
respiratory complications such as aspiration pneumonia.
Clinical examination confirms the weakness and fatiga
-
bility of affected muscles. In most cases, the extraocular 
muscles are involved, and this leads to ocular palsies and 
ptosis, which are commonly asymmetric. Pupillary 
responses are normal. The bulbar and limb muscles are 
often weak, but the pattern of involvement is variable. Sus
-
tained activity of affected muscles increases the weakness, 
which improves after a brief rest. Sensation is normal, and 
there are usually no reflex changes.
Life-threatening exacerbations of myasthenia (so-called 
myasthenic crisis)
 may lead to respiratory weakness 
requiring immediate admission to the intensive care unit, 
where respiratory function can be monitored and ventila
-
tor support is readily available.
Assay of serum for elevated levels of 
circulating acetylcho
-
line receptor antibodies
 is useful because it has a sensitiv
-
ity of 80–90% for the diagnosis of myasthenia gravis. 
Certain patients without antibodies to acetylcholine recep
-
tors have serum antibodies to muscle-specific tyrosine 
kinase (MuSK), which should therefore be determined; 
these patients are more likely to have facial, respiratory, 
and proximal muscle weakness than those with antibodies 
to acetylcholine receptors. Other antibodies associated 
with myasthenia gravis include low-density lipoprotein

with myasthenia gravis include low-density lipoprotein 
receptor-related protein 4 (LRP4) and agrin, but tests for 
these antibodies are not widely commercially available.
Electrophysiologic demonstration of a decrementing 
muscle response to repetitive 2- or 3-Hz stimulation of 
motor nerves indicates a disturbance of neuromuscular 
transmission. Such an abnormality may even be detected in 
clinically strong muscles with certain provocative proce
-
dures. Needle electromyography of affected muscles shows 
a marked variation in configuration and size of individual 
motor unit potentials, and single-fiber electromyography 
reveals an increased jitter, or variability, in the time interval 
between two muscle fiber action potentials from the same 
motor unit.
C. Imaging
A CT scan of the chest with and without contrast should be 
obtained to demonstrate a coexisting thymoma.
 
»
Treatment
Anticholinesterase medications provide symptomatic ben
-
efit without influencing the course of the disease. Neostig
-
mine, pyridostigmine, or both can be used, the dose being 
determined on an individual basis. The usual dose of neo
-
stigmine is 7.5–30 mg (average, 15 mg) orally taken four 
times daily; of pyridostigmine, 30–180 mg (average, 60 mg) 
orally four times daily. Overmedication may temporarily 
increase weakness. A wide range of medications (eg, ami
-
noglycosides) may exacerbate myasthenia gravis and 
CMDT19_Ch24_p0990-p1062.indd   1058

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CMDT 2019
Thymectomy should be performed when a thymoma is 
present. A multicenter randomized trial demonstrated the 
benefit of thymectomy even in the absence of a radiologi
-
cally identifiable thymoma, with improved strength, lower 
immunosuppression requirements, and fewer hospitaliza
-
tions in the surgically treated group. Thus, 
thymectomy 
should be considered in all patients younger than age 65
 
unless weakness is restricted to the extraocular muscles. If 
the disease is of recent onset and only slowly progressive, 
operation is sometimes delayed for a year or so, in the hope 
that spontaneous remission will occur.
Treatment with corticosteroids is indicated for patients 
who have responded poorly to anticholinesterase medica
-
tions. Some patients experience transient exacerbation of 
weakness and even develop respiratory failure within the 
first 1–2 weeks if corticosteroids are initiated at high doses 
(eg, prednisone 1 mg/kg/day). Therefore, in stable patients, 
corticosteroids are introduced gradually in the outpatient 
setting. Prednisone can be started at 20 mg orally daily and 
increased by 10 mg increments weekly to a target of 1 mg/
kg/day (maximum daily dose 100 mg). For patients hospi
-
talized with severe myasthenia and treated with intrave
-
nous immunoglobulin or plasmapheresis, the higher dose 
can be given initially because the more rapid onset of 
action of the former two therapies mitigates the initial dip 
in strength due to corticosteroids. Corticosteroids can be 
prescribed as alternate-day or daily treatment, with alter
-
nate-day therapy potentially mitigating side effects. Once 
the patient has stabilized at the initial high dose, corticoste
-
roids can gradually be tapered to a relatively low mainte
-
nance level (eg, 10 mg prednisone orally daily) as 
improvement occurs; total withdrawal is difficult, however. 
Treatment with azathioprine may be effective in allowing a 
lower dose of corticosteroids. The usual dose is 2–3 mg/kg 
orally daily after a lower initial dose. Other immunosup
-
pressive agents that are used in myasthenia gravis to reduce 
the corticosteroid dose include mycophenolate mofetil, 
rituximab, cyclosporine, methotrexate, and tacrolimus.
In patients with major disability, plasmapheresis or 
IVIG therapy may be beneficial and have similar efficacy. It 
is also useful for stabilizing patients before thymectomy 
and for managing acute crisis.
 
»
 
»
•	
Patients with acute exacerbation or respiratory 
•	
Patients requiring plasmapheresis.
•	
For thymectomy.
Sanders DB et al. International consensus guidance for manage
-
ment of myasthenia gravis: executive summary. Neurology. 
2016 Jul 26;87(4):419–25. [PMID: 27358333]
Wolfe GI et al; MGTX Study Group. Randomized trial of thy
-
mectomy in myasthenia gravis. N Engl J Med. 2016 Aug 11;
 
375(6):511–22. [PMID: 27509100]
2. Myasthenic Syndrome (Lambert-Eaton 
Myasthenic Syndrome)
 
»
Variable weakness, typically improving with 
activity.
 
»
Dysautonomic symptoms may also be present.
 
»
A history of malignant disease may be obtained.
 
»
Myasthenic syndrome may be associated with small cell 
carcinoma, sometimes developing before the tumor is 
diagnosed, and occasionally occurs with certain autoim
-
mune diseases. There is defective release of acetylcholine in 
response to a nerve impulse, caused by P/Q-type voltage-
gated calcium channel antibodies, and this leads to weak
-
ness, especially of the proximal muscles of the limbs. 
Unlike myasthenia gravis, however, power steadily 
increases
 
with sustained contraction. The diagnosis can be con
-
firmed electrophysiologically, because the muscle response 
to stimulation of its motor nerve increases remarkably after 
exercise or if the nerve is stimulated repetitively at high

-
exercise or if the nerve is stimulated repetitively at high 
rates (50 Hz), even in muscles that are not clinically weak.
Treatment with intravenous immunoglobulin, plasma
-
pheresis and immunosuppressive drug therapy (predni
-
sone and azathioprine) may lead to clinical and 
electrophysiologic improvement, in addition to therapy 
aimed at tumor when present. Prednisone is usually initi
-
ated in a daily dose of 60–80 mg orally and azathioprine in 
a daily dose of 2 mg/kg orally. Symptomatic therapy 
includes the use of potassium channel antagonists; of these, 
3,4-diaminopyridine (60–80 mg/day orally in three divided 
doses) has been best studied and appears efficacious. Gua
-
nidine hydrochloride (25–50 mg/kg/day orally in divided 
doses) is an alternative and is occasionally helpful in seri
-
ously disabled patients, but adverse effects of the drug 
include marrow suppression. The response to treatment 
with anticholinesterase medications such as pyridostig
-
mine or neostigmine is usually disappointing.
Hülsbrink R et al. Lambert-Eaton myasthenic syndrome—
 
diagnosis, pathogenesis and therapy. Clin Neurophysiol. 2014 Dec;
 
125(12):2328–36. [PMID: 25065299]
3. Botulism
The toxin of 
 prevents the release of 
acetylcholine at neuromuscular junctions and autonomic 
synapses. Botulism occurs most commonly following the 
ingestion of contaminated home-canned food; outbreaks 
have also occurred among drug abusers due to wound infec
-
tion after injection of contaminated heroin. The diagnosis 
should be suggested by the development of sudden, fluctuat
-
ing, severe weakness with preserved sensation in a previ
-
ously healthy person. Symptoms begin within 72 hours 
following ingestion of the toxin and may progress for several 
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days. Typically, there is diplopia, ptosis, facial weakness, 
dysphagia, and nasal speech, followed by respiratory diffi
-
culty and finally by weakness that appears last in the limbs. 
Blurring of vision (with unreactive dilated pupils) is charac
-
teristic, and there may be dryness of the mouth, constipation 
(paralytic ileus), and postural hypotension. The tendon 
reflexes are not affected unless the involved muscles are very 
weak. If the diagnosis is suspected, the local health authority 
should be notified and a sample of serum and contaminated 
food (if available) sent to be assayed for toxin. Support for 
the diagnosis may be obtained by electrophysiologic studies; 
with repetitive stimulation of motor nerves at fast rates, the 
muscle response increases in size progressively.
Patients should be hospitalized in case respiratory assis
-
tance becomes necessary. Treatment is with trivalent anti
-
toxin, once it is established that the patient is not allergic to 
horse serum. Potassium channel antagonists may provide 
symptomatic relief as they do in Lambert-Eaton myas
-
thenic syndrome. Anticholinesterase medications are of no 
value. Respiratory assistance and other supportive mea
-
sures should be provided as necessary. Further details are 
provided in Chapter 33.
Chalk CH et al. Medical treatment for botulism. Cochrane Data
-
base Syst Rev. 2014 Feb 20;(2):CD008123. [PMID: 24558013]
4. Disorders 
a
ssociated with Use 
of 
a
minogly
cosides
Aminoglycoside antibiotics, eg, gentamicin, may produce a 
clinical disturbance similar to botulism by preventing the 
release of acetylcholine from nerve endings, but symptoms 
subside rapidly as the responsible medication is eliminated 
from the body. These antibiotics are particularly dangerous 
in patients with preexisting disturbances of neuromuscular 
transmission and are therefore best avoided in patients 
with myasthenia gravis.
 
º
MYO
pa
T
h
IC DISORDERS
1. Muscular Dystrophies
 
»
Muscle weakness, often in a characteristic 
distribution.
 
»
Age at onset and inheritance pattern depend on 
the specific dystrophy.
 
»
These inherited myopathic disorders are characterized by 
progressive muscle weakness and wasting. They are sub
-
divided by mode of inheritance, age at onset, and clinical 
features, as shown in Table 24–9. In the 
Duchenne
 type, 
pseudohypertrophy of muscles frequently occurs at some 
stage; intellectual disability is common; and there may be 
skeletal deformities, muscle contractures, and cardiac 
involvement. The serum creatine kinase level is increased, 
especially in the Duchenne and Becker varieties, and 
mildly increased also in limb-girdle dystrophy. Electro
-
myography may help confirm that weakness is myopathic 
rather than neurogenic. Similarly, histopathologic exami
-
nation of a muscle biopsy specimen may help confirm 
that weakness is due to a primary disorder of muscle and 
to distinguish between various muscle diseases.
A genetic defect on the short arm of the X chromo
-
some has been identified in Duchenne dystrophy. The 
affected gene codes for the protein dystrophin, which is 
markedly reduced or absent from the muscle of patients 
with the disease. Dystrophin levels are generally normal in 
the Becker variety, but the protein is qualitatively altered. 
The diagnosis is usually made with genetic testing; muscle 
biopsy is needed occasionally. Duchenne muscular dystro
-
phy can be recognized early in pregnancy in about 95% of 
women by genetic studies; in late pregnancy, DNA probes 
can be used on fetal tissue obtained for this purpose by 
amniocentesis. The genes causing some of the other mus
-
cular dystrophies are listed in Table 24–9.
In 2016, the FDA provisionally approved the medication 
eteplirsen for Duchenne muscular dystrophy, an antisense 
oligonucleotide that may benefit the 13% of patients with

oligonucleotide that may benefit the 13% of patients with 
this disorder who have a dystrophin mutation that benefits 
from exon 51 skipping. Patients treated with eteplirsen had 
more functional dystrophin on muscle biopsy than controls 
and a slower rate of disease progression than matched his
-
torical controls. Prednisone (0.75 mg/kg orally daily or 
10  mg/kg orally given weekly over 2 days) or deflazacort 
(0.9 mg/kg orally daily) improves muscle strength and func
-
tion in boys with Duchenne dystrophy, but side effects need 
to be monitored. Although both corticosteroid preparations 
cause similar side effects, weight gain at 1 year is less with 
deflazacort. Prolonged bed rest must be avoided, as inactiv
-
ity often leads to worsening of the underlying muscle dis
-
ease. Physical therapy and orthopedic procedures may help 
counteract deformities or contractures.
Gloss D et al. Practice guideline update summary: corticosteroid 
treatment of Duchenne muscular dystrophy: report of the 
guideline development subcommittee of the American 
 
Academy of Neurology. Neurology. 2016 Feb 2;86(5):465–72. 
[PMID: 26833937]
Mendell JR et al. Longitudinal effect of eteplirsen versus histori
-
cal control on ambulation in Duchenne muscular dystrophy. 
Ann Neurol. 2016 Feb;79(2):257–71. [PMID: 26573217]
2. Myotonic Dystrophy
Myotonic dystrophy, a slowly progressive, dominantly 
inherited disorder, usually manifests itself in the third or 
fourth decade but occasionally appears early in childhood. 
Two types, with a different genetic basis, have been recog
-
nized. Myotonia leads to complaints of muscle stiffness and 
is evidenced by the marked delay that occurs before 
affected muscles can relax after a contraction. This can 
often be demonstrated clinically by delayed relaxation of 
the hand after sustained grip or by percussion of the belly 
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Feingold B et al. Management of cardiac involvement associated 
with neuromuscular diseases: a scientific statement from the 
American Heart Association. Circulation. 2017 Sep 26;136(13):
 
e200–31. [PMID: 28838934]
3. Myotonia Congenita
Myotonia congenita is commonly inherited as a dominant 
trait. Generalized myotonia without weakness is usually 
present from birth, but symptoms may not appear until 
early childhood. Patients complain of muscle stiffness that 
is enhanced by cold and inactivity and relieved by exercise. 
Muscle hypertrophy, at times pronounced, is also a feature. 
A recessive form with later onset is associated with slight 
weakness and atrophy of distal muscles. Treatment with 
procainamide, tocainide, mexiletine, or phenytoin may 
help the myotonia, as in myotonic dystrophy.
of a muscle. In addition, there is weakness and wasting of 
the facial, sternocleidomastoid, and distal limb muscles. 
Associated clinical features include cataracts, frontal bald
-
ness, testicular atrophy, diabetes mellitus, cardiac abnor
-
malities, and intellectual changes. Electromyographic 
sampling of affected muscles reveals myotonic discharges 
in addition to changes suggestive of myopathy.
It is difficult to determine whether medication therapy 
for myotonia is safe or effective. When myotonia is dis
-
abling, treatment with a sodium channel blocker—such as 
phenytoin (100 mg orally three times daily), procainamide 
(0.5–1 g orally four times daily), or mexiletine (150–200 mg 
orally three times daily)—may be helpful, but the associ
-
ated side effects, particularly for antiarrhythmic medica
-
tions, are often limiting. Neither the weakness nor the 
course of the disorder is influenced by treatment. Cardiac 
function should be monitored, and pacemaker placement 
may be considered if there is evidence of heart block.
Table 24–9.
 
Selected muscular dystrophies.
1
Disorder
a
ge a
t Onset 
(years)
Distribution
p
r
ognosis
Genetic 
a
ssociation
Duchenne type
X-linked 
recessive
1–5
Pelvic, then shoulder 
girdle; later, limb 
and respiratory 
muscles.
Rapid progression. 
Death within about 
15 years after onset.
Xp21; Dystrophin (loss of 
functional expression)
Becker
X-linked 
recessive
5–25
girdle.
Slow progression. 
May have normal 
life span.
Xp21; Dystrophin (reduced 
Limb-girdle (Erb)
Autosomal 
recessive, 
dominant, or 
sporadic
10–30
Pelvic or shoulder 
girdle initially, 
with later spread 
to the other.
Variable severity and 
rate of progression. 
Possible severe dis
-
ability in middle life.
Multiple
Facioscapulohumeral
Autosomal 
dominant
Any age
Face and shoulder 
girdle initially; 
later, pelvic girdle 
and legs.
Slow progression. Minor 
disability. Usually 
normal life span.
4q35.2; Double homeobox 
protein 4
18p11.32; Structural mainte
-
nance of chromosome’s 
flexible hinge domain-
containing protein 1
Emery-Dreifuss
X-linked reces
-
sive or auto
-
somal 
dominant
5–10
Humeroperoneal or 
scapuloperoneal.
Variable.
Multiple
Distal
Autosomal 
dominant or 
recessive
40–60
Onset distally in 
extremities; proxi
-
mal involvement 
later.
Slow progression.
Multiple
Oculopharyngeal
Autosomal 
dominant
Any age
Ptosis, external oph
-
thalmoplegia, and 
dysphagia.
Slow progression
14q11.2–q13; Poly (A)-binding 
protein-2
Autosomal 
dominant
Any age (usu
-
ally 20–40)
Face, neck, distal 
limbs.
19q13.32; Myotonin-protein 
kinase
3q21.3; Cellular nucleic 
 
acid-binding protein
1
Not all possible genetic loci are shown.
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4. 
p
olym
yositis & Dermatomyositis
See Chapter 20.
5. Inclusion Body Myositis
This disorder, of unknown cause, begins insidiously, usu
-
ally after middle age, with progressive proximal weakness 
of first the lower and then the upper extremities, and 
affecting facial and pharyngeal muscles. Weakness often 
begins in the quadriceps femoris in the lower limbs and the 
forearm flexors in the upper limbs. Distal weakness is usu
-
ally mild. Serum creatine kinase levels may be normal or 
increased. The diagnosis is confirmed by muscle biopsy. 
Anticytosolic 5’-nucleotidase 1A antibodies are detected in 
one-third of cases and may be associated with a more 
severe phenotype. Corticosteroid and immunosuppressive 
therapy is sometimes offered but is usually ineffective, and 
IVIG therapy is not recommended.
Lilleker JB et al. Cytosolic 5’-nucleotidase 1A autoantibody pro
-
file and clinical characteristics in inclusion body myositis. 
Ann Rheum Dis. 2017 May;76(5):862–8. [PMID: 28122761]
6. Mitochondrial Myopathies
The mitochondrial myopathies are a clinically diverse group 
of disorders that on pathologic examination of skeletal 
muscle with the modified Gomori stain show characteristic 
“ragged red fibers” containing accumulations of abnormal 
mitochondria. Patients may present with progressive exter
-
nal ophthalmoplegia or with limb weakness that is exacer
-
bated or induced by activity. Other patients present with 
central neurologic dysfunction, eg, myoclonic epilepsy 
(myoclonic epilepsy, ragged red fiber syndrome, or MERRF), 
or the combination of myopathy, encephalopathy, lactic aci
-
dosis, and stroke-like episodes (MELAS). These disorders 
result from separate abnormalities of mitochondrial DNA. 
Treatment is symptomatic and palliative, but various experi
-
mental approaches are being explored.
A mitochondrial myopathy may develop in patients 
receiving zidovudine for treatment of AIDS, and patients 
receiving combined antiretroviral therapy for HIV infec
-
tion may develop a lipodystrophy, with fat accumulating in 
muscle.
Sharp LJ et al. Metabolic and mitochondrial myopathies. Neurol 
Clin. 2014 Aug;32(3):777–99. [PMID: 25037090]
7. Myopathies 
a
ssociated with Other Disorders
Myopathy may occur in association with critical illness, 
typically in patients who received neuromuscular blocking 
agents and corticosteroids. It may also occur in chronic 
hypokalemia, any endocrinopathy, and in patients taking 
corticosteroids, chloroquine, colchicine, clofibrate, eme
-
tine, aminocaproic acid, or statin medications. Weakness is 
mainly proximal, and serum creatine kinase is typically 
normal, except in hypothyroidism and some of the toxic 
myopathies. Treatment is of the underlying cause. Myopa
-
thy also occurs with chronic alcoholism, whereas acute 
reversible muscle necrosis may occur shortly after acute 
alcohol intoxication. Inflammatory myopathy may occur 
in patients taking penicillamine; myotonia may be induced 
by clofibrate, and preexisting myotonia may be exacerbated 
or unmasked by depolarizing muscle relaxants (eg, suxa
-
methonium), beta-blockers (eg, propranolol), fenoterol, 
ritodrine and, possibly, certain diuretics.
 
»
All patients should be referred to establish the diagnosis 
and underlying cause.
 
»
•	
For respiratory assistance.
•	
For rhabdomyolysis.
 
º
p
ERIODIC 
pa
R
a
LYSIS SYNDROMES
Periodic paralysis may have a familial (dominant inheri
-
tance) basis. The syndromes to be described are 
channelo
-
pathies
 that manifest as abnormal, often potassium-sensitive, 
muscle-membrane excitability and lead clinically to epi
-
sodes of flaccid weakness or paralysis, sometimes in asso
-
ciation with abnormalities of the plasma potassium level. 
Strength is initially normal between attacks, but progres
-
sive myopathic weakness may develop in up to one-third of 
patients as they age. 
Hypokalemic periodic paralysis
 is

-
 is 
characterized by attacks that tend to occur on awakening, 
after exercise, or after a heavy meal and may last for several 
days. Patients should avoid excessive exertion. A low-
 
carbohydrate and low-salt diet may help prevent attacks. 
An ongoing attack may be aborted by potassium chloride 
given orally or by intravenous drip, provided the ECG can 
be monitored and kidney function is satisfactory. In young 
Asian men, it is commonly associated with hyperthyroid
-
ism; treatment of the endocrine disorder prevents recur
-
rences. A nonselective beta-adrenergic blocker may prevent 
attacks until the endocrine abnormality has been treated. 
In 
hyperkalemic periodic paralysis,
 attacks also tend to 
occur after exercise but usually last for less than 1 hour. 
They may be terminated by intravenous calcium gluconate 
(1–2 g) or by intravenous diuretics (furosemide, 20–40 mg), 
 
glucose, or glucose and insulin. 
Normokalemic periodic 
paralysis
 is similar clinically to the hyperkalemic variety, 
but the plasma potassium level remains normal during 
attacks. Several randomized trials support the use of 
dichlorphenamide (50–100 mg orally twice daily) for pre
-
vention of attacks in both hyperkalemic and hypokalemic 
periodic paralysis; acetazolamide (250–750 mg orally 
daily) is also effective. Chlorothiazide may also be used to 
prevent attacks in hyperkalemic periodic paralysis.
 
»
Sansone V A et al; Muscle Study Group. Randomized, placebo-
controlled trials of dichlorphenamide in periodic paralysis. 
Neurology. 2016 Apr 12;86(15):1408–16. [PMID: 26865514]
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The fifth edition of the American Psychiatric Associa
-
tion’s 
Diagnostic and Statistical Manual (DSM-5)
 is the 
common language that clinicians use for psychiatric con
-
ditions. It utilizes specific criteria with which to objec
-
tively assess symptoms for use in clinical diagnosis and 
communication.
 
º
COMMON PSYCHIATRIC DISORDERS
ADJUSTMENT DISORDERS
 
»
Anxiety or depression in reaction to an identifi
-
able stress, though out of proportion to the sever
-
ity of the stressor.
 
»
Symptoms are not at the severity of a major 
depressive episode or with the chronicity of gen
-
eralized anxiety disorder.
 
»
An individual experiences stress when the adaptive capac
-
ity of the individual is overwhelmed by events. The event 
may be an insignificant one when objectively considered, 
and even favorable changes (eg, promotion and transfer) 
requiring adaptive behavior can produce stress. For each 
individual, stress is subjectively defined, and the response 
to stress is a function of each person’s personality and 
physiologic endowment.
Opinion differs about what events are most apt to pro
-
duce stress reactions. The causes of stress are different at 
different ages—eg, in young adulthood, the sources of 
stress are found in the marriage or parent-child relation
-
ship, the employment relationship, and the struggle to 
achieve financial stability; in the middle years, the focus 
shifts to changing spousal relationships, problems with 
aging parents, and problems associated with having young 
adult offspring who themselves are encountering stressful 
situations; in old age, the principal concerns are apt to be 
retirement, loss of physical and mental capacity, major 
personal losses, and thoughts of death.
 
»
An individual may react to stress by becoming anxious or 
depressed, by developing a physical symptom, by running 
away, drinking alcohol, overeating, starting an affair, or in 
limitless other ways. Common subjective responses are 
anxiety, sadness, fear, rage, guilt, and shame. Acute and 
reactivated stress may be manifested by restlessness, irrita
-
bility, fatigue, increased startle reaction, and a feeling of 
tension. Inability to concentrate, sleep disturbances 
(insomnia, bad dreams), and somatic preoccupations often 
lead to self-medication, most commonly with alcohol or 
other central nervous system depressants. Emotional and 
behavioral distressing symptomatology in response to 
stress is called 
adjustment disorder
, with the major symp
-
tom specified (eg, “adjustment disorder with depressed 
mood”). Even with an identifiable stressor, if the patient 
meets syndromal criteria for another disorder such as 
major depression, then the convention would be to diag
-
nose a major depression and not an adjustment disorder 
with depressed mood.
 
»
Adjustment disorders are distinguished from anxiety dis
-
orders, mood disorders, bereavement, other stress disor
-
ders such as posttraumatic stress disorder (PTSD), and 
personality disorders exacerbated by stress and from 
somatic disorders with psychic overlay. Unlike many other 
psychiatric disorders, such as bipolar disorder or schizo
-
phrenia, adjustment disorders are wholly situational and 
usually resolve when the stressor resolves or the individual 
effectively adapts to the situation. Adjustment disorders 
may have symptoms that overlap with other disorders, such 
as anxiety symptoms, but they occur in reaction to an iden
-
tifiable life stressor such as a difficult work situation or 
romantic breakup. An adjustment disorder that persists 
and worsens can potentially evolve into another psychiatric 25
 
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disorder such as major depression or generalized anxiety 
disorder (GAD). However, that is not the case for most 
patients. Patients with adjustment disorders have marked 
distress after a stressor and significant impairment in social 
or occupational functioning but not to the degree experi
-
enced by patients with a more severe disorder such as 
major depressive disorder or PTSD. By definition, an 
adjustment disorder occurs within 3 months of an identifi
-
able stressor.
 
»
Treatment
A. Behavioral
Stress reduction techniques include immediate symptom 
reduction (eg, rebreathing in a bag for hyperventilation) or 
early recognition and removal from a stress source before 
full-blown symptoms appear. It is often helpful for the 
patient to keep a daily log of stress precipitators, responses, 
and alleviators. Relaxation, mindfulness-based stress 
reduction, and exercise techniques are also helpful in 
improving the reaction to stressful events.
B. Social
The stress reactions of life crisis problems are a function of 
psychosocial upheaval. While it is not easy for the patient to 
make necessary changes (or they would have been made long 
ago), it is important for the clinician to establish the frame
-
work of the problem, since the patient’s denial system may 
obscure the issues. Clarifying the problem in the patient’s 
psychosocial context allows the patient to begin viewing it 
within the proper frame and facilitates the difficult decisions 
the patient eventually must make (eg, change of job).
C. Psychological
Prolonged in-depth psychotherapy is seldom necessary in 
cases of isolated stress response or adjustment disorder. 
Supportive psychotherapy (see above) with an emphasis on 
strengthening of existing coping mechanisms is a helpful 
approach so that time and the patient’s own resiliency can 
restore the previous level of function. In addition, cognitive 
behavioral therapy has long been established to treat acute 
stress and facilitate recovery in patients with an adjustment 
disorder.
D. Pharmacologic
Judicious use of sedatives (eg, lorazepam, 0.5–1 mg two or 
three times daily orally) for a limited time and as part of an 
overall treatment plan can provide relief from acute anxiety 
symptoms. Problems arise when the situation becomes 
chronic through inappropriate treatment or when the treat
-
ment approach supports the development of chronicity. There 
are occasions where the short-term use of selective serotonin 
reuptake inhibitors (SSRIs) targeting dysphoria and anxiety 
 
»
Prognosis
Return to satisfactory function after a short period is part 
of the clinical picture of this syndrome. Resolution may be 
delayed if others’ responses to the patient’s difficulties are 
thoughtlessly harmful or if the secondary gains outweigh 
the advantages of recovery. The longer the symptoms per
-
sist, the worse the prognosis.
TRAUMA & STRESSOR-RELATED DISORDERS
 
»
Exposure to a traumatic or life-threatening event.
 
»
Flashbacks, intrusive images, and nightmares, 
often represent reexperiencing the event.
 
»
Avoidance symptoms, including numbing, social 
withdrawal, and avoidance of stimuli associated 
with the event.
 
»
Increased vigilance, such as startle reactions and 
difficulty falling asleep.
 
»
Symptoms impair functioning.
 
»
Posttraumatic stress disorder (PTSD)
 has been reclassi
-
fied from an anxiety disorder to a trauma and stressor-
related disorder in the 
DSM-5.
 PTSD is a syndrome 
characterized by “reexperiencing” a traumatic event (eg, 
sexual assault, severe burns, military combat) and decreased 
responsiveness and avoidance of current events associated 
with the trauma. Data indicate that 13% of veterans who 
served in Iraq and 6% of those who served in Afghanistan 
have experienced PTSD. The 2005 National Comorbidity 
Survey Report estimated the lifetime prevalence of PTSD

Survey Report estimated the lifetime prevalence of PTSD 
among adult Americans at 6.8% with a point prevalence of 
3.6% and with women having rates twice as high as men. 
PTSD is more common when the event is associated with 
physical injury than when it is not. Many individuals with 
PTSD (20–40%) have experienced other associated prob
-
lems, including divorce, parenting problems, difficulties 
with the law, and substance abuse.
 
»
The key to establishing the diagnosis of PTSD lies in the 
history of exposure to a perceived or actual life-threatening 
event, serious injury, or sexual violence. This can include 
serious medical illnesses, and the prevalence of PTSD is 
higher in people who have experienced serious illnesses 
such as cancer. The symptoms of PTSD include intrusive 
thoughts (eg, flashbacks, nightmares), avoidance (eg, with
-
drawal), negative thoughts and feelings, and increased 
reactivity. Patients with PTSD can experience physiologic 
hyperarousal, including startle reactions, illusions, over
-
generalized associations, sleep problems, nightmares, 
dreams about the precipitating event, impulsivity, difficul
-
ties in concentration, and hyperalertness. The symptoms 
may be precipitated or exacerbated by events that are a 
reminder of the original traumatic event. Symptoms 
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CMDT 2019
frequently arise after a long latency period (eg, child abuse 
can result in later-onset PTSD). 
DSM-5
 includes the 
requirement that the symptoms persist for at least 1 month. 
In some individuals, the symptoms fade over months or 
years, and in others they may persist for a lifetime.
 
»
In 75% of cases, PTSD occurs with comorbid depression or 
panic disorder, and there is considerable overlap in the 
symptom complexes of all three conditions. Acute stress 
disorder has many of the same symptoms as PTSD, but 
symptoms persist for only 3 days to a month after the 
trauma. The other major comorbidity is alcohol and sub
-
stance abuse. The Primary Care-PTSD Screen and the 
PTSD Checklist are two useful screening instruments in 
primary care clinics or community settings with popula
-
tions at risk for trauma exposure.
 
»
Treatment
A. Psychotherapy
Psychotherapy should be initiated 
as soon as possible
 after 
the traumatic event, and it should be brief (typically 8–12 
sessions), once the individual is in a safe environment. 
Cognitive processing therapy, prolonged exposure therapy, 
and eye-movement desensitization reprocessing have been 
effective in significantly reducing the duration of symp
-
toms. In all of these approaches, the individual confronts 
the traumatic situation and learns to view it with less reac
-
tivity. Psychological debriefing in a single session, once a 
mainstay in prevention of PTSD, is now considered to be 
ineffective and possibly harmful. Posttraumatic stress syn
-
dromes respond to interventions that help patients inte
-
grate the event in an adaptive way with some sense of 
mastery in having survived the trauma. Partner relation
-
ship problems are a major area of concern, and it is impor
-
tant that the clinician have available a dependable referral 
source when marriage counseling is indicated.
Treatment of any comorbid substance abuse is an essen
-
tial part of the recovery process for patients with PTSD. In 
patients with comorbid substance use disorders, there is 
some evidence for better outcomes when substance abuse 
treatment is delivered alongside trauma-focused psycho
-
therapy. Support groups and 12-step programs such as 
Alcoholic Anonymous are often very helpful.
Video telepsychiatry for psychotherapy or medication 
management allows for access to these resources that some 
patients, such as those in rural settings, may not otherwise 
have. There is similar efficacy in reduction of PTSD symp
-
toms in women veterans with video teletherapy as with in 
person therapy, and the practice of telepsychiatry is likely 
to expand.
B. Pharmacotherapy
SSRIs are helpful in ameliorating depression, panic 
attacks, sleep disruption, and startle responses in PTSD. 
Sertraline and paroxetine are approved by the US Food 
and Drug Administration (FDA) for this purpose, and the 
SSRIs are the only class of medications approved for 
the treatment of PTSD. They are, therefore, considered 
the pharmacotherapy of choice for PTSD. Early treatment 
of anxious arousal with beta-blockers (eg, propranolol, 
80–160 mg orally daily) may lessen the peripheral symp
-
toms of anxiety (eg, tremors, palpitations) but has not 
been shown to help prevent development of PTSD. Simi
-
larly, noradrenergic agents such as clonidine (titrated 
from 0.1 mg orally at bedtime to 0.2 mg three times a 
day) have been shown to help with the hyperarousal 
symptoms of PTSD. The alpha-adrenergic blocking agent 
prazosin (2–10 mg orally at bedtime) decreases night
-
mares and improves quality of sleep in PTSD. Antisei
-
zure medications such as carbamazepine (400–800 mg 
orally daily) will often mitigate impulsivity and difficulty 
with anger management. Benzodiazepines, such as clonaz
-
epam (1–4 mg orally daily, divided into one or two doses), 
will reduce anxiety and panic attacks when used in ade
-
quate dosage, but dependency problems are a concern,

-
-
quate dosage, but dependency problems are a concern, 
particularly when the patient has had such problems in 
the past. Trazodone (25–100 mg orally at bedtime) is 
commonly prescribed as a non–habit forming hypnotic 
agent. Second-generation antipsychotics have not dem
-
onstrated significant utility in the the treatment of PTSD, 
but agents such as quetiapine 50–300 mg/day may have a 
limited role in treating agitation and sleep disturbance in 
PTSD patients.
 
»
Prognosis
The sooner therapy is initiated after the trauma, the better 
the prognosis. Approximately half of patients experience 
chronic symptoms. Prognosis is best in those with good 
premorbid psychiatric functioning. Individuals experienc
-
ing an acute stress disorder typically do better long-term 
than those experiencing a delayed posttraumatic disorder. 
Individuals who experience trauma resulting from a natu
-
ral disaster (eg, earthquake or hurricane) tend to do better 
than those who experience a traumatic interpersonal 
encounter (eg, rape or combat).
Hoskins M et al. Pharmacotherapy for post-traumatic stress 
disorder: systematic review and meta-analysis. Br J Psychia
-
try. 2015 Feb;206(2):93–100. [PMID: 25644881]
Morland LA et al. Telemedicine versus in-person delivery of 
cognitive processing therapy for women with posttraumatic 
stress disorder: a randomized noninferiority trial. Depress 
Anxiety. 2015 Nov;32(11):811–20. [PMID: 26243685]
Roberts NP et al. Psychological therapies for post-traumatic 
stress disorder and comorbid substance use disorder. 
Cochrane Database Syst Rev. 2016 Apr 4;4:CD010204. 
[PMID: 27040448]
Spoont M. JAMA patient page. Posttraumatic stress disorder 
(PTSD). JAMA. 2015 Aug 4;314(5):532. [PMID: 26241611]
Spoont MR et al. Does this patient have posttraumatic stress 
disorder? Rational clinical examination systematic review. 
JAMA. 2015 Aug 4;314(5):501–10. Erratum in: JAMA. 2016 
Jan 5;315(1):90. [PMID: 26241601]
Swartzman S et al. Posttraumatic stress disorder after cancer diag
-
nosis in adults: a meta-analysis. Depress Anxiety. 2017 Apr;
 
34(4):327–39. [PMID: 27466972]
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ANXIETY DISORDERS
 
»
Persistent excessive anxiety or chronic fear and 
associated behavioural disturbances.
 
»
Somatic symptoms referable to the autonomic 
nervous system or to a specific organ system (eg, 
dyspnea, palpitations, paresthesias).
 
»
Not limited to an adjustment disorder.
 
»
Not a result of physical disorders, other psychiatric 
conditions (eg, schizophrenia), or drug abuse (eg, 
cocaine).
 
»
Stress, fear, and anxiety all tend to be interactive. The prin
-
cipal components of anxiety are 
psychological
 (tension, 
fears, difficulty in concentration, apprehension) and 
somatic
 (tachycardia, hyperventilation, shortness of 
breath, palpitations, tremor, sweating). Sympathomimetic 
symptoms of anxiety are both a response to a central ner
-
vous system state and a reinforcement of further anxiety. 
Anxiety can become self-generating, since the symptoms 
reinforce the reaction, causing it to spiral. This is often the 
case when the anxiety is an epiphenomenon of other medi
-
cal or psychiatric disorders. Additionally, avoidance of 
triggers of anxiety leads to reinforcement of the anxiety. 
The person continues to associate the trigger with anxiety 
and never relearns through experience that the trigger 
need not always result in fear, or that anxiety will naturally 
improve with prolonged exposure to an objectively neutral 
stressor.
Anxiety may be free-floating, resulting in acute anxiety 
attacks, occasionally becoming chronic. Lack of structure is 
frequently a contributing factor, as noted in those people 
who have “Sunday neuroses. ” They do well during the week 
with a planned work schedule but cannot tolerate the 
unstructured weekend. Planned-time activities tend to 
bind anxiety, and many people have increased difficulties 
when this is lost, as in retirement.
 
»
A. Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) becomes chronic in 
many patients with over half of patients having the disor
-
der for longer than 2 years. About 7% of women and 4% of 
men will meet criteria for GAD over a lifetime. The anxiety 
symptoms of apprehension, worry, irritability, difficulty in 
concentrating, insomnia, or somatic complaints are present 
more days than not for at least 6 months. Manifestations 
can include cardiac (eg, tachycardia, increased blood pres
-
sure), gastrointestinal (eg, increased acidity, nausea, epi
-
gastric pain), and neurologic (eg, headache, near-syncope) 
systems. The focus of the anxiety may be a number of 
everyday activities.
B. Panic Disorder
Panic attacks
 are recurrent, unpredictable episodes of 
intense surges of anxiety accompanied by marked physio
-
logic manifestations. 
Agoraphobia
, fear of being in places 
where escape is difficult, such as open spaces or public 
places where one cannot easily hide, may be present and 
may lead the individual to confine his or her life to the 
home environment. Distressing symptoms and signs such 
as dyspnea, tachycardia, palpitations, headaches, dizzi
-
ness, paresthesias, choking, smothering feelings, nausea, 
and bloating are associated with feelings of impending 
doom (alarm response). Although these symptoms may 
lead to overlap with some of the same bodily complaints 
found in the somatic symptom disorders, the key to the 
diagnosis of panic disorder is the psychic pain and suffer
-
ing the individual expresses. 
 is diagnosed 
when panic attacks are accompanied by a chronic fear of 
the recurrence of an attack or a maladaptive change in 
behavior to try to avoid potential triggers of the panic 
attack. Recurrent 
sleep panic attacks
 (not nightmares) 
occur in about 30% of panic disorders. 
Anticipatory anxiety
 
develops in all these patients and further constricts their 
daily lives. Panic disorder tends to be familial, with onset 
usually under age 25; it affects 3–5% of the population,

usually under age 25; it affects 3–5% of the population, 
and the female-to-male ratio is 2:1. The premenstrual 
period is one of heightened vulnerability. Patients fre
-
quently undergo emergency medical evaluations (eg, for 
“heart attacks” or “hypoglycemia”) before the correct 
diagnosis is made. Gastrointestinal symptoms (eg, stom
-
ach pain, heartburn, diarrhea, constipation, nausea and 
vomiting) are common, occurring in about one-third of 
cases. Myocardial infarction, pheochromocytoma, hyper
-
thyroidism, and various recreational drug reactions can 
mimic panic disorder and should be considered in the 
differential diagnosis. Mitral valve prolapse may be pres
-
ent but is not usually a significant factor. Patients who 
have recurrent panic disorder often become demoralized, 
hypochondriacal, agoraphobic, and depressed. These indi
-
viduals are at increased risk for major depression and the 
suicide attempts associated with that disorder. Alcohol 
abuse (in about 20%) results from self-treatment and is 
frequently combined with dependence on sedatives. Some 
patients have atypical panic attacks associated with sei
-
zure-like symptoms that often include psychosensory 
phenomena (a history of stimulant abuse often emerges). 
About 25% of panic disorder patients also have obsessive-
compulsive disorder (OCD).
C. Phobic Disorders
Phobias are fears of a specific object or situation (eg, spi
-
ders, height) that are out of proportion to the danger 
posed, and they tend to be chronic. 
Social phobias
 are 
global or specific; in the former, all social situations are 
poorly tolerated, while the latter group includes perfor
-
mance anxiety (eg, fear of public speaking). While patients 
with simple phobias such as fear of heights may function as 
long as they do not have to be in tall buildings or airplanes, 
a patient with agoraphobia may not be able to function 
vocationally or interpersonally.
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»
Treatment
In all cases, underlying medical disorders must be ruled 
out (eg, cardiovascular, endocrine, respiratory, and neuro
-
logic disorders and substance-related syndromes, both 
intoxication and withdrawal states).
A. Pharmacologic
1. Generalized anxiety disorder—
Antidepressants includ
-
ing the SSRIs and serotonin norepinephrine reuptake 
inhibitors (SNRIs) are safe and effective in the long-term 
management of GAD. The antidepressants appear to be as 
effective as the benzodiazepines without the risks of 
tolerance or dependence. However, benzodiazepines take 
effect more quickly if not immediately, which can be ben
-
eficial in acute management (Table 25–1).
All of the benzodiazepines may be given orally, and 
several are available in parenteral formulations. Benzodiaz
-
epines such as lorazepam are absorbed rapidly when given 
intramuscularly. In psychiatric disorders, the benzodiaze
-
pines are usually given orally; in controlled medical envi
-
ronments (eg, the intensive care unit [ICU]), where the 
rapid onset of respiratory depression can be assessed, they 
are often given intravenously. Diazepam and clorazepate are 
the most rapidly absorbed oral benzodiazepines, which may 
explain the popularity of diazepam. Lorazepam does not 
Table 25–1.
 
Commonly used antianxiety and hypnotic agents (listed in alphabetical order within classes).
Usual Daily Oral Doses
Usual Daily Maximum Doses
Cost for 30 Days Treatment 
Based on Maximum Dosage
1
Benzodiazepines (used for anxiety)
Alprazolam (Xanax)
2
0.5 mg
4 mg
$101.40
Chlordiazepoxide (Librium)
3
10–20 mg
100 mg
$51.60
Clonazepam (Klonopin)
3
1–2 mg
10 mg
$169.50
Clorazepate (Tranxene)
3
15–30 mg
60 mg
$260.40
Diazepam (Valium)
3
5–15 mg
30 mg
$28.80
Lorazepam (Ativan)
2
2–4 mg
4 mg
$69.00
Oxazepam (Serax)
2
10–30 mg
60 mg
$126.00
Benzodiazepines (used for sleep)
Estazolam (Prosom)
2
1 mg
2 mg
$29.70
Flurazepam (Dalmane)
3
15 mg
30 mg
$26.40
Midazolam (Versed)
4
5 mg
 
$1.20/dose
Quazepam (Doral)
3
7.5 mg
15 mg
$675.00
Temazepam (Restoril)
2
15 mg
30 mg
$24.30
Triazolam (Halcion)
5
0.125 mg
0.25 mg
$110.00
Miscellaneous (used for anxiety)
Buspirone (Buspar)
2
10–30 mg
60 mg
$218.40
3
15–30 mg
90 mg
$35.70
Miscellaneous (used for sleep)
Eszopiclone (Lunesta)
5
2–3 mg
3 mg
$350.40
Hydroxyzine (Vistaril)
2
50 mg
100 mg
$63.00
Suvorexant (Belsomra)
5–10 mg
20 mg
$397.80
Ramelteon (Rozerem)
8 mg
8 mg
$453.30
Zaleplon (Sonata)
6
5–10 mg
10 mg
$113.70
Zolpidem (Ambien)
5
5–10 mg
10 mg
$137.10
1
Red Book (electronic version)
, Truven Health 
Analytic Information, http://www.micormedexsolutions.com, accessed April 10, 2018. AWP may not accurately represent the actual phar
-
2
Intermediate physical half-life (10–20 hours).
3
Long physical half-life (> 20 hours).
4
Intravenously for procedures.
5
Short physical half-life (1–6 hours).
6
Short physical half-life (about 1 hour).
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produce active metabolites and has a half-life of 10–20 hours, 
characteristics useful in treating elderly patients or those 
with liver dysfunction. Ultra-short-acting agents such as 
triazolam have half-lives of 1–3 hours and may lead to 
rebound withdrawal anxiety. Longer-acting benzodiaze
-
pines such as flurazepam and diazepam produce active 
metabolites, have half-lives of 20–120 hours, and should be 
avoided in the elderly. Since people vary widely in their 
response and since the medications are long lasting, the 
dosage must be individualized. Once this is established, an 
adequate and scheduled dose early in the course of symp
-
tom development will obviate the need for “pill popping, ” 
which can contribute to dependency problems.
Antidepressants are the first-line medications for sus
-
tained treatment of GAD, having the advantage of not caus
-
ing physiologic dependency problems. 
Antidepressants can 
themselves be anxiogenic when first started
—thus, at the 
initiation of treatment, concomitant short-term treatment 
with a benzodiazepine is often indicated. The SNRIs venla
-
faxine and duloxetine are FDA-approved for the treatment 
of GAD in usual antidepressant doses. Initial daily dosing 
should start low (37.5–75 mg for venlafaxine and 30 mg for 
duloxetine) and be titrated upward as needed. SSRIs, such 
as escitalopram and paroxetine, are also FDA-approved. 
While most antidepressants including tricyclic antidepres
-
sants (TCAs) and monoamine oxidase (MAO) inhibitors 
are often effective in the treatment of anxiety disorders, 
their side effects and drug interactions make them second- 
or third-line agents. Bupropion may be the most anxiogenic 
antidepressant and has no clear usefulness in treatment of 
anxiety disorders. Buspirone, sometimes used as an aug
-
menting agent in the treatment of depression and compul
-
sive behaviors, is also effective for generalized anxiety. 
Buspirone is usually given in a total dose of 15–60 mg/day 
in three divided doses. Higher doses are sometimes associ
-
ated with side effects of gastrointestinal symptoms and diz
-
ziness. There is a 2- to 4-week delay before antidepressants 
and buspirone take effect, and patients require education 
regarding this lag. Sleep is sometimes negatively affected. 
Gabapentin (titrated to doses of 900–1800 mg orally daily) 
appears effective and lacks the habit-forming potential of 
the benzodiazepines. Unfortunately, like buspirone, many 
patients find gabapentin less effective than benzodiazepines 
in the management of acute anxiety. Beta-blockers, such as 
propranolol, may help reduce peripheral somatic symp
-
toms. Alcohol is the most frequently self-administered drug 
and should be interdicted.
2. Panic disorder—
Antidepressants are the first-line phar
-
macotherapy for panic disorder. Several SSRIs, including 
fluoxetine, paroxetine, and sertraline, are approved for the 
treatment of panic disorder. The SNRI venlafaxine is FDA 
approved for treatment of panic disorder. As with GAD, 
panic disorder is often a chronic condition; the long-term 
use of high-dose benzodiazepines can result in benzodiaz
-
epine dependence. While panic disorder often responds to 
high-potency benzodiazepines such as clonazepam and 
alprazolam, the best use of these agents is generally early in 
the course of treatment concurrently with an antidepres
-
sant. Once the antidepressant has begun working after 4 or 
more weeks, the benzodiazepine may be tapered.
Whether the indications for benzodiazepines are anxiety 
or insomnia, the medications should be used judiciously. The 
longer-acting benzodiazepines are used for the treatment of 
alcohol withdrawal and anxiety symptoms; the intermediate 
medications are useful as sedatives for insomnia (eg, loraze
-
pam), while short-acting agents (eg, midazolam) are used for 
medical procedures such as endoscopy.
The side effects of all the benzodiazepine antianxiety

-
The side effects of all the benzodiazepine antianxiety 
agents are patient and dose dependent. As the dosage 
exceeds the levels necessary for sedation, the side effects 
include disinhibition, ataxia, dysarthria, nystagmus, and 
delirium. (The patient should be told not to operate machin
-
ery and drive with caution until he or she is well stabilized 
without side effects.)
Paradoxical agitation, anxiety, psychosis, confusion, 
mood lability, and anterograde amnesia have been reported, 
particularly with the shorter-acting benzodiazepines. These 
agents produce cumulative clinical effects with repeated 
dosage (especially if the patient has not had time to metabo
-
lize the previous dose), additive effects when given with 
other classes of sedatives or alcohol, and residual effects 
after termination of treatment (particularly in the case of 
medications that undergo slow biotransformation).
Overdosage results in respiratory depression, hypoten
-
sion, shock syndrome, coma, and death. Flumazenil, a 
benzodiazepine antagonist, is effective in overdosage. 
Overdosage (see Chapter 38) and withdrawal states are 
medical emergencies
. Serious side effects of chronic exces
-
sive dosage are development of tolerance, resulting in 
increasing dose requirements, and physiologic depen
-
dence, resulting in withdrawal symptoms similar in appear
-
ance to alcohol and barbiturate withdrawal (withdrawal 
effects must be distinguished from reemergent anxiety). 
Abrupt withdrawal of sedative medications may cause seri
-
ous and even fatal convulsive seizures. Psychosis, delirium, 
and autonomic dysfunction have also been described. Both 
duration of action and duration of exposure are major fac
-
tors related to likelihood of withdrawal.
Common withdrawal symptoms after low to moderate 
daily use of benzodiazepines are classified as somatic (dis
-
turbed sleep, tremor, nausea, muscle aches), psychological 
(anxiety, poor concentration, irritability, mild depression), 
or perceptual (poor coordination, mild paranoia, mild con
-
fusion). The presentation of symptoms will vary depending 
on the half-life of the medication. Benzodiazepine interac
-
tions with other medications are listed in Table 25–2.
Antidepressants have been used in conjunction with beta-
blockers in resistant cases. Propranolol (40–160 mg/day 
orally) can mute the peripheral symptoms of anxiety without 
significantly affecting motor and cognitive performance. They 
block symptoms mediated by sympathetic stimulation (eg, 
palpitations, tremulousness) but not nonadrenergic symp
-
toms (eg, diarrhea, muscle tension). Contrary to common 
belief, they usually do 
not
 cause depression as a side effect and 
can be used cautiously in patients with depression.
3. Phobic disorders—
Social phobias and agoraphobia may 
be treated with SSRIs, such as paroxetine, sertraline, and 
fluvoxamine. In addition, phobic disorders often respond 
to SNRIs such as venlafaxine. Gabapentin, an antiseizure 
medication with anxiolytic properties, is an alternative to 
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antidepressants in the treatment of social phobia in a dos
-
age of 300–3600 mg/day, depending on response versus 
sedation. Specific phobias such as performance or test 
anxiety may respond to moderate doses of beta-blockers, 
such as propranolol, 20–40 mg 1 hour prior to exposure. 
Specific phobias tend to respond to behavioral therapies 
such as systematic desensitization, which is when the 
patient is gradually exposed to the feared object or situa
-
tion in a controlled setting. A meta-analysis has demon
-
strated that the antituberculous medication D-cycloserine 
(DCS) enhances extinction of fear responses with expo
-
sures. Importantly, such medications must be used in com
-
bination with cognitive behavioral exposure strategies.
B. Behavioral
Behavioral approaches are widely used in various anxiety 
disorders, often in conjunction with medication. Any of 
the behavioral techniques can be used beneficially in alter
-
ing the contingencies (precipitating factors or rewards) 
supporting any anxiety-provoking behavior. Relaxation 
techniques can sometimes be helpful in reducing anxiety. 
Desensitization, by exposing the patient to graded doses of 
a phobic object or situation, is an effective technique and 
one that the patient can practice outside the therapy ses
-
sion. Emotive imagery, wherein the patient imagines the 
anxiety-provoking situation while at the same time learn
-
ing to relax, helps decrease the anxiety when the patient 
faces the real-life situation. Physiologic symptoms in panic 
attacks respond well to relaxation training. Both GAD and 
panic disorder appear to respond as well to cognitive 
behavioral therapy as they do to medications.
Cognitive behavioral therapy
 is the first-line psychother
-
apy in treatment of panic disorder, GAD, and phobias 
when erroneous beliefs need correction. These approaches 
share a common cognitive component of examining the 
thoughts associated with the fear and behavioral technique 
of exposing the individual to the feared object or situation. 
The combination of medication and cognitive behavioral 
therapy is more effective than either alone. Mindfulness 
meditation can also be effective in decreasing symptoms of 
anxiety. Group therapy is the treatment of choice when the 
anxiety is clearly a function of the patient’s difficulties in 
dealing with social settings. Acceptance and commitment 
therapy has been used with some success in anxiety disor
-
ders. It encourages individuals to keep focused on life goals 
while they “accept” the presence of anxiety in their lives.
D. Social
Peer support groups for panic disorder and agoraphobia have 
been particularly helpful. Social modification may require 
measures such as family counseling to aid acceptance of the 
patient’s symptoms and avoid counterproductive behavior in 
behavioral training. Any help in maintaining the social struc
-
ture is anxiety-alleviating, and work, school, and social activi
-
ties should be maintained. School and vocational counseling 
may be provided by professionals, who often need help from 
the clinician in defining the patient’s limitations.
 
»
Prognosis
Anxiety disorders are usually long-standing and may be 
difficult to treat. All can be relieved to varying degrees with 
medications and behavioral techniques. Patients with panic 
disorder are less likely to respond to cognitive behavioral 
therapy if they have agoraphobia or if they think they have 
a low likelihood of improving with therapy. The prognosis 
is better if the commonly observed anxiety-panic-phobia-
depression cycle can be broken with a combination of the 
therapeutic interventions discussed above.
Craske MG et al. Anxiety. Lancet. 2016 Dec 17;388(10063):
 
3048–59. [PMID: 27349358]
Katzman MA et al; Canadian Anxiety Guidelines Initiative 
Group on behalf of the Anxiety Disorders Association of 
Canada and McGill University. Canadian clinical practice

Canada and McGill University. Canadian clinical practice 
guidelines for the management of anxiety, posttraumatic 
stress and obsessive-compulsive disorders. BMC Psychiatry. 
2014;14(Suppl 1):S1. [PMID: 25081580]
Pompoli A et al. Psychological therapies for panic disorder with 
or without agoraphobia in adults: a network meta-analysis. 
Cochrane Database Syst Rev. 2016 Apr 13;4:CD011004. 
[PMID: 27071857]
Porter E et al. A systematic review of predictors and moderators 
of improvement in cognitive-behavioral therapy for panic 
disorder and agoraphobia. Clin Psychol Rev. 2015 Dec;42:
 
179–92. [PMID: 26443228]
OBSESSIVE-COMPULSIVE DISORDER & 
RELATED DISORDERS
 
»
Preoccupations or rituals (repetitive psychologi
-
cally triggered behaviors) that are distressing to 
the individual.
 
»
Symptoms are excessive or persistent beyond 
potentially developmentally normal periods.
Table 25–2.
 
Benzodiazepine interactions with other 
medications (listed in alphabetical order).
Effects
Antacids
Decreased absorption of benzodiazepines
Increased half-life of diazepam and triazolam
Contraceptives
Increased levels of diazepam and triazolam
Digoxin
Alprazolam and diazepam raise digoxin level
Increased duration of action of sedatives
Isoniazid
Increased plasma diazepam
Levodopa
Inhibition of antiparkinsonism effect
Propoxyphene
Impaired clearance of diazepam
Rifampin
Decreased plasma diazepam
Warfarin
Decreased prothrombin time
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»
Obsessive-compulsive disorder (OCD), classified as an anxi
-
ety disorder in the 
DSM-IV ,
 now is part of a separate category 
of Obsessive-Compulsive Disorder and Related Disorders in 
DSM-
5. In OCD, the irrational idea or impulse repeatedly 
and unwantedly intrudes into awareness. 
Obsessions
 (recur
-
ring distressing thoughts, such as fears of exposure to 
germs) and 
compulsions
 (repetitive actions such as wash
-
ing the hands many times or cognitions such as counting 
rituals) are usually recognized by the individual as unwanted 
or unwarranted and are resisted, but anxiety often is allevi
-
ated only by ritualistic performance of the compulsion or by 
deliberate contemplation of the intruding idea or emotion. 
Some patients with OCD only experience obsessions, while 
some experience both obsessions and compulsions. Many 
patients do not volunteer the symptoms and must be asked 
about them. There is an overlapping of OCD with some 
features in other disorders (“OCD spectrum”), including 
tics, trichotillomania (hair pulling), excoriation disorder 
(skin picking), hoarding, and body dysmorphic disorder. 
The incidence of OCD in the general population is 2–3% 
and there is a high comorbidity with major depression: 
major depression will develop in two-thirds of OCD 
patients during their lifetime. Male to female ratios are 
similar, with the highest rates occurring in the young, 
divorced, separated, and unemployed (all high-stress cate
-
gories). Neurologic abnormalities of fine motor coordina
-
tion and involuntary movements are common. Under 
extreme stress, these patients sometimes exhibit paranoid 
and delusional behaviors, often associated with depression, 
and can mimic schizophrenia.
 
»
Treatment
OCD responds to serotonergic antidepressants including 
the SSRIs and clomipramine in about 60% of cases and usu
-
ally requires a longer time to response than depression (up 
to 12 weeks). Clomipramine has proved effective in doses 
equivalent to those used for depression. Fluoxetine has been 
widely used in this disorder but in doses higher than those 
used in depression (up to 60–80 mg orally daily). The other 
SSRI medications, such as sertraline, paroxetine, and flu
-
voxamine, are used with comparable efficacy each with its 
own side-effect profile. There is some evidence that antipsy
-
chotics and topiramate may be helpful as adjuncts to the 
SSRIs in treatment-resistant cases. Alternatively, low-dose 
clomipramine may be an effective adjunct to an SSRI in some 
patients, though caution should be used when prescribing 
multiple serotonergic agents given the risk of serotonin syn
-
drome. Plasma levels of clomipramine and its metabolite 
should be checked 2–3 weeks after a dosing of 50 mg/day has 
been achieved, with levels being kept under 500 ng/mL to 
avoid toxicity. Psychosurgery has a limited place in selected 
cases of severe unremitting OCD. Experimental work has 
suggested a role for deep brain stimulation in OCD and it is 
FDA approved on a humanitarian device exemption basis for 
refractory OCD patients.
OCD may respond to a variety of behavioral techniques. 
One common strategy is systematic desensitization. As in 
the treatment of simple phobias, systematic desensitization 
involves gradually exposing the OCD spectrum patient to 
situations that the patient fears, such as perceived germs or 
situations that a hoarder must part with things they are 
hoarding. By gradually exposing patients to increasingly 
stressful situations and helping them manage their anxiety 
without performing the unwanted behavior, OCD spec
-
trum patients are often able to develop some mastery over 
the behaviors.
In addition to behavioral techniques, OCD may respond to 
psychological therapies including cognitive behavioral 
therapy in which the patient learns to identify maladaptive

therapy in which the patient learns to identify maladaptive 
cognitions associated with obsessive thoughts and chal
-
lenge those cognitions. For example, an OCD patient may 
fear that if he does not wash his hands 50 times after shak
-
ing hands, he or someone close to him might develop a 
serious disease. These cognitions can be identified and 
gradually replaced with more rational thoughts. A tech
-
nique used to help quell obsessive thoughts is “thought 
stopping. ” In this technique, the patient is taught to identify 
an obsessive thought and then to derail it. For example, the 
patient may be taught to say 
“
STOP” any time an obsessive 
thought is present. In time, thought stopping can mitigate 
some of the obsessive thoughts.
D. Social
OCD can have devastating effects on the ability of a patient 
to lead a normal life. Educating both the patient and family 
about the course of illness and treatment options is 
extremely useful in setting appropriate expectations. Severe 
OCD is commonly associated with vocational disability, 
and the clinician may sometimes need to facilitate a leave 
of absence from work or encourage vocational rehabilita
-
tion to get the patient back to work.
 
»
Prognosis
OCD is usually a chronic disorder with a waxing and wan
-
ing course. As many as 40% of patients in whom OCD 
problems develop in childhood will experience remission 
as adults. However, it is less common for OCD to remit 
without treatment when it develops during adulthood.
Pepper J et al. Deep brain stimulation versus anterior capsulot
-
omy for obsessive-compulsive disorder: a review of the litera
-
ture. J Neurosurg. 2015 May;122(5):1028–37. [PMID: 
25635480]
FEEDING & EATING DISORDERS
See Chapters 29 and e6.
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SOMATIC SYMPTOM DISORDERS 
 
(
Abnormal Illness Behaviors
)
 
»
Prominent physical symptoms may involve one or 
more organ systems and are associated with dis
-
tress, impairment, or both.
 
»
Sometimes able to correlate symptom develop
-
ment with psychosocial stresses.
 
»
Combination of biogenetic and developmental 
patterns.
 
»
Any organ system can be affected in somatic symptom 
disorders. In 
DSM-5
, somatic symptom disorders encom
-
pass disorders that were listed under somatic disorders in 
DSM-IV
, including conversion disorder, hypochondriasis, 
somatization disorder, and pain disorder secondary to psy
-
chological factors. Vulnerability in one or more organ sys
-
tems and exposure to family members with somatization 
problems plays a major role in the development of particu
-
lar symptoms, and the “functional” versus “organic” 
dichotomy is a hindrance to good treatment. Clinicians 
should suspect psychiatric disorders in a number of condi
-
tions. For example, 45% of patients describing palpitations 
had lifetime psychiatric diagnoses including generalized 
anxiety, depression, panic, and somatic symptom disor
-
ders. Similarly, 33–44% of patients who undergo coronary 
angiography for chest pain but have negative results have 
been found to have panic disorder.
In any patient presenting with a condition judged to be 
somatic symptom disorder, depression must be considered 
in the diagnosis.
 
»
A. Conversion Disorder (Functional Neurologic 
Symptom Disorder)
“Conversion” of psychic conflict into physical neurologic 
symptoms in parts of the body innervated by the senso
-
rimotor system (eg, paralysis, aphonic) is a disorder that 
commonly occurs concomitantly with panic disorder or 
depression. The somatic manifestation that takes the place 
of anxiety is often paralysis, and in some instances the 
dysfunction may have symbolic meaning (eg, arm paralysis 
in marked anger so the individual cannot use the arm to 
strike someone). Nonepileptic seizures can be difficult to 
differentiate from intoxication states or panic attacks and 
can occur in patients who also have epileptic seizures. Lack 
of postictal confusion, closed eyes during the seizure, ictal 
crying, and a fluctuating course can suggest nonepileptic 
seizures; some symptoms such as asynchronous move
-
ments or pelvic thrusting can occur in both nonepileptic 
seizures and frontal lobe seizures. Electroencephalography, 
particularly in a video-electroencephalography assessment 
unit, during the attack is the most helpful diagnostic aid in 
excluding epileptic seizures. A serum prolactin levels rise 
more than twice baseline abruptly in the postictal state is 
more likely to be associated with an epileptic seizure. La 
belle indifférence (an unconcerned affect) is not a signifi
-
cant identifying characteristic, as commonly believed, 
since individuals even with genuine medical illness may 
exhibit a high level of denial. It is important to identify 
physical disorders with unusual presentations (eg, multiple 
sclerosis, systemic lupus erythematosus).
B. Somatic Symptom Disorder
Somatic symptom disorder is characterized by one or more 
somatic symptoms that are associated with significant dis
-
tress or disability. The somatic symptoms are associated with 
disproportionate and persistent thoughts about the serious
-
ness of the symptoms, a high level of anxiety about health, or 
excessive time and energy devoted to these symptoms. The 
patient’s focus on somatic symptoms is usually chronic. 
Panic, anxiety, and depression are often present, and major 
depression is an important consideration in the differential 
diagnosis. There is a significant relationship (20%) to a life
-
time history of panic-agoraphobia-depression. It usually 
occurs before age 30 and is ten times more common in 
women. Preoccupation with medical and surgical therapy

-
women. Preoccupation with medical and surgical therapy 
becomes a lifestyle that may exclude other activities. Patients 
most often first present to primary care phycians and experi
-
ence reassurance regarding their physical condition as only 
briefly helpful or dismissive. Patients’ complaints of symp
-
toms should always be first carefully medically evaluated.
C. Factitious Disorders
These disorders, in which symptom production is 
inten
-
tional
, are not somatic symptom conditions in that symptoms 
are produced consciously, in contrast to the unconscious 
process of the other somatic symptom disorders. They are 
characterized by self-induced or described symptoms or false 
physical and laboratory findings for the purpose of deceiving 
clinicians or other health care personnel. The deceptions may 
involve self-mutilation, fever, hemorrhage, hypoglycemia, 
seizures, and an almost endless variety of manifestations—
often presented in an exaggerated and dramatic fashion 
(Munchausen syndrome).
 Factitious disorder imposed on 
another, previously termed “Munchausen by proxy” is diag
-
nosed when someone (often a parent) creates an illness in 
another person (often a child) for perceived psychological 
benefit of the first person, such as sympathy or a relationship 
with clinicians. The duplicity may be either simple or 
extremely complex and difficult to recognize. The patients 
are frequently connected in some way with the health profes
-
sions and there is no apparent external motivation other than 
achieving the patient role. A poor clinician-patient relation
-
ship and “doctor shopping” tend to exacerbate the problem.
 
»
Sedative and analgesic dependency is the most common 
iatrogenic complication. Patients may pursue medical or 
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surgical treatments that induce iatrogenic problems. Thus, 
identifying patients with a potential somatic symptom dis
-
order and attempting to limit tests, procedures, and medi
-
cations that may lead to harm is quite important.
 
»
Treatment
A. Medical
Medical support with careful attention to building a thera
-
peutic clinician-patient relationship is the mainstay of 
treatment. It must be accepted that the patient’s distress is 
real. 
Every problem not found to have an organic basis is not 
necessarily a mental disease
. Diligent attempts should be 
made to relate symptoms to adverse developments in the 
patient’s life. It may be useful to have the patient keep a 
meticulous diary, paying particular attention to various 
pertinent factors evident in the history. Regular, frequent, 
short appointments that are not symptom-contingent may 
be helpful. Medications (frequently abused) should not be 
prescribed to replace appointments. One person should be 
the primary clinician, and consultants should be used 
mainly for evaluation. An empathic, realistic, optimistic 
approach must be maintained in the face of the expected 
ups and downs. Ongoing reevaluation is necessary, since 
somatization can coexist with a concurrent physical 
illness.
B. Psychological
The primary clinician can use psychological approaches 
when it is clear that the patient is ready to make some 
changes in lifestyle in order to achieve symptomatic relief. 
This is often best approached with orientation toward 
pragmatic current changes rather than an exploration of 
early experiences that the patient frequently fails to relate 
to current distress. Group therapy with other individuals 
who have similar problems is sometimes of value to 
improve coping, allow ventilation, and focus on interper
-
sonal adjustment. Hypnosis used early can be helpful in 
resolving conversion disorders. If the primary clinician has 
been working with the patient on psychological problems 
related to the physical illness, the groundwork is often laid 
for successful psychiatric referral.
For patients who have been identified as having a fac
-
titious disorder, early psychiatric consultation is indi
-
cated. There are two main treatment strategies for these 
patients. One consists of a conjoint confrontation of the 
patient by both the primary clinician and the psychiatrist. 
The patient’s disorder is portrayed as a cry for help, and 
psychiatric treatment is recommended. The second 
approach avoids direct confrontation and attempts to 
provide a face-saving way to relinquish the symptom 
without overt disclosure of the disorder’s origin. Tech
-
niques such as biofeedback and self-hypnosis may foster 
recovery using this strategy. Another face-saving approach 
is to use a double bind with the patient. For example, the 
patient is told there are two possible diagnoses: (1) an 
organic disease that should respond to the next medical 
intervention (usually modest and noninvasive), or (2) 
factitious disorder for which the patient will need psychi
-
atric treatment. Given these options, many patients will 
choose to recover and not have to admit the origin of 
their problem.
C. Behavioral
Behavioral therapy is probably best exemplified by biofeed
-
back techniques. In biofeedback, the particular abnormality 
(eg, increased peristalsis) must be recognized and moni
-
tored by the patient and therapist (eg, by an electronic 
stethoscope to amplify the sounds). This is immediate 
feedback, and after learning to recognize it, the patient can 
then learn to identify any change thus produced (eg, a 
decrease in bowel sounds) and so become a conscious origi
-
nator of the feedback instead of a passive recipient. Relief of 
the symptom operantly conditions the patient to utilize the 
maneuver that relieves symptoms (eg, relaxation causing a 
decrease in bowel sounds). With emphasis on this type of 
learning, the patient is able to identify symptoms early and

learning, the patient is able to identify symptoms early and 
initiate the countermaneuvers, thus decreasing the symp
-
tomatic problem. Migraine and tension headaches have 
been particularly responsive to biofeedback methods.
D. Social
Social endeavors include family, work, and other interper
-
sonal activity. Family members should come for some 
appointments with the patient so they can learn how best 
to live with the patient. This is particularly important in 
treatment of somatic and pain disorders. Peer support 
groups provide a climate for encouraging the patient to 
accept and live with the problem. Ongoing communication 
with the employer may be necessary to encourage long-
term continued interest in the employee. Employers can 
become just as discouraged as clinicians in dealing with 
employees who have chronic problems.
 
»
Prognosis
The prognosis is better if the primary clinician is able to 
intervene early before the situation has deteriorated. After 
the problem has crystallized into chronicity, it is more dif
-
ficult to effect change.
Katz J et al. Chronic pain, psychopathology, and DSM-5 somatic 
symptom disorder. Can J Psychiatry. 2015 Apr;60(4):160–7. 
[PMID: 26174215]
Tavel ME. Somatic symptom disorders without known physical 
causes: one disease with many names? Am J Med. 2015 Oct;
 
128(10):1054–8. [PMID: 26031885]
CHRONIC PAIN DISORDERS
 
»
Chronic complaints of pain.
 
»
Symptoms frequently exceed signs.
 
»
Minimal relief with standard treatment.
 
»
History of having seen many clinicians.
 
»
Frequent use of several nonspecific medications.
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»
A problem in the management of pain is the lack of dis
-
tinction between acute and chronic pain syndromes. Most 
clinicians are adept at dealing with acute pain problems 
but face greater challenges in treating a patient with a 
chronic pain disorder. Patients with chronic pain can fre
-
quently takes many medications, stay in bed a great deal, 
have seen many clinicians, have lost skills, and experience 
little joy in either work or play. All relationships suffer 
(including those with clinicians), and life becomes a con
-
stant search for relief. The search results in complex clini
-
cian-patient relationships that usually include many 
medication trials, particularly sedatives, with adverse 
consequences (eg, irritability, depressed mood) related to 
long-term use. Treatment failures provoke angry responses 
and depression from both the patient and the clinician, 
and the pain syndrome is exacerbated. When frustration 
becomes too great, a new clinician is found, and the cycle 
is repeated. The longer the existence of the pain disorder, 
the more important become the psychological factors of 
anxiety and depression. As with all other conditions, it is 
counterproductive to speculate about whether the pain is 
“real. ” It is real to the patient, and acceptance of the prob
-
lem must precede a mutual endeavor to alleviate the 
 
»
Components of the chronic pain syndrome consist of ana
-
tomic changes, chronic anxiety and depression, anger, and 
changed lifestyle. Usually, the anatomic problem is irrevers
-
ible, since it has already been subjected to many interven
-
tions with increasingly unsatisfactory results. An algorithm 
for assessing chronic pain and differentiating it from other 
psychiatric conditions is illustrated in Figure 25–1.
Chronic anxiety and depression produce heightened 
irritability and overreaction to stimuli. A marked decrease 
in pain threshold is apparent. This pattern develops into a 
preoccupation with the body and a constant need for reas
-
surance. Patients may have started avoiding usual behav
-
iors when they first developed pain, and then chronic 
avoidance of usual physical functioning can lead to the 
development of chronic pain. The pressure on the clinician 
complaints
Are symptoms and complaints
appropriate 
to
 the se
ve
ri
ty
 of disease?
Abnormal illness
behavior present
Fails 
to
respond well
P
sy
chiatric 
ev
aluation
for diagnosis of
comorbid psychiatric
disorders:
  • Depr
ession
  • P
anic or anxiety
  • P
osttraumatic
    stress disorder
Abnormal illness behaviors with
symptoms produced unconsciously:
  • Somatization disor
der
  • Hypochondr
iasis
  • P
ain disorder with psychological factors
Responds well
No p
sy
chiatric
ev
aluation
necessary
Is the motivation
for the behavior
apparent 
to
 the
clinician?
to
 assume the
patient role?
P
sy
chiatric treatment
(concurrently with
medical treatment)
physical
disorder
No
No
Do s
ymptoms appear 
to
 be
produced on a voluntary
(conscious) basis?
Ye
s
Ye
s
Medical treatment
 
▲
Figure 25–1.
 
Algorithm for assessing psychiatric component of chronic pain. 
(Adapted and reproduced, with 
permission, from Eisendrath SJ. Psychiatric aspects of chronic pain. Neurology. 1995 Dec;45(12 Suppl 9):S26–34.)
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becomes wearing and often leads to covert rejection of the 
patient, such as not being available or making referrals to 
This is perceived by the patient, who then intensifies 
the effort to find help, and the typical cycle is repeated. 
Anxiety and depression are seldom discussed, almost as if 
there is a tacit agreement not to deal with these issues.
Changes in lifestyle involve some of the pain behaviors. 
These usually take the form of a family script in which the 
patient accepts the role of being sick, and this role then 
becomes the focus of most family interactions and may 
become important in maintaining the family, so that nei
-
ther the patient nor the family wants the patient’s role to 
change. Cultural factors frequently play a role in the behav
-
ior of the patient and how the significant people around the 
patient cope with the problem. Some cultures encourage 
demonstrative behavior, while others value the stoic role.
Another secondary gain that can maintain the patient 
in the sick role is financial compensation or other benefits. 
Frequently, such systems are structured so that they rein
-
force the maintenance of sickness and discourage any 
attempts to give up the role. Clinicians unwittingly rein
-
force this role because of the very nature of the practice of 
medicine, which is to respond to complaints of illness. 
Helpful suggestions from the clinician are often met with 
responses like, “Y es, but…. ” Medications then become the 
principal approach, and drug dependency problems may 
develop.
 
»
Treatment
The cornerstone of a unified approach to chronic pain 
syndromes is a comprehensive behavioral program. This is 
necessary to identify and eliminate pain reinforcers, to 
decrease medication use, and to use effectively those posi
-
tive reinforcers that shift the focus from the pain. It is criti
-
cal that the patient be made a partner in the effort to 
manage and function better in the setting of ongoing pain 
symptoms. The clinician must shift from the idea of bio
-
medical cure to ongoing care of the patient. The patient 
should agree to discuss the pain only with the clinician and 
not with family members; this tends to stabilize the 
patient’s personal life, since the family is usually tired of the 
subject. At the beginning of treatment, the patient should 
be assigned self-help tasks graded up to maximal activity as 
a means of positive reinforcement. The tasks should not 
exceed capability. The patient can also be asked to keep a 
self-rating chart to log accomplishments, so that progress 
can be measured and remembered. Instruct the patient to 
record degrees of pain on a self-rating scale in relation to 
various situations and mental attitudes so that similar cir
-
cumstances can be avoided or modified.
Avoid positive reinforcers for pain such as marked sym
-
pathy and attention to pain. Emphasize a positive response 
to productive activities, which remove the focus of atten
-
tion from the pain. Activity is also desensitizing, since the 
patient learns to tolerate increasing activity levels.
Biofeedback techniques (see Somatic Symptom Disor
-
ders, above) and hypnosis have been successful in 
ameliorating some pain syndromes. Hypnosis tends to be 
most effective in patients with a high level of denial, who 
are more responsive to suggestion. Hypnosis can be used to 
lessen anxiety, alter perception of the length of time that 
pain is experienced, and encourage relaxation. Mindful
-
ness-based stress reduction programs have been useful in 
helping individuals develop an enhanced capacity to live a 
higher quality life with persistent pain.
B. Medical
A 
single clinician
 in charge of the comprehensive treatment 
approach is the highest priority. Consultations as indicated 
and technical procedures done by others are appropriate, 
but the care of the patient should remain in the hands of

but the care of the patient should remain in the hands of 
the primary clinician. Referrals should not be allowed to 
raise the patient’s hopes unrealistically or to become a way 
for the clinician to reject the case. The attitude of the clini
-
cian should be one of honesty, interest, and hopefulness—
not for a cure but for control of pain and improved 
function. If the patient manifests opioid addiction, detoxi
-
fication may be an early treatment goal.
Medical management of chronic pain is addressed in 
Chapter 5. 
The harms of opioids generally outweigh the ben
-
efits in chronic pain management
. A fixed schedule lessens 
the conditioning effects of these medications. SNRIs (eg, 
venlafaxine, milnacipran, and duloxetine) and TCAs (eg, 
nortriptyline), in doses up to those used in depression may 
be helpful, particularly in neuropathic pain syndromes. 
Both duloxetine and milnacipran are approved for the 
treatment of fibromyalgia; duloxetine is also indicated in 
chronic pain conditions. In general, the SNRIs tend to be 
safer in overdose than the TCAs; suicidality is often an 
important consideration in treating patients with chronic 
pain syndromes. Gabapentin and pregabalin, anticonvul
-
sants with possible applications in the treatment of anxiety 
disorders, have been shown to be useful in somatic symp
-
tom disorders and fibromyalgia.
In addition to medications, a variety of nonpharmaco
-
logic strategies may be offered, including physical therapy 
and acupuncture.
C. Social
Involvement of family members and other significant per
-
sons in the patient’s life should be an early priority. The 
best efforts of both patient and therapists can be unwit
-
tingly sabotaged by other persons who may feel that they 
are “helping” the patient. They frequently tend to reinforce 
the negative aspects of the chronic pain disorder. The 
patient becomes more dependent and less active, and 
the pain syndrome becomes an immutable way of life. The 
more destructive pain behaviors described by many experts 
in chronic pain disorders are the results of well-meaning 
but misguided efforts of family members. Ongoing therapy 
with the family can be helpful in the early identification 
and elimination of these behavior patterns.
D. Psychological
In addition to group therapy with family members and 
others, groups of patients can be helpful if properly led. 
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The major goal, whether of individual or group therapy, is 
to gain patient involvement. A group can be a powerful 
instrument for achieving this goal, with the development of 
group loyalties and cooperation. People will frequently 
make efforts with group encouragement that they would 
never make alone. Individual therapy should be directed 
toward strengthening existing coping mechanisms and 
improving self-esteem. For example, teaching patients to 
challenge expectations induced by chronic pain may lead 
to improved functioning. As an illustration, many chronic 
pain patients, making assumptions more derived from 
acute injuries, incorrectly believe they will damage them
-
selves by attempting to function. The rapport between 
patient and clinician, as in all psychotherapeutic efforts, is 
the major factor in therapeutic success.
Dale R et al. Multimodal treatment of chronic pain. Med Clin 
North Am. 2016 Jan;100(1):55–64. [PMID: 26614719]
Derry S et al. Nortriptyline for neuropathic pain in adults. 
Cochrane Database Syst Rev. 2015 Jan 8;1:CD011209. [PMID: 
25569864]
Mills S et al. Identification and management of chronic pain in 
primary care: a review. Curr Psychiatry Rep. 2016 Feb;18(2):22. 
[PMID: 26820898]
PSYCHOSEXUAL DISORDERS
The stages of sexual activity include 
excitement
 (arousal), 
orgasm,
 and 
 The precipitating excitement or 
arousal is psychologically determined. Arousal response 
leading to orgasm is a physiologic and psychological phe
-
nomenon of vasocongestion, a parasympathetic reaction 
causing erection in men and labial-clitoral congestion in 
women. The orgasmic response includes emission in men 
and clonic contractions of the analogous striated perineal 
muscles of both men and women. Resolution is a gradual 
return to normal physiologic status.
While the arousal stimuli—vasocongestive and orgas
-
mic responses—constitute a single response in a well-
adjusted person, they can be considered as separate stages 
that can produce different syndromes responding to differ
-
ent treatment procedures.
 
»
There are three major groups of sexual disorders.
A. Paraphilias
In these conditions, formerly called “deviations” or “variations, ” 
the excitement stage of sexual activity is associated with 
sexual objects or orientations different from those usually 
associated with adult sexual stimulation. The stimulus may 
be a woman’s shoe, a child, animals, instruments of tor
-
ture, or incidents of aggression. The pattern of sexual 
stimulation is usually one that has early psychological 
roots. When paraphilias are associated with distress, 
impairment, or risk of harm, they become paraphilic dis
-
orders. Some paraphilias or paraphilic disorders include 
exhibitionism, transvestism, voyeurism, pedophilia, incest, 
sexual sadism, and sexual masochism.
B. Gender Dysphoria
Gender dysphoria is the strong desire to be or the insis
-
tence that one is a gender other than the one assigned at 
birth. As a disorder, it is associated with significant distress 
or impairment. Screening should be done for conditions 
related to the oppression and stigmatization that transgen
-
der people face.
C. Sexual Dysfunctions
This category includes a large group of vasocongestive and 
orgasmic disorders. Often, they involve problems of sexual 
adaptation, education, and technique that are often initially 
discussed with, diagnosed by, and treated by the primary 
care provider.
There are two conditions common in men: erectile 
dysfunction and ejaculation disturbances.
 is inability to achieve or maintain 
an erection firm enough for satisfactory intercourse; 
patients sometimes use the term to mean premature ejacu
-
lation. Decreased nocturnal penile tumescence occurs in

-
lation. Decreased nocturnal penile tumescence occurs in 
some depressed patients. Psychological erectile dysfunc
-
tion is caused by interpersonal or intrapsychic factors (eg, 
partner disharmony, depression). Organic factors are dis
-
cussed in Chapter 23.
Ejaculation disturbances
 include premature ejacula
-
tion, inability to ejaculate, and retrograde ejaculation. 
(Ejaculation is possible in patients with erectile dysfunc
-
tion.) Ejaculation is usually connected with orgasm, and 
ejaculatory control is an acquired behavior that is minimal 
in adolescence and increases with experience. Pathogenic 
factors are those that interfere with learning control, most 
frequently sexual ignorance. Intrapsychic factors (anxiety, 
guilt, depression) and interpersonal maladaptation (part
-
ner problems, unresponsiveness of mate, power struggles) 
are also common. Organic causes include interference with 
sympathetic nerve distribution (often due to surgery or 
radiation) and the effects of pharmacologic agents (eg, 
SSRIs or sympatholytics).
In women, the most common forms of sexual dysfunc
-
tion are orgasmic disorder and hyposexual desire disorder 
(see Chapter 18).
Orgasmic disorder
 is a complex condition in which 
there is a general lack of sexual responsiveness. The woman 
has difficulty in experiencing erotic sensation and does not 
have the vasocongestive response. Sexual activity varies 
from active avoidance of sex to an occasional orgasm. 
Orgasmic dysfunction
—in which a woman has a vasocon
-
gestive response but varying degrees of difficulty in reach
-
ing orgasm—is sometimes differentiated from 
anorgasmia.
 
Causes for the dysfunctions include poor sexual tech
-
niques, early traumatic sexual experiences, interpersonal 
disharmony (partner struggles, use of sex as a means of 
control), and intrapsychic problems (anxiety, fear, guilt). 
Organic causes include any conditions that might cause 
pain in intercourse, pelvic pathology, mechanical obstruc
-
tion, and neurologic deficits.
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Hyposexual desire disorder
 consists of diminished or 
absent libido in either sex and may be a function of organic 
or psychological difficulties (eg, anxiety, phobic avoid
-
ance). Any chronic illness can reduce desire as can aging. 
Hormonal disorders, including hypogonadism or use of 
antiandrogen compounds such as cyproterone acetate, and 
chronic kidney disease contribute to deterioration in sex
-
ual desire. Although menopause may lead to diminution of 
sexual desire in some women, the relationship between 
menopause and libido is complicated and may be influ
-
enced by sociocultural factors. Alcohol, sedatives, opioids, 
marijuana, and some medications may affect sexual drive 
and performance.
 
»
Treatment
1. Psychological—
Paraphilias, particularly those of a more 
superficial nature (eg, voyeurism) and those of recent 
onset, are responsive to psychotherapy in some cases. The 
prognosis is much better if the motivation comes from the 
individual rather than the legal system; unfortunately, judi
-
cial intervention is frequently the only stimulus to treat
-
ment because the condition persists and is reinforced until 
conflict with the law occurs. Therapies frequently focus on 
barriers to normal arousal response; the expectation is that 
the variant behavior will decrease as normal behavior 
increases.
2. Behavioral—
In some cases, paraphilic disorders 
improve with modeling, role-playing, and conditioning 
3. Social—
Although they do not produce a change in sex
-
ual arousal patterns or gender role, self-help groups have 
facilitated adjustment to an often hostile society. Attention 
to the family is particularly important in helping people in 
such groups to accept their situation and alleviate their 
guilt about the role they think they had in creating the 
problem.
4. Pharmacologic—
Medroxyprogesterone acetate, a sup
-
pressor of libidinal drive, can be used to mute disruptive 
sexual behavior in men. Onset of action is usually within 
 
3 weeks, and the effects are generally reversible. Fluoxetine 
or other SSRIs at depression doses may reduce some of the 
compulsive sexual behaviors including the paraphilias. A 
focus of study in the treatment of severe paraphilia has 
been agonists of luteinizing hormone–releasing hormone 
(LHRH). Case reports and open label studies suggest that 
LHRH-agonists may play a role in preventing relapse in 
some patients with paraphilia.
Individuals with gender dysphoria 
often find benefit from psychotherapy, providing them 
with a safe place to explore and understand their thoughts 
and feelings, and to identify their own specific needs and 
desires and adjust to a changing life.
2. Social—
Peer support groups, parent psychoeducation 
and support, and community empowerment are important 
social components of treatment.
3. Medical—
The standard of care recommendations for 
eligibility for hormone therapy and surgery are that the 
gender dysphoria is persistent, the individual has capacity 
to consent to treatment, and medical or mental health 
symptoms are reasonably managed. A year of hormone 
therapy is recommended before gonadectomy, and living 
for a year as their gender identity is recommended for 
those seeking genital reconstructive surgery. Rates of sui
-
cide fall significantly after surgery but still remain much 
higher than the general population.
C. Sexual Dysfunction
1. Medical—
Even if the condition is not reversible, identifica
-
tion of the specific cause helps the patient to accept the condi
-
tion. Partner disharmony, with its exacerbating effects, may 
thus be avoided. Of all the sexual dysfunctions, erectile dys
-
function is the condition most likely to have an organic basis. 
Sildenafil, tadalafil, and vardenafil are phosphodiesterase type 
5 inhibitors that are effective oral agents for the treatment of 
penile erectile dysfunction (eg, sildenafil 25–100 mg orally

penile erectile dysfunction (eg, sildenafil 25–100 mg orally 
 
1 hour prior to intercourse). These agents are effective for 
SSRI-induced erectile dysfunction in men and in some cases 
for SSRI-associated sexual dysfunction in women. Use of the 
medications in conjunction with any nitrates can have signifi
-
cant hypotensive effects leading to death in rare cases. Because 
of their common effect in delaying ejaculation, the SSRIs have 
been effective in premature ejaculation.
Flibanserin is a 5-HT
1A
-agonist/5-HT
2
-antagonist that 
is FDA approved for the treatment of female hyposexual 
desire disorder. This is the first medication marketed to 
improve sexual desire in women. The data suggest that 
compared to placebo, women treated with flibanserin have 
a marginally higher number of sexual events. The medica
-
tion interacts with alcohol, causing hypotensive events, so 
patients need to be educated about this risk. Flibanserin is 
taken 100 mg orally at bedtime to circumvent the side 
effects of dizzinesss, sleepiness, and nausea.
Syndromes resulting from conditioned 
responses have been treated by conditioning techniques, 
with excellent results. Masters and Johnson have used 
behavioral approaches in all of the sexual dysfunctions, with 
concomitant supportive psychotherapy and with improve
-
ment of the communication patterns of the couple.
3. Psychological—
The use of psychotherapy by itself is 
best suited for those cases in which interpersonal difficul
-
ties or intrapsychic problems predominate. Anxiety and 
guilt about parental injunctions against sex may contribute 
to sexual dysfunction. Even in these cases, however, a com
-
bined behavioral-psychological approach usually produces 
results most quickly.
4. Social—
The proximity of other people (eg, a mother-in-
law) in a household is frequently an inhibiting factor in 
sexual relationships. In such cases, some social engineering 
may alleviate the problem.
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Jaspers L et al. Efficacy and safety of flibanserin for the treatment 
of hypoactive sexual desire disorder in women: a systematic 
review and meta-analysis. JAMA Intern Med. 2016. Apr;
 
176(4):453–62. [PMID: 26927498]
Wylie K et al. Serving transgender people: clinical care consider
-
ations and service delivery models in transgender health. 
Lancet. 2016 Jul 23;388(10042):401–11. [PMID: 27323926]
PERSONALITY DISORDERS
 
»
Long history dating back to childhood.
 
»
Recurrent maladaptive behavior.
 
»
Difficulties with interpersonal relationships or 
society.
 
»
Depression with anxiety when maladaptive 
behavior fails.
 
»
An individual’s personality structure, or character, is an inte
-
gral part of self-image. It reflects genetics, interpersonal influ
-
ences, and recurring patterns of behavior adopted in order to 
cope with the environment. The classification of subtypes of 
personality disorders depends on the predominant symptoms 
and their severity. The most severe disorders—those that 
bring the patient into greatest conflict with society—tend to 
be antisocial (psychopathic) or borderline.
 
»
Classification & Clinical Findings
See Table 25–3.
Table 25–3.
 
Personality disorders: Classification and clinical findings (listed in alphabetical order).
Personality Disorder
Antisocial
Selfish, callous, promiscuous, impulsive, unable to learn from experience, often has legal problems.
Avoidant
Fears rejection, hyperreacts to rejection and failure, with poor social endeavors and low self-esteem.
Borderline
Impulsive; has unstable and intense interpersonal relationships; is suffused with anger, fear, and guilt; lacks 
 
self-control and self-fulfillment; has identity problems and affective instability; is suicidal (a serious problem—up 
to 80% of hospitalized borderline patients make an attempt at some time during treatment, and the incidence of 
completed suicide is as high as 5%); aggressive behavior, feelings of emptiness, and occasional psychotic 
decompensation.
Dependent
Passive, overaccepting, unable to make decisions, lacks confidence, with poor self-esteem.
Histrionic (hysterical)
Dependent, immature, seductive, egocentric, vain, emotionally labile.
Narcissistic
Exhibitionist, grandiose, preoccupied with power, lacks interest in others, with excessive demands for attention.
Obsessive compulsive
Perfectionist, egocentric, indecisive, with rigid thought patterns and need for control.
Paranoid
Defensive, oversensitive, secretive, suspicious, hyperalert, with limited emotional response.
Schizoid
Shy, introverted, withdrawn, avoids close relationships.
Schizotypal
Superstitious, socially isolated, suspicious, with limited interpersonal ability, eccentric behaviors, and odd speech.
 
»
Patients with personality disorders tend to experience 
anxiety and depression when pathologic coping mecha
-
nisms fail and may first seek treatment when this occurs. 
Occasionally, the more severe cases may decompensate 
into psychosis under stress and mimic other psychotic 
 
»
Treatment
A. Social
Social and therapeutic environments such as day hospitals, 
halfway houses, and self-help communities utilize peer 
“pressure” to modify the self-destructive behavior. The 
patient with a personality disorder often has failed to profit 
from experience, and difficulties with authority can impair 
the learning experience. The use of peer relationships and 
the repetition possible in a structured setting of a helpful 
community enhance the behavioral treatment opportuni
-
ties and increase learning. When problems are detected 
early, both the school and the home can serve as foci of 
intensified social pressure to change the behavior, particu
-

-
-
larly with the use of behavioral techniques.
The behavioral techniques used are principally 
operant 
conditioning
 and 
aversive conditioning.
 The former sim
-
ply emphasizes the recognition of acceptable behavior and 
its reinforcement with praise or other tangible rewards. 
Aversive responses usually mean punishment, although 
this can range from a mild rebuke to some specific punitive 
responses such as deprivation of privileges. Extinction 
plays a role in that an attempt is made not to respond to 
inappropriate behavior, and the lack of response eventually 
causes the person to abandon that type of behavior. Pout
-
ing and tantrums, for example, diminish quickly when 
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such behavior elicits no reaction. These traits are less likely 
to develop in children at risk for development of antisocial 
tendencies due to a genetic predisposition when they are 
given positive reinforcement for positive behaviors. Dialec
-
tical behavioral therapy is a program of individual and 
group therapy specifically designed for patients with 
chronic suicidality and borderline personality disorder. It 
blends mindfulness and a cognitive-behavioral model to 
address self-awareness, interpersonal functioning, affective 
lability, and reactions to stress.
Psychological interventions can be conducted in group and 
individual settings. Group therapy is helpful when specific 
interpersonal behavior needs to be improved. This mode of 
treatment also has a place with so-called “acting-out” 
patients, ie, those who frequently act in an impulsive and 
inappropriate way. The peer pressure in the group tends to 
impose restraints on rash behavior. The group also quickly 
identifies the patient’s types of behavior and helps improve 
the validity of the patient’s self-assessment, so that the ante
-
cedents of the unacceptable behavior can be effectively 
handled, thus decreasing its frequency. Individual therapy 
should initially be supportive, ie, helping the patient to 
restabilize and mobilize coping mechanisms. If the indi
-
vidual has the ability to observe his or her own behavior, a 
longer-term and more introspective therapy may be war
-
ranted. The therapist must be able to handle countertrans
-
ference feelings (which are frequently negative), maintain 
appropriate boundaries in the relationship (no physical 
contact, however well-meaning), and refrain from prema
-
ture confrontations and interpretations.
Hospitalization is indicated in the case of serious suicidal or 
homicidal danger. In most cases, treatment can be accom
-
plished in the day treatment center or self-help community. 
Pharmacotherapy should be directed to specific symptom 
clusters. Antidepressants have improved anxiety, depres
-
sion, and sensitivity to rejection in some patients with bor
-
derline personality disorder. SSRIs also have a role in 
reducing aggressive behavior in impulsive aggressive 
patients (eg, fluoxetine 20–60 mg orally daily or sertraline 
50–200 mg orally daily). Antipsychotics may be helpful in 
targeting hostility, agitation, and as adjuncts to antidepres
-
sant therapy (eg, olanzapine [2.5–10 mg/day orally], risperi
-
done [0.5–2 mg/day orally], or haloperidol [0.5–2 mg/day 
orally, split into two doses]). In some cases, these medica
-
tions are required only for several days and can be discon
-
tinued after the patient has regained a previously established 
level of adjustment; they can also provide ongoing support. 
Anticonvulsants, including carbamazepine, 400–800 mg 
orally daily in divided doses, lamotrigine, 50–200 mg/day 
and valproate 500–2000 mg/day have been shown to 
decrease the severity of behavioral dyscontrol in some per
-
sonality disorder patients. Patients with a schizotypal per
-
sonality often improve with antipsychotics, while those with 
avoidant personality may benefit from strategies that reduce 
anxiety, including the use of SSRIs and benzodiazepines.
 
»
Prognosis
Antisocial and borderline categories generally have a 
guarded prognosis. Those patients with a history of paren
-
tal abuse and a family history of mood disorder tend to 
have the most challenging treatments.
Hyde LW et al. Heritable and nonheritable pathways to early 
callous-unemotional behaviors. Am J Psychiatry. 2016 Sep 1;
 
173(9):903–10. [PMID: 27056607]
Stoffers JM et al. Pharmacotherapy for borderline personality 
disorder—current evidence and recent trends. Curr Psychiatry 
Rep. 2015 Jan;17(1):534. [PMID: 25413640]
SCHIZOPHRENIA SPECTRUM DISORDERS
 
»
Social withdrawal, usually slowly progressive, with

»
Social withdrawal, usually slowly progressive, with 
decrease in emotional expression or motivation or 
both.
 
»
Deterioration in personal care with disorganized 
behaviors or decreased reactivity to the environ
-
ment or both.
 
»
Disorganized thinking, often inferred from speech 
that switches topics oddly or is incoherent.
 
»
Auditory hallucinations, often of a derogatory 
nature.
 
»
Delusions, fixed false beliefs despite conflicting 
evidence, frequently of a persecutory nature.
 
»
Schizophrenia is manifested by a massive disruption of 
thinking, mood, and overall behavior as well as poor filter
-
ing of stimuli. The cause of schizophrenia is believed to be 
multifactorial, with genetic, environmental, and neu
-
rotransmitter pathophysiologic components. Studies have 
demonstrated that schizophrenia is at least eight distinct 
disorders. At present, there is no laboratory method for 
confirming the diagnosis of schizophrenia. There may or 
may not be a history of a major disruption in the individu
-
al’s life (failure, loss, physical illness) before gross psychotic 
deterioration is evident.
Other psychotic disorders on this spectrum are condi
-
tions that are similar to schizophrenia in their acute symp
-
toms, but have a less pervasive influence over the long term. 
The patient usually attains higher levels of functioning. The 
acute psychotic episodes tend to be less disruptive of the 
person’s lifestyle, with a fairly quick return to previous levels 
of functioning.
 
»
A. Schizophrenia
Schizophrenia is the most common of the psychotic disor
-
ders that are all characterized by a loss of contact with reality. 
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The term psychosis is broad and most often refers to having 
paranoia, auditory hallucinations, delusions, or all of these 
symptoms. One percent of the population suffers from 
schizophrenia. Schizophrenia is a chronic disorder that is 
characterized by increasing social and vocational disability 
that begins in late adolescence or early adulthood and tends 
to continue through life. The average age of onset for men 
is 18 years and for women is 25 years. Symptoms have been 
classified into positive and negative categories. 
Positive 
symptoms
 include hallucinations, delusions, disorganized 
speech; these symptoms appear to be related to increased 
dopaminergic (D
2
) activity in the mesolimbic region, and 
all patients have at least one or two of these symptoms to 
meet criteria for diagnosis. There is often a component of 
paranoia involved. They may also have disorganized 
behavior, lack of emotional/cognitive responsiveness, or 
both. 
Negative symptoms
 include diminished sociability, 
restricted affect, and poverty of speech; these symptoms 
appear to be related to decreased D
2
 activity in the meso
-
cortical system. Level of functioning is markedly below 
that before the onset of symptoms, which must last at least 
6 months in some form.
B. Delusional Disorder
Delusional disorders are psychoses in which the predomi
-
nant symptoms are persistent delusions (ie, beliefs that are 
false yet fixed despite being shown evidence that they are 
unfounded) with minimal impairment of daily functioning. 
Intellectual and occupational activities are little affected, 
whereas social and partner functioning tends to be markedly 
involved. Hallucinations are not usually present. Common 
delusional themes include paranoid delusions of persecu
-
tion, delusions of being related to or loved by a well-known 
person, and delusions that one’s partner is unfaithful.
C. Schizoaffective Disorder
Schizoaffective disorders are those cases that fail to fit com
-
fortably either in the schizophrenia or in the affective cat
-
egories. They are usually cases with affective symptoms 
(either a major depressive episode, manic episode, or 
hypomanic episode) that precede or develop concurrently 
with psychotic manifestations and the psychotic symptoms 
occur in the absence of any mood symptoms. The psy
-
chotic symptoms usually begin before the mood episode 
begins and continue to linger for some time after resolu
-
tion of the mood episode but do not remain permanently. 
Because of this, the long-term prognosis is better than for 
schizophrenia.
D. Schizophreniform Disorders
Schizophreniform disorders are similar in their symptoms to 
schizophrenic disorders except that the duration of prodro
-
mal, acute, and residual symptoms is longer than 1 month 
but less than 6 months.
E. Brief Psychotic Disorders
Brief psychotic disorders are defined as psychotic symp
-
toms lasting less than 1 month. They are the result of 
psychological stress. The shorter duration is significant and 
correlates with a more acute onset and resolution as well as 
a much better prognosis.
 
»
The symptoms and signs of schizophrenia vary markedly 
among individuals as well as in the same person at different 
times. The patient’s 
appearance
 may be bizarre, although 
the usual finding is mildly to moderately unkempt. 
Motor 
activity
 is generally reduced, although extremes ranging 
from catatonic stupor to frenzied excitement occur. 
Social 
behavior
 is characterized by marked withdrawal coupled 
with disturbed interpersonal relationships and a reduced 
ability to experience pleasure. Dependency and a poor self-
image are common. 
Verbal utterances
 are variable, the 
language being concrete yet symbolic, with unassociated 
rambling statements (at times interspersed with mutism) 
during an acute episode. Neologisms (made-up words or 
phrases), echolalia (repetition of words spoken by others),

phrases), echolalia (repetition of words spoken by others), 
and verbigeration (repetition of senseless words or phrases) 
are occasionally present. 
Affect
 is usually flattened, with 
occasional inappropriateness. 
 is present in 
almost all cases but may be less apparent during the acute 
psychotic episode and more obvious during recovery. 
Depression is sometimes confused with akinetic side 
effects of antipsychotic medications. It is also related to 
boredom, which increases symptoms and decreases the 
response to treatment. Work is generally unavailable and 
time unfilled, providing opportunities for counterproduc
-
tive activities such as drug abuse, withdrawal, and increased 
psychotic symptoms.
Thought content
 may vary from a paucity of ideas to a 
rich complex of delusional fantasy with archaic thinking. 
One frequently notes after a period of conversation that 
little if any information has actually been conveyed. Incom
-
ing stimuli produce varied responses. In some cases a 
simple question may trigger explosive outbursts, whereas 
at other times there may be no overt response whatsoever 
(catatonia). When paranoid ideation is present, the patient is 
often irritable and less cooperative. 
Delusions
 (false beliefs) 
are characteristic of paranoid thinking, and they usually take 
the form of a preoccupation with the supposedly threatening 
behavior exhibited by other individuals. This ideation may 
cause the patient to adopt active countermeasures such as 
locking doors and windows, taking up weapons, covering 
the ceiling with aluminum foil to counteract radar waves, 
and other bizarre efforts. Somatic delusions revolve around 
issues of bodily decay or infestation. 
Perceptual distortions
 
usually include auditory hallucinations—visual hallucina
-
tions are more commonly associated with organic mental 
states—and may include illusions (distortions of reality) 
such as figures changing in size or lights varying in inten
-
sity. Cenesthetic hallucinations (eg, a burning sensation in 
the brain, feeling blood flowing in blood vessels) occasion
-
ally occur. Lack of humor, feelings of dread, depersonaliza
-
tion (a feeling of being apart from the self), and fears of 
annihilation may be present. Any of the above symptoms 
generate higher anxiety levels, with heightened arousal and 
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occasional panic and suicidal ideation, as the individual 
fails to cope.
The development of the acute episode in schizophrenia 
frequently is the end product of a gradual decompensation. 
Frustration and anxiety appear early, followed by depres
-
sion and alienation, along with progressive ineffectiveness 
in day-to-day coping. This often leads to feelings of panic 
and increasing disorganization, with loss of the ability to 
test and evaluate the reality of perceptions. The stage of so-
called 
psychotic resolution
 includes delusions, autistic 
preoccupations, and psychotic insight, with acceptance of 
the decompensated state. The process is frequently compli
-
cated by the use of caffeine, alcohol, and other recreational 
drugs. Life expectancy of patients with schizophrenia is as 
much as 20% shorter than that of cohorts in the general 
population and is often associated with comorbid condi
-
tions such as the metabolic syndrome, which may be 
induced or exacerbated by the atypical antipsychotic agents.
 may produce water intoxication with hypo
-
natremia—characterized by symptoms of confusion, leth
-
argy, psychosis, seizures, and occasionally death—in any 
psychiatric disorder, but most commonly in schizophrenia. 
These problems exacerbate the schizophrenic symptoms 
and can be confused with them. Possible pathogenetic fac
-
tors in polydipsia include a hypothalamic defect, inappro
-
priate antidiuretic hormone (ADH) secretion, antipsychotic 
medications (anticholinergic effects, stimulation of hypo
-
thalamic thirst center, effect on ADH), smoking (nicotine 
and syndrome of inappropriate antidiuretic hormone 
[SIADH]), psychotic thought processes (delusions), and 
other medications (eg, diuretics, antidepressants, lithium, 
alcohol) (see Chapter 21).
B. Imaging
Ventricular enlargement and cortical atrophy, as seen on 
CT scan, have been correlated with chronic course, severe 
cognitive impairment, and nonresponsiveness to antipsy
-
chotic medications. Decreased frontal lobe activity seen on 
PET scan has been associated with negative symptoms.
 
»
The diagnosis of schizophrenia is best made over time 
because repeated observations increase the reliability of the 
diagnosis. One should not hesitate to reconsider the diag
-
nosis of schizophrenia in any person who has received that 
diagnosis in the past, particularly when the clinical course 
has been atypical. A number of these patients have been 
found to actually have bipolar disorder, which has 
responded well to lithium. Manic episodes often mimic 
schizophrenia. However, schizophrenia is less likely to be 
associated with the decreased need for sleep, increase in 
goal directed activity, and overconfidence, symptoms that 
are typical of mania. However, thought disorder, auditory 
hallucinations, and delusions are commonly seen in manic 
Psychotic depressions, brief reactive psychosis, delu
-
sional disorder, and any illness with psychotic ideation 
tend to be confused with schizophrenia, partly because of 
the regrettable tendency to use the terms interchangeably.
Medical disorders such as thyroid dysfunction, adrenal and 
pituitary disorders, reactions to toxic materials (eg, mercury, 
PCBs), and almost all of the organic mental states in the 
early stages must be ruled out. Postpartum psychosis is dis
-
cussed under Mood Disorders. Complex partial seizures, 
especially when psychosensory phenomena are present, are 
an important differential consideration. Toxic drug states 
arising from prescription, over-the-counter, herbal and 
street drugs may mimic all of the psychotic disorders. The 
chronic use of amphetamines, cocaine, and other stimulants 
frequently produces a psychosis that is almost identical to 
the acute paranoid schizophrenic episode. Drug-induced 
psychoses can have all the positive symptoms of schizophre
-
nia but less commonly have the negative symptoms. The

-
nia but less commonly have the negative symptoms. The 
presence of formication (sensation of insects crawling on or 
under the skin) and stereotypy suggests the possibility of 
stimulant abuse. Phencyclidine, a common street drug, may 
cause a reaction that is difficult to distinguish from other 
psychotic disorders. Cerebellar signs, excessive salivation, 
dilated pupils, and increased deep tendon reflexes should 
alert the clinician to the possibility of a toxic psychosis. 
Industrial chemical toxicity (both organic and metallic), 
degenerative disorders, and metabolic deficiencies must be 
considered in the differential diagnosis.
Catatonia
, a psychomotor disturbance that may involve 
decreased motor activity, decreased interaction, or exces
-
sive and odd motor activity, is frequently assumed to exist 
solely as a component of schizophrenic disorders. How
-
ever, it can actually be the end product of a number of ill
-
nesses, including a number of organic conditions as well as 
other psychiatric disorders such as bipolar disorder. Neo
-
plasms, viral and bacterial encephalopathies, central ner
-
vous system hemorrhage, metabolic derangements such as 
diabetic ketoacidosis, sedative withdrawal, and liver and 
kidney malfunction have all been implicated. It is particu
-
larly important to realize that drug toxicity (eg, overdoses 
of antipsychotic medications such as fluphenazine or halo
-
peridol) can cause catatonic syndrome, which may be 
misdiagnosed as a catatonic schizophrenia and inappropri
-
ately treated with more antipsychotic medication. Catato
-
nia is also seen in other major psychiatric disorders, 
including bipolar disorder and major depression.
 
»
Treatment
A. Pharmacologic (see Side Effects, below)
Hospitalization is sometimes necessary, particularly when 
the patient’s behavior shows gross disorganization. The 
presence of competent family members or social support 
lessens the need for hospitalization, and each case should 
be judged individually. The major considerations are to 
prevent self-inflicted harm or harm to others and to pro
-
vide the patient’s basic needs. A full medical evaluation and 
CT scan or MRI of the brain should be considered in first 
episodes of psychosis.
Antipsychotic medications
 are the treatment of choice. 
The relapse rate can be reduced by 50% with proper main
-
tenance antipsychotic therapy. Long-acting, injectable 
depot antipsychotics are used in nonadherant patients or 
nonresponders to oral medication or patients who choose 
the ease of not taking a daily pill.
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Antipsychotic medications include the 
“typical
 or 
first-
generation”
 antipsychotics (phenothiazines, thioxanthenes, 
butyrophenones, dihydroindolones, dibenzoxazepines, and 
benzisoxazoles) and the newer 
“atypical
 or 
second-
 
 antipsychotics (clozapine, risperidone, olan
-
zapine, quetiapine, aripiprazole, ziprasidone, paliperidone, 
asenapine, iloperidone, lurasidone, and cariprazine) (Tables 
25–4 and 25–5). Generally, increasing milligram potency of 
the typical antipsychotics is associated with decreasing anti
-
cholinergic and adrenergic side effects and increasing extra
-
pyramidal symptoms. Data suggest similar antipsychotic 
efficacy for first- and second-generation antipsychotics, but 
a tendency for the second-generation antipsychotics to be 
better tolerated leading to enhanced compliance.
The phenothiazines comprise the bulk of the currently 
used “typical” antipsychotic medications. The only butyro
-
phenone commonly used in psychiatry is haloperidol, 
which is different in structure but similar in action and side 
effects to the piperazine phenothiazines such as fluphen
-
azine, perphenazine, and trifluoperazine. These medica
-
tions and haloperidol (dopamine [D
2
] receptor blockers) 
have high potency and a paucity of autonomic side effects 
and act to markedly lower arousal levels.
Clozapine, the first “atypical” (novel) antipsychotic medi
-
cation developed, has dopamine (D
4
) receptor-blocking 
activity as well as central serotonergic, histaminergic, and 
alpha-noradrenergic receptor-blocking activity. It is effec
-
tive in the treatment of about 30% of psychoses resistant to 
other antipsychotic medications, and it may have specific 
efficacy in decreasing suicidality in patients with schizo
-
phrenia. Risperidone is an antipsychotic that blocks some 
serotonin receptors (5-HT
2
) and dopamine receptors (D
2
). 
Risperidone causes fewer extrapyramidal side effects than 
the typical antipsychotics at doses less than 6 mg. It appears 
to be as effective as haloperidol and possibly as effective as 
clozapine in treatment-resistant patients without necessi
-
tating weekly white cell counts, as required with clozapine 
therapy. Risperidone is available in a long-acting injectable 
Olanzapine is a potent blocker of 5-HT
2
 and dopa
-
mine D
1
, D
2
, and D
4
 receptors. High doses of olanzapine 
(10–20 mg daily) appear to be more effective than lower 
doses. The medication is somewhat more effective than 
haloperidol in the treatment of negative symptoms, such as 
withdrawal, psychomotor retardation, and poor interper
-
sonal relationships. It is available in an orally disintegrating 
Table 25–4.
 
Commonly used antipsychotics and medications (listed in alphabetical order).
Usual Daily Oral 
 
Dose
Usual Daily Maximum 
Dose
1
2
Aripiprazole (Abilify)
10–15 mg
30 mg
$45.35/30 mg
$1360.50
Asenapine (Saphris)
10–20 mg
20 mg
$24.02/10 mg
$1441.20
Cariprazine (Vraylar)
1.5–6 mg
6 mg
$48.03/6 mg
$1440.90
Chlorpromazine (Thorazine; others)
100–400 mg
1 g
$17.86/200 mg
$2679.00
Clozapine (Clozaril)
300–450 mg
900 mg
$2.73/100 mg
$737.10
Fluphenazine (Permitil, Prolixin)
3
2–10 mg
60 mg
$1.67/10 mg
$300.60
Haloperidol (Haldol)
2–5 mg
60 mg
$2.76/20 mg
$248.40
Iloperidone (Fanapt)
12–24 mg
24 mg
$42.95/12 mg
$2577.00
Loxapine (Loxitane)
20–60 mg
200 mg
$2.57/50 mg
$308.40
Lurasidone (Latuda)
40–80 mg
80 mg
$48.94/80 mg
$1468.20
Olanzapine (Zyprexa)
5–10 mg
20 mg
$39.79/20 mg
$1193.70
Paliperidone (Invega)
6–12 mg
12 mg
$30.60/6 mg
$1836.00
Perphenazine (Trilafon)
3
16–32 mg
64 mg
$3.90/16 mg
$468.00
Quetiapine (Seroquel)
200–400 mg
800 mg
$19.93/400 mg
$1195.80
Risperidone (Risperdal)
4
2–6 mg
10 mg
$3.60/2 mg
$540.00
Thiothixene (Navane)
3
5–10 mg
80 mg
$0.65/10 mg
$156.00
Trifluoperazine (Stelazine)
5–15 mg
60 mg
$2.45/10 mg
$441.00
Ziprasidone (Geodon)
40–160 mg
160 mg

4
2–6 mg
10 mg
$3.60/2 mg
$540.00
3
5–10 mg
80 mg
$156.00
5–15 mg
60 mg
$441.00
40–160 mg
160 mg
$10.76/80 mg
$645.60
1
Can be higher in some cases.
2
Red Book
Analytics Information, http://www.micormedexsolutions.com, accessed April 10, 2018. AWP may not accurately represent the actual phar
-
3
Indicates piperazine structure.
4
For risperidone, daily doses above 6 mg increase the risk of extrapyramidal syndrome. Risperidone 6 mg is approximately equivalent to 
haloperidol 20 mg.
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form for patients who are unable to tolerate standard oral 
dosing and in an injectable form for the management of 
acute agitation associated with schizophrenia and bipolar 
disorder. Olanzapine is available in a long-term injectable 
preparation but this formulation tends to be used less com
-
monly than other depot formulations because some 
patients experience severe sedation and delirium which 
occurs in about 0.5–1% of patients.
Quetiapine is an antipsychotic with greater 5-HT
2
 rela
-
tive to D
2
 receptor blockade as well as a relatively high 
affinity for alpha-1- and alpha-2-adrenergic receptors. It 
appears to be as efficacious as haloperidol in treating posi
-
tive and negative symptoms of schizophrenia, with fewer 
extrapyramidal side effects even at high doses.
Ziprasidone has both anti-dopamine receptor and anti-
serotonin receptor effects, with good efficacy for both posi
-
tive and negative symptoms of schizophrenia. Aripiprazole 
is a partial agonist at the dopamine D
2
 and serotonin 5-HT
1
 
receptors and an antagonist at 5-HT
2
 receptors, and it is 
effective against positive and negative symptoms of schizo
-
phrenia. It functions as an antagonist or agonist, depending 
on the dopaminergic activity at the dopamine receptors. 
This may help decrease side effects. Aripiprazole is approved 
as an augmentation agent for treatment-resistant depression, 
even when psychosis is not present, and as a maintenance 
treatment for bipolar disorder. Aripiprazole is available as an 
acute injectable preparation as well as a long-term injectable 
preparation that is given once monthly in patients who are 
not able to adhere to daily oral dosing. Asenapine, approved 
for the treatment of schizophrenia and bipolar disorder 
(mixed or manic state), appears to be particularly helpful in 
treating negative symptoms of schizophrenia. Paliperidone, 
the active metabolite of risperidone, is available as a capsule 
and a monthly injection. Lurasidone is FDA-approved and 
has been shown to be effective in treating acute decompen
-
sation in patients with chronic schizophrenia. Cariprazine is 
a partial agonist of the D
2
 and D
3
 receptor and is approved 
by the FDA for the treatment of schizophrenia and bipolar 
disorder. Akithisia, weight gain, and insomnia are among 
the more commonly reported side effects with cariprazine. 
Because cariprazine is not a potent D
2
-antagonist, it is less 
likely to increase prolactin levels than most antipsychotics.
1. 
Clinical indications—
The antipsychotics are used to treat 
all forms of the schizophrenias as well as psychotic ideation 
in delirium, drug-induced psychoses, psychotic depression, 
augmentation of unipolar depression, acute mania, and the 
prevention of mood cycles in bipolar disorder. They are also 
effective in Tourette syndrome and behavioral dyscontrol 
in autistic patients. While frequently used to treat agita
-
tion in dementia patients, no antipsychotic has been 
shown to be reliably effective in this population and may 
increase the risk of early mortality in elderly dementia 
patients
. Antipsychotics quickly lower the arousal (activ
-
ity) level and, perhaps indirectly, gradually improve social
-
ization and thinking. The improvement rate for treating 
positive symptoms is about 80%. Patients whose behav
-
ioral symptoms worsen with use of antipsychotic medica
-
tions may have an undiagnosed organic condition such as 
anticholinergic toxicity.
Symptoms that are ameliorated by these medications 
include hyperactivity, hostility, aggression, delusions, hal
-
lucinations, irritability, and poor sleep. Individuals with 
acute psychosis and good premorbid function respond 
quite well. The most common cause of failure in the treat
-
ment of acute psychosis is inadequate dosage, and the most 
common cause of relapse is noncompliance.
Table 25–5.
 
Relative potency and side effects of antipsychotic medications (listed in alphabetical order).

Chlorpromazine: Drug 
Potency Ratio
Anticholinergic Effects
1
Extrapyramidal Effect
1
1:20
1
1
1:1
4
1
Clozapine
1:1
4
—
Fluphenazine
1:50
1
4
1:50
1
4
Iloperidone
1:25
1
1
Loxapine
1:10
2
3
Lurasidone
1:5
1
2
1:20
1
1
Perphenazine
1:10
2
3
1:1
1
1
Risperidone
1:50
1
3
Thiothixene
1:20
1
4
Trifluoperazine
1:20
1
4
Ziprasidone
1:1
1
1
1
1, weak effect; 4, strong effect.
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Although first-generation antipsychotics are efficacious 
in the treatment of positive symptoms of schizophrenia, 
such as hallucinations and delusions, second-generation 
antipsychotics are thought to have efficacy in reducing 
positive symptoms and some efficacy in treating negative 
symptoms. Antidepressant medications may be used in 
conjunction with antipsychotics if significant depression is 
present. Resistant cases may require concomitant use of 
lithium, carbamazepine, or valproic acid. The addition of a 
benzodiazepine medication to the antipsychotic regimen 
may prove helpful in treating the agitated or catatonic psy
-
chotic patient who has not responded to antipsychotics 
alone—lorazepam, 1–2 mg orally, can produce a rapid 
resolution of catatonic symptoms and may allow mainte
-
nance with a lower antipsychotic dose. Electroconvulsive 
therapy (ECT) has also been effective in treating catatonia 
and in treating schizophrenia when used in combination 
with medications.
2. Dosage forms and patterns—
The dosage range is quite 
broad (Table 25–4). For example, risperidone, 0.25–1 mg 
orally at bedtime, may be sufficient for the elderly person 
with mild dementia with psychosis (especially in view of the 
increased risk of stroke and death in the elderly), whereas 
up to 6 mg/day may be used in a young patient with acute 
schizophrenia. For quick response, an atypical antipsychotic 
may be started in combination with a benzodiazepine (eg, 
risperidone oral solution, 2 mg, or olanzapine, 10 mg orally, 
and lorazepam, 2 mg orally, every 2–4 hours as needed). In 
an acutely distressed, psychotic patient one might use halo
-
peridol, 10 mg intramuscularly, which is absorbed rapidly 
and achieves an initial tenfold plasma level advantage over 
equal oral doses. Psychomotor agitation, racing thoughts, 
and general arousal are quickly reduced. The dose can be 
repeated every 3–4 hours; when the patient is less symp
-
tomatic, oral doses can replace parenteral administration 
in most cases. In the elderly, both atypical (eg, risperidone 
0.25 mg–0.5 mg daily or olanzapine 1.25 mg daily) and 
typical (eg, haloperidol 0.5 mg daily or perphenazine 2 mg 
daily) antipsychotics, often used effectively in small doses 
for behavioral control, have been linked to premature 
death in some cases.
Absorption of oral medications may be increased or 
decreased by concomitant administration of other medica
-
tions (eg, antacids tend to decrease the absorption of antide
-
pressants). Previous gastrointestinal surgery may alter pH, 
motility, and surface areas available for drug absorption. 
There are racial genetic based enzyme differences in metab
-
olizing the antipsychotic medications—eg, many Asians 
require only about half the usual dosage. Bioavailability is 
influenced by other factors such as smoking or hepatic 
microsomal enzyme stimulation with alcohol or barbiturates 
and enzyme-altering medications such as carbamazepine or 
methylphenidate. Antipsychotic plasma drug level determi
-
nations are not currently of major clinical assistance.
Divided daily doses are not necessary after a mainte
-
nance dose has been established, and most patients can 
then be maintained on a single daily dose, usually taken at 
bedtime. This is particularly appropriate in a case where 
the sedative effect of the medication is desired for night
-
time sleep, and undesirable sedative effects can be avoided 
during the day. First-episode patients especially should be 
tapered off medications after about 6 months of stability 
and carefully monitored; their rate of relapse is lower than 
that of multiple-episode patients.
Psychiatric patients—particularly paranoid individuals— 
often neglect to take their medication. In these cases and in 
nonresponders to oral medication, the enanthate and dec
-
anoate (the latter is slightly longer-lasting and has fewer 
extrapyramidal side effects) forms of fluphenazine or the

-
extrapyramidal side effects) forms of fluphenazine or the 
decanoate form of haloperidol may be given by deep sub
-
cutaneous injection or intramuscularly to achieve an effect 
that will usually last 7–28 days. A patient who cannot be 
depended on to take oral medication (or who overdoses on 
minimal provocation) will generally agree to come to the 
clinician’s office for a “shot. ” The usual dose of the fluphen
-
azine long-acting preparations is 25 mg every 2 weeks. 
 
Dosage and frequency of administration vary from about 
100 mg weekly to 12.5 mg monthly. Use the smallest effec
-
tive amount as infrequently as possible. A monthly injection 
of 25 mg of fluphenazine decanoate is equivalent to about 
15–20 mg of oral fluphenazine daily. Risperidone was the 
first atypical antipsychotic available in a long-acting inject
-
able form (25–50 mg intramuscularly every 2 weeks). 
Concomitant use of a benzodiazepine (eg, lorazepam, 2 mg 
orally twice daily) may permit reduction of the required 
dosage of oral or parenteral antipsychotic medication. 
Long-acting injectables are now available for risperidone, 
paliperidone, aripiprazole, and olanzapine.
Intravenous haloperidol, the antipsychotic most com
-
monly used by this route, is often used in critical care units 
in the management of agitated, delirious patients. Intrave
-
nous haloperidol should be given no faster than 1 mg/min 
to reduce cardiovascular side effects, such as torsades de 
pointes. Current practice indicates that ECG monitoring 
should be used whenever haloperidol is being adminis
-
tered intravenously.
Some antipsychotic agents are available for intranasal 
administration. The intranasal form of loxapine has a more 
rapid onset of action for the treatment of agitation (about 
10 minutes) than either intramuscular or oral antipsychotic 
agents. Also, intranasal administration tends to be less 
traumatic to patients than getting an injection. However, 
intranasal loxapine requires the cooperation of the patient 
and is more expensive than generic antipsychotic injectable 
preparations.
3. Side effects—
For both typical and atypical antipsy
-
chotic agents, a range of side effects has been reported. 
The most common anticholinergic side effects include 
dry
 
mouth
 (which can lead to ingestion of caloric liquids 
and weight gain or hyponatremia), 
blurred
 
near
 
vision,
 
urinary
 
retention
 (particularly in elderly men with 
enlarged prostates), 
delayed gastric emptying, esopha
-
geal reflux, ileus, delirium,
 and precipitation of 
acute 
glaucoma
 in patients with narrow anterior chamber angles. 
Other autonomic effects include 
orthostatic hypotension
 
and 
sexual dysfunction
—problems in achieving erection, 
ejaculation (including retrograde ejaculation), and orgasm in 
men (approximately 50% of cases) and women (approxi
-
mately 30%). Delay in achieving orgasm is often a factor in 
medication noncompliance. 
Electrocardiographic changes
 
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occur frequently, but clinically significant arrhythmias are 
much less common. Elderly patients and those with preex
-
isting cardiac disease are at greater risk. The most frequently 
seen electrocardiographic changes include diminution of the 
T wave amplitude, appearance of prominent U waves, 
depression of the ST segment, and prolongation of the QT 
interval (Table 25–6). Ziprasidone can produce QTc prolon
-
gation. A pretreatment ECG is indicated for patients at risk 
for cardiac sequelae (including patients taking other medica
-
tions that might prolong the QTc interval). In some critical 
care patients, torsades de pointes has been associated with 
the use of high-dose intravenous haloperidol (usually greater 
than 30 mg/24 h).
Associations have been suggested between the atypical 
antipsychotics and 
new-onset diabetes, hyperlipidemia,
 
and 
weight gain
 (Table 25–6). The FDA has particularly 
noted the risk of hyperglycemia and new-onset diabetes in 
this class of medication that is not related to weight gain. The 
risk of diabetes mellitus is increased in patients taking clo
-
zapine and olanzapine. Monitoring of weight, fasting blood 
sugar and lipids prior to initiation of treatment and at regu
-
lar intervals thereafter is an important part of medication 
monitoring. The addition of metformin to olanzapine may 
improve drug-induced weight gain in patients with drug-
naïve, first-episode schizophrenia. Antipsychotic medica
-
tions in general may have 
metabolic
 
and
 
endocrine effects,
 
including weight gain, hyperglycemia, impaired temperature 
regulation in hot weather, and water intoxication, which may 
be due to inappropriate ADH secretion. 
Lactation and men
-
strual irregularities
 are common (antipsychotic medica
-
tions should be avoided, if possible, in breast cancer patients 
because of potential trophic effects of elevated prolactin 
levels on the breast). Both antipsychotic and antidepressant 
medications inhibit sperm motility. 
Bone marrow depres
-
sion
 and 
cholestatic jaundice
 occur rarely; these are hyper
-
sensitivity reactions, and they usually appear in the first 
 
2 months of treatment. They subside on discontinuance of 
the medication. There is cross-sensitivity among all of the 
phenothiazines, and a medication from a different group 
should be used when allergic reactions occur.
Clozapine is associated with a 1.6% risk of agranulocyto
-
sis (higher in persons of Ashkenazi Jewish ancestry), and its 
use must be strictly monitored with weekly blood counts 
during the first 6 months of treatment, with monitoring 
every other week thereafter. The risk of developing agranu
-
locytosis is approximately 2.5 times higher in patients with a 
polymorphism for 
HLADQB1
 gene. Thus, this genetic test 
may be worthwhile to perform before initiating clozapine. 
Discontinuation of the medication requires weekly monitor
-
ing of the white blood cell count for 1 month. Clozapine has 
been associated with fatal myocarditis and is contraindicated 
in patients with severe heart disease. In addition, clozapine 
lowers the seizure threshold and has many side effects, 
including sedation, hypotension, increased liver biochemical 
levels, hypersalivation, respiratory arrest, weight gain, and 
changes in both the ECG and the electroencephalogram. 
Notably, adynamic ileus is a rare side effect of clozapine that 
can be fatal, and patients should be closely monitored and 
treated quickly and preemptively for constipation.
Photosensitivity, retinopathy,
 and 
hyperpigmentation
 
are associated with use of fairly high dosages of chlor
-
promazine. The appearance of particulate melanin deposits 
in the lens of the eye is related to the total dose given, and 
patients on long-term medication should have periodic eye 
examinations. Teratogenicity has not been causally related 
to these medications, but prudence is indicated particularly

to these medications, but prudence is indicated particularly 
in the first trimester of pregnancy. The seizure threshold is 
lowered, but it is safe to use these medications in epileptics 
who take anticonvulsants.
The 
neuroleptic malignant syndrome (NMS)
 is a 
catatonia-like state manifested by extrapyramidal signs, 
blood pressure changes, altered consciousness, and hyper
-
pyrexia; it is an uncommon but serious complication of 
antipsychotic treatment. Muscle rigidity, involuntary move
-
ments, confusion, dysarthria, and dysphagia are accompa
-
nied by pallor, cardiovascular instability, fever, pulmonary 
congestion, and diaphoresis and may result in stupor, coma, 
and death. The cause may be related to a number of factors, 
including poor dosage control of antipsychotic medication, 
affective illness, decreased serum iron, dehydration, and 
Table 25–6.
 
Adverse factors associated with atypical antipsychotic medications (listed in alphabetical order).
Weight Gain
Hyperlipidemia
New-Onset Diabetes 
Mellitus
QTc Prolongation
1
+/–
–
–
++
Asenapine
+/–
+/–
+/–
+++
Clozapine
+++
+++
+++
+/–
–
–
–
–
+++
+++
+++
+/–
Paliperidone
+
+/–
+/–
+++
++
++
++
+++
++
++
++
+
+/–
–
–
+++
1
QTc prolongation is a side effect of many medications and suggests a possible risk for arrhythmia. Prescriber’s Letter 2011;18(12):271207.
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increased sensitivity of dopamine receptor sites. Lithium in 
combination with an antipsychotic drug may increase vul
-
nerability, which is already increased in patients with an 
affective disorder. In most cases, the symptoms develop 
within the first 2 weeks of antipsychotic drug treatment. 
The syndrome may occur with small doses of the medica
-
tions. Intramuscular administration is a risk factor. Elevated 
creatine kinase and leukocytosis with a shift to the left are 
present early in about half of cases. Treatment includes 
controlling fever and providing fluid support. Dopamine 
agonists such as bromocriptine, 2.5–10 mg orally three times 
a day, and amantadine, 100–200 mg orally twice a day, have 
also been useful. Dantrolene, 50 mg intravenously as needed, 
is used to alleviate rigidity (do not exceed 10 mg/kg/day due 
to hepatotoxicity risk). There is ongoing controversy about 
the efficacy of these three agents as well as the use of cal
-
cium channel blockers and benzodiazepines. ECT has been 
used effectively in resistant cases. Clozapine has been used 
with relative safety and fair success as an antipsychotic 
medication for patients who have had NMS.
Akathisia
 is the most common (about 20%) extrapyra
-
midal symptom. It usually occurs early in treatment (but 
may persist after antipsychotics are discontinued) and is 
frequently mistaken for anxiety or exacerbation of psychosis. 
It is characterized by a subjective desire to be in constant 
motion followed by an inability to sit or stand still and con
-
sequent pacing. It may induce suicidality or feelings of fright, 
rage, terror, or sexual torment. Insomnia is often present. It 
is crucial to educate patients in advance about these poten
-
tial side effects so that the patients do not misinterpret them 
as signs of increased illness. In all cases, reevaluate the dos
-
age requirement or the type of antipsychotic medication. 
One should inquire also about cigarette smoking, which in 
women has been associated with an increased incidence of 
akathisia. Antiparkinsonism medications (such as trihexy
-
phenidyl, 2–5 mg orally three times daily) may be helpful, 
but first-line treatment often includes a benzodiazepine 
(such as clonazepam 0.5–1 mg orally three times daily). In 
resistant cases, symptoms may be alleviated by propranolol, 
30–80 mg/day orally, diazepam, 5 mg orally three times 
daily, or amantadine, 100 mg orally three times daily.
Acute dystonias
 usually occur early, although a late 
(tardive) occurrence is reported in patients (mostly men after 
several years of therapy) who previously had early severe 
dystonic reactions and a mood disorder. Y ounger patients are 
at higher risk for acute dystonias. The most common signs 
are bizarre muscle spasms of the head, neck, and tongue. 
Frequently present are torticollis, oculogyric crises, swallow
-
ing or chewing difficulties, and masseter spasms. Laryngo
-
spasm is particularly dangerous. Back, arm, or leg muscle 
spasms are occasionally reported. Diphenhydramine, 50 mg 
intramuscularly, is effective for the acute crisis; one should 
then give benztropine mesylate, 2 mg orally twice daily, for 
several weeks, and then discontinue gradually, since few of 
the extrapyramidal symptoms require long-term use of the 
antiparkinsonism medications (all of which are about equally 
efficacious—though trihexyphenidyl tends to be mildly stim
-
ulating and benztropine mildly sedating).
Drug-induced parkinsonism
 is indistinguishable from 
idiopathic parkinsonism, but it is reversible, occurs later in 
treatment than the preceding extrapyramidal symptoms, 
and in some cases appears after antipsychotic withdrawal. 
The condition includes the typical signs of apathy and 
reduction of facial and arm movements (akinesia, which 
can mimic depression), festinating gait, rigidity, loss of 
postural reflexes, and pill-rolling tremor. Patients with

postural reflexes, and pill-rolling tremor. Patients with 
AIDS seem particularly vulnerable to extrapyramidal side 
effects. High-potency antipsychotics often require antipar
-
kinsonism medications (see Table 24–6). The antipsychotic 
dosage should be reduced, and immediate relief can be 
achieved with antiparkinsonism medications in the same 
dosages as above. After 4–6 weeks, these antiparkinsonism 
medications can often be discontinued with no recurrent 
symptoms. In any of the extrapyramidal symptoms, aman
-
tadine, 100–400 mg orally daily, may be used instead of the 
antiparkinsonism medications. Antipsychotic-induced 
catatonia is similar to catatonic stupor with rigidity, drool
-
ing, urinary incontinence, and cogwheeling. It usually 
responds slowly to withdrawal of the offending medication 
and use of antiparkinsonism agents.
Tardive dyskinesia
 is a syndrome of abnormal involun
-
tary stereotyped movements of the face, mouth, tongue, 
trunk, and limbs that may occur after months or (usually) 
years of treatment with antipsychotic agents. The syndrome 
affects 20–35% of patients who have undergone long-term 
antipsychotic therapy. Predisposing factors include older age, 
many years of treatment, cigarette smoking, and diabetes 
mellitus. Pineal calcification is higher in this condition by a 
margin of 3:1. There are no clearcut differences among the 
antipsychotic medications in the development of tardive dys
-
kinesia. (Although the atypical antipsychotics appear to offer 
a lower risk of tardive dyskinesia, long-term effects have not 
been investigated.) However, clozapine is unique in that it has 
been found to treat antipsychotic-induced tardive dyskinesia. 
Early manifestations of tardive dyskinesia include fine worm-
like movements of the tongue at rest, difficulty in sticking out 
the tongue, facial tics, increased blink frequency, or jaw 
movements of recent onset. Later manifestations may include 
bucco-linguo-masticatory movements, lip smacking, chew
-
ing motions, mouth opening and closing, disturbed gag 
reflex, puffing of the cheeks, disrupted speech, respiratory 
distress, or choreoathetoid movements of the extremities (the 
last being more prevalent in younger patients). The symp
-
toms do not necessarily worsen and in rare cases may lessen 
even though antipsychotic medications are continued. The 
dyskinesias do not occur during sleep and can be voluntarily 
suppressed for short periods. Stress and movements in other 
parts of the body will often aggravate the condition.
Early signs of dyskinesia must be differentiated from 
those reversible signs produced by ill-fitting dentures or 
nonantipsychotic medications such as levodopa, TCAs, 
antiparkinsonism agents, anticonvulsants, and antihista
-
mines. Other neurologic conditions such as Huntington 
chorea can be differentiated by history and examination.
The emphasis should be on prevention of side effects. Use 
the least amount of antipsychotic medication necessary to 
mute the psychotic symptoms. Detect early manifestations of 
dyskinesias. When these occur, stop anticholinergic medica
-
tions and gradually discontinue antipsychotic medications, if 
clinically feasible. Weight loss and cachexia sometimes 
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appear on withdrawal of antipsychotics. In an indeterminate 
number of cases, the dyskinesias will remit. Keep the patient 
off the medications until reemergent psychotic symptoms 
dictate their resumption, at which point they are restarted in 
low doses and gradually increased until there is clinical 
improvement. If antipsychotic medications are restarted, 
clozapine and olanzapine appear to offer less risk of recur
-
rence. The use of adjunctive agents such as benzodiazepines 
or lithium may help directly or indirectly by allowing control 
of psychotic symptoms with a low dosage of antipsychotics. If 
the dyskinesic syndrome recurs and it is necessary to con
-
tinue antipsychotic medications to control psychotic symp
-
toms, informed consent should be obtained. Benzodiazepines, 
buspirone (in doses of 15–60 mg/day orally), phosphatidyl
-
choline, clonidine, calcium channel blockers, vitamin E, 
omega-3 fatty acids, and propranolol all have had limited 
usefulness in treating the dyskinetic side effects.
B. Social
Environmental considerations are most important in the 
individual with a chronic illness, who usually has a history 
of repeated hospitalizations, a continued low level of func
-
tioning, and symptoms that never completely remit. Family 
rejection and work failure are common. In these cases, 
board and care homes staffed by personnel experienced in 
caring for psychiatric patients are most important. There is 
frequently an inverse relationship between stability of the 
living situation and the amounts of required antipsychotic 
medications, since the most salutary environment is one 
that reduces stimuli. Nonresidential self-help groups such 
as Recovery, Inc., should be utilized whenever possible. 
They provide a setting for sharing, learning, and mutual 
support and are frequently the only social involvement with 
which this type of patient is comfortable. Vocational reha
-
bilitation and work agencies (eg, Goodwill Industries, Inc.) 
provide assessment, training, and job opportunities at a 
level commensurate with the person’s clinical condition.
The need for psychotherapy varies markedly depending on 
the patient’s current status and history. In a person with a 
single psychotic episode and a previously good level of 
adjustment, supportive psychotherapy may help the patient 
reintegrate the experience, gain some insight into anteced
-
ent problems, and become a more self-observant individ
-
ual who can recognize early signs of stress. Research 
suggests that cognitive behavioral therapy—in conjunction 
with medication management—has efficacy in the treat
-
ment of symptoms of schizophrenia. Cognitive behavioral 
therapy for schizophrenia involves helping the individual 
challenge psychotic thinking and alters response to halluci
-
nations. Similarly, a form of psychotherapy called accep
-
tance and commitment therapy has shown value in helping 
prevent hospitalizations in schizophrenia. Cognitive reme
-
diation therapy is another approach to treatment that may 
help patients with schizophrenia become better able to 
focus their disorganized thinking. Family therapy may also 
help alleviate the patient’s stress and to assist relatives in 
coping with the patient.
D. Behavioral
Behavioral techniques (see above) are most frequently used 
in therapeutic settings such as day treatment centers, but 
they can also be incorporated into family situations or any 
therapeutic setting. Many behavioral techniques (eg, posi
-
tive reinforcement—whether it be a word of praise or an 
approving nod—after some positive behavior), can be a 
powerful instrument for helping a person learn behaviors 
that will facilitate social acceptance. Music from portable 
digital players with earphones is one of many ways to divert 
the patient’s attention from auditory hallucinations.
 
»
Prognosis
For most patients with any psychosis, the prognosis is good

»
Prognosis
For most patients with any psychosis, the prognosis is good 
for alleviation of positive symptoms such as hallucinations 
or delusions treated with medication. Negative symptoms 
such as diminished affect and sociability are much more 
difficult to treat but appear mildly responsive to atypical 
antipsychotics. Cognitive deficits, such as the executive 
dysfunction that is common to schizophrenia, also do not 
appear as responsive to antipsychotics as do positive symp
-
toms. Unfortunately, both negative symptoms and cogni
-
tive deficits appear to contribute more to long-term 
disability than do positive symptoms. Unavailability of 
structured work situations and lack of family therapy or 
access to other social support are two other reasons why 
the prognosis is so guarded in such a large percentage of 
patients.
Buckley PF et al. Schizophrenia research: a progress report. Psy
-
chiatr Clin North Am. 2015 Sep;38(3):373–7. [PMID: 
26300028]
Fleischhacker WW et al. Efficacy and safety of brexpiprazole 
(OPC-34712) as maintenance treatment in adults with schizo
-
phrenia: a randomized, double-blind, placebo-controlled 
study. Int J Neuropsychopharmacol. 2017 Jan 1;20(1):11–21. 
[PMID: 27566723]
Tseng PT et al. Significant effect of valproate augmentation 
therapy in patients with schizophrenia: a meta-analysis study. 
Medicine (Baltimore). 2016 Jan;95(4):e2475. [PMID: 
26825886]
MOOD DISORDERS (
Depression & Mania
)
Present in most depressions
 
»
Mood varies from mild sadness to intense despon
-
dency and feelings of guilt, worthlessness, and 
hopelessness.
 
»
Difficulty in thinking, including inability to con
-
centrate, ruminations, and lack of decisiveness.
 
»
Loss of interest, with diminished involvement in 
work and recreation.
 
»
Somatic complaints such as disrupted, lessened, 
or excessive sleep; loss of energy; change in appe
-
tite; decreased sexual drive.
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Present in some severe depressions
 
»
Psychomotor retardation or agitation.
 
»
Delusions of a somatic or persecutory nature.
 
»
Withdrawal from activities.
 
»
Physical symptoms of major severity, eg, anorexia, 
insomnia, reduced sexual drive, weight loss, and 
various somatic complaints.
 
»
Suicidal ideation.
Possible symptoms in mania
 
»
Mood ranging from euphoria to irritability.
 
»
Sleep disruption.
 
»
Hyperactivity.
 
»
Racing thoughts.
 
»
Grandiosity or extreme overconfidence.
 
»
Variable psychotic symptoms.
 
»
Depression is extremely common, with up to 30% of pri
-
mary care patients having depressive symptoms. Depres
-
sion may be the final expression of (1) genetic factors 
(neurotransmitter dysfunction), (2) developmental prob
-
lems (personality problems, childhood events), or (3) psy
-
chosocial stresses (divorce, unemployment). It frequently 
presents in the form of somatic complaints with negative 
medical workups. 
Although sadness and grief are normal 
responses to loss, depression is not
. Patients experiencing 
normal grief tend to produce sympathy and sadness in the 
clinician caregiver; depression often produces frustration 
and irritation in the clinician. Grief is usually accompanied 
by intact self-esteem, whereas depression is marked by a 
sense of guilt and worthlessness.
Mania is often combined with depression and may 
occur alone, together with depression in a mixed episode, 
or in cyclic fashion with depression.
 
»
In general, there are four major types of depression, with 
similar symptoms in each group.
A. Adjustment Disorder with Depressed Mood
Depression may occur in reaction to some identifiable 
stressor or adverse life situation, usually loss of a person by 
death (grief reaction), divorce, etc; financial reversal (crisis); 
or loss of an established role, such as being needed. 
Anger is frequently associated with the loss, and this in 
turn often produces a feeling of guilt. The disorder occurs 
within 3 months of the stressor and causes significant 
impairment in social or occupational functioning. The 
symptoms range from mild sadness, anxiety, irritability, 
worry, and lack of concentration, discouragement, and 
somatic complaints to the more severe symptoms of frank 
depression. When the full criteria for major depressive 
disorder are present, however, then that diagnosis should 
be made and treatment instituted even when there is a 
known stressor. The presence of a stressor is not the deter
-
mining diagnostic driver, it is the resultant syndromal 
complex. One should not neglect treatment for major 
depression simply because it may appear to be an under
-
standable reaction to a particular stress or difficulty.
B. Depressive Disorders
The subclassifications include major depressive disorder 
and dysthymia.
1. Major depressive disorder—
A major depressive disor
-
der consists of a syndrome of mood, physical and cognitive 
symptoms that occurs at any time of life. Many consider a 
physiologic or metabolic aberration to be causative. Com
-
plaints vary widely but most frequently include a loss of 
interest and pleasure (anhedonia), withdrawal from activi
-
ties, and feelings of guilt. Also included are inability to 
concentrate, some cognitive dysfunction, anxiety, chronic 
fatigue, feelings of worthlessness, somatic complaints 
(unexplained somatic complaints frequently indicate 
depression), loss of sexual drive, and thoughts of death. 
Unemployment has been associated with increase in 
depression risk. Diurnal variation with improvement as the 
day progresses is common. Vegetative signs that frequently 
occur are insomnia, anorexia with weight loss, and consti
-
pation. Occasionally, severe agitation and psychotic ide
-
ation are present. 
Psychotic major depression
 occurs up to 
14% of all patients with major depression and 25% of 
patients who are hospitalized with depression. Psychotic

-
patients who are hospitalized with depression. Psychotic 
symptoms (delusions, paranoia) are more common in 
depressed persons who are older than 50 years. Paranoid 
symptoms may range from general suspiciousness to ideas 
of reference with delusions. The somatic delusions fre
-
quently revolve around feelings of impending annihilation 
or somatic concerns (eg, that the body is rotting away with 
cancer). Hallucinations are less common than unusual 
beliefs and tend not to occur independent of delusions.
In addition to psychotic major depression, other subcat
-
egories include 
major depression with atypical features
 that 
is characterized by hypersomnia, overeating, lethargy, and 
mood reactivity in which the mood brightens in response to 
positive events or news. 
Melancholic major depression
 is 
characterized by a lack of mood reactivity seen in atypical 
depression, the presence of a prominent anhedonia and more 
severe vegetative symptoms. 
Major depression with a sea
-
sonal onset (seasonal affective disorder)
 is a dysfunction of 
circadian rhythms that occurs more commonly in the fall and 
winter months and is believed to be due to decreased expo
-
sure to full-spectrum light. Common symptoms include 
carbohydrate craving, lethargy, hyperphagia, and hypersom
-
nia. 
Major depression with peripartum onset
 occurs during 
pregnancy or starts up to 4 weeks after delivery.
Half of depressions associated with the peripartum 
period start during pregnancy. Most women (up to 80%) 
experience some mild letdown of mood in the postpartum 
period. For some of these (10–15%), the symptoms are 
more severe and similar to those usually seen in serious 
depression, with an increased emphasis on concerns related 
to the baby (obsessive thoughts about harming it or inabil
-
ity to care for it). When psychotic symptoms occur, there is 
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frequently associated sleep deprivation, volatility of behavior, 
and manic-like symptoms. Postpartum psychosis is much 
less common (less than 2%), often occurs within the first 
2 weeks, and requires early and aggressive management. 
Biologic vulnerability with hormonal changes and psycho
-
social stressors all play a role. The chances of a second 
episode are about 25% and may be reduced with prophy
-
lactic treatment.
2. Dysthymia—
Dysthymia is a chronic depressive distur
-
bance. Sadness, loss of interest, and withdrawal from 
activities over a period of 2 or more years with a relatively 
persistent course is necessary for this diagnosis. Generally, 
the symptoms are milder but longer-lasting than those in a 
major depressive episode.
3. Premenstrual dysphoric disorder—
Depressive symp
-
toms occur during the late luteal phase (last 2 weeks) of the 
menstrual cycle. (See also Chapter 18.)
C. Bipolar Disorder
Bipolar disorder consists of episodic mood shifts into 
mania, major depression, hypomania, and mixed mood 
states. The ability of bipolar disorder to mimic aspects of 
many other coincident major mental health disorders and 
a high comorbidity with substance abuse can make the 
initial diagnosis of bipolar disorder difficult. 
Bipolar I
 is 
diagnosed when an individual has manic episodes. For 
individuals who experience hypomanic episodes without 
frank mania, the diagnosis is 
Bipolar II
.
1. Mania—
A manic episode is a mood state characterized 
by elation with hyperactivity, overinvolvement in life 
activities, increased irritability, flight of ideas, easy distract
-
ibility, and little need for sleep. The overenthusiastic quality 
of the mood and the expansive behavior initially attract 
others, but the irritability, mood lability with swings into 
depression, aggressive behavior, and grandiosity usually 
lead to marked interpersonal difficulties. Activities may 
occur that are later regretted, eg, excessive spending, resig
-
nation from a job, a hasty marriage, sexual acting out, and 
exhibitionistic behavior, with alienation of friends and 
family. Atypical manic episodes can include gross delu
-
sions, paranoid ideation of severe proportions, and audi
-
tory hallucinations usually related to some grandiose 
perception. The episodes begin abruptly (sometimes pre
-
cipitated by life stresses) and may last from several days to 
months. Generally, the manic episodes are of shorter dura
-
tion than the depressive episodes. In almost all cases, the 
manic episode is part of a broader bipolar disorder. 
Patients with four or more discrete episodes of a mood 
disturbance in 1 year have “rapid cycling. ” (Substance 
abuse, particularly cocaine, can mimic rapid cycling.) 
These patients have a higher incidence of hypothyroidism. 
Patients with mania differ from patients with schizophre
-
nia in that the former use more effective interpersonal 
maneuvers, are more sensitive to the social maneuvers of 
others, and are more able to utilize weakness and vulnera
-
bility in others to their own advantage. Creativity has been 
positively correlated with mood disorders, but the best 
work done is between episodes of mania and depression.
2. Cyclothymic disorders—
These are chronic mood dis
-
turbances with episodes of subsyndromal depression and 
hypomania. The symptoms must have at least a 2-year 
duration and are milder than those that occur in depressive 
or manic episodes. Occasionally, the symptoms will esca
-
late into a full-blown manic or depressive episode, in which 
case reclassification as bipolar I or II would be warranted.
D. Mood Disorders Secondary to Illness and 
Any illness, severe or mild, can cause significant depres
-
sion. Conditions such as rheumatoid arthritis, multiple 
sclerosis, stroke, and chronic heart disease are particularly 
likely to be associated with depression, as are other chronic 
illnesses. Depression is common in cancer, as well, with a

illnesses. Depression is common in cancer, as well, with a 
particularly high degree of comorbidity in pancreatic cancer. 
Hormonal variations clearly play a role in some depres
-
sions. Varying degrees of depression occur at various times 
in schizophrenic disorders, central nervous system disease, 
and organic mental states. Alcohol dependency frequently 
coexists with serious depression.
The classic model of 
drug-induced depression
 occurred 
with the use of reserpine, both in clinical settings and as a 
pharmacologic probe in research settings. Corticosteroids 
and oral contraceptives are commonly associated with mood 
changes such as depression and hypomania. Antihyperten
-
sive medications such as methyldopa, guanethidine, and 
clonidine have been associated with the development of 
depressive syndromes, as have digitalis and antiparkinson
-
ism medications (eg, levodopa). Interferon is strongly asso
-
ciated with depressed mood and fatigue as a side effect; 
consultation with a psychiatrist prior to prescribing these 
agents is indicated in cases where there is a history of depres
-
sion. It is unusual for beta-blockers to produce depression 
when given for short periods, such as in the treatment of 
performance anxiety. Sustained use of beta-blockers for 
medical conditions such as hypertension may be associated 
with depression in some patients, although most individuals 
do not suffer this adverse effect. One study associated the 
use of beta-blockers with a significant reduction in risk of 
depressive symptoms 1 year after a percutaneous coro
-
nary intervention. Infrequently, disulfiram and anticholines
-
terase medications may be associated with symptoms of 
depression. All stimulant use results in a depressive syn
-
drome when the drug is withdrawn. Alcohol, sedatives, 
opioids, and most of the psychedelic drugs are depressants 
and, paradoxically, are often used in self-treatment of depres
-
sion. Corticosteroids may be associated with hypomania.
 
»
Since depression may be a part of any illness—either reac
-
tively or as a secondary symptom—careful attention must 
be given to personal life adjustment problems and the role 
of medications (eg, reserpine, corticosteroids, levodopa). 
Schizophrenia, partial complex seizures, organic brain syn
-
dromes, panic disorders, and anxiety disorders must be 
differentiated. Thyroid dysfunction and other endocrinopa
-
thies should be ruled out. Malignancies, including central 
and gastrointestinal tumors are sometimes associated with 
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depressive symptoms and may antecede the diagnosis of 
tumor. Strokes, particularly dominant hemisphere lesions, 
can occasionally present with a syndrome that looks like 
major depression. Medication-induced depressive symp
-
toms are also quite common.
 
»
The most important complication is 
suicide
, which often 
includes some elements of aggression. Suicide rates in the 
general population vary from 9 per 100,000 in Spain to 
20 per 100,000 in the United States to 58 per 100,000 in 
Hungary. In individuals hospitalized for depression, the life
-
time risk rises to 10–15%. In patients with bipolar I disor
-
der, the risk is higher, with up to 20% of individuals dying 
of suicide. Men over the age of 50 are more likely to com
-
plete a suicide because of their tendency to attempt suicide 
with more violent means, particularly guns. On the other 
hand, women make more attempts but are less likely to 
complete a suicide. An increased suicide rate is being 
observed in the younger population, aged 15–35. Patients 
with cancer, respiratory illnesses, AIDS, and those being 
maintained on hemodialysis have higher suicide rates. 
Alcohol use is a significant factor in many suicide attempts.
There are several groups of people who make suicide 
attempts. One group includes those individuals with acute 
situational problems. These individuals may be acutely dis
-
tressed by a recent breakup in a relationship or another type 
of disappointment. This group also includes those who may 
not be diagnosed as having depression, but who are over
-
whelmed by a stressful situation often with an aspect of 
public humiliation (eg, victims of cyber-bullying). A suicide 
attempt in such cases may be an impulsive or aggressive act 
not associated with significant depression.
Another high-risk group includes individuals with severe 
depression. Severe depression may be due to conditions such 
as medical illness (eg, AIDS, whose victims have a suicide 
rate over 20 times that of the general population) or comor
-
bid psychiatric disorders (eg, panic disorders). Anxiety, 
panic, and fear are major findings in suicidal behavior. A 
patient may seem to make a dramatic improvement, but the 
lifting of depression may be due to the patient’s decision to 
commit suicide. Another high-risk group are individuals 
with psychotic illness who tend not to verbalize their con
-
cerns and are often successful in their suicide attempt, 
although they make up only a small percentage of the total.
Suicide is 10 times more prevalent in patients with 
schizophrenia than in the general population, and jumping 
from bridges is a more common means of attempted sui
-
cide by patients with schizophrenia than by others. In one 
study of 100 people who jumped from bridges, 47% had 
The immediate goal of psychiatric evaluation is to 
assess the current suicidal risk and the need for hospitaliza
-
tion versus outpatient management. 
Perhaps the one most 
useful question is to ask the person how many hours per day 
he or she thinks about suicide
. If it is more than 1 hour, the 
individual is at high risk. Further assessing the risk by 
inquiring about intent, plans, means, and suicide-inhibit
-
ing factors (eg, strong ties to children or the church) is 
essential. Alcohol, hopelessness, delusional thoughts, and 
complete or nearly complete loss of interest in life or ability 
to experience pleasure are all positively correlated with 
suicide attempts. Other risk factors are previous attempts, 
a family history of suicide, medical or psychiatric illness 
(eg, anxiety, depression, psychosis), male sex, older age, 
contemplation of violent methods, a humiliating social 
stressor, and drug use (including long-term sedative or 
alcohol use), which contributes to impulsiveness or mood 
swings. Successful treatment of the patient at risk for sui
-
cide cannot be achieved if the patient continues to abuse

-
cide cannot be achieved if the patient continues to abuse 
drugs. An attempt is less likely to be suicidal, for example, 
if small amounts of poison or medication were ingested or 
scratching of wrists was superficial, if the act was per
-
formed in the vicinity of others or with early notification of 
others, or if the attempt was arranged so that early detec
-
tion would be anticipated.
The patient’s current mood status is best evaluated by 
direct evaluation of plans and concerns about the future, 
personal reactions to the attempt, and thoughts about the 
reactions of others. Measurement of mood is often facilitated 
by using a standardized instrument such as the Hamilton or 
Montgomery-Asberg clinician-administered rating scales 
or the self-administered Patient Health Questionnaire-9. 
Scales allow for initial assessment as well as ongoing treat
-
ment tracking. Suicide risk can be specifically assessed 
using an instrument such as the Columbia-Suicide Severity 
Risk Scale. The patient’s immediate resources should also 
be assessed—people who can be significantly involved 
(most important), family support, job situation, financial 
resources, etc.
If hospitalization is not indicated after a suicide attempt, 
the clinician must formulate and institute a treatment plan 
or make an adequate referral. (The National Suicide Pre
-
vention Lifeline, 1-800-273-8255, may be of assistance.) 
Medication should be dispensed in small amounts to at-
risk patients. Although TCAs and SSRIs are associated with 
an equal incidence of suicide attempts, the risk of a com
-
pleted suicide is much higher with TCA overdose. Guns 
and medications should be removed from the patient’s 
household. Driving should be interdicted until the patient 
improves. The problem is often worsened by the long-term 
complications of the suicide attempt, eg, brain damage due 
to hypoxia, peripheral neuropathies caused by staying for 
long periods in one position causing nerve compressions, 
and medical or surgical problems such as esophageal stric
-
tures and tendon dysfunctions.
 
»
Treatment of Depression
A. Medical
Milder forms of depression
 usually do not require medi
-
cation therapy and can be managed by psychotherapy and 
the passage of time. In severe cases—particularly when 
vegetative signs are significant and symptoms have per
-
sisted for more than a few weeks—antidepressant medica
-
tion therapy is often effective. Medication therapy is also 
suggested by a family history of major depression in first-
degree relatives or a past history of prior episodes.
The antidepressant medications may be classified into 
four groups: (1) the newer antidepressants, including the 
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SSRIs, SNRIs, and bupropion, vilazodone, vortioxetine, 
and mirtazapine, (2) the TCAs and clinically similar medi
-
cations, (3) the MAO inhibitors (Table 25–7), and (4) 
stimulants. ECT and repetitive transcranial magnetic stim
-
ulation are procedural treatments for depression. These 
modalities are described in greater detail below.
Hospitalization is necessary if suicide is a major consid
-
eration or if complex treatment modalities are required.
Medication selection is influenced by the history of pre
-
vious response or lack thereof if that information is avail
-
able. A positive family history of response to a particular 
medication suggests that the patient may respond similarly. 
If no background information is available, a medication 
such as sertraline, 25 mg orally daily and increasing gradu
-
ally up to 200 mg, or venlafaxine at 37.5 mg/day and titrated 
gradually to a maximum dose of 225 mg/day can be selected 
and a 
full trial
 instituted. The medication trial should be 
monitored for worsening mood or suicidal ideation with 
patient assessments every 1–2 weeks until week 6. The 
STAR
*
D trial suggests that if the response to the first medi
-
cation is inadequate, the best alternatives are to switch to a 
second agent that may be from the same or different class 
of antidepressant; another option is to try augmenting the 
first agent with bupropion (150–450 mg/day), lithium 
(eg, 300–900 mg/day orally), thyroid medication (eg, lio
-
thyronine, 25–50 mcg/day orally) or a second-generation 
antipsychotic (eg, aripiprazole [5–15 mg/day] or olanzap
-
ine [5–15 mg/day]). The latter course is often taken when 
there has been at least a partial response to the initial medi
-
cation. The Agency for Health Care Policy and Research 
has produced clinical practice guidelines that outline one 
algorithm of treatment decisions (Figure 25–2).
Psychotic depression
 should be treated with a combi
-
nation of an antipsychotic such as olanzapine and an anti
-
depressant such as an SSRI at their usual doses. Mifepristone 
may have specific and early activity against psychotic 
depression. ECT is generally regarded as the single most 
effective treatment for psychotic depression.
Major depression with atypical features
 or 
seasonal 
onset
 can be treated with bupropion or an SSRI with good 
results. MAO inhibitors appear more effective than TCAs, 
and an MAO inhibitor may be used if more benign antide
-
pressant strategies prove unsuccessful.
Melancholic depression
 may respond to ECT, TCAs, 
and SNRIs, which are preferable to SSRIs. However, SSRIs 
are often used in the treatment of melancholic depression 
and are effective in many cases.
Caution: Depressed patients often have suicidal 
thoughts, and the amount of medication dispensed should 
be appropriately controlled particularly if prescribing an 
MAO inhibitor, TCA, and to a lesser extent, venlafaxine. At 
the same time, adults with untreated depression are at 
higher risk for suicide than those who are treated suffi
-
ciently to reduce symptoms. It has been thought that in 
children and adolescent populations, antidepressants may 
be associated with some slightly increased risk of suicidality. 
One meta-analysis indicates that suicidality persists even 
after symptoms of depression are treated, suggesting other 
causes such as increased impulsivity among younger 
patients. After age 25, antidepressants may have neutral or 
possibly protective effects until age 65 years or older. The 
older TCAs have a narrow therapeutic index. One advan
-
tage of the newer medications is their wider margin of 
safety. Nonetheless, even with newer agents, because of the 
possibility of suicidality early in antidepressant treatment, 
close follow-up is indicated. In all cases of pharmacologic 
management of depressed states, caution is indicated until 
the risk of suicide is considered minimal.
1. SSRIs, SNRIs, and atypical antidepressants—
The SSRIs

The SSRIs 
include fluoxetine, sertraline, paroxetine, fluvoxamine, 
citalopram and its enantiomer escitalopram (Table 25–7). 
The chief advantages of these agents are that they are gen
-
erally well tolerated, the starting dose is typically a thera
-
peutic dose for most patients, and they have much lower 
lethality in overdose compared to TCAs or MAO inhibi
-
tors. (Notably, citalopram carries a warning regarding QT 
prolongation in doses above 40 mg, and 20 mg is consid
-
ered the maximum dose for patients older than 60 years. 
There is no similar FDA warning for escitalopram.) The 
SNRIs include venlafaxine, desvenlafaxine, duloxetine, 
milnacipran, and levomilnacipran. In addition to possess
-
ing the strong serotonin reuptake blocking properties of 
the SSRIs, the SNRIs are also norepinephrine reuptake 
blockers. The combined serotonergic-noradrenergic prop
-
erties of these medications may provide benefits in pain 
conditions such as neuropathy and fibromyalgia as well as 
conditions such as stress incontinence. The atypical antide
-
pressants are bupropion, nefazodone, trazodone, vilazo
-
done, vortioxetine, and mirtazapine (Table 25–7). All of 
these antidepressants are effective in the treatment of 
depression, both typical and atypical. The SSRI medica
-
tions have been effective in the treatment of panic disorder, 
bulimia, GAD, OCD, and PTSD.
Most of the medications in this group tend to be activat
-
ing and are given in the morning so as not to interfere with 
sleep. Some patients, however, may have sedation, requiring 
that the medication be given at bedtime. This reaction 
occurs most commonly with paroxetine, fluvoxamine, and 
mirtazapine. The SSRIs can be given in once-daily dosage. 
Nefazodone and trazodone are usually given twice daily. 
Bupropion and venlafaxine are available in extended-release 
formulations and can be given once daily. There is usually some 
delay in response; fluoxetine, for example, requires 2–6 weeks to 
act in depression, 4–8 weeks to be effective in panic disorder, 
and 6–12 weeks in treatment of OCD. The starting dose 
(10 mg) is given for 1 week before increasing to the average 
daily oral dose of 20 mg for depression, while OCD may 
require up to 80 mg daily. Some patients, particularly the 
elderly, may tolerate and benefit from as little as 10 mg/day 
or every other day. The other SSRIs have shorter half-lives 
and a lesser effect on hepatic enzymes, which reduces their 
impact on the metabolism of other medications (thus not 
increasing significantly the serum concentrations of other 
medications as much as fluoxetine). The shorter half-lives 
also allow for more rapid clearing if adverse side effects 
appear. Venlafaxine appears to be more effective with 
doses greater than 200 mg/day orally, although some indi
-
viduals respond to doses as low as 75 mg/day.
The side effects common to all of these medications are 
headache, nausea, tinnitus, insomnia, and nervousness. 
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Table 25–7.
 
Commonly used antidepressants (listed in alphabetical order within classes).
Usual 
Daily Oral 
Dose (mg)
Usual Daily 
Maximum 
Dose (mg)
Sedative 
Effects
1
Anticholinergic 
Effects
1
Cost for 30 Days 
Treatment Based on 
Maximum Dosage
2
SSRIs
Citalopram (Celexa)
20
40
< 1
1
$2.53/40 mg
$75.90
Escitalopram (Lexapro)
10
20
< 1
1
$4.51/20 mg
$135.30
Fluoxetine (Prozac, Sarafem)
5–40
80
< 1
< 1
$2.48/20 mg
$297.60
Fluvoxamine (Luvox)
100–300
300
1
< 1
$2.64/100 mg
$237.60
Paroxetine (Paxil)
20–30
50
1
1
$2.64/20 mg
$161.10
Sertraline (Zoloft)
50–150
200
< 1
< 1
$2.85/100 mg
$171.00
SNRIs
Desvenlafaxine (Pristiq)
50
100
1
< 1
$11.47/100 mg
$344.10
Duloxetine (Cymbalta)
40
60
2
3
$5.93/60 mg
$177.90
Levomilnacipran (Fetzima)
40
120
1
1
$14.35/80 mg
$430.50
Milnacipran (Savella)
100
200
1
1
$6.98/100 mg
$418.80
Venlafaxine XR (Effexor)
150–225
225
1
< 1
$4.67/75 mg
$420.30
Tricyclic and Clinically Similar Compounds
Amitriptyline (Elavil)
150–250
300
4
4
$2.14/150 mg
$128.40
Amoxapine (Asendin)
150–200
400
2
2
$1.98/100 mg
$237.60
Clomipramine (Anafranil)
100
250
3
3
$11.24/75 mg
$1348.80
Desipramine (Norpramin)
100–250
300
1
1
$5.74/100 mg
$498.60
Doxepin (Sinequan)
150–200
300
4
3
$1.97/100 mg
$177.30
Imipramine (Tofranil)
150–200
300
3
3
$1.22/50 mg
$219.60
Maprotiline (Ludiomil)
100–200
300
4
2
$2.34/75 mg
$280.80
Nortriptyline (Aventyl, Pamelor)
100–150
150
2
2
$0.29/75 mg
$17.40
Protriptyline (Vivactil)
15–40
60
1
3
$3.30/10 mg
$594.00
Trimipramine (Surmontil)
75–200
200
4
4
$9.44/100 mg
$566.40
Monoamine Oxidase Inhibitors
Phenelzine (Nardil)
45–60
90
…
…
$0.84/15 mg
$151.20
Selegiline transdermal (Emsam)
6 (skin 
patch)
12
…
…
$65.98/6 mg 
patch
$1979.50
Tranylcypromine (Parnate)
20–30
50
…
…
$8.41/10 mg
$1261.50
Other Compounds
Bupropion SR (Wellbutrin SR)
300
400
3
< 1
< 1
$3.38/200 mg
$202.80
Bupropion XL (Wellbutrin XL)
300
4
450
4
< 1
< 1
$0.55/300 mg
$32.10
Mirtazapine (Remeron)
15–45
45
4
2
$2.80/30 mg
$84.90
Nefazodone (Serzone)
150–600
600
3
1
$4.98/200 mg
$448.20
Trazodone (Desyrel)
100–300
400
4
< 1
$0.50/100 mg
$60.00
Vilazodone (Viibryd)
10–40
40
1
1
$9.94/40 mg
$298.20
Vortioxetine (Brintellix)
10
20
<1
< 1
$15.12/20 mg
$453.60
1
2
Red Book
Analytics, Information, http://www.micormedexsolutions.com, accessed April 10, 2018. AWP may not accurately represent the actual phar
-
3
200 mg twice daily.
4
Wellbutrin XL is a once-daily form of bupropion. Bupropion is still available as immediate release, and, if used, no single dose should exceed 
150 mg.
SSRIs, selective serotonin reuptake inhibitors.
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Akathisia has been common with the SSRIs; other extrapy
-
ramidal symptoms (eg, dystonias) have occurred infre
-
quently but particularly in withdrawal states. Because 
SSRIs affect platelet serotonin levels, abnormal bleeding 
can occur. Sertraline and citalopram appear to be the safest 
agents in this class when used with warfarin. Sexual side 
effects of erectile dysfunction, retrograde ejaculation, and 
dysorgasmia are very common with the SSRIs. Oral phos
-
phodiesterase-5 inhibitors (such as sildenafil, 25–50 mg; 
tadalafil, 5-20 mg; or vardenafil, 10–20 mg taken 1 hour 
prior to sexual activity) can improve erectile dysfunction in 
some patients and have been shown to improve other SSRI-
induced sexual dysfunction in both men and women. 
Adjunctive bupropion (75–150 mg orally daily) may also 
Make diagnosis
Somewhat bet
te
r
Not better at all
Clear
ly
 bet
te
r
Clear
ly
 bet
te
r
No
Relapse?
Select and initiate
treatment
Monitor treatment
(e
ve
ry
 1–2 weeks)
Assess response
(week 6)
1
Continue treatment
(adjust dosage)
Augment or change
treatment
for 6 more weeks
Complete
remission?
Medication continued
for 4–9 months
Consider maintenance
treatment
Re
fer or consult a
p
sy
chiatrist or other
mental health
professional
Change treatment
(e
ve
ry
 1–2 weeks)
(week 
12
)
1
Not bet
te
r
Ye
s
1
Times of assessment (weeks 6 and 12) rest on 
ve
ry
 modest data. It may be necessary
  
to
 
re
vise the treatment plan earlier for patients not responding at all.
 
▲
Figure 25–2.
 
Overview of treatment for depression. 
(Reproduced from Agency for Health Care Policy and Research: 
Depression in Primary Care. Vol. 2: Treatment of Major Depression. United States Department of Health and Human Services, 
1993.)
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enhance sexual arousal. Cyproheptadine, 4 mg orally prior 
to sexual activity, may be helpful in countering drug-
induced anorgasmia but also is quite sedating and may 
counter the therapeutic benefits of SSRIs as well. Taking a 
“drug holiday, ” ie, skipping a day of medication periodically 
when sexual activity is anticipated, can also decrease sexual 
side effects. The SSRIs are strong serotonin uptake blockers 
and may in high dosage or in combination with MAO 
inhibitors, including the antiparkinsonian drug selegiline, 
cause a 
“serotonin syndrome. ”
 This syndrome is mani
-
fested by rigidity, hyperthermia, autonomic instability, 
myoclonus, confusion, delirium, and coma. This syndrome 
can be a particularly troublesome problem in the elderly. 
Research indicates that SSRIs are safer agents to use than 
TCAs in patients with cardiac disease; the SSRI sertraline is 
a safe and effective antidepressant treatment in patients 
with acute myocardial infarction or unstable angina.
Withdrawal symptoms, including dizziness, paresthe
-
sias, dysphoric mood, agitation, and a flu-like state, have 
been reported for the shorter-acting SSRIs and SNRIs but 
may occur with other classes including the TCAs and 
MAO inhibitors. These medications should be discontin
-
ued gradually over a period of weeks or months to reduce 
the risk of withdrawal phenomena.
Fluoxetine, fluvoxamine, sertraline, venlafaxine, and 
citalopram in customary antidepressant doses may increase 
the risk of major fetal malformation when used during preg
-
nancy; however, the absolute risk of congenital defects is 
considered low. Maternal major mood disorder in pregnancy 
by itself carries its own risks to the mother and fetus and has 
been linked to low birth weight and preterm delivery. 
 
Postpartum effects of prenatal depression have not been 
studied. The decision to use SSRIs and other psychotropic 
agents during pregnancy and postpartum must be a col
-
laborative decision based on a thorough risk-benefit analy
-
sis for each individual.
Venlafaxine lacks significant anticholinergic side 
effects. Nausea, nervousness, and profuse sweating appear 
to be the major side effects. Venlafaxine appears to have 
few drug-drug interactions. It does require monitoring of 
blood pressure because dose-related hypertension may 
develop in some individuals. Venlafaxine prescribing in 
the United Kingdom has been restricted to psychiatrists. 
Venlafaxine appears to carry a greater risk of lethal 
arrhythmias in instances of overdose relative to the SSRIs, 
but less risk than with the TCAs. Desvenlafaxine, a newer 
form of the medication, is started at its target dose of 
50 mg/day orally and does not require upward titration 
although higher doses have been well studied and some 
patients benefit from 100 mg/day. Duloxetine may also 
result in small increases in blood pressure. Common side 
effects include dry mouth, dizziness, and fatigue. Inhibitors 
of 1A2 and 2D6 may increase duloxetine levels with a risk 
of toxicity. Milnacipran, approved for the treatment of 
fibromyalgia, and levomilnacipran, approved for the treat
-
ment of major depression, carry many of the side effects 
common to other SNRIs including a mild tachycardia, hyper
-
tension, sexual side effects, mydriasis, urinary constriction, 
and occasional abnormal bleeding. Levomilnacipran is 
started at 20 mg/day orally then increased to 40 mg/day 
 
after 2–3 days. The target dose is 40–120 mg given once 
daily. Milnacipran is typically started at 12.5 mg/day 
orally, titrated to 12.5 mg twice daily after 2 days, and then 
to 25 mg twice daily after 7 days. The target dose is typically 
100–200 mg/day given in in two divided doses. While not 
approved for the treatment of major depression, the evi
-
dence suggests that milnacipran, like levomilnacipran, is an 
effective antidepressant agent.
Nefazodone appears to lack the anticholinergic effects

-
Nefazodone appears to lack the anticholinergic effects 
of the TCAs and the agitation sometimes induced by SSRIs. 
Nefazodone should not be given with terfenadine, astem
-
izole, or cisapride, which are not commercially available in 
the United States. Because nefazodone inhibits the liver’s 
cytochrome P450 3A4 isoenzymes, concurrent use of these 
medications can lead to serious QT prolongation, ventricu
-
lar tachycardia, or death. Through the same mechanism of 
enzyme inhibition, nefazodone can elevate cyclosporine 
levels sixfold to tenfold. Nefazodone carries an FDA warn
-
ing given its association with liver failure in rare cases. 
Pretreatment and ongoing monitoring of liver enzymes are 
Mirtazapine is thought to enhance central noradrener
-
gic and serotonergic activity with minimal sexual side 
effects compared with the SSRIs. Its action as a potent 
antagonist of histaminergic receptors may make it a useful 
agent for patients with depression and insomnia. It is also 
an effective antiemetic due to its antagonism of the 5-HT
3
 
receptor. Its most common adverse side effects include 
somnolence, increased appetite, weight gain, lipid abnor
-
malities, and dizziness. The labeling for mirtazapine indi
-
cated that agranulocytosis was seen in 2 of 2796 patients in 
premarketing studies. An association of agranulocytosis or 
a clinically significant neutropenia with the medication 
appears to be modest. Although it is metabolized by P450 
isoenzymes, it is not an inhibitor of this system. It is given 
in a single oral dose at bedtime starting at 15 mg and 
increasing in 15-mg increments every week or every other 
week up to 45 mg.
Vortioxetine is a newer antidepressant that blocks sero
-
tonin reuptake, is a partial agonist of the 5-HT
1A
 receptor, 
and effects a variety of other serotonin receptor sites. The 
side effects attributed to its serotonergic effects include 
gastrointestinal upset and sexual dysfunction. Vortioxetine 
has demonstrated efficacy in improving cognitive symp
-
toms of depression and received regulatory approval for 
this indication in Europe. Vortioxetine is typically dosed at 
10 mg/day orally and may be increased to 20 mg/day.
2. Tricyclic antidepressants (TCAs) and clinically similar 
medications—
TCAs were the mainstay of medication 
therapy for depression for many years. They have also been 
effective in panic disorder, pain syndromes, and anxiety 
states. Specific ones have been studied and found to be 
effective in OCD (clomipramine), enuresis (imipramine), 
psychotic depression (amoxapine), and reduction of crav
-
ing in cocaine withdrawal (desipramine).
TCAs are characterized more by their similarities than 
by their differences. They tend to affect both serotonin and 
norepinephrine reuptake; some medications act mainly on 
the former and others principally on the latter neurotrans
-
mitter system. Individuals receiving the same dosages vary 
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markedly in therapeutic drug levels achieved (elderly 
patients require smaller doses), and determination of 
plasma drug levels is helpful when clinical response has 
been disappointing. Nortriptyline is usually effective when 
plasma levels are between 50 and 150 ng/mL; imipramine at 
plasma levels of 200–250 ng/mL; and desipramine at plasma 
levels of 100–250 ng/mL. High blood levels are not more 
effective than moderate levels and may be counterproduc
-
tive (eg, delirium, seizures). Patients with gastrointestinal 
side effects benefit from plasma level monitoring to assess 
absorption of the drug. Most TCAs can be given in a single 
dose at bedtime, starting at fairly low doses (eg, nortripty
-
line 25 mg orally) and increasing by 25 mg every several 
days as tolerated until the therapeutic response is achieved 
(eg, nortriptyline, 100–150 mg) or to maximum dose if 
necessary (eg, nortriptyline, 150 mg). The most common 
cause of treatment failure is an inadequate trial. A full trial 
consists of giving a therapeutic daily dosage for at least 6 weeks. 
Because of marked anticholinergic and sedating side effects, 
clomipramine is started at a low dose (25 mg/day orally) 
and increased slowly in divided doses up to 100 mg/day, 
held at that level for several days, and then gradually 
increased as necessary up to 250 mg/day. The TCAs have 
anticholinergic side effects to varying degrees (amitriptyline 
100 mg is equivalent to atropine 5 mg). One must be par
-
ticularly wary of the effect in elderly men with prostatic 
hyperplasia. The anticholinergic effects also predispose to 
other medical problems such as constipation, confusion, 
heat stroke, or dental problems from xerostomia. Ortho
-
static hypotension is fairly common, is not dose-dependent 
and may not remit with time on medication; this may pre
-
dispose to falls and hip fractures in the elderly.
Cardiac effects of the TCAs are functions of the anti
-
cholinergic effect, direct myocardial depression, quinidine-
like effect, and interference with adrenergic neurons. These 
factors may produce altered rate, rhythm, and contractility, 
particularly in patients with preexisting cardiac disease, 
such as bundle-branch or bifascicular block. Even relatively 
small overdoses (eg, 1500 mg of imipramine) have resulted 
in lethal arrhythmias. Electrocardiographic changes range 
from benign ST segment and T wave changes and sinus 
tachycardia to a variety of complex and serious arrhyth
-
mias, the latter requiring a change in medication. Because 
TCAs have class I antiarrhythmic effects, they should be 
used with caution in patients with ischemic heart dis
-
ease, arrhythmias, or conduction disturbances. SSRIs or 
the atypical antidepressants are better initial choices for 
this population.
TCAs lower the seizure threshold so this is of particular 
concern in patients with a propensity for seizures. Loss of 
libido and erectile, ejaculatory, and orgasmic dysfunction 
are fairly common and can compromise compliance. Trazo
-
done rarely causes priapism (1 in 9000), but when it occurs, 
it requires treatment within 12 hours (epinephrine 1:1000 
injected into the corpus cavernosum). Delirium, agitation, 
and mania are infrequent complications of the TCAs but 
can occur. Sudden discontinuation of some of these medi
-
cations can produce “cholinergic rebound, ” manifested by 
headaches and nausea with abdominal cramps. Overdoses 
of TCAs are often serious because of the narrow therapeutic 
index and quinidine-like effects (see Chapter 38).
3. Monoamine oxidase inhibitors—
The MAO inhibitors 
are generally used as third-line medications for depression 
(after a failure of SSRIs, SNRIs, TCAs, or the atypical anti
-
depressants) because of the dietary and other restrictions 
required (Table 25–8). They should be considered third-
line medications for refractory panic disorder as well as 
depression; however, this hierarchy has become more flex
-

-
ible since MAO inhibitor skin patches (selegiline) have 
become available. They deliver the MAO inhibitor to the 
bloodstream bypassing the gastrointestinal tract so that 
dietary restrictions are not necessary in the lowest dosage 
strength (6 mg/24 h).
The MAO inhibitors commonly cause symptoms of 
orthostatic hypotension (which may persist) and sympa
-
thomimetic effects of tachycardia, sweating, and tremor. 
Nausea, insomnia (often associated with intense afternoon 
drowsiness), and sexual dysfunction are common. Zolpi
-
dem 5–10 mg orally at bedtime can ameliorate MAO-
induced insomnia. Central nervous system effects include 
agitation and toxic psychoses. Dietary limitations (see 
Table 25–8) and abstinence from medication products 
containing phenylpropanolamine, phenylephrine, meperi
-
dine, dextromethorphan, and pseudoephedrine are man
-
datory for MAO-A type inhibitors (those marketed for 
treatment of depression), since the reduction of available 
MAO leaves the patient vulnerable to exogenous amines 
(eg, tyramine in foodstuffs).
4. Stimulants and other medications under investiga
-
tion—
Dextroamphetamine (5–30 mg/day orally) and 
methylphenidate (10–45 mg/day orally) may be effective 
for the short-term treatment of some depressive symptoms 
in medically ill and geriatric patients. The stimulants are 
notable for rapid onset of action (hours) and a paucity of 
side effects (tachycardia, agitation) in most patients. They 
are usually given in two divided doses early in the day (eg, 
7 am and noon) so as to avoid interfering with sleep. These 
agents may also be useful as adjunctive agents in refractory 
depression. Intravenous infusion of the dissociative anes
-
thetic ketamine has been shown to lead to a rapid improve
-
ment in depressive symptoms in 50–70% of patients with 
depression. The effects of a single treatment are short-lived 
(about 3–7 days). Ketamine and other NMDA antagonists 
continue to be evaluated in the treatment of resistant 
depression.
5. Switching and combination therapy—
If the therapeu
-
tic response has been poor after an adequate trial with the 
chosen medication, the diagnosis should be reassessed. 
Table 25–8.
 
Principal dietary restrictions in MAOI use.
1.
  
Cheese
, except cream cheese and cottage cheese and fresh 
yogurt
2.
  
F
ermented or aged meats such as bologna, salami
3.
  
Br
oad bean pods such as Chinese bean pods
4.
  
Liv
er of all types
5.
  
M
eat and yeast extracts
6.
  
Red wine
, sherry, vermouth, cognac, beer, ale
7.
  
S
oy sauce, shrimp paste, sauerkraut
MAOI, monoamine oxidase inhibitor.
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Assuming that the trial has been adequate and the diagno
-
sis is correct, a trial with a second medication is appropri
-
ate. In switching from one group to another, an adequate 
“washout time” must be allowed. This is critical in certain 
situations—eg, in switching from an MAO inhibitor to a 
TCA, allow 2–3 weeks between stopping one medication 
and starting another; in switching from an SSRI to an 
MAO inhibitor, allow 4–5 weeks for fluoxetine and at least 
2 weeks for other SSRIs. In switching within groups—eg, 
from one TCA to another (amitriptyline to desipramine, 
etc)—no washout time is needed, and one can rapidly 
decrease the dosage of one medication while increasing the 
other. In clinical practice, adjunctive treatment with lith
-
ium, buspirone, or thyroid hormone may be helpful in 
depression. The adjunctive use of low-dose atypical anti
-
psychotics such as aripiprazole, olanzapine, and quetiapine 
in the treatment of patients with refractory depression is 
supported by research. The side effect risk is the same as 
when treating psychosis. Adding an atypical agent requires 
monitoring body mass index, lipids, and glucose. Combin
-
ing two antidepressants, or adding an antipsychotic to an 
antidepressant, requires caution and is usually reserved for 
clinicians who feel comfortable managing this or after psy
-
chiatric consultation.
6. Maintenance and tapering—
When clinical relief of 
symptoms is obtained, medication is continued for 12 months 
in the effective maintenance dosage, which is the dosage 
required in the acute stage. The full dosage should be contin
-
ued indefinitely when the individual has a first episode 
before age 20 or after age 50, is over age 40 with two epi
-
sodes, at least one episode after age 50, or has had three 
episodes at any age. 
Major depression should often be consid
-
ered a chronic disease
. If the medication is being tapered, it 
should be done gradually over several months, monitoring 
closely for relapse.
7. Drug interactions—
Interactions with other medications 
are listed in Table 25–9.
8. Electroconvulsive therapy—
ECT causes a generalized 
central nervous system seizure (peripheral convulsion is 
not necessary) by means of electric current. The key objec
-
tive is to exceed the seizure threshold, which can be accom
-
plished by a variety of means. The mechanism of action is 
not known, but it is thought to involve major neurotrans
-
mitter responses at the cell membrane.
ECT is the most effective (about 70–85%) treatment of 
severe depression. It is particularly effective for the delu
-
sions and agitation commonly seen with depression in the 
elderly. It is indicated when medical conditions preclude 
the use of antidepressants, nonresponsiveness to these 
medications, and extreme suicidality. Comparative con
-
trolled studies of ECT in severe depression show that it is 
more effective than pharmacotherapy. It is also effective in 
the treatment of mania and psychoses during pregnancy 
(when medications may be contraindicated). It has also 
been shown to be helpful in chronic schizophrenic disor
-
ders when clozapine alone is not fully effective.
The most common side effects of ECT are memory dis
-
turbance and headache. Memory loss or confusion is usually 
related to the number and frequency of ECT treatments and 
proper oxygenation during treatment. Unilateral ECT is 
Table 25–9.
 
Antidepressant drug interactions with other 
medications (listed in alphabetical order within classes).
Effects
Tricyclic and Other Non-MAOI Antidepressants
Antacids
Decreased absorption of antidepressants
Increased hypoprothrombinemic effect
Increased antidepressant blood levels 
and psychosis
Clonidine
Decreased antihypertensive effect
Digitalis
Increased incidence of heart block
Increased antidepressant blood levels
Increased antidepressant levels
Insulin
Decreased blood sugar
Lithium

Digitalis
Insulin
Lithium
Increased lithium levels with fluoxetine
Other anticholinergic 
Marked anticholinergic responses
Phenytoin
Increased blood levels
Decreased ventricular conduction
Procarbazine
Hypertensive crisis
Increased hypotension
Quinidine
Rauwolfia derivatives
Increased stimulation
Sedatives
Increased sedation
Sympathomimetic 
Increased vasopressor effect
Terfenadine,
1
 
astemizole,
1
 cisapride
1
Torsades de pointes
MAOIs
Belladonna-like medications
Increased blood pressure
Dextromethorphan
Same as meperidine
Guanethidine
Decreased blood pressure
Insulin
Levodopa
Increased agitation, serotonin 
 
syndrome, death
Pseudoephedrine
Hypertensive crisis (increased blood 
pressure)
Reserpine
Increased blood pressure/ 
 
hypertensive crisis
Succinylcholine
Increased neuromuscular blockade
Sulfonylureas
Increased blood pressure/
 
SSRIs, SNRIs, triptans
Serotonin syndrome, death
1
Terfenadine, astemizole, and cisapride are not commercially 
MAOIs, monoamine oxidase inhibitors; SNRIs, serotonin norepi
-
nephrine reuptake inhibitors; SSRIs, selective serotonin reuptake 
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associated with less memory loss than bilateral ECT. Both 
anterograde and retrograde memory loss may occur, but 
short term-retrograde memory loss is more common. While 
some memory deficits may persist, memory loss tends to 
improve in a few weeks after the last ECT treatment. There 
have been reports that lithium administration concurrent 
with ECT resulted in greater memory loss.
Increased intracranial pressure is a relative contraindi
-
cation. Other problems such as cardiac disorders, aortic 
aneurysms, bronchopulmonary disease, and venous 
thrombosis must be evaluated in light of the severity of the 
medical problem versus the need for ECT. Serious compli
-
cations arising from ECT occur in less than 1 in 1000 cases. 
Most of these problems are cardiovascular or respiratory in 
nature (eg, aspiration of gastric contents, arrhythmias, 
myocardial infarction). Poor patient understanding and 
lack of acceptance of the technique by the public are the 
biggest obstacles to the use of ECT.
9. Phototherapy—
Phototherapy is used in major depres
-
sion with seasonal onset. It consists of indirect eye exposure 
to a light source of greater than 2500 lux for 2 hours daily or 
10,000 lux for 20 minutes daily to increase the photoperiod 
of the day. Light visors are an adaptation that provides 
greater mobility and an adjustable light intensity but may 
not be as effective. The dosage varies, with some patients 
requiring morning and night exposure. One effect is altera
-
tion of biorhythm through melatonin mechanisms.
10. Repetitive transcranial magnetic stimulation—
 
Repetitive transcranial magnetic stimulation (rTMS) is used 
to treat nonpsychotic treatment-resistant depression and 
involves the application of electromagnetic pulses to the 
dorslolateral prefrontal cortex. Its use in depression is 
approved by the FDA for individuals who have not tolerated 
or responded to at least one or more standard antidepressant 
medications. It is usually delivered in a course of 20–30 ses
-
sions over 4–6 weeks. rTMS neither requires general anes
-
thesia nor is it associated with cognitive side effects. Several 
meta-analyses have demonstrated that in nonpsychotic 
depression, rTMS is noninferior to ECT. There is a small risk 
of seizure (1:30,000 in post market research).
11. Other treatments—
Vagus nerve stimulation has 
shown promise in about one-third of extremely refractory 
cases and is approved by the FDA but has not been 
approved by insurers. Data has demonstrated that the 
effects plateau around 18 months to 2 years and are durable 
at 5 years. Deep brain stimulation continues to be explored 
for the treatment of refractory depression but two multisite 
randomized controlled studies in two separate targets (sub
-
genual cingulate and ventral capsule/ventral striatum) have 
not shown success to date. This is still considered an 
experimental approach and the appropriate target and 
methodology are unknown.
It is often challenging to engage an individual in penetrating 
psychotherapeutic endeavors during the acute stage of a 
severe depression. While medications may be taking effect, 
a supportive and behavioral approach to strengthen existing 
coping mechanisms and appropriate consideration of the 
patient’s continuing need to function at work, to engage in 
recreational activities, etc, are necessary as the severity of 
the depression lessens. Therapy during or just after the 
acute stage may focus on coping techniques, with some 
practice of alternative choices. If the patient is not seriously 
depressed, it is often appropriate to initiate intensive psy
-
chotherapeutic efforts, since flux periods are a good time to 
effect change. A catharsis of repressed anger and guilt may 
be beneficial. Depression-specific psychotherapies help 
improve self-esteem, increase assertiveness, and lessen 
dependency. Interpersonal psychotherapy for depression

dependency. Interpersonal psychotherapy for depression 
has shown efficacy in the treatment of acute depression, 
helping patients master interpersonal stresses and develop 
new coping strategies. Cognitive behavioral therapy for 
depression addresses patients’ patterns of negative thoughts, 
called cognitive distortions, which lead to feelings of 
depression and anxiety. Treatment usually includes home
-
work assignments such as keeping a journal of cognitive 
distortions and of positive responses to them. The combina
-
tion of medication therapy plus interpersonal psychother
-
apy or cognitive behavioral therapy is generally more 
effective than either modality alone. It is usually helpful to 
involve the spouse or other significant family members 
early in treatment. Mindfulness-based cognitive therapy 
has reduced relapse rates in several randomized controlled 
trials. In two studies, it was as effective as maintenance 
medication in preventing relapse. This therapy incorporates 
meditation and teaches patients to distance themselves 
from depressive thinking. It may be a preferable alternative 
for individuals who wish to have an alternative to long-term 
medications to stay free of depressive episodes.
C. Social
Flexible use of appropriate social services can be of major 
importance in the treatment of depression. Since alcohol 
abuse is often associated with depression, early involvement 
in alcohol treatment programs such as Alcoholics Anony
-
mous can be important to future success (see Alcohol Use 
Disorder [Alcoholism]). The structuring of daily activities 
during severe depression is often quite difficult for the 
patient, and loneliness is often a major factor. The help of 
family, employer, or friends is often necessary to mobilize 
the patient who experiences no joy in daily activities and 
tends to remain uninvolved and to deteriorate. Insistence on 
sharing activities will help involve the patient in simple but 
important daily functions. In some severe cases, the use of 
day treatment centers or support groups of a specific type 
(eg, mastectomy groups) is indicated. It is not unusual for a 
patient to have multiple legal, financial, and vocational prob
-
lems requiring legal and vocational assistance.
When depression is a function of self-defeating coping 
techniques such as passivity, the role-playing approach can 
be useful. Behavioral techniques, including desensitization, 
may be used in problems such as phobias where depression 
is a by-product. When depression is a regularly used inter
-
personal style, behavioral counseling to family members or 
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others can help in extinguishing the behavior in the 
patient. Behavioral activation, a technique of motivating 
depressed patients to begin engaging in pleasurable activi
-
ties, has been shown to be a useful depression-specific 
psychotherapy. Exercise, especially aerobic and supervised 
by exercise professionals, has evidence in improving 
depressive symptoms.
 
»
Treatment of Bipolar Disorder, Manic & 
Depressive Episodes
Acute manic or hypomanic symptoms will respond to 
lithium or valproic acid after several days of treatment, but 
it is increasingly common to use second-generation anti
-
psychotics as first-line agents. The antipsychotics do not 
require serum level monitoring. High-potency benzodiaz
-
epines (eg, clonazepam) may also be useful adjuncts in 
managing the agitation and sleep disturbance that are fea
-
tures of manic and hypomanic episodes.
A. Antipsychotics
Acute manic symptoms may be treated initially with a 
second-generation antipsychotic such as olanzapine, (eg, 
5–20 mg orally), risperidone (2–3 mg orally), or aripipra
-
zole (15–30 mg) in conjunction with a benzodiazepine if 
indicated. All of the available oral second-generation anti
-
psychotics and many of the first-generation agents appear 
to be more rapidly effective in the management of acute 
mania than are mood stabilizers such as lithium or valpro
-
ate. Alternatively, when behavioral control is immediately 
necessary, olanzapine in an injectable form (2.5–10 mg 
intramuscularly) or haloperidol, 5–10 mg orally or intra
-
muscularly repeated as needed until symptoms subside, 
may be used. The dosage of the antipsychotic may be gradu
-
ally reduced after lithium or another mood stabilizer is 
started. Olanzapine, quetiapine, ziprasidone, aripiprazole, 
and the long-acting injectable risperidone are approved as 
maintenance treatments for bipolar disorder to prevent 
subsequent cycles of both mania and depression.
B. Valproic Acid
Valproic acid (divalproex) is a first-line treatment for mania 
because it has a broader index of safety than lithium. This 
issue is particularly important in AIDS or other medically 
ill patients prone to dehydration or malabsorption with 
wide swings in serum lithium levels. Valproic acid has also 
been used effectively in panic disorder and migraine head
-
ache. Treatment is often started at a dose of 750 mg/day 
orally in divided doses, and dosage is then titrated to 
achieve therapeutic serum levels. Oral loading in acutely 
manic bipolar patients in an inpatient setting (initiated at a 
dosage of 20 mg/kg/day) can safely achieve serum thera
-
peutic levels in 2–3 days. Concomitant use of aspirin may 
increase valproate levels, carbamazepine or phenytoin may 
decrease valproate levels, while warfarin levels may be ele
-
vated by valproate. Gastrointestinal symptoms and weight 
gain are the main side effects. Liver function tests, complete 
blood counts, glucose levels, and weight should be moni
-
tored at 2 weeks, 4 weeks, and at 3 months initially and 
annually or more frequently thereafter based on clinical 
judgment. Significant teratogenic effects are a concern so 
pregnancy should be ruled out prior to initiation. In utero 
exposure to valproate has been associated with adversely 
affecting intellectual development in the fetus and there is 
an FDA warning to that effect. Thus, alternatives to valpro
-
ate should be considered in women of childbearing years 
who might become pregnant.
C. Lithium
Lithium significantly decreases the frequency and severity 
of both manic and depressive attacks in about 50–70% of 
patients, and is FDA approved for maintenance and manic 
episodes. Lithium appears to work best in patients with 
classic bipolar I disorder. Antipsychotics, valproate, 
lamotrigine, and carbamazepine may be more effective 
than lithium in the management of rapid cycling and 
mixed episodes. A positive response to lithium is more

mixed episodes. A positive response to lithium is more 
predictable if the patient has a low frequency of episodes 
(no more than two per year with intervals free of psycho
-
pathology). A positive response occurs more frequently in 
individuals who have blood relatives with a diagnosis of 
manic or hypomanic episodes.
In addition to its use in bipolar disorder, lithium is 
sometimes useful in the prophylaxis of recurrent unipolar 
depressions (perhaps undiagnosed bipolar disorder) and in 
lowering the risk of suicide. Lithium may ameliorate non
-
specific aggressive behaviors and dyscontrol syndromes. 
Most patients with bipolar disease can be managed long-
term with lithium alone, although some will require contin
-
ued or intermittent use of an antipsychotic, antidepressant, 
or carbamazepine. An excellent resource for information is 
the Lithium Information Center, http://www.miminc.org/
aboutlithinfoctr.html.
Before treatment, the clinical workup should include a 
medical history and physical examination; complete blood 
count; T4, thyroid-stimulating hormone, blood urea nitro
-
gen (BUN), serum creatinine, and serum electrolyte deter
-
minations; urinalysis; and electrocardiography (in patients 
over age 45 or with a history of cardiac disease). Compli
-
ance with lithium therapy is adversely affected by the loss 
of some hypomanic experiences valued by the patient. 
These include social extroversion and a sense of height
-
ened enjoyment in many activities such as sex and business 
dealings, often with increased productivity in the latter.
1. Dosage—
The common starting dosage of lithium car
-
bonate is 300 mg orally two or three times daily, with trough 
blood levels measured after 5 days of treatment. In a small 
minority of patients, a slow release form or units of different 
dosage may be required. Lithium citrate is available as a 
syrup. The dosage is that required to maintain blood levels 
in the therapeutic range. For acute attacks, this ranges from 
1 to 1.5 mEq/L. Although there is controversy about the 
optimal long-term maintenance dose, many clinicians 
reduce the acute level to 0.6–1 mEq/L in order to reduce 
side effects. The dose required to meet this need will vary in 
different individuals. For acute mania, doses of 1200–1800 
mg/day are generally recommended. Augmentation of anti
-
depressants is usually achieved with half of these doses. 
Once-a-day dosage is acceptable, but most patients have less 
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nausea when they take the 
 in divided doses with 
meals.
Lithium is readily absorbed, with peak serum levels 
occurring within 1–3 hours and complete absorption in 
8 hours. Half of the total body lithium is excreted in 
18–24 hours (95% in the urine). Blood for lithium levels 
should be drawn 12 hours after the last dose. Serum levels 
should be measured 5–7 days after initiation of treatment 
and changes in dose. For maintenance treatment, lithium 
levels should be monitored initially every 1–2 months but 
may be measured every 6–12 months in stable, long-term 
patients. Levels should be monitored more closely when 
there is any condition that causes volume depletion (eg, 
diarrhea, dehydration, use of diuretics).
2. Side effects—
Early side effects
 include mild gastroin
-
testinal symptoms (take lithium with food and in divided 
doses), fine tremors (treat with propranolol, 20–60 mg/day 
orally, only if persistent), slight muscle weakness, and some 
degree of somnolence can occur and are usually transient. 
Moderate polyuria (reduced renal responsiveness to ADH) 
and polydipsia (associated with increased plasma renin 
concentration) are often present. Potassium administration 
can blunt this effect, as may once-daily dosing of lithium. 
Weight gain (often a result of calories in fluids taken for 
polydipsia) and leukocytosis not due to infection are fairly 
common.
Thyroid side effects include goiter (3%; often euthyroid) 
and hypothyroidism (10%; concomitant administration of 
lithium and iodide or lithium and carbamazepine enhances 
the hypothyroid and goitrogenic effect of either medica
-
tion). Most clinicians treat lithium-induced hypothyroid
-
ism (more common in women) with thyroid hormone 
while continuing lithium therapy. Changes in the glucose 
tolerance test toward a diabetes-like curve, nephrogenic 
diabetes insipidus (usually resolving about 8 weeks after 
cessation of lithium therapy), nephrotic syndrome, edema, 
folate deficiency, and pseudotumor cerebri (ophthalmos
-
copy is indicated if there are complaints of headache or 
blurred vision) can occur. Thyroid and kidney function 
should be checked at 4- to 6-month intervals. Hypercalce
-
mia and elevated parathyroid hormone levels occur in some 
patients. Electrocardiographic abnormalities (principally 
T wave flattening or inversion) may occur during lithium 
administration but are not of major clinical significance. 
Sinoatrial block may occur, particularly in the elderly. Other 
medications that prolong intraventricular conduction, such 
as TCAs, must be used cautiously in conjunction with lith
-
ium. Lithium impairs ventilatory function in patients with 
airway obstruction. Lithium alone does not have a signifi
-
cant effect on sexual function, but when combined with 
benzodiazepines (clonazepam in most symptomatic 
patients) it causes sexual dysfunction in about 50% of men. 
Lithium may precipitate or exacerbate psoriasis in some 
patients and can also cause acne. Most of these side effects 
subside when lithium is discontinued; when residual side 
effects exist, they are usually not serious.
Side effects from long-term lithium therapy
 include 
the development of cogwheel rigidity and, occasionally, 
other extrapyramidal signs. Lithium potentiates the parkin
-
sonian effects of haloperidol. Long-term lithium therapy has 
also been associated with a relative lowering of the level of 
memory and perceptual processing (affecting compliance in 
some cases). Some impairment of attention and emotional 
reactivity has also been noted. Lithium-induced delirium 
with therapeutic lithium levels is an infrequent complication 
usually occurring in the elderly and may persist for several 
days after serum levels have become negligible. Encepha
-
lopathy has occurred in patients receiving combined lithium 
and antipsychotic therapy and in those who have cerebro
-

-
-
vascular disease, thus requiring careful evaluation of patients 
who develop neurotoxic signs at subtoxic blood levels.
Some reports have suggested that the long-term use of 
lithium may have adverse effects on kidney function (with 
interstitial fibrosis, tubular atrophy, or nephrogenic diabetes 
insipidus). Persistent polyuria should require an investiga
-
tion of the kidney’s ability to concentrate urine. A rise in 
serum creatinine levels is an indication for in-depth evalua
-
tion of kidney function and consideration of alternative 
treatments if the individual can tolerate a change. Inconti
-
nence has been reported in women, apparently related to 
changes in bladder cholinergic-adrenergic balance.
Prospective studies suggest that the overall risk imposed 
by lithium in pregnancy may be overemphasized. However, 
lithium exposure in early pregnancy does minimally 
increase the frequency of congenital anomalies, notably 
Ebstein and other major cardiovascular anomalies. For 
women who take psychotropic medications who become 
pregnant, the decision to make a change in medication is 
complex and requires informed consent regarding the rela
-
tive risks to the patient and fetus. Indeed, the risk of 
untreated bipolar disorder carries its own risks for preg
-
nancy. Mothers who take lithium should use formula to 
feed their newborn, since concentration in breast milk is 
one-third to half that in serum.
Frank toxicity usually occurs at blood lithium levels 
greater than 2 mEq/L. Because sodium and lithium are 
reabsorbed at the same loci in the proximal renal tubules, 
any sodium loss (diarrhea, use of diuretics, or excessive 
perspiration) results in increased lithium levels. Symptoms 
and signs include vomiting and diarrhea, the latter exacer
-
bating the problem since more sodium is lost and more 
lithium is absorbed. Other symptoms and signs, some of 
which may not be reversible, include tremors, marked 
muscle weakness, confusion, dysarthria, vertigo, choreo
-
athetosis, ataxia, hyperreflexia, rigidity, lack of coordina
-
tion, myoclonus, seizures, opisthotonos, and coma. Toxicity 
is more severe in the elderly, who should be maintained on 
slightly lower serum levels. Lithium overdosage may be 
accidental or intentional or may occur as a result of poor 
monitoring. Significant overdoses of lithium are typically 
managed with hemodialysis since the medication is 
excreted completely by the kidneys.
See Chapter 38 for the treatment of patients with mas
-
sive ingestions of lithium or blood lithium levels greater 
than 2.5 mEq/L.
3. Drug interactions—
Patients receiving lithium should 
use diuretics with caution and only under close medical 
supervision. The thiazide diuretics cause increased lithium 
reabsorption from the proximal renal tubules, resulting in 
increased serum lithium levels (Table 25–10), and 
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adjustment of lithium intake must be made to compensate 
for this. Reduce lithium dosage by 25–40% when the patient 
is receiving 50 mg of hydrochlorothiazide daily. Potassium-
sparing diuretics (spironolactone, amiloride, triamterene) 
may also increase serum lithium levels and require careful 
monitoring of lithium levels. Loop diuretics (furosemide, 
ethacrynic acid, bumetanide) do not appear to alter serum 
lithium levels. Concurrent use of lithium and angiotensin-
converting enzyme inhibitors requires a 50–75% reduction 
in lithium intake, as does prolonged concurrent use of non
-
steroidal anti-inflammatory medication.
D. Carbamazepine
Carbamazepine is used in the treatment of bipolar patients 
who cannot be satisfactorily treated with lithium (nonre
-
sponsive, excessive side effects, or rapid cycling). It is often 
effective at 800–1600 mg/day orally. It has also been used in 
the treatment of trigeminal neuralgias and alcohol with
-
drawal as well as in patients with behavioral dyscontrol. It 
has been used to treat residual symptoms in previous stimu
-
lant abusers (eg, PTSD with impulse control problems). 
Dose-related side effects include sedation and ataxia. Dos
-
ages start at 400–600 mg orally daily and are increased 
slowly to therapeutic levels. Skin rashes and a mild reduc
-
tion in white count are common. SIADH occurs rarely. 
Nonsteroidal anti-inflammatory medications (except aspi
-
rin), the antibiotics erythromycin and isoniazid, the cal
-
cium channel blockers verapamil and diltiazem (but not 
nifedipine), fluoxetine, propoxyphene, and cimetidine all 
increase carbamazepine levels. Carbamazepine can be 
effective in conjunction with lithium, although there have 
been reports of reversible neurotoxicity with the combina
-
tion. Carbamazepine stimulates hepatic microsomal 
enzymes and so tends to decrease levels of haloperidol and 
oral contraceptives. It also lowers T
4
, free T
4
, and T
3
 levels. 
Cases of fetal malformation (particularly spina bifida) have 
been reported along with growth deficiency and developmental 
delay. Liver biochemical tests and complete blood counts 
should be monitored in patients taking carbamazepine. Genetic 
studies suggest that screening for the HLA-B1502 allele in the 
Han Chinese population and the HLA-A3101 allele in northern 
Europeans may help target individuals more susceptible to a 
serious rash. 
Oxcarbazepine,
 a derivative of carbamazepine, 
does not appear to induce its own metabolism and is associated 
with fewer drug interactions, although it may impose a higher 
risk of hyponatremia. FDA-approved for partial seizures, oxcar
-
bazepine may have efficacy in acute mania. It appears to be a 
safer alternative to carbamazepine due to its lower risk of 
hepatotoxicity.
E. Lamotrigine
Lamotrigine is thought to inhibit neuronal sodium channels 
and the release of the excitatory amino acids, glutamate and 
aspartate. It is FDA approved for the maintenance treatment 
of bipolar disorder. Two double-blind studies support its 
efficacy in the treatment of acute bipolar depression as 
adjunctive therapy or as monotherapy but several other con
-
trolled studies failed to demonstrate benefit. Likewise, 
lamotrigine has not proven effective in the management of 
acute mania. Its metabolism is inhibited by coadministration 
of valproic acid—doubling its half-life—and accelerated by 
hepatic enzyme-inducing agents such as carbamazepine. 
More frequent mild side effects include headache, dizziness, 
nausea, and diplopia. Rash occurring in 10% of patients may 
be an indication for immediate cessation of dosing, since 
lamotrigine has been associated with Stevens-Johnson syn
-
drome (1:1000) and, rarely, toxic epidermal necrolysis. The 
medication should be stopped for a rash associated with 
systemic symptoms including fever, lymphadenopathy, oral 
mucosa ulcerations, and the patient sent to an emergency

mucosa ulcerations, and the patient sent to an emergency 
department. Any new rash associated with lamotrigine use 
should be evaluated by a dermatologist. Dosing starts at 
25–50 mg/day orally and is titrated upward slowly to 
decrease the likelihood of rash. Slower titration and a lower 
total dose are indicated for patients taking valproic acid.
 
»
Prognosis
Most depressive episodes are usually time-limited, and the 
prognosis with treatment is good if a pathologic pattern of 
adjustment does not intervene. Major affective disorders 
frequently respond well to a full trial of medication treat
-
ment. However, at least 20% of patients will have a more 
chronic illness lasting 2 or more years. Many patients do 
not sustain a complete remission of symptoms and most 
depressive episodes recur. At least 80% of patients who 
have a single major depressive episode will have one or 
more recurrences within 15 years of the index episode. 
Many patients, therefore, require long-term maintenance 
therapy with antidepressants.
Table 25–10.
 
Lithium interactions with other 
Effects
↑
 Lithium levels
Celecoxib
↑
↑
Ibuprofen
↑
Indomethacin
↑
Rigidity, mutism, fascicular 
twitching
Osmotic diuretics (urea, mannitol)
↑
 Lithium excretion
↑
Potassium-sparing diuretics 
 
(spironolactone, amiloride, 
triamterene)
↑
Sodium bicarbonate
↑
↑
 Duration of action of 
succinylcholine
Theophylline, aminophylline
↑
↑
↓
ACE, angiotensin-converting enzyme.
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Mania has a good prognosis with adequate treatment, 
although patient adherence to treatment is often quite chal
-
lenging. Few effective treatments exist for bipolar depression, 
which include quetiapine, lurasidone, and the combination of 
fluoxetine and olanzapine. Most patients with bipolar disor
-
der require treatment with two or more medications such as 
lithium, antipsychotics and sleeping agents. Breakthrough 
manic or depressive episodes are common, even with adher
-
ence to maintenance treatments, although maintenance 
therapy lessens the risk of recurrent episodes.
Beyer JL et al. Suicide behaviors in bipolar disorder: a review and 
update for the clinician. Psychiatr Clin North Am. 2016 Mar;
 
39(1):111–23. [PMID: 26876322]
Fountoulakis KN et al. The International College of Neuro-
 
Psychopharmacology (CINP) treatment guidelines for bipolar 
disorder in adults (CINP-BD-2017), part 3: the clinical guide
-
lines. Int J Neuropsychopharmacol. 2017 Feb 1;20(2):180–95. 
[PMID: 27941079]
Fountoulakis KN et al. The International College of Neuropsy
-
chopharmacology (CINP) treatment guidelines for bipolar 
disorder in adults (CINP-BD-2017), part 4: unmet needs in 
the treatment of bipolar disorder and recommendations for 
future research. Int J Neuropsychopharmacol. 2017 Feb 1;
 
20(2):196–205. [PMID: 27677983]
Kéri S et al. Blood biomarkers of depression track clinical 
changes during cognitive-behavioral therapy. J Affect Disord. 
2014 Aug;164:118–22. [PMID: 24856564]
Orsolini L et al. Serotonin reuptake inhibitors and breastfeeding: 
a systematic review. Hum Psychopharmacol. 2015 Jan;30(1):
 
4–20. [PMID: 25572308]
Robinson GE. Controversies about the use of antidepressants in 
pregnancy. J Nerv Ment Dis. 2015 Mar;203(3):159–63. 
[PMID: 25714252]
Schuch FB et al. Exercise as a treatment for depression: a meta-
analysis adjusting for publication bias. J Psychiatr Res. 2016 Jun;
 
77:42–51. [PMID: 26978184]
Viktorin A et al. Association of antidepressant medication use dur
-
ing pregnancy with intellectual disability in offspring. JAMA 
Psychiatry. 2017 Oct 1;74(10):1031–8. [PMID: 28700807]
Williams NR et al. NMDA antagonist treatment of depression. 
Curr Opin Neurobiol. 2016 Feb;36:112–7. [PMID: 26687375]
ATTENTION-DEFICIT/HYPERACTIVITY 
DISORDER
 
»
Persistent patterns of inability to sustain attention, 
excessive motor activity/restlessness/impulsivity, 
or both.
 
»
Symptoms interfere with daily functioning.
 
»
Symptoms began prior to age 12 and in at least 
two settings (ie, school/work, home, with friends/
family).
 
»
While attention-deficit/hyperactivity disorder (ADHD) 
begins in childhood, symptoms persist into adulthood in 
approximately two-thirds of patients, with half of those still 
requiring medication to aid in their functioning. The preva
-
lence of ADHD in adults is estimated to be 4–5%. ADHD is 
never diagnosed in some patients during childhood because 
they may not have presented for assessment at that time or 
were able to compensate for symptoms at the time. The spe
-
cific presenting symptoms in adulthood tend to be inatten
-
tion, restlessness, and impulsivity, whereas hyperactivity has 
often improved. At least five inattention symptoms (such as 
making careless mistakes, being easily sidetracked, trouble 
keeping deadlines or with organization, losing belongings, 
being forgetful in daily chores/tasks) are required to meet 
criteria for this subtype of ADHD, or five hyperactivity/
impulsivity symptoms (such as feeling restless and leaving a 
seat though expected to remain, feeling “driven by a motor, ” 
interrupting others, cannot wait his or her turn) for this 
subtype. It is often useful to have patients provide question
-
naires to other adult observers, including those who knew 
them during childhood, such as parents. This collateral data 
can help prevent diagnosing ADHD in someone who is

-
can help prevent diagnosing ADHD in someone who is 
seeking stimulants but without symptomatology as well as 
aid in making the diagnosis, since evidence shows that many 
adults who do have ADHD often underreport symptoms.
 
»
Treatment
Stimulants such as methylphenidate and amphetamine are 
the most effective treatment, with some of the largest effect 
sizes for medication treatment in psychiatric disorders. 
These come in both short-acting and long-acting formula
-
tions. Caution should be used to assess for potential sub
-
stance abuse or diversion as well as for comorbid mood 
disorders that may not respond well to a stimulant prior to 
prescribing these medications. Atomoxetine, a nonstimu
-
lant, is a second-line agent that is FDA-approved for 
ADHD; it affects norepinephrine and dopamine transport 
and makes more of these neurotransmitters available in the 
brain. Bupropion has evidence of efficacy as well and may 
be considered in patients in whom a stimulant is contrain
-
dicated or in those who also suffer from major depression. 
Desipramine, a tricyclic antidepressant, also can be effec
-
tive for ADHD and may be considered in patients who 
have additional needs, such as a concomitant depression or 
neuropathic pain. Guanfacine and clonidine are two addi
-
tional nonstimulant medications used primarily to treat 
blood pressure but with some efficacy in ADHD as well.
B. Behavioral and Other Treatments
Psychoeducation regarding ADHD should be given to all 
patients. Many patients are able to implement behavioral 
changes that either improve their functioning, such as cre
-
ating calendars and organizational schemes or doing tasks 
in multiple timed short spurts, or can help them avoid tasks 
that are challenging for them in favor of complementary 
tasks they are more suited to (ie, selecting jobs that value 
more activity rather than sustained focus, or sharing in the 
chores at home that do not require attention to detail). 
Cognitive behavioral therapy has some evidence for help
-
ing residual symptoms after medication management has 
been optimized.
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Clemow DB et al. Atomoxetine in patients with ADHD: a clini
-
cal and pharmacological review of the onset, trajectory, dura
-
tion of response and implications for patients. J 
Psychopharmacol. 2015 Dec;29(12):1221–30. [PMID: 
26349559]
Epstein T et al. Immediate-release methylphenidate for attention 
deficit hyperactivity disorder (ADHD) in adults. Cochrane 
Database Syst Rev. 2014 Sep 18;(9):CD005041. Update in: 
Cochrane Database Syst Rev. 2016;(5):CD005041. [PMID: 
25230710]
Fredriksen M et al. Long-term pharmacotherapy of adults with 
attention deficit hyperactivity disorder: a literature review 
and clinical study. Basic Clin Pharmacol Toxicol. 2016 Jan;
 
118(1):23–31. [PMID: 26404187]
Jensen CM et al. Cognitive behavioural therapy for ADHD in 
adults: systematic review and meta-analyses. Atten Defic 
Hyperact Disord. 2016 Mar;8(1):3–11. [PMID: 26801998]
Simon N et al. Methylphenidate in adults with attention deficit 
hyperactivity disorder and substance use disorders. Curr 
Pharm Des. 2015;21(23):3359–66. [PMID: 26088112]
Torgersen T et al. Optimal management of ADHD in older 
adults. Neuropsychiatr Dis Treat. 2016 Jan 8;12:79–87. 
[PMID: 26811680]
AUTISM SPECTRUM DISORDERS
 
»
Persistent issues with social communication and 
interactions.
 
»
Repetitive behaviors, interests, or activities.
 
»
Symptoms interfere with functioning.
 
»
May or may not have accompanying language or 
intellectual impairment.
 
»
Autism spectrum disorder is a neurodevelopmental disorder 
in which patients suffer from pervasive difficulties with social 
communication and have repetitive, restricted interests and 
behaviors. Autism spectrum disorder affects about 1% of the 
adult population with an estimated heritability of about 90%. 
Approximately 20–30% of individuals in whom autism is 
diagnosed also have a substance use problem as well as a 
higher risk of ADHD, mood, or obsessive-compulsive disor
-
ders. The National Institute of Health and Care Excellence 
(NICE) guidelines recommend that assessment of autism 
spectrum disorder should be a comprehensive and multidis
-
ciplinary approach that includes asking about core autism 
spectrum disorder difficulties, early development, medical 
and family history, behavior, education, employment, needs 
assessment, risks, physical examination with potential labo
-
ratory testing, and feedback to the individual.
 
»
Treatment
No treatments for the core symptoms of autism spectrum 
disorder in adults have been validated. There is some evi
-
dence for therapy to address social cognitions and behav
-
iors. Use of repetitive transcranial magnetic stimulation 
for the treatment of autism spectrum disorder is under 
Jin J. JAMA patient page. Screening for autism spectrum disor
-
der. JAMA. 2016 Feb 16;315(7):718. [PMID: 26881385]
Murphy CM et al. Autism spectrum disorder in adults: diagno
-
sis, management, and health services development. Neuro
-
psychiatr Dis Treat. 2016 Jul 7;12:1669–86. [PMID: 27462160]
SLEEP-WAKE DISORDERS
Sleep consists of two distinct states as shown by electroen
-
cephalographic studies: (1) REM (rapid eye movement) 
sleep, also called dream sleep, D state sleep, paradoxic sleep, 
and (2) NREM (non-REM) sleep, also called S stage sleep, 
which is divided into stages 1, 2, 3, and 4 and is recogniz
-
able by different electroencephalographic patterns. Stages 3 
and 4 are “delta” sleep. Dreaming occurs mostly in REM 
and to a lesser extent in NREM sleep.
Sleep is a cyclic phenomenon, with four or five REM 
periods during the night accounting for about one-fourth 
of the total night’s sleep (1.5–2 hours). The first REM 
period occurs about 80–120 minutes after onset of sleep 
and lasts about 10 minutes. Later REM periods are longer 
(15–40 minutes) and occur mostly in the last several hours 
of sleep. Most stage 4 (deepest) sleep occurs in the first 
several hours.

Age-related changes in normal sleep include an 
unchanging percentage of REM sleep and a marked decrease 
in stage 3 and stage 4 sleep, with an increase in wakeful 
periods during the night. These normal changes, early bed
-
times, and daytime naps play a role in the increased com
-
plaints of insomnia in older people. Variations in sleep 
patterns may be due to circumstances (eg, “jet lag”) or to 
idiosyncratic patterns (“night owls”) in persons who per
-
haps because of different “biologic rhythms” habitually go 
to bed late and sleep late in the morning. Creativity and 
rapidity of response to unfamiliar situations are impaired by 
loss of sleep. There are also rare individuals who have 
chronic difficulty in adapting to a 24-hour sleep-wake cycle 
(desynchronization sleep disorder), which can be resyn
-
chronized by altering exposure to light.
The three major sleep disorders are discussed below. 
Any persistent sleep disorder that is not attributable to 
another condition should be evaluated by a sleep specialist.
1. Insomnia
 
»
Patients may complain of difficulty getting to sleep or stay
-
ing asleep, intermittent wakefulness during the night, early 
morning awakening, or combinations of any of these. Tran
-
sient episodes are usually of little significance. Stress, caf
-
feine, physical discomfort, daytime napping, and early 
bedtimes are common factors.
Psychiatric disorders are often associated with persistent 
insomnia. 
 is usually associated with fragmented 
sleep, decreased total sleep time, earlier onset of REM sleep, 
a shift of REM activity to the first half of the night, and a loss 
of slow wave sleep—all of which are nonspecific findings. 
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In 
manic disorders,
 a reduced total sleep time and a 
decreased need for sleep are cardinal features and important 
early sign of impending mania. In addition to a decreased 
amount of sleep, manic episodes are characterized by a 
shortened REM latency and increased REM activity. Sleep-
related panic attacks occur in the transition from stage 2 to 
stage 3 sleep in some patients with a longer REM latency in 
the sleep pattern preceding the attacks.
Abuse of alcohol
 may cause or be secondary to the sleep 
disturbance. There is a tendency to use alcohol as a means of 
getting to sleep without realizing that it disrupts the normal 
sleep cycle. Acute alcohol intake produces a decreased sleep 
latency with reduced REM sleep during the first half of the 
night. REM sleep is increased in the second half of the night, 
with an increase in total amount of slow wave sleep (stages 3 
and 4). Vivid dreams and frequent awakenings are common. 
Chronic alcohol abuse increases stage 1 and decreases REM 
sleep (most medications delay or block REM sleep), with 
symptoms persisting for many months after the individual 
has stopped drinking. Acute alcohol or other sedative with
-
drawal causes delayed onset of sleep and REM rebound with 
intermittent awakening during the night.
Heavy smoking
 (more than a pack a day) causes difficulty 
falling asleep—apparently independently of the often associ
-
ated increase in coffee drinking. Excess intake near bedtime of 
caffeine, cocaine, and other stimulants (eg, over-the-counter 
cold remedies) causes decreased total sleep time—mostly 
NREM sleep—with some increased sleep latency.
Sedative-hypnotics
—specifically, the benzodiazepines, 
which are the most commonly prescribed medications to 
promote sleep—tend to increase total sleep time, decrease 
sleep latency, and decrease nocturnal awakening, with vari
-
able effects on NREM sleep. Nonbenzodiazepine hypnotics 
have similar effects on sleep as do the benzodiazepines, 
though some evidence shows improved slow wave sleep 
and less residual next-morning somnolence with non-
benzodiazepines, such as zolpidem. Withdrawal causes just 
the opposite effects and results in continued use of the drug 
for the purpose of preventing withdrawal symptoms. Anti
-
depressants decrease REM sleep (with marked rebound on 
withdrawal in the form of nightmares) and have varying 
effects on NREM sleep. The effect on REM sleep correlates 
with reports that REM sleep deprivation produces improve
-
ment in some depressions.
Persistent insomnias are also related to a wide variety of 
medical conditions, particularly delirium, pain, respiratory 
distress syndromes, uremia, asthma, thyroid disorders, and 
nocturia due to benign prostatic hyperplasia. Sleep apnea 
and restless leg movement are described below. Adequate 
analgesia and proper treatment of medical disorders will 
reduce symptoms and decrease the need for sedatives.
 
»
Treatment
In general, there are two broad classes of treatment for 
insomnia, and the two may be combined: psychological 
(cognitive-behavioral) and pharmacologic. In situations of 
acute distress, such as a grief reaction, pharmacologic mea
-
sures may be most appropriate. With primary insomnia, 
however, initial efforts should be psychologically based. 
This is particularly true in the elderly to avoid the potential 
adverse reactions of medications. The elderly population is 
at risk for complaints of insomnia because sleep becomes 
lighter and more easily disrupted with aging. Medical dis
-
orders that become more common with age may also pre
-
dispose to insomnia.
A. Psychological
Psychological strategies should include educating the 
patient regarding good 
sleep hygiene:
 (1) Go to bed only 
when sleepy. (2) Use the bed and bedroom only for sleep
-
ing and sex. (3) If still awake after 20 minutes, leave the 
bedroom, pursue a restful activity (such as a bath or medi
-

(1) Go to bed only 
-
-
tation), and only return when sleepy. (4) Get up at the same 
time every morning regardless of the amount of sleep dur
-
ing the night. (5) Discontinue caffeine and nicotine, at least 
in the evening if not completely. (6) Establish a daily exer
-
cise regimen. (7) Avoid alcohol as it may disrupt continuity 
of sleep. (8) Limit fluids in the evening. (9) Learn and 
practice relaxation techniques. (10) Establish a bedtime 
ritual and a routine time for going to sleep. Research sug
-
gests that cognitive behavioral therapy for insomnia is as 
effective as zolpidem with benefits sustained 1 year after 
B. Pharmacologic
When the above measures are insufficient, medications 
may be useful. Lorazepam (0.5 mg orally nightly); temaze
-
pam (7.5–15 mg orally nightly); and the nonbenzodiaze
-
pine hypnotics, zolpidem (5–10 mg orally nightly, with a 
limit of 5 mg indicated for women) and zaleplon (5–10 mg 
orally nightly), are often effective for the elderly population 
and can be given in larger doses—twice what is prescribed 
for the elderly—in younger patients. Zolpidem is also avail
-
able as a sublingual tablet to treat insomnia characterized 
by middle-of-the-night awakening with difficulty falling 
back to sleep. The dose is 1.75 mg for women and 3.5 mg 
for men, taken once per night. Eszopiclone (2–3 mg orally), 
is similar in action to zolpidem and zaleplon and like oral 
zolpidem, is approved for long-term use. A lower dose of 
1 mg is indicated in the elderly or those with hepatic 
impairment. It is important to note that short-acting agents 
like triazolam or zolpidem may lead to amnestic episodes if 
used on a daily ongoing basis. Longer-acting agents such as 
flurazepam (half-life of more than 48 hours) may accumu
-
late in the elderly and lead to cognitive slowing, ataxia, 
falls, and somnolence. In general, it is appropriate to use 
medications for short courses of 1–2 weeks. The medica
-
tions described above have largely replaced barbiturates as 
hypnotic agents because of their greater safety in overdose 
and their lesser hepatic enzyme induction effects. Antihis
-
tamines such as diphenhydramine (25 mg orally nightly) 
or hydroxyzine (25 mg orally nightly) may also be useful for 
sleep, as they produce no pharmacologic dependency; their 
anticholinergic effects may, however, produce confusion 
or urinary symptoms in the elderly. Trazodone, an atypical 
antidepressant, is a non–habit-forming, effective sleep 
medication in lower than antidepressant doses (25–150 mg 
orally at bedtime). Priapism is a rare side effect requiring 
emergent treatment. Ramelteon, 8 mg orally at bedtime, is 
a melatonin receptor agonist that helps with sleep onset 
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and does not appear to have abuse potential. It appears to 
be safe for ongoing use without the development of 
tolerance.
The class of hypnotics dual orexin receptor antagonists 
(DORAs) are approved to help initiate and maintain sleep. 
DORAs such as suvorexant may be more effective than other 
hypnotics for some patients. However, the role of suvorexant 
has not been established relative to other hypnotics and is 
more expensive since it is not generically available. DORAs 
have shown a significant increase in depressive symptoms in 
a subset of patients, so other hypnotics may be a better 
choice in depressed patients. The dose of suvorexant is 
10–20 mg orally given about 30 minutes before bedtime.
2. Hypersomnias (Disorders of Excessive 
Sleepiness)
 
»
A. Breathing-Related Sleep Disorders
 is by far the most common of the 
breathing-related sleep disorders that include 
central sleep 
apnea
 and 
sleep-related hypoventilation
. Obstructive 
sleep apnea hypopnea is characterized by snoring, gasping, 
or breathing pauses during sleep and five or more apneas or 
hypopneas per hour or evidence by polysomnography. (See 
Chapter 9.)
B. Narcolepsy Hypocretin Deficiency Syndrome
Narcolepsy consists of a tetrad of symptoms: (1) sudden, 
brief (about 15 minutes) sleep attacks that may occur during 
any type of activity; (2) cataplexy—sudden loss of muscle 
tone involving specific small muscle groups or generalized 
muscle weakness that may cause the person to slump to the 
floor, unable to move, often associated with emotional reac
-
tions and sometimes confused with seizure disorder; (3) 
sleep paralysis—a generalized flaccidity of muscles with full 
consciousness in the transition zone between sleep and wak
-
ing; and (4) hypnagogic hallucinations, visual or auditory, 
which may precede sleep or occur during the sleep attack. 
The attacks are characterized by an abrupt transition into 
REM sleep—a necessary criterion for diagnosis. The disor
-
der begins in early adult life, affects both sexes equally, and 
usually levels off in severity at about 30 years of age.
REM sleep behavior disorder, characterized by motor 
dyscontrol and often violent dreams during REM sleep, 
may be related to narcolepsy.
C. Kleine-Levin Syndrome
This syndrome, which occurs mostly in young men, is 
characterized by hypersomnic attacks three or four times a 
year lasting up to 2 days, with hyperphagia, hypersexuality, 
irritability, and confusion on awakening. It has often been 
associated with antecedent neurologic insults. It usually 
remits after age 40.
D. Periodic Limb Movement Disorder
Periodic lower leg movements occur only during sleep with 
subsequent daytime sleepiness, anxiety, depression, and 
cognitive impairment. Restless leg syndrome includes 
movements while awake as well.
E. Shift Work Sleep Disorder
Shift work sleep disorder occurs when there is excessive 
fatigue as a consequence of work occurring during the 
normal sleep period.
 
»
Treatment
Narcolepsy can be managed by daily administration of a stim
-
ulant such as dextroamphetamine sulfate, 10 mg orally in the 
morning, with increased dosage as necessary. Modafinil and its 
enantiomer armodafinil are schedule IV medications FDA-
approved for treating the excessive daytime fatigue of narco
-
lepsy, sleepiness associated with obstructive sleep apnea, as well 
as for shift work sleep disorder. Usual dosing is 200–400 mg 
orally each morning for modafinil and 150–250 mg orally in 
the morning for armodafinil. The mechanism of action of 
modafinil and armodafil is unknown, yet they are thought to 
be less of an abuse risk than stimulants that are primarily dopa
-
minergic. Common side effects include headache and anxiety; 
however, modafinil appears to be generally well tolerated. 
Modafinil may reduce the efficacy of cyclosporine, oral contra
-

-
-
ceptives, and other medications by inducing their hepatic 
metabolism. Imipramine, 75–100 mg orally daily, has been 
effective in treatment of cataplexy but not narcolepsy.
Periodic limb movement disorder and REM sleep 
behavior disorder can be treated with clonazepam with 
variable results. There is no treatment for Kleine-Levin 
syndrome though lithium can prevent recurrences in some.
Treatment of sleep apnea is discussed in Chapter 9.
3. Parasomnias (Abnormal Behaviors 
 
during Sleep)
These disorders (sleep terror, nightmares, sleepwalking, and 
enuresis) are fairly common in children and less so in adults.
Abbott SM et al. Circadian rhythm sleep-wake disorders. 
Psychiatr Clin North Am. 2015 Dec;38(4):805–23. [PMID: 
26600110]
Khoury J et al. Primary sleep disorders. Psychiatr Clin North 
Am. 2015 Dec;38(4):683–704. [PMID: 26600103]
Reid KJ et al. Jet lag and shift work disorder. Sleep Med Clin. 
2015 Dec;10(4):523–35. [PMID: 26568127]
Rhyne DN et al. Suvorexant in insomnia: efficacy, safety and 
place in therapy. Ther Adv Drug Saf. 2015 Oct;6(5):189–95. 
[PMID: 26478806]
Trauer JM et al. Cognitive behavioral therapy for chronic insom
-
nia: a systematic review and meta-analysis. Ann Intern Med. 
2015 Aug 4;163(3):191–204. [PMID: 26054060]
Winkelman JW . Clinical practice. Insomnia disorder. N Engl J 
Med. 2015 Oct 8;373(15):1437–44. [PMID: 26444730]
DISORDERS OF AGGRESSION
Aggression and violence are symptoms rather than dis
-
eases, and most frequently they are not necessarily associ
-
ated with an underlying medical condition. Clinicians are 
unable to predict dangerous behavior with greater than 
chance accuracy. Depression, schizophrenia, personality 
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disorders, mania, paranoia, temporal lobe dysfunction, and 
organic mental states may be associated with acts of aggres
-
sion. Impulse control disorders are characterized by physi
-
cal abuse (usually of the aggressor’s domestic partner or 
children), by pathologic intoxication, by impulsive sexual 
activities, and by reckless driving. Anabolic steroid usage 
by athletes has been associated with increased tendencies 
toward violent behavior.
In the United States, a significant proportion of all vio
-
lent deaths are alcohol related. The ingestion of even small 
amounts of alcohol can result in pathologic intoxication 
that resembles an acute organic mental condition. Amphet
-
amines, crack cocaine, and other stimulants are frequently 
associated with aggressive behavior. Phencyclidine is a 
drug commonly associated with violent behavior that is 
occasionally of a bizarre nature, partly due to lowering of 
the pain threshold. Domestic violence and rape are much 
more widespread than previously recognized. Awareness of 
the problem is to some degree due to increasing recogni
-
tion of the rights of women and the understanding by 
women that they do not have to accept abuse. Acceptance 
of this kind of aggressive behavior inevitably leads to more, 
with the ultimate aggression being murder—20–50% of 
murders in the United States occur within the family. 
Police are called more for domestic disputes than all other 
criminal incidents combined. Children living in such fam
-
ily situations frequently become victims of abuse.
Features of individuals who have been subjected to long-
term physical or sexual abuse are as follows: trouble express
-
ing anger, staying angry longer, general passivity in 
relationships, feeling “marked for life” with an accompany
-
ing feeling of deserving to be victimized, lack of trust, and 
dissociation of affect from experiences. They are prone to 
express their psychological distress with somatization symp
-
toms, often pain complaints. They may also have symptoms 
related to posttraumatic stress, as discussed above. The clini
-
cian should be suspicious about the origin of any injuries not 
fully explained, particularly if such incidents recur.
 
»
Treatment
Management of any acutely potentially violent individual 
includes appropriate psychological maneuvers. Move slowly, 
talk slowly with clarity and reassurance, and evaluate the situ
-
ation. Strive to create a setting that is minimally disturbing, 
and eliminate people or things threatening to the violent 
individual. Do not threaten and do not touch or crowd the 
person. Allow no weapons in the area (an increasing problem 
in hospital emergency departments). Proximity to a door is 
comforting to both the patient and the examiner. Use a nego
-
tiator who the violent person can relate to comfortably. Food 
and drink are helpful in defusing the situation (as are ciga
-
rettes for those who smoke). Honesty is important. Make no 
false promises, bolster the patient’s self-esteem, and continue 
to engage the subject verbally until the situation is under 
control. This type of individual does better with strong 
external controls to replace the lack of inner controls 
over the long term. Close probationary supervision and 
judicially mandated restrictions can be most helpful. 
There should be a major effort to help the individual 
avoid drug use (eg, Alcoholics Anonymous). Victims of 
abuse are essentially treated as any victim of trauma and, 
not infrequently, have evidence of PTSD.
Pharmacologic means are often necessary whether or not 
psychological approaches have been successful. This is 
particularly true in the agitated or psychotic patient. The 
medications of choice in seriously violent or psychotic 
aggressive states are antipsychotics, given intramuscularly 
if necessary, every 1–2 hours until symptoms are alleviated. 
A number of second-generation intramuscular antipsy
-

-
chotics are FDA approved in the management of acute 
agitation, and include aripiprazole (9.75 mg/1.3 mL), zipra
-
sidone (10-mg/0.5 mL), and olanzapine (10 mg/2 mL). The 
second-generation antipsychotics appear less likely than 
first-generation medications like haloperidol (2.5–5 mg) to 
cause acute extrapyramidal symptoms. However, the second-
generation medications appear no more effective than 
first-generation medications and generally are more expen
-
sive. Benzodiazepine sedatives (eg, diazepam, 5 mg orally 
or intravenously every several hours) can be used for mild 
to moderate agitation, but are sometimes associated with a 
disinhibition of aggressive impulses similar to alcohol. 
Chronic aggressive states, particularly in intellectual dis
-
abilities and brain damage (rule out causative organic 
conditions and medications such as anticholinergic medi
-
cations in amounts sufficient to cause confusion), have 
been ameliorated with risperidone, 0.5–2 mg/day orally, 
propranolol, 40–240 mg/day orally, or pindolol, 5 mg twice 
daily orally (pindolol causes less bradycardia and hypoten
-
sion than propranolol). Carbamazepine and valproic acid 
are effective in the treatment of aggression and explosive 
disorders, particularly when associated with known or 
suspected brain lesions. Lithium and SSRIs are also effec
-
tive for some intermittent explosive outbursts. Buspirone 
(10–45 mg/day orally) is helpful for aggression, particu
-
larly in patients with intellectual disabilities.
C. Physical
Physical management is necessary if psychological and 
pharmacologic means are not sufficient. It requires the 
active and visible presence of an adequate number of per
-
sonnel (five or six) to reinforce the idea that the situation is 
under control despite the patient’s lack of inner controls. 
Such an approach often precludes the need for actual physi
-
cal restraint. Seclusion rooms and restraints should be used 
only when necessary (ambulatory restraints are an alterna
-
tive), and the patient must then be observed at frequent 
intervals. Narrow corridors, small spaces, and crowded areas 
exacerbate the potential for violence in an anxious patient.
D. Other Interventions
The treatment of victims (eg, battered women) is challeng
-
ing and often complicated by their reluctance to leave the 
situation. Reasons for staying vary, but common themes 
include the fear of more violence because of leaving, the 
hope that the situation may ameliorate (in spite of steady 
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worsening), and the financial aspects of the situation, 
which are seldom to the woman’s advantage. Concerns for 
the children often finally compel the woman to seek help. 
An early step is to get the woman into a therapeutic situa
-
tion that provides the support of others in similar straits. 
Al-Anon is frequently a valuable asset when alcohol is a 
factor. The group can support the victim while she gathers 
strength to consider alternatives without being paralyzed 
by fear. Many cities offer temporary emergency centers and 
counseling. Use the available resources, attend to any medi
-
cal or psychiatric problems, and maintain a compassionate 
interest. Some states require physicians to report injuries 
caused by abuse or suspected abuse to police authorities. 
See Chapter e6 for detailed discussion.
Buckley P et al. Psychopharmacology of aggression in schizo
-
phrenia. Schizophr Bull. 2011 Sep;37(5):930–6. [PMID: 
21860038]
Johnson DM et al. Cognitive behavioral treatment of PTSD in 
residents in battered women’s shelters: results of a random
-
ized clinical trial. J Consult Clin Psychol. 2011 Aug;79(4):
 
542–51. [PMID: 21787052]
Rees S et al. Lifetime prevalence of gender-based violence in 
women and the relationship with mental disorders and psy
-
chosocial function. JAMA. 2011 Aug 3;305(5):513–21. 
[PMID: 21813429]
 
º
SUBSTANCE USE DISORDERS
The term “dependency” was previously used to describe a 
severe form of substance abuse and drug addiction charac
-
terized by the triad of: (1) a 
psychological dependence
 or 
craving and the behavior involved in procurement of the 
drug; (2) 
physiologic dependence,
 with withdrawal symp
-
toms on discontinuance of the drug; and (3) 
tolerance,
 ie, 
the need to increase the dose to obtain the desired effects. 
The terms “dependency” and “abuse” were dropped in 
DSM-5
 in favor of the single term “substance use disorder, ” 
ranging from mild to severe. Many patients could have a 
severe and life-threatening abuse problem without ever 
being dependent on a drug.
There is accumulating evidence that an impairment 
syndrome exists in many former (and current) drug users. 
It is believed that drug use produces damaged neurotrans
-
mitter receptor sites and that the consequent imbalance 
produces symptoms that may mimic other psychiatric ill
-
nesses. 
“Kindling”
—repeated stimulation of the brain—
renders the individual more susceptible to focal brain 
activity with minimal stimulation. Stimulants and depres
-
sants can produce kindling, leading to relatively spontane
-
ous effects no longer dependent on the original stimulus. 
These effects may be manifested as mood swings, panic, 
psychosis, and occasionally overt seizure activity. The 
imbalance also results in frequent job changes, partner 
problems, and generally erratic behavior. Patients with 
PTSD frequently have treated themselves with a variety of 
drugs. Chronic abusers of a wide variety of drugs exhibit 
cerebral atrophy on CT scans, a finding that may relate to 
the above symptoms. Early recognition is important, mainly 
to establish realistic treatment programs that are chiefly 
symptom-directed.
The clinician faces three problems with substance use 
disorders: (1) the prescribing of substances such as seda
-
tives, stimulants, or opioids that might produce depen
-
dency; (2) the treatment of individuals who have already 
abused drugs, most commonly alcohol; and (3) the detec
-
tion of illicit drug use in patients presenting with psychiat
-
ric symptoms. The usefulness of urinalysis for detection of 
drugs varies markedly with different drugs and under dif
-
ferent circumstances (pharmacokinetics is a major factor). 
Water-soluble drugs (eg, alcohol, stimulants, opioids) are 
eliminated in a day or so. Lipophilic substances (eg, barbitu
-
rates, tetrahydrocannabinol) appear in the urine over longer 
periods of time: several days in most cases, 1–2 months in

-
periods of time: several days in most cases, 1–2 months in 
chronic marijuana users. Sedative drug determinations are 
quite variable, amount of drug and duration of use being 
important determinants. False-positives can be a problem 
related to ingestion of some legitimate medications (eg, 
phenytoin for barbiturates, phenylpropanolamine for 
amphetamines, chlorpromazine for opioids) and some 
foods (eg, poppy seeds for opioids, coca leaf tea for 
cocaine). Manipulations can alter the legitimacy of the test
-
ing. Dilution, either in vivo or in vitro, can be detected by 
checking urine-specific gravity. Addition of ammonia, 
vinegar, or salt may invalidate the test, but odor and pH 
determinations are simple. Hair analysis can determine 
drug use over longer periods, particularly sequential drug-
taking patterns. The sensitivity and reliability of such tests 
are considered good, and the method may be complemen
-
tary to urinalysis.
Marlatt GA. Update on harm-reduction policy and intervention 
research. Annu Rev Clin Psychol. 2010 Apr 27;6:591–606. 
[PMID: 20192791]
ALCOHOL USE DISORDER (
)
 
»
Physiologic dependence as manifested by evi
-
dence of withdrawal when intake is interrupted.
 
»
Tolerance to the effects of alcohol.
 
»
Evidence of alcohol-associated illnesses, such as 
alcoholic liver disease, cerebellar degeneration.
 
»
Continued drinking despite strong medical and 
social contraindications and life disruptions.
 
»
Impairment in social and occupational 
 
»
Depression.
 
»
Blackouts.
 
»
Alcohol use disorder is a syndrome consisting of two 
phases: 
at-risk drinking
 and 
moderate to severe alcohol 
misuse.
 At-risk drinking is the repetitive use of alcohol, 
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often to alleviate anxiety or solve other emotional problems. 
A moderate to severe alcohol use disorder is similar to that 
which occurs following the repeated use of other sedative-
hypnotics and is characterized by recurrent use of alcohol 
despite disruption in social roles (family and work), alco
-
hol-related legal problems, and taking safety risks by oneself 
and with others. The National Institute on Alcohol Abuse 
and Alcoholism formally defines at-risk drinking as 
more 
than 4 drinks per day or 14 drinks per week for men
 or 
more than 3 drinks per day or 7 drinks per week for 
women.
 A drink is defined by the Centers for Disease Con
-
trol and Prevention (CDC) as 12 oz of beer, 8 oz of malt 
liquor, 5 oz of wine, or 1.3 oz or a “shot” of 80-proof distilled 
spirits of liquor. Individuals with at-risk drinking are at an 
increased risk for developing or are developing an alcohol 
use disorder. Alcohol and other drug abuse patients have a 
much higher prevalence of lifetime psychiatric disorders. 
While male-to-female ratios in alcoholic treatment agencies 
remain at 4:1, there is evidence that the rates are converging. 
Women delay seeking help, and when they do, they tend to 
seek it in medical or mental health settings. Adoption and 
twin studies indicate some genetic influence. Ethnic dis
-
tinctions are important—eg, 40% of Japanese have aldehyde 
dehydrogenase deficiency and are more susceptible to the 
effects of alcohol. Depression is often present and should be 
evaluated carefully. The majority of suicides and intrafamily 
homicides involve alcohol. Alcohol is a major factor in 
rapes and other assaults.
There are several screening instruments that may help 
identify an alcohol use disorder. One of the most useful is 
the 
Alcohol Use Disorder Identification Test (AUDIT)
 
(see Table 1–7).
McNeely J et al. A brief patient self-administered substance use 
screening tool for primary care: two-site validation study of 
the Substance Use Brief Screen (SUBS). Am J Med. 2015 Jul;
 
128(7):784.e9–19. [PMID: 25770031]
McNeely J et al. Performance of the Tobacco, Alcohol, Prescrip
-
tion Medication, and Other Substance Use (TAPS) tool for 
substance use screening in primary care patients. Ann Intern 
Med. 2016 Nov 15;165(10):690–9. [PMID: 27595276]
 
»
A. Acute Intoxication
The signs of alcoholic intoxication are the same as those of 
overdosage with any other central nervous system depres
-
sant: drowsiness, errors of commission, psychomotor dys
-
function, disinhibition, dysarthria, ataxia, and nystagmus. 
For a 70-kg person, an ounce of whiskey, a 4- to 6-oz glass 
of wine, or a 12-oz bottle of beer (roughly 15, 11, and 
 
13 grams of alcohol, respectively) may raise the level of 
alcohol in the blood by 25 mg/dL. For a 50-kg person, the 
blood alcohol level would rise even higher (35 mg/dL) with 
the same consumption. Blood alcohol levels below 50 mg/dL 
rarely cause significant motor dysfunction (the legal limit 
for driving under the influence is commonly 80 mg/dL). 
Intoxication as manifested by ataxia, dysarthria, and 
nausea and vomiting indicates a blood level greater than 
150 mg/dL, and lethal blood levels range from 350 mg/dL 
to 900 mg/dL. In severe cases, overdosage is marked by 
respiratory depression, stupor, seizures, shock syndrome, 
coma, and death. Serious overdoses are frequently due to a 
combination of alcohol with other sedatives.
B. Withdrawal
There is a wide spectrum of manifestations of alcohol with
-
drawal, ranging from anxiety, decreased cognition, and 
tremulousness, through increasing irritability and hyper
-
reactivity to full-blown 
delirium tremens (DTs)
. 
Alcohol 
withdrawal syndrome
 can be categorized as mild, moder
-
ate, or severe withdrawal, withdrawal seizures, and DTs. 
Symptoms of mild withdrawal, including tremor, anxiety, 
tachycardia, nausea, vomiting, and insomnia begin within

-
tachycardia, nausea, vomiting, and insomnia begin within 
6 hours after the last drink, often before the blood alcohol 
levels drop to zero, and usually have passed by day 2. Severe 
or major withdrawal occurs 48–96 hours after the last 
drink and is usually preceded by prolonged heavy alcohol 
use. Symptoms include disorientation, agitation, diaphore
-
sis, whole body tremor, vomiting, hypertension, and hal
-
lucinations (visual>tactile>auditory). Moderate withdrawal 
symptoms and signs fall between those of minor and major 
withdrawal. 
Withdrawal seizures
 can occur as early as 
8 hours after the last drink but usually do not manifest more 
than 48 hours after alcohol cessation. Seizures are more 
prevalent in persons who have a history of withdrawal syn
-
dromes. These seizures are generalized tonic-clonic sei
-
zures, are brief in duration, and resolve spontaneously. If 
withdrawal is untreated, these seizures can recur in about 
60% of patients. DTs will develop in approximately half of 
these patients. If seizures are focal, associated with trauma 
or fever, or have an onset more than 48 hours after the last 
drink, another etiology for seizures must be considered. 
DTs is the most severe form of alcohol withdrawal. It is an 
acute organic psychosis that usually manifests 48–72 hours 
after the last drink, but may occur up to 7–10 days later. It 
is characterized by extreme mental confusion, agitation, 
tremor, diaphoresis, sensory hyperacuity, visual hallucina
-
tions (often of snakes, bugs, etc) and autonomic hyperac
-
tivity (tachycardia and hypertension). Complications of 
DTs include (1) dehydration, (2) electrolyte disturbances 
(hypokalemia, hypomagnesemia), (3) arrhythmias and 
seizures, and (4) cardiovascular collapse and death. The 
acute withdrawal syndrome is often completely unex
-
pected, occurring when the patient has been hospitalized 
for some unrelated problem, thus presenting as a diagnos
-
tic dilemma. Suspect alcohol withdrawal in every unex
-
plained delirium. The mortality rate from DTs, which was 
upward of 35%, has steadily decreased with early diagnosis 
and improved treatment.
In addition to the immediate withdrawal symptoms, 
there is evidence of persistent longer-term ones, including 
sleep disturbances, anxiety, depression, excitability, fatigue, 
and emotional volatility. These symptoms may persist for 
3–12 months, and in some cases they become chronic.
C. Alcoholic (Organic) Hallucinosis
This syndrome occurs either during heavy drinking or on 
withdrawal and is characterized by a paranoid psychosis 
without the tremulousness, confusion, and clouded senso
-
rium seen in withdrawal syndromes. The patient appears 
normal except for the auditory hallucinations, which are 
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frequently persecutory and may cause the patient to behave 
aggressively and in a paranoid fashion.
D. Chronic Alcoholic Brain Syndromes
These encephalopathies are characterized by increasing 
erratic behavior, memory and recall problems, and emo
-
tional instability—the usual signs of organic brain injury due 
to any cause. Wernicke-Korsakoff syndrome due to thiamine 
deficiency may develop with a series of episodes. 
Wernicke 
encephalopathy
 consists of the triad of confusion, ataxia, 
and ophthalmoplegia (typically sixth nerve palsy). Early rec
-
ognition and treatment with thiamine can minimize damage. 
One of the possible sequelae is 
Korsakoff psychosis
, charac
-
terized by both anterograde and retrograde amnesia, with 
confabulation early in the course. Early recognition and treat
-
ment with intravenous thiamine and B complex vitamins can 
minimize damage. Excessive alcohol consumption in men 
has been associated with faster cognitive decline compared 
with light to moderate alcohol consumption.
E. Laboratory Findings
Ethanol may contribute to the presence of an otherwise 
unexplained osmolar gap. There may also be increased 
serum liver biochemical tests, uric acid, and triglycerides 
and decreased serum potassium and magnesium. The 
most definitive biologic marker for chronic alcoholism is 
carbohydrate deficient transferrin, which can detect heavy 
use (60 mg/day over 7–10 days) with high specificity. 
Other useful tests for diagnosing alcohol use disorder are 
gamma-glutamyl transpeptidase (GGT) measurement 
(levels greater than 30 units/L are suggestive of heavy 
drinking) and mean corpuscular volume (MCV) (more 
than 95 fL in men and more than 100 fL in women). If 
both are elevated, a serious alcohol problem is likely. Use 
of other recreational drugs with alcohol skews and negates 
the significance of these tests. Concomitant elevations of 
high-density lipoprotein (HDL) cholesterol and gamma-
glutamyl transpeptidase concentrations also can help 
identify heavy drinkers.
 
»
The differential diagnosis of alcoholism is essentially 
between 
primary alcohol use disorder
 (when no other 
major psychiatric diagnosis exists) and 
secondary alcohol 
use disorder
 (when alcohol is used as self-medication for 
major underlying psychiatric problems such as schizophre
-
nia or affective disorder). The differentiation is important, 
since the latter group requires treatment for the specific 
psychiatric problem. In primary and secondary alcoholism, 
at-risk drinking can be distinguished from alcohol addic
-
tion by taking a careful psychiatric history and evaluating 
the degree to which recurrent drinking impacts the social 
role functioning and physical safety of the individual.
The differential diagnosis of alcohol withdrawal includes 
other sedative withdrawals and other causes of delirium. 
Acute alcoholic hallucinosis must be differentiated from 
other acute paranoid states such as amphetamine psychosis 
or paranoid schizophrenia. The form of the brain syndrome 
is of little help—eg, chronic brain syndromes from systemic 
lupus erythematosus may be associated with confabulation 
similar to that resulting from longstanding alcoholism.
 
»
The medical, economic, and psychosocial problems of alco
-
holism are staggering. The central and peripheral nervous 
system complications include chronic brain syndromes, cere
-
bellar degeneration, cardiomyopathy, and peripheral neurop
-
athies. Direct effects on the liver include cirrhosis, esophageal 
varices, and eventual hepatic failure. Indirect effects include 
protein abnormalities, coagulation defects, hormone deficien
-
cies, and an increased incidence of liver neoplasms.
Fetal alcohol syndrome
 includes one or more of the 
following developmental defects in the offspring of alco
-
holic women: (1) low birth weight and small size with

-
holic women: (1) low birth weight and small size with 
failure to catch up in size or weight, (2) mental retardation, 
with an average IQ in the 60s, and (3) a variety of birth 
defects, with a large percentage of facial and cardiac abnor
-
malities. The risk is appreciably higher the more alcohol 
ingested by the mother each day.
 
»
Treatment of At-Risk Drinking
The most important consideration for the clinician is to 
suspect the problem early and take a nonjudgmental atti
-
tude, although this does not mean a passive one. The prob
-
lem of denial must be faced, preferably with significant 
family members at the first meeting. This means dealing 
from the beginning with any 
enabling behavior
 of the 
spouse or other significant people. Enabling behavior 
allows the patient with an alcohol use disorder to avoid 
facing the consequences of his or her behavior.
There must be an emphasis on the things that can be 
done. This approach emphasizes the fact that the clinician 
cares and strikes a positive and hopeful note early in treat
-
ment. Valuable time should not be wasted trying to find 
out why the patient drinks; come to grips early with the 
immediate problem of how to stop the drinking. Although 
total abstinence should be the ultimate goal, a 
harm reduc
-
tion model
 indicates that gradual progress toward absti
-
nence can be a useful treatment strategy.
Motivational interviewing
, a model of counseling that 
addresses both the patient’s ambivalence and motivation for 
change, may contribute to reduced consumption over time.
B. Social
Encourage the patient to attend Alcoholics Anonymous 
meetings and the spouse to attend Al-Anon meetings. Suc
-
cess is usually proportionate to the utilization of Alcoholics 
Anonymous, religious counseling, and other resources. 
The patient should be seen frequently for short periods.
Do not underestimate the importance of religion, par
-
ticularly since the patient with alcohol use disorder is often 
a dependent person who needs a great deal of support. 
Early enlistment of the help of a concerned religious 
adviser can often provide the turning point for a personal 
conversion to sobriety.
One of the most important considerations is the 
patient’s 
job
—fear of losing a job is one of the most powerful 
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motivations for giving up alcohol. The business community 
is aware of the problem; about 70% of the Fortune 500 com
-
panies offer programs to their employees to help with the 
problem of alcoholism. Some specific recommendations 
that can be offered to employers include (1) avoid place
-
ment in jobs where the alcoholic patient must be alone, eg, 
as a traveling buyer or sales executive, (2) use supervision 
but not surveillance, (3) keep competition with others to a 
minimum, and (4) avoid positions that require quick deci
-
sion making on important matters (high-stress situations). 
In general, commitment to abstinence and avoidance of 
situations that might be conducive to drinking are most 
predictive of a good outcome.
C. Medical
Hospitalization is not usually necessary. It is sometimes 
used to dramatize a situation and force the patient to face 
the problem of alcoholism, but generally it should be used 
for medical indications. Alcohol is responsible for about 
88,000 deaths in the United States each year.
Because of the many medical complications of alcohol
-
ism, a complete physical examination with appropriate 
laboratory tests is mandatory, with special attention to the 
liver and nervous system. Use of sedatives as a replacement 
for alcohol is not desirable. The usual result is concomitant 
use of sedatives and alcohol and worsening of the problem. 
Lithium is not helpful in the treatment of alcoholism.
Disulfiram (250–500 mg/day orally) has been used for 
many years as an aversive medication to discourage alcohol 
use. Disulfiram inhibits alcohol dehydrogenase, causing 
toxic reactions when alcohol is consumed. The results have 
generally been of limited effectiveness and depend on the 
motivation of the individual to be compliant.
Naltrexone, an opiate antagonist, in a dosage of 50 mg 
orally daily, lowers relapse rates over the 3–6 months after 
cessation of drinking, apparently by lessening the plea
-
surable effects of alcohol. One study suggests that naltrex
-
one is most effective when given during periods of 
drinking in combination with therapy that supports 
abstinence but accepts the fact that relapses occur. 
Naltrexone is FDA approved for maintenance therapy. 
Studies indicate that it reduces alcohol craving when used 
as part of a comprehensive treatment program. Acampro
-
sate (333–666 mg orally three times daily) helps reduce 
craving and maintain abstinence and can be continued 
even during periods of relapse. Both acamprosate and 
oral naltrexone have been associated with reduction in 
return to drinking.
Conditioning approaches historically have been used in 
some settings in the treatment of alcoholism, most com
-
monly as a type of aversion therapy. For example, the 
patient is given a drink of whiskey and then a shot of apo
-
morphine, and proceeds to vomit. In this way a strong 
association is built up between the drinking and vomiting. 
Although this kind of treatment has been successful in 
some cases, after appropriate informed consent, many 
people do not sustain the learned aversive response.
 
»
Treatment of Hallucinosis & Withdrawal
A. Hallucinosis
Alcoholic hallucinosis, which can occur either during or 
on cessation of a prolonged drinking period, is not a typical 
withdrawal syndrome and is handled differently. Since the 
symptoms are primarily those of a psychosis in the pres
-
ence of a clear sensorium, they are handled like any other 
psychosis: hospitalization (when indicated) and adequate 
amounts of antipsychotic medications. Haloperidol, 5 mg 
orally twice a day for the first day or so, usually ameliorates 
symptoms quickly, and the medication can be decreased 
and discontinued over several days as the patient improves. 
It then becomes necessary to deal with the chronic alcohol 
abuse, which has been discussed.
The onset of withdrawal symptoms is usually 6–36 hours

The onset of withdrawal symptoms is usually 6–36 hours 
and the peak intensity of symptoms is 48–72 hours after 
alcohol consumption is stopped. Providing adequate cen
-
tral nervous system depressants (eg, benzodiazepines) is 
important to counteract the excitability resulting from sud
-
den cessation of alcohol intake. The choice of a specific 
sedative is less important than using adequate doses to 
bring the patient to a level of moderate sedation, and this 
will vary from person to person.
All patients should be evaluated for their risk of alcohol 
withdrawal. Mild dependency requires “drying out. ” For 
outpatients, in some instances, a short course of tapering 
long-acting benzodiazepines—eg, diazepam, 20 mg/day 
orally initially, decreasing by 5 mg daily—may be a useful 
adjunct. When the history or presentation suggests that 
patients are actively in withdrawal or at significant risk for 
withdrawal, they should be 
hospitalized
. Risk factors 
include a recent drinking history, frequent alcohol con
-
sumption, a past history of withdrawal, seizures, hallucino
-
sis, or DTs, a past history of needing medication for 
detoxification, or a history of benzodiazepine or barbitu
-
rate use, abuse, or dependency.
For all hospitalized patients, general management 
includes ensuring adequate hydration, correction of elec
-
trolyte imbalances (particularly magnesium, calcium, and 
potassium), and administering the vitamins thiamine 
(100 mg intravenously daily for 3 days then orally daily), 
folic acid (1 mg orally daily), and a multivitamin orally 
daily. Thiamine should be given 
prior
 to any glucose-
containing solutions to decrease the risk of precipitating 
Wernicke encephalopathy or Korsakoff syndrome. Alcohol 
withdrawal is treated with benzodiazepines. Continual 
assessment is recommended to determine the severity of 
withdrawal, and 
symptom-driven medication regimens
, 
which have been shown to prevent undersedation as well as 
oversedation and to reduce total benzodiazepine usage 
over fixed-dose schedules, should be used. The severity of 
withdrawal will determine a patient’s level of care. For 
those at risk for withdrawal and with mild withdrawal 
symptoms, admission to a medical unit is adequate. For 
those with moderate withdrawal, a higher acuity hospital 
environment is recommended. Those with severe with
-
drawal should be admitted to the ICU.
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CMDT 2019
1. Assessing alcohol withdrawal symptom severity—
The 
Clinical Institute Withdrawal Assessment for Alcohol, 
Revised (CIW A-Ar)
 is a validated tool that is widely used 
to determine severity of alcohol withdrawal. This survey 
assesses symptoms in 10 areas and can be administered 
relatively quickly (Figure 25–3). One caveat is that the 
patient must be able to communicate his or her symptoms 
to the provider. The maximum attainable score is 67. Clini
-
cal judgment should be used to determine final dosing of 
medications to patients who are in alcohol withdrawal 
 
▲
Figure 25–3.
 
Alcohol withdrawal assessment. 
(Reproduced from Sullivan JT et al. Assessment of alcohol withdrawal: 
The revised clinical institute withdrawal assessment for alcohol scale [CIWA-Ar]. 
Br J Addict
 1989;84:1353. This scale is not 
copyrighted and may be used freely.)
Pa
tient:
Pu
lse or heart 
ra
te
, 
taken for 1 minute:
Time:
(24 hour clock, midnight = 00:00)
Date:
Blood pressure:
NAUSEA AND 
VO
MITING
 — Ask “Do you feel sick 
to
yo
ur stomach? Ha
ve
 
yo
u vomited?” Observation.
0  no nausea and no vomiting
1  mild nausea with no vomiting
2
3
4  intermi
tt
ent nausea with dry hea
ve
s
5
6
7  constant nausea, frequent dry heaves and vomiting         
TA
CTILE DISTURBANCES 
— Ask “H
av
e 
yo
u any itchin
g,
 pins
and needles sensation
s,
 any 
bu
rn
ing, any numbness, or do
yo
u feel 
bu
gs crawling on or under your skin?” Observation
. 
  
TREMOR
 — Arms 
ex
tended and fingers spread apart.
Observation.
0  no tremor
1  not visible, but can be felt fingertip 
to
 
fi
ngertip
2
3
4  moderat
e,
 with patient’s arms 
ex
tended
5
6
7 se
ve
re
, 
ev
en with arms not 
ex
tended  
AUDI
TO
RY
 DISTURBANCES
 — Ask 
“A
re
 you more 
aw
are of
sounds around 
yo
u? Are they harsh? Do they frighten you?
Are 
yo
u hearing anything that is disturbing 
to
 you? Are 
yo
u
hearing things you know are not there?” Observation.
0  not present
1  
ve
ry
 mild ha
rs
hness or abili
ty
 
to
 frighten
2  mild harshness or abili
ty
 
to
 frighten
3  moderate harshness or ability 
to
 frigh
te
n
4  moderately se
ve
re
 audi
to
ry
 hallucinations
5  se
ve
re
6  extremely se
ve
re
7  continuous hallucinations        
PA
RO
XYSMAL SWEATS
 — Observation.  
0  no 
sw
eat visible
1  barely perceptible 
sw
eating, palms moist
2
3
4  beads of 
sw
eat obvious on 
fo
rehead
5
6
7  drenching 
sw
eats     
VISUAL DI
ST
URBANCES
 — Ask “Does the light appear 
to
be too bright? Is its color dif
fe
rent? Does it hurt your 
ey
es?
Are 
yo
u seeing anything that is disturbing 
to
 you? Are 
yo
u
seeing things you know are not there?” Observation.
1  
ve
ry
 mild photosensitivi
ty
2  mild sensitivi
ty
3  moderate sensitivi
ty
ve
re
 visual hallucinations
5  se
ve
re
ve
re
7  continuous hallucinations    
ANXIETY
 — Ask “Do you feel nervous?” Observation.
0  no anxiet
y,
 at ease
1  mildly anxious
2
3
4  moderately anxious, or guarded, so anxiety is inferred
5
6
7  se
ve
rely
 anxious, equivalent…
HEA
DAC
HE
, 
FULLNESS IN HEAD
 — Ask “Does 
yo
ur head
feel dif
fe
rent? Does it feel li
ke
 there is a band around 
yo
ur
head?”
 Do not ra
te
 
fo
r dizziness or lightheadedness.
Otherwise
, ra
te
 se
ve
ri
ty
.
1  
ve
ry
 mild
2  mild
3  moderate
ve
re
5  se
ve
re
6  
ve
ry
 se
ve
re
7  extremely se
ve
re
       
0  none
1  
ve
ry
 mild itchin
g,
 pins and needle
s,
 
bu
rn
ing, or numbness
2  mild itchin
g,
s,
 
bu
rn
3  moderate itching, pins and needles, 
bu
rnin
g,
 or numbness
ve
re
 hallucinations (formications)
5  se
ve
re
6  extreme
ly
 se
ve
re
7  continuous hallucinations
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because dosing will vary between patients and degrees of 
2. Treating alcohol withdrawal symptoms based on 
CIWA-Ar score—
a. 
M
inimal withdrawal symptoms (
CIW A
-
A
r score 
less than 8)
—
Patients who have a history suggestive of 
alcohol withdrawal risk with minimal withdrawal symp
-
toms are suitable for withdrawal prophylaxis. The recom
-
mended benzodiazepine options include chlordiazepoxide 
or lorazepam orally, tapered over 3 days. The protocol calls 
for nursing assessment of sedation and withdrawal symp
-
toms (CIW A-Ar) every 6 hours. If prophylactic medication 
is indicated, a sample tapering regimen may include loraz
-
epam, 1 mg orally every 6 hours for 1 day, then 1 mg orally 
every 8 hours for 1 day, then 1 mg orally every 12 hours for 
1 day, then discontinue; or chlordiazepoxide 50 mg orally 
every 6 hours for 1 day, 25 mg orally every 6 hours for 
 
2 days, then discontinue. Avoid chlordiazepoxide in the 
elderly or in patients with liver disease. Lorazepam is pre
-
ferred in patients with liver disease. Sedation is assessed 
30–60 minutes after each medication dose. The benzodiaz
-
epine dose is held for oversedation or if the respiratory rate 
is less than 10 breaths per minute. For CIW A-Ar score 
greater than 8, the provider must be notified, because this 
is suggestive of active withdrawal, and escalation of treat
-
ment must occur.
b. 
M
ild withdrawal symptoms (
CIW A
-
A
r score 
8–15)
—
For patients in mild withdrawal, either chlordiaz
-
epoxide orally or lorazepam orally or intravenously can be 
used. Initially, chlordiazepoxide 50 mg orally or lorazepam 
1 or 2 mg orally or intravenously is given hourly for 2 hours. 
Patients must be assessed for level of sedation and with
-
drawal symptoms (CIW A-Ar) every 4 hours. Dosing is 
adjusted as necessary to control symptoms without exces
-
sive sedation. After the first 2 hours, chlordiazepoxide or 
lorazepam is given every 4 hours and as needed. Typical 
dosing may include chlordiazepoxide 25–50 mg orally or 
lorazepam 0.5–1 mg orally or intravenously every 4 hours 
as needed. Additional doses of benzodiazepines should be 
given if the CIW A-Ar score remains between 8 and 15.
c. 
M
oderate withdrawal (
CIW A
-
A
r score 16–20)
—
For patients in moderate withdrawal, chlordiazepoxide 
100 mg orally or lorazepam 3 or 4 mg orally or intravenously 
is given every hour for the first 2 hours. CIW A-Ar monitor
-
ing should occur every 2 hours. Dosing is adjusted to control 
symptoms without excessive sedation. After initial dosing, 
continued treatment could include chlordiazepoxide 50 mg 
orally or lorazepam 1–2 mg orally or intravenously every 
 
2 hours as needed for CIW A-Ar score between 16 and 20, 
and chlordiazepoxide 25 mg orally or lorazepam 0.5–1 mg 
orally or intravenously every 2 hours for CIW A-Ar score 
between 8 and 15. The maximum dose of chlordiazepoxide 
is 600 mg in 24 hours. Continuous pulse oximetry and car
-
diac monitoring should be considered. The degree of seda
-
tion should be monitored 30–60 minutes after each oral dose 
of medication and for 15 minutes after each parenteral dose.
d. 
S
evere withdrawal (
CIW A
-
A
r score greater 
than 21)
—
Patients with severe withdrawal are at risk for 
the development of DTs and should be transferred or admit
-
ted to the ICU. Intravenous lorazepam is the medication of 
choice for treating severe withdrawal. Lorazepam 1–2 mg 
intravenously every 15 minutes can be given until patient is 
calm and sedated but awake. Initial CIW A-Ar monitoring 
should occur every 30 minutes. The patient can then receive 
lorazepam 2 mg orally or intravenously every hour as 
needed when the CIW A-Ar score is between 16 and 20, and 
lorazepam 1–2 mg orally or intravenously every hour as 
needed when the CIW A-Ar score is between 8 and 15. If the 
patient requires more than 8 mg/h of lorazepam as an initial 
dose or continues to demonstrate observable agitation,

dose or continues to demonstrate observable agitation, 
tremors, tachycardia, or hypertension despite high doses of 
lorazepam, consider adding dexmedetomidine. Dexmedeto
-
midine, an alpha-2-agonist, produces sedation with minimal 
effect on respiratory drive. It is not recommended as a sole 
agent for the treatment of alcohol withdrawal but as therapy 
AGI
TA
TION
 — Observation.
0  normal activity
1  somewhat mo
re
 than normal activity
2
3
4  moderately fidgety and restless
5
6
7  paces back and 
fo
rth during most of the intervi
ew
,
or constantly thrashes about
ORIEN
TAT
ION AND CLOUDING OF SENSORIUM
 — Ask
“What is 
to
day's da
te
?… Who am I?”
. 
Serial additions: “Please
count up 
by
 5’s — 0, 5, 10…”
0  oriented and can do serial additions
1  cannot do serial additions or is unce
rt
ain about date
2  disorien
te
d for date 
by
 no more than 2 calendar da
ys
3  disorien
te
d for date 
by
 more than 2 calendar da
ys
4  disorien
te
d for date and place or person  
Maximum 
Po
ssible Sco
re
 67
To
tal 
CIWA-Ar
 Score
Rate
r’
s Initials
This assessment 
fo
r monitoring withdr
aw
al 
sy
mp
to
ms requires approximatel
y 5 minu
te
s 
to
 administer
. 
The maximum score
is 67 (see instrument). Patients scoring less than 8 (or 10, according 
to
 some experts) do not usual
ly
 need additional
medication for withdr
aw
al
. 
 
▲
 
(
continued
)
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1111
 
CMDT 2019
along with one of the benzodiazepines to decrease the 
hyperadrenergic output in patients with severe alcohol with
-
drawal not controlled by benzodiazepines or in patients at 
risk for respiratory depression from high-dose benzodiaze
-
pine administration. The recommended dosing of dexme
-
detomidine is 0.2–0.7 mcg/kg/h, with lorazepam 1–2 mg 
intravenously every 8 hours plus lorazepam 1–2 mg intrave
-
nously every hour as needed for agitation. In limited cases of 
severe withdrawal requiring frequent lorazepam boluses for 
at least 6 hours, continuous intravenous lorazepam infusion 
can be considered, but the patient must be monitored 
extremely carefully for signs of respiratory depression. Con
-
tinuous pulse oximetry and close observance of the patient’s 
respiratory status is required. Sedation is assessed 15 minutes 
after each intravenous dose. If withdrawal symptoms are 
refractory to escalating benzodiazepine usage, despite the 
addition of dexmedetomidine, escalation to propofol should 
be considered. Patients receiving large doses of benzodiaze
-
pines often require intubation for airway protection, at 
which time initiation of propofol infusion for sedation, in 
addition to treatment of refractory alcohol withdrawal, is 
recommended. Phenobarbital monotherapy for alcohol 
withdrawal is used at some institutions, but randomized 
controlled trials comparing the efficacy of phenobarbital to 
benzodiazepines are lacking.
In all cases, benzodiazepines should be held if the 
patient is too sedated or has a respiratory rate less than 10 
breaths per minute. Do not bolus lorazepam in doses 
greater than 4 mg intravenously. Mixing benzodiazepines, 
eg, chlordiazepoxide orally every 8 hours with lorazepam, is 
not recommended. Instead, select a single agent and titrate 
as needed. Once a patient has been stable for 24 hours, the 
benzodiazepine dose can be reduced by 20% daily until 
withdrawal is complete.
3. Managing other withdrawal-associated conditions—
Meticulous examination for other medical problems is 
necessary. Alcoholic hypoglycemia can occur with low 
blood alcohol levels (see Chapter 27). Patients with severe 
alcohol use disorder commonly have liver disease with 
associated clotting disorders and are also prone to injury—
and the combination all too frequently leads to undiag
-
nosed subdural hematoma.
Phenytoin does 
not
 appear to be useful in managing 
alcohol withdrawal seizures per se. Sedating doses of ben
-
zodiazepines are effective in treating alcohol withdrawal 
seizures. Thus, other anticonvulsants are not usually 
needed unless there is a preexisting seizure disorder.
Chronic brain syndromes secondary to a long history of 
alcohol intake are not clearly responsive to thiamine and 
vitamin replenishment. Attention to the social and envi
-
ronmental care of this type of patient is paramount.
4. Initiating psychological and social measures—
The 
psychological and behavioral treatment methods outlined 
under Treatment of At-Risk Drinking become the primary 
considerations after successful treatment of alcoholic hal
-
lucinosis or withdrawal. Psychological and social measures 
should be initiated in the hospital prior to discharge. This 
increases the possibility of continued posthospitalization 
Crispo AL et al. Comparison of clinical outcomes in nonintu
-
bated patients with severe alcohol withdrawal syndrome 
treated with continuous-infusion sedatives: dexmedetomi
-
dine versus benzodiazepines. Pharmacotherapy. 2014 Sep;
 
34(9):910–7. [PMID: 24898418]
Jonas DE et al. Pharmacotherapy for adults with alcohol use 
disorders in outpatient settings: a systematic review and 
meta-analysis. JAMA. 2014 May 14;311(18):1889–900. 
[PMID: 24825644]
Mehta AJ. Alcoholism and critical illness: a review. World J Crit 
Care Med. 2016 Feb 4;5(1):27–35. [PMID: 26855891]
Sabia S et al. Alcohol consumption and cognitive decline in early

Sabia S et al. Alcohol consumption and cognitive decline in early 
old age. Neurology. 2014 Jan 28;82(4):332–9. [PMID: 24431298]
Schmidt KJ et al. Treatment of severe alcohol withdrawal. Ann 
Pharmacother. 2016 May;50(5):389–401. [PMID: 26861990]
Soyka M et al; WFSBP Task Force on Treatment Guidelines for 
Substance Use Disorders. Guidelines for biological treatment 
of substance use and related disorders, part 1: Alcoholism, first 
revision. World J Biol Psychiatry. 2017 Mar;18(2):86–119. 
[PMID: 28006997]
OTHER DRUG & SUBSTANCE DEPENDENCIES
1. Opioids
While the terms “opioids” and “narcotics” both refer to a 
group of drugs with actions that mimic those of morphine, 
the term “opioids” is used when discussing medications pre
-
scribed in a controlled manner by a clinician, and the term 
“narcotics” is used to connote illicit drug use. All of the opioid 
analgesics can be reversed by the opioid antagonist naloxone.
The clinical symptoms and signs of mild narcotic 
intoxication include changes in mood, with feelings of 
euphoria; drowsiness; nausea with occasional emesis; nee
-
dle tracks; and miosis. The incidence of snorting and inhal
-
ing (“smoking”) heroin is increasing, particularly among 
cocaine users. This coincides with a decrease in the avail
-
ability of methaqualone (no longer marketed) and other 
sedatives used to temper the cocaine “high” (see discussion 
of cocaine under Stimulants, below). Overdosage causes 
respiratory depression, peripheral vasodilation, pinpoint 
pupils, pulmonary edema, coma, and death.
Tolerance and withdrawal are major concerns when 
continued use of opioids occurs, although withdrawal 
causes only moderate morbidity (similar in severity to a 
bout of “flu”). Addicted patients sometimes consider them
-
selves more addicted than they really are and may not 
require a withdrawal program. Grades of withdrawal are 
categorized from 0 to 4: 
grade 0
 includes craving and anxiety; 
grade 1,
 yawning, lacrimation, rhinorrhea, and perspiration; 
grade 2,
 previous symptoms plus mydriasis, piloerection, 
anorexia, tremors, and hot and cold flashes with generalized 
aching; 
grades 3
 
and 4,
 increased intensity of previous 
symptoms and signs, with increased temperature, blood 
pressure, pulse, and respiratory rate and depth. In with
-
drawal from the most severe addiction, vomiting, diarrhea, 
weight loss, hemoconcentration, and spontaneous ejacula
-
tion or orgasm commonly occur.
Treatment for overdosage
 (or suspected overdosage) is 
discussed in Chapter 38.
Treatment for withdrawal
 begins if grade 2 signs 
develop. If a withdrawal program is necessary, use 
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methadone, 10 mg orally (use parenteral administration if 
the patient is vomiting), and observe. If signs (piloerection, 
mydriasis, cardiovascular changes) persist for more than 
4–6 hours, give another 10 mg; continue to administer 
methadone at 4- to 6-hour intervals until signs are not pres
-
ent (rarely greater than 40 mg of methadone in 24 hours). 
Divide the total amount of drug required over the first 
24-hour period by 2 and give that amount every 12 hours. 
Each day, reduce the total 24-hour dose by 5–10 mg. Thus, 
a moderately addicted patient initially requiring 30–40 mg 
of methadone could be withdrawn over a 4- to 8-day 
period. Clonidine, 0.1 mg orally several times daily over a 
10- to 14-day period, is both an alternative and an adjunct 
to methadone detoxification; it is not necessary to taper the 
dose. Clonidine is helpful in alleviating cardiovascular 
symptoms but does not significantly relieve anxiety, insom
-
nia, or generalized aching. There is a protracted abstinence 
syndrome of metabolic, respiratory, and blood pressure 
changes over a period of 3–6 months. Alternative strategies 
for the treatment of opioid withdrawal have included rapid 
and ultrarapid detoxification techniques. However, data do 
not support the use of either method.
Opioid antagonists (eg, naltrexone) can also be used 
successfully for treatment of the patient who has been free 
of opioids for 7–10 days. Naltrexone blocks the narcotic 
“high” of heroin when 50 mg is given orally every 24 hours 
initially for several days and then 100 mg is given every 
48–72 hours. A monthly injectable form of naltrexone is 
available and may enhance compliance. Liver disorders are 
a major contraindication. Buprenorphine, a partial agonist, 
is a mainstay of office-based treatment of opiate depen
-
dency. Its use requires certified training.
Methadone maintenance programs are of some value in 
chronic recidivism. Under carefully controlled supervision, 
the narcotic addict is maintained on fairly high doses of 
methadone (40–120 mg/day) that satisfy craving and block 
the effects of heroin to a great degree.
2. Sedatives (Anxiolytics)
See Anxiety Disorders, this chapter.
3. Psychedelics
All of the common psychedelics (LSD, mescaline, psilocy
-
bin, dimethyltryptamine, and other derivatives of phenylala
-
nine and tryptophan) can produce similar behavioral and 
physiologic effects. An initial feeling of tension is followed 
by emotional release such as crying or laughing (1–2 hours). 
Later, perceptual distortions occur, with visual illusions and 
hallucinations, and occasionally there is fear of ego disinte
-
gration (2–3 hours). Major changes in time sense and mood 
lability then occur (3–4 hours). A feeling of detachment and 
a sense of destiny and control occur (4–6 hours). Of course, 
reactions vary among individuals, and some of the drugs 
produce markedly different time frames. Occasionally, the 
acute episode is terrifying (a “bad trip”), which may include 
panic, depression, confusion, or psychotic symptoms. Preex
-
isting emotional problems, the attitude of the user, and the 
setting where the drug is used affect the experience.
Treatment of the acute episode primarily involves protec
-
tion of the individual from erratic behavior that may lead to 
injury or death. A structured environment is usually suffi
-
cient until the drug is metabolized. In severe cases, antipsy
-
chotic medications with minimal side effects (eg, haloperidol, 
5 mg intramuscularly) may be given every several hours 
until the individual has regained control. In cases where 
“flashbacks” occur (mental imagery from a “bad trip” that is 
later triggered by mild stimuli such as marijuana, alcohol, or 
psychic trauma), a short course of an antipsychotic drug—
eg, olanzapine, 5–10 mg/day orally, or risperidone, 2 mg/day 
orally, initially, and up to 20 mg/day and 6 mg/day, respec
-
tively—is usually sufficient. Lorazepam or clonazepam,

-
tively—is usually sufficient. Lorazepam or clonazepam, 
1–2 mg orally every 2 hours as needed for acute agitation, 
may be a useful adjunct. An occasional patient may have 
“flashbacks” for much longer periods and may require 
small doses of antipsychotic medications over the longer 
term.
4. Phencyclidine
Phencyclidine (PCP , angel dust, peace pill, hog) is simple to 
produce and mimics to some degree the traditional psyche
-
delic drugs. PCP is a common deceptive substitute for LSD, 
tetrahydrocannabinol, and mescaline. It is available in crys
-
tals, capsules, and tablets to be inhaled, injected, swallowed, 
or smoked (it is commonly sprinkled on marijuana).
Absorption after smoking is rapid, with onset of symp
-
toms in several minutes and peak symptoms in 15–30 
minutes. Mild intoxication produces euphoria accompa
-
nied by a feeling of numbness. Moderate intoxication (5–10 
mg) results in disorientation, detachment from surround
-
ings, distortion of body image, combativeness, unusual feats 
of strength (partly due to its anesthetic activity), and loss of 
ability to integrate sensory input, especially touch and pro
-
prioception. Physical symptoms include dizziness, ataxia, 
dysarthria, nystagmus, retracted upper eyelid with blank 
stare, hyperreflexia, and tachycardia. There are increases in 
blood pressure, respiration, muscle tone, and urine produc
-
tion. Usage in the first trimester of pregnancy is associated 
with an increase in spontaneous abortion and congenital 
defects. Severe intoxication (20 mg or more) produces an 
increase in degree of moderate symptoms, with the addition 
of seizures, deepening coma, hypertensive crisis, and severe 
psychotic ideation. The drug is particularly long-lasting 
(several days to several weeks) owing to high lipid solubility, 
gastroenteric recycling, and the production of active metab
-
olites. Overdosage may be fatal, with the major causes of 
death being hypertensive crisis, respiratory arrest, and con
-
vulsions. Acute rhabdomyolysis has been reported and can 
result in myoglobinuric kidney failure.
Differential diagnosis involves the whole spectrum of 
street drugs, since in some ways phencyclidine mimics 
sedatives, psychedelics, and marijuana in its effects. Blood 
and urine testing can detect the acute problem.
Treatment is discussed in Chapter 38.
5. Marijuana
Cannabis sativa
, a hemp plant, is the source of marijuana. 
Mercury may be a contaminant in marijuana grown in 
volcanic soil. The drug is usually inhaled by smoking. 
Effects occur in 10–20 minutes and last 2–3 hours. “Joints” 
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CMDT 2019
of good quality contain about 500 mg of marijuana (which 
contains approximately 5–15 mg of tetrahydrocannabinol 
with a half-life of 7 days).
With moderate dosage, marijuana produces two phases: 
mild euphoria followed by sleepiness. In the acute state, the 
user has an altered time perception, less inhibited emotions, 
psychomotor problems, impaired immediate memory, and 
conjunctival injection. High doses produce transient psy
-
chotomimetic effects. No specific treatment is necessary 
except in the case of the occasional “bad trip, ” in which case 
the person is treated in the same way as for psychedelic 
usage. Marijuana frequently aggravates existing mental ill
-
ness and adversely affects motor performance.
Studies of long-term effects have conclusively shown 
abnormalities in the pulmonary tree. Laryngitis and rhini
-
tis are related to prolonged use, along with chronic obstruc
-
tive pulmonary disease. Electrocardiographic abnormalities 
are common, but no chronic cardiac disease has been 
linked to marijuana use. Long-term usage has resulted in 
depression of plasma testosterone levels and reduced 
sperm counts. Abnormal menstruation and failure to ovu
-
late have occurred in some women. Cognitive impairments 
are common. Health care utilization for a variety of health 
problems is increased in long-term marijuana smokers. 
Sudden withdrawal produces insomnia, nausea, myalgia, 
and irritability. Psychological effects of long-term mari
-
juana usage are still unclear. Urine testing is reliable if 
samples are carefully collected and tested. Detection peri
-
ods span 4–6 days in short-term users and 20–50 days in 
long-term users.
6. Stimulants: Amphetamines & Cocaine
Stimulant abuse is quite common, either alone or in com
-
bination with abuse of other drugs. The stimulants include 
illicit drugs such as methamphetamine (“speed”)—one 
variant is a smokable form called “ice, ” which gives an 
intense and fairly long-lasting high—and methylphenidate 
and dextroamphetamine, which are under prescription 
control. Street availability of amphetamines remains high. 
Moderate usage of any of the stimulants produces hyperac
-
tivity, a sense of enhanced physical and mental capacity, 
and sympathomimetic effects. The clinical picture of acute 
stimulant intoxication includes sweating, tachycardia, ele
-
vated blood pressure, mydriasis, hyperactivity, and an 
acute brain syndrome with confusion and disorientation. 
Tolerance develops quickly, and, as the dosage is increased, 
hypervigilance, paranoid ideation (with delusions of para
-
sitosis), stereotypy, bruxism, tactile hallucinations of insect 
infestation, and full-blown psychoses occur, often with 
persecutory ideation and aggressive responses. Stimulant 
withdrawal is characterized by depression with symptoms 
of hyperphagia and hypersomnia.
People who have used stimulants chronically (eg, 
anorexigenics) occasionally become sensitized (
“kindling”
) 
to future use of stimulants. In these individuals, even small 
amounts of mild stimulants such as caffeine can cause 
symptoms of paranoia and auditory hallucinations.
Cocaine
 is a stimulant. It is a product of the coca plant. 
The derivatives include seeds, leaves, coca paste, cocaine 
hydrochloride, and the free base of cocaine. Cocaine 
hydrochloride is the salt and the most commonly used 
form. Freebase, a purer (and stronger) derivative called 
“crack, ” is prepared by simple extraction from cocaine 
hydrochloride.
There are various modes of use. Coca leaf chewing 
involves toasting the leaves and chewing with alkaline 
material (eg, the ash of other burned leaves) to enhance 
buccal absorption. One achieves a mild high, with onset in 
5–10 minutes and lasting for about an hour. Intranasal use 
is simply snorting cocaine through a straw. Absorption is 
slowed somewhat by vasoconstriction (which may eventu
-
ally cause tissue necrosis and septal perforation); the onset

-
ally cause tissue necrosis and septal perforation); the onset 
of action is in 2–3 minutes, with a moderate high (euphoria, 
excitement, increased energy) lasting about 30 minutes. 
The purity of the cocaine is a major determinant of the 
high. Intravenous use of cocaine hydrochloride or “free
-
base” is effective in 30 seconds and produces a short-
 
lasting, fairly intense high of about 15 minutes’ duration. 
The combined use of cocaine and ethanol results in the 
metabolic production of cocaethylene by the liver. This 
substance produces more intense and long-lasting cocaine-
like effects. Smoking freebase (volatilized cocaine because 
of the lower boiling point) acts in seconds and results in an 
intense high lasting several minutes. The intensity of the 
reaction is related to the marked lipid solubility of the free
-
base form and produces by far the most severe medical and 
psychiatric symptoms.
Cardiovascular collapse, arrhythmias, myocardial 
infarction, and transient ischemic attacks have been 
reported. Seizures, strokes, migraine symptoms, hyper
-
thermia, and lung damage may occur, and there are several 
obstetric complications, including spontaneous abortion, 
abruptio placentae, teratogenic effects, delayed fetal 
growth, and prematurity. Cocaine can cause anxiety, mood 
swings, and delirium, and chronic use can cause the same 
problems as other stimulants.
Clinicians should be alert to cocaine use in patients 
presenting with unexplained nasal bleeding or septal perfo
-
rations, headaches, fatigue, insomnia, anxiety, depression, 
and chronic hoarseness. Sudden withdrawal of the drug is 
not life-threatening but usually produces craving, sleep 
disturbances, hyperphagia, lassitude, and severe depression 
(sometimes with suicidal ideation) lasting days to weeks.
Treatment is imprecise and difficult. Since the high is 
related to blockage of dopamine reuptake, the dopamine 
agonist bromocriptine, 1.5 mg orally three times a day, 
alleviates some of the symptoms of craving associated with 
acute cocaine withdrawal. Treatment of psychosis is the 
same as that of any psychosis: antipsychotic medications in 
dosages sufficient to alleviate the symptoms. Any medical 
symptoms (eg, hyperthermia, seizures, hypertension) are 
treated specifically. These approaches should be used in 
conjunction with a structured program, most often based 
on the Alcoholics Anonymous model. Hospitalization may 
be required if self-harm or violence toward others is a per
-
ceived threat (usually indicated by paranoid delusions).
7. Caffeine
Caffeine, along with nicotine and alcohol, is one of the 
most commonly used drugs worldwide. Tea, cocoa, and 
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cola drinks also contribute to an intake of caffeine that is 
often astoundingly high in a large number of people. Low 
to moderate doses (30–200 mg/day) tend to improve some 
aspects of performance (eg, vigilance). The approximate 
content of caffeine in a (180-mL) cup of beverage is as fol
-
lows: brewed coffee, 80–140 mg; instant coffee, 60–100 mg; 
decaffeinated coffee, 1–6 mg; black leaf tea, 30–80 mg; tea 
bags, 25–75 mg; instant tea, 30–60 mg; cocoa, 10–50 mg; and 
12-oz cola drinks, 30–65 mg. A 2-oz chocolate candy bar has 
about 20 mg. Some herbal teas (eg, “morning thunder”) 
contain caffeine. Caffeine-containing analgesics usually 
contain approximately 30 mg per unit. Symptoms of caffein
-
ism (usually associated with ingestion of over 500 mg/day) 
include anxiety, agitation, restlessness, insomnia, a feeling 
of being “wired, ” and somatic symptoms referable to the 
heart and gastrointestinal tract. It is common for a case of 
caffeinism to present as an anxiety disorder. It is also com
-
mon for caffeine and other stimulants to precipitate severe 
symptoms in compensated schizophrenic and manic-
depressive patients. Chronically depressed patients often 
use caffeine drinks as self-medication. This diagnostic clue 
may help distinguish some major affective disorders. Dis
-
continuation of caffeine (greater than 250 mg/day) can 
produce withdrawal symptoms, such as headaches, irrita
-
bility, lethargy, and occasional nausea.
8. Miscellaneous Drugs & Solvents
The principal over-the-counter drugs of concern are an 
assortment of antihistaminic agents, frequently in combi
-
nation with a mild analgesic promoted as cold remedies.
Antihistamines usually produce some central nervous 
system depression—thus their use as over-the-counter 
sedatives. Practically all of the so-called sleep aids are anti
-
histamines. The mixture of antihistamines with alcohol 
usually exacerbates the central nervous system effects. 
Scopolamine and bromides have generally been removed 
from over-the-counter products.
The abuse of laxatives sometimes can lead to electrolyte 
disturbances that may contribute to the manifestations of a 
delirium. The greatest use of laxatives tends to be in the 
elderly and in those with eating disorders, both of whom 
are the most vulnerable to physiologic changes.
Anabolic steroids are abused by people who wish to 
increase muscle mass for cosmetic reasons or for greater 
strength. In addition to the medical problems, the practice 
is associated with significant mood swings, aggressiveness, 
and paranoid delusions. Alcohol and stimulant use is 
higher in these individuals. Withdrawal symptoms of ste
-
roid dependency include fatigue, depressed mood, restless
-
ness, and insomnia.
Amyl nitrite is used as an “orgasm expander. ” The 
changes in time perception, “rush, ” and mild euphoria 
caused by the drug prompted its nonmedical use. Subjec
-
tive effects last from 5 seconds to 15 minutes. Tolerance 
develops readily, but there are no known withdrawal symp
-
toms. Abstinence for several days reestablishes the previ
-
ous level of responsiveness. Long-term effects may include 
damage to the immune system and respiratory difficulties.
Sniffing of solvents and inhaling of gases (including 
aerosols) produce a form of inebriation similar to that of 
the volatile anesthetics. Agents include gasoline, toluene, 
petroleum ether, lighter fluids, cleaning fluids, paint thin
-
ners, and solvents that are present in many household 
products (eg, nail polish). Typical intoxication states 
include euphoria, slurred speech, hallucinations, and con
-
fusion, and with high doses, acute manifestations are 
unconsciousness and cardiorespiratory depression or fail
-
ure; chronic exposure produces a variety of symptoms 
related to the liver, kidney, bone marrow, or heart. Lead 
encephalopathy can be associated with sniffing leaded 
gasoline. In addition, studies of workers chronically

gasoline. In addition, studies of workers chronically 
exposed to jet fuel showed significant increases in neuras
-
thenic symptoms, including fatigue, anxiety, mood changes, 
memory difficulties, and somatic complaints. These same 
problems have been noted in long-term solvent abuse.
The so-called designer drugs are synthetic substitutes 
for commonly used recreational drugs. Common designer 
drugs include methyl analogues of fentanyl used as heroin 
substitutes. MDMA (methylenedioxymethamphetamine), 
an amphetamine derivative sometimes called “ecstasy, ” is 
also a designer drug with high abuse potential and pur
-
ported neurotoxicity. Often not detected by standard toxi
-
cology screens, these substances can present a vexing 
problem for clinicians faced with symptoms from a totally 
Cicero TJ et al. The changing face of heroin use in the United 
States: a retrospective analysis of the past 50 years. JAMA 
Psychiatry. 2014 Jul 1;71(7):821–6. [PMID: 24871348]
Friedmann PD. Clinical practice. Alcohol use in adults. N Engl J 
Med. 2013 Jan 24;368(4):365–73. Erratum in: N Engl J Med. 
2013 Apr 25;368(17):1661. N Engl J Med. 2013 Feb 21;
 
368(8):781. [PMID: 23343065]
Merrill JO et al. Addiction disorders. Med Clin North Am.
 
 2014 Sep;98(5):1097–122. [PMID: 25134875]
Mirijello A et al. Identification and management of alcohol with
-
drawal syndrome. Drugs. 2015 Mar;75(4):353–65. [PMID: 
25666543]
Stehman CR et al. A rational approach to the treatment of alco
-
hol withdrawal in the ED. Am J Emerg Med. 2013 Apr;
 
31(4):734–42. [PMID: 23399338]
 
º
NEUROCOGNITIVE DISORDERS
 
»
Transient or permanent brain dysfunction with 
alterations in awareness or attention.
 
»
Cognitive impairment to varying degrees.
 
»
Impaired recall and recent memory, inability to 
focus attention and problems in perceptual pro
-
cessing, often with psychotic ideation.
 
»
Random psychomotor activity such as stereotypy.
 
»
Emotional disorders frequently present: depres
-
sion, anxiety, irritability.
 
»
Behavioral disturbances: impulse control, sexual 
acting-out, attention deficits, aggression, and 
exhibitionism.
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»
The organic problem may be a primary brain disorder or a 
secondary manifestation of some general disorder. All of 
the cognitive disorders show some degree of impaired 
thinking depending on the site of involvement, the rate of 
onset and progression, and the duration of the underlying 
brain lesion. Emotional disturbances (eg, depression) are 
often present as significant comorbidities. The behavioral 
disturbances tend to be more common with chronicity, 
more directly related to the underlying personality or cen
-
tral nervous system vulnerability to drug side effects, and 
not necessarily correlated with cognitive dysfunction.
The causes of cognitive disorders are listed in 
Table 25–11.
 
»
The many manifestations include problems with orienta
-
tion, short or fluctuating attention span, loss of recent 
memory and recall, impaired judgment, emotional lability, 
lack of initiative, impaired impulse control, inability to 
reason through problems, depression (worse in mild to 
moderate types), confabulation (not limited to alcohol 
organic brain syndrome), constriction of intellectual func
-
tions, visual and auditory hallucinations, and delusions. 
Physical findings will vary according to the cause. The 
electroencephalogram usually shows generalized slowing 
in delirium.
A. Delirium
Delirium (acute confusional state) is a transient global 
disorder of attention, with clouding of consciousness, usu
-
ally a result of systemic problems (eg, medications, hypox
-
emia). See Chapters 4 and 24. Onset is usually rapid. The 
mental status fluctuates (impairment is usually least in the 
morning), with varying inability to concentrate, maintain 
attention, and sustain purposeful behavior. There is a 
marked deficit of short-term memory and recall. Anxiety 
and irritability are common. Orientation problems follow 
the inability to retain information. Perceptual disturbances 
(often visual hallucinations) and psychomotor restlessness 
with insomnia are common. “Sundowning”—mild to mod
-
erate delirium at night—is more common in patients with 
preexisting dementia and may be precipitated by hospital
-
ization, medications, and sensory deprivation.
B. Dementia
Dementia is characterized by chronicity and deterioration 
of selective mental functions. See Chapters 4 and 24.
 
Etiology of delirium and other cognitive disorders.
Disorder
Possible Causes
Alcohol, sedatives, bromides, analgesics (eg, pentazocine), psychedelic drugs, stimulants, and household 
solvents.
Medication withdrawal
Withdrawal from alcohol, sedative-hypnotics, corticosteroids.
Long-term effects of alcohol
Wernicke-Korsakoff syndrome.
Septicemia; meningitis and encephalitis due to bacterial, viral, fungal, parasitic, or tuberculous organisms 
or to central nervous system syphilis; acute and chronic infections due to the entire range of microbio
-
logic pathogens.
Thyrotoxicosis, hypothyroidism, adrenocortical dysfunction (including Addison disease and Cushing 
 
syndrome), pheochromocytoma, insulinoma, hypoglycemia, hyperparathyroidism, 
 
hypoparathyroidism, panhypopituitarism, diabetic ketoacidosis.
Respiratory disorders
Hypoxia, hypercapnia.
Metabolic disturbances
Fluid and electrolyte disturbances (especially hyponatremia, hypomagnesemia, and hypercalcemia), 
 
acid-base disorders, hepatic disease (hepatic encephalopathy), kidney failure, porphyria.
Nutritional deficiencies
Deficiency of vitamin B
1
 (beriberi), vitamin B
12
 (pernicious anemia), folic acid, nicotinic acid (pellagra); 
 
protein-calorie malnutrition.
Trauma
Subdural hematoma, subarachnoid hemorrhage, intracerebral bleeding, concussion syndrome.
Cardiovascular disorders
Myocardial infarctions, cardiac arrhythmias, cerebrovascular spasms, hypertensive encephalopathy, 
 
hemorrhages, embolisms, and occlusions indirectly cause decreased cognitive function.

Neoplasms
Primary or metastatic lesions of the central nervous system, cancer-induced hypercalcemia.
Seizure disorders
Ictal, interictal, and postictal dysfunction.
Collagen-vascular and immuno
-
logic disorders
Autoimmune disorders, including systemic lupus erythematosus, Sjögren syndrome, and AIDS.
Degenerative diseases
Alzheimer disease, Pick disease, multiple sclerosis, parkinsonism, Huntington chorea, normal pressure 
Anticholinergic medications, antidepressants, H
2
-blocking agents, digoxin, salicylates (long-term use), 
 
and a wide variety of other over-the-counter and prescribed medications.
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In all types of dementia, loss of impulse control (sexual 
and language) is common. 
Pseudodementia
 is a term pre
-
viously applied to depressed patients who appear to be 
demented. These patients are often identifiable by their 
tendency to complain about memory problems vocifer
-
ously rather than try to cover them up. They usually say 
they cannot complete cognitive tasks but with encourage
-
ment can often do so. They can be considered to have 
depression-induced reversible dementia that improves 
when the depression resolves. In many geriatrics patients, 
however, the depression appears to be an insult that often 
unmasks a progressive dementia.
C. Amnestic Syndrome
This is a memory disturbance without delirium or demen
-
tia. It is usually associated with thiamine deficiency and 
chronic alcohol use (eg, Korsakoff syndrome). There is an 
impairment in the ability to learn new information or 
recall previously learned information.
D. Substance-Induced Hallucinosis
This condition is characterized by persistent or recurrent 
hallucinations (usually auditory) without the other symp
-
toms usually found in delirium or dementia. Alcohol or 
hallucinogens are often the cause. There does not have to 
be any other mental disorder, and there may be complete 
spontaneous resolution.
 
»
Treatment
See Chapters 4 and 24 for detailed discussion.
Barr J et al; American College of Critical Care Medicine. Clinical 
practice guidelines for the management of pain, agitation, and 
delirium in adult patients in the intensive care unit. Crit Care 
Med. 2013 Jan;41(1):263–306. [PMID: 23269131]
Deardorff WJ et al. The use of cholinesterase inhibitors across all 
stages of Alzheimer’s Disease. Drugs Aging. 2015 Jul;32(7):
 
537–47. [PMID: 26033268]
Gitlin LN et al. Nonpharmacologic management of behavioral 
symptoms in dementia. JAMA. 2012 Nov 21;308(19):2020–9. 
[PMID: 23168825]
Wong N et al. Managing delirium in the emergency department: 
tools for targeting underlying etiology. Emerg Med Pract. 
2015 Oct;17(10):1–20. [PMID: 26367083]
 
º
PSYCHIATRIC PROBLEMS ASSOCIATED 
WITH HOSPITALIZATION & ILLNESS
 
»
Diagnostic Categories
A. Acute Problems
1.
 
Delirium with psychotic features secondary to the 
medical or surgical problem, or compounded by effect 
of treatment.
2.
 
Acute anxiety, often related to ignorance and fear of the 
immediate problem as well as uncertainty about the future.
3.
 
Anxiety as an intrinsic aspect of the medical problem 
(eg, hyperthyroidism).
4.
 
Denial of illness, which may present during acute or 
intermediate phases of illness.
B. Intermediate Problems
1.
 
Depression as a function of the illness or acceptance of 
the illness, often associated with realistic or fantasied 
hopelessness about the future.
2.
 
Behavioral problems, often related to denial of illness 
and, in extreme cases, causing the patient to leave the 
hospital against medical advice.
C. Recuperative Problems
1.
 
Decreasing cooperation as the patient sees that improve
-
ment and compliance are not compelled.
2.
 
Readjustment problems with family, job, and society.
 
»
1. “Intensive care unit psychosis”—
The ICU environment 
may contribute to the etiology of delirium. Critical care 
unit factors include sleep deprivation, increased arousal, 
mechanical ventilation, and social isolation. Other causes 
include those common to delirium and require vigorous 
investigation (see Delirium).
2. Presurgical and postsurgical anxiety states—
Anxiety 
before or after surgery is common and commonly ignored. 
Presurgical anxiety is very common and is principally a 
fear of death (many surgical patients make out their wills). 
Patients may be fearful of anesthesia (improved by the 
preoperative anesthesia interview), the mysterious operat
-
ing room, and the disease processes that might be uncov
-
ered by the surgeon. Such fears frequently cause people to

-
-
ered by the surgeon. Such fears frequently cause people to 
delay examinations that might result in earlier surgery and 
a greater chance of cure.
The opposite of this is 
surgery proneness,
 the quest for 
surgery to escape from overwhelming life stresses. Some 
polysurgery patients may be classified as having factitious 
disorders. Dynamic motivations include the need to get 
medical care as a way of getting dependency needs met, the 
desire to outwit authority figures, unconscious guilt, or a 
masochistic need to suffer. Frequent surgery may also be 
related to a somatic symptom disorder, particularly body 
dysmorphic disorder (an obsession that a body part is dis
-
figured). More apparent reasons may include an attempt to 
get relief from pain and a lifestyle that has become almost 
exclusively medically oriented, with all of the risks entailed 
in such an endeavor.
Postsurgical anxiety states
 are usually related to pain, 
procedures, and loss of body image. Acute pain problems 
are quite different from chronic pain disorders (see Chronic 
Pain Disorders, this chapter); the former are readily han
-
dled with adequate analgesic medication (see Chapter 5). 
Alterations in body image, as with amputations, ostomies, 
and mastectomies, often raise concerns about relationships 
with others.
3. Iatrogenic problems—
These usually pertain to medica
-
tions, complications of diagnostic and treatment proce
-
dures, and impersonal and unsympathetic staff behavior. 
Polypharmacy is often a factor. Patients with unsolved 
diagnostic problems are at higher risk. They are desirous of 
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relief, and the quest engenders more diagnostic procedures 
with a higher incidence of complications. The upset patient 
and family may be very demanding. Excessive demands 
usually result from anxiety. Such behavior is best handled 
with calm and measured responses.
1. Prolonged hospitalization—
Prolonged hospitalization 
presents unique problems in certain hospital services, eg, 
burn units or orthopedic services. The acute problems of the 
severely burned patient are discussed in Chapter 37. The 
problems often are behavioral difficulties related to length of 
hospitalization and necessary procedures. For example, in 
burn units, pain is a major problem in addition to anxiety 
about procedures. Disputes with staff are common and often 
concern pain medication or ward privileges. Some patients 
regress to infantile behavior and dependency. Staff members 
must agree about their approach to the patient in order to 
ensure the smooth functioning of the unit.
Denial of illness may present in some patients. Inter
-
vention by an authority figure (eg, immediate work super
-
visor) may help the patient accept treatment and eventually 
abandon the coping mechanism of denial.
2. Depression—
Mood disorders ranging from mild adjust
-
ment disorder to major depressive disorder frequently 
occur during prolonged hospitalizations. A key to the diag
-
nosis of depression in the medical setting is the individual’s 
loss of self-esteem; they often think of themselves as worth
-
less and are guilt ridden. Therapeutic medications (eg, 
corticosteroids) may be a factor. Depression can contribute 
to irritability and overt anger. Severe depression can lead to 
anorexia, which further complicates healing and metabolic 
balance. It is during this period that the issue of disfigure
-
ment arises—relief at survival gives way to concern about 
future function and appearance.
1. Anxiety—
Anxiety about return to the posthospital envi
-
ronment can cause regression to a dependent position. 
Complications increase, and staff forbearance again is 
tested. Anxiety occurring at this stage usually is handled 
more easily than previous behavior problems.
2. Posthospital adjustment—
Adjustment difficulties after 
discharge are related to the severity of the deficits and the 
use of outpatient facilities (eg, physical therapy, rehabilita
-
tion programs, psychiatric outpatient treatment). Some 
patients may experience posttraumatic stress symptoms 
(eg, from traumatic injuries or even from necessary medi
-
cal treatments). Lack of appropriate follow-up can contrib
-
ute to depression in the patient, who may feel that he or she 
is making poor progress and may have thoughts of “giving 
up. ” Reintegration into work, educational, and social 
endeavors may be slow.
 
»
The symptoms that occur in these patients are similar to 
those discussed in previous sections of this chapter, eg, 
delirium, stress and adjustment disorders, anxiety, and 
depression. Behavior problems may include lack of coop
-
eration, increased complaints, demands for medication, 
sexual approaches to nurses, threats to leave the hospital, 
and actual signing out against medical recommendations. 
The stress of hospitalization often brings out these more 
primitive defense mechanisms than the patient displays in 
daily life.
 
»
Prolongation of hospitalization causes increased expense, 
deterioration of patient-staff relationships, and increased 
probabilities of iatrogenic and legal problems. The possibility 
of increasing posthospital treatment problems is enhanced.
 
»
Treatment
A. Medical
The most important consideration by far is to have one 
clinician in charge, a clinician whom the patient trusts and 
who is able to oversee multiple treatment approaches (see 
Somatic Symptom Disorders, above). In acute problems, 
attention must be paid to metabolic imbalance, alcohol

attention must be paid to metabolic imbalance, alcohol 
withdrawal, and previous drug use—prescribed, recre
-
ational, or over-the-counter. Adequate sleep and analgesia 
are important in enhancing a patient’s coping abilities.
Many clinicians are attuned to the early detection of the 
surgery-prone patient. Plastic and orthopedic surgeons are 
at particular risk. Appropriate consultations may help 
detect some problems and mitigate future ones.
 can be alleviated by personal 
attention from the surgeon. Anxiety is not so effectively 
lessened by ancillary medical personnel, whom the patient 
perceives as lesser authorities, until after the clinician has 
reassured the patient. “Patient-controlled analgesia” can 
improve pain control, decrease anxiety, and minimize side 
effects.
 should be recognized early. If severe, it may 
be treated by antidepressant medications (see Antidepres
-
sant Medications, above). High levels of 
anxiety
 can be 
lowered with judicious use of anxiolytic agents. Unneces
-
sary medications tend to reinforce the patient’s impression 
that there must be a serious illness or medication would 
not be required.
Prepare the patient and family for what is to come. This 
includes the types of units where the patient will be quar
-
tered, the procedures that will be performed, and any dis
-
figurements that will result from surgery. Repetition 
improves understanding. The nursing staff can be helpful, 
since patients frequently confide a lack of understanding to 
a nurse but are reluctant to do so to the physician.
Denial of illness is frequently a block to acceptance of 
treatment. This too should be handled with family mem
-
bers present (to help the patient face the reality of the situ
-
ation) in a series of short interviews (for reinforcement). 
Dependency problems resulting from long hospitalization 
are best handled by focusing on the changes to come as the 
patient makes the transition to the outside world. Key 
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figures are teachers, vocational counselors, and physical 
therapists. Challenges should be realistic and practical and 
handled in small steps.
Depression is usually related to the loss of familiar hos
-
pital supports, and the outpatient therapists and counselors 
help to lessen the impact of the loss. Some of the impact 
can be alleviated by anticipating, with the patient and fam
-
ily, the signal features of the common depression to help 
prevent the patient from assuming a permanent sick role.
Suicide is always a concern when a patient is faced with 
despair. An honest, compassionate, and supportive approach 
will help sustain the patient during this trying period.
Prior desensitization can significantly allay anxiety about 
medical procedures. A “dry run” can be done to reinforce 
the oral description. Cooperation during acute problem 
periods can be enhanced by the use of appropriate rein
-
forcers such as a favorite nurse or helpful family member. 
People who are positive reinforcers are even more helpful 
during the intermediate phases when the patient becomes 
resistant to the seemingly endless procedures (eg, debride
-
ment of burned areas).
Specific situations (eg, psychological dependency on 
the respirator) can be corrected by weaning with appropri
-
ate reinforcers (eg, watching a favorite movie on a DVD 
player or laptop when disconnected from the ventilator). 
Behavioral approaches should be used in a positive and 
optimistic way for maximal reinforcement.
Relaxation techniques, hypnosis, and attentional dis
-
traction can be used to block side effects of a necessary 
treatment (eg, nausea in cancer chemotherapy).
D. Social
A change in environment requires adaptation. Because of 
the illness, admission and hospitalization may be more eas
-
ily handled than discharge. A predischarge evaluation must 
be made to determine whether the family will be able to 
cope with the physical or mental changes in the patient. 
Working with the family while the patient is in the acute 
stage may presage a successful transition later on.
Development of a new social life can be facilitated by 
various self-help organizations (eg, the stoma club). Shar
-
ing problems with others in similar circumstances eases 
the return to a social life, which may be quite different 
from that prior to the illness.
 
»
Prognosis
The prognosis is good in all patients who have reversible 
medical and surgical conditions. It is guarded when there 
is serious functional loss that impairs vocational, educa
-
tional, or societal possibilities—especially in the case of 
progressive and ultimately life-threatening illness.
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º
DISEASES OF THE HYPOTHALAMUS & 
PITUITARY GLAND
ANTERIOR HYPOPITUITARISM
 
»
Adrenocorticotropic hormone (ACTH) deficiency:
 
reduced adrenal secretion of cortisol and epi
-
nephrine; aldosterone secretion remains intact.
 
»
Growth hormone (GH) deficiency:
 short stature in 
children; asthenia, obesity, and increased cardio
-
vascular risk in adults.
 
»
Prolactin (PRL) deficiency:
 postpartum lactation 
failure.
 
»
Thyroid-stimulating hormone (TSH) deficiency:
 sec
-
ondary hypothyroidism.
 
»
Luteinizing hormone (LH)
 and 
follicle-stimulating 
hormone (FSH) deficiency
:
 hypogonadism and 
infertility in men and women.
 
»
The anterior pituitary hormones are GH, PRL, ACTH, 
TSH, LH, and FSH. The posterior pituitary hormones are 
oxytocin and arginine vasopressin (AVP), also known as 
antidiuretic hormone (ADH).
1. Hypopituitarism with mass lesions—
Pituitary 
adenomas
 can cause anterior hypopituitarism, particularly 
when they are large macroadenomas (1 cm or more in 
diameter). Nonfunctioning pituitary adenomas are more 
likely than functioning pituitary adenomas to grow large 
enough to cause anterior hypopituitarism; they rarely cause 
diabetes insipidus. Other mass lesions include craniopha
-
ryngioma, meningioma, germinoma, glioma, chordoma, 
metastatic lesions, and cysts (Rathke cleft, dermoid, arach
-
noid). Vascular lesions include pituitary tumor apoplexy, 
acute Sheehan syndrome, intrasellar carotid aneurysm, 
and subarachnoid hemorrhage. Inflammatory/infiltrative 26
Endocrine Disorders
lesions include granulomatosis with polyangiitis, xantho
-
matosis, giant cell granuloma, Langerhans cell histiocytosis, 
sarcoidosis, syphilis, and tuberculosis. Infectious lesions 
can be bacterial, fungal, or parasitic.
Lymphocytic hypophysitis
 is an autoimmune disorder 
affecting the pituitary gland. Spontaneous lymphocytic 
hypophysitis is more common in women (71%) and most 
frequently presents during pregnancy or postpartum. The 
condition is often associated with other autoimmune condi
-
tions, such as systemic lupus erythematosus (SLE) or 
Hashimoto thyroiditis. Hypopituitarism typically presents 
with difficulty breastfeeding and amenorrhea due to hypogo
-
nadotropic hypogonadism (62%), diabetes insipidus (54%), 
headache (50%), hypothyroidism (48%), ACTH deficiency 
(47%), GH deficiency (37%), and hyperprolactinemia (36%), 
which clinicians may mistake for a prolactinoma. 
Immune 
checkpoint inhibitor hypophysitis
 can be caused by several 
immunity-enhancing drugs, particularly the anti-CTLA-4 
agents ipilimumab and tremelimumab (10–15%), but it has 
also been reported with the anti-PD-1 agents pembroli
-
zumab and nivolumab. Symptoms of hypophysitis develop 
on average 9 weeks after beginning the medication and as 
late as 19 months after commencing therapy.
2. Hypopituitarism without mass lesions—
Congenital 
combined hypopituitarism
 occurs in syndromes such as 
septo-optic dysplasia and in patients with various gene 
mutations that cause a progressive loss of anterior pituitary 
function in childhood. Congenital hypogonadotropic 
hypogonadism can be caused by mutations in any of the 
many genes that control the production or release of 
gonadotropin-releasing hormone (GnRH), LH, or FSH. 
Prader-Willi syndrome
 is a genetic disorder where genes 
on the paternal chromosome 15 are deleted or unexpressed. 
Kallmann syndrome
 is caused by various gene mutations 
that impair the development or migration of GnRH-
synthesizing neurons from the olfactory bulb to the hypo
-
thalamus. 
Congenital GH deficiency
 occurs as an isolated 
pituitary hormone deficiency in about one-third of cases.
Acquired hypopituitarism
 without a visible mass 
lesion on MRI can result from cranial radiation therapy, 
pituitary surgery, encephalitis, cerebral malaria, hemo
-
chromatosis, autoimmunity, or coronary artery bypass

without a visible mass 
-
chromatosis, autoimmunity, or coronary artery bypass 
grafting (CABG). Bexarotene chemotherapy causes a high 
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rate of pituitary insufficiency with central hypothyroidism. 
At least one pituitary hormone deficiency develops in 
about 25–30% of survivors of moderate to severe traumatic 
brain injury and in about 55% of survivors of aneurysmal 
subarachnoid hemorrhage. Some degree of hypopituita
-
rism, most commonly GH deficiency and hypogonado
-
tropic hypogonadism, occurs in one-third of ischemic 
stroke patients. Other cases of acquired hypopituitarism 
can be idiopathic or associated with an empty sella on MRI.
In functional hypopituitarism,
 
GH deficiency
 can occur 
with malnutrition, chronic kidney disease, opioid therapy, 
and normal aging. 
LH and FSH deficiency
 with hypogonado
-
tropic hypogonadism occurs in serious illness, malnutrition, 
anorexia nervosa, alcoholism, opioid therapy, Cushing syn
-
drome (spontaneous or iatrogenic), and hyperprolactinemia 
(drug-induced or spontaneous). Therapy with GnRH ago
-
nists (eg, leuprolide) also causes hypogonadotropic hypogo
-
nadism that can persist after therapy is stopped. Partial 
hypogonadotropic hypogonadism commonly develops in 
men with normal aging or obesity, since they have serum 
free testosterone levels that are low or near the lower end of 
normal reference ranges while serum FSH and LH levels 
remain normal. Hypothalamic amenorrhea frequently 
develops in women during periods of severe emotional or 
physical stress, intense exercise programs, severe caloric 
restriction, or eating disorders. 
ACTH suppression
 with 
functional isolated secondary adrenal insufficiency occurs 
in patients receiving megesterol acetate, high-dose opioid 
therapy (15%) and in patients exposed to excess endogenous 
or exogenous corticosteroids (parenteral, oral, inhaled, or 
topical). 
TSH deficiency
 can be caused by mitotane or bex
-
arotene, resulting in secondary hypothyroidism.
Sheehan syndrome
 refers to hypopituitarism caused by 
postpartum pituitary necrosis, usually following severe 
postpartum uterine hemorrhage. It is usually characterized 
by postpartum amenorrhea and inability to lactate. 
Hypo
-
pituitarism can occur acutely, usually with severe secondary 
adrenal insufficiency that may be fatal unless recognized and 
treated.
 Acute hypopituitarism may also be associated with 
diabetes insipidus. However, hypopituitarism in Sheehan 
syndrome usually occurs gradually over 10–20 years; the 
diagnosis is typically delayed an average of 9 years. Mani
-
festations in affected women are typically hyponatremia, 
hypoglycemia, or anemia. In acute Sheehan syndrome, 
MRI shows an enlarged pituitary with only a thin rim of 
enhancement with gadolinium. After 1 year, MRI shows 
atrophy of the pituitary and a partially empty sella.
 
»
When hypopituitarism is caused by a mass lesion or 
hypophysitis, patients may have headaches or visual field 
defects. Nonspecific symptoms, such as fatigue, dizziness 
and hypotension, confusion, cognitive dysfunction, sexual 
dysfunction, polydipsia, or cold intolerance, can develop.
1. GH (somatropin) deficiency—
Congenital GH defi
-
ciency
 can present in newborns with hypoglycemia, jaun
-
dice, and a small penis and later with short stature in 
childhood. 
Laron syndrome
 is an autosomal recessive 
disorder that is mainly caused by mutations in the gene 
that encodes the GH receptor, resulting in GH-resistance 
and a severe deficiency in serum insulin-like growth 
factor-1 (IGF-1), resulting in short stature (dwarfism) and 
characteristic features.
Acquired GH deficiency
 is quite common. The pituitary 
somatotroph cell is particularly sensitive to damage from 
radiation therapy, compression, or trauma. Also, when other 
more recognizable pituitary hormone deficits are present, 
there is a high likelihood of concurrent GH deficiency.
GH deficiency in adults is often undiagnosed, since 
maximum height has already been reached and other

maximum height has already been reached and other 
manifestations are nonspecific. Symptoms vary in severity 
from mild to severe, resulting in a variable spectrum of 
nonspecific symptoms that include mild to moderate cen
-
tral obesity, reduced physical and mental energy, impaired 
concentration and memory, and depression. Patients may 
also have variably reduced muscle and bone mass, increased 
low-density lipoprotein (LDL) cholesterol, and reduced 
cardiac output with exercise.
2. Gonadotropin deficiency (hypogonadotropic 
hypogonadism)—
In gonadotropin deficiency, insufficien
-
cies of LH and FSH cause hypogonadism and infertility.
Congenital gonadotropin deficiency
by partial or complete lack of pubertal development. Iso
-
lated hypogonadotropic hypogonadism occurs with an 
estimated prevalence between 1 in 4000 and 1 in 10,000 
males; it is less common in females. The sense of olfaction 
(smell) is entirely normal in 58% (normosmic isolated 
hypogonadotropic hypogonadism), or hyposmic or anos
-
mic in 42% (Kallmann syndrome). Patients frequently have 
abnormal genitalia (25%), kidney anomalies (28%), mid
-
line craniofacial defects (50%), neurologic deficits (42%), 
and musculoskeletal malformations. Some affected women 
have menarche followed by secondary amenorrhea. Some 
affected males also have congenital adrenal hypoplasia 
with X-linked inheritance; affected boys who survive child
-
hood can present with failure to enter puberty.
 presents with cryptorchidism, 
mental retardation, short stature, hyperflexibility, auto
-
nomic dysregulation, cognitive impairment, hyperphagia 
with obesity, hypogonadotropic hypogonadism, or primary 
hypogonadism.
Acquired gonadotropin deficiency
the gradual loss of facial, axillary, pubic, and body hair. 
Men may note diminished libido, erectile dysfunction, 
muscle atrophy, infertility, and osteopenia. Women have 
amenorrhea, infertility, and osteoporosis.
3. TSH deficiency—
TSH deficiency causes hypothyroidism 
(see Hypothyroidism, below).
4. ACTH deficiency—
This results in diminished cortisol. 
Adrenal mineralocorticoid secretion continues, so mani
-
festations of adrenal insufficiency in hypopituitarism are 
usually less striking than in bilateral adrenal gland destruc
-
tion (see Primary Adrenal Insufficiency [Addison disease], 
below). Patients with partial ACTH deficiency have some 
cortisol secretion and may not have symptoms until 
stressed by illness or surgery.
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5. PRL deficiency—
This presents in women with failure to 
lactate in the puerperium.
6. Panhypopituitarism—
This condition refers to a defi
-
ciency of several or all pituitary hormones.
7. Hypothalamic damage—
This can cause obesity and 
cognitive impairment. Hypopituitarism occurs but usually 
along with increased serum levels of PRL. Local tumor 
effects can cause headache or optic nerve compression with 
visual field impairment.
Initial laboratory studies may show hyponatremia or hypo
-
glycemia. Fasting hypoglycemia may be present with sec
-
ondary hypoadrenalism, hypothyroidism, or GH deficiency. 
Hyponatremia can be caused by hypothyroidism or hypo
-
adrenalism. Patients with lymphocytic hypophysitis fre
-
quently have elevated serum antinuclear or anticytoplasmic 
antibodies. Patients with hypopituitarism without an estab
-
lished etiology should be screened for hemochromatosis 
with a serum ferritin or iron and transferrin saturation.
Male hypogonadotropic hypogonadism
by drawing blood before 10 
am
 after an overnight fast in 
men without an acute or subacute illness. Affected men 
have a low fasting serum total or free serum testosterone 
with a low or normal serum LH. A serum PRL is also 
obtained, since hyperprolactinemia of any cause can result 
in hypogonadism.
Female hypogonadotropic hypogonadism
 is sus
-
pected in nonpregnant women with amenorrhea or oligo
-
menorrhea, who do not have acute illness, hyperthyroidism, 
or hyperandrogenism. The serum estradiol is low and the 
serum FSH is low or normal. In nonpregnant women, a 
serum PRL is obtained, since hyperprolactinemia of any 
cause can result in hypogonadism. In postmenopausal 
women, the absence of an elevated serum FSH (in a women 
not taking estrogen replacement) indicates gonadotropin 
Central hypothyroidism
 is diagnosed with a low 
serum free thyroxine (FT
4
) in the setting of pituitary dis
-
ease. The serum TSH can be low, normal, or even mildly 
elevated (oddly). Some patients with a low-normal serum 
FT
4
 and symptoms of hypothyroidism, in the setting of 
pituitary disease, may have an empiric trial of levothyrox
-
ine therapy. Central hypothyroidism can emerge when 
patients begin GH replacement, so thyroid levels must be 
monitored in that setting. Patients undergoing pituitary 
surgery should be assessed for central hypothyroidism 
preoperatively and again 6 weeks postoperatively.
Central adrenal insufficiency
 is caused by ACTH defi
-
ciency. There is functional atrophy of the adrenal cortex 
within 2 weeks of pituitary damage. Before testing, cortico
-
steroid replacement should be withheld for at least 
18–24 hours. Blood is drawn at 8–9 
am
 for plasma ACTH 
and serum cortisol. A serum cortisol less than 3 mcg/dL 
(80 nmol/L) usually indicates adrenal insufficiency, 
whereas an 8–9 
am
 serum cortisol higher than 15 mcg/dL 
(400 nmol/L) usually excludes adrenal insufficiency. For 
8–9 
am
 cortisol levels between 3 and 15 mcg/dL, a cosyn
-
tropin test is often required. For the cosyntropin test, 
patients should hold any corticosteroid replacement for at 
least 18–24 hours. At 8–9 
am
, blood is drawn for serum 
cortisol, ACTH, and dehydroepiandrosterone (DHEA); 
then cosyntropin (synthetic ACTH
1–24
) 0.25 mg is admin
-
istered intramuscularly or intravenously. Another serum 
cortisol is obtained 45 minutes after the cosyntropin injec
-
tion; a stimulated serum cortisol of less than 20 mcg/dL 
(550 nmol/L) indicates probable adrenal insufficiency. 
With gradual pituitary damage and early in the course of 
ACTH deficiency, patients can have a stimulated serum 
cortisol of 20 mcg/dL or more (550 nmol/L) but a baseline 
8 
am
 serum cortisol of 5 mcg/dL or less (138 nmol/L), 
which is suspicious for adrenal insufficiency. The baseline 
serum ACTH level is low or normal in secondary hypoad
-
renalism, distinguishing it from primary adrenal disease.

-
renalism, distinguishing it from primary adrenal disease. 
Serum DHEA is a proxy for ACTH; levels are usually low 
in patients with secondary adrenal deficiency, helping con
-
firm the diagnosis. Hyponatremia may occur, especially 
when ACTH and TSH deficiencies are both present.
For patients with signs of secondary adrenal insuffi
-
ciency (hyponatremia, hypotension, pituitary tumor) but 
borderline cosyntropin test results, treatment can be insti
-
tuted empirically and the test repeated at a later date. 
Patients undergoing pituitary surgery with normal preop
-
erative adrenal function should have an individualized 
clinical approach to postoperative corticosteroid replace
-
ment until ACTH-adrenal function can be retested 
postoperatively.
 in adults is difficult to diagnose, since 
GH secretion is normally pulsatile and serum GH levels are 
normally undetectable for much of the day. Also, adults 
(particularly men) physiologically tend to produce less GH 
when they are over age 50 or have abdominal obesity. 
Therefore, pathologic GH deficiency is often inferred by 
symptoms of GH deficiency in the presence of pituitary 
destruction or other pituitary hormone deficiencies. GH 
deficiency is present in 96% of patients with three or more 
other pituitary hormone deficiencies and a low serum 
IGF-1. While GH stimulates the production of IGF-1, the 
serum IGF-1 level is neither a sensitive (about 50%) nor 
specific test for GH deficiency in adults. While very low 
serum IGF-1 levels (less than 84 mcg/L) are usually indica
-
tive of GH deficiency, they also occur in malnutrition, pro
-
longed fasting, oral estrogen, hypothyroidism, uncontrolled 
diabetes mellitus, and liver failure. In GH deficiency (but 
also in most adults over age 40), exercise-stimulated serum 
GH levels remain at less than 5 ng/mL and usually fail to rise.
Provocative GH stimulation testing to help diagnose 
adult GH deficiency has a sensitivity of only 66%. There
-
fore, a therapeutic trial of GH therapy should be consid
-
ered for symptomatic patients who have either a serum 
IGF-1 less than 84 mcg/L or three other pituitary hormone 
deficiencies.
Provocative GH-stimulation tests are sometimes indi
-
cated or required for insurance coverage of GH therapy. In 
the absence of a serum IGF-1 level less than 84 mcg/L or 
multiple other pituitary hormone deficiencies, provocative 
GH-stimulation testing may be indicated for the following 
patients: (1) young adult patients who have completed GH 
therapy for childhood GH deficiency and have achieved 
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maximal linear growth; (2) patients who have a hypotha
-
lamic or pituitary tumor or who have received surgery or 
radiation therapy to these areas; and (3) patients who have 
had prior head trauma, cerebrovascular accident, or 
encephalitis. When required, such testing usually entails 
measuring serum GH following provocative stimuli. The 
glucagon stimulation test
 is a practical alternative to tra
-
ditional provocative GH stimulation testing to diagnose 
pathologic GH deficiency or functional GH deficiency due 
to aging or obesity. It should not be given to patients who 
are malnourished or who have not eaten for over 48 hours. 
Side effects are usually mild, but nausea or headache 
occurs in about 20% of patients. Glucagon 1.0 mg (or 
1.5 mg if greater than 200 lbs [90 kg]) is administered 
intramuscularly to patients who have not eaten for 
8–9 hours. Serum GH is measured before the injection and 
every 30 minutes for 4 hours. In patients with GH defi
-
ciency, the maximum serum GH is usually less than 
3 mcg/L. The test is quite sensitive (95%), but much less 
specific, mostly due to obesity. Therefore, for overweight or 
obese individuals (body mass index [BMI] is 25 kg/m
2
 or 
more), GH deficiency is considered likely if the stimulated 
GH is below 1 ng/mL. Late hypoglycemia can occur after 
glucagon, so patients are advised to eat immediately fol
-
lowing completion of the test.
C. Imaging
MRI may show a distinct lesion in the pituitary, infundibu
-
lum, or hypothalamus. However, for hypophysitis, MRI 
may show only some generalized pituitary enlargement or 
thickening of the pituitary stalk. The hypophysitis associ
-
ated with immune checkpoint inhibitor chemotherapy can 
appear on MRI as either a distinct mass or a diffusely 
enlarged pituitary. MRI is not warranted in cases of func
-
tional hypopituitarism associated with severe obesity, 
drugs, or nutritional disorders.
 
»
The failure to enter puberty may simply reflect delayed 
puberty, also known as constitutional delay in growth and 
puberty. Secondary adrenal insufficiency may persist for 
many months following high-dose corticosteroid therapy 
and may also be seen with inhaled or topical corticosteroid 
therapy.
Reversible, second hypothyroidism with suppression of 
TSH and T
4
 can be caused by severe illness, hyperthyroxin
-
emia, and administration of triiodothyronine (Cytomel), 
mitotane or bexarotene, resulting in temporary central 
hypothyroidism. Corticosteroids or megestrol reversibly 
suppress endogenous ACTH and cortisol secretion.
GH deficiency occurs normally with aging and 
physiologically with obesity (reversible with sufficient 
weight loss).
 
»
Among patients with craniopharyngiomas, diabetes insipi
-
dus is found in 16% preoperatively and in 60% postopera
-
tively. Hyponatremia often presents abruptly during the 
first 2 weeks following pituitary surgery. Visual field 
impairment may occur. Hypothalamic damage may result 
in morbid obesity as well as cognitive and emotional prob
-
lems. Conventional radiation therapy results in an 
increased incidence of small vessel ischemic strokes and 
second tumors.
Patients with untreated hypoadrenalism and a stressful 
illness may become febrile and comatose and die of hypo
-
natremia and shock.
Adults with GH deficiency have experienced an 
increased cardiovascular morbidity. Rarely, acute hemor
-
rhage may occur in large pituitary tumors, manifested by 
rapid loss of vision, headache, and evidence of acute pitu
-
itary failure (pituitary apoplexy) requiring emergency 
decompression of the sella.
 
»
Treatment
The therapy for hypopituitarism is lifetime hormone 
replacement.
A. Corticosteroid Replacement
Most patients do well with oral hydrocortisone 10–20 mg 
in the morning and 5–15 mg in the late afternoon. There is 
considerable variation in corticosteroid requirements, so

considerable variation in corticosteroid requirements, so 
corticosteroid dosing and timing are tailored to each indi
-
vidual. Patients with partial ACTH deficiency (basal morn
-
ing serum cortisol above 8 mg/dL [220 mmol/L]) require 
hydrocortisone replacement in lower doses of about 5 mg 
orally twice daily or even 10 mg every morning. Some 
patients feel poorly despite hydrocortisone replacement; 
they may feel better with the substitution of prednisone 
(2–7.5 mg/day orally) or methylprednisolone (2–6 mg/day 
orally), given in divided doses. Fludrocortisone is not 
required. To determine the optimal corticosteroid replace
-
ment dosage, it is necessary to monitor patients carefully 
for clinical signs of over- or under-replacement. A white 
blood cell (WBC) count with a differential can be useful, 
since a relative neutrophilia and lymphopenia can indicate 
corticosteroid overreplacement, and vice versa. Additional 
corticosteroid must be given during stress, eg, infection, 
trauma, or surgical procedures. For mild illness or mild-
moderate surgical stress, corticosteroid doses are doubled 
or tripled. For severe illness, trauma, or major surgical 
stress, hydrocortisone 100 mg is given intravenously, fol
-
lowed by 200 mg daily, given as either a continuous intra
-
venous infusion or as 50 mg boluses given every 6 hours 
intravenously or intramuscularly and then reduced to 
usual doses as the stress subsides. Patients with adrenal 
insufficiency are advised to wear a medical alert bracelet 
describing their condition and treatment.
Patients with secondary adrenal insufficiency due to 
treatment with corticosteroids require their usual daily 
dose of corticosteroid during surgery and acute illness; 
supplemental hydrocortisone is not usually required.
B. Thyroid Hormone Replacement
Levothyroxine is given to correct hypothyroidism only after 
the patient is assessed for cortisol deficiency or is already 
receiving corticosteroids. The typical maintenance dose is 
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about 1.6 mcg/kg body weight, averaging 125 mcg daily with 
a wide range of 25–300 mcg daily. Assessment of serum TSH 
is useless for monitoring patients with hypopituitarism. The 
optimal replacement dose of levothyroxine is determined 
clinically by raising or lowering the dose, according to the 
patient’s symptoms and clinical examination, until an opti
-
mal dose is found. In patients receiving clinically optimal 
levothyroxine replacement, serum FT
4
 levels are usually in 
the mid to high-normal range. Some patients do not feel 
clinically euthyroid until they receive levothyroxine in doses 
at which the serum FT
4
 levels are mildly elevated; however, 
serum T
3
 or FT
3
 levels should be in the low-normal range. 
During pregnancy, clinical status and serum FT
4
 or total T
4
 
levels need to be monitored frequently, since higher doses of 
levothyroxine are usually required.
C. Gonadotropin Replacement
Hypogonadotropic hypogonadism often develops in 
patients with hyperprolactinemia and usually resolves with 
its treatment. See Male Hypogonadism and Female 
Hypogonadism.
Women with panhypopituitarism have profound 
androgen deficiency caused by the combination of both 
secondary hypogonadism and adrenal insufficiency. When 
serum DHEA levels are less than 400 ng/mL, women may 
also be treated with compounded USP-grade DHEA 
50 mg/day orally. DHEA therapy tends to increase pubic 
and axillary hair and may modestly improve libido, alert
-
ness, stamina, and overall psychological well-being.
For men with oligospermia, human chorionic gonado
-
tropin (hCG) (equivalent to LH) may be given at a dosage of 
2000–3000 units intramuscularly three times weekly and 
testosterone replacement discontinued. The dose of hCG is 
adjusted to normalize serum testosterone levels. After 
6–12 months of hCG treatment, if the sperm count remains 
low, hCG injections are continued along with injections of 
follitropin beta (synthetic recombinant FSH) or urofollitrop
-
ins (urine-derived FSH). An alternative for patients with an 
intact pituitary is the use of leuprolide (GnRH analog) by 
intermittent subcutaneous infusion. With treatment, testicu
-
lar volumes increase within 5–12 months, and some sper
-
matogenesis occurs in most cases. With persistent treatment 
and the use of intracytoplasmic sperm injection for some 
cases, the pregnancy success rate is about 70%. Men often 
feel better during hCG therapy than during testosterone 
replacement. Therefore, some men may elect to continue 
hCG therapy long term.
Clomiphene, 25–50 mg/day orally, can sometimes stim
-
ulate men’s own pituitary gonadotropins (when his pitu
-
itary is intact), thereby increasing testosterone and sperm 
production. For fertility induction in females, ovulation 
may be induced with clomiphene, 50–100 mg/day orally 
for 5 days every 2 months. Ovulation induction with FSH 
and hCG can induce multiple births and should be used 
only by those experienced with their administration.
D. Human Growth Hormone (hGH) Replacement
Symptomatic adults with GH deficiency may be treated 
with a subcutaneous recombinant human growth hormone 
(rhGH, somatropin) injections starting at a dosage of about 
0.2 mg/day (0.6 international units/day), administered 
three times weekly. The dosage of rhGH is increased every 
2–4 weeks by increments of 0.1 mg (0.3 international units) 
until side effects occur or a sufficient salutary response and 
a normal serum IGF-1 level are achieved. In adults, if the 
desired effects (eg, improved energy and mentation, reduc
-
tion in visceral adiposity) are not seen within 3–6 months at 
maximum tolerated dosage, rhGH therapy is discontinued. 
Therapy with hGH can bring out central hypothyroidism, 
so serum FT
4
 levels require monitoring when beginning 
hGH therapy.
During pregnancy, rhGH may be safely administered to 
women with hypopituitarism at their usual pregestational

so serum FT
4
women with hypopituitarism at their usual pregestational 
dose during the first trimester, tapering the dose during the 
second trimester, and discontinuing rhGH during the third 
Oral estrogen replacement reduces hepatic IGF-1 pro
-
duction. Therefore, prior to commencing rhGH therapy, 
oral estrogen should be changed to transdermal or trans
-
vaginal estradiol.
Treatment of adult GH deficiency usually improves the 
patient’s overall quality of life, with better emotional sense 
of well-being, increased muscle mass, and decreased vis
-
ceral fat and waist circumference. Long-term treatment 
with rhGH does not appear to affect mortality.
Side effects of rhGH therapy may include peripheral 
edema, hand stiffness, arthralgias and myalgias, paresthe
-
sias, carpal tunnel syndrome, tarsal tunnel syndrome, 
headache, pseudotumor cerebri, gynecomastia, hyperten
-
sion, and proliferative retinopathy. Treatment with rhGH 
can also cause sleep apnea, insomnia, dyspnea, sweating, 
and fatigue. Side effects usually remit promptly after a suf
-
ficient reduction in dosage. Therapy with rhGH does not 
increase the risk of any malignancy or the regrowth of 
pituitary or brain neoplasms; serum IGF-1 levels should be 
kept in the normal range.
GH should not be administered during critical illness, 
since administration of very high doses of rhGH increased 
mortality in patients receiving intensive care. 
There is cur
-
rently no proven role for GH replacement for the physiologic 
GH deficiency that is seen with abdominal obesity or normal 
aging.
E. Other Treatment
Selective transsphenoidal surgery is usually performed to 
resect non-prolactinoma pituitary masses and Rathke cleft 
cysts that cause local symptoms or hypopituitarism. Such 
surgery reverses hypopituitarism in a minority of cases. 
Patients with lymphocytic hypophysitis have been treated 
with corticosteroid therapy and other immunosuppres
-
sants without much response and without reversing 
hypopituitarism.
 
»
Prognosis
Hypopituitarism resulting from a pituitary tumor may be 
reversible with dopamine agonists for prolactinomas or 
with careful selective resection of the tumor. Spontaneous 
recovery from hypopituitarism associated with pituitary 
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stalk thickening has been reported. Patients can also 
recover from functional hypopituitarism. Spontaneous 
reversal of idiopathic isolated hypogonadotropic hypogo
-
nadism occurs in about 10% of patients after several years 
of hormone replacement therapy (HRT). However, hypopi
-
tuitarism is usually permanent, and long-term HRT is 
ordinarily required.
Patients with hypopituitarism have an increased mor
-
tality risk, particularly women and those in whom diag
-
nosis was made at a younger age, who have a 
craniopharyngioma, or who required transcranial surgery 
or radiation therapy. There is also an increased risk of 
death from infections with adrenal crisis in patients with 
untreated secondary insufficiency. Some pituitary tumors 
are locally invasive. In patients who have received pitu
-
itary radiation therapy, there is an increased risk of a 
second intracranial neoplasm and small-vessel stroke. 
Asymptomatic Rathke cleft cysts may not require surgery 
but do require endocrine, ophthalmic, and scan 
Functionally, most patients with hypopituitarism do 
very well with hormone replacement. Men with infertility 
who are treated with hCG/FSH or GnRH are likely to 
resume spermatogenesis if they have a history of sexual 
maturation, descended testicles, and a baseline serum 
inhibin B level over 60 pg/mL. Women under age 40 years, 
with infertility due to hypogonadotropic hypogonadism, 
can usually have successful ovulation induction.
Capatina C et al. Hypopituitarism: growth hormone and cortico
-
tropin deficiency. Endocrinol Metab Clin North Am. 2015 
Mar;44(1):127–41. [PMID: 25732649]
Diri H et al. Sheehan’s syndrome: new insights into an old dis
-
ease. Endocrine. 2016 Jan;51(1):22–31. [PMID: 26323346]
Fleseriu M et al. Hormonal replacement in hypopituitarism in 
adults: an Endocrine Society clinical practice guideline. J Clin 
Endocrinol Metab. 2016 Nov;101(11):3888–921. [PMID: 
27736313]
Gordon MB et al. Trends in growth hormone stimulation testing 
and growth hormone dosing in adult growth hormone defi
-
ciency patients: results from the ANSWER program. Endocr 
Pract. 2016 Apr;22(4):396–405. [PMID: 26574788]
Honegger J et al; Pituitary Working Group of the German 
Society of Endocrinology. Diagnosis of primary hypophysitis 
in Germany. J Clin Endocrinol Metab. 2015 Oct;100(10):
 
3841–9. [PMID: 26262437]
Joshi MN et al. Immune checkpoint inhibitor-related hypophy
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sitis and endocrine dysfunction: clinical review. Clin Endocri
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nol (Oxf). 2016 Sep;85(3):331–9. [PMID: 26998595]
Molitch ME. Diagnosis and treatment of pituitary adenomas: a 
review. JAMA. 2017 Feb 7;317(5):516–24. [PMID: 28170483]
CENTRAL DIABETES INSIPIDUS
 
»
Antidiuretic hormone (ADH) deficiency with poly
-
uria (2–20 L/day) and polydipsia.
 
»
Hypernatremia occurs if fluid intake is inadequate.
 
»
Central diabetes insipidus is an uncommon disease caused 
by a deficiency in vasopressin (antidiuretic hormone 
[ADH]) from the posterior pituitary.
Primary central diabetes insipidus
 (without an identifi
-
able lesion noted on MRI of the pituitary and hypothalamus) 
accounts for about one-third of all cases of diabetes insipi
-
dus. Familial diabetes insipidus occurs as a dominant genetic 
trait with symptoms developing at about 2 years of age. 
Diabetes insipidus also occurs in Wolfram syndrome, a rare 
autosomal recessive disorder that is also known by the acro
-
nym DIDMOAD (diabetes insipidus, type 1 diabetes melli
-
tus, optic atrophy, and deafness). Central diabetes insipidus 
may also be due to autoimmunity against hypothalamic 
arginine vasopressin (AVP)-secreting cells. Reversible cen
-
tral diabetes insipidus can occur during chemotherapy with 
temozolomide and in the myelodysplastic preleukemic 
phase of acute myelogenous leukemia. 
Secondary central 
diabetes insipidus
 is due to damage to the hypothalamus or

 is due to damage to the hypothalamus or 
pituitary stalk by tumor, hypophysitis, infarction, hemor
-
rhage, anoxic encephalopathy, surgical or accidental trauma, 
infection (eg, encephalitis, tuberculosis, syphilis), or granu
-
lomas (sarcoidosis or Langerhans cell granulomatosis). 
Metastases to the pituitary are more likely to cause diabetes 
insipidus (33%) than are pituitary adenomas (1%). Central 
diabetes insipidus can also be idiopathic.
 
»
The symptoms of the disease are intense thirst, especially 
with a craving for ice water, the volume of ingested fluid 
varying from 2 L to 20 L daily, and polyuria, with large 
urine volumes and low urine specific gravity (usually less 
than 1.006 with ad libitum fluid intake). The urine is oth
-
erwise normal. Partial diabetes insipidus presents with less 
intense symptoms and should be suspected in patients with 
enuresis. Most patients with diabetes insipidus are able to 
maintain fluid balance by continuing to ingest large vol
-
umes of water. However, in patients without free access to 
water or with a damaged hypothalamic thirst center and 
altered thirst sensation, diabetes insipidus may present 
with hypernatremia and dehydration. Diabetes insipidus is 
aggravated by administration of high-dose corticosteroids, 
which increases renal free water clearance.
Diagnosis of central diabetes insipidus is a clinical one; 
there is no single diagnostic laboratory test. Evaluation 
should include a 24-hour urine collection for volume and 
creatinine. A urine volume of less than 2 L/24 h (in the 
absence of hypernatremia) rules out diabetes insipidus. 
The patient can be tested during ad libitum fluid intake. A 
random urine is tested for osmolality. Blood testing 
includes plasma vasopressin and serum glucose, urea 
nitrogen, calcium, potassium, sodium, and uric acid.
With central diabetes insipidus and primary polydipsia, 
the plasma AVP level is usually low (below 1 pg/mL), while 
the urine osmolarity is also low (less than 300 mOsm/L). 
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With nephrogenic diabetes insipidus, the plasma AVP level 
is normal or elevated (more than 2.5 pg/mL), while the urine 
osmolality is low (less than 300 mOsm/L). Hyperuricemia 
occurs in many patients with central diabetes insipidus, 
since reduced vasopressin stimulation of the renal V1 recep
-
tor causes a reduction in the renal tubular clearance of urate.
A supervised “vasopressin challenge test” may be done: 
Desmopressin acetate 0.05–0.1 mL (5–10 mcg) intranasally 
(or 1 mcg subcutaneously or intravenously) is given, with 
measurement of urine volume for 12 hours before and 
12 hours after administration. A serum sodium is obtained 
baseline, 12 hours after the desmopressin, and immediately 
if symptoms of hyponatremia develop. Patients with cen
-
tral diabetes insipidus notice a distinct reduction in thirst 
and polyuria; serum sodium usually remains normal. The 
dosage of desmopressin is doubled if the response is mar
-
ginal. In patients with primary polydipsia, a desmopression 
challenge causes no significant reduction in polydipsia, but 
does reduce polyuria that caused hyponatremia. Patients 
with nephrogenic diabetes insipidus show no response in 
polydipsia or urine volume.
C. Imaging
Distinguishing central diabetes insipidus from primary 
polydipsia usually requires an MRI of the pituitary gland. 
The normal posterior pituitary “bright spot” seen on T1 
weighted imaging is undetectable or small with central 
diabetes insipidus, whereas the pituitary bright spot is nor
-
mal or enlarged in primary polydipsia.
 
»
Central diabetes insipidus must be distinguished from 
polyuria caused by psychogenic polydipsia, diabetes melli
-
tus, Cushing syndrome, hypercalcemia, hypokalemia, and 
nocturnal polyuria of Parkinson disease.
Vasopressinase-induced diabetes insipidus may be seen 
in the last trimester of pregnancy, associated with oligohy
-
dramnios, preeclampsia, or hepatic dysfunction, and in the 
puerperium. Maternal circulating vasopressin is destroyed 
by placental vasopressinase; however, synthetic desmopres
-
sin is unaffected.
Nephrogenic diabetes insipidus is caused by unrespon
-
siveness of the kidney tubules to the normal secretion of 
vasopressin. A congenital form is familial and transmitted 
as an X-linked trait; it is caused by defective expression of 
renal vasopressin V2 receptors or vasopressin-sensitive 
water channels. Adults often also have hyperuricemia. 
Acquired forms are usually less severe and occur in pyelo
-
nephritis, renal amyloidosis, myeloma, potassium deple
-
tion, Sjögren syndrome, sickle cell anemia, chronic 
hypercalcemia, or recovery from acute tubular necrosis. 
Certain drugs (eg, corticosteroids, diuretics, demeclocy
-
cline, lithium, foscarnet, or methicillin) may induce neph
-
rogenic diabetes insipidus.
 
»
If water is not readily available, the excessive output of 
urine will lead to severe dehydration. Patients with an 
impaired thirst mechanism are very prone to 
hypernatremia, as are those with impaired mentation who 
forget to take their desmopressin. Excessive desmopressin 
acetate can induce water intoxication and hyponatremia.
 
»
Treatment
Mild cases of diabetes insipidus require no treatment other 
than adequate fluid intake. Reduction of aggravating fac
-
tors (eg, corticosteroids) will improve polyuria.
Desmopressin acetate is the treatment of choice for 
central diabetes insipidus and for vasopressinase-induced 
diabetes insipidus associated with pregnancy or the puer
-
perium. Desmopressin acetate (100 mcg/mL solution) is 
given intranasally every 12–24 hours as needed for thirst 
and polyuria. It may be administered via metered-dose 
nasal inhaler containing 0.1 mL (10 mcg/spray) or via a 
calibrated rhinal tube. The starting dose is one metered-
dose spray or 0.05–0.1 mL every 12–24 hours, and the dose 
is then individualized according to response. Desmopres
-

-
sin nasal may cause rhinitis or conjunctivitis. If the generic 
preparation is ineffective, switching to the DDAVP brand 
may provide relief.
Oral desmopressin, 0.1- and 0.2-mg tablets, is given in 
a starting dose of 0.05 mg twice daily and increased to a 
maximum of 0.4 mg every 8 hours, if required. Sublingual 
desmopressin (DDAVP melt), 60, 120, or 250 mcg, is not 
available in the United States; hyponatremia has been 
reported with this formulation. Oral desmopressin is par
-
ticularly useful for patients in whom rhinitis or conjuncti
-
vitis develops from the nasal preparation. Gastrointestinal 
symptoms, asthenia, and mild increases in hepatic enzymes 
can occur with the oral preparation.
Desmopressin can also be given intravenously, intra
-
muscularly, or subcutaneously in doses of 1–4 mcg every 
12–24 hours as needed.
Desmopressin may cause hyponatremia, but this is 
uncommon if minimum effective doses are used and the 
patient allows thirst to occur every 1–2 days. Desmopressin 
can sometimes cause agitation, emotional changes, and 
depression with an increased risk of suicide. Patients 
should be monitored by family, friends, and medical staff 
when desmopressin therapy is started.
 
»
Prognosis
Central diabetes insipidus after pituitary surgery or head 
trauma usually remits after days to weeks but may be per
-
manent if the hypothalamus or upper pituitary stalk is 
damaged.
Chronic central diabetes insipidus is ordinarily more an 
inconvenience than a dire medical condition. Treatment 
with desmopressin allows normal sleep and activity. 
Hypernatremia can occur, especially when the hypotha
-
lamic thirst center is damaged, but diabetes insipidus does 
not otherwise reduce life expectancy, and the prognosis is 
that of the underlying disorder.
Ananthakrishnan S. Diabetes insipidus during pregnancy. Best 
Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):305–15. 
[PMID: 27156766]
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Oiso Y et al. Clinical review: treatment of neurohypophyseal 
diabetes insipidus. J Clin Endocrinol Metab. 2013 
Oct;98(10):3958–67. [PMID: 23884783]
Robertson GL. Diabetes insipidus: differential diagnosis and 
management. Best Pract Res Clin Endocrinol Metab. 2016 
Mar;30(2):205–18. [PMID: 27156759]
ACROMEGALY & GIGANTISM
 
»
Pituitary tumor.
 
»
Gigantism
 before closure of epiphyses.
 
»
 excessive growth of hands, feet, jaw, 
internal organs.
 
»
Amenorrhea, hypertension, headaches, visual 
field loss, weakness.
 
»
Soft, doughy, sweaty handshake.
 
»
Elevated serum IGF-1.
 
»
GH exerts much of its growth-promoting effects by stimu
-
lating the release of IGF-1 from the liver and other tissues.
Acromegaly is nearly always caused by a pituitary ade
-
noma. Most are macroadenomas (over 1 cm in diameter). 
These tumors may be locally invasive, particularly into the 
cavernous sinus. Less than 1% are malignant. Acromegaly 
is usually sporadic but may rarely be familial, with less than 
3% being due to multiple endocrine neoplasia (MEN) types 
1 or 4. Acromegaly may also be seen rarely in McCune-
Albright syndrome and Carney complex. Acromegaly is 
very occasionally caused by ectopic secretion of GHRH or 
GH secreted by a lymphoma, hypothalamic tumor, bron
-
chial carcinoid, or pancreatic tumor.
 
»
Excessive GH causes tall stature and gigantism if it occurs 
in youth, before closure of epiphyses. Afterward, acro
-
megaly develops. The term “acromegaly, ” meaning extrem
-
ity enlargement, seriously understates the manifestations. 
The hands enlarge and a doughy, moist handshake is char
-
acteristic. The fingers widen, causing patients to enlarge 
their rings. Carpal tunnel syndrome is common. The feet 
also grow, particularly in shoe width. Facial features 
coarsen since the bones and sinuses of the skull enlarge; hat 
size increases. The mandible becomes more prominent, 
causing prognathism and malocclusion. Tooth spacing 
widens. Older photographs of the patient can be a useful 
comparison.
Macroglossia occurs, as does hypertrophy of pharyn
-
geal and laryngeal tissue; this causes a deep, coarse voice 
and sometimes makes intubation difficult. Obstructive 
sleep apnea may occur. A goiter may be noted. Hyperten
-
sion (50%) and cardiomegaly are common. At diagnosis, 
about 10% of acromegalic patients have a dilated left ven
-
tricle and heart failure with reduced ejection fraction. 
Weight gain is typical, particularly of muscle and bone. 
Insulin resistance is usually present and frequently causes 
diabetes mellitus (30%). Arthralgias and degenerative 
arthritis occur. Overgrowth of vertebral bone can cause 
spinal stenosis. Colon polyps are common, especially in 
patients with skin papillomas. The skin may also manifest 
hyperhidrosis, thickening, cystic acne, skin tags, and acan
-
thosis nigricans.
GH-secreting pituitary tumors usually cause some 
degree of hypogonadism, either by cosecretion of PRL or 
by direct pressure upon normal pituitary tissue. Decreased 
libido and erectile dysfunction are common in men and 
irregular menses or amenorrhea in women. Women who 
become pregnant have an increased risk of gestational dia
-
betes and hypertension. Secondary hypothyroidism some
-
times occurs; hypoadrenalism is unusual. Headaches are 
frequent. Temporal hemianopia may occur as a result of 
the optic chiasm being impinged by a suprasellar growth of 
the tumor.
For screening purposes, a random serum IGF-1 can be 
obtained. If it is normal for age, acromegaly is ruled out.
For further evaluation, the patient should be fasting for 
at least 8 hours (except for water), not be acutely ill, and not 
have exercised on the day of testing. Assay for the follow
-
ing: serum IGF-1 (increased and usually over five times 
normal in acromegalic patients), PRL (cosecreted by many

-
normal in acromegalic patients), PRL (cosecreted by many 
GH-secreting tumors), glucose (diabetes mellitus is com
-
mon in acromegaly), liver enzymes and serum creatinine 
or blood urea nitrogen (BUN) (liver failure or kidney dis
-
ease can misleadingly elevate GH), serum calcium (to 
exclude hyperparathyroidism), serum inorganic phospho
-
rus (frequently elevated), serum free T
4
, and TSH (second
-
ary hypothyroidism is common in acromegaly; primary 
hypothyroidism may increase PRL). Glucose syrup (100 g) 
is then administered orally, and serum GH is measured 
60 minutes afterward; acromegaly is excluded if the serum 
GH is less than 1 ng/mL. For ultrasensitive GH assays, GH 
should be suppressed to less than 0.3 ng/mL. The serum 
IGF-1 and glucose-suppressed GH are usually complemen
-
tary tests; however, disparities between the two occur in up 
to 30% of patients.
C. Imaging
MRI shows a pituitary tumor in 90% of acromegalic 
patients. MRI is generally superior to CT scanning, espe
-
cially in the postoperative setting. Radiographs of the skull 
may show an enlarged sella and thickened skull. Radio
-
graphs may also show tufting of the terminal phalanges of 
the fingers and toes. A lateral view of the foot shows 
increased thickness of the heel pad.
 
»
Active acromegaly must be distinguished from familial 
coarse features, large hands and feet, and isolated progna
-
thism and from inactive (“burned-out”) acromegaly in 
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which there has been a spontaneous remission due to 
infarction of the pituitary adenoma. GH-induced gigan
-
tism must be differentiated from familial tall stature and 
from aromatase deficiency.
Misleadingly high serum GH levels can be caused by 
exercise or eating just prior to the test; acute illness or agi
-
tation; liver failure or kidney disease; malnourishment; 
diabetes mellitus; or concurrent treatment with estrogens, 
beta-blockers, or clonidine. Acromegaly can be difficult to 
diagnose during pregnancy, since the placenta produces 
GH and commercial GH assays may not be able to distin
-
guish between pituitary and placental GH. During normal 
adolescence, serum IGF-1 is usually elevated and GH may 
fail to be suppressed.
 
»
Complications include hypopituitarism, hypertension, glu
-
cose intolerance or frank diabetes mellitus, cardiac enlarge
-
ment, and heart failure. Arthritis of hips, knees, and spine 
can be troublesome as can carpal tunnel syndrome. Cord 
compression may occur. Visual field defects may be severe 
and progressive. Acute loss of vision or cranial nerve palsy 
may occur if the tumor undergoes spontaneous hemor
-
rhage and necrosis (pituitary apoplexy). Colon polyps are 
more likely to be found in patients with acromegaly.
 
»
Treatment
A. Pituitary Microsurgery
Transsphenoidal pituitary microsurgery removes the ade
-
noma while preserving anterior pituitary function in most 
patients. Postoperatively, GH levels fall immediately; dia
-
phoresis and carpal tunnel syndrome often improve within 
a day after surgery. Transsphenoidal surgery is usually well 
tolerated, but complications occur in about 12% of patients, 
including infection, cerebrospinal fluid (CSF) leak, and 
Fluid and electrolyte disturbances occur in most 
patients postoperatively. Diabetes insipidus can occur 
within 2 days postoperatively, but is usually mild and self-
correcting. Hyponatremia can occur abruptly 4–13 days 
postoperatively in 21% of patients; symptoms may include 
nausea, vomiting, headache, malaise, or seizure. It is 
treated with free water and hypotonic fluid restriction. It is 
prudent to monitor serum sodium levels postoperatively.
Corticosteroids are administered perioperatively and 
tapered to replacement doses over 1 week; hydrocortisone 
is discontinued and a cosyntropin stimulation test is per
-
formed about 6 weeks after surgery. At that time, the 
patient is screened for secondary hypothyroidism (by a 
serum FT
4
) and secondary hypogonadism.
Acromegalic patients with an incomplete biochemical 
remission after pituitary surgery may benefit from medical 
therapy with dopamine agonists, somatostatin analogs, 
tamoxifen, or pegvisomant.
 is the dopamine agonist of choice. It may 
be used first, since it is an oral medication. Cabergoline 
therapy is most successful for tumors that secrete both PRL 
and GH but can also be effective for patients with normal 
serum PRL levels. Therapy with cabergoline will shrink 
one-third of acromegaly-associated pituitary tumors by 
more than 50%. It appears to be safe during pregnancy. The 
initial dose is 0.25 mg orally twice weekly, which is gradu
-
ally increased to a maximum dosage of 1 mg twice weekly 
(based on serum GH and IGF-1 levels). Side effects of 
cabergoline include nausea, fatigue, constipation, abdomi
-
nal pain, and dizziness.
Octreotide
 and 
lanreotide
 are somatostatin analogs 
that are given by monthly subcutaneous injection. Such 
long-acting somatostatin analogs can achieve serum GH 
levels under 2 ng/mL in 79% of patients and normal serum 
IGF-1 levels in 53% of patients.
Tamoxifen
 is a selective estrogen receptor modulator 
(SERM) that may be particularly useful for persistent acro
-
megaly in men and in women who are postmenopausal or 
who have had breast cancer. Tamoxifen in doses of 
20–40 mg orally daily does not reduce serum GH levels but

-
20–40 mg orally daily does not reduce serum GH levels but 
reduces serum IGF-1 levels in 82% of patients and normal
-
izes serum IGF-1 levels in 47%. Serum testosterone levels 
increase in men.
Pegvisomant
 is a GH receptor antagonist that is given 
by daily subcutaneous injection. It blocks hepatic IGF-1 
production, but does not shrink GH-secreting tumors. 
Patients need to be monitored carefully for growth of the 
pituitary tumor with visual field examinations, GH levels, 
and MRI scanning of the pituitary. Pegvisomant therapy 
produces symptomatic relief and normalizes serum IGF-1 
levels in over 90% of patients.
C. Stereotactic Radiosurgery
Acromegalic patients who do not achieve a complete 
remission with transsphenoidal surgery or medical therapy 
may be treated with one or a combination of three types of 
stereotactic radiosurgery: linear accelerator (eg, 
Cyberknife), gamma knife radiosurgery, and proton beam 
radiosurgery. Following any pituitary radiation therapy, 
patients are advised to take lifelong daily low-dose aspirin 
because of the increased risk of small-vessel stroke. Stereo
-
tactic radiosurgery to pituitary tumors causes anterior 
hypopituitarism in 35–60% of patients within 5 years, so 
patients must have regular monitoring of their pituitary 
function.
 
»
Prognosis
Acromegaly is usually chronic and progressive unless 
treated. Spontaneous remissions are rare but have been 
reported following clinical or subclinical apoplexy (hemor
-
rhage) within the tumor. Patients with acromegaly have 
increased morbidity and mortality from cardiovascular 
disorders and progressive acromegalic symptoms. Those 
who are treated and have a random serum GH under 
1.0 ng/mL or a glucose-suppressed serum GH under 
0.4 ng/mL with a normal age-adjusted serum IGF-1 level 
have reduced morbidity and mortality.
Transsphenoidal pituitary surgery achieves a remission 
in about 70% of patients followed over 3 years. In patients 
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Table 26–1.
 
Causes of hyperprolactinemia.
Physiologic 
Causes
Pharmacologic 
Causes
Pathologic Causes
Exercise
Familial (mutant 
prolactin 
receptor)
Macroprolactin 
(“big 
prolactin”)
Nipple 
stimulation
Pregnancy
Puerperium
Sleep (REM 
phase)
Stress (trauma, 
surgery)
Suckling
Amoxapine
Anesthetic agents
Antipsychotics 
(conventional 
and atypical)
Butyrophenones
Cimetidine and 
ranitidine (not 
famotidine or 
nizatidine)
Cocaine
Domperidone
Estrogens
Hydroxyzine
Locaserin
Opioids
Nicotine
Protease inhibitors
Progestins
Reserpine
Selective serotonin 
reuptake 
Testosterone
Tricyclic 
Verapamil
Chronic chest wall 
 
stimulation 
 
(thoracotomy, aug
-
mentation or reduc
-
tion mammoplasty, 
mastectomy, herpes 
zoster, mammoplasty, 
chest acupuncture, 
nipple rings, etc)
Cirrhosis
Hypothalamic disease
Kidney disease 
 
(especially with zinc 
deficiency)
Optic neuromyelitis
Pituitary stalk damage
Prolactin-secreting 
tumors
Pseudocyesis (false 
pregnancy)
Spinal cord lesions
with tumors smaller than 2 cm in diameter and GH levels 
below 50 ng/mL, transsphenoidal pituitary surgery is suc
-
cessful in 80%. Extrasellar extension of the pituitary tumor, 
particularly cavernous sinus invasion, reduces the likeli
-
hood of surgical cure.
Adjuvant medical therapy is successful in treating 
patients who are not cured by pituitary surgery. Postopera
-
tively, normal pituitary function is usually preserved. Soft 
tissue swelling regresses but bone enlargement is perma
-
nent. Hypertension frequently persists despite successful 
surgery. Conventional radiation therapy (alone) produces a 
remission in about 40% of patients by 2 years and 75% of 
patients by 5 years after treatment. Gamma knife or 
cyberknife radiosurgery reduces GH levels an average of 
77%, with 20% of patients having a full remission after 
12 months. Proton beam radiosurgery produces a remis
-
sion in about 70% of patients by 2 years and 80% of patients 
by 5 years. Radiation therapy eventually produces some 
degree of hypopituitarism in most patients. Conventional 
radiation therapy may cause some degree of organic brain 
syndrome and predisposes to small strokes. Patients must 
receive lifelong follow-up, with regular monitoring of 
serum GH and IGF-1 levels. Serum GH levels over 5 ng/mL 
and rising IGF-1 levels usually indicate a recurrent tumor. 
Most pregnant women with acromegaly do not have an 
increase in the size of the pituitary tumor and neonatal 
outcome is unaffected.
Giustina A et al. Expert consensus document: a consensus on the 
medical treatment of acromegaly. Nat Rev Endocrinol. 2014 
Apr;10(4):243–8. [PMID: 24566817]
Katznelson L et al. Acromegaly: An Endocrine Society clinical 
practice guideline. J Clin Endocrinol Metab. 2014 
Nov;99(11):3933–51. [PMID: 25356808]
Melmed S. New therapeutic agents for acromegaly. Nat Rev 
Endocrinol. 2016 Feb;12(2):90–8. [PMID: 26610414]
HYPERPROLACTINEMIA
 
»
Women:
 Oligomenorrhea, amenorrhea; galactor
-
rhea; infertility.
 
»
Men:
 Hypogonadism; decreased libido and erec
-
tile dysfunction; infertility.
 
»
Elevated serum PRL; PRL is normally elevated dur
-
ing pregnancy.
 
»
CT or MRI may show a pituitary adenoma.
 
»
The causes of hyperprolactinemia are shown in Table 26–1. 
In acromegaly, there may be cosecretion of GH and PRL. 
Hyperprolactinemia (without a pituitary adenoma) may 
also be familial. PRL-secreting pituitary tumors are more 
common in women than in men and are usually sporadic 
but may rarely be familial as part of MEN type 1 or 4. Most 
are microadenomas (smaller than 1 cm in diameter) that 
do not grow even with pregnancy or oral contraceptives. 
However, some giant prolactinomas (over 3 cm in diame
-

-
ter) can spread into the cavernous sinuses and suprasellar 
areas; rarely, they may erode the floor of the sella to invade 
the paranasal sinuses.
 
»
Hyperprolactinemia may cause hypogonadotropic hypo
-
gonadism and reduced fertility. Men usually have dimin
-
ished libido and erectile dysfunction that may not respond 
to testosterone replacement; gynecomastia sometimes 
occurs. The diagnosis of a prolactinoma is often delayed in 
men, such that pituitary adenomas may grow and present 
with late manifestations of a pituitary macroprolactinoma 
(diameter 10 mm or larger).
About 90% of premenopausal women with prolactino
-
mas experience amenorrhea, oligomenorrhea, or infertility. 
Estrogen deficiency can cause decreased vaginal lubrica
-
tion, irritability, anxiety, and depression. Galactorrhea 
(lactation in the absence of nursing) is common. During 
pregnancy, clinically significant enlargement of a microp
-
rolactinoma (diameter smaller than 10 mm) occurs in less 
than 3%; clinically significant enlargement of a macropro
-
lactinoma occurs in about 30%.
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Pituitary prolactinomas may cosecrete GH and cause 
acromegaly. Large tumors may cause headaches, visual 
symptoms, and pituitary insufficiency.
Aside from pituitary tumors, some women secrete an 
abnormal form of PRL that appears to cause peripartum 
cardiomyopathy. Suppression of PRL secretion with dopa
-
mine agonists can reverse the cardiomyopathy.
Evaluate for conditions known to cause hyperprolac
-
tinemia, particularly pregnancy (serum hCG), hypothy
-
roidism (serum FT
4
 and TSH), kidney disease (BUN and 
serum creatinine), cirrhosis (liver tests), and hyperparathy
-
roidism (serum calcium). Men are evaluated for hypogo
-
nadism with serum total and free testosterone, LH, and 
FSH. Women who have amenorrhea are assessed for hypo
-
gonadism with serum estradiol, LH, and FSH. Patients 
with pituitary macroadenomas larger than 3 cm in diame
-
ter should have PRL measured on serial dilutions of serum, 
since immunoradiometric assay assays may otherwise 
report falsely low titers, the “high-dose hook effect. ” 
Patients with macroprolactinomas or manifestations of 
possible hypopituitarism should be evaluated for hypopitu
-
itarism. Patients with hyperprolactinemia who are rela
-
tively asymptomatic and have no apparent cause for 
hyperprolactinemia should have an assay for macroprolac
-
tinemia, which is an increased circulating level of a high 
molecular weight PRL that is biologically inactive but is 
detected on assays.
C. Imaging
Patients with hyperprolactinemia not induced by drugs, 
hypothyroidism, or pregnancy should be examined by 
pituitary MRI. Small prolactinomas may thus be demon
-
strated, but clear differentiation from normal variants is 
not always possible. In the event that a woman with a mac
-
roprolactinoma becomes pregnant and elects not to take 
dopamine agonists during her pregnancy, MRI is usually 
not performed since the normal pituitary grows during 
pregnancy. However, if visual-field defects or other neuro
-
logic symptoms develop in a pregnant woman, a limited 
MRI study should be done, focusing on the pituitary with
-
out gadolinium contrast.
 
»
The differential diagnosis for galactorrhea includes the 
small amount of breast milk that can be expressed from the 
nipple in many parous women that is not cause for con
-
cern. Nipple stimulation from nipple rings, chest surgery, 
or acupuncture can cause galactorrhea; serum PRL levels 
may be normal or minimally elevated. Some women can 
have galactorrhea with normal serum PRL levels and no 
discernible cause (idiopathic). Normal breast milk may be 
various colors besides white. However, bloody galactorrhea 
requires evaluation for breast cancer.
Other pituitary lesions can produce hyperprolac
-
tinemia by damaging the hypothalamus or pituitary stalk, 
thereby reducing the amount of dopamine reaching 
pituitary lactotrophes that produce PRL unless inhibited 
by dopamine. About 40% of nonfunctional pituitary mac
-
roadenomas produce some degree of hyperprolactinemia. 
These and other lesions and malignancies can be misdiag
-
nosed as prolactinomas. One distinguishing characteristic 
is that the serum PRL is usually only marginally elevated 
in the latter tumors, whereas with pituitary macroprolac
-
tinomas the serum PRL typically exceeds 100 mcg/L.
Pregnant women have high serum PRL levels, with 
physiological hyperplastic enlargement of the pituitary on 
MRI. Increased pituitary size is a normal variant in young 
women. Primary hypothyroidism can cause hyperprolac
-
tinemia and hyperplasia of the pituitary that can be mis
-
taken for a pituitary adenoma. Macroprolactinemia occurs 
in 3.7% of the general population and accounts for 
10–25% of all cases of hyperprolactinemia; pituitary MRI 
shows a nonpathological abnormality in 22% of such 
patients.
 
»
Treatment
Medications known to increase PRL should be stopped if

patients.
 
»
Treatment
Medications known to increase PRL should be stopped if 
possible (Table 26–1). Hyperprolactinemia due to hypothy
-
roidism is corrected by thyroxine.
Women with microprolactinomas who have amenor
-
rhea or are desirous of contraception may safely take 
oral contraceptives or estrogen replacement—there is 
minimal risk of stimulating enlargement of the micro
-
adenoma. Patients with infertility and hyperprolac
-
tinemia may be treated with a dopamine agonist in an 
effort to improve fertility. Women with amenorrhea who 
elect to receive no treatment have an increased risk of 
developing osteoporosis; such women require periodic 
bone densitometry.
Pituitary macroprolactinomas have a higher risk of 
progressive growth, particularly during estrogen or testos
-
terone HRT or during pregnancy. Therefore, patients with 
macroprolactinomas should not be treated with HRT 
unless they are in remission with dopamine agonist medi
-
cation or surgery.
Pregnant women with macroprolactinomas should 
continue to receive treatment with dopamine agonists 
throughout the pregnancy to prevent tumor growth. If 
dopamine agonists are not used during pregnancy in a 
woman with a macroprolactinoma, visual field testing is 
required in each trimester. Measurement of PRL is not use
-
ful surveillance for tumor growth due to the fact that PRL 
increases greatly during normal pregnancy.
A. Dopamine Agonists
Dopamine agonists (cabergoline, bromocriptine, or quina
-
golide) are the initial treatment of choice for patients with 
giant prolactinomas and those with hyperprolactinemia 
desiring restoration of normal sexual function and fertility. 
Even cystic prolactinomas respond to dopamine agonists; 
in one report, median cyst volume was reduced by 83% and 
chiasmal compression resolved in four of five cases. Caber
-
goline is the most effective and usually the best-tolerated 
ergot-derived dopamine agonist. The beginning dosage is 
0.25 mg orally once weekly for 1 week, then 0.25 mg twice 
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weekly for the next week, then 0.5 mg twice weekly. Fur
-
ther dosage increases may be required monthly, based on 
serum PRL levels, up to a maximum of 1.5 mg twice 
weekly. Bromocriptine (1.25–20 mg/day orally) is an alter
-
native. Women who experience nausea with oral prepara
-
tions may find relief with deep vaginal insertion of 
cabergoline or bromocriptine tablets; vaginal irritation 
sometimes occurs. Quinagolide (Norprolac; not available 
in the United States) is a non–ergot-derived dopamine 
agonist for patients intolerant or resistant to ergot-derived 
medications; the starting dosage is 0.075 mg/day orally, 
increasing as needed and tolerated to a maximum of 
0.6 mg/day. Patients whose tumor is resistant to one dopa
-
mine agonist may be switched to another in an effort to 
induce a remission.
Dopamine agonists are given at bedtime to minimize 
side effects of fatigue, nausea, dizziness, and orthostatic 
hypotension. These symptoms usually improve with dos
-
age reduction and continued use. Erythromelalgia is rare. 
Cabergoline and bromocriptine are ergot-derived dopa
-
mine agonist treatments. In doses used for prolactinomas, 
dopamine agonists have not caused valvulopathy. Dopa
-
mine agonists can cause a variety of psychiatric side effects 
that are not dose related and may take weeks to resolve 
once the drug is discontinued.
Because dopamine agonists usually restore fertility 
promptly, many pregnancies have resulted; no increased 
risk of miscarriage or teratogenicity has been noted. How
-
ever, women with microadenomas may have treatment 
withdrawn during pregnancy and may safely breastfeed 
postpartum without dopamine agonist therapy. Macroad
-
enomas may enlarge significantly during pregnancy; if 
therapy is withdrawn, patients must be monitored with 
serum PRL determinations and computer-assisted visual 
fields. Women with macroprolactinomas who have 
responded to dopamine agonists may safely receive oral 
contraceptives as long as they continue receiving dopamine 
agonist therapy.
Transsphenoidal pituitary surgery may be urgently required 
for large tumors undergoing apoplexy or those severely 
compromising visual fields. It is also used electively for 
patients who do not tolerate or respond to dopamine ago
-
nists. Transsphenoidal pituitary surgery is generally well 
tolerated, with a mortality rate of less than 0.5%. For pitu
-
itary microprolactinomas, skilled neurosurgeons are suc
-
cessful in normalizing PRL in 87% of patients and some 
patients prefer surgery to lifetime therapy with dopamine 
agonists.
Complications, such as CSF leakage, meningitis, 
stroke, or visual loss, occur in about 3% of cases; sinusitis, 
nasal septal perforation, or infection complicates about 
6.5% of transsphenoidal surgeries. Diabetes insipidus can 
occur within 2 days postoperatively but is usually mild 
and self-correcting. Hyponatremia can occur abruptly 
4–13 days postoperatively in 21% of patients; symptoms 
may include nausea, vomiting, headache, malaise, or sei
-
zure. It is treated with free water and hypotonic fluid 
restriction.
Stereotactic radiosurgery is seldom required for prolacti
-
nomas, since they usually respond to cabergoline or sur
-
gery. It is reserved for patients with macroadenomas that 
are growing despite treatment with dopamine agonists.
D. Chemotherapy
Some patients with aggressive pituitary macroadenomas 
or carcinomas are not surgical candidates and do not 
respond to dopamine agonists or radiation therapy. A 
small percentage of patients with aggressive tumors 
respond to temozolomide (150–200 mg/m
2
 orally daily for 
5 days of each 28-day cycle); after three cycles, treatment 
efficacy is determined by PRL measurement and MRI 
scanning.
 
»
Prognosis
Pituitary prolactinomas generally respond well to dopa
-
mine agonist therapy. Ninety percent of patients with pro
-

scanning.
 
»
Prognosis
-
-
lactinomas experience a fall in serum PRL to 10% or less of 
pretreatment levels and about 80% of treated patients 
achieve a normal serum PRL level. Shrinkage of a pituitary 
adenoma occurs early, but the maximum effect may take 
up to 1 year. Nearly half of prolactinomas—even massive 
tumors—shrink more than 50%. Such shrinkage of inva
-
sive prolactinomas can result in CSF rhinorrhea. Women 
with microprolactinomas can take oral contraceptives with 
little risk of stimulating growth of the pituitary adenoma. 
During pregnancy, growth of a pituitary prolactinoma 
occurs in 2.7% of women with a microprolactinoma and 
in 22.9% of those with a macroprolactinoma. If cabergo
-
line is stopped after 2 years of therapy, hyperprolac
-
tinemia recurs in 68% of patients with idiopathic 
hyperprolactinemia, 79% with microprolactinomas, and 
84% with macroprolactinomas.
The 10-year recurrence rate is 13% for pituitary micro
-
adenomas after transsphenoidal surgery; pituitary function 
can be preserved in over 95% of cases. However, the surgi
-
cal success rate for macroprolactinomas is much lower, and 
the complication rates are higher.
Faje A et al. Dopamine agonists can reduce cystic prolactinomas. 
J Clin Endocrinol Metab. 2016 Oct;101(10):3709–15. [PMID: 
27459530]
Glezer A et al. Prolactinomas. Endocrinol Metab Clin North 
Am. 2015 Mar;44(1):71–8. [PMID: 25732643]
Losa M et al. Temozolomide therapy in patients with aggressive 
pituitary adenomas or carcinomas. J Neurooncol. 2016 
Feb;126(3):519–25. [PMID: 26614517]
Samson SL et al; AACE Neuroendocrine and Pituitary Scientific 
Committee; American College of Endocrinology (ACE). 
Clinical relevance of macroprolactin in the absence or pres
-
ence of true hyperprolactinemia. Endocr Pract. 2015 
Dec;21(12):1427–35. [PMID: 26642103]
Wong A et al. Update on prolactinomas. Part 1: Clinical manifes
-
tations and diagnostic challenges. J Clin Neurosci. 2015 
Oct;22(10):1562–7. [PMID: 26256063]
Wong A et al. Update on prolactinomas. Part 2: Treatment and 
management strategies. J Clin Neurosci. 2015 
Oct;22(10):1568–74. [PMID: 26243714]
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º
DISEASES OF THE THYROID GLAND
THYROIDITIS
 
»
Autoimmune thyroiditis (Hashimoto) most com
-
mon thyroiditis.
 
»
Thyroid function tests variable.
 
»
Antithyroperoxidase or antithyroglobulin anti
-
bodies usually high in autoimmune thyroiditis.
 
»
Thyroiditis may be classified as follows: (1) autoimmune 
thyroiditis (Hashimoto, lymphocytic thyroiditis), (2) sub
-
acute thyroiditis, (3) infectious (suppurative) thyroiditis, 
and (4) Riedel thyroiditis.
Autoimmune thyroiditis
 is the most common thyroid 
disorder in the United States. Cell-mediated autoimmunity 
is present with T-lymphocytes invading the thyroid gland, 
giving the microscopic appearance of “lymphocytic 
thyroiditis. ” Humoral autoimmunity, with detectable serum 
antithyroid antibodies, is present in most but not all 
affected patients. This condition is also known as 
“Hashimoto thyroiditis. ” Autoimmune thyroiditis presents 
in various ways, such as a painless goiter, hypothyroidism, 
hyperthyroidism caused by destructive release of thyroid 
hormones (followed by hypothyroidism), or hyperthyroid
-
ism caused by increased synthesis of thyroid hormones 
(Graves disease). Affected patients may have combinations 
of these presentations. For example, a patient with hypo
-
thyroidism might later develop hyperthyroidism that can 
wax and wane.
Autoimmune thyroiditis is a common disorder, with 
elevated serum levels of antithyroid antibodies (antithyro
-
peroxidase or antithyroglobulin antibodies, or both) being 
detectable in the general population in 3% of men and 13% 
of women. Women over the age of 60 years have a 25% 
incidence of elevated serum levels of antithyroid antibod
-
ies, yet thyroid dysfunction develops in only a small subset 
of such individuals. However, 1% of the population has 
serum antithyroid antibody titers greater than 1:640, and 
they are at particular risk for thyroid dysfunction. The 
incidence of autoimmune thyroiditis varies by kindred, 
race, and sex. It is commonly familial. In the United States, 
elevated levels of antithyroid antibodies are found in 14.3% 
of whites, 10.9% of Mexican Americans, and 5.3% of 
blacks.
Childhood or occupational exposure to head-neck 
external beam radiation increases the lifetime risk of auto
-
immune thyroiditis. Women with gonadal dysgenesis 
(Turner syndrome) have a 15% incidence of thyroiditis by 
age 40 years. Thyroiditis is also commonly seen in patients 
with hepatitis C. Subclinical thyroiditis is extremely com
-
mon; autopsy series have found focal thyroiditis in about 
40% of women and 20% of men.
Dietary iodine supplementation (especially when exces
-
sive) increases the risk of autoimmune thyroiditis. Certain 
drugs can trigger autoimmune thyroiditis, including tyro
-
sine kinase inhibitors, denileukin diftitox, alemtuzumab, 
interferon-alpha, interleukin-2, thalidomide, lenalidomide, 
lithium, amiodarone, and immune checkpoint inhibitors.
Autoimmune thyroiditis often progresses to hypothy
-
roidism, which may be linked to thyrotropin receptor–
blocking antibodies, detected in 10% of patients with 
Hashimoto thyroiditis. Hypothyroidism is more likely to 
develop in smokers than in nonsmokers, possibly due to 
the thiocyanates in cigarette smoke. High serum levels of 
thyroid peroxidase antibody also predict progression from 
subclinical to symptomatic hypothyroidism. Although the 
hypothyroidism is usually permanent, up to 11% of patients 
experience a remission after several years. Autoimmune 
thyroiditis is the most common cause for hyperthyroidism 
(Graves disease) and most patients with Graves disease 
have concomitant antithyroid antibodies.
Autoimmune thyroiditis is sometimes associated with 
other endocrine deficiencies as part of autoimmune poly
-
endocrine syndrome type 2 (APS-II). Adults with APS-II 
are prone to autoimmune thyroiditis, type 1 diabetes mel
-

-
-
litus, autoimmune gonadal failure, hypoparathyroidism, 
and adrenal insufficiency. Thyroiditis is frequently associ
-
ated with other autoimmune conditions: pernicious ane
-
mia, Sjögren syndrome, vitiligo, inflammatory bowel 
disease, celiac disease, and gluten sensitivity. It is less com
-
monly associated with alopecia areata, hypophysitis, 
encephalitis, myocarditis, primary pulmonary hyperten
-
sion, and membranous nephropathy.
Painless postpartum thyroiditis is an acute autoimmune 
thyroiditis that occurs soon after delivery in 7.2% of 
women. The affected thyroid releases stored thyroid hor
-
mone, resulting in transient hyperthyroidism (that may be 
mild and undiagnosed), followed by hypothyroidism. Most 
women recover normal thyroid function. Women in whom 
postpartum thyroiditis develops have a 70% chance of 
recurrence after subsequent pregnancies. It occurs most 
commonly in women who have high levels of antithyroper
-
oxidase antibody in the first trimester of pregnancy or 
immediately after delivery. It is also more common in 
women with preexistent type 1 diabetes mellitus, other 
autoimmunity, or a family history of Hashimoto 
thyroiditis.
Painless sporadic subacute
 thyroiditis is a form of auto
-
immune thyroiditis that is similar to painless postpartum 
thyroiditis, except that it is not related to pregnancy. 
 
It is caused by a release of stored thyroid hormone and 
accounts for about 1% of cases of thyrotoxicosis. It is fol
-
lowed by hypothyroidism that may or may not resolve 
spontaneously.
Painful subacute thyroiditis
—also called de Quervain 
thyroiditis, granulomatous thyroiditis, and giant cell thy
-
roiditis—is relatively common. Its hallmark is a tender 
thyroid gland associated with painful dysphagia. Low-
grade fever is common. The erythrocyte sedimentation 
rate (ESR) is often elevated. Multinucleated giant cells are 
found on histology. Some patients also have antithyroid 
antibodies. Like painless subacute thyroiditis, most affected 
CMDT19_Ch26_p1119-p1219.indd   1131

C
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patients have transient hyperthyroidism, followed by hypo
-
thyroidism. Painful subacute thyroiditis is likely caused by 
a viral infection and often follows an upper respiratory 
tract infection. Its incidence peaks in the summer. It affects 
both sexes, but young and middle-aged women are most 
commonly affected.
Infectious (suppurative) thyroiditis
, a nonviral infec
-
tion of the thyroid gland, is quite rare among immunocom
-
petent patients, since the thyroid is resistant to infection 
due to its vasculature, encapsulation, and high iodine con
-
tent. Congenital pyriform sinus fistulas are a cause for 
recurrent infectious thyroiditis. While infectious thyroid
-
itis is usually bacterial, mycobacterial, fungal, and parasitic 
infections can occur, particularly in immunosuppressed 
individuals. In affected patients who are appropriately 
treated, when immunosuppression is reduced, the patient 
may experience an immune reconstitution inflammatory 
syndrome (IRIS) from residual antigens triggering the nor
-
mal immune response.
Riedel thyroiditis,
 also called invasive fibrous thyroid
-
itis, Riedel struma, woody thyroiditis, ligneous thyroiditis, 
and invasive thyroiditis, is the rarest form of thyroiditis. It 
is found most frequently in middle-aged or elderly women 
and is usually part of a multifocal systemic fibrosis syn
-
drome. It may occur as a thyroid manifestation of IgG
4
-
related systemic disease.
 
»
In 
autoimmune thyroiditis
, the thyroid gland may be dif
-
fusely enlarged, firm, and finely nodular. One thyroid lobe 
may be asymmetrically enlarged, raising concerns about 
neoplasm. Although patients may complain of neck tight
-
ness, pain and tenderness are not usually present. Other 
patients have no palpable goiter and no neck symptoms. 
About 10% of cases are atrophic, the gland being fibrotic, 
particularly in elderly women.
Symptoms and signs are mostly related to ambient lev
-
els of thyroid hormone. However, depression and chronic 
fatigue are more common in such patients, even after cor
-
rection of hypothyroidism. About one-third of patients 
have mild dry mouth (xerostomia) or dry eyes (keratocon
-
junctivitis sicca) related to Sjögren syndrome. Associated 
myasthenia gravis is usually of mild severity, mainly affect
-
ing the extraocular muscles and having a relatively low 
incidence of detectable AChR Ab or thymic disease. Asso
-
ciated celiac disease or gluten intolerance can produce 
fatigue or depression, sometimes in the absence of gastro
-
intestinal symptoms.
Postpartum thyroiditis is typically manifested by hyper
-
thyroidism that begins 1–6 months after delivery and per
-
sists for only 1–2 months. Then, hypothyroidism tends to 
develop beginning 4–8 months after delivery.
In painless sporadic thyroiditis, thyrotoxic symptoms 
are usually mild; a small, nontender goiter may be palpated 
in about 50% of such patients. The course is similar to 
postpartum thyroiditis.
 presents with an acute, usually 
painful enlargement of the thyroid gland, often 
with dysphagia. The pain may radiate to the ears. Patients 
usually have a low-grade fever and fatigue. The manifesta
-
tions may persist for weeks or months and may be associ
-
ated with malaise. If there is no pain, it is called silent 
thyroiditis. Thyrotoxicosis develops in 50% of affected 
patients and tends to last for several weeks. Subsequently, 
hypothyroidism develops that lasts 4–6 months. Normal 
thyroid function typically returns within 12 months, but 
persistent hypothyroidism develops in 5% of patients.
infectious thyroiditis
 usually are febrile 
and have severe pain, tenderness, redness, and fluctuation 
in the region of the thyroid gland. In 
Riedel thyroiditis
, 
thyroid enlargement is often asymmetric; the gland is stony 
hard and adherent to the neck structures, causing signs of

, 
hard and adherent to the neck structures, causing signs of 
compression and invasion, including dysphagia, dyspnea, 
pain, and hoarseness. Related conditions include retroperi
-
toneal fibrosis, fibrosing mediastinitis, sclerosing cervicitis, 
subretinal fibrosis, and sclerosing cholangitis.
In 
Hashimoto thyroiditis
 with clinically evident disease, 
there are usually increased circulating levels of antithyro
-
peroxidase (90%) or antithyroglobulin (40%) antibodies. 
However, some patients with autoimmune thyroiditis have 
no detectable antithyroid antibodies. In patients with thy
-
roiditis caused by immune checkpoint inhibitors, most 
have no detectable antithyroid antibodies. Antithyroid 
antibodies decline during pregnancy and are often unde
-
tectable in the third trimester. Once Hashimoto thyroiditis 
has been diagnosed, monitoring of these antibody levels is 
not helpful. The serum TSH level is elevated if thyroid 
hormone is not released in adequate amounts by the thy
-
roid gland. High serum antithyroperoxidase antibody 
concentrations are found in only 50% of patients with 
painless sporadic thyroiditis.
Patients with Hashimoto thyroiditis have a 15% inci
-
dence of having serum antibodies (IgA tissue transgluta
-
minase [tTG] antibody) associated with celiac disease and 
at least 5% have clinically significant celiac disease. Sero
-
negative gluten sensitivity is even more common.
In 
subacute thyroiditis,
 the ESR is markedly elevated 
while antithyroid antibody titers are low, distinguishing it 
from autoimmune thyroiditis. In 
infectious (suppurative) 
thyroiditis,
 both the leukocyte count and ESR are usually 
elevated.
With hyperthyroidism due to Hashimoto thyroiditis or 
subacute thyroiditis, serum FT
4
 levels tend to be propor
-
tionally higher than T
3
 levels, since the hyperthyroidism is 
due to the passive release of stored thyroid hormone, which 
is predominantly T
4
; this is in contrast to Graves disease 
and toxic nodular goiter, where T
3
 is relatively more ele
-
vated. Because T
4
 is less active than T
3
, the hyperthyroid
-
ism seen in thyroiditis is usually less severe. Serum levels of 
TSH are suppressed in hyperthyroidism due to thyroiditis.
C. Imaging
The ultrasound in cases of Hashimoto thyroiditis typically 
shows a gland with characteristic diffuse heterogeneous 
density and reduced echogenicity. It helps distinguish 
CMDT19_Ch26_p1119-p1219.indd   1132

1133
 
CMDT 2019
thyroiditis from multinodular goiter or thyroid nodules 
that are suspicious for malignancy. It is also helpful in guid
-
ing FNA biopsy of small suspicious thyroid nodules. Color 
flow Doppler ultrasonography can help distinguish thy
-
roiditis from Graves disease; in thyroiditis, vascularity is 
normal or reduced vascularity, whereas in Graves disease, 
the thyroid gland is hypervascular.
RAI uptake and scan can help distinguish thyroiditis 
from Graves disease; subacute thyroiditis exhibits a very 
low RAI uptake. However, RAI uptake may be normal or 
high with uneven uptake on the scan in chronic Hashimoto 
thyroiditis (euthyroid or hypothyroid); scanning is not use
-
ful in diagnosis.
[
18
F] Fluorodeoxyglucose positron emission tomogra
-
phy (
18
FDG-PET) scanning frequently shows diffuse thy
-
roid uptake of isotope in cases of thyroiditis. In fact, of all 
18
FDG-PET scans, about 3% show such uptake. However, 
discrete thyroid nodules can also be discovered on 
18
FDG-
PET scanning; these nodules are known as “thyroid PET 
incidentalomas” and 50% are malignant.
D. Fine-Needle Aspiration Biopsy
Patients with autoimmune thyroiditis who have a thyroid 
nodule should have an ultrasound-guided FNA biopsy, 
since the risk of papillary thyroid cancer is about 8% in 
such nodules. When infectious (suppurative) thyroiditis is 
suspected, an FNA biopsy with Gram stain and culture is 
required. FNA biopsy is usually not required for subacute 
thyroiditis but shows characteristic giant multinucleated 
cells.
 
»
Autoimmnue thyroiditis may lead to hypothyroidism or 
transient thyrotoxicosis. Hyperthyroidism may develop, 
either due to the emergence of Graves disease or due to the 
release of stored thyroid hormone, which is caused by 
inflammation. Variably termed “hashitoxicosis” or “painless 
sporadic thyroiditis, ” it is known as postpartum painless 
thyroiditis when it occurs in women after delivery. Peri
-
menopausal women with high serum levels of antithyroper
-
oxidase antibodies have a higher relative risk of depression, 
independent of ambient thyroid hormone levels.
In the suppurative forms of thyroiditis, any of the com
-
plications of infection may occur. Subacute and chronic 
thyroiditis are complicated by the effects of pressure on the 
neck structures: dyspnea and, in Riedel struma, vocal cord 
palsy. Papillary thyroid carcinoma or thyroid lymphoma 
may rarely be associated with chronic thyroiditis and must 
be considered in the diagnosis of uneven painless enlarge
-
ments that continue despite treatment; such patients 
require FNA biopsy.
 
»
Thyroiditis must be considered in the differential diagnosis 
of all types of goiters, especially if enlargement is rapid. The 
very low RAI uptake in subacute thyroiditis with elevated 
T
4
 and T
3
 is helpful. Thyroid autoantibody tests have been 
helpful in the diagnosis of Hashimoto thyroiditis, but the 
tests are not specific (positive in patients with multinodu
-
lar goiters, malignancy [eg, thyroid carcinoma, lymphoma], 
and concurrent Graves disease). The subacute and suppu
-
rative forms of thyroiditis may resemble any infectious 
process in or near the neck structures. Chronic thyroiditis 
may resemble thyroid carcinoma, especially if the enlarge
-
ment is uneven and if there is pressure on surrounding 
structures; both disorders may be present in the same 
gland.
 
»
Treatment
A. Autoimmune (Hashimoto) Thyroiditis
If hypothyroidism is present, levothyroxine should be 
given in the usual replacement doses (0.05–0.2 mg orally 
daily). In patients with a large goiter and normal or ele
-
vated serum TSH, an attempt is made to shrink the goiter 
by administering levothyroxine in doses sufficient to drive 
the serum TSH below the reference range while maintain
-
ing clinical euthyroidism. Suppressive doses of T
4
 tend to 
shrink the goiter an average of 30% over 6 months. If the

-
4
 tend to 
shrink the goiter an average of 30% over 6 months. If the 
goiter does not regress, lower replacement doses of levo
-
thyroxine may be given. If the thyroid gland is only mini
-
mally enlarged and the patient is euthyroid, regular 
observation is in order, since hypothyroidism may develop 
subsequently—often years later.
Dietary supplementation with selenium 200 mcg/day 
reduces serum levels of antithyroperoxidase antibodies. 
However, whether selenium supplementation improves 
clinical outcome is unknown.
B. Subacute Thyroiditis
All treatment is empiric and must be continued for several 
weeks. Recurrence is common. The drug of choice is aspi
-
rin, which relieves pain and inflammation. Thyrotoxic 
symptoms are treated with propranolol, 10–40 mg every 
6 hours. Iodinated contrast agents cause a prompt fall in 
serum T
3
 levels and a dramatic improvement in thyrotoxic 
symptoms. Ipodate sodium (Bilivist, Oragrafin) or iopa
-
noic acid (Telepaque) is given orally in doses of 500 mg 
orally daily until serum FT
4
 levels return to normal. Tran
-
sient hypothyroidism is treated with T
4
 (0.05–0.1 mg orally 
daily) if symptomatic.
C. Suppurative Thyroiditis
Treatment is with antibiotics and with surgical drainage 
when fluctuation is marked. Immunocompromised indi
-
viduals are particularly at risk and coccidioidomycosis 
thyroiditis has been reported. Surgical thyroidectomy may 
D. Riedel Struma
The treatment of choice is tamoxifen, 20 mg orally twice 
daily, which must be continued for years. Tamoxifen can 
induce partial to complete remissions in most patients 
within 3–6 months. Its mode of action appears to be unre
-
lated to its antiestrogen activity. Short-term corticosteroid 
treatment may be added for partial alleviation of pain and 
compression symptoms. Surgical decompression usually 
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1134
 CMDT 2019
fails to permanently alleviate compression symptoms; such 
surgery is difficult due to dense fibrous adhesions, making 
surgical complications more likely. Rituximab may be use
-
ful for Riedel thyroiditis that is refractory to tamoxifen and 
 
»
Prognosis
Autoimmune (Hashimoto) thyroiditis is occasionally asso
-
ciated with other autoimmune disorders (celiac disease, 
diabetes mellitus, Addison disease, pernicious anemia, 
etc). In general, however, patients with Hashimoto thyroid
-
itis have an excellent prognosis, since the condition either 
remains stable for years or progresses slowly to hypothy
-
roidism, which is easily treated. Although 80% of women 
with postpartum thyroiditis subsequently recover normal 
thyroid function, permanent hypothyroidism eventually 
develops in about 50% within 7 years, more commonly in 
women who are multiparous or who have had a spontane
-
ous abortion. In subacute thyroiditis, spontaneous remis
-
sions and exacerbations are common; the disease process 
may smolder for months. Papillary thyroid carcinoma car
-
ries a relatively good prognosis when it occurs in patients 
with Hashimoto thyroiditis.
Luo Y et al. Iodine excess as an environmental risk factor for 
autoimmune thyroid disease. Int J Mol Sci. 2014 Jul 21;
 
15(7):12895–912. [PMID: 25050783]
Plowden TC et al. Subclinical hypothyroidism and thyroid auto
-
immunity are not associated with fecundity, pregnancy loss, 
or live birth. J Clin Endocrinol Metab. 2016 Jun;101(6):
 
2358–65. [PMID: 27023447]
Ranganath R et al. de Quervain’s thyroiditis: a review of experi
-
ence with surgery. Am J Otolaryngol. 2016 Nov–
Dec;37(6):534–7. [PMID: 27686396]
Wichman J et al. Selenium supplementation significantly reduces 
thyroid autoantibody levels in patients with chronic autoim
-
mune thyroiditis: a systematic review and meta-analysis. 
Thyroid. 2016 Dec;26(12):1681–92. [PMID: 27702392]
HYPOTHYROIDISM & MYXEDEMA
 
»
Fatigue, cold intolerance, constipation, weight 
change, depression, menorrhagia, hoarseness.
 
»
Dry skin, bradycardia, delayed return of deep 
tendon reflexes.
 
»
Anemia, hyponatremia, hyperlipidemia.
 
»
FT
4
 level is usually low.
 
»
TSH elevated in primary hypothyroidism.
 
»
Hypothyroidism is common, affecting over 1% of the gen
-
eral population and about 5% of individuals over age 
60 years. About 85% of affected individuals are women. 
Thyroid hormone deficiency affects almost all body func
-
tions. The degree of severity ranges from mild and 
unrecognized hypothyroid states to striking myxedema. 
Maternal hypothyroidism during pregnancy results in off
-
spring with IQ scores that are an average 7 points lower 
than those of euthyroid mothers. Congenital hypothyroid
-
ism occurs in about 1:4000 births; untreated, it causes 
cretinism with permanent cognitive impairment.
Hypothyroidism may be due to failure or resection of 
the thyroid gland itself or deficiency of pituitary TSH. The 
condition must be distinguished from the functional hypo
-
thyroidism that occurs in severe nonthyroidal illness, which 
does not require treatment with thyroxine. Hashimoto thy
-
roiditis is the most common cause of hypothyroidism. 
A hypothyroid phase also occurs in subacute (de Quervain) 
viral thyroiditis following initial hyperthyroidism.
Goiter
 may be present with thyroiditis, iodide defi
-
ciency, genetic thyroid enzyme defects, drug goitrogens 
(lithium, iodide, propylthiouracil or methimazole, sulfon
-
amides, amiodarone, interferon-alpha, interferon-beta, 
interleukin-2), food goitrogens in iodide-deficient areas 
(eg, turnips, cassavas) or, rarely, peripheral resistance to 
thyroid hormone or infiltrating diseases (eg, cancer, sar
-
coidosis). Goiter is often absent in patients with autoim
-
mune thyroiditis. Goiter is also usually absent when 
hypothyroidism is due to destruction of the gland by head-

-
-
neck or chest-shoulder radiation therapy or 
131
I therapy. 
Thyroidectomy causes hypothyroidism; after hemithyroid
-
ectomy, hypothyroidism develops in 22% of patients. 
, because of its high iodine content, causes 
clinically significant hypothyroidism in about 15–20% of 
patients as well as thyrotoxicosis (see Amiodarone-induced 
thyrotoxicosis, below). Hypothyroidism occurs most often 
in patients with preexisting autoimmune thyroiditis and in 
patients who are not iodine-deficient. The T
4
 level is low or 
low-normal, and the TSH is elevated, usually over 20 milli-
international units/L. Another 17% of patients taking 
amiodarone are asymptomatic with normal serum T
4
 levels 
despite elevations in serum TSH; they can be closely moni
-
tored without thyroxine therapy. Low-dose amiodarone is 
less likely to cause hypothyroidism. Patients with coronary 
insufficiency who have amiodarone-induced symptomatic 
hypothyroidism are treated with just enough thyroxine to 
relieve symptoms. Hypothyroidism usually resolves over 
several months if amiodarone is discontinued. Hypothy
-
roidism may also develop in patients with a high iodine 
intake from other sources, especially if they have underly
-
ing lymphocytic thyroiditis. 
Some malignancies
 overex
-
press thyroid hormone inactivating enzyme (type 3 
deiodinase) and cause “consumptive hypothyroidism. ” This 
has occurred with large hemangiomas or a heavy tumor 
burden of colon cancer, basal cell cancer, fibrous tumors, or 
gastrointestinal stromal tumors (GISTs).
 that can cause silent thy
-
roiditis include the following: tyrosine kinase inhibitors, 
denileukin diftitox, alemtuzumab, interferon-alpha, 
interleukin-2, thalidomide, and lenalidomide. Immune 
checkpoint inhibitors include pembrolizumab, ipilimumab, 
tremelimumab, and atezolizumab. This usually starts with 
hyperthyroidism (often unrecognized) and then progresses 
to hypothyroidism. Radioiodine-based targeted radioiso
-
tope therapy can also cause hypothyroidism.
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Chronic hepatitis C
 is associated with an increased risk 
of autoimmune thyroiditis, with 21% of affected patients 
having antithyroid antibodies and 13% having hypothy
-
roidism. Oral direct-acting anti–hepatitis C agents do not 
increase the risk of thyroid dysfunction that has been seen 
with interferon.
 
»
1. Common manifestations—
Mild hypothyroidism often 
escapes detection without a screening serum TSH. Patients 
typically have nonspecific symptoms of hypothyroidism 
that include weight gain, fatigue, lethargy, depression, 
weakness, dyspnea on exertion, arthralgias or myalgias, 
muscle cramps, menorrhagia, constipation, dry skin, head
-
ache, paresthesias, cold intolerance, carpal tunnel syn
-
drome, and Raynaud syndrome. Physical findings can 
include bradycardia; diastolic hypertension; thin, brittle 
nails; thinning of hair; peripheral edema; puffy face and 
eyelids; and skin pallor or yellowing (carotenemia). 
Delayed relaxation of deep tendon reflexes may be present. 
Patients often have a palpably enlarged thyroid (goiter) that 
arises due to elevated serum TSH levels or the underlying 
thyroid pathology.
2. Less common manifestations—
Less common symp
-
toms of hypothyroidism include diminished appetite and 
weight loss, hoarseness, decreased sense of taste and smell, 
and diminished auditory acuity. Some patients may com
-
plain of dysphagia or neck discomfort. Although most 
menstruating women have menorrhagia, some women 
have scant menses or amenorrhea. Physical findings may 
include thinning of the outer halves of the eyebrows; thick
-
ening of the tongue; hard pitting edema; and effusions into 
the pleural and peritoneal cavities as well as into joints. 
Galactorrhea may also be present. Cardiac enlargement 
(“myxedema heart”) and pericardial effusions may occur. 
Psychosis “myxedema madness” can occur from severe 
hypothyroidism or from toxicity of other drugs whose 
metabolism is slowed in hypothyroidism. Hypothermia 
and stupor or myxedema coma, which is often associated 
with infection (especially pneumonia), may develop in 
patients with severe hypothyroidism.
Some hypothyroid patients with Hashimoto thyroiditis 
have symptoms that are not due to hypothyroidism but 
rather to conditions associated with Hashimoto thyroiditis; 
these include Addison disease, hypoparathyroidism, diabe
-
tes mellitus, pernicious anemia, Sjögren syndrome, vitiligo, 
biliary cirrhosis, gluten sensitivity, and celiac disease.
Hypothyroidism is a common disorder and thyroid func
-
tion tests should be obtained for any patient with its non
-
specific symptoms or signs. The single best screening test 
for hypothyroidism is the serum TSH (Table 26–2). The 
normal reference range for ultrasensitive TSH levels is 
generally 0.4–4.0 milli-international units/L. Over 95% of 
normal adults have serum TSH concentrations under 
3.0 milli-international units/L. However, there is consider
-
able controversy about what represents “normal, ” such that 
Table 26–2.
 
Appropriate use of thyroid tests.
Test
Comment
For screening
Serum thyroid-stimulating hormone (TSH)
Most sensitive test for primary hypothyroidism and 
hyperthyroidism
Free thyroxine (FT
4
)
Excellent test
For hypothyroidism
Serum TSH
High in primary and low in secondary hypothyroidism
Antithyroperoxidase and antithyroglobulin 
Elevated in Hashimoto thyroiditis
For hyperthyroidism
Serum TSH
Suppressed except in TSH-secreting pituitary tumor or 
pituitary hyperplasia (rare)
Triiodothyronine (T
3
) or free triiodothyronine (FT
3
)
Elevated
123
I uptake and scan
Increased uptake; diffuse versus “hot” foci on scan
Elevated in Graves disease
Thyroid-stimulating immunoglobulin (TSI)
Usually (65%) positive in Graves disease
For thyroid nodules
Fine-needle aspiration (FNA) biopsy
Best diagnostic method for thyroid cancer

123
Cancer is usually “cold”; less reliable than FNA biopsy
99m
Tc scan
Vascular versus avascular
Useful to assist FNA biopsy. Useful in assessing the risk of 
malignancy (multinodular goiter or pure cysts are less 
likely to be malignant). Useful to monitor nodules and 
patients after thyroid surgery for carcinoma.
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Table 26–3.
 
Factors that may cause aberrations in 
laboratory tests that may be mistaken for primary 
hypothyroidism.
1
Low Serum T
4
 or T
3
High Serum TSH
Acute psychiatric problems
Cirrhosis
Familial thyroid-binding 
globulin deficiency
Laboratory error
Severe illness
Drugs
 
Androgens
 
Asparaginase
 
C
arbamazepine (T
4
)
 
Chlor
al hydrate
 
Diclof
enac (T
3
), 
 
Napr
oxen (T
3
)
 
Didanosine
 
Fenclofenac
 
5-Fluorouracil
 
Halofenate
 
Imatinib
 
Mitotane
 
N
icotinic acid
 
P
henytoin (T
4
 as low 
 
as 2 mcg/dL)
 
S
alicylates in large doses 
 
(T
3
 and T
4
)
 
Sertraline
 
Stavudine
 
T
3
 therapy (T
4
)
Acute psychiatric admissions 
(transient) (14%)
Anti-mouse antibodies
Antithyrotropin (TSH) antibodies
Autoimmune disease (assay 
interference)
Elderly (especially women) (11%)
Heterophile antibodies
Macro-thyrotropin
Recovery from nonthyroidal 
illness (transient)
Strenuous exercise (acute)
Sleep deprivation (acute)
1
True primary hypothyroidism may coexist.
T
4
, levothyroxine; T
3
, triiodothyronine; TSH, thyroid-stimulating 
hormone.
each laboratory uses a slightly different range. The normal 
range of TSH varies with age; for example, the reference 
range for elderly patients is higher than the reference range 
for younger patients.
In primary hypothyroidism, the serum TSH is increased, 
while the serum FT
4
 is low or low-normal. Other labora
-
tory abnormalities can include hyponatremia, hypoglyce
-
mia, or anemia (with normal or increased mean corpuscular 
volume). Additional frequent findings include increased 
serum levels of LDL cholesterol, triglycerides, lipoprotein 
(a), liver enzymes, creatine kinase, or PRL. Semen analysis 
shows an increase in abnormal sperm morphology. In 
patients with autoimmune thyroiditis, titers of antibodies 
against thyroperoxidase and thyroglobulin are high; serum 
antinuclear antibodies may be present but are not usually 
indicative of lupus.
 is defined as the state of 
having a normal serum FT
4
 with a serum TSH that is above 
the reference range. It occurs most often in persons aged 65 
years or older, in whom the prevalence is 13%. Subclinical 
hypothyroidism is often transient and the TSH normalizes 
spontaneously in about 35% of cases within 2 years. The 
likelihood of TSH normalization is higher in patients without 
antithyroid antibodies and those with a marginally elevated 
serum TSH. The term “subclinical” is somewhat misleading, 
since it does not refer to patients’ symptoms but rather refers 
only to serum hormone levels; in fact, such patients can have 
subtle manifestations of hypothyroidism (eg, fatigue, depres
-
sion, hyperlipidemia) that may improve with a trial of levo
-
thyroxine replacement. Patients without such symptoms do 
not require levothyroxine therapy but must be monitored 
regularly for the emergence of symptoms.
A retrospective analysis of 1954 patients aged 65 years 
and older with subclinical hypothyroidism found a thresh
-
old serum TSH above 6.38 milli-international units/L was 
associated with increased mortality; however, it is uncer
-
tain whether levothyroxine therapy reduces mortality risk 
in this group.
C. Imaging
Radiologic imaging is usually not necessary for patients 
with hypothyroidism. However, on CT or MRI, a goiter 
may be noted in the neck or in the mediastinum (retroster
-
nal goiter). An enlarged thymus is frequently seen in the 
mediastinum in cases of autoimmune thyroiditis. On MRI, 
the pituitary is often quite enlarged in primary hypothy
-
roidism, due to hyperplasia of TSH-secreting cells, which is 
reversible following thyroid therapy; concomitant hyperp
-
rolactinemia can lead to the mistaken diagnosis of a TSH-
secreting or PRL-secreting pituitary adenoma.
 
»
The differential diagnosis for subclinical hypothyroidism

-
 
»
The differential diagnosis for subclinical hypothyroidism 
includes antibody interference with the serum TSH assay, 
macro-TSH, sleep deprivation, exercise, recovery from 
nonthyroidal illness, acute psychiatric emergencies, and 
other conditions and medications that can cause a low 
serum T
4
 or high serum TSH in the absence of hypothy
-
roidism (Table 26–3).
Euthyroid sick syndrome
 should be considered in 
patients without known thyroid disease who are found to 
have a low serum FT
4
 with a serum TSH that is not ele
-
vated. This syndrome can be seen in patients with severe 
illness, caloric deprivation, or major surgery. Serum TSH 
tends to be suppressed in severe nonthyroidal illness, mak
-
ing the diagnosis of concurrent primary hypothyroidism 
quite difficult, although the presence of a goiter suggests 
The clinician must decide whether such severely ill 
patients (with a low serum T
4
 but no elevated TSH) 
might have hypothyroidism due to hypopituitarism. 
Patients without symptoms of prior brain lesion or hypo
-
pituitarism are very unlikely to suddenly develop hypopi
-
tuitarism during an unrelated illness. Patients with 
diabetes insipidus, hypopituitarism, or other signs of a 
central nervous system (CNS) lesion may be given T
4
 
empirically.
Patients receiving prolonged dopamine infusions can 
develop true secondary hypothyroidism caused by dopa
-
mine’s direct suppression of TSH-secreting cells.
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»
Patients with severe hypothyroidism have an increased 
susceptibility to bacterial pneumonia. Megacolon has been 
described in long-standing hypothyroidism. Organic psy
-
choses with paranoid delusions may occur (“myxedema 
madness”). Rarely, adrenal crisis may be precipitated by 
thyroid therapy. Hypothyroidism is a rare cause of infertil
-
ity, which may respond to thyroid replacement. Untreated 
hypothyroidism during pregnancy often results in miscar
-
riage. Preexistent coronary artery disease and heart failure 
may be exacerbated by levothyroxine therapy.
Myxedema crisis
 refers to severe, life-threatening man
-
ifestations of hypothyroidism. Myxedema crisis particu
-
larly affects elderly women and can occur spontaneously in 
severely hypothyroid patients with prolonged exposure to 
the cold, with resultant hypothermia. It can also be induced 
by a stroke, heart failure, infection (particularly pneumo
-
nia), or trauma. Metabolism of drugs is slowed in hypothy
-
roidism and myxedema crisis is often precipitated by the 
administration of sedatives, antidepressants, hypnotics, 
anesthetics, or opioids. The drugs further impair cognition 
and respiratory drive and can precipitate respiratory arrest. 
Affected patients have impaired cognition, ranging from 
confusion to somnolence to coma (myxedema coma). 
Convulsions and abnormal CNS signs may occur. Patients 
have profound hypothermia, hypoventilation, hyponatre
-
mia, hypoglycemia, hypoxemia, hypercapnia, and hypoten
-
sion. Rhabdomyolysis and acute kidney injury may occur. 
The mortality rate is high.
 
»
Treatment
Before beginning therapy with thyroid hormone, the hypo
-
thyroid patient requires at least a clinical assessment for 
adrenal insufficiency and angina. The presence of either 
condition requires further evaluation and management.
A. Treatment for Hypothyroidism
Synthetic levothyroxine is the preferred preparation for 
treating hypothyroid patients. However, some clinicians 
prescribe mixtures of levothyroxine and triiodothyronine 
for certain patients. Otherwise healthy young and middle-
aged adults with hypothyroidism may be treated initially 
with levothyroxine in average doses of about 1.6 mcg/kg/
day. Lower doses can be used for very mild hypothyroid
-
ism, while full doses are given for more symptomatic hypo
-
thyroidism. During pregnancy, women with mild 
hypothyroidism may be treated with initial levothyroxine 
doses of about  75–100 mcg daily. Pregnant women with 
overt hypothyroidism or myxedema should be treated 
immediately with levothyroxine at full replacement doses 
of 1.6 mcg/kg/day (about 100–150 mcg daily).  Thyroid 
function testing is repeated every 4–6 weeks during preg
-
nancy, with levothyroxine doses being adjusted to nor
-
malize the serum TSH and restore euthyroidism. For 
initial titration, the levothyroxine dosage may be 
increased according to clinical response and serum TSH, 
measuring serum TSH every 4–6 weeks and trying to 
keep the serum TSH level between 0.4 milli-international 
units/L and 2.0 milli-international units/L. However, some 
patients receiving levothyroxine replacement continue to 
feel hypothyroid despite having a serum TSH in the target 
range and may require higher replacement doses. Bedtime 
levothyroxine administration results in somewhat higher 
serum T
4
 and lower TSH levels than morning administra
-
tion. Therefore, the administration timing for levothyroxine 
should be kept constant. After beginning daily administra
-
tion, significant increases in serum T
4
 levels are seen within 
1–2 weeks, and near-peak levels are seen within 3–4 weeks.
Patients with stable coronary artery disease
 or those 
who are over age 60 years are treated with smaller initial 
doses of levothyroxine, 25–50 mcg orally daily; higher initial 
doses may be used if such patients are severely hypothyroid. 
The dose can be increased by 25 mcg every 1–3 weeks until

The dose can be increased by 25 mcg every 1–3 weeks until 
the patient is euthyroid. Ideally, patients with hypothyroid
-
ism and unstable coronary artery disease or uncontrolled 
atrial fibrillation should begin levothyroxine replacement 
following medical or interventional therapy.
 requires larger initial doses of levo
-
thyroxine intravenously, since myxedema itself can inter
-
fere with intestinal absorption of oral levothyroxine. 
Levothyroxine sodium 500 mcg is given intravenously as a 
loading dose, followed by 50–100 mcg intravenously daily; 
the lower dose is given to patients with suspected coronary 
artery disease. In patients with myxedema coma, liothyro
-
nine (T
3
, Triostat) can be given intravenously with a load
-
ing dose of 10–20 mcg, followed by 10 mcg every 4–6 hours 
for the first 48 hours. The hypothermic patient is warmed 
only with blankets, since faster warming can precipitate 
cardiovascular collapse. Hypoglycemic patients are given 
5% dextrose intravenously. Hyponatremic patients with a 
serum sodium 120–130 mEq/mL are administered 0.9% 
NaCl intravenously, while patients with a serum sodium 
below 120 mEq/mL are treated with boluses of 3% NaCl 
100 mL intravenously with intravenous furosemide 
20–40 mg to promote water diuresis; serum sodium levels 
must be followed closely and boluses of 3% NaCl can be 
repeated about every 6 hours until the serum sodium rises 
to 120 mmol/L or higher. When giving intravenous saline 
to myxedematous patients, care must be taken to avoid 
fluid overload.
Patients with hypercapnia require mechanical assis
-
tance with ventilation. Opioid medications must be stopped 
or used in very low doses. Infections must be detected and 
treated aggressively. Patients in whom concomitant adrenal 
insufficiency is suspected are treated with hydrocortisone, 
100 mg intravenously, followed by 25–50 mg every 8 hours.
B. Monitoring and Optimizing 
 
Treatment of Hypothyroidism
Regular clinical and laboratory monitoring is critical to 
determine the optimal levothyroxine dose for each patient. 
The initial goal should be to normalize the serum TSH 
within 1–2 months of commencing thyroid replacement 
therapy. The patient should be prescribed sufficient levothy
-
roxine to restore a clinically euthyroid state; this can usually 
be attained by maintaining the serum TSH, FT
4
 and FT
3
 
within their reference ranges. However, when patients take 
levothyroxine replacement in doses sufficient to normalize 
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serum TSH levels, their serum FT
3
 levels are lower and 
serum FT
4
 levels are higher, on average, than matched 
euthyroid individuals not taking levothyroxine. Perhaps for 
that reason, a significant number of patients taking levothy
-
roxine continue to feel hypothyroid while taking levothyrox
-
ine, despite having a normal serum TSH. Unless 
contraindicated by unstable angina, such patients may be 
carefully administered a slightly higher dose of levothyrox
-
ine that suppresses the serum TSH while achieving clinical 
euthyroidism and a serum FT
3
 near the low-normal range. 
For most patients with hypothyroidism, an ideal stable 
maintenance dose of levothyroxine can usually be found.
Different levothyroxine preparations vary in their bio
-
availability by up to 14% and such differences may have a 
subtle but significant clinical impact. It is optimal for 
patients to consistently take the same manufacturer’s brand 
of levothyroxine.
Pregnancy
 usually increases the levothyroxine dosage 
requirement; an increase in levothyroxine requirement has 
been noted as early as the fifth week of pregnancy. Ade
-
quate levothyroxine is critical to the health of the fetus. 
Therefore, it is prudent to increase levothyroxine dosages 
by approximately 20–30% as soon as pregnancy is con
-
firmed. The fetus is at least partially dependent on mater
-
nal T
4
 for its CNS development—particularly in the second 
trimester. By mid-pregnancy, women require an average of 
47% increase in their levothyroxine dosage. Postpartum, 
levothyroxine replacement requirement ordinarily returns 
to prepregnancy level.
Decreased levothyroxine dose requirements
 occur in 
women after delivery, after bilateral oophorectomy or natu
-
ral menopause, after cessation of oral estrogen replace
-
ment, or during therapy with GnRH agonists. Levothyroxine 
dosage may need to be titrated downward for patients who 
start taking teduglutide for short bowel syndrome.
1. Elevated serum TSH level—
This usually indicates 
underreplacement with levothyroxine. However, before 
increasing the T
4
 dosage, it is important to confirm that the 
patient is taking the levothyroxine as directed and does not 
have coronary insufficiency.
Increased levothyroxine dosage requirements (low 
serum T
4
 levels) can occur with drugs that increase the 
hepatic metabolism of levothyroxine (Table 26–3). Amio
-
darone can increase or decrease thyroxine dose require
-
ments. Malabsorption of thyroxine can be caused by 
coadministration of binding substances, such as iron (eg, 
in multivitamins); fiber; raloxifene; sucralfate; aluminum 
hydroxide antacids; sevelemer; orlistat; soy milk; bile acid–
binding resins (cholestyramine and colesevelam); and cal
-
cium, magnesium, and soy protein supplements.
Proton pump inhibitors interfere slightly with the 
absorption of levothyroxine. Gastrointestinal disorders can 
interfere with thyroxine absorption, including celiac disease, 
inflammatory bowel disease, lactose intolerance, 
Helico
-
 gastritis, and atrophic gastritis. Nephrotic syn
-
drome can increase the required dose of oral levothyroxine. 
Women with hypothyroidism may require increased doses 
of levothyroxine after commencing oral estrogen therapy.
Serum TSH may be elevated transiently in acute psychi
-
atric illness, with antipsychotics and phenothiazines, and 
during recovery from nonthyroidal illness. Autoimmune 
disease can cause false elevations of TSH by interfering 
with the assay. Very rarely, a high TSH can be caused by a 
thyrotropin-secreting pituitary tumor or hyperplasia.
2. Normal serum TSH level—
Most patients may be given 
levothyroxine in doses sufficient to achieve a serum TSH in 
the low-normal range. However, for patients with coronary 
artery disease or recurrent atrial fibrillation, it may be pru
-
dent to administer lower doses of levothyroxine to keep 
their serum TSH in the high-normal range or even at a

-
their serum TSH in the high-normal range or even at a 
slightly elevated level.
About 10% of otherwise healthy treated hypothyroid 
patients (taking levothyroxine with a normal serum TSH) 
continue to have hypothyroid-type symptoms, such as leth
-
argy, weight gain, depression, or cognitive problems. An 
even larger percentage has been found to have subtle but 
significantly reduced psychological wellbeing, compared to 
gender-matched and age-matched euthyroid controls. Such 
patients must be assessed for concurrent conditions, such 
as an adverse drug reaction, Addison disease, depression, 
hypogonadism, anemia, celiac disease, or gluten sensitivity. 
If such conditions are not present or are treated and hypo
-
thyroid-type symptoms persist, a serum T
3
 or free T
3
 level 
is often helpful. Low serum T
3
 levels may reflect inadequate 
peripheral deiodinase activity to convert inactive T
4
 to 
active T
3
. Such patients may be given a careful clinical trial 
of a slightly higher dose of levothyroxine that results in a 
low serum TSH and a low-normal serum T
3
 or free T
3
.
For such patients, some clinicians have found success 
with other strategies, such as using desiccated natural por
-
cine thyroid preparations containing both T
4
 and T
3
 (eg, 
Armour Thyroid, Nature-Throid, NP Thyroid). For prod
-
uct conversion purposes, 100 mcg of levothyroxine is 
equivalent to about 65 mg (1 grain) of desiccated thyroid. 
The use of desiccated thyroid preparations has been dis
-
couraged by several professional medical societies, but 
some patients prefer them.
3. Low or suppressed serum TSH level—
A serum TSH level 
below the reference range (adults 0.4–4.0 milli-international 
units/L) is either “low” (0.1–0.39 milli-international units/L) 
or “suppressed” (less than 0.1 milli-international units/L). 
Clinically euthyroid patients receiving levothyroxine who 
have “low” TSH levels do not have increased morbidity. 
However, a “suppressed” serum TSH often indicates overre
-
placement with levothyroxine and such patients may have 
symptoms of hyperthyroidism and have an increased risk for 
atrial fibrillation, osteoporosis, and clinical hyperthyroid
-
ism. When the serum TSH is suppressed, the dosage of 
levothyroxine is reduced. However, some patients feel 
unmistakably hypothyroid while taking the reduced dose 
of levothyroxine and have low serum T
3
 or free T
3
 levels. 
For such patients, a higher levothyroxine dose may be 
resumed with close surveillance for atrial fibrillation, 
osteoporosis, and manifestations of subtle hyperthyroid
-
ism. A suppressed serum TSH can also occur with hypopi
-
tuitarism, severe nonthyroidal illness, and certain 
medications (eg, nonsteroidal anti-inflammatory drugs 
[NSAIDs], opioids, nifedipine, verapamil, and high-dose 
[short-term] corticosteroids).
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»
Prognosis
Patients with mild hypothyroidism caused by Hashimoto 
thyroiditis have a remission rate of 11%. Hypothyroidism 
caused by interferon-alpha resolves within 17 months of 
stopping the drug in 50% of patients. With levothyroxine 
treatment of hypothyroidism, striking transformations take 
place both in appearance and mental function. Return to a 
normal state is usually the rule, but relapses will occur if 
treatment is interrupted. However, untreated patients with 
myxedema crisis have a mortality rate approaching 100%; 
even with optimal treatment, the mortality rate is 20–50%.
 
»
•	
Difficulty titrating levothyroxine replacement to nor
-
mal TSH or clinically euthyroid state.
•	
Any patient with significant coronary artery disease 
needing levothyroxine therapy.
 
»
•	
Suspected myxedema crisis.
•	
Hypercapnia.
De Groot L et al. Management of thyroid dysfunction during 
pregnancy and postpartum: an Endocrine Society clinical 
practice guideline. J Clin Endocrinol Metab. 2012 
Aug;97(8):2543–65. [PMID: 22869843]
Jonklaas J et al. Guidelines for the treatment of hypothyroidism: 
prepared by the American Thyroid Association Task Force on 
Thyroid Hormone Replacement. Thyroid. 2014 
Dec;24(12):1670–751. [PMID: 25266247]
Okosieme O et al. Management of primary hypothyroidism: 
statement by the British Thyroid Association executive com
-
mittee. Clin Endocrinol (Oxf). 2016 Jun;84(6):799–808. 
[PMID: 26010808]
Peeters RP . Subclinical hypothyroidism. N Engl J Med. 2017 Jun 29;
 
376(26):2556–65. [PMID: 28657873]
Peterson SJ et al. Is a normal TSH synonymous with “euthyroid
-
ism” in levothyroxine monotherapy? J Clin Endocrinol Metab. 
2016 Dec;101(12):4964–73. [PMID: 27700539]
Rabin AS et al. Clinical problem-solving. Springing a leak. 
N Engl J Med. 2015 Oct;373(14):1362–7. [PMID: 26422727]
Salomo LH et al. Myxoedema coma: an almost forgotten, yet still 
existing cause of multiorgan failure. BMJ Case Rep. 2014 Jan 
30;2014:2013203223. [PMID: 24481020]
HYPERTHYROIDISM (
)
 
»
Sweating, weight loss or gain, anxiety, palpita
-
tions, loose stools, heat intolerance, fatigue, men
-
strual irregularity.
 
»
Tachycardia; warm, moist skin; stare; tremor.
 
»
Graves disease: 
majority have a palpable goiter 
(sometimes with bruit); ophthalmopathy.
 
»
Suppressed TSH in primary hyperthyroidism; usu
-
ally increased T
4
, FT
4
, T
3
, FT
3
.
 
»
The term “thyrotoxicosis” refers to the clinical manifesta
-
tions associated with elevated serum levels of T
4
 or T
3
 that 
are excessive for the individual (hyperthyroidism). Serum 
TSH levels are suppressed in primary hyperthyroidism. 
However, certain drugs and conditions can affect labora
-
tory tests and lead to the erroneous diagnosis of hyperthy
-
roidism in euthyroid individuals (Table 26–4). The causes 
of hyperthyroidism are many and diverse, as described 
below.
A. Graves Disease
Graves disease (known as Basedow disease in Europe) is 
the most common cause of thyrotoxicosis. It is an autoim
-
mune disorder affecting the thyroid gland, characterized 
by an increase in synthesis and release of thyroid hor
-
mones; autoantibodies known as thyroid-stimulating 
immunoglobulins (TSI) or TSH receptor antibodies bind 
to the TSH receptor in thyroid cell membranes and stimu
-
late the gland to hyperfunction.
Table 26–4.
 
Factors that can cause aberrations in 
laboratory tests that may be mistaken for spontaneous 
clinical primary hyperthyroidism.
1
High Serum T
4
 or T
3
Low Serum TSH
Collection vial contains gel 
barrier for T
3
Acute psychiatric problems (30%)
Acute medical illness (eg, acute 
intermittent porphyria)
Acute or chronic active hepatitis, 
primary biliary cirrhosis
AIDS (increased thyroid-binding 
globulin)
Autoimmunity
Familial resistance to thyroid 
(Refetoff syndrome)

globulin)
Pregnancy: morning sickness, 
hyperemesis gravidarum
Drugs
 
Biotin supplemen
ts
 
Estr
ogens (oral)
 
Heparin 
(dialysis method)
 
Heroin
 
Methadone
 
Tamoxifen
 
T
hyroid hormone therapy 
 
(
excessive or factitious)
TSH variants not detected by 
commercial assays
Autonomous thyroid or 
thyroid nodule
Acute corticosteroid 
administration
Biotin supplements
Elderly euthyroid
hCG-secreting trophoblastic 
tumors
Nonthyroidal illness (severe)
Pregnancy (especially with 
morning sickness)
Drugs
 
C
alcium channel blockers 
 
(nif
edipine, verapamil)
 
Dopamine
 
D
opamine agonists
 
T
hyroid hormone
1
True clinical hyperthyroidism may coexist.
hCG, human chorionic gonadotropin; NSAIDs, nonsteroidal 
anti-inflammatory drugs; T
4
3
, triiodothyronine; 
TSH, thyroid-stimulating hormone.
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Graves disease is much more common in women than 
in men (8:1), and its onset is usually between the ages of 
20 and 40 years. It may be accompanied by infiltrative oph
-
thalmopathy (Graves exophthalmos) and, less commonly, 
by infiltrative dermopathy (pretibial myxedema). The 
thymus gland is typically enlarged and serum antinuclear 
antibody levels are usually elevated. Many patients with 
Graves disease have a family history of either Graves dis
-
ease or autoimmune (Hashimoto) thyroiditis.
Dietary iodine supplementation can trigger Graves 
disease. An increased incidence of Graves disease occurs in 
countries that have embarked on national programs to 
fortify commercial salt with potassium iodide; the increase 
in Graves disease lasts about 4 years. Similarly, patients 
being treated with potassium iodide or amiodarone (which 
contains iodine) have an increased risk of developing 
Graves disease.
Chemotherapy with immune checkpoint inhibitors 
(ipilimumab, pembrolizumab, tremelimumab, and atezoli
-
zumab) can precipitate Graves disease, which must be dis
-
tinguished from hyperthyroidism from destructive 
autoimmune thyroiditis (silent thyroiditis), which can be 
caused by these same medications.
Patients with Graves disease have an increased risk of 
other systemic autoimmune disorders, including Sjögren 
syndrome, celiac disease, pernicious anemia, Addison dis
-
ease, alopecia areata, vitiligo, type 1 diabetes mellitus, hypo
-
parathyroidism, myasthenia gravis, and cardiomyopathy.
B. Toxic Multinodular Goiter and Thyroid Nodules
Autonomous hyperfunctioning thyroid nodules that pro
-
duce hyperthyroidism are known as toxic multinodular 
goiter (Plummer disease) and are more prevalent among 
older adults and in iodine-deficient regions. A single 
hyperfunctioning nodule can also produce hyperthyroid
-
ism. Toxic multinodular goiter and Graves disease may 
sometimes coexist in the same gland (Marine-Lenhart 
syndrome). Thyroid cancer is found in about 4.7% of 
patients with toxic multinodular goiter.
C. Postpartum, Subacute, and Silent Thyroiditis
These conditions cause thyroid inflammation with release 
of stored hormone. They all produce a variable triphasic 
course: variable hyperthyroidism is followed by transient 
euthyroidism, and progresses to hypothyroidism.
Postpartum thyroiditis
 refers to autoimmune thyroid
-
itis that occurs in the first 12 months postpartum and 
occasionally after miscarriages. See Thyroiditis, above. 
About 22% of affected women experience hyperthyroidism 
followed by hypothyroidism, whereas 30% of such women 
have isolated thyrotoxicosis and 48% have isolated hypo
-
thyroidism. The thyrotoxic phase typically occurs 2–6 weeks 
postpartum and lasts 2–3 months. Over 80% have antithy
-
roid antibodies. Most women progress to a hypothyroid 
phase that usually lasts a few months but that can be 
permanent.
 is also known as “de Quervain” or 
“granulomatous” thyroiditis. It is typically caused by vari
-
ous viral infections. Women are affected four times more 
frequently than men. Patients typically experience a viral 
upper respiratory infection and develop an enlarged and 
extremely painful thyroid. About 50% of affected patients 
experience a symptomatic thyrotoxic phase that lasts 
3–6 weeks. It is important to differentiate subacute 
thyroiditis from infectious (suppurative bacterial) thyroid
-
itis. About 10% remain hypothyroid after 1 year. The recur
-
rence rate is 1–4%.
Silent thyroiditis
 is also known as subacute lympho
-
cytic thyroiditis or “Hashitoxicosis. ” It can occur spontane
-
ously; women are affected four times more frequently than 
men. About 50% have antithyroid antibodies. Silent thy
-
roiditis can also be caused by chemotherapeutic agents 
(such as tyrosine kinase inhibitors; denileukin diftitox; 
alemtuzumab; interferon-alpha; interleukin-2; and 
immune checkpoint inhibitors). Other drugs can cause

immune checkpoint inhibitors). Other drugs can cause 
silent thyroiditis, including lithium and amiodarone. In 
those with spontaneous silent thyroiditis, about 10–20% 
remain hypothyroid after 1 year. There is a recurrence rate 
of 5–10%; this rate is higher in Japan.
D. Medication-Induced Hyperthyroidism
1. Amiodarone-induced thyrotoxicosis—
Amiodarone is 
37% iodine by weight. The half-life of amiodarone and its 
metabolites is about 100 days. In the short term, amioda
-
rone normally increases the serum TSH, though usually 
not over 20 milli-international units/L (see Thyroiditis, 
above). Serum T
4
 and FT
4
 rise about 40% and may become 
frankly elevated in clinically euthyroid patients. Mean
-
while, serum T
3
 levels decline. Due to these short-term 
changes, it is best to not check thyroid function tests during 
the first 3 months of therapy with amiodarone, unless clini
-
cally indicated. After about 3 months, the serum TSH usu
-
ally normalizes. Since serum T
4
 levels can be misleadingly 
high, the serum TSH level must be suppressed to diagnose 
amiodarone-induced thyrotoxicosis. With amiodarone-
induced thyrotoxicosis, the serum T
3
 or FT
3
 is usually high 
or high-normal. In the United States, amiodarone causes 
thyrotoxicosis in about 3% of patients taking the drug. In 
Europe and iodine-deficient geographic areas, amiodarone 
induces thyrotoxicosis in about 20%. Thyrotoxicosis can 
occur suddenly at any time during treatment and may even 
develop several months after it has been discontinued. The 
manifestations of amiodarone-induced thyrotoxicosis can 
be missed, particularly since amiodarone tends to cause 
bradycardia. Therefore, thyroid function tests (TSH, FT
4
, T
3
) 
should be checked before starting amiodarone, again at 
3–6 months, and then every 6 months (or sooner if clini
-
cally indicated).
Amiodarone-induced thyrotoxicosis is categorized as 
type 1 or type 2; about 27% are mixed type 1–2. 
Type 1
 is 
caused by the 
active
 production of excessive thyroid hor
-
mone. 
Type 2
 is caused by thyroiditis with the 
passive
 
release of stored thyroid hormone.
2. Iodine-induced hyperthyroidism—
This is also known 
as 
Jod-Basedow disease
. The recommended iodine intake 
for nonpregnant adults is 150 mcg/day. Higher iodine 
intake can precipitate hyperthyroidism in patients with 
nodular goiters, autonomous thyroid nodules, or 
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asymptomatic Graves disease, and less commonly in 
patients with no detectable underlying thyroid disorder. 
Common sources of excess iodine include intravenous 
iodinated radiocontrast dye, certain foods (eg, kelp, nori), 
topical iodinated antiseptics (eg, povidine iodine), and 
medications (eg, amiodarone or potassium iodide). Intra
-
venous iodinated radiocontrast dye can rarely induce a 
painful, destructive subacute thyroiditis, similar to type 2 
amiodarone-induced thyrotoxicosis.
3. Tyrosine kinase inhibitors—
Silent thyroiditis that 
releases stored thyroid hormone, resulting in hyperthy
-
roidism, develops in about 3.2% of patients receiving che
-
motherapy with tyrosine kinase inhibitors (eg, axitinib, 
sorafenib, sunitinib). While this hyperthyroidism may be 
subclinical, thyrotoxic crisis has been reported. Hypothy
-
roidism usually follows hyperthyroidism and overall occurs 
in 19% of patients taking these drugs.
4. Immune checkpoint inhibitor cancer therapy—
Immune checkpoint inhibitor therapy directed against 
either PD-1/PD-L1 or CTLA-4/B7-1/B7-2 can be effective 
against certain malignancies but frequently precipitates 
autoimmune adverse reactions. Thyroid autoimmunity 
commonly causes thyroiditis, hypothyroidism (primary or 
secondary), or hyperthyroidism from either passive release 
of thyroid hormone or active production of thyroid hor
-
mone (Graves disease), in whom ophthalmopathy has been 
observed.
E. Pregnancy, hCG-Secreting Trophoblastic Tumors, 
and Testicular Choriocarcinoma
Human chorionic gonadotropin (hCG) can bind to the 
thyroid’s TSH receptors, so very high levels of serum hCG, 
particularly during the first 4 months of pregnancy, may 
cause sufficient receptor activation to cause hyperthyroid
-
ism. About 18% of pregnant women have a low serum TSH 
during pregnancy, but only about 10% of such women have 
clinical hyperthyroidism that requires treatment. Pregnant 
women are more likely to have hCG-induced thyrotoxico
-
sis if they have high levels of serum asialo-hCG, a subfrac
-
tion of hCG that has a greater affinity for TSH receptors. 
Such women are also more likely to suffer from hypereme
-
sis gravidarum. This condition must be distinguished from 
true Graves disease in pregnancy, which usually predates 
conception and may be associated with high serum levels 
of TSI and antithyroid antibodies or with exophthalmos.
High levels of hCG can also cause thyrotoxicosis in 
some cases of pregnancies with gestational trophoblastic 
disease (molar pregnancy, choriocarcinoma). Some such 
pregnancies have produced thyrotoxic crisis. Men have 
developed hyperthyroidism from high levels of serum hCG 
secreted by a testicular choriocarcinoma.
F. Rare Causes of Hyperthyroidism
Thyrotoxicosis factitia
 is due to intentional or accidental 
ingestion of excessive amounts of exogenous thyroid hor
-
mone. 
Struma ovarii
 refers to thyroid tissue contained in 
about 3% of ovarian dermoid tumors and teratomas. 
Pituitary TSH hypersecretion
 by a pituitary thyrotrophe 
tumor or hyperplasia can rarely cause hyperthyroidism. 
Serum TSH is elevated or inappropriately normal in the 
presence of true thyrotoxicosis. Pituitary hyperplasia may 
be detected on an MRI as a pituitary enlargement without 
a discrete adenoma being visible. 
Metastatic functioning 
thyroid carcinoma
 can cause hyperthyroidism in patients 
with a heavy tumor burden. 
Recombinant human 
thyroid-stimulating hormone (rhTSH)
 can rarely induce 
hyperthyroidism when it is given prior to radioiodine 
therapy or scanning for metastatic differentiated thyroid 
cancer.
 
»
Thyrotoxicosis due to any cause can produce nervousness, 
restlessness, heat intolerance, increased sweating, palpita
-
tions, pruritus, fatigue, muscle weakness, muscle cramps, 
frequent bowel movements, weight change (usually loss), 
or menstrual irregularities. There may be fine resting fin
-

-
-
ger tremors, moist warm skin, fever, hyperreflexia, fine 
hair, and onycholysis. Angina or atrial fibrillation may also 
be present, sometimes in the absence of other thyrotoxic 
symptoms 
(apathetic hyperthyroidism).
 Women with 
postpartum thyroiditis
 are often asymptomatic or experi
-
ence only minor symptoms, such as palpitations, heat 
intolerance, and irritability. Chronic thyrotoxicosis may 
cause osteoporosis. Even subclinical hyperthyroidism (sup
-
pressed serum TSH with normal FT
4
) may increase the risk 
of nonvertebral fractures. Clubbing and swelling of the 
fingers (acropachy) develop rarely. Tetany is a rare present
-
ing symptom; hyperthyroidism causes an increased renal 
excretion of magnesium, resulting in functional hypopara
-
thyroidism and hypocalcemia. 
Thyroid examination
 in 
patients with Graves disease usually reveals a diffusely 
enlarged thyroid, frequently asymmetric, often with a 
bruit. However, there may be no palpable thyroid enlarge
-
ment. The thyroid gland in subacute thyroiditis is usually 
moderately enlarged and tender. There is often dysphagia 
and pain that can radiate to the jaw or ear. In patients with 
toxic multinodular goiter, the thyroid usually has palpable 
nodules. Patients with silent thyroiditis or postpartum thy
-
roiditis have either no palpable goiter or a small, nontender 
goiter. 
Cardiopulmonary manifestations
 of thyrotoxicosis 
commonly include a forceful heartbeat, premature atrial 
contractions, and sinus tachycardia. Patients often have 
exertional dyspnea. Atrial fibrillation or atrial tachycardia 
occurs in about 8% of patients with thyrotoxicosis, more 
commonly in men, older adults, and those with ischemic 
or valvular heart disease. The ventricular response from 
the atrial fibrillation may be difficult to control. Thyrotoxi
-
cosis itself can cause a thyrotoxic cardiomyopathy, and the 
onset of atrial fibrillation can precipitate heart failure. 
Echocardiogram reveals pulmonary hypertension in 49% 
of patients with hyperthyroidism; of these, 71% have pul
-
monary artery hypertension while 29% have pulmonary 
venous hypertension. Even “subclinical hyperthyroidism” 
increases the risk for atrial fibrillation and overall mortal
-
ity. Hemodynamic abnormalities and pulmonary hyper
-
tension are reversible with restoration of euthyroidism.
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Thyrotoxic crisis or “storm”
 is an extreme form of 
severe thyrotoxicosis that is an immediate threat to life. It 
may be triggered by stressful illness, thyroid surgery, or 
RAI administration. Its manifestations typically include 
marked agitation or delirium, very high fever, severe tachy
-
cardia, vomiting, diarrhea, and dehydration. Cardiac 
arrhythmias, heart failure, and myocardial infarction are 
possible complications.
Eye manifestations
 that occur with hyperthyroidism of 
any etiology include: upper eyelid retraction, lid lag with 
downward gaze, and a staring appearance. See Thyroid Eye 
Disease, Chapter 7. Thyroid-associated ophthalmopathy 
with exophthalmos is clinically apparent in 20–40% of 
patients with Graves disease and some cases of amiodarone-
induced thyrotoxicosis. Aggravation of Graves eye disease 
has occurred after treatment with radioiodine or during 
therapy with thiazolidinediones (eg, pioglitazone). About 
5–10% of patients experience more severe exophthalmos, 
with the eye being pushed forward by increased retro-orbital 
fat and eye muscles that have been thickened by lymphocytic 
infiltration. Such patients can experience diplopia from 
extraocular muscle entrapment. The severity of eye disease 
is not closely correlated with the severity of thyrotoxicosis.
Exophthalmometry should be performed on all patients 
with Graves disease to document their degree of exoph
-
thalmos and detect progression of orbitopathy. The protru
-
sion of the eye beyond the orbital rim is measured with a 
prism instrument (Hertel exophthalmometer). Maximum 
normal eye protrusion varies between kindreds and races, 
being about 24 mm for blacks, 20 mm for whites, and 
18 mm for Asians.
It is important to determine whether thyroid-associated 
orbitopathy is in an acute stage of inflammation versus a 
stable “burned out” stage with exophthalmos. It is also 
important to distinguish active eye disease from congenital 
proptosis or asymmetry in orbital protrusion.
Graves dermopathy (pretibial myxedema)
 occurs in 
about 3% of patients with Graves disease. It usually affects 
the pretibial region, but can also affect the dorsal forearms 
and wrists and dorsum of the feet. It is more common in 
patients with high levels of serum TSI and severe Graves 
ophthalmopathy. Glycosaminoglycans accumulation and 
lymphoid infiltration occur in affected skin, which becomes 
erythematous with a thickened, rough texture. Elephantia
-
sis of the legs is a rare complication.
Thyroid acropachy
 is an extreme and unusual manifes
-
tation of Graves disease. It presents with digital clubbing, 
swelling of fingers and toes, and radiographic findings of 
periostitis involving phalangeal and metacarpal bones. 
Extremity skin can become very thickened, resembling 
elephantiasis. Thyroid acropachy is ordinarily associated 
with ophthalmopathy and thyroid dermopathy. Most 
affected patients are smokers.
Hyperthyroidism during pregnancy
 has a prevalence 
of about 0.2%. It may commence before conception or 
emerge during pregnancy, particularly the first trimester. 
Manifestations include many of the features of normal 
pregnancy: tachycardia, warm skin, heat intolerance, 
increased sweating, and a palpable thyroid. Pregnancy can 
have a beneficial effect on the thyrotoxicosis of Graves 
disease, with decreasing antibody titers and decreasing 
serum T
4
 levels as the pregnancy advances; about 30% of 
affected women experience a remission by late in the sec
-
ond trimester. However, undiagnosed or undertreated 
hyperthyroidism in pregnancy carries an increased risk of 
miscarriage, preeclampsia-eclampsia, preterm delivery, 
abruptio placenta, maternal heart failure, and thyrotoxic 
crisis (thyroid storm) (see Thyroid Disease, Chapter 19). 
Such thyrotoxic crisis can be precipitated by trauma, infec
-
tion, surgery, or delivery and confers a fetal/maternal mor
-
tality rate of about 25%.

-
-
 occurs in about 15% 
of Asian or Native American men with thyrotoxicosis. It 
usually presents abruptly with symmetric flaccid paralysis 
(and few thyrotoxic symptoms), often after intravenous 
dextrose, oral carbohydrate, or vigorous exercise. Attacks 
last 7–72 hours.
Serum FT
4
, T
3
, FT
3
, T
4
, thyroid resin uptake, and FT
4
 index 
are all usually increased. Sometimes the FT
4
 level may be 
normal but with an elevated serum T
3
 (T
3
 toxicosis). The 
severity of the elevation of serum FT
4
 and FT
3
 levels does 
not always correlate with the severity of thyrotoxic mani
-
festations; patients with thyrotoxic crisis tend to have 
serum thyroid levels that are not significantly higher than 
those with less pronounced symptoms. Serum T
3
 can be 
misleadingly elevated when blood is collected in tubes 
using a gel barrier, which causes certain immunoassays to 
report falsely elevated serum total T
3
 levels in 24% of nor
-
mal patients. Serum T
4
 or T
3
 can be elevated in other non
-
thyroidal conditions (Table 26–4).
Serum TSH is suppressed in hyperthyroidism (except 
in the very rare cases of pituitary inappropriate secretion of 
thyrotropin). Serum TSH may be misleadingly low in other 
nonthyroidal conditions (Table 26–4). The term 
“subclini
-
cal hyperthyroidism”
 is used to describe asymptomatic 
individuals with a low serum TSH but normal serum levels 
of FT
4
 and T
3
.
Hyperthyroidism can cause hypercalcemia, increased 
liver enzymes, increased alkaline phosphatase, anemia, and 
decreased neutrophils. Hypokalemia and hypophosphate
-
mia occur in thyrotoxic periodic paralysis. Hyperthyroid
-
ism also increases urinary magnesium excretion, which 
can lead to hypomagnesemia, resulting in functional hypo
-
parathyroidism with hypocalcemia.
Problems of diagnosis occur in patients with acute psy
-
chiatric disorders; about 30% of these patients have ele
-
vated serum T
4
 levels without clinical thyrotoxicosis. The 
TSH is not usually suppressed, distinguishing psychiatric 
disorder from true hyperthyroidism. T
4
 levels return to 
normal gradually.
In 
Graves disease
, serum TSI (TSHrAb) is usually 
detectable (65%). Antithyroperoxidase or antithyroglobulin 
antibodies are usually elevated but are nonspecific. Serum 
antinuclear antibodies are also usually elevated without any 
evidence of SLE or other rheumatologic disease.
With 
subacute thyroiditis
, patients often have an 
increased WBC, ESR, and C-reactive protein. About 25% 
have antithyroid antibodies (usually in low titer) and 
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serum TSI (TSHrAb) levels are normal. Patients with 
iodine-induced hyperthyroidism also have undetectable 
serum TSI (or TSHrAb), an absence of serum antithyro
-
peroxidase antibodies, and an elevated urinary iodine 
concentration. In thyrotoxicosis factitia, serum thyroglob
-
ulin levels are low, distinguishing it from other causes of 
With 
hyperthyroidism during pregnancy
, women 
have an elevated serum total T
4
 and FT
4
 while the TSH is 
suppressed. However, about 18% of normal pregnant 
women have a low serum TSH. An apparent lack of full 
TSH suppression in hyperthyroidism can be seen due to 
misidentification of hCG as TSH in certain assays. The 
serum FT
4
 assay is difficult in pregnancy. Although the 
serum T
4
 is elevated in most pregnant women, values over 
20 mcg/dL (257 nmol/L) are encountered only in hyper
-
thyroidism. On treatment, serum total T
4
 levels during 
pregnancy should be kept at about 1.5 × the pre-pregnancy 
level. The T
3
 resin uptake, which is low in normal preg
-
nancy because of high thyroxine-binding globulin (TBG) 
concentration, is normal or high in thyrotoxic persons.
Since high levels of T
4
 and FT
4
 are normally seen in 
patients taking 
amiodarone, a
 suppressed TSH must be 
present along with a greatly elevated T
4
 (greater than 
20 mcg/dL [257 nmol/L]) or T
3
 (greater than 200 ng/dL 
[3.1 nmol/L]) in order to diagnose hyperthyroidism. In 
type 1 amiodarone-induced thyrotoxicosis, the presence of 
proptosis and serum TSI (TSHrAb) is diagnostic. In type 2 
amiodarone-induced thyrotoxicosis, serum levels of inter
-
leukin-6 (IL-6) are usually quite elevated.
C. Radioisotope Uptake and Imaging
Note:
 
All radioisotope testing is contraindicated during 
pregnancy or breastfeeding.
Radioiodine (RAI)
 uptake and scanning can be helpful 
in determining the cause of hyperthyroidism. RAI uptake 
and scanning is not necessary for diagnosis in patients with 
obvious Graves disease who have elevated serum TSI or 
associated Graves ophthalmopathy. Women should ideally 
have the RAI scan extended to include the pelvis in order 
to screen for concomitant struma ovarii (rare). A high RAI 
uptake is seen in Graves disease and toxic nodular goiter. 
type 1 amiodarone-induced thyrotoxicosis
 
have RAI uptake that is usually detectable. A low RAI 
uptake is also characteristic of iodine-induced hyperthy
-
roidism and thyroiditis (subacute, silent, or postpartum), 
distinguishing them from Graves disease. In 
type 2 
 
amiodarone-induced thyrotoxicosis
, thyroid RAI uptake 
is usually below 3%.
Patients with Graves disease have increased or normal 
uptake of 
technetium (Tc-99m) pertechnetate
, whereas 
those with thyrotoxicosis from thyroiditis (silent, subacute, 
postpartum) have reduced uptake. Technetium (Tc-99m) 
pertechnetate mimics radioiodine scanning but is more 
convenient, costs less, and confers less radiation exposure.
Thyroid ultrasound
 can be helpful in patients with 
hyperthyroidism, particularly in patients with palpable 
thyroid nodules. Thyroid ultrasound shows a variably het
-
erogeneous, hypoechoic gland in thyroiditis. 
Color flow 
Doppler sonography
 is helpful to distinguish type 1 
amiodarone-induced thyrotoxicosis (normal to increased 
blood flow velocity and vascularity) from type 2 amiodarone-
induced thyrotoxicosis (reduced vascularity).
99mTc-sestamibi scanning
 usually shows normal or 
increased uptake with type 1 amiodarone-induced thyro
-
toxicosis and decreased uptake in type 2.
MRI and CT scanning
 of the orbits are the imaging 
methods of choice to visualize Graves ophthalmopathy 
affecting the extraocular muscles. Imaging is required only 
in severe or unilateral cases or in euthyroid exophthalmos 
that must be distinguished from orbital pseudotumor, 
tumors, and other lesions.
 
»
True thyrotoxicosis must be distinguished from those con
-
ditions that elevate serum T

»
-
4
 and T
3
 or suppress serum 
TSH without affecting clinical status (see Table 26–4). 
Serum TSH is commonly suppressed in early pregnancy 
and only about 10% of pregnant women with a low TSH 
have clinical hyperthyroidism.
Some states of hypermetabolism without thyrotoxicosis—
notably severe anemia, leukemia, polycythemia, cancer, 
and pheochromocytoma—rarely cause confusion. Acro
-
megaly may also produce tachycardia, sweating, and thy
-
roid enlargement. Appropriate laboratory tests will easily 
distinguish these entities.
The differential diagnosis for thyroid-associated oph
-
thalmopathy includes an orbital tumor (eg, lymphoma) or 
pseudotumor. Ocular myasthenia gravis is another autoim
-
mune condition that occurs more commonly in Graves 
disease but is usually mild, often with unilateral eye 
involvement. Acetylcholinesterase receptor antibody 
(AChR Ab) levels are elevated in only 36% of such patients, 
and a thymoma is present in 9%.
Diabetes mellitus and Addison disease may coexist with 
thyrotoxicosis and can aggravate the weight loss, fatigue, 
and muscle weakness seen with hyperthyroidism.
 
»
Hypercalcemia, osteoporosis, and nephrocalcinosis may 
occur in hyperthyroidism. Decreased libido, erectile dys
-
function, diminished sperm motility, and gynecomastia 
may be noted in men. Other complications include cardiac 
arrhythmias and heart failure, thyroid crisis, ophthalmopa
-
thy, dermopathy, and thyrotoxic hypokalemic periodic 
 
»
Treatment
A. Treatment of Graves Disease
1. Propranolol—
Propranolol is generally used for symp
-
tomatic relief of tachycardia, tremor, diaphoresis, and anxi
-
ety until the hyperthyroidism is resolved. It is the initial 
treatment of choice for thyrotoxic crisis and effectively 
treats thyrotoxic hypokalemic periodic paralysis. Propran
-
olol has no effect on thyroid hormone secretion. Treatment 
is usually begun with propranolol ER 60 mg orally once or 
twice daily, with dosage increases every 2–3 days to a maxi
-
mum daily dose of 320 mg. Propranolol ER is initially 
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given every 12 hours for patients with severe hyperthyroid
-
ism, due to accelerated metabolism of the propranolol; it 
may be given once daily as hyperthyroidism improves.
2. Thiourea drugs—
Methimazole or propylthiouracil is 
generally used for young adults or patients with mild thy
-
rotoxicosis, small goiters, or fear of isotopes. See Treatment 
of Hyperthyroidism during Pregnancy-Planning, Preg
-
nancy, and Lactation, below. Elderly patients usually 
respond particularly well. These drugs are also useful for 
preparing hyperthyroid patients for surgery and elderly 
patients for RAI treatment. When thiourea therapy is dis
-
continued, there is a high recurrence rate for hyperthyroid
-
ism (about 50%). A better likelihood of long-term remission 
is seen in patients with small goiters, mild hyperthyroid
-
ism, those requiring small doses of thiourea, and those 
with serum TSI (TSHrAb) less than 2 milli-units/L. Patients 
whose antithyroperoxidase and antithyroglobulin antibod
-
ies remain high after 2 years of therapy have been reported 
to have only a 10% rate of relapse. Some clinicians advocate 
RAI or surgery for patients with Graves disease who con
-
tinue to require thiourea therapy after 1 year. However, 
there should be no rush to discontinue thiourea therapy 
that may be continued long term for patients who are tol
-
erating it well.
All patients receiving thiourea therapy must be 
informed of the danger of agranulocytosis or pancytopenia 
and the need to stop the drug and seek medical attention 
immediately with the onset of any infection or unusual 
bleeding. Agranulocytosis (defined as an absolute neutro
-
phil count below 500/mcL) or pancytopenia usually occurs 
abruptly in about 0.4% of patients taking either methima
-
zole or propylthiouracil. Over 70% of agranulocytosis cases 
occur within the first 60 days and nearly 85% within 
90 days of commencing therapy, but continued long-term 
vigilance for this side effect is required. About half the 
cases are discovered because of fever, pharyngitis, or bleed
-
ing, but the other cases are discovered with routine com
-
plete blood cell counts. There is a genetic tendency to 
develop agranulocytosis with thiourea therapy; if a close 
relative has had this adverse reaction, other therapies 
should be considered. Agranulocytosis generally remits 
spontaneously with discontinuation of the thiourea and 
during antibiotic treatment. Recovery has not been 
improved by filgrastim (granulocyte colony-stimulating 
factor [G-CSF]). Surveillance of the WBC can be done 
when blood is drawn to check thyroid levels during the 
first few months of treatment. Such surveillance may be 
helpful, since some cases of agranulocytosis occur gradu
-
ally and many cases may be discovered while the patient is 
still asymptomatic.
Other side effects common to thiourea drugs include 
pruritus, allergic dermatitis, nausea, and dyspepsia. Anti
-
histamines may control mild pruritus without discontinu
-
ation of the drug. Since the two thiourea drugs are similar, 
patients who have a major allergic reaction to one should 
not be given the other.
The patient may become clinically hypothyroid for 
2 weeks or more before TSH levels rise, the pituitary gland 
having been suppressed by the preceding hyperthyroidism. 
Therefore, the patient’s changing thyroid status is best 
monitored clinically and with serum FT
4
 levels. Rapid 
growth of the goiter usually occurs if prolonged hypothy
-
roidism is allowed to develop; the goiter may sometimes 
become massive but usually regresses rapidly with reduc
-
tion or cessation of thiourea therapy or with thyroid hor
-
mone replacement.
a. 
M
ethimazole—
Except during the first trimester of 
pregnancy, methimazole is generally preferred over propyl
-
thiouracil, since methimazole is more convenient to use 
and is less likely to cause fulminant hepatic necrosis. 
Methimazole therapy is also less likely to cause 
131
I treat
-

-
131
I treat
-
ment failure. Methimazole is given orally in initial doses of 
30–60 mg once daily. Some patients with very mild hyper
-
thyroidism may respond well to smaller initial doses of 
methimazole (10–20 mg daily). Methimazole may also be 
administered twice daily to reduce the likelihood of gastro
-
intestinal upset. Rare complications peculiar to methima
-
zole include serum sickness, cholestatic jaundice, alopecia, 
nephrotic syndrome, hypoglycemia, and loss of taste. 
Methimazole use in pregnancy has been associated with an 
increased risk of major fetal anomalies (4.1% vs 2.1% in 
controls). If methimazole is used during pregnancy or 
breastfeeding, the dose should not exceed 20 mg daily. The 
dosage is reduced as manifestations of hyperthyroidism 
resolve and as the FT
4
 level falls toward normal. For 
patients receiving 
131
I therapy, methimazole is discontin
-
ued 4 days prior to receiving the 
131
I and is resumed at a 
lower dose 3 days afterward to avoid recurrence of hyper
-
thyroidism. Following 
131
I therapy, the dose of methima
-
zole is gradually reduced according to frequent thyroid 
function testing; most patients are able to discontinue 
methimazole within 1–3 months following RAI therapy.
b. 
P
ropylthiouracil—
Initially, propylthiouracil is 
given orally in doses of 300–600 mg daily in four divided 
doses. The dosage and frequency of administration are 
reduced as symptoms of hyperthyroidism resolve and the 
FT
4
 level approaches normal. Rare complications peculiar 
to propylthiouracil include arthritis, lupus, aplastic anemia, 
thrombocytopenia, and hypoprothrombinemia. With pro
-
pylthiouracil, acute hepatitis occurs rarely and is treated 
with prednisone. Acute liver failure occurs in about 1 in 
10,000 patients, making this a second-line drug, usually 
reserved for pregnancy, since it is not known to cause fetal 
anomalies. During pregnancy, the dose of propylthiouracil 
is kept below 200 mg/day to avoid goitrous hypothyroidism 
in the infant; the patient may be switched to methimazole 
in the second trimester. Propylthiouracil is preferred 
during breastfeeding since it is not concentrated in the 
milk as much as methimazole. Propylthiouracil is also 
favored during pregnancy, possibly causing fewer problems 
in the newborn.
3. Iodinated contrast agents—
These agents provide effec
-
tive temporary treatment for thyrotoxicosis of any cause. 
Iopanoic acid (Telepaque) or ipodate sodium (Bilivist, 
Oragrafin) is given orally in a dosage of 500 mg twice daily 
for 3 days, then 500 mg once daily. These agents inhibit 
peripheral 5
′
-monodeiodination of T
4
, thereby blocking its 
conversion to active T
3
. Within 24 hours, serum T
3
 levels 
fall an average of 62%. For patients with Graves disease, 
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1145
 
CMDT 2019
methimazole is begun first to block iodine organification; 
the next day, ipodate sodium or iopanoic acid may be 
added. The iodinated contrast agents are particularly use
-
ful for patients who are symptomatically very thyrotoxic. 
They offer a therapeutic option for patients with T
4
 over
-
dosage, subacute thyroiditis, and amiodarone-induced 
thyrotoxicosis; for those intolerant to thioureas; and for 
newborns with thyrotoxicosis (due to maternal Graves 
disease). Treatment periods of 8 months or more are pos
-
sible, but efficacy tends to wane with time. In Graves dis
-
ease, thyroid RAI uptake may be suppressed during 
treatment but typically returns to pretreatment uptake by 
7 days after discontinuation of the drug, allowing 
131
I 
4. Lithium carbonate—
Thioureas are greatly preferred 
over lithium for the medical treatment of hyperthyroidism 
in Graves disease. However, lithium may be used effectively 
in cases of methimazole or PTU-induced hepatic toxicity 
or leukopenia, while the patient receives supportive treat
-
ment. The regimen for lithium carbonate is 500–750 mg/
day orally in divided doses. Lithium should not be used 
during pregnancy. Most patients require concurrent treat
-
ment with propranolol and sometimes prednisone.
5. Radioactive iodine (
131
I, RAI)—
The administration of 
131
I is an excellent method of destroying overactive thyroid 
tissue (either diffuse or toxic nodular goiter). Adolescent 
and adult patients who have been treated with RAI in 
adulthood do not have an increased risk of subsequent 
thyroid cancer, leukemia, or other malignancies. Children 
born to parents previously treated with 
131
I show no 
increase in rates of congenital abnormalities.
Precautions:
 Because radiation is harmful to the fetus 
and children, 
RAI should not be given to pregnant or lactat
-
ing women or to mothers who lack childcare
. 
Women are 
advised to avoid pregnancy for at least 4 months following 
131
I therapy. A pregnancy test should be obtained within 
48 hours before therapy for any woman with childbearing 
potential. Men have been found to have abnormal spermato
-
zoa for up to 6 months following 
131
I therapy and are advised 
to use contraceptive methods during that time
.
Patients may receive 
131
I while being symptomatically 
treated with propranolol ER, which is then reduced in dos
-
age as hyperthyroidism resolves. A higher rate of 
131
I treat
-
ment failure has been reported in patients with Graves 
disease who have been receiving methimazole or propyl
-
thiouracil. However, therapy with 
131
I will usually be effec
-
tive if the methimazole is discontinued at least 3–4 days 
before RAI therapy and if the therapeutic dosage of 
131
I is 
adjusted (upward) according to RAI uptake on the pre
-
therapy scan. Prior to 
131
I therapy, patients are instructed 
against receiving intravenous iodinated contrast and 
should consume a low-iodine diet.
The presence of Graves ophthalmopathy is a relative con
-
traindication to 
131
I therapy
. Following 
131
I treatment for 
hyperthyroidism, Graves ophthalmopathy appears or 
worsens in 15% of patients (23% in smokers and 6% in 
nonsmokers) and improves in none, whereas during treat
-
ment with methimazole, ophthalmopathy worsens in 3% 
and improves in 2% of patients. Among patients receiving 
prednisone following 
131
I treatment, preexistent ophthal
-
mopathy worsens in none and improves in 67%. Therefore, 
patients with Graves ophthalmopathy who are to be treated 
with radioiodine should be considered for prophylactic 
prednisone (20–40 mg/day) for 2 months following admin
-
istration of 
131
I, particularly in patients who have severe 
orbital involvement.
Smoking increases the risk of having a flare in ophthal
-
mopathy following 
131
I treatment and also reduces the 
effectiveness of prednisone treatment. Patients who smoke 
are strongly encouraged to quit prior to RAI treatment.

-
131
are strongly encouraged to quit prior to RAI treatment. 
Smokers receiving RAI should be considered for prophy
-
lactic prednisone (see above).
FT
4
 levels may sometimes drop within 2 months after 
131
I treatment, but then rise again to thyrotoxic levels, at 
which time thyroid RAI uptake is low. This phenomenon is 
caused by a release of stored thyroid hormone from injured 
thyroid cells and does not indicate a treatment failure. In 
fact, serum FT
4
 then falls abruptly to hypothyroid levels.
There is a high incidence of hypothyroidism in the 
months to years after 
131
I, even when low activities are 
given. Patients with Graves disease treated with 
131
I also 
have an increased lifetime risk of developing hyperparathy
-
roidism, particularly when radioiodine therapy was admin
-
istered in childhood or adolescence. Lifelong clinical 
follow-up is mandatory, with measurements of serum TSH, 
FT
4
, and calcium when indicated.
6. Thyroid surgery—
The surgical procedure of choice for 
patients with Graves disease is a total resection of one lobe 
and a subtotal resection of the other lobe, leaving about 4 g 
of thyroid tissue (Hartley–Dunhill operation). Total thy
-
roidectomy of both lobes poses an increased risk of hypo
-
parathyroidism and damage to the recurrent laryngeal 
nerves. See below for surgical treatment of Graves disease 
Patients are ordinarily rendered euthyroid preopera
-
tively with a thiourea drug. Propranolol ER is given orally 
at initial doses of 60–80 mg twice daily and increased every 
2–3 days until the heart rate is less than 90 beats per 
minute. Propranolol is continued until the serum T
3
 
(or free T
3
) is normal preoperatively. If a patient undergoes 
surgery while thyrotoxic, larger doses of propranolol are 
given perioperatively to reduce the likelihood of thyroid 
crisis. Ipodate sodium or iopanoic acid (500 mg orally 
twice daily) may be used in addition to a thiourea to accel
-
erate the decline in serum T
3
. The patient should be euthy
-
roid by the time of surgery.
To reduce thyroid vascularity preoperatively, the patient 
may be treated for 3–10 days preoperatively with oral 
potassium iodide 25–50 mg (eg, ThyroShield 65 mg/mL, 
0.5 mL, or SSKI 1 g/mL, 1 drop) three times daily. However, 
preoperative potassium iodide often increases the volume 
of the thyroid, so the requirement for preoperative potas
-
sium iodide for Graves disease is debatable. Preoperative 
iodide supplementation is not recommended prior to sur
-
gery for multinodular goiter. Alternatively, iodinated 
radiocontrast agents (eg, iopanoic acid 500 mg orally twice 
daily) may be given for 1 week preoperatively.
Surgical morbidity includes possible damage to a 
recurrent laryngeal nerve, with resultant vocal cord 
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paralysis. If both recurrent laryngeal nerves are damaged, 
airway obstruction may develop, and the patient may 
require intubation and tracheostomy. Hypoparathy
-
roidism also occurs; serum calcium levels must be 
checked postoperatively. Patients should be admitted 
for thyroidectomy surgery for at least an overnight obser
-
vation period.
B. Treatment of Toxic Solitary Thyroid Nodules
Toxic solitary thyroid nodules are usually benign but may 
rarely be malignant. If a nonsurgical therapy is elected, the 
nodule should be evaluated with a fine-needle aspiration 
(FNA) biopsy. 
Medical therapy
 for hyperthyroidism caused 
by a single hyperfunctioning thyroid nodule may be treated 
symptomatically with propranolol ER and methimazole or 
propylthiouracil, as in Graves disease (see above). Patients 
who tolerate methimazole well may elect to continue it for 
long-term therapy. The dose of methimazole should be 
adjusted to keep the TSH slightly suppressed, so the risk of 
TSH-stimulated growth of the nodule is reduced. 
Surgery
 
is usually recommended for patients under age 40 years and 
for healthy older patients; they are made euthyroid with a 
thiourea preoperatively and given several days of iodine, 
ipodate sodium, or iopanoic acid before surgery (see 
above). Postoperative hypothyroidism usually resolves 
spontaneously, but permanent hypothyroidism occurs in 
about 14% of patients by 6 years after surgery. 
Radioiodine 
(
131
I) therapy
 may be offered to patients with a toxic soli
-
tary nodule who are over age 40 or in poor health. A preg
-
nancy test should be obtained within 48 before therapy for 
any premenopausal woman. RAI should not be given to 
women with Graves disease within 3 months prior to a 
planned conception. If the patient has been receiving 
methimazole preparatory to 
131
I, the TSH should be kept 
slightly suppressed in order to reduce the uptake of 
131
I by 
the normal thyroid. Nevertheless, permanent hypothyroid
-
ism occurs in about one-third of patients by 8 years after 
131
I therapy. The nodule remains palpable in 50% and may 
grow in 10% of patients after 
131
I.
C. Treatment of Toxic Nodular Goiter
 for patients with toxic nodular goiter con
-
sists of propranolol ER (while hyperthyroid) and a thiourea, 
as in Graves disease. Thioureas (methimazole or propyl
-
thiouracil) reverse hyperthyroidism but do not shrink the 
goiter. There is a 95% recurrence rate if the drug is stopped.
Surgery
 is the definitive treatment for patients with 
large toxic nodular goiter, following therapy with a thio
-
urea to render them euthyroid. Surgery is particularly 
indicated to relieve pressure symptoms or for cosmetic 
indications. Patients with toxic nodular goiter are not 
treated preoperatively with potassium iodide. Total or 
near-total thyroidectomy is recommended, since surgical 
pathology reveals unsuspected differentiated thyroid can
-
cer in 18.3% of cases.
Radioiodine
 
(RAI, 
131
I) therapy
 may be used to treat 
patients with toxic nodular goiter. See 
Precautions
 for RAI 
use, above. Any suspicious nodules should be evaluated 
beforehand for malignancy with FNA cytology. Patients are 
rendered euthyroid with methimazole, which is stopped 
3–4 days before a repeat RAI therapy.
Meanwhile, the patient follows a low-iodine diet in 
order to enhance the thyroid gland’s uptake of RAI, which 
may be relatively low in this condition (compared to 
Graves disease). Relatively high doses of 
131
I are usually 
required; hypothyroidism or recurrent thyrotoxicosis typi
-
cally occurs, so patients must be monitored closely. Pecu
-
liarly, in about 5% of patients with diffusely nodular toxic 
goiter, the administration of 
131
I therapy may induce 
Graves disease. Also, Graves eye disease has occurred 
rarely following 
131
I therapy for multinodular goiter.
D. Treatment of Hyperthyroidism from Thyroiditis

131
131
Patients with thyroiditis (subacute, postpartum, or silent) 
are treated with propranolol during the hyperthyroid 
phase, which usually subsides spontaneously within weeks 
to months. For symptomatic relief, begin propranolol ER 
60–80 mg twice daily and increase every 3 days until the 
heart rate is less than 90 beats per minute. Ipodate sodium 
or iopanoic acid, 500 mg orally daily, promptly corrects 
elevated T
3
 levels and is continued for 15–60 days until the 
serum FT
4
 level normalizes. Thioureas are ineffective, 
since thyroid hormone production is actually low in this 
condition. Patients are monitored carefully for the develop
-
ment of hypothyroidism and treated with levothyroxine as 
needed. With subacute thyroiditis, pain can usually be 
managed with NSAIDs and corticosteroids, but opioid 
analgesics are sometimes required.
E. Treatment of Hyperthyroidism During 
Pregnancy-Planning, Pregnancy, and Lactation
Both men and women with Graves disease who are planning 
pregnancy should not have RAI treatment within about 
4 months of conception. Women who are planning to 
become pregnant are encouraged to consider definitive 
therapy with RAI or surgery well before conception. See 
 for RAI use, above. Dietary iodine must not be 
restricted for such women. There is an increased risk of fetal 
anomalies associated with methimazole in the first trimes
-
ter. Therefore, women who are being treated with a thiourea 
should be treated with propylthiouracil through the first 
trimester and then switched to methimazole. Either thio
-
urea should be given in the smallest dose possible, permit
-
ting mild subclinical hyperthyroidism to occur since it is 
usually well tolerated. About 30% of women with Graves 
disease experience a remission by the late second trimester.
Both propylthiouracil and methimazole cross the pla
-
centa and can induce hypothyroidism, with fetal TSH 
hypersecretion and goiter. Fetal ultrasound at 20–32 weeks 
gestation can visualize any fetal goiter, allowing fetal thy
-
roid dysfunction to be diagnosed and treated. Thyroid 
hormone administration to the mother does not prevent 
hypothyroidism in the fetus, since T
4
 and T
3
 do not freely 
cross the placenta. Fetal hypothyroidism is rare if the 
mother’s hyperthyroidism is controlled with small daily 
doses of propylthiouracil (50–150 mg/day orally) or 
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1147
 
CMDT 2019
methimazole (5–15 mg/day orally). Maternal serum TSI 
levels over 500% at term predict an increased risk of neo
-
natal Graves disease in the infant.
Subtotal thyroidectomy is indicated for pregnant 
women with Graves disease or for fertile women of repro
-
ductive age who are sexually active and decline contracep
-
tives, under the following circumstances: (1) severe adverse 
reaction to thioureas; (2) high dosage requirement for 
thioureas (methimazole greater than or equal to 30 mg/day 
or propylthiouracil greater than or equal to 450 mg/day; 
(3) uncontrolled hyperthyroidism due to nonadherence to 
thiourea therapy. Surgery is best performed during the 
second trimester.
Both methimazole and propylthiouracil are secreted in 
breast milk, but not in amounts that affect the infant’s thy
-
roid hormone levels. No adverse reactions to these drugs 
(eg, rash, hepatic dysfunction, leukopenia) have been 
reported in breast-fed infants. Recommended doses are 
less than or equal to 20 mg orally daily for methimazole 
and less than or equal to 450 mg orally (in divided doses) 
daily for propylthiouracil. It is recommended that the 
medication be taken just after breastfeeding.
F. Treatment of Amiodarone-Induced 
Patients with either type 1 or type 2 amiodarone-induced 
thyrotoxicosis require treatment with propranolol ER for 
symptomatic relief and methimazole 30 mg orally daily. 
After two doses of methimazole, iopanoic acid or sodium 
ipodate may be added to the regimen to further block con
-
version of T
4
 to T
3
; the recommended dosage for each is 
500 mg orally twice daily for 3 days, followed by 500 mg 
once daily until thyrotoxicosis is resolved. If iopanoic acid 
or sodium ipodate is not available, the alternative is potas
-
sium perchlorate; it is given in doses of less than or equal 
to 1000 mg daily (in divided doses) for a course not to 
exceed 30 days in order to avoid the complication of aplas
-
tic anemia. Amiodarone may be withdrawn but this does 
not have a significant therapeutic impact for several 
months. For patients with type 1 amiodarone-induced 
thyrotoxicosis, therapy with 
131
I may be successful, but only 
for those with sufficient RAI uptake. Patients with clear-cut 
type 2 amiodarone-induced thyrotoxicosis are usually also 
treated with prednisone at an initial dose of about 
0.5–0.7 mg/kg orally daily; that dose of prednisone is con
-
tinued for about 2 weeks and then slowly tapered and 
finally withdrawn after about 3 months. Subtotal thyroid
-
ectomy should be considered for patients with amioda
-
rone-induced thyrotoxicosis that is resistant to treatment.
G. Treatment of Complications
1. Thyroid-associated orbitopathy—
131
I treatment can 
“flare” thyroid-associated orbitopathy (see Radioactive 
iodine, above). Thyroid-associated orbitopathy can also be 
aggravated by thiazolidinediones (eg, pioglitazone, rosigli
-
tazone); these oral diabetic agents should be avoided or 
withdrawn in patients with Graves disease. Patients with 
mild orbitopathy may be treated with selenium 100 mcg 
orally twice daily, which may slow its progression.
For active thyroid-associated orbitopathy, therapy with 
intravenous methylprednisolone, begun promptly, is supe
-
rior to oral prednisone. Methylprednisolone is given in 
intravenous pulses, 500 mg weekly for 6 weeks, and then 
250 mg weekly for 6 weeks. Oral prednisone, if chosen for 
treatment must be given promptly in doses of 40–60 mg/
day orally, with dosage reduction over several weeks. 
Higher initial prednisone doses of 80–120 mg/day are used 
when there is optic nerve compression. Prednisone allevi
-
ates acute eye symptoms in 64% of nonsmokers but in only 
14% of smokers.
Patients with corticosteroid-resistant acute Graves oph
-
thalmopathy may also be treated with monoclonal anti
-
body drugs that reduce immune-mediated inflammation. 
Teprotumumab, an experimental drug, or tocilizumab are

-
-
Teprotumumab, an experimental drug, or tocilizumab are 
administered intravenously, whereas rituximab may be 
given by retro-orbital injections.
Progressive active exophthalmos may be treated with 
retrobulbar radiation therapy over 2 weeks to the extraocu
-
lar muscles, avoiding the cornea and lens. Prednisone in 
high doses is given concurrently. Patients who respond well 
to orbital radiation include those with signs of acute 
inflammation, recent exophthalmos (less than 6 months), 
or optic nerve compression. Patients with chronic propto
-
sis and orbital muscle restriction respond less well. Retro
-
bulbar radiation does not cause cataracts or tumors; 
however, it can cause radiation-induced retinopathy (usu
-
ally subclinical) in about 5% of patients overall, mostly in 
patients with diabetes.
For severe cases, orbital decompression surgery may 
save vision, though diplopia often persists postoperatively. 
General eye protective measures include wearing glasses to 
protect the protruding eye and taping the lids shut during 
sleep if corneal drying is a problem. Methylcellulose drops 
and gels (“artificial tears”) may also help. Tarsorrhaphy or 
canthoplasty can frequently help protect the cornea and 
provide improved appearance. Hypothyroidism and hyper
-
thyroidism must be treated promptly.
2. Cardiac complications—
a. 
S
inus tachycardia—
Treatment consists of treating 
the thyrotoxicosis. A beta-blocker such as propranolol is 
used in the interim unless there is an associated 
b. 
A
trial fibrillation—
Hyperthyroidism must be 
treated immediately. Other drugs, including digoxin, beta-
blockers, and anticoagulants, may be required. Electrical 
cardioversion is unlikely to convert atrial fibrillation to 
normal sinus rhythm while the patient is thyrotoxic. Spon
-
taneous conversion to normal sinus rhythm occurs in 62% 
of patients with return of euthyroidism, but that likelihood 
decreases with age. Following conversion to euthyroidism, 
there is a 60% chance that atrial fibrillation will recur, 
despite normal thyroid function tests. Those with persis
-
tent atrial fibrillation may have elective cardioversion fol
-
lowing anticoagulation 4 months after resolution of 
(1) Digoxin—
Digoxin is used to slow a fast ventricular 
response to thyrotoxic atrial fibrillation; it must be used in 
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larger than normal doses. Digoxin doses are reduced as 
hyperthyroidism is corrected. 
(2) Beta-blockers—
Beta-blockers may also reduce the 
ventricular rate, but they must be used with caution—
particularly in patients with heart failure with reduced 
ejection fraction—since their negative inotropic effect may 
precipitate overt heart failure. Therefore, an initial trial of a 
short-duration beta-blocker should be considered, such as 
esmolol intravenously. If a beta-blocker is used, doses of 
digoxin must be reduced. 
(3) Anticoagulants—
The doses of warfarin required in 
thyrotoxicosis are smaller than normal because of an accel
-
erated plasma clearance of vitamin K–dependent clotting 
factors. Higher warfarin doses are usually required as 
hyperthyroidism subsides. Dabigatran malabsorption has 
been reported in thyrotoxicosis-induced diarrhea.
c. 
H
eart failure—
Thyrotoxicosis can cause heart failure 
due to extreme tachycardia, cardiomyopathy, or both. Very 
aggressive treatment of the hyperthyroidism is required in 
either case.
Heart failure may also occur as a result of low-output 
dilated cardiomyopathy. It is uncommon and may be 
caused by an idiosyncratic severe toxic effect of hyperthy
-
roidism upon certain hearts. Cardiomyopathy may occur 
at any age and without preexisting cardiac disease. See 
Chapter 10 for treatment of heart failure and dilated car
-
diomyopathy. The patient should be rendered euthyroid. 
However, the heart failure usually persists despite correc
-
tion of the hyperthyroidism.
d. 
A
pathetic hyperthyroidism
—
Apathetic hyperthy
-
roidism may present with angina pectoris. Treatment is 
directed at reversing the hyperthyroidism as well as provid
-
ing standard antianginal therapy. PCI or CABG can often 
be avoided by prompt diagnosis and treatment.
3. Thyroid crisis or “storm”—
A thiourea drug is given 
(eg, methimazole, 15–25 mg orally every 6 hours or propyl
-
thiouracil, 150–250 mg orally every 6 hours). Ipodate sodium 
(500 mg/day orally) can be helpful if begun 1 hour after the 
first dose of thiourea. Iodide is given 1 hour later as potas
-
sium iodide (10 drops three times daily orally). Propranolol 
is given (cautiously in the presence of heart failure; see above) 
in a dosage of 0.5–2 mg intravenously every 4 hours or 
20–120 mg orally every 6 hours. Hydrocortisone is usually 
given in doses of 50 mg orally every 6 hours, with rapid dos
-
age reduction as the clinical situation improves. Aspirin is 
avoided since it displaces T
4
 from thyroxine-binding globulin 
(TBG), raising FT
4
 serum levels. Definitive treatment with 
131
I or surgery is delayed until the patient is euthyroid.
4. Hyperthyroidism from postpartum thyroiditis—
 
Propranolol ER is given during the hyperthyroid phase fol
-
lowed by levothyroxine during the hypothyroidism phase.
5. Graves dermopathy—
Treatment involves application of 
a topical corticosteroid (eg, fluocinolone) with nocturnal 
plastic occlusive dressings. Compression stockings may 
improve any associated edema.
6. Thyrotoxic hypokalemic periodic paralysis—
Sudden 
symmetric flaccid paralysis, along with hypokalemia and 
hypophosphatemia, can occur with hyperthyroidism 
despite few, if any, of the classic signs of thyrotoxicosis. It is 
most prevalent in Asian and Native Americans with hyper
-
thyroidism and is 30 times more common in men than 
women. Therapy with oral propranolol, 3 mg/kg in divided 
doses, normalizes the serum potassium and phosphate 
levels and reverses the paralysis within 2–3 hours. No 
intravenous potassium or phosphate is ordinarily required. 
Intravenous dextrose and oral carbohydrate aggravate the 
condition and are to be avoided. Therapy is continued with 
propranolol, 60–80 mg orally every 8 hours (or sustained-
action propranolol ER daily at equivalent daily dosage), 
along with a thiourea drug such as methimazole to treat the 
7. Thyroid acropachy—

This rare complication of Graves 
disease is often mild and may not require therapy. More 
severe cases are treated with systemic immunosuppressant 
therapy that may include intravenous immune globulin 
and rituximab.
 
»
Prognosis
Mild or subclinical 
 may sometimes sub
-
side spontaneously. Graves disease that presents in early 
pregnancy has a 30% chance of spontaneous remission 
before the third trimester. The ocular, cardiac, and psy
-
chological complications can become serious and persis
-
tent even after treatment. Permanent hypoparathyroidism 
and vocal cord palsy are risks of surgical thyroidectomy. 
Recurrences are common following thiourea therapy but 
also occur after low-dose 
131
I therapy or subtotal thyroid
-
ectomy. With adequate treatment and long-term follow-
up, the results are usually good. However, despite 
treatment for their hyperthyroidism, women experience 
an increased long-term risk of death from thyroid disease, 
cardiovascular disease, stroke, and fracture of the femur. 
Posttreatment hypothyroidism is common. It may occur 
within a few months or up to several years after RAI 
therapy or subtotal thyroidectomy. Malignant exophthal
-
mos has a poor prognosis unless treated aggressively. 
Patients with thyrotoxic crisis have a high mortality rate 
despite treatment.
Subclinical hyperthyroidism
 generally subsides spon
-
taneously. Progression to symptomatic thyrotoxicosis 
occurs at a rate of 1–2% per year in patients without a 
goiter and at a rate of 5% per year in patients with a multi
-
nodular goiter. Most patients do well without treatment 
and the serum TSH usually reverts to normal within 
2 years. Most such patients do not have accelerated bone 
loss. However, if a baseline bone density shows significant 
osteopenia, bone densitometry may be performed periodi
-
cally. In persons over age 60 years, serum TSH is sup
-
pressed (less than 0.1 milli-international units/L) in 3% 
and mildly low (0.1–0.4 milli-international units/L) in 9%. 
The chance of developing atrial fibrillation is 2.8% yearly in 
elderly patients with very low TSH and 1.1% yearly in those 
with mildly low TSH. Asymptomatic persons with very low 
TSH are monitored closely but are not treated unless atrial 
fibrillation or other manifestations of hyperthyroidism 
develop.
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»
•	
Thyroid crisis.
•	
Hyperthyroidism-induced atrial fibrillation with severe 
•	
Thyroidectomy.
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management of Graves’ orbitopathy. Eur Thyroid J. 2016 
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De Leo S et al. Hyperthyroidism. Lancet. 2016 Aug 27;
 
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[PMID: 26650156]
Smith TJ et al. Graves’ disease. N Engl J Med. 2016 Oct 30;
 
375(16):1552–63. [PMID: 27797318]
Smith TJ et al. Teprotumumab for thyroid-associated oph
-
thalmopathy. N Engl J Med. 2017 May 4;376(1):174–61. 
[PMID: 28467880]
THYROID NODULES & 
MULTINODULAR GOITER
 
»
Single or multiple thyroid nodules are commonly 
palpated by the patient or clinician or discovered 
incidentally on imaging studies.
 
»
Thyroid function tests recommended.
 
»
Thyroid FNA cytology for thyroid nodules 1 cm or 
larger in diameter or for smaller nodules in 
patients with a history of prior head-neck or chest-
shoulder radiation.
 
»
Ultrasound examination useful to assist fine-
needle aspiration cytology and for follow-up.
 
»
Clinical follow-up required.
 
»
Thyroid nodules are extremely common. Palpable nodules 
occur in 4–7% of all adults in the United States. They are 
much more common in women than men and become 
more prevalent with age. About 90% of palpable thyroid 
nodules are benign adenomas, colloid nodules, or cysts, 
but some are primary thyroid malignancies or (less fre
-
quently) metastatic malignancy. The general use of scan
-
ning also incidentally detects nonpalpable thyroid nodules. 
On MRI, incidental small thyroid nodules are found in 
about 50% of adults. Thyroid nodules 1 cm or larger in 
diameter warrant follow-up and further testing for func
-
tion and malignancy. An occasional nodule smaller than 
1 cm in diameter requires follow-up if it has high-risk 
characteristics on ultrasound or if the patient is at high-risk 
for thyroid cancer due to prior head-neck radiation therapy 
during childhood. Thyroid nodules that are incidentally 
discovered with increased standard uptake value (SUV) on 
18
FDG-PET scanning have a 33% risk for being malignant 
and require FNA cytology.
Most patients with a thyroid nodule are euthyroid, but 
there is a high incidence of hypothyroidism or hyperthy
-
roidism. Patients with multiple thyroid nodules have the 
same overall risk of thyroid cancer as patients with solitary 
nodules. The risk of a thyroid nodule being malignant is 
higher in men and among patients with a history of head-
neck radiation, total body radiation for bone marrow 
transplantation, exposure to radioactive fallout as a child 
or teen, a family history of thyroid cancer or a thyroid can
-
cer syndrome (eg, Cowden syndrome, multiple endocrine 
neoplasia type 2, familial polyposis, Carney syndrome), or 
a personal history of another malignancy. The risk of 
malignancy is also higher for large solitary nodules and if 
there is hoarseness or vocal fold paralysis, adherence to the 
trachea or strap muscles, cervical lymphadenopathy. The 
presence of Hashimoto thyroiditis does not reduce the risk 
of malignancy; a nodule of 1 cm or larger in a gland with 
thyroiditis carries an 8% chance of malignancy.
 
»
Table 26–5 illustrates the approach to the evaluation of 
thyroid nodules based on the index of suspicion for 
Most small thyroid nodules cause no symptoms. They may

Most small thyroid nodules cause no symptoms. They may 
sometimes be detected only by having the patient swallow 
during careful inspection and palpation of the thyroid.
A thyroid nodule or multinodular goiter can grow to 
become visible and of concern to the patient. Particularly 
large nodular goiters can become a cosmetic embarrass
-
ment. Nodules can grow large enough to cause discomfort, 
hoarseness, or dysphagia. Nodules that cause ipsilateral 
recurrent laryngeal nerve palsy are more likely to be malig
-
nant. Retrosternal large multinodular goiters can cause 
dyspnea due to tracheal compression. Large substernal 
goiters may cause superior vena cava syndrome, mani
-
fested by facial erythema and jugular vein distention that 
progress to cyanosis and facial edema when both arms are 
kept raised over the head.
Depending on their cause, goiters and thyroid nodules 
may be associated with hypothyroidism (Hashimoto thy
-
roiditis, endemic goiter) or hyperthyroidism (Graves dis
-
ease, toxic nodular goiter, subacute thyroiditis, and thyroid 
cancer with metastases).
A serum TSH is essential. Patients with a subnormal serum 
TSH must have a radionuclide (
123
I or 
99m
Tc pertechnetate) 
thyroid scan to determine whether the nodule is hyperfunc
-
tioning; hyperfunctioning nodules are rarely malignant. 
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Very high levels of antithyroperoxidase antibodies and 
antithyroglobulin antibodies are found in Hashimoto thy
-
roiditis. However, thyroiditis frequently coexists with 
malignancy, so suspicious nodules should always be biop
-
sied. Serum calcitonin is obtained if a medullary thyroid 
carcinoma is suspected in a patient with a family history of 
medullary thyroid carcinoma or MEN types 2 or 3.
C. Imaging
Neck ultrasonography should be performed. The following 
ultrasound characteristics of thyroid nodules increase the 
likelihood of malignancy: irregular or indistinct margins, 
heterogeneous nodule echogenicity, intranodular vascular 
images, microcalcifications, complex cyst, being taller than 
wider, or diameter over 1 cm. Nodules that appear spongi
-
form or cystic are more likely benign. Malignant nodules 
are more likely to grow more than 2 mm/year. Ultrasonog
-
raphy is preferred over CT and MRI. CT scanning is help
-
ful for larger thyroid nodules and multinodular goiter; it 
can determine the degree of tracheal compression and the 
degree of extension into the mediastinum.
RAI (
123
I or 
131
I) scans are not helpful for assessing 
whether a thyroid nodule is benign or malignant. Hyper
-
functioning (hot) nodules are ordinarily benign (but may 
rarely be malignant). RAI uptake and scanning is helpful 
mainly for assessing the etiology of hyperthyroidism (eg, 
hyperfunctioning nodule).
D. Incidentally Discovered Thyroid Nodules
Thyroid nodules are frequently discovered as an incidental 
finding, with an incidence that depends on the imaging 
modality: Ultrasound, about 30% (20% are larger than 
1 cm in diameter); MRI, 50%; CT, 13%; and 
18
FDG-PET, 
2%. When MRI, CT, and 
18
FDG-PET detect a thyroid 
nodule, an ultrasound is performed to better determine the 
nodule’s risk for malignancy and the need for FNA cytol
-
ogy, and to establish a baseline for ultrasound follow-up. 
The malignancy risk is about 13–17% for nodules discov
-
ered incidentally on CT, MRI, or ultrasound and 25–50% 
for nodules discovered incidentally by 
18
FDG-PET. How
-
ever, most such malignancies are very low grade. For inci
-
dentally discovered thyroid nodules of borderline concern, 
follow-up thyroid ultrasound in 3–6 months may be help
-
ful; growing lesions should be assessed with FNA cytology 
or resected.
E. Fine-Needle Aspiration of Thyroid Nodules
FNA is the best method to assess a thyroid nodule for 
malignancy. FNA can be done while patients continue tak
-
ing anticoagulants or aspirin. For multinodular goiters, the 
four largest nodules (1 cm or larger in diameter) are usually 
biopsied to minimize the risk of missing a malignancy.
Thyroid nodules have been classified for malignancy 
risk according to their appearance on ultrasound. High-
risk nodules (80% malignancy risk) have microcalcifica
-
tions, irregular margins, extrathyroidal extension, 
extrusion of soft tissue into a calcified rim, or are taller 
than wide; such nodules require FNA if they are 1 cm or 
larger in diameter. Intermediate-risk nodules (15% malig
-
nancy risk) are hypoechoic and solid; they also usually 
require FNA if they are 1 cm or larger in diameter. Low-
risk nodules (7% malignancy risk) are partially cystic with 
eccentric solid areas; they require biopsy if they are 1.5 cm 
or larger in diameter. Very low-risk nodules (below 3% 
malignancy risk) are those that are spongiform or simple 
cysts; FNA is optional if they are 2 cm or larger in diameter. 
Using ultrasound guidance for FNA biopsy improves the 
diagnostic accuracy for both palpable and nonpalpable 
thyroid nodules. FNA cytology is typically reported using 
The Bethesda System for Reporting Thyroid Cytopathol
-
ogy (TBSRTC), which divides results into six categories:
Table 26–5.
 
Clinical evaluation of thyroid nodules.
1
Clinical Evidence
Low Index of Suspicion
High Index of Suspicion
History
Family history of goiter; residence in area of 
endemic goiter

1
History
Previous therapeutic radiation of head, neck, or 
chest; hoarseness
Physical characteristics
Older women; soft nodule; multinodular goiter
Young adults, men; solitary, firm nodule; vocal 
cord paralysis; enlarged lymph nodes; distant 
metastatic lesions
Serum factors
High titer of anti-thyroperoxidase antibody; 
hypothyroidism; hyperthyroidism
Elevated serum calcitonin
Fine-needle aspiration biopsy
Colloid nodule or adenoma
Papillary carcinoma, follicular lesion, medullary or 
anaplastic carcinoma
Scanning techniques
Uptake of 
123
I
Hot nodule
Cold nodule
Ultrasonogram
Cystic lesion
Solid lesion
Radiograph
Shell-like calcification
Punctate calcification
Response to thyroxine therapy
Regression after 0.05–0.1 mg/day for 6 months 
or more
Increase in size
1
Clinically suspicious nodules should be evaluated with fine-needle aspiration biopsy.
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1.
 
Nondiagnostic or unsatisfactory:
 The malignancy risk 
is 1–4%. The usual management is a repeat FNA under 
ultrasound guidance.
2.
 
Benign:
 The malignancy risk is about 2.5%. The usual 
management is clinical follow-up with palpation or 
ultrasound at 6–18 month intervals.
3.
 
Atypia of undetermined significance (AUS):
 The 
malignancy risk is about 14%, higher with sonographic 
features of malignancy. The usual management is clini
-
cal correlation and a repeat FNA.
4.
 
Suspicious for follicular neoplasm (SFN) or follicular 
neoplasm (FN):
 The malignancy risk is about 25%, 
higher when Hürthle cells are present and in patients 
over age 50. The usual management is usually direct 
surgical lobectomy.
5.
 
Suspicious for malignancy (SFM):
 The malignancy 
risk is about 70%. The usual management is usually 
direct thyroid lobectomy or near-total thyroidectomy.
6.
 
Malignant:
 The malignancy risk is about 99%. The 
usual management is a near-total thyroidectomy.
 
»
Treatment
All thyroid nodules, including those that are benign, need 
to be monitored by regular periodic palpation and ultra
-
sound about every 6 months initially. After several years of 
stability, yearly examinations are sufficient. Thyroid nod
-
ules should be rebiopsied if growth occurs. A toxic multi
-
nodular goiter and hyperthyroidism may develop in patients 
who have had exposure to large amounts of iodine, either 
orally (eg, amiodarone) or intravenously (eg, radiographic 
contrast). Therefore, excessive iodine intake should be 
minimized. Patients found to have hyperthyroidism may 
have a RAI uptake and scan, especially if 
131
I is a therapeutic 
consideration. Patients with toxic multinodular goiters may 
also be treated with methimazole, propranolol, or surgery.
A. Levothyroxine Suppression Therapy
Patients with elevated levels of serum TSH are treated with 
levothyroxine replacement. Patients with nodules larger 
than 2 cm and elevated or normal TSH levels may be con
-
sidered for TSH suppression with levothyroxine (starting 
doses of 50 mcg orally daily). Levothyroxine suppression 
therapy is not recommended for small benign thyroid nod
-
ules if the serum TSH level is normal. Thyroxine suppres
-
sion therapy is more successful in iodine-deficient areas of 
the world. Long-term levothyroxine suppression of TSH 
tends to keep nodules from enlarging but only 20% shrink 
more than 50%. Thyroid nodule size increased in 29% of 
patients treated with levothyroxine versus 56% of patients 
not receiving levothyroxine. Levothyroxine suppression 
also reduces the emergence of new nodules: 8% with levo
-
thyroxine and 29% without levothyroxine. Levothyroxine 
suppression therapy is not usually given to patients with 
ischemic heart disease, since it increases the risk for angina 
and atrial fibrillation. Levothyroxine suppression causes a 
small loss of bone density, particularly in postmenopausal 
women if the serum TSH is suppressed to less than 
0.05 milli-international units/L. Such patients are advised 
to have bone density testing every 3–5 years. For patients 
with a low baseline TSH level, levothyroxine should not be 
administered, since that is an indication of autonomous 
thyroid secretion; levothyroxine will be ineffective and 
could cause thyrotoxicosis.
Levothyroxine suppression needs to be carefully moni
-
tored, since it carries a 17% risk of inducing hyperthyroid
-
ism. All patients receiving levothyroxine suppression therapy 
should have serum TSH levels monitored at least annually, 
with the levothyroxine dose adjusted to keep the serum TSH 
mildly suppressed (between 0.1 milli-international units/L 
and 0.8 milli-international units/L).
B. Surgery
Total thyroidectomy is required for thyroid nodules that are 
malignant on FNA biopsy. More limited thyroid surgery is 
indicated for benign nodules with indeterminate or suspi
-
cious cytologic test results, compression symptoms, dis
-

-
-
comfort, or cosmetic embarrassment. Surgery may also be 
used to remove hyperfunctioning “hot” thyroid adenomas 
or toxic multinodular goiter causing hyperthyroidism.
C. Percutaneous Ethanol Injection
Percutaneous ethanol injection can shrink pure cysts; the 
success rate is 80%, although it must often be repeated. 
Percutaneous ethanol injection can also be used to shrink 
biopsy-proven benign nodules. While complications occur 
in about 9%, serious or permanent complications are rare. 
Thyroid cysts can be aspirated, but cystic fluid recurs in 
75% of patients.
D. Radioiodine (
131
I) Therapy
Radioactive 
131
I is a treatment option for hyperthyroid 
patients with toxic thyroid adenomas, multinodular goiter, 
or Graves disease. See 
 for RAI use, above. 
Therapy with 
131
I shrinks benign nontoxic thyroid nodules 
by an average of 40% by 1 year and 59% by 2 years after 
131
I 
therapy. Nodules that shrink after 
131
I therapy generally 
remain palpable and become firmer; they may develop 
unusual cytologic characteristics on FNA biopsy. 
131
I 
therapy may be used to shrink large multinodular goiters 
but may rarely induce Graves disease. Hypothyroidism 
may occur years after 
131
I therapy, so it is advisable to assess 
thyroid function every 3 months for the first year, every 
6 months thereafter, and immediately for symptoms of 
hypothyroidism or hyperthyroidism.
 
»
Prognosis
Benign thyroid nodules may involute but usually persist or 
grow slowly. About 90% of thyroid nodules will increase their 
volume by 15% or more over 5 years; about 11% of nodules 
increase their volume by more than 50% on follow-up. 
Growth is more common with multinodular goiter and 
larger nodules and in men; nodules are less likely to grow 
when they are solitary or cystic and when patients are over 
age 60. Multinodular goiters tend to persist or grow slowly. 
Cytologically benign nodules that grow are unlikely to be 
malignant; in one series, only 1 of 78 rebiopsied nodules was 
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found to be malignant. The risk of a given thyroid nodule 
being malignant decreases with age. The prognosis for 
patients with malignant thyroid nodules is determined by the 
histologic type and other factors, such as age. Thyroid can
-
cers tend to be more aggressive in children and in adults over 
age 45 years. Iodine supplementation in iodine-deficient 
areas does not usually shrink established goiters. Patients 
with very small (less than 1 cm diameter), incidentally dis
-
covered, nonpalpable thyroid nodules that have a benign 
ultrasound appearance require no FNA cytology and only 
yearly palpation and clinical follow-up, whereas such small 
nodules that have a slightly suspicious ultrasound appear
-
ance may require FNA cytology or thyroid ultrasound every 
1–2 years. Such nodules, if malignant and excised, have a 
minimal effect upon morbidity and mortality.
Angell TE et al. Differential growth rates of benign vs. malignant 
thyroid nodules. J Clin Endocrinol Metab. 2017 Dec 1;
 
102(12):4642–7. [PMID: 29040691]
Burman KD et al. Clinical practice. Thyroid nodules. N Engl J 
Med. 2015 Dec 10;373(24):2347–56. [PMID: 26650154]
Cohen RN et al. Management of adult patients with thyroid 
nodules and differentiated thyroid cancer. JAMA. 2017 Jan 24;
 
317(4):434–5. [PMID: 28118436]
Durante C et al. The natural history of benign thyroid nodules. 
JAMA. 2015 Mar;313(9):926–35. [PMID: 25734734]
Straccia P et al. A meta-analytic review of the Bethesda System 
for Reporting Thyroid Cytopathology: has the rate of malig
-
nancy in indeterminate lesions been underestimated? Cancer 
Cytopathol. 2015 Dec;123(12):713–22. [PMID: 26355876]
THYROID CANCER
 
»
Painless swelling in region of thyroid.
 
»
Thyroid function tests usually normal.
 
»
Possible history of childhood irradiation to head 
and neck region.
 
»
Positive thyroid FNA cytology.
 
»
The incidence of differentiated (papillary and follicular) 
thyroid carcinomas increases with age (Table 26–6). The 
overall female:male ratio is 3:1. The yearly incidence of 
thyroid cancer has been increasing in the United States, 
with the number of cases diagnosed annually reaching 
37,200, probably as a result of the wider use of ultrasound, 
CT, MRI, and PET that incidentally find small thyroid 
malignancies. Thyroid cancer mortality has been stable, 
accounting for about 1500 deaths in the United States 
annually. Clearly, the increasing incidence of thyroid can
-
cer has been mainly due to overdiagnosis; however, some 
true increase in cancer incidence is possible. In routine 
autopsy series, thyroid papillary microcarcinoma (10 mm 
diameter or smaller) is found with the surprising frequency 
of 11.5%. Most thyroid cancers remain microscopic and 
indolent. However, larger thyroid cancers (palpable or 
greater than or equal to 1 cm in diameter) are more malig
-
nant and require treatment.
Pure papillary (and mixed papillary-follicular) carci
-
noma
 comprises about 80% of all thyroid cancers. It usually 
presents as a single thyroid nodule, but it can arise out of a 
multinodular goiter. Papillary thyroid carcinoma is com
-
monly multifocal within the gland, with other foci usually 
arising de novo rather than representing intraglandular 
metastases. The tumor involves both lobes in 30% of patients.
Papillary thyroid carcinoma is generally the least 
aggressive thyroid malignancy. It tends to grow slowly and 
often remains confined to the thyroid and regional lymph 
nodes for years. In about 80% of patients, there are micro
-
scopic metastases to cervical lymph nodes. However, the 
malignancy may become more aggressive, especially in 
patients over age 45 years, and most particularly in older 
adults. The cancer may invade the trachea and local mus
-
cles and may spread to the lungs.
Exposure to head and neck radiation therapy poses a 
particular threat to children who then have an increased

-
particular threat to children who then have an increased 
lifetime risk of developing thyroid cancer, including papil
-
lary carcinoma. These cancers may emerge between 10 and 
40 years after exposure, with a peak occurrence 20–25 years 
later.
Table 26–6.
 
Some characteristics of thyroid cancer.
Papillary
Follicular
Medullary
Anaplastic
Incidence
Common
Uncommon
Uncommon
Average age
42
50
50
57
Females
70%
72%
56%
56%
Invasion
 
Juxtanodal
+++++
+
++++++
+++
 
Blood v
essels
+
+++
+++
+++++
 
Distan
t sites
+
+++
++
++++
123
I uptake
+
++++
0
0
10-year disease-specific survival
97%
92%
78%
7.3%
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Papillary thyroid carcinoma can occur in familial syn
-
dromes as an autosomal dominant trait, caused by loss of 
various tumor suppressor genes.
Microscopic “micropapillary” carcinoma (1 mm or 
smaller and invisible on thyroid ultrasound) is a variant of 
normal, being found in 24% of thyroidectomies performed 
for benign thyroid disease when 2-mm sections were care
-
fully examined. Thus, the overwhelming majority of these 
microscopic foci never become clinically significant. The 
surgical pathology report of such a tiny papillary carci
-
noma does not justify aggressive measures. All that may be 
required is yearly follow-up with palpation of the neck and 
mild TSH suppression by thyroxine.
Follicular thyroid carcinoma
 and its variants (eg, 
Hürthle cell carcinoma) account for about 14% of thyroid 
malignancies; follicular carcinomas are generally more 
aggressive than papillary carcinomas. Most follicular thy
-
roid carcinomas avidly absorb iodine, making possible 
diagnostic scanning and treatment with 
131
I after total 
thyroidectomy. The follicular histopathologic features that 
are associated with a high risk of metastasis and recurrence 
are poorly differentiated and Hürthle cell (oncocytic) vari
-
ants. The latter variants do not take up RAI.
Medullary thyroid carcinoma
 represents 2–3% of thy
-
roid cancers. About one-third of cases are sporadic, one-
third are familial, and one-third are associated with MEN 
type 2A or 2B. Medullary thyroid carcinoma is often 
caused by an activating mutation of the 
ret
 protooncogene 
on chromosome 10. Mutation analysis of the 
ret
 protoon
-
cogene exons 10, 11, 13, 14, and 16 detects most mutations 
causing MEN 2A, MEN2B, and the mutations causing 
familial medullary thyroid carcinoma. These germline 
mutations can be detected by DNA analysis of peripheral 
WBCs. Therefore, discovery of a medullary thyroid carci
-
noma makes genetic analysis mandatory. If a gene defect is 
discovered, related family members must have genetic 
screening for that specific gene defect. When a family 
member with MEN 2 or 3 or familial medullary thyroid 
carcinoma does not have an identifiable 
ret
mutation, gene carriers may still be identified using family 
linkage analysis. Even when no gene defect is detectable, 
family members should have thyroid surveillance every 
6 months. Medullary thyroid carcinoma arises from thy
-
roid parafollicular cells that can secrete calcitonin, prosta
-
glandins, serotonin, ACTH, corticotropin-releasing 
hormone (CRH), and other peptides. These peptides can 
cause symptoms and can be used as tumor markers.
Anaplastic thyroid carcinoma
 represents about 2% of 
thyroid cancers. It usually presents in an older patient as a 
rapidly enlarging mass in a multinodular goiter. It is the 
most aggressive thyroid carcinoma and metastasizes early 
to surrounding nodes and distant sites. This tumor does 
not concentrate iodine.
Other thyroid malignancies
 together represent about 
3% of thyroid cancers. 
Primary thyroid lymphomas
 are 
most commonly diffuse large B-cell lymphomas (50%), 
mucosa-associated lymphoid tissue lymphoma (23%), or 
mixed type; other types include follicular, small lympho
-
cytic, and Burkitt lymphoma and Hodgkin disease. Thy
-
roidectomy is rarely required. 
Other cancers
 may sometimes 
metastasize to the thyroid, particularly bronchogenic, 
breast, and renal carcinomas and malignant melanoma.
 
»
Thyroid carcinoma usually presents as a palpable, firm, non
-
tender nodule in the thyroid. Most thyroid carcinomas are 
asymptomatic, but large thyroid cancers can cause neck 
discomfort, dysphagia, or hoarseness (due to pressure on the 
recurrent laryngeal nerve). 
Papillary thyroid cancer
 pres
-
ents with palpable lymph node involvement in 10%; it may 
invade the trachea and local muscles. Occult metastases to 
the lung occur in 10–15%.

 pres
-
the lung occur in 10–15%. 
 
commonly metastasizes to neck nodes, bones, and lung, but 
nearly every organ can be involved. Metastatic functioning 
differentiated thyroid carcinoma can sometimes secrete 
enough thyroid hormone to produce thyrotoxicosis.
 typically metastases to 
local nodes and adjacent muscle and trachea as well as 
mediastinal lymph nodes. Eventually, metastases may 
appear in the bones, lungs, adrenals, or liver. Medullary 
thyroid carcinoma frequently causes flushing and persis
-
tent diarrhea (30%), which may be the initial clinical fea
-
ture. Patients with metastases often experience fatigue as 
well as other symptoms. Cushing syndrome develops in 
about 5% of patients from secretion of ACTH or CRH.
 is more apt to be 
advanced at the time of diagnosis, presenting with signs of 
pressure or invasion of surrounding tissue, resulting in 
dysphagia, hoarseness, or recurrent laryngeal nerve palsy. 
Patients may also have dyspnea with metastases to the 
lungs. 
Lymphoma
 usually presents as a rapidly enlarging, 
painful mass arising out of a multinodular or diffuse goiter 
affected by autoimmune thyroiditis, with which it may be 
confused microscopically. About 20% of cases have con
-
comitant hypothyroidism.
FNA biopsy is discussed in Thyroid Nodules, above. 
Thyroid function tests
 are generally normal unless there is 
concomitant thyroiditis. Follicular carcinoma may secrete 
enough T
4
 to suppress TSH and cause clinical 
Serum thyroglobulin
 is high in most metastatic papil
-
lary and follicular tumors, making this a useful marker for 
recurrent or metastatic disease. Caution must be exercised 
for the following reasons: (1) Circulating antithyroglobulin 
antibodies can cause erroneous thyroglobulin determina
-
tions. However, declining levels of antithyroglobulin anti
-
bodies are a good prognostic sign after treatment. 
(2) Thyroglobulin levels may be misleadingly elevated in 
thyroiditis, which often coexists with carcinoma. (3) Certain 
thyroglobulin assays falsely report the continued presence 
of thyroglobulin after total thyroidectomy and tumor 
resection, causing undue concern about possible metastases. 
Therefore, unexpected detectable thyroglobulin levels post-
thyroidectomy should prompt a repeat assay in another 
reference laboratory.
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Serum calcitonin
 levels are usually elevated in medul
-
lary thyroid carcinoma, making this a marker for meta
-
static disease. However, serum calcitonin may be elevated 
in many other conditions, such as thyroiditis; pregnancy; 
kidney disease; hypergastrinemia; hypercalcemia; and 
other malignancies, particularly neuroendocrine tumors 
(including pheochromocytomas, carcinoid tumors) and 
carcinomas of the lung, pancreas, breast, and colon. Serum 
calcitonin and carcinoembryonic antigen (CEA) determi
-
nations should be obtained before surgery, then regularly 
in postoperative follow-up: every 4 months for 5 years, 
then every 6 months for life. In patients with extensive 
metastases, serum calcitonin should be measured in the 
laboratory with serial dilutions. Calcitonin levels remain 
elevated in patients with persistent tumor but also in some 
patients with apparent cure or indolent disease. Therefore, 
serum calcitonin levels greater than 250 ng/L (73 pmol/L) 
or rising levels of calcitonin are the best indication for 
recurrence or metastatic disease. Serum CEA levels are also 
usually elevated with medullary thyroid carcinoma, mak
-
ing this a useful second marker; however, it is not specific 
for this cancer.
C. Imaging
1. Ultrasound of the neck—
Ultrasound of the neck should 
be performed on all patients with thyroid cancer for the 
initial diagnosis and for follow-up. Ultrasound is useful in 
determining the size and location of the malignancy as well 
as the location of any neck metastases.
2. Radioactive iodine scanning—
RAI (
131
I or 
123
I) thyroid 
and whole-body scanning is used after thyroidectomy for 
differentiated thyroid cancer utilizing the protocol 
described later. (See Radioactive Iodine (
131
I) Therapy for 
Differentiated Thyroid Cancer, later.)
3. CT and MRI scanning—
CT scanning may demonstrate 
metastases and is particularly useful for localizing and 
monitoring lung metastases but is less sensitive than ultra
-
sound for detecting metastases within the neck. Medullary 
carcinoma in the thyroid, nodes, and liver may calcify, but 
lung metastases rarely do so. MRI is particularly useful for 
imaging bone metastases.
4. PET scanning—
PET scanning is especially helpful for 
detecting thyroid cancer metastases that do not have suf
-
ficient iodine uptake to be visible on RAI scans. Metastases 
are best detected using 
18
FDG-PET whole-body scanning. 
The sensitivity of 
18
FDG-PET scanning for differentiated 
thyroid cancer is enhanced if the patient is hypothyroid or 
receiving thyrotropin, which increases the metabolic activ
-
ity of differentiated thyroid cancer.
 
»
RAI uptake occurs in many different tissues and can be mis
-
taken for metastatic differentiated thyroid carcinoma. Head-
neck RAI uptake is seen in normal thyroid, salivary glands, 
nasal mucosa, thyroglossal duct remnants, and sinusitis.
Negative RAI scans are common in early metastatic dif
-
ferentiated thyroid carcinoma. Unfortunately, negative RAI 
scans also occur frequently with more advanced metastatic 
thyroid carcinoma, making it more difficult to detect and 
to distinguish from nonthyroidal neoplasms. An elevated 
serum thyroglobulin in patients with a clear RAI scan 
should arouse suspicion for metastases that are not avid for 
radioiodine. Medullary thyroid carcinoma does not con
-
centrate iodine.
 
»
Hyperthyroidism can develop in patients with a heavy 
tumor burden. One-third of medullary thyroid carcinomas 
secrete serotonin and prostaglandins, producing flushing 
and diarrhea. The management of patients with medullary 
carcinomas may be complicated by the coexistence of 
pheochromocytomas or hyperparathyroidism.
 
»
Treatment of Differentiated 
Thyroid Carcinoma
A. Surgical Treatment
Surgical removal is the treatment of choice for thyroid 
carcinomas. Neck ultrasound is obtained preoperatively,

»
carcinomas. Neck ultrasound is obtained preoperatively, 
since suspicious cervical lymphadenoapathy is detected in 
about 25%. For differentiated papillary and follicular carci
-
noma larger than 1 cm diameter, total thyroidectomy is 
performed with limited removal of cervical lymph nodes.
Surgery consists of a thyroid lobectomy for an indeter
-
minate “follicular lesion” that is 4 cm diameter or smaller. 
If malignancy is diagnosed on pathology, a completion 
thyroidectomy is performed. For indeterminate follicular 
lesions larger than 4 cm diameter that are at higher risk for 
being malignant, a bilateral thyroidectomy is performed as 
the initial surgery. Higher-risk lesions include those with a 
FNA biopsy that shows marked atypia or that are suspi
-
cious for papillary carcinoma and those that occur in 
patients with a history of radiation exposure or a family 
history of thyroid carcinoma.
For biopsies that are diagnostic of malignancy, surgery 
involves lobectomy alone for papillary thyroid carcinomas 
smaller than 1 cm in diameter in patients under age 
45 years who have no history of head and neck irradiation 
and no evidence of lymph node metastasis on ultrasonog
-
raphy. Other patients should have a total or near total thy
-
roidectomy. The advantage of near-total thyroidectomy for 
differentiated thyroid carcinoma is that multicentric foci of 
carcinoma are more apt to be resected. Also, there is less 
normal thyroid tissue to compete with cancer for 
131
I 
administered later for scans or treatment. A central neck 
lymph node dissection is performed at the time of thyroid
-
ectomy for patients with nodal metastases that are clini
-
cally evident. A lateral neck dissection is performed for 
patients with biopsy-proven lateral cervical lymphadenop
-
athy. Metastases to the brain are best treated surgically, 
since treatment with radiation or RAI is ineffective. Levo
-
thyroxine is prescribed in doses of 0.05–0.1 mg orally daily 
immediately postoperatively. About 2–4 months after sur
-
gery, patients require reevaluation and often 
131
I therapy.
Permanent injury to one recurrent laryngeal nerve 
occurs in between 1–2% and 7% of patients, depending on 
the experience of the surgeon. Temporary recurrent 
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laryngeal nerve palsies occur in another 5% but often 
resolve within 6 months. After total thyroidectomy, tem
-
porary hypoparathyroidism occurs in 20% and becomes 
permanent in about 2%. The incidence of hypoparathy
-
roidism may be reduced if accidentally resected parathy
-
roids are immediately autotransplanted into the neck 
muscles. Thyroidectomy requires at least an overnight 
hospital admission, since late bleeding, airway problems, 
and tetany can occur. 
Ambulatory thyroidectomy is poten
-
tially dangerous and should not be done
. Following surgery, 
staging (Table 26–7) should be done to help determine 
prognosis and to plan therapy and follow-up.
In pregnant women with thyroid cancer, surgery is usu
-
ally delayed until after delivery, except for fast-growing 
tumors that may be resected after 24 weeks gestation; there 
has been no difference in survival or tumor recurrence rates 
in women who underwent surgery during or after their 
pregnancy. Differentiated thyroid carcinoma does not 
behave more aggressively during pregnancy. However, com
-
pared to nonpregnant women, there is a higher risk of com
-
plications in pregnant women undergoing thyroid surgery.
B. Active Surveillance for Papillary 
Thyroid Microcarcinoma
Most papillary thyroid microcarcinomas that are less than 
1 cm in diameter are indolent with an excellent prognosis. 
Therefore, for microcarcinomas, an ongoing active surveil
-
lance protocol used in some medical centers is to perform 
a clinical examination and neck ultrasound every 6 months. 
Such conservative management may be particularly war
-
ranted for patients who have a limited life expectancy, a 
high surgical risk, or very low-risk tumors.
C. Thyroxine Suppression for 
Differentiated Thyroid Cancer
Patients who have had a thyroidectomy for differenti
-
ated thyroid cancer must take thyroxine replacement 
for life. Oral thyroxine should be given in doses that 
suppress serum TSH without causing clinical thyrotoxi
-
cosis. Serum TSH should be suppressed below 
0.1 milli-international units/L for patients with stage II 
disease and below 0.05 milli-international units/L for 
patients with stage 3–4 disease. (See Table 26–7.) Although 
patients receiving thyroxine suppression therapy (TSH less 
than 0.05 milli-international units/L) are at risk for a lower 
bone density than age-matched controls, the adverse effect 
upon bone density and fracture risk is relatively minor for 
patients who remain clinically euthyroid. Nevertheless, 
patients receiving thyroxine suppression therapy should 
have periodic bone densitometry.
D. Radioactive Iodine (
131
There are two reasons to treat patients with 
131
I after 
thyroidectomy: (1) thyroid remnant ablation for patients at 
high risk for recurrence and (2) treatment of metastatic 
thyroid cancer. 
131
I is usually administered 2–4 months after 
surgery. However, the indications and optimal activity (dose) 
for 
131
I therapy for differentiated thyroid cancer remain con
-
troversial since there is an overwhelmingly good prognosis 
for most patients with differentiated thyroid cancer.
Before receiving 
131
I therapy, patients should follow a 
low-iodine diet for at least 2 weeks. Patients must not be 
given amiodarone or intravenous radiologic contrast dyes 
containing iodine. Despite restriction of dietary iodine, 
differentiated thyroid cancer frequently lacks sufficient 
radioiodine avidity to allow RAI therapy.
1. RAI thyroid remnant ablation—
A low activity
1
 of 
30 mCi (1.1 GBq) 
131
I is given for “remnant ablation” of 
residual normal thyroid tissues after surgery for differenti
-
ated thyroid cancer. This small amount of 
131
I is given to 
patients with no known lymph node involvement who are 
at low risk for metastases. However, 
131
I remnant ablation 
is not required for patients with low-risk cancer: with stage

131
131
is not required for patients with low-risk cancer: with stage 
I papillary thyroid carcinomas or carcinomas that are 
smaller than 1 cm in diameter (whether unifocal or multi
-
focal), except for patients with unfavorable histopathology 
(tall-cell, columnar cell, insular cell, Hūrthle cell, or diffuse 
sclerosing subtypes).
2. RAI treatment of metastases—
131
I 
improves survival and reduces recurrence rates for patients 
with stage III–IV cancer and those with stage II cancer 
having gross extrathyroidal extension. RAI therapy is also 
given to patients with stage II cancer who have distant 
metastases, a primary tumor larger than 4 cm in diameter, 
or primary tumors 1–4 cm diameter with lymph node 
metastases or other high-risk features. Brain metastases do 
not usually respond to 
131
I and are best resected or treated 
with gamma knife radiosurgery. A post-therapy whole-
body scan is performed 2–10 days after 
131
I therapy. About 
70% of small lung metastases resolve following 
131
I therapy; 
however, larger pulmonary metastases have only a 10% 
remission rate.
Table 26–7.
 
Staging and prognosis for patients with 
papillary thyroid carcinoma using MACIS scoring.
Total Score
1
 - Stage
Percent of 
Papillary Thyroid 
Carcinoma
20-Year Survival
< 6.0 = Stage I
74.2%
96–99%
6.0–6.99 = Stage II
8.5%
68–89%
7.0–7.99 = Stage III
9.2%
55–56%
≥ 8.0 = Stage IV
8.1%
17–24%
1
Total score = 3.1 × age (if aged ≤ 39 years) 
or
 0.08 × age (if aged 
≥ 40 yr) + 0.3 × tumor size (cm, if not completely resected), 
 
+1 (if locally invasive), +3 (if distant metastases).
MACIS, metastases, age, complete resection, invasion, size.
1
The amount of radioiodine radioactivity given in a procedure is 
referred to as radioactivity or “activity” and is expressed as Curies 
(Ci) or Becquerels (Bq), whereas the term “dose” is reserved to 
describe the amount of radiation absorbed by a given organ or tumor 
and is expressed as Gray (Gy) or radiation-absorbed dose (RAD).
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Staging with RAI scanning or 
18
FDG-PET/CT scanning 
assists with determining the activity of 
131
I to be adminis
-
tered. Treatment protocols vary among institutions. Gener
-
ally, patients with higher-risk stage I cancer or stage II 
cancer are treated with 
131
I activities of 50–100 mCi (1.8–
3.7 GBq). Patients with stage III–IV cancers typically 
receive 
131
I activities of 100–150 mCi (3.7–5.5 GBq). 
Repeated treatments may be required for persistent radio
-
iodine-avid metastatic disease. Patients with differentiated 
thyroid carcinoma who have little or no uptake of RAI into 
metastases (about 35% of cases) should not be treated 
with 
131
I. Patients with asymptomatic, stable, radioiodine-
resistant metastases should receive levothyroxine to sup
-
press serum TSH and should be carefully monitored for 
tumor progression.
Some patients have elevated serum thyroglobulin levels 
but a negative whole-body radioiodine scan and a negative 
neck ultrasound. In such patients, an 
18
F-FDG PET/CT 
scan is obtained. If all scans are negative, the patient has a 
good prognosis and empiric therapy with 
131
I is not useful.
Activities of 
131
I over 100 mCi (3.7 GBq) can cause gas
-
tritis, temporary oligospermia, sialadenitis, and xerosto
-
mia. Therapy with 
131
I can cause neurologic decompensation 
in patients with brain metastases; such patients are treated 
with prednisone 30–40 mg orally daily for several days 
before and after 
131
I therapy. Cumulative doses of 
131
I over 
500 mCi (18.5 GBq) can cause infertility, pancytopenia 
(4%), and leukemia (0.3%). Pulmonary fibrosis can occur 
in patients with diffuse lung metastases after receiving 
cumulative 
131
I activities over 600 mCi (22 GBq). The kid
-
neys excrete RAI, so patients receiving dialysis require only 
20% of the usual 
131
I activity.
3. Recombinant human TSH (rhTSH)-stimulated
131
I 
therapy
—
Recombinant human thyroid stimulating hor
-
mone (rhTSH, Thyrogen) is given to increase the sensitivity 
of serum thyroglobulin for residual cancer and to increase 
the uptake of 
131
I into residual thyroid tissue (thyroid rem
-
nant “ablation”) or cancer. Thyrogen must be kept refriger
-
ated and is administered according to the following protocol: 
Thyroxine replacement is held for 2 days before rhTSH and 
for 3 days afterward. For 2 consecutive days, rhTSH (0.9 mg/
day, reconstituted with 0.2 mL sterile saline) should be 
administered intragluteally (not intravenously). On the 
third day, blood is drawn: serum TSH is assayed to confirm 
that it is greater than 30 milli-units/L; serum hCG is mea
-
sured in reproductive-age women to exclude pregnancy; and 
serum thyroglobulin is measured as a tumor marker. RAI is 
then administered at the prescribed activity (see above).
Thyrogen should not be administered to patients with 
an intact thyroid gland because it can cause severe thyroid 
swelling and hyperthyroidism. Hyperthyroidism can also 
occur in patients with significant metastases or residual 
normal thyroid. Other side effects include nausea (11%) 
and headache (7%). Thyrotropin has caused neurologic 
deterioration in 7% of patients with CNS metastases.
4. Thyroxine-withdrawal stimulated 
131
I therapy—
 
Thyroxine withdrawal is sometimes used because of its 
lower cost, despite the discomforts of becoming hypothy
-
roid. Thyroxine is withdrawn for 14 days and the patient is 
allowed to become hypothyroid; high levels of endogenous 
TSH stimulate the uptake of RAI and production of thyro
-
globulin by thyroid cancer or residual thyroid. Just prior to 
131
I therapy, the following blood tests are obtained: serum 
TSH to confirm it is greater than 30 milli-units/L, serum 
hCG in reproductive-age women to screen for pregnancy, 
serum thyroglobulin as a tumor marker. Three days after 
131
I therapy, thyroxine therapy may be resumed at full 
replacement dose.
5. Side effects and contraindications to 
131
I therapy—

131
131
I therapy—
National Cancer Institute surveillance data for thousands 
of patients with thyroid cancer indicate that patients with 
differentiated thyroid cancer, treated with only surgery, 
have a 5% increased risk of developing a second non-
thyroid malignancy. Patients with thyroid cancer who 
received 
131
I therapy have a slightly increased risk of devel
-
oping a second non-thyroid malignancy (especially leuke
-
mia and lymphoma). The risk of second cancers peaks 
about 5 years following 
131
I therapy.
Sialadenitis and xerostomia are potential side effects, 
particularly in women, older-age patients, in patients with 
a prior history of sialadenitis and in those with autoim
-
mune diseases associated with Sjögren syndrome. See 
 about RAI use, above.
E. Other Therapies for Differentiated 
 
Thyroid Cancer
Patients with osteolytic metastases to bone from differenti
-
ated thyroid cancer may be treated with one of two anti-
bone resorptive drugs: (1) zoledronate, 4 mg intravenously; 
or (2) denosumab, 120 mg subcutaneously. The frequency 
and duration of therapy is individualized according to each 
patient’s symptoms and response. These drugs must be 
used judiciously; there is an increased risk of atypical 
femur fractures and osteonecrosis of the jaw with pro
-
longed therapy with either drug.
Patients with aggressive differentiated thyroid cancers 
may have metastases that are refractory to RAI therapy. 
Recurrence in the neck may be treated with surgical deb
-
ulking and external beam radiation therapy. Patients with 
RAI-refractory differentiated thyroid cancer metastases 
that are advanced and rapidly progressive may be treated 
with certain tyrosine kinase inhibitors. Vandetanib and 
sunitinib induce partial responses in about 40%, while 
lenvatinib induced partial responses in about 65%; how
-
ever, median progression-free survival has been only about 
18 months and all tyrosine kinase inhibitors can cause seri
-
ous adverse reactions, so the patient and clinician must 
decide whether this chemotherapy is worthwhile.
 
»
Treatment of Other Thyroid Malignancies
 is treated with local resec
-
tion and radiation. Lovastatin has been demonstrated to 
cause differentiation and apoptosis of anaplastic thyroid 
carcinoma cells in vitro, but clinical studies are lacking. 
Anaplastic thyroid carcinoma does not respond to 
131
I 
therapy and is resistant to most chemotherapy. Anaplastic 
thyroid cancers with mTOR mutations may be inhibited by 
everolimus.
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 is best treated with sur
-
gery for the primary tumor and metastases. Patients with a 
ret
 protooncogene mutation should have a prophylactic 
total thyroidectomy, ideally by age 6 years (MEN 2A) or at 
age 6 months (MEN 2B). Medullary thyroid carcinoma 
does not respond to 
131
I therapy and is relatively resistant to 
chemotherapy. Patients should be monitored closely, with 
serum calcitonin levels checked about every 3 months. 
Since medullary thyroid carcinoma can be indolent, patients 
should be considered for chemotherapy only if they have 
rapidly progressive metastases, as evidenced by a doubling 
time of serum calcitonin or CEA doubling time is within 
2 years. Scanning with 
18
FDG-PET is also useful for identi
-
fying rapidly progressive metastases. Vandetanib and cabo
-
zantinib are approved for use against rapidly progressive 
metastatic medullary thyroid carcinoma; both require close 
observation to avoid toxicity. Vandetanib should usually not 
be administered to patients with cardiac disease or a pro
-
longed QT interval. Cabozantinib should usually not be 
administered to patients with gastrointestinal disease or 
prior radiation to the neck or mediastinum, since it 
increases the risk for gastrointestinal perforation and tra
-
cheoesophageal fistula. Patients with medullary thyroid 
carcinoma and diabetes should not receive diabetic therapy 
with glucagon-like peptide-1 (GLP-1) agonists because they 
may stimulate the growth of medullary thyroid carcinoma.
Thyroid mucosa-associated lymphoid tissue 
lymphomas
 have a low risk of recurrence after simple 
thyroidectomy. Patients with other thyroid lymphomas are 
best treated with external radiation therapy; chemotherapy 
is added for extensive lymphoma (Table 39–2).
External beam radiation therapy
 may be delivered to 
bone metastases, especially those that are without radioio
-
dine uptake or are RAI-refractory. Local neck radiation 
therapy may also be given to patients with anaplastic thy
-
roid carcinoma. Brain metastases can be treated with 
gamma knife radiosurgery.
 
»
Follow-Up
Most differentiated thyroid carcinoma recurs within the 
first 5–10 years after thyroidectomy. While lifetime moni
-
toring is recommended, the follow-up protocol can be tai
-
lored to the staging and aggressiveness of the malignancy. 
All patients require at least a yearly thyroid ultrasound and 
serum thyroglobulin level (while taking levothyroxine). 
Patients at higher risk usually require at least two annual 
consecutively negative stimulated serum thyroglobulin 
determinations less than 1 ng/mL and normal RAI scans 
(if done) and neck ultrasound scans before they are consid
-
ered to be in remission. The first surveillance occurs with 
stimulated postoperative serum thyroglobulin, 
131
I therapy, 
and post-therapy scanning about 2–4 months after surgery. 
At 9–12 months postoperatively, patients may receive 
another stimulated serum thyroglobulin and RAI scan. 
Patients need not have repeated 
131
I therapies if persistent 
RAI uptake is confined to the thyroid bed and if neck ultra
-
sounds appear normal and stimulated serum thyroglobulin 
levels remain less than 2 ng/mL. Patients with differentiated 
thyroid carcinoma must be monitored long term for recur
-
rent or metastatic disease. Further radioiodine or other 
scans may be required for patients with more aggressive dif
-
ferentiated thyroid cancer, prior metastases, rising serum 
thyroglobulin levels, or other evidence of metastases.
1. Serum TSH suppression—
Patients with differentiated 
thyroid cancer are treated with thyroxine doses that are 
sufficient to suppress the serum TSH below the normal 
range. For intermediate- or high-risk patients, the serum 
TSH should be suppressed below 0.1 milli-international 
units/L, while the target TSH for low-risk patients is 0.1–
0.5 milli-international units/mL. Patients who are consid
-

-
ered cured should nevertheless be treated with sufficient 
thyroxine to keep the serum TSH less than 2 milli-
international units/L. Follow-up must include physical 
examinations and laboratory testing to ensure that patients 
remain clinically euthyroid with serum TSH levels in the 
target range. To achieve suppression of serum TSH, the 
required dose of thyroxine may be such that serum FT
4
 
levels may be slightly elevated; in that case, measurement of 
serum T
3
 or free T
3
 can be useful to ensure the patient is 
not frankly hyperthyroid. Thyrotoxicosis can be caused by 
over-replacement with thyroxine or by the growth of func
-
tioning metastases.
2. Serum thyroglobulin—
Thyroglobulin is produced by 
normal thyroid tissue and by most differentiated thyroid 
carcinomas. It is only after a total or near-total thyroidec
-
tomy and 
131
I remnant ablation that thyroglobulin becomes 
a useful tumor marker for patients with differentiated papil
-
lary or follicular thyroid cancer, particularly for patients 
who do not have serum antithyroglobulin antibodies.
Detectable thyroglobulin levels do not necessarily indi
-
cate the presence of residual or metastatic thyroid cancer. 
Conversely, baseline serum thyroglobulin levels are insen
-
sitive markers for disease recurrence. However, baseline or 
stimulated serum thyroglobulin levels 2 ng/mL or higher 
indicate the need for a repeat neck ultrasound and further 
scanning with RAI or 
18
FDG-PET. If serum thyroglobulin 
levels remain 2 ng/mL or higher in the presence of normal 
scanning, it is prudent to repeat the serum thyroglobulin in 
a national reference laboratory. In one series of patients 
with differentiated thyroid cancer following thyroidec
-
tomy, there was a 21% incidence of metastases in patients 
with serum thyroglobulin less than 1 ng/mL (while receiv
-
ing thyroxine for TSH suppression). Therefore, 
baseline
 
serum thyroglobulin levels are inadequately sensitive and 
stimulated
 serum thyroglobulin measurements should be 
used and 
always
 with neck ultrasound. The usefulness of 
routinely doing a radioiodine scan in low-risk patients is 
controversial but continues to be done in many centers 
during stimulation following either rhTSH or thyroid hor
-
mone withdrawal.
3. Neck ultrasound—
Neck ultrasound should be used in all 
patients with thyroid carcinoma to supplement neck palpa
-
tion; it should be performed preoperatively, 3 months post
-
operatively, and regularly thereafter. Ultrasound is more 
sensitive for lymph node metastases than either CT or MRI 
scanning. Small inflammatory nodes may be detected post
-
operatively and do not necessarily indicate metastatic dis
-
ease, but follow-up is necessary. Ultrasound-guided FNA 
biopsy should be performed on suspicious lesions.
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4. Radioactive iodine (RAI: 
131
I or 
123
I) neck and whole-
body scanning—
Despite its limitations, RAI scanning has 
traditionally been used to detect metastatic differentiated 
thyroid cancer and to determine whether the cancer is 
amenable to treatment with 
131
I. RAI scanning is particu
-
larly useful for high-risk patients and those with persistent 
antithyroglobulin antibodies that make serum thyroglobu
-
lin determinations unreliable.
The 
131
I radioisotope may be used in scanning activities 
provided it is given less than 2 weeks before scheduled 
131
I 
treatment to avoid “stunning” metastases such that they 
take up less of the RAI therapy activity. Alternatively, the 
123
I radioisotope may also be used and does not stun 
tumors; it allows single-photon emission computed tomog
-
raphy (SPECT) to better localize metastases. Initial RAI 
scanning is typically performed about 2–4 months follow
-
ing surgery for differentiated thyroid carcinoma.
About 65% of metastases are detectable by RAI scan
-
ning, but only after optimal preparation: Patients should 
ideally have a total or near-total thyroidectomy, since any 
residual normal thyroid competes for RAI with metastases, 
which are less avid for iodine. It is reasonable to perform a 
rhTSH-stimulated scan and thyroglobulin level 2–3 months 
after the initial neck surgery; if the scan is negative and the 
serum thyroglobulin is less than 2 ng/mL, low-risk patients 
may not require further scanning but should continue to be 
monitored with neck ultrasound and serum thyroglobulin 
levels every 6–12 months. For higher-risk patients, the 
rhTSH-stimulated thyroglobulin and RAI scan may be 
repeated about 1 year after surgery and then again if war
-
ranted. Serum thyroglobulin and radioiodine scanning are 
stimulated by either rhTSH or thyroid hormone with
-
drawal according to the protocols described above for 
131
I 
The combination of rhTSH-stimulated scanning and 
thyroglobulin levels detects a thyroid remnant or cancer 
with a sensitivity of 84%. However, the presence of antithy
-
roglobulin antibodies renders the serum thyroglobulin 
determination uninterpretable. In about 21% of low-risk 
patients, rhTSH stimulates serum thyroglobulin to above 
2 ng/mL; such patients have a 23% risk of local neck metas
-
tases and a 13% risk of distant metastases. The rhTSH-
stimulated radioiodine neck and whole-body scan detects 
only about half of these metastases because they are small 
or not avid for iodine. Some patients have persistent radio
-
iodine uptake in the neck on diagnostic scanning but have 
no visible tumor on neck ultrasound; such patients do not 
require additional radioiodine therapy, especially if the 
serum thyroglobulin level is very low.
5. Positron emission tomography scanning—
18
FDG-PET 
scanning is particularly useful for detecting thyroid cancer 
metastases in patients with a detectable serum thyroglobu
-
lin (especially serum thyroglobulin levels greater than 
10 ng/mL and rising) who have a normal whole-body RAI 
scan and an unrevealing neck ultrasound. It is also sensi
-
tive for detecting metastases from medullary thyroid carci
-
noma. Diabetic patients with serum glucose less than 
200 mg/dL (11.2 mmol/L) may be scanned. 
18
FDG-PET 
scanning can be combined with a CT scan; the resultant 
18
FDG-PET/CT fusion scan is 60% sensitive for detecting 
metastases that are not visible by other methods. This scan 
is less sensitive for small brain metastases. 
18
FDG-PET 
scanning detects the metabolic activity of tumor tissue; for 
differentiated thyroid carcinoma, this scan is more sensi
-
tive when the patient’s thyroid cancer is stimulated with 
rhTSH (Thyrogen). One problem with 
18
FDG-PET scan
-
ning is its lack of specificity. False-positives can occur with 
benign hepatic tumors, sarcoidosis, radiation therapy, 
suture granulomas, reactive lymph nodes, or inflammation

18
-
suture granulomas, reactive lymph nodes, or inflammation 
at surgical sites that can persist for months.
6. Other scanning—
Thallium-201 (
201
Tl) scans may be 
useful for detecting metastatic differentiated thyroid carci
-
noma when the 
131
I scan is normal but serum thyroglobu
-
lin is elevated. MRI scanning is particularly useful for 
imaging metastases in the brain, mediastinum, or bones. 
CT scanning is useful for imaging and monitoring pulmo
-
nary metastases.
 
»
Prognosis
Papillary thyroid carcinoma
 has an overall mortality rate 
of 3%. It is best staged using the MACIS (metastasis, age, 
completeness of resection, invasion, size) scoring system 
(Table 26–7). 
18
FDG-PET scanning independently predicts 
survival, with patients having few PET-avid metastases and 
low SUV
max
 (highest image-pixel standardized uptake 
value) having a generally good prognosis, particularly for 
adults under age 45 years. Unlike other forms of cancer, 
patients with papillary thyroid carcinoma who have pal
-
pable lymph node metastases do not have a particularly 
increased mortality rate; however, their risk of local recur
-
rence is increased. The following characteristics imply a 
worse prognosis: age over 45 years, male sex, bone or brain 
metastases, macronodular (greater than 1 cm) pulmonary 
metastases, and lack of 
131
I uptake into metastases. Y ounger 
patients with pulmonary metastases tend to respond better 
to 
131
I therapy than do older adults. Certain papillary his
-
tologic types are associated with a higher risk of recurrence 
and reduced survival: tall cell, columnar cell, and diffuse 
sclerosing types tend to be more aggressive than classic 
papillary thyroid cancer; the best prognosis has been with 
the follicular variant of papillary thyroid cancer. Brain 
metastases are detected in 1%; they reduce median survival 
to 12 months, but the patient’s prognosis is improved by 
surgical resection.
follicular thyroid carcinoma
 have a can
-
cer mortality rate that is 3.4 times higher than patients with 
papillary carcinoma. The Hürthle cell variant of follicular 
carcinoma is even more aggressive. Both follicular carci
-
noma and its Hürthle cell variant tend to present at a more 
advanced stage than papillary carcinoma. However, at a 
given stage, the different types of differentiated thyroid 
carcinoma have a similar prognosis. Patients with primary 
tumors larger than 1 cm in diameter who undergo limited 
thyroid surgery (subtotal thyroidectomy or lobectomy) 
have a 2.2-fold increased mortality over those having total 
or near-total thyroidectomies. Patients who have not 
received 
131
I ablation have mortality rates that are increased 
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twofold by 10 years and threefold by 25 years (over those 
who have received ablation). The risk of cancer recurrence 
is twofold higher in men than in women and 1.7-fold 
higher in multifocal than in unifocal tumors.
Patients with a normal 
18
FDG-PET scan have a 98% 
5-year survival, while those having more than 10 metasta
-
ses have a 20% 5-year survival. Those with a SUV
max
 of 
0.1-4.6 have a 5-year survival of 85%, while those with a 
SUV
max
 greater than 13.3 have a 5-year survival of 20%. 
Patients with only local metastases have a 5-year survival 
of 95%, while those with regional (supraclavicular, medi
-
astinal) metastases have a 5-year survival of 70%, and 
those with distant metastases have a 5-year survival 
of 35%.
 is more aggressive than 
differentiated thyroid cancer but is typically fairly indolent. 
However, medullary thyroid carcinoma with a somatic 
RET
 codon M918T mutation is the most aggressive medul
-
lary thyroid carcinoma and has a poorer prognosis. The 
overall 10-year survival rate is 90% when the tumor is 
confined to the thyroid, 70% for those with metastases to 
cervical lymph nodes, and 20% for those with distant 
metastases. When postoperative serum calcitonin levels are 
below 150 pg/mL (44 pmol/L), residual disease is likely 
confined to the neck, whereas when postoperative serum 
calcitonin levels above 500 pg/mL (146 pmol/L) distant 
metastases are likely. Patients with sporadic disease usually 
have lymph node involvement noted at the time of diagno
-
sis, whereas distal metastases may not be noted for years. 
For patients who have metastases to lymph nodes, modi
-
fied radical neck dissection is recommended. Familial 
cases and those associated with MEN 2A tend to be less 
aggressive; the 10-year survival rate is higher, in part due to 
earlier detection. Patients with metastatic medullary thy
-
roid carcinoma whose serum calcitonin doubling time is 
over 2 years also have a relatively good prognosis.
Medullary thyroid carcinoma that is seen in MEN 2B 
(MEN 3) is more aggressive, arises earlier in life, and car
-
ries a worse overall prognosis, especially when associated 
with a germline 
M918T
 mutation. Older adults tend to 
have more aggressive medullary thyroid carcinomas. 
Women with medullary thyroid carcinoma who are under 
age 40 years have a better prognosis. A better prognosis is 
also obtained in patients undergoing total thyroidectomy 
and neck dissection; radiation therapy reduces recurrence 
in patients with metastases to neck nodes. The mortality 
rate is increased 4.5-fold when primary or metastatic 
tumor tissue stains heavily for myelomonocytic antigen 
M-1. Conversely, tumors with heavy immunoperoxidase 
staining for calcitonin are associated with prolonged sur
-
vival even in the presence of significant metastases.
 carries a 1-year survival 
rate of about 10% and a 5-year survival rate of about 5%. 
Patients with fully localized tumors on MRI have a better 
Localized thyroid lymphoma
 carries a 5-year survival 
of nearly 100%. Those with disease outside the thyroid 
have a 63% 5-year survival. However, the prognosis is bet
-
ter for those with mucosa-associated lymphoid tissue 
lymphoma compared to diffuse large B-cell lymphoma. 
Patients presenting with stridor, pain, laryngeal nerve 
palsy, or mediastinal extension tend to fare worse.
Bibbins-Domingo K et al. Screening for thyroid cancer: US Pre
-
ventive Services Task Force recommendation statement. 
JAMA. 2017 May 9;317(18):1882–7. [PMID: 28492905]
Cabanillas ME et al. Thyroid cancer. Lancet. 2016 Dec 3;
 
388(10061):2783–95. [PMID: 27240885]
Fagin JA et al. Biologic and clinical perspectives on thyroid can
-
cer. N Engl J Med. 2016 Sep 15;375(11):1054–67. [PMID: 
27626519]
Haugen BR et al. 2015 American Thyroid Association manage
-
ment guidelines for adult patients with thyroid nodules and

-
27626519]
-
ment guidelines for adult patients with thyroid nodules and 
differentiated thyroid cancer. Thyroid. 2016 Jan;26(1):1–133. 
[PMID: 26462967]
Wells SA Jr et al. Revised American Thyroid Association guide
-
lines for the management of medullary thyroid carcinoma. 
Thyroid. 2015 Jun;25(6):567–610. [PMID: 25810047]
IODINE DEFICIENCY DISORDER & 
ENDEMIC GOITER
 
»
Common in regions with low-iodine diets.
 
»
High rate of congenital hypothyroidism and 
cretinism.
 
»
Goiters may become multinodular and enlarge.
 
»
Most adults with endemic goiter are euthyroid; 
however, some are hypothyroid or hyperthyroid.
 
»
Mild-to-moderate and sometimes severe iodine deficiency 
exists in 30 countries. An estimated 1.9 billion people have 
insufficient iodine intake. Severe iodine deficiency 
increases the risk of miscarriage and stillbirth. Cretinism 
occurs in about 0.5% of live births in iodine-deficient areas. 
Moderate iodine deficiency during gestation and infancy 
can cause manifestations of hypothyroidism, deafness, 
short stature, and lowers a child’s intelligence quotient by 
10–15 points. Even mild-to-moderate iodine deficiency 
appears to impair a child’s perceptual reasoning and global 
cognitive index.
Although iodine deficiency is the most common cause 
of endemic goiter, there are other natural goitrogens, 
including certain foods (eg, sorghum, millet, maize, cas
-
sava), mineral deficiencies (selenium, iron, zinc), and 
water pollutants, which can themselves cause goiter or 
aggravate a goiter proclivity caused by iodine deficiency. In 
iodine-deficient patients, smoking can induce goiter 
growth. Pregnancy aggravates iodine deficiency and can 
increase the size of thyroid nodules and cause new nodules. 
Some individuals are particularly susceptible to goiter 
owing to congenital partial defects in thyroid enzyme 
activity.
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»
Endemic goiters may become multinodular and very large. 
Growth often occurs during pregnancy and may cause 
compressive symptoms.
Substernal goiters are usually asymptomatic but can 
cause tracheal compression, respiratory distress and fail
-
ure, dysphagia, superior vena cava syndrome, gastrointesti
-
nal bleeding from esophageal varices, palsies of the phrenic 
or recurrent laryngeal nerves, or Horner syndrome. Cere
-
bral ischemia and stroke can result from arterial compres
-
sion or thyrocervical steal syndrome. Substernal goiters 
can rarely cause pleural or pericardial effusions. The inci
-
dence of significant malignancy is less than 1%.
Some patients with endemic goiter may become hypo
-
thyroid. Others may become thyrotoxic as the goiter grows 
and becomes more autonomous, especially if iodine is 
added to the diet.
The serum T
4
 and TSH are generally normal. TSH falls in 
the presence of hyperthyroidism if a multinodular goiter 
has become autonomous in the presence of sufficient 
amounts of iodine for thyroid hormone synthesis. TSH 
rises with hypothyroidism. Thyroid RAI uptake is usually 
elevated, but it may be normal if iodine intake has 
improved. Serum levels of antithyroid antibodies are usu
-
ally either undetectable or in low titers. Serum thyroglobu
-
lin is often elevated above 13 mcg/L. Urine iodine 
concentrations are below 100 mcg/L in children with 
iodine deficiency.
 
»
Endemic goiter must be distinguished from all other forms 
of nodular goiter that may coexist in an endemic region.
 
»
The minimum dietary requirement for iodine is about 
50 mcg daily, with optimal iodine intake being 150–300 mcg 
daily. Iodized salt contains iodine at about 20 mg per kg 
salt. Other sources of iodine include commercial bread, 
milk, and seafood. Initiating iodine supplementation in an 
iodine-deficient area greatly reduces the emergence of new 
goiters but causes an increased frequency of hyperthyroid
-
ism during the first year. One iodine-depleted area was 
Pescopagano, Italy, where 46% of adults had goiters. 
Salt was iodized (30 mg of potassium iodate per kg salt) 
and made available in 1985. After 15 years, the incidence of 
goiter declined to 23%. However, the prevalence of 
Hashimoto thyroiditis rose from 3.5% to 14.5% after 
15 years of iodine supplementation.
 
»
Treatment
Iodine supplementation has not proven effective for treat
-
ing adults with large multinodular goiter and actually 
increases their risk of developing thyrotoxicosis. Thy
-
roidectomy may be required for cosmesis, compressive 
symptoms, or thyrotoxicosis. There is a high goiter recur
-
rence rate in iodine-deficient geographic areas, so near-
total thyroidectomy is preferred when surgery is indicated. 
Certain patients may be treated with 
131
I for large compres
-
sive goiters.
 
»
Dietary iodine supplementation increases the risk of autoim
-
mune thyroid dysfunction, which may cause hypothyroidism 
or hyperthyroidism. Excessive iodine supplementation 
increases the risk of goiter. Suppression of TSH by administer
-
ing thyroxine carries the risk of inducing hyperthyroidism, 
particularly in patients with autonomous multinodular goi
-
ters; therefore, thyroxine suppression should not be started in 
patients with a low TSH level. Treating patients with 
131
I for 
large multinodular goiter may shrink the gland; however, 
Graves disease develops in some patients 3–10 months follow
-
ing therapy.
Doggui R et al. Iodine deficiency: physiological, clinical and 
epidemiological features, and pre-analytical considerations. 
Ann Endocrinol (Paris). 2015 Feb;76(1):59–66. [PMID: 
25613936]
Zimmerman MB et al. Iodine deficiency and thyroid disorders. 
Lancet Diabetes Endocrinol. 2015 Apr;3(4):286–95. [PMID: 
25591468]
 
º
DISEASES OF THE PARATHYROIDS

25613936]
25591468]
 
º
Parathyroid hormone (PTH) increases osteoclastic activity 
in bone, increases the renal tubular reabsorption of cal
-
cium, and stimulates the synthesis of 1,25-dihydroxychole
-
calciferol by the kidney. Meanwhile, PTH inhibits the 
reabsorption of phosphate and bicarbonate by the renal 
tubule. All of these effects cause a net increase in serum 
calcium.
HYPOPARATHYROIDISM & 
PSEUDOHYPOPARATHYROIDISM
 
»
Tetany, carpopedal spasms, tingling of lips and 
hands, cramps, irritability.
 
»
Chvostek sign and Trousseau phenomenon.
 
»
Serum calcium low; serum phosphate high; alka
-
line phosphatase normal; urine calcium excretion 
reduced.
 
»
Hypocalcemia with low serum PTH.
 
»
Serum magnesium may be low.
 
»
Acquired hypoparathyroidism
 is most commonly caused 
by anterior neck surgery, occurring after total thyroidec
-
tomy in about 25% of patients transiently, and in about 4% 
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of patients permanently. The risk of permanent postopera
-
tive hypoparathyroidism can be reduced during thyroid 
surgery by taking parathyroid glands with suspected vascu
-
lar damage and autotransplanting them into the sternoclei
-
domastoid muscle. Permanent hypoparathyroidism may 
occur after the resection of multiple parathyroid adeno
-
mas. It also occurs transiently after the surgical removal of 
a single parathyroid adenoma for primary hyperparathy
-
roidism due to suppression of the remaining normal para
-
thyroids and accelerated remineralization of the skeleton. 
This is known as “hungry bone syndrome. ” In such cases, 
hypocalcemia can be quite severe, particularly in patients 
with preoperative hyperparathyroid bone disease and vita
-
min D or magnesium deficiency. 
All patients undergoing 
thyroidectomy or parathyroidectomy must be observed 
closely overnight
. Neck irradiation is a rare cause of 
Autoimmune hypoparathyroidism may be isolated or 
combined with other endocrine deficiencies. Autoimmune 
polyendocrine syndrome type I (APS-I) is also known as 
autoimmune polyendocrinopathy-candidiasis-ectodermal 
dystrophy (APECED). In APS-I, mucocutaneous candidia
-
sis appears in the newborn period. Hypoparathyroidism is 
the most frequent and often the only endocrine deficiency. 
Addison disease is the next most common endocrinopathy 
and may present anytime from childhood to young adult
-
hood. Hypothyroidism, type 1 diabetes, or pituitary defi
-
ciency as well as cataracts, uveitis, alopecia, or vitiligo can 
also develop. Autoimmune gastrointestinal manifestations 
are also common. Fat malabsorption occurs in 20% of 
patients with APS-1; treatment of hypocalcemia can be 
challenging in patients with APS-1, since vitamin D
3
 is fat-
soluble. Hypoparathyroidism can also occur in SLE caused 
by antiparathyroid antibodies.
Parathyroid deficiency may also be the result of damage 
from heavy metals such as copper (Wilson disease) or iron 
(hemochromatosis, transfusion hemosiderosis), granulo
-
mas, Riedel thyroiditis, tumors, or infection.
Magnesium deficiency
 causes functional hypoparathy
-
roidism. Hypomagnesemia is most commonly caused by 
alcoholism, diuretics, intestinal malabsorption, and proton 
pump inhibitors. Hypomagnesemia can also be caused by 
aminoglycosides, amphotericin, and pentamidine. Chemo
-
therapy for colon cancer with epithelial growth factor 
inhibitors (panitumumab, cetuximab) also causes 
hypomagnesemia. Although mild hypomagnesemia stimu
-
lates PTH secretion, more severe hypomagnesemia (below 
1.2 mg/dL) inhibits PTH secretion. Hypomagnesemia also 
causes resistance to PTH in bone and renal tubules. Cor
-
rection of hypomagnesemia results in rapid disappearance 
of the condition.
Hypermagnesemia
 also suppresses PTH secretion. 
Hypermagnesemia occurs most commonly in patients with 
kidney dysfunction who take magnesium-containing ant
-
acids, laxatives, or dietary supplements.
Symptomatic hypoparathyroidism may be precipited by 
a proton pump inhibitor, since absorption of calcium 
decreases with reduced stomach acidity.
Congenital hypoparathyroidism
 causes hypocalcemia 
beginning in infancy. However, it may not be diagnosed for 
many years. Since hypoparathyroidism can be familial, 
screening is suggested for family members of any patient 
with idiopathic hypoparathyroidism.
 
»
Manifestations of hypocalcemia vary from subtle to life-
threatening. Patients have a reduced quality of life, with 
fatigue; irritability; depression; anxiety; cognitive impair
-
ment or “brain fog”; lethargy; and paresthesias in the cir
-
cumoral area, hands, and feet. More severe manifestations 
include muscle weakness or cramps, carpopedal spasm, 
convulsions, tetany, laryngospasm and stridor. Chronic 
hypocalcemia with hyperphosphatemia can cause calcifi
-

-
cations in soft tissues, such as joints, skin, and arteries. 
Brain calcifications in the basal ganglia and cerebral cortex 
can cause parkinsonian symptoms or choreoathetosis. 
However, some patients with chronic hypocalcemia are 
asymptomatic, even with very low levels of serum 
calcium.
Chvostek sign (facial muscle contraction on tapping 
the facial nerve in front of the ear) is positive, and Trous
-
seau phenomenon (carpal spasm after application of a 
sphygmomanometer cuff) is present. Cataracts may 
occur; the nails may be thin and brittle; the skin is dry 
and scaly, at times with fungus infection (candidiasis), 
and there may be loss of eyebrows; and deep tendon 
reflexes may be hyperactive. Pseudotumor cerebri with 
papilledema and elevated CSF pressure is occasionally 
seen. Teeth may be defective if the onset of the disease 
occurs in childhood.
Serum calcium is low, serum phosphate high, urinary cal
-
cium low, and alkaline phosphatase normal. Serum cal
-
cium is largely bound to albumin. In patients with 
hypoalbuminemia, the serum ionized calcium may be 
determined; it should be 4.6–5.3 mg/dL (1.15–1.32 mmol/L). 
Alternatively, the serum calcium level can be corrected for 
serum albumin level as follows: 
“Corrected” serum Ca
2+
 = Serum Ca
2+
mg/dL
 
 + (0.8 × 
[4.0 − Albumin g/dL])
Serum PTH levels are usually low or not elevated in 
the presence of hypocalcemia. Both hypomagnesemia 
and hypermagnesemia may exacerbate symptoms and 
decrease parathyroid function; serum magnesium levels 
should always be measured. Serum calcium should not 
be determined within 24 hours following intravenous 
gadolinium, since gadolinium interferes with the colori
-
metric calcium assay, thereby causing artefactual 
hypocalcemia.
C. Imaging
Radiographs or CT scans of the skull may show basal gan
-
glia calcifications. The bones may appear denser than 
normal and the bone mineral density is usually increased. 
Cutaneous calcification may occur.
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D. Other Examinations
Slit-lamp examination may show early posterior lenticular 
cataract formation. The electrocardiogram (ECG) may 
have a prolonged QTc interval and T wave abnormalities in 
the presence of hypocalcemia. Patients with chronic hypo
-
parathyroidism tend to have increased bone mineral den
-
sity, particularly in the lumbar spine.
 
»
Acute tetany with stridor, especially if associated with vocal 
cord palsy, may lead to respiratory obstruction requiring 
tracheostomy. There may be associated autoimmunity 
causing celiac disease, pernicious anemia, or Addison dis
-
ease. Ossification of the paravertebral ligaments may occur 
with nerve root compression; surgical decompression may 
be required. Seizures are common in untreated patients. 
Overtreatment with vitamin D and calcium may produce 
nephrocalcinosis and impairment of kidney function. 
Hypocalcemia can also cause heart failure and dysrhyth
-
mias. ECG may show heart block, a prolonged QTc inter
-
val, and changes suggesting ischemia.
 
»
Paresthesias, muscle cramps, or tetany due to respiratory 
alkalosis, in which the serum calcium is normal, can be 
confused with hypocalcemia. In fact, hyperventilation 
tends to accentuate hypocalcemic symptoms.
Hypocalcemia may be caused by certain drugs: loop 
diuretics, plicamycin, phenytoin, foscarnet, denosumab, 
and bisphosphonates. In addition, hypocalcemia may be 
seen in cases of rapid intravascular volume expansion or 
due to chelation from transfusions of large volumes of 
citrated blood. Hypocalcemia may also be due to malab
-
sorption of calcium, magnesium, or vitamin D; patients do 
not always have diarrhea. It is also observed in patients 
with acute pancreatitis. Hypocalcemia may develop in 
some patients with certain osteoblastic metastatic carcino
-
mas (especially breast, prostate) instead of the expected 
hypercalcemia. Hypocalcemia with hyperphosphatemia 
(simulating hypoparathyroidism) is seen in azotemia, but 
may also be caused by large doses of intravenous, oral, or 
rectal phosphate preparations and by chemotherapy of 
responsive lymphomas or leukemias.
Hypocalcemia with hypercalciuria
 may be due to a 
familial syndrome involving a mutation in the calcium-
sensing receptor; such patients have levels of serum PTH 
that are in the normal range, distinguishing it from hypo
-
parathyroidism. It is transmitted as an autosomal domi
-
nant disorder. Such patients are hypercalciuric; treatment 
with calcium and vitamin D may cause nephrocalcinosis.
Congenital pseudohypoparathyroidism
 is a group of 
disorders characterized by hypocalcemia due to resistance 
to PTH. Subtypes are caused by different mutations involv
-
ing the renal PTH receptor, the receptor’s G protein, or 
adenylyl cyclase.
 
»
Treatment
A. Prophylaxis Against Severe 
Postoperative Hypocalcemia
Post-thyroidectomy hypocalcemia can be detected early by 
closely monitoring serum PTH and calcium. If the serum 
calcium falls below 8.0 mg/dL (2.0 mmol/L) with a serum 
PTH below 10–15 pg/mL (1.0–1.5 pmol/L) after thyroid or 
parathyroid surgery, the patient is at high risk for hypocalce
-
mia and can be prophylactically treated with calcitriol and 
oral calcium. Calcitriol is typically given orally in doses of 
0.25–1 mcg twice daily. Prophylactic elemental calcium is 
given orally as calcium carbonate (with meals) 500–1000 mg 
twice daily.
B. Emergency Treatment for Acute Hypocalcemia 
(Hypoparathyroid Tetany)
1. Airway—
Be sure an adequate airway is present.
2. Intravenous calcium gluconate—
Calcium gluconate, 
10–20 mL of 10% solution intravenously, may be given 
slowly
 until tetany ceases. Ten to 50 mL of 10% calcium 
gluconate may be added to 1 L of 5% glucose in water or 
saline and administered by slow intravenous drip. The rate 
should be adjusted so that the serum calcium is maintained 
in the range of 8–9 mg/dL (2–2.25 mmol/L).
3. Oral calcium—

Calcium salts should be given orally as 
soon as possible to supply 1–2 g of calcium daily. Liquid 
calcium carbonate, 500 mg/5 mL, contains 40% calcium 
and may be especially useful. The dosage is 1–3 g calcium 
orally daily; it should be given with meals.
4. Vitamin D preparations—
(Table 26–8.) Therapy should 
be started as soon as oral calcium is begun. The active 
metabolite of vitamin D, 1,25-dihydroxycholecalciferol 
(calcitriol), has a very rapid onset of action and is not long-
lasting if hypercalcemia occurs. It is of great use in the 
Table 26–8.
 
Vitamin D preparations used in the treatment of hypoparathyroidism.
Available Preparations
Daily Dose
Duration of Action
Ergocalciferol, ergosterol 
(vitamin D
2
, calciferol)
50,000 international units capsules; 8000 international 
units/mL oral solution
2000–200,000 units
1–2 weeks
Cholecalciferol (vitamin D
3
)
50,000 international units capsules, not available 
commercially in United States; may be compounded
10,000–50,000 units
4–8 weeks
Calcitriol (Rocaltrol)
0.25 and 0.5 mcg capsules; 1 mcg/mL oral solution; 
 
1 mcg/mL for injection
0.25–4 mcg
½–2 weeks
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treatment of acute hypocalcemia. Therapy is commenced 
at a dosage of 0.25 mcg orally each morning with upward 
dosage titration to near normocalcemia. Ultimately, doses 
of 0.5–2 mcg/day are usually required.
5. Magnesium—
If hypomagnesemia (serum magnesium 
less than 1.8 mg/dL or less than 0.8 mmol/L) is present, it 
must be corrected to treat the resulting hypocalcemia. For 
critical hypomagnesemia (serum magnesium less than 
1.0 mg/dL or less than 0.45 mmol/L), 50% magnesium 
sulfate solution (5 g/10 mL) is diluted in 250 mL 0.9% saline 
or 5% dextrose in water and given by an intravenous 
infusion of 5 g over 3 hours, with further dosing based on 
serum magnesium levels. Long-term oral magnesium 
replacement may be given as magnesium oxide 500 mg (60% 
elemental magnesium) tablets, one to three times daily.
C. Maintenance Treatment of Hypoparathyroidism
Patients with mild hypoparathyroidism may require no 
therapy but need close monitoring for manifestations of 
hypocalcemia. Therapy is ordinarily required for patients 
with symptomatic hypocalcemia or serum calcium levels 
below 8.0 mg/dL (2 mmol/L).
Vitamin D, calcium, and magnesium therapy:
 Patients 
with hypoparathyroidism have a reduced renal tubular 
reabsorption of calcium and are thus prone to hypercalci
-
uria and kidney stones if the serum calcium is normalized 
with calcium and vitamin D therapy. Therefore, the goal is 
to maintain the serum calcium in a slightly low but asymp
-
tomatic range of 8–8.6 mg/dL (2–2.15 mmol/L). It is pru
-
dent to monitor urine calcium with “spot” urine 
determinations and keep the level below 30 mg/dL 
(7.5 mmol/L), if possible. Hypercalciuria may respond to 
oral hydrochlorothiazide, 25 mg daily, usually given with a 
potassium supplement. Serum magnesium should be mon
-
itored and kept in the normal range with supplemental 
magnesium, if required. Serum phosphate should also be 
monitored and the serum calcium × phosphate product 
kept below 55 mg
2
/dL
2
 (4.4 mmol
2
/L
2
).
Calcium supplements
 can be given in doses of 
800–1000 mg orally daily. Calcium carbonate 1 g contains 
400 mg of elemental calcium and should be given with 
meals; calcium citrate 1 g contains 211 mg of elemental 
calcium, but can be given any time and causes less gastro
-
intestinal intolerance. Calcium lactate (13% elemental cal
-
cium) and calcium gluconate (9% elemental calcium) are 
other options for calcium supplementation.
Vitamin D
 is generally required for patients with 
chronic hypoparathyroidism (Table 26–8). Monitoring of 
serum calcium at regular intervals (at least every 
3–4 months) is recommended. Calcitriol, a short-acting 
preparation, is given in doses that range from 0.25 mcg/day 
to 2.0 mcg orally daily. Ergocalciferol (vitamin D
2
) is 
derived from plants; the usual dose ranges from 25,000 to 
150,000 units/day. It is stored in fat, giving it a long dura
-
tion of action. If toxicity develops, hypercalcemia—treat
-
able with hydration and prednisone—may persist for 
weeks after it is discontinued. Despite this risk, ergocalcif
-
erol usually produces a more stable serum calcium level 
than do the shorter-acting preparations.
PTH
 is effective for treating patients with hypoparathy
-
roidism but is restricted to patients whose hypocalcemia 
cannot be adequately treated with calcium and vitamin D 
analogs (see above). Recombinant human parathyroid hor
-
mone (rhPTH) is an 84-amino acid polypeptide that is 
identical to native PTH (1–84). It is FDA approved and 
marketed as NATPARA as an adjunct to calcium and vita
-
min D analogs to control symptomatic hypocalcemia in 
patients with hypoparathyroidism. It must be given by 
subcutaneous injection every 1–2 days. Side effects of 
rhPTH include nausea, vomiting, diarrhea, arthralgias, and 
paresthesias. Also, osteosarcoma has occurred in rats 
receiving very high-dose PTH. The FDA requires that pre
-

-
scribers be certified before prescribing the drug and that 
patients and prescribers formally acknowledge the risk of 
osteosarcoma. rhPTH is expensive, which limits its use.
Transplantation of cryopreserved parathyroid tissue, 
removed during prior surgery, restores normocalcemia in 
about 23% of cases.
Hypoparathyroidism in pregnancy
 presents special 
challenges. Maternal hypocalcemia can adversely affect 
the skeletal development of the fetus and cause compensa
-
tory hyperparathyroidism in the newborn. Maternal 
hypercalcemia can suppress fetal parathyroid develop
-
ment, resulting in neonatal hypocalcemia. This requires 
very close clinical and biochemical monitoring during 
Caution:
 Phenothiazine drugs should be administered 
with caution, since they may precipitate extrapyramidal 
symptoms in hypocalcemic patients. Furosemide should be 
avoided, since it may worsen hypocalcemia.
 
»
Prognosis
Patients with mild hypoparathyroidism generally do well. 
Periodic serum calcium levels are required, since changes 
may call for modification of the treatment schedule. 
Hypercalcemia that develops in patients with seemingly 
stable, treated hypoparathyroidism may be a presenting 
sign of Addison disease.
Despite optimal therapy, patients with moderate-to-
severe hypoparathyroidism have been reported to have an 
overall reduced quality of life. Chronically affected patients 
frequently develop calcifications in their kidneys and basal 
ganglia. They have an increased risk of calcium kidney 
stones and kidney dysfunction as well as seizures, mood 
and psychiatric disorders, and a reduced overall sense of 
well-being. Therapy with rhPTH may prevent or improve 
these manifestations.
Bilezikian JP et al. Management of hypoparathyroidism: present 
and future. J Clin Endocrinol Metab. 2016 Jun;101(6):2313–24. 
[PMID: 26938200]
Brandi ML et al. Management of hypoparathyroidism: summary 
statement and guidelines. J Clin Endocrinol Metab. 2016 
Jun;101(6):2273–83. [PMID: 26943719]
Shoback DM et al. Presentation of hypoparathyroidism: etiolo
-
gies and clinical features. J Clin Endocrinol Metab. 2016 
Jun;101(6):2300–12. [PMID: 26943721]
Tafaj O et al. Pseudohypoparathyroidism: one gene, several syn
-
dromes. J Endocrinol Invest. 2017 Apr;40(4):347–56. [PMID: 
27995443]
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HYPERPARATHYROIDISM
 
»
Often found incidentally by routine blood testing.
 
»
Renal calculi, polyuria, hypertension, constipation, 
fatigue, mental changes.
 
»
Bone pain; rarely, cystic lesions and pathologic 
fractures.
 
»
Elevated PTH, serum and urine calcium, and urine 
phosphate; serum phosphate low to normal; alka
-
line phosphatase normal to elevated.
 
»
 is the most common cause 
of hypercalcemia, with a prevalence of 1000 to 4000 cases 
per 1 million persons. It occurs at all ages but most com
-
monly in the seventh decade and in women (74%). Before 
age 45, the prevalence is similar in men and women. It is 
more prevalent in blacks, followed by whites, then other 
races.
Parathyroid glands vary in number and location and 
ectopic parathyroid glands have been found within the 
thyroid gland, high in the neck or carotid sheath, in the 
retroesophageal space, and within the thymus or mediasti
-
num. Hyperparathyroidism is caused by hypersecretion of 
PTH, usually by a single parathyroid adenoma (80%), and 
less commonly by hyperplasia of two or more parathyroid 
glands (20%), or carcinoma (less than 1%). However, when 
hyperparathyroidism presents before age 30 years, there is 
a higher incidence of multiglandular disease (36%) and 
parathyroid carcinoma (5%). The size of the parathyroid 
adenoma correlates with the serum PTH level.
Hyperparathyroidism is familial in about 10% of cases; 
hyperparathyroidism presenting before age 45 has a higher 
chance of being familial. Parathyroid hyperplasia may arise 
in MEN types 1, 2 (2A), and 4. (See Table 26–12.) In 
MEN 1, multiglandular hyperparathyroidism is usually the 
initial manifestation and ultimately occurs in 90% of 
affected individuals. Hyperparathyroidism in MEN 2 (2A) 
is less frequent that in MEN 1 and is usually milder.
Hyperparathyroidism results in the excessive excretion 
of calcium and phosphate by the kidneys. PTH stimulates 
renal tubular reabsorption of calcium; however, hyperpara
-
thyroidism causes hypercalcemia and an increase in cal
-
cium in the glomerular filtrate that overwhelms tubular 
reabsorption capacity, resulting in hypercalciuria. At least 
5% of renal calculi are associated with this disease. Diffuse 
parenchymal calcification (nephrocalcinosis) is seen less 
commonly. Hyperparathyroidism causes demineralization 
of cortical bone and a gain of trabecular bone. Severe, 
chronic hyperparathyroidism can cause pathologic frac
-
tures, and cystic bone lesions throughout the skeleton, a 
condition known as 
osteitis fibrosa cystic
.
Parathyroid carcinoma
 is a rare cause of hyperparathy
-
roidism, accounting for less than 1% of hyperparathyroidism. 
There is typically a palpable neck mass (75%). About 90% of 
parathyroid carcinomas are functional and present with 
serum calcium levels greater than or equal to 14.0 mcg/dL 
(3.5 mmol/L) or serum PTH levels greater than 5 times 
normal. However, some cases present with smaller tumors, 
less severe hypercalcemia, and benign-appearing histologic 
features. Local recurrence is the rule if surgical margins are 
positive. Distant metastases arise most commonly in the 
lungs but also in bones, liver, brain, and mediastinum. 
Although parathyroid carcinoma is typically indolent, an 
increasing tumor burden is associated with critically severe 
hypercalcemia and death.
Secondary and tertiary hyperparathyroidism
 usually 
occurs in patients with chronic kidney disease, in which 
hyperphosphatemia and decreased renal production of 
1,25-dihydroxycholecalciferol (1,25[OH]
2
D
3
) initially pro
-
duce a decrease in ionized calcium. The parathyroid glands 
are stimulated (secondary hyperparathyroidism) and may 
enlarge, becoming autonomous (tertiary hyperparathyroid
-
ism). The bone disease seen in this setting is known as 
renal 
osteodystrophy
 (see Disorders of Mineral Metabolism,

-
renal 
 (see Disorders of Mineral Metabolism, 
Chapter 22). Hypercalcemia often occurs after kidney trans
-
plant. Secondary hyperparathyroidism predictably develops 
in patients with a deficiency in vitamin D. Serum calcium 
levels are typically in the normal range, but may rise to 
become borderline elevated with time, with tertiary hyper
-
parathyroidism due to parathyroid glandular hyperplasia.
 
»
In the developed world, hypercalcemia is typically discov
-
ered incidentally by routine chemistry panels. Many 
patients are asymptomatic or have mild symptoms that 
may be elicited only upon questioning. Parathyroid adeno
-
mas are usually so small and deeply located in the neck that 
they are almost never palpable; when a mass is palpated, it 
usually turns out to be an incidental thyroid nodule.
Symptomatic patients are said to have problems with 
“bones, stones, abdominal groans, psychic moans, with 
fatigue overtones. ”
1. Skeletal manifestations—
Low bone density is typically 
most prominent at the wrist and hip; there is a relatively 
higher spinal (trabecular) bone density compared to the 
wrist. Postmenopausal women are prone to asymptomatic 
vertebral fractures. Although significant bone demineral
-
ization is uncommon in mild hyperparathyroidism, osteitis 
fibrosa cystica may present as pathologic fractures or as 
“brown tumors” or cysts of the jaw. More commonly, 
patients experience arthralgias and bone pain, particularly 
involving the legs.
2. Hypercalcemia manifestations—
Mild hypercalcemia 
may be asymptomatic. However, hypercalcemia of hyper
-
parathyroidism usually causes a variety of manifestations 
whose severity is not entirely predictable by the level of 
serum calcium or PTH. In fact, patients with only mild 
hypercalcemia can have significant symptoms, particularly 
depression, constipation, and bone and joint pain. 
Neuro
-
muscular
 manifestations include paresthesias, muscle 
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cramps and weakness, and diminished deep tendon reflexes. 
 manifestations include malaise, 
headache, fatigue, intellectual weariness, insomnia, irrita
-
bility, and depression. Patients may have cognitive impair
-
ment that can vary from intellectual weariness to more 
severe disorientation, psychosis, or stupor. 
 
symptoms include hypertension, palpitations, prolonged 
P-R interval, shortened Q-T interval, bradyarrhythmias, 
heart block, asystole, and sensitivity to digitalis. 
Kidney
 
manifestations include polyuria and polydipsia, caused by 
hypercalcemia-induced nephrogenic diabetes insipidus. 
Among all patients with newly discovered hyperparathy
-
roidism, calcium-containing renal calculi have occurred or 
are detectable in about 18%. Patients with asymptomatic 
hyperparathyroidism have a 7% incidence of asymptomatic 
calcium nephrolithiasis, compared to 1.6% incidence in 
age-matched controls. 
 symptoms include 
anorexia, nausea, heartburn, vomiting, abdominal pain, 
weight loss, constipation, and obstipation. Pancreatitis 
occurs in 3%. Pruritus may be present. Calcium may pre
-
cipitate in the corneas (“band keratopathy”), in extravascu
-
lar tissues (calcinosis) and in small arteries, causing small 
vessel thrombosis and skin necrosis (calciphylaxis).
3. Normocalcemic primary hyperparathyroidism—
Patients with normocalcemic primary hyperparathyroid
-
ism generally have few symptoms. However, on average, 
such patients have a slightly more atherogenic lipid panel 
and higher blood pressures (systolic blood pressure 
10 mm Hg higher and diastolic blood pressure 7 mm Hg 
higher) than controls. Also, affected patients can have very 
subtle symptoms, such as mild fatigue, that may not be 
appreciated as abnormal.
4. Hyperparathyroidism during pregnancy—
Pregnant 
women having mild hyperparathyroidism with a serum 
calcium below 11.0 mg/dL (less than 2.75 mmol/L) gener
-
ally tolerate pregnancy well with normal outcomes. How
-
ever, the majority of women with more severe hypercalcemia 
during pregnancy experience complications such as neph
-
rolithiasis, hyperemesis, pancreatitis, muscle weakness, 
and cognitive changes. Hypercalcemic crisis may occur, 
especially postpartum. About 80% of fetuses experience 
complications of maternal hyperparathyroidism, including 
fetal demise, preterm delivery, and low birth weight. New
-
borns have hypoparathyroidism that can be permanent. 
Hypocalcemia in the infant can present with tetany even 
2–3 months after delivery.
5. Parathyroid carcinoma—
Parathyroid carcinoma must 
always be suspected in patients with a serum calcium 
greater than or equal to 14.0 mcg/dL (3.5 mmol/L), a 
serum PTH greater than or equal to 5 times the upper 
limit of normal, hyperparathyroidism with a large neck 
mass, or vocal fold paralysis from recurrent laryngeal 
nerve palsy. FNA biopsy is not recommended because it 
may seed the biopsy tract with tumor and cytologic dis
-
tinction between benign and malignant tumors is prob
-
lematic. Parathyroid carcinoma is more frequent in 
patients with hyperparathyroidism–jaw tumor (HP-JT) 
syndrome as well as patients with MEN 1 and MEN 2A. 
Therefore, patients should have genetic testing.
The hallmark of primary hyperparathyroidism is hypercal
-
cemia, with the serum adjusted total calcium greater than 
10.5 mg/dL (10.6 mmol/L). The adjusted total calcium = 
measured serum calcium in mg/dL + [0.8 × (4.0 – patient’s 
serum albumin in g/dL)]. Serum ionized calcium levels 
should be in the 4.6–5.3 mg/dL (1.15–1.32 mmol/L) range.
To confirm the diagnosis of hyperparathyroidism, an 
assessment of urinary calcium excretion is recommended, 
particularly for patients with mild hyperthyroidism. In pri
-
mary hyperparathyroidism the urine calcium excretion may 
be high or normal: 100–300 mg/day (25–75 mmol/day).

-
be high or normal: 100–300 mg/day (25–75 mmol/day). 
However, low urine calcium excretions (below 100 mg/day 
[25 mmol/day]) in the absence of thiazide diuretics, occurs 
in only 4% of cases of primary hyperthyroidism and raises 
the differential diagnosis of familial hypocalciuric 
The serum phosphate is often less than 2.5 mg/dL 
(0.8 mmol/L). There is an excessive loss of phosphate in the 
urine in the presence of hypophosphatemia (25% of cases), 
whereas the serum phosphate may be high in kidney 
disease, which causes secondary hyperparathyroidism. The 
alkaline phosphatase is elevated only if bone disease is 
present. The plasma chloride and uric acid levels may be 
elevated. Vitamin D deficiency is common in patients with 
hyperparathyroidism, and it is prudent to screen for 
vitamin D deficiency with a serum 25-OH vitamin D deter
-
mination. Serum 25-OH vitamin D levels below 20 mcg/L 
(50 nmol/L) can aggravate hyperparathyroidism and its 
bone manifestations; vitamin D replacement may be helpful 
in treating such patients with hyperparathyroidism.
Elevated serum levels of intact PTH confirm the diag
-
nosis of hyperparathyroidism. Patients with apparent 
hyperparathyroidism should be screened for familial 
benign hypocalciuric hypercalcemia with a 24-hour urine 
for calcium and creatinine. Patients should discontinue 
thiazide diuretics prior to this test. Calcium excretion of 
less than 50 mg/24 hours (12.5 mmol/24 hours) or less than 
5 mg/dL (1.25 mmol/L) on a random urine is not typical 
for primary hyperparathyroidism and indicates possible 
familial benign hypocalciuric hypercalcemia.
Patients with low bone density who have an elevated 
serum PTH but a normal serum calcium must be evaluated 
for causes of secondary hyperparathyroidism (eg, vitamin D 
or calcium deficiency, hyperphosphatemia, chronic kidney 
disease). In the absence of secondary hyperparathyroidism, 
patients with an elevated serum PTH but normal serum 
calcium are determined to have normocalcemic hyperpara
-
thyroidism. Such individuals require monitoring, since 
hypercalcemia develops in about 19% of patients over 
3 years of follow-up.
Genetic testing
 is recommended for patients with docu
-
mented primary hyperparathyroidism who are younger 
than age 40 or who have multiglandular disease or a family 
history of hyperparathyroidism.
C. Imaging
Parathyroid imaging is not necessary for the diagnosis of 
hyperparathyroidism. Imaging is performed for most 
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patients prior to parathyroid surgery and is particularly 
important for patients who have had prior neck surgery. 
The visualization of an apparent parathyroid adenoma 
helps secure the diagnosis when there is occasional diag
-
nostic difficulty and often allows for minimally invasive 
surgery.
Ultrasound
 of the neck should scan the neck from the 
mandible to the superior mediastinum in an effort to locate 
ectopic parathyroid adenomas. Ultrasound has a sensitivity 
of 79% for single adenomas but only 35% for multiglandu
-
Sestamibi scintigraphy
 with 
99m
Tc-sestamibi and sin
-
gle-photon emission computed tomography (SPECT) is 
most useful for localizing parathyroid adenomas. However, 
false-positive scans are common, caused by thyroid nod
-
ules, thyroiditis, or cervical lymphadenopathy. Sestamibi-
SPECT imaging improves sensitivity for single parathyroid 
adenomas. Small benign thyroid nodules are discovered 
incidentally in nearly 50% of patients with hyperparathy
-
roidism who have imaging with ultrasound or MRI.
18
F-flurocholine PET/MRI
 is a useful scan for patients 
with primary hyperparathyroidism and negative or discor
-
dant localization imaging on neck ultrasound and sesta
-
mibi scanning. In a small study, the sensitivity of this scan 
was 90%, with a 100% positive predictive value.
Conventional CT and MRI
 imaging are not usually 
required prior to a first neck surgery for hyperparathyroid
-
ism. However, a four-dimensional CT (4D-CT), with the 
fourth dimension referring to time, captures the rapid 
uptake and washout of contrast from parathyroid adeno
-
mas; it is particularly useful for preoperative imaging when 
ultrasonography and sestamibi scans are negative. It can 
also be helpful for patients who have had prior neck sur
-
gery and for those with ectopic glands. In such patients, 
4D-CT has a sensitivity of 88%, versus 54% for sestamibi 
SPECT and 21% for ultrasound. However, 4D-CT delivers 
more radiation to the thyroid and so is used mostly for 
older patients. MRI may also be useful for repeat neck 
operations and when ectopic parathyroid glands are sus
-
pected. MRI does not deliver radiation and shows better 
soft tissue contrast than CT.
Patients with hyperparathyroidism have a high risk of 
calcium nephrolithiasis. Therefore, it has been suggested 
that all patients with hyperparathyroidism have noncon
-
trast-enhanced CT scanning of the kidneys to determine 
whether calcium-containing stones are present. For 
patients with apparently asymptomatic hyperparathyroid
-
ism, the presence or absence of calcium nephrolithiasis can 
be a deciding factor about whether to have parathyroidec
-
tomy surgery.
Bone density measurements
 by dual energy x-ray 
absorptiometry (DXA) are helpful in determining the 
amount of bone loss in patients with hyperparathyroidism. 
Bone loss occurs mostly in long bones, and DXA should ide
-
ally include three areas: lumbar spine, hip, and distal radius.
Bone radiographs are usually normal and are not 
required to make the diagnosis of hyperparathyroidism. 
There may be demineralization, subperiosteal resorption 
of bone (especially in the radial aspects of the fingers), or 
loss of the lamina dura of the teeth. There may be cysts 
throughout the skeleton, mottling of the skull (“salt-and-
pepper appearance”), or pathologic fractures. Articular 
cartilage calcification (chondrocalcinosis) is sometimes 
found.
Patients with renal osteodystrophy may have ectopic 
calcifications around joints or in soft tissue. Such patients 
may exhibit radiographic changes of osteopenia, osteitis 
fibrosa cystica, or osteosclerosis, alone or in combination. 
Osteosclerosis of the vertebral bodies is known as “rugger 
jersey spine. ”
 
»
Pathologic long bone fractures are a complication of hyper
-
parathyroidism. Urinary tract infection due to stone and 
obstruction may lead to kidney disease and uremia. If the

»
-
obstruction may lead to kidney disease and uremia. If the 
serum calcium level rises rapidly, clouding of sensorium, 
kidney disease, and rapid precipitation of calcium through
-
out the soft tissues may occur. Peptic ulcer and pancreatitis 
may be intractable before surgery. Insulinomas or gastrino
-
mas may be associated, as well as pituitary tumors (MEN 
type 1). Pseudogout may complicate hyperparathyroidism 
both before and after surgical removal of tumors. Hypercal
-
cemia during gestation produces neonatal hypocalcemia.
In tertiary hyperparathyroidism due to chronic kidney 
disease, high serum calcium and phosphate levels may 
cause disseminated calcification in the skin, soft tissues, 
and arteries (calciphylaxis); this can result in painful isch
-
emic necrosis of skin and gangrene, cardiac arrhythmias, 
and respiratory failure. The actual serum levels of calcium 
and phosphate have not correlated well with calciphylaxis, 
but a calcium (mg/dL) × phosphate (mg/dL) product over 
70 is usually present.
 
»
Artefactual hypercalcemia
 is common, so a confirmatory 
serum calcium level should be drawn after an overnight fast 
along with a serum protein, albumin, and triglyceride while 
ensuring that the patient is well-hydrated. Hypercalcemia 
may be due to high serum protein concentrations; in the 
presence of very high or low serum albumin concentrations, 
an adjusted serum calcium or a serum ionized calcium is 
more dependable than the total serum calcium concentra
-
tion. Hypercalcemia may also be seen with dehydration.
Hypercalcemia of malignancy
 occurs most frequently 
with breast, lung, pancreatic, uterine, and renal cell carci
-
noma, and paraganglioma. Most of these tumors secrete 
PTH-related protein (PTHrP) that has tertiary structural 
homologies to PTH and causes bone resorption and hyper
-
calcemia similar to those caused by PTH. Serum PTH lev
-
els are low or low-normal while serum PTHrP levels are 
elevated; phosphate is often low. Other tumors can secrete 
excessive 1,25 (OH)
2
 vitamin D
3
, particularly lymphopro
-
liferative and ovarian malignancies. The clinical features of 
malignant hypercalcemia can closely simulate hyperpara
-
thyroidism. However, serum PTH levels are usually low. 
Serum PTHrP or 1,25 (OH)
2
 vitamin D
3
 may be elevated.
Pseudohyperparathyroidism of pregnancy
 presents 
with hypercalcemia during pregnancy. It is caused by 
hypersensitivity of the breasts to PRL. The breasts become 
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abnormally enlarged and secrete excessive amounts of 
PTHrP that causes hypercalcemia. Treatment with dopa
-
mine agonists reverses the hypercalcemia.
 causes hypercalcemia in older 
individuals. Many other hematologic cancers, such as mono
-
cytic leukemia, T cell leukemia and lymphoma, and Burkitt 
lymphoma, have also been associated with hypercalcemia.
Sarcoidosis and other granulomatous disorders
, such 
as tuberculosis, berylliosis, histoplasmosis, coccidioidomy
-
cosis, leprosy, and foreign-body granuloma, can cause 
hypercalcemia. Sarcoid granulomas can secrete PTHrP , but 
granulomas secrete 1,25(OH)
2
D
3
 and serum levels of 
1,25(OH)
2
D
3
 are usually elevated in the presence of hyper
-
calcemia. However, in hypercalcemia with disseminated 
coccidiomycosis, serum 1,25(OH)
2
D
3
 levels may not be 
elevated. Serum PTH levels are usually low.
Excessive calcium or vitamin D ingestion
 can cause 
hypercalcemia, especially in patients who concurrently 
take thiazide diuretics, which reduce urinary calcium loss. 
Hypercalcemia is reversible following withdrawal of cal
-
cium and vitamin D supplements. If hypercalcemia per
-
sists, the possibility of associated hyperparathyroidism 
should be considered. In vitamin D intoxication, hypercal
-
cemia may persist for several weeks. Serum levels of 
25-hydroxycholecalciferol (25[OH]D
3
) are helpful to con
-
firm the diagnosis. A brief course of corticosteroid therapy 
may be necessary if hypercalcemia is severe.
Familial hypocalciuric hypercalcemia (FHH)
 can be 
mistaken for mild hyperparathyroidism and vice versa. 
FHH is an uncommon autosomal dominant inherited dis
-
order the prevalence of primary hyperparathyroidism is 
about 200 times that of FHH. It is caused by a loss-of-
function mutation in the gene encoding the calcium sens
-
ing receptor (CaSR). Reduced function of the CaSR causes 
the parathyroid glands to falsely “sense” hypocalcemia and 
inappropriately release slightly excessive amounts of PTH. 
The renal tubule CaSRs are also affected, causing hypocal
-
ciuria. Patients with FHH are asymptomatic and have an 
excellent prognosis.
FHH is characterized by a mildly elevated serum calcium 
that is usually below 11.0 mg/dL (2.75 mmol/L) and a low 
urine calcium excretion that is usually less than 50 mg/24 h 
(13 mmol/24 h). Serum PTH levels are usually normal or 
minimally elevated. Serum phosphate levels are normal. 
These patients do not normalize their hypercalcemia after 
subtotal parathyroid removal and should not be subjected to 
surgery. Since about 4% of patients with true hyperparathy
-
roidism can have a low urine calcium (below 100 mg/day). 
FHH can be confirmed with genetic testing for CaSR recep
-
tor gene mutations, which is 90% sensitive for FHH.
Prolonged immobilization
 at bed rest commonly 
causes hypercalcemia, particularly in adolescents, critically 
ill patients, and patients with extensive Paget disease of 
bone. Hypercalcemia develops in about one-third of 
acutely ill patients being treated in intensive care units, 
particularly patients with acute kidney injury. Serum cal
-
cium elevations are typically mild but may reach 15 mg/dL 
(3.75 mmol/L). Serum PTH levels are usually slightly ele
-
vated, consistent with mild hyperparathyroidism but may 
be suppressed or normal.
Rare causes of hypercalcemia
 include untreated adre
-
nal insufficiency. Modest hypercalcemia is occasionally 
seen in patients taking thiazide diuretics or lithium; such 
patients may have an inappropriately nonsuppressed PTH 
level with hypercalcemia. Hyperthyroidism causes 
increased turnover of bone and occasional hypercalcemia. 
Bisphosphonates can increase serum calcium in 20% and 
serum PTH becomes high in 10%, mimicking hyperpara
-
thyroidism. Hypercalcemia may also occur following liver 
transplantation. Other causes of hypercalcemia are shown 
in Table 21–8.
 
»
Treatment

-
 
»
Treatment
A. “Asymptomatic” Primary Hyperparathyroidism
Patients with mild hyperparathyroidism should be consid
-
ered “asymptomatic” only after very close questioning. 
Many patients may not realize they have manifestations, 
such as cognitive slowing, having become accustomed to 
such symptoms over years. It is important to assess blood 
pressure, kidney function with a serum BUN and creati
-
nine, and to determine the presence of nephrolithiasis or 
nephrocalcinosis by radiography, ultrasonography, or CT 
scan of the kidneys. Truly asymptomatic patients may be 
closely monitored and advised to keep active, avoid immo
-
bilization, and drink adequate fluids. For postmenopausal 
women with hyperparathyroidism, estrogen replacement 
therapy reduces serum calcium by an average of 0.75 mg/
dL (0.19 mmol/L) and slightly improves bone density. For 
patients with hypercalciuria (more than 400 mg daily) or 
calcium nephrolithiasis, hydrochlorthiazide may be used 
in doses of 12.5–25 mg daily to reduce calciuria; however, 
serum calcium must be monitored carefully.
Affected patients should avoid large doses of thiazide 
diuretics, vitamin A, and calcium-containing antacids or 
supplements. Serum calcium and albumin are checked at 
least twice yearly, kidney function and urine calcium once 
yearly, and three-site bone density (distal radius, hip, and 
spine) every 2 years. Rising serum calcium should prompt 
further evaluation and determination of serum PTH 
levels.
If it is not clear whether a patient with primary hyper
-
parathyroid is symptomatic, it is reasonable to consider a 
trial of medical therapy with cinacalcet.
1. Fluids—
Hypercalcemia is treated with a large fluid 
intake unless contraindicated. Severe hypercalcemia 
requires hospitalization and intensive hydration with intra
-
venous saline.
2. CaSR activators—
Cinacalcet hydrochloride
 is a calcimi
-
metic agent that binds to sites of the parathyroid glands’ 
extracellular CaSRs to increase the glands’ affinity for 
extracellular calcium, thereby decreasing PTH secretion. 
Cinacalcet may be used as the initial therapy for patients 
with hyperparathyroidism or for failed surgical parathy
-
roidectomy. For mild hypercalcemia, an initial dose of 
15 mg (one-half of a 30-mg tablet) is advisable with weekly 
monitoring of serum calcium and an increased dose every 
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2 weeks if hypercalcemia persists until the patient becomes 
normocalcemic, which is successful in 73% of patients. 
Patients with parathyroid carcinoma and severe hypercal
-
cemia are treated with cinacalcet in addition to zoledro
-
nate. For parathyroid cancer, cinacalcet is administered in 
doses of 30 mg orally twice daily, increased progressively to 
60 mg twice daily, then 90 mg twice daily to a maximum of 
90 mg every 6–8 hours. Cinacalcet is usually well tolerated 
but may cause nausea and vomiting, which are usually 
transient. Hypocalcemia has occurred, even at 30 mg/day. 
About 50% of azotemic patients with secondary or tertiary 
hyperparathyroidism have hypercalcemia that is resistant 
to vitamin D analogs. Cinacalcet is given orally in starting 
doses of 30 mg daily to a maximum of 250 mg daily, with 
dosage adjustments to keep the serum PTH in the range of 
150–300 pg/mL (15.8–31.6 pmol/L). 
Etelcalcetide
 also acti
-
vates the parathyroid glands’ CaSR and reduces hypercalce
-
mia in dialysis patients; it is given intravenously at the end 
of hemodialysis sessions, thereby avoiding the gastrointes
-
tinal side effects of cinacalcet.
Intravenous bisphosphonates are 
potent inhibitors of bone resorption and can temporarily 
treat the hypercalcemia of hyperparathyroidism. Pamidro
-
nate in doses of 30–90 mg (in 0.9% saline) is administered 
intravenously over 2–4 hours. Zoledronate 5 mg is admin
-
istered intravenously over 15–20 minutes. These drugs 
cause a gradual decline in serum calcium over several days 
that may last for weeks to months. Such intravenous 
bisphosphonates are used generally for patients with severe 
hyperparathyroidism in preparation for surgery. Oral 
bisphosphonates, such as alendronate, are not effective for 
treating the hypercalcemia or hypercalciuria of hyperpara
-
thyroidism. However, oral alendronate has been shown to 
improve bone mineral density in the lumbar spine and hip 
(not distal radius) and may be used for asymptomatic 
patients with hyperparathyroidism who have a low bone 
mineral density. It may also be combined with cinacalcet 
for the medical treatment of osteoporosis in patients with 
persistent hyperparathyroidism.
4. Denosumab—
For patients with severe hypercalcemia 
due to parathyroid carcinoma, denosumab 120 mcg subcu
-
taneously monthly may be effective. However, high-dose 
denosumab increases the risk of jaw osteonecrosis and 
serious infections.
5. Vitamin D and vitamin D analogs—
a. 
P
rimary hyperparathyroidism—
vitamin D deficiency, vitamin D replacement may be ben
-
eficial to patients with hyperparathyroidism. Aggravation of 
hypercalcemia does not ordinarily occur. Serum PTH levels 
may fall with vitamin D replacement in doses of 800–2000 
international units daily or more to achieve serum 25-OH 
vitamin D levels 30 ng/mL or more (50 nmol/L or more).
b. 
S
econdary and tertiary hyperparathyroidism 
associated with azotemia—
Calcitriol
, given orally or 
intravenously after dialysis, suppresses parathyroid hyper
-
plasia of kidney disease. For patients with normal serum 
calcium levels, it is given orally in starting doses of 
0.25 mcg on alternate days or daily. Calcitriol often causes 
hypercalcemia, so that serum levels of calcium and 
phosphate must be monitored to ensure that the serum 
Ca
2+
 × PO
4
3
 product remains no greater than 70. If the 
product exceeds 70, the dose of calcitriol is decreased or 
the patient is switched to therapy with vitamin D analogs 
or cinacalcet.
The vitamin D analogs 
paricalcitol
 and 
doxercalciferol
 
suppress PTH secretion and cause less hypercalcemia than 
calcitriol. The doses are adjusted to keep serum PTH levels 
in the range of 150–300 pg/mL (15.9–31.8 pmol/L). 
Paricalcitol
 is administered intravenously during dialysis 
three times weekly in starting doses of 0.04–0.1 mcg/kg to a 
maximum dose of 0.24 mcg/kg three times weekly. Alterna
-

-
tively, paricalcitol may be administered orally at doses of 
1–2 mcg daily for serum PTH levels 100–500 pg/mL 
(10.5–53.7 pmol/L) or 2–4 mcg daily for serum PTH levels 
greater than 500 pg/mL (53.7 pmol/L). Dialysis patients 
receiving paricalcitol have improved survival compared 
with patients receiving calcitriol. 
Doxercalciferol
 is admin
-
istered intravenously three times weekly during hemodialy
-
sis to patients with azotemic secondary hyperparathyroidism 
in starting doses of 4 mcg three times weekly to a maxi
-
mum dose of 18 mcg three times weekly. Alternatively, 
doxercalciferol may be administered orally three times 
weekly at dialysis, starting with 10 mcg three times weekly 
at dialysis to a maximum of 60 mcg/wk.
6. Other measures—
Estrogen replacement reduces hyper
-
calcemia slightly in postmenopausal women with hyper
-
parathyroidism. Similarly, oral raloxifene (60 mg/day) may 
be given to postmenopausal women with hyperparathy
-
roidism; it reduces serum calcium an average of 0.4 mg/dL 
(0.1 mmol/L), while having an anti-estrogenic effect on 
breast tissue. Beta-blockers, such as propranolol, may also 
be useful for preventing the adverse cardiac effects of hyper
-
calcemia. Parathyroid carcinoma metastases may be treated 
with radiofrequency ablation or arterial embolization.
C. Surgical Parathyroidectomy
Parathyroidectomy is recommended for patients with 
hyperparathyroidism who are symptomatic or who have 
nephrolithiasis or bone disease. During pregnancy, para
-
thyroidectomy is performed in the second trimester for 
women who are symptomatic or have a serum calcium 
above 11 mg/dL (2.75 mmol/L).
Some patients with seemingly 
asymptomatic hyper
-
parathyroidism
 may be surgical candidates for other rea
-
sons such as (1) serum calcium 1 mg/dL (0.25 mmol/L) 
above the upper limit of normal with urine calcium excre
-
tion greater than 50 mg/24 h (off thiazide diuretics), 
(2) urine calcium excretion greater than 400 mg/day 
(10 mmol/day), (3) creatinine clearance less than 60 mL/min, 
(4) nephrolithiasis or nephrocalcinosis, (5) cortical bone 
density (wrist, hip, or distal radius) indicating osteoporosis 
(T score below –2.5) or previous fragility bone fracture, 
(6) relative youth (under age 50 years), (7) difficulty ensur
-
ing medical follow-up, or (8) pregnancy.
Surgery for patients with “asymptomatic” hyperpara
-
thyroidism may improve bone mineral density and confer 
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modest benefits in social and emotional well-being and 
overall quality of life in comparison to similar patients 
being monitored without surgery. Cognitive function may 
benefit with improvements in nonverbal abstraction and 
memory.
Preoperative parathyroid imaging has been used in an 
attempt to allow unilateral minimally invasive neck surgery 
(see Imaging, above). The reported success rates vary con
-
siderably. Even in patients with concordant sestamibi and 
ultrasound scans, and an intraoperative PTH drop of more 
than 50%, hyperparathyroidism may persist postopera
-
tively in up to 15% of patients.
Without preoperative localization studies, bilateral neck 
exploration is usually advisable for the following: 
(1) patients with a family history of hyperparathyroidism, 
(2) patients with a personal or family history of MEN, and 
(3) patients wanting an optimal chance of success with a 
single surgery. Patients undergoing unilateral neck explo
-
ration can have the incision widened for bilateral neck 
exploration if two abnormal glands are found or if the 
serum quick PTH level falls by less than 63% within 
10 minutes of the parathyroid resection. Parathyroid glands 
are often supernumerary (five or more) or ectopic (eg, 
intrathyroidal, carotid sheath, mediastinum). The optimal 
surgical management for patients with MEN type 1 is sub
-
total parathyroidectomy that usually results in a cure, 
although recurrent hyperparathyroidism develops in 18% 
and the rate of postoperative hypoparathyroidism is high.
Intraoperative quick serum PTH monitoring is helpful 
surgically. Serum PTH levels that fall greater than 63% 
within 10 minutes of a parathyroid adenoma resection indi
-
cates a high likelihood that the surgery will be curative.
Intraoperative near-infrared autofluorescence spectros
-
copy imaging may improve intraoperative localization of 
parathyroid glands in primary hyperparathyroidism, par
-
ticularly when preoperative localization studies have been 
negative or discrepant.
Parathyroid hyperplasia
 is commonly seen with second
-
ary or tertiary hyperparathyroidism associated with uremia. 
Cinacalcet is an alternative to surgery. When surgery is per
-
formed, a subtotal parathyroidectomy is optimal; three and 
one-half glands are usually removed, and a metal clip is left 
to mark the location of residual parathyroid tissue.
 surgery consists of en bloc 
resection of the tumor and ipsilateral thyroid lobe with care 
to avoid rupturing the tumor capsule. If the surgical mar
-
gins are not clear of tumor, postoperative neck radiation 
therapy may be given. Local and distant metastases may be 
debulked or irradiated. Preoperative MRI scanning is 
required to delineate the tumor. Zoledronate or denosumab 
is given preoperatively. Severe hypercalcemia requires mul
-
tiple medical measures, including hydration, furosemide, 
cinacalcet, zoledronate, or denosumab. Patients with refrac
-
tory metastases may receive combined chemotherapy with 
dacarbazine-based chemotherapy that has produced short-
term remissions but with adverse effects.
Complications—
Serum PTH levels fall below normal in 
70% of patients within hours after successful surgery, com
-
monly causing hypocalcemic paresthesias or even tetany. 
Hypocalcemia tends to occur the evening after surgery or 
on the next day. Therefore, frequent postoperative moni
-
toring of serum calcium (or serum calcium plus albumin) 
is advisable beginning the evening after surgery. Once 
hypercalcemia has resolved, liquid or chewable calcium 
carbonate is given orally to reduce the likelihood of hypo
-
calcemia. Symptomatic hypocalcemia is treated with larger 
doses of calcium; calcitriol (0.25–1 mcg daily orally) may 
be added, with the dosage depending on symptom severity. 
Magnesium salts are sometimes required postoperatively, 
since adequate magnesium is required for functional

since adequate magnesium is required for functional 
recovery of the remaining suppressed parathyroid glands.
In about 12% of patients having successful parathyroid 
surgery, PTH levels rise above normal (while serum cal
-
cium is normal or low) by 1 week postoperatively. This 
secondary hyperparathyroidism is probably due to “hun
-
gry bones” and is treated with calcium and vitamin D 
preparations. Such therapy is usually needed only for 
3–6 months but is required long term by some patients.
Hyperthyroidism commonly occurs immediately fol
-
lowing parathyroid surgery. It is caused by release of stored 
thyroid hormone during surgical manipulation of the thy
-
roid. In symptomatic patients, short-term treatment with 
propranolol may be required for several days.
 
»
Prognosis
Patients with symptomatic hyperparathyroidism usually 
experience worsening disease (eg, nephrolithiasis) unless 
they have treatment. Conversely, the majority of com
-
pletely asymptomatic patients with a serum calcium below 
11.0 mg/dL (2.75 mmol/L) remain stable with follow-up. 
However, worsening hypercalcemia, hypercalciuria, and 
reductions in cortical bone mineral density develop in 
about one-third of asymptomatic patients. Therefore, 
asymptomatic patients must be monitored carefully and 
treated with oral hydration and mobilization.
Surgical removal of apparently single sporadic parathy
-
roid adenomas is successful in 94%. Patients with MEN 1 
undergoing subtotal parathyroidectomy may experience 
long remissions, but hyperparathyroidism frequently 
recurs. Despite treatment for hyperparathyroidism, 
patients remain at increased risk for all-cause mortality, 
cardiovascular disease, renal calculi, and kidney dysfunc
-
tion. These increased risks are likely the residuals of pre
-
treatment hypertension and nephrolithiasis.
Spontaneous cure due to necrosis of the tumor has been 
reported but is exceedingly rare. The bones, in spite of 
severe cyst formation, deformity, and fracture, will heal if 
hyperparathyroidism is successfully treated. The presence 
of pancreatitis increases the mortality rate. Acute pancre
-
atitis usually resolves with correction of hypercalcemia, 
whereas subacute or chronic pancreatitis tends to persist. 
Significant kidney damage may progress even after removal 
of a parathyroid adenoma.
Parathyroid carcinoma is associated with 5- and 10-year 
survival rates of 78% and 49%, respectively. A better prog
-
nosis is associated with clear surgical margins and no 
detectable metastases postoperatively. Conversely, positive 
surgical margins or metastases predict a very poor 5-year 
survival. The prognosis is also poorer for nonfunctioning 
parathyroid carcinoma and those tumors that carry a 
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CDC73
 mutation, loss of fibromin, or loss of CaSR expres
-
sion. Repeat surgical debulking procedures may improve 
survival. Aggressive medical management can also prolong 
life. Metastases are relatively radiation-resistant, but addi
-
tional therapies such as radiofrequency ablation or arterial 
embolization may be palliative.
 
»
Refer to parathyroid surgeon for parathyroidectomy.
 
»
Patients with severe hypercalcemia for intravenous hydration.
Bilezikian JP et al. Guidelines for the management of asymptom
-
atic primary hyperparathyroidism: summary statement from 
the Fourth International Workshop. J Clin Endocrinol Metab. 
2014 Oct;99(10):3561–9. [PMID: 25162665]
Block GA et al. Effect of etelcalcetide vs cinacalcet on serum 
parathyroid hormone in patients receiving hemodialysis with 
secondary hyperparathyroidism: a randomized clinical trial. 
JAMA. 2017 Jan 10;317(2):156–64. [PMID: 28097356]
Cetani F et al. Update on parathyroid carcinoma. J Endocrinol 
Invest. 2016 Jun;39(6):595–606. [PMID: 27001435]
Khan AA et al. Primary hyperparathyroidism: review and rec
-
ommendations on evaluation, diagnosis, and management. 
A Canadian and international consensus. Osteoporos Int. 
2017 Jan;28(1):1–19. [PMID: 27613721]
Pawlowska M et al. An overview of normocalcemic primary 
hyperparathyroidism. Curr Opin Endocrinol Diabetes Obes. 
2015 Dec;22(6):413–21. [PMID: 26512768]
Tsvetov G et al. Thiazide treatment in primary hyperparathy
-
roidism—a new indication for an old medication? J Clin Endo
-
crinol Metab. 2017 Apr 1;102(4):1270–6. [PMID: 28388724]
Wilhelm SM et al. The American Association of Endocrine 
Surgeons guidelines for definitive management of primary 
hyperparathyroidism. JAMA Surg. 2016 Oct 1;151(10):959–68. 
[PMID: 27532368]
 
º
METABOLIC BONE DISEASE
The term “metabolic bone disease” denotes those condi
-
tions producing diffusely decreased bone density and 
diminished bone strength. It is categorized by histologic 
appearance: osteoporosis (bone matrix and mineral both 
decreased) and osteomalacia (bone matrix intact, mineral 
decreased). Osteoporosis and osteomalacia often coexist in 
the same patient.
OSTEOPOROSIS
 
»
Fracture propensity of spine, hip, pelvis, and wrist 
from depletion of bone matrix with subsequent 
demineralization.
 
»
Asymptomatic until a fracture has occurred.
 
»
Serum PTH, calcium, phosphorus, and alkaline 
phosphatase usually normal.
 
»
Serum 25-hydroxyvitamin D levels often low as a 
comorbid condition.
Table 26–9.
 
Causes of osteoporosis.
1
Aging
Hormone deficiency
 
Estr
adiol (women)
 
T
estosterone (men)
Hormone excess
 
C
ushing syndrome or 
 
corticosteroid 
 
Immobilization and 
microgravity
Malignancy, especially plasma 
cell myeloma
Tobacco
Medications (long-term)
 
Ar
omatase inhibitors
 
Heparin
 
Pioglitazone
 
P
 
S
elective serotonin reuptake 
 
SGL
T2 inhibitors
 
V
itamin A excess, vitamin D 
 
excess
Genetic disorders
 
Ar
omatase deficiency
 
C
ollagen disorders
 
Ehlers-Danlos 
syndrome
 
Homocystinuria
 
Idiopa
thic juvenile and adult 
 
osteoporosis
 
M
arfan syndrome
 
Ost
eogenesis imperfecta
Miscellaneous conditions
 
Anor
exia nervosa
 
C
 
C
 
Diabet
es mellitus 
 
(uncontrolled)
 
H
yponatremia (chronic)
 
Inflammatory bowel 
 
disease
 
Liv
er disease (chronic)
 
M
astocytosis (systemic)
 
P
rotein-calorie malnutrition
 
R
heumatoid arthritis
 
V
itamin C deficiency
1
See Table 26–10 for causes of osteomalacia.
 
»
Osteoporosis is a skeletal disorder characterized by a loss of 
bone osteoid that reduces bone integrity and bone strength, 
predisposing to an increased risk of fracture. Osteoporosis 
causes over 1.5 million fractures annually, most commonly

causes over 1.5 million fractures annually, most commonly 
vertebral fractures, followed by hip fractures (300,000 
annually) and pelvic fractures. In the United States, at least 
20% of men and women over age 50 years have one or more 
fractured vertebrae. White women age 50 years and older 
(who do not receive estrogen replacement) have a 46% risk 
of sustaining an osteoporotic fracture during the remain
-
der of their lives. Vertebral fractures are the most common 
fracture; they are associated with increased mortality, pain, 
and spinal kyphosis, although they are usually diagnosed 
incidentally on radiographs or CT scanning. Hip fractures 
are also associated with increased mortality, pain, reduced 
independence, and diminished quality of life.
The frequency of fragility fractures varies with ethnicity, 
sex, and age. The lifetime risk of hip fracture in the United 
States is 15.8% in white women and 6.0% in white men, 8.5% 
in Hispanic women and 3.8% in Hispanic men, and 2.4% in 
Chinese women and 1.9% in Chinese men. Blacks also have 
a lower risk for fracture due to higher bone mineral density 
and hip morphology that is less fracture-prone. There is 
much less ethnic variability for vertebral fractures. The 
prevalence of vertebral fractures in women older than 65 years 
is 70% for white women, 68% for Japanese women, 55% for 
Mexican women, and 50% in African American women.
Osteoporosis can be caused by a variety of factors, 
which are listed in Table 26–9. The most common causes 
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include aging, sex hormone deficiency, alcoholism, smok
-
ing, long-term proton pump inhibitor therapy, and high-
dose corticosteroid administration. Hypogonadal men 
frequently develop osteoporosis. Anti-androgen therapy 
for prostate cancer can cause osteoporosis and such men 
should be monitored with bone densitometry.
 
»
Osteoporosis is usually asymptomatic until fractures occur. 
It may present as backache of varying degrees of severity or 
as a spontaneous fracture or collapse of a vertebra. Loss of 
height is common. Once osteoporosis is identified, a care
-
fully directed history and physical examination must be 
performed to determine its cause (Table 26–9).
The objective for laboratory testing is to screen for second
-
ary causes of osteoporosis or concomitant osteomalacia. 
For primary osteoporosis, the BUN, creatinine, albumin, 
serum calcium, phosphate, and PTH are normal. The alka
-
line phosphatase is usually normal but may be slightly ele
-
vated, especially following a fracture. A low serum alkaline 
phosphatase (below 40 units/L in adults) may indicate 
hypophosphatasia. A complete blood count is obtained and 
is usually normal; for patients with anemia, further screen
-
ing is required, including a serum protein electrophoresis 
to screen for myeloma and intestinal malabsorption screen
-
ing, where indicated. Vitamin D deficiency is very com
-
mon and serum determination of 25-hydroxyvitamin D 
should be obtained for every individual with low bone 
density. Serum 25-hydroxyvitamin D levels below 20 ng/
mL (50 nmol/L) are considered frank vitamin D deficiency. 
Lesser degrees of vitamin D insufficiency (serum 
25-hydroxyvitamin D levels in the range of 20–30 ng/mL 
[50–75 nmol/L]) may also slightly increase the risk for hip 
fracture. Testing for thyrotoxicosis and hypogonadism may 
be required. If intestinal malabsorption is suspected, 
appropriate screening should be performed. Celiac disease 
may be screened for with serum tissue transglutaminase 
antibody determinations.
C. Bone Densitometry
Dual-energy x-ray absorptiometry (DXA)
 is used to 
determine the bone density of the lumbar spine, hip, and 
distal radius. Bone densitometry should be performed on 
all patients who are at risk for osteoporosis or osteomala
-
cia, including all postmenopausal women aged 65 years 
and older and all men aged 70 years and older. DXA 
screening should also be considered for younger post
-
menopausal women with elevated risk, especially women 
with early menopause and those with a family history of 
osteoporosis. It should also be performed in younger 
patients who have had pathologic fractures or radiographic 
evidence of diminished bone density. DXA delivers negli
-
gible radiation, and the measurements are quite accurate. 
However, DXA cannot distinguish osteoporosis from 
osteomalacia; in fact, both are often present. Also, the bone 
mineral density does not directly measure bone quality and 
is only fairly successful at predicting fractures. Vertebral 
bone mineral density may be misleadingly high in com
-
pressed vertebrae and in patients with extensive arthritis. 
DXA also overestimates the bone mineral density of taller 
persons and underestimates the bone mineral density of 
smaller persons.
Bone mineral density is typically expressed in g/cm
2
, for 
which there are different normal ranges for each bone and 
for each type of DXA-measuring machine. The “T score” is 
a simplified way of reporting bone density in which the 
patient’s bone mineral density is compared to the young 
normal mean and expressed as a standard deviation score. 
The World Health Organization has established criteria for 
defining osteoporosis based upon the T score:
T score ≥ –1.0: Normal.
T score –1.0 to –2.5: Osteopenia (“low bone density”).
T score < –2.5: Osteoporosis.
T score < –2.5 with a fracture: Severe osteoporosis.

It is prudent to obtain DXA bone density measure
-
ments at two or three sites, including total lumbar spine 
and total hip. DXA bone density of the non-dominant 
distal radius is helpful for patients with hyperparathyroid
-
ism, for men receiving androgen deprivation therapy, and 
for patients with conditions causing other DXA measure
-
ment artifacts. Such artifacts can be caused by hip arthro
-
plasties, spinal orthopedic hardware, severe spinal arthritis, 
or lumbar vertebral compression fractures; in such patients, 
only noncompressed vertebrae are relevant. Any bone den
-
sity classification is somewhat arbitrary and there really is 
no bone mineral density fracture threshold; instead, the 
fracture risk increases about twofold for each standard 
deviation drop in bone mineral density. Surveillance DXA 
bone densitometry is recommended for postmenopausal 
women and elderly men with a frequency according to 
their T scores: obtain DXA every 5 years for T scores –1.0 
to –1.5, every 3–5 years for scores –1.5 to –2.0, and every 
1–2 years for scores under –2.0.
The “Z score” is used to express bone density in pre
-
menopausal women and young adult men. The Z score is a 
statistical term expressing an individual’s bone density as 
standard deviation from age-matched, race-matched, and 
sex-matched means.
Pharmacologic treatment is recommended for patients 
with a spontaneous hip or vertebral fracture or a T score in 
any location less than or equal to –2.5.
Fracture Risk Assessment Tool (FRAX)
 was devel
-
oped by the World Health Organization to better predict an 
individual’s 10-year risk of hip or other major osteoporotic 
fracture. It is particularly useful for treatment decisions in 
patients with osteopenia and takes into consideration age, 
sex, ethnicity, bone mineral density, and other risk factors. 
Treatment is recommended for individuals with osteope
-
nia (T score between –1.0 and –2.5) with a computed 
10-year hip fracture risk of at least 3% or a 10-year risk of 
any major fracture of at least 20%. However, the FRAX 
model has limitations, only considering femoral neck bone 
mineral density and not considering vertebral bone min
-
eral density. Also, FRAX does not consider the 
dose
 of 
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exposure to corticosteroids, alcohol, smoking, or an indi
-
vidual’s proclivity to falls. So treatment decisions must 
always be individualized. FRAX is available for use online 
at http://www.shef.ac.uk/FRAX/.
 
»
Osteopenia and fractures can be caused by osteomalacia 
and bone marrow neoplasia such as myeloma or metastatic 
bone disease. These conditions coexist in many patients 
and cannot be distinguished with bone densitometry.
 
»
A. Nonpharmacologic Measures
For prevention and treatment of osteoporosis, the diet 
should be adequate in protein, total calories, calcium, and 
vitamin D. Pharmacologic corticosteroid (oral, parenteral, 
or inhaled) should be reduced or discontinued if possible. 
Cigarette smoking cessation is strongly urged. Excessive 
alcohol intake must be avoided. Exercise is strongly recom
-
mended to increase both bone density and strength, thereby 
reducing the risk of fractures due to frailty falls. Walking 
increases the bone density at both the spine and hip. Resis
-
tance exercise increases spine density. The patient must 
choose an enjoyable exercise regimen to facilitate long-term 
compliance. Other fall prevention measures include ade
-
quate home lighting, handrails on stairs, handholds in 
bathrooms, and physical therapy training in fall prevention 
and balance exercises. Patients who have weakness or bal
-
ance problems must use a cane or a walker; rolling walkers 
should have a brake mechanism. Medications that cause 
orthostasis, dizziness, or confusion should be avoided.
Generally, treatment is indicated for all patients with osteo
-
porosis (DXA T scores below –2.5), women with previous 
fragility fractures of the hip or vertebra, or a DXA T score 
between –2.5 and –1.0 with FRAX-determined (see above) 
10-year hip fracture risk greater than 3% or major osteopo
-
rotic fracture risk greater than 20%.
1. Vitamin D and calcium—
Deficiency of vitamin D or 
calcium causes osteomalacia, rather than osteoporosis, but 
they often coexist and cannot be distinguished by DXA 
bone densitometry; it is crucial to ensure sufficient vitamin 
D and calcium intake. Recommended daily vitamin D 
intake of 600–800 units/day is difficult to achieve by diet 
(unless high in fish) and sun exposure, particularly during 
winter months and for patients with intestinal malabsorp
-
tion or during prolonged hospitalization or nursing home 
care. Oral vitamin D
3
 (cholecalciferol) is given either as a 
universal supplement of 800–2000 units/day or in doses 
titrated to achieve 25-hydroxvitamin D (25-OHD) serum 
levels greater than or equal to 20 ng/mL (50 nmol/L) for 
most of the population. However, the 25-OHD serum 
levels should be maintained at 30 ng/mL (75 nmol/L) or 
higher for those “at risk”: pregnant women, older adults, 
and those with osteoporosis or fragility fractures. There are 
early observational data of adverse outcomes (increased 
heart disease and all-cause mortality) at 25-OHD serum 
levels greater than 50 ng/mL (125 nmol/L), so the optimal 
therapeutic range for 25-OHD serum levels appears to 
about 30–50 ng/mL (75–125 nmol/L).
A total elemental calcium intake at least 1000 mg/day is 
recommended for all adults and 1200 mg/day for post
-
menopausal women and men older than 70 years. Most 
healthy individuals do not require calcium supplementa
-
tion, and 74% of cohort studies showed no association 
between dietary calcium intake and fracture risk. Other 
studies have reported that associated calcium supplemen
-
tation (1 g/day or more) showed no reduced risk for hip or 
forearm fractures and a mere 14% reduction in vertebral 
fractures. Calcium supplements are generally reserved for 
patients with intestinal malabsorption or calcium-deficient 
diets that do not include dairy products, dark leafy greens, 
sardines, tofu, or fortified foods. Calcium citrate does not

sardines, tofu, or fortified foods. Calcium citrate does not 
require acid for absorption and is preferred for patients 
receiving acid blockers. Calcium carbonate should be taken 
with food to enhance calcium absorption. Calcium supple
-
ments are usually taken along with vitamin D
3
, and many 
commercial supplements contain the combination.
Some reports have indicated that calcium supplements 
increase the risk of myocardial infarction. However, the 
Women’s Health Initiative found that 7 years of vitamin D 
and calcium supplementation did not increase cardiovas
-
cular disease but did increase the risk of nephrolithiasis by 
13%. Taking calcium supplements with meals can reduce 
the risk of nephrolithiasis. Although calcium supplements 
are usually tolerated, some patients experience intestinal 
bloating and constipation.
2. Sex hormones—
Sex hormone replacement can prevent 
osteoporosis in hypogonadal women and men but is not an 
effective therapy for established osteoporosis. Low-dose 
transdermal systemic estrogen prevents osteoporosis in 
women with hypogonadism (see Hormone Replacement 
Therapy). Testosterone replacement therapy prevents osteo
-
porosis in hypogonadal men (see Male Hypogonadism).
Bisphosphonate therapy is indicated 
for patients with a pathologic spine fracture or a low-impact 
hip fracture, and for patients with osteoporosis, defined as a 
DXA T score of –2.5 or less in the spine, total hip, or femo
-
ral neck. They are also indicated for patients with osteope
-
nia (DXA T score between –2.5 and –1.5) and a 
FRAX-determined (see above) 10-year hip fracture risk 
greater than 3% or major osteoporotic fracture risk greater 
than 20%. Bisphosphonates all work similarly, inhibiting 
osteoclast-induced bone resorption. They increase bone 
density significantly and all reduce the incidence of verte
-
bral fractures; all but ibandronate have been demonstrated 
to also reduce the risk of nonvertebral fractures. Bisphos
-
phonates have also been effective in preventing corticoste
-
roid-induced osteoporosis. To ensure intestinal absorption, 
oral bisphosphonates must be taken in the morning with at 
least 8 oz of plain water at least 40 minutes before consump
-
tion of anything else. The patient must remain upright after 
taking bisphosphonates to reduce the risk of esophagitis. No 
dosage adjustments are required for patients with creatinine 
clearances above 35 mL/min. There has been little experi
-
ence giving bisphosphonates to patients with severe kidney 
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disease; if given, the dose would need to be greatly reduced 
and serum phosphate levels monitored. Bone density falls 
in 18% of patients during their first year of treatment with 
bisphosphonates, but 80% of such patients gain bone den
-
sity with continued bisphosphonate treatment. The half-life 
of bisphosphonates in bone is about 10 years. Therefore, 
after 3 years, a DXA bone densitometry may be obtained. If 
the patient’s T score has risen above –2.5 and the patient has 
a relatively low fracture risk, the bisphosphonate may be 
discontinued. However, for patients with continued osteo
-
porosis and a high fracture risk, the bisphosphonate may be 
continued another 2 years.
Alendronate
 is administered orally once weekly as either 
a 70-mg standard tablet (Fosamax) or a 70-mg effervescent 
tablet (Binosto). The effervescent tablet must be dissolved in 
4 oz plain water over at least 5 minutes and stirred 10 seconds 
before drinking; it is easier to swallow for some patients and 
may reduce esophageal injury, but there have been no stud
-
ies comparing it to standard alendronate tablets. 
Risedronate
 
(Actonel) may be given once monthly as a 150-mg tablet. 
Both medications reduce the risk of vertebral and nonverte
-
bral fractures, but alendronate appears to be superior to 
risedronate in preventing nonvertebral fractures. 
Ibandro
-
nate sodium
 (Boniva) is taken once monthly in a dose of 
150 mg orally. It reduces the risk of vertebral fractures but 
not nonvertebral fractures; its effectiveness has not been 
directly compared with other bisphosphonates. Oral 
bisphosphonates can cause nausea, chest pain, and hoarse
-
ness. Erosive esophagus can occur, particularly in patients 
with hiatal hernia and gastroesophageal reflux. Although no 
increased risk of esophageal cancer has been conclusively 
demonstrated, the FDA recommends that bisphosphonates 
not be used by patients with Barrett esophagus.
For patients who cannot take oral bisphosphonates, 
intravenous bisphosphonates are available. 
Zoledronate
 
(Zometa, Reclast) is a third-generation bisphosphonate 
and a potent osteoclast inhibitor. It can be given every 
12 months in doses of 2–5 mg intravenously over at least 
15–30 minutes. 
Pamidronate
 (Aredia) can be given in 
doses of 30–60 mg by slow intravenous infusion in normal 
saline solution every 3–6 months.
Bisphosphonate therapy can cause side effects that are 
collectively known as the acute-phase response. Such a 
response occurs in 42% of patients following the first infu
-
sion of zoledronate and usually starts within the first few 
days following the infusion. Among patients receiving their 
first infusion of zoledronate, these adverse side effects have 
included fever, chills, or flushing (20%); musculoskeletal 
pain (20%); nausea, vomiting, or diarrhea (8%); nonspe
-
cific symptoms, such as fatigue, dyspnea, edema, headache, 
or dizziness (22%); and ocular inflammation (0.6%). Intra
-
venous zoledronate has caused seizures that may be idio
-
syncratic or due to hypocalcemia. The acute-phase 
response tends to diminish with time. Symptoms are tran
-
sient, lasting several days and usually resolving spontane
-
ously but typically recurring with subsequent doses. 
Symptoms may be treated with acetaminophen or NSAIDs. 
Loratadine may reduce musculoskeletal pain. For patients 
experiencing a severe acute-phase response with 
zoledronate, intravenous pamidronate can be substituted 
for subsequent treatment. In addition, patients who experi
-
ence an especially severe acute-phase response can be 
given prophylactic corticosteroids and ondansetron prior 
to subsequent bisphosphonate infusions.
Osteonecrosis of the jaw is a rare complication of 
bisphosphonate therapy for osteoporosis. A painful, 
necrotic, nonhealing lesion of the jaw occurs, particularly 
after tooth extraction. It occurs twice as frequently in the

after tooth extraction. It occurs twice as frequently in the 
mandible compared to the maxilla. The risk is increased 
with older age, in women, and in patients concomitantly 
receiving chemotherapy or corticosteroid therapy. About 
95% of jaw osteonecrosis cases have occurred with high-
dose therapy with zoledronate or pamidronate for patients 
with osteolytic metastases. Only about 5% of cases have 
occurred in patients receiving oral (or, less frequently, 
intravenous) bisphosphonates for osteoporosis. The inci
-
dence of osteonecrosis is estimated to be about 1:100,000 
patients treated for osteoporosis with oral bisphosphonates 
and 1:100 patients being treated for cancer with intrave
-
nous bisphosphonates. The risk for osteonecrosis of the jaw 
with dental surgery can be approximated with a serum 
level of C-telopeptide, a fragment of collagen released dur
-
ing bone remodeling. Bisphosphonates reduce 
C-telopeptide levels. Serum C-telopeptide levels greater 
than or equal to 150 pg/mL are associated with a minimal 
risk of osteonecrosis, whereas C-telopeptide levels 
100–149 pg/mL are associated with a moderate risk, and 
C-telopeptide levels less than 100 pg/mL are associated 
with a high risk for osteonecrosis. Patients receiving 
bisphosphonates must receive regular dental care and try to 
avoid dental extraction. Ideally, elective dental surgery 
should be completed before starting bisphosphonates. If 
dental surgery is required, bisphosphonate therapy is ordi
-
narily stopped 3 months before the surgery and may be 
resumed about 1 month afterward if the bone has healed.
Atypical low-impact “chalkstick” fractures of the femo
-
ral shaft are a rare complication of bisphosphonate therapy. 
In more than 52,000 postmenopausal women taking 
bisphosphonates for 5 years or longer, a subtrochanteric 
fracture occurred in 0.22% during the subsequent 2 years; 
27% of such fractures were bilateral. About 70% of affected 
patients have had prodromal thigh pain prior to the frac
-
ture. The risk for atypical femoral fractures is particularly 
increased among Asian women and among patients taking 
high-dose corticosteroids and those receiving bisphospho
-
nate treatment for more than 5 years. Teriparatide may be 
helpful to promote healing of such fractures. Despite this 
rare complication, the overall risk of hip fracture is reduced 
among patients taking bisphosphonates for up to 5 years.
In patients taking bisphosphonates, hypercalcemia is 
seen in 20% and serum PTH levels increase above normal 
in 10%, mimicking primary hyperparathyroidism. Hypo
-
calcemia occurs frequently, resulting in secondary hyper
-
parathyroidism; such patients may be treated with oral 
calcium salt supplements (500–1000 mg/day) and with oral 
vitamin D
3
 (starting at 1000 units/day).
Denosumab (Prolia, Xgeva) is a monoclonal 
antibody that inhibits the proliferation and maturation of 
preosteoclasts into mature osteoclast bone-resorbing cells. 
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It does this by binding to the osteoclast receptor activator of 
nuclear factor-kappa B ligand (RANKL). It is indicated for 
treatment of osteoporosis, major fragility fractures, or osteo
-
penia with a high FRAX score in both men and women. It is 
also used for patients with high fracture risk who are receiving 
sex hormone suppression therapy for breast cancer or prostate 
cancer. Treatment reduces vertebral fractures by 68% and 
reduces hip fractures by 40%. Denosumab is administered in 
doses of 60 mg subcutaneously every 6 months. It increases 
bone mineral density more than oral alendronate. Unlike 
bisphosphonates, denosumab can be given to patients with 
severe kidney disease. It has been relatively well tolerated, with 
an 8% incidence of flu-like symptoms. It can decrease serum 
calcium and should not be administered to patients with 
hypocalcemia. Other side effects include hypercholesterol
-
emia, eczema and dermatitis, serious infections, new malig
-
nancies, and pancreatitis. Its efficacy is comparable to 
bisphosphonates. With prolonged use, it predisposes to atypi
-
cal femoral fractures and osteonecrosis of the jaw and is addi
-
tive to bisphosphonates in that regard. As with bisphosphonates, 
denosumab is usually administered for a 3- to 5-year course.
5. PTH analogs—
Teriparatide
 (Forteo) and 
abaloparatide
 
(Tymlos) are analogs of PTH and PTHrP , respectively. 
These analogs stimulate the production of new collagenous 
bone matrix, particularly in vertebral trabecular bone, 
which must be mineralized. Patients receiving teriparatide 
or abaloparatide must have sufficient intake of vitamin D 
and calcium. When given in a sequence with denosumab, 
the preferred sequence is to first give a course of PTH ana
-
log therapy followed by denosumab.
Teriparatide is administered subcutaneously in doses of 
20 mg daily, whereas abaloparatide is given subcutaneously 
in doses of 80 mg daily. When administered to patients 
with osteoporosis for 2 years, these drugs dramatically 
improve bone density in most bones except the distal 
radius. They may also be used to promote healing of atypi
-
cal femoral chalkstick fractures associated with bisphos
-
phonate therapy. The recommended dose should not be 
exceeded, since both drugs have caused osteosarcoma in 
rats when administered long-term in very high doses. Due 
to the potential risk for osteosarcoma, patients are excluded 
from receiving teriparatide or abaloparatide if they have an 
increased risk of osteosarcoma due to the following: Paget 
disease of bone, unexplained elevations in serum alkaline 
phosphatase, prior radiation therapy to bones, open epiph
-
yses, or a past history of osteosarcoma or chondrosarcoma. 
Side effects may include injection site reactions, orthostatic 
hypotension, arthralgia, muscle cramps, depression, or 
pneumonia. Hypercalcemia can occur and manifest as 
nausea, constipation, asthenia, or muscle weakness. These 
drugs are approved for only a 2-year course of treatment.
Teriparatide and abaloparatide should not be used for 
patients with hypercalcemia. Similarly, they should be used 
with caution in patients if they are also taking corticosteroids 
and thiazide diuretics along with oral calcium supplementa
-
tion because hypercalcemia may develop
.
Following a 2-year course of teriparatide or abalopara
-
tide, bisphosphonates should be considered in order to 
retain the improved bone density. Alternatively, for very 
severe osteoporosis, these drugs may be administered 
along with denosumab; combined treatment for 2 years is 
more effective than any other single therapy.
6. Selective estrogen receptor modulators (SERMs)—
SERMs can prevent osteoporosis but are not effective therapy 
for established osteoporosis. 
Raloxifene
 60 mg/day orally 
may be taken by postmenopausal women in place of estrogen 
for prevention of osteoporosis. Bone density increases about

for prevention of osteoporosis. Bone density increases about 
1% over 2 years in postmenopausal women versus 2% 
increases with estrogen replacement. It reduces the risk of 
vertebral fractures by about 40% but does not appear to 
reduce the risk of nonvertebral fractures. Raloxifene pro
-
duces a reduction in LDL cholesterol, but not the rise in 
high-density lipoprotein (HDL) cholesterol seen with estro
-
gen. It has no direct effect on coronary plaque. Unlike estro
-
gen, raloxifene does not reduce hot flushes; in fact, it often 
intensifies them. It does not relieve vaginal dryness. Unlike 
estrogen, however, raloxifene does not cause endometrial 
hyperplasia, uterine bleeding, or cancer, nor does it cause 
breast soreness. The risk of breast cancer is reduced 76% in 
women taking raloxifene for 3 years. Since it is a potential 
teratogen, it is relatively contraindicated in women capable of 
pregnancy. Raloxifene increases the risk for thromboembo
-
lism and should not be used by women with such a history. 
Leg cramps can also occur. 
Tamoxifen
 is another SERM that 
is commonly administered to women for up to 5 years after 
resection of breast cancer that is estrogen receptor positive.
Bazedoxifene
 is a SERM that is available as a fixed-dose 
combination medication with conjugated estrogens (dose: 
0.45 mg/20 mg [Duavee]). It is FDA approved for the pre
-
vention of osteoporosis in postmenopausal women with an 
intact uterus. However, unlike raloxifene, it has not been 
shown to reduce the risk of breast cancer. Women taking 
this combination medication long-term experience an 
increased risk of thromboembolic events.
7. Calcitonin—
Calcitonin therapy is much less effective 
than other treatments for osteoporosis. Long-term calcito
-
nin therapy increases the risk of liver cancer but reduces the 
risk of breast cancer. Calcitonin is used primarily for its 
analgesic effect for the pain of acute osteoporotic vertebral 
compression fractures. It is ineffective for chronic pain. Its 
analgesic effect may be seen within 2–4 weeks. If it appears 
to be effective for analgesia, it is continued for up to 
3 months. A nasal spray of calcitonin-salmon (Miacalcin) is 
available that contains 2200 units/mL in 2-mL metered-
dose bottles. The usual dose is one puff (0.09 mL, 200 inter
-
national units) once daily, alternating nostrils. Nasal 
symptoms such as rhinitis and epistaxis occur commonly; 
other less common adverse reactions include flu-like symp
-
toms, allergy, arthralgias, back pain, and headache. Calcito
-
nin reduces the incidence of vertebral fractures, but its 
effect upon nonvertebral fractures has not been established. 
If calcitonin is administered, other more effective treat
-
ments for osteoporosis should be given simultaneously.
8. Orthopedic surgery—
Percutaneous vertebroplasty or 
kyphoplasty may be considered for patients with vertebral 
compression fractures who fail conservative pain manage
-
ment. However, no prospective randomized study has 
adequately compared the effectiveness of these orthopedic 
procedures compared to conservative therapy.
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»
Prognosis
Osteoporosis should ideally be prevented, since it can be 
only partially reversed. Measures noted above are reason
-
ably effective in preventing and treating osteoporosis and 
reducing fracture risk.
Black DM et al. Clinical practice. Postmenopausal osteoporosis. 
Cappola AR et al. Osteoporosis therapy in postmenopausal 
women with high risk of fracture. JAMA. 2016 Aug 
16;316(7):715–6. [PMID: 27533154]
Dhillon S. Zoledronic acid (Reclast®, Aclasta®): a review in osteo
-
porosis. Drugs. 2016 Nov;76(17):1683–97. [PMID: 27864686]
Kendler DL et al. Vertebral fractures: clinical importance and 
management. Am J Med. 2016 Feb;129(2):e1–10. [PMID: 
26524708]
Leder BZ et al. Denosumab and teriparatide transitions in post
-
menopausal osteoporosis (the DATA-Switch study): exten
-
sion of a randomised controlled trial. Lancet. 2015 Sep 19;
 
386(9999):1147–55. [PMID: 26144908]
Sugerman DT. JAMA patient page. Osteoporosis. JAMA. 2014 
Jan 1;311(1):104. [PMID: 24381978]
Taylor CL et al. Questions about vitamin D for primary care 
practice: input from an NIH Conference. Am J Med. 2015 
Nov;128(11):1167–70. [PMID: 26071820]
RICKETS & OSTEOMALACIA
 
»
Low bone density from defective mineralization.
 
»
Caused by deficiency in calcium, phosphorus, or 
low alkaline phosphatase (hypophosphatasia).
 
»
Rickets:
 defective bone mineralization in child
-
hood or adolescence before epiphyseal fusion.
 
»
 defective bone mineralization in 
adults with fused epiphyses.
 
»
Painful proximal muscle weakness (especially pel
-
vic girdle); bone pain and tenderness.
 
»
Low 25-hydroxy-vitamin D, hypocalcemia, hypo
-
calciuria, hypophosphatemia, secondary 
hyperparathyroidism.
 
»
Classic radiologic features may be present.
 
»
Defective mineralization of the growing skeleton in child
-
hood causes permanent bone deformities (rickets). Defective 
skeletal mineralization in adults is known as osteomalacia. It 
is caused by any condition that results in inadequate calcium 
or phosphate mineralization of bone osteoid.
 
»
Etiology (Table 26–10)
A. Vitamin D Deficiency and Resistance
Vitamin D deficiency is the most common cause of osteo
-
malacia; its incidence is increasing throughout the world as 
a result of diminished exposure to sunlight caused by 
urbanization, automobile and public transportation, mod
-
est clothing, and sunscreen use. Significant vitamin D 
deficiency, with serum 25OHD less than 20 ng/mL 
(50 nmol/L), was found in 24.3% of postmenopausal 
women from 25 countries. The incidence varied: less than 
1% in Southeast Asia, 29% in the United States, and 36% in 
Italy. Patients in whom clinically severe osteomalacia 
develops typically have had chronic severe vitamin D defi
-
ciency (serum 25OHD under 25 nmol/L or under 10 ng/
mL). The prevalence of severe vitamin D deficiency is 3.5% 
in the United States and 12.5% in Italy. Among US men 
over age 65 years, 25% have serum 25OHD levels below 
20 ng/mL; men over age 75 with such low vitamin D levels 
have particularly accelerated bone loss. Vitamin D defi
-
ciency is particularly common in the institutionalized 
elderly, with the incidence exceeding 60% in some groups 
not receiving vitamin D supplementation. Deficiency of 
vitamin D may arise from insufficient sun exposure; mal
-
nutrition; or malabsorption (due to pancreatic insuffi
-
ciency, cholestatic liver disease, celiac disease, inflammatory 
bowel disease, jejunoileal bypass, Billroth type II gastrec
-
tomy); or orlistat use, which causes fat malabsorption. 
Cholestyramine binds bile acids necessary for vitamin D 
absorption. Patients with severe nephrotic syndrome lose 
large amounts of vitamin D–binding protein in the urine.
Table 26–10.
 
Causes of osteomalacia.
1
Vitamin disorders
 
D
ecreased availability of vitamin D
 
I
nsufficient sunlight exposure
 
K

1
 
D
 
I
 
K
idney: chronic kidney disease, nephrotic syndrome, kidney 
 
Liv
er disease
 
deficiency of vitamin D
 
M
alabsorption: aging, excess wheat bran, bariatric surgery, 
 
pancr
eatic enzyme deficiency, orlistat
 
V
itamin D–dependent rickets type I
 
P
henytoin, carbamazepine, valproate, or barbiturate therapy 
 
(long-term)
Dietary calcium deficiency
Phosphate deficiency
 
A
defovir therapy
 
F
anconi syndrome, renal tubular acidosis, and alcoholism
 
I
ntestinal malabsorption
 
deficiency of phosphorus
 
P
hosphate-binding antacid therapy
 
Renal loss
 
T
umoral hypophosphatemic osteomalacia
 
X
-linked hypophosphatemic rickets
 
Associa
tion with other disorders, including paraproteinemias, 
 
gly
cogen storage diseases, neurofibromatosis, Wilson disease
Inhibitors of mineralization
 
Aluminum
 
Disorders of bone matrix
 
Axial ost
eomalacia
 
F
ibrogenesis imperfecta
1
See Table 26–9 for causes of osteoporosis.
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Anticonvulsants (eg, phenytoin, carbamazepine, val
-
proate, phenobarbital) inhibit the hepatic production of 
25OHD and sometimes cause osteomalacia. Phenytoin can 
also directly inhibit bone mineralization.
Vitamin D–dependent rickets type I is caused by a rare 
autosomal recessive disorder with a defect in the renal 
enzyme 1-alpha-hydroxylase leading to defective synthe
-
sis of 1,25(OH)
2
D. It presents in childhood with rickets 
and alopecia; osteomalacia develops in adults with this 
condition unless treated with oral calcitriol in doses of 
0.5–1 mcg daily.
Vitamin D–dependent rickets type II (better known as 
hereditary 1,25[OH]
2
D-resistant rickets) is caused by a 
genetic defect in the 1,25(OH)
2
D receptor. Patients have 
hypocalcemia with childhood rickets and adult osteomala
-
cia. Alopecia is common. These patients respond variably 
to oral calcitriol in very large doses (2–6 mcg daily).
B. Deficient Calcium Intake
The total daily consumption of calcium should be at least 
1000 mg daily. Patients who have deficient calcium intake 
develop rickets (childhood) or osteomalacia (adulthood) 
despite sufficient vitamin D. A nutritional deficiency of 
calcium can occur in any severely malnourished patient. 
Some degree of calcium deficiency is common in older 
adults, since intestinal calcium absorption declines with 
age. Ingestion of excessive wheat bran also causes calcium 
C. Phosphate Deficiency
Osteomalacia develops in patients with hypophosphatemia 
due to lack of sufficient phosphate to mineralize bone oste
-
oid. Such patients typically have musculoskeletal pain, 
muscle weakness, and are prone to fractures.
1. Genetic disorders—
Fibroblast growth factor-23 
(FGF23) is a phosphaturic factor (phosphatonin) that is 
secreted by bone osteoblasts in response to elevated serum 
phosphate levels. Families with autosomal dominant hypo
-
phosphatemic rickets have a gain-of-function mutation in 
the gene encoding FGF23 that makes it resistant to proteo
-
lytic cleavage, thereby increasing serum FGF23 levels. In 
X-linked hypophosphatemic rickets, there is a mutation in 
the gene encoding PHEX endopeptidase, which fails to 
cleave FGF23, resulting in elevated serum FGF23 levels. An 
autosomal recessive form of hypophosphatemic rickets is 
caused by mutations in DMP1, a transcription factor that 
regulates FGF23 production in bone. All three conditions 
have high serum FGF23 levels causing hypophosphatemia 
and bone mineral depletion.
2. Tumor-induced osteomalacia—
A variety of mesenchy
-
mal tumors (87% benign) secrete fibroblast growth fac
-
tor-23 (FGF23) and cause marked hypophosphatemia due 
to renal phosphate wasting. Such tumors are usually phos
-
phaturic mesenchymal tumors (70%); other tumors include 
hemangiopericytomas, osteosarcomas, and giant cell 
tumors. The condition is characterized by hypophosphate
-
mia, excessive phosphaturia, reduced or normal serum 
1,25(OH)
2
D concentrations, and osteomalacia. Serum 
levels of FGF23 are elevated. Such tumors are often small 
and difficult to find, frequently lying in extremities.
3. Other causes of hypophosphatemia—
Osteomalacia 
from hypophosphatemia can be caused by severe intestinal 
malabsorption or poor nutrition. Severe hypophosphate
-
mia can occur with refeeding after starvation (eg, concen
-
tration camp victims, malnourished alcoholics). Other 
causes of hypophosphatemia include respiratory alkalosis, 
glucose infusions, salicylate intoxication, mannitol, and 
bisphosphonate therapy. Additional causes include chela
-
tion of phosphate in the gut by aluminum hydroxide antac
-
ids, calcium acetate (Phos-Lo), or sevelamer hydrochloride 
(Renagel). Excessive renal phosphate losses are also seen in 
proximal renal tubular acidosis and Fanconi syndrome.
D. Aluminum Toxicity
Bone mineralization is inhibited by aluminum. Osteomala
-
cia may occur in patients receiving long-term renal

-
cia may occur in patients receiving long-term renal 
 
hemodialysis with tap water dialysate or from aluminum-
containing antacids used to reduce phosphate levels.
E. Hypophosphatasia
 must not be confused with hypophos
-
phatemia. Hypophosphatasia refers to a severe deficiency of 
bone alkaline phosphatase. It is a rare genetic cause of osteo
-
malacia that is commonly misdiagnosed as osteoporosis.
F. Fibrogenesis Imperfecta Ossium
This rare condition sporadically affects middle-aged 
patients, who present with progressive bone pain and 
pathologic fractures. Bones have a dense “fishnet” appear
-
ance on radiographs. Serum alkaline phosphatase levels are 
elevated. Some patients have a monoclonal gammopathy, 
indicating a possible plasma cell dyscrasia causing an 
impairment in osteoblast function and collagen disarray. 
Remission has been reported after repeated courses of mel
-
phalan, corticosteroids, and vitamin D analog over 3 years.
 
»
The clinical manifestations of defective bone mineralization 
depend on the age at onset and the severity. In childhood 
and adolescence, this causes classic rickets. Manifestations 
include delayed growth, muscle weakness, and pain in the 
spine, pelvis, and legs. Deformities at epiphyses lead to 
thickened wrists and ankles as well as bowed legs or knock-
knees (adolescents). Kyphoscoliosis or lumbar lordosis is 
common. Thickening at the costochondral joints cause 
deformities known as a “rachitic rosary. ”
In adults, osteomalacia is typically asymptomatic at 
first. Eventually, bone and joint pain occurs, along with 
reduced muscle strength and endurance. Pathologic frac
-
tures may occur with little or no trauma. These manifesta
-
tions can occur with osteomalacia from either hypocalcemia 
or hypophosphatemia.
Hypocalcemia causes a reduced quality of life, with 
fatigue, irritability, depression, anxiety, cognitive impair
-
ment, lethargy, and paresthesias in the circumoral area, 
hands, and feet. More severe manifestations include muscle 
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weakness or cramps, carpopedal spasm, convulsions, tet
-
any, laryngospasm, and stridor. Hypophosphatemia can 
cause severe major muscle weakness, dysphagia, diplopia, 
cardiomyopathy, and respiratory muscle weakness. Patients 
may have impaired cognition.
 
»
Diagnostic Tests
Serum is obtained for calcium, albumin, phosphate, alka
-
line phosphatase, PTH, and 25[OH]D
3
 determinations.
1,25(OH)
2
D
3
 may be low even when 25(OH)D
2
 levels 
are normal. In one series of biopsy-proved osteomalacia, 
alkaline phosphatase was elevated in 94% of patients; the 
calcium or phosphorus was low in 47% of patients; 25(OH)
D
3
 was low in 29% of patients; and urinary calcium was low 
in 18% of patients. Pseudofractures were seen in 18% of 
patients. Radiographs may show diagnostic features. Bone 
densitometry helps document the degree of osteopenia.
Genetic testing can confirm the diagnosis of autosomal 
dominant hypophosphatemic rickets (
FGF23
), X-linked 
hypophosphatemic rickets (
PHEX
), and autosomal reces
-
sive hypophosphatemic rickets (
DMP1
).
Patients with apparent tumor-induced osteomalacia with 
hypophosphatemia require localization studies. Whole-body 
scanning with somatostatin analogs 
68
Ga-DOTATOC PET/
CT is the preferred imaging technique in this condition, 
detecting about 90% of tumors in small series.
To confirm the diagnosis of hypophosphatasia in 
patients with a low serum alkaline phosphatase, a 24-hour 
urine should be assayed for phosphoethanolamine, a sub
-
strate for tissue-nonspecific alkaline phosphatase whose 
excretion is always elevated in patients with hypophospha
-
tasia. The diagnosis is confirmed with genetic testing for 
ALPL
 gene.
 
»
Osteomalacia often coexists with osteoporosis. The relative 
contribution of the two entities to diminished bone density 
may not be apparent until treatment, since a dramatic rise 
in bone density is often seen with therapy for osteomalacia. 
Phosphate deficiency must be distinguished from hypo
-
phosphatemia seen in hyperparathyroidism.
 
»
To obtain adequate sunshine vitamin D, the face, arms, 
hands, or back must have sun exposure without sunscreen 
for 15 minutes at least twice weekly. The main natural food 
source of vitamin D is fish, particularly salmon, mackerel, 
cod liver oil, and sardines or tuna canned in oil. Most com
-
mercial cow’s milk is fortified with vitamin D at about 400 
international units per quart; however, skim milk and 
other dairy products contain much less vitamin D.
Many vitamin supplements contain plant-derived vitamin 
D
2
, which has variable biologic availability. Over-the-counter 
multivitamin/mineral supplements contain variable amounts 
of vitamin D, and vitamin D toxicity has occurred from two 
different multivitamins sold in the United States. Therefore, it 
is prudent to recommend that patients take a dedicated 
vitamin D supplement from a reliable manufacturer.
In sunlight-deprived individuals (eg, veiled women, 
confined patients, or residents of higher latitudes during 
winter), vitamin D
3
, 1000 international units daily, should 
be given prophylactically. Patients receiving long-term 
phenytoin therapy should also receive vitamin D
3
 
Frank vitamin D deficiency is treated with ergocalcif
-
erol (D
2
), 50,000 international units orally once weekly for 
8 weeks. Following that, vitamin D
3
 (cholecalciferol) sup
-
plementation is used at a dose of 2000 international units 
daily. Vitamin D
3
 is more effective than vitamin D
2
 in rais
-
ing serum levels of 25(OH)D. Some patients require long-
term supplementation with ergocalciferol of up to 50,000 
international units weekly. In patients with intestinal mal
-
absorption, oral doses of 25,000–100,000 international 
units of vitamin D
3
 daily may be required. Some patients 
with steatorrhea respond better to oral 25(OH)D
3
 (calcife
-

-
3
3
 (calcife
-
diol), 50–100 mcg/day. Serum levels of 25(OH)D should be 
monitored and the dosage of vitamin D adjusted to main
-
tain serum 25(OH)D levels above 30 ng/mL. During treat
-
ment with high-dose vitamin D, serum calcium should also 
be monitored to avoid hypercalcemia.
Beyond increasing the intestinal absorption of calcium, 
vitamin D supplementation may improve muscle strength 
and reduce fall risk, factors that reduce the risk of bone 
fracture.
The addition of calcium supplements to vitamin D is 
probably not necessary for the prevention of osteomalacia 
in the majority of otherwise well-nourished patients. How
-
ever, patients with malabsorption or poor nutrition should 
receive calcium supplementation. Recommended doses of 
calcium are as follows: calcium citrate (eg, Citracal), 0.4–
0.6 g elemental calcium per day, or calcium carbonate (eg, 
OsCal, Tums), 1–1.5 g elemental calcium per day. Calcium 
supplements are best administered with meals.
In hypophosphatemic rickets or osteomalacia
, nutri
-
tional deficiencies are corrected, aluminum-containing 
antacids are discontinued, and patients with renal tubular 
acidosis are given bicarbonate therapy. In patients with 
sporadic adult-onset hypophosphatemia, hyperphosphatu
-
ria, and low serum 1,25(OH)
2
D levels, a search is con
-
ducted for occult tumors; whole-body MRI scanning may 
For those with X-linked or idiopathic hypophosphate
-
mia and hyperphosphaturia, oral phosphate supplements 
must be given long term. Calcitriol, 0.25–0.5 mcg/day, is 
given also to improve the impaired calcium absorption 
caused by the oral phosphate. Oral phosphate causes diar
-
rhea at higher doses, and many patients do not achieve 
normal serum phosphate levels. If necessary, recombinant 
human growth hormone (rhGH) may be added to the 
above regimen to reduce phosphaturia. The hypophospha
-
temia of autosomal dominant hypophosphatemic rickets 
has been reported to resolve with high-dose dietary iron 
Patients with hypophosphatasia may be treated with 
asfotase alfa (Strensiq), which is administered subcutane
-
ously in doses of 2 mg/kg three times weekly; adverse 
effects include injection site reactions, lipodystrophy 
ectopic calcifications, and hypersensitivity reactions. 
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Patients have also been treated with teriparatide with 
improvement in bone pain and fracture healing.
Allgrove J et al. A practical approach to vitamin D deficiency and 
rickets. Endocr Dev. 2015;28:119–33. [PMID: 26138839]
Hautmann AH et al. Tumor-induced osteomalacia: an up-to-
date review. Curr Rheumatol Rep. 2015 Jun;17(6):512. 
[PMID: 25900190]
Mornet E. Hypophosphatasia. Metabolism. 2018 May;82:
 
142–55. [PMID: 28939177]
Munns CF et al. Global consensus recommendations on preven
-
tion and management of nutritional rickets. J Clin Endocrinol 
Metab. 2016 Feb;101(2):394–415. [PMID: 26745253]
PAGET DISEASE OF BONE 
 
(
Osteitis Deformans
)
 
»
 
»
Bone pain may be the first symptom.
 
»
Kyphosis, bowed tibias, large head, deafness, and 
frequent fractures.
 
»
Serum calcium and phosphate normal; alkaline 
phosphatase elevated; urinary hydroxyproline 
elevated.
 
»
Dense, expanded bones on radiographs.
 
»
Paget disease of bone is manifested by one or more bony 
lesions having high bone turnover and disorganized oste
-
oid formation. The involved bone first has increased 
osteoclast activity, causing lytic lesions in bone that may 
progress at about 1 cm/year. Increased osteoblastic activ
-
ity follows, producing a high rate of disorganized bone 
formation. Involved bones become vascular, weak, and 
deformed. Eventually, there appears to be a final burned-
out phase with markedly reduced bone cell activity and 
abnormal bones that may be enlarged with skeletal 
The prevalence of Paget disease has declined by about 
36% over the past 20 years. However, it remains a common 
disease in certain countries, with striking geographic varia
-
tion in prevalence. It is most common in the United Kingdom 
and in areas of European migration, particularly 
New Zealand, Australia, the United States, South Africa, 
Quebec, and Brazil. Interestingly, the disease appears 
equally common among different races in these countries. 
In the United States, Paget disease affects 3% of whites over 
age 55 years, with its prevalence increasing with age. It is 
uncommon in Africa, Asia, and Scandinavia. Usually diag
-
nosed in patients over age 40 years, its prevalence doubles 
with each decade thereafter, reaching an incidence of about 
10% after age 80. About 20% of cases are symptomatic, but 
most cases are discovered incidentally during radiology 
imaging or because of incidentally discovered elevations in 
serum alkaline phosphatase.
The cause of Paget disease is unknown. About 20% of 
cases are familial and transmitted as an autosomal domi
-
nant trait with incomplete penetrance. Mutations in the 
SQSTM1
 gene have been discovered in about 35% of 
patients with familial Paget disease and in 7% of patients 
with apparently sporadic Paget disease.
 
»
Paget disease is often mild and asymptomatic. Only 27% of 
affected individuals are symptomatic at the time of 
diagnosis. Paget disease involves multiple bones 
(polyostotic) in 72% and only a single bone (monostotic) 
in 28%. It occurs most commonly in the pelvis, vertebrae, 
femur, humerus, and skull. The affected bones are typically 
involved right away and the disease tends not to involve 
additional bones during its course. Pain, often described as 
aching and deep and often worse at night, is the usual first 
symptom. It may occur in the involved bone or in an 
adjacent joint, which can be involved with degenerative 
arthritis. Paget disease typically first affects long bones 
proximally and then advances distally, with bone pain at 
the osteolytic front being aggravated by weight bearing. 
Joint surfaces (such as the knee) can be involved and cause 
arthritic pain. The bones can become soft, leading to 
bowed tibias, kyphosis, and frequent “chalkstick” fractures 
with slight trauma. If the skull is involved, the patient may

with slight trauma. If the skull is involved, the patient may 
report headaches and an increased hat size; the finding of 
dilated scalp veins, present in half such patients, is known 
as the “scalp vein sign. ” Involvement of the petrous 
temporal bone frequently damages the cochlea and causes 
hearing loss (mixed sensorineural and conductive) and 
occasionally tinnitus or vertigo. Increased vascularity over 
the involved bones causes increased warmth and can cause 
vascular “steal” syndromes.
Serum alkaline phosphatase is usually markedly elevated. 
However, some patients with monostotic involvement may 
have normal serum alkaline phosphatase levels. A serum 
bone-specific alkaline phosphatase is usually high and is 
useful for patients with a normal serum alkaline phospha
-
tase and to distinguish the source of an elevated alkaline 
phosphatase as being from bone (rather than liver). How
-
ever, bone alkaline phosphatase is less useful for following 
the effectiveness of therapy. Other useful measures for 
bone turnover are serum N-terminal propeptide of type 1 
collagen (NTx) and serum beta C-terminal propeptide of 
type 1 collagen (betaCTx). However, such bone turnover 
markers may overestimate or underestimate the response 
to treatment. Serum calcium may be elevated, particularly 
if the patient is at bed rest. A serum 25-OH vitamin D 
determination should be obtained to screen for vitamin D 
deficiency, which can also present with an increased serum 
alkaline phosphatase and bone pain.
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C. Imaging
On radiographs, the initial lesions are typically osteolytic, 
with focal radiolucencies (“osteoporosis circumscripta”) in 
the skull or advancing flame-shaped lytic lesions in long 
bones. Bone lesions may subsequently become sclerotic 
and have a mixed lytic and sclerotic appearance. The 
affected bones eventually become thickened and deformed. 
Technetium-99m pyrophosphate bone scans are helpful in 
delineating activity of bone lesions even before any radio
-
logic changes are apparent.
 
»
Certain rare familial types of sclerosing bone dysplasias 
share phenotypic homologies with Paget disease of bone. 
The differential diagnosis also includes myelofibrosis, 
intramedullary osteosclerosis, Erdheim-Chester disease, 
Langerhans cell histiocytosis, and sickle cell disease.
Paget disease must be differentiated from primary bone 
lesions such as osteogenic sarcoma, plasma cell myeloma, 
and fibrous dysplasia and from secondary bone lesions 
such as osteitis fibrosa cystica and metastatic carcinoma to 
bone. Fibrogenesis imperfecta ossium is a rare symmetric 
disorder that can mimic the features of Paget disease; 
serum alkaline phosphatase is likewise elevated. This con
-
dition may be associated with paraproteinemias.
 
»
If immobilization occurs, hypercalcemia and renal calculi 
may develop. With severe polyostotic disease, the increased 
vascularity may give rise to high-output heart failure. Arthri
-
tis frequently develops in joints adjacent to involved bone.
Extensive skull involvement may cause cranial nerve 
palsies from impingement of the neural foramina. Skull 
involvement can also cause a vascular steal syndrome with 
somnolence or ischemic neurologic events; the optic nerve 
may be affected, resulting in loss of vision. Jaw involvement 
can cause the teeth to spread intraorally and become mis
-
aligned. Vertebral collapse can cause compression of spinal 
cord or spinal nerves, resulting in radiculopathy or paraly
-
sis. Vertebral involvement can also cause a vascular steal 
syndrome with paralysis. Surgery for fractured long bones 
is often complicated by excessive blood loss from these 
vascular lytic lesions.
A sarcoma or giant cell tumor may develop in long-
standing lesions but is rare (less than 1%). Sarcomatous 
change is suggested by a marked increase in bone pain, 
sudden rise in alkaline phosphatase, and appearance of a 
new lytic lesion.
 
»
Treatment
Asymptomatic patients may require only clinical surveil
-
lance and no treatment. However, treatment should be 
considered for asymptomatic patients who have significant 
involvement of the skull, long bones, or vertebrae. Patients 
must be monitored carefully before, during, and after treat
-
ment with clinical examinations and serial serum alkaline 
phosphatase determinations.
 are used to treat patients with 
Paget disease. Zoledronate is the treatment of choice. 
Administered intravenously as a single 5-mg dose, it 
normalizes the serum alkaline phosphatase in 89% of 
patients by 6 months and in 98% by 2 years.
Zoledronate should be administered prior to total 
arthroplasty for a Paget-involved joint in order to reduce 
the risk of intraoperative hemorrhaging and loosening of 
the prosthesis postoperatively. Zolendronate should also be 
administered before osteotomy for severe bowing of a 
lower extremity caused by Paget disease. For patients with 
paraplegia due to vertebral involvement, intravenous 
zolendronate should be given while neurosurgical consul
-
tation is obtained.
Patients frequently experience a paradoxical increase 
in pain at sites of disease soon after commencing bisphos
-
phonate therapy; this is the “first dose effect” and the pain 
usually subsides with further treatment. Following intra
-
venous zoledronate, patients frequently experience fever, 
fatigue, myalgia, bone pain, and ocular problems. Serious

-
fatigue, myalgia, bone pain, and ocular problems. Serious 
side effects are rare but include seizures, uveitis, and acute 
kidney disease. Asthma may occur in aspirin-sensitive 
patients. Hypocalcemia is common and may be severe, 
especially if intravenous bisphosphonates are given along 
with loop diuretics. Therefore, it is advisable to adminis
-
ter calcium and vitamin D supplements, especially during 
the first 2 weeks following treatment. Any vitamin D 
deficiency should be corrected before prescribing a 
bisphosphonate.
Oral bisphosphonate regimens are inferior to intrave
-
nous zolendronate for therapy of Paget disease. However, if 
they are given, to prevent esophageal complications, oral 
bisphosphonates should be taken with 8 oz of plain water 
only; they are relatively contraindicated in patients with a 
history of esophagitis, esophageal stricture, dysphagia, 
hiatal hernia, or achalasia.
 
»
Prognosis
The prognosis is good, but relapse can occur after an initial 
successful treatment with bisphosphonate. By 6.5 years 
after initial therapy, the recurrence rate is 12.5% after treat
-
ment with zoledronate and 62% after risedronate. There
-
fore, patients must be monitored long term, measuring 
serum alkaline phosphatase at least yearly. In general, the 
prognosis is worse the earlier in life the disease starts. Frac
-
tures usually heal well. In the severe forms, marked defor
-
mity, intractable pain, and high-output heart failure occur 
if not treated with bisphophonates. Osteosarcoma that 
arises at sites of Paget disease results in a 2-year survival of 
only 25%.
Guay-Bélanger S et al. Development of a molecular test of 
Paget’s disease of bone. Bone. 2016 Mar;84:213–21. [PMID: 
26772620]
Shah M et al. Paget’s disease: a clinical review. Br J Hosp Med 
(Lond). 2015 Jan;76(1):25–30. [PMID: 25585180]
Singer FR et al. Paget’s disease of bone: an Endocrine Society 
clinical practice guideline. J Clin Endocrinol Metab. 2014 
Dec;99(12):4408–22. [PMID: 25406796]
CMDT19_Ch26_p1119-p1219.indd   1179

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HAPTER
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1180
 CMDT 2019
 
º
DISEASES OF THE ADRENAL CORTEX
PRIMARY ADRENAL INSUFFICIENCY 
 
(
Addison Disease
)
 
»
Weakness, vomiting, diarrhea; abdominal pain, 
muscle and joint pains; amenorrhea.
 
»
Sparse axillary hair; increased skin pigmentation, 
especially of creases, pressure areas, and nipples.
 
»
Hypotension, small heart.
 
»
Hyponatremia; potassium, calcium, and BUN ele
-
vated; mild anemia and relative neutropenia, 
lymphocytosis, and eosinophilia.
 
»
Plasma ACTH level elevated; cosyntropin unable 
to stimulate an increase in serum cortisol to 
20 mcg/dL (550 nmol/L) or more.
 
»
Acute adrenal crisis:
 above manifestations become 
critical, with fever, shock, confusion, coma, death.
 
»
Primary adrenal insufficiency (Addison disease) is caused 
by dysfunction or absence of the adrenal cortices. It is dis
-
tinct from secondary adrenal insufficiency caused by defi
-
cient secretion of ACTH.
Addison disease is an uncommon disorder with a preva
-
lence of about 140 per million and an annual incidence of 
about 5 cases per million in the United States. Addison 
disease is characterized by a chronic deficiency of cortisol. 
Serum ACTH and alpha-MSH levels are consequently 
elevated, causing pigmentation that ranges from none to 
strikingly dark. Patients with destruction of the adrenal 
cortices or with classic 21-hydroxylase deficiency also have 
mineralocorticoid deficiency, typically with hyponatremia, 
volume depletion, and hyperkalemia. In contrast, mineralo
-
corticoid deficiency is not present in patients with familial 
corticosteroid deficiency and Allgrove syndrome.
Acute adrenal (addisonian) crisis
 is an emergency 
caused by insufficient cortisol. Crisis may occur in the 
course of treatment of chronic adrenal insufficiency, or it 
may be the presenting manifestation of adrenal insuffi
-
ciency. Acute adrenal crisis is more commonly seen in pri
-
mary adrenal insufficiency than in secondary adrenal 
Adrenal crisis may occur in the following situations: 
(1) during stress, (eg, infection, trauma, surgery, hyperthy
-
roidism, or prolonged fasting) in a patient with latent or 
treated adrenal insufficiency; (2) following sudden with
-
drawal of adrenocortical hormone in a patient with chronic 
insufficiency or in a patient with temporary insufficiency 
due to suppression by exogenous corticosteroids or meges
-
trol; (3) following bilateral adrenalectomy or removal of a 
functioning adrenal tumor that had suppressed the other 
adrenal gland; (4) following sudden destruction of the 
pituitary gland (pituitary necrosis), or when thyroid hor
-
mone is given to a patient with adrenal insufficiency; 
(5) following injury to both adrenals (by trauma, hemor
-
rhage, anticoagulant therapy, thrombosis, infection or, 
rarely, metastatic carcinoma); and (6) following adminis
-
tration of intravenous etomidate (used for rapid anesthesia 
induction or intubation).
 
»
Etiology
 is the most common cause of Addison dis
-
ease in industrialized countries, accounting for about 90% 
of spontaneous cases. With such autoimmunity, adrenal 
function decreases over several years as it progresses to 
overt adrenal insufficiency. Over half the cases of autoim
-
mune Addison disease occur as part of APS-I, also known 
as APECED syndrome. APS-I is caused by a defect in 
T cell–mediated immunity inherited as an autosomal reces
-
sive trait. Type 1 PGA usually presents in early childhood 
with mucocutaneous candidiasis, followed by hypoparathy
-
roidism and dystrophy of the teeth and nails; Addison dis
-
ease usually appears by age 15 years. Partial or late expression 
of the syndrome is common. A varied spectrum of associ
-
ated diseases may be seen in adulthood, including hypogo
-
nadism, hypothyroidism, pernicious anemia, alopecia, 
vitiligo, hepatitis, malabsorption, and Sjögren syndrome.
Tuberculosis is the most common infection of the adre
-

-
-
nals. Coccidioidomycosis, histoplasmosis, cytomegalovirus 
infection, and syphilitic gummas are rare causes and usu
-
ally occur in immunocompromised patients.
Infections of the adrenal glands, particularly with cyto
-
megalovirus, are found in nearly half of patients with 
untreated HIV at autopsy. However, a much lower percent
-
age have clinical Addison disease. The diagnosis of adrenal 
insufficiency in HIV patients is often problematic. A corti
-
sol resistance syndrome has been described in patients 
with HIV , and a revision of normal range for the cosyntro
-
pin test for these patients has been advocated (normal peak 
cortisol over 22 mcg/dL). Also, isolated hyperkalemia 
occurs commonly in HIV patients, particularly during 
therapy with pentamidine; this is usually due to isolated 
hypoaldosteronism and responds to mineralocorticoid 
(fludrocortisone) therapy alone.
Bilateral adrenal hemorrhage
 may occur with sepsis, 
heparin-associated thrombocytopenia, anticoagulation, or 
the antiphospholipid antibody syndrome. It may occur in 
association with major surgery or trauma, presenting 
about 1 week later with pain, fever, and shock. It may also 
occur spontaneously and present with flank pain. Menin
-
gococcemia may be associated with purpura and adrenal 
insufficiency secondary to adrenal infarction (Waterhouse-
Friderichsen syndrome).
Adrenoleukodystrophy
 is an X-linked peroxisomal 
disorder causing accumulation of very long-chain fatty 
acids in the adrenal cortex, testes, brain, and spinal cord. It 
may present at any age and accounts for one-third of cases 
of Addison disease in boys. Aldosterone deficiency occurs 
in 9%. Hypogonadism is common.
Rare causes of adrenal insufficiency include lym
-
phoma, metastatic carcinoma, scleroderma, amyloidosis, 
and hemochromatosis.
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CMDT 2019
Congenital adrenal insufficiency
 occurs in several 
conditions. Familial corticosteroid deficiency is an autoso
-
mal recessive disease that is caused by mutations in the 
adrenal ACTH receptor (melanocortin 2 receptor, MC2R). 
It is characterized by isolated cortisol deficiency and 
ACTH resistance and may present with neonatal hypogly
-
cemia, frequent infections, and dark skin pigmentation. 
Triple A (Allgrove) syndrome is caused by a mutation in 
the 
AAAS
 gene that encodes a protein known as ALADIN 
(
al
achrima, 
a
chalasia, a
d
renal 
i
nsufficiency, 
n
eurologic 
disorder). Cortisol deficiency usually presents in infancy 
but may not occur until the third decade of life. Congenital 
adrenal hypoplasia causes adrenal insufficiency due to 
absence of the adrenal cortex; patients may also have 
hypogonadotropic hypogonadism, myopathy, and high-
frequency hearing loss.
Congenital adrenal hyperplasia
 is caused by various 
genetic defects in the enzymes responsible for steroid syn
-
thesis. Due to defective cortisol synthesis, patients have 
variable degrees of adrenal insufficiency and increased lev
-
els of ACTH that causes hyperplasia of the adrenal cortex. 
The most common enzyme defect is 
P450c21 (21-hydroxylase 
. Patients with severely defective P450c21 (classic 
congenital adrenal hyperplasia) manifest a deficiency of 
mineralocorticoids (salt wasting) in addition to deficient 
cortisol and excessive androgens. Hypertension commonly 
develops in older adult patients. Testicular adrenal rests can 
be found in 44% of men with the condition. Women with 
milder enzyme defects have adequate cortisol, but develop 
hirsutism in adolescence or adulthood and are said to have 
“late-onset” congenital adrenal hyperplasia.
Drugs
 that cause primary adrenal insufficiency include 
mitotane and abiraterone acetate.
 
»
The onset of symptoms can occur suddenly but usually 
develops gradually over months or years. The diagnosis is 
often delayed, since many early symptoms are nonspecific. 
Nearly all patients complain of fatigue, reduced stamina, 
weakness, anorexia, and weight loss. Abdominal pain, nau
-
sea, and vomiting eventually develop in most patients; 
diarrhea can occur. Fevers and lymphoid tissue hyperplasia 
may also occur. Patients often have significant pain: 
arthralgias, myalgias, chest pain, abdominal pain, back 
pain, leg pain, or headache. Psychiatric symptoms include 
anxiety, irritability and depression. Cerebral edema can 
cause headache, vomiting, gait disturbance, and intellec
-
tual dysfunction that may progress to coma. Hypoglycemia 
can occur and worsen the patient’s weakness and mental 
functioning. Patients often have salt craving. Blood pres
-
sure is usually low and orthostatic; about 90% have systolic 
blood pressures under 110 mm Hg; blood pressure over 
130 mm Hg is rare. Hypotension is aggravated by dehydra
-
tion caused by nausea or vomiting.
Skin hyperpigmentation eventually occurs in most 
patients due to increased pituitary secretion of alpha-MSH 
(melanocyte-stimulating hormone). Skin hyperpigmenta
-
tion varies among affected patients (eg, from none to 
increased freckling to diffuse darkening that resembles a 
suntan or a bronze appearance). Sun-exposed areas darken 
the most, but nonexposed areas darken as well. Hyperpig
-
mentation is often especially prominent over the knuckles, 
elbows, knees, posterior neck, palmar creases, gingival 
mucosa, and vermilion border of the lips. Nail beds may 
develop longitudinal pigmented bands. Nipples and areolas 
tend to darken. The skin also darkens in pressure areas, 
such as the belt or brassiere lines and the buttocks. Skin 
folds and new scars may also become pigmented. Con
-
versely, patches of autoimmune vitiligo can be found in 
about 10% of patients. Scant axillary and pubic hair typi
-
cally develops in women.

-
-
In pregnancy, undiagnosed adrenal insufficiency is 
rare, since the condition tends to cause anovulation and 
reduced fertility. In the first trimester, symptoms such as 
fatigue, nausea, vomiting, abdominal pain, and orthostasis 
are typically attributed to the pregnancy, thus delaying the 
diagnosis. Worse, the increased skin pigmentation of adre
-
nal insufficiency may be mistaken for chloasma (melasma). 
Undiagnosed adrenal insufficiency can cause intrauterine 
growth retardation and fetal loss. Pregnant women with 
undiagnosed adrenal insufficiency can experience shock 
from adrenal crisis, particularly during the first trimester, 
concurrent illness, labor, or postpartum.
Patients with preexistent type 1 diabetes experience 
more frequent hypoglycemia with the onset of adrenal 
insufficiency, such that their insulin dosage must be reduced.
Acute adrenal crisis
 is an immediate threat to life. Nau
-
sea, vomiting, fever, dehydration, and profound hypoten
-
sion progresses to life-threatening shock that does not fully 
respond to intravenous fluids and vasopressors.
The WBC count typically shows moderate neutropenia, 
lymphocytosis, and eosinophilia (total eosinophil count 
over 300/mcL). Among patients with chronic adrenal 
insufficiency, the serum sodium is usually low (88%) and 
the potassium usually elevated (64%). (Patients with vom
-
iting or diarrhea may not be hyperkalemic.) Fasting hypo
-
glycemia is common. Hypercalcemia may be present.
A plasma cortisol less than 3 mcg/dL (83 nmol/L) at 
8 
am
 is diagnostic, especially if accompanied by simultane
-
ous elevation of the plasma ACTH level greater than 
200 pg/mL (44 pmol/L). The diagnosis is confirmed by a 
simplified 
cosyntropin stimulation test:
 (1) Synthetic 
ACTH
1–24
 (cosyntropin), 0.25 mg, is given intramuscularly. 
(2) Serum cortisol is obtained 45 minutes after cosyntropin 
is administered. Normally, serum cortisol rises to at least 
20 mcg/dL (550 pmol/L), whereas patients with adrenal 
insufficiency have stimulated serum cortisol levels less 
than 20 mcg/dL (550 pmol/L). For patients receiving corti
-
costeroid treatment, hydrocortisone must not be given for 
at least 8 hours before the test. Other corticosteroids (eg, 
prednisone, dexamethasone) do not interfere with specific 
assays for cortisol. Cosyntropin is usually well tolerated, 
but infrequent (less than 5%) side effects have included 
hypersensitivity reactions with nausea, headache, dizzi
-
ness, dyspnea, palpitations, flushing, edema, and local 
injection site reactions. Cosyntropin may be administered 
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during pregnancy; however, the test may lack sensitivity, 
since adrenal ACTH-responsiveness increases during 
Serum DHEA levels are less than 1000 ng/mL 
(350 nmol/L) in 100% of patients with adrenal insuffi
-
ciency but also in about 15% of the population, so the test 
is very sensitive but not specific.
Serum anti-adrenal antibodies are found in about 50% 
of cases of autoimmune Addison disease. The presence of 
serum antibodies to 21-hydroxylase helps confirm the 
diagnosis of autoimmune adrenal insufficiency. Antibodies 
to thyroid (45%) and other tissues may be present.
Salt-wasting congenital adrenal hyperplasia due to 
21-hydroxylase deficiency is usually diagnosed at birth in 
females due to ambiguous genitalia. Males and patients with 
milder enzyme defects may present later. The diagnosis of 
adrenal insufficiency is made as above. The specific diagno
-
sis requires elevated serum levels of 17-OH progesterone.
Elevated plasma renin activity (PRA) indicates the pres
-
ence of depleted intravascular volume and the need for 
fludrocortisone administration. Serum epinephrine levels 
are low in patients with adrenal insufficiency, since these 
patients do not have the high local concentrations of corti
-
sol that are required to induce the enzyme PNMT in adre
-
nal medulla for the synthesis of epinephrine from 
norepinephrine.
Y oung men with idiopathic Addison disease are 
screened for X-linked adrenoleukodystrophy by determin
-
ing plasma very long-chain fatty acid levels; affected 
patients have high levels.
In acute adrenal crisis, blood, sputum, or urine cul
-
tures may be positive if bacterial infection is the precipitat
-
ing cause.
C. Imaging
When adrenal insufficiency is not clearly autoimmune, a 
CT scan of the adrenal glands should be obtained. Small, 
noncalcified adrenals are seen in autoimmune Addison 
disease. The adrenals are enlarged in about 85% of cases 
related to metastatic or granulomatous disease. Adrenal 
calcifications occur in about 50% of cases of tuberculous 
Addison disease but are also seen with hemorrhage, fungal 
infection, pheochromocytoma, and melanoma.
 
»
Patients with ACTH deficiency have normal mineralocor
-
ticoid production and do not develop hyperkalemia. 
Patients with secondary adrenal insufficiency (see Hypo
-
pituitarism) lack ACTH and have normal to decreased 
skin pigmentation that has been described as “alabaster 
skin. ” This contrasts with the increased skin pigmentation 
in patients with Addison disease. Hemochromatosis 
 
also causes bronze skin hyperpigmentation, but hemo
-
chromatosis may in fact be the cause of Addison disease. 
Acute adrenal insufficiency must be distinguished from 
other causes of shock (eg, septic, hemorrhagic, 
cardiogenic).
The constitutional symptoms may be mistaken for 
occult cancer, anorexia nervosa, or emotional stress. Acute 
adrenal insufficiency must be distinguished from an acute 
abdomen in which neutrophilia is the rule, whereas in 
adrenal insufficiency there is lymphocytosis and eosino
-
philia. The neurologic manifestations of Allgrove syn
-
drome and adrenoleukodystrophy (especially in women) 
may mimic multiple sclerosis. Hyperkalemia can be 
caused by hyporeninemic hypoaldosteronism related to 
type IV renal tubular acidosis. Hyperkalemia is also seen 
with gastrointestinal bleeding, rhabdomyolysis, hyper
-
kalemic paralysis, and some drugs (eg, angiotensin-
converting enzyme [ACE] inhibitors, spironolactone, and 
drospirenone).
Hyponatremia is seen in many other conditions (eg, 
hypothyroidism, diuretic use, heart failure, cirrhosis, 
vomiting, diarrhea, severe illness, or major surgery) 
(Figure 21–1). Nearly 40% of critically ill patients have low 
serum cortisol levels due to low serum albumin levels, such 
that their total serum cortisol levels may be low but their 
serum free cortisol levels are normal.
 
»

»
Any of the complications of the underlying disease (eg, 
tuberculosis) are more likely to occur in adrenal insuffi
-
ciency, and intercurrent infections may precipitate an acute 
adrenal crisis. Associated autoimmune diseases are com
-
mon (see above).
 
»
Treatment
Patients with adrenal insufficiency (and family members) 
must be thoroughly educated about adrenal insufficiency. 
Patients are advised to wear a medical alert bracelet or medal 
reading, “ Adrenal insufficiency—takes hydrocortisone. ” 
They need to be provided with a dose escalation schedule for 
increased corticosteroids for illness, accidents, or prior to 
minor surgical procedures and for increased fludrocortisone 
for hot weather or prolonged strenuous exercise. Corticoste
-
roids and fludrocortisone must be prescribed in liberal 
amounts with automatic refills to avoid the patient’s running 
out of medication. It is also advisable to prescribe a routine 
antiemetic such as ondansetron ODT 8-mg tablets to be 
taken every 8 hours for nausea. Parenteral hydrocortisone 
(Solu-Cortef) 100 mg is also prescribed for patient self-
injection in the event of vomiting. Patients must also receive 
advance instructions to seek medical attention at an emer
-
gency facility immediately in the event of vomiting or severe 
illness. All infections should be treated immediately and 
vigorously, with hydrocortisone administered at appropri
-
ately increased doses.
B. Specific Therapy
Replacement therapy should include corticosteroids with 
mineralocorticoids for primary adrenal insufficiency. In 
mild cases, corticosteroids alone may be adequate.
1. Corticosteroid replacement therapy—
therapy for most patients with Addison disease involves 
15–30 mg of hydrocortisone orally daily in two or three 
divided doses (eg, 10 mg at 7 
am
, 10 mg at 1 
pm
, and 
CMDT19_Ch26_p1119-p1219.indd   1182

1183
 
CMDT 2019
5 mg at 7 
pm
). Some patients respond better to prednisone 
or methylprednisolone in doses of about 3–6 mg daily in 
divided doses. Adjustments in dosage are made according to 
the clinical response. The corticosteroid dose should be kept 
at the lowest level at which the patient feels clinically well.
Plenadren MR (5- or 20-mg modified-release tablets) is 
a once-daily dual-release preparation of hydrocortisone 
that may be administered in the morning (usual dose range 
is 20–30 mg daily). It is not available in the United States 
but is available in Canada and elsewhere.
A proper corticosteroid dose usually results in clinical 
improvement, a normal WBC count differential, and no 
manifestations of Cushing syndrome. Serum ACTH levels 
vary substantially and should not be used to determine 
dosing. 
Increased corticosteroid dosing
 is required in cir
-
cumstances of infection, trauma, surgery, stressful diag
-
nostic procedures, or other forms of stress. Rifampin use 
increases the clearance of hydrocortisone and necessitates 
increased dosing of hydrocortisone by up to 50%. During 
the third trimester of pregnancy, corticosteroid require
-
ments are higher, so usual corticosteroid doses are 
increased by 50%. For severe stress of major illness, sur
-
gery, or delivery, a maximum stress dose of hydrocortisone 
is given as 50–100 mg intravenously or intramuscularly, 
followed by 50 mg every 6 hours. Lower doses, oral or par
-
enteral, are used for less severe stress. The dose is reduced 
back to normal as the stress subsides. 
Decreased corticoste
-
roid dosing
 is required when medications are prescribed 
that inhibit corticosteroid metabolism by blocking the 
isoenzyme CYP34A, particularly the antifungals ketocon
-
azole or itraconazole, the antidepressant nefazodone, anti-
HIV protease inhibitors, and cobicistat.
2. Mineralocorticoid replacement therapy—
Fludrocortisone acetate
 has a potent sodium-retaining 
effect. The dosage is 0.05–0.3 mg orally daily or every other 
day. In the presence of postural hypotension, hyponatremia, 
or hyperkalemia, the dosage is increased. Similarly, in patients 
with fatigue, an elevated PRA indicates the need for a higher 
replacement dose of fludrocortisone. If edema, hypokalemia, 
or hypertension ensues, the dose is decreased. During treat
-
ment with hydrocortisone with maximum doses appropriate 
for stress, fludrocortisone replacement is not required. Some 
patients cannot tolerate fludrocortisone and must substitute 
NaCl tablets to replace renal sodium loss.
DHEA
 is given to some women with adrenal insuffi
-
ciency. In a double-blind clinical trial, women taking 
DHEA 50 mg orally each morning experienced an 
improved sense of well-being, increased muscle mass, and 
a reversal in bone loss at the femoral neck. DHEA replace
-
ment did not improve fatigue, cognitive problems, or sex
-
ual dysfunction; however, its placebo effect may be 
significant in that regard. Older women who receive 
DHEA should be monitored for androgenic effects. 
Because over-the-counter preparations of DHEA have 
variable potencies, it is best to have the pharmacy formu
-
late this with pharmaceutical-grade micronized DHEA.
3. Treatment of acute adrenal crisis—
If acute adrenal 
crisis is suspected but the diagnosis of adrenal insufficiency 
is not yet established, blood is drawn for routine 
emergency laboratory tests and blood cultures, as well as 
serum cortisol and ACTH levels. Without waiting for the 
results, treatment is initiated 
immediately
 with hydrocorti
-
sone phosphate or hydrocortisone sodium succinate 100–
300 mg intravenously along with saline solution. Thereafter, 
hydrocortisone is continued as intravenous infusions of 
50–100 mg every 6 hours for the first day. The dosage may 
then be reduced according to the clinical picture and labo
-
ratory test results.
Since bacterial infection frequently precipitates acute

-
Since bacterial infection frequently precipitates acute 
adrenal crisis, broad-spectrum antibiotics should be admin
-
istered empirically while waiting for the results of initial 
cultures. The patient must also be treated for electrolyte 
abnormalities, hypoglycemia, and dehydration, as indicated.
When the patient is able to take food by mouth, hydro
-
cortisone is administered orally in doses of 10–20 mg every 
6 hours, and the dosage is reduced to maintenance levels as 
needed. Most patients ultimately require hydrocortisone 
twice daily (10–20 mg in the morning; 5–10 mg in the 
evening). Mineralocorticoid replacement is not needed 
when large amounts of hydrocortisone are being given, but 
as its dose is reduced, it is usually necessary to add fludro
-
cortisone acetate, 0.05–0.2 mg orally daily. Some patients 
never require fludrocortisone or become edematous at 
doses of more than 0.05 mg once or twice weekly. Once the 
crisis has passed, the patient must be evaluated to assess the 
degree of permanent adrenal insufficiency and to establish 
the cause, if possible.
 
»
Prognosis
The life expectancy of patients with Addison disease is 
reasonably normal, as long as they are compliant with their 
medications and knowledgeable about their condition. 
However, one retrospective Swedish study of 1675 patients 
with Addison disease found an unexpected increase in all-
cause mortality, mostly from cardiovascular disease, malig
-
nancy, and infection. Adrenal crisis can occur in patients 
who stop their medication or who experience stress such as 
infection, trauma, or surgery without appropriately higher 
doses of corticosteroids. Patients who take excessive doses 
of corticosteroid replacement can develop Cushing syn
-
drome, which imposes its own risks.
Some patients feel residual fatigue, despite corticosteroid 
and mineralocorticoid replacement. This may be due, in 
part, to the inadequacy of oral replacement to duplicate 
cortisol’s normal circadian rhythm. Also, patients with Addi
-
son disease are deficient in epinephrine, but replacement 
epinephrine is not available. Fatigue may also be an indica
-
tion of suboptimal dosing of medication, electrolyte imbal
-
ance, or concurrent hypothyroidism or diabetes mellitus.
Rapid treatment is usually lifesaving in acute adrenal 
crisis. However, if adrenal crisis is unrecognized and 
untreated, shock that is unresponsive to fluid replacement 
and vasopressors can result in death.
Allolio B. Extensive expertise in endocrinology. Adrenal crisis. 
Eur J Endocrinol. 2015 Mar;172(3):R115–24. [PMID: 25288693]
Bensing S et al. Epidemiology, quality of life and complications 
of primary adrenal insufficiency: a review. Eur J Endocrinol. 
2016 Sep;175(3):R107–16. [PMID: 27068688]
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Bornstein SR et al. Diagnosis and treatment of primary adrenal 
insufficiency: an Endocrine Society clinical practice guide
-
line. J Clin Endocrinol Metab. 2016 Feb;101(2):364–89. 
[PMID: 26760044]
Husebye ES et al. Consensus statement on the diagnosis, treat
-
ment and follow-up of patients with primary adrenal insuffi
-
ciency. J Intern Med. 2014 Feb;275(2):104–15. [PMID: 
24330030]
Puar TH et al. Adrenal crisis: still a deadly event in the 21st 
century. Am J Med. 2016 Mar;129(3):339.e1–9. [PMID: 
26363354]
Quinkler M et al. Mineralocorticoid substitution and monitor
-
ing in primary adrenal insufficiency. Best Pract Clin Endocrinol 
Metab. 2015 Jan;29(1):17–24. [PMID: 25617169]
CUSHING SYNDROME (
Hypercortisolism
)
 
»
Central obesity, muscle wasting, hirsutism, purple 
striae.
 
»
Psychological changes.
 
»
Osteoporosis, hypertension, poor wound healing.
 
»
Hyperglycemia, leukocytosis, lymphocytopenia, 
 
»
Elevated serum cortisol and urinary free cortisol. 
Lack of normal suppression by dexamethasone.
 
»
The term Cushing “syndrome” refers to the manifestations 
of excessive corticosteroids, commonly due to supraphysi
-
ologic doses of corticosteroid drugs and rarely due to 
spontaneous production of excessive cortisol by the adre
-
nal cortex.
Cases of spontaneous Cushing syndrome are rare, with 
an incidence of 2.6 new cases yearly per million population 
in the United States. About 68% of cases are due to Cushing 
“disease, ” caused by a benign ACTH-secreting pituitary 
adenoma that is typically smaller than 5 mm and usually 
located in the anterior pituitary (94%); however, about 6% 
of such adenomas are ectopic in locations such as the cav
-
ernous sinus, sphenoid sinus, ethmoid sinus, or posterior 
pituitary. Cushing disease is at least three times more fre
-
quent in women than men.
About 7% of cases are due to nonpituitary ACTH-
secreting neuroendocrine neoplasms that produce ectopic 
ACTH. Ectopic locations include the lungs (55%), pancreas 
(9%), mediastinum-thymus (8%), adrenal (6%), gastroin
-
testinal tract (5%), thyroid (4%), and other sites (13%). 
About 15% of cases are due to ACTH from a source that 
cannot be initially located.
About 25% of cases are due to excessive autonomous 
secretion of cortisol by the adrenals. Cortisol secretion is 
independent of ACTH and plasma ACTH levels are usually 
low or low-normal. Most such cases are due to a unilateral 
adrenal tumor. Benign adrenal adenomas are generally small 
and produce mostly cortisol; adrenocortical carcinomas are 
usually large when discovered and can produce excessive 
cortisol as well as androgens but may be nonsecretory. 
ACTH-independent macronodular adrenal hyperplasia 
can also produce hypercortisolism due to the adrenal cor
-
tex cells’ abnormal stimulation by hormones such as cate
-
cholamines, arginine vasopressin, serotonin, hCG/LH, or 
gastric inhibitory polypeptide; in the latter case, hypercor
-
tisolism may be intermittent and food-dependent and 
plasma ACTH levels may not be completely suppressed.
 
»
The manifestations of Cushing syndrome vary consider
-
ably. Early in the course of the disease, patients frequently 
complain of nonspecific symptoms, such as fatigue or 
reduced endurance but may have few, if any, of the physical 
stigmata described below. Central obesity with a plethoric 
“moon face, ” “buffalo hump, ” supraclavicular fat pads, pro
-
tuberant abdomen, and thin extremities eventually develop 
in most patients with Cushing syndrome. Muscle atrophy 
causes weakness, with difficulty standing up from a seated 
position or climbing stairs. Patients may also experience 
backache, headache, hypertension, osteoporosis, avascular 
necrosis of bone, acne, superficial skin infections, and oli
-
gomenorrhea or amenorrhea in women or erectile dys
-

-
-
function in men. Patients may have thirst and polyuria 
(with or without glycosuria), renal calculi, glaucoma, pur
-
ple striae (especially around the thighs, breasts, and abdo
-
men), and easy bruisability. Unusual bacterial or fungal 
infections are common. Wound healing is impaired. Men
-
tal symptoms may range from diminished ability to con
-
centrate to increased lability of mood to frank psychosis. 
Patients are susceptible to opportunistic infections. Hyper
-
pigmentation is common with ectopic ACTH-secreting 
neoplasms but not with pituitary Cushing disease.
Adrenal carcinomas
 usually have gross metastases by 
the time of diagnosis. Microscopic metastases are not visi
-
ble by scanning but can be inferred from the presence of 
detectable cortisol levels following removal of the primary 
adrenal tumor in patients with a cortisol-secreting carci
-
noma and Cushing syndrome. The ENSAT staging system 
is used: stage 1 is a localized tumor 5 cm or smaller; stage 
2 is a localized tumor larger than 5 cm; stage 3, tumor with 
local metastases; stage 4, tumor with distant metastases.
Glucose tolerance is impaired as a result of insulin resis
-
tance. Polyuria is present as a result of increased free water 
clearance; diabetes mellitus with glycosuria may worsen it. 
Patients with Cushing syndrome often have leukocytosis 
with relative granulocytosis and lymphopenia. Hypokale
-
mia may be present, particularly in cases of ectopic ACTH 
secretion.
1. Diagnostic tests for hypercortisolism—
hypercortisolism involves determining whether the follow
-
ing characteristics of Cushing syndrome are present: 
(1) lack of cortisol diurnal variation, (2) reduced suppress
-
ibility of cortisol by dexamethasone, (3) increased cortisol 
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production rate, and (4) suppression of plasma ACTH by 
hypercortisolism from an adrenal nodule. Conflicting 
results are common.
Late-night (10–11 
pm
) salivary cortisol 
determinations
 
are 
particularly useful, particularly for ACTH-dependent 
hypercortisolism.
 Late-night salivary cortisol levels are 
normally 150 ng/dL (4.0 nmol/L) or less. Late-night sali
-
vary cortisol levels that are consistently greater than 
250 ng/dL (7.0 nmol/L) are considered very abnormal. The 
late-night salivary cortisol test has a relatively high sensi
-
tivity and specificity for Cushing syndrome.
The 
overnight dexamethasone suppression test
 is an 
easy screening test for hypercortisolism and is particularly 
sensitive for mild ACTH-independent hypercortisolism 
from an adrenal nodule. Dexamethasone 1 mg is given orally 
at 11 
pm
 and serum is collected for cortisol determination at 
8 
am
 the next morning; a cortisol level less than 1.8 mcg/dL 
(50 nmol/L, high-performance liquid chromatography 
[HPLC] assay) excludes Cushing syndrome with some cer
-
tainty. However, 8% of established patients with pituitary 
Cushing disease have dexamethasone-suppressed cortisol 
levels less than 2 mcg/dL (55 nmol/L). Antiseizure drugs (eg, 
phenytoin, phenobarbital, primidone) and rifampin acceler
-
ate the metabolism of dexamethasone, causing a lack of 
cortisol suppression by dexamethasone. Estrogens—during 
pregnancy or as oral contraceptives or HRT—may also cause 
lack of dexamethasone suppressibility.
A 24-hour urinary free cortisol and creatinine
 is usu
-
ally used to confirm hypercortisolism in patients with a 
high late-night salivary cortisol or an abnormal dexametha
-
sone suppression test. A high 24-hour urine free cortisol 
(greater than 50 mcg/day or 140 nmol/day in adults), or free 
cortisol to creatinine ratio of greater than 95 mcg cortisol/g 
creatinine, helps confirm hypercortisolism. However, many 
patients with mild hypercortisolism have a urinary free 
cortisol that is misleadingly within the reference range 
when measured by liquid chromatography-tandem mass 
spectrometry. A misleadingly high urine free cortisol excre
-
tion occurs with high fluid intake. In pregnancy, urine free 
cortisol is increased, while 17-hydroxycorticosteroids 
remain normal and diurnal variability of serum cortisol is 
normal. Carbamazepine and fenofibrate cause false eleva
-
tions of urine free cortisol when determined by HPLC.
2. Diagnostic tests for the source of hypercortisolism—
Once hypercortisolism is confirmed, a plasma ACTH is 
obtained. A plasma ACTH below 6 pg/mL (1.3 pmol/L) 
indicates a probable adrenal tumor, whereas higher levels 
are produced by pituitary or ectopic ACTH-secreting 
tumors. However, certain assays suffer interference and 
report low-normal plasma ACTH levels in patients with 
ACTH-independent hypercortisolism. Serum dehydroepi
-
androsterone sulfate (DHEAS) levels can be used as a 
proxy for ACTH, since its secretion is ACTH-independent; 
levels below the reference range imply ACTH-independent 
C. Imaging
In ACTH-independent Cushing syndrome
, CT of the 
adrenals usually detects a mass lesion, which is most often 
an adrenal adenoma. Adrenocortical carcinomas can usu
-
ally be distinguished from benign adrenal adenomas since 
they are generally larger (average 11 cm diameter) and 
many have metastases that are visible on preoperative 
scans.
In ACTH-dependent Cushing syndrome
, MRI of the 
pituitary demonstrates a pituitary lesion in about 50% of 
cases. Premature cerebral atrophy is often noted. When the 
pituitary MRI is normal or shows a tiny (less than 5 mm 
diameter) irregularity that may be incidental, selective 
catheterization of the inferior petrosal sinus veins draining 
the pituitary is performed. ACTH levels in the inferior 
petrosal sinus that are more than twice the simultaneous 
peripheral venous ACTH levels are indicative of pituitary

peripheral venous ACTH levels are indicative of pituitary 
Cushing disease. Inferior petrosal sinus sampling is also 
done during ovine CRH (oCRH or Acthrel) administra
-
tion, which ordinarily causes the ACTH levels in the infe
-
rior petrosal sinus to be over three times the peripheral 
ACTH level when the pituitary is the source of ACTH.
When inferior petrosal sinus ACTH concentrations are 
not above the requisite levels, a search for an ectopic source 
of ACTH is undertaken. Location of ectopic sources of 
ACTH commences with CT scanning of the chest and 
abdomen, with special attention to the lungs (for carcinoid 
or small cell carcinomas), the thymus, the pancreas, and 
the adrenals. In patients with ACTH-dependent Cushing 
syndrome, chest masses should not be assumed to be the 
source of ACTH, since opportunistic infections are com
-
mon, so it is prudent to biopsy a chest mass to confirm the 
pathologic diagnosis prior to resection.
For Cushing syndrome due to ectopic ACTH, CT scan
-
ning fails to detect the source of ACTH in about 34% of 
cases. In such cases, the most sensitive (82%) scanning 
technique is whole-body imaging with 
68
Ga-somatostatin 
receptor-PET/CT (
68
Ga-DOTATOTATE-PET/CT). The 
next most sensitive (58%) scanning technique is whole-
body imaging with 
18
F-DOPA-PET/CT.
 
»
Alcoholic patients can have hypercortisolism and many 
clinical manifestations of Cushing syndrome. Pregnant 
women have elevated serum ACTH levels, increased urine 
free cortisol, and high serum cortisol levels due to high 
serum levels of cortisol-binding globulin. Critically ill 
patients frequently have hypercortisolism, usually with sup
-
pression of serum ACTH. Depressed patients also have 
hypercortisolism that can be nearly impossible to distin
-
guish biochemically from Cushing syndrome but without 
clinical signs of Cushing syndrome. Cushing syndrome can 
be misdiagnosed as anorexia nervosa (and vice versa) 
owing to the muscle wasting and extraordinarily high urine 
free cortisol levels found in anorexia. Patients with severe 
obesity frequently have an abnormal dexamethasone sup
-
pression test, but the urine free cortisol is usually normal, as 
is diurnal variation of serum cortisol. Patients with familial 
cortisol resistance have hyperandrogenism, hypertension, 
and hypercortisolism without actual Cushing syndrome. 
Excessive ingestion of gamma-hydroxybutyric acid (GHB, 
sodium oxybate) can also induce ACTH-dependent Cush
-
ing syndrome that resolves after the drug is stopped.
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Some adolescents develop violaceous striae on the 
abdomen, back, and breasts; these are known as “striae 
distensae” and are not indicative of Cushing syndrome. 
Patients with familial partial lipodystrophy type I develop 
central obesity and moon facies, along with thin extremi
-
ties due to atrophy of subcutaneous fat. However, these 
patients’ muscles are strong and may be hypertrophic, dis
-
tinguishing this condition from Cushing syndrome. 
Patients receiving antiretroviral therapy for HIV-1 infec
-
tion frequently develop partial lipodystrophy with thin 
extremities and central obesity with a dorsocervical fat pad 
(“buffalo hump”) causing pseudo-Cushing syndrome.
 
»
Treatment
Patients must receive treatment for cortisol-dependent 
comorbidities, including osteoporosis, psychiatric disor
-
ders, diabetes mellitus, hypertension, hypokalemia, muscle 
weakness, and infections.
A. Surgical Therapy
Pituitary Cushing disease
 is best treated with transsphe
-
noidal selective resection of the pituitary adenoma. With 
an experienced pituitary neurosurgeon, remission rates 
range from 80% to 90%. Postoperative hyponatremia 
occurs frequently, so serum sodium should be monitored 
frequently for the first 2 weeks postoperatively. The patient 
should be screened for secondary hypothyroidism with a 
serum free T
4
 within 1–2 weeks after surgery. After suc
-
cessful pituitary surgery, the rest of the pituitary usually 
returns to normal function; however, the pituitary cortico
-
trophs remain suppressed and require 6–36 months to 
recover normal function. Therefore, patients receive 
empiric replacement-dose hydrocortisone postoperatively. 
Postoperative secondary adrenal insufficiency is a mark of 
successful pituitary surgery; screening may include a 
morning serum cortisol 8 hours following the prior eve
-
ning dose of hydrocortisone. The cosyntropin test becomes 
abnormal by 2 weeks following successful pituitary surgery. 
Patients with secondary adrenal insufficiency and their 
families require patient education about the condition and 
must continue corticosteroid replacement until a cosyntro
-
pin stimulation test is normal. A pituitary MRI is obtained 
about 3 months postoperatively and repeated as indicated 
for clinical evidence of recurrent Cushing disease or Nel
-
son syndrome, the progressive enlargement of ACTH-
secreting pituitary tumors following bilateral 
adrenalectomy.
Cushing disease may persist after pituitary surgery, 
particularly when there has been cavernous sinus involve
-
ment. After apparent successful pituitary surgery, Cushing 
disease recurs in 16% after a mean of 38 months. Patients 
must have repeated evaluations for recurrent Cushing dis
-
ease for years postoperatively. For patients with persistent 
or recurrent Cushing disease, repeat transsphenoidal pitu
-
itary surgery may be warranted if the recurrent tumor is 
visible and deemed resectable. Otherwise, bilateral laparo
-
scopic adrenalectomy is usually the best treatment option, 
particularly for patients with very severe disease, since it 
renders an immediate remission in a condition with 
significant morbidity and mortality. Residual or recurrent 
ACTH-secreting pituitary tumors may also be treated with 
stereotactic radiosurgery, which normalizes urine free cor
-
tisol in 70% of patients within a mean of 17 months, com
-
pared with a 23% remission rate with conventional 
radiation therapy. Pituitary radiosurgery can also be used 
to treat Nelson syndrome.
Ectopic ACTH-secreting tumors
 should be surgically 
resected. If the tumor cannot be localized or is metastatic, 
laparoscopic bilateral adrenalectomy is usually recom
-
mended. Medical treatment with a combination of mitotane 
(3–5 g/24 h), ketoconazole (0.4–1.2 g/24 h), and metyra
-
pone (3–4.5 g/24 h) often suppresses the hypercortisolism.
Metastatic ACTH-producing tumors that are visible 
with Octreoscan or 
68
Ga-DOTATATE-PET imaging have

-
68
Ga-DOTATATE-PET imaging have 
somatostatin receptors. Such tumors may respond to ther
-
apy with somatostatin analogs; 
pasireotide LAR
 (60 mg 
intramuscularly every 28 days) or 
octreotide LAR
 (30–40 mg 
intramuscularly every 28 days) slows progression of the 
malignancy and reduces ACTH secretion in up to half such 
patients. Potassium-sparing diuretics are often helpful. 
Radionuclide therapy with several cycles of 
177
Lu-
DOTATATE has produced remissions in some patients.
Patients who are successfully surgically treated for 
Cushing syndrome typically develop “cortisol withdrawal 
syndrome, ” even when given replacement corticosteroids 
for adrenal insufficiency. Manifestations can include hypo
-
tension, nausea, fatigue, arthralgias, myalgias, pruritus, 
and flaking skin. Increasing the hydrocortisone replace
-
ment to 30 mg orally twice daily can improve these symp
-
toms; the dosage is then reduced slowly as tolerated. 
Patients with Cushing syndrome are prone to develop 
osteoporosis. Bone densitometry is recommended for all 
patients and treatment is commenced for patients with 
osteoporosis.
Benign adrenal adenomas
 may be resected laparo
-
scopically if they are smaller than 6 cm in diameter; cure is 
achieved in most patients. However, most patients experi
-
ence prolonged secondary adrenal insufficiency. Patients 
with bilateral adrenal macronodular hyperplasia usually 
require bilateral adrenalectomies and an evaluation for 
Carney complex that can be confirmed with a genetic 
evaluation for activating mutations in the gene 
PRKAR1A
 
or genetic changes at chromosome 2p16.
Adrenocortical carcinomas
 are resected surgically. If 
the adrenocortical carcinoma was functional, postopera
-
tive secondary adrenal insufficiency is a good prognostic 
sign, with an increased chance that the tumor was com
-
pletely resected without metastases; however, detectable 
postoperative cortisol levels predict metastases, even if no 
metastases are visible on scans. Patients with secretory 
adrenocortical carcinomas are usually treated with mito
-
tane postoperatively, particularly if metastases are visible 
or cortisol is detectable postoperatively. Patients with 
nonsecretory metastatic adrenocortical carcinomas have 
also responded to mitotane. Mitotane is typically given 
for 2–5 years postoperatively. It is given orally with meals, 
beginning with 0.5 g twice daily, increasing to 1 g twice 
daily within 2 weeks, with subsequent increased doses 
every 2–3 weeks to reach serum levels of 14–20 mcg/mL. 
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Unfortunately, only half the patients are able to reach 
these levels due to side effects. Mitotane can cause hypo
-
gonadism and can suppress TSH and cause hypothyroid
-
ism. Mitotane often causes primary adrenal insufficiency. 
Replacement hydrocortisone or prednisone should be 
started when mitotane doses reach 2 g daily. The replace
-
ment dose of hydrocortisone starts at 15 mg in the morn
-
ing and 10 mg in the afternoon, but must often be 
doubled or tripled because mitotane increases cortisol 
metabolism and cortisol binding globulin levels; the lat
-
ter can artifactually raise serum cortisol levels. Com
-
bined chemotherapy with etoposide, doxorubicin, 
cisplatin, and mitotane (EDP-M) appears to be the most 
effective regimen for recurrent or metastatic adrenocorti
-
cal carcinoma.
For patients with Cushing syndrome who decline surgery 
or for whom surgery has been unsuccessful, mineralocor
-
ticoid hypertension can be treated with spironolactone, 
eplerenone, and dihydropyridine calcium channel block
-
ers. Women with hyperandrogenism may be treated with 
flutamide. Cabergoline, 0.5–3.5 mg orally twice weekly, 
was successful in 40% of patients with Cushing disease in 
one small study. Pasireotide, a multireceptor-targeting 
somatostatin analog, is a treatment option for refractory 
ACTH-secreting pituitary tumors causing Cushing disease 
or Nelson syndrome. Ketoconazole inhibits adrenal ste
-
roidogenesis and is another treatment option when given 
in doses of about 200 mg orally every 6 hours; however, it 
is marginally effective and can cause liver toxicity. Metyra
-
pone can suppress hypercortisolism; required median daily 
doses are 1250–1500 mg/day in divided doses. It may be 
combined with ketoconazole. Metyrapone also may be 
used for patients with secretory adrenocortical carcinoma 
whose hypercortisolism is not fully controlled with 
mitotane.
 
»
Prognosis
The manifestations of Cushing syndrome regress with 
time, but patients may have residual cognitive or psychiat
-
ric impairment, muscle weakness, osteoporosis, and 
sequelae from vertebral fractures. Continued impaired 
quality of life is more common in women compared to 
men. Y ounger patients have a better chance for full 
recovery.
Patients with Cushing syndrome from a benign adrenal 
adenoma experience a 5-year survival of 95% and a 10-year 
survival of 90%, following a successful adrenalectomy. 
Patients with Cushing disease from a pituitary adenoma 
experience a similar survival if their pituitary surgery is 
successful, which can be predicted if the postoperative 
nonsuppressed serum cortisol is less than 2 mcg/dL 
(55 nmol/L). Following successful treatment, overall 
mortality remains particularly higher for patients with 
older age at diagnosis, higher preoperative ACTH concen
-
trations, and longer duration of hypercortisolism.
Patients who have a complete remission after transsphe
-
noidal surgery have about a 15–20% chance of recurrence 
over the next 10 years. Patients with failed pituitary surgery 
may require pituitary radiation therapy, which has its own 
morbidity. Laparoscopic bilateral adrenalectomy may be 
required. Recurrence of hypercortisolism may occur as a 
result of growth of an adrenal remnant stimulated by high 
levels of ACTH. The prognosis for patients with ectopic 
ACTH-producing tumors depends on the aggressiveness 
and stage of the particular tumor. Patients with ACTH of 
unknown source have a 5-year survival rate of 65% and a 
10-year survival rate of 55%.
In patients with adrenocortical carcinoma, 5-year sur
-
vival rates of treated patients have correlated with the 
ENSAT stage. For stage 1, the 5-year survival was 81%; for 
stage 2, 61%; for stage 3, 50%; and for stage 4, 13%. In 
patients with stage 1 or 2 disease, long-term survival does 
occur. Improved survival has been associated with younger 
age, resection of the primary tumor, stage at diagnosis, and

age, resection of the primary tumor, stage at diagnosis, and 
adjuvant treatment with mitotane.
 
»
Following bilateral adrenalectomy for Cushing disease, a 
pituitary adenoma may enlarge progressively (Nelson syn
-
drome), causing local destruction (eg, visual field impair
-
ment, cranial nerve palsy) and hyperpigmentation. 
Following successful therapy for Cushing syndrome, sec
-
ondary adrenal insufficiency occurs and requires long-
term corticosteroid replacement. Five years after successful 
surgery, secondary hypoadrenalism resolves in about 58% 
of patients with pituitary Cushing disease, 82% of those 
with ectopic ACTH, and only 38% of those who had an 
adrenal tumor.
 
»
•	
Dexamethasone suppression test is abnormal.
 
»
•	
Transsphenoidal hypophysectomy.
•	
Adrenalectomy.
•	
Resection of ectopic ACTH-secreting tumor.
Asuzu D et al. Normalized early postoperative cortisol and 
ACTH values predict nonremission after surgery for Cushing 
disease. J Clin Endocrinol Metab. 2017 Jul;102(7):2179–87. 
[PMID: 28323961]
Loriaux DL. Diagnosis and differential diagnosis of Cushing’s 
Syndrome. N Engl J Med. 2017 Apr 13;376(15):1451–9. 
[PMID: 28402781]
Nieman LK et al. Treatment of Cushing’s syndrome: an 
Endocrine Society clinical practice guideline. J Clin Endocri
-
nol Metab. 2015 Aug;100(8):2807–31. [PMID: 26222757]
Raff H et al. Urine free cortisol in the diagnosis of Cushing’s 
syndrome: is it worth doing, and if so how? J Clin Endocrinol 
Metab. 2015 Feb;100(2):395–7. [PMID: 25423573]
Valassi E et al. Diagnostic tests for Cushing’s syndrome differ 
from published guidelines: data from ERCUSYN. Eur J 
Endocrinol. 2017 May;176(5):613–24. [PMID: 28377460]
Wang S et al. Prognostic factors of adrenocortical carcinoma: 
an analysis of the Surveillance Epidemiology and End Results 
(SEER) database. Asian Pac J Cancer Prev. 2017 
Oct;18(10):2817–23. [PMID: 29072424]
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PRIMARY ALDOSTERONISM
 
»
Hypertension may be severe or drug-resistant.
 
»
Hypokalemia (in minority of patients) may cause 
polyuria, polydipsia, muscle weakness.
 
»
Low plasma renin; elevated plasma and urine 
aldosterone levels.
 
»
Primary aldosteronism (hyperaldosteronism) refers to an 
inappropriately high aldosterone secretion that does not 
suppress adequately with sodium loading. Most affected 
patients have hypertension, although some may be nor
-
motensive. Primary aldosteronism is believed to account 
for 8–10% of all cases of hypertension and 20% of cases of 
resistant hypertension. It should be suspected with early-
onset hypertension or stroke before age 50 years (or 
both). It may be difficult to distinguish primary aldoste
-
ronism from cases of low renin essential hypertension, 
with which it may overlap. Patients of all ages may be 
affected, but the peak incidence is between 30 years and 
60 years. Excessive aldosterone production increases 
sodium retention and suppresses plasma renin. It 
increases renal potassium excretion, which can lead to 
hypokalemia. Cardiovascular events are more prevalent 
in patients with aldosteronism (35%) than in those with 
essential hypertension (11%).
Primary aldosteronism is caused by either a unilateral 
adrenal adenoma/hyperplasia or bilateral adrenal hyper
-
plasia. Each occurs with about equal frequency. It is impor
-
tant to distinguish the two, since a unilateral aldosteronoma 
(Conn syndrome) may be cured by surgical resection, 
whereas patients with bilateral adrenal hyperplasia are 
treated medically.
 
»
Primary aldosteronism is the most common cause of 
refractory hypertension in youths and middle-aged adults. 
Patients have hypertension that is typically moderate but 
may be severe. Some patients have only diastolic hyperten
-
sion, without other symptoms and signs. Edema is rarely 
seen in primary aldosteronism. Hypokalemia can produce 
muscle weakness, paresthesias with frank tetany, headache, 
polyuria, and polydipsia.
Plasma potassium should be determined in hypertensive 
individuals. However, hypokalemia, once thought to be the 
hallmark of hyperaldosteronism, is present in only 37% of 
affected patients: 50% of those with an adrenal adenoma 
and 17% of those with adrenal hyperplasia. An elevated 
serum bicarbonate (HCO
3
) concentration indicates meta
-
bolic alkalosis and is commonly present.
Testing for primary aldosteronism should be done for 
all hypertensive patients with any of the following: 
(1) sustained hypertension above 150/100 mm Hg on 3 dif
-
ferent days; (2) hypertension resistant to three conventional 
antihypertensive drugs, including a diuretic; (3) controlled 
blood pressure requiring four or more antihypertensive 
drugs; (4) hypokalemia, whether spontaneous or diuretic 
induced; (5) personal or family history of early-onset 
hypertension or cerebrovascular accident at age 40 or 
younger; (6) first-degree relative with primary 
aldosteronism; (7) presence of an adrenal mass; and (8) low 
plasma-renin activity.
For at least 2 weeks prior to testing, patients should 
consume a diet high in NaCl (more than 6 g/day) and ide
-
ally hold certain medications: all diuretics, ACE inhibitors, 
ARBs (stimulate PRA); beta-blockers, clonidine, NSAIDs 
(suppress PRA); oral estrogens and oral contraceptives 
should also ideally be held. Medications that are allowed 
include slow-release verapamil, hydralazine, terazosin, and 
doxazosin.
For blood testing, the patient should be out of bed for at 
least 2 hours and seated for 15–60 minutes before the blood 
draw, which should preferably be obtained between 8 
am
 
and 10 
am
. The blood should be drawn slowly with a 
syringe and needle (rather than a vacutainer) at least 
5 seconds after tourniquet release and without fist clench
-

am
 
and 10 
am
-
ing. Plasma potassium, rather than the routine serum 
potassium, should be measured in cases of unexpected 
hyperkalemia, with the separation of plasma from cells 
within 30 minutes of collection. Plasma potassium levels 
must be normal, since hypokalemia suppresses aldoste
-
rone. For practical purposes, the same blood draw can be 
used for simultaneous assays for plasma potassium, serum 
aldosterone, and PRA or direct renin assay (DRA). Patients 
with primary aldosteronism have a suppressed PRA less 
than 0.65 ng/mL/h or DRA less than 0.36 ng/mL. PRA of 
1 ng/mL/h (12.8 pmol/L/min) is equivalent to a DRA of 
5.2 ng/mL (8.2 milli-international units/L). Suppressed 
PRA or DRA with a serum aldosterone concentration 
greater than 12.5 ng/dL (416 pmol/L) indicates probable 
primary hyperaldosteronism. Serum aldosterone (ng/dL): 
PRA (ng/mL/h) ratios less than 24 exclude primary aldo
-
steronism; ratios between 24 and 30 are indeterminate; 
ratios between 30 and 67 are suspicious; ratios greater than 
67 are very suggestive of primary aldosteronism. In patients 
with a suppressed PRA or DRA plus a serum aldosterone 
of 20 ng/day or higher, the diagnosis of primary hyperaldo
-
steronism is confirmed. To further confirm the diagnosis 
and for patients with a suppressed PRA or DRA but lower 
serum aldosterone levels, a 24-hour urine is collected in an 
acidified container for aldosterone, cortisol, and creatinine; 
urine aldosterone greater than 20 mcg/24 h (55 nmol/24 h) 
confirms primary aldosteronism.
 is recommended for patients with con
-
firmed primary aldosteronism by age 20 years and those 
with a family history of primary aldosteronism or stroke at 
young age (under age 40). The testing is for familial corti
-
costeroid remediable aldosteronism.
CMDT19_Ch26_p1119-p1219.indd   1188

1189
 
CMDT 2019
C. Imaging
Some patients with undiagnosed primary aldosteronism 
are incidentally found to have an adrenal nodule (inciden
-
taloma) during abdominal or chest imaging. All patients 
with biochemically confirmed primary aldosteronism 
require a thin-section CT scan of the adrenals to screen for 
a rare adrenal carcinoma. In the absence of a large adrenal 
carcinoma, adrenal CT scanning cannot reliably distin
-
guish unilateral from bilateral aldosterone excess, having a 
sensitivity of 78% and a specificity of 78% for unilateral 
aldosteronism. Therefore, the decision to perform a unilat
-
eral adrenalectomy should not be based solely on the adre
-
nal CT scan. Adrenal vein sampling is often required.
D. Adrenal Vein Sampling
Unfortunately, bilateral selective adrenal vein sampling is 
invasive, expensive, not widely available, and often unsuc
-
cessful. The procedure (and surgery) may not be required 
for patients whose blood pressure is well controlled with 
spironolactone or eplerenone and for those with familial 
hyperaldosteronism. It is indicated only if surgery is con
-
templated in order to direct the surgeon to the correct 
adrenal gland. Adrenal vein sampling is probably not 
required in patients who have a classic adrenal adenoma 
(Conn syndrome), which is characterized by spontaneous 
hypokalemia and a unilateral adrenal adenoma 10 mm or 
larger in diameter on CT.
Before this procedure, the patient must be properly 
prepared (see Laboratory Findings). However, patients 
with a persistently suppressed PRA may continue miner
-
alocorticoid blockade. Lateralization is present when the 
aldosterone:cortisol ratio from one adrenal vein is at least 
four times that from the opposite adrenal vein.
Aldosterone hypersecretion that is lateralized to one 
adrenal usually indicates that adrenal has a unilateral aldo
-
steronoma or hyperplasia, particularly when aldosterone 
secretion from the contralateral adrenal is suppressed, in 
which case unilateral surgery improves hypertension in 
96%. Adrenal vein sampling has a sensitivity of 95% and a 
specificity of 100% but only when performed by an experi
-
enced radiologist. This procedure entails a 0.57% risk of 
major complications.
 
»
The differential diagnosis of primary aldosteronism 
includes other causes of hypokalemia in patients with 
essential hypertension, especially diuretic therapy; chronic 
depletion of intravascular volume stimulates renin secre
-
tion and secondary hyperaldosteronism.
Real (black) licorice (derived from anise) or anise-
 
flavored drinks (sambuca, pastis) contain glycyrrhizinic acid, 
which has a metabolite that inhibits the enzyme that nor
-
mally inactivates cortisol in the renal tubule. Oral contracep
-
tives may increase aldosterone secretion in some patients. 
Renal vascular disease can cause severe hypertension with 
hypokalemia but PRA is high. Excessive adrenal secretion of 
other corticosteroids (besides aldosterone), certain congeni
-
tal adrenal enzyme disorders, and primary cortisol resis
-
tance may also cause hypertension with hypokalemia. The 
differential diagnosis also includes Liddle syndrome, an 
autosomal dominant cause of hypertension and hypokale
-
mia resulting from excessive sodium absorption from the 
renal tubule; renin and aldosterone levels are low.
 
»
Cardiovascular complications occur more frequently in 
primary aldosteronism than in idiopathic hypertension. 
Following unilateral adrenalectomy for Conn syndrome, 
suppression of the contralateral adrenal may result in tem
-
porary postoperative hypoaldosteronism, characterized by 
hyperkalemia and hypotension.
 
»
Treatment
The 
unilateral adrenal adenoma
 of Conn syndrome is 
usually treated by laparoscopic adrenalectomy. During 
pregnancy, such surgery is best performed during the 
second trimester. However, long-term medical therapy is

of Conn syndrome is 
second trimester. However, long-term medical therapy is 
an option for unilateral hyperaldosteronism, if adequate 
blood pressure control can be maintained. 
Bilateral 
adrenal hyperplasia
 is best treated with medical therapy. 
Medical treatment must include a potassium-sparing 
diuretic, particularly spironolactone, eplerenone, or 
amiloride. Spironolactone is the most effective drug but 
also has antiandrogen activity and men frequently experi
-
ence breast tenderness, gynecomastia, or reduced libido; it 
is given at initial doses of 12.5–25 mg orally once daily; the 
dose may be titrated upward to 200 mg daily. Spironolac
-
tone might lead to undervirilization of male infants and is 
contraindicated in pregnancy; reproductive-age women 
are cautioned to use contraception during therapy. Eplere
-
none is favored during pregnancy (FDA pregnancy cate
-
gory B) and for men, since it does not have antiandrogen 
effects; it must be taken orally in doses of 25–50 mg twice 
daily. Blood pressure must be monitored daily when begin
-
ning these anti-mineralocorticoid medications; significant 
drops in blood pressure have occurred when these drugs 
are added to other antihypertensives. Other antihyperten
-
sive drugs may be required, particularly amlodipine, and 
ACE inhibitors or ARBs. Corticosteroid-remediable aldo
-
steronism is very rare, but may respond well to suppres
-
sion with low-dose corticosteroids.
 
»
Prognosis
The hypertension is reversible in about two-thirds of cases 
but persists or returns despite surgery in the remainder. 
The prognosis is much improved by early diagnosis and 
treatment. Only 2% of aldosterone-secreting adrenal 
tumors are malignant.
Funder JW et al. The management of primary aldosteronism: 
case detection, diagnosis, and treatment: an Endocrine Soci
-
ety clinical practice guideline. J Clin Endocrinol Metab. 2016 
May;101(5):1889–916. [PMID: 26934393]
Kline G et al. Adrenal venous sampling for primary aldosteron
-
ism: laboratory medicine best practice. J Clin Pathol. 2017 
Nov;70(11):911–6. [PMID: 28893861]
Vilela LAP et al. Diagnosis and management of primary aldoste
-
ronism. Arch Endocrinol Metab. 2017 May–Jun;61(3):305–12. 
[PMID: 28699986]
CMDT19_Ch26_p1119-p1219.indd   1189

C
HAPTER
 2
6
1190
 CMDT 2019
 
º
PHEOCHROMOCYTOMA & 
PARAGANGLIOMA
 
»
“Attacks” of headache, perspiration, palpitations, 
anxiety. Multisystem crisis.
 
»
Hypertension:
 sustained but often paroxysmal, 
especially during surgery or delivery; may be 
orthostatic.
 
»
Elevated urinary plasma free metanephrines. Nor
-
mal serum T
4
 and TSH.
 
»
Both pheochromocytomas and non–head-neck paragan
-
gliomas are rare tumors of the sympathetic nervous system. 
Pheochromocytomas arise from the adrenal medulla and 
usually secrete both epinephrine and norepinephrine. 
Paragangliomas (“extra-adrenal pheochromocytomas”) 
arise from sympathetic paraganglia and often metastasize. 
About 50% of paragangliomas secrete norepinephrine; the 
rest are nonfunctional or secrete only dopamine, normeta
-
nephrine, or serum chromogranin A (CgA). Tumoral 
secretion of norepinephrine or neuropeptide Y cause 
hypertension. Excessive epinephrine causes tachyarrhyth
-
mias. These tumors may be located in either or both adre
-
nals or anywhere along the sympathetic nervous chain, and 
sometimes in the mediastinum, heart, or bladder.
These tumors are particularly dangerous and deceptive 
and cause death in at least one-third of patients prior to 
diagnosis. They account for less than 0.4% of hypertension 
cases. The incidence is higher in children and patients with 
moderate to severe hypertension, particularly in the pres
-
ence of suspicious symptoms of headache, significant pal
-
pitations, or diaphoretic episodes. Over 10% of cases are 
discovered incidentally on imaging studies. They account 
for about 4% of adrenal incidentalomas. The yearly inci
-
dence is 2 to 4 new cases per million population. However, 
many cases are undiagnosed during life, since the preva
-
lence of pheochromocytomas and paragangliomas in 
autopsy series is 1 in 2000.
Nonsecretory paragangliomas arise in the head or neck, 
particularly in the carotid body, jugular-tympanic region, 
or vagal body; only about 4% secrete catecholamines. They 
often arise in patients who have 
SDHD
, 
SDHC
, or 
SDHB
 
germline mutations.
About 35% of patients with pheochromocytomas or 
paragangliomas harbor a germline mutation in 1 of at least 
16 known susceptibility genes that predispose to the tumor, 
usually in an autosomal dominant manner with incomplete 
penetrance. Thorough genetic testing is recommended for 
all patients with these tumors.
Pheochromocytoma eventually develops in about 30% 
of patients with 
von Hippel–Lindau (VHL) disease type 2;
 
it can present as early as age 5 years or later in adulthood. 
Pheochromocytomas in patients with VHL are usually 
adrenal, less likely to be malignant (3.5%), and more likely 
to be bilateral. About 25% of patients with VHL-1–related 
pheochromocytomas are asymptomatic and normotensive 
at diagnosis. The condition is also associated with heman
-
giomas of the retina, cerebellum, brainstem, and spinal 
cord; hyperparathyroidism; pancreatic cysts; endolym
-
phatic sac tumors; cystadenomas of the adnexa or epididy
-
mis; pancreatic neuroendocrine tumors; renal cysts, 
adenomas, and carcinomas; inheritance is autosomal 
dominant.
MEN 2 (MEN 2A)
 is associated with pheochromocyto
-
mas, hyperparathyroidism, cutaneous lichen amyloidosis, 
and medullary thyroid carcinoma. Pheochromocytomas 
are often silent in MEN 2; at diagnosis, only about 50% 
have symptoms and fewer are hypertensive. The lack of 
symptoms may be due to earlier diagnosis through yearly 
screening of mutation-carriers. 
MEN 3 (MEN 2B)
 may be 
familial, but usually arises from a de novo 
ret
 mutation; 
MEN 3 is associated with pheochromocytoma (50%), 
aggressive medullary thyroid carcinoma, mucosal neuro
-
mas, and Marfan-like habitus.
von Recklinghausen neurofibromatosis type 1
(NF-1)
 
is associated with an increased risk of pheochromocyto
-
mas/paragangliomas as well as cutaneous neurofibromas,

-
(NF-1)
 
-
mas/paragangliomas as well as cutaneous neurofibromas, 
optic and brainstem gliomas, astrocytomas, vascular 
anomalies, hamartomas, malignant nerve sheath tumors, 
and smooth-bordered café au lait spots.
Familial paraganglioma
 can be caused by mutations in 
the genes encoding succinate dehydrogenase (SDH) sub
-
units A, B, C, or D. Patients with such germline mutations 
are more apt to have bilateral pheochromocytomas or 
multicentric paragangliomas; they are also prone to pul
-
monary chondromas and gastric stromal sarcomas.
Pheochromocytomas are also more common in patients 
with Carney triad, Beckwith-Wiedemann syndrome, 
Sturge-Weber syndrome, and tuberous sclerosis.
 
»
Pheochromocytomas can be lethal unless they are diag
-
nosed and treated appropriately. Catastrophic hypertensive 
crisis and fatal cardiac arrhythmias can occur spontane
-
ously or may be triggered by needle biopsy or manipulation 
of the mass, intravenous contrast dye or glucagon injection, 
vaginal delivery, trauma, anesthesia, or surgery (both unre
-
lated to the tumor or for its removal). Exercise, bending, 
lifting, or emotional stress can trigger paroxysms. Bladder 
paragangliomas may present with paroxysms during mictu
-
rition. Certain drugs can precipitate attacks: decongestants, 
amphetamines, cocaine, epinephrine, corticosteroids, 
fluoxetine and other selective serotonin reuptake inhibitors 
(SSRIs), metoclopramide, monoamine oxidase (MAO) 
inhibitors, caffeine, nicotine, and ionic intravenous 
contrast.
Manifestations are variable, but typically include hyper
-
tension (81%) that may be paroxysmal or sustained, head
-
ache (60%), palpitations (60%), or diaphoresis (52%). 
About 58% of patients have episodic nonspecific “spells. ” 
Other symptoms include anxiety (often with a sense of 
CMDT19_Ch26_p1119-p1219.indd   1190

1191
 
CMDT 2019
impending doom), weakness/fatigue, dyspnea, nausea/
vomiting, tremor, dizziness, chest pain, abdominal pain, 
paresthesias, or constipation. Vasospasm during an attack 
can cause Raynaud syndrome, mottled cyanosis, or facial 
pallor. As the attack subsides, facial flushing and drenching 
sweats can occur. Epinephrine secretion by an adrenal 
pheochromocytoma can cause episodic tachyarrhythmias 
and sometimes orthostatic hypotension or even syncope. 
Cardiac manifestations include acute coronary syndrome, 
cardiomyopathy, heart failure, and potentially fatal dys
-
rhythmias. Confusion, psychosis, paresthesias, seizures, 
transient ischemic attacks, or stroke may occur with cere
-
brovascular vasoconstriction or hemorrhagic stroke. 
Aneurysms may dissect. Abdominal pain, nausea, vomit
-
ing, and even ischemic bowel can occur. Patients may 
experience increased appetite, loss of weight, numbness, or 
fevers. During pregnancy, pheochromocytomas can pro
-
duce hypertension and proteinuria, mimicking eclampsia; 
vaginal delivery can produce hypertensive crisis followed 
by postpartum shock. A minority of patients are normo
-
tensive and asymptomatic, particularly when the tumor is 
nonsecretory or discovered at an early stage.
Pheochromocytomas can also rarely produce other 
“ectopic” peptide hormones, resulting in Cushing syn
-
drome (ACTH), Verner-Morrison syndrome (VIP), or 
hypercalcemia (PTHrP). 
Multisystem crisis
 can occur, 
with manifestations of severe hypertension or hypotension, 
ARDS, cardiomyopathy with acute heart failure, kidney 
dysfunction, liver failure, and death. Multisystem crisis can 
occur spontaneously, or it may be provoked by surgery, 
vaginal delivery, or treatment of metastatic disease.
Pheochromocytomas are rare tumors, but they are deadly 
and a missed diagnosis can be catastrophic. However, 
less than 1% of biochemical evaluations in patients with 
suspicious symptoms lead to a diagnosis of pheochromo
-
cytoma. More commonly, testing yields misleading 
minor elevations in tumor markers, particularly when 
levels are less than three times the upper limit of normal 
(Table 26–11).
Plasma fractionated free metanephrines
 is the most 
sensitive test for secretory pheochromocytomas and para
-
gangliomas. However, plasma levels of free metanephrines 
fluctuate and are lower when the patient is supine than 
when ambulatory. For practicality, the blood specimen is 
usually obtained after the patient sits quietly in the labora
-
tory for at least 15 minutes. Normal levels rule out pheo
-
chromocytoma and paraganglioma with some certainty. 
The exceptions are patients who are being monitored 
because they harbor a germline mutation for familial pheo
-
chromocytoma; such patients with a pheochromocytoma 
are often asymptomatic early-on and frequently have nor
-
mal testing or only mild elevations in plasma metaneph
-
rines. However, for other patients with severe hypertension 
or “spells” caused by a pheochromocytoma, plasma frac
-
tionated free metanephrines are ordinarily at least three 
times the upper limit of normal. For less dramatic eleva
-
tions in plasma metanephrines, patients are retested while 
lying supine in a quiet room for 30–90 minutes before the 
Table 26–11.
 
Factors that can cause misleading 
catecholamine or metanephrine results.
1
Drugs
Foods
Conditions
2
Aldomet
2
3
Anesthetics (local)
4
Bronchodilators
3
Buspirone
2
Captopril
2
2
Cocaine
3
Codeine
2
Contrast media (meglu
-
mine acetrizoate, 
meglumine diatrizoate)
5
Cyclobenzaprine
Decongestants
3
Ephedrine and 
epinephrine
3
Fenfluramine
6
Halothane anesthesia
4
Isoproterenol
3
Labetalol
2,3
Levodopa
2
Mandelamine
2
Methenamine
6
Mesalamine
2
2
Monoamine oxidase 
4
3
Pheonthiazines
3,4
Phenoxybenzamine
2,3
Serotonin-norepinephrine 
reuptake inhibitors 
(SNRIs): desvenlafaxine, 
duloxetine, levomil
-

2
4
3
3,4
2,3
-
nacipran, venlafaxine,
3
Smoking
4
Sulfasalazine
2
Tricyclic antidepressants
2,3
Bananas
3
Caffeine
3
Coffee
2
Curry leaves
2
Peppers
2
Pineapples
3
Walnuts
3
Age (children and 
older adults)
4
Amyotrophic lateral 
sclerosis
3
Anxiety
3,4
Brain lesions
3
Carcinoid
3
Drug withdrawal 
(narcotic, alcohol, 
clonidine)
3,4
Eclampsia
3
Emotion (severe)
3,4
Essential 
3
Exercise (vigorous)
3,4
syndrome
3
3
Kidney 
3,4,6
3
Myocardial infarc
-
tion (acute)
3
Pain (severe)
3
Porphyria (acute)
3
Psychosis (acute)
3
Quadriplegia
3,4
Winter
4
1
Note that assays for metanephrine using tandem mass spectros
-
copy (MS/MS) are not prone to interference from drugs or foods, 
except those that increase catecholamine excretion.
2
May cause confounding peaks for catecholamines or metaneph
-
rines with an HPLC-ECD chromatogram.
3
Increases measured catecholamine excretion.
4
Increases plasma and urinary normetanephrine and metanephrine.
5
May decrease urine metanephrine excretion.
6
Decreases measured catecholamine excretion.
blood is drawn. False-positive test results should be par
-
ticularly suspected when the ratio of normetanephrine to 
norepinephrine is less than 0.52 or the ratio of metaneph
-
rine to epinephrine is less than 4.2. In such cases, it is best 
to repeat biochemical testing under optimal conditions, eg, 
after eliminating potentially interfering drugs. Most 
patients with elevated plasma fractionated free metaneph
-
rines require confirmation with a 24-hour urine for frac
-
tionated metanephrines and creatinine.
CMDT19_Ch26_p1119-p1219.indd   1191

C
HAPTER
 2
6
1192
 CMDT 2019
Urinary fractionated metanephrines and creati
-
nine
 effectively confirms most pheochromocytomas 
that were detected by elevated plasma fractionated 
metanephrines. A 24-hour urine specimen is usually 
obtained, although an overnight or shorter collection 
may be used; patients with pheochromocytomas gener
-
ally have more than 2.2 mcg of total metanephrine per 
milligram of creatinine, and more than 135 mcg total 
catecholamines per gram creatinine. Urinary assay for 
total metanephrines is about 97% sensitive for detecting 
functioning pheochromocytomas.
Serum CgA
 is elevated in about 85% of patients with 
pheochromocytoma and the levels correlate with tumor 
size, being higher in patients with metastatic disease. Serum 
CgA must be assayed in the fasting state, since levels rise 
after meals. Misleading elevated CgA levels also occur in 
patients with azotemia or hypergastrinemia, and in those 
treated with corticosteroids or proton pump inhibitors. 
Serum CgA is not specific for pheochromocytoma, so its 
measurement is not very useful for the initial diagnosis.
Clonidine suppression testing
 can help distinguish 
whether elevated plasma free normetanephrine levels are 
physiologic or indicative of pheochromocytoma. Plasma 
fractionated free metanephrines are measured before the 
administration of clonidine (0.3 mg orally) and 3 hours 
afterward. A fall of plasma normetanephrine into the nor
-
mal range or a fall of greater than 40% from baseline helps 
rule out the presence of a tumor.
Hyperglycemia is present in about 35% of patients but 
is usually mild. Proteinuria is present in about 10–20% of 
patients. Leukocytosis is common. Erythrocytosis or 
eosinophilia can occur. The ESR is sometimes elevated. 
PRA may be increased by catecholamines.
C. Imaging
1. CT and MRI scanning—
Imaging should be performed 
only in patients with suggestive laboratory findings, since 
adrenal pheochromocytomas can appear similar to com
-
monly found benign adrenal adenomas (2–4% of all scans). 
When a pheochromocytoma is suspected, a noncontrast 
CT scan of the abdomen is performed, with thin sections 
through the adrenals. If an adrenal mass is present, another 
CT is immediately performed, infusing nonionic contrast 
(to reduce the risk of stimulating catecholamine release 
from a pheochromocytoma) with a “washout” protocol. 
Pheochromocytomas are usually avid for contrast and 
about 80% of tumors retain greater than 40% of contrast 
after 15 minutes. Glucagon should not be used during 
scanning, since it can provoke hypertensive crisis.
MRI scanning has the advantage of not requiring 
intravenous contrast dye; its lack of radiation makes it the 
imaging of choice during pregnancy and childhood and 
for serial imaging. Both CT and MRI scanning have a 
sensitivity of about 90% for adrenal pheochromocytoma 
and a sensitivity of 95% for adrenal tumors over 0.5 cm in 
diameter. However, both CT and MRI are less sensitive 
for detecting recurrent tumors, metastases, and extra-
adrenal paragangliomas. If no adrenal tumor is found, the 
scan is extended to include the entire abdomen, pelvis, 
and chest.
2. Nuclear imaging—
A whole-body 
123
I-meta-iodobenzyl
-
guanidine (
123
I-MIBG) scan can localize tumors with a 
sensitivity of 94% and a specificity of 92%. However, it is 
less sensitive for MEN 2– or MEN 3–related pheochromo
-
cytomas and for metastases. Preoperative 
123
I-MIBG scan
-
ning may help confirm that a mass is a pheochromocytoma 
or paraganglioma. Whole-body 
123
I-MIBG scanning can 
also be useful to search for a nonadrenal paraganglioma 
when the adrenals and abdomen appear normal on CT 
scan in patients in whom a secretory paraganglioma is 
suspected. Drugs that reduce 
123
I-MIBG uptake should be 
avoided, including tricyclic antidepressants and cycloben
-
zaprine (6 weeks). Other drugs, such as amphetamines, 
diet pills, decongestants, cocaine, phenothiazines, halo
-

-
-
peridol, labetalol, and serotonin and norepinephrine reup
-
take inhibitors (venlafaxine, desvenlafaxine, duloxetine), 
can potentially reduce 
123
I-MIBG uptake for up to 2 weeks. 
Drug interference is suspected in negative 
123
I-MIBG scans 
that do not show normal uptake in salivary glands.
111
In-labeled octreotide scanning is quite sensitive for 
detecting extra-adrenal pheochromocytomas (paragangli
-
omas) and metastatic pheochromocytomas, sometimes 
locating tumors that were missed by 
123
I-MIBG scanning. 
However, only 25% of adrenal pheochromocytomas are 
visualized.
68
Ga-DOTATOC-PET/CT is the most sensitive scan, 
detecting nearly 90% of paragangliomas and metastases. 
18
FDG-PET/CT detects most primary paragangliomas but 
is not specific for pheochromocytoma or paraganglioma; 
46% of metastases are not avid for 
18
FDG, and indolent 
hepatic metastases are frequently not detected.
 
»
Certain conditions mimic pheochromocytoma: thyrotoxi
-
cosis, labile essential hypertension, myocarditis, glomeru
-
lonephritis or other renal lesions, eclampsia, acute 
intermittent porphyria, hypogonadal vascular instability 
(hot flushes), anxiety attacks, cocaine or amphetamine use, 
and clonidine withdrawal.
Patients taking nonselective MAO inhibitor antidepres
-
sants can have hypertensive crisis after eating foods that 
contain tyramine. Patients with erythromelalgia can have 
hypertensive crises. Renal artery stenosis can cause severe 
hypertension and may coexist with pheochromocytoma.
 
»
All of the complications of severe hypertension may be 
encountered. In addition, a catecholamine-induced car
-
diomyopathy may develop. Severe heart failure and car
-
diovascular collapse may develop in patients during a 
paroxysm. Sudden death may occur due to cardiac 
arrhythmia. ARDS and multisystem crisis can occur 
acutely and thus the initial manifestation of pheochromo
-
cytoma may be hypotension or even shock. Hypertensive 
crises with sudden blindness or cerebrovascular accidents 
are not uncommon.
After removal of the tumor, a state of severe hypotension 
and shock (resistant to epinephrine and norepinephrine) 
may ensue with precipitation of acute kidney injury or 
CMDT19_Ch26_p1119-p1219.indd   1192

1193
 
CMDT 2019
myocardial infarction. Hypotension and shock may occur 
from spontaneous infarction or hemorrhage of the tumor.
Pheochromocytomas and paragangliomas may metas
-
tasize. Cells can also be seeded within the peritoneum, 
either spontaneously or as a complication during surgical 
resection. Such seeding of the abdomen can result in mul
-
tifocal recurrent intra-abdominal tumors, a condition 
known as pheochromocytomatosis.
 
»
Patients must receive adequate treatment for hypertension 
and tachyarrhythmias prior to surgery for pheochromocy
-
toma/paraganglioma. Patients are advised to measure their 
blood pressures daily and immediately during paroxysms. 
Some patients with pheochromocytoma or paraganglioma 
are not hypertensive and do not require preoperative antihy
-
pertensive management. Alpha-blockers or calcium channel 
blockers can be used, either alone or in combination. Blood 
pressure should be controlled before cardioselective beta-
blockers are added for control of tachyarrhythmias. Normo
-
tensive patients with pheochromocytoma or sympathetic 
paraganglioma do not require preoperative alpha blockade, 
which increases their requirement for vasopressors and col
-
loid after the tumor resection.
Alpha-blockers
 are typically administered preparatory 
to surgery. Phenoxybenzamine is a long-acting nonselec
-
tive alpha-blocker with a half-life of 24 hours; it is given 
initially in a dosage of 10 mg orally every 12 hours, increas
-
ing gradually by about 10 mg/day about every 3 days until 
hypertension is controlled. Maintenance doses range from 
10 mg/day to 120 mg/day. Doxazosin (half-life 22 hours), a 
selective alpha-1-blocker, may also be used in doses of 
2–32 mg daily. Preoperative preparation with phenoxyben
-
zamine reduces intraoperative hypertension but may 
increase the risk post-resection compared to patients given 
a preoperative selective alpha-1-blocker. Optimal alpha-
blockade is achieved when supine arterial pressure is below 
140/90 mm Hg or as low as possible for the patient to have 
a standing arterial pressure above 80/45 mm Hg.
Calcium channel blockers
 (nifedipine ER or nicardip
-
ine ER) are very effective and are usually added to alpha-
blockers, but may be used alone. Nifedipine ER is initially 
given orally at a dose of 30 mg/day, increasing the dose 
gradually to a maximum of 60 mg twice daily. Calcium 
channel blockers are superior to phenoxybenzamine for 
long-term use, since they cause less fatigue, nasal conges
-
tion, and orthostatic hypotension. However, they should 
not be used for patients with severe heart failure. For acute 
hypertensive crisis (systolic blood pressure higher than 
170 mm Hg) a nifedipine 10-mg capsule may be chewed 
and swallowed. Nifedipine is quite successful for treating 
acute hypertension in patients with pheochromocytoma/
paraganglioma, even at home; it is reasonably safe as long 
as the blood pressure is carefully monitored.
 (eg, metoprolol XL) are often required 
after institution of alpha-blockade or calcium channel 
blockade. The use of a beta-blocker as initial antihyperten
-
sive therapy has resulted in an “unopposed alpha” status 
that causes paradoxical worsening of hypertension. Labet
-
alol has combined alpha- and beta-blocking activity and is 
an effective agent, but can cause paradoxical hypertension 
if used as the initial antihypertensive agent. Labetalol can 
also interfere with catecholamine determinations in some 
laboratories and reduces the tumor’s uptake of radioiso
-
topes, such that it must be discontinued for at least 
4–7 days before 
123
I-MIBG or 
18
FDG-PET scanning or 
therapy with high-dose 
131
I-MIBG.
 
»
Surgical Treatment
Surgical removal of pheochromocytomas or abdominal 
paragangliomas is the treatment of choice. For surgery, a 
team approach—endocrinologist, anesthesiologist, and 
surgeon—is critically important. Laparoscopic surgery is

surgeon—is critically important. Laparoscopic surgery is 
preferred, but large and invasive tumors require open lapa
-
rotomy. Patients with small familial or bilateral pheochro
-
mocytomas may undergo selective resection of the tumors, 
sparing the adrenal cortex; however, there is a recurrence 
rate of 10% over 10 years.
Prior to surgery, blood pressure control should be 
maintained for a minimum of 4–7 days or until optimal 
cardiac status is established. The ECG should be monitored 
until it becomes stable. (It may take a week or even months 
to correct ECG changes in patients with catecholamine 
myocarditis, and it may be prudent to defer surgery until 
then in such cases.) Patients must be very closely moni
-
tored during surgery to promptly detect sudden changes in 
blood pressure or cardiac arrhythmias.
Intraoperative severe hypertension is managed with 
continuous intravenous nicardipine (a short-acting cal
-
cium channel blocker), 2–6 mcg/kg/min, or nitroprusside, 
0.5–10 mcg/kg/min. Prolonged nitroprusside administra
-
tion can cause cyanide toxicity. Tachyarrhythmia is treated 
with intravenous atenolol (1 mg boluses), esmolol, or 
Autotransfusion of 1–2 units of blood at 12 hours pre
-
operatively plus generous intraoperative volume replace
-
ment reduces the risk of postresection hypotension and 
shock caused by desensitization of the vascular alpha-
1-receptors. Shock is treated with intravenous saline or 
colloid and high doses of intravenous norepinephrine. 
Intravenous 5% dextrose is infused postoperatively to pre
-
vent hypoglycemia.
 
»
Detecting & Managing Metastatic 
Pheochromocytoma & Paraganglioma
Surgical histopathology for pheochromocytoma and para
-
ganglioma cannot reliably determine whether a tumor is 
malignant. Therefore, all pheochromocytomas and para
-
gangliomas must be approached as possibly malignant. It is 
essential to recheck blood pressure and plasma fraction
-
ated metanephrine levels about 4–6 weeks postoperatively, 
at least every 6 months for 5 years, then once yearly for life 
and immediately if hypertension, suspicious symptoms, or 
metastases become evident.
Metastases from a pheochromocytoma or paragangli
-
oma are visible in only about 35% when the primary tumor 
is discovered. The other 65% of metastases emerge clini
-
cally an average of 5.5 years (range 0.3 and 53 years) after 
the initial diagnosis. Since some metastases are indolent, it 
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is important to tailor treatment to each individual accord
-
ing to their tumor’s aggressiveness. Most surgeons resect 
the main tumor and larger metastases (debulking). Asymp
-
tomatic, indolent metastases may be kept under close sur
-
veillance without treatment.
A. Chemotherapy
Various chemotherapy regimens have been used, but there 
have been no controlled clinical trials to prove the effec
-
tiveness of one regimen over another or whether any regi
-
men actually improves overall survival. The most common 
chemotherapy regimen combines intravenous cyclophos
-
phamide, vincristine, and dacarbazine over 2 days in cycles 
that are repeated every 3 weeks (Table 39–3). About one-
third of patients experience some degree of temporary 
remission. Sunitinib, a tyrosine kinase inhibitor, can also 
produce remissions, given orally in doses of 50 mg/day for 
4 weeks on and then 2 weeks off; alternatively, a dose of 
37.5 mg/day can be given continuously. Another chemo
-
therapy regimen uses temozolomide, 250 mg/day orally for 
5 days, repeating the cycle every 28 days; this is usually the 
best-tolerated chemotherapy and is particularly effective 
for metastatic pheochromocytoma or paraganglioma in 
patients with 
SDHB
 germline mutations. Each chemother
-
apy regimen has toxicities.
Metyrosine reduces catecholamine synthesis but does 
not impede the progressive growth of metastases; the initial 
metyrosine dosage is 250 mg four times daily, increased 
daily by increments of 250–500 mg to a maximum of 4 g/
day. Metyrosine causes CNS side effects and crystalluria; 
hydration must be ensured.
B. 
131
I-MIBG Therapy
About 60% of patients with metastatic pheochromocytoma 
or paraganglioma have tumors with sufficient uptake of 
123
I-MIBG on diagnostic scanning to allow for therapy with 
high-activity 
131
I-MIBG. Medications that reduce MIBG 
uptake must be avoided, particularly labetalol, phenothi
-
azines, tricyclics, and sympathomimetics. Myelodysplastic 
syndrome and leukemia can develop several years after 
131
I-MIBG therapy, with the risk proportional to the cumu
-
lative amount of isotope. ARDS and multisystem failure 
occur rarely after 
131
I-MIBG therapy, particularly in 
patients with pretreatment proteinuria.
C. Treatment for Bone Metastases
Patients with significant osteolytic bone metastases may be 
treated with external beam radiation therapy, which is 
often helpful in relieving pain and stabilizing local osseous 
disease. Patients with vertebral metastases and spinal cord 
compression require surgical decompression and kypho
-
plasty. Intravenous zoledronate or subcutaneous deno
-
sumab may also be administered to patients with osteolytic 
bone metastases.
 
»
Prognosis
A pheochromocytoma or sympathetic paraganglioma is 
considered malignant if metastases are present, but 
metastases may take many years to become clinically evi
-
dent. Therefore, lifetime surveillance is recommended. 
Malignancy is more likely for larger tumors and for para
-
gangliomas. The prognosis is good for patients with 
pheochromocytomas that are resected before causing 
cardiovascular damage. Hypertension usually resolves 
after successful surgery, but may persist or return in 25% 
of patients despite successful surgery. In such cases, bio
-
chemical reevaluation is required to detect a possible 
second or metastatic pheochromocytoma.
The surgical mortality is under 3% with the use of lapa
-
roscopic surgical techniques, intraoperative monitoring, 
and preoperative blood pressure control with alpha-
blockers or calcium channel blockers.
Patients with metastatic pheochromocytoma or paragan
-
glioma have an extremely variable prognosis. Some metasta
-
ses are extremely indolent and may not progress or may 
present clinically for several decades after the primary tumor 
diagnosis. Metastases from head-neck paragangliomas are 
particularly slow-growing. However, some of these tumors

particularly slow-growing. However, some of these tumors 
are extremely aggressive. Rapid disease progression has been 
associated with male sex, older age, larger primary tumor 
size, dopamine hypersecretion, failure to undergo primary 
tumor resection, very high tumor burden, and metastases 
that are visible at the time of primary tumor diagnosis.
Hamidi O et al. Malignant pheochromocytoma and paragangli
-
oma: 272 patients over 55 years. J Clin Endocrinol Metab. 
2017 Sep 1;102(9):3296–305. [PMID: 28605453]
Lenders JW et al. Pheochromocytoma and paraganglioma: an 
Endocrine Society clinical practice guideline. J Clin Endocrinol 
Metab. 2014 Jun;99(6):1915–42. [PMID: 24893135]
Plouin PF et al. European Society of Endocrinology clinical 
practice guidelines for long term follow-up of patients oper
-
ated on for a phaeochromocytoma or a paraganglioma. Eur J 
Endocrinol. 2016 May;175(5):G1–10. [PMID: 27048283]
Pourian M et al. Does this patient have pheochromocytoma? A 
systematic review of clinical signs and symptoms. J Diabetes 
Metab Disord. 2016 Mar 31;15:1–12. [PMID: 27034920]
Riester A et al. Life-threatening events in patients with pheo
-
chromocytoma. Eur J Endocrinol. 2015 Dec;173(6):757–64. 
[PMID: 26346138]
INCIDENTALLY DISCOVERED 
ADRENAL MASSES
Adrenal incidentalomas
 are defined as adrenal nodules 
that are discovered incidentally on up to 4% of abdominal 
CT or MRI scans obtained for other reasons. Although the 
overwhelming majority of adrenal incidentalomas are 
benign adrenal adenomas, it is always necessary to deter
-
mine whether such masses are malignant or pheochromo
-
cytomas and whether they secrete excessive cortisol or 
aldosterone. Patients with an adrenal nodule and any 
possible manifestation of hypercortisolism should be 
screened for Cushing syndrome with a plasma ACTH, 
serum cortisol, and serum DHEAS; patients with a low or 
low-normal ACTH, a suppressed DHEAS, or a high corti
-
sol should then be assessed with late-night salivary corti
-
sols or a 1-mg dexamethasone suppression test (see 
Cushing syndrome). Patients with hypertension are 
screened for primary aldosteronism with a PRA and serum 
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aldosterone (see Primary Aldosteronism). Most adrenal 
incidentalomas should be assessed for pheochromocy
-
toma, particularly when their diameter exceeds 3 cm, den
-
sity exceeds 10 HU, and in patients with hypertension or 
suspicious symptoms; screening is done with plasma frac
-
tionated free metanephrines.
When an adrenal incidentaloma larger than 4 cm in 
diameter is detected in a patient without a history of malig
-
nancy, it should be resected, unless it is an unmistakably 
benign myelolipoma, hemorrhage, or adrenal cyst. Masses 
3–4 cm in diameter may be resected if they have suspicious 
features (heterogeneity or irregularity). Smaller adrenal 
incidentalomas are usually observed after endocrine test
-
ing. A noncontrast CT scan can determine the density of 
the mass; adrenal incidentalomas with a density less than 
10 HU on CT are unlikely to be a pheochromocytoma or 
metastasis. For small adrenal incidentalomas with a density 
of greater than or equal to 10 HU, an adrenal intravenous 
contrast “washout” CT scan may be obtained; the density 
of the adrenal incidentaloma in HU is calculated 60 seconds 
after contrast and again 15 minutes after contrast; a reduc
-
tion (washout) of 40% or more is consistent with a benign 
adrenal adenoma. However, adrenal washout studies are 
only suggestive and about 20% of pheochromocytomas 
have adrenal washout of 40% or more; so, if the adrenal 
incidentaloma is not clinically a pheochromocytoma and 
not resected, a follow-up CT of the adrenals in 6–12 months 
is recommended to look for growth.
Gendy R et al. Incidental adrenal masses—a primary care 
approach. Aust Fam Physician. 2017 Jun;46(6):385–90. 
[PMID: 28609594]
Mayo-Smith WW et al. Management of incidental adrenal 
masses: a white paper of the ACR incidental findings com
-
mittee. J Am Coll Radiol. 2017 Aug;14(8):1038–44. [PMID: 
28651988]
 
º
GASTROENTEROPANCREATIC 
NEUROENDOCRINE TUMORS 
 
(GEP-NETS) & CARCINOID TUMORS
 
»
Secretory GEP-NETs’ manifestations depend on 
the hormones secreted.
 
»
Half of GEP-NETs are nonsecretory or secretory 
without clinical manifestations; they may be 
detected incidentally or may present with weight 
loss, abdominal pain, or jaundice.
 
»
Carcinoid tumors arise from the intestines or lung, 
secrete serotonin, and may metastasize.
 
»
GEP-NETs are a subset of neuroendocrine tumors (NETs) 
that arise from the stomach, intestines, or endocrine 
pancreas.
The reported incidence of GEP-NETs has increased to 
about 37 per million yearly in the United States due to the 
incidental detection of small tumors on abdominal scans. 
About 40% are functional, producing hormones that also 
serve as tumor markers, important for diagnosis and fol
-
low-up. At presentation, 65% of GEP-NETs are unresect
-
able or metastatic. Up to 25% of GEP-NETs are associated 
with one of four different inherited disorders: MEN 1, von 
Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1), 
and tuberous sclerosis complex (TSC). In MEN 1, GEP-
NETs are usually gastrinomas, carcinoids, or nonfunction
-
ing tumors and are a common cause of death. In VHL, 
GEP-NETs are usually benign and multiple.
Insulinomas
 are the most common functional type of 
GEP-NET and are usually small, intrapancreatic, and 
benign (90%) and secrete excessive amounts of insulin. 
Insulinomas also produce proinsulin and C-peptide. Insuli
-
nomas are solitary in 95% of sporadic cases but are multiple 
in about 90% of cases arising in MEN 1. (See Chapter 27.)
Gastrinomas
 secrete excessive quantities of the hor
-
mone gastrin (as well as “big” gastrin). About 50% of gas
-
trinomas are malignant and metastasize to the liver. 
Gastrinomas are typically found in the duodenum (49%), 
pancreas (24%), or lymph nodes (11%). Sporadic gastri
-
noma is rarely suspected at the onset of symptoms; typi
-
cally, there is a 5-year delay in diagnosis. About 22% of

-
-
cally, there is a 5-year delay in diagnosis. About 22% of 
gastrinomas arise in patients with MEN 1, who usually 
present at a younger age, often with multiple tumors; 
hyperparathyroidism can occur many years before or after 
the discovery of a gastrinoma.
Glucagonomas
 are rare and usually malignant, despite 
their benign histologic appearance. They usually arise as a 
large intrapancreatic tumor with 60% having liver metasta
-
ses apparent by the time of diagnosis. Besides glucagon, they 
usually secrete additional hormones, including gastrin.
Somatostatinomas
 are very rare and usually single. 
They arise in the pancreas (50%) or small intestine. They 
secrete somatostatin.
VIPomas
 are very rare and usually single intrapancreatic 
tumors with metastases usually evident (80%) at diagnosis. 
They produce vasoactive intestinal polypeptide (VIP).
CCKomas
 are rare tumors of the endocrine pancreas 
that secrete cholecystokinin.
Carcinoid
 tumors can arise from the small bowel (53%, 
particularly terminal ileum), colon (12%), esophagus 
through duodenum (6%), or lung (bronchial carcinoid 
[5%]). About 20% of cases present with metastases without 
a known primary location. Carcinoids are multiple in 
about 28% of cases. Although tumors are usually indolent, 
metastases are common, particularly to liver, lymph nodes, 
and peritoneum. Patients with carcinoid tumors have high 
serum levels of serotonin and CgA as well as elevated uri
-
nary excretion of 5-HIAAA.
 
»
Nonfunctioning tumors
 typically present with mass effect 
and metastases, such as pancreatitis, jaundice, abdominal 
pain, or weight loss.
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 secrete insulin and present with the symp
-
toms of fasting hypoglycemia. (See Chapter 27.)
 usually present with peptic ulcer disease—
abdominal pain (75%), heartburn (44%), bleeding (25%)—
or weight loss (17%) (Zollinger-Ellison syndrome). 
Endoscopy usually shows hyperplastic gastric rugae (94%).
 usually present with weight loss caused 
by glucagon-stimulated protein hepatic gluconeogenesis 
and related protein catabolism. Other common manifesta
-
tions include diarrhea, nausea, peptic ulcer, hypoaminoaci
-
demia, or necrolytic migratory erythema, known as 
“glucagonoma syndrome. ” Diabetes mellitus develops in 
about 35% of patients. The median survival is 34 months 
after diagnosis.
 can present with a classic triad of 
symptoms: diabetes mellitus due to its inhibition of insulin 
and glucagon secretion; cholelithiasis due to its inhibition 
of gallbladder motility; and steatorrhea due to its inhibition 
of pancreatic exocrine function. Diarrhea, hypochlorhy
-
dria, and anemia can also occur.
VIPomas
 present with profuse 
w
atery 
d
iarrhea, (unre
-
mitting) 
h
ypokalemia, and 
a
chlorhydria (“WDHA ”), the 
so-called Verner-Morrison syndrome.
CCKomas
 may present with liver metastases and symp
-
toms of diarrhea, peptic ulcer disease, and weight loss. Patients 
have elevated serum levels of cholecystokinin and CgA.
 can produce “carcinoid syndrome”: 
episodes of abdominal pain, diarrhea, bronchospasm, and 
weight loss. Dry skin and flushing typically affect the upper 
chest, neck, and face and lasts from 30 seconds to 30 min
-
utes, although flushing with bronchial carcinoids can per
-
sist for days. Although abdominal pain and diarrhea may 
occur at the same time as flushing, they usually occur at 
other times. Flushing can be unprovoked or precipitated by 
exercise, anesthesia, emotional stimuli, or foods (bananas, 
tomatoes, cheese, kiwi, eggplant, and alcohol). However, 
the full-blown carcinoid syndrome occurs with only about 
10% of tumors. Other manifestations include carcinoid 
heart disease caused by endocardial fibrotic plaques. 
Tumor-induced fibrosis can also occur in the retroperito
-
neum causing ureteral obstruction or in the penis causing 
Peyronie disease. Pellagra (glossitis, confusion, dry skin), 
which results from the conversion of tryptophan (a precur
-
sor to niacin) to serotonin by tumor cells, may develop in 
affected patients with widespread metastases.
Bronchial carcinoids secrete serotonin and can produce 
carcinoid syndrome even without hepatic metastases. Fore
-
gut carcinoids secrete serotonin that is metabolized by the 
liver and produce carcinoid syndrome only when they have 
metastasized to the liver. Appendiceal carcinoids are typi
-
cally discovered incidentally during appendectomy; hemi
-
colectomy is required if the tumor is 2 cm or larger or has 
unfavorable histopathology. Cecal carcinoids often present 
with intestinal obstruction or intestinal bleeding. Hindgut 
carcinoids rarely produce serotonin and do not cause car
-
cinoid syndrome.
Ectopic hormones
 can be secreted by GEP-NETs. Ecto
-
pic ACTH secretion from bronchial carcinoids or pancre
-
atic neuroendocrine tumors (pNETs) can produce Cushing 
syndrome.
About 40% of GEP-NETs are functional, producing hor
-
mones that serve as tumor markers. For carcinoid tumors, 
serum serotonin may be elevated along with urinary 
5-hydroindoleacetic acid (5-HIAA). Additionally, serum 
CgA may be elevated in neuroendocrine tumors and can be 
another useful tumor marker.
C. Imaging
Localization of noninsulinoma GEP-NETs and their metas
-
tases is best done with PET scanning with 
68
Ga-
DOTATATE, a radiolabeled somatostatin analog; it is 
extremely sensitive. 
111
In-pentreotide (Octreoscan) detects 
about 75% of noninsulinomas. 
18
F-DOPA PET/CT may 
also be helpful in detecting occult carcinoid tumors. MRI

111
18
also be helpful in detecting occult carcinoid tumors. MRI 
scanning is more useful than CT for imaging and following 
hepatic metastases.
For insulinomas, preoperative localization studies are 
less successful and have the following sensitivities: ultraso
-
nography 25%, CT 25%, endoscopic ultrasonography 27%, 
transhepatic portal vein sampling 40%, and arteriography 
45%. Nearly all insulinomas can be successfully located at 
surgery by the combination of intraoperative palpation 
(sensitivity 55%) and ultrasound (sensitivity 75%). An 
abdominal CT scan is usually obtained, but extensive pre
-
operative localization procedures, especially with invasive 
methods, are not required. Tumors may be located in the 
pancreatic head or neck (57%), body (15%), or tail (19%) 
or in the duodenum (9%). MRI is used to screen members 
of kindreds with genetic syndromes that predispose them 
to GEP-NETs.
 
»
Treatment
Surgery is the primary initial treatment for all types of 
GEP-NETs and is a reasonable option even for patients 
with stage IV disease. The aggressiveness of the surgery 
may vary from conservative debulking to radical resection 
and even liver transplantation.
With gastrinomas, the gastric hyperacidity of Zollinger-
Ellison syndrome is treated with a proton pump inhibitor 
at quadruple the usual doses. Proton pump inhibitors 
increase serum gastrin, which would otherwise be useful as 
a tumor marker for gastrinoma recurrence after surgical 
resection.
Tumor visualization on octreotide scanning indicates 
that they may respond to long-acting preparations of 
somatostatin analogs, including lanreotide (Somatuline 
Depot) and octreotide (Sandostatin LAR Depot). Subcuta
-
neous injections of Octreotide LAR 20–30 mg are required 
every 4 weeks. Treatment improves symptoms in patients 
with functioning tumors and also appears to improve 
progression-free survival in patients with either function
-
ing or nonfunctioning GEP-NETs. Enlarging hepatic 
metastases may be embolized with 
90
Y-labeled resin or 
glass microspheres. For patients with progressive meta
-
static disease, chemotherapy improves progression-free 
survival when added to somatostatin analog therapy 
(Table 39–2).
CMDT19_Ch26_p1119-p1219.indd   1196

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»
Prognosis
The prognosis for patients with GEP-NETs is variable, 
depending on the tumor grade and stage. Patients with well 
or moderately well differentiated GEP-NETs (Ki-67, a 
marker for cellular proliferation, less than 20%) have a 
much better survival than those with poorly differentiated 
tumors. Smaller tumors without detectable metastases have 
a much lower chance of recurrence after surgery. However, 
most patients with GEP-NETs are stage IV with hepatic 
metastases by the time of diagnosis. Nevertheless, low-
grade metastases may be indolent or slow-growing and 
may respond to octreotide or lanreotide. The overall prog
-
nosis for patients with GEP-NETs is much better than that 
for adenocarcinomas that arise from the same organs. The 
prognosis is worse for patients with serum pancreastatin 
levels above 500 pmol/L, since it correlates with the 
amount of hepatic metastases.
The surgical complication rate for GEP-NETs is about 
40%, with patients commonly developing fistulas and 
infections. Extensive pancreatic resection may cause dia
-
betes mellitus. The overall 5-year survival is higher with 
functional tumors (77%) than with nonfunctional ones 
(55%) and higher with benign tumors (91%) than with 
malignant ones (55%). For patients with gastrinomas, the 
5-, 10-, and 20-year survival rates with MEN 1 are 94%, 
75%, and 58%, respectively, while the survival rates for 
patients with sporadic gastrinomas are 62%, 50%, and 
31%, respectively.
Clancy TE. Surgical management of pancreatic neuroendocrine 
tumors. Hematol Oncol Clin North Am. 2016 Feb;30(1):103–
18. [PMID: 26614371]
Dasari A et al. Trends in the incidence, prevalence, and survival 
outcomes in patients with neuroendocrine tumors in the 
United States. JAMA Oncol. 2017 Oct 1;3(10):1335–42. 
[PMID: 28448665]
Liu EH et al. AACE/ACE disease state clinical review: diagnosis 
and management of midgut carcinoids. Endocr Pract. 2015 
May;21(5):534–45. [PMID: 25962092]
Raj N et al. Systemic therapies for advanced pancreatic neuroen
-
docrine tumors. Hematol Oncol Clin North Am. 2016 
Feb;30(1):119–33. [PMID: 26614372]
Singh S et al. Consensus recommendations for the diagnosis and 
management of pancreatic neuroendocrine tumors: guide
-
lines from a Canadian national expert group. Ann Surg 
Oncol. 2015 Aug;22(8):2685–99. [PMID: 25366583]
 
º
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
MEN TYPES 1–4
 
»
MEN 1:
 tumors of the parathyroid glands, endo
-
crine pancreas and duodenum, anterior pituitary, 
adrenal, thyroid; carcinoid tumors; lipomas and 
facial angiofibromas.
 
»
MEN 2 (MEN 2A):
 medullary thyroid cancers, pheo
-
chromocytomas, Hirschsprung disease.
 
»
MEN 3 (MEN 2B):
-
chromocytomas, Marfan-like habitus, mucosal neu
-
romas, intestinal ganglioneuroma, delayed puberty.
 
»
MEN 4:
 tumors of the parathyroid glands, anterior 
pituitary gland, adrenal gland, ovary, testicle, 
kidney.
Syndromes of MEN are inherited as autosomal domi
-
nant traits that cause a predisposition to the develop
-
ment of tumors of two or more different endocrine 
glands (Table 26–12). MEN syndromes are caused by 
different germline mutations and tumors arising when 
certain additional somatic mutations occur in predisposed 
organs. Patients with MEN should have genetic testing so 
that their first-degree relatives may then be tested for the 
specific mutation.
Table 26–12.
 
Multiple endocrine neoplasia (MEN) syndromes: incidence of tumor types.
Tumor Type
MEN 1
MEN 4
Parathyroid
95%
20–50%
Rare
Common
Pancreatic
54%
Common
Pituitary
42%
Common
> 90%
80%
Rare
20–35%
60%
Mucosal and gastrointestinal ganglioneuromas
Rare
> 90%
Subcutaneous lipoma
30%
Adrenocortical adenoma
30%
Common
Thoracic carcinoid
15%
Thyroid adenoma
55%
Common
Facial angiofibromas and collagenomas
85%
CMDT19_Ch26_p1119-p1219.indd   1197

Rare
> 90%
30%
30%
Common
15%
55%
Common
85%

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1. MEN 1
Multiple endocrine neoplasia type 1 (MEN 1, Wermer 
syndrome) is a tumor syndrome with a prevalence of 2–10 
per 100,000 persons in the United States. About 90% of 
affected patients harbor a detectable germline mutation in 
the 
menin
 gene.
The presentation of MEN 1 is quite variable, even in the 
same kindred. Affected patients are prone to many differ
-
ent tumors, particularly involving the parathyroids, endo
-
crine pancreas and duodenum, and anterior pituitary 
(Table 26–12). The initial biochemical manifestations (usu
-
ally hypercalcemia) can often be detected as early as 
age 14–18 years in patients with a MEN 1 gene mutation, 
although clinical manifestations usually present in the 
third or fourth decade.
 is the first clinical manifestation 
of MEN 1 in two-thirds of affected patients, but it may 
present at any time of life. The hyperparathyroidism of 
MEN 1 is notoriously difficult to treat surgically, due to 
multiple gland involvement and the frequency of supernu
-
merary glands and ectopic parathyroid tissue. Typically, 
three and one-half glands are resected, leaving one-half of 
the most normal-appearing gland intact. Also, during neck 
surgery, a thymectomy is performed to resect any intrathy
-
mic parathyroid glands or occult thymic carcinoid tumors. 
Nevertheless, the surgical failure rate is about 38%, and 
there is a recurrence rate of about 16%, with hypercalcemia 
often recurring many years after neck surgery.
GEP-NETs
 and carcinoids occur in up to 70% of 
patients with MEN 1. The GEP-NETs may secrete only 
pancreatic polypeptide or be nonsecretory altogether (20–
55%). 
 occur in about 40% of patients with 
MEN 1. Concurrent hypercalcemia, due to hyperparathy
-
roidism in MEN 1, stimulates gastrin and worsens gastric 
acid secretion; control of the hypercalcemia often reduces 
serum gastrin levels and gastric acid secretion. Gastrino
-
mas of MEN 1 tend to be small, multiple, and ectopic; they 
are frequently found outside the pancreas, usually in the 
duodenum. They can metastasize to the liver. Treatment of 
gastrinomas of MEN 1 is usually conservative, using long-
term high-dose proton pump inhibitor therapy and control 
of hypercalcemia; surgery is palliative and usually reserved 
for aggressive gastrinomas and those tumors arising in the 
duodenum. Carcinoid tumors can arise in the lung or 
abdomen and can metastasize, especially to the liver.
 occur in about 10% of patients with 
MEN 1. Surgery is usually attempted, but the tumors can 
be small, multiple, and difficult to detect. Glucagonomas 
occur in 1.6% of patients with MEN 1, VIPomas in 1%, and 
somatostatinomas in 0.7%. Extrapancreatic neuroendo
-
crine tumors are common in MEN 1, are frequently malig
-
nant, and include carcinoid tumors usually in foregut 
locations (69%), such as the lung, thymus, duodenum, or 
stomach.
Pituitary adenomas
 are the presenting tumor in 29% of 
patients with MEN 1 and eventually are found in about 
42% of patients with MEN 1. About 78% of these pituitary 
adenomas occur in women. In MEN 1 patients with a pitu
-
itary adenoma, hyperparathyroidism is more common 
(92%). About 42% of the pituitary adenomas secrete PRL, 
while others secrete GH (6%), ACTH (3%), gonadotro
-
phins (2%), or multiple hormones (5%). The prolactino
-
mas usually respond to medical therapy with cabergoline. 
In MEN 1, about 42% of pituitary adenomas are nonsecre
-
tory. While nonsecretory pituitary microadenomas (less 
than 1 cm diameter and detected on routine MRI screen
-
ing) are usually indolent, about 25% of nonsecretory pitu
-
itary adenomas are macroadenomas (1 cm or more in 
diameter) and more aggressive.
Adrenal adenomas
 or 
 occur in about 40% 
of patients with MEN 1 and 50% are bilateral. They are 
generally benign and nonfunctional. These adrenal lesions 
are ACTH-independent.
Thymic neuroendocrine tumors
 occur in 3.4% of

 occur in 3.4% of 
affected patients, mostly in males, with a 10-year survival 
of 25%. 
Lung neuroendocrine tumors
 occur in 13%, with 
a 10-year survival of 71%.
Benign thyroid adenomas
 or multinodular goiter 
occurs in about 55% of MEN 1 patients. Patients may 
undergo a thyroidectomy at the time of parathyroidectomy.
Nonendocrine tumors
 occur commonly in MEN 1, 
particularly small head-neck angiofibromas (85%) and 
lipomas (30%). Collagenomas are common (70%), present
-
ing as firm dermal nodules. Affected patients may also be 
more prone to meningiomas, breast cancer, colorectal 
cancers, prostate cancer, and malignant melanomas.
Overall, patients with MEN 1 have an increased mortal
-
ity rate with a mean life expectancy of only 55 years.
2. MEN 2 (MEN 2A)
Multiple endocrine neoplasia type 2 (MEN 2A, Sipple syn
-
drome) is a rare autosomal-dominant tumor syndrome that 
arises in patients with a germline 
ret
 protooncogene muta
-
tion. Genetic testing identifies about 95% of affected indi
-
viduals. Each kindred has a certain 
ret
 codon mutation that 
correlates with a particular variation in the MEN 2 (2A) 
syndrome. However, there is incomplete penetrance, and 
about 30% of those with germline 
ret
-
tions never manifest any of the following endocrine tumors.
 (greater than 90%); 
hyperparathyroidism
 (20–50%), with hyperplasia or ade
-
nomas of multiple parathyroid glands developing in over 
70% of cases; 
 (20–35%), which are 
often bilateral; or 
Hirschsprung disease
 may develop in 
patients with MEN 2 (2A). The medullary thyroid carci
-
noma is of mild to moderate aggressiveness. Children 
harboring an MEN 2A ret mutation are advised to have a 
prophylactic total thyroidectomy by age 6 years. No patients 
with MEN 2 should receive therapy for diabetes with glu
-
cagon-like peptide 1 (GLP 1) agonists that may increase the 
risk for medullary thyroid carcinoma. Before any surgical 
procedure, MEN 2 (2A) carriers should be screened for 
pheochromocytoma (see above) and for medullary thyroid 
3. MEN 3 (MEN 2B)
Multiple endocrine neoplasia type 3 (MEN 2B) is a famil
-
ial, autosomal dominant multiglandular syndrome that is 
also caused by a mutation of the 
ret
 protooncogene. 
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MEN 3 (2B) is characterized by mucosal neuromas (in 
more than 90% of affected patients) with bumpy and 
enlarged lips and tongue, Marfan-like habitus (75% of 
cases), adrenal pheochromocytomas (60%) that are rarely 
malignant and often bilateral, and medullary thyroid carci
-
noma (80%). Patients also have intestinal abnormalities 
(75%) such as intestinal ganglioneuromas, skeletal abnor
-
malities (87%), and delayed puberty (43%).
4. MEN 4
Multiple endocrine neoplasia type 4 (MEN 4) is a rare 
autosomal-dominant familial tumor syndrome caused by 
germline mutations in the gene 
CDKN1B
. Affected 
patients are particularly prone to adenomas of the pitu
-
itary, parathyroid glands, and neuroendocrine tumors of 
the pancreas. Unlike patients with MEN 1, those with 
MEN 4 are also appear to be prone to adrenal tumors, 
renal tumors, testicular cancer, and neuroendocrine cervi
-
OTHER SYNDROMES OF MULTIPLE 
ENDOCRINE NEOPLASIA
Carney complex,
 tumors develop in the 
adrenal cortex, pituitary, thyroid, and gonads as well as 
cardiac myxomas and hyperpigmentation. With 
McCune-
Albright syndrome
, precocious puberty (particularly 
girls) develops due to gonadal hypersecretion, Cushing 
syndrome is caused by multiple adrenal nodules, hyper
-
thyroidism results from autonomously functioning thy
-
roid nodules, and acromegaly is caused by GH-secreting 
pituitary tumors. Patients also have fibrous dysplasia of 
bones and hypophosphatemia, and bone fractures are 
common. Sudden death has been reported. 
Type 2
 
von 
Hippel Lindau (VHL) syndrome
 is associated with pheo
-
chromocytomas, pancreatic/duodenal neuroendocrine 
tumors, hyperparathyroidism, and pituitary tumors as 
well as hemangiomas and renal cell carcinomas. Patients 
with 
hypoxia inducible factor 2A (HIF2A)
 germline 
mutations develop pheochromocytomas, pancreatic/
duodenal somatostatinomas as well as erythrocytosis and 
retinal abnormalities. 
Neurofibromatosis type 1 (NF1)
 is 
associated with pheochromocytomas and pancreatic/
duodenal somatostatinomas as well as neurofibromas and 
hypothalamic hamartomas.
Norton JA et al. Multiple endocrine neoplasia: genetics and clini
-
cal management. Surg Oncol Clin N Am. 2015 Oct;24(4):795–
832. [PMID: 26363542]
Taïeb D et al. Diagnosis and preoperative imaging of multiple 
endocrine neoplasia type 2: current status and future direc
-
tions. Clin Endocrinol (Oxf). 2014 Sep;81(3):317–28. [PMID: 
24889858]
Thakker RV . Multiple endocrine neoplasia type 1 (MEN 1) and 
type 4 (MEN 4). Mol Cell Endocrinol. 2014 Apr 5;386(1–
2):2–15. [PMID: 23933118]
van Leeuwaarde RS et al. Impact of delay in diagnosis in out
-
comes in MEN1: results from the Dutch MEN1 Study Group. 
J Clin Endocrinol Metab. 2016 Mar;101(3):1159–65. [PMID: 
26751192]
 
º
DISEASES OF THE TESTES & MALE BREAST
MALE HYPOGONADISM
 
»
Diminished libido and erections.
 
»
Fatigue, depression, reduced exercise endurance.
 
»
Decreased growth of body hair.
 
»
Testes small or normal in size.
 
»
Low serum total testosterone or free testosterone.
 
»
Serum LH and FSH are low or normal in hypogo
-
nadotropic hypogonadism; they are high in testic
-
ular failure (hypergonadotropic hypogonadism).
 
»
Male hypogonadism is caused by deficient testosterone 
secretion by the testes. It may be classified according to 
whether it is due to (1) insufficient gonadotropin secre
-
tion by the pituitary (hypogonadotropic); (2) pathology 
in the testes themselves (hypergonadotropic); or (3) both 
(Table 26–13). Partial male hypogonadism may be diffi
-
cult to distinguish from the physiologic reduction in serum 
testosterone seen in normal aging, obesity, and illness.
Table 26–13.
 
Causes of male hypogonadism.
Hypogonadotropic 
 
(Low or Normal LH)
Hypergonadotropic 
(High LH)
Aging
Alcohol
Chronic illness
Congenital syndromes
Constitutional delay of growth and 
puberty

(High LH)
Aging
Alcohol
puberty
Cushing syndrome
Drugs
 
Estrogen
 
GnRH agonist 
(leuprolide)
 
Marijuana
 
P
rior androgens
 
Granulomatous diseases
Hypothalamic or pituitary tumors
Hypothyroidism, hyperthyroidism
Major medical or surgical illnesses
Malnourishment
Obesity (BMI > 30 kg/m
2
)
Aging
Anorchia (bilateral)
Klinefelter syndrome
Leprosy
Lymphoma
Male climacteric
Noonan syndrome
Orchiectomy (bilateral or 
unilateral)
Orchitis
Radiation or radioisotope 
therapy
Sertoli cell-only syndrome
Testicular trauma
Uremia
Viral infections (mumps)
BMI, body mass index; GnRH, gonadotropin-releasing hormone; 
LH, luteinizing hormone.
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»
Etiology
A. Hypogonadotropic Hypogonadism 
(Low Testosterone With Normal or Low LH)
A deficiency in FSH and LH may be isolated or associated 
with other pituitary hormonal abnormalities. (See Hypopi
-
tuitarism.) Hypogonadotropic hypogonadism can be 
primary
, defined as failure to enter puberty by age 14, with 
causes including isolated hypogonadotropic hypogonad
-
ism, hypopituitarism, or simple constitutional delay of 
growth and puberty; or it can be 
acquired
, with causes 
listed in Table 26–13. Genetic conditions (eg, Kallmann 
syndrome or 
PROKR2
 mutations, X-linked congenital 
adrenal hypoplasia, 17-ketosteroid reductase deficiency, 
Prader-Willis syndrome) account for about 40% of cases of 
isolated, and apparently idiopathic, acquired hypogonado
-
tropic hypogonadism with a serum testosterone level less 
than 150 ng/dL (5.2 nmol/L).
Partial male hypogonadotropic hypogonadism is defined 
as a serum testosterone in the range of 150–300 ng/dL 
(5.2–10.4 nmol/L). The main causes of acquired partial male 
hypogonadotropic hypogonadism include obesity, poor 
health, or normal aging, such that it is termed 
age-related 
hypogonadism
. Spermatogenesis is usually preserved.
B. Hypergonadotropic Hypogonadism 
 
(Testicular Failure With High LH)
A failure of the testicular Leydig cells to secrete adequate 
testosterone causes a rise in LH and FSH. Acquired condi
-
tions that can cause testicular failure are listed in Table 26–13. 
Male hypergonadotropic hypogonadism can also be caused 
by XY gonadal dysgenesis, partial 17-ketosteroid reductase 
deficiency and a congenital partial deficiency in the ste
-
roidogenic enzyme CYP17 (17-hydroxylase). CYP17 may be 
deliberately inhibited by abiraterone acetate, a drug for pros
-
tate cancer. In men who have had a unilateral orchiectomy 
for cancer, the remaining testicle frequently fails, even in the 
absence of radiation or chemotherapy.
 (47,XXY and its variants) is the 
most common chromosomal abnormality among males, 
with an incidence of about 1:500 (see Chapter 40). Although 
puberty occurs at the normal time, the degree of viriliza
-
tion is variable. Serum testosterone is usually low and 
gonadotropins are elevated. Other common findings 
include tall stature and abnormal body proportions that are 
unusual for hypogonadal men (eg, height more than 3 cm 
greater than arm span).
XY gonadal dysgenesis
 describes several conditions 
that result in the failure of the testes to develop normally. 
SRY
 is a gene on the Y chromosome that initiates male 
sexual development. Mutations in 
SRY
 result in testicular 
dysgenesis. Affected individuals lack testosterone, which 
results in sex reversal: female external genitalia with a blind 
vaginal pouch, no uterus, and intra-abdominal dysgenetic 
gonads. Affected individuals appear as normal girls until 
their lack of pubertal development and amenorrhea leads 
to the diagnosis. Intra-abdominal rudimentary testes have 
an increased risk of developing a malignancy and are usu
-
ally resected.
C. Androgen Insensitivity
Partial resistance to testosterone is a rare condition in 
which phenotypic males have variable degrees of apparent 
hypogonadism, hypospadias, cryptorchism, and gyneco
-
mastia. Serum testosterone levels are normal.
 
»
Hypogonadism that is congenital or acquired during child
-
hood presents as delayed puberty. Men with acquired 
hypogonadism have variable manifestations, known as 
“testosterone deficiency syndrome. ” Most men experience 
decreased libido. Others complain of erectile dysfunction, 
poor morning erection, or hot sweats. Men often have 
depression, fatigue, or decreased ability to perform vigor
-
ous physical activity. The presenting complaint may also be 
infertility, gynecomastia, headache, fracture, or other 
symptoms related to the cause or result of the hypogonad
-

-
-
ism. The patient’s history often gives a clue to the cause 
(Table 26–13).
Physical signs associated with hypogonadism may 
include decreased body, axillary, beard, or pubic hair, but 
only after years of severe hypogonadism. Men with hypogo
-
nadism lose muscle mass and gain weight due to an increase 
in subcutaneous fat. Examination should include measure
-
ments of arm span and height. Testicular size should be 
assessed with an orchidometer (normal volume is about 
10–25 mL; normal length is usually over 6 cm). Testicular 
size may decrease but usually remains within the normal 
range in men with postpubertal hypogonadotropic hypogo
-
nadism, but it may be diminished with testicular injury or 
Klinefelter syndrome. The testes must also be carefully pal
-
pated for masses, since Leydig cell tumors may secrete estro
-
gen and present with hypogonadism. The testicles must be 
carefully examined for evidence of trauma, infiltrative lesions 
(eg, lymphoma), or infection (eg, leprosy, tuberculosis).
The evaluation for hypogonadism begins with a morning 
serum testosterone or free testosterone measurement (or 
both). Serum testosterone levels are considered low if they 
are confirmed to be less than 320 ng/dL (11 nmol/L). 
Serum free testosterone levels are considered low if they are 
confirmed to be less than 64 pg/mL (220 pmol/L).
Normal ranges for serum testosterone have been 
derived from nonfasting morning blood specimens, which 
tend to be the highest of the day. Later in the day, serum 
testosterone levels can be 25–50% lower. Therefore, a 
serum testosterone drawn fasting or late in the day may be 
misleadingly below the “reference range. ”
Serum testosterone levels in men are highest at age 
20–30 years and slightly lower at age 30–40 years. After age 
40, serum total testosterone declines variably by an average 
of 1–2% annually; serum free testosterone levels decline 
even faster, since sex hormone binding globulin increases 
with age. Serum levels of free testosterone are lower in men 
aged 40–70 compared with younger men, without any 
increase in serum LH. A problem with the diagnosis of 
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age-related hypogonadism is that most laboratories provide 
reference ranges for testosterone that are derived from 
young men and may not provide age-adjusted reference 
ranges for serum testosterone and free testosterone. Among 
older men ages 60–79 years, 20% have serum total testoster
-
one levels less than 317 ng/dL (11 nmol/L) and 25% have 
serum free testosterone levels less than 65 pg/mL 
(225 pmol/L) below 317 ng/dL (25%) or a serum free testos
-
terone below 65 pg/mL (45%). The main conditions that 
contribute to the general decline in serum testosterone with 
aging include obesity, illness, and opioids. After age 70, LH 
levels tend to rise, indicating a contribution of primary 
gonadal dysfunction with advancing age. Testing for serum 
free testosterone is especially important for detecting hypo
-
gonadism in elderly men, who generally have high levels of 
sex hormone binding globulin. A low serum testosterone or 
free testosterone should be verified with a repeat morning 
nonfasting assay, along with a serum LH level. Serum LH 
levels are high in patients with hypergonadotropic hypogo
-
nadism but low or inappropriately normal in men with 
hypogonadotropic hypogonadism or normal aging. High 
serum estradiol levels are seen in men with obesity-related 
hypogonadotropic hypogonadism.
Testosterone stimulates erythropoiesis in men, causing 
the normal red blood count range to be higher in men than 
in women; mild anemia is common in men with hypogo
-
nadism. For men with longstanding severe male hypogo
-
nadism, osteoporosis is common, so a bone densitometry 
is recommended.
1. Hypogonadotropic hypogonadism—
A serum PRL 
determination is obtained to screen for a pituitary prolac
-
tinoma and other pituitary/hypothalamic lesions, but 
serum PRL may be elevated for many other reasons (see 
Table 26–1). The serum estradiol level may be elevated in 
patients with cirrhosis and in rare cases of estrogen-secret
-
ing tumors (testicular Leydig cell tumor or adrenal carci
-
noma). Men with no discernible definite cause for 
hypogonadotropic hypogonadism should be screened for 
hemochromatosis. Men with hypogonadotropic hypogo
-
nadism should have an MRI of the pituitary/hypothalamus 
to search for a mass lesion in presence of one or more of the 
following: (1) severe hypogonadism (serum testosterone 
below 150 ng/mL or 5.2 nmol/L), (2) elevated serum PRL, 
(3) other pituitary hormone deficiencies, or (4) symptoms 
of a mass lesion (headaches or visual field deficits).
2. Hypergonadotropic hypogonadism—
Men with hyper
-
gonadotropic hypogonadism have low serum testosterone 
levels with a compensatory increase in FSH and LH. Kline
-
felter syndrome can be confirmed by karyotyping or by 
measurement of leukocyte XIST. Testicular biopsy is usu
-
ally reserved for younger patients in whom the reason for 
primary hypogonadism is unclear.
 
»
Treatment
Testosterone replacement is reasonable for boys who 
have not entered puberty by age 14 years. It is also benefi
-
cial for most men with primary testicular failure (hyper
-
gonadotropic hypogonadism). Testosterone replacement 
or gonadal stimulation therapy is also warranted for men 
with severe hypogonadotropic hypogonadism of any eti
-
ology with serum testosterone levels less than 150 ng/mL 
(5.2 nmol/L). Testosterone therapy should also be consid
-
ered for men with low or low-normal serum testosterone 
or free testosterone, along with elevated serum LH levels. 
For other men without elevated serum LH levels and an 
average of at least two morning serum total testosterone 
levels below 275 ng/dL (9.5 nmol/L, “physiologic hypogo
-
nadism”), a trial of testosterone therapy may be consid
-
ered, particularly if they have at least three of the 
following six symptoms: erectile dysfunction, poor morn
-
ing erection, low libido, depression, fatigue, and inability 
to perform vigorous activity. Testosterone replacement

-
to perform vigorous activity. Testosterone replacement 
should be continued only if they clearly derive clinical 
benefit from therapy. Therapy can be adjusted with an 
aim to improve clinical symptoms while maintaining nor
-
mal serum levels of testosterone or free testosterone. Men 
with physiologic low-normal serum testosterone levels 
above 325 ng/dL (11.3 nmol/L) are unlikely to benefit 
from testosterone therapy.
Testosterone replacement or stimulation therapy carries 
certain risks. Therefore, testosterone therapy should only 
be given to men who have a documented low serum total 
or free testosterone. Testosterone therapy should not be 
given to men with active breast cancer or prostate cancer. It 
is also prudent to monitor the hematocrit and lipid profile 
of men receiving testosterone, since therapy can cause 
erythrocytosis and hyperlipidemia. Testosterone therapy 
can also cause gynecomastia. Testosterone therapy is not 
given to men with untreated sleep apnea or heart failure.
Drug interactions can occur. Testosterone should be 
administered cautiously to men receiving coumadin, since 
the combination can increase the INR and risk of bleeding. 
Similarly, testosterone therapy can increase serum levels of 
cyclosporine, tacrolimus, and tolvaptan. Testosterone can 
predispose to hypoglycemia in diabetic men receiving 
insulin or oral hypoglycemic agents, so close monitoring of 
blood sugars is advisable during initiation of testosterone 
therapy.
Oral androgen therapy with methyltestosterone is not 
advisable due to the potential for causing liver tumors, 
peliosis hepatis, and cholestatic jaundice.
Men with severe osteoporosis may require treatment 
with bisphosphonates and vitamin D, in addition to testos
-
terone replacement therapy.
A. Therapies for Male Hypogonadism
1. Testosterone topical gels—
Topical testosterone is usu
-
ally applied once daily in the morning after showering. One 
or two fingers are used to apply the gel evenly to skin. After 
the application of topical testosterone, the hands should be 
washed. Topical testosterone should not be applied to the 
breast or genitals. The gel should be allowed to air-dry 
(about 10 minutes) before dressing. Before close contact 
with women or children, a shirt must be worn or the areas 
of application washed with soap and water to prevent 
transfer of testosterone to them. The patient should avoid 
swimming, showering, or washing the application area for 
at least 2 hours following application.
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Testosterone topical generic 1% gel is available in pack
-
ets (12.5 mg/1.25 g, 25 mg/2.5 g, or 50 mg/5g) or tubes 
(50 mg/5 g). The recommended dose is 50–100 mg daily. 
Testosterone topical generic 2% gel is available in a gel 
pump (10 mg/0.5 g actuation). The recommended dose is 
40–70 mg daily. Androgel 1% gel is available in 2.5-g pack
-
ets (25 mg testosterone) and 5-g packets (50 mg testoster
-
one) and in a pump that dispenses 12.5 mg testosterone per 
pump actuation: the recommended dose is 50–100 mg 
applied daily to the shoulders. Androgel 1.6% gel is available 
in a pump that dispenses 20.25 mg testosterone per pump 
actuation; the recommended dose is 40.5–81 mg daily. 
Testim 1% gel is available in 5-g tubes (50 mg testosterone); 
the recommended dose is 50–100 mg applied daily. Fortesta 
2% gel is available in a pump that dispenses 10 mg testoster
-
one per pump actuation; the recommended dose is 
40–70 mg daily. Testogel is distributed in 5-g sachets (50 mg 
testosterone); this brand is not available in the United 
States. Testim, Fortesta, and Testogel may be applied to 
shoulders, upper arms, or abdomen. Axiron 2% solution is 
available in a pump that dispenses 30 mg per actuation; the 
recommended dose is 30–60 mg applied to each axilla daily. 
Vogelxo is a 1% testosterone gel that is available in packets 
or tubes (50 mg/5 g) or a gel pump (12.5 mg/1.25 g); it is 
applied to the shoulders in doses of 50–100 mg once daily.
The serum testosterone level should be determined 
about 14 days after starting therapy; if the level remains 
below normal or the clinical response is inadequate, the 
daily dose may be increased to 1.5 to 2 times the initial dose. 
Unfortunately, serum testosterone levels vary considerably 
during the day after topical testosterone gel application, such 
that a single serum testosterone level may not accurately 
reflect the average serum testosterone for that individual.
2. Transdermal testosterone patches—
Testosterone 
transdermal systems (skin patches) are applied to nongeni
-
tal skin. Androderm (2 or 4 mg/day) patches may be 
applied at bedtime in doses of 4–8 mg; it adheres tightly to 
the skin and may cause skin irritation.
3. Parenteral testosterone—
The dose and injection inter
-
vals are adjusted according to the patient’s clinical response 
and serum testosterone levels drawn just before the next 
injection is due. A target serum testosterone level of 
500 ng/dL (17.3 nmol/L) is suggested. 
Testosterone cypi
-
onate
 has been in use for decades; it is an intramuscular 
testosterone formulation that is available in solutions con
-
taining 200 mg/mL. Its main advantage is low cost. The 
usual dose is 200 mg every 2 weeks or 300 mg every 
3 weeks. It is usually injected into the gluteus medius 
muscle in the upper lateral buttock, alternating sides. The 
injection technique must include sterile precautions and 
draw-back prior to injection to ensure against intravenous 
injection, which can result in pulmonary oil embolism.
Testosterone pellets
 (Testopel) is a very long-lasting 
depot testosterone formulation that is available as individ
-
ual vials containing a single 75 mg implantable pellet in 
each vial. With sterile technique, the skin of the upper-
outer buttock is anesthetized with lidocaine; using a tro
-
char, the pellets are injected subcutaneously in doses of 
150–450 mg every 3–6 months as an in-office procedure.
Testosterone undecanoate
 (Aveed, Nebido) is a long-
lasting depot testosterone formulation. Its use is restricted 
to qualified health care facilities. It is usually injected into 
the gluteus medius muscle in the upper lateral buttock, 
alternating sides. Care must be taken to avoid intravascular 
injection by pulling back on the syringe plunger before 
injection; if any blood appears in the syringe, the needle is 
withdrawn and the syringe is discarded. Testosterone 
undecanoate (Aveed) is formulated as individual vials con
-

-
taining 750 mg/3 mL oily solution for intramuscular injec
-
tion. The initial injection of 750 mg is followed by another 
750 mg injection 4 weeks later and maintenance doses of 
750 mg every 10 weeks. Testosterone undecanoate (Nebido) 
is formulated as individual vials containing 1000 mg/4 mL 
oily solution for intramuscular injection. The initial injec
-
tion of 1000 mg is followed by another 1000 mg injection 
6 weeks later and maintenance doses of 1000 mg every 
12 weeks. A serum testosterone level is measured before 
the fourth dose; if the serum testosterone remains low, the 
dosing interval is shortened to every 10 weeks.
Caution:
 Testosterone undecanoate injections have 
caused serious pulmonary oil microembolism reactions 
that present with cough, dyspnea, tight throat, chest pain, 
and syncope. Anaphylaxis can also occur. 
Patients must be 
observed in the health care setting for 30 minutes after the 
injection in order to provide appropriate medical care for the 
complication
.
4. Buccal testosterone—
Testosterone buccal tablets 
(Striant) are placed between the upper lip and gingivae. 
One or two 30-mg tablets are thus retained and changed 
every 12 hours. They should not be chewed or swallowed.
5. Testosterone nasal gel—
Intranasal gel testosterone 
(Natesto) is self-administered by a metered-dose nasal 
pump: one pump actuation (5.5 mg) into each nostril three 
times daily. The nasal pump needs to be primed by invert
-
ing it and pressing the pump 10 times before it is used the 
first time. It should not be used concurrently with intrana
-
sal sympathomimetic decongestants. Adverse effects 
include nasopharyngitis, sinusitis, bronchitis, epistaxis, 
nasal discomfort, and headache.
6. Oral methyltestosterone—
Oral testosterone supple
-
mentation is available as methyltestosterone 10-mg tablets. 
The usual dose is 10–50 mg daily, given either once daily or 
given in divided doses. Oral methyltestosterone can pro
-
duce acute hepatitis and chronic high-dose use can cause 
peliosis hepatis, cholestatic hepatitis, and hepatocellular 
carcinoma. Therefore, its use is not recommended, and it is 
no longer available in some countries.
7. Clomiphene citrate—
Men with functional hypogonad
-
otropic hypogonadism usually respond well to clomiphene 
citrate that is administered orally in doses that are titrated 
to achieve the desired clinical response with a serum tes
-
tosterone level of about 500 ng/dL (17.3 nmol/L). Treat
-
ment with clomiphene is commenced with 25 mg on 
alternate days and increased to 50 mg on alternate days if 
necessary, with a maximum dose of 50 mg daily. Serum 
testosterone levels usually normalize while spermatogene
-
sis usually improves.
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8. Gonadotropins—
Patients with hypogonadotropic 
hypogonadism may require therapy with gonadotropins, 
particularly to induce fertility. Men may receive hCG 1000 
units subcutaneously three times weekly for 6 months; if 
the semen analysis shows inadequate sperm, FSH 75 units 
subcutaneously three times weekly is added. Many men 
prefer long-term therapy with hCG over testosterone 
therapy, but cost is an issue.
9. Weight loss—
When hypogonadotropic hypogonadism 
is due to morbid obesity, significant weight loss will 
improve serum testosterone levels. The rise in serum tes
-
tosterone is proportionate to the weight loss. Although 
diet-induced weight loss is beneficial, bariatric surgery has 
been much more effective and serum testosterone levels 
may normalize after dramatic weight loss.
B. Benefits of Testosterone Replacement Therapy
Testosterone therapy usually benefits men with low serum 
testosterone and at least three manifestations of hypogo
-
nadism. Testosterone therapy can improve overall mood, 
sense of well-being, sexual desire, and erectile function. It 
also increases physical vigor and muscle strength. Testos
-
terone replacement also improves exercise endurance and 
stair climbing ability. Long-term testosterone replacement 
causes significant weight loss and a reduction in waist cir
-
cumference. After 2 years of testosterone replacement, 
muscle mass increases about 4.5%, while fat mass decreases 
by about 9.1%. Appropriate testosterone replacement ther
-
apy also appears to improve longevity.
C. Risks of Testosterone 
 
Replacement or Stimulation Therapy
Testosterone therapy does not appear to significantly 
increase the risk of prostate cancer or benign prostatic 
hypertrophy above that of normal men, as long as serum 
testosterone levels are maintained in the normal reference 
range on therapy. However, testosterone therapy is contra
-
indicated in the presence of active prostate cancer. Hypo
-
gonadal men who have had a prostatectomy for low-grade 
prostate cancer, and who have remained in complete 
remission for several years, may have testosterone therapy 
given cautiously while monitoring serum PSA levels.
Erythrocytosis
 develops in some men who are treated 
with testosterone. Erythrocytosis is more common with 
intramuscular injections of testosterone enanthate than 
with transcutaneous testosterone. However, no increase in 
the incidence of thromboembolic events has been reported.
Testosterone therapy tends to aggravate sleep apnea in 
older men, likely through CNS effects. Surveillance for 
sleep apnea is recommended during testosterone therapy 
and a formal evaluation is recommended for all high-risk 
patients with snoring, obesity, partner’s report of apneic 
episodes, nocturnal awakening, unrefreshing sleep with 
daytime fatigue, or hypertension.
Men who are treated with testosterone frequently expe
-
rience some increase in acne that is usually mild and toler
-
ated; topical antiacne therapy or a reduction in testosterone 
replacement dosage may be required. Increases in intraoc
-
ular pressure have occurred during testosterone therapy. 
During the initiation of testosterone replacement therapy, 
gynecomastia develops in some men, which usually is mild 
and tends to resolve spontaneously; switching from testos
-
terone injections to testosterone transdermal gel may help 
this condition.
D. Risks of Performance-Enhancing 
 
Anabolic Steroids
Performance-enhancing agents, particularly androgenic 
anabolic steroids, are used by up to 2% of young athletes 
and by 20–65% of power sport athletes. They are often used 
as part of a “stacking” polypharmacy that may include 
nandrolone decanoate, dimethandrolone, testosterone pro
-
pionate, or testosterone enanthate. These androgens are 
usually illegal and often contaminated by toxic substances 
and can produce toxic hepatitis, dependence, aggression, 
depression, dyslipidemias, gynecomastia, acne, male pat
-

-
tern baldness, hepatitis, thromboembolism, and cardiomy
-
opathy. Shared needles may transmit hepatitis or HIV . 
Arsenic contamination has been reported to cause multior
-
gan failure and death.
 
»
Prognosis of Male Hypogonadism
If hypogonadism is due to a pituitary lesion, the prognosis 
is that of the primary disease (eg, tumor, necrosis). The 
prognosis for restoration of virility is good if testosterone is 
given. In one large study, cardiovascular risk was reduced 
in hypogonadal men over age 40 who were receiving testos
-
terone replacement therapy to maintain serum testosterone 
levels within the normal reference range.
Antonio L et al; European Male Ageing Study Study Group. Low 
free testosterone is associated with hypogonadal signs and symp
-
toms in men with normal total testosterone. J Clin Endocrinol 
Metab. 2016 Jul;101(7):2647–57. [PMID: 26909800]
Budoff MJ et al. Testosterone treatment and coronary artery 
plaque volume in older men with low testosterone. JAMA. 
2017 Feb 21;317(7):708–16. [PMID: 28241355]
Cheetham TC et al. Association of testosterone replacement with 
cardiovascular outcomes among men with androgen defi
-
ciency. JAMA Intern Med. 2017 Apr;177(4):491–9. [PMID: 
28241244]
Cunningham GR et al. Testosterone treatment and sexual function 
in older men with low testosterone levels. J Clin Endocrinol 
Metab. 2016 Aug;101(8):3096–104. [PMID: 27355400]
Dubruyne FM et al. Testosterone treatment is not associated 
with increased risk of prostate cancer or worsening of lower 
urinary tract symptoms: prostate health outcomes in the Reg
-
istry of Hypogonadism in Men. BJU Int. 2017 Feb;119(2):216–24.
 
 [PMID: 27409523]
Morales A et al; Canadian Men’s Health Foundation Multidisci
-
plinary Guidelines Task Force on Testosterone Deficiency. 
Diagnosis and management of testosterone deficiency syn
-
drome in men: clinical practice guideline. CMAJ. 2015 Dec 8;
 
187(18):1369–77. [PMID: 26504097]
-
 
Travison TG et al. Harmonized reference ranges for circulating 
testosterone levels in men of four cohort studies in the United 
States and Europe. J Clin Endocrinol Metab. 2017 Apr 1;
 
102(4):1161–73. [PMID: 28324103]
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Y eap BB et al. Endocrine Society of Australia position statement 
on male hypogonadism (part 1): assessment and indications 
for testosterone therapy. Med J Aust. 2016 Aug 15;20(4):
 
173–8. [PMID: 27510348]
on male hypogonadism (part 2): treatment and therapeutic 
considerations. Med J Aust. 2016 Sep 5;205(5):228–31. 
[PMID: 27581270]
CRYPTORCHISM
Cryptorchidism is found in 1–2% of males after 1 year of 
age but must be distinguished from retractile testes, which 
require no treatment. Infertility or subfertility occurs in up 
to 75% of men with bilateral cryptorchism and in 50% of 
men with unilateral cryptorchism. Some patients have 
underlying hypogonadism, including hypogonadotropic 
For a testis that is not palpable, it is important to locate 
the testis and bring it into the scrotum or prove its absence. 
About one-third of nonpalpable testes are located within 
the inguinal canal, one-third are intra-abdominal, and one-
third are absent. Ultrasound can detect an inguinal testis. If 
ultrasound is negative, MRI is performed to locate the 
testis.
The lifetime risk of testicular neoplasia is 0.002% in 
normal males. The risk of malignancy is higher for crypt
-
orchid testes (0.06%) and for intra-abdominal testes (5%). 
Orchiopexy decreases the risk of neoplasia when per
-
formed before 10 years of age. Orchiectomy after puberty 
is an option for intra-abdominal testes.
Berger C et al. Nonpalpable testes: ultrasound and contralateral 
testicular hypertrophy predict the surgical access, avoiding 
unnecessary laparoscopy. J Pediatr Urol. 2017 Nov 30. [Epub 
ahead of print] [PMID: 29199091]
 
»
Palpable enlargement of the male breast, often 
asymmetric or unilateral.
 
»
Glandular gynecomastia:
 characterized by 
 
»
Fatty gynecomastia: 
typically nontender.
 
»
Must be distinguished from carcinoma or 
mastitis.
 
»
Gynecomastia is defined as the presence of palpable glandu
-
lar breast tissue in males. Pubertal gynecomastia develops in 
about 60% of boys; the swelling usually subsides spontane
-
ously within a year. Gynecomastia is particularly common in 
teenagers who are very tall or overweight. The causes of 
gynecomastia are multiple and diverse (Table 26–14). About 
20% of adult gynecomastia is caused by drug therapy. 
Gynecomastia can develop in HIV-infected patients treated 
with antiretroviral therapy, especially in men receiving efavi
-
renz or didanosine; breast enlargement resolves spontane
-
ously in 73% of patients within 9 months. Gynecomastia 
develops in about 50% of athletes who abuse androgens and 
anabolic steroids. Fatty pseudogynecomastia is common 
among elderly men, particularly when there is associated 
weight gain. However, true glandular gynecomastia can be 
the first sign of a serious disorder in older men.
 
»
The male breasts must be palpated carefully to distinguish 
firm true glandular gynecomastia from softer fatty pseudo
-
gynecomastia in which only adipose tissue is felt. The 
breasts are best examined both seated and supine. Using 
Table 26–14.
 
Causes of gynecomastia.
Physiologic causes
 
Aging
 
Neona
tal period, puberty
 
Obesity
Endocrine diseases
 
Andr
ogen insensitivity syndrome
 
Ar
omatase excess syndrome 
 
(spor
adic or familial)
 
Diabetic 
lymphocytic mastitis
 
K
linefelter syndrome
 
M
ale hypogonadism (primary 
 
or sec
ondary)
 
P
artial 17-ketosteroid reductase 
 
Systemic diseases
 
Chr
onic liver disease
 
Chr
 
Hansen disease
 
Neur
ologic disorders
 
Ref
eeding after starvation
 
Spinal 
Neoplasms
 
A
drenal tumors
 
Br
onchogenic carcinoma
 
C
arcinoma of the breast
 
E
ctopic hCG: CNS 
 
germinoma, 
lung, hepatocellu
-
lar, gastric, renal carcinomas
 
P

Spinal 
Neoplasms
 
A
 
Br
 
C
 
E
 
-
 
P
ituitary prolactinoma
 
T
esticular hCG-secreting tumors
Drugs (partial list)
 
Alcohol
 
Alk
ylating chemotherapeutic 
 
agents
 
Anabolic 
steroids
 
Andr
ogens (testosterone)
 
Anti-androgens
Antipsychotics (first- and 
 
second-generation)
Antiretroviral agents
Calcium channel blockers 
(rare)
Chorionic gonadotropin
Clomiphene
Diazepam
Digitalis preparations
Dutasteride
Estrogens (oral or topical)
Ethionamide
Famotidine (rare)
Fenofibrate (rare)
GnRH analogs
Growth hormone
Isoniazid
Lavender (topical)
Marijuana
Methadone
Methotrexate (rare)
Metronidazole
Opioids
Proton pump inhibitors 
(uncommon)
Ranitidine (rare)
Soy ingestion
Statins (rare)
Spironolactone (common)
Sunitinib
Tea tree oil (topical)
GnRH, gonadotropin-releasing hormone.
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the thumb and forefinger as pincers, the subareolar tissue 
is compared to nearby adipose tissue. Fatty tissue is usually 
diffuse and nontender. True glandular enlargement beneath 
the areola may be tender. Pubertal gynecomastia is charac
-
terized by tender discoid enlargement of breast tissue 2–3 
cm in diameter beneath the areola. The following charac
-
teristics are worrisome for malignancy: asymmetry; loca
-
tion not immediately below the areola; unusual firmness; 
or nipple retraction, bleeding, or discharge. The examina
-
tion must also include an assessment of masculinization, 
examination of the testes for size and masses, and examina
-
tion of the penis for hypospadias.
In the presence of true glandular gynecomastia, a laboratory 
assessment should include liver biochemical tests, serum 
BUN, and creatinine. Endocrine testing, including serum 
testosterone, free testosterone, sex hormone binding globu
-
lin, LH, FSH, is obtained to determine whether primary or 
secondary hypogonadism or androgen resistance may be 
present. Primary hypogonadism is characterized by a low 
serum testosterone with a high LH. Secondary hypogonad
-
ism is present in men with a low serum testosterone with a 
low or normal serum LH. High serum testosterone levels 
plus high LH levels characterize partial androgen insensitiv
-
ity syndrome. A serum PRL is obtained to screen for hyper
-
prolactinemia and pituitary/hypothalamic lesions. Serum 
beta-hCG and estradiol levels are obtained to screen for 
malignancy-associated gynecomastia. Detectable levels of 
beta-hCG implicate a testicular tumor (germ cell or Sertoli 
cell) or other malignancy (usually lung or liver). Increased 
serum estradiol levels may result from testicular tumors, 
increased beta-hCG, liver disease, obesity, adrenal tumors 
(rare), true hermaphroditism (rare), or aromatase gene gain-
of-function mutations (rare). Serum TSH and FT
4
 levels are 
also obtained to screen for hyperthyroidism and hypothy
-
roidism. A karyotype for Klinefelter syndrome is obtained in 
men with persistent gynecomastia without obvious cause.
C. Imaging and Biopsy
Investigation of unclear cases should include bilateral 
mammography and a chest radiograph to search for bron
-
chogenic or metastatic carcinoma. Benign mammographic 
findings make malignancy very unlikely. Suspicious mam
-
mographic findings require ultrasound examination that 
includes the axilla. Needle biopsy with cytologic examina
-
tion may be performed on suspicious male breast lesions to 
distinguish gynecomastia from benign lesions (pseudogy
-
necomastia, lipoma, posttraumatic hematoma/fat necrosis, 
epidermal inclusion cyst), lymphoma, and male breast 
cancer. Male breast cancer and gynecomastia may coexist.
Men with a high serum hCG or estradiol levels should 
have the test confirmed with repeat testing. Confirmed 
increased levels warrant a testicular ultrasound. If the tes
-
ticular ultrasound is normal, high serum estradiol levels 
may warrant a CT of the adrenals; high serum hCG levels 
may warrant additional CT scanning to detect rare hCG-
secreting carcinomas of the lung, mediastinum, liver, stom
-
ach, or kidney.
 
»
Treatment
Pubertal gynecomastia often resolves spontaneously within 
1–2 years. Drug-induced gynecomastia resolves after the 
offending drug is removed (eg, spironolactone stopped, with 
substitution of eplerenone). Patients with painful or persistent 
gynecomastia may be treated with medical therapy, usually for 
9–12 months. Generally, it is prudent to treat patients for gyne
-
comastia only when it is a continuing troubling problem.
Selective estrogen receptor modulator (SERM)
 ther
-
apy is effective for true glandular gynecomastia. Raloxi
-
fene, 60 mg orally daily, may be somewhat more effective 
than tamoxifen, 10–20 mg orally daily.
Aromatase inhibitor (AI)
 therapy is also reasonably

-
 therapy is also reasonably 
effective; anastrozole reduces breast volume significantly 
over 6 months in adolescents given in a dose of 1 mg orally 
daily. Serum estradiol levels fall slightly while serum testos
-
terone levels rise. Long-term AI therapy in adolescents is 
not recommended because of the possibility of inducing 
osteoporosis and of delaying epiphyseal fusion, which 
could cause an increase in adult height.
Testosterone therapy
 for men with hypogonadism may 
improve or worsen preexistent gynecomastia.
 has been used prophylactically to 
prevent gynecomastia in men with prostate cancer being 
treated with antiandrogen therapy. Low-dose prophylactic 
radiation therapy reduces its incidence from 71% to 28%. 
Existing gynecomastia improves in 33% with radiation 
therapy. However, the long-term breast and other cancer 
risks of such radiation are unknown.
Surgical correction
 is reserved for patients with persis
-
tent or severe gynecomastia.
Ali SN et al. Which patients with gynaecomastia require more 
detailed investigation? Clin Endocrinol (Oxf). 2018 
Mar;88(3):360–3. [PMID: 29193251]
Chau A et al. Male breast: clinical and imaging evaluations of 
benign and malignant entities with histologic correlation. Am 
J Med. 2016 Aug;129(8):776–91. [PMID: 26844632]
MacDonald SM et al. Case records of the Massachusetts General 
Hospital. Case 32-2016. A 20-year-old man with gynecomastia. 
N Engl J Med. 2016 Oct 20;375(16):1567–79. [PMID: 27797319]
Nuttall FQ et al. Gynecomastia and drugs: a critical evaluation of 
the literature. Eur J Clin Pharmacol. 2015 May;71(5):569–78. 
[PMID: 25827472]
HIRSUTISM & VIRILIZATION
 
»
Hirsutism, acne, menstrual disorders.
 
»
Virilization: muscularity, androgenic alopecia, 
deepening voice, clitoromegaly.
 
»
Rarely, a palpable pelvic tumor.
 
»
Urinary 17-ketosteroids, serum DHEAS and andro
-
stenedione elevated in adrenal disorders; variable 
in others.
 
»
Serum testosterone is often elevated.
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»
Hirsutism is defined as cosmetically unacceptable terminal 
hair growth that appears in women in a male pattern. Sig
-
nificant hirsutism affects about 5–10% of non-Asian 
women of reproductive age and over 40% of women at 
some point during their life. The amount of hair growth 
deemed unacceptable depends on a woman’s ethnicity and 
familial and cultural norms. Virilization is defined as the 
development of male physical characteristics in women, 
such as pronounced muscle development, deep voice, male 
pattern baldness, and more severe hirsutism.
 
»
Etiology
Hirsutism may be idiopathic or familial or be caused by the 
following disorders: polycystic ovary syndrome (PCOS), 
ovarian hyperthecosis, steroidogenic enzyme defects, neo
-
plastic disorders; or rarely by medications, acromegaly, or 
ACTH-induced Cushing disease.
A. Idiopathic or Familial
Most women with hirsutism or androgenic alopecia have 
no detectable hyperandrogenism. Patients often have a 
strong familial predisposition to hirsutism that may be 
considered normal in the context of their genetic back
-
ground. Such patients may have elevated serum levels of 
androstenediol glucuronide, a metabolite of dihydrotestos
-
terone that is produced by skin in cosmetically unaccept
-
able amounts.
B. Polycystic Ovary Syndrome (PCOS, 
Hyperthecosis, Stein-Leventhal Syndrome)
PCOS is a common functional disorder of the ovaries of 
unknown etiology (see Chapter 18). It accounts for at least 
50% of all cases of hirsutism associated with elevated serum 
testosterone levels. It is familial and transmitted as a com
-
plex polygenic disorder whose phenotypic expression may 
involve both protective and susceptible genomic variants.
A diagnosis of PCOS must meet three criteria: 
(1) androgen excess with clinical hyperandrogenism or 
elevated serum free or total testosterone; (2) ovarian dys
-
function with oligoanovulation or polycystic ovary mor
-
phology; and (3) absence of other causes of testosterone 
excess or anovulation such as pregnancy, thyroid dysfunc
-
tion, 21-hydroxylase deficiency, neoplastic testosterone 
secretion, Cushing syndrome, or hyperprolactinemia.
Affected women usually have signs of hyperandrogen
-
ism, including hirsutism, acne, or male-pattern thinning of 
scalp hair; this persists after natural menopause. However, 
women of East Asian ancestry are less likely to exhibit hir
-
sutism. Most women also have elevated serum testosterone 
or free testosterone levels. About 70% of affected women 
have polycystic ovaries on pelvic ultrasound and 50% have 
oligomenorrhea or amenorrhea with anovulation. Of note, 
about 30% of women with PCOS do 
not
 have cystic ovaries 
and 25–30% of normal menstruating women 
have
 cystic 
ovaries.
Obesity and high serum insulin levels (due to insulin 
resistance) contribute to the syndrome in 70% of women. 
The serum LH:FSH ratio is often greater than 2.0. Both 
adrenal and ovarian androgen hypersecretion are com
-
monly present.
C. Steroidogenic Enzyme Defects
Congenital adrenal steroidogenic enzyme defects result in 
reduced cortisol secretion with a compensatory increase in 
ACTH that causes adrenal hyperplasia. The most common 
enzyme defect is 21-hydroxylase deficiency, with a preva
-
lence of about 1:18,000.
Partial deficiency in adrenal 21-hydroxylase can pres
-
ent in women as hirsutism. About 2% of patients with 
adult-onset hirsutism have been found to have a partial 
defect in adrenal 21-hydroxylase. The condition is more 
common in Ashkenazi Jews, Yupic Alaskans, and natives of 
La Reunion Island. The phenotypic expression is delayed 
until adolescence or adulthood; such patients do not have 
salt wasting. Polycystic ovaries and adrenal adenomas are 
more likely to develop in these women.
Some rare patients with hyperandrogenism and hyper
-
tension have 11-hydroxylase deficiency. This is distin
-
guished from cortisol resistance by high cortisol serum

-
-
guished from cortisol resistance by high cortisol serum 
levels in the latter and by high serum 11-deoxycortisol 
levels in the former.
D. Neoplastic Disorders
Ovarian tumors are uncommon causes of hirsutism (0.8%) 
and include arrhenoblastomas, Sertoli-Leydig cell tumors, 
dysgerminomas, and hilar cell tumors. Adrenal carcinoma 
is a rare cause of Cushing syndrome and hyperandrogenism 
that can be quite virilizing. Pure androgen-secreting adre
-
nal tumors occur very rarely; about 50% are malignant.
E. Rare Causes of Hirsutism & Virilization
Acromegaly and ACTH-induced Cushing syndrome are 
rare causes of hirsutism and virilization. Porphyria cutanea 
tarda can cause periorbital hair growth in addition to der
-
matitis in sun-exposed areas. Maternal virilization during 
pregnancy may occur as a result of a luteoma of pregnancy, 
hyperreactio luteinalis, or polycystic ovaries. In postmeno
-
pausal women, diffuse stromal Leydig cell hyperplasia is a 
rare cause of hyperandrogenism. Acquired hypertrichosis 
lanuginosa is manifested by the appearance of diffuse fine 
lanugo hair growth on the face and body along with stoma
-
tologic symptoms; the disorder is usually associated with an 
internal malignancy, especially colorectal cancer, and may 
regress after tumor removal. Pharmacologic causes include 
minoxidil, cyclosporine, phenytoin, anabolic steroids, inter
-
feron, cetuximab, diazoxide, and certain progestins.
 
»
Modest androgen excess from any source increases sexual 
hair (chin, upper lip, abdomen, and chest) and increases 
sebaceous gland activity, producing acne. Menstrual irreg
-
ularities, anovulation, and amenorrhea are common. If 
androgen excess is pronounced, defeminization (decrease 
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in breast size, loss of feminine adipose tissue) and viriliza
-
tion (frontal balding, muscularity, clitoromegaly, and deep
-
ening of the voice) occur. Virilization points to the presence 
of an androgen-producing neoplasm. Hirsutism is quanti
-
tated using the Ferriman-Gallwey score in which hirsutism 
is graded from 0 (none) to 4 (severe) in nine areas of the 
body with a maximum possible score of 36; scores 8–15 
indicate moderate hirsutism, while scores over 15 indicate 
severe hirsutism.
A pelvic examination may disclose clitoromegaly or 
ovarian enlargement that may be cystic or neoplastic. 
Hypertension may be present in Cushing syndrome, adrenal 
11-hydroxylase deficiency, or cortisol resistance syndrome.
B. Laboratory Testing and Imaging
Serum androgen testing is mainly useful to screen for rare 
occult adrenal or ovarian neoplasms.
Serum is assayed for total testosterone and free testos
-
terone. A serum testosterone level greater than 200 ng/dL 
(6.9 nmol/L) or free testosterone greater than 40 ng/dL 
(140 pmol/L) indicates the need for pelvic examination and 
ultrasound. If that is negative, an adrenal CT scan is per
-
formed. A serum androstenedione level greater than 
1000 ng/dL (34.9 nmol/L) also points to an ovarian or 
adrenal neoplasm. Patients with milder elevations of serum 
testosterone or androstenedione usually are treated with an 
oral contraceptive.
Patients with a serum DHEAS greater than 700 mcg/dL 
(35 nmol/L) have an adrenal source of androgen. This usu
-
ally is due to adrenal hyperplasia and rarely to adrenal 
carcinoma. An adrenal CT scan is performed.
No firm guidelines exist as to which patients (if any) 
with hyperandrogenism should be screened for “late-onset” 
21-hydroxylase deficiency. The evaluation requires levels 
of serum 17-hydroxyprogesterone to be drawn at baseline 
and at 30–60 minutes after the intramuscular injection 
of 0.25 mg of cosyntropin (ACTH
1–24
). Ideally, this test 
should be done during the follicular phase of a woman’s 
menstrual cycle. Patients with congenital adrenal hyperpla
-
sia will usually have a baseline 17-hydroxyprogesterone 
level greater than 300 ng/dL (9.1 nmol/L) or a stimulated 
level greater than 1000 ng/dL (30.3 nmol/L). Patients with 
any clinical signs of Cushing syndrome should receive a 
screening test.
Serum levels of FSH and LH are elevated if amenorrhea 
is due to ovarian failure. An LH:FSH ratio greater than 2.0 
is common in patients with PCOS. On abdominal ultra
-
sound, about 25–30% of normal young women have poly
-
cystic ovaries, so the appearance of ovarian cysts on 
ultrasound is not helpful. Pelvic ultrasound or MRI usually 
detects virilizing tumors of the ovary. However, small viril
-
izing ovarian tumors may not be detectable on imaging 
studies; selective venous sampling for testosterone may be 
used for diagnosis in such patients.
 
»
Treatment
Any drugs causing hirsutism (see above) should be stopped. 
Any underlying medical causes of hirsutism (eg, Cushing 
syndrome, acromegaly) should be treated.
A. Surgery
Androgenizing tumors of the adrenal or ovary are resected 
laparoscopically. Postmenopausal women with severe 
hyperandrogenism should undergo laparoscopic bilateral 
oophorectomy (if CT scan of the adrenals and ovaries is 
normal), since small hilar cell tumors of the ovary may not 
be visible on scans. Women with classic salt-wasting con
-
genital adrenal hyperplasia and infertility or treatment-
resistant hyperandrogenism may be treated with 
laparoscopic bilateral adrenalectomy.
B. Laser and Topical Treatments
Laser therapy
 (photoepilation) can be a very effective treat
-
ment for facial hirsutism, particularly for women with dark 
hair and light skin; longer-wavelength lasers are used for 
women with darker skin. In such women, laser removal of 
facial hair significantly improves their appearance and 
quality of life. A paradoxical increase in hair growth occurs

quality of life. A paradoxical increase in hair growth occurs 
infrequently. Repeated laser treatments are usually required.
Local treatment
 of facial hirsutism is by shaving or 
depilatories, waxing, electrolysis, or bleaching. Eflorni
-
thine (Vaniqa) 13.9% topical cream retards hair growth 
when applied twice daily to unwanted facial hair; improve
-
ment is noted within 4–8 weeks. However, local skin irrita
-
tion may occur. Hirsutism returns with discontinuation. It 
may be used in conjunction with laser therapy.
Topical minoxidil
 may be used to treat androgenic 
alopecia and is mildly effective when applied to the scalp 
twice daily. Only the 2% formulation is FDA approved for 
women.
 is effective for reducing hirsutism, acne, 
and androgenic alopecia in women and is a first-line medi
-
cal strategy for these women. It may be taken in doses of 
100–200 mg orally daily (taken as a single dose or in two 
divided doses) on days 5–25 of the menstrual cycle or daily 
if used concomitantly with an oral contraceptive. Spirono
-
lactone is contraindicated in pregnancy, so reproductive-
age women must use reliable contraception during this 
therapy. Hyperkalemia is an uncommon side effect, but 
serum potassium should be checked 1 month after begin
-
ning therapy or after dosage increases. Spironolactone 
should be avoided or used cautiously in women who are 
prone to hyperkalemia, including women with kidney dis
-
ease or who are taking an ACE inhibitor or ARB for hyper
-
tension. Trimethoprim-sulfamethoxazole should not be 
taken along with high-dose spironolactone due to the risk 
of hyperkalemia and sudden death. Side effects of spirono
-
lactone include breast tenderness, menstrual irregularity, 
headaches, nausea, and fatigue, which may improve with 
continued treatment or dose reduction; paradoxical scalp 
hair loss has been reported at higher doses. If necessary, 
metformin can be added and may enhance the anti-hirsut
-
ism effect of low-dose spironolactone.
Flutamide
 and 
bicalutamide
 inhibit testosterone bind
-
ing to androgen receptors and also suppress serum testos
-
terone. Flutamide is given orally in a dosage of 250 mg 
twice daily for the first year and then 125–250 mg/day for 
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maintenance. Bicalutamide is given in a dosage of 50 mg 
once daily. Used with an oral contraceptive, they may be 
more effective than spironolactone in improving hirsutism, 
acne, and male pattern baldness. Flutamide decreases cor
-
tisol renal clearance and corticosteroid replacement doses 
(eg, in congenital adrenal hyperplasia) should be reduced 
when flutamide is added. Hepatotoxicity has been reported 
but is rare. These drugs must be given only to nonpregnant 
women. Women must be counseled to take strict contra
-
ceptive measures, since antiandrogen drugs during preg
-
nancy causes malformations and disorders of sexual 
development (pseudohermaphroditism) in male infants.
 inhibits 5-alpha-reductase, the enzyme that 
converts testosterone to active dihydrotestosterone in the 
skin. Given as 5-mg doses orally daily, it provides inconsis
-
tent reduction in hirsutism and androgenic alopecia over 
6 months. Side effects are rare, but the drug is contraindi
-
cated in pregnancy and contraceptive measures are manda
-
tory in reproductive age women.
Newer combined oral contraceptives
 that contain 
antiandrogenic progestins such as desogestrel (Azurette, 
Kariva), drospirenone (Y az, Gianvi), norgestimate (Ortho 
Tri-Cyclen Lo), or cyproterone acetate (Diane 35, not avail
-
able in United States) reduce hirsutism and acne. These 
newer antiandrogenic oral contraceptives confer a six-fold 
risk of deep venous thromboembolism, particularly when 
combined with higher doses of ethinyl estradiol, and there
-
fore, oral contraceptives with the lowest possible dose of 
ethinyl estradiol should be selected (eg, ethinyl estradiol 35 
mcg with norgestimate 0.25 mg). Older combined oral 
contraceptives that contain the progestins norethindrone, 
norgestrel, or levonorgestrel are relatively ineffective for 
hirsutism and acne. The risk for arterial thrombosis is 
increased by 50–100% for all combined oral contracep
-
tives. For this reason, combined oral contraceptives are 
relatively contraindicated for women who are predisposed 
to thromboembolism: women who are smokers or who 
have migraines, hypertension or a personal history throm
-
boembolism. Metabolic syndrome and hypertriglyceride
-
mia are seen, particularly with antiandrogenic progestins. 
The risks of metabolic syndrome may be offset by 
metformin.
Metformin
 alone is ineffective in improving hirsutism, 
but can enhance the anti-hirsutism effect of spironolac
-
tone. Metformin therapy is usually given orally with meals 
and is started at a dose of 500 mg/day with breakfast for 1 
week, then increased to 500 mg with breakfast and dinner. 
If this dose is clinically insufficient but tolerated, the dose 
may be increased to 850–1000 mg twice daily. The most 
common side effects are dose-related gastrointestinal upset 
and diarrhea or constipation. Metformin appears to be 
nonteratogenic. Although metformin reduces insulin resis
-
tance, it does not cause hypoglycemia in nondiabetic 
patients. Metformin is contraindicated in kidney and liver 
disease.
Simvastatin
 can reduce hirsutism in women with 
PCOS. In one study, simvastatin 20 mg orally daily was 
given to women receiving an oral contraceptive for PCOS. 
Besides improving their serum lipid profiles, women 
receiving simvastatin had greater decreases in hirsutism 
and serum free testosterone levels than the women receiv
-
ing an oral contraceptive alone. Atorvastatin also reduced 
serum testosterone by an average of 25% in women with 
PCOS.
GLP-1 agonist
 therapy reduced weight and serum tes
-
tosterone levels in women with PCOS in one short-term 
study.
Women with classic congenital adrenal hyperplasia 
(21-hydroxylase deficiency) have hirsutism and adrenal 
insufficiency that requires corticosteroid and mineralocor
-
ticoid replacement. However, women with partial “late 
onset” 21-hydroxylase deficiency do not require hormone 
replacement. Treating such women with dexamethasone

-
replacement. Treating such women with dexamethasone 
risks iatrogenic Cushing syndrome and is not more effec
-
tive than other treatments for hirsutism.
GnRH agonist
 therapy has been successful in treating 
postmenopausal women with severe ovarian hyperan
-
drogenism when laparoscopic oophorectomy is contrain
-
dicated or declined by the patient.
Goodman NF et al; American Association of Clinical Endocri
-
nologists (AACE); American College of Endocrinology 
(ACE); Androgen Excess and PCOS Society (AES). Guide to 
the best practices in the evaluation and treatment of polycys
-
tic ovary syndrome—Part 1. Endocr Pract. 2015 
Nov;21(11):1291–300. [PMID: 26509855]
-
-
tic ovary syndrome—Part 2. Endocr Pract. 2015 
Dec;21(12):1415–26. [PMID: 26642102]
McCartney CR et al. Clinical Practice. Polycystic ovary syn
-
drome. N Engl J Med. 2016 Jul 7;375(1):54–64. [PMID: 
27406348]
McMahon GT et al. Case records of the Massachusetts General 
Hospital. Case 33-2015. A 57-year-old woman with hair loss 
and deepening voice. N Engl J Med. 2015 Oct 22;373(17):
 
1660–6. [PMID: 26488697]
Moretti C et al. Combined oral contraception and bicalutamide 
in polycystic ovary syndrome and severe hirsutism—a 
double-blind RTC. J Clin Endocrinol Metab. 2018 Mar 1; 
103(3):824–38. [PMID: 29211888]
 
º
AMENORRHEA & MENOPAUSE
PRIMARY AMENORRHEA
Menarche ordinarily occurs between ages 11 and 15 years 
(average in the United States: 12.7 years) (see also 
Chapter 18). The failure of any menses to appear is termed 
“primary amenorrhea, ” and evaluation is commenced (1) at 
age 14 years if neither menarche nor any breast develop
-
ment has occurred or if height is in the lowest 3%, or (2) at 
age 16 years if menarche has not occurred.
 
»
Etiology of Primary Amenorrhea
The differential diagnoses for primary amenorrhea include 
hypothalamic-pituitary causes, hyperandrogenism, ovar
-
ian causes (gonadal dysgenesis, Müllerian dysgenesis), 
disorders of sexual development (pseudohermaphrodit
-
ism), uterine causes, and pregnancy.
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A. Hypothalamic-Pituitary Causes 
 
(With Low or Normal FSH)
The most common cause of primary amenorrhea is a vari
-
ant of normal known as constitutional delay of growth and 
puberty, which accounts for about 30% of delayed puberty 
cases. There is a strong genetic basis for this condition; 
over 50% of girls with it have a family history of delayed 
puberty. However, constitutional delay of growth and 
puberty is a diagnosis of exclusion.
A genetic deficiency of GnRH and gonadotropins may 
be isolated or associated with other pituitary deficiencies or 
diminished olfaction (Kallmann syndrome). Hypotha
-
lamic lesions, particularly craniopharyngioma, may be 
present. Pituitary tumors may be nonsecreting or may 
secrete PRL or GH. Cushing syndrome may be caused by 
corticosteroid treatment, a cortisol-secreting adrenal 
tumor, or an ACTH-secreting pituitary tumor. Hypothy
-
roidism can delay adolescence. Head trauma or encephali
-
tis can cause gonadotropin deficiency. Primary amenorrhea 
may also be caused by severe illness, vigorous exercise (eg, 
ballet dancing, running), stressful life events, dieting, or 
anorexia nervosa; however, these conditions should not be 
assumed to account for amenorrhea without a full endocri
-
nologic evaluation.
B. Uterine Causes (With Normal FSH)
Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syn
-
drome) results in a missing uterus and variable degrees of 
upper vaginal hypoplasia. It is the most common cause of 
permanent primary amenorrhea. Affected women have 
intact ovaries and undergo an otherwise normal puberty. 
Such women ovulate and fertility is possible with in vitro 
fertilization and surrogacy.
An imperforate hymen is occasionally the reason for 
the absence of visible menses.
C. Hyperandrogenism (With Low or Normal FSH)
Polycystic ovaries and ovarian tumors can secrete excessive 
testosterone. Excess testosterone can also be secreted by 
adrenal tumors or by adrenal hyperplasia caused by ste
-
roidogenic enzyme defects such as P450c21 deficiency 
(salt-wasting) or P450c11 deficiency (hypertension). 
Androgenic steroid abuse may also cause this syndrome.
D. Ovarian Causes (With High FSH)
Gonadal dysgenesis (Turner syndrome and variants) is a 
frequent cause of primary amenorrhea. Autoimmune ovar
-
ian failure is another cause. Rare deficiencies in certain 
ovarian steroidogenic enzymes are causes of primary hypo
-
gonadism without virilization: 3-beta-hydroxysteroid 
dehydrogenase deficiency (adrenal insufficiency with low 
serum 17-hydroxyprogesterone) and P450c17 deficiency 
(hypertension and hypokalemia with high serum 
17-hydroxyprogesterone). Deficiency in P450 aromatase 
(P450arom) activity produces female hypogonadism asso
-
ciated with polycystic ovaries, tall stature, osteoporosis, 
and virilization.
E. 46 XY Disorders of Sexual Development 
(Pseudohermaphroditism)
Complete androgen insensitivity syndrome
 is caused by 
homozygous inactivating mutations in the androgen recep
-
tor. 46 XY individuals with complete androgen insensitiv
-
ity syndrome are born with completely normal external 
female genitalia, although some may have labial or inguinal 
swellings due to cryptorchid testes. Affected individuals are 
phenotypic girls and experience normal breast develop
-
ment at puberty, but fail to develop sexual hair and have 
primary amenorrhea.
Partial androgen insensitivity syndrome
 in 46 XY 
individuals results in variable degrees of ambiguous genita
-
lia. Newborns have micropenis, hypospadias, and bifid 
scrotum.
F. Pregnancy (With High hCG)
Pregnancy may be the cause of primary amenorrhea even 
when the patient refutes having had sexual intercourse.
 
»
Patients with primary amenorrhea require a thorough his
-
tory and physical examination to look for signs of the 
conditions noted above. Headaches or visual field abnor
-
malities implicate a hypothalamic or pituitary tumor. Signs

-
-
malities implicate a hypothalamic or pituitary tumor. Signs 
of pregnancy may be present. Blood pressure elevation, 
acne, and hirsutism should be noted. Short stature may be 
seen with an associated GH or thyroid hormone deficiency. 
Short stature with manifestations of gonadal dysgenesis 
indicates Turner syndrome. Olfactory deficits are seen in 
Kallmann syndrome. Obesity and short stature may be 
signs of Cushing syndrome. Tall stature may be due to 
eunuchoidism or acromegaly. Hirsutism or virilization 
suggests excessive testosterone.
An external pelvic examination plus a rectal examina
-
tion should be performed to assess hymen patency and the 
presence of a uterus.
B. Laboratory and Radiologic Findings
The initial endocrine evaluation should include serum 
determinations of FSH, LH, PRL, testosterone, TSH, FT
4
, 
and beta-hCG (pregnancy test). Patients who are virilized 
or hypertensive require serum electrolyte determinations 
and further hormonal evaluation (See Hirsutism & 
Virilization, above). MRI of the hypothalamus and pitu
-
itary is used to evaluate teens with primary amenorrhea 
and low or normal FSH and LH—especially those with 
high PRL levels. Pelvic duplex/color sonography is very 
useful. Girls who have a normal uterus and high FSH with
-
out the classic features of Turner syndrome may require a 
karyotype to diagnose X chromosome mosaicism.
 
»
Treatment
Treatment of primary amenorrhea is directed at the under
-
lying cause. Girls with permanent hypogonadism are 
treated with HRT.
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Choussein S et al. Mullerian dysgenesis: a critical review of the 
literature. Arch Gynecol Obstet. 2017 Jun;295(6):1369–81. 
[PMID: 28434104]
Marsh CA et al. Primary amenorrhea: diagnosis and manage
-
ment. Obstet Gynecol Surv. 2014 Oct;69(10):603–12. [PMID: 
25336070]
SECONDARY AMENORRHEA & MENOPAUSE
Secondary amenorrhea is defined as the absence of menses 
for 3 consecutive months in women who have passed men
-
arche. Menopause is defined as the terminal episode of 
naturally occurring menses; it is a retrospective diagnosis, 
usually made after 6 months of amenorrhea.
 
»
Etiology
The causes of secondary amenorrhea include pregnancy, 
hypothalamic-pituitary causes, hyperandrogenism, uterine 
causes, premature ovarian failure, and menopause.
A. Pregnancy (High hCG)
Pregnancy is the most common cause for secondary amen
-
orrhea in premenopausal women. The differential diagno
-
sis includes rare ectopic secretion of hCG by a 
choriocarcinoma or bronchogenic carcinoma.
B. Hypothalamic-Pituitary Causes 
 
The hypothalamus must release GnRH in a pulsatile man
-
ner for the pituitary to secrete gonadotropins. GnRH 
pulses occurring more than once per hour favor LH secre
-
tion, while less frequent pulses favor FSH secretion. In 
normal ovulatory cycles, GnRH pulses in the follicular 
phase are rapid and favor LH synthesis and ovulation; 
ovarian luteal progesterone is then secreted that slows 
GnRH pulses, causing FSH secretion during the luteal 
phase. Most women with hypothalamic amenorrhea have a 
persistently low frequency of GnRH pulses.
Secondary “hypothalamic” amenorrhea may be caused 
by stressful life events such as school examinations or 
leaving home. Such women usually have a history of nor
-
mal sexual development and irregular menses since men
-
arche. Amenorrhea may also be the result of strict dieting, 
vigorous exercise, organic illness, or anorexia nervosa. 
Intrathecal infusion of opioids causes amenorrhea in 
most women. These conditions should not be assumed to 
account for amenorrhea without a full physical and endo
-
crinologic evaluation. Y oung women in whom the results 
of evaluation and progestin withdrawal test are normal 
have noncyclic secretion of gonadotropins resulting in 
anovulation. Such women typically recover spontane
-
ously but should have regular evaluations and a progestin 
withdrawal test about every 3 months to detect loss of 
estrogen effect.
PRL elevation due to any cause may cause amenorrhea. 
Pituitary tumors or other lesions may cause hypopituita
-
rism. Corticosteroid excess of any cause suppresses 
gonadotropins.
C. Hyperandrogenism (With Low-Normal FSH)
Elevated serum levels of testosterone can cause hirsutism, 
virilization, and amenorrhea. In PCOS, GnRH pulses are 
persistently rapid, favoring LH synthesis with excessive 
androgen secretion; reduced FSH secretion impairs follicu
-
lar maturation. Progesterone administration can slow the 
GnRH pulses, thus favoring FSH secretion that induces 
follicular maturation. Rare causes of secondary amenor
-
rhea include adrenal P450c21 deficiency, ovarian or adre
-
nal malignancies, and Cushing syndrome. Anabolic 
steroids also cause amenorrhea.
D. Uterine Causes (With Normal FSH)
Infection of the uterus commonly occurs following deliv
-
ery or D&C but may occur spontaneously. Endometritis 
due to tuberculosis or schistosomiasis should be suspected 
in endemic areas. Endometrial scarring may result, causing 
amenorrhea (Asherman syndrome). Such women typically 
continue to have monthly premenstrual symptoms. The 
vaginal estrogen effect is normal.
E. Early and Premature Menopause 
 
(With High FSH)
Early menopause
 refers to primary ovarian failure that 
occurs before age 45. It affects approximately 5% of 
women. About 1% of women experience 
premature 
menopause
 that is defined as ovarian failure before age 
40; about 30% of such cases are due to autoimmunity

premature 
menopause
40; about 30% of such cases are due to autoimmunity 
against the ovary. X chromosome mosaicism accounts for 
8% of cases of premature menopause. Other causes 
include surgical bilateral oophorectomy, radiation ther
-
apy for pelvic malignancy, and chemotherapy. Women 
who have undergone hysterectomy are prone to prema
-
ture ovarian failure even though the ovaries were left 
intact. Myotonic dystrophy, galactosemia, and mumps 
oophoritis are additional causes. Early or premature 
menopause is frequently familial. Ovarian failure is usu
-
ally irreversible.
F. Normal Menopause (With High FSH)
Normal menopause
occurs after age 45. “Climacteric” is defined as the period 
of natural physiologic decline in ovarian function, gener
-
ally occurring over about 10 years. By about age 40 years, 
the remaining ovarian follicles are those that are the least 
sensitive to gonadotropins. Increasing titers of FSH are 
required to stimulate estradiol secretion. Estradiol levels 
may actually rise during early climacteric.
The normal age for menopause in the United States 
ranges between 48 and 55 years, with an average of about 
51.5 years. Serum estradiol levels fall and the remaining 
estrogen after menopause is estrone, derived mainly from 
peripheral aromatization of adrenal androstenedione. 
Such peripheral production of estrone is enhanced by 
obesity and liver disease. Individual differences in estrone 
levels partly explain why the symptoms noted above may 
be minimal in some women but severe in others.
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»
See Chapter 18 for symptoms and signs of the Menopausal 
Syndrome. Women with premature menopause (before age 
45 years), compared to women with normal menopause, 
have an 50% increased risk of coronary disease, a 23% 
increased risk for stroke, and a 12% increased overall 
mortality.
A careful pelvic examination is useful to check for 
uterine or adnexal enlargement and to obtain a Papanico
-
laou smear and a vaginal smear for assessment of estrogen 
effect. Vulvovaginal complaints are not always due to 
estrogen deficiency and direct inspection of the vulva is 
necessary to detect other conditions, such as lichen sclero
-
sis, contact dermatitis, squamous hyperplasia, or 
1. Premature amenorrhea—
An elevated hCG over
-
whelmingly indicates pregnancy; false-positive testing 
may occur very rarely with ectopic hCG secretion (eg, 
choriocarcinoma or bronchogenic carcinoma). Further 
laboratory evaluation for women who are not pregnant 
includes serum PRL, FSH, LH, and TSH. Hyperprolac
-
tinemia or hypopituitarism (without obvious cause) 
should prompt an MRI study of the pituitary region. Rou
-
tine testing of kidney and liver function (BUN, serum 
creatinine, bilirubin, alkaline phosphatase, and alanine 
aminotransferase) is also performed. A serum testosterone 
level is obtained in hirsute or virilized women. Patients 
with manifestations of hypercortisolism receive a 1-mg 
overnight dexamethasone suppression test for initial 
screening. Nonpregnant women without any laboratory 
abnormality may receive a 10-day course of a progestin 
(eg, medroxyprogesterone acetate, 10 mg/day); absence of 
withdrawal menses typically indicates a lack of estrogen or 
a uterine abnormality.
2. Typical menopause—
No laboratory testing is required 
to diagnose menopause, when amenorrhea occurs at the 
expected age. The expected age of menopause correlates 
with a woman’s mother’s age at menopause and varies 
among different kindreds and ethnic groups. An elevated 
serum FSH with a low or low-normal serum estradiol helps 
confirm the diagnosis.
 
»
Treatment
See Menopausal Syndrome, Chapter 18. Women with night 
sweats should sleep in a cool room and avoid the use of 
down comforters. They can try avoiding triggers for hot 
flushes, such as smoking, alcohol, caffeine, and hot spicy 
foods. Slow, deep breathing can ameliorate hot flushes. 
Aerobic training
 for 50 minutes four times weekly reduced 
all menopausal symptoms except vaginal dryness in a ran
-
domized controlled trial. 
Clinical hypnosis
 reduced hot 
flushes over 12 weeks in one study. Acupuncture may help 
alleviate symptoms in some women. Vaginal lubricants can 
be used daily or 2 hours prior to intercourse.
A. Non-Estrogen Medications
For women with severe hot flushes who cannot take estro
-
gen, SSRIs may offer modest relief effective within a week; 
escitalopram (10–20 mg/day) can reduce hot flushes sig
-
nificantly, but must not be used by women taking tamoxi
-
fen for breast cancer, since it inhibits its metabolism to its 
active metabolite. Venlafaxine extended release (75 mg/
day) may also be effective and does not have a drug interac
-
tion with tamoxifen. Sexual dysfunction has not been as 
significant with the latter drugs when used for vasomotor 
symptoms, compared to their use for depression. Gabapen
-
tin is also quite effective in oral doses titrated up to 200–
800 mg every 8 hours. Side effects such as drowsiness, 
fatigue, dizziness, and headache, which are most pro
-
nounced during the first 2 weeks of therapy, often improve 
within 4 weeks. An herb, black cohosh, may possibly 
relieve hot flushes. Tamoxifen and raloxifene offer bone 
protection but aggravate hot flushes. Women with low 
serum testosterone levels may experience hypoactive sex
-
ual desire disorder that may respond to low-dose testoster
-
one replacement.
B. Estrogen Replacement Therapy

-
-
Overall survival
 is improved among women who begin 
HRT before age 60 or within 10 years of menopause. How
-
ever, no survival advantage was found in older women, 
according to a meta-analysis of 43 randomized controlled 
trials. Specifically, HRT does not increase the risk of car
-
diac death or stroke. 
Breast cancer risk
 is increased among 
women taking combined daily estrogen and progestin 
HRT. Women taking estrogen alone have been variably 
found to have a decreased risk (Women’s Health Initiative, 
WHI) or an increased risk of breast cancer (California 
Teachers’ Study). 
Venous thromboembolic disease
 and 
stroke
 are increased by oral but not transdermal estrogen. 
Osteoporosis risk
 is reduced by even low-dose systemic 
estrogen replacement.
In light of these considerations, estrogen replacement is 
most commonly prescribed for women in early meno
-
pause, when symptoms are worst and the benefits are 
greatest. Transdermal estrogen is favored over oral therapy 
to reduce the risk of thromboembolism. In women with an 
intact uterus, estrogen replacement without a progestin 
risks endometrial hypertrophy and dysfunctional uterine 
bleeding. The addition of a progestin, however, increases 
the risk of breast cancer. Therefore, only the smallest effec
-
tive dose of estrogen should be used to avoid the need for 
progestins or use them in lower doses or intermittently. 
Also, progestin may be delivered directly to uterus with 
progesterone-eluting intrauterine devices. The decision to 
prescribe menopausal hormonal therapy and its type and 
duration are dictated by individual symptoms, risk profile, 
and personal preferences, while considering potential ben
-
efits and risks.
1. Benefits of HRT—
Estrogen replacement is the best treat
-
ment for hot flushes and sweats and eliminates these symp
-
toms or improves them by more than 70%, usually within 
a month. Vaginal moisture is improved and libido is 
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enhanced in some women. Estradiol vaginal rings can 
improve symptoms of an overactive bladder and vaginal 
dryness. Sleep disturbances are common in menopause 
and can be reversed with estrogen replacement. Some 
women notice a mild impairment in memory and cogni
-
tive function at menopause that may improve with HRT 
that is commenced soon after menopause. HRT does not 
reduce the risk of Alzheimer dementia. However, short-
term transdermal estradiol has been demonstrated to 
slightly improve memory in women with existent mild to 
moderate Alzheimer disease. Estrogen replacement may 
also improve the joint pains, generalized body pain, and 
reduced physical function experienced by some women at 
the time of menopause. Women with perimenopausal 
depression typically experience a significantly improved 
mood and overall sense of well-being with estrogen 
replacement. Estrogen replacement does not prevent facial 
skin wrinkling; however, it may improve facial skin mois
-
ture and thickness, reducing seborrhea and atrophy.
Estrogen replacement prevents postmenopausal osteo
-
porosis. The WHI study found that women who received 
estrogen therapy experienced a reduced number of hip 
fractures (six fewer fractures/year per 10,000 women) com
-
pared with placebo. Even “microdose” transdermal estra
-
diol (0.014 mg/day) preserves bone density.
Women aged 50–59 years in the WHI who received 
estrogen alone developed significantly lower CT coronary 
calcium scores (a marker for coronary atherosclerosis) 
than women receiving placebo. In the California Teachers 
Study, HRT in women under age 60 was associated with a 
dramatic 46% reduction in all-cause mortality, particularly 
cardiovascular disease. This association of HRT and lower 
mortality may suffer from self-selection bias. Nevertheless, 
there appears to be a survival advantage of HRT that 
requires longer-term administration (more than 5 years) to 
become apparent. The survival advantage is particularly 
strong for women under age 60 and diminishes with age; 
no reduction in mortality was noted in the group of women 
aged 85–94 years. The reduction in cardiovascular disease 
among younger postmenopausal women taking HRT may 
be explained by the reduction in serum levels of athero
-
genic lipoprotein(a) with HRT, with or without a progestin. 
Improvement in serum HDL cholesterol is greatest with 
unopposed estrogen but is also seen with the addition of a 
progestin.
a. 
E
strogen replacement without progestin 
(unopposed 
HRT
)—
The WHI study reported that post
-
menopausal women taking unopposed estrogen had a 
reduction in breast cancer risk
, whereas the California 
Teachers’ Study reported an 
increase in breast cancer risk
 
among such women. Unopposed estrogen replacement 
improves glycemic control in women with type 2 diabetes 
mellitus. Perimenopause-related depression is improved by 
unopposed estrogen replacement; the addition of a proges
-
tin may negate this effect. A 20-year study of 8801 women 
living in a retirement community found that estrogen use 
was associated with improved survival. Age-adjusted mor
-
tality rates were 56.4 (per 1000 person-years) among non
-
users and 50.4 among women who had used estrogen for 
15 years or longer.
b. 
E
strogen replacement therapy with proges
tins 
(combined 
HRT
)—
Women receiving conventional-dose 
daily conjugated estrogen and medroxyprogesterone ace
-
tate (0.625 mg and 2.5 mg, respectively) for an average of 
5.6 years, experienced a lower risk of developing diabetes 
mellitus (3.5%) versus those taking a placebo (4.2%).
2. Risks of HRT—
Oral estrogen increases the risk of arterial 
and venous thrombotic events in a dose-dependent manner, 
although the absolute risk is small. The WHI study found 
that women who received long-term conventional oral com
-
bined HRT had an increased risk of deep venous thrombosis 
(3.5 per 1000 person-years) compared with women receiv
-

-
-
ing placebo (1.7 per 1000 person-years). Oral estrogen also 
increases the risk of ischemic stroke by about 30%. Oral 
estrogen causes a particularly increased risk for thromboem
-
bolic disease among older women and those with increased 
stroke proclivity (current smokers and those with hyperten
-
sion, atrial fibrillation, prior thromboembolic event). Long-
term use of oral conjugated estrogens in women over age 65 
has been associated with poorer cognitive performance, 
perhaps due to small strokes. Transdermal or vaginal estro
-
gen administration avoids this risk. Urinary stress inconti
-
nence appears to be increased by conventional-dose oral 
estrogen replacement, whereas topical vaginal estrogen may 
have a beneficial effect. Estrogen replacement may cause 
mastalgia that typically responds to dose reduction. Estro
-
gen replacement also appears to increase the risk of seizures 
in women with epilepsy. Estrogen can stimulate the growth 
of untreated large pituitary prolactinomas. Oral estrogen 
and SERMs also increase the risk of gastroesophageal reflux 
disease. Oral HRT can increase the size of hepatic heman
-
giomas, but significant enlargement is uncommon. Conven
-
tional doses of estrogen carry higher risks than lower doses. 
The risks for HRT also depend on whether estrogen is 
administered alone (unopposed HRT) or with a progestin 
(combined HRT).
a. 
E
(
unopposed
 
HRT
)—
The California Teachers’ Study 
reported an 
increased breast cancer risk
 among such women 
while the WHI study reported that postmenopausal women 
taking unopposed estrogen had a 
reduced breast cancer risk
. 
Women taking lower-dose unopposed estrogen therapy 
would be expected to have a lower long-term risk of breast 
cancer compared to women taking high-dose estrogens.
Conventional-dose unopposed conjugated estrogen 
replacement (0.625–1.25 mg daily) increases the risk of 
endometrial hyperplasia and dysfunctional uterine bleed
-
ing, which often prompts patients to stop the estrogen. 
However, lower-dose unopposed estrogen confers a much 
lower risk of dysfunctional uterine bleeding. Recurrent 
dysfunctional bleeding necessitates a pelvic examination 
and possibly an endometrial biopsy. There has been con
-
siderable concern that unopposed estrogen replacement 
might increase the risk for endometrial carcinoma. How
-
ever, a Cochrane Database Review found no increased risk 
of endometrial carcinoma in a review of 30 randomized 
controlled trials. Therefore, lower-dose unopposed estro
-
gen replacement does not appear to confer any significant 
increased risk for endometrial cancer.
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Long-term conventional-dose unopposed estrogen 
increases the mortality risk from ovarian cancer, although 
the absolute risk is small. The annual age-adjusted ovarian 
cancer death rates for women taking estrogen replacement 
for 10 years or longer are 64:100,000 for current users, 
38:100,000 for former users, and 26:100,000 for women 
who had never taken estrogen. Lower-dose estrogen 
replacement is believed to confer a negligible increased risk 
for ovarian cancer.
The risk of stroke among women taking a conventional 
dose of unopposed estrogen is increased; the risk is about 
44 strokes per 10,000 person-years versus about 32 per 
10,000 person-years in women taking placebo. Transder
-
mal or transvaginal estrogen is not thought to increase the 
risk of stroke.
Oral estrogens can cause hypertriglyceridemia, particu
-
larly in women with preexistent hyperlipidemia, rarely 
resulting in pancreatitis. Postmenopausal estrogen therapy 
also slightly increases the risk of gallstones and cholecysti
-
tis. These side effects may be reduced or avoided by using 
transdermal or vaginal estrogen replacement.
b. 
E
strogen replacement with a progestin 
 
(com
bined 
HRT
)
—
Long-term conventional-dose oral 
combined HRT increases breast density and the risk for 
abnormal mammograms (9.4% versus 5.4% for placebo). 
There is also a higher risk of breast cancer (8 cases per 
10,000 women/year versus 6.5 cases per 10,000 women/year 
for placebo); the increased risk of breast cancer is highest 
shortly after menopause (about 2 cases per 1000 women 
annually). This increased risk for breast cancer appears to 
mostly affect relatively thin women with a BMI less than 
24.4. The Iowa Women’s Health Study reported an increase 
in breast cancer with HRT only in women consuming more 
than 1 oz of alcohol weekly. No accelerated risk of breast 
cancer has been seen in users of HRT who have benign 
breast disease or a family history of breast cancer. Women 
in whom new-onset breast tenderness develops with com
-
bined HRT have an increased risk of breast cancer, com
-
pared with women without breast tenderness.
The Women’s Health Initiative Mental Study (WHIMS) 
followed the effect of combined conventional-dose oral 
HRT on cognitive function in women 65–79 years old. 
HRT did not protect these older women from cognitive 
decline. In fact, they experienced an increased risk for 
severe dementia at a rate of 23 more cases/year for every 
10,000 women over age 65 years. It is unknown whether 
this finding applies to younger postmenopausal women.
In the WHI study, women receiving conventional-dose 
combined oral HRT experienced an increased risk of 
stroke (31 strokes per 10,000 women/year versus 26 strokes 
per 10,000 women/year for placebo). Stroke risk was also 
increased by hypertension, diabetes, and smoking.
Women taking combined oral estrogen–progestin 
replacement do not experience an increased risk of ovarian 
cancer. They do experience a slightly increased risk of 
developing asthma.
Progestins may cause moodiness, particularly in women 
with a history of premenstrual dysphoric disorder. Cycled 
progestins may trigger migraines in certain women. Many 
other adverse reactions have been reported, including breast 
tenderness, alopecia, and fluid retention. Contraindications 
to the use of progestins include thromboembolic disorders, 
liver disease, breast cancer, and pregnancy.
3. HRT agents—
Hormone replacement needs to be indi
-
vidualized. Ideally, in women with an intact uterus, very 
low-dose transdermal estradiol may be used alone or with 
intermittent progestin or a progesterone-eluting intrauter
-
ine device, in order to reduce the risk of endometrial 
hyperplasia, while avoiding the need for daily oral proges
-
tin. Vaginal estrogen can be added if low-dose systemic 
estradiol replacement is insufficient to relieve symptoms of 
vulvovaginal atrophy. Women who have had a hysterec
-

-
-
tomy may receive transdermal estrogen at whatever is the 
lowest dose that adequately relieves symptoms. However, 
some women cannot find sufficient relief with transdermal 
estradiol and must use an oral preparation.
a. 
T
ransdermal estradiol—
Estradiol can be delivered 
systemically with different systems of skin patches, mists, 
or gels. Transdermal estradiol works for most women, but 
some women have poor transdermal absorption. If a 
woman has a skin reaction to an estradiol patch, then a gel 
or mist may be tried at different doses until the ideal for
-
mulation is found.
(1) Estradiol patches mixed with adhesive—
These systems 
tend to cause minimal skin irritation. Generic estradiol trans
-
dermal is available as a patch that is replaced biweekly (0.025, 
0.0375, 0.05, 0.075, 0.1 mg/day) or weekly (0.025, 0.0375, 0.05, 
0.06, 0.075, 0.1 mg/day). Brand products include: Vivelle-Dot 
(0.025) or Minivivelle (0.0375, 0.05, 0.075, or 0.1 mg/day) or 
Alora (0.025, 0.05, 0.075, or 0.1 mg/day), replaced twice 
weekly; Climara (0.025, 0.0375, 0.05, 0.06, 0.075, or 
0.1 mg/day), replaced weekly; and Menostar (0.014 mg/day), 
replaced weekly. This type of estradiol skin patch can be cut in 
half and applied to the skin without proportionately greater 
loss of potency. Minivivelle patches are the smallest. 
(2) Estradiol mists and gels—
Evamist is available as a 
topical mist dispenser that dispenses 1.53 mg estradiol/
spray; 1–3 sprays are applied to the inner forearm daily; a 
single daily spray may provide sufficiently low-dose estra
-
diol to possibly obviate the need for daily progestin in 
women with an intact uterus. EstroGel 0.06% is available in 
a metered-dose pump that dispenses 1.25 g gel per actuation 
(dose: half to 2 actuations/day). Elestrin 0.06% is available in 
a metered-dose pump that dispenses 0.87 g gel per activa
-
tion (dose: half to 2 actuations/day). These gels are applied 
daily to one arm from the wrist to the shoulder after bathing. 
Divigel 0.1% gel (0.25, 0.5, 1 g/packet) is applied to the upper 
thigh daily. Estrasorb 2.5% is available in 1.74-g pouches 
(4.35 mg estradiol); 1–2 pouches of lotion are applied to the 
thigh/calf daily. To avoid spreading topical estradiol to oth
-
ers, the hands should be washed and precautions taken to 
avoid prolonged skin contact with children. Application of 
sunscreen prior to estradiol gel has been reported to 
increase
 
the transdermal absorption of estradiol.  
(3) Estradiol patches with progestin mixed with adhesive— 
These preparations mix estradiol with either norethin
-
drone acetate or levonorgestrel. Combipatch (0.05 mg E 
with 0.14 mg norethindrone acetate daily or 0.05 mg E with 
0.25 mg norethindrone acetate daily) is replaced twice 
CMDT19_Ch26_p1119-p1219.indd   1213

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 CMDT 2019
weekly. Climara Pro (0.045 mg E with 0.015 mg levonorg
-
estrel daily) is replaced once weekly. The addition of a 
progestin reduces the risk of endometrial hyperplasia, but 
breakthrough bleeding occurs commonly. The combined 
patch increases the risk of breast cancer. Scalp hair loss, 
acne, weight gain, skin reactions, and poor skin adherence 
have been reported with these patches.
b. Oral estrogen— 
(1) Oral estrogen-only preparations—
These prepara
-
tions include conjugated equine estrogens that are available 
as Premarin (0.3, 0.45, 0.625, 0.9, and 1.25 mg), conjugated 
plant-derived estrogens (eg, Menest, 0.3, 0.625, and 
2.5 mg), and conjugated synthetic estrogens that are avail
-
able as Cenestin (0.3, 0.45, 0.625, 0.9, and 1.25 mg) and 
Enjuvia (0.3, 0.45, 0.625, 0.9, and 1.25 mg). Other prepara
-
tions include estradiol (0.5, 1, and 2 mg), and estropipate 
(0.75, 1.5, and 3 mg).
(2) Oral estrogen plus progestin preparations—
 
Conjugated equine estrogens with medroxyprogesterone 
acetate is available as Prempro (0.3/1.5, 0.45/1.5, 0.625/2.5, 
and 0.625 mg/5 mg); conjugated equine estrogens for 
14 days cycled with conjugated equine estrogens plus 
medroxyprogesterone acetate for 14 days is available as 
Premphase (0.625/0, then 0.625 mg/5 mg); estradiol with 
norethindrone acetate (0.5/0.1 and 1 mg/0.5 mg); ethinyl 
estradiol with norethindrone acetate is available as Femhrt 
(2.5/0.5 and 5 mcg/1 mg) and Jinteli (5 mcg/1 mg); estradiol 
with drospirenone is available as Angeliq (0.5 mg/0.25 mg, 
and 1.0 mg/0.5 mg); estradiol with norgestimate is available 
as Prefest (estradiol 1 mg/day for 3 days, alternating with 
1 mg estradiol/0.09 mg norgestimate daily for 3 days). Oral 
contraceptives can also be used for combined HRT.
c. 
V
aginal estrogen
—
Vaginal estrogen is intended to 
deliver estrogen directly to local tissues and is moderately 
effective in reducing symptoms of urogenital atrophy, 
while minimizing systemic estrogen exposure. Some estro
-
gen is absorbed systemically and can relieve menopausal 
symptoms. Manufacturers recommend that these prepara
-
tions be used for only 3–6 months in women with an intact 
uterus, since vaginal estrogen can cause endometrial prolif
-
eration. However, most clinicians use them for longer 
periods. Vaginal estrogen can be administered in three 
different ways: creams, tablets, and rings.
(1) Estrogen vaginal creams—
These creams are admin
-
istered intravaginally with a measured-dose applicator 
daily for 2 weeks for atrophic vaginitis, then administered 
one to three times weekly. Available preparations include 
conjugated equine estrogens, which is available as Prema
-
rin Vaginal (0.625 mg/g cream), dosed as 0.25–2 g cream 
administered vaginally one to three times weekly. Estradiol 
is available as Estrace Vaginal (0.1 mg/g cream), 1 g cream 
administered vaginally one to two times weekly. 
(2) Estradiol vaginal tablets—
These tablets are sold pre
-
packaged in a disposable applicator and can be adminis
-
tered deep intravaginally daily for 2 weeks for atrophic 
vaginitis, then twice weekly. The tablets dissolve into a gel 
that gradually releases estradiol. This preparation is avail
-
able as Vagifem (10 mcg/tablet), administered vaginally 
two times weekly. 
(3) Estradiol vaginal rings—
These rings are inserted 
manually into the upper third of the vagina, worn continu
-
ously, and replaced every 3 months. Only a small amount 
of the released estradiol enters the systemic circulation. 
Vaginal rings do not usually interfere with sexual inter
-
course. If a ring is removed or descends into the introitus, 
it may be washed in warm water and reinserted. 
Estring
 
(2 mg estradiol/ring) releases estradiol 7.5 mcg/day with 
only 8% entering the systemic circulation, resulting in 
mean serum estradiol concentrations of only about 
10 pg/mL; it is most effective for local vaginal symptoms. 
Femring

Femring
 releases estradiol acetate that is quickly hydro
-
lyzed to estradiol and is available in two strengths: 12.4 mg/
ring releases estradiol acetate 0.05 mg/day or 24.8 mg/ring 
releases estradiol acetate 0.1 mg/day, resulting in mean 
serum estradiol concentrations of about 40 pg/mL and 
80 pg/mL, respectively; it is effective for both systemic and 
local vaginal symptoms. Both rings are replaced every 
90 days. For women with postmenopausal urinary urgency 
and frequency, even the low-dose Estring can successfully 
reduce urinary symptoms. 
(4) Estradiol with progestin vaginal rings—
The avail
-
able preparation is NuvaRing that releases a mixture of 
ethinyl estradiol 0.015 mg/day and etonogestrel 
0.12 mg/day. It is a contraceptive vaginal ring that is placed 
in the vagina on or before day 5 of the menstrual cycle, left 
for 3 weeks, removed for 1 week, and then replaced.
d. 
E
stradiol injections—
Parenteral estradiol should 
be used only for particularly severe menopausal symptoms 
when other measures have failed or are contraindicated. 
Estradiol cypionate (Depo-Estradiol 5 mg/mL) may be 
administered intramuscularly in doses of 1–5 mg every 
3–4 weeks. Estradiol valerate (20 or 40 mg/mL) may be 
administered intramuscularly in doses of 10–20 mg every 
4 weeks. Women with an intact uterus should receive pro
-
gestin for the last 10 days of each cycle.
e. 
O
ral progestins—
For a woman with an intact uterus, 
long-term conventional-dose unopposed systemic estro
-
gen therapy can cause endometrial hyperplasia, which 
typically results in dysfunctional uterine bleeding and 
might rarely lead to endometrial cancer. Progestin therapy 
transforms proliferative into secretory endometrium, caus
-
ing a possible menses when given intermittently or no 
bleeding when given continuously.
The type of progestin preparation, its dosage, and the 
timing of administration may be tailored to the given situ
-
ation. Progestins may be given daily, monthly, or at longer 
intervals. When given episodically, progestins are usually 
administered for 7–14 day periods. Bedtime administra
-
tion may improve sleep. Some women find that progestins 
produce adverse effects, such as irritability, nausea, fatigue, 
or headache; long-term progestins given with estrogen 
replacement increase the risk for breast cancer.
Oral progestins are available in different formulations: 
Micronized progesterone (100 mg and 200 mg/capsule), 
medroxyprogesterone (2.5, 5.0, and 10 mg/tablet), noreth
-
indrone acetate (5 mg/tablet), and norethindrone 
(0.35 mg/tablet). Topical progesterone (20–50 mg/day) 
may reduce hot flushes in women who are intolerant to 
CMDT19_Ch26_p1119-p1219.indd   1214

1215
 
CMDT 2019
oral HRT. It may be applied to the upper arms, thighs, or 
inner wrists daily. It may be compounded as micronized 
progesterone 250 mg/mL in a transdermal gel. Its effects 
upon the breast and endometrium are unknown. Proges
-
terone is also available as vaginal gels (eg, Prochieve, 4% = 
45 mg/applicatorful, and 8% = 90 mg/applicatorful) that 
are typically given for secondary amenorrhea and adminis
-
tered vaginally every other day for six doses.
f. 
P
rogestin-releasing intrauterine devices—
Intrauterine devices that release progestins can be useful 
for women receiving ERT, since they can reduce the inci
-
dence of dysfunctional uterine bleeding and endometrial 
carcinoma without exposing women to the significant risks 
of systemic progestins. The Mirena intrauterine device 
releases levonorgestrel and is inserted into the uterus by a 
clinician within 7 days of the onset of menses. It is equally 
effective at reducing endometrial hyperplasia as cycled 
medroxyprogesterone acetate and is associated with less 
hirsutism. It remains effective for up to 5 years. Parous 
women are generally better able to tolerate the Mirena 
intrauterine device than nulliparous women.
g. 
S
elective estrogen receptor modulators
—
SERMs (eg, raloxifene, ospemifene, tamoxifen) are an alter
-
native to estrogen replacement for hypogonadal women at 
risk for osteoporosis who prefer not to take estrogens 
because of their contraindications (eg, breast or uterine 
cancer) or side effects (see Osteoporosis, above). Raloxifene 
(Evista) does not reduce hot flushes, vaginal dryness, skin 
wrinkling, or breast atrophy; it does not improve cognition. 
However, in doses of 60 mg/day orally, it inhibits bone loss 
without stimulating effects upon the breasts or endome
-
trium. Raloxifene does not stimulate the endometrium and 
actually reduces the risk of endometrial carcinoma, so con
-
comitant progesterone therapy is not required. Another 
advantage to raloxifene is that it reduces the risk of invasive 
breast cancer by about 50%. Raloxifene slightly increases 
the risk of venous thromboembolism (though less so than 
tamoxifen), so it should not be used by women at prolonged 
bed rest or otherwise prone to thrombosis. Ospemifene 
(Osphena) is a SERM that has unique estrogen-like effects 
on the vaginal epithelium and is indicated for the treatment 
of postmenopausal dyspareunia when other therapies are 
ineffective. Given orally in doses of 60 mg/day, it commonly 
aggravates hot flushes, increases the risks of thromboembo
-
lism, and increases endometrial hyperplasia. Ospemifene 
has unknown long-term effects upon bone and breast.
Tibolone (Livial) is a SERM whose metabolites have 
mixed estrogenic, progestogenic, and weak androgenic 
activity. It is comparable to HRT for the treatment of cli
-
macteric-related complaints. It does not appear to signifi
-
cantly stimulate proliferation of breast or endometrial 
tissue. It depresses both serum triglycerides and HDL 
cholesterol. Long-term studies are lacking. It is not avail
-
able in the United States.
h. 
T
estosterone replacement therapy in women—
In premenopausal women, serum testosterone levels decline 
with age. Between 25 and 45 years of age, women’s testoster
-
one levels fall 50%. After natural menopause, the ovaries 
remain a significant source for testosterone and serum tes
-
tosterone levels do not fall abruptly. In contrast, very low 
serum testosterone levels are found in women after bilateral 
oophorectomy, autoimmune ovarian failure, or adrenalec
-
tomy, and in hypopituitarism. Testosterone deficiency con
-
tributes to hot flushes, loss of sexual hair, muscle atrophy, 
osteoporosis, and diminished libido, also known as hypoac
-
tive sexual desire disorder (see Chapter 25). 
Flibanserin
 is 
a centrally active neurotransmitter disinhibitor that is mod
-
estly effective for treating premenopausal women with

-
 is 
-
estly effective for treating premenopausal women with 
acquired hypoactive sexual desire disorder. It is adminis
-
tered orally 100 mg at bedtime; side effects may include 
hypotension, appendicitis, nausea, xerostomia, sleep disor
-
ders, and fatigue. Selected women may be treated with low-
dose testosterone. Methyltestosterone can be compounded 
into capsules and taken orally in doses of 1.25–2.5 mg daily. 
Testosterone can also be compounded as a cream contain
-
ing 1 mg/mL, with 1 mL applied to the abdomen daily. 
Methyltestosterone also is available combined with esteri
-
fied estrogens: 1.25 mg methyltestosterone/0.626 mg esteri
-
fied estrogens or 2.5 mg methyltestosterone/1.25 mg 
esterified estrogens. The latter formulations are convenient 
but carry the same disadvantages as oral estrogen—
particularly an increased risk of thromboembolism.
Women receiving testosterone therapy must be moni
-
tored for the appearance of any acne or hirsutism, and 
serum testosterone levels are determined periodically if 
women feel that they are benefitting and long-term testos
-
terone therapy is instituted. Side effects of low-dose testos
-
terone therapy are usually minimal but may include 
erythrocytosis, emotional changes, hirsutism, acne, an 
adverse effect on lipids, and potentiation of warfarin anti
-
coagulation therapy. Testosterone therapy tends to reduce 
both triglyceride and HDL cholesterol levels. Hepatocellu
-
lar neoplasms and peliosis hepatis, rare complications of 
oral androgens at higher doses, have not been reported 
with oral methyltestosterone doses of 2.5 mg or less daily.
Vaginal testosterone
 is an option for postmenopausal 
women who cannot use systemic or vaginal estrogen due to 
breast cancer. Testosterone 150–300 mcg/day vaginally 
appears to reduce vaginal dryness and dyspareunia without 
increasing systemic estrogen levels.
Caution:
 
Androgens should not be given to women with 
liver disease or during pregnancy or breastfeeding.
 Testoster
-
one replacement therapy for women should be used judi
-
ciously, since long-term prospective clinical trials are 
lacking. An analysis of the Nurses’ Health Study found that 
women who had been taking conjugated equine estrogens 
plus methyltestosterone experienced an increased risk of 
breast cancer, so breast cancer screening is recommended.
-
-
Benkhadra K et al. Menopausal hormone therapy and mortality: 
a systematic review and meta-analysis. J Clin Endocrinol 
Metab. 2015 Nov;100(11):4021–8. [PMID: 26544652]
Gordon CM et al. Update on primary ovarian insufficiency in 
adolescents. Curr Opin Pediatr. 2015 Aug;27(4):511–9. 
[PMID: 26087426]
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HAPTER
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Kaunitz AM et al. Management of menopausal symptoms. 
Obstet Gynecol. 2015 Oct;126(4):859–76. [PMID: 26348174]
Lovre D et al. Effect of menopausal hormone therapy on compo
-
nents of the metabolic syndrome. Ther Adv Cardiovasc Dis. 
2016 May;11(1):33–43. [PMID: 27234158]
Manson JE et al. Menopause management—getting clinical care 
back on track. N Engl J Med. 2016 Mar 3;374(9):803–6. 
[PMID: 26962899]
Muka T et al. Association of age at onset of menopause and time 
since onset of menopause with cardiovascular outcomes, 
intermediate vascular traits, and all-cause mortality: a sys
-
tematic review and meta-analysis. JAMA Cardiol. 2016 
Oct;1(7):767–76. [PMID: 27627190]
Santoro N et al. Menopausal symptoms and their management. 
Endocrinol Metab Clin North Am. 2015 Sep;44(3):497–515. 
[PMID: 26316239]
TURNER SYNDROME (
Gonadal Dysgenesis
)
 
»
Short stature with normal GH levels.
 
»
Primary amenorrhea or early ovarian failure.
 
»
Epicanthal folds, webbed neck, short fourth 
metacarpals.
 
»
Renal and cardiovascular anomalies.
Turner syndrome comprises a group of X chromosome 
disorders that are associated with spontaneous abortion, 
primary hypogonadism, short stature, and other phenotypic 
anomalies (Table 26–15). It affects 1–2% of fetuses, of which 
about 97% abort, accounting for about 10% of all spontane
-
ous abortions. Nevertheless, it affects about 1 in every 2500 
live female births. Patients with the classic syndrome (about 
50% of cases) lack one of the two X chromosomes (45,XO 
karyotype). About 12% of patients harbor mosaicism for Y 
chromosome sequences. Other patients with Turner syn
-
drome have X chromosome abnormalities, such as ring X or 
Xq (X/abnormal X) or X chromosome deletions affecting all 
or some somatic cells (mosaicism, XX/XO).
1. Classic Turner Syndrome 
 
(45,XO Gonadal Dysgenesis)
 
»
Features of Turner syndrome are variable and may be sub
-
tle in girls with mosaicism. Turner syndrome may be diag
-
nosed in infant girls at birth, since they tend to be small 
and may exhibit severe lymphedema. Evaluation for child
-
hood short stature often leads to the diagnosis. Girls and 
women with Turner syndrome have an increased risk of 
aortic coarctation (11%) and bicuspid aortic valves (16%); 
these cardiac abnormalities are more common in patients 
with a webbed neck. If a woman with Turner syndrome 
becomes pregnant, there is a 2% risk of death from aortic 
Table 26–15.
 
Manifestations of Turner syndrome.
Short stature (98%)
 
Head and 
neck features
 
H
igh-arched palate (35%)
 
L
ow posterior hairline (40%)
 
M
icrognathia (60% small 
 
mandible)
 
P
terygium colli (40% webbed 
 
neck)
Eye abnormalities
Cataracts, corneal opacities
Epicanthal folds (20%), stra
-
bismus (15%), ptosis (10%)
Gonadal abnormalities
Gonadal dysgenesis (primary 
amenorrhea 80%) or early 
ovarian failure (20%)
Skeletal and extremity 
Broad (shield) chest (30%) 
with wide-spaced 
hypoplastic nipples
Cubitus valgus of arms (50%) 
and Genu valgum of legs 
(35% knock knees)
Lymphedema of hands and 
feet (30%)
Madelung wrist deformity 
(5%)
Osteopenia (65%)
Scoliosis (10%)
Short fourth metacarpals 
(40%)
Ear abnormalities
Conductive hearing loss 
(30%) and recurrent otitis 
media (60%)
Low-set and posteriorly 
rotated ears
Cardiovascular anomalies
Aortic dilation or aneurysm 
(25%, higher with bicuspid 
aortic valve)
Bicuspid aortic valve (25%) 
with aortic stenosis or 
Coarctation (14%) and 
cystic medial necrosis of 
the aorta
Hypertension (50%, idio
-
pathic or due to coarcta
-
tion or kidney disease)
 
P
artial anomalous pulmonary 
 
v
enous return (18%)
Gastrointestinal disorders
Achlorhydria
Celiac disease (8%)
Colon carcinoma
Hepatic transaminases 
elevated (65%)
 
disease (3%)
 
T
elangiectasias with bleeding
Kidney abnormalities (60%)
 
Horseshoe k
idney (10%),

T
 
idney (10%), 
 
duplica
tion or abnormal 
 
positioning of renal pelvis 
 
or ureters (15%)
disorders
Emotional immaturity (40%)
Learning disabilities and 
attention deficit/
hyperactivity disorder 
(40%)
Sensorineural hearing loss
Skin and nail disorders
Hyperconvex nails
Keloid formation (eg, surgical 
scars or after ear piercing)
Pigmented nevi
Diabetes mellitus (10%) 
 
or glucose intolerance 
(35%)
Neuroblastoma (1%)
Obesity
dissection or rupture. Typical manifestations in adulthood 
include short stature, hypogonadism, webbed neck, high-
arched palate, wide-spaced nipples, hypertension, and 
kidney abnormalities (Table 26–15). Emotional disorders 
are common. Affected women are also more prone to auto
-
immune disease, particularly thyroiditis (37%), inflamma
-
tory bowel disease (4%), and celiac disease (3%).
Hypogonadism presents as “delayed adolescence” (pri
-
mary amenorrhea, 80%) or early ovarian failure (20%); 
girls with 45,XO Turner (blood karyotyping) who enter 
puberty are typically found to have mosaicism if other tis
-
sues are karyotyped.
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CMDT 2019
Hypogonadism is confirmed in girls who have high serum 
levels of FSH and LH. A blood karyotype showing 45,XO 
(or X chromosome abnormalities or mosaicism) estab
-
lishes the diagnosis. GH and IGF-1 levels are normal.
C. Imaging
A transthoracic ultrasound and MRI scan of the chest and 
abdomen should be done in all patients with Turner syn
-
drome to determine whether cardiac, aortic, and renal 
abnormalities are present.
 
»
Treatment
For short stature, GH therapy should be started early, ideally 
by age 4–6 and before age 12 years. GH is given subcutane
-
ously in doses of 50 mcg/kg/day or 4.5 international units/
m
2
/day; the GH dose is titrated to keep the serum IGF-I 
levels within 3 SD above the mean for age. Rarely, GH treat
-
ment causes pseudotumor cerebri. The oral androgen oxan
-
drolone (0.03–0.05 mg/kg/day) is added after age 10 for girls 
whose growth is inadequate with GH therapy alone. After 
age 12 years, estrogen therapy is begun with low doses of 
transdermal estradiol, with a gradual increase in dose over 
2–3 years. Progesterone is added after 2 years of estrogen 
therapy or if menstrual bleeding occurs. For girls age 
12 years or older with Turner mosaicism and spontaneous 
menses, early oocyte retrieval and cryopreservation should 
be considered, while weighing the risks of pregnancy.
 
»
Complications & Surveillance
Bicuspid aortic valves are associated with an increased risk 
of infective endocarditis, aortic valvular stenosis or regur
-
gitation, and ascending aortic aneurysm and dissection. 
Partial anomalous pulmonary vein connections occur in 
13% and can lead to left-to-right shunting of blood. Adults 
with Turner syndrome have a high incidence of ECG 
abnormalities.
Women with Turner syndrome have a reduced life 
expectancy due in part to their increased risk of diabetes 
mellitus (types 1 and 2), hypertension, dyslipidemia, and 
Diagnostic vigilance and aggressive treatment of these 
conditions reduce the risk of aortic aneurysm dissection, 
ischemic heart disease, stroke, and fracture. Patients are 
prone to keloid formation after surgery or ear piercing. 
Y early ocular examinations and periodic thyroid evalua
-
tions are recommended.
Repeat cardiovascular evaluations should be done every 
3–4 years. Patients with the classic 45,XO karyotype have a 
high risk of renal structural abnormalities, whereas those 
with 46 X/abnormal X are more prone to malformations of 
the urinary collecting system. The risk of aortic dissection is 
increased more than 100-fold in women with Turner syn
-
drome, particularly those with pronounced neck webbing 
and shield chest. Patients with aortic root enlargement are 
usually treated with beta-blockade and serial imaging. 
About 5% of women with Turner syndrome experience 
natural pregnancy and even more can become pregnant 
with oocyte donation. Such pregnancies are very high-risk, 
with high rates of fetal morbidity, preeclampsia, and aortic 
dissection. Women are usually advised to deliver via cesar
-
ean section because of the risk of aortic aneurysm rupture 
during vaginal delivery.
2. Turner Syndrome Variants
A. 46,X (Abnormal X) Karyotype
Patients with small distal short arm deletions of the X chro
-
mosome (Xp-) that include the 
SHOX
 gene often have short 
stature and skeletal abnormalities but have a low risk of 
ovarian failure. Transmission of Turner syndrome from 
mother to daughter can occur. There may be an increased 
risk of trisomy 21 in the conceptuses of women with Turner 
syndrome. Patients with deletions of the long arm of the X 
chromosome (distal to Xq24) often have amenorrhea with
-
out short stature or other features of Turner syndrome. 
Abnormalities or deletions of other genes located on both 
the long and short arms of the X chromosome can produce 
gonadal dysgenesis with few other somatic features.
B. 45,XO/46,XX and 45,XO/46,XY Mosaicism

45,XO/46,XX mosaicism results in a modified form of 
Turner syndrome. Such girls tend to be taller and may have 
more gonadal function and fewer other manifestations of 
Turner syndrome.
45,XO/46,XY mosaicism can produce some manifesta
-
tions of Turner syndrome. Patients may have ambiguous 
genitalia or male infertility with an otherwise normal phe
-
notype. Germ cell tumors, such as gonadoblastomas and 
seminomas, develop in about 10% of patients with 
45,XO/46,XY mosaicism; most such tumors are benign.
Cintron D et al. Effect of estrogen replacement therapy on bone 
and cardiovascular outcomes in women with Turner syn
-
drome: a systematic review and meta-analysis. Endocrine. 
2017 Feb;55(2):366–75. [PMID: 27473099]
Gravholt CH et al; International Turner Syndrome Consensus 
Group. Clinical practice guidelines for the care of girls and 
women with Turner syndrome: proceedings from the 2016 
Cincinnati International Turner Syndrome Meeting. Eur J 
Endocrinol. 2017 Sep;177(3):G1–70. [PMID: 28705803]
 
º
CLINICAL USE OF CORTICOSTEROIDS
Prolonged treatment with systemic high-dose corticoste
-
roids causes a variety of adverse effects that can be life 
threatening. Patients should be thoroughly informed of the 
major possible side effects of treatment such as insomnia, 
cognitive and personality changes, weight gain with central 
obesity, skin thinning and bruising, striae, muscle weak
-
ness, polyuria, renal calculi, diabetes mellitus, glaucoma, 
cataracts, sex hormone suppression, candidiasis, and 
opportunistic infections. High-dose corticosteroids have 
adverse cardiovascular effects, increasing the risk of hyper
-
tension, dyslipidemia, myocardial infarction, stroke, atrial 
fibrillation or flutter, and heart failure. Gastric ulceration is 
CMDT19_Ch26_p1119-p1219.indd   1217

C
HAPTER
 2
6
1218
 CMDT 2019
Table 26–16.
 
Management of patients receiving systemic corticosteroids.
Recommendations for prescribing
•  Do
 
not
 
administ
er
 
c
orticosteroids
 
unless
 
absolut
ely
 
indica
ted
 
or
 
mor
e
 
c
onservative
 
measur
es
 
ha
ve
 
failed
.
•  Keep
 
dosage
 
and
 
dur
ation
 
of
 
administr
ation
 
t
o
 
the
 
minimum
 
r
equired
 
f
or
 
adequa
te
 
tr
eatment.
Monitoring recommendations
•  Screen
 
f
or
 
tuber
culosis
 
with
 
a
 
purified
 
pr
otein
 
deriv
ative
 
(PPD
)
 
t
est
 
or
 
chest
 
r
adiograph
 
bef
ore
 
c
ommencing
 
long-t
erm
 
c
orticosteroid
 
ther
apy.
•  Screen
 
f
or
 
pr
egnancy
 
in
 
r
eproductive
 
age
 
w
omen;
 
r
ecommend
 
c
ontraceptive
 
measur
es.
•  Screen
 
f
or
 
diabet
es
 
mellitus
 
bef
ore
 
tr
eatment
 
and
 
a
t
 
each
 
clinician
 
visit
.
•  Teach
 
pa
tient
 
about
 
the
 
sympt
oms
 
of
 
h
yperglycemia.
•  Screen
 
f
or
 
h
 
bef
ore
 
tr
eatment
 
and
 
a
t
 
each
 
clinician
 
visit
.
•  Screen
 
f
or
 
glauc
oma
 
and
 
ca
taracts
 
bef
ore
 
tr
eatment,
 
3
 
mon
ths
 
af
ter
 
tr
eatment
 
inc
eption,
 
and
 
then
 
a
t
 
least
 
y
early.
•  Monitor
 
plasma
 
potassium
 
f
or
 
h
ypokalemia
 
and
 
tr
eat
 
as
 
indica
ted.
•  Obtain
 
bone
 
densit
ometry
 
bef
ore
 
tr
eatment
 
and
 
then
 
periodically
.
 
T
reat
 
ost
eoporosis.
•  Weigh
 
daily
.
 
U
se
 
dietar
y
 
measur
es
 
t
o
 
a
void
 
obesit
y
 
and
 
optimiz
e
 
nutrition.
•  Measure
 
heigh
t
 
fr
equently
 
t
o
 
documen
t
 
the
 
deg
ree
 
of
 
axial
 
spine
 
deminer
alization
 
and
 
c
ompression.
•  Watch
 
f
or
 
fungal
 
or
 
y
east
 
inf
ections
 
of
 
sk
in,
 
nails
,
 
mouth,
 
v
agina,
 
and
 
r
ectum,
 
and
 
tr
eat
 
appr
opriately.
•  With
 
dosage
 
r
eduction,
 
w
atch
 
f
or
 
sig
ns
 
of
 
adr
enal
 
insufficienc
y
 
or
 
c
 
withdr
awal
 
syndr
ome.
Patient information
•  Prepare
 
the
 
pa
tient
 
and
 
family
 
f
or
 
possible
 
adv
erse
 
eff
ects
 
on
 
mood
,
 
memor
y,
 
and
 
c
ognitive
 
func
tion.
•  Inform
 
the
 
pa
tient
 
about
 
other
 
possible
 
side
 
eff
ects,
 
par
ticularly
 
w
eight
 
gain,
 
ost
eoporosis,
 
and
 
aseptic
 
necr
osis
 
of
 
bone
.
•  Counsel
 
t
o
 
a
void
 
smok
ing
 
and
 
e
xcessive
 
ethanol
 
c
onsumption.
Prophylactic measures
•  Institute
 
a
 
vigor
ous
 
ph
ysical
 
e
xercise
 
and
 
isometric
 
r
egimen
 
tailor
ed
 
t
o
 
each
 
pa
tient’s
 
abilities
 
or
 
disabilities
.
•  Administer
 
calcium
 
(1
 
g
 
elemen
tal
 
calcium)
 
and
 
vitamin
 
D
3
, 400–800 units orally daily.
–Check spot morning urines for calcium; alter dosage to keep urine calcium concentration < 30 mg/dL (< 7.5 mmol/L).
–If the patient is receiving thiazide diuretics, check for hypercalcemia, and administer only 500 mg elemental calcium daily.
•  If
 
the
 
pa
tient
 
has
 
pr
eexistent
 
ost
eoporosis
 
or
 
has
 
been
 
r
eceiving
 
c
 
f
or
 
≥
 
3
 
mon
ths,
 
c
onsider
 
pr
ophylaxis:
– Bisphosphonate such as alendronate (70 mg every week orally), zoledronate (5 mg every year intravenously) for up to 3–5 years;
Or
– Denosumab (60 mg every 6 months subcutaneously) for up to 3–5 years.
•  Avoid
 
pr
olonged
 
bed
 
r
est
 
tha
t
 
will
 
ac
celerate
 
muscle
 
w
eakness
 
and
 
bone
 
miner
al
 
loss
.
 
Ambula
te
 
early
 
af
ter
 
fr
actures.
•  Avoid
 
elec
tive
 
sur
gery,
 
if
 
possible
.
 
V
itamin
 
A
 
in
 
a
 
daily
 
dose
 
of
 
20,000
 
units
 
or
ally
 
f
or
 
1
 
w
eek
 
ma
y
 
impr
ove
 
w
ound
 
healing
,
 
but
 
it
 
is
 
not
 
prescribed in pregnancy.
•  Fall
 
pr
evention
 
str
ategies:
 
w
alking
 
assistanc
e
 
(
cane,
 
w
alker,
 
wheelchair
,
 
handr
ails)
 
when
 
r
equired
 
due
 
t
o
 
w
eakness
 
or
 
balanc
e
 
pr
oblems;
 
a
void
 
activities that could cause falls or other trauma.
•  For
 
ulc
er
 
pr
ophylaxis,
 
if
 
administ
ering
 
c
 
with
 
nonst
eroidal
 
an
ti-inflammatory
 
drugs
,
 
pr
escribe
 
a
 
pr
oton
 
pump
 
inhibit
or

•  For
 
ulc
er
 
pr
 
if
 
administ
ering
 
c
 
with
 
nonst
eroidal
 
an
 
drugs
,
 
pr
escribe
 
a
 
pr
oton
 
pump
 
inhibit
or
 
(not
 
required for corticosteroids alone). Avoid large doses of antacids containing aluminum hydroxide (many popular brands) because aluminum 
hydroxide binds phosphate and may cause a hypophosphatemic osteomalacia that can compound corticosteroid osteoporosis.
•  Treat
 
h
ypogonadism.
•  Treat
 
inf
ections
 
agg
ressively.
 
C
onsider
 
unusual
 
pa
thogens.
•  Treat
 
edema
 
as
 
indica
ted.
more common with high-dose corticosteroids, particularly 
when patients take NSAIDs concurrently. Prolonged oral, 
inhaled, or intravenous corticosteroid therapy for systemic 
inflammatory disorders commonly suppresses pituitary 
ACTH secretion, causing secondary adrenal insufficiency.
Most corticosteroids (dexamethasone, prednisone, 
hydrocortisone, deflazacort, budesonide) are metabolized 
by the enzyme CYP34A. When drugs that inhibit CYP34A 
are administered along with even modest doses of cortico
-
steroids (oral, inhaled, intravenous), the blood levels of the 
corticosteroids rise and can cause iatrogenic Cushing syn
-
drome and secondary adrenal insufficiency. Medications 
that strongly inhibit CYP34A include itraconazole, keto
-
conazole, and nefazodone. Other strong CYP34A inhibi
-
tors include protease inhibitors and cobicistat, which is 
administered as a pharmacologic enhancer of antiretroviral 
therapy for the treatment of patients with HIV .
In pregnancy, corticosteroids taken by the mother are 
transmitted across the placenta to the fetus, causing adverse 
effects on fetal growth and development as well as 
childhood cognition and behavior. Therefore, women who 
are to receive high-dose corticosteroids should be screened 
for pregnancy and counseled to use contraception.
Bone fractures (especially spine and hip) ultimately 
occur in about 40% of patients receiving long-term cortico
-
steroid therapy. Osteoporotic fractures can also occur in 
patients who receive extensive topical, inhaled, or intermit
-
tent oral corticosteroids (eg, prednisone 10 mg/day or 
more and cumulative dose greater than 1 g). Osteoporotic 
fractures can occur even in patients receiving long-term 
corticosteroid therapy at relatively low doses (eg, 5–7.5 mg 
prednisone daily). Vertebral fractures occur at higher bone 
densities compared to patients without corticosteroid 
exposure. Patients at increased risk for corticosteroid 
osteoporotic fractures include those who are over age 60 or 
who have a low body mass index, pretreatment osteoporo
-
sis, a family history of osteoporosis, or concurrent disease 
that limits mobility. Avascular necrosis of bone (especially 
hips) develops in about 15% of patients who receive corti
-
costeroids at high doses (eg, prednisone 15 mg daily or 
CMDT19_Ch26_p1119-p1219.indd   1218

1219
 
CMDT 2019
more) for more than 1 month with cumulative prednisone 
doses of 10 g or more.
Bisphosphonates (eg, alendronate, 70 mg orally weekly) 
prevent the development of osteoporosis among patients 
receiving prolonged courses of corticosteroids. For 
patients who are unable to tolerate oral bisphosphonates 
(due to esophagitis, hiatal hernia, or gastritis), periodic 
intravenous infusions of pamidronate, 60–90 mg, or zole
-
dronate, 4 mg, should also be effective. Teriparatide, 
20 mcg subcutaneously daily for up to 2 years, is also effec
-
tive against corticosteroid-induced osteoporosis. It is wise 
to follow an organized treatment plan such as the one 
outlined in Table 26–16.
Elliott ER et al. Iatrogenic Cushing’s syndrome due to drug inter
-
action between glucocorticoids and the ritonavir or cobicistat 
containing HIV therapies. Clin Med (Lond.). 2016 
Oct;16(5):412–8. [PMID: 27697800]
Harris E et al. The prediction and monitoring of toxicity associ
-
ated with long-term systemic glucocorticoid therapy. Curr 
Rheumatol Rep. 2015 Jun;17(6):513. [PMID: 25903665]
Morin C et al. Systemic glucocorticoid therapy: risk factors for 
reported adverse events and beliefs about the drug. A cross-
sectional online survey of 820 patients. Clin Rheumatol. 2015 
Dec;34(12):2119–26. [PMID: 25956956]
Whittier X et al. Glucocorticoid-induced osteoporosis. Rheum 
Dis Clin North Am. 2016 Feb;42(1):177–89. [PMID: 
26611558]
CMDT19_Ch26_p1119-p1219.indd   1219

1220
 CMDT 2019
Type 1 diabetes
 
»
Polyuria, polydipsia, and weight loss associated 
with random plasma glucose of 200 mg/dL 
 
(11.1 mmol/L) or more.
 
»
Plasma glucose of 126 mg/dL (7.0 mmol/L) or 
more after an overnight fast, documented on 
more than one occasion.
 
»
Ketonemia, ketonuria, or both.
 
»
Islet autoantibodies are frequently present.
Type 2 diabetes
 
»
Many patients are over 40 years of age and obese.
 
»
Polyuria and polydipsia. Ketonuria and weight loss 
are uncommon at time of diagnosis. Candidal 
vaginitis in women may be an initial manifesta
-
tion. Many patients have few or no symptoms.
 
»
Plasma glucose of 126 mg/dL or more after an 
overnight fast on more than one occasion. Two 
hours after 75 g oral glucose, diagnostic values are 
200 mg/dL (11.1 mmol) or more.
 
»
HbA
1c
 6.5% or more.
 
»
Hypertension, dyslipidemia, and atherosclerosis 
are often associated.
 
»
Epidemiologic Considerations
An estimated 30.3 million people (9.4%) in the United 
States have diabetes mellitus, of which approximately 
1.5 million have type 1 diabetes and most of the rest have 
type 2 diabetes. A third group designated as “other specific 
types” by the American Diabetes Association (ADA) 
(Table 27–1) number in the thousands.
 
»
Classification & Pathogenesis
Diabetes mellitus is a syndrome with disordered metabo
-
lism and inappropriate hyperglycemia due to either a 
deficiency of insulin secretion or to a combination of insu
-
lin resistance and inadequate insulin secretion to compen
-
sate for the resistance.
A. Type 1 Diabetes Mellitus
This form of diabetes is due to pancreatic islet B cell destruc
-
tion predominantly by an autoimmune process in over 95% 
of cases (type 1A) and idiopathic in less than 5% (type 1B). 
The rate of pancreatic B cell destruction is quite variable, 
being rapid in some individuals and slow in others. It occurs 
at any age but most commonly arises in children and young 
adults with a peak incidence before school age and again at 
around puberty. It is a catabolic disorder in which circulat
-
ing insulin is virtually absent, plasma glucagon is elevated, 
and the pancreatic B cells fail to respond to all insulinogenic 
stimuli. Type 1 diabetes is usually associated with ketosis in 
its untreated state. Exogenous insulin is therefore required 
to reverse the catabolic state, prevent ketosis, reduce the 
hyperglucagonemia, and reduce blood glucose.
1. Immune-mediated type 1 diabetes mellitus (type 1A)—
 
Approximately one-third of the disease susceptibility is due 
to genes and two-thirds to environmental factors. Genes 
that are related to the HLA locus contribute about 40% of 
the genetic risk. About 95% of patients with type 1 diabetes 
possess either HLA-DR3 or HLA-DR4, compared with 
45–50% of white controls. 
HLA-DQ
 genes are even more 
specific markers of type 1 susceptibility, since a particular 
variety 
(HLA-DQB1
*
0302)
 is found in the DR4 patients 
with type 1, while a “protective” gene 
(HLA-DQB1
*
0602)
 is 
often present in the DR4 controls. The other important 
gene that contributes to about 10% of the genetic risk is 
found at the 5
′
 polymorphic region of the insulin gene. 
Mutations in genes associated with T cell tolerance can also 
cause autoimmune diabetes. The autoimmune regulatory 
gene (
AIRE
) product regulates the expression of several 
proteins in the thymus causing the deletion of self-reactive 
T cells. Type 1 diabetes mellitus as well as other autoim
-
mune disorders (autoimmune polyglandular syndrome 1) 
develop in 20% of individuals with homozygote mutations 
in 
AIRE
. Most patients with type 1 diabetes mellitus have 
circulating antibodies to islet cells (ICA), glutamic acid 
decarboxylase 65 (GAD65), insulin (IAA), tyrosine phos
-
phatase IA2 (ICA-512), and zinc transporter 8 (ZnT8) at 27
Diabetes Mellitus & 
CMDT19_Ch27_p1220-p1266.indd   1220

-
04/07/18   12:22 PM

DIABETES MELLITUS & HYPOGLYCEMIA
1221
 
CMDT 2019
the time the diagnosis is made (Table 27–2). These anti
-
bodies facilitate screening for an autoimmune cause of 
diabetes, particularly screening siblings of affected chil
-
dren, as well as adults with atypical features of type 2 
diabetes mellitus. Also, low levels of anti-insulin antibodies 
develop in almost all patients once they are treated with 
insulin.
Family members of diabetic probands are at increased 
lifetime risk for developing type 1 diabetes mellitus. A child 
whose mother has type 1 diabetes has a 3% risk of develop
-
ing the disease and a 6% risk if the child’s father has it. The 
risk in siblings is related to the number of HLA haplotypes 
that the sibling shares with the diabetic proband. If one 
haplotype is shared, the risk is 6% and if two haplotypes are 
shared, the risk increases to 12–25%. The highest risk is for 
identical twins, where the concordance rate is 25–50%.
Some patients with a milder expression of type 1 
diabetes mellitus initially retain enough B cell function to 
avoid ketosis, but as their B cell mass diminishes later in 
life, dependence on insulin therapy develops. Islet cell anti
-
body surveys among northern Europeans indicate that up 
to 15% of “type 2” diabetic patients may actually have this 
mild form of type 1 diabetes (latent autoimmune diabetes 
of adulthood; LADA). Evidence for environmental factors 
playing a role in the development of type 1 diabetes include 
the observation that the disease is more common in Scan
-
dinavian countries and becomes progressively less frequent 
in countries nearer and nearer to the equator. Also, the risk 
for type 1 diabetes increases when individuals who nor
-
mally have a low risk emigrate to the Northern Hemi
-
sphere. For example, Pakistani children born and raised in 
Bradford, England, have a higher risk for developing type 1 
diabetes compared with children who lived in Pakistan all 
their lives.
Which environmental factor is responsible for the 
increased risk is not known. Breastfeeding in the first 
6 months of life appears to be protective. There is accumu
-
lating evidence that improvements in public health and 
reduced infections (especially parasitic) lead to immune 
system dysregulation and development of autoimmune 
disorders such as asthma and type 1 diabetes.
Check point inhibitor immunotherapies for advanced 
malignancies, such as nivolumab, pembrolizumab, and 
ipilimumab, can precipitate autoimmune disorders, includ
-
ing type 1 diabetes. Patients receiving these drugs should 
be monitored for the development of diabetes.
2. Idiopathic type 1 diabetes mellitus (type 1B)—
Approx
-
imately 5% of subjects have no evidence of pancreatic B cell 
autoimmunity to explain their insulinopenia and ketoaci
-
dosis. This subgroup has been classified as “idiopathic type 
1 diabetes” and designated as “type 1B. ” Although only a 
minority of patients with type 1 diabetes fall into this 
group, most of these individuals are of Asian or African 
origin. About 4% of the West Africans with ketosis-prone 
diabetes are homozygous for a mutation in 
PAX-4
 
(
Arg133Trp
)—a transcription factor that is essential for the 
development of pancreatic islets.
B. Type 2 Diabetes Mellitus
This represents a heterogeneous group of conditions that 
used to occur predominantly in adults, but it is now more 
frequently encountered in children and adolescents. Circu
-
lating endogenous insulin is sufficient to prevent ketoaci
-
dosis but is inadequate to prevent hyperglycemia in the 
face of increased needs owing to tissue insensitivity (insu
-
lin resistance).
Genetic and environmental factors combine to cause 
both the insulin resistance and the beta cell loss. Most epi
-
demiologic data indicate strong genetic influences, since in 
monozygotic twins over 40 years of age, concordance 
develops in over 70% of cases within a year whenever type 
2 diabetes develops in one twin. So far, more than 30

2 diabetes develops in one twin. So far, more than 30 
genetic loci have been associated with an increased risk of 
type 2 diabetes. A significant number of the identified loci 
appear to code for proteins that have a role in beta cell 
function or development. One of the genetic loci with the 
largest risk effect is 
TCF7L2
. This gene codes for a tran
-
scription factor involved in the WNT signaling pathway 
that is required for normal pancreatic development.
Early in the disease process, hyperplasia of pancreatic B 
cells occurs and probably accounts for the fasting hyperin
-
sulinism and exaggerated insulin and proinsulin responses 
Table 27–1.
 
Other specific types of diabetes mellitus.
Genetic defects of pancreatic B cell function
 
MOD
Y 1 (HNF-4alpha); rare
 
MOD
Y 2 (glucokinase); less rare
 
MOD
Y 3 (HNF-1alpha); accounts for two-thirds of all MODY
 
MOD
Y 4 (PDX1); very rare
 
MOD
Y 5 (HNF-1beta); very rare
 
MOD
Y 6 (neuroD1); very rare
 
M
itochondrial DNA
Genetic defects in insulin action
 
T
ype A insulin resistance
 
Leprechaunism
 
R
abson-Mendenhall syndrome
 
Lipoa
trophic diabetes
Diseases of the exocrine pancreas
Drug- or chemical-induced diabetes
Other genetic syndromes (Down, Klinefelter, Turner, others) 
sometimes associated with diabetes
MODY, maturity-onset diabetes of the young; PDX1, pancreatic 
duodenal homeobox 1.
Table 27–2.
 
Diagnostic sensitivity and specificity of 
autoimmune markers in patients with newly diag
-
nosed type 1 diabetes mellitus.
Sensitivity
Specificity
ICA antibody
44–100%
96%
Glutamic acid decarboxylase 
(GAD65)
70–90%
99%
Insulin (IAA)
40–70%
99%
Tyrosine phosphatase (IA-2)
50–70%
99%
Zinc transporter 8 (ZnT8)
50–70%
99%
CMDT19_Ch27_p1220-p1266.indd   1221

C
HAPTE
r 27
1222
 CMDT 2019
to glucose and other stimuli. With time, chronic deposition 
of amyloid in the islets may combine with inherited genetic 
defects progressively to impair B cell function.
Obesity is the most important environmental factor 
causing insulin resistance.
 The degree and prevalence of 
obesity varies among different racial groups with type 2 
diabetes. While obesity is apparent in no more than 30% of 
Chinese and Japanese patients with type 2, it is found in 
60–70% of North Americans, Europeans, or Africans with 
type 2 and approaches 100% of patients with type 2 among 
Pima Indians or Pacific Islanders from Nauru or Samoa.
Visceral obesity, due to accumulation of fat in the 
omental and mesenteric regions, correlates with insulin 
resistance; subcutaneous abdominal fat seems to have less 
of an association with insulin insensitivity. There are many 
patients with type 2 diabetes who, while not overtly obese, 
have increased visceral fat; they are termed the “metaboli
-
cally obese. ” Exercise may affect the deposition of visceral 
fat as suggested by CT scans of Japanese wrestlers, whose 
extreme obesity is predominantly subcutaneous. Their 
daily vigorous exercise program prevents accumulation of 
visceral fat, and they have normal serum lipids and eugly
-
cemia despite daily intakes of 5000–7000 kcal and develop
-
ment of massive subcutaneous obesity.
C. Other Specific Types of Diabetes Mellitus
1. Maturity-onset diabetes of the young (MODY)—
This 
subgroup of monogenic disorders is characterized by non
-
insulin requiring diabetes with autosomal dominant inheri
-
tance and an age at onset of 25 years or younger. Patients are 
nonobese, and their hyperglycemia is due to impaired glu
-
cose-induced secretion of insulin. Six types of MODY have 
been described (Table 27–1). Except for MODY 2, in which 
a glucokinase gene is defective, all other types involve muta
-
tions of a nuclear transcription factor that regulates islet 
gene expression. Patients younger than 30 years with 
endogenous insulin production (urinary C-peptide/creati
-
nine ratio of 0.2 nmol/mmol or higher) and negative auto
-
antibodies are candidates for genetic screening for MODY . 
The enzyme glucokinase is a rate-limiting step in glycolysis 
and determines the rate of adenosine triphosphate (ATP) 
production from glucose and the insulin secretory response 
in the beta cell. MODY 2, due to glucokinase mutations, is 
usually quite mild, associated with only slight fasting hyper
-
glycemia and few if any microvascular diabetic complica
-
tions. It generally responds well to hygienic measures or low 
doses of oral hypoglycemic agents. MODY 3, due to muta
-
tions in hepatic nuclear factor 1 alpha is the most common 
form, accounting for two-thirds of all MODY cases. Ini
-
tially, patients with MODY 3 are responsive to sulfonylurea 
therapy but the clinical course is of progressive beta cell 
failure and eventual need for insulin therapy. Mutations in 
both alleles of glucokinase present with more severe neona
-
tal diabetes. Mutation in one allele of the pancreatic duode
-
nal homeobox 1 (PDX1) causes diabetes usually at a later 
age (
∼
 35 years) than other forms of MODY; mutations in 
both alleles of PDX1 causes pancreatic agenesis.
2. Diabetes mellitus associated with a mutation of mito
-
chondrial DNA—
Since sperm do not contain mitochondria, 
only the mother transmits mitochondrial genes to her off
-
spring. Diabetes due to mutations of mitochondrial DNA 
occurs in less than 2% of patients with diabetes. The most 
common cause is the A3243G mutation in the gene coding 
for the tRNA (Leu, UUR). Diabetes usually develops in these 
patients in their late 30s, and characteristically, they also 
have hearing loss (maternally inherited diabetes and deaf
-
ness [MIDD]).
3. Wolfram syndrome—
Wolfram syndrome is an autoso
-
mal recessive neurodegenerative disorder first evident in

-
-
mal recessive neurodegenerative disorder first evident in 
childhood. It consists of diabetes insipidus, diabetes melli
-
tus, optic atrophy, and deafness, hence the acronym DID
-
MOAD. It is due to mutations in a gene named 
WFS1
, 
which encodes a 100.3 KDa transmembrane protein local
-
ized in the endoplasmic reticulum. Cranial diabetes insipi
-
dus and sensorineural deafness develop during the second 
decade in 60–75% of patients. Ureterohydronephrosis, 
neurogenic bladder, cerebellar ataxia, peripheral neuropa
-
thy, and psychiatric illness develop later in many patients.
4. Autosomal recessive syndromes—
Homozygous muta
-
tions in a number of pancreatic transcription factors, 
NEU
-
ROG3, PTF1A, RFX6
, and 
GLI-similar 3 (GLIS3)
, cause 
neonatal or childhood diabetes. Homozygous 
PTF1A
 
mutations result in absent pancreas and cerebellar atrophy; 
NEUROG3
 mutations cause severe malabsorption and 
diabetes before puberty. Homozygous mutations in 
RFX6
 
cause the Mitchell-Riley syndrome characterized by 
absence of all islet cell types apart from pancreatic poly
-
peptide cells, hypoplasia of the pancreas and gallbladder, 
and intestinal atresia. 
GLIS3
 gene plays a role in transcrip
-
tion of insulin gene, and homozygous mutations cause 
neonatal diabetes and congenital hypothyroidism. The 
gene 
EIF2AK3
 encodes PKR-like ER kinase (PERK), which 
controls one of the pathways of the unfolded protein 
response. Absence of PERK leads to inadequate response to 
ER stress and accelerated beta cell apoptosis. Patients with 
mutation in this gene have neonatal diabetes, epiphyseal 
dysplasia, developmental delay, and liver and kidney dys
-
function (Wolcott-Rallison syndrome).
5. Diabetes mellitus secondary to other causes—
Endo
-
crine tumors secreting growth hormone, glucocorticoids, 
catecholamines, glucagon, or somatostatin can cause glu
-
cose intolerance (Table 27–3). In the first four of these situ
-
ations, peripheral responsiveness to insulin is impaired. 
With excess of glucocorticoids, catecholamines, or gluca
-
gon, increased hepatic output of glucose is a contributory 
factor; in the case of catecholamines, decreased insulin 
release is an additional factor in producing carbohydrate 
intolerance, and with somatostatin, inhibition of insulin 
secretion is the major factor. Diabetes mainly occurs in 
individuals with underlying defects in insulin secretion, 
and hyperglycemia typically resolves when the hormone 
excess is resolved.
High-titer anti-insulin receptor antibodies that inhibit 
insulin binding cause a clinical syndrome characterized by 
severe insulin resistance, glucose intolerance or diabetes 
mellitus, and acanthosis nigricans. These patients usually 
have other autoimmune disorders. There are reports of 
spontaneous remission or remission with cytotoxic therapy.
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Many medications are associated with carbohydrate 
intolerance or frank diabetes (Table 27–3). The medica
-
tions act by decreasing insulin secretion or by increasing 
insulin resistance or both. Cyclosporine and tacrolimus 
impair insulin secretion; sirolimus principally increases 
insulin resistance. These agents contribute to the develop
-
ment of new-onset diabetes after transplantation. Cortico
-
steroids increase insulin resistance but may also have an 
effect on beta cell function; in a case control study and a 
large population cohort study, oral corticosteroids doubled 
the risk for development of diabetes. Thiazide diuretics and 
beta-blockers modestly increase the risk for diabetes. 
Treating the hypokalemia due to thiazides may reverse the 
hyperglycemia. Atypical antipsychotics, particularly olan
-
zapine and clozapine, are associated with increased risk of 
glucose intolerance. These medications cause weight gain 
and insulin resistance but may also impair beta cell func
-
tion; an increase in rates of diabetic ketoacidosis (DKA) 
has been reported.
Chronic pancreatitis or subtotal pancreatectomy 
reduces the number of functioning B cells and can result in 
a metabolic derangement very similar to that of genetic 
type 1 diabetes except that a concomitant reduction in 
pancreatic A cells may reduce glucagon secretion so that 
relatively lower doses of insulin replacement are needed.
 
»
Insulin Resistance Syndrome 
 
(Metabolic Syndrome)
Twenty-five percent of the general nonobese, nondiabetic 
population has insulin resistance of a magnitude similar to 
that seen in type 2 diabetes. These insulin-resistant 
nondiabetic individuals are at much higher risk for devel
-
oping type 2 diabetes than insulin-sensitive persons. These 
individuals also have a cluster of abnormalities termed 
 that significantly increases their risk 
of atherosclerotic disease: elevated plasma triglycerides 
and small, dense, low-density lipoproteins (LDLs); lower 
high-density lipoproteins (HDLs); higher blood pressure; 
hyperuricemia; abdominal obesity; prothrombotic state 
with increased levels of plasminogen activator inhibitor 
type 1 (PAI-1); and proinflammatory state.
It has been postulated that hyperinsulinemia and insu
-
lin resistance play a direct role in these metabolic abnor
-
malities, but supportive evidence is inconclusive. The main 
value of grouping these disorders as a syndrome, however, 
is to remind clinicians that the therapeutic goals are not 
only to correct hyperglycemia but also to manage the ele
-
vated blood pressure and dyslipidemia that result in 
increased cerebrovascular and cardiac morbidity and mor
-
tality in these patients.
American Diabetes Association. Standards of medical care in 
diabetes—2018. Diabetes Care. 2018 Jan;41(Suppl):S1–159. 
[PMID: 29222369]
Thompson AE. JAMA patient page. Hypoglycemia. JAMA. 2015 
Mar 24–31;313(12):1284. [PMID: 25803359]
 
»
1. Type 1 diabetes—
A characteristic symptom complex of 
hyperosmolality and hyperketonemia from the accumula
-
tion of circulating glucose and fatty acids typically presents 
in patients with type 1 diabetes. Increased urination and 
thirst are consequences of osmotic diuresis secondary to 
sustained hyperglycemia. The diuresis results in a loss of 
glucose as well as free water and electrolytes in the urine. 
Blurred vision often develops as the lenses are exposed to 
hyperosmolar fluids.
Weight loss despite normal or increased appetite is a 
common feature of type 1 when it develops subacutely. The 
weight loss is initially due to depletion of water, glycogen, 
and triglycerides; thereafter, reduced muscle mass occurs 
as amino acids are diverted to form glucose and ketone 
bodies.
Lowered plasma volume produces symptoms of postural 
hypotension. Total body potassium loss and the general

bodies.
hypotension. Total body potassium loss and the general 
catabolism of muscle protein contribute to the weakness.
Paresthesias may be present at the time of diagnosis, 
particularly when the onset is subacute. They reflect a tem
-
porary dysfunction of peripheral sensory nerves, which 
clears as insulin replacement restores glycemic levels closer 
to normal, suggesting neurotoxicity from sustained 
hyperglycemia.
When absolute insulin deficiency is of acute onset, the 
above symptoms develop abruptly. Ketoacidosis exacer
-
bates the dehydration and hyperosmolality by producing 
anorexia and nausea and vomiting, interfering with oral 
fluid replacement.
The patient’s level of consciousness can vary depending 
on the degree of hyperosmolality. When insulin deficiency 
develops relatively slowly and sufficient water intake is main
-
tained, patients remain relatively alert and physical findings 
may be minimal. When vomiting occurs in response to wors
-
ening ketoacidosis, dehydration progresses and compensa
-
tory mechanisms become inadequate to keep serum 
osmolality below 320–330 mOsm/L. Under these circum
-
stances, stupor or even coma may occur. The fruity breath 
odor of acetone further suggests the diagnosis of DKA.
Hypotension in the recumbent position is a serious 
prognostic sign. Loss of subcutaneous fat and muscle 
Table 27–3.
 
Secondary causes of hyperglycemia.
Hyperglycemia due to tissue insensitivity to insulin
Hormonal tumors (acromegaly, Cushing syndrome, 
glucagonoma, pheochromocytoma)
Pharmacologic agents (corticosteroids, sympathomimetic 
drugs, niacin)
Liver disease (cirrhosis, hemochromatosis)
Muscle disorders (myotonic dystrophy)
Adipose tissue disorders (lipodystrophy, truncal obesity)
Insulin receptor disorders (acanthosis nigricans syndromes, 
leprechaunism)
Hyperglycemia due to reduced insulin secretion
Hormonal tumors (somatostatinoma, pheochromocytoma)
Pancreatic disorders (pancreatitis, hemosiderosis, 
hemochromatosis)
Pharmacologic agents (thiazide diuretics, phenytoin, 
pentamidine, calcineurin inhibitors)
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wasting are features of more slowly developing insulin 
deficiency. In occasional patients with slow, insidious onset 
of insulin deficiency, subcutaneous fat may be considerably 
depleted.
2. Type 2 diabetes—
While increased urination and thirst 
may be presenting symptoms in some patients with type 2 
diabetes, many other patients have an insidious onset of 
hyperglycemia and are asymptomatic initially. This is par
-
ticularly true in obese patients, whose diabetes may be 
detected only after glycosuria or hyperglycemia is noted 
during routine laboratory studies. Occasionally, when the 
disease has been occult for some time, patients with type 2 
diabetes may have evidence of neuropathic or cardiovascu
-
lar complications at the time of presentation. Chronic skin 
infections are common. Generalized pruritus and symp
-
toms of vaginitis are frequently the initial complaints of 
women. Diabetes should be suspected in women with 
chronic candidal vulvovaginitis as well as in those who 
have delivered babies larger than 9 lb (4.1 kg) or have had 
polyhydramnios, preeclampsia, or unexplained fetal losses. 
Balanoposthitis (inflammation of the foreskin and glans in 
uncircumcised males) may occur.
Many patients with type 2 diabetes are overweight or 
obese. Even those who are not significantly obese often have 
characteristic localization of fat deposits on the upper seg
-
ment of the body (particularly the abdomen, chest, neck, 
and face) and relatively less fat on the appendages, which 
may be quite muscular. This centripetal fat distribution is 
characterized by a high waist circumference; a waist circum
-
ference larger than 40 inches (102 cm) in men and 35 inches 
(88 cm) in women is associated with an increased risk of 
diabetes. Some patients may have acanthosis nigricans, 
which is associated with significant insulin resistance; the 
skin in the axilla, groin, and back of neck is hyperpigmented 
and hyperkeratotic (Figure 27–1). Mild hypertension is 
often present in obese patients with diabetes. Eruptive xan
-
thomas on the flexor surface of the limbs and on the but
-
tocks and lipemia retinalis due to hyperchylomicronemia 
can occur in patients with uncontrolled type 2 diabetes who 
also have a familial form of hypertriglyceridemia.
Hyperglycemic hyperosmolar coma can also be present; 
in these cases, patients are profoundly dehydrated, hypo
-
tensive, lethargic or comatose but without Kussmaul 
respirations.
1. Urine glucose—
A convenient method to detect glucos
-
uria is the paper strip impregnated with glucose oxidase and 
a chromogen system (Clinistix, Diastix), which is sensitive 
to as little as 100 mg/dL (5.5 mmol) glucose in urine. Diastix 
can be directly applied to the urinary stream, and differing 
color responses of the indicator strip reflect glucose concen
-
tration. A normal renal threshold for glucose as well as reli
-
able bladder emptying is essential for interpretation.
Nondiabetic glycosuria (renal glycosuria) is a benign 
asymptomatic condition wherein glucose appears in the 
urine despite a normal amount of glucose in the blood, 
either basally or during a glucose tolerance test. Its cause 
may vary from mutations in the 
SGLT2
 gene coding for 
sodium-glucose transporter 2 (familial renal glycosuria) to 
one associated with dysfunction of the proximal renal 
tubule (Fanconi syndrome, chronic kidney disease), or it 
may merely be a consequence of the increased load of glu
-
cose presented to the tubules by the elevated glomerular 
filtration rate (GFR) during pregnancy. As many as 50% of 
pregnant women normally have demonstrable sugar in the 
urine, especially during the third and fourth months. This 
sugar is practically always glucose except during the late 
weeks of pregnancy, when lactose may be present.
2. Urine and blood ketones—
Qualitative detection of 
ketone bodies can be accomplished by nitroprusside tests

ketone bodies can be accomplished by nitroprusside tests 
(Acetest or Ketostix). Although these tests do not detect 
beta-hydroxybutyric acid, which lacks a ketone group, the 
semiquantitative estimation of ketonuria thus obtained is 
nonetheless usually adequate for clinical purposes. Many 
laboratories measure beta-hydroxybutyric acid, and there 
are meters available (Precision Xtra; Nova Max Plus) for 
patient use that measures beta-hydroxybutyric acid levels 
in capillary glucose samples. Beta-hydroxybutyrate levels 
greater than 0.6 mmol/L require evaluation. Patients with 
levels greater than 3.0 mmol/L, equivalent to very large 
urinary ketones, require hospitalization.
3. Plasma or serum glucose—
The glucose concentration 
is 10–15% higher in plasma or serum than in whole blood 
because structural components of blood cells are absent. A 
plasma glucose level of 126 mg/dL (7 mmol/L) or higher on 
more than one occasion after at least 8 hours of fasting is 
diagnostic of diabetes mellitus (Table 27–4). Fasting plasma 
glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are 
associated with increased risk of diabetes (impaired fasting 
glucose tolerance).
4. Oral glucose tolerance test—
If the fasting plasma glu
-
cose level is less than 126 mg/dL (7 mmol/L) when diabetes 
is nonetheless suspected, then a standardized oral glucose 
tolerance test may be done (Table 27–4). In order to opti
-
mize insulin secretion and effectiveness, especially when 
patients have been on a low-carbohydrate diet, a minimum 
of 150–200 g of carbohydrate per day should be included in 
 
▲
Figure 27–1.
 
Acanthosis nigricans of the nape of the 
neck, with typical dark and velvety appearance. 
permission, from Umesh Masharani, MB, BS, MRCP [UK].)
CMDT19_Ch27_p1220-p1266.indd   1224

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CMDT 2019
Table 27–4.
 
Criteria for the diagnosis of diabetes.
Normal 
 
Glucose 
 
Tolerance
Impaired 
Glucose 
Tolerance
Diabetes 
Mellitus
2
Fasting plasma 
glucose mg/
dL (mmol/L)
< 100 (5.6)
100–125 
(5.6–6.9)
≥ 126 (7.0)
Two hours after 
glucose 
load
1
 mg/dL 
(mmol/L)
< 140 (7.8)
≥ 140–199 
(7.8–11.0)
≥ 200 (11.1)
HbA
1c
 (%)
< 5.7
5.7–6.4
≥ 6.5
1
Give 75 g of glucose dissolved in 300 mL of water after an over
-
night fast in persons who have been receiving at least 150–200 g 
of carbohydrate daily for 3 days before the test.
2
A fasting plasma glucose ≥ 126 mg/dL (7.0 mmol) or HbA
1c
 of 
≥ 6.5% is diagnostic of diabetes if confirmed by repeat testing.
the diet for 3 days preceding the test. The patient should eat 
nothing after midnight prior to the test day. On the morning 
of the test, patients are then given 75 g of glucose in 300 mL 
of water. The glucose load is consumed within 5 minutes. 
The test should be performed in the morning because there 
is some diurnal variation in oral glucose tolerance, and 
patients should not smoke or be active during the test.
Blood samples for plasma glucose are obtained at 0 and 
120 minutes after ingestion of glucose. An oral glucose 
tolerance test is normal if the fasting venous plasma 
glucose value is less than 100 mg/dL (5.6 mmol/L) and the 
2-hour value falls below 140 mg/dL (7.8 mmol/L). A fast
-
ing value of 126 mg/dL (7 mmol/L) or higher or a 2-hour 
value of greater than 200 mg/dL (11.1 mmol/L) is diagnos
-
tic of diabetes mellitus. Patients with 2-hour value of 
140–199 mg/dL (7.8–11.1 mmol/L) have impaired glucose 
tolerance. False-positive results may occur in patients who 
are malnourished, bedridden, or afflicted with an infection 
or severe emotional stress.
5. Glycated hemoglobin (hemoglobin A
1
) measure
-
ments—
Office-based immunoassays for HbA
1c
 using cap
-
illary blood give a result in about 9 minutes and this allows 
for nearly immediate feedback to the patients regarding 
their glycemic control.
Since HbA
1c
 circulates within red blood cells whose life 
span lasts up to 120 days, it generally reflects the state of 
glycemia over the preceding 8–12 weeks, thereby providing 
an improved method of assessing diabetic control. The 
HbA
1c
 value, however, is weighted to more recent glucose 
levels (previous month) and this explains why significant 
changes in HbA
1c
 are observed with short-term (1 month) 
changes in mean plasma glucose levels. Measurements 
should be made in patients with either type of diabetes 
mellitus at 3- to 4-month intervals. In patients monitoring 
their own blood glucose levels, HbA
1c
 values provide a 
valuable check on the accuracy of monitoring. In patients 
who do not monitor their own blood glucose levels, HbA
1c
 
values are essential for adjusting therapy. The A
1c
 Derived 
Average Glucose Study reported that the relationship 
between average glucose in the previous 3 months and 
HbA
1c
 was (28.7 × HbA
1c
) – 46.7. There is, however, sub
-
stantial individual variability; for HbA
1c
 values between 
6.9% and 7.1%, the glucose levels range from 125 mg/dL to 
205 mg/dL (6.9–11.4 mmol/L; 95% CIs). For HbA
1c
 of 6%, 
the mean glucose levels range from 100 mg/dL to 152 mg/dL 
(5.5–8.5 mmol/L); and for 8% they range from 147 mg/dL 
to 217 mg/dL (8.1–12.1 mmol/L). For this reason, caution 
should be exercised in estimating average glucose levels 
from measured HbA
1c
.
The accuracy of HbA
1c
 values can be affected by hemo
-
globin variants or traits. In patients with high levels of 
hemoglobin F, immunoassays give falsely low values of 
HbA
1c
. The National Glycohemoglobin Standardization 
Program website (www.ngsp.org) has information on the 
impact of frequently encountered hemoglobin variants and 
traits on the results obtained with the commonly used 
HbA
1c
 assays.
Any condition that shortens erythrocyte survival or 
decreases mean erythrocyte age (eg, recovery from acute

HbA
1c
 assays.
decreases mean erythrocyte age (eg, recovery from acute 
blood loss, hemolytic anemia) will falsely lower HbA
1c
 
irrespective of the assay method used. Intravenous iron 
and erythropoietin therapy for treatment of anemia in 
chronic kidney disease also falsely lower HbA
1c
 levels. 
Alternative methods such as fructosamine should be con
-
sidered for these patients. Vitamins C and E are reported to 
falsely lower test results possibly by inhibiting glycation of 
hemoglobin. Conditions that increase erythrocyte survival 
such as splenectomy for hereditary spherocytosis will 
falsely raise HbA
1c
 levels. Iron deficiency anemia is also 
associated with higher HbA
1c
 levels.
HbA
1c
 is endorsed by the ADA as a diagnostic test for 
type 1 and type 2 diabetes (Table 27–4). A cutoff value of 
6.5% (48 mmol/mol) was chosen because the risk for reti
-
nopathy increases substantially above this value. The 
advantages of using the HbA
1c
 to diagnose diabetes is that 
there is no need to fast; it has lower intraindividual vari
-
ability than the fasting glucose test and the oral glucose 
tolerance test; and it provides an estimate of glucose con
-
trol for the preceding 2–3 months. People with HbA
1c
 lev
-
els of 5.7–6.4% (39–46 mmol/mol) should be considered at 
high risk for developing diabetes (prediabetes). The diag
-
nosis should be confirmed with a repeat HbA
1c
 test, unless 
the patient is symptomatic with plasma glucose levels 
greater than 200 mg/dL (11.1 mmol/L). This test is not 
appropriate to use in populations with high prevalence of 
hemoglobinopathies or in conditions with increased red 
cell turnover. Also, the testing is performed using a 
National Glycohemoglobin Standardization Program 
(NGSP) certified method and standardized to the Diabetes 
Control and Complication Trial assay. In the European 
Union, the tests are standardized to the International Fed
-
eration of Clinical Chemistry (IFCC), which defines HbA
1c
 
as mmol glycated hexapeptide per mol (glycated and non
-
glycated hexapeptides) and reported as mmol HbA
1c
/mol 
Hb. The conversion factor for NGSP and IFCC results is 
NGSP (USA) result = (0.09148
*
IFCC result) + 2.152. 
There is worldwide consensus that HbA
1c
 should be 
reported in both NGSP (%) and IFCC (mmol/mol) units.
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6. Serum fructosamine—
Serum fructosamine is formed 
by nonenzymatic glycosylation of serum proteins (pre
-
dominantly albumin). Since serum albumin has a much 
shorter half-life than hemoglobin, serum fructosamine 
generally reflects the state of glycemic control for only the 
preceding 1–2 weeks. Reductions in serum albumin (eg, 
nephrotic state, protein-losing enteropathy, or hepatic dis
-
ease) will lower the serum fructosamine value. When 
abnormal hemoglobins or hemolytic states affect the inter
-
pretation of glycohemoglobin or when a narrower time 
frame is required, such as for ascertaining glycemic control 
at the time of conception in a diabetic woman who has 
recently become pregnant, serum fructosamine assays offer 
some advantage. Normal values vary in relation to the 
serum albumin concentration and are 200–285 mcmol/L 
when the serum albumin level is 5 g/dL. HbA
1c
 values and 
serum fructosamine are highly correlated. Serum fructos
-
amine levels of 300, 367, and 430 mcmol/L approximate to 
HbA
1c
 values of 7%, 8%, and 9%, respectively. Substantial 
individual variability exists, though, when estimating the 
likely HbA
1c
 value from the fructosamine measurement.
7. Self-monitoring of blood glucose—
Capillary blood 
glucose measurements performed by patients themselves, 
as outpatients, are extremely useful. In type 1 patients in 
whom “tight” metabolic control is attempted, they are 
indispensable. A large number of blood glucose meters are 
available. All are accurate, but they vary with regard to 
speed, convenience, size of blood samples required, report
-
ing capability, and cost. Popular models include those 
manufactured by LifeScan (One Touch), Bayer Corpora
-
tion (Breeze, Contour), Roche Diagnostics (Accu-Chek), 
and Abbott Laboratories (Precision, FreeStyle). These 
blood glucose meters are relatively inexpensive, ranging 
from $50 to $100 each. Test strips remain a major expense, 
costing about $.25 to $1.50 apiece. Each glucose meter also 
comes with a lancet device and disposable 26- to 33-gauge 
lancets. Most meters can store from 100 to 1000 glucose 
values in their memories and have capabilities to download 
the values into a computer or smartphone. Some meters are 
designed to communicate with a specific insulin pump. 
Contour Next Link meter, for example, communicates with 
the MiniMed Medtronic pump). The accuracy of data 
obtained by home glucose monitoring does require educa
-
tion of the patient in sampling and measuring procedures 
as well as in properly calibrating the instruments.
The clinician should be aware of the limitations of the 
self-monitoring glucose systems. The strips have limited 
lifespans and improper storage (high temperature; open 
vial) can affect their function. Patients should also be 
advised not to use expired strips. Increases or decreases in 
hematocrit can decrease or increase the measured glucose 
values. Meters and the test strips are calibrated over the 
glucose concentrations ranging from 60 mg/dL (3.3 
mmol/L) to 160 mg/dL (8.9 mmol/L) and the accuracy is 
not as good for higher and lower glucose levels. When the 
glucose is less than 60 mg/dL (3.3 mmol/L), the difference 
between the meter and the laboratory value may be as 
much as 20%. Glucose oxidase–based amperometric sys
-
tems underestimate glucose levels in the presence of high 
oxygen tension. This may be important in the critically ill 
who are receiving supplemental oxygen; under these cir
-
cumstances, a glucose dehydrogenase–based system may 
be preferable. Glucose-dehydrogenase pyrroloquinoline 
quinone (GDH-PQQ) systems may report falsely high 
glucose levels in patients who are receiving parenteral 
products containing nonglucose sugars such as maltose, 
galactose, or xylose or their metabolites. Some meters 
have been approved for measuring glucose in blood sam
-
ples obtained at alternative sites such as the forearm and

-
ples obtained at alternative sites such as the forearm and 
thigh. There is, however, a 5- to 20-minute lag in the glu
-
cose response on the arm with respect to the glucose 
response on the finger. Forearm blood glucose measure
-
ments could therefore result in a delay in detection of 
rapidly developing hypoglycemia. Impaired circulation to 
the fingers (for example, in patients with Raynaud disease) 
will artificially lower fingerstick glucose measurements 
(pseudohypoglycemia).
8. Continuous glucose monitoring systems—
Systems 
manufactured by Medtronic Minimed, DexCom systems, 
and Abbott Diagnostics involve inserting a subcutaneous 
sensor (rather like an insulin pump cannula) that measures 
glucose concentrations continuously in the interstitial fluid 
for 6–10 days. The DexCom system transmits glucose data 
wirelessly to a separate pager-like device with a screen. The 
DexCom system also has the option of displaying data on 
smartphones or smart watches or on the screens of several 
insulin pumps. The FreeStyle Libre (Abbott Diagnostics) 
sensor system requires the patient to hold a reading device 
close to the sensor patch for about a second to see the real 
time glucose value. The Minimed and Dexcom systems 
also display directional arrows indicating rate and direc
-
tion of change, and alarms can be set for dangerously low 
or high glucose values. Patients still have to calibrate the 
devices with periodic fingerstick glucose levels. The Free
-
Style Libre system does not require calibration and glucose 
readings are available 12 hours after insertion of sensors. A 
6-month randomized controlled study of type 1 patients 
showed that adults (25 years and older) using these con
-
tinuous glucose monitoring systems had improved glyce
-
mic control without an increase in the incidence of 
hypoglycemia. A randomized controlled study of continu
-
ous glucose monitoring during pregnancy showed 
improved glycemic control in the third trimester, lower 
birth weight, and reduced risk of macrosomia. The indi
-
vidual glucose values are not that critical—what matters is 
the direction and the rate at which the glucose is changing, 
allowing the user to take corrective action. The wearer also 
gains insight into the way particular foods and activities 
affect their glucose levels. The other main benefit is the low 
glucose alert warning. The MiniMed insulin pump can be 
programmed to automatically suspend insulin delivery for 
up to 2 hours when the glucose levels on its continuous 
glucose monitoring device falls to a preset level and the 
patient does not respond to the alert. This insulin suspen
-
sion feature has been shown to reduce the amount of time 
patients are in the hypoglycemic range at night. Many of 
these systems are covered by insurance. The initial cost is 
about $800 to $1000, and the sensor, which has to be 
changed every 6 to 10 days, costs $35 to $60; the out-of-
pocket expense of about $4000 annually.
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9. Closed loop systems—
Algorithms have been devised to 
use glucose data from the continuous glucose monitoring 
systems to automatically deliver insulin by continuous 
subcutaneous insulin infusion pump. These closed loop 
systems (artificial pancreas) have been shown in short-
term clinical studies to improve nighttime glucose control 
and reduce the risk of nocturnal hypoglycemia. The Min
-
imed 670 G closed loop system is FDA approved for clini
-
cal use. This system uses glucose data from a sensor to 
automatically adjust basal insulin doses every 5 minutes, 
targeting a sensor glucose level of 120 mg/dL (6.7 mmol/L). 
Insulin delivery is suspended when the sensor glucose level 
falls below or is predicted to fall below target level. The 
glucose target can be adjusted up to 150 mg/dL (8.3 
mmol/L) for physical activity. The patient is still responsi
-
ble for bolusing insulin for meals and snacks. Successful 
use of this closed loop system requires the patient to be 
proficient at using both the insulin pump and continuous 
glucose monitor.
10. Lipoprotein abnormalities in diabetes—
Circulating 
lipoproteins are just as dependent on insulin as is the 
plasma glucose. In type 1 diabetes, moderately deficient 
control of hyperglycemia is associated with only a slight 
elevation of LDL cholesterol and serum triglycerides and 
little if any change in HDL cholesterol. Once the hypergly
-
cemia is corrected, lipoprotein levels are generally normal. 
However, in patients with type 2 diabetes, a distinct “dia
-
betic dyslipidemia” is characteristic of the insulin resis
-
tance syndrome. Its features are a high serum triglyceride 
level (300–400 mg/dL [3.4–4.5 mmol/L]), a low HDL cho
-
lesterol (less than 30 mg/dL [0.8 mmol/L]), and a qualita
-
tive change in LDL particles, producing a smaller dense 
particle whose membrane carries supranormal amounts of 
free cholesterol. These smaller dense LDL particles are 
more susceptible to oxidation, which renders them more 
atherogenic. Measures designed to correct the obesity and 
hyperglycemia, such as exercise, diet, and hypoglycemic 
therapy, are the treatment of choice for diabetic dyslipid
-
emia, and in occasional patients in whom normal weight 
was achieved, all features of the lipoprotein abnormalities 
cleared. Since primary disorders of lipid metabolism may 
coexist with diabetes, persistence of lipid abnormalities 
after restoration of normal weight and blood glucose 
should prompt a diagnostic workup and possible pharma
-
cotherapy of the lipid disorder. Chapter 28 discusses these 
matters in detail.
Selph S et al. Screening for type 2 diabetes mellitus: a systematic 
review for the U.S. Preventive Services Task Force. Ann Intern 
Med. 2015 Jun 2;162(11):765–76. [PMID: 25867111]
 
»
Clinical Trials in Diabetes
Findings of the Diabetes Complications and Control Trial 
(DCCT) and of the United Kingdom Prospective Diabetes 
Study (UKPDS) have confirmed the beneficial effects of 
improved glycemic control in both type 1 and type 2 
diabetes.
The Diabetes Control and Complications Trial
, a 
long-term therapeutic study involving 1441 patients with 
type 1 diabetes mellitus, reported that “near” normaliza
-
tion of blood glucose resulted in a delay in the onset and a 
major slowing of the progression of established microvas
-
cular and neuropathic complications of diabetes during a 
follow-up period of up to 10 years. Multiple insulin injec
-
tions (66%) or insulin pumps (34%) were used in the inten
-
sively treated group, who were trained to modify their 
therapy in response to frequent glucose monitoring. The 
conventionally treated groups used no more than two insu
-
lin injections, and clinical well-being was the goal with no 
attempt to modify management based on HbA
1c
 determi
-
nations or the glucose results.
In half of the patients, a mean hemoglobin A
1c
 of 7.2%

1c
 determi
-
1c
 of 7.2% 
(normal: less than 6%) and a mean blood glucose of 155 mg/
dL (8.6 mmol/L) were achieved using intensive therapy, 
while in the conventionally treated group HbA
1c
 averaged 
8.9% with an average blood glucose of 225 mg/dL (12.5 
mmol/L). Over the study period, which averaged 7 years, 
there was an approximately 60% reduction in risk between 
the two groups in regard to diabetic retinopathy, nephropa
-
thy, and neuropathy. The intensively treated group also had 
a nonsignificant reduction in the risk of macrovascular dis
-
ease of 41% (95% CI, –10 to 68). Intensively treated patients 
had a threefold greater risk of serious hypoglycemia as well 
as a greater tendency toward weight gain. However, there 
were no deaths definitely attributable to hypoglycemia in 
any persons in the DCCT study, and no evidence of posthy
-
poglycemic cognitive damage was detected.
Subjects participating in the DCCT study were subse
-
quently enrolled in a follow-up observational study, the 
Epidemiology of Diabetes Interventions and Complica
-
tions (EDIC) study. Even though the between-group differ
-
ences in mean HbA
1c
 narrowed over 4 years, the group 
assigned to intensive therapy had a lower risk of retinopa
-
thy at 4 years, microalbuminuria at 7 to 8 years, and 
impaired GFR (less than 60 mL/min/1.73 m
2
) at 22 years of 
continued study follow-up. Moreover, by the end of the 
11-year follow-up period, the intensive therapy group had 
significantly reduced their risk of any cardiovascular dis
-
ease events by 42% (95% CI, 9% to 23%; 
P
 = 0.02). Thus, it 
seems that the benefits of good glucose control persist even 
if control deteriorates at a later date.
The general consensus of the ADA is that intensive 
insulin therapy associated with comprehensive self-
management training should become standard therapy in 
patients with type 1 diabetes mellitus after the age of 
puberty. Exceptions include those with advanced chronic 
kidney disease and older adults since in these groups the 
detrimental risks of hypoglycemia outweigh the benefits of 
tight glycemic control.
The United Kingdom Prospective Diabetes Study
, a 
multicenter study, was designed to establish, in type 2 dia
-
betic patients, whether the risk of macrovascular or micro
-
vascular complications could be reduced by intensive 
blood glucose control with oral hypoglycemic agents or 
insulin and whether any particular therapy was of 
advantage.
Intensive treatment with either sulfonylureas, metfor
-
min, combinations of those two, or insulin achieved mean 
HbA
1c
 levels of 7%. This level of glycemic control decreased 
CMDT19_Ch27_p1220-p1266.indd   1227

C
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1228
 CMDT 2019
the risk of microvascular complications (retinopathy and 
nephropathy) in comparison with conventional therapy 
(mostly diet alone), which achieved mean levels of HbA
1c
 
of 7.9%. Weight gain occurred in intensively treated 
patients except when metformin was used as monotherapy. 
No adverse cardiovascular outcomes were noted regardless 
of the therapeutic agent. In the overweight or obese sub
-
group, metformin therapy was more beneficial than diet 
alone in reducing the number of cases that progressed to 
diabetes as well as decreasing the number of patients who 
suffered myocardial infarctions and strokes. Hypoglycemic 
reactions occurred in the intensive treatment groups, but 
only one death from hypoglycemia was documented dur
-
ing 27,000 patient-years of intensive therapy.
Tight control of blood pressure (median value 144/82 
mm Hg vs 154/87 mm Hg) substantially reduced the risk of 
microvascular disease and stroke but not myocardial 
infarction. In fact, reducing blood pressure by this amount 
had substantially greater impact on microvascular out
-
comes than that achieved by lowering HbA
1c
 from 7.9% to 
7%. An epidemiologic analysis of the UKPDS data did 
show that every 10 mm Hg decrease in updated mean sys
-
tolic blood pressure was associated with 11% reduction in 
risk for myocardial infarction. More than half of the 
patients needed two or more medications for adequate 
therapy of their hypertension, and there was no demon
-
strable advantage of angiotensin-converting enzyme (ACE) 
inhibitor therapy over therapy with beta-blockers with 
regard to diabetes end points. Use of a calcium channel 
blocker added to both treatment groups appeared to be safe 
over the long term in this diabetic population despite some 
controversy in the literature about its safety in patients with 
diabetes.
Like the DCCT trialists, the UKPDS researchers per
-
formed post-trial monitoring to determine whether there 
were long-term benefits of having been in the intensively 
treated glucose and blood pressure arms of the study. The 
intensively treated group had significantly reduced risk of 
myocardial infarction (15%, 
P
 = 0.01) and death from any 
cause (13%, 
P
 = 0.007) during the follow-up period. The 
subgroup of overweight or obese subjects who were ini
-
tially randomized to metformin therapy showed sustained 
reduction in risk of myocardial infarction and death from 
any cause in the follow-up period. Unlike the sustained 
benefits seen with glucose control, there were no sustained 
benefits from having been in the more tightly controlled 
blood pressure group. Both blood pressure groups were at 
similar risk for microvascular events and diabetes-related 
end points during the follow-up period.
Thus, the follow-up of the UKPDS type 2 diabetes 
cohort showed that, as in type 1 diabetes, the benefits of 
good glucose control persist even if control deteriorates at 
a later date. Blood pressure benefits, however, last only as 
long as the blood pressure is well controlled.
The Diabetes Control and Complications Trial Research Group. 
The effect of intensive treatment of diabetes on the develop
-
ment and progression of long-term complications in insulin-
dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;
 
329(14):977–86. [PMID: 8366922]
UK Prospective Diabetes Study (UKPDS) Group. Intensive 
blood-glucose control with sulphonylureas or insulin com
-
pared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998 
Sep 12;352(9131):837–53. [PMID: 9742976]
 
»
Treatment Regimens
A. Diet
A well-balanced, nutritious diet remains a fundamental 
element of therapy. There is no specific recommendation 
on the percentage of calories that should come from carbo
-
hydrate, protein, and fat. The macronutrient proportions 
should be individualized based on the patient’s eating pat
-
terns, preferences, and metabolic goals. In general, most

-
-
terns, preferences, and metabolic goals. In general, most 
patients with diabetes consume about 45% of their total 
daily calories in the form of carbohydrates, 25–35% in the 
form of fat, and 10–35% in the form of protein. In patients 
with type 2 diabetes, limiting the carbohydrate intake and 
substituting some of the calories with monounsaturated 
fats, such as olive oil, rapeseed (canola) oil, or the oils in 
nuts and avocados, can lower triglycerides and increase 
HDL cholesterol. A Mediterranean-style eating pattern (a 
diet supplemented with walnuts, almonds, hazelnuts, and 
olive oil) has been shown to improve glycemic control 
and lower combined endpoints for cardiovascular events 
and stroke. In those patients with obesity and type 2 
diabetes, weight reduction by caloric restriction is an impor
-
tant goal of the diet (see Chapter 29). Patients with 
type 1 diabetes or type 2 diabetes who take insulin should be 
taught “carbohydrate counting, ” so they can administer their 
insulin bolus for each meal based on its carbohydrate content.
The current recommendations for saturated fats and 
dietary cholesterol intake for people with diabetes are 
the same as for the general population. Saturated fats 
should be limited to less than 10% of daily calories and 
dietary cholesterol intake should be less than 300 mg/day. 
For those patients with kidney disease, dietary protein 
should be maintained at the recommended daily allowance 
of 0.8g/kg/day. Exchange lists for meal planning can be 
obtained from the American Diabetes Association and its 
affiliate associations or from the American Dietetic Asso
-
ciation (http://www.eatright.org), 216 W . Jackson Blvd., 
Chicago, IL 60606 (312-899-0040).
1. Dietary fiber—
Plant components such as cellulose, 
gum, and pectin are indigestible by humans and are termed 
dietary “fiber. ” Insoluble fibers such as cellulose or hemi
-
cellulose, as found in bran, tend to increase intestinal tran
-
sit and may have beneficial effects on colonic function. In 
contrast, soluble fibers such as gums and pectins, as found 
in beans, oatmeal, or apple skin, tend to retard nutrient 
absorption rates so that glucose absorption is slower and 
hyperglycemia may be slightly diminished. Although its 
recommendations do not include insoluble fiber supple
-
ments such as added bran, the ADA recommends food 
such as oatmeal, cereals, and beans with relatively high 
soluble fiber content as staple components of the diet in 
diabetics. High soluble fiber content in the diet may also 
have a favorable effect on blood cholesterol levels.
CMDT19_Ch27_p1220-p1266.indd   1228

1229
 
CMDT 2019
2. Glycemic index—
The glycemic index of a carbohy
-
drate containing food is determined by comparing the 
glucose excursions after consuming 50 g of test food 
with glucose excursions after consuming 50 g of reference 
food (white bread): 
Glyc
em
ic
inde
x
Bl
ood
/uni00A0g
lucose
/uni00A0are
au
nder
th
e
curve/uni00A0(3h)/uni00A0f
or
/uni00A0test/uni00A0f
ood
Bl
ood
/uni00A0glucose/uni00A0are
au
nder
th
e
or
/uni00A0reference/uni00A0f
ood
100
=×
Eating low glycemic index foods results in lower glucose 
levels after meals. Low glycemic index foods have values of 
55 or less and include many fruits, vegetables, grainy breads, 
pasta, and legumes. High glycemic index foods have values 
of 70 or greater and include baked potato, white bread, and 
white rice. Glycemic index is lowered by presence of fats 
and protein when food is consumed in a mixed meal. Even 
though it may not be possible to accurately predict the gly
-
cemic index of a particular food in the context of a meal, it 
is reasonable to choose foods with low glycemic index.
3. Artificial and other sweeteners—
Saccharin (Sweet N 
Low), sucralose (Splenda), acesulfame potassium (Sweet 
One), and rebiana (Truvia) are “artificial” sweeteners that 
can be used in cooking and baking. Aspartame (NutraSweet) 
lacks heat stability, so it cannot be used in cooking. None 
of these sweeteners raise blood glucose levels.
Fructose represents a “natural” sugar substance that is a 
highly effective sweetener, induces only slight increases in 
plasma glucose levels, and does not require insulin for its 
metabolism. However, because of potential adverse effects of 
large amounts of fructose on raising serum cholesterol, tri
-
glycerides, and LDL cholesterol, it does not have any advan
-
tage as a sweetening agent in the diabetic diet. This does not 
preclude, however, ingestion of fructose-containing fruits 
and vegetables or fructose-sweetened foods in moderation.
Sugar alcohols, also known as polyols or polyalcohol, are 
commonly used as sweeteners and bulking agents. They 
occur naturally in a variety of fruits and vegetables but are 
also commercially made from sucrose, glucose, and starch. 
Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, 
maltitol, and hydrogenated starch hydrolysates (HSH). They 
are not as easily absorbed as sugar, so they do not raise blood 
glucose levels as much. Therefore, sugar alcohols are often 
used in food products that are labeled as “sugar free, ” such as 
chewing gum, lozenges, hard candy, and sugar-free ice 
cream. However, if consumed in large quantities, they will 
raise blood glucose and can cause bloating and diarrhea.
B. Medications for Treating Hyperglycemia
The medications for treating type 2 diabetes are listed in 
Table 27–5.
1. Medications that primarily stimulate insulin secretion 
by binding to the sulfonylurea receptor on the beta cell—
a. 
S
ulfonylureas—
The primary mechanism of action of 
the sulfonylureas is to stimulate insulin release from pan
-
creatic B cells.
Sulfonylureas are used in patients with type 2 but not 
type 1 diabetes, since these medications require function
-
ing pancreatic B cells to produce their effect on blood glu
-
cose. Sulfonylureas are metabolized by the liver and apart 
from acetohexamide, whose metabolite is more active than 
the parent compound, the metabolites of all the other sul
-
fonylureas are weakly active or inactive. The metabolites 
are excreted by the kidney and, in the case of the second-
generation sulfonylureas, partly excreted in the bile.
Hypoglycemia is a common adverse reaction with the 
sulfonylureas. Weight gain is also common, especially in 
the first year of use. The mechanisms of the weight gain 
include improved glucose control and increased food 
intake in response to hypoglycemia.
Idiosyncratic reactions are rare, with skin rashes or 
hematologic toxicity (leukopenia, thrombocytopenia)

hematologic toxicity (leukopenia, thrombocytopenia) 
occurring in less than 0.1% of users.
(1) First-generation sulfonylureas (tolbutamide, tolaza
-
mide, acetohexamide, chlorpropamide)—
Tolbutamide
 is 
rapidly oxidized in the liver to inactive metabolites, and its 
approximate duration of effect is relatively short 
(6–10 hours). Tolbutamide is probably best administered 
in divided doses (eg, 500 mg before each meal and at bed
-
time); however, some patients require only one or two 
tablets daily with a maximum dose of 3000 mg/day. 
Because of its short duration of action, which is indepen
-
dent of kidney function, tolbutamide is relatively safe to 
use in kidney disease. Prolonged hypoglycemia has been 
reported rarely with tolbutamide, mostly in patients receiv
-
ing antibacterial sulfonamides (sulfisoxazole), phenylbuta
-
zone for arthralgias, or the oral azole antifungal medications 
to treat candidiasis. These medications apparently compete 
with tolbutamide for oxidative enzyme systems in the liver, 
resulting in maintenance of high levels of unmetabolized, 
active sulfonylurea in the circulation.
Tolazamide, acetohexamide, and chlorpropamide are 
rarely used. Chlorpropamide has a prolonged biologic 
effect, and severe hypoglycemia can occur especially in 
older adults as their renal clearance declines with aging. Its 
other side effects include alcohol-induced flushing and 
hyponatremia due to its effect on vasopressin secretion and 
action. 
(2) Second-generation sulfonylureas (glyburide, glipi
zide, 
gliclazide, glimepiride)—
Glyburide, glipizide, gliclazide, 
and glimepiride are 100–200 times more potent than tolbu
-
tamide. These medications should be used with caution in 
patients with cardiovascular disease or in elderly patients, 
in whom prolonged hypoglycemia would be especially 
dangerous.
The usual starting dose of 
glyburide
 is 2.5 mg/day, and 
the average maintenance dose is 5–10 mg/day given as a 
single morning dose; maintenance doses higher than 
20 mg/day are not recommended. Some reports suggest 
that 10 mg is a maximum daily therapeutic dose, with 
15–20 mg having no additional benefit in poor responders 
and doses over 20 mg actually worsening hyperglycemia. A 
“Press Tab” formulation of “micronized” glyburide—easy 
to divide in half with slight pressure if necessary—is avail
-
able. Glyburide is metabolized in the liver and the meta
-
bolic products of glyburide have hypoglycemic activity.
CMDT19_Ch27_p1220-p1266.indd   1229

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1230
 CMDT 2019
 
Drugs for treatment of type 2 diabetes mellitus.
Drug
Tablet Size
Daily Dose
Acetohexamide (Dymelor)
250 and 500 mg
0.25–1.5 g as single dose or in two divided doses
8–24 hours
Chlorpropamide (Diabinese)
100 and 250 mg
0.1–0.5 g as single dose
24–72 hours
Gliclazide (not available in 
80 mg
40–80 mg as single dose; 160–320 mg as divided 
dose
12 hours
Glimepiride (Amaryl)
1, 2, and 4 mg
1–4 mg once a day is usual dose; 8 mg once a day 
is maximal dose
Up to 24 hours
Glipizide
 
(Glucotrol)
5 and 10 mg
2.5–40 mg as a single dose or in two divided doses 
30 minutes before meals
6–12 hours
 
(
Glucotrol XL)
2.5, 5, and 10 mg
2.5 to 10 mg once a day is usual dose; 20 mg once 
a day is maximal dose
Glyburide
 
(Dia B
eta, Micronase)
1.25, 2.5, and 5 mg
1.25–20 mg as single dose or in two divided doses
 
(Glynase)
1.5, 3, and 6 mg
1.5–12 mg as single dose or in two divided doses
Tolazamide (Tolinase)
100, 250, and 500 mg
0.1–1 g as single dose or in two divided doses
Tolbutamide (Orinase)
0.5–2 g in two or three divided doses
6–12 hours
Meglitinide Analogs
Mitiglinide (available in Japan)
5 and 10 mg
5 or 10 mg three times a day before meals
2 hours
Repaglinide (Prandin)
0.5, 1, and 2 mg
0.5 to 4 mg three times a day before meals
3 hours
d
-Phenylalanine Derivative
Nateglinide (Starlix)
60 and 120 mg
60 or 120 mg three times a day before meals
1.5 hours
Biguanides
Metformin (Glucophage)
500, 850, and 1000 mg
1–2.5 g; 1 tablet with meals two or three times 
daily
7–12 hours
Metformin, extended release 
(Glucophage XR)
500 and 750 mg
500–2000 mg once a day
Thiazolidinediones
Pioglitazone (Actos)
15, 30, and 45 mg
15–45 mg daily
Rosiglitazone (Avandia)
2, 4, and 8 mg
4–8 mg daily (can be divided)
Alpha-Glucosidase Inhibitors
Acarbose (Precose)
50 and 100 mg
25–100 mg three times a day just before meals
4 hours
Miglitol (Glyset)
25, 50, and 100 mg
4 hours
Voglibose (not available in 
0.2 and 0.3 mg
0.2–0.3 mg three times a day just before meals
4 hours
GLP-1 
r
eceptor Agonists
Albiglutide (Tanzeum)
30-, 50-mg single-dose pen 
(powder)
Mix with diluent and inject subcutaneously. 30 mg 
is usual dose. Dose can be increased to 50 mg if 
1 week
Dulaglutide (Trulicity)
0.75-, 1.5-mg single-dose 
pen or prefilled syringe
0.75 mg subcutaneously. Dose can be increased to 
1.5 mg if necessary.
1 week
Exenatide (Byetta)
1.2 mL and 2.4 mL prefilled 
pens delivering 5 mcg 
and 10 mcg doses
5 mcg subcutaneously twice a day within 1 hour of 
breakfast and dinner. Increase to 10 mcg subcu
-
taneously twice a day after about a month
AVOID
 when CrCl < 30 mL/min
6 hours
Exenatide, long-acting release 
(Byetta LAR, Bydureon)
2 mg (powder)
Suspend in provided diluent and inject 
subcutaneously.
1 week
(
continued
 
)
CMDT19_Ch27_p1220-p1266.indd   1230

1231
 
CMDT 2019
 
Drug
Daily Dose
Liraglutide (Victoza)
Prefilled, multi-dose pen 
that delivers doses of 
0.6 mg, 1.2 mg, or 
 
1.8 mg
0.6 mg subcutaneously once a day (starting dose). 
Increase to 1.2 mg after a week if no adverse 
reactions. Dose can be further increased to 
1.8 mg, if necessary.
24 hours
Lixisenatide (Adlyxin, Lyxumia)
3-mL prefilled pens 
delivering 10- or 
20-mcg doses
10 mcg daily. Increase to 20 mcg daily after 
2 weeks.
24 hours
Semaglutide (Ozempic)
Prefilled pens delivering 
0.25 mg or 0.5 mg; and 
1 mg
0.25 mg weekly for 1 month and increase to 
0.5 mg weekly if no adverse reactions. Dose 
can be further increased to 1 mg weekly
1 week
DPP-4 Inhibitors
Alogliptin (Nesina)
6.25, 12.5, and 25 mg
25 mg once daily; CrCl 30–59 mL/min: 12.5 mg 
daily; CrCl < 30 mL/min: 6.25 mg daily.
24 hours
Linagliptin (Tradjenta)
5 mg
5 mg daily
24 hours
Saxagliptin (Onglyza)
2.5 and 5 mg
2.5 mg or 5 mg once daily. CrCl ≤ 50 mL/min or 
 
if also taking drugs that are strong CYP3A4/5 
inhibitors such as ketoconazole: 2.5 mg daily.
24 hours
Sitagliptin (Januvia)
100 mg once daily; CrCl 30–50 mL/min: 50 mg 
once daily; CrCl < 30 mL/min: 25 mg once 
 
daily
24 hours
Vildagliptin (Galvus) (not avail
-
able in United States)
50 mg
50 mg once or twice daily.
AVOID
 if CrCl ≤ 60 mL/min or AST/ALT three 
 
times upper limit of normal
24 hours
SGLT2 Inhibitors
Canagliflozin (Invokana)
100 and 300 mg
100 mg daily is usual dose. 
Do not use if eGF
r
 
< 45 mL/min/1.72 m
2
.
300-mg dose can be used if normal eGFR, 
resulting in lowering the HbA
1c
 an 
 
additional 
∼
 0.1–0.25%.
24 hours
Dapagliflozin (Farxiga)
5 and 10 mg
10 mg daily. Use 5-mg dose in hepatic failure.
24 hours
Empagliflozin (Jardiance)
10 and 25 mg
10 mg daily. 25-mg dose can be used if necessary.
24 hours
Others
Bromocriptine (Cycloset)
0.8 mg
0.8 mg daily. Increase weekly by 1 tablet until 
maximal tolerated dose of 1.6–4.8 mg daily.
24 hours
Colesevelam (Welchol)
625 mg
3 tablets twice a day
24 hours
Pramlintide (Symlin)
5-mL vial containing 
0.6 mg/mL; also available 
as prefilled pens. Symlin 
pen 60 or Symlin pen 
 
120 (subcutaneous 
injection)
For insulin-treated type 2 patients, start at 
60-mcg dose three times a day (10 units on 
U100 insulin syringe). Increase to 120 mcg 
three times a day (20 units on U100 insulin 
syringe) if no nausea for 3–7 days. Give 
immediately before meal.
2 hours
For type 1 patients, start at 15 mcg three times a 
day (2.5 units on U100 insulin syringe) and 
increase by increments of 15 mcg to a 
 
maximum of 60 mcg three times a day, as 
To avoid hypoglycemia, lower insulin dose by 
 
50% on initiation of therapy.
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CrCl, creatinine clearance by estimated glomerular filtration rate.
 
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Glyburide has few adverse effects other than its poten
-
tial for causing hypoglycemia, which at times can be pro
-
longed. Flushing has rarely been reported after ethanol 
ingestion. It does not cause water retention, as chlorprop
-
amide does, but rather slightly enhances free water clear
-
ance. Glyburide should not be used in patients with liver 
failure and chronic kidney disease because of the risk of 
hypoglycemia. Elderly patients are at particular risk for 
hypoglycemia even with relatively small daily doses.
The recommended starting dose of 
glipizide
 is 
5 mg/day, with up to 15 mg/day given as a single daily dose 
before breakfast. When higher daily doses are required, 
they should be divided and given before meals. The maxi
-
mum dose recommended by the manufacturer is 40 mg/d, 
although doses above 10–15 mg probably provide little 
additional benefit in poor responders and may even be 
less
 
effective than smaller doses. For maximum effect in reduc
-
ing postprandial hyperglycemia, glipizide should be 
ingested 30 minutes before meals, since rapid absorption is 
delayed when the medication is taken with food.
At least 90% of glipizide is metabolized in the liver to 
inactive products, and 10% is excreted unchanged in the 
urine. Glipizide therapy should therefore not be used in 
patients with liver failure. Because of its lower potency and 
shorter duration of action, it is preferable to glyburide in 
elderly patients and for those patients with kidney disease. 
Glucotrol-XL provides extended release of glipizide during 
transit through the gastrointestinal tract with greater effec
-
tiveness in lowering prebreakfast hyperglycemia than the 
shorter-duration immediate-release standard glipizide tab
-
lets. However, this formulation appears to have sacrificed 
its lower propensity for severe hypoglycemia compared 
with longer-acting glyburide without showing any demon
-
strable therapeutic advantages over glyburide.
Gliclazide
 (not available in the United States) is another 
intermediate duration sulfonylurea with a duration of 
action of about 12 hours. The recommended starting dose 
is 40–80 mg/day with a maximum dose of 320 mg. Doses 
of 160 mg and above are given as divided doses before 
breakfast and dinner. The medication is metabolized by the 
liver; the metabolites and conjugates have no hypoglycemic 
effect. An extended release preparation is available.
Glimepiride
 has a long duration of effect with a half-
life of 5 hours allowing once or twice daily dosing. 
Glimepiride achieves blood glucose lowering with the low
-
est dose of any sulfonylurea compound. A single daily dose 
of 1 mg/day has been shown to be effective, and the maxi
-
mal recommended dose is 8 mg. It is completely metabo
-
lized by the liver to relatively inactive metabolic products.
b. 
M
eglitinide analogs—
Repaglinide
 is structurally 
similar to glyburide but lacks the sulfonic acid-urea moiety. 
It acts by binding to the sulfonylurea receptor and closing 
the adenosine triphosphate (ATP)-sensitive potassium 
channel. It is rapidly absorbed from the intestine and then 
undergoes complete metabolism in the liver to inactive 
biliary products, giving it a plasma half-life of less than 
1 hour. The medication therefore causes a brief but rapid 
pulse of insulin. The starting dose is 0.5 mg three times a 
day 15 minutes before each meal. The dose can be titrated 
to a maximum daily dose of 16 mg. Like the sulfonylureas, 
repaglinide can be used in combination with metformin. 
Hypoglycemia is the main side effect. Like the sulfonyl
-
ureas, repaglinide causes weight gain. Metabolism is by 
cytochrome P450 3A4 isoenzyme, and other medications 
that induce or inhibit this isoenzyme may increase or 
inhibit (respectively) the metabolism of repaglinide. The 
medication may be useful in patients with kidney impair
-
ment or in older adults.
Mitiglinide
 is a benzylsuccinic acid derivative that

-
 is a benzylsuccinic acid derivative that 
binds to the sulfonylurea receptor and is similar to repa
-
glinide in its clinical effects. It is approved for use in Japan.
c. 
D
-phenylalanine derivative—
Nateglinide
 stimu
-
lates insulin secretion by binding to the sulfonylurea recep
-
tor and closing the ATP-sensitive potassium channel. This 
compound is rapidly absorbed from the intestine, reaching 
peak plasma levels within 1 hour. It is metabolized in the 
liver and has a plasma half-life of about 1.5 hours. Like 
repaglinide, it causes a brief rapid pulse of insulin, and 
when given before a meal it reduces the postprandial rise in 
blood glucose. For most patients, the recommended start
-
ing and maintenance dose is 120 mg three times a day 
before meals. Use 60 mg in patients who have mild eleva
-
tions in HbA
1c
. Like the other insulin secretagogues, its 
main side effects are hypoglycemia and weight gain.
2. Medications that primarily lower glucose levels by 
their actions on the liver, muscle, and adipose tissue—
a. 
M
etformin—
Metformin is the first-line therapy for 
patients with type 2 diabetes. It can be used alone or in 
conjunction with other oral agents or insulin in the treat
-
ment of patients with type 2 diabetes. It is ineffective in 
patients with type 1 diabetes.
Metformin’s therapeutic effects primarily derive from 
the increasing hepatic adenosine monophosphate-
 
activated protein kinase activity, which reduces hepatic 
gluconeogenesis and lipogenesis.
Metformin has a half-life of 1.5–3 hours, is not bound 
to plasma proteins or metabolized, being excreted 
unchanged by the kidneys.
The current recommendation is to start metformin at 
diagnosis. A side benefit of metformin therapy is its ten
-
dency to improve both fasting and postprandial hypergly
-
cemia and hypertriglyceridemia in obese patients with 
diabetes without the weight gain associated with insulin or 
sulfonylurea therapy. Patients with chronic kidney disease 
should not be given this medication because failure to 
excrete it would produce high blood and tissue levels of 
metformin that could stimulate lactic acid overproduction. 
In the United States, metformin use is not recommended at 
or above a serum creatinine level of 1.4 mg/dL in women 
and 1.5 mg/dL in men. In the United Kingdom, the recom
-
mendations are to review metformin use when the serum 
creatinine exceeds 130 mcmol/L (1.5 mg/dL) or the esti
-
mated glomerular filtration rate (eGFR) falls below 
45 mL/min per 1.73 m
2
. The medication should be stopped 
if the serum creatinine exceeds 150 mcmol/L (1.7mg/dL) 
or the eGFR is below 30 mL/min per 1.73 m
2
liver failure or persons with excessive alcohol intake should 
not receive this medication—lactic acid production 
from the gut and other tissues, which rises during 
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metformin therapy, could result in lactic acidosis when 
defective hepatocytes cannot remove the lactate or when 
alcohol-induced reduction of nucleotides interferes with 
lactate clearance.
The maximum dosage of metformin is 2550 mg, 
although little benefit is seen above a total dose of 2000 mg. 
It is important to begin with a low dose and increase the 
dosage very gradually in divided doses—taken with 
meals—to reduce minor gastrointestinal upsets. A com
-
mon schedule would be one 500-mg tablet three times a 
day with meals or one 850- or 1000-mg tablet twice daily at 
breakfast and dinner. Up to 2000 mg of the extended-
release preparation can be given once a day. Lower doses 
should be used in patients with eGFRs between 30 and 
2
. Lower doses should also be used 
in the elderly who have reduced renal functional reserve 
and are at higher risk for acute kidney injury.
The most frequent side effects of metformin are gastro
-
intestinal symptoms (anorexia, nausea, vomiting, abdomi
-
nal discomfort, diarrhea), which occur in up to 20% of 
patients. These effects are dose-related, tend to occur at 
onset of therapy, and often are transient. However, in 3–5% 
of patients, therapy may have to be discontinued because of 
persistent diarrheal discomfort. Patients switching from 
immediate-release metformin to comparable dose of 
extended-release metformin may experience fewer gastro
-
intestinal side effects.
Hypoglycemia does not occur with therapeutic doses of 
metformin, which permits its description as a “euglycemic” 
or “antihyperglycemic” medication rather than an oral 
hypoglycemic agent. Dermatologic or hematologic toxicity 
is rare. Metformin interferes with the calcium dependent 
absorption of vitamin B
12
-intrinsic complex in the terminal 
ileum; vitamin B
12
 deficiency can occur after many years of 
metformin use. Periodic screening with vitamin B
12
 levels 
should be considered, especially in patients with peripheral 
neuropathy or if a macrocytic anemia develops. Increased 
intake of dietary calcium may prevent the metformin-
induced B
12
 malaborption.
Lactic acidosis has been reported as a side effect but is 
uncommon with metformin in contrast to phenformin. 
Almost all reported cases have involved persons with associ
-
ated risk factors that should have contraindicated its use 
(kidney, liver, or cardiorespiratory insufficiency and alco
-
holism). Acute kidney injury can occur rarely in certain 
patients receiving radiocontrast agents. Metformin therapy 
should therefore be temporarily halted on the day of radio
-
contrast administration and restarted a day or two later after 
confirmation that kidney function has not deteriorated.
b. 
T
hiazolidinediones—
Two medications of this class, 
rosiglitazone and pioglitazone, are available for clinical use. 
These medications sensitize peripheral tissues to insulin. 
They bind the nuclear receptor peroxisome proliferator-
activated receptor gamma (PPAR-gamma) and affect the 
expression of a number of genes. Like the biguanides, this 
class of medications does not cause hypoglycemia.
Both rosiglitazone and pioglitazone are effective as 
monotherapy and in combination with sulfonylureas or 
metformin or insulin, lowering HbA
1c
 by 1–2%. When used 
in combination with insulin, they can result in a 30–50% 
reduction in insulin dosage, and some patients can come off 
insulin completely. The dosage of rosiglitazone is 4–8 mg 
daily and of pioglitazone, 15–45 mg daily, and the medica
-
tions do not have to be taken with food. Rosiglitazone is 
primarily metabolized by the CYP 2C8 isoenzyme and 
pioglitazone is metabolized by CYP 2C8 and CYP 3A4.
The combination of a thiazolidinedione and metformin 
has the advantage of not causing hypoglycemia. Patients inad
-
equately managed on sulfonylureas can do well on a combi
-
nation of sulfonylurea and rosiglitazone or pioglitazone.

-
-
These medications have some additional effects apart 
from glucose lowering. Rosiglitazone therapy is associated 
with increases in total cholesterol, LDL cholesterol (15%), 
and HDL cholesterol (10%). There is a reduction in free 
fatty acids of about 8–15%. The changes in triglycerides are 
generally not different from placebo. Pioglitazone in clini
-
cal trials lowered triglycerides (9%) and increased HDL 
cholesterol (15%) but did not cause a consistent change in 
total cholesterol and LDL cholesterol levels. A prospective 
randomized comparison of the metabolic effects of piogli
-
tazone and rosiglitazone showed similar effects on HbA
1c
 
and weight gain. Small prospective studies have demon
-
strated that treatment with these medications leads to 
improvements in the biochemical and histologic features of 
nonalcoholic fatty liver disease. The thiazolidinediones 
also may limit vascular smooth muscle proliferation after 
injury, and there are reports that pioglitazone can reduce 
neointimal proliferation after coronary stent placement. In 
one double-blind, placebo-controlled study, rosiglitazone 
was shown to be associated with a decrease in the ratio of 
urinary albumin to creatinine excretion.
Safety concerns
 and some troublesome side effects 
limit the use of this class of medication. Rosiglitazone use 
declined when a meta-analysis of 42 randomized clinical 
trials suggested that this medication increases the risk of 
angina pectoris or myocardial infarction; the European 
Medicines Agency suspended the use of rosiglitazone in 
Europe. In the United States, the FDA established a 
restricted distribution program. A subsequent large pro
-
spective clinical trial (the RECORD study) failed to con
-
firm the meta-analysis finding and the restrictions were 
lifted in the United States.
Edema occurs in about 3–4% of patients receiving 
monotherapy with rosiglitazone or pioglitazone. The edema 
occurs more frequently (10–15%) in patients receiving con
-
comitant insulin therapy and may result in heart failure. The 
medications are contraindicated in diabetic individuals with 
New Y ork Heart Association class III and IV cardiac status. 
Thiazolidinediones have also been reported as being associ
-
ated with new onset or worsening macular edema. Appar
-
ently, this is a rare side effect, and most of these patients also 
had peripheral edema. The macular edema resolved or 
improved once the medication was discontinued.
An increase in fracture risk in women (but not men) 
has been reported with both rosiglitazone and piogli
-
tazone. The fracture risk is in the range of 1.9 per 100 
patient-years with the thiazolidinedione compared to 1.1 
per 100 patient-years on comparison treatment. In at least 
one study of rosiglitazone, the fracture risk was increased 
in premenopausal as well as postmenopausal women.
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Other side effects include anemia, which occurs in 4% 
of patients treated with these medications; it may be due to 
a dilutional effect of increased plasma volume rather than 
a reduction in red cell mass. Weight gain occurs, especially 
when the medication is combined with a sulfonylurea or 
insulin. Some of the weight gain is fluid retention, but there 
is also an increase in total fat mass. There have been con
-
cerns regarding an association of bladder cancer with pio
-
glitazone use. Clinical studies have reported conflicting 
results. A 10-year observational cohort study of patients 
taking pioglitazone failed to find an association with blad
-
der cancer. A large multipopulation pooled analysis 
(1.01 million persons over 5.9 million person-years) also 
failed to find an association between cumulative exposure 
of pioglitazone or rosiglitazone and incidence of bladder 
cancer. Another population based study, however, generat
-
ing 689,616 person-years of follow-up did find that piogli
-
tazone but not rosiglitazone was associated with an 
increased risk of bladder cancer.
Troglitazone, the first medication in this class, was 
withdrawn from clinical use because of medication-
associated fatal liver failure. Although rosiglitazone and 
pioglitazone have not been reported to cause liver injury, 
the FDA recommends that they should not be used in 
patients with clinical evidence of active liver disease or 
pretreatment elevation of the alanine aminotransferase 
(ALT) level that is 2.5 times greater than the upper limit of 
normal. Liver biochemical tests should be performed prior 
to initiation of treatment and periodically thereafter.
3. Medications that affect absorption of glucose—
Alpha-
glucosidase inhibitors competitively inhibit the alpha-
glucosidase enzymes in the gut that digest dietary starch 
and sucrose. Two of these medications—acarbose and 
miglitol—are available for clinical use in the United States. 
Voglibose, another alpha-glucosidase inhibitor is available 
in Japan, Korea, and India. Acarbose and miglitol are 
potent inhibitors of glucoamylase, alpha-amylase, and 
sucrase but have less effect on isomaltase and hardly any on 
trehalase and lactase.
a. 
A
carbose—
The recommended starting dose of acar
-
bose is 50 mg twice daily, gradually increasing to 100 mg 
three times daily. For maximal benefit on postprandial 
hyperglycemia, acarbose should be given with the first 
mouthful of food ingested. In diabetic patients, it reduces 
postprandial hyperglycemia by 30–50%, and its overall 
effect is to lower the HbA
1c
 by 0.5–1%.
The principal adverse effect, seen in 20–30% of patients, 
is flatulence. This is caused by undigested carbohydrate 
reaching the lower bowel, where gases are produced by 
bacterial flora. In 3% of cases, troublesome diarrhea occurs. 
This gastrointestinal discomfort tends to discourage exces
-
sive carbohydrate consumption and promotes improved 
compliance of type 2 patients with their diet prescriptions. 
When acarbose is given alone, there is no risk of hypoglyce
-
mia. However, if combined with insulin or sulfonylureas, it 
might increase the risk of hypoglycemia from these agents. 
A slight rise in hepatic aminotransferases has been noted in 
clinical trials with acarbose (5% vs 2% in placebo controls, 
and particularly with doses greater than 300 mg/day). The 
levels generally return to normal on stopping the 
medication.
b. 
M
iglitol—
Miglitol is similar to acarbose in terms of its 
clinical effects. It is indicated for use in diet- or sulfonyl
-
urea-treated patients with type 2 diabetes. Therapy is initi
-
ated at the lowest effective dosage of 25 mg three times a 
day. The usual maintenance dose is 50 mg three times a 
day, although some patients may benefit from increasing 
the dose to 100 mg three times a day. Gastrointestinal side 
effects occur as with acarbose. The medication is not 
metabolized and is excreted unchanged by the kidney.

metabolized and is excreted unchanged by the kidney. 
Miglitol should not be used in end-stage chronic kidney 
disease, when its clearance would be impaired.
4. Incretins—
Oral glucose provokes a threefold to fourfold 
higher insulin response than an equivalent dose of glucose 
given intravenously. This is because the oral glucose causes 
a release of gut hormones, principally glucagon-like peptide 
1 (GLP-1) and glucose-dependent insulinotropic polypep
-
tide (GIP1), that amplify the glucose-induced insulin 
release. This “incretin effect” of GLP-1 secretion (but not 
GIP1 secretion) is reduced in patients with type 2 diabetes 
and when GLP-1 is infused in patients with type 2 diabetes, 
it stimulates insulin secretion and lowers glucose levels. 
GLP-1, unlike the sulfonylureas, has only a modest insulin 
stimulatory effect at normoglycemic concentrations. This 
means that GLP-1 has a lower risk for hypoglycemia than 
the sulfonylureas.
In addition to its insulin stimulatory effect, GLP-1 also 
has a number of other pancreatic and extrapancreatic 
effects. It suppresses glucagon secretion and so may ame
-
liorate the hyperglucagonemia that is present in people 
with diabetes and improve postprandial hyperglycemia. 
GLP-1 acts on the stomach delaying gastric emptying; the 
importance of this effect on glucose lowering is illustrated 
by the observation that antagonizing the deceleration of 
gastric emptying markedly reduces the glucose lowering 
effect of GLP-1. GLP-1 receptors are present in the central 
nervous system and may play a role in the anorectic effect 
of the drugs. Type 2 diabetic patients undergoing GLP-1 
infusion are less hungry; it is unclear whether this is mainly 
due to a deceleration of gastric emptying or whether there 
is a central nervous system effect as well.
a. 
GLP
-1 receptor agonists—
GLP-1’s half-life is only 
1–2 minutes. It is rapidly proteolyzed by dipeptidyl pepti
-
dase 4 (DPP-4) and by other enzymes, such as endopepti
-
dase 24.11, and is also cleared quickly by the kidney. The 
native peptide, therefore, cannot be used therapeutically. 
Six GLP-1 receptor agonists with longer half-lives, exena
-
tide, liraglutide, albiglutide, dulaglutide, lixisenatide and 
semaglutide are available for clinical use.
(1) Dosages and pharmacokinetics—
Exenatide
 (Exen
-
din 4) is a GLP-1 receptor agonist isolated from the saliva of 
the Gila monster (a venomous lizard) that is more resistant 
to DPP-4 action and cleared by the kidney. Its half-life is 
2.4 hours, and its glucose lowering effect is about 6 hours. 
Exenatide is dispensed as two fixed-dose pens (5 mcg and 
10 mcg). It is injected 60 minutes before breakfast and 
before dinner. Patients with type 2 diabetes should be pre
-
scribed the 5 mcg pen for the first month and, if tolerated, 
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the dose can then be increased to 10 mcg twice a day. The 
medication is not recommended in patients with eGFR less 
than 30 mL/min. In clinical trials, adding exenatide therapy 
to patients with type 2 diabetes already taking metformin or 
a sulfonylurea, or both, further lowered the HbA
1c
 value by 
0.4% to 0.6% over a 30-week period. These patients also 
experienced a weight loss of 3–6 pounds. Exenatide LAR is 
a once-weekly preparation that is dispensed as a powder 
(2 mg). It is suspended in the provided diluent just prior to 
injection. In comparative clinical trials, the long-acting 
drug lowers the HbA
1c
 level a little more than the twice 
daily drug. Low-titer antibodies against exenatide develop 
in over one-third (38%) of patients, but the clinical effects 
are not attenuated. High-titer antibodies develop in a subset 
of patients (
∼
6%), and in about half of these cases, an 
attenuation of glycemic response has been seen.
Liraglutide
 is a soluble fatty acid acylated GLP-1 ana
-
log. The half-life is approximately 12 hours, allowing the 
medication to be injected once a day. The dosing is initi
-
ated at 0.6 mg daily, increased after 1 week to 1.2 mg daily. 
Some patients may benefit from increasing the dose to 
1.8 mg. In clinical trials lasting 26 and 52 weeks, adding 
liraglutide to the therapeutic regimen (metformin, sulfo
-
nylurea, thiazolidinedione) of patients with type 2 diabetes 
further lowered the HbA
1c
 value. Depending on the dose 
and design of the study, the HbA
1c
 decline was in the range 
of 0.6% to 1.5%. The patients had sustained weight loss of 
1–6 pounds. Liraglutide at a dose of 3 mg daily has been 
approved for weight loss.
In a postmarketing multinational study of 9340 patients 
with type 2 diabetes with known cardiovascular disease, the 
addition of liraglutide was associated with a lower primary 
composite outcome of death from cardiovascular causes, 
nonfatal myocardial infarction, or nonfatal stroke (hazard 
ratio 0.87, 
P
 = 0.01). Patients taking liraglutide had lower 
HbA
1c
 levels, weight loss of 2.3 kg, lower systolic blood pres
-
sure, and fewer episodes of severe hypoglycemia.
Albiglutide
 is a human GLP-1 dimer fused to human 
albumin. It is rendered resistant to DPP-4 action by a gly
-
cine substitution for alanine at position 8. The half-life of 
albiglutide is about 5 days and a steady state is reached after 
4–5 weeks of once-weekly administration. The usual dose 
is 30 mg weekly by subcutaneous injection. The dose can 
be increased to 50 mg weekly if necessary. The pen con
-
tains a lyophilized powder that is reconstituted just prior to 
administration. Albiglutide monotherapy and combination 
therapy lowers HbA
1c
 by about 0.8%. Weight loss is much 
less than with exenatide and liraglutide.
Dulaglutide
 consists of two GLP-1 analog molecules 
covalently linked to an Fc fragment of human IgG
4
. The 
GLP-1 molecule has amino acid substitutions that resist 
DPP-4 action. The half-life of dulaglutide is about 5 days. 
The usual dose is 0.75 mg weekly by subcutaneous injec
-
tion. The maximum recommended dose is 1.5 mg weekly. 
Dulaglutide monotherapy and combination therapy lowers 
HbA
1c
 by about 0.7% to 1.6%. Weight loss ranged from 
2 pounds to 7 pounds.
Lixisenatide
 is a synthetic analog of exendin 4 (deletion 
of a proline and addition of 6 lysines to the C-terminal 
region) with a half-life of 3 hours. It is dispensed as two 
fixed-dose pens (10 mcg and 20 mcg). The 10-mcg dose is 
injected once daily before breakfast for the first 2 weeks, 
and if tolerated, the dose is then increased to 20 mcg daily. 
Its clinical effect is about the same as exenatide with HbA
1c
 
lowering in the 0.4–0.6% range. Weight loss ranges from 
2 pounds to 6 pounds. Antibodies to lixisenatide occur 
frequently (70%) and 
∼
 2.4% with the highest antibody 
titers have attenuated glycemic response.
Semaglutide

∼
 is a synthetic analog of GLP-1 with an 
alpha-aminoisobutyric acid substitution at position 8 that 
makes the molecule resistant to DPP4 action and a C-18 
fatty di-acid chain attached to lysine at position 26 that 
binds to albumin and prolongs the drug half-life to about 
1 week. Semaglutide is dispensed as two pens: one pen 
delivers 0.25-mg or 0.5-mg dose and the other pen delivers 
1-mg dose. The recommended dosing is 0.25 mg weekly 
for 4 weeks and if tolerated the dose is then increased to 
0.5 mg per week. The 1-mg per week dose can provide 
additional glucose lowering effect. Semaglutide mono
-
therapy and combination therapy lowers HbA
1c
 from 1.5% 
to 1.8%. An increase in diabetic retinopathy was observed 
in the semaglutide treated group in one of the clinical tri
-
als. It is thought that this might have been secondary to the 
rapid glucose lowering with the drug. 
(2) Adverse effects of GLP-1 receptor agonists—
The most 
frequent adverse reactions of the GLP1 receptor agonists are 
nausea (11–40%), vomiting (4–13%), and diarrhea (9–17%). 
The reactions are more frequent at the higher doses. Albig
-
lutide tends to have the lowest rates of these reactions. In 
clinical trials about 1–5% of participants withdrew from the 
studies because of the gastrointestinal symptoms.
The GLP-1 receptor agonists have been associated with 
increased risk of pancreatitis. The pancreatitis was severe 
(hemorrhagic or necrotizing) in 6 instances, and 2 of these 
patients died. In the liraglutide, albiglutide, and dulaglutide 
clinical trials, there were 13, 6, and 5 cases of pancreatitis 
in the drug-treated groups versus 1, 2, and 1 case(s) in the 
comparator groups, respectively. This translates to about 
1.4–2.2 vs 0.6–0.9 cases of pancreatitis per 1000 patient-
years. 
Patients taking GLP-1 receptor agonists should be 
advised to seek immediate medical care if they experience 
unexplained persistent severe abdominal pain
.
There have been rare reports of acute kidney injury in 
patients taking exenatide. Some of these patients had pre
-
existing kidney disease, and others had one or more risk 
factors for kidney disease. A number of the patients 
reported nausea, vomiting, and diarrhea, and it is possible 
that these side effects caused volume depletion and con
-
tributed to the development of the kidney injury. For this 
reason, the GLP-1 receptors agonists should be prescribed 
cautiously in patients with kidney impairment.
GLP-1 receptor agonists stimulate C-cell neoplasia and 
cause medullary thyroid carcinoma in rats. Human C-cells 
express very few GLP1-receptors, and the relevance to 
human therapy is unclear. The medications, however, 
should not be used in patients with personal or family his
-
tory of medullary thyroid carcinoma or multiple endocrine 
neoplasia (MEN) syndrome type 2.
b. 
DPP
-4 inhibitors—
An alternate approach to the use 
of GLP-1 receptor agonists is to inhibit the enzyme DPP-4 
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and prolong the action of endogenously released GLP-1 
and GIP . Four oral DPP-4 inhibitors, sitagliptin, saxa
-
gliptin, linagliptin, and alogliptin, are available in the 
United States for the treatment of type 2 diabetes. An addi
-
tional DPP-4 inhibitor, vildagliptin, is available in Europe. 
Other DPP-4 inhibitors—gemigliptin, anagliptin, teneli
-
gliptin, trelagliptin, omarigliptin, evogliptin, and goso
-
gliptin—have been approved outside the United States and 
European Union (Korea, India, Thailand, Japan, Russia, 
and several South American countries).
Sitagliptin
, when used alone or in combination with 
other diabetes medications lowers HbA
1c
 by approximately 
0.5%. The usual dose of sitagliptin is 100 mg once daily, but 
the dose is reduced to 50 mg daily if the calculated creati
-
nine clearance is 30–50 mL/min and to 25 mg for clear
-
ances less than 30 mL/min. Unlike exenatide, sitagliptin 
does not cause nausea or vomiting. It also does not result 
in weight loss. The main adverse effect appears to be a 
predisposition to nasopharyngitis or upper respiratory 
tract infection. A small increase in neutrophil count of 
∼
200 cells/mcL has also occurred. There have been reports 
of serious allergic reactions to sitagliptin, including ana
-
phylaxis, angioedema, and exfoliative skin conditions 
including Stevens-Johnson syndrome. There have also 
been reports of pancreatitis. The frequency of these events 
is unclear.
Saxagliptin
, when added to the therapeutic regimen 
(metformin, sulfonylurea, thiazolidinedione) of patients 
with type 2 diabetes, further lowered the HbA
1c
 value by 
about 0.7–0.9%. The dose is 2.5 mg or 5 mg orally once a 
day. The 2.5-mg dose should be used in patients with cal
-
culated creatinine clearance less than 50 mL/min. The 
medication is weight neutral. The main adverse reactions 
are upper respiratory tract infection, nasopharyngitis, 
headache, and urinary tract infection. There is also small 
reversible dose-dependent reduction in absolute lympho
-
cyte count, which remains within normal limits. Hypersen
-
sitivity reactions, such as urticaria and facial edema, 
occurred in 1.5% of patients taking the medication com
-
pared with 0.4% receiving placebo. The metabolism of 
saxagliptin is by CYP3A4/5; thus, strong inhibitors or 
inducers of CYP3A4/5 (eg, ketoconazole, some anticonvul
-
sants, rifampin, and rifabutin) will affect the pharmacoki
-
netics of saxagliptin and its active metabolite. Saxagliptin 
may increase the risk of heart failure. In a post-marketing 
study of 16,492 type 2 diabetes patients, there were 289 
cases of heart failure in the saxagliptin group (3.5%) and 
228 cases in the placebo group (2.8%)—a hazard ratio of 
1.27. Patients at the highest risk for heart failure were those 
who had a history of heart failure or had elevated levels of 
N-terminal of the prohormone brain natriuretic peptide 
(NT-pBNP) or had kidney impairment.
Alogliptin
 lowers HbA
1c
 by about 0.5–0.6% when 
added to metformin, sulfonylurea, or pioglitazone. The 
usual dose is 25 mg orally daily. The 12.5-mg dose is used 
in patients with calculated creatinine clearance of 30 to 
60 mLs/min; and 6.25 mg for clearance less than 30 mL/min. 
In clinical trials, pancreatitis occurred in 11 of 5902 
patients on alogliptin (0.2%) and in 5 of 5183 patients 
receiving all comparators (less than 0.1%). There have been 
reports of hypersensitivity reactions (anaphylaxis, angio
-
edema, Stevens-Johnson syndrome). Cases of hepatic fail
-
ure have been reported but it is unclear if alogliptin was the 
cause. The medication, however, should be discontinued in 
the event of liver failure.
In a large post-marketing study, alogliptin, like saxa
-
gliptin, was associated with a slightly increased rate of 
Linagliptin
 lowers HbA
1c
 by about 0.4–0.6% when 
added to metformin, sulfonylurea, or pioglitazone. The

-
 lowers HbA
1c
dose is 5 mg orally daily, and, since it is primarily excreted 
unmetabolized via the bile, no dose adjustment is needed 
in patients with kidney disease. The adverse reactions 
include nasopharyngitis and hypersensitivity reactions 
(urticaria, angioedema, localized skin exfoliation, bron
-
chial hyperreactivity). In one study, there were eight cases 
of pancreatitis in 4687 patients exposed to drug (4311 
patient-years) with 0 cases in 1183 patients receiving pla
-
cebo (433 patient-years).
Vildagliptin
 lowers HbA
1c
 by about 0.5–1% when 
added to the therapeutic regimen of patients with type 2 
diabetes. The dose is 50 mg once or twice daily. Adverse 
reactions include upper respiratory tract infections, naso
-
pharyngitis, dizziness, and headache. Rare cases of hepatic 
dysfunction, including hepatitis, have been reported. Liver 
biochemical testing is recommended quarterly during the 
first year of use and periodically thereafter.
The FDA has issued a warning that the DPP-4 inhibi
-
tors can occasionally cause joint pains that resolve after 
stopping the drug.
5. Sodium-glucose co-transporter 2 inhibitors—
Glucose 
is freely filtered by the kidney glomeruli and is reabsorbed 
in the proximal tubules by the action of sodium-glucose 
co-transporters (SGLT). Sodium-glucose co-transporter 2 
(SGLT2) accounts for about 90% of glucose reabsorption 
and its inhibition causes glycosuria in people with diabetes, 
lowering plasma glucose levels. The SGLT2 inhibitors 
canagliflozin, dapagliflozin, and empagliflozin are 
approved for clinical use in the United States.
Canagliflozin
 reduces the threshold for glycosuria from 
a plasma glucose threshold of 
∼
180 mg/dL to 70–90 mg/dL. 
It has been shown to reduce HbA
1c
 by 0.6–1% when used 
alone or in combination with other oral agents or insulin. It 
also results in modest weight loss of 2–5 kg. The usual dose 
is 100 mg daily but up to 300 mg daily can be used in 
patients with normal kidney function.
Dapagliflozin
 is an SGLT2 inhibitor that has been 
shown to reduce HbA
1c
 levels by 0.5–0.8% when used alone 
or in combination with other oral agents or insulin. It also 
results in modest weight loss of about 2–4 kg. The usual 
dose is 10 mg daily but 5 mg daily is the recommended 
initial dose in patients with hepatic failure.
Empagliflozin
 reduces HbA
1c
 by 0.5–0.7% when used 
alone or in combination with other oral agents or insulin. 
It also results in modest weight loss of about 2–3 kg. The 
usual dosage is 10 mg daily but a higher dose of 25 mg daily 
can be used.
In a postmarketing multinational study of 7020 patients 
with type 2 diabetes with known cardiovascular disease, 
the addition of empagliflozin was associated with a lower 
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primary composite outcome of death from cardiovascular 
causes, nonfatal myocardial infarction, or nonfatal stroke 
(hazard ratio 0.86, 
P
 = 0.04). The mechanisms regarding 
the benefit remain unclear. Weight loss, lower blood pres
-
sure, and diuresis may have played a role since there were 
fewer deaths from heart failure in the treated group 
whereas the rates of myocardial infarction were unaltered. 
A similar multinational study was performed with the 
addition of canagliflozin. This was a study of 10,142 
patients with type 2 diabetes with known or at increased 
risk for cardiovascular disease. The canagliflozin treated 
group had a lower primary composite outcome of death 
from cardiovascular causes, nonfatal myocardial infarc
-
tion, or nonfatal stroke (hazard ratio 0.86, 
P
 = 0.02). There 
was, however, increased risk of amputations, especially of 
the toes. This study also showed benefit in terms of pro
-
gression of albuminuria.
As might be expected, the efficacy of the SGLT2 inhibi
-
tors is reduced in chronic kidney disease. They can also 
increase creatinine and decrease eGFR, especially in patients 
with kidney impairment. Canagliflozin is contraindicated in 
patients with eGFR less than 45 mL/min/1.73 m
2
. The 
main side effects are increased incidence of genital mycotic 
infections and urinary tract infections affecting 
∼
8–9% of 
patients. There have also been reports of cases of pyelone
-
phritis and septicemia requiring hospitalization. The gly
-
cosuria can cause intravascular volume contraction and 
hypotension.
Canagliflozin has been reported to cause a decrease in 
bone mineral density at the lumbar spine and the hip. In a 
pooled analysis of eight clinical trials (mean duration 
68 weeks), a 30% increase in fractures was observed in 
patients taking canagliflozin. It is likely that the effect on 
the bones is a class effect and not restricted to cana
-
gliflozin. All the SGLT2 inhibitors cause a modest increase 
in LDL cholesterol levels (3–8%). Also, in clinical trials, 
patients taking dapagliflozin had higher rates of breast 
cancer (nine cases vs none in comparator arms) and blad
-
der cancer (10 cases vs 1 in placebo arm). These cancer 
rates exceeded the expected rates in age-matched reference 
diabetes population.
Cases of DKA have been reported with off-label use of 
SGLT2 inhibitors in patients with type 1 diabetes. Type 1 
patients are taught to give less insulin if their glucose levels 
are not elevated. SGLT2 inhibitors lower glucose levels by 
changing the renal threshold and not by insulin action. 
Type 1 patients taking an SGLT2 inhibitor, because the 
glucose levels are not elevated, may either withhold or 
reduce their insulin doses to such a degree as to induce 
ketoacidoisis. SGLT2 inhibitors should not be used in 
patients with type 1 diabetes and in those patients labeled 
as having type 2 diabetes but who are very insulin deficient 
and ketosis-prone.
6. Others—
Pramlintide
 is a synthetic analog of islet amy
-
loid polypeptide (IAPP or amylin). When given subcutane
-
ously, it delays gastric emptying, suppresses glucagon 
secretion, and decreases appetite. It is approved for use both 
in type 1 diabetes and in insulin-treated type 2 diabetes. In 
6-month clinical studies with type 1 and insulin-treated 
type 2 patients, those taking the medication had an 
approximately 0.4% reduction in HbA
1c
 and about 1.7 kg 
weight loss compared with placebo. The HbA
1c
 reduction 
was sustained for 2 years but some of the weight was 
regained. The medication is given by injection immediately 
before the meal. Hypoglycemia can occur, and it is recom
-
mended that the short-acting or premixed insulin doses be 
reduced by 50% when the medication is started. Since the 
medication slows gastric emptying, recovery from hypogly
-
cemia can be a problem because of delay in absorption of 
fast-acting carbohydrates. Nausea was the other main side

-
fast-acting carbohydrates. Nausea was the other main side 
effect, affecting 30–50% of persons but tended to improve 
with time. In patients with type 1 diabetes, the initial dose 
of pramlintide is 15 mcg before each meal and titrated up by 
15-mcg increments to a maintenance dose of 30 mcg or 
60 mcg before each meal. In patients with type 2 diabetes, 
the starting dose is 60 mcg premeals increased to 120 mcg 
in 3 to 7 days if no significant nausea occurs.
Bromocriptine,
 a dopamine 2 receptor agonist, has 
been shown to modestly lower HbA
1c
 by 0.1–0.5% when 
compared to baseline and 0.4–0.5% compared to placebo. 
The tablet dose is 0.8 mg and the daily dose is 2 (1.6 g) to 
6 (4.8 mg) tablets as tolerated. Common side effects are 
nausea, vomiting, dizziness, and headache.
Colesevelam
, the bile acid sequesterant, when added to 
metformin or sulfonylurea or insulin lowered HbA
1c
 
0.3– 0.4 % when compared to baseline and 0.5–0.6% com
-
pared to placebo. HbA
1c
 lowering, however, was not 
observed in a single monotherapy clinical trial comparing 
colesevelam to placebo. Colesevelam use is associated with 
∼
20% increase in triglyceride levels. Other adverse effects 
include constipation and dyspepsia.
With their modest glucose lowering and significant side 
effects, using bromocriptine or colesevelam to treat diabe
-
tes is not recommended.
7. Medication combinations—
Several medication combi
-
nations are available in different dose sizes, including gly
-
buride and metformin (Glucovance); glipizide and 
metformin (Metaglip); repaglinide and metformin (Prandi-
Met); rosiglitazone and metformin (Avandamet); piogli
-
tazone and metformin (ACTOplusMet); rosiglitazone and 
glimepiride (Avandaryl); pioglitazone and glimepiride 
(Duetact); sitagliptin and metformin (Janumet); saxa
-
gliptin and metformin XR (Kombiglyze XR); linagliptin 
and metformin (Jentadueto); alogliptin and metformin 
(Kazano); alogliptin and pioglitazone (Oseni); dapa
-
gliflozin and metformin (Xigduo); canagliflozin and met
-
formin (Invokamet); empagliflozin and metformin 
(Synjardy); empagliflozin and linagliptin (Glyxambi); insu
-
lin degludec and liraglutide (Xultophy); and insulin 
glargine and lixisenatide (Soliqua). These medication com
-
binations, however, limit the clinician’s ability to optimally 
adjust dosage of the individual medications and for that 
reason are not recommended.
C. Insulin
Insulin is indicated for type 1 diabetes as well as for type 2 
diabetic patients with insulinopenia whose hyperglycemia 
does not respond to diet therapy either alone or combined 
with other hypoglycemic medications.
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1. Characteristics of available insulin preparations—
Human insulin is dispensed as either regular (R) or NPH 
(N) formulations. Six analogs of human insulin—three 
rapidly acting (insulin lispro, insulin aspart, insulin gluli
-
sine) and three long-acting (insulin glargine, insulin 
detemir, and insulin degludec)—are approved by the FDA 
for clinical use. Commercial insulin preparations differ 
with respect to the time of onset and duration of their bio
-
logic action (Table 27–6). All currently available insulins 
contain less than 10 ppm of proinsulin and are labeled as 
“purified. ” These purified insulins preserve their potency, 
so that refrigeration is recommended but not crucial. Dur
-
ing travel, reserve supplies of insulin can be readily trans
-
ported for weeks without losing potency if protected from 
extremes of heat or cold. All the insulins in the United 
States are available in a concentration of 100 units/mL 
(U100) and dispensed in 10-mL vials or 0.3-mL cartridges 
or prefilled disposable pens. Several insulins are available 
at higher concentrations: insulin glargine, 300 units/mL 
(U300); insulin degludec, 200 units/mL (U200); insulin 
lispro, 200 units/mL (U200); and regular insulin, 
500 units/mL (U500).
2. Insulin preparations—
See Table 27–7. The rapidly act
-
ing insulin analogs and the long-acting insulins are 
designed for subcutaneous administration, while regular 
insulin can also be given intravenously.
a. 
S
hort-acting insulin preparations— 
(1) Regular insulin—
Regular insulin is a short-acting 
soluble crystalline zinc insulin whose effect appears within 
30 minutes after subcutaneous injection and lasts 5–7 hours 
when usual quantities are administered. Intravenous infu
-
sions of regular insulin are particularly useful in the treat
-
ment of DKA and during the perioperative management of 
patients with diabetes who require insulin. For markedly 
insulin-resistant persons who would otherwise require 
large volumes of insulin solution, a U500 preparation of 
human regular insulin is available both in a vial form and a 
disposable pen. A U500 insulin syringe should be used if 
the vial form is dispensed. U500 regular insulin is much 
more expensive than the U100 concentration and is rarely 
needed. There is a U300 preparation of insulin glargine, a 
U200 preparation of insulin lispro, and a U200 preparation 
of insulin degludec. 
(2) Rapidly acting insulin analogs—
Insulin lispro 
(Humalog), is an insulin analog where the proline at posi
-
tion B28 is reversed with the lysine at B29. Insulin aspart 
(Novolog), is a single substitution of proline by aspartic 
acid at position B28. In insulin glulisine (Apidra) the 
asparagine at position B3 is replaced by lysine and the 
lysine in position B29 by glutamic acid. These three ana
-
logs have less of a tendency to form hexamers, in contrast 
to human insulin. When injected subcutaneously, the ana
-
logs quickly dissociate into monomers and are absorbed 
very rapidly, reaching peak serum values in as soon as 
1 hour—in contrast to regular human insulin, whose 
hexamers require considerably more time to dissociate and 
become absorbed. The amino acid changes in these analogs 
Table 27–6.
 
Summary of bioavailability characteristics of the insulins.
Insulin Preparations
Peak Action
Effective Duration
Insulins lispro, aspart,
1
 glulisine
1–1.5 hours
3–4 hours
Human regular
30–60 minutes
2 hours
6–8 hours
Human NPH
2–4 hours
6–7 hours
10–20 hours
Insulin glargine
0.5–1 hour
Flat
∼
24 hours
Insulin detemir
0.5–1 hour
Flat
17 hours
Insulin degludec
0.5–1.5 hours
Flat
More than 42 hours
Technosphere inhaled insulin
1 hour
3 hours
1
Insulin aspart formulated with niacinamide has 
∼
10 minutes faster onset of action.
Table 27–7.
 
Insulin preparations available in the 
1
r
apidly ac
ting human insulin analogs
 
I
nsulin lispro (Humalog, Lilly)
 
I

∼
 
1
r
apidly ac
 
I
 
I
nsulin aspart (Novolog, FiAsp, Novo Nordisk)
 
I
nsulin glulisine (Apidra, Sanofi Aventis)
Short-acting regular insulin
 
Regular 
insulin (Lilly, Novo Nordisk)
 
T
echnosphere inhaled regular insulin (Afrezza)
Intermediate-acting insulins
 
NPH insulin 
(Lilly, Novo Nordisk)
Premixed insulins
 
70% NPH/30% 
regular (70/30 insulin—Lilly, Novo Nordisk)
 
70% NPL/25% 
insulin lispro (Humalog Mix 75/25—Lilly)
 
50% NPL/50% 
insulin lispro (Humalog Mix 50/50—Lilly)
 
70% insulin aspar
t protamine/30% insulin aspart (Novolog Mix 
 
70/30—No
vo Nordisk)
 
70% insulin degludec/30 insulin aspar
t (Ryzodeg, Novo Nordisk)
Long-acting human insulin analogs
 
I
nsulin glargine (Lantus (U100), Toujeo (U300), Sanofi Aventis; 
 
Basaglar 
(U100), Lilly)
 
I
nsulin detemir (Levemir, Novo Nordisk)
 
I
nsulin degludec (Tresiba, Novo Nordisk)
1
All insulins available in the United States are recombinant human 
or human insulin analog origin. All the above insulins are dis
-
pensed at U100 concentration. There is an additional U500 prepa
-
ration of regular insulin; U300 preparation of insulin glargine; U200 
preparation of insulin lispro; U200 preparation of insulin degludec.
NPH, neutral protamine Hagedorn.
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do not interfere with their binding to the insulin receptor, 
with the circulating half-life, or with their immunogenicity, 
which are all identical with those of human regular insulin. 
An insulin aspart formulation (FiAsp) that contains nia
-
cinamide (vitamin B3) has a more rapid initial absorption 
and its onset of action is about 10 minutes faster than the 
standard insulin aspart formulation. Because of this more 
rapid onset of action, the 1-hour (but not 2-hour) post
-
prandial glucose excursions are lower compared to the 
standard formulation.
Clinical trials have demonstrated that the optimal times 
of preprandial subcutaneous injection of comparable doses 
of the rapidly acting insulin analogs and of regular human 
insulin are 20 minutes and 60 minutes, respectively, before 
the meal. While this more rapid onset of action has been 
welcomed as a great convenience by diabetic patients who 
object to waiting as long as 60 minutes after injecting regu
-
lar human insulin before they can begin their meal, 
patients must be taught to ingest adequate absorbable car
-
bohydrate early in the meal to avoid hypoglycemia during 
the meal. Another desirable feature of rapidly acting insu
-
lin analogs is that their duration of action remains at about 
4 hours irrespective of dosage. This contrasts with regular 
insulin, whose duration of action is prolonged when larger 
doses are used.
The rapidly acting analogs are also commonly used in 
pumps. In a double-blind crossover study comparing insu
-
lin lispro with regular insulin in insulin pumps, persons 
using insulin lispro had lower HbA
1c
 values and improved 
postprandial glucose control with the same frequency of 
hypoglycemia. In the event of pump failure, however, users 
of the rapidly acting insulin analogs will have more rapid 
onset of hyperglycemia and ketosis.
While insulin aspart has been approved for intravenous 
use (eg, in hyperglycemic emergencies), there is no advan
-
tage in using insulin aspart over regular insulin by this 
route. A U200 concentration of insulin lispro is available in 
a disposable prefilled pen. The only advantage of the U200 
over the U100 insulin lispro preparation is that it delivers 
the same dose in half the volume.
b. 
L
ong-acting insulin preparations— 
(1) NPH (neutral protamine Hagedorn or isophane) 
insulin—
NPH is an intermediate-acting insulin whose 
onset of action is delayed to 2–4 hours, and its peak 
response is generally reached in about 6–7 hours. The 
onset of action is delayed by combining 2 parts soluble 
crystalline zinc insulin with 1 part protamine zinc insulin. 
This produces equivalent amounts of insulin and prot
-
amine, so that neither is present in an uncomplexed form 
(“isophane”). Because its duration of action is often less 
than 24 hours (with a range of 10–20 hours), most patients 
require at least two injections daily to maintain a sustained 
insulin effect. Occasional vials of NPH insulin have tended 
to show unusual clumping of their contents or “frosting” of 
the container, with considerable loss of bioactivity. This 
instability is rare and occurs less frequently if NPH human 
insulin is refrigerated when not in use and if bottles are 
discarded after 1 month of use. 
(2) Insulin glargine—
In this insulin, the asparagine at 
position 21 of the insulin A chain is replaced by glycine and 
two arginines are added to the carboxyl terminal of the B 
chain. The arginines raise the isoelectric point of the mol
-
ecule closer to neutral making it more soluble in an acidic 
environment. In contrast, human insulin has an isoelectric 
point of pH 5.4. Insulin glargine is a clear insulin, which, 
when injected into the neutral pH environment of the sub
-
cutaneous tissue, forms microprecipitates that slowly 
release the insulin into the circulation. This insulin lasts for 
about 24 hours without any pronounced peaks and is given

-
about 24 hours without any pronounced peaks and is given 
once a day to provide basal coverage. This insulin cannot 
be mixed with the other human insulins because of its 
acidic pH. When this insulin was given as a single injection 
at bedtime to type 1 patients in clinical trials, fasting hyper
-
glycemia was better controlled with less nocturnal hypo
-
glycemia when compared to NPH insulin.
A more concentrated form of insulin glargine (U300) is 
available as an insulin pen. In pharmacodynamic studies in 
type 1 patients, the U300 compared to the U100 prepara
-
tion had approximately 5 hours longer duration of action. 
In clinical trials in type 1 patients, U300 use did not result 
in better control or reduce the rates of hypoglycemia. 
Although limited clinical data suggest that insulin glargine 
is safe in pregnancy, it is not approved for this use. 
(3) Insulin detemir—
In this insulin analog, the threo
-
nine at position B30 has been removed and a 14-C fatty 
acid chain (tetradecanoic acid) is attached to the lysine at 
position 29 by acylation. Its prolonged action is due to 
dihexamerization and binding of hexamers and dimers to 
albumin at the injection site as well as binding of the 
monomer via its fatty acid side chain to albumin in the 
circulation. The affinity of insulin detemir is fourfold to 
fivefold lower than that of human soluble insulin and 
therefore the U100 formulation of insulin detemir has an 
insulin concentration of 2400 nmol/mL compared with 
600 nmol/mL for NPH. The duration of action for insulin 
detemir is about 17 hours at therapeutically relevant doses. 
It is recommended that the insulin be injected once or 
twice a day to achieve a stable basal coverage. It has been 
approved for use during pregnancy. 
(4) Insulin degludec—
-
nine at position B30 has been removed, and the lysine at 
position B29 is conjugated to hexdecanoic acid via a 
gamma-L-glutamyl spacer. In the vial, in the presence of 
phenol and zinc, the insulin is in the form of dihexamers 
but when injected subcutaneously, it self associates into 
large multihexameric chains consisting of thousands of 
dihexamers. The chains slowly dissolve in the subcutane
-
ous tissue and insulin monomers are steadily released into 
the systemic circulation. The half-life of insulin degludec is 
25 hours. Its onset of action is in 30–90 minutes and its 
duration of action is more than 42 hours. It is recom
-
mended that the insulin be injected once or twice a day to 
achieve a stable basal coverage. Insulin degludec is avail
-
able in two concentrations, U100 and U200, and dispensed 
in prefilled disposable pens.
c. 
M
ixed insulin preparations—
Patients with type 2 
diabetes can sometimes achieve reasonable glucose control 
with just prebreakfast and predinner injections of mixtures 
of short acting and NPH insulins. The regular insulin or 
rapidly acting insulin analog is withdrawn first, then the 
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NPH insulin and then injected immediately. Stable pre
-
mixed insulins (70% NPH and 30% regular) are available as 
a convenience to patients who have difficulty mixing insulin 
because of visual problems or impairment of manual 
dexterity (Table 27–7). Premixed preparations of insulin 
lispro and NPH insulins are unstable; stability is achieved by 
replacing the NPH insulin with NPL (neutral protamine 
lispro). This insulin has the same duration of action as NPH 
insulin. Premixed combinations of NPL and insulin lispro 
(75% NPL/25% insulin lispro mixture [Humalog Mix 75/25] 
and 50% NPL/50% insulin lispro mixture [Humalog Mix 
50/50]) are available for clinical use. Similarly, a 70% insulin 
aspart protamine/30% insulin aspart (NovoLog Mix 70/30) 
is available. The main advantages of these mixtures are that 
they can be given within 15 minutes of starting a meal and 
they are superior in controlling the postprandial glucose rise 
after a carbohydrate rich meal. These benefits have not 
translated into improvements in HbA
1c
 levels when com
-
pared with the usual 70% NPH/30% regular mixture. The 
longer-acting insulin analogs, insulin glargine and insulin 
detemir, cannot be mixed with either regular insulin or the 
rapidly acting insulin analogs. Insulin degludec, however, 
can be mixed and is available as 70% insulin degludec/30% 
insulin aspart and is injected once or twice a day.
3. Methods of insulin administration—
a. 
I
nsulin syringes and needles—
Plastic disposable 
syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. 
The “low-dose” 0.3-mL syringes are popular because many 
patients with diabetes do not take more than 30 units of 
insulin in a single injection except in rare instances of 
extreme insulin resistance. Three lengths of needles are 
available: 6 mm, 8 mm, and 12.7 mm. Long needles are 
preferable in obese patients to reduce variability of insulin 
absorption. The needles are of 28, 30, and 31 gauges. The 
31-gauge needles are almost painless. “Disposable” syringes 
may be reused until blunting of the needle occurs (usually 
after three to five injections). Sterility adequate to avoid 
infection with reuse appears to be maintained by recapping 
syringes between uses. Cleansing the needle with alcohol 
may not be desirable since it can dissolve the silicone coat
-
ing and can increase the pain of skin puncturing.
b. 
S
ites of injection
—
Any part of the body covered by 
loose skin can be used, such as the abdomen, thighs, upper 
arms, flanks, and upper buttocks. Preparation with alcohol 
is not required prior to injection as long as the skin is clean. 
Rotation of sites is recommended to avoid delayed absorp
-
tion when fibrosis or lipohypertrophy occurs from repeated 
use of a single site. Regular insulin is absorbed more rap
-
idly when injected in the deltoid or abdomen compared to 
thighs and buttocks. Exercise can increase absorption 
when the injection site is adjacent to the exercise muscle. 
For most patients, the abdomen is the recommend region 
for injection because it provides adequate area in which to 
rotate sites. The effect of anatomic regions appears to be 
much less pronounced with the analog insulins.
c. 
I
nsulin pen injector devices—
Insulin pens elimi
-
nate the need for carrying insulin vials and syringes. Car
-
tridges of insulin lispro and insulin aspart are available for 
reusable pens (Eli Lilly, Novo Nordisk, and Owen Mum
-
ford). Disposable prefilled pens are also available for regu
-
lar insulin (U100 and U500), insulin lispro, insulin aspart, 
insulin glulisine, insulin detemir, insulin glargine, insulin 
degludec, NPH, 70% NPH/30% regular, 75% NPL/25% 
insulin lispro, 50% NPL/50% insulin lispro, 70% insulin 
aspart protamine/30% insulin aspart, and 70% insulin 
degludec/30% insulin aspart. Pen needles are available in 
29, 31, and 32 gauges and 4-, 5-, 6-, 8-, and 12.7-mm 
lengths (Novofine; BD).
d. 
I
nsulin pumps—

d. 
I
In the United States, Medtronic Mini-
Med, Insulet, and Tandem make battery operated continu
-
ous subcutaneous insulin infusion (CSII) pumps. These 
pumps are small (about the size of a pager) and easy to 
program. They offer many features, including the ability to 
set a number of different basal rates throughout the 24 hours 
and to adjust the time over which bolus doses are given. 
They also are able to detect pressure build-up if the catheter 
is kinked. The catheter connecting the insulin reservoir to 
the subcutaneous cannula can be disconnected, allowing 
the patient to remove the pump temporarily (eg, for bath
-
ing). Ominpod (Insulet Corporation) is an insulin infusion 
system in which the insulin reservoir and infusion set are 
integrated into one unit (pod), so there is no catheter (elec
-
tronic patch pump). The pod, placed on the skin, delivers 
subcutaneous basal and bolus insulin based on wirelessly 
transmitted instructions from a personal digital assistant. 
The great advantage of continuous subcutaneous insulin 
infusion (CSII) is that it allows for establishment of a basal 
profile tailored to the patient allowing for better overnight 
and between meals glucose control. The ability to adjust the 
basal insulin infusion makes it easier for the patient to man
-
age glycemic excursions that occur with exercise. The 
pumps have software that can assist the patient to calculate 
boluses based on glucose reading and carbohydrates to be 
consumed. They keep track of the time elapsed since last 
insulin bolus and the patient is reminded of this when he or 
she attempts to give additional correction bolus before the 
effect of the previous bolus has worn off (“insulin on board” 
feature). This feature reduces the risk of overcorrecting and 
subsequent hypoglycemia.
CSII therapy is appropriate for patients with type 1 
diabetes who are motivated, mechanically inclined, edu
-
cated about diabetes (diet, insulin action, treatment of 
hypoglycemia and hyperglycemia), and willing to monitor 
their blood glucose four to six times a day. Known compli
-
cations of CSII include ketoacidosis, which can occur when 
insulin delivery is interrupted, and skin infections. Another 
disadvantage is its cost and the time demanded of the clini
-
cian and staff in initiating therapy. Almost all patients use 
rapid-acting insulin analogs in their pumps.
V-go (Valeritas) is a mechanical patch pump designed 
specifically for people with type 2 diabetes who use a basal/
bolus insulin regimen. The device is preset to deliver one of 
three fixed and flat basal rates (20, 30, or 40 units) for 
24 hours (at which point it must be replaced) and there is a 
button that delivers two units per press to help cover meals.
e. 
I
nhaled insulin—
Technosphere insulin (Afrezza) is a 
dry-powder formulation of recombinant human regular 
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insulin that can be inhaled. It consists of 2- to 2.5-mcm 
crystals of the excipient fumaryl diketopiperazine that pro
-
vide large surface area for adsorption of proteins like insu
-
lin. The technosphere insulin is rapidly absorbed with peak 
insulin levels reached in 12–15 minutes and declining to 
baseline in 3 hours; the median time to maximum effect 
with inhaled insulin is approximately 1 hour and declines 
to baseline by about 3 hours. In contrast, the median time 
to maximum effect with subcutaneous insulin lispro is 
about 2 hours and declines to baseline by 4 hours. In clini
-
cal trials, technosphere insulin combined with basal insu
-
lin was as effective in glucose lowering as rapid-acting 
insulin analogs combined with basal insulin. It is formu
-
lated as a single-use, color-coded cartridge delivering 4, 8, 
or 12 units immediately before the meal. The manufacturer 
provides a dose conversion table; patients injecting up to 4 
units of rapid-acting insulin analog should use the 4-unit 
cartridge. Those injecting 5 to 8 units should use the 8-unit 
cartridge. If the dose is 9–12 units of rapid-acting insulin 
premeal then one 4-unit cartridge and one 8-unit cartridge 
or one 12-unit cartridge should be used. The inhaler is 
about the size of a referee’s whistle.
The most common adverse reaction of the inhaled insulin 
is a cough affecting about 27% of patients. A small decrease in 
pulmonary function (forced expiratory volume in 1 second 
[FEV
1
]) is seen in the first 3 months of use, which persists over 
2 years of follow-up. Inhaled insulin is contraindicated in 
smokers and patients with chronic lung disease, such as 
asthma and chronic obstructive pulmonary disease. Spirom
-
etry should be performed to identify potential lung disease 
prior to initiating therapy. During clinical trials, there were 
two cases of lung cancer in patients who were taking inhaled 
insulin and none in the comparator-treated patients. All the 
patients in whom lung cancer developed had a history of prior 
cigarette smoking. There were also two cases of squamous cell 
carcinoma of the lung in nonsmokers exposed to inhaled 
insulin; these cases occurred after completion of the clinical 
trials. Cases of lung cancer were also reported in cigarette 
smokers using a previously available inhaled insulin prepara
-
tion (Exubera). The incidence rate in the Exubera treated 
group was 0.13 per 1000 patient-years and 0.03 per 1000 
patient-years in the comparator-treated group.
D. Transplantation
1. Pancreas transplantation—
All patients with end-stage 
kidney disease and type 1 diabetes who are candidates for 
a kidney transplant should be considered potential candi
-
dates for a pancreas transplant. Eligibility criteria include 
age younger than 55 and minimal cardiovascular risk. 
Contraindications include noncorrectable coronary artery 
disease, extensive peripheral vascular disease, and signifi
-
cant obesity (weight greater than 100 kg). The pancreas 
transplant may occur at the same time as kidney transplant 
or after kidney transplant. Patients undergoing simultane
-
ous pancreas and kidney transplantation have an 83% 
chance of pancreatic graft survival at 1 year and 69% at 
5 years. Solitary pancreatic transplantation in the absence 
of a need for kidney transplantation is considered only in 
those rare patients who do not respond to all other insulin 
therapeutic approaches and who have frequent severe 
hypoglycemia, or who have life-threatening complications 
related to their lack of metabolic control. Solitary pancreas 
transplant graft survival is 78% at 1 year and 54% at 5 years.
2. Islet transplantation—
Total pancreatectomy is curative 
for severe pain syndrome associated with chronic pancre
-
atitis. The pancreatectomy, however, results in surgical 
diabetes. Harvesting islets from the removed pancreas and 
autotransplanting them into the liver (via portal vein) can

-
autotransplanting them into the liver (via portal vein) can 
prevent the development of diabetes or result in “mild” 
diabetes (partial islet function) that is easier to manage. 
Since the islets are autologous no immunosuppression is 
required. The number of islets transplanted is the main 
predictor of insulin independence.
People with type 1 diabetes can become insulin inde
-
pendent after receiving islets isolated from a donor pan
-
creas (alloislet transplant). The islets are infused into the 
portal vein using a percutaneous transhepatic approach, 
and they lodge in the liver releasing insulin in response to 
physiologic stimuli. Long-term immunosuppression is 
necessary to prevent allograft rejection and to suppress the 
autoimmune process that led to the disease in the first 
place. Insulin independence for more than 5 years has been 
demonstrated in patients who got anti-CD3 antibody or 
anti-thymocyte globulin induction immunosuppression 
and calcineurin inhibitors, mTor inhibitors, and mycophe
-
nolate mofetil as maintenance immunosuppression. One 
major limitation is the need for more than one islet infu
-
sion to achieve insulin independence. This is because of 
significant loss of islets during isolation and the period 
prior to engraftment. Widespread alloislet transplantation 
will depend on improving insulin independence rates with 
one infusion and also demonstrating that the long-term 
outcomes are as good as those of pancreas transplant alone.
DeFronzo RA et al. Renal, metabolic and cardiovascular consid
-
erations of SGLT2 inhibition. Nat Rev Nephrol. 2017 Jan;
 
13(1):11–26. [PMID: 27941935]
Nauck M. Incretin therapies: highlighting common features and 
differences in the modes of action of glucagon-like peptide-1 
receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes 
Obes Metab. 2016 Mar;18(3):203–16. [PMID: 26489970]
Qaseem A et al. Oral pharmacologic treatment of type 2 diabetes 
mellitus: a clinical practice guideline update from the American 
College of Physicians. Ann Intern Med. 2017 Feb 21;
 
166(4):279–90. [PMID: 28055075]
 
»
Steps in the Management of 
 
the Diabetic Patient
A. Diagnostic Examination
An attempt should be made to characterize the diabetes as 
type 1 or type 2 or other specific types such as MODY , 
based on the clinical features present and on whether or 
not ketonuria accompanies the glycosuria. Features that 
suggest end-organ insulin insensitivity to insulin, such as 
visceral obesity, acanthosis nigricans, or both, must be 
identified. The family history should document not only 
the incidence of diabetes in other members of the family 
but also the age at onset, association with obesity, the need 
for insulin, and whether there were complications. For the 
CMDT19_Ch27_p1220-p1266.indd   1241

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occasional patient, measurement of GAD65, IAA, ICA 512, 
and zinc transporter 8 antibodies can help distinguish 
between type 1 and type 2 diabetes (Table 27–2). Many 
patients with newly diagnosed type 1 diabetes still have 
significant endogenous insulin production, and C peptide 
levels do not reliably distinguish between type 1 and type 2 
diabetes. Other factors that increase cardiac risk, such as 
smoking history, presence of hypertension or hyperlipid
-
emia, or oral contraceptive pill use, should be recorded.
Laboratory diagnosis of diabetes should document fast
-
ing plasma glucose levels above 126 mg/dL (7 mmol/L) or 
postprandial values consistently above 200 mg/dL (11.1 
mmol/L) or HbA
1c
 of at least 6.5% and whether ketonuria 
accompanies the glycosuria. An HbA
1c
 measurement is 
also useful for assessing the effectiveness of future therapy. 
Baseline values include fasting plasma triglycerides, total 
cholesterol and HDL-cholesterol, electrocardiography, kid
-
ney function studies, peripheral pulses, and neurologic, 
podiatric, and ophthalmologic examinations to help guide 
future assessments.
B. Patient Education (Self-Management Training)
Since diabetes is a lifelong disorder, education of the 
patient and the family is probably the most important 
obligation of the clinician who provides initial care.
 The 
best persons to manage a disease that is affected so mark
-
edly by daily fluctuations in environmental stress, exercise, 
diet, and infections are the patients themselves and their 
families. The “teaching curriculum” should include expla
-
nations by the clinician or nurse of the nature of diabetes 
and its potential acute and chronic hazards and how they 
can be recognized early and prevented or treated. Self-
monitoring of blood glucose should be emphasized, espe
-
cially in insulin-requiring diabetic patients, and instructions 
must be given on proper testing and recording of data.
Patients taking insulin should have an understanding of 
the actions of basal and bolus insulins. They should be 
taught to determine whether the basal dose is appropriate 
and how to adjust the rapidly acting insulin dose for the 
carbohydrate content of a meal. Patients and their families 
and friends should be taught to recognize signs and symp
-
toms of hypoglycemia and how to treat low glucose reac
-
tions. Strenuous exercise can precipitate hypoglycemia, 
and patients must therefore be taught to reduce their insu
-
lin dosage in anticipation of strenuous activity or to take 
supplemental carbohydrate. Injection of insulin into a site 
farthest away from the muscles most involved in the exer
-
cise may help ameliorate exercise-induced hypoglycemia, 
since insulin injected in the proximity of exercising muscle 
may be more rapidly mobilized. Exercise training also 
increases the effectiveness of insulin and insulin doses 
should be adjusted accordingly. Infections can cause insu
-
lin resistance, and patients should be instructed on how to 
manage the hyperglycemia with supplemental rapidly act
-
ing insulin.
Advice on personal hygiene, including detailed instruc
-
tions on foot and dental care, should be provided. All infec
-
tions (especially pyogenic ones) provoke the release of high 
levels of insulin antagonists, such as catecholamines or 
glucagon, and thus bring about a marked increase in 
insulin requirements. Patients who are taking oral agents 
may decompensate and temporarily require insulin. 
Patients should be told about community agencies, such as 
Diabetes Association chapters, that can serve as a continu
-
ing source of instruction.
Finally, vigorous efforts should be made to persuade 
patients with newly diagnosed diabetes who smoke to give 
up the habit, since large vessel peripheral vascular disease 
and debilitating retinopathy are less common in nonsmok
-
ing diabetic patients.
C. Therapy
Treatment must be individualized on the basis of the type

-
C. Therapy
Treatment must be individualized on the basis of the type 
of diabetes and specific needs of each patient. However, 
certain general principles of management can be outlined 
for hyperglycemic states of different types.
Traditional once- or twice-daily insu
-
lin regimens are usually ineffective in type 1 patients with
-
out residual endogenous insulin. In these patients, 
information and counseling based on the findings of the 
the DCCT, which showed that near normalization of blood 
glucose in patients with type 1 diabetes resulted in a delay 
in the onset and a major slowing of the progression of 
established microvascular and neuropathic complications 
of diabetes, should be provided about the advantages of 
taking multiple injections of insulin in conjunction with 
self–blood glucose monitoring. If near-normalization of 
blood glucose is attempted, at least four measurements of 
capillary blood glucose and three or four insulin injections 
are necessary.
A combination of rapidly acting insulin analogs and 
long-acting insulin analogs allows for more physiologic 
insulin replacement. The rapidly acting insulin analogs 
have been advocated as a safer and much more convenient 
alternative to regular human insulin for preprandial use. 
However, because of their relatively short duration (no 
more than 3–4 hours), the rapidly acting insulin analogs 
need to be combined with longer-acting insulins to provide 
basal coverage and avoid hyperglycemia prior to the next 
meal. In addition to carbohydrate content of the meal, the 
effect of simultaneous fat ingestion must also be consid
-
ered a factor in determining the rapidly acting insulin 
analog dosage required to control the glycemic increment 
during and just after the meal. With low-carbohydrate 
content and high-fat intake, there is an increased risk of 
hypoglycemia from insulin lispro within 2 hours after the 
meal. Table 27–8 illustrates a regimen with a rapidly acting 
insulin analog and insulin detemir or insulin glargine that 
might be appropriate for a 70-kg person with type 1 diabetes 
eating meals providing standard carbohydrate intake and 
moderate to low fat content.
Insulin glargine or insulin degludec is usually given 
once in the evening to provide 24-hour coverage. There are 
occasional patients in whom insulin glargine does not 
seem to last for 24 hours, and in such cases it needs to be 
given twice a day. As shown, insulin detemir may also need 
to be given twice a day to get adequate 24-hour basal cover
-
age. Alternatively, small doses of NPH (
∼
3–4 units) can be 
given with each meal to provide daytime basal coverage 
CMDT19_Ch27_p1220-p1266.indd   1242

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CMDT 2019
Table 27–8.
 
Examples of intensive insulin regimens 
using rapidly acting insulin analogs (insulin lispro, 
aspart, or glulisine) and insulin detemir, or insulin 
glargine or degludec in a 70-kg man with type 1 
diabetes.
1–3
Pre-
breakfast
Pre-
lunch
Pre-
dinner
At 
Bedtime
Rapidly acting 
insulin analog
5 units
4 units
6 units
3
6–7 units
8–9 units
OR
5 units
4 units
6 units
—
Insulin glargine 
or degludec
3
—
15–16 units
1
Assumes that patient is consuming approximately 75 g carbohy
-
drate at breakfast, 60 g at lunch, and 90 g at dinner.
2
The dose of rapidly acting insulin can be raised by 1 or 2 units if 
extra carbohydrate (15–30 g) is ingested or if premeal blood glu
-
cose is > 170 mg/dL (9.4 mmol/L).
3
Insulin glargine or insulin detemir must be given as a separate 
injection.
with a larger dose at night. Unlike the long-acting insulin 
analogs, NPH can be mixed in the same syringe as the 
insulin lispro, insulin aspart, and insulin glulisine.
CSII by portable battery-operated “open loop” devices 
currently provides the most flexible approach, allowing the 
setting of different basal rates throughout the 24 hours and 
permitting bolus dose adjustments by as little as 0.05-unit 
increments. The 24-hour basal dosage is usually based on 
age and body weight. An adolescent might need as much as 
0.4 unit/kg/day; young adult (less than 25 years), 0.35 unit 
per/kg/day; and older adults, 0.25 unit/kg/day. For example, 
a 70-kg, 30-year-old man may require a basal rate of 
0.7 unit per hour throughout the 24 hours with the excep
-
tion of 3 
am
 to 8 
am
, when 0.8 unit per hour might be 
appropriate (given the “dawn phenomenon”—reduced tis
-
sue sensitivity to insulin between 5 
am
 and 8 
am
). The 
meal bolus varies based on the time of day and the person’s 
age. Adolescents and young adults usually require 1 unit 
for about 10 g of carbohydrate. Older adults usually require 
about 1 unit for 15 g of carbohydrate. The correction 
factor—how much insulin is needed to lower glucose levels 
by 50 mg/dL—can be calculated from the insulin-to-
carbohydrate ratios. For example, if 1 unit is required for 
15 g of carbohydrate, then 1 unit will lower glucose levels 
by 50 mg/dL. If 1.5 units of insulin is required for 15 g of 
carbohydrate (that is, 1 unit for 10 g carbohydrate), then 
1.5 units of insulin will lower glucose levels by 50 mg/dL 
(that is, 1 unit will lower glucose level by 33 mg/dL). For a 
70-kg 30-year-old man, bolus ratios of 1 unit for 12–15 g of 
carbohydrate plus 1 unit for 50 mg/dL of blood glucose 
over a target value of 120 mg/dL would be reasonable start
-
ing point. Further adjustments to basal and bolus dosages 
would depend on the results of blood glucose monitoring. 
One of the more difficult therapeutic problems in manag
-
ing patients with type 1 diabetes is determining the proper 
adjustment of insulin dose when the prebreakfast blood 
glucose level is high. Occasionally, the prebreakfast hyper
-
glycemia is due to the 
Somogyi effect,
 in which nocturnal 
hypoglycemia leads to a surge of counterregulatory hor
-
mones to produce high blood glucose levels by 7 
am
. How
-
ever, a more common cause for prebreakfast hyperglycemia 
is the waning of circulating insulin levels by the morning.
The diagnosis of the cause of prebreakfast hyperglyce
-
mia can be facilitated by self-monitoring of blood glucose 
at 3 
am
 in addition to the usual bedtime and 7 
am
 mea
-
surements (Table 27–9). This is required for only a few 
nights, and when a particular pattern emerges from moni
-
toring blood glucose levels overnight, appropriate thera
-
peutic measures can be taken. The Somogyi effect can be 
treated by eliminating the dose of intermediate insulin at 
dinnertime and giving it at a lower dosage at bedtime or by 
supplying more food at bedtime. When a waning insulin

supplying more food at bedtime. When a waning insulin 
level is the cause, then either increasing the evening dose or 
shifting it from dinnertime to bedtime (or both) can be 
effective. A bedtime dose either of insulin glargine or insu
-
lin detemir provides more sustained overnight insulin lev
-
els than human NPH and may be effective in managing 
refractory prebreakfast hyperglycemia. If this fails, insulin 
pump therapy may be required.
Therapeutic recommendations are 
based on the relative contributions of beta cell insuffi
-
ciency and insulin insensitivity in individual patients. 
Table 27–9.
 
Prebreakfast hyperglycemia: classification by blood glucose and insulin levels.
Blood Glucose (mg/dL [mmol/L])
Free Immunoreactive Insulin (microunit/mL)
10:00 
pm
3:00 
am
7:00 
am
10:00 
pm
3:00 
am
7:00 
am
Somogyi effect
90 [5]
40 [2.2]
200 [11.1]
High
Slightly high
Normal
Dawn phenomenon
110 [6.1]
110 [6.1]
150 [8.3]
Normal
Normal
Normal
Waning of insulin dose plus dawn 
110 [6.1]
190 [10.6]
220 [12.2]
Normal
Low
Low
phenomenon plus Somogyi effect
110 [6.1]
40 [2.2]
380 [21.1]
High
Normal
Low
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Weight loss + exercise + metformin
Metformin + another agent
Metformin + two other agents
Factors in Therapeutic Decision
(single agent or combination)
Seven main classes of agents
• Metformin
• Sulfonylureas (includes nateglinide, repaglinide)
• Pioglitazone
• GLP-1 receptor agonists
• DPP-4 inhibitor
s
• SGLT2 inhibitor
s
• Insulins
If HbA
1c
 target not reached
after ~ 3 months
If HbA
1c
If HbA
1c
Efficacy
• DPP-4 inhibitors are of moderate efficacy
• All other agents are of high efficacy
Cost
• All agents except metformin and
  sulfonylureas are expensive
• Insulins are expensive if the additional cost
  of monitoring is taken into consideration
Hypoglycemic risk    
• Sulfonylureas and insulins have increased
   risk of hypoglycemia
Effect on weight
• Metformin and DPP-4 inhibitors are weight neutral
• GLP-1 receptor agonists and SGLT2 inhibitors
  promote weight loss
• Sulfonylureas, insulins, and pioglitazone ar
e
  associated with weight gain
Major side effects
• Metformin can cause lactic acidosis
• Pioglitazone is associated with fluid retention,
  
fracture risk, and possibly bladder cancer
• GLP-1 receptor agonists are associated with
   nausea, vomiting and pancreatitis
• DPP-4 inhibitors may be associated with
  
pancreatitis 
• SGLT2 inhibitors can cause urinary tract infections
;
  
genital mycotic infections; dehydration; cannot
  
use in renal impairment
Metformin + more complex insuli
n
regimen ± other noninsulin agent
 
▲
Figure 27–2.
 
Algorithm for the treatment of type 2 
diabetes based on the 2012 and 2015 recommendations 
of the consensus panel of the American Diabetes Associ
-
ation/European Association for the Study of Diabetes.
The possibility that the individual patient has a specific 
etiologic cause for their diabetes should always be consid
-
ered, especially when the patient does not have a family 
history of type 2 diabetes or does not have any evidence of 
central obesity or insulin resistance. Such patients should 
be evaluated for other types of diabetes such as LADA or 
MODY (Table 27–1). Patients with LADA should be pre
-
scribed insulin when the disease is diagnosed and treated 
like patients with type 1 diabetes. It is also important to 
note that many patients with type 2 diabetes mellitus have 
a progressive loss of beta cell function and will require 
additional therapeutic interventions with time.
a. 
W
eight reduction
—
One of the primary modes of 
therapy in the obese patient with type 2 diabetes is weight 
reduction. Normalization of glycemia can be achieved by 
weight loss and improvement in tissue sensitivity to insu
-
lin. A combination of caloric restriction, increased exer
-
cise, and behavior modification is required if a weight 
reduction program is to be successful. Understanding the 
risks associated with the diagnosis of diabetes may moti
-
vate the patient to lose weight.
For selected patients, medical or surgical options for 
weight loss should be considered. Orlistat, phentermine/
topiramate, lorcaserin, naltrexone/extended-release bupro
-
pion, and high-dose liraglutide (3 mg daily) are weight loss 
medications approved for use in combination with diet and 
exercise (see Chapter 29).
Bariatric surgery (Roux-en-Y , gastric banding, gastric 
sleeve, biliopancreatic diversion/duodenal switch) typically 
results in substantial weight loss and improvement in glu
-
cose levels. A meta-analysis examining the impact of bar
-
iatric surgery on patients with diabetes and BMI of 
40 kg/m
2
 or greater noted that 82% of patients had resolu
-
tion of clinical and laboratory manifestations of diabetes in 
the first 2 years after surgery and 62% remained free of 
diabetes more than 2 years after surgery. The improvement 
was most marked in the procedure that caused the greatest 
weight loss (biliopancreatic diversion/duodenal switch).

weight loss (biliopancreatic diversion/duodenal switch). 
There was, however, a high attrition of patients available 
for follow-up, and there was little information about differ
-
ent ethnic types. Weight regain does occur after bariatric 
surgery, and it can be expected that 20–25% of the lost 
weight will be regained over 10 years. The impact of this 
weight gain on diabetes recurrence depends principally on 
the degree of beta cell dysfunction.
Nonobese patients with type 2 diabetes frequently have 
increased visceral adiposity—the so-called metabolically 
obese normal weight patient. There is less emphasis on 
weight loss, but exercise remains an important aspect of 
b. 
G
lucose lowering agents—
Figure 27–2 outlines the 
treatment approach based on the consensus algorithm 
proposed by the American Diabetes Association and the 
European Association for the Study of Diabetes. The cur
-
rent recommendation is to start 
metformin
 therapy at 
diagnosis and not wait to see whether the patient can 
achieve target glycemic control with weight management 
and exercise. See discussion of the individual medications, 
above.
CMDT19_Ch27_p1220-p1266.indd   1244

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CMDT 2019
When diabetes is not well controlled with initial therapy 
(usually metformin), then a second agent should be added. 
 have been available for many years and their 
use in combination with metformin is well established. They 
do, however, have the propensity of causing hypoglycemia 
and weight gain. In patients who experience hyperglycemia 
after a carbohydrate-rich meal (such as dinner), a short-
acting secretagogue (repaglinide or nateglinide) before 
meals may suffice to get the glucose levels into the target 
range. Patients with severe insulin resistance may be candi
-
dates for pioglitazone. Patients who are very concerned 
about weight gain may benefit from a trial of GLP-1 recep
-
tor agonist or DPP-4 inhibitor or SGLT2 inhibitor. Presence 
of cardiovascular disease should be considered; liraglutide, 
empagliflozin, and canagliflozin have been shown to have 
improved cardiovascular outcomes. If two agents are inad
-
equate, then a third agent is added, although data regarding 
efficacy of such combined therapy are limited.
When the combination of oral agents (and injectable 
GLP-1 receptor agonists) fail to achieve euglycemia in 
patients with type 2 diabetes, then insulin treatment should 
be instituted. Various insulin regimens may be effective. 
One proposed regimen is to continue the oral combination 
therapy and then simply add a bedtime dose of NPH or 
long-acting insulin analog (insulin glargine or insulin 
detemir) to reduce excessive nocturnal hepatic glucose 
output and improve fasting glucose levels. If the patient 
does not achieve target glucose levels during the day, then 
daytime insulin treatment can be initiated. A convenient 
insulin regimen under these circumstances is a split dose of 
70/30 NPH/regular mixture (or Humalog Mix 75/25 or 
NovoLogMix 70/30) before breakfast and before dinner. 
If this regimen fails to achieve satisfactory glycemic goals 
or is associated with unacceptable frequency of hypoglyce
-
mic episodes, then a more intensive regimen of multiple 
insulin injections can be instituted as in patients with type 
1 diabetes. Metformin principally reduces hepatic glucose 
output, and it is reasonable to continue with this medica
-
tion when insulin therapy is instituted. Pioglitazone, which 
improves peripheral insulin sensitivity, can be used 
together with insulin but this combination is associated 
with more weight gain and peripheral edema. The sulfonyl
-
ureas, the GLP1-receptor agonists, and the DPP-4 inhibi
-
tors also have been shown to be of continued benefit. 
Weight-reducing interventions should continue even after 
initiation of insulin therapy and may allow for simplifica
-
tion of the therapeutic regimen in the future.
D. Acceptable Levels of Glycemic Control
A reasonable aim of therapy is to approach normal glyce
-
mic excursions without provoking severe or frequent hypo
-
glycemia. Table 27–10 summarizes blood glucose and 
HbA
1c
 goals for different patient groups. The UKPDS study 
demonstrated that blood pressure control was as signifi
-
cant or more significant than glycemic control in patients 
with type 2 diabetes regarding the prevention of microvas
-
cular as well as macrovascular complications.
Inzucchi SE et al. Management of hyperglycemia in type 2 diabe
-
tes, 2015: a patient-centered approach: update to a position 
statement of the American Diabetes Association and the 
European Association for the Study of Diabetes. Diabetes 
Care. 2015 Jan;38(1):140–9. [PMID: 25538310]
Table 27–10.
 
Glycemic targets for different groups of patients with diabetes.
Blood Glucose Targets (mg/dL [mmol/L])
HbA
1c
 Target (% [mmol/mol])
Nonpregnant healthy adults
Premeal glucose 90–130 (5–7.2)
1-hour peak < 180 (10)
2-hour peak < 150 (8.3)
< 7 (53). Aim for < 6.5 (48) if it can be achieved 
without significant hypoglycemia or 
polypharmacy)
Pregnancy
Premeal glucose ≤ 95 (5.3)
1-hour peak ≤ 140 (7.8)

Pregnancy
2-hour peak ≤ 120 (6.7)
6–6.5 (42–48). Aim for < 6 (42) if possible with
-
out significant hypoglycemia
Older adults
 
Healthy
 
F
rail with limited life expectancy
Premeal 90–130 (5–7.2)
Bedtime 90–150 (5–8.3)
Premeal 100–180 (5.6–10)
Bedtime 110–200 (6.1–11.1)
< 7.5 (58)
< 8.5 (69)
History of severe hypoglycemia
Premeal 90–150 (5–8.3)
Bedtime 100–180 (5.6–10)
< 8 (64)
Hospitalized patient
140–180 (7.8–10)
—
CKD
Glycemic targets in CKD are the same as those 
without CKD. HbA
1c
 and fructosamine values 
may not be accurate in end-stage renal disease 
and greater reliance should be placed on the 
home glucose measurements
 
Children and adolescents
Bedtime/overnight 90–150 (5–8.3)
< 7.5 (58)
CKD, chronic kidney disease.
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Jin J. JAMA patient page. Starting insulin treatment for diabetes. 
JAMA. 2014 Jun 11;311(22):2347. [PMID: 24915279]
Mingrone G et al. Bariatric surgery versus conventional medical 
therapy for type 2 diabetes. N Engl J Med. 2012 Apr 26;
 
366(17):1577–85. [PMID: 22449317]
Switzer SM et al. Intensive insulin therapy in patients with type 1 
diabetes mellitus. Endocrinol Metab Clin North Am. 2012 Mar;
 
41(1):89–104. [PMID: 22575408]
E. Complications of Insulin Therapy
1. Hypoglycemia—
Hypoglycemic reactions are the most 
common complications that occur in patients with diabetes 
who are treated with insulin. The signs and symptoms of 
hypoglycemia may be divided into those resulting from 
stimulation of the autonomic nervous system and those 
from neuroglycopenia (insufficient glucose for normal 
central nervous system function). When the blood glucose 
falls to around 54 mg/dL (3 mmol/L), the patient starts to 
experience both sympathetic (tachycardia, palpitations, 
sweating, tremulousness) and parasympathetic (nausea, 
hunger) nervous system symptoms. If these autonomic 
symptoms are ignored and the glucose levels fall further (to 
around 50 mg/dL [2.8 mmol/L]), then neuroglycopenic 
symptoms appear, including irritability, confusion, blurred 
vision, tiredness, headache, and difficulty speaking. A fur
-
ther decline in glucose can then lead to loss of conscious
-
ness or even a seizure. With repeated episodes of 
hypoglycemia, there is adaptation, and autonomic symp
-
toms do not occur until the blood glucose levels are much 
lower and so the first symptoms are often due to neurogly
-
copenia. This condition is referred to as “hypoglycemic 
unawareness. ” It has been shown that hypoglycemic 
unawareness can be reversed by keeping glucose levels high 
for a period of several weeks. Except for sweating, most of 
the sympathetic symptoms of hypoglycemia are blunted in 
patients receiving beta-blocking agents. Though not abso
-
lutely contraindicated, these medications must be used 
with caution in patients with diabetes who require insulin, 
and beta-1-selective blocking agents are preferred.
Hypoglycemia can occur in patient taking sulfonylureas, 
repaglinide, and nateglinide, particularly if the patient is 
elderly, has kidney or liver disease, or is taking certain other 
medications that alter metabolism of the sulfonylureas (eg, 
phenylbutazone, sulfonamides, or warfarin). It occurs more 
frequently with the use of long-acting sulfonylureas than 
when shorter-acting agents are used. Otherwise, hypoglyce
-
mia in insulin-treated patients with diabetes occurs as a 
consequence of three factors: behavioral issues, impaired 
counterregulatory systems, and complications of diabetes.
Behavioral issues
 include injecting too much insulin 
for the amount of carbohydrates ingested. Drinking alcohol 
in excess, especially on an empty stomach, can also cause 
hypoglycemia. In patients with type 1 diabetes, hypoglyce
-
mia can occur during or even several hours after exercise, 
and so glucose levels need to be monitored and food and 
insulin adjusted. Some patients do not like their glucose 
levels to be high, and they treat every high glucose level 
aggressively. These individuals who “stack” their insulin—
that is, give another dose of insulin before the first injection 
has had its full action—can develop hypoglycemia.
Counterregulatory issues
 resulting in hypoglycemia 
include impaired glucagon response, sympatho-adrenal 
responses, and cortisol deficiency. Patients with diabetes of 
greater than 5 years duration lose their glucagon response 
to hypoglycemia. As a result, they are at a significant disad
-
vantage in protecting themselves against falling glucose 
levels. Once the glucagon response is lost, their sympatho-
adrenal responses take on added importance. Unfortu
-
nately, aging, autonomic neuropathy, or hypoglycemic 
unawareness due to repeated low glucose levels further

-
unawareness due to repeated low glucose levels further 
blunts the sympatho-adrenal responses. Occasionally, 
Addison disease develops in persons with type 1 diabetes 
mellitus; when this happens, insulin requirements fall sig
-
nificantly, and unless insulin dose is reduced, recurrent 
hypoglycemia will develop.
Complications of diabetes
 that increase the risk for 
hypoglycemia include autonomic neuropathy, gastropare
-
sis, and end-stage chronic kidney disease. The sympathetic 
nervous system is an important system alerting the indi
-
vidual that the glucose level is falling by causing symptoms 
of tachycardia, palpitations, sweating, and tremulousness. 
Failure of the sympatho-adrenal responses increases the 
risk of hypoglycemia. In addition, in patients with gastro
-
paresis, if insulin is given before a meal, the peak of insulin 
action may occur before the food is absorbed causing the 
glucose levels to fall. Finally, in end-stage chronic kidney 
disease, hypoglycemia can occur presumably because of 
decreased insulin clearance as well as loss of renal contri
-
bution to gluconeogenesis in the postabsorptive state.
To prevent and treat insulin-induced hypoglycemia
, 
the diabetic patient should carry glucose tablets or juice at 
all times. For most episodes, ingestion of 15 grams of car
-
bohydrate is sufficient to reverse the hypoglycemia. The 
patient should be instructed to check the blood glucose in 
15 minutes and treat again if the glucose level is still low. A 
parenteral glucagon emergency kit (1 mg) should be pro
-
vided to every patient with diabetes who is receiving insu
-
lin therapy. Family or friends should be instructed how to 
inject it subcutaneously or intramuscularly into the but
-
tock, arm, or thigh in the event that the patient is uncon
-
scious or refuses food. The medication can occasionally 
cause vomiting, and the unconscious patient should be 
turned on his or her side to protect the airway. The gluca
-
gon mobilizes glycogen from the liver, raising the blood 
glucose by about 36 mg/dL (2 mmol/L) in about 15 minutes. 
After the patient recovers consciousness, additional oral 
carbohydrate should be given. People with diabetes receiv
-
ing hypoglycemic medication therapy should also wear an 
identification MedicAlert bracelet or necklace or carry a 
card in his or her wallet (1-800-ID-ALERT, www
 
.medicalert.org).
Medical personnel treating severe hypoglycemia can 
give 50 mL of 50% glucose solution by rapid intravenous 
infusion. If intravenous access is not available, 1 mg of 
glucagon can be injected intramuscularly.
2. Immunopathology of insulin therapy—
At least five 
molecular classes of insulin antibodies are produced dur
-
ing the course of insulin therapy in diabetes, including 
IgA, IgD, IgE, IgG, and IgM. With the switch to human 
and purified pork insulin, the various immunopathologic 
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syndromes such as insulin allergy, immune insulin resis
-
tance, and lipoatrophy have become quite rare since the 
titers and avidity of these induced antibodies are generally 
quite low.
a. 
I
nsulin allergy—
Insulin allergy, or immediate-type 
hypersensitivity, is a rare condition in which local or sys
-
temic urticaria is due to histamine release from tissue mast 
cells sensitized by adherence of anti-insulin IgE antibodies. 
In severe cases, anaphylaxis results. When only human 
insulin has been used from the onset of insulin therapy, 
insulin allergy is exceedingly rare. Antihistamines, cortico
-
steroids, and even desensitization may be required, espe
-
cially for systemic hypersensitivity. There have been case 
reports of successful use of insulin lispro in those rare 
patients who have a generalized allergy to human insulin or 
insulin resistance due to a high titer of insulin antibodies.
b. 
I
mmune insulin resistance—
A low titer of circulat
-
ing IgG anti-insulin antibodies that neutralize the action of 
insulin to a small extent develops in most insulin-treated 
patients. With the old animal insulins, a high titer of circu
-
lating antibodies sometimes developed, resulting in 
extremely high insulin requirements—often more than 
200 units daily. This is now rarely seen with the switch to 
human or highly purified pork insulins and has not been 
reported with the analogs.
c. 
L
ipodystrophy—
Atrophy of subcutaneous fatty tissue 
leading to disfiguring excavations and depressed areas may 
rarely occur at the site of injection. This complication 
results from an immune reaction, and it has become rarer 
with the development of human and highly purified insu
-
lin preparations. Lipohypertrophy, on the other hand, is a 
consequence of the pharmacologic effects of insulin being 
deposited in the same location repeatedly. It can occur with 
purified insulins as well. Rotation of injection sites will 
prevent lipohypertrophy.
International Hypoglycaemia Study Group. Minimizing hypo
-
glycemia in diabetes. Diabetes Care. 2015 Aug;38(8):1583–91. 
[PMID: 26207052]
 
»
Chronic Complications of Diabetes
Late clinical manifestations of diabetes mellitus include a 
number of pathologic changes that involve small and large 
blood vessels, cranial and peripheral nerves, the skin, and 
the lens of the eye. These lesions lead to hypertension, end-
stage chronic kidney disease, blindness, autonomic and 
peripheral neuropathy, amputations of the lower extremi
-
ties, myocardial infarction, and cerebrovascular accidents. 
These late manifestations correlate with the duration of the 
diabetic state subsequent to the onset of puberty. In type 1 
diabetes, end-stage chronic kidney disease develops in up 
to 40% of patients, compared with less than 20% of patients 
with type 2 diabetes. Proliferative retinopathy ultimately 
develops in both types of diabetes but has a slightly higher 
prevalence in type 1 patients (25% after 15 years’ duration). 
In patients with type 1 diabetes, complications from end-
stage chronic kidney disease are a major cause of death, 
whereas patients with type 2 diabetes are more likely to 
have macrovascular diseases leading to myocardial infarc
-
tion and stroke as the main causes of death. Cigarette use 
adds significantly to the risk of both microvascular and 
macrovascular complications in diabetic patients.
A. Ocular Complications
1. Diabetic cataracts—
Premature cataracts occur in dia
-
betic patients and seem to correlate with both the duration 
of diabetes and the severity of chronic hyperglycemia. 
Nonenzymatic glycosylation of lens protein is twice as high 
in diabetic patients as in age-matched nondiabetic persons 
and may contribute to the premature occurrence of 
cataracts.
2. Diabetic retinopathy—
There are two main categories of 
diabetic retinopathy: nonproliferative and proliferative (see

diabetic retinopathy: nonproliferative and proliferative (see 
Chapter 7). Diabetic macular edema can occur at any stage. 
Nonproliferative (“background”) retinopathy
 represents 
the earliest stage of retinal involvement by diabetes and is 
characterized by such changes as microaneurysms, dot 
hemorrhages, exudates, and retinal edema. The prevalence 
of nonproliferative retinopathy in patients with type 2 
diabetes is 60% after 16 years.
 involves the growth of new 
capillaries and fibrous tissue within the retina and into the 
vitreous chamber. It is a consequence of small vessel occlu
-
sion, which causes retinal hypoxia; this in turn stimulates 
new vessel growth. New vessel formation may occur at the 
optic disk or elsewhere on the retina. Prior to proliferation 
of new capillaries, a preproliferative phase often occurs in 
which arteriolar ischemia is manifested as cotton-wool spots 
(small infarcted areas of retina). Vision is usually normal 
until vitreous hemorrhage or retinal detachment occurs.
Proliferative retinopathy can occur in both types of diabe
-
tes but is more common in type 1, developing about 7–10 years 
after onset of symptoms, with a prevalence of 25% after 
15 years’ duration. Vision-threatening retinopathy virtually 
never appears in type 1 patients in the first 3–5 years of 
diabetes or before puberty. Up to 20% of patients with type 2 
diabetes have retinopathy at the time of diagnosis, because 
many were probably diabetic for an extensive period of time 
before diagnosis. Annual consultation with an ophthalmolo
-
gist should be arranged for patients who have had type 1 dia
-
betes for more than 3–5 years and for all patients with type 2 
diabetes. Chapter 7 describes the treatment of retinopathy and 
macular edema. There is no contraindication to using aspirin 
in patients with proliferative retinopathy.
3. Glaucoma—
Glaucoma occurs in approximately 6% of 
persons with diabetes. It is responsive to the usual therapy 
for open-angle disease. Neovascularization of the iris in 
patients with diabetes can predispose to closed-angle glau
-
coma, but this is relatively uncommon except after cataract 
extraction, when growth of new vessels has been known to 
progress rapidly, involving the angle of the iris and obstruct
-
ing outflow.
B. Diabetic Nephropathy
Diabetic nephropathy is initially manifested by albumin
-
uria; subsequently, as kidney function declines, urea and 
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creatinine accumulate in the blood (see Chapter 22). Sensi
-
tive radioimmunoassay methods detect small amounts of 
urinary albumin—in contrast to the less sensitive dipstick 
strips, whose minimal detection limit is 0.3–0.5%. Conven
-
tional 24-hour urine collections, in addition to being 
inconvenient for patients, also show wide variability of 
albumin excretion, since several factors such as sustained 
erect posture, dietary protein, and exercise tend to increase 
albumin excretion rates. For these reasons, an albumin-
creatinine ratio in an early morning spot urine collected 
upon awakening is preferable. In the early morning spot 
urine, a ratio of albumin (mcg/L) to creatinine (mg/L) of 
less than 30 mcg/mg creatinine is normal, and a ratio of 
30–300 mcg/mg creatinine suggests abnormal microalbu
-
minuria. At least two early morning spot urine collections 
over a 3- to 6-month period should be abnormal before a 
diagnosis of microalbuminuria is justified. Short-term 
hyperglycemia, exercise, urinary tract infections, heart 
failure, and acute febrile illness can cause transient albu
-
minuria and so testing for microalbuminuria should be 
postponed until resolution of these problems.
Subsequent end-stage chronic kidney disease can be 
predicted by persistent urinary albumin excretion rates 
exceeding 30 mcg/mg creatinine. Glycemic control as well 
as a protein diet of 0.8 g/kg/day may reduce both the 
hyperfiltration and the elevated microalbuminuria in 
patients in the early stages of diabetes and those with 
incipient diabetic nephropathy. Antihypertensive therapy 
also decreases microalbuminuria. Evidence from some 
studies supports a specific role for ACE inhibitors in reduc
-
ing intraglomerular pressure in addition to their lowering 
of systemic hypertension. An ACE inhibitor (captopril, 
50 mg twice daily) in normotensive diabetic patients 
impedes progression to proteinuria and prevents the 
increase in albumin excretion rate. Since microalbumin
-
uria has been shown to correlate with elevated 
nocturnal
 
systolic blood pressure, it is possible that “normotensive” 
diabetic patients with microalbuminuria have slightly ele
-
vated systolic blood pressure during sleep, which is lowered 
during antihypertensive therapy. This action may contrib
-
ute to the reported efficacy of ACE inhibitors in reducing 
microalbuminuria in “normotensive” patients.
If treatment is inadequate, then the disease progresses 
with proteinuria of varying severity occasionally leading to 
nephrotic syndrome with hypoalbuminemia, edema, and 
an increase in circulating LDL cholesterol, as well as pro
-
gressive azotemia. In contrast to all other kidney disorders, 
the proteinuria associated with diabetic nephropathy does 
not diminish with progressive end-stage chronic kidney 
disease (patients continue to excrete 10–11 g daily as cre
-
atinine clearance diminishes). As end-stage chronic kidney 
disease progresses, there is an elevation in the renal thresh
-
old at which glycosuria appears.
Diabetic patients with normal kidney function do not 
appear to be at increased risk for contrast nephropathy. If a 
contrast study is considered essential, patients with a 
serum creatinine of 1.5–2.5 mg/dL should be adequately 
hydrated before the procedure. Hydration with saline has 
been the cornerstone of contrast nephropathy prevention: 
intravenous saline 1 mL/kg/h is started 12 hours before the 
procedure and continued for 12 hours afterward. Some 
studies suggest that sodium bicarbonate infusions are more 
effective, and an alternate option is to infuse sodium bicar
-
bonate: 150 mL of sodium bicarbonate (1 mEq/mL) is 
added to 1 L of 5% dextrose and infused at 3.5 mL/kg/h for 
1 hour before the procedure; 1.2 mg/kg/h is given during 
the procedure and for 6 hours afterward. N-acetylcysteine 
has also been shown in some trials to decrease the inci
-
dence of contrast nephropathy. One regimen consists of

-
dence of contrast nephropathy. One regimen consists of 
using oral N-acetylcysteine 600 mg twice a day starting the 
day before the procedure for a total of four doses. A com
-
bination of N-acetylcysteine and intravenous saline or 
intravenous sodium bicarbonate may be more beneficial. 
Radiographic contrast material should not be given to a 
patient with a serum creatinine greater than 3 mg/dL 
unless the potential benefit outweighs the high risk of acute 
C. Diabetic Neuropathy
Diabetic neuropathies are the most common complications 
of diabetes affecting up to 50% of older patients with type 2 
diabetes.
1. Peripheral neuropathy—
a. 
D
istal symmetric polyneuropathy—
This is the 
most common form of diabetic peripheral neuropathy 
where loss of function appears in a stocking-glove pattern 
and is due to an axonal neuropathic process. Longer nerves 
are especially vulnerable, hence the impact on the foot. 
Both motor and sensory nerve conduction is delayed in the 
peripheral nerves, and ankle jerks may be absent.
Sensory involvement usually occurs first and is gener
-
ally bilateral, symmetric, and associated with dulled per
-
ception of vibration, pain, and temperature. The pain can 
range from mild discomfort to severe incapacitating symp
-
toms. The sensory deficit may eventually be of sufficient 
degree to prevent patients from feeling pain. Patients who 
have a sensory neuropathy should therefore be examined 
with a 5.07 Semmes-Weinstein filament and those who 
cannot feel the filament must be considered at risk for 
unperceived neuropathic injury.
The denervation of the small muscles of the foot results 
in clawing of the toes and displacement of the submetatar
-
sal fat pads anteriorly. These changes, together with the 
joint and connective tissue changes, alter the biomechanics 
of the foot and increase plantar pressures. This combina
-
tion of decreased pain threshold, abnormally high foot 
pressures, and repetitive stress (such as from walking) can 
lead to calluses and ulcerations in the high-pressure areas 
such as over the metatarsal heads (Figure 27–3). Peripheral 
neuropathy, autonomic neuropathy, and trauma also pre
-
disposes to the development of Charcot arthropathy. An 
acute case of Charcot foot arthropathy presents with pain 
and swelling, and if left untreated, leads to a “rocker bot
-
tom” deformity and ulceration. The early radiologic 
changes show joint subluxation and periarticular fractures. 
As the process progresses, there is frank osteoclastic 
destruction leading to deranged and unstable joints par
-
ticularly in the midfoot. Not surprisingly, the key issue for 
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CMDT 2019
the healing of neuropathic ulcers in a foot with good vas
-
cular supply is mechanical unloading. In addition, any 
infection should be treated with debridement and appro
-
priate antibiotics; healing duration of 8–10 weeks is typical. 
Occasionally, when healing appears refractory, platelet-
derived growth factor (becaplermin [Regranex]) should be 
considered for local application. A post-marketing epide
-
miologic study showed increased cancer deaths in patients 
who had used three or more tubes of becaplermin on their 
leg or feet ulcers, resulting in a “black box” warning on the 
medication label. Once ulcers are healed, therapeutic foot
-
wear is key to preventing recurrences. Custom molded 
shoes are reserved for patients with significant foot defor
-
mities. Other patients with neuropathy may require accom
-
modative insoles that distribute the load over as wide an 
area as possible. Patients with foot deformities and loss of 
their protective threshold should get regular care from a 
podiatrist. Patients should be educated on appropriate 
footwear and those with loss of their protective threshold 
should be instructed to inspect their feet daily for reddened 
areas, blisters, abrasions, or lacerations.
In some patients, hypersensitivity to light touch and 
occasionally severe “burning” pain, particularly at night, 
can become physically and emotionally disabling. Nortrip
-
tyline or desipramine in doses of 25–150 mg/day orally 
may provide dramatic relief for pain from diabetic neu
-
ropathy, often within 48–72 hours. This rapid response is 
in contrast to the 2 or 3 weeks required for an antidepres
-
sive effect. Patients often attribute the benefit to having a 
full night’s sleep. Mild to moderate morning drowsiness is 
a side effect that generally improves with time or can be 
lessened by giving the medication several hours before 
bedtime. This medication should not be continued if 
improvement has not occurred after 5 days of therapy. 
Amitriptyline, 25–75 mg orally at bedtime can also be used 
but has more anticholinergic effects. Tricyclic antidepres
-
sants, in combination with fluphenazine (3 mg daily in 
three divided doses) have been shown in two studies to be 
efficacious in painful neuropathy, with benefits unrelated 
to relief of depression. Gabapentin (900–1800 mg orally 
daily in three divided doses) has also been shown to be 
effective in the treatment of painful neuropathy and should 
be tried if the tricyclic medications prove ineffective. Pre
-
gabalin, a congener of gabapentin, has been shown in an 
8-week study to be more effective than placebo in treating 
painful diabetic peripheral neuropathy. However, this 
medication was not compared with an active control. Also, 
because of its abuse potential, it has been categorized as a 
schedule V controlled substance. Duloxetine (60–120 mg), 
a serotonin and norepinephrine reuptake inhibitor, is 
approved for the treatment of painful diabetic neuropathy. 
Capsaicin, a topical irritant, is effective in reducing local 
nerve pain; it is dispensed as a cream (Zostrix 0.025%, 
Zostrix-HP 0.075%) to be rubbed into the skin over the 
painful region two to four times daily. Gloves should be 
used for application since hand contamination could result 
in discomfort if the cream comes in contact with eyes or 
sensitive areas such as the genitalia. Application of a 5% 
lidocaine patch over an area of maximal pain has been 
reported to be of benefit. It is approved for treatment of 
postherpetic neuralgia.
Diabetic neuropathic cachexia
 is a syndrome charac
-
terized by a symmetric peripheral neuropathy associated 
with profound weight loss (up to 60% of total body weight) 
and painful dysesthesias affecting the proximal lower limbs, 
the hands, or the lower trunk. Treatment is usually with 
insulin and analgesics. The prognosis is generally good, and 
patients typically recover their baseline weight with resolu
-

-
tion of the painful sensory symptoms within 1 year.
b. 
I
solated peripheral neuropathy—
Involvement of 
the distribution of only one nerve (“mononeuropathy”) or 
of several nerves (“mononeuropathy multiplex”) is charac
-
terized by sudden onset with subsequent recovery of all or 
most of the function. This neuropathology has been attrib
-
uted to vascular ischemia or traumatic damage. Cranial and 
femoral nerves are commonly involved, and motor abnor
-
malities predominate. The patient with cranial nerve 
involvement usually has diplopia and single third, fourth, or 
sixth nerve weakness on examination but the pupil is 
spared. A full recovery of function occurs in 6–12 weeks. 
Diabetic amyotrophy presents with onset of severe pain in 
the front of the thigh. Within a few days or weeks of the 
onset of pain, weakness and wasting of the quadriceps 
develops. As the weakness appears, the pain tends to 
improve. Management includes analgesia and improved 
diabetes control. The symptoms improve over 6–18 months.
2. Autonomic neuropathy—
Neuropathy of the autonomic 
system occurs principally in patients with diabetes of long 
duration. It affects many diverse visceral functions includ
-
ing blood pressure and pulse, gastrointestinal activity, blad
-
der function, and erectile dysfunction. Treatment is 
directed specifically at each abnormality.
Involvement of the gastrointestinal system may be 
manifested by nausea, vomiting, postprandial fullness, 
reflux or dysphagia, constipation or diarrhea (or both), and 
fecal incontinence. Gastroparesis should be considered in 
type 1 diabetic patients in whom unexpected fluctuations 
and variability in their blood glucose levels develops 
 
▲
Figure 27–3.
 
Diabetic foot ulcer over head of first 
metatarsal (arrow).
 (Used, with permission, from Dean 
SM, Satiani B, Abraham WT. 
Color Atlas and Synopsis of 
 
Vascular Diseases.
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after meals. Metoclopramide has been of some help in 
treating diabetic gastroparesis. It is given in a dose of 10 mg 
orally three or four times a day, 30 minutes before meals 
and at bedtime. Drowsiness, restlessness, fatigue, and las
-
situde are common adverse effects. Tardive dyskinesia and 
extrapyramidal effects can occur, especially when used for 
longer than 3 months, and the FDA has cautioned against 
the long-term use of metoclopramide.
Erythromycin appears to bind to motilin receptors in 
the stomach and has been found to improve gastric empty
-
ing over the short term in doses of 250 mg three times 
daily, but its effectiveness seems to diminish over time. In 
selected patients, injections of botulinum toxin into the 
pylorus can reduce pylorus sphincter resistance and 
enhance gastric emptying. Gastric electrical stimulation 
has been reported to improve symptoms and quality of life 
indices in patients with gastroparesis refractory to pharma
-
cologic therapy.
Diarrhea associated with autonomic neuropathy has 
occasionally responded to broad-spectrum antibiotic ther
-
apy (such as rifaximin, metronidazole, amoxicillin/clavula
-
nate, ciprofloxacin, or doxycycline), although it often 
undergoes spontaneous remission. Refractory diabetic 
diarrhea is often associated with impaired sphincter con
-
trol and fecal incontinence. Therapy with loperamide, 
4–8 mg daily, or diphenoxylate with atropine, two tablets 
up to four times a day, may provide relief. In more severe 
cases, tincture of paregoric or codeine (60-mg tablets) may 
be required to reduce the frequency of diarrhea and 
improve the consistency of the stools. Clonidine has been 
reported to lessen diabetic diarrhea; however, its usefulness 
is limited by its tendency to lower blood pressure in these 
patients who already have autonomic neuropathy, resulting 
in orthostatic hypotension. Constipation usually responds 
to stimulant laxatives such as senna.
Incomplete emptying of the bladder can sometimes 
occur. Bethanechol in doses of 10–50 mg orally three times 
a day has occasionally improved emptying of the atonic 
urinary bladder. Catheter decompression of the distended 
bladder has been reported to improve its function, and 
considerable benefit has been reported after surgical sever
-
ing of the internal vesicle sphincter.
Use of Jobst fitted stockings, tilting the head of the bed, 
and arising slowly from the supine position can be helpful 
in treating symptoms of orthostatic hypotension. When 
such measures are inadequate, then treatment with fludro
-
cortisone 0.1–0.2 mg orally daily can be considered. This 
medication, however, can result in supine hypertension 
and hypokalemia. Midodrine (10 mg orally three times a 
day), an alpha-agonist, can also be used.
Erectile dysfunction can result from neurologic, psy
-
chological or vascular causes, or a combination of these 
causes. Sildenafil (Viagra), vardenafil (Levitra), and 
tadalafil (Cialis) have been shown in placebo-controlled 
clinical trials to improve erections in response to sexual 
stimulation. The recommended dose of sildenafil for most 
patients is one 50-mg tablet taken approximately 1 hour 
before sexual activity. The peak effect is at 1.5–2 hours, 
with some effect persisting for 4 hours. Patients with diabe
-
tes mellitus using sildenafil reported 50–60% improvement 
in erectile function. The maximum recommended dose is 
100 mg. The recommended dose of both vardenafil and 
tadalafil is 10 mg. The doses may be increased to 20 mg or 
decreased to 5 mg based on efficacy and side effects. 
Tadalafil has been shown to improve erectile function for 
up to 36 hours after dosing. Low doses are available for 
daily use. In clinical trials, only a few adverse effects have 
been reported—transient mild headache, flushing, 
dyspepsia, and some altered color vision. Priapism can 
occur with these medications, and patients should be

occur with these medications, and patients should be 
advised to seek immediate medical attention if an erection 
persists for longer than 4 hours. These phosphodiesterase 
type 5 (PDE5) inhibitors potentiate the hypotensive effects 
of nitrates and their use is contraindicated in patients who 
are concurrently using organic nitrates in any form. Cau
-
tion is advised for men who have suffered a heart attack, 
stroke, or life-threatening arrhythmia within the previous 
6 months; men who have resting hypotension or hyperten
-
sion; and men who have a history of heart failure or have 
unstable angina. Rarely, a decrease in vision or permanent 
visual loss has been reported after PDE5 inhibitor use.
Intracorporeal injection of vasoactive medications 
causes penile engorgement and erection. Medications most 
commonly used include papaverine alone, papaverine with 
phentolamine, and alprostadil (prostaglandin E
1
). Alprosta
-
dil injections are relatively painless, but careful instruction 
is essential to prevent local trauma, priapism, and fibrosis. 
Intraurethral pellets of alprostadil avoid the problem of 
injection of the medication.
External vacuum therapy (Erec-Aid System) is a non
-
surgical treatment consisting of a suction chamber oper
-
ated by a hand pump that creates a vacuum around the 
penis. This draws blood into the penis to produce an erec
-
tion that is maintained by a specially designed tension ring 
inserted around the base of the penis and which can be 
kept in place for up to 20–30 minutes. While this method 
is generally effective, its cumbersome nature limits its 
appeal.
Surgical implants of penile prostheses remain an option 
for those patients in whom the nonsurgical approaches are 
ineffective.
D. Cardiovascular Complications
1. Heart disease—
Microangiopathy occurs in the heart 
and may explain the etiology of congestive cardiomyopa
-
thies in diabetic patients who do not have demonstrable 
coronary artery disease. More commonly, however, heart 
disease in patients with diabetes is due to coronary athero
-
sclerosis. Myocardial infarction is three to five times more 
common in diabetic patients and is the leading cause of 
death in patients with type 2 diabetes. Cardiovascular dis
-
ease risk is increased in patients with type 1 diabetes as well, 
although the absolute risk is lower than in patients with 
type 2 diabetes. Premenopausal women who normally have 
lower rates of coronary artery disease lose this protection 
once diabetes develops. The increased risk in patients with 
type 2 diabetes reflects the combination of hyperglycemia, 
hyperlipidemia, abnormalities of platelet adhesiveness, 
coagulation factors, hypertension, oxidative stress, and 
inflammation. Large intervention studies of risk factor 
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reduction in diabetes are lacking, but it is reasonable to 
assume that reducing these risk factors would have a bene
-
ficial effect. Lowering LDL cholesterol reduces first events 
in patients without known coronary disease and secondary 
events in patients with known coronary disease. These 
intervention studies included some patients with diabetes, 
and the benefits of LDL cholesterol lowering was apparent 
in this group. The National Cholesterol Education Program 
clinical practice guidelines have designated diabetes as a 
coronary risk equivalent and have recommended that 
patients with diabetes should have an LDL cholesterol goal 
of less than 100 mg/dL (2.6 mmol/L). Lowering LDL cho
-
lesterol to 70 mg/dL (1.8 mmol/L) may have additional 
benefit and is a reasonable target for most patients with 
type 2 diabetes who have multiple risk factors for cardio
-
vascular disease.
The ADA also recommends lowering systolic blood 
pressure to less than 140 mm Hg and diastolic pressure to 
less than 90 mm Hg in patients with diabetes. The systolic 
target of 130 mm Hg or less and diastolic of 80 mm Hg or 
less is recommended for the younger patient if it can be 
achieved without undue treatment burden. The Systolic 
Blood Pressure Intervention Trial (SPRINT) reported that 
treating to a systolic blood pressure of less than 120 mm Hg 
reduced cardiovascular events by 25% and death from car
-
diovascular causes by 43% during 3.26 years of follow-up. 
People with diabetes, however, were excluded from this 
study, and it is unclear if the results are applicable to this 
population. Patients with type 2 diabetes who already have 
cardiovascular disease or microalbuminuria should be 
considered for treatment with an ACE inhibitor. More 
clinical studies are needed to address the question of 
whether patients with type 2 diabetes who do not have 
cardiovascular disease or microalbuminuria would specifi
-
cally benefit from ACE inhibitor treatment.
Aspirin at a dose of 81–325 mg daily is effective in 
reducing cardiovascular morbidity and mortality in 
patients who have a history of myocardial infarction or 
stroke (secondary prevention). It is unclear if aspirin pre
-
vents primary cardiovascular events in people with 
diabetes. The current recommendation is to give aspirin to 
people with diabetes who have a greater than 10% 10-year 
risk of cardiovascular events. Typically, this includes most 
diabetic patients aged 50 years or older with one or more 
additional risk factors (smoking, hypertension, dyslipid
-
emia, family history of premature cardiovascular disease, 
or albuminuria). Contraindications for aspirin therapy are 
patients with aspirin allergy, bleeding tendency, recent 
gastrointestinal bleeding, or active hepatic disease. Based 
on the Early Treatment Diabetic Retinopathy Study 
(ETDRS), there does not appear to be a contraindication to 
aspirin use to achieve cardiovascular benefit in diabetic 
patients who have proliferative retinopathy. Aspirin also 
does not seem to affect the severity of vitreous/preretinal 
hemorrhages or their resolution.
2. Peripheral vascular disease—
Atherosclerosis is mark
-
edly accelerated in the larger arteries. It is often diffuse, 
with localized enhancement in certain areas of turbulent 
blood flow, such as at the bifurcation of the aorta or other 
large vessels. Clinical manifestations of peripheral vascular 
disease include ischemia of the lower extremities, erectile 
dysfunction, and intestinal angina.
The incidence of 
gangrene of the feet
 in patients with 
diabetes is 30 times that in age-matched controls. The fac
-
tors responsible for its development, in addition to periph
-
eral vascular disease, are small vessel disease, peripheral 
neuropathy with loss of both pain sensation and neurogenic 
inflammatory responses, and secondary infection. In two-
thirds of patients with ischemic gangrene, pedal pulses are

thirds of patients with ischemic gangrene, pedal pulses are 
not palpable. In the remaining one-third who have palpable 
pulses, reduced blood flow through these vessels can be 
demonstrated by plethysmographic or Doppler ultrasound 
examination. Prevention of foot injury is imperative. Agents 
that reduce peripheral blood flow such as tobacco should be 
avoided. Control of other risk factors such as hypertension 
is essential. Beta-blockers are relatively contraindicated 
because of presumed negative peripheral hemodynamic 
consequences but data that support this are lacking. 
Cholesterol-lowering agents are useful as adjunctive therapy 
when early ischemic signs are detected and when 
dyslipidemia is present. Patients should be advised to seek 
immediate medical care if a diabetic foot ulcer develops. 
Improvement in peripheral blood flow with endarterec
-
tomy and bypass operations is possible in certain patients.
E. Skin and Mucous Membrane Complications
Chronic pyogenic infections of the skin may occur, espe
-
cially in poorly controlled diabetic patients. 
Candidal 
infection
 can produce erythema and edema of intertrigi
-
nous areas below the breasts, in the axillas, and between the 
fingers. It causes vulvovaginitis in women with chronically 
uncontrolled diabetes who have persistent glucosuria and 
is a frequent cause of pruritus. While antifungal creams 
containing miconazole or clotrimazole offer immediate 
relief of vulvovaginitis, recurrence is frequent unless glu
-
cosuria is reduced.
In some patients with type 2 diabetes, poor glycemic 
control can cause a severe hypertriglycemia, which can 
present as 
eruptive cutaneous xanthomas
 and pancreatitis. 
The skin lesions appear as yellow morbilliform eruptions 
2–5 mm in diameter with erythematous areolae. They 
occur on extensor surfaces (elbows, knees, buttocks) and 
disappear after triglyceride levels are reduced.
Necrobiosis lipoidica diabeticorum
 is usually located 
over the anterior surfaces of the legs or the dorsal surfaces 
of the ankles. They are oval or irregularly shaped plaques 
with demarcated borders and a glistening yellow surface 
and occur in women two to four times more frequently 
than in men. Pathologically, the lesions show degeneration 
of collagen, granulomatous inflammation of subcutaneous 
tissues and blood vessels, capillary basement membrane 
thickening and obliteration of vessel lumina. The condition 
is associated with type 1 diabetes, although it can occur in 
patients with type 2 diabetes, and also in patients without 
diabetes. First-line therapy includes topical and subcutane
-
ous corticosteroids. Improving glycemic control may help 
the condition.
“Shin spots”
 are not uncommon in adults with diabe
-
tes. They are brownish, rounded, painless atrophic lesions 
of the skin in the pretibial area.
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F. Bone and Joint Complications
Long-standing diabetes can cause progressive stiffness of 
the hand secondary to contracture and tightening of skin 
over the joints (diabetic cheiroarthropathy), frozen shoul
-
der (adhesive capsulitis), carpal tunnel syndrome, and 
Dupuytren contractures. These complications are believed 
to be due to glycosylation of collagen and perhaps other 
proteins in connective tissue. There may also be an inflam
-
matory component.
Data on bone mineral density and fracture risk in peo
-
ple with diabetes are contradictory. Patients with type 2 
diabetes do appear to be at increased risk for nonvertebral 
fractures. Women with type 1 diabetes have an increased 
risk of fracture when compared with women without 
diabetes. Other factors, such as duration of diabetes, 
and diabetes complications, such as neuropathy and 
kidney disease, likely affect both the bone mineral den
-
sity and fracture risk.
Diffuse idiopathic skeletal hyperostosis (DISH) is char
-
acterized by ossification of the anterior longitudinal liga
-
ments of the spine and various extraspinal ligaments. It 
causes stiffness and decreased range of spinal motion. The 
peripheral joints most commonly affected are the metacar
-
pophalangeal joints, elbows, and shoulders. Diabetes, obe
-
sity, hypertension, and dyslipidemia are risk factors for this 
Hyperuricemia and acute and tophaceous gout are 
more common in type 2 diabetes.
Bursitis, particularly of the shoulders and hips, occurs 
more frequently than expected in patients with diabetes.
Chin JA et al. Diabetes mellitus and peripheral vascular disease: 
diagnosis and management. Clin Podiatr Med Surg. 2014 Jan;
 
31(1):11–26. [PMID: 24296015]
Gregg EW et al. Changes in diabetes-related complications in the 
United States, 1990–2010. N Engl J Med. 2014 Apr 17;
 
370(16):1514–23. [PMID: 24738668]
Razmaria AA. Diabetic neuropathy. JAMA Patient Page. JAMA. 
2015 Nov 24;314(20):2202. [PMID: 26599195]
Stitt AW et al. The progress in understanding and treatment of 
diabetic retinopathy. Prog Retin Eye Res. 2016 Mar;51:
 
156–86. [PMID: 26297071]
Waanders F et al. Current concepts in the management of dia
-
betic nephropathy. Neth J Med. 2013 Nov;71(9):448–58. 
[PMID: 24218418]
Wright JT Jr et al; SPRINT research group. A randomized trial of 
intensive versus standard blood-pressure control. N Engl J 
 
»
Special Situations
A. Diabetes Management in the Hospital
Most patients with diabetes are hospitalized for reasons 
other than their diabetes. Indeed, up to 10–15% of all hos
-
pitalized patients have diabetes. It is challenging using 
outpatient oral therapies or insulin regimens in the hospital 
because patients are not eating as usual; they are often fast
-
ing for procedures; clinical events increase adverse reac
-
tions associated with diabetes medicines, eg, 
thiazolidinediones can cause fluid retention and worsen 
heart failure; metformin should not be used in patients 
with significant chronic kidney or liver disease, or those 
getting contrast for radiographic studies. Subcutaneous or 
intravenous insulin therapy is frequently substituted for 
other diabetes medicines because the insulin dose can be 
adjusted to match changing inpatient needs and it is safe to 
use insulin in patients with heart, kidney, and liver 
disease.
Surgery
 represents a stress situation during which most 
of the insulin antagonists (eg, catecholamines, growth hor
-
mone, and corticosteroids) are mobilized. In the diabetic 
patient, this can lead to a worsening of hyperglycemia and 
perhaps even ketoacidosis. The aim of medical manage
-
ment of people with diabetes during the perioperative 
period is to minimize these stress-induced changes. Rec
-
ommendations for management depend both on the 
patient’s usual diabetic regimen and on the type of surgery 
(major or minor) to be done (see also Chapter 3).

-
For people with diabetes controlled with diet alone, no 
special precautions must be taken unless diabetic control is 
markedly disturbed by the procedure. If this occurs, small 
doses of short-acting insulin as needed will correct the 
Patients taking oral agents should not take them on the 
day of surgery. If there is significant hyperglycemia, small 
doses of short-acting insulin are given as needed. If this 
approach does not provide adequate control, an insulin 
infusion should be started in the manner indicated below. 
The oral agents can be restarted once the patient is eating 
normally after the operation. It is important to order a 
postoperative serum creatinine level to ensure adequate 
kidney function prior to restarting metformin therapy.
Patients taking insulin represent the only serious chal
-
lenge to management of diabetes when surgery is necessary. 
However, with careful attention to changes in the clinical or 
laboratory picture, glucose control can be managed success
-
fully. The protocol used to control the glucose depends on 
the kind of diabetes (type 1 or type 2); whether it is minor 
surgery (lasting less than 2 hours and patient eating after
-
wards) or major surgery (lasting more than 2 hours, with 
invasion of a body cavity, and patient not eating after
-
wards); and the preoperative insulin regimen (basal bolus 
or premixed insulin twice a day or premeal bolus only or 
regular insulin before meals and NPH at bedtime). Patients 
with type 1 diabetes must be receiving some insulin to pre
-
vent the development of DKA. Many patients with type 2 
diabetes who are taking insulin do well perioperatively 
without insulin for a few hours. Ideally, patients with 
diabetes should undergo surgery early in the morning. 
Table 27–11 summarizes the approach for these patients.
One insulin infusion method adds 10 units of regular 
insulin to 1 L of 5% dextrose in 0.45% saline, and this is 
infused intravenously at a rate of 100–180 mL/h. This gives 
the patient 1–1.8 units of insulin per hour which, except in 
the most severe cases, generally keeps the blood glucose 
within the range of 100–250 mg/dL (5.5–13.9 mmol/L). 
The infusion may be continued for several days, if neces
-
sary. Perioperatively, plasma glucose or blood glucose 
should be determined every 2–4 hours to be sure metabolic 
control is adequate. If it is not, adjustments in the ratio of 
insulin to dextrose in the intravenous solution can be made.
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An alternative method consists of separate infusions of 
insulin and glucose delivered by pumps to permit indepen
-
dent adjustments of each infusion rate, depending on 
hourly variation of blood glucose values. There are a num
-
ber of different algorithms available for insulin infusions 
(see http://www.hospitalmedicine.org).
After surgery, when the patient has resumed an ade
-
quate oral intake, subcutaneous administration of insulin 
can be resumed and intravenous administration of insulin 
and dextrose can be stopped 30 minutes after the first sub
-
cutaneous dose. Insulin needs may vary in the first several 
days after surgery because of continuing postoperative 
stresses and because of variable caloric intake. In this situa
-
tion, multiple doses of short-acting insulin plus some long-
acting basal insulin, guided by blood glucose determinations, 
can keep the patient in acceptable metabolic control.
In the 
intensive care units (ICUs)
, glucose levels are 
controlled most frequently using insulin infusions. Patients 
receiving total parenteral nutrition can have insulin added 
to the bag. Standard total parenteral nutrition contains 
25% dextrose so an infusion rate of 50 mL/h delivers 12.5 g 
of dextrose per hour.
On the 
general surgical and medical wards
, most 
patients are treated with subcutaneous insulin regimens. 
Limited cross-sectional and prospective studies suggest 
that the best glucose control is achieved on a combination 
of basal and bolus regimen with 50% of daily insulin needs 
provided by intermediate- or long-acting insulins. Stan
-
dardized order sets can reduce errors, and they often 
include algorithms for recognition and treatment of hypo
-
glycemia (see http://ucsfinpatientdiabetes.pbworks.com 
for examples).
The morbidity and mortality in diabetic patients is 
twice that of nondiabetic patients. Those with new-onset 
hyperglycemia (ie, those without a preadmission diagnosis 
of diabetes) have even higher mortality—almost eightfold 
that of nondiabetic patients in one study. These observa
-
tions have led to the question of whether tight glycemic 
control in the hospital improves outcomes.
Based on the evidence available, ICU patients with 
diabetes and new-onset hyperglycemia with blood glu
-
cose levels above 180 mg/dL (10 mmol/L) should be 
treated with insulin, aiming for target glucose levels 
between 140 mg/dL (7.8 mmol/L) and 180 mg/dL 
(10 mmol/L).
 In the ICU setting, aiming for blood glucose 
levels close to 100 mg/dL (5.6 mmol/L) is not beneficial 
and may even be harmful. When patients leave the ICU, 
target glucose values between 100 mg/dL (5.6 mmol/L) and 
180 mg/dL (10 mmol/L) may be appropriate, although this 
view is based on clinical observations rather than conclu
-
sive evidence.
Kansagara D et al. Intensive insulin therapy in hospitalized 
patients: a systematic review. Ann Intern Med. 2011 Feb 15;
 
154(4):268–82. [PMID: 21320942]
B. Pregnancy and the Diabetic Patient
See Chapter 19. Tight glycemic control with normal HbA
1c
 
levels is very important during pregnancy. Early in preg
-
nancy, poor control increases the risk of spontaneous abor
-
tion and congenital malformations. Late in pregnancy, 
poor control can result in polyhydramnios, preterm labor, 
stillbirth, and fetal macrosomia with its associated prob
-
lems. Diabetes complications can impact both maternal 
and fetal health. Diabetic retinopathy can first develop 
during pregnancy or retinopathy that is already present can 
worsen. Diabetic women with microalbuminuria can have 
worsening albuminuria during pregnancy and are at higher 
risk for preeclampsia. Aspirin can reduce the risk of pre
-
eclampsia and should be prescribed after 12 weeks of gesta
-
tion. Patients who have preexisting kidney failure 
(prepregnancy creatinine clearance less than 80 mL/min) 
are at high risk for further decline in kidney function dur
-

-
-
ing the pregnancy, and this may not reverse after delivery. 
Diabetic gastroparesis can severely exacerbate the nausea 
and vomiting of pregnancy and some patients may require 
fluid and nutritional support.
Although there is evidence that glyburide is safe during 
pregnancy, the current practice is to control diabetes with 
insulin therapy. Every effort should be made, utilizing multi
-
ple injections of insulin or a continuous infusion of insulin by 
pump, to maintain near-normalization of fasting and pre
-
prandial blood glucose values while avoiding hypoglycemia.
Table 27–11.
 
Recommendations for management of insulin-treated diabetes during surgery.
Type of Diabetes
Minor Surgical Procedures 
 
(< 2 hours; eating afterward)
Major Surgical Procedures (> 2 hours; 
invasion of body cavity; not eating 
immediately after recovery)
Type 2:
 Patients taking basal bolus insulin 
regimen; twice daily premixed insulin
No insulin on the day of operation. Start 5% dex
-
trose infusion; monitor fingerstick blood glu
-
cose and give subcutaneous short-acting 
insulin every 4 or 6 hours
Same regimen as minor procedure. If 
control is not satisfactory, then intra
-
venous insulin infusion
Type 1:
regimen or using insulin pump
Patients using pump should discontinue the 
pump the evening before procedure and given 
24-hour basal insulin. On day of procedure, 
start 5% dextrose; monitor blood glucose and 
give subcutaneous short-acting insulin every 4 
or 6 hours
Initiate insulin infusion on morning of 
procedure and transition back to usual 
regimen when eating
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Regular and NPH insulin and the insulin analogs lispro, 
aspart, and detemir are labeled pregnancy category B. Insu
-
lin glargine, glulisine, and degludec are labeled category C 
because of lack of clinical safety data. A small study using 
insulin glargine in 32 pregnancies did not reveal any 
problems.
Unless there are fetal or maternal complications, dia
-
betic women should be able to carry the pregnancy to full-
term, delivering at 38 to 41 weeks. Induction of labor before 
39 weeks may be considered if there is concern about 
increasing fetal weight. See Chapter 19 for further details.
Blumer I et al. Diabetes and pregnancy: an endocrine society 
clinical practice guideline. J Clin Endocrinol Metab. 2013 
Nov;98(11):4227–49. [PMID: 24194617]
 
»
Prognosis
The DCCT showed that the previously poor prognosis for 
as many as 40% of patients with type 1 diabetes is markedly 
improved by optimal care. DCCT participants were gener
-
ally young and highly motivated and were cared for in 
academic centers by skilled diabetes educators and endo
-
crinologists who were able to provide more attention and 
services than are usually available. Improved training of 
primary care providers may be beneficial.
For type 2 diabetes, the UKPDS documented a reduction 
in microvascular disease with glycemic control, although 
this was not apparent in the obese subgroup. Cardiovascular 
outcomes were not improved by glycemic control, although 
antihypertensive therapy showed benefit in reducing the 
number of adverse cardiovascular complications as well as in 
reducing the occurrence of microvascular disease among 
hypertensive patients. In patients with visceral obesity, suc
-
cessful management of type 2 diabetes remains a major chal
-
lenge in the attempt to achieve appropriate control of 
hyperglycemia, hypertension, and dyslipidemia. Once safe 
and effective methods are devised to prevent or manage 
obesity, the prognosis of type 2 diabetes with its high cardio
-
vascular risks should improve considerably.
In addition to poorly understood genetic factors relat
-
ing to differences in individual susceptibility to develop
-
ment of long-term complications of hyperglycemia, it is 
clear that in both types of diabetes, the diabetic patient’s 
intelligence, motivation, and awareness of the potential 
complications of the disease contribute significantly to the 
ultimate outcome.
 
»
•	
All patients should receive self-management education 
when diabetes is diagnosed and at intervals thereafter. 
The instructional team should include a registered 
dietitian and registered nurse; they must be Certified 
Diabetes Educators (CDEs).
•	
Patients with type 1 diabetes should be referred to an 
endocrinologist for comanagement with a primary care 
provider.
•	
Patients with type 2 diabetes should be referred to an 
endocrinologist if treatment goals are not met or if the 
patient requires an increasingly complex regimen to 
maintain glycemic control.
•	
ophthalmologist or optometrist for a dilated eye exami
-
nation when the diabetes is diagnosed, and patients 
with type 1 diabetes should be referred 5 years after the 
diagnosis is made.
•	
Patients with peripheral neuropathy, especially those 
with loss of protective threshold (unable to detect 5.07 
Semmes-Weinstein filament) or structural foot prob
-
lems, should be referred to a podiatrist.
•	
Referrals to other specialists may be required for man
-
agement of chronic complications of diabetes.
Academy of Nutrition and Dietetics. http://www.eatright.org
American Association of Diabetes Educators. https://www
 
.diabeteseducator.org/
American Diabetes Association. http://www.diabetes.org
American Diabetes Association. Standards of Medical Care in 
Diabetes—2015. Diabetes Care. 2015 Jan;38(Suppl 1):S11–90. 
[PMID: 25537706]
Juvenile Diabetes Research Foundation. http://www.jdrf.org
DIABETIC COMA

Coma may be due to a variety of causes not directly related 
to diabetes. Certain causes directly related to diabetes 
require differentiation: (1) Hypoglycemic coma resulting 
from excessive doses of insulin or oral hypoglycemic 
agents. (2) Hyperglycemic coma associated with either 
severe insulin deficiency (DKA) or mild to moderate insu
-
lin deficiency (hyperglycemic hyperosmolar state). (3) 
Lactic acidosis associated with diabetes, particularly in 
patients with diabetes stricken with severe infections or 
with cardiovascular collapse.
DIABETIC KETOACIDOSIS
 
»
Hyperglycemia greater than 250 mg/dL 
 
(13.9 mmol/L).
 
»
Metabolic acidosis with blood pH < 7.3; serum 
bicarbonate less than 15 mEq/L.
 
»
Serum positive for ketones.
 
»
Diabetic ketoacidosis (DKA) may be the initial manifesta
-
tion of type 1 diabetes or may result from increased insulin 
requirements in type 1 diabetes patients during the course 
of infection, trauma, myocardial infarction, or surgery. It is 
a life-threatening medical emergency with a mortality rate 
just under 5% in individuals under 40 years of age, but with 
a more serious prognosis in older adults, who have mortal
-
ity rates over 20%. The National Data Group reports an 
annual incidence of five to eight episodes of DKA per 1000 
diabetic persons. Ketoacidosis may develop in patients 
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with type 2 diabetes when severe stress such as sepsis or 
trauma is present. DKA is one of the more common serious 
complications of insulin pump therapy, occurring in 
approximately 1 per 80 patient-months of treatment. Many 
patients who monitor capillary blood glucose regularly 
ignore urine ketone measurements, which signals the pos
-
sibility of insulin leakage or pump failure before serious 
illness develops. Poor compliance, either for psychological 
reasons or because of inadequate education, is one of the 
most common causes of recurrent DKA.
 
»
The appearance of DKA is usually preceded by a day or more 
of polyuria and polydipsia associated with marked fatigue, 
nausea, and vomiting. If untreated, mental stupor ensues 
that can progress to coma. Drowsiness is fairly common, but 
frank coma only occurs in about 10% of patients. On physi
-
cal examination, evidence of dehydration in a stuporous 
patient with rapid deep breathing and a “fruity” breath odor 
of acetone strongly suggests the diagnosis. Hypotension with 
tachycardia indicates profound fluid and electrolyte deple
-
tion, and mild hypothermia is usually present. Abdominal 
pain and even tenderness may be present in the absence of 
abdominal disease. Conversely, cholecystitis or pancreatitis 
may occur with minimal symptoms and signs.
Typically, the patient with moderately severe DKA has a 
plasma glucose of 350–900 mg/dL (19.4–50 mmol/L), 
serum ketones at a dilution of 1:8 or greater or beta-
hydroxybutyrate more than 4 nmol/L, hyperkalemia 
(serum potassium level of 5–8 mEq/L), slight hyponatre
-
mia (serum sodium of approximately 130 mEq/L), hyper
-
phosphatemia (serum phosphate level of 6–7 mg/dL 
[1.9–2.3 mmol/L]), and elevated blood urea nitrogen and 
serum creatinine levels (Table 27–12). Acidosis may be 
severe (pH ranging from 6.9 to 7.2 and serum bicarbonate 
ranging from 5 mEq/L to 15 mEq/L); PCO
2
 is low (15–20 
mm Hg) related to compensatory hyperventilation. Fluid 
depletion is marked, typically about 100 mL/kg.
The difference between venous and arterial pH is 0.02 to 
0.15 pH units and venous and arterial bicarbonate is 1.88 
mEq/L. These small differences will not affect either the 
diagnosis or the management of DKA, and there is no need 
to collect arterial blood for measuring the acid-base status.
The hyperkalemia occurs despite total body potassium 
depletion because of the shift of potassium from the intracel
-
lular to extracellular spaces that occurs in systemic acidosis. 
The average total body potassium deficit resulting from 
osmotic diuresis, acidosis, and gastrointestinal losses is 
about 3–5 mEq/kg. Similarly, despite the elevated serum 
phosphate, total body phosphate is generally depleted. 
Serum sodium is generally reduced due to loss of sodium 
ions (7–10 mEq/kg) by polyuria and vomiting and because 
severe hyperglycemia shifts intracellular water into the inter
-
stitial compartment. For every 100 mg/dL of plasma glucose, 
serum sodium decreases by 1.6 mEq/L (5.56 mmol/L). The 
decrease in serum sodium may be greater when patients 
have more severe hyperglycemia (greater than 400 mg/dL, 
22.2 mmol/L) and a correction factor of 2.4 mEq/L may be 
used. Hypertriglyceridemia should be considered if the cor
-
rected sodium is very low. Serum osmolality can be directly 
measured by standard tests of freezing point depression or 
can be estimated by calculating the molarity of sodium, chlo
-
ride, and glucose in the serum. A convenient method of 
estimating effective serum osmolality is as follows (normal 
values in humans are 280–300 mOsm/kg): 
mOsm/k
g2
/uni00A0[
me
asured/uni00A0N
a]
Gl
uc
os
e(
mg/dL)
18
=+
+
These calculated estimates are usually 10–20 mOsm/kg 
lower than values measured by standard cryoscopic 
Table 27–12.
 
Laboratory diagnosis of coma in diabetic patients.
Urine Glucose
Urine 
Ketones
Plasma

Urine 
Ketones
Plasma 
Glucose
Plasma 
Plasma 
Ketones
r
elated to Diabetes
0
1
0 or +
Low
Normal
0
++++
++++
High
Low
++++
Hyperglycemic hyperosmolar state coma
++++
0
High
Normal or slightly 
low
0
0 or +
0 or +
Normal or low or 
high
Low
0 or +
Unrelated to Diabetes
Alcohol or other toxic drugs
0 or +
0 or +
May be low
Normal or low
2
0 or +
Cerebrovascular accident or head trauma
+ or 0
0
Often high
Normal
0
Uremia
0 or +
0
High or normal
Low
0 or +
1
Leftover urine in bladder might still contain glucose from earlier hyperglycemia.
2
Alcohol can elevate plasma lactate as well as keto acids to reduce pH.
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techniques. Central nervous system depression or coma 
occurs when the effective serum osmolality exceeds 320–
330 mOsm/L. Coma in a diabetic patient with a lower 
osmolality should prompt a search for cause of coma other 
than hyperosmolality (see Table 27–12 and Chapter 24).
Ketoacidemia represents the effect of insulin lack at 
multiple enzyme loci. Insulin lack associated with elevated 
levels of growth hormone, catecholamines, and glucagon 
contributes to increases in lipolysis from adipose tissue and 
in hepatic ketogenesis. In addition, reduced ketolysis by 
insulin-deficient peripheral tissues contributes to the keto
-
acidemia. The only true “keto” acid present is acetoacetic 
acid which, along with its by-product acetone, is measured 
by nitroprusside reagents (Acetest and Ketostix). The sen
-
sitivity for acetone, however, is poor, requiring over 
10 mmol/L, which is seldom reached in the plasma of 
ketoacidotic patients—although this detectable concentra
-
tion is readily achieved in urine. Thus, in the plasma of 
ketotic patients, only acetoacetate is measured by these 
reagents. The more prevalent beta-hydroxybutyric acid has 
no ketone group and is therefore not detected by conven
-
tional nitroprusside tests. This takes on special importance 
in the presence of circulatory collapse during DKA, 
wherein an increase in lactic acid can shift the redox state 
to increase beta-hydroxybutyric acid at the expense of the 
readily detectable acetoacetic acid. Bedside diagnostic 
reagents are then unreliable, suggesting no ketonemia in 
cases where beta-hydroxybutyric acid is a major factor in 
producing the acidosis. Combined glucose and ketone 
meter (Precision Xtra, Nova Max Plus) that measure blood 
beta-hydroxybutyrate concentration on capillary blood are 
available. Many clinical laboratories also offer direct blood 
beta-hydroxybutyrate measurement.
Nonspecific elevations of serum amylase and lipase 
occurs in about 16–25% of cases of DKA, and an imaging 
study may be necessary if the diagnosis of acute pancreati
-
tis is being seriously considered. Leukocytosis as high as 
25,000/mcL with a left shift may occur with or without 
associated infection. The presence of an elevated or even a 
normal temperature can suggest the presence of an infec
-
tion, since patients with DKA are generally hypothermic if 
uninfected.
 
»
Treatment
Patients with mild DKA are alert and have pH levels 
between 7.25 and 7.30 and beta-hydroxybutyrate levels of 
3–4 mmol/L; those with moderate ketoacidosis are either 
alert or little drowsy and have pH levels between 7.0 and 
7.24 and beta-hydroxybutyrate levels of 4–8 mmol/L; and 
those with severe ketoacidosis are stuporose and have a pH 
< 7.0 and beta-hydroxybutyrate levels of greater than 
8 mmol/L. Those with mild ketoacidosis can be treated in 
the emergency department, but those with moderate or 
severe ketoacidosis require admission to the ICU or step-
down unit. Therapeutic goals are to restore plasma volume 
and tissue perfusion, reduce blood glucose and osmolality 
toward normal, correct acidosis, replenish electrolyte 
losses, and identify and treat precipitating factors. Gastric 
intubation is recommended in the comatose patient to 
prevent vomiting and aspiration that may occur as a result 
of gastric atony, a common complication of DKA. An 
indwelling catheter may also be necessary. In patients with 
preexisting heart or kidney failure or those in severe car
-
diovascular collapse, a central venous pressure catheter 
should be inserted to evaluate the degree of hypovolemia 
and to monitor subsequent fluid administration.
A comprehensive flow sheet that includes vital signs, 
serial laboratory data, and therapeutic interventions (eg, 
fluids, insulin) should be meticulously maintained by the 
clinician responsible for the patient’s care. Plasma glucose 
should be recorded hourly and electrolytes and pH at least

should be recorded hourly and electrolytes and pH at least 
every 2–3 hours during the initial treatment period. Bed
-
side glucose meters should be used to titrate the insulin 
therapy. The patient should not receive sedatives or opioids 
in order to avoid masking signs and symptoms of impeding 
cerebral edema.
A. Fluid Replacement
In most patients, the fluid deficit is 4–5 L. Initially, 0.9% 
saline solution is the solution of choice to help reexpand the 
contracted vascular volume and should be started in the 
emergency department as soon as the diagnosis is estab
-
lished. The saline should be infused rapidly to provide 1 L/h 
over the first 1–2 hours. After the first 2 L of fluid have been 
given, the intravenous infusion should be at the rate of 
300–400 mL/h. Use 0.9% (“normal”) saline unless the serum 
sodium is greater than 150 mEq/L, when 0.45% (“half 
normal”) saline solution should be used. The volume status 
should be very carefully monitored. Failure to give enough 
volume replacement (at least 3–4 L in 8 hours) to restore 
normal perfusion is one of the most serious therapeutic 
shortcomings adversely influencing satisfactory recovery. 
Excessive fluid replacement (more than 5 L in 8 hours) may 
contribute to acute respiratory distress syndrome or cerebral 
edema. When blood glucose falls to approximately 
250 mg/dL (13.9 mmol/L), the fluids should be changed to a 
5% glucose-containing solution to maintain serum glucose 
in the range of 250–300 mg/dL (13.9–16.7 mmol/L). This 
will prevent the development of hypoglycemia and will also 
reduce the likelihood of cerebral edema, which could result 
from too rapid decline of blood glucose.
B. Insulin Replacement
Immediately after initiation of fluid replacement, regular 
insulin can be given intravenously in a loading dose of 
0.1 unit/kg as a bolus to prime the tissue insulin receptors. 
Following the initial bolus, intravenous doses of insulin as 
low as 0.1 unit/kg/h are continuously infused or given 
hourly as an intramuscular injection; this is sufficient to 
replace the insulin deficit in most patients. A prospective 
randomized study showed that a bolus dose is not required 
if patients are given hourly insulin infusion at 0.14 unit/kg. 
Replacement of insulin deficiency helps correct the acido
-
sis by reducing the flux of fatty acids to the liver, reducing 
ketone production by the liver, and also improving removal 
of ketones from the blood. Insulin treatment reduces the 
hyperosmolality by reducing the hyperglycemia. It accom
-
plishes this by increasing removal of glucose through 
peripheral utilization as well as by decreasing production 
of glucose by the liver. This latter effect is accomplished by 
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direct inhibition of gluconeogenesis and glycogenolysis as 
well as by lowered amino acid flux from muscle to liver and 
reduced hyperglucagonemia.
The insulin infusion should be “piggy-backed” into the 
fluid line so the rate of fluid replacement can be changed 
without altering the insulin delivery rate. If the plasma 
glucose level fails to fall at least 10% in the first hour, a 
repeat loading dose (0.1 or 0.14 unit/kg) is recommended. 
Rarely, a patient with immune insulin resistance is encoun
-
tered, and this requires doubling the insulin dose every 
2–4 hours if hyperglycemia does not improve after the first 
two doses of insulin. The insulin dose should be adjusted 
to lower the glucose concentration by about 50–70 mg/dL/h 
(2.8–3.9 mmol/L). If clinical circumstances prevent use of 
insulin infusion, then the insulin can be given intramuscu
-
larly. An initial 0.15 unit/kg of regular insulin is given 
intravenously, and at the same time, the same size dose is 
given intramuscularly. Subsequently, regular insulin is 
given intramuscularly hourly at a dose of 0.1 unit/kg until 
the blood glucose falls to around 250 mg/dL, when the 
insulin can be given subcutaneously. Patients who nor
-
mally take insulin glargine or insulin detemir can be given 
their usual maintenance doses during initial treatment of 
their DKA. The continuation of their subcutaneous basal 
insulins means that lower doses of intravenous insulin will 
be needed, and there will be a smoother transition from 
intravenous insulin infusion to the subcutaneous regimen.
C. Potassium
Total body potassium loss from polyuria and vomiting may 
be as high as 200 mEq. However, because of shifts of potas
-
sium from cells into the extracellular space as a conse
-
quence of acidosis, serum potassium is usually normal to 
slightly elevated prior to institution of treatment. As the 
acidosis is corrected, potassium flows back into the cells, 
and hypokalemia can develop if potassium replacement is 
not instituted. If the patient is not uremic and has an ade
-
quate urinary output, potassium chloride in doses of 
10–30 mEq/h should be infused during the second and 
third hours after beginning therapy as soon as the acidosis 
starts to resolve. Replacement should be started sooner if 
the initial serum potassium is inappropriately normal or 
low and should be delayed if serum potassium fails to 
respond to initial therapy and remains above 5 mEq/L, as in 
cases of chronic kidney disease. Occasionally, a patient may 
present with a serum potassium level less than 3.5 mEq/L, 
in which case insulin therapy should be delayed until the 
potassium level is corrected to greater than 3.5 mEq/L. An 
ECG can be of help in monitoring the patient’s potassium 
status: High peaked T waves are a sign of hyperkalemia, and 
flattened T waves with U waves are a sign of hypokalemia. 
Foods high in potassium content should be prescribed 
when the patient has recovered sufficiently to take food 
orally. Tomato juice has 14 mEq of potassium per 240 mL, 
and a medium-sized banana provides about 10 mEq.
D. Sodium Bicarbonate
The use of sodium bicarbonate in management of DKA has 
been questioned since clinical benefit was not demon
-
strated in one prospective randomized trial and because of 
the following potentially harmful consequences: (1) devel
-
opment of hypokalemia from rapid shift of potassium into 
cells if the acidosis is overcorrected; (2) tissue anoxia from 
reduced dissociation of oxygen from hemoglobin when 
acidosis is rapidly reversed (leftward shift of the oxygen 
dissociation curve); and (3) cerebral acidosis resulting 
from lowering of cerebrospinal fluid pH. It must be empha
-
sized, however, that these considerations are less important 
when very severe acidosis exists. Therefore, it is recom
-
mended that bicarbonate be administered in DKA if the 
arterial blood pH is 7.0 or less, with careful monitoring to

-
arterial blood pH is 7.0 or less, with careful monitoring to 
prevent overcorrection. One or two ampules of sodium 
bicarbonate (one ampule contains 44 mEq/50 mL) should 
be added to 1 L of 0.45% saline with 20 mEq KCl or to 400 
mL of sterile water with 20 mEq KCl and infused over 1 to 
2 hours. (
Note:
 Addition of sodium bicarbonate to 0.9% 
saline would produce a markedly hypertonic solution that 
could aggravate the hyperosmolar state already present.) It 
can be repeated until the arterial pH reaches 7.1, but 
it 
should not be given if the pH is 7.1 or greater
 since addi
-
tional bicarbonate would increase the risk of rebound 
metabolic alkalosis as ketones are metabolized. Alkalosis 
shifts potassium from serum into cells, which could pre
-
cipitate a fatal cardiac arrhythmia.
E. Phosphate
Phosphate replacement is seldom required in treating 
DKA. However, if severe hypophosphatemia of less than 
1 mg/dL (0.32 mmol/L) develops during insulin therapy, a 
small amount of phosphate can be replaced per hour as the 
potassium salt. However, three randomized studies in 
which phosphate was replaced in patients with DKA did 
not show any apparent clinical benefit from phosphate 
administration. Moreover, attempts to use potassium phos
-
phate as the sole means of replacing potassium have led to 
a number of reported cases of severe hypocalcemia with 
tetany. To minimize the risk of inducing tetany from too-
rapid replacement of phosphate, the average deficit of 
40–50 mmol of phosphate should be replaced intrave
-
nously at a rate 
no greater than 3–4 mmol/h
 in a 60- to 
70-kg person. A stock solution (Abbott) provides a mixture 
of 1.12 g KH
2
PO
4
 and 1.18 g K
2
HPO
4
 in a 5-mL single-dose 
vial (this equals 22 mmol of potassium and 15 mmol of 
phosphate). One-half of this vial (2.5 mL) should be added 
to 1 L of either 0.45% saline or 5% dextrose in water. Two 
liters of this solution, infused at a rate of 400 mL/h, will 
correct the phosphate deficit at the optimal rate of 3 mmol/h 
while providing 4.4 mEq of potassium per hour. (Addi
-
tional potassium should be administered as potassium 
chloride to provide a total of 10–30 mEq of potassium per 
hour, as noted above.) If the serum phosphate remains 
below 2.5 mg/dL (0.8 mmol/L) after this infusion, a repeat 
5-hour infusion can be given.
F. Hyperchloremic Acidosis During Therapy
Because of the considerable loss of keto acids in the urine 
during the initial phase of therapy, substrate for subse
-
quent regeneration of bicarbonate is lost and correction of 
the total bicarbonate deficit is hampered. A portion of the 
bicarbonate deficit is replaced with chloride ions infused 
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in large amounts as saline to correct the dehydration. In 
most patients, as the ketoacidosis clears during insulin 
replacement, a hyperchloremic, low-bicarbonate pattern 
emerges with a normal anion gap. This is a relatively 
benign condition that reverses itself over the subsequent 
12–24 hours once intravenous saline is no longer being 
administered. Using a balanced electrolyte solution with a 
pH of 7.4 and 98 mEq/L chloride instead of normal saline 
(pH 
∼
 5.5; chloride 154 mEq/L) similar to serum in chlo
-
ride concentration and pH during resuscitation instead of 
normal saline has been reported to prevent the hyperchlo
-
remic acidosis.
G. Treatment of Associated Infection
Antibiotics are prescribed as indicated. Cholecystitis and 
pyelonephritis may be particularly severe in these patients.
H. Transition to Subcutaneous Insulin Regimen
Once the DKA is controlled and the patient is awake and 
able to eat, subcutaneous insulin therapy can be initiated. 
The patient with type 1 diabetes may have persistent sig
-
nificant tissue insulin resistance and may require a total 
daily insulin dose of approximately 0.6 unit/kg. The 
amount of insulin required in the previous 8 hours can also 
be helpful in estimating the initial insulin doses. Half the 
total daily dose can be given as a long-acting basal insulin 
and the other half as short-acting insulin premeals. The 
patient should receive subcutaneous basal insulin and 
rapid-acting insulin analog with the first meal and the 
insulin infusion discontinued an hour later. The overlap of 
the subcutaneous insulin action and insulin infusion is 
necessary to prevent relapse of the DKA. In patients with 
preexisting diabetes, giving their basal insulin by subcuta
-
neous injection at initiation of treatment simplifies the 
transition from intravenous to subcutaneous regimen. The 
increased insulin resistance is only present for a few days, 
and it is important to reduce both the basal and bolus insu
-
lins to avoid hypoglycemia. A patient with new-onset type 
1 diabetes usually still has significant beta cell function and 
may not need any basal insulin and only very low doses of 
rapid-acting insulin before meals after recovery from the 
ketoacidosis. Patients with type 2 diabetes and DKA due to 
severe illness may initially require insulin therapy but can 
often transition back to oral agents during outpatient 
follow-up.
 
»
Prognosis
Low-dose insulin infusion and fluid and electrolyte 
replacement combined with careful monitoring of 
patients’ clinical and laboratory responses to therapy have 
dramatically reduced the mortality rates of DKA to less 
than 5%. However, this complication remains a signifi
-
cant risk in the aged who have mortality rates greater than 
20% and in patients in profound coma in whom treat
-
ment has been delayed. Acute myocardial infarction and 
infarction of the bowel following prolonged hypotension 
worsen the outlook. A serious prognostic sign is end-stage 
chronic kidney disease, and prior kidney dysfunction 
worsens the prognosis considerably because the kidney 
plays a key role in compensating for massive pH and elec
-
trolyte abnormalities. Symptomatic cerebral edema occurs 
primarily in the pediatric population. Risk factors for its 
development include severe baseline acidosis, rapid correc
-
tion of hyperglycemia, and excess volume administration 
in the first 4 hours. Onset of headache or deterioration in 
mental status during treatment should lead to consider
-
ation of this complication. Intravenous mannitol at a dos
-
age of 1–2 g/kg given over 15 minutes is the mainstay of 
treatment. Excess crystalloid infusion can precipitate pul
-
monary edema. Acute respiratory distress syndrome is a 
rare complication of treatment of DKA.
After recovery and stabilization, patients should be 
instructed on how to recognize the early symptoms and 
signs of ketoacidosis. Urine ketones or capillary blood

signs of ketoacidosis. Urine ketones or capillary blood 
beta-hydroxybutyrate should be measured in patients 
with signs of infection or in insulin pump-treated patients 
when capillary blood glucose remains unexpectedly and 
persistently high. When heavy ketonuria and glycosuria 
persist on several successive examinations, supplemental 
rapid acting insulin should be administered and liquid 
foods such as lightly salted tomato juice and broth should 
be ingested to replenish fluids and electrolytes. The 
patient should be instructed to contact the clinician if 
ketonuria persists, and especially if there is vomiting and 
inability to keep down fluids. Recurrent episodes of 
severe ketoacidosis often indicate poor compliance with 
the insulin regimen, and these patients will require inten
-
sive counseling.
Savage MW et al. Joint British Diabetes Societies guideline for 
the management of diabetic ketoacidosis. Diabet Med. 2011 
May;28(5):508–15. [PMID: 21255074]
HYPERGLYCEMIC HYPEROSMOLAR STATE
 
»
Hyperglycemia greater than 600 mg/dL (33.3 
mmol/L).
 
»
Serum osmolality greater than 310 mOsm/kg.
 
»
No acidosis; blood pH > 7.3.
 
»
Serum bicarbonate greater than 15 mEq/L.
 
»
Normal anion gap (less than 14 mEq/L).
 
»
This second most common form of hyperglycemic coma is 
characterized by severe hyperglycemia in the absence of 
significant ketosis, with hyperosmolality and dehydration. 
It occurs in patients with mild or occult diabetes, and most 
patients are typically middle-aged to elderly. Accurate fig
-
ures are not available as to its true incidence, but from data 
on hospital discharges it is rarer than DKA even in older 
age groups. Underlying chronic kidney disease or heart 
failure is common, and the presence of either worsens the 
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prognosis. A precipitating event such as infection, myocar
-
dial infarction, stroke, or recent operation is often present. 
Certain medications such as phenytoin, diazoxide, cortico
-
steroids, and diuretics have been implicated in its patho
-
genesis, as have procedures associated with glucose loading 
such as peritoneal dialysis.
 
»
A partial or relative insulin deficiency may initiate the 
syndrome by reducing glucose utilization of muscle, fat, 
and liver while inducing hyperglucagonemia and increas
-
ing hepatic glucose output. With massive glycosuria, oblig
-
atory water loss ensues. If a patient is unable to maintain 
adequate fluid intake because of an associated acute or 
chronic illness or has suffered excessive fluid loss, marked 
dehydration results. As the plasma volume contracts, kid
-
ney function becomes impaired, limiting the urinary glu
-
cose losses and exacerbating the hyperglycemia. Severe 
hyperosmolality develops that causes mental confusion 
and finally coma. It is not clear why ketosis is virtually 
absent under these conditions of insulin insufficiency, 
although reduced levels of growth hormone may be a fac
-
tor, along with portal vein insulin concentrations sufficient 
to restrain ketogenesis.
 
»
Onset may be insidious over a period of days or weeks, 
with weakness, polyuria, and polydipsia. The lack of fea
-
tures of ketoacidosis may retard recognition of the syn
-
drome and delay therapy until dehydration becomes 
more profound than in ketoacidosis. Reduced intake of 
fluid is not an uncommon historical feature, due to either 
inappropriate lack of thirst, nausea, or inaccessibility of 
fluids to elderly, bedridden patients. A history of inges
-
tion of large quantities of glucose-containing fluids, such 
as soft drinks or orange juice, can occasionally be 
obtained. Lethargy and confusion develop as serum 
osmolality exceeds 310 mOsm/kg, and convulsions and 
coma can occur if osmolality exceeds 320–330 mOsm/kg. 
Physical examination confirms the presence of profound 
dehydration in a lethargic or comatose patient without 
Kussmaul respirations.
Severe hyperglycemia is present, with blood glucose values 
ranging from 800 mg/dL to 2400 mg/dL (44.4 mmol/L to 
133.2 mmol/L) (Table 27–12). In mild cases, where dehy
-
dration is less severe, dilutional hyponatremia as well as 
urinary sodium losses may reduce serum sodium to 
120–125 mEq/L, which protects to some extent against 
extreme hyperosmolality. However, as dehydration pro
-
gresses, serum sodium can exceed 140 mEq/L, producing 
serum osmolality readings of 330–440 mOsm/kg. Ketosis 
and acidosis are usually absent or mild. Prerenal azotemia 
is the rule, with serum urea nitrogen elevations over 
100 mg/dL (35.7 mmol/L) being typical.
 
»
Treatment
Fluid replacement is of paramount importance in treating 
nonketotic hyperglycemic coma. The onset of hyperosmo
-
larity is more insidious in elderly people without ketosis 
than in younger individuals with high serum ketone levels, 
which provide earlier indicators of severe illness (vomiting, 
rapid deep breathing, acetone odor, etc). Consequently, 
diagnosis and treatment are often delayed until fluid deficit 
has reached levels of 6–10 L.
If hypovolemia is present as evidenced by hypotension 
and oliguria, fluid therapy should be initiated with 0.9% 
saline. In all other cases, 0.45% saline appears to be prefera
-
ble as the initial replacement solution because the body flu
-
ids of these patients are markedly hyperosmolar. As much as 
4–6 L of fluid may be required in the first 8–10 hours. Care
-
ful monitoring of the patient is required for proper sodium 
and water replacement. An important end point of fluid 
therapy is to restore urinary output to 50 mL/h or more. 
Once blood glucose reaches 250 mg/dL (13.9 mmol/L), fluid

Once blood glucose reaches 250 mg/dL (13.9 mmol/L), fluid 
replacement should include 5% dextrose in either water, 
0.45% saline solution, or 0.9% saline solution. The rate of 
dextrose infusion should be adjusted to maintain glycemic 
levels of 250–300 mg/dL (13.9–16.7 mmol/L) in order to 
reduce the risk of cerebral edema.
B. Insulin
Less insulin may be required to reduce the hyperglycemia in 
nonketotic patients as compared to those with diabetic keto
-
acidotic coma. In fact, fluid replacement alone can reduce 
hyperglycemia considerably by correcting the hypovolemia, 
which then increases both glomerular filtration and renal 
excretion of glucose. Insulin treatment should therefore be 
delayed unless the patient has significant ketonemia (beta-
hydroxybutyrate more than 1 mmol/L). Start the insulin 
infusion rate at 0.05 unit/kg/h (bolus is not needed) and 
titrate to lower blood glucose levels by 50–70 mg/dL per 
hour (2.8–3.9 mmol/L/h). Once the patient has stabilized 
and the blood glucose falls to around 250 mg/dL 
(13.9 mmol/L), insulin can be given subcutaneously.
With the absence of acidosis, there may be no initial hyper
-
kalemia unless associated end-stage chronic kidney disease is 
present. This results in less severe total potassium depletion 
than in DKA, and less potassium replacement is therefore 
needed. However, because initial serum potassium is usually 
not elevated and because it declines rapidly as a result of 
insulin’s effect on driving potassium intracellularly, it is rec
-
ommended that potassium replacement be initiated earlier 
than in ketotic patients, assuming that no chronic kidney 
disease or oliguria is present. Potassium chloride (10 mEq/L) 
can be added to the initial bottle of fluids administered if the 
patient’s serum potassium is not elevated.
D. Phosphate
If severe hypophosphatemia (serum phosphate less than 
1 mg/dL [0.32 mmol/L]) develops during insulin therapy, 
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phosphate replacement can be given as described for keto
-
acidotic patients (at 3 mmol/h).
 
»
Prognosis
The severe dehydration and low output state may predis
-
pose the patient to complications such as myocardial 
infarction, stroke, pulmonary embolism, mesenteric vein 
thrombosis, and disseminated intravascular coagulation. 
Fluid replacement remains the primary approach to the 
prevention of these complications. Low-dose heparin pro
-
phylaxis is reasonable but benefits of routine anticoagula
-
tion remain doubtful. Rhabdomyolysis is a recognized 
complication and should be looked for and treated.
The overall mortality rate of hyperglycemic hyperos
-
molar state coma is more than ten times that of DKA, 
chiefly because of its higher incidence in older patients, 
who may have compromised cardiovascular systems or 
associated major illnesses and whose dehydration is often 
excessive because of delays in recognition and treatment. 
(When patients are matched for age, the prognoses of 
these two hyperglycemic emergencies are reasonably 
comparable.) When prompt therapy is instituted, the mor
-
tality rate can be reduced from nearly 50% to that related to 
the severity of coexistent disorders.
After the patient is stabilized, the appropriate form of 
long-term management of the diabetes must be deter
-
mined. Insulin treatment should be continued for a few 
weeks but patients usually recover sufficient endogenous 
insulin secretion to make a trial of diet or diet plus oral 
agents worthwhile. When the episode occurs in a patient 
who has known diabetes, then education of the patient and 
caregivers should be instituted. They should be taught how 
to recognize situations (nausea and vomiting, infection) 
that predispose to recurrence of the hyperglycemic, hyper
-
osmolar state, as well as detailed information on how to 
prevent the escalating dehydration that culminates in 
hyperosmolar coma (small sips of sugar-free liquids, 
increase in usual hypoglycemic therapy, or early contact 
with the clinician).
ketoacidosis and hyperglycemic hyperosmolar state. Med 
Clin North Am. 2017 May;101(3):587–606. [PMID: 
28372715]
Scott AR; Joint British Diabetes Societies (JBDS) for Inpatient 
Care; JBDS hyperosmolar hyperglycaemic guidelines group. 
Management of hyperosmolar hyperglycaemic state in adults 
with diabetes. Diabet Med. 2015 Jun;32(6):714–24. [PMID: 
25980647]
LACTIC ACIDOSIS
 
»
Severe metabolic acidosis with compensatory 
hyperventilation.
 
»
Blood pH < 7.30.
 
»
Serum bicarbonate less than 15 mEq/L.
 
»
Anion gap greater than 15 mEq/L.
 
»
Absent serum ketones.
 
»
Serum lactate greater than 5 mmol/L.
 
»
Lactic acidosis is characterized by accumulation of excess 
lactic acid in the blood. Normally, the principal sources of 
this acid are the erythrocytes (which lack enzymes for 
aerobic oxidation), skeletal muscle, skin, and brain. Con
-
version of lactic acid to glucose and its oxidation princi
-
pally by the liver but also by the kidneys represent the chief 
pathways for its removal. Hyperlactatemia occurs when 
lactate production exceeds lactate consumption. Causes 
include tissue hypoxia (global or local), disorders that 
increase epinephrine levels (severe asthma with excess 
beta-adrenergic agonist use, cardiogenic or hemorrhagic 
shock, pheochromocytoma), and drugs that impair oxida
-
tive phosphorylation (antiretroviral agents and propofol). 
Most cases of metformin-associated lactic acidosis occur in 
patients in whom there were contraindications to the use of 
metformin, in particular kidney failure. Metformin levels 
are usually greater than 5 mcg/L when metformin is impli
-
cated as the cause of lactic acidosis. Other causes of lactic 
acidosis include several inborn errors of metabolism and 
the MELAS syndrome (mitochondrial encephalopathy,

-
the MELAS syndrome (mitochondrial encephalopathy, 
lactic acidosis and stroke-like episodes). D-lactic acidosis 
can occur in patients with short bowel syndrome when 
unabsorbed carbohydates are presented as substrate for 
fermentation by colonic bacteria.
 
»
The main clinical feature of lactic acidosis is marked 
hyperventilation. When lactic acidosis is secondary to tis
-
sue hypoxia or vascular collapse, the clinical presentation is 
variable, being that of the prevailing catastrophic illness. 
However, in the idiopathic, or spontaneous, variety, the 
onset is rapid (usually over a few hours), blood pressure is 
normal, peripheral circulation is good, and there is no 
cyanosis.
Plasma bicarbonate and blood pH are quite low, indicating 
the presence of severe metabolic acidosis. Ketones are usu
-
ally absent from plasma and urine or at least not promi
-
nent. The first clue may be a high anion gap (serum 
sodium minus the sum of chloride and bicarbonate anions 
[in mEq/L] should be no greater than 15). A higher value 
indicates the existence of an abnormal compartment of 
anions. If this cannot be clinically explained by an excess of 
keto acids (diabetes), inorganic acids (uremia), or anions 
from medication overdosage (salicylates, methyl alcohol, 
ethylene glycol), then lactic acidosis is probably the correct 
diagnosis. (See also Chapter 21.) In the absence of azote
-
mia, hyperphosphatemia may be a clue to the presence of 
lactic acidosis for reasons that are not clear. The diagnosis 
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is confirmed by a plasma lactic acid concentration of 
5 mmol/L or higher (values as high as 30 mmol/L have 
been reported). Normal plasma values average 1 mmol/L, 
with a normal lactate/pyruvate ratio of 10:1. This ratio is 
greatly exceeded in lactic acidosis.
1
 
»
Treatment
Aggressive treatment of the precipitating cause of lactic 
acidosis is the main component of therapy, such as ensur
-
ing adequate oxygenation and vascular perfusion of tissues. 
Empiric antibiotic coverage for sepsis should be given after 
culture samples are obtained in any patient in whom the 
cause of the lactic acidosis is not apparent.
Alkalinization with intravenous sodium bicarbonate to 
keep the pH above 7.2 has been recommended by some in 
the emergency treatment of lactic acidosis; as much as 
2000 mEq in 24 hours has been used. However, there is no 
evidence that the mortality rate is favorably affected by 
administering bicarbonate, and its use remains controver
-
sial. Hemodialysis may be useful in cases where large 
sodium loads are poorly tolerated and in cases associated 
with metformin toxicity.
 
»
Prognosis
The mortality rate of spontaneous lactic acidosis is high. 
The prognosis in most cases is that of the primary disorder 
that produced the lactic acidosis.
DeFronzo R et al. Metformin-associated lactic acidosis: current 
perspectives on causes and risk. Metabolism. 2016 Feb;
 
65(2):20–9. [PMID: 26773926]
 
º
THE HYPOGLYCEMIC STATES
Spontaneous hypoglycemia in adults is of two principal 
types: fasting and postprandial. Symptoms begin at plasma 
glucose levels in the range of 60 mg/dL (3.3 mmol/L) and 
impairment of brain function at approximately 50 mg/dL 
(2.8 mmol/L). Fasting hypoglycemia is often subacute or 
chronic and usually presents with neuroglycopenia as its 
principal manifestation; postprandial hypoglycemia is rela
-
tively acute and is often heralded by symptoms of neuro
-
genic autonomic discharge (sweating, palpitations, anxiety, 
tremulousness).
 
»
Differential Diagnosis (Table 27–13)
Fasting hypoglycemia
 may occur in certain endocrine 
disorders, such as hypopituitarism, Addison disease, or 
myxedema; in disorders related to liver malfunction, such 
as acute alcoholism or liver failure; and in instances of end-
stage chronic kidney disease, particularly in patients 
requiring dialysis. These conditions are usually obvious, 
with hypoglycemia being only a secondary feature. When 
fasting hypoglycemia is a primary manifestation develop
-
ing in adults without apparent endocrine disorders or 
inborn metabolic diseases from childhood, the principal 
diagnostic possibilities include (1) hyperinsulinism, due to 
either pancreatic B cell tumors, iatrogenic or surreptitious 
administration of insulin or sulfonylurea; and (2) hypogly
-
cemia due to extrapancreatic tumors.
Postprandial (reactive) hypoglycemia
 may be seen 
after gastrointestinal surgery and is particularly associated 
with the dumping syndrome after gastrectomy and Roux-
en-Y gastric bypass surgery. Occult diabetes very occasion
-
ally present with postprandial hypoglycemia. Rarely, it 
occurs with islet cell hyperplasia—the so-called noninsuli
-
noma pancreatogenous hypoglycemia syndrome.
Alcohol-related hypoglycemia
 is due to hepatic glyco
-
gen depletion combined with alcohol-mediated inhibition 
of gluconeogenesis. It is most common in malnourished 
individuals with excessive alcohol intake but can occur in 
anyone who is unable to ingest food after an acute alcoholic 
episode followed by gastritis and vomiting.
Immunopathologic hypoglycemia
 is an extremely rare 
condition in which anti-insulin antibodies or antibodies to 
insulin receptors develop spontaneously.
HYPOGLYCEMIA DUE TO PANCREATIC 
 
B CELL TUMORS
 
»
Hypoglycemic symptoms—frequently neurogly
-
copenic (confusion, blurred vision, diplopia, anxiety, 
convulsions).
 
»
Immediate recovery upon administration of

»
-
 
»
Immediate recovery upon administration of 
glucose.
 
»
Blood glucose less than 45 mg/dL (2.5 mmol/L) with 
a serum insulin level of 6 microunit/mL or more.
Table 27–13.
 
Common causes of hypoglycemia in 
adults.
1
 
P
ancreatic B cell tumor
 
Surr
eptitious administration of insulin or sulfonylureas
 
Ex
trapancreatic tumors
Postprandial hypoglycemia
 
Alimentary
 
Noninsulinoma 
pancreatogenous hypoglycemia syndrome
 
Functional
 
O
ccult diabetes mellitus
 
Idiopa
thic anti-insulin antibodies (which release their 
 
bound insulin)
 
An
tibodies to insulin receptors (which act as agonists)
Drug-induced hypoglycemia
1
In the absence of clinically obvious endocrine, kidney, or liver 
disorders and exclusive of diabetes mellitus treated with hypogly
-
cemic agents.
1
In collecting samples, it is essential to rapidly chill and separate the 
blood in order to remove red cells, whose continued glycolysis at 
room temperature is a common source of error in reports of high 
plasma lactate. Frozen plasma remains stable for subsequent assay.
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»
Fasting hypoglycemia in an otherwise healthy, well-
nourished adult is rare and is most commonly due to an 
adenoma of the islets of Langerhans. Ninety percent of 
such tumors are single and benign, but multiple adenomas 
can occur as well as malignant tumors with functional 
metastases. Adenomas may be familial, and multiple 
adenomas have been found in conjunction with tumors of 
the parathyroids and pituitary (MEN type 1 [MEN 1]). It 
has been reported that about 30% of sporadic insulinoma 
tumors have a somatic mutation in the YY1 gene (T372R) 
that encodes the transcriptional repressor YY1. Over 99% 
of insulinomas are located within the pancreas and less 
than 1% in ectopic pancreatic tissue.
 
»
The most important prerequisite to diagnosing an insulin
-
oma is simply to consider it, particularly in relatively 
healthy-appearing persons who have fasting hypoglycemia 
associated with some degree of central nervous system dys
-
function such as confusion or abnormal behavior. A delay 
in diagnosis can result in unnecessary treatment for psycho
-
motor epilepsy or psychiatric disorders and may cause 
irreversible brain damage. In long-standing cases, obesity 
can result as a consequence of overeating to relieve 
symptoms.
The so-called Whipple triad is characteristic of hypo
-
glycemia regardless of the cause. It consists of (1) a history 
of hypoglycemic symptoms, (2) an associated low plasma 
glucose level (40–50 mg/dL), and (3) relief of symptoms 
upon ingesting fast-acting carbohydrates in approximately 
15 minutes. The hypoglycemic symptoms in insulinoma 
often develop in the early morning or after missing a meal. 
Occasionally, they occur after exercise.
Patients typically complain of neuroglycopenic symp
-
toms such as blurred vision or diplopia, headache, feelings 
of detachment, slurred speech, and weakness. Personality 
and mental changes vary from anxiety to psychotic behav
-
ior, and neurologic deterioration can result in convulsions 
or coma. Hypoglycemic unawareness is very common and 
adrenergic symptoms of palpitations and sweating may be 
blunted. With the ready availability of home blood glucose–
monitoring systems, patients sometimes present with doc
-
umented fingerstick blood glucose levels in 40s and 50s at 
time of symptoms. Access to diabetic medications (sulfo
-
nylureas or insulin) should be explored—does a family 
member have diabetes, or does the patient or family 
member work in the medical field? Medication-dispensing 
errors should be excluded—has the patient’s prescription 
medication changed in shape or color? Patients with insu
-
linoma or factitious hypoglycemia usually have a normal 
B cell adenomas do not reduce secretion of insulin in the 
presence of hypoglycemia, and the critical diagnostic test is 
to demonstrate inappropriately elevated serum insulin, 
proinsulin, and C-peptide levels at a time when plasma 
glucose level is below 45 mg/dL.
The diagnostic criteria for insulinoma after a 72-hour 
fast are listed in Table 27–14. Other causes of hyperinsulin
-
emic hypoglycemia must be considered, including facti
-
tious administration of insulin or sulfonylureas. Factitious 
use of insulin will result in suppression of endogenous 
insulin secretion and low C-peptide levels. In patients who 
have injected insulin, the insulin/C-peptide ratio (pmol/L) 
will be greater than 1. An elevated circulating proinsulin 
level in the presence of fasting hypoglycemia is characteris
-
tic of most B cell adenomas and does not occur in factitious 
hyperinsulinism. Thus, C-peptide levels (by immunoche
-
miluminometric assays [ICMA]) of greater than 200 pmol/L 
and proinsulin levels (by radioimmunoassay [RIA]) of 
greater than 5 pmol/L are characteristic of insulinomas. In 
patients with insulinoma, plasma beta-hydroxybutyrate

patients with insulinoma, plasma beta-hydroxybutyrate 
levels are suppressed to 2.7 mmol/L or less. No single hor
-
mone measurement (insulin, proinsulin, C-peptide) is 
100% sensitive and specific for the diagnosis of insulinoma, 
and insulinoma cases have been reported with insulin levels 
below 3 microunit/mL (ICMA assay) or proinsulin level 
below 5 pmol/L. These hormonal assays are also not stan
-
dardized between laboratories, and there can be significant 
variation in the results. Therefore, the diagnosis should be 
based on multiple biochemical parameters.
In patients with epigastric distress, a history of renal 
calculi, or menstrual or erectile dysfunction, a serum cal
-
cium, gastrin, or prolactin level may be useful in screening 
for MEN 1 associated with insulinoma.
C. Diagnostic Tests
If the history is consistent with episodic spontaneous hypo
-
glycemia, patients should be given a home blood glucose 
monitor and advised to monitor blood glucose levels at the 
time of symptoms and before consumption of carbohy
-
drates, if this can be done safely. Patients with insulinomas 
frequently report fingerstick blood glucose levels between 
40 mg/dL (2.2 mmol/L) and 50 mg/dL (2.8 mmol/L) at the 
Table 27–14.
 
Diagnostic criteria for insulinoma after a 
72-hour fast.
Laboratory Test
r
esult
Plasma glucose
< 45 mg/dL (2.5 mmol/L)
Plasma insulin (RIA)
1
≥ 6 microunit/mL (36 pmol/L)
Plasma insulin (ICMA)
1
≥ 3 microunit/mL (18 pmol/L)
Plasma C-peptide
≥ 200 pmol/L (0.2 nmol/L, 
0.6 ng/mL)
Plasma proinsulin
≥ 5 pmol/L
Beta-hydroxybutyrate
≤ 2.7 mmol/L
Sulfonylurea screen (including 
repaglinide and nateglinide)
Negative
1
Conversion factors: insulin microunit/mL × 6.0 = pmol/L; 
C-peptide ng/mL × 0.333 = nmol/L
RIA, radioimmunoassay; ICMA, immunochemiluminometric assays.
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time of symptoms. The diagnosis, however, cannot be 
made based on a fingerstick blood glucose. It is necessary 
to have a low laboratory glucose concomitantly with ele
-
vated plasma insulin, proinsulin, and C-peptide levels and 
a negative sulfonylurea screen. When patients give a his
-
tory of symptoms after only a short period of food with
-
drawal or with exercise, then an outpatient assessment can 
be attempted. The patient should be brought by a family 
member to the office after an overnight fast and observed 
in the office. Activity such as walking should be encour
-
aged and fingerstick blood glucose measured repeatedly 
during observation. If symptoms occur or fingerstick blood 
glucose is below 50 mg/dL (2.8 mmol/L) then samples for 
plasma glucose, insulin, C-peptide, proinsulin, sulfonyl
-
urea screen, serum ketones, and antibodies to insulin 
should be sent. If outpatient observation does not result in 
symptoms or hypoglycemia and if the clinical suspicion 
remains high, then the patient should undergo an inpatient 
supervised 72-hour fast. A suggested protocol for the 
supervised fast is shown in Table 27–15.
In 30% of patients with insulinoma, the blood glucose 
levels often drop below 45 mg/dL (2.5 mmol/L) after an 
overnight fast, but some patients require up to 72 hours to 
develop symptomatic hypoglycemia. However, the term 
“72-hour fast” is actually a misnomer in most cases since 
the fast should be immediately terminated as soon as 
symptoms appear and laboratory confirmation of hypogly
-
cemia is available. In normal male subjects, the blood glu
-
cose does not fall below 55–60 mg/dL (3.1–3.3 mmol/L) 
during a 3-day fast. In contrast, in normal premenopausal 
women who have fasted for only 24 hours, the plasma glu
-
cose may fall normally to such an extent that it can reach 
values as low as 35 mg/dL (1.9 mmol/L). In these cases, 
however, the women are not symptomatic, presumably 
owing to the development of sufficient ketonemia to supply 
energy needs to the brain. Insulinoma patients, on the 
other hand, become symptomatic when plasma glucose 
drops to subnormal levels, since inappropriate insulin 
secretion restricts ketone formation. Moreover, the demon
-
stration of a nonsuppressed insulin level of 3 microunit/mL 
or more using a ICMA assay (greater than 6 microunit/mL 
using an RIA assay) in the presence of hypoglycemia sug
-
gests the diagnosis of insulinoma. If hypoglycemia does not 
develop in a male patient after fasting for up to 72 hours—
and particularly when this prolonged fast is terminated 
with a period of moderate exercise—insulinoma must be 
considered an unlikely diagnosis.
Stimulation with pancreatic B cell secretagogues such as 
tolbutamide, glucagon, or leucine has been devised to dem
-
onstrate exaggerated and prolonged insulin secretion in the 
presence of insulinomas. However, because insulin-secreting 
tumors have a wide range of granule content and degrees of 
differentiation, they are variably responsive to these secreta
-
gogues; and a negative response does not necessarily rule out 
an insulinoma. For these reasons, stimulation tests are not 
recommended in the diagnostic workup of insulinoma.
An oral glucose tolerance test is of no value in the diag
-
nosis of insulin secreting tumors. HbA
1c
 levels may be low 
but there is considerable overlap with normal patients and 
no particular value is diagnostic.
D. Preoperative Localization of B Cell Tumors
After the diagnosis of insulinoma has been unequivocally 
made by clinical and laboratory findings, studies to localize 
the tumor should be initiated. The focus of attention 
should be directed to the pancreas since that is where virtu
-
ally all insulinomas originate. Ectopic cases are very rare.
Because of the small size of these tumors (averaging 
1.5 cm in diameter in one large series), imaging studies do 
not necessarily identify all of them. A pancreatic dual phase

not necessarily identify all of them. A pancreatic dual phase 
helical CT scan with thin section can identify 82–94% of the 
lesions. MRI scans with gadolinium can be helpful in detect
-
ing a tumor in 85% of cases. One case report suggests that 
diffusion-weighted MRI can be useful for detecting and 
localizing small insulinomas, especially for those with no 
hypervascular pattern. 
111
In-octreotide scans for insulino
-
mas, which typically express somatostatin receptor type 3, is 
positive in only 50–70% of cases. Newer PET/CT scans, 
using gallium-labeled somtatostatin analogs such as DOTA-
1-NaI3-octreotide (DOTA-NOC), which have a higher 
affinity for somatostatin receptor subtypes 2, 3 and 5, have 
been reported to be useful in localizing the tumors. Insulino
-
mas express GLP1-receptors and radiolabeled GLP1-receptor 
agonists such as Lys(40)(Ahx-hydrazinonicotinamide 
[HYNIC]-[(99m)Tc)NH(2)]-exendin-4 for SPECT/CT have 
also been reported to visualize the tumors. The imaging 
study used will depend on local availability and local radio
-
logic skill. If the imaging study is normal, then an endo
-
scopic ultrasound should be performed. In experienced 
Table 27–15.
 
Suggested hospital protocol for super
-
vised fast in diagnosis of insulinoma.
(1)
  
P
lace intravenous cannula and obtain baseline plasma 
glucose, insulin, proinsulin, beta-hydroxybutyrate and 
C-peptide measurements at onset of fast.
(2)
  
P
ermit only calorie-free and caffeine-free fluids and encourage 
supervised activity (such as walking).
(3)
  
Obtain capillar
y glucose measurements with a reflectance 
meter every 4 hours until values < 60 mg/dL are obtained. 
Then increase the frequency of fingersticks to each hour, and 
when capillary glucose value is < 45 mg/dL send a venous 
blood sample to the laboratory for plasma glucose.
1
 Check 
frequently for manifestations of neuroglycopenia.
(4)
  
A
t 48 hours into the fast, send venous blood sample for 
plasma glucose, insulin, proinsulin, C-peptide, beta-hydroxy
-
butyrate, and sulfonylurea measurement.
(5)
  
I
f symptoms of hypoglycemia occur 
or
 if a laboratory value of 
serum glucose is < 45 mg/dL, or if 72 hours have elapsed then 
conclude the fast with a final blood sample for plasma glucose,
1
 
insulin, proinsulin, C-peptide, beta-hydroxybutyrate and sulfo
-
nylurea measurements. Then give oral fast-acting carbohydrate 
followed by a meal. If the patient is confused or unable to take 
oral agents, then administer 50 mL of 50% dextrose intrave
-
nously over 3 to 5 minutes. Do not conclude a fast based simply 
on a capillary blood glucose measurement—wait for the 
laboratory glucose value—unless the patient is very 
symptomatic and it would be dangerous to wait.
1
Glucose sample should be collected in sodium fluoride contain
-
ing tube on ice to prevent glycolysis and the plasma separated 
immediately upon receipt at the laboratory. Arrange for the labora
-
tory to run the glucose samples “stat.”
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hands, about 80–90% of tumors can be detected with this 
procedure. Fine-needle aspiration of the identified lesion 
can be attempted to confirm the presence of a neuroendo
-
crine tumor. If the tumor is not identified or the imaging 
result is equivocal, then the patient should undergo selective 
calcium-stimulated angiography, which has been reported to 
localize the tumor to a particular region of the pancreas 
approximately 90% of the time. In this test, angiography is 
combined with injections of calcium gluconate into the gas
-
troduodenal, splenic, and superior mesenteric arteries, and 
insulin levels are measured in the hepatic vein effluent. The 
procedure is performed after an overnight fast. Calcium 
gluconate 10% solution diluted to a volume of 5 mL with 
0.95% saline is bolused into the selected artery at a dose of 
0.0125 mmol calcium/kg (0.005 mmol calcium/kg for obese 
patients). Small samples of blood (5 mL) are taken from the 
hepatic effluent at times 0, 30, 60, 90, 120, and 180 seconds 
after the calcium injection. Fingerstick blood glucose levels 
are measured at intervals and a dextrose infusion is main
-
tained throughout the procedure to prevent hypoglycemia. 
Calcium stimulates insulin release from insulinomas but not 
normal islets, and so a step-up from baseline in insulin levels 
at 30 or 60 seconds (twofold or greater) regionalizes the 
source of the hyperinsulinism to the head of the pancreas for 
the gastroduodenal artery, the uncinate process for the supe
-
rior mesenteric artery, and the body and tail of the pancreas 
for the splenic artery calcium infusions. A less than twofold 
elevation of insulin in the 120-second sample may represent 
effects of recirculating calcium and is not considered a posi
-
tive localization. In a single insulinoma, the response is in 
one artery alone unless the tumor resides in an area fed by 
two arteries or if there are multiple insulinomas (eg, in 
MEN 1). Patients who have diffuse islet hyperplasia (the 
noninsulinoma pancreatogenous hypoglycemia syndrome) 
will have positive responses in multiple arteries. Because 
diazoxide may interfere with this test, it should be discon
-
tinued for at least 48–72 hours before sampling. Patients 
should be closely monitored during the procedure to avoid 
hypoglycemia (as well as hyperglycemia, which could affect 
insulin gradients). These studies combined with careful 
intraoperative ultrasonography and palpation by a surgeon 
experienced in insulinoma surgery identifies up to 98% of 
tumors.
 
»
Treatment
The treatment of choice for insulin-secreting tumors is 
surgical resection. While waiting for surgery, patients 
should be given oral diazoxide. Divided doses of 
300–400 mg/day usually suffice although an occasional 
patient may require up to 800 mg/day. Side effects include 
edema due to sodium retention, gastric irritation, and mild 
hirsutism. Hydrochlorothiazide, 25–50 mg daily, can be 
used to counteract the sodium retention and edema as well 
potentiate diazoxide’s hyperglycemic effect.
In patients with a single benign pancreatic B cell ade
-
noma, 90–95% have a successful cure at the first surgical 
attempt when intraoperative ultrasound is used by a skilled 
surgeon. Diazoxide should be administered on the day of 
the surgery because it reduces the risk of hypoglycemia 
during surgery. Typically, it does not mask the glycemic 
rise indicative of surgical cure. Blood glucose should be 
monitored throughout surgery, and 5% or 10% dextrose 
infusion should be used to maintain euglycemia. In cases 
where the diagnosis has been established but no adenoma 
is located after careful palpation and use of intraoperative 
ultrasound, it is no longer advisable to blindly resect the 
body and tail of the pancreas, since a nonpalpable tumor 
missed by ultrasound is most likely embedded within the 
fleshy head of the pancreas that is left behind with subtotal

fleshy head of the pancreas that is left behind with subtotal 
resections. Most surgeons prefer to close the incision and 
schedule a selective arterial calcium stimulation with 
hepatic venous sampling to locate the tumor site prior to a 
repeat operation. Laparoscopy using ultrasound and enu
-
cleation has been successful with a single tumor of the 
body or tail of the pancreas, but open surgery remains 
necessary for tumors in the head of the pancreas.
In patients with inoperable functioning islet cell carci
-
noma with and without hepatic metastasis and in approxi
-
mately 5–10% of MEN 1 cases when subtotal removal of 
the pancreas has failed to produce cure, the treatment 
approach is the same as for other types of pancreatic neu
-
roendocrine tumors (pNETs). Diazoxide is the treatment 
of choice in preventing hypoglycemia. Frequent carbohy
-
drate feedings (every 2–3 hours) can also be helpful, 
although weight gain can become a problem. Somatostatin 
analogs, octreotide or lanreotide, should be considered if 
diazoxide is ineffective or if there is tumor progression. 
Surgery or embolization (bland, chemo- and radio-) or 
thermal ablation (radiofrequency, microwave, and cryoab
-
lation) can be used to reduce tumor burden and also pro
-
vide symptomatic relief. Chemotherapy regimens that can 
be considered include combination of streptozocin, 5–
fluorouracil, and doxorubicin; capecitabine and oxalipla
-
tin; and capecitabine and temozolomide. Targeted therapies 
against multiple steps in PI3K/AKT/mTor pathway have 
been shown to be helpful. Everolimus, an inhibitor of mTor, 
has been approved for treatment of advanced pNETs. Suni
-
tinib, a monoclonal antibody against VEGF receptors 2 and 
3, PDGFR alpha and beta and c-kit, has been shown to 
slow growth of pNETs. Treatment with radioisotopes 
(indium -111 or yttrium-90 or lutetium-177) linked to a 
somatostatin analog have been reported to show benefit in 
a proportion of patients.
Cryer PE et al. Evaluation and management of adult hypoglyce
-
mic disorders: an Endocrine Society Clinical Practice Guide
-
line. J Clin Endocrinol Metab. 2009 Mar;94(3):709–28. 
[PMID: 19088155]
Mathur A et al. Insulinoma. Surg Clin North Am. 2009 Oct;
 
89(5):1105–21. [PMID: 19836487]
NONISLET CELL TUMOR HYPOGLYCEMIA
These rare causes of hypoglycemia include mesenchymal 
tumors such as retroperitoneal sarcomas, hepatocellular 
carcinomas, adrenocortical carcinomas, and miscellaneous 
epithelial-type tumors. The tumors are frequently large and 
readily palpated or visualized on CT scans or MRI.
In many cases the hypoglycemia is due to the expres
-
sion and release of an incompletely processed insulin-like 
growth factor 2 (IGF-2) by the tumor.
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The diagnosis is supported by laboratory documenta
-
tion of serum insulin levels below 5 microunit/mL with 
plasma glucose levels of 45 mg/dL (2.5 mmol/L) or lower. 
Values for growth hormone and IGF-1 are also decreased. 
Levels of IGF-2 may be increased but often are “normal” in 
quantity, despite the presence of the immature, higher-
molecular-weight form of IGF-2, which can be detected 
only by special laboratory techniques.
Not all the patients with nonislet cell tumor hypoglyce
-
mia have elevated pro-IGF-II. Ectopic insulin production 
has been described in bronchial carcinoma, ovarian carci
-
noma, and small cell carcinoma of the cervix. Hypoglycemia 
due to IgF-1 released from a metastatic large cell carcinoma 
of the lung has also been reported. GLP-1 secreting tumors 
(ovarian and pNETs) can also cause hypoglycemia by stimu
-
lating insulin release from normal pancreatic islets.
The prognosis for these tumors is generally poor, and 
surgical removal should be attempted when feasible. Dietary 
management of the hypoglycemia is the mainstay of medi
-
cal treatment, since diazoxide is usually ineffective.
Bodnar TW et al. Management of non-islet-cell tumor hypogly
-
cemia: a clinical review. J Clin Endocrinol Metab. 2014 Mar;
 
99(3):713–22. [PMID: 24423303]
POSTPRANDIAL HYPOGLYCEMIA
1. Hypoglycemia Following Gastric Surgery
Hypoglycemia sometimes develops in patients who have 
undergone gastric surgery (eg, gastrectomy, vagotomy, 
pyloroplasty, gastrojejunostomy, Nissan fundoplication, 
Bilroth II procedure, and Roux-en-Y), especially when they 
consume foods containing high levels of readily absorbable 
carbohydrates. This late dumping syndrome occurs about 
1–3 hours after a meal and is a result of rapid delivery of 
high concentration of carbohydrates in the proximal small 
bowel and rapid absorption of glucose. The hyperinsulin
-
emic response to the high carbohydrate load causes hypo
-
glycemia. Excessive release of gastrointestinal hormones 
such as GLP-1 likely play a role in the hyperinsulinemic 
response. The symptoms include lightheadedness, sweat
-
ing, confusion and even loss of consciousness after eating 
a high carbohydrate meal. In terms of documenting hypo
-
glycemia, it is reasonable to request the patient to con
-
sume a meal that leads to symptoms during everyday life. 
An oral glucose tolerance test is not recommended 
because many normal persons have false-positive test 
results. There have been case reports of insulinoma and 
noninsulinoma pancreatogenous hypoglycemia syndrome 
in patients with hypoglycemia post Roux-en-Y surgery. It is 
unclear how often this occurs. A careful history may iden
-
tify patients who have a history of hypoglycemia with exer
-
cise or missed meals, and these individuals may require a 
formal 72-hour fast to rule out an insulinoma.
Treatment for secondary dumping includes dietary 
modification, but this may be difficult to sustain. Patients 
can try more frequent meals with smaller portions of less 
rapidly digested carbohydrates. Alpha-glucosidase therapy 
may be a useful adjunct to a low carbohydrate diet. Octreo
-
tide 50 mcg administered subcutaneously two or three 
times a day 30 minutes prior to each meal has been 
reported to improve symptoms due to late dumping syn
-
drome. Treatment with exendin 9-39, a GLP-1 receptor 
agonist may prevent post gastric bypass hypoglycemia. 
Various surgical procedures to delay gastric emptying have 
been reported to improve symptoms but long-term efficacy 
studies are lacking.
2. Functional Alimentary Hypoglycemia
Patients have symptoms suggestive of increased sympathetic 
activity, including anxiety, weakness, tremor, sweating or 
palpitations after meals. Physical examination and labora
-
tory tests are normal. It is not recommended that patients 
with symptoms suggestive of increased sympathetic activity 
undergo either a prolonged oral glucose tolerance test or a

-
undergo either a prolonged oral glucose tolerance test or a 
mixed meal test. Instead, the patients should be given home 
blood glucose monitors (with memories) and instructed to 
monitor fingerstick glucose levels at the time of symptoms. 
Only patients who have symptoms when their fingerstick 
blood glucose is low (less than 50 mg/dL) and who have 
resolution of symptoms when the glucose is raised by eating 
rapidly released carbohydrate need additional evaluation. 
Patients who do not have evidence for low glucose levels at 
time of symptoms are generally reassured by their findings. 
Counseling and support should be the mainstays in therapy, 
with dietary manipulation only an adjunct.
3. Occult Diabetes
This condition is characterized by a delay in early insulin 
release from pancreatic B cells, resulting in initial exaggera
-
tion of hyperglycemia during a glucose tolerance test. In 
response to this hyperglycemia, an exaggerated insulin 
release produces a late hypoglycemia 4–5 hours after inges
-
tion of glucose. These patients are often obese and fre
-
quently have a family history of diabetes mellitus.
Patients with this type of postprandial hypoglycemia 
often respond to reduced intake of refined sugars with 
multiple, spaced, small feedings high in dietary fiber. In the 
obese, treatment is directed at weight reduction to achieve 
ideal weight. These patients should be considered to have 
prediabetes or early diabetes (type 1 or 2) and advised to 
have periodic medical evaluations.
4. Autoimmune Hypoglycemia
Patients with autoimmune hypoglycemia have early 
postprandial hyperglycemia followed by hypoglycemia 
3–4 hours later. The hypoglycemia is attributed to a disso
-
ciation of insulin-antibody immune complexes, releasing 
free insulin.
The disorder is associated with methimazole treatment 
for Graves disease, although it can also occur in patients 
treated with various other sulfhydryl-containing medica
-
tions (captopril, penicillamine) as well as other drugs such 
as hydralazine, isoniazid, and procainamide. In addition, it 
has been reported in patients with autoimmune disorders 
such as rheumatoid arthritis, systemic lupus erythemato
-
sus, and polymyositis as well as in plasma cell myeloma 
(formerly multiple myeloma) and other plasma cell dyscra
-
sias where paraproteins or antibodies cross-react with 
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insulin. There is also an association with the HLA class II 
alleles (DRB1
*
0406, DQA1
*
0301, and DQB1
*
0302). 
These alleles are 10 to 20 times more common in Japanese 
and Korean populations, which explains why the disorder 
has been reported mostly in Japanese patients.
High titers of insulin autoantibodies, usually IgG class, 
can be detected. Insulin, proinsulin, and C-peptide levels 
may be elevated, but the results may be erroneous because 
of the interference of the insulin antibodies with the immu
-
noassays for these peptides.
In most cases, the hypoglycemia is transient and usually 
resolves spontaneously within 3–6 months of diagnosis, 
particularly when the offending medications are stopped. 
The most consistent therapeutic benefit in management of 
this syndrome has been achieved by dietary treatment with 
small, frequent low-carbohydrate meals. Prednisone 
(30–60 mg orally daily) has been used to lower the titer of 
insulin antibodies.
Lupsa BC et al. Autoimmune forms of hypoglycemia. Medicine 
(Baltimore). 2009 May;88(3):141–53. [PMID: 19440117]
FACTITIOUS HYPOGLYCEMIA
Factitious hypoglycemia may be difficult to document. A 
suspicion of self-induced hypoglycemia is supported when 
the patient is associated with the health professions or has 
access to insulin or sulfonylurea medications taken by a 
diabetic member of the family. The triad of hypoglycemia, 
high immunoreactive insulin, and suppressed plasma C 
peptide immunoreactivity is pathognomonic of exogenous 
insulin administration. Insulin and C peptide is secreted in 
a 1:1 molar ratio. A large fraction of the endogenous insu
-
lin is cleared by the liver whereas C peptide, which is 
cleared by the kidney, has a lower metabolic clearance rate. 
For this reason, the molar ratio of insulin and C peptide in 
a hypoglycemic patient should be less than 1.0 in cases of 
insulinoma and is greater than 1.0 in cases of exogenous 
insulin administration. When sulfonylureas, repaglinide 
and nateglinide are suspected as a cause of factitious hypo
-
glycemia, a plasma level of these medications to detect 
their presence may be required to distinguish laboratory 
findings from those of insulinoma.
HYPOGLYCEMIA DUE TO INSULIN 
 
RECEPTOR ANTIBODIES
Hypoglycemia due to insulin receptor autoantibodies is an 
extremely rare syndrome; most cases have occurred in 
women often with a history of autoimmune disease. Almost 
all of these patients have also had episodes of insulin-resis
-
tant diabetes and acanthosis nigricans. Their hypoglycemia 
may be either fasting or postprandial and is often severe and 
is attributed to an agonistic action of the antibody on the 
insulin receptor. Balance between the antagonistic and ago
-
nistic effects of the antibodies determines whether insulin-
resistant diabetes or hypoglycemia occurs. Hypoglycemia 
was found to respond to corticosteroid therapy but not to 
plasmapheresis or immunosuppression.
Kim CH et al. Autoimmune hypoglycemia in a type 2 diabetic 
patient with anti-insulin and insulin receptor antibodies. 
Diabetes Care. 2004 Jan;27(1):288–9. [PMID: 14694017]
MEDICATION-INDUCED HYPOGLYCEMIA
A number of medications apart from the sulfonylureas can 
occasionally cause hypoglycemia. Common offenders 
include the fluoroquinolones such as gatifloxacin and levo
-
floxacin, pentamidine, quinine, ACE inhibitors, salicylates 
and beta-adrenergic blocking agents. The fluoroquino
-
lones, particularly gatifloxacin, have been associated with 
both hypoglycemia and hyperglycemia. It is thought that 
the drug acts on the ATP sensitive potassium channels in 
the beta cell. Hypoglycemia is an early event, and hypergly
-
cemia occurs several days into therapy. Intravenous pent
-
amidine is cytotoxic to beta cells and causes acute 
hyperinsulinemia and hypoglycemia followed by insulino
-
penia and hyperglycemia. Fasting patients taking noncar
-
dioselective beta-blockers can have an exaggerated

-
-
dioselective beta-blockers can have an exaggerated 
hypoglycemic response to starvation. The beta-blockade 
inhibits fatty acids and gluconeogenesis substrate release 
and reduces plasma glucagon response. Therapy with ACE 
inhibitors increases the risk of hypoglycemia in patients 
who are taking insulin or sulfonylureas presumably because 
these drugs increase sensitivity to circulating insulin by 
increasing blood flow to the muscle. Some opioids cause 
hypoglycemia. Tramadol use has been associated with 
increased risk of hospitalization for hypoglycemia. Metha
-
done overdose has also been reported to cause hypoglyce
-
mia and a rapid dose escalation of methadone in cancer 
patients can lower glucose levels.
Ethanol-associated hypoglycemia may be due to hepatic 
alcohol dehydrogenase activity depleting NAD. The resul
-
tant change in the redox state—increase in NADH to NAD
+
 
ratio—causes a partial block at several points in the 
gluconeogenic pathway. With prolonged starvation, glycogen 
reserves become depleted within 18–24 hours and hepatic 
glucose output becomes totally dependent on gluconeogen
-
esis. Under these circumstances, a blood concentration of 
ethanol as low as 45 mg/dL (9.8 mmol/L) can induce 
profound hypoglycemia by blocking gluconeogenesis. 
Neuroglycopenia in a patient whose breath smells of alcohol 
may be mistaken for alcoholic stupor. Prevention consists of 
adequate food intake during ethanol ingestion. Therapy 
consists of glucose administration to replenish glycogen 
stores until gluconeogenesis resumes.
When sugar-containing soft drinks are used as mixers 
to dilute alcohol in beverages (gin and tonic, rum and 
cola), there seems to be a greater insulin release than when 
the soft drink alone is ingested and a tendency for more of 
a late hypoglycemic overswing to occur 3–4 hours later. 
Prevention would consist of avoiding sugar mixers while 
ingesting alcohol and ensuring supplementary food intake 
to provide sustained absorption.
Vue MH et al. Drug-induced glucose alterations part 1: drug-
induced hypoglycemia. Diabetes Spectrum. 2011 Aug;
 
24(3):171–7.
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For patients with known cardiovascular disease (secondary 
prevention), studies have shown that cholesterol lowering 
leads to a consistent reduction in total mortality and in 
recurrent cardiovascular events in men and women; other 
studies have documented lowered mortality and events in 
middle-aged and older patients. Among patients without 
cardiovascular disease (primary prevention), the data are 
less conclusive, with rates of cardiovascular events, heart 
disease mortality, and all-cause mortality differing among 
studies. Nonetheless, treatment guidelines have been 
designed to assist clinicians in selecting patients for choles
-
terol-lowering therapy based on their overall risk of devel
-
oping cardiovascular disease.
LIPID FRACTIONS & THE RISK OF CORONARY 
In serum, cholesterol is carried primarily on three different 
lipoproteins—the VLDL, LDL, and HDL molecules. Total 
cholesterol equals the sum of these three components:
Total cholesterol = 
 
HDL cholest
erol + VLDL cholesterol 
+ LDL cholesterol
Most clinical laboratories measure the total cholesterol, 
the total triglycerides, and the amount of cholesterol found 
in the HDL fraction, which is easily precipitated from 
serum. Most triglyceride is found in VLDL particles, which 
contain five times as much triglyceride by weight as choles
-
terol. The amount of cholesterol found in the VLDL frac
-
tion can be estimated by dividing the triglyceride by 5:
VLDL
ch
ol
es
te
ro
l
Triglyceride
s
5
=
Because the triglyceride level is used as a proxy for 
the amount of VLDL, this estimation formula works 
only when the triglyceride level is less than 400 mg/dL 
(4.52 mmol/L). At higher triglyceride levels, LDL and 
VLDL cholesterol levels can be determined after ultracen
-
trifugation or by direct chemical measurement.
The total cholesterol is reasonably stable over time; 
however, measurements of HDL and especially triglycer
-
ides may vary because of analytic error in the laboratory 
and biologic variation in a patient’s lipid level. Thus, the 
LDL should always be estimated as the mean of at least two 
determinations; if those two estimates differ by more than 
10%, a third lipid profile should be obtained. The LDL is 
estimated as follows:
LDL Total HDL
cholesterol = 
c
holesterol – cholesterol 
–
 
(mg/dL) (mg/dL
)
Triglycerides
(mg/dL)
5
When using SI units, the formula becomes
c
–
 
(mmol/L) (mmol/L)
(mmol/L)
2.2
Some authorities use the ratio of the total to HDL cho
-
lesterol as an indicator of lipid-related coronary risk: the 
lower this ratio is, the better. Although ratios are useful 
predictors within populations of patients, they may obscure 
important information in individual patients. (A total cho
-
lesterol of 300 mg/dL [7.76 mmol/L] and an HDL of 
60 mg/dL [1.56 mmol/L] result in the same ratio of 5.0 as a 
total cholesterol of 150 mg/dL [3.88 mmol/L] with an HDL 
of 30 mg/dL [0.78 mmol/L], yet the second profile is obvi
-
ously a more favorable one.) Moreover, the total choles
-
terol-to-HDL cholesterol ratio will magnify the importance 
of any variations in HDL measurement.
There is no true “normal” range for serum lipids. In 
Western populations, cholesterol values are about 20% 
higher than in Asian populations and exceed 300 mg/dL 
(7.76 mmol/L) in nearly 5% of adults. About 10% of adults 
have LDL cholesterol levels above 200 mg/dL (5.17 mmol/L). 
Total and LDL cholesterol levels tend to rise with age even 
in persons who are otherwise in good health.
Declines are seen in acute illness, and lipid studies in such 
patients are of little value with the exception of the serum 
triglyceride level in a patient with pancreatitis. Cholesterol 
levels (even when expressed as an age-matched percentile 
rank, such as the highest 20%) do not remain constant over 
time, especially from childhood through adolescence and

time, especially from childhood through adolescence and 
young adulthood. Thus, children and young adults with 28
Lipid Disorders
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relatively high cholesterol may have lower levels later in life, 
whereas those with low cholesterol may show increases.
THERAPEUTIC EFFECTS OF LOWERING 
CHOLESTEROL
Reducing cholesterol levels in healthy middle-aged men 
without CHD (primary prevention) reduces their risk in 
proportion to the reduction in LDL cholesterol. Treated 
adults have statistically significant and clinically important 
reductions in the rates of myocardial infarctions, strokes, 
new cases of angina, and need for coronary artery bypass 
procedures. The West of Scotland Study showed a 31% 
decrease in myocardial infarctions in middle-aged men 
treated with pravastatin compared with placebo. The Air 
Force/Texas Coronary Atherosclerosis Prevention Study 
(AFCAPS/TexCAPS) study showed similar results with 
lovastatin. As with any primary prevention interventions, 
large numbers of healthy patients need to be treated to pre
-
vent a single event. The numbers of patients needed to treat 
(NNT) to prevent one nonfatal myocardial infarction or 
one coronary artery disease death in these two studies were 
46 and 50, respectively. The Anglo-Scandinavian Cardiac 
Outcomes Trial (ASCOT) study of atorvastatin in persons 
with hypertension and other risk factors but without CHD 
demonstrated a 36% reduction in CHD events. The Justifi
-
cation for the Use of Statins in Prevention: an Intervention 
Trial Evaluating Rosuvastatin (JUPITER) study showed a 
44% reduction in a combined end point of myocardial 
infarction, stroke, revascularization, hospitalization for 
unstable angina, or death from cardiovascular causes in 
both men and women. The NNT for 1 year to prevent one 
event was 169. The Heart Outcomes Prevention Evaluation 
(HOPE-3) trial of rosuvastatin showed a 24% reduction in 
cardiovascular events. The NNT over 5.6 years was 91.
Primary prevention studies
 have found a less consis
-
tent effect on total mortality. The West of Scotland study 
found a 20% decrease in total mortality, tending toward 
statistical significance. The AFCAPS/TexCAPS study with 
lovastatin showed no difference in total mortality. The 
Antihypertensive and Lipid-Lowering Treatment to Pre
-
vent Heart Attack Trial (ALLHAT-LLT) also showed no 
reduction either in all-cause mortality or in CHD events 
when pravastatin was compared with usual care. Subjects 
treated with atorvastatin in the ASCOT study had a 13% 
reduction in mortality, but the result was not statistically 
significant. This study, however, was stopped early due to 
the marked reduction in CHD events. The JUPITER trial 
demonstrated a statistically significant 20% reduction in 
death from any cause. The NNT for 1 year was 400. The 
HOPE-3 trial showed a 7% reduction in all-cause mortal
-
ity, but the result was not statistically significant.
In patients with CHD
, the benefits of cholesterol low
-
ering are clearer. Major studies with statins have shown 
significant reductions in cardiovascular events, cardiovas
-
cular deaths, and all-cause mortality in men and women 
with coronary artery disease. The NNT to prevent a non-
fatal myocardial infarction or a coronary artery disease 
death in these studies was between 12 and 34. Aggressive 
cholesterol lowering with these agents causes regression of 
atherosclerotic plaques in some patients, reduces the pro
-
gression of atherosclerosis in saphenous vein grafts, and 
can slow or reverse carotid artery atherosclerosis. Results 
with other classes of medications have been less consistent. 
For example, patients treated with gemfibrozil had fewer 
cardiovascular events, but there was no benefit in all-cause 
mortality when compared with placebo.
The disparities in results between primary and second
-
ary prevention studies highlight several important points. 
The benefits and adverse effects of cholesterol lowering may 
be specific to each type of drug; the clinician cannot assume 
that the effects will generalize to other classes of medica
-

-
tion. Second, the net benefits from cholesterol lowering 
depend on the underlying risk of CHD and of other disease. 
In patients with atherosclerosis, morbidity and mortality 
rates associated with CHD are high, and measures that 
reduce it are more likely to be beneficial even if they have no 
effect—or even slightly harmful effects—on other diseases.
Blaha MJ. Personalizing treatment: between primary and 
 
secondary prevention. Am J Cardiol. 2016 Sep 15;118
 
(6 Suppl):4A–12A. [PMID: 27620358]
Collins R et al. Interpretation of the evidence for the efficacy and 
safety of statin therapy. Lancet. 2016 Nov 19;388(10059):
 
2532–61. Erratum in: Lancet. 2017 Feb 11;389(10069):602. 
[PMID: 27616593]
Driver SL et al. Fasting or nonfasting lipid measurements: it 
depends on the question. J Am Coll Cardiol. 2016 Mar 15;
 
67(10):1227–34. [PMID: 26965545]
Hirsh BJ et al. Utilization of and adherence to guideline-
recommended lipid-lowering therapy after acute coronary 
syndrome: opportunities for improvement. J Am Coll Cardiol. 
2015 Jul 14;66(2):184–92. [PMID: 26160634]
Rader DJ et al. HDL and cardiovascular disease. Lancet. 2014 
Aug 16;384(9943):618–25. [PMID: 25131981]
Silverman MG et al. Association between lowering LDL-C and 
cardiovascular risk reduction among different therapeutic 
interventions: a systematic review and meta-analysis. JAMA. 
2016 Sep 27;316(12):1289–97. [PMID: 27673306]
blood cholesterol to reduce atherosclerotic cardiovascular 
risk in adults: a report of the American College of Cardiology/
-
lines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889–934. 
[PMID: 24239923]
Svatikova A et al. Cholesterol management in the era of 
PCSK9 inhibitors. Curr Cardiol Rep. 2017 Sep;19(9):83. 
[PMID: 28779284]
Wilkins JT et al. Coronary heart disease risks associated with 
high levels of HDL cholesterol. J Am Heart Assoc. 2014 Mar 13;
 
3(2):e000519. [PMID: 24627418]
intermediate-risk persons without cardiovascular disease. 
 
N Engl J Med. 2016 May 26;374(21):2021–31. [PMID: 
27040132]
SECONDARY CONDITIONS THAT AFFECT 
LIPID METABOLISM
Several factors, including drugs, can influence serum lip
-
ids. These are important for two reasons: abnormal lipid 
levels (or changes in lipid levels) may be the presenting 
sign of some of these conditions, and correction of the 
underlying condition may obviate the need to treat an 
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apparent lipid disorder. Diabetes mellitus and alcohol use, 
in particular, are commonly associated with high triglycer
-
ide levels that decline with improvements in glycemic 
control or reduction in alcohol use, respectively. Thus, 
secondary causes of high blood lipids should be considered 
in each patient with a lipid disorder before lipid-lowering 
therapy is started. In most instances, special testing is not 
needed: a history and physical examination are sufficient.
CLINICAL PRESENTATIONS
Most patients with high cholesterol levels have no specific 
symptoms or signs. The vast majority of patients with lipid 
abnormalities are detected by the laboratory, either as part 
of the workup of a patient with cardiovascular disease or as 
part of a preventive screening strategy. Extremely high 
levels of chylomicrons or VLDL particles (triglyceride level 
above 1000 mg/dL or 10 mmol/L) result in the formation 
of 
eruptive xanthomas
 (Figure 28–1) (red-yellow papules, 
especially on the buttocks). High LDL concentrations 
result in 
tendinous xanthomas
 on certain tendons 
(Achilles, patella, back of the hand). Such xanthomas usu
-
ally indicate one of the underlying genetic hyperlipidemias. 
Lipemia retinalis
 (cream-colored blood vessels in the fun
-
dus) is seen with extremely high triglyceride levels (above 
2000 mg/dL or 20 mmol/L).
SCREENING & TREATMENT OF HIGH 
BLOOD CHOLESTEROL
Patients with cardiovascular disease and diabetes should 
have their lipids measured. These patients are at the highest 
risk for suffering additional manifestations in the near 
term and thus have the most to gain from lipid lowering. 
Additional risk reduction measures for atherosclerosis are 
discussed in Chapter 10; lipid lowering should be just one 
aspect of a program to reduce the progression and effects 
of atherosclerosis.
In patients with cardiovascular disease, a complete lipid 
profile (total cholesterol, HDL cholesterol, and triglyceride 
levels) should be obtained. According to the 2013 American 
College of Cardiology/American Heart Association 
(ACC/AHA) guidelines, however, such patients are 
treated with statins independent of their lipid levels. 
Similarly, patients aged 40–75 with diabetes should also 
have a complete lipid profile. Those with diabetes and 
LDL greater than or equal to 70 mg/dL (1.81 mmol/L) 
should be treated with statins.
The best screening and treatment strategy for adults 
who do not have atherosclerotic cardiovascular disease is 
less clear. Several algorithms have been developed to guide 
the clinician in treatment decisions, but management 
decisions are individualized based on the patient’s risk. The 
2013 ACC/AHA guidelines recommend screening of all 
adults aged 21 years or older for high blood cholesterol. 
The 2016 United States Preventive Services Task Force 
(USPSTF) guidelines recommend beginning at age 20 years 
only if there are other cardiovascular risk factors such as 
tobacco use, diabetes, hypertension, obesity, or a family 
history of premature cardiovascular disease. For men with
-
out other risk factors, screening is recommended begin
-
ning at age 35 years. For women and for men aged 20 to 
35 without increased risk, the USPSTF makes no recom
-
mendation for or against routine screening for lipid disor
-
ders. Although there is no established interval for screening, 
screening can be repeated every 5 years for those with aver
-
age or low risk and more often for those whose levels are 
close to therapeutic thresholds.
Individuals without cardiovascular disease should have 
their 10-year risk of CHD calculated. Although those with 
LDL cholesterol greater than 190 mg/dL (4.91 mmol/L) are 
recommended for treatment independent of their 10-year 
risk of cardiovascular disease, all other patients are recom
-
mended for treatment based on their overall cardiovascular 
risk. The best method for estimating 10-year risk is contro
-

-
-
versial. The 2013 ACC/AHA guidelines include a risk cal
-
culator that measures cardiovascular risk. It can be found 
at http://www.cvriskcalculator.com/. It has been criticized 
by some authors as overestimating risk. The older Fram
-
ingham 10-year calculator includes CHD but not stroke 
risk. One approach is to use both risk calculators until bet
-
ter data are available.
Numerous other risk factors have been studied in an 
attempt to better predict future CHD events. These include 
serum high-sensitivity C-reactive protein (hs-CRP) homo
-
cysteine, fibrinogen, lipoprotein (a), LDL subfractions; 
electron beam computed tomography (EBCT); ankle-
brachial index; and others. Several of these, particularly 
hs-CRP and EBCT, may add additional prognostic ability 
to traditional risk factors, but no clinical trials have ade
-
quately examined the effect of adding these screening tests 
on health outcomes. Clinical guidelines suggest limiting 
the use of additional risk factors such as hs-CRP to selected 
patients only if additional data are likely to change a thera
-
peutic decision.
Several strategies for obtaining the initial cholesterol 
measurement have been proposed, including (1) measur
-
ing total cholesterol alone, (2) measuring total cholesterol 
and HDL cholesterol, or (3) measuring (or calculating) 
LDL cholesterol alone. Initial measurement of the LDL 
 
▲
Figure 28–1.
 
Eruptive xanthoma on the arm of a man 
with untreated hyperlipidemia and diabetes mellitus. 
(Used, with permission, from Richard P . Usatine, MD.)
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cholesterol is least likely to lead to patient misinformation 
and misclassification and is the strategy recommended by 
the 2013 ACC/AHA guidelines.
Treatment decisions are based on the presence of clini
-
cal cardiovascular disease or diabetes, patient age, LDL 
cholesterol greater than 190 mg/dL (4.91 mmol/L), and 
the estimated 10-year risk of developing cardiovascular 
disease. The 2013 ACC/AHA guidelines define four 
groups of patients who benefit from statin medications: 
(1) individuals with clinical atherosclerotic cardiovascular 
disease; (2) individuals with primary elevation of LDL 
cholesterol greater than 190 mg/dL (4.91 mmol/L); (3) 
individuals aged 40–75 with diabetes and LDL greater 
than or equal to 70 mg/dL (1.81 mmol/L); and (4) indi
-
viduals aged 40–75 without clinical atherosclerotic cardio
-
vascular disease or diabetes, with LDL 70–189 mg/dL 
(1.81–4.91 mmol/L), and estimated 10-year CVD risk of 
7.5% or higher.
 
»
Screening & Treatment in Women
The foregoing screening and treatment guidelines are 
designed for both men and women. Y et several observa
-
tional studies suggest that a low HDL cholesterol is a 
more important risk factor for CHD in women than a 
high LDL cholesterol. Meta-analysis of studies including 
women with known heart disease, however, has found 
that statins prevent recurrent myocardial infarctions in 
women. There is less evidence to be certain of a similar 
effect from statins in women without evidence of CHD. 
Although most experts recommend application of the 
same primary prevention guidelines for women as for 
men, clinicians should be aware of the uncertainty in this 
area. Estimating the 10-year cardiovascular risk is par
-
ticularly important in women since a larger percentage of 
women than men will have estimated 10-year cardiovas
-
cular risks below 7.5% per year and be advised not to take 
statins unless their LDL is very high (greater than 
190 mg/dL [4.91 mmol/L]).
 
»
Screening & Treatment in Older Patients
Meta-analysis of evidence relating cholesterol to CHD in 
older adults suggests that cholesterol is not a risk factor for 
CHD for persons over age 75 years. Clinical trials have 
rarely included such individuals. One exception is the Pro
-
spective Study of Pravastatin in the Elderly at Risk (PROS
-
PER). In this study, elderly patients with cardiovascular 
disease (secondary prevention) benefited from statin ther
-
apy, whereas those without cardiovascular disease (pri
-
mary prevention) did not. The 2013 ACC/AHA guidelines 
suggest continuing statin treatment in patients over age 75 
who have cardiovascular disease. The guidelines, however, 
suggest not screening or treating patients over the age of 75 
who do not have evidence of cardiovascular disease. Indi
-
vidual patient decisions to discontinue statin therapy 
should be based on overall functional status and life expec
-
tancy, comorbidities, and patient preference and should be 
made in context with overall therapeutic goals and end-of-
life decisions.
Bell DA et al. Progress in the care of familial hypercholesterolae
-
mia: 2016. Med J Aust. 2016 Sep 5;205(5):232–6. [PMID: 
27581271]
Catapano AL et al. 2016 ESC/EAS Guidelines for the Manage
-
ment of Dyslipidaemias: the Task Force for the Management 
of Dyslipidaemias of the European Society of Cardiology 
(ESC) and European Atherosclerosis Society (EAS) developed 
with the special contribution of the European Association for 
Cardiovascular Prevention & Rehabilitation (EACPR). Ath
-
erosclerosis. 2016 Oct;253:281–344. [PMID: 27594540]
Chang Y et al. Dyslipidemia management update. Curr Opin 
Pharmacol. 2017 Apr;33:47–55. [PMID: 28527325]
Chaudhary R et al. PCSK9 inhibitors: a new era of lipid lowering 
therapy. World J Cardiol. 2017 Feb 26;9(2):76–91. [PMID: 
28289523]
Goff DC Jr et al. 2013 ACC/AHA Guideline on the Assessment 
of Cardiovascular Risk: a report of the American College of

28289523]
of Cardiovascular Risk: a report of the American College of 
-
tice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt 
B):2935–59. [PMID: 24239921]
Keaney JF Jr et al. A pragmatic view of the new cholesterol treat
-
ment guidelines. N Engl J Med. 2014 Jan 16;370(3):275–8. 
[PMID: 24283199]
Khera AV et al. Diagnostic yield and clinical utility of sequenc
-
ing familial hypercholesterolemia genes in patients with 
severe hypercholesterolemia. J Am Coll Cardiol. 2016 Jun 7;
 
67(22):2578–89. [PMID: 27050191]
Ogura M. PCSK9 inhibition in the management of familial 
hypercholesterolemia. J Cardiol. 2018 Jan;71(1):1–7. [PMID: 
28784313]
Page MM et al. PCSK9 in context: a contemporary review of an 
important biological target for the prevention and treatment 
of atherosclerotic cardiovascular disease. Diabetes Obes 
Metab. 2018 Feb;20(2):270–82. [PMID: 28736830]
Pencina MJ et al. Application of new cholesterol guidelines to a 
population-based sample. N Engl J Med. 2014 Apr 10;
 
370(15):1422–31. [PMID: 24645848]
Singh S et al. Familial hypercholesterolemia–epidemiology, diag
-
nosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. 
[PMID: 25612857]
Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of 
Blood Cholesterol to Reduce Atherosclerotic Cardiovascular 
Risk in Adults: a report of the American College of 
Cardiology/ American Heart Association Task Force on 
Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):
 
2889–934. [PMID: 24239923]
U.S. Preventive Services Task Force; Bibbins-Domingo K et al. 
Screening for lipid disorders in children and adolescents: U.S. 
JAMA. 2016 Aug 9;316(6):625–33. [PMID: 27532917]
Statin use for the primary prevention of cardiovascular dis
-
ease in adults: U.S. Preventive Services Task Force recommen
-
dation statement. JAMA. 2016 Nov 15;316(19):1997–2007. 
[PMID: 27838723]
TREATMENT OF HIGH LDL CHOLESTEROL
Reduction of LDL cholesterol with statins is just one part of 
a program to reduce the risk of cardiovascular disease. 
Other measures—including smoking cessation, hyperten
-
sion control, and aspirin—are also of central importance. 
Less well studied but of potential value is raising the HDL 
cholesterol level. Quitting smoking reduces the effect of 
other cardiovascular risk factors (such as a high cholesterol 
level); it may also increase the HDL cholesterol level. Exer
-
cise (and weight loss) may reduce the LDL cholesterol and 
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increase the HDL. Modest alcohol use (1–2 ounces a day) 
also raises HDL levels and appears to have a salutary effect 
on CHD rates.
The use of medications to raise the HDL cholesterol has 
not been demonstrated to provide additional benefit. For 
example, cholesteryl ester transfer protein inhibitors are a 
class of medicines being investigated to raise HDL levels. 
Agents in this class, however, have not been shown to be 
effective. The use of niacin in addition to statins has also 
been carefully studied in the AIM-HIGH study and the 
HPS2-THRIVE study and shown not to be effective.
 
»
Diet Therapy
Studies of nonhospitalized adults have reported only mod
-
est cholesterol-lowering benefits of dietary therapy, typi
-
cally in the range of a 5–10% decrease in LDL cholesterol, 
with even less in the long term. The effect of diet therapy, 
however, varies considerably among individuals, as some 
patients will have striking reductions in LDL cholesterol—
up to a 25–30% decrease—whereas others will have clini
-
cally important increases. Thus, the results of diet therapy 
should be assessed about 4 weeks after initiation.
Cholesterol-lowering diets may also have a variable 
effect on lipid fractions. Diets very low in total fat or in 
saturated fat may lower HDL cholesterol as much as LDL 
cholesterol. It is not known how these diet-induced changes 
affect coronary risk.
Several nutritional approaches to diet therapy are avail
-
able. Most Americans currently eat over 35% of calories as 
fat, of which 15% is saturated fat. A traditional cholesterol-
lowering diet recommends reducing total fat to 25–30% 
and saturated fat to less than 7% of calories. These diets 
replace fat, particularly saturated fat, with carbohydrate. 
Other diet plans, including the Dean Ornish Diet, the Pri
-
tikin Diet, and most vegetarian diets, restrict fat even fur
-
ther. Low-fat, high-carbohydrate diets may, however, result 
in reductions in HDL cholesterol.
An alternative strategy is the Mediterranean diet, which 
maintains total fat at approximately 35–40% of total calories 
but replaces saturated fat with monounsaturated fat such as 
that found in canola oil and in olives, peanuts, avocados, 
and their oils. This diet is equally effective at lowering LDL 
cholesterol, but is less likely to lead to reductions in HDL 
cholesterol. Several studies have suggested that this 
approach may also be associated with reductions in endo
-
thelial dysfunction, insulin resistance, and markers of 
vascular inflammation and may result in better resolution 
of the metabolic syndrome than traditional cholesterol-
lowering diets. A clinical trial demonstrated reduced 
cardiovascular events in persons on a Mediterranean diet 
supplemented with additional nuts or extra-virgin olive oil 
compared to persons on a less intensive Mediterranean diet.
Other dietary changes may also result in beneficial 
changes in blood lipids. Soluble fiber, such as that found in 
oat bran or psyllium, may reduce LDL cholesterol by 
5–10%. Plant stanols and sterols can reduce LDL choles
-
terol by 10%. Intake of garlic, soy protein, vitamin C, and 
pecans, may also yield modest reductions of LDL choles
-
terol. Because oxidation of LDL cholesterol is a potential 
initiating event in atherogenesis, diets rich in antioxidants, 
found primarily in fruits and vegetables, may be helpful 
(see Chapter 29). Studies have suggested that when all of 
these elements are combined into a single dietary prescrip
-
tion, the impact of diet on LDL cholesterol may approach 
that of statin medications, lowering LDL cholesterol by 
close to 30%.
Chalvon-Demersay T et al. A systematic review of the effects of 
plant compared with animal protein sources on features of 
metabolic syndrome. J Nutr. 2017 Mar;147(3):281–92. 
[PMID: 28122929]
Eckel RH et al. 2013 AHA/ACC Guideline on lifestyle manage
-
ment to reduce cardiovascular risk: a report of the American

-
ment to reduce cardiovascular risk: a report of the American 
Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 
Suppl 2):S76–99. [PMID: 24222015]
Estruch R et al; PREDIMED Study Investigators. Primary 
prevention of cardiovascular disease with a Mediterranean 
diet. N Engl J Med. 2013 Apr 4;368(14):1279–90. [PMID: 
23432189]
Griffin BA. Nonpharmacological approaches for reducing serum 
low-density lipoprotein cholesterol. Curr Opin Cardiol. 2014 
Jul;29(4):360–5. [PMID: 24837072]
Hooper L et al. Reduction in saturated fat intake for cardiovas
-
cular disease. Cochrane Database Syst Rev. 2015 Jun 10;
 
(6):CD011737. [PMID: 26068959]
Khera AV et al. Genetic risk, adherence to a healthy lifestyle, and 
coronary disease. N Engl J Med. 2016 Dec 15;375(24):2349–58. 
 
[PMID: 27959714]
Lu M et al. Effects of low-fat compared with high-fat  diet  on 
cardiometabolic indicators in people with overweight and 
obesity without overt metabolic disturbance: a systematic 
review and meta-analysis of randomised controlled trials. Br 
J Nutr. 2018 Jan;119(1):96–108. [PMID: 29212558]
 
»
Most patients whose risk from CHD is considered high 
enough to warrant pharmacologic therapy of an elevated 
LDL cholesterol should be given aspirin prophylaxis at a 
dose of 81 mg/day unless there are contraindications 
such as aspirin sensitivity, bleeding diatheses, or active 
peptic ulcer disease. Other CHD risk factors, such as 
hypertension or smoking, should also be controlled or 
There are six types of medications to benefit patients 
who require drug treatment of an elevated LDL cholesterol. 
As discussed above, the guidelines define four groups of 
patients who benefit from statin medications.
A. Statins (Hydroxymethylglutaryl-Coenzyme A 
[HMG-CoA] Reductase Inhibitors)
The statins (HMG-CoA reductase inhibitors) work by 
inhibiting the rate-limiting enzyme in the formation of 
cholesterol. They reduce myocardial infarctions and total 
mortality in secondary prevention, as well as in older 
middle-aged men free of CHD. A meta-analysis has dem
-
onstrated significant reduction in risk of stroke. Choles
-
terol synthesis in the liver is reduced, with a compensatory 
increase in hepatic LDL receptors (presumably so that the 
liver can take more of the cholesterol that it needs from the 
blood) and a reduction in the circulating LDL cholesterol 
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level by up to 35%. There are also modest increases in HDL 
levels and decreases in triglyceride levels.
The 2013 ACC/AHA guidelines divide statins into 
high-intensity and moderate-intensity statin therapy 
(Table 28–1). High-intensity statins lower LDL cholesterol 
by approximately 50%. Examples include atorvastatin 
40–80 mg and rosuvastatin 20–40 mg/day (Table 28–2). 
Moderate-intensity statins lower LDL cholesterol by 
approximately 30–50%. Examples include atorvastatin 
10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, 
pravastatin 40–80 mg, and lovastatin 40 mg. All statins are 
given once daily in the morning or evening. The most com
-
mon side effects are muscle aches, occurring in up to 10% 
of patients, and mild gastrointestinal effects. Statins are 
associated with a 10% increase in the risk of diabetes. 
Other serious, but extremely uncommon, side effects 
include liver failure and muscle disease including myositis 
and rhabdomyolysis. Some patients experience muscle 
pain even when the serum creatine kinase levels are nor
-
mal. Liver disease is more common in patients who are also 
taking fibrates or niacin. Manufacturers of statins recom
-
mend monitoring liver enzymes before initiating therapy 
and as clinically indicated thereafter. Muscle disease is 
more common with statins and fibrates and niacin as well 
as with erythromycin, antifungal medications, nefazadone, 
and cyclosporine. Simvastatin at the highest approved 
dose—80 mg—is associated with a higher risk of muscle 
injury or myopathy. This dose should be used only in those 
who have been taking the medication for longer than 1 year 
without muscle toxicity.
B. Niacin (Nicotinic Acid)
Niacin was the first lipid-lowering agent that was associ
-
ated with a reduction in total mortality. Long-term follow-
up of a secondary prevention trial of middle-aged men 
with previous myocardial infarction disclosed that about 
half of those who had been previously treated with niacin 
had died, compared with nearly 60% of the placebo group. 
This favorable effect on mortality was not seen during the 
trial itself, though there was a reduction in the incidence of 
recurrent coronary events. A meta-analysis of 10 random
-
ized trials using niacin has also shown a 27% reduction in 
cardiovascular events.
Niacin reduces the production of VLDL particles, with 
secondary reduction in LDL and increases in HDL choles
-
terol levels. The average effect of full-dose niacin therapy, 
3–4.5 g/day, is a 15–25% reduction in LDL cholesterol and 
a 25–35% increase in HDL cholesterol. Full doses are 
required to obtain the LDL effect, but the HDL effect is 
observed at lower doses, eg, 1 g/day. Niacin will also reduce 
triglycerides by half and will lower lipoprotein(a) (Lp[a]) 
levels and will increase plasma homocysteine levels. Intoler
-
ance to niacin is common; only 50–60% of patients can take 
full doses. Niacin causes a prostaglandin-mediated flushing 
that patients may describe as “hot flashes” or pruritus and 
that can be decreased with aspirin (81–325 mg/day) or 
other nonsteroidal anti-inflammatory agents taken during 
the same day. Flushing may also be decreased by initiating 
niacin therapy with a very small dose, eg, 100 mg with the 
evening meal. The dose can be doubled each week until 
1.5 g/day is tolerated. After rechecking blood lipids, the 
dose is increased and divided over three meals until the goal 
of 3–4.5 g/day is reached (eg, 1 g with each meal). Extended-
release niacin is better tolerated by most patients. It is not 
known whether routine monitoring of liver enzymes results 
in early detection and thus reduced severity of hepatocel
-
lular hepatitis with jaundice. Niacin can also exacerbate 
gout and peptic ulcer disease. Although niacin may increase 
blood sugar in some patients, clinical trials have shown that 
niacin can be safely used in diabetic patients.
C. Bile Acid–Binding Resins

The bile acid–binding resins include cholestyramine, cole
-
sevelam, and colestipol. Treatment with these agents 
reduces the incidence of coronary events in middle-aged 
men by about 20%, with no significant effect on total mor
-
tality. The resins work by binding bile acids in the intestine. 
The resultant reduction in the enterohepatic circulation 
causes the liver to increase its production of bile acids, 
using hepatic cholesterol to do so. Thus, hepatic LDL 
receptor activity increases, with a decline in plasma LDL 
levels. The triglyceride level tends to increase slightly in 
some patients treated with bile acid–binding resins; they 
should be used with caution in those with elevated triglyc
-
erides and probably not at all in patients who have triglyc
-
eride levels above 500 mg/dL. The clinician can anticipate 
a reduction of 15–25% in the LDL cholesterol level, with 
insignificant effects on the HDL level.
The usual dose of cholestyramine is 12–36 g of resin per 
day in divided doses with meals, mixed in water or, more 
Table 28–1.
 
Indications for high-intensity and 
moderate-intensity statins: recommendations of the 
2013 ACC/AHA Guidelines.
t
r
eatment 
r
Presence of clinical atheroscle
-
rotic cardiovascular disease
or
moderate-intensity statin if 
over age 75
Primary elevation of LDL 
cholesterol ≥ 190 mg/dL 
(4.91 mmol/L)
Age 40–75
Presence of diabetes
LDL ≥ 70 mg/dL (1.81 mmol/L)
or
high-intensity statin if 10-year 
CVD risk 7.5% or higher
Aged 40–75
No clinical atherosclerotic 
cardiovascular disease or 
diabetes
LDL 70–189 mg/dL 
(1.81–4.91 mmol/L)
Estimated 10-year CVD risk 
7.5% or higher
Treat with moderate- to high-
intensity statin
ACC/AHA, American College of Cardiology/American Heart 
Association; CVD, cardiovascular disease; HDL, high-density lipo
-
protein; LDL, low-density lipoprotein.
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Table 28–2.
 
Effects of selected lipid-modifying drugs (listed alphabetically).
 Drug
Lipid-Modifying 
e
ff
ects
 
t
rigly
ceride
 Initial Daily 
Dose
 Maximum 
Daily Dose
 Cost for 30 Days 
t
r
eatment With 
Dose Listed
1
LDL
h
DL
Alirocumab (Praluent)
–45 to –60%
±
±
75 mg once every 
2 weeks
150 mg once 
every 2 weeks
$1344.00 (75 mg 
every 2 weeks)
Atorvastatin (Lipitor)
–25 to –40%
+5 to 10%
↓↓
10 mg once
80 mg once
$15.75 (20 mg once)
Cholestyramine 
(Questran, others)
–15 to –25%
+5%
±
4 g twice a day
24 g divided
$21.00 (8 g divided)
Colesevelam 
 
(WelChol)
–10 to –20%
+10%
±
625 mg, 6–7 
tablets once
625 mg, 6–7 
$749.52 (6 tablets 
once)
Colestipol (Colestid)
–15 to –60%
+5%
±
5 g twice a day
30 g divided
$235.82 (10 g 
divided)
Evolocumab 
 
(Repatha)
–50 to –60%
±
±
140 mg once 
420 mg once 
monthly
$1340.59 (140 mg 
Ezetimibe (Zetia)
–20%
+5%
±
10 mg once
10 mg once
$308.43 (10 mg once)
Fenofibrate (Tricor, 
others)
–10 to –15%
+15 to 25%
↓↓
48 mg once
145 mg once
$37.20 (145 mg once)
Fenofibric acid 
 
(Trilipix)
–10 to –15%
+15 to 25%
↓↓
45 mg once
135 mg once
$160.20 (135 mg 
once)
Fluvastatin (Lescol)
–20 to –30%
+5 to 10%
↓
20 mg once
40 mg once
$113.40 (20 mg once)
Gemfibrozil (Lopid, 
others)
–10 to –15%
+15 to 20%
↓↓
600 mg once
1200 mg divided
$71.40 (600 mg twice 
a day)
Lomitapide 
 
(Juxtapid)
2,3
–40 to –50%
4
–7%
4
↓↓
5 mg once
60 mg once
$44,390.40 (any dose)
Lovastatin 
 
(Mevacor, others)
–25 to –40%
+5 to 10%
↓
10 mg once
80 mg divided
$63.00 (20 mg once)
Mipomersen 
(Kynamro)
2,3
–20 to  –25%
5
+11%
5
↓
200 mg subcuta
-
neously once 
weekly
-
weekly
$36,532.96 (200 mg 
weekly)
Niacin (OTC, Niaspan)
–15 to –25%
+25 to 35%
↓↓
100 mg once
3–4.5 g divided
$9.00 (1.5 g twice a 
day, OTC)
$449.40 (2 g Niaspan)
Omega-3 fatty acid 
ethyl esters (Lovaza)
 
↓↓
4 g once
4 g once
$348.76 (4 g daily)
icosapent ethyl 
(Vascepa)
 
↓↓
2 g twice
2 g twice
$334.30 
 
(2 g twice day)
Pitavastatin (Livalo)
–30 to 40%
+10 to 25%
↓↓
2 mg once
4 mg once
$331.50 (2 mg once)
Pravastatin (Pravachol)
–25 to –40%
+5 to 10%
↓
20 mg once
80 mg once
$75.00 (20 mg once)
Rosuvastatin (Crestor)
–40 to –50%
+10 to 15%
↓↓
10 mg once
40 mg once
$43.20 (20 mg once)
Simvastatin (Zocor, 
others)
–25 to –40%
+5 to 10%
↓↓
5 mg once
80 mg once
$6.00 (10 mg once)
1
Red Book
Analytics Information, http://www.micromedexsolutions.com/, accessed April 10, 2018. AWP may not accurately represent the actual phar
-
2
Restricted to patients with homozygous familial hypercholesterolemia.
3
FDA Black Box warning regarding hepatotoxicity.
4
62% of patients also received plasma lipoprotein apheresis.
5
No plasma lipoprotein apheresis allowed in clinical trial.
HDL, high-density lipoprotein; LDL, low-density lipoprotein; ± variable, if any; others, indicates availability of less expensive generic 
preparations; OTC, over the counter.
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palatably, juice. Doses of colestipol are 20% higher (each 
packet contains 5 g of resin). The dose of colesevelam is 
625 mg, 6–7 tablets per day.
These agents often cause gastrointestinal symptoms, 
such as constipation and gas. They may interfere with the 
absorption of fat-soluble vitamins (thereby complicating 
the management of patients receiving warfarin) and may 
bind other drugs in the intestine. Concurrent use of psyl
-
lium may ameliorate the gastrointestinal side effects.
D. Fibric Acid Derivatives
The fibrates are peroxisome proliferative-activated receptor-
alpha (PPAR-alpha) agonists that result in potent reductions 
of plasma triglycerides and increases in HDL cholesterol. 
They reduce LDL levels by about 10–15% (although the 
result is quite variable) and triglyceride levels by about 40% 
and raise HDL levels by about 15–20%. The fibric acid 
derivatives or fibrates approved for use in the United States 
are gemfibrozil and fenofibrate. Ciprofibrate and bezafibrate 
are also available for use internationally.
Gemfibrozil reduced CHD rates in hypercholesterol
-
emic middle-aged men free of coronary disease in the 
Helsinki Heart Study. The effect was observed only among 
those who also had lower HDL cholesterol levels and high 
triglyceride levels. In a V A study, gemfibrozil was also 
shown to reduce cardiovascular events in men with exist
-
ing CHD whose primary lipid abnormality was a low HDL 
cholesterol. There was no effect on all-cause mortality.
The usual dose of gemfibrozil is 600 mg once or twice a 
day. Side effects include cholelithiasis, hepatitis, and myo
-
sitis. The incidence of the latter two conditions may be 
higher among patients also taking other lipid-lowering 
agents. In the largest clinical trial that used clofibrate, there 
were significantly more deaths—especially due to cancer—
in the treatment group; it should not be used.
E. Ezetimibe
Ezetimibe is a lipid-lowering drug that inhibits the intesti
-
nal absorption of dietary and biliary cholesterol across the 
intestinal wall by inhibiting a cholesterol transporter. The 
usual dose of ezetimibe is 10 mg/day orally. Ezetimibe 
reduces LDL cholesterol between 15% and 20% when used 
as monotherapy and can further reduce LDL in patients 
taking statins who are not yet at therapeutic goal. However, 
beneficial effects of ezetimibe monotherapy on cardiovas
-
cular outcomes have not been demonstrated.
One study has shown that adding ezetimibe to a statin 
resulted in a small incremental benefit on cardiovascular 
outcomes. At the end of 7 years of study, patients taking 
ezetimibe-simvastatin had a 2% absolute reduction in car
-
diovascular events compared to patients taking simvastatin 
alone.
F. Proprotein Convertase Subtilisin/Kexin Type 9 
(PCSK9) Inhibitors
PCSK9 inhibitors are monoclonal antibodies that reduce liver 
LDL-receptor degradation and lower LDL cholesterol levels 
by 50–60%. Two agents, alirocumab and evolocumab, are 
approved for use in the United States for patients with familial 
hypercholesterolemia or cardiovascular disease who require 
additional lowering of LDL cholesterol. The medications are 
injected subcutaneously every 2–4 weeks. No significant 
increase in adverse events has been observed compared to 
placebo. The FOURIER (Further Cardiovascular Outcomes 
Research with PCSK9 Inhibition in Subjects with Elevated 
Risk) trial compared evolocumab with placebo in 27,564 
patients with atherosclerotic disease already taking statin 
therapy; participants were monitored for a median of 2.2 years. 
LDL cholesterol was reduced by 59%. Patients receiving the 
evolocumab plus statin had a 15% reduction in the primary 
composite endpoint of cardiovascular death, myocardial 
infarction, stroke, hospital admission for unstable angina, or 
coronary revascularization and a 20% reduction in the 
secondary outcome of cardiovascular death, myocardial

secondary outcome of cardiovascular death, myocardial 
infarction, or stroke. However, despite such encouraging 
results, cost-effectiveness models suggest that PCSK9 inhibi
-
tors, at current prices, are not cost-effective.
 
»
Initial Selection of Medication
For patients who require a lipid-modifying medication, an 
HMG-CoA reductase inhibitor is recommended. Although 
other medications will also have beneficial effects on lipids, 
there is little evidence demonstrating the desired effects on 
cardiovascular disease and all-cause mortality. Resins are 
the only lipid-modifying medication considered safe in 
Combination therapy is rarely indicated. Despite 
improvements in the lipid profile, there are few data demon
-
strating improved clinical outcomes of combination therapy 
when compared with HMG-CoA reductase inhibitors alone. 
The AIM-High Study of niacin added to simvastatin, for 
example, was stopped early due to a lack of efficacy. The use 
of extended-release niacin with laropiprant (a prostaglandin 
antagonist) in high-risk patients taking a statin also did not 
reduce the risk of cardiovascular events. The addition of 
ezetimibe to simvastatin in the IMPROVE-IT study resulted 
in a statistically significant benefit on cardiovascular events 
but the absolute reduction was small.
Combinations may also increase the risk of complica
-
tions of drug therapy. The combination of gemfibrozil and 
HMG-CoA reductase inhibitors increases the risk of mus
-
cle and liver disease more than either drug alone. An 
increase in adverse events was also seen when niacin plus 
laropiprant was added to statins.
Bonaca MP et al. Low-density lipoprotein cholesterol lowering 
with evolocumab and outcomes in patients with peripheral 
artery disease: insights from the FOURIER trial (Further 
Cardiovascular Outcomes Research With PCSK9 Inhibition 
in Subjects With Elevated Risk). Circulation. 2018 Jan 
23;137(4):338–50. [PMID: 29133605]
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy 
and safety of LDL-lowering therapy among men and women: 
meta-analysis of individual data from 174,000 participants in 
27 randomised trials. Lancet. 2015 Apr 11;385(9976):
 
1397–405. [PMID: 25579834]
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Hovingh GK et al. Identification and management of patients 
with statin-associated symptoms in clinical practice: a 
clinician survey. Atherosclerosis. 2016 Feb;245:111–7. [PMID: 
26717273]
HPS2-THRIVE Collaborative Group. Effects of extended-release 
niacin with laropiprant in high-risk patients. N Engl J Med. 
2014 Jul 17;371(3):203–12. [PMID: 25014686]
Karmali KN et al. Drugs for primary prevention of atherosclerotic 
cardiovascular disease: an overview of systematic reviews. 
JAMA Cardiol. 2016 Jun 1;1(3):341–9. [PMID: 27438118]
Kazi DS et al. Cost-effectiveness of PCSK9 inhibitor therapy in 
patients with heterozygous familial hypercholesterolemia or 
atherosclerotic cardiovascular disease. JAMA. 2016 Aug 16;
 
316(7):743–53. [PMID: 27533159]
Mark DB et al. PCSK9 inhibitors and the choice between innova
-
tion, efficiency, and affordability. JAMA. 2017 Aug 22;
 
318(8):711–2. [PMID: 28829851]
Raal FJ et al; RUTHERFORD-2 Investigators. PCSK9 inhibition 
with evolocumab (AMG 145) in heterozygous familial hyper
-
cholesterolaemia (RUTHERFORD-2): a randomised, double-
blind, placebo-controlled trial. Lancet. 2015 Jan 24;
 
385(9965):331–40. [PMID: 25282519]
Robinson JG et al; LAPLACE-2 Investigators. Effect of evolocumab 
or ezetimibe added to moderate- or high-intensity statin 
therapy on LDL-C lowering in patients with hypercholesterol
-
emia: the LAPLACE-2 randomized clinical trial. JAMA. 2014 
May 14;311(18):1870–82. [PMID: 24825642]
Tice JA et al. Proprotein convertase subtilisin/kexin type 9 
(PCSK9) inhibitors for treatment of high cholesterol levels: 
effectiveness and value. JAMA Intern Med. 2016 Jan 1;
 
176(1):107–8. [PMID: 26662572]
Wiggins BS et al. Recommendations for management of clini
-
cally significant drug-drug interactions with statins and 
select agents used in patients with cardiovascular disease: 
a scientific statement from the American Heart Associa
-
tion. Circulation. 2016 Nov 22;134(21):e468–95. [PMID: 
27754879]
HIGH BLOOD TRIGLYCERIDES
Patients with very high levels of serum triglycerides (greater 
than 1000 mg/dL) are at risk for pancreatitis. The patho
-
physiology is not certain, since pancreatitis never develops 
in some patients with very high triglyceride levels. Most 
patients with congenital abnormalities in triglyceride metab
-
olism present in childhood; hypertriglyceridemia-induced 
pancreatitis first presenting in adults is more commonly due 
to an acquired problem in lipid metabolism.
Although there are no clear triglyceride levels that pre
-
dict pancreatitis, most clinicians treat fasting levels above 
500 mg/dL (5 mmol/L). The risk of pancreatitis may be 
more related to the triglyceride level following consump
-
tion of a fatty meal. Because postprandial increases in 
triglyceride are inevitable if fat-containing foods are eaten, 
fasting triglyceride levels in persons prone to pancreatitis 
should be kept well below that level.
The primary therapy for high triglyceride levels is 
dietary, avoiding alcohol, simple sugars, refined starches, 
saturated and trans fatty acids, and restricting total calo
-
ries. Control of secondary causes of high triglyceride levels 
may also be helpful. In patients with fasting triglycerides 
greater than or equal to 500 mg/dL (5 mmol/L) despite 
adequate dietary compliance—and certainly in those 
 
with a previous episode of pancreatitis—therapy with a 
 
triglyceride-lowering drug (eg, niacin, fibric acid deriva
-
tive, omega-3-acid ethyl esters, or HMG-CoA reductase 
inhibitor) is indicated. Combinations of these medications 
Whether patients with triglycerides greater than 
150 mg/dL (1.5 mmol/L) should be treated to prevent CHD 
is not known. Meta-analysis of 17 observational studies 
suggests that after adjustment for other risk factors, ele
-
vated triglycerides increased CHD risk in men by 14% and 
in women by 37%. Elevated triglycerides are also an impor
-

-
-
tant feature of the metabolic syndrome. Other data, how
-
ever, suggest that triglyceride measurements do not 
improve discrimination between those with and without 
CHD events, and clinical trial data are not available to sup
-
port the routine treatment of high triglycerides in all 
patients.
Agrawal N et al. Triglyceride treatment in the age of cholesterol 
reduction. Prog Cardiovasc Dis. 2016 Sep–Oct;59(2):107–18. 
[PMID: 27544319]
Backes J et al. The clinical relevance of omega-3 fatty acids in the 
management of hypertriglyceridemia. Lipids Health Dis. 
 
2016 Jul 22;15(1):118. [PMID: 27444154]
Dallinga-Thie GM et al. Triglyceride-rich lipoproteins and rem
-
nants: targets for therapy? Curr Cardiol Rep. 2016 Jul;18(7):67. 
[PMID: 27216847]
Karalis DG. A review of clinical practice guidelines for the man
-
agement of hypertriglyceridemia: a focus on high dose 
omega-3 fatty acids. Adv Ther. 2017 Feb;34(2):300–23. 
[PMID: 27981496]
Klempfner R et al. Elevated triglyceride level is independently 
associated with increased all-cause mortality in patients with 
established coronary heart disease: twenty-two-year follow-
up of the Bezafibrate Infarction Prevention Study and Registry. 
Circ Cardiovasc Qual Outcomes. 2016 Mar;9(2):100–8. 
[PMID: 26957517]
Kushner PA et al. Hypertriglyceridemia: the importance of iden
-
tifying patients at risk. Postgrad Med. 2016 Nov;128(8):
 
848–58. [PMID: 27710158]
Valdivielso P et al. Current knowledge of hypertriglyceridemic 
pancreatitis. Eur J Intern Med. 2014 Oct;25(8):689–94. 
[PMID: 25269432]
Wiesner P et al. Triglycerides: a reappraisal. Trends Cardiovasc 
Med. 2017 Aug;27(6):428–32. [PMID: 28438398]
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Nutritional Disorders
29
 
º
NUTRITIONAL DISORDERS
PROTEIN–ENERGY MALNUTRITION
 
»
Decreased intake of energy or protein, increased 
nutrient losses, or increased nutrient 
requirements.
 
»
 caused by protein deficiency.
 
»
Marasmus:
 caused by combined protein and 
energy deficiency.
 
»
Protein loss correlates with weight loss: 35–40% 
total body weight loss is usually fatal.
 
»
Protein–energy malnutrition occurs as a result of a relative 
or absolute deficiency of energy and protein. It may be 
primary, due to inadequate food intake, or secondary, as a 
result of other illness. For most developing nations, pri
-
mary protein–energy malnutrition remains among the 
most significant health problems. It occurs in two distinct 
syndromes. 
Kwashiorkor,
 caused by a deficiency of protein 
in the presence of adequate energy, is typically seen in 
weaning infants at the birth of a sibling in areas where 
foods containing protein are insufficient. 
Marasmus,
 
caused by combined protein and energy deficiency, is seen 
where adequate quantities of food are simply not 
In industrialized societies, protein–energy malnutri
-
tion is most often secondary to other diseases. 
 
Kwashiorkor-like secondary protein–energy malnutri
-
tion
 occurs primarily in association with hypermetabolic 
acute illnesses such as trauma, burns, and sepsis. 
Marasmus-
like secondary protein–energy malnutrition
 typically 
results from chronic diseases such as chronic obstructive 
pulmonary disease (COPD), heart failure, cancer, or 
AIDS. These two syndromes are estimated to be present 
in at least 20% of hospitalized patients. A substantially 
greater number of patients have risk factors that could 
result in them. In both syndromes, protein–energy malnu
-
trition is caused either by decreased intake of energy and 
protein or by increased nutrient losses or increased nutri
-
ent requirements from the underlying illness. For example, 
diminished energy intake may result from poor dentition 
or various gastrointestinal disorders. Increased nutrient 
losses result from malabsorption, diarrhea, and glycosuria. 
Increased nutrient requirements occur with fever, surgery, 
neoplasia, and burns.
 
»
Clinical manifestations of protein–energy malnutrition 
range from mild growth retardation and weight loss to a 
number of distinct clinical syndromes. In the developing 
world, children manifest marasmus and kwashiorkor. In 
industrialized nations, clinical manifestations of secondary 
protein–energy malnutrition are affected by the patient’s 
nutritional status prior to illness, illness resulting in the 
protein and energy deficiency, and degree of the 
Progressive wasting that begins with weight loss and 
proceeds to more severe cachexia typically develops in 
most patients with marasmus-like secondary protein–
energy malnutrition. In the most severe form of this disor
-
der, most body fat stores disappear and muscle mass 
decreases, most noticeably in the temporalis and interosse
-
ous muscles. Laboratory studies may be unremarkable—
serum albumin, for example, may be normal or slightly 
decreased, rarely decreasing to less than 2.8 g/dL (28 g/L). 
In contrast, owing to its rapidity of onset, kwashiorkor-like 
secondary protein–energy malnutrition may develop in 
patients with normal subcutaneous fat and muscle mass or, 
if the patient is obese, even in patients with excess fat and 
muscle. The serum protein level, however, typically declines 
and the serum albumin is often less than 2.8 g/dL (28 g/L). 
Dependent edema, ascites, or anasarca may develop. As 
with primary protein–energy malnutrition, combinations 
of the marasmus-like and kwashiorkor-like syndromes can 
occur simultaneously, typically in patients with progressive 
chronic disease in whom a superimposed acute illness 
develops.

develops.
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»
Treatment
The treatment of severe protein–energy malnutrition is a 
slow process requiring great care. Initial efforts should be 
directed at correcting fluid and electrolyte abnormalities 
and infections. Of particular concern are depletion of 
potassium, magnesium, and calcium and acid–base abnor
-
malities. The second phase of treatment is directed at 
repletion of protein, energy, and micronutrients. Treat
-
ment is started with modest quantities of protein and calo
-
ries calculated based on the patient’s actual body weight. 
Adult patients are given 1 g/kg of protein and 30 kcal/kg of 
calories. Concomitant administration of vitamins and 
minerals is obligatory. Either the enteral or parenteral 
route can be used, although the former is preferable. 
Enteral fat and lactose are withheld initially. Patients with 
less severe protein–calorie undernutrition can be given 
calories and protein simultaneously with the correction of 
fluid and electrolyte abnormalities. Similar quantities of 
protein and calories are recommended for initial 
Patients treated for protein–energy malnutrition 
require close follow-up. In adults, both calories and protein 
are advanced as tolerated, adults to 1.5 g/kg/day of protein 
and 40 kcal/kg/day of calories.
Patients who are refed too rapidly may develop a num
-
ber of untoward clinical sequelae. During refeeding, circu
-
lating potassium, magnesium, phosphorus, and glucose 
move intracellularly and can result in low serum levels of 
each. The administration of water and sodium with carbo
-
hydrate refeeding can result in heart failure in persons with 
depressed cardiac function. Enteral refeeding can lead to 
malabsorption and diarrhea due to abnormalities in the 
Refeeding edema is a benign condition to be differenti
-
ated from heart failure. Changes in renal sodium reabsorp
-
tion and poor skin and blood vessel integrity result in the 
development of dependent edema without other signs of 
heart disease. Treatment includes reassurance, elevation of 
the dependent area, and modest sodium restriction. 
Diuretics are usually ineffective, may aggravate electrolyte 
deficiencies, and should not be used.
The prevention and early detection of protein–energy 
malnutrition in hospitalized patients require awareness of 
its risk factors and early symptoms and signs. Patients at 
risk require formal assessment of nutritional status and 
close observation of dietary intake, body weight, and nutri
-
tional requirements during the hospital stay.
Bell CL et al. Malnutrition in the nursing home. Curr Opin Clin 
Nutr Metab Care. 2015 Jan;18(1):17–23. [PMID: 25394167]
Chao A et al. Malnutrition and nutritional support in alcoholic 
liver disease: a review. Curr Gastroenterol Rep. 2016 Dec; 
18(12):65. [PMID: 27787787]
Guyonnet S et al. Screening for malnutrition in older people. 
Clin Geriatr Med. 2015 Aug;31(3):429–37. [PMID: 
26195101]
Marshall S. Why is the skeleton still in the hospital closet? A look 
at the complex aetiology of protein-energy malnutrition and 
its implications for the nutrition care team. J Nutr Health 
Aging. 2018;22(1):26–9. [PMID: 29300418]
Marshall S et al. A systematic review and meta-analysis of the 
criterion validity of nutrition assessment tools for diagnosing 
protein-energy malnutrition in the older community setting 
(the MACRo study). Clin Nutr. 2017 Oct 12. [Epub ahead of 
print] [PMID: 29102322]
McClave SA et al. Guidelines for the provision and assessment of 
nutrition support therapy in the adult critically ill patient: 
Society of Critical Care Medicine (SCCM) and American 
Society for Parenteral and Enteral Nutrition (A.S.P .E.N.). J 
Parenter Enteral Nutr. 2016 Feb;40(2):159–211. [PMID: 
26773077]
Pereira GF et al. Malnutrition among cognitively intact, non
-
critically ill older adults in the emergency department. Ann 
Emerg Med. 2015 Jan;65(1):85–91. [PMID: 25129819]

26773077]
-
Zha Y et al. Protein nutrition and malnutrition in CKD and 
ESRD. Nutrients. 2017 Feb 27;9(3):208. [PMID: 28264439]
OBESITY
 
»
Excess adipose tissue; body mass index (BMI) 
greater than 30.
 
»
Upper body obesity (abdomen and flank) of 
greater health consequence than lower body obe
-
sity (buttocks and thighs).
 
»
Associated with health consequences, including 
diabetes mellitus, hypertension, and hyperlipidemia.
 
»
Obesity is one of the most common disorders in medical 
practice and among the most frustrating and difficult to 
manage. Relatively little progress has been made in preven
-
tion or treatment, yet major changes have occurred in our 
understanding of its causes and its implications for health.
 
»
Definition & Measurement
Obesity is defined as an excess of adipose tissue. Physical 
examination is usually sufficient to detect excess body fat. 
More quantitative evaluation is performed by calculating 
the BMI.
The 
BMI
 closely correlates with excess adipose tissue. It 
is calculated by dividing measured body weight in kilo
-
grams by the height in meters squared.
The National Institutes of Health (NIH) defines a nor
-
mal BMI as 18.5–24.9. Overweight is defined as BMI = 
25–29.9. Class I obesity is 30–34.9, class II obesity is 
35–39.9, and class III (extreme) obesity is BMI greater than 
40. Factors other than total weight, however, are also 
important. Upper body obesity (excess fat around the waist 
and flank) is a greater health hazard than lower body obe
-
sity (fat in the thighs and buttocks). Obese patients with 
increased abdominal circumference (greater than 102 cm 
in men and 88 cm in women) or with high waist–hip ratios 
(greater than 1.0 in men and 0.85 in women) have a greater 
risk of diabetes mellitus, stroke, coronary artery disease, 
and early death than equally obese patients with lower 
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ratios. Furthermore, visceral fat within the abdominal cav
-
ity is more hazardous to health than subcutaneous fat 
around the abdomen.
US survey data demonstrate that 37.7% of Americans 
are obese. Women in the United States are more apt to be 
obese than men, and African American and Mexican 
American women are more obese than whites. The poor 
are more obese than the rich regardless of race. Approxi
-
mately 60% of individuals with obesity in the United States 
have the metabolic syndrome (including three or more of 
the following factors: elevated abdominal circumference, 
blood pressure, blood triglycerides, and fasting blood 
sugar, and low high-density lipoprotein [HDL] 
cholesterol).
 
»
Etiology
Obesity has been considered to be the direct result of a 
sedentary lifestyle plus chronic ingestion of excess calories. 
Y et, as much as 40–70% of obesity may be explained by 
genetic influences. Twin studies demonstrate substantial 
genetic influences on BMI with little influence from the 
childhood environment.
Five genes affecting control of appetite have been iden
-
tified in mice. Mutations of each gene result in obesity, and 
each has a human homolog. One gene codes for a protein 
expressed by adipose tissue—leptin—and another for the 
leptin receptor in the brain. The other three genes affect 
brain pathways downstream from the leptin receptor. 
Numerous other candidate genes for human obesity have 
been identified. Only a small percentage of human obesity 
is thought to be due to single gene mutations. Most human 
obesity undoubtedly develops from the interactions of 
multiple genes, environmental factors, and behavior. The 
rapid increase in obesity in the last several decades clearly 
points to major roles for environmental and behavioral fac
-
tors in its development.
 
»
Medical Evaluation of the Obese Patient
Historical information should be obtained about age at 
onset, recent weight changes, family history of obesity, 
occupational history, eating and exercise behavior, cigarette 
and alcohol use, previous weight loss experience, and psy
-
chosocial factors including assessment for depression and 
eating disorders. Particular attention should be directed at 
use of laxatives, diuretics, hormones, nutritional supple
-
ments, and over-the-counter medications.
Physical examination should assess the BMI, degree 
and distribution of body fat, overall nutritional status, and 
signs of secondary causes of obesity.
Less than 1% of obese patients have an identifiable sec
-
ondary, nonpsychiatric, cause of obesity. Hypothyroidism 
and Cushing syndrome are important examples that can 
usually be diagnosed by physical examination in patients 
with unexplained recent weight gain. Such patients require 
further endocrinological evaluation, including serum thy
-
roid-stimulating hormone (TSH) determination and dexa
-
methasone suppression testing (see Chapter 26).
All obese patients should be assessed for medical con
-
sequences of their obesity by screening for the metabolic 
syndrome. Blood pressure, waist circumference, fasting 
glucose, low-density lipoprotein (LDL) and HDL choles
-
terol, and triglycerides should be measured.
 
»
Treatment
Using conventional dietary techniques, only 20% of 
patients will lose 20 lb and maintain the loss for over 
 
2 years; only 5% maintain a 40-lb loss. Average weight loss 
is approximately 7% of baseline weight. Continued close 
provider–patient contact appears to be more important for 
success of treatment than the specific features of any given 
treatment regimen. Careful patient selection improves suc
-
cess rates and decreases frustration of both patients and 
therapists. Only sufficiently motivated patients should 
enter active treatment programs. Specific attempts to iden
-
tify motivated patients—eg, requesting a 3-day diet 
record—are often useful.
Most successful programs employ a multidisciplinary

-
Most successful programs employ a multidisciplinary 
approach to weight loss, with hypocaloric diets, behavior 
modification to change eating behavior, aerobic exercise, 
and social support. Emphasis must be on 
maintenance
 of 
Dietary instructions
 for most patients incorporate the 
same principles that apply to healthy people who are not 
obese. These instructions emphasize intake of a wide vari
-
ety of predominantly “unprocessed” foods, with special 
attention to limiting foods that provide large amounts of 
calories without other nutrients, ie, fat, added sugars, and 
alcohol. There is no physiologic advantage to diets that 
restrict carbohydrates, advocate relatively larger amounts 
of protein or fats, or recommend ingestion of foods one at 
a time. Diets that are restricted in carbohydrates (such as 
the Atkins and South Beach diets), however, can be effec
-
tive in achieving a lower total calorie intake. Several studies 
have demonstrated that low-carbohydrate diets can be used 
safely and effectively for weight loss without adverse effects 
on lipids or other metabolic parameters. Meal replacement 
diets can also be used effectively and safely to achieve 
Long-term changes in eating behavior are required to 
maintain weight loss. Although formal 
behavior modifica
-
tion
 programs are available to which patients can be 
referred, the clinician caring for obese patients can teach a 
number of useful behavioral techniques. The most impor
-
tant technique is to emphasize planning and record keep
-
ing. Patients can be taught to plan menus and exercise 
sessions and to record their actual behavior. Record keep
-
ing not only aids in behavioral change, but also helps the 
provider make specific suggestions for problem solving. 
Patients can be taught to recognize “eating cues” (emo
-
tional, situational, etc) and how to avoid or control them. 
Regular self-monitoring of weight is also associated with 
improved long-term weight maintenance.
Exercise
 offers a number of advantages to patients try
-
ing to lose weight and keep it off. Aerobic exercise directly 
increases the daily energy expenditure and is particularly 
useful for long-term weight maintenance. Exercise will 
 
also preserve lean body mass and partially prevent the 
decrease in basal energy expenditure (BEE) seen with 
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semistarvation. Compared to no treatment, exercise alone 
results in small amounts of weight loss. Exercise plus diet 
results in slightly greater weight loss than diet alone. A 
greater intensity of exercise is associated with a greater 
amount of weight loss. Up to 1 hour of moderate exercise 
per day is associated with long-term weight maintenance in 
individuals who have successfully lost weight. 
Social 
support
 is essential for a successful weight loss program. 
Continued close contact with clinicians and involvement of 
the family and peer group are useful techniques for rein
-
forcing behavioral change and preventing social isolation.
Patients with severe obesity may require more aggres
-
sive treatment regimens. 
Very-low-calorie diets
 (typically 
800–1000 kcal/day) result in rapid weight loss and marked 
initial improvement in obesity-related metabolic complica
-
tions. Patients are commonly maintained on such pro
-
grams for 4–6 months. Patients who adhere to the program 
lose an average of 2 lb per week. Average maximum weight 
loss is approximately 15% of initial weight. Most programs 
use meal replacement diets to achieve the very-low-calorie 
intake. Long-term weight maintenance following meal 
replacement programs is less predictable and requires con
-
current behavior modification, long-term use of low-
calorie diets, careful self-monitoring, and regular exercise. 
Side effects such as fatigue, orthostatic hypotension, cold 
intolerance, and fluid and electrolyte disorders are observed 
in proportion to the degree of calorie reduction and require 
regular supervision by a clinician. Other less common 
complications include gout, gallbladder disease, and car
-
diac arrhythmias. Although weight loss is more rapidly 
achieved with very-low-calorie diets as compared with 
traditional diets, long-term outcomes are equivalent.
 for the treatment of obesity are available 
both over the counter and by prescription. Considerable 
controversy exists as to the appropriate use of medications 
for obesity. NIH clinical obesity guidelines state that obe
-
sity drugs may be used as part of a comprehensive weight 
loss program for patients with BMI greater than 30 or those 
with BMI greater than 27 with obesity-related risk factors. 
However, few data suggest that medications can improve 
long-term outcomes associated with obesity.
Several medications are approved by the US Food and 
Drug Administration (FDA) for treatment of obesity. Cat
-
echolaminergic medications (eg, phentermine, diethylpro
-
pion, benzphetamine, and phendimetrazine) are approved 
for short-term use only and have limited utility. 
Orlistat
 
(120 mg orally up to three times daily with each fat-
containing meal) is available by prescription for longer-
term treatment of obesity. A nonprescription lower-dose 
formulation (60 mg) is available. Rather than in the central 
nervous system, orlistat works in the gastrointestinal tract 
to inhibit intestinal lipase, reducing fat absorption. Not 
unexpectedly, it may cause diarrhea, gas, and cramping and 
perhaps reduced absorption of fat-soluble vitamins. In 
randomized trials with up to 2 years of follow-up, orlistat 
resulted in 2–4 kg greater weight loss than placebo. A ben
-
eficial impact on long-term obesity-related clinical out
-
comes has not been established.
Four additional medications are approved for use in the 
Lorcaserin
, a selective serotonin receptor 
agonist given in a dose of 10 mg orally twice daily, is associ
-
ated with modest weight loss, about 3% of initial weight 
more than placebo. Approximately twice as many patients 
(38% vs 16%) lose more than 5% of initial weight on lorca
-
serin compared to placebo. Post-marketing surveillance is 
focused on concerns about increased breast tumors in 
animal studies, valvular heart disease in patients receiving 
earlier drugs of this class, and psychiatric side effects.

The combination of 
phentermine hydrochloride
 and 
topiramate
 (3.75 mg/23 mg orally daily for 14 days, then 
7.5 mg/46 mg orally daily, to a maximum dosage of 15 mg/
 
92 mg orally daily) results in dose-dependent weight loss. 
In clinical trials, patients receiving the lowest dose lost 
7.8% more weight than those receiving placebo; with the 
higher dose, 9.8% more weight was lost. Common side 
effects include mood changes, fatigue, and insomnia. Since 
the medications increase heart rate, a large clinical trial to 
assess cardiovascular risk is being conducted. The combi
-
nation is also associated with increased birth defects and 
should not be used during pregnancy. Its distribution is 
restricted in the United States (telephone 1-888-998-4887 
or visit www.QsymiaREMS.com).
naltrexone
 and 
bupropion hydro
-
chloride
 (8 mg ER/90 mg ER, increasing from 1 tablet 
orally daily by 1 additional daily tablet each week to a 
maximum of 2 tablets twice daily) is also approved by the 
FDA for weight loss. Clinical trials demonstrated a 2–4% 
weight loss compared to placebo after 1 year. Concerns 
include an increased risk of suicidal thoughts and behav
-
iors, other neuropsychiatric events, seizures, and elevation 
of blood pressure and heart rate. Other side effects include 
nausea and vomiting, diarrhea and constipation, headache, 
and dry mouth. A cardiovascular outcome trial to further 
assess safety is in progress.
Liraglutide (Saxenda)
, an injectable incretin (a 
glucagon-like peptide-1 receptor agonist), is FDA approved 
for obesity treatment in a dose of 0.6 mg subcutaneously 
daily, increasing by 0.6 mg daily each week to a maximum 
of 3 mg subcutaneously daily. Clinical trials demonstrated 
a 3.7–4.5% weight loss compared to placebo at 1 year. 
Concerns include thyroid tumors in animal studies, pan
-
creatitis, gallbladder disease, renal impairment, increased 
heart rate, and suicidal thoughts. Common side effects 
include nausea and vomiting, diarrhea and constipation, 
and hypoglycemia. A cardiovascular outcomes trial is 
being conducted.
 is an increasingly prevalent treatment 
option for patients with severe obesity. In the United States, 
gastric operations are considered the procedures of choice. 
Most popular is the Roux-en-Y gastric bypass (RYGB). In 
most centers, the operation can be done laparoscopically. 
RYGB typically results in substantial amounts of weight 
loss—over 30% of initial body weight in some studies. 
Complications occur in up to 40% of persons undergoing 
RYGB surgery and include peritonitis due to anastomotic 
leak; abdominal wall hernias; staple line disruption; gall
-
stones; neuropathy; marginal ulcers; stomal stenosis; 
wound infections; thromboembolic disease; gastrointesti
-
nal symptoms; and nutritional deficiencies, including iron, 
vitamin B
12
, folate, calcium, and vitamin D. Operative 
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mortality rates within 30 days are nil to 1% in low-risk 
populations but have been reported to be substantially 
higher in Medicare beneficiaries. One-year mortality rates 
have been reported as high as 7.5% in men with Medicare. 
Surgical volume (number of cases performed by the sur
-
geon or hospital) has been demonstrated to be an impor
-
tant predictor of outcome.
Another operation is gastric banding. Gastric banding 
results in less dramatic weight loss than RYGB and has 
fewer short-term complications. Frequent follow-up, how
-
ever, is required to adjust the gastric band. Longer-term 
follow-up has shown a 39% rate of major complications 
and a 60% rate of re-operation.
A third operation, sleeve gastrectomy, is gaining in 
popularity. With this procedure, approximately three-
quarters of the stomach is resected, but the gastrointestinal 
tract is otherwise left intact. Weight loss results are some
-
what less than RYGB but greater than gastric banding.
NIH consensus panel recommendations are to limit 
obesity surgery to patients with BMIs over 40, or over 35 if 
obesity-related comorbidities are present. The procedure is 
cost-effective for patients with severe obesity and most 
third-party payers cover the procedure in selected patients. 
A large Swedish study suggested that bariatric surgery is 
associated with a significant reduction in deaths at 11-year 
follow-up. The number needed to treat to prevent one 
death in 11 years was 77 operations. A US Veterans 
Administration study, however, did not show a mortality 
benefit.
 
»
Patients with BMI over 40 (or over 35 with obesity-related 
morbidities) who are interested in considering weight loss 
surgery.
Dietz WH. Obesity and excessive weight gain in young adults: 
new targets for prevention. JAMA. 2017 Jul 18;318(3):241–2. 
[PMID: 28719674]
Igel LI et al. Practical use of pharmacotherapy for obesity. Gas
-
troenterology. 2017 May;152(7):1765–79. [PMID: 28192104]
Ikramuddin S et al. Lifestyle intervention and medical manage
-
ment with vs without Roux-en-Y gastric bypass and control of 
hemoglobin A1c, LDL cholesterol, and systolic blood pressure 
at 5 years in the Diabetes Surgery Study. JAMA. 2018 Jan 16; 
319(3):266–78. [PMID: 29340678]
Jakobsen GS et al. Association of bariatric surgery vs medical 
obesity treatment with long-term medical complications and 
obesity-related comorbidities. JAMA. 2018 Jan 16;319(3): 
291–301. [PMID: 29340680]
Jin J. JAMA patient page. Medications for weight loss: indica
-
tions and usage. JAMA. 2015 Jun 2;313(21):2196. [PMID: 
26034970]
Lean ME et al. Primary care-led weight management for remis
-
sion of type 2 diabetes (DiRECT): an open-label, cluster-
randomised trial. Lancet. 2018 Feb 10;391(10120):541–51. 
[PMID: 29221645]
Ma C et al. Effects of weight loss interventions for adults who are 
obese on mortality, cardiovascular disease, and cancer: sys
-
tematic review and meta-analysis. BMJ. 2017 Nov 14; 
359:j4849. [PMID: 29138133]
Puzziferri N et al. JAMA patient page. Sleeve gastrectomy for 
weight loss. JAMA. 2018 Jan 16;319(3):316. [PMID: 29340681]
Reges O et al. Association of bariatric surgery using laparoscopic 
banding, Roux-en-Y gastric bypass, or laparoscopic sleeve 
gastrectomy vs usual care obesity management with all-cause 
mortality. JAMA. 2018 Jan 16;319(3):279–90. [PMID: 
29340677]
Thom G et al. Is there an optimal diet for weight management 
and metabolic health? Gastroenterology. 2017 May; 
152(7):1739–51. [PMID: 28214525]
Vidal J et al. Metabolic and bariatric surgery for obesity. Gastro
-
enterology. 2017 May;152(7):1780–90. [PMID: 28193516]
Webb VL et al. Intensive lifestyle intervention for obesity: prin
-
ciples,  practices,  and results. Gastroenterology. 2017 May; 
152(7):1752–64. [PMID: 28192109]
Zheng Y et al. Associations of weight gain from early to middle 
adulthood with major health outcomes later in life. JAMA.

adulthood with major health outcomes later in life. JAMA. 
2017 Jul 18;318(3):255–69. [PMID: 28719691]
 
º
EATING DISORDERS
ANOREXIA NERVOSA
 
»
Disturbance of body image and intense fear of 
becoming fat.
 
»
Weight loss leading to body weight 15% below 
expected.
 
»
In females, absence of three consecutive men
-
strual cycles.
 
»
Anorexia nervosa typically begins in the years between 
adolescence and young adulthood. Ninety percent of 
patients are females, most from the middle and upper 
socioeconomic strata.
The prevalence of anorexia nervosa is greater than pre
-
viously suggested. In Rochester, Minnesota, for example, 
the prevalence per 100,000 population is estimated to be 
270 for females and 22 for males. Many other adolescent 
girls have features of the disorder without the severe weight 
loss.
The cause of anorexia nervosa is not known. Although 
multiple endocrinological abnormalities exist in these 
patients, most authorities believe they are secondary to mal
-
nutrition and not primary disorders. Most experts favor a 
primary psychiatric origin, but no hypothesis explains all 
cases. The patient characteristically comes from a family 
whose members are highly goal and achievement oriented. 
Interpersonal relationships may be inadequate or destruc
-
tive. The parents are usually overly directive and concerned 
with slimness and physical fitness, and much of the family 
conversation centers around dietary matters. One theory 
holds that the patient’s refusal to eat is an attempt to regain 
control of her body in defiance of parental control. The 
patient’s unwillingness to inhabit an “adult body” may also 
represent a rejection of adult responsibilities and the 
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implications of adult interpersonal relationships. Patients are 
commonly perfectionistic in behavior and exhibit obses
-
sional personality characteristics. Marked depression or 
anxiety may be present.
 
»
Patients with anorexia nervosa may exhibit severe emacia
-
tion and may complain of cold intolerance or constipation. 
Amenorrhea is almost always present. Bradycardia, hypo
-
tension, and hypothermia may be present in severe cases. 
Examination demonstrates loss of body fat, dry and scaly 
skin, and increased lanugo body hair. Parotid enlargement 
and edema may also occur.
Laboratory findings are variable but may include anemia, 
leukopenia, electrolyte abnormalities, and elevations of 
blood urea nitrogen (BUN) and serum creatinine. Serum 
cholesterol levels are often increased. Endocrine abnor
-
malities include depressed levels of luteinizing and 
follicle-stimulating hormones and impaired response of 
luteinizing hormone to luteinizing hormone-releasing 
hormone.
 
»
Diagnosis & Differential Diagnosis
The diagnosis is based on weight loss to a body weight 15% 
below expected, distorted body image, fear of weight gain 
or of loss of control over food intake and, in females, 
absence of at least three consecutive menstrual cycles. 
Other medical or psychiatric illnesses that can account for 
anorexia and weight loss must be excluded.
Behavioral features required for the diagnosis include 
intense fear of becoming obese, disturbance of body image, 
and refusal to exceed a minimal normal weight.
The differential diagnosis includes endocrine and met
-
abolic disorders (eg, panhypopituitarism, Addison disease, 
hyperthyroidism, and diabetes mellitus); gastrointestinal 
disorders (eg, Crohn disease and gluten enteropathy); 
chronic infections (eg, tuberculosis); cancers, (eg, lym
-
phoma); and rare central nervous system disorders (eg, 
hypothalamic tumor).
 
»
Treatment
The goal of treatment is restoration of normal body weight 
and resolution of psychological difficulties. Hospitalization 
may be necessary. Treatment programs conducted by expe
-
rienced teams are successful in about two-thirds of cases, 
restoring normal weight and menstruation. One-half con
-
tinue to experience difficulties with eating behavior and 
psychiatric problems. Two to 6% of patients die of the 
complications of the disorder or commit suicide.
Various treatment methods have been used without 
clear evidence of superiority of one over another. Support
-
ive care by clinicians and family is probably the most 
important feature of therapy. Cognitive-behavioral therapy, 
intensive psychotherapy, and family therapy may be tried. 
A variety of medications including tricyclic antidepres
-
sants, selected serotonin reuptake inhibitors (SSRIs), and 
lithium carbonate are effective in some cases; overall, how
-
ever, clinical trial results have been disappointing. Patients 
with severe malnutrition must be hemodynamically stabi
-
lized and may require enteral or parenteral feeding. Forced 
feedings should be reserved for life-threatening situations, 
since the goal of treatment is to reestablish normal eating 
behavior.
 
»
•	
Adolescents and young adults with otherwise unex
-
plained weight loss should be evaluated by a 
•	
All patients with diagnosed anorexia nervosa should be 
co-managed with a psychiatrist.
 
»
•	
Signs of hypovolemia, major electrolyte disorders, and 
severe protein–energy malnutrition.
•	
Dalle Grave R et al. Cognitive behavioral therapy for anorexia 
nervosa: an update. Curr Psychiatry Rep. 2016 Jan;18(1):2. 
[PMID: 26689208]
Hay PJ et al. Individual psychological therapy in the outpa
-
tient treatment of adults with anorexia nervosa. Cochrane 
Database Syst Rev. 2015 Jul 27;(7):CD003909. [PMID: 
26212713]

-
26212713]
Hirst RB et al. Anorexia nervosa and bulimia nervosa: a meta-
analysis of executive functioning. Neurosci Biobehav Rev. 
2017 Dec;83:678–90. [PMID: 28851577]
Khalsa SS et al. What happens after treatment? A systematic 
review of relapse, remission, and recovery in anorexia ner
-
vosa. J Eat Disord. 2017 Jun 14;5:20. [PMID: 28630708]
Mascolo M et al. Gastrointestinal comorbidities which compli
-
cate the treatment of anorexia nervosa. Eat Disord. 2017 
Mar–Apr;25(2):122–33. [PMID: 27869566]
McElroy SL et al. Psychopharmacologic treatment of eating dis
-
orders: emerging findings. Curr Psychiatry Rep. 2015 May; 
17(5):35. [PMID: 25796197]
Treasure J. Applying evidence-based management to anorexia 
nervosa. Postgrad Med J. 2016 Sep;92(1091):525–31. [PMID: 
26944338]
Westmoreland P et al. Medical complications of anorexia ner
-
vosa and bulimia. Am J Med. 2016 Jan;129(1):30–7. [PMID: 
26169883]
BULIMIA NERVOSA
 
»
Uncontrolled episodes of binge eating at least 
twice weekly for 3 months.
 
»
Recurrent inappropriate compensation to prevent 
weight gain such as self-induced vomiting, laxa
-
tives, diuretics, fasting, or excessive exercise.
 
»
Overconcern with weight and body shape.
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»
Bulimia nervosa is the episodic uncontrolled ingestion of 
large quantities of food followed by recurrent inappropriate 
compensatory behavior to prevent weight gain such as self-
induced vomiting, diuretic or cathartic use, or strict dieting 
or vigorous exercise.
Like anorexia nervosa, bulimia nervosa is predomi
-
nantly a disorder of young, white, middle- and upper-class 
women. It is more difficult to detect than anorexia, and 
some studies have estimated that the prevalence may be as 
high as 19% in college-aged women.
 
»
Patients with bulimia nervosa typically consume large 
quantities of easily ingested high-calorie foods, usually in 
secrecy. Some patients may have several such episodes a 
day for a few days; others report regular and persistent pat
-
terns of binge eating. Binging is usually followed by vomit
-
ing, cathartics, or diuretics and accompanied by feelings of 
guilt or depression. Periods of binging may be followed by 
intervals of self-imposed starvation. Body weights may 
fluctuate but generally are within 20% of desirable weights.
Some patients with bulimia nervosa also have a cryptic 
form of anorexia nervosa with significant weight loss and 
amenorrhea. Family and psychological issues are generally 
similar to those of patients with anorexia nervosa. Bulimic 
patients, however, have a higher incidence of premorbid obe
-
sity, greater use of cathartics and diuretics, and more impul
-
sive or antisocial behavior. Menstruation is usually preserved.
Medical complications are numerous. Gastric dilatation 
and pancreatitis have been reported after binges. Vomiting 
can result in poor dentition, pharyngitis, esophagitis, aspi
-
ration, and electrolyte abnormalities. Cathartic and diuretic 
abuse also cause electrolyte abnormalities or dehydration. 
Constipation and hemorrhoids are common.
 
»
Treatment
Treatment of bulimia nervosa requires supportive care and 
psychotherapy. Individual, group, family, and behavioral 
therapy have all been utilized. Antidepressant medications 
may be helpful. The best results have been with fluoxetine 
hydrochloride and other SSRIs. Although death from buli
-
mia is rare, the long-term psychiatric prognosis in severe 
bulimia is worse than that in anorexia nervosa.
 
»
All patients with diagnosed bulimia should be co-managed 
with a psychiatrist.
Linardon J et al. Psychotherapy for bulimia nervosa on symp
-
toms of depression: a meta-analysis of randomized controlled 
trials. Int J Eat Disord. 2017 Oct;50(10):1124–36. [PMID: 
28804915]
Palavras MA et al. The efficacy of psychological therapies in 
reducing weight and binge eating in people with bulimia 
nervosa and binge eating disorder who are overweight or 
obese—a critical synthesis and meta-analyses. Nutrients. 2017 
Mar 17;9(3):299. [PMID: 28304341]
Waller G et al. Cognitive-behavioral therapy for bulimia nervosa 
and atypical bulimic nervosa: effectiveness in clinical settings. 
Int J Eat Disord. 2014 Jan;47(1):13–7. [PMID: 23996224]
-
26169883]
 
º
DISORDERS OF VITAMIN METABOLISM
THIAMINE (B
1
) DEFICIENCY
 
»
Most common in patients with chronic 
 
»
Early symptoms of anorexia, muscle cramps, par
-
esthesias, irritability.
 
»
Advanced syndromes of high-output heart failure 
(“wet beriberi”), peripheral nerve disorders, and 
Wernicke-Korsakoff syndrome (“dry beriberi”).
 
»
Most thiamine deficiency in the United States is due to 
chronic alcoholism, with poor dietary intake of thiamine 
and impaired thiamine absorption, metabolism, and stor
-
age. Thiamine deficiency is also associated with malab
-
sorption, dialysis, and other causes of chronic 
protein–calorie undernutrition. Thiamine deficiency can

-
-
protein–calorie undernutrition. Thiamine deficiency can 
be precipitated in patients with marginal thiamine status 
with intravenous dextrose solutions.
 
»
Early manifestations of thiamine deficiency include 
anorexia, muscle cramps, paresthesias, and irritability. 
Advanced deficiency primarily affects the cardiovascular 
system (“wet beriberi”) or the nervous system (“dry 
beriberi”). Wet beriberi occurs in thiamine deficiency 
accompanied by severe physical exertion and high carbo
-
hydrate intake. Dry beriberi occurs in thiamine deficiency 
accompanied by inactivity and low-calorie intake.
Wet beriberi
 is characterized by marked peripheral 
vasodilation resulting in high-output heart failure with 
dyspnea, tachycardia, cardiomegaly, and pulmonary and 
peripheral edema, with warm extremities mimicking 
Dry beriberi
 involves both the peripheral and the cen
-
tral nervous systems. Peripheral nerve involvement is typi
-
cally a symmetric motor and sensory neuropathy with 
pain, paresthesias, and loss of reflexes. The legs are affected 
more than the arms. Central nervous system involvement 
results in Wernicke-Korsakoff syndrome. Wernicke 
encephalopathy consists of nystagmus progressing to oph
-
thalmoplegia, truncal ataxia, and confusion. Korsakoff 
syndrome includes amnesia, confabulation, and impaired 
learning.
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»
Diagnosis
In most instances, the clinical response to empiric thia
-
mine therapy is used to support a diagnosis of thiamine 
deficiency. The most commonly used biochemical tests 
measure erythrocyte transketolase activity and urinary 
thiamine excretion. A transketolase activity coefficient 
greater than 15–20% suggests thiamine deficiency.
 
»
Treatment
Thiamine deficiency is treated with large parenteral doses of 
thiamine. Fifty to 100 mg/day is administered intravenously 
for the first few days, followed by daily oral doses of 5–10 
mg/day. All patients should simultaneously receive thera
-
peutic doses of other water-soluble vitamins. Although 
treatment results in complete resolution in half of patients 
(one-fourth immediately and another one-fourth over days), 
the other half obtain only partial resolution or no benefit.
 
»
Patients with signs of beriberi or Wernicke-Korsakoff syn
-
drome should be referred to a neurologist.
THIAMINE TOXICITY
There is no known toxicity of thiamine.
Katta N et al. Does long-term furosemide therapy cause thiamine 
deficiency in patients with heart failure? A focused review. 
Am J Med. 2016 Jul;129(7):753.e7–11. [PMID: 26899752]
Kröll D et al. Wernicke encephalopathy: a future problem even 
after sleeve gastrectomy? A systematic literature review. Obes 
Surg. 2016 Jan;26(1):205–12. [PMID: 26476834]
Isenberg-Grzeda E et al. Wernicke-Korsakoff syndrome in 
patients with cancer: a systematic review. Lancet Oncol. 
 
2016 Apr;17(4):e142–8. [PMID: 27300674]
Scalzo SJ et al. Wernicke-Korsakoff syndrome not related to 
alcohol use: a systematic review. J Neurol Neurosurg 
Psychiatry. 2015 Dec;86(12):1362–8. [PMID: 25589780]
RIBOFLAVIN (B
2
 
»
Riboflavin deficiency almost always occurs in combination 
with deficiencies of other vitamins. Dietary inadequacy, 
interactions with a variety of medications, alcoholism, and 
other causes of protein–calorie undernutrition are the 
most common causes of riboflavin deficiency.
Manifestations of riboflavin deficiency include cheilo
-
sis, angular stomatitis, glossitis, seborrheic dermatitis, 
weakness, corneal vascularization, and anemia.
 
»
Diagnosis
Riboflavin deficiency can be confirmed by measuring the 
riboflavin-dependent enzyme erythrocyte glutathione 
reductase. Activity coefficients greater than 1.2–1.3 are 
suggestive of riboflavin deficiency. Urinary riboflavin 
excretion and serum levels of plasma and red cell flavins 
can also be measured.
 
»
Treatment
Riboflavin deficiency is usually treated empirically when 
the diagnosis is suspected. It is easily treated with foods 
such as meat, fish, and dairy products or with oral prepara
-
tions of the vitamin. Administration of 5–15 mg/day until 
clinical findings are resolved is usually adequate. Ribofla
-
vin can also be given parenterally, but it is poorly soluble in 
aqueous solutions.
RIBOFLAVIN TOXICITY
There is no known toxicity of riboflavin.
Manole A et al. Clinical, pathological and functional character
-
ization of riboflavin-responsive neuropathy. Brain. 2017 Nov 1; 
140(11):2820–37. [PMID: 29053833]
NIACIN DEFICIENCY
 
»
“Niacin” is a generic term for nicotinic acid and other 
derivatives with similar nutritional activity. Unlike most 
other vitamins, niacin can be synthesized from the amino 
acid tryptophan. Niacin is an essential component of the 
co-enzymes nicotinamide adenine dinucleotide (NAD) 
and nicotinamide adenine dinucleotide phosphate 
(NADP), which are involved in many oxidation-reduction 
reactions. The major food sources of niacin are protein 
foods containing tryptophan and numerous cereals, vege
-
tables, and dairy products.
Historically, niacin deficiency occurred when corn, 
which is relatively deficient in both tryptophan and niacin, 
was the major source of calories. Currently, niacin defi
-
ciency is more commonly due to alcoholism and nutrient–

-
drug interactions. Niacin deficiency can also occur in 
inborn errors of metabolism. Niacin in the form of nico
-
tinic acid is used therapeutically for the treatment of hyper
-
cholesterolemia and hypertriglyceridemia. Niacinamide 
(the form of niacin usually used to treat niacin deficiency) 
does not exhibit the lipid-lowering effects of nicotinic acid.
 
»
As with other B vitamins, early manifestations of niacin 
deficiency are nonspecific—anorexia, weakness, irritability, 
mouth soreness, glossitis, stomatitis, and weight loss. More 
advanced deficiency results in the classic triad of pellagra: 
dermatitis, diarrhea, and dementia. The dermatitis is sym
-
metric, involving sun-exposed areas. Skin lesions are dark, 
dry, and scaling. The dementia begins with insomnia, irri
-
tability, and apathy and progresses to confusion, memory 
loss, hallucinations, and psychosis. The diarrhea can be 
severe and may result in malabsorption due to atrophy of 
the intestinal villi. Advanced pellagra can result in death.
 
»
Diagnosis
In early deficiency, diagnosis requires a high index of sus
-
picion and attempts at confirmation of niacin deficiency. 
Niacin metabolites, particularly 
N
-methylnicotinamide, 
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can be measured in the urine. Low levels suggest niacin 
deficiency but may also be found in patients with general
-
ized under-nutrition. Serum and red cell levels of NAD and 
NADP are also low but are similarly nonspecific. In 
advanced cases, the diagnosis of pellagra can be made on 
clinical grounds.
 
»
Treatment
Niacin deficiency can be effectively treated with oral nia
-
cin, usually given as nicotinamide (10–150 mg/day).
NIACIN TOXICITY
At the high doses of niacin used to treat hyperlipidemia, 
side effects are common. These include cutaneous flushing 
(partially prevented by pretreatment with aspirin, 81–325 
mg/day, and use of extended-release preparations) and 
gastric irritation. Elevation of liver enzymes, hyperglyce
-
mia, and gout are less common untoward effects.
Goldie C et al. Niacin therapy and the risk of new-onset diabetes: 
a meta-analysis of randomised controlled trials. Heart. 
 
2016 Feb;102(3):198–203. [PMID: 26370223]
López M et al. Pellagra encephalopathy in the context of alcohol
-
ism: review and case report. Alcohol Alcohol. 2014 Jan–Feb; 
49(1):38–41. [PMID: 23926211]
Streja E et al. Niacin and progression of CKD. Am J Kidney Dis. 
2015 May;65(5):785–98. [PMID: 25708553]
VITAMIN B
6
Vitamin B
6
 deficiency most commonly occurs as a result of 
interactions with medications—especially isoniazid, cyclo
-
serine, penicillamine, and oral contraceptives—or of alco
-
holism. A number of inborn errors of metabolism and 
other pyridoxine-responsive syndromes, particularly pyri
-
doxine-responsive anemia, are not clearly due to vitamin 
deficiency but commonly respond to high doses of the 
vitamin. Patients with common variable immunodefi
-
ciency may have concomitant vitamin B
6
 
»
Vitamin B
6
 deficiency results in clinical symptoms similar 
to those of other B vitamin deficiencies, including mouth 
soreness, glossitis, cheilosis, weakness, and irritability. 
Severe deficiency can result in peripheral neuropathy, ane
-
mia, and seizures. Studies have suggested a potential rela
-
tionship of low vitamin B
6
 levels and a variety of clinical 
conditions including cardiovascular diseases, inflamma
-
tory diseases, and certain cancers.
 
»
Diagnosis
6
 deficiency can be confirmed 
by measurement of pyridoxal phosphate in blood. Normal 
levels are greater than 50 ng/mL.
 
»
Treatment
Vitamin B
6
 deficiency can be effectively treated with vita
-
min B
6
 supplements (10–20 mg/day orally). Some patients 
taking medications that interfere with pyridoxine metabo
-
lism (such as isoniazid) may need doses as high as 50–100 
mg/day orally to prevent vitamin B
6
 deficiency. This is 
particularly true for patients who are more likely to have 
diets marginally adequate in vitamin B
6
, such as older 
patients, alcoholic patients, or the urban poor. Inborn 
errors of metabolism and pyridoxine-responsive syn
-
dromes often require doses up to 600 mg/day orally.
VITAMIN B
6
 TOXICITY
A sensory neuropathy, at times irreversible, occurs in patients 
receiving large doses of vitamin B
6
 (200–2000 mg/day).
Ghavanini AA et al. Revisiting the evidence for neuropathy 
caused by pyridoxine deficiency and excess. J Clin Neuro
-
muscul Dis. 2014 Sep;16(1):25–31. [PMID: 25137514]
Kulkantrakorn K. Pyridoxine-induced sensory ataxic neuronop
-
athy and neuropathy: revisited. Neurol Sci. 2014 Nov; 
35(11):1827–30. [PMID: 25056196]
Van Arsdale S et al. Pyridoxine  deficiency after solid organ 
transplant. Prog Transplant. 2017 Sep;27(3):251–6. [PMID: 
29187089]
VITAMIN B
12
 & FOLATE
Vitamin B
12
 (cobalamin) and folate are discussed in 
Chapter 13.
VITAMIN C (
Ascorbic Acid
Most cases of vitamin C deficiency seen in the United 
States are due to dietary inadequacy in the urban poor, 
older patients, and patients with chronic alcoholism. 
Patients with chronic illnesses such as cancer and chronic

Patients with chronic illnesses such as cancer and chronic 
kidney disease and individuals who smoke cigarettes are 
also at risk.
 
»
Early manifestations of vitamin C deficiency are nonspe
-
cific and include malaise and weakness. In more advanced 
stages, the typical features of scurvy develop. Manifesta
-
tions include perifollicular hemorrhages, perifollicular 
hyperkeratotic papules, petechiae and purpura, splinter 
hemorrhages, bleeding gums, hemarthroses, and subperi
-
osteal hemorrhages. Anemia is common, and wound heal
-
ing is impaired. The late stages of scurvy are characterized 
by edema, oliguria, neuropathy, intracerebral hemorrhage, 
and death.
 
»
Diagnosis
The diagnosis of advanced scurvy can be made clinically 
on the basis of the skin lesions in the proper clinical situa
-
tion. Atraumatic hemarthrosis is also highly suggestive. 
The diagnosis can be confirmed with decreased plasma 
ascorbic acid levels, typically below 0.1 mg/dL.
 
»
Treatment
Adult scurvy can be treated with ascorbic acid 300–1000 
mg/day orally. Improvement typically occurs within days.
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VITAMIN C TOXICITY
Very large doses of vitamin C can cause gastric irritation, 
flatulence, or diarrhea. Oxalate kidney stones are of theoretic 
concern because ascorbic acid is metabolized to oxalate, but 
stone formation has not been frequently reported. Vitamin C 
can also confound common diagnostic tests by causing false-
negative results for some fecal occult blood tests and both 
false-negative and false-positive results for urine glucose.
Al-Khudairy L et al. Vitamin C supplementation for the primary 
prevention of cardiovascular disease. Cochrane Database Syst 
Rev. 2017 Mar 16;3:CD011114. [PMID: 28301692]
Ferrari C et al. Rheumatic manifestations of scurvy. Curr Rheu
-
matol Rep. 2015 Apr;17(4):26. [PMID: 25854491]
Gabb G et al. Scurvy not rare. Aust Fam Physician. 2015 Jul; 
44(7):438–40. [PMID: 26922826]
Hagel AF et al. Plasma concentrations of ascorbic acid in a cross 
section of the German population. J Int Med Res. 2018 Jan; 
46(1):168–74. [PMID: 2876008]
Monacelli F et al. Vitamin C, aging and Alzheimer’s disease. 
Nutrients. 2017 Jun 27;9(7):670. [PMID: 28654021]
VITAMIN A DEFICIENCY
 
»
Vitamin A deficiency is one of the most common vitamin 
deficiency syndromes, particularly in developing countries. In 
many such regions, it is the most common cause of blindness. 
In the United States, vitamin A deficiency is usually due to fat 
malabsorption syndromes or mineral oil laxative abuse and 
occurs most commonly in older adults and the urban poor.
Night blindness is the earliest symptom. Dryness of the 
conjunctiva (xerosis) and the development of small white 
patches on the conjunctiva (Bitot spots) are early signs. 
Ulceration and necrosis of the cornea (keratomalacia), 
perforation, endophthalmitis, and blindness are late mani
-
festations. Xerosis and hyperkeratinization of the skin and 
loss of taste may also occur.
 
»
Diagnosis
Abnormalities of dark adaptation are strongly suggestive of 
vitamin A deficiency. Serum levels below the normal range of 
30–65 mg/dL are commonly seen in advanced deficiency.
 
»
Treatment
Night blindness, poor wound healing, and other signs of 
early deficiency can be effectively treated with vitamin A 
30,000 international units orally daily for 1 week. Advanced 
deficiency with corneal damage calls for administration of 
20,000 international units/kg orally for at least 5 days. The 
potential antioxidant effects of beta-carotene can be 
achieved with supplements of 25,000–50,000 international 
units of beta-carotene.
VITAMIN A TOXICITY
Excess intake of beta-carotenes (hypercarotenosis) results 
in staining of the skin a yellow-orange color but is other
-
wise benign. Skin changes are most marked on the palms 
and soles, while the scleras remain white, clearly distin
-
guishing hypercarotenosis from jaundice.
Excessive vitamin A (hypervitaminosis A), on the other 
hand, can be quite toxic. Chronic toxicity usually occurs 
after ingestion of daily doses of over 50,000 international 
units/day for more than 3 months. Early manifestations 
include dry, scaly skin, hair loss, mouth sores, painful hyper
-
ostoses, anorexia, and vomiting. More serious findings 
include hypercalcemia; increased intracranial pressure, with 
papilledema, headaches, and decreased cognition; and hepa
-
tomegaly, occasionally progressing to cirrhosis. Excessive 
vitamin A is also related to increased risk of hip fracture. 
Acute toxicity can result from ingestion of massive doses of 
vitamin A, such as in drug overdoses or consumption of 
polar bear liver. Manifestations include nausea, vomiting, 
abdominal pain, headache, papilledema, and lethargy.
The diagnosis can be confirmed by elevations of serum 
vitamin A levels. The only treatment is withdrawal of 
vitamin A from the diet. Most symptoms and signs 
improve rapidly.
Benn CS et al. An enigma: why vitamin A supplementation does 
not always reduce mortality even though vitamin A defi
-

-
ciency is associated with increased mortality. Int J Epidemiol. 
2015 Jun;44(3):906–18. [PMID: 26142161]
Lu Z et al. Rapid diagnostic testing platform for iron and vitamin 
A  deficiency. Proc Natl Acad Sci U S A. 2017 Dec 19; 
114(51):13513–8. [PMID: 29203653]
McCauley ME et al. Vitamin A supplementation during preg
-
nancy for maternal and newborn outcomes. Cochrane Data
-
base Syst Rev. 2015 Oct 27;(10):CD008666. [PMID: 26503498]
VITAMIN D
Vitamin D is discussed in Chapter 26.
 
»
Clinical deficiency of vitamin E is most commonly due to 
severe malabsorption or abetalipoproteinemia in adults or 
chronic cholestatic liver disease, biliary atresia, or cystic 
fibrosis in children. Manifestations of deficiency include 
areflexia, disturbances of gait, decreased vibration and 
proprioception, and ophthalmoplegia.
 
»
Diagnosis
Plasma vitamin E levels can be measured; normal levels are 
0.5–0.7 mg/dL or higher. Since vitamin E is normally trans
-
ported in lipoproteins, the serum level should be inter
-
preted in relation to circulating lipid levels.
 
»
Treatment
The optimum therapeutic dose of vitamin E has not been 
clearly defined. Large doses, often administered parenter
-
ally, can be used to improve the neurologic complications 
seen in abetalipoproteinemia and cholestatic liver disease. 
Several trials of supplemental vitamin E have shown slower 
cognitive decline in patients with Alzheimer disease.
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VITAMIN E TOXICITY
Clinical trials have suggested an increase in all-cause mor
-
tality with high dose (400 international units/day or more) 
vitamin E supplements. Large doses of vitamin E can also 
increase the vitamin K requirement and can result in 
bleeding in patients taking oral anticoagulants.
Okebukola PO et al. Vitamin E supplementation in people with 
cystic fibrosis. Cochrane Database Syst Rev. 2017 Mar 6; 
3:CD009422. [PMID: 28262916]
Traber MG. Vitamin E inadequacy in humans: causes and con
-
sequences. Adv Nutr. 2014 Sep;5(5):503–14. [PMID: 
25469382]
VITAMIN K
Vitamin K is discussed in Chapter 14.
 
º
DIET T
h
ERA
p
Y
In consultation with a registered dietician, specific thera
-
peutic diets can be designed to facilitate the medical man
-
agement of most common illnesses. Diet therapy is a 
difficult process, though, and not all patients are able to 
adhere to dietary recommendations. Requesting the patient 
to record dietary intake for 3–5 days may provide useful 
insight into the patient’s motivation as well as providing 
nutrient information about the current diet.
Therapeutic diets can be divided into three groups: (1) 
diets that alter the consistency of food, (2) diets that restrict 
or otherwise modify dietary components, and (3) diets that 
supplement dietary components.
DIETS THAT ALTER CONSISTENCY
 
»
Clear Liquid Diet
This diet provides adequate water, 500–1000 kcal as simple 
sugar, and some electrolytes. It is fiber free and requires 
minimal digestion or intestinal motility.
A clear liquid diet is useful for patients with resolving 
postoperative ileus, acute gastroenteritis, partial intestinal 
obstruction, and as preparation for diagnostic gastrointes
-
tinal procedures. It is commonly used as the first diet for 
patients who have been taking nothing by mouth for long 
periods. Because of the low calorie and minimal protein 
content of the clear liquid diet, it is used only for short 
periods.
 
»
Full Liquid Diet
The full liquid diet provides adequate water and can be 
designed to provide adequate calories and protein. Vitamins 
and minerals—especially folic acid, iron, and vitamin B
6
—
may be inadequate and should be provided in the form of 
supplements. Dairy products, soups, eggs, and soft cereals are 
used to supplement clear liquids. Commercial oral supple
-
ments can also be incorporated into the diet or used alone.
This diet is low in residue and can be used in many 
instances instead of the clear liquid diet described 
above—especially in patients with difficulty in chewing or 
swallowing, with partial obstructions, or in preparation for 
some diagnostic procedures. Full liquid diets are com
-
monly used following clear liquid diets to advance diets in 
periods.
 
»
Soft Diets
Soft diets are designed for patients unable to chew or swal
-
low hard or coarse food. Tender foods are used, and most 
raw fruits and vegetables and coarse breads and cereals are 
eliminated. Soft diets are commonly used to assist in pro
-
gression from full liquid diets to regular diets in postopera
-
tive patients, in patients who are too weak or those whose 
dentition is too poor to handle a general diet, in head and 
neck surgical patients, in patients with esophageal stric
-
tures, and in other patients who have difficulty with chew
-
ing or swallowing.
The soft diet can be designed to meet all nutritional 
DIETS THAT RESTRICT NUTRIENTS
Diets can be designed to restrict (or eliminate) virtually 
any nutrient or food component. The most commonly 
used restricted diets are those that limit sodium, fat, and 
protein. Other restrictive diets include gluten restriction in 
gluten enteropathy, potassium and phosphate reduction in 
chronic kidney disease, and various elimination diets for 
food allergies.
 
»
Sodium-Restricted Diets
Low-sodium diets are useful in the management of hyperten
-

»
-
sion and in conditions in which sodium retention and edema 
are prominent features, particularly heart failure, chronic 
liver disease, and chronic kidney disease. Sodium restriction 
is beneficial with or without diuretic therapy. When used in 
conjunction with diuretics, sodium restriction allows lower 
dosage of the diuretic medication and may prevent side 
effects. Potassium excretion, in particular, is directly related 
to distal renal tubule sodium delivery, and sodium restriction 
will decrease diuretic-related potassium losses.
Typical American diets contain 4–6 g (175–260 mEq) of 
sodium per day. A no-added-salt diet contains approxi
-
mately 3 g (132 mEq) of sodium per day. Further restric
-
tion can be achieved with diets of 2 or 1 g of sodium per 
day. Diets with more severe restriction are poorly accepted 
by patients and are rarely used. Current Institute of Medi
-
cine guidelines recommend 2.3 g of sodium per day, which 
is approximately 1 teaspoon of salt.
Dietary sodium includes sodium naturally occurring in 
foods, sodium added during food processing, and sodium 
added by the consumer during cooking and at the table. 
About 80% of the current US dietary intake is from pro
-
cessed and pre-prepared foods. Diets designed for 2.3 g of 
sodium per day require elimination of most processed 
foods, added salt, and foods with particularly high sodium 
content. Patients who follow such diets for 2–3 months lose 
their craving for salty foods and can often continue to 
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restrict their sodium intake indefinitely. Many patients 
with mild hypertension will achieve significant reductions 
in blood pressure (approximately 5 mm Hg diastolic) with 
this degree of sodium restriction.
Diets allowing 1 g of sodium require further restriction 
of commonly eaten foods. Special “low-sodium” products 
are available to facilitate such diets. These diets are difficult 
for most people to follow and are generally reserved for 
hospitalized patients, most commonly those with severe 
liver disease and ascites.
 
»
Fat-Restricted Diets
Traditional fat-restricted diets are useful in the treatment of 
fat malabsorption syndromes. Such diets will improve the 
symptoms of diarrhea with steatorrhea independently of the 
primary physiologic abnormality by limiting the quantity of 
fatty acids that reach the colon. The degree of fat restriction 
necessary to control symptoms must be individualized. 
Patients with severe malabsorption can be limited to 40–60 g 
of fat per day. Diets containing 60–80 g of fat per day can be 
designed for patients with less severe abnormalities.
In general, fat-restricted diets require broiling, baking, 
or boiling meat and fish; discarding the skin of poultry and 
fish and using those foods as the main protein source; 
using nonfat dairy products; and avoiding desserts, sauces, 
and gravies.
 
»
Low-Saturated-Fat Diets
Fat-restricted diets that specifically restrict saturated fats 
are the mainstay of dietary treatment of hyperlipidemia 
(see Chapter 28). Similar diets are often recommended for 
diabetes mellitus (see Chapter 27) and for the prevention of 
coronary artery disease (see Chapter 10). The large 
Women’s Health Initiative Dietary Modification Trial, 
however, did not show any significant benefit of a low-fat 
diet on weight control or prevention of cardiovascular dis
-
ease or cancer. In contrast, a study of Mediterranean diets, 
supplemented by nuts or extra-virgin olive oil, did demon
-
strate a reduction in cardiovascular events.
The aim of low-fat diets is to restrict total fat to less than 
30% of calories and to achieve a normal body weight by 
caloric restriction and increased physical activity. Saturated 
fat is restricted to 7% of calories. Saturated fat and total fat 
can be restricted further, but studies suggest that more 
extreme restriction offers little further advantage in overall 
modification of serum lipids. Low-fat diets can be aug
-
mented with the addition of plant stanols and sterols and 
with soluble dietary fiber to further reduce serum lipids.
 
»
Protein-Restricted Diets
Protein-restricted diets are most commonly used in 
patients with hepatic encephalopathy due to chronic liver 
disease and in patients with advanced chronic kidney dis
-
ease to slow the progression of early disease and to decrease 
symptoms of uremia in more severe disease. Patients with 
selected inborn errors of amino acid metabolism and other 
abnormalities resulting in hyperammonemia also require 
restriction of protein or of specific amino acids.
Protein restriction is intended to limit the production of 
nitrogenous waste products. Energy intake must be adequate 
to facilitate the efficient use of dietary protein. Proteins must 
be of high biologic value and be provided in sufficient quan
-
tity to meet minimal requirements. For most patients, the diet 
should contain at least 0.6 g/kg/day of protein. Patients with 
encephalopathy who do not respond to this degree of restric
-
tion are unlikely to respond to more severe restriction.
DIETS THAT SUPPLEMENT NUTRIENTS
 
»
High-Fiber Diet
Dietary fiber is a diverse group of plant constituents that is 
resistant to digestion by the human digestive tract. Guide
-
lines suggest that men eat 30–38 g/day and women 21–25 
g/day. Typical US diets, however, contain about half of that 
amount. Epidemiologic evidence has suggested that popu
-
lations consuming greater quantities of fiber have a lower

-
lations consuming greater quantities of fiber have a lower 
incidence of certain gastrointestinal disorders, including 
diverticulitis and, in some studies, colon cancer and a 
lower risk of cardiovascular disease. A meta-analysis of 22 
studies suggested that each 7 g of dietary fiber was associ
-
ated with a 9% decrease in first cardiovascular events.
Diets high in dietary fiber (21–38 g/day) are also com
-
monly used in the management of a variety of gastrointesti
-
nal disorders, particularly irritable bowel syndrome and 
recurrent diverticulitis. Diets high in fiber, particularly solu
-
ble fiber, may also be useful to reduce blood sugar in patients 
with diabetes and to reduce cholesterol levels in patients 
with hypercholesterolemia. Good sources of soluble fiber are 
oats, nuts, seeds, legumes, and most fruits. Foods with 
insoluble fiber include whole wheat, brown rice, other whole 
grains, and most vegetables. For some patients, the addition 
of psyllium seed (2 tsp per day) or natural bran (one-half cup 
per day) may be a useful adjunct to increase dietary fiber.
 
»
High-Potassium Diets
Potassium-supplemented diets are used most commonly to 
compensate for potassium losses caused by diuretics. 
Although potassium losses can be partially prevented by 
using lower doses of diuretics, concurrent sodium 
restriction, and potassium-sparing diuretics, some patients 
require additional potassium to prevent hypokalemia. 
High-potassium diets may also have a direct antihyperten
-
sive effect. Typical American diets contain about 3 g 
(80 mEq) of potassium per day. High-potassium diets com
-
monly contain 4.5–7 g (120–180 mEq) of potassium per day.
Most fruits, vegetables, and their juices contain high 
concentrations of potassium. Supplemental potassium can 
also be provided with potassium-containing salt substitutes 
(up to 20 mEq in one-quarter tsp) or as potassium chloride 
in solution or capsules, but this is rarely necessary if the 
above measures are followed to prevent potassium losses 
and to supplement dietary potassium.
 
»
High-Calcium Diets
Additional intakes of dietary calcium have been recom
-
mended for the prevention of postmenopausal osteoporosis, 
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the prevention and treatment of hypertension, and the 
prevention of colon cancer. The Women’s Health Initiative, 
however, suggested that calcium and vitamin D supple
-
mentation did not prevent fractures or colon cancer. 
Observational studies have also suggested that calcium 
supplements, especially when taken without vitamin D, 
may be associated with an increased risk of coronary heart 
disease. The recommended dietary allowance for the total 
calcium intake (from food and supplements) in adults 
ranges from 1000 mg/day to 1200 mg/day. Average 
American daily intakes are approximately 700 mg/day.
Dairy products are the primary dietary sources of cal
-
cium in the United States. An 8-ounce glass of milk, for 
example, contains approximately 300 mg of calcium. 
Patients with lactose intolerance who cannot tolerate liquid 
dairy products may be able to use lactose-free milk, take 
supplemental lactase enzyme supplements, or tolerate non
-
liquid products such as yogurt and aged cheeses. Leafy 
green vegetables and canned fish with bones also contain 
high concentrations of calcium, although the latter is also 
high in sodium.
Altobelli E et al. Low-FODMAP diet improves irritable bowel 
syndrome symptoms: a meta-analysis. Nutrients. 2017 
Aug 26;9(9):940. [PMID: 28846594]
Anderson CA et al. Nutrition interventions in chronic kidney 
disease. Med Clin North Am. 2016 Nov;100(6):1265–83. 
[PMID: 27745594]
Dinu M et al. A heart-healthy diet: recent insights and practical 
recommendations. Curr Cardiol Rep. 2017 Aug 24;19(10):95. 
[PMID: 28840462]
-
cular disease. Cochrane Database Syst Rev. 2015 Jun 10; 
Rehm CD et al. Dietary intake among US adults, 1999–2012. 
JAMA. 2016 Jun 21;315(23):2542–53. [PMID: 27327801]
 
º
NUTRITIONAL SU
pp
ORT
Nutritional support is the provision of nutrients to patients 
who cannot meet their nutritional requirements by eating 
standard diets. Nutrients may be delivered enterally, using 
oral nutritional supplements, nasogastric and nasoduode
-
nal feeding tubes, and tube enterostomies, or parenterally, 
using lines or catheters placed in peripheral or central 
veins, respectively. Current nutritional support techniques 
permit adequate nutrient delivery to most patients. Nutri
-
tion support should be utilized, however, only if it is likely 
to improve the patient’s clinical outcome. The financial 
costs and risks of side effects must be balanced against the 
potential advantages of improved nutritional status in each 
clinical situation.
INDICATIONS FOR NUTRITIONAL SUPPORT
The precise indications for nutritional support remain 
controversial. Most authorities agree that nutritional sup
-
port is indicated for at least four groups of adult patients: 
(1) those with inadequate bowel syndromes, (2) those with 
severe prolonged hypercatabolic states (eg, due to extensive 
burns, multiple trauma, mechanical ventilation), (3) those 
requiring prolonged therapeutic bowel rest, and (4) those 
with severe protein–calorie undernutrition with a treatable 
disease who have sustained a loss of over 25% of body 
weight.
It has been difficult to prove the efficacy of nutritional 
support in the treatment of most other conditions. In most 
cases it has not been possible to show a clear advantage of 
treatment by means of nutritional support over treatment 
without such support.
The American Society for Parenteral and Enteral 
Nutrition (ASPEN) has published recommendations for 
the rational use of nutritional support. The recommenda
-
tions emphasize the need to individualize the decision to 
begin nutritional support, weighing the risks and costs 
against the benefits to each patient. They also reinforce the 
need to identify high-risk malnourished patients by nutri
-
tional assessment.
 
»
Nutritional Support Methods
Selection of the most appropriate nutritional support

-
 
»
Selection of the most appropriate nutritional support 
method involves consideration of gastrointestinal function, 
the anticipated duration of nutritional support, and the 
ability of each method to meet the patient’s nutritional 
requirements. The method chosen should meet the patient’s 
nutritional needs with the lowest risk and lowest cost pos
-
sible. For most patients, enteral feeding is safer and cheaper 
and offers significant physiologic advantages. An algo
-
rithm for selection of the most appropriate nutritional 
support method is presented in Figure 29–1.
Prior to initiating specialized enteral nutritional sup
-
port, efforts should be made to supplement food intake. 
Attention to patient preferences, timing of meals and diag
-
nostic procedures and use of medications, and the use of 
foods brought to the hospital by family and friends can 
often increase oral intake. Patients unable to eat enough at 
regular mealtimes to meet nutritional requirements can be 
given 
oral supplements
 as snacks or to replace low-calorie 
beverages. Oral supplements of differing nutritional com
-
position are available for the purpose of individualizing the 
diet in accordance with specific clinical requirements. 
Fiber and lactose content, caloric density, protein level, 
amino acid profiles, vitamin K, and calcium can all be 
modified as necessary.
Patients unable to take adequate oral nutrients who 
have functioning gastrointestinal tracts and who meet the 
criteria for nutritional support are candidates for 
liquid 
artificial nutrition (“tube feedings”)
. Small-bore feeding 
tubes are placed via the nose into the stomach or duode
-
num. Patients able to sit up in bed who can protect their 
airways can be fed into the stomach. Because of the 
increased risk of aspiration, patients who cannot ade
-
quately protect their airways should be fed nasoduodenally 
(though, as noted below, this may not prevent all aspira
-
tions, particularly if the pylorus is patulous). Feeding tubes 
can usually be passed into the duodenum by leaving an 
extra length of tubing in the stomach and placing the 
patient in the right decubitus position. Metoclopramide, 
10 mg intravenously, can be given 20 minutes prior to 
insertion and continued every 6 hours thereafter to 
CMDT19_Ch29_p1276-p1293.indd   1288

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facilitate passage through the pylorus. Occasionally, patients 
will require fluoroscopic or endoscopic guidance to insert 
the tube distal to the pylorus. Placement of nasogastric and, 
particularly, nasoduodenal tubes should be confirmed 
radiographically before delivery of feeding solutions.
Feeding tubes can also be placed directly into the gastro
-
intestinal tract using 
tube enterostomies
. Most tube enteros
-
tomies are placed in patients who require long-term enteral 
nutritional support. Gastrostomies have the advantage of 
allowing bolus feedings, while jejunostomies require contin
-
uous infusions. Gastrostomies—like nasogastric feeding—
should be used only in patients at low risk for aspiration. 
Gastrostomies can also be placed percutaneously with the aid 
of endoscopy. These tubes can then be advanced into the 
jejunum. Tube enterostomies can also be placed surgically.
Patients who require nutritional support but whose 
gastrointestinal tracts are nonfunctional should receive 
parenteral nutritional support
. Most patients receive par
-
enteral feedings via a central vein—most commonly the 
subclavian vein. Peripheral veins can be used in some 
patients, but because of the high osmolality of parenteral 
solutions this is rarely tolerated for more than a few weeks.
Peripheral vein nutritional support
 is most com
-
monly used in patients with nonfunctioning gastrointesti
-
nal tracts who require immediate support but whose 
clinical status is expected to improve within 1–2 weeks, 
allowing enteral feeding. Peripheral vein nutritional sup
-
port is administered via standard intravenous lines. Solu
-
tions should always include lipid and dextrose in 
combination with amino acids to provide adequate non
-
protein calories. Serious side effects are infrequent, but 
there is a high incidence of phlebitis and infiltration of 
intravenous lines.
Central vein nutritional support
 is delivered via intra
-
venous catheters placed percutaneously using aseptic tech
-
nique. Proper placement in the superior vena cava is 
documented radiographically before the solution is infused. 
Catheters must be carefully maintained by experienced 
nursing personnel and used solely for nutritional support to 
prevent infection and other catheter-related complications.
NUTRITIONAL REQUIREMENTS
Each patient’s nutritional requirements should be determined 
independently of the method of nutritional support. In most 
situations, solutions of equal nutrient value can be designed 
for delivery via enteral and parenteral routes, but differences 
in absorption must be considered. A complete nutritional 
support solution must contain water, energy, amino acids, 
electrolytes, vitamins, minerals, and essential fatty acids.
 
»
Water
For most patients, water requirements can be calculated by 
allowing 1500 mL for the first 20 kg of body weight plus 
20 mL for every kilogram over 20. Additional losses should 
be replaced as they occur. For average-sized adult patients, 
fluid needs are about 30–35 mL/kg, or approximately 
1 mL/kcal of energy required.
 
»
Energy
Energy requirements can be estimated by one of three 
methods: (1) by using standard equations to calculate BEE 
plus additional calories for activity and illness, (2) by 
applying a simple calculation based on calories per kilo
-
gram of body weight, or (3) by measuring energy expendi
-
ture with indirect calorimetry.
BEE can be estimated by the 
Harris–Benedict equation
: 
for men, BEE = 666 + (13.7 × weight in kg) + (5 × height in 
cm) – (6.8 × age in years). For women, BEE = 655 + (9.5 × 
weight in kg) + (1.8 × height in cm) – (4.7 × age in years). 
For undernourished patients, actual body weight should be 
used; for obese patients, ideal body weight should be used. 
For most patients, an additional 20–50% of BEE is admin
-
istered as nonprotein calories to accommodate energy 
expenditures during activity or relating to the illness.

-
expenditures during activity or relating to the illness. 
Occasional patients are noted to have energy expenditures 
greater than 150% of BEE.
Energy requirements can be estimated also by multiply
-
ing actual body weight in kilograms (for obese patients, 
ideal body weight) by 30–35 kcal.
Gastrointestinal tract can be 
used safely and effectively?
Ye
sN
o
No
Pa
renteral nutrition
Support needed 
fo
r
longer than 6 weeks?
Ye
s
Tube
enterostomy
Nasoenteric tube
At high risk
for aspiration?
Nasoduodenal
tube
Nasogastric
tube
Support needed for longer
than 2–3 weeks?
Adequate peripheral
access and fluid tolerance?
No
No
Ye
s
No
Ye
s
Ye
s
Pe
ripheral vein
nutritional support
Central vein
 
▲
Figure 29–1.
 
Nutritional support method decision tree.
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Both of these methods provide imprecise estimates of 
actual energy expenditures, especially for the markedly 
underweight, overweight, and critically ill patient. Studies 
using indirect calorimetry have demonstrated that as many 
as 30–40% of patients will have measured expenditures 
10% above or below estimated values. For accurate deter
-
mination of energy expenditure, indirect calorimetry 
should be used.
 
»
Protein
Protein and energy requirements are closely related. If ade
-
quate calories are provided, most patients can be given 
0.8–1.2 g of protein per kilogram per day. Patients undergoing 
moderate to severe stress should receive up to 1.5 g/kg/day. 
 
As in the case of energy requirements, actual weights should 
be used for normal and underweight patients and ideal 
weights for patients with significant obesity.
Patients who are receiving protein without adequate calo
-
ries will catabolize protein for energy rather than utilizing it 
for protein synthesis. Thus, when energy intake is low, excess 
protein is needed for nitrogen balance. If both energy and 
protein intakes are low, extra energy will have a more signifi
-
cant positive effect on nitrogen balance than extra protein.
 
»
Electrolytes & Minerals
Requirements for sodium, potassium, and chloride vary 
widely. Most patients require 45–145 mEq/day of each. The 
actual requirement in individual patients will depend on 
the patient’s cardiovascular, renal, endocrine, and gastroin
-
testinal status as well as measurements of serum 
concentration.
Patients receiving enteral nutritional support should 
receive adequate vitamins and minerals according to the 
recommended daily allowances. Most premixed enteral 
solutions provide adequate vitamins and minerals as long 
as adequate calories are administered.
Patients receiving parenteral nutritional support require 
smaller amounts of minerals: calcium, 10–15 mEq/day; 
phosphorus, 15–20 mEq per 1000 nonprotein calories; and 
magnesium, 16–24 mEq/day. Most patients receiving 
nutritional support do not require supplemental iron 
because body stores are adequate. Iron nutrition should be 
monitored closely by following the hemoglobin concentra
-
tion, mean corpuscular volume, and iron studies. Paren
-
teral administration of iron is associated with a number of 
adverse effects and should be reserved for iron-deficient 
patients unable to take oral iron.
Patients receiving parenteral nutritional support should be 
given the trace elements zinc (about 5 mg/day) and copper 
(about 2 mg/day). Patients with diarrhea will require addi
-
tional zinc to replace fecal losses. Additional trace elements—
especially chromium, manganese, and selenium—are 
provided to patients receiving long-term parenteral nutrition.
Parenteral vitamins are provided daily. Standardized 
multivitamin solutions are currently available to provide 
adequate quantities of vitamins A, B
12
, C, D, E, thiamine, 
riboflavin, niacin, pantothenic acid, pyridoxine, folic acid, 
and biotin. Vitamin K is not given routinely but adminis
-
tered when the prothrombin time becomes abnormal.
 
»
Essential Fatty Acids
Patients receiving nutritional support should be given 
2–4% of their total calories as linoleic acid to prevent 
essential fatty acid deficiency. Most prepared enteral solu
-
tions contain adequate linoleic acid. Patients receiving 
parenteral nutrition should be given at least 250 mL of a 
20% intravenous fat (emulsified soybean or safflower oil) 
about two or three times a week. Intravenous fat can also 
be used as an energy source in place of dextrose.
ENTERAL NUTRITIONAL SUPPORT 
SOLUTIONS
Most patients who require enteral nutritional support can 
be given commercially prepared enteral solutions 
(Table 29–1). Nutritionally complete solutions have been 
designed to provide adequate proportions of water, energy, 
protein, and micronutrients. Nutritionally incomplete

protein, and micronutrients. Nutritionally incomplete 
solutions are also available to provide specific macronutri
-
ents (eg, protein, carbohydrate, and fat) to supplement 
Table 29–1.
 
Enteral solutions.
Complete
Blenderized (eg, Compleat Regular, Compleat Modified,
1
 
Vitaneed
1
)
Whole protein, lactose-containing (eg, Mentene, Carnation and 
Delmark Instant Breakfast, Forta Shake)
Whole protein, lactose-free, low-residue:
1 kcal/mL (eg, Ensure, Isocal, Osmolite, Nutren 1.0,
1
 Nutrilan, 
Isolan,
1
 Sustacal, Resource)
1.5 kcal/mL (eg, Ensure Plus, Sustacal HC, Comply, 
 
Nutren 1.5, Resource Plus)
2 kcal/mL (eg, Isocal HCN, Magnacal, TwoCal HN)
High-nitrogen: > 15% total calories from protein (eg, Ensure 
HN, Attain,
1
 Osmolite HN,
1
 Replete, Entrition HN,
1
 Isolan,
1
 
Isocal HN,
1
 Sustacal HC, Isosource HN,
1
 Ultralan)
Whole protein, lactose-free, high-residue:
1 kcal/mL (eg, Jevity,
1
 Profiber,
1
 Nutren 1.0 with fiber,
1
 
Fiberian,
1
 Sustacal with fiber, Ultracal,
1
 Ensure with fiber, 
Fibersource)
Chemically defined peptide- or amino acid–based (eg, 
 
Accupep HPF, CriticareHN, Peptamen,
1
 Reabfin, Vital HN, 
 
AlitraQ, Tolerex, Vivonex TEN)
“Disease-specific” formulas
Advanced chronic kidney disease: with essential amino acids 
(eg, Amin-Aid, Travasorb Renal, Aminess)
Malabsorption: with medium-chain triglycerides (eg, 
 
Portagen,
1
 Travasorb MCT)
Respiratory failure: with > 50% calories from fat (eg, 
 
Pulmocare, NutriVent)
Hepatic encephalopathy: with high amounts of branched-
 
chain amino acids (eg, Hepatic-Acid II, Travasorb Hepatic)
Incomplete (modular)
Protein (eg, Nutrisource Protein, Promed, Propac)
Carbohydrate (eg, Nutrisource Carbohydrate, Polycose, 
Sumacal)
Fat (eg, MCT Oil, Microlipid, Nutrisource Lipid)
Vitamins (eg, Nutrisource Vitamins)
Minerals (eg, Nutrisource Minerals)
1
Isotonic.
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complete solutions for patients with unusual requirements 
or to design solutions that are not available commercially.
Nutritionally complete solutions are characterized as fol
-
lows: (1) by osmolality (isotonic or hypertonic), (2) by lactose 
content (present or absent), (3) by the molecular form of the 
protein component (intact proteins; peptides or amino acids), 
(4) by the quantity of protein and calories provided, and (5) 
by fiber content (present or absent). For most patients, iso
-
tonic solutions containing no lactose or fiber are preferable. 
Such solutions generally contain moderate amounts of fat 
and intact protein. Most commercial isotonic solutions con
-
tain 1000 kcal and about 37–45 g of protein per liter.
Solutions containing hydrolyzed proteins or crystalline 
amino acids and with no significant fat content are called 
elemental solutions, since macronutrients are provided in 
their most “elemental” form. These solutions have been 
designed for patients with malabsorption, particularly pan
-
creatic insufficiency and limited fat absorption. Elemental 
diets are extremely hypertonic and often result in more 
severe diarrhea. Their use should be limited to patients 
who cannot tolerate isotonic solutions.
Although formulas have been designed for specific 
clinical situations—solutions containing primarily essen
-
tial amino acids (for advanced chronic kidney disease), 
medium-chain triglycerides (for fat malabsorption), more 
fat (for respiratory failure and CO
2
 retention), and more 
branched-chain amino acids (for hepatic encephalopathy 
and severe trauma)—they have not been shown to be supe
-
rior to standard formulas for most patients.
Enteral solutions should be administered via continuous 
infusion, preferably with an infusion pump. Isotonic feed
-
ings should be started at full strength at about 25–33% of 
the estimated final infusion rate. Feedings can be advanced 
by similar amounts every 12 hours as tolerated. Hypertonic 
feedings should be started at half strength. The strength and 
the rate can then be advanced every 6 hours as tolerated.
COMPLICATIONS OF ENTERAL 
 
NUTRITIONAL SUPPORT
Minor complications of tube feedings occur in 10–15% of 
patients. Gastrointestinal complications include diarrhea 
(most common), inadequate gastric emptying, emesis, 
esophagitis, and occasionally gastrointestinal bleeding. 
Diarrhea associated with tube feeding may be due to intol
-
erance to the osmotic load or to one of the macronutrients 
(eg, fat, lactose) in the solution. Patients being fed in this 
way may also have diarrhea from other causes (as side 
effects of antibiotics or other drugs, associated with infec
-
tion, etc), and these possibilities should always be investi
-
gated in appropriate circumstances.
Mechanical complications of tube feedings are poten
-
tially the most serious. Of particular importance is aspira
-
tion. All patients receiving nasogastric tube feedings are at 
risk for this life-threatening complication. Limiting naso
-
gastric feedings to those patients who can adequately pro
-
tect their airway and careful monitoring of patients being 
fed by tube should limit these serious complications to 
1–2% of cases. Minor mechanical complications are com
-
mon and include tube obstruction and dislodgment.
Metabolic complications during enteral nutritional sup
-
port are common but are easily managed in most cases. 
The most important problem is hypernatremic dehydra
-
tion, most commonly seen in elderly patients given exces
-
sive protein intake who are unable to respond to thirst. 
Abnormalities of potassium, glucose, CO
2
 production, and 
acid–base balance may also occur.
Elke G et al. Enteral versus parenteral nutrition in critically ill 
patients: an updated systematic review and meta-analysis of 
randomized controlled trials. Crit Care. 2016 Apr 29; 
20(1):117. [PMID: 27129307]
Escuro AA et al. Enteral formulas in nutrition support practice:

Escuro AA et al. Enteral formulas in nutrition support practice: 
is there a better choice for your patient? Nutr Clin Pract. 
 
2016 Dec;31(6):709–22. [PMID: 27694642]
Reignier J et al. Enteral versus parenteral early nutrition in ven
-
tilated adults with shock: a randomised, controlled, multicen
-
tre, open-label, parallel-group study (NUTRIREA-2). Lancet. 
2018 Jan 13;391(10116):133–43. [PMID: 29128300]
Reintam Blaser A et al. Early enteral nutrition in critically ill 
patients: ESICM clinical practice guidelines. Intensive Care 
Med. 2017 Mar;43(3):380–98. [PMID: 28168570]
Y ao H et al. Enteral versus  parenteral  nutrition  in critically ill 
patients with severe pancreatitis: a meta-analysis. Eur J Clin 
Nutr. 2018 Jan;72(1):66–8. [PMID: 28901335]
PARENTERAL NUTRITIONAL 
 
SUPPORT SOLUTIONS
Parenteral nutritional support solutions can be designed to 
deliver adequate nutrients to most patients. The basic par
-
enteral solution is composed of dextrose, amino acids, and 
water. Electrolytes, minerals, trace elements, vitamins, and 
medications can also be added. Most commercial solutions 
contain the monohydrate form of dextrose that provides 
3.4 kcal/g. Crystalline amino acids are available in a variety 
of concentrations, so that a broad range of solutions can be 
made up that will contain specific amounts of dextrose and 
amino acids as required.
Typical solutions for central vein nutritional support 
contain 25–35% dextrose and 2.75–6% amino acids 
depending upon the patient’s estimated nutrient and water 
requirements. These solutions typically have osmolalities 
in excess of 1800 mOsm/L and require infusion into a cen
-
tral vein. A typical formula for patients without organ 
failure is shown in Table 29–2.
Solutions with lower osmolalities can also be designed 
for infusion into peripheral veins. Typical solutions for 
peripheral infusion contain 5–10% dextrose and 2.75–
4.25% amino acids. These solutions have osmolalities 
between 800 and 1200 mOsm/L and result in a high inci
-
dence of thrombophlebitis and line infiltration. These solu
-
tions will provide adequate protein for most patients but 
inadequate energy. Additional energy must be provided in 
the form of emulsified soybean or safflower oil. Such intra
-
venous fat solutions are currently available in 10% and 25% 
solutions providing 1.1 and 2.2 kcal/mL, respectively. 
Intravenous fat solutions are isosmotic and well tolerated 
by peripheral veins.
Typical patients are given 200–500 mL of a 20% solu
-
tion each day. As much as 60% of total calories can be 
administered in this manner.
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Intravenous fat can also be provided to patients receiv
-
ing central vein nutritional support. In this instance, dex
-
trose concentrations should be decreased to provide a fixed 
concentration of energy. Intravenous fat has been shown to 
be equivalent to intravenous dextrose in providing energy 
to spare protein. Intravenous fat is associated with less 
glucose intolerance, less production of carbon dioxide, and 
less fatty infiltration of the liver and has been increasingly 
utilized in patients with hyperglycemia, respiratory failure, 
and liver disease. Intravenous fat has also been increasingly 
used in patients with large estimated energy requirements. 
The maximum glucose utilization rate is approximately 
5–7 mg/min/kg. Patients who require additional calories 
can be given them as fat to prevent excess administration 
of dextrose. Intravenous fat can also be used to prevent 
essential fatty acid deficiency. The optimal ratio of carbo
-
hydrate and fat in parenteral nutritional support has not 
been determined.
Infusion of parenteral solutions should be started 
slowly to prevent hyperglycemia and other metabolic com
-
plications. Typical solutions are given initially at a rate of 
50 mL/h and advanced by about the same amount every 
24 hours until the desired final rate is reached.
Derenski K et al. Parenteral nutrition basics for the clinician car
-
ing for the adult patient. Nutr Clin Pract. 2016 Oct;31(5):
 
578–95. [PMID: 27440772]
Table 29–2.
 
Typical parenteral nutrition solution (for 
stable patients without organ failure).
Dextrose (3.4 kcal/g)
25%
Amino acids (4 kcal/g)
6%
Na
+
50 mEq/L
K
+
40 mEq/L
Ca
2+
5 mEq/L
Mg
2+
8 mEq/L
Cl
–
60 mEq/L
P
12 mEq/L
Acetate
Balance
MVI-12 (vitamins)
10 mL/day
MTE (trace elements)
5 mL/day
Fat emulsion 20%
250 mL five times a week
Typical rate
Day 1: 30 mL/h
 
Day 2: 60 mL/h
By day 2, solution provides:
Calories: 1925 kcal total
 
Protein: 86 g
 
Fat: 19% of total kcal
 
Fluid: 1690 mL
Kirby DF et al. Overview of home  parenteral  nutrition: an 
update. Nutr Clin Pract. 2017 Dec;32(6):739–52. [PMID: 
29035672]
Lembeck ME et al. The role of intravenous fluids and enteral or 
parenteral nutrition in patients with life-limiting illness. Med 
Clin North Am. 2016 Sep;100(5):1131–41. [PMID: 27542432]
Mitra A et al. Liver disease in patients on total parenteral nutri
-
tion. Clin Liver Dis. 2017 Nov;21(4):687–95. [PMID: 
28987256]
Oshima T et al. Supplemental parenteral nutrition is the key to 
prevent energy deficits in critically ill patients. Nutr Clin 
Pract. 2016 Aug;31(4):432–7. [PMID: 27256992]
Wanten GJ. Parenteral approaches in malabsorption: home par
-
enteral nutrition. Best Pract Res Clin Gastroenterol. 
COMPLICATIONS OF PARENTERAL 
Complications of central vein nutritional support occur in 
up to 50% of patients. Although most are minor and easily 
managed, significant complications will develop in about 
5% of patients. Complications of central vein nutritional 
support can be divided into catheter-related complications 
and metabolic complications.
Catheter-related complications can occur during inser
-
tion or while the catheter is in place. Pneumothorax, 
hemothorax, arterial laceration, air emboli, and brachial 
plexus injury can occur during catheter placement. The 
incidence of these complications is inversely related to the 
experience of the physician performing the procedure but 
will occur in at least 1–2% of cases even in major medical 
centers. Each catheter placement should be documented by 
chest radiograph prior to initiation of nutritional support.
Catheter thrombosis and catheter-related sepsis are the

Catheter thrombosis and catheter-related sepsis are the 
most important complications of indwelling catheters. 
Patients with indwelling central vein catheters in whom 
fever develops without an apparent source should have 
their lines changed over a wire or removed immediately, 
the tip quantitatively cultured, and antibiotics begun 
empirically. Quantitative tip cultures and blood cultures 
will help guide further antibiotic therapy. Catheter-related 
sepsis occurs in 2–3% of patients even if maximal efforts 
are made to prevent infection.
Metabolic complications of central vein nutritional sup
-
port occur in over 50% of patients (Table 29–3). Most are 
minor and easily managed, and termination of support is 
seldom necessary.
McCleary EJ et al. Parenteral nutrition and infection risk in the 
intensive care unit: a practical guide for the bedside clinician. 
Nutr Clin Pract. 2016 Aug;31(4):476–89. [PMID: 27317614]
Mundi MS et al. Home parenteral nutrition: fat emulsions and 
potential complications. Nutr Clin Pract. 2016 Oct;31(5):
 
629–41. [PMID: 27533943]
PATIENT MONITORING DURING 
Every patient receiving enteral or parenteral nutritional 
support should be monitored closely. Formal nutritional 
support teams composed of a physician, a nurse, a 
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dietitian, and a pharmacist have been shown to decrease 
the rate of complications.
Patients should be monitored both for the adequacy of 
treatment and to prevent complications or detect them 
early when they occur. Because estimates of nutritional 
requirements are imprecise, frequent reassessment is 
necessary. Daily intakes should be recorded and compared 
with estimated requirements. Body weight, hydration sta
-
tus, and overall clinical status should be followed. Patients 
who do not appear to be responding as anticipated can be 
evaluated for nitrogen balance by means of the following 
equation:
Nitrog
en
balanc
e
24
-h
ou
rp
rotein
intake
(g
)
6.25
24
-h
ou
r
urinar
y
nitrogen
(g
)
4
=−
+










Patients with positive nitrogen balances can be contin
-
ued on their current regimens; patients with negative bal
-
ances should receive moderate increases in calorie and 
protein intake and then be reassessed. Monitoring for 
metabolic complications includes daily measurements of 
electrolytes; serum glucose, phosphorus, magnesium, cal
-
cium, and creatinine; and BUN until the patient is stabi
-
lized. Once the patient is stabilized, electrolytes, 
phosphorus, calcium, magnesium, and glucose should be 
obtained at least twice weekly. Red blood cell folate, zinc, 
and copper should be checked at least once a month.
Bally MR et al. Nutritional support and outcomes in malnour
-
ished medical inpatients: a systematic review and meta-
analysis. JAMA Intern Med. 2016 Jan 1;176(1):43–53. [PMID: 
26720894]
McClave SA et al. ACG Clinical Guideline: nutrition therapy in 
the adult hospitalized patient. Am J Gastroenterol. 2016 Mar; 
111(3):315–34. [PMID: 26952578]
26773077]
Parikh HG et al. Calorie delivery and clinical outcomes in the 
critically ill: a systematic review and meta-analysis. Crit Care 
Resusc. 2016 Mar;18(1):17–24. [PMID: 26947412]
Table 29–3.
 
Metabolic complications of parenteral 
nutritional suppor
t.
Complication
Common Causes
p
ossible S
olutions
Too rapid infusion of 
dextrose, “stress, ” 
Decrease glucose 
infusion; insulin; 
replacement of 
dextrose with fat
Hyperosmolar non
-
ketotic 
dehydration
Severe, undetected 
hyperglycemia
Insulin, hydration, 
potassium
Hyperchloremic 
metabolic 
acidosis
High chloride 
Decrease chloride
Azotemia
Excessive protein 
Decrease amino acid 
concentration
Hyperphosphate
-
mia, hypokalemia, 
hypomagnesemia
Extracellular to intra
-
cellular shifting 
with refeeding
Increase solution 
Liver enzyme 
Lipid trapping in 
hepatocytes, fatty 
liver
Decrease dextrose
Acalculous 
cholecystitis
Biliary stasis
Oral fat
Zinc deficiency
Diarrhea, small 
bowel fistulas
Increase 
Copper deficiency
Biliary fistulas
Increase 
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Peter V. Chin-Hong, MD 
 
Common Problems in 
Infectious Diseases & 
Antimicrobial Therapy
30
after 3 days of investigation with at least 2 days for cultures 
to incubate (see Chapter 31). Although not usually consid
-
ered separately, 
FUO in solid organ transplant recipients
 
and 
FUO in the returning traveler
 are common scenarios, 
each with a unique differential diagnosis, and are also dis
-
cussed in this chapter.
For a general discussion of fever, see the section on 
fever and hyperthermia in Chapter 2.
A. Common Causes
Most cases represent unusual manifestations of common 
diseases and not rare or exotic diseases—eg, tuberculosis, 
endocarditis, gallbladder disease, and HIV (primary infec
-
tion or opportunistic infection) are more common causes 
of FUO than Whipple disease or familial Mediterranean 
fever.
B. Age of Patient
In adults, infections (25–40% of cases) and cancer (25–40% 
of cases) account for the majority of FUOs. In children, 
infections are the most common cause of FUO (30–50% of 
cases) and cancer a rare cause (5–10% of cases). Autoim
-
mune disorders occur with equal frequency in adults and 
children (10–20% of cases), but the diseases differ. Juvenile 
rheumatoid arthritis is particularly common in children, 
whereas systemic lupus erythematosus, granulomatosis 
with polyangiitis (formerly Wegener granulomatosis), and 
polyarteritis nodosa are more common in adults. Still dis
-
ease, giant cell arteritis, and polymyalgia rheumatica occur 
exclusively in adults. In adults over 65 years of age, multi
-
system immune-mediated diseases such as temporal arteri
-
tis, polymyalgia rheumatica, sarcoidosis, rheumatoid 
arthritis, and granulomatosis with polyangiitis account for 
25–30% of all FUOs.
C. Duration of Fever
The cause of FUO changes dramatically in patients who have 
been febrile for 6 months or longer. Infection, cancer, and 
autoimmune disorders combined account for only 20% of 
FUOs in these patients. Instead, other entities such as granu
-
lomatous diseases (granulomatous hepatitis, Crohn disease, 
ulcerative colitis) and factitious fever become important 
 
º
COMMON PROBLEMS IN 
INFECTIOUS DISEASES
FEVER OF UNKNOWN ORIGIN (FUO)
 
»
Illness of at least 3 weeks duration.
 
»
Fever over 38.3
°
C on several occasions.
 
»
Diagnosis has not been made after three 
 
outpatient visits or 3 days of hospitalization.
 
»
The intervals specified in the criteria for the diagnosis of 
FUO are arbitrary ones intended to exclude patients with 
protracted but self-limited viral illnesses and to allow time 
for the usual radiographic, serologic, and cultural studies 
to be performed. Because of costs of hospitalization and 
the availability of most screening tests on an outpatient 
basis, the original criterion requiring 1 week of hospitaliza
-
tion has been modified to accept patients in whom a diag
-
nosis has not been made after 3 outpatient visits or 3 days 
of hospitalization.
Several additional categories of FUO have been added: 
(1) 
Hospital-associated FUO
 refers to the hospitalized 
patient with fever of 38.3
°
C or higher on several occasions, 
due to a process not present or incubating at the time of 
admission, in whom initial cultures are negative and the 
diagnosis remains unknown after 3 days of investigation 
(see Health Care–Associated Infections below). 
(2) 
Neutropenic FUO
 includes patients with fever of 
38.3
°
C or higher on several occasions with less than 500 
neutrophils per microliter in whom initial cultures are 
negative and the diagnosis remains uncertain after 3 days 
(see Chapter 2 and Infections in the Immunocompromised 
Patient, below). (3) 
HIV-associated FUO
 pertains to HIV-
positive patients with fever of 38.3
°
C or higher who have 
been febrile for 4 weeks or more as an outpatient or 3 days 
as an inpatient, in whom the diagnosis remains uncertain

pertains to HIV-
°
as an inpatient, in whom the diagnosis remains uncertain 
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causes. One-fourth of patients who say they have been 
febrile for 6 months or longer actually have no true fever or 
underlying disease. Instead, the usual normal circadian 
variation in temperature (temperature 0.5–1
°
C higher in the 
afternoon than in the morning) is interpreted as abnormal. 
episodic
 or 
recurrent fever
 (ie, those who 
meet the criteria for FUO but have fever-free periods of 
 
2 weeks or longer) are similar to those with 
prolonged fever. 
Infection, malignancy, and autoimmune disorders account 
for only 20–25% of such fevers, whereas various miscella
-
neous diseases (Crohn disease, familial Mediterranean fever, 
allergic alveolitis) account for another 25%. Approximately 
50% of cases remain undiagnosed but have a benign course 
with eventual resolution of symptoms.
D. Immunologic Status
In the neutropenic patient, fungal infections and occult 
bacterial infections are important causes of FUO. In the 
patient taking immunosuppressive medications (particu
-
larly organ transplant patients), cytomegalovirus (CMV) 
infections are a frequent cause of fever, as are fungal infec
-
tions, nocardiosis, 
 pneumonia, and 
mycobacterial infections.
E. Classification of Causes of FUO
Most patients with FUO will fit into one of five categories.
1. Infection—
Both systemic and localized infections can 
cause FUO. Tuberculosis and endocarditis are the most 
common systemic infections associated with FUO, but 
mycoses, viral diseases (particularly infection with Epstein-
Barr virus and CMV), toxoplasmosis, brucellosis, Q fever, 
cat-scratch disease, salmonellosis, malaria, and many other 
less common infections have been implicated. Primary 
infection with HIV or opportunistic infections associated 
with AIDS—particularly mycobacterial infections—can 
also present as FUO. The most common form of localized 
infection causing FUO is an occult abscess. Liver, spleen, 
kidney, brain, and bone abscesses may be difficult to 
detect. A collection of pus may form in the peritoneal 
cavity or in the subdiaphragmatic, subhepatic, paracolic, or 
other areas. Cholangitis, osteomyelitis, urinary tract infec
-
tion, dental abscess, or paranasal sinusitis may cause pro
-
longed fever.
2. Neoplasms—
Many cancers can present as FUO. The 
most common are lymphoma (both Hodgkin and non-
Hodgkin) and leukemia. Posttransplant lymphoprolifera
-
tive disorders may also present with fever. Other diseases of 
lymph nodes, such as angioimmunoblastic lymphoma and 
Castleman disease, can also cause FUO. Primary and meta
-
static tumors of the liver are frequently associated with 
fever, as are renal cell carcinomas. Atrial myxoma is an 
often forgotten neoplasm that can result in fever. Chronic 
lymphocytic leukemia and multiple myeloma are rarely 
associated with fever, and the presence of fever in patients 
with these diseases should prompt a search for infection.
3. Autoimmune disorders—
Still disease, systemic lupus 
erythematosus, cryoglobulinemia, and polyarteritis nodosa 
are the most common causes of autoimmune-associated 
FUO. Giant cell arteritis and polymyalgia rheumatica are 
seen almost exclusively in patients over 50 years of age and 
are nearly always associated with an elevated erythrocyte 
sedimentation rate (greater than 40 mm/h).
4. Miscellaneous causes—
Many other conditions have 
been associated with FUO but less commonly than the 
foregoing types of illness. Examples include thyroiditis, 
sarcoidosis, Whipple disease, familial Mediterranean fever, 
recurrent pulmonary emboli, alcoholic hepatitis, drug 
fever, and factitious fever.
5. Undiagnosed FUO—
Despite extensive evaluation, the 
diagnosis remains elusive in 15% or more of patients. Of 
these patients, the fever abates spontaneously in about 75% 
with no diagnosis; in the remainder, more classic manifes
-
tations of the underlying disease appear over time.

-
 
»
Because the evaluation of a patient with FUO is costly and 
time-consuming, it is imperative to first document the 
presence of fever. This is done by observing the patient 
while the temperature is being taken to ascertain that fever 
is not factitious (self-induced). Associated findings that 
accompany fever include tachycardia, chills, and piloerec
-
tion. A thorough history—including family, occupational, 
social (sexual practices, use of injection drugs), dietary 
(unpasteurized products, raw meat), exposures (animals, 
chemicals), and travel—may give clues to the diagnosis. 
Repeated physical examination may reveal subtle, evanes
-
cent clinical findings essential to diagnosis.
A. Laboratory Tests
In addition to routine laboratory studies, blood cultures 
should always be obtained, preferably when the patient has 
not taken antibiotics for several days, and should be held by 
the laboratory for 2 weeks to detect slow-growing organ
-
isms. Cultures on special media are requested if 
Legionella, 
Bartonella
, or nutritionally deficient streptococci are pos
-
sible pathogens. “Screening tests” with immunologic or 
microbiologic serologies (“febrile agglutinins”) are of low 
yield and should 
not
 be done. If the history or physical 
examination suggests a specific diagnosis, specific sero
-
logic tests with an associated fourfold rise or fall in titer 
may be useful. Because infection is the most common 
cause of FUO, other body fluids are usually cultured, ie, 
urine, sputum, stool, cerebrospinal fluid, and morning 
gastric aspirates (if one suspects tuberculosis). Direct 
examination of blood smears may establish a diagnosis of 
malaria or relapsing fever (
Borrelia
).
B. Imaging
All patients with FUO should have a chest radiograph. Stud
-
ies such as sinus CT, upper gastrointestinal series with small 
bowel follow-through, barium enema, proctosigmoidos
-
copy, and evaluation of gallbladder function are reserved for 
patients who have symptoms, signs, or a history that suggest 
disease in these body regions. CT scan of the abdomen and 
pelvis is also frequently performed and is particularly useful 
for looking at the liver, spleen, and retroperitoneum. 
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When the CT scan is abnormal, the findings often lead to a 
specific diagnosis. A normal CT scan is not quite as useful; 
more invasive procedures such as biopsy or exploratory 
laparotomy may be needed. The role of MRI in the investiga
-
tion of FUO has not been evaluated. In general, however, 
MRI is better than CT for detecting lesions of the nervous 
system and is useful in diagnosing various vasculitides. 
Ultrasound is sensitive for detecting lesions of the kidney, 
pancreas, and biliary tree. Echocardiography should be used 
if one is considering endocarditis or atrial myxoma. Trans
-
esophageal echocardiography is more sensitive than surface 
echocardiography for detecting valvular lesions, but even a 
negative transesophageal study does not exclude endocardi
-
tis (10% false-negative rate). The usefulness of radionuclide 
studies in diagnosing FUO is variable. Some experts use 
positron emission tomography (PET) in conjunction with 
CT scans early in the investigation of FUO. However, more 
studies are needed before this practice can be more fully 
integrated into clinical practice. Theoretically, a gallium or 
PET scan would be more helpful than an indium-labeled 
white blood cell scan because gallium and fluorodeoxyglu
-
cose may be useful for detecting infection, inflammation, 
and neoplasm whereas the indium scan is useful only for 
detecting infection. Indium-labeled immunoglobulin may 
prove to be useful in detecting infection and neoplasm and 
can be used in the neutropenic patient. It is not sensitive for 
lesions of the liver, kidney, and heart because of high back
-
ground activity. In general, radionuclide scans are plagued 
by high rates of false-positive and false-negative results that 
are not useful when used as screening tests and, if done at all, 
are limited to those patients whose history or examination 
suggests local inflammation or infection.
C. Biopsy
Invasive procedures are often required for diagnosis. Any 
abnormal finding should be aggressively evaluated: Head
-
ache calls for lumbar puncture to rule out meningitis; skin 
rash should be biopsied for cutaneous manifestations of 
collagen vascular disease or infection; and enlarged lymph 
nodes should be aspirated or biopsied for neoplasm and 
sent for culture. Bone marrow aspiration with biopsy is a 
relatively low-yield procedure (15–25%; except in HIV-
positive patients, in whom mycobacterial infection is a 
common cause of FUO), but the risk is low and the proce
-
dure should be done if other less invasive tests have not 
yielded a diagnosis, particularly in persons with hemato
-
logic abnormalities. Liver biopsy will yield a specific diag
-
nosis in 10–15% of patients with FUO and should be 
considered in any patient with abnormal liver tests even if 
the liver is normal in size. CT scanning and MRI have 
decreased the need for exploratory laparotomy; however, 
surgical visualization and biopsies should be considered 
when there is continued deterioration or lack of diagnosis.
 
»
Treatment
Although an empiric course of antimicrobials is sometimes 
considered for FUO, it is 
rarely
 helpful and may impact 
infectious diseases diagnoses (eg, by reducing the sensitiv
-
ity of blood cultures).
 
»
•	
Any patient with FUO and progressive weight loss and 
other constitutional signs.
•	
Any immunocompromised patient (eg, transplant 
recipients and HIV-infected patients).
•	
Infectious diseases specialists may also be able to coor
-
dinate and interpret specialized testing (eg, Q fever 
serologies) with outside agencies, such as the US Cen
-
ters for Disease Control and Prevention.
 
»
•	
Any patient who is rapidly declining with weight loss 
where hospital admission may expedite workup.
•	
If FUO is present in immunocompromised patients, 
such as those who are neutropenic from recent chemo
-
therapy or those who have undergone transplantation 
(particularly in the previous 6 months).

•	
-
Brown M. Pyrexia of unknown origin 90 years on: a paradigm of 
modern clinical medicine. Postgrad Med J. 2015 Dec; 
91(1082):665–9. [PMID: 26489766]
Hu L et al. Diagnostic value of PCT and CRP for detecting seri
-
ous bacterial infections in patients with fever of unknown 
origin: a systematic review and meta-analysis. Appl Immuno
-
histochem Mol Morphol. 2017 Sep;25(8):e61–9. [PMID: 
28885233]
Loizidou A et al. Fever of unknown origin in cancer patients. 
Crit Rev Oncol Hematol. 2016 May;101:125–30. [PMID: 
26995082]
Takeuchi M et al. Nuclear imaging for classic fever of unknown 
origin: meta-analysis. J Nucl Med. 2016 Dec;57(12):1913–9. 
[PMID: 27339873]
INFECTIONS IN THE 
IMMUNOCOMPROMISED PATIENT
 
»
Fever and other symptoms may be blunted 
because of immunosuppression.
 
»
A contaminating organism in an immunocompe
-
tent individual may be a pathogen in an immuno
-
compromised one.
 
»
The interval since transplantation and the degree 
of immunosuppression can narrow the differential 
 
»
Empiric broad-spectrum antibiotics may be appro
-
priate in high-risk patients whether or not symp
-
toms are localized.
 
»
Immunocompromised patients have defects in their natural 
defense mechanisms resulting in an increased risk 
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PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1297
 
CMDT 2019
for infection. In addition, infection is often severe, rapidly 
progressive, and life threatening. Organisms that are not usu
-
ally problematic in the immunocompetent person may be 
important pathogens in the compromised patient (eg, 
Staph
-
ylococcus epidermidis, Corynebacterium jeikeium, Propioni
-
bacterium acnes, Bacillus
 species). Therefore, culture results 
must be interpreted with caution, and isolates should not be 
disregarded as solely contaminants. Although the type of 
immunodeficiency is associated with specific infectious dis
-
ease syndromes, any pathogen can cause infection in any 
immunosuppressed patient at any time. Thus, a systematic 
evaluation is required to identify a specific organism.
A. Impaired Humoral Immunity
Defects in humoral immunity are often congenital, 
although hypogammaglobulinemia can occur in multiple 
myeloma, chronic lymphocytic leukemia, small lympho
-
cyte lymphoma, and in patients who have undergone sple
-
nectomy. Patients with ineffective humoral immunity lack 
opsonizing antibodies and are at particular risk for infec
-
tion with 
encapsulated organisms
, such as 
Haemophilus 
influenzae, Neisseria meningitides
, and 
Streptococcus pneu
-
moniae
. Although rituximab is normally thought of as 
being linked to impaired cellular immunity, it has been 
associated with the development of 
 
infection as well as with hepatitis B reactivation.
B. Granulocytopenia (Neutropenia)
Granulocytopenia is common following hematopoietic cell 
transplantation (“stem cell transplantation”) and among 
patients with solid tumors—as a result of myelosuppressive 
chemotherapy—and in acute leukemias. The risk of infec
-
tion begins to increase when the absolute granulocyte 
count falls 
below 1000/mcL,
 with a dramatic increase in 
frequency and severity when the granulocyte count falls 
below 100/mcL. The infection risk is also increased with a 
rapid rate of decline of neutrophils and with a prolonged 
period of neutropenia. The granulocytopenic patient is 
particularly susceptible to infections with gram-negative 
enteric organisms, 
, gram-positive cocci (par
-
ticularly 
, 
S epidermidis
, and viridans 
streptococci), 
Candida, Aspergillus
, and other fungi that 
have recently emerged as pathogens such as 
Trichosporon, 
Scedosporium, Fusarium
, and the mucormycoses.
C. Impaired Cellular Immunity
Patients with cellular immune deficiency encompass a large 
and heterogeneous group, including patients with HIV infec
-
tion (see Chapter 31); patients with lymphoreticular malig
-
nancies, such as Hodgkin disease; and patients receiving 
immunosuppressive medications, such as corticosteroids, 
cyclosporine, tacrolimus, and other cytotoxic medications. 
This latter group—those who are immunosuppressed as a 
result of medications—includes patients who have under
-
gone solid organ transplantation, many patients receiving 
therapy for solid tumors, and patients receiving prolonged 
high-dose corticosteroid treatment (eg, for asthma, temporal 
arteritis, systemic lupus erythematosus). Patients taking 
tumor necrosis factor (TNF) inhibitors, such as etanercept 
and infliximab, are also included in this category. Patients 
with cellular immune dysfunction are susceptible to infec
-
tions by a large number of organisms, particularly ones that 
replicate intracellularly. Examples include bacteria, such as 
Listeria, Legionella, Salmonella
, and 
Mycobacterium;
 viruses, 
such as herpes simplex, varicella, and CMV; fungi, such as 
Cryptococcus, Coccidioides, Histoplasma
, and 
Pneumocystis;
 
and protozoa, such as 
.
D. Hematopoietic Cell Transplant Recipients
The length of time it takes for complications to occur in 
hematopoietic cell transplant recipients can be helpful in 
determining the etiologic agent. In the 
early (preengraft
-

-
ment) posttransplant period (days 1–21),
 patients will 
become severely neutropenic for 7–21 days. Patients are at 
risk for gram-positive (particularly catheter-related) and 
gram-negative bacterial infections, as well as herpes sim
-
plex virus, respiratory syncytial virus, and fungal infec
-
tions. In contrast to solid organ transplant recipients, the 
source of fever is unknown in 60–70% of hematopoietic 
cell transplant patients. 
Between 3 weeks and 3 months 
posttransplant,
 infections with CMV , adenovirus, 
Asper
-
gillus
, and 
Candida
 are most common. 
 pneumo
-
nia is possible, particularly in patients who receive 
additional immunosuppression for treatment of graft-
versus-host disease. Patients continue to be at risk for 
infectious complications 
beyond 3 months following 
transplantation,
 particularly those who have received 
allogeneic transplantation and those who are taking immu
-
nosuppressive therapy for chronic graft-versus-host dis
-
ease. Varicella-zoster is common, and 
 and 
CMV infections are increasingly seen in this period as well.
E. Solid Organ Transplant Recipients
The length of time it takes for infection to occur following 
solid organ transplantation can also be helpful in determin
-
ing the infectious origin. 
Immediate postoperative infec
-
tions
 often involve the transplanted organ. Following lung 
transplantation, pneumonia and mediastinitis are particu
-
larly common; following liver transplantation, intra-
abdominal abscess, cholangitis, and peritonitis may be seen; 
after kidney transplantation, urinary tract infections, peri
-
nephric abscesses, and infected lymphoceles can occur.
Most infections that occur in the 
first 2–4 weeks post
-
transplant
 are related to the operative procedure and to 
hospitalization itself (wound infection, intravenous catheter 
infection, urinary tract infection from a Foley catheter) or 
are related to the transplanted organ. In rare instances, 
donor-derived infections (eg, West Nile virus, tuberculosis) 
may present during this time period. Compensated organ 
transplants obtained abroad through “medical tourism” can 
introduce additional risk of infections, which vary by coun
-
try and by transplant setting. Infections that occur between 
the 
first and sixth months
 are often related to immunosup
-
pression. During this period, reactivation of viruses, such as 
herpes simplex, varicella-zoster, and CMV is quite common. 
Opportunistic infections with fungi (eg, 
Candida, Aspergillus, 
), 
, 
 
Nocardia
, and 
 are also common. 
After 6 months,
 
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if immunosuppression has been reduced to maintenance 
levels, infections that would be expected in any population 
occur. Patients with poorly functioning allografts receiving 
long-term immunosuppression therapy continue to be at 
risk for opportunistic infections.
F. Tumor Necrosis Factor Inhibitor Recipients
Patients taking TNF inhibitors have specific defects that 
increase risk of bacterial, mycobacterial (particularly 
tuberculosis), viral (HBV reactivation and HCV progres
-
sion), and fungal infections (
, molds, and 
endemic mycoses). Infection risk may be highest shortly 
after therapy is initiated (within the first 3 months) and 
with a higher dose of medications.
G. Recipients of Other Biologics
In addition to TNF inhibitors, other biologics target a vari
-
ety of immunologic pathways that are involved in immuno
-
logic mediated disease and in cancer replication. Disruption 
of these pathways include, but are not limited to impact on 
B cells, T cells, complement and leukocytes. This may result 
in not only serious infections, but the development of auto
-
immune disease and malignancies as well. Some medica
-
tions have been observed to have specific associations with 
opportunistic infections (eg, natalizumab and progressive 
multifocal leukoencephalopathy, or eculizumab and menin
-
gococcal disease). Other biologics such as chimeric antigen 
receptor T cells may have unintended infectious risks that 
are currently unknown, or may have adverse effects that 
mimic infection (eg, cytokine release syndrome). As more 
biologics are developed and used, clinicians must remain 
vigilant for the possibility of serious infectious disease risk.
H. Other Immunocompromised States
A large group of patients who are not specifically immuno
-
deficient are at increased risk for infection due to debilitating 
injury (eg, burns or severe trauma), invasive procedures 
(eg, chronic central intravenous catheters, Foley catheters, 
dialysis catheters), central nervous system dysfunction 
(which predisposes patients to aspiration pneumonia and 
decubitus ulcers), obstructing lesions (eg, pneumonia due to 
an obstructed bronchus, pyelonephritis due to nephrolithia
-
sis, cholangitis secondary to cholelithiasis), and use of 
broad-spectrum antibiotics. Patients with diabetes mellitus 
have alterations in cellular immunity, resulting in mucormy
-
cosis, emphysematous pyelonephritis, and foot infections.
 
»
Routine evaluation includes complete blood count with 
differential, chest radiograph, and blood cultures; urine 
and respiratory cultures should be obtained if indicated 
clinically or radiographically. Any focal complaints (local
-
ized pain, headache, rash) should prompt imaging and 
cultures appropriate to the site.
Patients who remain febrile without an obvious source 
should be evaluated for viral infection (serum CMV antigen 
test or polymerase chain reaction), abscesses (which usually 
occur near previous operative sites), candidiasis involving the 
liver or spleen, or aspergillosis. Serologic evaluation may be 
helpful if toxoplasmosis or an endemic fungal infection (coc
-
cidioidomycosis, histoplasmosis) is a possible cause. Antigen-
based assays may be useful for the diagnosis of aspergillosis 
(detected by galactomannan level in serum or bronchoalveo
-
lar lavage fluid), or other invasive fungal disease, including 
 infection (serum [1 
→ 
3]-beta-D-glucan level).
B. Special Diagnostic Procedures
Special diagnostic procedures should also be considered. 
The cause of pulmonary infiltrates can be easily deter
-
mined with simple techniques in some situations—eg, 
induced sputum yields a diagnosis of 
 pneu
-
monia in 50–80% of AIDS patients with this infection. In 
other situations, more invasive procedures may be required 
(bronchoalveolar lavage, transbronchial biopsy, open lung

 pneu
-
(bronchoalveolar lavage, transbronchial biopsy, open lung 
biopsy). Skin, liver, or bone marrow biopsy may be helpful 
in establishing a diagnosis. Next generation DNA-sequenc
-
ing analysis is being evaluated as an option for diagnosis of 
infectious diseases in immunocompromised persons.
 
»
Transplant rejection, organ ischemia and necrosis, throm
-
bophlebitis, and lymphoma (posttransplant lymphoprolif
-
erative disease) may all present as fever and must be 
 
»
While prophylactic antimicrobial medications are used com
-
monly, the optimal medications or dosage regimens are 
debated. 
Hand washing
 is the simplest and most effective 
means of decreasing hospital-associated infections, especially 
in the compromised patient. Invasive devices such as central 
and peripheral lines and Foley catheters are potential sources 
of infection. Some centers use laminar airflow isolation or 
high-efficiency particulate air (HEPA) filtering in hemato
-
poietic cell transplant patients. Rates of infection and epi
-
sodes of febrile neutropenia, but not mortality, are decreased 
if colony-stimulating factors are used (typically in situations 
where the risk of febrile neutropenia is 20% or higher) during 
chemotherapy or during stem-cell transplantation.
A. 
 & Herpes Simplex Infections
Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-
strength tablet orally three times a week, one double-
strength tablet twice daily on weekends, or one 
single-strength tablet daily for 3–6 months, is frequently 
used to prevent 
 infections in transplant 
patients. In patients allergic to TMP-SMZ, dapsone, 50 mg 
orally daily or 100 mg three times weekly, is recommended. 
Glucose-6-phosphate dehydrogenase (G6PD) levels should 
be assessed before dapsone is instituted. Acyclovir prevents 
herpes simplex infections in bone marrow and solid organ 
transplant recipients and is given to seropositive patients 
who are not receiving ganciclovir or valganciclovir for 
CMV prophylaxis. The usual dose is 200 mg orally three 
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times daily for 4 weeks (hematopoietic cell transplants) to 
12 weeks (other solid organ transplants).
B. CMV
No uniformly accepted approach has been adopted for 
prevention of CMV . Prevention strategies often depend on 
the serologic status of the donor and recipient and the 
organ transplanted, which determines the level of immu
-
nosuppression after transplant. In solid organ transplants 
(liver, kidney, heart, lung), the greatest risk of developing 
CMV disease is in seronegative recipients who receive 
organs from seropositive donors. These high-risk patients 
usually receive oral valganciclovir, 900 mg daily for 
3–6 months (longer in lung transplant recipients). Other 
solid organ transplant recipients (seropositive recipients) 
are at lower risk for developing CMV disease, but still usu
-
ally receive oral valganciclovir for 3 months. The lowest-
risk group for the development of CMV disease is in 
seronegative patients who receive organs from seronegative 
donors. Typically, no CMV prophylaxis is used in this 
group. Ganciclovir and valganciclovir also prevent herpes 
virus reactivation. Because immunosuppression is 
increased during periods of rejection, patients treated for 
rejection usually receive CMV prophylaxis during rejec
-
tion therapy. Alternatively, in a preemptive approach, 
patients can be monitored without specific prophylaxis by 
having blood sampled weekly to look for CMV by poly
-
merase chain reaction techniques. If CMV is detected, then 
therapy is instituted with oral valganciclovir, 900 mg orally 
twice daily for a minimum of 2–3 weeks.
Recipients of hematopoietic cell transplants are more 
severely immunosuppressed than recipients of solid organ 
transplants, are at greater risk for developing serious CMV 
infection (usually CMV reactivation), and thus usually 
receive more aggressive prophylaxis. Like in solid organ 
transplant recipients, two approaches have been used: 
uni
-
versal prophylaxis
 or 
preemptive therapy.
 In the former, all 
high-risk patients (seropositive patients who receive allo
-
geneic transplants) may receive oral valganciclovir, 900 mg 
daily to day 100. However, valganciclovir is associated with 
significant bone marrow toxicity. Letermovir is being used 
increasingly, and it is not associated with bone marrow 
toxicity. Universal prophylaxis may be costly. Because of 
the possibility of bone marrow toxicity and the expense, 
many clinicians traditonally preferred the preemptive 
approach over the universal prophylaxis approach for 
recipients of hematopoietic stem cell transplants. However, 
while this preemptive approach is effective, it does miss a 
small number of patients in whom CMV disease would 
have been prevented had prophylaxis been used. Other 
preventive strategies include use of CMV-negative or leu
-
kocyte-depleted blood products for CMV-seronegative 
C. Other Organisms
Routine decontamination of the gastrointestinal tract to pre
-
vent bacteremia in the neutropenic patient is not recom
-
mended. The use of prophylactic antibiotics in the afebrile, 
asymptomatic neutropenic patient is debated, although many 
centers have adopted this strategy. Rates of bacteremia are 
decreased, but overall mortality is not affected and emer
-
gence of resistant organisms takes place. Use of intravenous 
immunoglobulin is reserved for the small number of patients 
with severe hypogammaglobulinemia following hematopoi
-
etic stem cell transplantation and should not be routinely 
administered to all transplant patients.
Prophylaxis with antifungal agents to prevent invasive 
mold (primarily 
) and yeast (primarily 
Candida
) 
infections is routinely used, but the optimal agent, dose, and 
duration are also debated. Lipid-based preparations of 
amphotericin B, aerosolized amphotericin B, intravenous 
and oral fluconazole or voriconazole, and oral posaconazole

and oral fluconazole or voriconazole, and oral posaconazole 
solution and tablets are all prophylactic options in the neu
-
tropenic patient. Because voriconazole is superior to ampho
-
tericin for documented 
 infections and because 
posaconazole prophylaxis (compared with fluconazole) has 
been shown to result in fewer cases of invasive aspergillosis 
among allogeneic stem cell transplant recipients with graft-
versus-host disease, one approach to prophylaxis is to use 
oral fluconazole (400 mg/day) for patients at low risk for 
developing fungal infections (those who receive autologous 
stem cell transplants) and oral voriconazole (200 mg twice 
daily) or oral posaconazole (200 mg suspension three times 
daily or 300 mg [three 100-mg tablets] sustained-release 
tablets once daily) for those at high risk (allogeneic trans
-
plants, graft-versus-host disease) at least until engraftment 
(usually 30 days). In solid organ transplant recipients, the 
risk of invasive fungal infection varies considerably (1–2% in 
liver, pancreas, and kidney transplants and 6–8% in heart 
and lung transplants). Whether universal prophylaxis or 
observation with preemptive therapy is the best approach 
has not been determined. Although fluconazole is effective 
in preventing yeast infections, emergence of fluconazole-
resistant 
Candida
 and molds (
Fusarium, Aspergillus, Mucor
) 
has raised concerns about its routine use as a prophylactic 
agent in the general solid organ transplant population. How
-
ever, liver transplant recipients with additional risk factors, 
such as having undergone a choledochojejunostomy, having 
had a high transfusion requirement or having developed 
kidney disease, may benefit from abbreviated postoperative 
Candida
 prophylaxis.
Given the high risk of reactivation of tuberculosis in 
patients taking TNF inhibitors, all patients should be 
screened for latent tuberculosis infection (LTBI) with a 
tuberculin skin test or an interferon-gamma release assay 
prior to the start of therapy. If LTBI is diagnosed, treatment 
with the TNF inhibitors should be delayed until treatment 
for LTBI is completed. There is also a marked risk of reac
-
tivation of hepatitis B and hepatitis C in patients taking 
TNF inhibitors; patients should also be screened for these 
viruses when TNF inhibitor treatment is being considered. 
Providers should also ensure that patients’ vaccinations are 
up-to-date before starting TNF inhibitors therapy.
 
»
Treatment
Because infections in the immunocompromised patient 
can be rapidly progressive and life-threatening, diagnostic 
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procedures must be performed promptly, and empiric 
therapy is usually instituted.
While reduction or discontinuation of immunosup
-
pressive medication may jeopardize the viability of the 
transplanted organ, this measure may be necessary if the 
infection is life-threatening. Hematopoietic growth factors 
(granulocyte and granulocyte-macrophage colony-
 
stimulating factors) stimulate proliferation of bone marrow 
stem cells, resulting in an increase in peripheral leukocytes. 
These agents shorten the period of neutropenia and have 
been associated with reduction in infection.
Antimicrobial medication therapy ultimately should be 
tailored to culture results. While combinations of antimi
-
crobials are used with the intent of providing synergy or 
preventing resistance, the primary reason for empiric com
-
bination therapy is broad-spectrum coverage of all likely 
pathogens.
Empiric therapy is often instituted at the earliest sign of 
infection in the immunosuppressed patient because 
prompt therapy favorably affects outcome. The antibiotic 
or combination of antibiotics used depends on the degree 
of immune compromise and the site of infection. For 
example, in the febrile neutropenic patient, an 
algorithmic 
approach
 to therapy is often used. Febrile neutropenic 
patients should be empirically treated with broad-spectrum 
agents active against selected gram-positive bacteria, 
Pseu
-
domonas aeruginosa
, and other aerobic gram-negative 
bacilli (such as cefepime 2 g every 8 hours intravenously). 
The addition of vancomycin, 10–15 mg/kg/dose intrave
-
nously every 12 hours, should be considered in those 
patients with suspected infection due to methicillin-
resistant 
 (MRSA), 
, 
enterococcus, and resistant viridans streptococci. Contin
-
ued neutropenic fever necessitates broadening of antibac
-
terial coverage from cefepime to agents such as imipenem 
500 mg every 6 hours or meropenem 1 g every 8 hours 
intravenously with or without tobramycin 5–7 mg/kg 
intravenously every 24 hours. Antifungal agents (such as 
voriconazole, 200 mg intravenously or orally every 
12 hours, or caspofungin, 50 mg daily intravenously) 
should be added if fevers continue after 5–7 days of broad-
spectrum antibacterial therapy. Regardless of whether the 
patient becomes afebrile, 
therapy is continued until resolu
-
tion of neutropenia
. Failure to continue antibiotics through 
the period of neutropenia has been associated with 
increased morbidity and mortality.
Patients with fever and low-risk neutropenia (neutrope
-
nia expected to persist for less than 10 days, no comorbid 
complications requiring hospitalization, and cancer ade
-
quately treated) can be treated with oral antibiotic regi
-
mens, such as ciprofloxacin, 750 mg every 12 hours, plus 
amoxicillin-clavulanic acid, 500 mg every 8 hours. Antibi
-
otics are continued as long as the patient is neutropenic 
even if a source is not identified. In the organ transplant 
patient with interstitial infiltrates, the main concern is 
infection with 
 or 
 species, so that 
empiric treatment with a macrolide or fluoroquinolone 
(
) and TMP-SMZ, 15 mg/kg/day orally 
or intravenously, based on trimethoprim component 
(
) would be reasonable in those patients not 
receiving TMP-SMZ prophylaxis. If the patient does not 
respond to empiric treatment, a decision must be made to 
add more antimicrobial agents or perform invasive proce
-
dures (see above) to make a specific diagnosis. By making 
a definite diagnosis, therapy can be specific, thereby reduc
-
ing selection pressure for resistance and superinfection.
 
»
•	
Any immunocompromised patient with an opportunistic 
•	
Patients with potential drug toxicities and drug interac
-
tions related to antimicrobials where alternative agents 
are sought.
•

•	
-
•	
Patients with latent tuberculosis, HBV , and HCV infec
-
tion in whom therapy with TNF inhibitors is planned.
 
»
Immunocompromised patients who are febrile, or those 
without fevers in whom an infection is suspected, particu
-
larly in the following groups: solid-organ or hematopoietic 
stem cell transplant recipient (particularly in the first 
6 months), neutropenic patients, patients receiving TNF 
inhibitors, transplant recipients who have had recent rejec
-
tion episodes (including graft-versus-host disease).
Beyar-Katz O et al. Empirical antibiotics targeting gram-positive 
bacteria for the treatment of febrile neutropenic patients with 
cancer. Cochrane Database Syst Rev. 2017 Jun 3;6:CD003914. 
[PMID: 28577308]
Maertens JA et al. Isavuconazole versus voriconazole for primary 
treatment of invasive mould disease caused by 
 and 
other filamentous fungi (SECURE): a phase 3, randomised-
controlled, non-inferiority trial. Lancet. 2016 Feb 20; 
387(10020):760–9. [PMID: 26684607]
Marr KA et al. Combination antifungal therapy for invasive 
aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20; 
162(2):81–9. Erratum in: Ann Intern Med. 2015 Mar 17; 
162(6):463. [PMID: 25599346]
Marty FM et al. Letermovir prophylaxis for cytomegalovirus in 
hematopoietic-cell transplantation. N Engl J Med. 2017 Dec 21; 
377(25):2433–44. [PMID: 29211658]
Patterson TF et al. Executive summary: practice guidelines for 
the diagnosis and management of aspergillosis: 2016 update 
by the Infectious Diseases Society of America. Clin Infect Dis. 
2016 Aug 15;63(4):433–42. [PMID: 27481947]
Vallabhaneni S et al. Investigation of the first seven reported 
cases of 
Candida auris
, a globally emerging invasive, multi
-
drug-resistant fungus—United States, May 2013–August 
2016. MMWR Morb Mortal Wkly Rep. 2016 Nov 11; 
65(44):1234–7. [PMID: 27832049]
HEALTH CARE–ASSOCIATED INFECTIONS
 
»
Health care–associated infections are acquired 
during the course of receiving health care treat
-
ment for other conditions.
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»
Hospital-associated infections are a subset of 
health care–associated infections defined as those 
not present or incubating at the time of hospital 
admission and developing 48 hours or more after 
admission.
 
»
Most health care–associated infections are 
preventable.
 
»
Hand washing is the most effective means of pre
-
venting health care–associated infections and 
should be done routinely even when gloves are 
worn.
 
»
In the United States, approximately 5% of patients acquire 
a health care–associated infection, resulting in prolonga
-
tion of the hospital stay, increase in cost of care, and signifi
-
cant morbidity and mortality. The most common infections 
are urinary tract infections, usually associated with Foley 
catheters or urologic procedures; bloodstream infections, 
most commonly from indwelling catheters but also from 
secondary sites, such as surgical wounds, abscesses, pneu
-
monia, the genitourinary tract, and the gastrointestinal 
tract; pneumonia in intubated patients or those with 
altered levels of consciousness; surgical wound infections; 
MRSA infections; and 
 colitis.
Some general principles are helpful in preventing, diag
-
nosing, and treating health care–associated infections:
1.
 
Many infections are a direct result of the use of 
invasive 
devices
 for monitoring or therapy, such as intravenous 
catheters, Foley catheters, shunts, surgical drains, cath
-
eters placed by interventional radiology for drainage, 
nasogastric tubes, and orotracheal or nasotracheal 
tubes for ventilatory support. Early removal of such 
devices reduces the possibility of infection.
2.
 
Patients in whom health care–associated infections 
develop are often critically ill, have been hospitalized 
for extended periods, and have received several courses 
of broad-spectrum antibiotic therapy. As a result, health 
care–associated infections are often due to 
multidrug 
resistant pathogens
 and differ from those encountered 
in community-acquired infections. For example, 
 
S aureus
 and 
 (a frequent cause of pros
-
thetic device infection) are often resistant to methicillin 
and most cephalosporins (ceftaroline is active against 
MRSA) and require vancomycin for therapy; 
Enterococcus faecium
 resistant to ampicillin and vanco
-
mycin; gram-negative infections caused by 
Pseudomonas, Citrobacter, Enterobacter, Acinetobacter
, 
Stenotrophomonas,
 extended-spectrum beta-lactamases 
(ESBL)–producing 
E coli,
 and 
 may be resis
-
tant to most antibacterials. When choosing antibiotics 
to treat the seriously ill patient with a health care–
associated infection, antimicrobial history and the 
“local ecology” must be considered. In the most seri
-
ously ill patients, broad-spectrum coverage with vanco
-
mycin and a carbapenem with or without an 
aminoglycoside is recommended. Once a pathogen is 
isolated and susceptibilities are known, the most nar
-
row-spectrum, least toxic, most cost-effective regimen 
Widespread use of antimicrobial medications contributes 
to the selection of drug-resistant organisms, thus 
every effort 
should be made to limit the spectrum of coverage and unneces
-
sary duration
. All too often, unreliable or uninterpretable 
specimens are obtained for culture that result in unnecessary 
use of antibiotics. The best example of this principle is the 
diagnosis of line-related or bloodstream infection in the 
febrile patient. To avoid unnecessary use of antibiotics, 
thoughtful consideration of culture results is mandatory. 
 
A positive wound culture without signs of inflammation or 
infection, a positive sputum culture without pulmonary infil
-
trates on chest radiograph, or a positive urine culture in a 
catheterized patient without symptoms or signs of pyelone
-
phritis are all likely to represent 
colonization,
 not infection.
 
»

-
-
 
»
Catheter-associated infections have a variable presentation, 
depending on the type of catheter used (peripheral or cen
-
tral venous catheters, nontunneled or tunneled). Local 
signs of infection may be present at the insertion site, with 
pain, erythema, and purulence. Fever is often absent in 
uncomplicated infections and if present, may indicate 
more disseminated disease such as bacteremia, cellulitis 
and septic thrombophlebitis. Often signs of infection at the 
insertion site are absent.
1. Fever in an intensive care unit patient—
Fever compli
-
cates up to 70% of patients in intensive care units, and the 
etiology of the fever may be infectious or noninfectious. 
Common infectious causes include catheter-associated infec
-
tions, hospital-acquired and ventilator-associated pneumo
-
nia (see Chapter 9), surgical site infections, urinary tract 
infections, and sepsis. Clinically relevant sinusitis is relatively 
uncommon in the patient in the intensive care unit.
An important noninfectious cause is thromboembolic 
disease. Fever in conjunction with refractory hypotension 
and shock may suggest sepsis; however, adrenal insuffi
-
ciency, thyroid storm, and transfusion reaction may have a 
similar clinical presentation. Drug fever is difficult to diag
-
nose and is usually a diagnosis of exclusion unless there are 
other signs of hypersensitivity, such as a typical maculo
-
papular rash (most common with beta-lactams).
2. Fever in the postoperative patient—
fever is very common and noninfectious fever resolves 
spontaneously. Timing of the onset of the fever in relation 
to the surgical procedure may be of diagnostic benefit.
a. Immediate fever (in the first few hours after 
surgery)—
Immediate fever can be due to medications 
that were given perioperatively, to surgical trauma, or to 
infections that were present before surgery. Necrotizing 
fasciitis due to group A streptococci or mixed organisms 
may present in this period. Malignant hyperthermia is rare 
and presents 30 minutes to several hours following 
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inhalational anesthesia and is characterized by extreme 
hyperthermia, muscle rigidity, rhabdomyolysis, electrolyte 
abnormalities, and hypotension. Aggressive cooling and 
dantrolene are the mainstays of therapy. Aspiration of 
acidic gastric contents during surgery can result in a 
chemical pneumonitis (
Mendelson syndrome
) that devel
-
ops rapidly, is transient, and does not require antibiotics. 
Fever due to surgical trauma usually resolves in 2–3 days; 
however, it may be longer in more complicated operative 
cases and in patients with head trauma.
b. Acute fever (within 1 week of surgery)—
Acute 
fever is usually due to common causes of hospital-
associated infections, such as ventilator-associated pneu
-
monia (including aspiration pneumonia in patients with 
decreased gag reflex) and line infections. Noninfectious 
causes include alcohol withdrawal, gout, pulmonary embo
-
lism, and pancreatitis. Atelectasis following surgery is com
-
monly invoked as a cause of postoperative fever but there is 
no good evidence
 to support a causal association between 
the presence or degree of atelectasis and fever.
c. Subacute fever (at least 1 week after surgery)—
Surgical site infections commonly present at least 1 week 
after surgery. The type of surgery that was performed pre
-
dicts specific infectious etiologies. Patients undergoing 
cardiothoracic surgery may be at higher risk for pneumo
-
nia and deep and superficial sternal wound infections. 
Meningitis without typical signs of meningismus may 
complicate neurosurgical procedures. Postoperative deep 
abdominal abscesses may require drainage.
Blood cultures are universally recommended, and chest 
radiographs are frequently obtained. A properly prepared 
sputum Gram stain and semi-quantitative sputum cultures 
may be useful in selected patients where there is a high 
pretest probability of pneumonia but multiple exclusion 
criteria probably limit generalizability in most patients, 
such as immunocompromised patients and those with 
drug resistance. Other diagnostic strategies will be dictated 
by the clinical context (eg, transesophageal echocardio
-
gram in a patient with 
S aureus
 bacteremia).
Any fever in a patient with a central venous catheter 
should prompt the collection of blood. The best method to 
evaluate bacteremia is to gather 
at least two peripherally 
obtained blood cultures.
 Blood cultures from unidentified 
sites, a single blood culture from any site, or a blood culture 
through an existing line will often be positive for coagulase-
positive staphylococci, particularly 
, often 
resulting in the inappropriate use of vancomycin. Unless 
two separate venipuncture cultures are obtained—not 
through catheters—interpretation of results is impossible, 
and unnecessary therapy often results. Each 
“pseudobacteremia” increases laboratory costs, antibiotic 
use, and length of stay. Microbiologic evaluation of the 
removed catheter can sometimes be helpful, but only in 
addition to (not instead of) blood cultures drawn from 
peripheral sites. The 
differential time to positivity
 mea
-
sures the difference in time that cultures simultaneously 
drawn through a catheter and a peripheral site become 
positive. A positive test (at least 120 minutes’ difference in 
time) supports a catheter-related bloodstream infection, 
while a negative test suggests catheters may be retained.
 
»
Complications such as septic thrombophlebitis, endocardi
-
tis, or metastatic foci of infection (particularly with 
S aureus
) 
may be suspected in patients with persistent bacteremia and 
fever despite removal of the infected catheter. Additional 
studies such as venous Doppler studies, transesophageal 
echocardiogram, and chest radiographs may be indicated, 
and 4–6 weeks of antibiotics may be needed. In the case of 
septic thrombophlebitis, anticoagulation with heparin is also

septic thrombophlebitis, anticoagulation with heparin is also 
recommended if there are no contraindications.
 
»
Although most fevers are due to infections, about 25% of 
patients will have fever of noninfectious origin, including 
drug fever, nonspecific postoperative fevers (tissue damage 
or necrosis), hematoma, pancreatitis, pulmonary embo
-
lism, myocardial infarction, and ischemic bowel disease.
 
»
The concept of universal precautions emphasizes that all 
patients are treated as though they have a potential blood-
borne transmissible disease, and thus all body secretions 
are handled with care to prevent spread of disease. Body 
substance isolation requires use of gloves whenever a 
health care worker anticipates contact with blood or other 
body secretions. Even though gloves are worn, 
health care 
workers should routinely wash their hands,
 since it is the 
easiest and most effective means of preventing hospital-
associated infections. Application of a rapid drying, alco
-
hol-based antiseptic is simple, takes less time than 
traditional hand washing with soap and water, is more 
effective at reducing hand colonization, and promotes 
compliance with hand decontamination. For prevention of 
transmission of 
 infection, hand washing is more 
effective than alcohol-based antiseptics. Consequently, 
even after removing gloves, providers should always wash 
hands in cases of proven or suspected 
Peripheral intravenous lines should be replaced no more 
frequently than every 3–4 days. Some clinicians replace 
only when clinically indicated or if the line was put in emer
-
gently. Arterial lines and lines in the central venous circula
-
tion (including those placed peripherally) can be left in 
place indefinitely and are changed or removed when they 
are clinically suspected of being infected, when they are 
nonfunctional, or when they are no longer needed. Using 
sterile barrier precautions (including cap, mask, gown, 
gloves, and drape) is recommended while inserting central 
venous catheters. Antibiotic-impregnated (minocycline 
plus rifampin or chlorhexidine plus silver sulfadiazine) 
venous catheters reduce line infections. Silver alloy–
impregnated Foley catheters reduce the incidence of 
catheter-associated bacteriuria, but not consistently cathe
-
ter-associated urinary tract infections. Best practices to 
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prevent ventilator-associated pneumonia include avoiding 
intubation if possible, minimizing and daily interruption of 
sedation, pooling/draining of subglottic secretions above 
the tube cuff, and elevating the head of the bed. Silver-
coated endotracheal tubes may reduce the incidence of 
ventilator-associated pneumonia but has limited impact on 
hospital stay duration or mortality, so they are not generally 
recommended. Catheter-related urinary tract infections 
and intravenous catheter-associated infections are not 
Medicare-reimbursable conditions in the United States. 
Preoperative skin preparation with chlorhexidine and alco
-
hol (versus povidone-iodine) reduces the incidence of 
infection following surgery. Another strategy that can pre
-
vent surgical-site infections is the identification and treat
-
ment of 
S aureus
 nasal carriers with 2% mupirocin nasal 
ointment and chlorhexidine soap. Daily bathing of ICU 
patients with chlorhexidine-impregnated washcloths versus 
soap and water results in lower incidence of health care–
associated infections and colonization. Selective decon
-
tamination of the digestive tract with nonabsorbable or 
parenteral antibiotics, or both, may prevent hospital-
acquired pneumonia and decrease mortality but is in lim
-
ited use because of the concern of the development of 
antibiotic resistance.
Attentive nursing care (positioning to prevent pressure 
injuries [formerly pressure ulcers], wound care, elevating 
the head during tube feedings to prevent aspiration) is criti
-
cal in preventing hospital-associated infections. In addition, 
monitoring of high-risk areas by hospital epidemiologists is 
critical in the prevention of infection. Some guidelines 
advocate rapid screening (active surveillance cultures) for 
MRSA on admission to acute care facilities among certain 
subpopulations of patients (eg, those recently hospitalized, 
admission to the intensive care unit, patients undergoing 
hemodialysis). However, outside the setting of an MRSA 
outbreak, it is not clear whether this strategy decreases the 
incidence of hospital-associated MRSA infections.
Vaccines, including hepatitis A, hepatitis B, and the 
varicella, pneumococcal, and influenza vaccinations, are 
important adjuncts. (See section below titled Immuniza
-
tion Against Infectious Diseases.)
 
»
Treatment
A. Fever in an Intensive Care Unit Patient
Unless the patient has a central neurologic injury with ele
-
vated intracranial pressure or has a temperature higher than 
41
°
C, there is less physiologic need to maintain euthermia. 
Empiric broad-spectrum antibiotics (see Table 30–5) are 
recommended for neutropenic and other immunocompro
-
mised patients and in patients who are clinically unstable.
B. Catheter-Associated Infections
Factors that inform treatment decisions include the type of 
catheter, the causative pathogen, the availability of alter
-
nate catheter access sites, the need for ongoing intravascu
-
lar access, and the severity of disease.
In general, catheters should be removed if there is puru
-
lence at the exit site; if the organism is 
S aureus
, 
gram-negative rods, or 
Candida
 species; if there is persistent 
bacteremia (more than 48 hours while receiving antibiotics); 
or if complications, such as septic thrombophlebitis, endo
-
carditis, or other metastatic disease exist. Central venous 
catheters may be exchanged over a guidewire provided there 
is no erythema or purulence at the exit site and the patient 
does not appear to be septic. Methicillin-resistant, coagulase-
negative staphylococci are the most common pathogens; 
thus, empiric therapy with vancomycin, 15 mg/kg/dose 
intravenously twice daily, should be given assuming normal 
kidney function. Empiric gram-negative coverage should be 
used in patients who are immunocompromised or who are 
critically ill (see Table 30–5).

Antibiotic treatment duration depends on the pathogen 
and the extent of disease. For uncomplicated bacteremia, 
5–7 days of therapy is usually sufficient for coagulase-
negative staphylococci, even if the original catheter is 
retained. Fourteen days of therapy is generally recom
-
mended for uncomplicated bacteremia caused by gram-
negative rods, 
Candida
S aureus
. 
Antibiotic 
lock therapy
 involves the instillation of supratherapeutic 
concentrations of antibiotics with heparin in the lumen of 
catheters. The purpose is to achieve adequate concentra
-
tions of antibiotics to kill microbes in the biofilm. Antibi
-
otic lock therapy can be used for catheter-related 
bloodstream infections caused by coagulase-negative 
staphylococci or enterococci and when the catheter is 
being retained in a salvage situation.
 
»
•	
Any patient with multidrug-resistant infection.
•	
Any patient with fungemia or persistent bacteremia.
•	
Patients with multisite infections.
•	
Patients with impaired or fluctuating kidney function 
for assistance with dosing of antimicrobials.
•	
Patients with refractory or recurrent 
 colitis.
Baur D et al. Effect of antibiotic stewardship on the incidence of 
infection and colonization with antibiotic-resistant bacteria 
and 
 infection: a systematic review and 
meta-analysis. Lancet Infect Dis. 2017 Sep;17(9):990–1001. 
[PMID: 28629876]
Cortegiani A et al. Antifungal agents for preventing fungal infec
-
tions in non-neutropenic critically ill patients Cochrane 
Database Syst Rev. 2016 Jan 16;(1):CD004920. [PMID: 
26772902]
Dare RK et al. Health care-acquired viral respiratory diseases. 
Infect Dis Clin North Am. 2016 Dec;30(4):1053–70. [PMID: 
27816139]
ventilator-associated pneumonia: 2016 clinical practice 
guidelines by the Infectious Diseases Society of America and 
the American Thoracic Society. Clin Infect Dis. 2016 Sep 1; 
 
infection: a randomized clinical trial. JAMA. 2017 Nov 28; 
Clostridium diffi
-
cile
 infection. N Engl J Med. 2017 Jan 26;376(4):305–17. 
[PMID: 28121498]
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INFECTIONS OF THE CENTRAL 
 
»
Central nervous system infection is a medical 
emergency.
 
»
Symptoms and signs common to all central ner
-
vous system infections include headache, fever, 
sensorial disturbances, neck and back stiffness, 
positive Kernig and Brudzinski signs, and cerebro
-
spinal fluid abnormalities.
 
»
Infections of the central nervous system can be caused by 
almost any infectious agent, including bacteria, mycobac
-
teria, fungi, spirochetes, protozoa, helminths, and viruses.
 
»
Etiologic Classification
Central nervous system infections can be divided into sev
-
eral categories that usually can be readily distinguished 
from each other by cerebrospinal fluid examination as the 
first step toward etiologic diagnosis (Table 30–1).
A. Purulent Meningitis
Patients with bacterial meningitis usually seek medical 
attention within hours or 1–2 days after onset of symp
-
toms. The organisms responsible depend primarily on the 
age of the patient as summarized in Table 30–2. The diag
-
nosis is usually based on the Gram-stained smear (positive 
in 60–90%) or culture (positive in over 90%) of the cere
-
B. Chronic Meningitis
The presentation of chronic meningitis is less acute than 
purulent meningitis. Patients with chronic meningitis usu
-
ally have a history of symptoms lasting weeks to months. 
The most common pathogens are 
, atypical mycobacteria, fungi (
Cryptococcus, 
Coccidioides, Histoplasma
), and spirochetes (
Treponema 
pallidum
 and 
). The diagnosis is made 
by culture or in some cases by serologic tests (cryptococ
-
cosis, coccidioidomycosis, syphilis, Lyme disease).
C. Aseptic Meningitis
Aseptic meningitis—a much more benign and self-limited 
syndrome than purulent meningitis—is caused principally 
by viruses, especially herpes simplex virus and the enterovi
-
rus group (including coxsackieviruses and echoviruses). 
Infectious mononucleosis may be accompanied by aseptic 
meningitis. Leptospiral infection is also usually placed in 
the aseptic group because of the lymphocytic cellular 
response and its relatively benign course. This type of men
-
ingitis also occurs during secondary syphilis and dissemi
-
nated Lyme disease. Prior to the routine administration of 
measles-mumps-rubella (MMR) vaccines, mumps was the 
most common cause of viral meningitis. Drug-induced 
aseptic meningitis has been reported with nonsteroidal 
anti-inflammatory drugs, sulfonamides, and certain mono
-
clonal antibodies.
D. Encephalitis
Encephalitis (due to herpesviruses, arboviruses, rabies 
virus, flaviviruses [West Nile encephalitis, Japanese 
encephalitis], and many others) produces disturbances of 
the sensorium, seizures, and many other manifestations. 
Patients are more ill than those with aseptic meningitis. 
Cerebrospinal fluid may be entirely normal or may show 
some lymphocytes and in some instances (eg, herpes 
Table 30–1.
 
Typical cerebrospinal fluid findings in various central nervous system diseases.
Diagnosis
Cells/mcL
Glucose 
 
(mg/dL)
Protein 
 
(mg/dL)
Opening Pressure
Normal
0–5 lymphocytes
45–85
1
15–45
70–180 mm H
2
O
Purulent meningitis (bacterial)
2
 
community-acquired
200–20,000 polymorphonuclear 
neutrophils
Low (< 45)
High (> 50)
Granulomatous meningitis 
(mycobacterial, fungal)
3
100–1000, mostly lymphocytes
3
Low (< 45)
High (> 50)
Moderately elevated
Spirochetal meningitis
3
Normal
High (> 50)
Normal to slightly elevated
Aseptic meningitis, viral meningitis 
or meningoencephalitis
4
25–2000, mostly lymphocytes
3
High (> 50)
Slightly elevated
“Neighborhood reaction”
5
Variably increased
Normal
Normal or high
Variable
1
Cerebrospinal fluid glucose must be considered in relation to blood glucose level. Normally, cerebrospinal fluid glucose is 20–30 mg/dL

5
Normal
Variable
1
Cerebrospinal fluid glucose must be considered in relation to blood glucose level. Normally, cerebrospinal fluid glucose is 20–30 mg/dL 
lower than blood glucose, or 50–70% of the normal value of blood glucose.
2
Organisms in smear or culture of cerebrospinal fluid; counterimmunoelectrophoresis or latex agglutination may be diagnostic.
3
Polymorphonuclear neutrophils may predominate early.
4
Viral isolation from cerebrospinal fluid early; antibody titer rise in paired specimens of serum; polymerase chain reaction for herpesvirus.
5
May occur in mastoiditis, brain abscess, epidural abscess, sinusitis, septic thrombus, brain tumor. Cerebrospinal fluid culture results usually negative.
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simplex) red cells as well. Influenza has been associated 
with encephalitis, but the relationship is not clear. An auto
-
immune form of encephalitis associated with N-methyl-D-
aspartate receptor antibodies should be suspected in 
younger patients with encephalitis and associated seizures, 
movement disorders, and psychosis.
E. Partially Treated Bacterial Meningitis
Previous effective antibiotic therapy given for 12–24 hours 
will decrease the rate of positive cerebrospinal fluid Gram 
stain results by 20% and culture by 30–40% but will have 
little effect on cell count, protein, or glucose. Occasion
-
ally, previous antibiotic therapy will change a predomi
-
nantly polymorphonuclear response to a lymphocytic 
pleocytosis, and some of the cerebrospinal fluid findings 
may be similar to those seen in aseptic meningitis.
F. Neighborhood Reaction
As noted in Table 30–1, this term denotes a purulent infec
-
tious process in close proximity to the central nervous 
system that spills some of the products of the inflammatory 
process—white blood cells or protein—into the cerebrospi
-
nal fluid. Such an infection might be a brain abscess, osteo
-
myelitis of the vertebrae, epidural abscess, subdural 
empyema, or bacterial sinusitis or mastoiditis.
G. Noninfectious Meningeal Irritation
Carcinomatous meningitis, sarcoidosis, systemic lupus ery
-
thematosus, chemical meningitis, and certain medications—
nonsteroidal anti-inflammatory drugs, OKT3, TMP-SMZ, 
and others—can also produce symptoms and signs of men
-
ingeal irritation with associated cerebrospinal fluid 
Table 30–2.
 
Initial antimicrobial therapy for purulent meningitis of unknown cause.
Population
Usual Microorganisms
Standard Therapy
18–50 years
Streptococcus pneumoniae, Neisseria meningitidis
1
 
plus
 ceftriaxone
2
Over 50 years
S pneumoniae, N meningitidis, Listeria monocytogenes
, 
 
gram-negative bacilli, group B streptococcus
1
 
plus
 ampicillin,
3
 
plus
2
Impaired cellular immunity
L monocytogenes
, gram-negative bacilli, 
1
 
plus
 ampicillin
3
 
plus
 cefepime
4
Postsurgical or posttraumatic
Staphylococcus aureus, S pneumoniae
, aerobic gram-negative 
bacilli, coagulase-negative staphylococci, diphtheroids 
 
(eg, 
) (uncommon)
1
 
plus
 cefepime
4
1
Given to cover highly penicillin- or cephalosporin-resistant pneumococci. The dose of vancomycin is 15 mg/kg/dose intravenously every 
8 hours. Vancomycin trough levels should be maintained at > 15 mcg/mL. Stopped if the causative organism is susceptible to ceftriaxone.
2
Ceftriaxone can often be used safely in meningitis patients with a history of penicillin allergy (aztreonam can be considered for empiric 
coverage of gram-negative bacilli in patients with serious penicillin and cephalosporin allergy). The usual dose of ceftriaxone is 2 g intrave
-
nously every 12 hours. If the organism is sensitive to penicillin, 3–4 million units intravenously every 4 hours is given.
3
In severely ill patients, ampicillin is used when 
 infection is a consideration. For confirmed infection due to 
L monocyto
-
genes
, gentamicin is sometimes added to ampicillin. (For patients allergic to penicillin, trimethoprim-sulfamethoxazole [TMP-SMZ] in a 
dosage of 15–20 mg/kg/day of TMP in 3 or 4 divided doses can be considered.) The dose of ampicillin is usually 2 g intravenously every 
4 hours.
4
Cefepime is given in a dose of 2–3 g intravenously every 8 hours.
Adapted from 
Treat Guide Med Lett
. 2013 Jul; 11(131):65–73.
pleocytosis, increased protein, and low or normal glucose. 
Meningismus with normal cerebrospinal fluid findings 
occurs in the presence of other infections such as pneumo
-
nia and shigellosis.
H. Brain Abscess
Brain abscess presents as a space-occupying lesion; symp
-
toms may include vomiting, fever, change of mental status,

-
-
toms may include vomiting, fever, change of mental status, 
or focal neurologic manifestations. When brain abscess is 
suspected, a CT scan should be performed. If positive, 
lumbar puncture should 
not
 be performed since results 
rarely provide clinically useful information and herniation 
can occur. The bacteriology of brain abscess is usually 
polymicrobial and includes 
S aureus
streptococci, and mouth anaerobes (including anaerobic 
streptococci and 
Prevotella
 species).
I. Health Care–Associated Meningitis
This infection may arise as a result of invasive neurosur
-
gical procedures (eg, craniotomy, internal or external 
ventricular catheters, external lumbar catheters), compli
-
cated head trauma, or from hospital-acquired blood
-
stream infections. Outbreaks have been associated with 
contaminated epidural or paraspinal corticosteroid injec
-
tions. In general, the microbiology is distinct from 
community-acquired meningitis, with gram-negative 
organisms (eg, 
), 
S aureus
, and coagulase-
negative staphylococci and, in the outbreaks associated 
with contaminated corticosteroids, mold and fungi 
(
Exserohilum rostratum
 and 
) play
-
ing a larger role.
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»
The classic triad of fever, stiff neck, and altered mental 
status has a low sensitivity (44%) for bacterial meningitis. 
However, nearly all patients with bacterial meningitis have 
at least two of the following symptoms—fever, headache, 
stiff neck, or altered mental status.
B. Laboratory Tests
Evaluation of a patient with suspected meningitis includes a 
blood count, blood culture, lumbar puncture followed by 
careful study and culture of the cerebrospinal fluid, and a 
chest film. The fluid must be examined for cell count, glu
-
cose, and protein, and a smear stained for bacteria (and acid-
fast organisms when appropriate) and cultured for pyogenic 
organisms and for mycobacteria and fungi when indicated. 
Latex agglutination tests can detect antigens of encapsulated 
organisms 
(S pneumoniae, H influenzae, N meningitidis
, and 
Cryptococcus neoformans)
 but are rarely used except for 
Cryptococcus
 or in partially treated patients. 
Polymerase chain reaction (PCR) testing of cerebrospinal 
fluid has been used to detect bacteria 
(S pneumoniae, 
 
H influenzae, N meningitidis, M tuberculosis, B burgdorferi
, 
and 
Tropheryma whipplei)
 and viruses (herpes simplex, vari
-
cella-zoster, CMV , Epstein-Barr virus, and enteroviruses) in 
patients with meningitis. The greatest experience is with PCR 
for herpes simplex, varicella-zoster, and JC virus. These tests 
are very sensitive (greater than 95%) and specific. In addition 
to its use in meningitis, molecular methods such as PCR and 
next-generation sequencing are being used increasingly for 
the diagnosis of encephalitis, transverse myelitis, and brain 
abscess. In general, molecular diagnostic tests may provide a 
more sensitive and rapid alternative to traditional culture and 
serology methods. However, it is difficult to ascertain the true 
sensitivity of many molecular tests for CNS infections given 
the absence of a gold standard. In some cases, tests to detect 
several organisms may not be any more sensitive than culture 
(or serology), but the real value is the rapidity with which 
results are available, ie, hours compared with days or weeks.
C. Lumbar Puncture and Imaging
Since performing a lumbar puncture in the presence of a 
space-occupying lesion (brain abscess, subdural hematoma, 
subdural empyema, necrotic temporal lobe from herpes 
encephalitis) may result in brainstem herniation, a CT scan 
is performed 
prior
 
to
 lumbar puncture if a space-occupying 
lesion is suspected on the basis of papilledema, seizures, or 
focal neurologic findings. Other indications for CT scan are 
an immunocompromised patient or moderately to severely 
impaired level of consciousness. If delays are encountered in 
obtaining a CT scan and bacterial meningitis is suspected, 
blood cultures should be drawn and antibiotics and cortico
-
steroids administered even before cerebrospinal fluid is 
obtained for culture to avoid delay in treatment (Table 30–1). 
Antibiotics given within 4 hours before obtaining cerebro
-
spinal fluid probably do 
not
 affect culture results. MRI with 
contrast of the epidural injection site and surrounding areas 
is recommended (sometimes repeatedly) for those with 
symptoms following a possibly contaminated corticosteroid 
injection to exclude epidural abscess, phlegmon, vertebral 
osteomyelitis, discitis, or arachnoiditis.
 
»
Treatment
Although it is difficult to prove with existing clinical data that 
early antibiotic therapy improves outcome in bacterial menin
-
gitis, prompt therapy is still recommended. In purulent menin
-
gitis, the identity of the causative microorganism may remain 
unknown or doubtful for a few days and initial antibiotic treat
-
ment as set forth in Table 30–2 should be directed against the 
microorganisms most common for each age group.
The duration of therapy for bacterial meningitis varies 
depending on the etiologic agent: 

, 7 days; 
N meningitidis
, 3–7 days; 
, 10–14 days; 
 
, 14–21 days; and gram-negative bacilli, 
 
21 days.
For adults with pneumococcal meningitis, dexametha
-
sone 10 mg administered intravenously 15–20 minutes 
before or simultaneously with the first dose of antibiotics and 
continued every 6 hours for 4 days decreases morbidity and 
mortality. Patients most likely to benefit from corticosteroids 
are those infected with gram-positive organisms (
Streptococ
-
cus pneumoniae
 or 
S suis
), and those who are HIV negative. 
It is unknown whether patients with meningitis due to 
 and other bacterial pathogens benefit from 
the use of adjunctive corticosteroids. Increased intracranial 
pressure due to brain edema often requires therapeutic atten
-
tion. Hyperventilation, mannitol (25–50 g intravenously as a 
bolus), and even drainage of cerebrospinal fluid by repeated 
lumbar punctures or by placement of intraventricular cathe
-
ters have been used to control cerebral edema and increased 
intracranial pressure. Dexamethasone (4 mg intravenously 
every 4–6 hours) may also decrease cerebral edema.
Therapy of brain abscess consists of drainage (excision or 
aspiration) in addition to 3–4 weeks of systemic antibiotics 
directed against organisms isolated. An empiric regimen often 
includes metronidazole, 500 mg intravenously or orally every 
 
8 hours, plus ceftriaxone, 2 g intravenously every 12 hours, with 
or without vancomycin, 10–15 mg/kg/dose intravenously every 
12 hours. Vancomycin trough serum levels should be greater 
than 15 mcg/mL in such patients. In cases where abscesses are 
smaller than 2 cm, where there are multiple abscesses that 
 
cannot be drained, or if an abscess is located in an area where 
significant neurologic sequelae would result from drainage, 
antibiotics for 6–8 weeks can be used without drainage.
In addition to antibiotics, in cases of health care–
associated meningitis associated with an external intra
-
ventricular catheter, the probability of cure is increased if 
the catheter is removed. In infections associated with 
internal ventricular catheters, removal of the internal 
components and insertion of an external drain is recom
-
mended. After collecting cerebrospinal fluid, epidural 
aspirate, or other specimens for culture, empiric antifun
-
gal therapy with voriconazole as well as routine empiric 
treatment for other pathogens (as above) is recommended 
until the specific cause of the patient’s central nervous 
system or parameningeal infection has been identified. In 
addition, early consultation with a neurosurgeon is 
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CMDT 2019
recommended for those found to have an epidural abscess, 
phlegmon, vertebral osteomyelitis, discitis, or arachnoiditis 
to discuss possible surgical management (eg, debridement).
Therapy of other types of meningitis is discussed else
-
where in this book (fungal meningitis, Chapter 36; syphilis 
and Lyme borreliosis, Chapter 34; tuberculous meningitis, 
Chapter 33; herpes encephalitis, Chapter 32).
 
»
•	
Patients with acute meningitis, particularly if culture 
negative or atypical (eg, fungi, syphilis, Lyme disease, 
), or if the patient is immunosuppressed.
•	
Patients with chronic meningitis.
•	
All patients with brain abscesses and encephalitis.
•	
Patients with suspected hospital-acquired meningitis 
(eg, in patients who have undergone recent neurosur
-
gery or epidural or paraspinal corticosteroid injection).
•	
Patients with recurrent meningitis.
 
»
•	
Patients with suspected acute meningitis, encephalitis, 
and brain or paraspinous abscess should be admitted 
for urgent evaluation and treatment.
•	
There is less urgency to admit patients with chronic 
meningitis; these patients may be admitted to expedite 
diagnostic procedures and coordinate care, particularly 
if no diagnosis has been made in the outpatient setting.
Gelfand JM et al. Encephalitis of unclear origin diagnosed by 
brain biopsy: a diagnostic challenge. JAMA Neurol. 2015 Jan 1; 
72(1):66–72. [PMID: 25365755]
McGill F et al. Acute bacterial meningitis in adults. Lancet. 2016 
Dec 17;388(10063):3036–47. [PMID: 27265346]
Prasad K et al. Corticosteroids for managing tuberculous men
-
ingitis. Cochrane Database Syst Rev. 2016 Apr 28;4:CD002244. 
[PMID: 27121755]
Tunkel AR et al. 2017 Infectious Diseases Society of America's 
clinical practice guidelines for healthcare-associated 
ventriculitis and meningitis. Clin Infect Dis. 2017 Feb 14. 
[Epub ahead of print] [PMID: 28203777]
Wilson M et al. Emerging diagnostic and therapeutic tools for 
central nervous system infections. JAMA Neurol. 2016 Dec 1; 
73(12):1389–90. [PMID: 27695862]
ANIMAL & HUMAN BITE WOUNDS
 
»
Cat and human bites have higher rates of infection 
than dog bites.
 
»
Hand bites are particularly concerning for the 
possibility of closed-space infection.
 
»
Antibiotic prophylaxis indicated for noninfected 
bites of the hand and hospitalization required for 
infected hand bites.
 
»
All infected wounds need to be cultured to direct 
therapy.
 
»
About 1000 dog bite injuries require emergency depart
-
ment attention each day in the United States, most often in 
urban areas. Dog bites occur most commonly in the sum
-
mer months. Biting animals are usually known by their 
victims, and most biting incidents are provoked (ie, bites 
occur while playing with the animal or after surprising the 
animal while eating or waking it abruptly from sleep). Fail
-
ure to elicit a history of provocation is important, because 
an 
unprovoked attack
 raises the possibility of rabies. Human 
bites are usually inflicted by children while playing or 
fighting; in adults, bites are associated with alcohol use and 
closed-fist injuries that occur during fights.
The animal inflicting the bite, the location of the bite, and 
the type of injury inflicted are all important determinants of 
whether they become infected. Cat bites are more likely to 
become infected than human bites—between 30% and 50% 
of all cat bites become infected. Infections following human 
bites are variable. Bites inflicted by children rarely become 
infected because they are superficial, and bites by adults 
become infected in 15–30% of cases, with a particularly high 
rate of infection in closed-fist injuries. Dog bites, for unclear 
reasons, become infected only 5% of the time. Bites of the 
head, face, and neck are less likely to become infected than

head, face, and neck are less likely to become infected than 
bites on the extremities. “Through and through” bites 
(eg, involving the mucosa and the skin) have an infection 
rate similar to closed-fist injuries. Puncture wounds become 
infected more frequently than lacerations, probably because 
the latter are easier to irrigate and debride.
The bacteriology of bite infections is polymicrobial. Fol
-
lowing dog and cat bites, over 50% of infections are caused 
by aerobes and anaerobes and 36% are due to aerobes alone. 
Pure anaerobic infections are rare. 
Pasteurella
the single most common isolate (75% of infections caused 
by cat bites and 50% of infections caused by dog bites). 
Other common aerobic isolates include streptococci, staph
-
ylococci, 
Moraxella
, and 
Neisseria;
 the most common 
anaerobes are 
Fusobacterium, Bacteroides, Porphyromonas
, 
and 
. The median number of isolates following 
human bites is four (three aerobes and one anaerobe). Like 
dog and cat bites, infections caused by most human bites are 
a mixture of aerobes and anaerobes (54%) or are due to 
aerobes alone (44%). Streptococci and 
S aureus
common aerobes. 
Eikenella corrodens
 (found in up to 30% 
of patients), 
, and 
common anaerobes. Although the organisms noted are the 
most common, innumerable others have been isolated—
including 
Capnocytophaga
 (dog and cat), 
, and 
—emphasizing the point that 
all infected bites 
should be cultured
 to define the microbiology.
HIV can be transmitted from bites (either from biting 
or receiving a bite from an HIV-infected patient) but has 
rarely been reported.
 
»
Treatment
A. Local Care
Vigorous cleansing and irrigation of the wound as well as 
debridement of necrotic material are the most important 
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factors in decreasing the incidence of infections. Radio
-
graphs should be obtained to look for fractures and the 
presence of foreign bodies. Careful examination to assess 
the extent of the injury (tendon laceration, joint space pen
-
etration) is critical to appropriate care.
B. Suturing
If wounds require closure for cosmetic or mechanical rea
-
sons, suturing can be done. However, one should never 
suture an infected wound, and wounds of the hand should 
generally not be sutured since a closed-space infection of 
the hand can result in loss of function.
C. Prophylactic Antibiotics
Prophylaxis is indicated in high-risk bites and in high-risk 
patients. 
Cat bites in any location
 and 
hand bites
 by any ani
-
mal, including humans, should receive prophylaxis. Individ
-
uals with certain comorbidities (diabetes, liver disease) are at 
increased risk for severe complications and should receive 
prophylaxis even for low-risk bites, as should patients with
-
out functional spleens who are at increased risk for over
-
whelming sepsis (primarily with 
 species). 
Amoxicillin-clavulanate (Augmentin) 500 mg orally three 
times daily for 5–7 days is the regimen of choice. For patients 
with serious allergy to penicillin, a combination of clindamy
-
cin 300 mg orally three times daily together with one of the 
following is recommended for 5–7 days: doxycycline 100 mg 
orally twice daily, or double-strength TMP-SMZ orally twice 
daily, or a fluoroquinolone (ciprofloxacin 500 mg orally twice 
daily or levofloxacin 500–750 mg orally once daily). Moxi
-
floxacin, a fluoroquinolone with good aerobic and anaerobic 
activity, may be suitable as monotherapy at 400 mg orally 
once daily for 5–7 days. Agents such as dicloxacillin, cepha
-
lexin, macrolides, and clindamycin should not be used alone 
because they lack activity against 
 species. TMP-
SMZ has poor activity against anaerobes and should only be 
used in combination with clindamycin.
Because the risk of HIV transmission is so low follow
-
ing a bite, routine postexposure prophylaxis is 
not
 recom
-
mended. Each case should be evaluated individually and 
consideration for prophylaxis should be given to those who 
present within 72 hours of the incident, the source is 
known to be HIV infected, and the exposure is high risk.
D. Antibiotics for Documented Infection
For wounds that are infected, antibiotics are clearly indi
-
cated. How they are given (orally or intravenously) and the 
need for hospitalization are individualized clinical deci
-
sions. The most commonly encountered pathogens require 
treatment with ampicillin-sulbactam (Unasyn), 1.5–3.0 g 
intravenously every 6–8 hours; or amoxicillin-clavulanate 
(Augmentin), 500 mg orally three times daily; or with 
ertapenem, 1 g intravenously daily. For the patient with 
severe penicillin allergy, a combination of clindamycin 
600–900 mg intravenously every 8 hours plus a fluoroqui
-
nolone (ciprofloxacin, 400 mg intravenously every 12 hours; 
levofloxacin, 500–750 mg intravenously once daily) or 
TMP-SMZ (10 mg/kg of trimethoprim daily in two or three 
*
Reportable to public health authorities.
divided doses) is indicated. Duration of therapy is usually 
2–3 weeks unless complications such as septic arthritis or 
osteomyelitis are present; if these complications are present, 
therapy should be extended to 4 and 6 weeks, respectively.
E. Tetanus and Rabies
All patients must be evaluated for the need for tetanus (see 
Chapter 33) and rabies (see Chapter 32) prophylaxis.
 
»
•	
If septic arthritis or osteomyelitis is suspected.
•	
For exposure to bites by dogs, cats, reptiles, amphibians, 
and rodents.
•	
When rabies is a possibility.
 
»
•	
Patients with infected hand bites.
•	
Deep bites, particularly if over joints.
Edens MA et al. Mammalian bites in the emergency department: 
recommendations for wound closure, antibiotics, and postex
-

•	
-
posure prophylaxis. Emerg Med Pract. 2016 Apr;18(4):1–20. 
PMID: 27104678]
Giordano A et al. Clinical features and outcomes of 
Pasteurella 
multocida
 infection. Medicine (Baltimore). 2015 Sep;94(36):
 
e1285. [PMID: 26356688]
Smith HR et al. Predicting serious complications and high cost 
of treatment of tooth-knuckle injuries: a systematic literature 
review. Eur J Trauma Emerg Surg. 2016 Dec;42(6):701–10. 
[PMID: 27363840]
Wilde H et al. Worldwide rabies deaths prevention—a focus on 
the current inadequacies in postexposure prophylaxis of 
animal bite victims. Vaccine. 2016 Jan 4;34(2):187–9. 
[PMID: 26626211]
SEXUALLY TRANSMITTED DISEASES
 
»
All sexually transmitted diseases (STDs) have sub
-
clinical or latent periods, and patients may be 
 
»
Simultaneous infection with several organisms is 
common.
 
»
All patients who seek STD testing should be 
screened for syphilis and HIV.
 
»
Partner notification and treatment are important 
to prevent further transmission and reinfection of 
the index case.
 
»
The most common STDs are gonorrhea,
*
 syphilis,
*
 human 
papillomavirus (HPV)–associated condyloma acuminatum, 
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PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1309
 
CMDT 2019
chlamydial genital infections,
*
 herpesvirus genital infections, 
trichomonas vaginitis, chancroid,
*
 granuloma inguinale, 
scabies, louse infestation, and bacterial vaginosis (among 
women who have sex with women). However, shigellosis
*
; 
hepatitis A, B, and C
*
; amebiasis; giardiasis
*
; cryptosporidio
-
sis
*
; salmonellosis
*
; and campylobacteriosis may also be 
transmitted by sexual (oral-anal) contact, especially in men 
who have sex with men. Ebola virus and Zika virus have both 
been associated with sexual transmission. Both homosexual 
and heterosexual contact are risk factors for the transmission 
of HIV (see Chapter 31). All STDs have 
subclinical
 or 
latent 
phases
 that play an important role in long-term persistence of 
the infection or in its transmission from infected (but largely 
asymptomatic) persons to other contacts. Simultaneous infec
-
tion by several different agents is common.
Infections typically present in one of several ways, each 
of which has a defined differential diagnosis, which should 
prompt appropriate diagnostic tests.
A. Genital Ulcers
Common etiologies include herpes simplex virus, primary 
syphilis, and chancroid. Other possibilities include lym
-
phogranuloma venereum (see Chapter 33), granuloma 
inguinale caused by 
Klebsiella granulomatis
 (see Chapter 33), 
as well as lesions caused by infection with Epstein-Barr 
virus and HIV . Noninfectious causes are Behçet disease 
(see Chapter 20), neoplasm, trauma, drugs, and irritants.
B. Urethritis With or Without Urethral Discharge
The most common infections causing urethral discharge 
are 
 and 
. 
 and 
 are also frequent causes 
of prostatitis among sexually active men. Other sexually 
transmitted infections that can cause urethritis include 
Ureaplasma 
urealyticum
 and 
. Noninfectious 
causes of urethritis include reactive arthritis (Reiter 
syndrome) with associated urethritis.
C. Vaginal Discharge
Common causes of vaginitis are bacterial vaginosis (caused 
by overgrowth of anaerobes such as 
), 
candidiasis, and 
 (see Chapter 18). Less common 
infectious causes of vaginitis include HPV-associated con
-
dylomata acuminata and group A streptococcus. Nonin
-
fectious causes are physiologic changes related to the 
menstrual cycle, irritants, and lichen planus. Even though 
 and 
 are frequent causes of 
cervicitis, they 
rarely
 produce vaginal discharge.
 
»
Screening & Prevention
All persons who seek STD testing should undergo routine 
screening for HIV infection, using rapid HIV testing 
(if patients may not follow up for results obtained by stan
-
dard methods) or nucleic acid amplification followed by 
confirmatory serology (if primary HIV infection may be a 
*
possibility) as indicated. Patients in whom certain STDs 
have been diagnosed and treated (chlamydia or gonorrhea, 
and trichomonas in women) are at a high risk for reinfec
-
tion and should be encouraged to be rescreened for STDs 
at 3 months following the initial STD diagnosis.
Asymptomatic patients often request STD screening at the 
time of initiating a new sexual relationship. Routine HIV test
-
ing and hepatitis B serology testing should be offered to all 
such patients. In sexually active women who have not been 
recently screened, cervical Papanicolaou testing and nucleic 
acid amplification testing of a urine specimen for gonorrhea 
and chlamydia are recommended. Among men who have sex 
with men, additional screening is recommended for syphilis; 
hepatitis A; urethral, pharyngeal, and rectal gonorrhea; as well 
as urethral and rectal chlamydia. Nucleic acid amplification 
testing is recommended for gonorrhea or chlamydia. There

testing is recommended for gonorrhea or chlamydia. There 
are no recommendations to screen heterosexual men for ure
-
thral chlamydia, but this could be considered in STD clinics, 
adolescent clinics, or correctional facilities. The periodicity of 
screening thereafter depends on sexual risk, but most screen
-
ing should be offered at least annually to sexually active adults 
(particularly to those 25 years old and under). Clinicians 
should also evaluate transgender men and women for STD 
screening, based on current anatomy and behaviors practiced. 
If not immune, hepatitis B vaccination is recommended for all 
sexually active adults, and hepatitis A vaccination in men who 
have sex with men. Persons between the ages of 9 and 26 
should be routinely offered vaccination against HPV (quadri
-
valent or 9-valent).
The risk of developing an STD following a sexual assault 
is difficult to accurately ascertain given high rates of baseline 
infections and poor follow-up. Victims of assault have a high 
baseline rate of infection (
, 6%; 
, 
10%; 
, 15%; and bacterial vaginosis, 34%), and the 
risk of acquiring infection as a result of the assault is signifi
-
cant, but is often lower than the preexisting rate (
N gonor
-
rhoeae
, 6–12%; 
, 4–17%; 
, 12%; 
syphilis, 0.5–3%; and bacterial vaginosis, 19%). Victims 
should be evaluated within 24 hours after the assault, and 
nucleic acid amplification tests for 
 and 
C tra
-
chomatis
 should be performed. Vaginal secretions are 
obtained for 
 wet mount and culture, or point-
of-care testing. If a discharge is present, if there is itching, or 
if secretions are malodorous, a wet mount should be exam
-
ined for 
Candida
 and bacterial vaginosis. In addition, a blood 
sample should be obtained for immediate serologic testing 
for syphilis, hepatitis B, and HIV . Follow-up examination for 
STDs should be repeated within 1–2 weeks, since concentra
-
tions of infecting organisms may not have been sufficient to 
produce a positive test at the time of initial examination. If 
prophylactic treatment was given (may include postexposure 
hepatitis B vaccination without hepatitis B immune globulin; 
treatment for chlamydial, gonorrheal, or trichomonal infec
-
tion; and emergency contraception), tests should be repeated 
only if the victim has symptoms. If prophylaxis was not 
administered, the individual should be seen in 1 week so that 
any positive tests can be treated. Follow-up serologic testing 
for syphilis and HIV infection should be performed in 6, 12, 
and 24 weeks if the initial tests are negative. The usefulness of 
presumptive therapy is controversial, some feeling that all 
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patients should receive it and others that it should be limited 
to those in whom follow-up cannot be ensured or to patients 
who request it.
Although seroconversion to HIV has been reported fol
-
lowing sexual assault when this was the only known risk, 
this risk is believed to be low. The likelihood of HIV trans
-
mission from vaginal or anal receptive intercourse when 
the source is known to be HIV positive is 1 per 1000 and 
 
5 per 1000, respectively. Although prophylactic antiretrovi
-
ral therapy has not been studied in this setting, the Depart
-
ment of Health and Human Services recommends the 
prompt institution of postexposure prophylaxis with anti
-
retroviral therapy if the person seeks care within 72 hours 
of the assault, the source is known to be HIV positive, and 
the exposure presents a substantial risk of transmission.
In addition to screening asymptomatic patients with 
STDs, other strategies for preventing further transmission 
include evaluating sex partners and administering preexpo
-
sure vaccination of preventable STDs to individuals at risk; 
other strategies include the consistent use of male and female 
condoms and male circumcision. Adult male circumcision 
has been shown to decrease the transmission of HIV by 50%, 
and of herpes simplex virus and HPV by 30% in heterosexual 
couples in sub-Saharan Africa. For each patient, there are one 
or more sexual contacts who require diagnosis and treatment. 
Prompt treatment of contacts by giving antibiotics to the 
index case to distribute to all sexual contacts (
patient-
delivered therapy
) is an important strategy for preventing 
further transmission and to prevent reinfection of the index case.
Note that vaginal spermicides and condoms containing 
nonoxynol-9 provide no additional protection against 
STDs. Early initiation of antiretroviral therapy in HIV-
infected individuals can prevent HIV acquisition in an 
uninfected sex partner. Also, preexposure prophylaxis with 
a once-daily pill containing emtricitabine plus tenofovir 
disoproxil fumarate (TDF) has been shown to be effective 
in preventing HIV infection among high-risk men who 
have sex with men, heterosexual women and men, trans
-
gender women, and persons who inject drugs.
 
»
•	
Patients with a new diagnosis of HIV .
•	
Patients with persistent, refractory or recurrent STDs, 
particularly when drug resistance is suspected.
Rodger AJ et al; PARTNER Study Group. Sexual activity without 
condoms and risk of HIV transmission in serodifferent cou
-
ples when the HIV-positive partner is using suppressive 
antiretroviral therapy. JAMA. 2016 Jul 12;316(2):171–81. 
[PMID: 27404185]
Seña AC et al. Sexual assault and sexually transmitted infections 
in adults, adolescents, and children. Clin Infect Dis. 2015 Dec 
15;61(Suppl 8):S856–64. [PMID: 26602623]
Sonawane K et al. Oral human papillomavirus infection: differ
-
ences in prevalence between sexes and concordance with 
genital human papillomavirus infection, NHANES 2011 to 
2014. Ann Intern Med. 2017 Nov 21;167(10):714–24. [PMID: 
29049523]
Unemo M et al. Sexually transmitted infections: challenges 
ahead. Lancet Infect Dis. 2017 Aug;17(8):e235–79. [PMID: 
28701272]
Wiesenfeld HC. Screening for 
 infections 
in women. N Engl J Med. 2017 Feb 23;376(8):765–73. [PMID: 
28225683]
2015. MMWR Recomm Rep. 2015 Jun 5;64(RR–03):1–137. 
INFECTIONS IN PERSONS WHO 
INJECT DRUGS
 
»
Common infections that occur with greater fre
-
quency in persons who inject drugs include:
– Skin infections, aspiration pneumonia, tuberculosis.
– Hepatitis A, B, C, D; STDs; HIV/AIDS.
– Pulmonary septic emboli, infective endocarditis.
– Osteomyelitis and septic arthritis.
 
»

»
There is a high incidence of infection among drug users, 
particularly those who inject drugs. Increased risk of infec
-
tion is likely associated with poor hygiene and colonization 
with potentially pathogenic organisms, contamination of 
drugs and equipment, increased sexual risk behaviors, and 
impaired immune defenses. The use of parenterally admin
-
istered recreational drugs has increased enormously in 
recent years, fueled in part by an epidemic of prescription 
opioid misuse and abuse. More than 775,000 persons in the 
United States are estimated to have used injection drugs in 
the past year.
Skin infections
 are associated with poor hygiene and 
use of nonsterile technique when injecting drugs. 
S aureus
 
strains) and oral flora (streptococci, 
Eikenella, Fusobacte
-
rium, Peptostreptococcus
) are the most common organisms, 
with enteric gram-negatives generally more likely seen in 
those who inject into the groin. Cellulitis and subcutaneous 
abscesses occur most commonly, particularly in association 
with subcutaneous (“skin-popping”) or intramuscular 
injections and the use of cocaine and heroin mixtures 
(probably due to ischemia). Myositis, clostridial myonecro
-
sis, and necrotizing fasciitis occur infrequently but are life-
threatening. Wound botulism in association with black tar 
heroin occurs sporadically but often in clusters.
Aspiration pneumonia
 and its complications (lung 
abscess, empyema, brain abscess) result from altered con
-
sciousness associated with drug use. Mixed aerobic and 
anaerobic mouth flora are usually involved.
 also occurs in persons who use drugs, and 
infection with HIV has fostered the spread of tuberculosis 
in this population. Morbidity and mortality rates are 
increased in HIV-infected individuals with tuberculosis. 
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CMDT 2019
Classic radiographic findings are often absent; tuberculosis 
is suspected in any patient with infiltrates who does not 
respond to antibiotics.
Hepatitis
 is very common among habitual drug users 
and is transmissible both by the parenteral (hepatitis B, C, 
and D) and by the fecal-oral route (hepatitis A). Multiple 
episodes of hepatitis with different agents can occur.
Pulmonary septic emboli
 may originate from venous 
thrombi or right-sided endocarditis.
STDs
 are not directly related to drug use, but the prac
-
tice of exchanging sex for drugs has resulted in an increased 
frequency of STDs. Syphilis, gonorrhea, and chancroid are 
the most common.
HIV/AIDS
 has a high incidence among persons who 
inject drugs and their sexual contacts and among the off
-
spring of infected women (see Chapter 31).
Infective endocarditis
 in persons who use injection 
drugs is most commonly caused by 
S aureus
, 
Candida
 
(usually 
C albicans
 or 
C parapsilosis
), 
, 
other streptococci, and gram-negative bacteria (especially 
 and 
Serratia marcescens
). See Chapter 33.
Other vascular infections
 include septic thrombophle
-
bitis and mycotic aneurysms. Mycotic aneurysms resulting 
from direct trauma to a vessel with secondary infection 
most commonly occur in femoral arteries and less com
-
monly in arteries of the neck. Aneurysms resulting from 
hematogenous spread of organisms frequently involve 
intracerebral vessels and thus are seen in association with 
Osteomyelitis and septic arthritis
 involving vertebral 
bodies, sternoclavicular joints, the pubic symphysis, the 
sacroiliac joints, and other sites usually results from hema
-
togenous distribution of injected organisms or septic 
venous thrombi. Pain and fever precede radiographic 
changes, sometimes by several weeks. While 
S aureus
—
often methicillin-resistant—is most common, 
Serratia, 
Pseudomonas, Candida
 (often not 
C albicans
), and other 
pathogens rarely encountered in spontaneous bone or joint 
disease are found in persons who inject drugs.
 
»
Treatment
A common and difficult clinical problem is management of a 
person known to inject drugs who presents with fever. In 
general, after obtaining appropriate cultures (blood, urine, 
and sputum if the chest radiograph is abnormal), empiric 
therapy is begun. If the chest radiograph is suggestive of a 
community-acquired pneumonia (consolidation), therapy for 
outpatient pneumonia is begun with ceftriaxone, 1 g intrave
-
nously every 24 hours, plus either azithromycin (500 mg 
orally or intravenously every 24 hours) or doxycycline 
(100 mg orally or intravenously twice daily). If the chest radio
-
graph is suggestive of septic emboli (nodular infiltrates), 
therapy for presumed endocarditis is initiated, usually with 
vancomycin 15 mg/kg/dose every 12 hours intravenously 
(due to the high prevalence of MRSA and the possibility of 
enterococcus). If the chest radiograph is normal and no focal 
site of infection can be found, endocarditis is presumed. 
While awaiting the results of blood cultures, empiric treat
-
ment with vancomycin is started. If blood cultures are positive 
for organisms that frequently cause endocarditis in drug users 
(see above), endocarditis is presumed to be present and 
treated accordingly. If blood cultures are positive for an organ
-
ism that is an unusual cause of endocarditis, evaluation for an 
occult source of infection should go forward. In this setting, a 
transesophageal echocardiogram may be quite helpful since it 
is 90% sensitive in detecting vegetations and a negative study 
is strong evidence against endocarditis. If blood cultures are 
negative and the patient responds to antibiotics, therapy 
should be continued for 7–14 days (oral therapy can be given 
once an initial response has occurred). In every patient, care
-

-
ful examination for an occult source of infection (eg, genito
-
urinary, dental, sinus, gallbladder) should be done.
 
»
•	
Any patient with suspected or proven infective 
•	
Patients with persistent bacteremia.
 
»
•	
Persons who inject drugs with fever.
•	
Patients with abscesses or progressive skin and soft tis
-
sue infection that require debridement.
Conrad C et al; Centers for Disease Control and Prevention 
(CDC). Community outbreak of HIV infection linked to 
injection drug use of oxymorphone—Indiana, 2015. 
MMWR Morb Mortal Wkly Rep. 2015 May 1;64(16):443–4. 
[PMID: 25928470]
Hartman L et al. Opiate injection-associated infective endo
-
carditis in the southeastern United States. Am J Med Sci. 
2016 Dec;352(6):603–8. [PMID: 27916215]
Ip EJ et al. Infectious disease, injection practices, and risky 
sexual behavior among anabolic steroid users. AIDS Care. 
2016 Mar;28(3):294–9. [PMID: 26422090]
ACUTE INFECTIOUS DIARRHEA
 
»
Acute diarrhea:
 lasts less than 2 weeks
 
»
Chronic diarrhea:
 lasts longer than 2 weeks.
 
»
Mild diarrhea:
 3 or fewer stools per day.
 
»
Moderate diarrhea:
 4 or more stools per day with 
local symptoms (abdominal cramps, nausea, 
tenesmus).
 
»
Severe diarrhea:
systemic symptoms (fever, chills, dehydration).
 
»
Acute diarrhea can be caused by a number of different factors, 
including emotional stress, food intolerance, inorganic agents 
(eg, sodium nitrite), organic substances (eg, mushrooms, 
shellfish), drugs, and infectious agents (including viruses, 
bacteria, and protozoa) (Table 30–3). From a diagnostic and 
therapeutic standpoint, it is helpful to classify infectious 
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Table 30–3.
 
Acute bacterial diarrheas and “food poisoning” (listed in alphabetical order).
Organism
Incubation Period
Vomiting
Diarrhea
Fever
Associated Foods
Diagnosis
Clinical Features and Treatment
B cereus
 (diarrheal 
toxin)
10–16 hours
±
+++
–
Toxin in meats, stews, and gravy.
Clinical. Food and stool 
can be tested for toxin.
Abdominal cramps, watery diarrhea, 
 
and nausea lasting 24–48 hours. 
 
Supportive care.
 
(preformed toxin)
1–8 hours
+++
±
–
Reheated fried rice causes vomiting 
or diarrhea.
Acute onset, severe nausea and vomiting 
lasting 24 hours. Supportive care.
C botulinum
±
–
–
Clostridia grow in anaerobic acidic 
environment eg, canned foods, 
fermented fish, foods held warm 
for extended periods.
Stool, serum, and food 
can be tested for toxin. 
Stool and food can be 
cultured.
Diplopia, dysphagia, dysphonia, respira
-
tory embarrassment. Treatment requires 
clear airway, ventilation, and intrave
-
nous polyvalent antitoxin (see text). 
Symptoms can last for days to months.
Usually occurs after 7–10 
days of antibiotics. Can 
occur after a single dose 
or several weeks after 
completion of 
–
+++
++
Associated with antimicrobial drugs; 
clindamycin and beta-lactams 
most commonly implicated. 
 
Fluoroquinolones associated with 
hypervirulent strains.
Stool tested for toxin.
Abrupt onset of diarrhea that may be 
bloody; fever. Oral metronidazole for 
mild to moderate cases. Oral vancomy
-
cin for more severe disease.
2–5 days
±
+++
+
Raw or undercooked poultry, 
 
unpasteurized milk, water.
Stool culture on special 
medium.
Fever, diarrhea that can be bloody, cramps. 
Usually self-limited in 2–10 days. Treat 
with azithromycin or fluoroquinolones 
for severe disease. May be associated 
with Guillain-Barré syndrome.
8–16 hours
±
+++
–
Clostridia grow in rewarmed meat 
and poultry dishes and produce 
an enterotoxin.
Stools can be tested for 
enterotoxin or cultured.
Abrupt onset of profuse diarrhea, 
 
abdominal cramps, nausea; vomiting 
occasionally. Recovery usual without 
treatment in 24–48 hours. Supportive 
care; antibiotics not needed.
Enterohemorrhagic 
, 
including Shiga-
toxin–producing 
 
E coli
 strains (STEC)
1–8 days
+
+++
–
Undercooked beef, especially 
 
hamburger; unpasteurized milk 
and juice; raw fruits and 
vegetables.
 
E coli
 can be cultured 
on special medium. 
Other toxins can be 
detected in stool.
Usually abrupt onset of diarrhea, often 
bloody; abdominal pain. In adults, it is 
usually self-limited to 5–10 days. In 
 
children, it is associated with 
 
hemolytic-uremic syndrome (HUS). 
Antibiotic therapy may increase risk of 
HUS. Plasma exchange may help 
patients with STEC-associated HUS.
Enterotoxigenic 
E coli
 
(ETEC)
1–3 days
±
+++
±
Water, food contaminated with 
feces.
Stool culture. Special tests 
required to identify 
toxin-producing strains.
Watery diarrhea and abdominal cramps, 
usually lasting 3–7 days. In travelers, 
 
fluoroquinolones shorten disease.
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CMDT 2019
Noroviruses and other 
caliciviruses
++
+++
+
Shellfish and fecally contaminated 
foods touched by infected food 
handlers.
Clinical diagnosis with 
negative stool cultures. 
PCR available on stool.
Nausea, vomiting (more common in 
 
children), diarrhea (more common in 
adults), fever, myalgias, abdominal 
cramps. Lasts 12–60 hours. Supportive 
care.
Rotavirus
1–3 days
++
+++
+
Fecally contaminated foods touched 
by infected food handlers.
Immunoassay on stool.
Acute onset, vomiting, watery diarrhea 
that lasts 4–8 days. Supportive care.
 species
1–3 days
–
++
+
Eggs, poultry, unpasteurized milk, 
cheese, juices, raw fruits and 
Routine stool culture.
Gradual or abrupt onset of diarrhea and 
low-grade fever. No antimicrobials 
unless high risk (see text) or systemic 
dissemination is suspected, in which 
case give a fluoroquinolone. Prolonged 
carriage can occur.
Shigella
 species 
 
(mild cases)
24–48 hours
±
+
+
Food or water contaminated with 
human feces. Person to person 
spread.
Abrupt onset of diarrhea, often with 
 
blood and pus in stools, cramps, 
 
tenesmus, and lethargy. Stool cultures 
are positive. Therapy depends on 
 
sensitivity testing, but the fluoroquino
-
lones are most effective. Do not give 
opioids. Often mild and self-limited.
 
1–8 hours
+++
±
±
Staphylococci grow in meats, dairy, 
and bakery products and produce 
enterotoxin.
Abrupt onset, intense nausea and 
 
vomiting for up to 24 hours, recovery 
 
in 24–48 hours. Supportive care.
Vibrio cholerae
+
+++
–
Contaminated water, fish, shellfish, 
street vendor food.
medium.
Abrupt onset of liquid diarrhea in endemic 
area. Needs prompt intravenous or oral 
replacement of fluids and electrolytes. 
Tetracyclines and azithromycin shorten 
excretion of vibrios.
Vibrio 
parahaemolyticus
2–48 hours
+
+
±
Undercooked or raw seafood.
medium.
Abrupt onset of watery diarrhea, 
 
abdominal cramps, nausea and 
 
vomiting. Recovery is usually complete 
in 2–5 days.
±
+
+
Undercooked pork, contaminated 
water, unpasteurized milk, tofu.
medium.
Severe abdominal pain (appendicitis-like 
symptoms), diarrhea, fever. Polyarthritis, 
erythema nodosum in children. If 
severe, give tetracycline or 
 
fluoroquinolone. Without treatment, 
self-limited in 1–3 weeks.
PCR, polymerase chain reaction.
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diarrhea into syndromes that produce inflammatory or 
bloody diarrhea and those that are noninflammatory, 
nonbloody, or watery. In general, the term “
inflammatory 
diarrhea
” suggests colonic involvement by invasive bacteria 
or parasites or by toxin production. Patients complain of fre
-
quent bloody, small-volume stools, often associated with fever, 
abdominal cramps, tenesmus, and fecal urgency. Common 
causes of this syndrome include 
Shigella, Salmonella, Campy
-
lobacter, Yersinia
, invasive strains of 
, and other 
Shiga-toxin–producing strains of 
E
 
coli
 (STEC), 
Entamoeba 
histolytica
, and 
. Tests for fecal leukocytes or the 
neutrophil marker lactoferrin are frequently positive, and 
definitive etiologic diagnosis requires stool culture. 
Nonin
-
flammatory diarrhea
 is generally milder and is caused by 
viruses or toxins that affect the small intestine and interfere 
with salt and water balance, resulting in large-volume watery 
diarrhea, often with nausea, vomiting, and cramps. Common 
causes of this syndrome include viruses (eg, rotavirus, norovi
-
rus, astrovirus, enteric adenoviruses), vibriones 
(Vibrio 
cholerae, Vibrio parahaemolyticus)
, enterotoxin-producing 
 
E coli, Giardia lamblia
, cryptosporidia, and agents that can 
cause food-borne gastroenteritis. In developed countries, 
viruses (particularly norovirus) are an important cause of 
hospitalizations due to acute gastroenteritis among adults.
The term “food poisoning” denotes diseases caused by 
toxins present in consumed foods. When the incubation 
period is short (1–6 hours after consumption), the toxin is usu
-
ally 
preformed.
 Vomiting is usually a major complaint, and 
fever is usually absent. Examples include intoxication from 
 
S aureus
 or 
, and toxin can be detected in the 
food. When the incubation period is longer—between 8 hours 
and 16 hours—the organism is present in the food and 
pro
-
duces toxin after being ingested.
 Vomiting is less prominent, 
abdominal cramping is frequent, and fever is often absent. The 
best example of this disease is that due to 
Clostridium perfrin
-
gens
. Toxin can be detected in food or stool specimens.
The inflammatory and noninflammatory diarrheas dis
-
cussed above can also be transmitted by food and water and 
usually have incubation periods between 12 and 72 hours. 
, cryptosporidia, and 
Isospora
 are protozoans 
capable of causing disease in both immunocompetent and 
immunocompromised patients. Characteristics of disease 
include profuse watery diarrhea that is prolonged but usu
-
ally self-limited (1–2 weeks) in the immunocompetent 
patient but can be chronic in the compromised host. Epide
-
miologic features may be helpful in determining etiology. 
Recent hospitalization or antibiotic use suggests 
C difficile;
 
recent foreign travel suggests 
Salmonella, Shigella, Campylo
-
bacter, E coli
, or 
V cholerae;
 undercooked hamburger sug
-
gests STEC; outbreak in long-term care facility, school, or 
cruise ship suggests norovirus (including newly identified 
strains, eg, GII.4 Sydney); and fried rice consumption is 
associated with 
B cereus
 toxin. Prominent features of some 
of these causes of diarrhea are listed in Table 30–3.
 
»
Treatment
most cases of acute gastroenteritis are self-limited
 
and do not require therapy other than supportive 
measures. Treatment usually consists of replacement of 
fluids and electrolytes and, very rarely, management of 
hypovolemic shock and respiratory compromise. In mild 
diarrhea, increasing ingestion of juices and clear soups is 
adequate. In more severe cases of dehydration (postural 
light-headedness, decreased urination), oral glucose-based 
rehydration solutions can be used (Ceralyte, Pedialyte).
In immunocompetent adults, empiric antimicrobial ther
-
apy for bloody diarrhea while waiting for results is recom

-
-
mended only with the following circumstances: 
(1) documented fever, abdominal pain, bloody diarrhea, 
and bacillary dysentery (frequent scant bloody stools, 
fever, abdominal cramps, tenesmus) presumptively due to 
Shigella
; and (2) returning travelers with a temperature of 
at least 38.5
°
C or signs of sepsis.
Either a fluoroquinolone or azithromycin should be 
used as empiric antimicrobial therapy. Empiric antibacterial 
treatment should be considered in immunocompromised 
people with severe illness and bloody diarrhea. Loperamide 
may be given to immunocompetent adults with acute 
watery diarrhea, but should be avoided in suspected or 
proven toxic megacolon. Therapeutic recommendations for 
specific agents can be found elsewhere in this book.
Ahmed SM et al. Global prevalence of norovirus in cases of 
gastroenteritis: a systematic review and meta-analysis. Lancet 
Infect Dis. 2014 Aug;14(8):725–30. [PMID: 24981041]
Nelson RL et al. Antibiotic treatment for 
-
associated diarrhoea in adults. Cochrane Database Syst Rev. 
2017 Mar 3;3:CD004610. [PMID: 28257555]
Shane AL et al. 2017 Infectious Diseases Society of America 
clinical practice guidelines for the diagnosis and management 
of infectious diarrhea. Clin Infect Dis. 2017 Nov 29; 
65(12):e45–80. [PMID: 29053792]
Wikswo ME et al. Outbreaks of acute gastroenteritis transmitted 
by person-to-person contact, environmental contamination, 
and unknown modes of transmission—United States, 
2009–2013. MMWR Surveill Summ. 2015 Dec 11;64(12): 
 
1–16. [PMID: 26656915]
INFECTIOUS DISEASES IN THE 
RETURNING TRAVELER
 
»
Most infections are common and self-limited.
 
»
Identify patients with transmissible diseases that 
require isolation.
 
»
The incubation period may be helpful in 
 
»
Less than 3 weeks following exposure may sug
-
gest dengue, leptospirosis, and yellow fever; more 
than 3 weeks suggest typhoid fever, malaria, and 
CMDT19_Ch30_p1294-p1337.indd   1314

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1315
 
CMDT 2019
 
»
The differential diagnosis of fever in the returning traveler 
is broad, ranging from self-limited viral infections to life-
threatening illness. The evaluation is best done by identify
-
ing whether a particular syndrome is present, then refining 
the differential diagnosis based on an exposure history. 
The travel history should include directed questions 
regarding geography (rural versus urban, specific country 
visited), time of year, animal or arthropod contact, unpro
-
tected sexual intercourse, ingestion of untreated water or 
raw foods, historical or pretravel immunizations, and 
adherence to malaria prophylaxis.
 
»
Etiologies
The most common infectious causes of fever—excluding 
simple causes such as upper respiratory infections, bacterial 
pneumonia and urinary tract infections—in returning travel
-
ers are malaria (see Chapter 35), diarrhea (see next section), 
and dengue (see Chapter 32). Others include mononucleosis 
(associated with Epstein-Barr virus or cytomegalovirus), 
respiratory infections, including seasonal influenza, influ
-
enza A/H1N1 “swine” influenza, and influenza A/H5N1 or 
A/H7N9 “avian” influenza (see Chapter 32); leptospirosis (see 
Chapter 34); typhoid fever (see Chapter 33); and rickettsial 
infections (see Chapter 32). Foreign travel is increasingly 
recognized as a risk factor for colonization and disease with 
resistant pathogens, such as ESBL-producing gram-negative 
organisms. Systemic febrile illnesses without a diagnosis also 
occur commonly, particularly in travelers returning from 
sub-Saharan Africa or Southeast Asia.
A. Fever and Rash
Potential etiologies include dengue, Ebola, Chikungunya, 
and Zika viruses, viral hemorrhagic fever, leptospirosis, 
meningococcemia, yellow fever, typhus, 
Salmonella typhi
, 
and acute HIV infection.
B. Pulmonary Infiltrates
Tuberculosis, ascaris, 
Paragonimus
, and 
 can 
all cause pulmonary infiltrates.
C. Meningoencephalitis
Etiologies include 
, leptospirosis, arbovi
-
ruses, rabies, and (cerebral) malaria.
D. Jaundice
Consider hepatitis A, yellow fever, hemorrhagic fever, lep
-
tospirosis, and malaria.
E. Fever Without Localizing Symptoms or Signs
Malaria, typhoid fever, acute HIV infection, rickettsial ill
-
ness, visceral leishmaniasis, trypanosomiasis, and dengue 
are possible etiologies.
F. Traveler’s Diarrhea
See next section.
 
»
Fever and rash
 in the returning traveler should prompt 
blood cultures and serologic tests based on the exposure 
history. The workup of a 
pulmonary infiltrate
 should 
include the placement of a PPD or use of an interferon-
gamma release assay, examination of sputum for acid-fast 
bacilli and possibly for ova and parasites. Patients with evi
-
dence of 
meningoencephalitis
 should receive lumbar 
puncture, blood cultures, thick/thin smears of peripheral 
blood, history-guided serologies, and a nape biopsy (if rabies 
is suspected). 
Jaundice
 in a returning traveler should be 
evaluated for hemolysis (for malaria), and the following 
tests should be performed: liver biochemical tests, thick/
thin smears of peripheral blood, and directed serologic test
-
ing. The workup of 
traveler’s diarrhea
 is presented in the 
following section. Finally, patients with 
fever
 but no local
-
izing signs or symptoms should have blood cultures per
-
formed. Routine laboratory studies usually include complete 
blood count with differential, electrolytes, liver biochemical 
tests, urinalysis, and blood cultures. Thick and thin periph
-
eral blood smears should be done (and repeated in 
12–24 hours if clinical suspicion remains high) for malaria 
if there has been travel to endemic areas. Other studies are 
directed by the results of history, physical examination, and 
initial laboratory tests. They may include stool for ova and

initial laboratory tests. They may include stool for ova and 
parasites, chest radiograph, HIV test, and specific serologies 
(eg, dengue, leptospirosis, rickettsial disease, schistosomia
-
sis, 
). Bone marrow biopsy to diagnose typhoid 
fever could be helpful in the appropriate patient.
 
»
Travelers with fever, particularly if immunocompromised.
 
»
Any evidence of hemorrhage, respiratory distress, hemo
-
dynamic instability, and neurologic deficits.
Fischer M et al; Arboviral Diseases Branch, National Center for 
Emerging and Zoonotic Infectious Diseases, CDC. Notes from 
the field: chikungunya virus spreads in the Americas—
Caribbean and South America, 2013–2014. MMWR Morb 
Mortal Wkly Rep. 2014 Jun 6;63(22):500–1. [PMID: 24898168]
Hahn WO et al. Malaria in the traveler: how to manage before 
departure and evaluate upon return. Med Clin North Am. 
2016 Mar;100(2):289–302. [PMID: 26900114]
Rasmussen SA et al. Zika virus and birth defects—reviewing the 
evidence for causality. N Engl J Med. 2016 May 19;374(20):
 
1981–7. [PMID: 27074377]
Rello J et al. Management of infections in critically ill returning 
travellers in the intensive care unit—II: Clinical syndromes 
and special considerations in immunocompromised patients. 
Int J Infect Dis. 2016 Jul;48:104–12. [PMID: 27134159]
Sanford CA et al. Illness in the returned international traveler. 
Med Clin North Am. 2016 Mar;100(2):393–409. [PMID: 
26900121]
Thwaites GE et al. Approach to fever in the returning traveler. 
N Engl J Med. 2017 Feb 9;376(6):548–60. [PMID: 28177860]
travelers. Am J Clin Dermatol. 2016 Oct;17(5):451–62. 
[PMID: 27344566]
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TRAVELER’S DIARRHEA
 
»
Usually a benign, self-limited disease occurring 
about 1 week into travel.
 
»
Prophylaxis 
not
 recommended unless there is a 
comorbid disease (inflammatory bowel syndrome, 
HIV, immunosuppressive medication).
 
»
Single-dose therapy of a fluoroquinolone usually 
effective if significant symptoms develop.
 
»
Whenever a person travels from one country to another—
particularly if the change involves a marked difference in 
climate, social conditions, or sanitation standards and 
facilities—diarrhea may develop within 2–10 days. Bacte
-
ria cause 80% of cases of traveler’s diarrhea, with entero
-
toxigenic 
E coli
, 
Shigella
 
being the most common pathogens. Less common are 
Aeromonas, Salmonella
, noncholera vibriones, 
, 
and 
G lamblia
. Contributory causes include unusual food 
and drink, change in living habits, occasional viral infec
-
tions (adenoviruses or rotaviruses), and change in bowel 
flora. Chronic watery diarrhea may be due to amebiasis or 
giardiasis or, rarely, tropical sprue.
 
»
There may be up to ten or even more loose stools per day, 
often accompanied by abdominal cramps and nausea, 
occasionally by vomiting, and rarely by fever. The stools are 
usually watery and not associated with fever when caused 
by enterotoxigenic 
E coli
. With invasive bacterial pathogens 
(
Shigella, Campylobacter, Salmonella
), stools can be bloody 
and fever may be present. The illness usually subsides 
spontaneously within 1–5 days, although 10% remain 
symptomatic for 1 week or longer, and symptoms persist 
for longer than 1 month in 2%. Traveler’s diarrhea is also a 
significant risk factor for developing irritable bowel 
syndrome.
In patients with fever and bloody diarrhea, stool culture is 
indicated, but in most cases, cultures are reserved for those 
who do not respond to antibiotics.
 
»
Avoidance of fresh foods and water sources that are likely 
to be contaminated is recommended for travelers to devel
-
oping countries, where infectious diarrheal illnesses are 
endemic.
Because not all travelers will have diarrhea and because 
most episodes are brief and self-limited, the currently rec
-
ommended approach is to 
provide the traveler with a supply 
of antimicrobials
 to be taken if significant diarrhea occurs 
during the trip. Prophylaxis is recommended for those with 
significant underlying disease (inflammatory bowel dis
-
ease, AIDS, diabetes mellitus, heart disease in older adults, 
conditions requiring immunosuppressive medications) 
and for those whose full activity status during the trip is so 
essential that even short periods of diarrhea would be 
unacceptable.
Prophylaxis is started upon entry into the destination 
country and is continued for 1 or 2 days after leaving. For 
stays of more than 3 weeks, prophylaxis is not recom
-
mended because of the cost and increased toxicity. For 
prophylaxis, several oral antimicrobial once-daily regimens 
are effective, such as ciprofloxacin, 500 mg, or rifaximin, 
200 mg. Bismuth subsalicylate is effective but turns the 
tongue and the stools black and can interfere with doxycy
-
cline absorption, which may be needed for malaria prophy
-
laxis; it is rarely used.
 
»
Treatment
For most individuals, the affliction is short-lived, and 
symptomatic therapy with loperamide is all that is required, 
provided the patient is not systemically ill (fever 39
°
C or 
higher) and does not have dysentery (bloody stools), in 
which case antimotility agents should be avoided. Packages 
of oral rehydration salts to treat dehydration are available 
over the counter in the United States (Infalyte, Pedialyte, 
others) and in many foreign countries.
When treatment is necessary, in areas where toxin-

producing bacteria are the major cause of diarrhea (Latin 
America and Africa), loperamide (4 mg oral loading dose, 
then 2 mg after each loose stool to a maximum of 
16 mg/day) with a single oral dose of ciprofloxacin 
(750 mg), levofloxacin (500 mg), or ofloxacin (200 mg), 
cures most cases of traveler’s diarrhea. If diarrhea is associ
-
ated with bloody stools or persists despite a single dose of 
a fluoroquinolone, 1000 mg of azithromycin should be 
taken. In pregnant women and in areas where invasive 
bacteria more commonly cause diarrhea (Indian subconti
-
nent, Asia, especially Thailand where fluoroquinolone-
resistant 
 is prevalent), azithromycin is the 
medication of choice. Rifaximin, a nonabsorbable agent, is 
also approved for therapy of traveler’s diarrhea at a dose of 
200 mg orally three times per day or 400 mg twice a day for 
3 days. Because luminal concentrations are high, but tissue 
levels are insufficient, it should not be used in situations 
where there is a high likelihood of invasive disease 
(eg, fever, systemic toxicity, or bloody stools).
 
»
•	
Cases refractory to treatment.
•	
Persistent infection.
•	
Immunocompromised patient.
CMDT19_Ch30_p1294-p1337.indd   1316

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1317
 
CMDT 2019
 
»
Patients who are severely dehydrated or hemodynamically 
unstable should be admitted to the hospital.
Giddings SL et al. Traveler’s diarrhea. Med Clin North Am. 2016 
Mar;100(2):317–30. [PMID: 26900116]
Steffen R et al. Traveler’s diarrhea: a clinical review. JAMA. 2015 
Jan 6;313(1):71–80. [PMID: 25562268]
 
º
ANTIMICROBIAL T
h
ERAPY
SELECTED PRINCIPLES OF 
ANTIMICROBIAL THERAPY
Specific steps (outlined below) are required when consid
-
ering antibiotic therapy for patients. Medications within 
classes, medications of first choice, and alternative medica
-
tions are presented in Table 30–4.
A. Etiologic Diagnosis
Based on the organ system involved, the organism causing 
infection can often be predicted. See Tables 30–5 and 30–6.
B. “Best Guess”
Select an empiric regimen that is likely to be effective 
against the suspected pathogens.
C. Laboratory Control
Specimens for laboratory examination should be obtained 
before institution of therapy to determine susceptibility.
D. Clinical Response
Based on clinical response and other data, the laboratory 
reports are evaluated and then the desirability of changing 
the regimen is considered. If the specimen was obtained 
from a normally sterile site (eg, blood, cerebrospinal fluid, 
pleural fluid, joint fluid), the recovery of a microorganism 
in significant amounts is meaningful even if the organism 
recovered is different from the clinically suspected agent, 
and this may force a change in treatment. Isolation of 
unexpected microorganisms from the respiratory tract, 
gastrointestinal tract, or surface lesions (sites that have a 
complex flora) may represent colonization or contamina
-
tion, and cultures must be critically evaluated before 
medications are abandoned that were judiciously selected 
on a “best guess” basis.
E. Drug Susceptibility Tests
Some microorganisms are predictably inhibited by certain 
medications; if such organisms are isolated, they need not 
be tested for drug susceptibility. For example, all group A 
hemolytic streptococci are inhibited by penicillin. Other 
organisms (eg, enteric gram-negative rods) are variably 
susceptible and generally require susceptibility testing 
whenever they are isolated. Organisms that once had 
 
predictable susceptibility patterns are now associated with 
resistance and require testing. Examples include the 
 
pneumococci, which may be resistant to multiple medica
-
tions (including penicillin, macrolides, and TMP-SMZ); 
the enterococci, which may be resistant to penicillin, ami
-
noglycosides, and vancomycin; and ESBL producing–
E coli
 
resistant to third-generation cephalosporins and 
fluoroquinolones.
Over the past several years, the pharmaceutical indus
-
try has shifted away from developing and producing anti
-
bacterial medications, particularly those active against 
gram-negative pathogens. However, in 2015, two cephalo
-
sporin beta-lactamase inhibitor combinations were 
approved by the FDA that offer much-needed options in 
the treatment of resistant 
 and 
ESBL-producing Enterobacteriaceae. Similarly, in 2017, 
meropenem-vaborbactam, an agent active against car
-
bapenemase-producing Enterobacteriaceae (CPE) was 
approved. Nonetheless, the paucity of new medications and 
increasing bacterial resistance reinforce the need to use all 
antimicrobials judiciously. When culture and susceptibility 
results have been finalized, clinicians must use the most 
narrow-spectrum agent and the shortest duration possible 
to decrease the selection pressure for antibacterial 
resistance.
Antimicrobial drug susceptibility tests may be per
-
formed on solid media as disk diffusion tests, in broth, in 
tubes, in wells of microdilution plates, or as E-tests (strips 
with increasing concentration of antibiotic). The latter 
three methods yield results expressed as MIC (minimal

three methods yield results expressed as MIC (minimal 
inhibitory concentration). In most infections, the MIC is 
the appropriate in vitro test to guide selection of an anti
-
bacterial agent. When there appear to be marked discrep
-
ancies between susceptibility testing and clinical response, 
the following possibilities must be considered:
1.
 
Selection of an inappropriate medication, medication 
dosage, or route of administration.
2.
 
Failure to drain a collection of pus or to remove a 
foreign body.
3.
 
Failure of a poorly diffusing drug to reach the site of 
infection (eg, central nervous system) or to reach intra
-
cellular phagocytosed bacteria.
4.
 
Superinfection in the course of prolonged 
 
5.
 
Emergence of drug resistance in the original pathogen 
or superinfection with a new more resistant organism.
6.
 
Participation of two or more microorganisms in the 
infectious process, of which only one was originally 
detected and used for medication selection.
7.
 
Inadequate host defenses, including immunodeficien
-
cies and diabetes mellitus.
8.
 
Noninfectious causes, including drug fever, malig
-
nancy, and autoimmune disease.
F. Promptness of Response
Response depends on a number of factors, including the 
patient (immunocompromised patients respond slower 
than immunocompetent patients), the site of infection 
(deep-seated infections such as osteomyelitis and 
 
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Table 30–4.
 
Medication of choice for suspected or documented microbial pathogens (listed in alphabetical order, 
within classes).
Suspected or Proved 
Etiologic Agent
Medication(s) of First Choice
Alternative Medication(s)
Gram-negative Cocci
Cefuroxime, amoxicillin-clavulanic acid
Ceftriaxone, cefuroxime axetil, a fluoroquinolone
1
 
a macrolide,
2
 a tetracycline,
3
 TMP-SMZ
4
 
(gonococcus)
Ceftriaxone plus azithromycin or 
doxycycline
Cefixime plus azithromycin or doxycycline
5
 
(meningococcus)
6
Ceftriaxone, ampicillin
Gram-positive Cocci
Ampicillin ± gentamicin
7
Vancomycin ± gentamicin
7
Linezolid,
8
 quinupristin-dalfopristin,
8
 daptomycin,
8
 
tigecycline,
8
 tedizolid,
8
 oritavancin
8
, hemolytic, 
 
groups A, B, C, G
6
Macrolide,
2
 a cephalosporin,
9
 vancomycin, clindamycin
, 
methicillin-resistant
TMP-SMZ,
4
 doxycycline, minocycline, linezolid,
8
8
 
daptomycin,
8
 televancin,
8
 dalbavancin,
8
 oritavancin,
8
 
ceftaroline, delafloxacin
, methicillin-
 
susceptible
Penicillinase-resistant penicillin
10
Vancomycin, a cephalosporin,
9
 clindamycin, 
 
amoxicillin-clavulanic acid, ampicillin-sulbactam
11
 
(pneumococcus)
6
2
9
 vancomycin, clindamycin, 
 
a tetracycline,
3
 respiratory fluoroquinolones
1
Viridans streptococci
6
Cephalosporin,
9
 vancomycin
Gram-negative Rods
Acinetobacter
Imipenem, meropenem
Tigecycline, minocycline, doxycycline, aminoglycosides,
12
 colistin
, gastrointestinal 
 
strains
Ampicillin-sulbactam, piperacillin-tazobactam, ertapenem
Brucella
Doxycycline + rifampin
3
TMP-SMZ
4
 ± gentamicin; ciprofloxacin + rifampin
Burkholderia mallei
 (glanders)
Streptomycin + tetracycline
3
Chloramphenicol + streptomycin
Burkholderia pseudomallei
 
(melioidosis)
Ceftazidime
Tetracycline,
3
 TMP-SMZ,
4
 amoxicillin-clavulanic acid, 
 
imipenem or meropenem
Azithromycin
A fluoroquinolone
1
Enterobacter
Ertapenem, imipenem, meropenem, 
cefepime
Aminoglycoside, a fluoroquinolone,
1
 TMP-SMZ
4
 (uncomplicated 
 
outpatient urinary infection)
Nitrofurantoin, fosfomycin
Fluoroquinolones,
1
 TMP-SMZ,
4
 oral cephalosporin
 (sepsis)
13
Cefotaxime, ceftriaxone
Ertapenem
13
 imipenem
13
 or meropenem,
13
 aminoglycosides,
12
 
a fluoroquinolone,
1
 aztreonam, ticarcillin-clavulanate, 
piperacillin-tazobactam, ceftazidime-avibactam,
13
 
ceftolozane-tazobactam,
13,14
 meropenem/vaborbactam
15
 (respiratory 
 
infections, otitis)
Ampicillin-clavulanate
Doxycycline, azithromycin, ceftriaxone, cefuroxime, 
cefuroxime axetil, TMP-SMZ
4
 (serious infection)
Ceftriaxone
Aztreonam
Bismuth subsalicylate, tetracycline, 
metronidazole and proton pump 
inhibitor (PPI)
Amoxicillin, clarithromycin, metronidazole and PPI
13
A cephalosporin
TMP-SMZ,
4
 aminoglycoside,
12
 ertapenem,
13
 imipenem
13
 or 
meropenem,
13
 a fluoroquinolone,
1
 aztreonam, ticarcillin-
clavulanate, piperacillin-tazobactam, ceftazidime-avibactam,
13
 
13,14
15
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1318

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1319
 
CMDT 2019
 
within classes). (continued)
 species (pneumonia)
Azithromycin, or fluoroquinolones
1
 ± 
rifampin
Doxycycline ± rifampin
, oropharyngeal strains
Clindamycin
Proteus mirabilis
Ampicillin
An aminoglycoside,
12
 TMP-SMZ,
4
1
 
a cephalosporin
9
Proteus vulgaris
 and other species 
(Morganella, Providencia)
Aminoglycoside,
12
 ertapenem, imipenem or meropenem, 
TMP-SMZ,
4
 a fluoroquinolone
1
Piperacillin-tazobactam or 
 
ceftazidime or cefepime, or 
imipenem or meropenem or 
doripenem or aztreonam ± 
aminoglycoside
12
Ciprofloxacin (or levofloxacin) ± piperacillin-tazobactam; 
ciprofloxacin (or levofloxacin) ± ceftazidime; ciprofloxacin 
(or levofloxacin) ± cefepime; ceftazidime-avibactam
13
; 
ceftolozane-tazobactam
13
 (bacteremia)
1
Serratia
Carbapenem
TMP-SMZ,
4
12
1
Shigella
1
Azithromycin, TMP-SMZ,
4
Vibrio
 (cholera, sepsis)
A tetracycline
3
TMP-SMZ,
4
1
Yersinia pestis
 (plague)
Streptomycin ± a tetracycline
3
Chloramphenicol, TMP-SMZ
5
Gram-positive Rods
Actinomyces
6
3
 clindamycin
Bacillus
 (including anthrax)
6
A macrolide,
2
1
Clostridium
 (eg, gas gangrene, 
 
tetanus)
6
Metronidazole, clindamycin, imipenem or meropenem
Corynebacterium diphtheria
Macrolide
2
6
Corynebacterium jeikeium
Linezolid
Listeria
Ampicillin ± aminoglycoside
12
TMP-SMZ
4
Acid-fast Rods
 complex
Clarithromycin or azithromycin + 
 
ethambutol, ± rifabutin
Amikacin, ciprofloxacin
 
fortuitum-chelonei
Cefoxitin + clarithromycin
Amikacin, rifampin, sulfonamide, doxycycline, linezolid
INH + rifampin ± ethambutol
Clarithromycin, azithromycin, ethionamide, cycloserine
Mycobacterium leprae
Dapsone + rifampin ± clofazimine
Minocycline, ofloxacin, clarithromycin
16
Isoniazid (INH) + rifampin + 
pyrazinamide ± ethambutol
Other antituberculous drugs (see Tables 9–14 and 9–15)
Nocardia
TMP-SMZ
4
Minocycline, imipenem or meropenem, linezolid
Spirochetes
 
(Lyme disease)
Doxycycline, amoxicillin, 
cefuroxime axetil
Ceftriaxone, penicillin, azithromycin
 
(relapsing fever)
Doxycycline
3
6
Leptospira
6
Doxycycline,
3
 (syphilis)
6
Doxycycline, ceftriaxone
Treponema pertenue
 (yaws)
6
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1319

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 CMDT 2019
 
Mycoplasmas
Azithromycin or doxycycline
1
Chlamydiae
C pneumoniae
3
Azithromycin, a fluoroquinolone
1,17
C psittaci
 (urethritis or 
 
pelvic inflammatory disease)
Doxycycline or azithromycin
Levofloxacin, ofloxacin
Rickettsiae
3
Chloramphenicol, a fluoroquinolone
1
1
Fluoroquinolones include ciprofloxacin, levofloxacin, moxifloxacin, and others. Gemifloxacin, levofloxacin, and moxifloxacin, the so-called 
respiratory fluoroquinolones, demonstrate the most reliable activity against penicillin-resistant 
 and other respiratory infec
-
tion pathogens. Delafloxacin is predictably active against methicillin-resistant 
S aureus
 (MRSA).
2
Azithromycin is the preferred macrolide due to increased safety profile and minimal drug interaction potential.
3
All tetracyclines have similar activity against most microorganisms. Minocycline (the most active tetracycline), and doxycycline are more 
active than tetracycline against 
S aureus
.
4
TMP-SMZ is a mixture of 1 part trimethoprim and 5 parts sulfamethoxazole.
5
Test of cure required if ceftriaxone not used.
6
Penicillin G is preferred for parenteral injection; penicillin V for oral administration.
7
Addition of gentamicin indicated only for severe enterococcal infections (eg, endocarditis, meningitis).
8
Linezolid, tedizolid, daptomycin, televancin, dalbavancin, oritavancin should be reserved for the treatment of vancomycin-resistant isolates 
or in patients intolerant of vancomycin.
9
Most intravenous cephalosporins (with the exception of ceftazidime) are active against streptococci and staphylococci.
10
Parenteral nafcillin or oxacillin; oral dicloxacillin, cloxacillin, or oxacillin.
11
Infections caused by isolates with intermediate resistance may respond to high dose penicillin or ceftriaxone or the respiratory fluoroqui
-
nolones (gemifloxacin, levofloxacin, and moxifloxacin). Infections caused by highly penicillin-resistant isolates should be treated with 
 
vancomycin. Penicillin-resistant pneumococci are often resistant to macrolides, tetracyclines, and TMP-SMZ.
12
Aminoglycosides—gentamicin, tobramycin, amikacin, netilmicin—should be chosen on the basis of local patterns of susceptibility.
13
Extended beta-lactamase–producing (ESBL) isolates should be treated with a carbapenem. If a carbapenem cannot be used, ceftazidime-
avibactam or possibly ceftolozane-tazobactam can be considered.
14
Ceftazidime-avibactam and ceftolozane-tazobactam may be active against multidrug-resistant 
.
15
Consider in cases of infection due to carbapenemase-producing Enterobacteriaceae.
16
Resistance is common and susceptibility testing must be performed.
17
Ciprofloxacin has inferior antichlamydial activity compared with levofloxacin or ofloxacin.
±, alone or combined with.
Adapted, with permission, and updated, from 
. 2010 June;6(94):43–52; 
Med Lett Drugs Therapeut
. 2012 Jul 23(1395); 
 
. 2013 Jul;11(131):65; and 
. 2014 May 12 (1442). www.medicalletter.org
endocarditis respond more slowly than superficial infec
-
tions such as cystitis or cellulitis), the pathogen (virulent 
organisms such as 
S aureus
 respond more slowly than 
viridans streptococci; mycobacterial and fungal infections 
respond slower than bacterial infections), and the duration 
of illness (in general, the longer the symptoms are present, 
the longer it takes to respond). Thus, depending on the 
clinical situation, persistent fever and leukocytosis several 
days after initiation of therapy may not indicate improper 
choice of antibiotics but may be due to the natural history

choice of antibiotics but may be due to the natural history 
of the disease being treated. In most infections, either a 
bacteriostatic or a bactericidal agent can be used. In some 
infections (eg, infective endocarditis and meningitis), a 
bactericidal agent should be used. When potentially toxic 
medications (eg, aminoglycosides, flucytosine) are used, 
serum levels of the medication are measured to minimize 
toxicity and ensure appropriate dosage. In patients with 
altered renal or hepatic clearance of medications, the dos
-
age or frequency of administration must be adjusted; it is 
best to measure levels in older adults, in morbidly obese 
patients, or in those with altered kidney function when 
possible and adjust therapy accordingly.
G. Duration of Antimicrobial Therapy
Generally, effective antimicrobial treatment results in 
reversal of the clinical and laboratory parameters of active 
infection and marked clinical improvement. However, 
varying periods of treatment may be required for cure. Key 
factors include (1) the type of infecting organism (bacterial 
infections generally can be cured more rapidly than fungal 
or mycobacterial ones), (2) the location of the process 
(eg, endocarditis and osteomyelitis require prolonged 
therapy), and (3) the immunocompetence of the patient.
CMDT19_Ch30_p1294-p1337.indd   1320

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1321
 
CMDT 2019
Table 30–5.
 
Examples of initial antimicrobial therapy for acutely ill, hospitalized adults pending identification of 
causative organism (in alphabetical order).
Suspected Clinical Diagnosis
Likely Etiologic Diagnosis
Medication of Choice
Brain abscess
Mixed anaerobes, pneumococci, 
streptococci
Ceftriaxone, 2 g intravenously every 12 hours 
plus
 
metronidazole, 500 mg orally every 8 hours 
plus
 
vancomycin, 15 mg/kg intravenously every 8 hours
Endocarditis, acute (including 
injection drug user)
S aureus
, 
E faecalis
, viridans 
 
Vancomycin, 15 mg/kg/dose intravenously every 12 hours, 
 
plus
 gentamicin, 1 mg/kg/dose every 8 hours
Fever in neutropenic patient 
receiving cancer 
chemotherapy
S aureus
, 
, 
, 
 
E coli
Cefepime, 2 g intravenously every 8 hours
Intra-abdominal sepsis (eg, 
 
postoperative, peritonitis, 
cholecystitis)
Gram-negative bacteria, 
, 
anaerobic bacteria, enterococcus
Piperacillin-tazobactam, 4.5 g intravenously every 6 hours, 
 
or
 ertapenem, 1 g every 24 hours
Meningitis, bacterial, age > 50, 
Pneumococcus, meningococcus, 
 
,
1
 gram-
 
negative bacilli, group B 
streptococcus
Ampicillin, 2 g intravenously every 4 hours, 
plus
 ceftriaxone, 
 
2 g intravenously every 12 hours, 
plus
 vancomycin, 
 
15 mg/kg intravenously every 8 hours
Meningitis, bacterial, 
 
(pneumococcus),
2
 
Neisseria 
 
meningitidis
 (meningococcus)
Ceftriaxone, 2 g intravenously every 12 hours,
1
 
plus
 
Meningitis, postoperative 
 
(or posttraumatic)
S aureus
 
coagulase-negative staphylococci, 
 
diphtheroids (eg, 
acnes
) (uncommon) pneumococcus 
(in posttraumatic)
Vancomycin, 15 mg/kg intravenously every 8 hours, 
 
plus
 cefepime, 3 g intravenously every 8 hours
3
S aureus
Nafcillin, 2 g intravenously every 4 hours; 
or
 cefazolin, 
 
2 g intravenously every 8 hours
Pneumonia, acute, community-
acquired, non-ICU hospital 
admission
Pneumococci, 
, 
 
, 
Ceftriaxone, 1 g intravenously every 24 hours or ampicillin, 
 
2 g intravenously every 6 hours) 
plus
 azithromycin, 500 mg 
intravenously every 24 hours; 
or
 a respiratory fluoroquino
-
lone
4
 alone
Pneumonia, postoperative or 
nosocomial
S aureus
, mixed anaerobes, gram-
 
negative bacilli
Cefepime, 2 g intravenously every 8 hours; 
or
 ceftazidime, 
 
2 g intravenously every 8 hours; 
or
 piperacillin-tazobactam, 
4.5 g intravenously every 6 hours; 
or
 imipenem, 500 mg 
intravenously every 6 hours; 
or
 meropenem, 1 g intrave
-
nously every 8 hours 
plus
 tobramycin, 5–7 mg/kg intrave
-
nously every 24 hours; 
or
 ciprofloxacin, 400 mg 
 
intravenously every 12 hours; 
or
 levofloxacin, 500 mg 
 
intravenously every 24 hours 
plus
 
15 mg/kg/dose intravenously every 12 hours
Pyelonephritis with flank pain 
and fever (recurrent urinary 
tract infection)
E coli
, 
, 
, 
Ceftriaxone, 1 g intravenously every 24 hours; 
or
 ciprofloxacin, 
400 mg intravenously every 12 hours (500 mg orally); 
 
or
 levofloxacin, 500 mg once daily (intravenously/orally)
S aureus
, 
Ceftriaxone, 1–2 g intravenously every 24 hours
Septic thrombophlebitis 
 
(eg, IV tubing, IV shunts)
S aureus
, gram-negative aerobic 
bacteria
 
plus
 ceftriaxone, 1 g intravenously every 24 hours
1
TMP-SMZ can be used to treat 
 in patients allergic to penicillin in a dosage of 15–20 mg/kg/day of TMP in three or 
four divided doses.
2
Including penicillin nonsusceptible isolates.
3

2
3
Cefepime 3 g is a higher dose than sometimes recommended in order to provide better coverage of Pseudomonas and Enterobacter.
4
Levofloxacin 750 mg/day, moxifloxacin 400 mg/day.
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Table 30–6.
 
Examples of empiric choices of antimicrobials for adult outpatient infections (in alphabetical order).
Suspected Clinical 
Diagnosis
Likely Etiologic Agents
Medications of Choice
Alternative Medications
Acute sinusitis
Haemophilus influenzae, 
Augmentin,
1
 875 mg orally twice 
 
daily for 10 days
For patients allergic to penicillin, doxycy
-
cline, 100 mg twice daily for 10 days
Aspiration 
 
pneumonia
Mixed oropharyngeal flora, 
including anaerobes
Clindamycin, 300 mg orally four 
 
times daily for 10–14 days
Penicillin V, 500 mg orally four times daily 
 
for 10–14 days
Cystitis
Escherichia coli, 
saprophyticus, Klebsiella 
pneumoniae, Proteus
 
species, other gram-
negative rods or 
enterococci
Nitrofurantoin monohydrate 
macrocrystals 100 mg twice daily 
for  5–7 days (unless pregnant); 
fosfomycin 3 g orally as a single 
dose
Cephalexin, 500 mg orally four times daily 
for 7 days, for uncomplicated cystitis. 
 
Due to increasing resistance, TMP-SMZ 
and fluoroquinolones should not be used 
as first-line therapy for empiric treatment
Erysipelas, impetigo, 
cellulitis, ascending 
lymphangitis
Group A streptococcus
Penicillin V, 500 mg orally four times 
daily for 7–10 days
for 7–10 days; 
or
on day 1 and 250 mg on days 2–5
Furuncle with 
surrounding cellulitis
Dicloxacillin, 500 mg orally four times 
daily for 7–10 days for MSSA. For 
CA-MRSA: TMP-SMZ
2
 one double-
strength tablet twice daily for 
 
7–10 days; 
or
 clindamycin 300 mg 
orally three times daily for 
 
7–10 days
for 7–10 days for MSSA. For CA-MRSA, 
 
doxycycline is a reasonable alternative
Salmonella, Shigella, 
Campylobacter, 
See footnote 3
 
S pneumoniae, H influenzae, 
Amoxicillin, 500 mg–1 g orally 
three times daily for 10 days
Amoxicillin-clavulanate,
1
 875 mg orally 
or
 cefuroxime, 500 mg orally 
or
 cefpodoxime, 200–400 mg 
daily; 
or
 doxycycline, 100 mg twice daily
Pelvic inflammatory 
disease
Neisseria gonorrhoeae, 
, 
anaerobes, 
 
gram-negative rods
Ceftriaxone 250 mg intramuscularly 
once plus doxycycline 100 mg 
orally twice daily for 14 days +/– 
metronidazole 500 mg orally twice 
daily for 14 days; 
or
 Cefoxitin 2 g 
intramuscularly once plus probene
-
cid 1 g orally once, plus doxycycline 
100 mg orally twice daily for 
 
14 days +/– metronidazole 500 mg 
orally twice daily for 14 days
Levofloxacin 500 mg orally daily, 
or
 ofloxa
-
cin, 400 mg orally twice dailyor moxiflox
-
acin 400 mg once daily for 14 days 
plus
 
metronidazole, 500 mg orally twice daily 
 
for 14 days
daily, 
or
 amoxicillin, 500 mg–1 g 
orally three times daily, for 10 days
For patients with history of mild penicillin 
allergy, cephalexin, 500 mg orally four 
times daily for 10 days; for patients with 
IgE-mediated reaction, clindamycin, 300 
mg orally four times daily for 10 days; 
or
 
azithromycin, 500 mg on day 1 and 
 
250 mg on days 2–5
Pneumonia
S pneumoniae, Mycoplasma 
pneumoniae, Legionella 
pneumophila, 
Chlamydophila 
Doxycycline, 100 mg orally twice daily
Amoxicillin, 1.0 g orally three times daily 
plus azithromycin 500 mg orally on day 1 
and 250 mg on days 2–5. A respiratory 
fluoroquinolone
4
 for patients at high risk 
for infection due to resistant 
pneumococci
E coli, K pneumoniae, 
Proteus
 species, 
S saprophyticus
5
 for 7 days 
 
if prevalence of resistance 
 
among uropathogens is 
 
< 10%
TMP-SMZ,
2
 one double-strength tablet 
twice daily for 7–14 days for susceptible 
pathogens. Oral beta-lactams are less 
effective
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1322

< 10%
TMP-SMZ,
2
effective
(
continued
)

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1323
 
CMDT 2019
 
Examples of empiric choices of antimicrobials for adult outpatient infections (in alphabetical order). 
Diagnosis
Urethritis, 
 
epididymitis
N gonorrhoeae, 
 
Ceftriaxone, 250 mg intramuscularly 
once 
plus
 azithromycin 
 
(or doxycycline) for 
; 
azithromycin 1 g orally once, 
or
 
doxycycline, 100 mg orally twice 
daily for 7 days, 
 
for 
Cefixime 400 mg orally once for 
N
 
gonorrhoeae
6
Syphilis
Early syphilis 
 
(primary, secondary, 
or latent of < 1 year’s 
duration)
Benzathine penicillin G, 
 
2.4 million units intramuscularly 
 
once
Doxycycline, 100 mg orally twice daily for 
 
2 weeks. Ceftriaxone 1–2 g intravenously 
once daily for 10–14 days
Latent syphilis of 
 
> 1 year’s duration 
 
or cardiovascular 
syphilis
T pallidum
 
once a week for 3 weeks (total: 
7.2 million units)
Doxycycline, 100 mg orally twice daily, 
 
for 4 weeks
T pallidum
Aqueous penicillin G, 18–24 million 
units/day intravenously for 
10–14 days
 
1
Amoxicillin-clavulante is available as a combination of amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid. Augmentin 
XR is a combination of amoxicillin 1 g and clavulanic acid 62.5 mg.
2
TMP-SMZ is a fixed combination of 1 part trimethoprim and 5 parts sulfamethoxazole. Single-strength tablets: 80 mg TMP , 400 mg SMZ; 
double-strength tablets: 160 mg TMP , 800 mg SMZ.
3
The diagnosis should be confirmed by culture before therapy. 
 gastroenteritis does not require therapy. For susceptible 
Shigella
 
isolates, give ciprofloxacin, 500 mg orally twice daily for 5 days. For 
 infection, give azithromycin, 1 g orally times one dose, 
or ciprofloxacin, 500 mg orally twice daily for 5 days. For 
 infection, give metronidazole, 750 mg orally three times daily for 5–10 
days, followed by diiodohydroxyquinoline (not available in United States), 650 mg orally three times daily for 3 weeks.
4
Fluoroquinolones with activity against 
, including penicillin-resistant isolates, include gemifloxacin (not available in United 
States) (320 mg orally once daily), levofloxacin (500–750 mg orally once daily) and moxifloxacin (400 mg orally once daily). Use fluoroqui
-
nolones as drug of choice if recent antibiotic use within 3 months or comorbidities present.
5
Fluoroquinolones and dosages include ciprofloxacin, 500 mg orally twice daily; ofloxacin, 400 mg orally twice daily; levofloxacin, 500 mg 
6
Test of cure recommended if ceftriaxone is not used.
CA-MRSA, community-acquired methicillin-resistant 
; MRSA, methicillin-resistant 
S aureus
; MSSA, methicillin-sensitive 
S aureus;
 TMP-SMZ, trimethoprim-sulfamethoxazole.
Adapted from Drugs for Bacterial Infections. Treat Guide Med Lett. 2013 Jul;11(131):65–73. Med Lett. 2017; Oct 23 (59): 171–177.
H. Adverse Reactions and Toxicity
These include hypersensitivity reactions, direct toxicity, 
superinfection by drug-resistant microorganisms, and 
drug interactions. If the infection is life-threatening and 
treatment cannot be stopped, the reactions are managed 
symptomatically or another medication is chosen that does 
not cross-react with the offending one (Table 30–4). If the 
infection is less serious, it may be possible to stop all anti
-
microbials and monitor the patient closely.
I. Route of Administration
Intravenous therapy is preferred for acutely ill patients with 
serious infections (eg, endocarditis, meningitis, sepsis, severe 
pneumonia) when dependable levels of antibiotics are 
required for successful therapy. Certain medications 
(eg, doxycycline, fluconazole, voriconazole, rifampin,

(eg, doxycycline, fluconazole, voriconazole, rifampin, 
metronidazole, TMP-SMZ, and fluoroquinolones) are so well 
absorbed that they generally can be administered orally in 
seriously ill—but not hemodynamically unstable—patients.
Food does not significantly influence the bioavailability 
of most oral antimicrobial agents. However, the tetracy
-
clines (particularly tetracycline) and the quinolones chelate 
multivalent cations resulting in decreased oral 
bioavailability. Azithromycin capsules are associated with 
decreased bioavailability when taken with food and thus 
should be given 1 hour before or 2 hours after meals. Posacon
-
azole suspension should always be administered with food.
A major complication of intravenous antibiotic therapy is 
infection due to the manipulation of the intravenous cathe
-
ter. Peripheral catheters are changed every 48–72 hours to 
decrease the likelihood of catheter-associated infection, and 
antimicrobial-coated central venous catheters (minocycline 
and rifampin, chlorhexidine and sulfadiazine) have been 
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associated with a decreased incidence of these infections. 
Most of these infections present with local signs of infection 
(erythema, tenderness) at the insertion site. In a patient with 
fever who is receiving intravenous therapy, the catheter must 
always be considered a potential source. Small-gauge 
(20–23F) peripherally inserted silicone or polyurethane 
catheters (Per Q Cath, A-Cath, Ven-A-Cath, and others) are 
associated with a low infection rate and can be maintained 
for 3–6 months without replacement. Such catheters are 
ideal for long-term outpatient antibiotic therapy.
J. Cost of Antibiotics
The cost of these agents can be substantial. In addition to 
acquisition costs and monitoring costs (drug levels, liver 
biochemical tests, electrolytes, etc), the cost of treating 
adverse reactions, the cost of treatment failure and super
-
infection, and the costs associated with drug administra
-
tion must be considered.
Chambers HF et al. Antibacterial resistance leadership group: 
open for business. Clin Infect Dis. 2014 Jun;58(11):1571–6. 
[PMID: 24610430]
Tamma PD et al. Association of adverse events with antibiotic 
use in hospitalized patients. JAMA Intern Med. 2017 Sep 1; 
177(9):1308–15. [PMID: 28604925]
HYPERSENSITIVITY TESTS & 
DESENSITIZATION
 
»
Penicillin Allergy
All penicillins are cross-sensitizing and cross-reacting. 
Skin tests using penicilloyl-polylysine and undegraded 
penicillin can identify most individuals with IgE-mediated 
reactions (hives, bronchospasm). In those patients with 
positive reaction to skin tests, the incidence of subsequent 
immediate severe reactions associated with penicillin 
administration is high. A history of a penicillin reaction in 
the past is often not reliable. Only a small proportion (less 
than 5%) of patients with a stated history of penicillin 
allergy experience an adverse reaction when challenged 
with the medication. The decision to administer penicillin 
or related medications (other beta-lactams) to patients 
with an allergic history depends on the severity of the 
reported reaction, the severity of the infection being 
treated, and the availability of alternative medications. For 
patients with a history of severe reaction (anaphylaxis), 
alternative medications should be used. In the rare situa
-
tions when there is a strong indication for using penicillin 
(eg, syphilis in pregnancy) in allergic patients, desensitiza
-
tion can be performed. If the reaction is mild (nonurticar
-
ial rash), the patient may be rechallenged with penicillin or 
may be given another beta-lactam antibiotic.
Allergic reactions include anaphylaxis, serum sickness 
(urticaria, fever, joint swelling, angioedema 7–12 days after 
exposure), skin rashes, fever, interstitial nephritis, eosino
-
philia, hemolytic anemia, other hematologic disturbances, 
and vasculitis. The incidence of hypersensitivity to penicillin 
is estimated to be 1–5% among adults in the United States. 
Life-threatening anaphylactic reactions are very rare (0.05%). 
Ampicillin produces maculopapular skin rashes more fre
-
quently than other penicillins, but many ampicillin (and 
other beta-lactam) rashes are not allergic in origin. The 
nonallergic ampicillin rash usually occurs after 3–4 days of 
therapy, is maculopapular, is more common in patients with 
coexisting viral illness (especially Epstein-Barr infection), 
and resolves with continued therapy. The maculopapular 
rash may or may not reappear with rechallenge. Beta-
lactams can induce nephritis with primary tubular lesions 
associated with anti-basement membrane antibodies.
If the intradermal test described below is negative, 
desensitization is not necessary, and a full dose of the peni
-
cillin may be given. If the test is positive, alternative medi
-
cations should be strongly considered. If that is not feasible, 
desensitization is necessary.
Patients with a history of allergy to penicillin are also at

-
Patients with a history of allergy to penicillin are also at 
an increased risk for having a reaction to cephalosporins or 
carbapenems. A common approach to these patients is to 
assess the severity of the reaction. If an IgE-mediated reac
-
tion to penicillin can be excluded by history, a cephalospo
-
rin can be administered. When the history justifies concern 
about an immediate-type reaction, penicillin skin testing 
should be performed. If the test is negative, the cephalo
-
sporin or carbapenem can be given. If the test is positive, 
there is a 5–10% chance of cross reactivity with cephalo
-
sporins, and the decision whether to use cephalosporins 
depends on the availability of alternative agents and the 
severity of the infection. While carbapenems historically 
have been considered highly cross reactive with penicillins, 
the cross reactivity appears to be minimal (1%).
 
»
Intradermal Test for Hypersensitivity
Penicillin is the medication that most frequently serves as 
an indication for sensitivity testing and desensitization. 
A clinical history of penicillin allergy has a positive predic
-
tive value of only 15%. IgG-mediated delayed reactions 
such as erythematous or maculopapular skin rash or serum 
sickness should be distinguished from immediate-type 
IgE-mediated reactions, such as urticaria, angioedema, and 
anaphylaxis.
 
»
Desensitization
A. Precautions
1.
 
The desensitization procedure is not innocuous—
deaths from anaphylaxis have been reported. If extreme 
hypersensitivity is suspected, it is advisable to use an 
alternative structurally unrelated medication and to 
reserve desensitization for situations when treatment 
cannot be withheld and no alternative drug is available.
2.
 
An antihistaminic drug (25–50 mg of hydroxyzine or 
diphenhydramine intramuscularly or orally) should be 
administered before desensitization is begun in order to 
lessen any reaction that occurs.
3.
 
Desensitization should be conducted in an intensive 
care unit where cardiac monitoring and emergency 
endotracheal intubation can be performed.
4.
 
Epinephrine, 1 mL of 1:1000 solution, must be ready for 
immediate administration.
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CMDT 2019
B. Desensitization Method
Several methods of desensitization have been described for 
penicillin, including use of both oral and intravenous 
preparations. All methods start with very small doses of 
medication and gradually increase the dose until therapeu
-
tic doses are achieved. For penicillin, 1 unit of medication 
is given intravenously and the patient observed for 
15–30 minutes. If there is no reaction, some recommend 
doubling the dose while others recommend increasing it 
tenfold every 15–30 minutes until a dosage of 2 million units 
is reached; then give the remainder of the desired dose.
For recommendations on skin testing and desensitiza
-
tion for other preparations (eg, botulism antitoxin, and 
diphtheria antitoxin), the manufacturer’s package inserts 
should be consulted.
Leis JA et al. Point-of-care beta-lactam allergy skin testing by 
antimicrobial stewardship programs: a pragmatic multicenter 
prospective evaluation. Clin Infect Dis. 2017 Jun 1. [Epub 
ahead of print] [PMID: 28575226]
MacFadden DR et al. Impact of reported beta-lactam allergy on 
inpatient outcomes: a multicenter prospective cohort study. 
Clin Infect Dis. 2016 Oct 1;63(7):904–10. [PMID: 27402820]
Sacco KA et al. Clinical outcomes following inpatient penicillin 
allergy testing: a systematic review and meta-analysis. Allergy. 
2017 Sep;72(9):1288–96. [PMID: 28370003]
 
º
IMMUNIZATION AGAINST 
RECOMMENDED IMMUNIZATION OF 
INFANTS, CHILDREN, & ADOLESCENTS
The recommended schedules and dosages of vaccination 
change often, so the manufacturer’s package inserts should 
always be consulted.
The schedule for active immunizations in children can 
be accessed at https://www.cdc.gov/vaccines/index.html. 
All adolescents should see a health care provider to ensure 
vaccination of those who have not received varicella or 
hepatitis B vaccine, to make certain that a second dose of 
MMR has been given, to receive a booster of tetanus 
toxoid, reduced diphtheria toxoid and acellular pertussis 
vaccine (Tdap adolescent preparation), to receive menin
-
gococcal vaccine conjugate vaccine, to obtain HPV vaccine 
if not given previously, and to receive immunizations 
(influenza and pneumococcal vaccines) that may be indi
-
cated for certain high-risk individuals.
RECOMMENDED IMMUNIZATION 
FOR ADULTS
Immunization is one of the most important tools (along 
with sanitation) used to prevent morbidity and mortality 
from infectious diseases. In general, the administration of 
most vaccinations induces a durable antibody response 
(
active immunity
). In contrast, 
passive immunization
 
occurs when preformed antibodies are given (eg, immune 
globulin from pooled serum), resulting in temporary pro
-
tection which is a less durable response. The two variants 
of active immunization are 
live attenuated vaccines
 (which 
are believed to result in an immunologic response more 
like natural infection), and 
inactivated or killed vaccines.
The schedule of vaccinations varies based on the risk of 
the disease being prevented by vaccination, whether a vac
-
cine has been given previously, the immune status of the 
patient (probability of responding to vaccine) and safety of 
the vaccine (live versus killed product, as well as implica
-
tions for the fetus in pregnant women). Recommendations 
for healthy adults as well as special populations based on 
medical conditions are summarized in Table 30–7, which 
can be accessed online at https://www.cdc.gov/vaccines/
schedules.
1. 
h
ealthy Adults
Vaccination recommendations are made by the Advisory 
Committee on Immunization Practices (ACIP) of the US 
Centers for Disease Control and Prevention (Table 30–7).
2. Pregnant Women
Given the uncertainty of risks to the fetus, vaccination dur
-
ing pregnancy is generally avoided with the following 
exceptions: tetanus (transfer of maternal antibodies across

-
exceptions: tetanus (transfer of maternal antibodies across 
the placenta is important to prevent neonatal tetanus), 
diphtheria, and influenza. Live vaccines are avoided during 
Influenza can be a serious infection if acquired in preg
-
nancy, and all pregnant women should be offered influenza 
(inactivated) vaccination. The live attenuated (intranasal) 
influenza vaccine is 
not
 recommended during pregnancy.
3. 
h
IV-Infected Adults
HIV-infected patients have impaired cellular and B cell 
responses. Inactivated or killed vaccinations can generally 
be given without any consequence, but the recipient may 
not be able to mount an adequate antibody response. Live 
or attenuated vaccines are generally avoided with some 
exceptions (ie, in patients with CD4
+
 T lymphocytes 
greater than 200 cells/mcL). Guidelines for vaccinating 
HIV-infected patients have been issued jointly by the Cen
-
ters for Disease Control and Prevention, the US National 
Institutes of Health, and the HIV Medical Association of 
the Infectious Diseases Society of America. Timing of 
vaccination is important to optimize response. If possible, 
vaccination should be given early in the course of HIV 
disease or following immune reconstitution.
4. 
h
ematopoietic Cell Transplant Recipients
Hematopoietic cell transplant (HCT) recipients have vary
-
ing rates of immune reconstitution following transplanta
-
tion, depending on (1) the type of chemotherapy or 
radiotherapy used pretransplant (in autologous HCT), 
(2) the preparative regimen used for the transplant, 
(3) whether graft-versus-host disease is present, and (4) the 
type of immunosuppression used posttransplantation (in 
allogeneic HCT). Vaccines may not work immediately in 
the posttransplant period. B cells may take 3–12 months to 
return to normal posttransplant, and naïve T cells that can 
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 CMDT 2019
Table 30–7.
 
Recommended adult immunization schedule—United States, 2018.
Re
co
mmended Immunization Schedule for Adults Aged 19 
Ye
ars or Olde
r,
 United States, 2018
U.S. Depa
rt
ment of Health and Human Se
rv
ices
Centers for Disease Control and Preventio
n
In F
ebrua
ry
 2018, the
 
Recommended Immunization 
Sched
ule for Adults A
ged 19 Years or Older, United
 
States, 2018
 became eﬀ
ec
tive
, as 
re
commended by the Advisor
y 
Co
mmittee on Immunization 
Pr
ac
tice
s 
(A
CIP) and approved by the 
Ce
nters for Disease Control and 
Pr
evention (
CDC). 
The adult immunization
 
schedule was also approved by the
 
American 
Co
llege of Ph
ysicians
, the 
American 
Ac
a
dem
y of 
Fa
mily
 
Physician
s
, the 
American College of Obstetricians and Gynecologist
s
, and the 
American College of
 
Nurse-M
idwive
s
.
CDC announced the availability of the 2018 adult immunization schedule in the 
Morbidit
y and Mo
rt
alit
y 
W
eekly Repor
t 
(
MMWR
)
.
1
 
The schedule is published in its entire
ty in the 
Annals of In
ternal Medicin
e
.
2
T
he adult immunization schedule consists of ﬁgures that summarize 
ro
utinely recommended vaccines
 
fo
r adults by age groups and medical conditions and other indications, f
ootnotes 
fo
r the ﬁgure
s,
 an
d 
a table of vaccine contraindications and precautions. Note the following when reviewing the adul
t 
immunization schedule:
• 
The ﬁgures in the adult immunization schedule should be reviewed with the accompanying
 
fo
otnote
s.
• 
The ﬁgures and footnotes display indications for which vaccines, if not previously administered
, 
should be administered unless noted other
wise
.
• 
The table of contraindications and precautions identiﬁes populations and situations for whic
h 
vaccines should not be used or should be used with caution.
• 
W
hen indicated
, administer recommended vaccines to adults whose vaccination histor
y is
 
incomplete or un
kn
own.
• 
In
cr
eased inte
rv
al between doses of a multidose vaccine series does not diminish vaccin
e 
eﬀectiv
eness; it is not necessar
y to restar
t the vaccine series or add doses to the series because of
 
an ex
tended inte
rv
al between doses
.
• 
C
ombination vaccines may be used when any component of the combination is indicated an
d 
when the other components of the combination are not contraindicated
.
• 
The use of trade names in the adult immunization schedule is for identiﬁcation pu
rposes only and 
does not imply endorsement by the 
AC
IP or CDC.
Special populations that need additional considerations include:
• 
Pr
egnant w
omen. 
Pr
egnant women should 
re
ceive the tetanus, diphther
i
a, and acellular pe
rt
ussi
s 
vaccine 
(T
dap) during pregnanc
y and the inﬂuenza vaccine during or be
fo
re
 pregnanc
y.
 Live
 
vaccines (e.g
., measles, mump
s,
 and rubella vaccine [MMR]) ar
e contraindicate
d.
 
• 
A
splenia. 
Ad
ults with asplenia have speciﬁc vaccination recommendations because of thei
r 
increased risk f
or in
fe
c
tion by encapsulated bacteria. Anatomical or functional aspleni
a 
includes congenital or acquired asplenia, splenic dysfunc
tion, sic
kl
e cell disease and other
 
hemoglobinopathie
s,
 and splenec
tomy
.
• 
Im
munocompromising conditions. 
Ad
ults with immunosuppression should generally avoid
 
live vaccine
s.
 Inac
tivated vaccines (e
.g
., pneumococcal vaccines) are generally acceptabl
e.
 
Hi
gh-level immunosuppression includes HIV in
fe
c
tion with a CD4 cell count <200 cells//uni03BCL
, 
receipt of daily cor
ticosteroid therapy with ≥20 mg of prednisone or equivalent for ≥14 days
, 
prima
ry
 immunodeﬁciency diso
rd
er (e
.g
., seve
re
 combined immunodeﬁcienc
y or complement
 
component deﬁcienc
y), and receipt of cancer chemotherapy
. 
Ot
her immunocompr
omisin
g 
conditions and immunosuppressive medications to consider when vaccinating adults ca
n 
be 
fo
und in
 
IDSA Clinic
al 
Pr
actice Guideline for 
Va
ccination of the Immunocompromised Host
.
3
 
Ad
ditional in
fo

n 
be 
fo
und in
 
al 
Pr
Va
.
3
 
Ad
fo
rmation on vaccinating immuno
compromised adults is in
 
Gener
al Best 
Pr
actice
 
Guidelines for Immunization
.
4
Ad
ditional resour
ces for health care providers include:
• 
Details on vaccines 
re
commended for adults and complete ACIP statements at
 
ww
w.
cdc.gov/
vaccines/hcp/aci
p-
recs/index.htm
l
• 
Va
ccine 
In
fo
rmation Statements that explain beneﬁts and risks of vaccines at
 
ww
w.
cdc.gov/
vaccines/hcp/vis/index.htm
l
• 
In
fo
rmation and 
resources on vaccinating pregnant women at
 
ww
w.
cdc.gov/vaccines/adults/
re
cvac/p
regnant.htm
l
• 
In
fo
rmation on tr
avel vaccine requirements and recommendations at
 
ww
w.
cdc.gov/travel
/
destinations/lis
t
• 
CDC 
Va
ccine 
Schedules App 
fo
r immunization se
rv
ice providers to download at
 
ww
w.
cdc.gov/
vaccines/schedules/hcp/schedul
e-
ap
p.
html
• 
Ad
ult 
Va
ccination Quiz for self-assessment of vaccination needs based on age, health conditions
, 
and other indications at
 
ww
w2.cdc.gov/nip/adultimmsched/default.as
p
 
• 
Sc
hedule for Children and Adolescents Aged 18 Y
ears or 
Yo
unger
 at
 
ww
w.
cdc.gov/vaccines/schedules/hcp/child-adolescent.html
 
Repo
rt
 suspec
ted cases of repo
rt
able vaccin
e-
preventable diseases to the local or state health
 
depar
tment, and repo
rt
 all clinically signiﬁcant postvaccination events to the 
Va
ccine Adverse Even
t 
Repor
ting System at
 
ww
w.
vaers.hhs.go
v
 or by telephon
e,
 800-822-7967. All vaccines included in th
e 
adult immunization schedule ex
cept 23-valent pneumococcal polysaccharide and zoster vaccines ar
e 
covered by the 
Va
ccine 
Inju
ry
 
Com
pensation 
Pr
ogram. In
fo
rmation on ho
w to ﬁle a vaccine inju
ry
 claim
 
is available at
 
ww
w.
hrsa.gov/vaccinecompensatio
n
e,
 800-338-2382. Submit question
s 
and 
comments to CDC through 
www
.cdc.gov/cdc-inf
o
e,
 800-CDC-INFO (800-232
-
4636), in English and Spanish, 8:00am–8:00pm 
ET
, Monday–F
rida
y,
 ex
cluding holidays
.
The following abbreviations are used for vaccines in the adult immunization schedule (in the order of
 
their appearance)
:
II
Vi
nac
tivated inﬂuenza vaccin
e
RI
Vr
ecombinant inﬂuenza vaccin
e
Td
ap
tetanus toxoid, reduced diphtheria toxoid, and acellular pe
rt
ussis vaccin
e
Td
tetanus and diphtheria toxoids
MM
Rm
easles
, mump
s,
 and rubella vaccin
e
VA
Rv
aricella vaccin
e 
RZ
Vr
ecombinant zoster vaccin
e
ZV
Lz
oster vaccine live
HPV vaccin
eh
uman papillomavirus vaccin
e
PC
V1
31
3-valent pneumococcal conjugate vaccin
e
PPSV23
23-valent pneumococcal polysaccharide vaccin
e
HepA
hepatitis A vaccin
e
HepA-Hep
Bh
epatitis A vaccine and hepatitis B vaccin
e
HepB
hepatitis B vaccin
e
MenA
CW
Ys
erog
ro
ups A, C, 
W,
 and 
Y meningococcal vaccin
e
MenB
serogroup B meningococcal vaccin
e
Hi
b
H
aemophilus inﬂuenza
e
 type b vaccin
e
1. 
MMWR Morb Mo
rt
al 
Wk
ly Re
p.
 2018;66(5). 
Av
ailable at
 
ww
w.
cdc.gov/mmwr/volumes/67/wr/mm6705e3.ht
m
.
2. 
Ann Intern Med. 2018;168:210–220. 
Av
ailable at
 
annal
s.
org/aim/article/doi/10.7326/M17-3439
.
3. 
Clin In
fe
ct
 Di
s.
 2014;58:e44-100. 
Av
ailable at
 
ww
w.
idsociet
y.
org/
Te
mpla
tes/Content.aspx?id=32212256011
.
4. 
AC
IP . 
Av
ailable at
 
ww
w.
cdc.gov/vaccines/hcp/acip-recs/general-recs/index.htm
l
.
CMDT19_Ch30_p1294-p1337.indd   1326

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1327
 
CMDT 2019
F
igure 1. Re
co
mmended immunization schedule for adults aged 19 y
ears or older by age grou
p,
T
his ﬁgur
e should be review
ed with the accompan
y
ing 
fo
otnote
s.
 T
his ﬁgure and the 
fo
otnotes describe indications 
fo
r which vacc
ines, if not previously administered, should be administered unless noted othe
rw
is
e.
Va
ccine
19
–
21 years
22
–
26 years
27
–
49 years
50
–
64 years
≥
65 years
Inﬂuenza
1
Tdap
2
 or 
Td
2
MMR
3
VA
R
4
RZV
5
ZVL
5
HPV
–
Female
6
HPV
–
Male
6
PCV13
7
 
PPSV23
7
HepA
8
HepB
9
MenA
CW
Y
10
MenB
10
Hib
11
1 dose annuall
y
1 dose ZV
L
2 doses RZV (preferred
)
1 dose
1 dose
2 or 3 doses depending on age at series initiatio
n
n
1 or 2 doses depending on indication (if born in 1957 or later)
1 dose 
Td
ap
, then 
Td
 booster ev
er
y 10 yr
s
1 or 2 doses depending on indication
2 or 3 doses depending on vaccin
e
3 doses
2 doses
1 or 2 doses depending on indication, then booster ev
er
y 5 yrs if risk remains
e
1 or 3 doses depending on indication
Recommended for adults who meet the  
age requirement, lack documentation of 
vaccination, or lack evidence of past infec
tion
Recommended f
or adults with other 
No recommendation
or
or
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1327

Ch
APTER
 3
0
1328
 CMDT 2019
 
Recommended adult immunization schedule—United States, 2018. (continued)
Fi
gure 2. Re
co
mmended immunization schedule for adults aged 19 
ye
ars or older by medical 
co
ndition and other indications, Unit
e
d States, 201
8
T
his ﬁgure should be review
ying f
ootnote
s.
 
This ﬁgure and the footnotes describe indications for which vacc
i
ne
s,
 if not previously administer
ed
, should be administe
re
d unless noted othe
rw
is
e.
Va
ccine Pregnancy
1-6
Immun
o-
co
mpromised
 
(e
x
cluding HI
V 
3-7,11
HIV infe
ct
io
n
CD4+ 
co
un
t
 (cells//uni03BCL)
3-7,9-10
Asplenia
, 
c
omplemen
t 
deﬁciencies
7,10
,1
1
End-stage rena
l 
diseas
e,
 on
 
hemodialysi
s
7,9
Hear
t or
lung disease
, 
al
co
holism
7
Chronic li
ve
r 
disease
7-
9
Diabetes
7,
9
Health care
personnel
3,4,
9
M
en wh
o 
ha
ve
 se
x 
with men
6,8,9
<200 ≥200
Inﬂuenza
1
Tdap
2
 or 
Td
2
1 dose
 
Td
ap each
 
pregnanc
y
MMR
VA
R
4
RZV
5
ZVL
5
HP
V–
Fe
male
6
3 doses through age 26 yr
s
HPV–Male
6
2 or 3 dose
s  
through ag
e 
26 yr
s
PCV13
7
PPSV23
7
HepA
8
HepB
9
MenA
CW
Y
10
MenB
10
Hib
11
3 doses HS
CT 
recipients only
or adults who meet the 
tion
3 dose
s
2 or 3 doses depending on va
cc
in
e
1 dose
1 dose
1, 2, or 3 doses depending on indicatio
n
cc
in
e
1 or 2 doses depending on indication , then booster ev
er
y 5 yrs if risk remain
s
2 doses RZV at age 
>50 yrs (preferred
)
co
ntraindi
ca
te
d
co
ntraindi
ca
te
d
1 or 2 doses depending on indicatio
n
2 or 3 doses through age 26 yrs
2 dose
s
3 doses through age 26 yrs
y
1 dose 
Td
ap
, then 
Td
 booster ev
er
y 10 yrs
2 or 3 doses through age 21 yrs
1 dose ZVL at age >60 yr
s
co
ntraindi
ca
te
d
or
or
3
CMDT19_Ch30_p1294-p1337.indd   1328

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1329
 
CMDT 2019
Footnotes. Recommended immunization schedule for adults aged 19 years or older, United States, 2018
1.
 
Influenza vaccination
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html
  
General information
•	
Administer 1 dose of age-appropriate inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV) annually
•	
Live attenuated influenza vaccine (LAIV) is not recommended for the 2017–2018 influenza season
•	
A list of currently available influenza vaccines is available at www.cdc.gov/flu/protect/vaccine/vaccines.htm
  
Special populations
•	
Administer age-appropriate IIV or RIV to:
–
 
Pregnant women
–
 
A
dults with 
hives-only egg allergy
–
 
A
dults with 
egg allergy other than hives
 (e.g., angioedema or respiratory distress): Administer IIV or RIV in a medical setting under supervision of a health care provider who can recognize 
and manage severe allergic conditions
2.
 
T
etanus, diphtheria, and pertussis vaccination
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/tdap-td.html
  
•	
Administer to adults who previously did not receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) as an adult or child (routinely recommended at 
age 11–12 years) 1 dose of Tdap, followed by a dose of tetanus and diphtheria toxoids (Td) booster every 10 years
•	
Information on the use of Tdap or Td as tetanus prophylaxis in wound management is available at www.cdc.gov/mmwr/preview/mmwrhtml/rr5517a1.htm
  
•	
Pregnant women:
 Administer 1 dose of Tdap during each pregnancy, preferably in the early part of gestational weeks 27–36
3.
 
Measles, mumps, and rubella vaccination
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/mmr.html
  
G
eneral information
•	
Administer 1 dose of measles, mumps, and rubella vaccine (MMR) to adults with no evidence of immunity to measles, mumps, or rubella
•	
Evidence of immunity is:
–
 
Bor
n before 1957 (except for health care personnel, see below)
–
 
D
ocumentation of receipt of MMR
–
 
Laborat
ory evidence of immunity or disease
•	
Documentation of a health care provider-diagnosed disease without laboratory confirmation is not considered evidence of immunity
  
•	
Pregnant women and nonpregnant women of childbearing age
 with no evidence of immunity to rubella: Administer 1 dose of MMR (if pregnant, administer MMR after pregnancy and before 
discharge from health care facility)
•	
HIV infection and CD4 cell count ≥200 cells/μL for at least 6 months
 and no evidence of immunity to measles, mumps, or rubella: Administer 2 doses of MMR at least 28 days apart
•	
Students in postsecondary educational institutions, international travelers,
 and 
household contacts of immunocompromised persons:
 Administer 2 doses of MMR at least 28 days apart 
(or 1 dose of MMR if previously administered 1 dose of MMR)
•	
Health care personnel born in 1957 or later
 with no evidence of immunity: Administer 2 doses of MMR at least 28 days apart for measles or mumps, or 1 dose of MMR for rubella (if born 
before 1957, consider MMR vaccination)
•	
Adults who 
previously received ≤2 doses of mumps-containing vaccine and are identified by public health authority to be at increased risk for mumps in an outbreak:
 Administer 
 
1 dose of MMR
•	
MMR is contraindicated for pregnant women and adults with severe immunodeficiency
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1329

Ch
APTER
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1330
 CMDT 2019
 
4.
 
Varicella vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/varicella.html
  
•	
Administer to adults without evidence of immunity to varicella 2 doses of varicella vaccine (VAR) 4–8 weeks apart if previously received no varicella-containing vaccine (if previously received 
 
1 dose of varicella-containing vaccine, administer 1 dose of VAR at least 4 weeks after the first dose)
•	
Evidence of immunity to varicella is:
–
 
U
.S.-born before 1980 (except for pregnant women and health care personnel, see below)
–
 
D
ocumentation of receipt of 2 doses of varicella or varicella-containing vaccine at least 4 weeks apart
–
 
Diag
nosis or verification of history of varicella or herpes zoster by a health care provider
–
 
Laborat
  
Special popula
tions
•	
Administer 2 doses of VAR 4–8 weeks apart if previously received no varicella-containing vaccine (if previously received 1 dose of varicella-containing vaccine, administer 1 dose of VAR at least 
 
4 weeks after the first dose) to:
–
 
Pregnant women without evidence of immunity:
 Administer the first of the 2 doses or the second dose after pregnancy and before discharge from health care facility
–
 
Health care personnel without evidence of immunity
•	
Adults with 
HIV infection and CD4 cell count ≥200 cells/μL:
 May administer, based on individual clinical decision, 2 doses of VAR 3 months apart
•	
VAR is contraindicated for pregnant women and adults with severe immunodeficiency
5.
 
Zoster vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/shingles.html
  
•	
Administer 2 doses of recombinant zoster vaccine (RZV) 2–6 months apart to adults aged 50 years or older regardless of past episode of herpes zoster or receipt of zoster vaccine live (ZVL)
•	
Administer 2 doses of RZV 2–6 months apart to adults who previously received ZVL at least 2 months after ZVL
•	
For adults aged 60 years or older, administer either RZV or ZVL (RZV is preferred)
  
•	
ZVL is contraindicated for pregnant women and adults with severe immunodeficiency
6.
 
Human papillomavirus vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hpv.html
  
G
•	
Administer human papillomavirus (HPV) vaccine to 
females through age 26 years
 and 
males through age 21 years
 (males aged 22 through 26 years may be vaccinated based on individual 
clinical decision)
•	
The number of doses of HPV vaccine to be administered depends on age at initial HPV vaccination
–
 
No previous dose of HPV vaccine:
 Administer 3-dose series at 0, 1–2, and 6 months (minimum intervals: 4 weeks between doses 1 and 2, 12 weeks between doses 2 and 3, and 5 months 
between doses 1 and 3; repeat doses if given too soon)
–
 
Aged 9–14 years at HPV vaccine series initiation and received 1 dose or 2 doses less than 5 months apart:
 Administer 1 dose
–
 
Aged 9–14 years at HPV vaccine series initiation and received 2 doses at least 5 months apart:
 No additional dose is needed
CMDT19_Ch30_p1294-p1337.indd   1330

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1331
 
CMDT 2019
  
tions
•	
immunocompromising conditions (including HIV infection)
 through age 26 years: Administer 3-dose series at 0, 1–2, and 6 months
•	
Men who have sex with men
 through age 26 years: Administer 2- or 3-dose series depending on age at initial vaccination (see above); if no history of HPV vaccine, administer 3-dose series 
 
at 0, 1–2, and 6 months
•	
 through age 26 years: HPV vaccination is not recommended during pregnancy, but there is no evidence that the vaccine is harmful and no intervention needed for women 
who inadvertently receive HPV vaccine while pregnant; delay remaining doses until after pregnancy; pregnancy testing is not needed before vaccination
7.
 
Pneumococcal vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/pneumo.html
  
G
•	
Administer to immunocompetent adults aged 65 years or older 1 dose of 13-valent pneumococcal conjugate vaccine (PCV13), if not previously administered, followed by 1 dose of 23-valent 
pneumococcal polysaccharide vaccine (PPSV23) at least 1 year after PCV13; if PPSV23 was previously administered but not PCV13, administer PCV13 at least 1 year after PPSV23
•	
When both PCV13 and PPSV23 are indicated, administer PCV13 first (PCV13 and PPSV23 should not be administered during the same visit); additional information on vaccine timing is available 
at www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf
  
tions
•	
Administer to adults aged 19 through 64 years with the following chronic conditions 1 dose of PPSV23 (at age 65 years or older, administer 1 dose of PCV13, if not previously received, and another 
dose of PPSV23 at least 1 year after PCV13 and at least 5 years after PPSV23):
–
 
Chronic heart disease
 (excluding hypertension)
–
 
Chronic lung disease
–
 
Chronic liver disease
–
 
–
 
–
 
•	
Administer to adults aged 19 years or older with the following indications 1 dose of PCV13 followed by 1 dose of PPSV23 at least 8 weeks after PCV13, and a second dose of PPSV23 at least 
 
5 years after the first dose of PPSV23 (if the most recent dose of PPSV23 was administered before age 65 years, at age 65 years or older, administer another dose of PPSV23 at least 5 years after 
the last dose of PPSV23):
–
 
Immunodeficiency disorders
 (including B- and T-lymphocyte deficiency, complement deficiencies, and phagocytic disorders)
–
 
–
 
Anatomical or functional asplenia
 (including sickle cell disease and other hemoglobinopathies)
–
 
Chronic renal failure and nephrotic syndrome
•	
Administer to adults aged 19 years or older with the following indications 1 dose of PCV13 followed by 1 dose of PPSV23 at least 8 weeks after PCV13 (if the dose of PPSV23 was administered 
before age 65 years, at age 65 years or older, administer another dose of PPSV23 at least 5 years after the last dose of PPSV23):
–
 
Cerebrospinal fluid leak
–
 
Cochlear implant
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1331

Ch
APTER
 3
0
1332
 CMDT 2019
 
8.
 
Hepatitis A vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hepa.html
  
•	
Administer to adults who have a specific risk (see below), or lack a risk factor but want protection, 2-dose series of single antigen hepatitis A vaccine (HepA; Havrix at 0 and 6–12 months or Vaqta 
at 0 and 6–18 months; minimum interval: 6 months) or a 3-dose series of combined hepatitis A and hepatitis B vaccine (HepA-HepB) at 0, 1, and 6 months; minimum intervals: 4 weeks between 
first and second doses, 5 months between second and third doses
  
•	
Administer HepA or HepA-HepB to adults with the following indications:
–
 
Travel 
to or work in countries with high or intermediate hepatitis A endemicity
–
 
–
 
Injection or noninjection drug use
–
 
Work with hepatitis A virus in a research laboratory or with nonhuman primates infected with hepatitis A virus
–
 
Clotting factor disorders
–
 
–
 
Close
, personal 
contact with an international adoptee
 (e.g., household or regular babysitting) during the first 60 days after arrival in the United States from a country with high or interme
-
diate endemicity (administer the first dose as soon as the adoption is planned)
–
 
Health
y adults 
through age 40 years who have recently been exposed to hepatitis A virus;
 adults older than age 40 years may receive HepA if hepatitis A immunoglobulin cannot be 
obtained
9.
 
Hepatitis B vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hepb.html
  
•	
Administer to adults who have a specific risk (see below), or lack a risk factor but want protection, 3-dose series of single antigen hepatitis B vaccine (HepB) or combined hepatitis A and hepati
-
tis B vaccine (HepA-HepB) at 0, 1, and 6 months (minimum intervals: 4 weeks between doses 1 and 2 for HepB and HepA-HepB; between doses 2 and 3, 8 weeks for HepB and 5 months for 
HepA-HepB)
  
•	
Administer HepB or HepA-HepB to adults with the following indications:
–
 
 (e.g., hepatitis C infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 
level greater than twice the upper limit of normal)
–
 
–
 
Percutaneous or mucosal risk of exposure to blood
 (e.g., 
household contacts
 of hepatitis B surface antigen [HBsAg]-positive persons; adults younger than age 60 years with 
diabetes 
mellitus
 or aged 60 years or older with diabetes mellitus based on individual clinical decision; adults in predialysis care or receiving 
hemodialysis or peritoneal dialysis;
 recent or current 
injection drug users; health care and public safety workers
 at risk for exposure to blood or blood-contaminated body fluids)
–
 
Sexual exposure
 risk (e.g., sex partners of HBsAg-positive persons; sexually active persons not in a mutually monogamous relationship; persons seeking evaluation or treatment for a sexually 
transmitted infection; and 
men who have sex with men
 [MSM])
–
 
R
eceive care in 
settings where a high proportion of adults have risks for hepatitis B infection
 (e.g., facilities providing sexually transmitted disease treatment, drug-abuse treatment and 
prevention services, hemodialysis and end-stage renal disease programs, institutions for developmentally disabled persons, health care settings targeting services to injection drug users or 
MSM, HIV testing and treatment facilities, and correctional facilities)
–
 
Travel
 to countries with high or intermediate hepatitis B endemicity
CMDT19_Ch30_p1294-p1337.indd   1332

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1333
 
CMDT 2019
10.
 
Meningococcal vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/mening.html
  
Special populations: Serogroups A, C, W, and Y meningococcal vaccine (MenACWY)
•	
Administer 2 doses of MenACWY at least 8 weeks apart and revaccinate with 1 dose of MenACWY every 5 years, if the risk remains, to adults with the following indications:
–
 
–
 
–
 
Persistent complement component deficiency
–
 
Eculizumab use
•	
Administer 1 dose of MenACWY and revaccinate with 1 dose of MenACWY every 5 years, if the risk remains, to adults with the following indications:
–
 
Travel to or live in countries where meningococcal disease is hyperendemic or epidemic,
 including countries in the African meningitis belt or during the Hajj
–
 
A
t risk from a 
meningococcal disease outbreak attributed to serogroup A, C, W, or Y
–
 
Microbiologists
 routinely exposed to 
–
 
Military recruits
–
 
First-year college students who live in residential housing
 (if they did not receive MenACWY at age 16 years or older)
  
General Information: Serogroup B meningococcal vaccine (MenB)
–
 
M
ay administer, based on individual clinical decision, to young adults and adolescents aged 16–23 years (preferred age is 16–18 years) who are not at increased risk 2-dose series of 
 
MenB-4C (Bexsero) at least 1 month apart or 2-dose series of MenB-FHbp (Trumenba) at least 6 months apart
–
 
M
enB-4C and MenB-FHbp are not interchangeable
  
Special populations: MenB
•	
Administer 2-dose series of MenB-4C at least 1 month apart or 3-dose series of MenB-FHbp at 0, 1–2, and 6 months to adults with the following indications:
–
 
 (including sickle cell disease)
–
 
–
 
–
 
A
meningococcal disease outbreak attributed to serogroup B
–
 
11. 
 type b vaccination
  
w
ww.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hib.html
  
•	
Administer 
 type b vaccine (Hib) to adults with the following indications:
–
 
 (including sickle cell disease) or undergoing elective splenectomy: Administer 1 dose if not previously vaccinated (preferably at least 14 days before 
 
elective splenectomy)
–
 
Hematopoietic stem cell transplant
 (HSCT): Administer 3-dose series with doses 4 weeks apart starting 6 to 12 months after successful transplant regardless of Hib vaccination history
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1333

Ch
APTER
 3
0
1334
 CMDT 2019
 
Va
cc
ine(s)
Ad
ditional 
Co
ntraindi
ca
tion
sA
dditional 
Prec
aution
s
II
V
1
• 
Hist
or
y of Guillain-Barré syndrome within 6 weeks af
ter previous inﬂuenza vaccinatio
n
• 
Egg allergy other than hives, e.g., angioedema, respiratory distress
, lightheadednes
s,
 or recurrent
 
emesis; or required epineph
rine or another emer
gency medical inte
rv
ention (IIV may be
 
administered in an inpatient or outpatient medical setting and 
under the supe
rv
ision of a health 
care provider who is able to recognize and manage severe allerg
ic conditions
)
RI
V
1
• 
Hist
or
n
Td
ap
, 
Td
• 
Fo
r pe
rt
ussis
-c
ontaining vaccines: encephalopath
y,
 
e.
g.
, coma, decreased level of consciousness
, 
or prolonged seizures, not attributable to another identiﬁable 
cause within 7 days of
 
administration of a previous dose of a vaccine containing tetan
us or diphtheria to
xo
id or acellular 
per
tussis
• Guillain-Barré syndrome within 6 weeks af
ter a previous dose of tetanus toxoid
-c
ontaining
 
vaccin
e
• 
Hist
or
y of Ar
thus-type 
hy
persensitivity reactions af
ter a previous dose of tetanus or diphtheria
 
toxoid
-c
ontaining vaccin
e.
 De
fe
r vaccination until at least 10 years have elapsed since the la
st
 
tetanus toxoid
-c
e
• 
Fo
r pe
rt
ussis-
containing vaccine, progressive or unstable neurologic disorder, uncontrolled
 
seizures, or progressive encephalopathy (until a treatment regimen has been established and the 
condition has stabilized)
MM
R
2
• 
Se
vere immunodeﬁcienc
y,
 
e.
g
., hematologic and solid tumors
, chemotherap
y,
 congenital
 
immunodeﬁcien
cy
 or long-term immunosuppressive therap
y
3
, human immunodeﬁcien
cy
 virus 
(HIV
) in
fe
ct
ion with severe immunocompromise
• 
Pr
egnanc
y
• Recent (within 11 months) 
receipt of antibody
-c
ontaining blood produc
t (speciﬁc inte
rv
al
 
depends on produc
t)
4
• 
Hist
or
y of thrombocytopenia or thromboc
ytopenic purpur
a
• 
Need 
fo
r tuberculin skin testin
g
5
VA
R
2
• 
Se
y,
 
e.
g
y,
 
cy
y
3
, HIV in
fe
ct
ion with severe 
immunocompromise
• 
Pr
egnanc
y
-c
rv
al
 
t)
4
• Receipt of speciﬁc antiviral drugs (a
cy
clovir
, famciclovi
r,
 or vala
cy
clovir) 24 hours be
fo
re
 
vaccination (avoid use of these antiviral drugs for 14 days after vaccination)
ZV
L
2
• 
Se
y,
 
e.
g
y,
 
cy
y
3
, HIV in
fe
ct
immunocompromis
e
• 
Pr
egnanc
y
cy
clovir
r,
 or vala
cy
fo
re
 
HPV vaccin
e
• 
Pr
egnanc
y
PC
V1
3•
 
Se
vere allergic reac
tion to any vaccine containing diphtheria to
xo
id
1. 
F
or additional in
fo
rmation on use of inﬂuenza vaccines among persons with egg alle
rg
y,
 see: CDC. 
Pr
ev
ention and control of 
s
easonal inﬂuenza with vaccines: recommendations of the 
Ad
visory 
Co
Pr
ac
tices—United States
, 2016–17 inﬂuenza season. MMWR. 2016;65(RR-5):1–54. 
Av
ailable at
 
www
.cdc.gov/m
mw
r/volumes/65/rr/rr6505a1.htm
.
2. 
MMR may be administer
ed together with 
V
AR or ZVL on the same da
y.
 If not administered on the same da
y,
 separate live vaccin
e
s by at least 28 days
. 
3. 
Immunosuppr
essive steroid dose is considered to be daily receipt of 20 mg 
or more prednisone or equivalent 
fo
r 2 or more we
e
ks. 
Va
ccination should be deferred for at least 1 month af
ter discontinuation of

fo
e
ks. 
Va
 
immunosuppressive steroid therap
y.
 
Prov
iders should consult ACIP 
re
commendations for complete information on the use of speciﬁ
c
 live vaccines among persons on immun
e-
suppressing medications or with immune 
suppression because of other reasons.
4. 
Va
ccine should be deferred for the approp
riate in
te
rv
al if replacement immune globulin produc
ts are being administered. See:
 Best prac
tices guidance of the 
Ad
visory 
Co
Pr
ac
tices 
(A
CIP). 
Av
ailable at
 
www
.cdc.gov/vaccines/hcp/aci
p-
r
ecs/general-recs/index.htm
l
. 
5. 
Measles vaccination ma
y temporarily suppress tuberculin reac
tivity
. Measles-
containing vaccine may be administered on the same day as tuberculin skin testin
g,
 or should be postponed f
or at least 4 weeks after vaccination.
T
able
. 
Co
ntraindications and precautions for vaccines recomm
ended for adults aged 19 years or older*
T
he Adviso
ry
 Committee on Immunization 
Pr
actices 
(A
CIP) recommendations and pack
age inser
ts 
fo
r vaccines provide in
fo
rmation on
 contraindications and precautions related to vaccines
. 
Co
ntraindications are conditions 
that increase chances of a serious adverse reac
tion in vaccine recipients and the vaccine should not be admini
stered when a co
n
traindication is present. 
Pre
cautions should be reviewed 
fo
r potential risks and beneﬁts 
fo
r vaccine 
r
ecipients
. 
Va
cc
ine(s)
Co
ntraindication
s
Prec
aution
s
All va
ccines routinely
 
recommended for adults
• 
Se
vere reac
tion, 
e.
g.
, anap
hy
laxis, af
ter a previous dose or to a vaccine componen
t•
 
Modera
te or severe acute illness with or
 without 
fe
ve
r
Ad
d
itional 
co
ntraindi
ca
tions and precautions for vac
cines routinely rec
ommended for adult
s
Co
ntraindi
ca
tions and precautions for va
cc
ines routinely recommended for adults
* 
 
Ad
apted from: CDC. 
Ta
ble 6. 
Co
ntraindications and precautions to commonly used vaccines. Gene
ral recommendations on immunizatio
n: recommendations of the A
dvisory 
Co
Pr
actices
. MMWR.
 
2011;60(No. RR-2):40–1 and from: Hamborsky 
J,
 Kroger A, 
Wo
lfe S, eds
. Appendix A. Epidemiology and prevention of vaccine preven
table diseases. 13th ed. 
W
ashington, DC: 
Pu
blic Health 
Fo
undation, 2015. 
Av
ailable at 
 
www
.cdc
.gov/vaccines/pubs/pinkbook/index.ht
ml
. 
Abbr
eviations of vaccines
IIV 
inactivated inﬂuenza vaccin
e
RIV 
re
combinant inﬂuenza vaccin
e
T
dap  
tetanus toxoid, reduced diphtheria toxoid, an
d 
acellular per
tussis vaccine
Td
  
tetanus and diphtheria toxoid
s
MMR  
measle
s,
 mumps
, and rubella vaccin
e
VA
R varicella vaccin
e
R
ZV 
recombinant zoster vaccin
e
ZVL 
zoster vaccine live
HPV vaccine 
human papillomavirus vaccine
PC
V13  
13-valent pneumococcal conjugate vaccin
e 
PPSV23  23-valent pneumococcal polysaccharide vaccine
HepA hepatitis A vaccine
HepA-HepB 
hepatitis A and hepatitis B vaccines
HepB hepatitis B vaccin
e
MenA
CW
Y 
serogroups A, C, 
W,
 and Y meningococcal vaccin
e
MenB  
e
Hi
b 
 
Haemophilus inﬂuenzae
 type b vaccine
CS270457-
L
CMDT19_Ch30_p1294-p1337.indd   1334

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1335
 
CMDT 2019
Table 30–8.
 
Adverse effects and contraindications to commonly used vaccines in adults (listed in alphabetical order).
Vaccine
Adverse Effects
Contraindications
1
 
Type b (Hib)
Minimal
Consist mainly of pain at the injection site
Any severe allergic reaction (eg, anaphylaxis) after a 
previous dose or to a vaccine component.
Hepatitis A
Minimal
Hepatitis B
Minimal
Human papillomavirus
Minimal
Consist mainly of mild to moderate localized 
pain, erythema, swelling
Systemic reactions, mainly fever, seen in 4% of 
recipients
Influenza (intramuscular 
inactivated and 
intranasal live 
attenuated vaccines)
Intramuscular, inactivated vaccine:
 Local 
reactions (erythema and tenderness) at the 
site of injection are common, but fevers, 
chills, and malaise (which last in any case 
only 2–3 days) are rare.
Either inactivated or live attenuated vaccine:
 
A potential association between Guillain-
Barré syndrome (3000–6000 cases per year 
in the United States, usually following 
respiratory infections) and vaccination with 
intramuscular, inactivated influenza vaccine 
has been reported (possibly, 1–2 persons 
per million persons vaccinated), but this 
rate is lower than the risk of the syndrome 
developing after influenza itself (given that 
approximately 750 persons per million 
adults are hospitalized annually with 
influenza, and many more cases remain as 
outpatients). Influenza vaccination may be 
associated with multiple false-positive 
serologic tests to HIV, HTLV-1, and hepatitis C, 
but it is self-limited, lasting 2–5 months.
Contraindication to both inactivated and live attenuated 
vaccine:
History of Guillain-Barré syndrome, especially within 
 
6 weeks of receiving a previous influenza vaccine.
Any severe allergic reaction (eg, anaphylaxis) after a previ
-
ous dose or to a vaccine component, including egg 
protein.
2
Intranasal, live attenuated vaccine [FluMist] should not be 
used in:
  •
   
P
eople
 
50
 
y
ears
 
of
 
age
 
and
 
o
ver
  •
   
I
mmunosuppressed
 
individuals
 
and
 
those
 
on
 
immu
-
nosuppressive therapy
  •
 
Household
 
members
 
of
 
immunosuppr
essed
 
  •
   
Health
 
car
e
 
w
orkers,
 
or
 
others
 
with
 
close
 
c
ontact
 
with
 
immunosuppressed persons
  •
   
P
resence
 
of
 
r
eactive
 
air
way
 
disease
 
(
eg,
 
asthma)
 
or
 
chronic underlying metabolic (eg, kidney), pulmonary, 
or heart diseases (use intramuscular inactivated 
vaccine)
  •
   
P
regnancy
3
It is recommended that salicylates should be avoided for 
6 weeks following vaccination (to prevent Reye 
Measles, mumps, and 
rubella (MMR)
4
Fever will develop in about 5–15% of 
unimmunized individuals, and a mild rash 
will develop in about 5% 5–12 days after 
vaccination.
Fever and rash are self-limited, lasting only 
2–3 days.
Local swelling and induration are particularly 
common in individuals previously vacci
-
nated with inactivated vaccine.
Pregnancy
5
Known severe immunodeficiency (eg, from hematologic 
and solid cancers, receipt of chemotherapy, congenital 
immunodeficiency, long-term immunosuppressive ther
-
apy (eg, > 2 weeks of prednisone 20 mg daily or higher), 
other disease- or therapy-related immune suppression, 
or patients with HIV infection who are severely 
immunocompromised.
May be used in asymptomatic HIV-infected individuals 
whose CD4 count is > 200/mcL).
Severe allergic reaction (eg, anaphylaxis) to a previous 
dose or to a vaccine component, (eg, neomycin or to 
related agents such as streptomycin).

Meningococcal, oligosac
-
charide conjugate; 
(MCV4 or MenACWY 
[Menactra, Menveo]; 
meningococcal poly
-
saccharide conjugate 
MPSV4 [Menomune]); 
meningococcal group B, 
recombinant (MenB 
[Bexsero, Trumenba])
Minor reactions (fever, redness, swelling, ery
-
thema, pain) occur slightly more commonly 
with MCV4. Major reactions are rare.
A potential association between Guillain-Barré 
syndrome (3000–6000 cases per year in the 
United States, usually following respiratory 
infections) and vaccination with MCV4 has 
been reported, but current recommendations 
favor continued use of MCV4, since the bene
-
fits of preventing the serious consequences of 
meningococcal infection outweigh the theo
-
retical risk of Guillain-Barré syndrome.
Any severe allergic reaction (eg, anaphylaxis) to a previous 
dose or to a vaccine component, (eg, persons with his
-
tory of adverse reaction to diphtheria toxoid should not 
receive meningococcal oligosaccharide conjugate and 
polysaccharide conjugate vaccines since the protein 
conjugate used in them is diphtheria toxoid).
(
continued
)
CMDT19_Ch30_p1294-p1337.indd   1335

Ch
APTER
 3
0
1336
 CMDT 2019
 
Adverse effects and contraindications to commonly used vaccines in adults (listed in alphabetical 
order).
Vaccine
1
Pneumococcal conjugate 
(PCV13 [Prevnar]); 
Pneumococcal poly
-
saccharide (PPSV23) 
[Pneumovax])
Mild local reactions (erythema and tender
-
ness) occur in up to 50% of recipients, but 
systemic reactions are uncommon.
Similarly, revaccination at least 5 years after 
initial vaccination is associated with mild 
self-limited local but not systemic reactions.
-
ous dose or to a vaccine component (eg, for PCV13 to 
any vaccine containing diphtheria toxoid).
Tetanus, diphtheria, and 
pertussis (DTP , Tdap); 
tetanus, diphtheria 
( Td)
Minimal
-
ous dose or to a vaccine component.
For pertussis-containing vaccines: any history of unex
-
plained encephalopathy (eg, coma, decreased level of 
consciousness, or prolonged seizures) within 7 days of 
administration of a previous dose of Tdap or diphtheria 
and tetanus toxoids and pertussis (DTP) or diphtheria 
and tetanus toxoids and acellular pertussis (Tdap) 
vaccine.
Varicella
Can occur as late as 4–6 weeks after 
Tenderness and erythema at the injection site 
are seen in 25%, fever in 10–15%, and a 
localized maculopapular or vesicular rash in 
5%; a diffuse rash, usually with five or fewer 
vesicular lesions, develops in a smaller 
percentage.
Spread of virus from vaccinees to susceptible 
individuals is possible, but the risk of such 
transmission even to immunocompromised 
patients is small and disease, when it devel
-
ops, is mild and treatable with acyclovir.
-
apy [eg, > 2 weeks of prednisone 20 mg daily or higher; 
other immunosuppressive medications], other disease- 
or therapy-related immune suppression, or patients 
with HIV infection who are severely 
immunocompromised).
Pregnancy.
Severe allergic reaction (eg, anaphylaxis) after a previous 
dose or to a vaccine component (eg, neomycin).
For theoretic reasons, it is recommended that salicylates 
should be avoided for 6 weeks following vaccination 
(to prevent potential for Reye syndrome).
Zoster
Mild and limited to local reactions
Although it is theoretically possible to transmit 
the virus to susceptible contacts, no such 
cases have been reported.
-
apy (eg, > 2 weeks of prednisone 20 mg daily or higher; 
other immunosuppressive medications), other disease- 
with HIV infection who are severely immunocompro
-
mised. May be used in asymptomatic HIV-infected indi
-
viduals whose CD4 count is > 200/mcL).
-
ous dose or to a vaccine component (eg, gelatin or 
neomycin).
1
Adapted from Centers for Disease Control and Prevention. Contraindications and precautions to commonly used vaccines in adults. 
General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices, 2016. https://www
 
.cdc.gov/vaccines/schedules/hcp/imz/adult-contraindications-shell.html; and from Hamborsky J et al (editors). Appendix A. Epidemiology 
and prevention of vaccine preventable diseases. 13th edition. Washington, DC, Public Health Foundation, 2015. Available at www.cdc.gov/
vaccines/pubs/pinkbook/index.html.
2
The vaccine has typically been prepared using embryonated chicken eggs. However, a new vaccine using mammalian cell culture is now 
FDA approved.
3

2
3
The inactivated influenza vaccine can be given during any trimester.
4
MMR vaccine can be safely given to patients with a history of egg allergy even when severe.
5
Although vaccination of pregnant women is 
not
 recommended, with the currently available RA27/3 vaccine strain the congenital rubella 
syndrome does not occur in the offspring of those inadvertently vaccinated during pregnancy or within 3 months before conception.
 
CMDT19_Ch30_p1294-p1337.indd   1336

PROBLEMS IN INFECTIOUS DISEASES & ANTIMICROBIAL THERAPY1337
 
CMDT 2019
respond to new antigens appear only 6–12 months post
-
transplant. B cells of posttransplant patients treated with 
rituximab may take up to 6 months to fully recover after 
the last dose of the medication. Vaccines are therefore 
administered 6–12 months following transplantation with 
a minimum of 1 month between doses to maximize the 
probability of response.
5. Solid Organ Transplant Recipients
Solid organ transplant recipients demonstrate a broad spec
-
trum of immunosuppression, depending on the reason for 
and type of organ transplantation and the nature of the 
immunosuppression (including T-cell-depleting agents dur
-
ing treatment of organ rejection). These factors affect the 
propensity for infection posttransplantation and the ability 
to develop antibody responses to vaccination. In many cases, 
the time between placing a patient on a transplant list and 
undergoing the transplantation takes months or years. Pro
-
viders should take this opportunity to ensure that indicated 
vaccines are given during this pretransplant period to 
opti
-
mize antibody responses
. If this is not possible, most experts 
give vaccines 3–6 months following transplantation. Live 
vaccines are contraindicated in the posttransplant period.
RECOMMENDED IMMUNIZATIONS 
 
FOR TRAVELERS
Individuals traveling to other countries frequently require 
immunizations in addition to those routinely recom
-
mended and may benefit from chemoprophylaxis against 
various diseases. Vaccinations against yellow fever and 
meningococcus are the only ones required by certain coun
-
tries. These and other travel-specific vaccines are listed at 
http://wwwnc.cdc.gov/travel/destinations/list.
Various vaccines can be given simultaneously at differ
-
ent sites. Some, such as cholera, plague, and typhoid 
vaccine, cause significant discomfort and are best given at 
different times. In general, live attenuated vaccines 
(measles, mumps, rubella, yellow fever, and oral typhoid 
vaccine) should not be given to immunosuppressed 
individuals or household members of immunosuppressed 
people or to pregnant women. Immunoglobulin should not 
be given for 3 months before or at least 2 weeks after live virus 
vaccines, because it may attenuate the antibody response.
Chemoprophylaxis of malaria is discussed in Chapter 35.
VACCINE SAFETY
Most vaccines are safe to administer. In general, it is rec
-
ommended that the use of live vaccines be avoided in 
immunocompromised patients, including pregnant 
women. Vaccines are generally not contraindicated in the 
following situations: mild, acute illness with low-grade 
fevers (less than 40.5
°
C); concurrent antibiotic therapy; 
soreness or redness at the site; family history of adverse 
reactions to vaccinations. Absolute contraindications to 
vaccines are rare (Table 30–8).
immunization schedules—United States, 2018. https://www
 
.cdc.gov/vaccines/schedules/index.html
Centers for Disease Control and Prevention (CDC). Health 
Information for International Travel 2018. https://wwwnc
 
.cdc.gov/travel/page/yellowbook-home
Centers for Disease Control and Prevention (CDC). Vaccine 
safety. https://www.cdc.gov/vaccinesafety/index.html
Grohskopf LA et al. Prevention and control of seasonal influenza 
with vaccines: recommendations of the Advisory Committee 
on Immunization Practices—United States, 2017–18 Influ
-
enza Season. MMWR Recomm Rep. 2017 Aug 25;66(2):1–20. 
[PMID: 28841201]
Kim DK et al. Advisory Committee on Immunization Practices 
Recommended Immunization Schedule for Adults Aged 19 
Y ears or Older—United States, 2017. MMWR Morb Mortal 
Wkly Rep. 2017 Feb 10;66(5):136–8. [PMID: 28182599]
MacNeil JR et al. Recommendations for use of meningococcal 
conjugate vaccines in HIV-infected persons—Advisory Com
-
mittee on Immunization Practices, 2016. MMWR Morb

-
mittee on Immunization Practices, 2016. MMWR Morb 
Mortal Wkly Rep. 2016 Nov 4;65(43):1189–94. [PMID: 
27811836]
Paules CI et al. Chasing seasonal influenza—the need for a uni
-
versal influenza vaccine. N Engl J Med. 2018 Jan 4;378(1):7–9. 
[PMID: 29185857]
CMDT19_Ch30_p1294-p1337.indd   1337

1338
 CMDT 2019
Mitchell H. Katz, MD 
HIV Infection & AIDS
31
effective antiretroviral therapy. The prognosis of persons 
with HIV/AIDS has dramatically improved due to the 
development of effective antiretroviral treatment. One con
-
sequence is that fewer persons with HIV ever develop an 
infection or malignancy or have a low enough CD4 count to 
classify them as having AIDS, which means that the CDC 
definition has become a less useful measure of the impact of 
HIV/AIDS in the United States. Conversely, persons in 
whom AIDS had been diagnosed based on a serious oppor
-
tunistic infection, malignancy, or immunodeficiency may 
now be markedly healthier, with high CD4 counts, due to 
the use of antiretroviral treatment. Therefore, the Social 
Security Administration as well as most social service agen
-
cies focus on functional assessment for determining eligibil
-
ity for benefits rather than the simple presence or absence 
of an AIDS-defining illness.
 
»
Epidemiology
The modes of transmission of HIV are similar to those of 
hepatitis B, in particular with respect to sexual, parenteral, 
and vertical transmission. Although certain sexual practices 
(eg, receptive anal intercourse) are significantly riskier than 
other sexual practices (eg, oral sex), it is difficult to quantify 
per-contact risks. The reason is that studies of sexual trans
-
mission of HIV show that most people at risk for HIV infec
-
tion engage in a variety of sexual practices and have sex with 
multiple persons, only some of whom may actually be HIV 
infected. Thus, it is difficult to determine which practice 
with which person actually resulted in HIV transmission.
Nonetheless, the best available estimates indicate that 
the risk of HIV transmission with receptive anal inter
-
course is between 1:100 and 1:30, with insertive anal inter
-
course 1:1000, with receptive vaginal intercourse 1:1000, 
with insertive vaginal intercourse 1:10,000, and with recep
-
tive fellatio with ejaculation 1:1000. The per-contact risk of 
HIV transmission with other behaviors, including recep
-
tive fellatio without ejaculation, insertive fellatio, and cun
-
nilingus, is not known.
A number of cofactors are known to increase the risk of 
HIV transmission during a given encounter, including the 
presence of ulcerative or inflammatory sexually transmitted 
diseases, trauma, menses, and lack of male circumcision.
 
»
Modes of transmission: sexual contact with an 
infected person, parenteral exposure to infected 
blood (transfusion or needle sharing), perinatal 
exposure.
 
»
Prominent systemic complaints: sweats, diarrhea, 
weight loss, and wasting.
 
»
Opportunistic infections due to diminished 
cellular immunity—often life-threatening.
 
»
Aggressive cancers, particularly non-Hodgkin 
lymphoma.
 
»
Neurologic manifestations, including dementia, 
aseptic meningitis, and neuropathy.
 
»
The Centers for Disease Control and Prevention (CDC) 
AIDS case definition (Table 31–1) includes opportunistic 
infections and malignancies that rarely occur in the absence 
of severe immunodeficiency (eg, 
 pneumonia, 
central nervous system lymphoma). It also classifies persons 
as having AIDS if they have positive HIV serology and cer
-
tain infections and malignancies that can occur in immuno
-
competent hosts but that are more common among persons 
infected with HIV (pulmonary tuberculosis, invasive cervi
-
cal cancer). Several nonspecific conditions, including 
dementia and wasting (documented weight loss)—in the 
presence of a positive HIV serology—are considered AIDS. 
The definition includes criteria for both definitive and pre
-
sumptive diagnoses of certain infections and malignancies. 
Finally, persons with positive HIV serology who have ever 
had a CD4 lymphocyte count below 200 cells/mcL or a CD4 
lymphocyte percentage below 14% are considered to have 
AIDS. Inclusion of persons with low CD4 counts as AIDS

AIDS. Inclusion of persons with low CD4 counts as AIDS 
cases reflects the recognition that immunodeficiency is the 
defining characteristic of AIDS. The choice of a cutoff point 
at 200 cells/mcL is supported by several cohort studies 
showing that AIDS will develop within 3 years in over 80% 
of persons with counts below this level in the absence of 
CMDT19_Ch31_p1338-p1376.indd   1338
03/07/18   11:35 AM

HIV INFECTION & AIDS
1339
 
CMDT 2019
Table 31–1.
 
CDC AIDS case definition for surveillance of adults and adolescents.
Definitive AIDS Diagnoses (with or without laboratory evidence of HIV infection)
 
1.
 
C
andidiasis of the esophagus, trachea, bronchi, or lungs.
 
2.
 
Cr
yptococcosis, extrapulmonary.
 
3.
 
Cr
yptosporidiosis with diarrhea persisting longer than 1 month.
 
4.
 
C
ytomegalovirus disease of an organ other than liver, spleen, or lymph nodes.
 
5.
 
Herpes simple
x virus infection causing a mucocutaneous ulcer that persists longer than 1 month; or bronchitis, pneumonitis, 
 
or esophagitis of any duration.
 
6.
 
K
aposi sarcoma in a patient younger than 60 years of age.
 
7.
 
L
ymphoma of the brain (primary) in a patient younger than 60 years of age.
 
8.
 
 complex or 
 disease, disseminated (at a site other than or in addition to lungs, skin, 
 
or cervical or hilar lymph nodes).
 
9.
 
10.
 
P
rogressive multifocal leukoencephalopathy.
 
11.
 
T
oxoplasmosis of the brain.
Definitive AIDS Diagnoses (with laboratory evidence of HIV infection)
 
1.
 
C
occidioidomycosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes).
 
2.
 
HIV enc
ephalopathy.
 
3.
 
H
istoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes).
 
4.
 
Isosporiasis 
with diarrhea persisting longer than 1 month.
 
5.
 
K
aposi sarcoma at any age.
 
6.
 
L
ymphoma of the brain (primary) at any age.
 
7.
 
O
ther non-Hodgkin lymphoma of B cell or unknown immunologic phenotype.
 
8.
 
An
y mycobacterial disease caused by mycobacteria other than 
, disseminated (at a site other than or in 
addition to lungs, skin, or cervical or hilar lymph nodes).
 
9.
 
Disease caused 
by extrapulmonary 
.
10.
 
S
almonella (nontyphoid) septicemia, recurrent.
11.
 
HIV w
asting syndrome.
12.
 
CD4 lymphoc
yte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14%.
13.
 
P
ulmonary tuberculosis.
14.
 
Recurr
ent pneumonia.
15.
 
I
nvasive cervical cancer.
Presumptive AIDS Diagnoses (with laboratory evidence of HIV infection)
 
1.
 
C
andidiasis of esophagus: (a) recent onset of retrosternal pain on swallowing; and (b) oral candidiasis.
 
2.
 
C
ytomegalovirus retinitis. A characteristic appearance on serial ophthalmoscopic examinations.
 
3.
 
M
ycobacteriosis. Specimen from stool or normally sterile body fluids or tissue from a site other than lungs, skin, or cervical or hilar 
lymph nodes, showing acid-fast bacilli of a species not identified by culture.
 
4.
 
K
aposi sarcoma. Erythematous or violaceous plaque-like lesion on skin or mucous membrane.
 
5.
 
 pneumonia: (a) a history of dyspnea on exertion or nonproductive cough of recent onset (within the past 
 
3 months); and (b) chest film evidence of diffuse bilateral interstitial infiltrates or gallium scan evidence of diffuse bilateral pulmonary 
disease; and (c) arterial blood gas analysis showing an arterial oxygen partial pressure of less than 70 mm Hg or a low respiratory 
 
diffusing capacity of less than 80% of predicted values or an increase in the alveolar-arterial oxygen tension gradient; and (d) no 
 
evidence of a bacterial pneumonia.
 
6.
 
T
oxoplasmosis of the brain: (a) recent onset of a focal neurologic abnormality consistent with intracranial disease or a reduced level of 
consciousness; and (b) brain imaging evidence of a lesion having a mass effect or the radiographic appearance of which is enhanced by 
injection of contrast medium; and (c) serum antibody to toxoplasmosis or successful response to therapy for toxoplasmosis.
 
7.
 
Recurr
ent pneumonia: (a) more than one episode in a 1-year period; and (b) acute pneumonia (new symptoms, signs, or radiologic

7.
 
Recurr
ent pneumonia: (a) more than one episode in a 1-year period; and (b) acute pneumonia (new symptoms, signs, or radiologic 
 
evidence not present earlier) diagnosed on clinical or radiologic grounds by the patient’s clinician.
 
8.
 
P
ulmonary tuberculosis: (a) apical or miliary infiltrates and (b) radiographic and clinical response to antituberculous therapy.
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The risk of acquiring HIV infection from a needlestick 
with infected blood is approximately 1:300. Factors known 
to increase the risk of transmission include depth of pene
-
tration, hollow bore needles, visible blood on the needle, 
and advanced stage of disease in the source. The risk of 
HIV transmission from a mucosal splash with infected 
blood is unknown but is assumed to be significantly lower.
The risk of acquiring HIV infection from illicit drug use 
with sharing of needles from an HIV-infected source is esti
-
mated to be 1:150. Use of clean needles markedly decreases 
the chance of HIV transmission, but does not eliminate it if 
other drug paraphernalia are shared (eg, cookers).
When blood transfusion from an HIV-infected donor 
occurs, the risk of transmission is 95%. Fortunately, since 
1985, blood donor screening using the HIV enzyme-linked 
immunosorbent assay (ELISA) has been universally prac
-
ticed in the United States. Also, persons who have recently 
engaged in unsafe behaviors (eg, sex with a person at risk 
for HIV , injection drug use) are not allowed to donate. This 
essentially eliminates donations from persons who are HIV 
infected but have not yet developed antibodies (ie, persons 
in the “window” period). HIV antigen and viral load testing 
have been added to the screening of blood to further lower 
the chance of HIV transmission. With these precautions, 
the chance of HIV transmission with receipt of blood trans
-
fusion in the United States is about 1:1,000,000. Between 
13% and 40% of children born to HIV-infected mothers 
contract HIV infection when the mother has not received 
treatment or when the child has not received perinatal HIV 
prophylaxis. The risk is higher with vaginal than with cesar
-
ean delivery, higher among mothers with high viral loads, 
and higher among those who breast-feed their children. 
The combination of prenatal HIV testing and counseling, 
antiretroviral treatment for infected mothers during preg
-
nancy and for the infant immediately after birth, scheduled 
cesarean delivery when the mother has a viral load of 
greater than 1000 copies/mL, and avoidance of breastfeed
-
ing has reduced the rate of perinatal transmission of HIV to 
less than 2% in the United States and Europe.
HIV has not been shown to be transmitted by respira
-
tory droplet spread, by vectors such as mosquitoes, or by 
casual nonsexual contact. Saliva, sweat, stool, and tears are 
not considered infectious fluids.
Since the epidemic began in the early 1980s, a total of 
1,232,346 Americans have been diagnosed with AIDS. There 
are an estimated 1.1 million adults and adolescents in the 
United States living with HIV , 15% of whom are undiagnosed. 
Y oung people (age 13 to 24) are the most likely to not know 
they are infected (44%). In 2016, 39,782 Americans were 
newly diagnosed with HIV infection. Gay and bisexual men 
accounted for most of the new diagnoses (67%), and among 
them, black/African-American men accounted for more new 
diagnoses (10,223) than Latinos (7425) or whites (7390). 
Between 2011 and 2015, new HIV diagnoses decreased by 
10% among white gay and bisexual males, but increased 
4% among African-American gay and bisexual males, and 
14% among Latino gay and bisexual men. Heterosexual con
-
tacts accounted for 24% (9578) of new HIV diagnoses, 
women accounted for 19% (7529) and injection drug users for 
9% (3425) of new HIV diagnoses, including gay and bisexual 
men who inject drugs. In 2016, African Americans and Lati
-
nos were disproportionately hard hit by the epidemic. Though 
representing 12% of the US population, African Americans 
accounted for 44% of new HIV diagnoses (17,528 cases). 
Latinos, who represent about 18% of the US population, 
accounted for 25% of new HIV diagnoses (9766 cases).
In general, the progression of HIV-related illness is 
similar in men and women. However, there are some

similar in men and women. However, there are some 
important differences. Women are at risk for gynecologic 
complications of HIV , including recurrent candidal vagini
-
tis, pelvic inflammatory disease, and cervical dysplasia. 
Violence directed against women, pregnancy, and frequent 
occurrence of drug use and poverty all complicate the 
treatment of HIV-infected women.
Worldwide there are an estimated 37 million persons 
infected with HIV , with heterosexual spread being the most 
common mode of transmission for men and women. The 
reason for the greater risk for transmission with heterosexual 
intercourse in Africa and Asia than in the United States may 
relate to cofactors such as general health status, the presence 
of genital ulcers, relative lack of male circumcision, the num
-
ber of sexual partners, and different HIV serotypes. It is esti
-
mated that in 2016, 19.5 million persons infected with HIV 
were receiving treatment (53%), up from 17.1 million in 2015.
Centers for Disease Control and Prevention. HIV in the United 
States: at a glance. Updated November 29, 2017. https://www
 
.cdc.gov/hiv/statistics/overview/ataglance.html
DiNenno EA et al. Recommendations for HIV screening of gay, 
bisexual, and other men who have sex with men—United 
States, 2017. MMWR Morb Mortal Wkly Rep. 2017 Aug 11; 
66(31):830–2. [PMID: 28796758]
Hess KL et al. Lifetime risk of a diagnosis of HIV infection in the 
United States. Ann Epidemiol. 2017 Apr;27(4):238–43. 
[PMID: 28325538]
Malani PN. JAMA patient page. Human immunodeficiency 
virus. JAMA. 2016 Jul 12;316(2):238. [PMID: 27404205]
The global HIV/AIDS epidemic—progress and challenges 
[editorial]. Lancet. 2017 Jul;390(10092):333. [PMID: 28745587]
World Health Organization. HIV/AIDS Fact sheet. Updated 
February 15, 2018. http://www.who.int/en/news-room/fact-
sheets/detail/hiv-aids
 
»
Pathophysiology
Clinically, the syndromes caused by HIV infection are 
usually explicable by one of three known mechanisms: 
immunodeficiency, autoimmunity, and allergic and hyper
-
sensitivity reactions.
A. Immunodeficiency
Immunodeficiency is a direct result of the effects of HIV 
upon immune cells as well as the indirect impact of a gen
-
eralized state of inflammation and immune activation due 
to chronic viral infection. A spectrum of infections and 
neoplasms is seen, as in other congenital or acquired 
immunodeficiency states. Two remarkable features of HIV 
immunodeficiency are the low incidence of certain infec
-
tions such as listeriosis and aspergillosis and the frequent 
occurrence of certain neoplasms such as lymphoma or 
Kaposi sarcoma. This latter complication has been seen 
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primarily in men who have sex with men (MSM) or in 
bisexual men, and its incidence steadily declined through 
the first 15 years of the epidemic. A herpesvirus (KSHV or 
HHV-8) is the cause of Kaposi sarcoma.
B. Autoimmunity/Allergic and 
Autoimmunity can occur as a result of disordered cellular 
immune function or B lymphocyte dysfunction. Examples 
of both lymphocytic infiltration of organs (eg, lymphocytic 
interstitial pneumonitis) and autoantibody production 
(eg, immunologic thrombocytopenia) occur. These phe
-
nomena may be the only clinically apparent disease or may 
coexist with obvious immunodeficiency. Moreover, HIV-
infected individuals appear to have higher rates of allergic 
reactions to unknown allergens as seen with eosinophilic 
pustular folliculitis (“itchy red bump syndrome”) as well as 
increased rates of hypersensitivity reactions to medications 
(for example, the fever and sunburn-like rash seen with 
trimethoprim-sulfamethoxazole reactions).
 
»
The complications of HIV-related infections and neo
-
plasms affect virtually every organ. The general approach 
to the HIV-infected person with symptoms is to evaluate 
the organ systems involved, aiming to diagnose treatable 
conditions rapidly. As can be seen in Figure 31–1, the CD4 
lymphocyte count result enables the clinician to focus on 
the diagnoses most likely to be seen at each stage of 
immunodeficiency. Certain infections may occur at any 
CD4 count, while others rarely occur unless the CD4 lym
-
phocyte count has dropped below a certain level. For 
example, a patient with a CD4 count of 600 cells/mcL, 
cough, and fever may have a bacterial pneumonia but 
would be very unlikely to have 
Many individuals with HIV infection remain asymptom
-
atic for years even without antiretroviral treatment, with a 
mean time of approximately 10 years between infection 
and development of AIDS. When symptoms occur, they 
may be remarkably protean and nonspecific. Since virtually 
all the findings may be seen with other diseases, a combi
-
nation of complaints is more suggestive of HIV infection 
than any one symptom.
Physical examination may be entirely normal. Abnormal 
findings range from completely nonspecific to highly specific 
for HIV infection. Those that are specific for HIV infection 
include hairy leukoplakia of the tongue, disseminated Kaposi 
sarcoma, and cutaneous bacillary angiomatosis. Generalized 
lymphadenopathy is common early in infection.
The specific presentations and management of the vari
-
ous complications of HIV infection are discussed under the 
Complications section below.
Henn A et al. Primary HIV infection: clinical presentation, 
testing, and treatment. Curr Infect Dis Rep. 2017 Sep 7; 
19(10):37. [PMID: 28884279]
Bacterial infections
Vaginal candidiasis
Kaposi sarcoma
Pneumoc
ys
tosis
To
xoplasmosis
Cryptococcosis
Coccidioidomycosis
Cryptosporidiosis
Disseminated MAC
   infection
Histoplasmosis
CNS lymphoma
500
200
50
Absolute CD4 lymphocyte count (/mcL)
 
▲
Figure 31–1.
 
Relationship of CD4 count to development of opportunistic infections. MAC, 
 
complex; CMV, cytomegalovirus; CNS, central nervous system.
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Specific tests for HIV include antibody and antigen detec
-
tion (Table 31–2). Conventional HIV antibody testing is 
done by ELISA. Positive specimens are then confirmed by 
a different method (eg, Western blot). The sensitivity of 
screening serologic tests is greater than 99.9%. The speci
-
ficity of positive results by two different techniques 
approaches 100% even in low-risk populations. False-
positive screening tests may occur as normal biologic vari
-
ants or in association with recent influenza vaccination or 
other disease states, such as connective tissue disease. These 
are usually detected by negative confirmatory tests. Anti
-
bodies will be detectable with current screening serologic 
tests in 95% of persons within 6 weeks after infection.
Rapid HIV antibody tests of blood or oral fluid provide 
results within 10–20 minutes and can be performed in clini
-
cian offices, including by personnel without laboratory 
training and without a Clinical Laboratory Improvement 
Amendment (CLIA)–approved laboratory. Persons who test 
positive on a rapid test should be told that they may be HIV-
infected or their test may be falsely reactive. Standard testing 
(ELISA with Western blot confirmation) should be per
-
formed to distinguish these two possibilities. Rapid testing is 
particularly helpful in settings where a result is needed 
immediately (eg, a woman in labor who has not recently 
been tested for HIV) or when the patient is unlikely to 
return for a result. Rapid HIV home tests that allow the tes
-
ters to learn their status privately by simply swabbing along 
their gum lines are also available (www.oraquick.com).
Nonspecific laboratory findings with HIV infection 
may include anemia, leukopenia (particularly lympho- 
 
penia), and thrombocytopenia in any combination, eleva
-
tion of the erythrocyte sedimentation rate, polyclonal 
hypergammaglobulinemia, and hypocholesterolemia. 
Cutaneous anergy is common.
The absolute CD4 lymphocyte count is the most widely 
used marker to provide prognostic information and to 
guide therapy decisions (Table 31–2). As counts decrease, 
the risk of serious opportunistic infection over the subse
-
quent 3–5 years increases (Figure 31–1). There are many 
limitations to using the CD4 count, including diurnal 
variation, depression with intercurrent illness, and intra-
laboratory and interlaboratory variability. Therefore, 
the trend is more important than a single determination. 
The frequency of performance of counts depends on the 
patient’s health status and whether or not they are receiving 
antiretroviral treatment. All patients regardless of CD4 
count should be offered antiretroviral treatment; CD4 
counts should be monitored every 3–6 months in patients 
taking antiretroviral treatment consistently. Initiation of 
 prophylactic therapy is recom
-
mended when the CD4 count drops below 200 cells/mcL, 
and initiation of 
 prophylaxis is rec
-
ommended when the CD4 count drops below 75–100 cells/
mcL. Some studies suggest that the percentage of CD4 
lymphocytes is a more reliable indicator of prognosis than 
the absolute counts because the percentage does not 
depend on calculating a manual differential. While the 
CD4 count measures immune dysfunction, it does not 
provide a measure of how actively HIV is replicating in the 
body. 
HIV viral load
 tests assess the level of viral replica
-
tion and provide useful prognostic information that is 
independent of the information provided by CD4 counts.
 
»
HIV infection may mimic a variety of other medical 
illnesses. Specific differential diagnosis depends on the 
mode of presentation. In patients presenting with constitu
-
tional symptoms such as weight loss and fevers, differential 
considerations include cancer, chronic infections such as 
Table 31–2.
 
Laboratory findings with HIV infection.
Test

-
 
Test
HIV enzyme-linked 
immunosorbent assay 
(ELISA)
Screening test for HIV infection. Of ELISA tests 50% are positive within 22 days after HIV transmission; 
95% are positive within 6 weeks after transmission. Sensitivity greater than 99.9%; to avoid false-positive 
results, repeatedly reactive results must be confirmed with Western blot.
Western blot
Confirmatory test for HIV. Specificity when combined with ELISA greater than 99.99%. Indeterminate results 
with early HIV infection, HIV-2 infection, influenza vaccine, autoimmune disease, pregnancy, and recent 
tetanus toxoid administration.
HIV rapid antibody test
Screening test for HIV. Produces results in 10–20 minutes. Can be performed by personnel with limited training. 
Positive results must be confirmed with standard HIV tests (ELISA and Western blot).
Complete blood count
Anemia, neutropenia, and thrombocytopenia common with advanced HIV infection.
Absolute CD4 lymphocyte 
count
Most widely used predictor of HIV progression. Risk of progression to an AIDS opportunistic infection or 
malignancy is high with CD4 less than 200 cells/mcL in the absence of treatment.
CD4 lymphocyte 
percentage
Percentage may be more reliable than the CD4 count. Risk of progression to an AIDS opportunistic infection or 
malignancy is high with percentage less than 14% in the absence of treatment.
HIV viral load tests
These tests measure the amount of actively replicating HIV virus. Correlate with disease progression and 
response to antiretroviral medications. Best tests available for diagnosis of acute HIV infection (prior to 
seroconversion); however, caution is warranted when the test result shows low-level viremia (ie, less than 
500 copies/mL) as this may represent a false-positive test.
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CMDT 2019
tuberculosis and endocarditis, and endocrinologic diseases 
such as hyperthyroidism. When pulmonary processes 
dominate the presentation, acute and chronic lung infec
-
tions must be considered as well as other causes of diffuse 
interstitial pulmonary infiltrates. When neurologic disease 
is the mode of presentation, conditions that cause mental 
status changes or neuropathy—eg, alcoholism, liver dis
-
ease, kidney dysfunction, thyroid disease, and vitamin 
deficiency—should be considered. If a patient presents 
with headache and a cerebrospinal fluid pleocytosis, other 
causes of chronic meningitis enter the differential. When 
diarrhea is a prominent complaint, infectious enterocolitis, 
antibiotic-associated colitis, inflammatory bowel disease, 
and malabsorptive symptoms must be considered.
 
»
A. Systemic Complaints
Fever, night sweats, and weight loss are common symptoms in 
HIV-infected patients and may occur without a complicating 
opportunistic infection. Patients with persistent fever and no 
localizing symptoms should nonetheless be carefully exam
-
ined, and evaluated with a chest radiograph (
 
pneumonia can present without respiratory symptoms), bac
-
terial blood cultures if the fever is greater than 38.5
°
C, serum 
cryptococcal antigen, and mycobacterial cultures of the blood. 
Sinus CT scans should be considered to evaluate occult sinus
-
itis. If these studies are normal, patients should be observed 
closely. Antipyretics are useful to prevent dehydration.
Bolduc P et al. Care of patients with HIV infection: medical 
complications and comorbidities. FP Essent. 2016 Apr;443: 
16–22. [PMID: 27092563]
Chu C et al. HIV-associated complications: a systems-based 
approach. Am Fam Physician. 2017 Aug 1;96(3):161–9. 
[PMID: 28762691]
1. Weight loss and wasting syndrome—
Weight loss is a 
particularly distressing complication of long-standing HIV 
infection. Patients typically have disproportionate loss of 
muscle mass, with maintenance or less substantial loss of 
fat stores. The mechanism of HIV-related weight loss is not 
completely understood but appears to be multifactorial.
a. Presentation—
AIDS patients frequently suffer from 
anorexia, nausea, and vomiting, all of which contribute to 
weight loss by decreasing caloric intake. In some cases, 
these symptoms are secondary to a specific infection, such 
as viral hepatitis. In other cases, however, evaluation of the 
symptoms yields no specific pathogen, and it is assumed to 
be due to a primary effect of HIV . Malabsorption also plays 
a role in decreased caloric intake. Patients may suffer diar
-
rhea from infections with bacterial, viral, or parasitic 
agents.
Exacerbating the decrease in caloric intake, many AIDS 
patients have an increased metabolic rate. This increased 
rate has been shown to exist even among asymptomatic 
HIV-infected persons, but it accelerates with disease pro
-
gression and secondary infection. AIDS patients with sec
-
ondary infections also have decreased protein synthesis, 
which makes maintaining muscle mass difficult.
b. Management—
Several strategies have been developed 
to slow AIDS wasting. In the long term, nothing is as effec
-
tive as antiretroviral treatment, since it treats the underly
-
ing HIV infection. In the short term, effective fever control 
decreases the metabolic rate and may slow the pace of 
weight loss, as does treating the underlying opportunistic 
infection. Food supplementation with high-calorie drinks 
may enable patients with not much appetite to maintain 
their intake. Selected patients with otherwise good func
-
tional status and weight loss due to unrelenting nausea, 
vomiting, or diarrhea may benefit from total parenteral 
nutrition (TPN). It should be noted, however, that TPN is 
more likely to increase fat stores than to reverse the muscle 
wasting process.
Two pharmacologic approaches for increasing appetite

Two pharmacologic approaches for increasing appetite 
and weight gain are the progestational agent 
megestrol 
acetate
 liquid suspension (400–800 mg orally daily in 
divided doses) and the antiemetic agent 
dronabinol
 
(2.5–5 mg orally three times a day), but neither of these 
agents increases lean body mass. Side effects from meges
-
trol acetate are rare, but thromboembolic phenomena, 
edema, nausea, vomiting, and rash have been reported. 
Euphoria, dizziness, paranoia, and somnolence and even 
nausea and vomiting have been reported in 3–10% of 
patients using dronabinol. Dronabinol contains only one of 
the active ingredients in marijuana, and many patients 
report better relief of nausea and improvement of appetite 
with 
medical cannabis
 (administered via smoking, vapor
-
ization, essential oils, or cooked in food). In the United 
States, at least 23 states and the District of Columbia have 
legalized medical marijuana, and some states have legal
-
ized recreational use. However, the use and sale of mari
-
juana is still illegal under federal law.
Two regimens that have resulted in increases in lean 
body mass are growth hormone and anabolic steroids. 
 at a dose of 0.1 mg/kg/day (up to 6 mg) 
subcutaneously for 12 weeks has resulted in modest 
increases in lean body mass. Treatment with growth hor
-
mone can cost as much as $10,000 per month. 
Anabolic 
steroids
 also increase lean body mass among HIV-infected 
patients. They seem to work best for patients who are able 
to do weight training. The most commonly used regimens 
are testosterone enanthate or testosterone cypionate (100–
200 mg intramuscularly every 2–4 weeks). Testosterone 
transdermal system (apply 5 mg system each evening) and 
testosterone gel (1%; apply a 5-g packet [50 mg testosterone] 
to clean, dry skin daily) are also available. The anabolic 
steroid oxandrolone (20 mg orally in two divided doses) 
has also been found to increase lean body mass.
Badowski ME et al. Clinical utility of dronabinol in the treat
-
ment of weight loss associated with HIV and AIDS. HIV 
AIDS (Auckl). 2016 Feb 10;8:37–45. [PMID: 26929669]
2. Nausea—
Nausea leading to weight loss is sometimes due 
to esophageal candidiasis. Patients with oral candidiasis and 
nausea should be empirically treated with an oral antifungal 
agent. Patients with weight loss due to nausea of unclear ori
-
gin may benefit from use of antiemetics prior to meals (pro
-
chlorperazine, 10 mg three times daily; metoclopramide, 
 
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10 mg three times daily; or ondansetron, 8 mg three times 
daily). Dronabinol (5 mg three times daily) or medical canna
-
bis can also be used to treat nausea. Depression and adrenal 
insufficiency are two potentially treatable causes of weight loss.
Whiting PF et al. Cannabinoids for medical use: a systematic 
review and meta-analysis. JAMA. 2015 Jun 23–30; 
313(24):2456–73. Erratum in: JAMA. 2016 Apr 12; 
315(14):1522. JAMA. 2015 Dec 1;314(21):2308. JAMA. 2015 
Aug 4;314(5):520. JAMA. 2015 Aug 25;314(8):837. [PMID: 
26103030]
B. Pulmonary Disease
1. 
 pneumonia—
(See also Chapter 36.) 
 
 pneumonia is the most common opportunistic 
infection associated with AIDS. 
 pneumonia 
may be difficult to diagnose because the symptoms—fever, 
cough, and shortness of breath—are nonspecific. Further
-
more, the severity of symptoms ranges from fever and no 
respiratory symptoms through mild cough or dyspnea to 
frank respiratory distress.
Hypoxemia may be severe, with a PO
2
 less than 60 mm Hg. 
The cornerstone of diagnosis is the chest radiograph. Diffuse 
or perihilar infiltrates are most characteristic, but only two-
thirds of patients with 
 pneumonia have this 
finding. Normal chest radiographs are seen in 5–10% of 
 pneumonia, while the remainder 
have atypical infiltrates. Apical infiltrates are commonly seen 
among patients with 
 pneumonia who have been 
receiving aerosolized pentamidine prophylaxis. Large pleural 
effusions are uncommon with 
 pneumonia; their 
presence suggests bacterial pneumonia, other infections such 
as tuberculosis, or pleural Kaposi sarcoma.
Definitive diagnosis can be obtained in 50–80% of cases by 
Wright-Giemsa stain or direct fluorescence antibody (DFA) 
test of induced sputum. Sputum induction is performed by 
having patients inhale an aerosolized solution of 3% saline 
produced by an ultrasonic nebulizer. Patients should not eat 
for at least 8 hours and should not use toothpaste or mouth
-
wash prior to the procedure since they can interfere with test 
interpretation. The next step for patients with negative spu
-
tum examinations in whom 
 pneumonia is still 
suspected should be bronchoalveolar lavage. This technique 
establishes the diagnosis in over 95% of cases.
In patients with symptoms suggestive of 
 
pneumonia but with negative or atypical chest radiographs 
and negative sputum examinations, other diagnostic tests 
may provide additional information in deciding whether to 
proceed to bronchoalveolar lavage. Elevation of serum lac
-
tate dehydrogenase occurs in 95% of cases of 
 
pneumonia, but the specificity of this finding is at best 75%. 
A serum beta-glucan test is a more sensitive and specific 
test for 
 pneumonia compared with serum 
lactate dehydrogenase and may avoid more invasive tests 
when used in the appropriate clinical setting. Either a nor
-
mal diffusing capacity of carbon monoxide (DL
CO
) or a 
high-resolution CT scan of the chest that demonstrates no 
interstitial lung disease makes the diagnosis of 
Pneumocys
-
tis
 pneumonia very unlikely. In addition, a CD4 count 
greater than 250 cells/mcL within 2 months prior to 
evaluation of respiratory symptoms makes a diagnosis of 
 pneumonia unlikely; only 1–5% of cases 
occur above this CD4 count level (Figure 31–1). This is true 
even if the patient previously had a CD4 count lower than 
200 cells/mcL but has had an increase with antiretroviral 
treatment. Pneumothoraces can be seen in HIV-infected 
patients with a history of 
Trimethoprim-sulfamethoxazole is the preferred treat
-
ment of 
 pneumonia (Table 31–3). In addition to 
specific anti-
 treatment, corticosteroid therapy 
has been shown to improve the course of patients with mod
-
erate to severe 

pneumonia (Table 31–3). In addition to 
-
 pneumonia (PaO
2
 less than 
70 mm Hg on room air or alveolar-arterial O
2
 gradient greater 
or equal to 35 mm Hg) when administered within 72 hours of 
the start of anti-
 treatment. It should be started 
as early as possible after initiation of treatment, using predni
-
sone 40 mg orally twice daily for days 1–5, 40 mg daily for 
days 6–10, and 20 mg daily for days 11–21 (for patients who 
cannot take oral medication, intravenous methylprednisolone 
can be substituted at 75% of the dose). The mechanism of 
action is presumed to be a decrease in alveolar inflammation.
Huang YS et al. Treatment of 
 pneumonia 
in HIV-infected patients: a review. Expert Rev Anti Infect 
Ther. 2017 Sep;15(9):873–92. [PMID: 28782390]
Siegel M et al. 
 pneumonia in human 
immunodeficiency virus infection. Semin Respir Crit Care 
Med. 2016 Apr;37(2):243–56. [PMID: 26974301]
2. Other infectious pulmonary diseases—
Other infectious causes of pulmonary 
disease in AIDS patients include bacterial, mycobacterial, 
and viral pneumonias. Community-acquired pneumonia is 
the most common cause of pulmonary disease in HIV-
infected persons. An increased incidence of pneumococcal 
pneumonia with septicemia and 
 
pneumonia has been reported. 
 is 
an important respiratory pathogen in advanced disease 
and, more rarely, pneumonia from 
Rhodococcus equi
 infec
-
tion can occur. The incidence of infection with 
 has markedly increased in 
metropolitan areas because of HIV infection as well as 
homelessness. Tuberculosis occurs in an estimated 4% of 
persons in the United States who have AIDS. Patients with 
active tuberculosis and CD4 counts above 350 cells/mcL 
are likely to present with findings similar to those of unin
-
fected persons. With advanced immunodeficiency, lower 
lobe, middle lobe, interstitial and miliary infiltrates are 
more common, along with mediastinal adenopathy and 
extrapulmonary involvement. Although a purified protein 
derivative (PPD) test or an 
interferon gamma release 
assay
 (
IGRA,
 including the QuantiFERON and T-SPOT 
tests) should be performed on all HIV-infected persons in 
whom a diagnosis of tuberculosis is being considered, the 
lower the CD4 cell count, the greater the likelihood of 
either test being falsely negative or indeterminate (in the 
case of the IGRA). Because “anergy” skin test panels do not 
accurately classify those patients who are infected with 
tuberculosis but unreactive to the PPD, they are not 
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Table 31–3.
 
Treatment of AIDS-related opportunistic infections and malignancies.
1
Infection or 
Treatment
2
 
infection
3
Preferred regimen: Trimethoprim-sulfamethoxazole, 15 mg/kg/day 
(based on trimethoprim component) intravenously or one dou
-
ble-strength tablet orally three times a day for 21 days. Add pred
-
nisone when PaO
2
 < 70 mm Hg on room air or alveolar-arterial O
2
 
gradient > 35 mm Hg: 40 mg orally twice a day on days 1–5, 
 
40 mg orally daily on days 6–10, 20 mg orally daily on days 11–21
Nausea, neutropenia, anemia, hepatitis, 
rash, Stevens-Johnson syndrome
 
Pentamidine, 3–4 mg/kg/day intravenously for 21 days plus predni
-
sone when indicated as above
Hypotension, hypoglycemia, anemia, 
neutropenia, pancreatitis, hepatitis
 
Primaquine, 30 mg/day orally, and clindamycin, 600 mg every 
 
8 hours orally, for 21 days plus prednisone when indicated as 
above
Primaquine: hemolytic anemia in G6PD-
deficient patients,
3
 methemoglobinemia, 
neutropenia, colitis
Clindamycin: rash, nausea, abdominal pain, 
colitis
 
Not recommended for severe disease: Trimethoprim, 15 mg/kg/day 
orally in three divided doses, with dapsone, 100 mg/day orally, 
for 21 days,
3
 plus prednisone when indicated as above
Nausea, rash, hemolytic anemia in G6PD
3
-
deficient patients; methemoglobinemia 
(weekly levels should be less than 10% of 
total hemoglobin)
 
Not recommended for severe disease: Atovaquone, 750 mg orally 
twice daily with food for 21 days, plus prednisone when indi
-
cated as above
Rash, elevated aminotransferases, anemia, 
neutropenia
 
complex infection
Clarithromycin, 500 mg orally twice daily with ethambutol, 15 mg/
kg/day orally (maximum, 1 g). May also add:
Clarithromycin: hepatitis, nausea, diarrhea
Ethambutol: hepatitis, optic neuritis
 
Rifabutin, 300 mg orally daily.
Rash, hepatitis, uveitis
Toxoplasmosis
Preferred regimen: Pyrimethamine, 200 mg orally as loading dose, 
followed by 50 mg daily (weight ≤ 60 kg) or 75 mg daily (weight 
> 60 kg), combined with sulfadiazine, 1000 mg orally four times 
daily (weight ≤ 60 kg) or 1500 mg orally four times daily (weight 
 
> 60 kg) and leucovorin 10–25 mg orally daily for at least 
 
6 weeks. Longer courses are necessary for extensive disease or 
incomplete clinical or radiographic resolution. Maintenance 
 
therapy with pyrimethamine 25–50 mg orally plus sulfadiazine 
2000–4000 mg in two to four divided doses plus leucovorin 
10–25 mg orally daily. Long-term treatment should be maintained 
until immune reconstitution with antiretroviral treatment occurs.
Pyrimethamine: leukopenia, anorexia, 
vomiting
Sulfadiazine: nausea, vomiting, Stevens-
 
For patients who are intolerant of sulfa who cannot be desensitized: 
substitute clindamycin 600 mg intravenously or orally every 
 
6 hours for the sulfadiazine in the above regimen
vomiting
colitis
 
If pyrimethamine not available: trimethoprim-sulfamethoxazole, 
 
10 mg/kg/day (based on trimethoprim component)
Non-Hodgkin 
lymphoma
Combination chemotherapy (eg, EPOCH with rituximab and G-CSF) 
Central nervous system disease: radiation treatment with dexa
-
methasone for edema
Nausea, vomiting, anemia, neutropenia, 
thrombocytopenia, cardiac toxicity (with 
doxorubicin)
Preferred regimen: Liposomal amphotericin B, 3–4 mg/kg/day 
 
intravenously, with flucytosine, 25 mg/kg/dose orally four times 
daily for 2 weeks (adjust dose for kidney function), then flucon
-
azole, 400 mg orally daily for 8 weeks, then 200 mg orally daily to 
complete 1 year of therapy
Liposomal amphotericin: fever, chills, 
hypokalemia, kidney disease
Flucytosine: bone marrow suppression, 
kidney disease, hepatitis
Fluconazole: hepatitis

Amphotericin B, 0.7 mg/kg/day intravenously, with flucytosine, 
 
25 mg/kg/dose orally four times daily for 2 weeks (adjust dose for 
kidney function), then fluconazole, 400 mg orally daily for 8 
weeks, then 200 mg orally daily to complete 1 year of therapy
Amphotericin: fever, chills, hypokalemia, 
kidney disease
(
continued
)
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1
 (continued)
Treatment
2
Fluconazole, used alone, is inferior to amphotericin B as induction ther
-
apy; it is recommended only for patients who cannot tolerate or do 
not respond to the preferred regimen above. If used for primary 
induction therapy, give fluconazole, 1200 mg orally daily for 2 weeks, 
then 400 mg orally daily for 8 weeks, then 200 mg orally daily to com
-
plete 1 year of therapy . Give with flucytosine, 25 mg/kg/dose orally 
four times daily for > 2 weeks (adjust dose for kidney function).
Hepatitis
Cytomegalovirus 
retinitis (immediate 
sight-threatening)
Preferred regimen: Intravitreal ganciclovir (2 mg/injection) or 
foscarnet (2.4 mg/injection) for 1–4 doses for 7–10 days plus 
valganciclovir, 900 mg orally twice a day with food for 14–21 
days followed by 900 mg daily (maintenance)
Neutropenia, anemia, thrombocytopenia
 
Ganciclovir, 10 mg/kg/day intravenously in two divided doses for 
14 days, followed by 5 mg/kg daily or valganciclovir 900 mg 
orally daily (maintenance)
Neutropenia (especially when used 
concurrently with zidovudine), anemia, 
Adjust ganciclovir dose for kidney function
 
Foscarnet, 60 mg/kg intravenously every 8 hours or 90 mg/kg 
intravenously every 12 hours for 14–21 days, followed by 
90–120 mg/kg once daily
Nausea, hypokalemia, hypocalcemia, 
hyperphosphatemia, azotemia
Adjust foscarnet dose for kidney function
 
Cidofovir, 5 mg/kg/week intravenously for 2 weeks, then 5 mg/kg 
every other week with probenecid 2 g orally 3 hours before dose, 
1 g orally 2 hours after dose, and 1 g orally 8 hours after dose
Nephrotoxicity (to reduce likelihood, 
 
pre- and post-saline hydration, along 
with probenecid), neutropenia
Avoid in patients with sulfa allergy because 
of cross hypersensitivity with probenecid
Esophageal candidiasis 
or recurrent vaginal 
candidiasis
Fluconazole, 100–200 mg orally daily for 14–21 days for esophageal 
disease and > 7 days for recurrent vaginal disease
Hepatitis, development of azole resistance
Herpes simplex 
infection
Acyclovir, 400 mg orally three times daily for 5–10 days; or acyclovir, 
 
5 mg/kg intravenously every 8 hours for severe cases
Resistant herpes simplex with long-term 
therapy
 
Famciclovir, 500 mg orally twice daily for 5–10 days
Nausea
 
Valacyclovir, 1 g orally twice daily for 5–10 days
Nausea
 
Foscarnet, 40 mg/kg intravenously every 8 hours, for acyclovir-
resistant cases.
Preferred regimen: Valacyclovir, 1000 mg orally three times daily for 
7–10 days
Nausea
 
Preferred regimen: Famciclovir, 500 mg orally three times daily for 
7–10 days
Nausea
 
Acyclovir, 800 mg orally five times daily for 7–10 days. Intravenous 
therapy at 10 mg/kg every 8 hours for extensive cutaneous or 
visceral disease until clinical improvement, then switch to oral 
therapy to complete a 10- to 14-day course. For ocular involve
-
ment, consult an ophthalmologist immediately.
Nausea
 
M
ild to moderate
Initiation or optimization of antiretroviral treatment
Side effects of antiretroviral treatment
Advanced disease
Combination chemotherapy (eg, daunorubicin, bleomycin, 
vinblastine)
Bone marrow suppression, cardiac toxicity 
(with daunorubicin), fever
1
Recommendations drawn from Centers for Disease Control and Prevention. Guidelines for the prevention and treatment of opportunistic 
infections in HIV-infected adults and adolescents. 2015. Downloaded from https://aidsinfo.nih.gov/guidelines on May 8, 2018.
2
List of complications is not exhaustive.
3
Prior to use of primaquine or dapsone, check glucose-6-phosphate dehydrogenase (G6PD) level in black patients and those of 
Mediterranean origin.

2
3
EPOCH, etoposide, prednisolone, vincristine (Oncovin), cyclophosphamide, doxorubicin (hydroxydaunomycin); G-CSF, granulocyte-colony 
stimulating factor (filgrastim).
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Treatment of HIV-infected persons with 
active tuberculosis is similar to treatment of HIV-uninfected 
tubercular individuals. However, rifampin should not be given 
to patients receiving a boosted protease inhibitor (PI) regimen. 
In these cases, rifabutin may be substituted, but it may require 
dosing modifications depending on the antiretroviral regi
-
men. Multidrug-resistant tuberculosis has been a major prob
-
lem in several metropolitan areas of the developed world, and 
reports from South Africa of “extremely resistant” tuberculosis 
in AIDS patients is a growing global concern. Noncompliance 
with prescribed antituberculous medications is a major risk 
factor. Several of the reported outbreaks appear to implicate 
nosocomial spread. The emergence of medication resistance 
makes it essential that antibiotic sensitivities be performed on 
all positive cultures. Medication therapy should be individual
-
ized. Patients with multidrug-resistant 
 infec
-
tion should receive at least three medications to which their 
organism is sensitive. Atypical mycobacteria can cause pulmo
-
nary disease in AIDS patients with or without preexisting lung 
disease and responds variably to treatment. Making a distinc
-
tion between 
 and atypical mycobacteria 
requires culture of sputum specimens. If culture of the sputum 
produces acid-fast bacilli, definitive identification may take 
several weeks using traditional techniques. DNA probes allow 
for presumptive identification usually within days of a positive 
culture. While awaiting definitive diagnosis, clinicians should 
err on the side of treating patients as if they have 
 
infection. In cases in which the risk of atypical mycobacteria is 
very high (eg, a person without risk for tuberculosis exposure 
with a CD4 count under 50 cells/mcL—see Figure 31–1), 
clinicians may wait for definitive diagnosis if the person is 
smear-negative for acid-fast bacilli, clinically stable, and not 
living in a communal setting. Isolation of cytomegalovirus 
(CMV) from bronchoalveolar lavage fluid occurs commonly 
in AIDS patients but does not establish a definitive diagnosis. 
Diagnosis of CMV pneumonia requires biopsy; response to 
treatment is poor. Histoplasmosis, coccidioidomycosis, and 
cryptococcal disease as well as more common respiratory viral 
infections should also be considered in the differential diagno
-
sis of unexplained pulmonary infiltrates.
Almeida A et al. Community-acquired pneumonia in HIV-positive 
patients: an update on etiologies, epidemiology and manage
-
ment. Curr Infect Dis Rep. 2017 Jan;19(1):2. [PMID: 28160220]
Centers for Disease Control and Prevention. Tuberculosis treat
-
ment of persons living with HIV . Updated August 11, 2016. 
https://www.cdc.gov/tb/topic/treatment/tbhiv.htm
Hu Z et al. Radiological characteristics of pulmonary cryptococ
-
cosis in HIV-infected patients. PLoS One. 2017 Mar 16;
 
12(3):e0173858. [PMID: 28301552]
Limper AH et al. Fungal infections in HIV/AIDS. Lancet Infect 
Dis. 2017 Nov;17(11):e334–43. [PMID: 28774701]
Scott L et al. Diagnosis of opportunistic infections: HIV 
 
co-infections—tuberculosis. Curr Opin HIV AIDS. 2017 
Mar;12(2):129–38. [PMID: 28059955]
Skolnik K et al. Cryptococcal lung infections. Clin Chest Med. 
2017 Sep;38(3):451–64. [PMID: 28797488]
Tiberi S et al. The cursed duet today: tuberculosis and HIV-coinfec
-
tion. Presse Med. 2017 Mar;46(2 Pt 2):e23–39. [PMID: 28256380]
3. Noninfectious pulmonary diseases—
a. 
Presentation—
Noninfectious causes of lung disease 
include Kaposi sarcoma, non-Hodgkin lymphoma, interstitial 
pneumonitis, and increasingly, in the current antiretroviral 
treatment era, lung cancer. In patients with known Kaposi 
sarcoma, pulmonary involvement complicates the course in 
approximately one-third of cases. However, pulmonary 
involvement is rarely the presenting manifestation of Kaposi

involvement is rarely the presenting manifestation of Kaposi 
sarcoma. Non-Hodgkin lymphoma may involve the lung as 
the sole site of disease, but more commonly involves other 
organs as well, especially the brain, liver, and gastrointestinal 
tract. Both of these processes may show nodular or diffuse 
parenchymal involvement, pleural effusions, and mediastinal 
adenopathy on chest radiographs.
Nonspecific interstitial pneumonitis may mimic 
 pneumonia. Lymphocytic interstitial pneu
-
monitis seen in lung biopsies has a variable clinical course. 
Typically, these patients present with several months of 
mild cough and dyspnea; chest radiographs show intersti
-
tial infiltrates. Many patients with this entity undergo 
transbronchial biopsies in an attempt to diagnose 
Pneumo
-
cystis
 pneumonia. Instead, the tissue shows interstitial 
inflammation ranging from an intense lymphocytic infil
-
tration (consistent with lymphoid interstitial pneumonitis) 
to a mild mononuclear inflammation.
Corticosteroids may be helpful in 
some cases refractory to antiretroviral treatment.
Presti RM et al. Mechanisms underlying HIV-associated nonin
-
fectious lung disease. Chest. 2017 Nov;152(5):1053–60. 
[PMID: 28427967]
Sigel K et al. Lung malignancies in HIV infection. Semin Respir 
Crit Care Med. 2016 Apr;37(2):267–76. [PMID: 26974303]
Triplette M et al. Non-infectious pulmonary diseases and HIV . 
Curr HIV/AIDS Rep. 2016 Jun;13(3):140–8. [PMID: 27121734]
4. Sinusitis—
Chronic sinusitis can be a frustrating 
problem for HIV-infected patients. Symptoms include 
sinus congestion and discharge, headache, and fever. Some 
patients may have radiographic evidence of sinus disease 
on sinus CT scan in the absence of significant symptoms.
HIV-infected patients with purulent 
drainage should be treated for possible 
 with 
amoxicillin-potassium clavulanate (500 mg orally three 
times a day) (see Chapter 8). A 7-day course of pseudo
-
ephedrine 60 mg twice daily may be helpful in decreasing 
congestion. Prolonged treatment (3–6 weeks) with an anti
-
biotic and guaifenesin (600 mg orally twice daily) is some
-
times necessary. For patients not responding to 
amoxicillin-potassium clavulanate, levofloxacin may be 
tried (400 mg orally daily). In patients with advanced 
immunodeficiency, 
 infections should be sus
-
pected, especially if there is not a response to first-line 
antibiotics. Some patients may require referral to an otolar
-
yngologist for sinus drainage and culture for possible fun
-
gal infection (
, 
Histoplasma capsulatum
).
C. Central Nervous System Disease
Central nervous system disease in HIV-infected patients can 
be divided into intracerebral space-occupying lesions, 
encephalopathy, meningitis, and spinal cord processes. 
 
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Many of these complications have declined markedly in 
prevalence in the era of effective antiretroviral treatment. 
Cognitive declines, however, may be more common in HIV 
patients especially as they age (older than 50 years), even those 
who are taking fully suppressive antiretroviral treatment.
Bowen LN et al. HIV-associated opportunistic CNS infections: 
pathophysiology, diagnosis and treatment. Nat Rev Neurol. 
2016 Oct 27;12(11):662–74. [PMID: 27786246]
1. Toxoplasmosis—
Toxoplasmosis is the most common 
space-occupying lesion in HIV-infected patients. Headache, 
focal neurologic deficits, seizures, or altered mental status may 
be presenting symptoms. The diagnosis is usually made pre
-
sumptively based on the characteristic appearance of cerebral 
imaging studies in an individual known to be seropositive for 
Toxoplasma.
 Typically, toxoplasmosis appears as multiple 
contrast-enhancing lesions on CT scan. Lesions tend to be 
peripheral, with a predilection for the basal ganglia.
Single lesions are atypical of toxoplasmosis. When a 
single lesion has been detected by CT scanning, MRI scan
-
ning may reveal multiple lesions because of its greater 
sensitivity. If a patient has a single lesion on MRI and is 
neurologically stable, clinicians may pursue a 2-week 
empiric trial of toxoplasmosis therapy. A repeat scan 
should be performed at 2 weeks. If the lesion has not 
diminished in size, biopsy of the lesion should be per
-
formed. A positive 
 serologic test does not 
confirm the diagnosis because many HIV-infected patients 
have detectable titers without having active disease. Con
-
versely, less than 3% of patients with toxoplasmosis have 
negative titers. Therefore, negative 
 titers in an 
HIV-infected patient with a space-occupying lesion should 
be a cause for aggressively pursuing an alternative diagno
-
sis. The preferred treatment of toxoplasmosis is with pyri
-
methamine and sulfadiazine (Table 31–3). If pyrimethamine 
is not available, patients can be treated with 
trimethoprim-sulfamethoxazole.
Basavaraju A. Toxoplasmosis in HIV infection: an overview. 
Trop Parasitol. 2016 Jul–Dec;6(2):129–35. [PMID: 27722101]
Mahmoudi S et al. Early detection of 
Toxoplasma gondii
 infec
-
tion by using a interferon gamma release assay: a review. Exp 
Parasitol. 2017 Jan;172:39–43. [PMID: 27988201]
Martin-Iguacel R et al. Incidence, presentation and outcome 
of toxoplasmosis in HIV infected in the combination antiret
-
roviral therapy era. J Infect. 2017 Sep;75(3):263–73. [PMID: 
28579301]
2. Central nervous system lymphoma—
Primary non-
Hodgkin lymphoma is the second most common space-
occupying lesion in HIV-infected patients. Symptoms are 
similar to those with toxoplasmosis. While imaging tech
-
niques cannot distinguish these two diseases with certainty, 
lymphoma more often is solitary. Other less common 
lesions should be suspected if there is preceding bactere
-
mia, positive tuberculin test, fungemia, or injection drug 
use. These include bacterial abscesses, cryptococcomas, 
tuberculomas, and 
Nocardia
 lesions.
Stereotactic brain biopsy should be strongly consid
-
ered if lesions are solitary or do not respond to 
toxoplasmosis treatment, especially if they are easily 
accessible. Diagnosis of lymphoma is important because 
many patients benefit from treatment (radiation therapy). 
Although a positive polymerase chain reaction (PCR) 
assay of cerebrospinal fluid for Epstein–Barr virus DNA is 
consistent with a diagnosis of lymphoma, the sensitivity 
and specificity of the test are not high enough to obviate 
the need for a brain biopsy.
Y ang M et al. Diagnostic accuracy of SPECT, PET, and MRS for 
primary central nervous system lymphoma in HIV patients: a 
systematic review and meta-analysis. Medicine (Baltimore). 
2017 May;96(19):e6676. [PMID: 28489744]
3. HIV-associated dementia—
Patients with HIV-

associated dementia typically have difficulty with cognitive 
tasks (eg, memory, attention), exhibit diminished motor 
function, and have emotional or behavioral problems. 
Patients may first notice a deterioration in their handwrit
-
ing. The manifestations of dementia may wax and wane, 
with persons exhibiting periods of lucidity and confusion 
over the course of a day. The diagnosis of HIV-associated 
dementia is one of exclusion based on a brain imaging 
study and on spinal fluid analysis that excludes other 
pathogens. Neuropsychiatric testing is helpful in distin
-
guishing patients with dementia from those with depres
-
sion. Many patients improve with effective antiretroviral 
treatment. However, slowly progressive neurocognitive 
deficits may still develop in patients taking antiretroviral 
treatment as they age.
Metabolic abnormalities may also cause changes in 
mental status: hypoglycemia, hyponatremia, hypoxia, and 
drug overdose are important considerations in this popula
-
tion. Other less common infectious causes of encephalopa
-
thy include progressive multifocal leukoencephalopathy 
(discussed below), CMV , syphilis, and herpes simplex 
encephalitis.
Calcagno A et al. Treating HIV infection in the central nervous 
system. Drugs. 2017 Feb;77(2):145–57. [PMID: 28070871]
Eggers C et al; German Association of Neuro-AIDS und Neuro-
Infectiology (DGNANI). HIV-1-associated neurocognitive 
disorder: epidemiology, pathogenesis, diagnosis, and treat
-
ment. J Neurol. 2017 Aug;264(8):1715–27. [PMID: 28567537]
Vera JH et al. PET brain imaging in HIV-associated neurocogni
-
tive disorders (HAND) in the era of combination antiretrovi
-
ral therapy. Eur J Nucl Med Mol Imaging. 2017 
May;44(5):895–902. [PMID: 28058461]
4. Cryptococcal meningitis—
Cryptococcal meningitis typ
-
ically presents with fever and headache. Less than 20% of 
patients have meningismus. Diagnosis is based on a posi
-
tive latex agglutination test of serum that detects crypto
-
coccal antigen (or “CRAG”) or positive culture of spinal 
fluid for 
. Seventy to 90% of patients with 
cryptococcal meningitis have a positive serum CRAG. 
Thus, a negative serum CRAG test makes a diagnosis of 
cryptococcal meningitis unlikely and can be useful in the 
initial evaluation of a patient with headache, fever, and 
normal mental status. The preferred treatment is liposomal 
amphotericin with flucytosine (Table 31–3).
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Maziarz EK et al. Cryptococcosis. Infect Dis Clin North Am. 
2016 Mar;30(1):179–206. [PMID: 26897067]
Srichatrapimuk S et al. Integrated therapy for HIV and crypto
-
coccosis. AIDS Res Ther. 2016 Nov 29;13(1):42. [PMID: 
27906037]
Williamson PR et al. Cryptococcal meningitis: epidemiology, 
immunology, diagnosis and therapy. Nat Rev Neurol. 2017 
Jan;13(1):13–24. [PMID: 27886201]
5. Meningococcal meningitis—
An opportunistic infection, 
HIV-infected persons are at increased risk for meningo
-
coccal disease. Treatment is the same as in uninfected 
persons. Therefore, the Advisory Committee on Immuni
-
zation Practices recommends the meningococcal conjugate 
vaccine (serogroups A, C, W , and Y) for all HIV-infected 
persons aged 2 months or older.
-
27811836]
6. HIV meningitis and HIV myelopathy—
HIV meningitis, 
characterized by lymphocytic pleocytosis of the spinal fluid 
with negative culture, is common early in HIV infection.
Spinal cord function may also be impaired in HIV-
infected individuals. HIV myelopathy presents with leg weak
-
ness and incontinence. Spastic paraparesis and sensory ataxia 
are seen on neurologic examination. Myelopathy is usually a 
late manifestation of HIV disease, and most patients will have 
concomitant HIV encephalopathy. Pathologic evaluation of 
the spinal cord reveals vacuolation of white matter. Because 
HIV myelopathy is a diagnosis of exclusion, symptoms sug
-
gestive of myelopathy should be evaluated by lumbar punc
-
ture to rule out CMV polyradiculopathy (described below) 
and an MRI or CT scan to exclude epidural lymphoma.
7. Progressive multifocal leukoencephalopathy (PML)—
PML is a viral infection of the white matter of the brain seen 
in patients with very advanced HIV infection. It typically 
results in focal neurologic deficits such as aphasia, hemipa
-
resis, and cortical blindness. Imaging studies are strongly 
suggestive of the diagnosis if they show nonenhancing white 
matter lesions without mass effect. Extensive lesions may be 
difficult to differentiate from the changes caused by HIV . 
Several patients have stabilized or improved after the institu
-
tion of effective antiretroviral treatment, and due to wide use 
of antiretroviral treatment, PML is now rarely seen.
Pavlovic D et al; Progressive Multifocal Leukoencephalopathy 
Consortium. Progressive multifocal leukoencephalopathy: 
current treatment options and future perspectives. Ther Adv 
Neurol Disord. 2015 Nov;8(6):255–73. [PMID: 26600871]
White MK et al. Diagnostic assays for polyomavirus JC and 
progressive multifocal leukoencephalopathy. Rev Med Virol. 
2016 Mar;26(2):102–14. [PMID: 26663440]
D. Peripheral Nervous System
Peripheral nervous system syndromes 
include inflammatory polyneuropathies, sensory neuropa
-
thies, and mononeuropathies.
An 
inflammatory demyelinating polyneuropathy
 
similar to Guillain-Barré syndrome occurs in HIV-infected 
patients, usually prior to frank immunodeficiency. The 
syndrome in many cases improves with plasmapheresis, 
supporting an autoimmune basis of the disease. CMV can 
cause an ascending polyradiculopathy characterized by 
lower extremity weakness and a neutrophilic pleocytosis 
on spinal fluid analysis with a negative bacterial culture. 
Transverse myelitis can be seen with herpes zoster or CMV .
 is common among HIV-infected 
persons. Patients typically complain of numbness, tingling, 
and pain in the lower extremities. Symptoms are dispropor
-
tionate to findings on gross sensory and motor evaluation. 
Beyond HIV infection itself, the most common cause is 
prior antiretroviral treatment with stavudine or didanosine. 
Although not used commonly in Western countries, stavu
-

-
dine is still being used in resource-limited settings through 
national antiretroviral treatment programs. Caution should 
be used when administering these agents to patients with a 
history of peripheral neuropathy. Unfortunately, medica
-
tion-induced neuropathy is not always reversed when the 
offending agent is discontinued. Patients with advanced 
disease may also develop peripheral neuropathy even if they 
have never taken antiretroviral treatment. Evaluation should 
rule out other causes of sensory neuropathy such as alcohol
-
ism, thyroid disease, vitamin B
12
 deficiency, and syphilis.
b. Management
—
Treatment of peripheral neuropathy is 
aimed at symptomatic relief. Patients should be initially 
treated with gabapentin (start at 300 mg at bedtime and 
increase to 300–900 mg orally three times a day) or other co-
analgesics for neuropathic pain (see Chapter 5). Opioid anal
-
gesics should be avoided because the condition tends to be 
chronic and patients are likely to become dependent on these 
agents without significant improvement in their well-being.
Mochan A et al. CIDP [chronic  inflammatory  demyelinating 
polyradiculoneuropathy] in a HIV endemic population: 
 
a prospective case series from Johannesburg, South Africa. 
 
J Neurol Sci. 2016 Apr 15;363:39–42. [PMID: 27000218]
E. Rheumatologic and Bone Manifestations
Arthritis, involving single or multiple joints, with or without 
effusion, has been commonly noted in HIV-infected 
patients. Involvement of large joints is most common. 
Although the cause of HIV-related arthritis is unknown, 
most patients will respond to nonsteroidal anti-inflammatory 
medications. Patients with a sizable effusion, especially if the 
joint is warm or erythematous, should have the joint aspi
-
rated, followed by culture of the fluid to rule out suppurative 
arthritis as well as fungal and mycobacterial disease.
Several rheumatologic syndromes, including reactive arthri
-
tis, psoriatic arthritis, sicca syndrome, and systemic lupus ery
-
thematosus, have been reported in HIV-infected patients (see 
Chapter 20). However, it is unclear if the prevalence is greater 
than in the general population. Cases of avascular necrosis of 
the femoral heads have been reported sporadically, generally in 
the setting of advanced disease with long-standing infection 
and in patients receiving long-term antiretroviral treatment. 
The etiology is not clear but is probably multifactorial in nature.
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Osteoporosis and osteopenia appear to be more common 
in HIV-infected patients with chronic infection and perhaps 
associated with long-term use of antiretroviral treatment. 
Vitamin D deficiency appears to be quite common among 
HIV-infected populations and monitoring vitamin D levels 
and replacement therapy for detected deficiency are recom
-
mended. Bone mineral density scans for postmenopausal 
women and for men over the age of 50 is also recommended.
Compston J. HIV infection and bone disease. J Intern Med. 2016 
Oct;280(4):350–8. [PMID: 27272530]
Pretell-Mazzini J et al. HIV and orthopaedics: musculoskeletal 
manifestations and outcomes. J Bone Joint Surg Am. 2016 
May 4;98(9):775–86. [PMID: 27147691]
Roszkiewicz J et al. Kaleidoscope of autoimmune diseases in 
HIV infection. Rheumatol Int. 2016 Nov;36(11):1481–91. 
[PMID: 27544391]
Walker-Bone K et al. Assessment and management of musculo
-
skeletal disorders among patients living with HIV . Rheuma
-
tology (Oxford). 2017 Oct 1;56(10):1648–61. [PMID: 
28013196]
commonly seen as a white lesion on the lateral aspect of the 
tongue. It may be flat or slightly raised, is usually corru
-
gated, and has vertical parallel lines with fine or thick 
(“hairy”) projections. 
Oral candidiasis
 can be bothersome 
to patients, many of whom report an unpleasant taste or 
mouth dryness. The two most common forms of oral can
-
didiasis seen are pseudomembranous (removable white 
plaques) and erythematous (red friable plaques).
Treatment of oral candidiasis is with 
topical agents such as clotrimazole 10-mg troches (one 
troche four or five times a day). Patients with candidiasis 
who do not respond to topical antifungals can be treated 
with fluconazole (50–100 mg orally once a day for 
3–7 days). 
Angular cheilitis
—fissures at the sides of the 
mouth—is usually due to 
Candida
 as well and can be 
treated topically with ketoconazole cream (2%) twice a day.
Gingival disease
 is common in HIV-infected patients 
and is thought to be due to an overgrowth of microorgan
-
isms. It usually responds to professional dental cleaning 
and chlorhexidine rinses. A particularly aggressive gingivi
-
tis or periodontitis will develop in some HIV-infected 
patients; these patients should be given antibiotics that 
cover anaerobic oral flora (eg, metronidazole, 250 mg four 
times a day for 4 or 5 days) and referred to oral surgeons 
with experience with these entities.
Aphthous ulcers
 are painful and may interfere with eat
-
ing. They can be treated with fluocinonide (0.05% ointment 
mixed 1:1 with plain Orabase and applied six times a day to 
the ulcer). For lesions that are difficult to reach, patients 
should use dexamethasone swishes (0.5 mg in 5 mL elixir 
three times a day). The pain of the ulcers can be relieved 
with use of an anesthetic spray (10% lidocaine). Other 
lesions seen in the mouths of HIV-infected patients include 
 (usually on the hard palate) and 
warts.
Batavia AS et al. Diagnosis of HIV-associated oral lesions in rela
-
tion to early versus delayed antiretroviral therapy: results 
from the CIPRA HT001 Trial. PLoS One. 2016 Mar 1;
 
11(3):e0150656. [PMID: 26930571]
de Almeida VL et al. Impact of highly active antiretroviral ther
-
apy on the prevalence of oral lesions in HIV-positive patients: 
a systematic review and meta-analysis. Int J Oral Maxillofac 
Surg. 2017 Nov;46(11):1497–504. [PMID: 28684301]
27109280]
Millsop JW et al. Oral candidiasis. Clin Dermatol. 2016 
Jul–Aug;34(4):487–94. [PMID: 27343964]
Nittayananta W . Oral fungi in HIV: challenges in antifungal 
therapies. Oral Dis. 2016 Apr;22(Suppl 1):107–13. [PMID: 
27109279]
I. Gastrointestinal Manifestations
1. Candidal esophagitis—
(See also Chapter 15.) Esopha
-
geal candidiasis is a common AIDS complication. In a

27109279]
-
geal candidiasis is a common AIDS complication. In a 
patient with characteristic symptoms, empiric antifungal 
treatment is begun with fluconazole (100–200 mg orally 
daily for 14–21 days). Improvement in symptoms should be 
apparent within 1–2 days of antifungal treatment. If there is 
no improvement, further evaluation to identify other causes 
of esophagitis (herpes simplex, CMV) is recommended.
F. Myopathy
Myopathies are infrequent in the era of effective antiretrovi
-
ral treatment but can be related to either HIV-infection or 
antiretroviral treatment, particularly with use of zidovudine 
(azidothymidine [AZT]). Proximal muscle weakness is typi
-
cal, and patients may have varying degrees of muscle tender
-
ness. Given its long-term toxicities, zidovudine is no longer 
recommended when alternative treatments are available.
G. Retinitis
In HIV-infected patients, complaints of visual changes must 
be evaluated immediately by an ophthalmologist familiar 
with the manifestations of HIV disease. 
CMV retinitis,
 
characterized by perivascular hemorrhages and white fluffy 
exudates, is the most common retinal infection in AIDS 
patients and can be rapidly progressive. In contrast, cotton 
wool spots, which are also common in HIV-infected patients, 
are benign, remit spontaneously, and appear as small indis
-
tinct white spots without exudation or hemorrhage. Other 
rare retinal processes include other herpesvirus infections or 
toxoplasmosis. Choice of treatment for CMV retinitis 
(Table 31–3) depends on severity and location of lesions,  
and the patient’s overall condition and circumstances.
Port AD et al. Cytomegalovirus retinitis: a review. J Ocul Phar
-
macol Ther. 2017 May;33(4):224–34. [PMID: 28355091]
H. Oral Lesions
The presence of oral candidiasis or 
hairy leukoplakia is significant for several reasons. First, 
these lesions are highly suggestive of HIV infection in 
patients who have no other obvious cause of immunodefi
-
ciency. Second, several studies have indicated that patients 
with candidiasis have a high rate of progression to AIDS 
even with statistical adjustment for CD4 count.
 is caused by the Epstein-Barr virus. 
The lesion is not usually troubling to patients and some
-
times regresses spontaneously. Hairy leukoplakia is 
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-
2. Hepatic disease—
Autopsy studies have demonstrated 
that the liver is a frequent site of infections and neoplasms 
in HIV-infected patients. However, many of these infec
-
tions are not clinically symptomatic. Mild elevations of 
alkaline phosphatase and aminotransferases are often 
noted on routine chemistry panels. 
Mycobacterial disease, 
CMV , hepatitis B virus, hepatitis C virus,
 and 
lymphoma
 
cause liver disease and can present with varying degrees of 
nausea, vomiting, right upper quadrant abdominal pain, 
and jaundice. Sulfonamides, imidazole medications, anti
-
tuberculous medications, pentamidine, clarithromycin, 
and didanosine have also been associated with hepatitis. 
All nucleoside reverse transcriptase inhibitors cause lactic 
acidosis, which can be fatal. Lactic acidosis, however, 
occurs most commonly when didanosine is used with 
stavudine; this combination is no longer recommended in 
antiretroviral treatment regimens. HIV-infected patients 
with chronic hepatitis may have more rapid progression of 
liver disease because of the concomitant immunodefi
-
ciency or hepatotoxicity of antiretroviral treatment. Percu
-
taneous liver biopsy may be helpful in diagnosing liver 
disease, but some common causes of liver disease 
(eg, 
M avium
 complex, lymphoma) can be determined by 
less invasive measures (eg, blood culture, biopsy of a more 
accessible site).
With patients living longer as a result 
of advances in antiretroviral treatment, advanced liver dis
-
ease and hepatic failure due to chronic active hepatitis B 
and/or C are increasing causes of morbidity and mortality. 
HIV-infected individuals who are coinfected with hepatitis 
B should be treated with antiretroviral regimens that 
include medications with activity against both viruses 
(tenofovir disoproxil fumarate [TDF] or tenofovir alafen
-
amide [TAF], lamivudine [3TC], or emtricitabine). Enteca
-
vir may be used if HIV viral load is suppressed; otherwise, 
its use can lead to lamivudine/emtricitabine-resistant HIV . 
It is important to be extremely cautious about discontinu
-
ing these medications in coinfected patients as sudden 
discontinuation could lead to a fatal flare of hepatitis B 
Hepatitis C is more virulent in persons with HIV and 
should be treated using the new HCV direct-acting antivi
-
rals (Table 16-6). For treatment-naïve coinfected patients 
with genotype 1a (the most common hepatitis C genotype 
in the United States) the recommended regimens are (1) 
fixed-dose ledipasvir (90 mg)/sofosbuvir (400 mg) daily for 
12 weeks, (2) fixed-dose paritaprevir (150 mg)/ritonavir 
(100 mg)/ombitasvir (25 mg) plus dasabuvir (250 mg twice 
daily) and weight-based ribavirin (1000 mg for patients 
weighing less than 75 kg and 1200 mg for patients weighing 
more than 75 kg) for 12 weeks (24 weeks for patients with 
cirrhosis), (3) sofosbuvir (400 mg) plus simeprevir (150 
mg) with or without weight-based ribavirin (see previous 
regimen) for 12 weeks (24 weeks in patients with cirrhosis). 
Because there are no data to support one regimen over 
another, the least expensive regimen may be preferred. At 
the moment, all are very expensive, but it is hoped that 
competition between the regimens will ultimately reduce 
the price. Acid-reducing medicines should be avoided with 
ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir.
Although the recommended regimens are the same for 
HIV-infected patients, potential drug interactions with 
antiretroviral treatment may complicate treatment. Ledi
-
pasvir increases tenofovir levels. These two medications 
should be avoided in patients with creatinine clearance 
below 60 mL/min or in those taking these two medications

-
below 60 mL/min or in those taking these two medications 
and a ritonavir-boosted protease inhibitor (PI). Paritapre
-
vir/ritonavir/ombitasvir/dasabuvir can be used safely with 
raltegravir, enfuvirtide, tenofovir, emtricitabine, lamivudine, 
and atazanavir. Simeprevir can be used safely with raltegra
-
vir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtric
-
itabine, lamivudine, and abacavir. For hepatitis C treatment 
recommendations in patients with other scenarios (other 
medication interactions, genotypes, prior treatment, renal 
impairment), clinicians should consult the guidelines listed 
in the references below (see also Table 16–6).
Liver transplants have been performed successfully in 
HIV-infected patients. This strategy is most likely to be 
successful in persons who have CD4 counts greater than 
100 cells/mcL and nondetectable viral loads.
Scott JA et al. Treatment optimization for HIV/HCV co-infected 
patients. Ther Adv Infect Dis. 2017 Jan;4(1):18–36. [PMID: 
28357062]
Singh KP et al. HIV-hepatitis B virus co-infection: epidemiology, 
pathogenesis, and treatment. AIDS. 2017 Sep 24;31(15):2035–
52. [PMID: 28692539]
3. Biliary disease—
 presents with manifesta
-
tions similar to those seen in immunocompetent hosts, but 
is more likely to be acalculous. 
Sclerosing cholangitis
 and 
papillary stenosis
 have also been reported in HIV-infected 
patients. Typically, the syndrome presents with severe nau
-
sea, vomiting, and right upper quadrant pain. Liver 
enzymes generally show alkaline phosphatase elevations 
disproportionate to elevation of the aminotransferases. 
Although dilated ducts can be seen on ultrasound, the 
diagnosis is made by endoscopic retrograde cholangiopan
-
creatography, which reveals intraluminal irregularities of 
the proximal intrahepatic ducts with “pruning” of the ter
-
minal ductal branches. Stenosis of the distal common bile 
duct at the papilla is commonly seen with this syndrome. 
CMV , 
, and microsporidia are thought to 
play inciting roles in this syndrome, but these conditions 
are rarely seen unless the patient is suffering with very 
advanced HIV-related immunodeficiency.
4. Enterocolitis—
Enterocolitis
 is a common problem in 
HIV-infected individuals. Organisms known to cause 
enterocolitis include bacteria (
, 
, 
Shigella
), viruses (CMV , adenovirus), and protozoans 
(
, 
, 
Giardia
, 
Isospora
, 
microsporidia). HIV itself may cause enterocolitis. 
 
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Several of the organisms causing enterocolitis in HIV-
infected individuals also cause diarrhea in immunocompe
-
tent persons. However, HIV-infected patients tend to have 
more severe and more chronic symptoms, including high 
fevers and severe abdominal pain that can mimic acute 
abdominal catastrophes. Bacteremia and concomitant bili
-
ary involvement are also more common with enterocolitis 
in HIV-infected patients. Relapses of enterocolitis follow
-
ing adequate therapy have been reported with both 
Salmo
-
nella
 and 
Shigella
 infections.
Because of the wide range of agents known to cause 
enterocolitis, a stool culture and multiple stool examinations 
for ova and parasites (including modified acid-fast staining 
for 
) should be performed. Those patients 
who have 
 in one stool with improvement 
in symptoms in less than 1 month should not be considered 
to have AIDS, as 
 is a cause of self-limited 
diarrhea in HIV-negative persons. More commonly, HIV-
infected patients with 
 infection have per
-
sistent enterocolitis with profuse watery diarrhea.
To date, no consistently effective treat
-
ments have been developed for 
 infection. 
The most effective treatment of cryptosporidiosis is to 
improve immune function through the use of effective 
antiretroviral treatment. The diarrhea can be treated symp
-
tomatically with diphenoxylate with atropine (one or two 
tablets orally three or four times a day). Those who do not 
respond may be given paregoric with bismuth (5–10 mL 
orally three or four times a day). Octreotide in escalating 
doses (starting at 0.05 mg subcutaneously every 8 hours for 
48 hours) has been found to ameliorate symptoms in 
approximately 40% of patients with cryptosporidia or idio
-
pathic HIV-associated diarrhea although the benefit is 
often short-lived.
Patients with a negative stool examination and persis
-
tent symptoms should be evaluated with colonoscopy and 
biopsy. Patients whose symptoms last longer than 1 month 
with no identified cause of diarrhea are considered to have 
a presumptive diagnosis of 
AIDS enteropathy.
 Patients 
may respond to institution of effective antiretroviral treat
-
ment. Upper endoscopy with small bowel biopsy is not 
recommended as a routine part of the evaluation.
Berahmat R et al. Human cryptosporidiosis in Iran: a systematic 
review and meta-analysis. Parasitol Res. 2017 Apr; 
116(4):1111–28. [PMID: 28110441]
5. Other disorders—
Two other important gastrointestinal 
abnormalities in HIV-infected patients are 
gastropathy
 
and malabsorption. It has been documented that some 
HIV-infected patients do not produce normal levels of 
stomach acid and therefore are unable to absorb medica
-
tions that require an acid medium. This decreased acid 
production may explain, in part, the susceptibility of HIV-
infected patients to 
, 
, and 
Shigella
, all of which are sensitive to acid concentration. 
There is no evidence that 
 is more com
-
mon in HIV-infected persons.
A 
malabsorption
 syndrome occurs commonly in 
AIDS patients. It can be due to infection of the small 
bowel with 
M avium
 complex, 
, or 
microsporidia.
Logan C et al. HIV and diarrhoea: what is new? Curr Opin Infect 
Dis. 2016 Oct;29(5):486–94. [PMID: 27472290]
J. Endocrinologic Manifestations
Hypogonadism
 is probably the most common endocrino
-
logic abnormality in HIV-infected men. The adrenal gland is 
also a commonly afflicted endocrine gland in patients with 
AIDS. Abnormalities demonstrated on autopsy include infec
-
tion (especially with CMV and 
M avium
 complex), infiltra
-
tion with Kaposi sarcoma, and injury from hemorrhage and 
presumed autoimmunity. The prevalence of clinically signifi
-
cant adrenal insufficiency is low. Patients with suggestive 
symptoms should undergo a cosyntropin stimulation test.

-
Although frank deficiency of cortisol is rare, an isolated 
defect in mineralocorticoid metabolism may lead to salt-
wasting and hyperkalemia. Such patients should be treated 
with fludrocortisone (0.1–0.2 mg orally daily).
AIDS patients appear to have abnormalities of thyroid 
function tests different from those of patients with other 
chronic diseases. AIDS patients have been shown to have 
high levels of triiodothyronine (T
3
4
), and 
thyroid-binding globulin and low levels of reverse triiodo
-
thyronine (rT
3
). The causes and clinical significance of 
these abnormalities are unknown.
Gomes AR et al. Prevalence of testosterone deficiency in HIV-
infected men under antiretroviral therapy. BMC Infect Dis. 
2016 Nov 3;16(1):628. [PMID: 27809804]
Lachâtre M et al. HIV and hypogonadism: a new challenge for 
young-aged and middle-aged men on effective antiretroviral 
therapy. AIDS. 2017 Jan 28;31(3):451–3. [PMID: 28081039]
Wong N et al. Hypogonadism in the HIV-infected man. Curr 
Treat Options Infect Dis. 2017;9(1):104–16. [PMID: 
28344518]
K. Skin Manifestations
The skin manifestations that commonly develop in HIV-
infected patients can be grouped into viral, bacterial, fun
-
gal, neoplastic, and nonspecific dermatitides.
1. Viral dermatitides—
a. Herpes simplex infections—
These infections occur 
more frequently, tend to be more severe, and are more 
likely to disseminate in AIDS patients than in immuno
-
competent persons. Because of the risk of progressive local 
disease, all herpes simplex attacks should be treated for 
5–10 days with acyclovir (400 mg orally three times a day), 
famciclovir (500 mg orally twice daily), or valacyclovir 
(500 mg orally twice daily) (Table 31–3). To avoid the com
-
plications of attacks, many clinicians recommend suppres
-
sive therapy for HIV-infected patients with a history of 
recurrent herpes. Options for suppressive therapy include 
acyclovir (400 mg orally twice daily), famciclovir (250 mg 
orally twice daily), and valacyclovir (500 mg orally daily). 
Long-term suppressive herpes prophylaxis with acyclovir 
does not reduce HIV transmission between heterosexual 
men and women from developing countries.
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Andrei G et al. The anti-HIV drug tenofovir, a reverse transcrip
-
tase inhibitor, also targets the herpes simplex virus (HSV) 
DNA polymerase. J Infect Dis. 2018 Feb 14;217(5):790–801. 
[PMID: 29186456]
b. Herpes zoster—
This is a common manifestation of 
HIV infection. As with herpes simplex infections, patients 
with zoster should be treated for 7–10 days with famciclo
-
vir (500 mg orally three times a day) or valacyclovir 
(500 mg three times a day). Acyclovir can also be used, but 
it requires very frequent dosing (800 mg orally four or five 
times per day for 7 days). Vesicular lesions should be cul
-
tured if there is any question about their origin, since her
-
pes simplex responds to much lower doses of acyclovir. 
Disseminated zoster and cases with ocular involvement 
should be treated with intravenous (10 mg/kg every 
8 hours for 7–10 days) rather than oral acyclovir. The zos
-
ter vaccine appears to be safe and immunogenic in HIV-
infected patients over the age of 50 years with CD4 greater 
than 200/mcL, although the long-term benefit in prevent
-
ing recurrences has yet to be established.
Shafran SD. Live attenuated herpes zoster vaccine for HIV-infected 
adults. HIV Med. 2016 Apr;17(4):305–10. [PMID: 26315285]
c. Molluscum contagiosum—
This infection is caused 
by a pox virus and is seen in HIV-infected patients, as in 
other immunocompromised patients. The characteristic 
umbilicated fleshy papular lesions have a propensity for 
spreading widely over the patient’s face and neck and 
should be treated with topical liquid nitrogen.
26991246]
van der Wouden JC et al. Interventions for cutaneous mollus
-
cum contagiosum. Cochrane Database Syst Rev. 2017 May 17; 
5:CD004767. [PMID: 28513067]
2. Bacterial dermatitides—
a. Staphylococcal infection—
 is the 
most common bacterial cause of skin disease in HIV-
infected patients; it usually presents as 
folliculitis, 
 
superficial abscesses (furuncles),
 or 
bullous impetigo
. 
These lesions should be treated aggressively since sepsis can 
occur. Folliculitis is initially treated with topical clindamy
-
cin or mupirocin, and patients may benefit from regular 
washing with an antibacterial soap such as chlorhexidine. 
Intranasal mupirocin has been used successfully for staphy
-
lococcal decolonization in other settings. In HIV-infected 
patients with recurrent staphylococcal infections, weekly 
intranasal mupirocin should be considered in addition to 
topical care and systemic antibiotics. Abscesses often 
require incision and drainage. Patients may need antistaph
-
ylococcal antibiotics as well. Due to high frequency of 
 (MRSA) skin 
infections in HIV-infected populations, lesions should be 
cultured prior to initiating empiric antistaphylococcal 
therapy. Recommendations for empiric treatment are either 
 
(1) trimethoprim-sulfamethoxazole (one double-strength 
tablet orally twice daily) with or without clindamycin 
 
(500 mg orally three times daily); or (2) doxycycline 
 
(100 mg orally twice daily) with close follow-up.
Hemmige V et al. Predictors of skin and soft tissue infections in 
HIV-infected outpatients in the community-associated meth
-
icillin resistant 
 era. Eur J Clin Micro
-
biol Infect Dis. 2015 Feb;34(2):339–47. [PMID: 25213720]
b. Bacillary angiomatosis—
It is caused by two closely 
related organisms: 
Bartonella henselae
 and 
Bartonella 
quintana.
 The epidemiology of these infections suggests 
zoonotic transmission from fleas of infected domestic cats. 
The most common manifestation is raised, reddish, highly 
vascular skin lesions that can mimic the lesions of Kaposi 
sarcoma. Fever is a common manifestation of this infec
-

-
tion; involvement of bone, lymph nodes, and liver has also 
been reported. The infection responds to doxycycline, 
100 mg orally twice daily, or erythromycin, 250 mg orally 
four times daily. Therapy is continued for at least 14 days, 
and patients who are seriously ill with visceral involvement 
may require months of therapy.
Markowicz M et al. Bacillary angiomatosis presenting with facial 
tumor and multiple abscesses: a case report. Medicine 
(Baltimore). 2016 Jul;95(28):e4155. [PMID: 27428207]
3. Fungal rashes—
a. Rashes due to dermatophytes and candida—
Most 
fungal rashes
 afflicting AIDS patients are due to 
dermatophytes and 
Candida.
 While particularly common 
in the inguinal region, they may occur anywhere on the 
body. Fungal rashes generally respond well to topical 
clotrimazole (1% cream twice a day) or ketoconazole 
(2% cream twice a day).
b. Seborrheic dermatitis—
This is more common in 
HIV-infected patients. Scrapings of seborrhea have 
revealed 
Malassezia furfur (Pityrosporum ovale)
, implying 
that the seborrhea is caused by this fungus. Consistent with 
the isolation of this fungus is the clinical finding that seb
-
orrhea responds well to topical clotrimazole (1% cream) as 
well as hydrocortisone (1% cream).
Forrestel AK et al. Diffuse HIV-associated seborrheic 
dermatitis—a case series. Int J STD AIDS. 2016 Dec; 
27(14):1342–5. [PMID: 27013615]
4. Neoplastic dermatitides—
See Chapter 6 and the Kaposi 
sarcoma section below.
5. Nonspecific dermatitides—
a. Xerosis—
This condition presents in HIV-infected 
patients with severe pruritus. The patient may have no 
rash, or nonspecific excoriations from scratching. Treat
-
ment is with emollients (eg, absorption base cream) and 
antipruritic lotions (eg, camphor 9.5% and menthol 0.5%).
b. Psoriasis—
Psoriasis can be very severe in HIV-infected 
patients. Phototherapy and etretinate (0.25–9.75 mg/kg/day 
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orally in divided doses) may be used for recalcitrant cases 
in consultation with a dermatologist.
L. HIV-Related Malignancies
Four cancers are currently included in the CDC classifica
-
tion of AIDS: Kaposi sarcoma, non-Hodgkin lymphoma, 
primary lymphoma of the brain, and invasive cervical car
-
cinoma. Epidemiologic studies have shown that between 
1973 and 1987 among single men in San Francisco, the risk 
of Kaposi sarcoma increased more than 5000-fold and the 
risk of non-Hodgkin lymphoma more than 10-fold. The 
increase in incidence of malignancies is probably a func
-
tion of impaired cell-mediated immunity. In the current 
treatment era, cancers not classified as AIDS-related, such 
as lung cancer, are being increasingly diagnosed in aging 
HIV-infected individuals despite optimal antiretroviral 
treatment treatment. Cohort studies suggest that HIV-
infected adults are at increased risk for a variety of cancers 
compared to age-matched uninfected populations. Mortal
-
ity secondary to malignancies represents an increasing 
cause of death in HIV-infected populations.
Hernández-Ramírez RU et al. Cancer risk in HIV-infected 
people in the USA from 1996 to 2012: a population-based, 
registry-linkage study. Lancet HIV . 2017 Nov;4(11):e495–504. 
[PMID: 28803888]
Shiels MS et al. Evolving epidemiology of HIV-associated malig
-
nancies. Curr Opin HIV AIDS. 2017 Jan;12(1):6–11. [PMID: 
27749369]
1. Kaposi sarcoma—
Lesions may appear anywhere; careful 
examination of the eyelids, conjunctiva, pinnae, palate, and 
toe webs is mandatory to locate potentially occult lesions. 
In light-skinned individuals, Kaposi lesions usually appear 
as purplish, nonblanching lesions that can be papular or 
nodular. In dark-skinned individuals, the lesions may 
appear more brown. In the mouth, lesions are most often 
palatal papules, though exophytic lesions of the tongue and 
gingivae may also be seen. Kaposi lesions may be confused 
with other vascular lesions such as angiomas and pyogenic 
granulomas. Kaposi sarcoma lesions can occur shortly after 
initiating antiretroviral treatment, especially in patients 
starting antiretroviral treatment who have advanced 
immunodeficiency. In this situation, Kaposi sarcoma is 
likely to be an immune reconstitution reaction (see Inflam
-
matory Reactions below). Kaposi sarcoma can also cause 
visceral disease (eg, gastrointestinal, pulmonary).
Patients with mild to moderate forms 
of Kaposi sarcoma do not require specific treatment as the 
lesions usually resolve with effective antiretroviral treat
-
ment. However, it should be noted that the lesions may 
flare when antiretroviral treatment is first initiated—
probably as a result of an immune reconstitution process. 
Advanced disease is treated with combination chemother
-
apy (Table 31–3).
Gonçalves PH et al. HIV-associated Kaposi sarcoma and related 
diseases. AIDS. 2017 Sep 10;31(14):1903–16. [PMID: 28609402]
2. Non-Hodgkin lymphoma—
Non-Hodgkin lymphoma in HIV-
infected persons tends to be very aggressive. The malig
-
nancies are usually of B cell origin and characterized as 
diffuse large-cell tumors. Over 70% of the malignancies are 
extranodal.
The prognosis of patients with sys
-
temic non-Hodgkin lymphoma depends primarily on the 
degree of immunodeficiency at the time of diagnosis. 
Patients with high CD4 counts do markedly better than 
those diagnosed at a late stage of illness. Patients with pri
-
mary central nervous system lymphoma are treated with 
radiation. Response to treatment is good, but prior to the 
availability of antiretroviral treatment, most patients died 
within a few months after diagnosis due to their underlying 
disease. Systemic disease is treated with combination che
-
motherapy (eg, EPOCH [etoposide, prednisolone, vincris
-
tine, cyclophosphamide, doxorubicin]) with rituximab.

-
-
tine, cyclophosphamide, doxorubicin]) with rituximab. 
Granulocyte colony-stimulating factor (G-CSF; filgrastim) 
is used to maintain white blood counts.
Cingolani A et al; ICONA Foundation Study group. Survival and 
predictors of death in people with HIV-associated lymphoma 
compared to those with a diagnosis of lymphoma in general 
population. PLoS One. 2017 Oct 31;12(10):e0186549. [PMID: 
29088223]
Qian L et al. Advances in the treatment of newly diagnosed pri
-
mary central nervous system lymphomas. Blood Res. 2017 
Sep;52(3):159–66. [PMID: 29043230]
Re A et al. Early consolidation with high-dose therapy and 
autologous stem cell transplantation is a feasible and effective 
treatment option in HIV-associated non-Hodgkin lymphoma 
at high risk. Bone Marrow Transplant. 2018 Feb; 
53(2):228–30. [PMID: 28991244]
3. Hodgkin disease—
Although Hodgkin disease is not 
included as part of the CDC definition of AIDS, studies 
have found that HIV infection is associated with a fivefold 
increase in the incidence of Hodgkin disease. HIV-infected 
persons with Hodgkin disease are more likely to have 
mixed cellularity and lymphocyte depletion subtypes of 
Hodgkin disease and to seek medical attention at an 
advanced stage of disease.
Lawal IO et al. The role of F-18 FDG PET/CT in evaluating the 
impact of HIV infection on tumor burden and therapy out
-
come in patients with Hodgkin lymphoma. Eur J Nucl Med 
Mol Imaging. 2017 Nov;44(12):2025–33. [PMID: 28660348]
Sorigué M et al. HIV-infection has no prognostic impact on 
advanced-stage classical Hodgkin lymphoma. AIDS. 
2017 Jun 19;31(10):1445–9. [PMID: 28358739]
4. Anal dysplasia and squamous cell carcinoma—
These 
lesions have been strongly correlated with previous infec
-
tion by human papillomavirus (HPV) and have been noted 
in HIV-infected men and women. Although many of the 
infected MSM report a history of anal warts or have visible 
warts, a significant percentage have silent papillomavirus 
infection. Cytologic (using Papanicolaou smears) and pap
-
illomavirus DNA studies can easily be performed on speci
-
mens obtained by anal swab. Because of the risk of 
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progression from dysplasia to cancer in immunocompro
-
mised patients, some experts suggest that annual anal 
swabs for cytologic examination should be done in all HIV-
infected persons. An anal Papanicolaou smear is per
-
formed by rotating a moistened Dacron swab about 2 cm 
into the anal canal. The swab is immediately inserted into 
a cytology bottle. However, there is no evidence that 
screening for anal cancer with Papanicolaou smears 
decreases the incidence of invasive cancer.
HPV also appears to play a causative role in 
cervical 
dysplasia
 and 
neoplasia
. The incidence and clinical course of 
cervical disease in HIV-infected women are discussed below.
Oette M et al. HIV-associated anal dysplasia and anal carcinoma. 
Oncol Res Treat. 2017;40(3):100–5. [PMID: 28253522]
M. Gynecologic Manifestations
Vaginal candidiasis, cervical dysplasia and neoplasia, and 
pelvic inflammatory disease are more common in HIV-
infected women than in uninfected women. These mani
-
festations also tend to be more severe when they occur in 
association with HIV infection. Therefore, HIV-infected 
women need frequent gynecologic care. 
 
may be treated with topical agents or a single dose of oral 
fluconazole (150 mg) (see Chapter 36). Recurrent vaginal 
candidiasis should be treated with fluconazole (100–200 mg) 
for at least 7 days.
cervical dysplasia
 in HIV-infected 
women is 40%. Because of this finding, recommended 
screening for HIV-infected women is more extensive than 
for uninfected women (see Chapter 18). For women 
younger than age 30 years, a Papanicolaou smear should be 
performed within a year of the onset of sexual activity, but 
no later than age 21 years. If normal, Papanicolaou smears 
should be performed yearly. After three negative examina
-
tions, screening should be done every 3 years. HPV DNA 
testing of the cervical specimen is not recommended for 
women younger than age 30 years.
For women age 30 and older, screening should continue 
beyond age 65 unlike the general population. There are two 
accepted screening protocols, one using cytology alone, the 
other using cytology with HPV DNA cotesting. A Papani
-
colaou smear is done when HIV is diagnosed and every 
 
12 months thereafter and after three negative examina
-
tions, ongoing screening should be performed every 
3 years. Alternatively, a Papanicolaou smear with cotesting 
for HPV DNA can be performed when HIV is diagnosed 
or starting when patients are age 30 years old. If Papanico
-
laou is normal and HPV test is negative, then the next 
screening should be in 3 years.
The management of abnormal Papanicolaou tests and 
positive HPV tests is the same in infected women as in 
uninfected women. Treatment should follow the consensus 
guidelines in the references below.
While 
pelvic inflammatory disease
 appears to be more 
common in HIV-infected women, the bacteriology of this 
condition appears to be the same as among HIV-uninfected 
women. HIV-infected women with pelvic inflammatory 
disease should be treated with the same regimens as unin
-
fected women (see Chapter 18).
Ghebre RG et al. Cervical cancer control in HIV-infected 
women: past, present and future. Gynecol Oncol Rep. 
2017 Jul 21;21:101–8. [PMID: 28819634]
N. Coronary Artery Disease
HIV-infected persons are at higher risk for coronary artery 
disease than age- and sex-matched controls. Part of this 
increase in coronary artery disease is due to changes in 
lipids caused by antiretroviral agents (see Treatment sec
-
tion on Antiretroviral Therapy below), especially stavudine 
and several of the PIs. However, some of the risk appears to 
be due to HIV infection, independent of its therapy. It is 
important that clinicians pay close attention to this issue 
because myocardial infarctions tend to present at a younger 
age in HIV-infected individuals than in HIV-uninfected

age in HIV-infected individuals than in HIV-uninfected 
individuals. HIV-infected patients with symptoms of coro
-
nary artery disease such as chest pain or dyspnea should be 
rapidly evaluated. Clinicians should aggressively treat con
-
ditions that result in increased risk of heart disease, espe
-
cially smoking, hypertension, hyperlipidemia, obesity, 
diabetes mellitus, and sedentary lifestyle.
Ballocca F et al. Cardiovascular disease in patients with HIV . Trends 
Cardiovasc Med. 2017 Nov;27(8):558–63. [PMID: 28779949]
Maggi P et al. Cardiovascular risk and dyslipidemia among per
-
sons living with HIV: a review. BMC Infect Dis. 2017 Aug 9; 
17(1):551. [PMID: 28793863]
Manga P et al. HIV and nonischemic heart disease. J Am Coll 
Cardiol. 2017 Jan 3;69(1):83–91. [PMID: 28057254]
O. Inflammatory Reactions (Immune 
Reconstitution Inflammatory Syndromes)
With initiation of antiretroviral treatment, some patients 
experience 
inflammatory reactions
 that appear to be asso
-
ciated with immune reconstitution as indicated by a rapid 
increase in CD4 count. These inflammatory reactions may 
present with generalized signs of fevers, sweats, and mal
-
aise with or without more localized manifestations that 
usually represent unusual presentations of opportunistic 
infections. For example, vitreitis has developed in patients 
with CMV retinitis after they have been treated with anti
-
retroviral treatment.
M avium
 can present as focal even suppurative lymph
-
adenitis or granulomatous masses in patients receiving 
antiretroviral treatment. Tuberculosis may paradoxically 
worsen with new or evolving pulmonary infiltrates and 
lymphadenopathy. PML and cryptococcal meningitis may 
also behave atypically. Clinicians should be alert to these 
syndromes, which are most often seen in patients who have 
initiated antiretroviral treatment in the setting of advanced 
disease and who show rapid increases in CD4 counts with 
treatment. The diagnosis of 
immune reconstitution 
inflammatory syndrome (IRIS)
 is one of exclusion and 
can be made only after recurrence or new opportunistic 
infection has been ruled out as the cause of the clinical 
deterioration. Management of IRIS is conservative and sup
-
portive with use of corticosteroids only for severe reactions. 
Most authorities recommend that antiretroviral treatment 
be continued unless the reaction is life-threatening.
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Shahani L et al. Therapeutics targeting inflammation in the 
immune reconstitution inflammatory syndrome. Transl Res. 
2016 Jan;167(1):88–103. [PMID: 26303886]
 
»
A. Primary Prevention
Until vaccination is a reality, prevention of HIV infection will 
depend on HIV testing and counseling, including precautions 
regarding sexual practices and injection drug use, initiation of 
antiretroviral treatment as a prevention tool for transmission 
to others, preexposure and postexposure use of antiretroviral 
treatment, perinatal management including antiretroviral 
treatment of the mother, screening of blood products, and 
infection control practices in the health care setting.
1. HIV testing and counseling—
Primary care clinicians 
should routinely obtain a sexual history and provide risk fac
-
tor assessment of their patients. Because approximately one-
fifth of the HIV-infected persons in the United States do not 
know they are infected, the 
US Preventive Services Task Force
 
recommends that clinicians screen for HIV infection in ado
-
lescents and adults ages 15 to 65 years. Y ounger adolescents 
and older adults who are at increased risk should also be 
screened. Clinicians should review the risk factors for HIV 
infection with the patient and discuss safer sex and safer nee
-
dle use as well as the meaning of a positive test. Although the 
CDC recommends “opt-out” testing in medical settings, some 
states require specific written consent. For persons whose test 
results are positive, it is critically important that they be con
-
nected to ongoing medical care. Referrals for partner-notifica
-
tion services, social services, mental health services, and 
HIV-prevention services should also be provided. Prevention 
interventions focused on the importance of HIV-infected 
persons not putting others at risk have been successful.
For patients whose test results are negative, clinicians 
should review safer sex and needle use practices, including 
counseling not to exchange bodily fluids unless they are in a 
long-term mutually monogamous relationship with someone 
who has tested HIV antibody-negative and has not engaged in 
unsafe sex, injection drug use, or other HIV risk behaviors for 
at least 6 months prior to or at any time since the negative test.
To prevent sexual transmission of HIV , only latex or 
polyurethane condoms should be used, along with a water-
soluble lubricant. Although nonoxynol-9, a spermicide, 
kills HIV , it is contraindicated because in some patients it 
may cause genital ulcers that could facilitate HIV transmis
-
sion. Patients should be counseled that condoms are not 
100% effective. They should be made familiar with the use 
of condoms, including, specifically, the advice that con
-
doms must be used every time, that space should be left at 
the tip of the condom as a receptacle for semen, that inter
-
course with a condom should not be attempted if the penis 
is only partially erect, that men should hold on to the base 
of the condom when withdrawing the penis to prevent slip
-
page, and that condoms should not be reused. Although 
anal intercourse remains the sexual practice at highest risk 
for transmitting HIV , seroconversions have been docu
-
mented with vaginal and oral intercourse as well. There
-
fore, condoms should be used when engaging in these 
activities. Women as well as men having sex with men 
should understand how to use condoms to be sure that 
their partners are using them correctly. Partners of HIV-
infected women should use latex or polyurethane barriers 
such as dental dams (available at dental supply stores) to 
prevent direct oral contact with vaginal secretions. Several 
randomized trials in Africa demonstrated that male cir
-
cumcision significantly reduced HIV incidence in men, but 
there are a number of barriers to performing widespread 
circumcisions among men in Africa.
Persons using injection drugs should be cautioned

Persons using injection drugs should be cautioned 
never to share needles or other drug paraphernalia. When 
sterile needles are not available, bleach does appear to inac
-
tivate HIV and should be used to clean needles.
2. Antiretroviral treatment for decreasing transmission 
of HIV to others—
Besides preventing progression of HIV 
disease, effective antiretroviral treatment likely decreases 
the risk of HIV transmission between sexual partners. 
Among serodiscordant couples, stably suppressing HIV 
with antiretroviral treatment almost completely eliminates 
the risk of HIV transmission to the uninfected partner. 
Although HIV-negative persons in stable long-term part
-
nerships with HIV-infected persons represent only one 
group of at-risk persons, theoretically increasing the use of 
antiretroviral treatment among the population of HIV-
infected persons could decrease community-wide trans
-
mission of HIV . Despite major improvements in 
effectiveness and tolerability of antiretroviral treatment, 
only about half of HIV-infected persons in the United 
States are virally suppressed. Even patients who have been 
treated with antiretrovirals and have undetectable viral 
loads must practice safer sex and not share needles so as to 
avoid the possibility of transmitting HIV .
Centers for Disease Control and Prevention. National Center for 
HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Selected 
National HIV Prevention and Care Outcomes, 2015. https://www
 
.cdc.gov/hiv/pdf/library/slidesets/cdc-hiv-prevention-and-
care-outcomes.pdf
Günthard HF et al. Antiretroviral drugs for treatment and pre
-
vention of HIV infection in adults: 2016 recommendations of 
the International Antiviral Society-USA Panel. JAMA. 2016 
Jul 12;316(2):191–210. [PMID: 27404187]
Kalapila AG et al. Antiretroviral therapy for prevention of 
human immunodeficiency virus infection. Med Clin North 
Am. 2016 Jul;100(4):927–50. [PMID: 27235622]
3. Preexposure antiretroviral treatment prophylaxis—
Several large randomized double-blind placebo-controlled 
trials demonstrated that administering emtricitabine/TDF 
(Truvada) can reduce the risk of sexual transmission of HIV 
among uninfected individuals at high risk for infection; one 
study was of HIV-negative men and transgender women who 
have sex with men, two studies were of heterosexual HIV-
discordant couples. Preexposure tenofovir has also been 
shown to reduce HIV infection among injection drug users 
from Thailand. In addition, real-world studies of men who 
have sex with men, where adherence with emtricitabine/TDF 
has been high, have found 
preexposure prophylaxis (PrEP)
 
to be highly effective in preventing HIV infection. 
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Emtricitabine/TAF (Descovy) is under study for PrEP , but is 
not currently recommended because of questions of whether 
it has as good penetration into genital fluids.
Who should be prescribed PrEP is not a simple question. 
PrEP is best thought of as one “option” for HIV prevention, 
rather than as the only option. Whether it is the “best” 
option depends on three things: (1) the likelihood that a 
person will have HIV-infected partners or use the needles of 
infected persons, (2) whether there is a better option avail
-
able to prevent HIV , and (3) the patient’s ability to take a 
daily medication. CDC guidelines recommend offering 
PrEP to persons at “substantial risk” for HIV . Risk for HIV 
is a combination of the likelihood of having a partner who 
is HIV-infected and the likelihood that the behavior (eg, 
type of intercourse, shared needles) transmits HIV . Men 
who have sex with men, and transgender male-to-females 
are the groups with the highest HIV seroprevalence in the 
United States, and they are likely to have partners who are 
known to be or at risk for being HIV-infected. Those who 
have receptive anal intercourse have the highest risk of HIV 
because the behavior is much more efficient at transmitting 
HIV than other sexual practices. Heterosexual drug users 
are also at high risk for HIV-infection if they do not consis
-
tently use clean needles of if they trade drugs for sex. It can 
be hardest to assess the risk of heterosexual non-drug users 
because it requires assessing the likelihood that their part
-
ners have HIV risks such as being bisexual men or using 
injection drugs. Factors known to increase the risk of HIV 
transmission and therefore make PrEP a good choice for 
particular groups of patients are shown in Table 31–4.
How does PrEP compare to other options for preventing 
HIV? Latex or polyurethane condoms are an excellent 
choice for preventing sexual transmission of HIV because 
they are inexpensive, have no side effects, and prevent other 
sexually transmitted diseases and pregnancy. However, for a 
variety of reasons, people do not always use condoms even 
when taught to do so. In addition, condoms break or slip on 
occasion, so even persons who always use condoms may 
want the extra protection of PrEP if they have a known 
HIV-infected partner. History of sexually transmitted dis
-
eases is proof of unprotected sex and increases the likeli
-
hood that PrEP is a good option for a patient.
Finally, for PrEP to be effective, patients have to be willing 
to take it. Taking one pill right before sex would not be 
expected to offer protection because the medicine would not 
have adequate drug levels in the body. Maximum concentra
-
tions are achieved in various locations in the body at different 
treatment intervals: in blood, maximum levels are achieved 
after 20 days of daily dosing; in rectal tissue, after 7 days; in 
cervicovaginal tissue, after 20 days. Study participants who 
took at least 4 daily doses in a week were protected almost as 
well as those who took the drug every day, indicating that 
missed doses do not render the treatment ineffective; how
-
ever, adherence to daily dosing is the safest method.
Recommendations on initial and follow-up assessments 
are shown in Table 31-4. Emtricitabine/TDF is contraindi
-
cated for persons with kidney disease (creatinine clearance 
less than 60 mL) because of the small risk of kidney toxicity 
with TDF. Decreases in bone mineral density have been 
documented in persons taking emtricitabine/TDF for PrEP 
Table 31–4.
 
Recommendations for preexposure 
prophylaxis (PrEP) of HIV infection.
Patients for whom PrEP should be considered as an option for 
HIV prevention
Sexually active homosexual and bisexual men, male-to-female 
transgender persons, and heterosexuals and bisexual women 
who are likely to have partners with HIV risks
Injection drug users

Factors that increase the likelihood that PrEP is a good option
Patient has receptive anal intercourse
Patient has a known HIV-infected partner
Patient has a history of sexually transmitted diseases
Patient has a high number of sex partners
Commercial sex workers
Patient with inconsistent or no condom use
Patient with sharing needles or related paraphernalia (“works”)
Initial assessment before prescribing PrEP
HIV antibody test to confirm HIV negative
Symptom review to exclude primary HIV infection (eg, no 
 
history of acute illness with fever and rash in prior month)
STD tests: syphilis; gonorrhea (at risk site-specific); and 
chlamydia (at risk site-specific)
Serum creatinine and eGFR
1
Confirm immunity to HBV or vaccinate if nonimmune
2
Discuss risks, including that PrEP is not 100% effective, does 
 
not protect against other STDs, and may have side effects
Counsel patients to use latex or polyurethane condoms and 
clean needles, in addition to PrEP
Assess substance use and offer treatment, if needed
Discuss importance of daily medication adherence
PrEP prescription
Emtricitabine/TDF daily (Truvada) 1 tablet orally daily, initially 
for 90 days
Follow-up assessment
HIV antibody test every 3 months
Serum creatinine every 6 months
Pregnancy test every 3 months
STD tests: syphilis, gonorrhea (at risk site-specific); and 
 
Assess and support daily medication adherence
Reinforce benefits of using latex or polyurethane condoms and 
clean needles with PrEP
1
Emtricitabine/TDF is contraindicated if creatinine clearance 
 
< 60 mL/min.
2
HBV-infected persons may experience HBV reactivation and liver 
damage if emtricitabine/TDF is stopped.
eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; 
STD, sexually transmitted disease; TDF, tenofovir diproxil fumarate.
PrEP checklists for providers and patients available at https://www
 
.cdc.gov/hiv/pdf/guidelines/PrEPProviderSupplement2014.pdf
at 24 weeks; whether this decrease will have clinical signifi
-
cance is unknown. In someone with osteoporosis or at high 
risk for osteoporosis, clinical judgement would be needed 
to assess whether the benefits of emtricitabine/TDF justi
-
fied the risks of worsening bone density. If emtricitabine/
TAF is found to be effective as PrEP , it would be a good 
alternative to emtricitabine/TDF for patients with kidney 
disease or osteoporosis since TAF appears to have less 
effect on the kidney and bone than TDF.
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Substantial increases in sexual transmitted diseases 
have also been seen in persons taking PrEP , indicating the 
importance of regular follow-up in patients using PrEP . 
Some patients are reluctant to use insurance to cover the 
cost of the medication for fear of revealing that they are at 
risk for HIV; without insurance, the cost is high. Compas
-
sionate use programs are available from the medication 
manufacturer for low-income uninsured persons.
Fonner V A et al. Effectiveness and safety of oral HIV preexpo
-
sure prophylaxis for all populations. AIDS. 2016 Jul 31; 
30(12):1973–83. [PMID: 27149090]
Jenness SM et al. Impact of the Centers for Disease Control’s 
HIV preexposure prophylaxis guidelines for men who have 
sex with men in the United States. J Infect Dis. 2016 Dec 15; 
214(12):1800–7. [PMID: 27418048]
McCormack S et al. Pre-exposure prophylaxis to prevent the 
acquisition of HIV-1 infection (PROUD): effectiveness results 
from the pilot phase of a pragmatic open-label randomised 
trial. Lancet. 2016 Jan 2;387(10013):53–60. [PMID: 26364263]
Pialoux G et al. Pre-exposure prophylaxis: a useful tool to pre
-
vent human immunodeficiency virus infection? Clin 
Microbiol Infect. 2016 Sep;22(9):757–67. [PMID: 27615724]
Scott HM et al. Sexually transmitted infections and pre-exposure 
prophylaxis: challenges and opportunities among men who 
have sex with men in the US. AIDS Res Ther. 2016 Jan 19; 
13:5. [PMID: 26793265]
Seidman D et al. Integrating preexposure prophylaxis for human 
immunodeficiency virus prevention into women’s health care 
in the United States. Obstet Gynecol. 2016 Jul;128(1):37–43. 
[PMID: 27275793]
Seidman DL et al. Use of HIV pre-exposure prophylaxis during 
the preconception, antepartum and postpartum periods 
at two United States medical centers. Am J Obstet Gynecol. 
2016 Nov;215(5):632.e1–7. [PMID: 27448959]
4. Postexposure prophylaxis for sexual and drug use 
exposures to HIV—
The goal of 
postexposure prophylaxis
 
is to reduce or prevent local viral replication prior to dissemi
-
nation such that the infection can be aborted. Although there 
is no proof that administration of antiretroviral medications 
following a sexual or parenteral drug use exposure reduces 
the likelihood of infection, there is suggestive data from ani
-
mal models, perinatal experience, and a case-control study of 
health care workers who experienced a needle stick.
Treatment of persons who have been exposed to HIV 
should be within 72 hours, but sooner is better. All exposed 
persons should first receive HIV testing to exclude the pos
-
sibility that they are already infected. If rapid tests are not 
available, treatment should begin pending the results of a 
standard HIV test.
The choice of antiretroviral agents and the duration of 
treatment are the same as those for exposures that occur 
through the occupational route; the preferred regimen is 
tenofovir 300 mg with emtricitabine 200 mg daily with 
raltegravir 400 mg twice a day. In contrast to those with 
occupational exposures, some individuals may present very 
late after exposure. Because the likelihood of success 
declines with length of time from HIV exposure, treatment 
is not recommended after more than 72 hours after expo
-
sure. In addition, because the psychosocial issues involved 
with postexposure prophylaxis for sexual and drug use 
exposures are complex, it should be offered with prevention 
counseling. Counseling should focus on how to prevent 
future exposures. Individuals with ongoing risk for HIV 
infection should be considered candidates for PrEP . Clini
-
cians needing more information on postexposure prophy
-
laxis for occupational or nonoccupational exposures should 
contact the National Clinicians’ Post-exposure Prophylaxis 
Hotline (1-888-448-4911; http://nccc.ucsf.edu/clinician-
consultation/pep-post-exposure-prophylaxis/).
Centers for Disease Control and Prevention. Updated guidelines

Centers for Disease Control and Prevention. Updated guidelines 
for antiretroviral postexposure prophylaxis after sexual, 
injection drug use, or other nonoccupational exposure to 
HIV—United States, 2016. https://www.cdc.gov/hiv/pdf/
 
programresources/cdc-hiv-npep-guidelines.pdf
O’Donnell S et al. Missed opportunities for HIV prophylaxis 
among emergency department patients with occupational 
and nonoccupational body fluid exposures. Ann Emerg Med. 
2016 Sep;68(3):315–23. [PMID: 27112264]
5. Prevention of perinatal transmission of HIV—
Prevention of perinatal transmission of HIV begins by offering 
HIV counseling and testing to all women who are pregnant or 
considering pregnancy. HIV-infected women who are preg
-
nant should start antiretroviral treatment with at least three 
medications. Recommended regimens are zidovudine and 
lamivudine with either ritonavir-boosted lopinavir or ritona
-
vir-boosted atazanavir. Cesarean delivery should be planned if 
HIV viral load is greater than 1000 copies near the time of 
delivery. Zidovudine should be given to the infant after birth 
for 6 weeks. When possible, breastfeeding should be avoided.
Heffron R et al. PrEP as peri-conception HIV prevention for 
women and men. Curr HIV/AIDS Rep. 2016 Jun;13(3):131–9. 
[PMID: 26993627]
Seidman DL et al. Offering pre-exposure prophylaxis for HIV 
prevention to pregnant and postpartum women: a clinical 
approach. J Int AIDS Soc. 2017 Mar 8;20(Suppl 1):24–30. 
[PMID: 28361503]
6. Prevention of HIV transmission in health care 
settings
—
In health care settings, universal body fluid pre
-
cautions should be used, including use of gloves when han
-
dling body fluids and the addition of gown, mask, and goggles 
for procedures that may result in splash or droplet spread, and 
use of specially designed needles with sheath devices to 
decrease the risk of needle sticks. Because transmission of 
tuberculosis may occur in health care settings, all patients 
with cough should be encouraged to wear masks. Hospitalized 
HIV-infected patients with cough should be placed in respira
-
tory isolation until tuberculosis can be excluded by chest 
radiograph and sputum smear examination.
Epidemiologic studies show that needle sticks occur com
-
monly among health care professionals, especially among 
surgeons performing invasive procedures, inexperienced hos
-
pital housestaff, and medical students. Efforts to reduce nee
-
dle sticks should focus on avoiding recapping needles and use 
of safety needles whenever doing invasive procedures under 
controlled circumstances. The risk of HIV transmission from 
a needle stick with blood from an HIV-infected patient is 
about 1:300. The risk is higher with deep punctures, large 
inoculum, and source patients with high viral loads. The risk 
from mucous membrane contact is too low to quantitate.
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Health care professionals who sustain needle sticks should 
be counseled and offered HIV testing as soon as possible. HIV 
testing is done to establish a negative baseline for worker’s 
compensation claims in case there is a subsequent conversion. 
Follow-up testing is usually performed at 6 weeks, 3 months, 
and 6 months. With the patient’s permission, their blood can 
be tested for HIV antibody and HIV viral load.
A case-control study by the CDC indicates that admin
-
istration of zidovudine following a needle stick decreases 
the rate of HIV seroconversion by 79%. Therefore, provid
-
ers should be offered antiretroviral treatment as soon as 
possible after exposure and continued for 4 weeks. The 
preferred regimen is TDF 300 mg with emtricitabine 
200 mg (Truvada) daily with raltegravir 400 mg twice a day. 
Providers who have exposures to persons who are likely to 
have antiretroviral medication resistance (eg, persons 
receiving therapy who have detectable viral loads) should 
have their therapy individualized, using at least two medi
-
cations to which the source is unlikely to be resistant. 
Because reports have noted hepatotoxicity due to nevirap
-
ine in this setting, this agent should be avoided. Unfortu
-
nately, there have been documented cases of seroconversion 
following potential parenteral exposure to HIV despite 
prompt use of zidovudine prophylaxis. Counseling of the 
provider should include “safer sex” guidelines.
7. Prevention of transmission of HIV through blood or 
blood products—
Current efforts in the United States to 
screen blood and blood products have lowered the risk of 
HIV transmission with transfusion of a unit of blood to 
1:1,000,000. Use of blood and blood products should be 
judicious, with patients receiving the least amount neces
-
sary, and patients should be encouraged to donate their 
own blood prior to elective procedures.
8. HIV vaccine—
Primate model data have suggested that 
development of a protective vaccine may be possible, but 
clinical trials in humans have been disappointing. Only one 
vaccine trial has shown any degree of efficacy. In this ran
-
domized, double-blind, placebo-controlled trial, a recombi
-
nant canarypox vector vaccine plus two booster injections of 
a recombinant gp120 vaccine was moderately efficacious 
(26–31%) in reducing the risk of HIV among a primarily 
heterosexual population in Thailand. Vaccine development 
efforts are aimed at identifying broadly neutralizing antibod
-
ies to the highly conserved regions of the HIV envelope.
Centers for Disease Control and Prevention. HIV/AIDS Pre-
Exposure Prophylaxis (PrEP), May 15, 2018. https://www.cdc.
gov/hiv/risk/prep/index.html
Cohen MS et al; HPTN 052 Study Team. Antiretroviral therapy 
for the prevention of HIV-1 transmission. N Engl J Med. 2016 
Sep 1;375(9):830–9. [PMID: 27424812]
Fauci AS. Viewpoint: An HIV vaccine is essential for ending the 
HIV/AIDS pandemic. JAMA. 2017 Oct 24;318(16):1535–6. 
[PMID: 29052689]
-
HIV Clinical Guidelines Program, Johns Hopkins School of 
Medicine, Division of Infectious Diseases. Adult HIV , 
Adolescent HIV , PEP , PrEP , Pregnancy, other topics. https://
www.hivguidelines.org/
Lyon J. Hunt for an HIV vaccine intensifies. JAMA. 2017 Jun 27; 
317(24):2475. [PMID: 28654994]
-
In the era prior to the development of effective antiretroviral 
treatment, cohort studies of individuals with documented 
dates of seroconversion demonstrate that AIDS developed 
within 10 years in approximately 50% of untreated seroposi
-

-
tive persons. With currently available treatment, progression 
of disease has been markedly decreased. In addition to anti
-
retroviral treatment, prophylactic regimens can prevent 
opportunistic infections and improve survival. Prophylaxis 
and early intervention prevent several infectious diseases, 
including tuberculosis and syphilis, which are transmissible 
to others. Recommendations for screening tests, vaccina
-
tions, and prophylaxis are listed in Table 31–5.
1. Tuberculosis—
Because of the increased occurrence of 
tuberculosis among HIV-infected patients, all such individuals 
should undergo an intradermal 
PPD test
 or an 
interferon-
gamma release assay (IGRA)
 blood test at baseline and yearly 
thereafter if they remain at risk of exposure (eg, incarcerated, 
living in congregate settings). Those with a positive PPD 
(defined for HIV-infected patients as greater than 5 mm of 
induration) or a positive IGRA assay (results that are reported 
as positive and not negative or indeterminate) should be clini
-
cally evaluated for active tuberculosis, including by a chest 
radiograph. Patients with an infiltrate in any location, espe
-
cially if accompanied by mediastinal adenopathy, should have 
sputum sent for acid-fast staining. 
Patients with active tubercu
-
losis should be treated as outlined in Chapter 9 (see Tables 9-14 
and 9-15).
 Patients with a positive PPD or IGRA assay, a nor
-
mal chest radiograph, or negative sputum sample for active 
tuberculosis infection are classified as having latent tuberculo
-
sis infection. Patients with latent tuberculosis infection who 
have not been previously treated for (active or latent) tubercu
-
losis should receive isoniazid (300 mg orally daily or twice 
weekly) with pyridoxine (50 mg orally daily) for 9 months. In 
patients with advanced immunodeficiency, both the PPD and 
IGRA assay are more likely to be falsely negative or (for IGRA 
assay) indeterminant. Therefore, it may be worth retesting 
patients with initially low CD4 counts once they have received 
antiretroviral treatment and have immune reconstitution 
(CD4 count greater than or equal to 200 cells/mcL).
Jacobson KR. Tuberculosis. Ann Intern Med. 2017 Feb 7;
 
166(3):ITC17–32. [PMID: 28166561]
2. Syphilis—
Because of the increased number of cases of 
syphilis among MSM, including those who are HIV-infected, 
all such men should be screened for syphilis by a rapid plasma 
reagin (RPR) or Venereal Disease Research Laboratories 
(VDRL) test every 6 months. Increases of syphilis cases among 
HIV-infected persons are of particular concern because these 
individuals are at increased risk for reactivation of syphilis and 
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progression to tertiary syphilis despite standard treatment. 
Because the only widely available tests for syphilis are serologic 
and because HIV-infected individuals are known to have dis
-
ordered antibody production, there is concern about the 
interpretation of these titers. This concern has been fueled by 
a report of an HIV-infected patient with secondary syphilis 
and negative syphilis serologic testing. Furthermore, HIV-
infected individuals may lose fluorescent treponemal antibody 
absorption (FTA-ABS) reactivity after treatment for syphilis, 
particularly if they have low CD4 counts. Thus, in this popula
-
tion, a nonreactive treponemal test does not rule out a past 
history of syphilis. In addition, persistence of treponemes in 
the spinal fluid after one dose of benzathine penicillin has 
been demonstrated in HIV-infected patients with primary and 
secondary syphilis. Therefore, the CDC has recommended an 
aggressive diagnostic approach to HIV-infected patients with 
reactive RPR or VDRL tests of longer than 1 year (or unknown) 
duration. All such patients should have a lumbar puncture 
with cerebrospinal fluid cell count and cerebrospinal fluid 
VDRL. Those with a normal cerebrospinal fluid evaluation are 
treated as having late latent syphilis (benzathine penicillin G, 
2.4 million units intramuscularly weekly for 3 weeks) with 
follow-up titers. Those with a pleocytosis or a positive cerebro
-
spinal fluid-VDRL test are treated as having neurosyphilis 
(aqueous penicillin G, 2–4 million units intravenously every 4 
hours, or procaine penicillin G, 2.4 million units intramuscu
-
larly daily, with probenecid, 500 mg four times daily, for 10 
days) followed by weekly benzanthine penicillin G 2.4 million 
units intramuscularly for 3 weeks. Some clinicians take a less 
aggressive approach to patients who have low titers (less than 
1:8), a history of having been treated for syphilis, and a normal 
neurologic examination. Close follow-up of titers is manda
-
tory if such a course is taken. For a more detailed discussion of 
this topic, see Chapter 34.
Cantor AG et al. Screening for syphilis: updated evidence report 
and systematic review for the U.S. Preventive Services Task 
Force. JAMA. 2016 Jun 7;315(21):2328–37. [PMID: 27272584]
Hook EW 3rd. Syphilis. Lancet. 2017 Apr 15;389(10078):1550–7. 
[PMID: 27993382]
U.S. Preventive Services Task Force (USPSTF), Bibbins-Domingo 
K et al. Screening for syphilis infection in nonpregnant adults 
and adolescents: U.S. Preventive Services Task Force Recom
-
mendation Statement. JAMA. 2016 Jun 7;315(21):2321–7. 
[PMID: 27272583]
Table 31–5.
 
Health care maintenance and monitoring of HIV-infected individuals.
For all HIV-infected individuals:
CD4 counts every 3–6 months (can decrease to every 12 months if viral load suppressed on antiretroviral treatment for 2 years and CD4 
count greater than 300 cells/mcL)
Viral load tests every 3–6 months and 1 month following a change in therapy
Genotypic resistance testing at baseline and if viral load not fully suppressed and patient taking antiretroviral treatment
Complete blood count, chemistry profile, transaminases and total bilirubin, at baseline and every 3–6 months
Urinalysis at baseline and annually during antiretroviral treatment (every 6 months if antiretroviral treatment regimen includes TDF)
Fasting glucose or hemoglobin A
1c
 at baseline and annually during antiretroviral treatment
Fasting lipid panel at baseline, 4–8 weeks after starting or changing an antiretroviral treatment regimen that affects lipids, and annually 
for everyone over 40 years of age
PPD or interferon-gamma release assay (IGRA) at baseline and annually if at high risk for exposure to persons with active TB
INH for those with positive PPD or IGRA, normal chest radiograph, and no history of treatment for active or latent TB
RPR or VDRL at entry and periodically based on sexual activity
Toxoplasma IgG serology at baseline

Hepatitis serologies: hepatitis A antibody, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, 
 
hepatitis C antibody
Pneumococcal vaccine
Meningococcal vaccine Herpes zoster vaccine*
Inactivated influenza vaccine annually in season
Hepatitis A vaccine for those without immunity to hepatitis A
Hepatitis B vaccine for those who are hepatitis B surface antigen and antibody negative. (Use 40 mcg formulation at 0, 1, and 6 months; 
repeat if no immunity 1 month after three-vaccine series.)
Combined tetanus, diphtheria, pertussis vaccine
Human papillomavirus vaccine for HIV-infected women age 26 years or less
Bone mineral density monitoring for postmenopausal women and men 50 years of age or older
Papanicolaou smears annually; if three smears are negative, can switch to longer intervals (see Complications, Section M. Gynecologic 
Manifestations)
Consider anal swabs for cytologic evaluation
For HIV-infected individuals with CD4 less than 200 cells/mcL:
 prophylaxis (see Treatment, Section B. Prophylactic Treatment of Complications of HIV Infection)
For HIV-infected individuals with CD4 less than 75 cells/mcL:
 complex prophylaxis (see Treatment, Section A. Complications of HIV Infection)
For HIV-infected individuals with CD4 less than 50 cells/mcL:
Consider CMV prophylaxis
*Consider in patients age > 50 years with history of varicella immunity and T cells > 200 cells/mcL  BUN, blood urea nitrogen; CMV, cyto
-
megalovirus; IgG, immunoglobulin G; IGRA, interferon gamma release assay; INH, isoniazid; PPD, purified protein derivative; RPR, rapid 
plasma reagin; TB, tuberculosis; TDF, tenofovir diproxil fumarate; VDRL, Venereal Disease Research Laboratories.
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3. Immunizations—
HIV-infected individuals should 
receive immunizations as outlined in Table 31–5. Patients 
without evidence of hepatitis B surface antigen or surface 
antibody should receive hepatitis B vaccination, using the 
40-mcg formulation; the higher dose is to increase the 
chance of developing protective immunity. If the patient 
does not have immunity 1 month after the three-shot series, 
then the series should be repeated. HIV-infected persons 
should also receive the standard inactivated vaccines such as 
tetanus and diphtheria boosters that would be given to unin
-
fected persons. Most live vaccines, such as yellow fever vac
-
cine, should be avoided. Measles vaccination, while a live 
virus vaccine, appears relatively safe when administered to 
HIV-infected individuals and should be given if the patient 
has never had measles or been adequately vaccinated. The 
new recombinant adjuvanted herpes zoster vaccine (Shin
-
grix), two doses 
2-6 months
 apart, has been found to be 
reasonably safe for HIV-infected persons with CD4 counts 
greater than 200 cells/mL and undetectable viral loads even 
though it is a live vaccine. Even though, it is not known if it 
is efficacious in preventing herpes zoster in this population, 
it should nonetheless be given to individuals who received 
the older, much less efficacious zoster vaccine (Zostavax).
4. Other measures—
A randomized study found that mul
-
tivitamin supplementation decreased HIV disease progres
-
sion and mortality in HIV-infected women in Africa. 
However, supplementation is unlikely to be as effective in 
well-nourished populations.
HIV-infected individuals should be counseled with regard 
to the importance of practicing safer sex even with other HIV-
infected persons because of the possibility of contracting a 
sexually transmitted disease, such as gonorrhea or syphilis. 
There is also the possibility of transmission of a particularly 
virulent or a drug-resistant strain between HIV-infected per
-
sons. Substance abuse treatment should be recommended for 
persons who are using recreational drugs. They should be 
warned to avoid consuming raw meat, eggs, or shellfish to 
avoid infections with 
Toxoplasma, Campylobacter
, and 
Salmo
-
nella
. HIV-infected patients should wash their hands thor
-
oughly after cleaning cat litter or should forgo this household 
chore to avoid possible exposure to toxoplasmosis. To reduce 
the likelihood of infection with 
 species, patients 
should avoid activities that might result in cat scratches or 
bites. Although the data are not conclusive, many clinicians 
recommend that HIV-infected persons—especially those 
with low CD4 counts—drink bottled water instead of tap 
water to prevent cryptosporidia infection.
Because of the emotional impact of HIV infection and 
subsequent illness, many patients will benefit from sup
-
portive counseling.
 
»
Treatment
Treatment for HIV infection can be broadly divided into 
the following categories: (1) prophylaxis for opportunistic 
infections, malignancies, and other complications of HIV 
infection; (2) treatment of opportunistic infections, malig
-
nancies, and other complications of HIV infection; and 
 
(3) treatment of the HIV infection itself with combination 
antiretroviral treatment.
A. Prophylaxis for Complications of HIV Infection
In general, decisions about prophylaxis of opportunistic 
infections are based on the CD4 count, recent HIV viral 
load, and a history of having had the infection in the past. 
In the era prior to antiretroviral treatment, patients who 
started taking prophylactic regimens were maintained on 
them indefinitely. However, studies have shown that in 
patients with robust improvements in immune function—
as measured by increases in CD4 counts above the levels 
that are used to initiate treatment—prophylactic regimens 
can safely be discontinued.
Because individuals with advanced HIV infection are

Because individuals with advanced HIV infection are 
susceptible to a number of opportunistic pathogens, the 
use of agents with activity against more than one pathogen 
is preferable.
1. Prophylaxis against 
Patients with CD4 counts below 200 cells/mcL, a CD4 
lymphocyte percentage below 14%, or weight loss or oral 
candidiasis should be offered primary prophylaxis for 
 pneumonia. Patients with a history of 
 pneumonia should receive secondary prophy
-
laxis until their viral load is undetectable and they have main
-
tained a CD4 count of 200 cells/mcL or more while receiving 
antiretroviral treatment for longer than 3 months. Regimens 
for 
 prophylaxis are given in Table 31–6.
2. Prophylaxis against 
M avium
 complex infection—
Patients whose CD4 counts fall to below 75–100 cells/mcL 
should be given prophylaxis against 
M avium
 complex 
infection. Clarithromycin (500 mg orally twice daily) and 
azithromycin (1200 mg orally weekly) have both been 
shown to decrease the incidence of disseminated 
M avium
 
complex infection by approximately 75%, with a low rate of 
breakthrough of resistant disease. The azithromycin regi
-
men is generally preferred based on high compliance and 
low cost. Prophylaxis against 
M avium
 complex infection 
may be discontinued in patients whose CD4 counts rise 
above 100 cells/mcL in response to antiretroviral treatment 
for longer than 3 months.
3. Prophylaxis against toxoplasmosis—
Toxoplasmosis 
prophylaxis is desirable in patients with a positive IgG 
toxoplasma serology and CD4 counts below 100 cells/mcL. 
Trimethoprim-sulfamethoxazole (one double-strength 
tablet daily) offers good protection against toxoplasmosis, 
as does a combination of pyrimethamine, 25 mg orally 
once a week, plus dapsone, 50 mg orally daily, plus leucovo
-
rin, 25 mg orally once a week. A glucose-6-phosphate 
dehydrogenase (G6PD) level should be checked prior to 
dapsone therapy, and a methemoglobin level should be 
checked at 1 month. Prophylaxis can be discontinued when 
the CD4 cells have increased to greater than 200 cells/mcL 
for more than 3 months.
B. Treatment of Complications of HIV Infection
Treatment of common AIDS-related complications is 
detailed above and in Table 31–3. In the era prior to the use 
of antiretroviral treatment, patients required lifelong treat
-
ment for many infections, including CMV retinitis, 
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toxoplasmosis, and cryptococcal meningitis. However, 
among patients who have a good response to antiretroviral 
treatment, maintenance therapy for some opportunistic 
infections can be terminated. For example, in consultation 
with an ophthalmologist, maintenance treatment for CMV 
infection can be discontinued when persons receiving anti
-
retroviral treatment have had a sustained increase in CD4 
count to greater than 100 cells/mcL for at least 3–6 months. 
Similar results have been observed in patients with 
 
M avium
 complex bacteremia, who have completed a year or 
more of therapy for 
M avium
 complex and have an increase 
in their CD4 count to 100 cells/mcL for greater than 6 
months while receiving antiretroviral treatment. Cessation 
of secondary prophylaxis for 
 pneumonia is 
described above.
Treating patients with repeated episodes of the same 
opportunistic infection can pose difficult therapeutic chal
-
lenges. For example, patients with second or third episodes 
of 
 pneumonia may have developed allergic 
reactions to standard treatments with a prior episode. For
-
tunately, there are several alternatives available for the 
 infection. Trimethoprim with 
dapsone and primaquine with clindamycin are two combi
-
nations that often are tolerated in patients with a prior 
allergic reaction to trimethoprim-sulfamethoxazole and 
intravenous pentamidine. Patients in whom second epi
-
sodes of 
 pneumonia develop while taking 
prophylaxis tend to have milder courses.
Adjunctive Treatments—
Epoetin alfa (erythropoietin)
 is 
approved for use in HIV-infected patients with anemia, 
including those with anemia secondary to zidovudine use. 
As zidovudine is rarely used now, especially at high doses, 
the use of epoetin alfa has also decreased. An erythropoi
-
etin level less than 500 milli-units/mL should be demon
-
strated before starting therapy. The starting dose of epoetin 
alfa is 8000 units subcutaneously three times a week. 
Hypertension is the most common side effect.
Human G-CSF (filgrastim) and granulocyte-macrophage 
colony-stimulating factor (GM-CSF [sargramostim]) have 
been shown to increase the neutrophil counts of 
Table 31–6.
 
 prophylaxis, in order of preference.
Dose
Limitations
Trimethoprim-
 
sulfamethoxazole
One double-strength tablet three 
times a week to one tablet daily
Rash, neutropenia, hepatitis, 
 
Stevens-Johnson syndrome
Hypersensitivity reaction is common but, if 
mild, it may be possible to treat through.
Dapsone
50–100 mg orally daily or 100 mg 
two or three times per week
Anemia, nausea, methemoglo
-
binemia, hemolytic anemia
Less effective than above. Glucose-6-
 
phosphate dehydrogenase (G6PD) level 
should be checked prior to therapy. 
Check methemoglobin level after 
 
1 month of treatment.
Atovaquone
1500 mg orally daily with a meal
Rash, diarrhea, nausea
Less effective than suspension 
trimethoprim-sulfamethoxazole; equal 
efficacy to dapsone, but more expensive.
Aerosolized 
pentamidine
300 mg monthly
Bronchospasm (pretreat with 
bronchodilators); rare reports 
of pancreatitis
Apical 
extrapulmonary 
 infections, 
HIV-infected patients. Because of the high cost of this 
therapy, the dosage should be closely monitored and mini
-
mized, aiming for a neutrophil count of 1000/mcL. When 
the medication is used for indications other than cytotoxic 
chemotherapy, one or two doses at 5 mcg/kg per week 
subcutaneously are usually sufficient.
C. Antiretroviral Therapy
The availability of agents that in combination suppress 
HIV replication (Table 31–7) has had a profound impact 
on the natural history of HIV infection. Indeed, with the 
advent of effective antiretroviral treatment, the life expec
-
tancy of HIV-infected persons approaches that of unin
-

-
-
fected persons when treatment is initiated early in the 
course of the disease and maintained.
The recognition that HIV damages the immune system 
from the beginning of infection, even when the damage is not 
easily measured by conventional tests, combined with the 
greater potency, the improved side-effect profile, and the 
decreased pill burden of modern HIV regimens, have led to 
the recommendation to start treatment for all HIV-infected 
persons regardless of CD4 count. The START trial demon
-
strated that immediate treatment is associated with a greater 
than 50% reduction in risk for serious illness or death, com
-
pared to delaying treatment until the CD4 count falls below 
350 cells/mcL. Because 5–20% of patients in developed coun
-
tries who are treatment-naïve have a virus that is resistant to 
some medications, resistance testing is recommended for all 
patients prior to initiating antiretroviral treatment.
Once a decision to initiate therapy has been made, sev
-
eral important principles should guide therapy. First, 
because medication resistance to antiretroviral agents 
develops in HIV-infected patients, a primary goal of ther
-
apy should be complete suppression of viral replication as 
measured by the serum viral load. Therapy that achieves 
undetectable viral load has been shown to provide a dura
-
ble response to the therapy. To achieve this and maintain 
virologic control over time, combination therapy with at 
least three medications from at least two different classes is 
necessary. Partially suppressive combinations such as dual 
CMDT19_Ch31_p1338-p1376.indd   1362

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CMDT 2019
Table 31–7.
 
Antiretroviral therapy agents by class (alphabetical order within class).
Dose
Common Side 
Effects
Special 
1
Cost
2
Cost/Month
Nucleoside 
r
everse Transcriptase Inhibitors (N
r
TIs)
Abacavir (Ziagen)
300 mg orally twice daily
Rash, fever—if occur, 
rechallenge may 
be fatal
No special 
$9.64/300 mg
$578.56
Didanosine (ddI) 
(Videx)
400 mg orally daily (enteric-
coated capsule) for persons 
greater or equal to 60 kg
250 mg orally daily (enteric-
coated capsule) for 
 
persons 30–59 kg
Peripheral neuropa
-
thy, pancreatitis, 
dry mouth, 
hepatitis
Bimonthly neurologic 
questionnaire for 
neuropathy, potas
-
sium, amylase, bili
-
rubin, triglycerides
$12.29/400 mg
$368.72
Emtricitabine 
(Emtriva)
200 mg orally once daily
Skin discoloration 
palms/soles (mild)
No special 
$21.46/200 mg
$643.82
Lamivudine (3TC) 
(Epivir)
150 mg orally twice daily or 
300 mg daily
Rash, peripheral 
No special 
$7.16/150 mg
$429.60
Stavudine (d4T) 
(Zerit)
40 mg orally twice daily for 
persons ≥ 60 kg
30 mg orally twice daily for 
persons < 60 kg
Peripheral 
 
neuropathy, 
 
hepatitis, 
Monthly neurologic 
amylase
$6.85/40 mg
$410.70
Zidovudine (AZT) 
(Retrovir)
600 mg orally daily in two 
divided doses
Anemia, neutropenia, 
nausea, malaise, 
headache, insom
-
nia, myopathy
CBC with differential 
4–8 weeks after 
starting AZT
$0.90/300 mg
$54.00
Nucleotide 
r
r
TI)
Tenofovir alafen
-
amide (TAF)/
emtricitabine
 
(Descovy)
25 mg of TAF with 200 mg of 
 
emtricitabine once daily
Nephrotoxicity; 
 
hepatoxicity (if 
HBsAg positive, 
HBV exacerbation 
after discontinua
-
tion); bone 
resorption
Creatinine at base
-
line, at 2–8 weeks, 
every 3–6 months; 
urine analysis at 
baseline (if at renal 
risk), every 
 
6 months; HBsAg, 
liver enzymes at 
baseline at 
 
2–8 weeks, every 
3–6 months, 
 
continue for 
months after dis
-
continuation; con
-
sider bone 
densitometry 
$67.03/tablet
$2010.95
Tenofovir (TDF) 
(Viread)
Kidney dysfunction, 
bone resorption, 
distress
-
urinalysis at base
-
line (if at risk for 
kidney dysfunc
-
tion), every 
 
6 months; consider 
bone densitometry 
$3.65/300 mg
$109.50
Nonnucleoside 
r
everse Transcriptase Inhibitors (NN
r
TIs)
Delavirdine 
(Rescriptor)
400 mg orally three times 
daily
Rash
No special 
$2.97/200 mg
$533.89
Efavirenz (Sustiva)
600 mg orally daily
 
disturbances, rash
No special 
$37.26/600 mg
$1117.80
(
continued
)
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 CMDT 2019
 
Antiretroviral therapy agents by class (alphabetical order within class). (continued)
Dose
Effects
Special 
1
Cost
2
Etravirine (Intelence)
200 mg orally twice daily
No special 
$12.69/100 mg
$1522.94
Nevirapine 
(Viramune)
200 mg orally daily for 
 
2 weeks, then 200 mg orally 
Rash
No special 
$10.83/200 mg
$649.80
Rilpivirine (Edurant)
25 mg daily
Depression, rash
No special 
$41.73/25 mg
$1251.76
Protease Inhibitors (PIs)
Atazanavir (Reyataz)
400 mg orally once daily or
300 mg atazanavir with 
100 mg ritonavir daily
Bilirubin level every 
3–4 months
$26.34/200 mg 
or $43.91/
 
300 mg
$1580.32 (plus 
cost of ritonavir) 
$1317.30 (plus cost 
of ritonavir)
Atazanavir/cobicistat 
(Evotaz)
300 mg of atazanavir with 
150 mg cobicistat orally 
once daily
3–4 months
$64.22/tablet
$1926.56
Darunavir/cobicistat 
(Prezcobix)
800 mg of darunavir and 
 
150 mg of cobicistat orally 
once daily
Rash
No special 
$72.27/tablet
$2167.96
Darunavir/ritonavir 
(Prezista/Norvir)
 
PI-experienced patients:
 
600 mg of darunavir and 
100 mg of ritonavir orally 
For PI-naïve patients:
 
daily
Rash
No special 
$31.61/600 mg 
(darunavir)
$9.26/100 mg 
(ritonavir)
$63.23/800 mg 
$2452.37 (for 
combination)
$2174.57 (for 
Fosamprenavir 
(Lexiva)
For PI-experienced patients:
 
700 mg orally twice daily 
and 100 mg of ritonavir 
orally twice daily
 
1400 mg orally twice daily 
or 1400 mg orally once 
daily and 200 mg of 
 
ritonavir orally once daily
Gastrointestinal, rash
No special 
$20.83/700 mg
$1249.86 2499.72 
(plus cost of 
ritonavir)
$2780.56/1400 
mg (plus cost 
Indinavir (Crixivan)
800 mg orally three times 
daily
Renal calculi
3–4 months
$3.05/400 mg
$548.12
Lopinavir/ritonavir 
(Kaletra)
400 mg/100 mg orally twice 
daily
Diarrhea
No special 
$10.24/200 mg 
(lopinavir)
$10.29/100 mg 
$1228.97 (plus 
cost of 
Nelfinavir (Viracept)
750 mg orally three times 
daily or 1250 mg twice daily
Diarrhea
No special 
$4.86/250 mg or
$12.14/625 mg
$1212.30
or $1349.64
$1456.80
Ritonavir (Norvir)
600 mg orally twice daily or in 
lower doses (eg, 100 mg 
orally once or twice daily) 
for boosting other PIs
Gastrointestinal dis
-
tress, peripheral 
paresthesias
No special 
$9.26/100 mg
$3333.60 
($555.60 in 
lower doses)
Saquinavir hard gel 
(Invirase)
1000 mg orally twice daily 
with 100 mg ritonavir orally 
distress
No special 
$12.02/500 mg
$1442.09 (plus 
cost of 
Tipranavir/ritonavir 
(Aptivus/Norvir)
500 mg of tipranavir and 
 
200 mg of ritonavir orally 
No special 
$15.78/250 mg 
(tipranavir)
$3005.14 (for 
(
continued
)
CMDT19_Ch31_p1338-p1376.indd   1364

1365
 
CMDT 2019
 
Dose
Effects
Special 
1
Cost
2
Entry Inhibitors
Enfuvirtide (Fuzeon)
90 mg subcutaneously twice 
daily
Injection site pain 
and allergic 
reaction
No special 
$71.71/90 mg
$4302.67
Maraviroc 
 
(Selzentry)
150 mg orally twice daily 
or 300 mg orally twice daily
Cough, fever, rash
No special 
$30.22/150 mg 
or $28.86/ 
300 mg
$1536.00
 
or $1731.60 
$1813.04
Integrase Inhibitors
Bictegravir
50 mg orally daily No longer 
marketed as a single agent; 
used in antiretroviral com
-
bination (Table 31–8)
Diarrhea, nausea, 
headache
No special 
 
Dolutegravir 
 
(Tivicay)
Treatment-naïve or integrase-
naïve patients: 50 mg daily.
When administered with efavi
-
renz, fosamprenavir/ritona
-
vir, tipranavir/ritonavir, or 
rifampin: 50 mg twice daily.
When administered to integrase-
experienced patients with 
suspected integrase resis
-
tance: 50 mg twice daily.
Hypersensitivity, 
insomnia, fatigue, 
headache, rash
No special 
$66.30/50 mg 
/50 mg daily 
or $122.86/50 
mg twice 
daily
$1989.13/50 mg 
daily or 
$3,685.80/50 
mg twice daily
Elvitegravir
No longer marketed as a 
 
single agent; used in 
 
antiretroviral combinations 
(Table 31–8)
Diarrhea, headache
No special 
 
Raltegravir 
 
(Isentress)
400 mg orally twice daily
headache
No special 
$30.00/400 mg
$1800.00
1
Standard monitoring is complete blood count (CBC) and differential, basic chemistries, serum aminotransferases and total bilirubin every 
3–6 months, urinalysis at baseline and annually during antiretroviral treatment, fasting glucose or hemoglobin A
1c
 at baseline and annually 
during antiretroviral treatment, fasting lipid profile at baseline, 4–8 weeks after starting an antiretroviral treatment regimen that affects 
lipids, and annually for everyone over 40 years of age.
2
Red Book
Analytics Information, http://www.micromedexsolutions.com/, accessed April 10, 2018. AWP may not accurately represent the actual 
nucleoside therapy should be avoided. Similarly, if toxicity 
develops, it is preferable to change the offending medica
-
tion rather than reduce individual doses. One exception to 
the “three drugs from at least two different classes” rule is 
use of the coformulation of dolutegravir and rilpivirine 
(Juluca); this combination is now FDA approved as an 
alternative treatment for patients who have been success
-
fully virally suppressed for at least 6 months, have no his
-
tory of treatment failure, and are not resistant to either of 
the two component agents.
The presence of an acute opportunistic infection in most 
cases does not preclude the initiation of antiretroviral treat
-
ment. Randomized trials compared early initiation of anti
-
retroviral treatment (within 2 weeks of starting treatment 
for an opportunistic infection or tuberculosis) with antiret
-
roviral treatment that was deferred until after treatment of 
the opportunistic infection was completed (6 weeks after its 
start); results demonstrated that early initiation reduced 
death or AIDS progression by 50%. The reduced progression 
rates were related to more rapid improvements in CD4 
counts in patients with advanced immunodeficiency. Fur
-
thermore, IRIS and other adverse events were no more fre
-
quent in the early antiretroviral treatment arm.
Several randomized studies have also demonstrated 
improved clinical outcomes in HIV/tuberculosis coin
-
fected patients who initiate antiretroviral treatment early in 
the setting of active treatment for tuberculosis and whose

-
the setting of active treatment for tuberculosis and whose 
CD4 counts are less than 50 cells/mcL. The exception to 
early antiretroviral treatment in the setting of active infec
-
tions may be in patients with a CNS-associated infection, 
such as cryptococcal or tuberculosis meningitis. Several 
studies from low-income countries have shown high mor
-
tality rates with early antiretroviral treatment initiation in 
For hospitalized patients, initiating treatment in patients 
with opportunistic infections requires close coordination 
between inpatient and outpatient clinicians to ensure that 
treatment is continued once patients are discharged.
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D. Choosing an Antiretroviral Treatment Regimen
Although the ideal combination of medications has not yet 
been defined for all possible clinical situations, optimal 
regimens can be better understood after a review of the 
available agents. These medications can be grouped into 
five major categories: nucleoside and nucleotide reverse 
transcriptase inhibitors (NRTIs); nonnucleoside reverse 
transcriptase inhibitors (NNRTIs); protease inhibitors (PI); 
entry inhibitors, which include a fusion inhibitor and 
CCR5 antagonists; and integrase inhibitors.
1. Nucleoside and nucleotide reverse transcriptase 
 (NRTI)—
There are currently eight NRTI agents 
available (counting TDF and TAF as separate agents) for 
use. The choice of which agent to use depends primarily on 
the patient’s prior treatment experience, results of resis
-
tance testing, medication side effects, other underlying 
conditions, and convenience of formulation. However, 
most clinicians use fixed-dose combinations (see 
Table 31–8) of either emtricitabine/TDF, emtricitabine/
TAF or abacavir/lamivudine (ABC/3TC), all of which can 
be given once a day. Abacavir should be given only to 
HLA-B*5701-negative persons. In patients with viral loads 
greater than 100,000 copies/mL, ABC/3TC was less effec
-
tive than emtricitabine/TDF when combined with efavi
-
renz or ritonavir-boosted atazanavir. However, ABC/3TC 
appears to be equally efficacious as emtricitabine/TDF in 
patients with viral loads greater than 100,000 copies/mL 
when combined with dolutegravir or raltegravir. In some 
studies, abacavir increased risks of myocardial infarction, 
and therefore should be avoided in patients at high risk for 
cardiovascular disease. Zidovudine/lamivudine (AZT/3TC) 
is usually reserved for second- or third-line regimens 
because of toxicity and dosing schedule. Of the available 
agents, zidovudine is the most likely to cause anemia. Zid
-
ovudine and didanosine are the most likely to cause neu
-
tropenia. Stavudine is the most likely to cause lipoatrophy 
(loss of fat in the face, extremities, and buttocks) followed 
by zidovudine. Didanosine is the most likely to cause 
peripheral neuropathy. Emtricitabine, TDF, TAF, and lami
-
vudine have activity against hepatitis B. Didanosine, 
emtricitabine, TDF, TAF, and lamivudine can be adminis
-
tered once daily. Information specific to each medication is 
given below and in Table 31–7.
a. Zidovudine—
Zidovudine was the first approved anti
-
viral medication for HIV infection. It is administered at a 
dose of 300 mg orally twice daily. A combination of zidovu
-
dine 300 mg and lamivudine 150 mg (Combivir) is avail
-
able. Approximately 40% of patients experience subjective 
side effects that usually remit within 6 weeks. The common 
dose-limiting side effects are anemia and neutropenia, 
which require ongoing laboratory monitoring. Long-term 
use has been associated with lipoatrophy.
b. Lamivudine—
Lamivudine (3TC) is a safe and well-
tolerated agent. The dosage is 150 mg orally twice daily or 
300 mg orally once a day. The dose should be reduced with 
chronic kidney disease. There are no significant side effects 
with lamivudine; it has activity against hepatitis B, though 
HBV resistance to it is an increasing problem.
c. Emtricitabine—
Emtricitabine is dosed at 200 mg 
orally once daily. Emtricitabine has activity against hepati
-
tis B. Its dosage should be reduced in patients with chronic 
d. Abacavir
—
Abacavir is dosed at 300 mg orally twice 
daily. Prior to initiation of abacavir, patients should 
undergo testing for HLA typing. Those with the B
*
5701 
allele should not be treated with abacavir because the likeli
-
hood of a hypersensitivity reaction developing is high; the 
reaction is characterized by a flu-like syndrome with rash 
and fever that worsens with successive doses. Unfortu
-
nately, the absence of this allele does not guarantee that the

-
nately, the absence of this allele does not guarantee that the 
patient will avoid the hypersensitivity reaction. Individuals 
in whom the hypersensitivity reaction develops 
should not
 
be rechallenged with this agent because subsequent hyper
-
sensitivity reactions can be fatal. Abacavir has also been 
associated with an increased risk of myocardial infarction 
in some cohort studies, generally in patients who have 
underlying risks for cardiovascular disease. Consequently, 
abacavir should not be used in such patients if effective 
alternative nucleoside or nucleotide analog agents exist. 
Abacavir is usually prescribed as a fixed-dose combination 
pill with lamivudine for use as a once-daily pill (Epzicom; 
Table 31–8).
Abacavir is also formulated with zidovudine and lami
-
vudine in a single pill (Trizivir, one tablet orally twice daily; 
Table 31–8). Trizivir is not recommended as solo treatment 
for HIV because it is not as efficacious as combining two 
nucleoside/nucleotide analogs with a ritonavir-boosted PI, 
an NNRTI, or an integrase inhibitor.
e. Tenofovir—
Tenofovir is the only licensed nucleotide 
analog. It comes in two forms: tenofovir disoproxil fuma
-
rate (TDF) and tenofovir alafenamide (TAF). TDF is avail
-
able for use both in the form of a single pill at an oral dose 
of 300 mg once daily and as an oral fixed-dose combination 
pill with emtricitabine 200 mg (Truvada; Table 31–8) once 
daily. Several other single-tablet once-a-day complete regi
-
mens include TDF (Atripla, Complera, Stribild) 
(Table 31–8). Tenofovir is active against hepatitis B, includ
-
ing isolates that have resistance to lamivudine. TDF is 
associated with a clinically modest loss of kidney function, 
a small increased risk of acute renal injury, and increased 
rate of bone resorption. It should not be used in patients at 
risk for kidney disease or without dose adjustment in those 
with creatinine clearance below 60 mL/min or in those 
with or at risk for osteopenia/osteoporosis. For these 
patients, TAF is the better choice.
TAF attains higher levels in cells with a much lower 
plasma level. For this reason, it appears to cause less harm 
to kidneys and less bone resorption. It is not available as a 
single agent but is available in a combination tablet with 
emtricitabine (Descovy, Table 31–8). Single-tablet once-a-
day regimens that include TAF (Genvoya and Odefsey) are 
also available (Table 31–8). TAF should not be used with 
rifamycins.
f. Didanosine
—
The most convenient formulation of 
didanosine (ddI) is the enteric-coated capsule. For adults 
weighing at least 60 kg, the dose is one 400-mg 
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Table 31–8.
 
Fixed-dose antiretroviral combinations (alphabetical order by brand name).
Name
Components
Dosing and Special Considerations
Atripla
TDF 300 mg
Emtricitabine 200 mg
Efavirenz 600 mg
One pill daily constitutes a complete antiretroviral treatment regimen.
$3268.88
Complera
TDF 300 mg
Rilpivirine 25 mg
One pill daily constitutes complete antiretroviral treatment regimen. Only for 
patients with HIV viral load less than 100,000/mL.
$3216.92
Descovy
TAF 25 mg
One pill daily with an NNRTI, protease inhibitor, integrase inhibitor, or maraviroc 
(entry inhibitor). The difference between Descovy and Truvada is that Descovy 
has a different form of tenofovir (TAF) that appears to be safer than tenofovir 
(TDF) because it has less effect on renal function and bone mineral density. 
Not approved for use as PrEP .
$2010.95
Epzicom
Abacavir 600 mg
Lamivudine 300 mg
(entry inhibitor).
$1550.05
Genvoya
TAF 10 mg
Elvitegravir 150 mg
Cobicistat 150 mg
One pill daily constitutes a complete antiretroviral treatment regimen. Although 
it contains four medications, one component (cobicistat) is a medication 
booster only. The only difference between Stribild and Genvoya is that 
Genvoya has a different form of tenofovir (TAF) that appears to be safer than 
tenofovir (TDF) with less effect on kidney function and bone mineral density.
$3534.78
Juluca
Dolutegravir 50 mg
One pill daily with a meal for patients who have been virologically suppressed 
(viral load < 50 copies) on a stable antiretroviral treatment regimen for 
 
6 months or more and no history of treatment failure or resistance to 
dolutegravir or rilpivirine.
$3094.80
Odefsey
TAF 25 mg
patients with no history of HIV viral load greater or equal to 100,000/mL or 
replacement of stable antiretroviral regimen in patients fully suppressed for 
more than 6 months, with no history of treatment failure, and with no known 
resistance to components of the drug combination.
$3216.92
Stribild
TDF 300 mg
One pill daily constitutes a complete antiretroviral treatment regimen. 
Although it contains four medications, one component (cobicistat) is a 
medication booster only.
$3707.99
Symtuza
TAF 10 mg
Darunavir 800 mg
Approved by the 
European Com
-
mission; not yet 
FDA approved or 
marketed in 
Triumeq
One pill constitutes a complete antiretroviral treatment regimen.
$3366.24
Trizivir
Abacavir 300 mg
Lamivudine 150 mg
Zidovudine 300 mg
One tablet twice daily with an NNRTI, protease inhibitor, integrase inhibitor, or 
maraviroc (entry inhibitor). Although it contains three medications it 
does not
 
constitute a complete antiretroviral treatment regimen.
$1931.64
Truvada
TDF 300 mg
(entry inhibitor). TDF is the most commonly used NRTI backbone.
$2010.95
NNRTI, non-nucleoside reverse transcriptase inhibitor (eg, delavirdine, efavirenz, etravirine, nevirapine, rilpivirine);
NRTI, nucleoside/nucleotide reverse transcriptase inhibitor (eg, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, 
zidovudine); PrEP , preexposure prophylaxis; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Red Book

Red Book
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enteric-coated capsule orally daily; for those 30–59 kg, the 
dose is one 250-mg enteric-coated capsule orally daily. 
Didanosine should be taken on an empty stomach.
Didanosine has been associated with pancreatitis. The 
incidence of pancreatitis with didanosine is 5–10%—of 
fatal pancreatitis, less than 0.4%. Patients with a history of 
pancreatitis, as well as those taking other medications asso
-
ciated with pancreatitis (including trimethoprim-
sulfamethoxazole and intravenous pentamidine) are at 
higher risk for this complication. Other common side 
effects with didanosine include a dose-related, reversible, 
painful peripheral neuropathy, which occurs in about 15% 
of patients, and dry mouth. Fulminant hepatic failure and 
electrolyte abnormalities, including hypokalemia, hypocal
-
cemia, and hypomagnesemia, have been reported in 
patients taking didanosine. Because of the side-effect pro
-
file, didanosine is rarely used today.
2. Nonnucleoside reverse transcriptase inhibitors—
NNRTIs inhibit reverse transcriptase at a site different 
from that of the nucleoside and nucleotide agents described 
above. The major advantage of NNRTIs is that three of 
them (efavirenz, rilpivirine, and nevirapine) have potencies 
comparable to that of PI (next section), at least for patients 
with viral loads under 100,000 copies/mL—with lower pill 
burden and fewer side effects. In particular, they do not 
appear to cause lipodystrophy; patients with cholesterol 
and triglyceride elevations who are switched from a PI to 
an NNRTI may have improvement in their lipids. The 
resistance patterns of NNRTIs are distinct from those of 
the PI, so their use still leaves open the option for future 
 
PI use.
NNRTIs can be used with PI in patients who are diffi
-
cult to suppress on simpler regimens or when it is difficult 
to identify at least two NRTI agents to which the patient is 
not resistant. Because these agents may cause alterations in 
the clearance of PIs, dose modifications may be necessary 
when these two classes of medications are administered 
concomitantly. There is a high degree of cross-resistance 
among the “first-generation” NNRTIs, such that resistance 
to one medication in this class uniformly predicts resis
-
tance to other medications. However, the “second-
generation” NNRTI etravirine appears to have consistent 
antiviral activity in patients with prior exposure and resis
-
tance to nevirapine, efavirenz, or delavirdine. In particular, 
the K103N mutation does not appear to have an impact on 
etravirine (or rilpivirine). There is no therapeutic reason 
for using more than one NNRTI at the same time.
a. Efavirenz—
The major advantages of efavirenz is that 
it can be given once daily in a single dose (600 mg orally), 
and it is available in a once-daily fixed-dose combination 
with TDF and emtricitabine in a single pill (Atripla; 
Table 31–8). The major side effects are rash and psychiat
-
ric/neurologic complaints, with patients reporting symp
-
toms ranging from lack of concentration and strange 
dreams to delusions and mania. These side effects tend to 
wane over time, usually within a month or so; however, 
there are some patients who cannot tolerate these effects, 
especially if they persist longer than a month. Participant 
level data from four randomized trials of efavirenz 
regimens versus non-efavirenz containing regimens found 
increased suicidality (hazard ratio of 2.6) among those tak
-
ing efavirenz. Administration of efavirenz with food, espe
-
cially fatty food, may increase its serum levels and 
consequent neurotoxicity. Therefore, it should be taken on 
an empty stomach; taking before bedtime may also reduce 
patients’ experience of neuropsychiatric symptoms.
b. Rilpivirine—
This medication, dosed at 25 mg once 
daily, is equal in efficacy to efavirenz in patients with HIV 
viral loads below 100,000 copies/mL. Rilpivirine should

viral loads below 100,000 copies/mL. Rilpivirine should 
not be used in patients with baseline viral loads of 
100,000 copies/mL or greater or those with CD4 counts 
below 200 cells/mcL because of greater risk of viral failure. 
As is true of efavirenz, rilpivirine is available in a once-
daily fixed-dose combination with TDF and emtricitabine 
(Complera; Table 31–8) and with TAF and emtricitabine 
(Odefsey; Table 31–8) to be taken with a meal. It is also 
available in a two-drug regimen with dolutegravir (Juluca, 
Table 31–8). Proton pump inhibitors should not be given 
with rilpivirine. Rilpivirine has fewer neurologic side 
effects than efavirenz.
c. Nevirapine—
The dose of nevirapine is 400 mg orally 
daily (extended release), but it is initiated at a dose of 
200 mg once a day to decrease the incidence of rash, which 
is as high as 40% when full doses are begun immediately. If 
rash develops while the patient is taking 200 mg daily, liver 
enzymes should be checked and the dose should not be 
increased until the rash resolves. Patients with mild rash 
and no evidence of hepatotoxicity can continue to be 
treated with nevirapine. Nevirapine should not be used in 
treatment-naïve women with CD4 counts greater than 
250 cells/mcL or in males with CD4 counts greater than 
400 cells/mcL because they have greater risk of hepatotox
-
icity. In general, because of the risk of fatal hepatotoxicity, 
nevirapine should be used only when there is not a better 
d. Delavirdine—
Of the available NNRTIs, delavirdine is 
used the least largely because of its inconvenient dosing 
and pill burden compared with the other available NNRTIs. 
Unlike nevirapine and efavirenz, delavirdine inhibits P450 
cytochromes rather than inducing these enzymes. This 
means that delavirdine can act like ritonavir and boost 
other antiretrovirals, although delavirdine is not as potent 
as ritonavir in this capacity. The dosage is 400 mg orally 
three times a day. The major side effect is rash.
e. Etravirine—
Etravirine is an NNRTI approved for the 
treatment of patients with prior NNRTI intolerance or 
resistance. Etravirine has been shown to be effective even 
when some degree of NNRTI resistance is present, making 
it a true “second-generation” medication in this class. Etra
-
virine dosage is one 200-mg tablet twice daily. It should be 
used with a PI and an NRTI and not just with two NRTIs. 
The most common side effects are nausea and rash; rarely, 
the rash can be severe (toxic epidermal necrolysis). Patients 
with signs of severe rash or hypersensitivity reactions 
should immediately discontinue the medication. Prior rash 
due to treatment with one of the other NNRTIs does not 
make rash more likely with etravirine. Etravirine should 
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not be taken by people with severe liver disease or admin
-
istered with tipranavir/ritonavir, fosamprenavir/ritonavir, 
atazanavir/ritonavir, full-dose ritonavir, or PI without low-
dose ritonavir.
3. Protease inhibitors—
Ten PIs—indinavir, nelfinavir, 
ritonavir, saquinavir, amprenavir, fosamprenavir, lopinavir 
(in combination with ritonavir), atazanavir, darunavir, and 
tipranavir—are available. PIs are potent suppressors of HIV 
replication and are administered as part of a combination 
regimen.
All of the PIs—to differing degrees—are metabolized by 
the cytochrome P450 system, and each can inhibit and 
induce various P450 isoenzymes. Therefore, medication 
interactions are common and difficult to predict. Clinicians 
should consult the product inserts before prescribing PIs 
with other medications. Medications such as rifampin that 
are known to induce the P450 system should be avoided.
The fact that the PIs are dependent on metabolism 
through the cytochrome P450 system has led to the use of 
ritonavir to boost the medication levels of saquinavir, lopi
-
navir, indinavir, atazanavir, tipranavir, darunavir and 
amprenavir, allowing use of lower doses and simpler dos
-
ing schedules of these PIs. A second boosting agent, cobi
-
cistat, is coformulated with the PI atazanavir (Evotaz) and 
darunavir (Prescobix). Similar to ritonavir, cobicistat also 
inhibits liver enzymes that metabolize other HIV 
In fact, guidelines recommend that all PI-containing 
regimens except nelfinavir use boosting if possible.
When choosing which PI to use, prior patient experi
-
ence, resistance patterns, side effects, and ease of adminis
-
tration are the major considerations. The first three PIs to 
be developed—indinavir, saquinavir, and ritonavir (as 
single agents)—are now rarely used because of the superi
-
ority of the second generation of PIs. Amprenavir has been 
almost entirely replaced by its prodrug, fosamprenavir. 
Unfortunately, all PIs, with the exception of unboosted 
atazanavir have been linked to a constellation of metabolic 
abnormalities, including elevated cholesterol levels, ele
-
vated triglyceride levels, insulin resistance, diabetes melli
-
tus, and changes in body fat composition (eg, buffalo 
hump, abdominal obesity). The lipid abnormalities and 
body habitus changes are referred to as 
lipodystrophy.
 
Although lipodystrophy is commonly associated with PIs, 
it has been seen also in HIV-infected persons who have 
never been treated with these agents. In particular, the 
lipoatrophy effects seen in patients receiving antiretroviral 
treatment appears to be more related to the nucleoside 
toxicity and in particular to the thymidine analogs (stavu
-
dine and zidovudine).
Of the different manifestations of lipodystrophy, the 
dyslipidemias that occur are of particular concern because 
of the likelihood that increased levels of cholesterol and 
triglycerides will result in increased prevalence of heart 
disease. All patients taking PIs or NRTIs should have fast
-
ing serum cholesterol, low-density lipoprotein (LDL) cho
-
lesterol, and triglyceride levels performed every 12 months. 
Clinicians should assess for coronary heart disease risk (see 
Chapter 28) and consider initiating dietary changes or 
medication therapy (or both). PIs inhibit statin metabo
-
lism. Lovastatin and simvastatin should be avoided. In 
general, the least interaction is with pravastatin (20 mg 
daily orally). Atorvastatin (10 mg daily orally) or rosuvas
-
tatin (5 mg/day orally initially; maximum 10 mg/day) may 
also be used cautiously. Fish oil (3000 mg daily) combined 
with exercise and dietary counseling has been found to 
decrease triglyceride levels by 25%. Patients with persis
-
tently elevated fasting serum triglyceride levels of 
500 mg/dL or more who do not respond to dietary inter
-
vention should be treated with gemfibrozil (600 mg twice

-
-
vention should be treated with gemfibrozil (600 mg twice 
daily prior to the morning and evening meals). PIs are 
associated with abnormalities in cardiac conduction, 
especially prolongation of the PR interval.
a. Indinavir—
Indinavir is usually dosed at 800 mg twice 
daily in combination with 100 mg of ritonavir twice daily. 
Nausea and headache are common complaints with this 
medication. Indinavir crystals are present in the urine in 
approximately 40% of patients; this results in clinically 
apparent nephrolithiasis in about 15% of patients receiving 
indinavir. Lower urinary tract symptoms and acute kidney 
injury also have been reported. Patients taking this medica
-
tion should be instructed to drink at least 48 ounces of 
fluid a day to ensure adequate hydration in an attempt to 
limit these complications. Mild indirect hyperbilirubine
-
mia is also commonly observed in patients taking indinavir 
but is not an indication for discontinuation of the 
b. Saquinavir—
Saquinavir is formulated only as a hard-
gel capsule (Invirase). It should be used only with ritonavir 
(1000 mg of hard-gel saquinavir with 100 mg of ritonavir 
orally twice daily). The most common side effects with 
saquinavir are diarrhea, nausea, dyspepsia, and abdominal 
pain.
c. Ritonavir—
Use of this potent PI at full dose (600 mg 
orally twice daily) has been limited by its inhibition of the 
cytochrome P450 pathway causing a large number of drug-
drug interactions and by its frequent side effects of fatigue, 
nausea, and paresthesias. However, it is widely used in 
lower dose (eg, 100 mg daily to 100 mg twice daily) as a 
booster of other PIs.
d. Nelfinavir—
Nelfinavir is the only PI for which ritona
-
vir boosting is not recommended. Unboosted nelfinavir is 
generally not as potent as a boosted PI regimen (eg, lopina
-
vir plus ritonavir). The dose of nelfinavir is 1250 mg orally 
twice daily. Diarrhea is a side effect in 25% of patients tak
-
ing nelfinavir, but this symptom may be controlled with 
over-the-counter antidiarrheal agents in most patients.
e. Amprenavir—
Amprenavir has efficacy and side effects 
similar to those of other PIs. Common side effects are nau
-
sea, vomiting, diarrhea, rash, and perioral paresthesia. The 
dose is 1200 mg orally twice daily. The concentration of 
amprenavir decreases when coadministered with ethinyl 
estradiol; therefore, amprenavir should be used with cir
-
cumspection in the treatment of transgender persons 
requiring high-dose estrogen.
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f. Fosamprenavir—
Fosamprenavir is a prodrug of 
amprenavir. Its major advantage over using amprenavir is a 
much lower pill burden. For PI-naïve patients, it can be 
dosed at 1400 mg orally twice daily (four capsules a day) or 
at 1400 mg orally daily (two capsules) with ritonavir 
200 mg orally daily (two capsules) or at 700 mg orally with 
ritonavir 100 mg orally twice daily. Patients previously 
treated with a PI should receive 700 mg orally with ritona
-
vir 100 mg orally twice daily. Side effects are similar to 
those with amprenavir—most commonly gastrointestinal 
distress and hyperlipidemia. As with amprenavir, the con
-
centration of fosamprenavir decreases when coadminis
-
tered with ethinyl estradiol; therefore, fosamprenavir 
should be used with circumspection in the treatment of 
transgender persons requiring high-dose estrogen.
g. Lopinavir/R—
Lopinavir/r is lopinavir (200 mg) cofor
-
mulated with a low dose of ritonavir (50 mg) to maximize 
the bioavailability of lopinavir. It has been shown to be 
more effective than nelfinavir when used in combination 
with stavudine and lamivudine. The usual dose is 400-mg 
lopinavir with 100 mg of ritonavir (two tablets) orally twice 
daily with food. When given along with efavirenz or nevi
-
rapine, a higher dose (600 mg/150 mg—three tablets) is 
usually prescribed. The most common side effect is diar
-
rhea, and lipid abnormalities are frequent. Because of these 
side effects, lopinavir/r has fallen off the list of medications 
recommended as part of first-line treatment regimens.
h. Atazanavir—
Atazanavir is available alone and cofor
-
mulated with cobicistat (Evotaz). Atazanavir can be dosed 
as 400 mg (two 200-mg capsules) daily with food or it can 
be dosed as 300 mg in combination with 100 mg of ritona
-
vir once daily with food. When coformulated with cobici
-
stat, it is dosed at 300-mg atazanavir and 150-mg cobicistat. 
The most common side effect is mild hyperbilirubinemia 
that resolves with discontinuation of the medication. 
Nephrolithiasis and cholelithiasis have also been reported 
with this PI. Both tenofovir and efavirenz lower the serum 
concentration of atazanavir. Therefore, when either of 
these two medications is used with atazanavir, it should be 
boosted by administering ritonavir or given coformulated 
with cobicistat. Proton pump inhibitors are contraindi
-
cated in patients taking atazanavir because atazanavir 
requires an acidic pH to remain in solution.
i. Tipranavir—
Tipranavir is the only nonpeptidic PI 
approved by the US Food and Drug Administration (FDA). 
Because of its unique structure, it is active against some 
strains of HIV that are resistant to other PIs. It is dosed with 
ritonavir (two 250-mg capsules of tipranavir with two 100-mg 
capsules of ritonavir orally twice daily with food). The most 
common side effects are nausea, vomiting, diarrhea, fatigue, 
and headache. Tipranavir/ritonavir has been also associated 
with liver damage and should be used very cautiously in 
patients with underlying liver disease. Reports of intracranial 
hemorrhage in patients taking tipranavir-containing regi
-
mens have raised additional safety concerns about this potent 
PI. Because it is a sulfa-containing medication, its use should 
be closely monitored in patients with sulfa allergy.
j. Darunavir
—
Darunavir has impressive antiviral activ
-
ity in the setting of significant PI resistance and in treat
-
ment-naïve patients. It is formulated by itself and 
coformulated with cobicistat (Prezcobix). When formu
-
lated without cobicistat it requires boosting with ritonavir. 
For initial treatment of HIV or for treatment-experienced 
patients without darunavir-related resistance mutations, 
daily dosing is 800 mg of darunavir with 100 mg of ritona
-
vir or with 150 mg of cobicistat. Darunavir 800 mg is also 
available in a coformulated tablet with emtricitabine, TAF,

-
available in a coformulated tablet with emtricitabine, TAF, 
and cobicistat (Symtuza, Table 31–8). It has been approved 
for use by the European Commission, and FDA approval in 
the United States is pending. For patients with prior PI 
treatment experience or PI resistance (with mutations 
known to impact darunavir), darunavir should be dosed at 
600 mg orally twice daily, with ritonavir, 100 mg orally 
twice daily. Darunavir has a safety profile similar to other 
PIs, such as ritonavir-boosted lopinavir, but is generally 
better tolerated. Like tipranavir, darunavir is a sulfa-containing 
medication, and its use should be closely monitored in 
patients with sulfa allergy.
4. Entry inhibitors—
a. Enfuvirtide—
Enfuvirtide (Fuzeon) is known as a 
fusion inhibitor; it blocks the entry of HIV into cells by 
blocking the fusion of the HIV envelope to the cell mem
-
brane. The addition of enfuvirtide to an optimized antiret
-
roviral regimen improved CD4 counts and lowered viral 
loads in heavily pretreated patients with multidrug-
resistant HIV . Unfortunately, resistance develops rapidly in 
patients receiving nonsuppressive treatment. The dose is 
90 mg by subcutaneous injection twice daily; unfortu
-
nately, painful injection site reactions develop in most 
patients, which makes long-term use problematic.
b. Maraviroc—
Maraviroc is a CCR5 co-receptor antag
-
onist. Medications in this class prevent the virus from 
entering uninfected cells by blocking the CCR5 co-receptor. 
Before starting therapy, a viral tropism assay should be 
performed because this class of entry inhibitors is only 
active against “CCR5-tropic virus. ” This form of the 
HIV-1 virus tends to predominate early in infection, 
while so-called dual/mixed tropic virus (which utilizes 
either R5 or CXCR4 co-receptors) emerges later as infec
-
tion progresses. Approximately 50–60% of previously 
treated HIV-infected patients have circulating CCR5-
tropic HIV . The medication has been shown to be effec
-
tive in HIV-infected persons with ongoing viral replication 
despite being heavily treated and who have CCR5-tropic 
virus. The dose of maraviroc is 150–300 mg orally twice 
daily, based on the other medications the patient is taking 
at the time—in combination with a ritonavir boosted PI, 
150 mg daily of maraviroc has been used successfully. 
Common side effects are cough, fever, rash, musculoskel
-
etal problems, abdominal pain, and dizziness; however, 
maraviroc is generally well tolerated with limited impact 
on serum lipids.
5. Integrase inhibitors—
Integrase inhibitors slow HIV 
replication by blocking the HIV integrase enzyme needed 
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for the virus to multiply. They are now the preferred regi
-
mens for initiating therapy because of the combination of 
efficacy, ease of administration, and low incidence of side 
effects. 
Four
 integrase inhibitors are currently available: 
raltegravir, elvitegravir, dolutegravir
 and bictegravir;
 elvite
-
gravir (Vitekta) production was suspended by its manufac
-
turer in late 2016 due to lack of demand for it as a single 
agent though it remains available coformulated with 
emtricitabine/TDF along with cobicistat, a boosting agent, 
or with emtricitabine/TAF along with cobicistat boosting. 
A fifth agent, cabotegravir, currently in phase 3 testing, can 
be coformulated with rilpivirine in a long-acting injectable 
form; it may prove to be an effective two-drug antiretrovi
-
ral treatment regimen for patients successfully suppressed 
on a three-drug regimen. Clinical trials of available inte
-
grase inhibitors reveal a consistent pattern of more rapid 
decline in viral load compared with more standard PI/r or 
NNRTI-based regimens. Integrase inhibitors are effective 
(when combined with other active medications) in the 
treatment of HIV-infected patients with documented resis
-
tance to each of the three main classes of antiretroviral 
medications (nucleoside analogs, PIs, NNRTIs). Avoid 
administering integrase inhibitors with antacids or other 
medications with divalent cations (Ca
2+
, Mg
2+
, Al
2+
, Fe
2+
) 
because chelation of the integrase inhibitor by the cation 
reduces absorption. When these medications must be 
taken with integrase inhibitors, consult a pharmacist to 
determine the best separation of times of administration.
a. Raltegravir—
The dose of raltegravir is 400 mg orally 
twice daily. It has been found to be superior to efavirenz 
and ritonavir-boosted darunavir and ritonavir-boosted 
atazanavir. Common side effects are diarrhea, nausea, and 
headache, but overall it is well tolerated and has the addi
-
tional advantage over PI-based regimens and efavirenz-
based regimens in that it appears to have little impact on 
lipid profiles or glucose metabolism.
b. Elvitegravir—
Elvitegravir is no longer manufactured 
as a single agent; it can be prescribed in a once-a-day com
-
bination pill (Stribild) that contains 125 mg of elvitegravir 
and 150 mg of cobicistat, a boosting agent, along with stan
-
dard doses of TDF and emtricitabine (Table 31–8). Stribild 
has been shown to be noninferior to two preferred first-line 
regimens: Atripla and boosted atazanavir with emtricitabine/ 
TDF. The main side effect of Stribild is an increase in serum 
creatinine levels that has been shown to be related to the 
cobicistat inhibition of tubular secretion of creatinine by the 
kidney and is thought to be nonpathologic and reversible. 
However, because of this effect, Stribild is recommended in 
patients with estimated creatinine clearance greater than 70 
mL/min. A urine analysis should be done at baseline and at 
initial follow-up to look for proteinuria and glycosuria, 
which are signs of tubulopathy. Diarrhea and rash may also 
occur, although overall the medication is well tolerated. 
Elvitegravir is also coformulated with emtricitabine and 
TAF along with cobicistat boosting in a single once-a-day 
pill (Genvoya, Table 31–8). Since TAF appears to have fewer 
side effects than TDF, this is likely to become the preferred 
elvitegravir regimen.
c. Dolutegravir—
Dolutegravir shows excellent potency 
and tolerability and is dosed once a day in most circumstances. 
Unlike elvitegravir, dolutegravir does not require a boosting 
agent and has fewer drug-drug interactions. Similar to cobici
-
stat, it inhibits tubular secretion of creatinine by the kidney, 
resulting in small increases in serum creatinine levels. The 
standard dosage used in treatment-naïve, integrase-naïve 
patients is 50 mg/day. It is available combined with abacavir

patients is 50 mg/day. It is available combined with abacavir 
and lamivudine in a single once a day tablet (Triumeq, 
Table 31–8). In patients receiving efavirenz, fosamprenavir/
ritonavir, tipranavir/ritonavir, or rifampin, the dose should be 
increased to 50 mg twice daily. It should also be dosed at 50 mg 
twice daily in integrase-experienced patients in whom inte
-
grase resistance is suspected. Indeed, when combined with 
other active medications, it has been shown to provide some 
activity in patients with integrase resistance who have not 
responded to prior raltegravir- or elvitegravir-containing regi
-
mens. Dolutegravir has demonstrated impressive results in 
clinical trials of treatment-naïve patients, in terms of effective
-
ness, tolerability, and high barrier to resistance, when com
-
pared with the more standard NNRTI, boosted PI, and 
raltegravir-containing regimens. Dolutegravir is coformulated 
in combination with rilpivirine (Juluca, Table 31–8) for use as 
a once-a-day (to be taken with a meal) treatment for patients 
who are virologically suppressed (viral load less than 50 copies/
mL) on a stable regimen for at least 6 months, with no history 
of treatment failures or resistance to either of the two agents.
d. Bictegravir—
Similar to dolutegravir, bictegravir is 
dosed once daily, does not require boosting, and has a high 
barrier to resistance. It is dosed at 50 mg daily. A fixed-dose 
combination of bictegravir with emtricitabine and TAF was  
approved by the FDA in 2018.
6. Constructing an initial regimen—
Initial treatment 
should consist of three or more medications from two or 
more classes.
Consensus guidelines of the International Antiviral 
Society—USA Panel recommend starting antiretroviral 
treatment with one of four integrase inhibitor-containing 
regimens (Table 31–9). For the three regimens that use 
tenofovir, the TAF form is recommended due to less kidney 
and bone toxicity. Studies have shown dolutegravir/abacavir/
lamivudine to be superior to efavirenz/TDF/emtricitabine 
and have shown dolutegravir to be superior to ritonavir-
boosted darunavir (both combined with either abacavir/
lamivudine or TDF/emtricitabine). A network meta-
analysis adjusting for NRTI backbone found that 
dolutegravir had superior efficacy in suppressing viral load 
compared with regimens containing ritonavir-boosted ata
-
zanavir, ritonavir-boosted darunavir, efavirenz, or ritonavir-
boosted lopinavir. Discontinuation due to adverse events 
was also statistically lower in the dolutegravir regimens.
The drug combinations incorporating the integrase 
inhibitor raltegravir have done well in comparative studies. 
Among treatment-naïve patients, raltegravir in combina
-
tion with TDF/emtricitabine is as effective as efavirenz/
TDF/emtricitabine for daily treatment and has fewer side 
effects. In a 5-year follow-up to the double-blind trial, the 
raltegravir arm outperformed the efavirenz combination 
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Table 31–9.
 
Recommended and alternative initial antiretroviral regimens and other commonly used three-drug 
 
regimens.
1
 (alphabetical order)
r
egimen
Advantages
r
ecommended Initial 
r
egimens
Dolutegravir + abacavir + 
 
lamivudine
2
 (Triumeq)
Single pill once-a-day regimen
Has activity in some patients with integrase 
Superior to Atripla
Dolutegravir plus either abacavir/lamivudine 
or emtricitabine/TDF is superior to 
 
darunavir/ritonavir plus either of the NRTI 
backbones
Abacavir should be used only in HLA-B*5701-negative 
persons
When used in patients with integrase resistance or 
combined with certain other medications, requires 
twice-a-day dosing
Avoid antacids and other medications with divalent 
cations (Ca
2+
, Mg
2+
, Al
2+
+, Fe
2+
)
Dolutegravir (50 mg daily) + 
 
emtricitabine/TAF (Descovy)
Once-a-day regimen
No single tablet available
2+
, Mg
2+
, Al
2+
, Fe
2+
)
Emtricitabine/TAF/elvitegravir with 
cobicistat boosting (Genvoya)
Single tablet once-a-day regimen
Excellent response across broad range of 
 
CD4 and viral loads
Cobicistat boosting causes similar drug-drug interac
-
tions as ritonavir; increases in serum creatinine 
(nonpathologic)
No dosage adjustment with estimated creatinine 
 
clearance > 30 mL/min
2+
, Mg
2+
, Al
2+
, Fe
2+
)
Raltegravir (400 mg twice daily) + 
Superior to Atripla over 5 years of follow-up 
(when studied with TDF form of tenofovir)
Requires twice-a-day dosing
2+
, Mg
2+
, Al
2+
, Fe
2+
)
Alternative Initial 
r
egimens for Patients Who Cannot Take an Integrase Inhibitor
Darunavir (800 mg daily) with 
 
ritonavir (100 mg daily) 
 
boosting + either emtricitabine/
TDF (Truvada) or emtricitabine/
TAF (Descovy)
Potent boosted PI
Can be given once daily
Limited risk of resistance with poor 
adherence
Not available as a single tablet
May cause rash in patients with sulfa allergy
Ritonavir boosting required
Has metabolic side effects
Efavirenz/emtricitabine/TDF 
(Atripla)
Longest-term clinical experience
Highly effective across broad range of initial 
CD4 counts and viral loads
Avoid in patients with transmitted K103N resistance
Neuropsychiatric symptoms common and can be 
Rilpivirine/emtricitabine/TDF 
 
(Complera) or with emtricitabine/ 
TAF (Odefsey)
Noninferior to Atripla in patients with 
 
baseline viral load < 100,000/mcL
Limited metabolic side effects
Requires taking with a meal
Cannot be used with proton pump inhibitors
Use only in patients with viral loads < 100,000/mL 
 
and CD4 counts > 200 cells/mcL
Do not use in patients with viral loads > 100,000/mL 
 
or CD4 counts < 200 cells/mcL
Other Commonly Used 
r
egimens
Elvitegravir with cobicistat 
 
boosting + emtricitabine/TDF 
(Stribild)
 
-
Requires estimated creatinine clearance ≥ 70 mL/min
2+
, Mg
2+
, Al
2+
, Fe
2+
)
(
continued
)
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CMDT 2019
 
regimens.
1
 (alphabetical order) (continued)
r
egimen
Atazanavir (300 mg daily) 
 
coformulated with 150 mg 
 
cobicistat + either emtricitabine/
TDF (Truvada) or with emtri-
 
citabine/TAF (Odefsey)
adherence
Resistance to atazanavir generally does not 
confer resistance to other PI
Increases in bilirubin (nonpathologic)
Increased risk of cholelithiasis, nephrolithiasis, and 
chronic kidney injury
Should be taken with food; H
2
-blockers and proton 
pump inhibitors should be avoided
Requires estimated creatinine clearance > 70 mL/min
Atazanavir (300 mg daily) with 
 
adherence
2
Darunavir (800 mg daily) coformu
-
lated with cobicistat (150 mg 
daily) + abacavir/lamivudine 
(Epzicom)
adherence
Darunavir (800 mg daily) with rito
-
navir (100 mg daily) boosting + 
abacavir/lamivudine (Epzicom)
adherence
-
daily) + emtricitabine/TDF 
(Truvada)
adherence
Requires creatinine clearance >70 mL/min
1
These recommended and alternative initial regimens are drawn from Günthard HF et al. Antiretroviral drugs for treatment and prevention 
of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA. 2016 Jul 12;316(2):191–210. The 
DHHS Panel on antiretroviral guidelines for adults and adolescents (2016) considers the regimen of darunavir/ritonavir plus either 
emtricitabine/TDF or emtricitabine/TAF (listed above under regimens for persons who cannot tolerate an integrase inhibitor) as an equally 
good choice as the recommended initial integrase-containing regimens.
2
Usual medication doses are supplied when not part of a fixed-dose preparation.
TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
regimen largely due to better long-term tolerability. Fur
-
thermore, the CD4 response appeared better in patients 
treated with the raltegravir combination.
Two of the recommended integrase inhibitor/NRTI regi
-
mens are available in a single pill that can be dosed just once 
a day (Triumeq [abacavir, dolutegravir, and lamivudine] and 
Genvoya [elvitegravir/cobicistat/emtricitabine/TAF]). For 
patients who cannot take an integrase inhibitor, three alter
-
native regimens are recommended (Table 31–9). The DHHS 
Panel on antiretroviral guidelines for adults and adolescents 
(2016) considers the regimen of darunavir/ritonavir plus 
either TDF/emtricitabine or TAF/emtricitabine (listed above 
and in Table 31–9 under regimens for persons who cannot 
tolerate an integrase inhibitor) as an equally good choice as 
the recommended integrase regimens.
Resistance testing should be performed prior to starting

Resistance testing should be performed prior to starting 
antiretroviral treatment. Of newly infected persons in some 
urban areas of the United States, 8–10% have NNRTI resis
-
tance (primarily K103N). Patients with NNRTI resistance 
would not be expected to respond fully to an efavirenz-based 
regimen. The most important determinant of treatment effi
-
cacy is adherence to the regimen. Therefore, it is vitally 
important that the regimen chosen be one to which the 
patient can easily adhere (Figure 31–2). In general, patients 
are more compliant with medication regimens (Table 31–9) 
that offer a complete regimen in one pill that needs to be taken 
only once or twice a day, do not require special timing with 
regard to meals, can be taken at the same time as other medi
-
cations, do not require refrigeration or special preparation, 
and do not have bothersome side effects. Given the high level 
of effectiveness of recommended regimens, patients for whom 
the viral load does not fully suppress are likely noncompliant. 
Pharmacists and other specially trained clinicians can be very 
effective in helping patients improve their adherence by taking 
the time to understand why patients miss their medications 
and problem solve (eg, take medicine at same time every day, 
keep a supply in the car or at work in case you forget.) For 
certain populations (eg, unstably housed individuals), spe
-
cially tailored programs that include medication dispensing 
are needed.
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E. Monitoring Antiretroviral Treatment
1. Goals of monitoring antiretroviral treatment—
Monitoring of antiretroviral treatment (Figure 31–2) has 
two goals: evaluate for toxicity and measure efficacy using 
objective markers to determine whether to maintain or 
change regimens. Laboratory evaluation for toxicity 
depends on the specific medications in the combination 
but generally should be done approximately every 
3–4 months once a patient is on a stable regimen. Patients 
who are intolerant of their initial regimen should be 
changed to one of the other initial recommended or alterna
-
tive regimens in Table 31–9. The second aspect of monitor
-
ing is to measure objective markers of efficacy. The CD4 cell 
count and HIV viral load should be repeated 1–2 months 
after the initiation or change of antiretroviral regimen and 
every 3–6 months thereafter in clinically stable patients. 
With integrase regimens, approximately 80% of patients 
will have undetectable HIV viral load at 1 month. All 
patients should have undetectable viral loads by 3 months; 
if not, the usual problem is compliance (see next section). 
(Patients receiving antiretroviral treatment with undetect
-
able viral load for 2 years and CD4 counts 300 cells/mcL or 
more may need CD4 testing only every 12 months.)
2. The challenge of compliance—
In a patient who is 
adherent to an effective regimen, viral loads should be unde
-
tectable within 4–12 weeks. For patients in whom viral loads 
are not suppressed or who have viral rebound after suppres
-
sion, the major question facing the clinician is whether the 
patient is nonadherent or has resistance to the regimen, or 
both. The issue is complicated because many patients report 
being more compliant than they really are. Patients who are 
having trouble adhering to their treatment should receive 
counseling on how to better comply with their treatment. In 
patients who are adherent or who have missed enough doses 
to make resistance possible, resistance testing should be 
performed. Based on the results of resistance testing, and 
assessment of the patient’s ability to comply with 
complicated regimens or to tolerate predictable side effects, 
the clinician should prescribe a combination of three medi
-
cations to which there is no or only minimal resistance.
Once antiretroviral treatment has been initiated, it is 
not advisable to stop the therapy unless there is a compel
-
ling reason (eg, toxicity, poor adherence, etc). So-called 
drug holidays or structured treatment interruptions have 
been shown to increase risk of AIDS-related complications, 
increase CD4 declines, and increase morbidity from non–
AIDS-related complications (eg, myocardial infarctions 
and liver failure) and are not recommended.
3. The challenge of medication resistance—
HIV-1 medi
-
cation resistance limits the ability to fully control HIV 
replication and remains an important cause for antiretrovi
-
ral regimen failure. Resistance has been documented for all 
currently available antiretrovirals including the newer 
classes of fusion inhibitor, CCR5 inhibitors, and integrase 
inhibitors. The problem of medication resistance is wide
-
spread in HIV-infected patients undergoing treatment in 
countries where antiretroviral treatment is widely avail
-
able. However, reports suggest that the degree of high level 
resistance is declining in the past few years, which is likely 
related to better tolerated, easier to use, and more effica
-
cious antiretroviral agents. Resistance also occurs in 
patients who are antiretroviral treatment-naïve, but who 
have been infected with a medication resistant strain—
primary resistance or transmitted medication resistance. 
Cohort studies of antiretroviral treatment-naïve patients 
entering care in North America and Western Europe show 
that roughly 10–12% (and as high as 25%) of recently 
infected individuals have been infected with a medication-
resistant strain of HIV-1.

In addition to being performed as part of a standard 
baseline, resistance testing is also recommended for 
patients who are receiving antiretroviral treatment and 
have suboptimal viral suppression (ie, viral loads greater 
than 200 copies/mL). Both genotypic and phenotypic tests 
are commercially available and in randomized controlled 
Repeatedly positive ELISA and Western blot confirmation of HIV
Intolerance 
to
 regimen Viral load detectable after 4–12 weeks of 
treatment or viral rebound after suppression
Change 
to
 alternative
drug or regimen
Assess adherence
. 
If not adherent, initiate
adherence counseling
. 
If adherent, or if
prolonged period of partial or nonadherence,
Perform resistance testing and change 
to
 a
regimen with three drugs 
to
 which the patient
is not resistant from at least 
tw
o dif
fe
rent classes.
Perform HIV viral load and resistance testing and begin a recommended
antiretroviral treatment regimen (Table 31
–9
)
 
▲
Figure 31–2.
 
Approach to monitoring initial and subsequent antiretroviral therapy.
CMDT19_Ch31_p1338-p1376.indd   1374

1375
 
CMDT 2019
studies their use has been shown to result in improved 
short-term virologic outcomes compared to making treat
-
ment choices without resistance testing. Furthermore, 
multiple retrospective studies have conclusively demon
-
strated that resistance tests provide prognostic informa
-
tion about virologic response to newly initiated therapy 
that cannot be gleaned from standard clinical information 
(ie, treatment history, examination, CD4 count, and viral 
load tests).
Because of the complexity of resistance tests, many clini
-
cians require expert interpretation of results. In the case of 
genotypic assays, results may show that the mutations that 
are selected for during antiretroviral treatment are medica
-
tion-specific or contribute to broad cross-resistance to 
multiple medications within a therapeutic class. An exam
-
ple of a medication-specific mutation for the reverse tran
-
scriptase inhibitors would be the M184V mutation that is 
selected for by lamivudine or emtricitabine therapy—this 
mutation causes resistance only to those two medications. 
Conversely, the thymidine analog mutations (“TAMs”) of 
M41L, D67N, K70R, L210W , T215Y/F, and T219Q/K/E are 
selected for by either zidovudine or stavudine therapy, but 
cause resistance to all the medications in the class and often 
extend to the nucleotide inhibitor tenofovir when three or 
more of these TAMs are present. Further complicating the 
interpretation of genotypic tests is the fact that some muta
-
tions that cause resistance to one medication can actually 
make the virus that contains this mutation more sensitive to 
another medication. The M184V mutation, for example, is 
associated with increased sensitivity to zidovudine, stavu
-
dine, and tenofovir. The most common mutations associ
-
ated with medication resistance and cross-resistance 
patterns for NRTIs, NNRTIs, PIs, and integrase inhibitors 
can be found at https://hivdb.stanford.edu (see specific ref
-
erences below). Phenotypic tests also require interpretation 
in that the distinction between a resistant virus and sensi
-
tive one is not fully defined for all available medications.
Both methods of resistance testing are limited by the fact 
that they may measure resistance in only some of the viral 
strains present in an individual. Resistance results may also 
be misleading if a patient is not taking antiretroviral medica
-
tions at the time of testing because the dominant virus is 
likely the wild-type, even if there are resistant viruses in the 
body that can become dominant with the selective pressure 
of antivirals. Thus, resistance results do not replace a careful 
history of what medications a patient has taken in the past 
and for how long. Also, the results of resistance testing should 
be viewed cumulatively—ie, if resistance is reported to an 
agent on one test, it should be presumed to be present there
-
after even if subsequent tests do not give the same result.
Stanford University HIV Drug Resistance Database Home Page 
(https://hivdb.stanford.edu/) provides Genotypic Resistance 
Interpretation Algorithm, HIVdb Program, version 8.5, April 
16, updated version 2.2.5-1, April 23, 2018 (https://hivdb.
stanford.edu/hivdb/by-mutations/); Genotype-Phenotype 
Correlations
  
(https://hivdb.stanford.edu/pages/genotype-
phenotype.html); Genotype-Treatment Correlations (https://
hivdb.stanford.edu/pages/genotype-rx.html);
  
Genotype-
 
Clinical Outcome Correlations (https://hivdb.stanford.edu/
pages/genotype-clinical.html)
F. Constructing Alternative Antiretroviral 
In designing second-line regimens for patients with resis
-
tance to initial therapy, the goal is to identify three medica
-
tions from at least two different classes to which the virus is 
not resistant. Even without resistance testing, certain forms of 
cross-resistance between medications within a class can be 
assumed. For example, the resistance patterns of lopinavir/

ritonavir and indinavir are overlapping, and patients with 
virus resistant to these agents are unlikely to respond to nel
-
finavir or saquinavir even though they have never received 
treatment with these agents. Similarly, the resistance patterns 
of nevirapine and efavirenz are overlapping—as are the resis
-
tance patterns between raltegravir and elvitegravir.
In constructing regimens, toxicities should be nonover
-
lapping and agents that are either virologically antagonistic 
or incompatible in terms of drug-drug interactions should 
be avoided. For example, the combination of stavudine plus 
didanosine should be avoided, since there is increased risk 
of toxicities, in particular in pregnant women because of 
the increased risk of lactic acidosis, which can be fatal. 
Moreover, the nucleoside pair of zidovudine and stavudine 
should be avoided because of increased toxicity and the 
potential for antagonism that results from intracellular 
competition for phosphorylation. The combination of 
didanosine with tenofovir should be avoided because of 
observed declines in CD4 counts. Etravirine should not be 
used with boosted tipranavir because of drug-drug interac
-
tions. Lamivudine and emtricitabine are essentially the 
same medication and so are not used together.
Given the availability of new class medications and new 
generation medications, a combination of antiretroviral 
treatment can successfully treat virtually all patients—no 
matter how much resistance is present.
 
»
With improvements in therapy, patients who are compliant 
with treatment should have near normal life spans. A 
population-based study conducted in Denmark found that 
HIV-infected persons at age 25 years without hepatitis C had 
a life expectancy similar to that of an uninfected 25-year-old. 
Unfortunately, not all HIV-infected persons have access to 
treatment. Studies consistently show less access to treatment 
for blacks, the homeless, and injection drug users. For patients 
whose disease progresses even though they are receiving 
appropriate treatment, meticulous palliative care must be 
provided (see Chapter 5), with attention to pain control, spiri
-
tual needs, and family (biologic and chosen) dynamics.
 
»
•	
HIV-infected patients in whom viral loads cannot be 
fully suppressed on one of the initial recommended 
regimens should be referred to specialists.
•	
Specialty consultation is particularly important for those 
patients with detectable viral loads on antiretroviral treat
-
ment; those intolerant of standard medications; those in 
need of systemic chemotherapy; and those with compli
-
cated opportunistic infections, particularly when invasive 
procedures or experimental therapies are needed.
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»
Patients with opportunistic infections who are acutely ill 
(eg, who are febrile, who have had rapid change of mental 
status, or who are in respiratory distress) or who require 
intravenous medications.
Gallant J et al. Bictegravir, emtricitabine, and tenofovir alafen
-
amide versus dolutegravir, abacavir, and lamivudine for initial 
treatment of HIV-1 infection (GS-US-380-1489): a double-
blind, multicenter, phase 3 randomised controlled non-
inferiority trial. Lancet. 2017 Nov 4;390 (10107):2063–72. 
[PMID: 28867497]
-
INSIGHT START Study Group; Lundgren JD et al. Initiation of 
antiretroviral therapy in early asymptomatic HIV infection. N 
Engl J Med. 2015 Aug 27;373(9):795–807. [PMID: 26192873]
Johnson SC. Antiretroviral therapy for HIV infection: when to 
initiate therapy, which regimen to use, and how to monitor 
patients on therapy. Top Antivir Med. 2016 Dec–2017 Jan; 
23(5):161–7. [PMID: 27398769]
Kanters S et al. Comparative efficacy and safety of first-line anti
-
retroviral therapy for the treatment of HIV infection: a sys
-
tematic review and network meta-analysis. Lancet HIV . 2016 
Nov;3(11):e510–20. [PMID: 27658869]
Kanters S et al. Comparative efficacy and safety of second-line 
antiretroviral therapy for treatment of HIV/AIDS: a system
-
atic review and network meta-analysis. Lancet HIV . 2017 
Oct;4(10):e433–441. [PMID: 28784426] 
Margolis DA et al. Long-acting intramuscular cabotegravir and 
rilpivirine in adults with HIV-1 infection (LATTE-2): 
96-week results of a randomized, open-label, phase 2b, non-
inferiority trial. Lancet. 2017 Sept 23;390(10101):1499–510. 
[PMID: 28750935]
Mbuagbaw L et al. Efavirenz or nevirapine in three-drug combi
-
nation therapy with two nucleoside or nucleotide-reverse 
transcriptase inhibitors for initial treatment of HIV infection 
in antiretroviral-naïve individuals. Cochrane Database Syst 
Rev. 2016 Dec 10;12:CD004246. [PMID: 27943261]
Patel DA et al. 48-week efficacy and safety of dolutegravir rela
-
tive to commonly used third agents in treatment-naive HIV-
1-infected patients: a systematic review and network 
meta-analysis. PLoS One. 2014 Sep 4;9(9):e105653. [PMID: 
25188312]
Rockstroh JK et al. A randomized, double-blind comparison of 
coformulated elvitegravir/cobicistat/emtricitabine/tenofovir 
DF vs ritonavir-boosted atazanavir plus coformulated emtric
-
itabine and tenofovir DF for initial treatment of HIV-1 
infection: analysis of week 96 results. J Acquir Immune Defic 
Syndr. 2013 Apr 15;62(5):483–6. [PMID: 23337366]
Sax PE et al. Coformulated bictegravir, emtricitabine, and 
tenofovir alafenamide versus dolutegravir, abacavir, and 
lamivudine for initial treatment of HIV-1 infection 
 
(GS-US-380-1490): a double-blind, multicenter, phase 
 
3 randomised controlled non-inferiority trial. Lancet. 2017 
Nov 4;390(10107):2073–82. [PMID: 28867499]
U.S. Department of Health and Human Services. Guidelines for 
the prevention and treatment of opportunistic infections in 
HIV-infected adults and adolescents. Last updated October 18, 
2017. https://aidsinfo.nih.gov/contentfiles/lvguidelines/
adult_oi.pdf
the use of antiretroviral agents in HIV-1-infected adults and 
adolescents. Last updated October 17, 2017. https://aidsinfo.
nih.gov/ContentFiles/lvguidelines/AdultandAdolescentGL.pdf
U.S. Food and Drug Administration. FDA Drug Safety 
Communication: interactions between certain HIV or hepati
-
tis C drugs and cholesterol-lowering statin drugs can increase

-
tis C drugs and cholesterol-lowering statin drugs can increase 
the risk of muscle injury. https://www.fda.gov/Drugs/
DrugSafety/ucm293877.htm
Wang H et al. The efficacy and safety of tenofovir alafenamide 
versus tenofovir disoproxil fumarate in antiretroviral regi
-
mens for HIV-1 therapy: meta-analysis. Medicine (Baltimore). 
2016 Oct;95(41):e5146. [PMID: 27741146]
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º
VIRAL DISEASES
HUMAN HERPESVIRUSES
1. Herpesviruses 1 & 2
 
»
Spectrum of illness: stomatitis, urogenital lesions, 
Bell palsy, encephalitis.
 
»
Variable intervals between exposure and clinical 
disease, since HSV causes both primary (often 
subclinical) and reactivation disease.
 
»
Herpes simplex viruses 1 and 2 affect primarily the oral 
and genital areas, respectively. Asymptomatic shedding of 
either virus is common, but it is more common with 
HSV-2 and from genital areas, with most infected individ
-
uals shedding virus at least once a month, which may be 
responsible for transmission. Asymptomatic HSV-2–
infected individuals shed the virus less often than those 
with symptomatic infection. Disease typically indicates 
reactivation. Total and subclinical shedding of HSV-2 virus 
decrease after the first year of initial infection, although 
viral shedding continues for years thereafter.
Although HSV-2 is the most common cause of genital 
ulcers in the developed world, epidemiologic studies show 
that HSV-1 is a more common cause of both genital and 
oral lesions than HSV-2 in young women in the United 
States. Most HSV-2–infected persons in the United States 
are unaware that they are infected.
HSV-2 seropositivity increases the risk of HIV acquisition 
(it is threefold higher among persons who are HSV-2 sero
-
positive than among those who are HSV-2 seronegative), and 
HSV-2 reactivates more often in advanced HIV infection. 
HIV replication is increased by interaction with HSV pro
-
teins. Suppression of HSV-2 decreases HIV-1 plasma levels 
and genital tract shedding of HIV , which can contribute to a 
reduction in the sexual transmission of HIV-1.32
Wayne X. Shandera, MD 
 
Viral & Rickettsial 
 
»
1. Mucocutaneous disease—
See Chapter 6 for HSV-1 
mucocutaneous disease (“herpes labialis” or 
“gingivostomatitis”). Digital lesions (whitlows) 
 
(Figure 32–1) are an occupational hazard in medicine and 
dentistry. Contact sports (eg, wrestling) are associated with 
outbreaks of skin infections (“herpes gladiatorum”).
Vesicles form moist ulcers after several days and epithe
-
lialize over 1–2 weeks if untreated. Primary infection is 
usually more severe than recurrences but may be asymp
-
tomatic. Recurrences often involve fewer lesions, tend to be 
labial, heal faster, and are induced by stress, fever, infection, 
sunlight, chemotherapy (eg, fludarabine, azathioprine) or 
other undetermined factors.
HSV-2 lesions largely involve the genital tract, with the 
virus remaining latent in the presacral ganglia (see 
Chapter 6). Occasionally, lesions arise in the perianal 
region or on the buttocks and upper thighs. Dysuria, cervi
-
citis, and urinary retention may occur in women. Proctitis 
and extensive, ulcerating, weeping sacral lesions may be 
presenting symptoms in HIV-infected persons with CD4 
cytopenia. Large ulcerations and atypical lesions suggest 
drug-resistant isolates. The initiation of antiretroviral 
therapy (ART) is associated with transient increases in 
HSV-2–related genital ulcer disease.
2. Ocular disease—
HSV can cause uveitis, keratitis, bleph
-
aritis, and keratoconjunctivitis (see Chapter 7). Lesions 
limited to the epithelium usually heal without affecting 
vision, whereas stromal involvement can cause uveitis, 
scarring, and eventually blindness. HSV is the second most 
common cause, after VZV , of acute retinal necrosis.
3. Neonatal and congenital infection—
Both herpesvi
-
ruses rarely infect the fetus and induce congenital malfor
-
mations (organomegaly, bleeding, and central nervous 
system [CNS] abnormalities). Maternal infection during 
the third trimester is associated with the highest risk of 
neonatal transmission, but about 70% of these infections 
are asymptomatic or unrecognized. Neonatal transmission

are asymptomatic or unrecognized. Neonatal transmission 
during delivery, however, is more common than intrauter
-
ine infection. Invasive fetal monitoring and vacuum or 
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forceps delivery increase the risk of herpesvirus 
transmission.
4. CNS disease—
Traditionally, herpes simplex encephalitis 
is associated with HSV-1 infection and aseptic meningitis 
with HSV-2 infection. Both viruses, however, can cause 
encephalitis (and in one report, simultaneously). Encepha
-
litis presents with nonspecific symptoms: a flu-like pro
-
drome, followed by headache, fever, behavioral and speech 
disturbances, and focal or generalized seizures. The tempo
-
ral lobe is often involved. Untreated disease and presenta
-
tion with coma carry a high mortality. Many survivors 
suffer neurologic sequelae, which are observed more fre
-
quently among patients with HSV-1 infection. Both HSV-1 
and HSV-2 can cause mild, nonspecific neurologic symp
-
toms and are also associated with benign recurrent lym
-
phocytic (Mollaret) meningitis.
5. Disseminated infection—
Disseminated HSV infection 
occurs in the setting of immunosuppression, either pri
-
mary or iatrogenic, or rarely with pregnancy. In dissemi
-
nated disease, skin lesions are not always present. 
Disseminated skin lesions are a particular complication in 
patients with atopic eczema (eczema herpeticum) and 
burns. Pneumonia can occur regardless of immune 
status.
6. Bell palsy—
HSV-1 is a cause of Bell palsy (facial nerve 
paralysis).
7. Esophagitis and proctitis—
HSV-1 can cause esophagi
-
tis in immunocompromised patients, particularly those 
with AIDS. The lesions are smaller and deeper than those 
observed in patients with cytomegalovirus (CMV) esopha
-
gitis or with other herpesviruses known to cause esophagi
-
tis in immunocompromised persons. Proctitis occurs 
mainly in men who have sex with men.
8. Erythema multiforme—
Herpes simplex viruses and 
certain drugs are a leading cause of erythema multiforme 
minor (“herpes-associated erythema multiforme”) and of 
the more severe condition Stevens-Johnson syndrome/
toxic epidermal necrolysis (see also Chapter 6).
 
▲
Figure 32–1.
 
Herpetic whitlow. 
9. Other—
HSV is the cause of approximately 1% of cases 
of acute liver failure, particularly in pregnant women and 
immunosuppressed patients. The mortality of such rare 
fulminant hepatitis is nearly 75%. An HSV lower respira
-
tory tract infection of unknown clinical significance is 
common in mechanically ventilated patients. Evidence 
suggests that this finding is usually an indicator rather than 
the cause of a poor clinical condition. HSV-1 pneumonia is 
associated with high morbidity in patients with solid 
tumors. HSV-1 is reported to be a cause of perinephric 
abscess, febrile neutropenia, chronic urticaria, and esopha
-
gitis and enteritis in systemic lupus erythematosus. HSV is 
also associated with 
–negative upper 
gastrointestinal tract ulcers.
See Chapter 6.
Herpes keratitis is diagnosed by 
branching (dendritic) ulcers that stain with fluorescein. 
The extent of epithelial injury in herpes keratitis correlates 
well with polymerase chain reaction (PCR) positivity. Uve
-
itis from HSV is often diagnosed clinically. although PCR 
assays on anterior chamber aspirated material may assist in 
making the diagnosis.
3. Encephalitis and recurrent meningitis—
Cerebrospinal 
fluid (CSF) pleocytosis is common, with a similar increase 
in the number of red cells although CSF findings may be 
atypical in immunosuppressed patients. HSV real-time 
DNA PCR of the CSF is a rapid, sensitive, and specific tool 
for early diagnosis and can be included in a multiple rapid 
array panel. Viral detection by this method can be used if 
the clinical picture is consistent, especially if initial studies 
are negative. Antibodies to HSV in CSF can confirm the 
diagnosis but appear late in disease. Viral culture shows a 
sensitivity of only 10%. MRI scanning is often a useful

sensitivity of only 10%. MRI scanning is often a useful 
adjunct showing increased signal in the temporal and fron
-
tal lobes. Temporal lobe seizure foci may be shown on 
electroencephalograms (EEGs).
4. Esophagitis, proctitis, and other gastrointestinal 
disease
—
Esophagitis is diagnosed by endoscopic biopsy 
with real-time PCR and cultures. Proctitis may be diag
-
nosed by rectal swab for PCR, culture, or both. Compli
-
cated cases may require biopsy. Concomitant hepatitis and 
colitis has been reported with herpes simplex.
5. Pneumonia—
Pneumonia is diagnosed by clinical, 
pathologic, and radiographic findings. The CT findings 
include diffuse or multifocal areas of ground-glass attenu
-
ation or consolidative changes or both and are best con
-
firmed by using high-resolution CT techniques.
 
»
Treatment & Prophylaxis
Medications that inhibit replication of HSV-1 and HSV-2 
include trifluridine and vidarabine (both for keratitis), 
acyclovir and related compounds, foscarnet, and cidofovir 
(Table 32–1). Agents under study include helicase-primase 
inhibitors (amenavir and pritelivir) with promising pre
-
liminary (phase II) data.
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Table 32–1.
 
Agents for viral infections.
1
Drug
Dosing
2
Spectrum
t
o
xicities
Acyclovir
HSV and VZV infections: 200–800 mg orally five times daily; 
250–500 mg/m
2
 intravenously every 8 hours for 7 days
Acute herpes encephalitis: 10 mg/kg intravenously every 8 hours 
for 10–21 days
HSV, VZV
Neurotoxic reactions, 
reversible kidney 
dysfunction, local 
reactions
Cidofovir
5 mg/kg intravenously weekly for 2 weeks, then every other week
CMV
Neutropenia, kidney dis
-
ease, ocular hypotonia
Famciclovir
500 mg orally three times daily for 7 days for acute VZV; 250 mg 
three times daily for 7–10 days for genital or cutaneous 
HSV-1/HSV-2 infection; 125 mg twice daily for 5 days for 
recurrences (500 mg twice daily for 7 days if HIV-infected)
HSV, VZV
Early angioedema; later 
rarely, gastrointestinal 
symptoms, headaches, 
rashes
Foscarnet
Induction: 90 mg/kg intravenously (90- to 120-minute infusion) every 
12 hours or 60 mg/kg intravenously (minimum 1-hour infusion) 
every 8 hours over 2–3 weeks depending on clinical response 
Maintenance: 90–120 mg/kg intravenously (2-hour infusion) 
 
once daily
CMV, HSV resistant 
to acyclovir, VZV, 
HIV-1
Nephrotoxicity, genital 
ulcerations, calcium 
disturbances
Ganciclovir
Induction: 5 mg/kg intravenously every 12 hours for 14–21 days 
Maintenance: 6 mg/kg/day intravenously for 5 days each week
CMV
Neutropenia, 
thrombocytopenia, 
 
CNS side effects
Idoxuridine
Topical, 0.1% every 1–2 hours for 3–5 days
HSV keratitis
Local reactions
Interferon alfa-2b
HBV infection: 10 million international units subcutaneously three 
times weekly or 5 million units daily
1
Condylomata: 1 million international units intralesionally in up to 
five warts three times weekly for 3 weeks
HBV, HCV, HPV
Influenza-like syndrome, 
myelosuppression, 
neurotoxicity
Interferon alfa-n3
Refractory or recurring external condylomata acuminata: 0.05 mL 
(250,000 international units) per wart intralesionally twice 
weekly for up to 8 weeks; 0.5 mL (2.5 million international units) 
is the maximum dose per treatment session
HPV
HCV
Oseltamivir
75 mg orally twice daily for 5 days
Influenza A and B
Dose needs to be adjusted 
for kidney dysfunction
Palivizumab
15 mg/kg intramuscularly every month in RSV season
RSV
Upper respiratory 
infection symptoms
Penciclovir
Topical 1% cream every 2 hours for 4 days
HSV
Peramivir
Intravenous, 600-mg single dose
Influenza A
Nausea, vomiting, 
diarrhea, neutropenia
Ribavirin
RSV infection: one vial (6 g) dissolved and delivered through a 
Small Particle Aerosol Generator (SPAG-2) over a continuous 
12- to 18-hour period daily for 5 consecutive days
RSV, severe influenza 
A or B, Lassa fever
Wheezing, hemolytic 
anemia
Trifluridine
Topical, 1% drops every 2 hours to 9 drops/day
Valacyclovir
Acute VZV: 1 g orally three times daily for 7 days
Primary genital HSV-1/HSV-2 infection: 1 g twice daily for 10 days
Recurrent genital HSV-1/HSV-2 infection: 500 mg twice daily for 
 
3 days
Suppressive therapy: 1 g daily; 500 mg if fewer than 9 recurrences/
year (Dose depends on immune status and number of 
recurrences.)
VZV, HSV
Thrombotic 
thrombocytopenic 
purpura or hemolytic-
uremic syndrome in 
AIDS
Valganciclovir
900 mg orally twice daily for 3 weeks; 900 mg daily as maintenance
CMV
See ganciclovir
Zanamivir
5 mg inhalations twice daily for 5 days
Bronchospasm in patients 
with asthma
Sources: Data from Drugs.com and Lexicomp Online.
1
Agents used exclusively in the management of HIV infection and AIDS are found in Chapter 31. Agents used in the management of HBV 
and HCV infections are found in Chapter 16.
2
Dosing varies considerably by indication and may require adjustment based on patient’s clinical state and type of viral infection.

2
Dosing varies considerably by indication and may require adjustment based on patient’s clinical state and type of viral infection. 
Consultation with a pharmacist is recommended.
CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human 
papillomavirus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella-zoster virus.
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A. Mucocutaneous Disease
B. Keratitis and Uveitis
For the treatment of acute epithelial keratitis, oral antiviral 
agents such as valacyclovir or famciclovir are first-line 
therapies (see Chapter 7). The usage of topical corticoste
-
roids may exacerbate the infection, although systemic cor
-
ticosteroids may help with selected cases of stromal 
infection. Long-term treatment (more than 1 year) with 
acyclovir at a dosage of 800 mg/day orally decreases recur
-
rence rates of keratitis, conjunctivitis, or blepharitis due to 
HSV .
Uveitis is best managed with oral systemic (not topical) 
acyclovir, although HSV resistance among HIV-infected 
patients is reported because of the diversity of the HSV 
quasispecies often present.
C. Neonatal Disease
Counseling with serologic screening should be offered to 
pregnant mothers. The use of maternal antenatal suppres
-
sive therapy with acyclovir (typically, 400 mg three times 
daily) beginning at 36 weeks’ gestation decreases the pres
-
ence of detectable HSV , the rates of recurrence at delivery, 
and the need for cesarean delivery. Cesarean delivery is 
recommended for pregnant women with active genital 
lesions or typical prodromal symptoms.
D. Encephalitis and CNS Meningitis
Because of the need for rapid treatment to decrease mortal
-
ity and neurologic sequelae, intravenous acyclovir 
(10 mg/kg every 8 hours for 10 days or more, adjusting for 
kidney disease) should be started in those patients with 
suspected HSV encephalitis, stopping only if another diag
-
nosis is established. If the PCR of CSF is negative but clini
-
cal suspicion remains high, treatment should be continued 
for 10 days because the false-negative rate for PCR can be 
as high as 25% (especially in children) and acyclovir is rela
-
tively nontoxic. HSV viral load does not appear to correlate 
with outcome of meningitis, and it is not recommended to 
follow viral load over time.
Long-term neurologic sequelae of HSV encephalitis are 
common, and late pediatric relapse is recognized. Acyclo
-
vir resistance in a case of herpes simplex encephalitis is 
reported. Aseptic meningitis may also require a course of 
intravenous acyclovir or valacyclovir. Long-term oral pro
-
phylaxis with valacyclovir, however, does not appear to 
prevent recurrences of aseptic meningitis with HSV-2.
E. Disseminated Disease
Disseminated disease responds best to parenteral acyclovir 
when treatment is initiated early.
F. Bell Palsy
Prednisolone, 25 mg orally twice daily for 10 days started 
within 72 h of onset, significantly increases the rate of 
recovery. Data on antiherpes antiviral agents are equivocal 
and therefore HSV assays are not routinely recommended; 
according to one study, valacyclovir (but not acyclovir), 1 g 
orally daily for 5 days, plus corticosteroid therapy may be 
beneficial if started within 7 days of symptom onset. In 
patients with severe or complete facial paralysis, such anti
-
viral therapy is often administered but without proof of 
efficacy.
G. Esophagitis and Proctitis
Patients with esophagitis should receive either intravenous 
acyclovir (5–10 mg/kg every 8 hours) or oral acyclovir 
(400 mg five times daily) through resolution of symptoms, 
typically 3–5 days; however, longer treatment may be nec
-
essary for immunosuppressed patients. Maintenance ther
-
apy for AIDS patients is also with acyclovir (400 mg three 
to five times daily). Proctitis is treated with similar dosages 
and usually responds within 5 days.
H. Erythema Multiforme
Suppressive therapy with oral acyclovir (400 mg twice a day 
for 6 months) decreases the recurrence rate of HSV-
associated erythema multiforme. Valacyclovir (500 mg twice 
a day) may be effective in cases unresponsive to acyclovir.
 
»
Besides antiviral suppressive therapy (see Erythema multi
-
forme, above and in Chapter 6), prevention also requires 
counseling and the use of condom barrier precautions dur
-

»
-
-
ing sexual activity. Disclosure to sexual partners of HSV-
seropositive status is associated with about a 50% reduction 
in HSV-2 acquisition. Male circumcision is associated with 
a lower incidence of acquiring HSV-2 infection.
Preventing spread to hospital staff and other patients 
from cases with mucocutaneous, disseminated, or genital 
disease requires isolation and usage of hand washing and 
gloving–gowning precautions. Staff with active lesions 
 
(eg, whitlows) should not have contact with patients. There 
is no approved herpes vaccine, although studies continue 
with lentiviral vector-based glycoprotein B vaccines and 
oligonucleotide TLR9 inhibitory vaccines.
Bender Ignacio RA et al. Oral and vaginal tenofovir for genital 
herpes simplex virus type 2 shedding in immunocompetent 
women: a double-blind, randomized, cross-over trial. J Infect 
Dis. 2015 Dec 15;212(12):1949–56. [PMID: 26044291]
Birkmann A et al. HSV antivirals—current and future treatment 
options. Curr Opin Virol. 2016 Jun;18:9–13. [PMID: 
26897058]
Fife KH et al; Partners in Prevention HSV/HIV Transmission 
Study Team. Transient increase in herpes simplex virus type 
 
2 (HSV-2)-associated genital ulcers following initiation of 
antiretroviral therapy in HIV/HSV-2-coinfected individuals. 
 
J Infect Dis. 2016 May 15;213(10):1573–8. [PMID: 26704611]
Whitley RJ. Herpes simplex virus infections of the central 
nervous system. Continuum (Minneap Minn). 2015 Dec; 
21(6 Neuroinfectious Disease):1704–13. [PMID: 26633784]
-
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2. Varicella (Chickenpox) & 
 
Herpes Zoster (Shingles)
 
»
Varicella rash:
 pruritic, centrifugal, papular chang
-
ing to vesicular (“dewdrops on a rose petal”), 
pustular, and finally crusting.
 
»
Zoster rash:
 tingling, pain, eruption of vesicles in 
a dermatomal distribution, evolving to pustules 
and then crusting.
 
»
Varicella zoster virus (VZV), or HHV-3, disease manifesta
-
tions include chickenpox (varicella) and shingles (herpes 
zoster). Chickenpox generally presents during childhood; 
has an incubation period of 10–20 days (average 2 weeks); 
and is highly contagious, spreading by inhalation of infec
-
tive droplets or contact with lesions.
The incidence and severity of herpes zoster (“shingles”), 
which affects up to 25% of persons during their lifetime, 
increases with age due to an age-related decline in immunity 
against VZV . More than half of all patients in whom herpes 
zoster develops are older than 60 years, and the incidence of 
herpes zoster reaches 10 cases per 1000 patient-years by age 
80 (by which time 50% are infected with VZV). The annual 
incidence in the United States of 1 million cases is increasing 
as the population ages. Populations at increased risk for 
varicella-zoster–related diseases include immunosuppressed 
persons and persons receiving biologic agents, including 
tumor necrosis factor (TNF) inhibitors for many inflamma
-
tory diseases, bortezomib for plasma cell myeloma, and 
natalizumab in multiple sclerosis patients.
 
»
A. Varicella
1. Symptoms and signs—
Fever and malaise are mild in 
children and more marked in adults. The pruritic rash 
begins prominently on the face, scalp, and trunk, and later 
involves the extremities (Table 32–2). Maculopapules 
change within a few hours to vesicles that become pustular 
and eventually form crusts (Figures 32–2 and 32–3). New 
lesions may erupt for 1–5 days, so that different stages of 
the eruption are usually present simultaneously. The crusts 
Table 32–2.
 
Diagnostic features of some acute exanthems.
Disease
p
r
odromal Signs 
and Symptoms
Nature of Eruption
Other Diagnostic 
Features
t
ests
Atypical measles
Same as measles.
Maculopapular centripetal rash, 
becoming confluent.
History of measles 
Measles antibody present 
 
in past, with titer rise 
during illness.
Chikungunya fever
2–4 (sometimes 1–12) 
days, fever, head
-
aches, abdominal 
complaints, myal
-
gias, arthralgias.
Maculopapular, centrally 
distributed, pruritus, can be 
bullous with sloughing in 
children, occasional facial 
edema and petechiae.
History of mosquito 
bites, epidemio
-
logic factors.
ELISA-based IgM or IgG 
(fourfold increase in 
titers); PCR and 
cultures are infrequently 
Eczema herpeticum
None.
Vesiculopustular lesions in area 
of eczema.
 
Herpes simplex virus 
isolated in cell culture. 
Multinucleate giant cells 
in smear of lesion.
Ehrlichiosis
Headache, malaise.
Rash in one-third, similar to 
Rocky Mountain spotted fever.
Pancytopenia, 
 
elevated liver 
 
biochemical tests.
Polymerase chain 
 
reaction, immunofluores
-
cent antibody.
Enterovirus infections
1–2 days of fever, 
malaise.
Maculopapular rash resembling 
rubella, rarely papulovesicular 
or petechial.
Aseptic meningitis.
Virus isolation from stool 
 
or cerebrospinal fluid; 
complement fixation 
 
titer rise.
Erythema infectiosum 
(erythrovirus)
None. Usually in 
epidemics.
Red, flushed cheeks; circumoral 
pallor; maculopapules on 
“Slapped face” 
White blood count normal.
Exanthema subitum 
(HHV-6, 7; roseola)
3–4 days of high 
 
fever.
As fever falls, pink maculopapules 
appear on chest and trunk; 
fade in 1–3 days.
 
White blood count low.
Infectious mononucleosis 
(EBV)
Fever, adenopathy, 
sore throat.
rubella, rarely papulovesicular.
Splenomegaly, 
 
tonsillar exudate.

(EBV)
 
Atypical lymphocytes in 
blood smears; hetero
-
phile agglutination 
(Monospot test).
(
continued
)
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slough in 7–14 days. The vesicles and pustules are superfi
-
cial and elliptical, with slightly serrated borders. Pitted 
scars are frequent. Although the disease is often mild, 
complications (such as secondary bacterial infection, 
pneumonitis, and encephalitis) occur in about 1% of cases 
and often lead to hospitalization.
Varicella is more severe in older patients and immuno
-
compromised persons. In the latter, atypical presentations, 
including widespread dissemination in the absence of skin 
lesions, are often described. After the primary infection, 
the virus remains dormant in cranial nerve sensory ganglia 
and spinal dorsal root ganglia. Latent VZV will reactivate 
as herpes zoster in about 10–30% of persons. There is a 
small increased risk of Guillain-Barré syndrome for at least 
2 months after an acute herpes zoster attack.
2. Laboratory findings—
Diagnosis is usually made clini
-
cally, with confirmation by direct immunofluorescent 
 
Diagnostic features of some acute exanthems. (continued) 
Disease
p
r
Features
t
ests
Kawasaki disease
conjunctivitis.
Cracked lips, strawberry tongue, 
maculopapular polymorphous 
rash, peeling skin on fingers 
and toes.
Edema of extremities. 
Angiitis of 
 
coronary arteries.
Thrombocytosis, 
electrocardiographic 
changes.
Measles (rubeola)
3–4 days of fever, 
coryza, conjuncti
-
vitis, and cough.
Maculopapular, brick red; begins 
on head and neck; spreads 
downward and outward, in 
5–7 days rash brownish, 
desquamating. See Atypical 
measles, above.
Koplik spots on 
 
buccal mucosa.
White blood count low. 
Virus isolation in cell 
 
culture. Antibody tests 
 
by hemagglutination 
inhibition or 
neutralization.
Meningococcemia
Hours of fever, 
vomiting.
Maculopapules, petechiae, 
purpura.
Meningeal signs, 
toxicity, shock.
Cultures of blood, 
cerebrospinal fluid. 
 
White blood count high.
Rocky Mountain spotted 
fever
vomiting.
Maculopapules, petechiae, initial 
distribution centripetal 
(extremities to trunk, 
including palms).
History of tick bite.
Indirect fluorescent 
antibody; complement 
fixation.
Rubella
Little or no prodrome.
Maculopapular, pink; begins on 
head and neck, spreads 
downward, fades in 3 days. 
 
No desquamation.
Lymphadenopathy, 
postauricular or 
occipital.
White blood count normal 
 
or low. Serologic tests for 
immunity and definitive 
diagnosis (hemaggluti
-
nation inhibition).
One-half to 2 days of 
malaise, sore 
throat, fever, 
vomiting.
Generalized, punctate, red; 
prominent on neck, in axillae, 
groin, skin folds; circumoral 
pallor; fine desquamation 
involves hands and feet.
Strawberry tongue, 
exudative tonsillitis.
Group A beta-hemolytic 
streptococci in cultures 
from throat; 
antistreptolysin O 
 
Smallpox
Fever, malaise, 
Maculopapules to vesicles to 
pustules to scars (lesions 
develop at the same pace).
Centrifugal rash; 
fulminant sepsis in 
small percentage 
of patients, gastro
-
intestinal and skin 
Contact CDC
1
 for 
 
suspicious rash; 
 
EM and gel diffusion 
assays.
Typhus
chills, severe 
headaches.
distribution centrifugal (trunk 
to extremities).
Endemic area, lice.
Complement fixation.
Varicella (chickenpox)
0–1 day of fever, 
anorexia, headache.
Rapid evolution of macules to 
papules, vesicles, crusts; all 
stages simultaneously present; 
lesions superficial, distribution 
centripetal.
Lesions on scalp 
 
and mucous 
membranes.
Specialized complement 
fixation and virus 
neutralization in cell 
 
culture. Fluorescent 
 
antibody test of smear 
 
of lesions.
1
http://www.bt.cdc.gov/agent/smallpox/response-plan/
EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; EM, electron microscopy; HHV, human herpesvirus; Ig, immunoglobulin;

1
EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; EM, electron microscopy; HHV, human herpesvirus; Ig, immunoglobulin; 
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▲
Figure 32–2.
 
Primary varicella (chickenpox) skin 
lesions. 
 
▲
Figure 32–3.
 
Chickenpox (varicella) with classic 
“dew drop on rose petal” appearance. 
antibody staining or PCR of scrapings from lesions. Multi
-
nucleated giant cells are usually apparent on a Tzanck 
smear of material from the vesicle base. Leukopenia and 
subclinical transaminase elevation are often present and 
thrombocytopenia occasionally occurs. A varicella skin 
test and interferon-gamma enzyme-linked immunospot 
(ELISPOT) can screen for VZV susceptibility.
B. Herpes Zoster
Herpes zoster (“shingles”) usually occurs among adults, but 
cases are reported among infants and children. Skin lesions 
resemble those of chickenpox (see Chapter 6). Pain is often 
severe and commonly precedes the appearance of rash. 
Lesions follow a dermatomal distribution, with thoracic and 
lumbar roots being the most common. In most cases, a 
single unilateral dermatome is involved, but occasionally, 
neighboring and distant areas are involved. Lesions on the 
tip of the nose, inner corner of the eye, and root and side of 
the nose (Hutchinson sign) indicate involvement of the tri
-
geminal nerve (herpes zoster ophthalmicus). Facial palsy, 
lesions of the external ear with or without tympanic mem
-
brane involvement, vertigo and tinnitus, or deafness signify 
geniculate ganglion involvement (Ramsay Hunt syndrome 
or herpes zoster oticus). Shingles is a particularly common 
and serious complication among immunosuppressed 
patients. Other rare risk factors include statin therapy and 
possibly anti-TNF therapy.
 
»
Secondary bacterial skin superinfections, particularly with 
group A streptococcus and 
, are the 
most common complications. Cellulitis, erysipelas, and 
scarlet fever are described. Bullous impetigo and necrotiz
-
ing fasciitis are less often seen. Other associations with 
varicella include epiglottitis, necrotizing pneumonia, 
osteomyelitis, septic arthritis, epidural abscess, meningitis, 
endocarditis, pancreatitis, giant cell arteritis, inflammatory 
bowel disease, and purpura fulminans. Toxic shock syn
-
drome can also develop.
Interstitial VZV pneumonia is more common in adults 
(especially smokers, HIV-infected patients, and pregnant 
women) and may result in acute respiratory distress syn
-
drome (ARDS). After healing, numerous densely calcified 
lesions are seen throughout the lung fields on chest 
radiographs.
Historically, neurologic complications developed in 
about 1 in 2000 children. Cerebellar ataxia occurs at a fre
-
quency of 1:4000 in the young. A limited course and com
-
plete recovery are the rule. Encephalitis is similarly 
infrequent, occurs mostly in adults, and is characterized by 
delirium, seizures, and focal neurologic signs. The rates for 
both mortality and long-term neurologic sequelae are about 
10%. Ischemic strokes in the wake of acute VZV infection 
present at a mean of 4 months after rashes and may be due 
to an associated vasculitis. Multifocal encephalitis, ventric
-
ulitis, myeloradiculitis, arterial aneurysm formation, and 
arteritis are also described in immunosuppressed, especially 
HIV-infected, patients.
Clinical hepatitis is uncommon and mostly presents in 
the immunosuppressed patient but can be fulminant and 
fatal. Reye syndrome (fatty liver with encephalopathy) also 
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complicates varicella (and other viral infections, especially 
influenza B virus), usually in childhood, and is associated 
with aspirin therapy (see Influenza, below).
When contracted during the first or second trimesters 
of pregnancy, varicella carries a very small risk of congeni
-
tal malformations, including cicatricial lesions of an 
extremity, growth retardation, microphthalmia, cataracts, 
chorioretinitis, deafness, and cerebrocortical atrophy. 
 
If varicella develops around the time of delivery, the new
-
born is at risk for disseminated disease.
Postherpetic neuralgia occurs in 60–70% of patients who 
have herpes zoster and are older than 60 years. The pain 
can be prolonged and debilitating. Risk factors for posther
-
petic neuralgia include advanced age, female sex, the pres
-
ence of a prodrome, and severity of rash or pain but not 
family history.
Other complications include the following: (1) bacterial 
skin superinfections; (2) herpes zoster ophthalmicus, 
which occurs with involvement of the trigeminal nerve and 
is a sight-threatening complication (especially when it 
involves the iris), and is a marker for stroke over the ensu
-
ing year (Hutchinson sign is a marker of ocular involve
-
ment in the HIV-positive population); (3) rarely, unilateral 
ophthalmoplegia; (4) involvement of the geniculate gan
-
glion of cranial nerve VII as well as cranial nerves V , 
 
VIII, IX, and X; (5) aseptic meningitis; (6) peripheral 
motor neuropathy; (7) transverse myelitis; (8) encephalitis; 
(9) acute cerebellitis; (10) stroke; (11) vasculopathy; 
(12) acute retinal necrosis; (13) progressive outer retinal 
necrosis (largely among HIV infected persons); (14) temporal 
arteritis; and (15) sacral meningoradiculitis (Elsberg syn
-
drome). VZV is a major cause of Bell palsy in patients who 
are HSV seronegative.
Diagnosis of neurologic complications requires the 
detection of VZV DNA in CSF or the detection of VZV 
DNA in tissue. Diagnosis by examination of saliva may be 
possible. Zoster sine herpete (pain without rash) can also 
be associated with most of the above complications.
 
»
Treatment
In general, patients with varicella should be isolated until 
primary lesions have crusted. The skin is kept clean. Pruri
-
tus can be relieved with antihistamines, calamine lotion, 
and colloidal oatmeal baths. Fever can be treated with 
acetaminophen (not aspirin). Fingernails can be closely 
cropped to avoid skin excoriation and infection.
B. Antiviral Therapy
1. Varicella—
Acyclovir, 20 mg/kg (up to 800 mg per dose) 
orally four times daily for 5 days, should be given within the 
first 24 hours after the onset of varicella rash and should be 
considered for patients older than 12 years, secondary 
household contacts (disease tends to be more severe in sec
-
ondary cases), patients with chronic cutaneous and cardio
-
pulmonary diseases, and children receiving long-term 
therapy with salicylates (to decrease the risk of Reye syn
-
drome). Acyclovir hastens defervescence and healing of 
lesions but does not impact complication rates. Experience 
with valacyclovir and famciclovir in these settings is scant 
and while these agents are often used, their use is not FDA-
approved in the United States. Nonsteroidal anti-
inflammatory drug (NSAID) use in varicella-infected 
children appears to be associated with an increase in bacte
-
rial infections.
In immunocompromised patients, in pregnant women 
during the third trimester, and in patients with extracuta
-
neous disease (encephalitis, pneumonitis), antiviral ther
-
apy with high-dose acyclovir (30 mg/kg/day in three 
divided doses intravenously for at least 7 days) should be 
started once the diagnosis is suspected. Corticosteroids 
may be useful in the presence of pneumonia. Prolonged 
prophylactic acyclovir is important to prevent VZV reacti
-
vation in profoundly immunosuppressed patients.
2. Herpes zoster—

-
For uncomplicated herpes zoster, vala
-
cyclovir or famciclovir is preferable to acyclovir due to dos
-
ing convenience and higher drug levels in the body (Table 
32–1). Therapy should start within the first 72 hours of the 
onset of the lesions and be continued for 7 days or until the 
lesions crust over. Antiviral therapy reduces the duration of 
herpetic lesions and associated episodes of acute pain but 
does not in all studies decrease the risk of postherpetic neu
-
ralgia. Corticosteroids (a tapering course starting at 60 mg/
day, for 2–3 weeks) are safe in immunocompetent patients 
and may be useful in the acute management of disease to 
hasten the resolution of acute lesions. Corticosteroids do 
not prevent the development of postherpetic neuralgia.
Intravenous acyclovir is used for extradermatomal com
-
plications of zoster. Adjunctive therapy may be considered in 
retinal disease (foscarnet) and acute herpes zoster (sorivu
-
dine, a topical antiviral). In cases of prolonged or repeated 
acyclovir use, immunosuppressed patients may require a 
switch to foscarnet due to the development of acyclovir-
resistant VZV infections. VZV associated with the Ramsay 
Hunt syndrome is more resistant to antiviral therapy.
C. Treatment of Postherpetic Neuralgia
Once established, postherpetic neuralgia may respond to 
neuropathic pain agents such as gabapentin or lidocaine 
patches. Tricyclic antidepressants, opioids, and capsaicin 
cream are also widely used and effective. The epidural 
injection of corticosteroids and local anesthetics appears to 
modestly reduce herpetic pain at 1 month but, as with oral 
corticosteroids, is not effective for prevention of long-term 
postherpetic neuralgia. There is reported success using 
transcutaneous electrical nerve stimulation.
 
»
Prognosis
The total duration of varicella from onset of symptoms to 
disappearance of crusts rarely exceeds 2 weeks. Fatalities 
are rare except in immunosuppressed patients.
Herpes zoster resolves in 2–6 weeks. Antibodies persist 
longer and at higher levels than with primary varicella. Eye 
involvement with herpes zoster necessitates periodic future 
examinations.
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»
Health care workers should be screened for varicella and 
vaccinated if seronegative. Patients with active varicella or 
herpes zoster are promptly separated from seronegative 
patients. For patients with varicella, airborne and contact 
isolation is recommended, whereas for those with zoster, 
contact precautions are sufficient. For immunosuppressed 
patients with zoster, precautions should be the same as if 
the patient had varicella. Exposed serosusceptible patients 
should be placed in isolation and exposed serosusceptible 
employees should stay away from work between days 10 
and 21 after exposure. Health care workers with zoster 
should receive antiviral agents during the first 72 hours of 
disease and withdraw from work until lesions are crusted. 
The need for postexposure prophylaxis should be assessed.
1. Vaccination—
Universal childhood vaccination against 
varicella is effective. The varicella vaccine is live and 
attenuated, safe, and over 98.1% effective when given after 
13 months of age. A single antigen live attenuated vaccine 
(V ARIV AX, V ARILRIX) or a quadrivalent measles, mumps, 
rubella, and varicella vaccine (ProQuad) are available (the 
combination is immunogenic). The first dose should be 
administered at 12–15 months of age and the second at 
4–6 years. Aspirin should be avoided for at least 6 weeks 
because of the risk of Reye syndrome. This vaccine is safe, 
well tolerated, but the quadrivalent vaccine is associated 
with a small risk of febrile seizures 5–12 days after vaccina
-
tion among infants aged 12–23 months (and this risk is 
increased with quadrivalent combined MMR and varicella 
vaccines). Rashes, when secondary to the varicella vaccine, 
appear 15–42 days after vaccination. Rare cases of keratitis 
are associated with zoster and varicella vaccines.
For serosusceptible individuals older than 13 years, two 
doses of varicella vaccine (single antigen) administered 
4–8 weeks apart are recommended. For those who received 
a single dose in the past, a catch-up second dose is advised, 
especially in the epidemic setting (where it is effective 
when it can be given during the first 5 days postexposure). 
Household contacts of immunocompromised patients 
should adhere to these recommendations. Susceptible 
pregnant women (who should not be vaccinated with 
live varicella-zoster vaccines during pregnancy) need to 
receive the first dose of vaccine before discharge after deliv
-
ery and the second dose 4–8 weeks later. The quadrivalent 
vaccine MMRV can be used for the second doses of MMR 
and varicella in patients aged 15 months to 12 years and for 
the first dose in patients aged 48 months or older. The vac
-
cine, administered as two doses 3 months apart, should 
also be considered for HIV-infected adolescents and adults 
with CD4 T lymphocyte counts 200 cells/mcL or more.
The vaccine may also be given to patients with impaired 
humoral immunity, to patients receiving corticosteroids, to 
pediatric oncology patients receiving chemotherapy, and to 
patients with juvenile rheumatoid arthritis who receive 
methotrexate. Patients receiving high doses of corticosteroids 
for over 2 weeks may be vaccinated a month after discontinu
-
ation of the therapy. Patients with leukemia, lymphoma, or 
other malignancies whose disease is in remission and who 
have not undergone chemotherapy for at least 3 months may 
be vaccinated. Kidney and liver transplant patients should be 
vaccinated if they are susceptible to varicella.
The incidence of varicella in the United States is signifi
-
cantly reduced with the varicella vaccine. Meanwhile, the 
varicella vaccine is associated with a small increase in the 
incidence of herpes zoster, with the latter occurring more 
often in warm months. It is thought that vaccination 
against varicella provides less protection against future

against varicella provides less protection against future 
zoster than does natural varicella infection. The incidence 
of varicella-associated group A streptococcal infection and 
varicella neurologic complications are both diminished 
with the advent of varicella vaccination.
The FDA no longer maintains a registry for exposed 
pregnant women because of the low rate of such incidents 
and the general safety of varicella vaccines. Incidents can 
be reported to Merck (877-888-4231) or through the 
Vaccine Adverse Events Registry System Vaccine (https://
vaers.hhs.gov/index).
2. Postexposure—
Postexposure vaccination is recom
-
mended for unvaccinated persons without other evidence 
of immunity. Varicella-zoster immune globulin available in 
the United States only as VariZIG should be considered for 
susceptible exposed patients (for up to 10 days after expo
-
sure but as soon as feasible) who cannot receive the 
vaccine, including immunosuppressed patients, neonates 
from mothers with varicella around the time of delivery, 
exposed premature infants born from serosusceptible 
mothers at greater than 28 weeks of gestation, neonates 
born at less than 28 weeks of gestation regardless of mater
-
nal serostatus, and pregnant women. No controlled studies 
have evaluated the use of acyclovir in this setting. VariZIG 
is given by intramuscular injection in a dosage of 125 inter
-
national units/10 kg, to a maximum of 625 international 
units with a weight-based (2-kg cutoff) minimum dose of 
62.5 or 125 international units), with a repeat identical 
dose in 3 weeks if a high-risk patient remains exposed. 
VariZIG has no place in therapy of established disease; 
however, it reduces severity of varicella in high-risk chil
-
dren or adults (ie, those with impaired immunity, pregnant 
women, and infants exposed peripartum) if given within 
4 days of exposure. Varicella vaccination should be delayed 
at least 5 months after VariZIG administration.
Further information may be obtained by calling the 
Centers for Disease Control and Prevention’s Immuniza
-
tion Information Hotline (800-232-2522).
A live attenuated VZV vaccine (ZOSTAV AX, 19,400 plaque 
forming units [pfu] of Oka/Merck strain) contains at least 
14 times the concentration of varicella virus found in 
V ARIV AX. It is recommended for persons 60 years and 
older because it reduces the incidence of herpes zoster and 
postherpetic neuralgia by 51% and 67%, respectively. 
Even 
if the person has had a prior episode of herpes zoster, 
 
the vaccine has efficacy and can be administered.
 No 
specific recommendations exist regarding how long to wait 
between a zoster outbreak and administering the vaccine; 
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the Centers for Disease Control and Prevention (CDC) 
recommends waiting at least until the outbreak has resolved. 
The attenuated VZV vaccine is safe, but only moderately 
immunogenic among HIV-infected persons with a CD4 
count of at least 200 cells/mcL. Decreased efficacy occurs in 
patients older than 70, and this vaccine should not be given 
to immunosuppressed persons. Nonetheless, hematologic 
oncology patients taking anti-CD20 monoclonal antibodies 
may be successfully vaccinated. An increased risk of herpes 
zoster during a 6-week interval following vaccination is 
reported among patients taking immunosuppressant medi
-
cations. This vaccine provides protection for about 3 years. 
A new FDA-approved adjuvanted recombinant subunit vac
-
cine (Shingrix, HZ/su, GlaxoSmithKline Biologicals) is 
particularly effective in overcoming immunosenescence of 
older patients and reduces the risk of postherpetic neuralgia 
among adults 70 years of age or older. Two doses of this 
vaccine given 2 months apart had 97% efficacy with no 
significant decrease with age. It also appeared to be safe in 
HIV-infected persons with CD4 counts above 50 cells/mcL 
and recipients of autologous stem cell transplants.
Concurrent administration of the live attenuated VZV 
vaccine with pneumococcal vaccine is safe. If a varicella vac
-
cine is mistakenly administered to an adult instead of a live 
attenuated zoster vaccine, the dose should be considered 
invalid and the patient should be administered a dose of zoster 
vaccine at the same visit. The zoster vaccine cannot be used in 
children in place of varicella vaccine; if the vaccine is acciden
-
tally given to a child, the event should be reported to the CDC.
Cunningham AL et al; ZOE-70 Study Group. Efficacy of the 
herpes zoster subunit vaccine in adults 70 years of age or 
older. N Engl J Med. 2016 Sep 15;375(11):1019–32. [PMID: 
27626517]
older adults. Cochrane Database Syst Rev. 2016 Mar 3; 
3:CD008858. [PMID: 26937872]
Grillo AP et al. Keratitis in association with herpes zoster and 
varicella vaccines. Drugs Today (Barc). 2017 Jul;53(7):393–7. 
[PMID: 28837183]
Han Y et al. Corticosteroids for preventing postherpetic neural
-
gia. Cochrane Database Syst Rev. 2013 Mar 28;3:CD005582. 
[PMID: 23543541]
3. Epstein-Barr Virus & Infectious 
 
»
Malaise, fever, and (exudative) sore throat.
 
»
Palatal petechiae, lymphadenopathy, splenomeg
-
aly, and, occasionally, a maculopapular rash.
 
»
Positive heterophile agglutination test (Monospot).
 
»
Atypical large lymphocytes in blood smear; 
lymphocytosis.
 
»
Complications:
 hepatitis, myocarditis, neuropa
-
thy, encephalitis, airway obstruction from adenitis, 
hemolytic anemia, thrombocytopenia.
 
»
Epstein-Barr virus (EBV , or human herpes virus-4 
[HHV-4]) is one of the most ubiquitous human viruses, 
infecting more than 95% of the adult population world
-
wide and persisting for the lifetime of the host. Infectious 
mononucleosis is a common manifestation of EBV and 
may occur at any age. In the United States the incidence of 
EBV infection is declining although prevalence of EBV 
remains high for those aged 12–19 years. In the developing 
world, infectious mononucleosis occurs at younger ages 
and tends to be less symptomatic. Rare cases in older adults 
occur usually without the full symptomatology. EBV is 
largely transmitted by saliva but can also be recovered from 
genital secretions. Saliva may remain infectious during 
convalescence, for 6 months or longer after symptom 
onset. The incubation period lasts several weeks 
(30–50 days). Patients with immunodeficiency disorders 
are at risk for the full spectrum of EBV-associated disorders.
 
»
Fever, sore throat, fatigue, malaise, anorexia, and myalgia

»
Fever, sore throat, fatigue, malaise, anorexia, and myalgia 
typically occur in the early phase of the illness. Physical 
findings include lymphadenopathy (discrete, nonsuppura
-
tive, slightly painful, especially along the posterior cervical 
chain), transient bilateral upper lid edema (Hoagland 
sign), and splenomegaly (in up to 50% of patients and 
sometimes massive). A maculopapular or occasionally 
petechial rash occurs in less than 15% of patients unless 
ampicillin is given (in which case rash is seen in more than 
90%). Conjunctival hemorrhage, exudative pharyngitis, 
uvular edema, tonsillitis, or gingivitis may occur and soft 
palatal petechiae may be noted. Complications of acute 
disease are more common among older adults.
Other manifestations include hepatitis, interstitial 
pneumonitis (sometimes with pleural involvement), cho
-
lestasis, gastritis, kidney disease (mostly interstitial 
nephritis), epiglottitis, and nervous system involvement in 
1–5% (mononeuropathies and occasionally aseptic menin
-
gitis, encephalitis, cerebellitis, peripheral and optic neuritis, 
transverse myelitis, or Guillain-Barré syndrome). Vaginal 
ulcers are rare but may be present. Airway obstruction 
from lymph node enlargement can occur.
An initial phase of granulocytopenia is followed within 
 
1 week by lymphocytic leukocytosis (greater than 50% of all 
leukocytes) with atypical lymphocytes (larger than normal 
mature lymphocytes, staining more darkly, and showing 
vacuolated, foamy cytoplasm and dark nuclear chromatin) 
comprising more than 10% of the leukocyte count. Hemolytic 
anemia, with antibodies, occurs occasionally as does throm
-
bocytopenia (at times marked and life-threatening).
Diagnosis is made on the basis of characteristic 
manifestations and serologic evidence of infection (the 
heterophile sheep cell agglutination [HA] antibody tests or 
the correlated mononucleosis spot test [Monospot]). 
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These tests usually become positive within 4 weeks after 
onset of illness and are specific but often not sensitive in 
early illness. Heterophile antibodies may be absent in 
young children and in as many as 20% of adults. During 
acute illness, there is a rise and fall in immunoglobulin M 
(IgM) antibody to EB virus capsid antigen (VCA) and a rise 
in IgG antibody to VCA, which persists for life. Antibodies 
(IgG) to EBV nuclear antigen (EBNA) appear after 4 weeks 
of onset and also persist. Absence of IgG and IgM VCA or 
the presence of IgG EBNA should make one reconsider the 
diagnosis of acute EBV infection.
PCR for EBV DNA is useful in the evaluation of malig
-
nancies associated with EBV . For instance, detection of 
EBV DNA in CSF shows a sensitivity of 90% and specificity 
of nearly 100% for the diagnosis of primary CNS lym
-
phoma in patients with AIDS.
 
»
CMV infection, toxoplasmosis, acute HIV infection, sec
-
ondary syphilis, HHV-6 infection, rubella, and drug hyper
-
sensitivity reactions may be indistinguishable from 
infectious mononucleosis due to EBV , but exudative phar
-
yngitis is usually absent and the heterophile antibody tests 
are negative. With acute HIV infection, rash and mucocuta
-
neous ulceration are common but atypical lymphocytosis is 
much less common. Heterophile-negative infectious mono
-
nucleosis with nonsignificant lymphocytosis (especially if 
rash or mucocutaneous ulcers are present) should prompt 
investigation for acute HIV infection. CMV , toxoplasmosis 
and, on occasion, EBV can cause heterophile-negative 
infectious mononucleosis with atypical lymphocytosis. 
Mycoplasma infection may also present as pharyngitis, 
though lower respiratory symptoms usually predominate. A 
hypersensitivity syndrome induced by carbamazepine or 
phenytoin may mimic infectious mononucleosis.
The differential diagnosis of acute exudative pharyngi
-
tis includes gonococcal and streptococcal infections, and 
infections with adenovirus and herpes simplex. Head and 
neck soft tissue infections (pharyngeal and tonsillar 
abscesses) may occasionally be mistaken as the lymphade
-
nopathy of mononucleosis.
 
»
Secondary bacterial pharyngitis can occur and is often 
streptococcal. Splenic rupture (0.5–1%) is a rare but dra
-
matic complication, and a history of preceding trauma can 
be elicited in 50% of the cases. Acalculous cholecystitis, 
fulminant hepatitis with massive necrosis, pericarditis and 
myocarditis are also infrequent complications.
 
»
Treatment
Over 95% of patients with acute EBV-associated infectious 
mononucleosis recover without specific antiviral therapy. 
Treatment is symptomatic with NSAIDs or acetaminophen 
and warm saline throat irrigations or gargles three or four 
times daily. Acyclovir decreases viral shedding but shows 
no clinical benefit. Corticosteroid therapy, although wide
-
spread, is not recommended in uncomplicated cases; its 
use is reserved for impending airway obstruction from 
enlarged lymph nodes, hemolytic anemia, and severe 
thrombocytopenia. The value of corticosteroid therapy in 
impending splenic rupture, pericarditis, myocarditis, and 
nervous system involvement is less well established. If a 
throat culture grows beta-hemolytic streptococci, a 10-day 
course of penicillin or azithromycin is indicated. 
Ampicillin 
and amoxicillin are avoided because of the frequent associa
-
tion with rash.
Hepatitis, myocarditis, and encephalitis are treated symp
-
tomatically. Rupture of the spleen requires splenectomy 
and is most often caused by deep palpation of the spleen or 
vigorous activity. Patients should avoid contact or collision 
sports for at least 4 weeks to decrease the risk of splenic 
rupture (even if splenomegaly is not detected by physical 
examination, which can be insensitive).
 
»
Prognosis & Prevention

»
In uncomplicated cases, fever disappears in 10 days and 
lymphadenopathy and splenomegaly in 4 weeks. The debil
-
ity sometimes lingers for 2–3 months.
Death is uncommon and is usually due to splenic rup
-
ture, hypersplenic phenomena (severe hemolytic anemia, 
thrombocytopenic purpura), or encephalitis.
A glycoprotein vaccine and a two-protein vaccine are 
under development. Neither vaccine is currently commer
-
cially available. Hand washing after contact and avoidance 
of close personal contact with active cases is prudent.
4. Other EBV-Associated Syndromes
EBV viral antigens are found in more than 90% of patients 
with endemic (African) Burkitt lymphoma and nasopha
-
ryngeal carcinoma (among whom quantified EBV DNA 
can be used to follow disease). Risk factors for Burkitt 
lymphoma include a history of malaria (which may 
decrease resistance to EBV infection) while risk factors for 
nasopharyngeal carcinoma include long-term heavy ciga
-
rette smoking and seropositive EBV serologies (VCA and 
deoxyribonuclease [DNase]). VCA-IgA in peripheral blood 
is a sensitive and specific predictor for nasopharyngeal 
carcinoma in an endemic area.
Among Hodgkin lymphoma patients, EBV seropositiv
-
ity is common when the disease is found in the developing 
world or is associated with HIV infection, when pathologic 
specimens show mixed cellularity, and when patients are 
younger than 10 years or older than 45 years at onset of the 
lymphoma. The EBV-seropositive have a worse prognosis 
for early stages of Hodgkin lymphoma.
Chronic EBV infection is associated with aberrant cel
-
lular immunity (a low frequency of EBV-specific CD8
+
 
T cells), an X-linked lymphoproliferative syndrome (Dun
-
can disease), lymphomatoid granulomatosis, and a fatal 
T-cell lymphoproliferative disorder in children.
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EBV is an important trigger for hemophagocytic lym
-
phohistiocytosis among immunodeficient patients and 
causes B-cell lymphomas (such as primary CNS lym
-
phoma in HIV-infected individuals), natural killer/T-cell 
lymphoma, and posttransplant lymphoproliferative disor
-
ders. CD30 and EBV viral loads are prognostic markers for 
EBV-associated lymphoproliferative disease. Posttrans
-
plant lymphoproliferative disorders (PTLD) are com
-
monly associated with EBV , especially in children. 
EBV-naïve patients who receive a donor organ from an 
EBV-infected donor are at the highest risk for the develop
-
ment of PTLD. EBV serostatus, however, is not associated 
with overall survival among patients with PTLD. Decreas
-
ing the iatrogenic immunosuppression given to prevent 
graft rejection is the initial step in managing such patients, 
while rituximab (CD20 monoclonal antibody) is effective 
in treating more than two-thirds of cases. The efficacy of 
rituximab or various forms of traditional chemotherapy 
often can be assessed by monitoring levels of EBV DNA 
load in the blood and, if indicated, CNS. Infusion of EBV-
specific cytotoxic T-cell lymphocytes (adoptive cell 
therapy) is also used but with a less established role. Oral 
mucocutaneous ulcerative disease in the HIV-infected 
may be due to EBV .
Age is a major determinant of the type of tumor associ
-
ated with EBV . T and NK cell lymphoma caused by 
chronic active EBV infections are more frequent in child
-
hood while peripheral T-cell lymphomas and diffuse large 
B-cell lymphomas are more common in older patients due 
to waning immunity. EBV is also associated with leiomyo
-
mas in children with AIDS and with nasal T-cell 
lymphomas.
 
»
Presence of severe complications of EBV disease including 
•	
Acute meningitis, encephalitis, or Guillain-Barré 
syndrome.
•	
Severe thrombocytopenia; significant hemolysis.
•	
Potential splenic rupture.
•	
Airway obstruction from severe adenitis.
•	
Pericarditis.
•	
Abdominal findings mimicking an acute abdomen.
Ebell MH. JAMA patient page. Infectious mononucleosis. 
JAMA. 2016 Apr 12;315(14):1532. [PMID: 27115282]
Linke-Serinsöz E et al. Human immunodeficiency virus (HIV) 
and Epstein-Barr virus (EBV) related lymphomas, pathology 
view point. Semin Diagn Pathol. 2017 Jul;34(4):352–63. 
[PMID: 28506687]
Myriam BD et al. Prognostic significance of Epstein-Barr virus 
(EBV) infection in  Hodgkin lymphoma patients. J Infect 
Chemother. 2017 Mar;23(3):121–30. [PMID: 28034523]
Okamoto A et al. The prognostic significance of EBV DNA load 
and EBER status in diagnostic specimens from diffuse large 
B-cell lymphoma patients. Hematol Oncol. 2017 Mar; 
35(1):87–93. [PMID: 26177728]
Shabani M et al. Primary immunodeficiencies associated with 
EBV-induced lymphoproliferative disorders. Crit Rev Oncol 
Hematol. 2016 Dec;108:109–27. [PMID: 27931829]
5. Cytomegalovirus Disease
 
»
Mononucleosis-like syndrome.
 
»
Frequent pathogen seen in transplant 
populations.
 
»
Diverse clinical syndromes in HIV (retinitis, esoph
-
agitis, pneumonia, encephalitis).
 
»
Most cytomegalovirus (CMV) infections are asymptomatic. 
After primary infection, the virus remains latent in most 
body cells. Seroprevalence in adults of Western developed 
countries is about 60–80%, but is higher in developing 
countries. The virus can be isolated from a variety of tissues 
under nonpathogenic conditions. Transmission occurs 
through sexual contact, breastfeeding, blood products, or 
transplantation; it may also occur person-to-person (eg, day 
care centers) or be congenital. Serious disease occurs pri
-
marily in immunocompromised persons, including those 
with inflammatory bowel disease.
There are three recognizable clinical syndromes: 
 
(1) perinatal disease and CMV inclusion disease, (2) diseases 
in immunocompetent persons, and (3) diseases in immu
-

-
nocompromised persons. 
Congenital CMV infection
 is 
the most common congenital infection in developed coun
-
tries (about 0.6% of live births, with higher rates in under
-
developed areas and among lower socioeconomic groups). 
Transmission is much higher from mothers with primary 
disease than those with reactivation (40% vs 0.2–1.8%). 
About 10% of infected newborns will be symptomatic with 
CMV inclusion disease.
In 
immunocompetent persons
, acute CMV infection 
is the most common cause of the mononucleosis-like syn
-
drome with negative heterophile antibodies. In critically ill 
immunocompetent adults, CMV reactivation is associated 
with prolonged hospitalization and death. CMV appears to 
be involved in the malignant manifestations of glioblas
-
toma multiforme.
In 
immunocompromised persons
, solid organ and 
bone marrow transplant patients are at highest risk for a year 
after allograft transplantation (but especially during the first 
100 days afterward) and in particular when graft-versus-
host disease is present or when the donor is CMV seroposi
-
tive and the recipient is seronegative. Depending on the 
serostatus of the donor and recipient, disease may present as 
primary infection or reactivation. The risk of CMV disease 
is proportionate to the degree of immunosuppression and 
manifestations may differ by the cause. CMV may contrib
-
ute to transplanted organ dysfunction, which often mimics 
organ rejection. CMV retinitis may develop after solid organ 
or bone marrow transplantation. CMV disease in HIV-
infected patients (retinitis, serious gastrointestinal disease) 
occurs most prominently when the CD4 count is less than 
50 cells/mcL and can be a marker for increased mortality. 
ART reduces the frequency of retinitis and may reverse 
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active disease. Patients with immune recovery with CD4 cell 
count greater than 100 cells/mcL show decreased mortality. 
CMV retinitis associated with intravitreal delivery of corti
-
costeroids (injections or implants) or systemic anti-TNF 
antibodies is also described. Occasionally, CMV retinitis 
presents in immunocompetent persons. Serious gastrointes
-
tinal CMV disease also occurs after organ transplantation, 
cancer chemotherapy, or corticosteroid therapy. CMV may 
exist alongside other pathogens, such as 
, in 
up to 15% of patients with AIDS cholangiopathy. CMV 
pneumonitis occurs in transplant recipients (mainly bone 
marrow and lung) with a mortality rate up to 60–80%, and 
less often in AIDS patients. CMV pneumonitis in hemato
-
logic malignancies (eg, lymphoma) is increasingly reported. 
Neurologic CMV in patients with advanced AIDS is usually 
associated with disseminated CMV infection.
 
»
1. Perinatal disease and CMV inclusion disease—
CMV 
inclusion disease in infected newborns is characterized by 
hepatitis, thrombocytopenia, microcephaly, periventricu
-
lar CNS calcifications, mental retardation, and motor dis
-
ability. Hearing loss develops in more than 50% of infants 
who are symptomatic at birth. Most infected neonates are 
asymptomatic, but neurologic deficits may ensue later in 
life, including hearing loss in 15% and mental retardation 
in 10–20%. Perinatal infection acquired through breast
-
feeding or blood products typically shows a benign clinical 
course.
2. Disease in immunocompetent persons—
Acute CMV 
infection is characterized by fever, malaise, myalgias, 
arthralgias, and splenomegaly. Exudative pharyngitis or 
cervical lymphadenopathies are uncommon, but cutaneous 
rashes (including the typical maculopapular rash after 
exposure to ampicillin) are common. The mean duration 
of symptoms is 7–8 weeks. Complications include mucosal 
gastrointestinal damage, encephalitis, severe hepatitis, 
thrombocytopenia (on occasion, refractory), the Guillain-
Barré syndrome, pericarditis, and myocarditis. A mononu
-
cleosis-like syndrome due to CMV can also occur 
postsplenectomy, often years later and associated with a 
protracted fever, marked lymphocytosis, and impaired 
anti-CMV IgM response.
3. Disease in immunocompromised persons—
Distinguishing between CMV infection (with evidence of 
CMV replication) and CMV disease (evidence for systemic 
symptoms or organ invasion by pathologic diagnosis) is 
important. In addition to patients infected with HIV , those 
who have undergone transplantation (solid organ or hema
-
topoietic stem cell) show a wide spectrum of disease 
including gastrointestinal (eg, acute cholecystitis), kidney, 
and CNS disease, as outlined above. CMV viral loads serve 
as an important predictor of disease presence.
a. CMV retinitis
—
A funduscopic examination reveals 
neovascular, proliferative lesions (“pizza-pie” retinopathy). 
Immune restoration with ART is associated with CMV 
vitreitis and cystoid macular edema.
b. Gastrointestinal and hepatobiliary CMV—
Esophagitis presents with odynophagia. Gastritis can occa
-
sionally cause bleeding, and small bowel disease may 
mimic inflammatory bowel disease or may present as 
ulceration or perforation. Colonic CMV disease causes 
diarrhea, hematochezia, abdominal pain, fever, and weight 
loss and may mimic inflammatory bowel disease. CMV 
hepatitis commonly complicates liver transplantation and 
appears to be increased in those with hepatitis B or 
hepatitis C viral infection.
c. Respiratory CMV—
CMV pneumonitis is character
-
ized by cough, dyspnea, and relatively little sputum pro
-
duction. Concomitant infection with 
 
occurs among patients regardless of HIV status.
d. Neurologic CMV—
Neurologic syndromes associated 
with CMV include polyradiculopathy, transverse myelitis,

with CMV include polyradiculopathy, transverse myelitis, 
ventriculoencephalitis (suspected with ependymitis), and 
focal encephalitis. These manifestations are more promi
-
nent in patients with advanced AIDS in whom the enceph
-
alitis has a subacute onset.
1. Mothers and newborns—
Pregnant women should be 
tested for CMV viremia every 3 months if an assay during 
the first trimester is seropositive. Congenital CMV disease 
is confirmed by presence of the virus in amniotic fluid or 
an IgM assay from fetal blood. Amniocentesis is less reli
-
able before 21 weeks of gestation (due to inadequate fetal 
urinary development and release into the amniotic fluid), 
but amniocentesis is attendant with greater risk when per
-
formed after 21 weeks of gestation. PCR assays of dried 
blood samples from newborns, micro-enzyme-linked 
immunosorbent assay (ELISA), shell-vial culture, or cul
-
ture of urine, saliva, or blood specimens obtained during 
the first 3 weeks of life are used to diagnose congenital 
CMV infection.
2. Immunocompetent persons—
The acute mononucleo
-
sis-like syndrome is characterized by initial leukopenia; 
within 1 week, it is followed by absolute lymphocytosis 
with atypical lymphocytes. Abnormal liver biochemical 
tests are common in the first 2 weeks of the disease (often 
2 weeks after the fever). Detection of CMV DNA, specific 
IgM, or a fourfold increase of specific IgG levels support 
the diagnosis of acute infection.
3. Immunocompromised persons—
CMV retinitis is diag
-
nosed on the basis of the characteristic ophthalmoscopic 
findings. In HIV-infected patients, negative CMV serolo
-
gies lower the possibility of the diagnosis but do not elimi
-
nate it. Cultures alone are of little use in diagnosing 
AIDS-related CMV infections, since viral shedding of 
CMV is common. Detection of CMV by quantitative DNA 
PCR should be used to diagnose CNS infection since cul
-
tures are not specific for disease.
Detection of CMV by quantitative DNA PCR is also 
used in posttransplant patients to guide both treatment and 
prevention and should be interpreted in the context of 
clinical and pathologic findings. CMV viral loads are inter
-
nationally standardized and have replaced conventional 
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CMV antigenemia tests in many settings. The PCR is sensi
-
tive in predicting clinical disease. Serial PCR should be 
performed and compared using the same specimen type 
(ie, whole blood or plasma). To assist in the diagnosis CMV 
pneumonia, bronchoalveolar lavage fluid can be tested to 
quantify CMV viral load. Rapid shell-vial cultures detect 
early CMV antigens with fluorescent antibodies in 
24–48 hours. Shell-vial cultures are more useful on bron
-
choalveolar lavage fluid than in routine blood monitoring. 
CMV colitis can occur in the absence of a detectable viremia.
C. Imaging
The chest radiographic findings of CMV pneumonitis are 
consistent with interstitial pneumonia.
D. Biopsy
Tissue confirmation is especially useful in diagnosing CMV 
pneumonitis and CMV gastrointestinal disease; the diagno
-
sis of colonic CMV disease is made by mucosal biopsy 
showing characteristic CMV histopathologic findings of 
intranuclear (“owl’s eye”) and intracytoplasmic inclusions. 
In situations where histopathologic or immunohistochemi
-
cal findings are not seen but CMV colitis is suspected, CMV 
DNA PCR can be used to identify additional cases.
 
»
Treatment
 is discussed in Chapter 7. The 
role of ART in HIV infections in reducing the need for 
CMV antiviral agents is essential. Because recurrence 
occurs even at high CD4 cell counts, ongoing ophthalmo
-
logic surveillance is necessary. Other forms of CMV dis
-
ease in AIDS are managed initially with intravenous 
ganciclovir and subsequently with oral valganciclovir; 
alternative agents are used when resistance evolves.
The treatment of other systemic CMV infection (colitis, 
encephalitis, pneumonia) involves valganciclovir or ganci
-
clovir. Foscarnet and cidofovir are reserved for treatment of 
resistant infections. The efficacy of ganciclovir is established 
in childhood pneumonia. The length of therapy depends on 
the state of immunosuppression, and secondary prophylaxis 
is typically maintained until immune restoration (with two 
CD4 T-cell counts greater than 100 cells/mcL present for at 
least 6 months in the setting of HIV infection). Prolonged 
prophylaxis may be necessary in other immunosuppressed 
patients, such as those receiving TNF inhibitors.
For non-severe, posttransplant CMV disease
, oral 
valganciclovir (900 mg twice daily) or intravenous ganci
-
clovir (5 mg/kg every 12 hours) are the recommended 
first-line agents. Valganciclovir has been shown to be non
-
inferior to intravenous ganciclovir-based therapy in solid 
organ transplant patients and is associated with less clinical 
resistance than ganciclovir. 
For severe CMV disease
, intra
-
venous ganciclovir is the treatment of choice. Dosage 
adjustments of all medications are needed for kidney dis
-
ease. Reduction of immunosuppression should be 
attempted when possible (especially for muromonab, aza
-
thioprine, or mycophenolate mofetil). Treatment should be 
continued for at least 2 weeks until viral clearance is 
achieved. Two consecutive negative results from CMV 
DNA PCR or antigenemia-based assay ensure viral clear
-
ance. Other agents that may be useful in resistant CMV 
infections include CMV immunoglobulin, leflunomide, 
sirolimus-based therapy, artesunate and adoptive immuno
-
therapy. New anti-CMV drugs under development include 
brincidofovir and maribavir.
Letermovir is useful in 
prophylaxis against CMV 
 in adult allogenic hematopoietic stem cell trans
-
plant recipients; it is given as 480 mg orally daily with dose 
adjustments for cyclosporine administration and for 
advanced kidney dysfunction (less than a creatinine clear
-
ance of 10 mL/min). Major side effects reported to date 
include cough, diarrhea, headache, nausea, stomach pain, 
weakness, and vomiting.
 
»
A major source of CMV for pregnant women is their own 
young children, particularly those in childcare. These

»
young children, particularly those in childcare. These 
women can decrease their risk of contracting primary CMV 
just before pregnancy or during pregnancy by practicing 
hand hygiene after changing diapers and after contact with 
respiratory secretions; avoiding kissing young children on 
the face; and avoiding sharing utensils, food, and cleansing 
objects that have been in contact with children’s secretions.
ART is effective in preventing CMV infections in HIV-
infected patients. Primary prevention is best accomplished 
by good hand hygiene and use of barrier methods during 
sexual contacts with persons who are members of high-
prevalence groups (ie, men who have sex with men, 
injection drug users, and those who have exposure to chil
-
dren in child care).
The use of leukocyte-depleted blood products effec
-
tively reduces the incidence of CMV disease in patients 
who have undergone transplantation. Prophylactic and 
preemptive strategies (eg, antiviral agents only when anti
-
gen detection or PCR assays show evidence of active CMV 
replication) appear equally effective in preventing invasive 
disease and mortality after hematopoietic stem cell trans
-
plant. The appropriate management of transplant patients 
is based on the serostatus of the donor and the recipient. 
All effective anti-CMV agents can serve as prophylactic 
agents for CMV-seropositive transplants or for CMV-
seronegative recipients of CMV-positive organ transplants, 
although starting CMV prophylaxis 14 days after trans
-
plant may help reduce late-onset CMV end-organ disease. 
Acyclovir may also be used. The dose for valganciclovir 
prophylaxis is 450 mg orally twice daily.
CMV immune globulin may also be useful in reducing 
the incidence of bronchiolitis obliterans in the bone marrow 
transplant population and is used in some centers as part of 
the prophylaxis in kidney, liver, and lung transplantation 
patients. CMV immune globulin as prophylaxis is not recom
-
mended in hematopoietic stem cell transplant recipients.
 
»
•	
AIDS patients with retinitis, esophagitis, colitis, hepato
-
biliary disease, or encephalitis.
•	
Organ and hematopoietic stem cell transplants with 
suspected reactivation CMV .
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»
•	
Escalating CMV viral load at the onset of illness.
•	
Risk of colonic perforation.
•	
Evaluation of unexplained, advancing encephalopathy.
•	
Initiation of treatment with intravenous anti-CMV 
agents.
Boekh M et al. Valganciclovir for the prevention of complica
-
tions of late cytomegalovirus infection after allogeneic hema
-
topoietic cell transplantation: a randomized trial. Ann Intern 
Med. 2015 Jan 6;162(1):1–10. [PMID: 25560711]
Kimberlin DW et al; National Institute of Allergy and Infectious 
Diseases Collaborative Antiviral Study Group. Valganciclovir 
for symptomatic congenital cytomegalovirus disease. N Engl 
J Med. 2015 Mar 5;372(10):933–43. [PMID: 25738669]
Liu J et al. Patients with refractory cytomegalovirus (CMV) 
infection following allogeneic haematopoietic stem cell trans
-
plantation are at high risk for CMV disease and non-relapse 
mortality. Clin Microbiol Infect. 2015 Dec;21(12):1121.e9–15. 
[PMID: 26093077]
U.S. Department of Health and Human Services (HHS). AID
-
Sinfo. Guidelines for the prevention and treatment of oppor
-
tunistic infections in HIV-infected adults and adolescents. 
Cytomegalovirus. 2017 Jan 17. https://aidsinfo.nih.gov/
guidelines/html/4/adult-and-adolescent-opportunistic-
infection/337/cytomegalovirus-disease
Yu Q et al. Outcomes and prognostic factors of non-HIV 
 pneumonia and pulmo
-
nary CMV co-infection: a retrospective cohort study. BMC 
Infect Dis. 2017 Jun 5;17(1):392. [PMID: 28583135]
6. Human Herpesviruses 6, 7, & 8
HHV-6
 is a B-cell lymphotropic virus that is the principal 
cause of exanthema subitum (roseola infantum, sixth dis
-
ease). Primary HHV-6 infection occurs most commonly in 
children under 2 years of age and is a major cause of infantile 
febrile seizures (21% in one recent series). HHV-6 is also 
associated with encephalitis (symptoms may include insom
-
nia, seizures, and hallucinations), Hashimoto thyroiditis, 
myocarditis, and acute liver failure. Primary infection in 
immunocompetent adults is not common but can produce a 
mononucleosis-like illness. Pathologically, HHV-6 is associ
-
ated with mesial temporal sclerosis, which may lead to mesial 
temporal lobe epilepsy. Reactivation of HHV-6 in immuno
-
competent adults is rare and can present as encephalitis. 
Imaging studies in HHV-6 encephalitis typically show lesions 
in the hippocampus, amygdala, and limbic structures.
Infection during pregnancy and congenital transmis
-
sion is recognized. Most cases of reactivation occur in 
immunocompromised persons. Reactivation is associated 
with graft rejection, graft-versus-host disease, and bone 
marrow suppression in transplant patients and with 
encephalitis and pneumonitis in AIDS patients. In recipi
-
ents of hematopoietic stem cell transplants, HHV-6 may 
cause fever. It is also associated with an HHV-6–induced 
encephalitis that is correlated strongly with umbilical cord 
hematopoietic cell transplants (although HHV-6 is not 
associated with survival in such patients and surveillance 
for the virus may not be needed).
HHV-6 is on occasion also associated with drug-induced 
hypersensitivity syndromes. HHV-6 may cause fulminant 
hepatic failure and acute decompensation of chronic liver 
disease in children. Purpura fulminans and corneal inflam
-
mation are reported with HHV-6 infection. Two variants 
(A and B) of HHV-6 have been identified. HHV-6B is the 
predominant strain found in both normal and immunocom
-
promised persons. Ganciclovir, cidofovir, and foscarnet (but 
not acyclovir) appear to be clinically active against HHV-6.
HHV-7
 is a T-cell lymphotropic virus that is associated 
with roseola seizures and, rarely, encephalitis, even in 
immunocompetent adults. Pregnant women are often 
infected. Infection with HHV-7 is synergistic with CMV in 
kidney transplant recipients.
HHV-8
 (see also Chapter 31) is associated with Kaposi

HHV-8
 (see also Chapter 31) is associated with Kaposi 
sarcoma, multicentric Castleman disease, and primary 
effusion (body cavity) lymphoma. HHV-8 infection is 
endemic in Africa; transmission seems to be primarily 
horizontal in childhood from intrafamilial contacts and 
continues through adulthood possibly by nonsexual routes.
Komaroff AL et al. Summary of the 9th international conference 
on human herpesviruses 6 and 7 (HHV-6A, HHV-6B, and 
HHV-7). J Med Virol. 2016 Dec;88(12):2038–43. [PMID: 
27124385]
Mohammadpour Touserkani F et al. HHV-6 and seizure: a sys
-
tematic review and meta-analysis. J Med Virol. 2017 Jan; 
89(1):161–9. [PMID: 27272972]
Riva N et al. Acute human herpes virus 7 (HHV-7) encephalitis 
in an immunocompetent adult patient: a case report and 
review of literature. Infection. 2017 Jun;45(3):385–8. [PMID: 
28386807]
Sultanova A et al. Association of active human herpesvirus-6 
(HHV-6) infection with autoimmune thyroid gland diseases. 
Clin Microbiol Infect. 2017 Jan;23(1):50.e1–5. [PMID: 
27693656]
MAJOR VACCINE-PREVENTABLE 
VIRAL INFECTIONS
1. Measles
 
»
Exposure 7–18 days before onset of fever in an 
unvaccinated patient.
 
»
Prodrome of fever, coryza, cough, conjunctivitis, 
malaise, irritability, photophobia, Koplik spots.
 
»
Rash: brick red, maculopapular; appears 3–4 days 
after onset of prodrome; begins on the face and 
proceeds “downward and outward, ” affecting the 
palms and soles last.
 
»
Leukopenia.
 
»
Measles is a reportable acute systemic paramyxoviral infec
-
tion transmitted by direct contact with infectious droplets or 
by airborne spread. It is highly contagious with 
communicability greatest during the preeruptive and catarrhal 
stages but continues 4 days after the appearance of rash. 
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Measles elimination is defined as the absence of endemic mea
-
sles virus transmission in an area lasting 12 months or longer.
Between 2000 and 2016, the annual incidence of measles 
decreased by 87%. Only one World Health Organization 
region (Americas) has been verified as having eliminated 
measles. Since the elimination of measles in 2000 in the United 
States, outbreaks in the United States occurred predominantly 
among intentionally unvaccinated children (59–93%).
As of October 2017, 120 cases of measles from 15 states 
are reported to the CDC, surpassing the number of cases 
reported in 2016; 65 confirmed cases were identified in a 
Somali-American community from Minnesota due to a 
decline in MMR vaccination coverage. In addition, impor
-
tations of measles from endemic countries to the United 
States continue to occur, contributing to outbreaks. Despite 
sporadic outbreaks, elimination of measles in the United 
States appears to have been sustained as of 2011, but rising 
rates of intentional undervaccination undermine measles 
elimination programs.
 
»
The incubation period for measles is 10–14 days. The 
illness starts with a prodromal phase manifested by high-
grade fever (often as high as 40–40.6
°
C), malaise, coryza 
(nasal obstruction, sneezing, and sore throat resembling 
upper respiratory infections), persistent cough, conjuncti
-
vitis (redness, swelling, photophobia, and discharge). 
These symptoms intensify over 2–4 days before onset of the 
rash and peak on the first day of the rash. The fever persists 
through the early rash (about 5–7 days) (Table 32–2).
The characteristic measles rash appears on the face and 
behind the ears. Initial lesions are pinhead-sized papules 
that coalesce to form a brick red, irregular, blotchy maculo
-
papular rash. The rash spreads to the trunk and extremities, 
including the palms and soles. It lasts for 3–7 days and fades 
in the same manner it appeared. Other findings include 
pharyngeal erythema, tonsillar exudate, moderate general
-
ized lymphadenopathy and, at times, splenomegaly.
Koplik spots
 (small, irregular, and red with whitish 
center on the mucous membranes) are pathognomonic of 
measles (Figure 32–4). They appear about 2 days before the 
 
▲
Figure 32–4.
 
Koplik spots 
(Public Health Image 
rash and last 1–4 days as tiny “table salt crystals” on the 
palatal or buccal mucosa opposite the molars.
Leukopenia is usually present unless secondary bacterial 
complications exist. A lymphocyte count under 2000/mcL 
is a poor prognostic sign. Thrombocytopenia is common. 
Proteinuria is often observed.
Detection of IgM measles antibodies with ELISA or a 
fourfold rise in serum hemagglutination inhibition anti
-
body supports the diagnosis. IgM assays can be falsely 
negative the first few days of infection and falsely positive 
in the presence of rheumatoid factor or with acute rubella, 
erythrovirus (formerly parvovirus B19), or HHV-6 
Measles virus is technically difficult to culture. Real-
time reverse transcriptase-PCR (RT-PCR), available from 
the CDC and some public health laboratories, can help 
establish a diagnosis promptly.
 
»
Measles is usually diagnosed clinically but may be mis
-
taken for Kawasaki disease and other exanthematous infec
-
tions (Table 32–2). Frequent difficulty in establishing a 
diagnosis suggests that measles may be more prevalent 
than is recognized.
 
»
A. Central Nervous System
Postinfectious encephalomyelitis occurs in 0.05–0.1% of 
cases, with higher rates occurring in adolescents. It is an 
acute demyelinating disease that usually starts 3–7 days 
after the rash. Seizures, coma, and other neurologic symp
-
toms and signs may develop. Treatment is symptomatic 
and supportive. Virus isolation from the CNS is uncom
-
mon. There is an appreciable mortality (10–20%) and

-
-
mon. There is an appreciable mortality (10–20%) and 
morbidity (33% of survivors are left with neurologic 
deficits).
Measles inclusion body encephalitis is another form of 
neurologic complication that results in neurologic deterio
-
ration and death within months of the acute illness among 
patients with impaired cellular immunity. Treatment is 
supportive, including stopping immunosuppressants 
when feasible. Interferon and ribavirin are variably 
successful.
Subacute sclerosing panencephalitis is a very rare, and 
fatal CNS complication that occurs 5–15 years after infec
-
tion. It is characterized by progressive deterioration of 
motor and cognitive function leading to death. It is more 
common in persons who are infected with measles before 
2 years of age.
B. Respiratory Tract Disease
Early in the course of the disease, bronchopneumonia or 
bronchiolitis due to the measles virus may occur in up to 
5% of patients and result in serious respiratory difficulties. 
Bronchiectasis may occur in up to a quarter of nonvacci
-
nated children. The incidence of severe respiratory disease 
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may be increased among immunocompromised children 
and pregnant women.
C. Other Complications
Immediately following measles, secondary bacterial infec
-
tion, particularly cervical adenitis, otitis media (the most 
common complication), and pneumonia, occurs in about 
15% of patients. Keratoconjunctivitis is a serious complica
-
tion that caused blindness before the widespread use of 
measles vaccine and vitamin A supplementation. Diarrhea 
and protein-losing enteropathy (prodromal rectal Koplik 
spots may occur) are significant complications among mal
-
nourished children. Some data implicate the measles virus 
in the pathogenesis of rheumatoid arthritis.
 
»
Treatment
Treatment is symptomatic, including antipyretics and flu
-
ids as needed. Vitamin A supplementation for children 
reduces pediatric morbidity and measles-associated mor
-
tality. Data are less substantial for adult supplementation, 
although many advocate megadose vitamin A at the time of 
delivery in order to boost infant levels of the vitamin.
Measles virus is susceptible to ribavirin and other anti
-
virals in vitro. Ribavirin is used in selected severe cases of 
pneumonitis, but there is not enough evidence to recom
-
mend antiviral use. Zinc has a role in the maintenance of 
normal immune functions, but insufficient data are avail
-
able to recommend zinc supplementation to children with 
measles.
 
»
Prognosis
During 2000–2016, annual estimated measles deaths 
decreased by 84%. It is estimated that 20.4 million deaths 
have been prevented from measles vaccination. In the 
United States, the case fatality rate is around 2 per 1000 
reported cases, with deaths principally due to neurologic 
and respiratory complications. Death in the developing 
world is mainly related to diarrhea and protein-losing 
enteropathy. Pregnant women with measles may be at 
increased risk for death.
 
»
Because measles is highly contagious, the vaccine coverage 
rates must exceed 95% to prevent outbreaks. Illness confers 
permanent immunity. One vaccine dose is about 93% 
effective. Two doses of vaccine are estimated to be 97% 
protective.
In the United States, based on the 2016 National Immu
-
nization Survey, 91.1% of children aged 19–35 months 
received one or more doses of measles, mumps, and rubella 
vaccine (MMR) and 90.9% of adolescents aged 13–17 years 
received two or more doses). There is considerable geo
-
graphic disparity in this value. Clustering of unvaccinated 
individuals also increases the likelihood of an outbreak. 
One study predicted that a 5% decline in MMR vaccination 
would increase the annual number of measles cases by 
threefold among children aged 2–11 years and the financial 
cost by $2.1 million.
At 6 months of age, more than 99% of infants of vacci
-
nated women and 95% of infants of naturally immune 
women lose maternal antibodies. The susceptibility to 
measles is 2.4-fold higher if the vaccine is given prior to 
15 months. Thus, in the United States, children receive 
their first vaccine dose at 12–15 months of age. The second 
dose is given at age 4–6 years, prior to school entry. For 
individuals born before 1957, herd immunity is assumed. 
All adults born after 1957, without evidence of immunity 
should get at least 1 dose of MMR vaccine. Persons at high 
risk for measles exposure (teachers, health care workers, 
post–high school students, travelers to developing 
countries) should receive two vaccination doses at least 
28 days apart. Immigrants and refugees should be screened 
and vaccinated if necessary. Combination measles-mumps-
rubella-varicella vaccines (MMRV) can be used in place of 
the traditional MMR vaccine.
MMR and MMRV vaccine should not be administered 
to pregnant women, patients with anaphylactic reactions to 
neomycin, and patients with known primary or acquired 
immunodeficiency. Asymptomatic patients living with

immunodeficiency. Asymptomatic patients living with 
HIV with CD4 counts higher than 200 cells/mcL should 
receive MMR vaccine but not MMRV vaccine.
Repeated studies fail to show an association between 
vaccination and autism. MMR vaccine can cause fever and 
transient rash. Severe allergic reactions are rare. Quadriva
-
lent MMRV vaccine is associated with an increased risk of 
febrile seizures that appears to be age-related; the risk is 
highest when MMRV is given to infants between 12 and 
23 months of age.
In case of an outbreak, when susceptible individuals are 
exposed to measles, MMR vaccine can prevent disease if 
given within 3 days of exposure. Immunoglobulin (IG) 
should be administered within 6 days of exposure in any 
high-risk person exposed to measles, followed by active 
immunization 3 months later. All infants less than 1 year of 
age should receive intramuscular IG (0.5 mL/kg, maximum 
dose 15 mL). For infants between 6 months and 11 months, 
MMR vaccination with repeat at 15 months can be given in 
place of intramuscular IG. Pregnant women and severely 
immunocompromised persons who are exposed should 
receive intravenous IG (IVIG) (400 mg/kg).
Patients with measles should be isolated for 4 days after 
rash onset. In the hospital setting, patients with measles 
should be placed under air-borne precautions.
An aerosolized measles vaccine remains under study.
 
»
•	
Any suspect cases should be reported to public health 
authorities.
•	
•	
 
»
•	
Meningitis, encephalitis, or myelitis.
•	
Severe pneumonia.
•	
Diarrhea that significantly compromises fluid or 
electrolyte status.
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Hall V et al. Measles outbreak—Minnesota April–May 2017. 
MMWR Morb Mortal Wkly Rep. 2017 Jul 14;66(27):713–7. 
[PMID: 28704350]
Lo NC et al. Public health and economic consequences of vac
-
cine hesitancy for measles in the United States. JAMA Pediatr. 
2017 Sep 1;171(9):887–92. [PMID: 28738137]
Moss WJ. Measles. Lancet. 2017 Dec 2;390(10111):2490–502. 
[PMID: 28673424]
Ortac Ersoy E et al. Severe measles pneumonia in adults with 
respiratory failure: role of ribavirin and high-dose vitamin A. 
Clin Respir J. 2016 Sep;10(5):673–5. [PMID: 25619709]
26978210]
Thompson AE. JAMA patient page. Recognizing measles. 
JAMA. 2015 Apr 21;313(15):1584. [PMID: 25898066]
Trentini F et al. Measles immunity gaps and the progress towards 
elimination: a multi-country modelling analysis. Lancet 
Infect Dis. 2017 Oct;17(10):1089–97. [PMID: 28807627]
common physical findings and typically develop within 
 
48 hours of the prodromal symptoms. Usually, one parotid 
gland enlarges before the other, but unilateral parotitis 
occurs in 25% of patients. The parotid duct (orifice of 
Stensen) may be red and swollen. Trismus may result from 
parotitis. The parotid glands return to normal within 
1 week. Involvement of other salivary glands (submaxillary 
and sublingual) occurs in 10% of cases. Fever and malaise 
are variable but often minimal in young children. The 
entire course of mumps rarely exceeds 2 weeks.
The testes are the most common extrasalivary disease site 
in adults. High fever, testicular swelling, and tenderness (uni
-
lateral in 75% of cases) denote orchitis, which usually 
develops 7–10 days after the onset of parotitis. In recent out
-
breaks in the United States, complications from mumps were 
rare; 3.3–10% of adolescent and adult males developed 
orchitis (which occurred less frequently in persons who have 
received two doses of vaccine). Lower abdominal pain and 
ovarian enlargement suggest oophoritis, which is usually 
unilateral and occurs in less than 1% of postpubertal women.
Other rare complications, occurring in less than 1% of 
cases, are meningitis, encephalitis, Guillain-Barré syn
-
drome, hearing loss, priapism or testicular infarction from 
orchitis, pancreatitis, thyroiditis, keratitis, neuritis, 
hepatitis, myocarditis, thrombocytopenia, migratory 
arthralgias, and nephritis. No mumps-related deaths have 
occurred in the United States in recent outbreaks.
Some epidemiologic studies have suggested an associa
-
tion between mumps and risk of type 1 diabetes mellitus. 
Further studies do not provide evidence of this association.
Mild leukopenia with relative lymphocytosis may be pres
-
ent. Elevated serum amylase usually reflects salivary gland 
 
▲
Figure 32–5.
 
Mumps. 
(Public Health Image Library, 
CDC.)
2. Mumps
 
»
Exposure 12–25 days before onset.
 
»
Painful, swollen salivary glands, usually parotid.
 
»
Frequent involvement of testes, pancreas, and 
meninges in unvaccinated individuals.
 
»
Mumps occurs in appropriately vaccinated 
persons in highly vaccinated communities.
 
»
Mumps is a paramyxoviral disease spread by respiratory 
droplets. Children are most commonly affected; however, 
in outbreaks, infection can affect patients in their second or 
third decades of life. Mumps can spread rapidly in congre
-
gate settings, such as colleges and schools. The incubation 
period is 12–25 days (average, 16–18 days). The mumps 
virus spreads through direct contact with respiratory secre
-
tions or saliva or infected surfaces. Transmission can also 
be airborne or via droplets. Up to one-third of affected 
individuals have subclinical infection, which is still trans
-

-
-
missible. Despite high vaccination rates, several mumps 
outbreaks were reported over the past few years in an 
increasing number. Between 2016 and 2017, the largest 
outbreak occurred in Arkansas involving 3000 cases. A 
combination of factors contributes to outbreaks, including 
efficacy of vaccines; waning individual immunity; and 
crowded conditions, which promote transmission.
 
»
Mumps is more serious in adults than in children and 
appears to occur more commonly in males. Parotid tender
-
ness and overlying facial edema (Figure 32–5) are the most 
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involvement rather than pancreatitis. Mild kidney injury is 
found in up to 60% of patients.
The characteristic clinical picture usually suffices for 
diagnosis. An elevated serum IgM is considered diagnostic. 
Repeat testing 2–3 weeks after the onset of symptoms is 
recommended if the first assay is negative because the rise 
in IgM may be delayed, especially in vaccinated persons. 
 
A fourfold rise in complement-fixing antibodies to mumps 
virus in paired serum IgG also confirms infection. Anti-
mumps IgM and IgG in the CSF can confirm the diagnosis 
of meningitis. Nucleic acid amplification techniques, such 
as real-time RT-PCR, are more sensitive than viral cultures 
and are available from some commercial laboratories, 
selected state laboratories, and the CDC. Diagnostic yield 
is highest if collected during the first 3 days of illness. Con
-
firmatory diagnosis of mumps is also made by isolating the 
virus preferably from a swab of the duct of the parotid or 
other affected salivary gland. The virus can also be isolated 
from CSF early in aseptic meningitis. Vaccinated persons 
may shed virus for shorter periods of time compared to 
those who are unvaccinated.
 
»
Swelling of the parotid gland may be due to calculi in the 
parotid ducts, tumors, or cysts. Other causes include sar
-
coidosis, cirrhosis, diabetes, bulimia, pilocarpine usage, 
and Sjögren syndrome. Parotitis may be produced by pyo
-
genic organisms (eg, 
S aureus
, gram-negative organisms 
[particularly in debilitated individuals with poor oral 
intake]), drug reaction (phenothiazines, propylthiouracil), 
and other viruses (HIV , influenza A, parainfluenza, EBV 
infection, coxsackieviruses, adenoviruses, HHV-6). Swell
-
ing of the parotid gland must be differentiated from 
inflammation of the lymph nodes located more posteriorly 
and inferiorly than the parotid gland.
 
»
Treatment
Treatment is symptomatic. Topical compresses may relieve 
parotid discomfort. Some clinicians advocate IVIG for 
complicated disease (eg, thrombocytopenia), although its 
definitive role is unproven. There is no specific treatment 
for orchitis.
 
»
Vaccination is the most effective way to prevent mumps.
Monovalent mumps vaccine is no longer available in the 
United States. Mumps vaccine is now administered as com
-
bined vaccine in MMR or MMRV vaccine. The vaccination 
schedule, indications, and contraindications are described 
in the measles section. The mumps vaccine component of 
the MMR is less effective than the measles and rubella com
-
ponents. One dose is 78% (range: 49–92%) protective. Two 
doses of the vaccine are 88% (range: 66–95%) effective.
A 2017 study, evaluating the effect of third dose of 
MMR vaccine after a mumps outbreak, showed that the 
attack rate was significantly lower among students who 
received a third dose compared with two doses, especially 
if the second dose was given more than 13 years prior to 
the outbreak. The CDC recommends considering a third 
dose of vaccine in case of an outbreak but did not issue a 
formal recommendation.
The patient should be isolated. For outbreak control, 
the most important step is to vaccinate all susceptible indi
-
viduals. MMR vaccine is not effective in preventing the 
disease in unvaccinated patients who already have been 
exposed to the virus. In the healthcare setting, the follow
-
ing steps should be taken: implement droplet and standard 
precaution, isolate patients until swelling subsides (about 
 
9 days from onset), and provide vaccination to healthcare 
workers with no evidence of immunity.
 
»
 
»
•	
Trismus; meningitis; encephalitis; myocarditis; 
•	
Severe testicular pain; priapism.
•	
Severe thrombocytopenia.
Bockelman C et al. Mumps: an emergency medicine-focused

•	
•	
•	
Bockelman C et al. Mumps: an emergency medicine-focused 
update. J Emerg Med. 2018 Feb;54(2):207–14. [PMID: 
29110978]
Cardemil CV et al. Effectiveness of a third dose of MMR vaccine 
for mumps outbreak control. N Engl J Med. 2017 Sep 7; 
377(10):947–56. [PMID: 28877026]
Gouma S et al. Severity of mumps disease is related to MMR 
vaccination status and viral shedding. Vaccine. 2016 Apr 7; 
34(16):1868–73. [PMID: 26954106]
Woo TM. Postexposure management of vaccine-preventable 
diseases. J Pediatr Health Care. 2016 Mar–Apr;30(2):173–82. 
[PMID: 26896379]
3. Rubella
 
»
Exposure 14–21 days before onset.
 
»
No prodrome in children, mild prodrome in adults; 
mild symptoms (fever, malaise, coryza) coincide 
with eruption.
 
»
Posterior cervical and postauricular lymphade
-
nopathy 5–10 days before rash.
 
»
Fine maculopapular rash of 3 days’ duration; face 
to trunk to extremities.
 
»
Leukopenia, thrombocytopenia.
 
»
Rubella is a systemic disease caused by a togavirus trans
-
mitted by inhalation of infective droplets. It is moderately 
communicable. Infection usually confers permanent 
immunity. The incubation period is 14–21 days. The dis
-
ease is transmissible from 1 week before the rash appears 
until 15 days afterward.
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The last cases of endemic rubella and congenital rubella 
syndrome were reported in 2009 from the Americas 
region. In 2015, the WHO declared the Americas region 
free of rubella and congenital rubella syndrome. Some 
European countries are facing a challenge with lower 
immunization coverage among refugees and migrants. 
Worldwide, cases are decreasing from an estimated 670,894 
in 2000 to 22,361 in 2016 due to widespread implementa
-
tion of rubella-containing vaccines, which was added to 
the national vaccine schedule in 152 (78%) countries as of 
2016. On the other hand, the number of cases of congenital 
rubella syndrome is increasing particularly in Southeast 
Asia. This increase may be secondary to an increase in 
surveillance and reporting of congenital rubella cases. The 
WHO set a goal to eliminate rubella in at least five of the 
six WHO regions by 2020.
 
»
A. Postnatal Rubella
Rubella is a common childhood disease; the majority of the 
cases are asymptomatic. The clinical picture of rubella is 
difficult to distinguish from other viral illnesses, such as 
infectious mononucleosis, measles, echovirus infections, 
and coxsackievirus infections. Fever and malaise, usually 
mild, accompanied by tender suboccipital adenitis, may 
precede the eruption by 1 week. Early posterior cervical 
and postauricular lymphadenopathy is common. A fine, 
pink maculopapular rash appears and fades from the face, 
trunk, and extremities in rapid progression (2–3 days), 
usually lasting 1 day in each area (Table 32–2).
B. Congenital Rubella
The principal importance of rubella lies in its devastating 
effects on the fetus in utero causing fetal death, preterm 
delivery, and teratogenic effects. The severity of symptoms 
is directly related to the gestational age; fetal infection dur
-
ing the first trimester leads to congenital rubella in at least 
80% of fetuses; however, an infection during the fourth 
month can lead to 10% risk of a single congenital defect. In 
the second trimester of pregnancy, deafness is the primary 
complication.
When rubella is suspected, the diagnosis requires serologic 
confirmation. Diagnosis of acute rubella infection is based 
on elevated IgM antibody, fourfold or greater rise in IgG 
antibody titers, or isolation of the virus.
IgM is detectable in 50% of persons on day 1 of the rash 
but in most on day 5 after rash onset. Antibody testing can 
be performed on sera or saliva. An isolated IgM-positive 
test does not necessarily imply acute infection. IgM anti
-
bodies can persist after an infection or could be false-
positive due to cross-reactivity with other antigens such as 
EBV , CMV , erythrovirus, and rheumatoid factor. This dis
-
tinction is very important to make when infection is sus
-
pected in pregnancy. High-avidity anti-rubella IgG assays 
can distinguish between recent and remote infection. Low-
avidity IgG is observed in acute rubella infections and lasts 
up to 3 months postinfection. After 3 months, low-avidity 
antibodies are replaced by high-avidity antibodies indicat
-
ing remote infection.
The CDC can test for virus by RT-PCR from throat 
swabs, oral fluids, or nasopharyngeal secretions. The tim
-
ing of sample collection is important and is best if collected 
within the first 3 days of an acute illness and within 
 
3 months in case of congenital rubella syndrome. After 
 
3 months of age, up to 50% of infants with congenital 
rubella syndrome will not shed the virus.
 
»
Complications of rubella are rare. Polyarticular arthritis 
and arthralgia occur more commonly in adult women; 
involve the fingers, wrists, and knees; and usually subside 
within 7 days but may persist for weeks. Hemorrhagic 
manifestations due to thrombocytopenia and vascular 
damage occur more commonly in children, unlike other 
complications. Hepatitis has been reported. Encephalitis,

complications. Hepatitis has been reported. Encephalitis, 
another rare complication, occurs more commonly in 
adults and has a high mortality rate.
 
»
Treatment
Rubella infection, including complications, is treated 
symptomatically.
 
»
Patients with rubella should be isolated for 7 days after rash 
onset.
In the United States, monovalent rubella vaccine is no 
longer produced. Live attenuated rubella virus vaccine is 
primarily given as combination with the measles and 
mumps vaccine (MMR) or in combination with measles, 
mumps, and varicella (MMRV). It is recommended that 
the first dose be given between at 12–15 months. The sec
-
ond dose is given between age 4 and 6 years, prior to school 
entry. More details on scheduling, side effects, and contra
-
indications are explained in the measles section. It is 
important that girls are immune to rubella prior to men
-
arche. In the United States, about 80% of 20-year-old 
women are immune to rubella.
Rubella vaccine is safe and highly efficacious; a single 
dose of MMR vaccine is about 97% effective at preventing 
rubella.
The immune status of pregnant women should be 
evaluated because antibody titers fall in about 10% of vac
-
cinated individuals within 12 years of vaccination. There is 
no evidence of adverse pregnancy outcomes with MMR 
immunization of pregnant women, yet it is still recom
-
mended that women avoid pregnancy for at least 3 months 
after vaccination.
The administration of live vaccines to immunocompro
-
mised patients is controversial. In patients receiving immu
-
nosuppressive therapy as well as in patients who have 
undergone solid organ or bone marrow transplantation, 
seroconversion is higher in rubella compared with measles, 
mumps, and varicella. In addition, response to live attenu
-
ated vaccines may be lessened due to presence of 
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antibodies from IVIG or other blood products. Safety is 
another concern when administering live attenuated 
vaccines to immunocompromised patients. Because MMR 
vaccine is contraindicated in solid organ transplant recipi
-
ents, current evidence recommends that seronegative 
patients receive one or two doses of the MMR vaccine at 
least 4 weeks prior to solid organ transplant. Patients who 
have undergone bone marrow transplant lose antigen-
specific antibodies and should be revaccinated regardless 
of their vaccination history. The revised guidelines recom
-
mend MMR and varicella vaccines be given to seronegative 
patients without graft-versus-host disease 2 years after 
hematopoietic stem cell transplantation.
 
»
Prognosis
Rubella is a mild illness and rarely lasts more than 
3–4 days. Congenital rubella has a high fetal mortality rate 
and the associated congenital defects are largely permanent.
 
»
•	
•	
Meningitis/encephalitis.
•	
Significant vaccination reactions.
•	
Croce E et al. Safety of live vaccinations on immunosuppressive 
therapy in patients with immune-mediated inflammatory 
diseases, solid organ transplantation or after bone-marrow 
transplantation—a systematic review of randomized trials, 
observational studies and case reports. Vaccine. 2017 Mar 1; 
35(9):1216–26. [PMID: 28162821]
de Martino M. Dismantling the taboo against vaccines in preg
-
nancy. Int J Mol Sci. 2016 Jun 7;17(6):894. [PMID: 27338346]
Mipatrini D et al. Vaccinations in migrants and refugees: a chal
-
lenge for European health systems. A systematic review of 
current scientific evidence. Pathog Glob Health. 2017 Mar; 
111(2):59–68. [PMID: 28165878]
World Health Organization. Rubella (crs) reported cases: WHO 
vaccine-preventable diseases: monitoring system 2016 global 
summary. 2017 Sep 06. http://apps.who.int/immunization_
monitoring/globalsummary/timeseries/tsincidencecrs.html
4. 
p
oliom
yelitis
 
»
Incubation period 7–14 days from exposure.
 
»
Headache, stiff neck, fever, vomiting, sore throat.
 
»
Lower motor neuron lesion (flaccid paralysis) with 
decreased deep tendon reflexes and muscle 
wasting.
 
»
Poliomyelitis virus, an enterovirus, is highly contagious 
through fecal-oral route, especially during the first week 
of infection. There are three wild poliovirus serotypes; 
however, only wild poliovirus type 1 has been detected 
since 2012. Pakistan, Afghanistan, and Nigeria remain the 
only countries with endemic poliovirus transmission 
since 2014.
Cases of acute flaccid paralysis resembling polio with 
residual weakness are increasingly being reported. In 2016, 
Germany reported a total of 16 cases and France reported 
59 cases. The CDC reported 144 cases in 2016 that met the 
definition of acute flaccid myelitis. Enterovirus outbreaks 
are implicated but a causal association has not been 
established.
 
»
At least 95% of infections are asymptomatic. Patients who 
become symptomatic can present with abortive poliomy
-
elitis, nonparalytic poliomyelitis, or paralytic poliomyelitis. 
Post-poliomyelitis syndrome
 is the constellation of symp
-
toms that affect polio survivors and is not infectious.
1. Abortive poliomyelitis—
Nonspecific symptoms of this 
minor illness include fever, headache, vomiting, diarrhea, 
constipation, and sore throat lasting 2–3 days.
2. Nonparalytic poliomyelitis—
In addition to the above 
symptoms, signs of meningeal irritation and muscle spasm 
occur in the absence of frank paralysis.
3. Paralytic poliomyelitis—
Characterized as a flaccid 
asymmetric paralysis affecting mostly the proximal mus
-
cles of the lower extremities; the febrile period is present 
over 2–3 days. Sensory loss is very rare. Paralytic polio
-
myelitis is divided into two forms, which may coexist:

-
-
myelitis is divided into two forms, which may coexist: 
 
(1) spinal poliomyelitis involving the muscles innervated 
by the spinal nerves, and (2) bulbar poliomyelitis involv
-
ing the muscles supplied by the cranial nerves (especially 
nerves IX and X) and of the respiratory and vasomotor 
centers. The most life-threatening aspect of bulbar polio
-
myelitis is respiratory paralysis. The incidence of para
-
lytic poliomyelitis is higher when infections are acquired 
later in life.
4. Post-poliomyelitis syndrome—
The syndrome presents 
with signs of chronic and new denervation. The most fre
-
quent symptoms are progressive muscle limbs paresis with 
muscle atrophy, with fasciculations and fibrillation during 
rest activity.
The virus may be recovered from throat washings (early) 
and stools (early and late) and PCR of washings, stool, or 
CSF can also facilitate diagnosis. CSF findings include the 
following: (1) normal or slightly increased pressure and 
protein, (2) glucose is not decreased, and (3) white blood 
cells usually number less than 500/mcL and are principally 
lymphocytes after the first 24 hours. CSF findings are nor
-
mal in 5% of patients. Neutralizing and complement-fixing 
antibodies appear during the first or second week of illness. 
Serologic testing cannot distinguish between wild type and 
vaccine-related virus infections.
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»
Acute inflammatory polyneuritis (Guillain-Barré 
syndrome), Japanese encephalitis virus infection, West Nile 
virus infection, and tick paralysis may resemble poliomy
-
elitis. In Guillain-Barré syndrome (see Chapter 24), the 
weakness is more symmetric and ascending in most cases, 
but the Miller Fisher variant of Guillain-Barré is similar to 
bulbar poliomyelitis. Paresthesia is uncommon in poliomy
-
elitis but common in Guillain-Barré syndrome. The CSF 
usually has high protein content but normal cell count in 
Guillain-Barré syndrome. Acute flaccid paralysis resem
-
bling polio with residual weakness are increasingly recog
-
nized with no evidence of polio infection. Enterovirus is 
isolated in some of these cases.
 
»
Treatment
In the acute phase of paralytic poliomyelitis, patients 
should be hospitalized. In cases of respiratory weakness or 
paralysis, intensive care is needed. Intensive physiotherapy 
may help recover some motor function with paralysis. 
Attention to psychological disorders in longstanding dis
-
ease is also important.
Immunodeficient individuals have prolonged excretion 
of poliovirus leading to virus circulation and threatening 
the polio eradication efforts. Pocapavir, an experimental 
capsid inhibitor antiviral agent, was tested in healthy adults 
given monovalent live oral poliovirus vaccine (OPV) type 
1 and was shown to be safe and effective in reducing the 
duration of viral excretion in stool; resistance emerged in 
44% of treated participants in this study.
Immune modulators, such as prednisone, interferon, 
and IVIG, do not show any clear benefit in the treatment of 
post-poliomyelitis syndrome.
 
»
Prognosis
The death-to-case ratio for paralytic polio ranges between 
2% and 30%, depending on age. Bulbar poliomyelitis car
-
ries a mortality rate of up to 75%.
 
»
Given the epidemiologic distribution of poliomyelitis and 
the continued concern about vaccine-associated disease 
with the trivalent live OPV , the inactive (Salk) parenteral 
vaccine is currently used in the United States for all four 
recommended doses (at ages 2 months, 4 months, 
6–18 months, and at 4–6 years). Inactivated vaccine is also 
routinely used elsewhere in the developed world where one 
dose is often administered, although immunogenicity is 
improved with additional doses.
Because most of circulating vaccine-derived poliovirus 
and vaccine-associated poliomyelitis are live OPV type 2, 
the WHO replaced worldwide the trivalent live OPV (con
-
taining types 1, 2, and 3) with the bivalent live OPV (type 1 
and 3) in 2016. The goal is to replace all live OPV with 
inactive parenteral vaccination to eliminate poliovirus cir
-
culation. The advantages of oral vaccination are the ease of 
administration, low cost, effective local gastrointestinal 
and circulating immunity, and herd immunity.
Routine immunization of adults in the United States is 
no longer recommended because of the low incidence of 
the disease. Vaccination should be considered for adults 
not vaccinated within the prior decade who are exposed to 
poliomyelitis or who plan to travel to endemic areas and 
adults engaged in high-risk activities (eg, laboratory work
-
ers handling stools).
 
»
Any suspicious cases should be referred to public health 
Collett MS et al. Antiviral activity of pocapavir in a randomized, 
blinded, placebo-controlled human oral poliovirus vaccine 
challenge model. J Infect Dis. 2017 Feb 1;215(3):335–43. 
[PMID: 27932608]
Elhamidi Y et al. Progress toward poliomyelitis eradication—
Pakistan, January 2016–September 2017. MMWR Morb 
Mortal Wkly Rep. 2017 Nov 24;66(46):1276–80. [PMID: 
29166363]
Messacar K et al. Acute flaccid myelitis: a clinical review of US 
cases 2012–2015. Ann Neurol. 2016 Sep;80(3):326–38. 
[PMID: 27422805]
Pastuszak Ż et al. Post-polio syndrome. Cases report and review

Pastuszak Ż et al. Post-polio syndrome. Cases report and review 
of literature. Neurol Neurochir Pol. 2017 Mar–Apr;51(2): 
140–5. [PMID: 28209439]
World Health Organization. Global Polio Eradication Initiative. 
Polio today. http://polioeradication.org/polio-today
OTHER NEUROTROPIC VIRUSES
1. Rabies
 
»
History of animal bite.
 
»
Paresthesias, hydrophobia, rage alternating 
 
with calm.
 
»
Convulsions, paralysis, thick tenacious saliva.
 
»
Rabies is a viral (rhabdovirus) encephalitis transmitted by 
infected saliva that gains entry into the body by an animal 
bite or an open wound. Worldwide, 17.4 million cases of 
animal bites are reported every year, and it is estimated that 
about 60,000 deaths annually are attributable to rabies. 
Rabies is endemic in over 150 countries; on the basis of 
interviews, it is estimated that over 40% of the world’s 
population lives in areas without rabies surveillance. Most 
cases of rabies occur in rural areas of Africa and Asia. India 
has the highest incidence, accounting for 36% of global 
deaths (http://www.who.int/rabies/epidemiology/en/). In 
developing countries, more than 90% of human cases and 
99% of human deaths from rabies are secondary to bites 
from infected dogs. Rabies among travelers to rabies-
endemic areas is usually associated with animal injuries 
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(including dogs in North Africa and India, cats in the 
Middle East, and nonhuman primates in sub-Saharan 
Africa and Asia), with most travel-associated cases occur
-
ring within 10 days of arrival. Rare but related viruses are 
the Australian lyssavirus, transmitted by bats including one 
referred to as the black flying fox, and which has caused 3 
deaths over the last 20 years, and the European lyssavirus, 
with cases from Germany and the United Kingdom.
In the United States, domestically acquired rabies 
cases are rare (approximately 92% of cases are associated 
with wildlife) but probably underreported. Reports 
largely from the East Coast show an increase in rabies 
among cats, with about 1% of tested cats showing rabies 
seropositivity. Between 2008 and 2017, 23 cases were 
reported in the United States (8 of which were acquired 
abroad). The annual caseload in the United States is 
1–3 cases (https://www.cdc.gov/rabies/location/usa/
surveillance/human_rabies.html). Surveillance for ani
-
mal rabies in 2014 showed 6033 cases occurring in 
49 states and Puerto Rico. Wildlife reservoirs, with each 
species having its own rabies variant(s), follow a unique 
geographic distribution in the United States: raccoons on 
the East Coast; skunks in the Midwest, Southwest, and 
California; and foxes in the Southwest and in Alaska. 
However, some areas have all four wildlife reservoirs 
(eg, the hill country of Texas). Hawaii is the only rabies-
free state to date. Most of Western Europe and much of 
Oceania is rabies-free.
Raccoons, bats, and skunks account for 84% of the rabid 
animals found in the United States; other rabid animals 
include foxes, cats, cattle, and dogs. Rodents and lago
-
morphs (eg, rabbits) are unlikely to spread rabies because 
they cannot survive the disease long enough to transmit it 
(woodchucks and groundhogs are exceptions). Wildlife epi
-
zootics present a constant public health threat in addition to 
the danger of reintroducing rabies to domestic animals. Vac
-
cination is the key to controlling rabies in small animals and 
preventing rabies transmission to human beings.
The virus enters the salivary glands of dogs 5–7 days 
before their death from rabies, thus limiting their period of 
infectivity. Less common routes of transmission include 
contamination of mucous membranes with saliva or brain 
tissue, aerosol transmission, and corneal transplantation. 
Recognized mutations in rabies virus proteins can subvert 
the host immune system. Transmission through solid 
organ and vascular segment transplantation from donors 
with unrecognized infection is also reported. A number of 
transplantation-associated cases are reported, including 
two clusters in the United States. Postexposure prophylaxis 
can be administered in these patients and may prevent 
development of disease.
The incubation period may range from 10 days to 
many years but is usually 3–7 weeks depending in part on 
the distance of the wound from the CNS. The virus travels 
in the nerves to the brain, multiplies there, and then 
migrates along the efferent nerves to the salivary glands. 
Rabies virus infection forms cytoplasmic inclusion bodies 
similar to Negri bodies. These Negri body-like structures 
are thought to be the sites of viral transcription and 
replication.
 
»
While there is usually a history of animal bite, bat bites may 
not be recognized. The prodromal syndrome consists of 
pain at the site of the bite in association with fever, malaise, 
headache, nausea, and vomiting. The skin is sensitive to 
changes of temperature, especially air currents (aerophobia). 
Percussion myoedema (a mounding of muscles after a light 
pressure stimulus) can be present and persist throughout 
the disease. The CNS stage begins about 10 days after the 
prodrome and may be either encephalitic (“furious”) or

prodrome and may be either encephalitic (“furious”) or 
paralytic (“dumb”). The encephalitic form (about 80% of 
the cases) produces the classic rabies manifestations of 
delirium alternating with periods of calm, extremely pain
-
ful laryngeal spasms on attempting drinking (hydrophobia), 
autonomic stimulation (hypersalivation), and seizures. In 
the less common paralytic form, an acute ascending paral
-
ysis resembling Guillain-Barré syndrome predominates 
with relative sparing of higher cortical functions initially. 
Both forms progress relentlessly to coma, autonomic ner
-
vous system dysfunction, and death.
Biting animals that appear well should be quarantined and 
observed for 10 days. Sick or dead animals should be tested 
for rabies. A wild animal, if captured, should be sacrificed 
and the head shipped on ice to the nearest laboratory quali
-
fied to examine the brain for evidence of rabies virus. 
When the animal cannot be examined, raccoons, skunks, 
bats, and foxes should be presumed to be rabid.
Direct fluorescent antibody testing of skin biopsy mate
-
rial from the posterior neck (where hair follicles are highly 
innervated) has a sensitivity of 60–80%.
Quantitative RT-PCR, nucleic acid sequence-based 
amplification, direct rapid immunohistochemical test and 
viral isolation from the CSF or saliva are advocated as defini
-
tive diagnostic assays. Antibodies can be detected in the 
serum and the CSF. Pathologic specimens often demonstrate 
round or oval eosinophilic inclusion bodies (Negri bodies) in 
the cytoplasm of neuronal cells, but the finding is neither 
sensitive nor specific. MRI signs are diffuse and nonspecific.
 
»
Management requires intensive care with attention to the 
airway, maintenance of oxygenation, and control of sei
-
zures. Universal precautions are essential. Corticosteroids 
are of no use. Survival is rare, and data are insufficient to 
provide estimate of success.
If postexposure prophylaxis (discussed below) is given 
expediently, before clinical signs develop, it is nearly 100% 
successful in prevention of disease. Once the symptoms 
have appeared, death almost inevitably occurs after 7 days, 
usually from respiratory failure. Most deaths occur in per
-
sons with unrecognized disease who do not seek medical 
care or in individuals who do not receive postexposure 
prophylaxis. The very rare cases in which patients recover 
without intensive care are referred to as “abortive rabies. ”
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»
Immunization of household dogs and cats and active 
immunization of persons with significant animal exposure 
(eg, veterinarians) are important. The most important 
decisions, however, concern animal bites. Animals that are 
frequent sources of infection to travelers are dogs, cats, and 
nonhuman primates.
In the developing world, education, surveillance, and 
animal (particularly dog) vaccination programs (at recur
-
rent intervals) are preferred over mass destruction of dogs, 
which is followed typically by invasion of susceptible feral 
animals into urban areas. In some Western European 
countries, campaigns of oral vaccination of wild animals 
led to the elimination of rabies in wildlife.
A. Local Treatment of Animal Bites and Scratches
Thorough cleansing, debridement, and repeated flushing of 
wounds with soap and water are important. Rabies immune 
globulin or antiserum should be given as stated below. 
Wounds caused by animal bites should not be sutured.
B. Postexposure Immunization
The decision to treat should be based on the circumstances of 
the bite, including the extent and location of the wound, the 
biting animal, the history of prior vaccination, and the local 
epidemiology of rabies. 
Any contact or suspect contact with a 
bat, skunk, or raccoon is usually deemed a sufficient indication 
to warrant prophylaxis.
 Consultation with state and local 
health departments is recommended. Postexposure treatment 
including both immune globulin and vaccination should be 
administered as promptly as possible when indicated.
The optimal form of 
 is human 
rabies immune globulin (HRIG; 20 international units/kg), 
administered once. As much as possible of the full dose 
should be infiltrated around the wound, with any remaining 
injected intramuscularly at a site distant from the wound. 
Finger spaces can be safely injected without development of 
a compartment syndrome. If HRIG is not available and 
appropriate tests for horse serum sensitivity are done, equine 
rabies antiserum (40 international units/kg) can be used.
Two vaccines
 are licensed and available for use in 
humans in the United States: a human diploid cell vaccine 
and a purified chick embryo cell vaccine. The current vac
-
cines may be given as four injections of 1 mL intramuscu
-
larly in the deltoid or, in small children, into the anterolateral 
thigh muscles on days 0, 3, 7, and 14 after exposure. (The 
fifth dose at 28 days after exposure is no longer recom
-
mended except among immunosuppressed patients.) The 
vaccine should not be given in the gluteal area due to sub
-
optimal response. An alternative vaccination strategy that 
takes only 1 week, with injections on days 0, 3, and 7 after 
exposure with a Vero cell vaccine is reportedly successful in 
achieving adequate neutralizing titers at days 14 and 28 in 
a study from Thailand. Immune thrombocytopenia (ITP) 
is a reported complication of rabies vaccination.
Rabies vaccines and HRIG should never be given in the 
same syringe or at the same site.
 Allergic reactions to the 
vaccine are rare and include a report of sudden unilateral 
sensorineural hearing loss and immune thrombocytopenic 
purpura, although local reactions (pruritus, erythema, 
tenderness) occur in about 25% and mild systemic reac
-
tions (headaches, myalgias, nausea) in about 20% of recipi
-
ents. Adverse reactions to HRIG seem to be more frequent 
in women and rare in young children. The vaccine is com
-
mercially available or can be obtained through health 
Globally, diverse anti-rabies vaccines are used. In some 
countries, the full spectrum of vaccines, from human dip
-
loid rabies to chromatographically purified rabies vaccine is 
available, whereas in others, the gamut is smaller. Intrader
-
mal application of smaller vaccine doses at multiple sites 
and at different times, commonly practiced in an attempt to

-
and at different times, commonly practiced in an attempt to 
lower costs, and is deemed safe and effective by the WHO.
In patients with history of past vaccination, the need for 
HRIG is eliminated (HRIG is in short supply worldwide), but 
postexposure vaccination is still required. The vaccine should 
be given 1 mL in the deltoid twice (on days 0 and 3). Neither 
the passive nor the active form of postexposure prophylaxis is 
associated with fetal abnormalities and thus pregnancy is not 
considered a contraindication to vaccination. Peripartum 
rabies transmission occurs but is rare. Neonates may also 
receive both forms of postexposure prophylaxis at birth.
The World Health Organization is embarking on a pro
-
gram to eliminate dog-transmitted human rabies by 2030.
C. Preexposure Immunization
Preexposure prophylaxis with three injections of human dip
-
loid cell vaccine intramuscularly (1 mL on days 0, 7, and 21 or 
28) is recommended for persons at high risk for exposure: 
veterinarians (who should have rabies antibody titers checked 
every 2 years and be boosted with 1 mL intramuscularly); 
animal handlers; laboratory workers; Peace Corps workers; 
and travelers with stays over 1 month to remote areas in 
endemic countries in Africa, Asia, and Latin America. An 
intradermal route is also available (0.1 mL on days 0, 7, and 21 
over the deltoid) but not in the United States. Immunosup
-
pressive illnesses and agents including corticosteroids as well 
as antimalarials—in particular chloroquine—may diminish 
the antibody response. A single dose booster at 10 years after 
initial immunization increases the level of antibody titers. 
Unfortunately, data from travel services indicate that only a 
small proportion of travelers with anticipated lengthy stays in 
rabies-impacted areas receive the vaccine as recommended.
 
»
Suspicion of rabies requires contact with public health 
personnel to initiate appropriate passive and active prophy
-
laxis and observation of suspect cases.
 
»
•	
Respiratory, neuromuscular, or CNS dysfunction con
-
sistent with rabies.
•	
Patients with suspect rabies require initiation of therapy 
until the disease is ruled out in suspect animals, and this 
requires coordination of care based on likelihood of 
patient compliance, availability of inpatient and outpa
-
tient facilities, and response of local public health teams.
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Davis BM et al. Everything you always wanted to know about 
rabies virus (but were afraid to ask). Annu Rev Virol. 2015 
Nov;2(1):451–71. [PMID: 26958924]
Willoughby RE Jr. Rabies: rare human infection—common 
questions. Infect Dis Clin North Am. 2015 Dec;29(4):637–50. 
[PMID: 26384549]
viremias high enough to allow continued transmission to 
other mosquitoes and ticks between humans and vectors. 
Human-to-human transmission is usually related to blood 
transfusion and organ transplantation. Since 2003, all blood 
donations in the United States are screened with nucleic 
acid amplification assays for West Nile virus.
Most California serogroup viruses are caused by La 
Crosse encephalitis virus. The number of La Crosse virus 
neuroinvasive cases reported annually varies with an aver
-
age of 63 cases. Most of the cases are reported from Mid
-
western states, occurring primarily from late spring 
through early fall. Less severe forms of California sero
-
group viruses include Jamestown Canyon virus and 
California encephalitis virus.
 
»
West Nile virus infection has an incubation period of 
2–14 days. The infection is symptomatic in only 10% of the 
cases; of those, about 10% progress to neuroinvasive dis
-
ease, including meningitis, encephalitis, and flaccid paraly
-
sis. The case fatality rate is about 10%.
Symptoms include acute febrile illness, and a nonpru
-
ritic maculopapular rash is variably present. Meningitis is 
indistinguishable from other viral meningitis. West Nile 
virus encephalitis presents with fever and altered mental 
status. Other signs include tremors, seizures, cranial nerve 
palsies, and pathologic reflexes. Acute flaccid (poliomyelitis-
like) paralysis, which is asymmetric and can involve facial 
and respiratory muscles, is a well-known complication and 
is less commonly seen with other arboviruses infection. 
West Nile virus can also present as Guillain-Barré syn
-
drome with radiculopathy. The disease manifestations 
associated with West Nile virus infection are strongly age-
dependent: the acute febrile syndrome and mild neurologic 
symptoms are more common in the young, aseptic menin
-
gitis and poliomyelitis-like syndromes are seen in middle-
aged persons, and frank encephalopathy is seen more often 
in older adults. All forms of disease tend to be severe in 
immunocompromised persons in whom neuroinvasive 
manifestations and associated high mortality are more apt 
to develop. Other risk factors for development of neuroin
-
vasive disease and increased mortality include black race, 
diabetes, chronic kidney disease, and hepatitis C virus 
Host genetic variation in the interferon response path
-
way is associated with both risk for symptomatic West Nile 
virus infection and increased likelihood of West Nile virus 
disease progression.
The peripheral white blood cell count is usually normal. 
Usually a CSF lymphocytic pleocytosis is present, and poly
-
morphonuclear cells predominate early. The diagnosis of 
arboviral encephalitides depends on serologic tests. For 
West Nile virus, an IgM capture ELISA in serum or CSF is 
almost always positive by the time the disease is clinically 
evident, and the presence of IgM in CSF indicates 
2. Arbovirus Encephalitides
 
»
Fever, malaise, stiff neck, sore throat, and vomiting, 
progressing to stupor, coma, and convulsions.
 
»
Upper motor neuron lesion signs: exaggerated 
deep tendon reflexes, absent superficial reflexes, 
and spastic paralysis.
 
»
CSF opening pressure and protein are often 
increased with lymphocytic pleocytosis.
 
»
The arboviruses are arthropod-borne viral pathogens carried 
by mosquitoes or ticks that produce clinical manifestations in 
humans. The 
mosquito-borne pathogens
 include three 
togaviruses (causing Western, Eastern, and Venezuelan

togaviruses (causing Western, Eastern, and Venezuelan 
equine encephalitis), four flaviviruses (causing West Nile 
fever, St. Louis encephalitis, Japanese encephalitis, and 
Murray Valley encephalitis), and bunyaviruses (the California 
serogroup of viruses, including the La Crosse virus). The 
tick-borne
 causes of encephalitis include the flavivirus of the 
Powassan encephalitis (North America), tick-borne encepha
-
litis virus (Europe and Asia), and the Colorado tick fever 
reovirus. Tick-borne encephalitis virus, Colorado tick fever, 
and the arboviruses associated with viral hemorrhagic fever 
are discussed below, and only those viruses causing primarily 
encephalitis in the United States will be discussed here.
West Nile virus is the leading cause of domestically 
acquired arboviral disease in the United States.
 West Nile 
virus disease is a nationally notifiable condition. In 2017, 
cases were reported to the CDC from 47 states, 67% were 
classified as neuroinvasive disease and 33% were classified 
as non-neuroinvasive disease. Most cases are identified in 
Texas and California. There is no West Nile virus activity 
reported in Maine, Alaska, and Hawaii. Outbreaks with 
West Nile infection tend to occur between mid-July and 
early September. Climatic factors, including elevated mean 
temperatures and rainfall, correlate with increased West 
Nile infection. West Nile virus circulates between mosqui
-
toes (mainly 
Culex
 species) and birds. In case of West Nile 
virus outbreak, infected birds develop high levels viremia 
that lead to substantial avian mortality and a high incidence 
of mosquito infection. Infected mosquitoes can also bite 
and infect people and other mammals. However, humans 
and other mammals are “dead end” hosts, since they do not 
transmit the virus on to other biting mosquitoes; only den
-
gue and Venezuelan equine encephalitis viruses produce 
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neuroinvasive disease. Documentation of a fourfold 
increase in acute/convalescent IgG titers is confirmatory 
for all arboviruses. Antibodies to arboviruses persist for 
life, and the presence of IgG in the absence of a rising titer 
of IgM may indicate past exposure rather than acute infec
-
tion. Serologic tests are available commercially and through 
local and state health departments. Cross-reactivity exists 
among the different flaviviruses, so a plaque reduction 
assay may be needed to definitively distinguish between 
West Nile fever, St. Louis encephalitis, and others. PCR 
assays (available through state laboratories and the CDC) 
can be used to detect viral RNA in serum, CSF, or tissue 
early after illness onset and may be particularly useful in 
immunocompromised patients with abnormal antibody 
responses. Individuals with chronic symptoms after West 
Nile virus infection may show persistent kidney infection 
for up to 6 years with West Nile virus RNA present in urine. 
Blood products are best screened using nucleic acid assays. 
MRI of the brain may reveal leptomeningeal, basal ganglia, 
thalamic, or periventricular enhancement.
however, a randomized, controlled trial of IVIG did not 
show a benefit.
 
»
Mild forms of encephalitis must be differentiated from 
aseptic meningitis, lymphocytic choriomeningitis, and 
nonparalytic poliomyelitis.
Severe forms of arbovirus encephalitides are to be dif
-
ferentiated from other causes of viral encephalitis (HSV , 
mumps virus, poliovirus or other enteroviruses, HIV), 
encephalitis accompanying exanthematous diseases of child
-
hood (measles, varicella, infectious mononucleosis, rubella), 
encephalitis following vaccination or infection (a demyelin
-
ating type seen after rabies, measles, pertussis vaccination), 
toxic encephalitis (from drugs, poisons, or bacterial toxins 
such as 
Shigella dysenteriae
 type 1), Reye syndrome, and 
severe forms of stroke, brain tumors, brain abscess, autoim
-
mune processes such as lupus cerebritis, and intoxications. 
In the California Encephalitis Project, anti-
N
-methyl-D-
aspartate receptor (anti-NMDAR) encephalitis is a more 
common cause of encephalitis than viral diseases especially 
in the young, with 65% of encephalitis due to anti-NMDAR 
occurring among patients 18 or younger.
 
»
Bronchial pneumonia, urinary retention and infection, 
prolonged weakness, and pressure injuries (formerly pres
-
sure ulcers) may occur. Retinopathy occurs in 24% of 
patients with a history of West Nile virus infection and is 
associated with increased risk in those with encephalitis. 
Few studies suggest that West Nile virus infection can per
-
sist in the kidneys, but in a subset of patients following 
West Nile virus infection, kidney infection may lead to 
progressive renal pathology.
 
»
Treatment
Although specific antiviral therapy is not available for most 
causative entities, vigorous supportive measures can be 
helpful. Some studies suggest improved outcomes with the 
use of IVIG enriched with West Nile virus antibody; 
 
»
Prognosis
Although most infections are mild or asymptomatic, the 
prognosis is always guarded, especially at the extremes of 
age. Most fatalities occur with neuroinvasive disease. The 
majority of patients with non-neuroinvasive West Nile virus 
disease or West Nile virus meningitis recover completely, 
but a syndrome of fatigue, malaise, and weakness can linger 
for weeks or months. Patients who recover from West Nile 
virus encephalitis or poliomyelitis often have residual neu
-
rologic deficits. The recovery of persons with severe neuro
-
logic compromise may take months. The sequelae of West 
Nile virus infection include a poliomyelitis-like syndrome, 
cognitive complaints, movement disorders, epilepsy, and 
depression; and they may become apparent late in the 
course of what appears to be a successful recovery.

Another entity, nonprimary infection, characterized by 
elevated serum IgG, absent serum IgM, and occasional 
detection of West Nile virus RNA in blood or CSF, is asso
-
ciated with underlying psychiatric disorders, hospitaliza
-
tion during times not associated with peak West Nile 
transmission, fever, and increased in-hospital mortality.
The long-term prognosis is generally better for Western 
equine than for Eastern equine or St. Louis encephalitis.
 
»
Mosquito avoidance (repellents, protective clothing, and 
insecticide spraying) is effective prevention. Laboratory 
precautions are indicated for handling all these pathogens. 
No human vaccine is currently available for the arboviruses 
prevalent in North America. A chimeric live attenuated 
West Nile virus vaccine is tested in phase I clinical trials and 
is shown to be safe and immunogenic in healthy adults.
Lyons JL et al. Case 34-2017. A 76-year old man with fever, 
weight loss, and weakness. N Engl J Med. 2017 Nov 9; 
377(19):1878–86. [PMID: 29117489]
Rahav G et al. Primary versus nonprimary West Nile virus infec
-
tion: a cohort study. J Infect Dis. 2016 Mar 1; 213(5):755–61. 
[PMID: 26508125]
Y eung MW et al. Epidemiologic and clinical parameters of West 
Nile virus infections in humans: a scoping review. BMC Infect 
Dis. 2017 Sep 6:17(1):609. [PMID: 28877682]
3. Japanese Encephalitis
 
»
Most important vaccine-preventable cause of 
encephalitis in the Asia-Pacific region.
 
»
The virus is transmitted by mosquitoes, especially 
Culex
 species.
 
»
Wide symptom spectrum; most infections 
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»
The Japanese encephalitis virus is a flavivirus akin to those 
causing West Nile infection and St. Louis encephalitis. It is 
the most common cause of encephalitis in East Asia with 
over 68,000 estimated annual cases. It is geographically 
contained to East Asia. Most cases occur in the summer 
and late fall, although in tropical and subtropical areas 
transmission occurs throughout the year. Major outbreaks 
every 2–15 years often correlate with patterns of agricul
-
tural development. The virus is transmitted by mosquitoes, 
Culex
 species. Wading birds and pigs more com
-
monly sustain the infection as reservoirs in nature, since 
the viremia in humans is transient and not usually high 
enough to sustain transmission. In endemic countries, 
Japanese encephalitis is primarily a disease of children. 
Travelers to major urban areas for less than 1 month, are at 
minimal risk for Japanese encephalitis.
 
»
Treatment
Treatment is supportive, including antipyretics, analgesics, 
bed rest, and fluids.
 
»
The median incubation period is 5–15 days. Most persons 
asymptomatically seroconvert.
The 1% of patients in whom disease develops report 
sudden-onset headaches, nausea and vomiting, followed by 
mental status changes, parkinsonian movement disorders, 
and in a smaller percentage, seizures, typically in children. 
The infections that most closely mimic Japanese encepha
-
litis are St. Louis encephalitis and West Nile encephalitis, 
although epidemiologic data readily distinguishes these 
infections in most instances.
B. Laboratory Findings and Diagnosis
The disease should be suspected in persons with symptoms 
of CNS infection who recently visited or who reside in an 
Common laboratory abnormalities include leukocyto
-
sis, mild anemia, and hyponatremia. CSF typically has a 
mild to moderate pleocytosis with a lymphocytic predomi
-
nance, slightly elevated protein, and normal glucose.
Diagnosis is confirmed by finding anti-Japanese 
encephalitis IgM in CSF or serum using ELISA. Definitive 
diagnosis requires fourfold increase in virus-specific IgG 
confirmed by plaque reduction neutralization assay. 
Because of low levels of viremia in humans, RT-PCR is not 
In severe disease, brain imaging reveals thalamic 
lesions, with the hippocampus, midbrain, basal ganglia, 
and cerebral cortex affected to varying degrees.
 
»
A variety of cognitive, neurologic, and psychiatric compli
-
cations, including memory impairment and intellectual 
impairment in adults and children, are recognized to occur 
in as many as 50% of survivors and to persist at least 1–2 
years after the acute infection. The mortality is reportedly 
as high as 30%.
 
»
Using mosquito repellents; wearing long sleeves, long 
pants, and socks; and using air-conditioned facilities and 
bed nets are essential means of protection.
In the United States, inactivated Vero-cell culture-
derived Japanese encephalitis vaccine (IXIARO) is licensed 
for the prevention of Japanese encephalitis in persons 
 
2 months of age and older. Travelers who plan to spend 
more than 1 month in rural East Asia during Japanese 
encephalitis virus transmission season should receive the 
vaccine. Primary vaccination requires two doses adminis
-
tered 28 days apart, to be completed more than 1 week 
before travel. For adults, a booster dose is recommended in 
case of potential reexposure or of continued risk for infec
-
tion if the primary series of the vaccine was administered 
over a 1 year before. Four effective types of vaccine against 
Japanese encephalitis are available worldwide, including live 
attenuated and inactivated vaccines. The risk of serious reac
-
tions, including potential encephalitis, with live vaccines, is 
very low. There are no studies about the safety of IXIARO in

-
very low. There are no studies about the safety of IXIARO in 
pregnant women. Therefore, administration of this vaccine 
to pregnant women should be deferred, unless the risk of 
infection outweighs the risk of vaccine complications.
Heffelfinger JD et al. Japanese encephalitis surveillance and 
immunization—Asia and Western Pacific regions, 2016. 
MMWR Morb Mortal Wkly Rep. 2017 Jun 9;66(22):579–83. 
[PMID: 28594790]
Hills SL et al. Japanese encephalitis. In: Centers for Disease Con
-
trol and Prevention. Chapter 3 (83): Infectious Diseases 
Related to Travel. 
CDC Health Information for International 
Travel 2018
. New Y ork: Oxford University Press, 2018. https://
wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-
related-to-travel/japanese-encephalitis
Sunwoo JS et al. Clinical characteristics of severe Japanese 
encephalitis: a case series from South Korea. Am J Trop Med 
Hyg. 2017 Aug;97(2):369–75. [PMID: 28829730]
World Health Organization. Japanese encephalitis: fact sheet 
No. 386. December 2015. http://www.who.int/mediacentre/
factsheets/fs386/en/
4. 
t
ick
-Borne Encephalitis
 
»
Flaviviral encephalitis found in Eastern, Central, 
and occasionally Northern Europe and Asia.
 
»
Transmitted via ticks or ingestion of unpasteur
-
ized milk.
 
»
Long-term neurologic sequelae in 2–25% of cases.
 
»
Therapy is largely supportive.
 
»
Prevention: avoid tick exposure, pasteurize milk, 
and vaccinate.
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»
Tick-borne encephalitis (TBE) is a flaviviral infection 
caused by TBE virus with three subtypes: European, 
Siberian, and Far Eastern. The principal reservoirs and 
vectors for TBE virus are ticks with small rodents as the 
amplifying host; humans are an accidental host. The vec
-
tors for most cases are 
Ixodes ricinus
 (European subtype) 
and 
Ixodes persulcatus
 (Siberian and Far Eastern subtype). 
Infection results from tick bites during outdoor activities in 
forested areas, predominantly in the late spring through 
fall. Ingestion of unpasteurized milk from viremic livestock 
(goats, sheep, cows) is also a recognized mode of transmis
-
sion. Transmission by transplantation of solid organs is 
reported leading to fatal outcomes. TBE is endemic in cer
-
tain parts of Europe and Asia. The number of cases 
reported annually fluctuates significantly depending on 
surveillance, human activities, socioeconomic factors, ecol
-
ogy, and climate. The incubation period is 7–14 days for 
tick-borne exposures but only 3–4 days for milk ingestion.
Powassan virus is the only North American member of 
the tick-borne encephalitis, vectored by several 
Ixodes
 spe
-
cies ticks. The incubation period can range from 1 to 
 
5 weeks.
 
»
Most cases are subclinical, and many resemble an influenza-
like syndrome with 2–10 days of fever (usually with malaise, 
headache, and myalgias). In some cases, the disease is 
biphasic where the initial flu-like period is followed by a 
 
1 to 21-day symptom-free interval followed by a second 
phase with fevers and neurologic symptoms. The neuro
-
logic manifestations range from febrile headache to aseptic 
meningitis and encephalitis with or without myelitis (pref
-
erentially of the cervical anterior horn) and spinal paralysis 
(usually flaccid). A myeloradiculitic form can also develop 
but is less common. Peripheral facial palsies, sometimes 
bilateral, tend to occur infrequently late in the course of 
infection, usually after encephalitis and usually are associ
-
ated with a favorable outcome within 30–90 days. The main 
sequela of disease is paresis. Other causes of long-term 
morbidity include protracted cognitive dysfunction and 
persistent spinal nerve paralysis. The 
post-encephalitic 
syndrome
 is characterized by headache, difficulties concen
-
trating, balance disorders, dysphasia, hearing defects, and 
chronic fatigue. A progressive motor neuron disease and 
partial continuous epilepsy are complications. Longstand
-
ing psychiatric complications are reported and include 
attention deficits, slowness of thought and learning impair
-
ment, depression, lability, and mutism.
Mortality in TBE is usually a consequence of brain 
edema or bulbar involvement.
Leukocytosis and neutrophilia are common. Abnormal CSF 
findings include an inconsistent pleocytosis that may persist 
for up to 4 months. Hyponatremia is more commonly seen 
than with other viral encephalitides. Neuroimaging might 
show hyperintense lesions in the thalamus, brainstem, and 
basal ganglia, and cerebral atrophy.
When neurologic symptoms develop, the TBE virus is 
typically no longer detectable in blood and CSF samples. 
Virus detection by RT-PCR in ticks from TBE patients, if 
available, can help with the diagnosis. TBE virus IgM and 
IgG are detected by ELISA techniques when neurologic 
symptoms occur. Cross-reactivity with other flaviviruses or 
a vaccinated state may require confirmation by detection of 
TBE virus–specific antibodies by plaque-reduction neu
-
tralization tests.
 
»
The differential diagnosis includes other causes of aseptic 
meningitis, such as enteroviral infections; poliomyelitis (no 
longer reported from Eastern Europe); herpes simplex 
encephalitis; and a variety of tick-borne pathogens, includ
-

-
ing tularemia, the rickettsial diseases, babesiosis, Lyme 
disease, and other flaviviral infections. Coinfections are 
documented with 
Anaplasma, Babesia
, and 
Borrelia
 
»
Treatment
There is no specific antiviral treatment and therapy is 
largely supportive.
 
»
Prognosis
The three subtypes of TPE have different prognoses. The 
European subtype
 is usually milder with up to 2% mortal
-
ity and 30% neuroinvasive disease. The 
Siberian subtype
 is 
associated with 3% mortality and chronic, progressive dis
-
ease. The 
Far Eastern subtype
 is usually more severe with 
up to 40% mortality and higher likelihood of neurologic 
involvement. All three subtypes are more severe among 
elderly adults compared with children. Coinfection with 
 (the agent of Lyme disease; transmitted 
by the same tick vector) may result in more severe disease.
 
»
There is no available TBE vaccine in the United States. There 
are four different inactivated TBE virus vaccines for adults 
and children licensed in Europe and 1 available in China. 
The vaccine is safe and effective and should provide cross-
protection against all three TBE virus subtypes. The initial 
vaccination schedule requires two to three doses given over 
6 or more months with boosters every 3–5 years. Break
-
through TBE in vaccinated individuals is reported, espe
-
cially among recipients who are over 50 years of age and 
among persons who are immunosuppressed, such as those 
receiving anti-TNF therapy or methotrexate, indicating the 
need for a modified immunization strategy in such patients. 
Neuritis and neuropathies of peripheral nerves (plexus 
neuropathy—paresis of lower limb muscles, polyradiculopa
-
thy) are recognized complications of TBE vaccination.
Poor uptake of the vaccine in endemic countries is 
responsible for limited abilities to control the disease. 
Other prevention recommendations include avoidance of 
tick exposure and pasteurization of cow and goat milk.
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Fischer M et al. Tickborne encephalitis. In: Centers for Disease 
Control and Prevention. Chapter 3 (83): 
CDC Health Infor
-
mation for International Travel 2018
. New Y ork: Oxford 
University Press, 2018. https://wwwnc.cdc.gov/travel/yellow
-
book/2018/infectious-diseases-related-to-travel/tickborne-
 
encephalitis
Hira V et al. Human tick-borne encephalitis, the Netherlands. 
Emerg Infect Dis. 2017 Jan;23(1):169. [PMID: 27938522]
Lipowski D et al. A cluster of fatal tick-borne encephalitis virus 
infection in organ transplant setting. J Infect Dis. 
2017 Mar 15; 215(6):896–901. [PMID: 28453842]
Lotrič-Furlan S et al. Tick-borne encephalitis in patients vacci
-
nated against this disease. J Intern Med. 2017 Aug;282(2): 
142–55. [PMID: 28440879]
 
»
The incubation period is 8–13 days to the appearance of 
systemic manifestations and 15–21 days to the appearance 
of meningeal symptoms. Symptoms are biphasic, with a 
prodromal illness characterized by fever, chills, headache, 
myalgia, cough, and vomiting, occasionally with lymph
-
adenopathy and maculopapular rash. After 3–5 days the 
fever subsides only to return after 2–4 days alongside the 
meningeal phase, characterized by headache, nausea and 
vomiting, lethargy, and variably present meningeal signs. 
Arthralgias can develop late in the course. Transverse 
myelitis, deafness, Guillain-Barré syndrome, and transient 
and permanent hydrocephalus are reported. Lymphocytic 
choriomeningitis virus is a well-known, albeit underrecog
-
nized, cause of congenital infection frequently complicated 
with obstructive hydrocephalus and chorioretinitis. In 
fetuses and newborns with ventriculomegaly or other 
abnormal neuroimaging findings, screening for congenital 
lymphocytic choriomeningitis may be considered; mothers 
are asymptomatic half the time. In over one-third of cases, 
rodent exposure is reported retrospectively. Occasionally, a 
syndrome resembling the viral hemorrhagic fevers is 
described in transplant recipients of infected organs and in 
patients with lymphoma.
Leukocytosis or leukopenia and thrombocytopenia may be 
initially present. During the meningeal phase, CSF analysis 
frequently shows lymphocytic pleocytosis (total count is 
often 500–3000/mcL) alongside a slight increase in protein, 
while a low to normal glucose is seen in at least 25%. The 
virus may be recovered from the blood and CSF by mouse 
inoculation. Complement-fixing antibodies appear during 
or after the second week. Detection of specific IgM by 
ELISA is widely used. Detection of lymphocytic chorio
-
meningitis virus by PCR is available in research settings.
 
»
The influenza-like prodrome and latent period may dis
-
tinguish this from other aseptic meningitides, and bacte
-
rial and granulomatous meningitis. A history of exposure 
to mice or other potential vectors is an important diagnos
-
tic clue.
 
»
Treatment
Treatment is supportive. In the survivor of a transplant-
associated outbreak, ribavirin (which is effective against 
other arenaviruses) was used successfully along with 
decreasing immunosuppression.
 
»
Prognosis
Complications and fatalities are rare in the general popula
-
tion. The illness usually lasts 1–2 weeks, though convales
-
cence may be prolonged. Congenital infection is more severe 
with about 30% mortality rate among infected infants, and 
more than 90% of survivors suffering long-term neurologic 
5. Lymphocytic Choriomeningitis
 
»
“Influenza-like” prodrome of fever, chills, and 
cough, followed by a meningeal phase.
 
»
Aseptic meningitis: stiff neck, headache, vomiting, 
lethargy.
 
»
CSF: slight increase of protein, lymphocytic pleo
-
cytosis (500–3000/mcL).
 
»
Complement-fixing antibodies within 2 weeks.
 
»
The lymphocytic choriomeningitis virus is an arenavirus

-
 
»
 
»
The lymphocytic choriomeningitis virus is an arenavirus 
(related to the pathogen causing Lassa fever, discussed 
below) that primarily infects the CNS. Its main reservoir is 
the house mouse (
Mus musculus
). Other rodents (such as 
rats, guinea pigs, and even pet hamsters), monkeys, dogs, 
and swine are also potential reservoirs. The infected animal 
sheds lymphocytic choriomeningitis virus in nasal secre
-
tions, urine, and feces; transmission to humans probably 
occurs through aerosolized particles and mucosal expo
-
sure, percutaneous inoculation, direct contact, or animal 
bites. The disease in humans is underdiagnosed and occurs 
most often in autumn. The lymphocytic choriomeningitis 
virus is typically not spread person to person, although 
vertical transmission is reported, and it is considered as an 
underrecognized teratogen. Rare cases related to solid 
organ transplantation and autopsies of infected individuals 
are also reported. All reported cases were donor derived. 
Outbreaks are uncommon, and usually occur in laboratory 
settings among those workers with significant rodent 
exposure.
The ubiquitous nature of its reservoir and the wide 
distribution of the reported cases suggest a widespread 
geographic risk for lymphocytic choriomeningitis virus 
infection. Serologic surveys in the southern and eastern 
United States suggest past infection in approximately 3–5% 
of those tested, although later data from upstate New Y ork 
showed less than 1% seroprevalence. Infection risk can be 
reduced by limiting contact with pet rodents and rodent 
trappings.
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abnormalities. Lymphocytic choriomeningitis in solid organ 
transplant recipients is associated with a poor prognosis; of 
reported cases, the mortality rate is more than 80%.
 
»
Pregnant women should be advised of the dangers to their 
unborn children inherent in exposure to rodents.
Aebischer O et al. Lymphocytic choriomeningitis virus infection 
induced by percutaneous exposure. Occup Med (Lond). 
2016 Mar;66(2):171–3. [PMID: 26416845]
Talley P et al. Notes from the field: lymphocytic choriomeningi
-
tis virus meningoencephalitis from a household rodent 
infestation—Minnesota, 2015. MMWR Morb Mortal Wkly 
Rep. 2016 Mar 11;65(9):248–9. Erratum in: MMWR Morb 
Mortal Wkly Rep. 2016;65(11):295. [PMID: 26963688]
6. 
p
rion D
iseases
 
»
Rare in humans.
 
»
Cognitive decline.
 
»
Myoclonic fasciculations, ataxia, visual distur
-
bances, pyramidal and extrapyramidal symptoms.
 
»
Variant form presents in younger persons with 
prominent psychiatric or sensory symptoms.
 
»
Specific EEG patterns.
 
»
The transmissible spongiform encephalopathies are a 
group of fatal neurodegenerative diseases affecting humans 
and animals. They are caused by 
proteinaceous infectious 
particles
 or 
prions.
 These agents show slow replicative 
capacity and long latent intervals in the host. They induce 
the conformational change (“misfolding”) of a normal brain 
protein (prion protein; PrP[C]) into an abnormal isoform 
(PrP[Sc]) that accumulates and causes neuronal vacuolation 
(spongiosis), reactive proliferation of astrocytes and 
microglia and, in some cases, the deposition of beta-amyloid 
oligomeric plaques.
Prion disease can be hereditary, sporadic, or transmissible 
in humans. Hereditary disorders are caused by germ line 
mutations in the PrP[C] gene causing 
familial Creutzfeldt–
Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker 
syndrome (GSS)
, and 
fatal familial insomnia.
 Another 
uncommon hereditary disorder is PrP systemic amyloidosis.
Sporadic Creutzfeldt-Jakob disease (sCJD)
 is the most 
common of the human prion diseases, accounting for 
approximately 85% of cases; it has no known cause. Trans
-
missible prion disease is described only for kuru and 
Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and variant 
(vCJD) form. Iatrogenic transmission of CJD is associated 
with prion contaminated human corneas, dura mater grafts, 
growth hormone, gonadotropins, stereotactic electroen
-
cephalography, electrodes, and neurosurgical instruments. 
Abnormal prion proteins have been detected in the nasal 
mucosa and urine of patients with Creutzfeldt-Jakob disease, 
raising health concerns about possibility of transmission.
Kuru
, once prevalent in central New Guinea, is now 
rare, a decline in prevalence that started after the abandon
-
ment of cannibalism in the late 1950s (a protective allele of 
the PrP gene is now identified at codon 127).
More than 200 cases of vCJD 
(bovine spongiform 
encephalopathy [BSE]
 or 
“mad cow disease”)
 were 
reported in the United Kingdom since the first docu
-
mented cases there in the mid-1990s. It is far less common 
in North America, with only four cases reported in the 
United States (the last one in 2014) and two deaths in 
Canada from definite or probable vCJD. Of the US-
reported cases, none are confirmed to have acquired the 
disease locally (two of them acquired the infection in the 
United Kingdom, one in Saudi Arabia, one possibly in a 
Middle Eastern or Eastern European country). This disease 
is characterized by its bovine-to-human transmission 
through ingestion of meat from cattle infected with BSE. 
There is no animal-to-animal spread of BSE, and milk and 
its derived products are not considered infectious. Reports 
of secondary transmission of vCJD due to blood transfu
-
sions from asymptomatic donors are reported in the 
United Kingdom. Although iCJD and vCJD are not associ
-

-
-
ated with a known PrP gene mutation, a polymorphism in 
codon 129 is prevalent and seems to determine susceptibil
-
ity and expression of clinical disease.
The overall annual incidence of prion disease world
-
wide is approximately 1–2/1 million person-years. In the 
United States, among the 3524 cases reported through 
July 30, 2016, to the US National Prion Disease Pathology 
Surveillance Center, 3137 (89%) were sporadic, 356 (10.1%) 
familial, 12 (0.3%) iatrogenic, and 4 (0.1%) vCJD.
 
»
Both sCJD and fCJD usually present in the sixth or seventh 
decade of life, whereas the iCJD form tends to occur in a 
much younger population. Clinical features of these three 
forms of disease usually involve mental deterioration 
(dementia, behavioral changes, loss of cortical function) 
progressive over several months, as well as myoclonus, 
extrapyramidal (hypokinesia) and cerebellar manifesta
-
tions (ataxia, dysarthria). Finally, coma ensues, usually 
associated with an akinetic state and less commonly 
decerebrate/decorticate posturing. Like iCJD, vCJD usually 
affects younger patients (averaging 
∼
28 years), but the 
duration of disease is longer (about 1 year). The degree of 
organ involvement is often extensive, and the clinical 
symptoms are unique, mainly characterized by prominent 
psychiatric and sensory symptoms.
CJD should be considered as a diagnosis in the proper 
clinical scenario, in the absence of alternative diagnoses 
after routine investigations. Abnormalities in CSF are sub
-
tle and rarely helpful. The detection of 14-3-3 protein in 
the CSF is helpful for the diagnosis of sCJD but not in vCJD 
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and fCJD. Its sensitivity and specificity are widely variable 
among different studies and may be increased with use of 
tau protein assays. CSF detection of total PrP can differen
-
tiate CJD from atypical Alzheimer disease with 82% sensi
-
tivity and 91% specificity.
A blood-based assay and PCR in CSF may help with the 
diagnosis of vCJD with high specificity but 71% sensitivity. 
The assay as well as 14-3-3 protein assay and a “quaking 
induced conversion” assay are all available through the 
National Prion Disease Surveillance Center at Case 
Western University in Cleveland. Other referral laborato
-
ries with variable availability of assays include state health 
departments, academic centers, and the National Prion 
Clinics in the United Kingdom. It is also recognized that 
the presence of a variant with low titers (“very low periph
-
eral prion colonization”) in peripheral tissue, including 
frequently biopsied tonsillar tissue, may be responsible for 
the underrecognition of vCJD.
Probable diagnosis requires the presence of rapidly pro
-
gressive dementia plus two of four clinical features (myoclo
-
nus, visual or cerebellar signs, pyramidal/extrapyramidal 
signs, and akinetic mutism) as well as a positive laboratory 
assay (typical EEG, positive 14-3-3 CSF assay with duration 
under 2 years), MRI high signal in the caudate and/or puta
-
men on diffuse-weighted or fluid attenuated inversion recov
-
ery (DWI or FLAIR) imaging. In sCJD, the EEG typically 
shows a pattern of paroxysms with high voltages and slow 
waves, while the MRI is characteristic for bilateral areas of 
increased signal intensity, predominantly in the caudate and 
putamen. An MRI can improve early diagnosis of sCJD 
because clinical findings are often missed. When an experi
-
enced neuroradiologist or a prion disease expert reviews the 
MRI, diagnostic sensitivity of MRI for sCJD increases to 91%.
 
»
Autoimmune encephalitis can have a similar clinical pic
-
ture. The presence of high titer autoantibodies (eg, to the 
NMDA receptor) in the CSF is consistent with autoim
-
mune encephalitis.
 
»
Treatment & Prevention
There is no specific treatment for CJD. Once symptoms 
appear, the infection invariably leads to death. Flupirtine 
(an analgesic drug) is sometimes useful in slowing the 
associated cognitive decline but does not affect survival. 
Studies are in progress to identify epitopes for vaccine 
development, but no promising candidates exist to date.
Iatrogenic CJD can be prevented by limiting patient 
exposure to potentially infectious sources as mentioned 
above. Prevention of vCJD relies on monitoring livestock 
for possible infection. The American Red Cross does not 
accept blood donations from persons with a family history 
of CJD or with a history of dural grafts or pituitary-derived 
growth hormone injections.
An international referral and database for CJD is avail
-
able at http://www.cjdsurveillance.com.
Reference centers are available at Case Western Reserve 
University in the United States and the University College 
London Hospitals in the United Kingdom.
Annus Á et al. Prion diseases: new considerations. Clin Neurol 
Neurosurg. 2016 Nov;150:125–32. [PMID: 27656779]
Giles K et al. Developing therapeutics for PrP prion diseases. 
Cold Spring Harb Perspect Med. 2017 Apr 3;7(4). pii: a023747. 
[PMID: 28096242]
Stopschinski BE et al. The prion model for progression and 
diversity of neurodegenerative diseases. Lancet Neurol. 
2017 Apr;16(4):323–32. [PMID: 28238712]
7. 
p
r
ogressive Multifocal 
 
Leukoencephalopathy (
p
ML)
PML is a rare demyelinating CNS disorder caused by the 
reactivation of the JC virus (John Cunningham virus or 
JCV). This polyomavirus usually causes its primary infec
-
tion during childhood with about 80% of adults typically 
being seropositive. The virus remains latent in the kidneys,

-
being seropositive. The virus remains latent in the kidneys, 
lymphoid tissues, epithelial cells, peripheral blood leuko
-
cytes, bone marrow, and possibly brain until reactivation 
occurs and symptoms become evident. This reactivation is 
usually seen in adults with impaired cell-mediated immu
-
nity, especially AIDS patients (5–10% of whom develop 
PML), as well as those with idiopathic CD4 lymphopenia 
syndrome. It is also reported among those with lymphop
-
roliferative and myeloproliferative disorders; granuloma
-
tous, inflammatory, and rheumatic diseases (systemic 
lupus erythematosus and rheumatoid arthritis in 
particular); as well as in those who have undergone solid 
and hematopoietic cell transplantation; and occasionally in 
those who have other medical states, including cirrhosis 
and kidney disease.
Diagnostic criteria that use clinical, imaging, patho
-
logic, and virologic manifestations of JCV are available 
from the American Academy of Neurology.
Medication-associated PML
 is described with the use 
of natalizumab, rituximab, infliximab (one case), azathio
-
prine with corticosteroids (one case), and mycophenolate 
mofetil. Natalizumab, a monoclonal antibody used in the 
treatment of multiple sclerosis, is associated with the risk of 
PML developing in 4 per 1000 treated patients, with the 
rate increasing with duration of therapy. The risk of clinical 
PML appears to increase up to 36 months of therapy and 
levels off thereafter. The mean interval between use of the 
drug to the diagnosis of PML is 5.5 months. An immune 
reconstitution inflammatory state (IRIS) may follow cessa
-
tion of natalizumab or other monoclonal antibody therapy, 
although the JCV presence and the residual neurologic 
deficits may not clear for years after therapy is stopped. The 
risk of developing PML associated with rituximab is at least 
1 in 25,000 exposed patients with cases reported in various 
autoimmune conditions treated with rituximab (systemic 
lupus erythematosus, rheumatoid arthritis, multiple 
sclerosis). The virus is detected in the CSF of up to one-half 
of all patients treated (studied with natalizumab), although 
the exact relationship between latent JCV and frank PML 
remains unclear, with higher JC viral loads detected among 
patients who are immunosuppressed and among those 
who have HIV infection with lower CD4 counts.
Smoking is reportedly associated with an increased risk 
of PML.
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»
JCV causes lytic infection of oligodendrocytes in the white 
matter and symptoms presenting subacutely reflect the 
diverse areas of CNS involvement. Symptoms include altered 
mental status, aphasia, ataxia, hemiparesis or hemiplegia and 
visual field disturbances. Seizures occur in about 18%. 
Involvement of cranial nerves and the cervical spine is rare.
PCR for JCV in CSF is used for diagnosis in patients with 
compatible clinical and radiologic findings. Persistent JC 
viremia and increasing urinary JCV DNA may be predic
-
tive of PML. An anti-JCV immunoglobulin G (IgG) was 
higher 6 months before diagnosis but was not predictive of 
PML in a cohort of HIV-infected persons.
MRI of the brain shows multifocal areas of white matter 
demyelination without mass effect or, usually, contrast 
enhancement. These findings may not be distinguishable 
from immune reconstitution inflammatory syndrome. 
Increased uptake of methionine with concomitant decreased 
uptake of fluorodeoxyglucose in positron emission tomog
-
raphy may be helpful for diagnosis. In HIV-infected 
patients, a syndrome of cerebellar degeneration is described.
 
»
Limiting the immunosuppressed state without inducing an 
IRIS represents the mainstay of therapy for PML. Treatment 
of HIV with ART reduces the incidence of PML, improves the 
clinical symptoms, reverses some of the radiographic abnor
-
malities, and improves the 1-year mortality rate, regardless of 
baseline CD4 count. Immune recovery can induce worsening 
of the clinical picture in a small number of cases. Immune 
reconstitution syndromes do not alter mortality but are asso
-
ciated with a form of PML called non-determined leukoen
-
cephalopathy associated with a chemokine polymorphism. 
Significant neurologic sequelae to PML infections are the rule 
and deficits may persist for years.
Decreasing immunosuppression in non-AIDS patients 
with PML (eg, multiple sclerosis or transplant patients) is 
also typically beneficial. Cidofovir may be beneficial in 
non–AIDS-related cases, while corticosteroids may be useful 
with immune reconstitution. Because the JCV infects cells 
through serotonin receptors, some clinicians recommend 
the use of risperidone and mirtazapine. Anecdotal reports 
show that premature stopping of natalizumab in multiple 
sclerosis may itself lead to IRIS states. Plasma exchange, 
which theoretically reduces the plasma level of agents associ
-
ated with PML, may be useful in natalizumab-associated 
PML but is associated with a high risk of IRIS. A variety of 
lymphocyte markers studied have not been shown to predict 
in which patients with multiple sclerosis PML will develop. 
In kidney transplant patients, a preinduction regimen with 
IVIG and rituximab and transplantation with lymphocyte 
depleted cells appears to reduce the risk of PML. Similarly, 
titers of JC antibody are not shown to significantly increase 
prior to clinical onset of PML. The course of post-PML in 
multiple sclerosis–related PML can be followed by magnetic 
resonance spectroscopy, tracking chemical ratios such as 
choline/creatine and the JV viral load.
Clifford DB. Progressive multifocal leukoencephalopathy ther
-
apy. J Neurovirol. 2015 Dec;21(6):632–6. [PMID: 25227934]
Epperla N et al. Mirtazapine and mefloquine therapy for 
non-AIDS-related progressive multifocal leukoencephalopathy. 
WMJ. 2014 Dec;113(6):242–5. [PMID: 25745699]
Loignon M et al. Treatment options for progressive multifocal 
leukoencephalopathy in HIV-infected persons: current status 
and future directions. Expert Rev Anti Infect Ther. 
2016;14(2):177–91. [PMID: 26655489]
Major EO et al. JC viremia in natalizumab-treated patients with 
multiple sclerosis. N Engl J Med. 2013 Jun 6;368(23):2240–1. 
[PMID: 23738566]
Schneider R et al. Metabolic profiles by 1H-magnetic resonance

Schneider R et al. Metabolic profiles by 1H-magnetic resonance 
spectroscopy in natalizumab-associated post-PML lesions of 
multiple sclerosis patients who survived progressive multifo
-
cal leukoencephalopathy (PML). PLoS One. 2017 Apr 26; 
12(4):e0176415. [PMID: 28445498]
Sospedra M et al. Treating progressive multifocal leukoencepha
-
lopathy with interleukin 7 and vaccination with JC virus 
capsid protein VP1. Clin Infect Dis. 2014 Dec 1;59(11): 
1588–92. [PMID: 25214510]
8. Human 
t
-
Cell Lymphotropic Virus (H
t
LV)
HTLV-1 and -2
 are retroviruses that infect CD4 and CD8 
T cells respectively, where they persist as a lifelong latent 
infection. HTLV-1 currently infects approximately 
20 million individuals worldwide. It is endemic to many 
regions in the world including southern Japan, the 
Caribbean, much of sub-Saharan Africa, South America, 
Eastern Europe, and Oceania. The Caribbean basin and 
southwestern Japan show the highest prevalence of infec
-
tion (4–37%). Conversely, HTLV-2 is mainly found in 
native populations of South (1–58%), Central (8–10%), 
and North America (2–13%) as well as African pygmy 
tribes. In some areas of Africa (eg, Malawi), HTLV-2 sero
-
prevalence is higher than HTLV-1 seroprevalence.
In the United States, studies done in blood donors show a 
seroprevalence of HTLV-1 of 0.005% and HTLV-2 of 0.014%, 
a decline since the early 1990s. The virus is transmitted hori
-
zontally (sex), vertically (intrauterine, peripartum, and pro
-
longed breastfeeding), and parenterally (injection drug use 
and blood transfusion). Hence, a higher prevalence is seen 
among injection drug users. Coinfection with HIV-1 occurs 
but is often underrecognized. Transmission via organ trans
-
plant has been reported. Disease may flare when biologic 
agents are used for rheumatoid conditions.
 
»
HTLV-1
 infection is associated with HTLV-1 adult T-cell 
lymphoma/leukemia (ATL) and HTLV-1 associated 
myelopathy/tropical spastic paraparesis (HAM/TSP). In 
contrast, 
HTLV-2
 is significantly less pathogenic, with few 
reported cases of HAM/TSP as well as other neurologic 
manifestations. The causative association of HTLV-1 with 
ATL, attributed to the virally encoded oncoprotein 
tax
, is 
well established. The lifetime risk of developing ATL 
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among seropositive persons is estimated to be 3% in 
women and 7% in men, with an incubation period of at least 
15 years. The mean age at diagnosis of ATL is 40–50 years 
in Central and South America and 60 years in Japan.
ATL clinical syndromes may be classified as chronic, 
acute (leukemic), smoldering, or lymphomatous. A primary 
cutaneous tumor is also described and shows a worse prog
-
nosis compared with the smoldering type. Clinical features 
of ATL include diffuse lymphadenopathy, maculopapular 
skin lesions that may evolve into erythroderma, a bron
-
choalveolar disorder, organomegaly, lytic bone lesions, and 
hypercalcemia. Opportunistic infections, such as 
 
pneumonia and cryptococcal meningitis, are common.
HAM/TSP , associated with both HTLV-1 and HTLV-2, 
develops in 0.3–4% of seropositive individuals and is more 
common in women and in older individuals. A chronic 
inflammation of the spinal cord leads to intense and pro
-
gressive motor weakness and symmetric spastic paraparesis, 
bilateral facial palsies, falls, nociceptive low back pain, and 
paraplegia with hyperreflexia. Bladder and sexual disorders 
(eg, dyspareunia, erectile dysfunction), sensory distur
-
bances, and constipation are also common. A progressive 
cognitive impairment is seen with HAM/TSP in children. 
Both viruses can also induce motor abnormalities, such as 
leg weakness, impaired tandem walk, and vibration sense, 
without overt HTLV-associated myelopathy.
An HTLV-1 provirus load in peripheral blood mono
-
nuclear cells and CSF cells, and an HTLV-1 mRNA load are 
proposed as markers of HAM risk and progression. HTLV 
positivity is associated with erythrocytosis, lymphocytosis 
(HTLV-2), and with thrombocytosis (HTLV-1).
HTLV-1 seropositivity is associated with an increased 
risk of tuberculosis, 
Strongyloides stercoralis
 hyperinfec
-
tion, crusted scabies, and infective dermatitis. Inflamma
-
tory states associated with HTLV-1 infection include 
arthropathy, recurrent facial palsies, polymyositis, uveitis, 
sicca but inconsistently Sjögren syndrome, vasculitis, cryo
-
globulinemia, infiltrative pneumonitis, and ichthyosis. 
Bronchioloalveolar carcinoma is increased in frequency in 
the presence of HTLV-1.
HTLV-2 appears to cause a myelopathy that is milder 
and slower to progress than HAM. All-cause and cancer 
mortality is higher among HTLV-2 seropositive patients.
HTLV-1/HIV coinfection is associated both with higher 
CD4 counts and a higher risk of HAM.
The peripheral smear can show atypical lymphoid cells 
with basophilic cytoplasm and convoluted nuclei (flower 
cells) but the diagnostic standard is evidence of clonal inte
-
gration of the proviral DNA genome into tumor cell. The 
identification of HTLV-1 antibodies supports the diagnosis. 
Serum neopterin levels may indicate disease activity.
 
»
Treatment, Prevention, & Prognosis
Management of ATL consists mainly of chemotherapy, 
with allogeneic stem cell transplantation and the use of 
monoclonal antibodies (anti-CCR4 and anti-CD25). 
 
A chemotherapy regimen in Japan using eight different 
agents shows a higher response rate than traditional 
biweekly CHOP (40% vs 25%). Combination therapy with 
interferon-alpha has been used with success. A therapeutic 
vaccine is in early clinical trials. Prophylaxis against infec
-
tions is needed in ATL because patients show a profound 
HAM is treated with a variety of immune-modulating 
agents (including corticosteroids) without consistent 
results. Combination therapy with antiretrovirals does not 
show benefit. Interferon-alpha may be of some efficacy. 
 
A significant response is reported with the combined regi
-
men of prednisolone, pegylated interferon, and sodium 
valproate. Small, uncontrolled studies suggest plasmapher
-
esis results in improvement in gait and sensory disturbance

-
-
esis results in improvement in gait and sensory disturbance 
among some patients and improvement in muscle pain 
with pulsed methylprednisolone. In general, however, no 
agent is effective.
Screening of the blood supply for HTLV-1 is required in 
the United States. There is significant cross-reactivity 
between HTLV-1 and HTLV-2 by serologic studies, but 
PCR can distinguish the two. Improved assays to screen 
organ donors for HTLV-1 and -2 infections are needed, 
although such screening is not currently required.
Patients who are coinfected with HIV-1 and HTLV 
reportedly do respond to ART for HIV .
Boostani R et al. Triple therapy with prednisolone, pegylated 
interferon and sodium valproate improves clinical outcome 
and reduces human T-cell leukemia virus type 1 (HTLV-1) 
proviral load, tax and HBZ mRNA expression in patients with 
HTLV-1-associated myelopathy/tropical spastic paraparesis. 
Neurotherapeutics. 2015 Oct;12(4):887–95. [PMID: 
26174324]
Khan MY et al. HTLV-1 associated neurological disorders. Curr 
Top Med Chem. 2017;17(12):1320–30. [PMID: 28017149]
Terada Y et al. Treatment of rheumatoid arthritis with biologics 
may exacerbate HTLV-1-associated conditions: a case report. 
Medicine (Baltimore). 2017 Feb;96(6):e6021. [PMID: 
28178142]
Y amakawa et al. Human T-cell lymphotropic virus type-1 
(HTLV-1)-associated bronchioloalveolar disorder presenting 
with mosaic perfusion. Intern Med. 2015;54(23):3039–43. 
[PMID: 26631889]
VIRAL HEMORRHAGIC FEVERS
1. Ebola Viral Disease (EVD)
 
»
Early stage EVD:
 a nonspecific febrile illness.
 
»
Later stage EVD
: severe gastrointestinal symp
-
toms, then neurologic symptoms and hypovole
-
mic shock.
 
»
Hemorrhagic manifestations are rare.
 
»
Travel and contact history from an Ebola-affected 
country raise suspicion.
 
»
Virus is detected with a real-time RT-PCR.
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»
Genus 
Ebolavirus
 is a single-stranded RNA virus in the 
Filoviridae family. Four different species of 
 
have been identified to cause human disease. Fruit bats 
are possible reservoir for 
. Zoonotic transmis
-
sion to humans occur via contact with the reservoir or an 
infected primate. 
 can continue to be transmit
-
ted among humans who have direct contact with infected 
body fluids. To acquire EVD, the virus must enter the 
body via mucous membranes, nonintact skin, sexual 
intercourse, breastfeeding, or needlesticks. Traditional 
burial practices in Africa (which entail considerable con
-
tact with the corpse) and unprotected direct care of per
-
sons with EVD are associated with highest transmission 
risk. 
 has been detected in semen up to 
 
9 months after recovery from infection.
EVD has a 2–21-day incubation period. Prior to mani
-
festation of symptoms, 
 is not transmissible. 
Even at symptom onset, the risk of transmission is low but 
increases over time.
The first Ebola outbreak occurred in 1976 as a simulta
-
neous epidemic in Congo and South Sudan. Subsequent 
outbreaks were confined to Congo, Uganda, and Sudan 
until March 2014 when the first Ebola case in West Africa 
was identified in Guinea. 
Zaire ebolavirus
 was the associ
-
ated species. This Ebola outbreak grew to be larger than all 
prior Ebola outbreaks combined. The number of EVD 
cases spread rapidly; there were at least 10 affected coun
-
tries, especially Guinea, Liberia, and Sierra Leone. Many 
cases and deaths in these countries occurred among 
healthcare workers. In the United States, 11 persons were 
treated for Ebola. Most were healthcare workers who were 
evacuated to the United States and 4 patients were diag
-
nosed in the United States. Sierra Leone contained its last 
EVD outbreak as of March 2016. Guinea was declared free 
of EVD transmission in June 2016. Liberia declared the 
end of its last outbreak in June 2016. Other affected coun
-
tries have remained free of EVD for 42 days (two 21-day 
incubation period) after the last confirmed case, since 
October 20, 2015.
 
»
At symptom onset, early-stage EVD most typically pres
-
ents as a nonspecific febrile illness. Along with fever, 
patients tend to experience headache, weakness, dizziness, 
malaise, fatigue, myalgia, and arthralgia. After 3–5 days, 
patients with later stage EVD may develop abdominal 
pain, severe nausea, vomiting, and diarrhea accompanying 
the febrile illness. This stage of the illness may continue for 
a week during which time neurologic symptoms gain 
prominence. Encephalitis is commonly observed and 
manifested as confusion, slowed cognition, agitation, and 
occasional seizures. Shock develops in most patients, but 
hemorrhagic manifestations develop in only 1–5% of 
patients. Respiratory symptoms are not typical for EVD, 
although interstitial pneumonia and respiratory failure are 
reported.
During the first few days of symptoms, diagnosis may be 
made via several modalities, including antigen-capture 
ELISA, IgM ELISA, RT-PCR, or virus isolation. Blood 
samples obtained within the first 3 days of illness and 
tested by RT-PCR should be repeated if results are negative 
and clinical symptoms and signs persist. RNA levels peak a 
median of 7 days after illness onset. Later in the disease 
course or after recovery, IgM and IgG serologic tests may 
be sent. After about 10 days, IgM antibodies begin to 
develop, and, after approximately 2 weeks, an IgG antibody 
response develops. Postmortem diagnosis may be made by 
using immunohistochemistry, RT-PCR, or virus isolation.
Given that filoviruses infect dendritic cells and then 
hepatocytes and renal cortical cells, laboratory findings 
typically include a low platelet count, leukopenia, transa
-

-
minitis (aspartate aminotransferase [AST] greater than 
alanine aminotransferase [ALT]). Additional observed 
laboratory abnormalities include hypoalbuminemia, elec
-
trolytes imbalance, and increased serum creatinine level. 
Elevated blood urea nitrogen, AST, and creatinine upon 
presentation are associated with higher mortality.
 
»
The differential diagnosis varies with the stage of illness. 
Early-stage EVD is commonly mistaken for malaria, 
typhoid, and other viral illnesses. As gastrointestinal symp
-
toms develop, health providers should also consider viral 
hepatitis, toxins, leptospirosis, and rickettsial diseases. In 
later stage EVD, bacterial, viral, and parasitic illnesses, 
including cholera and, in children, rotavirus infection can 
present with severe gastroenteritis and shock. Encephalitis 
must be differentiated from the confusion associated with 
uremia. Hemorrhagic manifestations raise suspicion for 
EVD but could be due to leukemia, thrombotic thrombo
-
cytopenic purpura, hemolytic-uremic syndrome, or dis
-
seminated intravascular coagulation. Travel and contact 
history are crucial when considering the differential diag
-
nosis in areas where Ebola is not endemic.
 
»
Hypovolemic shock and multiorgan failure are the most 
common complications of EVD. Rhabdomyolysis is 
reported frequently and may explain many of the associated 
laboratory abnormalities. Coinfections with malaria or bac
-
teria (or both) are important considerations and can occur 
before presentation and during treatment of EVD. Virus is 
known to persist in immunologically privileged sites, such 
as the CNS, eye, and testes; however, viral relapse is uncom
-
mon. Post-EVD, musculoskeletal pain, headache, auditory 
symptoms, and ocular symptoms (including uveitis) may 
develop. EVD survivors exhibit high rates of neuropsycho
-
logical long-term sequelae including depression, anxiety, 
and posttraumatic stress disorder.
 
»
Treatment
Treatment is supportive. Several studies have shown that 
intravenous fluids can reduce the mortality rates to less 
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than 50%. Despite oral rehydration salts, mortality rates 
approximate 70% in endemic areas. In these studies, the 
amount of intravenous fluid replacement was relatively less 
than what would be used in countries with developed 
health systems. Among patients treated in the United States 
or Europe, almost all received intravenous fluids, electro
-
lyte supplementation, and empiric antibiotic therapy. Inva
-
sive or noninvasive mechanical ventilation and continuous 
renal replacement therapy are necessary in many cases. 
This increased level of care likely contributed to the 
decreased mortality (19%) among these patients.
There are no approved medications for the treatment 
of EVD. A number of drugs have advanced to clinical tri
-
als; however, some were terminated due to low enroll
-
ment or lack of efficacy. Administration of convalescent 
plasma does not result in improved survival. ZMapp is an 
antiviral monoclonal antibody combination developed 
against 
Zaire ebolavirus.
 ZMapp showed some therapeutic 
benefit, but many of these patients received multiple 
agents and were not part of randomized controlled trials. 
The PREV AIL II study evaluated ZMapp for treatment of 
EVD and found it to be safe and well tolerated but failed 
to establish efficacy due to low enrollment numbers. The 
efficacy data of favipiravir, an RNA-dependent RNA poly
-
merase inhibitor, is also inconclusive. One study found 
favipiravir to be effective in patients with low to moderate 
viremia.
Aside from Ebola treatment and experimental thera
-
pies, patients typically receive empiric antimalarial agents 
in endemic areas and broad-spectrum antibiotics. GS-5734 
is an experimental medication that showed therapeutic 
efficacy in a non-human primate model of Ebola virus 
infection. It has been administered under compassionate 
use to two Ebola patients, both of whom survived, and is 
currently in phase 2 clinical development for the treatment 
of EVD and long-term clearance of Ebola virus in male 
survivors with virus persistence in semen.
 
»
Prognosis
Children under 5 years of age and adults older than 
40-years-old have a high risk of death from EVD. Preg
-
nancy is a risk factor for severe illness and death. In the 
2014–2016 outbreak, the average maternal mortality was 
86%. Immunosuppressed patients had shorter incubation 
time, rapid progression of disease, and poor outcomes. 
 
A higher baseline viral load was strong predictor of 
mortality. In general, poor overall medical care confers a 
poor prognosis. Among survivors, protective antibodies 
persist for at least 10 years.
 
»
Risk reduction should focus on preventing wildlife to 
human transmission and reducing human to human trans
-
mission by surveillance, early detection and isolation of 
cases, contact tracing, containment measures (disinfection, 
hygiene, and sanitation), strict droplet and contact precau
-
tions in health care setting, and reduction of sexual trans
-
mission in Ebola survivors. The WHO recommends that 
men avoid sexual activity or use barrier protection during 
intercourse for 12 months from onset of symptoms or until 
their semen tests negative twice for Ebola virus.
The experimental recombinant vesicular stomatitis 
virus (rVSV)-based vaccine expressing 
 
(ZEBOV) glycoprotein is found to be highly effective in 
disease prevention after 10 days from receiving the vaccine. 
Side effects, such fever, myalgia, chills, fatigue, headaches 
and oligo-arthritis, developed in most of the persons who 
received the vaccine. A phase III clinical trial is currently 
underway to evaluate the safety and immunogenicity of 
rVSV-ZEBOV . Other vaccine trials including Adenovirus 
vector vaccine are being studied.
Risk stratification may be useful in deciding when and 
to whom to administer antiviral postexposure prophylaxis. 
A high-risk exposure is defined as penetrating sharps

A high-risk exposure is defined as penetrating sharps 
injury from used device or through contaminated gloves 
 
or clothing, direct contact with an infected patient (alive or 
deceased) or their bodily fluids with broken skin or 
mucous membranes such as eyes, nose, or mouth. The 
ZEBOV vaccine was used in the setting of postexposure 
prophylaxis, among healthcare workers, and found to be 
effective, but the evidence is limited to case series. In addi
-
tion, the vaccine designed against 
 might 
not be effective for infection with other species. The 
vaccine-mediated immunity requires an average of 10 days 
to develop and might not be fast enough in certain cases to 
prevent infection.
Current studies focus on isolation of cross-reactive 
monoclonal antibodies across Ebola virus species. The use 
of different preparations of combination monoclonal anti
-
bodies (ZMapp and MIL77) as postexposure prophylaxis is 
very limited. The use of antiviral agents in postexposure 
prophylaxis is also considered although to date shows no 
clear survival benefit.
 
»
Persons living in or returning from a country with high 
rates of Ebola transmission should be monitored for 
 
21 days and admitted to a health care facility when symp
-
toms meeting the WHO case definition of a suspected 
EVD case develop, in accordance with the screening proto
-
col designated by the respective country’s governmental 
health decision-making body.
Centers for Disease Control and Prevention (CDC). MMWR 
ebola reports. http://www.cdc.gov/mmwr/ebola_reports.html
Fischer W A 2nd et al. Ebola virus disease: an update on post-
exposure prophylaxis. Lancet Infect Dis. 2017 Nov 15. [Epub 
ahead of print] [PMID: 29153266]
PREV AIL II Writing Group; Davey RT Jr et al. A randomized, 
controlled trial of zmapp for Ebola virus infection. N Engl J 
Med. 2016 Oct 13;375(15):1448–1456. [PMID: 27732819]
Trad MA et al. Ebola virus disease: an update on current preven
-
tion and management strategies. J Clin Virol. 2017 Jan;86:
 
5–13. [PMID: 27893999]
Walldorf JA et al; CDC Emergency Ebola Vaccine Taskforce. 
Considerations for use of Ebola vaccine during an emergency 
response. Vaccine. 2017 Sep 7. [Epub ahead of print] [PMID: 
28890191]
World Health Organization. Ebola virus disease. http://www
 
.who.int/ebola/en/
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2. Other Hemorrhagic Fevers
This diverse group of illnesses results from infection with 
one of several single-stranded RNA viruses (members of 
the families Arenaviridae, Bunyaviridae, Filoviridae, and 
Flaviviridae). Flaviviruses, such as the pathogens causing 
dengue and yellow fever, and Filoviridae, causing EVD, are 
discussed in separate sections.
Lassa fever is a rodent-associated disease caused by an 
Old-World 
arenavirus
. Rodents shed the virus in urine and 
droppings and transmit the virus to humans either by 
direct contact with these materials, ingestion, or inhalation 
of aerosolized particles. Lassa fever is mostly endemic in 
West Africa. Other arenaviruses include South American 
arenaviruses and Lujo virus. Lujo virus was first described 
in 2008 in Zambia causing a small cluster of nosocomial 
The bunyaviruses include hantaviruses (discussed 
separately); Crimean-Congo hemorrhagic fever is a dis
-
ease transmitted from ticks and livestock animals. 
Human-to-human transmission can occur in the com
-
munity or hospital setting by contact with infected body 
secretions. The geographic distribution is widespread 
with cases reported from Africa, Asia, Middle East, and 
Eastern Europe, with increased incidence recently in the 
East Mediterranean region. In 2002, Turkey reported the 
largest outbreak with over 2500 cases and almost 10,000 
to date.
Rift Valley fever is transmitted from livestock ani
-
mals, infected mosquitoes, and flies. To date, there is no 
human-to-human transmission. Risk factors for acquir
-
ing Rift Valley fever include working with abortive ani
-
mal tissue; slaughtering, skinning, or sheltering animals; 
and drinking unpasteurized milk. Rift Valley fever causes 
outbreaks in Africa, Madagascar, and Arabian 
Peninsula.
A new bunyavirus, a phlebovirus, was identified in 2010 
in Central and northeastern China and was named for its 
symptoms: severe fever with thrombocytopenia syndrome 
(SFTS) virus. STFS is transmitted by tick bite (Ixodidae 
family) and is also transmitted between humans through 
direct contact with infected blood or secretions. Another 
virus (Heartland virus), identified in the United States, is 
similar to the SFTS virus. Transmission occurs via the Lone 
Star tick (
Amblyomma americanum
). The virus appears to 
be amplified in deer and raccoons. As of July 2017, more 
than 30 cases are reported in states in the Midwestern and 
southern United States.
 
»
The incubation period varies between species, ranging 
from 2 to 21 days. The clinical symptoms in the early 
phase of a viral hemorrhagic fever are indistinguishable 
from other viral illnesses. Due to lack of specific symp
-
toms on presentation, viral hemorrhagic fevers are an 
important cause to consider in fever of unknown origin in 
children in endemic areas. The late phase is more specific 
and is characterized by organ failure, altered mental sta
-
tus, and hemorrhage. Exanthems and mucosal lesions can 
occur.
In advanced stages, significant edema, pleural effusion, 
and fewer hemorrhagic manifestations compared with 
EVD can develop in patients with Lassa fever and Lujo 
virus infection. Hearing loss in various degrees is the most 
common complication of Lassa fever infection. Mortality 
in pregnant patients during the third trimester and fetal 
mortality is very high.
Crimean-Congo hemorrhagic fever has more promi
-
nent hemorrhagic manifestations. Patients have red eyes, 
flushed face, red throat, and petechiae that progress to 
severe uncontrollable bleeding.
Rift Valley fever disease can present with three distinct 
syndromes: (1) ocular disease; retinitis is the most com
-
mon complication; permanent vision loss develops in 
1–10% of patients; (2) a meningoencephalitis form that 
occurs in less than 1% of cases; patients have headache, 
coma, or seizures 1–4 weeks after initial symptoms and a

coma, or seizures 1–4 weeks after initial symptoms and a 
low mortality but a high morbidity with neurologic defi
-
cits that can be severe; (3) a hemorrhagic fever form in 
which patients present 2–4 days after illness and show 
evidence of severe liver impairment and later hemor
-
rhages; the hemorrhagic state occurs in less than 1% of 
patients but the case-fatality ratio of such patients reaches 
about 50%.
Laboratory features usually include thrombocytopenia, 
leukopenia (although with Lassa fever leukocytosis is 
noted), anemia, elevated liver biochemical tests, and abnor
-
malities consistent with disseminated intravascular 
coagulation.
Special care should be taken for handling clinical speci
-
mens of suspected cases. Laboratory personnel should be 
warned about the diagnostic suspicion, and the CDC must 
be contacted for guidance. The diagnosis may be made by 
antigen detection (by ELISA), PCR, or by demonstration of 
a fourfold rise in antibody titer. Crimean-Congo hemor
-
rhagic fever is best diagnosed with an IgM serology, 
although IgG ELISA or immunofluorescence and quantita
-
tive RT-PCR are nearly as effective. These viruses can be 
isolated in culture but requires a biosafety level 4 laboratory. 
Newer technologies are emerging with increased sensitivi
-
ties for detection of viruses causing viral hemorrhagic 
fever, such as the Luminex MagPix platform using 
microspheres.
 
»
The differential diagnosis for hemorrhagic fever includes 
meningococcemia or other septicemias, Rocky Mountain 
spotted fever, dengue, typhoid fever, and malaria. SFTS 
differential diagnosis includes anaplasmosis, hemor
-
rhagic fever with renal syndrome, or leptospirosis. The 
likelihood of acquiring hemorrhagic fevers among travel
-
ers is low.
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»
Patients should be placed in private rooms with standard 
contact and droplet precautions. Barrier precautions to 
prevent contamination of skin or mucous membranes 
should also be adopted by the caring personnel. Airborne 
precautions should be considered in patients with signifi
-
cant pulmonary involvement or undergoing procedures 
that stimulate cough.
Supportive therapy is the mainstay of therapy. There is 
no approved antiviral medication, but ribavirin is shown to 
be effective in vitro and in vivo against certain viruses 
(Lassa virus, Crimean-Congo hemorrhagic fever, and Rift 
Valley fever pathogens). Early diagnosis and management 
can reduce mortality.
The efficacy for postexposure ribavirin in the manage
-
ment of Lassa fever, other arenaviruses, or Crimean-
Congo hemorrhagic fever remains anecdotal. The 
antitrypanosomal agent suramin may be effective against 
the Rift Valley fever virus. Sorafenib, a tyrosine kinase 
inhibitor approved for treatment of renal cell and hepato
-
cellular carcinoma, has antiviral activity against Rift Valley 
fever virus. A combination of monoclonal antibodies that 
cross-react with the glycoproteins of Lassa virus, are tested 
in non-human primates and shows promising results.
An inactivated vaccine is available for Rift Valley fever but 
is not licensed and is not commercially available. There are 
no vaccines approved for other viruses causing viral hemor
-
rhagic fever. A DNA vaccine against Crimean-Congo hemor
-
rhagic fever is developed and shows high humoral immune 
responses with significant protection in mouse models.
 
»
•	
Persons with symptoms of any hemorrhagic fever and 
who have been in possible endemic area should be iso
-
lated for diagnosis and symptomatic treatment.
•	
Isolation is particularly important because diseases due 
to some of these agents, such as Lassa virus, are highly 
transmissible to health care workers.
Al-Abri SS et al. Current status of Crimean-Congo haemor
-
rhagic fever in the World Health Organization Eastern 
Mediterranean Region: issues, challenges, and future 
directions. Int J Infect Dis. 2017 May;58:82–9. [PMID: 
28259724]
Brahms A et al. Sorafenib impedes Rift Valley Fever virus egress 
by inhibiting valosin-containing protein function in the 
cellular secretory pathway. J Virol. 2017 Oct 13;91(21). pii: 
e00968–17. [PMID: 28794043]
Fill MA et al. Novel clinical and pathologic findings in a Heart
-
land virus-associated death. Clin Infect Dis. 2017 Feb 15; 
64(4):510–2. [PMID: 27927857]
Mire CE et al. Human-monoclonal-antibody therapy protects 
nonhuman primates against advanced Lassa fever. Nat Med. 
2017 Oct;23(10):1146–9. [PMID: 28869611]
Silvas JA et al. The emergence of severe fever with thrombocyto
-
penia syndrome virus. Am J Trop Med Hyg. 2017 Oct; 
97(4):992–6. [PMID: 28820686]
Spengler JR et al. Crimean-Congo hemorrhagic fever in Spain—
new arrival or silent resident? N Engl J Med. 2017 Jul 13; 
377(2):106–8. [PMID: 28700846]
3. Dengue
 
»
Incubation period 7–10 days.
 
»
Sudden onset of high fever, chills, severe myalgias 
and arthralgias, headache, and retroorbital pain.
 
»
Severe dengue is defined by the presence of plasma 
leakage, hemorrhage, or organ involvement.
 
»
Signs of hemorrhage such as ecchymoses, gastro
-
intestinal bleeding, and epistaxis appear later in 
the disease.
 
»
Dengue virus belongs to the genus flavirus and has four 
distinct serotypes that can cause infection. Infection with 
one serotype does not confer immunity to the other sero
-
types. Dengue is transmitted primarily from human to 
human by the bite of the 
Aedes
 mosquito. Healthcare-
associated transmission (needlestick or mucocutaneous 
exposure) and vertical transmission occur rarely. WHO 
reports that dengue is currently endemic in more than

Aedes
reports that dengue is currently endemic in more than 
 
100 countries, mostly in tropical and subtropical regions. 
Up to 100 million cases of dengue fever occur annually 
(with 500,000 severe) and the surge of cases is associated 
with climatic factors, travel, and urbanization. Thus, along 
with malaria, dengue is one of the two most common vec
-
tor-borne diseases of humans.
There are several factors that contribute to intermittent 
outbreaks in these regions, including the season of the year 
when rainfall is optimal for mosquito breeding, large popu
-
lation with no previous immunity to the specific serotype, 
and frequent contact between the people and the vector.
In the United States, despite the fact that dengue is 
endemic in Northern Mexico and the 
Aedes
 mosquito is 
common in the southern states, outbreaks are uncommon. 
Most cases occur in travelers or inhabitants of US territories 
that are endemic to the dengue virus. Puerto Rico experi
-
ences periodic large outbreaks. In 2010, 26,766 cases of sus
-
pected dengue infections were reported. In 2015, an outbreak 
of locally acquired cases of dengue fever was reported from 
Hawaii where 107 dengue patients were identified.
The incubation period is usually 7–10 days. When the 
virus is introduced into susceptible populations, usually by 
viremic travelers, epidemic attack rates range from 50% to 
70%. Dengue is the second overall cause of a febrile illness 
(after malaria and excluding common upper respiratory 
viral infections) in travelers returning from developing 
countries.
 
»
A history of travel to a dengue-endemic area within 14 days 
of symptom onset is helpful in establishing a diagnosis. 
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Most infected patients are asymptomatic, only 20% devel
-
ops symptoms ranging from mild disease (dengue fever) to 
severe hemorrhagic fever to fatal shock (dengue shock 
syndrome). In 2009, WHO classified dengue as dengue 
without warning signs, dengue with warning signs, and 
severe dengue.
After the incubation period, febrile phase begins 
abruptly with nonspecific symptoms, high fever, chills, 
facial flushing, malaise, retroorbital eye pain, generalized 
body pain, and arthralgia. Some patients might have macu
-
lopapular rash, sore throat, and conjunctival injection. Not 
all patients have all symptoms or fever. Mild hemorrhagic 
manifestations can be seen. Most of the patients will 
recover and fever is usually cleared by day 8.
A subset of patients may progress to severe dengue, 
which is defined by the presence of plasma leakage, hemor
-
rhage, or organ involvement. Hematocrit drop could be the 
earliest sign and an indicator of the severity of plasma leak
-
age. Pleural effusion and ascites develop and are detected 
first by lateral decubitus chest radiograph and ultrasound 
before clinical detection. Increasing liver size, persistent 
vomiting and severe abdominal pain are indications of 
plasma leakage. Signs of hemorrhage such as ecchymoses, 
gastrointestinal bleeding, and epistaxis appear. Severe 
organ involvement may develop such as severe hepatitis, 
encephalitis, and myocarditis.
Shock develops in patients when a critical volume of 
plasma is lost through leakage. Decrease in the level of 
consciousness, hypothermia, hypoperfusion resulting in 
metabolic acidosis, progressive organ impairment, and dis
-
seminated intravascular coagulation leading to severe 
hemorrhage should raise concern about shock. Acute kid
-
ney injury in dengue largely occurs with shock syndrome 
and shows a high mortality.
Leukopenia is characteristic, and elevated transaminases 
are found frequently in dengue fever. Thrombocytopenia, 
fibrinolysis, and hemoconcentration occur more often in 
the hemorrhagic form of the disease. The erythrocyte sedi
-
mentation rate is often normal in most cases.
The nonspecific nature of the illness mandates labora
-
tory verification for diagnosis, usually with IgM and IgG 
ELISAs after the febrile phase. Virus is recovered from the 
blood by PCR or detection of the specific viral protein NS1 
by ELISA during the first few days of infection. Immuno
-
histochemistry for antigen detection in tissue samples and 
dried blood spots can also be used.
 
»
Distinguishing between dengue and other causes of 
febrile illness in endemic areas is difficult. Fevers due to 
dengue are more often associated with neutropenia and 
thrombocytopenia and with myalgias, arthralgias/arthri
-
tis, and lethargy among adults. Chikungunya is more apt 
to develop a chronic arthritis. The arboviral encephaliti
-
des require additional epidemiologic information and 
serologic data to make the diagnosis. Influenza and 
malaria are easily confused early in disease although the 
rhinitis and malaise should help distinguish influenza, 
and the cyclicity of fevers and presence of splenomegaly 
should suggest malaria.
 
»
Usual complications include pneumonia, bone marrow 
failure, hepatitis, iritis, retinal hemorrhages and 
maculopathy, orchitis, and oophoritis. Neurologic compli
-
cations (such as encephalitis, Guillain-Barré syndrome, 
phrenic neuropathy, subdural hematoma, and transverse 
myelitis) are less common. Bacterial superinfection can occur.
Maternal infection poses a risk for premature birth and 
hemorrhage in both the mother and the infant if infection 
occurs near term.
 
»
Treatment
There are no specific therapeutic options for the clinical 
management of dengue besides supportive care. Treat
-
ment entails the appropriate use of volume support, blood 
products, and vasopressors. Acetaminophen is recom
-

-
-
mended for analgesic and antipyretic treatment. NSAID 
usage should be minimized and preferably avoided to 
decrease the risk of gastritis and bleeding, particularly in 
patients with a predilection for hemorrhage or when 
there are abnormalities in platelet, liver function, or clot
-
ting factors.
Platelet counts do not usefully predict clinically signifi
-
cant bleeding. Platelet transfusions may be considered for 
severe thrombocytopenia (less than 10,000/mcL) or when 
there is evidence of bleeding. However, benefit in the 
absence of bleeding may not be observed, and harm may be 
caused by delay in count recovery. Monitoring vital signs 
and blood volume may help in anticipating the complica
-
tions of dengue hemorrhagic fever or shock syndrome.
Repurposed drugs, such as chloroquine, statins, and 
balapiravir are being explored for the treatment of dengue, 
although none has shown clear therapeutic benefit. New 
research is focusing on monoclonal antibodies as therapeu
-
tic option as well as drugs that target structural and non
-
structural proteins of dengue virus essential to its 
 
»
Prognosis
Fatalities are rare but do occur, especially during epidemic 
outbreaks with hemorrhagic fever (seen with recurrent 
disease), and with occasional patients dying of fulminant 
hepatitis. Thrombocytopenia and acute hepatitis are pre
-
dictors of severe dengue and higher mortality. Acute kid
-
ney injury in dengue shock syndrome portends poor 
prognosis. In general, the more advanced forms of disease 
(hemorrhagic fever and shock) occur more often in Asia 
than in Americas.
 
»
Preventive measures should be encouraged, such as control 
of mosquitoes by screening and insect repellents including 
long-lasting insecticides, particularly during early morning 
and late afternoon exposures. Screening blood transfusions 
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for dengue is of increasing importance, especially in 
endemic areas.
Dengvaxia, a recombinant, live, attenuated, tetravalent 
dengue vaccine (CYD-TDV), is the first vaccine to be 
approved and is now licensed for use in six countries. Trials 
evaluating the efficacy of this vaccine reported overall 60% 
efficacy; however, efficacy was lower in younger age group, 
seronegative individuals at the time of vaccination, and 
infection with dengue serotype 2.
Muller DA et al. Clinical and laboratory diagnosis of dengue 
virus infection. J Infect Dis. 2017 Mar 1;215(Suppl 2):S89–95. 
[PMID: 28403441]
Toledo J et al. Relevance of non-communicable comorbidities 
for the development of the severe forms of dengue: a system
-
atic literature review. PLoS Negl Trop Dis. 2016 Jan 4; 
10(1):e0004284. [PMID: 26727113]
World Health Organization. Dengue and severe dengue: http://
www.who.int/mediacentre/factsheets/fs117/en/
4. Hantaviruses
 
»
Transmitted by rodents and cause two clinical 
syndromes.
 
»
Hantavirus pulmonary syndrome (HPS):
 40% 
mortality rate.
 
»
Hemorrhagic fever with renal syndrome (HFRS):
 
mild to severe illness.
 
»
Hantaviruses are enveloped RNA bunyaviruses naturally 
hosted in rodents, moles, and shrews. Hantavirus infection 
in humans can cause several disease syndromes. HFRS is 
primarily caused by Dobrava-Belgrade virus, Puumala 
virus, Seoul virus, and Hantaan virus in Asia and Europe; 
these viruses are called Old World hantaviruses. Nephro
-
pathia epidemica is a milder form of HFRS. Puumala virus 
is the most prevalent pathogen and is present throughout 
Europe. The HPS, also known as hantavirus cardiopulmo
-
nary syndrome, is caused mainly by Sin Nombre virus and 
Andes virus, the New World Hantaviruses in Americas. 
While they share many clinical features, a specific strain is 
not associated with a specific syndrome and overlap is seen 
between the syndromes.
As of January 2017, a total of 728 cases of hantavirus 
infection have been reported in the United States, with an 
average case fatality rate of 36%.
Aerosols of virus-contaminated rodent urine and feces 
are thought to be the main vehicle for transmission to 
humans. Person-to-person transmission is observed only 
with the Andes virus. Occupation is the main risk factor 
for transmission of all hantaviruses: animal trappers, for
-
estry workers, laboratory personnel, farmers, and military 
personnel are at highest risk. Climate change appears to be 
impacting the incidence of hantavirus infection mainly 
through effects on reservoir ecology.
 
»
Vascular leakage is the hallmark of the disease for both 
syndromes, with lungs being the main target with variants 
associated with HPS and the kidneys with variants associ
-
ated with HFRS.
The clinical course of HPS is divided into a febrile pro
-
drome, a cardiopulmonary stage, oliguric and diuretic 
phase, followed by convalescence. A 14- to 17-day incuba
-
tion period is followed by a prodromal phase, typically 
lasting 3–6 days, that is associated with myalgia; malaise; 
abdominal pain along with nausea, vomiting, and diarrhea; 
headache; chills; and fever of abrupt onset. An ensuing 
cardiopulmonary phase is characterized by the acute onset 
of pulmonary edema. In this stage, cough is generally pres
-
ent, abdominal pain and symptoms as above may dominate 
the clinical presentation, and in severe cases, significant 
myocardial depression occurs. Acute kidney injury and 
myositis may occur. Sequelae include neuropsychological 
impairments in some HPS survivors.
HFRS manifests as mild, moderate, or severe illness 
depending on the causative strain. A 2- to 3-week incuba
-
tion period is followed by a protracted clinical course, typi
-
cally consisting of five distinct phases: febrile period, 
hypotension, oliguria, diuresis, and convalescence phase.

-
-
hypotension, oliguria, diuresis, and convalescence phase. 
Various degrees of renal involvement are usually seen, 
occasionally with frank hemorrhage. Disseminated intra
-
vascular coagulation and thromboembolic phenomena are 
recognized complications. Pulmonary edema is not typi
-
cally seen but when present usually occurs in the final 
stages of disease (oliguric and diuretic phase). Encephalitis 
and pituitary involvement are rare findings with hantavirus 
infection, although a few cases are reported with Puumala 
virus. Patients may have persistent hematuria, proteinuria, 
or hypertension up to 35 months after infection. Smoking 
appears to exacerbate the viremia with the Puumula vari
-
ant of HFRS.
Laboratory features include hemoconcentration and eleva
-
tion in lactate dehydrogenase, serum lactate, and hepato
-
cellular enzymes. Early thrombocytopenia and leukocytosis 
(as high as 90,000 cells/mcL in HPS) are seen in both HFRS 
and HPS. In HPS, immunoblasts (activated lymphocytes 
with plasmacytoid features) can be seen in blood, lungs, 
kidneys, bone marrow, liver, and spleen.
An indirect fluorescent assay and enzyme immunoassay 
are available for detection of specific IgM or low-avidity IgG 
virus-specific antibodies. A quantitative RT-PCR is devel
-
oped; however, the viremia of human hantavirus infections 
is short-term, and therefore, viral RNA cannot be readily 
detected in the blood or urine of patients unless for the 
more readily detected early viremia of the Andes variant.
A plaque reduction neutralization test remains a gold 
standard serologic assay and distinguishes between the dif
-
ferent hantavirus species, although cross reaction between 
Old and New World viruses exist. This test needs to be per
-
formed in a laboratory with appropriate biosafety (level 3).
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»
The differential diagnosis of the acute febrile syndrome 
seen with HFRS or early HPS includes scrub typhus, lepto
-
spirosis, and dengue. HPS requires differentiation from 
other respiratory infections caused by such pathogens as 
Legionella, Chlamydia
, and 
. Coxsackievirus 
infection should also be considered in the differential 
 
»
Treatment
Treatment is mainly supportive. Cardiorespiratory support 
with vasopressors is frequently needed; extracorporeal 
membrane oxygenation may be required in severe cases of 
HPS. Intravenous ribavirin is used in HFRS (Hantaan 
virus) with some success in decreasing the severity of the 
kidney injury. Its effectiveness in HPS, however, is not 
 
»
Because infection is thought to occur by inhalation of 
rodent waste, prevention is aimed at eradication of rodents 
in houses and avoidance of exposure to rodent excreta, 
including forest service facilities. While inactivated vac
-
cines have been used in the past in Korea and China, there 
is currently no commercially available vaccine and the 
WHO does not recommend preventive vaccination. None
-
theless, multiple vaccines, including inactivated, virus-like 
particle, and recombinant ones, remain under develop
-
ment in preclinical stages.
 
»
Prognosis
The outcome is highly variable depending on severity of 
disease. HPS is a more severe disease than HFRS, with a 
mortality rate of about 40%. In Sin Nombre virus infec
-
tions, the persistence of elevated IgG titers correlates with 
a favorable outcome.
de St Maurice A et al. Exposure characteristics of hantavirus 
pulmonary syndrome patients, United States, 1993–2015. 
Emerg Infect Dis. 2017 May;23(5):733–9. [PMID: 
28418312]
Szabó R. Antiviral therapy and prevention against hantavirus 
infections. Acta Virol. 2017;61(1):3–12. [PMID: 28105849]
5. Yellow Fever
 
»
Endemic area exposure: tropical and subtropical 
areas in South America and Africa.
 
»
Sudden onset of severe headache, aching in legs, 
and tachycardia.
 
»
Brief (1 day) remission, followed by bradycardia, 
hypotension, jaundice, hemorrhagic tendency.
 
»
Albuminuria, leukopenia, bilirubinemia.
 
»
Y ellow fever is a zoonotic flavivirus infection transmitted 
by 
Aedes
 mosquitoes bite. There are three types of trans
-
mission cycles; sylvatic (or jungle; humans working or 
travelling in the forest are bitten by infected mosquitoes), 
intermediate (most common type of outbreak in Africa; 
mosquitoes infect both monkeys and people leading to 
outbreaks in separate villages), and urban (seen in large 
epidemics; infected mosquitoes transmit the virus from 
person to person).
Y ellow fever occurs in 47 endemic countries in Africa in 
Central and South America. Around 90% of cases reported 
every year occur in sub-Saharan Africa. Adults and chil
-
dren are equally susceptible, though attack rates are highest 
among adult males because of their work habits.
 
»
The majority of persons have no illness or only mild illness. 
The incubation period is 3–6 days in persons in whom 
symptoms develop.
1. Mild form—
Symptoms are malaise, headache, fever, 
retroorbital pain, nausea, vomiting, and photophobia. Rel
-
ative bradycardia, conjunctival injection, and facial flush
-
ing may be present.
2. Severe form—
Severe illness develops in about 15%. 
Initial symptoms are similar to the mild form, but brief 
fever remission lasting hours to a few days is followed by a 
“period of intoxication” manifested by fever and relative 
bradycardia (Faget sign), hypotension, jaundice, hemor
-
rhage (gastrointestinal, nasal, oral), and delirium that may 
progress to coma.
Leukopenia, elevated liver enzymes, and bilirubin can 
occur. Proteinuria is present and usually disappears com
-
pletely with recovery. Bleeding dyscrasias with elevated

-
pletely with recovery. Bleeding dyscrasias with elevated 
prothrombin and partial thromboplastin times, decreased 
platelet count, and presence of fibrin-split products, can 
also occur.
In the early stages of the disease (up to 10 days), diag
-
nosis is confirmed if yellow fever virus RNA is detected by 
RT-PCR in blood from a person with no history of recent 
yellow fever vaccination.
In later stages, serologic diagnosis can be made by 
using ELISA to measure IgM 3 days after the onset of 
symptoms; however, yellow fever vaccine and other flavi
-
viruses, including dengue, West Nile, and Zika viruses, 
may give a false-positive ELISA test. Thus, the presence of 
yellow fever virus–specific IgM antibody and negative 
ELISA panel for other relevant flaviviruses confirm the 
diagnosis. If ELISA is positive for other flaviviruses, the 
more specific plaque reduction neutralization assay should 
be done in reference laboratories, which measures the titer 
of the neutralizing antibodies in the serum toward the 
infecting virus.
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»
It may be difficult to distinguish yellow fever from hepati
-
tis, malaria, leptospirosis, louse-borne relapsing fever, 
dengue, and other hemorrhagic fevers on clinical evidence 
alone. Albuminuria is a constant feature in yellow fever 
patients, and its presence helps differentiate yellow fever 
from other viral hepatitides. Serologic confirmation is 
often needed.
 
»
Treatment
No specific antiviral therapy is available. Treatment is 
directed toward symptomatic relief and management of 
 
»
Prognosis
The mortality rate of the severe form is 20–50%, with death 
occurring most commonly between the sixth and the tenth 
days. Convalescence is prolonged, including 1–2 weeks of 
asthenia. Infection confers lifelong immunity to those who 
recover.
 
»
The yellow fever vaccine, which is derived from the live 
attenuated 17D strain, and currently given as a single dose 
for a lifetime, is the most effective way to prevent and con
-
trol disease. A single dose of vaccine is considered to pro
-
vide lifelong immunity. The 10-year booster dose is no 
longer recommended; however, some groups may consider 
receiving a second dose of vaccine after 10 years (these 
groups are listed at https://www.cdc.gov/yellowfever/
healthcareproviders/vaccine-info.html).
Y ellow fever vaccine is recommended for persons 
aged over 9 months who are traveling to or living in 
areas at risk for yellow fever virus transmission. WHO 
recommends that all endemic countries should include 
yellow fever vaccine in their national immunization 
programs.
The vaccine is contraindicated in persons with severe 
egg allergies or who are severely immunocompromised, 
including patients with primary immunodeficiencies, HIV 
infection with CD4+ count below 200/mcL, thymus disor
-
der with abnormal immune function, malignant neo
-
plasms, transplantation, immunosuppressive and 
immunomodulatory therapies. Caution should be taken 
when administering the vaccine to patients over 60 years of 
age as well as breastfeeding women. Pregnant women 
should receive the vaccine only if they cannot defer travel 
to endemic areas (Chapter 30). Clinicians should be aware 
of rare but frequently fatal vaccine-induced reactions, 
including anaphylaxis, yellow fever vaccine–associated 
viscerotropic disease, and yellow fever vaccine–associated 
neurologic disease.
The best personal protective measures are to avoid 
mosquito bites. If not in an endemic area, the patient 
should be isolated from mosquitoes to prevent transmis
-
sion, since blood in the acute phase is potentially 
infectious.
Staples JE et al; Centers for Disease Control and Prevention 
(CDC). Y ellow fever vaccine booster doses: recommendations 
of the Advisory Committee on Immunization Practices, 2015. 
MMWR Morb Mortal Wkly Rep. 2015 Jun 19;64(23):647–50. 
[PMID: 26086636]
Wieten RW et al. A single 17D yellow fever vaccination provides 
lifelong immunity; characterization of yellow-fever-specific 
neutralizing antibody and T-cell responses after vaccination. 
PLoS One. 2016 Mar 15;11(3):e0149871. [PMID: 26977808]
World Health Organization. Y ellow fever. http://www.who.int/
csr/disease/yellowfev/en/
OTHER SYSTEMIC VIRAL DISEASES
1. Zika Virus
 
»
Most infected persons asymptomatically 
seroconvert.
 
»
Clinical symptoms are akin to those of chikungu
-
nya virus infection.
 
»
Complications include microcephaly and ocular 
complications in infants born to mothers infected 
during pregnancy as well as Guillain-Barré.
 
»
There is no effective antiviral or vaccine.
 
»
Zika virus is a flavivirus, akin to the viruses that cause 
dengue fever, Japanese encephalitis, and West Nile 
The virus was noted in Africa and Asia during the 
1950s–1980s, but first spread beyond those two continents 
during 2007 when an outbreak occurred in Y ap State,

during 2007 when an outbreak occurred in Y ap State, 
Federated States of Micronesia. A large outbreak occurred 
in French Polynesia in 2013. A smaller outbreak occurred 
on Easter Island during 2014. The virus then spread to the 
Western hemisphere and was first noted in northeastern 
Brazil in 2015. Up to 1.3 million cases occurred in Brazil 
during that year. Zika virus then spread rapidly throughout 
the Americas, including the United States and worldwide 
http://www.who.int/csr/disease/zika/en/. The current 
count (as of February 21, 2018) is 653 for US territories 
(82% in Puerto Rico, the remainder in the US Virgin Islands 
and American Samoa) and 427 for US states (Florida with 
25%, but another 38% in New Y ork, California, and Texas). 
Global WHO reports show that transmission as of March 
2017 is ongoing in 79 nations, interrupted in 5, and poten
-
tial with presence of vectors in 64.
Aedes
 species mosquitoes, particularly 
Aedes aegypti
, 
are primarily responsible for transmission of Zika virus. 
The biodistribution of the species largely determines the 
area of prevalence for Zika virus. 
Aedes
 species mosquitoes 
are found primarily in the southeastern United States, but 
one species 
Aedes albopictus
 (the Asian tiger mosquito 
known to sequester in tires) may be seen as far north as 
Pennsylvania and New Jersey. Rarely, a few other mosquito 
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species including 
Anopheles
 and 
Culex
 may be competent 
for the Zika virus. Sexual transmission is reported from 
males and females to partners via vaginal, anal, or oral sex. 
Vertical transmission from pregnant woman to fetus is 
prominent. Transmission via platelet transfusion is also 
reported.
 
»
The incubation period is about 10 days. Symptoms include 
acute onset fever, maculopapular rash that is usually pru
-
ritic, nonpurulent conjunctivitis, and arthralgias, the latter 
mimicking the symptoms of the chikungunya virus. Rash 
may outlast the fever but is not always present. Symptoms 
last up to 7 days. Most infections are asymptomatic. Viral 
infections most often confused with Zika include dengue 
and chikungunya virus infections.
The CDC recommends that persons with symptoms of 
Zika infection be tested if they live in or have traveled 
recently to an area with active transmission, as well as all 
pregnant women who have lived in or visited affected 
regions.
Diagnosis is made by detecting viral RNA or neutral
-
izing antibody, IgM 4 days or more after symptom onset 
or IgG after 7 days or more. The Trioplex real-time RT-
PCR assay, which detects Zika virus, chikungunya virus 
and dengue virus RNA, and the Zika MAC-ELISA, which 
detects Zika virus IgM antibodies, are available in some 
laboratories. The real-time RT-PCR detects the virus in 
blood or urine and should be performed within 2 weeks 
of illness onset. Matched serum and urine specimens 
should be tested simultaneously. Although not routinely 
recommended, RT-PCR can be performed on amniotic 
fluid, CSF, and placental tissue. A positive real-time RT-
PCR test definitively makes the diagnosis of Zika virus 
infection and does not require additional confirmatory 
testing. A negative test does not exclude the presence of 
the virus in other tissues and does not rule out infection. 
Persons with negative tests should undergo further test
-
ing for Zika virus IgM antibody and other arboviral 
Persons being tested 14 days or more after symptom 
onset should be tested for IgM and neutralizing antibodies. 
Asymptomatic pregnant women should be tested for IgM 2 
to 12 weeks, and on occasion longer, after travel to an area 
with Zika activity or if they have had sexual contact with a 
man with confirmed Zika virus infection. In areas with 
active Zika transmission, asymptomatic pregnant women 
should be tested for IgM antibody as part of routine obstet
-
ric care. Real-time RT-PCR testing is recommended for 
pregnant women more than 2 weeks after exposure who 
test positive for Zika IgM antibody. Persistent Zika virus 
RNA in serum has been reported in pregnancy. The Zika 
MAC-ELISA can be performed on serum or CSF. Neutral
-
izing antibodies can cross-react with dengue and other 
flaviviruses, so samples testing positive should be sent to 
public health laboratories for confirmation. Pregnant 
women with confirmed or suspected Zika virus infection 
(positive IgM antibodies not yet confirmed to be due to 
Zika infection) may be monitored by serial ultrasounds at 
3- to 4-week intervals, assessing fetal anatomy and growth. 
With a declining prevalence of Zika virus infection, posi
-
tive antibody tests run the risk of more likely being false-
positives and thus the need for the outlined assessments 
exists.
 
»
Two neurologic complications are of particular concern: 
(1) microcephaly, often associated with brain calcifications 
and other abnormalities, first noted during the outbreak in 
Brazil and subsequently recognized to have occurred in 
French Polynesia as well; and (2) Guillain-Barré syndrome, 
first noted during the outbreak in French Polynesia. Other 
congenital anomalies, including arthrogryposis among 
congenitally infected fetuses and infants, and spontaneous

congenitally infected fetuses and infants, and spontaneous 
abortions are also observed. Rare deaths related to Zika 
virus infection are reported.
Ocular findings in Zika, reported in those congenitally 
infected, include focal macular pigment mottling, chorio
-
retinal atrophy (especially in the macular area), congenital 
glaucoma with optical nerve hypoplasia, and optic disk 
 
»
Treatment
There are no antivirals approved for treatment of Zika 
virus. Sofosbuvir, FDA-approved to treat hepatitis C, 
another flavivirus, shows some ability to inhibit Zika repli
-
cation and infection in vitro and in mice. Aspirin and 
NSAIDs are avoided during illness caused by the flavivirus 
dengue because of its propensity to cause hemorrhage. 
Zika virus infections, however, do not appear to be associ
-
ated with major hemorrhagic complications.
 
»
The most effective means is environmental control of mos
-
quitoes and removal of areas where water is stagnant or 
builds up. Such measures include screens on houses; 
removal of old tires and debris from endemic areas of 
infection; and movement toward better living conditions, 
including air conditioning in impoverished areas. Because 
of the association between microcephaly and Zika virus 
infection during pregnancy, pregnant women are advised 
to avoid travel to areas where Zika virus is circulating 
http://www.who.int/csr/disease/zika/information-for-
travelers/en/. Guidelines for testing of pregnant women 
potentially exposed are available through CDC. Infected 
individuals should refrain from blood donations for several 
months.
No approved vaccine against Zika virus exists, although 
a promising candidate containing two Zika virus proteins 
was protective in mice. Four candidates, including a live-
attenuated vaccine that is analogous to a vaccine against 
dengue virus and another DNA vaccine, are in phase 1–2 
clinical trials.
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Bullard-Feibelman KM et al. The FDA-approved drug sofosbu
-
vir inhibits Zika virus infection. Antiviral Res. 2017 Jan; 
137:134–40. [PMID: 27902933]
Chibueze EC et al. Zika virus infection in pregnancy: a system
-
atic review of disease course and complications. Reprod 
Health. 2017 Feb 28;14(1):28. [PMID: 28241773]
de Fatima Vasco Aragao M et al. Clinical features and neuroim
-
aging (CT and MRI) findings in presumed Zika virus related 
congenital infection and microcephaly: retrospective case 
series study. BMJ. 2016 Apr 13;353:i1901. [PMID: 27075009]
Hills SL et al. Epidemiology of Zika virus infection. J Infect Dis. 
2017 Dec 16;216(Suppl 10):S868–74. [PMID: 29267914]
Jin J. JAMA patient page. Zika virus disease. JAMA. 2016 Jun 
14;315(22):2482. [PMID: 27074312]
Oduyebo T et al. Update: interim guidance for health care pro
-
viders caring for pregnant women with possible Zika virus 
exposure—United States (including U.S. territories), 
July 2017. MMWR Morb Mortal Wkly Rep. 2017 Jul 28; 
66(29): 781–93. [PMID: 28749921]
Y epez JB et al; Johns Hopkins Zika Center. Ophthalmic manifes
-
tations of congenital Zika syndrome in Colombia and 
Venezuela. JAMA Ophthalmol. 2017 May 1;135(5):440–5. 
[PMID: 28418539]
2. Chikungunya Fever
Chikungunya (“that which bends up” in the Bantu lan
-
guage Kimakonde) fever is an alphavirus infection trans
-
mitted to humans by 
A aegypti
 and 
A albopictus
 and is 
considered a classic “arthritogenic” virus. The virus is 
indigenous to tropical Africa and Asia. Outbreaks origi
-
nated in Kenya in 2004 and subsequently were reported 
from areas that adjoin the Indian Ocean, Southeast Asia 
and its neighboring islands (2005–2007), South India 
(2005), the island of La Réunion (2005–2006), with subse
-
quent spread including autochthonous cases in Italy and 
France (2007). In 2013, the first autochthonous case of 
chikungunya occurred on Saint Martin in the Caribbean. 
Other autochthonous cases have been reported in the 
Americas except for Canada http://www.paho.org/hq/index
 
.php?option=com_topics&view=readall&cid=5927&Itemi
d=40931&lang=en, https://www.cdc.gov/chikungunya/geo/
united-states-2015.html. In 2017, through December 22, 
the total case load for the year in the Americas was 123,087 
with 101 deaths. In the United States, the CDC reports for 
2017 (through December 19), 104 travel-associated cases 
in 24 states (with the largest number of reports from New 
Y ork, California, and Texas) and 33 endemic cases from 
Puerto Rico. The virus’ prevalence is ubiquitous with 
endemic countries in Africa, the Americas, Asia, and 
Europe.
Among naïve populations, attack rates are often as high 
as 50%. On Saint Martin, 39% of infections were asymp
-
tomatic. Vertical transmission is documented if the mother 
is viremic during parturition. Infectious virus was isolated 
from saliva, although transmission from oral secretions is 
not observed among humans. Endemicity of 
A aegypti
 in 
the Americas and the introduction of 
 into 
Europe and the New World raise concern for further exten
-
sion of the epidemic. Case reports show that chikungunya 
virus may coinfect patients with yellow fever virus, plas
-
modia, and dengue virus.
 
»
After an incubation period of 1–12 days (estimated 
median 3), there is abrupt onset of fever; headache; intesti
-
nal complaints, including diarrhea, vomiting, or abdominal 
pain; myalgias; and arthralgias/arthritis affecting small, 
large, and axial joints. The simultaneous involvement of 
more than 10 joints and the presence of tenosynovitis (espe
-
cially in the wrist) are characteristic. The stooped posture of 
patients gives the disease its name. Joint symptoms persist 
for 4 months in 33% and linger for years in about 10%. 
A centrally distributed pigmented or pruritic maculopapu
-
lar rash is reported in 10–40% of patients; it can be bullous

-
lar rash is reported in 10–40% of patients; it can be bullous 
with sloughing in children. Mucosal disease occurs in 
about 15%. Facial edema and localized petechiae are 
reported. Neurologic complications, including encephalitis, 
myelopathy, peripheral neuropathy, myeloneuropathy, and 
myopathy, are usually associated with a good outcome. 
Encephalitis occurred in 8.6 per 100,000 persons infected in 
La Réunion during 2005–2006 with 17% mortality and 
increased risk of encephalitis among those older than 65 
years. Hemorrhagic fever–like presentations are exceptional. 
Coinfection with other respiratory viruses and with dengue is 
common. Some of the pathology may be immune mediated. 
Death is rare and usually related to underlying comorbidities.
Diagnosis is made epidemiologically and clinically. Mild 
leukopenia occurs as does thrombocytopenia, which is sel
-
dom severe. Elevated inflammatory markers do not correlate 
well with the severity of arthritis. Radiographs of affected 
joints are normal during the acute phase. Bone lesions are 
visible in some patients with chronic symptoms.
Serologic confirmation requires elevated IgM titers or 
fourfold increase in convalescent IgG levels using an 
ELISA. RT-PCR and ELISA are commercially available; no 
ELISA kit is FDA-cleared. Culture techniques (viral isola
-
tion in insect or mammalian cell lines or by inoculation of 
mosquitoes or mice) require BSL-3 containment. Direc
-
tions on submitting specimens for testing may be obtained 
from the CDC Arboviral Diseases Branch, 970-221-6400. 
Suspected cases in the United States should be promptly 
reported to public health authorities. The differential diag
-
nosis includes other tropical febrile diseases, such as 
malaria, leishmaniasis, or dengue.
 
»
Complications & Prognosis
A common complication of chikungunya fever is long-term 
weakness, asthenia, myalgia, arthralgia, and arthritis, noted 
to occur in 25–66.5% of cases at 1 year. Risk factors for 
long-term arthralgias include the presence of such symp
-
toms at 4 months after onset of disease and age over 35 years. 
Persons with preexisting arthritis are also at increased risk 
for prolonged symptoms after chikungunya infection. Nasal 
skin necrosis is rarely reported. The Guillain-Barré syn
-
drome is reported from the French West Indies during an 
outbreak in 2014, and more recently from New Delhi, India.
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»
Treatment is supportive with NSAIDs. Chloroquine may be 
useful for managing refractory arthritis. In a retrospective 
study on La Réunion, methotrexate was associated with a 
positive response. No licensed vaccine exists, although a live 
recombinant measles virus–based vaccine and a virus-like 
particle vaccine are in early clinical trials. At this time, pre
-
vention relies on avoidance of mosquito vectors.
Abdelnabi R et al. Chikungunya virus infections: time to act, 
time to treat. Curr Opin Virol. 2017 Jun;24:25–30. [PMID: 
28414993]
Balavoine S et al. Guillain-Barré syndrome and Chikungunya: 
description of all cases diagnosed during the 2014 outbreak in 
the French West Indies. Am J Trop Med Hyg. 2017 
Aug;97(2):356–60. [PMID: 28722564]
Brizzi K. Neurologic manifestation of Chikungunya virus. Curr 
Infect Dis Rep. 2017 Feb;19(2):6. [PMID: 28233188]
3. Colorado 
t
ick F
ever
 
»
Onset 1–19 days (average, 4 days) following 
 
tick bite.
 
»
Fever, chills, myalgia, headache, prostration.
 
»
 
»
Second attack of fever after remission lasting 
 
2–3 days.
 
»
Colorado tick fever is a reportable biphasic, febrile illness 
caused by a reovirus infection transmitted by 
Dermacentor 
andersoni
 tick bite. About five cases occur annually, largely 
among men over age 40. The disease is limited to the west
-
ern United States and Canada and is most prevalent during 
the tick season (March to November). There is a discrete 
history of tick bite or exposure in 90% of cases. The virus 
infects the marrow erythrocyte precursors. Blood transfu
-
sions can be a vehicle of transmission.
 
»
The incubation period is 3–6 days, rarely as long as 19 days. 
The onset is usually abrupt with a high fever. Severe myal
-
gia, headache, photophobia, anorexia, nausea and vomiting, 
and generalized weakness are prominent. Physical findings 
are limited to an occasional faint rash. The acute symptoms 
resolve within a week. Remission is followed in 50% of cases 
by recurrent fever and a full recrudescence lasting 2–4 days. 
In an occasional case, there may be three bouts of fever.
The differential diagnosis includes influenza, Rocky 
Mountain spotted fever, numerous other viral infections 
and, in the right setting, relapsing fevers.
Leukopenia with a shift to the left and atypical lympho
-
cytes occurs, reaching a nadir 5–6 days after the onset of 
illness. Thrombocytopenia may occur. An RT-PCR assay 
may be used to detect early viremia. Detection of IgM by 
capture ELISA or plaque reduction neutralization is possi
-
ble after 2 weeks from symptom onset and is the most fre
-
quently used diagnostic tool.
 
»
Aseptic meningitis (particularly in children), encephalitis, 
and hemorrhagic fever occur rarely. Malaise may last weeks 
to months. Fatalities are very uncommon. Rarely, sponta
-
neous abortion or multiple congenital anomalies may 
complicate Colorado tick fever infection acquired during 
 
»
Treatment
No specific treatment is available. Ribavirin has shown 
efficacy in an animal model. Antipyretics are used, 
although salicylates should be avoided due to potential 
bleeding with the thrombocytopenia seen in patients with 
Colorado tick fever.
 
»
Prognosis
The disease is usually self-limited and benign.
 
»
Tick avoidance is the best prevention. The tick season is 
primarily from March to November, and the ticks mostly 
live at high altitudes (over 7000 feet) in sagebrush.
Geissler AL et al. Infection with Colorado tick fever virus among 
humans and ticks in a national park and forest, Wyoming, 
2010. Vector Borne Zoonotic Dis. 2014 Sep;14(9):675–80. 
[PMID: 25229706]
Y endell SJ et al. Colorado tick fever in the United States, 2002–
2012. Vector Borne Zoonotic Dis. 2015 May;15(5):311–6. 
[PMID: 25988440]

COMMON VIRAL RESPIRATORY INFECTIONS
1. Respiratory Syncytial Virus (RSV) 
 
& Other 
p
ar
amyxoviruses
 
»
RSV is a major cause of morbidity and mortality at 
the extremes of age (younger than 5 and older 
than 65).
 
»
Treatment is largely supportive.
 
»
No active vaccination for RSV is available.
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»
Respiratory syncytial virus (RSV)
 is a paramyxovirus that 
causes annual outbreaks during the wintertime with usual 
onset of pulmonary symptoms between mid-October and 
early January in the continental United States (excluding 
Florida). Outside the United States, RSV usually peaks dur
-
ing wet months in areas with high annual precipitation and 
during cooler months in hot and dry areas. It occurs earlier 
in urban areas. An outbreak on a hematology ward was 
reported in Portugal.
There are two major subtypes, A and B, and it appears 
that the A genotype is associated with disease severity. RSV 
is the leading cause of hospitalization in US children, with 
annual hospitalization rates of 6 per 1000 children younger 
than 5 years. Prematurity is a major risk factor for severe 
disease. Early RSV bronchiolitis in children, along with a 
family history of asthma, are associated with persistence of 
airway reactivity later in life.
RSV also causes upper and lower respiratory tract 
infection in adults, with the virus entering through contact 
with mucous membranes. RSV occurs with increasingly 
recognized severity in those with comorbid conditions, 
older adults (accounting for a rate of 4 per 1000 hospital
-
izations and 14,000 deaths annually), persons with severe 
combined immunodeficiency, and in patients following 
lung or bone marrow transplantation (because CD8 T cells 
are not available for viral clearance). Recurrences occur 
throughout life. The average incubation period is 5 days. 
Up to 10% of disease classified as invasive pneumococcal 
disease is thought to be RSV or influenza.
In immunocompromised patients, such as bone mar
-
row transplant recipients, serious pneumonia can occur, 
and outbreaks with a high mortality rate (greater than 
70%) are reported.
Other paramyxoviruses important in human disease 
include human metapneumovirus, parainfluenza virus, 
and Nipah virus.
Human metapneumovirus
 is a ubiquitous seasonal 
virus circulating during late winter to early spring. It is 
divided into subgroups A and B. Metapneumovirus 
accounted for 7.3% of childhood (younger than 16 years 
old) pneumonia in a Norwegian series of 3650 patients in 
which RSV accounted for 28.7%. Clinical presentations 
range from mild upper respiratory tract infections to 
severe lower respiratory tract infections (eg, bronchiolitis, 
croup, and pneumonia). Lower respiratory tract (some
-
times severe) infections have been observed among immu
-
nocompromised and elderly adults, especially residents of 
nursing homes. In lung transplant recipients, human meta
-
pneumovirus is a common cause of respiratory illness and 
is thought to increase the risk of acute and chronic graft 
rejection. Ribavirin appears to be well tolerated in lung 
transplant recipients with metapneumovirus infection.
Human parainfluenza viruses (HPIVs)
 are commonly 
seen in children and are the most common cause of laryn
-
gotracheitis (croup). Four different serotypes are described, 
and they differ in their clinical presentations as well as 
epidemiology. HPIV-1 and HPIV-2 are responsible for 
croup. HPIV-3 is associated with bronchiolitis and 
pneumonia. HPIV-4 is a less frequently reported pathogen. 
Reinfections are common throughout life. HPIVs can also 
cause severe disease in older individuals, immunocompro
-
mised persons, and patients with chronic illnesses.
Nipah virus
 is a highly virulent paramyxovirus first 
described in 1999. Cases are concentrated mainly in 
Southeast Asia (Malaysia, Singapore, Bangladesh and 
India). Fruit bats are identified as the natural host of the 
virus. An outbreak of 14 cases, 8 fatal, occurred in 
Bangladesh associated with drinking date palm sap 
between 2010 and 2014. Direct pig-human, cow-human, 
human-human, and nosocomial transmission are reported. 
Nipah virus causes acute encephalitis with a high fatality

Nipah virus causes acute encephalitis with a high fatality 
rate (67–92%), although respiratory symptoms are also 
described. Cranial nerve palsies, encephalopathy, and dys
-
tonia are among neurologic sequelae (15–32%) seen in 
infected individuals. Relapses occurring weeks and months 
after initial infection are described (3.4–7.5%).
Bocavirus infections are discussed under Erythrovirus 
(parvovirus) infections below.
 
»
In RSV bronchiolitis, proliferation and necrosis of bron
-
chiolar epithelium develop, producing obstruction from 
sloughed epithelium and increased mucus secretion. An 
interleukin-1 receptor polymorphism is shown to be asso
-
ciated with more severe bronchiolitis. Signs of infection 
include low-grade fever, tachypnea, and wheezes. Apnea is 
a common presenting symptom. Hyperinflated lungs, 
decreased gas exchange, and increased work of breathing 
are present. Pulmonary hemorrhage is reported. In 
children, RSV is globally the most common cause of acute 
lower respiratory infection and also a common cause of 
acute and recurrent otitis media. In patients with Down 
syndrome, RSV develops at a later age and is associated 
with more protracted hospitalizations.
A rapid diagnosis of RSV infection is made by viral antigen 
identification of nasal washings using an ELISA or immu
-
nofluorescent assay. PCR is increasingly used. Multiplex 
assays in conjunction with influenza A and B tests are 
available commercially. RSV viral load assay values at day 3 
of infection may correlate with requirement of intensive 
care and respiratory failure in children.
Human metapneumovirus is best diagnosed by PCR. 
Tests for rapid detection of viral antigens with immuno
-
fluorescence or ELISA, and PCR techniques are also widely 
available for detection of HPIV . Culture may also be used. 
ELISA (serum and CSF) and PCR (urine, respiratory secre
-
tions but not blood) are both used for Nipah virus infec
-
tion diagnosis.
 
»
Treatment of RSV consists of supportive care, including 
hydration, humidification of inspired air, antibiotic therapy 
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(to reduce other respiratory morbidity), and ventilatory 
support as needed. Neither bronchodilating agents nor 
corticosteroids have demonstrated efficacy in bronchiolitis 
although individual patients with significant broncho
-
spasm or history of asthma might respond to them. Oral 
antiviral agents remain under study.
The use of aerosolized ribavirin can be considered in high-
risk patients, such as those with a history of bone marrow 
transplantation, and appears to lessen mortality. The prophy
-
lactic monoclonal antibody palivizumab, while effective in 
high-risk infants (congenital heart and lung diseases, Down 
syndrome), is not of proven efficacy among adults with RSV .
No RSV vaccine is currently commercially available. 
 
A subunit live attenuated intranasal vaccine candidate is 
under study and remains the most promising. Vaccines for 
use in pregnant women designed to protect infants during 
their period of highest vulnerability are in early clinical trials.
Prevention in hospitals entails rapid diagnosis, hand 
washing contact isolation, and perhaps passive immuniza
-
tion. (Passive immunization is costly, but is associated with 
improved antiviral titers in hematologic stem cell transplant 
recipients). The use of conjugated pneumococcal vaccina
-
tion appears to decrease the incidence of concomitant pneu
-
monia associated with viral infections in children in some 
countries. Viral shedding averages 11 days and correlates 
inversely with age and directly with severity of infection.
Therapeutic modalities for human metapneumovirus 
and parainfluenza virus infections under investigation 
include intravenous ribavirin administration.
Campbell H et al. Respiratory syncytial virus (RSV) disease—
new data needed to guide future policy. J Glob Health. 2015 
Dec;5(2):020101. [PMID: 26755941]
Clayton BA. Nipah virus: transmission of a zoonotic paramyxo
-
virus. Curr Opin Virol. 2017 Feb;22:97–104. [PMID: 
28088124]
Noveroske DB et al. Local variations in the timing of RSV epi
-
demics. BMC Infect Dis. 2016 Nov 11;16(1):674. [PMID: 
27835988]
Volling C et al. Respiratory syncytial virus infection-associated 
hospitalization in adults: a retrospective cohort study. BMC 
Infect Dis. 2014 Dec 13;14:665. [PMID: 25494918]
2. Seasonal Influenza
 
»
Cases usually in epidemic pattern.
 
»
Onset with fever, chills, malaise, cough, coryza, 
and myalgias.
 
»
Aching, fever, and prostration out of proportion to 
catarrhal symptoms.
 
»
 
»
Influenza (an orthomyxovirus) is a highly contagious dis
-
ease transmitted by the respiratory route in humans. 
Transmission occurs primarily by droplet nuclei rather 
than fomites or direct contact. There are three types of 
influenza viruses that infect humans. While type A can 
infect a variety of mammals (humans, swine, horses, etc) 
and birds, types B and C almost exclusively infect humans. 
Type A viruses are further divided into subtypes based on 
the hemagglutinin (H) and the neuraminidase (N) 
expressed on their surface. There are 18 subtypes of hem
-
agglutinin and 11 subtypes of neuraminidase.
Annual epidemics usually appear in the fall or winter in 
temperate climates. Up to 5 million cases of severe influ
-
enza are estimated by the WHO to occur annually, with up 
to 0.5 million annual deaths. Influenza epidemics affect 
10–20% of the global population on average each year and 
are typically the result of minor antigenic variations of the 
virus, or antigenic drift, which occur often in influenza A 
virus. On the other hand, pandemics—associated with 
higher mortality—appear at longer and varying intervals 
(decades) as a consequence of major genetic reassortment 
of the virus (antigenic shift) or adaptation of an avian or 
swine virus to humans (as with the pandemic H1N1 virus 
of 1918). (http://www.who.int/influenza/surveillance_
monitoring/updates/latest_update_GIP_surveillance/en/).

The highly pathogenic avian influenza subtypes are 
discussed in the next section. The novel swine-origin influ
-
enza A (pandemic H1N1) virus emerged in Mexico in 2009 
and quickly spread throughout North America and the 
world causing a pandemic. This virus originated from tri
-
ple-reassortment of North American swine, human, and 
avian virus lineages and Eurasian swine virus lineages and 
replaced the previous H1N1 seasonal virus.
 
»
Type A and B seasonal influenza viruses produce clinically 
indistinguishable infections, whereas type C usually causes 
mild illness. The incubation period is 1–4 days. In unvac
-
cinated persons, uncomplicated influenza often begins 
abruptly. Symptoms range widely from nearly asymptom
-
atic to a constellation of systemic symptoms (including 
fever, chills, headache, malaise, and myalgias) and respira
-
tory symptoms (including runny/stuffy nose, sore throat, 
hoarseness, cough, and substernal soreness). Gastrointestinal 
symptoms and signs may occur, particularly among young 
children with influenza B virus infections. Fever lasts 
 
1–7 days (usually 3–5). Coryza, nonproductive cough, and 
sore throat are present. Elderly patients especially may pres
-
ent with lassitude and confusion, often without fever or 
respiratory symptoms. Signs include mild pharyngeal injec
-
tion, flushed face, and conjunctival redness. Moderate 
enlargement of the cervical lymph nodes and tracheal ten
-
derness may be observed. The presence of fever (higher 
than 38.2
°
C) and cough during influenza season is highly 
predictive of influenza infection in those older than 4 years.
Rapid influenza diagnostic tests for detection of influenza 
antigens from nasal or throat swabs are widely available, 
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highly specific, and produce fast results but have low sensi
-
tivity leading to high false-negative results. Not all com
-
mercial rapid influenza diagnostic tests can differentiate 
between influenza A and influenza B, and none of the 
available rapid influenza diagnostic tests can provide infor
-
mation on influenza A subtypes.
More sensitive PCR techniques are available, although 
their sensitivity is compromised early in the season during 
low prevalence periods. A nasopharyngeal swab, nasal 
aspirate, combined nasopharyngeal swab with oropharyn
-
geal swab, or material from a bronchoalveolar lavage can be 
tested for any influenza strain. When influenza pneumonia 
is suspected, lower respiratory tract specimens should be 
collected and tested for influenza viruses by RT-PCR.
 
»
The differential diagnoses for influenza-like infections 
include a variety of viral respiratory infections (parainflu
-
enza, RSV , atypical dengue, adenovirus, enterovirus, coro
-
navirus) or other viral infections (flavivirus, CMV , EBV , 
acute HIV infection), as well as bacterial infections such as 
mycobacterial infection (atypical pneumonia), pertussis, 
and Legionnaire disease. Epidemiologic factors can suggest 
Legionnaire (elderly smokers). Chronicity of cough may 
suggest adenovirus, mycobacterial, or pertussis infection. 
Leukocytosis and lymphadenopathy are more often seen 
with CMV and EBV . Distinguishing influenza from dengue 
requires attention to rhinitis (influenza) and thrombocyto
-
penia (dengue).
 
»
Hospitalization or ICU admission for influenza is often a 
consequence of diffuse viral pneumonitis with severe 
hypoxemia and sometimes shock. Patients with asthma, 
residents of nursing homes and long-term care facilities, 
adults aged 65 years or older, persons who are morbidly 
obese, and persons with underlying medical conditions 
(pulmonary, renal, cardiovascular, hepatic, hematologic, 
neurologic and neurodevelopmental conditions and 
immune-deficient conditions such as HIV) are at high risk 
for complications. Infection during pregnancy increases the 
risk for hospitalization and may be associated with severe 
illness, sepsis, pneumothorax and respiratory failure, spon
-
taneous abortion, preterm labor, and fetal distress.
Influenza causes necrosis of the respiratory epithelium, 
increased adherence of bacteria to infected cells, and ciliary 
dysfunction, which predispose to secondary bacterial 
infections due to pneumococci, staphylococci, or 
 spp. In turn, bacterial enzymes (eg, proteases, 
trypsin-like compounds, and streptokinase) activate influ
-
enza viruses. Frequent complications are acute sinusitis, 
otitis media, purulent bronchitis, and pneumonia.
Cardiovascular diseases are a complication of influenza 
infection, in particular among older adults, and influenza is 
postulated to be a significant trigger for myocardial infarc
-
tion, cerebrovascular disease, and sudden death. Several 
studies suggest that influenza vaccination has protective 
effect against major adverse cardiovascular events. Neuro
-
logic complications, including seizures and encephalopathy, 
may occur. Encephalopathic complications of influenza are 
uncommon.
Reye syndrome
 (fatty liver with encephalopathy) is a 
rare and severe complication of influenza (usually B type) 
and other viral diseases (especially varicella), particularly 
in young children. It consists of rapidly progressive hepatic 
failure and encephalopathy, and there is a 30% mortality 
rate. The pathogenesis is unknown, but the syndrome is 
associated with aspirin use in the management of viral 
 
»
Treatment
Treatment is supportive. Antiviral therapy should be consid
-
ered for all persons with acute illness, in particular those at 
high risk for developing complications who have a sugges
-
tive clinical presentation or with laboratory-confirmed

-
-
tive clinical presentation or with laboratory-confirmed 
influenza. Clinical trials show a reduction in the duration of 
symptoms, hospital admissions, as well as secondary compli
-
cations, such as otitis, sinusitis, or pneumonia, but not mor
-
tality when using these agents. Maximum benefit is expected 
with the earliest initiation of therapy. Although the benefit of 
antiviral therapy after 48 hours of illness is reduced, it should 
be initiated if the patient is hospitalized or critically ill. 
Benefit has been noted up to 4–5 days into illness.
The antiviral treatment of choice should be based on 
the susceptibility of the circulating virus. Currently, since 
high levels of resistance to the adamantanes (amantadine 
and rimantadine) persist among seasonal H1N1 and H3N2 
influenza A viruses and these agents are not effective 
against influenza B viruses, amantadine and rimantadine 
are not recommended for treatment.
Three neuraminidase inhibitors are FDA approved for 
treatment of influenza A and B: oral oseltamivir, inhaled 
zanamivir, and intravenous peramivir. The CDC recom
-
mends treatment with oral oseltamivir (75 mg twice daily 
for 5 days) as the drug of choice for patients of any age, 
pregnant women, and patients who are hospitalized or 
have complicated infection. Absorption of oral oseltamivir 
is considered reliable, except in patients with impaired 
gastric motility or gastrointestinal bleeding.
Inhaled zanamivir (10 mg, 2 inhalations twice daily for 
5 days) is indicated for uncomplicated acute influenza in 
patients 7 years and older, is relatively contraindicated 
among persons with asthma because of the risk of bron
-
chospasm and is not formulated for use in mechanically 
ventilated patients. Inhaled zanamivir lacks efficacy in 
pneumonia, probably due to poor bioavailability in the 
peripheral lungs.
Intravenous 
peramivir
 (600 mg in single dose) is used 
for outpatient treatment of uncomplicated infection in 
patients 18 years and older and is recommended when 
there is a concern about inadequate oral absorption of 
oseltamivir. The efficacy of peramivir in patients with 
severe illness and in patients with influenza B is not well 
established. Some studies demonstrated that repeated 
doses for up to 5 days of intravenous peramivir is safe, 
effective and shorten the duration of influenza illness.
Resistance to neuraminidase inhibitors (oseltamivir, 
zanamivir, and peramivir) can occur during or after 
 
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prolonged use in immunocompromised patients, particu
-
larly in persons who have undergone hematopoietic stem 
cell transplant. Intravenous zanamivir is an investigational 
drug that could be requested for clinical use if there is a 
concern for oseltamivir-resistant influenza strain. Lanina
-
mivir is a long-acting inhaled neuraminidase inhibitor used 
for the treatment of seasonal influenza, including infection 
caused by oseltamivir-resistant virus. It is licensed in Japan 
and South Korea and is currently in phase III clinical trials 
in the United States. The first class of organosilanes have 
potent antiviral activity against influenza A viruses that are 
resistant to amantadine and oseltamivir. Dapivirine, an 
FDA-approved HIV nonnucleoside reverse transcriptase 
inhibitor has broad-spectrum antiviral against multiple 
strains of influenza A and B viruses. Updated advice is 
available at http://www.cdc.gov/flu/index.htm.
 
»
Prognosis
The duration of the uncomplicated illness is 1–7 days, and 
the prognosis is excellent in healthy, nonelderly adults. 
Hospitalization typically occurs in those with underlying 
medical disease, at the extremes of age, and in pregnant 
women. Most fatalities are due to bacterial pneumonia 
although exacerbations of other disease processes, in par
-
ticular cardiac diseases, occur. Pneumonia resulting from 
influenza has a high mortality rate among pregnant women 
and persons with a history of rheumatic heart disease. 
Mortality among adults hospitalized with influenza ranges 
from 4% to 8%, although higher mortality (greater than 
10–15%) may be seen during pandemics and among 
immunocompromised individuals. During the 2015–2016 
season, 64% of pneumonia and influenza deaths occurred 
among elderly persons in the United States, who comprised 
only 15% of the population.
If the fever recurs or persists for more than 4 days with 
productive cough and white cell count over 10,000/mcL, 
secondary bacterial infection should be suspected. Pneu
-
mococcal pneumonia is the most common secondary infec
-
tion, and staphylococcal pneumonia is the most serious.
 
»
Annual administration of influenza vaccine is the most 
effective measure for preventing influenza and its complica
-
tions. Seasonal influenza vaccines can reduce influenza 
hospitalizations by an estimated 61%. Vaccination of health
-
care workers is associated with decreased mortality among 
hospitalized patients and those in long-term care facilities.
The Advisory Committee on Immunization Practices 
(ACIP) and the American College of Obstetricians and 
Gynecologists’ Committee recommend annual influenza 
vaccination for all persons over 6 months of age with no 
contraindications. Vaccination is emphasized for high-risk 
groups and their contacts and caregivers.
Multiple influenza vaccine products are licensed in the 
United States and available from different manufacturers. 
These include inactivated influenza vaccines (standard- or 
high-dose, trivalent [IIV3] or quadrivalent [IIV4], adjuvanted 
or unadjuvanted), recombinant vaccines (trivalent [RIV3] or 
quadrivalent [RIV4]), and live attenuated influenza vaccine 
(LAIV4). All trivalent vaccines contain antigens from one 
strain each of influenza A (H1N1), influenza A (H3N2), and 
influenza B. Quadrivalent vaccines include an additional 
influenza B strain. The CDC does not endorse one influenza 
vaccine product over another, although each influenza vaccine 
product has different age indications and contraindications. 
The CDC publishes its annual influenza recommendations in 
the late summer (www.cdc.gov/mmwr).
LAIV4 use is not recommended by the CDC for the last 
two seasons due to concerns about its effectiveness against 
influenza viruses in prior years.
Adults over the age of 18 years, including pregnant 
women, can receive any influenza vaccine, with few excep
-
tions. Patients 65 years or older should receive a high-dose

-
tions. Patients 65 years or older should receive a high-dose 
trivalent inactivated influenza vaccine containing four times 
more hemagglutinin than standard dose, or Fluad, a triva
-
lent inactivated influenza vaccine that contains an adjuvant 
(MF59), which enhances the immune response to the 
vaccine. Fluzone intradermal inactivated quadrivalent vac
-
cine is equally immunogenic and safe but more expensive 
than the intramuscular vaccine and is not recommended for 
persons older than 65 years. Adults older than 65 years can 
use any IIV or RIV intramuscular vaccine; in a large ran
-
domized trial, high-dose IIV3 showed superior efficacy over 
standard-dose IIV3 and may provide better protection.
For patients with cancer, chemotherapeutic regimens 
containing rituximab show persistent perturbations of B-cell 
and Ig synthesis, and these modifications decrease humoral 
responses to the influenza vaccine. Adjuvanted vaccine is 
efficacious but has resulted in brief disease exacerbation in 
persons with psoriatic arthritis taking TNF alpha inhibitors.
Vaccination is contraindicated for persons with a history 
of severe allergic reaction to influenza. Precautions should 
be taken if patients report a history of Guillain-Barré syn
-
drome 6 weeks following an influenza vaccine and if patients 
have a moderate to severe acute illness with or without fever 
until clinical improvement. Persons with a history of egg 
allergy with hives only may receive any recommended influ
-
enza vaccine. Those with more severe allergic reactions to 
eggs may receive any recommended vaccine under close 
observation in a health care facility under the supervision of 
a provider with experience treating severe allergic reactions. 
Only the recombinant vaccine is completely egg-free.
Additional vaccines information can be found at http://
www.cdc.gov/flu/professionals/vaccination/index.htm.
When antiviral chemoprophylaxis is used, it prevents 
70–90% of influenza infections. Chemoprophylaxis is not 
routinely recommended and is not recommended prior to 
exposure to prevent development of resistance. Chemopro
-
phylaxis may be considered for persons at increased risk for 
complications from infection who are exposed to an infected 
patient within 2 weeks of vaccination, for persons unlikely to 
respond to vaccination because of immunosuppression after 
exposure to an infected person, for persons for whom vac
-
cination is contraindicated and who are at high risk for 
complications after exposure to an infected person, and for 
prevention of infection in residents of institutions during an 
outbreak. Alternatively, a person can be monitored closely 
and antiviral therapy initiated at the first onset of symptoms 
after exposure. Initiation of chemoprophylaxis is not 
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recommended more than 48 hours after exposure. Patients 
taking chemoprophylaxis should seek urgent medical care if 
an influenza-like illness develops.
Chemoprophylaxis against influenza A and B is accom
-
plished with daily administration of the neuraminidase inhib
-
itors oseltamivir (75 mg/day, oral) or zanamivir (10 mg/day, 
inhaled) to continue through 7 days after last known expo
-
sure. For outbreak control in long-term care facilities and 
hospitals, a minimum of 2 weeks is recommended, including 
in vaccinated persons if the seasonal vaccine is not well 
matched to the circulating strain, to continue until 1 week 
after identification of the last known case. Zanamivir should 
not be given as chemoprophylaxis to asthmatic persons, nurs
-
ing home residents, or children younger than 5 years.
Breakthrough infections with influenza occur with neur
-
aminidase inhibitors (in a study with zanamivir) and with 
vaccination. The efficacy of chemoprophylaxis is proven for 
individuals and households but not community settings.
Hand hygiene and surgical facemasks appear to prevent 
household transmission of influenza virus isolates when 
implemented within 36 hours of recognition of symptoms in 
an index patient. Such nonpharmaceutical interventions 
assist in mitigating the spread of pandemic and interpan
-
demic influenza to nonvaccinated persons. In one study, 
patients with seasonal H1N1 influenza infection were infec
-
tious from 1 day before to about 7 days following illness 
onset. Children and immunosuppressed persons exhibit 
prolonged viral shedding and may be infectious longer. Win
-
ter school breaks during periods of high influenza transmis
-
sion appear to decrease rates of visits to primary care 
practitioners for influenza illness among children and adults.
Any hospital patient in whom the infection is suspected 
should be isolated in an individual room with standard and 
droplet precautions. CDC guidelines recommend the 
equivalent of N95 masks for aerosol generating procedures 
(eg, bronchoscopy, elective intubation, suctioning, admin
-
istering nebulized medications). For such procedures, an 
airborne infection isolation room can be used, with air 
exhausted directly outside or recirculated after filtration by 
a high efficiency particulate air (HEPA) filter. Strict adher
-
ence to hand hygiene with soap and water or an alcohol-
based hand sanitizer and immediate removal of gloves and 
other equipment after contact with respiratory secretions is 
essential. Precautions should be maintained until 7 days 
from symptom onset or until 24 hours after symptom reso
-
lution, whichever is longer. Postexposure prophylaxis or 
close monitoring and early treatment should be considered 
for close contacts of patients who are at high risk for com
-
plications of influenza and may be considered for health 
care personnel, public health workers, or first responders 
who experienced a recognized, unprotected close contact 
exposure to a person with influenza virus infection during 
that person’s infectious period.
 
»
•	
Limited availability of supporting services.
•	
Pneumonia or decreased oxygen saturation.
•	
Changes in mental status.
•	
Consider with pregnancy.
Black S et al. Influence of statins on influenza vaccine response 
in elderly individuals. J Infect Dis. 2016 Apr 15;213(8):1224–8. 
[PMID: 26516142]
Centers for Disease Control and Prevention (CDC). FluView: 
 
a weekly U.S. influenza surveillance report. http://www.cdc
 
.gov/flu/weekly
Chiang MH et al. Association between influenza vaccination 
and reduced risks of major adverse cardiovascular events in 
elderly patients. Am Heart J. 2017 Nov;193:1–7. [PMID: 
29129247]
Domnich A et al. Effectiveness of MF59-adjuvanted seasonal 
influenza vaccine in the elderly: a systematic review and 
meta-analysis. Vaccine. 2017 Jan 23;35(4):513–20. [PMID: 
28024956]

29129247]
28024956]
Dugan VG et al. Update: influenza Activity—United States, 
October 1-November 25, 2017. MMWR Morb Mortal Wkly 
Rep. 2017 Dec 8;66(48):1318–26. [PMID: 29216030]
Hu Y et al. Design and expeditious synthesis of organosilanes as 
potent antivirals targeting multidrug-resistant influenza A 
viruses. Eur J Med Chem. 2017 Jul 28;135:70–6. [PMID: 
28433777]
Hu Y et al. Discovery of dapivirine, a nonnucleoside HIV-1 
reverse transcriptase inhibitor, as a broad-spectrum antiviral 
against both influenza A and B viruses. Antiviral Res. 2017 Sep; 
145:103–13. [PMID: 28778830]
Turner PJ et al; SNIFFLE-2 Study Investigators. Safety of live 
attenuated influenza vaccine in young people with egg allergy: 
multicentre prospective cohort study. BMJ. 2015 Dec 8; 
351:h6291. [PMID: 26645895]
3. Avian Influenza
 
»
Most human cases occur after exposure to infected 
poultry.
 
»
Clinically indistinguishable from seasonal 
influenza.
 
»
Epidemiologic factors assist in diagnosis.
 
»
Rapid antigen assays confirm diagnosis but do not 
distinguish avian from seasonal influenza.
 
»
Zoonotic influenza viruses are distinct from human sea
-
sonal influenza viruses and do not easily transmit between 
humans. In addition, a number of viral genetic changes are 
required for adaptation to humans. For avian influenza 
viruses, birds are the natural hosts. Around the world and 
in North America, avian influenza A outbreaks occur in 
poultry from time to time and the virus has become 
endemic in poultry in some countries, mostly in Southeast 
Asia and Egypt. Occasionally, avian influenza viruses may 
infect humans or other mammals, including domestic cats 
and dogs. Illness in humans ranges from mild disease to 
rapid progressive severe disease and death depending on 
the subtype.
The primary risk factor for human infection is direct or 
indirect exposure to infected live or dead poultry or con
-
taminated environments, such as live bird markets. 
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Slaughtering and handling carcasses of infected poultry are 
also risk factors.
The emergence of H5, H7, and H9 avian influenza virus 
subtypes in humans raises concern that the virus may 
undergo genetic reassortment or mutations in some of the 
genes and develop greater human-to-human transmissibil
-
ity with the potential to produce a global pandemic.
Human infections with H5N1 viruses have been 
reported to WHO from 16 countries, the first report in the 
Americas was in Canada in 2014, and approximately 60% 
of the cases have died. Infection with avian influenza 
(H7N9) virus was first reported in China in 2013. Since 
then, many cases have been reported around the world 
with an average case fatality rate of 40%. Infections with 
other H7 avian influenza viruses (H7N2, H7N3, and 
H7N7) have occurred sporadically around the world. Rare 
human cases of influenza H9N2 are also reported.
 
»
Distinguishing avian influenza from regular influenza is 
difficult. History of exposure to dead or ill birds or live 
poultry markets in the prior 10 days, recent travel to South
-
east Asia or Egypt, or contact with known cases should be 
investigated. Patients infected by H5N1 or H7N9 avian 
influenza A viruses have an aggressive clinical course. The 
symptoms and signs include fever followed by lower respi
-
ratory symptoms (cough, dyspnea). Upper respiratory tract 
symptoms are less common. Gastrointestinal symptoms 
are reported more frequently in H5N1 infections. Con
-
junctivitis is reported in influenza H7 infections. Other 
systems can also be involved leading to neurologic mani
-
festations (encephalopathy, seizure) and liver impairment. 
Prolonged febrile states and generalized malaise are com
-
mon. Respiratory failure, multiorgan dysfunction, and 
septic shock are the usual cause of death. Bacterial super
-
infections are reported.
For human infections with avian influenza A(H7N7) 
and A(H9N2) viruses, most cases have been mild with a 
few cases hospitalized and very few reports of deaths 
resulting from infection.
Current commercial rapid antigen tests are not optimally 
sensitive or specific for detection of H5N1 influenza and 
should not be the definitive test for influenza. More sensi
-
tive RT-PCR assays are available through many hospitals 
and state health departments. Diagnostic yield can be 
improved by early collection of samples, preferably within 
7 days of illness onset. Throat swabs or lower respiratory 
specimens (such as tracheal aspirate or bronchoalveolar 
lavage fluid) may provide higher yield of detection than 
nasal swabs. When highly pathogenic strains (eg, H5N1) 
are suspected, extreme care in the handling of these sam
-
ples must be observed during preliminary testing. Positive 
samples must then be forwarded to the appropriate public 
health authorities for further investigation (eg, culture) in 
laboratories with the adequate level of biosafety (level 3).
 
»
Treatment
Persons with severe illness and confirmed and probable 
cases with mild disease should receive treatment as soon as 
possible. The current first-line recommendation is to use 
the neuraminidase inhibitor oseltamivir, 75 mg orally twice 
daily for 5 days administered within 48 hours from onset of 
illness. Longer courses of therapy (eg, 10 days) should be 
considered in hospitalized patients with severe illness and 
persistent viral shedding. Data are lacking for use of 
inhaled zanamivir or peramivir for severe avian influenza. 
Overall oseltamivir, by modeling, is associated with a 49% 
reduction in mortality from H5N1 infections. As with sea
-
sonal influenza, enteric oseltamivir is well absorbed in 
critically ill persons without gastric stasis, known malab
-
sorption, or gastrointestinal bleeding. Daily intravenous 
peramivir for a minimum of 5 days or zanamivir may be 
considered in such patients. A higher dose (150 mg twice

-
considered in such patients. A higher dose (150 mg twice 
daily in patients with normal kidney function) and possible 
combination therapy with amantadine or rimantadine 
 
(in countries where A [H5N1] viruses are likely to be sus
-
ceptible to adamantanes) may be considered in patients 
with pneumonia or progressive disease. Resistance of avian 
H5N1 influenza strains to amantadine and rimantadine is 
present in most geographic areas. Resistance to neuramini
-
dase inhibitors (oseltamivir, zanamivir, and peramivir) can 
occur in avian (H5N1)- and (H7N9)-infected patients. 
Successful treatment with administration of convalescent 
plasma is reported.
 
»
The most effective method of prevention is avoidance of 
exposure. Persons who work with poultry should practice 
good hand hygiene and use appropriate personal protective 
equipment. These workers should also be vaccinated 
against seasonal influenza, since this can reduce the likeli
-
hood of coinfection with avian and seasonal influenza. 
Persons should avoid visiting live poultry markets when 
able and should avoid contact with ill birds. There is no risk 
of acquiring avian influenza through the consumption of 
well-cooked poultry products. The US government bans 
the importation of poultry from infected areas. Culling of 
animals has been effective in ending outbreaks of highly 
pathogenic avian influenza but is difficult with H7-infected 
poultry because most are asymptomatic.
Persons with exposure should monitor themselves for 
10 days after the last known exposure and should seek 
prompt medical attention if new fever or respiratory symp
-
toms develop. Postexposure prophylaxis is not recom
-
mended in persons working with noninfected birds or who 
used appropriate personal protective equipment while 
working with infected birds. For persons with exposure to 
infected persons, postexposure prophylaxis is recom
-
mended for household and family members and may be 
considered for health care personnel with close unpro
-
tected contact. Postexposure prophylaxis regimens include 
75 mg of oseltamivir orally or 10 mg inhaled zanamivir 
twice daily for 5 or 10 days from the last known exposure, 
depending on the length of the exposure. Careful surveil
-
lance for human cases and prudent stockpiling of 
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medications with establishment of an infrastructure for 
dissemination are essential modalities of control. Non
-
pharmacologic means of control include masks, social dis
-
tancing, quarantine, travel limitations, and infrastructure 
development, particularly for emergency departments.
Current vaccines do not provide cross-protection 
against strains of the H5, H7, and H9 influenza viruses. 
The United States government has prepandemic stockpiles 
of adjuvanted H5N1 vaccines and H7N9 vaccines that are 
not available to the public. The highly diverse genetic 
nature and the rapid evolution of the avian influenza 
viruses has resulted in the emergence of viruses that are 
distinct from stockpiled vaccines. New vaccine develop
-
ment is ongoing to generate vaccines against H7N9 and 
H5N1 with broadened protection against unmatched 
strains. Some of these vaccines are under study in preclini
-
cal and clinical trials; however, no vaccines are currently 
commercially available for humans.
Because the potential for pandemic influenza for many 
of the new reassortment viruses is not fully known, contin
-
ued surveillance is essential, and stockpiling of vaccines, 
adjuvant, and medications (oseltamivir and zanamivir) is 
warranted at the public health level.
Hassan AO et al. Adenovirus vector-based multi-epitope vaccine 
provides partial protection against H5, H7, and H9 avian 
influenza viruses. PLoS One. 2017 Oct 12;12(10):e0186244. 
[PMID: 29023601]
Pitisuttithum P et al. Safety and immunogenicity of a live attenu
-
ated influenza H5 candidate vaccine strain A/17/turkey/
Turkey/05/133 H5N2 and its priming effects for potential 
pre-pandemic use: a randomised, double-blind, placebo-
controlled trial. Lancet Infect Dis. 2017 Aug;17(8):833–42. 
[PMID: 28533093]
Sha J et al. Differences in the epidemiology and virology of mild, 
severe and fatal human infections with avian influenza A 
(H7N9) virus. Arch Virol. 2016 May;161(5):1239–59. [PMID: 
26887968]
Sun X et al. Stockpiled pre-pandemic H5N1 influenza virus vac
-
cines with AS03 adjuvant provide cross-protection from 
H5N2 clade 2.3.4.4 virus challenge in ferrets. Virology. 
2017 Aug;508:164–9. [PMID: 28554058]
4. Middle East Respiratory Syndrome–
Coronavirus (MERS-CoV)
 
»
Mild, moderate, or severe respiratory illness.
 
»
Travel to endemic area, including Saudi Arabia, 
United Arab Emirates, Qatar, and Jordan, within 
 
14 days before symptom onset.
 
»
Contact with camels reported in many cases.
 
»
Fever, cough, and dyspnea.
 
»
CDC can assist with real-time PCR using serum and 
respiratory samples, or serology.
 
»
Supportive treatment; mortality 36% to 45%.
 
»
Middle East respiratory syndrome (MERS) is a syndrome 
associated with a coronavirus similar to the cause of severe 
acute respiratory syndrome (SARS). Patients with MERS 
have had a history of residence or travel in the Middle East, 
in particular Saudi Arabia, or contact with such patients. 
The virus is probably transmitted through direct or indirect 
contact of mucous membranes with infectious respiratory 
droplets. The virus is shed in stool, but the role of fecal-oral 
transmission is unknown. The earliest cases were identified 
in 2012 in the Kingdom of Saudi Arabia, and 75% of all 
cases have occurred there. Additional cases have occurred 
throughout the Middle East, Africa, and Europe, with a 
reported death rate of 36%. As of December 22, 2017, the 
WHO reports 2122 laboratory-confirmed cases of infection 
with MERS-CoV and at least 740 related deaths globally 
(http://www.who.int/emergencies/mers-cov/en/). So-called 
super-spreaders are often responsible for propagating the 
pathogen in the early stages of an outbreak.
Person-to-person transmission can occur within fami
-
lies; hospital-associated cases comprise 25% of cases. The 
median incubation period is 5 days (range, 2–13) with the

-
median incubation period is 5 days (range, 2–13) with the 
mean age of 50 (range 9 months to 99 years) and 65% 
occurring among men. Over 90% of patients have an 
underlying medical condition, including diabetes mellitus 
(68%), hypertension (34%), or chronic heart or kidney 
disease. Those with diabetes, kidney disease, chronic lung 
disease, or other immunocompromising conditions are 
considered to be at highest risk for severe disease.
Camels appear to be the principal reservoir, and several 
studies show that contact with dromedary herds of camels 
is greater among cases than controls. Raw camel milk is 
considered a potential source. Persons who work with 
camels are more likely to have antibody evidence of past 
 
»
MERS is an acute respiratory syndrome, with the most 
common symptoms being fever (98%), cough (83%), and 
dyspnea (72%). Chills and rigors are common (87%). 
Gastrointestinal symptoms may occur with diarrhea being 
most common (26%), followed by nausea and abdominal 
pain, and may precede respiratory symptoms. Mild and 
asymptomatic cases are reported.
Hematologic findings in the largest series to date include 
thrombocytopenia (36%), lymphopenia (34%), and lym
-
phocytosis (11%). Moderate elevations in lactate dehydro
-
genase (49%), AST (15%), and ALT (11%) are recognized. 
Chest radiograph abnormalities are nearly universal and 
include increased bronchovascular markings, patchy infil
-
trates or consolidations, interstitial changes, opacities 
(reticular and nodular) as well as pleural effusions and total 
lung opacification. Ground-glass opacities and consolida
-
tion are most commonly seen. The findings mimic those of 
many other causes of pneumonia.
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Serum serologies and RT-PCR are available through 
CDC (contact information below, on MMWR reference 
site). Highest viral loads are found in lower respiratory tract 
specimens, including bronchoalveolar lavage fluid, sputum, 
and tracheal aspirates. These samples are preferred for 
diagnosis. The CDC recommends sending lower respira
-
tory tract specimens, nasopharyngeal and oropharyngeal 
swabs, and serum for testing. In confirmed cases, serial 
sample collection (perhaps every 2–4 days) from multiple 
sites is recommended to increase understanding of virus 
shedding kinetics. In cases in which symptom onset 
occurred more than 14 days prior and symptoms are ongo
-
ing, serum should be sent to the CDC for serologic testing 
and the above specimens should be sent for RT-PCR.
C. Case Definition
A patient with 
severe illness
 shows the following character
-
istics: fever (38
°
C, 100.4
°
F or higher) and pneumonia or 
ARDS (based on clinical or radiologic evidence); and 
either
 
history of travel in or near the Arabian Peninsula (Bahrain, 
Iraq, Iran, Israel, Jordan, Kuwait, Lebanon, Oman, 
Palestinian territories, Qatar, Saudi Arabia, Syria, the United 
Arab Emirates [UAE], and Y emen) within 14 days before 
symptom onset; 
or
 close contact with a symptomatic trav
-
eler in whom fever and acute respiratory illness (not neces
-
sarily pneumonia) developed within 14 days after traveling 
in or near the Arabian Peninsula (above); 
or
 is a member of 
a cluster of patients with severe acute respiratory illness (eg, 
fever and pneumonia requiring hospitalization) of unknown 
etiology in which MERS-CoV is being evaluated, in consul
-
tation with state and local health departments.
In milder illness, patients have fever and symptoms of 
respiratory illness (not necessarily pneumonia; eg, cough, 
shortness of breath) and history of having close contact 
with a confirmed MERS case as well as a history of being 
in a health care facility (as a patient, worker, or visitor) 
within 14 days of symptom onset in a country or territory 
within the Arabian Peninsula in which recent health care–
 
associated cases of MERS have been identified.
Of note, fever may not be present in certain patients, 
including the very young, elderly persons, immunosup
-
pressed individuals, or those taking certain medications.
 
»
Respiratory failure is such a common complication that in 
a series from Saudi Arabia, 89% of patients required inten
-
sive care and mechanical ventilation. Patients with MERS-
CoV appear to advance faster to respiratory failure than do 
those with SARS.
 
»
Treatment
Respiratory support is essential. A small retrospective 
study found improved survival at 14 days with ribavirin 
and interferon-alpha but not at 28 days.
 
»
Prognosis
The overall mortality rate of identified cases is about 36%. 
Advanced age is associated with a poor prognosis.
 
»
Isolation and quarantine of cases is authorized by CDC. 
Strict infection control measures are essential as well as care 
and management of household contacts and hospital work
-
ers engaged in the care of patients. Travelers to Saudi Arabia 
(including the many pilgrims to the holy sites) should prac
-
tice frequent hand washing and avoid contact with those 
who have respiratory symptoms. Evaluation of patients with 
suspect symptoms within 14 days of return from Saudi 
Arabia is essential. Because healthcare workers engaged in 
procedures that involve contact with respiratory droplets 
are at risk, isolation of high-risk patients is essential, as are 
simple hygienic measures. Control measures, including 
quarantining in the home for high-risk exposed persons 
and the use of facemasks for preventing hospital-acquired 
infections, are important. Assisting public health authorities 
with case reporting and surveillance is essential.
Camel workers including slaughterhouse and market

Camel workers including slaughterhouse and market 
workers, veterinarians, and racing personnel should wear 
facial protection and protective clothing and practice good 
personal hygiene, including frequent hand washing after 
touching animals. Family members of such personnel 
should not be exposed to work paraphernalia including 
clothing and shoes and workers should shower at the site of 
employment rather than the home. Avoid direct contact 
with camels (who may be asymptomatic but who can trans
-
mit the virus though nasal or ocular discharge, milk, urine, 
and feces). All infected animals should be kept off the mar
-
ket, including their meat products, and buried or destroyed.
MMWR and the WHO periodically update the infec
-
tion control recommendations and the status of ongoing 
outbreaks.
Das KM et al. Acute Middle East respiratory syndrome corona
-
virus: temporal lung changes observed on the chest radio
-
graphs of 55 patients. AJR Am J Roentgenol. 2015 Sep; 
205(3):W267–74. [PMID: 26102309]
Liu S et al. Comparative epidemiology of human infections with 
middle east respiratory syndrome and severe acute respira
-
tory syndrome coronaviruses among healthcare personnel. 
PLoS One. 2016 Mar 1;11(3):e0149988. [PMID: 26930074]
Wong G et al. MERS, SARS, and Ebola: the role of super-
spreaders in infectious disease. Cell Host Microbe. 2015 
Oct 14; 18(4):398–401. [PMID: 26468744]
ADENOVIRUS INFECTIONS
 
»
At least 56 serotypes of adenovirus are described to date 
and divided into 7 subgroups A–G. About half of these 
subgroups produce a variety of clinical syndromes. 
Adenoviruses show a worldwide distribution and occur 
throughout the year. These infections are usually self-
 
limited or clinically inapparent and occur most commonly 
among infants, young children, and military recruits. How
-
ever, these infections may cause significant morbidity and 
mortality in immunocompromised persons, such as HIV-
infected persons and COPD patients, as well as in patients 
who have undergone solid organ and hematopoietic stem 
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cell transplantation or cardiac surgery or in those who have 
received cancer chemotherapy. A few cases of donor-
transmitted adenoviral infection have been reported in 
past years. An outbreak with adenovirus type 55 was 
reported in 2017 from a neurosurgical unit in China.
Adenoviruses, although a common cause of human 
disease, also receive particular recognition through their 
role as vectors in gene therapy.
 
»
The incubation period is 4–9 days. Clinical syndromes of 
adenovirus infection, often overlapping, include the 
following. The common cold (Chapter 8) is characterized by 
rhinitis, pharyngitis, and mild malaise without fever. Con
-
junctivitis is often present. Nonstreptococcal exudative phar
-
yngitis is characterized by fever lasting 2–12 days and 
accompanied by malaise and myalgia. Lower respiratory tract 
infection may occur, including bronchiolitis, suggested by 
cough and rales, or pneumonia. (Types 1, 2, 3, 4, and 7 com
-
monly cause acute respiratory disease and atypical pneumo
-
nia; coinfections or serial infections are documented to 
occur.) Infections are especially severe in Native American 
children. Adenovirus type 14 is increasingly reported as a 
cause of severe and sometimes fatal pneumonia in those with 
chronic lung disease, but is also seen in healthy young adults 
and military recruit outbreaks. Viral or bacterial coinfections 
occur with adenovirus in 15–20% of cases. Pharyngocon
-
junctival fever is manifested by fever and malaise, conjuncti
-
vitis (often unilateral), mild pharyngitis, and cervical adenitis. 
Epidemic keratoconjunctivitis (transmissible person-to-
person, most often types 8 [and showing considerable varia
-
tion by season], 19, and 37) occurs in adults and is manifested 
by bilateral conjunctival redness, pain, tearing, and an 
enlarged preauricular lymph node (multiple types may be 
involved in a single outbreak). Various outbreaks (types 3, 8, 
19) were reported from four US states in 2008–2010. Keratitis 
may lead to subepithelial opacities (especially with the above 
types). Acute hemorrhagic cystitis is a disorder of children 
often associated with adenovirus type 11 and 21.
Sexually transmitted genitourinary ulcers and urethritis 
may be caused by types 2, 8, and 37 in particular. Adenovi
-
ruses also cause acute gastroenteritis (types 40 and 41), 
mesenteric adenitis, acute appendicitis, rhabdomyolysis, 
and intussusception. Rarely, they are associated with 
encephalitis, meningitis, acute respiratory distress syn
-
drome (ARDS), acute flaccid paralysis, and pericarditis. 
Adenovirus is commonly identified in endomyocardial 
tissue of patients with myocarditis and dilated cardiomy
-
opathy. Risk factors associated with severity of infection 
include youth, chronic underlying infections, recent trans
-
plantation, and serotypes 5 or 21.
Hepatitis (type 5 adenovirus), pneumonia, and hemor
-
rhagic cystitis (types 11 and 34) tend to develop in infected 
liver, lung, or kidney transplant recipients, respectively. 
Disease states that may develop in hematopoietic stem cell 
transplant patients include hepatitis, pneumonia, diarrhea, 
hemorrhagic cystitis, tubulointerstitial nephritis, colitis, 
and encephalitis.
Antigen detection assays including direct fluorescence assay 
or enzyme immunoassay are rapid and show sensitivity of 
40–60% compared with viral culture (considered the 
standard). Samples with negative rapid assays require PCR 
assays or viral cultures for diagnosis. Quantitative real-time 
rapid-cycle PCR is useful in distinguishing disease from 
colonization, especially in hematopoietic stem cell trans
-
plant patients. Multiplex nucleic acid amplification assays 
can test for multiple respiratory viruses simultaneously with 
increased sensitivity. Adenovirus differs from other viral

-
increased sensitivity. Adenovirus differs from other viral 
and bacterial respiratory infections seen on chest CT imag
-
ing, appearing as a multifocal consolidation or ground-glass 
opacity without airway inflammatory findings.
 
»
Treatment is symptomatic. Ribavirin or cidofovir is used in 
immunocompromised individuals with occasional success, 
although cidofovir is attendant with significant renal toxic
-
ity. The nucleoside analog brincidofovir appears to be use
-
ful in patients infected after stem cell transplantation, but it 
is only available through compassionate use policies. IVIG 
is also used in immunocompromised patients and can be 
used in combination with other therapies, but data are still 
limited. Reduced immunosuppression is often required. 
Typing of isolates is useful epidemiologically and in distin
-
guishing transmission from endogenous reactivation. Top
-
ical steroids or tacrolimus may be used to treat adenoviral 
keratoconjunctivitis. Complications of adenovirus pneu
-
monia in children include bronchiolitis obliterans. Deaths 
are reported on occasion (eight in one season among the 
American military).
The control of epidemic adenoviral conjunctivitis is 
often difficult and requires meticulous attention to hand 
hygiene, use of disposable gloves, sterilization of equip
-
ment (isopropyl alcohol is insufficient, recommendations 
of manufacturers are preferred), cohorting of cases, and 
furloughing of employees.
Vaccines are not available for general use. Use of live 
oral vaccines containing attenuated type 4 and type 7 was 
reinstated in military personnel in 2013 and has been asso
-
ciated with significant decrease in adenoviral disease.
Voigt S et al. Brincidofovir clearance of acyclovir-resistant her
-
pes simplex virus-1 and adenovirus infection after stem cell 
transplantation. Transpl Infect Dis. 2016 Oct;18(5):791–4. 
[PMID: 27482652]
Yi L et al. A cluster of adenovirus type B55 infection in a neuro
-
surgical inpatient department of a general hospital in Guang
-
dong, China. Influenza Other Respir Viruses. 2017 Jul; 
11(4):328–36. [PMID: 28488368]
OTHER EXANTHEMATOUS VIRAL INFECTIONS
1. Erythrovirus Infections
Erythrovirus, formerly parvovirus B19, infects human ery
-
throid precursor cells. It is quite widespread (by age 
15 years about 50% of children have detectable IgG), and its 
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transmission occurs through respiratory secretions and 
saliva, through the placenta (vertical transmission with 
30–50% of pregnant women nonimmune), and through 
administration of blood products. The incubation period is 
4–14 days. Chronic forms of the infection can occur. 
Bocavirus, another erythrovirus (parvovirus), is a cause of 
winter acute respiratory disease in children and adults.
 
»
Erythrovirus causes several syndromes and manifests 
differently in various populations.
1. Children—
In children, an exanthematous illness (“fifth 
disease, ” erythema infectiosum) is characterized by a fiery 
red “slapped cheek” appearance, circumoral pallor, and a 
subsequent lacy, maculopapular, evanescent rash on the 
trunk and limbs. Eosinophilic cellulitis (Well syndrome) is 
also reported with erythrovirus as are microvesicular erup
-
tions and atypical rashes. Erythrovirus is also one of the 
most common causes of myocarditis in childhood.
2. Immunocompromised patients—
A transient aplastic 
crisis and pure red blood cell aplasia may occur. Bone mar
-
row aspirates reveal absence of mature erythroid precur
-
sors and characteristic giant pronormoblasts. The 
erythrovirus gene is detected in 16–19% of acute leukemia 
and chronic myeloid leukemia patients.
3. Adults—
A limited nonerosive symmetric polyarthritis 
that mimics lupus erythematosus and rheumatoid arthritis, 
which may in some cases be a type II mixed cryoglobuline
-
mia, can develop in middle-aged persons (especially 
women). Rashes, especially facial, are less common in 
adults.
Chloroquine and its derivatives exacerbate erythrovi
-
rus-associated anemia and are linked with significantly 
lower hematocrit in hospital admissions in malaria 
endemic areas. Rare reported presentations include myo
-
carditis with infarction, constrictive pericarditis, chronic 
dilated cardiomyopathy (although recent analyses from the 
Netherlands dispute some cardiac findings), Hashimoto 
thyroiditis, hepatitis, pneumonitis, neutropenia, thrombo
-
cytopenia, a lupus-like syndrome, glomerulonephritis, 
CNS vasculitis, papular-purpuric “gloves and socks” syn
-
drome, complications of drug hypersensitivity, and a 
chronic fatigue syndrome. A subclinical infection is docu
-
mented among patients with sickle cell disease. Other CNS 
manifestations of erythrovirus include encephalitis, men
-
ingitis, stroke (usually in sickle cell anemia patients with 
aplastic crises), and peripheral neuropathy (brachial plexi
-
tis and carpal tunnel syndrome) with occasional chronic 
residua.
The symptoms of erythrovirus infection can mimic 
those of autoimmune states such as lupus, systemic sclero
-
sis, antiphospholipid syndrome, or vasculitis. The molecu
-
lar mimicry of erythrovirus to human cytokeratin and 
transcription factors engaged in hematopoiesis is the basis 
for theories that implicate erythrovirus in the pathogenesis 
of these autoimmune states. A more specific entity entitled 
relapsing symmetric seronegative synovitis with edema is 
reported in two cases to be associated serologically with 
erythrovirus infection.
In pregnancy, premature labor, hydrops fetalis, and fetal 
loss are reported sequelae. Pregnant women with a recent 
exposure or with suggestive symptoms should be tested for 
the disease and carefully monitored if results are positive.
A serosurvey from France suggests erythrovirus infec
-
tion may occur more commonly in patients with 
The diagnosis is clinical (Table 32–2) but may be con
-
firmed by either an elevated titer of IgM anti-erythrovirus 
(parvovirus) antibodies in serum or with PCR in serum or 
bone marrow. By the time common presenting symptoms 
manifest, in particular a rash or polyarthropathy in an 
immunocompetent patient, the viremia may have cleared 
but IgM antibodies are likely present. In immunocompro
-

-
mised patients, RT-PCR is the optimal test. Autoimmune 
antibodies (antiphospholipid and antineutrophil cytoplas
-
mic antibodies) can be present and are thought to be a 
consequence of molecular mimicry. False-positive serolo
-
gies also occur in the presence of recent IVIG and anti–B-
cell therapy. Also, remnant erythrovirus, from tissue and 
serum is thought to explain some false-positive findings. 
Assays on marrow tissue are indicated only if a marrow is 
deemed necessary for other hematologic reasons.
 
»
Uncommon complications include the CNS diseases listed 
above, chronic hemolytic anemia, thrombotic thrombocy
-
topenic purpuric syndrome, acute postinfectious glomeru
-
lonephritis, and hepatitis.
 
»
Treatment
Treatment in healthy persons is symptomatic (NSAIDs are 
used to treat arthralgias, and transfusions are used to treat 
transient aplastic crises). In immunosuppressed patients 
including those infected with HIV , IVIG is very effective in 
the short-term reduction of anemia. Relapses tend to occur 
about 4 months after administration of IVIG. There is no 
reduction in encephalitic complications with IVIG. Intra
-
uterine blood transfusion can be considered in severe fetal 
anemia, although such transfusions have been linked to 
impaired neurologic development.
 
»
Prevention & Prognosis
Several nosocomial outbreaks are documented. In these 
cases, standard containment guidelines, including hand 
washing after patient exposure and avoiding contact with 
pregnant women are paramount.
The prognosis is generally excellent in immunocompe
-
tent individuals. In immunosuppressed patients, persistent 
anemia may require prolonged transfusion dependence. 
Remission of erythrovirus (parvovirus) infection in AIDS 
patients may occur with ART, though the immune restora
-
tion syndrome is also reported.
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Drago F et al. Remitting seronegative symmetrical synovitis with 
pitting edema associated with parvovirus B19 infection: two 
new cases and review of the comorbidities. Int J Dermatol. 
2015 Oct;54(10):e389–93. [PMID: 26147127]
Verdonschot J et al. Relevance of cardiac parvovirus B19 in 
myocarditis and dilated cardiomyopathy: review of the litera
-
ture. Eur J Heart Fail. 2016 Dec;18(12):1430–41. [PMID: 
27748022]
Wolfromm A et al. Spectrum of adult parvovirus B19 infection 
according to the underlying predisposing condition and pro
-
posals for clinical practice. Br J Haematol. 2015 Jul;170(2): 
192–9. [PMID: 25920561]
2. 
p
o
xvirus Infections
Among the poxviruses causing disease in humans, the fol
-
lowing are the most clinically important: variola/vaccinia, 
molluscum contagiosum, orf and paravaccinia, and 
monkeypox.
1. Variola/vaccinia—
Smallpox (variola) was a highly con
-
tagious disease associated with high mortality and dis
-
abling sequelae. Its manifestations include severe headache, 
acute onset of fever, prostration and a rash characterized by 
uniform progression from macules to papules to firm, 
deep-seated vesicles or pustules. The synchronous progres
-
sion in smallpox readily differentiates lesions from those of 
varicella (see also Chapter 6).
Complications of smallpox include bacterial superin
-
fections (cellulitis and pneumonia), encephalitis, and kera
-
titis with corneal ulcerations (risk factor for blindness). 
Effective vaccination led to its global elimination by 
1979 and routine vaccination stopped in 1985.
 Recom
-
mendations to destroy remaining samples of this virus have 
not been acted upon thus far, and significant concern exists 
for potential misuse of these repositories in military or 
terrorist activities.
Smallpox should be considered, in concordance with 
the CDC Smallpox Response Plan (https://emergency
 
.cdc.gov/agent/smallpox/prep/post-event-guidance.asp), in 
any patient with fever and a characteristic rash (see above) 
for which other etiologies—such as herpes infections 
(eczema herpeticum may be differentiated from suspect 
smallpox by appropriate serologic stains and clinical 
appearance), erythema multiforme, drug reactions, or 
other infections—are unlikely. Patients with suspected 
infection should be placed in airborne and contact isola
-
tion and the official agency contacted (CDC Poxvirus and 
Rabies Branch help desk may be reached at 404-639-4129 
and the Director’s Emergency Operation Center at 
770-488-7100).
Guidelines regarding smallpox vaccination are available 
at https://www.cdc.gov/smallpox/vaccine-basics/index.html.
2. Molluscum contagiosum—
Molluscum contagiosum 
may be transmitted sexually or by other close contact. The 
disease is manifested by pearly, raised, umbilicated skin 
nodules sparing the palms and soles. Keratoconjunctivitis 
can occur. Most ocular lesions are typical umbilicated 
dome-shaped lesions, but a variety of atypical ocular 
lesions are reported often in immunocompetent patients, 
more often in females and young adults (mean age 19).
There may be an association with atopic dermatitis or 
eczema. Marked and persistent lesions in AIDS patients 
respond readily to combination ART. Treatment options 
include destructive therapies (curettage, cryotherapy, can
-
tharidin, and keratolytics, among others), immunomodu
-
lators (imiquimod, cimetidine, and 
Candida
 antigen), and 
antiviral agents (topical cidofovir is effective anecdotally in 
refractory cases; brincidofovir, an agent under investiga
-
tion for treating other viral infections [particularly CMV], 
has shown some efficacy). No treatment is uniformly effec
-
tive, and multiple courses of therapy are often needed. 
 
A recent meta-analysis recommends natural resolution of 
lesions. Cryptococcal skin lesions can mimic molluscum 
contagiosum.
3. Orf and paravaccinia—
Orf (contagious pustular der
-

-
matitis, or ecthyma contagiosa) and paravaccinia (milker’s 
nodules) are occupational diseases acquired by contact 
with sheep/goats and cattle, respectively. Household meat 
processing and animal slaughter have been implicated as 
risk factors. A new poxvirus akin to parapoxviruses was 
reported in 2015 in two patients from rural Tennessee 
and Missouri (the latter had also traveled to Tanzania). 
The use of nonporous gloves for persons handling ani
-
mals is recommended, especially if the persons are immu
-
nosuppressed. Orf anecdotally responds to imiquimod.
4. Monkeypox—
First identified in 1970, monkeypox is 
enzootic in the rain forests of equatorial Africa and pres
-
ents in humans as a syndrome similar to smallpox. The 
incubation period is about 13 days (range, 6–28 in a recent 
Central African Republic outbreak) and limited person-to-
person spread occurs. African mortality rates vary from 3% 
to 11% depending on the immune status of the patient. 
Secondary attack rates appear to be about 10%. African 
outbreaks have been reported from the Sudan and the 
Democratic Republic of Congo. Risk factors identified 
from the Democratic Republic of Congo include being bit
-
ten by rodents, working as a hunter, and being male over 
 
18 years of age. Confusion with smallpox and varicella 
occurs; however, both lymphadenopathy (seen in up to 
90% of unvaccinated persons) and a febrile prodrome are 
prominent features in monkeypox infection. The mon
-
keypox rash is distinguished by its deep-seated and well-
circumscribed nature, lesions at the same stage of 
development (unlike varicella but like smallpox), and its 
centrifugal progression (including palms and soles). Sus
-
pected cases should be placed on standard, contact, and 
droplet precautions; local and state public health officials 
and the CDC should be notified for assistance with con
-
firmation of the diagnosis (by electron microscopy, viral 
culture, ELISA, PCR, and a GeneXpert assay referred to as 
MPX/OPX [monkeypox/orthopox]). Cidofovir is effec
-
tive in vitro against monkeypox, and vaccinia immune 
globulin can be used in selected cases.
Other general precautions that should be taken are 
avoidance of contact with prairie dogs and Gambian giant 
rats (whose illness is manifested by alopecia, rash, and 
ocular or nasal discharge), appropriate care and isolation of 
those exposed within 3 prior weeks to such animals, and 
veterinary examination and investigation of 
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suspect animals through health departments. Vaccinia 
immunization is effective against monkeypox and is rec
-
ommended for those involved in the investigation of the 
outbreak and for health care workers caring for those 
infected with monkeypox if no contraindication exists 
(outlined above). Post-exposure vaccination is also advised 
for documented contacts of infected persons or animals. 
US federal agencies prohibit the importation of African 
rodents.
5. Novel orthopoxviruses—
Two cases in the country of 
Georgia with a novel orthopox virus occurred in 2013 with 
a third diagnosed serologically from 2010. All cases had 
animal contact, cattle for two, and serologic data showed 
possible associations with rodents and shrews as well as 
cattle. None had been vaccinated for smallpox. Another 
novel orthopoxvirus was identified in a patient who had 
undergone kidney transplantation in North America 
 
during 2015.
interim CDC guidance for use of smallpox vaccine, cidofovir, 
and vaccinia immune globulin (VIG) for prevention and 
treatment in the setting of an outbreak of monkeypox infec
-
tions. http://www.cdc.gov/ncidod/monkeypox/treatment
-
guidelines.htm
Osadebe LU et al. Novel poxvirus infection in 2 patients from the 
United States. Clin Infect Dis. 2015 Jan 15;60(2):195–202. 
[PMID: 25301210]
Petersen BW et al. Clinical guidance for smallpox vaccine use in 
a postevent vaccination program. MMWR Recomm Rep. 
2015 Feb 20;64(RR-02):1–26. [PMID: 25695372]
Petersen BW et al. Use of vaccinia virus smallpox vaccine in 
laboratory and health care personnel at risk for occupational 
exposure to orthopoxviruses—recommendations of the advi
-
sory committee on immunization practices (ACIP), 2015. 
MMWR Morb Mortal Wkly Rep. 2016 Mar 18;65(10):257–62. 
[PMID: 26985679]
Quiner CA et al. Presumptive risk factors for monkeypox in 
rural communities in the Democratic Republic of the 
Congo. PLoS One. 2017 Feb 13;12(2):e0168664. [PMID: 
28192435]
-
VIRUSES & GASTROENTERITIS
Viruses are responsible for at least 30–40% of cases of 
infectious diarrhea in the United States. These agents 
include rotaviruses; caliciviruses, including noroviruses 
such as Norwalk virus; astroviruses; enteric adenoviruses; 
and, less often, toroviruses, coronaviruses, picornaviruses 
(including the Aichi virus), and pestiviruses. Rotaviruses 
and noroviruses are responsible for most nonbacterial 
cases of gastroenteritis.
Rotaviruses
 are reoviruses with eight species and sig
-
nificant animal reservoirs. They are the leading worldwide 
cause of dehydrating gastroenteritis in very young children 
and are associated with significant morbidity and mortal
-
ity. Each year, over 400,000 children die of rotavirus infec
-
tion worldwide. Children aged 6 months to 2 years are the 
most affected, although adults are affected occasionally as 
well. By age 5, virtually every child has been infected with 
this pathogen. The diverse set of rotaviruses (classified by 
glycoproteins and protease-sensitive proteins [G-type and 
P-type antigens] which segregate independently) results in 
a constellation of phenotypes, although only about four of 
these are responsible for over 90% of disease. Rotavirus 
infections follow an endemic pattern, especially in the 
tropics and low-income countries, but they peak during 
the winter in temperate regions. The virus is transmitted by 
fecal-oral route and can be shed in feces for up to 3 weeks 
in severe infections. In outbreak settings (eg, day care 
centers), the virus is ubiquitously found in the environ
-
ment, and secondary attack rates are between 16% and 30% 
(including household contacts). Nosocomial outbreaks are 
reported.
The disease is usually mild and self-limiting. A 2- to

-
reported.
The disease is usually mild and self-limiting. A 2- to 
3-day prodrome of fever and vomiting is followed by non
-
bloody diarrhea (up to 10–20 bowel movements per day) 
lasting for 1–4 days. It is thought that systemic disease 
occurs rarely and unusual reported presentations include 
cerebellitis and pancreatitis. Patients with gastroenteritis 
are not routinely tested for rotavirus because the results do 
not alter treatment. Oral and intravenous rehydration solu
-
tions are the primary treatment options, but effective 
adjunctive therapies include specific probiotics (eg, 
 GG or 
Saccharomyces boulardii
), nitazoxanide, 
diosmectite, or racecadotril. Adjunctive therapies shorten 
the median duration of diarrhea and hospitalization. Local 
intestinal immunity gives protection against successive 
Vaccines have been highly successful in reducing the 
global burden of rotavirus. They should be given to infants 
older than 6 weeks but younger than 2 years. Two oral 
rotavirus vaccines are available in the United States: a live, 
oral, pentavalent human-bovine reassortment rotavirus 
vaccine (PRV , RotaTeq; to be given at 2, 4, and 6 months of 
age) and a live, oral attenuated monovalent human rotavi
-
rus vaccine (HRV , Rotarix; to be given at 2 and 4 months of 
age). The vaccines showed 85–98% efficacy against severe 
rotavirus gastroenteritis in trials based in the Americas and 
Europe. Reduced efficacy (50–64%) has been noted in 
studies conducted in Asia and Africa. One advantage of 
these vaccines is the evidence of heterotypic immunity 
(prevention against rotavirus strains not included in the 
vaccine). Accordingly, some data from the Americas sug
-
gests that rotavirus confers herd immunity to children 
under 1 year of age.
Vaccine coverage is inadequate in the United States for 
rotavirus (74.6% in the 2016 National Immunization 
Study), particularly among the poor. National immuniza
-
tion programs of over 80 countries include rotavirus vac
-
cine, and the different rotavirus vaccines are available 
commercially in 100 countries.
Other rotavirus vaccines available throughout the world 
include the live, oral monovalent vaccine Rotavin-M1 used 
in Vietnam; a live, oral vaccine derived from a lamb rotavi
-
rus, Lanzhou, used in China; and the monovalent live 
vaccine used in India and given in three doses, RotaVac.
With the control of rotavirus, noroviruses, such as 
Norwalk virus (one of a variety of small round viruses 
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divided into 6 genogroups (3 causing disease in man) and 
at least 25 genotypes), are now the major cause of diarrhea 
globally. Noroviruses are a leading cause of food-borne 
disease in the United States (with food handlers largely 
responsible and associated foods most often leafy vegeta
-
bles, fruits/nuts, and molluscs) and are significantly associ
-
ated with military deployment as well as travel-associated 
and nosocomial infections.
Norovirus gastroenteritis is responsible for up to 20% 
of all diarrhea in both children and adults and an esti
-
mated 800 deaths annually in the United States and 
200,000 deaths globally. The efficacy of the rotavirus vac
-
cination is increasing the percentage of gastroenteritis 
caused by norovirus. The noroviruses appear to evolve by 
antigenic drift (similar to influenza). While 90% of young 
adults show serologic evidence of past infection, no long-
lasting protective immunity develops and reinfections are 
common.
Outbreak environments include long-term care facili
-
ties (nursing homes in particular), restaurants, hospitals, 
schools, day care centers, vacation destinations (including 
cruise ships), and military bases. Persons at particular 
risk are younger individuals, older adults, those who are 
institutionalized, and those who are immunosuppressed. 
A strain that began in Australia (GII.4 Sydney) is respon
-
sible for increasing proportions of US cases and is trans
-
mitted most often in long-term care facilities. Although 
transmission is usually fecal-oral, airborne, person-to-
person, and waterborne transmission are also docu
-
mented. A short incubation period (24–48 hours), a short 
symptomatic illness (12–60 hours, but up to 5 days in 
hospital-associated cases), a high frequency (greater than 
50%) of vomiting, and absence of bacterial pathogens in 
stool samples are highly predictive of norovirus 
gastroenteritis.
RT-PCR of stool samples is used for diagnostic and 
epidemiologic purposes. Several licensed multiple patho
-
gen platform assays are available, but they are expensive 
and interpretation of the cause of illness in a given patient 
may be difficult. Treatment options are similar to rotavirus 
(see above) and rely mostly on oral and intravenous rehy
-
dration. Deaths are rare in the developed world, and the 
more common associated diseases are aspiration pneumo
-
nia, septicemia, and necrotizing enterocolitis.
A number of vaccines, intramuscularly and intranasally 
administered, for norovirus remain under development 
and most entail the use of Norwalk viral-like proteins 
(VLP) or nano-particles vaccines (NPVs).
Outbreak control
 for both rotavirus and norovirus 
infections include strict adherence to general hygienic 
measures. Despite the promise of alcohol-based sanitizers 
for the control of pathogen transmission, such cleansers 
may be relatively ineffective against the noroviruses com
-
pared with antibacterial soap and water, reinforcing the 
need for new hygienic agents against this prevalent group 
of viruses. Cohorting of sick patients, contact precautions 
for symptomatic hospitalized patients, exclusion from 
work of symptomatic staff until symptom resolution 
(or 48–72 h after this for norovirus disease), and proper 
decontamination procedures are crucial.
Aliabadi N et al; Centers for Disease Control and Prevention 
(CDC). Sustained decrease in laboratory detection of rotavi
-
rus after implementation of routine vaccination—United 
States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2015 
Apr 10;64(13):337–42. [PMID: 25856253]
Kuate Defo Z et al. New approaches in oral rotavirus vaccines. 
Crit Rev Microbiol. 2016 May;42(3):495–505. [PMID: 
25268934]
Lopman BA et al. The vast and varied global burden of norovi
-
rus: prospects for prevention and control. PLoS Med. 2016 
Apr 26;13(4):e1001999. [PMID: 27115709]
Nguyen GT et al. A systematic review and meta-analysis of the

-
Nguyen GT et al. A systematic review and meta-analysis of the 
prevalence of norovirus in cases of gastroenteritis in develop
-
ing countries. Medicine (Baltimore). 2017 Oct;96(40):e8139. 
[PMID: 28984764]
Rosen CJ. Program for Appropriate Technology in Health 
(PATH). Rotavirus Disease and Vaccines: Frequently 
 
Asked Questions, 2016. http://vaccineresources.org/files/
PATH%20Rotavirus%20Disease%20and%20Vaccines%
 
20FAQs%20EN.pdf
ENTEROVIRUSES THAT PRODUCE 
SEVERAL SYNDROMES
The most famous enterovirus, the poliomyelitis virus, is 
discussed above under Major Vaccine-Preventable Viral 
Infections. Other clinically relevant enteroviral infections 
are discussed in this section.
1. Coxsackievirus Infections
Coxsackievirus infections cause several clinical syndromes. 
As with other enteroviruses, infections are most common 
during the summer. Two groups, A and B, are defined 
either serologically or by mouse bioassay. There are more 
than 50 serotypes.
 
»
The clinical syndromes associated with coxsackievirus 
infection are summer grippe; herpangina; epidemic pleu
-
rodynia; aseptic meningitis and other neurologic syn
-
dromes; acute nonspecific pericarditis; myocarditis; hand, 
foot, and mouth disease; epidemic conjunctivitis; and other 
1. Summer grippe (A and B)—
A febrile illness, principally 
of children, summer grippe usually lasts 1–4 days. Minor 
upper respiratory tract infection symptoms are often 
present.
2. Herpangina (A2–6, 10; B3)—
There is sudden onset of 
fever, which may be as high as 40.6
°
C, sometimes with 
febrile convulsions. Other symptoms are headache, myal
-
gia, and vomiting. The sore throat is characterized early by 
petechiae or papules on the soft palate that ulcerate in 
about 3 days and then heal. An outbreak in Taiwan with A2 
was associated with herpangina and coincided with an 
enterovirus 71 (below) outbreak, characterized by hand, 
foot, and mouth disease. Dual A6/A10 outbreaks are 
reported from Europe. Treatment is symptomatic.
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3. Epidemic pleurodynia (Bornholm disease) (B1–5)—
 
Pleuritic pain is prominent. Tenderness, hyperesthesia, and 
muscle swelling are present over the area of diaphragmatic 
attachment. Other findings include headache, sore throat, 
malaise, nausea, and fever. Orchitis and aseptic meningitis 
occur in less than 10% of patients. Most patients are ill for 
4–6 days.
4. Aseptic meningitis (A and B) and other neurologic 
syndromes—
Fever, headache, nausea, vomiting, stiff neck, 
drowsiness, and CSF lymphocytosis without chemical 
abnormalities may occur, and pediatric clusters of group B 
(especially B5) meningitis are reported. Focal encephalitis 
and transverse myelitis are reported with coxsackievirus 
group A and acute flaccid paralysis with group B in India. 
Disseminated encephalitis occurs after group B infection, 
and acute flaccid paralysis is reported with both coxsacki
-
evirus groups A and B. An outbreak of aseptic meningitis 
occurred in central China (Gansu Province) in 2008, with 
85 cases reported of coxsackie A9 disease.
5. Acute nonspecific pericarditis (B types)—
Sudden onset 
of anterior chest pain, often worse with inspiration and in 
the supine position, is typical. Fever, myalgia, headache, 
and pericardial friction rub appear early and these symp
-
toms are often transient. Evidence for pericardial effusion 
on imaging studies is often present, and the occasional 
patient has a paradoxical pulse. Electrocardiographic evi
-
dence of pericarditis is often present. Relapses may occur.
6. Myocarditis (B1–5)—
Heart failure in the neonatal 
period secondary to in utero myocarditis and over 20% of 
adult cases of myocarditis and dilated cardiomyopathy are 
associated with group B (especially B3) infections.
7. Hand, foot, and mouth disease (A5, 6, 10, 12, and 
 
16, B5)—
This disease is sometimes epidemic and is char
-
acterized by stomatitis, a vesicular rash on hands and feet, 
nail dystrophies, and onychomadesis (nail shedding). 
Enterovirus 71 is also a causative agent of usually more 
severe disease. A16 disease is usually mild. A6 may be 
atypical but is usually self-limited. Rare fatalities are 
reported among surveillance programs in China.
8. Epidemic conjunctivitis—
As with enterovirus 70, the 
A24 variant of coxsackievirus is associated with acute epi
-
demic hemorrhagic conjunctivitis in tropical areas with 
outbreaks reported in southern China, Pakistan, southern 
Sudan, the Comoros, Uganda, Cuba, and Thailand. It is 
also reported as a cause of corneal endothelitis after cata
-
ract surgery.
9. Other syndromes associated with coxsackievirus 
—
These include rhabdomyolysis, fulminant 
neonatal hepatitis (occurs rarely), pancreatitis with con
-
comitant hepatitis and myocarditis (A4), glomerulopathy 
(group B infections), onychomadesis (B1), neonatal hemo
-
phagocytic lymphohistocytosis (B1), types 1 and 2 diabetes 
mellitus (mainly group B infections), and thyroid disease 
(group B4), although definitive causality is not established. 
A pathogenic role in primary Sjögren syndrome and acute 
myocardial infarction has also been proposed for group B 
coxsackievirus infections. A report of confirmed infective 
endocarditis due to coxsackievirus B2 in a patient with a 
prosthetic cardiac device suggests that viral etiologies of 
culture-negative infective endocarditis should be 
Routine laboratory studies show no characteristic abnor
-
malities. Neutralizing antibodies appear during convales
-
cence. The virus may be isolated from throat washings or 
stools inoculated into suckling mice. Viral culture is expen
-
sive, labor intensive, and requires several days for results. 
 
A PCR test for enterovirus RNA is available and, although 
it cannot identify the serotype, may be useful, particularly 
in cases of meningitis.
 
»
Treatment is symptomatic. With the exception of meningi
-

»
-
tis, myocarditis, pericarditis, diabetes, and rare illnesses 
such as pancreatitis or poliomyelitis-like states, the syn
-
dromes caused by coxsackieviruses are benign and self-
limited. Two controlled trials showed a potential clinical 
benefit with pleconaril for patients with enteroviral menin
-
gitis although the compassionate use of this medication has 
stopped (clinicians can contact Schering Plough for 
updates). There are anecdotal reports of success with IVIG 
in severe disease. Traditional work on coxsackievirus vac
-
cines in China dealt with type A16, although surveillance 
studies suggest a range of coxsackievirus is responsible for 
disease, in particular hand, foot, and mouth disease.
Abzug MJ. The enteroviruses: problems in need of treatments. 
J Infect. 2014 Jan;68(Suppl 1):S108–14. [PMID: 24119825]
Chansaenroj J et al. Epidemic outbreak of acute haemorrhagic 
conjunctivitis caused by coxsackievirus A24 in Thailand, 
2014. Epidemiol Infect. 2015 Oct;143(14):3087–93. [PMID: 
25824006]
Greninger AL et al. A novel outbreak enterovirus D68 strain 
associated with acute flaccid myelitis cases in the USA 
(2012–14): a retrospective cohort study. Lancet Infect Dis. 
2015 Jun; 15(6):671–82. [PMID: 25837569]
Xing W et al. Hand, foot, and mouth disease in China, 2008–12: 
an epidemiological study. Lancet Infect Dis. 2014 Apr; 
14(4):308–18. [PMID: 24485991]
2. Echovirus Infections
Echoviruses are enteroviruses that produce several clinical 
syndromes, particularly in children. Infection is most com
-
mon during summer. Among reported specimens, death 
ensues in about 3%. Males younger than 20 years are more 
commonly infected than other persons.
Over 30 serotypes of echoviruses are recognized and the 
most common serotypes for disease are types 6, 9, 11, 19, 
and 30. Most can cause aseptic meningitis, which may be 
associated with a rubelliform rash. Outbreaks in South Asia 
occur with type 19. Transmission is primarily fecal-oral. 
Hand washing is an effective control measure in outbreaks 
of aseptic meningitis. Outbreaks related to fecal contamina
-
tion of water sources, including drinking water and swim
-
ming and bathing pools, were reported previously.
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Besides meningitis, other conditions associated with 
echoviruses range from common respiratory diseases and 
epidemic diarrhea to myocarditis, a hemorrhagic obstetric 
syndrome, keratoconjunctivitis, severe hepatitis with coagu
-
lopathy, leukocytoclastic vasculitis, encephalitis with sepsis, 
interstitial pneumonitis, pleurodynia, hemophagocytic syn
-
dromes (in children with cancer), sudden deafness, enceph
-
alitis, acute flaccid paralysis (a leading cause in India), optic 
neuritis, uveitis, and septic shock. Echoviruses and enterovi
-
ruses are also a common cause of nonspecific exanthems.
As with other enterovirus infections, diagnosis is best 
established by correlation of clinical, epidemiologic, and 
laboratory evidence. Cytopathic effects are produced in 
tissue culture after recovery of virus from throat washings, 
blood, or CSF. An enterovirus PCR of the CSF can assist in 
the diagnosis and is associated with a shorter duration of 
hospitalization in febrile neonates. Fourfold or greater rises 
in antibody titer signify systemic infection.
Treatment is usually symptomatic, and the prognosis is 
excellent, though there are reports of mild paralysis after 
CNS infection. In vitro data suggest some role for amanta
-
dine or ribavirin but clinical studies supporting these find
-
ings are not available.
From a public health standpoint, clustered illnesses, 
such as among travelers swimming in sewage-infested sea
-
water, suggest point-source exposure. Prevention of fecal-
oral contamination and maintenance of pool hygiene 
through chlorination and pH control are important public 
health control measures.
Iwasaki J et al. Lower anti-echovirus antibody responses in chil
-
dren presenting to hospital with asthma exacerbations. 
Clin Exp Allergy. 2015 Oct;45(10):1523–30. [PMID: 25640320]
3. Enteroviruses 68, 70, 71, & Related Agents
Several distinct clinical syndromes are described in asso
-
ciation with enteroviruses.
Enterovirus D68 (EV-D68)
 is a unique enterovirus that 
shares epidemiologic characteristics with human rhinovi
-
rus and is typically associated with respiratory illness. 
Several clusters are reported from the Netherlands, Japan, 
the Philippines, and Thailand. An outbreak in the United 
States was reported during 2014–2015, with 1153 cases 
reported from 49 states. The outbreak was also associated 
with cases of acute flaccid myelitis but not definitively 
linked thus far. The agent is implicated also in aseptic men
-
ingitis and encephalitis.
Enterovirus 70 (EV-70)
, a ubiquitous agent first identi
-
fied in 1969 and responsible for abrupt bilateral eye dis
-
charge and subconjunctival hemorrhage with occasional 
systemic symptoms, is most commonly associated with 
acute hemorrhagic conjunctivitis.
Enterovirus 71 (EV-71)
 almost always occurs in the 
Asia-Pacific region and is associated with hand, foot, and 
mouth disease (HFMD), which can be severe or even fatal, 
herpangina as well as a form of epidemic encephalitis asso
-
ciated on occasion with pulmonary edema, and acute flac
-
cid paralysis often mimicking poliomyelitis. A recombinant 
virus (between EV-71 and coxsackievirus A16) caused an 
outbreak of HFMD in Fuyang, China, in 2008. In Taiwan, 
29% of EV-71 in children is asymptomatic. There is an 
association reported between gastrointestinal enterovirus 
infection and type 1 diabetes.
Human enteroviruses are neurotropic. They may have a 
role in amyotropic lateral sclerosis. EV-D68 has been 
reported in a case of fatal meningitis/encephalitis. A num
-
ber of nonpolio type C enteroviruses are associated with 
polio-like syndromes, and surveillance for these is most 
active in China. Enterovirus infection of the pancreas can 
trigger cell-mediated autoimmune destruction of beta cells 
resulting in diabetes. Enterovirus myocarditis can be a seri
-
ous infection in neonates, complicated by cardiac dysfunc
-
tion and arrhythmias.

-
-
Mortality is especially high in EV-71–associated brain
-
stem encephalitis, which is often complicated by pulmonary 
edema, particularly when it occurs in children younger than 
5 years. A complication is autonomic nervous system dys
-
regulation, which may precede the pulmonary edema. 
Because of lower herd immunity, HFMD tends to infect the 
very young (under age 5) in nonendemic areas. Clinical and 
epidemiologic findings aided by isolation of the suspect 
agent from conjunctival scraping for EV-70; vesicle swabs, 
body secretions, or CSF for EV-71; and respiratory secre
-
tions for D68 facilitate diagnosis of these enteroviral enti
-
ties. Enzyme immunoassays and complement fixation tests 
show good specificity but poor sensitivity (less than 80%). 
RT-PCR may increase the detection rate in enterovirus 
infections and is useful in the analysis of CSF samples 
among patients with meningitis and of blood samples 
among infants with a sepsis-like illness.
Treatment of these entities remains largely symptom
-
atic. A study in China showed that recombinant human 
interferon-alpha1b in EV-71–associated hand, foot, and 
mouth disease was associated with decreased fever dura
-
tion, healing time of typical skin or oral mucosal lesions, 
and EV-71 viral load. There is anecdotal success in manag
-
ing myocarditis with immunoglobulins.
The major complication associated with EV-70 is the rare 
development of an acute neurologic illness with motor 
paralysis akin to poliomyelitis. Treatment of acute flaccid 
paralysis related to EV-71 with IVIG does not appear to 
improve neurologic outcomes. Attention-deficit with hyper
-
activity occurs in about 20% with confirmed infection.
EV-D68 requires supportive care with particular atten
-
tion to respiratory support. The CDC’s National Enterovi
-
rus Surveillance System should receive reports of disease at 
wnix@cdc.gov.
Household contacts, especially children under 6 months 
of age, are at particular risk for EV-71 acquisition. A com
-
mercial disinfectant, Virkon S at 1–2% application, appears 
to reduce infectivity of fomites. A stage-based supportive 
treatment for EV-71 infections, recognizing the potential 
for late-onset CNS disease and cardiopulmonary failure is 
important. There is no commercially available EV-71 
vaccine in the United States although vaccines produced in 
China appear to be successful against EV-71–associated 
hand, foot, and mouth disease and herpangina. Decreases 
in antibody titers suggest booster doses of these vaccines 
may be needed.
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Enterovirus 72 (EV-72)
 is another term for hepatitis A 
virus (see Chapter 16). Enterovirus EV-104A is related to 
rhinoviruses and associated with respiratory illness in 
reports from Italy and Switzerland.
2015 Jun;15(6):671–82. [PMID: 25837569]
Huang X et al. Clinical efficacy of therapy with recombinant 
human interferon α1b in hand, foot, and mouth disease with 
enterovirus 71 infection. PLoS One. 2016 Feb 16; 
11(2):e0148907. [PMID: 26882102]
Y ee PT et al. Development of novel vaccines against 
enterovirus-71. Viruses. 2015 Dec 30;8(1):E1. [PMID: 26729152]
4. Human 
p
ar
echovirus Infection (H
p
eV
)
HPeV is 1 of 17 genotypes among a distinct genus of picor
-
naviruses and causes a wide variety of disease in humans, 
especially in infants. The pathogen mainly affects small 
children during the summer and early fall, although dis
-
ease can also occur in older adults. Cases are reported 
worldwide. During 2009–2013, HPeV3 was most com
-
monly reported among isolates in the United States. Clini
-
cal presentation is mainly driven by gastrointestinal and 
respiratory illness, although otitis, neonatal sepsis, fever 
without a detectable source, gastroenteritis, flaccid paraly
-
sis, myalgias (which may be epidemic), diffuse maculo
-
papular and palmar-plantar rashes, aseptic meningitis, 
intracranial hemorrhage, seizures, and an acute dissemi
-
nated encephalitis are described in the literature.
HPeV6 affects individuals older than 20 years. HPeV3 
is responsible for meningitis/encephalitis, neonatal sepsis 
(13% of late-onset neonatal sepsis [between 4 and 120 days 
of life] in one series was due to parechovirus) and was 
reported in association with necrotizing enterocolitis and 
hepatitis. It is the most common cause of neonatal menin
-
gitis and is the picornavirus most often found in CSF 
samples of CNS-related infections in very young children. 
CSF parameters include a normal count in over 90% and an 
abnormal protein in less than 50%. CNS infection may be 
seen with HPeV4 as well. Respiratory and gastrointestinal 
illnesses are seen with types HPeV4–HPeV6, HPeV10, 
HPeV13-HPeV15.
Treatment is largely supportive and rapid identification 
of the viral antigen by PCR in stools, respiratory samples, 
and CSF may decrease use of unnecessary antibiotics and 
shorten hospital stay, although current PCR assays are not 
always sufficiently sensitive to exclude parechoviruses. 
Intravenous immunoglobulin was anecdotally successful in 
one case of parechovirus dilated cardiomyopathy and 
maternal antibodies to parechovirus type 3 are protective. 
Reported complications of neonatal cerebral infections 
include learning disabilities, epilepsy, and cerebral palsy. 
Because intrafamilial transmission is well documented, it 
may help isolate the affected children.
Abedi GR et al. Enterovirus and human parechovirus 
surveillance—United States, 2009–2013. MMWR Morb 
Mortal Wkly Rep. 2015 Sep 4;64(34):940–3. [PMID: 26334674]
 
º
RICKE
t
t
SIAL
 DISEASES
TYPHUS GROUP
1. Epidemic (Louse-Borne) 
t
yphus
 
»
Prodrome of headache, then chills and fever.
 
»
Severe, intractable headaches, prostration, 
persisting high fever.
 
»
Macular rash appearing on days 4–7 on the trunk 
and in the axillae, spreading to the rest of the 
body but sparing the face, palms, and soles.
 
»
Diagnosis confirmed by complement fixation, 
microagglutination, or immunofluorescence.
 
»
Epidemic louse-borne typhus is caused by 
Rickettsia prowa
-
zekii
, an obligate parasite of the body louse 
Pediculus 
humanus corporis
 (other lice do not contribute) 
(Table 32–3). Transmission is favored by crowded, unsani
-
tary living conditions, famine, war, or any circumstances

Pediculus 
-
tary living conditions, famine, war, or any circumstances 
that predispose to heavy infestation with lice. After biting a 
person infected with 
R prowazekii
, the louse becomes 
infected by the organism, which persists in the louse gut 
and is excreted in its feces. When the same louse bites an 
uninfected individual, the feces gain entry into the blood
-
stream when the person scratches the itching wound. Dry, 
infectious louse feces may also enter via the respiratory 
tract. Cases can be acquired by travel to pockets of infec
-
tion (eg, central and northeastern Africa, Central and 
South America). Outbreaks have been reported from Peru, 
Burundi, and Russia. Because of aerosol transmissibility, 
 
 is considered a possible bioterrorism agent. In 
the United States, cases occur among the homeless, refu
-
gees, and the unhygienic, most often in the winter.
 can survive in lymphoid and adipose (in 
endothelial reservoirs) tissues after primary infection, and 
years later, produce recrudescence of disease (Brill-Zinsser 
disease) without exposure to infected lice. This phenome
-
non can serve as a point source for future outbreaks.
An extrahuman reservoir of 
 in the 
United States is flying squirrels, 
Glaucomys volans
. Transmis
-
sion to humans can occur through their ectoparasites, known 
as sylvatic typhus, usually causing atypical mild disease. A 
case of recrudescent (Brill-Zinsser) disease 11 years after 
disease acquired by contact with flying squirrels is reported. 
Foci of sylvatic typhus are found in the eastern United States 
and are reported to occur in Brazil, Ethiopia, and Mexico.
 
»
Prodromal malaise, cough, headache, backache, arthralgia, 
myalgia, and chest pain begin after an incubation period of 
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Table 32–3.
 
Rickettsial diseases.
Disease
Rickettsial 
p
a
thogen
Geographic Areas 
 
of 
p
r
evalence
Insect 
Vector
Mammalian 
Reservoir
t
r
avel 
Association
t
yphus Gr
oup
Epidemic (louse-borne) typhus
Rickettsia 
 
prowazekii
South America, Northeastern 
and Central Africa
Louse
Humans, flying 
squirrels
Rare
Endemic (murine) typhus
Rickettsia typhi
Worldwide; small foci 
(United States: 
southeastern Gulf Coast)
Flea
Rodents, 
opossums
Often
Scrub 
t
yphus 
Group
Scrub typhus
Orientia 
tsutsugamushi
Southeast Asia, Japan, 
Australia, Western Siberia
Mite
1
Rodents
Often
Spotted Fever Group
Rocky Mountain spotted fever
Western Hemisphere; 
 
United States (especially 
mid-Atlantic coast region)
Tick
1
Rodents, dogs, 
porcupines
Rare
California flea rickettsiosis
Rickettsia felis
Worldwide
Flea
Cats, opossums
 
Mediterranean spotted fever, 
Boutonneuse fever, Kenya tick 
typhus, South African tick fever, 
Indian tick typhus
Rickettsia conorii
Africa, India, Mediterranean 
regions
Tick
1
Rodents, dogs
Often
Queensland tick typhus
Rickettsia australis
Eastern Australia
Tick
1
Rodents, 
marsupials
Rare
Siberian Asian tick typhus
Rickettsia sibirica
Siberia, Mongolia
Tick
1
Rodents
Rare
African tick bite fever
Rickettsia africae
Rural sub-Saharan Africa, 
Eastern Caribbean
Tick
1
Cattle
Often
Lymphangitis-associated rickettsiosis
R sibirica 
mongolitimonae
Europe, Africa, Mongolia
Tick
1
Unknown
Unknown
Tick-borne lymphadenopathy/
Dermacentor-borne necrosis 
erythema lymphadenopathy/scalp 
eschar neck lymphadenopathy
R slovaca, R raoultii, 
Candidatus R rioja
Europe
Tick
Unknown
Rickettsialpox
Rickettsia akari
United States, Korea, former 
USSR
Mite
1
Mice
Other
Ehrlichiosis and anaplasmosis, human
Monocytic
Ehrlichia chaffeensis, 
Anaplasma equi, 
Ehrlichia canis
Southeastern United States
Tick
1
Dogs
Granulocytic
Anaplasma 
phagocytophilum, 
Ehrlichia ewingii
Northeastern United States
Tick
1
Rodents, deer, 
sheep
Q fever
Coxiella burnetii
Worldwide
None
2
Cattle, sheep, 
goats
1
Also serve as arthropod reservoirs by maintaining rickettsiae through transovarian transmission.
2
Human infection results from inhalation of dust.
10–14 days, followed by an abrupt onset of chills, high 
fever, and prostration, with flu-like symptoms progressing 
to delirium and stupor. The headache is severe, and the 
fever is prolonged. (Table 32–2).
Other findings consist of conjunctivitis, mild vitritis, 
retinal lesions, optic neuritis, and hearing loss from neu
-
ropathy of the eighth cranial nerve, abdominal pain, and 
often splenomegaly. Flushed faces and macular rash (that 
may become confluent) appears first in the axillae and 
then over the trunk, spreading to the extremities on the 
fifth or sixth day of illness; sparing the palms of hands and 
soles of feet. In severely ill patients, the rash becomes hem
-
orrhagic, and hypotension becomes marked. Pneumonia, 
thromboses, vasculitis with major vessel obstruction and 
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gangrene, circulatory collapse, myocarditis, uremia, sei
-
zure may occur. Improvement begins 13–16 days after 
onset with a rapid drop of fever and typically a spontane
-
ous recovery.
Brill-Zinsser disease has a more gradual onset than 
primary 
 infection; fever and rash are of 
shorter duration, and the disease is milder.
The white blood cell count is variable. Thrombocytopenia, 
elevated liver enzymes, proteinuria, and hematuria com
-
monly occur. Serum obtained 5–12 days after onset of 
symptoms usually shows specific antibodies for 
 
antigens as demonstrated by complement fixation, microag
-
glutination, or immunofluorescence. In primary rickettsial 
infection, early antibodies are IgM; in recrudescence (Brill-
Zinsser disease), early antibodies are predominantly IgG. A 
PCR test exists, but its availability is limited.
C. Imaging
Radiographs of the chest may show patchy consolidation.
 
»
The prodromal symptoms and the early febrile stage lack 
enough specificity to permit diagnosis in nonepidemic sit
-
uations. The rash is sufficiently distinctive for diagnosis, 
but it may be absent in up to 50% of cases or may be diffi
-
cult to observe in dark-skinned persons. A variety of other 
acute febrile diseases should be considered, including 
typhoid fever, meningococcemia, and measles.
 
»
Treatment
Treatment consists of 100 mg orally twice daily for 
7–10 days or for at least 3 days after the fever subsides. A 
single dose of 200 mg doxycycline may be effective; how
-
ever, some patients may relapse. Chloramphenicol is con
-
sidered less effective than doxycycline, but it is still the 
drug of choice in pregnancy.
 
»
Prognosis
The prognosis depends greatly on the patient’s age and 
immune status. The mortality rate is 10% in the second and 
third decades but in the past reached 60% in the sixth 
decade. Brill-Zinsser disease is rarely fatal.
 
»
Prevention consists of louse control with insecticides, par
-
ticularly by applying chemicals to clothing or treating it 
with heat, and frequent bathing.
A deloused and bathed typhus patient is not infectious. 
The disease is not transmitted from person to person. 
Patients are infectious from the lice during the febrile 
period and perhaps 2–3 days after the fever returns to 
normal.
No vaccine is available for the prevention of 
 
Akram SM et al. 
Rickettsia prowazekii
 (epidemic typhus). 2017 
Oct 9. [PMID: 28846313] http://www.ncbi.nlm.nih.gov/books/
 
NBK448173/
Centers for Disease Control and Prevention (CDC). Typhus 
Fevers. https://www.cdc.gov/typhus/healthcare-providers/
index.html
2. Endemic (Murine) 
t
yphus
, a ubiquitous pathogen recognized on all 
continents, is transmitted from rat to rat through the rat 
flea (Table 32–3). Serosurveys of animals show high preva
-
lence of antibodies to 
R typhi
 in opossums, followed by 
dogs and cats. Humans usually acquire the infection in an 
urban or suburban setting when bitten by an infected flea. 
Rare human cases in the developed world occur in travel
-
ers, usually to Southeast Asia, Africa, or the Mediterranean 
area, although other pockets of infection are also known to 
occur in the Andes and the Yucatán. In the United States, 
cases are mainly reported from Texas and Southern 
California.
 
»
The presentation is nonspecific, including fever, headache, 
myalgia, and chills. Relative bradycardia is reported. Macu
-
lopapular rash occurs in around 50% of cases; it is concen
-
trated on the trunk, mostly sparing the palms and soles, 
and fades rapidly.
The illness may be associated with maternal death, mis
-
carriage, preterm birth, and low birth weight if acquired 
early during pregnancy.
Serologic confirmation may be necessary for differentia
-
tion, with complement-fixing or immunofluorescent anti
-

-
-
bodies detectable within 15 days after onset, with specific 
R typhi
 antigens. A fourfold rise in serum antibody titers 
between the acute and the convalescent phase is diagnostic. 
It is important to note that 
R
 
typhi
 antigens frequently 
cross-react with those of 
R prowazekii.
 The PCR can distin
-
guish between these two infections depending on the 
sample type, the timing of sample collection, bacterial load, 
and severity of disease. During the first week of illness, 
PCR is the most sensitive test if samples are taken before 
doxycycline administration.
 
»
The most common entity in the differential diagnosis is 
Rocky Mountain spotted fever, usually occurring after 
rural exposure and with a different rash (centripetal versus 
centrifugal for epidemic or endemic typhus).
 
»
The most common complication is pulmonary, in the form 
of pneumonia, followed by pleural effusion and respiratory 
failure. Other complications include neurologic (periph
-
eral facial paralysis, meningism, ataxia, seizures), acute 
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kidney injury, and multiorgan failure. Rare complications 
include ocular findings, disseminated intravascular coagu
-
lation, and hemophagocytosis syndrome. Anemia, throm
-
bocytopenia, leukopenia, hyponatremia, and elevated 
levels of liver enzymes commonly occur.
 
»
Treatment
Doxycycline is the drug of choice, except during preg
-
nancy. Ciprofloxacin (500–750 mg orally twice a day) and 
ampicillin (500 mg orally three times a day) are reportedly 
successful in pregnant women. Azithromycin is frequently 
used but is not associated with improved fetal outcomes.
 
»
Preventive measures are directed at control of rats and 
ectoparasites (rat fleas) with insecticides, rat poisons, and 
rat-proofing of buildings.
 
»
Prognosis
Endemic typhus is usually a self-limited disease. A large 
case series from Texas reported a fatality rate of 0.4%.
Paris DH et al. State of the art of diagnosis of rickettsial diseases: 
the use of blood specimens for diagnosis of scrub typhus, 
spotted fever group rickettsiosis, and murine typhus. Curr 
Opin Infect Dis. 2016 Oct; 29(5):433–9. [PMID: 27429138]
Pieracci EG et al. Fatal Flea-borne typhus in Texas: a retrospec
-
tive case series, 1985–2015. Am J Trop Med Hyg. 2017 May; 
96(5):1088–93. [PMID: 28500797]
Tsioutis C et al. Clinical and laboratory characteristics, epidemi
-
ology, and outcomes of murine typhus: a systematic review. 
Acta Trop. 2017 Feb;166:16–24. [PMID: 27983969]
3. Scrub 
t
yphus (
t
sutsugamushi F
ever)
 
»
Exposure to mites in endemic South and East Asia, 
the western Pacific (including Korea), and 
Australia.
 
»
Black eschar at site of the bite, with regional and 
generalized lymphadenopathy.
 
»
High fever, relative bradycardia, headache, myal
-
gia, and a short-lived macular rash.
 
»
Frequent pneumonitis, encephalitis, and 
myocarditis.
 
»
Scrub typhus is caused by 
Orientia tsutsugamushi
, which is 
a parasite of rodents and is transmitted by larval trombicu
-
lid mites (chiggers). Multiple strains exist and are associ
-
ated with geographic areas. The disease is endemic in 
Korea; China; Taiwan; Japan; Pakistan; India; Thailand; 
Malaysia; Vietnam; Laos; and Queensland, Australia 
(Table 32–3), which form an area known as the 
“tsutsugamushi triangle. ” Scrub typhus is an increasingly 
recognized cause of acute febrile illness in India and China 
and is a recognized cause of fever of unknown origin. Cases 
are also reported in the Middle East, Kenya, and South 
America. Transmission is often more common at higher 
altitudes. The mites live on vegetation (grass and brush) 
but complete their maturation cycle by biting humans who 
come in contact with infested vegetation. Risk factors in 
China include female sex, ages between 60 and 69 years, 
and farming. Therefore, the disease is more common in 
rural areas, but urban cases have also been described. Ver
-
tical transmission occurs, and blood transfusions may 
transmit the pathogen as well. Rare occupational transmis
-
sion via inhalation is documented among laboratory work
-
ers. Cases among travelers to endemic areas are increasingly 
recognized.
 
»
After a 1- to 3-week incubation period, malaise, chills, 
severe headache, and backache develop. At the site of the 
bite, a papule evolves into a flat black eschar (the groin and 
the abdomen being the most common sites followed by the 
chest and axilla), a finding that is usually helpful for diag
-
nosis. The regional lymph nodes are commonly enlarged 
and tender, and sometimes a more generalized adenopathy 
occurs. Fever rises gradually during the first week of infec
-
tion, and the rash is usually macular and primarily on the 
trunk area. The rash can be fleeting or more severe, peak
-
ing at 8 days but lasting up to 21 days after onset of infec
-
tion. Relative bradycardia, defined as an increase in heart

-
-
tion. Relative bradycardia, defined as an increase in heart 
rate of fewer than 10 beats/minutes for a 1-degree Celsius 
increase in temperature, frequently accompanies scrub 
typhus infection. The occurrence of relative bradycardia 
has no effect on clinical outcome. Gastrointestinal symp
-
toms, including nausea, vomiting, and diarrhea, occur in 
nearly two-thirds of patients and correspond to the pres
-
ence of superficial mucosal hemorrhage, multiple erosions, 
or ulcers in the gastrointestinal tract. Acute kidney injury 
and other renal abnormalities are frequently present.
Severe complications, such as pneumonitis, myocarditis, 
encephalitis or aseptic meningitis, peritonitis, granuloma
-
tous hepatitis, hemophagocytic syndrome, disseminated 
intravascular coagulation, cerebrovascular hemorrhage or 
infarction, cranial nerve palsies, parkinsonian symptoms, 
ARDS, or hemophagocytosis may develop during the second 
or third week. An attack confers prolonged immunity against 
homologous strains and transient immunity against heterol
-
ogous strains. Heterologous strains produce mild disease if 
infection occurs within a year after the first episode.
Thrombocytopenia and elevation of liver enzymes, biliru
-
bin, and creatinine are common. Indirect immunofluores
-
cent assay and indirect immunoperoxidase assays are the 
gold standard for scrub typhus diagnosis. These tests are 
expensive and have limited availability. An ELISA detect
-
ing 
Orientia
 specific antibodies in serum is available. PCR 
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(from the eschar or blood) is the most sensitive diagnostic 
test but remains positive even after initiation of treatment. 
Culture of the organism from blood obtained in the first 
few days of illness is another diagnostic modality but 
requires a specialized biological safety level 3 laboratory. It 
is suggested to combine IgM detection by ELISA and con
-
ventional PCR to improve the diagnosis of scrub typhus.
 
»
Leptospirosis, typhoid, dengue, malaria, Q fever, hemor
-
rhagic fevers, and other rickettsial infections should be 
considered. The headache may mimic trigeminal neural
-
gia. Scrub typhus is a recognized cause of obscure tropical 
fevers, especially in children.
 
»
Without treatment, fever subsides spontaneously after 
 
2 weeks, but the mortality rate may be 10–30%. The treat
-
ment of choice is doxycycline (100 mg orally twice daily) or 
minocycline (100 mg intravenously twice daily) until there 
is evidence of clinical improvement for at least 3 days after 
the fever subsides. Shorter duration of therapy is associated 
with relapse. Alternative therapy for pregnant women and 
patients with doxycycline allergy include chloramphenicol, 
although chloramphenicol- and tetracycline-resistant 
strains have been reported from Southeast Asia. Azithro
-
mycin is shown to be as effective as doxycycline with less 
side effects. Azithromycin may not prevent poor fetal out
-
comes in infected pregnant women.
Poor prognostic factors include hypotension requir
-
ing vasopressors, ICU care, aged over 60 years, absence 
of an eschar (making the diagnosis difficult), pregnancy, 
and laboratory findings such as leukocytosis or 
hypoalbuminemia.
 
»
Repeated application of long-acting miticides can make 
endemic areas safe. Insect repellents on clothing and skin 
as well as protective clothing are effective preventive mea
-
sures. Although chemoprophylaxis with doxycycline has 
been used, the CDC does not recommend prophylaxis with 
antibiotics for asymptomatic travelers. No effective vac
-
cines are available.
Jung LY et al. Relative bradycardia in scrub typhus. Am J Trop 
Med Hyg. 2017 Nov;97(5):1316–8. [PMID: 29016300]
Lee SC et al. Comparative effectiveness of azithromycin for treat
-
ing scrub typhus: a PRISMA-compliant systematic review and 
meta-analysis. Medicine (Baltimore). 2017 Sep;96(36):e7992. 
[PMID: 28885357]
Rajan SJ et al. Scrub typhus in pregnancy: maternal and fetal 
outcomes. Obstet Med. 2016 Dec; 9(4):164–6. [PMID: 
27829876]
Weitzel T et al. Endemic scrub typhus in South America. N Engl 
J Med. 2016 Sep; 375(10):954–61. [PMID: 27602667]
Zhao M et al. Comparison of minocycline and azithromycin for 
the treatment of mild scrub typhus in northern China. Int J 
Antimicrob Agents. 2016 Sep;48(3):317–20. [PMID: 
27449540]
SPOTTED FEVERS
1. Rocky Mountain Spotted Fever
 
»
Exposure to tick bite in an endemic area.
 
»
An influenza-like prodrome followed by fever, 
severe headache, and myalgias; occasionally, 
delirium and coma.
 
»
Red macular rash appears between days 2 and 6 of 
fever, first on the wrists and ankles and then 
spreading centrally; it may become petechial.
 
»
Serial serologic examinations by indirect 
fluorescent antibody confirm the diagnosis 
retrospectively.
 
»
Despite its name, most cases of Rocky Mountain spotted 
fever (RMSF) occur outside the Rocky Mountain area. Pas
-
sive surveillance data from 2002 to 2007 reported cases 
from 46 states and the District of Columbia. More than half 
(64%) of these cases were from only five states: North 
Carolina, Tennessee, Oklahoma, Missouri, and Arkansas. 
RMSF is endemic in Central and South America with a 
small fatal familial cluster reported from Panama 
(Table 32–3). Native Americans are at high risk for infec
-
tion. The causative agent, 
R rickettsii
, is transmitted to

-
, is transmitted to 
humans by the bite of ticks, including the Rocky Mountain 
wood tick, 
Dermacentor andersoni
, in the western United 
States, and the American dog tick, 
D variabilis
, in the eastern 
United States. Several hours of contact between the tick and 
the human host are required for transmission. The brown 
dog tick, 
Rhipicephalus sanguineus
, is a vector in eastern 
Arizona and responsible for many Native American cases. 
Other hard-bodied ticks transmit the organism in the south
-
ern United States and in Central and South America and are 
responsible for transmitting it among rodents, dogs, porcu
-
pines, and other animals. Human cases reemerged recently 
in Mexico after decades of quiescence (since the 1940s).
There are 25 genotypes of 
 in four different 
groups, and potential genomic-clinical correlations are 
underway. Several other rickettsial species cause mild, 
nonlethal infections in the United States, including 
 
R parkeri, R phillipi
, and 
R massiliae
. These are discussed in 
the “tick typhus” section.
In the United States, the estimated annual incidence of 
RMSF is increasing to as high as seven cases per million 
persons (primarily occurring from April through 
September), with a higher incidence among children and 
men. Better diagnostic capacity and improved surveillance 
are thought responsible for the changing epidemiology.
A Brazilian spotted fever with higher mortality than 
RMSF is thought to be due to a virulent strain of 
rickettsii
. A host of spotted fever species have been identi
-
fied from human patients over the last 20 years throughout 
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the world including species from China (
Rickettsia
 sp. 
XY99), Slovakia (
R slovaca
), Morocco (
R aeschlimannii
), 
Sicily (
R massiiliae
), China, and Egypt (
R sibirica 
monolitimonae
).
 
»
RMSF can cause severe multiorgan dysfunction and 
fatality rates of up to 73% if left untreated, making it the 
most serious rickettsial disease.
 Two to 14 days (mean, 
 
7 days) after the bite of an infectious tick, symptoms begin 
with the abrupt onset of high fever, chills, headache, nausea 
and vomiting, myalgias, restlessness, insomnia, and irrita
-
bility. The characteristic rash (faint macules that progress 
to maculopapules and then petechiae) appears between 
days 2 and 6 of fever. It initially involves the wrists and 
ankles, spreading 
centrally
 to the arms, legs, and trunk over 
the next 2–3 days. Involvement of the palms and soles is 
characteristic. Facial flushing, conjunctival injection, and 
hard palate lesions (Figure 32–6) may occur. In about 10% 
of cases, however, no rash or only a minimal rash is seen. 
Cough and pneumonitis may develop and delirium, leth
-
argy, seizures, stupor, and coma may also appear in more 
severe cases. Splenomegaly, hepatomegaly, jaundice, myo
-
carditis (which may mimic an acute coronary syndrome), 
adrenal hemorrhage, polyarticular arthritis, or uremia is 
occasionally present. ARDS and necrotizing vasculitis, 
when present, are of greatest concern.
A group of four cases from Sonora, Mexico, among 
pregnant women, three of whom sustained spontaneous 
abortions, is a reminder of the risk of this infection for 
pregnant women and their fetuses.
Thrombocytopenia, hyponatremia, elevated aminotrans
-
ferases, and hyperbilirubinemia are common. CSF may 
show hypoglycorrhachia and mild pleocytosis. Dissemi
-
nated intravascular coagulation is observed in severe cases. 
Diagnosis during the acute phase of the illness can be made 
 
▲
Figure 32–6.
 
Hard palate lesion caused by Rocky 
Mountain spotted fever. 
CDC.)
by immunohistologic or PCR demonstration of 
 
in skin biopsy specimens (or cutaneous swabs of eschars or 
skin lesions). Performing such studies as soon as skin 
lesions become apparent and before antibiotics commence 
maximizes sensitivity.
Serologic studies confirm the diagnosis, but most patients 
do not mount an antibody response until the second week of 
illness. The indirect fluorescent antibody test is most com
-
monly used. No commercial PCR technique is validated.
 
»
The diagnosis is challenging because early symptoms 
resemble those of many other infections. The classic triad 
of fever, rash, and tick bite is rarely recognized, with up to 
40% of patients not recalling a tick bite. Moreover, the rash 
may be confused with that of measles, typhoid, and 
ehrlichiosis, or—most importantly—meningococcemia. 
Blood cultures and examination of CSF establish the latter. 
Coinfections may mask the diagnosis. Some spotted fever 
rickettsioses may also mimic RMSF but will not be detected 
by routine serologic testing for RMSF.
 
»
Treatment with doxycycline at similar doses and duration 
as for epidemic typhus (100 mg orally twice daily for 
4–10 days) is recommended. Similarly, chloramphenicol 
(50–100 mg/kg/day in four divided doses, orally or intrave
-
nously for 4–10 days) is the preferred alternative during 
pregnancy. Patients usually defervesce within 48–72 hours, 
and therapy should be continued for at least 3 days after 
defervescence occurs.
The reported mortality rate for treated patients in the 
United States is about 3–5%. The following features are 
associated with increased mortality: (1) infection in older 
adults or Native Americans; (2) the presence of atypical 
clinical features (absence of headache, no history of tick

clinical features (absence of headache, no history of tick 
attachment, gastrointestinal symptoms) and 
underlying
 
chronic diseases; and (3) a delay in initiation of appropriate 
antibiotic therapy. The usual cause of death is pneumonitis 
with respiratory or cardiac failure. A fulminant form of 
RMSF can be seen in patients with glucose-6-phosphate 
dehydrogenase deficiency. Sequelae may include seizures, 
encephalopathy, peripheral neuropathy, paraparesis, bowel 
and bladder incontinence, cerebellar and vestibular dys
-
function, hearing loss, and motor deficits.
Unfavorable prognostic factors for mortality from a 2017 
Brazilian series of spotted fever cases included male sex, 
shock, seizures, and hypotension, and favorable prognostic 
factors were urban exposure, recognition of a tick, and lymph
-
adenopathy. Recent Mexican cases were more severe among 
children under 10 years of age and among the very poor.
 
»
Protective clothing, tick-repellent chemicals, and the 
removal of ticks at frequent intervals are helpful measures. 
The effectiveness of aggressive campaigns to decrease ticks 
in the community is under investigation in Native 
American communities with high RMSF attack rates. 
Prophylactic therapy after a tick bite is not recommended.
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Álvarez-Hernández G et al. Rocky Mountain spotted fever in 
Mexico: past, present, and future. Lancet Infect Dis. 2017 Jun; 
17(6):e189–96. [PMID: 28365226]
Licona-Enriquez JD et al. Rocky Mountain spotted fever and 
pregnancy: four cases from Sonora, Mexico. Am J Trop 
Med Hyg. 2017 Sep;97(3):795–8. [PMID: 28722584]
2. Rickettsialpox
Rickettsialpox is an acute, self-limiting, febrile illness caused 
by 
, a parasite of mice, transmitted by the 
mite 
Liponyssoides sanguineus
 (Table 32–3). Infections are 
reported globally. Seroprevalence studies among injection 
drug users in Baltimore show seropositivity as high as 16%. 
In New Y ork, its association with poverty is very strong. The 
illness has also been found in farming communities. 
Crowded conditions and mouse-infested housing allow 
transmission of the pathogen to humans. The primary 
lesion is a painless red papule that vesiculates and forms a 
black eschar followed by an incubation period of 7–12 days. 
Onset of symptoms—chills, fever, headache, photophobia, 
and disseminated aches and pains—is sudden. Two to 
 
4 days later, a widespread papular eruption appears. The 
rash becomes vesicular and forms crusts that are shed in 
about 10 days. Early lesions may resemble those of chicken
-
pox (typically vesicular versus papulovesicular in rickettsi
-
alpox). Pathologic findings include dermal edema, 
subepidermal vesicles, and at times a lymphocytic vasculitis.
Transient leukopenia and thrombocytopenia and acute 
hepatitis can occur. A fourfold rise in serum antibody titers 
to rickettsial antigen, detected by complement fixation or 
indirect fluorescent assays, is diagnostic. Conjugated anti-
rickettsial globulin can identify antigen in punch biopsies 
of skin lesions. PCR detection of rickettsial DNA in fresh 
tissue also appears of value. 
R akari
 can reportedly also be 
isolated from eschar biopsy specimens.
Treatment consists of oral doxycycline (200 mg/day) for 
7 days. The disease is usually mild and self-limited without 
treatment, but occasionally severe symptoms may require 
hospitalization. Control requires the elimination of mice 
from human habitations and insecticide applications.
Eremeeva ME et al. Investigation of an outbreak of rickettsial 
febrile illness in Guatemala, 2007. Int J Infect Dis. 2013 May; 
17(5):e304–11. [PMID: 23266334]
3. 
t
ick 
t
yphus 
(Rickettsial Fever)
The term “tick typhus” denotes a variety of spotted rickettsial 
fevers, often named by their geographic location (eg, Medi
-
terranean spotted fever, Queensland tick typhus, Oriental 
spotted fever, African tick bite fever, Siberian tick typhus, 
North Asian tick typhus), or by morphology (eg, bouton
-
neuse fever). These illnesses are caused by various rickettsial 
R africae, R australis, R conorii, R japonica, R 
massiliae, R parkeri
, and 
R sibirica
, and 
R 364D—
recognized 
in California in 2013) and are transmitted by various tick 
species. Lymphangitis-associated rickettsiosis (LAR), caused 
by 
R sibirica mongolitimonae
, was first described in 1996 and 
has been reported in Europe only thus far, including a small 
outbreak in Spain (Table 32–3). Dogs and wild animals, 
usually rodents and even reptiles, may serve as reservoirs for 
rickettsial fevers. Travel is a risk factor for disease, particu
-
larly among elderly ecotourists. In a series of 280 interna
-
tional travelers with rickettsial disease, the most common 
cause was spotted fever rickettsiosis (231 cases, 82.5% of the 
total) followed by scrub typhus (16, 5.7%).
Tick-borne rickettsioses are the main source of rickettsia 
infections in Europe and cause a syndrome similar to that 
seen in Mediterranean spotted fever. Newly recognized spe
-
cies include 
R helvetica
, 
R monacensis
, 
, and 
 
. Another described syndrome is tick-borne 
lymphadenopathy/Dermacentor-borne-necrosis-erythema-

-
, 
, 
, and 
 
lymphadenopathy/scalp eschar neck lymphadenopathy 
(TIBOLA/DEBONEL or SENLAT) associated with 
R slovaca
, 
, and 
R raoultii
 and characterized by tick 
bite, eschar on the scalp, and cervical lymphadenopathy.
The pathogens usually produce an eschar or black spot 
(tâche noire) at the site of the tick bite that may be useful 
in diagnosis, though spotless boutonneuse fever occurs. 
Symptoms include fever, headache, myalgias, and rash. 
Painful lymphadenopathy or lymphangitis may also occur. 
Rarely, papulovesicular lesions may resemble rickettsial
-
pox. Endothelial injury produces perivascular edema and 
dermal necrosis. Regional adenopathy, disseminated 
lesions, kidney disease, splenic rupture, and focal hepatic 
necrosis are observed. Neurologic manifestations, includ
-
ing encephalitis, internuclear ophthalmoplegia, coronary 
involvement, and the hemophagocytic syndrome, are rare.
The diagnosis is clinical, with serologic or PCR (culture 
can be used but is less sensitive than either) of the buffy coat 
of blood, or an eschar if one is available, used for confirma
-
tion. Treatment should be started upon clinical suspicion 
since delayed therapy is the usual cause of increased morbid
-
ity. Oral treatment with doxycycline (200 mg/day) or chlor
-
amphenicol (50–75 mg/kg/day in four divided doses) for 
7–10 days is indicated. Caution is advised with the use of 
ciprofloxacin because it is associated with a poor outcome 
and increases the severity of disease in Mediterranean spot
-
ted fever. The combination of azithromycin and rifampin is 
effective and safe in pregnancy. Prevention entails protective 
clothing, repellents, and inspection for and removal of ticks.
Formerly classified as an endemic or murine typhus, the 
cat-flea typhus, caused by 
 is more properly 
classified as a spotted fever. The causative agent has been 
linked to the cat flea and opossum exposure. While the dis
-
eases appear to be ubiquitous (with recent reports from 
Madagascar), most cases in the United States (southern Texas 
and California, and possibly Hawaii) occur in the spring and 
summer. Treatment is the same as for other rickettsial fevers.
Cases of non-rickettsiae–associated spotted fever tend 
to have a better prognosis than due those due to 
R rickettsiae
 
de Oliveira SV et al. Predictive factors for fatal tick-borne spot
-
ted fever in Brazil. Zoonoses Public Health. 2017 Nov; 
64(7):e44–50. [PMID: 28169507]
Drexler NA et al. National surveillance of spotted fever group 
rickettsioses in the United States, 2008–2012. Am J Trop 
Med Hyg. 2016 Jan 6;94(1):26–34. [PMID: 26324732]
Portillo A et al. Rickettsioses in Europe. Microbes Infect. 2015 
Nov–Dec;17(11-12):834–8. [PMID: 26384814]
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OTHER RICKETTSIAL & RICKETTSIAL-
 
LIKE DISEASES
1. Ehrlichiosis & Anaplasmosis
 
»
Infection of monocyte or granulocyte by tick-
borne gram-negative bacteria.
 
»
Nine-day incubation period; clinical disease 
ranges from asymptomatic to life-threatening.
 
»
Malaise, nausea, fever, and headaches.
 
»
US cases are largely in elderly white men in the 
summer.
 
»
Excellent response to therapy with tetracyclines.
 
»
Human ehrlichiosis and anaplasmosis are endemic in the 
Ehrlichia chaffeensis
 (Table 32–3), the most common 
species infecting humans, is seen primarily in the south-
central United States (especially Arkansas, Missouri, and 
Oklahoma). 
 causes human granulocytic 
ehrlichiosis similar to anaplasmosis and constitutes almost 
10% of ehrlichiosis cases; most cases in the United States 
are reported from the Midwest and Southeast. New species 
of 
Ehrlichia
 referred to as 
Ehrlichia muris-
like, are seen in 
the upper Midwestern United States. Human granulocytic 
anaplasmosis is caused by 
Anaplasma phagocytophilum;
 
most cases in the United States are reported from Minnesota 
and Wisconsin.
In North America, the major tick-borne rickettsial dis
-
ease vectors for these pathogens are (1) the Lone Star tick 
(
Amblyomma americanus
), which is the vector for 
 
E chaffeensis
 and 
E ewingii
; (2) the black-legged tick 
(Ixodes 
scapularis),
 which is a vector for 
B burgdorferi
 (Lyme dis
-
ease), 
Babesia microti
 (babesiosis), and 
A phagocytophi
-
lum
  (anaplasmosis), and a possible vector for 
Ehrlichia 
muris
-like agent; (3) Western black-legged tick (
Ixodes 
pacificus
), which is a vector for 
A phagocytophilum
 along 
the Pacific coast of the United States. The principal reser
-
voirs for human monocytic ehrlichiosis and human granu
-
locytic anaplasmosis are the white tail deer and the 
white-footed mouse, respectively. Other mammals are 
implicated as well. Transfusion-transmitted anaplasmosis 
have been reported.
CDC reports indicate that the incidence of both human 
monocytic and granulocytic ehrlichiosis are increasing; 
cases are reportable to local and state health departments. 
Because more than one agent may coexist in the same area, 
cases of human ehrlichiosis and anaplasmosis may be 
reported as “human ehrlichiosis/anaplasmosis undeter
-
mined” in the absence of species identification.
The case fatality rate is 1% with 
and 0.3% among cases of human anaplasmosis. Contrary to 
earlier reports, most recent cases of 
E ewingii
 infection 
have occurred among immunocompetent patients and no 
deaths have been reported.
 
»
Clinical disease of human monocytic ehrlichiosis ranges 
from mild to life-threatening. Typically, after a 1- to 2-week 
incubation period and a prodrome consisting of malaise, 
rigors, and nausea, high fever and headache develop. A 
pleomorphic rash may occur. Presentation in immunosup
-
pressed patients (including transplant patients) and older 
patients tends to be more severe. Rare serious sequelae 
include acute respiratory failure and ARDS; neurologic 
complications, the most common being meningoencepha
-
litis and aseptic meningitis; acute kidney disease (which 
may mimic thrombotic thrombocytopenic purpura); 
hemophagocytic syndrome, and multiorgan failure.
The clinical manifestations of human granulocytic 
ehrlichiosis and anaplasmosis are similar to those seen 
with human monocytic ehrlichiosis. Rash, however, is 
infrequent. If a rash is present, coinfection with other tick-
borne diseases or an alternative diagnosis should be sus
-
pected. Persistent fever and malaise are reported to occur 
for 2 or more years.
Coinfection with anaplasmosis and Lyme disease or 
babesiosis may occur, but the clinical manifestations 
(including fever and cytopenias) are more severe with ana

-
plasmosis than with Lyme disease. A spirochete, 
Borrelia 
miyamotoi
, may mimic anaplasmosis in its clinical 
Diagnosis can be made by the history of tick exposure fol
-
lowed by a characteristic clinical presentation. Leukopenia, 
absolute lymphopenia, thrombocytopenia, and transami
-
nitis occur often. Thrombocytopenia occurs more often 
than leukopenia in human granulocytic ehrlichiosis. 
Examination of peripheral blood with Giemsa stain may 
reveal characteristic intraleukocytic vacuoles (morulae) in 
up to 20% of patients. An indirect fluorescent antibody 
assay is available through the CDC and requires acute and 
convalescent sera. A PCR assay can be helpful for making 
the diagnosis early in the disease course. PCR assay is most 
sensitive in the first week of illness and can be used as a 
confirmatory test.
 
»
Treatment for human  ehrlichiosis  and anaplasmosis is 
with doxycycline, 100 mg twice daily (orally or intrave
-
nously) for 10–14 days or until 3 days of defervescence. 
Rifampin is an alternative in pregnant women. Treatment 
should not be withheld while awaiting confirmatory serol
-
ogy when suspicion is high. Lack of clinical improvement 
and defervescence 48 hours after doxycycline initiation 
suggests an alternate diagnosis. Some patients may con
-
tinue to have headache, weakness, and malaise for weeks 
despite adequate treatment. Tick control is the essence of 
prevention.
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Biggs HM et al. Diagnosis and management of tickborne rickett
-
sial diseases: Rocky Mountain spotted fever and other spotted 
fever group rickettsioses, ehrlichioses, and anaplasmosis—
United States. MMWR Recomm Rep. 2016 May 13;65(2): 
 
1–44. [PMID: 27172113]
Dahlgren FS et al. Undetermined human ehrlichiosis and ana
-
plasmosis in the United States, 2008–2012: a catch-all for 
passive surveillance. Am J Trop Med Hyg. 2016 Feb;94(2): 
299–301. [PMID: 26621564]
2. Q Fever
 
»
Exposure to sheep, goats, cattle, or their products; 
some infections are laboratory acquired.
 
»
Acute or chronic febrile illness: headache, cough, 
prostration, and abdominal pain.
 
»
Pneumonitis, hepatitis, or encephalopathy; less 
often, endocarditis, vascular infections, or chronic 
 
»
A common cause of culture-negative endocarditis.
 
»
Q fever, a reportable and significantly underestimated dis
-
ease in the United States, is caused by the gram-negative 
intracellular coccobacillus 
. 
Coxiella
 infec
-
tions occur globally, mostly in cattle, sheep, and goats, in 
which they cause mild or subclinical disease (Table 32–3). 
In these animals, reactivation of the infection occurs dur
-
ing pregnancy and causes abortions or low birth weight 
offspring. 
Coxiella
 is resistant to heat and drying and 
remains infective in the environment for months.
Human infection occurs via inhalation of aerosolized 
bacteria (in dust or droplets) from feces, urine, milk, or 
products of conception of infected animals. Ingestion and 
skin penetration are other recognized routes of transmis
-
sion. A major outbreak in the Netherlands during 
2007–2010 was thought to be due inhalation of aborted 
cattle products of conception associated with changes in 
breeding practices. There is a known occupational risk for 
animal handlers, slaughterhouse workers, veterinarians, 
laboratory workers, and other workers exposed to animal 
products. In the United States, over 60% of cases do not 
report an exposure to potentially infectious animals, but 
cases are more than twice as likely as non-cases to report 
drinking raw milk.
Human-to-human transmission does not seem to 
occur, but maternal-fetal infection can occur.
 
»
Asymptomatic infection is common. For the remaining 
cases, a febrile illness develops after an incubation period 
of 2–3 weeks, usually accompanied by headache, relative 
bradycardia, prostration, and muscle pains. The clinical 
course may be acute, chronic (duration 6 months or lon
-
ger), or relapsing. Pneumonia and granulomatous hepatitis 
are the predominant manifestations in the acute form, 
whereas other less common manifestations include skin 
rashes (maculopapular or purpuric), fever of unknown 
origin, myocarditis, pericarditis, aortic aneurysms, aseptic 
meningitis, encephalitis, orchitis, iliopsoas abscess, spon
-
dylodiscitis, tenosynovitis, granulomatous osteomyelitis 
(more often seen in children), and regional (mediastinal) 
or diffuse lymphadenopathies.
It has been recommended that the term “chronic Q 
fever” be abandoned to avoid confusion and be replaced 
with “persistent focalized infections” . The most common 
presentation in patients with persistent focalized infections 
is culture-negative endocarditis. Risk factors for endocar
-
ditis are the immunocompromised state, having preexist
-
ing valvular conditions, male sex, and age above 40 years. 
Valvular prosthesis (mechanical or bioprosthesis) repre
-
sents the most important risk factor. The clinical manifes
-
tations of endocarditis are nonspecific with fever, night 
sweats, and weight loss. Sudden cardiac insufficiency, 
stroke, or other embolic and mycotic aneurysms can also 
develop. Vascular infections, particularly of the aorta 
(causing mycotic aneurysms) and of graft prostheses, are

(causing mycotic aneurysms) and of graft prostheses, are 
the second most common presentation and are associated 
with a high mortality (25%). A post–Q fever chronic 
fatigue syndrome (1 year after acute infection with chronic 
symptoms) is controversial and of unknown pathophysiol
-
ogy. Cognitive behavioral therapy is effective in reducing 
fatigue severity in patients with Q fever fatigue syndrome; 
long-term treatment with doxycycline has not been shown 
to be effective.
New infection or reactivation of Q fever can occur in 
pregnant women and is associated with spontaneous abor
-
tions, intrauterine growth retardation, intrauterine fetal 
death, and premature delivery. 
C burnetii
 infection during 
the first trimester can cause oligohydramnios.
Laboratory examination during the acute phase may show 
elevated liver biochemical tests and occasional leukocyto
-
sis. Patients with acute Q fever usually produce antibodies 
to 
C burnetii
 phase II antigen. A fourfold rise between 
acute and convalescent sera by indirect immunofluores
-
cence is diagnostic of the infection. Real-time PCR for 
 
C burnetii
 DNA is helpful only in early diagnosis of Q fever. 
C burnetii
 DNA becomes undetectable in serum as sero
-
logic responses develop. The positive predictive value of 
antibodies to phase II antigens in acute disease is at most 
65%. Diagnostic tests using Immuno-PCR and combining 
PCR with ELISA improve the sensitivity and specificity 
during the first 2 weeks after the onset of symptoms.
While persistent infection can be diagnosed based on 
serologic tests done at 3- and 6-month intervals (with an 
IgG titer against phase I antigen of 1:1600 or greater), the 
sensitivity of such serologies is often low, and it is recom
-
mended that clinical criteria be used for diagnosis. A novel 
automated epifluorescence assay is developed with greater 
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than 95% sensitivity for the detection of phase I antigens in 
persistent infection. 
C burnetii–
specific interferon-gamma, 
interferon-gamma/IL-2 ratio has a sensitivity of 79% and a 
specificity and 97% for the diagnosis of persistent 
Diagnosis of endocarditis is often made at the time of 
valve replacement with PCR of tissue samples. 
C burnetii
 
may also be isolated from affected valves using the shell-
vial technique.
C. Imaging
Radiographs of the chest can show patchy pulmonary infil
-
trates. All patients with acute Q fever should be screened 
for underlying valvular disease with echocardiography. 
Initial imaging and follow-up with serial 18-FDG PET/CT 
scan may be helpful in identifying chronic infection and 
monitoring treatment response.
 
»
Viral, mycoplasmal, and bacterial pneumonias, viral hepa
-
titis, brucellosis, Legionnaire disease, Kawasaki disease, 
tuberculosis, psittacosis, and other animal-borne diseases 
can have similar clinical presentations to Q fever. Q fever 
should be considered in cases of unexplained fevers with 
negative blood cultures in association with embolic or car
-
diac disease. Cases of Q fever can mimic autoimmune 
disease.
 
»
Doxycycline is the most effective drug against 
C burnetii
; 
there are rare reports of doxycycline resistance. Isolates 
remain susceptible to levofloxacin, moxifloxacin, and 
 
to a lesser extent ciprofloxacin. No resistance to 
sulfamethoxazole-trimethoprim is reported to date.
For acute infection, treatment with doxycycline (100 mg 
orally twice daily) for 14 days or at least 3 full days after 
defervescence is recommended. Even in untreated patients, 
the mortality rate is usually low, except when endocarditis 
develops.
There are no clear guidelines on the treatment of persis
-
tent 
C burnetii
 infections. To date, there is no antibiotic 
that has bactericidal effect against 
C burnetii
. Most experts 
recommend a combination oral therapy with doxycycline 
(100 mg twice a day) plus quinolone or rifampin or 
hydroxychloroquine for approximately 18 months for 
native valve endocarditis and 24 months for prosthetic 
valve endocarditis.
Serologic responses can be monitored during and after 
completion of therapy and treatment can be extended in 
the absence of favorable serologic response. The general 
variability of serologic data, however, limits their useful
-
ness and providers usually rely on clinical criteria. Patients 
should be monitored for at least 5 years due to risk of 
relapse.
For patients with endocarditis, clinical cure is possible 
without valve replacement. Heart valve replacement is not 
associated with better survival, except in the group of 
patients with a valvular prosthesis. Given the difficulty in 
treating endocarditis, transthoracic echocardiography is 
recommended to screen for predisposing valvulopathy in 
all patients with acute Q fever, and the same therapy for 
 
1 year should be offered in the presence of valvulopathy. In 
addition, patients undergoing routine valve surgery should 
have routine Q fever serologies in endemic countries and 
appropriate treatment if tests are positive for Q fever.
All infected pregnant women should be given long-
term trimethoprim-sulfamethoxazole (320/1600 mg orally 
for the duration of pregnancy, but not beyond 32 weeks’ 
gestation) to prevent the obstetric complications.
In retrospective studies, an increased risk of diffuse 
B-cell lymphoma and follicular lymphoma was found in 
patients with Q fever compared with the general population. 
Patients with persistent focalized infections were at higher 
risk for lymphadenitis and progression to lymphoma.
 
»
Prevention is based on detection of the infection in live
-
stock, reduction of contact with infected and parturient 
animals or contaminated dust; special care when working

»
-
animals or contaminated dust; special care when working 
with animal tissues; and effective pasteurization of milk. 
No vaccine is approved for use in the United States, 
although a whole-cell Q fever vaccine, with a 5-year effi
-
cacy of greater than 95%, is available in Australia for per
-
sons with high-risk exposures.
The organism is highly transmissible to laboratory 
workers and culture techniques require a biosafety level 3 
setting. 
C burnetii
 is a category B bioterrorism agent. In the 
setting of a bioterrorist attack, postexposure prophylaxis 
with doxycycline 100 mg orally twice a day for 5–7 days 
should be administered within 8–12 days of exposure. 
Pregnant women may take trimethoprim-sulfamethoxa
-
zole as an alternative.
Eldin C et al. From Q fever to 
 infection: a para
-
digm change. Clin Microbiol Rev. 2017 Jan;30(1):115–90. 
[PMID: 27856520]
Keijmel SP et al. Effectiveness of long-term doxycycline treat
-
ment and cognitive-behavioral therapy on fatigue severity in 
patients with Q fever fatigue syndrome (Qure Study): a ran
-
domized controlled trial. Clin Infect Dis. 2017 Apr 15; 
64(8):998–1005. [PMID: 28329131]
Million M et al. No such thing as chronic Q fever. Emerg Infect 
Dis. 2017 May;23(5):856–7. [PMID: 28418317]
Sloan-Gardner TS et al. Trends and risk factors for human Q 
fever in Australia, 1991–2014. Epidemiol Infect. 2017 Mar; 
145(4):787–95. [PMID: 27927265]
 
º
KAWASAKI DISEASE
 
»
Fever, conjunctivitis, oral mucosal changes, rash, 
cervical lymphadenopathy, peripheral extremity 
changes.
 
»
Elevated erythrocyte sedimentation rate and 
C-reactive protein levels.
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»
Kawasaki disease is a worldwide multisystem disease. It is 
also known as the “mucocutaneous lymph node syn
-
drome. ” It occurs mainly in children between the ages of 
 
3 months and 5 years, but can occur occasionally in adults 
as well. Kawasaki disease occurs more significantly in 
Asians or native Pacific Islanders. It is an acute, self-
limiting, mucocutaneous vasculitis characterized by the 
infiltration of vessel walls with mononuclear cells and later 
by IgA secreting plasma cells that can result in the destruc
-
tion of the tunica media and aneurysm formation. The 
cause of Kawasaki disease remains unknown. Epidemio
-
logic studies show an increased risk with advanced mater
-
nal age, mother of foreign birth, maternal group B 
streptococcus colonization, and early infancy hospitaliza
-
tion for a bacterial illness. Genetic factors are considered to 
play an important role in the pathogenesis of the disease. A 
recent meta-analysis examining the roles of genetic factors 
identified 23 gene polymorphisms significantly correlated 
with Kawasaki disease susceptibility.
 
»
A clinical diagnosis of classic or “complete” Kawasaki dis
-
ease requires the presence of at least 5 days of fever, usually 
high-grade (over 39
°
C to 40
°
C) and four of the following 
five criteria: (1) bilateral nonexudative conjunctivitis 
(begins shortly after the onset of fever), (2) oral changes 
(erythema and cracking of lips, strawberry tongue, ery
-
thema of oral and pharyngeal mucosa, ulcers and pharyn
-
geal exudates are not consistent with Kawasaki disease), (3) 
peripheral extremity changes (erythema and edema of the 
hands and feet in the acute phase, and/or periungual des
-
quamation within 2 to 3 weeks after the onset of fever), (4) 
polymorphous rash, and (5) cervical lymphadenopathy 
(larger than 1.5 cm diameter, usually unilateral, least com
-
mon of the clinical features). Revised case definition 
allowed the diagnosis on day 4 in the presence of more 
than 4 principal clinical criteria, particularly when redness 
and swelling of the hands and feet are present.
A diagnosis of atypical or “incomplete” Kawasaki dis
-
ease could be diagnosed in patients with unexplained fever 
and fewer than four principal criteria if accompanied by 
compatible laboratory or findings of aneurysms detected 
by echocardiography or angiography.
Laboratory findings in the acute phase are typical for 
leukocytosis with neutrophilic predominance, anemia, ele
-
vated erythrocyte sedimentation rate, C-reactive protein. 
High platelet counts are characteristic but occur in the 
second week. N-terminal moiety of B-type natriuretic peptide 
(NT-proBNP), likely indicative of myocardial involvement, 
may be elevated in some patients with Kawasaki disease.
Major complications include arteritis and aneurysms of 
the coronary vessels, occurring in about 25% of untreated 
patients, on occasion causing myocardial infarction. Coro
-
nary complications are more common among patients 
older than 6 years or younger than 1 year of age; males; 
those unresponsive to IVIG, who received a smaller dose of 
IVIG, or did not receive treatment within 10 days of symp
-
tom onset. Other cardiac complications include (1) 
myocarditis, which can occur during the acute stage; (2) 
left ventricular dysfunction, which usually normalizes 
promptly with IVIG therapy; and (3) mitral regurgitation, 
which occurs early and does not appear to persist. Nonin
-
vasive diagnosis of coronary complications can be made 
with CT coronary angiography (the most sensitive test), 
magnetic resonance angiography, or transthoracic echocar
-
diography (advocated for early screening). Kawasaki shock 
syndrome is a complication, with an estimated incidence of 
7%, possibly caused by decrease in peripheral vascular 
resistance, myocarditis with or without myocardial isch
-
emia, and capillary leakage. The administration of IVIG

-
emia, and capillary leakage. The administration of IVIG 
has been shown to improve left ventricular function. 
Kawasaki disease is a systemic disease that affects medium-
sized arteries and multiple organs, causing elevations in 
serum transaminases, interstitial pneumonitis, abdominal 
pain, vomiting, diarrhea, gallbladder hydrops, pancreatitis, 
lymphadenopathy,  hypoalbuminemia, and pyuria. CSF 
pleocytosis with a mononuclear cell predominance, normal 
glucose levels, and protein levels is seen in one-third of 
children who undergo lumbar puncture.
Other diseases with similar presentation that should be 
considered, include measles in unimmunized children as 
well as other viral infections, such as adenovirus, scarlet 
fever, and toxic shock syndrome; rickettsial infections; or 
leptospirosis and drug hypersensitivity reactions.
 
»
All patients meeting the diagnostic criteria for Kawasaki 
disease (complete and incomplete), including patients with 
recurrent Kawasaki disease should be treated as soon as the 
diagnosis is suspected to reduce inflammation and arterial 
damage.
Single dose of IVIG should be given in the first 10 days 
of the illness. Patients in whom the diagnosis was made 
later than the tenth day, they might still benefit from IVIG 
treatment if they have elevated inflammatory markers 
(erythrocyte sedimentation rate or C-reactive protein), with 
persistent fever or have coronary artery aneurysms. When 
IVIG treatment is not given, coronary artery aneurysms 
occur in one of five 5 children. It is important to note that 
even when treated with IVIG within the first 10 days of ill
-
ness, coronary artery aneurysms can still develop in 5% of 
patients. Rare cases of aseptic meningitis are reported with 
IVIG. Coombs-positive hemolytic anemia, especially in 
individuals with AB blood type and anaphylactic reactions 
to immunoglobulins with selective IgA deficiency are other 
complications associated with IVIG administration.
Although aspirin does not lower the frequency of devel
-
opment of coronary abnormalities, it has important anti-
inflammatory activity and antiplatelet activity. Concomitant 
aspirin with IVIG should be started at 80–100 mg/kg/day 
orally (divided into four doses and not exceeding 4 g/day) 
until the patient is afebrile for 48 hours and then reduced 
to 3–5 mg/kg/day until markers of acute inflammation 
normalize. Since ibuprofen antagonizes the irreversible 
platelet inhibition induced by aspirin, it should be avoided.
The use of corticosteroids for children with Kawasaki 
disease is controversial. According to the most recent 
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published guidelines by the American Heart Association, 
single-dose pulse methylprednisolone should not be used 
routinely for patients with Kawasaki disease. A course of 
corticosteroid therapy with tapering over 2–3 weeks could 
be considered in addition to IVIG and aspirin for patients 
at high-risk for not responding to IVIG.
Resistant Kawasaki disease, defined as having recrudes
-
cent or persistent fever at least 36 hours after the end of the 
first IVIG infusion and no other source of fever is found, 
develops in about 10–20% of patients. Options for refrac
-
tory cases include a second dose of IVIG, high-dose pulse 
corticosteroids over 3 days with or without a subsequent 
oral taper course, longer oral tapering course of corticoste
-
roids over 2–3 weeks together with IVIG and aspirin, inf
-
liximab, and cyclosporine. Other immunomodulatory 
monoclonal antibody therapy and cytotoxic agents, or 
(rarely) plasma exchange should be considered only in 
highly refractory cases in which other therapy has failed.
The most common serious complication in the acute 
phase is thrombotic occlusion of a coronary artery aneu
-
rysm leading to myocardial infarction or sudden death. An 
echocardiogram is recommended within 1–2 weeks and 
4–6 weeks after treatment  for uncomplicated patients. 
More frequent imaging is recommended for patients with 
significant and evolving coronary artery abnormalities. 
Anticoagulation with warfarin or low-molecular-weight 
heparin is indicated, along with aspirin, in patients with 
rapidly expanding coronary artery aneurysms. Aspirin, a 
second antiplatelet agent, and anticoagulation with warfa
-
rin or low-molecular-weight heparin may be considered 
for patients with large or giant aneurysms (at least 8 mm) 
and a recent history of coronary artery thrombosis. If myo
-
cardial infarction occurs, therapy with thrombolytics, per
-
cutaneous coronary intervention, coronary artery bypass 
grafts, and even cardiac transplantation should be consid
-
ered. Manifestations of coronary artery aneurysms can 
occur as late as in the third or fourth decade of life with a 
study showing a prevalence of 5% coronary sequelae from 
Kawasaki disease among young adults evaluated with 
 
»
Prognosis
The reported recurrence rate is 3% in one study from 
Japan. The highest risk of recurrence occurs in the first 
 
2 years after the first episode.
The mortality peaks between 15 and 45 days after the 
onset of fever, at the time of coronary artery vasculitis, 
thrombocytosis, and a hypercoagulable state.
On the long-term, the risk for clinical cardiac events in 
patients with no coronary artery abnormalities is similar to 
the general population. For patients in whom coronary 
artery abnormalities developed, the risk for cardiac com
-
plications, such as thrombosis, stenosis, myocardial infarc
-
tion, and death, ranges between 1% and 48%. The AHA 
recommends risk stratification based on the assessment of 
coronary luminal dimensions by echocardiogram, under 
cardiologic supervision. The frequency of clinical follow-
up, diagnostic testing, reproductive counseling, indications 
for medical therapy (beta-blockers, statins) and thrombo
-
prophylaxis (aspirin and anticoagulation) depends on the 
individual’s risk assessment.
 
»
All cases of Kawasaki disease merit referral to specialists.
McCrindle BW et al. Diagnosis, treatment, and long-term man
-
agement of Kawasaki disease: a scientific statement for health 
professionals from the American Heart Association. Circula
-
tion. 2017 Apr 25;135(17):e927–99. [PMID: 28356445]
Newburger JW . Kawasaki disease: medical therapies. Congenit 
Heart Dis. 2017 Sep;12(5):641–3. [PMID: 28580631]
Newburger JW . Kawasaki disease: state of the art. Congenit 
Heart Dis. 2017 Sep;12(5):633–5. [PMID: 28580712]
Xie X et al. The roles of genetic factors in Kawasaki disease: a

Xie X et al. The roles of genetic factors in Kawasaki disease: a 
systematic review and meta-analysis of genetic association 
studies. Pediatr Cardiol. 2018 Feb;39(2):207–25. [PMID: 
29098351]
Y oun Y et al. Infliximab as the first retreatment in patients with 
Kawasaki disease resistant to initial intravenous immuno
-
globulin. Pediatr Infect Dis J. 2016 Apr;35(4):457–9. [PMID: 
26673981]
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Bryn A. Boslett, MD 
 
Bacterial & Chlamydial 
33
with circumoral pallor, and the tongue is coated with 
enlarged red papillae (strawberry tongue).
Leukocytosis with neutrophil predominance is common. 
Throat culture onto a single blood agar plate has a 
sensitivity of 80–90%. Rapid diagnostic tests based on 
detection of streptococcal antigen are slightly less sensitive 
than culture. Clinical criteria, such as the Centor criteria, 
are useful for identifying patients in whom a rapid antigen 
test or throat culture is indicated. Patients who meet two or 
more of these criteria merit further testing. When three of 
the four are present, laboratory sensitivity of rapid antigen 
testing exceeds 90%. When only one criterion is present, 
streptococcal pharyngitis is unlikely. In high-prevalence 
settings or if clinical suspicion for streptococcal pharyngi
-
tis is high, a negative antigen test or culture should be 
confirmed by a follow-up culture.
 
»
Suppurative complications include sinusitis, otitis media, 
mastoiditis, peritonsillar abscess, and cervical lymphadenitis.
Nonsuppurative complications are rheumatic fever and 
glomerulonephritis. Rheumatic fever may follow recurrent 
episodes of pharyngitis beginning 1–4 weeks after the 
onset of symptoms. Glomerulonephritis follows a single 
infection with a nephritogenic strain of streptococcus 
group A (eg, types 4, 12, 2, 49, and 60), more commonly on 
the skin than in the throat, and begins 1–3 weeks after the 
onset of the infection. These complications are more com
-
mon in children.
 
»
Streptococcal sore throat resembles (and cannot be reliably 
distinguished clinically from) pharyngitis caused by viruses 
such as adenoviruses, Epstein-Barr virus, or other bacteria 
such as 
 and 
Arcanobacterium 
haemolyticum
 (which also may cause a rash). Pharyngitis 
and lymphadenopathy are common findings in acute HIV 
infection. Generalized lymphadenopathy, splenomegaly, 
atypical lymphocytosis, and a positive serologic test 
 
º
INFECTIONS CAUSED BY GRAM-POSITIVE 
BACTERIA
STREPTOCOCCAL INFECTIONS
1. Pharyngitis
 
»
Abrupt onset of sore throat, fever, malaise, 
nausea.
 
»
Throat red and edematous, with or without exu
-
date; cervical nodes tender.
 
»
Diagnosis confirmed by culture of throat.
 
»
Group A beta-hemolytic streptococci 
(Streptococcus 
pyogenes)
 are the most common bacterial cause of pharyn
-
gitis. Transmission occurs by droplets of infected secre
-
tions. Group A streptococci producing erythrogenic toxin 
may cause scarlet fever in susceptible persons.
 
»
“Strep throat”
 is characterized by a sudden onset of fever, 
sore throat, pain on swallowing, tender cervical adenopa
-
thy, malaise, and nausea. The pharynx, soft palate, and 
tonsils are red and edematous. There may be a purulent 
exudate. The Centor clinical criteria for the diagnosis of 
streptococcal pharyngitis are temperature greater than 
38
°
C, tender anterior cervical adenopathy, lack of a cough, 
and pharyngotonsillar exudate.
The rash of 
scarlet fever
 (also called scarletina) is dif
-
fusely erythematous, resembles a sunburn, and superim
-
posed fine red papules give the skin a sandpaper 
consistency; it is most intense in the groin and axillas. It 
blanches on pressure, may become petechial, and fades in 
2–5 days, leaving a fine desquamation. The face is flushed, 
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distinguish mononucleosis from streptococcal pharyngitis. 
Diphtheria is characterized by a pseudomembrane; oropha
-
ryngeal candidiasis shows white patches of exudate and less 
erythema; and necrotizing ulcerative gingivostomatitis 
(Vincent fusospirochetal gingivitis or stomatitis) presents 
with shallow ulcers in the mouth. 
Chlamydia trachomatis,
 and primary herpes simplex virus 
should be considered in those with risk factors. Retropha
-
ryngeal abscess or bacterial epiglottitis should be considered 
when odynophagia and difficulty in handling secretions are 
present and when the severity of symptoms is disproportion
-
ate to findings on examination of the pharynx. 
F necrophorum
 
causes pharyngitis at a similar rate as group A beta-hemolytic 
streptococci in adolescents and young adults. 
 
pharyngitis is associated with Lemierre syndrome, suppura
-
tive thrombophlebitis of the internal jugular vein, bactere
-
mia, and metastatic infections. Early recognition and 
treatment of this syndrome is important.
 
»
Treatment
Antimicrobial therapy has a modest effect on resolution of 
symptoms and primarily is administered for prevention of 
complications. Antibiotic therapy can be safely delayed 
until the diagnosis is established on the basis of a positive 
antigen test or culture. Empiric therapy usually is not a cost-
effective approach to the management of most adults with 
pharyngitis because the prevalence of streptococcal pharyn
-
gitis is likely to be no more than 10–20% in typical clinical 
settings. The positive predictive value of clinical criteria is 
low. Since macrolides are not reliable against 
 
infection, adolescents or young adults with pharyngitis and 
unconfirmed streptococcal infection should be given peni
-
cillin or amoxicillin preferentially at the doses listed below. 
If the pharyngitis does not resolve quickly, symptoms 
worsen, or unilateral neck swelling develops, clinicians 
should consider suppurative complications such as periton
-
sillar abscess and Lemierre syndrome.
A. Benzathine Penicillin G
Benzathine penicillin G, 1.2 million units intramuscularly 
as a single dose, is optimal therapy.
B. Penicillin VK
Penicillin VK, 250 mg orally four times daily or 500 mg 
orally twice daily for 10 days, is effective.
C. Amoxicillin
Amoxicillin, 1000 mg orally once daily or 500 mg orally 
twice daily for 10 days, is another option.
D. Cephalosporins
Cephalexin, 500 mg orally twice daily for 10 days, cefdinir, 
300 mg orally twice daily for 5–10 days or 600 mg orally 
once daily for 10 days, cefadroxil, 1000 mg orally once daily 
for 10 days, and cefpodoxime, 100 mg orally twice daily for 
5–10 days, should be reserved for penicillin-allergic patients 
who do not have immediate-type hypersensitivity.
E. Macrolides
Erythromycin, 500 mg orally four times a day, or azithro
-
mycin, 500 mg orally once daily for 5 days, is an alternative 
for the penicillin-allergic patient. Macrolides are less effec
-
tive than penicillins and are considered second-line agents. 
Macrolide-resistant strains almost always are susceptible to 
clindamycin, a suitable alternative to penicillins; a 10-day 
course of 300 mg orally three times daily is effective.
 
»
Effectively controlling rheumatic fever depends on identi
-
fication and treatment of primary streptococcal infection 
and secondary prevention of recurrences. Patients who 
have had rheumatic fever should be treated with a continu
-
ous course of antimicrobial prophylaxis for at least 5 years. 
Effective regimens are erythromycin, 250 mg orally twice 
daily, or penicillin G, 500 mg orally daily.
 
»
Patients with peritonsillar or retropharyngeal abscess 
should be referred to an otolaryngologist.
 
»
•	
Odynophagia resulting in dehydration.
•	
Suspected or known epiglottitis.

»
•	
•	
Harris AM et al. Appropriate antibiotic use for acute respiratory 
tract infection in adults: advice for high-value care from the 
American College of Physicians and the Centers for Disease 
Control and Prevention. Ann Intern Med. 2016 Mar 15; 
Shulman ST et al. Clinical practice guideline for the diagnosis 
and management of group A streptococcal pharyngitis: 
2012 update by the Infectious Diseases Society of America. 
Clin Infect Dis. 2012 Nov 15;55(10):1279–82. [PMID: 
23091044]
van Driel ML et al. Different antibiotic treatments for group A 
streptococcal pharyngitis. Cochrane Database Syst Rev. 2016 
Sep 11;9:CD004406. [PMID: 27614728]
2. Streptococcal Skin Infections
Group A beta-hemolytic streptococci are not normal skin 
flora. Streptococcal skin infections result from colonization 
of normal skin by contact with other infected individuals or 
by preceding streptococcal respiratory infection.
 
»
Erysipelas
 is a painful superficial cellulitis that frequently 
involves the face. It is well demarcated from the surround
-
ing normal skin. It affects skin with impaired lymphatic 
drainage, such as edematous lower extremities or wounds 
(Figure 33–1).
Impetigo
 is a focal, vesicular, pustular lesion with a 
thick, amber-colored crust with a “stuck-on” appearance 
(see Chapter 6).
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Cultures obtained from a wound or pustule are likely to 
grow group A streptococci. Blood cultures are occasionally 
positive.
 
»
Treatment
Parenteral antibiotics are indicated for patients with facial 
erysipelas or evidence of systemic infection. Penicillin, 
2 million units intravenously every 4 hours, is the drug of 
choice. However, staphylococcal infections may at times be 
difficult to differentiate from streptococcal infections. 
 
▲
Figure 33–1.
 
Erysipelas of the central face that 
responded well to oral antibiotic therapy. 
permission, from Ernesto Samano Ayon, MD in Usatine RP , 
Table 33–1.
 
Empiric treatment of common skin and soft tissue infections (SSTIs).
SSTI Type
Common Pathogens
Treatment
Purulent (abscess, 
furuncle, carbuncle, 
cellulitis with 
purulence)
Incision and drainage is the primary treatment
Consider the addition of antibiotics in select situations
1
Oral antibiotic regimens
Cephalexin 500 mg four times daily 
or
 dicloxacillin 500 mg four times daily
Clindamycin 300–450 mg three or four times daily
2
 
or
 one double-strength tablet of 
trimethoprim-sulfamethoxazole twice daily
2
 
or
 doxycycline 100 mg twice daily
2
Intravenous antibiotic regimens
3
Cefazolin 1 g three times daily 
or
 nafcillin 1–2 g four to six times daily
Vancomycin 1 g twice daily
2
 
or
 daptomycin 4 mg/kg once daily
2
Nonpurulent (cellulitis, 
erysipelas)
Beta-hemolytic 
streptococci 
(
S aureus
 less likely)
or
2
 
or
 amoxicillin 875 mg twice daily 
plus
 one double-strength tablet of trimethoprim-sulfamethoxazole twice daily
2
3
or
2
 
or
1
Antibiotic therapy should be given in addition to incision and drainage for purulent SSTI if the patient has any of the following: severe or 
extensive disease, symptoms and signs of systemic illness, purulent cellulitis/wound infection, comorbidities and extremes of age, abscess 
in area difficult to drain or on face/hand, associated septic phlebitis, or lack of response to incision and drainage alone.
2
Regimens with activity against methicillin-resistant 
S aureus
.
3
Other regimens approved by the FDA for treatment of complicated skin and soft tissue infections include tigecycline at 100 mg 
intravenously once followed by 50 mg intravenously twice a day, ceftaroline at 600 mg twice a day for 7–14 days, dalbavancin at 1 g 
intravenously on day 1 and then 500 mg intravenously on day 8, oritavancin as a single intravenous dose of 1200 mg, and telavancin at 
10 mg/kg intravenously once daily for 7–14 days.
In practice, initial therapy for patients with risk factors for 
 (eg, injection drug use, diabetes mel
-
litus, wound infection) should cover this organism. Either 
nafcillin, 1–2 g every 4–6 hours intravenously, or cefazolin, 
1 g intravenously or intramuscularly every 8 hours, is a 
reasonable choice. In the patient at risk for methicillin-
resistant 
S aureus
 infection or with a serious penicillin 
allergy (ie, anaphylaxis), vancomycin, 1 g intravenously 
every 12 hours, or daptomycin 4 mg/kg intravenously daily, 
should be used (Table 33–1).
Patients who do not require parenteral therapy may be 
treated with amoxicillin, 500 mg three times daily or 
875 mg twice daily for 7–10 days. A first-generation oral 
cephalosporin, eg, cephalexin, 500 mg four times daily, or 
clindamycin, 300 mg orally three times daily, is an alter
-
native to amoxicillin. In patients with recurrent cellulitis 
of the leg, maintenance therapy (for at least 1 year) with

-
of the leg, maintenance therapy (for at least 1 year) with 
penicillin, 250 mg orally twice daily, may reduce relapses.
Cranendonk DR et al. Cellulitis: current insights into patho
-
physiology and clinical management. Neth J Med. 2017 Nov; 
75(9):366–78. [PMID: 29219814]
-
3. Other Group A Streptococcal Infections
Arthritis, pneumonia, empyema, endocarditis, and necro
-
tizing fasciitis are relatively uncommon infections that may 
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be caused by group A streptococci. Toxic shock–like syn
-
drome also occurs.
Arthritis
 generally occurs in association with cellulitis. 
In addition to intravenous therapy with penicillin G, 
2 million units every 4 hours (or cefazolin or vancomycin 
in doses recommended above for penicillin-allergic 
patients), frequent percutaneous needle aspiration should 
be performed to remove joint effusions. Open surgical 
drainage may be necessary in many cases.
Pneumonia
 and 
empyema
 often are characterized by 
extensive tissue destruction and an aggressive, rapidly pro
-
gressive clinical course associated with significant morbid
-
ity and mortality. High-dose penicillin and chest tube 
drainage are indicated for treatment of empyema. Vanco
-
mycin is an acceptable substitute in penicillin-allergic 
patients.
Group A streptococci can cause 
endocarditis
 in rare 
instances. Endocarditis should be treated with 4 million 
units of penicillin G intravenously every 4 hours for 
4–6 weeks. Vancomycin, 1 g intravenously every 12 hours, 
is recommended for persons allergic to penicillin.
Necrotizing fasciitis
 is a rapidly spreading infection 
involving the fascia of deep muscle. The clinical findings at 
presentation may be those of severe cellulitis, but the pres
-
ence of systemic toxicity and severe pain, which may be 
followed by anesthesia of the involved area due to destruc
-
tion of nerves as infection advances through the fascial 
planes, is a clue to the diagnosis. Surgical exploration is 
mandatory when the diagnosis is suspected. Early and 
extensive debridement is essential for survival.
Any streptococcal infection—and necrotizing fasciitis 
in particular—can be associated with 
streptococcal toxic 
shock syndrome
, typified by invasion of skin or soft tis
-
sues, acute respiratory distress syndrome, and kidney 
failure. Persons who are very young, older adults, and those 
with underlying medical conditions are at particularly high 
risk for invasive disease. Bacteremia occurs in most cases. 
Skin rash and desquamation may not be present. Mortality 
rates can be up to 80%. The syndrome is due to elaboration 
of pyrogenic erythrotoxin (which also causes 
), 
a superantigen that stimulates massive release of inflam
-
matory cytokines believed to mediate the shock. A beta-
lactam, such as penicillin, remains the drug of choice for 
treatment of serious streptococcal infections, but clindamy
-
cin, which is a potent inhibitor of toxin production, should 
also be administered at a dose of 600 mg every 8 hours 
intravenously for invasive disease, especially in the pres
-
ence of shock. Intravenous immune globulin can be con
-
sidered for streptococcal toxic shock syndrome for possible 
therapeutic benefit from specific antibody to streptococcal 
exotoxins in immune globulin preparations. Many dosing 
regimens have been used, including 0.5 g/kg once daily for 
5–6 days or a single dose of 2 g/kg with a repeat dose at 
48 hours if the patient remains unstable.
Outbreaks of invasive disease have been associated with 
colonization by invasive clones that can be transmitted to 
close contacts who, though asymptomatic, may be a reser
-
voir for disease. Tracing contacts of patients with invasive 
disease is controversial.
Kadri SS et al. Impact of intravenous immunoglobulin on sur
-
vival in necrotizing fasciitis with vasopressor-dependent 
shock: a propensity score-matched analysis from 130 US 
hospitals. Clin Infect Dis. 2017 Apr 1;64(7):877–85. [PMID: 
28034881]
Nelson GE et al. Epidemiology of invasive group A streptococcal 
infections in the United States, 2005–2012. Clin Infect Dis. 
2016 Aug 15;63(4):478–86. [PMID: 27105747]
Stevens DL et al. Necrotizing soft-tissue infections. N Engl J 
Med. 2017 Dec 7;377(23):2253–65. [PMID: 29211672]
4. Non–Group A Streptococcal Infections
Non–group A hemolytic streptococci (eg, groups B, C,

Non–group A hemolytic streptococci (eg, groups B, C, 
and G) produce a spectrum of disease similar to that of 
group A streptococci. The treatment of infections caused 
by these strains is similar to group A streptococci.
Group B streptococci are an important cause of sepsis, 
bacteremia, and meningitis in the neonate. Antepartum 
screening to identify carriers and peripartum antimicrobial 
prophylaxis are recommended in pregnancy. This organ
-
ism, part of the normal vaginal flora, may cause septic 
abortion, endometritis, or peripartum infections and, less 
commonly, cellulitis, bacteremia, and endocarditis in 
adults. Treatment of infections caused by group B strepto
-
cocci is with either penicillin or vancomycin in doses rec
-
ommended for group A streptococci. Because of in vitro 
synergism, some experts recommend the addition of low-
dose gentamicin, 1 mg/kg every 8 hours.
Viridans streptococci, which are nonhemolytic or alpha-
hemolytic (ie, producing a green zone of hemolysis on blood 
agar), are part of the normal oral flora. Although these 
strains may produce focal pyogenic infection, they are most 
notable as the leading cause of native valve endocarditis.
Group D streptococci include 
Streptococcus gallolyticus 
(bovis)
 and the enterococci. 
S gallolyticus (bovis)
 is a cause 
of endocarditis in association with bowel neoplasia or cir
-
rhosis and is treated like viridans streptococci.
Baddour LM et al. Infective endocarditis in adults: diagnosis, 
antimicrobial therapy, and management of complications: a 
scientific statement for healthcare professionals from the 
American Heart Association. Circulation. 2015 Oct 13; 
132(15):1435–86. Erratum in: Circulation. 2015 Oct 27; 
132(17):e215. [PMID: 26373316]
Bruun T et al. Etiology of cellulitis and clinical prediction of 
streptococcal disease: a prospective study. Open Forum 
Infect Dis. 2015 Nov 25;3(1):ofv181. [PMID: 26734653]
ENTEROCOCCAL INFECTIONS
Two species, 
 and 
, 
are responsible for most human enterococcal infections. 
Enterococci cause wound infections, urinary tract infec
-
tions, bacteremia, and endocarditis. Infections caused by 
penicillin-susceptible strains should be treated with ampicil
-
lin 2 g every 4 hours or penicillin 3–4 million units every 
4 hours; if the patient is penicillin-allergic, vancomycin 
15 mg/kg every 12 hours intravenously can be given. If the 
patient has endocarditis or meningitis, gentamicin 1 mg/kg 
every 8 hours intravenously should be added to the regimen 
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for a duration of 2–3 weeks in order to achieve the bacteri
-
cidal activity that is required to cure these infections. In cases 
of endocarditis, ceftriaxone 2 g every 12 hours may be given 
instead of gentamicin in combination with the ampicillin.
Resistance to vancomycin, penicillin, and gentamicin is 
common among enterococcal isolates, especially 
E faecium;
 
it is essential to determine antimicrobial susceptibility of 
isolates. Infection control measures that may be indicated to 
limit their spread include isolation, barrier precautions, and 
avoidance of overuse of vancomycin and gentamicin. Con
-
sultation with an infectious diseases specialist is strongly 
advised when treating infections caused by resistant strains 
of enterococci. Quinupristin/dalfopristin and linezolid are 
approved by the FDA for treatment of infections caused by 
vancomycin-resistant strains of enterococci. Daptomycin, 
tigecycline, tedizolid, and oritavancin are not approved by 
the FDA for the treatment for vancomycin-resistant strains 
of enterococci, although they are frequently active in vitro.
Quinupristin/dalfopristin is not active against strains of 
E faecalis
 and should be used only for infections caused by 
E faecium
. The dose is 7.5 mg/kg intravenously every 
8–12 hours. Phlebitis and irritation at the infusion site 
(often requiring a central line) and an arthralgia-myalgia 
syndrome are relatively common side effects. Linezolid, an 
oxazolidinone, is active against both 
E faecalis
 and 
E faecium
. The dose is 600 mg twice daily, and both intra
-
venous and oral preparations are available. Its two princi
-
pal side effects are thrombocytopenia and bone marrow 
suppression; however, peripheral neuropathy, optic neuri
-
tis, and lactic acidosis have been observed with prolonged 
use (typically greater than 6 weeks) due to mitochondrial 
toxicity. Emergence of resistance has occurred during 
therapy with both quinupristin/dalfopristin and linezolid.
Britt NS et al. Comparative effectiveness and safety of standard-, 
medium-, and high-dose daptomycin strategies for the treat
-
ment of vancomycin-resistant enterococcal bacteremia 
among Veterans Affairs patients. Clin Infect Dis. 2017 Mar 1; 
64(5):605–13. [PMID: 28011602]
PNEUMOCOCCAL INFECTIONS
1. Pneumococcal Pneumonia
 
»
Productive cough, fever, rigors, dyspnea, early 
pleuritic chest pain.
 
»
Consolidating lobar pneumonia on chest 
 
»
Gram-positive diplococci on Gram stain of 
sputum.
 
»
Pneumococcus is the most common cause of community-
acquired pyogenic bacterial pneumonia. Alcoholism, 
asthma, HIV infection, sickle cell disease, splenectomy, and 
hematologic disorders are predisposing factors. Mortality 
rates remain high in cases of advanced age, multilobar 
disease, hypoxemia, extrapulmonary complications, and 
bacteremia.
 
»
Presenting symptoms and signs include high fever, produc
-
tive cough, occasional hemoptysis, and pleuritic chest pain. 
Rigors may occur initially but are uncommon later in the 
course. Bronchial breath sounds are an early sign.
Pneumococcal pneumonia classically is a lobar pneumonia 
with radiographic findings of consolidation and occasion
-
ally effusion. However, differentiating it from other pneu
-
monias is not possible radiographically or clinically 
because of significant overlap in presentations. Diagnosis 
requires isolation of the organism in culture, although the 
Gram stain appearance of sputum can be suggestive. Spu
-

-
tum and blood cultures, positive in 60% and 25% of cases 
of pneumococcal pneumonia, respectively, should be 
obtained prior to initiation of antimicrobial therapy in 
patients who are admitted to the hospital. A good-quality 
sputum sample (less than 10 epithelial cells and greater 
than 25 polymorphonuclear leukocytes per high-power 
field) shows gram-positive diplococci in 80–90% of cases. 
A rapid urinary antigen test for 
, 
with sensitivity of 70–80% and specificity greater than 
95%, can assist with early diagnosis.
 
»
Parapneumonic (sympathetic) effusion is common and 
may cause recurrence or persistence of fever. These sterile 
fluid accumulations need no specific therapy. Empyema 
occurs in 5% or less of cases and is differentiated from 
sympathetic effusion by the presence of organisms on 
Gram-stained fluid or positive pleural fluid cultures.
Pneumococcal pericarditis is a rare complication that 
can cause tamponade. Pneumococcal arthritis also is 
uncommon. Pneumococcal endocarditis usually involves 
the aortic valve and often occurs in association with men
-
ingitis and pneumonia (sometimes referred to as Austrian 
or Osler triad). Early heart failure and multiple embolic 
events are typical.
 
»
Treatment
Initial antimicrobial therapy for pneumonia is empiric (see 
Table 9–9) pending isolation and identification of the caus
-
ative agent. Once 
 is identified as the infect
-
ing pathogen, any of several antimicrobial agents may be 
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used depending on the clinical setting, community pat
-
terns of penicillin resistance, and susceptibility of the par
-
ticular isolate. Uncomplicated pneumococcal pneumonia 
(ie, arterial PO
2
 greater than 60 mm Hg, no coexisting 
medical problems, and single-lobe disease without signs of 
extrapulmonary infection) caused by penicillin-susceptible 
strains of pneumococcus may be treated on an outpatient 
basis with amoxicillin, 750 mg orally twice daily for 
7–10 days. Cephalosporins including cefpodoxime, 200 mg 
orally twice daily, and cefdinir 300 mg twice daily, may also 
be used. For penicillin-allergic patients, alternatives are 
azithromycin, one 500-mg dose orally on the first day and 
250 mg for the next 4 days; clarithromycin, 500 mg orally 
twice daily for 10 days; doxycycline, 100 mg orally twice 
daily for 10 days; levofloxacin, 750 mg orally for 5 days; or 
moxifloxacin, 400 mg orally for 7–14 days. Patients should 
be monitored for clinical response (eg, less cough, defer
-
vescence within 2–3 days) because pneumococci have 
become increasingly resistant to penicillin and the second-
line agents.
Parenteral therapy is generally recommended for the 
hospitalized patient at least until there has been clinical 
improvement. Aqueous penicillin G, 2 million units intra
-
venously every 4 hours, or ceftriaxone, 1 g intravenously 
every 24 hours, is effective for strains that are penicillin-
susceptible (ie, strains for which the minimum inhibitory 
concentration [MIC] of penicillin is 2 mcg/mL or less for 
non-CNS specimens). For serious penicillin allergy or 
infection caused by a highly penicillin-resistant strain, 
vancomycin, 1 g intravenously every 12 hours, is effective. 
Alternatively, a respiratory fluoroquinolone (eg, levofloxa
-
cin, 750 mg) can be used. The total duration of therapy is 
not well defined but 5 days is appropriate for patients who 
have an uncomplicated infection and demonstrate a good 
clinical response. Corticosteroid use remains controversial 
in community-acquired pneumonia and should not be 
administered routinely.
Pleural effusions developing after initiation of antimicro
-
bial therapy usually are sterile, and thoracentesis need not 
be performed if the patient is otherwise improving. Thora
-
centesis is indicated for an effusion present prior to initia
-
tion of therapy and in the patient who has not responded 
to antibiotics after 3–4 days. Chest tube drainage may be 
required if pneumococci are identified by culture or Gram 
stain, especially if aspiration of the fluid is difficult.
Echocardiography should be done if pericardial effusion 
is suspected. Patients with pericardial effusion who are 
responding to antibiotic therapy and have no signs of tam
-
ponade may be monitored and treated with indomethacin, 
50 mg orally three times daily, for pain. In patients with 
increasing effusion, unsatisfactory clinical response, or evi
-
dence of tamponade, pericardiocentesis will determine 
whether the pericardial space is infected. Infected fluid 
must be drained either percutaneously (by tube placement 
or needle aspiration), by placement of a pericardial window, 
or by pericardiectomy. Pericardiectomy eventually may be 
required to prevent or treat constrictive pericarditis.
Endocarditis should be treated for 4 weeks with 
3–4 million units of penicillin G every 4 hours intrave
-
nously; ceftriaxone, 2 g once daily intravenously; or vanco
-
mycin, 15 mg/kg every 12 hours intravenously. Mild heart 
failure due to valvular regurgitation may respond to medi
-
cal therapy, but moderate to severe heart failure is an indi
-
cation for prosthetic valve implantation, as are systemic 
emboli or large friable vegetations as determined by 
echocardiography.
C. Penicillin-Resistant Pneumococci
Resistance breakpoints for parenterally administered 
penicillin and high-dose oral amoxicillin (2 g twice daily) are

penicillin and high-dose oral amoxicillin (2 g twice daily) are 
as follows: susceptible, penicillin MIC 2 mcg/mL or less; 
intermediate, MIC = 4 mcg/mL; resistant, MIC 8 mcg/mL or 
more. Note, however, that these breakpoints do not apply to 
orally administered penicillin, which are the same as for use 
of penicillin in treatment of meningitis. In cases of pneumo
-
coccal pneumonia where the isolate has a penicillin MIC 
greater than 2 mcg/mL, cephalosporin cross-resistance is 
common, and a non–beta-lactam antimicrobial, such as van
-
comycin, 1 g intravenously every 12 hours or a fluoroquino
-
lone with enhanced gram-positive activity (eg, levofloxacin, 
750 mg intravenously or orally once daily or moxifloxacin, 
400 mg intravenously or orally once daily), is recommended. 
Penicillin-resistant strains of pneumococci may be resistant 
to macrolides, trimethoprim-sulfamethoxazole, and chlor
-
amphenicol, and susceptibility must be documented prior to 
their use. All blood and cerebrospinal fluid isolates should 
still be tested for resistance to penicillin. There has been no 
change to the penicillin susceptibility breakpoint for pneu
-
mococcal isolates causing meningitis, nor any change in 
treatment recommendations.
 
»
See Chapter 30 for discussion of pneumococcal vaccines. 
All patients should have screening for smoking cessation.
 
»
•	
All patients with suspected pneumococcal endocarditis 
or meningitis to an infectious disease specialist.
•	
Extensive disease.
•	
Seriously ill patient with pneumonia, particularly in the 
setting of comorbid conditions (eg, liver disease).
•	
Progression of pneumonia or failure to improve on 
 
»
•	
All patients in whom pneumococcal endocarditis or 
meningitis is suspected or documented should be 
admitted for observation and empiric therapy.
•	
All patients with pneumococcal pneumonia that is mul
-
tilobar or associated with significant hypoxemia.
•	
Failure of outpatient pneumonia therapy, including 
inability to maintain oral intake and medications.
•	
by pneumonia that would benefit from hospitalization.
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Jain S et al; CDC EPIC Study Team. Community-acquired pneu
-
monia requiring hospitalization among U.S. adults. N Engl J 
Med. 2015 Jul 30;373(5):415–27. [PMID: 26172429]
27455166]
Wunderink RG et al. Advances in the causes and management of 
community acquired pneumonia in adults. BMJ. 2017 Jul 10; 
358:j2471. [PMID: 28694251]
2. Pneumococcal Meningitis
 
»
Fever, headache, altered mental status.
 
»
Meningismus.
 
»
cerebrospinal fluid.
 
»
 is the most common cause of meningitis in 
adults. Head trauma with cerebrospinal fluid leaks, sinus
-
itis, and pneumonia may precede it.
 
»
The onset is rapid, with fever, headache, meningismus, and 
altered mentation. Pneumonia may be present. Compared 
with meningitis caused by the meningococcus, pneumo
-
coccal meningitis lacks a rash. Obtundation, focal neuro
-
logic deficits, and cranial nerve palsies are more prominent 
features and may lead to long-term sequelae.
The cerebrospinal fluid typically has greater than 1000 
white blood cells per microliter, over 60% of which are 
polymorphonuclear leukocytes; the glucose concentration 
is less than 40 mg/dL (2.22 mmol/L), or less than 50% of 
the simultaneous serum concentration; and the protein 
usually exceeds 150 mg/dL (1500 mg/L) (see Chapter 30). 
Not all cases of meningitis will have these typical findings, 
and alterations in cerebrospinal fluid cell counts and chem
-
istries may be surprisingly minimal, overlapping with 
those of aseptic meningitis.
Gram stain of cerebrospinal fluid shows gram-positive 
cocci in 80–90% of cases, and in untreated cases, blood or 
cerebrospinal fluid cultures are almost always positive.
 
»
Treatment
Antibiotics should be given as soon as the diagnosis is sus
-
pected. If lumbar puncture must be delayed (eg, while 
awaiting results of an imaging study to exclude a mass 
lesion), the patient should be treated empirically for pre
-
sumed meningitis with intravenous ceftriaxone, 2 g, plus 
vancomycin, 15 mg/kg, plus dexamethasone, 0.15 mg/kg 
administered concomitantly after blood cultures (positive 
in 50% of cases) have been obtained. Once susceptibility to 
penicillin has been confirmed, penicillin, 24 million units 
intravenously daily in six divided doses, or ceftriaxone, 2 g 
every 12 hours intravenously, is continued for 10–14 days in 
documented cases.
The best therapy for penicillin-resistant strains is not 
known. Penicillin-resistant strains (MIC greater than 
0.06 mcg/mL) are often cross-resistant to the third-
generation cephalosporins as well as other antibiotics. 
Susceptibility testing is essential to proper management of 
this infection. If the MIC of ceftriaxone or cefotaxime is 
0.5 mcg/mL or less, single-drug therapy with either of these 
cephalosporins is likely to be effective; when the MIC is 
1 mcg/mL or more, treatment with a combination of ceftri
-
axone, 2 g intravenously every 12 hours, plus vancomycin, 
30 mg/kg/day intravenously in two or three divided doses, 
is recommended. If a patient with a penicillin-resistant 
organism is slow to respond clinically, repeat lumbar punc
-
ture may be indicated to assess bacteriologic response.
Dexamethasone administered with antibiotic to adults 
has been associated with a 60% reduction in mortality and 
a 50% reduction in unfavorable outcomes. It is recom
-
mended that dexamethasone be given immediately prior to 
or concomitantly with the first dose of appropriate antibi
-
otic and continued in those with pneumococcal disease 
every 6 hours thereafter for a total of 4 days. The effect of 
dexamethasone on outcome of meningitis caused by

-
dexamethasone on outcome of meningitis caused by 
penicillin-resistant organisms is not known.
Costerus JM et al. Community-acquired bacterial meningitis. 
Curr Opin Infect Dis. 2017 Feb;30(1):135–41. [PMID: 
27828810]
Glimåker M et al. Adult bacterial meningitis: earlier treatment 
and improved outcome following guideline revision promot
-
ing prompt lumbar puncture. Clin Infect Dis. 2015 Apr 15; 
60(8):1162–9. [PMID: 25663160]
STAPHYLOCOCCUS AUREUS
 INFECTIONS
1. Skin & Soft Tissue Infections
 
»
Localized erythema with induration and purulent 
drainage.
 
»
Abscess formation.
 
»
Folliculitis commonly observed.
 
»
Gram stain of pus shows gram-positive cocci in 
clusters; cultures usually positive.
 
»
Approximately one-quarter of people are asymptomatic 
nasal carriers of 
S aureus
, which is spread by direct contact. 
Carriage often precedes infection, which occurs as a 
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consequence of disruption of the cutaneous barrier or 
impairment of host defenses. 
S aureus
 tends to cause more 
purulent skin infections than streptococci, and abscess for
-
mation is common. The prevalence of methicillin-resistant 
strains in many communities is high and should influence 
antibiotic choices when antimicrobial therapy is needed.
 
»
S aureus
 skin infections may begin around one or more hair 
follicles, causing folliculitis; may become localized to form 
boils (or furuncles); or may spread to adjacent skin and 
deeper subcutaneous tissue (ie, a carbuncle) (Figure 33–2). 
Deep abscesses involving muscle or fascia may occur, often 
in association with a deep wound or other inoculation or 
injection. Necrotizing fasciitis, a rare form of 
S aureus
 skin 
and soft tissues infection, has been reported with commu
-
nity strains of methicillin-resistant 
S aureus
.
Cultures of the wound or abscess material will almost 
always yield the organism. In patients with systemic signs 
of infection, blood cultures should be obtained because of 
potential bacteremia, endocarditis, osteomyelitis, or meta
-
static seeding of other sites. Patients who are bacteremic 
should have blood cultures taken early during therapy to 
exclude persistent bacteremia, an indicator of severe or 
complicated infection.
 
»
Treatment
Proper drainage of abscess fluid or other focal infections is 
the mainstay of therapy. Incision and drainage alone is 
highly effective for the treatment of most uncomplicated 
cutaneous abscesses. A small benefit can be obtained from 
the addition of antimicrobials following incision and 
drainage. In areas where methicillin-resistance among 
community 
S aureus
 isolates is high, recommended oral 
antimicrobials agents include clindamycin, 300 mg three 
times daily; trimethoprim-sulfamethoxazole, given in two 
divided doses based on 5–10 mg/kg/day of the trime
-
thoprim component; or doxycycline or minocycline, 
100 mg twice daily. When the risk of methicillin resistance 
is low or methicillin susceptibility has been confirmed by 
testing of the isolate, consider dicloxacillin or cephalexin, 
500 mg four times a day (see Table 33–1). Seven days of 
treatment is sufficient in most cases.
For complicated infections with extensive cutaneous or 
deep tissue involvement or fever, initial parenteral therapy 
is often indicated. When methicillin resistance rates are 
high (above 10%) empiric therapy with vancomycin, 1 g 
intravenously every 12 hours, is a drug of choice. Cefazolin 
1 g intravenously or intramuscularly or a penicillinase-
resistant penicillin such as nafcillin or oxacillin in a dosage 
of 1.5 g every 6 hours intravenously is preferred for infec
-
tions caused by methicillin-susceptible isolates.
Linezolid is FDA approved for treatment of skin and 
skin-structure infections as well as hospital-acquired pneu
-
monia caused by methicillin-resistant strains of 
S aureus
 
and clinically is as effective as vancomycin for these indica
-
tions. The dose is 600 mg orally or intravenously twice a 
day for 10–14 days. Its considerable cost makes it an unat
-
tractive choice for most routine outpatient infections, and 
its safety in treatment courses lasting longer than 2–3 weeks 
is not well characterized. Tedizolid (an oxazolidinone, like 
linezolid) is also approved for treating skin and soft tissue 
infection at a dose of 200 mg orally once daily for 6 days. 
Other drugs FDA approved for treating skin and soft tissue 
infections include daptomycin, 4 mg/kg intravenously once 
daily for 7–14 days; tigecycline (a glycylcycline class anti
-
microbial), 100 mg intravenously once followed by 50 mg 
intravenously twice a day for 5–14 days; ceftaroline 
 
(a novel cephalosporin with activity against methicillin-
resistant 
S aureus
), 600 mg twice a day for 7–14 days;

resistant 
S aureus
), 600 mg twice a day for 7–14 days; 
 
dalbavancin (a lipoglycopeptide), a single intravenous dose 
of 1500 mg; oritavancin (a lipoglycopeptide), a single intra
-
venous dose of 1200 mg; telavancin (a lipoglycopeptide), 
10 mg/kg intravenously once daily for 7–14 days; and 
 
delafloxacin 450 mg orally or 300 intravenously twice daily 
for 5–14 days. Telavancin is also approved for the treatment 
of hospital-acquired 
S aureus
 pneumonia but has been 
associated with nephrotoxicity.
Miller LG et al; DMID 07-0051 Team. Clindamycin versus 
trimethoprim-sulfamethoxazole for uncomplicated skin 
infections. N Engl J Med. 2015 Mar 19;372(12):1093–103. 
[PMID: 25785967]
Moran GJ et al. Effect of cephalexin plus trimethoprim-
sulfamethoxazole vs cephalexin alone on clinical cure of 
uncomplicated cellulitis: a randomized clinical trial. JAMA. 
2017 May 23;317(20):2088–96. [PMID: 28535235]
Pullman J et al; PROCEED Study Group. Efficacy and safety of 
delafloxacin compared with vancomycin plus aztreonam for 
acute bacterial skin and skin structure infections: a Phase 3, 
double-blind, randomized study. J Antimicrob Chemother. 
2017 Dec 1;72(12):3471–80. [PMID: 29029278]
for uncomplicated skin abscess. N Engl J Med. 2016 Mar 3; 
 
▲
Figure 33–2.
 
Methicillin-resistant 
aureus
 (MRSA) abscess of the neck. 
(From Edward Wright, 
MD; Reproduced, with permission, from Usatine RP , 
 
The Color 
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2. Osteomyelitis
S aureus
 causes approximately 60% of all cases of osteomyeli
-
tis. Osteomyelitis may be caused by direct inoculation, 
eg, from an open fracture or as a result of surgery; by extension 
from a contiguous focus of infection or open wound; or by 
hematogenous spread. Long bones and vertebrae are the usual 
sites. Epidural abscess is a common complication of vertebral 
osteomyelitis and should be suspected if fever and severe back 
or neck pain are accompanied by radicular pain or symptoms 
or signs indicative of spinal cord compression (eg, inconti
-
nence, extremity weakness, pathologic extremity reflexes).
 
»
The infection may be acute, with abrupt development of 
local symptoms and systemic toxicity, or indolent, with 
insidious onset of vague pain over the site of infection, 
progressing to local tenderness and constitutional symp
-
toms (fever, malaise, anorexia, night sweats). Fever is 
absent in one-third or more of cases. Back pain is often the 
only symptom in vertebral osteomyelitis and may be asso
-
ciated with an epidural abscess and spinal cord compres
-
sion. Draining sinus tracts occur in chronic infections or 
infections of foreign body implants.
The diagnosis is established by isolation of 
S aureus
 from 
the blood, bone, or a contiguous focus of a patient with 
symptoms and signs of focal bone infection. Blood culture 
will be positive in approximately 60% of untreated cases. 
Bone biopsy and culture are indicated if blood cultures are 
sterile. Inflammatory markers (C-reactive protein, erythro
-
cyte sedimentation rate) are typically elevated.
C. Imaging
Bone scan and gallium scan, each with a sensitivity of 
approximately 95% and a specificity of 60–70%, are useful in 
identifying or confirming the site of bone infection. Plain 
bone films early in the course of infection are often normal 
but will become abnormal in most cases even with effective 
therapy. Spinal infection (unlike malignancy) traverses the 
disk space to involve the contiguous vertebral body. CT is 
more sensitive than plain films and helps localize associated 
abscesses. MRI is slightly less sensitive than bone scan, but 
has a specificity of 90%. It is indicated when epidural abscess 
is suspected in association with vertebral osteomyelitis.
 
»
Treatment
Prolonged therapy is required to cure staphylococcal osteo
-
myelitis. Durations of 4–6 weeks or longer are recommended. 
Intravenous therapy is preferred, particularly during the acute 
phase of the infection for patients with systemic toxicity. 
Cefazolin, 2 g every 8 hours, or alternatively, nafcillin or 
oxacillin, 9–12 g/day in six divided doses, are the drugs of 
choice for infection with methicillin-sensitive isolates. Patients 
with infections due to methicillin-resistant strains of 
S aureus
 
or who have severe penicillin allergies should be treated with 
vancomycin, 30 mg/kg/day intravenously divided in two or 
three doses. Doses should be adjusted to achieve a vancomy
-
cin trough level of 15–20 mcg/mL. In patients with 
S aureus
 
isolates susceptible to a fluoroquinolone and rifampin, that 
combination has been shown to be effective if given for 
4 weeks following 2 weeks of induction therapy with an intra
-
venous agent as above. Consultation with an infectious 
diseases specialist is recommended. The role of newer agents, 
such as daptomycin or linezolid, remains to be defined.
Surgical treatment is often indicated under the follow
-
ing circumstances: (1) staphylococcal osteomyelitis with 
associated epidural abscess and spinal cord compression, 
(2) other abscesses (psoas, paraspinal), (3) extensive dis
-
ease, or (4) recurrent or persistent infection despite stan
-
dard medical therapy. Follow-up imaging may not be 
needed in patients who demonstrate improvement in 
symptoms and normalization of inflammatory markers.

-
Berbari EF et al. 2015 Infectious Diseases Society of America 
(IDSA) clinical practice guidelines for the diagnosis and 
treatment of native vertebral osteomyelitis in adults. Clin 
Infect Dis. 2015 Sep 15;61(6):e26–46. [PMID: 26229122]
Bernard L et al; Duration of Treatment for Spondylodiscitis 
(DTS) study group. Antibiotic treatment for 6 weeks versus 
 
12 weeks in patients with pyogenic vertebral osteomyelitis: an 
open-label, non-inferiority, randomised, controlled trial. 
Lancet. 2015 Mar 7;385(9971):875–82. [PMID: 25468170]
3. Staphylococcal Bacteremia
S aureus
 readily invades the bloodstream and infects sites 
distant from the primary site of infection. Whenever 
 
S aureus
 is recovered from blood cultures, the possibility of 
endocarditis, osteomyelitis, or other metastatic deep infec
-
tion must be considered. Bacteremia that persists for more 
than 48–96 hours after initiation of therapy is strongly 
predictive of worse outcome and complicated infection. 
Given the relatively high risk of infective endocarditis in 
S aureus
 bacteremia, transesophageal echo
-
cardiography is recommended for most patients as a sensi
-
tive and cost-effective method for excluding underlying 
endocarditis. However, transthoracic echocardiography 
may be sufficient in select patients considered to be at low 
risk for endocarditis, namely those who meet all the follow
-
ing criteria: (1) no permanent intracardiac device, 
 
(2) sterile follow-up blood cultures within 4 days after the 
initial set, (3) no hemodialysis dependence, (4) nosocomial 
acquisition of 
S aureus
 bacteremia, and (5) no clinical signs 
of infective endocarditis or secondary foci of infection.
Empiric therapy of staphylococcal bacteremia should be 
with vancomycin, 15–20 mg/kg/dose intravenously every 
8–12 hours, or daptomycin 6 mg/kg/day intravenously until 
results of susceptibility tests are known. If the 
S aureus
 iso
-
late is methicillin-susceptible, treatment should be narrowed 
to cefazolin, 2 g every 8 hours or nafcillin or oxacillin, 2 g 
intravenously every 4 hours. Cefazolin is as effective as 
nafcillin or oxacillin and has been associated with fewer 
adverse events during treatment. In patients with methicillin-
resistant 
S aureus
, treatment should be with vancomycin, 
15–20 mg/kg/dose intravenously every 8–12 hours. 
Maintaining a vancomycin trough concentration of 
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15–20 mcg/mL may improve outcomes and is recom
-
mended. Daptomycin 6 mg/k/day is also an FDA-approved 
option as long as the patient does not require treatment for 
concomitant 
S aureus
 pneumonia. Duration of therapy for 
 
S aureus
 bacteremia is 4–6 weeks of antibiotic therapy but a 
subset of patients with uncomplicated infection may be able 
to be treated for 14 days. A patient with uncomplicated bac
-
teremia must meet all the following criteria: (1) infective 
endocarditis has been excluded, (2) no implanted prostheses 
are present, (3) follow-up blood cultures drawn 2–4 days 
after the initial set are sterile, (4) the patient defervesces 
within 72 hours of initiation of effective antibiotic therapy, 
and (5) no evidence of metastatic infection is present on 
examination. When present at the time of diagnosis, central 
venous catheters should be removed. Vancomycin treatment 
failures are relatively common, particularly for complicated 
bacteremia and among infections involving foreign bodies. 
Improved outcomes have been demonstrated when consul
-
tation is obtained with an infectious diseases specialist and 
should be considered in all cases of 
S aureus
 bacteremia.
Holland TL et al. Clinical management of 
 
bacteremia: a review. JAMA. 2014 Oct 1;312(13):1330–41. 
[PMID: 25268440]
Li J et al. β-Lactam therapy for methicillin-susceptible 
  bacteremia: a comparative review 
of cefazolin versus antistaphylococcal penicillins. Pharma
-
cotherapy. 2017 Mar; 37(3):346–60. [PMID: 28035690]
Liu C et al. Clinical practice guidelines by the Infectious Diseases 
Society of America for the treatment of methicillin-resistant 
 infections in adults and children. Clin 
Infect Dis. 2011 Feb 1;52(3):e18–55. [PMID: 21208910]
Rao SN et al. Treatment outcomes with cefazolin versus oxacillin 
for deep-seated methicillin-susceptible 
 
bloodstream infections. Antimicrob Agents Chemother. 
2015 Sep;59(9):5232–8. Erratum in: Antimicrob Agents 
Chemother. 2015 Nov;59(11):7159. [PMID: 26077253]
4. Toxic Shock Syndrome
S aureus
 produces toxins that cause three important 
entities: “scalded skin syndrome” in children, toxic shock 
syndrome in adults, and enterotoxin food poisoning. Toxic 
shock syndrome is characterized by abrupt onset of high 
fever, vomiting, and watery diarrhea. Sore throat, myalgias, 
and headache are common. Hypotension with kidney and 
heart failure is associated with a poor outcome. A diffuse 
macular erythematous rash and nonpurulent conjunctivitis 
are common, and desquamation, especially of palms and 
soles, is typical during recovery (Figure 33–3). Fatality rates 
may be as high as 15%. Although originally associated with 
tampon use, any focus (eg, nasopharynx, bone, vagina, 
rectum, abscess, or wound) harboring a toxin-producing 
 
S aureus
 strain can cause toxic shock syndrome. Classically, 
blood cultures are negative because symptoms are due to 
the effects of the toxin and not systemic infection.
Important aspects of treatment include rapid rehydra
-
tion, antistaphylococcal drugs, management of kidney or 
heart failure, and addressing sources of toxin, eg, removal 
of tampon or drainage of abscess. Intravenous clindamy
-
cin, 900 mg every 8 hours, is often added to inhibit toxin 
production. Intravenous immune globulin may be 
considered, although there are limited data compared with 
streptococcus toxic shock syndrome.
5. Infections Caused by Coagulase-
 
Negative Staphylococci
Coagulase-negative staphylococci are an important cause 
of infections of intravascular and prosthetic devices and of 
wound infection following cardiothoracic surgery. These 
organisms infrequently cause infections such as osteomy
-
elitis and endocarditis in the absence of a prosthesis. Most 
human infections are caused by 
Staphylococcus epidermidis,

-
Staphylococcus epidermidis, 
S haemolyticus, S hominis, S warnerii, S saprophyticus, 
 
S saccharolyticus
, and 
S cohnii
. These common hospital-
acquired pathogens are less virulent than 
S aureus
, and 
infections caused by them tend to be more indolent.
Because coagulase-negative staphylococci are normal 
inhabitants of human skin, it is difficult to distinguish infec
-
tion from contamination, the latter perhaps accounting for 
three-fourths of blood culture isolates. Infection is more likely 
if the patient has a foreign body (eg, sternal wires, prosthetic 
joint, prosthetic cardiac valve, pacemaker, intracranial pres
-
sure monitor, cerebrospinal fluid shunt, peritoneal dialysis 
catheter) or an intravascular device in place. Purulent or sero
-
sanguineous drainage, erythema, pain, or tenderness at the site 
of the foreign body or device suggests infection. Joint instabil
-
ity and pain are signs of prosthetic joint infection. Fever, a new 
murmur, instability of the prosthesis, or signs of systemic 
embolization are evidence of prosthetic valve endocarditis.
Infection is also more likely if the same strain is consis
-
tently isolated from two or more blood cultures (particu
-
larly if samples were obtained at different times) and from 
the foreign body site. Contamination is more likely when a 
single blood culture is positive or if more than one strain is 
isolated from blood cultures. The antimicrobial suscepti
-
bility pattern and speciation are used to determine whether 
one or more strains have been isolated.
Whenever possible, the intravascular device or foreign 
body suspected of being infected should be removed. How
-
ever, removal and replacement of some devices (eg, pros
-
thetic joint, prosthetic valve, cerebrospinal fluid shunt) 
 
▲
Figure 33–3.
 
Marked desquamation due to toxic 
shock syndrome, which develops late in the disease. 
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can be a difficult or risky procedure, and it may sometimes 
be preferable to treat with antibiotics alone with the under
-
standing that the probability of cure is reduced and that 
surgical management may eventually be necessary.
Coagulase-negative staphylococci are commonly resistant 
to beta-lactams and multiple other antibiotics. For patients 
with normal kidney function, vancomycin, 1 g intravenously 
every 12 hours, is the treatment of choice until susceptibility 
to penicillinase-resistant penicillins or other agents has been 
confirmed. Duration of therapy has not been established for 
relatively uncomplicated infections, such as those secondary 
to intravenous devices, which may be eliminated by simply 
removing the device. Infection involving bone or a prosthetic 
valve should be treated for 6 weeks. A combination regimen 
of vancomycin plus rifampin, 300 mg orally twice daily, plus 
gentamicin, 1 mg/kg intravenously every 8 hours, is recom
-
mended for treatment of prosthetic valve endocarditis caused 
by methicillin-resistant strains.
Tan EM et al. Outcomes in patients with cardiovascular implant
-
able electronic  device  infection managed with chronic 
antibiotic suppression. Clin Infect Dis.  2017 Jun 1; 
64(11):1516–21. [PMID: 28329125]
CLOSTRIDIAL DISEASES
1. Clostridial Myonecrosis (Gas Gangrene)
 
»
Sudden onset of pain and edema in an area of 
wound contamination.
 
»
Prostration and systemic toxicity.
 
»
Brown to blood-tinged watery exudate, with skin 
discoloration of surrounding area.
 
»
Gas in the tissue by palpation or radiograph.
 
»
Gram-positive rods in culture or smear of exudate.
 
»
Gas gangrene or clostridial myonecrosis is produced by any 
one of several clostridia (
Clostridium perfringens, C ramosum, 
C bifermentans, C histolyticum, C novyi
, etc). Trauma and 
injection drug use are common predisposing conditions. 
Toxins produced in devitalized tissues under anaerobic condi
-
tions result in shock, hemolysis, and myonecrosis.
 
»
The onset is usually sudden, with rapidly increasing pain in 
the affected area, hypotension, and tachycardia. Fever is 
present, but is not proportionate to the severity of the 
infection. In the last stages of the disease, severe prostra
-
tion, stupor, delirium, and coma occur.
The wound becomes swollen, and the surrounding skin 
is pale. There is a foul-smelling brown, blood-tinged serous 
discharge. As the disease advances, the surrounding tissue 
changes from pale to dusky and finally becomes deeply 
discolored, with coalescent, red, fluid-filled vesicles. Gas 
may be palpable in the tissues.
Gas gangrene is a clinical diagnosis, and empiric therapy is 
indicated if the diagnosis is suspected. Radiographic stud
-
ies may show gas within the soft tissues, but this finding is 
not sensitive nor specific. The smear shows absence of 
neutrophils and the presence of gram-positive rods. 
Anaerobic culture confirms the diagnosis.
 
»
Other bacteria can produce gas in infected tissue, eg, enteric 
gram-negative organisms, or anaerobes.
 
»
Treatment
Adequate surgical debridement and exposure of infected 
areas are essential, with radical surgical excision often nec
-
essary. Penicillin, 2 million units every 3 hours intrave
-
nously, is an effective adjunct. Clindamycin may decrease 
the production of bacterial toxin, and some experts recom
-
mend the addition of clindamycin, 600–900 mg every 
 
8 hours intravenously, to penicillin. Hyperbaric oxygen

-
 
8 hours intravenously, to penicillin. Hyperbaric oxygen 
therapy has been used empirically, but must be used in 
conjunction with administration of an appropriate 
antibiotic and surgical debridement.
De Prost N et al. Therapeutic targets in necrotizing soft tissue 
infections. Intensive Care Med. 2017 Nov;43(11):1717–9. 
[PMID: 28474117]
-
Y ang Z et al. Interventions for treating gas gangrene. Cochrane 
Database Syst Rev. 2015 Dec 3;12:CD010577. [PMID: 
26631369]
2. Tetanus
 
»
History of wound and possible contamination.
 
»
Jaw muscle stiffness (“lock jaw”), then spasms 
(trismus).
 
»
Stiffness of the neck and other muscles, dysphagia, 
irritability, hyperreflexia.
 
»
Finally, painful convulsions precipitated by mini
-
mal stimuli.
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»
Tetanus is caused by the neurotoxin tetanospasmin, elabo
-
rated by 
C tetani
. Spores of this organism are ubiquitous in 
soil and may germinate when introduced into a wound. 
Tetanospasmin interferes with neurotransmission at spinal 
synapses of inhibitory neurons. As a result, minor stimuli 
result in uncontrolled spasms, and reflexes are exaggerated. 
The incubation period is 5 days to 15 weeks, with the aver
-
age being 8–12 days.
Most cases occur in unvaccinated individuals. Persons 
at risk are older adults, migrant workers, newborns, and 
injection drug users. While puncture wounds are particu
-
larly prone to causing tetanus, any wound, including bites 
or decubiti, may become colonized and infected by 
 
C tetani
.
 
»
The first symptom may be pain and tingling at the site of 
inoculation, followed by spasticity of the muscles nearby. 
Stiffness of the jaw, neck stiffness, dysphagia, and irritability 
are other early signs. Hyperreflexia develops later, with 
spasms of the jaw muscles (trismus) or facial muscles and 
rigidity and spasm of the muscles of the abdomen, neck, and 
back. Painful tonic convulsions precipitated by minor stim
-
uli are common. Spasms of the glottis and respiratory mus
-
cles may cause acute asphyxia. The patient is awake and alert 
throughout the illness. The sensory examination is normal. 
The temperature is normal or only slightly elevated.
The diagnosis of tetanus is made clinically.
 
»
Tetanus must be differentiated from various acute central 
nervous system (CNS) infections such as meningitis. Tris
-
mus may occasionally develop with the use of phenothi
-
azines. Strychnine poisoning should also be considered.
 
»
Airway obstruction is common. Urinary retention and 
constipation may result from spasm of the sphincters. 
Respiratory arrest and cardiac failure are late, life-
threatening events.
 
»
Tetanus is preventable by
 active
 immunization (see 
Table 30–7). For primary immunization of adults, Td 
(tetanus and diphtheria toxoids vaccine) is administered as 
two doses 4–6 weeks apart, with a third dose 6–12 months 
later. For one of the three doses, Tdap (tetanus toxoid, 
reduced-dose diphtheria toxoid, acellular pertussis vaccine) 
should be substituted for Td. Booster Td doses are given 
every 10 years or at the time of major injury if it occurs more 
than 5 years after a dose; a single dose of Tdap is preferred to 
Td for wound prophylaxis if the patient has not been previ
-
ously vaccinated with Tdap. Women should receive Tdap 
with each pregnancy, preferably between 27 and 36 weeks.
Passive
 immunization should be used in nonimmu
-
nized individuals and those whose immunization status is 
uncertain whenever a wound is contaminated or likely to 
have devitalized tissue; tetanus immune globulin, 250 
units, is given intramuscularly. Active immunization with 
tetanus toxoid vaccine is started concurrently. Table 33–2 
provides a guide to prophylactic management.
 
»
Treatment
Human tetanus immune globulin, 500 units, should be 
administered intramuscularly within the first 24 hours of 
presentation. Whether intrathecal administration has any 
additional benefit is controversial. An unblinded, random
-
ized trial comparing intramuscular tetanus immune globu
-
lin to intramuscular plus intrathecal tetanus immune 
globulin found clinical benefit in the intrathecal group. 
However, the exact immunoglobulin preparation was not 
specified and the total dose was 4000 units. Tetanus does 
not produce natural immunity, and a full course of 
Table 33–2.
 
Guide to tetanus prophylaxis in wound management.
Clean, Minor Wounds
All Other Wounds
1
History of Absorbed 
Tetanus Toxoid
Tdap or Td
2
TIG
3
Tdap or Td
2
TIG
3
Unknown or < 3 doses
Yes
No
Yes
Yes
3 or more doses
No
4
No
No
5
No
1

1
Tdap or Td
2
TIG
3
Tdap or Td
2
TIG
3
Yes
No
Yes
Yes
No
4
No
No
5
No
1
Such as, but not limited to, wounds contaminated with dirt, feces, soil, saliva, etc; puncture wounds; avulsions; and wounds resulting from 
missiles, crushing, burns, and frostbite.
2
Td indicates tetanus toxoid and diphtheria toxoid vaccine, adult form. Tdap indicates tetanus toxoid, reduced diphtheria toxoid, and 
acellular pertussis vaccine, which may be substituted as a single dose for Td. Unvaccinated individuals should receive a complete series of 
three doses, one of which is Tdap.
3
Human tetanus immune globulin, 250 units intramuscularly.
4
Yes if more than 10 years have elapsed since last dose.
5
Yes if more than 5 years have elapsed since last dose. (More frequent boosters are not needed and can enhance side effects.) Tdap has 
been safely administered within 2 years of Td vaccination, although local reactions to the vaccine may be increased.
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immunization with tetanus toxoid should be administered 
once the patient has recovered.
Debridement of wounds should be undertaken if impli
-
cated as the source. Metronidazole 7.5 mg/kg administered 
intravenously or orally every 6 hours (maximum 4 g daily) 
is now preferred and should be administered to all patients. 
Penicillin, 20 million units intravenously daily in divided 
doses, is an alternative. Minimal stimuli can provoke 
spasms, so the patient should be placed at bed rest and 
monitored under the quietest conditions possible. Seda
-
tion, paralysis with curare-like agents, and mechanical 
ventilation are often necessary. Enteral nutritional support 
should be given early.
 
»
Prognosis
High mortality rates are associated with a short incubation 
period, early onset of convulsions, and delay in treatment. 
Contaminated lesions about the head and face are more 
dangerous than wounds on other parts of the body.
Y en C et al; Centers for Disease Control and Prevention (CDC). 
Missed opportunities for tetanus postexposure prophylaxis—
California, January 2008–March 2014. MMWR Morb Mortal 
Wkly Rep. 2015 Mar 13;64(9):243–6. [PMID: 25763876]
 
»
Recent ingestion of home-canned or smoked 
foods; recovery of toxin in serum or food.
 
»
Injection drug use.
 
»
Onset of diplopia, dry mouth, dysphagia, dyspho
-
nia, and muscle weakness progressing to respira
-
tory paralysis.
 
»
Pupils are fixed and dilated in most cases.
 
»
Botulism is a paralytic disease caused by botulinum toxin, 
which is produced by 
, a ubiquitous, strictly 
anaerobic, spore-forming bacillus found in soil. Four toxin 
types—A, B, E, and F—cause human disease. Botulinum 
toxin is extremely potent and is classified by the CDC as a 
high-priority agent because of its potential for use as an 
agent of bioterrorism. Naturally occurring botulism exists 
in three forms: food-borne botulism, infant botulism, or 
wound botulism. Food-borne botulism is caused by inges
-
tion of preformed toxin present in canned, smoked, or 
vacuum-packed foods such as home-canned vegetables, 
smoked meats, and vacuum-packed fish. Commercial 
foods have been associated with outbreaks of botulism. 
Infant botulism (associated with ingestion of honey) and 
wound botulism (often occurs in association with injection 
drug use) result from organisms present in the gut or 
wound that secrete toxin.
 
»
Twelve to 36 hours after ingestion of the toxin, visual dis
-
turbances appear, particularly diplopia and loss of accom
-
modation. Ptosis, cranial nerve palsies with impairment of 
extraocular muscles, and fixed dilated pupils are character
-
istic signs. The sensory examination is normal. Other 
symptoms are dry mouth, dysphagia, and dysphonia. 
Nausea and vomiting may be present, particularly with type 
E toxin. The sensorium remains clear and the temperature 
normal. Paralysis progressing to respiratory failure and 
death may occur unless mechanical assistance is provided.
Toxin in foods and patients’ serum can be demonstrated by 
mouse inoculation and identified with specific antiserum.
 
»
Because the clinical presentation of botulism is so distinc
-
tive and the differential diagnosis limited, botulism once 
considered is not easily confused with other diseases. Cra
-
nial nerve involvement may be seen with vertebrobasilar 
insufficiency, the C. Miller Fisher variant of Guillain-Barré 
syndrome, myasthenia gravis, or any basilar meningitis 
(infectious or carcinomatous). Intestinal obstruction or 
other types of food poisoning are considered when nausea 
and vomiting are present.
 
»
Treatment
If botulism is suspected, the practitioner should contact the 
state health authorities or the CDC for advice and help 
with procurement of equine serum heptavalent botulism

»
Treatment
with procurement of equine serum heptavalent botulism 
antitoxin and for assistance in obtaining assays for toxin in 
serum, stool, or food. Skin testing is recommended to 
exclude hypersensitivity to the antitoxin preparation. 
Antitoxin should be administered as early as possible, ide
-
ally within 24 hours of the onset of symptoms or signs, to 
arrest progression of disease; its administration should not 
be delayed for laboratory confirmation of the diagnosis. 
Respiratory failure is managed with intubation and 
mechanical ventilation. Parenteral fluids or alimentation 
should be given while swallowing difficulty persists. The 
removal of unabsorbed toxin from the gut may be 
attempted. Any remnants of suspected foods should be 
assayed for toxin. Persons who might have eaten the sus
-
pected food must be located and observed.
Adalja AA et al. Clinical management of potential bioterrorism-
related conditions. N Engl J Med. 2015 Mar 5;372(10):954–62. 
[PMID: 25738671]
-
base Syst Rev. 2014 Feb 20;2:CD008123. [PMID: 24558013]
Schulte M et al. Effective and rapid treatment of wound botu
-
lism, a case report. BMC Surg. 2017 Oct 26;17(1):103. [PMID: 
29073888]
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ANTHRAX
 
»
Epidemiologic setting: exposure to animals or 
animal hides or potential exposure from 
bioterrorism.
 
»
A painless cutaneous black eschar on exposed 
skin, with marked surrounding edema and 
vesicles.
 
»
Nonspecific flu-like symptoms that rapidly prog
-
ress to extreme dyspnea and shock; mediastinal 
widening and pleural effusions on chest 
 
»
Naturally occurring anthrax is a disease of sheep, cattle, 
horses, goats, and swine. 
B anthracis
 is a gram-positive 
spore-forming aerobic rod. Spores—not vegetative 
bacteria—are the infectious form of the organism. These 
are transmitted to humans from contact with contami
-
nated animals, animal products, or animal hides, or from 
soil by inoculation of broken skin or mucous membranes; 
by inhalation of aerosolized spores; or, rarely, by ingestion 
resulting in cutaneous, inhalational, or gastrointestinal 
forms of anthrax, respectively. Inhalation of aerosolized 
spores that were deliberately placed in the mail as an act of 
bioterrorism occurred in the United States in 2001. Spores 
germinate into vegetative bacteria that multiply locally in 
cutaneous and gastrointestinal anthrax but may also dis
-
seminate to cause systemic infection. Inhaled spores are 
ingested by pulmonary macrophages and carried via lym
-
phatics to regional lymph nodes, where they germinate. 
The bacteria rapidly multiply within the lymphatics, caus
-
ing a hemorrhagic lymphadenitis. Invasion of the blood
-
stream leads to overwhelming sepsis, killing the host.
 
»
1. Cutaneous anthrax—
This occurs within 2 weeks after 
exposure to spores; there is no latency period for cutaneous 
disease as there is with inhalational anthrax. The initial 
lesion is an erythematous papule, often on an exposed area 
of skin that vesiculates and then ulcerates and undergoes 
necrosis, ultimately progressing to a purple to black eschar. 
The eschar typically is painless; pain indicates secondary 
bacterial infection. The surrounding area is edematous and 
vesicular but not purulent. Regional adenopathy, fever, 
malaise, headache, and nausea and vomiting may be pres
-
ent. The infection is self-limited in most cases, but hema
-
togenous spread with sepsis or meningitis may occur.
2. Inhalational anthrax—
Illness occurs in two stages, 
beginning on average 10 days after exposure, but may have 
a latent onset 6 weeks after exposure. Nonspecific viral-like 
symptoms such as fever, malaise, headache, dyspnea, cough, 
and congestion of the nose, throat, and larynx are charac
-
teristic of the initial stage. Anterior chest pain is an early 
symptom of mediastinitis. Within hours to a few days, pro
-
gression to the fulminant stage of infection occurs in which 
symptoms or signs of overwhelming sepsis predominate. 
Delirium, obtundation, or findings of meningeal irritation 
suggest an accompanying hemorrhagic meningitis.
3. Gastrointestinal anthrax—
Fever, diffuse abdominal 
pain, rebound abdominal tenderness, vomiting, constipa
-
tion, and diarrhea occur 2–5 days after ingestion of food 
products contaminated with anthrax spores. The primary 
lesion is ulcerative, producing emesis that may be blood-
tinged or coffee-grounds and stool that may be blood-
tinged or melenic. Bowel perforation can occur. The 
oropharyngeal form of the disease is characterized by local 
lymphadenopathy, cervical edema, dysphagia, and upper 
respiratory tract obstruction.
Laboratory findings are nonspecific. The white blood cell 
count initially may be normal or modestly elevated, with 
polymorphonuclear predominance and an increase in 
immature forms. Pleural fluid from patients with inhala
-
tional anthrax is typically hemorrhagic with few white 
cells. Cerebrospinal fluid from meningitis cases is also 
hemorrhagic. Gram stain of pleural fluid, cerebrospinal

-
hemorrhagic. Gram stain of pleural fluid, cerebrospinal 
fluid, unspun blood, blood culture, or fluid from a cutane
-
ous lesion may show the characteristic boxcar-shaped 
encapsulated rods in chains.
The diagnosis is established by isolation of the organism 
from culture of the skin lesion (or fluid expressed from it), 
blood, or pleural fluid—or cerebrospinal fluid in cases of 
meningitis. In the absence of prior antimicrobial therapy, 
cultures are invariably positive. Cultures obtained after ini
-
tiation of antimicrobial therapy may be negative. If anthrax 
is suspected on clinical or epidemiologic grounds, immuno
-
histochemical tests (eg, to detect capsular antigen), poly
-
merase chain reaction assays, and serologic tests (useful for 
documenting past cutaneous infection) are available through 
the CDC and should be used to establish the diagnosis. Any 
suspected case of anthrax should be immediately reported to 
the CDC so that an investigation can be conducted.
C. Imaging
The chest radiograph is the most sensitive test for inhala
-
tional disease, being abnormal (though the findings can be 
subtle) initially in every case of bioterrorism-associated 
disease. Mediastinal widening due to hemorrhagic lymph
-
adenitis, a hallmark feature of the disease, was present in 
70% of the bioterrorism-related cases. Pleural effusions 
were present initially or occurred over the course of illness 
in all cases, and approximately three-fourths had pulmo
-
nary infiltrates or signs of consolidation.
 
»
Cutaneous anthrax, despite its characteristic appearance, 
can be confused with a variety of other also uncommon or 
rare conditions such as ecthyma gangrenosum, rat-bite 
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fever, ulceroglandular tularemia, plague, glanders, rickett
-
sialpox, orf (parapoxvirus infection), or cutaneous myco
-
bacterial infection. Inhalational anthrax must be 
differentiated from mediastinitis due to other bacterial 
causes, fibrous mediastinitis due to histoplasmosis, coc
-
cidioidomycosis, atypical or viral pneumonia, silicosis, 
sarcoidosis, and other causes of mediastinal widening 
 
(eg, superior vena cava syndrome or aortic aneurysm or 
dissection). Gastrointestinal anthrax shares clinical 
 
features with a variety of common intra-abdominal disor
-
ders, including bowel obstruction, perforated viscus, 
peritonitis, gastroenteritis, and peptic ulcer disease.
 
»
Treatment
Strains of 
 (including the strain isolated in the 
bioterrorism cases) are susceptible in vitro to penicillin, 
amoxicillin, chloramphenicol, clindamycin, imipenem, 
doxycycline, ciprofloxacin (as well as other fluoroquino
-
lones), macrolides, rifampin, and vancomycin. 
 
may express beta-lactamases that confer resistance to 
cephalosporins and penicillins. For this reason, penicillin 
or amoxicillin is not recommended for use as a single agent 
in treatment of disseminated disease. Based on results of 
animal experiments and because of concern for engineered 
drug resistance in strains of 
 used in bioterror
-
ism, ciprofloxacin is considered the drug of choice for 
treatment and for prophylaxis following exposure to 
anthrax spores. Other fluoroquinolones with activity 
against gram-positive bacteria (eg, levofloxacin, 
moxifloxacin) are likely to be just as effective as ciprofloxa
-
cin. Doxycycline is an alternative first-line agent. Combi
-
nation therapy with at least one additional agent is 
recommended for inhalational or disseminated disease and 
in cutaneous infection involving the face, head, and neck or 
associated with extensive local edema or systemic signs of 
infection, eg, fever, tachycardia and elevated white blood 
cell count. Single-drug therapy is recommended for pro
-
phylaxis following exposure to spores.
The required duration of therapy is poorly defined. In 
naturally occurring disease, treatment for 7–10 days for 
cutaneous disease and for at least 2 weeks following clinical 
response for disseminated, inhalational, or gastrointestinal 
infection have been standard recommendations. Because 
of concern about relapse from latent spores acquired by 
inhalation of aerosol in bioterrorism-associated cases, the 
initial recommendation was treatment for 60 days. 
Raxibacumab, a human monoclonal antibody directed 
against the protective antigen component of lethal toxin, is 
FDA approved for the treatment of inhalation anthrax 
when used in combination with recommended antibacte
-
rial treatments. A vaccine is also available for postexposure 
prophylaxis (and preexposure prophylaxis). This vaccine is 
administered at 0, 2, and 4 weeks postexposure combined 
with antimicrobial therapy.
 
»
In 2001, the CDC offered one of two options for postal work
-
ers receiving prophylaxis for exposure to contaminated mail: 
(1) antibiotics for 100 days (fearing that even with 60 days of 
treatment late relapses might occur) or (2) vaccination with 
an investigative agent (three doses administered over a 
1-month period) in conjunction with 40 days of antibiotic 
administration to cover the time required for a protective 
antibody response to develop. Insufficient information exists 
to favor one recommendation over the other.
The FDA has approved a vaccine for persons at high risk 
for exposure to anthrax spores. The vaccine is cell-free anti
-
gen prepared from an attenuated strain of 
. 
Multiple injections over 18 months and an annual booster 
dose are required to achieve and maintain protection. Exist
-
ing supplies have been reserved for vaccination of military 
personnel. Raxibacumab, a human monoclonal antibody, is

-
personnel. Raxibacumab, a human monoclonal antibody, is 
also approved for prevention of inhalation anthrax when 
other treatments are not available or appropriate.
 
»
Prognosis
The prognosis in cutaneous infection is excellent. Death is 
unlikely if the infection has remained localized, and lesions 
heal without complications in most cases. By contrast, the 
reported mortality rate for gastrointestinal and inhala
-
tional infections is up to 85%. Y et, the experience with 
bioterrorism-associated inhalational cases in which six of 
eleven victims survived suggests a somewhat better out
-
come with modern supportive care and antibiotics pro
-
vided that treatment is initiated before the patient has 
progressed to the fulminant stage of disease. No cases of 
anthrax have occurred among the several thousand indi
-
viduals receiving antimicrobial prophylaxis following 
exposure to spores.
Bower W A et al; Centers for Disease Control and Prevention 
(CDC). Clinical framework and medical countermeasure use 
during an anthrax mass-casualty incident. MMWR Recomm 
Rep. 2015 Dec 4;64(4):1–22. [PMID: 26632963]
DIPHTHERIA
 
»
Tenacious gray membrane at portal of entry in 
pharynx.
 
»
Sore throat, nasal discharge, hoarseness, fever.
 
»
Myocarditis, neuropathy.
 
»
Culture confirms the diagnosis.
 
»
Diphtheria is an acute infection caused by 
Corynebacte
-
rium diphtheriae
 that usually attacks the respiratory tract 
but may involve any mucous membrane or skin wound. 
The organism is spread chiefly by respiratory secretions. 
Exotoxin produced by the organism is responsible for myo
-
carditis and neuropathy.
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»
Nasal, laryngeal, pharyngeal, and cutaneous forms of diph
-
theria occur. Nasal infection produces few symptoms other 
than a nasal discharge. Laryngeal infection may lead to 
upper airway and bronchial obstruction. In pharyngeal 
diphtheria, the most common form, a tenacious gray mem
-
brane covers the tonsils and pharynx. Mild sore throat, 
fever, and malaise are followed by toxemia and prostration.
Myocarditis and neuropathy are the most common and 
most serious complications. Myocarditis causes cardiac 
arrhythmias, heart block, and heart failure. The neuropa
-
thy usually involves the cranial nerves first, producing 
diplopia, slurred speech, and difficulty in swallowing.
The diagnosis is made clinically but can be confirmed by 
culture of the organism.
 
»
Diphtheria must be differentiated from streptococcal phar
-
yngitis, infectious mononucleosis, adenovirus or herpes 
simplex infection, Vincent angina, pharyngitis due to 
Arcanobacterium haemolyticum
, and candidiasis. A pre
-
sumptive diagnosis of diphtheria should be made on clini
-
cal grounds without waiting for laboratory verification, 
since emergency treatment is needed.
 
»
Active immunization with diphtheria toxoid is part of rou
-
tine childhood immunization with appropriate booster 
injections. The immunization schedule for adults is the 
same as for tetanus (see Table 30–7). Women should 
receive Tdap with each pregnancy, preferably between 27 
and 36 weeks.
Susceptible persons exposed to diphtheria should 
receive a booster dose of diphtheria toxoid (or a complete 
series if previously unimmunized), as well as a course of 
penicillin or erythromycin.
 
»
Treatment
Removal of membrane by direct laryngoscopy or bron
-
choscopy may be necessary to prevent or alleviate airway 
obstruction. Antitoxin, which is prepared from horse 
serum, must be given in all cases when diphtheria is sus
-
pected. For mild early pharyngeal or laryngeal disease, the 
dose is 20,000–40,000 units; for moderate nasopharyngeal 
disease, 40,000–60,000 units; for severe, extensive, or late 
(3 days or more) disease, 80,000–100,000 units. Diphtheria 
equine antitoxin can be obtained from the CDC.
Either penicillin, 250 mg orally four times daily, or 
erythromycin, 500 mg orally four times daily, for 14 days is 
effective therapy, although erythromycin is slightly more 
effective in eliminating the carrier state. Azithromycin or 
clarithromycin is probably as effective as erythromycin. The 
patient should be isolated until three consecutive cultures at 
the completion of therapy have documented elimination of 
the organism from the oropharynx. Contacts to a case 
should receive erythromycin, 500 mg orally four times daily 
for 7 days, to eradicate carriage.
recommendations for use of tetanus toxoid, reduced diphthe
-
ria toxoid, and acellular pertussis vaccine (Tdap) in pregnant 
McMillan M et al. Safety of tetanus, diphtheria, and pertussis 
vaccination during pregnancy: a systematic review. Obstet 
Gynecol. 2017 Mar;129(3):560–73. [PMID: 28178054]
LISTERIOSIS
 
»
Ingestion of contaminated food product.
 
»
Undifferentiated fever in a pregnant woman in her 
third trimester.
 
»
Altered mental status and fever in an elderly or 
immunocompromised patient.
 
»
Obtain blood and cerebrospinal fluid cultures to 
 
»
 is a facultative, motile, gram-posi
-
tive rod that is capable of invading several cell types and 
causes intracellular infection. Most cases of infection 
caused by 
 are sporadic, but outbreaks

-
caused by 
 are sporadic, but outbreaks 
have been traced to eating contaminated food, including 
unpasteurized dairy products, hot dogs, delicatessen meats, 
cantaloupes, and ricotta cheese. Outbreaks have been asso
-
ciated with significant morbidity and mortality in infected 
persons.
 
»
Five types of infection are recognized:
(1) 
Infection during pregnancy
, usually in the last tri
-
mester, is a mild febrile illness without an apparent primary 
focus and may resolve without specific therapy. However, 
approximately one in five pregnancies complicated by liste
-
riosis result in spontaneous abortion or stillbirth and sur
-
viving infants are at risk for clinical neonatal listeriosis.
(2) 
Granulomatosis infantisepticum
 is a neonatal 
infection acquired in utero, characterized by disseminated 
abscesses, granulomas, and a high mortality rate.
(3) 
Bacteremia
 with or without sepsis syndrome is an 
infection of neonates or immunocompromised adults. The 
presentation is of a febrile illness without a recognized 
source.
(4) 
 caused by 
 affects 
infants under 2 months of age as well as older adults, rank
-
ing third after pneumococcus and meningococcus as com
-
mon causes of bacterial meningitis. Cerebrospinal fluid 
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shows a 
neutrophilic
 pleocytosis. Adults with meningitis 
are often immunocompromised, and cases have been asso
-
ciated with HIV infection and therapy with tumor necrosis 
factor (TNF) inhibitors such as infliximab.
(5) 
Focal infections
, including adenitis, brain abscess, 
endocarditis, osteomyelitis, and arthritis, occur rarely.
 
»
At-risk patients (eg, pregnant women) should avoid unpas
-
teurized milk products. Smoked seafoods, cold cuts, hot 
dogs, and meat spreads also carry risk. Thoroughly cook 
animal source food and wash raw vegetables.
 
»
Treatment
Ampicillin, 8–12 g/day intravenously in four to six divided 
doses (the higher dose for meningitis) is considered the 
treatment of choice. Gentamicin, 5 mg/kg/day intrave
-
nously once or in divided doses is synergistic with ampicil
-
lin against 
Listeria
 in vitro and in animal models, and the 
use of combination therapy may be considered during the 
first few days of treatment to enhance eradication of organ
-
isms. In patients with penicillin allergies, trimethoprim-
sulfamethoxazole has excellent intracellular and 
cerebrospinal fluid penetration and is considered an appro
-
priate alternative. The dose is 10–20 mg/kg/day intrave
-
nously of the trimethoprim component. Mortality and 
morbidity rates still are high. Therapy should be adminis
-
tered for at least 2–3 weeks. Longer durations—between 
 
3 and 6 weeks—have been recommended for treatment of 
meningitis, especially in immunocompromised persons.
Allerberger F et al. Pregnancy related listeriosis: treatment and 
control. Expert Rev Anti Infect Ther. 2015 Mar;13(3):
 
395–403. [PMID: 25604158]
Jackson BR et al; Centers for Disease Control and Prevention 
(CDC). Notes from the field: listeriosis associated with stone 
fruit—United States, 2014. MMWR Morb Mortal Wkly Rep. 
2015 Mar 20;64(10):282–3. [PMID: 25789745]
Madjunkov M et al. Listeriosis during pregnancy. Arch Gynecol 
Obstet. 2017 Aug;296(2):143–52. [PMID: 28536811]
 
º
INFECTIVE ENDOCARDITIS
 
»
Fever.
 
»
Preexisting organic heart lesion.
 
»
Positive blood cultures.
 
»
Evidence of vegetation on echocardiography.
 
»
Evidence of systemic emboli.
 
»
Endocarditis is a bacterial or fungal infection of the valvular 
or endocardial surface of the heart. The clinical presenta
-
tion depends on the infecting organism and the valve or 
valves that are infected. More virulent organisms—
S aureus
 
in particular—tend to produce a more rapidly progressive 
and destructive infection. Endocarditis caused by more 
virulent organisms often presents as an acute febrile ill
-
nesses and is complicated by early embolization, acute val
-
vular regurgitation, and myocardial abscess formation. 
Viridans strains of streptococci, enterococci, other bacteria, 
yeasts, and fungi tend to cause a more subacute picture.
Predisposing valvular abnormalities include rheumatic 
involvement of any valve, bicuspid aortic valves, calcific or 
sclerotic aortic valves, hypertrophic subaortic stenosis, mitral 
valve prolapse, and a variety of congenital disorders such as 
ventricular septal defect, tetralogy of Fallot, coarctation of the 
aorta, or patent ductus arteriosus. Rheumatic disease is no 
longer the major predisposing factor in developed countries. 
Regurgitation lesions are more susceptible than stenotic ones.
The initiating event in native valve endocarditis is colo
-
nization of the valve by bacteria or yeast that gain access to 
the bloodstream. Transient bacteremia is common during 
dental, upper respiratory, urologic, and lower gastrointesti
-
nal diagnostic and surgical procedures. It is less common 
during upper gastrointestinal and gynecologic procedures. 
Intravascular devices are increasingly implicated as a portal 
of access of microorganisms into the bloodstream. A large 
proportion of cases of 
S aureus
 endocarditis are attribut
-

S aureus
-
able to health care–associated bacteremia.
Native valve endocarditis
 is usually caused by 
S aureus
, 
viridans streptococci, enterococci, or HACEK organisms 
(an acronym for 
Haemophilus aphrophilus
 [now 
Aggregati
-
bacter aphrophilus
], 
Actinobacillus actinomycetemcomitans
 
[now 
Aggregatibacter actinomycetemcomitans
], 
Cardiobac
-
terium hominis, Eikenella corrodens
, and 
Kingella
 species). 
Streptococcal species formerly accounted for the majority 
of native valve endocarditis cases; 
S aureus
 is now the lead
-
ing cause. Gram-negative organisms and fungi account for 
a small percentage.
In injection drug users
, 
S aureus
 accounts for over 60% 
of all endocarditis cases and for 80–90% of cases in which 
the tricuspid valve is infected. Enterococci and streptococci 
comprise the balance in about equal proportions. Gram-
negative aerobic bacilli, fungi, and unusual organisms may 
cause endocarditis in injection drug users.
The microbiology of 
prosthetic valve endocarditis
 also 
is distinctive. Early infections (ie, those occurring within 
 
2 months after valve implantation) are commonly caused 
by staphylococci—both coagulase-positive and coagulase-
negative—gram-negative organisms, and fungi. In late 
prosthetic valve endocarditis, streptococci are commonly 
identified, although coagulase-negative and coagulase-
positive staphylococci still cause many cases.
 
»
Virtually all patients have fever at some point in the illness, 
although it may be very low grade (less than 38
°
C) in 
elderly individuals and in patients with heart failure or 
kidney failure. Rarely, there may be no fever at all.
The duration of illness typically is a few days to a few 
weeks. Nonspecific symptoms are common. The initial 
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symptoms and signs of endocarditis may be caused by 
direct arterial, valvular, or cardiac damage. Although a 
changing regurgitant murmur is significant diagnostically, 
it is the exception rather than the rule. Symptoms also may 
occur as a result of embolization, metastatic infection or 
immunologically mediated phenomena. These include 
cough; dyspnea; arthralgias or arthritis; diarrhea; and 
abdominal, back, or flank pain.
The characteristic peripheral lesions—petechiae (on the 
palate or conjunctiva or beneath the fingernails), subungual 
(“splinter”) hemorrhages (Figure 33–4), Osler nodes (pain
-
ful, violaceous raised lesions of the fingers, toes, or feet) 
(Figure 33–5), Janeway lesions (painless erythematous 
lesions of the palms or soles), and Roth spots (exudative 
lesions in the retina)—occur in about 25% of patients. 
Strokes and major systemic embolic events are present in 
about 25% of patients and tend to occur before or within the 
first week of antimicrobial therapy. Hematuria and protein
-
uria may result from emboli or immunologically mediated 
glomerulonephritis, which can cause kidney dysfunction.
B. Imaging
Chest radiograph may show evidence for the underlying 
cardiac abnormality and, in right-sided endocarditis, pul
-
monary infiltrates. The electrocardiogram is nondiagnostic, 
but new conduction abnormalities suggest myocardial 
abscess formation. Echocardiography is useful in identify
-
ing vegetations and other characteristic features suspicious 
for endocarditis and may provide adjunctive information 
about the specific valve or valves that are infected. The 
sensitivity of transthoracic echocardiography is between 
55% and 65%; it cannot reliably rule out endocarditis but 
may confirm a clinical suspicion. Transesophageal echo
-
cardiography is 90% sensitive in detecting vegetations and 
is particularly useful for identifying valve ring abscesses as 
well as prosthetic valve endocarditis.
1. Blood cultures—
Three sets of blood cultures are recom
-
mended before starting antibiotics to maximize microbio
-
logic diagnosis. To maximize the yield of blood cultures, 
adequate volume is important. Each culture bottle should 
be filled with 10 mL of blood since half of adults have less 
than 1 colony forming unit of bacteria per mL blood. The 
yield of bacteria may be up to 5% higher for every addi
-
tional milliliter collected.  Optimal yield is with two or 
three sets of cultures from different sites. There is no differ
-
ence in yield if blood is collected simultaneously or 
several hours apart.
Approximately 5% of cases will be culture-negative, 
usually attributable to administration of antimicrobials 
prior to cultures. If antimicrobial therapy has been 
 
▲
Figure 33–4.
 
Splinter hemorrhages appearing as 
red lineal streaks under the nail plate and within the 
nail bed, in endocarditis, psoriasis, and trauma. 
 
(Reproduced, with permission, from Richard P . Usatine, MD.)
 
▲
Figure 33–5.
 
Osler node causing pain within the 
pulp of the big toe and multiple painless flat Janeway 
lesions over the sole of the foot. 
from David A. Kasper, DO, MBA in Usatine RP , Smith MA, 
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administered prior to obtaining cultures and the patient is 
clinically stable, it is reasonable to withhold antimicrobial 
therapy for 2–3 days so that appropriate cultures can be 
obtained. Culture-negative endocarditis may also be due to 
organisms that require special media for growth (eg, 
Legionella, Bartonella, Abiotrophia
 species, formerly 
referred to as nutritionally deficient streptococci), organ
-
isms that do not grow on artificial media (
Tropheryma 
whipplei
, or pathogens of Q fever or psittacosis), or those 
that may require prolonged incubation (eg, 
Brucella
, anaer
-
obes, HACEK organisms). 
 is an impor
-
tant cause of culture-negative endocarditis.
2. Modified Duke criteria—
The Modified Duke criteria 
are useful for the diagnosis of endocarditis. Major criteria 
include (1) two positive blood cultures for a microorgan
-
ism that typically causes infective endocarditis or persistent 
bacteremia, or a single positive blood culture for 
Coxiella 
burnetii
 or anti–phase 1 IgG antibody titer greater than or 
equal to 1:800; (2) evidence of endocardial involvement 
documented by echocardiography showing definite vegeta
-
tion, myocardial abscess, new partial dehiscence of a pros
-
thetic valve, or new valvular regurgitation (increase or 
change in murmur is not sufficient). Minor criteria include 
the presence of a predisposing condition; fever of 38
°
C or 
higher; vascular phenomena, such as cutaneous hemor
-
rhages, aneurysm, systemic emboli, pulmonary infarction; 
immunologic phenomena, such as glomerulonephritis, 
Osler nodes, Roth spots, rheumatoid factor; and positive 
blood cultures not meeting the major criteria or serologic 
evidence of an active infection. A definite diagnosis can be 
made with 80% accuracy if two major criteria, one major 
criterion and three minor criteria, or five minor criteria 
 
are fulfilled. A possible diagnosis of endocarditis is made if 
one major and one minor criterion or three minor criteria 
are met. If fewer criteria are found, or a sound alternative 
explanation for illness is identified, or the patient’s febrile 
illness has resolved within 4 days, endocarditis is unlikely.
 
»
The course of infective endocarditis is determined by the 
degree of damage to the heart, by the site of infection 
(right-sided versus left-sided, aortic versus mitral valve), 
by the presence of metastatic foci of infection, by the 
occurrence of embolization, and by immunologically 
mediated processes. Destruction of infected heart valves is 
especially common and precipitous with 
S aureus
, but can 
occur with any organism and can progress even after bac
-
teriologic cure. The infection can also extend into the 
myocardium, resulting in abscesses leading to conduction 
disturbances, and involving the wall of the aorta, creating 
sinus of Valsalva aneurysms.
Peripheral embolization to the brain and myocardium 
may result in infarctions. Embolization to the spleen and 
kidneys is also common. Peripheral emboli may initiate 
metastatic infections or may become established in vessel 
walls, leading to mycotic aneurysms. Right-sided endocar
-
ditis, which usually involves the tricuspid valve, causes 
septic pulmonary emboli, occasionally with infarction and 
lung abscesses.
 
»
The American Heart Association recommends antibiotic 
prophylaxis for infective endocarditis in a relatively small 
group of patients with predisposing congenital or valvular 
anomalies (Table 33–3) undergoing select dental proce
-
dures, operations involving the respiratory tract, or opera
-
tions of infected skin, skin structure, or musculoskeletal 
tissue (Table 33–4). Current antimicrobial recommenda
-
tions are given in Table 33–5.
 
»
Treatment
Empiric regimens for endocarditis while culture results are 
pending should include agents active against staphylococci, 
streptococci, and enterococci. Vancomycin 1 g every

»
Treatment
streptococci, and enterococci. Vancomycin 1 g every 
 
12 hours intravenously plus ceftriaxone 2 g every 24 hours 
provides appropriate coverage pending definitive diagno
-
sis; consultation with an infectious disease expert is 
strongly recommended when initiating treatment.
A. Viridans Streptococci
For penicillin-susceptible viridans streptococcal endocardi
-
tis (ie, MIC 0.1 mcg/mL or less), penicillin G, 18 million 
units intravenously either continuously or in four to six 
equally divided doses or ceftriaxone 2 g intravenously once 
daily for 4 weeks, is recommended. The duration of therapy 
can be shortened to 2 weeks if gentamicin, 3 mg/kg intrave
-
nously every 24 hours, is used with penicillin or ceftriaxone. 
The 2-week regimen is reasonable and can be considered in 
patients with uncomplicated endocarditis, rapid response to 
therapy, and no underlying kidney disease. For the patient 
unable to tolerate penicillin or ceftriaxone, vancomycin, 
 
15 mg/kg intravenously every 12 hours for 4 weeks, is given 
with a desired trough level of 10–15 mcg/mL. Prosthetic 
Table 33–3.
 
Cardiac conditions with high risk of 
adverse outcomes from endocarditis for which prophy
-
laxis with dental procedures is recommended.
1,2
Prosthetic cardiac valve
Previous infective endocarditis
Congenital heart disease (CHD)
3
Unrepaired cyanotic CHD, including palliative shunts and 
conduits
Completely repaired congenital heart defect with prosthetic 
material or device, whether placed by surgery or by catheter 
intervention, during the first 6 months after the procedure
4
Repaired CHD with residual defects at the site or adjacent to 
 
the site of a prosthetic patch or prosthetic device
Cardiac transplantation recipients in whom cardiac valvulopathy 
develops
1
Reproduced, with permission, from Wilson W et al. Prevention of 
infective endocarditis. Circulation. 2007 Oct 9;116(15):1736–54. 
Copyright © 2007 American Heart Association, Inc.
2
See Table 33–5 for prophylactic regimens.
3
Except for the conditions listed above, antibiotic prophylaxis is no 
longer recommended for other forms of CHD.
4
Prophylaxis is recommended because endothelialization of pros
-
thetic material occurs within 6 months after procedure.
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valve endocarditis is treated with a 6-week course of 
penicillin or ceftriaxone and the clinician can consider 
adding 2 weeks of gentamicin at the start of therapy.
Viridans streptococci relatively resistant to penicillin 
(ie, MIC greater than 0.12 mcg/mL but less than or equal to 
0.5 mcg/mL) should be treated for 4 weeks. Penicillin G, 
 
24 million units intravenously either continuously or in 
four to six equally divided doses, is combined with genta
-
micin, 3 mg/kg intravenously every 24 hours for the first 
2 weeks. Ceftriaxone may be a reasonable alternative treat
-
ment option for isolates that are susceptible to ceftriaxone. 
In the patient with IgE-mediated allergy to penicillin, 
vancomycin alone, 15 mg/kg intravenously every 12 hours 
for 4 weeks, should be administered. Prosthetic valve endo
-
carditis is treated with a 6-week course of penicillin or 
ceftriaxone plus gentamicin as above.
Endocarditis caused by viridans streptococci with an 
MIC greater than 0.5 mcg/mL or by nutritionally deficient 
streptococci should be treated the same as enterococcal 
B. Other Streptococci
Endocarditis caused by 
S pneumoniae, S pyogenes
 (group A 
streptococcus), or groups B, C, and G streptococci is 
unusual. 
 sensitive to penicillin (MIC less 
than 0.1 mcg/mL) can be treated with penicillin 18 million 
equally divided doses or cefazolin 6 g intravenously either 
continuously or in three equally divided doses, or ceftriax
-
one 2 g daily intravenously for 4 weeks. High-dose 
penicillin (24 million units) or a third-generation cephalo
-
sporin may be required for the treatment of endocarditis 
(without meningitis) caused by strains resistant to penicil
-
lin (MIC greater than 0.1 mcg/mL). The addition of vanco
-
mycin and rifampin to ceftriaxone may be considered in 
 strains with cefotaxime MIC 
greater than 2 mcg/mL. Group A streptococcal infection 
can be treated with penicillin or ceftriaxone for 4–6 weeks. 
Groups B, C, and G streptococci tend to be more resistant to 
penicillin than group A streptococci, and some experts have 
recommended adding gentamicin, 3 mg/kg intravenously 
Table 33–4.
 
Recommendations for administration of 
bacterial endocarditis prophylaxis for patients accord
-
ing to type of procedure.
1
Prophylaxis Recommended
Prophylaxis Not 
Recommended
Dental procedures
All dental procedures that 
involve manipulation of gin
-
gival tissue or the periapical 
region of the teeth or perfo
-
ration of the oral mucosa
Respiratory tract procedures
Only respiratory tract proce
-
dures that involve incision of 
the respiratory mucosa
Procedures on infected skin, 
skin structure, or musculo
-
skeletal tissue
Routine anesthetic injections 
through noninfected tissue, 
taking dental radiographs, 
placement of removable 
prosthodontic or orthodontic 
appliances, adjustment of 
orthodontic appliances, 
placement of orthodontic 
brackets, shedding of decidu
-
ous teeth, and bleeding from 
trauma to the lips or oral 
mucosa
Gastrointestinal tract 
Genitourinary tract 
1
Table 33–5.
 
American Heart Association recommendations for endocarditis prophylaxis for dental procedures for 
patients with cardiac conditions.
1–3
Oral
Amoxicillin
2 g 1 hour before procedure
 
P
enicillin allergy
600 mg 1 hour before procedure
 
or
 
Cephalexin
2 g 1 hour before procedure (contraindicated if there is history of a beta-lactam immediate 
hypersensitivity reaction)
 
or
 
Azithromycin or 
clarithromycin
500 mg 1 hour before procedure
2 g intramuscularly or intravenously 30 minutes before procedure
 
P

or
 
P
600 mg intravenously 1 hour before procedure
 
or
 
Cefazolin
1 g intramuscularly or intravenously 30 minutes before procedure (contraindicated if there is 
history of a beta-lactam immediate hypersensitivity reaction)
1
Data from the American Heart Association. Circulation. 2007 Oct 9;116(15):1736–54.
2
For patients undergoing respiratory tract procedures involving incision of respiratory tract mucosa to treat an established infection or a 
procedure on infected skin, skin structure, or musculoskeletal tissue known or suspected to be caused by 
S aureus
, the regimen should 
contain an anti-staphylococcal penicillin or cephalosporin. Vancomycin can be used to treat patients unable to tolerate a beta-lactam or if 
the infection is known or suspected to be caused by a methicillin-resistant strain of 
S aureus
.
3
See Table 33–3 for list of cardiac conditions.
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every 24 hours, to penicillin for the first 2 weeks of a 4- to 
6-week course. Endocarditis caused by 
 
is associated with liver disease, especially cirrhosis, and 
gastrointestinal abnormalities, especially colon cancer. 
Colonoscopy should be performed to exclude the latter.
C. Enterococci
For enterococcal endocarditis, penicillin or ampicillin 
alone is inadequate. One recommended regimen is ampi
-
cillin, 2 g intravenously every 4 hours, or penicillin G, 
18–30 million units intravenously continuously or in six 
equally divided doses plus gentamicin, 1 mg/kg intrave
-
nously every 8 hours. The second recommended regimen 
is ampicillin (2 g intravenously every 4 hours) plus ceftri
-
axone 2 g intravenously every 12 hours. The recommended 
duration of therapy is 4–6 weeks (the longer duration for 
patients with symptoms for more than 3 months, relapse, 
or prosthetic valve endocarditis). The combination of 
ampicillin plus ceftriaxone is recommended for patients 
with creatinine clearance less than 50 mL/min or whose 
enterococcal isolates are resistant to gentamicin. In patients 
intolerant of penicillin and ampicillin or who have entero
-
coccal isolate resistant to these agents, vancomycin plus 
gentamicin can be used.
Endocarditis caused by strains resistant to penicillin and 
vancomycin are difficult to treat and should always be man
-
aged in consultation with an infectious diseases specialist.
D. Staphylococci
For methicillin-susceptible 
S aureus
 isolates, nafcillin or 
oxacillin, 12 g intravenously daily given continuously or in 
four to six divided doses or cefazolin, 6 g intravenously 
daily given continuously or in three divided doses for 
 
6 weeks, is the preferred therapy. In cases of brain abscess 
resulting from methicillin-susceptible 
S aureus
 endocardi
-
tis, nafcillin should be used instead of cefazolin. For 
patients with history of immediate type hypersensitivity to 
beta-lactams, a desensitization protocol should be under
-
taken. For patients with a history of nonanaphylactoid 
reactions to penicillins, cefazolin should be used. Patients 
who are infected with methicillin-resistant 
S aureus
 or who 
are unable to tolerate beta-lactam therapy should receive 
three doses to achieve a goal trough level of 15–20 mcg/kg, 
or daptomycin intravenously at greater than or equal to 
 
8 mg/kg/day. Aminoglycoside combination regimens are 
not recommended. The effect of rifampin with antistaphy
-
lococcal drugs is variable, and its routine use is not 
Because coagulase-negative staphylococci—a common 
cause of prosthetic valve endocarditis—are routinely resis
-
tant to methicillin, beta-lactam antibiotics should not be 
used for this infection unless the isolate is demonstrated to 
be susceptible. A combination of vancomycin, 30 mg/kg/day 
intravenously divided in two or three doses for 6 weeks; 
rifampin, 300 mg every 8 hours for 6 weeks; and gentamicin, 
3 mg/kg intravenously every 8 hours for the first 2 weeks is 
recommended for prosthetic valve infection. If the organism 
is sensitive to methicillin, either nafcillin or oxacillin or 
cefazolin can be used in combination with rifampin and 
gentamicin. Combination therapy with nafcillin or oxacillin 
(vancomycin or daptomycin for methicillin-resistant 
strains), rifampin, and gentamicin is also recommended for 
S aureus
 prosthetic valve infection.
E. HACEK Organisms
HACEK organisms are slow-growing, fastidious gram-
negative coccobacilli or bacilli (
H aphrophilus
 [now 
 
A aphrophilus
], 
A actinomycetemcomitans
, 
C hominis, 
 
E corrodens
, and 
Kingella
 species) that are normal oral flora 
and cause less than 5% of all cases of endocarditis. They 
may produce beta-lactamase, and thus the treatment of 
choice is ceftriaxone (or another third-generation cephalo
-

-
sporin), 2 g intravenously once daily for 4 weeks. Prosthetic 
valve endocarditis should be treated for 6 weeks. In the 
penicillin-allergic patient, experience is limited, but fluoro
-
quinolones have in vitro activity and should be considered.
F. Culture-Negative Endocarditis
Failure to culture microorganisms from patients with sus
-
pected infective endocarditis may be due to infection from 
organisms not recovered in routine microbiology testing or 
previous administration of antimicrobial agents before 
blood cultures were obtained. These cases must be man
-
aged with the assistance of an infectious disease specialist. 
Pathogens that are not able to be cultured by commonly 
used techniques include 
 species, 
Chlamydia
 spe
-
cies, 
Brucella
. Serologic 
testing should be performed in patients who have epide
-
miologic risk factors for these infections. Treatment should 
be directed at likely pathogens while awaiting serologic 
results; treatment of patients given prior antimicrobials 
before cultures were obtained must also consider likely 
G. Role of Surgery
While many cases can be successfully treated medically, 
operative management is frequently required. Acute heart 
failure unresponsive to medical therapy is an indication for 
valve replacement even if active infection is present. Infec
-
tions unresponsive to appropriate antimicrobial therapy 
after 7–10 days (ie, persistent fevers, positive blood cul
-
tures despite therapy) are more likely to be eradicated if the 
valve is replaced. Surgery is nearly always required for cure 
of fungal endocarditis and is more often necessary with 
highly resistant bacteria. It is also indicated when the infec
-
tion involves the sinus of Valsalva or produces septal 
abscesses. Recurrent infection with the same organism 
prompts an operative approach, especially with infected 
prosthetic valves. Continuing embolization presents a dif
-
ficult problem when the infection is otherwise responding; 
surgery may be the proper approach. Particularly challeng
-
ing is a large and fragile vegetation demonstrated by echo
-
cardiography in the absence of embolization. Most 
clinicians favor an operative approach with vegetectomy 
and valve repair if the patient is a good candidate. Emboli
-
zation after bacteriologic cure does not necessarily imply 
recurrence of endocarditis.
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H. Role of Anticoagulation
Anticoagulation is contraindicated in native valve endocar
-
ditis because of an increased risk of intracerebral hemor
-
rhage from mycotic aneurysms or embolic phenomena. 
The role of anticoagulant therapy during prosthetic valve 
endocarditis is more controversial. Reversal of anticoagula
-
tion may result in thrombosis of the mechanical prosthesis, 
particularly in the mitral position. Conversely, anticoagula
-
tion during active prosthetic valve endocarditis caused by 
 
S aureus
 has been associated with fatal intracerebral hem
-
orrhage. One approach is to discontinue anticoagulation 
during the septic phase of 
S aureus
 prosthetic valve endo
-
carditis. In patients with 
S aureus
 prosthetic valve endocar
-
ditis complicated by a CNS embolic event, anticoagulation 
should be discontinued for the first 2 weeks of therapy. 
Indications for anticoagulation following prosthetic valve 
implantation for endocarditis are the same as for patients 
with prosthetic valves without endocarditis (eg, nonpor
-
cine mechanical valves and valves in the mitral position).
 
»
Response to Therapy
If infection is caused by viridans streptococci, enterococci, 
or coagulase-negative staphylococci, defervescence occurs 
in 3–4 days on average; with 
S aureus
 or 
 
, fever may persist for longer. Blood cultures 
should be obtained every 1–2 days to document sterilization. 
Other causes of persistent fever are myocardial or metastatic 
abscess, sterile embolization, superimposed hospital-
acquired infection, and drug reaction. Most relapses occur 
within 1–2 months after completion of therapy. Obtaining 
one or two blood cultures during this period is prudent.
 
»
•	
Consider consulting an infectious diseases specialist in 
all cases of suspected infective endocarditis.
•	
Consult a cardiac surgeon in the situations mentioned 
in the Role of Surgery section above to prevent further 
embolic disease, heart failure, and other complications 
including death.
 
»
Patients with infective endocarditis should be hospitalized 
for expedited evaluation and treatment.
Wilson W et al. Prevention of infective endocarditis: guidelines 
from the American Heart Association: a guideline from the 
American Heart Association Rheumatic Fever, Endocarditis, 
and Kawasaki Disease Committee, Council on Cardiovascular 
Disease in the Y oung, and the Council on Clinical Cardiology, 
Council on Cardiovascular Surgery and Anesthesia, and the 
Quality of Care and Outcomes Research Interdisciplinary 
Working Group. Circulation. 2007 Oct 9; 116(15):1736–54. 
[PMID: 17446442]
 
º
INFECTIONS CAUSED BY 
 
GRAM-NEGATIVE BACTERIA
BORDETELLA PERTUSSIS 
INFECTION 
(
Whooping Cough
)
 
»
Predominantly in infants under age 2 years. 
 
Adolescents and adults are reservoirs of infection.
 
»
Two-week prodromal catarrhal stage of malaise, 
cough, coryza, and anorexia.
 
»
Paroxysmal cough ending in a high-pitched 
 
inspiratory “whoop. ”
 
»
Absolute lymphocytosis, often striking; culture 
 
»
Pertussis is an acute infection of the respiratory tract 
caused by 
B pertussis
 that is transmitted by respiratory 
droplets. The incubation period is 7–17 days. Half of all 
cases occur before age 2 years. Neither immunization 
nor disease confers lasting immunity to pertussis. Con
-
sequently, adults are an important reservoir of the 
disease.
 
»
The symptoms of classic pertussis last about 6 weeks and 
are divided into three consecutive stages. The

-
disease.
 
»
are divided into three consecutive stages. The 
catarrhal 
stage
 is characterized by its insidious onset, with lacrima
-
tion, sneezing, and coryza, anorexia and malaise, and a 
hacking night cough that becomes diurnal. The 
paroxysmal 
stage
 is characterized by bursts of rapid, consecutive 
coughs followed by a deep, high-pitched inspiration 
(whoop). The 
convalescent stage
 begins 4 weeks after 
onset of the illness with a decrease in the frequency and 
severity of paroxysms of cough. The diagnosis often is not 
considered in adults, who may not have a typical presenta
-
tion. Cough persisting more than 2 weeks is suggestive. 
Infection may also be asymptomatic.
The white blood cell count is usually 15,000–20,000/mcL 
(rarely, as high as 50,000/mcL or more), 60–80% of which 
are lymphocytes. The diagnosis is established by isolating 
the organism from nasopharyngeal culture. A special 
medium (eg, Bordet-Gengou agar) must be requested. 
Polymerase chain reaction assays for diagnosis of pertussis 
may be available in some clinical or health department 
laboratories.
 
»
Acellular pertussis vaccine is recommended for all infants, 
combined with diphtheria and tetanus toxoids (DTaP). 
Infants and susceptible adults with significant exposure 
should receive prophylaxis with an oral macrolide. In rec
-
ognition of their importance as a reservoir of disease, 
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vaccination of adolescents and adults against pertussis is 
recommended (see Table 30–7 and www.cdc.gov/vaccines/
schedules). Adolescents aged 11–18 years (preferably 
between 11 and 12 years of age) who have completed the 
DTP or DTaP vaccination series should receive a single 
dose of either Tdap product instead of Td (tetanus and 
diphtheria toxoids vaccine) for booster immunization 
against tetanus, diphtheria, and pertussis. Adults of all 
ages (including those older than age 64 years) should 
receive a single dose of Tdap. In addition, pregnant women 
should receive a dose of Tdap during each pregnancy 
regardless of prior vaccination history, ideally between 27 
and 36 weeks of gestation, in order to maximize the anti
-
body response of the woman and the passive antibody 
transfer to the infant. For any woman who was not previ
-
ously vaccinated with Tdap and for whom the vaccine was 
not given during her pregnancy, Tdap should be adminis
-
tered immediately postpartum. The CDC has eliminated 
the recommendation that a 2-year period window is 
needed between receiving the Td and Tdap vaccines based 
on data showing that there is not an increased risk of 
adverse events.
 
»
Treatment
Antibiotic treatment should be initiated in all suspected 
cases. Treatment options include erythromycin, 500 mg 
four times a day orally for 7 days; azithromycin, 500 mg 
orally on day 1 and 250 mg for 4 more days; or clarithro
-
mycin, 500 mg orally twice daily for 7 days. Trimethoprim-
sulfamethoxazole, 160 mg–800 mg orally twice a day for 
7 days, also is effective. Treatment shortens the duration 
of carriage and may diminish the severity of coughing 
paroxysms. These same regimens are indicated for pro
-
phylaxis of contacts to an active case of pertussis that are 
exposed within 3 weeks of the onset of cough in the index 
case.
DeSilva M et al. Tdap vaccination during pregnancy and micro
-
cephaly and other structural birth defects in offspring. JAMA. 
2016 Nov 1;316(17):1823–5. [PMID: 27802536]
Sukumaran L et al. Association of Tdap vaccination with acute 
events and adverse birth outcomes among pregnant women 
with prior tetanus-containing immunizations. JAMA. 2015 
Oct 20;314(15):1581–7. [PMID: 26501534]
Winter K et al. Effectiveness of prenatal versus postpartum teta
-
nus, diphtheria, and acellular pertussis vaccination in pre
-
venting infant pertussis. Clin Infect Dis. 2017 Jan 1;64(1):3–8. 
[PMID: 27624955]
OTHER 
BORDETELLA
Bordetella bronchiseptica
 is a pleomorphic gram-negative 
coccobacillus causing kennel cough in dogs. On occasion 
it causes upper and lower respiratory infection in humans, 
principally HIV-infected patients. Infection has been asso
-
ciated with contact with dogs and cats, suggesting animal-
to-human transmission. Treatment of 
B bronchiseptica
 
infection is guided by results of in vitro susceptibility 
tests.
MENINGOCOCCAL MENINGITIS
 
»
Fever, headache, vomiting, delirium, convulsions.
 
»
Petechial rash of skin and mucous membranes in 
many.
 
»
Neck and back stiffness with positive Kernig and 
Brudzinski signs is characteristic.
 
»
Purulent spinal fluid with gram-negative intracel
-
lular and extracellular diplococci.
 
»
Culture of cerebrospinal fluid, blood, or petechial 
aspiration confirms the diagnosis.
 
»
Meningococcal meningitis is caused by 
Neisseria 
 of groups A, B, C, Y , and W-135, among others. 
Meningitis due to serogroup A is uncommon in the 
United States. Serogroup B generally causes sporadic cases. 
Serogroup C meningococcus is the most common cause of 
epidemic disease in the United States. Up to 40% of persons 
are nasopharyngeal carriers of meningococci, but disease 
develops in relatively few of these persons. Infection is 
transmitted by droplets. The clinical illness may take the 
form of meningococcemia (a fulminant form of septicemia

form of meningococcemia (a fulminant form of septicemia 
without meningitis), meningococcemia with meningitis, or 
meningitis. Recurrent meningococcemia with fever, rash, 
and arthritis is seen rarely in patients with certain terminal 
complement deficiencies. Asplenic patients are also at risk.
 
»
High fever, chills, nausea, vomiting, and headache as well as 
back, abdominal, and extremity pains are typical. Rapidly 
developing confusion, delirium, seizures, and coma occur 
in some. On examination, nuchal and back rigidity are 
typical. Positive Kernig and Brudzinski signs (Kernig sign is 
pain in the hamstrings upon extension of the knee with the 
hip at 90-degree flexion; Brudzinski sign is flexion of the 
knee in response to flexion of the neck) are specific but not 
sensitive findings. A petechial rash appearing in the lower 
extremities and at pressure points is found in most cases. 
Petechiae may vary in size from pinpoint lesions to large 
ecchymoses or even skin gangrene that may later slough.
Lumbar puncture typically reveals a cloudy or purulent 
cerebrospinal fluid, with elevated pressure, increased pro
-
tein, and decreased glucose content. The fluid usually 
contains greater than 1000 cells/mcL, with polymorpho
-
nuclear cells predominating and containing gram-negative 
intracellular diplococci. The absence of organisms in a 
Gram-stained smear of the cerebrospinal fluid sediment 
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does not rule out the diagnosis. The capsular polysaccha
-
ride can be demonstrated in cerebrospinal fluid or urine by 
latex agglutination; this is useful in partially treated 
patients, though sensitivity is 60–80%. The organism is 
usually demonstrated by smear and culture of the cerebro
-
spinal fluid, oropharynx, blood, or aspirated petechiae.
Disseminated intravascular coagulation is an important 
complication of meningococcal infection and is typically 
present in toxic patients with ecchymotic skin lesions.
 
»
Meningococcal meningitis must be differentiated from 
other meningitides. In small infants and in older adults, 
fever or stiff neck is often missing, and altered mental sta
-
tus may dominate the picture.
Rickettsial, echovirus and, rarely, other bacterial infec
-
tions (eg, staphylococcal infections, scarlet fever) also 
cause petechial rash.
 
»
Four meningococcal vaccines are available. There are two 
vaccines with coverage against meningococcal serogroups 
A, C, Y , and W-135 and two with coverage against menin
-
gococcal serogroup B. The two vaccines effective for 
meningococcal serogroups A, C, Y , and W-135 are the 
meningococcal polysaccharide vaccine (MPSV4) indicated 
for vaccination of persons over age 55 and the conjugate 
vaccine (MCV4) indicated for persons aged 2–55 years. 
The two vaccines against meningococcal serogroup B are 
MenB-FHbp and MenB-4C are approved for persons aged 
10–25 years and are not interchangeable.
recommends immunization with a dose of MCV4 for pre
-
adolescents aged 11–12 with a booster at age 16 (see www
 
.cdc.gov/vaccines/schedules/hcp/child-adolescent.html). For 
ease of program implementation, persons aged 21 years or 
younger should have documentation of receipt of a dose of 
MCV4 not more than 5 years before enrollment to college. If 
the primary dose was administered before the sixteenth 
birthday, a booster dose should be administered before 
enrollment. Vaccine is also recommended as a two-dose 
 
primary series administered 2 months apart for persons aged 
2 through 54 years with persistent complement deficiency, 
persons with functional or anatomic asplenia, and for adoles
-
cents with HIV infection. All other persons at increased risk 
for meningococcal disease (eg, military recruits, microbiolo
-
gists, or travelers to an epidemic or highly endemic country) 
should receive a single dose. One of the meningococcal 
serogroup B vaccines may be administered to persons 
 
10 years of age or older who are at increased risk for menin
-
gococcal disease. These persons include those with persistent 
complement component deficiencies; persons with anatomic 
or functional asplenia; microbiologists routinely exposed to 
isolates of 
; and persons identified to be 
at increased risk because of a serogroup B meningococcal 
disease outbreak. Vaccination of persons aged 16–23 years 
may provide short-term protection against most strains of 
serogroup B meningococcal disease.
Eliminating nasopharyngeal carriage of meningococci 
is an effective prevention strategy in closed populations 
and to prevent secondary cases in household or otherwise 
close contacts. Rifampin, 600 mg orally twice a day for 
2 days, ciprofloxacin, 500 mg orally once, or one intramus
-
cular 250-mg dose of ceftriaxone is effective. Cases of 
fluoroquinolone-resistant meningococcal infections have 
been identified in the United States. However, ciprofloxa
-
cin remains a recommended empiric agent for eradication 
of nasopharyngeal carriage. School and work contacts 
ordinarily need not be treated. Hospital contacts receive 
therapy only if intense exposure has occurred (eg, mouth-
to-mouth resuscitation). Accidentally discovered carriers 
without known close contact with meningococcal disease 
do not require prophylactic antimicrobials.
 
»

»
Treatment
Blood cultures must be obtained and intravenous antimi
-
crobial therapy started immediately. This may be done 
prior to lumbar puncture in patients in whom the diagno
-
sis is not straightforward and for those in whom MR or CT 
imaging is indicated to exclude mass lesions. Aqueous 
penicillin G is the antibiotic of choice (24 million 
units/24 h intravenously in divided doses every 4 hours). 
The prevalence of strains of 
 with intermedi
-
ate resistance to penicillin in vitro (MICs 0.1 to 1 mcg/mL) 
is increasing, particularly in Europe. At what level of resis
-
tance penicillin treatment failure can occur is not known. 
Penicillin-intermediate strains thus far remain fully sus
-
ceptible to ceftriaxone and other third-generation cephalo
-
sporins used to treat meningitis, and these should be 
effective alternatives to penicillin. In penicillin-allergic 
patients or those in whom 
 or 
gram-negative meningitis is a consideration, ceftriaxone, 
 
2 g intravenously every 12 hours, should be used. Treatment 
should be continued in full doses by the intravenous route 
until the patient is afebrile for 5 days. Shorter courses—as 
few as 4 days if ceftriaxone is used—are also effective.
 
»
All patients with suspected meningococcal infection includ
-
ing meningitis and meningococcemia should be admitted 
for evaluation and empiric intravenous antibiotic therapy.
Di Caprio G et al. Increased rate of penicillin non-susceptible 
strains of 
N. meningitidis
 in Naples, Italy. J Chemother. 
2017 Dec;29(6):389–90. [PMID: 28728477]
MacNeil JR et al. Use of serogroup B meningococcal vaccines in 
adolescents and young adults: recommendations of the Advi
-
sory Committee on Immunization Practices, 2015. MMWR 
Morb Mortal Wkly Rep. 2015 Oct 23;64(41):1171–6. [PMID: 
26492381]
 
HAEMOPHILUS
 SPECIES
 and other 
 species may cause 
sinusitis, otitis, bronchitis, epiglottitis, pneumonia, celluli
-
tis, arthritis, meningitis, and endocarditis. Nontypeable 
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strains are responsible for most disease in adults. 
Alcoholism, smoking, chronic lung disease, advanced age, 
and HIV infection are risk factors. 
 species 
colonize the upper respiratory tract in patients with chronic 
obstructive pulmonary disease and frequently cause puru
-
lent bronchitis.
Beta-lactamase–producing strains are less common in 
adults than in children. For adults with sinusitis, otitis, or 
respiratory tract infection, oral amoxicillin, 750 mg twice 
daily for 10–14 days, is adequate. For beta-lactamase–
producing strains, use of the oral fixed-drug combination 
of amoxicillin, 875 mg, with clavulanate, 125 mg, is indi
-
cated. For the penicillin-allergic patient, oral cefuroxime 
axetil, 250 mg twice daily; or a fluoroquinolone (cipro
-
floxacin, 500 mg orally twice daily; levofloxacin, 
500–750 mg orally once daily; or moxifloxacin, 400 mg 
orally once daily) for 7 days is effective. Azithromycin, 
500 mg orally once followed by 250 mg daily for 4 days, is 
preferred over clarithromycin when a macrolide is the pre
-
ferred agent. Trimethoprim-sulfamethoxazole (160/800 mg 
orally twice daily) can be considered, but resistance rates 
have been reported to be up to 25%.
In the more seriously ill patient (eg, the toxic patient 
with multilobar pneumonia), ceftriaxone, 1 g/day intrave
-
nously is recommended pending determination of whether 
the infecting strain is a beta-lactamase producer. A fluoro
-
quinolone (see above for dosages) can be used for the 
penicillin-allergic patients for a 10- to 14-day course of 
therapy.
Epiglottitis
 is characterized by an abrupt onset of high 
fever, drooling, and inability to handle secretions. An 
important clue to the diagnosis is complaint of a severe 
sore throat despite an unimpressive examination of the 
pharynx. Stridor and respiratory distress result from laryn
-
geal obstruction. The diagnosis is best made by direct 
visualization of the cherry-red, swollen epiglottis at laryn
-
goscopy. Because laryngoscopy may provoke laryngospasm 
and obstruction, especially in children, it should be per
-
formed in an intensive care unit or similar setting, and only 
at a time when intubation can be performed promptly. 
Ceftriaxone, 1 g intravenously every 24 hours for 7–10 days, 
is the drug of choice. Trimethoprim-sulfamethoxazole or a 
fluoroquinolone (see above for dosage) may be used in the 
patient with serious penicillin allergy.
, rare in adults, is a consideration in the 
patient who has meningitis associated with sinusitis or 
otitis. Initial therapy for suspected 
 meningitis 
should be with ceftriaxone, 4 g/day in two divided doses, 
until the strain is proved not to produce beta-lactamase. 
Meningitis is treated for at least 7 days. Dexamethasone, 
0.15 mg/kg intravenously every 6 hours may reduce the 
incidence of long-term sequelae, principally hearing loss.
Brouwer MC et al. Epidemiology of community-acquired bacte
-
rial meningitis. Curr Opin Infect Dis. 2018 Feb;31(1):78–84. 
[PMID: 29176349]
Sriram KB et al. Nontypeable 
 and 
chronic obstructive pulmonary disease: a review for clini
-
cians. Crit Rev Microbiol. 2018 Mar;44(2):125–42. [PMID: 
28539074]
 
MORAXELLA CATARRHALIS
 is a gram-negative aerobic coccus morphologi
-
cally and biochemically similar to 
Neisseria
. It causes sinus
-
itis, bronchitis, and pneumonia. Bacteremia and meningitis 
have also been reported in immunocompromised patients. 
The organism frequently colonizes the respiratory tract, 
making differentiation of colonization from infection diffi
-
cult. If 
 is the predominant isolate, therapy is 
directed against it. 
 typically produces beta-
lactamase and therefore is usually resistant to ampicillin and 
amoxicillin. It is susceptible to amoxicillin-clavulanate, 
ampicillin-sulbactam, trimethoprim-sulfamethoxazole, cip
-

-
rofloxacin, and second- and third-generation cephalosporins.
LEGIONNAIRES DISEASE
 
»
Patients are often immunocompromised, smokers, 
or have chronic lung disease.
 
»
Scant sputum production, pleuritic chest pain, 
toxic appearance.
 
»
Chest radiograph:
 focal patchy infiltrates or 
consolidation.
 
»
Gram stain of sputum:
 polymorphonuclear leuko
-
cytes and no organisms.
 
»
 infection ranks among the three or four most 
common causes of community-acquired pneumonia and is 
considered whenever the etiology of a pneumonia is in 
question. Legionnaires disease is more common in immu
-
nocompromised persons, in smokers, and in those with 
chronic lung disease. Outbreaks have been associated with 
contaminated water sources, such as showerheads and fau
-
cets in patient rooms and air conditioning cooling towers.
 
»
Legionnaires disease is one of the atypical pneumonias, so 
called because a Gram-stained smear of sputum does not 
show organisms. However, many features of Legionnaires 
disease are more like typical pneumonia, with high fevers, 
toxic appearance, pleurisy, and grossly purulent sputum. 
Nausea, vomiting, and diarrhea may be prominent. Classi
-
cally, this pneumonia is caused by 
Legionella pneumophila
, 
though other species can cause identical disease.
There may be hyponatremia, elevated liver enzymes, and 
elevated creatine kinase. Culture of 
 species has a 
80–90% sensitivity. Dieterle silver staining of tissue, pleural 
fluid, or other infected material is also a reliable method for 
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detecting 
 species. Direct fluorescent antibody 
stains and serologic testing such as urinary antigen are less 
sensitive because these will detect only 
L pneumophila
 
serotype 1. In addition, making a serologic diagnosis 
requires that the host respond with sufficient specific anti
-
body production.
 
»
Treatment
Azithromycin (500 mg orally once daily), clarithromycin 
(500 mg orally twice daily), or a fluoroquinolone (eg, levo
-
floxacin, 750 mg orally once daily), and not erythromycin, 
are the drugs of choice for treatment of legionellosis 
because of their excellent intracellular penetration and in 
vitro activity, as well as desirable pharmacokinetic proper
-
ties that permit oral administration and once or twice daily 
dosing. Duration of therapy is 10–14 days, although a 
21-day course of therapy is recommended for immuno
-
compromised patients.
Cunha CB et al. Legionnaire’s disease since Philadelphia: lessons 
learned and continued progress. Infect Dis Clin North Am. 
2017 Mar;31(1):1–5. [PMID: 27979687]
Del Castillo M et al. Atypical presentation of 
 
pneumonia among patients with underlying cancer: a fifteen-
year review. J Infect. 2016 Jan;72(1):45–51. [PMID: 26496794]
GRAM-NEGATIVE BACTEREMIA & SEPSIS
Gram-negative bacteremia can originate in a number of 
sites, the most common being the genitourinary system, 
hepatobiliary tract, gastrointestinal tract, and lungs. Less 
common sources include intravenous lines, infusion fluids, 
surgical wounds, drains, and pressure injuries.
Patients with potentially fatal underlying conditions in 
the short term such as neutropenia or immunoparesis have 
a mortality rate of 40–60%; those with serious underlying 
diseases likely to be fatal in 5 years, such as solid tumors, 
cirrhosis, and aplastic anemia, die in 15–20% of cases; and 
individuals with no underlying diseases have a mortality 
rate of 5% or less.
 
»
Most patients have fevers and chills, often with abrupt 
onset. However, 15% of patients are hypothermic 
(temperature 36.4
°
C or less) at presentation, and 5% never 
develop a temperature above 37.5
°
C. Hyperventilation 
with respiratory alkalosis and changes in mental status are 
important early manifestations. Hypotension and shock, 
which occur in 20–50% of patients, are unfavorable prog
-
nostic signs.
Neutropenia or neutrophilia, often with increased numbers of 
immature forms of polymorphonuclear leukocytes, is the 
most common laboratory abnormality in septic patients. 
Thrombocytopenia occurs in 50% of patients, laboratory evi
-
dence of coagulation abnormalities in 10%, and overt 
disseminated intravascular coagulation in 2–3%. Both clinical 
manifestations and the laboratory abnormalities are nonspe
-
cific and insensitive, which accounts for the relatively low rate 
of blood culture positivity (approximately 20–40%). If 
possible, three blood cultures from separate sites should be 
obtained in rapid succession before starting antimicrobial 
therapy. The chance of recovering the organism in at least one 
of the three blood cultures is greater than 95%. The false-
negative rate for a single culture of 5–10 mL of blood is 30%. 
This may be reduced to 5–10% (albeit with a slight false-
positive rate due to isolation of contaminants) if a single vol
-
ume of 30 mL is inoculated into several blood culture bottles. 
Because blood cultures may be falsely negative, when a patient 
with presumed septic shock, negative blood cultures, and inad
-
equate explanation for the clinical course responds to antimi
-
crobial agents, therapy should be continued for 10–14 days.
 
»
Treatment
Several factors are important in the management of patients 
with sepsis.
A. Removal of Predisposing Factors
This usually means decreasing or stopping immunosup
-
pressive medications and, in certain circumstances, giving

-
pressive medications and, in certain circumstances, giving 
granulocyte colony-stimulating factor (filgrastim; G-CSF) 
to the neutropenic patient.
B. Identifying the Source of Bacteremia
By simply finding the source of bacteremia and removing 
it (central venous catheter) or draining it (abscess), a fatal 
disease becomes easily treatable.
C. Supportive Measures
The use of fluids, vasopressors, and corticosteroids in sep
-
tic shock are discussed in Chapter 14; management of dis
-
seminated intravascular coagulation is discussed in 
D. Antibiotics
-
pected, since delays in therapy have been associated with 
increased mortality rates, particularly once hypotension 
develops. In general, bactericidal antibiotics should be 
used and given intravenously to ensure therapeutic serum 
levels. Penetration of antibiotics into the site of primary 
infection is critical for successful therapy—ie, if the infec
-
tion originates in the CNS, antibiotics that penetrate the 
blood-brain barrier should be used—eg, third- or fourth-
generation cephalosporin—but not first-generation cepha
-
losporins or aminoglycosides, which penetrate poorly. 
Sepsis caused by gram-positive organisms cannot be dif
-
ferentiated on clinical grounds from that due to gram-
negative bacteria. Therefore, initial therapy should include 
antibiotics active against both types of organisms.
The number of antibiotics necessary remains controver
-
sial and depends on the cause. Table 30–4 provides a guide 
for empiric therapy. Although a combination of antibiotics 
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is often recommended for “synergism, ” combination ther
-
apy has not been shown to be superior to a single-drug regi
-
men with any of several broad-spectrum antibiotics (eg, a 
third-generation cephalosporin, piperacillin-tazobactam, 
carbapenem). If multiple drugs are used initially, the regi
-
men should be modified and coverage narrowed based on 
the results of culture and sensitivity testing.
Aillet C et al. Bacteraemia in emergency departments: effective 
antibiotic reassessment is associated with a better outcome. 
Eur J Clin Microbiol Infect Dis. 2018 Feb;37(2):325–31. 
[PMID: 29164361]
Amaral AC et al; Cooperative Antimicrobial Therapy of Septic 
Shock Database Research Group. Patient and organizational 
factors associated with delays in antimicrobial therapy for 
septic shock. Crit Care Med. 2016 Dec;44(12):2145–53. 
[PMID: 27441899]
SALMONELLOSIS
Salmonellosis includes infection by any of approximately 
2000 serotypes of salmonellae. All 
 serotypes are 
members of a single species, 
Salmonella enterica
. Human 
infections are caused almost exclusively by 
S enterica
 subsp 
enterica
, of which three serotypes—
typhi
, 
typhimurium
, and 
choleraesuis
—are predominantly isolated. Three clinical pat
-
terns of infection are recognized: (1) enteric fever, the best 
example of which is typhoid fever, due to serotype 
typhi;
 
(2) acute enterocolitis, caused by serotype 
, 
among others; and (3) the “septicemic” type, characterized by 
bacteremia and focal lesions, exemplified by infection with 
serotype 
. All types are transmitted by ingestion 
of the organism, usually from tainted food or drink.
1. Enteric Fever (Typhoid Fever)
 
»
Gradual onset of malaise, headache, nausea, vom
-
iting, abdominal pain.
 
»
Rose spots, relative bradycardia, splenomegaly, 
and abdominal distention and tenderness.
 
»
Slow (stepladder) rise of fever to maximum and 
then slow return to normal.
 
»
Leukopenia; blood, stool, and urine cultures posi
-
tive for salmonella.
 
»
Enteric fever is a clinical syndrome characterized by gastroin
-
testinal symptoms as well as constitutional symptoms such as 
fever, malaise, and headache. It may have a long incubation 
period (6–30 days), and  the gastrointestinal symptoms 
may  resolve but then recur. Progressive infection often 
evolves with delirium. Enteric fever  can be caused by any 
  species, including 
S  typhi
  (typhoid fever)  and 
non-typhoidal strains, especially 
S paratyphi
 subtype A in the 
United States. Infection begins when organisms breach the 
mucosal epithelium of the intestines. Having crossed the 
epithelial barrier, organisms invade and replicate in macro
-
phages in Peyer patches, mesenteric lymph nodes, and the 
spleen. Serotypes other than 
typhi
 usually do not cause inva
-
sive disease, presumably because they lack the necessary 
human-specific virulence factors. Bacteremia occurs, and the 
infection then localizes principally in the lymphoid tissue of 
the small intestine. Peyer patches become inflamed and may 
ulcerate, with involvement greatest during the third week of 
disease. The organism may disseminate to the lungs, gall
-
bladder, kidneys, or CNS.
 
»
During the prodromal stage, there is increasing malaise, head
-
ache, cough, and sore throat, often with abdominal pain and 
constipation, while the fever ascends in a stepwise fashion. 
After about 7–10 days, it reaches a plateau and the patient is 
much more ill. There may be marked constipation, especially 
early, or “pea soup” diarrhea; marked abdominal distention 
occurs as well. If there are no complications, the patient’s con
-
dition will gradually improve over 7–10 days. However, 
relapse may occur for up to 2 weeks after defervescence.
During the early prodrome, physical findings are few.

-
During the early prodrome, physical findings are few. 
Later, splenomegaly, abdominal distention and tenderness, 
relative bradycardia, and occasionally meningismus appear. 
The rash (rose spots) commonly appears during the second 
week of disease. The individual spot, found principally on 
the trunk, is a pink papule 2–3 mm in diameter that fades 
on pressure. It disappears in 3–4 days.
Leukopenia is typical. Typhoid fever is best diagnosed by 
blood culture, which is positive in the first week of illness in 
80% of patients who have not taken antimicrobials. The rate 
of positivity declines thereafter, but one-fourth or more of 
patients still have positive blood cultures in the third week. 
Cultures of bone marrow occasionally are positive when 
blood cultures are not. Stool culture is unreliable because it 
may be positive in gastroenteritis without typhoid fever.
 
»
Enteric fever must be distinguished from other gastrointes
-
tinal illnesses and from other infections that have few local
-
izing findings. Examples include tuberculosis, infective 
endocarditis, brucellosis, lymphoma, and Q fever. Often 
there is a history of recent travel to endemic areas, and viral 
hepatitis, malaria, or amebiasis may be in the differential.
 
»
Complications occur in about 30% of untreated cases and 
account for 75% of deaths. Intestinal hemorrhage, mani
-
fested by a sudden drop in temperature and signs of shock 
followed by dark or fresh blood in the stool, or intestinal 
perforation, accompanied by abdominal pain and tender
-
ness, is most likely to occur during the third week. Appear
-
ance of leukocytosis and tachycardia should suggest these 
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complications. Urinary retention, pneumonia, thrombo
-
phlebitis, myocarditis, psychosis, cholecystitis, nephritis, 
osteomyelitis, and meningitis are less often observed.
 
»
Immunization is not always effective, but should be consid
-
ered for household contacts of a typhoid carrier, for travel
-
ers to endemic areas, and during epidemic outbreaks. A 
multiple-dose oral vaccine and a single-dose parenteral 
vaccine are available. Their efficacies are similar, but oral 
vaccine causes fewer side effects. Boosters, when indicated, 
should be given every 5 years and 2 years for oral and par
-
enteral preparations, respectively.
Adequate waste disposal and protection of food and 
water supplies from contamination are important public 
health measures to prevent salmonellosis. Carriers cannot 
work as food handlers.
 
»
Treatment
Because of increasing antimicrobial resistance, 
fluoroquinolones—such as ciprofloxacin 750 mg orally 
twice daily or levofloxacin 500 mg orally once daily, 
 
5–7 days for uncomplicated enteric fever and 10–14 days for 
severe infection—are the agents of choice for treatment of 
salmonella infections. Ceftriaxone, 2 g intravenously for 
 
7 days, is also effective. Although resistance to fluoroquino
-
lones or cephalosporins occurs uncommonly, the preva
-
lence is increasing. When an infection is caused by a 
multidrug-resistant strain, select an antibiotic to which the 
isolate is susceptible in vitro. Alternatively, increasing the 
dose of ceftriaxone to 4 g/day and treating for 10–14 days or 
using azithromycin 500 mg orally for 7 days in uncompli
-
cated cases may be effective. In years past, ampicillin, chlor
-
amphenicol, and trimethoprim-sulfamethoxazole had been 
effective treatments but resistance has spread globally.
B. Treatment of Carriers
Ciprofloxacin, 750 mg orally twice a day for 4 weeks, has 
proved to be highly effective in eradicating the carrier state. 
Cholecystectomy may also achieve this goal. When the 
isolate is susceptible, treatment of carriage with ampicillin, 
trimethoprim-sulfamethoxazole, or chloramphenicol may 
be successful.
 
»
Prognosis
The mortality rate of typhoid fever is about 2% in treated 
cases. Elderly or debilitated persons are likely to do worse. 
With complications, the prognosis is poor. Relapses occur 
in up to 15% of cases. A residual carrier state frequently 
persists in spite of therapy.
Wain J et al. Typhoid fever. Lancet. 2015 Mar 21;385(9973): 
1136–45. [PMID: 25458731]
Zuckerman JN et al. Review of current typhoid fever vaccines, 
cross-protection against paratyphoid fever, and the European 
guidelines. Expert Rev Vaccines. 2017 Oct;16(10):1029–43. 
[PMID: 28856924]
2. 
 Gastroenteritis
By far the most common form of salmonellosis is acute 
enterocolitis, which can be caused by both typhoidal and 
non-typhoidal 
. The incubation period is 
8–48 hours after ingestion of contaminated food or liquid.
Symptoms and signs consist of fever (often with 
chills), nausea and vomiting, cramping abdominal pain, 
and diarrhea, which may be grossly bloody, lasting 
 
3–5 days. Differentiation must be made from viral gas
-
troenteritis, food poisoning, shigellosis, amebic dysen
-
tery, and acute ulcerative colitis. The diagnosis is made 
by culturing the organism from the stool. The disease is 
usually self-limited, but bacteremia with localization in 
joints or bones may occur, especially in patients with 
In most cases, treatment of uncomplicated enterocolitis 
is symptomatic only. However, patients who are malnour
-
ished or severely ill, patients with sickle cell disease, and 
patients who are immunocompromised (including those 
who are HIV-positive) should be treated with ciprofloxa
-
cin, 500 mg orally twice a day; ceftriaxone, 1 g intrave
-
nously once daily; trimethoprim-sulfamethoxazole, 160 mg/

-
-
 
80 mg orally twice a day; or azithromycin, 500 mg orally 
once daily for 7–14 days (14 days for immunocompro
-
mised patients).
65(12):1963–73. [PMID: 29194529]
Williams S et al. 
 in the tropical household 
environment—everyday, everywhere. J Infect. 2015 
Dec;71(6):642–8. [PMID: 26416474]
3. 
 Bacteremia
 infection may be manifested by prolonged or 
recurrent fevers accompanied by bacteremia and local 
infection in bone, joints, pleura, pericardium, lungs, or 
other sites. Mycotic abdominal aortic aneurysms may 
also occur. Serotypes other than typhi usually are iso
-
lated. This complication of bacteremia tends to occur in 
immunocompromised persons, including HIV-infected 
individuals, who typically have bacteremia without an 
obvious source. Treatment is the same as for typhoid 
fever, plus drainage of any abscesses. In HIV-infected 
patients, relapse is common, and lifelong suppressive 
therapy may be needed. Ciprofloxacin, 750 mg orally 
twice a day, is effective both for therapy of acute infec
-
tion and for suppression of recurrence. Incidence of 
infections caused by drug-resistant strains may be on 
the rise.
Crump JA et al. Epidemiology, clinical presentation, laboratory 
diagnosis, antimicrobial resistance, and antimicrobial man
-
agement of invasive salmonella infections. Clin Microbiol 
Rev. 2015 Oct;28(4):901–37. [PMID: 26180063]
Gibani MM et al. Control of invasive salmonella disease in 
Africa: is there a role for human challenge models? Clin Infect 
Dis. 2015 Nov 1;61(Suppl 4):S266–71. [PMID: 26449941]
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SHIGELLOSIS
 
»
Diarrhea, often with blood and mucus.
 
»
Crampy abdominal pain and systemic toxicity.
 
»
White blood cells in stools; organism isolated on 
stool culture.
 
»
Shigella
 dysentery is a common disease, often self-limited 
and mild but occasionally serious. 
S sonnei
 is the leading 
cause in the United States, followed by 
S flexneri. 
 
S dysenteriae
 causes the most serious form of the illness. 
Shigellae are invasive organisms. The infective dose is low 
at 10
2
–10
3
 organisms. There has been a rise in strains resis
-
tant to multiple antibiotics.
 
»
The illness usually starts abruptly, with diarrhea, lower 
abdominal cramps, and tenesmus. The diarrheal stool 
often is mixed with blood and mucus. Systemic symptoms 
are fever, chills, anorexia and malaise, and headache. The 
abdomen is tender. Sigmoidoscopic examination reveals an 
inflamed, engorged mucosa with punctate and sometimes 
large areas of ulceration.
The stool shows many leukocytes and red cells. Stool cul
-
ture is positive for shigellae in most cases, but blood cul
-
tures grow the organism in less than 5% of cases.
 
»
Bacillary dysentery must be distinguished from salmonella 
enterocolitis and from disease due to enterotoxigenic 
Escherichia coli, Campylobacter
, and 
. 
Amebic dysentery may be similar clinically and is diagnosed 
by finding amoebas in the fresh stool specimen. Ulcerative 
colitis is also an important cause of bloody diarrhea.
 
»
Temporary disaccharidase deficiency may follow the diar
-
rhea. Reactive arthritis is an uncommon complication, 
usually occurring in HLA-B27 individuals infected by 
Shigella
. Hemolytic-uremic syndrome occurs rarely.
 
»
Treatment
Treatment of dehydration and hypotension is lifesaving in 
severe cases. Recommended empiric antimicrobial therapy 
is either a fluoroquinolone (ciprofloxacin, 750 mg orally 
twice daily for 7–10 days, or levofloxacin, 500 mg orally 
once daily for 3 days) or ceftriaxone, 1 g intravenously once 
daily for 5 days. If the isolate is susceptible, trimethoprim-
sulfamethoxazole, 160/80 mg orally twice daily for 5 days 
or azithromycin, 500 mg orally once daily for 3 days, is also 
effective. High rates of resistance to amoxicillin make it a 
less effective treatment option.
Goulart MA et al. Shigellosis in men who have sex with men: an 
overlooked opportunity to counsel with pre-exposure pro
-
phylaxis for HIV . Int J STD AIDS. 2016 Nov;27(13):1236–8. 
[PMID: 26945593]
Puzari M et al. Emergence of antibiotic resistant Shigella species: 
a matter of concern. J Infect Public Health. 2017 Oct 20. 
[Epub ahead of print] [PMID: 29066021]
GASTROENTERITIS CAUSED 
 
BY 
ESCHERICHIA COLI
E coli
 causes gastroenteritis by a variety of mechanisms. 
E coli
 (ETEC) elaborates either a heat-
stable or heat-labile toxin that mediates the disease. ETEC 
is an important cause of traveler’s diarrhea. Enteroinvasive 
E coli
 (EIEC) differs from other 
E coli
 bowel pathogens in 
that these strains invade cells, causing bloody diarrhea and 
dysentery similar to infection with 
Shigella
 species. EIEC is 
uncommon in the United States. Neither ETEC nor EIEC 
strains are routinely isolated and identified from stool cul
-
tures because there is no selective medium. Antimicrobial 
therapy against 
 and 
Shigella
, such as ciprofloxa
-
cin 500 mg orally twice daily, shortens the clinical course, 
but the disease is self-limited.
E coli
 (STEC) infection can 
result in asymptomatic carrier stage, nonbloody diarrhea,

E coli
result in asymptomatic carrier stage, nonbloody diarrhea, 
hemorrhagic colitis, hemolytic-uremic syndrome, or 
thrombotic thrombocytopenic purpura. Although 
E coli
 
O157:H7 is responsible for most cases of STEC infection in 
the United States, other STEC strains that cause severe 
disease (such as 
E coli
 O104:H4) have been reported in 
Europe. 
E coli
 O157:H7 has caused several outbreaks of 
diarrhea and hemolytic-uremic syndrome related to con
-
sumption of undercooked hamburger, unpasteurized apple 
juice, and spinach, while 
E coli
 O145 was linked to the 
consumption of contaminated lettuce. Older individuals 
and young children are most affected, with hemolytic-
uremic syndrome being more common in the latter group. 
STEC identification can be difficult and the CDC recom
-
mends that all stools submitted for routine testing from 
patients with acute community-acquired diarrhea be 
simultaneously cultured for 
E coli
 O157:H7 and tested with 
an assay that detects Shiga toxins to detect non-O157 
STEC, such as 
E coli
 O145. Antimicrobial therapy does not 
alter the course of the disease and may increase the risk of 
hemolytic-uremic syndrome. Treatment is primarily sup
-
portive. Hemolytic-uremic syndrome or thrombotic 
thrombocytopenic purpura occurring in association with a 
diarrheal illness suggests the diagnosis and should prompt 
evaluation for STEC. Confirmed infections should be 
reported to public health officials.
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Lübbert C. Antimicrobial therapy of acute diarrhoea: a clinical 
review. Expert Rev Anti Infect Ther. 2016;14(2):193–206. 
[PMID: 26641310]
Marder EP et al. Incidence and trends of infections with patho
-
gens transmitted commonly through food and the effect of 
increasing use of culture-independent diagnostic tests on 
surveillance—Foodborne Diseases Active Surveillance Net
-
work, 10 U.S. Sites, 2013–2016. MMWR Morb Mortal Wkly 
Rep. 2017 Apr 21;66(15):397–403. [PMID: 28426643]
CHOLERA
 
»
History of travel in endemic area or contact with 
infected person.
 
»
Voluminous diarrhea (up to 15 L/day).
 
»
Characteristic “rice water stool. ”
 
»
Rapid development of marked dehydration.
 
»
Positive stool cultures and agglutination of vibrios 
with specific sera.
 
»
Cholera is an acute diarrheal illness caused by certain sero
-
types of 
. The disease is toxin-mediated, and 
fever is unusual. The toxin activates adenylyl cyclase in 
intestinal epithelial cells of the small intestines, producing 
hypersecretion of water and chloride ion and a massive diar
-
rhea of up to 15 L/day. Death results from profound hypovo
-
lemia. Cholera occurs in epidemics under conditions of 
crowding, war, and famine (eg, in refugee camps) and where 
sanitation is inadequate. Infection is acquired by ingestion of 
contaminated food or water. For over a century, cholera was 
rarely seen in the Western Hemisphere until an outbreak 
occurred in Peru, starting in the early 1990s and ending by 
2001; the outbreak resulted in almost 400,000 cholera cases 
and more than 4000 deaths. Cholera again became a rare 
disease in the Western Hemisphere until late 2010, when 
there was a massive earthquake in Haiti followed by a chol
-
era outbreak that resulted in thousands of deaths.
 
»
Cholera is characterized by a sudden onset of severe, fre
-
quent watery diarrhea (up to 1 L/h). The liquid stool is 
gray; turbid; and without fecal odor, blood, or pus (“rice 
water stool”). Dehydration and hypotension develop rap
-
idly. Stool cultures are positive, and agglutination of vibrios 
with specific sera can be demonstrated.
 
»
A vaccine is available that confers short-lived, limited protec
-
tion and may be required for entry into or reentry after travel 
to some countries. It is administered in two doses 1–4 weeks 
apart. A booster dose every 6 months is recommended for 
persons remaining in areas where cholera is a hazard.
Vaccination programs are expensive and not particu
-
larly effective in managing outbreaks of cholera. When 
outbreaks occur, efforts should be directed toward estab
-
lishing clean water and food sources and proper waste 
disposal.
 
»
Treatment
Treatment is by replacement of fluids. In mild or moderate 
illness, oral rehydration usually is adequate. A simple oral 
replacement fluid can be made from 1 teaspoon of table 
salt and 4 heaping teaspoons of sugar added to 1 L of water. 
Intravenous fluids are indicated for persons with signs of 
severe hypovolemia and those who cannot take adequate 
fluids orally. Lactated Ringer infusion is satisfactory.
Antimicrobial therapy will shorten the course of illness. 
Antimicrobials active against 
V cholerae
 include tetracy
-
cline, ampicillin, chloramphenicol, trimethoprim-
sulfamethoxazole, fluoroquinolones, and azithromycin. 
Multiple drug-resistant strains are increasingly encoun
-
tered, so susceptibility testing, if available, is advisable. 
A single 1 g oral dose of azithromycin is effective for severe 
cholera caused by strains with reduced susceptibility to 
fluoroquinolones, but resistance is emerging to this drug as 
well.
Wong KK et al. Recommendations of the Advisory Committee 
on Immunization Practices for use of cholera vaccine. 
MMWR Morb Mortal Wkly Rep. 2017 May 12;66(18):482–5. 
[PMID: 28493859]
INFECTIONS CAUSED BY OTHER 
 
VIBRIO
 SPECIES

VIBRIO
 SPECIES
Vibrios other than 
V cholerae
 that cause human disease are 
Vibrio parahaemolyticus, V vulnificus
, and 
V alginolyticus
. 
All are halophilic marine organisms. Infection is acquired 
by exposure to organisms in contaminated, undercooked, 
or raw crustaceans or shellfish and warm (greater than 
20
°
C [82.4
°
F]) ocean waters and estuaries. Infections are 
more common during the summer months from regions 
along the Atlantic coast and the Gulf of Mexico in the 
United States and from tropical waters around the world. 
Oysters are implicated in up to 90% of food-related cases. 
V parahaemolyticus
 causes an acute watery diarrhea with 
crampy abdominal pain and fever, typically occurring 
within 24 hours after ingestion of contaminated shellfish. 
The disease is self-limited, and antimicrobial therapy is 
usually not necessary. 
 may also cause 
cellulitis and sepsis, though these findings are more char
-
acteristic of 
V vulnificus
 and 
—neither of which is 
associated with diarrheal illness—are important causes of 
cellulitis and primary bacteremia following ingestion of 
contaminated shellfish or exposure to sea water. Cellulitis 
with or without sepsis may be accompanied by bulla for
-
mation and necrosis with extensive soft tissue destruction, 
at times requiring debridement and amputation. The 
infection can be rapidly progressive and is particularly 
severe in immunocompromised individuals—especially 
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those with cirrhosis—with death rates as high as 50%. 
Patients with chronic liver disease and those who are 
immunocompromised should be cautioned to avoid eating 
raw oysters.
Tetracycline at a dose of 500 mg orally four times a day 
for 7–10 days is the drug of choice for treatment of sus
-
pected or documented primary bacteremia or cellulitis 
caused by 
Vibrio
 species. 
 is susceptible in vitro 
to penicillin, ampicillin, cephalosporins, chloramphenicol, 
aminoglycosides, and fluoroquinolones, and these agents 
may also be effective. 
 and 
 
produce beta-lactamase and therefore are resistant to peni
-
cillin and ampicillin, but susceptibilities otherwise are 
similar to those listed for 
.
Baker-Austin C et al. 
Vibrio vulnificus
: new insights into a deadly 
opportunistic pathogen. Environ Microbiol. 2018 Feb; 
20(2):423–30. [PMID: 29027375]
Wong KC et al. Antibiotic use for 
Vibrio
 infections: important 
insights from surveillance data. BMC Infect Dis. 2015 Jun 11; 
15:226. [PMID: 26062903]
 
CAMPYLOBACTER
 SPECIES
 organisms are microaerophilic, motile, 
gram-negative rods. Two species infect humans: 
Campylo
-
bacter jejuni
, an important cause of diarrheal disease, and 
C fetus
 subsp 
fetus
, which typically causes systemic infec
-
tion and not diarrhea. Dairy cattle and poultry are an 
important reservoir for campylobacters. Outbreaks of 
enteritis have been associated with consumption of raw 
milk. 
 gastroenteritis is associated with 
fever, abdominal pain, and diarrhea characterized by loose, 
watery, or bloody stools. The differential diagnosis includes 
shigellosis, 
 gastroenteritis, and enteritis caused 
by 
 or invasive 
E coli
. The disease is self-
limited, but its duration can be shortened with antimicro
-
bial therapy. Either azithromycin, 1 g orally as a single 
dose, or ciprofloxacin, 500 mg orally twice daily for 3 days, 
is effective therapy. However, fluoroquinolone resistance 
among 
C jejuni
 isolates has been increasing, particularly in 
Southeast Asia, and susceptibility testing should be rou
-
tinely performed.
C fetus
 causes systemic infections that can be fatal, 
including primary bacteremia, endocarditis, meningitis, 
and focal abscesses. It infrequently causes gastroenteritis. 
Patients infected with 
C fetus
 are often older, debilitated, or 
immunocompromised. Closely related species, collectively 
termed “campylobacter-like organisms, ” cause bacteremia 
in HIV-infected individuals. Systemic infections respond 
to therapy with gentamicin, chloramphenicol, ceftriaxone, 
or ciprofloxacin. Ceftriaxone or chloramphenicol should 
be used to treat infections of the CNS because of their abil
-
ity to penetrate the blood-brain barrier.
BRUCELLOSIS
 
»
History of animal exposure, ingestion of unpas
-
teurized milk or cheese.
 
»
Insidious onset: easy fatigability, headache, 
arthralgia, anorexia, sweating, irritability.
 
»
Intermittent and persistent fever.
 
»
Cervical and axillary lymphadenopathy; 
hepatosplenomegaly.
 
»
Lymphocytosis, positive blood culture, positive 
serologic test.
 
»
The infection is transmitted from animals to humans. 
Brucella abortus
 (cattle), 
B suis
 (hogs), and 
B melitensis
 
(goats) are the main agents. Transmission to humans 
occurs by contact with infected meat (slaughterhouse 
workers), placentae of infected animals (farmers, veteri
-
narians), or ingestion of infected unpasteurized milk or 
cheese. The incubation period varies from a few days to 
several weeks. Brucellosis is a systemic infection that may

-
several weeks. Brucellosis is a systemic infection that may 
become chronic. In the United States, brucellosis is very 
rare. Almost all US cases are imported from countries 
where brucellosis is endemic (eg, Mexico, Mediterranean 
Europe, Spain, South American countries).
 
»
The onset may be acute, with fever, chills, and sweats, but 
more often is insidious with symptoms of weakness, weight 
loss, low-grade fevers, sweats, and exhaustion upon minimal 
activity. Headache, abdominal or back pain with anorexia 
and constipation, and arthralgias are also common. The 
chronic form may assume an undulant nature, with periods 
of normal temperature between acute attacks; symptoms 
may persist for years, either continuously or intermittently.
Fever, hepatosplenomegaly, and lymphadenopathy are 
the most common physical findings. Infection may present 
with or be complicated by specific organ involvement 
with signs of endocarditis, meningitis, epididymitis, 
orchitis, arthritis (especially sacroiliitis), spondylitis, or 
The organism can be recovered from cultures of blood, 
cerebrospinal fluid, urine, bone marrow, or other sites. 
Cultures are more likely to be negative in chronic cases. 
The diagnosis often is made by serologic testing.
 
»
Brucellosis must be differentiated from any other acute 
febrile disease, especially influenza, tularemia, Q fever, 
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mononucleosis, and enteric fever. In its chronic form it 
resembles Hodgkin disease, tuberculosis, HIV infection, 
malaria, and disseminated fungal infections such as histo
-
plasmosis and coccidioidomycosis.
 
»
The most frequent complications are bone and joint lesions 
such as spondylitis and suppurative arthritis (usually of a 
single joint), endocarditis (often culture negative), and 
meningoencephalitis. Less common complications are 
pneumonitis with pleural effusion, hepatitis, and 
cholecystitis.
 
»
Treatment
Single-drug regimens are not recommended because the 
relapse rate may be as high as 50%. Combination regimens 
of two or three drugs are most effective. Regimens of 
doxycycline (200 mg/day orally for 6 weeks) plus rifampin 
(600 mg/day orally for 6 weeks) or streptomycin (1 g/day 
intramuscularly for 2 weeks) or gentamicin (240 mg intra
-
muscularly once daily for 7 days) have the lowest recur
-
rence rates. Longer courses of therapy may be required to 
prevent relapse of meningitis, osteomyelitis, or 
Herrick JA et al. 
Brucella
 arteritis: clinical manifestations, treat
-
ment, and prognosis. Lancet Infect Dis. 2014 Jun;14(6):520–6. 
[PMID: 24480149]
Vilchez G et al. Brucellosis in pregnancy: clinical aspects and 
obstetric outcomes. Int J Infect Dis. 2015 Sep;38:95–100. 
[PMID: 26159844]
TULAREMIA
 
»
History of contact with rabbits, other rodents, and 
biting ticks in summer in endemic area.
 
»
Fever, headache, nausea, and prostration.
 
»
Papule progressing to ulcer at site of inoculation.
 
»
Enlarged regional lymph nodes.
 
»
Serologic tests or culture of ulcer, lymph node 
aspirate, or blood confirm the diagnosis.
 
»
Tularemia is a zoonotic infection of wild rodents and rab
-
bits caused by 
. Humans usually 
acquire the infection by contact with animal tissues 
(eg, trapping muskrats, skinning rabbits) or from a tick or 
insect bite. Hamsters and prairie dogs also may carry the 
organism. An outbreak of pneumonic tularemia on 
Martha’s Vineyard in Massachusetts was linked to lawn-
mowing and brush-cutting as risk factors for infection, 
underscoring the potential for probable aerosol transmis
-
sion of the organism. 
F tularensis
 has been classified as a 
high-priority agent for potential bioterrorism use because 
of its virulence and relative ease of dissemination. Infection 
in humans often produces a local lesion and widespread 
organ involvement but may be entirely asymptomatic. The 
incubation period is 2–10 days.
 
»
Fever, headache, and nausea begin suddenly, and a local 
lesion—a papule at the site of inoculation—develops and 
soon ulcerates. Regional lymph nodes may become 
enlarged and tender and may suppurate. The local lesion 
may be on the skin of an extremity or in the eye. Pneumonia 
may develop from hematogenous spread of the organism 
or may be primary after inhalation of infected aerosols, 
which are responsible for human-to-human transmission. 
Following ingestion of infected meat or water, an enteric 
form may be manifested by gastrointestinal symptoms, 
stupor, and delirium. In any type of involvement, the 
spleen may be enlarged and tender and there may be non
-
specific rashes, myalgias, and prostration.
Culturing the organism from blood or infected tissue 
requires special media. For this reason and because cul
-
tures of 
 may be hazardous to laboratory per
-
sonnel, the diagnosis is usually made serologically. 
A positive agglutination test (greater than 1:80) develops in 
the second week after infection and may persist for several 
years.
 
»
Tularemia must be differentiated from rickettsial and 
meningococcal infections, cat-scratch disease, infectious 
mononucleosis, and various bacterial and fungal diseases.
 
»

»
Hematogenous spread may produce meningitis, perisple
-
nitis, pericarditis, pneumonia, and osteomyelitis.
 
»
Treatment
Streptomycin is drug of choice for treatment of tularemia. 
The recommended dose is 7.5 mg/kg intramuscularly 
every 12 hours for 7–14 days. Gentamicin, which has good 
in vitro activity against 
, is generally less toxic 
than streptomycin and probably just as effective. Doxycy
-
cline (200 mg/day orally) is also effective but has a higher 
relapse rate. A variety of other agents (eg, fluoroquino
-
lones) are active in vitro, but their clinical effectiveness is 
less well established.
Maurin M et al. Tularaemia: clinical aspects in Europe. Lancet 
Infect Dis. 2016 Jan;16(1):113–24. [PMID: 26738841]
Y anes H et al. Evaluation of in-house and commercial serological 
tests for diagnosis of human tularemia. J Clin Microbiol. 
2018 Jan;56(1). pii: e01440–17. [PMID: 29118164]
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PLAGUE
 
»
History of exposure to rodents in endemic area.
 
»
Sudden onset of high fever, muscular pains, and 
 
»
Axillary, cervical, or inguinal lymphadenitis (bubo).
 
»
Pustule or ulcer at inoculation site.
 
»
Pneumonia or meningitis is often fatal.
 
»
Positive smear and culture from bubo and positive 
blood culture.
 
»
Plague is an infection of wild rodents with 
, a 
small bipolar-staining gram-negative rod. It is endemic in 
California, Arizona, Nevada, and New Mexico. It is trans
-
mitted among rodents and to humans by the bites of fleas 
or from contact with infected animals. Following a fleabite, 
the organisms spread through the lymphatics to the lymph 
nodes, which become greatly enlarged (buboes). They may 
then reach the bloodstream to involve all organs. When 
pneumonia or meningitis develops, the outcome is often 
fatal. The patient with pneumonia can transmit the infec
-
tion to other individuals by droplets. The incubation 
period is 2–10 days. Because of its extreme virulence, its 
potential for dissemination and person-to-person trans
-
mission, and efforts to develop the organism as an agent of 
biowarfare, plague bacillus is considered a high-priority 
agent for bioterrorism.
 
»
The onset is sudden, with high fever, malaise, tachycardia, 
intense headache, delirium, and severe myalgias. The 
patient appears profoundly ill. If pneumonia develops, 
tachypnea, productive cough, blood-tinged sputum, and 
cyanosis also occur. There may be signs of meningitis. 
A pustule or ulcer at the site of inoculation and lymphan
-
gitis may be observed. Axillary, inguinal, or cervical lymph 
nodes become enlarged and tender and may suppurate and 
drain. With hematogenous spread, the patient may rapidly 
become toxic and comatose, with purpuric spots (black 
plague) appearing on the skin.
Primary plague pneumonia is a fulminant pneumonitis 
with bloody, frothy sputum and sepsis. It is usually fatal 
unless treatment is started within a few hours after onset.
The plague bacillus may be found in smears from aspirates 
of buboes examined with Gram stain. Cultures from bubo 
aspirate or pus and blood are positive but may grow slowly. 
In convalescing patients, an antibody titer rise may be 
demonstrated by agglutination tests.
 
»
The lymphadenitis of plague is most commonly mistaken 
for the lymphadenitis accompanying staphylococcal or 
streptococcal infections of an extremity, sexually transmit
-
ted diseases such as lymphogranuloma venereum or syphi
-
lis, and tularemia. The systemic manifestations resemble 
those of enteric or rickettsial fevers, malaria, or influenza. 
The pneumonia resembles other bacterial pneumonias, 
and the meningitis is similar to those caused by other 
bacteria.
 
»
Avoiding exposure to rodents and fleas in endemic areas is 
the best prevention strategy. Drug prophylaxis may provide 
temporary protection for persons exposed to the risk of 
plague infection, particularly by the respiratory route. 
Doxycycline, 100 mg twice daily for 7 days, is effective. No 
vaccine is available at this time.
 
»
Treatment
Therapy should be started immediately once plague is sus
-
pected. Either streptomycin (the agent with which there is 
greatest experience), 1 g every 12 hours intravenously, or 
gentamicin, administered as a 2-mg/kg loading dose, then 
1.7 mg/kg every 8 hours intravenously, is effective. Alterna
-
tively, doxycycline, 100 mg orally or intravenously, may be 
used. The duration of therapy is 10 days. Patients with 
plague pneumonia are placed in strict respiratory isolation, 
and prophylactic therapy is given to any person who came 
in contact with the patient.
Runfola JK et al; Centers for Disease Control and Prevention 
(CDC). Outbreak of human pneumonic plague with dog-to-

human and possible human-to-human transmission—
Colorado, June–July 2014. MMWR Morb Mortal Wkly Rep. 
2015 May 1;64(16):429–34. [PMID: 25928467]
Y ang R. Plague: recognition, treatment, and prevention. J Clin 
Microbiol. 2018 Jan;56(1). pii: e01519–17. [PMID: 29070654]
GONOCOCCAL INFECTIONS
 
»
Purulent, profuse urethral discharge with dysuria, 
especially in men; yields positive smear.
 
»
Men:
 epididymitis, prostatitis, periurethral inflam
-
mation, proctitis, pharyngitis.
 
»
Women:
 cervicitis with purulent discharge, or 
asymptomatic, yielding positive culture; vaginitis, 
salpingitis, proctitis also occur.
 
»
Disseminated disease:
 fever, rash, tenosynovitis, 
and arthritis.
 
»
Gram-negative intracellular diplococci seen in a 
smear or cultured from the urethra, cervix, 
pharynx, or rectum.
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»
Gonorrhea is caused by 
, a gram-
negative diplococcus typically found inside polymorpho
-
nuclear cells. It is transmitted during sexual activity and 
has its greatest incidence in the 15- to 29-year-old age 
group. The incubation period is usually 2–8 days.
 
»
A. Urethritis and Cervicitis
Initial symptoms seen in men
 include burning on urina
-
tion and a serous or milky discharge. One to 3 days later, 
the urethral pain is more pronounced and the discharge 
becomes yellow, creamy, and profuse, sometimes blood-
tinged. The disorder may regress and become chronic or 
progress to involve the prostate, epididymis, and periure
-
thral glands with painful inflammation. Chronic infection 
leads to prostatitis and urethral strictures. Rectal infection 
is common in men who have sex with men. Atypical sites 
of primary infection (eg, the pharynx) must always be con
-
sidered. Asymptomatic infection is common and occurs in 
both sexes.
Gonococcal infection in women
 often becomes symp
-
tomatic during menses. Women may have dysuria, urinary 
frequency, and urgency, with a purulent urethral discharge. 
Vaginitis and cervicitis with inflammation of Bartholin 
glands are common. Infection may be asymptomatic, with 
only slightly increased vaginal discharge and moderate 
cervicitis on examination. Infection may remain as a 
chronic cervicitis—an important reservoir of gonococci. It 
can progress to involve the uterus and tubes with acute and 
chronic salpingitis, with scarring of tubes and sterility. In 
pelvic inflammatory disease, anaerobes and chlamydiae 
often accompany gonococci. Rectal infection may result 
from spread of the organism from the genital tract or from 
anal coitus.
Nucleic acid amplification tests are the preferred 
method for diagnosing all types of gonorrhea given their 
excellent sensitivity and specificity. In women with sus
-
pected cervical infection, endocervical or vaginal swabs 
(clinician- or self-collected) as well as first catch 
am
 urine 
specimen (later specimens have 10% reduced sensitivity) 
are options. In men with urethral infection, first catch 
am
 
urine is recommended. Nucleic acid amplification tests are 
also recommended by the CDC for oropharyngeal and 
rectal sites testing although they are not FDA approved for 
these specimen types. Gram stain of urethral or rectal dis
-
charge in men, especially during the first week after onset, 
shows gram-negative diplococci in polymorphonuclear 
leukocytes. Gram stain is less often positive in women. 
Cultures should still be obtained when evaluating a treat
-
ment failure to assess for antimicrobial resistance.
B. Disseminated Disease
Systemic complications follow the dissemination of gono
-
cocci from the primary site via the bloodstream. Two dis
-
tinct clinical syndromes—either purulent arthritis or the 
triad of rash, tenosynovitis, and arthralgias—are com
-
monly observed in patients with disseminated gonococcal 
infection, although overlap can be seen. The skin lesions 
can range from maculopapular to pustular or hemorrhagic, 
which tend to be few in number and peripherally located. 
The tenosynovitis is often found in the hands and wrists 
and feet and ankles. These unique findings can help distin
-
guish among other infectious syndromes. The arthritis can 
occur in one or more joints and may be migratory. Gono
-
cocci are isolated by culture from less than half of patients 
with gonococcal arthritis. Rarely, gonococcal endocarditis 
or meningitis develops.
C. Conjunctivitis
The most common form of eye involvement is direct inocu
-
lation of gonococci into the conjunctival sac. In adults, this 
occurs by autoinoculation of a person with genital infec
-
tion. The purulent conjunctivitis may rapidly progress to 
panophthalmitis and loss of the eye unless treated promptly. 
A single 1-g dose of ceftriaxone is effective.
 
»

-
 
»
Gonococcal urethritis or cervicitis must be differentiated 
from nongonococcal urethritis; cervicitis or vaginitis due 
to 
Chlamydia trachomatis, Gardnerella vaginalis, 
Trichomonas, Candida
, and many other pathogens associ
-
ated with sexually transmitted diseases; and pelvic inflam
-
matory disease, arthritis, proctitis, and skin lesions. Often, 
several such pathogens coexist in a patient. Reactive 
arthritis (urethritis, conjunctivitis, arthritis) may mimic 
gonorrhea or coexist with it.
 
»
Prevention is based on education and mechanical or 
chemical prophylaxis. The condom, if properly used, can 
reduce the risk of infection. Partner notification and refer
-
ral of contacts for treatment has been the standard method 
used to control sexually transmitted diseases. Early treat
-
ment of contacts can halt the development of symptoms as 
well. Expedited treatment of sex partners by patient-
delivered partner therapy is more effective than partner 
notification in reducing persistence and recurrence rates 
of gonorrhea and chlamydia.
 
»
Treatment
Therapy typically is administered before antimicrobial 
susceptibilities are known. The choice of which regimen to 
use should be based on the national prevalences of antibi
-
otic-resistant organisms. Nationwide, strains of gonococci 
that are resistant to penicillin, tetracycline, or ciprofloxacin 
have been increasingly observed. Consequently, these 
drugs can no longer be considered first-line therapy. All 
sexual partners should be treated and tested for HIV infec
-
tion and syphilis, as should the patient.
A. Uncomplicated Gonorrhea
Due to increasing resistance of 
 to cephalo
-
sporins, the CDC recommends a higher dose of intramus
-
cular ceftriaxone in combination with a second drug 
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(azithromycin or doxycycline) regardless of concern for 
possible secondary infection with chlamydia. For uncom
-
plicated gonococcal infections of the cervix, urethra, and 
rectum, the recommended treatment is ceftriaxone (250 mg 
intramuscularly) plus azithromycin (1000 mg orally as a 
single dose). In cases where an oral cephalosporin is the 
only option, cefixime, 400 mg orally as a single dose, can be 
combined with azithromycin as above. When azithromycin 
is not an option, doxycycline at 100 mg orally twice daily 
for 7 days can be substituted. Fluoroquinolones are no 
longer recommended for treatment due to high rates of 
microbial resistance. Spectinomycin, 1 g intramuscularly 
once, may be used for the penicillin-allergic patient but is 
not currently available in the United States. Pharyngeal 
gonorrhea is also treated with ceftriaxone (250 mg intra
-
muscularly) plus azithromycin (1000 mg orally as a single 
dose) but for conjunctival gonorrhea the recommendation 
is for ceftriaxone (1 g intramuscularly) plus azithromycin 
(1000 mg orally as a single dose).
B. Treatment of Other Infections
Disseminated gonococcal infection (including arthritis and 
arthritis-dermatitis syndromes) should be treated with 
ceftriaxone (1 g intravenously daily) plus azithromycin 
(1000 mg orally as a single dose), until 48 hours after 
improvement begins, at which time therapy may be 
switched to cefixime (400 mg orally daily) to complete at 
least 1 week of antimicrobial therapy. Endocarditis should 
be treated with ceftriaxone (2 g every 24 hours intrave
-
nously) for at least 4 weeks.
Pelvic inflammatory disease requires cefoxitin (2 g par
-
enterally every 6 hours) or cefotetan (2 g intravenously 
every 12 hours) plus doxycycline (100 mg every 12 hours). 
Clindamycin (900 mg intravenously every 8 hours) plus 
gentamicin (administered intravenously as a 2-mg/kg load
-
ing dose followed by 1.5 mg/kg every 8 hours) is also effec
-
tive. Ceftriaxone (250 mg intramuscularly as a single dose) 
or cefoxitin (2 g intramuscularly) plus probenecid (1 g 
orally as a single dose) plus doxycycline (100 mg twice a 
day for 14 days), with or without metronidazole (500 mg 
twice daily for 14 days) is an effective outpatient regimen.
Fifer H et al. Failure of dual antimicrobial therapy in treatment 
of gonorrhea. N Engl J Med. 2016 Jun 23;374(25):2504–6. 
[PMID: 27332921]
CHANCROID
Chancroid is a sexually transmitted disease caused by the 
short gram-negative bacillus 
Haemophilus ducreyi
. The 
incubation period is 3–5 days. At the site of inoculation, a 
vesicopustule develops that breaks down to form a painful, 
soft ulcer with a necrotic base, surrounding erythema, and 
undermined edges. There may be multiple lesions due to 
autoinoculation. The adenitis is usually unilateral and 
consists of tender, matted nodes of moderate size with 
overlying erythema. These may become fluctuant and rup
-
ture spontaneously. With lymph node involvement, fever, 
chills, and malaise may develop. Balanitis and phimosis are 
frequent complications in men. Women may have no 
external signs of infection. The diagnosis is established by 
culturing a swab of the lesion onto a special medium.
Chancroid must be differentiated from other genital 
ulcers. The chancre of syphilis is clean and painless, with a 
hard base. Mixed sexually transmitted disease is very com
-
mon (including syphilis, herpes simplex, and HIV infec
-
tion), as is infection of the ulcer with fusiforms, spirochetes, 
and other organisms.
A single dose of either azithromycin, 1 g orally, or cef
-
triaxone, 250 mg intramuscularly, is effective treatment. 
Effective multiple-dose regimens are erythromycin, 500 mg

-
Effective multiple-dose regimens are erythromycin, 500 mg 
orally four times a day for 7 days, or ciprofloxacin, 500 mg 
orally twice a day for 3 days.
GRANULOMA INGUINALE
Granuloma inguinale is a chronic, relapsing granuloma
-
tous anogenital infection due to 
Calymmatobacterium 
(Donovania) granulomatis
. The pathognomonic cell, found 
in tissue scrapings or secretions, is large (25–90 mcm) and 
contains intracytoplasmic cysts filled with bodies (Donovan 
bodies) that stain deeply with Wright stain.
The incubation period is 8 days to 12 weeks. The onset 
is insidious. The lesions occur on the skin or mucous 
membranes of the genitalia or perineal area. They are rela
-
tively painless infiltrated nodules that soon slough. A shal
-
low, sharply demarcated ulcer forms, with a beefy-red 
friable base of granulation tissue. The lesion spreads by 
contiguity. The advancing border has a characteristic 
rolled edge of granulation tissue. Large ulcerations may 
advance onto the lower abdomen and thighs. Scar forma
-
tion and healing occur along one border while the oppo
-
site border advances.
Superinfection with spirochete-fusiform organisms is 
common. The ulcer then becomes purulent, painful, foul-
smelling, and extremely difficult to treat.
Several therapies are available. Because of the indolent 
nature of the disease, duration of therapy is relatively long. 
The following recommended regimens should be given for 
3 weeks or until all lesions have healed: doxycycline, 
100 mg orally twice daily; or azithromycin, 1 g orally once 
weekly; or ciprofloxacin, 750 mg orally twice daily; or 
erythromycin, 500 mg orally four times a day.
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BARTONELLA
 SPECIES
 species are responsible for a wide variety of 
clinical syndromes. 
Bacillary angiomatosis
, an important 
manifestation of bartonellosis, is discussed in Chapter 31. 
A variety of atypical infections, including retinitis, enceph
-
alitis, osteomyelitis, and persistent bacteremia and endo
-
carditis (especially consider in culture-negative 
endocarditis) have been described.
Trench fever
 is a self-limited, louse-borne relapsing 
febrile disease caused by 
B quintana
. The disease has 
occurred epidemically in louse-infested troops and civilians 
during wars and endemically in residents of scattered geo
-
graphic areas (eg, Central America). An urban equivalent of 
trench fever has been described among the homeless. 
Humans acquire infection when infected lice feces enter sites 
of skin breakdown. Onset of symptoms is abrupt and fever 
lasts 3–5 days, with relapses. The patient complains of weak
-
ness and severe pain behind the eyes and typically in the 
back and legs. Lymphadenopathy, splenomegaly, and a tran
-
sient maculopapular rash may appear. Subclinical infection 
is frequent, and a carrier state is recognized. The differential 
diagnosis includes other febrile, self-limited states such as 
dengue, leptospirosis, malaria, relapsing fever, and typhus. 
Recovery occurs regularly even in the absence of treatment.
Cat-scratch disease
 is an acute infection of children 
and young adults caused by 
. It is trans
-
mitted from cats to humans as the result of a scratch or bite. 
Within a few days, a papule or ulcer will develop at the 
inoculation site in one-third of patients. One to 3 weeks 
later, fever, headache, and malaise occur. Regional lymph 
nodes become enlarged, often tender, and may suppurate. 
Lymphadenopathy from cat scratches resembles that due to 
neoplasm, tuberculosis, lymphogranuloma venereum, and 
bacterial lymphadenitis. The diagnosis is usually made 
clinically. Special cultures for bartonellae, serology, or exci
-
sional biopsy, though rarely necessary, confirm the diagno
-
sis. The biopsy reveals necrotizing lymphadenitis and is 
itself not specific for cat-scratch disease. Cat-scratch dis
-
ease is usually self-limited, requiring no specific therapy. 
Encephalitis occurs rarely.
Disseminated forms of the disease—bacillary angioma
-
tosis, peliosis hepatis, and retinitis—occur most commonly 
in immunocompromised patients such as persons with late 
stages of HIV or solid organ transplant recipients. The 
lesions are vasculoproliferative and histopathologically 
distinct from those of cat-scratch disease. Unexplained 
fever in patients with late stages of HIV infection is not 
uncommonly due to bartonellosis. 
B quintana
, the agent of 
trench fever, can also cause bacillary angiomatosis and 
persistent bacteremia or endocarditis (which will be 
“culture-negative” unless specifically sought), the latter two 
entities being associated with homelessness. Due to the 
fastidious nature of the organism and its special growth 
requirements, serologic testing (eg, demonstration of a 
high antibody titer in an indirect immunofluorescence 
assay) or nucleic acid amplification tests are often required 
to establish a diagnosis.
The disseminated forms of the disease (bacillary angio
-
matosis, peliosis hepatis, and retinitis) require a prolonged 
course of antibiotic therapy often in combination with a 
second agent. Bacteremia and endocarditis can be effec
-
tively treated with a 6-week course of doxycycline (200 mg 
orally or intravenously in two divided doses per day) plus 
either gentamicin 3 mg/kg/day intravenously or rifampin 
600 mg/day orally in two divided doses. Relapse may occur.
Edouard S et al. 
, a common cause of endocarditis: a 
report on 106 cases and review. J Clin Microbiol. 2015 Mar; 
53(3):824–9. [PMID: 25540398]
Okaro U et al. 
 species, an emerging cause of blood-

culture-negative endocarditis. Clin Microbiol Rev. 2017 Jul; 
30(3):709–46. [PMID: 28490579]
ANAEROBIC INFECTIONS
Anaerobic infections tend to be polymicrobial and 
abscesses are common. Pus and infected tissue often are 
malodorous. Septic thrombophlebitis and metastatic infec
-
tion are frequent and may require incision and drainage. 
Diminished blood supply that favors proliferation of anaer
-
obes because of reduced tissue oxygenation may interfere 
with the delivery of antimicrobials to the site of anaerobic 
infection. Cultures, unless carefully collected under anaer
-
obic conditions, may yield negative results.
Important types of infections that are most commonly 
caused by anaerobic organisms are listed below. Treatment 
of all these infections consists of surgical exploration and 
judicious excision in conjunction with administration of 
antimicrobial drugs.
1. Head & Neck Infections
 (formerly 
Bacteroides melanino
-
genicus
) and anaerobic spirochetes are commonly involved 
in periodontal infections. These organisms, fusobacteria, 
and peptostreptococci may cause chronic sinusitis, peri
-
tonsillar abscess, chronic otitis media, and mastoiditis. 
 has been recognized as a common cause of 
pharyngitis in adolescents and young adults. 
 
infection has been associated with septic internal jugular 
thrombophlebitis (Lemierre syndrome) and causes septic 
pulmonary embolization. Hygiene, drainage, and surgi
-
cal debridement are as important in treatment as antimi
-
crobials. Penicillin alone is inadequate treatment for 
infections from oral anaerobic organisms because of 
increasing penicillin resistance, usually due to beta-
lactamase production. Therefore, ampicillin/sulbactam 
1.5–3 g intravenously every 6 hours (if parenteral therapy 
is required) or amoxicillin/clavulanic acid 875 mg/
 
125 mg orally twice daily, or clindamycin can be used 
(600 mg intravenously every 8 hours or 300 mg orally 
every 6 hours). Antimicrobial treatment is continued for 
a few days after symptoms and signs of infection have 
resolved. Indolent, established infections (eg, mastoiditis 
or osteomyelitis) may require prolonged courses of 
therapy, eg, 4–6 weeks or longer.
Brook I. Spectrum and treatment of anaerobic infections. J Infect 
Chemother. 2016 Jan;22(1):1–13. [PMID: 26620376]
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2. Chest Infections
Usually in the setting of poor oral hygiene and periodontal 
disease, aspiration of saliva (which contains 10
8
 anaerobic 
organisms per milliliter in addition to aerobes) may lead to 
necrotizing pneumonia, lung abscess, and empyema. Poly
-
microbial infection is the rule and anaerobes—particularly 
P melaninogenica
, fusobacteria, and peptostreptococci—
are common etiologic agents. Most pulmonary infections 
respond to antimicrobial therapy alone. Percutaneous chest 
tube or surgical drainage is indicated for empyema.
Penicillin-resistant 
Bacteroides fragilis
 and 
P melanino
-
genica
 are commonly isolated and have been associated with 
clinical failures. Clindamycin, 600 mg intravenously once, 
followed by 300 mg orally every 6–8 hours, is the treatment 
of choice for these infections. Metronidazole does not cover 
facultative streptococci, which often are present, and if used, 
a second agent that is active against streptococci, such as 
ceftriaxone 1 g intravenously or intramuscularly daily, should 
be added. Penicillin, 2 million units intravenously every 
4 hours, followed by amoxicillin, 500 mg every 8 hours orally, 
is an alternative; however, increasing prevalence of beta-
lactamase producing organisms is a concern. Moxifloxacin, 
400 mg orally or intravenously once daily, may be used. 
Because these infections respond slowly, a prolonged course 
of therapy (eg, 4–6 weeks) is generally recommended.
3. CNS
Anaerobes are a common cause of brain abscess, subdural 
empyema, or septic CNS thrombophlebitis. The organisms 
reach the CNS by direct extension from sinusitis, otitis, or 
mastoiditis or by hematogenous spread from chronic lung 
infections. Antimicrobial therapy—eg, ceftriaxone, 2 g 
intravenously every 12 hours, plus metronidazole, 500 mg 
intravenously every 8 hours—is an important adjunct to 
surgical drainage. Duration of therapy is 6–8 weeks but 
should be based on follow-up imaging. Some small multi
-
ple brain abscesses can be treated with antibiotics alone 
without surgical drainage.
4. Intra-Abdominal Infections
In the colon there are up to 10
11
 anaerobes per gram of 
content—predominantly 
B fragilis
, clostridia, and pepto
-
streptococci. These organisms play a central role in most 
intra-abdominal abscesses following trauma to the colon, 
diverticulitis, appendicitis, or perirectal abscess and may 
also participate in hepatic abscess and cholecystitis, often 
in association with aerobic coliform bacteria. The bacteri
-
ology includes anaerobes as well as enteric gram-negative 
rods and on occasion enterococci. Therapy should be directed 
both against anaerobes and gram-negative aerobes. Agents 
that are active against 
B fragilis
 include metronidazole, 
chloramphenicol, moxifloxacin, tigecycline, ertapenem, 
imipenem, doripenem, ampicillin-sulbactam, ticarcillin-
clavulanic acid, piperacillin-tazobactam, and ceftolozane/
tazobactam. Resistance to cefoxitin, cefotetan, and 
clindamycin is increasingly encountered. Most third-
generation cephalosporins have poor efficacy.
Table 33–6 summarizes the antibiotic regimens for 
management of moderate to moderately severe infections 
(eg, patient hemodynamically stable, good surgical drain
-
age possible or established, low APACHE score, no multi
-
ple organ failure) and severe infections (eg, major peritoneal 
soilage, large or multiple abscesses, patient hemodynami
-
cally unstable), particularly if drug-resistant organisms are 
suspected. An effective oral regimen for patients able to 
take it is presented also.

Sawyer RG et al. Trial of short-course antimicrobial therapy for 
intraabdominal infection. N Engl J Med. 2015 May 21; 
372(21):1996–2005. [PMID: 25992746]
5. Female Genital Tract & Pelvic Infections
The normal flora of the vagina and cervix includes several 
species of bacteroides, peptostreptococci, group B strepto
-
cocci, lactobacilli, coliform bacteria, and, occasionally, spi
-
rochetes and clostridia. These organisms commonly cause 
genital tract infections and may disseminate from there.
While salpingitis is often caused by gonococci and chla
-
mydiae, tubo-ovarian and pelvic abscesses are associated 
with anaerobes in most cases. Postpartum infections may 
be caused by aerobic streptococci or staphylococci, but 
Table 33–6.
 
Treatment of anaerobic intra-abdominal 
Community-onset
Oral therapy
Moxifloxacin 400 mg every 24 hours
Intravenous therapy
Moderate to moderately severe infections:
Ertapenem 1 g intravenously every 24 hours
or
Ceftriaxone 1 g intravenously every 24 hours plus 
metronidazole intravenously or orally, 500 mg every 
 
8 hours. If penicillin allergic, can replace ceftriaxone with 
ciprofloxacin 400 mg intravenously (or 500 mg orally) 
every 12 hours.
Severe infections:
Imipenem, 0.5 g intravenously every 6–8 hours or 
 
meropenem 1 g every 8 hours or doripenem 0.5 g every 
 
8 hours or piperacillin/tazobactam 3.75 g every 6 hours
Health care–associated
 
8 hours or piperacillin/tazobactam 4.5 g every 6 hours
or
Ceftazidime or cefepime 2 g intravenously every 8 hours 
 
plus metronidazole 500 mg intravenously or orally every 
8 hours
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anaerobes are often found, and the worst cases of postpar
-
tum or postabortion sepsis are associated with clostridia 
and bacteroides. These have a high mortality rate, and 
treatment requires both antimicrobials directed against 
anaerobes and coliforms and abscess drainage or early 
hysterectomy.
-
tritis. Cochrane Database Syst Rev. 2015 Feb 2;2:CD001067. 
6. Bacteremia & Endocarditis
Anaerobic bacteremia usually originates from the gastroin
-
testinal tract, the oropharynx, pressure injuries, or the 
female genital tract. Endocarditis due to anaerobic and 
microaerophilic streptococci and bacteroides originates 
from the same sites. Most cases of anaerobic or microaero
-
philic streptococcal endocarditis can be effectively treated 
with 12–20 million units of penicillin G intravenously daily 
for 4–6 weeks, but optimal therapy of other types of anaer
-
obic bacterial endocarditis must rely on laboratory guid
-
ance. Propionibacteria, clostridia, and bacteroides 
occasionally cause endocarditis.
7. Skin & Soft Tissue Infections
Anaerobic infections of the skin and soft tissue usually 
follow trauma, inadequate blood supply, or surgery and 
are most common in areas that are contaminated by oral 
or fecal flora. These infections also occur in injection 
drug users and persons sustaining animal bites. There 
may be progressive tissue necrosis (Figure 33–6) and a 
putrid odor.
Several terms, such as bacterial synergistic gangrene, 
synergistic necrotizing cellulitis, necrotizing fasciitis, 
and non-clostridial crepitant cellulitis, have been used to 
classify these infections. Although there are some differ
-
ences in microbiology among them, their differentiation 
on clinical grounds alone is difficult. All are mixed infec
-
tions caused by aerobic and anaerobic organisms and 
require aggressive surgical debridement of necrotic tis
-
sue for cure.
Broad-spectrum antibiotics active against both anaer
-
obes and gram-positive and gram-negative aerobes (eg, 
vancomycin plus piperacillin-tazobactam) should be insti
-
tuted empirically and modified by culture results (see 
Table 30–5). They are given for about a week after progres
-
sive tissue destruction has been controlled and the margins 
of the wound remain free of inflammation.
de Prost N et al. Therapeutic targets in necrotizing soft tissue 
 
º
PROCALCITONIN
Procalcitonin is a peptide released by human cells in 
response to exposure to bacterial toxins and is measurable 
in the serum. Procalcitonin is also downregulated in the 
setting of viral infection. Therefore, it is more specific than 
C-reactive protein or white blood cell count. Procalcitonin 
has been studied as marker to determine both when to start 
antibiotic therapy and duration of antibiotic therapy in 
infection. In these trials, antibiotics were safely held 
 
or withdrawn when the procalcitonin level was normal or 
decreasing by a substantial amount. Systematic reviews of 
available literature support the use of procalcitonin to guide 
treatment in patients presenting with acute respiratory 
infections and sepsis. Antibiotic consumption is signifi
-
cantly reduced across different clinical settings when guided 
by procalcitonin levels; procalcitonin can be used effectively 
in these settings only when used as a point of care test.
Branche AR et al. Serum procalcitonin measurement and viral 
testing to guide antibiotic use for respiratory infections in

testing to guide antibiotic use for respiratory infections in 
hospitalized adults: a randomized controlled trial. J Infect 
Dis. 2015 Dec 1;212(11):1692–700. [PMID: 25910632]
de Jong E et al. Efficacy and safety of procalcitonin guidance in 
reducing the duration of antibiotic treatment in critically ill 
patients: a randomised, controlled, open-label trial. Lancet 
Infect Dis. 2016 Jul;16(7):819–27. [PMID: 26947523]
 
▲
Figure 33–6.
 
Left foot gangrene, with plantar 
extension. 
(Used, with permission, from Dean SM, 
 
Diseases
. McGraw-Hill, 2014.)
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º
ACTINOMYCOSIS
 
»
History of recent dental infection, abdominal 
trauma, or intrauterine contraception device 
 
»
Chronic pneumonia or indolent cervicofacial or 
intra-abdominal abscess.
 
»
Sinus tract formation.
 
»
Actinomyces israelii
 and other species of 
 occur 
in the normal flora of the mouth and tonsillar crypts. They 
are anaerobic, gram-positive, branching filamentous 
bacteria (1 mcm in diameter) that may fragment into 
bacillary forms. When introduced into traumatized tissue 
and associated with other anaerobic bacteria, these actino
-
mycetes become pathogens.
The most common site of infection is the cervicofacial 
area (about 60% of cases). Infection typically follows 
extraction of a tooth or other trauma. Lesions may develop 
in the gastrointestinal tract or lungs following ingestion or 
aspiration of the organism from its endogenous source in 
the mouth. Interestingly, 
T whipplei
, the causative agent of 
Whipple disease, is an actinomycete and therefore is 
related to the species that cause actinomycosis.
 
»
1. Cervicofacial actinomycosis—
Cervicofacial actinomy
-
cosis develops slowly. The area becomes markedly indu
-
rated, and the overlying skin becomes reddish or cyanotic. 
Abscesses eventually draining to the surface persist for 
long periods. “Sulfur granules”—masses of filamentous 
organisms—may be found in the pus. There is usually little 
pain unless there is secondary infection. Trismus indicates 
that the muscles of mastication are involved. Radiography 
may reveal bony involvement. Cervicofacial or thoracic 
disease may occasionally involve the CNS, most commonly 
brain abscess or meningitis.
2. Thoracic actinomycosis—
Thoracic involvement begins 
with fever, cough, and sputum production with night 
sweats and weight loss. Pleuritic pain may be present. Mul
-
tiple sinuses may extend through the chest wall, to the 
heart, or into the abdominal cavity. Ribs may be involved. 
Radiography shows areas of consolidation and in many 
cases pleural effusion.
3. Abdominal actinomycosis—
Abdominal actinomycosis 
usually causes pain in the ileocecal region, spiking fever 
and chills, vomiting, and weight loss; it may be confused 
with Crohn disease. Irregular abdominal masses may be 
palpated. Pelvic inflammatory disease caused by actinomy
-
cetes has been associated with prolonged use of an 
intrauterine contraceptive device. Sinuses draining to the 
exterior may develop. CT scanning reveals an inflamma
-
tory mass extended to involve bone.
The anaerobic, gram-positive organism may be demon
-
strated as a granule or as scattered branching gram-positive 
filaments in the pus. Anaerobic culture is necessary to 
distinguish actinomycetes from nocardiae because specific 
therapy differs for the two infections. Histopathology 
examination of affected tissue and bone is useful in identi
-
fying organisms that are fastidious and slow to culture.
 
»
Treatment
Penicillin G is the drug of choice. Ten to 20 million units are 
given via a parenteral route for 4–6 weeks, followed by oral 
penicillin V , 500 mg four times daily. Alternatives include 
ampicillin, 12 g/day intravenously for 4–6 weeks followed 
by oral amoxicillin 500 mg three times daily or doxycycline 
100 mg twice daily intravenously or orally. Response to 
therapy is slow. Therapy should be continued for weeks to 
months after clinical manifestations have disappeared in 
order to ensure cure. Surgical procedures such as drainage 
and resection may be beneficial. With penicillin and sur
-
gery, the prognosis is good. The difficulties of diagnosis, 
however, may permit extensive destruction of tissue before 
the diagnosis is identified and therapy is started.
Könönen E et al. 
 and related organisms in human 
infections. Clin Microbiol Rev. 2015 Apr;28(2):419–42.

infections. Clin Microbiol Rev. 2015 Apr;28(2):419–42. 
[PMID: 25788515]
Steininger C et al. Resistance patterns in clinical isolates of 
pathogenic 
 species. J Antimicrob Chemother. 
2016 Feb;71(2):422–7. [PMID: 26538502]
 
º
NOCARDIOSIS
Nocardia
 species are aerobic filamentous soil bacteria that 
can cause pulmonary and systemic nocardiosis. Common 
Nocardia
 species include members of the 
Nocardia 
asteroides
 complex and 
Nocardia brasiliensis
. 
Bronchopulmonary abnormalities (eg, alveolar proteino
-
sis) predispose to colonization, but infection is unusual 
unless the patient is also receiving systemic corticosteroids 
or is otherwise immunosuppressed.
 
»
Pulmonary involvement usually begins with malaise, loss 
of weight, fever, and night sweats. Cough and production 
of purulent sputum are the chief complaints. Radiography 
may show infiltrates accompanied by pleural effusion. The 
lesions may penetrate to the exterior through the chest 
wall, invading the ribs.
Dissemination involves any organ. Brain abscesses and 
subcutaneous nodules are most frequent. Even in the 
absence of clinical symptoms and signs of CNS infection, 
clinicians should consider brain imaging in patients with 
nocardiosis to rule out an occult abscess.
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Nocardia
 species are usually found as delicate, branch
-
ing, gram-positive filaments. They may be weakly acid-
fast, occasionally causing diagnostic confusion with 
tuberculosis. Identification is made by culture.
 
»
Treatment
For isolated cutaneous infections, therapy is initiated with 
trimethoprim-sulfamethoxazole administered at a dosage 
of 5–10 mg/kg/day (based on trimethoprim) as an oral or 
intravenous formulation. Surgical procedures such as 
drainage and resection may be needed as adjunctive ther
-
apy. A higher dose of 15 mg/kg/day (based on trime
-
thoprim) should be used for disseminated or pulmonary 
infections. Resistance to trimethoprim-sulfamethoxazole is 
increasing and initiating treatment with two drugs while 
awaiting antibiotic susceptibilities in cases of disseminated 
or severe localized disease should be considered. Alterna
-
tive agents or drugs that can be given in combination with 
trimethoprim-sulfamethoxazole include imipenem, 
500 mg intravenously every 6 hours; amikacin, 7.5 mg/kg 
intravenously every 12 hours; or minocycline, 100–200 mg 
orally or intravenously twice daily. Consultation with an 
infectious diseases expert is encouraged.
Response may be slow, and therapy should be contin
-
ued for at least 6 months. The prognosis in systemic nocar
-
diosis is poor when diagnosis and therapy are delayed.
Anagnostou T et al. Nocardiosis of the central nervous system: 
experience from a general hospital and review of 84 cases 
from the literature. Medicine (Baltimore). 2014 Jan;93(1): 
19–32. [PMID: 24378740]
Fatahi-Bafghi M. Nocardiosis from 1888 to 2017. Microb 
Pathog. 2018 Jan;114:369–84. [PMID: 29146497]
 
º
INFECTIONS CAUSED BY MYCOBACTERIA
NONTUBERCULOUS MYCOBACTERIAL 
DISEASES
About 10% of mycobacterial infections are caused by non
-
tuberculous mycobacteria. Nontuberculous mycobacterial 
infections are among the most common opportunistic 
infections in advanced HIV disease. These organisms have 
distinctive laboratory characteristics, occur ubiquitously in 
the environment, are not communicable from person to 
person, and are often resistant to standard antituberculous 
drugs.
Egelund EF et al. Medications and monitoring in nontubercu
-
lous mycobacteria infections. Clin Chest Med. 2015 Mar; 
36(1):55–66. [PMID: 25676519]
Henkle E et al. Nontuberculous mycobacteria infections in 
immunosuppressed hosts. Clin Chest Med. 2015 Mar; 
36(1):91–9. [PMID: 25676522]
1. Pulmonary Infections
 complex (MAC) causes a chronic, 
slowly progressive pulmonary infection resembling tuber
-
culosis in immunocompetent patients who typically have 
underlying pulmonary disease. Susceptibility testing for 
macrolide-resistance should be performed on clinical iso
-
lates. Treatment of nodular or bronchiectatic pulmonary 
disease is clarithromycin (1000 mg orally three times per 
week) or azithromycin (500 mg orally three times per 
week) plus rifampin (600 mg orally three times per week) 
or rifabutin (300 mg orally three times per week) plus eth
-
ambutol (25 mg/kg orally three times per week). Patients 
with fibrocavitary lung disease or severe nodular or bron
-
chiectatic disease should receive three-drug therapy with 
clarithromycin (500–1000 mg orally daily) or azithromycin 
(500 mg orally daily) plus rifampin (600 mg orally daily) or 
rifabutin (300 mg orally daily) plus ethambutol (15 mg/kg 
orally daily). Therapy is continued for at least 12 months 
after sterilization of cultures.
M kansasii
 can produce clinical disease resembling 
tuberculosis, but the illness progresses more slowly. Most 
such infections occur in patients with preexisting lung 
disease, though 40% of patients have no known pulmonary 
disease. Microbiologically, 
M kansasii
 and is sensitive to the same drugs except 
pyrazinamide, to which it is resistant. Therapy with 
isoniazid, ethambutol, and rifampin for 2 years (or 1 year

M kansasii
isoniazid, ethambutol, and rifampin for 2 years (or 1 year 
after sputum conversion) has been successful.
Less common causes of pulmonary disease include 
 
M xenopi, M szulgai
, and 
M gordonae
. These organisms 
have variable sensitivities, and treatment is based on results 
of sensitivity tests. The rapid growing mycobacteria, 
 
M abscessus, M chelonae
, and 
, also can cause 
pneumonia in the occasional patient.
Floto RA et al. US Cystic Fibrosis Foundation and European 
Cystic Fibrosis Society consensus recommendations for the 
management of non-tuberculous mycobacteria in individuals 
with cystic fibrosis: executive summary. Thorax. 2016 Jan; 
71(1):88–90. [PMID: 26678435]
Griffith DE et al; ATS Mycobacterial Diseases Subcommittee; 
American Thoracic Society; Infectious Disease Society of 
America. An official ATS/IDSA statement: diagnosis, treat
-
ment, and prevention of nontuberculous mycobacterial dis
-
eases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367–416. 
[PMID: 17277290]
Jarand J et al. Long-term follow-up of 
 
complex lung disease in patients treated with regimens 
including clofazimine and/or rifampin. Chest. 2016 May; 
149(5):1285–93. [PMID: 26513209]
2. Lymphadenitis
Most cases of lymphadenitis (scrofula) in adults are caused 
by 
 and can be a manifestation of dissemi
-
nated disease. In children, the majority of cases are due to 
nontuberculous mycobacterial species. Infection with non
-
tuberculous mycobacteria can be successfully treated by 
surgical excision without antituberculous therapy.
3. Skin & Soft Tissue Infections
Skin and soft tissue infections such as abscesses, septic 
arthritis, and osteomyelitis can result from direct inocula
-
tion or hematogenous dissemination or may occur as a 
complication of surgery.
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, and 
 are frequent 
causes of these types of infections. Most cases occur in the 
extremities and initially present as nodules. Ulceration 
with abscess formation often follows. The organisms are 
resistant to the usual antituberculosis drugs and may have 
susceptibility to clarithromycin, azithromycin, doxycy
-
cline, amikacin, cefoxitin, sulfonamides, imipenem, and 
ciprofloxacin. Given the multidrug-resistant nature of 
these organisms, obtaining antibiotic susceptibility testing 
is recommended. Therapy often includes surgical debride
-
ment along with at least two active antibiotics. Antibiotic 
therapy is usually continued for 3 months, although this 
must be determined based on clinical response.
M marinum
 infection (“swimming pool granuloma”) 
presents as a nodular skin lesion following exposure to 
nonchlorinated water. The lesions respond to therapy with 
clarithromycin, doxycycline, minocycline, or 
M ulcerans
 infection (Buruli ulcer) is seen mainly in 
Africa and Australia and produces a large ulcerative lesion. 
Therapy consists of surgical excision and skin grafting.
4. Disseminated 
 Infection
MAC causes disseminated disease in immunocompro
-
mised patients, most commonly in patients in the late 
stages of HIV infection, when the CD4 cell count is less 
than 50/mcL. Persistent fever and weight loss are the most 
common symptoms. The organism can usually be cultured 
from multiple sites, including blood, liver, lymph node, or 
bone marrow. Blood culture is the preferred means of 
establishing the diagnosis and has a sensitivity of 98%.
Agents with proved activity against MAC are rifabutin, 
azithromycin, clarithromycin, and ethambutol. Amikacin 
and ciprofloxacin work in vitro, but clinical results are 
inconsistent. A combination of two or more active agents 
should be used to prevent rapid emergence of secondary 
resistance. Clarithromycin, 500 mg orally twice daily, plus 
ethambutol, 15 mg/kg/day orally as a single dose, with or 
without rifabutin, 300 mg/day orally, is the treatment of 
choice. Azithromycin, 500 mg orally once daily, may be 
used instead of clarithromycin. Insufficient data are avail
-
able to permit specific recommendations about second-line 
regimens for patients intolerant of macrolides or those with 
macrolide-resistant organisms. MAC therapy may be dis
-
continued in patients who have been treated with 12 months 
of therapy for disseminated MAC, who have no evidence 
of active disease, and whose CD4 counts exceed 
100 cells/mcL for 6 months while receiving antiretroviral 
therapy (ART).
Antimicrobial prophylaxis of MAC prevents dissemi
-
nated disease and prolongs survival. It is the standard of 
care to offer it to all HIV-infected patients with CD4 
counts of 50/mcL or less. In contrast to active infection, 
single-drug oral regimens of clarithromycin, 500 mg twice 
daily, azithromycin, 1200 mg once weekly, or rifabutin, 
300 mg once daily, are appropriate. Clarithromycin or 
azithromycin is more effective and better tolerated than 
rifabutin, and therefore preferred. Primary prophylaxis for 
MAC infection can be stopped in patients who have 
responded to antiretroviral combination therapy with 
elevation of CD4 counts of greater than 100 cells/mcL for 
3 months.
-
-
Masur H et al. Prevention and treatment of opportunistic infec
-
tions in HIV-infected adults and adolescents: updated guide
-
lines from the Centers for Disease Control and Prevention, 
National Institutes of Health, and HIV Medicine Association

-
-
National Institutes of Health, and HIV Medicine Association 
of the Infectious Diseases Society of America. Clin Infect Dis. 
2014 May;58(9):1308–11. [PMID: 24585567]
MYCOBACTERIUM TUBERCULOSIS
 
INFECTIONS
Tuberculosis is discussed in Chapter 9. Further informa
-
tion and expert consultation can be obtained from the 
Curry International Tuberculosis Center at the website 
www.currytbcenter.ucsf.edu or by telephone, 510-238-5100.
TUBERCULOUS MENINGITIS
 
»
Gradual onset of listlessness and anorexia.
 
»
Headache, vomiting, and seizures common.
 
»
Cranial nerve abnormalities typical.
 
»
Tuberculosis focus may be evident elsewhere.
 
»
Cerebrospinal fluid shows several hundred lym
-
phocytes, low glucose, and high protein.
 
»
Tuberculous meningitis is caused by rupture of a menin
-
geal tuberculoma resulting from earlier hematogenous 
seeding of tubercle bacilli from a pulmonary focus, or it 
may be a consequence of miliary spread.
 
»
The onset is usually gradual, with listlessness, irritability, 
anorexia, and fever, followed by headache, vomiting, con
-
vulsions, and coma. In older patients, headache and 
behavioral changes are prominent early symptoms. Nuchal 
rigidity and cranial nerve palsies occur as the meningitis 
progresses. Evidence of active tuberculosis elsewhere or a 
history of prior tuberculosis is present in up to 75% of 
patients.
The spinal fluid is frequently yellowish, with increased 
pressure, 100–500 cells/mcL (predominantly lymphocytes, 
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though neutrophils may be present early during infection), 
increased protein, and decreased glucose. Acid-fast stains 
of cerebrospinal fluid usually are negative, and cultures 
also may be negative in 15–25% of cases. Nucleic acid 
amplification tests for rapid diagnosis of tuberculosis have 
variable sensitivity and specificity and none are FDA 
approved for use in meningitis. Chest radiographs often 
reveal abnormalities compatible with tuberculosis but may 
be normal.
 
»
Tuberculous meningitis may be confused with any other 
type of meningitis, but the gradual onset, the predomi
-
nantly lymphocytic pleocytosis of the spinal fluid, and 
evidence of tuberculosis elsewhere often point to the diag
-
nosis. The tuberculin skin test is usually (not always) posi
-
tive. Fungal and other granulomatous meningitides, 
syphilis, and carcinomatous meningitis are in the differen
-
tial diagnosis.
 
»
Complications of tuberculous meningitis include seizure 
disorders, cranial nerve palsies, stroke, and obstructive 
hydrocephalus with impaired cognitive function. These 
result from inflammatory exudate primarily involving the 
basilar meninges and arteries.
 
»
Treatment
Presumptive diagnosis followed by early, empiric antitu
-
berculous therapy is essential for survival and to minimize 
sequelae. Even if cultures are not positive, a full course of 
therapy is warranted if the clinical setting is suggestive of 
tuberculous meningitis.
Regimens that are effective for pulmonary tuberculosis 
are effective also for tuberculous meningitis (see 
Table 9–15). Rifampin, isoniazid, and pyrazinamide all 
penetrate into cerebrospinal fluid well. The penetration of 
ethambutol is more variable, but therapeutic concentra
-
tions can be achieved, and the drug has been successfully 
used for meningitis. Aminoglycosides penetrate less well. 
Regimens that do not include both isoniazid and rifampin 
may be effective but are less reliable and generally must be 
given for longer periods.
Many authorities recommend the addition of cortico
-
steroids for patients with focal deficits or altered mental 
status. Dexamethasone, 0.15 mg/kg intravenously or orally 
four times daily for 1–2 weeks, then discontinued in a 
tapering regimen over 4 weeks, may be used.
Heemskerk AD et al. Intensified antituberculosis therapy in 
adults with tuberculous meningitis. N Engl J Med. 2016 Jan 14; 
374(2):124–34. [PMID: 26760084]
Khonga M et al. Xpert MTB/RIF Ultra: a gamechanger for tuber
-
culous meningitis? Lancet Infect Dis. 2018 Jan;18(1):6–8. 
[PMID: 28919337]
-
LEPROSY (
Hansen Disease
)
 
»
Pale, anesthetic macular—or nodular and 
 
erythematous—skin lesions.
 
»
Superficial nerve thickening with resultant 
anesthesia.
 
»
History of residence in endemic area in childhood.
 
»
Acid-fast bacilli in skin lesions or nasal scrapings, 
or characteristic histologic nerve changes.
 
»
Leprosy (Hansen disease) is a chronic infectious disease 
caused by the acid-fast rod 
M leprae
. The mode of trans
-
mission probably is respiratory and involves prolonged 
exposure in childhood. The disease is endemic in tropical 
and subtropical Asia, Africa, Central and South America, 
and the Pacific regions, and rarely seen sporadically in the 
 
»
The onset is insidious. The lesions involve the cooler body 
tissues: skin, superficial nerves, nose, pharynx, larynx, 
eyes, and testicles. Skin lesions may occur as pale, anes
-
thetic macular lesions 1–10 cm in diameter; discrete ery
-
thematous, infiltrated nodules 1–5 cm in diameter; or 
diffuse skin infiltration. Neurologic disturbances are 
caused by nerve infiltration and thickening, with resultant

-
caused by nerve infiltration and thickening, with resultant 
anesthesia, and motor abnormalities. Bilateral ulnar neu
-
ropathy is highly suggestive. In untreated cases, disfigure
-
ment due to the skin infiltration and nerve involvement 
may be extreme, leading to trophic ulcers, bone resorption, 
and loss of digits.
The disease is divided clinically and by laboratory tests 
into two distinct types: lepromatous and tuberculoid. The 
lepromatous
 
type
 (also referred to as multibacillary lep
-
rosy) occurs in persons with defective cellular immunity. 
The course is progressive and malignant, with nodular skin 
lesions; slow, symmetric nerve involvement; abundant 
acid-fast bacilli in the skin lesions; and a negative lepromin 
skin test. In the 
tuberculoid type
 (paucibacillary leprosy), 
cellular immunity is intact and the course is more benign 
and less progressive, with macular skin lesions, severe 
asymmetric nerve involvement of sudden onset with few 
bacilli present in the lesions, and a positive lepromin skin 
test. Intermediate (“borderline”) cases are frequent. Eye 
involvement (keratitis and iridocyclitis), nasal ulcers, epi
-
staxis, anemia, and lymphadenopathy may occur.
Laboratory confirmation of leprosy requires the demon
-
stration of acid-fast bacilli in a skin biopsy. Biopsy of skin 
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or of a thickened involved nerve also gives a typical histo
-
logic picture. 
M leprae
 does not grow in artificial media, 
but does grow in the foot pads of armadillos.
 
»
The skin lesions of leprosy often resemble those of lupus 
erythematosus, sarcoidosis, syphilis, erythema nodosum, 
erythema multiforme, cutaneous tuberculosis, and 
vitiligo.
 
»
Kidney failure and hepatomegaly from secondary amyloi
-
dosis may occur with long-standing disease.
 
»
Treatment
Combination therapy is recommended for treatment of all 
types of leprosy. Single-drug treatment is accompanied by 
emergence of resistance, and primary resistance to dapsone 
also occurs. For borderline and lepromatous cases (ie, mul
-
tibacillary disease), the World Health Organization recom
-
mends a triple oral drug regimen of rifampin, 600 mg once 
a month; dapsone, 100 mg daily; and clofazimine, 300 mg 
once a month and 50 mg daily for 12 months although lon
-
ger courses may be needed for patients with high burden of 
disease. For indeterminate and tuberculoid leprosy (pauci
-
bacillary disease), the recommendation is rifampin, 600 mg 
once a month, plus dapsone, 100 mg daily for 6 months.
Two reactional states—erythema nodosum leprosum 
and reversal reactions—may occur as a consequence of 
therapy. The reversal reaction, typical of borderline lepro
-
matous leprosy, probably results from enhanced host 
immunity. Skin lesions and nerves become swollen and 
tender, but systemic manifestations are not seen. Erythema 
nodosum leprosum, typical of lepromatous leprosy, is a 
consequence of immune injury from antigen-antibody 
complex deposition in skin and other tissues; in addition to 
skin and nerve manifestations, fever and systemic involve
-
ment may be seen. Prednisone, 60 mg/day orally, or thalido
-
mide, 300 mg/day orally (in the nonpregnant patient only), 
is effective for erythema nodosum leprosum. Improvement 
is expected within a few days after initiating prednisone, 
and thereafter the dose may be tapered over several weeks 
to avoid recurrence. Thalidomide is also tapered over sev
-
eral weeks to a 100-mg bedtime dose. Erythema nodosum 
leprosum is usually confined to the first year of therapy, and 
prednisone or thalidomide can be discontinued. Thalido
-
mide is ineffective for reversal reactions, and prednisone, 
60 mg/d, is indicated. Reversal reactions tend to recur, and 
the dose of prednisone should be slowly tapered over weeks 
to months. Therapy for leprosy should not be discontinued 
during treatment of reactional states.
Kamath S et al. Recognizing and managing the immunologic 
reactions in leprosy. J Am Acad Dermatol. 2014 Oct;71(4): 
795–803. [PMID: 24767732]
Van Veen NH et al. Corticosteroids for treating nerve damage in 
leprosy. Cochrane Database Syst Rev. 2016 May 23; 
(5):CD005491. [PMID: 27210895]
 
º
INFECTIONS CAUSED BY CHLAMYDIAE
Chlamydiaceae is a family of obligate intracellular parasites 
closely related to gram-negative bacteria. They include two 
important genera of human pathogens—
Chlamydia
, which 
includes the species of 
, and 
Chlamydophila
, which includes the species 
psittaci
 (formerly known as 
Chlamydia psittaci
) and 
Chlamydia 
). 
 causes many different human 
infections involving the eye (trachoma, inclusion conjunc
-
tivitis), the genital tract (lymphogranuloma venereum, 
nongonococcal urethritis, cervicitis, salpingitis), or the 
respiratory tract in infants (pneumonitis). 
C psittaci
 causes 
psittacosis and 
 is a cause of respiratory tract 
1. Lymphogranuloma Venereum
 
»
Evanescent primary genital lesion.
 
»
Inguinal buboes with suppuration and draining 
sinuses.
 
»
Proctitis and rectal stricture in women or in men 
who have sex with men.
 
»

»
 
»
sinuses.
 
»
 
»
Positive complement fixation test.
 
»
Lymphogranuloma venereum (LGV) is an acute and 
chronic sexually transmitted disease caused by 
 types L1–L3. The disease is acquired during 
intercourse or through contact with contaminated exudate 
from active lesions. The incubation period is 5–21 days. 
After the genital lesion disappears, the infection spreads to 
lymph channels and lymph nodes of the genital and rectal 
areas. Inapparent infections and latent disease are not 
uncommon.
 
»
In men, the initial vesicular or ulcerative lesion (on the 
external genitalia) is evanescent and often goes unno
-
ticed. Inguinal buboes appear 1–4 weeks after exposure, 
are often bilateral, and have a tendency to fuse, soften, 
and break down to form multiple draining sinuses, with 
extensive scarring. In women, the genital lymph drainage 
is to the perirectal glands. Early anorectal manifestations 
are proctitis with tenesmus and bloody purulent dis
-
charge; late manifestations are chronic cicatrizing inflam
-
mation of the rectal and perirectal tissue. These changes 
lead to obstipation and rectal stricture and, occasionally, 
rectovaginal and perianal fistulas. They are also seen with 
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The complement fixation test may be positive (titers 
greater than 1:64), but cross-reaction with other chlamyd
-
iae occurs. Although a positive reaction may reflect remote 
infection, high titers usually indicate active disease. Nucleic 
acid detection tests are sensitive, but not FDA approved for 
rectal specimens and cannot differentiate LGV from non-
LGV strains.
 
»
The early lesion of LGV must be differentiated from the 
lesions of syphilis, genital herpes, and chancroid; lymph 
node involvement must be distinguished from that due to 
tularemia, tuberculosis, plague, neoplasm, or pyogenic 
infection; and rectal stricture must be distinguished from 
that due to neoplasm and ulcerative colitis.
 
»
Treatment
If diagnostic testing for LGV is not available, patients with 
a clinical presentation suggestive of LGV should be treated 
empirically. The antibiotic of choice is doxycycline (contra
-
indicated in pregnancy), 100 mg orally twice daily for 
21 days. Erythromycin, 500 mg orally four times a day for 
21 days, is also effective. Azithromycin, 1 g orally once 
weekly for 3 weeks, may also be effective.
de Vries HJ et al. 2013 European guideline on the management 
of lymphogranuloma venereum. J Eur Acad Dermatol 
Venereol. 2015 Jan;29(1):1–6. [PMID: 24661352]
2. Chlamydial Urethritis & Cervicitis
 
»
: common cause of urethritis, cervici
-
tis, and postgonococcal urethritis.
 
»
Diagnosis made by nucleic acid amplification of 
urine or swab specimen.
 
»
 immunotypes D–K are isolated in about 50% 
of cases of nongonococcal urethritis and cervicitis. In other 
cases, 
 or 
 
can be grown as a possible etiologic agent. 
 is 
an important cause of postgonococcal urethritis. Coinfec
-
tion with gonococci and chlamydiae is common, and post
-
gonococcal (ie, chlamydial) urethritis may persist after 
successful treatment of the gonococcal component. Occa
-
sionally, epididymitis, prostatitis, or proctitis is caused by 
chlamydial infection. Chlamydiae are a leading cause of 
infertility in females in the United States.
 
»
Women infected with chlamydiae may be asymptomatic or 
may have symptoms and signs of cervicitis, salpingitis, or 
pelvic inflammatory disease. The urethral or cervical dis
-
charge due to 
 tends to be less painful, less 
purulent, and watery compared with gonococcal 
A patient with clinical signs and symptoms of urethritis or 
cervicitis is assumed to have chlamydial infection until 
proven otherwise. The diagnosis should be confirmed, 
whenever possible, by the FDA-approved, highly sensitive 
nucleic acid amplification tests for use with urine or vagi
-
nal swabs. A negative nucleic acid amplification test for 
chlamydia reliably excludes the diagnosis of chlamydial 
urethritis or cervicitis and therapy need not be 
administered.
C. Screening
Active screening for chlamydial infection is recommended 
in certain settings: pregnant women; all sexually active 
women 25 years of age and under; older women with risk 
factors for sexually transmitted diseases; and men with 
risk factors for sexually transmitted diseases, such as HIV-
positive men or men who have sex with men.
 
»
Treatment
Recommended regimens are a single oral 1-g dose of 
azithromycin (preferred and safe in pregnancy), 100 mg of 
doxycycline orally for 7 days (contraindicated in preg
-
nancy), or 500 mg of levofloxacin once daily for 7 days

-
nancy), or 500 mg of levofloxacin once daily for 7 days 
(also contraindicated in pregnancy). Presumptively 
administered therapy still may be indicated for some 
patients, such as for an individual with gonococcal infec
-
tion in whom no chlamydial testing was performed or a 
test other than a nucleic acid amplification test was used to 
exclude the diagnosis, or an individual for whom a test 
result is pending but is considered unlikely to follow up, 
and for sexual contacts of documented cases. As for all 
patients in whom sexually transmitted diseases are diag
-
nosed, studies for HIV and syphilis should also be 
Geisler WM et al. Azithromycin versus doxycycline for urogeni
-
tal 
 infection. N Engl J Med. 2015 
Dec 24;373(26):2512–21. [PMID: 26699167]
Workowski KA et al; Centers for Disease Control and 
Prevention(CDC). Sexually transmitted diseases treatment 
guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5; 
64(RR-03):1–137. Erratum in: MMWR Recomm Rep. 2015 
Aug 28; 64(33):924. [PMID: 26042815]
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CHLAMYDOPHILA PSITTACI
 & 
PSITTACOSIS (
Ornithosis
)
 
»
Fever, chills, and cough; headache common.
 
»
Atypical pneumonia with slightly delayed appear
-
ance of signs of pneumonitis.
 
»
Contact with infected bird (psittacine, pigeons, 
many others) 7–15 days previously.
 
»
Isolation of chlamydiae or rising titer of comple
-
ment-fixing antibodies.
 
»
Psittacosis is acquired from contact with birds (parrots, 
parakeets, pigeons, chickens, ducks, and many others), 
which may or may not be ill. The history may be difficult 
to obtain if the patient acquired infection from an illegally 
imported bird.
 
»
The onset is usually rapid, with fever, chills, myalgia, dry 
cough, and headache. Signs include temperature-pulse dis
-
sociation, dullness to percussion, and rales. Pulmonary 
findings may be absent early. Dyspnea and cyanosis may 
occur later. Endocarditis, which is culture-negative, may 
occur. The radiographic findings in typical psittacosis are 
those of atypical pneumonia, which tends to be interstitial 
and diffuse in appearance, though consolidation can occur. 
Psittacosis is indistinguishable from other bacterial or viral 
pneumonias by radiography.
The organism is rarely isolated from cultures. The diag
-
nosis is usually made serologically; antibodies appear dur
-
ing the second week and can be demonstrated by 
complement fixation or immunofluorescence. Antibody 
response may be suppressed by early chemotherapy.
 
»
The illness is indistinguishable from viral, mycoplasmal, or 
other atypical pneumonias except for the history of contact 
with birds. Psittacosis is in the differential diagnosis of 
culture-negative endocarditis.
 
»
Treatment
Treatment consists of giving tetracycline, 0.5 g orally every 
6 hours or 0.5 g intravenously every 12 hours, for 
14–21 days. Erythromycin, 500 mg orally every 6 hours, 
may be effective as well.
Lagae S et al. Emerging 
 infections in chickens 
and examination of transmission to humans. J Med Microbiol. 
2014 Mar;63(Pt 3):399–407. [PMID: 24324029]
CHLAMYDOPHILA PNEUMONIAE
 INFECTION
 causes pneumonia and bronchitis. The clini
-
cal presentation of pneumonia is that of an atypical pneu
-
monia. The organism accounts for approximately 10% of 
community-acquired pneumonias, ranking second to 
mycoplasma as an agent of atypical pneumonia. A putative 
role in coronary artery disease has not held up to close 
scientific scrutiny.
Like 
C psittaci
, strains of 
 are resistant to 
sulfonamides. Erythromycin or tetracycline, 500 mg orally 
four times a day for 10–14 days, appears to be effective 
therapy. Fluoroquinolones, such as levofloxacin (500 mg 
once daily for 7–14 days) or moxifloxacin (400 mg once 
daily for 7–14 days), are active in vitro against 
 
and probably are effective. It is unclear if empiric coverage 
for atypical pathogens in hospitalized patients with com
-
munity-acquired pneumonia provides a survival benefit or 
improves clinical outcome.
Fajardo KA et al. Pneumonia outbreak caused by 
 among US Air Force Academy cadets, Colorado, 
USA. Emerg Infect Dis. 2015 Jun;21(6):1049–51. [PMID: 
25988545]
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º
SYPHILIS
NATURAL HISTORY & PRINCIPLES OF 
DIAGNOSIS & TREATMENT
Syphilis is a complex infectious disease caused by 
, a spirochete capable of infecting 
almost any organ or tissue in the body and causing protean 
clinical manifestations (Table 34–1). Transmission occurs 
most frequently during sexual contact (including oral sex). 
The risk of acquiring syphilis after unprotected sex with an 
individual with infectious syphilis is approximately 
30–50%. Rarely, it can also be transmitted through non
-
sexual contact, blood transfusion, or via the placenta from 
mother to fetus (congenital syphilis).
The natural history of acquired syphilis is generally 
divided into two major stages: 
early (infectious) syphilis
 
and 
late syphilis.
 Infectious syphilis includes primary 
lesions (chancre and regional lymphadenopathy) appear
-
ing during primary syphilis, secondary lesions (commonly 
involving skin and mucous membranes, occasionally bone, 
central nervous system [CNS], or liver) appearing during 
secondary syphilis (when dissemination of 
T pallidum
 
produces systemic signs), relapsing lesions during early 
latency, and congenital lesions. The hallmark of these 
lesions is an abundance of spirochetes; tissue reaction is 
usually minimal. Late (tertiary) syphilis consists of so-
called benign (gummatous) lesions involving skin, bones, 
and viscera; cardiovascular disease (principally aortitis); 
and a variety of CNS and ocular syndromes. These forms 
of syphilis are not contagious. The lesions contain few 
demonstrable spirochetes, but tissue reactivity (vasculitis, 
necrosis) is severe and suggestive of hypersensitivity phe
-
nomena. Between these stages are symptom-free latent 
phases. In early latent syphilis, which is defined as the 
symptom-free interval lasting up to 1 year after initial 
infection, infectious lesions can recur.
Public health efforts to control syphilis focus on the 
diagnosis and treatment of early (infectious) cases and 
their partners.
Most cases of syphilis in the United States continue to 
occur in men who have sex with men (MSM). Globally, the 
World Health Organization (WHO) estimates 5.6 million 34
Spirochetal Infections
total incident syphilis infections in 2012, equally in both 
men and women, and a prevalence of 1% among pregnant 
women attending antenatal clinics. Preventing congenital 
syphilis is a major public health goal for the Centers for 
Disease Control and Prevention (CDC) and WHO.
COURSE & PROGNOSIS
The lesions associated with primary and secondary syphi
-
lis are self-limiting, even without treatment, and resolve 
with few or no residua. Ocular and otologic syphilis has 
been associated with permanent vision and hearing loss. 
Tertiary and congenital syphilis may be highly destructive 
and permanently disabling and may lead to death. Many 
experts now believe that while infection is almost never 
completely eradicated in the absence of treatment, most 
infections remain latent without sequelae, and only a 
small number of latent infections progress to further 
disease.
CLINICAL STAGES OF SYPHILIS
1. Primary Syphilis
 
»
Painless ulcer on genitalia, perianal area, rectum, 
pharynx, tongue, lip, or elsewhere.
 
»
Nontender enlargement of regional lymph nodes.
 
»
Fluid expressed from lesion contains 
T pallidum
 by 
immunofluorescence or darkfield microscopy.
 
»
Serologic nontreponemal and treponemal tests 
 
»
The typical lesion is the 
chancre
 at the site or sites of 
inoculation, most frequently located on the penis 
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(Figure 34–1), labia, cervix, or anorectal region. Anorectal 
lesions are especially common among MSM. Chancres also 
occur occasionally in the oropharynx (lip, tongue, or ton
-
sil) and rarely on the breast or finger or elsewhere. An ini
-
tial small erosion appears 10–90 days (average, 3–4 weeks) 
after inoculation then rapidly develops into a painless 
superficial ulcer with a clean base and firm, indurated mar
-
gins. This is associated with enlargement of regional lymph 
nodes, which are rubbery, discrete, and nontender. Healing 
occurs without treatment, but a scar may form, especially 
with secondary bacterial infection. Multiple chancres may 
be present, particularly in HIV-positive patients. Although 
the “classic” ulcer of syphilis has been described as non
-
tender, nonpurulent, and indurated, only 31% of patients 
have this triad.
1. Microscopic examination—
In early (infectious) syphi
-
lis, darkfield microscopic examination by a skilled observer 
of fresh exudate from moist lesions or material aspirated 
from regional lymph nodes is up to 90% sensitive for diag
-
nosis but is usually only available in select clinics that spe
-
cialize in sexually transmitted disease.
An immunofluorescent staining technique for demon
-
strating 
T pallidum
 in dried smears of fluid taken from 
early syphilitic lesions is also performed in only a few 
T pallidum
 polymerase chain reaction (PCR) is avail
-
able as a 'home brew' test in select research, referral and 
public health laboratories and has the highest yield in pri
-
mary and secondary lesions. Organisms can also be 
detected in blood, especially in congenital and secondary 
syphilis cases.
2. Serologic tests for syphilis—
(Table 34–2) Serologic 
tests (the mainstay of syphilis diagnosis) fall into two gen
-
eral categories: (1) Nontreponemal tests detect antibodies 
to lipoidal antigens present in the host after modification 
by 
T pallidum.
 (2) Treponemal tests use live or killed 
T pallidum
 as antigen to detect antibodies specific for 
pathogenic treponemes.
a. Nontreponemal antibody tests—
The most com
-
monly used nontreponemal antibody tests are the Venereal 
Disease Research Laboratory (VDRL) and rapid plasma 
reagin (RPR) tests, which measure the ability of heated 
serum to flocculate a suspension of cardiolipin-cholesterol-
lecithin. The flocculation tests are inexpensive, rapid, and 
easy to perform and have therefore been commonly used 
for routine screening. Quantitative expression of the reac
-
tivity of the serum, based on titration of dilutions of serum, 
is valuable in establishing the diagnosis and in evaluating 
Table 34–1.
 
Stages of syphilis and common clinical 
Primary syphilis
Chancre: painless ulcer with clean base and firm indurated 
borders
Regional lymphadenopathy
Secondary syphilis
Skin and mucous membranes
Rash: diffuse (may include palms and soles), macular, 
papular, pustular, and combinations
Condylomata lata
Mucous patches: painless, silvery ulcerations of mucous 
membrane with surrounding erythema
Generalized lymphadenopathy
Constitutional symptoms
Fever, usually low-grade
Malaise, anorexia
Arthralgias and myalgias
Cranial neuropathies (II–VIII)
Other
Ocular: iritis, iridocyclitis
Renal: glomerulonephritis, nephrotic syndrome
Hepatitis
Bone and joint: arthritis, periostitis
t
er
tiary (late) syphilis
Late benign (gummatous): granulomatous lesion usually 
involving skin, mucous membranes, and bones but any 
organ can be involved
Aortic regurgitation
Coronary ostial stenosis
Aortic aneurysm
Meningovascular
Tabes dorsalis
General paresis
Note: Central nervous system involvement may occur at any stage.
 
▲
Figure 34–1.
 
Primary syphilis with a large chancre 
on the glans of the penis. The multiple small 
surrounding ulcers are part of the syphilis and not a

▲
 
surrounding ulcers are part of the syphilis and not a 
second disease. 
Chumley H. 
, 2nd ed. 
McGraw-Hill, 2013.) 
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the efficacy of treatment, since titers usually correlate with 
disease activity. A different, enzyme immunoassay (EIA)–
based screening algorithm is discussed below.
Nontreponemal tests generally become positive 
4–6 weeks after infection or 1–3 weeks after the appearance 
of a primary lesion; they are almost invariably positive in 
the secondary stage. These tests are nonspecific and may be 
positive in patients with non–sexually transmitted trepone
-
matoses (see below). More important, false-positive sero
-
logic reactions are frequently encountered in a wide variety 
of other conditions, including connective tissue diseases, 
infectious mononucleosis, malaria, febrile diseases, leprosy, 
injection drug use, infective endocarditis, old age, hepatitis 
C viral infection, and pregnancy. False-positive nontrepo
-
nemal tests are usually of low titer and transient and may be 
distinguished from true positives by correlating with clini
-
cal findings and performing a treponemal specific-antibody 
test. False-negative results can be seen when very high 
antibody titers are present (
the prozone phenomenon
). If 
syphilis is strongly suspected and the nontreponemal test is 
negative, the laboratory should be instructed to dilute the 
specimen to detect a positive reaction.
Nontreponemal antibody titers are used to monitor the 
response to therapy and should decline over time. The rate 
of decline depends on various factors. In general, persons 
with repeat infections, higher initial titers, more advanced 
stages of disease, or those who are HIV-infected at the time 
of treatment have a slower seroconversion rate and are 
more likely to remain serofast (ie, titers decline but do not 
become nonreactive). Data based on recommended treat
-
ment regimens suggest that in primary and secondary 
syphilis it may take 6–12 months to see a fourfold decrease 
in titer; up to 20% of patients may not demonstrate a 
decline at 12 months. (See Follow-Up Care below.) The 
RPR and VDRL tests are equally reliable, but RPR titers 
tend to be higher than the VDRL. Thus, when these tests 
are used to follow disease activity, the same testing method 
should be used and preferably performed at the same 
laboratory.
b. Treponemal antibody tests—
These tests measure 
antibodies capable of reacting with 
T pallidum
 antigens. 
Traditionally, they have been used to confirm a diagnosis 
following a positive nontreponemal test. The TPPA test has 
been one of the most commonly used treponemal tests, 
along with the fluorescent treponemal antibody absorption 
test (FTA-ABS). Newer treponemal tests used in reverse 
screening algorithms include EIA and chemiluminescence 
assay (CIA).
In the traditional screening algorithm, the treponemal 
tests are used to determine whether a positive nontrepone
-
mal test is a false-positive result (see above) or is indicative 
of syphilis. Because of their sensitivity, particularly in the 
late stages of the disease, these tests are also of value when 
there is clinical evidence of syphilis, but the nontrepone
-
mal serologic test for syphilis is negative. Treponemal tests 
are reactive in many patients with primary syphilis and in 
almost all patients with secondary syphilis (Table 34–2). 
Although a reactive treponemal-specific serologic test 
remains reactive throughout a patient's life in most cases, it 
may (like nontreponemal antibody tests) revert to negative 
with adequate therapy. Final decisions about the signifi
-
cance of the results of serologic tests for syphilis must be 
based on a total clinical appraisal and may require expert 
c. 
Enzyme immunoassay (EIA)- or chemiluminescence 
immunoassay (CIA)-based screening 
algorithms
—
Newer screening algorithms reverse the traditional test 
order and begin with an automated treponemal antibody 
test, (eg, EIA or CIA) and then follow up with a non
-
treponemal test (RPR or VDRL) if the treponemal test is

-
treponemal test (RPR or VDRL) if the treponemal test is 
positive. This algorithm is faster and decreases labor 
costs to laboratories when compared with traditional 
The reverse algorithms can cause challenges in clinical 
management. A positive treponemal test with a negative 
RPR or VDRL may represent prior, treated syphilis; 
untreated latent syphilis; or a false-positive treponemal 
test. Such results should be evaluated with a second trepo
-
nemal test as a “tie-breaker, ” but interpretation of discor
-
dant results is not yet fully standardized and a clinician 
may benefit from an expert opinion. Reverse algorithms 
are recommended by several international organizations 
including the International Union against Sexually Trans
-
mitted Infections (IUSTI), but the CDC still recommends 
the traditional algorithm.
d. Rapid treponemal tests
—
A single rapid point of 
care treponemal test is approved for use in the United States, 
including in outreach and other nonlaboratory settings. 
Other tests are available internationally and are commonly 
used in limited-resource settings. Sensitivity ranges from 
62% to 100% and specificity from 83% to 95%.
3. Polymerase chain reaction—
In the United States, there 
is no FDA-cleared PCR test or method for 
T pallidum
 PCR, 
but it is available as a laboratory developed test in select 
research, referral, and public health laboratories and has 
the highest yield in primary and secondary lesions. There 
are no standards for these tests, but PCR has many 
Table 34–2.
 
Percentage of patients with positive 
serologic tests for syphilis.
1
t
est
Stage
Primary
Secondary
t
er
tiary
VDRL or RPR
75–85%
99–100%
40–95%
FTA-ABS, TPPA, 
 
or MHA-TP
69–100%
100%
94–98%
MHA-TP
46–89%
90–100%
NA
EIA or CIA
54–100%
100%
NA
1
Based on untreated cases.
CIA, chemiluminescence assay; EIA, enzyme immunoassay; 
FTA-ABS, fluorescent treponemal antibody absorption assay; 
MHA-TP , microhemagglutination assay for 
T pallidum
; RPR, rapid 
plasma reagin test; TPPA, 
T pallidum
 particle agglutination; VDRL, 
Venereal Disease Research Laboratory test.
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advantages as a tool for direct detection, including high 
sensitivity and ability to use a wide range of clinical speci
-
men types, including cerebrospinal fluid. PCR testing of 
blood has low sensitivity and is not recommended; the 
exception is for evaluation of congenital syphilis.
4. Cerebrospinal fluid examination—
See Neurosyphilis 
section.
 
»
The syphilitic chancre may be confused with genital her
-
pes, chancroid (usually painful and uncommon in the 
United States), lymphogranuloma venereum, or neoplasm. 
Any genital ulcer should be considered a possible primary 
syphilitic lesion. Simultaneous evaluation for herpes sim
-
plex virus types 1 and 2 using PCR or culture should also 
be done in these cases.
 
»
Prevention & Screening
Avoidance of sexual contact is the only completely reliable 
method of prevention but is an impractical public health 
measure. Latex or polyurethane condoms are effective but 
protect covered areas only. Men who have sex with men 
should be screened every 6–12 months, and as often as 
every 3 months in high-risk individuals (those who have 
multiple encounters with anonymous partners or who have 
sex in conjunction with the use of drugs). Pregnant women 
should be screened at the first prenatal visit and again in 
the third trimester; a third screen at delivery should be 
performed if there are risk indicators, including poverty, 
sex work, illicit drug use, history of other sexually trans
-
mitted diseases, and residence in a community with high 
syphilis morbidity. Patients treated for other sexually trans
-
mitted diseases should also be tested for syphilis, and per
-
sons who have known or suspected sexual contact with 
patients who have syphilis should be evaluated and pre
-
sumptively treated to abort development of infectious 
syphilis (see Treating Syphilis Contacts below).
 
»
Treatment
A. Antibiotic Therapy
Penicillin remains the preferred treatment for syphilis, since 
there have been no documented cases of penicillin resistant 
T pallidum
 (Table 34–3). In pregnant women, penicillin is 
the only option that reliably treats the fetus (see below).
There are some alternatives to penicillin for nonpreg
-
nant patients, including doxycycline. There are also limited 
data for ceftriaxone, although optimum dose and duration 
are not well defined. Azithromycin has been shown to be 
effective but should be used with caution; it should not be 
used at all in MSM due to demonstrated resistance. All 
patients treated with a non-penicillin regimen must have 
particularly close clinical and serologic follow-up.
Table 34–3.
 
Recommended treatment for syphilis.
1
Stage of Syphilis
t
r
eatment
a
lt
ernative
2
Comment
e
arly
Primary, secondary, 
or early latent
Benzathine penicillin G 
2.4 million units 
intramuscularly once
Doxycycline 100 mg orally twice daily for 14 days
or
Tetracycline 500 mg orally four times daily for 
14 days
or
Ceftriaxone 1 g intramuscularly or intravenously 
daily for 8–10 days
3
 
Late
Late latent or uncer
-
tain duration
intramuscularly weekly for 
3 weeks
Doxycycline 100 mg orally twice daily for 28 days
or
Tetracycline 500 mg orally four times a day for 
28 days
No routine cerebrospinal fluid 
evaluation unless neurologic, 
otologic or ocular 
Tertiary without 
neurosyphilis
3 weeks
or
28 days
Cerebrospinal fluid evaluation 
recommended in all patients
Aqueous penicillin G 
18–24 million units 
intravenously daily, given 
every 3–4 hours or as 
continuous infusion for 
10–14 days
Procaine penicillin, 2.4 million units 
intramuscularly daily with probenecid 500 mg 
orally four times a day for 10–14 days
or
Ceftriaxone 2 g intramuscularly or intravenously

10–14 days
or
Ceftriaxone 2 g intramuscularly or intravenously 
daily for 10–14 days
Follow treatment with 
benzathine penicillin G 
intramuscularly weekly for up 
to 3 weeks
1
Penicillin is the only documented effective treatment in pregnancy, so pregnant patients with true allergy should be desensitized and 
treated with penicillin according to stage of disease as above.
2
Patients treated with alternative therapies require close clinical and serologic monitoring.
3
Fewer data for ceftriaxone treatment, optimal dose or duration not known.
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B. Managing Jarisch–Herxheimer Reaction
The Jarisch–Herxheimer reaction, manifested by fever and 
aggravation of the existing clinical picture in the hours fol
-
lowing treatment is not an IgE-mediated allergic reaction. 
It is most common in early syphilis, particularly secondary 
syphilis where it can occur in 66% of cases.
The reaction may be blunted by simultaneous adminis
-
tration of antipyretics, although no proven method of pre
-
vention exists. In cases with increased risk of morbidity 
due to the Jarisch–Herxheimer reaction (including CNS or 
cardiac involvement and pregnancy), consultation with an 
infectious disease expert is recommended. Patients should 
be reminded that the reaction does not signify an allergy to 
penicillin.
C. Local Measures (Mucocutaneous Lesions)
Local treatment is usually not necessary. No local antisep
-
tics or other chemicals should be applied to a suspected 
syphilitic lesion until specimens for microscopy have been 
obtained.
D. Public Health Measures
Patients with infectious syphilis must abstain from sexual 
activity for 7–10 days after treatment. All cases of syphilis 
must be reported to the appropriate local public health 
agency in order to identify and treat sexual contacts. In 
addition, all patients with syphilis should have an HIV test 
at the time of diagnosis. In areas of high HIV prevalence, a 
repeat HIV test should be performed in 3 months if the 
initial test result was negative.
E. Treating Syphilis Contacts
Patients who have been sexually exposed to infectious 
syphilis within the preceding 3 months may be infected but 
seronegative and thus should be treated as for early syphilis 
even if serologic tests are negative. Persons exposed more 
than 3 months previously should be treated based on sero
-
logic results; however, if the patient is unreliable for follow-
up, empiric therapy is indicated.
 
»
Because treatment failures and reinfection may occur, 
patients treated for syphilis should be monitored clinically 
and serologically with nontreponemal titers every 
3–6 months. In primary and secondary syphilis, titers had 
been expected to decrease fourfold by 12 months; however, 
up to 20% of patients may fail to decrease. Optimal man
-
agement of these patients is unclear, but at a minimum, 
close clinical and serologic follow-up is indicated. In HIV-
uninfected patients, an HIV test should be repeated (all 
patients with syphilis should have an HIV test at the time 
of diagnosis); a thorough neurologic history and examina
-
tion should be performed and lumbar puncture considered 
since unrecognized neurosyphilis can be a cause of treat
-
ment failure. If symptoms or signs persist or recur after 
initial therapy or there is a fourfold or greater increase in 
nontreponemal titers, the patient has been reinfected 
(more likely) or the therapy failed (if a non-penicillin regi
-
men was used). In those individuals, an HIV test should be 
performed, a lumbar puncture done (unless reinfection is a 
certainty), and re-treatment given as indicated above.
2. Secondary Syphilis
 
»
Generalized maculopapular skin rash.
 
»
Mucous membrane lesions.
 
»
Condyloma lata in moist skin areas.
 
»
Generalized nontender lymphadenopathy.
 
»
Fever may be present.
 
»
Meningitis, hepatitis, osteitis, arthritis, iritis.
 
»
Many treponemes in moist lesions by immunoflu
-
orescence or darkfield microscopy.
 
»
Positive serologic tests for syphilis.
 
»
The secondary stage of syphilis usually appears a few 
weeks (or up to 6 months) after development of the chan
-
cre, when dissemination of 
T
 
pallidum
 produces systemic 
signs (fever, lymphadenopathy) or infectious lesions at 
sites distant from the site of inoculation. The most com
-
mon manifestations are skin and mucosal lesions. The 
skin lesions are nonpruritic, macular, papular, pustular, or

-
skin lesions are nonpruritic, macular, papular, pustular, or 
follicular (or combinations of any of these types, but gen
-
erally 
not
 vesicular) and generalized; involvement of the 
palms and soles (Figure 34–2) occurs in 80% of cases. 
Mucous membrane lesions may include mucous patches 
(Figure 34–3), which can be found on the lips, mouth, 
throat, genitalia, and anus. Specific lesions—condylomata 
lata (Figure 34–4)—are fused, weeping papules on the 
moist areas of the skin and mucous membranes and are 
sometimes mistaken for genital warts. Unlike the dry skin 
rashes, the mucous membrane lesions are highly 
Meningeal (aseptic meningitis or acute basilar 
meningitis), hepatic, renal, bone, and joint invasion may 
occur, with resulting cranial nerve palsies, jaundice, 
nephrotic syndrome, and periostitis. Alopecia (moth-eaten 
appearance) and uveitis may also occur.
The serologic tests for syphilis are positive in almost all 
cases (see Primary Syphilis and Table 34–2). The moist 
cutaneous and mucous membrane lesions often show 
 
T pallidum
 on darkfield microscopic examination. A tran
-
sient cerebrospinal fluid (CSF) pleocytosis is seen in 40% 
of patients with secondary syphilis. There may be evidence 
of hepatitis or nephritis (immune complex type) as circu
-
lating immune complexes are deposited in blood vessel 
walls.
Skin lesions may be confused with the infectious exan
-
thems, pityriasis rosea, and drug eruptions. Visceral lesions 
may suggest nephritis or hepatitis due to other causes.
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»
Treatment
Treatment is as for primary syphilis unless CNS or ocular 
disease or neurologic signs or symptoms are present, in which 
case a lumbar puncture should be performed and, if positive, 
treatment for neurosyphilis given (Table 34–3). See Primary 
Syphilis for follow-up care and treatment of contacts.
3. Latent Syphilis
 
»
Early latent syphilis:
 infection less than 1 year.
 
»
Late latent syphilis:
 infection more than 1 year.
 
»
No physical signs.
 
»
History of syphilis with inadequate treatment.
 
»
 
»
Latent syphilis is the clinically quiescent phase in the 
absence of primary or secondary lesions; the diagnosis is 
made by positive serologic tests. 
Early latent syphilis
 is 
defined as the first year after primary infection and may 
relapse to secondary syphilis if undiagnosed or inade
-
quately treated. Relapse is almost always accompanied by a 
rising titer in quantitative serologic tests; indeed, a rising 
titer may be the first or only evidence of relapse. About 
90% of relapses occur during the first year after infection.
Early latent infection can be diagnosed if there was 
documented seroconversion or a fourfold increase in non
-
treponemal titers in the past 12 months; the patient can 
recall symptoms of primary or secondary syphilis; or the 
patient had a sex partner with documented primary, sec
-
ondary, or early latent syphilis.
After the first year of latent syphilis, the patient is said 
to be in the 
late latent stage
 and noninfectious to sex part
-
ners. Transmission to the fetus, however, is possible in any 
phase. A diagnosis of late latent syphilis is justified only 
 
▲
Figure 34–3.
 
Secondary syphilis mucous patch of 
the tongue. 
(Used with permission from Kenneth Katz, 
MD, MSc, MSCE.)
 
▲
Figure 34–4.
 
Secondary syphilis perianal condylo
-
mata lata. 
(Used with permission from Joseph Engelman, 
MD; San Francisco City Clinic.)
A
B
 
▲
Figure 34–2.
 
A:
 Papular squamous eruption of the 
hands of a woman with secondary syphilis. 
B:
 Papular 
squamous eruption on the foot of the woman in figure 
A. 
(
Used, with permission, from Richard P . Usatine, MD in 
The Color 
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when the history and physical examination show no evi
-
dence of tertiary disease or neurosyphilis. The latent stage 
may last from months to a lifetime.
 
»
Treatment
Treatment of early latent syphilis and follow-up is as for 
primary syphilis unless CNS disease is present (Table 34–3). 
Treatment of late latent syphilis is shown in Table 34–3. 
The treatment of this stage of the disease is intended to 
prevent late sequelae. If there is evidence of CNS involve
-
ment, a lumbar puncture should be performed and, if posi
-
tive, the patient should receive treatment for neurosyphilis. 
Titers may not decline as rapidly following treatment 
compared to early syphilis. Nontreponemal serologic tests 
should be repeated at 6, 12, and 24 months. If titers 
increase fourfold or if initially high titers (1:32 or higher) 
fail to decrease fourfold by 12–24 months or if symptoms 
or signs consistent with syphilis develop, an HIV test 
should be repeated in HIV-uninfected patients, lumbar 
puncture should be performed, and re-treatment given 
according to the stage of the disease.
4. 
t
er
tiary (Late) Syphilis
 
»
Infiltrative tumors of skin, bones, liver (gummas).
 
»
Aortitis, aneurysms, aortic regurgitation.
 
»
CNS disorders: meningovascular and degenera
-
tive changes, paresthesias, shooting pains, abnor
-
mal reflexes, dementia, or psychosis.
 
»
This stage may occur at any time after secondary syphilis, 
even after years of latency, and is rarely seen in developed 
countries in the modern antibiotic era. Late lesions are 
thought to represent a delayed hypersensitivity reaction of 
the tissue to the organism and are usually divided into two 
types: (1) a localized gummatous reaction with a relatively 
rapid onset and generally prompt response to therapy and 
(2) diffuse inflammation of a more insidious onset that 
characteristically involves the CNS and large arteries, may 
not improve despite treatment, and is often fatal if 
untreated. Gummas may involve any area or organ of the 
body but most often affect the skin or long bones. Cardio
-
vascular disease is usually manifested by aortic aneurysm, 
aortic regurgitation, or aortitis. Various forms of diffuse or 
localized CNS involvement may occur.
Late syphilis must be differentiated from neoplasms of 
the skin, liver, lung, stomach, or brain; other forms of men
-
ingitis; and primary neurologic lesions.
Although almost any tissue and organ may be involved 
in late syphilis, the following are the most common types 
of involvement: skin, mucous membranes, skeletal system, 
eyes, respiratory system, gastrointestinal system, cardio
-
vascular system, and nervous system.
 
»
1. Skin—
Cutaneous lesions of late syphilis are of two 
varieties: (1) multiple nodular lesions that eventually ulcer
-
ate (lues maligna) or resolve by forming atrophic, pig
-
mented scars and (2) solitary gummas that start as painless 
subcutaneous nodules, then enlarge, attach to the overlying 
skin, and eventually ulcerate (Figure 34–5).
2. Mucous membranes—
Late lesions of the mucous mem
-
branes are nodular gummas or leukoplakia, highly destruc
-
tive to the involved tissue.
3. Skeletal system—
Bone lesions are destructive, causing 
periostitis, osteitis, and arthritis with little or no associated 
redness or swelling but often marked myalgia and myositis 
of the neighboring muscles. The pain is especially severe at 
night.
4. Eyes—
Late ocular lesions are gummatous iritis, chorio
-
retinitis, optic atrophy, and cranial nerve palsies, in addi
-
tion to the lesions of CNS syphilis.
5. Respiratory system—
Respiratory involvement by is 
caused by gummatous infiltrates into the larynx, trachea, 
and pulmonary parenchyma, producing discrete pulmo
-
nary densities. There may be hoarseness, respiratory dis
-
tress, and wheezing secondary to the gummatous lesion

-
-
tress, and wheezing secondary to the gummatous lesion 
itself or to subsequent stenosis occurring with healing.
6. Gastrointestinal system—
Gummas involving the liver 
may be benign but can cause cirrhosis. Gastric involvement 
can consist of diffuse infiltration into the stomach wall or 
focal lesions that endoscopically and microscopically can 
be confused with lymphoma or carcinoma. Epigastric pain, 
early satiety, regurgitation, belching, and weight loss are 
common symptoms.
7. Cardiovascular system—
Cardiovascular lesions 
(10–15% of tertiary syphilitic lesions) are often progressive, 
disabling, and life-threatening. CNS lesions are often pres
-
ent concomitantly. Involvement usually starts as an arteritis 
in the supracardiac portion of the aorta and progresses to 
one or more of the following: (1) narrowing of the coronary 
 
▲
Figure 34–5.
 
Gumma of the nose due to long-
standing tertiary syphilis. 
(From J. Pledger, Public Health 
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ostia, with resulting decreased coronary circulation, angina, 
and acute myocardial infarction; (2) scarring of the aortic 
valves, producing aortic regurgitation, and eventually heart 
failure; and (3) weakness of the wall of the aorta, with sac
-
cular aneurysm formation (Figure 34–6) and associated 
pressure symptoms of dysphagia, hoarseness, brassy cough, 
back pain (vertebral erosion), and occasionally rupture of 
the aneurysm. Recurrent respiratory infections are com
-
mon as a result of pressure on the trachea and bronchi.
8. Nervous system (neurosyphilis)—
 
»
Treatment
Treatment of tertiary syphilis (excluding neurosyphilis) is 
the same as late latent syphilis (Table 34–3); symptoms may 
not resolve after treatment. Positive serologic tests do not 
usually become negative. Viable spirochetes are occasion
-
ally found in the eyes, in CSF, and elsewhere in patients 
with “adequately” treated syphilis, but claims for their 
capacity to cause progressive disease are speculative.
The pretreatment clinical and laboratory evaluation 
should include neurologic, ocular, cardiovascular, psychi
-
atric, and CSF examinations. In the presence of definite 
CSF or neurologic abnormalities, one should treat for 
5. Neurosyphilis
 
»
Can occur at any stage of disease.
 
»
Consider both clinical presentation and laboratory 
data.
 
»
Carefully evaluate the neurologic examination in 
all patients and consider CSF evaluation for atypi
-
cal symptoms or lack of decrease in nontrepone
-
mal serology titers.
 
»
Neurosyphilis can occur at any stage of disease and can be a 
progressive, disabling, and life-threatening complication. 
Asymptomatic CSF abnormalities and meningovascular 
syphilis occur earlier (months to years after infection, some
-
times coexisting with primary and secondary syphilis) than 
tabes dorsalis and general paresis (2–50 years after infection).
 
»
A. Classification
1. Asymptomatic neuroinvasion—
This form has been 
reported in up to 40% of patients with early syphilis and is 
characterized by spinal fluid abnormalities (positive spinal 
fluid serology, increased cell count, occasionally increased 
protein) without symptoms or signs of neurologic involve
-
ment. There are no clear data to support that these asymp
-
tomatic CSF abnormalities have clinical significance; 
therefore, unless treatment failure is suspected, routine CSF 
evaluation of asymptomatic patients is not recommended.
2. Meningovascular syphilis—
This form is characterized 
by meningeal involvement or changes in the vascular struc
-
tures of the brain (or both), producing symptoms of acute or 
chronic meningitis (headache, irritability); cranial nerve 
palsies (basilar meningitis); unequal reflexes; irregular pupils 
with poor light and accommodation reflexes; and when large 
vessels are involved, cerebrovascular accidents. The CSF 
shows increased cells (100–1000/mcL), elevated protein, and 
may have a positive serologic test (CSF VDRL) for syphilis. 
The symptoms of acute meningitis are rare in late syphilis.
3. Tabes dorsalis—
This form is a chronic progressive 
degeneration of the parenchyma of the posterior columns of 
the spinal cord and of the posterior sensory ganglia and 
nerve roots. The symptoms and signs are impairment of 
proprioception and vibration sense, Argyll Robertson 
pupils (which react poorly to light but accommodate for 
near focus), and muscular hypotonia and hyporeflexia. 
Impaired proprioception results in a wide-based gait and 
inability to walk in the dark. Paresthesias, analgesia, or 
sharp recurrent pains in the muscles of the leg (“shooting” 
or “lightning” pains) may occur. Joint damage may occur as 
a result of lack of sensory innervation (Charcot joint, 
Figure 34–7). The CSF may have a normal or increased cell 
count, elevated protein, and variable results of serologic tests.

4. General paresis—
This is generalized involvement of the 
cerebral cortex with insidious onset of symptoms. There is 
usually a decrease in concentrating power, memory loss, 
dysarthria, tremor of the fingers and lips, irritability, and 
mild headaches. Most striking is the change of personality; 
the patient may become slovenly, irresponsible, confused, 
and psychotic. The CSF findings resemble those of tabes 
dorsalis. Combinations of the various forms of neurosyphi
-
lis (especially tabes and paresis) are not uncommon.
See Serologic Tests for Syphilis, above; these tests should 
also be performed in cases of suspected neurosyphilis.
 
▲
Figure 34–6.
 
Ascending saccular aneurysm of the 
thoracic aorta in tertiary syphilis. 
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1. Indications for a lumbar puncture—
In early syphilis 
(primary and secondary syphilis and early latent syphilis of 
less than 1 year's duration), invasion of the CNS by 
T pallidum
 with CSF abnormalities occurs commonly, but 
clinical neurosyphilis rarely develops in patients who have 
received standard therapy. Thus, unless clinical symptoms 
or signs of neurosyphilis or ocular involvement (uveitis, 
neuroretinitis, optic neuritis, iritis) are present, a lumbar 
puncture is not routinely recommended. CSF evaluation is 
recommended, however, if neurologic or ophthalmologic 
symptoms or signs are present, if there is evidence of treat
-
ment failure (see earlier discussion), or if there is evidence 
of active tertiary syphilis (eg, aortitis, iritis, optic atrophy, 
the presence of a gumma).
2. Spinal fluid examination—
CSF findings in neurosyphi
-
lis are variable. In “classic” cases, there is an elevation of 
total protein, lymphocytic pleocytosis, and a positive CSF 
reagin test. VDRL is more sensitive, and prefered over 
RPR. The serum nontreponemal titers will be reactive in 
most cases. In later stages of syphilis, normal CSF analysis 
in the presence of infection can occur, but it is unusual. 
Because the CSF VDRL may be negative in 30–70% of 
cases of neurosyphilis, 
a negative test does not exclude neu
-
rosyphilis
, while a positive test confirms the diagnosis
.
 The 
CSF FTA-ABS is sometimes used; it is a highly sensitive test 
but lacks specificity, and a high serum titer of FTA-ABS 
may result in a positive CSF titer in the absence of 
 
»
Treatment
Neurosyphilis is treated with high doses of aqueous peni
-
cillin to achieve better penetration and higher levels of 
medication in the CSF than is possible with benzathine 
penicillin G (Table 34–3). There are limited data for using 
ceftriaxone to treat neurosyphilis as well, but because other 
regimens have not been adequately studied, patients with a 
history of an IgE-mediated reaction to penicillin may 
require skin testing for allergy to penicillin and, if positive, 
should be desensitized. Because of concerns about slowly 
dividing organisms that may persist after completing 
10–14 days of therapy with short-acting aqueous 
penicillin G, many experts recommend subsequent admin
-
istration of 2.4 million units of the longer-acting benza
-
thine penicillin G intramuscularly once weekly for up to 
3 weeks at the conclusion of treatment.
All patients treated for neurosyphilis should have non
-
treponemal serologic tests done every 3–6 months. Guide
-
lines established by the CDC recommend spinal fluid 
examinations at 6-month intervals until the CSF cell count is 
normal; however, there are data to suggest that normalization 
of serum titers are an acceptable surrogate for CSF response. 
In general, CSF white blood cell count and CSF VDRL nor
-
malize more quickly (usually in 12 months) than CSF protein 
concentration, which can remain abnormal for extended 
periods. If the serum nontreponemal titers do not normalize, 
the CSF analysis should be repeated. A second course of 
penicillin therapy may be given if the CSF cell count has not 
decreased at 6 months or is not normal at 2 years.
6. Syphilis in HIV-Infected Patients
Syphilis is common among HIV-infected individuals. Some 
data suggest that syphilis coinfection is associated with an 
increase in HIV viral load and a decrease in CD4 count that 
normalizes with therapy; other studies have not found an 
association with HIV disease progression. Overall, for opti
-
mal patient care as well as prevention of transmission to 
partners, guidelines for the primary care of HIV-infected 
patients recommend at least annual syphilis screening.
Interpretation of serologic tests should be the same for 
HIV-positive and HIV-negative persons. If the diagnosis of 
syphilis is suggested on clinical grounds but nontrepone
-

-
mal tests are negative, consider the prozone effect caused 
by very high antibody titers (see nontreponemal tests, 
above), or try direct examination of primary or secondary 
lesions for spirochetes.
HIV-positive patients with primary and secondary 
syphilis should have careful clinical and serologic follow-
up at 3-month intervals. The use of antiretroviral therapy 
has been associated with reduced serologic failure rates 
after syphilis treatment.
The diagnosis of neurosyphilis in HIV-infected patients 
is complicated by the fact that mild CSF abnormalities may 
be found in HIV infection alone. Like in HIV-uninfected 
patients, routine lumbar puncture is not recommended in 
asymptomatic patients; it should be reserved for cases in 
which neurologic symptoms or signs are present or there is 
concern for treatment failure. Following treatment, CSF 
white blood cell counts should normalize within 12 months 
regardless of HIV status, while the CSF VDRL may take 
longer. As discussed above, the same criteria for failure 
apply to HIV-positive and HIV-negative patients, and re-
treatment regimens are the same.
Because clinical experience in treating HIV-infected 
patients with syphilis is based on penicillin regimens, few 
options exist for treating the penicillin-allergic patient. 
Doxycycline or tetracycline regimens can be used for pri
-
mary, secondary, and early latent syphilis as well as for late 
latent syphilis and latent syphilis of unknown duration 
though with caution and close follow-up (Table 34–3). 
 
▲
Figure 34–7.
 
Neuropathic arthropathy (Charcot 
joint) from tertiary syphilis. 
(From Susan Lindsley, Public 
Health Image Library, CDC.)
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For neurosyphilis, limited efficacy data exist for ceftriax
-
one; close clinical and serologic follow-up after treatment is 
essential. Whenever possible, penicillin regimens are opti
-
mal even if this requires skin testing and desensitization.
7. Syphilis in Pregnancy
All pregnant women should have a nontreponemal sero
-
logic test for syphilis at the time of the first prenatal visit 
(see Chapter 19). In women who may be at increased risk 
for syphilis or for populations in which there is a high 
prevalence of syphilis, additional nontreponemal tests 
should be performed during the third trimester at 28 weeks 
and again at delivery. The serologic status of all women 
who have delivered should be known before discharge 
from the hospital. Seropositive women should be consid
-
ered infected and should be treated unless prior treatment 
with fall in antibody titer is medically documented.
The only recommended treatment for syphilis in 
pregnancy is penicillin in dosage schedules appropriate 
for the stage of disease
. Penicillin prevents congenital 
syphilis in 90% of cases, even when treatment is given late 
in pregnancy. Women with a history of penicillin allergy 
should be skin tested and desensitized if necessary. Tetra
-
cycline and doxycycline are contraindicated in pregnancy.
The infant should be evaluated immediately at birth, and, 
depending on the likelihood of infection, monitored for 
clinical and serologic manifestations in the first year of life.
 
»
•	
Consultation with the local public health department 
may help obtain all prior positive syphilis serologic 
results and may be helpful in complicated or atypical 
cases.
•	
Early (infectious) syphilis cases may be contacted for 
partner notification and treatment by local public 
health authorities.
 
»
•	
Pregnant women with syphilis and true penicillin 
allergy should be admitted for desensitization and 
•	
Women in late pregnancy treated for early syphilis 
should have close outpatient monitoring or be admitted 
because the Jarisch-Herxheimer reaction can induce 
premature labor.
•	
Patients with neurosyphilis usually require admission 
for treatment with aqueous penicillin.
World Health Organization (WHO). WHO guidelines for the 
 (syphilis). Geneva; 2016. 
[PMID: 27631046]
 
º
NON–S
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tre
PON
e
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a
t
OS
e
S
A variety of treponemal diseases other than syphilis occur 
endemically in many tropical areas of the world. They are 
distinguished from disease caused by 
T pallidum
 by their 
nonsexual transmission via direct skin contact, their rela
-
tively high incidence in certain geographic areas and 
among children, and their tendency to produce less severe 
visceral manifestations. As in syphilis, skin, soft tissue, and 
bone lesions may develop, organisms can be demonstrated 
in infectious lesions with darkfield microscopy or immu
-
nofluorescence, but cannot be cultured in artificial media; 
the serologic tests for syphilis are positive; molecular meth
-
ods such as PCR and genome sequencing are available, but 
not widely used in endemic areas; the diseases have pri
-
mary, secondary, and sometimes tertiary stages. Treatment 
with 2.4 million units of benzathine penicillin G intramus
-
cularly is generally curative in any stage of the non–
sexually transmitted treponematoses. In cases of penicillin 
hypersensitivity, tetracycline, 500 mg orally four times a 
day for 10–14 days, is usually the recommended alterna
-
tive. In randomized controlled trials, oral azithromycin

-
tive. In randomized controlled trials, oral azithromycin 
(30 mg/kg once) was noninferior to benzathine penicillin 
G for the treatment of yaws in children.
YAWS (FRAMBESIA)
Y aws is a contagious disease largely limited to tropical 
regions that is caused by 
T pallidum
 subspecies 
pertenue.
 It 
is characterized by granulomatous lesions of the skin, 
mucous membranes, and bone. Y aws is rarely fatal, though 
if untreated it may lead to chronic disability and disfigure
-
ment. Y aws is acquired by direct nonsexual contact, usually 
in childhood, although it may occur at any age. The 
“mother yaw, ” a painless papule that later ulcerates, appears 
3–4 weeks after exposure. There is usually associated 
regional lymphadenopathy. Six to 12 weeks later, secondary 
lesions that are raised papillomas and papules that weep 
highly infectious material appear and last for several 
months or years. Painful ulcerated lesions on the soles are 
called “crab yaws” because of the resulting gait. Late gum
-
matous lesions may occur, with associated tissue destruc
-
tion involving large areas of skin and subcutaneous tissues. 
The late effects of yaws, with bone change, shortening of 
digits, and contractions, may be confused with similar 
changes occurring in leprosy. CNS, cardiac, or other vis
-
ceral involvement is rare. See above for therapy. The World 
Health Organization has set a goal of eliminating yaws by 
the year 2020 using mass treatment with azithromycin.
PINTA
Pinta is a non–sexually transmitted spirochetal infection 
caused by 
T pallidum
carateum.
 It occurs 
endemically in rural areas of Latin America, especially in 
Mexico, Colombia, and Cuba, and in some areas of the 
Pacific. A nonulcerative, erythematous primary papule 
spreads slowly into a papulosquamous plaque showing a 
variety of color changes (slate, lilac, black). Secondary 
lesions resemble the primary one and appear within a year 
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after it. These appear successively, new lesions together 
with older ones; are most common on the extremities; and 
later show atrophy and depigmentation. Some cases show 
pigmentary changes and atrophic patches on the soles and 
palms, with or without hyperkeratosis, that are indistin
-
guishable from “crab yaws. ” See above for therapy.
ENDEMIC SYPHILIS (
Bejel
)
Endemic syphilis is an acute or chronic infection caused by 
T pallidum
endemicum
. It has been reported in 
a number of countries, particularly in the eastern Mediter
-
ranean area, often with local names: bejel in Syria, 
Saudi Arabia, and Iraq, and dichuchwa, njovera, and siti in 
Africa. It also occurs in Southeast Asia. The local forms 
have distinctive features. Moist ulcerated lesions of the skin 
or oral or nasopharyngeal mucosa are the most common 
manifestations. Generalized lymphadenopathy and sec
-
ondary and tertiary bone and skin lesions are also com
-
mon. Deep leg pain points to periostitis or osteomyelitis. In 
the late stages of disease, destructive gummatous lesions 
similar to those seen in yaws can develop, resulting in loss 
of cartilage and saber shin deformity. Cardiovascular and 
CNS involvement are rare. See above for therapy.
Giacani L et al. The endemic treponematoses. Clin Microbiol 
Rev. 2014 Jan;27(1):89–115. [PMID: 24396138]
Marks M. Y aws: towards the WHO eradication target. Trans R 
Soc Trop Med Hyg. 2016 Jun;110(6):319–20. [PMID: 
27268712]
 
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RELAPSING FEVER
The infectious organisms in relapsing fever are spirochetes 
of the genus 
Borrelia
. The infection has two forms: tick-
borne and louse-borne. The main reservoir for 
 
relapsing fever is rodents, which serve as the source of 
infection for ticks. Tick-borne relapsing fever may be 
transmitted transovarially from one generation of ticks to 
the next. Humans can be infected by tick bites or by rub
-
bing crushed tick tissues or feces into the bite wound. Tick-
borne relapsing fever is endemic, but is not transmitted 
from person to person. In the United States, infected ticks 
are found throughout the West, especially in mountainous 
areas, but clinical cases are uncommon in humans.
The 
louse-borne
 form is primarily seen in the develop
-
ing world, and humans are the only reservoir. Large epidem
-
ics may occur in louse-infested populations, and transmission 
is favored by crowding, malnutrition, and cold climate.
 
»
There is an abrupt onset of fever, chills, tachycardia, nausea 
and vomiting, arthralgia, and severe headache. Hepato
-
megaly and splenomegaly may develop, as well as various 
types of rashes (macular, papular, petechial) that usually 
occur at the end of a febrile episode. Delirium occurs with 
high fever, and there may be various neurologic and psy
-
chic abnormalities. The attack terminates, usually abruptly, 
after 3–10 days. After an interval of 1–2 weeks, relapse 
occurs, but often it is somewhat milder. Three to ten 
relapses may occur before recovery in tick-borne disease, 
whereas louse-borne disease is associated with only one or 
two relapses.
During episodes of fever, large spirochetes are seen in thick 
and thin blood smears stained with Wright or Giemsa 
stain. The organisms can be cultured in special media but 
rapidly lose pathogenicity. The spirochetes can multiply in 
injected rats or mice and can be seen in their blood.
A variety of anti-borrelia antibodies develop during the 
illness; sometimes the Weil–Felix test for rickettsioses and 
nontreponemal serologic tests for syphilis may also be 
falsely positive. Infection can cause false-positive indirect 
fluorescent antibody and Western blot tests for 
Borrelia 
, causing some cases to be misdiagnosed as 
Lyme disease. PCR assays have been developed but are not

Borrelia 
Lyme disease. PCR assays have been developed but are not 
widely available. CSF abnormalities occur in patients with 
meningeal involvement. Mild anemia and thrombocytope
-
nia are common, but the white blood cell count tends to be 
normal.
 
»
The manifestations of relapsing fever may be confused with 
malaria, leptospirosis, meningococcemia, yellow fever, 
typhus, or rat-bite fever.
 
»
Prevention of tick bites (as described for rickettsial dis
-
eases) and delousing procedures applicable to large groups 
can prevent illness. Arthropod vectors should be controlled 
if possible.
Postexposure prophylaxis with doxycycline 200 mg 
orally on day 1 and 100 mg daily for 4 days has been shown 
to prevent recurrent fever following tick bites in highly 
 
»
Treatment
A single dose of tetracycline or erythromycin, 0.5 g orally, 
or a single dose of procaine penicillin G, 600,000–800,000 
units intramuscularly (adults) or 400,000 units intramus
-
cularly (children), probably constitutes adequate treatment 
for louse-borne relapsing fevers; however, some experts 
advocate for longer courses of treatment to prevent persis
-
tent infection. Because of higher relapse rates, tick-borne 
disease is routinely treated with 0.5 g of tetracycline or 
erythromycin given orally four times daily for 10 days. If 
CNS invasion is suspected, penicillin G, 3 million units 
intravenously every 4 hours, or ceftriaxone, 1 g intrave
-
nously daily, should be given for 10–14 days. Jarisch–
Herxheimer reactions occur commonly following 
treatment and may be life-threatening, so patients should 
be closely monitored (see Syphilis, above). One study in 
patients with louse-borne relapsing fever showed that 
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administration of anti-TNF antibodies prior to antibiotic 
therapy can be effective in preventing the reaction.
 
»
Prognosis
The overall mortality rate is usually about 5%. Fatalities are 
most common in older, debilitated, or very young patients. 
With treatment, the initial attack is shortened and relapses 
are largely prevented.
Cutler SJ. Relapsing fever 
Borreliae
: a global review. Clin Lab 
Med. 2015 Dec;35(4):847–65. [PMID: 26593261]
RAT-BITE FEVER
Rat-bite fever is an uncommon acute infectious disease 
caused by the treponeme 
Spirillum minus
 (Asia), or the 
bacteria 
 (North America). It is 
transmitted to humans by the bite of a rat. Inhabitants of 
rat-infested dwellings, owners of pet rats, and laboratory 
workers are at greatest risk.
 
»
In 
Spirillum
 infections, the original rat bite, unless second
-
arily infected, heals promptly, but 1 to several weeks later 
the site becomes swollen, indurated, and painful; assumes 
a dusky purplish hue; and may ulcerate. Regional lymphan
-
gitis and lymphadenitis, fever, chills, malaise, myalgia, 
arthralgia, and headache are present. Splenomegaly may 
occur. A sparse, dusky-red maculopapular rash appears on 
the trunk and extremities in many cases, and there may be 
frank arthritis.
After a few days, both the local and systemic symptoms 
subside, only to reappear several days later. This relapsing 
pattern of fever for 3–4 days alternating with afebrile peri
-
ods lasting 3–9 days may persist for weeks. The other fea
-
tures, however, usually recur only during the first few 
relapses. Endocarditis is a rare complication of infection.
Leukocytosis is often present, and the nontreponemal test for 
syphilis is often falsely positive. The organism may be identi
-
fied in darkfield examination of the ulcer exudate or aspi
-
rated lymph node material; more commonly, it is observed 
after inoculation of a laboratory animal with the patient's 
exudate or blood. It has not been cultured in artificial media.
 
»
Rat-bite fever must be distinguished from the rat-bite–
induced lymphadenitis and rash of streptobacillary fever. 
Clinically, the severe arthritis and myalgias seen in strepto
-
bacillary disease are rarely seen in disease caused by 
 
S minus.
 Reliable differentiation requires an increasing titer 
of agglutinins against 
S moniliformis
 or isolation of the 
causative organism. Other diseases in the differential 
include tularemia, rickettsial disease, 
Pasteurella multocida
 
infections, and relapsing fever.
 
»
Treatment
In acute illness, intravenous penicillin, 1–2 million units 
every 4–6 hours is given initially; ceftriaxone 1 g intrave
-
nously daily is another option. Once improvement has 
occurred, therapy may be switched to oral penicillin 
V 500 mg four times daily, or amoxicillin 500 mg three 
times daily, to complete 10–14 days of therapy. For the 
penicillin-allergic patient, tetracycline 500 mg orally four 
times daily or doxycycline 100 mg twice a day can be used.
 
»
Prognosis
The reported mortality rate of about 10% should be mark
-
edly reduced by prompt diagnosis and antimicrobial 
Rahman S et al. Fever, petechiae, and joint pain. J Fam Pract. 
2017 May;66(5):323–5. [PMID: 28459894]
LEPTOSPIROSIS
 
»
Clinical illness can vary from asymptomatic to fatal 
liver and kidney disease.
 
»
Anicteric leptospirosis:
 
more common and milder 
form of the disease.
 
»
Icteric leptospirosis (Weil syndrome):
 
impaired 
kidney and liver function, abnormal mental status, 
and hemorrhagic pneumonia; 5–40% mortality rate.
 
»
Leptospirosis is an acute and sometimes severe treponemal 
infection that is caused by 21 species within the genus 
Leptospira.
 The disease is distributed worldwide, and it is 
among the most common zoonotic infections. The lepto
-

-
spires are often transmitted to humans by the ingestion of 
food and drink contaminated by the urine of an infected 
animal. The organism may also enter through minor skin 
lesions and probably via the conjunctiva. Cases have 
occurred in international travelers after swimming or raft
-
ing in contaminated water, and occupational cases occur 
among sewer workers, rice planters, abattoir workers, and 
farmers. Sporadic urban cases have been seen in the home
-
less exposed to rat urine.
 
»
Anicteric leptospirosis,
 the more common and milder form 
of the disease, is often biphasic. After an incubation period 
of 2–20 days, the initial or “septicemic” phase begins with 
abrupt fever to 39–40
°
C, chills, abdominal pain, severe 
headache, and myalgias, especially of the calf muscles. There 
may be marked conjunctival suffusion. Leptospires can be 
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isolated from blood, CSF, and tissues. Following a 1- to 3-day 
period of improvement in symptoms and absence of fever, 
the second or “immune” phase begins; however, in severe 
disease the phases may appear indistinct. Leptospires are 
absent from blood and CSF but are still present in the kid
-
ney, and specific antibodies appear. A recurrence of symp
-
toms is seen as in the first phase of disease with the onset of 
meningitis. Uveitis (which can be unilateral or bilateral and 
usually involves the entire uveal tract), rash, and adenopathy 
may occur. A rare but severe manifestation is hemorrhagic 
pneumonia. The illness is usually self-limited, lasting 
4–30 days, and complete recovery is the rule.
Icteric leptospirosis
 
(Weil syndrome)
 is the more severe 
form of the disease, characterized by impaired kidney and 
liver function, abnormal mental status, hemorrhagic pneu
-
monia, hypotension, and a 5–40% mortality rate. Symptoms 
and signs often are continuous and not biphasic.
Leptospirosis with jaundice must be distinguished from 
hepatitis, yellow fever, rickettisal disease, and relapsing fever.
The leukocyte count may be normal or as high as 
50,000/mcL (0.05/L), with neutrophils predominating. The 
urine may contain bile, protein, casts, and red cells. 
Oliguria is common, and in severe cases uremia may occur. 
Elevated bilirubin and aminotransferases are seen in 75%, 
and elevated creatinine (greater than 1.5 mg/dL) 
(132.6 mcmol/L) is seen in 50% of cases. Serum creatine 
kinase is usually elevated in persons with leptospirosis and 
normal in persons with hepatitis. In cases with meningeal 
involvement, organisms may be found in the CSF during the 
first 10 days of illness. Early in the disease, the organism may 
be identified by darkfield examination of the patient's blood 
(a test requiring expertise since false-positives are frequent 
in inexperienced hands) or by culture on a semisolid 
medium (eg, Fletcher EMJH). Cultures take 1–6 weeks to 
become positive but may remain negative if antibiotics were 
started before culture was obtained. The organism may also 
be grown from the urine from the tenth day to the sixth 
week. Diagnosis is usually made by means of serologic tests, 
including the microscopic agglutination test (considered the 
gold standard but not widely available), and enzyme-linked 
immunosorbent assay (ELISA). PCR molecular diagnostics 
are not widely available but appear to be sensitive, specific, 
positive early in disease, and able to detect leptospiral DNA 
in blood, urine, CSF, and aqueous humor.
 
»
Myocarditis, aseptic meningitis, acute kidney injury, and 
pulmonary infiltrates with hemorrhage are not common 
but are the usual causes of death. Iridocyclitis may occur.
 
»
The mainstay of prevention is avoidance of potentially 
contaminated food and water.
Prophylaxis with doxycycline has been effective in trials 
but is not routinely recommended. Human vaccine is used in 
some limited settings but is not available in the United States.
 
»
Treatment
Many cases are self-limited without specific treatment. 
Various antimicrobial medications, including penicillin, 
ceftriaxone, and tetracyclines, show antileptospiral activity; 
however, meta-analysis has not demonstrated a clear sur
-
vival benefit for any antibiotic. Doxycycline (100 mg every 
12 hours orally or intravenously), penicillin (eg, 1.5 million 
units every 6 hours intravenously), and ceftriaxone 
(1 g daily intravenously) are used in severe leptospirosis. 
Jarisch–Herxheimer reactions may occur (see Syphilis, 
above). Although therapy for mild disease is controversial, 
most clinicians treat with doxycycline, 100 mg orally twice 
daily, for 7 days, or amoxicillin 50 mg/kg, divided into 
three doses daily. Azithromycin is also active, but clinical 
experience is limited.
 
»
Prognosis

»
Prognosis
Without jaundice, the disease is almost never fatal. With 
jaundice, the mortality rate is 5% for those under age 
30 years and 40% for those over age 60 years.
 
»
Patients with jaundice or other evidence of severe disease 
should be admitted for close monitoring and may require 
admission to an intensive care unit.
Jiménez JIS et al. Leptospirosis: report from the task force on 
tropical diseases by the World Federation of Societies of 
Intensive and Critical Care Medicine. J Crit Care. 2018 Feb; 
43:361–5. [PMID: 29129539]
Waggoner JJ et al. Molecular diagnostics for human leptospiro
-
sis. Curr Opin Infect Dis. 2016 Oct;29(5):440–5. [PMID: 
27537829]
LYME DISEASE (
Lyme Borreliosis
)
 
»
Erythema migrans: a flat or slightly raised red 
lesion that expands with central clearing.
 
»
Headache or stiff neck.
 
»
Arthralgias, arthritis, and myalgias; arthritis is 
often chronic and recurrent.
 
»
This illness, named after the town of Old Lyme, Connecti
-
cut, is the most common tick-borne disease in the 
United States and Europe and is caused by genospecies of 
the spirochete 
. Most US cases are reported 
from the mid-Atlantic, northeastern, and north central 
regions of the country. The true incidence of Lyme disease 
is not known for a number of reasons: (1) serologic tests are 
not standardized (see below); (2) clinical manifestations 
are nonspecific; and (3) even with reliable testing, serology 
is insensitive in early disease.
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The tick vector of Lyme disease varies geographically and 
is 
Ixodes scapularis
 in the northeastern, north central, and 
mid-Atlantic regions of the United States; 
Ixodes pacificus
 on 
the West Coast; 
 in Europe; and 
Ixodes persul
-
catus
 in Asia. The disease also occurs in Australia. Mice and 
deer make up the major animal reservoir of 
, 
but other rodents and birds may also be infected. Domestic 
animals such as dogs, cattle, and horses can also develop 
clinical illness, usually manifested as arthritis.
Under experimental conditions, ticks must feed for 
24–36 hours or longer to transmit infections. Most cases 
are reported in the spring and summer months. In addi
-
tion, the percentage of ticks infected varies on a regional 
basis. In the northeastern and midwestern United States, 
15–65% of 
I scapularis
 ticks are infected with the spiro
-
chete; in the west, only 2% of 
I pacificus
 are infected. These 
are important epidemiologic features in assessing the likeli
-
hood that tick exposure will result in disease. Eliciting a 
history of brushing a tick off the skin (ie, the tick was not 
feeding) or removing a tick on the same day as exposure 
(ie, the tick did not feed long enough) decreases the likeli
-
hood that infection will develop.
Because the 
Ixodes
 tick is so small, the bite is usually 
painless and goes unnoticed. After feeding, the tick drops 
off in 2–4 days. If a tick is found, it should be removed 
immediately. The best way to accomplish this is to use fine-
tipped tweezers to pull firmly and repeatedly on the tick's 
mouth part—not the tick's body—until the tick releases its 
hold. Saving the tick in a bottle of alcohol for future identi
-
fication may be useful, especially if symptoms develop.
 
»
Prior clinical description of Lyme disease divided the ill
-
ness into three stages: stage 1, flu-like symptoms and a typi
-
cal skin rash (erythema migrans, see Figure 6–27); stage 2, 
weeks to months later, facial (cranial nerve VII) palsy or 
meningitis; and stage 3, months to years later, arthritis. The 
problem with this simplified scheme is that there is a great 
deal of overlap, and the skin, CNS, and musculoskeletal 
system can be involved early or late. A more accurate clas
-
sification divides disease into early and late manifestations 
and specifies whether disease is localized or disseminated.
1. Stage 1, early localized infection—
Stage 1 infection is 
characterized by erythema migrans. About 1 week after the 
tick bite (range, 3–30 days; median 7–10 days), a flat or 
slightly raised red lesion appears at the site, which is com
-
monly seen in areas of tight clothing such as the groin, 
thigh, or axilla. This lesion expands over several days. 
Although originally described as a lesion that progresses 
with central clearing (“bulls-eye” lesion), often there is a 
more homogeneous appearance or even central intensifica
-
tion. About 10–20% of patients either do not have typical 
skin lesions or the lesions go unnoticed. Most patients with 
erythema migrans will have a concomitant viral-like illness 
(the “summer flu”) characterized by myalgias, arthralgias, 
headache, and fatigue. Fever may or may not be present. 
Even without treatment, the symptoms and signs 
of erythema migrans resolve in 3–4 weeks. Although the 
classic lesion of erythema migrans is not difficult to recog
-
nize, atypical forms can occur that may lead to misdiagnosis. 
Chemical reactions to tick and spider bites (these usually 
recede in 24–48 hours, whereas erythema migrans increases 
in size in this time period), drug eruptions, urticaria, and 
staphylococcal and streptococcal cellulitis have been mis
-
taken for erythema migrans. Southern tick–associated rash 
illness (STARI) has a similar appearance, but it occurs in 
geographically distinct areas of the United States.
Completely asymptomatic disease, without erythema

Completely asymptomatic disease, without erythema 
migrans or flu-like symptoms, can occur but is very 
uncommon in the United States.
2. Stage 2, early disseminated infection—
Up to 50–60% 
of patients with erythema migrans are bacteremic and 
within days to weeks of the original infection, secondary 
skin lesions develop in about 50% of patients. These lesions 
are similar in appearance to the primary lesion but are usu
-
ally smaller. Malaise, fatigue, fever, headache (sometimes 
severe), neck pain, and generalized achiness are common 
with the skin lesions. Most symptoms are transient, although 
fatigue may persist for months. After hematogenous spread, 
some patients experience cardiac (4–10% of patients) or 
neurologic (10–15% of patients) manifestations, including 
myopericarditis, with atrial or ventricular arrhythmias and 
heart block. Neurologic manifestations include both the 
central and peripheral nervous systems. The most common 
CNS manifestation is aseptic meningitis with mild head
-
ache and neck stiffness. The most common peripheral 
manifestation is a cranial nerve VII neuropathy, ie, facial 
palsy (usually unilateral but can be bilateral, see 
Figure 24–2). A sensory or motor radiculopathy and mono
-
neuritis multiplex occur less frequently. Conjunctivitis, 
keratitis and, rarely, panophthalmitis can also occur. Rarely, 
skin involvement can be manifested as a cutaneous hypopig
-
mented lesion called a borrelial lymphocytoma.
3. Stage 3, late persistent infection—
Stage 3 infection 
occurs months to years after the initial infection and again 
primarily manifests itself as musculoskeletal, neurologic, 
and skin disease. In early reports, musculoskeletal com
-
plaints developed in up to 60% of patients, but with early 
recognition and treatment of disease, this has decreased to 
less than 10%. The classic manifestation of late disease is a 
monarticular or oligoarticular arthritis most commonly 
affecting the knee or other large weight bearing joints. 
While these joints may be quite swollen, these patients 
generally report less pain compared to patients with bacte
-
rial septic arthritis. Even if untreated, the arthritis is self-
limited, resolving in a few weeks to months. Multiple 
recurrences are common but are usually less severe than 
the original disease. Joint fluid reflects an inflammatory 
arthritis with a mean white blood cell count of 25,000/mcL 
(0.025/L) with a predominance of neutrophils. Chronic 
arthritis develops in about 10% of patients. The pathogen
-
esis of chronic Lyme arthritis may be an immunologic 
phenomenon rather than persistence of infection.
Rarely, the nervous system (both central and peripheral) 
can be involved in late Lyme disease. In the United States, a 
subacute encephalopathy, characterized by memory loss, 
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mood changes, and sleep disturbance, is seen. In Europe, a 
more severe encephalomyelitis caused by 
B garinii
 is seen 
and presents with cognitive dysfunction, spastic parapare
-
sis, ataxia, and bladder dysfunction. Peripheral nervous 
system involvement includes intermittent paresthesias, 
often in a stocking glove distribution, or radicular pain.
The cutaneous manifestation of late infection, which 
can occur up to 10 years after infection, is acrodermatitis 
chronicum atrophicans. It has been described mainly in 
Europe after infection with 
B afzelii
, a genospecies that 
commonly causes disease in Europe but not the United 
States. There is usually bluish-red discoloration of a distal 
extremity with associated swelling. These lesions become 
atrophic and sclerotic with time and eventually resemble 
localized scleroderma. Cases of diffuse fasciitis with eosin
-
ophilia, an entity that resembles scleroderma, have been 
rarely associated with infection with 
B burgdorferi.
The diagnosis of Lyme disease is based on both clinical 
manifestations and laboratory findings. 
The US Surveil
-
lance Case Definition specifies a person with
 
exposure 
to a potential tick habitat (within the 30 days just prior 
to developing erythema migrans) with (1) erythema 
migrans diagnosed by a physician or (2) at least one late 
manifestation of the disease and (3) laboratory confir
-
mation as fulfilling the criteria for Lyme disease.
Nonspecific laboratory abnormalities can be seen, par
-
ticularly in early disease. The most common are an ele
-
vated sedimentation rate of more than 20 mm/h seen in 
50% of cases, and mildly abnormal liver biochemical tests 
are present in 30%. The abnormal liver biochemical tests 
are transient and return to normal within a few weeks of 
treatment. A mild anemia, leukocytosis (11,000–18,000/
mcL) (0.011–0.018/L), and microscopic hematuria have 
been reported in 10% or less of patients.
Laboratory confirmation requires serologic tests to 
detect specific antibodies to 
 in serum, prefer
-
ably by ELISA and not by indirect immunofluorescence 
assay (IFA), which is less sensitive and specific and can 
cause misdiagnosis. A two-test approach is recommended 
for the diagnosis of active Lyme disease, with all specimens 
positive or equivocal by ELISA then confirmed with a 
Western immunoblot assay that can detect both IgM and 
IgG antibodies. A positive immunoblot requires that anti
-
bodies are detected against two (for IgM) or five (for IgG) 
specific protein antigens from 
.
If a patient with suspected early Lyme disease has nega
-
tive serologic studies, acute and convalescent titers should be 
obtained since up to 50% of patients with early disease can 
be antibody negative in the first several weeks of illness. 
 
A fourfold rise in antibody titer would be diagnostic of 
recent infection. In patients with later stages of disease, 
almost all are antibody positive. False-positive reactions in 
the ELISA and IFA have been reported in juvenile rheuma
-
toid arthritis, rheumatoid arthritis, systemic lupus erythe
-
matosus, infectious mononucleosis, subacute infective 
endocarditis, syphilis, relapsing fever, leptospirosis, enterovi
-
ral and other viral illnesses, and patients with gingival 
disease (presumably because of cross-reactivity with oral 
treponemes). False-negative serologic reactions occur early 
in illness, and antibiotic therapy early in disease can abort 
subsequent seroconversion.
The diagnosis of late nervous system Lyme disease is 
often difficult since clinical manifestations, such as subtle 
memory impairment, may be difficult to document. Most 
patients have a history of previous erythema migrans or 
monarticular or polyarticular arthritis, and the vast major
-
ity have antibody present in serum. Patients with late dis
-
ease and peripheral neuropathy almost always have positive

-
-
ease and peripheral neuropathy almost always have positive 
serum antibody tests, usually have abnormal electrophysi
-
ology tests, and may have abnormal nerve biopsies show
-
ing perivascular collections of lymphocytes; however, the 
CSF is usually normal and does not demonstrate local 
antibody production.
Caution should be exercised in interpreting serologic 
tests because they are not subject to national standards, and 
inter-laboratory variation is a major problem. In addition, 
some laboratories perform tests that are entirely unreliable 
and should never be used to support the diagnosis of Lyme 
disease (eg, the Lyme urinary antigen test, immunofluores
-
cent staining for cell wall–deficient forms of 
, 
lymphocyte transformation tests, using PCR on inappro
-
priate specimens such as blood or urine). Finally, testing is 
often done in patients with nonspecific symptoms such as 
headache, arthralgia, myalgia, fatigue, and palpitations. 
Even in endemic areas, the pretest probability of having 
Lyme disease is low in these patients, and the probability of 
a false-positive test result is greater than that of a true-
positive result. For these reasons, the CDC has established 
guidelines for laboratory evaluation of patients with sus
-
pected Lyme disease:
1.
 
The diagnosis of early Lyme disease is clinical (ie, expo
-
sure in an endemic area, with physician-documented 
erythema migrans), and does 
not
 require laboratory 
confirmation. (Tests are often negative at this stage.)
2.
 
Late disease requires objective evidence of clinical 
manifestations (recurrent brief attacks of monarticular 
or oligoarticular arthritis of the large joints; lympho
-
cytic meningitis, cranial neuritis [facial palsy], periph
-
eral neuropathy or, rarely, encephalomyelitis—but 
not
 
headache, fatigue, paresthesias, or stiff neck alone; 
atrioventricular conduction defects with or without 
myocarditis) and laboratory evidence of disease (two-
stage testing with ELISA or IFA followed by Western 
blot, as described above).
3.
 
Patients with nonspecific symptoms without objective 
signs of Lyme disease should 
not
 have serologic testing 
done. It is in this setting that false-positive tests occur 
more commonly than true-positive tests.
4.
 
The role of serologic testing in nervous system Lyme 
disease is unclear, as sensitivity and specificity of CSF 
serologic tests have not been determined. However, it is 
rare for a patient to have positive serologic tests on CSF 
without positive tests on serum (see below).
5.
 
Other tests such as the T cell proliferative assay and 
urinary antigen detection have not yet been studied 
well enough to be routinely used.
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 CMDT 2019
 can be performed but are not 
routine and are usually reserved for clinical studies.
PCR is very specific for detecting the presence of 
Borrelia
 
DNA, but sensitivity is variable and depends on which body 
fluid is tested, the stage of the disease, and collection and test
-
ing technique. In general, PCR is more sensitive than culture, 
especially in chronic disease but is not available in many 
clinical laboratories. Testing should not be done on blood or 
urine but has been successfully performed on synovial fluid 
and CSF. A negative PCR result does not rule out disease.
 
»
Based on several observational studies, 
 infec
-
tion in pregnant women has 
not
 been associated with 
congenital syndromes, unlike other spirochetal illnesses 
such as syphilis.
Some patients and advocacy groups have claimed either 
a post–Lyme syndrome (in the presence of positive labora
-
tory tests and after appropriate treatment) or “chronic Lyme 
disease” in which tests may all be negative. Both entities 
include nonspecific symptoms such as fatigue, myalgias, 
and cognitive difficulties (see Prognosis below). Expert 
groups are in agreement that there are no data to support 
that ongoing infection is the cause of either syndrome.
 
»
There is no human vaccine currently available. Simple pre
-
ventive measures such as avoiding tick-infested areas, cover
-
ing exposed skin with long-sleeved shirts and wearing long 
trousers tucked into socks, wearing light-colored clothing, 
using repellents, and inspecting for ticks after exposure will 
greatly reduce the number of tick bites. Environmental con
-
trols directed at limiting ticks on residential property would 
be helpful, but trying to limit the deer, tick, or white-footed 
mouse populations over large areas is not feasible.
Prophylactic antibiotics following tick bites is recom
-
mended in certain high-risk situations if all of the following 
criteria are met: (1) a tick identified as an adult or nymphal 
 has been attached for at least 36 hours; (2) pro
-
phylaxis can be started within 72 hours of the time the tick 
was removed; (3) more than 20% of ticks in the area are 
known to be infected with 
B burgdorferi;
 and (4) there is no 
contraindication to the use of doxycycline (not pregnant, 
age greater than 8 years, not allergic). The medication of 
choice for prophylaxis is a single 200-mg dose of doxycy
-
cline. If doxycycline is contraindicated, no prophylaxis 
should be given and the patient should be closely monitored 
for early disease, since short course prophylactic therapy 
with other agents has not been studied, and if early disease 
does develop, appropriate therapy is very effective in pre
-
venting long-term sequelae. Individuals who have removed 
ticks (including those who have had prophylaxis) should be 
monitored carefully for 30 days for possible coinfections.
 
»
Coinfections
Lyme disease, babesiosis (see Chapter 35), and human 
granulocytic anaplasmosis (formerly human granulocytic 
ehrlichiosis) (see Chapter 32) are endemic in similar areas 
of the country and are transmitted by the same tick, 
 
I scapularis.
 Coinfection with two or even all three of these 
organisms can occur, causing a clinical picture that is not 
“classic” for any of these diseases. The presence of ery
-
thema migrans is highly suggestive of Lyme disease, 
whereas flu-like symptoms without rash are more sugges
-
tive of babesiosis or anaplasmosis. Coinfection should be 
considered and excluded in patients who have persistent 
high fevers 48 hours after starting appropriate therapy for 
Lyme disease; in patients with persistent symptoms despite 
resolution of rash; and in those with anemia, leukopenia, 
or thrombocytopenia.
 
»
Treatment
Present recommendations for therapy are outlined in 
Table 34–4. For erythema migrans, antibiotic therapy

»
Treatment
Table 34–4. For erythema migrans, antibiotic therapy 
shortens the duration of rash and prevents late sequelae. 
Table 34–4.
 
Treatment of Lyme disease.
Drug and Dosage
t
ick bit
e
No treatment in most circumstances 
(see text); observe
e
rythema migrans
1
Doxycycline, 100 mg orally twice daily 
for 10–14 days, or amoxicillin, 500 mg 
orally three times daily for 2–3 weeks, 
or cefuroxime axetil, 500 mg orally 
twice daily for 2–3 weeks
Facial palsy (without 
meningitis)
Doxycycline, amoxicillin, or cefuroxime 
axetil as above for 2–3 weeks
Other central nervous 
system disease
Ceftriaxone, 2 g intravenously once 
daily, or penicillin G, 18–24 million 
units daily intravenously in six 
divided doses, or cefotaxime, 2 g 
intravenously every 8 hours—all for 
2–4 weeks
Cardiac disease
Atrioventricular block 
and myopericarditis
2
An oral or parenteral (if more severe 
 
disease) regimen as described above 
can be used
a
r
thritis
Oral dosage
axetil as above for 28 days (see text)
Parenteral dosage
Ceftriaxone, cefotaxime, or penicillin G 
as above for 2–4 weeks
a
cr
odermatitis chroni
-
cum atrophicans
axetil as above for 3 weeks
“Chronic Lyme 
 
disease” or “post-
Lyme disease 
syndrome”
Symptomatic therapy; prolonged antibi
-
otics are 
not
 recommended
1
Patients who cannot tolerate tetracyclines or beta-lactams can be 
treated with azithromycin 500 mg orally daily for 10 days.
2
Symptomatic patients, those with second- or third-degree 
block and those with first-degree block with a PR interval 
≥300 milliseconds should be hospitalized for observation.
CMDT19_Ch34_p1493-p1509.indd   1508

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CMDT 2019
Doxycycline is most commonly used and has the advantage 
of being active against 
Anaplasma phagocytophilum
 
(formerly 
Ehrlichia
). It has proven effective in shorter 
courses of 10–14 days compared to other regimens. Amox
-
icillin is also effective and is recommended for pregnant or 
lactating women and for those who cannot tolerate doxy
-
cycline. Cefuroxime axetil is as effective as doxycycline, but 
because of its cost, it should be considered an alternative 
choice for those who cannot tolerate doxycycline or amoxi
-
cillin or for those in whom the medications are contraindi
-
cated. Erythromycin and azithromycin are less effective, 
associated with higher rates of relapse, and are not recom
-
mended as first-line therapy.
Isolated facial palsy (without meningitis or peripheral 
neuropathy) can be treated with doxycycline, amoxicillin, 
or cefuroxime axetil for 2–3 weeks. Although therapy does 
not affect the rate of resolution of the cranial neuropathy, it 
does prevent development of late manifestations of disease.
The need for a lumbar puncture in patients with sev
-
enth nerve palsy is controversial. Some clinicians perform 
lumbar puncture on all patients with facial palsy and others 
only if there are symptoms or signs of meningitis. If men
-
ingitis is present, therapy with a parenteral antibiotic is 
indicated. Ceftriaxone is most commonly used, but peni
-
cillin is equally efficacious. In European countries, doxycy
-
cline 400 mg/d orally for 14 days is frequently used and is 
comparable in efficacy to ceftriaxone.
Patients with atrioventricular block or myopericarditis 
(or both) can be treated with either oral or parenteral 
agents for 2–3 weeks. Hospitalization and observation is 
indicated for symptomatic patients, those with second- or 
third-degree block, and those with first-degree block with 
a PR interval of 300 milliseconds or more. Once stabilized, 
hospitalized patients can be transitioned to one of the oral 
regimens to complete therapy.
Therapy of arthritis is difficult because some patients 
do not respond to any therapy, and those who do respond 
may do so slowly. Oral agents (doxycycline, amoxicillin, or 
cefuroxime axetil) are as effective as intravenous regimens 
(ceftriaxone, cefotaxime, or penicillin). A reasonable 
approach to the patient with Lyme arthritis is to start with 
oral therapy for 28 days, and if this fails (persistent or 
recurrent joint swelling), to re-treat with an oral regimen 
for 28 days or switch to an intravenous regimen for 
2–4 weeks. If arthritis persists after re-treatment, symp
-
tomatic therapy with nonsteroidal anti-inflammatory 
drugs is recommended. For severe refractory pain, syno
-
vectomy may be required.
Based on the limited published data, therapy of Lyme 
disease in pregnancy should be the same as therapy in 
other patients with the exception that doxycycline should 
not be used.
 
»
Prognosis
Most patients respond to appropriate therapy with prompt 
resolution of symptoms within 4 weeks. True treatment fail
-
ures are thus uncommon, and in most cases re-treatment or 
prolonged treatment of Lyme disease is instituted because of 
misdiagnosis or misinterpretation of serologic results (both 
IgG and IgM antibodies can persist for prolonged periods 
despite adequate therapy) rather than inadequate therapy or 
response. Prolonged courses of antibiotic therapy for non
-
specific symptoms that persist after completion of appropri
-
ate assessment (and treatment, if necessary) for Lyme 
disease is not recommended.
The long-term outcome of adult patients with Lyme 
disease is generally favorable, but some patients have 
chronic complaints. Joint pain, memory impairment, and 
poor functional status secondary to pain are common sub
-
jective complaints in patients with Lyme disease, but physi
-
cal examination and neurocognitive testing fail to 
document the presence of these symptoms as objective

-
-
document the presence of these symptoms as objective 
sequelae. Similarly, in highly endemic areas, patients with a 
diagnosis of Lyme disease commonly complain of pain, 
fatigue, and an inability to perform certain physical activi
-
ties when followed for several years. However, these com
-
plaints occur just as commonly in age-matched controls 
without a history of Lyme disease.
Immunity is not complete after Lyme disease. Reinfec
-
tion, although uncommon, is predominantly seen in 
patients successfully treated for early disease (erythema 
migrans) in whom antibody titers do not develop. Clinical 
manifestations and serologic response is similar to an ini
-
tial infection.
 
»
Consultation with an infectious diseases specialist with 
experience in diagnosing and treating Lyme disease can be 
helpful in atypical or prolonged cases.
 
»
Admission for parenteral antibiotics is indicated for any 
patient with symptomatic CNS or cardiac disease as well as 
those with second- or third-degree atrioventricular block, 
or first-degree block with a PR interval of 300 milliseconds 
or more.
Berende A et al. Randomized trial of longer-term therapy for 
symptoms attributed to Lyme disease. N Engl J Med. 2016 
Mar 31;374(13):1209–20. [PMID: 27028911]
Steere AC et al. Lyme borreliosis. Nat Rev Dis Primers. 
2016 Dec 15;2:16090. Erratum in: Nat Rev Dis Primers. 2017 
Aug 03; 3:17062. [PMID: 27976670]
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 CMDT 2019
Protozoal & Helminthic 
35
 
º
PROTOZOAL INFECTIONS
AFRICAN TRYPANOSOMIASIS 
 
(
Sleeping Sickness
)
 
»
Exposure to tsetse flies; chancre at bite site 
uncommon.
 
»
Hemolymphatic disease:
 Irregular fever, head
-
ache, joint pain, rash, edema, lymphadenopathy.
 
»
Meningoencephalitic disease:
 Somnolence, 
severe headache, progressing to coma.
 
»
Trypanosomes in blood or lymph node aspirates; 
positive serologic tests.
 
»
Trypanosomes and increased white cells and pro
-
tein in cerebrospinal fluid.
 
»
African trypanosomiasis is caused by the hemoflagellates 
Trypanosoma brucei rhodesiense
 and 
Trypanosoma brucei 
gambiense
. The organisms are transmitted by bites of 
tsetse flies (genus 
Glossina
), which inhabit shaded areas 
along streams and rivers. Trypanosomes ingested in a 
blood meal develop over 18–35 days in the fly; when the 
fly feeds again on a mammalian host, the infective stage 
is injected. Human disease occurs in rural areas of sub-
Saharan Africa from south of the Sahara to about 
30 degrees south latitude. 
T b gambiense
 causes West 
African trypanosomiasis, and is transmitted in the moist 
sub-Saharan savannas and forests of west and central 
Africa. 
T b rhodesiense
 causes East African trypanoso
-
miasis, and is transmitted in the savannas of east and 
southeast Africa.
 infection is primarily a zoonosis of 
game animals and cattle; humans are infected sporadically. 
Humans are the principal mammalian host for 
, 
but domestic animals can be infected. The number of 
reported cases increased from the 1960s to the 1990s and 
has since decreased greatly, although cases are reported 
from over 20 countries. Total incidence has been estimated 
at less than 5000 cases per year, mostly due to 
, 
with the largest number in the Democratic Republic of the 
Congo. Infections are rare among travelers, including visi
-
tors to game parks.
 
»
1. West African trypanosomiasis—
Chancres at the site of 
the bite are uncommon. After an asymptomatic period that 
may last for months, 
hemolymphatic disease
 presents 
with fever, headache, myalgias, arthralgias, weight loss, and 
lymphadenopathy, with discrete, nontender, rubbery 
nodes, referred to as Winterbottom sign when in a poste
-
rior cervical distribution. Other common signs are mild 
splenomegaly, transient edema, and a pruritic erythema
-
tous rash. Febrile episodes may be broken by afebrile peri
-
ods of up to several weeks. The hemolymphatic stage 
progresses over months to 
meningoencephalitic disease
, 
with somnolence, irritability, personality changes, severe 
headache, and parkinsonian symptoms progressing to 
coma and death.
2. East African trypanosomiasis—
Chancres at the bite site 
are more commonly recognized with 
 
infection, with a painful lesion of 3–10 cm and regional 
lymphadenopathy that appears about 48 hours after the 
tsetse fly bite and lasts 2–4 weeks. East African disease 
follows a much more acute course, with the onset of symp
-
toms usually within a few days of the insect bite. The 
hemolymphatic stage includes intermittent fever and rash, 
but lymphadenopathy is less common than with West 
African disease. Myocarditis can cause tachycardia and 
death due to arrhythmias or heart failure. If untreated, 
East African trypanosomiasis progresses over weeks to 
months to meningoencephalitic disease, somnolence, 
coma, and death.
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CMDT 2019
Diagnosis can be difficult, and definitive diagnosis 
requires identification of trypanosomes. Microscopic 
examination of fluid expressed from a chancre or lymph 
node may show motile trypanosomes or, in fixed speci
-
mens, parasites stained with Giemsa. During the 
hemo
-
lymphatic stage
, detection of parasites in Giemsa-stained 
blood smears is common in East African disease but dif
-
ficult in West African disease. Serial specimens should be 
examined, since parasitemias vary greatly over time. 
Meningoencephalitic (or second stage) disease
 is defined 
by the World Health Organization (WHO) as cerebrospi
-
nal fluid (CSF) showing at least five mononuclear cells per 
microliter, elevated protein, or presence of trypanosomes. 
Concentration techniques can aid identification of para
-
sites in blood or CSF. Serologic tests are also available. The 
card agglutination test for trypanosomes (CATT) has 
excellent sensitivity and specificity for West African dis
-
ease and can be performed in the field, but the diagnosis 
should be confirmed by identification of the parasites. 
Field-applicable immunochromatographic lateral flow 
rapid diagnostic tests that cost less than CATT and are 
simpler to perform are available; combining tests improves 
sensitivity and specificity. Molecular diagnostic tests, 
including PCR and field-friendly loop-mediated isother
-
mal amplification (LAMP) are available, but these are not 
yet standardized or routinely available.
 
»
Treatment
Detection of trypanosomes is a prerequisite for treatment of 
African trypanosomiasis because of the significant toxicity of 
most available therapies. Treatment recommendations 
depend on the type of trypanosomiasis (Table 35–1), which is 
determined by geography, and stage of disease, which requires 
examination of CSF. Eflornithine, nifurtimox, suramin, and 
melarsoprol are available in the United States from the CDC 
Drug Service (www.cdc.gov/laboratory/drugservice).
A. West African Trypanosomiasis
1. Early stage infection—
Pentamidine (4 mg/kg intramus
-
cularly or intravenously every day or every other day for 
 
Table 35–1.
 
Treatment of African trypanosomiasis.
Treatment
Disease
Stage
First Line
Alternative
West African
Early
Pentamidine
Suramin
Eflornithine
 
CNS involvement
Eflornithine + 
nifurtimox
Melarsoprol
East African
Early
Suramin
CNS, central nervous system.
7 days) is used to treat infection that does not involve the 
central nervous system (CNS). The side effects of pentami
-
dine include immediate hypotension; tachycardia; 
gastrointestinal symptoms during administration; sterile 
abscesses; and pancreatic (hypoglycemia), liver, and kidney 
abnormalities. An alternate drug is eflornithine 
(100 mg/kg/day intravenously every 6 hours for 14 days).
2. Late stage infection—
The treatment of choice for CNS 
infection is a combination of intravenous eflornithine 
(400 mg/kg/day in two doses for 7 days) and oral nifurti
-
mox (15 mg/kg/day in three doses for 10 days), which has 
improved efficacy and less toxicity than older regimens. 
Eflornithine, though less toxic than older trypanocidal drugs, 
can cause gastrointestinal symptoms, bone marrow suppres
-
sion, seizures, and alopecia. The alternative agent is 
melarsoprol.
B. East African Trypanosomiasis
Pentamidine and eflornithine are not reliably effective, and 
early disease is treated with suramin. The dosing regimens 
of suramin vary (eg, 100–200 mg test dose, then 20 mg/kg 
[maximum 1 g] intravenously on days 1, 3, 7, 14, and 21 or 
weekly for five doses). Suramin toxicities include vomiting 
and, rarely, seizures and shock during infusions as well as 
subsequent fever, rash, headache, neuropathy, and kidney 
and bone marrow dysfunction.
Suramin does not enter the CNS, so East African try
-
panosomiasis involving the CNS is treated with melarsop
-

-
-
rol (three series of 3.6 mg/kg/day intravenously for 3 days, 
with 7-day breaks between the series or a 10-day intrave
-
nous course with 0.6 mg/kg on day 1, 1.2 mg/kg on day 2, 
and 1.8 mg/kg on days 3–10). Melarsoprol also acts against 
West African disease, but eflornithine plus nifurtimox is 
preferred due to its lower toxicity. Immediate side effects 
of melarsoprol include fever and gastrointestinal symp
-
toms. The most important side effect is a reactive enceph
-
alopathy that can progress to seizures, coma, and death. To 
help avoid this side effect, corticosteroids are coadminis
-
tered (dexamethasone 1 mg/kg/day intravenously for 
2–3 days or oral prednisolone 1 mg/kg/day for 5 days, and 
then 0.5 mg/kg/day until treatment completion). In addition, 
increasing resistance to melarsoprol is a serious concern.
 
»
Prevention & Control
Individual prevention in endemic areas should include long 
sleeves and pants, insect repellents, and mosquito nets. 
Control programs focusing on vector elimination and treat
-
ment of infected persons and animals have shown good 
success in many areas but suffer from limited resources.
Aksoy S et al. Human African trypanosomiasis control: achieve
-
ments and challenges. PLoS Negl Trop Dis. 2017 Apr 20; 
11(4):e0005454. [PMID: 28426685]
Büscher P et al. Human African trypanosomiasis. Lancet. 2017 
Nov 25;390(10110):2397–409. [PMID: 28673422]
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 CMDT 2019
AMERICAN TRYPANOSOMIASIS 
 
(
Chagas Disease
)
Acute stage
 
»
Inflammatory lesion at inoculation site.
 
»
Fever.
 
»
Hepatosplenomegaly; lymphadenopathy.
 
»
Myocarditis.
 
»
Parasites in blood is diagnostic.
Chronic stage
 
»
Heart failure, cardiac arrhythmias.
 
»
Thromboembolism.
 
»
Megaesophagus; megacolon.
 
»
Serologic tests are usually diagnostic.
 
»
Chagas disease is caused by 
, a proto
-
zoan parasite found only in the Americas; it infects wild 
animals and to a lesser extent humans from southern South 
America to the southern United States. An estimated 
8–10 million people are infected, mostly in rural areas, 
with the highest national prevalence in Bolivia, Argentina, 
Paraguay, Ecuador, El Salvador, and Guatemala. Control 
efforts in endemic countries have decreased disease inci
-
dence to about 40,000 new infections and 12,500 deaths 
per year. The disease is often acquired in childhood. In 
many countries in South America, Chagas disease is the 
most important cause of heart disease. In the United States, 
the vector is found, some animals are infected, and a few 
instances of local transmission have been reported.
T cruzi
 is transmitted by reduviid (triatomine) bugs 
infected by ingesting blood from animals or humans who 
have circulating trypanosomes. Multiplication occurs in 
the digestive tract of the bug and infective forms are elimi
-
nated in feces. Infection in humans occurs when the para
-
site penetrates the skin through the bite wound, mucous 
membranes, or the conjunctiva. Transmission can also 
occur by blood transfusion, organ or bone marrow trans
-
plantation, congenital transfer, or ingestion of food con
-
taminated with vector feces. From the bloodstream, 
T cruzi
 
invades many cell types but has a predilection for myocar
-
dium, smooth muscle, and CNS glial cells. Multiplication 
causes cellular destruction, inflammation, and fibrosis, 
with progressive disease over decades.
 
»
As many as 70% of infected persons remain asymptomatic. 
The 
acute stage
 is seen principally in children and lasts 
1–2 months. The earliest findings are at the site of 
inoculation either in the eye—Romaña sign (unilateral edema, 
conjunctivitis, and lymphadenopathy)—or in the skin—a 
chagoma (swelling with local lymphadenopathy). Subsequent 
findings include fever, malaise, headache, mild hepatospleno
-
megaly, and generalized lymphadenopathy. Acute myocarditis 
and meningoencephalitis are rare but can be fatal.
An asymptomatic 
latent period (indeterminate phase)
 
may last for life, but symptomatic disease develops in 
10–30% of infected individuals, commonly many years 
after infection.
Chronic Chagas disease
 generally manifests as abnor
-
malities in cardiac and smooth muscle. Cardiac disease 
includes arrhythmias, heart failure, and embolic disease. 
Smooth muscle abnormalities lead to megaesophagus and 
megacolon, with dysphagia, regurgitation, aspiration, con
-
stipation, and abdominal pain. These findings can be com
-
plicated by superinfections. In immunosuppressed persons, 
including AIDS patients and transplant recipients, latent 
Chagas disease may reactivate; findings have included 
brain abscesses and meningoencephalitis.
The diagnosis is made by detecting parasites in persons 
with suggestive findings who have resided in an endemic 
area. With 
acute infection
, evaluation of fresh blood or 
buffy coats may show motile trypanosomes, and fixed 
preparations may show Giemsa-stained parasites. Concen
-
tration methods increase diagnostic yields. Trypanosomes 
may be identified in lymph nodes, bone marrow, or peri
-
cardial or spinal fluid. PCR is highly sensitive, and can be 
used to detect parasites in organ transplant recipients or 
after accidental exposure. When initial tests are unreveal
-

-
-
ing, xenodiagnosis using laboratory vectors, laboratory 
culture, or animal inoculation may provide a diagnosis, but 
these methods are expensive and slow.
 is usually diagnosed serologi
-
cally. Many different serologic assays are available, but 
sensitivity and specificity are not ideal; confirmatory assays 
are advised after an initial positive test, as is standard for 
blood bank testing in South America. The diagnosis of 
chronic disease with PCR remains suboptimal.
 
»
Treatment
Treatment is inadequate because the two drugs used, ben
-
znidazole and nifurtimox, often cause severe side effects, 
must be used for long periods, and are ineffective against 
chronic infection. In acute and congenital infections, the 
drugs can reduce the duration and severity of infection, but 
cure is achieved in only about 70% of patients. During the 
chronic phase of infection, although parasitemia may dis
-
appear in up to 70% of patients, treatment does not clearly 
alter the progression of the disease. In a 2015 trial for 
Chagas cardiomyopathy, benznidazole significantly 
reduced parasite detection but not progression of cardiac 
disease. Nevertheless, there is general consensus that treat
-
ment should be considered in all 
T cruzi
–infected persons 
regardless of clinical status or time since infection. In par
-
ticular, treatment is recommended for acute, congenital, 
and reactivated infections and for children and young 
CMDT19_Ch35_p1510-p1549.indd   1512

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CMDT 2019
adults with chronic disease. Both benznidazole and nifur
-
timox are available in the United States from the CDC 
Benznidazole is generally preferred due to better effi
-
cacy and safety profiles. It is given orally at a dosage of 
 
5 mg/kg/day in two divided doses for 60 days. Its side effects 
include granulocytopenia, rash, and peripheral neuropathy. 
Nifurtimox is given orally in daily doses of 8–10 mg/kg in 
four divided doses after meals for 90–120 days. Side effects 
include gastrointestinal (anorexia, vomiting) and neuro
-
logic (headaches, ataxia, insomnia, seizures) symptoms, 
which appear to be reversible and to lessen with dosage 
reduction. For both drugs, some recommendations suggest 
higher dosing for acute infections. Patients with chronic 
Chagas disease may also benefit from antiarrhythmic ther
-
apy, standard therapy for heart failure, and conservative and 
surgical management of megaesophagus and megacolon.
 
»
In South America, a major eradication program based on 
improved housing, use of residual pyrethroid insecticides 
and pyrethroid-impregnated bed curtains, and screening of 
blood donors has achieved striking reductions in new 
infections. In endemic areas and ideally in donors from 
endemic areas, blood should not be used for transfusion 
unless at least two serologic tests are negative.
Bern C. Chagas’ disease. N Engl J Med. 2015 Jul 30;373(5): 
456–66. [PMID: 26222561]
Morillo CA et al; BENEFIT Investigators. Randomized trial of 
benznidazole for chronic Chagas’ cardiomyopathy. N Engl J 
Med. 2015 Oct;373(14):1295–306. [PMID: 26323937]
Pérez-Molina JA et al. Chagas disease. Lancet. 2018 Jan 6; 
391(10115):82–94. [PMID: 28673423]
LEISHMANIASIS
 
»
Sand fly bite in an endemic area.
 
»
Visceral leishmaniasis:
 irregular fever, progressive 
hepatosplenomegaly, pancytopenia, wasting.
 
»
Cutaneous leishmaniasis:
 chronic, painless, moist 
ulcers or dry nodules.
 
»
Mucocutaneous leishmaniasis:
 destructive naso
-
pharyngeal lesions.
 
»
Amastigotes in macrophages in aspirates, touch 
preparations, or biopsies.
 
»
Positive culture, serologic tests, PCR, or skin test.
 
»
Leishmaniasis is a zoonosis transmitted by bites of sand 
flies of the genus 
Lutzomyia
 in the Americas and 
Phlebotomus
 elsewhere. When sand flies feed on an infected 
host, the parasitized cells are ingested with the blood meal. 
Leishmaniasis is caused by about 20 species of 
Leishmania;
 
taxonomy is complex. Clinical syndromes are generally 
dictated by the infecting species, but some species can 
cause more than one syndrome.
An estimated 350 million persons are at risk for leish
-
maniasis. The estimated annual incidence of disease is 
1–1.5 million new cases of cutaneous and 400,000 cases of 
visceral disease, leading to an estimated 40,000 deaths.
Visceral leishmaniasis
 (kala azar) is caused mainly by 
Leishmania donovani
 in the Indian subcontinent and East 
Africa; 
Leishmania infantum
 in the Mediterranean, Middle 
East, China, parts of Asia, and Horn of Africa; and 
Leishmania chagasi
 in South and Central America. Other 
species may occasionally cause visceral disease. Over 90% 
of cases occur in five countries: India, Bangladesh, Nepal, 
Sudan, and Brazil. The incubation period is usually 
4–6 months (range: 10 days to 24 months). Without treat
-
ment, the fatality rate reaches 90%. Early diagnosis and 
treatment reduces mortality to 2–5%.
Old World cutaneous leishmaniasis
 is caused mainly by 
Leishmania tropica, Leishmania major
, and 
Leishmania aethi
-
opica
 in the Mediterranean, Middle East, Africa, Central 
Asia, and Indian subcontinent. 
New World cutaneous leish
-
maniasis
Leishmania mexicana, Leishmania 
amazonensis
, and the species listed below for mucocutaneous 
disease in Central and South America. 
Mucocutaneous

-
maniasis
Mucocutaneous 
leishmaniasis
 (espundia) occurs in lowland forest areas of 
the Americas and is caused by 
Leishmania braziliensis, Leish
-
mania panamensis
, and 
Leishmania peruviana
.
 
»
1. Visceral leishmaniasis (kala azar)—
Most infections are 
subclinical, but a small number progress to full-blown 
disease. A local nonulcerating nodule at the site of the sand 
fly bite may precede systemic manifestations but usually is 
inapparent. The onset of illness may be acute, within 
2 weeks of infection, or insidious. Symptoms and signs 
include fever, chills, sweats, weakness, anorexia, weight 
loss, cough, and diarrhea. The spleen progressively 
becomes greatly enlarged, firm, and nontender. The liver is 
somewhat enlarged, and generalized lymphadenopathy 
may occur. Hyperpigmentation of skin can be seen, leading 
to the name kala azar (“black fever”). Other signs include 
skin lesions, petechiae, gingival bleeding, jaundice, edema, 
and ascites. As the disease progresses, severe wasting and 
malnutrition are seen; death eventually occurs, often due to 
secondary infections, within months to a few years. 
Post–
kala azar dermal leishmaniasis
 may appear after apparent 
cure in the Indian subcontinent and Sudan. It may simulate 
leprosy, with hypopigmented macules or nodules develop
-
ing on preexisting lesions. 
Viscerotropic leishmaniasis
 
has been reported in small numbers of American military 
personnel in the Middle East, with mild systemic febrile 
illnesses after 
L tropica
2. Old World and New World cutaneous leishmaniasis—
Cutaneous swellings appears 1 week to several months 
after sand fly bites and can be single or multiple. 
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Characteristics of lesions and courses of disease vary 
depending on the leishmanial species and host immune 
response. Lesions begin as small papules and develop into 
nonulcerated dry plaques or large encrusted ulcers with 
well-demarcated raised and indurated margins 
(Figure 35–1). Satellite lesions may be present. The lesions 
are painless unless secondarily infected. Local lymph nodes 
may be enlarged. Systemic symptoms are uncommon, but 
fever, constitutional symptoms, and regional lymphadenop
-
athy may be seen. For most species, healing occurs sponta
-
neously in months to a few years, but scarring is common.
Leishmaniasis recidivans
 is a relapsing form of 
 
L tropica
 infection associated with hypersensitivity, in 
which the primary lesion heals centrally, but spreads later
-
ally, with extensive scarring. 
Diffuse cutaneous leishmani
-
asis
 involves spread from a primary lesion, with local 
dissemination of nodules and a protracted course. 
Dissemi
-
nated cutaneous leishmaniasis
 involves multiple nodular 
or ulcerated lesions, often with mucosal involvement.
3. Mucocutaneous leishmaniasis (espundia)—
In Latin 
America, mucosal lesions develop in a small percentage of 
persons infected with 
L braziliensis
 and some other species, 
usually months to years after resolution of a cutaneous 
lesion. Nasal congestion is followed by ulceration of the 
nasal mucosa and septum, progressing to involvement of 
the mouth, lips, palate, pharynx, and larynx. Extensive 
destruction can occur, and secondary bacterial infection is 
common.
4. Infections in patients with AIDS—
Leishmaniasis is an 
opportunistic infection in persons with AIDS. Visceral 
leishmaniasis can present late in the course of HIV infec
-
tion, with fever, hepatosplenomegaly, and pancytopenia. 
The gastrointestinal tract, respiratory tract, and skin may 
also be involved.
Identifying amastigotes within macrophages in tissue sam
-
ples provides a definitive diagnosis. In 
visceral 
, fine-needle aspiration of the spleen for culture 
and tissue evaluation is generally safe, and yields a diagnosis 
in over 95% of cases. Bone marrow aspiration is less sensitive 
but safer and diagnostic in most cases, and Giemsa-stained 
buffy coat of peripheral blood may occasionally show organ
-
isms. Cultures with media available from the CDC will grow 
promastigotes within a few days to weeks. PCR can also 
identify the infection. Serologic tests may facilitate diagnosis, 
but none are sufficiently sensitive or specific to be used alone. 
Numerous antibody-based rapid diagnostic tests are avail
-
able; these have shown good specificity but limitations in 
sensitivity outside of India. For 
cutaneous lesions
, biopsies 
should be taken from the raised border of a skin lesion, with 
samples for histopathology, touch preparation, and culture. 
The histopathology shows inflammation with mononuclear 
cells. Macrophages filled with amastigotes may be present, 
especially early in infection. An intradermal leishmanin 
(Montenegro) skin test is positive in most individuals with 
cutaneous disease but negative in those with progressive vis
-
ceral or diffuse cutaneous disease; this test is not approved in 
the United States. In 
mucocutaneous leishmaniasis
, diagno
-
sis is established by detecting amastigotes in scrapings, biopsy 
preparations, or aspirated tissue fluid, but organisms may be 
rare. Cultures from these samples may grow organisms. Sero
-
logic studies are often negative, but the leishmanin skin test is 
usually positive.
 
»
Treatment
A. Visceral Leishmaniasis
The treatment of choice for visceral leishmaniasis is liposo
-
mal amphotericin B (approved by the FDA), which is gener
-
ally effective and well tolerated but expensive. Standard 
dosing is 3 mg/kg/day intravenously on days 1–5, 14, 
and 21. Simpler regimens that have shown good efficacy in

-
and 21. Simpler regimens that have shown good efficacy in 
India include four doses of 5 mg/kg over 4–10 days and a 
single dose of 15 mg/kg, but efficacy appears to be lower in 
Africa. Conventional amphotericin B deoxycholate, which 
is much less expensive, is also highly effective but with more 
toxicity. It is administered as a slow intravenous infusion of 
1 mg/kg/day for 15–20 days or 0.5–1 mg/kg every second 
day for up to 8 weeks. A single infusion of an amphotericin 
B lipid emulsion, which is more affordable than liposomal 
preparations, showed excellent efficacy, albeit lower than 
that of the liposomal formulation. Infusion-related side 
effects with conventional or liposomal amphotericin B 
include gastrointestinal symptoms, fever, chills, dyspnea, 
hypotension, and hepatic and renal toxicity.
Pentavalent antimonials remain the most commonly 
used drugs to treat leishmaniasis in most areas. Response 
rates are good outside India, but in India, resistance is a 
major problem. Two preparations are available, sodium 
stibogluconate in the United States and many other areas 
and meglumine antimonate in Latin America and franco
-
phone countries; the compounds appear to have compara
-
ble activities. In the United States, sodium stibogluconate 
can be obtained from the CDC Drug Service (www.cdc
 
.gov/laboratory/drugservice).
Treatment with either antimonial is given once daily at 
a dose of 20 mg/kg/day intravenously (preferred) or 
 
▲
Figure 35–1.
 
Skin ulcer due to cutaneous leishmani
-
asis. 
(From D. S. Martin, Public Health Image Library, CDC.)
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intramuscularly for 20 days for cutaneous leishmaniasis 
and 28 days for visceral or mucocutaneous disease. Toxicity 
increases over time, with development of gastrointestinal 
symptoms, fever, headache, myalgias, arthralgias, pancre
-
atitis, and rash. Intramuscular injections can cause sterile 
abscesses. Monitoring should include serial ECGs, and 
changes are indications for discontinuation to avoid pro
-
gression to serious arrhythmias.
Miltefosine is the first oral drug for the treatment of 
leishmaniasis, and it is registered in India for this indica
-
tion. It has demonstrated excellent results in India, but 
after over a decade of use, efficacy is decreasing due to drug 
resistance. It can be administered at a daily oral dose of 
2.5 mg/kg in two divided doses for 28 days. A 28-day 
course of miltefosine (2.5 mg/kg/day) is also effective for 
the treatment of New World cutaneous leishmaniasis. 
Vomiting, diarrhea, and elevations in transaminases and 
kidney function studies are common, but generally short-
lived, side effects.
The aminoglycoside paromomycin (11 mg/kg/day 
intramuscularly for 21 days) was shown to be similarly 
efficacious to amphotericin B for the treatment of visceral 
disease in India, where it is approved for this indication. It 
is much less expensive than liposomal amphotericin B or 
miltefosine. Paromomycin has shown relatively poor effi
-
cacy in Africa. The drug is well tolerated; side effects 
include ototoxicity and reversible elevations in liver 
enzymes.
The use of drug combinations to improve treatment 
efficacy, shorten treatment courses, and reduce the selec
-
tion of resistant parasites has been actively studied. In 
India, compared to a standard 30-day (treatment on alter
-
nate days) course of amphotericin, noninferior efficacy and 
decreased adverse events were seen with a single dose of 
liposomal amphotericin plus a 7-day course of miltefosine, 
a single dose of liposomal amphotericin plus a 10-day 
course of paromomycin, or a 10-day course of miltefosine 
plus paromomycin. In East Africa, compared to a standard 
30-day course of sodium stibogluconate, similar efficacy 
was seen with a 17-day course of sodium stibogluconate 
plus paromomycin.
B. Cutaneous Leishmaniasis
In the Old World, cutaneous leishmaniasis is generally self-
healing over some months and does not metastasize to the 
mucosa, so it may be justified to withhold treatment in 
regions without mucocutaneous disease if lesions are small 
and cosmetically unimportant. Lesions on the face or 
hands are generally treated. New World leishmaniasis has a 
greater risk of progression to mucocutaneous disease, so 
treatment is more often warranted. Standard therapy is 
with pentavalent antimonials for 20 days, as described 
above. Other treatments include those discussed above for 
visceral disease, azole antifungals, and allopurinol. In stud
-
ies in South America, a 28-day course of miltefosine was 
superior to a 20-day course of meglumine antimoniate, and 
oral fluconazole also showed good efficacy. Topical therapy 
has included intralesional antimony, intralesional pentami
-
dine, paromomycin ointment, cryotherapy, local heat, and 
surgical removal. Diffuse cutaneous leishmaniasis and 
related chronic skin processes generally respond poorly to 
therapy.
C. Mucocutaneous Leishmaniasis
Cutaneous infections from regions where parasites include 
those that cause mucocutaneous disease (eg, 
 
in parts of Latin America) should all be treated to help 
prevent disease progression. Treatment of mucocutaneous 
disease with antimonials is disappointing, with responses 
in only about 60% in Brazil. Other therapies listed above 
for visceral leishmaniasis may also be used, although they 
have not been well studied for this indication.
 
»
Personal protection measures for avoidance of sand fly

»
Personal protection measures for avoidance of sand fly 
bites include use of insect repellants, fine-mesh insect net
-
ting, long sleeves and pants, and avoidance of warm shaded 
areas where flies are common. Disease control measures 
include destruction of animal reservoir hosts, mass treat
-
ment of humans in disease-prevalent areas, residual insec
-
ticide spraying in dwellings, limiting contact with dogs and 
other domesticated animals, and use of permethrin-
impregnated collars for dogs.
Aronson N et al. Diagnosis and treatment of leishmaniasis: clini
-
cal practice guidelines by the Infectious Diseases Society of 
America (IDSA) and the American Society of Tropical Medi
-
cine and Hygiene (ASTMH). Clin Infect Dis. 2016 Dec 15; 
63(12):1539–57. [PMID: 27941143]
Sundar S et al. Recent developments and future prospects in the 
treatment of visceral leishmaniasis. Ther Adv Infect Dis. 
2016 Jun;3(3–4):98–109. [PMID: 27536354]
Torres-Guerrero E et al. Leishmaniasis: a review. F1000Res. 2017 
May 26;6:750. [PMID: 28649370]
MALARIA
 
»
Exposure to anopheline mosquitoes in a malaria-
 
»
Intermittent attacks of chills, fever, and sweating.
 
»
Headache, myalgia, vomiting, splenomegaly; ane
-
mia, thrombocytopenia.
 
»
Intraerythrocytic parasites identified in thick or 
thin blood smears or positive rapid diagnostic 
tests.
 
»
Falciparum malaria complications:
 cerebral 
malaria, severe anemia, hypotension, pulmonary 
edema, acute kidney injury, hypoglycemia, acido
-
sis, and hemolysis.
 
»
Malaria is the most important parasitic disease of humans, 
causing hundreds of millions of illnesses and hundreds of 
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thousands of deaths each year. The disease is endemic in 
most of the tropics, including much of South and Central 
America, Africa, the Middle East, the Indian subcontinent, 
Southeast Asia, and Oceania. Transmission, morbidity, and 
mortality are greatest in Africa, where most deaths from 
malaria are in young children. Malaria is also common in 
travelers from nonendemic areas to the tropics. Although 
the disease remains a major problem, impressive advances 
have been made in many regions. A 2016 study estimated a 
57% decrease in the malaria death rate and 37% decrease in 
the annual number of malaria deaths in the past 15 years. 
However, after marked gains, morbidity and mortality 
appear to have stabilized, with WHO estimates essentially 
unchanged between 2015 and 2016 (216 million cases and 
445,000 deaths).
Four species of the genus 
Plasmodium
 classically cause 
human malaria. 
Plasmodium falciparum
 is responsible for 
nearly all severe disease. It is endemic in most malarious 
areas and is by far the predominant species in Africa. 
Plasmodium vivax
 is about as common as 
P falciparum
, 
except in Africa. 
P vivax
 uncommonly causes severe dis
-
ease, although this outcome may be more common than 
previously appreciated. 
Plasmodium ovale
 and 
Plasmodium 
malariae
 are much less common causes of disease, and 
generally do not cause severe illness. 
Plasmodium knowlesi
, 
a parasite of macaque monkeys, is now recognized to cause 
occasional illnesses, including some severe disease, in 
humans in Southeast Asia.
Malaria is transmitted by the bite of infected female 
anopheline mosquitoes. During feeding, mosquitoes inject 
sporozoites, which circulate to the liver, and rapidly infect 
hepatocytes, causing asymptomatic liver infection. 
Merozoites are subsequently released from the liver, and 
they rapidly infect erythrocytes to begin the asexual erythro
-
cytic stage of infection that is responsible for human disease. 
Multiple rounds of erythrocytic development, with produc
-
tion of merozoites that invade additional erythrocytes, lead 
to large numbers of circulating parasites and clinical illness. 
Some erythrocytic parasites also develop into sexual game
-
tocytes, which are infectious to mosquitoes, allowing com
-
pletion of the life cycle and infection of others.
Malaria may uncommonly be transmitted from mother 
to infant (congenital malaria), by blood transfusion, and in 
nonendemic areas by mosquitoes infected after biting 
infected immigrants or travelers. In 
P vivax
 and 
P ovale
, 
parasites also form dormant liver hypnozoites, which are 
not killed by most drugs, allowing subsequent relapses of 
illness after initial elimination of erythrocytic infections. 
For all plasmodial species, parasites may recrudesce fol
-
lowing initial clinical improvement after suboptimal 
therapy.
In highly endemic regions, where people are infected 
repeatedly, antimalarial immunity prevents severe disease in 
most older children and adults. However, young children, 
who are relatively nonimmune, are at high risk for severe 
disease from 
 infection, and this population is 
responsible for most deaths from malaria. Pregnant women 
are also at increased risk for severe falciparum malaria. In 
areas with lower endemicity, individuals of all ages com
-
monly present with uncomplicated or severe malaria. 
Travelers, who are generally nonimmune, are at high risk for 
severe disease from falciparum malaria at any age.
 
»
An acute attack of malaria typically begins with a pro
-
drome of headache and fatigue, followed by fever. A classic 
malarial paroxysm includes chills, high fever, and then 
sweats. Patients may appear to be remarkably well between 
febrile episodes. Fevers are usually irregular, especially 
early in the illness, but without therapy may become regu
-
lar, with 48-hour (
P vivax
 and 
P ovale
) or 72-hour 
(
P malariae

-
P vivax
 and 
P ovale
(
P malariae
) cycles, especially with non-falciparum dis
-
ease. Headache, malaise, myalgias, arthralgias, cough, chest 
pain, abdominal pain, anorexia, nausea, vomiting, and 
diarrhea are common. Seizures may represent simple 
febrile convulsions or evidence of severe neurologic dis
-
ease. Physical findings may be absent or include signs of 
anemia, jaundice, splenomegaly, and mild hepatomegaly. 
Rash and lymphadenopathy are not typical in malaria, and 
thus suggestive of another cause of fever.
In the developed world, it is imperative that all persons 
with suggestive symptoms, in particular fever, who have 
traveled in an endemic area be evaluated for malaria. The 
risk for falciparum malaria is greatest within 2 months of 
return from travel; other species may cause disease many 
months—and occasionally more than a year—after return 
from an endemic area.
Severe malaria
 is characterized by signs of severe ill
-
ness, organ dysfunction, or a high parasite load (peripheral 
parasitemia greater than 5% or greater than 200,000 para
-
sites/mcL). It is principally a result of 
 infec
-
tion because this species uniquely infects erythrocytes of 
all ages and mediates the sequestration of infected erythro
-
cytes in small blood vessels, thereby evading clearance of 
infected erythrocytes by the spleen.
Severe falciparum malaria can include dysfunction of 
any organ system, including neurologic abnormalities pro
-
gressing to alterations in consciousness, repeated seizures, 
and coma (cerebral malaria); severe anemia; hypotension 
and shock; noncardiogenic pulmonary edema and the 
acute respiratory distress syndrome; acute kidney injury 
due to acute tubular necrosis or, less commonly, severe 
hemolysis; hypoglycemia; acidosis; hemolysis with jaun
-
dice; hepatic dysfunction; retinal hemorrhages and other 
fundoscopic abnormalities; bleeding abnormalities, includ
-
ing disseminated intravascular coagulation; and secondary 
bacterial infections, including pneumonia and 
 
bacteremia. In the developing world, severe malaria and 
deaths from the disease are mostly in young children, in 
particular from cerebral malaria and severe anemia. Cere
-
bral malaria is a consequence of a single severe infection 
while severe anemia follows multiple malarial infections, 
intestinal helminths, and nutritional deficiencies. In a large 
trial of African children, acidosis, impaired consciousness, 
convulsions, renal impairment, and underlying chronic ill
-
ness were associated with poor outcome.
Uncommon disorders resulting from immunologic 
responses to chronic infection are massive splenomegaly 
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and, with 
P malariae
 infection, immune complex glomeru
-
lopathy with nephrotic syndrome. HIV-infected individu
-
als are at increased risk for malaria and for severe disease, 
in particular with advanced immunodeficiency.
Giemsa-stained blood smears remain the mainstay of diag
-
nosis (Figures 35–2, 35–3, 35–4, and 35–5), although other 
routine stains (eg, Wright stain) will also demonstrate para
-
sites. Thick smears provide efficient evaluation of large vol
-
umes of blood, but thin smears are simpler for inexperienced 
personnel and better for discrimination of parasite species. 
Single smears are usually positive in infected individuals, 
although parasitemias may be very low in nonimmune indi
-
viduals. If illness is suspected, repeating smears at 8- to 
24-hour intervals is appropriate. The severity of malaria cor
-
relates only loosely with the quantity of infecting parasites, 
but high parasitemias (especially greater than 10–20% of 
erythrocytes infected or greater than 200,000–500,000 
parasites/mcL) or the presence of malarial pigment (a break
-
down product of hemoglobin) in more than 5% of neutro
-
phils is associated with a particularly poor prognosis.
A second means of diagnosis is rapid diagnostic tests to 
identify circulating plasmodial antigens with a simple “dip
-
stick” format. These tests are not well standardized but are 
widely available. At best, they offer sensitivity and specific
-
ity near that of high-quality blood smear analysis and are 
simpler to perform. However, 
 lacking the 
most common rapid diagnostic test antigen, histidine-rich 
protein 2 (HRP2), has been identified in some areas, lead
-
ing to concern that HRP2-based tests may miss some cases 
of falciparum malaria.
Serologic tests indicate history of disease but are not 
useful for diagnosis of acute infection. PCR and related 
molecular tests (eg, LAMP) are highly sensitive but not 
available for routine diagnosis. In immune populations, 
highly sensitive tests, such as PCR, have limited value 
because subclinical infections, which are not routinely 
treated, are common.
 
▲
Figure 35–2.
 
Thin film Giemsa-stained micrograph 
with 
 ring forms. 
(From Steven 
Glenn, Laboratory & Consultation Division, Public Health 
 
▲
Figure 35–4.
 
with 
 schizont. 
(From Steven Glenn, 
Laboratory & Consultation Division, Public Health Image 
 
▲
Figure 35–3.
 
with 
Plasmodium malariae
 trophozoite. 
 
▲
Figure 35–5.
 
with 
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Other diagnostic findings with uncomplicated malaria 
include thrombocytopenia, anemia, leukocytosis or leuko
-
penia, liver function abnormalities, and hepatospleno
-
megaly. Severe malaria can present with the laboratory 
abnormalities expected for the advanced organ dysfunc
-
tion discussed above.
 
»
Treatment
Malaria is the most common cause of fever in much of the 
tropics and in travelers seeking medical attention after return 
from endemic areas. Fevers are often treated presumptively 
in endemic areas, but ideally, treatment should follow defini
-
tive diagnosis, especially in non-immune individuals.
Symptomatic malaria is caused only by the erythrocytic 
stage of infection. Available antimalarial drugs (Table 35–2) 
act against this stage, except for primaquine, which acts 
principally against hepatic parasites.
A. Non-Falciparum Malaria
The first-line drug for non-falciparum malaria from most 
areas remains chloroquine. Due to increasing resistance of 
P vivax
 to chloroquine, alternative therapies are recom
-
mended when resistance is suspected, particularly for 
infections acquired in Indonesia, Oceania, and South 
America. These infections can be treated with artemisinin-
based combination therapies (ACTs) or other first-line 
regimens for 
 infections as discussed below. 
For 
P vivax
 or 
P ovale
, eradication of erythrocytic parasites 
with chloroquine should be accompanied by treatment 
with primaquine (after evaluating for glucose-6-phosphate 
dehydrogenase [G6PD] deficiency; see below) to eradicate 
dormant liver stages (hypnozoites), which may lead to 
relapses with recurrent erythrocytic infection and malaria 
symptoms after weeks to months if left untreated. 
Tafenoquine, which is related to primaquine, appears to 
offer similar efficacy with simpler dosing, but it also engen
-
ders potential toxicity in those with G6PD deficiency, and 
it remains under study. 
P malariae
 infections need only be 
treated with chloroquine.
B. Uncomplicated Falciparum Malaria
 is resistant to chloroquine and sulfadoxine-
pyrimethamine in most areas, with the exceptions of Central 
America west of the Panama Canal and Hispaniola. Falci
-
parum malaria from other areas should not be treated with 
these older drugs, and decisions regarding chemoprophy
-
laxis should follow the same geographic considerations.
ACTs, all including a short-acting artemisinin and 
longer-acting partner drug, are first-line therapies in nearly 
all endemic countries. WHO recommends six ACTs to 
treat falciparum malaria (Table 35–3), but the efficacy of 
these regimens varies. Other combination therapies are 
under development. Quinine generally remains effective 
for falciparum malaria, but it must be taken for 7 days and 
Table 35–2.
 
Major antimalarial drugs.
Drug
Class
Use
Chloroquine
4-Aminoquinoline
Treatment and chemoprophylaxis of infection with sensitive parasites
Amodiaquine
1
, optimally in fixed combination with 
artesunate
Piperaquine
1
 in fixed combination with dihydroartemisinin
Quinine
Quinoline methanol
Oral and intravenous
1
 (for severe infections) treatment of 
Quinidine
Intravenous therapy of severe infections with 
Mefloquine
Chemoprophylaxis and treatment of infections with 
Primaquine
8-Aminoquinoline
Radical cure and terminal prophylaxis of infections with 
 and 
; alternative for malaria chemoprophylaxis
Sulfadoxine-pyrimethamine 
(Fansidar)
Folate antagonist 
, optimally in combination with artesunate; intermit
-
tent preventive therapy
Atovaquone-proguanil 
(Malarone)
Quinone-folate antagonist 
Treatment and chemoprophylaxis of 
 infection

-
 infection
Treatment (with quinine) of infections with 
; chemoprophylaxis
Halofantrine
1
Phenanthrene methanol
Treatment of infections with some chloroquine-resistant 
Lumefantrine
Amyl alcohol
 malaria in fixed combination with artemether 
(Coartem)
Pyronaridine
Benzonaphthyridine
 malaria in fixed combination artesunate
Artemisinins (Artesunate, 
artemether, 
dihydroartemisinin)
Sesquiterpene lactone 
endoperoxides
 in oral combination regimens for uncomplicated 
disease and parenterally for severe malaria
1
Not available in the United States.
Modified, with permission, from Katzung BG. 
Basic & Clinical Pharmacology
. 11th edition. McGraw-Hill, 2009.
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is poorly tolerated, and should best be reserved for the 
treatment of severe malaria and for treatment after another 
regimen has failed (Table 35–4).
In developed countries, malaria is an uncommon but 
potentially life-threatening infection of travelers and immi
-
grants, many of whom are nonimmune, so they are at risk 
for rapid progression to severe disease. Nonimmune indi
-
viduals with falciparum malaria should generally be admit
-
ted to the hospital due to risks of rapid progression of 
disease. A number of options are available for the treat
-
ment of uncomplicated falciparum malaria in the United 
States (Table 35–4).
C. Severe Malaria
Severe malaria is a medical emergency. Parenteral treat
-
ment is indicated for severe malaria, as defined above, and 
with inability to take oral drugs. With appropriate prompt 
therapy and supportive care, rapid recoveries may be seen 
even in very ill individuals.
The standard of care for severe malaria is intravenous 
artesunate, which has demonstrated superior efficacy and 
better tolerability than quinine. In the United States, intra
-
venous artesunate is available on an investigational basis 
through the CDC (for enrollment call 770-488-7788); if 
approved, the drug is provided emergently from CDC 
Quarantine Stations. The drug is administered in four 
doses of 2.4 mg/kg over 3 days, every 12 hours on day 1, 
and then daily. If artesunate cannot be obtained promptly, 
severe malaria should be treated with intravenous quinine 
(available in most countries but not the United States) or 
quinidine (available in the United States). In endemic 
regions, if parenteral therapy is not available, intrarectal 
administration of artemether or artesunate is also effective. 
Patients receiving intravenous quinine or quinidine should 
receive continuous cardiac monitoring; if QTc prolonga
-
tion exceeds 25% of baseline, the infusion rate should be 
reduced. Blood glucose should be monitored every 
4–6 hours, and 5–10% dextrose may be coadministered to 
decrease the likelihood of hypoglycemia.
Appropriate care of severe malaria includes mainte
-
nance of fluids and electrolytes; respiratory and hemody
-
namic support; and consideration of blood transfusions, 
anticonvulsants, antibiotics for bacterial infections, and 
hemofiltration or hemodialysis. With high parasitemia 
(greater than 5–10%), exchange transfusion has been used, 
but beneficial effects have not clearly been demonstrated 
and it is generally no longer recommended.
D. Antimalarial Drugs
1. Chloroquine—
Chloroquine remains the drug of choice 
for the treatment of sensitive 
malaria parasites (Table 35–4). Chloroquine is active against 
erythrocytic parasites of all human malaria species. It does not 
eradicate hepatic stages, so it must be used with primaquine to 
eradicate 
P vivax
 and 
P ovale
 infections. Chloroquine-
resistant 
 is widespread in nearly all areas of the 
world with falciparum malaria, with the exceptions of Central 
America west of the Panama Canal and Hispaniola. Chloro
-
quine-resistant 
P vivax
 has been reported from a number of 
areas, most notably Southeast Asia and Oceania.
Chloroquine is the drug of choice for the treatment of 
non-falciparum and sensitive falciparum malaria. It rap
-
idly terminates fever (in 24–48 hours) and clears parasit
-
emia (in 48–72 hours) caused by sensitive parasites. 
Chloroquine is also the preferred chemoprophylactic agent 
in malarious regions without resistant falciparum malaria.
Chloroquine is usually well tolerated, even with pro
-
longed use. Pruritus is common, primarily in Africans. 
Nausea, vomiting, abdominal pain, headache, anorexia, 
malaise, blurring of vision, and urticaria are uncommon. 
Dosing after meals may reduce some adverse events.
2. Amodiaquine, piperaquine, and pyronaridine—
Amodiaquine is a 4-aminoquinoline that is closely related

Amodiaquine is a 4-aminoquinoline that is closely related 
to chloroquine. Amodiaquine has been widely used to treat 
malaria because of its low cost, limited toxicity and, in 
some areas, effectiveness against chloroquine-resistant 
strains of 
. Use of amodiaquine decreased after 
recognition of rare but serious side effects, notably agranu
-
locytosis, aplastic anemia, and hepatotoxicity. However, 
serious side effects are rare with short-term use, and arte
-
sunate-amodiaquine is one of the standard ACTs recom
-
mended to treat falciparum malaria (Table 35–3). 
Chemoprophylaxis with amodiaquine is best avoided 
because of increased toxicity with long-term use.
Piperaquine is another 4-aminoquinoline that has been 
coformulated with dihydroartemisinin in an ACT. Pipera
-
quine appears to be well tolerated and in combination with 
dihydroartemisinin to offer a highly efficacious therapy for 
falciparum and vivax malaria. Due to the long half-life of 
piperaquine (
∼
3 weeks), dihydroartemisinin-piperaquine 
Table 35–3.
 
WHO recommendations for the treatment 
of uncomplicated falciparum malaria.
Regimen
Notes
Artemether-lumefantrine 
(Coartem, Riamet)
Coformulated, first-line therapy in 
many countries. Approved in the 
Artesunate-amodiaquine 
(ASAQ)
multiple African countries.
Artesunate-mefloquine
First-line therapy in parts of 
Southeast Asia and South 
America but efficacy decreasing 
in parts of Thailand.
Artesunate- pyronaridine
Coformulated. Most recently 
approved regimen; used in some 
Southeast Asian countries.
Artesunate-sulfadoxine-
pyrimethamine
First-line in some countries, but 
efficacy lower than other 
regimens in most areas.
Dihydroartemisinin–
piperaquine
Coformulated. First-line in some 
Southeast Asian countries but 
efficacy decreasing in parts of 
Cambodia.
Data from World Health Organization: Guidelines for the Treatment 
of Malaria. World Health Organization. Geneva 2015.
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offers the longest period of posttreatment prophylaxis of 
available ACTs. However, resistance to piperaquine has 
emerged in southeast Asia, with consequent treatment 
failures of dihydroartemisinin-piperaquine in that region.
Pyronaridine is a benzonaphthyridine that was also 
previously used as a monotherapy to treat malaria in China 
and acts against many drug-resistant strains of 
. 
The combination of artesunate plus pyronaridine has 
shown excellent efficacy against falciparum and vivax 
malaria and has been well tolerated, although elevated 
transaminases can be seen.
3. Mefloquine—
Mefloquine is effective against many 
chloroquine-resistant strains of 
 and against 
other malarial species. Although toxicity is a concern, 
mefloquine is also a recommended chemoprophylactic 
drug. Resistance to mefloquine has been reported sporadi
-
cally from many areas, but it appears to be uncommon 
except in regions of Southeast Asia with high rates of mul
-
tidrug resistance (especially border areas of Thailand).
For treatment of uncomplicated malaria, mefloquine 
can be administered as a single dose or in two doses over 
 
1 day. It is used in combination with artesunate as an 
 
Table 35–4.
 
Treatment of malaria.
Drug Therapy
1
Alternative Drugs
Chloroquine-sensitive 
 
and 
 
Chloroquine phosphate, 1 g at 0, followed by 
 
500 mg at 6, 24, and 48 hours
or–
Chloroquine phosphate, 1 g at 0 and 24 hours, 
 
then 0.5 g at 48 hours
 
 and 
 
Chloroquine (as above), then (if G6PD normal) 
 
primaquine, 30-mg base daily for 14 days
For infections from Indonesia, Papua New 
Guinea, and other areas with suspected 
resistance: therapies listed for 
 
uncomplicated chloroquine-resistant 
 
 plus primaquine
Uncomplicated infections with 
chloroquine-resistant 
P 
falciparum
Coartem (artemether 20 mg, lumefantrine 120 mg), 
 
four tablets twice daily for 3 days
or–
Malarone, four tablets (total of 1-g atovaquone, 
 
400-mg proguanil) daily for 3 days
or–
Quinine sulfate, 650 mg three times daily for 3–7 days
Plus one of the following
(when quinine given for < 7 days)
Doxycycline, 100 mg twice daily for 7 days
or–
Clindamycin, 600 mg twice daily for 7 days
Mefloquine, 15 mg/kg once or 750 mg, then 
500 mg in 6–8 hours
or–
Dihydroartemisinin-piperaquine
2
 
(dihydroartemisinin 40 mg, piperaquine 
320 mg), 4 tablets daily for 3 days
or–
ASAQ
2
 (artesunate 100 mg, amodiaquine 
 
270 mg), two tablets daily for 3 days
Severe or complicated 
 
infections with 
Artesunate 2.4 mg/kg intravenously every 12 hours 
 
for 1 day, then daily
3,6
Quinidine gluconate,
4–6
 10 mg/kg 
 
intravenously over 1–2 hours, then 
 
0.02 mg/kg intravenously/min
or–
4–6
 15 mg/kg 
 
intravenously over 4 hours, then 7.5 mg/kg 
intravenously over 4 hours every 8 hours
or–
Quinine dihydrochloride,
2,4–6
 20 mg/kg 
 
intravenously over 4 hours, then 10 mg/kg 
intravenously every 8 hours
or–
Artemether,
2,6
 3.2 mg/kg intramuscularly, 
 
then 1.6 mg/kg/day intramuscularly
1
All dosages are oral and refer to salts unless otherwise indicated. See text for additional information on all agents, including toxicities and 
cautions. See Centers for Disease Control and Prevention’s guidelines (phone: 877-FYI-TRIP; http://www.cdc.gov/malaria/) for additional 
information and pediatric dosing.
2
3
Available in the United States only on an investigational basis through the CDC (phone: 770-488-7788).
4
Cardiac monitoring should be in place during intravenous administration of quinidine or quinine.
5
Avoid loading doses in persons who have received quinine, quinidine, or mefloquine in the prior 24 hours.
6
With all parenteral regimens, change to an oral regimen as soon as the patient can tolerate it.

6
G6PD, glucose-6-phosphate dehydrogenase.
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artemisinin-based combination therapy (ACT) for falci
-
parum malaria, although resistance limits efficacy in 
Southeast Asia. It should be taken with meals and swal
-
lowed with a large amount of water. Mefloquine is recom
-
mended by the CDC for chemoprophylaxis in all malarious 
areas except those with no chloroquine resistance (where 
chloroquine is preferred) and some rural areas of Southeast 
Asia with a high prevalence of mefloquine resistance.
Adverse effects with weekly dosing of mefloquine for 
chemoprophylaxis include nausea, vomiting, dizziness, 
sleep and behavioral disturbances, epigastric pain, diar
-
rhea, abdominal pain, headache, rash and, uncommonly, 
seizures and psychosis. There is an FDA black box warning 
about neuropsychiatric toxicity, possibly including rare, 
irreversible effects. Mefloquine should be avoided in per
-
sons with histories of psychiatric disease or seizures.
Adverse effects are more common (up to 50% of treat
-
ments) with the higher dosages of mefloquine required for 
treatment. These effects may be lessened by splitting 
administration into two doses separated by 6–8 hours. 
Serious neuropsychiatric toxicities (depression, confusion, 
acute psychosis, or seizures) have been reported in less 
than 1 in 1000 treatments, but some authorities believe that 
these are more common. Mefloquine can also alter cardiac 
conduction, and so it should not be coadministered with 
quinine, quinidine, or halofantrine, and caution is required 
if these drugs are used to treat malaria after mefloquine 
chemoprophylaxis. Mefloquine is generally considered safe 
in young children and pregnant women.
4. Quinine and quinidine—
Quinine dihydrochloride and 
quinidine gluconate remain first-line therapies for falciparum 
malaria, especially severe disease, although toxicity concerns 
complicate therapy (Table 35–4). Quinine acts rapidly against 
the four species of human malaria parasites. Quinidine, the 
dextrorotatory stereoisomer of quinine, is at least as effective 
as quinine in the treatment of severe falciparum malaria.
Resistance of 
 to quinine is common in some 
areas of Southeast Asia, where the drug may fail if used alone 
to treat falciparum malaria. However, quinine still provides 
at least a partial therapeutic effect in most patients.
Quinine and quinidine are effective treatments for 
severe falciparum malaria, although intravenous artesu
-
nate is the standard of care. The drugs can be administered 
in divided doses or by continuous intravenous infusion; 
treatment should begin with a loading dose to rapidly 
achieve effective plasma concentrations. Intravenous qui
-
nine and quinidine should be administered with cardiac 
monitoring because of their cardiac toxicity and the rela
-
tive unpredictability of their pharmacokinetics. Therapy 
should be changed to an oral agent as soon as the patient 
has improved and can tolerate oral medications.
In areas without newer combination regimens, oral qui
-
nine sulfate is an alternative first-line therapy for uncompli
-
cated falciparum malaria, although poor tolerance may 
limit compliance. Quinine is commonly used with a second 
drug (most often doxycycline) to shorten the duration of 
use (to 3 days) and to limit toxicity. Therapeutic dosages of 
quinine and quinidine commonly cause tinnitus, headache, 
nausea, dizziness, flushing, and visual disturbances. 
Hematologic abnormalities include hemolysis (especially 
with G6PD deficiency), leukopenia, agranulocytosis, and 
thrombocytopenia. Therapeutic doses may cause hypogly
-
cemia through stimulation of insulin release; this is a par
-
ticular problem in severe infections and in pregnant 
patients, who have increased sensitivity to insulin. Overly 
rapid infusions can cause severe hypotension. ECG abnor
-
malities (QT prolongation) are fairly common, but danger
-
ous arrhythmias are uncommon when the drugs are

-
-
ous arrhythmias are uncommon when the drugs are 
administered appropriately. Quinine should not be given 
concurrently with mefloquine and should be used with cau
-
tion in a patient who has previously received mefloquine.
5. Primaquine—
Primaquine phosphate, a synthetic 
8-aminoquinoline, is the drug of choice for the eradication of 
dormant liver forms of 
P vivax
 and 
P ovale
 (Table 35–4). 
Primaquine is active against hepatic stages of all human 
malaria parasites. This action is optimal soon after therapy 
with chloroquine or quinine. Primaquine also acts against 
erythrocytic stage parasites, although this activity is too weak 
for the treatment of active disease, and against gametocytes. As 
a new strategy to lower transmission, a single low dose of pri
-
maquine in conjunction with an ACT to treat uncomplicated 
falciparum malaria was well tolerated and lowered transmis
-
sion to mosquitoes in subjects with normal G6PD levels.
For 
P vivax
 and 
P ovale
 infections, chloroquine or other 
drugs are used to eradicate erythrocytic forms, and if the 
G6PD level is normal, a 14-day course of primaquine 
(52.6 mg primaquine phosphate [30 mg base] daily) is ini
-
tiated to eradicate liver hypnozoites and prevent a subse
-
quent relapse. Some strains of 
P vivax
, particularly in New 
Guinea and Southeast Asia, are relatively resistant to pri
-
maquine, and the drug may fail to eradicate liver forms.
Standard chemoprophylaxis does not prevent a relapse 
of 
P vivax
 or 
P ovale
 infections, since liver hypnozoites are 
not eradicated by chloroquine or other standard treat
-
ments. To diminish the likelihood of relapse, some authori
-
ties advocate the use of a treatment course of primaquine 
after the completion of travel to an endemic area. Prima
-
quine can also be used for chemoprophylaxis to prevent 
 and 
P vivax
 infection in persons with normal 
levels of G6PD.
Primaquine in recommended doses is generally well 
tolerated. It infrequently causes nausea, epigastric pain, 
abdominal cramps, and headache, especially when taken 
on an empty stomach. Rare adverse effects include leuko
-
penia, agranulocytosis, leukocytosis, and cardiac arrhyth
-
mias. Standard doses of primaquine may cause hemolysis 
or methemoglobinemia (manifested by cyanosis), espe
-
cially in persons with G6PD deficiency or other hereditary 
metabolic defects. Patients should be tested for G6PD 
deficiency before primaquine is prescribed. Primaquine 
should be discontinued if there is evidence of hemolysis or 
anemia and should be avoided in pregnancy.
6. Inhibitors of folate synthesis—
Inhibitors of two para
-
site enzymes involved in folate metabolism, dihydrofolate 
reductase (DHFR) and dihydropteroate synthase (DHPS), 
are used, generally in combination regimens, for the treat
-
ment and prevention of malaria, although the drugs are 
rather slow acting and now limited by resistance.
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Fansidar is a fixed combination of sulfadoxine (500 mg) 
and pyrimethamine (25 mg). It is no longer advised for 
chemoprophylaxis due to rare serious side effects with 
long-term dosing. For treatment, advantages of sulfadox
-
ine-pyrimethamine include ease of administration (a single 
oral dose) and low cost. However, resistance is now a major 
problem.
Sulfadoxine-pyrimethamine plus artesunate has shown 
efficacy for malaria treatment in some areas but is best 
replaced by more effective ACTs. Sulfadoxine-pyrimeth
-
amine is recommended by WHO for monthly preventive 
therapy in pregnant women in areas of high endemicity, 
although its efficacy is limited by resistance. Amodiaquine 
plus sulfadoxine-pyrimethamine is recommended monthly 
during the rainy season for chemoprophylaxis in regions of 
West Africa with seasonal malaria transmission and lim
-
ited drug resistance. Another antifolate combination, trim
-
ethoprim-sulfamethoxazole (TMP-SMZ), is widely used to 
prevent coinfections in patients infected with HIV , and it 
offers partial protection against malaria.
7. Artemisinins—
Artemisinin (qinghaosu) is a sesquiter
-
pene lactone endoperoxide, the active component of an 
herbal medicine that has been used for various indications 
in China for over 2000 years. Analogs have been synthe
-
sized to increase solubility and improve antimalarial effi
-
cacy. The most important of these analogs are artesunate, 
artemether, and dihydroartemisinin. WHO encourages 
availability of oral artemisinins only in coformulated com
-
bination regimens.
Artemisinins act very rapidly against all erythrocytic-
stage human malaria parasites. Of concern, delayed clear
-
ance of parasites and clinical failures have been seen after 
treatment with artesunate in parts of Southeast Asia, herald
-
ing the emergence of artemisinin resistance in this region.
Artemisinins play a vital role in the treatment of malaria, 
including multidrug-resistant 
 malaria. Due to 
their short plasma half-lives, recrudescence rates are unac
-
ceptably high after short-course therapy, leading to 
approved use only as initial therapy for severe malaria and 
in ACTs for uncomplicated malaria. The ACTs that are cur
-
rently most advocated in Africa are artesunate plus amodia
-
quine (ASAQ) and artemether plus lumefantrine (Coartem), 
each of which is available as a coformulated product. 
Another ACT, artesunate plus mefloquine is used mostly 
outside of Africa; its efficacy may be declining in parts of 
Asia. Dihydroartemisinin-piperaquine has shown excellent 
efficacy and is the first-line regimen in some countries in 
Southeast Asia, but recent studies have shown declining 
efficacy in Cambodia due to decreased activity of both com
-
ponents of the regimen. The newest approved ACT, artesu
-
nate-pyronaridine, is approved in some countries, but little 
used to date. Other ACTs not recommended by the WHO 
are available in some countries and have shown good effi
-
cacy in limited studies, including arterolane-piperaquine, 
artemisinin-piperaquine, and artemisinin-naphthoquine.
In studies of severe malaria, intramuscular artemether 
was at least as effective as intramuscular quinine, and intra
-
venous artesunate was superior to intravenous quinine in 
terms of efficacy and tolerability. Thus, the standard of care 
for severe malaria is intravenous artesunate, when it is 
available, although parenteral quinine and quinidine 
remain acceptable alternatives. Artesunate and artemether 
have also been effective in the treatment of severe malaria 
when administered rectally, offering a valuable treatment 
modality when parenteral therapy is not available.
Artemisinins are very well tolerated. The most commonly 
reported adverse effects have been nausea, vomiting, and diar
-
rhea, which may often be due to acute malaria, rather than 
drug toxicity. Neutropenia, anemia, hemolysis, and elevated

-
drug toxicity. Neutropenia, anemia, hemolysis, and elevated 
levels of liver enzymes have been noted rarely. Hemolysis may 
occur weeks after therapy with intravenous artesunate. Arte
-
misinins are teratogenic in animals, but with good safety seen 
in humans, and the importance of effectively treating malaria 
during pregnancy, the WHO now recommends ACTs to treat 
uncomplicated malaria and intravenous artesunate to treat 
complicated malaria during all trimesters of pregnancy.
8. Atovaquone plus proguanil (Malarone)—
Atovaquone, 
a hydroxynaphthoquinone, is not effective when used 
alone, due to rapid development of drug resistance. How
-
ever, Malarone, a fixed combination of atovaquone (250 mg) 
and the antifolate proguanil (100 mg), is highly effective for 
both the treatment and chemoprophylaxis of falciparum 
malaria, and it is approved for both indications in the 
United States (Table 35–4). It also appears to be active 
against other species of malaria parasites. Unlike most 
other antimalarials, Malarone provides activity against 
both erythrocytic and hepatic stage parasites.
For treatment, Malarone is given at an adult dose of 
four tablets daily for 3 days. For chemoprophylaxis, Malar
-
one must be taken daily. It has an advantage over meflo
-
quine and doxycycline in requiring shorter durations of 
treatment before and after the period at risk for malaria 
transmission, due to activity against liver-stage parasites. It 
should be taken with food.
Malarone is generally well tolerated. Adverse effects 
include abdominal pain, nausea, vomiting, diarrhea, head
-
ache, and rash, and these are more common with the 
higher dose required for treatment. Reversible elevations in 
liver enzymes have been reported. The safety of atova
-
quone in pregnancy is unknown.
9. Antibiotics—
A number of antibacterials in addition to 
the folate antagonists and sulfonamides are slow-acting 
antimalarials. None of the antibiotics should be used as 
single agents for the treatment of malaria due to their slow 
rate of action.
Doxycycline is commonly used in the treatment of falci
-
parum malaria in conjunction with quinidine or quinine, 
allowing a shorter and better-tolerated course of those 
drugs (Table 35–4). Doxycycline is also a standard chemo
-
prophylactic drug, especially for use in areas of Southeast 
Asia with high rates of resistance to other antimalarials, 
including mefloquine. Doxycycline side effects include gas
-
trointestinal symptoms, candidal vaginitis, and photosensi
-
tivity. The drug should be taken while upright with a large 
amount of water to avoid esophageal irritation. Clindamy
-
cin can be used in conjunction with quinine or quinidine in 
those for whom doxycycline is not recommended, such as 
children and pregnant women (Table 35–4). The most com
-
mon toxicities with clindamycin are gastrointestinal.
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Lumefantrine, an aryl alcohol related to halofantrine, is 
available only as a fixed-dose combination with artemether 
(Coartem or Riamet). Oral absorption is highly variable 
and improved when the drug is taken with food. Use of 
Coartem with a fatty meal is recommended. Coartem is 
highly effective for the treatment of falciparum malaria, 
but it requires twice-daily dosing. Despite this limitation, 
due to its reliable efficacy against falciparum malaria, 
Coartem is the first-line therapy for malaria in many 
malarious countries. Coartem is well tolerated; side effects 
include headache, dizziness, loss of appetite, gastrointesti
-
nal symptoms, and palpitations. Importantly, Coartem 
does not generally cause QT prolongation or the serious 
cardiac toxicity seen with halofantrine.
 
»
Malaria is transmitted by night-biting anopheline mosqui
-
toes. Bed nets, in particular nets treated with permethrin 
insecticides, are heavily promoted as inexpensive means of 
antimalarial protection, but effectiveness varies in part due 
to widespread insecticide resistance. Indoor spraying of 
insecticides is generally highly effective in Africa but lim
-
ited by resource constraints.
Extensive efforts are underway to develop a malaria 
vaccine, but a vaccine offering a high level of protection is 
not anticipated in the near future. RTS,S vaccine, which is 
based on a sporozoite antigen, is the most advanced vac
-
cine candidate. Multiple clinical trials showed about 
25–50% protection against malaria in children in the year 
after immunization, but lower levels of protection in very 
young children, in areas of highest malaria exposure, and 
over longer periods of time. A new concept is seasonal 
malaria immunization, using short-acting vaccines during 
the high transmission season. Other approaches under 
study include vaccines containing erythrocytic, liver-stage, 
and sexual-stage antigens, and use of radiation-attenuated 
or molecularly attenuated sporozoites.
When travelers from nonendemic to endemic countries 
are counseled on the prevention of malaria, it is imperative 
to emphasize measures to prevent mosquito bites (insect 
repellents, insecticides, and bed nets), since parasites are 
increasingly resistant to multiple drugs and no chemopro
-
phylactic regimen is fully protective. Chemoprophylaxis is 
recommended for all travelers from nonendemic regions to 
endemic areas, although risks vary greatly for different 
locations, and some tropical areas entail no risk; specific 
recommendations for travel to different locales are avail
-
able from the CDC (www.cdc.gov; 877-FYI-TRIP). Rec
-
ommendations from the CDC include the use of 
chloroquine for chemoprophylaxis in the few areas with 
only chloroquine-sensitive malaria parasites (principally 
the Caribbean and Central America west of the Panama 
Canal), mefloquine or Malarone for most other malarious 
areas, and doxycycline for areas with a high prevalence of 
multidrug-resistant falciparum malaria (principally parts 
of Southeast Asia) (Table 35–5). Recommendations should 
be checked regularly because they may change in response 
to changing resistance patterns and increasing experience 
with new drugs. In some circumstances, it may be appro
-
priate for travelers to not use chemoprophylaxis but to 
carry supplies of drugs with them in case a febrile illness 
develops and medical attention is unavailable. Regimens 
for self-treatment include ACTs, Malarone, and quinine. 
Most authorities do not recommend routine terminal che
-
moprophylaxis with primaquine to eradicate dormant 
hepatic stages of 
P vivax
 and 
P ovale
 after travel, but this 
may be appropriate in some circumstances, especially for 
travelers with major exposure to these parasites.
Regular chemoprophylaxis is not a standard management 
practice in developing world populations due to the expense

practice in developing world populations due to the expense 
and potential toxicities of long-term therapy. However, 
Table 35–5.
 
Drugs for the prevention of malaria in travelers.
1
Drug
Use
2
Adult Dosage (all oral)
3
Areas without resistant 
500 mg weekly
Malarone
Areas with multidrug-resistant 
1 tablet (250-mg atovaquone/100-mg proguanil) daily
Areas with chloroquine-resistant 
250 mg weekly
100 mg daily
4
Terminal prophylaxis of 
 and 
 infections; alternative for 
 
 prophylaxis
30-mg base daily for 14 days after travel
1
Recommendations may change, as resistance to all available drugs is increasing. See text for additional information on toxicities and 
cautions. For additional details and pediatric dosing, see Centers for Disease Control and Prevention’s guidelines (phone: 800-CDC-INFO; 
http://wwwnc.cdc.gov/travel/). Travelers to remote areas should consider carrying effective therapy (see text) for use if a febrile illness 
develops, and they cannot reach medical attention quickly.
2
Areas without known chloroquine-resistant 
 are Central America west of the Panama Canal, Haiti, Dominican Republic, Egypt, 
and most malarious countries of the Middle East. Malarone or mefloquine is currently recommended for other malarious areas except for 
border areas of Thailand, where doxycycline is recommended.
3
For drugs other than primaquine, begin 1–2 weeks before departure (except 2 days before for doxycycline and Malarone) and continue 
for 4 weeks after leaving the endemic area (except 1 week for Malarone). All dosages refer to salts unless otherwise indicated.
4
Screen for glucose-6-phosphate dehydrogenase deficiency before using primaquine.
Reproduced, with permission, from Katzung BG. 
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intermittent preventive therapy, whereby at-risk populations 
(in particular pregnant women and children) receive antima
-
larial therapy at set intervals, is of increasing interest. This 
strategy may decrease the incidence of malaria while allowing 
antimalarial immunity to develop. During pregnancy, inter
-
mittent preventive therapy with sulfadoxine-pyrimethamine, 
provided once during both the second and third trimesters, 
has improved pregnancy outcomes. With increasing resis
-
tance the preventive efficacy of sulfadoxine-pyrimethamine is 
likely falling, and the long-acting ACT dihydroartemisinin-
piperaquine is a promising replacement. In areas with sea
-
sonal malaria transmission and limited drug resistance, 
principally the Sahel subregion of West Africa, the policy is to 
administer amodiaquine and sulfadoxine-pyrimethamine to 
children monthly during the transmission season.
 
»
Prognosis
When treated appropriately, uncomplicated malaria gener
-
ally responds well, with resolution of fevers within 1–2 days 
and a mortality of about 0.1%. Severe malaria can com
-
monly progress to death, but many children respond well 
to therapy. In the developed world, mortality from malaria 
is mostly in adults, and often follows extended illnesses and 
secondary complications long after eradication of the 
malarial infection. Pregnant women are at particular risk 
during their first pregnancy. Malaria in pregnancy also 
increases the likelihood of poor pregnancy outcomes, with 
increased prematurity, low birth weight, and mortality.
 
»
Referral to an expert on infectious diseases or travel medi
-
cine is important with all cases of malaria in the United 
States, and in particular for falciparum malaria; referral 
should not delay initial diagnosis and therapy, since delays 
in therapy can lead to severe illness or death.
 
»
•	
Admission for non-falciparum malaria is warranted 
only if specific problems that require hospital manage
-
ment are present.
•	
Patients with falciparum malaria are generally admitted 
because the disease can progress rapidly to severe illness; 
exceptions may be made with individuals who are from 
malaria-endemic areas, and thus expected to have a 
degree of immunity, who are without evidence of severe 
disease, and who are judged able to return promptly for 
medical attention if their disease progresses.
Amaratunga C et al. Dihydroartemisinin-piperaquine resistance 
in 
 malaria in Cambodia: a multisite 
prospective cohort study. Lancet Infect Dis. 2016 Mar; 
16(3):357–65. [PMID: 26774243]
Ashley EA et al; Tracking Resistance to Artemisinin Collabora
-
tion (TRAC). Spread of artemisinin resistance in 
 malaria. N Engl J Med. 2014 Jul 31;371(5):411–23. 
[PMID: 25075834]
Cowman AF et al. Malaria: biology and disease. Cell. 2016 
Oct 20;167(3):610–24. [PMID: 27768886]
Kremsner PG et al. Intramuscular artesunate for severe malaria 
in African children: a multicenter randomized controlled 
trial. PLoS Med. 2016 Jan 12;13(1):e1001938. [PMID: 
26757276]
Olotu A et al. Seven-year efficacy of RTS, S/AS01 malaria 
vaccine among young African children. N Engl J Med. 2016 
Jun 30; 374(26):2519–29. [PMID: 27355532]
PREGACT Study Group. Four artemisinin-based treatments in 
African pregnant women with malaria. Malawi Med J. 
2016 Sep;28(3):139–49. [PMID: 27895848]
Rosenthal PJ. Artesunate for the treatment of severe falciparum 
malaria. N Engl J Med. 2008 Apr 24;358(17):1829–36. [PMID: 
18434652]
Sirima SB et al. Comparison of artesunate-mefloquine and 
artemether-lumefantrine fixed-dose combinations for treat
-
ment of uncomplicated 
 malaria in 
children younger than 5 years in sub-Saharan Africa: a 
randomised, multicentre, phase 4 trial. Lancet Infect Dis. 
2016 Oct; 16(10):1123–33. [PMID: 27430374]
White NJ et al. Malaria. Lancet. 2014 Feb 22;383(9918):723–35. 
[PMID: 23953767]

World Health Organization. 
Guidelines for the treatment of 
malaria
, 3rd edition. Geneva, Switzerland, 2015. http://www
 
.who.int/malaria/publications/atoz/9789241549127/en/
World Malaria Report 2017
. Geneva, 
Switzerland: WHO, 2017. http://www.who.int/malaria/
publications/world-malaria-report-2017/en/
Y eka A et al. Artesunate/amodiaquine versus artemether/lume
-
fantrine for the treatment of uncomplicated malaria in 
Uganda: a randomized trial. J Infect Dis. 2016 Apr 1; 
213(7):1134–42. [PMID: 26597254]
BABESIOSIS
 
»
History of tick bite or exposure to ticks.
 
»
Fever, flu-like symptoms, anemia.
 
»
Intraerythrocytic parasites on Giemsa-stained 
blood smears.
 
»
Positive serologic tests.
 
»
Babesiosis is an uncommon intraerythrocytic infection 
caused mainly by two 
Babesia
 species and transmitted by 
Ixodes
 ticks. In the United States, hundreds of cases of 
babesiosis have been reported, and infection is caused by 
, which also infects wild mammals. Most 
babesiosis in the United States occurs in the coastal north
-
east, with some cases also in the upper midwest, following 
the geographic range of the vector 
, and 
Lyme disease and anaplasmosis, which are spread by the 
same vector. The incidence of the disease appears to be 
increasing in some areas. Babesiosis is caused by 
Babesia 
divergens
 in Europe and by 
Babesia venatorum
 in China. 
Babesiosis due to 
Babesia duncani
 and other Babesia-like 
organisms have been reported uncommonly from the 
western United States. Babesiosis can also be transmitted 
by blood transfusion, but blood supplies are not screened. 
A survey of a large set of blood samples from endemic 
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regions of the United States identified 
∼
0.4% as potentially 
infectious for 
B microti
.
 
»
Serosurveys suggest that asymptomatic infections are com
-
mon in endemic areas. With 
B microti
 infections, symp
-
toms appear 1 to several weeks after a tick bite; parasitemia 
is evident after 2–4 weeks. Patients usually do not recall the 
tick bite. The typical flu-like illness develops gradually and 
is characterized by fever, fatigue, headache, arthralgia, and 
myalgia. Other findings may include nausea, vomiting, 
abdominal pain, sore throat, depression, emotional lability, 
anemia, thrombocytopenia, and splenomegaly. Parasitemia 
may continue for months to years, with or without symp
-
toms, and the disease is usually self-limited. Severe compli
-
cations are most likely to occur in older persons or in those 
who have had splenectomy. Serious complications include 
respiratory failure, hemolytic anemia, disseminated intra
-
vascular coagulation, heart failure, and acute kidney injury. 
In a study of hospitalized patients, the mortality rate was 
6.5%. Most recognized 
B divergens
 infections in Europe 
have been in patients who have had splenectomy. These 
infections progress rapidly with high fever, severe hemo
-
lytic anemia, jaundice, hemoglobinuria, and acute kidney 
injury, with death rates over 40%.
Identification of the intraerythrocytic parasite on Giemsa-
stained blood smears establishes the diagnosis 
(Figure 35–6). These can be confused with malaria para
-
sites, but the morphology is distinctive. Repeated smears 
are often necessary because well under 1% of erythrocytes 
may be infected, especially early in infection, although 
parasitemias can exceed 10%. Diagnosis can also be made 
by PCR, which is more sensitive than blood smear. An 
indirect immunofluorescent antibody test for 
B microti
 is 
available from the CDC; antibody is detectable within 
2–4 weeks after the onset of symptoms and persists for 
months.
 
»
Treatment
Most patients have a mild illness and recover without 
therapy. Standard therapy for mild to moderate disease is a 
7-day course of atovaquone (750 mg orally every 12 hours) 
plus azithromycin (600 mg orally once daily), which is 
equally effective and better tolerated than the alternative 
regimen, a 7-day course of quinine (650 mg orally three 
times daily) plus clindamycin (600 mg orally three times 
daily). However, there is more experience using quinine 
plus clindamycin, and this regimen is recommended for 
severe disease. Exchange transfusion has been used suc
-
cessfully in severely ill asplenic patients and those with 
parasitemia greater than 10%.
Moritz ED et al. Screening for 
 in the U.S. blood 
supply. N Engl J Med. 2016 Dec 8;375(23):2236–45. [PMID: 
27959685]
Sanchez E et al. Diagnosis, treatment, and prevention of Lyme 
disease, human granulocytic anaplasmosis, and babesiosis: a 
review. JAMA. 2016 Apr 26;315(16):1767–77. [PMID: 
27115378]
Vannier EG et al. Babesiosis. Infect Dis Clin North Am. 
2015 Jun;29(2):357–70. [PMID: 25999229]
TOXOPLASMOSIS
 
»
Infection confirmed by isolation of 
Toxoplasma 
gondii
 or identification of tachyzoites in tissue or 
body fluids.
Primary infection
 
»
Fever, malaise, headache, sore throat.
 
»
 
»
Positive IgG and IgM serologic tests.
Congenital infection
 
»
Follows acute infection of seronegative mothers 
and leads to CNS abnormalities and 
retinochoroiditis.
Infection in immunocompromised persons
 
»
Reactivation leads to encephalitis, retinochoroidi
-
tis, pneumonitis, myocarditis.
 
»
Positive IgG but negative IgM serologic tests.
 
»
T gondii
, an obligate intracellular protozoan, is found 
worldwide in humans and in many species of mammals 
and birds. The definitive hosts are cats. Humans are

»
T gondii
and birds. The definitive hosts are cats. Humans are 
infected after ingestion of cysts in raw or undercooked 
meat, ingestion of oocysts in food or water contaminated 
by cats, transplacental transmission of trophozoites or, 
rarely, direct inoculation of trophozoites via blood transfu
-
sion or organ transplantation. 
 seroprevalence 
varies widely. It has decreased in the United States to 
 
▲
Figure 35–6.
 
Blood smear showing 
Babesia
 spp. 
rings with basophilic stippling. 
(From Dr. Mae Melvin, 
Public Health Image Library, CDC.)
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20–30% or less, but it is much higher in other countries in 
both the developed and developing worlds, where it may 
exceed 80%. In the United States, 
T gondii
 is estimated to 
infect 1.1 million persons each year, with resultant chorio
-
retinitis developing in 21,000 and vision loss in 4800.
 
»
The clinical manifestations of toxoplasmosis may be 
grouped into four syndromes.
1. Primary infection in the immunocompetent person—
After ingestion, 
T gondii
 infection progresses from the gas
-
trointestinal tract to lymphatics, and then dissemination. 
Most acute infections are asymptomatic. About 10–20% are 
symptomatic after an incubation period of 1–2 weeks. 
Acute infections in immunocompetent persons typically 
present as mild, febrile illnesses that resemble infectious 
mononucleosis. Nontender cervical or diffuse lymphade
-
nopathy may persist for weeks to months. Systemic findings 
may include fever, malaise, headache, sore throat, rash, 
myalgias, hepatosplenomegaly, and atypical lymphocytosis. 
Rare severe manifestations are pneumonitis, meningoen
-
cephalitis, hepatitis, myocarditis, polymyositis, and retino
-
choroiditis. Symptoms may fluctuate, but most patients 
recover spontaneously within at most a few months.
2. Congenital infection—
Congenital transmission occurs 
as a result of infection, which may be symptomatic or 
asymptomatic, in a nonimmune woman during pregnancy. 
Fetal infection follows maternal infection in 30–50% of 
cases, but this risk varies by trimester: 10–25% during the 
first, 30–50% during the second, and 60% or higher during 
the third trimester. In the United States, an estimated 400 
to 4000 congenital infections occur yearly. While the risk of 
fetal infection increases, the risk of severe fetal disease 
decreases over the course of pregnancy. Early fetal infec
-
tions commonly lead to spontaneous abortion, stillbirths, 
or severe neonatal disease, including neurologic manifesta
-
tions. Retinochoroiditis and other sight-threatening eye 
lesions may develop. Infections later in pregnancy less 
commonly lead to major fetal problems. Most infants 
appear normal at birth, but they may have subtle abnor
-
malities and progress to symptoms and signs of congenital 
toxoplasmosis later in life.
3. Retinochoroiditis—
The most common late presenta
-
tion of congenital toxoplasmosis is retinochoroiditis, which 
presents weeks to years after congenital infection, com
-
monly in teenagers or young adults. Retinochoroiditis is 
also seen in persons who acquire infection early in life, and 
these patients more often present with unilateral disease. 
Uveitis is also seen. Disease presents with pain, photopho
-
bia, and visual changes, usually without systemic symp
-
toms. Signs and symptoms eventually improve, but visual 
defects may persist. Rarely, progression may result in glau
-
coma and blindness.
4. Disease in the immunocompromised person—
Reacti
-
vated toxoplasmosis occurs in patients with AIDS, cancer, 
or those given immunosuppressive drugs. In patients with 
advanced AIDS, the most common manifestation is 
encephalitis, with multiple necrotizing brain lesions. The 
encephalitis usually presents subacutely, with fever, head
-
ache, altered mental status, focal neurologic findings, and 
other evidence of brain lesions. Less common manifesta
-
tions of toxoplasmosis in patients with AIDS are chorio
-
retinitis and pneumonitis. Chorioretinitis presents with 
ocular pain and alterations in vision. Pneumonitis presents 
with fever, cough, and dyspnea. Toxoplasmosis can develop 
in seronegative recipients of solid organ or bone marrow 
transplants due to reactivation or, more rarely, transmis
-
sion of infection. Reactivation also can occur in those with 
hematologic malignancies or treated with immunosup
-
pressive drugs. With primary or reactivated disease in 
those with immunodeficiency due to malignancy or immu
-

-
-
nosuppressive drugs, toxoplasmosis is similar to that in 
individuals with AIDS, but pneumonitis and myocarditis 
are more common.
1. Identification of parasites—
Organisms can be seen in 
tissue or body fluids, although they may be difficult to 
identify; special staining techniques can facilitate identifi
-
cation. The demonstration of tachyzoites indicates acute 
infection; cysts may represent either acute or chronic infec
-
tion. With lymphadenopathy due to toxoplasmosis, exami
-
nation of lymph nodes usually does not show organisms. 
Parasite identification can also be made by inoculation of 
tissue culture or mice. PCR can be used for sensitive iden
-
tification of organisms in amniotic fluid, blood, CSF, aque
-
ous humor, and bronchoalveolar lavage fluid.
2. Serologic diagnosis—
Multiple serologic methods are 
used, including the Sabin-Feldman dye test, enzyme-linked 
immunosorbent assay (ELISA), indirect fluorescent anti
-
body test, and agglutination tests. IgG antibodies are seen 
within 1–2 weeks of infection, and usually persist for life. 
IgM antibodies peak earlier than IgG and decline more 
rapidly, although they may persist for years. In immuno
-
compromised individuals in whom reactivation is sus
-
pected, a positive IgG assay indicates distant infection, and 
thus the potential for reactivated disease; a negative IgG 
argues strongly against reactivation toxoplasmosis. With 
reactivation in immunocompromised persons, IgM tests 
are generally negative.
3. During pregnancy and in newborns—
Conversion from 
a negative to positive serologic test or rising titers are sug
-
gestive of acute infection, but tests are not routinely per
-
formed during pregnancy. When pregnant women are 
screened, negative IgG and IgM assays exclude active infec
-
tion, but indicate the risk of infection during the preg
-
nancy. Positive IgG with negative IgM is highly suggestive 
of chronic infection, with no risk of congenital disease 
unless the mother is severely immunocompromised. A 
positive IgM test is concerning for new infection because of 
the risk of congenital disease. Confirmatory testing should 
be performed before consideration of treatment or possible 
termination of pregnancy due to the limitations of available 
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tests. Tests of the avidity of anti-IgG antibodies can be help
-
ful, but a battery of tests is needed for confirmation of 
acute infection during pregnancy. When acute infection 
during pregnancy is suspected, PCR of amniotic fluid 
offers a sensitive assessment for congenital disease. In new
-
borns, positive IgM or IgA antibody tests are indicative of 
congenital infection, although the diagnosis is not ruled 
out by a negative test. Positive IgG assays may represent 
transfer of maternal antibodies without infection of the 
infant, but persistence of positive IgG beyond 12 months of 
age is diagnostic of congenital infection. PCR of blood, 
CSF, or urine can also be helpful for early diagnosis of con
-
genital disease.
4. In immunocompetent individuals—
Individuals with a 
suggestive clinical syndrome should be tested for IgG and 
IgM antibodies. Seroconversion, a 16-fold rise in antibody 
titer, or an IgM titer greater than 1:64 are suggestive of acute 
infection, although false-positive results may occur. Acute 
infection can also be diagnosed by detection of tachyzoites 
in tissue, culture of organisms, or PCR of blood or body 
fluids. Histologic evaluation of lymph nodes can show char
-
acteristic morphology, with or without organisms.
5. In immunodeficient individuals—
A presentation con
-
sistent with toxoplasmic encephalitis warrants imaging of 
the brain. CT and MRI scans typically show multiple ring-
enhancing cerebral lesions, most commonly involving the 
corticomedullary junction and basal ganglia. MRI is the 
more sensitive imaging modality. In AIDS patients with a 
positive IgG serologic test and no recent antitoxoplasma or 
antiviral therapy, the predictive value of a typical imaging 
study is about 80%. The other common diagnosis in this 
setting is CNS lymphoma, which more typically causes a 
single brain lesion. The differential diagnosis also includes 
tuberculoma, bacterial brain abscess, fungal abscess, and 
carcinoma. Diagnosis of CNS toxoplasmosis is most typi
-
cally made after a therapeutic trial, with clinical and radio
-
logic improvement expected within 2–3 weeks. Definitive 
diagnosis requires brain biopsy and search for organisms 
and typical histology. In retinochoroiditis, funduscopic 
examination shows vitreous inflammatory reaction, white 
retinal lesions, and pigmented scars. Diagnosis of other 
clinical entities in immunocompromised individuals is 
generally based on histology.
 
»
Treatment
A. Approach to Treatment
Therapy is generally not necessary in immunocompetent 
persons, since primary illness is self-limited. However, for 
severe, persistent, or visceral disease, treatment for 2–4 weeks 
may be considered. Treatment is appropriate for primary 
infection during pregnancy because the risk of fetal trans
-
mission or the severity of congenital disease may be reduced. 
For retinochoroiditis, most episodes are self-limited, and 
opinions vary on indications for treatment. Treatment is 
often advocated for episodes with decreases in visual acuity, 
multiple or large lesions, macular lesions, significant inflam
-
mation, or persistence for over a month. Immunocompro
-
mised patients with active infection must be treated. For 
those with transient immunodeficiency, therapy can be con
-
tinued for 4–6 weeks after cessation of symptoms. For those 
with persistent immunodeficiency, such as AIDS patients, 
full therapy for 4–6 weeks is followed by maintenance ther
-
apy with lower doses of drugs. Immunodeficient patients 
who are asymptomatic but have a positive IgG serologic test 
should receive long-term chemoprophylaxis.
Drugs for toxoplasmosis are active only against tachyzoites, 
so they do not eradicate infection. Standard therapy is the 
combination of pyrimethamine (200-mg loading dose, 
then 50–75 mg [1 mg/kg] orally once daily) plus sulfadia
-
zine (1–1.5 g orally four times daily), with folinic acid

-
zine (1–1.5 g orally four times daily), with folinic acid 
(10–20 mg orally once daily) to prevent bone marrow sup
-
pression. Patients should be screened for a history of sul
-
fonamide sensitivity (skin rashes, gastrointestinal 
symptoms, hepatotoxicity). To prevent crystal-induced 
nephrotoxicity, good urinary output should be maintained. 
Pyrimethamine side effects include headache and gastroin
-
testinal symptoms. Even with folinic acid therapy, bone 
marrow suppression may occur; platelet and white blood 
cell counts should be monitored at least weekly. A first-line 
alternative is clindamycin (600 mg orally four times daily) 
replacing sulfadiazine as the standard therapy regimen. 
Another alternative is replacement of sulfadiazine with 
TMP-SMZ. Pyrimethamine is not used during the first 
trimester of pregnancy due to its teratogenicity. Standard 
therapy for acute toxoplasmosis during pregnancy is spira
-
mycin (1 g orally three times daily until delivery) to 
decrease the risk of fetal infection; it reduces the frequency 
of transmission to the fetus by about 60%. Spiramycin does 
not cross the placenta, so when fetal infection is docu
-
mented or for acute infections late in pregnancy (which 
commonly lead to fetal transmission) treatment with com
-
bination regimens as described above is indicated.
 
»
Prevention of primary infection centers on avoidance of 
undercooked meat or contact with material contaminated 
by cat feces, particularly for seronegative pregnant women 
and immunocompromised persons. Irradiation, cooking to 
66
°
C, or freezing to –20
°
C kills tissue cysts. Thorough 
cleaning of hands and surfaces is needed after contact with 
raw meat or areas contaminated by cats. Oocysts passed in 
cat feces can remain infective for a year or more, but fresh 
oocysts are not infective for 48 hours. For best protection, 
litter boxes should be changed daily and soaked in boiling 
water for 5 minutes, gloves should be worn when garden
-
ing, fruits and vegetables should be thoroughly washed, 
and ingestion of dried meat should be avoided.
Universal screening of pregnant women for 
T gondii
 
antibodies is conducted in some countries but not the 
United States. Pregnant women should ideally have their 
serum examined for IgG and IgM antibody, and those with 
negative titers should adhere to the prevention measures 
described above. Seronegative women who continue to 
have environmental exposure should undergo repeat sero
-
logic screening several times during pregnancy.
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For immunocompromised individuals, chemoprophy
-
laxis to prevent primary or reactivated infection is war
-
ranted. For hematopoietic cell transplant recipients and 
advanced AIDS patients, chemoprophylaxis with TMP-
SMZ (one double-strength tablet daily or two tablets three 
times weekly), used for protection against 
, is 
effective against 
T gondii
. Alternatives are pyrimethamine 
plus either sulfadoxine or dapsone (various regimens). In 
AIDS patients, chemoprophylaxis can be discontinued if 
antiretroviral therapy leads to immune reconstitution.
Gajurel K et al. 
 prophylaxis in haematopoietic cell 
transplant recipients: a review of the literature and recom
-
mendations. Curr Opin Infect Dis. 2015 Aug;28(4):283–92. 
[PMID: 26098500]
Jones JL et al. Neglected parasitic infections in the United States: 
toxoplasmosis. Am J Trop Med Hyg. 2014 May;90(5):794–9. 
[PMID: 24808246]
Pomares C et al. Laboratory diagnosis of congenital 
toxoplasmosis. J Clin Microbiol. 2016 Oct;54(10):2448–54. 
[PMID: 27147724]
AMEBIASIS
 
»
Organisms or antigen present in stools or abscess 
aspirate.
 
»
Positive serologic tests with colitis or hepatic 
abscess, but these may represent prior infections.
 
»
Mild to moderate colitis with recurrent diarrhea.
 
»
Severe colitis including bloody diarrhea, fever, and 
abdominal pain, with potential progression to 
hemorrhage or perforation.
 
»
Hepatic abscess with fever, hepatomegaly, and 
abdominal pain.
 
»
The 
Entamoeba
 complex contains three morphologically 
identical species: 
Entamoeba dispar
 and 
Entamoeba mosh
-
kovskii
, which are avirulent, and 
, which 
may be an avirulent intestinal commensal or lead to serious 
disease. Disease follows penetration of the intestinal wall, 
resulting in diarrhea, and with severe involvement, dysentery 
or extraintestinal disease, most commonly liver abscess.
 infections are present worldwide but are 
most prevalent in subtropical and tropical areas under 
conditions of crowding, poor sanitation, and poor nutri
-
tion. Of the estimated 500 million persons worldwide 
Entamoeba
, most are infected with 
E dispar
 
and an estimated 10% with 
. The prevalence 
 
of 
E moshkovskii
 is unknown. Mortality from invasive 
 
 infections is estimated at 100,000 per year.
Humans are the only established 
 host. Trans
-
mission occurs through ingestion of cysts from fecally con
-
taminated food or water, facilitated by person-to-person 
spread, flies and other arthropods as mechanical vectors, and 
use of human excrement as fertilizer. Urban outbreaks have 
occurred because of common-source water contamination.
 
»
1. Intestinal amebiasis—
In most infected persons, the 
organism lives as a commensal, and the carrier is without 
symptoms. With symptomatic disease, diarrhea may begin 
within a week of infection, although an incubation period of 
2–4 weeks is more common, with gradual onset of abdominal 
pain and diarrhea. Fever is uncommon. Periods of remission 
and recurrence may last days to weeks or longer. Abdominal 
examination may show distention, tenderness, hyperperistalsis, 
and hepatomegaly. Microscopic hematochezia is common. 
More severe presentations include colitis and dysentery, with 
more extensive diarrhea (10–20 stools per day) and bloody 
stools. With dysentery, physical findings include high fevers, 
prostration, vomiting, abdominal pain and tenderness, 
hepatic enlargement, and hypotension. Severe presentations 
are more common in young children, pregnant women, 
those who are malnourished, and those receiving corticoste
-
roids. Thus, in endemic regions, corticosteroids should not 
be started for presumed inflammatory bowel disease without 
first ruling out amebiasis. Fulminant amebic colitis can prog
-

-
-
ress to necrotizing colitis, intestinal perforation, mucosal 
sloughing, and severe hemorrhage, with mortality rates over 
40%. More chronic complications of intestinal amebiasis 
include chronic diarrhea with weight loss, which may last for 
months to years; bowel ulcerations; and amebic appendicitis. 
Localized granulomatous lesions (amebomas) can present 
after either dysentery or chronic intestinal infection. Clinical 
findings include pain, obstructive symptoms, and hemor
-
rhage and may suggest intestinal carcinoma.
2. Extraintestinal amebiasis—
The most common extrain
-
testinal manifestation is amebic liver abscess. This can 
occur with colitis, but more frequently presents without 
history of prior intestinal symptoms. Patients present with 
the acute or gradual onset of abdominal pain, fever, an 
enlarged and tender liver, anorexia, and weight loss. 
Diarrhea is present in a small number of patients. Physical 
examination may show intercostal tenderness. Abscesses 
are most commonly single and in the right lobe of the liver, 
and they are much more common in men. Without prompt 
treatment, amebic abscesses may rupture into the pleural, 
peritoneal, or pericardial space, which is often fatal. 
Amebic infections may rarely occur throughout the body, 
including the lungs, brain, and genitourinary system.
Laboratory studies with intestinal amebiasis show leukocy
-
tosis and hematochezia, with fecal leukocytes not present 
in all cases. With extraintestinal amebiasis, leukocytosis 
and elevated liver function studies are seen.
C. Diagnostic Testing
Diagnosis is by finding 
 or its antigen or by 
serologic tests. However, each method has limitations.
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Diagnosis is most commonly 
made by identifying organisms in the stool. 
 and 
E dispar
 cannot be distinguished, but the identification of 
amebic trophozoites or cysts in a symptomatic patient is 
highly suggestive of amebiasis. Stool evaluation for organisms 
is not highly sensitive (
∼
30–50% for amebic colitis), and at 
least three stool specimens should be evaluated after concen
-
tration and staining. Multiple serologic assays are available; 
these tests are fairly sensitive, although sensitivity is lower 
(
∼
70% in colitis) early in illness, and they cannot distinguish 
recent and old disease, as they remain positive for years after 
infection. A commercially available stool antigen test 
(TechLab II) offers improved sensitivity (more than 90% for 
colitis); it requires fresh or frozen (not preserved) stool speci
-
mens. PCR-based tests are available but not used routinely. 
Colonoscopy of uncleansed bowel typically shows no specific 
findings in mild intestinal disease; in severe disease, ulcers 
may be found with intact intervening friable mucosa, resem
-
bling inflammatory bowel disease (Figure 35–7). Examina
-
tion of fresh ulcer exudate for motile trophozoites and for 
 
 antigen may yield a diagnosis.
2. Hepatic abscess—
Serologic tests for anti-amebic anti
-
bodies are almost always positive, except very early in the 
infection. Thus, a negative test in a suspicious case should 
 
be repeated in about a week. The TechLab II antigen test can 
be used to test serum, with good sensitivity if used before the 
initiation of therapy. Examination of stools for organisms or 
antigen is frequently negative; the antigen test is positive in 
∼
40% of cases. As imaging studies cannot distinguish ame
-
bic and pyogenic abscesses, when a diagnosis is not available 
from serologic studies, percutaneous aspiration may be 
indicated, ideally with an image-guided needle. Aspiration 
typically yields brown or yellow fluid. Detection of organisms 
in the aspirate is uncommon, but detection of 
 
antigen is very sensitive and diagnostic. The key risk of aspi
-
ration is peritoneal spillage leading to peritonitis from ame
-
bas or other (pyogenic or echinococcal) organisms.
D. Imaging
Liver abscesses can be identified by ultrasonography, CT, 
or MRI, typically with round or oval low-density 
nonhomogeneous lesions, with abrupt transition from 
normal liver to the lesion, and hypoechoic centers. 
Abscesses are most commonly single, but more than one 
may be present. The right lobe is usually involved.
 
»
Treatment
Treatment of amebiasis generally entails the use of metro
-
nidazole or tinidazole to eradicate tissue trophozoites and 
a luminal amebicide to eradicate intestinal cysts 
(Table 35–6). Asymptomatic infection with 
E dispar
 does 
not require therapy. This organism cannot be differentiated 
morphologically from 
, but with negative serol
-
ogy 
E dispar
 colonization is likely, and treatment is not 
indicated. Colonization with 
 is generally 
treated with a luminal agent. Effective luminal agents are 
diloxanide furoate (500 mg orally three times daily with 
meals for 10 days), iodoquinol (diiodohydroxyquin; 650 mg 
orally three times daily for 21 days), and paromomycin 
(30-mg/kg base orally, maximum 3 g, in three divided 
doses after meals daily for 7 days). Side effects associated 
with luminal agents are flatulence with diloxanide furoate, 
mild diarrhea with iodoquinol, and gastrointestinal symp
-
toms with paromomycin. Relative contraindications are 
thyroid disease for iodoquinol and kidney disease for iodo
-
quinol or paromomycin.
Treatment of intestinal amebiasis requires tinidazole 
(2 g orally once daily for 3 days for mild disease and 5 days 
for serious disease) or metronidazole (750 mg orally three 
times daily for 10 days) plus a luminal agent (Table 35–6).

times daily for 10 days) plus a luminal agent (Table 35–6). 
Tinidazole offers simpler dosing and fewer side effects than 
metronidazole whose side effects include transient nausea, 
vomiting, epigastric discomfort, headache, or a metallic 
taste. A disulfiram-like reaction may occur if alcohol is 
coingested. Metronidazole should be avoided in pregnant 
or nursing mothers if possible. The same toxicities and 
concerns probably apply for tinidazole, although it appears 
to be better tolerated. Fluid and electrolyte replacement is 
also important for patients with significant diarrhea. Surgi
-
cal management of acute complications of intestinal ame
-
biasis is best avoided whenever possible. Successful therapy 
of severe amebic colitis may be followed by postdysenteric 
colitis, with continued diarrhea without persistent infec
-
tion; this syndrome generally resolves in weeks to months.
Alternatives for the treatment of intestinal amebiasis are 
tetracycline (250–500 mg orally four times daily for 
 
10 days) plus chloroquine (500 mg orally daily for 7 days). 
Emetine or dehydroemetine, which are not available in the 
United States, can be given subcutaneously or intramuscu
-
larly in a dose of 1–1.5 mg/kg/day; the maximum daily 
dose is 90 mg for dehydroemetine and 65 mg for emetine). 
These agents are effective but cardiotoxic with a narrow 
therapeutic range and should be used only until severe 
disease is controlled. They cause nausea, vomiting, and 
pain at the injection site.
Amebic liver abscess is also treated with metronidazole 
or tinidazole plus a luminal agent (even if intestinal infec
-
tion is not documented; Table 35–6). Metronidazole can be 
used intravenously when necessary. With failure of initial 
response to metronidazole or tinidazole, chloroquine, 
 
▲
Figure 35–7.
 
Gross pathology showing intestinal 
ulcers due to amebiasis. 
(From Dr. Mae Melvin, Public 
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emetine or dehydroemetine may be added. Needle aspira
-
tion may be helpful for large abscesses (over 5–10 cm), in 
particular if the diagnosis remains uncertain, if there is an 
initial lack of response, or if a patient is very ill, suggesting 
imminent abscess rupture. With successful therapy, 
abscesses disappear slowly (over months).
 
»
Prevention requires safe water supplies; sanitary disposal of 
human feces; adequate cooking of food; protection of food 
from fly contamination; hand washing; and, in endemic 
areas, avoidance of fruits and vegetables that cannot be 
cooked or peeled. Water supplies can be boiled, treated 
with iodine (0.5-mL tincture of iodine per liter for 20 minutes; 
cysts are resistant to standard concentrations of chlorine), 
or filtered.
Gonzales ML et al. Antiamoebic drugs for treating amoebic 
colitis. Cochrane Database Syst Rev. 2009 Apr 15; (2): 
CD006085. [PMID: 19370624]
Wright SG. Protozoan infections of the gastrointestinal tract. 
Infect Dis Clin North Am. 2012 Jun;26(2):323–39. [PMID: 
22632642]
COCCIDIOSIS (
Cryptosporidiosis, 
 
Isosporiasis, Cyclosporiasis, Sarcocystosis
) & 
MICROSPORIDIOSIS
 
»
Acute diarrhea, especially in children in develop
-
ing countries.
 
»
Outbreaks of diarrhea secondary to contaminated 
water or food.
 
»
Prolonged diarrhea in immunocompromised 
persons.
 
»
Diagnosis mostly by identifying organisms in 
specially stained stool specimens.
 
»
The causes of coccidiosis are 
 species 
(
C parvum, C hominis,
 and others); 
Isospora belli; Cyclospora 
cayetanensis;
 and 
Sarcocystis
 species. Microsporidiosis is 
caused by at least 14 species, most commonly 
Enterocytozoon 
Table 35–6.
 
Treatment of amebiasis.
1
Drugs of Choice and Adult Dosage
Alternative Drugs and Adult Dosage
Asymptomatic intestinal 
infection
Luminal agent:
 Diloxanide furoate,
2
 500 mg orally three 
times daily for 10 days
or–
Iodoquinol, 650 mg orally three times daily for 21 days
or–
Paromomycin, 10 mg/kg orally three times daily for 7 days
 
Mild to moderate 
 
intestinal infection
Metronidazole, 750 mg orally three times daily (or 500 mg 
intravenously every 6 hours) for 10 days
or–
Tinidazole, 2 g orally daily for 3 days
plus–
Luminal agent (see above)
plus either–
Tetracycline, 250 mg orally three times daily for 
10 days
or–
Erythromycin, 500 mg orally four times daily for 
10 days
Severe intestinal infection
or–
plus–
10 days
or–
Dehydroemetine
2
 or emetine,
2
 1 mg/kg subcuta
-
neously or intramuscularly for 3–5 days
Hepatic abscess, 
 
ameboma, and other 
extraintestinal disease
or–
plus–
2
2
-
neously or intramuscularly for 8–10 days, 
 
followed by (liver abscess only) chloroquine, 
500 mg orally twice daily for 2 days, then 
 
500 mg daily for 21 days
plus–
1
See text for additional details and cautions.
2
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bieneusi
 and 
Encephalitozoon intestinalis
. These infections 
occur worldwide, particularly in the tropics and in regions 
where hygiene is poor. They are causes of endemic child
-
hood gastroenteritis (particularly in malnourished chil
-
dren in developing countries); institutional and community 
outbreaks of diarrhea; traveler’s diarrhea; and acute and 
chronic diarrhea in immunosuppressed patients, in par
-
ticular those with AIDS. They are all notable for the poten
-
tial to cause prolonged diarrhea, often lasting for a number 
of weeks. Clustering occurs in households, day care cen
-
ters, and among sexual partners.
The infectious agents are oocysts (coccidiosis) or spores 
(microsporidiosis) transmitted from person to person or 
by contaminated drinking or swimming water or food. 
Ingested oocysts release sporozoites that invade and multi
-
ply in enterocytes, primarily in the small bowel. Coccidian 
oocysts and microsporidian cysts can remain viable in the 
environment for years.
I belli
 and 
C cayetanensis
 appear to infect only humans. 
 has caused a number of food-borne out
-
breaks in the United States in recent years, most commonly 
associated with imported fresh produce. 
 infects 
many species; humans are intermediate hosts (infected by 
ingestion of fecal sporocysts) for some species but defini
-
tive hosts for 
Sarcocystis bovihominis
 and 
Sarcocystis 
suihominis
 (infected by ingestion of tissue cysts in under
-
cooked beef and pork, respectively).
Cryptosporidiosis is a zoonosis 
(C parvum
 principally 
infects cattle), but most human infections are acquired 
from humans, in particular with 
C hominus
. Cryptospo
-
ridia are highly infectious and readily transmitted in day 
care settings and households. They have caused large com
-
munity outbreaks due to contaminated water supplies 
(causing 
∼
400,000 illnesses in Milwaukee in 1993) and are 
the leading cause of recreational water–associated out
-
breaks of gastroenteritis. In the developing world crypto
-
sporidiosis is a leading cause of childhood diarrhea. In a 
study of causes of moderate-to-severe diarrhea in Asia and 
Africa, 
 was the second most commonly 
identified pathogen in children under 2 years of age.
 
»
1. Cryptosporidiosis—
The incubation period appears to 
be 1–14 days. In developing countries, disease is primarily 
in children under 5 years of age, causing 5–10% of child
-
hood diarrhea. Presenting symptoms include acute watery 
diarrhea, abdominal pain, and cramps, with rapid resolu
-
tion in most patients; however, symptoms quite commonly 
persist for 2 weeks or more. In developed countries, most 
patients are adults. Diarrhea in immunocompetent indi
-
viduals typically lasts from 5 to 10 days. It is usually watery, 
with accompanying abdominal pain and cramps, nausea, 
vomiting, and fever. Relapses may follow initial resolution 
of symptoms. Mild illness and asymptomatic infection are 
also common.
Cryptosporidiosis is a well-characterized cause of diar
-
rhea in those with AIDS. It was common before the advent 
of highly active antiretroviral therapy, particularly with 
advanced immunosuppression. Clinical manifestations are 
variable, but patients commonly have chronic diarrhea 
with frequent foul smelling stools, malabsorption, and 
weight loss. Severe, life-threatening watery diarrhea may 
be seen. Cryptosporidiosis also causes extraintestinal dis
-
ease with AIDS, including pulmonary infiltrates with dys
-
pnea and biliary tract infection with sclerosing cholangitis 
and AIDS cholangiopathy.
2. Isosporiasis—
The incubation period for 
I belli
 is about 
1 week. In immunocompetent persons, it usually causes a 
self-limited watery diarrhea lasting 2–3 weeks, with 
abdominal cramps, anorexia, malaise, and weight loss. 
Fever is unusual. Chronic symptoms may persist for

Fever is unusual. Chronic symptoms may persist for 
months. In immunocompromised patients, isosporiasis 
more commonly causes severe and chronic diarrhea, with 
complications including marked dehydration, malnutri
-
tion, and hemorrhagic colitis. Extraintestinal disease has 
been reported rarely.
3. Cyclosporiasis—
 oocysts must undergo a 
period of sporulation of 7 days or more after shedding 
before they become infectious. Therefore, person-to-
person spread is unlikely, and spread has typically been due 
to contaminated food (especially fresh produce) and water. 
The incubation period is 1–11 days. Infections can be 
asymptomatic. Cyclosporiasis causes an illness similar to 
that described for the other pathogens described in this 
section, with watery diarrhea, abdominal cramps, nausea, 
fatigue, and anorexia. Fever is seen in 25% of cases. Symp
-
toms typically continue for 2 weeks or longer and may 
persist for months. Relapses of diarrhea are common. Diar
-
rhea may be preceded by a flu-like prodrome and followed 
by persistent fatigue. In immunocompromised patients, 
cyclosporiasis is typically more severe and prolonged, with 
chronic fulminant watery diarrhea and weight loss.
4. Sarcocystosis—
 infection may be common in 
some developing countries, but it is usually asymptomatic. 
Infection appears to most commonly follow the ingestion 
of undercooked beef or pork, leading to the development 
of cysts in muscle, with myalgias, fever, bronchospasm, 
pruritic rash, lymphadenopathy, and subcutaneous nod
-
ules. Ingestion of fecal sporocysts may lead to gastrointes
-
tinal symptoms.
5. Microsporidiosis—
Microsporidia are obligate intracel
-
lular protozoans that cause a wide spectrum of diseases. 
Many infections are of zoonotic origin, but human-to-
human transmission has been documented. Infection is 
mainly by ingestion of spores, but also by direct inocula
-
tion of the eyes. In immunocompetent hosts, microsporid
-
ian infections most commonly present as self-limited 
diarrhea. Ocular infections have also been described. Dis
-
ease from microsporidia is seen mainly in immunocom
-
promised persons, particularly those with AIDS. Infections 
in AIDS patients are most commonly with 
E bieneusi
 and 
E intestinalis
. They cause chronic diarrhea, with anorexia, 
bloating, weight loss, and wasting, especially in those with 
advanced immunodeficiency. Fever is usually not seen. 
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Other illnesses in immunocompromised persons associ
-
ated with microsporidians (including the genera 
Enterocy
-
tozoon, Encephalitozoon, Brachiola, Vittaforma, 
Pleistophora, Trachipleistophora
, and 
Microsporidium
) 
include biliary tract disease (AIDS cholangiopathy), geni
-
tourinary infection with cystitis, kidney disease, hepatitis, 
peritonitis, myositis, respiratory infections including 
sinusitis, central nervous system infections including 
granulomatous encephalitis, and disseminated infections. 
Ocular infections with 
Encephalitozoon
 species cause 
conjunctivitis and keratitis, presenting as redness, photo
-
phobia, and loss of visual acuity.
Typically, stool is without blood or 
leukocytes. Diagnosis is traditionally made by detecting 
the organism in stool using a modified acid-fast stain; 
this technique is relatively insensitive, and multiple 
specimens should be evaluated before ruling out the 
diagnosis. Of note, routine evaluation for ova and para
-
sites typically does not include a modified acid-fast stain, 
so this must be specifically requested in many laborato
-
ries. Various antigen detection methods, including 
immunofluorescence microscopy, ELISA, and immuno
-
chromatography, offer improved sensitivity and specific
-
ity, both over 90% with available assays, and these 
methods may be considered the optimal means of diag
-
nosis. Molecular diagnostic panels that recognize 
Cryp
-
tosporidium
 and other enteropathogens in stool are 
available but expensive.
Diagnosis of isosporiasis is by examina
-
tion of stool wet mounts or after modified acid-fast stain
-
ing, in which the organism is clearly distinguishable from 
other parasites. Other stains also show the organism. Shed
-
ding of oocysts may be intermittent, so the sensitivity of 
stool evaluation is not high, and multiple samples should 
be examined. The organism may also be identified in duo
-
denal aspirates or small bowel biopsies.
Diagnosis is made by examination of 
stool wet mounts or after modified acid-fast staining. Mul
-
tiple specimens may need to be examined to make a diag
-
nosis. The organism can also be identified in small bowel 
aspirates or biopsy specimens.
Eosinophilia and elevated creatine 
kinase may be seen. Diagnosis is by identification of the 
acid-fast organisms in stool or by identification of tropho
-
zoites or bradyzoites in tissue biopsies.
Diagnosis can be made by identifica
-
tion of organisms in specially stained stool, fluid, or tissue 
specimens, for example with Weber chromotrope-based 
stain. Electron microscopy is helpful for confirmation of 
the diagnosis and speciation. PCR and culture techniques 
are available but not used routinely.
 
»
Treatment
Most acute infections with these pathogens in immuno
-
competent persons are self-limited and do not require 
treatment. Supportive treatment for severe or chronic diar
-
rhea includes fluid and electrolyte replacement and, in 
some cases, parenteral nutrition.
Treatment of cryptosporidiosis is 
challenging. No agent is clearly effective. Modest bene
-
fits have been seen in some (but not other) studies with 
paromomycin, a nonabsorbed aminoglycoside (25–35 
mg/kg orally for 14 days has been used), and nitazoxanide 
(500 mg–1 g orally twice daily for 3 days in nonimmu
-
nocompromised and 2–8 weeks in advanced AIDS 
patients), which is approved in the United States for 
 
this indication. Other agents that have been used with 
mixed success in AIDS patients with cryptosporidiosis 
include azithromycin, spiramycin, bovine hyperimmune 
colostrum, and octreotide. Reversing immunodeficiency 
with effective antiretroviral therapy is of greatest 
importance.
Isosporiasis is effectively treated in immu
-
nocompetent and immunosuppressed persons with TMP-

-
SMZ (160 mg/800 mg orally two to four times daily for 
 
10 days, with the higher dosage for patients with AIDS). 
An alternative therapy is pyrimethamine (75 mg orally in 
four divided doses) with folinic acid (10–25 mg/day 
orally). Maintenance therapy with low-dose TMP-SMZ 
(160 mg/800 mg daily or three times per week) or Fansidar 
(1 tablet weekly) prevents relapse in those with persistent 
Cyclosporiasis is also treated with 
TMP-SMZ (dosing as for isosporiasis). With AIDS, long-
term maintenance therapy (160 mg/ 800 mg three times 
weekly) helps prevent relapse. For patients intolerant of 
TMP-SMZ, ciprofloxacin (500 mg orally twice daily for 
 
7 days) showed efficacy, albeit with less ability to clear the 
organism than TMP-SMZ.
For sarcocystosis, no specific treatment 
is established, but patients may respond to therapy with 
albendazole or TMP-SMZ.
Treatment of microsporidiosis is 
complex. Infections with most species, including those 
causing gastrointestinal and other manifestations, should 
be treated with albendazole (400 mg orally twice daily for 
2–4 weeks), which has activity against a number of species, 
but relatively poor efficacy (about 50%) against 
E bieneusi
, 
the most common microsporidial cause of diarrhea in 
AIDS patients. Fumagillin, which is used to treat honey
-
bees and fish with microsporidian infections, has shown 
benefit in clinical trials at a dose of 20 mg three times per 
day for 14 days; treatment was accompanied by reversible 
thrombocytopenia. As with cryptosporidiosis, the best 
means of controlling microsporidiosis in AIDS patients is 
to restore immune function with effective antiretroviral 
therapy. Ocular microsporidiosis can be treated with fuma
-
gillin solution (3 mg/mL); this probably should be given 
with concurrent systemic therapy with albendazole. 
Adjunctive management may include corticosteroids to 
decrease inflammation and keratoplasty.
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»
Water purification is important for control of these infec
-
tions. Chlorine disinfection is not effective against crypto
-
sporidial oocysts, so other purification measures are 
needed. Immunocompromised patients should boil or fil
-
ter drinking water and should consider avoidance of lakes 
and swimming pools. Routine precautions (hand washing, 
gloves, disinfection) should prevent institutional patient-
to-patient spread. Optimal means of preventing microspo
-
ridial infections are not well understood, but water 
purification and body substance precautions for immuno
-
compromised and hospitalized individuals are likely 
effective.
Checkley W et al. A review of the global burden, novel diagnos
-
tics, therapeutics, and vaccine targets for cryptosporidium. 
Lancet Infect Dis. 2015 Jan;15(1):85–94. [PMID: 25278220]
GIARDIASIS
 
»
Acute diarrhea may be profuse and watery.
 
»
Chronic diarrhea with greasy, malodorous stools.
 
»
Abdominal cramps, distention, flatulence, and 
malaise.
 
»
Cysts or trophozoites in stools.
 
»
Giardiasis is a protozoal infection of the upper small intes
-
tine caused by the flagellate 
 (also called 
Giardia intestinalis
 and 
Giardia duodenalis
). The parasite 
occurs worldwide, most abundantly in areas with poor sani
-
tation. In developing countries, young children are very 
commonly infected. In the United States and Europe, the 
infection is the most common intestinal protozoal pathogen; 
the US estimate is 100,000 to 2.5 million new infections lead
-
ing to 5000 hospital admissions yearly. Groups at special risk 
include travelers to 
Giardia
-endemic areas, those who swal
-
low contaminated water during recreation or wilderness 
travel, men who have sex with men, and persons with 
impaired immunity. Outbreaks are common in households, 
children’s day care centers, and residential facilities, and may 
occur as a result of contamination of water supplies.
The organism occurs in feces as a flagellated trophozo
-
ite and as a cyst. Only the cyst form is infectious by the oral 
route; trophozoites are destroyed by gastric acidity. Humans 
are a reservoir for the pathogen; dogs, cats, beavers, and 
other mammals have been implicated but not confirmed as 
reservoirs. Under suitable moist, cool conditions, cysts can 
survive in the environment for weeks to months. Cysts are 
transmitted as a result of fecal contamination of water or 
food, by person-to-person contact, or by anal-oral sexual 
contact. The infectious dose is low, requiring as few as ten 
cysts. After the cysts are ingested, trophozoites emerge in 
the duodenum and jejunum. Epithelial damage and muco
-
sal invasion are uncommon. Hypogammaglobulinemia, 
low secretory IgA levels in the gut, achlorhydria, and mal
-
nutrition favor the development of infection.
 
»
It is estimated that about 50% of infected persons have no 
discernable infection, about 10% become asymptomatic 
cyst passers, and 25–50% develop an acute diarrheal syn
-
drome. Acute diarrhea may clear spontaneously but is 
commonly followed by chronic diarrhea. The incubation 
period is usually 1–3 weeks but may be longer. The illness 
may begin gradually or suddenly. Cysts may not be 
detected in the stool at the onset of the illness. The acute 
phase may last days or weeks, and is usually self-limited, 
although cyst excretion may be prolonged. The initial ill
-
ness may include profuse watery diarrhea, and hospitaliza
-
tion may be required due to dehydration, particularly in 
young children. Typical symptoms of chronic disease are 
abdominal cramps, bloating, flatulence, nausea, malaise, 
and anorexia. Fever and vomiting are uncommon. Diar
-
rhea is usually not severe in the chronic stage of infection; 
stools are greasy or frothy and foul smelling, without

-
stools are greasy or frothy and foul smelling, without 
blood, pus, or mucus. The diarrhea may be daily or recur
-
rent; intervening periods may include constipation. Symp
-
toms can persist for weeks to months. Weight loss is 
frequent. Chronic disease can include malabsorption, 
including fat and protein-losing enteropathy and vitamin 
Most patients seek medical attention after having been ill 
for over a week, commonly with weight loss of 5 kg or 
more. Stool is generally without blood or leukocytes. 
Diagnosis is traditionally made by the identification of 
trophozoites or cysts in stool. A wet mount of liquid stool 
may identify motile trophozoites. Stained fixed specimens 
may show cysts or trophozoites. Sensitivity of stool analy
-
sis is not ideal, estimated at 50–80% for a single specimen 
and over 90% for three specimens. Sampling of duodenal 
contents with a string test or biopsy is no longer generally 
recommended, but biopsies may be helpful in very ill or 
immunocompromised patients. When giardiasis is sus
-
pected, antigen assays are simpler and cheaper than 
repeated stool examinations, but these tests will not iden
-
tify other stool pathogens. Multiple tests, which identify 
antigens of trophozoites or cysts, are available. They are 
generally quite sensitive (85–98%) and specific (90–100%). 
Molecular diagnostic panels that recognize 
Giardia
 and 
other enteropathogens in stool are available but 
expensive.
 
»
Treatment
The treatments of choice for giardiasis are metronidazole 
(250 mg orally three times daily for 5–7 days) or tinida
-
zole (2 g orally once). The drugs are not universally 
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effective; cure rates for single courses are typically about 
80–95%. Toxicities are as described for treatment of 
amebiasis, but the lower dosages used for giardiasis limit 
side effects. Albendazole (400 mg orally once daily for 
 
5 days) and nitazoxanide (500 mg orally twice daily for 
 
3 days) both appear to have similar efficacy and fewer 
side effects compared with metronidazole, although data 
are limited, and a recent meta-analysis suggested superi
-
ority in efficacy of tinidazole over albendazole. 
Nitazoxanide is generally well tolerated but may cause 
mild gastrointestinal side effects. Other drugs with activ
-
ity against 
Giardia
 include furazolidone (100 mg orally 
four times a day for 7 days), which is about as effective as 
the other named drugs but causes gastrointestinal side 
effects, and paromomycin (500 mg orally three times a 
day for 7 days), which appears to have somewhat lower 
efficacy but unlike metronidazole, tinidazole, and fura
-
zolidone is safe in pregnancy. Symptomatic giardiasis 
should always be treated. Treatment of asymptomatic 
patients should be considered, since they can transmit the 
infection. With a suggestive presentation but negative 
diagnostic studies, an empiric course of treatment may be 
appropriate. Household or day care contacts with an 
index case should be tested and treated if infected.
 
»
Community chlorination (0.4 mg/L) of water is relatively 
ineffective for inactivating cysts, so filtration is required. 
For wilderness or international travelers, bringing water 
to a boil for 1 minute or filtration with a pore size less 
than 1 mcm are adequate. In day care centers, appropriate 
disposal of diapers and frequent hand washing are 
essential.
Escobedo AA et al. A meta-analysis of the efficacy of albenda
-
zole compared with tinidazole as treatments for 
Giardia
 infec
-
tions in children. Acta Trop. 2016 Jan;153:120–7. [PMID: 
26476393]
Watkins RR et al. Treatment of giardiasis: current status and 
future directions. Curr Infect Dis Rep. 2014 Feb;16(2):396. 
[PMID: 24493628]
TRICHOMONIASIS
 
»
Women:
 copious vaginal discharge.
 
»
Men:
 nongonococcal urethritis.
 
»
Motile trichomonads on wet mounts.
 
»
Trichomoniasis is caused by the protozoan 
vaginalis
 and is among the most common sexually trans
-
mitted diseases, causing vaginitis in women and 
nongonococcal urethritis in men. It can also occasionally 
be acquired by other means, since it can survive in moist 
environments for several hours.
 
»
 is often harbored asymptomatically. For women 
with symptomatic disease, after an incubation period of 
 
5 days to 4 weeks, a vaginal discharge develops, often with 
vulvovaginal discomfort, pruritus, dysuria, dyspareunia, or 
abdominal pain. Examination shows a copious discharge, 
which is usually not foul smelling but is often frothy and 
yellow or green in color. Inflammation of the vaginal walls 
and cervix with punctate hemorrhages are common. Most 
men infected with 
 are asymptomatic, but it can 
be isolated from about 10% of men with nongonococcal 
urethritis. In men with trichomonal urethritis, the urethral 
discharge is generally more scanty than with other causes 
of urethritis.
Diagnosis is traditionally made by identifying the organ
-
ism in vaginal or urethral secretions. Examination of wet 
mounts will show motile organisms. Tests for bacterial 
vaginosis (pH > 4.5, fishy odor after addition of potassium 
hydroxide) are often positive with trichomoniasis. Newer 
point-of-care antigen detection and nucleic acid probe 
hybridization tests and nucleic acid amplification assays 
offer improved sensitivity compared to wet mount micros
-
copy and excellent specificity.
 
»
Treatment
The treatment of choice is tinidazole or metronidazole,

-
 
»
Treatment
The treatment of choice is tinidazole or metronidazole, 
each as a 2 g single oral dose. Tinidazole may be better 
tolerated and active against some resistant parasites. Tox
-
icities of these drugs are discussed in the section on amebi
-
asis. If the large single dose cannot be tolerated, an 
alternative metronidazole dosage is 500 mg orally twice 
daily for 1 week. A meta-analysis suggested that multiple 
dose regimens offer improved efficacy, although this is not 
standard. All infected persons should be treated, even if 
asymptomatic, to prevent subsequent symptomatic disease 
and limit spread. Treatment failure suggests reinfection, 
but metronidazole-resistant organisms have been reported. 
These may be treated with tinidazole, longer courses of 
metronidazole, intravaginal paromomycin, or other exper
-
imental therapies (see Chapter 18).
Howe K et al. Single-dose compared with multidose metronida
-
zole for the treatment of trichomoniasis in women: a meta-
analysis. Sex Transm Dis. 2017 Jan;44(1):29–34. [PMID: 
27898571]
Meites E et al. A review of evidence-based care of symptomatic 
trichomoniasis and asymptomatic 
 
infections. Clin Infect Dis. 2015 Dec 15;61(Suppl 8):S837–48. 
[PMID: 26602621]
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º
HELMINTHIC INFECTIONS
TREMATODE (FLUKE) INFECTIONS
SCHISTOSOMIASIS (
Bilharziasis
)
 
»
History of freshwater exposure in an endemic 
area.
 
»
Acute schistosomiasis:
 fever, headache, myalgias, 
cough, urticaria, diarrhea, and eosinophilia.
 
»
Intestinal schistosomiasis:
 abdominal pain, diar
-
rhea, and hepatomegaly, progressing to anorexia, 
weight loss, and features of portal hypertension.
 
»
Urinary schistosomiasis:
 hematuria and dysuria, 
progressing to hydronephrosis and urinary 
 
»
Diagnosis:
 characteristic eggs in feces or urine; 
biopsy of rectal or bladder mucosa; positive 
serology.
 
»
Schistosomiasis, which affects more than 200 million per
-
sons worldwide, leads to severe consequences in 20 million 
persons and about 100,000 deaths annually. The disease is 
caused by six species of trematode blood flukes. Five spe
-
cies cause intestinal schistosomiasis, with infection of 
mesenteric venules: 
Schistosoma mansoni
, which is present 
in Africa, the Arabian peninsula, South America, and the 
Caribbean; 
Schistosoma japonicum
, which is endemic in 
China and Southeast Asia; 
Schistosoma mekongi
, which is 
endemic near the Mekong River in Southeast Asia; and 
Schistosoma intercalatum
 and 
Schistosoma guineensis
, 
which occur in parts of Africa. 
Schistosoma haematobium
 
causes urinary schistosomiasis, with infection of venules of 
the urinary tract, and is endemic in Africa and the Middle 
East. Transmission of schistosomiasis is focal, with greatest 
prevalence in poor rural areas. Control efforts have dimin
-
ished transmission significantly in many areas, but high 
level transmission remains common in sub-Saharan Africa 
and some other areas. Prevalence of infection and illness 
typically peaks at about 15–20 years of age.
Humans are infected with schistosomes after contact 
with freshwater containing cercariae released by infected 
snails. Infection is initiated by penetration of skin or 
mucous membranes. After penetration, schistosomulae 
migrate to the portal circulation, where they rapidly 
mature. After about 6 weeks, adult worms mate, and 
migrate to terminal mesenteric or bladder venules, where 
females deposit their eggs. Some eggs reach the lumen of 
the bowel or bladder and are passed with feces or urine, 
while others are retained in the bowel or bladder wall or 
transported in the circulation to other tissues, in particular 
the liver. Disease in endemic areas is primarily due to a 
host response to eggs, with granuloma formation and 
inflammation, eventually leading to fibrosis. Chronic 
infection can result in scarring of mesenteric or vesicular 
blood vessels, leading to portal hypertension and altera
-
tions in the urinary tract. In previously uninfected indi
-
viduals, such as travelers with freshwater contact in 
endemic regions, acute schistosomiasis may occur, with a 
febrile illness 2–8 weeks after infection.
 
»
1. Cercarial dermatitis—
Following cercarial penetration, 
localized erythema develops in some individuals, which can 
progress to a pruritic maculopapular rash that persists for 
some days. Dermatitis can be caused by human schisto
-
somes and, in nontropical areas, by bird schistosomes that 
cannot complete their life cycle in humans (swimmer’s itch).
2. Acute schistosomiasis (Katayama syndrome)—
A febrile illness may develop 2–8 weeks after exposure in 
persons without prior infection, most commonly after 
heavy infection with 
S mansoni
 or 
S japonicum
. Presenting 
symptoms and signs include acute onset of fever; headache; 
myalgias; cough; malaise; urticaria; diarrhea, which may be 
bloody; hepatosplenomegaly; lymphadenopathy; and pul
-
monary infiltrates. Localized lesions may occasionally cause 
severe manifestations, including CNS abnormalities and 
death. Acute schistosomiasis usually resolves in 2–8 weeks.

-
3. Chronic schistosomiasis—
Many infected persons have 
light infections and are asymptomatic, but an estimated 
50–60% have symptoms and 5–10% have advanced organ 
damage. Asymptomatic infected children may suffer from 
anemia and growth retardation. Symptomatic patients with 
intestinal schistosomiasis typically experience abdominal 
pain, fatigue, diarrhea, and hepatomegaly. Over years, 
anorexia, weight loss, weakness, colonic polyps, and fea
-
tures of portal hypertension develop. Late manifestations 
include hematemesis from esophageal varices, hepatic 
failure, and pulmonary hypertension. Urinary schistoso
-
miasis may present within months of infection with hema
-
turia and dysuria, most commonly in children and young 
adults. Fibrotic changes in the urinary tract can lead to 
hydroureter, hydronephrosis, bacterial urinary infections 
and, ultimately, kidney disease or bladder cancer.
Microscopic examination of stool or urine for eggs, evalua
-
tion of tissue, or serologic tests establish the diagnosis. Char
-
acteristic eggs can be identified on smears of stool or urine. 
The most widely used stool test is the Kato-Katz technique. 
Quantitative tests that yield more than 400 eggs per gram of 
feces or 10 mL of urine are indicative of heavy infections 
with increased risk of complications. Diagnosis can also be 
made by biopsy of the rectum, colon, liver, or bladder. Sero
-
logic tests include an ELISA available from the CDC that is 
99% specific for all species, but cannot distinguish acute and 
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past infection. Sensitivity of the test is 99% for 
S mansoni
, 
95% for 
S haematobium
, but less than 50% for 
. 
Serology is of limited use in endemic settings, but can be 
helpful in travelers from nonendemic regions. Point-of-care 
assays to detect circulating schistosome antigens in serum 
and urine are also available; the most widely used tests target 
circulating anodic and cathodic antigens. Antigen tests have 
better sensitivity than stool smears, especially for 
S mansoni
; 
sensitivity is lower for 
. Molecular tests for 
schistosomiasis have been developed but are not routinely 
used for diagnosis. In acute schistosomiasis, leukocytosis 
and marked eosinophilia may occur; serologic tests may 
become positive before eggs are seen in stool or urine. After 
therapy, eggs may be shed in stool or urine for months, and 
so the identification of eggs in fluids or tissue cannot distin
-
guish past or active disease. With a diagnosis of schistoso
-
miasis, evaluation for the extent of disease is warranted, 
including liver function studies and imaging of the liver with 
intestinal disease and ultrasound or other imaging studies of 
the urinary system in urinary disease.
 
»
Treatment
Treatment is indicated for all schistosome infections. In 
areas where recurrent infection is common, treatment is 
valuable in reducing worm burdens and limiting clinical 
complications. The drug of choice for schistosomiasis is 
praziquantel. The drug is administered for 1 day at an oral 
dose of 40 mg/kg (in one or two doses) for 
S mansoni, 
 
S haematobium, S intercalatum
, and 
S guineensis
and a dose of 60 mg/kg (in two or three doses) for 
 and 
S mekongi
. Cure rates are generally greater 
than 80% after a single treatment, and those not cured have 
marked reduction in the intensity of infection. Praziquantel 
is active against invading cercariae but not developing schis
-
tosomulae. Therefore, the drug may not prevent illness when 
given after exposure and, for recent infections, a repeat 
course after a few weeks may be appropriate. Praziquantel 
may be used during pregnancy. Resistance to praziquantel 
has been reported. Toxicities include abdominal pain, diar
-
rhea, urticaria, headache, nausea, vomiting, and fever, and 
may be due both to direct effects of the drug and responses 
to dying worms. Alternative therapies are oxamniquine for 
 
S mansoni
 infection and metrifonate for 
S haemotobium
 
infection. Both of these drugs currently have limited avail
-
ability (they are not available in the United States), and 
resistance may be a problem. No second-line drug is avail
-
able for 
 infections. The antimalarial drug arte
-
mether has activity against schistosomulae and adult worms 
and may be effective in chemoprophylaxis; however, it is 
expensive, and long-term use in malarious areas might select 
for resistant malaria parasites. With severe disease, use of 
corticosteroids in conjunction with praziquantel may 
decrease complications. Treatment should be followed by 
repeat examinations for eggs about every 3 months for 1 year 
after therapy, with re-treatment if eggs are seen.
 
»
Travelers to endemic areas should avoid freshwater expo
-
sure. Vigorous toweling after exposure may limit cercarial 
penetration. Chemoprophylaxis with artemether has 
shown efficacy but is not standard practice. Community 
control of schistosomiasis includes improved sanitation 
and water supplies, elimination of snail habitats, and inter
-
mittent treatment to limit worm burdens.
Colley DG et al. Human schistosomiasis. Lancet. 2014 Jun 28; 
383(9936):2253–64. [PMID: 24698483]
Olveda RM et al. Efficacy and safety of praziquantel for the treat
-
ment of human schistosomiasis during pregnancy: a phase 2, 
randomised, double-blind, placebo-controlled trial. Lancet 
Infect Dis. 2016 Feb;16(2):199–208. [PMID: 26511959]

-
Utzinger J et al. New diagnostic tools in schistosomiasis. 
Clin Microbiol Infect. 2015 Jun;21(6):529–42. [PMID: 
25843503]
LIVER, LUNG, & INTESTINAL FLUKES
FASCIOLIASIS
Infection by 
Fasciola hepatica
, the sheep liver fluke, results 
from ingestion of encysted metacercariae on watercress or 
other aquatic vegetables. Infection is prevalent in sheep-
raising areas in many countries, especially parts of South 
America, the Middle East, and southern Europe, and it has 
increasingly been recognized in travelers to these areas. 
Fasciola gigantica
 has a more restricted distribution in Asia 
and Africa and causes similar findings. Eggs are passed from 
host feces into freshwater, leading to infection of snails, and 
then deposition of metacercariae on vegetation. In humans, 
metacercariae excyst, penetrate into the peritoneum, migrate 
through the liver, and mature in the bile ducts, where they 
cause local necrosis and abscess formation.
Two clinical syndromes are seen, related to acute migra
-
tion of worms and chronic infection of the biliary tract. 
Symptoms related to migration of larvae present 
6–12 weeks after ingestion. Typical findings are abdominal 
pain, fever, malaise, weight loss, urticaria, eosinophilia, and 
leukocytosis. Tender hepatomegaly and elevated liver bio
-
chemical tests may be seen. Rarely, migration to other organs 
may lead to localized disease. The symptoms of worm migra
-
tion subside after 2–4 months, followed by asymptomatic 
infection by adult worms or intermittent symptoms of biliary 
obstruction, with biliary colic and, at times, findings of chol
-
angitis. Early diagnosis is difficult, as eggs are not found in 
the feces during the acute migratory phase of infection. Clini
-
cal suspicion should be based on clinical findings and 
marked eosinophilia in at risk individuals. CT and other 
imaging studies show hypodense migratory lesions of the 
liver. Definitive diagnosis is made by the identification of 
characteristic eggs in stool. Repeated examinations may be 
necessary. In chronic infection, imaging studies show masses 
obstructing the extrahepatic biliary tract. Serologic assays 
have sensitivity and specificity greater than 90%, but cannot 
distinguish between past and current infection. Antigen tests 
with excellent sensitivity and specificity are available in vet
-
erinary medicine and show promise for humans.
Fascioliasis is unusual among fluke infections, in that it 
does not respond well to treatment with praziquantel. The 
treatment of choice is triclabendazole, which is also used in 
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veterinary medicine. It is not routinely available in the 
United States, but is available through the CDC under an 
investigational protocol. Standard dosing of 10 mg/kg orally 
in a single dose or two doses over 12 hours achieves a cure 
rate of about 80%, but repeat dosing is indicated if abnormal 
radiologic findings or eosinophilia do not resolve. Of con
-
cern, resistance to triclabendazole has been widely reported 
in animal infections. The second-line drug for fascioliasis is 
bithionol (30–50 mg/kg/day orally in three divided doses 
on alternate days for 10–15 days); this drug is no longer 
available in the United States. Treatment with either drug 
can be accompanied by abdominal pain and other gastroin
-
testinal symptoms. Other potential therapies are emetine 
and dehydroemetine, both widely used in the past but quite 
toxic, and nitazoxanide. Prevention of fascioliasis involves 
avoidance of ingestion of raw aquatic plants.
CLONORCHIASIS & OPISTHORCHIASIS
Clonorchis sinensis
, the Chinese liver fluke, is 
endemic in areas of Japan, Korea, China, Taiwan, Southeast 
Asia, and the far eastern part of Russia. An estimated 
15 million people are infected (13 million in China); in some 
communities, prevalence can reach 80%. Opisthorchiasis is 
principally caused by 
Opisthorchis felineus
 (regions of the 
former Soviet Union) or 
Opisthorchis viverrini
 (Thailand, 
Laos, Vietnam). Clonorchiasis and opisthorchiasis are clini
-
cally indistinguishable. Parasite eggs are shed into water in 
human or animal feces, where they infect snails, which 
release cercariae, which infect fish. Human infection follows 
ingestion of raw, undercooked, or pickled freshwater fish 
containing metacercariae. These parasites excyst in the duo
-
denum and ascend into the biliary tract, where they mature 
and remain for many years, shedding eggs in the bile.
Most patients harbor few parasites and are asymptom
-
atic. An acute illness can occur 2–3 weeks after initial 
infection, with fever, abdominal pain, tender hepatomeg
-
aly, urticaria, and eosinophilia. The acute syndrome is dif
-
ficult to diagnose, since ova may not appear in the feces 
until 3–4 weeks after onset of symptoms. In chronic heavy 
infections, findings include abdominal pain, anorexia, 
weight loss, and tender hepatomegaly. More serious find
-
ings can include recurrent bacterial cholangitis and sepsis, 
cholecystitis, liver abscess, and pancreatitis. An increased 
risk of cholangiocarcinoma has been documented.
Early diagnosis is presumptive, based on clinical find
-
ings and epidemiology. Subsequent diagnosis is made by 
finding characteristic eggs in stool or duodenal or biliary 
contents. The stool Kato-Katz test is widely used; perform
-
ing repeated tests improves sensitivity. Imaging studies 
show characteristic biliary tract dilatations with filling 
defects due to flukes. Serologic assays for clonorchiasis 
with excellent sensitivity are available but cannot distin
-
guish between past and current infection. Molecular tests 
have been developed but are not widely used.
The drug of choice is praziquantel, 25 mg/kg orally 
three times daily for 2 days, which provides cure rates over 
95%. One day of treatment may be sufficient. Re-treatment 
may be required, especially in some areas with known 
decreased praziquantel efficacy. The second-line drug is 
albendazole (400 mg orally twice daily for 7 days), which 
appears to be somewhat less effective. Tribendimidine, 
which is approved in China, has shown efficacy for clonor
-
chiasis similar to that of praziquantel.
PARAGONIMIASIS
Eight species of 
 lung flukes cause human 
disease. The most important is 
Paragonimus westermani. 
 species are endemic in East Asia, Oceania, 
West Africa, and South America, where millions of persons 
are infected; rare infections caused by 
Paragonimus 
kellicotti

 have occurred in North America. Eggs are released 
into freshwater, where parasites infect snails, and then 
cercariae infect crabs and crayfish. Human infection fol
-
lows consumption of raw, undercooked, or pickled fresh
-
water shellfish. Metacercariae then excyst, penetrate into 
the peritoneum, and pass into the lungs, where they mature 
into adult worms over about 2 months.
Most persons have moderate worm burdens and are 
asymptomatic. In symptomatic cases, abdominal pain and 
diarrhea develop 2 days to 2 weeks after infection, followed 
by fever, cough, chest pain, urticaria, and eosinophilia. Acute 
symptoms may last for several weeks. Chronic infection can 
cause cough productive of brown sputum, hemoptysis, dys
-
pnea, and chest pain, with progression to chronic bronchitis, 
bronchiectasis, bronchopneumonia, lung abscess, and pleu
-
ral disease. Ectopic infections can cause disease in other 
organs, most commonly the CNS, where disease can present 
with seizures, headaches, and focal neurologic findings due 
to parasite meningitis and to intracerebral lesions.
The diagnosis of paragonimiasis is made by identifying 
characteristic eggs in sputum or stool or identifying worms 
in biopsied tissue. Multiple examinations and concentration 
techniques may be needed. Serologic tests may be helpful; 
an ELISA available from the CDC has sensitivity and speci
-
ficity more than 95%. Chest radiographs may show varied 
abnormalities of the lungs or pleura, including infiltrates, 
nodules, cavities, and fibrosis, and the findings can be con
-
fused with those of tuberculosis. With CNS disease, skull 
radiographs can show clusters of calcified cysts, and CT or 
MRI can show clusters of ring-enhancing lesions.
Treatment is with praziquantel (25 mg/kg orally three 
times daily for 2 days), which provides efficacy of at least 
90%. Alternative therapies are bithionol and triclabenda
-
zole. As with cysticercosis, for cerebral paragonimiasis, 
praziquantel should generally be used with corticosteroids. 
Chronic infection may lead to permanent lung dysfunction 
and pleural disease requiring drainage procedures.
INTESTINAL FLUKES
The large intestinal fluke, 
Fasciolopsis buski
, is a common 
parasite of pigs and humans in eastern and southern Asia. 
Eggs shed in stools hatch in freshwater, followed by infec
-
tion of snails, and release of cercariae that encyst on aquatic 
plants. Humans are infected by eating uncooked plants, 
including water chestnuts, bamboo shoots, and watercress. 
Adult flukes mature in about 3 months and live in the small 
intestine attached to the mucosa, leading to local inflam
-
mation and ulceration. Other intestinal flukes that cause 
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similar syndromes include 
Heterophyes
 (North Africa and 
Turkey) and 
Metagonimus
 (East Asia) species; these species 
are transmitted by undercooked freshwater fish.
Infections with intestinal flukes are often asymptomatic, 
although eosinophilia may be marked. In symptomatic 
cases, after an incubation period of 1–2 months, manifesta
-
tions include epigastric pain and diarrhea. Other gastroin
-
testinal symptoms, ileus, edema, and ascites may be seen 
uncommonly. Diagnosis is based on identification of charac
-
teristic eggs or adult flukes in the stool. In contrast to other 
fluke infections, illness more than 6 months after travel in an 
endemic area is unlikely. The drug of choice is praziquantel, 
25 mg/kg orally as a single dose. Alternative therapies are 
triclabendazole and niclosamide (for most species).
Ashrafi K et al. Fascioliasis: a worldwide parasitic disease of 
importance in travel medicine. Travel Med Infect Dis. 2014 
Nov–Dec;12(6 Pt A):636–49. [PMID: 25287722]
Blair D. Paragonimiasis. Adv Exp Med Biol. 2014;766:115–52. 
[PMID: 24903365]
Qian MB et al. Clonorchiasis. Lancet. 2016 Feb 20; 
387(10020):800–10. [PMID: 26299184]
CESTODE INFECTIONS
NONINVASIVE CESTODE INFECTIONS
The four major tapeworms that cause noninvasive infections 
in humans are the beef tapeworm 
Taenia saginata
, the pork 
tapeworm 
Taenia solium
, the fish tapeworm 
Diphyllobothrium 
latum
, each of which can reach many meters in length, and 
the dwarf tapeworm 
Hymenolepis nana. Taenia
 and 
Hymenol
-
epis
 species are broadly distributed, especially in the tropics; 
 
D latum
 is most prevalent in temperate regions. Other tape
-
worms that can cause noninvasive human disease include the 
rodent tapeworm 
Hymenolepis diminuta
, the dog tapeworm 
Dipylidium caninum
, and other 
Taenia
 and 
Diphyllobothrium
 
species. Invasive tapeworm infections, including 
T solium
 
(when infective eggs, rather than cysticerci are ingested) and 
Echinococcus
 species, will be discussed separately.
1. Beef Tapeworm
Infection is most common in cattle breeding areas. Humans 
are the definitive host. Gravid segments of 
T saginata
 are 
passed in human feces to soil, where they are ingested by 
grazing animals, especially cattle. The eggs then hatch to 
release embryos that encyst in muscle as cysticerci. Humans 
are infected by eating raw or undercooked infected beef. 
Most individuals infected with 
T saginata
 are asymptomatic, 
but abdominal pain and other gastrointestinal symptoms 
may be present. Eosinophilia is common. The most common 
presenting finding is the passage of proglottids in the stool.
2. Pork Tapeworm
T solium
 is transmitted to pigs that ingest human feces. 
Humans can be either the definitive host (after consuming 
undercooked pork, leading to tapeworm infection) or the 
intermediate host (after consuming food contaminated 
with human feces containing 
T solium
 eggs, leading to 
cysticercosis, which is discussed under Invasive Cestode 
Infections). As with the beef tapeworm, infection with 
 
T solium
 adult worms is generally asymptomatic, but gas
-
trointestinal symptoms may occur. Infection is generally 
recognized after passage of proglottids. Autoinfection with 
eggs can progress to cysticercosis.
3. Fish Tapeworm
D latum
 follows ingestion of undercooked 
freshwater fish, most commonly in temperate regions. Eggs 
from human feces are taken up by crustaceans, these are 
eaten by fish, which are then infectious to humans. Infec
-
tion with multiple worms over many years can occur. 
Infections are most commonly asymptomatic, but nonspe
-
cific gastrointestinal symptoms, including diarrhea, may 
occur. Diagnosis usually follows passage of proglottids. 
Prolonged heavy infection can lead to megaloblastic ane
-
mia and neuropathy from vitamin B
12
 deficiency, which is 
due to infection-induced dissociation of the vitamin from

-
12
due to infection-induced dissociation of the vitamin from 
intrinsic factor and to utilization of the vitamin by worms.
4. Dwarf Tapeworm
H nana
 is the only tapeworm that can be transmitted 
between humans. Infections are common in warm areas, 
especially with poor hygiene and institutionalized popula
-
tions. Infection follows ingestion of food contaminated with 
human feces. Eggs hatch in the intestines, where oncospheres 
penetrate the mucosa, encyst as cysticercoid larvae, and then 
rupture after about 4 days to release adult worms. Autoinfec
-
tion can lead to amplification of infection. Infection with 
 
H nana
, the related rodent tapeworm 
H diminuta
, or the dog 
tapeworm 
D caninum
 can also follow accidental ingestion of 
infected insects. 
H nana
 are dwarf in size relative to other 
tapeworms but can reach 5 cm in length. Heavy infection is 
common, especially in children, and can be accompanied by 
abdominal discomfort, anorexia, and diarrhea.
 
»
Diagnosis is usually made based on the identification of 
characteristic eggs or proglottids in stool. Egg release may 
be irregular, so examination of multiple specimens or con
-
centration techniques may be needed.
 
»
Treatment
The treatment of choice for noninvasive tapeworm infec
-
tions is praziquantel. A single dose of praziquantel (5–10 
mg/kg orally) is highly effective, except for 
H nana
, for 
which the dosage is 25 mg/kg. Treatment of 
H nana
 is more 
difficult, as the drug is not effective against maturing cysts. 
Therefore, a repeat treatment after 1 week and screening 
after therapy to document cure are appropriate with heavy 
infections. Therapy can be accompanied by headache, mal
-
aise, dizziness, abdominal pain, and nausea.
The alternative therapy for these infections is niclosamide. 
A single dose of niclosamide (2 g chewed) is effective against 
D latum, Taenia
, and 
D caninum
 infections. For 
H nana
, 
therapy is continued daily for 1 week. Niclosamide may 
cause nausea, malaise, and abdominal pain.
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Craig P et al. Intestinal cestodes. Curr Opin Infect Dis. 2007 Oct; 
20(5):524–32. [PMID: 17762788]
INVASIVE CESTODE INFECTIONS
1. Cysticercosis
 
»
Exposure to 
T solium
 through fecal contamination 
of food.
 
»
Focal CNS lesions; seizures, headache.
 
»
Brain imaging shows cysts; positive serologic tests.
 
»
Cysticercosis is due to tissue infection with cysts of 
T solium
 
that develop after humans ingest food contaminated with 
eggs from human feces, thus acting as an intermediate host 
for the parasite. Prevalence is high where the parasite is 
endemic, in particular Mexico, Central and South America, 
the Philippines, and Southeast Asia. An estimated 20 million 
persons are infected with cysticerci yearly, leading to about 
400,000 persons with neurologic symptoms and 
50,000 deaths. Antibody prevalence rates up to 10% are 
recognized in some endemic areas, and the infection is one 
of the most important causes of seizures in the developing 
world and in immigrants to the United States from endemic 
countries. In Latin America, it is estimated that 0.5–1.5 million 
people suffer from epilepsy secondary to cysticercosis.
 
»
Neurocysticercosis can cause intracerebral, subarachnoid, 
and spinal cord lesions and intraventricular cysts. Single 
or multiple lesions may be present. Lesions may persist for 
years before symptoms develop, generally due to local 
inflammation or ventricular obstruction. Presenting 
symptoms include seizures, focal neurologic deficits, 
altered cognition, and psychiatric disease. Symptoms 
develop more quickly with intraventricular cysts, with 
findings of hydrocephalus and meningeal irritation, 
including severe headache, vomiting, papilledema, and 
visual loss. A particularly aggressive form of the disease, 
racemose cysticercosis, involves proliferation of cysts at 
the base of the brain, leading to alterations of conscious
-
ness and death. Spinal cord lesions can present with pro
-
gressive focal findings.
Cysticercosis of other organ systems is usually clinically 
benign. Involvement of muscles can uncommonly cause 
discomfort and is identified by radiographs of muscle 
showing multiple calcified lesions. Subcutaneous involve
-
ment presents with multiple painless palpable skin lesions. 
Involvement of the eyes can present with ptosis due to 
extraocular muscle involvement or intraocular 
CSF examination may show lymphocytic or eosinophilic 
pleocytosis, decreased glucose, and elevated protein. Serol
-
ogy plays an important role in diagnosis. ELISAs and 
related immunoblot assays have excellent sensitivity and 
specificity, but sensitivity is lower with only single or calci
-
fied lesions.
C. Imaging
With neuroimaging by CT or MRI, multiple parenchymal 
cysts are most typically seen. Parenchymal calcification is 
also common. Ventricular cysts may be difficult to visual
-
ize, with MRI offering better sensitivity than CT.
 
»
Treatment
The medical management of neurocysticercosis is contro
-
versial, as the benefits of cyst clearance must be weighed 
against potential harm of an inflammatory response to 
dying worms. Antihelminthic therapy hastens radiologic 
improvement in parenchymal cysticercosis, but some ran
-
domized trials have shown that corticosteroids alone are as 
effective as specific therapy plus corticosteroids for con
-
trolling seizures. Overall, most authorities recommend 
treatment of active lesions, in particular lesions with a high 
likelihood of progression, such as intraventricular cysts. At 
the other end of the spectrum, inactive calcified lesions 
probably do not benefit from therapy. In addition, cysti
-
cidal therapy should be avoided if there is a high risk of 
hydrocephalus, as with subarachnoid involvement. When 
treatment is deemed appropriate, standard therapy consists

-
treatment is deemed appropriate, standard therapy consists 
of albendazole (10–15 mg/kg/day orally for 8 days) or pra
-
ziquantel (50 mg/kg/day orally for 15–30 days). Albenda
-
zole is probably preferred, since it has shown better efficacy 
in some comparisons and since corticosteroids appear to 
lower circulating praziquantel levels but increase albenda
-
zole levels. Increasing the dosage of albendazole to 30 mg/
kg/day orally may improve outcomes. Combining albenda
-
zole plus praziquantel improved outcomes compared to 
albendazole alone in patients with multiple viable intrapa
-
renchymal cysts. Corticosteroids are usually administered 
concurrently, but dosing is not standardized. Patients 
should be observed for evidence of localized inflammatory 
responses. Anticonvulsant therapy is provided if needed, 
and shunting is performed if required for elevated intracra
-
nial pressure. Surgical removal of cysts may be helpful for 
some difficult cases of neurocysticercosis and for symp
-
tomatic non-neurologic disease.
Garcia HH et al. Clinical symptoms, diagnosis, and treatment of 
neurocysticercosis. Lancet Neurol. 2014 Dec;13(12):1202–15. 
[PMID: 25453460]
Garcia HH et al; Cysticercosis Working Group in Peru. Efficacy 
of combined antiparasitic therapy with praziquantel and 
albendazole for neurocysticercosis: a double-blind, ran
-
domised controlled trial. Lancet Infect Dis. 2014 Aug; 
14(8):687–95. [PMID: 24999157]
Gripper LB et al. Neurocysticercosis infection and disease—a 
review. Acta Trop. 2017 Feb;166:218–24. [PMID: 27880878]
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2. Echinococcosis
 
»
History of exposure to dogs or wild canines in an 
 
»
Large cystic lesions, most commonly of the liver or 
lung.
 
»
 
»
Echinococcosis occurs when humans are intermediate 
hosts for canine tapeworms. Infection is acquired by 
ingesting food contaminated with canine feces containing 
parasite eggs. The principal species that infect humans are 
Echinococcus granulosus
, which causes cystic hydatid dis
-
ease, and 
Echinococcus multilocularis
, which causes alveo
-
lar hydatid disease. 
E granulosus
 is transmitted by domestic 
dogs in areas with livestock (sheep, goats, camels, and 
horses) as intermediate hosts, including Africa, the Middle 
East, southern Europe, South America, Central Asia, 
Australia, New Zealand, and the southwestern United 
States. 
E multilocularis
, which much less commonly causes 
human disease, is transmitted by wild canines, and endemic 
in northern forest areas of the Northern Hemisphere, 
including central Europe, Siberia, northern Japan, north
-
western Canada, and western Alaska. An increase in the 
fox population in Europe has been associated with an 
increase in human cases. The disease range has also 
extended southward in Central Asia and China. Other spe
-
cies that cause limited disease in humans are endemic in 
South America and China.
After humans ingest parasite eggs, the eggs hatch in the 
intestines to form oncospheres, which penetrate the 
mucosa, enter the circulation, and encyst in specific 
organs as hydatid cysts. 
 forms cysts most 
commonly in the liver (65%) and lungs (25%), but the 
cysts may develop in any organ, including the brain, 
bones, skeletal muscles, kidneys, and spleen. Cysts are 
most commonly single. The cysts can persist and slowly 
grow for many years.
 
»
Infections are commonly asymptomatic and may be noted 
incidentally on imaging studies or present with symptoms 
caused by an enlarging or superinfected mass. Findings 
may include abdominal or chest pain, biliary obstruction, 
cholangitis, portal hypertension, cirrhosis, bronchial 
obstruction leading to segmental lung collapse, and 
abscesses. Cyst leakage or rupture may be accompanied by 
a severe allergic reaction, including fever and hypotension. 
Seeding of cysts after rupture may extend the infection to 
new areas.
 generally causes a more aggressive dis
-
ease than 
, with initial infection of the liver, 
but then local and distant spread commonly suggesting a 
malignancy. Symptoms based on the areas of involvement 
gradually worsen over years, with the development of 
obstructive findings in the liver and elsewhere.
Serologic tests, including ELISA and immunoblot, offer 
sensitivity and specificity over 80% for 
 liver 
infections, but lower sensitivity for involvement of other 
organs. Serologic tests may also distinguish the two major 
echinococcal infections.
C. Imaging
Diagnosis is usually based on imaging studies, including 
ultrasonography, CT, and MRI. In 
 infection, a 
large cyst containing daughter cysts is highly suggestive of 
the diagnosis. In 
 infection, imaging shows 
an irregular mass, often with areas of calcification.
 
»
Treatment
The treatment of cystic hydatid disease is with albenda
-
zole, often with cautious surgical resection of cysts. When 
used alone, as in cases where surgery is not possible, 
albendazole (10–15 mg/kg/day orally) has demonstrated 
efficacy, with courses of 3 months or longer duration, in 
some cases with alternating cycles of treatment and rest. 
Mebendazole (40–50 mg/kg/day orally) is an alternative 
drug, and praziquantel may also be effective. In some 
cases, medical therapy is begun, with surgery performed if 
disease persists after some months of therapy. Another

disease persists after some months of therapy. Another 
approach, in particular with inoperable cysts, is percuta
-
neous aspiration, injection, and reaspiration (PAIR). In 
this approach (which should not be used if cysts commu
-
nicate with the biliary tract), patients receive antihelmin
-
thic therapy, and the cyst is partially aspirated. After 
diagnostic confirmation by examination for parasite pro
-
toscolices, a scolicidal agent (95% ethanol, hypertonic 
saline, or 0.5% cetrimide) is injected, and the cyst is 
reaspirated after about 15 minutes. PAIR includes a small 
risk of anaphylaxis, which has been reported in about 2% 
of procedures, but death due to anaphylaxis has been rare. 
Treatment of alveolar cyst disease is challenging, generally 
relying on wide surgical resection of lesions. Therapy with 
albendazole before or during surgery may be beneficial 
and may also provide improvement or even cure in inop
-
erable cases.
Agudelo Higuita NI et al. Cystic echinococcosis. J Clin Microbiol. 
2016 Mar;54(3):518–23. [PMID: 26677245]
Gomez I Gavara C et al. Review of the treatment of liver hydatid 
cysts. World J Gastroenterol. 2015 Jan 7;21(1):124–31. 
[PMID: 25574085]
Meinel TR et al. Vertebral alveolar echinococcosis—a case 
report, systematic analysis, and review of the literature. 
Lancet Infect Dis. 2018 Mar;18(3):e87–e98. [PMID: 
28807628]
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CMDT 2019
INTESTINAL NEMATODE 
 
(ROUNDWORM) INFECTIONS
ASCARIASIS
 
»
Transient cough, urticaria, pulmonary infiltrates, 
eosinophilia.
 
»
Nonspecific abdominal symptoms.
 
»
Eggs in stool; adult worms occasionally passed.
 
»
 is the most common of the intestinal 
helminths, causing about 800 million infections, 12 million 
acute cases, and 10,000 or more deaths annually. Preva
-
lence is high wherever there is poor hygiene and sanitation 
or where human feces are used as fertilizer. Heavy infec
-
tions are most common in children.
Infection follows ingestion of eggs in contaminated food. 
Larvae hatch in the small intestine, penetrate into the blood
-
stream, migrate to the lungs, and then travel via airways back to 
the gastrointestinal tract, where they develop to adult worms, 
which can be up to 40 cm in length, and live for 1–2 years.
 
»
Most persons with 
Ascaris
 infection are asymptomatic. In a 
small proportion of patients, symptoms develop during 
migration of worms through the lungs, with fever, nonpro
-
ductive cough, chest pain, dyspnea, and eosinophilia, occa
-
sionally with eosinophilic pneumonia. Rarely, larvae lodge 
ectopically in the brain, kidney, eye, spinal cord, and other 
sites and may cause local symptoms.
Light intestinal infections usually produce no symp
-
toms. With heavy infection, abdominal discomfort may be 
seen. Adult worms may also migrate and be coughed up, be 
vomited, or may emerge through the nose or anus. They 
may also migrate into the common bile duct, pancreatic 
duct, appendix, and other sites, which may lead to cholan
-
gitis, cholecystitis, pyogenic liver abscess, pancreatitis, 
obstructive jaundice, or appendicitis. With very heavy 
infestations, masses of worms may cause intestinal obstruc
-
tion, volvulus, intussusception, or death. Although severe 
manifestations of infection are uncommon, the very high 
prevalence of ascariasis leads to large numbers of individu
-
als, especially children, with important sequelae. Moderate 
to high worm loads in children are also associated with 
nutritional abnormalities due to decreased appetite and 
food intake, and also decreased absorption of nutrients.
The diagnosis of ascariasis is made after adult worms 
emerge from the mouth, nose, or anus, or by identifying 
characteristic eggs in the feces, usually with the Kato-Katz 
technique. Imaging studies demonstrate worms, with filling 
defects in contrast studies and at times evidence of intestinal 
or biliary obstruction. Eosinophilia is marked during worm 
migration but may be absent during intestinal infection.
 
»
Treatment
All infections should ideally be treated. Treatments of 
choice are albendazole (single 400-mg oral dose), meben
-
dazole (single 500-mg oral dose or 100 mg twice daily for 
|3 days), or pyrantel pamoate (single 11-mg/kg oral dose, 
maximum 1 g). These drugs are all well tolerated but may 
cause mild gastrointestinal toxicity. They are considered 
safe for children above 1 year of age and in pregnancy, 
although use in the first trimester is best avoided. An alter
-
native is ivermectin (single 200 mcg/kg oral dose). In 
endemic areas, reinfection after treatment is common. 
Intestinal obstruction usually responds to conservative 
management and antihelminthic therapy. Surgery may be 
required for appendicitis and other gastrointestinal 
TRICHURIASIS
Trichuris trichiura
, the whipworm, infects about 500 million 
persons throughout the world, particularly in humid tropi
-
cal and subtropical environments. Infection is heaviest and 
most frequent in children. Infections are acquired by inges
-
tion of eggs. The larvae hatch in the small intestine and 
mature in the large bowel to adult worms of about 4 cm in 
length. The worms do not migrate through tissues.
Most infected persons are asymptomatic. Heavy infec
-

-
tions may be accompanied by abdominal cramps, tenes
-
mus, diarrhea, distention, nausea, and vomiting. The 
Trichuris
 dysentery syndrome may develop, particularly in 
malnourished young children, with findings resembling 
inflammatory bowel disease including bloody diarrhea and 
rectal prolapse.
Trichuriasis is diagnosed by identification of character
-
istic eggs and sometimes adult worms in stools. Eosinophilia 
is common. Treatment is typically with albendazole 
(400 mg/day orally) or mebendazole (200 mg/day orally), 
for 1–3 days for light infections or 3–7 days for heavy infec
-
tions, but cure rates are lower than for ascariasis or hook
-
worm infection. An alternative is ivermectin (200 mcg/kg 
orally once daily for 3 days). Oxantel pamoate (one dose of 
15–30 mg/kg) has shown good efficacy in clearing infec
-
tions, and randomized trials showed albendazole plus 
oxantel pamoate (31% cure; 96% egg reduction) to be supe
-
rior to mebendazole, and albendazole plus oxantel pamoate 
(69% cure; 99% egg reduction) and albendazole plus iver
-
mectin (28% cure; 95% egg reduction) to be superior to 
albendazole plus mebendazole. Oxantel pamoate has low 
efficacy against 
Ascaris
 and hookworm infection.
HOOKWORM DISEASE
 
»
Transient pruritic skin rash and lung symptoms.
 
»
Anorexia, diarrhea, abdominal discomfort.
 
»
Iron deficiency anemia.
 
»
Characteristic eggs and occult blood in the stool.
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»
Infection with the hookworms 
Ancylostoma duodenale
 and 
Necator americanus
 is very common, especially in most 
tropical and subtropical regions. Both worms are broadly 
distributed. Prevalence is estimated at about 500 million, 
causing approximately 65,000 deaths each year. When eggs 
are deposited on warm moist soil they hatch, releasing 
larvae that remain infective for up to a week. With contact, 
the larvae penetrate skin and migrate in the bloodstream to 
the pulmonary capillaries. In the lungs, the larvae pene
-
trate into alveoli and then are carried by ciliary action 
upward to the bronchi, trachea, and mouth. After being 
swallowed, they reach and attach to the mucosa of the 
upper small bowel, where they mature to adult worms. 
Ancylostoma
 infection can also be acquired by ingestion of 
the larvae in food or water. Hookworms attach to the intes
-
tinal mucosa and suck blood. Blood loss is proportionate to 
the worm burden.
 
»
Most infected persons are asymptomatic. A pruritic macu
-
lopapular rash (ground itch) may occur at the site of larval 
penetration, usually in previously sensitized persons. Pul
-
monary symptoms may be seen during larval migration 
through the lungs, with dry cough, wheezing, and low-
grade fever, but these symptoms are less common than 
with ascariasis. About 1 month after infection, as maturing 
worms attach to the small intestinal mucosa, gastrointesti
-
nal symptoms may develop, with epigastric pain, anorexia, 
and diarrhea, especially in previously unexposed individu
-
als. Persons chronically infected with large worm burdens 
may have abdominal pain, anorexia, diarrhea, and findings 
of marked iron-deficiency anemia and protein malnutri
-
tion. Anemia can lead to pallor, weakness, dyspnea, and 
heart failure, and protein loss can lead to hypoalbumin
-
emia, edema, and ascites. These findings may be accompa
-
nied by impairment in growth and cognitive development 
in children. Infection with the dog hookworm 
Ancylostoma 
caninum
 can uncommonly lead to abdominal pain, diar
-
rhea, and eosinophilia, with intestinal ulcerations and 
regional lymphadenitis.
Diagnosis is based on the demonstration of characteristic 
eggs in feces; concentration techniques are usually not 
needed. Microcytic anemia, occult blood in the stool, and 
hypoalbuminemia are common. Eosinophilia is common, 
especially during worm migration.
 
»
Treatment
Treatment is with albendazole (single 400-mg oral dose) or 
mebendazole (100 mg orally twice daily for 3 days). Occa
-
sional adverse effects are diarrhea and abdominal pain. 
Pyrantel pamoate and levamisole are also effective. Anemia 
should be managed with iron replacement and, for severe 
symptomatic anemia, blood transfusion. Mass treatment of 
children with single doses of albendazole or mebendazole 
at regular intervals limits worm burdens and the extent of 
disease and is advocated by WHO.
STRONGYLOIDIASIS
 
»
 
»
 
»
Larvae detected in stool.
 
»
Hyperinfection in the immunocompromised; 
larvae detected in sputum or other fluids.
 
»
Eosinophilia.
 
»
Strongyloidiasis is caused by infection with 
Strongyloides 
stercoralis
. Although much less prevalent than ascariasis, 
trichuriasis, or hookworm infections, strongyloidiasis is 
nonetheless a significant problem, infecting tens of millions 
of individuals in tropical and subtropical regions. Infec
-
tion is also endemic in some temperate regions of North 
America, Europe, Japan, and Australia. Of particular 
importance is the predilection of the parasite to cause 
severe infections in immunocompromised individuals due 
to its ability to replicate in humans. A related parasite, 
Strongyloides fuelleborni
, infects humans in parts of Africa

, infects humans in parts of Africa 
and New Guinea.
Among nematodes, 
S stercoralis
 is uniquely capable of 
maintaining its full life cycle both within the human host 
and in soil. Infection occurs when filariform larvae in soil 
penetrate the skin, enter the bloodstream, and are carried 
to the lungs, where they escape from capillaries into alve
-
oli, ascend the bronchial tree, and are then swallowed and 
carried to the duodenum and upper jejunum, where matu
-
ration to the adult stage takes place. Females live embed
-
ded in the mucosa for up to 5 years, releasing eggs that 
hatch in the intestines as free rhabditiform larvae that pass 
to the ground via the feces. In moist soil, these larvae 
metamorphose into infective filariform larvae. Autoinfec
-
tion can occur in humans, when some rhabditiform larvae 
develop into filariform larvae that penetrate the intestinal 
mucosa or perianal skin, and enter the circulation. The 
most dangerous manifestation of 
 infection is 
the 
hyperinfection syndrome
, with dissemination of large 
numbers of filariform larvae to the lungs and other tissues 
in immunocompromised individuals. Mortality with this 
syndrome approaches 100% without treatment and has 
been about 25% with treatment. The hyperinfection syn
-
drome is seen in patients receiving corticosteroids and 
other immunosuppressive medications; patients with 
hematologic malignancies, malnutrition, or alcoholism; or 
persons with AIDS. The risk seems greatest for those 
receiving corticosteroids.
CMDT19_Ch35_p1510-p1549.indd   1542

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CMDT 2019
 
»
As with other intestinal nematodes, most infected persons 
are asymptomatic. An acute syndrome can be seen at the 
time of infection, with a pruritic, erythematous, maculo
-
papular rash, usually of the feet. These symptoms may be 
followed by pulmonary symptoms (including dry cough, 
dyspnea, and wheezing) and eosinophilia after a number of 
days, followed by gastrointestinal symptoms after some 
weeks, as with hookworm infections. Chronic infection 
may be accompanied by epigastric pain, nausea, diarrhea, 
and anemia. Maculopapular or urticarial rashes of the but
-
tocks, perineum, and thighs, due to migrating larvae, may 
be seen. Large worm burdens can lead to malabsorption or 
intestinal obstruction. Eosinophilia is common but may 
fluctuate.
With hyperinfection large numbers of larvae can 
migrate to many tissues, including the lungs, CNS, kidneys, 
and liver. Gastrointestinal symptoms can include abdomi
-
nal pain, nausea, vomiting, diarrhea, and more severe find
-
ings related to intestinal obstruction, perforation, or 
hemorrhage. Bacterial sepsis, probably secondary to intes
-
tinal ulcerations, is a common presenting finding. Pulmo
-
nary findings include pneumonitis, cough, hemoptysis, 
and respiratory failure. Sputum may contain adult worms, 
larvae, and eggs. CNS disease includes meningitis and 
brain abscesses; the CSF may contain larvae. Various pre
-
sentations can progress to shock and death.
The diagnosis of strongyloidiasis can be difficult, as eggs 
are seldom found in feces. Diagnosis is usually based on 
the identification of rhabditiform larvae in the stool or 
duodenal contents. These larvae must be distinguished 
from hookworm larvae, which may hatch after stool collec
-
tion. Repeated examinations of stool or examination of 
duodenal fluid may be required for diagnosis because the 
sensitivity of individual tests is only about 30%. Hyperin
-
fection is diagnosed by the identification of large numbers 
of larvae in stool, sputum, or other body fluids. An ELISA 
from the CDC offers about 90% sensitivity and specificity, 
but cross-reactions with other helminths may occur. Eosin
-
ophilia and mild anemia are common, but eosinophilia 
may be absent with hyperinfection. Hyperinfection may 
include extensive pulmonary infiltrates, hypoproteinemia, 
and abnormal liver function studies.
It is important to be aware of the possibility of strongyloi
-
diasis in persons with even a distant history of residence in 
an endemic area, since the infection can be latent for 
decades. Screening of at-risk individuals for infection is 
appropriate before institution of immunosuppressive 
therapy. Screening can consist of serologic tests, with stool 
examinations in those with positive serologic tests, but 
consideration of presumptive treatment even if the stool 
evaluations are negative (see below).
 
»
Treatment
Full eradication of 
 is more important than with 
other intestinal helminths due to the ability of the parasite 
to replicate in humans. The treatment of choice for routine 
infection is ivermectin (200 mcg/kg orally daily for 
1–2 days). Less effective alternatives are albendazole 
(400 mg orally twice daily for 3 days) and thiabendazole 
(25 mg/kg orally twice daily for 3 days). For hyperinfec
-
tion, ivermectin should be administered daily until the 
clinical syndrome has resolved and larvae have not been 
identified for at least 2 weeks. Follow-up examinations for 
larvae in stool or sputum are necessary, with repeat dosing 
if the infection persists. With continued immunosuppres
-
sion, eradication may be difficult, and regular repeated 
therapy (eg, monthly ivermectin) may be required.
ENTEROBIASIS
 
»
Nocturnal perianal pruritus.
 
»
Identification of eggs or adult worms on perianal 
skin or in stool.
 
»

»
 
»
 
»
Enterobius vermicularis
, the pinworm, is a common cause 
of intestinal infections worldwide, with maximal preva
-
lence in school-aged children. Enterobiasis is transmitted 
person-to-person via ingestion of eggs after contact with 
the hands or perianal region of an infected individual, food 
or fomites that have been contaminated by an infected 
individual, or infected bedding or clothing. Autoinfection 
also occurs. Eggs hatch in the duodenum and larvae 
migrate to the cecum. Females mature in about a month, 
and remain viable for about another month. During this 
time, they migrate through the anus to deposit large num
-
bers of eggs on the perianal skin. Due to the relatively short 
life span of these helminths, continuous reinfection, as in 
institutional settings, is required, for long-standing 
 
»
Most individuals with pinworm infection are asymptom
-
atic. The most common symptom is perianal pruritus, 
particularly at night, due to the presence of the female 
worms or deposited eggs. Insomnia, restlessness, and 
enuresis are common in children. Perianal scratching may 
result in excoriation and impetigo. Many mild gastrointes
-
tinal symptoms have also been attributed to enterobiasis, 
but associations are not proven. Serious sequelae are 
uncommon. Rarely, worm migration results in inflamma
-
tion or granulomatous reactions of the gastrointestinal or 
genitourinary tracts. Colonic ulceration and eosinophilic 
colitis have been reported.
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Pinworm eggs are usually not found in stool. Diagnosis is 
made by finding adult worms or eggs on the perianal skin. 
A common test is to apply clear cellophane tape to the peri
-
anal skin, ideally in the early morning, followed by micro
-
scopic examination for eggs. The sensitivity of the tape test 
is reported to be about 50% for a single test and 90% for 
three tests. Nocturnal examination of the perianal area or 
gross examination of stools may reveal adult worms, which 
are about 1 cm in length. Eosinophilia is rare.
 
»
Treatment
Treatment is with single oral doses of albendazole (400 mg), 
mebendazole (100 mg) or pyrantel pamoate (11 mg/kg, to 
a maximum of 1 g). The dose is repeated in 2 weeks due to 
frequent reinfection. Other infected family members 
should be treated concurrently, and treatment of all close 
contacts may be appropriate when rates of reinfection are 
high in family, school, or institutional settings. Standard 
hand washing and hygiene practices are helpful in limiting 
spread. Perianal scratching should be discouraged. Washing 
of clothes and bedding should kill pinworm eggs.
Jourdan PM et al. Soil-transmitted helminth infections. Lancet. 
2017 Sep 4. [Epub ahead of print] [PMID: 28882382]
Moser W et al. Efficacy and safety of oxantel pamoate in school-
aged children infected with 
 on Pemba 
Island, Tanzania: a parallel, randomised, controlled, dose-
ranging study. Lancet Infect Dis. 2016 Jan;16(1):53–60. 
[PMID: 26388169]
Nutman TB. Human infection with 
 and 
other related 
 species. Parasitology. 2017 Mar; 
144(3):263–73. [PMID: 27181117]
Speich B et al. Efficacy and safety of albendazole plus ivermectin, 
albendazole plus mebendazole, albendazole plus oxantel 
pamoate, and mebendazole alone against 
 
and concomitant soil-transmitted helminth infections: a four-
arm, randomised controlled trial. Lancet Infect Dis. 
2015 Mar;15(3):277–84. [PMID: 25589326]
INVASIVE NEMATODE 
 
TRICHINOSIS
 
»
Ingestion of inadequately cooked pork or game.
 
»
Transient intestinal symptoms followed by fever, 
myalgias, and periorbital edema.
 
»
Eosinophilia and elevated serum muscle enzymes.
 
»
Trichinosis (or trichinellosis) is caused worldwide by 
Trichinella spiralis
 and related 
 species. The dis
-
ease is spread by ingestion of undercooked meat, most 
commonly pork in areas where pigs feed on garbage. When 
infected raw meat is ingested, 
 larvae are freed 
from cyst walls by gastric acid and pass into the small intes
-
tine. The larvae then invade intestinal epithelial cells, 
develop into adults, and the adults release infective larvae. 
These parasites travel to skeletal muscle via the blood
-
stream. They invade muscle cells, enlarge, and form cysts. 
These larvae may be viable for years. Pigs and other ani
-
mals become infected by eating infected uncooked food 
scraps or other animals, such as rats.
The worldwide incidence of trichinosis has decreased, 
but human infections continue to occur sporadically or in 
outbreaks, with estimates of 
∼
10,000 cases annually. In 
addition to undercooked pork, infections have been trans
-
mitted by ingestion of game and other animals, including 
bear and walrus in North America and wild boar and horse 
in Europe. In the United States, about 20 infections are 
reported annually, mostly from ingesting wild game.
 
»
Most infections are asymptomatic. In symptomatic cases, 
gastrointestinal symptoms, including diarrhea, vomiting, 
and abdominal pain, develop within the week after inges
-
tion of contaminated meat. These symptoms usually last 
for less than a week but can occasionally persist for much 
longer. During the following week, symptoms and signs

-
longer. During the following week, symptoms and signs 
related to migrating larvae are seen. These findings include, 
most notably, fever, myalgias, periorbital edema, and 
eosinophilia. Additional findings may include headache, 
cough, dyspnea, hoarseness, dysphagia, macular or pete
-
chial rash, and subconjunctival and retinal hemorrhages. 
Systemic symptoms usually peak within 2–3 weeks, and 
commonly persist for about 2 months. In severe cases, 
generally with large parasite burdens, muscle involvement 
can be pronounced, with severe muscle pain, edema, and 
weakness, especially in the head and neck. Muscle pain 
may persist for months. Uncommon severe findings 
include myocarditis, pneumonitis, and meningoencephali
-
tis, sometimes leading to death.
The clinical diagnosis is supported by findings of elevated 
serum muscle enzymes (creatine kinase, lactate dehydroge
-
nase, aspartate aminotransferase). The erthryocyte sedi
-
mentation rate is usually normal, which may help 
distinguish trichinosis from autoimmune myopathies. 
 
A commercial ELISA assay is available in the United States. 
Serologic tests become positive 2 or more weeks after infec
-
tion, but cross-reactivity can be seen with other parasites. 
Rising antibody titers are highly suggestive of the diagnosis. 
Muscle biopsy can usually be avoided, but if the diagnosis 
is uncertain, biopsy of a tender, swollen muscle may iden
-
tify 
 larvae. For maximal yield, biopsy material 
should be examined histologically, and a portion enzymati
-
cally digested to release larvae, but evaluation before 
 
3 weeks after infection may not show muscle larvae. Serum 
and muscle biopsy analysis are available from the CDC.
CMDT19_Ch35_p1510-p1549.indd   1544

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»
Treatment
No effective specific therapy for full-blown trichinosis 
has been identified. However, if infection is suspected 
early in the course of illness, treatment with mebenda
-
zole (2.5 mg/kg orally twice daily) or albendazole 
(5–7.5 mg/kg orally twice daily) will kill intestinal worms 
and may limit progression to tissue invasion. Supportive 
therapy for systemic disease consists of analgesics, anti
-
pyretics, bed rest and, in severe illness, corticosteroids. 
Infection is prevented by cooking to a temperature of at 
least 71
°
C for at least 1 minute. Irradiation of meat is also 
effective in eliminating 
 larvae, but freezing is 
not reliable.
Gottstein B et al. Epidemiology, diagnosis, treatment, and con
-
trol of trichinellosis. Clin Microbiol Rev. 2009 Jan;22(1): 
127–45. [PMID: 19136437]
TOXOCARIASIS
 
»
The dog roundworm 
Toxocara canis
, the cat roundworm 
Toxocara cati
, and less commonly other helminths may 
cause visceral larva migrans. 
T canis
 is highly prevalent in 
dogs. Humans are infected after ingestion of eggs in mate
-
rial contaminated by dog or other feces. Infection is spread 
principally by puppies and lactating females, and the eggs 
must be on the ground for several weeks before they are 
infectious. After ingestion by humans, larvae migrate to 
various tissues but cannot complete their life cycle.
 
»
Visceral larva migrans is seen principally in young chil
-
dren. Most infections are asymptomatic. The most com
-
monly involved organs are the liver and lungs. Presentations 
include cough, fever, wheezing, hepatomegaly, splenomeg
-
aly, lymphadenopathy, pulmonary infiltrates, and eosino
-
philia. Involvement of the CNS can occur rarely, leading to 
eosinophilic meningitis and other abnormalities. Ocular 
larva migrans is a distinct syndrome, usually in children 
older than is typical for visceral larva migrans. Children 
present with visual deficits, pain, and a retinal mass, which 
can be confused with retinoblastoma. 
Baylisascaris 
procyonis
, a roundworm of raccoons, can rarely cause 
visceral larva migrans in humans, typically with similar, 
but more severe manifestations than 
T canis
.
The diagnosis of visceral larva migrans is suggested by 
the finding of eosinophilia in a child with hepatomegaly or 
other signs of the disease, especially with a history of expo
-
sure to puppies. The diagnosis is confirmed by the identi
-
fication of larvae in a biopsy of infected tissue, usually 
performed when other diseases are suspected. Serologic 
tests may be helpful; an ELISA against a group of excreted 
antigens has shown good sensitivity and specificity. Molec
-
ular assays can identify specific pathogens. Most patients 
recover without specific therapy, although symptoms may 
persist for months.
 
»
Treatment
Treatment with antihelminthics or corticosteroids may be 
considered in severe cases. No drugs have been proven to 
be effective, but albendazole (400 mg orally twice daily for 
5 days), mebendazole, diethylcarbamazine, and ivermectin 
have been used, and albendazole has been recommended 
as the treatment of choice.
Ma G et al. Human toxocariasis. Lancet Infect Dis. 2018 Jan; 
18(1):e14–24. [PMID: 28781085]
CUTANEOUS LARVA MIGRANS 
 
(
Creeping Eruption
)
Cutaneous larva migrans is caused principally by larvae of 
the dog and cat hookworms, 
Ancylostoma braziliense
 and 
A 
caninum
. Other animal hookworms, gnathostomiasis, and 
strongyloidiasis may also cause this syndrome. Infections 
are common in warm areas, including the southeastern 
United States. They are most common in children. The 
disease is caused by the migration of worms through skin; 
the nonhuman parasites cannot complete their life cycles, 
so only cause cutaneous disease.
 
»
Intensely pruritic erythematous papules develop, usually 
on the feet or hands, followed within a few days by serpigi
-

»
-
nous tracks marking the course of the parasite, which may 
travel several millimeters per day (Figure 35–8). Several 
tracks may be present. The process may continue for 
weeks, with lesions becoming vesiculated, encrusted, or 
secondarily infected. Systemic symptoms or eosinophilia 
are uncommon.
The diagnosis is based on the characteristic appearance 
of the lesions. Biopsy is usually not indicated.
 
»
Treatment
Without treatment, the larvae eventually die and are 
absorbed. Mild cases do not require treatment. 
 
▲
Figure 35–8.
 
Cutaneous larva migrans on the foot. 
(Used, with permission, from Richard P . Usatine, MD, in 
The Color 
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Thiabendazole (10% aqueous suspension) can be applied 
topically three times daily for 5 or more days. Systemic 
therapy with albendazole (400 mg orally once or twice 
daily for 3–5 days) or ivermectin (200 mcg/kg orally single 
dose) is highly effective.
Kincaid L et al. Management of imported cutaneous larva 
migrans: a case series and mini-review. Travel Med Infect Dis. 
2015 Sep–Oct;13(5):382–7. [PMID: 26243366]
FILARIASIS
LYMPHATIC FILARIASIS
 
»
Episodic attacks of lymphangitis, lymphadenitis, 
and fever.
 
»
Chronic progressive swelling of extremities and 
genitals; hydrocele; chyluria; lymphedema.
 
»
Microfilariae in blood, chyluria, or hydrocele fluid; 
 
»
Lymphatic filariasis is caused by three filarial nematodes: 
, and 
Brugia timori
, 
and is among the most important parasitic diseases of man. 
Approximately 120 million people are infected with these 
organisms in tropical and subtropical countries, about a 
third of these suffer clinical consequences of the infections, 
and many are seriously disfigured. 
W bancrofti
 causes 
about 90% of episodes of lymphatic filariasis. It is transmit
-
ted by 
Culex, Aedes
, and 
Anopheles
 mosquitoes and is 
widely distributed in the tropics and subtropics, including 
sub-Saharan Africa, Southeast Asia, the western Pacific, 
India, South America, and the Caribbean. 
B malayi
 is 
transmitted by 
Mansonia
 and 
Anopheles
endemic in parts of China, India, Southeast Asia, and the 
Pacific. 
B timori
 is found only in islands of southeastern 
Indonesia. 
Mansonella
 are filarial worms transmitted by 
midges and other insects in Africa and South America.
Humans are infected by the bites of infected mosqui
-
toes. Larvae then move to the lymphatics and lymph nodes, 
where they mature over months to thread-like adult 
worms, and then can persist for many years. The adult 
worms produce large numbers of microfilariae, which are 
released into the circulation, and infective to mosquitoes, 
particularly at night (except for the South Pacific, where 
microfilaremia peaks during daylight hours).
 
»
Many infections remain asymptomatic despite circulating 
microfilariae. Clinical consequences of filarial infection are 
principally due to inflammatory responses to developing, 
mature, and dying worms. The initial manifestation of 
infection is often acute lymphangitis, with fever, painful 
lymph nodes, edema, and inflammation spreading periph
-
erally from involved lymph nodes (in contrast to bacterial 
lymphangitis, which spreads centrally). Lymphangitis and 
lymphadenitis of the upper and lower extremities is com
-
mon (Figure 35–9); genital involvement, including epidid
-
ymitis and orchitis, with scrotal pain and tenderness, 
occurs principally only with 
 infection. Acute 
attacks of lymphangitis last for a few days to a week and 
may recur a few times per year. Filarial fevers may also 
occur without lymphatic inflammation.
The most common chronic manifestation of lymphatic 
filariasis is swelling of the extremities or genitals due to 
chronic lymphatic inflammation and obstruction. Extrem
-
ities become increasingly swollen, with a progression over 
time from pitting edema, to nonpitting edema, to sclerotic 
changes of the skin that are referred to as elephantiasis. 
Genital involvement, particularly with 
, occurs 
more commonly in men, progressing from painful epididy
-
mitis to hydroceles that are usually painless but can 
become very large, with inguinal lymphadenopathy, thick
-
ening of the spermatic cord, scrotal lymphedema, thicken
-
ing and fissuring of the scrotal skin, and occasionally 
chyluria. Lymphedema of the female genitalia and breasts 
Tropical pulmonary eosinophilia is a distinct syn
-

-
-
drome principally affecting young adult males with either 
 or 
B malayi
 infection, but typically without 
microfilaremia. This syndrome is characterized by 
asthma-like symptoms, with cough, wheezing, dyspnea, 
and low-grade fevers, usually at night. Without treatment, 
tropical pulmonary eosinophilia can progress to intersti
-
tial fibrosis and chronic restrictive lung disease. 
 
can inhabit serous cavities, the retroperitoneum, the eye, 
or the skin, and cause abnormalities related to inflamma
-
tion at these sites.
 
▲
Figure 35–9.
 
Elephantiasis of legs due to filariasis. 
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The diagnosis of lymphatic filariasis is strongly suggested 
by characteristic findings of lymphangitis or lymphatic 
obstruction in persons with risk factors for the disease. The 
diagnosis is confirmed by finding microfilariae, usually in 
blood, but microfilariae may be absent, especially early in 
the disease progression (first 2–3 years) or with chronic 
obstructive disease. To increase yields, blood samples are 
obtained at about midnight in most areas, but during day
-
light hours in the South Pacific. Smears are evaluated by 
wet mount to identify motile parasites and by Giemsa 
staining; these examinations can be delayed until the fol
-
lowing morning, with storage of samples at room tempera
-
ture. Of note, the periodicity of microfilaremia is variable, 
and daytime samples may yield positive results. Microfi
-
lariae may also be identified in hydrocele fluid or chylous 
urine. Eosinophilia is usually absent, except during acute 
inflammatory syndromes. Serologic tests may be helpful 
but cannot distinguish past and active infections. Rapid 
antigen tests with sensitivity and specificity over 90% are 
available for detection of 
. These can be consid
-
ered the diagnostic tests of choice and are increasingly used 
to guide control programs. However, cross-reactivity with 
Loa loa
 infections has been described. Due to potential 
severe toxicity, caution is appropriate before treatment with 
ivermectin for positive 
 antigen tests in areas 
also endemic for 
L loa
 infection. Multiple molecular tests, 
including field-friendly LAMP assays, have been devel
-
oped. Adult worms may also be found in lymph node 
biopsy specimens (although biopsy is not usually clinically 
indicated) or by ultrasound of a scrotal hydrocele or 
lymphedematous breast. When microfilaremia is lacking, 
especially if sophisticated techniques are not available, 
diagnoses may need to be made on clinical grounds.
 
»
Treatment & Control
A. Drug Treatment
Diethylcarbamazine is the drug of choice, but it cannot 
cure infections due to its limited action against adult 
worms. Asymptomatic infection and acute lymphangitis 
are treated with this drug (2 mg/kg orally three times daily) 
for 10–14 days, leading to a marked decrease in microfila
-
remia. Therapy may be accompanied by allergic symptoms, 
including fever, headache, malaise, hypotension, and bron
-
chospasm, probably due to release of antigens from dying 
worms. For this reason, treatment courses may begin with 
a lower dosage, with escalation over the first 4 days of treat
-
ment. Single annual doses of diethylcarbamazine (6 mg/kg 
orally), alone or with ivermectin (400 mcg/kg orally) or 
albendazole (400 mg orally) may be as effective as longer 
courses of diethylcarbamazine. A single dose of all three 
drugs offered superior clearance of parasites compared to 
diethylcarbamazine plus albendazole. When onchocercia
-
sis or loiasis is suspected, it may be appropriate to withhold 
diethylcarbamazine to avoid severe reactions to dying 
microfilariae; rather, ivermectin plus albendazole may be 
given, although these drugs are less active than diethylcar
-
bamazine against adult worms. Appropriate management 
of advanced obstructive disease is uncertain. Drainage of 
hydroceles provides symptomatic relief, although they will 
recur. Therapy with diethylcarbamazine cannot reverse 
chronic lymphatic changes, but is typically provided to 
lower worm burdens. An interesting approach under study 
is to treat with doxycycline (100–200 mg/day orally for 
4–6 weeks), which kills obligate intracellular 
Wolbachia
 
bacteria, leading to death of adult filarial worms. 
Doxycycline was also effective at controlling 
Mansonella 
perstans
 infection, which does not respond well to standard 
antifilarial drugs. Secondary bacterial infections must be 
treated. Surgical correction may be helpful in some cases.

perstans
B. Disease Control
Avoidance of mosquitoes is a key measure; preventive mea
-
sures include the use of screens, bed nets (ideally treated 
with insecticide), and insect repellents. Community-based 
treatment with single annual doses of effective drugs offers 
a highly effective means of control. The current WHO 
strategy for control includes mass treatment of at risk com
-
munities with single annual doses of diethylcarbamazine 
plus albendazole or, for areas with onchocerciasis, albenda
-
zole plus ivermectin; in some circumstances, more fre
-
quent dosing offers improved control.
Thomsen EK et al. Efficacy, safety, and pharmacokinetics of 
coadministered diethylcarbamazine, albendazole, and iver
-
mectin for treatment of Bancroftian Filariasis. Clin Infect Dis. 
2016 Feb 1;62(3):334–41. [PMID: 26486704]
ONCHOCERCIASIS
 
»
Conjunctivitis progressing to blindness.
 
»
Severe pruritus; skin excoriations, thickening, and 
depigmentation; and subcutaneous nodules.
 
»
Microfilariae in skin snips and on slit-lamp exami
-
nation; adult worms in subcutaneous nodules.
 
»
Onchocerciasis, or river blindness, is caused by 
Oncho
-
cerca volvulus
. An estimated 37 million persons are 
infected, of whom 3–4 million have skin disease, 500,000 
have severe visual impairment, and 300,000 are blinded. 
Over 99% of infections are in sub-Saharan Africa, espe
-
cially the West African savanna, with about half of cases in 
Nigeria and Congo. In some hyperendemic African 
villages, close to 100% of individuals are infected, and 10% 
or more of the population is blind. The disease is also 
prevalent in the southwestern Arabian peninsula and 
Latin America, including southern Mexico, Guatemala, 
Venezuela, Colombia, Ecuador, and northwestern Brazil. 
Onchocerciasis is transmitted by simulium flies (black
-
flies). These insects breed in fast-flowing streams and bite 
during the day.
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After the bite of an infected blackfly, larvae are depos
-
ited in the skin, where adults develop over 6–12 months. 
Adult worms live in subcutaneous connective tissue or 
muscle nodules for a decade or more. Microfilariae are 
released from the nodules and migrate through subcutane
-
ous and ocular tissues. Disease is due to responses to 
worms and to intracellular 
Wolbachia
 bacteria.
 
»
After an incubation period of up to 1–3 years, the disease 
typically produces an erythematous, papular, pruritic 
rash, which may progress to chronic skin thickening and 
depigmentation. Itching may be severe and unresponsive 
to medications, such that more disability-adjusted life 
years are lost to onchocercal skin problems than to blind
-
ness. Numerous firm, nontender, movable subcutaneous 
nodules of about 0.5–3 cm, which contain adult worms, 
may be present. Due to differences in vector habits, these 
nodules are more commonly on the lower body in Africa 
but on the head and upper body in Latin America. Ingui
-
nal and femoral lymphadenopathy is common, at times 
resulting in a “hanging groin, ” with lymph nodes hanging 
within a sling of atrophic skin. Patients may also have 
systemic symptoms, with weight loss and musculoskele
-
tal pain.
The most serious manifestations of onchocerciasis 
involve the eyes. Microfilariae migrating through the eyes 
elicit host responses that lead to pathology. Findings 
include punctate keratitis and corneal opacities, progress
-
ing to sclerosing keratitis and blindness. Iridocyclitis, glau
-
coma, choroiditis, and optic atrophy may also lead to vision 
loss. The likelihood of blindness after infection varies 
greatly based on geography, with the risk greatest in 
savanna regions of West Africa.
The diagnosis is made by identifying microfilariae in skin 
snips, by visualizing microfilariae in the cornea or anterior 
chamber by slit-lamp examination, by identification of 
adult worms in a biopsy or aspirate of a nodule or, uncom
-
monly, by identification of microfilariae in urine. Skin 
snips from the iliac crest (Africa) or scapula (Americas) are 
allowed to stand in saline for 2–4 hours or longer, and then 
examined microscopically for microfilariae. Deep punch 
biopsies are not needed, and if suspicion persists after a 
skin snip is negative, the procedure should be repeated. 
Ultrasound may identify characteristic findings suggestive 
of adult worms in skin nodules. When the diagnosis 
remains difficult, the Mazzotti test can be used; exacerba
-
tion of skin rash and pruritus after a 50-mg dose of dieth
-
ylcarbamazine is highly suggestive of the diagnosis. This 
test should only be used after other tests are negative, since 
treatment can elicit severe skin and eye reactions in heavily 
infected individuals. A related and safer test using topical 
diethylcarbamazine is also available. Eosinophilia is a com
-
mon, but inconsistent finding. Antigen and antibody 
detection tests are under study.
 
»
The treatment of choice is ivermectin, which kills microfi
-
lariae, but not adult worms, so disease control requires repeat 
administrations. Treatment is with a single oral dose of 
150 mcg/mL, but schedules for re-treatment have not been 
standardized. One regimen is to treat every 3 months for 
 
1 year, followed by treatment every 6–12 months for the sus
-
pected life span of adult worms (about 15 years). Treatment 
results in marked reduction in numbers of microfilariae in the 
skin and eyes, although its impact on the progression of visual 
loss remains uncertain. Toxicities of ivermectin are generally 
mild; fever, pruritus, urticaria, myalgias, edema, hypotension, 
and tender lymphadenopathy may be seen, presumably due 
to reactions to dying worms. Ivermectin should be used with 
caution in patients also at risk for loiasis, since it can elicit

caution in patients also at risk for loiasis, since it can elicit 
severe reactions including encephalopathy. As with other 
filarial infections, doxycycline acts against 
O volvulus
 by kill
-
ing intracellular 
Wolbachia
 bacteria. A course of 100 mg/day 
for 4–6 weeks kills the bacteria and prevents parasite embryo
-
genesis for at least 18 months. Doxycycline shows promise as 
a first-line agent to treat onchocerciasis because of its 
improved activity against adult worms compared to other 
agents and limited toxicity due to the slow action of the drug.
Protection against onchocerciasis includes avoidance of 
biting flies. Major efforts are underway to control insect 
vectors in Africa. In addition, mass distribution of iver
-
mectin for intermittent administration at the community 
level is ongoing, and the prevalence of severe skin and eye 
disease is decreasing.
Debrah AY et al. Doxycycline leads to sterility and enhanced 
killing of female 
Onchocerca volvulus
 worms in an area with 
persistent microfilaridermia after repeated ivermectin treat
-
ment: a randomized, placebo-controlled, double-blind trial. 
Clin Infect Dis. 2015 Aug 15;61(4):517–26. [PMID: 25948064]
LOIASIS
 
»
Subcutaneous swellings; adult worms migrating 
across the eye.
 
»
Encephalitis, which may be brought on by 
 
»
Microfilariae in the blood.
 
»
Loiasis is a chronic filarial disease caused by infection with 
Loa loa
. The infection occurs in humans and monkeys in 
rainforest areas of West and central Africa. An estimated 
3–13 million persons are infected. The disease is transmit
-
ted by chrysops flies, which bite during the day. Over 
6–12 months after infection, larvae develop into adult 
worms, which migrate through subcutaneous tissues, 
including the subconjunctiva (leading to the term “eye 
worm”). Adults can live for up to 17 years.
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»
Many infected persons are asymptomatic, although they 
may have high levels of microfilaremia and eosinophilia. 
Transient subcutaneous swellings (Calabar swellings) 
develop in symptomatic persons. The swellings are nonery
-
thematous, up to 20 cm in diameter, and may be preceded 
by local pain or pruritus. They usually resolve after 
2–4 days but occasionally persist for several weeks. Calabar 
swellings are commonly seen around joints and may recur 
at the same or different sites. Visitors from nonendemic 
areas are more likely to have allergic-type reactions, includ
-
ing pruritus, urticaria, and angioedema. Adult worms may 
be seen to migrate across the eye, with either no symptoms 
or conjunctivitis, with pain and edema. The most serious 
complication of loiasis is encephalitis, which is most com
-
mon in those with high-level microfilaremia and microfi
-
lariae in the CSF. Symptoms may range from headache and 
insomnia to coma and death. Encephalitis may be brought 
on by treatment with diethylcarbamazine or ivermectin. 
Other complications of loiasis include kidney disease, with 
hematuria and proteinuria; endomyocardial fibrosis; and 
The diagnosis is established by identifying microfilariae in 
blood. Blood is evaluated as for lymphatic filariasis, but for 
loiasis blood should be obtained during the day. The failure 
to find microfilariae does not rule out the diagnosis. Iden
-
tification of a migrating eye worm is also diagnostic. Sero
-
logic tests may be helpful in persons from nonendemic 
areas who may be acutely ill without detectable microfila
-
remia, but such tests have limited utility for residents of 
endemic areas because most of them will have positive test 
results. Molecular methods, including field-friendly LAMP 
assays, are available to rule out loiasis before administra
-
tion of ivermectin for the control of other filarial 
 
»
Treatment
The treatment of choice is diethylcarbamazine, which 
eliminates microfilariae and has some activity against adult 
worms. Treatment is with 8–10 mg/kg/day orally for 
21 days; repeat courses may be needed. Mild side effects are 
common, including fever, pruritus, arthralgias, nausea, 
diarrhea, and Calabar swellings. These symptoms may be 
lessened by antihistamines or corticosteroids. Patients with 
large worm burdens are at greater risk for serious compli
-
cations of therapy, including kidney injury, shock, enceph
-
alitis, coma, and death. Treatment with ivermectin, which 
is highly active against microfilariae, but not adult worms, 
entails a higher risk of severe reactions. To attempt to avoid 
these sequelae, pretreatment with corticosteroids and anti
-
histamines, and escalating dosage of diethylcarbamazine 
have been used, but this strategy does not prevent 
encephalitis. The circulating parasite load that indicates 
particular risk for severe complications with therapy has 
been estimated at 2500/mL. Strategies to treat patients with 
high parasite loads include (1) no treatment; (2) apheresis, 
if available, to remove microfilariae prior to therapy with 
diethylcarbamazine; or (3) therapy with albendazole, 
which appears to be well tolerated due to its slow antipara
-
sitic effects, prior to therapy with diethylcarbamazine or 
ivermectin. Doxycycline is not effective for loiasis.
Kamgno J et al. Effect of two or six doses 800 mg of albendazole 
every two months on 
Loa loa
 microfilaraemia: a double blind, 
randomized, placebo-controlled trial. PLoS Negl Trop Dis. 
2016 Mar 11;10(3):e0004492. [PMID: 26967331]
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36
Samuel A. Shelburne III, MD, PhD 
 
CANDIDIASIS
 
»
Common normal flora but opportunistic 
pathogen.
 
»
Mucosal disease, particularly vaginitis and 
 
»
Risk factors for fungemia: neutropenia, intrave
-
nous catheter, abdominal surgery, total parenteral 
nutrition, kidney disease, broad-spectrum 
 
»
 can be cultured from the mouth, vagina, 
and feces of most people. Cutaneous and oral lesions are 
discussed in Chapters 6 and 8, respectively. The risk factors 
for invasive candidiasis include prolonged neutropenia, 
recent abdominal surgery, broad-spectrum antibiotic ther
-
apy, kidney disease, and the presence of intravascular cath
-
eters (especially when providing total parenteral nutrition). 
Cellular immunodeficiency predisposes to mucocutaneous 
disease. When no other underlying cause is found, persis
-
tent oral or vaginal candidiasis should arouse a suspicion of 
 
»
A. Mucosal Candidiasis
Esophageal involvement
 is the most frequent type of sig
-
nificant mucosal disease. Presenting symptoms include 
substernal odynophagia, gastroesophageal reflux, or nau
-
sea without substernal pain. Oral candidiasis, though often 
associated, is not invariably present. Diagnosis is best con
-
firmed by endoscopy with biopsy and culture.
Vulvovaginal candidiasis
 occurs in an estimated 75% 
of women during their lifetime. Risk factors include 
pregnancy, uncontrolled diabetes mellitus, broad-spectrum 
antimicrobial treatment, corticosteroid use, and HIV 
infection. Symptoms include acute vulvar pruritus, burning 
vaginal discharge, and dyspareunia.
B. Candidal Funguria
Most cases of candidal funguria are asymptomatic and 
represent specimen contamination or bladder colonization. 
However, symptoms and signs of true 
Candida
 urinary 
tract infections are indistinguishable from bacterial uri
-
nary tract infections and can include urgency, hesitancy, 
fever, chills, or flank pain.
C. Invasive Candidiasis
Invasive candidiasis can be (1) candidemia without deep-
seated infection; (2) candidemia with deep-seated infection 
(typically eyes, kidney, or abdomen); and (3) deep-seated 
candidiasis in the absence of bloodstream infection. Vary
-
ing ratios of these clinical entities depends on the predomi
-
nating risk factors for affecting patients (ie, neutropenia, 
dialysis, postsurgical). The clinical presentation of candi
-
demia varies from minimal fever to septic shock that can 
resemble a severe bacterial infection. The diagnosis of 
invasive 
Candida
 infection is problematic because 
Candida
 
species are often isolated from mucosal sites in the absence 
of invasive disease while blood cultures are positive only 
50% of the time in invasive infection. Consecutively positive 
(1,3)-beta-D-glucan results may be used to guide empiric 
therapy in high-risk patients even in the absence of positive 
blood cultures.
Hepatosplenic candidiasis can occur following pro
-
longed neutropenia in patients with underlying hemato
-
logic cancers, but this entity is less common in the era of 
widespread antifungal prophylaxis. Typically, fever and 
variable abdominal pain present weeks after chemotherapy, 
when neutrophil counts have recovered. Blood cultures are 
generally negative.
D. Candidal Endocarditis
Candidal endocarditis is a rare infection that is most fre
-
quently associated with exposure to a health care setting. 
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Candidal endocarditis occurs with increased frequency on 
prosthetic valves in the first few months following surgery. 
The diagnosis is established definitively by culturing 
Candida
 from emboli or from vegetations at the time of 
valve replacement.
 
»
Treatment
Therapy of 
esophageal candidiasis
 depends on the sever
-
ity of disease. If patients are able to swallow and take ade
-
quate amounts of fluid orally, fluconazole, 100 mg/day (or 
itraconazole solution, 10 mg/mL, 200 mg/day), for 
10–14 days usually suffices. In the individual who is more 
ill or in whom esophagitis has developed while taking 
fluconazole, options include oral or intravenous voricon
-
azole, 200 mg twice daily; intravenous amphotericin B, 
0.3 mg/kg/day; intravenous caspofungin, 50 mg/day; intra
-
venous anidulafungin, 100 mg on day 1, then 50 mg/day; 
or intravenous micafungin, 150 mg/day. Relapse is com
-
mon with all agents when there is underlying HIV infec
-
tion without adequate immune reconstitution.
Various topical azole preparations (eg, clotrimazole, 
100-mg vaginal tablet for 7 days, or miconazole, 200-mg 
vaginal suppository for 3 days) are effective against 
vulvovaginal candidiasis
. One 150-mg oral dose of fluco
-
nazole has been shown to have equivalent efficacy with 
better patient acceptance. Disease recurrence is common 
but can be decreased with weekly fluconazole therapy 
 
(150 mg weekly).
Candidal funguria frequently resolves with discontinuance 
of antibiotics or removal of bladder catheters. Clinical ben
-
efit from treatment of asymptomatic candiduria has not 
been demonstrated, but persistent funguria should raise 
the suspicion of invasive infection. When symptomatic 
funguria persists, oral fluconazole, 200 mg/day for 
7–14 days, can be used.
The 2016 guidelines for management of candidiasis recom
-
mend an echinocandin such as caspofungin (loading dose 
of 70 mg intravenously once, then 50 mg intravenously 
daily), micafungin (100 mg intravenously daily), or anidu
-
lafungin (loading dose of 200 mg intravenously once, then 
100 mg intravenously daily). Fluconazole (loading dose of 
800 mg [12 mg/kg] intravenously, then 400 mg [6 mg/kg] 
intravenously daily) is an acceptable alternative for less 
critically ill patients without recent azole exposure. Ther
-
apy for candidemia should be continued for 2 weeks after 
the last positive blood culture and resolution of symptoms 
and signs of infection. A dilated fundoscopic examination 
is recommended for patients with candidemia to exclude 
endophthalmitis and repeat blood cultures should be 
drawn to demonstrate organism clearance. Once patients 
have become clinically stable, parenteral therapy can be 
discontinued and oral fluconazole, 200–800 mg orally 
given as one or two doses daily, is used to complete treat
-
ment for isolates known to be or likely to be susceptible to 
fluconazole. Removal or exchange of intravascular cathe
-
ters is generally recommended for patients with candi
-
demia in whom the catheter is the suspected source of 
Non-
albicans
 species of 
Candida
 account for over 50% 
of clinical bloodstream isolates and often have resistance 
patterns that are different from 
C albicans
. An echinocan
-
din is recommended for treatment of 
Candida glabrata
 
infection with a transition to oral fluconazole or voricon
-
azole reserved for patients whose isolates are known to be 
susceptible to these agents. 
C glabrata
 that is resistant to 
azoles and echinocandins is being increasingly reported. 
Similarly, 
Candida krusei
 is generally fluconazole-resistant 
and so should be treated with an alternative agent, such as 
echinocandin or voriconazole. Fluconazole may be optimal 
for 
Candida parapsilosis
 due to possible echinocandin 
resistance in such isolates. Cases of health care–associated 
infections due to multidrug-resistant 

for 
 have 
been described from several countries, including the 
United States, with most cases having been treated with 
echinocandins.
Although the isolation of 
Candida
 species from muco
-
sal sites raises the possibility of invasive candidiasis, ran
-
domized trials of empiric antifungal agents in such 
situations have not shown clear clinical benefit. Hepato
-
splenic candidiasis generally requires treatment for several 
months until lesion resolution.
Best results are achieved with a combination of medical 
and surgical therapy. Lipid formulation amphotericin B 
(3–5 mg/kg/day) or high-dose echinocandin (caspofungin 
150 mg/day, micafungin 150 mg/day, or anidulafungin 
200 mg/day) is recommended as initial therapy. Step-down 
or long-term suppressive therapy for nonsurgical candi
-
dates may be done with fluconazole at 6–12 mg/kg/day for 
susceptible organisms.
In high-risk patients undergoing induction chemo
-
therapy, bone marrow transplantation, or liver transplan
-
tation, prophylaxis with antifungal agents has been shown 
to prevent invasive fungal infections, although the effect 
on mortality and the preferred agent remain debated.
Pappas PG et al. Clinical practice guideline for the management 
of candidiasis: 2016 update by the Infectious Diseases Society 
of America. Clin Infect Dis. 2016 Feb 15;62(4):e1–50. [PMID: 
26679628]
Timsit JF et al. Empirical micafungin treatment and survival 
without invasive fungal infection in adults with ICU-acquired 
sepsis, 
Candida
 colonization, and multiple organ failure: the 
EMPIRICUS randomized clinical trial. JAMA. 2016 Oct 18; 
316(15):1555–64. [PMID: 27706483]
Tsay S et al. Approach to the investigation and management of 
Candida auris,
 an emerging multi-drug resistant 
yeast. Clin Infect Dis. 2018 Jan 6;66(2):306–11. [PMID: 
29020224]
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HISTOPLASMOSIS
 
»
Exposure to bird and bat droppings; common 
along river valleys (especially the Ohio River and 
the Mississippi River valleys).
 
»
Most patients asymptomatic; respiratory illness 
most common clinical problem.
 
»
Disseminated disease common in AIDS or other 
immunosuppressed states; poor prognosis.
 
»
Blood and bone marrow cultures as well as urine 
polysaccharide antigen, useful in diagnosis of dis
-
seminated disease.
 
»
Histoplasmosis is caused by 
, 
 
a dimorphic fungus that has been isolated from soil con
-
taminated with bird or bat droppings in endemic areas 
 
(central and eastern United States, eastern Canada, Mexico, 
Central America, South America, Africa, and Southeast Asia). 
Infection presumably takes place by inhalation of conidia. 
These convert into small budding cells that are engulfed by 
phagocytes in the lungs. The organism proliferates and under
-
goes lymphohematogenous spread to other organs.
 
»
Most cases of histoplasmosis are asymptomatic or mild and 
thus go unrecognized. Past infection is recognized by pul
-
monary and splenic calcification noted on incidental 
radiographs. Symptomatic infection may present with mild 
influenza-like illness, often lasting 1–4 days. Moderately 
severe infections are frequently diagnosed as atypical 
pneumonia. These patients have fever, cough, and mild 
central chest pain lasting 5–15 days.
Clinically evident infections occur in several forms: 
 
(1) 
Acute pulmonary histoplasmosis
 frequently occurs in 
epidemics, often when soil containing infected bird or bat 
droppings is disturbed. Clinical manifestations can vary 
from a mild influenza-like illness to severe pneumonia. 
The illness may last from 1 week to 6 months but is almost 
never fatal. (2) 
Progressive disseminated histoplasmosis
 
is commonly seen in patients with underlying HIV infec
-
tion (with CD4 cell counts usually less than 100 cells/mcL) 
or other conditions of impaired cellular immunity. Dis
-
seminated histoplasmosis has also been reported in patients 
from endemic areas taking tumor necrosis factor (TNF)–
blocking agents. It is characterized by fever and multiple 
organ system involvement. Chest radiographs may show a 
miliary pattern. Presentation may be fulminant, simulating 
septic shock, with death ensuing rapidly unless treatment is 
provided. Symptoms usually consist of fever, dyspnea, 
cough, loss of weight, and prostration. Ulcers of the 
mucous membranes of the oropharynx may be present. 
The liver and spleen are nearly always enlarged, and all the 
organs of the body are involved, particularly the adrenal 
glands; this results in adrenal insufficiency in about 50% 
 
of patients. Gastrointestinal involvement may mimic 
inflammatory bowel disease. (3) 
Chronic pulmonary 
histoplasmosis
 is usually seen in older patients who have 
underlying chronic lung disease. Chest radiographs show 
various lesions including apical cavities, infiltrates, and 
nodules. (4) 
Complications of pulmonary histoplasmosis
 
include granulomatous mediastinitis characterized by per
-
sistently enlarged mediastinal lymph nodes and fibrosing 
mediastinitis in which an excessive fibrotic response to 
Histoplasma
 infection results in compromise of pulmonary 
vascular structures.
Most patients with chronic pulmonary disease show ane
-
mia of chronic disease. Bone marrow involvement with 
pancytopenia may be prominent in disseminated forms. 
Marked lactate dehydrogenase (LD) and ferritin elevations 
are also common as are mild elevations of serum aspartate 
aminotransferase.
With pulmonary involvement, sputum culture is rarely 
positive except in chronic disease; antigen testing of bron
-
choalveolar lavage fluid may be helpful in acute disease. 
The combination of a first morning urine and serum poly
-

-
-
saccharide antigen assays has an 83% sensitivity for the 
diagnosis of acute pulmonary histoplasmosis. Blood or 
bone marrow cultures from immunocompromised patients 
with acute disseminated disease are positive more than 
80% of the time, but may take several weeks for growth. 
The urine antigen assay has a sensitivity of greater than 
90% for disseminated disease in immunocompromised 
patients and a declining titer can be used to follow response 
to therapy.
 
»
Treatment
For progressive localized disease and for mild to moder
-
ately severe nonmeningeal disseminated disease in 
immunocompetent or immunocompromised patients, 
itraconazole, 200–400 mg/day orally divided into two 
doses, is the treatment of choice with an overall response 
rate of approximately 80%. The oral solution is better 
absorbed than the capsule formulation, which requires 
gastric acid for absorption. Therapeutic drug monitoring 
of itraconazole levels should be performed to assess ade
-
quacy of drug absorption. Duration of therapy ranges from 
weeks to several months depending on the severity of 
illness. Intravenous amphotericin B formulations are used 
in patients with more severe illness such as meningitis, 
with guidelines favoring the use of liposomal or lipid com
-
plex amphotericin formulations at a dose of 3 mg/kg/day 
over amphotericin B deoxycholate. Patients with AIDS-
related histoplasmosis require lifelong suppressive therapy 
with itraconazole, 200 mg/day orally, although secondary 
prophylaxis may be discontinued if immune reconstitution 
occurs in response to antiretroviral therapy. Criteria for 
discontinuing secondary prophylaxis include 1 year of suc
-
cessful antifungal therapy and a CD4 cell count of greater 
CMDT19_Ch36_p1550-p1563.indd   1552

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CMDT 2019
than 150 cells/mcL and 6 months or more of antiretroviral 
treatment (ART). There is no clear evidence that antifungal 
or anti-inflammatory agents are of benefit for patients with 
granulomatous mediastinitis or fibrosing mediastinitis 
although oral itraconazole is often used. Reported out
-
comes in patients with fibrosing mediastinitis treated with 
either surgical procedures or nonsurgical intravascular 
interventions appear to be relatively good.
Azar MM et al. Clinical perspectives in the diagnosis and man
-
agement of histoplasmosis. Clin Chest Med. 2017 Sep; 
38(3):403–15. [PMID: 28797485]
Azar MM et al. Laboratory diagnostics for histoplasmosis. J Clin 
Microbiol. 2017 Jun;55(6):1612–20. [PMID: 28275076]
COCCIDIOIDOMYCOSIS
 
»
Influenza-like illness: malaise, fever, backache, 
headache, and cough.
 
»
Erythema nodosum common with acute 
 
»
Dissemination may result in meningitis, bony 
lesions, or skin and soft tissue abscesses.
 
»
Chest radiograph findings vary from pneumonitis 
to cavitation.
 
»
Serologic tests useful; large spherules containing 
endospores demonstrable in sputum or tissues.
 
»
Coccidioidomycosis should be considered in the diagnosis 
of any obscure illness in a patient who has lived in or vis
-
ited an endemic area. Infection results from the inhalation 
of arthroconidia of 
Coccidioides immitis
 or 
C posadasii
; 
both organisms are molds that grow in soil in certain arid 
regions of the southwestern United States, in Mexico, and 
in Central and South America. Less than 1% of immuno
-
competent persons show dissemination, but among these 
patients, the mortality rate is high.
In HIV-infected people in endemic areas, coccidioido
-
mycosis is a common opportunistic infection. In these 
patients, disease manifestations range from focal pulmo
-
nary infiltrates to widespread miliary disease with multiple 
organ involvement and meningitis; severity is inversely 
related to the extent of control of the HIV infection.
 
»
primary coccidioidomycosis
 occur in about 
40% of infections. Symptom onset (after an incubation 
period of 10–30 days) is usually that of a respiratory tract 
illness with fever and occasionally chills. Coccidioidomy
-
cosis is a common, frequently unrecognized, etiology of 
community-acquired pneumonia in endemic areas.
Erythema nodosum may appear 2–20 days after 
onset of symptoms. Persistent pulmonary lesions, vary
-
ing from cavities and abscesses to parenchymal nodular 
densities or bronchiectasis, occur in about 5% of diag
-
Disseminated disease
 occurs in about 0.1% of white 
and 1% of nonwhite patients. Filipinos and blacks are espe
-
cially susceptible, as are pregnant women of all races. Any 
organ may be involved. Pulmonary findings usually 
become more pronounced, with mediastinal lymph node 
enlargement, cough, and increased sputum production. 
Lung abscesses may rupture into the pleural space, produc
-
ing an empyema. These may also extend to bones and skin. 
Fungemia may occur and is characterized clinically by a 
diffuse miliary pattern on chest radiograph and by early 
death. The course may be particularly rapid in immuno
-
suppressed patients. Clinicians caring for immunosup
-
pressed patients in endemic areas need to consider that 
patients may be latently infected.
Meningitis occurs in 30–50% of cases of dissemination. 
Subcutaneous abscesses and verrucous skin lesions are 
especially common in fulminating cases. HIV-infected 
persons with disseminated disease have a higher incidence 
of miliary infiltrates, lymphadenopathy, and meningitis, 
but skin lesions are uncommon.
In 
, there may be moderate 
leukocytosis and eosinophilia. Serologic testing is useful 
for both diagnosis and prognosis. The immunodiffusion

In 
for both diagnosis and prognosis. The immunodiffusion 
tube precipitin test and enzyme-linked immunosorbent 
assay (ELISA) detect IgM antibodies and are both useful 
for diagnosis early in the disease process. A persistent 
rising IgG complement fixation titer (1:16 or more) is 
suggestive of disseminated disease; in addition, immuno
-
diffusion complement fixation titers can be used to 
assess the adequacy of therapy. Serum complement fixa
-
tion titer may be low when there is meningitis but no 
other disseminated disease. In patients with HIV-related 
coccidioidomycosis, the false-negative rate may be as 
high as 30%.
Demonstrable complement-fixing antibodies in spinal 
fluid are diagnostic of coccidioidal meningitis. These are 
found in over 90% of cases; 
Coccidioides
 antigen or 
(1,3)-beta-D-glucan testing may augment (not replace) 
CSF antibody testing. Spinal fluid findings include 
increased cell count with lymphocytosis and reduced 
glucose. Spinal fluid culture is positive in approximately 
30% of meningitis cases. Spherules filled with endospores 
may be found in biopsy specimens of soft tissues and bone; 
though they are not infectious, they convert to the highly 
contagious arthroconidia when grown in culture media. 
Blood cultures are rarely positive.
C. Imaging
Radiographic findings vary, but patchy, nodular, and 
lobar upper lobe pulmonary infiltrates are most common. 
Hilar lymphadenopathy may be visible and is seen in 
localized disease; mediastinal lymphadenopathy suggests 
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Chap
TE
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 CMDT 2019
dissemination. There may be pleural effusions and lytic 
lesions in bone with accompanying complicated soft tissue 
collections.
 
»
Treatment
General symptomatic therapy is given as needed for dis
-
ease limited to the chest with no evidence of progression. 
For progressive pulmonary or extrapulmonary disease, 
amphotericin B intravenously is used although oral azoles 
may be used for mild cases (see Chapter 30). Duration of 
therapy is determined by a declining complement fixation 
titer and a favorable clinical response. For meningitis, 
treatment usually is with high-dose oral fluconazole 
(400–1200 mg/day), although lumbar or cisternal 
intrathecal administration of amphotericin B daily in 
increasing doses up to 1–1.5 mg/day is used initially by 
some clinicians or in cases refractory to fluconazole. 
Systemic therapy with amphotericin B, 0.6 mg/kg/day 
intravenously, is generally given concurrently with intra
-
thecal therapy, but is not sufficient alone for the treatment 
of meningeal disease. Once the patient is clinically stable, 
oral therapy with an azole, usually with fluconazole 
(400 mg daily) and given lifelong, is the recommended 
alternative to intrathecal amphotericin B therapy.
Itraconazole, 400 mg orally daily divided into two 
doses, or fluconazole, 200–400 mg, or higher, orally once 
or twice daily should be given for disease in the chest, 
bones, and soft tissues; however, therapy must be contin
-
ued for 6 months or longer after the disease is inactive to 
prevent relapse. Response to therapy should be monitored 
by following the clinical response and progressive decrease 
in serum complement fixation titers.
Surgical drainage is necessary for management of soft 
tissue abscesses, necrotic bone, and complicated pulmo
-
nary disease (eg, rupture of coccidioidal cavity).
 
»
Prognosis
The prognosis for patients with limited disease is good, 
but persistent pulmonary cavities may cause complica
-
tions such as hemoptysis or rupture producing pyopneumo-
 
thorax. Serial complement fixation titers should be per
-
formed after therapy for patients with coccidioidomycosis; 
rising titers warrant reinstitution of therapy because 
relapse is likely. Late central nervous system complications 
of adequately treated meningitis include cerebral vasculitis 
with stroke and hydrocephalus that may require shunting. 
There may be a benefit from short-term systemic cortico
-
steroids following cerebrovascular events associated with 
coccidioides meningitis. Disseminated and meningeal 
forms still have mortality rates exceeding 50% in the 
absence of therapy.
Gabe LM et al. Diagnosis and management of coccidioidomycosis. 
Clin Chest Med. 2017 Sep;38(3):417–33. [PMID: 28797486]
Galgiani JN et al. Executive summary: 2016 Infectious Diseases 
Society of America (IDSA) clinical practice guideline for the 
treatment of coccidioidomycosis. Clin Infect Dis. 2016 
Sep 15;63(6):717–22. [PMID: 27559032]
PNEUMOCYSTOSIS 
 
(
 Pneumonia
)
 
»
Fever, dyspnea, dry cough, hypoxia.
 
»
Often only slight lung physical findings.
 
»
Chest radiograph: diffuse interstitial disease or 
normal.
 
»
 in sputum, bronchoalveolar lavage fluid, 
or lung tissue; PCR of bronchoalveolar lavage; 
(1,3)-beta-D-glucan in blood.
 
»
, the 
 species that affects 
humans, is distributed worldwide. Although symptomatic 
 
 disease is rare in the general population, serologic 
evidence indicates that asymptomatic infections have 
occurred in most persons by a young age. Accumulating 
evidence suggests airborne transmission. Following asymp
-
tomatic primary infection, latent and presumably inactive 
organisms are sparsely distributed in the alveoli. De novo 
infection and reactivation of latent disease likely contribute to 
the mechanism of acute disease in older children and adults.

The overt infection is an acute interstitial plasma cell 
pneumonia that occurs with high frequency among two 
groups: (1) as epidemics of primary infections among pre
-
mature or debilitated or marasmic infants on hospital 
wards in underdeveloped parts of the world, and (2) as 
sporadic cases among older children and adults who have 
an abnormal or altered cellular immunity. Cases occur 
commonly in patients with cancer or severe malnutrition 
and debility, in patients treated with immunosuppressive 
or cytotoxic drugs or irradiation for the management of 
organ transplants and cancer and, most frequently, in 
patients with AIDS (Chapter 31).
 pneumonia occurs in up to 80% of AIDS 
patients not receiving prophylaxis and is a major cause of 
death. Its incidence increases in direct proportion to the 
fall in CD4 cells, with most cases occurring at CD4 cell 
counts less than 200/mcL. In non-AIDS patients receiving 
immunosuppressive therapy, symptoms frequently begin 
after corticosteroids have been tapered or discontinued.
 
»
Findings are usually limited to the pulmonary parenchyma. 
In the sporadic form of the disease associated with deficient 
cell-mediated immunity, the onset is typically abrupt, with 
fever, tachypnea, shortness of breath, and usually nonpro
-
ductive cough. Pulmonary physical findings may be slight 
and disproportionate to the degree of illness and the radio
-
logic findings; many patients have bibasilar crackles. 
Without treatment, the course is usually one of rapid 
deterioration and death. Adult patients may present with 
CMDT19_Ch36_p1550-p1563.indd   1554

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CMDT 2019
spontaneous pneumothorax, usually in patients with previ
-
ous episodes or those receiving aerosolized pentamidine 
prophylaxis. Patients with AIDS will usually have other 
evidence of HIV-associated disease, including fever, fatigue, 
and weight loss, for weeks or months preceding the illness.
Chest radiographs most often show diffuse “interstitial” 
infiltration, which may be heterogeneous, miliary, or 
patchy early in infection. There may also be diffuse or focal 
consolidation, cystic changes, nodules, or cavitation within 
nodules. Pleural effusions are not seen. About 5–10% of 
 pneumonia have normal chest 
films. High-resolution chest CT scans may be quite sugges
-
tive of 
 pneumonia, helping distinguish it from 
other causes of pneumonia.
Arterial blood gas determinations usually show hypox
-
emia with hypocapnia but may be normal; however, rapid 
desaturation occurs if patients exercise before samples are 
drawn. Serologic tests are not helpful in diagnosis; mea
-
surement of serum (1,3)-beta-D-glucan levels has good 
sensitivity, although specificity is compromised by being 
positive in other fungal infections. The organism cannot be 
cultured, and definitive diagnosis depends on morphologic 
demonstration of the organisms in respiratory specimens 
using specific stains. Polymerase chain reaction (PCR) of 
bronchoalveolar lavage is overly sensitive in that the test 
can be positive in colonized, noninfected persons but 
quantitative values may help with identifying infected 
patients, although precise cutoffs have not been estab
-
lished. A negative PCR from bronchoalveolar lavage rules 
out disease. Open lung biopsy and needle lung biopsy are 
infrequently done but may need to be performed to diag
-
nose a granulomatous form of 
 
»
Treatment
(See Table 31–6.) It is appropriate to start empiric therapy 
for 
 pneumonia if the disease is suspected clini
-
cally; however, in both AIDS patients and non-AIDS 
patients with mild to moderately severe disease, continued 
treatment should be based on a proved diagnosis because 
of clinical overlap with other infections, the toxicity of 
therapy, and the possible coexistence of other infectious 
organisms. Oral trimethoprim-sulfamethoxazole (TMP-
SMZ) is the preferred agent because of its low cost and 
excellent bioavailability in both AIDS patients and non-
AIDS patients with mild to moderately severe disease. 
Patients suffering from nausea and vomiting or intractable 
diarrhea should be given intravenous TMP-SMZ until they 
can tolerate the oral formulation. The best-studied second-
line option is a combination of primaquine and clindamy
-
cin, although dapsone/trimethoprim, pentamidine, and 
atovaquone have also been used. Therapy should be con
-
tinued with the selected medication for at least 5–10 days 
before considering changing agents, as fever, tachypnea, 
and pulmonary infiltrates persist for 4–6 days after starting 
treatment. Some patients have a transient worsening of 
their disease during the first 3–5 days, which may be 
related to an inflammatory response secondary to the 
presence of dead or dying organisms. Early addition of 
corticosteroids may attenuate this response (see below). 
Some clinicians prefer to treat episodes of AIDS-associated 
 pneumonia for 21 days rather than the usual 
14 days recommended for non-AIDS cases.
A. Trimethoprim-Sulfamethoxazole
The dosage of TMP/SMZ is 15–20 mg/kg/day (based on 
trimethoprim component) given orally or intravenously 
daily in three or four divided doses for 14–21 days. Patients 
with AIDS have a high frequency of hypersensitivity reac
-
tions (approaching 50%), which may include fever, rashes 
(sometimes severe), malaise, neutropenia, hepatitis, 
nephritis, thrombocytopenia, hyperkalemia, and 
hyperbilirubinemia.
B. Primaquine/Clindamycin

A meta-analysis suggested that primaquine, 15–30 mg/day, 
plus clindamycin, 600 mg three times daily, is the best 
second-line therapy with superior results when compared 
with pentamidine. Primaquine may cause hemolytic ane
-
mia in patients with glucose-6-phosphate dehydrogenase 
(G6PD)-deficiency.
C. Pentamidine Isethionate
The use of pentamidine has decreased as alternative agents 
have been studied. This medication is administered intra
-
venously (preferred) or intramuscularly as a single dose of 
3–4 mg (salt)/kg/day for 14–21 days. Pentamidine causes 
side effects in nearly 50% of patients. Hypoglycemia (often 
clinically inapparent), hyperglycemia, hyponatremia, and 
delayed nephrotoxicity with azotemia may occur.
D. Atovaquone
Atovaquone is FDA approved for patients with mild to 
moderate disease who cannot tolerate TMP-SMZ or pent
-
amidine, but failure is reported in 15–30% of cases. Mild 
side effects are common, but no serious reactions have been 
reported. The dosage is 750 mg three times daily for 21 days. 
Atovaquone should be administered with a fatty meal.
E. Other Medications
Trimethoprim, 15 mg/kg/day in three divided doses daily, 
plus dapsone, 100 mg/day, is an alternative oral regimen for 
mild to moderate disease or for continuation of therapy 
after intravenous therapy is no longer needed.
F. Prednisone
Based on studies done in patients with AIDS, prednisone is 
given for moderate to severe pneumonia (when Pao
2
 on 
admission is less than 70 mm Hg or oxygen saturation is 
less than 90%) in conjunction with antimicrobials. The 
dosage of prednisone is 40 mg twice daily orally for 5 days, 
then 40 mg daily for 5 days, and then 20 mg daily until 
therapy is completed. The role of prednisone in non-AIDS 
patients is unclear, especially in patients in whom symp
-
toms develop following tapering doses of corticosteroids.
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 CMDT 2019
 
»
Primary prophylaxis for 
 pneumonia in HIV-
infected patients should be given to persons with CD4 
counts less than 200 cells/mcL, a CD4 percentage below 
14%, or weight loss or oral candidiasis (see Table 31–5). 
Primary prophylaxis is often used in patients with hemato
-
logic malignancy and transplant recipients, although the 
clinical characteristics of persons with these conditions 
who would benefit from 
 prophylaxis have 
not been clearly defined. Patients with a history of 
 pneumonia should receive secondary pro
-
phylaxis until they have had a durable virologic response to 
antiretroviral therapy for at least 3–6 months and main
-
tained a CD4 count of greater than 200 cells/mcL.
 
»
Prognosis
In the absence of early and adequate treatment, the fatality 
rate for the endemic infantile form of 
 pneu
-
monia is 20–50%; for the sporadic form in immunodefi
-
cient persons, the fatality rate is nearly 100%. Early 
treatment reduces the mortality rate to about 3% in the 
former and 10–20% in AIDS patients. The mortality rate in 
other immunodeficient patients is still 30–50%, probably 
because of failure to make a timely diagnosis. In immuno
-
deficient patients who do not receive prophylaxis, recur
-
rences are common (30% in AIDS).
Alanio A et al. ECIL guidelines for the diagnosis of 
jirovecii
 pneumonia in patients with haematological malig
-
nancies and stem cell transplant recipients. J Antimicrob 
Chemother. 2016 Sep;71(9):2386–96. [PMID: 27550991]
Fauchier T et al. Detection of 
 by quantita
-
tive PCR to differentiate colonization and pneumonia in 
immunocompromised HIV-positive and HIV-negative 
patients. J Clin Microbiol. 2016 Jun;54(6):1487–95. [PMID: 
27008872]
CRYPTOCOCCOSIS
 
»
Most common cause of fungal meningitis.
 
»
Predisposing factors: chemotherapy for hemato
-
logic malignancies, Hodgkin lymphoma, cortico
-
steroid therapy, transplant recipients, TNF inhibitor 
therapy, HIV infection.
 
»
Headache, abnormal mental status; meningismus 
seen occasionally, though rarely in HIV-infected 
patients.
 
»
Demonstration of capsular polysaccharide anti
-
gen or positive culture in cerebrospinal fluid is 
diagnostic.
 
»
Cryptococcosis is mainly caused by 
Cryptococcus 
neoformans
, an encapsulated budding yeast that has been 
found worldwide in soil and on dried pigeon dung. 
C gattii
 
is a closely related species that also causes disease in humans, 
although 
C gattii
 may affect more ostensibly immunocom
-
petent persons. It is a major cause of cryptococcosis in the 
Pacific northwestern region of the United States and may 
result in more severe disease than 
C neoformans
.
Infections are acquired by inhalation. In the lung, the 
infection may remain localized, heal, or disseminate. 
Clinically apparent cryptococcal pneumonia rarely devel
-
ops in immunocompetent persons. Progressive lung dis
-
ease and dissemination most often occur in the setting of 
cellular immunodeficiency, including underlying hemato
-
logic malignancies under treatment, Hodgkin lymphoma, 
long-term corticosteroid therapy, solid-organ transplant, 
TNF-inhibitor therapy, or HIV infection.
 
»
Pulmonary disease ranges from simple nodules to wide
-
spread infiltrates leading to respiratory failure. Dissemi
-
nated disease may involve any organ, but central nervous 
system disease predominates. Headache is usually the first 
symptom of meningitis. Confusion and other mental status 
changes as well as cranial nerve abnormalities, nausea, and 
vomiting may be seen as the disease progresses. Nuchal 
rigidity and meningeal signs occur about 50% of the time 
but are uncommon in HIV-infected patients. Communi
-
cating hydrocephalus may complicate the course. 
C gattii
 
infection frequently presents with respiratory symptoms

-
C gattii
 
infection frequently presents with respiratory symptoms 
along with neurologic signs caused by space-occupying 
lesions in the central nervous system. Primary 
 
infection of the skin may mimic bacterial cellulitis, espe
-
cially in persons receiving immunosuppressive therapy 
such as corticosteroids. Paradoxical clinical worsening 
associated with improved immunologic status has been 
reported in HIV-positive and transplant patients with 
cryptococcosis; this entity has been labeled the immune 
reconstitution inflammatory syndrome (IRIS).
Respiratory tract disease is diagnosed by culture of respira
-
tory secretions or pleural fluid. For suspected meningeal 
disease, lumbar puncture is the preferred diagnostic 
procedure. Spinal fluid findings include increased opening 
pressure, variable pleocytosis, increased protein, and 
decreased glucose, though as many as 50% of AIDS patients 
have no pleocytosis. Gram stain of the cerebrospinal fluid 
usually reveals budding, encapsulated fungi. Cryptococcal 
capsular antigen in cerebrospinal fluid and culture together 
establish the diagnosis over 90% of the time. Patients with 
AIDS often have the antigen in both cerebrospinal fluid and 
serum, and extrameningeal disease (lungs, blood, urinary 
tract) is common. In patients with AIDS, the serum crypto
-
coccal antigen is also a sensitive screening test for meningitis, 
being positive in over 95% of cases. MRI is more sensitive 
than CT in finding central nervous system abnormalities 
such as cryptococcomas. Antigen testing by lateral flow 
assay appears to have improved sensitivity and specificity 
CMDT19_Ch36_p1550-p1563.indd   1556

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CMDT 2019
over the conventional latex agglutination test and can pro
-
vide more rapid diagnostic results.
 
»
Treatment
Because of decreased efficacy, initial therapy with an azole 
alone is not recommended for treatment of acute 
cryptococcal meningitis. Liposomal amphotericin 
B, 3–4 mg/kg/day intravenously for 14 days is the preferred 
agent for induction therapy, followed by an additional 
 
8 weeks of fluconazole, 400 mg/day orally. This regimen 
has been quite effective, achieving clinical responses and 
cerebrospinal fluid sterilization in about 70% of patients. 
The addition of flucytosine has been associated with 
improved survival, but toxicity is common. Flucytosine is 
administered orally at a dose of 100 mg/kg/day divided 
into four equal doses and given every 6 hours. Hematologic 
parameters should be closely monitored during flucytosine 
therapy, and it is important to adjust the dose for any 
decreases in kidney function. Fluconazole (800–1200 mg 
orally daily) may be given with amphotericin B when flu
-
cytosine is not available or patients cannot tolerate it. 
Frequent, repeated lumbar punctures or ventricular shunt
-
ing should be performed to relieve high cerebrospinal fluid 
pressures or if hydrocephalus is a complication. 
Corticosteroids should not be used. 
Failure to adequately 
relieve raised intracranial pressure is a major cause of 
morbidity and mortality.
 The end points for amphotericin 
B therapy and for switching to oral fluconazole are a favor
-
able clinical response (decrease in temperature; improve
-
ment in headache, nausea, vomiting, and Mini-Mental 
State Examination scores), improvement in cerebrospinal 
fluid biochemical parameters and, most importantly, con
-
version of cerebrospinal fluid culture to negative.
A similar approach is reasonable for patients with cryp
-
tococcal meningitis in the absence of AIDS, though the 
mortality rate is higher. Therapy is generally continued 
until cerebrospinal fluid cultures become negative. Mainte
-
nance antifungal therapy is important after treatment of an 
acute episode in HIV-related cases, since otherwise the rate 
of relapse is greater than 50%. Fluconazole, 200 mg/day 
orally, is the maintenance therapy of choice, decreasing the 
relapse rate approximately tenfold compared with placebo 
and threefold compared with weekly amphotericin B in 
patients whose cerebrospinal fluid has been sterilized by 
the induction therapy. After successful therapy of crypto
-
coccal meningitis, it is possible to discontinue secondary 
prophylaxis with fluconazole in individuals with AIDS who 
have had a satisfactory response to antiretroviral therapy 
(eg, CD4 cell count greater than 100–200 cells/mcL for at 
least 6 months). Among clinicians treating patients without 
AIDS, there has been a trend in recent years to prescribe a 
course (eg, 6–12 months) of fluconazole as maintenance 
therapy following successful treatment of the acute illness; 
published guidelines suggest this as an option.
 
»
Prognosis
Factors that indicate a poor prognosis include the activity 
of the predisposing conditions, older age, organ failure, 
lack of spinal fluid pleocytosis, high initial antigen titer in 
either serum or cerebrospinal fluid, decreased mental sta
-
tus, increased intracranial pressure, and the presence of 
disease outside the nervous system.
ASPERGILLOSIS
 
»
Most common cause of non-candidal invasive 
fungal infection in transplant recipients and in 
patients with hematologic malignancies.
 
»
Predisposing factors: leukemia, bone marrow or 
organ transplant, late HIV infection.
 
»
Pulmonary, sinus, and central nervous system are 
most common disease sites.
 
»
Detection of galactomannan by ELISA or PCR in

»
 
»
Detection of galactomannan by ELISA or PCR in 
serum or other body fluids is useful for early diag
-
nosis and treatment.
 
»
 is the usual cause of aspergillosis, 
though many species of 
 may cause a wide spec
-
trum of disease. The lungs, sinuses, and brain are the organs 
most often involved. Clinical illness results either from an 
aberrant immunologic response or tissue invasion.
 
»
1. Allergic forms of aspergillosis—
Allergic bronchopul
-
monary aspergillosis (ABPA) occurs in patients with pre
-
existing asthma or cystic fibrosis who develop worsening 
bronchospasm and fleeting pulmonary infiltrates accom
-
panied by eosinophilia, high levels of IgE, and IgG 
 precipitins in the blood. Allergic aspergillus 
sinusitis produces a chronic sinus inflammation characterized 
by eosinophilic mucus and noninvasive hyphal elements.
2. Chronic aspergillosis—
Chronic pulmonary aspergillosis 
produces a spectrum of disease that usually occurs when 
there is preexisting lung damage but not significant immu
-
nocompromise. Disease manifestations range from asper
-
gillomas that develop in a lung cavity to chronic fibrosing 
pulmonary aspergillosis in which the majority of lung tissue 
is replaced with fibrosis. Long-standing (longer than 
3 months) pulmonary and systemic symptoms such as cough, 
shortness of breath, weight loss, and malaise are common.
3. Invasive aspergillosis—
Invasive aspergillosis most 
commonly occurs in profoundly immunodeficient patients, 
such as those who have undergone hematopoietic stem cell 
transplantation or have prolonged, severe neutropenia, but 
CMDT19_Ch36_p1550-p1563.indd   1557

Chap
TE
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 CMDT 2019
it can occur among critically ill immunocompetent patients 
as well. Specific risk factors in patients who have under
-
gone a hematopoietic stem cell transplant include cytope
-
nias, corticosteroid use, iron overload, cytomegalovirus 
disease, and graft-versus-host disease. Pulmonary disease 
is most common, with patchy infiltration leading to a 
severe necrotizing pneumonia. Invasive sinus disease also 
occurs. At any time, there may be hematogenous dissemi
-
nation to the central nervous system, skin, and other 
organs. Early diagnosis and reversal of any correctable 
immunosuppression are essential.
There is eosinophilia, high levels of total IgE, and IgE and IgG 
specific for 
 in the blood of patients with ABPA.
Blood cultures have very low yield in any form of asper
-
gillosis. Detection of galactomannan by ELISA or 
 DNA by PCR, or both, has been used for the 
early diagnosis of invasive disease, though multiple deter
-
minations should be done and usefulness is decreased in 
patients receiving anti-mold prophylaxis (ie, voriconazole 
or posaconazole). Galactomannan levels and 
 
DNA PCR can be tested in serum or in bronchoalveolar 
lavage fluid, which may be more sensitive than serum. 
Higher galactomannan levels are correlated with increased 
mortality, and failure of galactomannan levels to fall in 
response to therapy portends a worse outcome. Isolation of 
 from pulmonary secretions does not necessarily 
imply invasive disease, although its positive predictive 
value increases with more advanced immunosuppression. 
Therefore, a definitive diagnosis requires demonstration of 
 in tissue or culture from a sterile site. CT scan 
of the chest may show characteristics quite suggestive of 
invasive aspergillosis (eg, “halo sign, ” which is a zone of 
diminution of ground glass around a consolidation).
 
»
The high mortality rate and difficulty in diagnosis of 
invasive aspergillosis often leads clinicians to institute 
prophylactic therapy for patients with profound immuno
-
suppression. The best-studied agents include voricon
-
azole and posaconazole, although patient and agent 
selection criteria remain undefined. Widespread use of 
broad-spectrum azoles raises concern for development of 
invasive disease by highly resistant fungi.
 
»
Treatment
For acute exacerbations 
of ABPA, oral prednisone is begun at a dose of 0.5 mg/kg/day 
and then tapered slowly over several months. Itraconazole 
at a dose of 200 mg daily for 16 weeks appears to improve 
pulmonary function and decrease corticosteroid require
-
ments in these patients, although voriconazole is increas
-
ingly being used. Itraconazole is the best studied agent for 
the treatment of allergic aspergillus sinusitis with topical 
corticosteroids being the cornerstone of therapy.
The most effective therapy for 
symptomatic aspergilloma remains surgical resection. 
Other forms of chronic aspergillosis are generally treated 
with at least 4–6 months of oral triazole therapy (itracon
-
azole 200 mg twice daily, voriconazole 200 mg twice daily, 
or posaconazole 300 mg daily).
The 2016 Infectious Diseases 
Society of America guidelines consider voriconazole 
(6 mg/kg intravenously twice on day 1 and then 4 mg/kg 
every 12 hours thereafter) as optimal therapy for invasive 
aspergillosis. A randomized controlled trial did not find an 
overall benefit with the addition of anidulafungin (200 mg 
on day 1 and then 100 mg daily) to voriconazole, but among 
patients in whom galactomannan was detected, those who 
received combination therapy had better outcomes. 
Isavuconazole (372 mg of prodrug on days 1 and 2 and then 
372 mg once daily) was equivalent to voriconazole. 
Alternatives include a lipid formulation of amphotericin B

Alternatives include a lipid formulation of amphotericin B 
(3–5 mg/kg/day), caspofungin (70 mg intravenously on day 
1 and then 50 mg/day thereafter), and posaconazole oral 
tablets (300 mg twice daily on day 1 and then 300 mg daily 
thereafter). Oral dosing of voriconazole at 4 mg/kg twice daily 
can be used for less serious infections or as a step-down strat
-
egy after intravenous therapy. Therapeutic drug monitoring 
should be considered for both voriconazole and posaconazole 
given variations in metabolism and absorption.
Surgical debridement is generally done for sinusitis, 
and can be useful for focal pulmonary lesions, especially 
for treatment of life-threatening hemoptysis and infections 
recalcitrant to medical therapy. The mortality rate of pul
-
monary or disseminated disease in the immunocompro
-
mised patient remains high, particularly in patients with 
refractory neutropenia.
Colombo AL et al. Candida and invasive mould diseases in non-
neutropenic critically ill patients and patients with haemato
-
logical cancer. Lancet Infect Dis. 2017 Nov;17(11):e344–56. 
[PMID: 28774702]
aspergillosis: a randomized trial. Ann Intern Med. 
2015 Jan 20;162(2):81–9. Erratum in: Ann Intern Med. 2015 
Mar 17; 162(6):463. [PMID: 25599346]
Patterson TF et al. Practice guidelines for the diagnosis and 
management of aspergillosis: 2016 update by the Infectious 
Diseases Society of America. Clin Infect Dis. 2016 Aug 15; 
63(4):e1–60. [PMID: 27365388]
MUCORMYCOSIS
 
»
Most common cause of non-
 invasive 
mold infection.
 
»
Predisposing factors:
 poorly controlled diabetes, 
leukemia, transplant recipient, wound contamina
-
tion by soil.
 
»
Pulmonary, rhinocerebral, and skin are most com
-
mon disease sites.
 
»
Rapidly fatal without multidisciplinary 
interventions.
CMDT19_Ch36_p1550-p1563.indd   1558

1559
 
CMDT 2019
 
»
The term “mucormycosis” is applied to opportunistic infec
-
tions caused by members of the genera 
Rhizopus, Mucor, 
Lichtheimia
 (formerly 
Absidia)
, and 
Cunninghamella
. Pre
-
disposing conditions include hematologic malignancy, stem 
cell transplantation, solid organ transplantation, diabetic 
ketoacidosis, chronic kidney disease, and treatment with 
desferoxamine, corticosteroids or cytotoxic drugs.
 
»
Invasive disease of the sinuses, orbits, and the lungs may 
occur. Necrosis is common due to hyphal tissue invasion 
that may manifest as ulceration of the hard palate or nasal 
palate or hemoptysis. Widely disseminated disease can 
occur. No serologic or laboratory findings assist with diag
-
nosis, and blood cultures are unhelpful. A reverse “halo 
sign” (focal area of ground glass diminution surrounded by 
a ring of consolidation) may be seen on chest CT. Biopsy of 
involved tissue remains the cornerstone of diagnosis, 
although cultures are frequently negative. The organisms 
appear in tissues as broad, branching nonseptate hyphae.
 
»
Treatment
Optimal therapy of mucormycosis involves reversal of pre
-
disposing conditions (if possible), surgical debridement, and 
prompt antifungal therapy. A prolonged course of a lipid 
preparation of intravenous liposomal amphotericin B 
(5 mg/kg with higher doses possibly given for CNS disease) 
should be started early. Depending on in vitro susceptibility, 
posaconazole 300 mg/day orally can be used after disease 
has been stabilized. Combination therapy with amphotericin 
and posaconazole is not proven, but is commonly used 
because of the poor response to monotherapy. Isavuconazole 
has been shown to have some clinical activity. Other azoles 
are not effective. There are limited data suggesting beneficial 
synergistic activity when amphotericin and caspofungin are 
used in combination for rhino-orbital mucormycosis in 
diabetic patients. Despite favorable animal studies, a pilot 
study in humans incorporating adjunctive iron chelation 
therapy with deferasirox demonstrated a higher mortality 
rate than antifungal therapy alone. Control of diabetes and 
other underlying conditions, along with extensive repeated 
surgical removal of necrotic, nonperfused tissue, is essential. 
Even when these measures are introduced in a timely fash
-
ion, the prognosis remains guarded.
Arif S et al. Emergence of molds other than 
 in immu
-
nocompromised patients. Clin Chest Med. 2017 Sep; 
38(3):555–73. [PMID: 28797495]
Jung J et al. Comparison of computed tomographic findings in 
pulmonary mucormycosis and invasive pulmonary aspergil
-
losis. Clin Microbiol Infect. 2015 Jul;21(7):684.e11–8. [PMID: 
25882362]
BLASTOMYCOSIS
Blastomycosis occurs most often in men infected during 
occupational or recreational activities outdoors and in a 
geographically limited area of the south central and 
midwestern United States and Canada. Disease usually 
occurs in immunocompetent individuals.
Chronic pulmonary infection is most common and 
may be asymptomatic. When dissemination takes place, 
lesions are most frequently seen in the skin, bones, and 
urogenital system.
Cough, moderate fever, dyspnea, and chest pain are com
-
mon. These may resolve or progress, with purulent sputum 
production, pleurisy, fever, chills, loss of weight, and prostra
-
tion. Radiologic studies, either chest radiographs or CT 
scans, usually reveal lobar consolidation or masses.
Raised, verrucous cutaneous lesions are commonly pres
-
ent in disseminated blastomycosis. Bones—often the ribs 
and vertebrae—are frequently involved. Epididymitis, pros
-
tatitis, and other involvement of the male urogenital system 
may occur. Although they do not appear to be at greater risk 
for acquisition of disease, infection in HIV-infected persons 
may progress rapidly, with dissemination common.
Laboratory findings usually include leukocytosis and

Laboratory findings usually include leukocytosis and 
anemia, though these are not specific. The organism is 
found in clinical specimens, such as expectorated sputum or 
tissue biopsies, as a thick-walled cell 5–20 mcm in diameter 
that may have a single broad-based bud. It grows readily on 
culture. A urinary antigen test is available, but it has consid
-
erable cross reactivity with other dimorphic fungi; it may be 
useful in monitoring disease resolution or progression. 
A serum enzyme immunoassay based on the surface protein 
BAD-1 has much better sensitivity and specificity than the 
urinary antigen test, but it is not yet commercially available.
Itraconazole, 200–400 mg/day orally for at least 
6–12 months, is the therapy of choice for nonmeningeal 
disease, with a response rate of over 80%. Liposomal 
amphotericin B, 3–5 mg/kg/day intravenously, is given 
initially for severe disease, treatment failures, or central 
nervous system involvement.
Clinical follow-up for relapse should be made regularly 
for several years so that therapy may be resumed or 
another drug instituted.
McBride JA et al. Clinical manifestations and treatment of 
blastomycosis. Clin Chest Med. 2017 Sep;38(3):435–49. 
[PMID: 28797487]
PARACOCCIDIOIDOMYCOSIS 
 
(
South American Blastomycosis
)
Paracoccidioides brasiliensis
 and 
Paracoccidioides lutzii
 
infections have been found only in patients who have 
resided in South or Central America or Mexico. Long 
asymptomatic periods enable patients to travel far from the 
endemic areas before developing clinical problems. An 
acute form of the disease affects predominately younger 
patients and involves the mononuclear phagocytic system, 
resulting in progressive lymphadenopathy. A more chronic 
form affects mostly adult men and involves the lung, skin, 
mucous membranes, and lymph nodes. Weight loss, pulmo
-
nary complaints, or mucosal ulcerations are the most com
-
mon symptoms. Extensive coalescent ulcerations may 
eventually result in destruction of the epiglottis, vocal cords, 
and uvula. Extension to the lips and face may occur. Lymph 
CMDT19_Ch36_p1550-p1563.indd   1559

Chap
TE
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 CMDT 2019
node enlargement may follow mucocutaneous lesions, 
eventually ulcerating and forming draining sinuses; in some 
patients, it is the presenting symptom. Hepatosplenomegaly 
may be present as well. HIV-infected patients with paracoc
-
cidioidomycosis are more likely to have extrapulmonary 
dissemination and a more rapid clinical disease course.
Laboratory findings are nonspecific. Serology by immu
-
nodiffusion is positive in more than 80% of cases. Comple
-
ment fixation titers correlate with progressive disease and fall 
with effective therapy. The fungus is found in clinical speci
-
mens as a spherical cell that may have many buds arising 
from it. If direct examination of secretions does not reveal the 
organism, biopsy with Gomori staining may be helpful.
Itraconazole, 100 mg twice daily orally, is the treatment 
of choice and generally results in a clinical response within 
1 month and effective control after 2–6 months. TMP-SMZ 
(480 mg/1200 mg) twice daily orally is equally effective and 
less costly but associated with more adverse effects and 
longer time to clinical cure. Amphotericin B, 0.7–1.0 mg/
kg/day intravenously, is the medication of choice for severe 
and life-threatening infection.
Nery AF et al. Therapeutic response in adult patients with non
-
severe chronic paracoccidioidomycosis treated with 
sulfamethoxazole-trimethoprim: a retrospective study. Am J 
Trop Med Hyg. 2017 Aug;97(2):556–62. [PMID: 28722596]
Shikanai-Y asuda MA et al. Brazilian guidelines for the clinical 
management of paracoccidioidomycosis. Rev Soc Bras Med 
Trop. 2017 Sep–Oct;50(5):715–40. [PMID: 28746570]
SPOROTRICHOSIS
Sporotrichosis is a chronic fungal infection caused by organ
-
isms of the 
Sporothrix schenckii
 complex. It is worldwide in 
distribution; most patients have had contact with soil, 
sphagnum moss, or decaying wood. Infection takes place 
when the organism is inoculated into the skin—usually on 
the hand, arm, or foot, especially during gardening.
The most common form of sporotrichosis begins with a 
hard, nontender subcutaneous nodule. This later becomes 
adherent to the overlying skin and ulcerates. Within a few 
days to weeks, lymphocutaneous spread along the lym
-
phatics draining this area occurs, which may result in 
ulceration. Cavitary pulmonary disease occurs in individu
-
als with underlying chronic lung disease.
Disseminated sporotrichosis is rare in immunocompe
-
tent persons but may present with widespread cutaneous, 
lung, bone, joint, and central nervous system involvement in 
immunocompromised patients, especially those with cellu
-
lar immunodeficiencies, including AIDS and alcohol abuse.
Cultures are needed to establish diagnosis. The useful
-
ness of serologic tests is limited, but may be helpful in 
diagnosing disseminated disease, especially meningitis.
Itraconazole, 200–400 mg orally daily for several 
months, is the treatment of choice for localized disease and 
some milder cases of disseminated disease. Terbinafine, 
500 mg orally twice daily, also appears to have good effi
-
cacy in lymphocutaneous disease. Amphotericin B intrave
-
nously, 0.7–1.0 mg/kg/day, or a lipid amphotericin B 
preparation, 3–5 mg/kg/day are used for severe systemic 
infection. Surgery may be indicated for complicated 
pulmonary cavitary disease, and joint involvement may 
require arthrodesis.
The prognosis is good for lymphocutaneous sporotri
-
chosis; pulmonary, joint, and disseminated disease respond 
less favorably.
Orofino-Costa R et al. Sporotrichosis: an update on epidemiol
-
ogy, etiopathogenesis, laboratory and clinical therapeutics. 
An Bras Dermatol. 2017 Sep–Oct;92(5):606–20. [PMID: 
29166494]
MYCETOMA (
Eumycetoma & 
Actinomycetoma
)
Mycetoma is a chronic local, slowly progressive destructive 
infection that usually involves the foot; it begins in subcuta
-
neous tissues, frequently after implantation trauma, and then 
spreads to contiguous structures with sinus tracts and extrud

-
-
ing grains. Eumycetoma (also known as maduromycosis) is 
the term used to describe mycetoma caused by true fungi. 
The disease begins as a papule, nodule, or abscess that over 
months to years progresses slowly to form multiple abscesses 
and sinus tracts ramifying deep into the tissue. Secondary 
bacterial infection may result in large open ulcers. Radio
-
graphs may show destructive changes in the underlying bone. 
Causative species can often be suggested by the color of the 
characteristic grains and hyphal size within the infected tis
-
sues but definitive diagnosis requires culture.
The prognosis for eumycetoma is poor, though surgical 
debridement along with prolonged oral itraconazole ther
-
apy, 200 mg twice daily, or combination therapy including 
itraconazole and terbinafine may result in a response rate 
of 70%. The various etiologic agents may respond differ
-
ently to antifungal agents, so culture results are invaluable. 
Amputation is necessary in far advanced cases.
Relhan V et al. Mycetoma: an update. Indian J Dermatol. 2017 
Jul–Aug;62(4):332–40. [PMID: 28794542]
van de Sande W et al. Closing the mycetoma knowledge 
gap. Med Mycol. 2018 Apr 1;56(suppl_1):153–64. [PMID: 
28992217]
OTHER OPPORTUNISTIC MOLD INFECTIONS
Fungi previously considered to be harmless colonizers, 
including 
Pseudallescheria boydii (Scedosporium 
apiospermum)
, 
Scedosporium prolificans
, 
Fusarium, Paecilo
-
myces
, 
Trichoderma longibrachiatium
, and 
Trichosporon
, are 
now significant pathogens in immunocompromised patients. 
This occurs most often in patients being treated for hemato
-
poietic malignancies and in those receiving broad-spectrum 
antifungal prophylaxis. Infection may be localized in the skin, 
lungs, or sinuses, or widespread disease may appear with 
lesions in multiple organs. Fusariosis should be suspected in 
severely immunosuppressed persons in whom multiple, 
painful skin lesions develop; blood cultures are often positive. 
Sinus infection may cause bony erosion. Infection in subcu
-
taneous tissues following traumatic implantation may 
develop as a well-circumscribed cyst or as an ulcer.
Nonpigmented septate hyphae are seen in tissue and are 
indistinguishable from those of 
 when infections 
CMDT19_Ch36_p1550-p1563.indd   1560

1561
 
CMDT 2019
are due to 
S apiospermum
 or species of 
Fusarium
, 
Paecilomyces
, 
Penicillium
, or other hyaline molds. Spores or 
mycetoma-like granules are rarely present in tissue. The 
differentiation of 
 and 
 is particu
-
larly important, since the former is uniformly resistant to 
amphotericin B but may be sensitive to azole antifungals 
(eg, voriconazole). Infection by any of a number of black 
molds is designated as phaeohyphomycosis. These black 
molds (eg, 
Exophiala, Bipolaris, Cladophialophora, 
Curvularia, Alternaria
) are common in the environment, 
especially on decaying vegetation. In tissues of patients with 
phaeohyphomycosis, the mold is seen as black or faintly 
brown hyphae, yeast cells, or both. Culture on appropriate 
medium is needed to identify the agent. Histologic demon
-
stration of these organisms is definitive evidence of invasive 
infection; positive cultures must be interpreted cautiously 
and not assumed to be contaminants in immunocompro
-
mised hosts.
Skiada A et al. Rare fungal infectious agents: a lurking enemy. 
F1000Res. 2017 Oct 31;6:1917. [PMID: 29152230]
HOUSEHOLD MOLDS
 
»
Molds are very common indoors where moisture 
exists in enclosed spaces.
 
»
Most common indoor molds are 
Cladosporium
, 
, 
, and 
Alternaria.
 
»
People most at risk for health problems include 
those with allergies, asthma, and underlying 
immunocompromising conditions.
Molds are commonly present in homes, particularly in the 
presence of moisture, and patients will commonly seek 
assessment for whether their illness is due to molds. Inva
-
sive disease due to environmental fungi can occur in the 
immunocompromised patient (eg, see section on Invasive 
Aspergillosis), but there are no data that mold exposure 
can induce immune dysfunction. Similarly, the concept of 
toxic-mold syndrome or cognitive impairment due to 
inhalation of mycotoxins has not been validated despite 
scrutiny by expert panels. Allergic symptoms (eg, asthma, 
hypersensitivity pneumonitis) can be worsened by envi
-
ronmental mold exposure, and reduction of household 
mold in such patients may lead to clinical improvement. 
The presence of mold in the household is typically easily 
discernable with visual inspection or detection by odor; if 
present, predisposing conditions should be corrected by 
individuals experienced in mold remediation.
Borchers AT et al. Mold and human health: a reality check. Clin 
Rev Allerg Immunol. 2017 Jun;52(3):305–22. [PMID: 
28299723]
ANTIFUNGAL THERAPY
Table 36–1 summarizes the major properties of currently 
available antifungal agents. Two different lipid-based 
amphotericin B formulations are used to treat systemic 
invasive fungal infections. Their principal advantage 
appears to be substantially reduced nephrotoxicity, allowing 
administration of much higher doses. Three agents of the 
echinocandin class, caspofungin acetate, anidulafungin, 
and micafungin sodium, are approved for use. The echino
-
candins have relatively few adverse effects and are useful for 
the treatment of invasive 
Candida
 infections, although 
resistance is beginning to emerge clinically; 
C glabrata
 in 
particular has shown resistance to this class of antifungals. 
Table 36–1.
 
Agents for systemic mycoses (listed in alphabetical order).
Drug
Dosing
r
enal 
Clearance?
CSF 
p
enetr
ation?
Toxicities
Spectrum of 
a
c
tivity
0.3–1.5 mg/kg/day 
No
Poor
Rigors, fever, azotemia, 
hypokalemia, 
hypomagnesemia, 
renal tubular acidosis, 
anemia
All major pathogens 
except 
Scedosporium
Amphotericin B 
lipid complex
5 mg/kg/day intravenously
No
Poor
Fever, rigors, nausea, 
hypotension, anemia, 
azotemia, tachypnea
Same as amphotericin B, 
above
Amphotericin B, 
liposomal
3–6 mg/kg/day intravenously
No
Poor
hypotension, azotemia, 
anemia, tachypnea, 
chest tightness
Same as amphotericin B,

above
liposomal
No
Poor
above
Anidulafungin
100-mg intravenous loading 
dose, followed by 50 mg/
day intravenously in one 
dose
< 1%
Poor
Diarrhea, hepatic enzyme 
elevations, histamine-
mediated reactions
Mucosal and invasive 
(
continued
)
CMDT19_Ch36_p1550-p1563.indd   1561

Chap
TE
r 36
1562
 CMDT 2019
 
Agents for systemic mycoses. (continued)
Drug
Dosing
r
enal 
CSF 
p
enetr
ation?
a
c
tivity
Caspofungin 
acetate
70-mg intravenous loading 
dose, followed by 
 
50 mg/day intravenously 
 
in one dose
< 50%
1
Poor
Transient neutropenia; 
hepatic enzyme 
elevations when used 
with cyclosporine
Aspergillosis, mucosal 
 
and invasive 
 
candidiasis, empiric 
antifungal therapy in 
febrile neutropenia
100–800 mg/day in one or 
 
two doses intravenously or 
orally
Yes
Yes
Nausea, rash, alopecia, 
headache, hepatic 
enzyme elevations
Mucosal candidiasis 
(including urinary 
 
tract), cryptococcosis, 
histoplasmosis, 
coccidioidomycosis
Flucytosine 
(5-FC)
100–150 mg/kg/day orally in 
four divided doses
Yes
Yes
Leukopenia,
2
 rash, 
diarrhea, hepatitis, 
nausea, vomiting
Cryptococcosis,
3
 
candidiasis,
3
 
chromomycosis
Isavuconazole
200 mg/day orally or 
intravenously once daily
No
Low in CSF, 
high in brain
Nausea, diarrhea, upper 
abdominal pain, 
dizziness
Broad range of activity 
including the 
Mucorales
Itraconazole
100–400 mg/day orally in one 
or two doses with a meal 
 
or carbonated beverage
No
Variable
Nausea, hypokalemia, 
edema, hypertension, 
peripheral neuropathy
Histoplasmosis, 
 
coccidioidomycosis, 
 
blastomycosis, 
 
paracoccidioidomycosis, 
mucosal candidiasis 
(except urinary), sporo
-
trichosis, aspergillosis, 
200–800 mg/day orally in one 
or two doses with a meal or 
carbonated beverage
No
Poor
Anorexia, nausea, sup
-
pression of testoster
-
one and cortisol, rash, 
enzyme elevations, 
hepatic failure
Nonmeningeal histoplas
-
mosis and coccidioido
-
mycosis, blastomycosis, 
(except urinary)
Micafungin 
sodium
150 mg intravenously  once 
daily (treatment); 50 mg 
intravenously once daily 
(prophylaxis)
No
Poor
Rash, rigors, headache, 
phlebitis
 
candidiasis, prophylaxis 
in hematopoietic stem 
 
cell transplantation
Posaconazole
400–800 mg/day orally in one 
or two doses (oral suspen
-
sion) or 300 mg orally once 
daily (tablets) or 300 mg 
intravenously twice daily 
 
for 2 days loading dose fol
-
lowed by 300 mg once daily
No
Yes
 
diarrhea, and headache
Mucorales
Terbinafine
250 mg once or twice daily 
orally
Yes
Poor
Nausea, abdominal pain, 
taste disturbance, rash, 
diarrhea, and hepatic 
Dermatophytes, sporotri
-
chosis, chromomycosis, 
eumycetoma
Voriconazole
200–400 mg/day orally in two 
doses or 12 mg/kg intrave
-
nously as loading dose 
 
for 2 days followed by 
 
6 mg/kg/day intravenously 
in two doses
5
Yes
Yes
Transient visual distur
-
bances, rash, photosen
-
sitivity, fluoride excess 
with periostitis, periph
-
eral neuropathy, squa
-
mous cell skin cancers, 
elevations
4
except the 
Mucorales
 
and sporotrichosis
1
No dosage adjustment required for chronic kidney disease; dosage adjustment necessary with moderate to severe hepatic dysfunction.
2
Use should be monitored with blood levels to prevent this or the dose adjusted according to creatinine clearance.
3
In combination with amphotericin B.
4
Administration with drugs that are metabolized by the cytochrome P450 system is contraindicated or requires careful monitoring.
5
Some authorities advocate therapeutic drug monitoring in patients who are not responding to therapy.
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Caspofungin acetate is also approved for use in refractory 
cases of invasive aspergillosis. Voriconazole has excellent 
activity against a broad range of fungal pathogens and has 
been FDA approved for use in invasive 
 cases, 
Fusarium
 and 
Candida
 esophagi
-
tis, deep 
Candida
 infections, and candidemia. Posaconazole 
has good activity against a broad range of filamentous fungi, 
Mucorales
. Some experts recommend thera
-
peutic drug monitoring in individuals with severe invasive 
fungal infections receiving these newer azoles because of 
unreliable serum levels due to either metabolic alterations 
as a result of genetic polymorphisms (voriconazole) or 
erratic absorption (posaconazole). A delayed-release tablet 
preparation of posaconazole provides more reliable phar
-
macokinetics. Isavuconazole has been approved for the 
treatment of aspergillosis and mucormycosis; it is available 
in an intravenous form that does not utilize the cyclodex
-
trin carrier like previous azoles as well as an oral form with 
relatively reliable pharmacokinetic properties.
Carmona EM et al. Overview of treatment approaches for fungal 
infections. Clin Chest Med. 2017 Sep;38(3):393–402. [PMID: 
28797484]
Nett JE et al. Antifungal agents: spectrum of activity, pharmacol
-
ogy, and clinical indications. Infect Dis Clin North Am. 
2016 Mar;30(1):51–83. [PMID: 26739608]
CMDT19_Ch36_p1550-p1563.indd   1563

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Disorders Related to 
Environmental 
 
37
Jacqueline A. Nemer, MD, FACEP 
 
COLD & HEAT
The human body maintains a steady temperature through 
the balance of internal heat production and environmental 
heat loss. Heat exchange between the body and environ
-
ment occurs via four common processes: radiation, 
evaporation, conduction, and convection. In extreme tem
-
peratures, the body’s thermoregulation may fail. This 
results in the core body temperature moving toward the 
temperature of the external environment. Cold and heat 
exposure may cause a wide spectrum of conditions; the 
severity varies considerably among individuals. Many of 
these conditions are preventable with appropriate educa
-
tion and planning. Preventive measures must be imple
-
mented on an individual and population level.
The likelihood and severity of extreme temperature-
related conditions depend on physiologic and environmen
-
tal factors. Physiologic risk factors include extremes of age; 
cognitive impairment; poor physical conditioning, seden
-
tary lifestyle or immobility; poor acclimatization; concur
-
rent injury; prior temperature-related injury; and numerous 
underlying medical conditions, especially those affecting 
cognition and thermoregulation. Pharmacologic risk factors 
include medications, holistic or alternative treatments, illicit 
drugs, tobacco, and alcohol. There is a subset of medications 
associated with a particularly high likelihood of worsening 
temperature-related conditions, such as those that impact 
sweating and the central nervous system and those that 
affect cutaneous blood flow such as peripheral vasoconstric
-
tors or vasodilators. Environmental risk factors include 
changing weather conditions inadequate clothing or housing 
(homelessness, or housing with inadequate temperature 
control), and occupational or recreational exposure.
DISORDERS DUE TO HEAT
 
»
Spectrum of preventable heat-related illnesses: 
heat cramps, heat exhaustion, heat syncope, and 
heat stroke.
 
»
Heat stroke:
 hyperthermia with cerebral dysfunc
-
tion in a patient with heat exposure.
 
»
Best outcome:
 early recognition, initiation of 
rapid cooling, and avoidance of shivering during 
cooling.
 
»
Best choice of cooling method:
 whichever can 
be instituted the fastest with the least compro
-
mise to the patient. Delays in cooling result in 
higher morbidity and mortality in heat stroke 
victims.
 
»
Heat-related illnesses are among the most commonly seen 
environmental emergencies seen in emergency depart
-
ments. The amount of heat retained in the body is deter
-
mined by internal metabolic function and environmental 
conditions, including temperature and humidity. Hyper
-
thermia results from the body’s inability to maintain nor
-
mal internal temperature through heat loss. Hyperthermia 
results from either compromised heat dissipation mecha
-
nisms or abnormally high heat production. Heat loss 
occurs primarily through sweating and peripheral vasodi
-
lation. The direct transfer of heat from the skin to the sur
-
rounding air, by convection or conduction, occurs with 
diminishing efficiency as ambient temperature rises, espe
-
cially above 37.2
°
C, the point at which heat transfer 
reverses direction. At normal temperatures, evaporation 
accounts for approximately 20% of the body’s heat loss, but 
at high temperatures it becomes the major mechanism for 
dissipation of heat. This mechanism diminishes as humid
-
ity rises.
There is a spectrum of preventable heat-related illnesses 
related to environmental exposure, ranging from mild 
forms, such as heat cramps, to severe forms, such as heat 
stroke. Risk factors include longer duration of exertion, hot 
environment, insufficient acclimatization, and dehydra
-
tion. Additional risk factors include skin disorders or other 
medical conditions that inhibit sweat production or evapo
-

-
-
ration, obesity, prolonged seizures, hypotension, reduced 
cutaneous blood flow, reduced cardiac output, the use of 
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DISORDERS RELATED TO ENVIRONMENTAL EMERGENCIES 
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drugs that increase metabolism or muscle activity or impair 
sweating, and withdrawal syndromes. Medications that 
impair sweating include anticholinergics, antihistamines, 
phenothiazines, tricyclic antidepressants, monoamine oxi
-
dase inhibitors, and diuretics. Illicit drugs, including stimu
-
lants and some hallucinogens, and antipsychotic agents, can 
cause increased muscle activity and thus generate increased 
body heat.
Classic (nonexertional) heat-related illness may occur 
in any individual in a hot, relaxing environment (eg, hot 
bath, steam room, sunbathing, or sauna) with increased 
severity in individuals with the risk factors mentioned 
above, even despite minimal physical activity.
Heat cramping
 results from dilutional hyponatremia as 
sweat losses are replaced with water alone. 
 
results from prolonged strenuous activity in a hot environ
-
ment without adequate water or salt intake. It is character
-
ized by dehydration, sodium depletion, or isotonic fluid 
loss with accompanying cardiovascular changes.
Heat syncope
 or sudden collapse may result in uncon
-
sciousness from volume depletion and cutaneous vasodila
-
tion with subsequent systemic and cerebral hypotension. 
Exercise-associated postural hypotension is usually the 
cause of heat syncope and may occur during or immedi
-
ately following exercise. 
, the hallmark of 
which is cerebral dysfunction with core body temperature 
over 40
°
C, presents in one of two forms: classic and exer
-
tional. 
Classic (nonexertional) heat stroke
 occurs in 
patients with impaired thermoregulatory mechanisms or 
in extreme environmental conditions. 
Exertional heat 
stroke
 occurs in healthy persons undergoing strenuous 
exertion in a hot or humid environment. Persons at great
-
est risk are those who are at the extremes of age, chronically 
debilitated, and taking medications that interfere with 
heat-dissipating mechanisms.
 
»
When diagnosing and treating heat-related illnesses, use of 
an internal rectal, Foley, or esophageal thermometer is 
necessary because the skin temperature may not accurately 
reflect core body temperature. 
Heat cramps
 are painful 
skeletal muscle contractions and severe muscle spasms 
with onset during or shortly after exercise. Examination 
findings typically include stable vital signs; normal or 
slightly increased core body temperature; moist and cool 
skin; and tender, hard, lumpy, painful muscles that may be 
twitching. The diagnosis is made clinically.
 is diagnosed based on symptoms and 
clinical findings of a core body temperature slightly ele
-
vated but less than 40
°
C, tachycardia, and moist skin. 
Symptoms are similar to those of heat syncope and heat 
cramps. Additional symptoms include nausea, vomiting, 
malaise, myalgias, hyperventilation, thirst, and weakness. 
Central nervous system symptoms include headache, dizzi
-
ness, fatigue, anxiety, paresthesias, impaired judgment, and 
occasionally psychosis. Heat exhaustion may progress to 
heat stroke if sweating ceases and mental status declines.
 generally occurs in the setting of pro
-
longed vigorous physical activity or prolonged standing in 
a hot humid environment followed by a sudden collapse. 
Physical examination may reveal cool and moist skin, a 
weak pulse, and low systolic blood pressure.
 is a life-threatening emergency. The hall
-
mark of heat stroke is cerebral dysfunction when the core 
body temperature is over 40
°
C. Presenting symptoms 
include all findings seen in heat exhaustion with additional 
neurologic symptoms such as dizziness, weakness, emo
-
tional lability, confusion, delirium, blurred vision, convul
-
sions, collapse, and unconsciousness. Physical examination 
findings may be variable and therefore unreliable. Exer
-
tional heat stroke may present with sudden collapse and

-
-
tional heat stroke may present with sudden collapse and 
loss of consciousness followed by irrational behavior. 
Sweating may not be present. Providers must be vigilant in 
monitoring for kidney injury, liver failure, metabolic 
derangements, respiratory compromise, coagulopathy, and 
ischemia. Initial laboratory findings are nonspecific to this 
 
»
Treatment
A. Heat Cramps
The patient must be moved to a shaded, cool environment 
and given oral rehydration solution to replace both electro
-
lytes and water. 
Oral salt tablets are not recommended.
 The 
patient may have to rest for at least 2 days with continued 
dietary supplementation before returning to work or 
resuming strenuous activity in the heat.
B. Heat Exhaustion
Treatment consists of moving patients to a shaded, cool 
environment, providing adequate fluid and electrolyte 
replacement, and initiating active cooling measures if nec
-
essary. Physiologic saline or isotonic glucose solution may 
be administered intravenously when oral administration is 
not appropriate. At least 48 hours of rest and rehydration 
are recommended.
C. Heat Syncope
Treatment consists of rest and recumbency in a shaded, 
cool place, and fluid and electrolyte replacement by mouth, 
or intravenously if necessary.
D. Heat Stroke
Initially, the patient’s ABCs (airway, breathing, circulation) 
must be addressed and stabilized, then treatment is aimed 
at rapidly reducing the core body temperature within 
 
1 hour while supporting circulation and perfusion. Patients 
should be observed using pulse oximetry and cardiac 
monitors while continuing to measure core body tempera
-
ture and fluid input and output. The patient should also be 
observed for complications such as hypovolemic or cardio
-
genic shock, metabolic abnormalities, cardiac arrhythmias, 
coagulopathy, acute respiratory distress syndrome (ARDS), 
hypoglycemia, rhabdomyolysis, seizures, organ dysfunc
-
tion, infection, and severe edema that can progress to a 
compartment syndrome. Circulatory failure in heat-related 
illness is mostly due to shock from relative or absolute 
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hypovolemia. Oral or intravenous fluid administration 
must be provided to ensure adequate urinary output. Clini
-
cians must also assess for and treat concurrent conditions 
such as infection, trauma, and drug effects.
Choice of cooling method depends on which can be 
instituted the fastest with the least compromise to the over
-
all care of the patient. Evaporative cooling is preferred for 
nonexertional heat stroke and conductive-based cooling 
for exertional heat stroke. 
Evaporative cooling
 is a nonin
-
vasive, effective, quick and easy way to reduce temperature. 
This is accomplished by placing the undressed patient in 
lateral recumbent position or supported in a hands-and-
knees position to expose maximum skin surface to the air 
while the entire undressed body is sprayed with lukewarm 
water (20
°
C) and cooled by large fans circulating room air. 
Addition of inhaled cool air or oxygen may aid in cooling 
but must not be used alone. 
Conductive-based cooling
 
involves cool fluid infusion, gastric or bladder lavage, ice 
packs, and immersion into ice water or cool water. When 
immersion in ice water or cold water is available in the 
field, it is the preferred method of cooling for exertional 
heat stroke. Ice packs are most effective when covering the 
whole body, as opposed to the traditional method of plac
-
ing in the axilla and groin only. Intravascular heat exchange 
catheter systems as well as hemodialysis using cold dialy
-
sate (30–35
°
C) have been successful in reducing core body 
Shivering must be avoided because it inhibits the effec
-
tiveness of cooling by increasing internal heat production. 
Medications can be used to suppress shivering including 
magnesium, quick-acting opioid analgesics, benzodiaze
-
pines, and quick-acting anesthetic agents. Skin massage is 
recommended to prevent cutaneous vasoconstriction. 
Antipyretics (aspirin, acetaminophen) have no effect on envi
-
ronmentally induced hyperthermia and are contraindicated
. 
Treatment must be continued until the core body tempera
-
ture drops to 39
°
C.
 
»
Public education is necessary to improve prevention and 
early recognition of heat-related disorders. Individuals may 
take steps to reduce personal risk factors and to gradually 
acclimatize to hot environments.
Coaches, athletic trainers, athletes, and parents of 
young athletes must be educated about heat-related illness, 
specifically about prevention, risks, symptoms and signs, 
and treatment. Medical evaluation and monitoring should 
be used to identify the individuals and the weather condi
-
tions that increase the risk of heat-related disorders.
Those who are physically active in a hot environment 
must increase fluid consumption before, during, and after 
physical activities. Fluid consumption should include bal
-
anced electrolyte fluids and water. Water consumption 
alone may lead to electrolyte imbalance, particularly hypo
-
natremia. 
It is not recommended to have salt tablets avail
-
able for use because of the risk of hypertonic hypernatremia
. 
Close monitoring of fluid and electrolyte intake and early 
intervention are recommended in situations necessitating 
exertion or activity in hot environments.
 
»
Prognosis
Mortality is high from heat stroke, most frequently second
-
ary to multiorgan dysfunction. The patient is also at risk 
for rhabdomyolysis, ARDS, and inflammation even after 
temperature has normalized. Following heat stroke, imme
-
diate reexposure to ambient heat must be avoided.
 
»
Potential consultants include a surgeon for suspicion of 
compartment syndrome, nephrologist for kidney injury, 
and transplant surgeon for fulminant liver failure.
 
»
All patients with suspected heat stroke must be admitted to a 
hospital with intensive care capability for close monitoring.
Chen GM et al. Therapy of severe heatshock in combination

»
Chen GM et al. Therapy of severe heatshock in combination 
with multiple organ dysfunction with continuous renal 
replacement therapy: a clinical study. Medicine (Baltimore). 
2015 Aug;94(31):e1212. [PMID: 26252279]
Gaudio FG et al. Cooling methods in heat stroke. J Emerg Med. 
2016 Apr;50(4):607–16. [PMID: 26525947]
Leon LR et al. Heat stroke. Compr Physiol. 2015 Apr;5(2): 
611–47. [PMID: 25880507]
Lipman GS et al. Wilderness Medical Society practice guidelines 
for the prevention and treatment of heat-related illness: 2014 
update. Wilderness Environ Med. 2014 Dec;25(4 Suppl): 
S55–65. [PMID: 25498263]
Peiris AN et al. Heat stroke. JAMA patient page. 2017 Dec 26; 
318(24):2503. [PMID: 29279936]
Pryor RR et al. Exertional heat illness: emerging concepts and 
advances in prehospital care. Prehosp Disaster Med. 2015 Jun; 
30(3):297–305. [PMID: 25860637]
ACCIDENTAL SYSTEMIC HYPOTHERMIA
 
»
Systemic hypothermia is a core body temperature 
below 35
°
C.
 
»
Accurate core body temperature measurement 
must be obtained using a low-reading core tem
-
perature probe that measures as low as 25
°
C.
 
»
Core body temperature must be over 32
°
C before 
terminating resuscitation efforts.
 
»
Extracorporeal membrane oxygenation (ECMO) or 
cardiopulmonary bypass may be considered in 
hypothermic patients with hemodynamic instabil
-
ity or cardiac arrest.
 
»
Systemic hypothermia is defined as core body temperature 
below 35
°
C. This may be primary, from exposure to pro
-
longed ambient, extremely low temperature, or secondary, 
due to thermoregulatory dysfunction. Both may be present 
at the same time.
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Hypothermia must be considered in any patient with 
prolonged exposure to an ambient cold environment, espe
-
cially in any patients with prior cold weather injury as well 
as risk factors listed in the Cold & Heat section. In pro
-
longed or repetitive cold exposure, hypothermia ensues if 
the body’s thermoregulatory responses become impaired.
 
»
Symptoms and signs of hypothermia are typically nonspe
-
cific and markedly variable based on the patient’s underly
-
ing health and circumstances of cold exposure. Laboratory 
studies must assess acid-base status, electrolyte derange
-
ments (particularly potassium and glucose), coagulopathy, 
kidney failure, rhabdomyolysis and liver or pancreas 
dysfunction. Inaccurate laboratory values will occur if the 
blood sample is warmed to 37
°
C for testing. All patients 
must be evaluated for associated conditions including 
hypoglycemia, trauma, infection, overdose, and peripheral 
cold injury.
Accurate core body temperature measurements must be 
obtained using a low-reading core temperature probe that 
measures as low as 25
°
C. 
Stage I hypothermia
 is typically 
seen when the core body temperature is between 32
°
C and 
35
°
C and is defined by shivering and possibly poor judg
-
ment or coordination but with hemodynamic stability and 
a normal level of consciousness. 
Stage II
 
hypothermia
 
correlates with core body temperature 28–32
°
C. Shivering 
stops. Bradycardia, dilated pupils, slowed reflexes, cold 
diuresis, and confusion and lethargy ensue. The electrocar
-
diogram (ECG) may reveal a J wave or Osborn wave (posi
-
tive deflection in the terminal portion of the QRS complex, 
most notable in leads II, V
5
, and V
6
) (Figure 37–1). When 
the core body temperature is below 28
°
C, the likelihood of 
hemodynamic instability and cardiac arrest increase 
dramatically. 
Stage III hypothermia
 (core body tempera
-
ture 24–28
°
C) is characterized by loss of consciousness but 
present vital signs. 
Stage IV
 
 (core body 
temperature less than 24
°
C) is the loss of vital signs. Coma, 
loss of reflexes, asystole, or ventricular fibrillation may 
falsely lead the clinician to assume the patient is dead 
despite reversible hypothermia.
 
»
Treatment
Rewarming is the initial, imperative treatment for all 
hypothermic patients
. Resuscitation begins with rapid assess
-
ment and support of airway, breathing and circulation, simul
-
taneously with the initiation of rewarming, and prevention of 
further heat loss. All cold, wet clothing must be removed and 
replaced with warm, dry clothing and blankets.
Mild or stage I hypothermia can be treated with passive 
external rewarming (ie, removing and replacing wet clothes 
with dry ones) or by active external rewarming. In contrast 
to those with more severe hypothermia, it is safe and rec
-
ommended for the uninjured patient with mild hypother
-
mia to become physically active to generate heat. 
Active 
external rewarming
 is noninvasive, highly effective, and 
safe for mild hypothermia. It involves applying external 
heat to the patient’s skin. Examples include warm bedding, 
heated blankets, heat packs, and immersion into a 40
°
C 
bath. Warm bath immersion limits the ability to monitor 
the patient or treat other coexisting conditions. Patients 
with mild hypothermia and previous good health usually 
respond well to passive and active external warming.
Stage II and III hypothermia are treated as above with 
the addition of more aggressive rewarming strategies. This 
requires close monitoring of vital signs and cardiac rhythm 
during rewarming. Warm intravenous fluids (38–42
°
C) are 
considered minimally invasive and effective.
As hypothermia becomes more severe, there are increased 
complications of both hypothermia itself and of rewarming. 
Complications of rewarming occur as colder peripheral

Complications of rewarming occur as colder peripheral 
blood returns to central circulation. This may result in core 
temperature afterdrop, rewarming lactic acidosis from shunt
-
ing lactate into the circulation, rewarming shock from 
peripheral vasodilation and hypovolemia, ventricular fibrilla
-
tion, and other cardiac arrhythmias. Afterdrop can be less
-
ened by active external rewarming of the trunk but not 
 
the extremities and by avoiding any muscle movement by the 
patient. Extreme caution must be taken when handling the 
hypothermic patient to avoid triggering potentially fatal 
arrhythmias in a phenomenon known as rescue collapse.
Treatment of patients with stage IV hypothermia cardiac 
arrest calls for modification of typical resuscitation algo
-
rithms. 
High-quality CPR must be continued until the 
patient’s core body temperature is at least 32
°
C
. There is a 
discrepancy between the recommendations on use and dos
-
ing of epinephrine in cardiac arrest of the severely hypo
-
thermic patient. The European Resuscitation Council 
recommends withholding epinephrine until warmed to 
30
°
C, and decreasing the frequency from 30
°
C to 35
°
C. The 
American Heart Association permits dosage as usual in 
conjunction with rewarming. ECMO or cardiopulmonary 
bypass may be done in patients with hypothermia who are 
in cardiac arrest except when patients have fatal hyperkale
-
mia (10–12 mmol/L) or evidence of death from a traumatic 
cause such as decapitation or asphyxiation in an avalanche.
 
▲
Figure 37–1.
 
Electrocardiogram shows leads II and 
V5 in a patient whose body temperature is 24
°
C. Note 
the bradycardia and Osborn waves. These findings 
become more prominent as the body temperature low
-
ers, and gradually resolve with rewarming. Osborn 
waves have an extra positive deflection in the terminal 
portion of the QRS complex and are best seen in the 
inferior and lateral precordial leads (most notably in 
leads II, V
5
, and V
6
).
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Any hypothermic patient with return of spontaneous 
circulation must be monitored very closely because of the 
high likelihood of subsequent multiorgan system failure.
 
»
Hypothermia patients must undergo close monitoring for 
potential complications. This is typically done during an 
inpatient admission or prolonged emergency department 
Gordon L et al. Severe accidental hypothermia. BMJ. 
2014 Feb 21;348:g1675. [PMID: 24563453]
Rischall ML et al. Evidence-based management of accidental 
hypothermia in the emergency department. Emerg Med 
Pract. 2016 Jan;18(1):1–19. [PMID: 26655247]
Zafren K. Out-of-hospital evaluation and treatment of acciden
-
tal hypothermia. Emerg Med Clin North Am. 2017 May; 
35(2):261–79. [PMID: 28411927]
HYPOTHERMIA OF THE EXTREMITIES
 
»
Extremities suffering cold-induced injuries must 
not be exercised, rubbed, or massaged during 
rewarming.
 
»
Rewarming of extremities affected by cold-
induced injuries must be performed as soon as 
possible once there is no risk of refreezing.
 
»
Cold exposure of the extremities produces immediate local
-
ized and then generalized vasoconstriction, which may 
result in a wide range of injuries. Tissue damage occurs 
because of ischemia and intravascular thromboses, endo
-
thelial damage, or actual freezing. Freezing (frostbite) may 
occur when skin temperatures drop or in the presence of 
wind, water, immobility, malnutrition, or vascular disease.
 
»
“Keep warm, keep dry, and keep moving. ”
 For optimal preven
-
tion of frostbite, individuals must wear warm, dry clothing. 
Arms, legs, fingers, and toes must be exercised to maintain 
circulation. Wet clothing, socks, and shoes must be replaced 
with dry ones. Those most at risk are people with underlying 
diseases or medications that decrease tissue perfusion and 
those with environmental exposure to a prolonged cold 
environment. Caution must be taken to avoid cramped posi
-
tions; constrictive clothing; prolonged dependency of the 
feet; use of tobacco, alcohol, and sedative medications; and 
exposure to wet muddy ground and windy conditions.
FROSTNIP & CHILBLAIN (
Erythema Pernio
)
Frostnip
 is a mild temporary form of cold-induced injury 
causing local paresthesias of the involved area that com
-
pletely resolve with passive external rewarming.
Chilblains
 or 
erythema pernio
 are inflammatory skin 
changes caused by exposure to cold without actual freezing 
of the tissues. These skin lesions may be red or purple 
papular lesions, which are painful or pruritic, with burning 
or paresthesias. They may be associated with edema or 
blistering and aggravated by warmth. With continued 
exposure, ulcerative or hemorrhagic lesions may appear 
and progress to scarring, fibrosis, and atrophy.
Treatment consists of elevating and passively externally 
rewarming the affected part. Caution must be taken to 
avoid rubbing or massaging injured tissues and to avoid 
applying ice or heat. The area must be protected from 
trauma, secondary infection, and further cold exposure.
IMMERSION FOOT OR TRENCH FOOT
Immersion foot (or hand)
 is caused by prolonged immer
-
sion in cold water or mud, usually below 10
°
C. 
Prehyperemic stage
 is marked by early symptoms of cold 
and anesthesia of the affected area. 
Hyperemic stage
 fol
-
lows with a hot sensation, intense burning, and shooting 
pains. 
Posthyperemic stage
 occurs with ongoing cold 
exposure; the affected part becomes pale or cyanotic with 
diminished pulsations due to vasospasm. This may result 
in blistering, swelling, redness, ecchymoses, hemorrhage, 
necrosis, peripheral nerve injury, or gangrene.
 Treatment consists of air drying, protecting the extrem
-
ities from trauma and secondary infection, and gradual 
rewarming by exposure to air at room temperature (not ice 
or heat). Caution must be taken to avoid massaging or

-
or heat). Caution must be taken to avoid massaging or 
moistening the skin and to avoid further cold injury and 
water immersion. Affected parts are elevated to aid in 
removal of edema fluid. Pressure sites are protected with 
cushions. Bed rest is required until all ulcers have healed.
FROSTBITE
Frostbite
 is injury from tissue freezing and formation of 
ice crystals in the tissue. Most tissue destruction follows 
reperfusion of the frozen tissues, with damaged endothelial 
cells and progressive microvascular thrombosis resulting in 
further tissue damage. In mild cases, only the skin and 
subcutaneous tissues are involved. Symptoms include 
numbness, prickling, itching, and pallor. With increasing 
severity, deeper structures become involved. The skin 
appears white or yellow, loses elasticity, and becomes 
immobile. Edema, hemorrhagic blisters, necrosis, gan
-
grene, paresthesias, and stiffness may occur.
 
»
Treatment
Evaluate and treat the patient for associated systemic hypo
-
thermia, concurrent conditions, and injury. Avoid second
-
ary exposure to cold. Early use of systemic analgesics is 
recommended for nonfrozen injuries. Hydrate patients 
orally or parenterally to avoid hypovolemia and to improve 
perfusion.
1. Rewarming—
Rapid rewarming at temperatures slightly 
above normal body temperature may significantly decrease 
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tissue necrosis and reverse the tissue crystallization. 
If there 
is any possibility of refreezing, the frostbitten part must 
not be thawed.
 Ideally, the frozen extremity must not be 
used. Rewarming is best accomplished by warm bath 
immersion. The frozen extremity is immersed for several 
minutes in a moving water bath heated to 40–42
°
C until the 
distal tip of the part being thawed flushes. In the absence of 
a thermometer, the temperature may be checked by an 
unaffected extremity, ideally of a caregiver rather than the 
patient. Water in this temperature range feels warm but not 
hot to the normal hand or wrist. If warm water is not avail
-
able, then passive thawing in a warm environment must be 
allowed. Dry heat is not recommended because it is more 
difficult to regulate and increases the likelihood of acciden
-
tal burns. Thawing may cause tenderness and burning pain. 
Once the frozen part has thawed and returned to normal 
temperature (usually in about 30 minutes), discontinue 
external heat. 
In the early stage, rewarming by exercise, 
rubbing, or friction is contraindicated.
 The patient must 
be kept at bed rest with the affected parts elevated and 
uncovered at room temperature. Avoid application of casts, 
occlusive dressings, or bandages. Blisters must be left intact 
unless signs of infection supervene.
2. Anti-infective measures and wound care—
Frostbite 
increases susceptibility to tetanus and infection. Tetanus 
prophylaxis status must be verified and updated as needed. 
Infection risk may be reduced by aseptic wound care. Non
-
adherent sterile gauze and fluffy dressing must be loosely 
applied to wounds and cushions used for all areas of pres
-
sure. Antibiotics should not be administered empirically.
B. Medical and Surgical Treatment Options
With the availability of telemedicine, specialists are able to 
provide advice on early field treatment of cold-injured 
patients in remote areas, thereby improving outcomes. 
Clinicians must watch for evidence of compartment syn
-
drome and need for fasciotomy. Eschar formation without 
evidence of infection may be conservatively treated. The 
underlying skin may heal spontaneously with the eschar 
acting as a biologic dressing. Rates of amputation have been 
reduced with the use of intravenous infusions of synthetic 
prostaglandins and of a tissue plasminogen activators, and 
with intra-arterial administration of a thrombolytic within 
 
24 hours of exposure. There is insufficient evidence to rec
-
ommend hyperbaric oxygen, heparin, or sympathectomy.
C. Follow-Up Care
Patient education must include ongoing care of the cold 
injury and prevention of future hypothermia and cold 
injury. Gentle, progressive physical therapy to promote 
circulation should be instituted as tolerated. Debridement 
and amputation may be considered only after it is estab
-
lished that the tissues are necrotic.
 
»
Prognosis
Recovery from frostbite depends on the underlying comor
-
bidities, the extent of initial tissue damage, the rewarming 
reperfusion injury, and the late sequelae. The involved 
extremity may be at increased susceptibility for discomfort 
and injury upon re-exposure to cold. Neuropathic sequelae 
include pain, numbness, tingling, hyperhidrosis, and cold 
sensitivity of the extremities. Nerve conduction abnormali
-
ties may persist for many years after a cold injury.
 
»
•	
Management of tissue damage, comorbidities, associ
-
ated injuries.
•	
Need for hospital-based interventions.
•	
Psychosocial factors (cognitive impairment, inadequate 
living situation) that could compromise patient safety 
or recovery.
Cauchy E et al. A new proposal for management of severe frost
-
bite in the austere environment. Wilderness Environ Med. 
2016 Mar;27(1):92–9. [PMID: 26948558]
Fudge JR et al. Medical evaluation for exposure extremes: cold. 
Wilderness Environ Med. 2015 Dec;26(4 Suppl):S63–8.

Wilderness Environ Med. 2015 Dec;26(4 Suppl):S63–8. 
[PMID: 26617380]
Handford C et al. Frostbite. Emerg Med Clin North Am. 
2017 May;35(2):281–99. [PMID: 28411928]
Heil K et al. Freezing and non-freezing cold weather injuries: a 
systematic review. Br Med Bull. 2016 Mar;117(1):79–93. 
[PMID: 26872856]
Ibrahim AE et al. The emerging role of tissue plasminogen acti
-
vator in the management of severe frostbite. J Burn Care Res. 
2015 Mar–Apr;36(2):e62–6. [PMID: 25687362]
 
º
DROWNING
 
»
The first requirement of rescue is immediate res
-
cue breathing and CPR.
 
»
Clinical manifestations include hypoxemia, pul
-
monary edema, and hypoventilation. 
 
»
The patient must also be assessed for hypother
-
mia, hypoglycemia, alcohol intake, concurrent 
injuries, and medical conditions.
 
»
Drowning, as defined by the World Health Organization, is 
the “process resulting in primary respiratory impairment 
from submersion in a liquid medium. ” Drowning may 
result in aspiration, laryngospasm, hypoxemia, and acide
-
mia. Outcomes from drowning range from life without 
morbidity to death. Morbidity may be immediate or 
delayed. The asphyxia of drowning is usually due to aspira
-
tion of fluid, but it may result from airway obstruction 
caused by laryngeal spasm while the victim is gasping 
under water. A patient may be deceptively asymptomatic 
during the initial recovery period only to deteriorate or die 
as a result of acute respiratory failure within the following 
12–24 hours. Disseminated intravascular coagulation may 
also lead to bleeding after asphyxiation from drowning.
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»
The patient’s appearance may vary from asymptomatic to 
marked distress with abnormal vital signs. Symptoms and 
signs include dyspnea, cough, wheezing, chest pain, dys
-
rhythmia, hypotension, cyanosis, and apnea. The patient 
may experience headache, neurologic deficits, and altered 
level of consciousness. Hypothermia is highly likely with 
cold water or prolonged submersion.
Metabolic acidosis is common and arterial blood gas 
results may be helpful in determining the degree of injury 
since initial clinical findings may appear benign. PaO
2
 is 
usually decreased; PaCO
2
 may be increased or decreased; 
pH is decreased. Bedside blood sugar must be checked 
rapidly. Other testing is based on clinical scenario.
 
»
Education and prevention are critical given the high bur
-
den of disease from drowning.
Preventive measures must be taken to reduce morbidity 
and mortality from drowning. Conditions that increase risk of 
submersion injury include the use of alcohol or other drugs, 
inadequate water safety skills, poor physical health, hyperven
-
tilation, sudden acute illness, acute trauma, venomous stings 
or bites, decompression sickness, dangerous water conditions, 
and carbon monoxide exposure from boat motors.
 
»
Treatment
A. First Aid
1.
 
The first requirement of rescue is immediate basic life sup
-
port treatment and CPR.
 At the scene, immediate measures 
to combat hypoxemia are critical to improve outcome.
2.
 
Patient must be assessed for hypothermia, hypoglyce
-
mia, concurrent medical conditions, and associated 
trauma, especially brain and cervical spine injury.
3.
 
Rescuer must not attempt to drain water from the 
victim’s lungs.
4.
 
Resuscitation and basic life support efforts must be 
continued until core body temperature reaches 32
°
C.
B. Subsequent Management
1. Ensure optimal ventilation and oxygenation—
The 
onset of hypoxemia exists even in the alert, conscious 
patient who appears to be breathing normally. Oxygen 
must be administered immediately at the highest available 
concentration. Oxygen saturation must be maintained at 
90% or higher via supplemental oxygen, continuous posi
-
tive airway pressure (CPAP), positive end-expiratory pres
-
sure (PEEP) or intubation and mechanical ventilation.
Serial physical examinations and chest radiographs 
must be performed to detect possible pneumonitis, atelec
-
tasis, and pulmonary edema. Bronchodilators may be used 
to treat wheezing. Nasogastric suctioning can decompress 
the stomach.
2. Cardiovascular support—
Intravascular volume status 
must be monitored and supported by vascular fluid 
replacement, vasopressors, or diuretics as needed.
3. Correction of blood pH and electrolyte 
—
Metabolic acidosis is present in 70% of drowning victims, 
but this typically corrects through adequate ventilation and 
oxygenation. Glycemic control improves outcome.
4. Cerebral and spinal cord injury—
Central nervous sys
-
tem damage may progress despite apparently adequate 
treatment of hypoxia and shock.
5. Hypothermia—
Core body temperature must be mea
-
sured and managed as appropriate (see Accidental Sys
-
temic Hypothermia, above).
 
»
Respiratory damage is often severe in the minutes to hours 
following a drowning. With respiratory supportive treat
-
ment, improvements typically occur quickly over the first 
few days following the drowning. Long-term complications 
of drowning may include neurologic impairment, seizure 
disorder, and pulmonary or cardiac damage. Prognosis is 
directly correlated with the patient’s age, submersion time, 
rapidity of prehospital resuscitation and subsequent trans
-
port to a medical facility, clinical status at time of arrival to 
hospital, Glasgow Coma Scale score, pupillary reactivity, 
and overall health assessment (APACHE II score).
 
»

-
 
»
Most patients with significant drowning or concurrent 
medical or traumatic conditions require inpatient monitor
-
ing following the event. This includes continuous monitor
-
ing of cardiorespiratory, neurologic, renal and metabolic 
function. Pulmonary edema may not appear for 24 hours.
Bierens JJ et al. Physiology of drowning: a review. Physiology 
(Bethesda). 2016 Mar;31(2):147–66. [PMID: 26889019]
Champigneulle B et al. Extracorporeal life support (ECLS) for 
refractory cardiac arrest after drowning: an 11-year experi
-
ence. Resuscitation. 2015 Mar;88:126–31. [PMID: 25484021]
Engel SC. Drowning episodes: prevention and resuscitation tips. 
J Fam Pract. 2015 Feb;64(2):E1–6. [PMID: 25671539]
Mott TF et al. Prevention and treatment of drowning. Am Fam 
Physician. 2016 Apr 1;93(7):576–82. [PMID: 27035042]
Schmidt A et al. Drowning in the adult population: emergency 
department resuscitation and treatment. Emerg Med Pract. 
2015 May;17(5):1–18. [PMID: 26301918]
 
º
T
h
ERMAL BURNS
 
»
Estimates of the burn location, size, and depth 
greatly determine treatment plan.
 
»
The first 48 hours of burn care offer the greatest 
impact on morbidity and mortality of a burn 
victim.
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Worldwide, burns are a common cause of injury and 
potential morbidity and mortality. Burn prognosis is 
affected by the type of environment where the burn 
occurred. Low-resource settings (wilderness or low-income 
areas) are associated with delays in and suboptimal access 
to standard burn treatments.
The first 48 hours after thermal burn injury offer the 
greatest opportunity to impact the survival of the patient. 
Early surgical intervention, wound care, enteral feeding, 
glucose control and metabolic management, infection con
-
trol, and prevention of hypothermia and compartment 
syndrome have contributed to significantly lower mortality 
rates and shorter hospitalizations. Research utilizing sev
-
eral different well-established burn severity scores has 
shown the importance of patient comorbidities to the 
prognosis of patients with severe burn injuries.
 
»
Burns are classified by extent, depth, patient age, and asso
-
ciated illness or injury. Accurate estimation of burn size 
and depth is important since these estimations will quan
-
tify the parameters of resuscitation.
1. Extent—
In adults, the “rule of nines” (Figure 37–2) is 
useful for rapidly assessing the extent of a burn. It is impor
-
tant to view the entire patient to make an accurate assess
-
ment of skin findings on initial and subsequent 
examinations. One rule of thumb is that the palm of an 
open hand of the patient constitutes 1% total body surface 
area (TBSA) in adults. Partial- and full-thickness burns are 
included in calculating the TBSA.
2. Depth—
Judgment of depth of injury is difficult. 
Super
-
ficial burns
 (previously referred to as first-degree burns) 
may be red or gray but will demonstrate excellent capillary 
refill and are not blistered initially. If the wound is blistered 
and appears pink and wet, this represents a 
superficial 
partial-thickness burn
 (previously, second-degree burn). 
Deep partial-thickness burns
 appear white and wet, and 
they bleed if poked; cutaneous sensation is maintained. 
Full-thickness burns
 (previously, third-degree burns) 
result in a loss of adnexal structures and may appear white-
yellow in color, or may have a black charred appearance, 
and its stiff, dry skin does not bleed when poked; cutane
-
ous sensation is lost.
Deep partial-thickness and full-thickness burns are 
treated in a similar fashion. Neither will heal appropriately 
without early debridement and grafting; without such 
treatment, the resultant skin is thin and scarred.
B. Survival After Burn Injury
Transfer to a burn unit is determined by large burn size, 
circumferential burn, or burn involving a joint or high-risk 
body part, and by comorbidities. Mortality rates have been 
significantly reduced due to treatment advances including 
improvements in wound care, treatment of infection, early 
burn excision, skin substitute usage, and early nutritional 
support.
C. Associated Injuries or Illnesses
Smoke inhalation, associated trauma, and electrical inju
-
ries are commonly associated with burns. Severe burns 
from any source may result in similar complications 
(ie, infections, respiratory compromise, multiorgan dys
-
function, venous thromboembolism, and gastrointestinal 
complications).
D. Systemic Reactions to Burn Injury
When burns greater than approximately 20% of TBSA are 
present, systemic metabolic derangements may occur and 
require intensive support. The inflammatory cascade can 
result in shock and coagulopathy.
 
»
Treatment
A. Initial Resuscitation
1. Primary survey—
Burn patients require a full trauma 
assessment, starting with “ ABCDE” (airway, breathing, 
circulation, disability, exposure).
a. Airway control—
Serial assessments of airway and 
breathing are necessary because airway compromise and 
ARDS may develop, particularly in those with inhalation 
injury.
b. V ascular access—
Vascular access must be obtained

injury.
Vascular access must be obtained 
on all burn patients.
c. Fluid resuscitation—
Patients with burns of greater 
than 15% of TBSA require intravascular fluid administration 
of large volumes of crystalloid. The most widely recognized 
Entire head and
neck = 9%
Entire arm
= 9%
9%
9%
9%
9%
9%
9% 9%
Posterior surface
of upper trunk
= 9%
of lower trunk
= 9%
of each leg = 9%
Adult
Rule of Nines
1%
 
▲
Figure 37–2.
 
Estimation of body surface area in 
burns.
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guideline for fluid resuscitation is the 
Parkland formula
 
(http://www.mdcalc.com/parkland-formula-burns/) 
 
in which the fluid requirement in the first 24 hours is esti
-
mated as 4 mL/kg × body weight per percent of body surface 
area burned. Half the calculated fluid is given in the first 
8-hour period from the time of injury, not the time of arrival 
to medical care. The remaining fluid is delivered over the next 
16 hours. An extremely large volume of fluid may be required. 
Crystalloid solutions alone may be insufficient to restore car
-
diac preload during the period of burn shock. Conversely, 
clinicians must watch for clinical signs of volume overload as 
it may lead to pulmonary complications and to a compart
-
ment syndrome from edema. Electrical burns and inhalation 
injury may increase the fluid requirement.
B. Management
1. Pain control—
Pain control is critical in these patients. 
Treatment is with (oral or intravenous) nonsteroidal anti-
inflammatory drugs and opioids.
2. Chemoprophylaxis—
a. Tetanus immunization—
Tetanus prophylaxis status 
needs to be verified and updated in all burn patients. 
 
(See Chapter 33.)
b. Antibiotics—
All nonsuperficial wounds need to be 
covered with topical antibiotics. Prophylaxis with systemic 
antibiotics is not indicated.
3. Surgical management—
a. Escharotomy—
As tissue swelling occurs, ischemia 
may develop under any constricting eschar of an extremity, 
neck, chest, or trunk if the full-thickness burn is circumfer
-
ential. Escharotomy incisions through the eschar can save 
life and limb.
b. Fasciotomy—
Fasciotomy is indicated for any compart
-
ment syndrome. Clinicians must frequently monitor 
patients for development of early signs of a compartment 
syndrome, particularly in those with circumferential burns.
c. Debridement, dressings, and topical and 
systemic
 antibiotic therapy
—
Minor burn wounds 
must be debrided to determine the depth of the burn and 
then thoroughly cleansed. Thereafter, daily wound care 
must consist of debridements as needed, topical antibiotics, 
and wound dressings. Patient compliance and adequate 
pain control is essential for successful outpatient treatment. 
The wound must be reevaluated by the treating clinician 
within 24–72 hours to evaluate for signs of infection.
The goal of burn wound management is to protect the 
wound from desiccation and avoid further injury or infec
-
tion. Regular and thorough cleansing of burned areas is a 
critically important intervention. Topical antibiotics may 
be applied after wound cleansing. Silver sulfadiazine is no 
longer recommended.
Systemic infection remains a leading cause of morbidity 
among patients with major burn injuries, therefore close 
monitoring and early treatment for systemic infection is 
imperative. Health care–associated infections are increas
-
ingly common.
d. Wound management—
The goal of therapy after fluid 
resuscitation is rapid and stable closure of the wound. 
Wounds that do not heal spontaneously in 7–10 days (ie, 
deep partial-thickness or full-thickness burns) are best 
treated by a specialist through excision and autograft; other
-
wise, granulation and infection may develop, and the quality 
of the skin in regenerated deep partial thickness burns is 
marginal because of the very thin dermis that emerges.
Cultured allogeneic keratinocyte grafts can provide 
rapid early coverage for superficial burn injuries. With 
severe burns, skin substitution with cultured grafts can be 
lifesaving. However, although the replaced dermis does 
have nearly normal histologic dermal elements, there are no 
adnexal structures present and very few, if any, elastic fibers.
e. Abdominal compartment syndrome—
Abdominal 
compartment syndrome is emerging as a potentially lethal 
condition in severely burned patients with mortality rates of 
approximately 60% despite surgical intervention. Diagnosis is 
confirmed by bladder pressures greater than 30 mm Hg in at-

risk patients. Surgical abdominal decompression may improve 
ventilation and oxygen delivery but may not impact survival.
C. Patient Support
Burn patients require extensive supportive care, both 
physiologically and psychologically. It is important to 
maintain normal core body temperature and avoid hypo
-
thermia (by maintaining environmental temperature at or 
above 30
°
C) in patients with burns over more than 20% of 
TBSA. Burn patients are at risk for many complications 
such as respiratory injury, ARDS, sepsis, multiorgan fail
-
ure, and venous thromboembolism.
Burn patients have increased metabolic and energy 
needs for wound healing and require careful assessment 
and provision of optimal nutrition. Early aggressive nutri
-
tion (by parenteral or enteral routes) reduces infections, 
recovery time, noninfectious complications, length of hos
-
pital stay, long-term sequelae, and mortality.
Occasionally, ARDS or respiratory failure unresponsive to 
maximal ventilatory support may develop in burn patients.
Prevention of long-term scars remains a formidable 
problem in seriously burned patients.
 
»
Prognosis
Prognosis depends on the extent and location of the burn 
tissue damage, associated injuries, comorbidities, and com
-
plications. Hyperglycemia is a predictor of worse out
-
comes. Common complications include sepsis; gangrene 
requiring limb amputation; or neurologic, cardiac, cogni
-
tive, or psychiatric dysfunction. Psychiatric support may be 
necessary following burn injury.
 
»
•	
Transfer to a burn unit is indicated for large burn size 
(for partial-thickness burns, greater than 10% of TBSA 
or for full-thickness burns, greater than 5% of TBSA), 
circumferential burn, inhalation injury, or burn involv
-
ing a joint or high-risk body part (face, hands, feet, 
genitalia), and for patients with comorbidities.
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»
•	
All burn patients require extensive supportive care, 
both physiologically and psychologically.
•	
Significant burns (based on location and extent).
•	
Patients with significant comorbidities and suboptimal 
home situations.
•	
Burn center consultation can advise which patients 
require transfer and which can be managed via tele
-
medicine/telephone consultation.
•	
Monitoring includes vital signs, wound care, and obser
-
vation for potential complications of electrolyte abnor
-
malities, acute kidney injury, hepatic failure, 
cardiopulmonary compromise, hypoglycemia, and 
Bitter CC et al. Management of burn injuries in the wilderness: 
lessons from low-resource settings. Wilderness Environ Med. 
2016 Dec;27(4):519–25. [PMID: 28029455]
Heng JS et al. Revised Baux score and updated Charlson comor
-
bidity index are independently associated with mortality in 
burns intensive care patients. Burns. 2015 Nov;41(7):1420–7. 
[PMID: 26187055]
Otterness K et al. Emergency department management of smoke 
inhalation injury in adults. Emerg Med Pract. 2018 Mar; 
20(3):1–24. [PMID: 29489306]
Porter C et al. The metabolic stress response to burn trauma: 
current understanding and therapies. Lancet. 2016 Oct 1; 
388(10052):1417–26. [PMID: 27707498]
 
º
ELECTRICAL INJURY
 
»
Extent of injury is determined by the type, amount, 
duration, and pathway of electrical current.
 
»
Clinical findings of death are unreliable; therefore, 
resuscitation efforts must be attempted before 
assuming the electrical injury victim is dead.
 
»
Skin findings may be misleading and are not 
indicative of the degree of deeper tissue injury.
 
»
Electricity-induced injuries are common and yet most are 
preventable. These injuries occur by exposure to electrical 
current of low voltage, high voltage, or lightning. Electri
-
cal current type is either alternating current (AC) or 
direct current (DC). Electricity causes acute injury by 
direct tissue damage, muscle tetany, direct thermal injury 
and coagulation necrosis, and associated trauma.
Alternating current (AC)
 is an electric current that 
periodically reverses direction in a sine wave pattern and 
may cause muscle tetany, which prolongs the duration and 
amount of current exposure. AC can be low voltage or high 
voltage. Most households and businesses use electric power 
in the form of AC at 
low voltages
 (less than 1000 V). Low 
voltage electrical injuries can range from minor to 
significant damage and death. 
High voltage
1000 V) electrical injuries are often related to occupational 
exposure and associated with deep tissue damage and 
higher morbidity and mortality. 
Direct current (DC)
 is 
unidirectional electrical flow (ie, lightning, batteries, and 
automotive electrical systems). It is more likely to cause a 
single intense muscle contraction and asystole. 
Lightning
 
differs from other high-voltage electrical shock in that 
lightning delivers a direct current of millions of volts in a 
fraction of a second.
The extent of damage from electrical injuries depends 
on the following factors: voltage, current type, tissue resis
-
tance, moisture, pathway, duration of exposure, associated 
trauma, and comorbidities. Current is the most important 
determinant of tissue damage. Current passes through the 
tissues of least resistance as energy which produces heat 
and causes direct thermal injury. Tissue resistance varies 
throughout the body with nerve cells being the most vul
-
nerable, and bone, the most resistant to electrical current.
 
»
Electrical burns are of three distinct types: flash (arcing) 
burns, flame (clothing) burns, and the direct heating effect 
of tissues by the electrical current.
Skin damage does not correlate with the degree of injury.
 
Not all electrical injuries cause skin damage; very minor skin

Not all electrical injuries cause skin damage; very minor skin 
damage may be present with massive internal injuries. 
Symptoms and signs may range from very subtle to death. 
The presence of entrance and exit burns signifies an 
increased risk of deep tissue damage. Current passing 
through skeletal muscle can cause muscle necrosis and con
-
tractions severe enough to result in bone fracture. If the 
current passes through the heart or brainstem, death may be 
immediate due to ventricular fibrillation, asystole, or apnea.
Resuscitation must be initiated on all victims of electri
-
cal injury since clinical findings are deceptive and 
unreliable.
 
»
Complications include cardiac or respiratory arrest; dys
-
rhythmias; neurologic dysfunction, such as autonomic 
dysfunction (resulting in pupils that are fixed, dilated, or 
asymmetric); altered mental status; seizures; paralysis; 
headache; vascular injury; tissue edema and necrosis; com
-
partment syndrome; associated traumatic injuries (ruptured 
ear drums, fractures); pneumothorax; rhabdomyolysis; 
acute kidney injury; hypovolemia; infections; ocular com
-
plications; sepsis; gangrene; cognitive or psychiatric dys
-
function. Psychiatric support may be necessary following 
electrical injury.
 
»
Treatment
The patient must be assessed and treated as a trauma vic
-
tim. The victim must be safely separated from the electrical 
current prior to initiation of CPR or any treatment. 
Resuscitation must then be initiated since clinical findings of 
death are unreliable.
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B. Hospital Measures
The initial assessment involves airway, breathing, and circula
-
tion followed by a full trauma protocol. Fluid resuscitation is 
important to maintain adequate urinary output. Initial evalu
-
ation includes cardiac monitoring and ECG, complete blood 
count, electrolytes, kidney function tests, liver chemistries, 
creatine phosphokinase or urine myoglobin, urinalysis, and 
cardiac enzymes. ECG does not show typical patterns of isch
-
emia since the electrical damage is epicardial. Victims must be 
evaluated for hidden injury, organ injury, blunt trauma, dehy
-
dration, skin burns, hypertension, acid-base disturbances, and 
neurological as well as psychological damage.
Electrical burn wounds are an underrecognized and yet 
devastating form of burn injury with wide-ranging and 
significant complications.
When electrical injury occurs, there must be a high 
suspicion for extensive deep tissue necrosis. Superficial 
skin may appear deceivingly benign, leading to a delayed or 
completely overlooked diagnosis of deep tissue injury. 
Deep tissue necrosis leads to profound tissue swelling, 
which results in a high risk of a compartment syndrome. 
Early debridement of devitalized tissues and tetanus pro
-
phylaxis may reduce the risks of infection.
Pain management is important before, during, and after 
initial treatment and subsequent rehabilitation.
 
»
Prognosis
Prognosis depends on the degree and location of electrical 
injury, initial tissue damage, associated injuries, comor
-
bidities, and complications.
 
»
•	
Specialists may be needed to perform fasciotomy for 
compartment syndrome or devitalized tissue debride
-
ment or microvascular reconstruction.
•	
Ophthalmologists should evaluate patients for possible 
ocular complications, and subsequent ENT physicians 
should evaluate for tympanic membrane rupture or 
 
»
Indications for hospitalization include high-voltage expo
-
sure; dysrhythmia or ECG changes; large burn; neurologic, 
pulmonary, or cardiac symptoms; suspicion of significant 
deep tissue or organ damage; transthoracic current path
-
way; history of cardiac disease or other significant comor
-
bidities or injuries; and need for surgery.
Andrews CJ et al. Neurological and neuropsychological conse
-
quences of electrical and lightning shock: review and theories 
of causation. Neural Regen Res. 2017 May;12(5):677–86. 
[PMID: 28616016]
Clark AT et al. JAMA patient page. Electrical injury. JAMA. 2017 
Sep 26;318(12):1198. [PMID: 28973623]
Davis C et al. Wilderness Medical Society practice guidelines for 
the prevention and treatment of lightning injuries: 2014 
S86–95. [PMID: 25498265]
Saracoglu A et al. Prognostic factors in electrical burns: a review 
of 101 patients. Burns. 2014 Jun;40(4):702–7. [PMID: 24054987]
Waldmann V et al. Electrical cardiac injuries: current concepts 
and management. Eur Heart J. 2018 Apr 21;39(16):1459–65. 
[PMID: 28444167]
 
º
RADIATION EX
p
OSURE
 
»
Damage from radiation is determined by the 
source, type, quantity, duration, bodily location, 
and susceptibility and accumulation of exposures 
of the person.
 
»
Clinicians and patients must be educated regard
-
ing the risks of medical diagnostic radiation. These 
radiation risks must be weighed against the ben
-
efits of the medical imaging needed.
 
»
Radiation exposure may occur from environmental, occu
-
pational, medical care, accidental, or intentional causes. 
The extent of damage from radiation exposure depends on 
the type, quantity, and duration of radiation exposure; the 
organs exposed; the degree of disruption to DNA; meta
-
bolic and cellular function; and the age, underlying condi
-
tion, susceptibility, comorbidities, and accumulative 
exposures of the victim.
Radiation occurs from both nonionizing and ionizing 
radiation sources.

-
radiation sources. 
Nonionizing radiation
 is low energy, 
resulting in injuries related to local thermal damage (ie, 
microwave, ultraviolet, visible light, and radiowave). 
Ion
-
izing radiation
 is high energy, causing bodily damage in 
several ways. Ionizing radiation is either electromagnetic 
(ie, x-rays and gamma rays) or particulate (ie, alpha or beta 
particles, neutrons, and protons). Exposure may be exter
-
nal, internal, or both.
International Commission on Radiological Protection 
(ICRP) website provides the most up-to-date recommenda
-
tions for protection against ionizing radiation (http://www
 
.icrp.org/index.asp). The World Health Organization 
(WHO) has published a series of guidelines on radiation 
emergencies (eg, see http://www.who.int/ionizing_radiation/
a_e/en/). These guidelines include recommended interven
-
tions during the early, intermediate, and late emergency 
phases and the management of their psychosocial impact.
 
»
Radiation exposure results in acute and delayed effects. 
Acute effects involve damage of the rapidly dividing cells 
 
(ie, the mucosa, skin, and bone marrow). This may be mani
-
fested as mucositis, nausea, vomiting, gastrointestinal edema 
and ulcers, skin burns, and bone marrow suppression over 
hours to days after exposure. Delayed effects include malig
-
nancy, reproduction abnormalities, liver, kidney, and central 
nervous system and immune system dysfunction.
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Clinicians must be educated to recognize and treat acute 
radiation sickness also referred to as 
acute radiation 
syndrome
. Acute radiation syndrome is due to an exposure 
to high doses of ionizing radiation over a brief time course. 
The symptom onset is within hours to days depending on 
the dose. Symptoms include anorexia, nausea, vomiting, 
weakness, exhaustion, lassitude and, in some cases, prostra
-
tion; these symptoms may occur singly or in combination. 
Dehydration, anemia, and infection may follow. The Cen
-
ters for Disease Control and Prevention offers web-based 
information regarding acute radiation syndrome (https://
emergency.cdc.gov/radiation/arsphysicianfactsheet.asp).
In 
acute radiation exposure
, medical care includes 
close monitoring of the gastrointestinal, cutaneous, hema
-
tologic, cardiopulmonary, and cerebrovascular symptoms 
and signs from initial exposure and over time.
 
»
Therapeutic Radiation Exposure
Radiation therapy has been a successful component in the 
treatment of many malignancies. These radiation-treated 
cancer survivors have a higher risk of development of a 
second malignancy; obesity; and pulmonary, cardiac and 
thyroid dysfunction as well as an increased overall risk for 
chronic health conditions and mortality.
 
»
Medical Imaging Radiation Exposure
Medical imaging with ionizing radiation exposure has dra
-
matically increased over the past few decades. Medical 
imaging radiation exposure is a growing concern for the 
health care professionals and the public. With the rising 
use of medical imaging, there are urgent safety needs for 
standardization and regulation of radiation dosing in 
medical diagnostics and for clinician and public education 
about this issue.
 The American College of Radiology (ACR) offers 
“ ACR Appropriateness Criteria” which are evidence-based 
guidelines created by expert panels to serve as a reference 
for best practices for imaging decisions by health care 
providers (https://www.acr.org/Clinical-Resources/ACR-
Appropriateness-Criteria). Clinicians and patients must 
carefully weigh the risks and benefits of radiation expo
-
sure when deciding on an imaging test.
 
»
Occupational & Environmental 
Radiation Exposure
The National Nuclear Security Administration’s Radiation 
Emergency Assistance Center provides 24-hour access to 
expert consultation services over the telephone or via email 
(telephone: 1-865-576-1005 or email: https://orise.orau
 
.gov/reacts/). The Centers for Disease Control and Preven
-
tion “Radiation Emergency” website (http://emergency
 
.cdc.gov/radiation/) is a useful resource for professionals.
 
»
Treatment
Treatment is focused on decontamination, symptomatic 
relief, supportive care, and psychosocial support. Specific 
treatments focus on the dose, route, and effects of 
exposure.
 
»
Prognosis
Prognosis is determined by the radiation dose, duration, 
and frequency as well as by the underlying condition of the 
victim. Death is usually due to hematopoietic failure, gas
-
trointestinal mucosal damage, central nervous system dam
-
age, widespread vascular injury, or secondary infection.
Carcinogenesis is related to the radiation type, total 
dose, duration, accumulation of exposure, and to the sus
-
ceptibility of the victim. The younger the victim’s age at the 
time of exposure, the greater the risk of acute and long-
term damage from radiation. Radiation-related cancer 
risks persist throughout the exposed person’s life span.
With the increased use of ionizing radiation for medical 
diagnostics and treatments, there is a growing concern for 
the iatrogenic increase in radiation-induced cancer risks. 
There are age-related sensitivities to radiation; prenatal and 
younger age victims are more susceptible to carcinogenesis.
 
»
Most patients with significant ionizing radiation exposure 
require admission for close monitoring and supportive 

»
Bréchignac F et al. Addressing ecological effects of radiation on 
populations and ecosystems to improve protection of the 
environment against radiation: agreed statements from a 
Consensus Symposium. J Environ Radioact. 2016 Jul; 
158–159:21–9. [PMID: 27058410]
Carr Z et al. Using the GRADE [Grading of Recommendations 
Assessment, Development and Evaluation] approach to sup
-
port the development of recommendations for public health 
interventions in radiation emergencies. Radiat Prot Dosimetry. 
2016 Sep;171(1):144–55. [PMID: 27521205]
Hasegawa A et al. Health effects of radiation and other health 
problems in the aftermath of nuclear accidents, with an 
emphasis on Fukushima. Lancet. 2015 Aug 1;386(9992):479–88. 
[PMID: 26251393]
Kamiya K et al. Long-term effects of radiation exposure on 
health. Lancet. 2015 Aug 1;386(9992):469–78. [PMID: 
26251392]
 
º
ENVIRONMENTAL DISORDERS 
 
RELATED TO ALTITUDE
DYSBARISM & DECOMPRESSION SICKNESS
 
»
Symptoms temporally related to recent altitude or 
pressure changes.
 
»
Early recognition and prompt treatment of 
decompression illness are extremely important.
 
»
Patient must also be assessed for hypothermia, 
hypoglycemia, concurrent injuries, and medical 
 
»
Consultation with diving medicine or hyperbaric 
oxygen specialist is indicated.
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»
Dysbarism and decompression illness are physiologic 
problems that result from altitude changes and the effects 
of environmental pressure on the gases in the body during 
underwater descent and ascent. These are most likely 
 
to occur when scuba diving is followed closely by travel to 
high altitudes, or when the scuba diver is not adherent to 
the conservative dive guidelines for dive duration, course, 
depth, and surface times.
As a diver descends, the gases in the body compress; 
gases dissolve in blood and tissues. During the ascent, 
gases in the body expand.
Dysbarism
 results from barotrauma when gas com
-
pression or expansion occurs in parts of the body that are 
noncompressible or have limited compliance. Pulmonary 
overinflation syndrome is one of the most serious and 
potentially fatal results of barotrauma. This syndrome is 
due to an inappropriately rapid ascent causing alveoli rup
-
ture and air bubble extravasation into tissue planes or even 
the cerebral circulation.
Decompression illness
 occurs when the ascent is too 
rapid and gas bubbles form and cause damage depending 
on their location (ie, coronary, pulmonary, spinal or cere
-
bral blood vessels, joints, soft tissue). Decompression ill
-
ness symptoms depends on the size and number and 
location of gas bubbles released (notably nitrogen). Risk of 
decompression illness depends on the dive details (depth, 
duration, number of dives, and interval surface time 
between dives, water conditions) as well as the diver’s age, 
weight, physical condition, physical exertion, the rate of 
ascent, and the length of time between the low altitude 
(scuba dive) and high altitude (air travel or ground ascent). 
Predisposing factors include obesity, injury, hypoxia, lung 
or cardiac disease, right to left cardiac shunt, diver’s overall 
health, dehydration, alcohol and medication effects, and 
panic attacks. Decompression illness may also occur in 
those who take hot showers after cold dives. There have 
been clinical case reports of delayed decompression illness 
presentation following post-dive exercise.
Preventive measures include diver education; pre-dive 
medical screening and dive planning; strict adherence to 
dive course, timing, and depths; and a slow and controlled 
ascent plus proper control of buoyancy. Conservative rec
-
ommendation is to avoid high altitudes (air travel or 
ground ascent) for at least 24 hours after surfacing from the 
dive, especially following multiple dives.
 
»
The range of clinical manifestations varies depending on the 
location of the gas bubble formation or the compressibility 
of gases in the body. Symptom onset may be immediate, 
within minutes or hours (in the majority), or present up to 
48 hours later. Decompression illness symptoms include 
pain in the joints (“the bends”); skin pruritus or burning 
(skin bends); cardiac symptoms (acute coronary syndrome, 
conduction abnormalities); spinal cord or cerebral symp
-
toms (focal neurologic dysfunction or “dissociation” symp
-
toms that do not follow typical distribution neuroanatomy 
patterns); labyrinthine decompression illness (“the staggers, ” 
central vertigo); pulmonary decompression illness 
(“the chokes, ” inspiratory pain, cough, and respiratory dis
-
tress); arterial gas embolism (cerebral, pulmonary); baro
-
trauma of the lungs, ear and sinus; coma and death.
Decompression illness involving the brain and spinal cord 
may occur by different mechanisms due to air bubbles caus
-
ing arterial occlusion, venous obstruction, or in situ toxicity.
The clinician must assess for associated conditions of 
hypothermia, hypoglycemia, hypovolemia, drowning, 
trauma, envenomations, or concurrent medical conditions.
 
»
Treatment
Early recognition and prompt treatment are extremely 
important. Decompression illness must be considered if 
symptoms are temporally related to recent diving or alti
-

»
Treatment
-
tude or pressure changes within the past 48 hours. Con
-
tinuous administration of 100% oxygen is indicated and 
beneficial for all patients. Hyperbaric oxygen treatment is 
commonly recommended for decompression illness symp
-
toms. Immediate consultation with a diving medicine or 
hyperbaric oxygen specialist is indicated even if mild 
decompression illness symptoms resolve. Nonsteroidal 
anti-inflammatory drugs, acetaminophen or aspirin may 
be given for pain control if there are no contraindications. 
Opioids must be used very cautiously,
 since these may 
obscure the response to recompression.
 
»
Rapid transportation to a hyperbaric treatment facility for 
recompression is imperative for decompression illness. The 
Divers Alert Network is an excellent worldwide resource 
for emergency advice 24 hours daily for the management of 
diving-related conditions (www.diversalertnetwork.org).
Madden D et al. Intrapulmonary shunt and SCUBA diving: 
another risk factor? Echocardiography. 2015 Feb;32(Suppl 3): 
S205–10. [PMID: 25693625]
Moon RE. Hyperbaric oxygen treatment for decompression sick
-
ness. Undersea Hyperb Med. 2014 Mar–Apr;41(2):151–7. 
[PMID: 24851553]
Pollock NW et al. Updates in decompression illness. Emerg Med 
Clin North Am. 2017 May;35(2):301–19. [PMID: 28411929]
Smart D et al. Joint position statement on persistent foramen 
ovale (PFO) and diving. South Pacific Underwater Medicine 
Society (SPUMS) and the United Kingdom Sports Diving 
Medical Committee (UKSDMC). Diving Hyperb Med. 
2015 Jun;45(2):129–31. [PMID: 26165538]
HIGH-ALTITUDE ILLNESS
 
»
The severity of the high-altitude illness is affected 
by the rate and height of ascent, and the individu
-
al’s susceptibility.
 
»
Prompt recognition and medical treatment of 
early symptoms of high-altitude illness may pre
-
vent progression.
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»
Clinicians must assess other conditions that may 
coexist or mimic symptoms of high-altitude 
illness.
 
»
Immediate descent is the definitive treatment for 
high-altitude cerebral edema and high-altitude 
pulmonary edema.
 
»
As altitude increases, hypobaric hypoxia results due to a 
decrease in both barometric pressure and oxygen partial 
pressure. High-altitude illnesses are due to hypobaric 
hypoxia at high altitudes (usually greater than 2000 meters 
or 6562 feet). High-altitude illness includes a spectrum of 
disorders categorized by end-organ effects (mostly cerebral 
and pulmonary), and exposure duration (acute and long-
term). Acute high-altitude illnesses are 
acute hypoxia, 
acute mountain sickness (AMS), high-altitude cerebral 
edema (HACE),
 and 
high-altitude pulmonary edema 
(HAPE).
Acclimatization occurs as a physiologic response to the 
rise in altitude and increasing hypobaric hypoxia. High-
altitude illness results when the hypoxic stress is greater 
than the individual’s ability to acclimatize. Risk factors for 
high-altitude illness include increased physical activity 
with insufficient acclimatization, inadequate education 
and preparation, and individual susceptibility, and previ
-
ous high-altitude illness. The key determinants of high-
altitude illness risk and severity include both individual 
susceptibility factors and altitudinal factors (rapid rate and 
height of ascent and total change in altitude).
Individual susceptibility factors include underlying 
conditions such as cardiac and pulmonary dysfunction, 
patent foramen ovale, blood disorders, pregnancy, neuro
-
logic conditions, recent surgery, diabetes and many other 
chronic medical conditions, and cigarette smoking. Those 
with symptomatic cardiac or pulmonary disease must 
avoid high altitudes.
Patient assessment for high-altitude illness must also 
include evaluation for other conditions, which may coexist 
or may present in a similar manner.
1. 
h
igh-
Altitude–Associated Neurologic 
Conditions: AMS & 
h
ACE
There is a spectrum of neurologic conditions caused by 
high altitude, ranging from 
acute mountain sickness 
(AMS)
 to the more serious form 
high-altitude cerebral 
edema (HACE).
 Clinicians may utilize various diagnostic 
tools to assess the level of cerebral impairment due to high 
altitude.
AMS
 includes symptoms such as headache (most 
severe and persistent symptom), lassitude, drowsiness, diz
-
ziness, chilliness, nausea and vomiting, difficulty sleeping. 
Later symptoms include irritability, difficulty concentrat
-
ing, anorexia, insomnia, and increased headaches.
HACE
 includes the severe symptoms of AMS and 
results from cerebral vasogenic edema and cerebral cellular 
hypoxia. It usually occurs at elevations above 2500 meters 
(8202 feet) but may occur at lower elevations. Hallmarks 
are altered mental status, ataxia, severe lassitude, and 
encephalopathy. Examination findings may include confu
-
sion, ataxia, urinary retention or incontinence, focal neu
-
rologic deficits, papilledema, and seizures. Symptoms may 
progress to obtundation, coma, and death.
 
»
Treatment
Definitive treatment is immediate descent of at least 
610 meters (2001 feet), and descent must continue until 
symptoms improve. Descent is essential if the symptoms 
are persistent, severe, worsening or if HACE or HAPE are 
present. If immediate descent is not possible, portable 
hyperbaric chambers can provide symptomatic relief, but 
they must not delay descent.
Initial treatment involves oxygen administration to 
keep the pulse oximetry S
p
O
2
 to greater than 90%.
Acetazolamide (250 mg twice daily) is an effective 
medication for both prophylaxis and treatment of mild 
symptoms of AMS.
Dexamethasone is given for moderate to severe AMS 
(4 mg orally every 6 hours). Dexamethasone is the primary 
treatment for HACE (8 mg once then 4 mg every 6 hours).

treatment for HACE (8 mg once then 4 mg every 6 hours). 
Acetazolamide can be added as an adjunct in severe HACE 
cases. In most individuals, symptoms clear within 
24–48 hours. HACE treatment must continue until 
 
24 hours after resolution of symptoms or until descent is 
completed. Dexamethasone should not be given for longer 
than 7 days.
It is imperative that the clinician also assess for other 
conditions that may mimic or coexist with AMS and HACE.
If HAPE symptoms and signs are present along with 
HACE, nifedipine or a selective phosphodiesterase inhibitor 
may be added for pulmonary vasodilation. The clinician 
must be cautious when using combinations of vasodilators.
2. Acute 
h
A
p
E
HAPE
 is the leading cause of death from high-altitude 
illness. The hallmark is markedly elevated pulmonary 
artery pressure followed by pulmonary edema. It usually 
occurs at altitudes above 3000 meters (9840 feet), although 
it may occur at lower levels. Early symptoms may appear 
within 6–36 hours after arrival at a high-altitude area. 
These include incessant dry cough, shortness of breath 
disproportionate to exertion, headache, decreased exercise 
performance, fatigue, dyspnea at rest, and chest tightness. 
Recognition of the early symptoms may enable the patient 
to descend before incapacitating pulmonary edema devel
-
ops. Strenuous exertion must be avoided. Later, wheezing, 
orthopnea, and hemoptysis may occur as pulmonary 
edema worsens.
Physical findings may include tachycardia, mild fever, 
tachypnea, cyanosis, prolonged respiration, rales, and 
rhonchi. The clinician must assess for other potential 
medical conditions because the clinical picture may resem
-
ble other entities. Diagnosis is usually clinical; ancillary 
tests are nonspecific or unavailable on site. Prompt recog
-
nition and medical attention of early symptoms of HAPE 
may prevent progression.
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»
Treatment
Immediate descent (at least 610 meters [2000 feet]) is 
essential, although this may not be immediately possible 
and may not alone improve symptoms.
The patient must rest, reclined with head elevated. 
Supplemental oxygen must be administered to maintain 
pulse oximetry reading S
p
O
2
 greater than 90%. Recompres
-
sion in a portable hyperbaric bag will temporarily reduce 
symptoms if rapid or immediate descent is not possible, but 
must not delay descent.
Nifedipine (60-mg slow extended-release tablets daily, 
given in divided doses) can be used as an adjunct if the 
other therapies (descent, oxygen, or portable hyperbarics) 
are not successful or available. Selective phosphodiesterase 
inhibitors may be used for HAPE prevention but may also 
provide effective symptom relief as an alternative or if nife
-
dipine is not available. 
Administering nifedipine plus a 
phosphodiesterase inhibitor as pulmonary vasodilators is not 
 because this combination may also lower the 
mean arterial pressure and decrease cerebral perfusion. 
Treatment for ARDS (see Chapter 9) is required for some 
patients. If neurologic symptoms are present concurrently 
with HAPE and do not resolve with improved oxygenation, 
dexamethasone may be added according to HACE treat
-
ment guidelines.
3. Subacute Mountain Sickness
This occurs most frequently in unacclimatized individuals 
and at high altitudes (above 4500 meters) for a prolonged 
period of time. Treatment consists of rest, oxygen adminis
-
tration, diuretics, and return to lower altitudes.
4. Chronic Mountain Sickness (Monge Disease)
This uncommon condition is seen in residents of high-
altitude communities who have lost their acclimatization to 
such a hypobaric hypoxic environment. It is difficult to 
differentiate from chronic pulmonary disease.
 
»
Prevention of High-Altitude Disorders
Pre-trip preventive measures include participant educa
-
tion, medical preparticipation evaluation, pre-trip plan
-
ning, optimal physical conditioning before travel, and 
adequate rest and sleep the day before travel and during the 
trip. Preventive efforts during ascent include reduced food 
intake and avoidance of alcohol, tobacco, and unnecessary 
physical activity during travel.
Gradual ascent is the most effective way to allow accli
-
matization. Low-risk ascension rate is 2 or more days to 
arrive at 2500–3000 meters. The altitude reached during 
waking hours is not as important as the altitude at which 
the hiker sleeps. If the terrain does not allow a sleeping 
elevation increase below 500 meters, an extra rest day must 
be added before or after the increased sleep elevation more 
than 500 meters.
Drug prophylaxis may be prescribed for AMS and 
HACE if no contraindications exist. Prophylactic low-dose 
acetazolamide (125 mg twice daily orally) has been shown 
to reduce the incidence and severity of AMS and HACE 
when started 3 days prior to ascent and continued for 
48–72 hours at high altitude. Dexamethasone is an alterna
-
tive prophylactic medication for AMS and HACE.
Individuals with a past history of HAPE should use 
drug prophylaxis to reduce the risk of recurrence. 
Nifedipine started the day before ascent and continued 
through the fourth day at target elevation, or through the 
seventh day if the ascent rate was faster, is recommended. 
Salmeterol can be added beginning 24 hours prior to 
ascent. This can be used as an adjunct to nifedipine but not 
as monotherapy.
Phosphodiesterase inhibitors may be beneficial in the 
treatment of HAPE based on their physiologic effects of 
decreased pulmonary arterial pressures and pulmonary 
 
»
•	
All patients with HACE or HAPE must be hospitalized 
for further observation.
•	
Hospitalization must also be considered for any 
patient who remains symptomatic after treatment and 
descent.
•	
Pulmonary symptoms and hypoxia may be worsened by

•	
descent.
•	
Pulmonary symptoms and hypoxia may be worsened by 
complications such as pulmonary embolism, secondary 
respiratory infection, bronchospasm, mucous plugging, 
or acute coronary syndrome.
Campbell AD et al. Risk stratification for athletes and 
adventurers in high-altitude environments: recommenda
-
tions for preparticipation evaluation. Wilderness Environ 
Med. 2015 Dec; 26(4 Suppl):S30–9. [PMID: 26617376]
Jin J. JAMA patient page. Acute mountain sickness. JAMA. 2017 
Nov 14;318(18):1840. [PMID: 29136446]
Luks AM et al. Acute high-altitude sickness. Eur Respir Rev. 
2017 Jan 31;26(143). pii: 160096. [PMID: 28143879]
Meier D et al. Does this patient have acute mountain sickness? 
The Rational Clinical Examination Systematic Review. JAMA. 
2017 Nov 14;318(18):1810–19. [PMID: 29136449]
Nieto Estrada VH et al. Interventions for preventing high alti
-
tude illness: Part 1. Commonly-used classes of drugs. 
Cochrane Database Syst Rev. 2017 Jun 27;6:CD009761. 
[PMID: 28653390]
SAFETY OF AIR TRAVEL & SELECTION OF 
PATIENTS FOR AIR TRAVEL
The medical safety of air travel depends on the nature and 
severity of the traveler’s preflight condition and factors 
such as travel duration, frequency and use of inflight exer
-
cise, cabin altitude pressure, availability of medical sup
-
plies, and presence of health care professionals on board. 
Air travel passengers are susceptible to a wide range of 
flight-related problems: pulmonary (hypoxemia, gas 
expansion), venous thromboembolism (VTE), infectious, 
cardiac, gastrointestinal, ocular, immunologic, syncope, 
neuropsychiatric, metabolic, trauma, and substance-
related. These air-travel risks are higher for those air travel
-
ers with preexisting medical conditions.
Hypobaric hypoxia is the underlying etiology of most 
serious medical emergencies in flight due to cabin altitude. 
Despite commercial aircraft pressurization requirements, 
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there is significant hypoxemia, dyspnea, gas expansion, 
and stress in travelers.
Any form of prolonged travel involving immobilization 
has been associated with increased risk of VTE (referred 
to as “traveler’s thrombosis”), although air travel has been 
the main focus of medical review. Conditions that place 
long-distance travelers at high risk for VTE include the 
following: (1) travel involving immobilization for 4 or 
more hours, (2) hypercoagulable disorders, and (3) acquired 
risks.
Air travel is not advised for anyone who is “incapaci
-
tated” or has any “unstable conditions. ” The Air Transport 
Association of America defines an 
incapacitated 
passenger
 as “one who is suffering from a physical or 
mental disability and who, because of such disability or 
the effect of the flight on the disability, is incapable of 
self-care; would endanger the health or safety of such 
person or other passengers or airline employees; or would 
cause discomfort or annoyance of other passengers. ” 
Unstable conditions
 include active pneumothorax, 
advanced pulmonary hypertension, acute worsening of 
an underlying lung disease, poorly controlled hyperten
-
sion, dysrhythmias, angina, valvular disease, heart failure, 
or acute psychiatric condition; severe anemia or symp
-
tomatic sickle cell disease; recent myocardial infarction; 
cerebrovascular accident; poorly controlled seizure disor
-
der; deep venous thrombosis; postsurgery, especially 
heart surgery (unless approved by surgeon); and any 
active communicable disease.
 
»
Pregnancy
Traveling during pregnancy is becoming more common. 
Pregnant travelers have unique travel-related and location-
specific risks. Pregnant women may be permitted to fly dur
-
ing the first 8 months of pregnancy unless there is a history 
of pregnancy complications or premature birth. A clinician’s 
authorization is required if travel is essential during the 
ninth month of pregnancy or earlier in a complicated 
Long travel increases risk of VTE for the pregnant trav
-
eler. Pregnant travelers are at higher risk from infection 
transmission and air travel radiation exposure.
 
»
Air travel complications may be reduced by the following 
preventive measures: passenger prescreening, passenger edu
-
cation, and in-flight positioning and activity. Prescreening 
evaluation is recommended for all high-risk patients including 
preexisting requirement of oxygen, continuous positive pres
-
sure or ventilator support, underlying restrictive or obstructive 
lung disease, comorbidities worsened by hypoxemia, previous 
respiratory distress during air travel, recent pneumothorax, 
and recent (within 6 weeks) acute respiratory illness. Patients 
at risk for hypoxia must be assessed prior to air travel to deter
-
mine if there is a need for supplemental in-flight oxygen.
Air travel education must include risk reduction mea
-
sures for VTE, infectious diseases, and exacerbations of 
underlying medical conditions. Patients and clinicians can 
check the World Health Organization website for the most 
updated information on travel health risks and infectious 
diseases (http://www.who.int/ith/en/).
All long-distance travelers can reduce VTE risk by 
avoiding constrictive clothing, staying well-hydrated, 
changing position frequently, avoiding cramped position, 
avoiding leg crossing, engaging in frequent in-flight leg 
stretching exercises at least every hour, and walking for 
 
5 minutes every hour. Clinicians must assess those with 
high risk of VTE prior to air travel to determine whether 
anticoagulation is indicated (see Table 14–14).
Antony KM et al. Travel during pregnancy: considerations for 
the obstetric provider. Obstet Gynecol Surv. 2017 Feb; 
72(2):97–115. [PMID: 28218771]
thrombosis in airline passengers. Cochrane Database Syst Rev.

thrombosis in airline passengers. Cochrane Database Syst Rev. 
2016 Sep 14;9:CD004002. [PMID: 27624857]
George PM et al. Hypoxic challenge testing for fitness to fly with 
severe asthma. Aerosp Med Hum Perform. 2016 Jun; 
87(6):571–4. [PMID: 27208681]
Mangili A et al. Infectious risks of air travel. Microbiol Spectr. 
2015 Oct;3(5):IOL5–0009. [PMID: 26542037]
Thibeault C et al. AsMA medical guidelines for air travel: airline 
special services. Aerosp Med Hum Perform. 2015 Jul; 
86(7):657–8. [PMID: 26102149]
Thibeault C et al; Aerospace Medical Association. AsMA medi
-
cal guidelines for air travel: in-flight medical care. Aerosp 
Med Hum Perform. 2015 Jun;86(6):5723. [PMID: 26099132]
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Poisoning
38
 
º
INITIAL EVALUATION: POISONING OR 
OVERDOSE
Patients with drug overdoses or poisoning may initially 
have no symptoms or they may have varying degrees of 
overt intoxication. The asymptomatic patient may have 
been exposed to or may have ingested a lethal dose, but not 
yet exhibit any manifestations of toxicity. It is important to 
(1) quickly assess the potential danger, (2) consider gut and 
skin decontamination to prevent absorption, (3) treat com
-
plications if they occur, and (4) observe the asymptomatic 
patient for an appropriate interval.
 
»
Assess the Danger
If the drug or poison is known, its danger can be assessed 
by consulting a text or computerized information resource 
or by calling a regional poison control center. (In the 
United States, dialing 1-800-222-1222 will direct the call to 
the regional poison control center.) Assessment will usually 
take into account the dose ingested; the time since inges
-
tion; the presence of any symptoms or clinical signs; preex
-
isting cardiac, respiratory, kidney, or liver disease; and, 
occasionally, specific serum drug or toxin levels. Be aware 
that the history given by the patient or family may be 
incomplete or unreliable.
IMMEDIATE 24-HOUR TOXICOLOGY 
CONSUL TATION
Call your regional poison control center
U.S. toll-free 1-800-222-1222
psychiatric evaluation should be performed to assess suicide 
risk. Intentional ingestions in adolescents should raise the 
possibility of unwanted pregnancy or sexual abuse.
 
º
THE SYMPTOMATIC PATIENT
In symptomatic patients, treatment of life-threatening com
-
plications takes precedence over in-depth diagnostic evalu
-
ation. Patients with mild symptoms may deteriorate rapidly, 
which is why all potentially significant exposures should be 
observed in an acute care facility. The following complica
-
tions may occur, depending on the type of poisoning.
COMA
 
»
Assessment & Complications
Coma is commonly associated with ingestion of large doses 
of antihistamines (eg, diphenhydramine), benzodiazepines 
and other sedative-hypnotic drugs, ethanol, opioids, antipsy
-
chotic drugs, or antidepressants. The most common cause of 
death in comatose patients is respiratory failure, which may 
occur abruptly. Pulmonary aspiration of gastric contents may 
also occur, especially in victims who are deeply obtunded or 
convulsing. Hypoxia and hypoventilation may cause or 
aggravate hypotension, arrhythmias, and seizures. Thus, pro
-
tection of the airway and assisted ventilation are the most 
important treatment measures for any poisoned patient.
 
»
Treatment
A. Emergency Management
The initial emergency management of coma can be remem
-
bered by the mnemonic 
ABCD
, for 
A
irway, 
B
reathing, 
C
irculation, and 
D
rugs (dextrose, thiamine, and naloxone 
or flumazenil), respectively.
1. Airway—
Establish a patent airway by positioning, suc
-
tion, or insertion of an artificial nasal or oropharyngeal 
airway. If the patient is deeply comatose or if airway 
reflexes are depressed, perform endotracheal intubation. 
These airway interventions may not be necessary if the 
patient is intoxicated by an opioid or a benzodiazepine and 
responds to intravenous naloxone or flumazenil.
 
»
Observe the Patient
Asymptomatic or mildly symptomatic patients should be 
observed for at least 4–6 hours.
 Longer observation is indi
-
cated if the ingested substance is a sustained-release prepara
-
tion or is known to slow gastrointestinal motility (eg, opioids, 
anticholinergics, aspirin) or may cause a delayed onset of 
symptoms (such as acetaminophen, colchicine, or hepato
-
toxic mushrooms). After that time, the patient may be dis
-
charged if no symptoms have developed. Before discharge, 
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2. Breathing—
Clinically assess the quality and depth of 
respiration and provide assistance if necessary with a 
bag-valve-mask device or mechanical ventilator. Adminis
-
ter supplemental oxygen, if needed. The arterial or venous 
blood CO
2
 tension is useful in determining the adequacy of 
ventilation. The arterial blood PO
2
 determination may 
reveal hypoxemia, which may be caused by respiratory 
depression, bronchospasm, pulmonary aspiration, or non
-
cardiogenic pulmonary edema. Pulse oximetry provides an 
assessment of oxygenation, but is not reliable in patients 
with methemoglobinemia or carbon monoxide poisoning, 
unless a pulse oximetry device capable of detecting these 
forms of hemoglobin is used.
3. Circulation—
Measure the pulse and blood pressure and 
estimate tissue perfusion (eg, by measurement of urinary 
output, skin signs, arterial blood pH). Place the patient on 
continuous ECG monitoring. Insert an intravenous line, and 
draw blood for glucose, electrolytes, serum creatinine and 
liver tests, and possible quantitative toxicologic testing.
4. Drugs—
a. Dextrose and thiamine—
Unless promptly treated, 
severe hypoglycemia can cause irreversible brain damage. 
Therefore, in all obtunded, comatose or convulsing patients, 
give 50% dextrose, 50–100 mL by intravenous bolus, unless 
a rapid point-of-care blood sugar test rules out hypoglyce
-
mia. In alcoholic or very malnourished patients who may 
have marginal thiamine stores, give thiamine, 100 mg intra
-
muscularly or in the intravenous fluids.
b. Opioid antagonists
—
Naloxone, 0.4–2 mg intrave
-
nously or 2–4 mg by intranasal spray, may reverse opioid-
induced respiratory depression and coma. It is often given 
empirically to any comatose patient with depressed respira
-
tions. If opioid overdose is strongly suspected, give additional 
doses of naloxone (up to 5–10 mg may be required to reverse 
the effects of potent opioids). 
Note:
 Naloxone has a shorter 
duration of action (2–3 hours) than most common opioids; 
repeated doses may be required, and continuous observation 
for at least 3–4 hours after the last dose is mandatory.
c. Flumazenil—
Flumazenil, 0.2–0.5 mg intravenously, 
repeated as needed up to a maximum of 3 mg, may reverse 
benzodiazepine-induced coma. 
Caution: 
In most circum
-
stances, use of flumazenil is not advised as the potential risks 
outweigh its benefits.
 Flumazenil should 
not
 be given if the 
patient has coingested a potential convulsant drug, is a user of 
high-dose benzodiazepines, or has a seizure disorder because 
its use in these circumstances may precipitate seizures. 
Note:
 
Flumazenil has a short duration of effect (2–3 hours), and 
resedation requiring additional doses may occur.
 
»
Hypothermia commonly accompanies coma due to opioids, 
ethanol, hypoglycemic agents, phenothiazines, barbiturates, 
benzodiazepines, and other sedative-hypnotics and central 
nervous system depressants. Hypothermic patients may 
have a barely perceptible pulse and blood pressure. 
Hypothermia may cause or aggravate hypotension, which 
will not reverse until the temperature is normalized.
 
»
Treatment
Treatment of hypothermia is discussed in Chapter 37. 
Gradual rewarming is preferred unless the patient is in 
cardiac arrest.
HYPOTENSION
 
»
Hypotension may be due to poisoning by many different 
drugs and poisons, including antihypertensive drugs, beta-
blockers, calcium channel blockers, disulfiram (ethanol 
interaction), iron, trazodone, quetiapine, and other antipsy
-
chotic agents and antidepressants. Poisons causing hypoten
-
sion include cyanide, carbon monoxide, hydrogen sulfide, 
aluminum or zinc phosphide, arsenic, and certain 
mushrooms.
Hypotension in the poisoned or drug-overdosed patient 
may be caused by venous or arteriolar vasodilation, hypo
-
volemia, depressed cardiac contractility, or a combination 
of these effects.
 
»

-
 
»
Treatment
Most hypotensive poisoned patients respond to empiric 
treatment with repeated 200 mL intravenous boluses of 
0.9% saline or other isotonic crystalloid up to a total of 
1–2 L; much larger amounts may be needed if the victim is 
profoundly volume depleted (eg, as with massive diarrhea 
due to 
 mushroom poisoning). 
Monitoring the central venous pressure (CVP) can help 
determine whether further fluid therapy is needed. If fluid 
therapy is not successful after adequate volume replace
-
ment, give dopamine or norepinephrine by intravenous 
infusion. Consider bedside cardiac ultrasound or pulmo
-
nary artery catheterization (or both) to assess CVP .
Hypotension caused by certain toxins may respond to 
specific treatment. For hypotension caused by overdoses of 
tricyclic antidepressants or other sodium channel blockers, 
administer sodium bicarbonate, 50–100 mEq by intrave
-
nous bolus injection. Norepinephrine 4–8 mcg/min by 
intravenous infusion is more effective than dopamine in 
some patients with overdoses of tricyclic antidepressants or 
of drugs with predominantly vasodilating effects. For beta-
blocker overdose, glucagon (5–10 mg intravenously) may 
be of value. For calcium channel blocker overdose, admin
-
ister calcium chloride, 1–2 g intravenously (repeated doses 
may be necessary; doses of 5–10 g and more have been 
given in some cases). High-dose insulin (0.5–1 unit/kg/h 
intravenously) euglycemic therapy may also be used (see 
the sections Beta-Adrenergic Blockers and Calcium 
Channel Blockers, below). Intralipid 20% lipid emulsion 
has been reported to improve hemodynamics in some 
cases of intoxication by highly lipid-soluble drugs such as 
bupivacaine, bupropion, clomipramine, and verapamil. 
Intravenous methylene blue and extracorporeal membrane 
oxygenation (ECMO) have been employed in a few 
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refractory cases; ECMO may offer temporary hemody
-
namic stabilization while the offending drug is eliminated.
Heise CW et al. Two cases of refractory cardiogenic shock sec
-
ondary to bupropion successfully treated with veno-arterial 
extracorporeal membrane oxygenation. J Med Toxicol. 
2016 Sep;12(3):301–4. [PMID: 26856351]
Laes JR et al. Improvement in hemodynamics after methylene 
blue administration in drug-induced vasodilatory shock: a 
case report. J Med Toxicol. 2015 Dec;11(4):460–3. [PMID: 
26310944]
Woodward C et al. High dose insulin therapy, an evidence-based 
approach to beta blocker/calcium channel blocker toxicity. 
Daru. 2014 Apr 8;22(1):36. [PMID: 24713415]
 
»
Hypertension may be due to poisoning with amphetamines 
and synthetic stimulants, anticholinergics, cocaine, 
performance-enhancing products (containing caffeine, 
phenylephrine, ephedrine, or yohimbine), monoamine 
oxidase (MAO) inhibitors, and other drugs.
Severe hypertension (eg, diastolic blood pressure 
greater than 105–110 mm Hg in a person who does not 
have chronic hypertension) can result in acute intracranial 
hemorrhage, myocardial infarction, or aortic dissection.
 
»
Treatment
Treat hypertension if the patient is symptomatic or if the 
diastolic pressure is higher than 105–110 mm Hg—
especially if there is no prior history of hypertension.
Hypertensive patients who are agitated or anxious may 
benefit from a sedative (such as lorazepam, 2–3 mg 
intravenously) or an antipsychotic drug (eg, haloperidol or 
olanzapine). For persistent hypertension, administer phen
-
tolamine, 2–5 mg intravenously, or nitroprusside sodium, 
0.25–8 mcg/kg/min intravenously. If excessive tachycardia 
is present, 
add
 esmolol, 25–100 mcg/kg/min intravenously, 
or labetalol, 0.2–0.3 mg/kg intravenously. 
Caution:
 Do not 
give beta-blockers alone, since doing so may paradoxically 
worsen hypertension as a result of unopposed alpha-
adrenergic stimulation.
Richards JR et al. Treatment of toxicity from amphetamines, related 
derivatives, and analogues: a systematic clinical review. Drug 
Alcohol Depend. 2015 May 1;150:1–13. [PMID: 25724076]
ARRHYTHMIAS
 
»
Arrhythmias may occur with a variety of drugs or toxins 
(Table 38–1). They may also occur as a result of hypoxia, 
metabolic acidosis, or electrolyte imbalance (eg, hyperkale
-
mia, hypokalemia, hypomagnesemia or hypocalcemia), or 
following exposure to chlorinated solvents or chloral 
hydrate overdose. Atypical ventricular tachycardia 
(torsades de pointes) is often associated with drugs that 
prolong the QT interval.
 
»
Treatment
Hypoxia or electrolyte imbalance should be sought and 
treated. If ventricular arrhythmias persist, administer 
lidocaine or amiodarone at usual antiarrhythmic doses. 
Note:
 Wide QRS complex tachycardia in the setting of 
tricyclic antidepressant overdose (or diphenhydramine or 
class Ia antiarrhythmic drugs) should be treated with 
sodium bicarbonate, 50–100 mEq intravenously by bolus 
infusion. 
Caution:
 Avoid class Ia antiarrhythmic agents 
(eg, procainamide, disopyramide) and amiodarone, 
which may aggravate arrhythmias caused by tricyclic 
antidepressants. Torsades de pointes associated with pro
-
longed QT interval may respond to intravenous magne
-
sium (2 g intravenously over 2 minutes) or overdrive 
pacing. Treat digitalis-induced arrhythmias with digoxin-
specific antibodies.
Table 38–1.
 
Common toxins or drugs causing 
1
Arrhythmia
Beta-blockers, calcium channel 
 
blockers, clonidine, digitalis 
 
glycosides, organophosphates
Atrioventricular block
 
blockers, class Ia antiarrhythmics 
(including quinidine), 
 
carbamazepine, clonidine, digitalis 
glycosides, lithium
Beta-agonists (eg, albuterol), 
 
amphetamines, anticholinergics, 
antihistamines, caffeine, cocaine,

antihistamines, caffeine, cocaine, 
pseudoephedrine, tricyclic and 
other antidepressants
Wide QRS complex
Class Ia and class Ic antiarrhythmics, 
phenothiazines (eg, thioridazine), 
potassium (hyperkalemia), 
 
propranolol, tricyclic 
 
antidepressants, bupropion, 
lamotrigine, diphenhydramine 
(severe overdose)
QT interval prolongation 
and torsades de 
 
pointes
Arsenic, class Ia and class III antiar
-
rhythmics, citalopram, droperidol, 
lithium, methadone, pentamidine, 
sertraline, sotalol, and many other 
drugs
2
Ventricular premature 
beats and ventricular 
tachycardia
Amphetamines, cocaine, ephedrine, 
caffeine, chlorinated or fluorinated 
hydrocarbons, digoxin, aconite 
(found in some Chinese herbal 
preparations), fluoride, 
 
theophylline. QT prolongation 
 
can lead to atypical ventricular 
tachycardia (torsades de pointes).
1
Arrhythmias may also occur as a result of hypoxia, metabolic aci
-
dosis, or electrolyte imbalance (eg, hyperkalemia or hypokalemia, 
hypocalcemia, hypomagnesemia).
2
https://crediblemeds.org/
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For tachyarrhythmias induced by chlorinated solvents, 
chloral hydrate, Freons, or sympathomimetic agents, use 
propranolol or esmolol (see doses given above in Hyper
-
tension section).
Al-Abri SA et al. Ventricular dysrhythmias associated with poi
-
soning and drug overdose: a 10-year review of statewide poi
-
son control center data from California. Am J Cardiovasc 
Drugs. 2015 Feb;15(1):43–50. [PMID: 25567789]
Bruccoleri RE et al. A literature review of the use of sodium 
bicarbonate for the treatment of QRS widening. J Med Toxicol. 
2016 Mar;12(1):121–9. [PMID: 26159649]
Laskowski LK et al. Start me up! Recurrent ventricular tachydys
-
rhythmias following intentional concentrated caffeine inges
-
tion. Clin Toxicol (Phila). 2015;53(8):830–3. [PMID: 
26279469]
Paratz ED et al. The cardiac complications of methamphet
-
amines. Heart Lung Circ. 2016 Apr;25(4):325–32. [PMID: 
26706652]
SEIZURES
 
»
Seizures may be caused by many poisons and drugs, includ
-
ing amphetamines, antidepressants (especially tricyclic anti
-
depressants, bupropion, and venlafaxine), antihistamines 
(especially diphenhydramine), antipsychotics, camphor, 
synthetic cannabinoids and cathinones, cocaine, isoniazid 
(INH), chlorinated insecticides, piperazines, tramadol, and 
theophylline. The onset of seizures may be delayed for up to 
18–24 hours after extended-released bupropion overdose.
Seizures may also be caused by hypoxia, hypoglycemia, 
hypocalcemia, hyponatremia, withdrawal from alcohol or 
sedative-hypnotics, head trauma, central nervous system 
infection, or idiopathic epilepsy.
Prolonged or repeated seizures may lead to hypoxia, 
metabolic acidosis, hyperthermia, and rhabdomyolysis.
 
»
Treatment
Administer lorazepam, 2–3 mg, or diazepam, 5–10 mg, 
intravenously, or—if intravenous access is not immediately 
available—midazolam, 5–10 mg intramuscularly. If convul
-
sions continue, administer phenobarbital, 15–20 mg/kg 
slowly intravenously over no less than 30 minutes. (For 
drug-induced seizures, phenobarbital is preferred over phe
-
nytoin or levetiracetam.) Propofol infusion has also been 
reported effective for some resistant drug-induced seizures.
Seizures due to a few drugs and toxins may require anti
-
dotes or other specific therapies (as listed in Table 38–2).
Chen HY et al. Treatment of drug-induced seizures. Br J Clin 
Pharmacol. 2016 Mar;81(3):412–9. [PMID: 26174744]
HYPERTHERMIA
 
»
Hyperthermia may be associated with poisoning by 
amphetamines and other synthetic stimulants (cathinones, 
piperazines), atropine and other anticholinergic drugs, 
cocaine, salicylates, strychnine, tricyclic antidepressants, 
and various other medications. Overdoses of serotonin 
reuptake inhibitors (eg, fluoxetine, paroxetine, sertraline) 
or their use in a patient taking an MAO inhibitor may cause 
agitation, hyperactivity, myoclonus, and hyperthermia 
(“serotonin syndrome”). Antipsychotic agents can cause 
rigidity and hyperthermia (neuroleptic malignant syn
-
drome [NMS]). (See Chapter 25.) Malignant hyperthermia 
is a rare disorder associated with general anesthetic agents.
Hyperthermia is a rapidly life-threatening complication. 
Severe hyperthermia (temperature higher than 40–41
°
C) 
can rapidly cause brain damage and multiorgan failure, 
including rhabdomyolysis, acute kidney injury, and coagu
-
lopathy (see Chapter 37).
 
»
Treatment
Treat hyperthermia aggressively by removing the patient’s 
clothing, spraying the skin with tepid water, and high-
volume fanning. If this is not rapidly effective, as shown by 
a normal rectal temperature within 30–60 minutes, or if 
there is significant muscle rigidity or hyperactivity, induce 
neuromuscular paralysis with a nondepolarizing neuro
-
muscular blocker (eg, rocuronium, vecuronium). Once 
paralyzed, the patient must be intubated and mechanically 
ventilated and sedated. While the patient is paralyzed, the

-
ventilated and sedated. While the patient is paralyzed, the 
absence of visible muscular convulsive movements may 
give the false impression that brain seizure activity has 
ceased; bedside electroencephalography may be useful in 
recognizing continued nonconvulsive seizures.
Dantrolene (2–5 mg/kg intravenously) may be effective 
for hyperthermia associated with muscle rigidity that does 
Table 38–2.
 
Seizures related to toxins or drugs 
requiring special consideration.
1
Toxin or Drug
Comments
Methylenedioxymeth
-
amphetamine 
(MDMA; “Ecstasy”)
Seizures may also be due to 
hyponatremia or hyperthermia.
Isoniazid
Administer pyridoxine.
Lithium
May indicate need for hemodialysis.
Administer pralidoxime (2-PAM) and 
atropine in addition to usual 
anticonvulsants.
Strychnine
“Seizures” are actually spinally 
mediated muscle spasms and 
usually require neuromuscular 
paralysis and mechanical ventilation.
Seizures indicate need for 
hemodialysis.
Hyperthermia and cardiotoxicity are 
common complications of repeated 
seizures; paralyze early with 
neuromuscular blockers to reduce 
muscular hyperactivity.
1
See text for dosages.
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not respond to neuromuscular blockade (ie, malignant 
hyperthermia). Bromocriptine, 2.5–7.5 mg orally daily, has 
been recommended for neuroleptic malignant syndrome. 
Cyproheptadine, 4 mg orally every hour for three or four 
doses, or chlorpromazine, 25 mg intravenously or 50 mg 
intramuscularly, has been used to treat serotonin 
syndrome.
Katus LE et al. Management of serotonin syndrome and neuro
-
leptic malignant syndrome. Curr Treat Options Neurol. 
2016 Sep;18(9):39. [PMID: 27469512]
Walter E et al. Drug-induced hyperthermia in critical care. 
 
J Intensive Care Soc. 2015 Nov;16(4):306–11. [PMID: 
28979436]
 
º
ANTIDOTES & OTHER TREATMENT
ANTIDOTES
Give an antidote (if available) when there is reasonable 
certainty of a specific diagnosis (Table 38–3). Be aware that 
some antidotes themselves may have serious side effects. 
The indications and dosages for specific antidotes are dis
-
cussed in the respective sections for specific toxins.
Table 38–3.
 
Some toxic agents for which there are 
specific antidotes.
1
Toxic Agent
Specific Antidote
N
-Acetylcysteine
Anticholinergics (eg, atropine)
Physostigmine
Anticholinesterases (eg, 
 
organophosphate pesticides)
Atropine and pralidoxime 
(2-PAM)
Flumazenil (rarely used)
2
Carbon monoxide
Oxygen (hyperbaric oxygen of 
uncertain benefit)
Cyanide
Sodium nitrite, sodium thiosul
-
fate; hydroxocobalamin
Digitalis glycosides
Digoxin-specific Fab antibodies
Heavy metals (eg, lead, 
mercury, iron) and arsenic
Specific chelating agents
Isoniazid
Pyridoxine (vitamin B
6
)
Methanol, ethylene glycol
Ethanol (ethyl alcohol) or 
fomepizole 
(4-methylpyrazole)
Opioids
Naloxone, nalmefene
Snake venom
Specific antivenin
Sulfonylurea oral hypoglycemic 
drugs
Glucose, octreotide
1
See text for indications and dosages.
2
May induce seizures in patients with preexisting seizure disorder, 
benzodiazepine addiction, or concomitant tricyclic antidepressant 
or other convulsant overdose. If seizures occur, diazepam and 
other benzodiazepine anticonvulsants will not be effective. As with 
naloxone, the duration of action of flumazenil is short (2–3 hours) 
and resedation may occur, requiring repeated doses.
Dzeshka MS et al. Direct oral anticoagulant reversal: how, when 
and issues faced. Expert Rev Hematol. 2017 Nov;10(11): 
1005–22. [PMID: 28901221]
Graudins A et al. Calcium channel antagonist and beta-blocker 
overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 
2016 Mar;81(3):453–61. [PMID: 26344579]
Iyengar AR et al. Organophosphate-hydrolyzing enzymes as 
first-line of defence against nerve agent-poisoning: perspec
-
tives and the road ahead. Protein J. 2016 Dec;35(6):424–39. 
[PMID: 27830420]
Mazer-Amirshahi M et al. Drug shortages: implications for 
medical toxicology. Clin Toxicol (Phila). 2015 Jul;53(6):
 
519–24. [PMID: 25951876]
McMartin K et al. Antidotes for poisoning by alcohols that form 
toxic metabolites. Br J Clin Pharmacol. 2016 Mar;81(3): 
505–15. [PMID: 26551875]
DECONTAMINATION OF THE SKIN
Corrosive agents rapidly injure the skin and eyes and must 
be removed immediately. In addition, many toxins are 
readily absorbed through the skin, and systemic absorption 
can be prevented only by rapid action.
Wash the affected areas with copious quantities of luke
-
warm water or saline, taking care to limit exposure to health 
care providers. Wash carefully behind the ears, under the 
nails, and in skin folds. For oily substances (eg, pesticides), 
wash the skin at least twice with plain soap and shampoo the 
hair. Specific decontaminating solutions or solvents (eg, 
alcohol) are rarely indicated and in some cases may paradoxi
-
cally enhance absorption. For exposure to chemical warfare 
poisons such as nerve agents or vesicants, some authorities 
recommend use of a dilute hypochlorite solution (household 
bleach diluted 1:10 with water), but not in the eyes.
DECONTAMINATION OF THE EYES

Act quickly to prevent serious damage. Flush the eyes with 
copious amounts of saline or water. (If available, instill local 
anesthetic drops in the eye before beginning irrigation.) 
Remove contact lenses if present. Lift the tarsal conjunctiva 
to look for undissolved particles and to facilitate irrigation. 
Continue irrigation for 15 minutes or until each eye has been 
irrigated with at least 1 L of solution. If the toxin is an acid 
or a base, check the pH of the tears after irrigation, and con
-
tinue irrigation until the pH is between 6 and 8. An ampho
-
teric decontamination solution (Diphoterine, Prevor) is used 
in some countries for treatment of alkali injuries to the eye.
After irrigation is complete, perform a careful examina
-
tion of the eye, using fluorescein and a slit lamp or Wood 
lamp to identify areas of corneal injury. Patients with seri
-
ous conjunctival or corneal injury should be immediately 
GASTROINTESTINAL DECONTAMINATION
Removal of ingested poisons by induced emesis or gastric 
lavage was a routine part of emergency treatment for 
decades. However, prospective randomized studies have 
failed to demonstrate improved clinical outcome after gas
-
tric emptying. For small or moderate ingestions of most 
substances, toxicologists generally recommend oral acti
-
vated charcoal alone without prior gastric emptying; 
 
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in some cases, when the interval after ingestion has been 
more than 1–2 hours and the ingestant is non–life-
threatening, even charcoal is withheld (eg, if the estimated 
benefit is outweighed by the potential risk of pulmonary 
aspiration of charcoal). Exceptions are large ingestions of 
anticholinergic compounds and salicylates, which often 
delay gastric emptying, and ingestion of sustained-release 
or enteric-coated tablets, which may remain intact for sev
-
eral hours. In these cases, delayed gut decontamination 
may be indicated.
Gastric emptying is not generally used for ingestion of 
corrosive agents or petroleum distillates, because further 
esophageal injury or pulmonary aspiration may result. 
However, in certain cases, removal of the toxin may be 
more important than concern over possible complications. 
Consult a medical toxicologist or regional poison control 
center (1-800-222-1222) for advice.
A. Activated Charcoal
Activated charcoal effectively adsorbs almost all drugs and 
poisons. Poorly adsorbed substances include iron, lithium, 
potassium, sodium, mineral acids, and alcohols.
Activated charcoal can be used for prompt 
adsorption of drugs or toxins in the stomach and intestine. 
However, evidence of benefit in clinical studies is lacking. 
Administration of charcoal, especially if mixed with sorbi
-
tol, can provoke vomiting, which could lead to pulmonary 
aspiration in an obtunded patient.
2. Contraindications—
Activated charcoal should not be 
used for comatose or convulsing patients unless it can be 
given by gastric tube and the airway is first protected by a 
cuffed endotracheal tube. It is also contraindicated for 
patients with ileus or intestinal obstruction or those who 
have ingested corrosives for whom endoscopy is planned.
3. Technique—
Administer activated charcoal, 60–100 g 
orally or via gastric tube, mixed in aqueous slurry. Repeated 
doses may be given to ensure gastrointestinal adsorption or 
to enhance elimination of some drugs.
B. Whole Bowel Irrigation
Whole bowel irrigation uses large volumes of a balanced 
polyethylene glycol-electrolyte solution to mechanically 
cleanse the entire intestinal tract. Because of the composi
-
tion of the irrigating solution, there is no significant gain or 
loss of systemic fluids or electrolytes.
Whole bowel irrigation is particularly 
effective for massive iron ingestion in which intact tablets 
are visible on abdominal radiographs. It has also been used 
for ingestions of lithium, sustained-release and enteric-
coated tablets, and swallowed drug-filled packets.
Do not use in patients with suspected 
intestinal obstruction. Use with caution in patients who are 
obtunded or have depressed airway protective reflexes.
Administer a balanced polyethylene glycol-
electrolyte solution (CoLyte, GoLYTELY) into the stomach 
via gastric tube at a rate of 1–2 L/h until the rectal effluent 
is clear. This may take several hours. It is most effective 
when patients are able to sit on a commode to pass the 
intestinal contents.
C. Increased Drug Removal
1. Urinary manipulation—
Forced diuresis is hazardous; 
the risk of complications (fluid overload, electrolyte 
imbalance) usually outweighs its benefits. Some drugs (eg, 
salicylates, phenobarbital) are more rapidly excreted with 
an alkaline urine. To alkalinize the urine, add 100 mEq 
(two ampules) of sodium bicarbonate to 1 L of 5% dextrose 
in 0.2% saline, and infuse this solution intravenously at a 
rate of about 150–200 mL/h. Acidification (sometimes 
promoted for amphetamines, phencyclidine) is 
not
 very 
effective and is contraindicated in the presence of rhabdo
-
myolysis or myoglobinuria.
2. Hemodialysis—
The indications for dialysis are as 
follows: (1) known or suspected potentially lethal amounts 
of a dialyzable drug (Table 38–4); (2) poisoning with deep

of a dialyzable drug (Table 38–4); (2) poisoning with deep 
coma, apnea, severe hypotension, fluid and electrolyte or 
acid-base disturbance, or extreme body temperature 
changes that cannot be corrected by conventional mea
-
sures; or (3) poisoning in patients with severe kidney, car
-
diac, pulmonary, or hepatic disease who will not be able to 
eliminate toxin by the usual mechanisms.
Continuous renal replacement therapy (including con
-
tinuous venovenous hemodiafiltration and similar 
techniques) is of uncertain benefit for elimination of most 
poisons but has the advantage of gradual removal of the toxin 
and correction of any accompanying acidosis, and its use has 
been reported in the management of lithium intoxication.
Table 38–4.
 
Recommended use of hemodialysis in 
Poison
Common Indications
1
Seizures, severe cardiotoxicity; serum level 
> 60 mg/L
Ethylene glycol
Acidosis, serum level > 50 mg/dL
Lithium
Severe symptoms; level > 4–5 mEq/L, 
especially if kidney impairment
Note: dialysis of uncertain value; consult with 
medical toxicologist
Methanol
Intractable hypotension, acidosis despite 
maximal supportive care
Salicylate
Severe acidosis, CNS symptoms, serum level
> 100 mg/dL (acute overdose) or
> 60 mg/dL (chronic intoxication)
Serum level > 90–100 mg/L (acute) or seizures 
and serum level
Serum level > 900–1000 mg/L or deep coma, 
severe acidosis
1
See text for further discussion of indications.
CNS, central nervous system; CVVHD, continuous venovenous 
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3. Repeat-dose charcoal—
Repeated doses of activated 
charcoal, 20–30 g orally or via gastric tube every 3–4 hours, 
may hasten elimination of some drugs (eg, phenytoin, car
-
bamazepine, dapsone) by absorbing drugs excreted into 
the gut lumen (“gut dialysis”). However, clinical studies 
have failed to prove better outcome using repeat dose char
-
coal. Sorbitol or other cathartics should 
not
 be used with 
each dose, or else the resulting large stool volumes may 
lead to dehydration or hypernatremia.
Corcoran G et al. Use and knowledge of single dose activated 
charcoal: a survey of Australian doctors. Emerg Med 
Australas. 2016 Oct;28(5):578–85. [PMID: 27555040]
Lavergne V et al. Guidelines for reporting case studies on extra
-
corporeal treatments in poisonings: methodology. Semin 
Dial. 2014 Jul–Aug;27(4):407–14. [PMID: 24890576]
Mirrakhimov AE et al. The role of renal replacement therapy in 
the management of pharmacologic poisonings. Int J Nephrol. 
2016;2016:3047329. [PMID: 28042482]
Ouellet G et al. Available extracorporeal treatments for poison
-
ing: overview and limitations. Semin Dial. 2014 Jul–Aug; 
27(4):342–9. [PMID: 24697909]
Patel N et al. Developments in extracorporeal therapy for the 
poisoned patient. Adv Drug Deliv Rev. 2015 Aug 1;90:3–11. 
[PMID: 26050528]
Villarreal J et al. A retrospective review of the prehospital use of 
activated charcoal. Am J Emerg Med. 2015 Jan;33(1):56–9. 
[PMID: 25455049]
 
º
DIAGNOSIS OF POISONING
The identity of the ingested substance or substances is usu
-
ally known, but occasionally a comatose patient is found 
with an unlabeled container or the patient is unable or 
unwilling to give a coherent history. By performing a 
directed physical examination and ordering common clini
-
cal laboratory tests, the clinician can often make a tentative 
diagnosis that may allow empiric interventions or may 
suggest specific toxicologic tests.
 
»
Important diagnostic variables in the physical examination 
include blood pressure, pulse rate, temperature, pupil size, 
sweating, and the presence or absence of peristaltic activity. 
Poisonings may present with one or more of the following 
common syndromes.
A. Sympathomimetic Syndrome
The blood pressure and pulse rate are elevated, though with 
severe hypertension reflex bradycardia may occur. The tem
-
perature is often elevated, pupils are dilated, and the skin is 
sweaty, though mucous membranes are dry. Patients are 
usually agitated, anxious, or frankly psychotic.
Examples:
 Amphetamines, cocaine, ephedrine, pseu
-
doephedrine, synthetic cathinones and cannabinoids.
B. Sympatholytic Syndrome
The blood pressure and pulse rate are decreased and body 
temperature is low. The pupils are small or even pinpoint. 
Patients are usually obtunded or comatose.
Examples:
 Barbiturates, benzodiazepines and other 
sedative hypnotics, gamma-hydroxybutyrate (GHB), cloni
-
dine and related antihypertensives, ethanol, opioids.
C. Cholinergic Syndrome
Stimulation of muscarinic receptors causes bradycardia, 
miosis, sweating, and hyperperistalsis as well as bronchor
-
rhea, wheezing, excessive salivation, and urinary inconti
-
nence. Nicotinic receptor stimulation may produce initial 
hypertension and tachycardia as well as fasciculations and 
muscle weakness. Patients are usually agitated and anxious.
Examples:
 Carbamates, nicotine, organophosphates 
(including nerve agents), physostigmine.
D. Anticholinergic Syndrome
Tachycardia with mild hypertension is common, and the 
body temperature is often elevated. Pupils are widely dilated. 
The skin is flushed, hot, and dry. Peristalsis is decreased, and 
urinary retention is common. Patients may have myoclonic 
jerking or choreoathetoid movements. Agitated delirium is 
frequently seen, and severe hyperthermia may occur.
Examples:
 Atropine, scopolamine, other naturally 
occurring and pharmaceutical anticholinergics, antihista
-

Examples:
-
mines, tricyclic antidepressants.
 
»
The following clinical laboratory tests are recommended 
for screening of the overdosed patient: measured serum 
osmolality and calculated osmol gap, electrolytes and anion 
gap, glucose, creatinine, blood urea nitrogen (BUN), cre
-
atine kinase, urinalysis (eg, oxalate crystals with ethylene 
glycol poisoning, myoglobinuria with rhabdomyolysis), 
and electrocardiography. Quantitative serum acetamino
-
phen and ethanol levels should be determined in all 
patients with drug overdoses.
A. Osmol Gap
The osmol gap (Table 38–5) is increased in the presence of 
large quantities of low-molecular-weight substances, most 
commonly ethanol. Other common poisons associated 
Table 38–5.
 
Use of the osmol gap in toxicology.
The osmol gap (Delta osm) is determined by subtracting the cal
-
culated serum osmolality from the measured serum osmolality.
Calc
ulat
ed
osmola
lity
2[Na
(m
Eq/L)]
Gl
uc
os
e
(m
g/dL
)
18
BU
N
(m
g/dL
)
2.
8
(o
sm
)
=+
+
+
Delta osm = Measured osmolality – Calculated osmolality = 0 ± 10
Serum osmolality may be increased by contributions of exogenous 
substances such as alcohols and other low-molecular-weight sub
-
stances. Since these substances are not included in the calculated 
osmolality, there will be a gap proportionate to their serum con
-
centration. Contact a medical toxicologist or poison control center 
for assistance in calculating and interpreting the osmol gap.
Adapted, with permission, from Stone CK, Humphries RL (editors): 
, 5th ed. McGraw-Hill, 2004.
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with increased osmol gap are acetone, ethanol, ethylene 
glycol, isopropyl alcohol, methanol, and propylene glycol. 
 
Note:
 Severe alcoholic ketoacidosis and diabetic ketoacido
-
sis can also cause an elevated osmol gap resulting from the 
production of ketones and other low-molecular-weight 
substances.
B. Anion Gap
Metabolic acidosis associated with an elevated anion gap is 
usually due to an accumulation of lactic acid or other acids 
(see Chapter 21). Common causes of elevated anion gap in 
poisoning include carbon monoxide, cyanide, ethylene 
glycol, propylene glycol, medicinal iron, INH, methanol, 
metformin, ibuprofen, and salicylates. Massive acetamino
-
phen overdose can cause early-onset anion gap metabolic 
acidosis.
The osmol gap should also be checked; combined ele
-
vated anion and osmol gaps suggests poisoning by methanol 
or ethylene glycol, though this may also occur in patients 
with diabetic ketoacidosis and alcoholic ketoacidosis.
C. Toxicology Laboratory Testing
A comprehensive toxicology screen is of little value in the 
initial care of the poisoned patient because results usually 
do not return in time to influence clinical management. 
Specific quantitative levels of certain drugs may be 
extremely helpful (Table 38–6), however, especially if spe
-
cific antidotes or interventions (eg, dialysis) would be 
indicated based on the results.
Many hospitals can perform a quick but limited urine 
screen for “drugs of abuse” (typically these screens include 
only opiates, amphetamines, and cocaine, and some add 
benzodiazepines, barbiturates, methadone, oxycodone, and 
tetrahydrocannabinol [marijuana]). There are numerous 
false-positive and false-negative results. For example, syn
-
thetic opioids, such as fentanyl, oxycodone, and methadone, 
are often not detected by routine opiate immunoassays.
 
»
Abdominal Imaging
A plain film (or CT scan) of the abdomen may reveal radi
-
opaque iron tablets, drug-filled condoms, or other toxic 
material. Studies suggest that few tablets are predictably 
visible (eg, ferrous sulfate, sodium chloride, calcium car
-
bonate, and potassium chloride). Thus, the radiograph is 
useful only if abnormal.
 
»
Consultation with a regional poison control center 
(1-800-222-1222) or a medical toxicologist is recommended 
when the diagnosis is uncertain; there are questions about 
what laboratory tests to order; when dialysis is being consid
-
ered to remove the drug or poison; or when advice is needed 
regarding the indications, dose, and side effects of antidotes.
 
»
•	
The patient has symptoms and signs of intoxication that 
are not expected to clear within a 6- to 8-hour observa
-
tion period.
•	
Delayed absorption of the drug might be predicted to 
cause a later onset of serious symptoms (eg, after inges
-
tion of a sustained-release product).
•	
Continued administration of an antidote is required 
(eg, 
N
-acetylcysteine for acetaminophen overdose).
•	
Psychiatric or social services evaluation is needed for 
suicide attempt or suspected drug abuse.
Goldfrank LR (editor). 
Goldfrank’s Toxicologic Emergencies
, 
 
10th ed. McGraw-Hill, 2014.
Malek N et al. Common toxidromes in movement disorder neu
-
rology. Postgrad Med J. 2017 Jun;93(1100):326–32. [PMID: 
28546460]
Martins SS et al. Worldwide prevalence and trends in uninten
-
tional drug overdose: a systematic review of the literature. Am 
J Public Health. 2015 Nov;105(11):2373. [PMID: 26451757]
Table 38–6.
 
Specific quantitative levels and potential 
therapeutic interventions.
1
Drug or Toxin
Treatment
Specific antidote (
N
-acetylcysteine) based 
on serum level
High carboxyhemoglobin level indicates 
need for 100% oxygen, consideration of 
hyperbaric oxygen
High level may indicate need for 
hemodialysis
Digoxin
On basis of serum digoxin level and 
 
severity of clinical presentation, 
 
treatment with Fab antibody fragments

Digoxin
 
treatment with Fab antibody fragments 
(eg, DigiFab) may be indicated
Ethanol
Low serum level may suggest nonalcoholic 
cause of coma (eg, trauma, other drugs, 
other alcohols); serum ethanol may also 
be useful in monitoring ethanol therapy 
for methanol or ethylene glycol poisoning
Iron
Level may indicate need for chelation with 
deferoxamine
Lithium
Serum levels can guide decision to institute 
Methanol, ethylene 
glycol
Acidosis, high levels indicate need for 
hemodialysis, therapy with ethanol or 
fomepizole
Methemoglobin
Methemoglobinemia can be treated with 
methylene blue intravenously
High level may indicate need for hemodialy
-
sis, alkaline diuresis
Immediate hemodialysis or hemoperfusion 
may be indicated based on serum level
Elevated levels may indicate need to 
 
consider hemodialysis or L-carnitine 
 
therapy, or both
1
Some drugs or toxins may have profound and irreversible toxicity 
unless rapid and specific management is provided outside of 
routine supportive care. For these agents, laboratory testing may 
provide the serum level or other evidence required for administer
-
ing a specific antidote or arranging for hemodialysis.
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Olson KR (editor). 
Poisoning & Drug Overdose
, 7th ed. 
McGraw-Hill, 2017.
Rasimas JJ et al. Assessment and management of toxidromes in 
the critical care unit. Crit Care Clin. 2017 Jul;33(3):521–41. 
[PMID: 28601133]
 
º
SELECTED POISONINGS
ACETAMINOPHEN
Acetaminophen (paracetamol in the United Kingdom, 
Europe) is a common analgesic found in many nonprescrip
-
tion and prescription products. After absorption, it is metabo
-
lized mainly by glucuronidation and sulfation, with a small 
fraction metabolized via the P450 mixed-function oxidase 
system (2E1) to a highly toxic reactive intermediate. This toxic 
intermediate is normally detoxified by cellular glutathione. 
With acute acetaminophen overdose (greater than 
150–200 mg/kg, or 8–10 g in an average adult), hepatocellular 
glutathione is depleted and the reactive intermediate attacks 
other cell proteins, causing necrosis. Patients with enhanced 
P450 2E1 activity, such as those who chronically abuse alcohol 
and patients taking INH, are at increased risk for developing 
hepatotoxicity. Hepatic toxicity may also occur after overuse 
of acetaminophen—eg, as a result of taking two or three 
acetaminophen-containing products concurrently or exceed
-
ing the recommended maximum dose of 4 g/day for several 
days. The amount of acetaminophen in US oral prescription 
combination products (eg, hydrocodone/acetaminophen) is 
limited by the FDA to no more than 325 mg per tablet.
 
»
Shortly after ingestion, patients may have nausea or vomit
-
ing, but there are usually no other signs of toxicity until 
24–48 hours after ingestion, when hepatic aminotransfer
-
ase levels begin to increase. With severe poisoning, fulmi
-
nant hepatic necrosis may occur, resulting in jaundice, 
hepatic encephalopathy, acute kidney injury, and death. 
Rarely, massive ingestion (eg, serum levels greater than 
500–1000 mg/L [33–66 mmol/L]) can cause early onset of 
acute coma, seizures, hypotension, and metabolic acidosis 
unrelated to hepatic injury.
The diagnosis after acute overdose is based on measure
-
ment of the serum acetaminophen level. Plot the serum 
level versus the time since ingestion on the acetaminophen 
nomogram shown in Figure 38–1. Ingestion of sustained-
release products or coingestion of an anticholinergic agent, 
salicylate, or opioid drug may cause delayed elevation of 
serum levels which can make it difficult to interpret the 
nomogram. The nomogram is also not useful after chronic 
or staggered overdose.
 
»
Treatment
A. Emergency and Supportive Measures
Administer activated charcoal if it can be given within 
1–2 hours of the ingestion. Although charcoal may inter
-
fere with absorption of the oral antidote acetylcysteine, 
this is not considered clinically significant.
0
0123456789
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
0
10
20
30
40
50
60
70
80
Serum acetaminophen concentration (mg/L)
90
100
110
120
130
140
150
160
Time (hours)
100
200
300
400
500
600
Serum acetaminophen concentration (mcmol/L)
700
800
900
1000
 
▲
Figure 38–1.
 
Nomogram for prediction of acetaminophen hepatotoxicity following acute overdosage. Patients 
with serum levels above the line after acute overdose should receive antidotal treatment. 
from Daly FF et al. Guidelines for the management of paracetamol poisoning in Australia and New Zealand–explanation 
and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information 
centres. Med J Austr. 2008;188:296. © Copyright 2008 The Medical Journal of Australia. The Medical Journal of Australia 
does not accept responsibility for any errors in translation.)
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B. Specific Treatment
If the serum or plasma acetaminophen level falls above the 
line on the nomogram (Figure 38–1), treatment with 
N
-acetylcysteine is indicated; it can be given orally or intra
-
venously. Oral treatment begins with a loading dose of 
N
-acetylcysteine, 140 mg/kg, followed by 70 mg/kg every 
 
4 hours. Dilute the solution to about 5% with water, juice, 
or soda. If vomiting interferes with oral 
N
administration, consider giving the antidote intravenously. 
The conventional oral 
N
-acetylcysteine protocol in the 
United States calls for 72 hours of treatment. However, 
other regimens have demonstrated equivalent success with 
20–48 hours of treatment.
The FDA-approved 21-hour intravenous regimen of 
acetylcysteine (Acetadote) calls for a loading dose of 
 
150 mg/kg given intravenously over 60 minutes, followed 
by a 4-hour infusion of 50 mg/kg, and a 16-hour infusion 
of 100 mg/kg. (If Acetadote is not available, the conven
-
tional oral formulation may also be given intravenously 
using a micropore filter and a slow rate of infusion. Call a 
regional poison control center or medical toxicologist for 
assistance.)
N
-acetylcysteine is most effective if it is 
started within 8–10 hours after ingestion. Hemodialysis is 
rarely indicated, but might be needed in some patients with 
massive overdose.
Ghannoum M et al. Massive acetaminophen overdose: effect of 
hemodialysis on acetaminophen and acetylcysteine kinetics. 
Clin Toxicol (Phila). 2016 Jul;54(6):519–22. [PMID: 
27118496]
Gosselin S et al. Extracorporeal treatment for acetaminophen 
poisoning: recommendations from the EXTRIP workgroup. 
Clin Toxicol (Phila). 2014 Sep–Oct;52(8):856–67. [PMID: 
25133498]
Park BK et al. Paracetamol (acetaminophen) poisoning. BMJ 
Clin Evid. 2015 Oct 19;2015:2101. [PMID: 26479248]
Wong A et al. Risk prediction of hepatotoxicity in paracetamol 
poisoning. Clin Toxicol (Phila). 2017 Sep;55(8):879–92. 
[PMID: 28447858]
ACIDS, CORROSIVE
The strong mineral acids exert primarily a local corrosive 
effect on the skin and mucous membranes. Symptoms 
include severe pain in the throat and upper gastrointestinal 
tract; bloody vomitus; difficulty in swallowing, breathing, 
and speaking; discoloration and destruction of skin and 
mucous membranes in and around the mouth; and shock. 
Severe systemic metabolic acidosis may occur both as a 
result of cellular injury and from systemic absorption of 
the acid.
Severe deep destructive tissue damage may occur after 
exposure to hydrofluoric acid because of the penetrating 
and highly toxic fluoride ion. Systemic hypocalcemia and 
hyperkalemia may also occur after fluoride absorption, 
even following skin exposure.
Inhalation of volatile acids, fumes, or gases such as 
chlorine, fluorine, bromine, or iodine causes severe irrita
-
tion of the throat and larynx and may cause upper airway 
obstruction and noncardiogenic pulmonary edema.
 
»
Treatment
A. Ingestion
Dilute immediately by giving a glass (4–8 oz) of water to 
drink. Do 
not
 give bicarbonate or other neutralizing 
agents, and do 
not
 induce vomiting. Some experts recom
-
mend immediate cautious placement of a small flexible 
gastric tube and removal of stomach contents followed by 
lavage, particularly if the corrosive is a liquid or has impor
-
tant systemic toxicity.
In symptomatic patients, perform flexible endoscopic 
esophagoscopy to determine the presence and extent of 
injury. CT scan or plain radiographs of the chest and abdo
-
men may also reveal the extent of injury. Perforation, peri
-
tonitis, and major bleeding are indications for surgery.
B. Skin Contact
Flood with water for 15 minutes. Use no chemical anti
-
dotes; the heat of the reaction may cause additional injury.
For hydrofluoric acid burns, soak the affected area in 
benzalkonium chloride solution or apply 2.5% calcium glu
-
conate gel (prepared by adding 3.5 g calcium gluconate to

-
conate gel (prepared by adding 3.5 g calcium gluconate to 
 
5 oz of water-soluble surgical lubricant, eg, K-Y Jelly); then 
arrange immediate consultation with a plastic surgeon or 
other specialist. Binding of the fluoride ion may be achieved 
by injecting 0.5 mL of 5% calcium gluconate per square 
centimeter under the burned area. (
Caution: 
Do not use 
calcium chloride.
) Use of a Bier-block technique or intra-
arterial infusion of calcium is sometimes required for exten
-
sive burns or those involving the nail bed; consult with a 
hand surgeon or poison control center (1-800-222-1222).
C. Eye Contact
Anesthetize the conjunctiva and corneal surfaces with topi
-
cal local anesthetic drops (eg, proparacaine). Flood with 
water for 15 minutes, holding the eyelids open. Check pH 
with pH 6.0–8.0 test paper, and repeat irrigation, using 
0.9% saline, until pH is near 7.0. Check for corneal damage 
with fluorescein and slit-lamp examination; consult an 
ophthalmologist about further treatment.
D. Inhalation
Remove from further exposure to fumes or gas. Check skin 
and clothing. Observe for and treat chemical pneumonitis 
or pulmonary edema.
Cowan T et al. Acute esophageal injury and strictures following 
corrosive ingestions in a 27 year cohort. Am J Emerg Med. 
2017 Mar;35(3):488–92. [PMID: 27955797]
Struck MF et al. Acute emergency care and airway management 
of caustic ingestion in adults: single center observational 
study. Scand J Trauma Resusc Emerg Med. 2016 Apr 11;24:45. 
[PMID: 27068119]
Wang X et al. A review of treatment strategies for hydrofluoric 
acid burns: current status and future prospects. Burns. 2014 
Dec;40(8):1447–57. [PMID: 24946967]
Wightman RS et al. Evidence-based management of caustic 
exposures in the emergency department. Emerg Med Pract. 
2016 May;18(5):1–17. [PMID: 27074641]
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Zhang Y et al. Injuries following a serious hydrofluoric acid leak: 
first aid and lessons. Burns. 2015 Nov;41(7):1593–8. [PMID: 
26188892]
ALKALIES
The strong alkalies are common ingredients of some house
-
hold cleaning compounds and may be suspected by their 
“soapy” texture. Those with alkalinity above pH 12.0 are 
particularly corrosive. Disk (or “button”) batteries are also a 
source. Alkalies cause liquefactive necrosis, which is deeply 
penetrating. Symptoms include burning pain in the upper 
gastrointestinal tract, nausea, vomiting, and difficulty in 
swallowing and breathing. Examination reveals destruction 
and edema of the affected skin and mucous membranes and 
bloody vomitus and stools. Radiographs may reveal evi
-
dence of perforation or the presence of radiopaque disk 
batteries in the esophagus or lower gastrointestinal tract.
 
»
Treatment
Dilute immediately with a glass of water. Do 
not
 induce 
emesis. Some gastroenterologists recommend immediate 
cautious placement of a small flexible gastric tube and 
removal of stomach contents followed by gastric lavage 
after ingestion of liquid caustic substances, in order to 
remove residual material. However, others argue that pas
-
sage of a gastric tube is contraindicated due to the risk of 
perforation or reexposure of the esophagus to the corrosive 
material from vomiting around the tube.
Prompt endoscopy is recommended in symptomatic 
patients to evaluate the extent of damage; CT scanning may 
also aid in assessment. If a radiograph reveals ingested disk 
batteries lodged in the esophagus, immediate endoscopic 
removal is mandatory.
The use of corticosteroids to prevent stricture forma
-
tion is of no proved benefit and is definitely contraindi
-
cated if there is evidence of esophageal perforation.
Wash with running water until the skin no longer feels 
soapy. Relieve pain and treat shock.
Anesthetize the conjunctival and corneal surfaces with topi
-
cal anesthetic (eg, proparacaine). Irrigate with water or saline 
continuously for 20–30 minutes, holding the lids open. 
Amphoteric solutions may be more effective than water or 
saline and some are available in Europe (Diphoterine, 
Prevor). Check pH with pH test paper and repeat irrigation 
for additional 30-minute periods until the pH is near 7.0. Check 
for corneal damage with fluorescein and slit-lamp examination; 
consult an ophthalmologist for further treatment.
Brent J. Water-based solutions are the best decontaminating flu
-
ids for dermal corrosive exposures: a mini review. Clin Toxicol 
(Phila). 2013 Sep–Oct;51(8):731–6. [PMID: 24003912]
in the United States. JAMA Ophthalmol. 2016 Oct 1; 
AMPHETAMINES & COCAINE
Amphetamines and cocaine are widely abused for their 
euphorigenic and stimulant properties. Both drugs may 
be smoked, snorted, ingested, or injected. Amphet
-
amines and cocaine produce central nervous system 
stimulation and a generalized increase in central and 
peripheral sympathetic activity. The toxic dose of each 
drug is highly variable and depends on the route of 
administration and individual tolerance. The onset of 
effects is most rapid after intravenous injection or smok
-
ing. Amphetamine derivatives and related drugs include 
methamphetamine (“crystal meth, ” “crank”), MDMA 
(“Ecstasy”), ephedrine (“herbal ecstasy”), and methcathi
-
none (“cat” or “khat”). Methcathinone derivatives and 
related synthetic chemicals such as methylenedioxypy
-
rovalerone (MDPV) have become popular drugs of abuse 
and are often sold as purported “bath salts. ” Amphet
-
amine-like reactions have also been reported after use of 
synthetic cannabinoids (eg, “Spice” and “K2”). Nonpre
-
scription medications and nutritional supplements may 
contain stimulant or sympathomimetic drugs such as

-
contain stimulant or sympathomimetic drugs such as 
ephedrine, yohimbine, or caffeine (see also Theophylline 
& Caffeine section).
 
»
Presenting symptoms may include anxiety, tremulous
-
ness, tachycardia, hypertension, diaphoresis, dilated 
pupils, agitation, muscular hyperactivity, and psychosis. 
Muscle hyperactivity may lead to metabolic acidosis and 
rhabdomyolysis. In severe intoxication, seizures and 
hyperthermia may occur. Sustained or severe hyperten
-
sion may result in intracranial hemorrhage, aortic dissec
-
tion, or myocardial infarction; chronic use may cause 
cardiomyopathy. Ischemic colitis has been reported. 
Hyponatremia has been reported after MDMA use; the 
mechanism is not known but may involve excessive water 
intake, syndrome of inappropriate antidiuretic hormone 
(SIADH), or both.
The diagnosis is supported by finding amphetamines or 
the cocaine metabolite benzoylecgonine in the urine. Note 
that many drugs can give false-positive results on the 
immunoassay for amphetamines, and most synthetic stim
-
ulants do not react with the immunoassay, giving false-
negative results.
 
»
Treatment
Maintain a patent airway and assist ventilation, if neces
-
sary. Treat seizures as described at the beginning of this 
chapter. Rapidly lower the body temperature in patients 
who are hyperthermic (temperature higher than 39–40
°
C). 
Give intravenous fluids to prevent myoglobinuric kidney 
injury in patients who have rhabdomyolysis.
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Treat agitation, psychosis, or seizures with a benzodiaze
-
pine such as diazepam, 5–10 mg, or lorazepam, 2–3 mg 
intravenously. Add phenobarbital 15 mg/kg intravenously 
for persistent seizures. Treat hypertension with a vasodila
-
tor drug such as phentolamine (1–5 mg intravenously) or 
nitroprusside, or a combined alpha- and beta-adrenergic 
blocker such as labetalol (10–20 mg intravenously). Do 
not
 
administer a pure beta-blocker such as propranolol alone, 
as this may result in paradoxic worsening of the hyperten
-
sion as a result of unopposed alpha-adrenergic effects.
Treat tachycardia or tachyarrhythmias with a short-acting 
beta-blocker such as esmolol (25–100 mcg/kg/min by intra
-
venous infusion). Treat hyperthermia as described above. 
Treat hyponatremia as outlined in Chapter 21.
Tait RJ et al. A systematic review of adverse events arising from 
the use of synthetic cannabinoids and their associated treat
-
ment. Clin Toxicol (Phila). 2016 Jan;54(1):1–13. [PMID: 
26567470]
Tyndall JA et al. An outbreak of acute delirium from exposure to 
the synthetic cannabinoid AB-CHMINACA. Clin Toxicol 
(Phila). 2015 Dec;53(10):950–6. [PMID: 26555732]
Vallersnes OM et al. Psychosis associated with acute recreational 
drug toxicity: a European case series. BMC Psychiatry. 2016 
Aug 18;16:293. [PMID: 27538886]
White CM. The pharmacologic and clinical effects of illicit syn
-
thetic cannabinoids. J Clin Pharmacol. 2017 Mar;57(3):
 
297–304. [PMID: 27610597]
ANTICOAGULANTS
Warfarin and related compounds (including ingredients of 
many commercial rodenticides, the so-called superwarfarins 
such as brodifacoum, difenacoum, and related compounds) 
inhibit the normal clotting system by blocking hepatic syn
-
thesis of vitamin K–dependent clotting factors. After inges
-
tion of “superwarfarins, ” inhibition of clotting factor 
synthesis may persist for several weeks or even months after 
a single dose. Newer oral anticoagulants include the direct 
thrombin inhibitor dabigatran and the factor Xa inhibitors 
rivaroxaban, apixiban, and edoxaban. Some of these, espe
-
cially dabigatran, are largely eliminated by the kidney and 
may accumulate in patients with kidney dysfunction.
Excessive anticoagulation may cause hemoptysis, gross 
hematuria, bloody stools, hemorrhages into organs, wide
-
spread bruising, and bleeding into joint spaces.
 
»
Treatment
Discontinue the drug at the first sign of gross bleeding, and 
determine the prothrombin time (international normal
-
ized ratio, INR). The prothrombin time is increased within 
12–24 hours (peak 36–48 hours) after overdose of warfarin 
or “superwarfarins. ” 
Note:
 The newer oral anticoagulants 
(dabigatran, rivaroxaban, apixiban, and edoxaban) do not 
predictably alter the prothrombin time; however, a normal 
INR suggests no significant toxicity.
If the patient has ingested an acute overdose, administer 
activated charcoal.
1. Warfarin—
In cases of warfarin and “superwarfarin” 
overdose, do not treat prophylactically with vitamin K—
wait 
for evidence of anticoagulation (elevated prothrombin time). 
See Table 14–21 for the management of INR above therapeu
-
tic range. Doses as high as 200 mg/day have been required 
after ingestion of “superwarfarins. ” Give fresh-frozen plasma, 
prothrombin complex concentrate, or activated Factor VII as 
needed to rapidly correct the coagulation factor deficit if 
there is serious bleeding. If the patient is chronically antico
-
agulated and has strong medical indications for being main
-
tained in that status (eg, prosthetic heart valve), give much 
smaller doses of vitamin K (1 mg orally) and fresh-frozen 
plasma (or both) to titrate to the desired prothrombin time. 
If the patient has ingested brodifacoum or a related super
-
warfarin, prolonged observation (over weeks) and repeated 
administration of large doses of vitamin K may be required.

-
2. Direct-acting oral anticoagulants—
Vitamin K does not 
reverse the anticoagulant effects of the direct-acting oral 
anticoagulants (dabigatran, rivaroxaban, apixiban, and 
edoxaban). 
Idarucizumab
 has been approved by the FDA 
for reversal of the thrombin inhibitor dabigatran; 
andexanet
 remains under investigation for reversal of the 
factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). 
The efficacy of fresh-frozen plasma and clotting factor 
concentrates is uncertain.
Berling I et al. Warfarin poisoning with delayed rebound toxicity. 
J Emerg Med. 2017 Feb;52(2):194–6. [PMID: 27838137]
Escolar G et al. Andexanet alfa: a recombinant mimetic of 
human factor Xa for the reversal of anticoagulant therapies. 
Drugs Today (Barc). 2017 May;53(5):271–82. [PMID: 28650000]
Nafee T et al. Andexanet alfa for the reversal of anticoagulant 
activity in patients treated with direct and indirect factor 
 
Xa inhibitors. Expert Rev Cardiovasc Ther. 2017 Apr;15(4): 
237–45. Erratum in: Expert Rev Cardiovasc Ther. 2017 Apr; 
15(4):iii. [PMID: 28282497]
Pollack CV Jr et al. Idarucizumab for dabigatran reversal - full 
cohort analysis. N Engl J Med. 2017 Aug 3;377(5):431–41. 
[PMID: 28693366]
Zhang XY et al. Reversal of direct oral anticoagulants. Br J Hosp 
Med (Lond). 2017 Mar 2;78(3):165–9. [PMID: 28277769]
ANTICONVULSANTS
Anticonvulsants (carbamazepine, phenytoin, valproic acid, 
and many newer agents) are widely used in the manage
-
ment of seizure disorders and some are also used for treat
-
ment of mood disorders or pain.
Phenytoin
 can be given orally or intravenously. Rapid 
intravenous injection of phenytoin can cause acute myo
-
cardial depression and cardiac arrest owing to the solvent 
propylene glycol (fosphenytoin does not contain this 
diluent). Chronic phenytoin intoxication can occur 
following only slightly increased doses because of zero-
order kinetics and a small toxic-therapeutic window. 
Phenytoin intoxication can also occur following acute 
intentional or accidental overdose. The overdose syndrome 
is usually mild even with high serum levels. The most com
-
mon manifestations are ataxia, nystagmus, and drowsiness. 
Choreoathetoid movements have been described.
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 intoxication causes drowsiness, stupor 
and, with high levels, atrioventricular block, coma, and 
seizures. Dilated pupils and tachycardia are common. 
 
Toxicity may be seen with serum levels over 20 mg/L 
 
(85 mcmol/L), although severe poisoning is usually associ
-
ated with concentrations greater than 30–40 mg/L 
 
(127–169 mcmol/L). Because of erratic and slow absorp
-
tion, intoxication may progress over several hours to days.
 intoxication produces a unique syn
-
drome consisting of hypernatremia (from the sodium 
component of the salt), metabolic acidosis, hypocalcemia, 
elevated serum ammonia, and mild liver aminotransferase 
elevation. Hypoglycemia may occur as a result of hepatic 
metabolic dysfunction. Coma with small pupils may be 
seen and can mimic opioid poisoning. Encephalopathy and 
cerebral edema can occur.
The newer anticonvulsants 
gabapentin, levetiracetam, 
vigabatrin,
 and 
zonisamide
 generally cause somnolence, 
confusion, and dizziness; there is one case report of hypo
-
tension and bradycardia after a large overdose of leveti
-
racetam. 
Felbamate
 can cause crystalluria and kidney 
injury after overdose and may cause idiosyncratic aplastic 
anemia with therapeutic use. 
Lamotrigine, topiramate,
 
and 
tiagabine
 have been reported to cause seizures after 
overdose; lamotrigine has sodium-channel blocking prop
-
erties and may cause QRS prolongation and heart block.
 
»
Treatment
For recent ingestions, give activated charcoal orally or by 
gastric tube. For large ingestions of carbamazepine or val
-
proic acid—especially of sustained-release formulations—
consider whole bowel irrigation. Combined multiple-dose 
activated charcoal and whole-bowel irrigation may be 
beneficial in ensuring gut decontamination for selected 
large ingestions.
There are no specific antidotes. Naloxone was reported to 
have reversed valproic acid overdose in one anecdotal case. 
Carnitine may be useful in patients with valproic acid–
induced hyperammonemia. Consider hemodialysis for 
massive intoxication with valproic acid or carbamazepine 
(eg, carbamazepine levels greater than 60 mg/L 
[254 mcmol/L] or valproic acid levels greater than 800 mg/L 
[5544 mcmol/L]).
Chavez P et al. Evolving electrocardiographic changes in 
lamotrigine overdose: a case report and literature review. 
Cardiovasc Toxicol. 2015 Oct;15(4):394–8. [PMID: 25448877]
Ghannoum M et al. Extracorporeal treatment for valproic acid 
poisoning: systematic review and recommendations from the 
EXTRIP workgroup. Clin Toxicol (Phila). 2015 Jun;53(5): 
454–65. [PMID: 25950372]
Mahmoud SH. Antiepileptic drug removal by continuous renal 
replacement therapy: a review of the literature. Clin Drug 
Investig. 2017 Jan;37(1):7–23. [PMID: 27587068]
Page CB et al. Cardiovascular toxicity with levetiracetam over
-
dose. Clin Toxicol (Phila). 2016;54(2):152–4. [PMID: 
26795744]
ANTIPSYCHOTIC DRUGS
Promethazine, prochlorperazine, chlorpromazine, halo
-
peridol, droperidol, risperidone, olanzapine, ziprasidone, 
quetiapine, and aripiprazole are used as antipsychotic 
agents, and sometimes as antiemetics and potentiators of 
analgesic and hypnotic drugs.
Therapeutic doses of conventional phenothiazines 
(particularly chlorpromazine) induce drowsiness and mild 
orthostatic hypotension in as many as 50% of patients. 
Larger doses can cause obtundation, miosis, severe hypo
-
tension, tachycardia, convulsions, and coma. Abnormal 
cardiac conduction may occur, resulting in prolongation of 
QRS or QT intervals (or both) and ventricular arrhythmias. 
Among the newer agents, quetiapine is more likely to cause 
coma and hypotension.
With therapeutic or toxic doses, an acute extrapyrami
-
dal dystonic reaction may develop in some patients, with 
spasmodic contractions of the face and neck muscles, 
extensor rigidity of the back muscles, carpopedal spasm,

-
extensor rigidity of the back muscles, carpopedal spasm, 
and motor restlessness. This reaction is more common 
with haloperidol and other butyrophenones and less com
-
mon with newer atypical antipsychotics such as ziprasi
-
done, lurasidone, olanzapine, aripiprazole, and quetiapine. 
Severe rigidity accompanied by hyperthermia and meta
-
bolic acidosis (“neuroleptic malignant syndrome”) may 
occasionally occur and is life-threatening (see Chapter 25).
 
»
Treatment
Administer activated charcoal for large or recent inges
-
tions. For severe hypotension, treatment with intrave
-
nous fluids and vasopressor agents may be necessary. 
Treat hyperthermia as outlined. Maintain cardiac 
monitoring.
Hypotension and cardiac arrhythmias associated with 
widened QRS intervals on the ECG in a patient with thio
-
ridazine poisoning may respond to intravenous sodium 
bicarbonate as used for tricyclic antidepressants. Prolon
-
gation of the QT interval and torsades de pointes is usu
-
ally treated with intravenous magnesium or overdrive 
pacing.
For extrapyramidal signs, give diphenhydramine, 
 
0.5–1 mg/kg intravenously, or benztropine mesylate, 
 
0.01–0.02 mg/kg intramuscularly. Treatment with oral 
doses of these agents should be continued for 24–48 hours.
Bromocriptine (2.5–7.5 mg orally daily) may be effec
-
tive for mild or moderate neuroleptic malignant syn
-
drome. Dantrolene (2–5 mg/kg intravenously) has also 
been used for muscle rigidity but is not a true antidote. 
For severe hyperthermia, rapid neuromuscular paralysis 
is preferred.
Berling I et al. Prolonged QT risk assessment in antipsychotic 
overdose using the QT nomogram. Ann Emerg Med. 
2015 Aug;66(2):154–64. [PMID: 25639523]
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Berling I et al. The antipsychotic story: changes in prescriptions 
and overdose without better safety. Br J Clin Pharmacol. 
2016 Jul;82(1):249–54. [PMID: 26945707]
Miura N et al. Risk factors for QT prolongation associated with 
acute psychotropic drug overdose. Am J Emerg Med. 
2015 Feb;33(2):142–9. [PMID: 25445869]
ARSENIC
Arsenic is found in some pesticides and industrial chemi
-
cals and is used as a chemotherapeutic agent. Chronic 
arsenic poisoning has been associated with contaminated 
aquifers used for drinking water. Symptoms of acute poi
-
soning usually appear within 1 hour after ingestion but 
may be delayed as long as 12 hours. They include abdomi
-
nal pain, vomiting, watery diarrhea, and skeletal muscle 
cramps. Profound dehydration and shock may occur. In 
chronic poisoning, symptoms can be vague but often 
include pancytopenia, painful peripheral sensory neuropa
-
thy, and skin changes including melanosis, keratosis, and 
desquamating rash. Cancers of the lung, bladder, and skin 
have been reported. Urinary arsenic levels may be falsely 
elevated after certain meals (eg, seafood) that contain large 
quantities of a nontoxic form of organic arsenic.
 
»
Treatment
After recent ingestion (within 1–2 hours), perform gastric 
lavage. Activated charcoal is of uncertain benefit because it 
binds arsenic poorly. Administer intravenous fluids to 
replace losses due to vomiting and diarrhea.
B. Antidote
For patients with severe acute intoxication, administer 
 
a chelating agent. The preferred drug is 2,3-
 
dimercaptopropanesulfonic acid (DMPS, Unithiol) 
 
(3–5 mg/kg intravenously every 4 hours); although there 
is no FDA-approved commercial formulation of DMPS in 
the United States, it can be obtained from some com
-
pounding pharmacies. An alternative parenteral chelator 
is dimercaprol (British anti-Lewisite, BAL), which comes 
as a 10% solution in peanut oil, and is given 3–5 mg/kg 
intramuscularly every 4–6 hours for 2 days. The side 
effects include nausea, vomiting, headache, and hyperten
-
sion. When gastrointestinal symptoms allow, switch to 
the oral chelator succimer (dimercaptosuccinic acid, 
DMSA), 10 mg/kg every 8 hours, for 1 week. Consult a 
medical toxicologist or regional poison control center 
(1-800-222-1222) for advice regarding chelation.
Arslan B et al. Arsenic: a review on exposure pathways, accumu
-
lation, mobility and transmission into the human food chain. 
Rev Environ Contam Toxicol. 2017;243:27–51. [PMID: 
28005215]
Pinto B et al. Chronic arsenic poisoning following ayurvedic 
medication. J Med Toxicol. 2014 Dec;10(4):395–8. [PMID: 
24696169]
Shumy F et al. Acute arsenic poisoning diagnosed late. Trop 
Doct. 2016 Apr;46(2):93–6. [PMID: 26508422]
ATROPINE & ANTICHOLINERGICS
Atropine, scopolamine, belladonna, diphenoxylate with 
atropine, 
Datura stramonium, Hyoscyamus niger
, some 
mushrooms, tricyclic antidepressants, and antihistamines are 
antimuscarinic agents with variable central nervous system 
effects. Symptoms of toxicity include dryness of the mouth, 
thirst, difficulty in swallowing, and blurring of vision. Physical 
signs include dilated pupils, flushed skin, tachycardia, fever, 
delirium, myoclonus, ileus, and flushed appearance. Antide
-
pressants and antihistamines may induce convulsions.
Antihistamines are commonly available with or without 
prescription. Diphenhydramine commonly causes delir
-
ium, tachycardia, and seizures. Massive diphenhydramine 
overdose may mimic tricyclic antidepressant cardiotoxic 
 
»
Treatment
Administer activated charcoal. External cooling and seda
-
tion, or neuromuscular paralysis in rare cases, are indicated 
to control high temperatures.
For severe anticholinergic syndrome (eg, agitated delirium), 
give physostigmine salicylate, 0.5–1 mg slowly intrave
-
nously over 5 minutes, with ECG monitoring; repeat as

-
nously over 5 minutes, with ECG monitoring; repeat as 
needed to a total dose of no more than 2 mg. 
Caution:
 
Bradyarrhythmias and convulsions are a hazard with phy
-
sostigmine administration, and the drug should be avoided 
in patients with evidence of cardiotoxic effects from tricy
-
clic antidepressants or other sodium channel blockers.
Chan TY . Herbal medicines induced anticholinergic poisoning 
in Hong Kong. Toxins (Basel). 2016 Mar 18;8(3). [PMID: 
26999208]
Dawson AH et al. Pharmacological management of anticholin
-
ergic delirium—theory, evidence and practice. Br J Clin 
Pharmacol. 2016 Mar;81(3):516–524. [PMID: 26589572]
Phillips MA et al. Use of a physostigmine continuous infusion 
for the treatment of severe and recurrent antimuscarinic tox
-
icity in a mixed drug overdose. J Med Toxicol. 2014 
Jun;10(2):205–9. [PMID: 24798647]
Watkins JW et al. The use of physostigmine by toxicologists in 
anticholinergic toxicity. J Med Toxicol. 2015 Jun;11(2):
 
179–84. [PMID: 25510306]
BETA-ADRENERGIC BLOCKERS
There are a wide variety of beta-adrenergic blocking drugs, 
with varying pharmacologic and pharmacokinetic proper
-
ties (see Table 11–7). The most toxic beta-blocker is pro
-
pranolol, which not only blocks beta-1 and beta-2 
adrenoceptors but also has direct membrane-depressant 
and central nervous system effects.
 
»
The most common findings with mild or moderate intoxi
-
cation are hypotension and bradycardia. Cardiac depres
-
sion from more severe poisoning is often unresponsive to 
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conventional therapy with beta-adrenergic stimulants such 
as dopamine and norepinephrine. In addition, with pro
-
pranolol and other lipid-soluble drugs, seizures and coma 
may occur. Propranolol, oxprenolol, acebutolol, and alpre
-
nolol also have membrane-depressant effects and can cause 
conduction disturbance (wide QRS interval) similar to tri
-
cyclic antidepressant overdose.
The diagnosis is based on typical clinical findings. Rou
-
tine toxicology screening does not usually include 
 
»
Treatment
Attempts to treat bradycardia or heart block with atropine 
(0.5–2 mg intravenously), isoproterenol (2–20 mcg/min by 
intravenous infusion, titrated to the desired heart rate), or an 
external transcutaneous cardiac pacemaker are often inef
-
fective, and specific antidotal treatment may be necessary.
For drugs ingested within an hour of presentation (or 
longer after ingestion of an extended-release formulation), 
administer activated charcoal.
For persistent bradycardia and hypotension, give glucagon, 
5–10 mg intravenously, followed by an infusion of 
 
1–5 mg/h. Glucagon is an inotropic agent that acts at a 
 
different receptor site and is therefore not affected by 
beta-blockade. High-dose insulin (0.5–1 unit/kg/h intrave
-
nously) along with glucose supplementation has been used 
to reverse severe cardiotoxicity. Membrane-depressant 
effects (wide QRS interval) may respond to boluses of 
sodium bicarbonate (50–100 mEq intravenously) as for 
tricyclic antidepressant poisoning. Intravenous lipid emul
-
sion (Intralipid 20%, 1.5 mL/kg) has been used successfully 
in severe propranolol overdose.
Cole JB et al. A blinded, randomized, controlled trial of three 
doses of high-dose insulin in poison-induced cardiogenic 
shock. Clin Toxicol (Phila). 2013 May;51(4):201–7. [PMID: 
23530460]
overdose: antidotes and adjunct therapies. Br J Clin 
Pharmacol. 2016 Mar;81(3):453–461. [PMID: 26344579]
Heise CW et al. Massive atenolol, lisinopril, and chlorthalidone 
overdose treated with endoscopic decontamination, hemodi
-
alysis, Impella percutaneous left ventricular assist device, and 
ECMO. J Med Toxicol. 2015 Mar;11(1):110–4. [PMID: 
25146229]
CALCIUM CHANNEL BLOCKERS
In therapeutic doses, nifedipine, nicardipine, amlodipine, 
felodipine, isradipine, nisoldipine, and nimodipine act 
mainly on blood vessels, while verapamil and diltiazem act 
mainly on cardiac contractility and conduction. However, 
these selective effects can be lost after acute overdose. 
Patients may present with bradycardia, atrioventricular 
(AV) nodal block, hypotension, or a combination of these 
effects. Hyperglycemia is common due to blockade of insu
-
lin release. With severe poisoning, cardiac arrest may occur.
 
»
Treatment
For ingested drugs, administer activated charcoal. In addi
-
tion, whole bowel irrigation should be initiated as soon as 
possible if the patient has ingested a sustained-release 
product.
Treat symptomatic bradycardia with atropine (0.5–2 mg 
intravenously), isoproterenol (2–20 mcg/min by intrave
-
nous infusion), or a transcutaneous cardiac pacemaker. For 
hypotension, give calcium chloride 10%, 10 mL, or calcium 
gluconate 10%, 20 mL. Repeat the dose every 3–5 minutes. 
The optimum (or maximum) dose has not been established, 
but many toxicologists recommend raising the ionized 
serum calcium level to as much as twice the normal level. 
Calcium is most useful in reversing negative inotropic 
effects and is less effective for AV nodal blockade and bra
-
dycardia. High doses of insulin (0.5–1 unit/kg intravenous 
bolus followed by 0.5–1 unit/kg/h infusion) along with suf
-
ficient dextrose to maintain euglycemia have been reported 
to be beneficial, but there are no controlled studies. Infusion

-
to be beneficial, but there are no controlled studies. Infusion 
of Intralipid 20% lipid emulsion has been reported to 
improve hemodynamics in animal models and case reports 
of calcium channel blocker poisoning. Methylene blue 
 
(1–2 mg/kg) was reported to reverse refractory shock due to 
profound vasodilation in a patient with amlodipine poison
-
ing. ECMO has been recommended for refractory shock.
Olson KR. What is the best treatment for acute calcium channel 
blocker overdose? Ann Emerg Med. 2013 Sep;62(3):259–61. 
[PMID: 23567061]
St-Onge M et al. Experts consensus recommendations for the 
management of calcium channel blocker poisoning in adults. 
Crit Care Med. 2017 Mar;45(3):e306–15. [PMID: 27749343]
CARBON MONOXIDE
Carbon monoxide is a colorless, odorless gas produced by 
the combustion of carbon-containing materials. Poisoning 
may occur as a result of suicidal or accidental exposure to 
automobile exhaust, smoke inhalation in a fire, or acciden
-
tal exposure to an improperly vented gas heater, generator, 
or other appliance. Some carbon monoxide can be gener
-
ated during degradation of anesthetic gases. Carbon mon
-
oxide avidly binds to hemoglobin, with an affinity 
approximately 250 times that of oxygen. This results in 
reduced oxygen-carrying capacity and altered delivery of 
oxygen to cells (see also Smoke Inhalation in Chapter 9).
 
»
At low carbon monoxide levels (carboxyhemoglobin satura
-
tion 10–20%), victims may have headache, dizziness, 
abdominal pain, and nausea. With higher levels, confusion, 
dyspnea, and syncope may occur. Hypotension, coma, and 
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seizures are common with levels greater than 50–60%. 
Survivors of acute severe poisoning may develop permanent 
obvious or subtle neurologic and neuropsychiatric deficits. 
The fetus and newborn may be more susceptible because of 
high carbon monoxide affinity for fetal hemoglobin.
Carbon monoxide poisoning should be suspected in 
any person with severe headache or acutely altered mental 
status, especially during cold weather, when improperly 
vented heating systems may have been used. Diagnosis 
depends on specific measurement of the arterial or venous 
carboxyhemoglobin saturation, although the level may 
have declined if high-flow oxygen therapy has already been 
administered, and levels do not always correlate with clini
-
cal symptoms. Routine arterial blood gas testing and pulse 
oximetry are not useful because they give falsely normal 
PaO
2
 and oxyhemoglobin saturation determinations, 
respectively. (A specialized pulse oximetry device, the 
Masimo pulse CO-oximeter, is capable of distinguishing 
oxyhemoglobin from carboxyhemoglobin.)
 
»
Treatment
-
sary. Remove the victim from exposure. Treat patients with 
coma, hypotension, or seizures as described at the begin
-
ning of this chapter.
The half-life of the carboxyhemoglobin (CoHb) complex is 
about 4–5 hours in room air but is reduced dramatically by 
high concentrations of oxygen. Administer 100% oxygen by 
tight-fitting high-flow reservoir face mask or endotracheal 
tube. Hyperbaric oxygen (HBO) can provide 100% oxygen 
under higher than atmospheric pressures, further shorten
-
ing the half-life; it may also reduce the incidence of subtle 
neuropsychiatric sequelae. Randomized controlled studies 
disagree about the benefit of HBO, but commonly recom
-
mended indications for HBO in patients with carbon mon
-
oxide poisoning include a history of loss of consciousness, 
CoHb greater than 25%, metabolic acidosis, age over 50 years, 
and cerebellar findings on neurologic examination.
Bleecker ML. Carbon monoxide intoxication. Handb Clin Neurol. 
2015;131:191–203. [PMID: 26563790]
Levy RJ. Anesthesia-related carbon monoxide exposure: toxicity 
and potential therapy. Anesth Analg. 2016 Sep;123(3):670–81. 
[PMID: 27537758]
Rose JJ et al. Carbon monoxide poisoning: pathogenesis, man
-
agement, and future directions of therapy. Am J Respir Crit 
Care Med. 2017 Mar 1;195(5):596–606. [PMID: 27753502]
Weaver LK. Hyperbaric oxygen therapy for carbon monoxide 
poisoning. Undersea Hyperb Med. 2014 Jul–Aug;41(4):339–4. 
[PMID: 25109087]
CHEMICAL WARFARE: NERVE AGENTS
Nerve agents used in chemical warfare work by cholinester
-
ase inhibition and are most commonly organophosphorus 
compounds. Agents such as 
tabun
 (GA), 
sarin
 (GB), 
soman
 
(GD), and 
VX
 are similar to insecticides such as malathion 
but are vastly more potent. They may be inhaled or absorbed 
through the skin. Systemic effects due to unopposed action of 
acetylcholine include miosis, salivation, abdominal cramps, 
diarrhea, and muscle paralysis producing respiratory arrest. 
Inhalation also produces severe bronchoconstriction and 
copious nasal and tracheobronchial secretions.
 
»
Treatment
Perform thorough decontamination of exposed areas with 
repeated soap and shampoo washing. Personnel caring for 
such patients must wear protective clothing and gloves, since 
cutaneous absorption may occur through normal skin.
Give atropine in an initial dose of 2 mg intravenously and 
repeat as needed to reverse signs of acetylcholine excess. 
(Some victims have required several hundred milligrams.) 
Treat also with the cholinesterase-reactivating agent prali
-
doxime, 1–2 g intravenously initially followed by an infu
-
sion at a rate of 200–400 mg/h.
Agency for Toxic Substances and Disease Registry. Toxic

-
-
Agency for Toxic Substances and Disease Registry. Toxic 
Substances Portal: Medical Management Guidelines for 
Nerve Agents: Tabun (GA); Sarin (GB); Soman (GD); and 
VX. October 21, 2014. https://www.atsdr.cdc.gov/mmg/
mmg.asp?id=523&tid=93
Candiotti K. A primer on nerve agents: what the emergency 
responder, anesthesiologist, and intensivist needs to know. 
Can J Anaesth. 2017 Oct;64(10):1059–70. [PMID: 28766156]
-
CHEMICAL WARFARE: RICIN
Ricin is a naturally occurring toxin found in minute quantities 
in the castor bean (
Ricinus communis
). It can cause toxicity if 
castor beans are thoroughly chewed or blenderized, although 
the quantity of ricin is small and it is poorly absorbed from the 
gastrointestinal tract, so symptoms following castor bean 
ingestion are usually limited to diarrhea and abdominal pain. 
Less commonly, severe gastroenteritis can lead to volume 
depletion and advanced chronic kidney disease. On the other 
hand, purified ricin is extremely toxic if administered paren
-
terally: the LD
50
 for injected ricin in animals is as low as 
 
0.1 mcg/kg. A fatal case of suspected ricin poisoning by homi
-
cidal injection of an estimated 0.28 mg of ricin was associated 
with diffuse organ damage and death from cardiac failure 
after 2 days. Inhalation of ricin powder has not been reported 
in humans, but animal studies suggest it could cause hemor
-
rhagic tracheobronchitis and pneumonia.
 
»
Treatment
After suspected ricin inhalation or exposure to powdered 
ricin, remove clothing and wash skin with water. Personnel 
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caring for such patients should wear protective respiratory 
gear, clothing, and gloves.
There is no known antidote or other specific treatment. 
 
A vaccine has been developed and has been granted an 
Orphan Drug designation by the FDA. Provide supportive 
care for volume loss due to gastroenteritis and cardiac and 
respiratory support as needed.
Centers for Disease Control and Prevention. Ricin: Diagnosis & 
Laboratory Guidance for Clinicians. https://emergency.cdc.
gov/agent/ricin/clinicians/diagnosis.asp
-
Kaland ME et al. Toxalbumin exposures: 12 years' experience of 
U.S. poison centers. Toxicon. 2015 Jun 1;99:125–9. [PMID: 
25817002]
CLONIDINE & OTHER SYMPATHOLYTIC 
ANTIHYPERTENSIVES
Overdosage with these agents (clonidine, guanabenz, 
guanfacine, methyldopa) causes bradycardia, hypotension, 
miosis, respiratory depression, and coma. (Transient 
hypertension occasionally occurs after acute overdosage, a 
result of peripheral alpha-adrenergic effects in high doses.) 
Symptoms are usually resolved in less than 24 hours, and 
deaths are rare. Similar symptoms may occur after inges
-
tion of topical nasal decongestants chemically similar to 
clonidine (oxymetazoline, tetrahydrozoline, naphazoline). 
Brimonidine and apraclonidine are used as ophthalmic 
preparations for glaucoma. Tizanidine is a centrally acting 
muscle relaxant structurally related to clonidine; it pro
-
duces similar toxicity in overdose.
 
»
Treatment
Give activated charcoal. Maintain the airway and sup
-
port respiration if necessary. Symptomatic treatment is 
usually sufficient even in massive overdose. Maintain 
blood pressure with intravenous fluids. Dopamine can 
also be used. Atropine is usually effective for 
There is no specific antidote. Although tolazoline has been 
recommended for clonidine overdose, its effects are unpre
-
dictable and it should not be used. Naloxone has been 
reported to be successful in a few anecdotal and poorly 
substantiated cases.
Isbister GK et al. Adult clonidine overdose: prolonged bradycar
-
dia and central nervous system depression, but not severe 
toxicity. Clin Toxicol (Phila). 2017 Mar;55(3):187–92. [PMID: 
28107093]
Lowry JA et al. Significance of the imidazoline receptors in toxi
-
cology. Clin Toxicol (Phila). 2014 Jun;52(5):454–69. [PMID: 
24666288]
Pomerleau AC et al. Dermal exposure to a compounded pain 
cream resulting in severely elevated clonidine concentration. 
J Med Toxicol. 2014 Mar;10(1):61–4. [PMID: 24129834]
COCAINE
See Amphetamines & Cocaine.
CYANIDE
Cyanide is a highly toxic chemical used widely in research 
and commercial laboratories and many industries. Its gas
-
eous form, hydrogen cyanide, is an important component 
of smoke in fires. Cyanide-generating glycosides are also 
found in the pits of apricots and other related plants. 
Cyanide is generated by the breakdown of nitroprusside, 
and poisoning can result from rapid high-dose infusions. 
Cyanide is also formed by metabolism of acetonitrile, a 
solvent found in some over-the-counter fingernail glue 
removers. Cyanide is rapidly absorbed by inhalation, skin 
absorption, or ingestion. It disrupts cellular function by 
inhibiting cytochrome oxidase and preventing cellular 
oxygen utilization.
 
»
The onset of toxicity is nearly instantaneous after inhala
-
tion of hydrogen cyanide gas but may be delayed for min
-
utes to hours after ingestion of cyanide salts or cyanogenic 
plants or chemicals. Effects include headache, dizziness, 
nausea, abdominal pain, and anxiety, followed by confu
-
sion, syncope, shock, seizures, coma, and death. The odor 
of “bitter almonds” may be detected on the victim’s breath

-
of “bitter almonds” may be detected on the victim’s breath 
or in vomitus, though this is not a reliable finding. The 
venous oxygen saturation may be elevated (greater 
than 90%) in severe poisonings because tissues have failed 
to take up arterial oxygen.
 
»
Treatment
Remove the victim from exposure, taking care to avoid 
exposure to rescuers. For suspected cyanide poisoning due 
to nitroprusside infusion, stop or slow the rate of infusion. 
(Metabolic acidosis and other signs of cyanide poisoning 
usually clear rapidly.)
For cyanide ingestion, administer activated charcoal. 
Although charcoal has a low affinity for cyanide, the usual 
doses of 60–100 g are adequate to bind typically ingested 
lethal doses (100–200 mg).
In the United States, there are two available cyanide anti
-
dote regimens. The conventional cyanide antidote package 
(Nithiodote) contains sodium nitrite (to induce methemo
-
globinemia, which binds free cyanide) and sodium thiosul
-
fate (to promote conversion of cyanide to the less toxic 
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thiocyanate). Administer 3% sodium nitrite solution, 10 mL 
intravenously followed by 25% sodium thiosulfate solution, 
50 mL intravenously (12.5 g). 
Caution:
 Nitrites may induce 
hypotension and dangerous levels of methemoglobin.
The other approved cyanide treatment in the 
United States is hydroxocobalamin (Cyanokit, EMD Phar
-
maceuticals), a newer and potentially safer antidote. The 
adult dose of hydroxocobalamin is 5 g intravenously (chil
-
dren’s dose is 70 mg/kg). 
Note:
 Hydroxocobalamin causes 
red discoloration of skin and body fluids that may last 
several days and can interfere with some laboratory tests.
Hamad E et al. Case files of the University of Massachusetts 
Toxicology Fellowship: does this smoke inhalation victim 
require treatment with cyanide antidote? J Med Toxicol. 
2016 Jun;12(2):192–8. [PMID: 26831054]
Udeh CI et al. Delayed presentation of nitroprusside-induced 
cyanide toxicity. Ann Thorac Surg. 2015 Apr;99(4):1432–4. 
[PMID: 25841829]
Zakharov S et al. Successful use of hydroxocobalamin and 
sodium thiosulfate in acute cyanide poisoning: a case report 
with follow-up. Basic Clin Pharmacol Toxicol. 2015 Sep; 
117(3):209–12. [PMID: 25645744]
DIETARY SUPPLEMENTS & 
 
HERBAL PRODUCTS
Unlike prescription and over-the-counter pharmaceuticals, 
dietary supplements do not require FDA approval, do not 
undergo the same premarketing evaluation of safety and 
efficacy as drugs, and purveyors may or may not adhere to 
good manufacturing practices and quality control 
standards. Supplements may cause illness as a result of 
intrinsic toxicity, misidentification or mislabeling, drug-herb 
reactions, or intentional adulteration with pharmaceuticals. 
If you suspect a dietary supplement or herbal product may 
be the cause of an otherwise unexplained illness, contact the 
FDA (1-888-463-6332) or the regional poison control center 
(1-800-222-1222), or consult one of the following online 
databases: and http://www.fda.gov/food/dietarysupplements/
default.htm.
Table 38–7 lists selected examples of clinical toxicity 
from some of these products.
Avigan MI et al. Scientific and regulatory perspectives in herbal 
and dietary supplement associated hepatotoxicity in the 
United States. Int J Mol Sci. 2016 Mar 3;17(3):331. [PMID: 
26950122]
Cohen PA et al. Presence of banned drugs in dietary supple
-
ments following FDA recalls. JAMA. 2014 Oct 22–29; 
312(16):1691–3. [PMID: 25335153]
Wong LL et al. Urgent liver transplantation for dietary supple
-
ments: an under-recognized problem. Transplant Proc. 2017 
Mar;49(2):322–5. [PMID: 28219592]
DIGITALIS & OTHER CARDIAC GLYCOSIDES
Cardiac glycosides paralyze the Na
+
-K
+
-ATPase pump and 
have potent vagotonic effects. Intracellular effects include 
enhancement of calcium-dependent contractility and 
shortening of the action potential duration. A number of 
plants (eg, oleander, foxglove, lily-of-the-valley) contain 
cardiac glycosides. Bufotenin, a cardiotoxic steroid found 
in certain toad secretions and used as an herbal medicine 
and a purported aphrodisiac, has pharmacologic proper
-
ties similar to cardiac glycosides.
 
»
Intoxication may result from acute single exposure or 
chronic accidental overmedication. After acute overdos
-
age, nausea and vomiting, bradycardia, hyperkalemia, and 
AV block frequently occur. Patients in whom toxicity 
develops gradually during long-term therapy may be 
Table 38–7.
 
Examples of potential toxicity associated with some dietary supplements and herbal medicines.
Product
Common Use
Possible Toxicity
Azarcon (Greta)
Mexican folk remedy for abdominal pain, colic
Contains lead
Comfrey
Gastric upset, diarrhea
Contains pyrrolizidine alkaloids, can cause hepatic 
 
veno-occlusive disease
Creatine
Athletic performance enhancement
Nausea, diarrhea, abdominal cramps; elevated serum 
Ginkgo
Memory improvement, tinnitus
Antiplatelet effects, hemorrhage; abdominal pain, diarrhea
Ginseng

Ginkgo
Ginseng
Immune system; stress
Decreased glucose; increased cortisol
Guarana
Athletic performance enhancement, appetite suppression
Contains caffeine: can cause tremor, tachycardia, vomiting
Kava
Anxiety, insomnia
Drowsiness, hepatitis, skin rash
Ma huang
Stimulant; athletic performance enhancement
Contains ephedrine: anxiety, insomnia, hypertension, 
tachycardia, seizures
Spirulina
Body building
Niacin-like flushing reaction
Yohimbine
Sexual enhancement
Hallucinations, hypertension, tachycardia
Zinc
Cold/flu symptoms
Nausea, oral irritation, anosmia
Adapted, with permission, from Table II-30 by Haller C in “Herbal and Alternative Products,” In: Olson KR (ed.) 
Poisoning & Drug Overdose,
 
6th edition. McGraw Hill, 2011.
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hypokalemic and hypomagnesemic owing to concurrent 
diuretic treatment and more commonly present with ven
-
tricular arrhythmias (eg, ectopy, bidirectional ventricular 
tachycardia, or ventricular fibrillation). Digoxin levels may 
be only slightly elevated in patients with intoxication from 
cardiac glycosides other than digoxin because of limited 
cross-reactivity of immunologic tests.
 
»
Treatment
After acute ingestion, administer activated charcoal. 
Monitor potassium levels and cardiac rhythm closely. 
Treat bradycardia initially with atropine (0.5–2 mg 
intravenously) or a transcutaneous external cardiac 
For patients with significant intoxication, administer 
digoxin-specific antibodies (digoxin immune Fab [ovine]; 
DigiFab). Estimation of the dose is based on the body bur
-
den of digoxin calculated from the ingested dose or the 
steady-state serum digoxin concentration, as described 
below. More effective binding of digoxin may be achieved 
if the dose is given partly as a bolus and the remainder as 
an infusion over a few hours.
1. From the ingested dose—
Number of vials = 
approximately 1.5–2 × ingested dose (mg).
2. From the serum concentration—
serum digoxin (ng/mL) × body weight (kg) × 10
–2
. 
 
Note:
 This is based on the equilibrium digoxin level; after 
acute overdose, serum levels may be falsely high for several 
hours before tissue distribution is complete, and overesti
-
mation of the DigiFab dose is likely.
3. Empiric dosing—
Empiric titration of DigiFab may be 
used if the patient’s condition is relatively stable and an 
underlying condition (eg, atrial fibrillation) favors retaining 
a residual level of digitalis activity. Start with one or two 
vials and reassess the patient’s clinical condition after 
20–30 minutes. For cardiac glycosides other than digoxin or 
digitoxin, there is no formula for estimation of vials needed 
and treatment is entirely based on response to empiric dosing.
Note:
 After administration of digoxin-specific Fab anti
-
body fragments, serum digoxin levels may be falsely ele
-
vated depending on the assay technique.
Chhabra N et al. Digoxin-specific antibody fragment dosing: a 
case series. Am J Ther. 2016 Nov/Dec;23(6):e1597–601. 
[PMID: 26057142]
Mowry JB et al. Extracorporeal treatment for digoxin poisoning: 
systematic review and recommendations from the EXTRIP 
Workgroup. Clin Toxicol (Phila). 2016;54(2):103–14. [PMID: 
26795743]
Nordt SP et al. Assessment of digoxin-specific Fab fragment dos
-
ages in digoxin poisoning. Am J Ther. 2016 Jan–Feb; 
23(1):e63–7. [PMID: 25379735]
Roberts DM et al. Pharmacological treatment of cardiac glyco
-
side poisoning. Br J Clin Pharmacol. 2016 Mar;81(3):488–95. 
[PMID: 26505271]
ETHANOL, BENZODIAZEPINES, & 
 
OTHER SEDATIVE-HYPNOTIC AGENTS
The group of agents known as sedative-hypnotic drugs 
includes a variety of products used for the treatment of 
anxiety, depression, insomnia, and epilepsy. Besides com
-
mon benzodiazepines, such as lorazepam, alprazolam, 
clonazepam, diazepam, oxazepam, chlordiazepoxide, and 
triazolam, this group includes the newer benzodiazepine-
like hypnotics zolpidem and zaleplon, and the muscle 
relaxant carisoprodol. Ethanol and other selected agents 
are also popular recreational drugs. All of these drugs 
depress the central nervous system reticular activating 
system, cerebral cortex, and cerebellum.
 
»
Mild intoxication produces euphoria, slurred speech, and 
ataxia. Ethanol intoxication may produce hypoglycemia, 
even at relatively low concentrations, in children and in 
fasting adults. With more severe intoxication, stupor, 
coma, and respiratory arrest may occur. Carisoprodol 
(Soma) commonly causes muscle jerking or myoclonus. 
Death or serious morbidity is usually the result of pulmo
-
nary aspiration of gastric contents. Bradycardia, hypoten
-

-
-
sion, and hypothermia are common. Patients with massive 
intoxication may appear to be dead, with no reflex 
responses and even absent electroencephalographic activ
-
ity. Diagnosis and assessment of severity of intoxication 
are usually based on clinical findings. Ethanol serum 
levels over 300 mg/dL (0.3 g/dL; 65 mmol/L) can produce 
coma in persons who are not chronically abusing the 
drug, but regular users may remain awake at much higher 
levels.
 
»
Treatment
Administer activated charcoal if the patient has ingested a 
massive dose and the airway is protected. Repeat-dose 
charcoal may enhance elimination of phenobarbital, but it 
has not been proved to improve clinical outcome. Hemodi
-
alysis may be necessary for patients with severe phenobar
-
bital intoxication.
Flumazenil is a benzodiazepine receptor-specific 
antagonist; it has no effect on ethanol, barbiturates, or 
other sedative-hypnotic agents. If used, flumazenil is 
given slowly intravenously, 0.2 mg over 30–60 seconds, 
and repeated in 0.2–0.5 mg increments as needed up to a 
total dose of 3–5 mg. 
Caution: 
Flumazenil should rarely 
be used because it may induce seizures in patients with 
preexisting seizure disorder, benzodiazepine addiction, or 
concomitant tricyclic antidepressant or other convulsant 
overdose
. If seizures occur, diazepam and other benzodi
-
azepine anticonvulsants will not be effective. As with 
naloxone, the duration of action of flumazenil is short 
(2–3 hours) and resedation may occur, requiring repeated 
doses.
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-
25666543]
Penninga EI et al. Adverse events associated with flumazenil 
treatment for the management of suspected benzodiazepine 
intoxication—a systematic review with meta-analyses of ran
-
domised trials. Basic Clin Pharmacol Toxicol. 2016 Jan; 
118(1):37–44. [PMID: 26096314]
Vallersnes OM et al. Patients presenting with acute poisoning 
[ethanol, heroin, benzodiazepines, amphetamine, fire smoke, 
gamma-hydroxybutyrate and cannabis] to an outpatient 
emergency clinic: a one-year observational study in Oslo, 
Norway. BMC Emerg Med. 2015 Aug 13;15:18. [PMID: 
26268351]
GAMMA-HYDROXYBUTYRATE (GHB)
GHB is a popular drug of abuse. It originated as a short-
 
acting general anesthetic and is occasionally used in the treat
-
ment of narcolepsy. It gained popularity among bodybuilders 
for its alleged growth hormone stimulation and found its way 
into social settings, where it is consumed as a liquid. It has 
been used to facilitate sexual assault (“date-rape” drug). 
Symptoms after ingestion include drowsiness and lethargy 
followed by coma with respiratory depression. Muscle twitch
-
ing and seizures are sometimes observed. Recovery is usually 
rapid, with patients awakening within a few hours. Other 
related chemicals with similar effects include butanediol and 
gamma-butyrolactone (GBL). A prolonged withdrawal syn
-
drome has been described in some heavy users.
 
»
Treatment
Monitor the airway and assist breathing if needed. There is 
no specific treatment. Most patients recover rapidly with sup
-
portive care. GHB withdrawal syndrome may require very 
large doses of benzodiazepines; baclofen has also been used.
Liakoni E et al. Presentations to an urban emergency depart
-
ment in Switzerland due to acute γ-hydroxybutyrate toxicity. 
Scand J Trauma Resusc Emerg Med. 2016 Aug 31;24(1):107. 
[PMID: 27581664]
Lingford-Hughes A et al. Improving GHB withdrawal with 
baclofen: study protocol for a feasibility study for a ran
-
domised controlled trial. Trials. 2016 Sep 27;17(1):472. 
[PMID: 27677382]
Miró Ò et al. Intoxication by gamma hydroxybutyrate and 
related analogues: clinical characteristics and comparison 
between pure intoxication and that combined with other 
substances of abuse. Toxicol Lett. 2017 Aug 5;277:84–91. 
[PMID: 28579487]
HYPOGLYCEMIC DRUGS
Medications used for diabetes mellitus include insulin, 
sulfonylureas and other insulin secretagogues, alpha-
glucosidase inhibitors (acarbose, miglitol), biguanides 
(metformin), thiazolidinediones (pioglitazone, rosigli
-
tazone), and peptide analogs (pramlintide, exenatide) or 
enhancers (sitagliptin) (see Chapter 27). Of these, insulin 
and the insulin secretagogues are the most likely to cause 
hypoglycemia. Metformin can cause lactic acidosis, espe
-
cially in patients with impaired kidney function or after 
intentional drug overdose. Table 27–5 lists the duration of 
hypoglycemic effect of oral hypoglycemic agents and Table 
27–6 the extent and duration of various types of insulins.
 
»
Hypoglycemia may occur quickly after injection of short-
acting insulins or may be delayed and prolonged, especially 
if a large amount has been injected into a single area, creat
-
ing a “depot” effect. Hypoglycemia after sulfonylurea inges
-
tion is usually apparent within a few hours but may be 
delayed several hours, especially if food or glucose-
containing fluids have been given.
 
»
Treatment
Give sugar and carbohydrate-containing food or liquids by 
mouth, or intravenous dextrose if the patient is unable to 
swallow safely. For severe hypoglycemia, start with D50W , 
 
50 mL intravenously (25 g dextrose); repeat, if needed. Follow 
up with dextrose-containing intravenous fluids (D5W or 
D10W) to maintain a blood glucose greater than 70–80 mg/dL.
For hypoglycemia caused by sulfonylureas and related

For hypoglycemia caused by sulfonylureas and related 
insulin secretagogues, consider use of octreotide, a syn
-
thetic somatostatin analog that blocks pancreatic insulin 
release. A dose of 50–100 mcg octreotide subcutaneously 
every 6–12 hours can reduce the need for exogenous dex
-
trose and prevent rebound hypoglycemia from excessive 
dextrose dosing.
Admit all patients with symptomatic hypoglycemia 
after sulfonylurea overdose. Observe asymptomatic over
-
dose patients for at least 12 hours.
Consider hemodialysis for patients with metformin 
overdose accompanied by severe lactic acidosis (lactate 
greater than 20 mmol/L or pH < 7.0).
Calello DP et al. Extracorporeal treatment for metformin poi
-
soning: systematic review and recommendations from the 
extracorporeal treatments in poisoning workgroup. Crit Care 
Med. 2015 Aug;43(8):1716–30. [PMID: 25860205]
Elling R et al. Prolonged hypoglycemia after a suicidal ingestion 
of repaglinide with unexpected slow plasma elimination. Clin 
Toxicol (Phila). 2016;54(2):158–60. [PMID: 26692235]
Klein-Schwartz W et al. Treatment of sulfonylurea and insulin 
overdose. Br J Clin Pharmacol. 2016 Mar;81(3):496–504. 
[PMID: 26551662]
ISONIAZID
INH is an antibacterial drug used mainly in the treatment 
and prevention of tuberculosis. It may cause hepatitis with 
long-term use, especially in alcoholic patients and elderly 
persons. It produces acute toxic effects by competing with 
pyridoxal 5-phosphate, resulting in lowered brain gamma-
aminobutyric acid (GABA) levels. Acute ingestion of as little 
as 1.5–2 g of INH can cause toxicity, and severe poisoning is 
likely to occur after ingestion of more than 80–100 mg/kg.
 
»
Confusion, slurred speech, and seizures may occur abruptly 
after acute overdose. Severe lactic acidosis—out of 
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proportion to the severity of seizures—is probably due to 
inhibited metabolism of lactate. Peripheral neuropathy and 
acute hepatitis may occur with long-term use.
Diagnosis is based on a history of ingestion and the 
presence of severe acidosis associated with seizures. INH is 
not usually included in routine toxicologic screening, and 
serum levels are not readily available.
 
»
Treatment
Seizures may require higher than usual doses of benzodiaz
-
epines (eg, lorazepam, 3–5 mg intravenously) or adminis
-
tration of pyridoxine as an antidote.
Administer activated charcoal after large recent inges
-
tion, but with caution because of the risk of abrupt onset of 
seizures.
6
) is a specific antagonist of the acute 
toxic effects of INH and is usually successful in controlling 
convulsions that do not respond to benzodiazepines. Give 
 
5 g intravenously over 1–2 minutes or, if the amount 
ingested is known, give a gram-for-gram equivalent amount 
of pyridoxine. Patients taking INH are usually given 25–50 mg 
of pyridoxine orally daily to help prevent neuropathy.
Gray EL et al. Baseline abnormal liver function tests are more 
important than age in the development of isoniazid-induced 
hepatoxicity for patients receiving preventive therapy for 
latent tuberculosis infection. Intern Med J. 2016 Mar; 
46(3):281–7. [PMID: 26648478]
Li X et al. Liver transplantation in antituberculosis drugs-
induced fulminant hepatic failure: a case report and review of 
the literature. Medicine (Baltimore). 2015 Dec;94(49):e1665. 
[PMID: 26656321]
Miyazawa S et al. Isoniazid-induced acute liver failure during 
preventive therapy for latent tuberculosis infection. Intern 
Med. 2015;54(6):591–5. [PMID: 25786447]
Skinner K et al. Isoniazid poisoning: pharmacokinetics and 
effect of hemodialysis in a massive ingestion. Hemodial Int. 
2015 Oct;19(4):E37–40. [PMID: 25779481]
LEAD
Lead is used in a variety of industrial and commercial 
products, such as firearms ammunition, storage batteries, 
solders, paints, pottery, plumbing, and gasoline and is 
found in some traditional Hispanic and Ayurvedic ethnic 
medicines. Lead toxicity usually results from chronic 
repeated exposure and is rare after a single ingestion. Lead 
produces a variety of adverse effects on cellular function 
and primarily affects the nervous system, gastrointestinal 
tract, and hematopoietic system.
 
»
Lead poisoning often goes undiagnosed initially because 
presenting symptoms and signs are nonspecific and expo
-
sure is not suspected. Common symptoms include colicky 
abdominal pain, constipation, headache, and irritability. 
Severe poisoning may cause coma and convulsions. 
Chronic intoxication can cause learning disorders (in 
children) and motor neuropathy (eg, wrist drop). Lead-
containing bullet fragments in or near joint spaces can 
result in chronic lead toxicity.
Diagnosis is based on measurement of the blood lead 
level. Whole blood lead levels above 5 mcg/dL warrant pub
-
lic health investigation. Levels between 10 and 25 mcg/dL 
have been associated with impaired neurobehavioral devel
-
opment in children. Levels of 25–50 mcg/dL may be associ
-
ated with headache, irritability, and subclinical neuropathy. 
Levels of 50–70 mcg/dL are associated with moderate toxic
-
ity, and levels greater than 70–100 mcg/dL are often associ
-
ated with severe poisoning. Other laboratory findings of 
lead poisoning include microcytic anemia with basophilic 
stippling and elevated free erythrocyte protoporphyrin.
 
»
Treatment
For patients with encephalopathy, maintain a patent airway 
and treat coma and convulsions as described at the begin
-
For recent acute ingestion, if a large lead-containing 
object (eg, fishing weight) is still visible in the stomach on

-
object (eg, fishing weight) is still visible in the stomach on 
abdominal radiograph, whole bowel irrigation, endoscopy, 
or even surgical removal may be necessary to prevent sub
-
acute lead poisoning. (The acidic gastric contents may 
corrode the metal surface, enhancing lead absorption. 
Once the object passes into the small intestine, the risk of 
toxicity declines.)
Conduct an investigation into the source of the lead 
exposure.
Workers with a single lead level over 60 mcg/dL (or 
three successive monthly levels greater than 50 mcg/dL) or 
construction workers with any single blood lead level 
above 50 mcg/dL must by federal law be removed from the 
site of exposure. Contact the regional office of the United 
States Occupational Safety and Health Administration 
(OSHA) for more information. Several states mandate 
reporting of cases of confirmed lead poisoning.
The indications for chelation depend on the blood lead 
level and the patient’s clinical state. A medical toxicologist 
or regional poison control center (1-800-222-1222) should 
be consulted for advice about selection and use of these 
antidotes.
Note:
 It is impermissible under the law to treat asymp
-
tomatic workers with elevated blood lead levels in order to 
keep their levels under 50 mcg/dL rather than remove 
them from the exposure.
1. Severe toxicity—
Patients with severe intoxication 
(encephalopathy or levels greater than 70–100 mcg/dL) 
should receive edetate calcium disodium (ethylenediami
-
netetraacetic acid, EDTA), 1500 mg/m
2
/kg/day (approxi
-
mately 50 mg/kg/day) in four to six divided doses or as a 
continuous intravenous infusion. Most clinicians also add 
dimercaprol (BAL), 4–5 mg/kg intramuscularly every 
 
4 hours for 5 days, for patients with encephalopathy.
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2. Less severe toxicity—
Patients with less severe symp
-
toms and asymptomatic patients with blood lead levels 
between 55 and 69 mcg/dL may be treated with edetate 
calcium disodium alone in dosages as above. An oral chela
-
tor, succimer (DMSA), is available for use in patients with 
mild to moderate intoxication. The usual dose is 10 mg/kg 
orally every 8 hours for 5 days, then every 12 hours for 
 
2 weeks.
Gidlow DA. Lead toxicity. Occup Med (Lond). 2015 
Jul;65(5):348–56. Erratum in: Occup Med (Lond). 2015 Dec; 
65(9):770. [PMID: 26187801]
Laidlaw MA et al. Lead exposure at firing ranges--a review. 
Environ Health. 2017 Apr 4;16(1):34. [PMID: 28376827]
Mehta V et al. Lead intoxication due to ayurvedic medications as 
a cause of abdominal pain in adults. Clin Toxicol (Phila). 2016 
Dec 13:1–5. [PMID: 27957879]
Orchard GR et al. Lead poisoning in Australia associated with 
privately imported Ayurvedic complementary medicine. 
Anaesth Intensive Care. 2015 Sep;43(5):669–70. [PMID: 
26310426]
LITHIUM
Lithium is widely used for the treatment of bipolar depres
-
sion and other psychiatric disorders. The only normal route 
of lithium elimination is via the kidney, so patients with 
acute or chronic kidney disorders are at risk for accumula
-
tion of lithium resulting in gradual onset (chronic) toxicity. 
Intoxication resulting from chronic accidental overmedica
-
tion or kidney impairment is more common and usually 
more severe than that seen after acute oral overdose.
 
»
Mild to moderate toxicity causes lethargy, confusion, tremor, 
ataxia, and slurred speech. This may progress to myoclonic 
jerking, delirium, coma, and convulsions. Recovery may be 
slow and incomplete following severe intoxication. 
Laboratory studies in patients with chronic intoxication 
often reveal an elevated serum creatinine and an elevated 
BUN/creatinine ratio due to underlying volume contraction. 
The white blood cell count is often elevated. ECG findings 
include T-wave flattening or inversion, and sometimes bra
-
dycardia or sinus node arrest. Nephrogenic diabetes insipi
-
dus can occur with overdose or with therapeutic doses.
Lithium levels may be difficult to interpret. Lithium has 
a low toxic: therapeutic ratio and chronic intoxication can 
be seen with levels only slightly above the therapeutic 
range (0.8–1.2 mEq/L). In contrast, patients with acute 
ingestion may have transiently very high levels (up to 
 
10 mEq/L reported) without any symptoms before the 
lithium fully distributes into tissues. 
Note:
 Falsely high 
lithium levels (as high as 6–8 mEq/L) can be measured if a 
green-top blood specimen tube (containing lithium 
heparin) is used for blood collection.
 
»
Treatment
After acute oral overdose, consider gastric lavage or whole 
bowel irrigation to prevent systemic absorption (
Note:
 
lithium is not adsorbed by activated charcoal). In all 
patients, evaluate kidney function and volume status, and 
give intravenous saline-containing fluids as needed. Moni
-
tor serum lithium levels and seek assistance with their 
interpretation and the need for dialysis from a medical toxi
-
cologist or regional poison control center (1-800-222-
1222). Consider hemodialysis if the patient is markedly 
symptomatic or if the serum level exceeds 4–5 mEq/L, 
especially if kidney function is impaired. Continuous renal 
replacement therapy may be an effective alternative to 
Decker BS et al. Extracorporeal treatment for lithium poisoning: 
Workgroup. Clin J Am Soc Nephrol. 2015 May 7;10(5):875–87. 
[PMID: 25583292]
Gitlin M. Lithium side effects and toxicity: prevalence and man
-
agement strategies. Int J Bipolar Disord. 2016 Dec;4(1):27. 
[PMID: 27900734]
Gong R et al. What we need to know about the effect of lithium 
on the kidney. Am J Physiol Renal Physiol. 2016 Dec 1; 
311(6):F1168–71. [PMID: 27122541]

Lavonas EJ et al. Hemodialysis for lithium poisoning. Cochrane 
Database Syst Rev. 2015 Sep 16;9:CD007951. [PMID: 
26374731]
LSD & OTHER HALLUCINOGENS
A variety of substances—ranging from naturally occurring 
plants and mushrooms to synthetic substances such as 
phencyclidine (PCP), toluene and other solvents, dextro
-
methorphan, and lysergic acid diethylamide (LSD)—are 
abused for their hallucinogenic properties. The mechanism 
of toxicity and the clinical effects vary for each substance.
Many hallucinogenic plants and mushrooms produce 
anticholinergic delirium, characterized by flushed skin, dry 
mucous membranes, dilated pupils, tachycardia, and uri
-
nary retention. Other plants and mushrooms may contain 
hallucinogenic indoles such as mescaline and LSD, which 
typically cause marked visual hallucinations and perceptual 
distortion, widely dilated pupils, and mild tachycardia. PCP , 
a dissociative anesthetic agent similar to ketamine, can pro
-
duce fluctuating delirium and coma, often associated with 
vertical and horizontal nystagmus. Toluene and other 
hydrocarbon solvents (butane, trichloroethylene, “chemo, ” 
etc) cause euphoria and delirium and may sensitize the 
myocardium to the effects of catecholamines, leading to 
fatal dysrhythmias. Other drugs used for their psychostim
-
ulant effects include synthetic cannabinoid receptor 
agonists, 
Salvia divinorum
, synthetic tryptamines, and 
phenylethylamines, and mephedrone and related cathinone 
derivatives. See www.erowid.org for very thorough descrip
-
tions of a variety of hallucinogenic substances.
 
»
Treatment
Maintain a patent airway and assist respirations if neces
-
sary. Treat coma, hyperthermia, hypertension, and seizures 
as outlined at the beginning of this chapter. For recent large 
ingestions, consider giving activated charcoal orally or by 
gastric tube.
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Patients with anticholinergic delirium may benefit from a 
dose of physostigmine, 0.5–1 mg intravenously, not to 
exceed 1 mg/min. Dysphoria, agitation, and psychosis 
associated with LSD or mescaline intoxication may respond 
to benzodiazepines (eg, lorazepam, 1–2 mg orally or intra
-
venously) or haloperidol (2–5 mg intramuscularly or intra
-
venously) or another antipsychotic drug (eg, olanzapine or 
ziprasidone). Monitor patients who have sniffed solvents 
for cardiac dysrhythmias (most commonly premature ven
-
tricular contractions, ventricular tachycardia, ventricular 
fibrillation); treatment with beta-blockers such as propran
-
olol (1–5 mg intravenously) or esmolol (250–500 mcg/kg 
intravenously, then 50 mcg/kg/min by infusion) may be 
more effective than lidocaine or amiodarone.
Araújo AM et al. The hallucinogenic world of tryptamines: an 
updated review. Arch Toxicol. 2015 Aug;89(8):1151–73. 
[PMID: 25877327]
Bäckberg M et al. Phencyclidine analog use in Sweden—
intoxication cases involving 3-MeO-PCP and 4-MeO-PCP 
from the STRIDA project. Clin Toxicol (Phila). 2015 Nov; 
53(9):856–64. [PMID: 26295489]
MERCURY
Mercury poisoning may occur by ingestion of inorganic mer
-
curic salts, organic mercury compounds, or inhalation of 
metallic mercury vapor. Ingestion of the mercuric salts causes 
a burning sensation in the throat, discoloration and edema of 
oral mucous membranes, abdominal pain, vomiting, bloody 
diarrhea, and shock. Direct nephrotoxicity causes acute 
kidney injury. Inhalation of high concentrations of metallic 
mercury vapor may cause acute fulminant chemical 
pneumonia. Chronic mercury poisoning causes weakness, 
ataxia, intention tremors, irritability, and depression. 
Exposure to alkyl (organic) mercury derivatives from highly 
contaminated fish or fungicides used on seeds has caused 
ataxia, tremors, convulsions, and catastrophic birth defects. 
Nearly all fish have some traces of mercury contamination; 
the US Environmental Protection Agency (EPA) advises 
consumers to avoid swordfish, shark, king mackerel, and 
tilefish because they contain higher levels. Fish and shellfish 
that are generally low in mercury content include shrimp, 
canned light tuna (not albacore “white” tuna), salmon, pol
-
lock, and catfish. Dental fillings composed of mercury amal
-
gam pose a very small risk of chronic mercury poisoning and 
their removal is rarely justified. Some imported skin lighten
-
ing creams contain toxic quantities of mercury.
 
»
Treatment
A. Acute Poisoning
There is no effective specific treatment for mercury vapor 
pneumonitis. Remove ingested mercuric salts by lavage 
and administer activated charcoal. For acute ingestion of 
mercuric salts, give dimercaprol (BAL) at once, as for arse
-
nic poisoning. Unless the patient has severe gastroenteritis, 
consider succimer (DMSA), 10 mg/kg orally every 8 hours 
for 5 days and then every 12 hours for 2 weeks. Unithiol 
(DMPS) is a chelator that can be given orally or parenter
-
ally but is not commonly available in the United States; it 
can be obtained from some compounding pharmacies. 
Maintain urinary output. Treat oliguria and anuria if they 
occur.
B. Chronic Poisoning
Remove from exposure. Neurologic toxicity is not consid
-
ered reversible with chelation, although some authors rec
-
ommend a trial of succimer or unithiol (contact a regional 
poison center or medical toxicologist for advice).
Budnik LT et al. Alternative drugs go global: possible lead and/ 
or mercury intoxication from imported natural health prod
-
ucts and a need for scientifically evaluated poisoning moni
-
toring from environmental exposures. J Occup Med Toxicol. 
2016 Nov 8;11:49. [PMID: 27833648]
Mo T et al. Mercury poisoning caused by Chinese folk prescrip
-
tion (CFP): a case report and analysis of both CFP and 
quackery. Medicine (Baltimore). 2016 Nov;95(44):e5162. 
[PMID: 27858849]

-
Pelclova D et al. Is chelation therapy efficient for the treatment 
of intravenous metallic mercury intoxication? Basic Clin 
Pharmacol Toxicol. 2017 Jun;120(6):628–33. [PMID: 
27911474]
METHANOL & ETHYLENE GLYCOL
Methanol (wood alcohol) is commonly found in a variety of 
products, including solvents, duplicating fluids, record 
cleaning solutions, and paint removers. It is sometimes 
ingested intentionally by alcoholic patients as a substitute for 
ethanol and may also be found as a contaminant in bootleg 
whiskey. Ethylene glycol is the major constituent in most 
antifreeze compounds. The toxicity of both agents is caused 
by metabolism to highly toxic organic acids—methanol to 
formic acid; ethylene glycol to glycolic and oxalic acids. 
Diethylene glycol is a nephrotoxic solvent that has been 
improperly substituted for glycerine in various liquid medi
-
cations (cough syrup, teething medicine, acetaminophen), 
causing numerous deaths in Haiti, Panama, and Nigeria.
 
»
Shortly after ingestion of methanol or ethylene glycol, 
patients usually appear “drunk. ” The serum osmolality 
(measured with the freezing point device) is usually 
increased, but acidosis is often absent early. After several 
hours, metabolism to toxic organic acids leads to a severe 
anion gap metabolic acidosis, tachypnea, confusion, con
-
vulsions, and coma. Methanol intoxication frequently 
causes visual disturbances, while ethylene glycol often 
produces oxalate crystalluria and acute kidney injury. 
Note:
 Point-of-care analytical devices common used in the 
emergency department may falsely measure glycolic acid 
 
(a toxic metabolite of ethylene glycol) as lactic acid.
 
»
Treatment
For patients presenting within 30–60 minutes after inges
-
tion, empty the stomach by aspiration through a 
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nasogastric tube. Charcoal is not very effective but should 
be administered if other poisons or drugs have also been 
ingested.
Patients with significant toxicity (manifested by severe 
metabolic acidosis, altered mental status, and markedly 
elevated osmol gap) should undergo hemodialysis as soon 
as possible to remove the parent compound and the toxic 
metabolites. Treatment with folic acid, thiamine, and pyri
-
doxine may enhance the breakdown of toxic metabolites.
Ethanol blocks metabolism of the parent compounds by 
competing for the enzyme alcohol dehydrogenase. 
Fomepizole (4-methylpyrazole; Antizol) blocks alcohol 
dehydrogenase and is much easier to use than ethanol. If 
started before onset of acidosis, fomepizole may be used as 
the sole treatment for ethylene glycol ingestion in some 
cases. A regional poison control center (1-800-222-1222) 
should be contacted for indications and dosing.
Beauchamp GA et al. Toxic alcohol ingestion: prompt recogni
-
tion and management in the emergency department. Emerg 
Med Pract. 2016 Sep;18(9):1–20. [PMID: 27538060]
Imam YZ et al. Neurological manifestation of recreational fatal 
and near-fatal diethylene glycol poisonings: case series and 
review of literature. Medicine (Baltimore). 2014 Aug; 
93(10):e62. [PMID: 25170933]
Roberts DM et al. Recommendations for the role of extracorpo
-
real treatments in the management of acute methanol 
poisoning: a systematic review and consensus statement. Crit 
Care Med. 2015 Feb;43(2):461–72. [PMID: 25493973]
Thanacoody RH et al. Management of poisoning with ethylene 
glycol and methanol in the UK: a prospective study con
-
ducted by the National Poisons Information Service (NPIS). 
Clin Toxicol (Phila). 2016;54(2):134–40. [PMID: 26594941]
Zakharov S et al. Long-term visual damage after acute methanol 
poisonings: longitudinal cross-sectional study in 50 patients. 
Clin Toxicol (Phila). 2015 Nov;53(9):884–92. [PMID: 
26364866]
METHEMOGLOBINEMIA-INDUCING AGENTS
A large number of chemical agents are capable of oxidizing 
ferrous hemoglobin to its ferric state (methemoglobin), a 
form that cannot carry oxygen. Drugs and chemicals 
known to cause methemoglobinemia include benzocaine 
(a local anesthetic found in some topical anesthetic sprays 
and a variety of nonprescription products), aniline, propa
-
nil (an herbicide), nitrites, nitrogen oxide gases, nitroben
-
zene, dapsone, phenazopyridine (Pyridium), and many 
others. Dapsone has a long elimination half-life and may 
produce prolonged or recurrent methemoglobinemia.
 
»
Methemoglobinemia reduces oxygen-carrying capacity and 
may cause dizziness, nausea, headache, dyspnea, confusion, 
seizures, and coma. The severity of symptoms depends on 
the percentage of hemoglobin oxidized to methemoglobin; 
severe poisoning is usually present when methemoglobin 
fractions are greater than 40–50%. Even at low levels 
 
(15–20%), victims appear cyanotic because of the 
“chocolate brown” color of methemoglobin, but they have 
normal PO
2
 results on arterial blood gas determinations. 
Conventional pulse oximetry gives inaccurate oxygen satura
-
tion measurements; the reading is often between 85% and 
90%. (A newer pulse oximetry device [Masimo Pulse CO-
oximeter] is capable of estimating the methemoglobin level.) 
Severe metabolic acidosis may be present. Hemolysis may 
occur, especially in patients susceptible to oxidant stress (ie, 
those with glucose-6-phosphate dehydrogenase deficiency).
 
»
Treatment
Administer high-flow oxygen. If the causative agent was 
recently ingested, administer activated charcoal. Repeat-
dose activated charcoal may enhance dapsone 
elimination.
Methylene blue enhances the conversion of methemoglo
-
bin to hemoglobin by increasing the activity of the 
enzyme methemoglobin reductase. For symptomatic

-
enzyme methemoglobin reductase. For symptomatic 
patients, administer 1–2 mg/kg (0.1–0.2 mL/kg of 1% 
solution) intravenously. The dose may be repeated once 
in 15–20 minutes if necessary. Patients with hereditary 
methemoglobin reductase deficiency or glucose-
6-phosphate dehydrogenase deficiency may not respond 
to methylene blue treatment. In severe cases where 
methylene blue is not available or is not effective, exchange 
blood transfusion may be necessary.
Kim YJ et al. Difference of the clinical course and outcome 
between dapsone-induced methemoglobinemia and other 
toxic-agent-induced methemoglobinemia. Clin Toxicol 
(Phila). 2016 Aug;54(7):581–4. [PMID: 27412886.]
Messmer AS et al. P-chloroaniline poisoning causing methemo
-
globinemia: a case report and review of the literature. Case 
Rep Emerg Med. 2015;2015:208732. [PMID: 25861488]
Salim SA et al. Upward trend of dapsone-induced methemoglo
-
binemia in renal transplant community. Clin Nephrol. 
2017 Sep;88(9):156–61. [PMID: 28699887]
Sewell CR et al. A case report of benzocaine-induced methemo
-
globinemia. J Pharm Pract. 2017 Jan 1:897190017723211. 
[PMID: 28803519]
MUSHROOMS
There are thousands of mushroom species that cause a 
variety of toxic effects. The most dangerous species of 
mushrooms are 
 and related species, 
which contain potent cytotoxins (amatoxins). Ingestion of 
even a portion of one amatoxin-containing mushroom 
may be sufficient to cause death.
The characteristic pathologic finding in fatalities from 
amatoxin-containing mushroom poisoning is acute mas
-
sive necrosis of the liver.
 
»
Amatoxin-containing mushrooms typically cause a delayed 
onset (8–12 hours after ingestion) of severe abdominal 
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cramps, vomiting and profuse diarrhea, followed in 
1–2 days by acute kidney injury, hepatic necrosis, and 
hepatic encephalopathy. Cooking the mushrooms does not 
prevent poisoning.
Monomethylhydrazine poisoning (
Gyromitra
 and 
Helvella
 species) is more common following ingestion of 
uncooked mushrooms, as the toxin is water-soluble. Vom
-
iting, diarrhea, hepatic necrosis, convulsions, coma, and 
hemolysis may occur after a latent period of 8–12 hours.
 
»
Treatment
After the onset of symptoms, efforts to remove the toxic agent 
are probably useless, especially in cases of amatoxin or 
gyromitrin poisoning, where there is usually a delay of 
8–12 hours or more before symptoms occur and patients seek 
medical attention. However, activated charcoal is recom
-
mended for any recent ingestion of an unidentified or poten
-
tially toxic mushroom. Administer intravenous fluids 
liberally to replace massive losses from vomiting and diar
-
rhea; monitor central venous pressure, urinary output, and 
kidney function tests to help guide volume replacement.
A variety of purported antidotes (eg, thioctic acid, 
penicillin, corticosteroids) have been suggested for ama
-
toxin-type mushroom poisoning, but controlled studies are 
lacking and experimental data in animals are equivocal. 
Aggressive fluid replacement for diarrhea and intensive 
supportive care for hepatic failure are the mainstays of 
treatment. Silymarin (silibinin), a derivative of milk thistle, 
is commonly used in Europe, but is currently commercially 
available only in the United States as an oral nutritional 
supplement. The European intravenous product (Legalon-
SIL) can be obtained in the United States under an emergency 
IND provided by the FDA. Contact the regional poison 
control center (1-800-222-1222) for more information.
Liver transplant may be the only hope for survival in 
gravely ill patients—contact a liver transplant center early.
Bonacini M et al. Features of patients with severe hepatitis due to 
mushroom poisoning and factors associated with outcome. 
Clin Gastroenterol Hepatol. 2017 May;15(5):776–9. [PMID: 
28189696]
Garcia J et al. poisoning: mechanisms of toxicity and treat
-
ment. Food Chem Toxicol. 2015 Dec;86:41–55. [PMID: 
26375431]
Karvellas CJ et al; United States Acute Liver Failure Study Group. 
Acute liver injury and acute liver failure from mushroom 
poisoning in North America. Liver Int. 2016 Jul;36(7):1043–50. 
[PMID: 26837055]
Kim T et al. Predictors of poor outcomes in patients with wild 
mushroom-induced acute liver injury. World J Gastroenterol. 
2017 Feb 21;23(7):1262–7. [PMID: 28275306]
OPIATES & OPIOIDS
Prescription and illicit opiates and opioids (morphine, 
heroin, codeine, oxycodone, fentanyl, hydromorphone, 
etc) are popular drugs of misuse and abuse and the cause of 
frequent hospitalizations for overdose. These drugs have 
widely varying potencies and durations of action; for 
example, some of the illicit fentanyl derivatives are up to 
2000 times more potent than morphine. All of these agents 
decrease central nervous system activity and sympathetic 
outflow by acting on opiate receptors in the brain. Tramadol 
is an analgesic that is unrelated chemically to the opioids 
but acts on opioid receptors. Buprenorphine is a partial 
agonist-antagonist opioid used for the outpatient treatment 
of opioid addiction.
 
»
Mild intoxication is characterized by euphoria, drowsiness, 
and constricted pupils. More severe intoxication may cause 
hypotension, bradycardia, hypothermia, coma, and respi
-
ratory arrest. Pulmonary edema may occur. Death is usu
-
ally due to apnea or pulmonary aspiration of gastric 
contents. Methadone may cause QT interval prolongation 
and torsades de pointes. While the duration of effect for 
heroin is usually 3–5 hours, methadone intoxication may 
last for 48–72 hours or longer. Tramadol, dextrometho
-

-
rphan, and meperidine also occasionally cause seizures. 
With meperidine, the metabolite normeperidine is proba
-
bly the cause of seizures and is most likely to accumulate 
with repeated dosing in patients with chronic kidney dis
-
ease. Propoxyphene prolongs the QRS interval and may 
cause seizures; it is no longer available in the United States. 
Wound botulism has been associated with skin-popping, 
especially involving “black tar” heroin. Buprenorphine 
added to an opioid regimen may produce acute narcotic 
withdrawal symptoms. Many opioids, including fentanyl, 
tramadol, oxycodone, and methadone, are not detected on 
routine urine toxicology “opiate” screening.
 
»
Treatment
Protect the airway and assist ventilation. Administer acti
-
vated charcoal for recent large ingestions.
Naloxone is a specific opioid antagonist that can rapidly 
reverse signs of narcotic intoxication. Although it is structur
-
ally related to the opioids, it has no agonist effects of its own. 
Administer 0.2–2 mg intravenously and repeat as needed to 
awaken the patient and maintain airway protective reflexes 
and spontaneous breathing. Very large doses (10–20 mg) 
may be required for patients intoxicated by some opioids (eg, 
codeine, fentanyl derivatives). 
Caution:
 The duration of 
effect of naloxone is only about 2–3 hours; repeated doses 
may be necessary for patients intoxicated by long-acting 
drugs such as methadone. Continuous observation for at 
least 3 hours after the last naloxone dose is mandatory.
Alford DP et al. JAMA patient page. Misuse of opioid medication. 
JAMA. 2013 May 15;309(19):2055. [PMID: 23677318]
Dowell D et al. CDC Guideline for prescribing opioids for 
chronic pain—United States, 2016. JAMA. 2016 Apr 19; 
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Lozier MJ et al. Acetyl fentanyl, a novel fentanyl analog, causes 
14 overdose deaths in Rhode Island, March–May 2013. J Med 
Toxicol. 2015 Jun;11(2):208–17. [PMID: 25934111]
Rudd RA et al. Increases in drug and opioid overdose deaths—
United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 
2016 Jan 1;64(50–51):1378–82. [PMID: 26720857]
Schneir A et al. Near death from a novel synthetic opioid labeled 
U-47700: emergence of a new opioid class. Clin Toxicol 
(Phila). 2017 Jan;55(1):51–4. [PMID: 27448790]
Srivastava A et al. Primary care management of opioid use 
disorders: abstinence, methadone, or buprenorphine-
naloxone? Can Fam Physician. 2017 Mar;63(3):200–5. 
[PMID: 28292795]
Vignali C et al. Methadone-related deaths. A ten year overview. 
Forensic Sci Int. 2015 Dec;257:172–6. [PMID: 26360592]
PESTICIDES: CHOLINESTERASE INHIBITORS
Organophosphorus and carbamate insecticides (organo
-
phosphates: parathion, malathion, etc; carbamates: carbaryl, 
aldicarb, etc) are widely used in commercial agriculture and 
home gardening and have largely replaced older, more envi
-
ronmentally persistent organochlorine compounds such as 
DDT and chlordane. The organophosphates and carbamates—
also called anticholinesterases because they inhibit the 
enzyme acetylcholinesterase—cause an increase in acetyl
-
choline activity at nicotinic and muscarinic receptors and in 
the central nervous system. There are a variety of chemical 
agents in this group, with widely varying potencies. Most of 
them are poorly water-soluble, are often formulated with an 
aromatic hydrocarbon solvent such as xylene and are well 
absorbed through intact skin. Most chemical warfare “nerve 
agents” (such as GA [tabun], GB [sarin], GD [soman] and 
VX) are organophosphates.
 
»
Inhibition of cholinesterase results in abdominal cramps, 
diarrhea, vomiting, excessive salivation, sweating, lacrima
-
tion, miosis (constricted pupils), wheezing and bronchor
-
rhea, seizures, and skeletal muscle weakness. Initial 
tachycardia is usually followed by bradycardia. Profound 
skeletal muscle weakness, aggravated by excessive bron
-
chial secretions and wheezing, may result in respiratory 
arrest and death. Symptoms and signs of poisoning may 
persist or recur over several days, especially with highly 
lipid-soluble agents such as fenthion or dimethoate.
The diagnosis should be suspected in patients who 
present with miosis, sweating, and hyperperistalsis. Serum 
and red blood cell cholinesterase activity is usually 
depressed at least 50% below baseline in those victims who 
have severe intoxication.
 
»
Treatment
If the agent was recently ingested, consider gut decontamina
-
tion by aspiration of the liquid using a nasogastric tube fol
-
lowed by administration of activated charcoal. If the agent is 
on the victim’s skin or hair, wash repeatedly with soap or 
shampoo and water. Providers should take care to avoid skin 
exposure by wearing gloves and waterproof aprons. Dilute 
hypochlorite solution (eg, household bleach diluted 1:10) is 
reported to help break down organophosphate pesticides and 
nerve agents on equipment or clothing.
Atropine reverses excessive muscarinic stimulation and is 
effective for treatment of salivation, bronchial hypersecre
-
tion, wheezing, abdominal cramping, and sweating. However, 
it does not interact with nicotinic receptors at autonomic 
ganglia and at the neuromuscular junction and has no direct 
effect on muscle weakness. Administer 2 mg intravenously, 
and if there is no response after 5 minutes, give repeated 
boluses in rapidly escalating doses (eg, doubling the dose 
each time) as needed to dry bronchial secretions and decrease 
wheezing; as much as several hundred milligrams of atropine 
has been given to treat severe poisoning.
Pralidoxime (2-PAM, Protopam) is a more specific 
antidote that reverses organophosphate binding to the cho
-

-
linesterase enzyme; therefore, it should be effective at the 
neuromuscular junction as well as other nicotinic and 
muscarinic sites. It is most likely to be clinically effective if 
started very soon after poisoning, to prevent permanent 
binding of the organophosphate to cholinesterase. However, 
clinical studies have yielded conflicting results regarding 
the effectiveness of pralidoxime in reducing mortality. 
Administer 1–2 g intravenously as a loading dose and 
begin a continuous infusion (200–500 mg/h, titrated to 
clinical response). Continue to give pralidoxime as long as 
there is any evidence of acetylcholine excess. Pralidoxime 
is of questionable benefit for carbamate poisoning, because 
carbamates have only a transitory effect on the cholinester
-
ase enzyme. Other, unproven therapies for organophos
-
phate poisoning include magnesium, sodium bicarbonate, 
clonidine, and extracorporeal removal.
Gorecki L et al. Progress in acetylcholinesterase reactivators and 
in the treatment of organophosphorus intoxication: a patent 
review (2006–2016). Expert Opin Ther Pat. 2017 Sep; 
27(9):971–85. [PMID: 28569609]
King AM et al. Organophosphate and carbamate poisoning. 
Emerg Med Clin North Am. 2015 Feb;33(1):133–51. [PMID: 
25455666]
PETROLEUM DISTILLATES & SOLVENTS
Petroleum distillate toxicity may occur from inhalation of 
the vapor or as a result of pulmonary aspiration of the liq
-
uid during or after ingestion. Acute manifestations of 
aspiration pneumonitis are vomiting, coughing, and bron
-
chopneumonia. Some hydrocarbons—ie, those with aro
-
matic or halogenated subunits—can also cause severe 
systemic poisoning after oral ingestion. Hydrocarbons can 
also cause systemic intoxication by inhalation. Vertigo, 
muscular incoordination, irregular pulse, myoclonus, and 
seizures occur with serious poisoning and may be due to 
hypoxemia or the systemic effects of the agents. Chlorinated 
and fluorinated hydrocarbons (trichloroethylene, Freons, 
etc) and many other hydrocarbons can cause ventricular 
arrhythmias due to increased sensitivity of the myocar
-
dium to the effects of endogenous catecholamines.
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»
Treatment
Remove the patient to fresh air. For simple aliphatic hydro
-
carbon ingestion, gastric emptying and activated charcoal 
are not recommended, but these procedures may be indi
-
cated if the preparation contains toxic solutes (eg, an insec
-
ticide) or is an aromatic or halogenated product. Observe 
the victim for 6–8 hours for signs of aspiration pneumoni
-
tis (cough, localized crackles or rhonchi, tachypnea, and 
infiltrates on chest radiograph). Corticosteroids are not 
recommended. If fever occurs, give a specific antibiotic 
only after identification of bacterial pathogens by labora
-
tory studies. Because of the risk of arrhythmias, use bron
-
chodilators with caution in patients with chlorinated or 
fluorinated solvent intoxication. If tachyarrhythmias occur, 
use esmolol intravenously 25–100 mcg/kg/min.
Cates AL et al. Severe cardiomyopathy after huffing Dust-Off.
™
. 
Case Rep Emerg Med. 2016;2016:9204790. [PMID: 27313914]
Chen X et al. Successful treatment of propafenone-induced car
-
diac arrest by calcium gluconate. Am J Emerg Med. 2017 Aug; 
35(8):1209.e1–2. [PMID: 28390833]
Dinsfriend W et al. Inhalant-abuse myocarditis diagnosed by 
cardiac magnetic resonance. Tex Heart Inst J. 2016 Jun 1; 
43(3):246–8. [PMID: 27303242]
Jayanth SH et al. Glue sniffing. Med Leg J. 2017 Mar;85(1): 
 
38–42. [PMID: 27694447]
Tormoehlen LM et al. Hydrocarbon toxicity: a review. Clin 
Toxicol (Phila). 2014 Jun;52(5):479–89. [PMID: 24911841]
SALICYLATES
Salicylates (aspirin, methyl salicylate, bismuth subsalicy
-
late, etc) are found in a variety of over-the-counter and 
prescription medications. Salicylates uncouple cellular 
oxidative phosphorylation, resulting in anaerobic metabo
-
lism and excessive production of lactic acid and heat, and 
they also interfere with several Krebs cycle enzymes. A 
single ingestion of more than 200 mg/kg of salicylate is 
likely to produce significant acute intoxication. Poisoning 
may also occur as a result of chronic excessive dosing over 
several days. Although the half-life of salicylate is 2–3 hours 
after small doses, it may increase to 20 hours or more in 
patients with intoxication.
 
»
Acute ingestion often causes nausea and vomiting, occa
-
sionally with gastritis. Moderate intoxication is character
-
ized by hyperpnea (deep and rapid breathing), tachycardia, 
tinnitus, and elevated anion gap metabolic acidosis. 
 
(A normal anion gap sometimes occurs due to salicylate 
interference with the chemistry analyzer, falsely raising the 
measured chloride.) Serious intoxication may result in 
agitation, confusion, coma, seizures, cardiovascular col
-
lapse, pulmonary edema, hyperthermia, and death. The 
prothrombin time is often elevated owing to salicylate-
induced hypoprothrombinemia. Central nervous system 
intracellular glucose depletion can occur despite normal 
measured serum glucose levels.
Diagnosis of salicylate poisoning is suspected in any 
patient with metabolic acidosis and is confirmed by 
measuring the serum salicylate level. Patients with levels 
greater than 100 mg/dL (1000 mg/L or 7.2 mcmol/L) after 
an acute overdose are more likely to have severe poisoning. 
On the other hand, patients with subacute or chronic 
intoxication may suffer severe symptoms with levels of 
only 60–70 mg/dL (4.3–5 mcmol/L). The arterial blood gas 
typically reveals a respiratory alkalosis with an underlying 
metabolic acidosis.
 
»
Treatment
Administer activated charcoal orally. Gastric lavage fol
-
lowed by administration of extra doses of activated char
-
coal may be needed in patients who ingest more than 10 g 
of aspirin. The desired ratio of charcoal to aspirin is about 
10:1 by weight; while this cannot always be given as a 
single dose, it may be administered over the first 24 hours 
in divided doses every 2–4 hours along with whole bowel 
irrigation. Give glucose-containing fluids to reduce the

irrigation. Give glucose-containing fluids to reduce the 
risk of cerebral hypoglycemia. Treat metabolic acidosis 
with intravenous sodium bicarbonate. This is critical 
because acidosis (especially acidemia, pH < 7.40) promotes 
greater entry of salicylate into cells, worsening toxicity. 
Warning:
 Sudden and severe deterioration can occur after 
rapid sequence intubation and controlled ventilation if the 
pH is allowed to fall due to hypercarbia during the apneic 
period.
Alkalinization of the urine enhances renal salicylate excre
-
tion by trapping the salicylate anion in the urine. Add 
100 mEq (two ampules) of sodium bicarbonate to 1 L of 5% 
dextrose in 0.2% saline, and infuse this solution intrave
-
nously at a rate of about 150–200 mL/h. Unless the patient 
is oliguric or hyperkalemic, add 20–30 mEq of potassium 
chloride to each liter of intravenous fluid. Patients who are 
volume-depleted often fail to produce an alkaline urine 
(paradoxical aciduria) unless potassium is given.
Hemodialysis may be lifesaving and is indicated for 
patients with severe metabolic acidosis, markedly altered 
mental status, or significantly elevated salicylate levels 
 
(eg, greater than 100–120 mg/dL [1000–1200 mg/L or 
7.2–8.6 mcmol/L] after acute overdose or greater than 
60–70 mg/dL [600–700 mg/L or 4.3–5 mcmol/L] with 
 
subacute or chronic intoxication).
Juurlink DN et al. Extracorporeal treatment for salicylate poi
-
EXTRIP Workgroup. Ann Emerg Med. 2015 Aug;66(2): 
165–81. [PMID: 25986310]
McCabe DJ et al. The association of hemodialysis and survival in 
intubated salicylate-poisoned patients. Am J Emerg Med. 
2017 Jun;35(6):899–903. [PMID: 28438446]
Papacostas MF et al. Use of continuous renal replacement ther
-
apy in salicylate toxicity: a case report and review of the litera
-
ture. Heart Lung. 2016 Sep–Oct;45(5):460–3. [PMID: 
27531848]
Shively RM et al. Acute salicylate poisoning: risk factors for 
severe outcome. Clin Toxicol (Phila). 2017 Mar;55(3):175–80. 
[PMID: 28064509]
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SEAFOOD POISONINGS
A variety of intoxications may occur after eating certain 
types of fish or other seafood. These include scombroid, 
ciguatera, paralytic shellfish, and puffer fish poisoning. 
The mechanisms of toxicity and clinical presentations are 
described in Table 38–8. In the majority of cases, the sea
-
food has a normal appearance and taste (scombroid may 
have a peppery taste).
 
»
Treatment
Caution:
 Abrupt respiratory arrest may occur in patients 
with acute paralytic shellfish and puffer fish poisoning. 
Observe patients for at least 4–6 hours. Replace fluid and 
electrolyte losses from gastroenteritis with intravenous 
saline or other crystalloid solution.
For recent ingestions, it may be possible to adsorb 
residual toxin in the gut with activated charcoal, 50–60 g 
orally.
There is no specific antidote for paralytic shellfish or puffer 
fish poisoning.
1. Ciguatera—
There are anecdotal reports of successful 
treatment of acute neurologic symptoms with mannitol, 
 
1 g/kg intravenously, but this approach is not widely accepted.
2. Scombroid—
Antihistamines such as diphenhydramine, 
25–50 mg intravenously, and the H
2
-blocker cimetidine, 
300 mg intravenously, are usually effective.
Table 38–8.
 
Common seafood poisonings.
Type of Poisoning
Mechanism
Ciguatera
Reef fish ingest toxic dinoflagellates, whose toxins 
accumulate in fish meat. Commonly implicated fish 
in the United States are barracuda, jack, snapper, 
and grouper.
1–6 hours after ingestion, victims develop abdominal pain, 
vomiting, and diarrhea accompanied by a variety of 
 
neurologic symptoms, including paresthesias, reversal of 
hot and cold sensation, vertigo, headache, and intense 
itching. Autonomic disturbances, including hypotension 
and bradycardia, may occur.
Scombroid
Improper preservation of large fish results in bacterial 
degradation of histidine to histamine. Commonly 
implicated fish include tuna, mahimahi, bonita, 
mackerel, and kingfish.
Allergic-like (anaphylactoid) symptoms are due to 
 
histamine, usually begin within 15–90 minutes, and 
include skin flushing, itching, urticaria, angioedema, 
 
bronchospasm, and hypotension as well as abdominal 
pain, vomiting, and diarrhea.
Paralytic shellfish 
poisoning
Dinoflagellates produce saxitoxin, which is concen
-
trated by filter-feeding mussels and clams. Saxitoxin 
blocks sodium conductance and neuronal transmis
-
sion in skeletal muscles.
Onset is usually within 30–60 minutes. Initial symptoms 
include perioral and intraoral paresthesias. Other symp
-
toms include nausea and vomiting, headache, dizziness, 
dysphagia, dysarthria, ataxia, and rapidly progressive 
muscle weakness that may result in respiratory arrest.
Puffer fish 
 
poisoning
Tetrodotoxin is concentrated in liver, gonads, intestine, 
and skin. Toxic effects are similar to those of 
saxitoxin. Tetrodotoxin is also found in some 
 
North American newts and Central American frogs.
Onset is usually within 30–40 minutes but may be as short 
as 10 minutes. Initial perioral paresthesias are followed 
 
by headache, diaphoresis, nausea, vomiting, ataxia, and 
rapidly progressive muscle weakness that may result in 
respiratory arrest.
Armstrong P et al. Ciguatera fish poisoning. N Z Med J. 2016 
Oct 28;129(1444):111–4. [PMID: 27806035]
Feng C et al. Histamine (scombroid) fish poisoning: a compre
-
hensive review. Clin Rev Allergy Immunol. 2016 Feb;50(1): 
64–9. [PMID: 25876709]
SNAKE BITES
The venom of poisonous snakes and lizards may be pre
-
dominantly neurotoxic (coral snake) or predominantly 
cytolytic (rattlesnakes, other pit vipers). Neurotoxins cause 
respiratory paralysis; cytolytic venoms cause tissue destruc
-
tion by digestion and hemorrhage due to hemolysis and 
destruction of the endothelial lining of the blood vessels. 
The manifestations of rattlesnake envenomation are mostly

-
The manifestations of rattlesnake envenomation are mostly 
local pain, redness, swelling, and extravasation of blood. 
Perioral tingling, metallic taste, nausea and vomiting, 
hypotension, and coagulopathy may also occur. Thrombo
-
cytopenia can persist for several days after a rattlesnake 
bite. Neurotoxic envenomation may cause ptosis, dysphagia, 
diplopia, and respiratory arrest.
 
»
Treatment
Immobilize the patient and the bitten part in a neutral 
position. Avoid manipulation of the bitten area. Transport 
the patient to a medical facility for definitive treatment. Do 
not
 give alcoholic beverages or stimulants; do 
not
 apply ice; 
do 
not
 apply a tourniquet. The potential trauma to under
-
lying tissues resulting from incision and suction performed 
by unskilled people is probably not justified in view of the 
small amount of venom that can be recovered.
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B. Specific Antidote and General Measures
1. Pit viper (eg, rattlesnake) envenomation—
For local 
signs such as swelling, pain, and ecchymosis but no sys
-
temic symptoms, give 4–6 vials of crotalid antivenin 
 
(CroFab) by slow intravenous drip in 250–500 mL saline. 
Repeated doses of 2 vials every 6 hours for up to 18 hours 
have been recommended, but many clinicians give addi
-
tional doses only if needed. For more serious envenom
-
ation with marked local effects and systemic toxicity 
 
(eg, hypotension, coagulopathy), higher doses and addi
-
tional vials may be required. Monitor vital signs and the 
blood coagulation profile. Type and cross-match blood. 
The adequacy of venom neutralization is indicated by 
improvement in symptoms and signs, and the rate that 
swelling slows. Prophylactic antibiotics are not indicated 
after a rattlesnake bite.
2. Elapid (coral snake) envenomation—
Give 1–2 vials of 
specific antivenom as soon as possible. 
Note:
 Pfizer/Wyeth 
no longer makes coral snake antivenom in the United 
States and remaining supplies are dwindling. To locate 
antisera for this or exotic snakes, call a regional poison 
control center (1-800-222-1222).
Berling I et al. Hematologic effects and complications of snake 
envenoming. Transfus Med Rev. 2015 Apr;29(2):82–9. 
[PMID: 25556574]
Emswiler MP et al. Clinically significant envenomation from 
postmortem copperhead (
Agkistrodon contortrix
). Wilderness 
Environ Med. 2017 Mar;28(1):43–5. [PMID: 27876196]
Kanaan NC et al. Wilderness Medical Society practice guidelines 
for the treatment of pitviper envenomations in the 
United States and Canada. Wilderness Environ Med. 2015 Dec; 
26(4):472–87. [PMID: 26433731]
Valenta J et al. Severe snakebite envenoming in intensive care. 
Prague Med Rep. 2016;117(4):153–63. [PMID: 27930893]
SPIDER BITES & SCORPION STINGS
The toxin of most species of spiders in the United States 
causes only local pain, redness, and swelling. That of the 
more venomous black widow spiders 
(Latrodectus mactans)
 
causes generalized muscular pains, muscle spasms, and 
rigidity. The brown recluse spider 
(Loxosceles reclusa)
 
causes progressive local necrosis as well as hemolytic reac
-
tions (rare).
Stings by most scorpions in the United States cause only 
local pain. Stings by the more toxic 
Centruroides
 species 
(found in the southwestern United States) may cause 
muscle cramps, twitching and jerking, and occasionally 
hypertension, convulsions, and pulmonary edema. Stings 
by scorpions from other parts of the world are not dis
-
cussed here.
 
»
Treatment
A. Black Widow Spider Bites
Pain may be relieved with parenteral opioids or muscle 
relaxants (eg, methocarbamol, 15 mg/kg). Calcium gluco
-
nate 10%, 0.1–0.2 mL/kg intravenously, may transiently 
relieve muscle rigidity, though its effectiveness is unproven. 
Latrodectus
 antivenom is possibly more effective, but 
because of concerns about acute hypersensitivity reactions 
(horse serum–derived), it is often reserved for very young 
or elderly patients or those who do not respond promptly 
to the above measures. Horse serum sensitivity testing is 
required. (Instruction and testing materials are included in 
the antivenin kit.)
B. Brown Recluse Spider Bites
Because bites occasionally progress to extensive local 
necrosis, some authorities recommend early excision of the 
bite site, whereas others use oral corticosteroids. Anecdotal 
reports have claimed success with dapsone and colchicine. 
All of these treatments remain of unproved value.
C. Scorpion Stings
No specific treatment other than analgesics is required for 
envenomations by most scorpions found in the 
United States. An FDA-approved specific antivenom is 
available for 
 stings.
Erickson TB et al. Arthropod envenomation in North America. 
Emerg Med Clin North Am. 2017 May;35(2):355–75. [PMID: 
28411932]
Isbister GK et al. Randomized controlled trial of intravenous

stings.
28411932]
Isbister GK et al. Randomized controlled trial of intravenous 
antivenom versus placebo for latrodectism: the second Red
-
back Antivenom Evaluation (RAVE-II) study. Ann Emerg 
Med. 2014 Dec;64(6):620–8.e2. [PMID: 24999282]
Isbister GK et al. Scorpion envenomation. N Engl J Med. 
2014 Jul 31;371(5):457–63. [PMID: 25075837]
Santos MS et al. Clinical and epidemiological aspects of scorpi
-
onism in the world: a systematic review. Wilderness Environ 
Med. 2016 Dec;27(4):504–18. [PMID: 27912864]
THEOPHYLLINE & CAFFEINE
Theophylline may cause intoxication after an acute single 
overdose, or intoxication may occur as a result of chronic 
accidental repeated overmedication or reduced elimination 
resulting from hepatic dysfunction or interacting drug 
(eg, cimetidine, erythromycin). The usual serum half-life 
of theophylline is 4–6 hours, but this may increase to more 
than 20 hours after overdose. Caffeine in energy drinks or 
herbal or dietary supplement products can produce similar 
toxicity.
 
»
Mild intoxication causes nausea, vomiting, tachycardia, 
and tremulousness. Severe intoxication is characterized by 
ventricular and supraventricular tachyarrhythmias, hypo
-
tension, and seizures. Status epilepticus is common and 
often intractable to the usual anticonvulsants. After acute 
overdose (but not chronic intoxication), hypokalemia, 
hyperglycemia, and metabolic acidosis are common. 
Seizures and other manifestations of toxicity may be delayed 
for several hours after acute ingestion, especially if a 
sustained-release preparation such as Theo-Dur was taken.
Diagnosis is based on measurement of the serum the
-
ophylline concentration. Seizures and hypotension are 
likely to develop in acute overdose patients with serum 
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CMDT 2019
levels greater than 100 mg/L (555 mcmol/L). Serious 
 
toxicity may develop at lower levels (ie, 40–60 mg/L 
 
[222–333 mcmol/L]) in patients with chronic intoxication. 
Serum caffeine levels are not routinely available in clinical 
practice, but in a study of 51 fatal cases the median level 
was 180 mg/L (range 33–567 mg/L).
 
»
Treatment
Repeated doses of activated charcoal may enhance theophyl
-
line elimination by “gut dialysis. ” Addition of whole bowel 
irrigation should be considered for large ingestions involving 
sustained-release preparations.
Hemodialysis is effective in removing theophylline and 
is indicated for patients with status epilepticus or markedly 
elevated serum theophylline levels (eg, greater than 
 
100 mg/L [555 mcmol/L] after acute overdose or greater 
than 60 mg/L [333 mcmol/L] with chronic intoxication).
Treat seizures with benzodiazepines (lorazepam, 2–3 mg 
intravenously, or diazepam, 5–10 mg intravenously) or 
phenobarbital (10–15 mg/kg intravenously). Phenytoin is 
not effective. Hypotension and tachycardia—which are 
mediated through excessive beta-adrenergic stimulation—
may respond to beta-blocker therapy even in low doses. 
Administer esmolol, 25–50 mcg/kg/min by intravenous 
infusion, or propranolol, 0.5–1 mg intravenously.
Ghannoum M et al. Extracorporeal treatment for theophylline 
EXTRIP workgroup. Clin Toxicol (Phila). 2015 May; 
53(4):215–29. [PMID: 25715736]
Jones AW . Review of caffeine-related fatalities along with post
-
mortem blood concentrations in 51 poisoning deaths. J Anal 
Toxicol. 2017 Apr 1;41(3):167–72. [PMID: 28334840]
TRICYCLIC & OTHER ANTIDEPRESSANTS
Tricyclic and related cyclic antidepressants are among the 
most dangerous drugs involved in suicidal overdose. These 
drugs have anticholinergic and cardiac depressant proper
-
ties (“quinidine-like” sodium channel blockade). Tricyclic 
antidepressants produce more marked membrane-depres
-
sant cardiotoxic effects than the phenothiazines.
Newer-generation antidepressants such as trazodone, 
fluoxetine, citalopram, paroxetine, sertraline, bupropion, 
venlafaxine, and fluvoxamine are not chemically related to 
the tricyclic antidepressant agents and, with the exception 
of bupropion, do not generally produce quinidine-like 
cardiotoxic effects. However, they may cause seizures in 
overdoses and they may cause serotonin syndrome.
 
»
Signs of severe intoxication may occur abruptly and with
-
out warning within 30–60 minutes after acute tricyclic 
overdose. Anticholinergic effects include dilated pupils, 
tachycardia, dry mouth, flushed skin, muscle twitching, 
and decreased peristalsis. Quinidine-like cardiotoxic 
effects include QRS interval widening (greater than 0.12 s; 
Figure 38–2), ventricular arrhythmias, AV block, and 
hypotension. Rightward-axis deviation of the terminal 
 
40 ms of the QRS has also been described. Prolongation of 
the QT interval and torsades de pointes have been reported 
with several of the newer antidepressants. Seizures and 
coma are common with severe intoxication. Life-
threatening hyperthermia may result from status 
 
epilepticus and anticholinergic-induced impairment of 
sweating. Among newer agents, bupropion and venlafaxine 
have been associated with a greater risk of seizures.
The diagnosis should be suspected in any overdose 
patient with anticholinergic side effects, especially if there 
is widening of the QRS interval or seizures. For intoxica
-
tion by most tricyclic antidepressants, the QRS interval 
correlates with the severity of intoxication more reliably 
than the serum drug level.
Serotonin syndrome should be suspected if agitation, 
delirium, diaphoresis, tremor, hyperreflexia, clonus (spon
-
taneous, inducible, or ocular), and fever develop in a

-
taneous, inducible, or ocular), and fever develop in a 
patient taking serotonin reuptake inhibitors.
 
»
Treatment
Observe patients for at least 6 hours and admit all patients 
with evidence of anticholinergic effects (eg, delirium, 
dilated pupils, tachycardia) or signs of cardiotoxicity.
Administer activated charcoal and consider gastric lavage 
after recent large ingestions. All of these drugs have large 
volumes of distribution and are not effectively removed by 
hemodialysis procedures.
A
B
C
 
▲
Figure 38–2.
 
Cardiac arrhythmias resulting from tri
-
cyclic antidepressant overdose. 
A:
 Delayed intraventric
-
ular conduction results in prolonged QRS interval (0.18 s). 
B
 and 
C:
 Supraventricular tachycardia with progressive 
widening of QRS complexes mimics ventricular tachy
-
cardia. 
(Reproduced, with permission, from Benowitz NL, 
Goldschlager N. Cardiac disturbances in the toxicologic 
patient. In: Haddad LM, Winchester JF [editors], 
Clinical 
Management of Poisoning and Drug Overdose
, 3rd edition. 
Saunders/Elsevier, 1998. Copyright © Elsevier.)
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Cardiotoxic sodium channel-depressant effects of tricyclic 
antidepressants may respond to boluses of sodium bicar
-
bonate (50–100 mEq intravenously). Sodium bicarbonate 
provides a large sodium load that alleviates depression of 
the sodium-dependent channel. Reversal of acidosis may 
also have beneficial effects at this site. Maintain the pH 
between 7.45 and 7.50. Alkalinization does not promote 
excretion of tricyclic antidepressants. Prolongation of the 
QT interval or torsades de pointes is usually treated with 
intravenous magnesium or overdrive pacing. Severe car
-
diotoxicity in patients with overdoses of lipid-soluble drugs 
(eg, amitriptyline, bupropion) has reportedly responded to 
intravenous lipid emulsion (Intralipid), 1.5 mL/kg repeated 
one or two times if needed. Plasma exchange using albu
-
min has been reported successful in a few cases.
Mild serotonin syndrome may be treated with benzodi
-
azepines and withdrawal of the antidepressant. Moderate 
cases may respond to cyproheptadine (4 mg orally or via 
gastric tube hourly for three or four doses) or chlorproma
-
zine (25 mg intravenously). Severe hyperthermia should be 
treated with neuromuscular paralysis and endotracheal 
intubation in addition to external cooling measures.
Clark S et al. Rapid diagnosis and treatment of severe tricyclic 
antidepressant toxicity. BMJ Case Rep. 2015 Oct 14; 
2015:211428. [PMID: 26468220]
Ramasubbu B et al. Serum alkalinisation is the cornerstone of 
treatment for amitriptyline poisoning. BMJ Case Rep. 
2016 Apr 11;2016:214685. [PMID: 27068728]
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CMDT 2019
Charles J. Ryan, MD 
Cancer
39
tobacco-related cancer continue to use tobacco products, 
increasing their risk of yet another cancer.
Tobacco cessation directed toward the individual 
should start with clinician counseling. Simple, concise 
advice from a clinician can yield cessation rates of 10–20%. 
Additive strategies include more intensive counseling; 
nicotine replacement therapy with patches, gum, or 
lozenges; and prescription medication with bupropion or 
varenicline (see Chapter 1).
On a societal level, state or local laws regulating 
tobacco use in restaurants, workplace, and other public 
places have resulted in declines in tobacco use. Counter
-
marketing with aggressive anti-tobacco advertisements 
has also contributed to tobacco cessation and abstinence. 
The key targets of these messages are children; 80% of 
smokers start by age 18.
There are encouraging signs of success with tobacco 
control. The prevalence of smoking for US adults based on 
the 2016 National Health Interview Survey is 16.0%, which 
is a remarkable reduction from the 1955 peak of 57% for 
males and the 1965 peak of 34% for females.
For those Americans who do not use tobacco, the most 
modifiable risk factors would be nutrition and physical 
activity. Prudent recommendations to reduce cancer risk 
are to (1) avoid tobacco; (2) be physically active; (3) main
-
tain a healthy weight; (4) consume a diet rich in fruits, 
vegetables, and whole grains; (5) lower consumption of 
saturated and trans dietary fats; (6) limit alcohol use; and 
(7) avoid excess sun exposure.
Another modifiable cancer risk factor is radiation from 
radiographic studies. A 2009 study reported that the use of 
computed tomography (CT) in diagnostic algorithms 
exposes individuals to significant radiation doses that may 
increase their lifetime risk of cancer. Both standardization 
of CT radiation doses and limiting testing have been 
important steps in minimizing this risk. The American 
Society of Hematology and American Society of Clinical 
Oncology have guidelines, inspired by the American Board 
of Internal Medicine Foundation’s “Choosing Wisely” cam
-
paign, for limiting radiographic testing, particularly when 
used in surveillance for treated cancer patients.
 
º
INTRODUCTION TO CANCER
Tiffany O. Dea, PharmD
 
»
Etiology
Cancer is the second most common cause of death in the 
United States. In 2017, an estimated 1,688,780 cases of 
cancer were diagnosed, and 600,920 persons died of cancer. 
Based on current statistics, almost 40% of Americans will 
be diagnosed with cancer at some point during their 
lifetime. Table 39–1 lists the 10 leading cancer types in men 
and women by site.
However, the death rates from cancer are decreasing. 
Compared to the 1991 cancer death rate of 215.1 
per 100,000 population, the 2012 rate of 171.2 per 
100,000 represents a 20% reduction in its death rate. 
Importantly, death rates have declined in the four most 
common cancer types (lung, colon-rectum, breast, and 
prostate). The largest declines in death rates in women 
have been in non-Hodgkin lymphoma and colorectal 
cancer and in men, in prostate and stomach cancers. 
Reductions in cancer mortality reflect successful imple
-
mentation of a broad strategy of prevention, detection, 
and treatment. Due to these improvements, the number 
of cancer survivors is increasing. In 2015, an estimated 
14.5 million people were alive in whom cancer had been 
previously diagnosed; that number is projected to grow to 
18.9 million in 2024.
 
»
Modifiable Risk Factors
Tobacco is the most common preventable cause of cancer 
death; at least 30% of all cancer deaths in the United States 
are directly linked to tobacco. In 2014, an estimated 
167,133 cancer deaths in the United States could be directly

167,133 cancer deaths in the United States could be directly 
attributed to tobacco. Clear evidence links tobacco use to at 
least 15 cancers. The most dramatic link is with lung 
cancer; 80% of lung cancer cases occur in smokers. 
Remarkably, almost 10% of long-term survivors of a 
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American Cancer Society. Cancer Facts & Figures 2017. https://
www.cancer.org/research/cancer-facts-statistics/all-cancer-
facts-figures/cancer-facts-figures-2017.html
Office of Disease Prevention and Health Promotion. Healthy 
People 2020. Tobacco use objectives: reduce tobacco use by 
adults. https://www.healthypeople.gov/2020/topics-
objectives/topic/tobacco-use/objectives?
Siegel RL et al. Cancer statistics, 2018. CA Cancer J Clin. 
2018 Jan;68(1):7–30. [PMID: 29313949]
Table 39–1.
 
Estimated 10 most common cancer cases 
in the United States in males and females (all races).
Males
Females
Rank
Total Cases = 836,150 
 
(percent)
Total Cases = 852,630 
 
(percent)
1
Prostate (19)
Breast (30)
2
Lung and bronchus (14)
Lung and bronchus (12)
3
Colon and rectum (9)
Colon and rectum (8)
4
Urinary bladder (7)
Uterine corpus (7)
5
Melanoma (6)
Thyroid (5)
6
Kidney and renal pelvis (5)
Melanoma (4)
7
Non-Hodgkin lymphoma 
(5)
(4)
8
Leukemia (4)
Leukemia (3)
9
Oral cavity and pharynx (4)
Pancreas (3)
10
Liver and intrahepatic bile 
duct (3)
Kidney and renal pelvis (3)
Other sites (24)
Other sites (21)
Data from the American Cancer Society, 2017.
 
»
Staging
The most commonly used staging system at the time of 
diagnosis is the TNM (Tumor, Nodes, Metastasis) system 
(see https://www.cancerstaging.org). Rules for staging for 
individual cancers are established and published by the 
American Joint Committee on Cancer (AJCC). The ele
-
ments used for staging are tumor location, size and level of 
tumor invasion (T), absence or presence and extent of nodal 
metastases (N), and absence or presence of systemic metas
-
tases (M). Once the TNM designations have been deter
-
mined, an overall stage is assigned, stage I, II, III, or IV . 
Clinical staging utilizes physical examination, laboratory 
and imaging tests as well as results from biopsies; patho
-
logic staging relies on the results from surgery. In some 
instances, other classifications may be used for certain can
-
cers such as the Ann Arbor staging system for lymphomas.
Other characteristics of cancers, not reflected in the 
TNM stage, may be used to indicate prognosis and guide 
treatment. Pathologic features seen on routine histologic 
examination for some cancers are very important; exam
-
ples include the Gleason score for prostate cancer and the 
grade of sarcomas. Cancer specimens should also be sent 
for targeted molecular diagnostic testing, when appropriate. 
Examples include testing for 
HER2
 in breast and gastric 
cancer; 
K-ras
 and 
BRAF
 mutations in colorectal cancer; 
BRAF
 mutations in melanoma; epidermal growth factor 
receptor (EGFR), 
K-ras
 mutations, and the 
ALK
 fusion 
gene in lung cancer; and programmed death-ligand 1 
(PD-L1) expression testing in a variety of cancers.
 
»
Treatment 
See Primary Cancer Treatment section below. Table 39–2 
outlines treatment choices by cancer type for those respon
-
sive to systemic agents, and Table 39–3 provides a listing of 
common chemotherapeutic agents.
Table 39–2.
 
Treatment choices for cancers responsive to systemic agents.
Diagnosis
Current Treatment of Choice
Other Treatments
Acute lymphoblastic 
leukemia (ALL)
Induction combination chemotherapy: 
Vincristine, prednisone, 
daunorubicin, asparaginase, intrathecal methotrexate
Consolidation combination chemotherapy:
 Cyclophosphamide, 
vincristine, doxorubicin, dexamethasone (hyper-CVAD) 
 
alternated with cytarabine, methotrexate
Maintenance chemotherapy:
 Methotrexate, 6-mercaptopurine
p
hiladelphia chromosome–positive ALL:
 Add imatinib or 
 
dasatinib or nilotinib or ponatinib to above regimen
Blinatumomab, inotuzumab ozogamicin, 
 
tisagenlecleucel, liposomal vincristine, 
 
clofarabine, nelarabine (T-cell ALL), nilotinib, 
bosutinib, ponatinib (Philadelphia 
 
chromosome-positive ALL), autologous or 
allogeneic transplantation for high risk or at 
relapse
Acute myeloid leu
-
kemia (AML)

relapse
-
Combination chemotherapy:
 Cytarabine, daunorubicin or 
 
Cytarabine, idarubicin or Cytarabine, daunomycin, cladribine
Mitoxantrone, doxorubicin, fludarabine, 
 
5-azacytidine, decitabine, clofarabine, 
midostaurin (FLT3 mutation +)
Chronic myeloid 
leukemia (CML)
Nilotinib or Dasatinib or Imatinib mesylate
Ponatinib, bosutinib, omacetaxine, allogeneic 
bone marrow transplantation
Chronic lymphocytic 
leukemia (CLL)
 Fludarabine, cyclophosphamide, 
rituximab (FCR) or Bendamustine, rituximab
Single-agent chemotherapy:
 Ibrutinib or obinutuzumab or 
 
ofatumumab or chlorambucil
Alemtuzumab, idelalisib, venetoclax, 
 
lenalidomide, pentostatin, cladribine, 
 
cyclophosphamide, vincristine, doxorubicin, 
prednisone
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1612

CANCER
1613
 
CMDT 2019
 
Treatment choices for cancers responsive to systemic agents. (continued) 
Diagnosis
Cladribine (2-chlorodeoxyadenosine)
Pentostatin, rituximab, interferon-alpha, 
 
vemurafenib, ibrutinib
Hodgkin lymphoma 
(stages III and IV)
 Doxorubicin, bleomycin, vinblastine, 
dacarbazine (ABVD), or
Doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, 
bleomycin, prednisone (Stanford V), or
Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, 
procarbazine, prednisone (BEACOPP)
Combination chemotherapy second line:
Dexamethasone, cisplatin, cytarabine (DHAP),
or
Etoposide, methylprednisolone, cytarabine, 
 
cisplatin (ESHAP), or
Ifosfamide, carboplatin, etoposide (ICE), or
Mesna, ifosfamide, mitoxantrone, etoposide 
(MIME); stem cell transplantation for high 
 
risk or first relapse
Brentuximab vedotin, nivolumab, pembroli
-
zumab, bendumustine, everolimus
 
lymphoma 
 
(intermediate 
 
and high grade)
 Cyclophosphamide, doxorubicin, 
 
vincristine, prednisone, rituximab (CHOP-R), or
Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, 
rituximab (Dose-adjusted R-EPOCH) (for double rearrangements
)
Dexamethasone, cisplatin, cytarabine (DHAP), or
(MIME); transplantation for high risk or first 
relapse
 
lymphoma (low 
grade)
Bendamustine, rituximab, or
Cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab 
(CHOP-R), or
Cyclophosphamide, vincristine, prednisone, rituximab (CVP-R), or
Lenalidomide, rituximab
Chlorambucil, fludarabine, copanlisib, 
 
obinutuzumab, 
90
Y ibritumomab tiuxetan, 
bendamustine, lenalidomide, idelalisib, 
 
ibrutinib, belinostat (T-cell lymphoma), 
 
autologous or allogeneic transplantation
Plasma cell 
myeloma 
 
(formerly 
 
multiple 
myeloma)
Combination chemotherapy (transplant candidates):
Bortezomib, dexamethasone, cyclophosphamide, or
Bortezomib, dexamethasone, lenalidomide, or
Dexamethasone, lenalidomide, or
Ixazomib/lenalidomide/dexamethasone, or
Carfilzomib/lenalidomide/dexamethasone
Followed by autologous or miniallogeneic stem cell transplantation
Combination chemotherapy (non-transplant candidates):
Lenalidomide, dexamethasone, or
Melphalan, prednisone, bortezomib, or
Melphalan, prednisone, lenalidomide, or
Melphalan, prednisone, thalidomide
Liposomal doxorubicin, pomalidomide, 
 
panobinostat, elotuzumab, daratumumab
Waldenström 
macroglobulin
-
emia
p
lasmapheresis alone or followed by combination chemotherapy:
Bortezomib with or without rituximab, or
Thalidomide with or without rituximab, or 
Rituximab, cyclophosphamide, prednisone, or
Carfilzomib, rituximab, dexamethasone or ibrutinib
Cladribine, ofatumumab, chlorambucil, 
 
bendamustine, alemtuzumab, everolimus, 
autologous bone marrow transplantation
Phlebotomy, hydroxyurea, aspirin
Ruxolitinib, radiophosphorus 
32
P,  
interferon-alpha
Non–small cell lung 
cancer
 Cisplatin, vinorelbine, or
Cisplatin, etoposide, or
Paclitaxel, carboplatin, or
Cisplatin, gemcitabine (squamous histology)
Cisplatin, pemetrexed (nonsquamous histology)
All regimens with or without bevacizumab
Erlotinib, gefitinib, osimertinib or afatinib (
EGFR
 mutation positive), or
Crizotinib, alectinib, ceritinib, brigatinib (
ALK
 mutation positive)
Certitinib, crizotinib (
ROS1
 rearrangement)
Dabrafenib/trametinib (
BRAF
 V600F mutation)
Pembrolizumab (PD-L1 expression)
Docetaxel, cetuximab, pembrolizumab, 
nivolumab, atezolizumab, osimertinib, 
 
necitumumab, ramucirumab, cabozantinib 
(
RET
 rearrangement), trastuzumab, afatinib 
(
HER2
 mutation positive), alectinib,

(
RET
(
HER2
 mutation positive), alectinib, 
 
brigatinib, ceritinib (
ALK
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1613

Ch
A
p
TER
 3
9
1614
 CMDT 2019
 
Diagnosis
Small cell lung 
cancer
Carboplatin, etoposide, or
Cisplatin, irinotecan
Irinotecan, cyclophosphamide, doxorubicin, 
 
vincristine, topotecan, gemcitabine, 
 
paclitaxel, bendamustine, temozolomide, 
nivolumab, ipilimumab
Mesothelioma
Cisplatin, pemetrexed, or
Carboplatin, pemetrexed, or
Gemcitabine, cisplatin
Vinorelbine, nivolumab with or without 
 
ipilimumab, pembrolizumab
Head and neck 
cancer
Cisplatin, fluorouracil, or
Docetaxel, cisplatin, fluorouracil, or
Cisplatin or cetuximab with radiation therapy
Methotrexate, afatinib, pembrolizumab, 
nivolumab
Esophageal and 
esophagogastric 
junction cancer
 Cisplatin, fluorouracil, or 
Oxaliplatin, fluorouracil or 
Docetaxel, cisplatin, fluorouracil
Irinotecan, oxaliplatin, capecitabine, epirubicin, 
docetaxel, trastuzumab or ramucirumab 
(esophagogastric junction cancer), 
pembrolizumab
Uterine cancer
h
ormone therapy:
 Progestins, tamoxifen, aromatase inhibitors, 
fulvestrant or
Cisplatin, doxorubicin, or
Docetaxel, carboplatin, or
Carboplatin, paclitaxel
Liposomal doxorubicin, bevacizumab, 
 
topotecan, temsirolimus, pembrolizumab
Ovarian cancer
Paclitaxel, carboplatin with or without bevacizumab, or
Paclitaxel, cisplatin
Gemcitabine, liposomal doxorubicin, topotecan, 
cyclophosphamide, etoposide, pemetrexed, 
olaparib, pazopanib, rucaparib
Cervical cancer
With radiation:
 Cisplatin
Cisplatin, paclitaxel with or without bevacizumab, or
Cisplatin, topotecan, or
Carboplatin, paclitaxel with or without bevacizumab, or
Cisplatin, gemcitabine, or
Topotecan, paclitaxel with or without bevacizumab
Docetaxel, ifosfamide, vinorelbine, irinotecan, 
mitomycin, fluorouracil, pemetrexed, 
 
bevacizumab, pembrolizumab
Breast cancer
Adjuvant hormone therapy:
 
Premenopausal:
 Tamoxifen
Postmenopausal:
 Aromatase inhibitors (anastrozole, letrozol, 
exemestane)
Adjuvant chemotherapy (without trastuzumab):
Doxorubicin, cyclophosphamide, paclitaxel, or
Docetaxel, cyclophosphamide, or
Doxorubicin, cyclophosphamide, or
Doxorubicin, cyclophosphamide, docetaxel
Adjuvant chemotherapy (with trastuzumab):
Doxorubicin, cyclophosphamide, paclitaxel, trastuzumab with or 
without pertuzumab, or
Docetaxel, carboplatin, trastuzumab with or without pertuzumab
Eribulin, capecitabine, mitoxantrone, cisplatin, 
etoposide, vinblastine, fluorouracil, 
ixabepilone, pertuzumab, gemcitabine, 
 
lapatinib, toremifene, fulvestrant, palbociclib, 
raloxifene, abemaciclib, ribociclib, olaparib
Choriocarcinoma 
(trophoblastic 
neoplasms)
 Methotrexate or dactinomycin for 
low-risk disease
 Etoposide, methotrexate, 
 
dactinomycin, cyclophosphamide, vincristine (EMA-CO) for 
 
high-risk disease
Vinblastine, cisplatin, mercaptopurine, 
 
chlorambucil, doxorubicin
Testicular cancer
 Cisplatin, etoposide (EP), or
Bleomycin, etoposide, cisplatin (BEP), or
Etoposide, mesna, ifosfamide, cisplatin (VIP)
Vinblastine, paclitaxel, gemcitabine, oxaliplatin
Kidney (renal cell) 
cancer
 Sunitinib or temsirolimus or 
 
bevacizumab or sorafenib or pazopanib or axitinib or 
interleukin-2
Interferon-alpha, cabozantinib, nivolumab, 
lenvatinib
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1614

CANCER
1615
 
CMDT 2019
 
Diagnosis
Bladder cancer
 Gemcitabine, cisplatin, or 
Methotrexate, vinblastine, doxorubicin, cisplatin (MVAC), or
Cisplatin, methotrexate, vinblastine (CMV)
Atezolizumab, carboplatin, paclitaxel, docetaxel, 
fluorouracil, pemetrexed, pembrolizumab, 
durvalumab, avelumab
Prostate cancer
h
 Luteinizing hormone–releasing agonist 
(leuprolide, goserelin, triptorelin, histrelin, degarelix) with or 
without an antiandrogen (flutamide, bicalutamide, nilutamide)
Chemotherapy:
 Tocetaxel, prednisone
Ketoconazole, abiraterone, enzalutamide, 
 
mitoxantrone, cabazitaxel, sipuleucel-T, 
 
prednisone, Radium (Ra)-223
Brain cancer 
 
(anaplastic 
 
astrocytoma and 
glioblastoma 
multiforme)
Single-agent chemotherapy with radiation therapy:
 
Temozolomide
Bevacizumab, irinotecan, procarbazine, 
 
carmustine, lomustine, cyclophosphamide, 
etoposide
Neuroblastoma
 
cisplatin, etoposide
Vincristine, topetecan, irinotecan, ifosfamide, 
carboplatin, 13-cis-retinoic acid, 
131
I-MIBG, 
dinutuximab, autologous or allogeneic 
Thyroid cancer
 Radioiodine (
131
I) or sorafenib, or 
sunitinib or pazopanib or lenvatinib, vandetanib or cabozantinib 
(medullary thyroid cancer)
 Paclitaxel/carboplatin or docetaxel/
doxorubicin (anaplastic carcinoma)
Doxorubicin, dacarbazine
Adrenal cancer
 Mitotane
Doxorubicin, etoposide, cisplatin
Stomach (gastric) 
cancer
 Epirubicin, cisplatin, fluorouracil, or
Cisplatin, fluorouracil,
Fluorouracil, oxaliplatin
Trastuzumab added for 
HER2
-overexpressing adenocarcinomas
Capecitabine, irinotecan, paclitaxel, 
 
ramucirumab, pembrolizumab (MSI-H or 
dMMR tumors)
Pancreatic cancer
Gemcitabine, nab-paclitaxel, or
5-Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX)
 Gemcitabine
Gemcitabine, capecitabine
5-Fluorouracil, leucovorin, nanoliposomal 
irinotecan
5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX)
Pembrolizumab (MSI-H or dMMR or PD-LI 
 
positive tumors)
Capecitabine
Colon cancer
 Fluorouracil, leucovorin, oxaliplatin 
(FOLFOX), or
Capecitabine, oxaliplatin (CapeOx), or
Fluorouracil, leucovorin, irinotecan (FOLFIRI)
each regimen with or without bevacizumab
Cetuximab, panitumumab, regorafenib, 
 
ziv-aflibercept, trifluridine/tipiracil, 
nivolumab or pembrolizumab 
 
(dMMR/MSI-H only)
Rectal cancer
Chemotherapy with radiation:
 Fluorouracil or capecitabine;
For adjuvant or advanced disease treatment, same regimens used 
with colon cancer
ziv-aflibercept, trifluridine/tipiracil, nivolumab 
 
or pembrolizumab (dMMR/MSI-H only)
Anal cancer
Combination chemotherapy with radiation:
 Fluorouracil, 
 
mitomycin or capecitabine, mitomycin
Cisplatin
Carcinoid
Octreotide LAR or lanreotide
Doxorubicin, dacarbazine, temozolomide, 
capecitabine, streptozocin, oxaliplatin, 
 
fluorouracil, everolimus
 Cisplatin, doxorubicin, or
Methotrexate, cisplatin, doxorubicin, or
Ifosfamide, cisplatin, epirubicin
Cyclophosphamide, gemcitabine, docetaxel, 
etoposide, sorafinib, everolimus, Radium 
(Ra)-233, Samarium (Sm)-153 
 
(lexidronam)-ethylene diamine 
 
tetramethylene phosphate (EDTMP), 
 
pembrolizumab (MSI-H or dMMR tumors) 
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1615

Ch
A
p
TER
 3
9
1616
 CMDT 2019
 
Diagnosis
Soft tissue sarcomas
Doxorubicin, dacarbazine (AD), or
Doxorubicin, ifosfamide, mesna (AIM), or
Mesna, doxorubicin, ifosfamide, dacarbazine (MAID), or
Doxorubicin, olaratumab
 Eribulin, pazopanib; imatinib or 
 
sunitinib or regorafenib (gastrointestinal stromal tumors)
Liposomal doxorubicin, methotrexate, 
 
gemcitabine, docetaxel, temozolomide, 
 
epirubicin, pazopanib, eribulin, trabectedin; 
sorafenib, nilotinib, dasatinib, pazopanib, 
regorafenib, everolimus (gastrointestinal 
stromal tumors)
Melanoma
Combination chemotherapy
 (non-
BRAF
 mutation): nivolumab/
ipilimumab
 (
BRAF
 mutation): dabrafenib/
trametinib or vemurafenib/cobimetinib
Single-agent chemotherapy
 (non-
BRAF
 mutation): pembroli
-
zumab or nivolumab
 (
BRAF
 mutation): vemurafenib or 
dabrafenib
Dacarbazine, temozolomide, imatinib, 
 
paclitaxel, carboplatin, IL-2, interferon alfa-2b
Hepatocellular 
cancer
 Sorafenib
Regorafenib, nivolumab
 Liposomal doxorubicin or liposomal 
daunorubicin
Paclitaxel, vinblastine, vincristine, etoposide, 
thalidomide, gemcitabine, sirolimus
dMMR, deficiency in mismatch repair proteins; MSI-H, microsatellite instability-high; PD-L1, programmed death-ligand 1.
Table 39–3.
 
Common chemotherapeutic agents.
1
Agent
Usual Adult Dosage
Alkylating Agents—Nitrogen Mustards
Bendamustine 
(Treanda)
100–120 mg/m
2
 intravenously every 3–4 weeks
Acute: hypersensitivity, nausea, vomiting
Delayed: myelosuppression, rash, pyrexia, fatigue
Cyclophosphamide 
(Cytoxan)
500–1000 mg/m
2
 intravenously every 3 weeks; 100 mg/
m
2
/day orally for 14 days every 4 weeks; various doses
Acute: nausea and vomiting
Delayed: myelosuppression, alopecia, hemorrhagic 
 
cystitis, cardiotoxicity (high dose)
Ifosfamide (Ifex)
1200 mg/m
2
 intravenously daily for 5 days every 
3 weeks; various doses
Delayed: alopecia, myelosuppression, hemorrhagic 
 
cystitis, neurotoxicity
Melphalan (Alkeran)
0.25 mg/kg/day or 8–10 mg/m
2
/day orally for 4 days 
every 4–6 weeks; 16 mg/m
2
 intravenously every 
 
2–4 weeks; various doses
Acute: nausea, vomiting, diarrhea, hypersensitivity 
(intravenously)
Delayed: mucositis (intravenously), myelosuppression, 
increased risk of secondary malignancies
Alkylating Agents—
p
latinum Analogs
Carboplatin 
(Paraplatin)
Area under the curve (AUC)-based dosing use Calvert 
equation
[Dose (mg) = AUC × (GFR + 25)]
AUC = 2–7 mg/mL/min every 2–4 weeks
Delayed: myelosuppression, electrolyte disturbances, 
peripheral neuropathy, nephrotoxicity, 
hypersensitivity
Cisplatin (Platinol)
50–100 mg/m
2
 intravenously every 3–4 weeks; 20 mg/
m
2
/day intravenously for 5 days every 3 weeks; 
 
various doses
Delayed: nephrotoxicity, ototoxicity, neurotoxicity, 
myelosuppression, electrolyte disturbances
Oxaliplatin (Eloxatin)
85–130 mg/m
2
 intravenously every 2–3 weeks
Acute: peripheral neuropathy exacerbated by cold, 
 
nausea, vomiting, diarrhea
Delayed: myelosuppression, elevated transaminases
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1616

CANCER
1617
 
CMDT 2019
 
1
Agent
Alkylating Agents—Triazenes
Dacarbazine 
(DTIC-Dome)
375 mg/m
2
 intravenously on day 1 and 15 every 
 
4 weeks; 900–1000 mg/m
2
 intravenously over 
 
3 to 4 days; various doses
Acute: nausea, vomiting, photosensitivity
Delayed: myelosuppression, anorexia, hypotension, 
 
flu-like syndrome
Procarbazine 
(Matulane)
60–100 mg/m
2
 orally for 14 days every 4 weeks; various 
doses
Delayed: myelosuppression, disulfiram-like reaction, 
MAO inhibition, rash
Temozolomide 
(Temodar)
75 mg/m
2
 orally daily during radiation for 42 days; 
 
150–200 mg/m
2
 orally for 5 days every 4 weeks
Acute: nausea, vomiting, constipation
Delayed: myelosuppression, fatigue
Alkylating Agent—Miscellaneous
Busulfan (Myleran)
1–8 mg orally daily; 0.8 mg/kg intravenously every 
 
6 hours for 4 days
Delayed: myelosuppression, mucositis, rash, edema, 
electrolyte disturbances, hepatic veno-occlusive 
 
disease (high dose)
Chlorambucil 
(Leukeran)
0.1–0.2 mg/kg/day orally for 3–6 weeks; 0.4 mg/kg pulse 
Acute: nausea
Delayed: myelosuppression, rash
Antimetabolites—Folate Antagonists
Methotrexate (MTX; 
Trexall)
Intrathecal:
 12 mg
h
igh dose:
 1000–12,000 mg/m
2
 
2–3 weeks
Acute: nausea, vomiting, mucositis
Delayed: myelosuppression, nephrotoxicity, hepatotoxicity, 
neurotoxicity, photosensitivity, pulmonary toxicity
Pemetrexed (Alimta)
500 mg/m
2
 intravenously every 3 weeks
Acute: nausea, vomiting, diarrhea, rash
Delayed: myelosuppression, fatigue, mucositis
Antimetabolites—
p
urine A
nalogs
Cladribine (Leustatin)
0.1 mg/kg/day subcutaneously daily for 5 days or 
 
0.09 mg/kg/day intravenously via continuous 
 
infusion for 7 days
Acute: nausea, injection site reaction
Delayed: myelosuppression, immunosuppression, fever, 
fatigue, rash
Clofarabine (Clolar)
52 mg/m
2
 
2–6 weeks (for patients < 21 years of age)
Acute: nausea, vomiting, diarrhea
Delayed: myelosuppression, hepatotoxicity, 
 
nephrotoxicity, rash, capillary leak syndrome
Fludarabine (Fludara)
25 mg/m
2
 intravenously for 5 days every 4 weeks
Acute: fever, nausea, vomiting
Delayed: asthenia, myelosuppression, 
 
immunosuppression, neurotoxicity, anorexia
Mercaptopurine (6-MP; 
Purinethol)
Induction: 2.5–5 mg/kg/day orally
Maintenance: 1.5–2.5 mg/kg/day orally
Delayed: myelosuppression, immunosuppression, hepa
-
totoxicity, mucositis
Pentostatin (Nipent)
2–4 mg/m
2
Acute: nausea, vomiting, rash
Delayed: myelosuppression, fever, myalgia, 
 
immunosuppression, hepatotoxicity, cough
p
yrimidine A
nalogs
Azacitidine (Vidaza)
75–100 mg/m
2
 subcutaneously or intravenously for 
 
7 days every 4 weeks
Acute: injection site reaction (subcutaneously), nausea, 
diarrhea, fever
Delayed: myelosuppression, dyspnea, arthralgia
Capecitabine (Xeloda)
1000–1250 mg/m
2
 orally twice a day for 14 days every 
 
3 weeks
Delayed: hand-foot syndrome, mucositis, 
 
hyperbilirubinemia, myelosuppression
Cytarabine (Ara-C, 
Cytosar U)
Standard dose: 100 mg/m
2
/day intravenously via contin
-
uous infusion for 7 days
High dose: 1000–3000 mg/m
2
 
12 hours for 2–6 days
Acute: nausea, vomiting, rash, flu-like syndrome
Delayed: myelosuppression
High-dose: neurotoxicity, ocular toxicities
Decitabine (Dacogen)
15 mg/m
2
 intravenously every 8 hours for 3 days every 
 
8 weeks; 20 mg m
2
 intravenously daily for 5 days
Acute: nausea, vomiting, hyperglycemia
Delayed: myelosuppression, fever, fatigue, cough
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1617

Ch
A
p
TER
 3
9
1618
 CMDT 2019
 
1
Agent
Fluorouracil (Adrucil)
400 mg/m
2
 intravenous bolus followed by 2400 mg/m
2
 
intravenously over 46 hours every 2 weeks; 
 
1000 mg/m
2
 intravenously via continuous infusion 
 
for 4–5 days every 3–4 weeks; various doses
Delayed: myelosuppression, hand-foot syndrome, 
 
mucositis, photosensitivity, cardiotoxicity (rare)
Gemcitabine (Gemzar)
2
 intravenously on days 1 and 8 every 
3 weeks or days 1, 8, 15 every 4 weeks
Acute: nausea, vomiting, rash, flu-like symptoms, fever, 
diarrhea
Delayed: myelosuppression, edema, elevated 
transaminases
Antimicrotubules—Vinca Alkaloids
Vinblastine (Velban)
6 mg/m
2
 intravenously on days 1 and 15 every 4 weeks; 
Acute: constipation
Delayed: myelosuppression, alopecia, bone pain, malaise
Vincristine (Oncovin)
0.5–1.4 mg/m
2
 intravenously every 3 weeks; various 
doses; maximum single dose usually limited to 2 mg
Acute: constipation, nausea
Delayed: peripheral neuropathy, alopecia
Vinorelbine 
(Navelbine)
25–30 mg/m
2
 intravenously weekly
Acute: nausea, vomiting
Delayed: myelosuppression, peripheral neuropathy, 
 
constipation, alopecia, asthenia
Antimicrotubules—Taxanes
Cabazitaxel (Jevtana)
25 mg/m
2
Acute: diarrhea, nausea, vomiting, hypersensitivity
fatigue
Docetaxel (Taxotere)
2
Acute: nausea, vomiting, diarrhea, hypersensitivity, rash
Delayed: myelosuppression, asthenia, peripheral neu
-
ropathy, alopecia, edema, mucositis
Paclitaxel (Taxol)
135–175 mg/m
2
 intravenously every 3 weeks; 
 
50–80 mg/m
2
 intravenously weekly; various doses
 
alopecia, mucositis, arthralgia
Paclitaxel protein-
bound (Abraxane)
100–125 mg/m
2
 on days 1, 8, 15 every 3–4 weeks; 
 
260 mg/m
2
 
alopecia, asthenia
Enzyme Inhibitors—Anthracyclines
Daunorubicin 
(Cerubidine)
30–60 mg/m
2
 intravenously for 3 days
Acute: nausea, vomiting, diarrhea, red/orange 
 
discoloration of urine, infusion-related reactions 
 
(liposomal products)
Delayed: myelosuppression, mucositis, alopecia, 
 
hand-foot syndrome (liposomal doxorubicin), 
 
cardiotoxicity (dose related)
Doxorubicin 
(Adriamycin)
45–75 mg/m
2
doses
Epirubicin (Ellence)
60–120 mg/m
2
Idarubicin (Idamycin)
10–12 mg/m
2
Liposomal Daunorubi
-
cin (Daunoxome)
40 mg/m
2
 intravenously every 2 weeks
Liposomal Doxorubicin 
(Lipodox)
20–50 mg/m
2
Enzyme Inhibitors—Topoisomerase Inhibitors
Etoposide (Vepesid)
2
 intravenously for 3–5 days every 3 weeks
Acute: nausea, vomiting, diarrhea, hypersensitivity, fever, 
hypotension
Delayed: myelosuppression, alopecia, fatigue
Etoposide phosphate 
(Etopophos)
35–100 mg/m
2
 intravenously for 3–5 days every 
 
3–4 weeks
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1618

CANCER
1619
 
CMDT 2019
 
1
Agent
Irinotecan (Camptosar)
180 mg/m
2
 intravenously every other week; various 
doses
Acute: diarrhea, cholinergic syndrome, nausea, vomiting
Delayed: myelosuppression, alopecia, asthenia
Topotecan (Hycamtin)
1.5 mg/m
2
 intravenously for 5 days every 3 weeks; 
 
2.3 mg/m
2
 orally for 5 days every 3 weeks
Immunomodulatory Therapy
Lenalidomide 
(Revlimid)
5–25 mg orally once daily on days 1–21 of 28-day cycle; 
or continuously
Acute: diarrhea, rash
Delayed: myelosuppression, fatigue, venous 
 
thromboembolism, potential for birth defects
Pomalidomide 
(Pomalyst)
4 mg orally once daily on days 1–21 of 28-day cycle
Acute: nausea, diarrhea, dizziness
Delayed: myelosuppression, fatigue, neuropathy, 
 
upper respiratory tract infections, venous 
 
Thalidomide 
(Thalomid)
50–800 mg orally once daily
Acute: sedation, constipation, rash
Delayed: edema, peripheral neuropathy, venous 
 
p
r
oteasome Inhibitors
Bortezomib (Velcade)
1.3 mg/m
2
 intravenous bolus or subcutaneously on days 
1, 4, 8, 11 followed by a 10-day rest, or weekly for 
4 weeks followed by 13-day rest
Delayed: peripheral neuropathy, fatigue, 
myelosuppression
Carfilzomib (Kyprolis)
20 mg/m
2
 or 27 mg/m
2
 intravenously on days 1, 2, 8, 9, 
15, 16 followed by a 12-day rest (28-day cycle)
Acute: nausea, dyspnea, diarrhea, infusion-related 
reaction
Delayed: fatigue, myelosuppression, elevated serum 
Ixazomib (Ninlaro)
4 mg orally on days 1, 8, 15 of a 28-day treatment cycle
Acute: diarrhea, constipation, nausea, vomiting
peripheral edema, rash, hepatotoxicity (rare)
Targeted Therapy—Monoclonal Antibodies
Ado-trastuzumab 
emtansine (Kadcyla)
3.6 mg/kg intravenously every 3 weeks
Acute: infusion-related reaction, nausea
Delayed: fatigue, musculoskeletal pain, 
 
thrombocytopenia, cardiotoxicity, heptatotoxicity
Alemtuzumab 
(Campath)
3–10 mg intravenously or subcutaneously three times 
weekly
Acute: infusion-related reaction, nausea, vomiting, 
 
hypotension, rash
Delayed: myelosuppression, immunosuppression
Atezolizumab 
(Tecentriq)
1200 mg intravenously every 3 weeks
Acute: infusion-related reaction
Delayed: immune-mediated reactions, fatigue, 
decreased appetite
Bevacizumab (Avastin)
5–15 mg/kg intravenously every 2–3 weeks
Delayed: hypertension, proteinuria, wound healing 
 
complications, gastrointestinal perforation, 
Brentuximab vedotin 
(Adcetris)
1.8 mg/kg intravenously every 3 weeks
diarrhea
fatigue, rash, cough
Cetuximab (Erbitux)
Loading dose 400 mg/m
2
 intravenously, maintenance 
dose 250 mg/m
2
Acute: infusion-related reaction, nausea, diarrhea
Delayed: acneiform skin rash, hypomagnesemia, 
 
asthenia, paronychial inflammation, dyspnea
Daratumumab 
(Darzalex)
16 mg/kg intravenously weekly for weeks 1–8, every 
 
2 weeks for weeks 9–24, and every 4 weeks from 
week 25 until disease progression
Delayed: myelosuppression, fatigue, upper respiratory 
tract infection
Elotuzumab (Empliciti)
10 mg/kg intravenously every week for the first 2 cycles 
and every 2 weeks thereafter
Acute: infusion-related reaction, diarrhea
Delayed: fatigue, peripheral neuropathy, risk
for opportunistic infections
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1619

Ch
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 CMDT 2019
 
1
Agent
Ipilimumab (Yervoy)
3 mg/kg intravenously every 3 weeks for a total of four 
doses
Delayed: immune-related reactions, fatigue
Necitumumab 
(Portrazza)
800 mg intravenously over 60 mins prior to gemcitabine 
and cisplatin on days 1 and 8 of 21-day cycle
Acute: infusion-related reaction, vomiting, diarrhea
Delayed: electrolyte abnormalities (especially 
 
hypomagnesemia), rash, cardiopulmonary arrest (rare)
Nivolumab (Opdivo)
3 mg/kg intravenously over 1 hour every 2 weeks
Acute: vomiting
Delayed: fatigue, musculoskeletal pain, rash, pruritus, 
cough, elevated transaminases
Obinutuzumab 
(Gazyva)
Cycle 1: 100 mg intravenously on day 1, 900 mg on day 
2, 1000 mg on day 8 and 15 of a 28-day cycle; Cycles 
2–6: 1000 mg intravenously on day 1
Acute: infusion-related reaction, tumor lysis syndrome
Delayed: myelosuppression, pyrexia, cough, 
 
musculoskeletal disorder, potential hepatitis 
 
B reactivation
Ofatumumab (Arzerra)
300 mg initial dose intravenously, followed 1 week later 
by 2000 mg intravenously weekly for 7 doses, followed 
4 weeks later by 2000 mg intravenously every 4 weeks 
for four doses; or 300 mg initial dose intravenously, 
 
followed 1 week later by 1000 mg intravenously, then 
1000 mg intravenously every 4 weeks
Acute: infusion-related reaction, diarrhea, nausea
Delayed: neutropenia, infections, pyrexia, rash, fatigue, 
potential hepatitis B reactivation
Olaratumab (Lartruvo)
15 mg/kg intravenously on days 1 and 8 of a 
 
21-day cycle
Acute: nausea, vomiting, infusion-related reaction
Delayed: fatigue, musculoskeletal pain, mucositis, 
alopecia
Panitumumab 
(Vectibix)
6 mg/kg intravenously every 2 weeks
 
asthenia, paronychia, fatigue, dyspnea
Pembrolizumab 
(Keytruda)
2 mg/kg intravenously every 3 weeks
Delayed: immune-mediated reactions, fatigue, cough
Pertuzumab (Perjeta)
840 mg intravenously once followed by 420 mg 
 
intravenously every 3 weeks
Delayed: fatigue, alopecia, neutropenia, rash, peripheral 
neuropathy, cardiomyopathy
Ramucirumab 
(Cyramza)
8 mg/kg intravenously every 2 weeks or 10 mg/kg 
 
Acute: infusion-related reaction, hypertension, diarrhea
Delayed: fatigue, neutropenia, epistaxis
Rituximab (Rituxan)
375 mg/m
2
 intravenously weekly for 4 weeks, or every 
3–4 weeks
Delayed: lymphopenia, asthenia, rash, potential 
 
hepatitis B reactivation
Trastuzumab 
(Herceptin)
Initial dose 4 mg/kg intravenously, then 2 mg/kg 
 
intravenously weekly; or initial dose 8 mg/kg then 
 
6 mg/kg, intravenously every 3 weeks
Acute: headache, nausea, diarrhea, infusion-related 
reaction
Delayed: myelosuppression, pyrexia, cardiomyopathy, 
pulmonary toxicity (rare)
Targeted Therapy—Kinase Inhibitors
Afatinib (Gilotrif)
40 mg orally once daily without food
Acute: diarrhea
Delayed: acneiform rash, stomatitis, paronychia
Alectinib (Alecensa)
600 mg orally twice daily with food
Acute: none
Delayed: myelosuppression, fatigue, edema, myalgia, 
dyspnea, elevated transaminases
Axitinib (Inlyta)
5–10 mg orally twice daily
Acute: diarrhea, nausea, vomiting
Delayed: hypertension, fatigue, dysphonia, hand-foot 
syndrome, elevated transaminases
Bosutinib (Bosulif)
500–600 mg orally once daily with food
Delayed: myelosuppression, rash, abdominal pain, 
 
hepatotoxicity, fluid retention
Ceritinib (Zykadia)
740 mg orally once daily
Delayed: elevated transaminases, abdominal pain, 
fatigue, decreased appetite
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1620

CANCER
1621
 
CMDT 2019
 
1
Agent
Cobimetinib (Cotellic)
60 mg orally once daily on days 1 to 21 of a 28-day cycle
Acute: diarrhea, photosensitivity reaction, nausea, 
vomiting
Delayed: myelosuppression, hepatotoxicity, rash, 
 
cardiomyopathy (with vemurafenib)
Crizotinib (Xalkori)
Acute: nausea, vomiting, diarrhea, constipation
Delayed: vision disorder, edema, elevated transaminases, 
fatigue
Dabrafenib (Tafinlar)
150 mg orally twice daily without food
Acute: headache
Delayed: hyperkeratosis, fever, hand-foot syndrome, 
hyperglycemia, hypophosphatemia
Dasatinib (Sprycel)
100–180 mg orally once daily
Delayed: myelosuppression, fluid retention, fatigue, 
 
dyspnea, musculoskeletal pain, rash
Erlotinib (Tarceva)
100 or 150 mg orally once daily without food
Delayed: acneiform skin rash, fatigue, anorexia, dyspnea
Everolimus (Afinitor)
10 mg orally once daily
Acute: mucositis, diarrhea, nausea
Delayed: myelosuppression, fatigue, edema, 
 
hypercholesterolemia, hypertriglyceridemia, 
Gefitinib (Iressa)
250 mg orally once daily
Delayed: acneiform skin rash
Ibrutinib (Imbruvica)
420 mg or 560 mg orally once daily
Acute: diarrhea, nausea
Delayed: myelosuppression, fatigue, edema, rash, 
 
elevated serum creatinine, hemorrhage
Idelalisib (Zydelig)
150 mg orally twice daily
Delayed: hepatotoxicity, pneumonitis, intestinal 
 
perforation, pyrexia, fatigue, neutropenia, 
 
hypertriglyceridemia, hyperglycemia
Imatinib (Gleevec)
100–800 mg orally once daily with food
Delayed: edema, muscle cramps, rash, 
 
myelosuppression, hepatotoxicity
Lapatinib (Tykerb)
1250 mg or 1500 mg orally once daily
Delayed: hand-foot syndrome, fatigue, hepatotoxicity 
(rare)
Lenvatinib (Lenvima)
24 mg orally daily
Acute: hypertension, nausea, vomiting, diarrhea
Delayed: fatigue, arthralgia/myalgia, stomatitis, 
 
hand-foot syndrome
Nilotinib (Tasigna)
300 or 400 mg orally twice daily without food
Delayed: rash, fatigue, myelosuppression, prolonged QT 
interval (rare)
Osimertinib (Tagrisso)
80 mg orally once daily
Delayed: myelosuppression, rash, dry skin, nail toxicity, 
cardiomyopathy (rare), QTc interval prolongation 
(rare)
Palbociclib (Ibrance)
125 mg orally daily with food for 21 days followed by 
 
7 days off
Acute: nausea, diarrhea, vomiting
infection, stomatitis, alopecia
Pazopanib (Votrient)
800 mg orally once daily without food
Delayed: hypertension, hair color changes, 
hepatotoxicity, hemorrhage
Regorafenib (Stivarga)
160 mg orally once daily with food (low-fat breakfast)
Delayed: asthenia, hand-foot syndrome, anorexia, 
 
hypertension, mucositis, myelosuppression, 
hepatotoxicity
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1621

Ch
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 CMDT 2019
 
1
Agent
Sorafenib (Nexavar)
400 mg orally twice daily without food
Acute: diarrhea and nausea
Delayed: fatigue, hand-foot syndrome, rash, 
 
hypertension, hemorrhage
Sunitinib (Sutent)
50 mg orally once daily for 4 weeks followed by 2 weeks 
rest; 37.5 mg orally daily
Delayed: hypertension, hand-foot syndrome, rash, 
 
yellow discoloration of skin, fatigue, hypothyroidism, 
mucositis, left ventricular dysfunction, bleeding, 
Temsirolimus (Torisel)
25 mg intravenously weekly
Acute: hypersensitivity, rash
Delayed: myelosuppression, asthenia, hyperglycemia, 
hyperlipidemia, elevated serum creatinine
Trametinib (Mekinist)
2 mg orally once daily without food
Acute: rash, diarrhea
Delayed: elevated transaminases, lymphedema, 
Vemurafenib 
(Zelboraf)
960 mg orally twice daily
Acute: nausea, hypersensitivity (rare)
Delayed: photosensitivity, rash, arthralgia, alopecia, 
fatigue, prolonged QT interval, cutaneous squamous 
cell carcinoma
Miscellaneous Agents
Arsenic trioxide 
(Trisenox)
0.15 mg/kg intravenously daily
Acute: nausea, dizziness
Delayed: acute promyelocytic leukemia differentiation 
syndrome, prolonged QT interval
Asparaginase Erwinia 
chrysanthemi 
(Erwinaze)
25,000 international units/m
2
 intramuscularly three 
times weekly
Delayed: coagulation abnormalities, hepatotoxicity, 
 
pancreatitis, neurotoxicity
Bleomycin (Blenoxane)
10 units/m
2
 intravenously on days 1 and 15 every 
28 days; 30 units intravenously on day 2, 9, and 
16 every 21 days
Acute: hypersensitivity, fever
Delayed: skin reaction (rash, hyperpigmentation of skin, 
striae), mucositis, pneumonitis
Dactinomycin 
(Cosmegen)
15 mcg/kg or 400–600 mcg/m
2
 intravenously daily for 
 
5 days
Delayed: myelosuppression, mucositis, rash, diarrhea, 
hepatoveno-occlusive disease (rare)
Hydroxyurea (Hydrea)
20–30 mg/kg orally daily
Mitomycin 
(Mutamycin)
10–20 mg/m
2
 intravenously every 4–8 weeks; 20–40 mg 
intravesically
Acute: cystitis (intravesically), nausea, vomiting
Delayed: myelosuppression, mucositis, anorexia
Mitoxantrone 
(Novantrone)
12–14 mg/m
2
 intravenously every 3 weeks; 12 mg/m
2
 
intravenously for 2–3 days
Acute: nausea, vomiting, diarrhea, mucositis, blue-green 
discoloration of urine
Delayed: myelosuppression, alopecia, cardiotoxicity
Omacetaxine mepe
-
succinate (Synribo)
Induction: 1.25 mg/m
2
 subcutaneously twice daily for 
 
14 days every 28 days
Maintenance: 1.25 mg/m
2
 subcutaneously twice daily 
for 7 days every 28 days
Acute: diarrhea, nausea, fatigue, injection site reaction
Delayed: myelosuppression, infection
Panobinostat (Farydak)
20 mg orally per day on days 1, 3, 5, 8, 10, 12 of each 
Delayed: myelosuppression, electrolyte abnormalities, 
Tretinoin (All-
Trans-Retinoic Acid, 
ATRA, Vesanoid)
45 mg/m
2
 orally divided twice daily for 45–90 days or 
30 days past complete remission
Acute: headache, nausea
Delayed: vitamin A toxicity, retinoic acid-acute 
 
promyelocytic leukemia syndrome
Trifluridine/tipiracil 
(Lonsurf)
35 mg/m
2
 based on trifluridine component orally twice 
daily within 1 hour of meal on days 1–5 and 8–12 
 
(28-day cycle)
Delayed: myelosuppression, fatigue, anorexia
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1622

CANCER
1623
 
CMDT 2019
 
1
Agent
Venetoclax (Venclexta)
20 mg orally daily during week 1; 50 mg daily during 
week 2; 100 mg daily during week 3; 200 mg daily 
during week 4; then 400 mg orally daily thereafter
Acute: diarrhea, nausea, vomiting, tumor lysis syndrome
Delayed: myelosuppression, upper respiratory infections, 
fatigue
Ziv-aflibercept 
(Zaltrap)
4 mg/kg intravenously every 2 weeks
Delayed: myelosuppression, proteinuria, elevated 
 
transaminases, stomatitis, fatigue, hypertension
Antiandrogens
Bicalutamide 
(Casodex)
Delayed: hot flashes, back pain, asthenia
Enzalutamide (Xtandi)
160 mg orally once daily
Acute: asthenia, diarrhea
Delayed: hot flashes, arthralgia, peripheral edema
Flutamide (Eulexin)
250 mg orally every 8 hours
Delayed: hot flashes, hepatotoxicity
Nilutamide (Nilandron)
300 mg orally for 30 days, then 150 mg orally once daily
Delayed: visual disturbances (impaired adaptation to 
dark), hot flashes, disulfiram-like reaction
Selective Estrogen Receptor Modulators
Tamoxifen (Nolvadex)
20–40 mg orally once daily
Delayed: hot flashes, vaginal discharge, menstrual 
 
irregularities, arthralgia
Toremifene (Fareston)
Delayed: hot flashes, vaginal discharge
Aromatase Inhibitors
1 mg orally once daily
Delayed: hot flashes, peripheral edema, asthenia, 
 
hypercholesterolemia, arthralgia/myalgia, osteoporosis
Exemestane 
(Aromasin)
2.5 mg orally once daily
p
ur
e Estrogen Receptor Antagonist
500 mg intramuscularly on days 1, 15, 29, then monthly
Acute: injection site reaction, nausea
Delayed: hot flashes, bone pain, elevated transaminases
L
h
R
h
 Analogs
Goserelin acetate 
(Zoladex)
3.6 mg subcutaneously every month; 10.8 mg subcuta
-
neously every 3 months
Acute: injection site discomfort
Delayed: hot flashes, tumor flare, edema, decreased 
libido, erectile dysfunction, osteoporosis
Leuprolide (Lupron)
7.5 mg intramuscularly or subcutaneously every month; 
22.5 mg intramuscularly or subcutaneously every 
 
3 months; 30 mg intramuscularly or subcutaneously 
every 4 months; 45 mg intramuscularly or 
 
subcutaneously every 6 months
Triptorelin pamoate 
(Trelstar)
3.75 mg intramuscularly every 4 weeks; 11.25 mg 
 
intramuscularly every 12 weeks; 22.5 mg every 
 
24 weeks
L
h
R
h
 Antagonist
Degarelix (Firmagon)
240 mg subcutaneously once, then 80 mg 
 
subcutaneously every 28 days
Acute: injection site reaction
Delayed: hot flashes, weight gain, elevated transami
-
nases, QT prolongation
(
continued
)
CMDT19_Ch39_p1611-p1680.indd   1623

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 CMDT 2019
 
º
TY
p
ES OF CANCER
LUNG CANCER
BRONCHOGENIC CARCINOMA
 
»
New cough or change in chronic cough.
 
»
Dyspnea, hemoptysis, anorexia, weight loss.
 
»
Enlarging nodule or mass; persistent opacity, 
atelectasis, or pleural effusion on chest radiograph 
or CT scan.
 
»
Cytologic or histologic findings of lung cancer in 
sputum, pleural fluid, or biopsy specimen.
 
»
Lung cancer is the leading cause of cancer deaths in both 
men and women. The American Cancer Society estimates 
222,500 new diagnoses and 155,870 deaths from lung can
-
cer in the United States in 2017, accounting for approxi
-
mately 13% of new cancer diagnoses and 26% of all cancer 
deaths.
Cigarette smoking causes 85–90% of cases of lung 
cancer. The causal connection between cigarettes and lung 
cancer is established not only epidemiologically but also 
through identification of carcinogens in tobacco smoke 
 
1
Agent
Adrenocorticosteroid
Abiraterone (Zytiga)
1000 mg orally once daily
Acute: diarrhea, edema
Delayed: adrenal insufficiency, hepatotoxicity, joint pain, 
hypokalemia
Biologic Response Modifiers
Aldesleukin (IL-2, 
Proleukin)
600,000 international units/kg intravenously every 
 
8 hours for 14 doses, repeat after 9 days rest
Acute: hypotension, nausea, vomiting, diarrhea, flu-like 
syndrome, capillary leak syndrome
Delayed: myelosuppression, confusion, somnolence, 
oliguria
Interferon-alpha-2b 
(Intron A)
20 million international units/m
2
 intravenously 5 days a 
week for 4 weeks, then 10 million international units/
m
2
 subcutaneously three times a week for 48 weeks
Acute: flu-like syndrome, nausea, vomiting, diarrhea
Delayed: myelosuppression, anorexia, alopecia, 
 
depression, elevated transaminases
Sipuleucel-T 
(Provenge)
One dose (minimum of 50 million autologous CD54 
cells) intravenously every 2 weeks for three doses
Acute: infusion-related reaction, nausea, vomiting
Delayed: fatigue, back pain, arthralgia
1
For altretamine, belinostat, blinatumomab, denileukin diftitox, ibritumomab, irinotecan liposome, ixabepilone, ketoconazole, liposomal 
vincristine, lomustine, mechlorethamine, megestrol, olaparib, pralatrexate, romidepsin, siltuximab, vandetanib, and vismodegib, 
see Table 39–3 in 
 at www.accessmedicine.com.
GFR, glomerular filtration rate; LHRH, luteinizing hormone–releasing hormone; MAO, monoamine oxidase; MCV, mean corpuscular volume.
and analysis of the effect of these carcinogens on specific 
oncogenes expressed in lung cancer.
Other environmental risk factors for the development of 
lung cancer include exposure to environmental tobacco 
smoke, radon, asbestos, diesel exhaust, ionizing radiation, 
metals (arsenic, chromium, nickel, iron oxide), and indus
-
trial carcinogens. A familial predisposition to lung cancer is 
recognized. Certain diseases are associated with an 
increased risk of lung cancer, including pulmonary fibrosis, 
chronic obstructive pulmonary disease, and sarcoidosis.
The median age at diagnosis of lung cancer in the 
United States is 70; it is unusual under the age of 40. The 
combined relative 5-year survival rate for all stages of lung 
cancer is currently 18%.
There are five main histologic categories of broncho
-
genic carcinoma. 
Squamous cell carcinomas
 (23% of 
cases, based on US SEER data 2010–2014) arise from the 
bronchial epithelium and often present as an intraluminal 
mass. They are usually centrally located and can present 
with hemoptysis. Squamous cell carcinomas stain for P63 
and P40 on immunohistochemistry. 
Adenocarcinomas
 
(47% of cases) arise from mucous glands or from any epi
-
thelial cell within or distal to the terminal bronchioles. 
They usually present as peripheral nodules or masses and 
stain for TTF-1 and Napsin-A on immunohistochemistry. 
Adenocarcinomas in situ

-
 (formerly 
bronchioloalveolar 
cell carcinomas)
 spread along preexisting alveolar struc
-
tures (lepidic growth) without evidence of invasion. 
Large 
cell carcinomas
 (2% of cases) are a heterogeneous group of 
undifferentiated cancers that share large cells and do not fit 
into other categories. Large cell carcinomas are typically 
aggressive and have rapid doubling times. They present as 
central or peripheral masses. Cancers that are not better 
differentiated on pathologic review other than non–small 
CMDT19_Ch39_p1611-p1680.indd   1624

CANCER
1625
 
CMDT 2019
cell carcinomas (NSCLC) or carcinomas not otherwise 
specified make up about 15% of cases. 
Small cell 
carcinomas
 (13% of cases) are tumors of bronchial origin 
that typically begin centrally, infiltrating submucosally to 
cause narrowing of the bronchus without a discrete 
luminal mass. They are aggressive cancers that often 
involve regional or distant metastasis on presentation.
For purposes of staging and treatment, bronchogenic 
carcinomas are divided into small cell lung cancer (SCLC) 
and the other four types, labeled NSCLC.
 
»
Lung cancer is symptomatic at diagnosis in a majority of 
patients. The clinical presentation depends on the type and 
location of the primary tumor, the extent of local spread, 
and the presence of distant metastases and any paraneo
-
plastic syndromes.
Anorexia, weight loss, or asthenia occurs in 55–90% of 
patients presenting with a new diagnosis of lung cancer. Up 
to 60% of patients have a new cough or a change in a 
chronic cough; 6–31% have hemoptysis; and 25–40% com
-
plain of pain, either nonspecific chest pain or pain from 
bony metastases to the vertebrae, ribs, or pelvis. Local 
spread may cause endobronchial obstruction with 
atelectasis and postobstructive pneumonia, pleural effu
-
sion (12–33%), change in voice (compromise of the recur
-
rent laryngeal nerve), superior vena cava syndrome 
(obstruction of the superior vena cava with supraclavicular 
venous engorgement), and Horner syndrome (ipsilateral 
ptosis, miosis, and anhidrosis from involvement of the 
inferior cervical ganglion and the paravertebral sympa
-
thetic chain). Distant metastases to the liver are associated 
with asthenia and weight loss. Brain metastases (10% in 
NSCLC, more common in adenocarcinoma, and 20–30% 
in SCLC) may present with headache, nausea, vomiting, 
seizures, dizziness, or altered mental status.
Paraneoplastic syndromes
 are patterns of organ dys
-
function related to immune-mediated or secretory effects of 
neoplasms. These syndromes occur in 10–20% of lung 
cancer patients. They may precede, accompany, or follow the 
diagnosis of lung cancer. In patients with small cell carci
-
noma, the syndrome of inappropriate antidiuretic hormone 
(SIADH) can develop in 10–15%; in those with squamous 
cell carcinoma, hypercalcemia can develop in 10%. Digital 
clubbing is seen in up to 20% of patients at diagnosis (see 
Figure 6–41). Other common paraneoplastic syndromes 
include increased ACTH production, anemia, hypercoagu
-
lability, peripheral neuropathy, and the Lambert-Eaton 
myasthenic syndrome. Their recognition is important 
because treatment of the primary tumor may improve or 
resolve symptoms even when the cancer is not curable.
The diagnosis of lung cancer rests on examination of a tis
-
sue or cytology specimen. 
 is highly spe
-
cific but insensitive; the yield is highest when there are 
lesions in the central airways. 
Thoracentesis
 (sensitivity 
50–65%) can be used to establish a diagnosis of lung cancer 
in patients with malignant pleural effusions. Fine-needle 
aspiration (FNA) of palpable supraclavicular or cervical 
lymph nodes is frequently diagnostic.
Fiberoptic bronchoscopy
 allows visualization of the 
major airways, cytology brushing of visible lesions or lavage 
of lung segments with cytologic evaluation of specimens, 
direct biopsy of endobronchial abnormalities, blind trans
-
bronchial biopsy of the pulmonary parenchyma or periph
-
eral nodules, and FNA biopsy of mediastinal lymph nodes. 
The use of fluorescence bronchoscopy improves the ability 
to identify early endobronchial lesions, and endobronchial 
and transesophageal endoscopic ultrasound enhance the 
direction and yield of FNA of mediastinal nodes. Electro
-
magnetic navigational bronchoscopy allows bronchoscopic 
approaches to small peripheral nodules. While the diagnos
-

-
-
tic yield of CT-guided biopsies of peripheral nodules 
approaches 80–90%, the rates of pneumothorax are signifi
-
cant (15–30%), especially in those with emphysema.
C. Imaging
Nearly all patients with lung cancer have abnormal find
-
ings on chest radiography or CT scan (Figure 39–1). These 
findings are rarely specific for a particular diagnosis. Inter
-
pretation of characteristic findings in isolated nodules is 
described in Chapter 9.
1. Staging—
Accurate staging is crucial (1) to provide the 
clinician with information to guide treatment, (2) to pro
-
vide the patient with accurate information regarding prog
-
nosis, and (3) to standardize entry criteria for clinical trials 
to allow interpretation of results.
There are two essential principles of staging 
NSCLC
. 
First, the more extensive the disease, the worse the prognosis; 
second, surgical resection offers the best chance for cure. 
Staging of NSCLC uses two integrated systems. The 
TNM 
international staging system
 attempts a physical description 
of the neoplasm: T describes the size and location of the pri
-
mary tumor; N describes the presence and location of nodal 
metastases; and M refers to the presence or absence of distant 
metastases. These TNM stages are grouped into summary 
stages I–IV , and these are used to guide therapy. Many 
patients with stage I and stage II disease are cured through 
surgery. Patients with stage IIIB and stage IV disease do not 
benefit from surgery (Table 39–4). Patients with stage IIIA 
disease have locally invasive disease that may benefit from 
surgery in selected cases as part of multimodality therapy.
SCLC
 is traditionally divided into two categories: 
limited disease
 (30%), when the tumor is limited to the 
unilateral hemithorax (including contralateral mediastinal 
nodes); or 
extensive disease
 (70%), when the tumor 
extends beyond the hemithorax (including pleural effu
-
sion). It is also recommended to stage SCLC according to 
the TNM staging system.
For both SCLC and NSCLC, staging begins with a 
thorough history and physical examination. A complete 
examination is essential to exclude obvious metastatic 
CMDT19_Ch39_p1611-p1680.indd   1625

Ch
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 CMDT 2019
disease to lymph nodes, skin, and bone. A detailed history 
is essential because the patient’s performance status is a 
powerful predictor of disease course. All patients should 
have measurement of a complete blood count (CBC), 
serum electrolytes, calcium, creatinine, liver tests, lactate 
dehydrogenase, and albumin.
NSCLC patients being considered for surgery require 
meticulous evaluation to identify those with resectable dis
-
ease. CT imaging is key for staging candidates for resection. 
The sensitivity and specificity of CT imaging for identifying 
lung cancer metastatic to the mediastinal lymph nodes are 
57% (49–66%) and 82% (77–86%), respectively. Therefore, 
chest CT imaging alone does not provide definitive staging 
information. CT imaging helps determine where to biopsy, 
and how the mediastinum should be sampled.
Positron emission tomography (PET) using 2-[
18
F] 
fluoro-2-deoxyglucose (FDG) is an important modality for 
identifying metastatic foci in the mediastinum or distant 
sites. The sensitivity and specificity of PET for detecting 
mediastinal spread of primary lung cancer depend on the 
size of mediastinal nodes or masses. When mediastinal 
lymph nodes smaller than 1 cm are present, the sensitivity 
and specificity of PET for tumor involvement of nodes are 
74% and 96%, respectively. When CT shows lymph nodes 
larger than 1 cm, the sensitivity and specificity are 95% and 
76%, respectively.
The combination of PET and CT imaging has improved 
preoperative staging compared with CT or PET alone. 
Whole body fusion PET-CT imaging is most useful to con
-
firm lack of regional or metastatic disease in NSCLC 
patients who are candidates for surgical resection.
Disadvantages of PET imaging include limited resolu
-
tion below 1 cm and false-positive scans due to sarcoidosis, 
tuberculosis, or fungal infections. PET-CT scans are also 
inadequate for evaluating brain metastases due to normal 
physiologic FDG uptake in the brain. Obtaining an MRI of 
the brain is important to rule out brain metastases in 
patients with SCLC and in patients with NSCLC with at 
least stage II disease or poorly differentiated histologies.
2. Preoperative assessment—
See Chapter 3.
3. Pulmonary function testing—
Many patients with 
NSCLC have moderate to severe chronic lung disease that 
increases the risk of perioperative complications as well as 
long-term pulmonary insufficiency following lung resection. 
All patients considered for surgery require spirometry. In the 
absence of other comorbidities, patients with good lung 
Table 39–4.
 
Five-year survival rates for non–small cell 
lung cancer, based on TNM staging.
Stage
TNM Subset
5-Year 
 
Survival for 
Clinical TNM
5-Year Survival 
 
for 
p
a
thologic 
TNM
0
situ
1A1
T1aN0M0
92%
90%
1A2
T1bN0M0
83%
85%
IA3
T1cN0M0
77%
80%
IB
T2aN0M0
68%
73%
IIA
T2bN0M0
60%
65%
IIB
T1/T2, N1M0
T3N0M0
53%
56%
IIIA
T1/T2, N2M0
T3N1M0
T4, N0/N1, M0
36%
41%
IIIB
T1/T2, N3M0
T3/T4, N2M0
26%
24%
IIIC
T3/T4, N3M0
13%
12%
IVA
Any T, Any N, 
M1a/M1b
10%
-
IVB
M1c
0%
-
Data from multiple sources. Modified and reproduced, with 
permission, from Detterbeck FC et al. The Eighth Edition Lung 
Cancer Stage Classification. Chest. 2017;151(1):193-203. Copyright 
 
© Elsevier; and data from Goldstraw P et al. The IASLC Lung Cancer 
Staging Project: proposals for revision of the TNM stage groupings 
in the forthcoming (eighth) edition of the TNM classification for 
lung cancer. J Thorac Oncol. 2015 Sept;11(1):39-51
A
B
 
▲
Figure 39–1.
 
Squamous cell carcinoma of the left 
lung on chest radiograph (A) and CT scan (B). 
permission, from David A. Kasper, DO, MBA in Usatine RP , 
 
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function (preoperative FEV
1
 2 L or more) are at low risk for 
complications from lobectomy or pneumonectomy. High-
risk patients include those with a predicted postoperative 
FEV
1
 less than 700 mL (or less than 40% of predicted FEV
1
).
4. Screening—
Screening with low-dose helical CT scans 
has been shown to improve mortality rates for lung cancer. 
The National Lung Screening Trial, a multicenter random
-
ized US trial involving over 53,000 current and former 
heavy smokers, showed that screening annually with low-
dose helical CT for 3 years yielded a 20% relative reduction 
in lung cancer mortality and 6.7% reduction in all-cause 
mortality compared to chest radiography. Given these find
-
ings, US professional organizations, including the US Pre
-
ventive Services Task Force (USPSTF), have recommended 
screening with low-dose helical CT for lung cancer. Smok
-
ing cessation policies and efforts should be integrated with 
any screening program.
 
»
Treatment
A. Non–Small Cell Lung Carcinoma
Surgical resection offers the best chance for cure of 
NSCLC. Therefore, the initial approach to the patient is 
determined by answering two questions: (1) Is complete 
surgical resection technically feasible? (2) If yes, is the 
patient able to tolerate the surgery with acceptable morbid
-
ity and mortality? Clinical features that preclude complete 
resection include extrathoracic metastases or a malignant 
pleural effusion; or tumor involving the heart, pericar
-
dium, great vessels, esophagus, recurrent laryngeal or 
phrenic nerves, trachea, main carina, or contralateral 
mediastinal lymph nodes. Accordingly, stage I and stage II 
patients are treated with surgical resection where possible. 
Stage II and select cases of stage IB are additionally recom
-
mended to receive adjuvant chemotherapy. Stage IIIA 
patients have poor outcomes if treated with resection 
alone. They should undergo multimodality treatment that 
includes chemotherapy or radiotherapy, or both. Inoperable 
stage IIIA and stage IIIB patients treated with concurrent 
chemotherapy and radiation therapy have improved 
survival. Stage IV patients are treated with systemic ther
-
apy (targeted therapy, chemotherapy, or immunotherapy) 
or symptom-based palliative therapy, or both.
Surgical approach affects outcome. In 1994, the North 
American Lung Cancer Study Group conducted a prospec
-
tive trial of stage IA patients randomized to lobectomy 
versus limited resection. They reported a threefold increased 
rate of local recurrence in the limited resection group 
 
(
P
 = 0.008) and a trend toward an increase in overall death 
rate (increase of 30%, 
P
 = 0.08) and increase in cancer-
related death rate (increase of 50%, 
P
 = 0.09), compared 
with patients receiving lobectomy. However, for patients 
who cannot tolerate lobectomy, a sublobar resection (wedge 
resection or segmentectomy) may be considered.
Patients with clinical stage I primary NSCLC, who are 
not candidates for surgery because of significant comor
-
bidity or other surgical contraindication, are candidates 
for stereotactic body radiotherapy. Stereotactic body 
radiotherapy, which is composed of multiple non-parallel 
radiation beams that converge, allows the delivery of a rela
-
tively large dose of radiation to a small, well-defined target. 
For clinical stage I NSCLC, 3-year local control rates with 
stereotactic body radiotherapy exceed 90%, and large 
meta-analyses of nonrandomized data have shown 2-year 
survival at 70% and 5-year survival at 40%. Patients with 
locally advanced disease (stages IIIA and IIIB) who are not 
surgical candidates have improved survival when treated 
with concurrent chemotherapy and radiation therapy com
-
pared with no therapy, radiation alone, or even sequential 
chemotherapy and radiation.
Neoadjuvant chemotherapy
 consists of giving antineo
-
plastic drugs in advance of surgery or radiation therapy.

-
plastic drugs in advance of surgery or radiation therapy. 
Neoadjuvant therapy is more widely used in selected 
patients with stage IIIA or select stage IIIB disease. Some 
studies suggest a survival advantage.
Adjuvant chemotherapy
 consists of administering 
antineoplastic drugs following surgery or radiation ther
-
apy. Cisplatin-containing regimens have been shown to 
confer an overall survival benefit in at least stage II disease 
and a subset of stage IB disease where primary tumor size 
exceeds 4 cm. The Lung Adjuvant Cisplatin Evaluation 
Collaborative Group, a meta-analysis of the five largest 
cisplatin-based adjuvant trials, reported a 5% absolute ben
-
efit in 5-year overall survival with a cisplatin-containing 
doublet regimen following surgery (
P
 = 0.005) in patients 
with at least stage II disease.
For stage IIIB and stage IV NSCLC, options for therapy 
include targeted therapy (Table 39–3), cytotoxic chemo
-
therapy, and immunotherapy (checkpoint inhibitors) 
(Table 39–2). The approach to therapy is individualized 
based on up-front molecular profiling and PD-L1 testing. 
Molecular profiling is offered as next-generation sequenc
-
ing multi-gene assays. The key driver mutations in lung 
cancer currently include 
EGFR, ALK, BRAF, 
and
 ROS1
, but 
only a minority of all lung cancer cases harbor these muta
-
tions. 
K-ras
 mutation is more commonly found among 
smokers but has not been targeted effectively. Difficulties in 
testing may arise when only small fine-needle aspirate biop
-
sies are obtained; it is recommended that clinicians obtain 
core biopsies for sufficient tissue for analysis. PD-L1 expres
-
sion is a flawed but currently actively used biomarker to 
assess possible response to checkpoint inhibitor therapy 
(specifically, programmed death-1 (PD-1) inhibitors).
Targeted therapy has played a pivotal role in advanced 
NSCLC (Tables 39–2 and 39–3). Activating 
EGFR
 muta
-
tions are found in approximately 10–20% of the white 
population and 30–48% in the Asian population and are 
usually found among nonsmokers to light smokers, females, 
and persons with nonsquamous histologies (particularly 
adenocarcinomas). For patients with 
EGFR
 mutations, an 
EGFR 
tyrosine kinase inhibitor (erlotinib, gefitinib, or afa
-
tinib) rather than platinum-based chemotherapy is the 
first-line treatment. Response rates with 
EGFR
 inhibitors in 
EGFR
 mutation are at least 70%, and median 
overall survival is estimated at 21–33 months. Resistance to 
erlotinib or gefitinib generally occurs in 1 year, and a com
-
mon mechanism of resistance is the development of a 
T790M 
mutation. Osimertinib, a third-generation irrevers
-
ible 
EGFR
 tyrosine kinase inhibitor, has been FDA approved 
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for the treatment of patients with the 
T790M
 mutation, 
with response rates up to 60%.
Approximately 5% of all patients with NSCLC carry 
translocations of 
ALK 
resulting in novel fusion gene prod
-
ucts with oncogenic activity. This is usually found in a 
comparatively younger population, with adenocarcinoma 
histology, and nonsmoking to light-smoking history. In 
 
a phase III trial of 
ALK
-rearranged lung cancer patients, 
treatment with crizotinib (an 
ALK
, 
cMET
 and 
ROS1
 tyro
-
sine kinase inhibitor) showed a response rate over 70% 
compared with a rate of 45% among those treated with 
standard first-line chemotherapy, and an improvement in 
median progression-free survival of 10.9 vs 7 months, 
respectively. At 1 year, however, resistance develops in 
most patients taking crizotinib. Ceritinib, alectinib, and 
brigatinib, second-generation 
ALK
 inhibitors, have been 
shown to induce response rates of 50% in those patients 
with 
ALK
-rearranged lung cancers resistant to crizotinib. 
One recent randomized trial has shown that alectinib com
-
pared to crizotinib in first-line treatment of 
ALK
-
rearranged lung cancers has superior response rates 
(83% vs 75%) and progression-free survival. Approximately 
1–2% of NSCLC harbor 
ROS1
 rearrangements and are usu
-
ally found among nonsmokers or light smokers with lung 
adenocarcinomas. 
ROS1
 rearranged lung cancers also 
respond to crizotinib with response rates over 70%. 
BRAF
 
mutations have been found in 2% of NSCLC patients. The 
combination of dabrafenib (
BRAF
 inhibitor) and tra
-
metinib (
MEK
 inhibitor) has shown response rates of over 
60% in patients with 
BRAF
 
V600E
 mutations. Finally, 
K-ras
 
mutations are found among 25% of patients with adenocar
-
cinomas, are associated with smoking, and indicate a poor 
prognosis. Unfortunately, there is still no effective targeted 
approach to therapy for 
K-ras
 mutated lung cancers.
If no targetable mutations are found and there is inade
-
quate PD-L1 expression on tumor cells, patients are offered 
cytotoxic chemotherapy (Table 39–2). Although not cura
-
tive, chemotherapy has been shown in multiple clinical trials 
to provide a modest increase in overall survival in patients 
with stage IIIB and stage IV NSCLC compared with sup
-
portive care alone, with the median survival increased from 
5 months to a range of 8–12 months and 1-year survival rate 
to 30–40%. Palliative chemotherapy also leads to improved 
quality of life and symptom control, with first-line therapy 
involving a platinum-based regimen. Platinum-based dou
-
blet regimens consist of cisplatin or carboplatin combined 
with another agent, such as pemetrexed, gemcitabine, 
taxane, or vinorelbine. The choice of chemotherapeutic 
agent should be tailored to histologic subtype in NSCLC.
Immune checkpoint inhibition with PD-1 or PD-L1 
inhibitors (nivolumab, pembrolizumab, atezolizumab, and 
durvalumab) are playing increasingly important roles in the 
treatment of NSCLC (Tables 39–2 and 39–3). Checkpoint 
inhibitors release T cells from the inhibitory signals they 
receive from tumor cells via the PD-1 pathway, restoring 
antitumor immunity. For patients with tumors staining 
greater than 50% for PDL-1, pembrolizumab outperforms 
first-line platinum-based chemotherapy, with response rates 
of 45% vs 28% and median progression-free survival of 
 
10 months vs. 6 months. Regardless of PDL-1 staining intensity, 
PD-1 inhibitors are recommended as second-line treatment of 
both nonsquamous and squamous cell lung cancers, with 
approximately 20% response rates, with durable responses, 
and with superior overall and progression-free survival com
-
pared to standard second-line chemotherapy. Significant side 
effects and toxicity have been reported with autoimmune 
manifestations, such as hepatitis, thyroiditis, hypophysitis, 
colitis, pneumonitis, and type 1 diabetes mellitus.
B. Small Cell Lung Carcinoma

Response rates of SCLC to cisplatin and etoposide 
(Table 39–2) are excellent with 80–90% response in lim
-
ited-stage disease (50–60% complete response), and 
60–80% response in extensive-stage disease (15–20% com
-
plete response). However, remissions tend to be short-lived 
with a median duration of 6–8 months. Once the disease has 
recurred, median survival is 3–4 months. Overall 2-year 
survival is 20–40% in limited-stage disease and 5% in 
extensive-stage disease (Table 39–5). Thoracic radiation 
therapy improves survival in patients with limited SCLC and 
is given concurrently with chemotherapy. Consolidative 
thoracic radiation therapy may be indicated for patients with 
extensive disease who have a significant response to chemo
-
therapy and remain free of brain metastases. There is a high 
rate of brain metastasis in patients with SCLC, even follow
-
ing a good response to chemotherapy. Prophylactic cranial 
irradiation has been shown to decrease the incidence of 
central nervous system disease and improve survival in 
patients with limited-stage disease who respond to chemo
-
therapy and a subset of patients with extensive-stage disease 
who have had an excellent response to chemotherapy.
C. Palliative Therapy
Photoresection with the Nd:YAG laser is sometimes per
-
formed on central tumors to relieve endobronchial obstruc
-
tion, improve dyspnea, and control hemoptysis. External beam 
radiation therapy is also used to control dyspnea, hemoptysis, 
endobronchial obstruction, pain from bony metastases, 
obstruction from superior vena cava syndrome, and symp
-
tomatic brain metastases. Resection of a 
solitary
 brain metasta
-
sis improves quality of life and survival when combined with 
radiation therapy if there is no evidence of other metastatic 
disease. Stereotactic radiation therapy is offered for limited 
brain metastases. Repeated thoracenteses, pleurodesis, or 
pleurex catheter tube placement are key interventions for 
Table 39–5.
 
Median survival for small cell lung 
 
carcinoma following treatment.
Stage
Mean 2-Year 
Survival
Median Survival
Limited
20–40%
15–20 months
Extensive
5%
8–13 months
Data from multiple sources, including Van Meerbeeck JP et al. 
Small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1741–55.
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palliation of symptomatic malignant pleural effusions. Pain is 
very common in advanced disease. As patients approach the 
end of life, meticulous efforts at pain control are essential (see 
Chapter 5). In addition to standard oncologic care, early refer
-
ral to a palliative care specialist is recommended in advanced 
disease to aid in symptom management and such palliative 
care can modestly improve survival.
 
»
Prognosis
The 5-year survival rate for lung cancer is approximately 
18%. Predictors of survival include the type of tumor 
(SCLC versus NSCLC), molecular profiling, the stage of 
the tumor, the patient’s performance status, and weight loss 
in the past 6 months. Patients with targetable mutations 
have better overall survival when compared with those 
without mutations due to superior efficacy of targeted drug 
therapy.
Detterbeck FC et al. The eighth edition lung cancer stage classi
-
fication. Chest. 2017 Jan;151(1):193–203. [PMID: 27780786]
Goldstraw P et al. The IASLC Lung Cancer Staging Project: pro
-
posals for the revision of the TNM stage groupings in the 
forthcoming (eighth) edition of the TNM classification for 
lung cancer. J Thorac Oncol. 2016 Jan;11(1):39–51. [PMID: 
26762738]
Gould MK. Clinical practice. Lung-cancer screening with low-
dose computed tomography. N Engl J Med. 2014 Nov 6; 
371(19):1813–20. [PMID: 25372089]
Reck M et al; KEYNOTE-024 Investigators. Pembrolizumab 
versus chemotherapy for PD-L1-positive non-small-cell lung 
cancer. N Engl J Med. 2016 Nov 10;375(19):1823–33. [PMID: 
27718847]
Reck M et al. Precision diagnosis and treatment for advanced 
non-small-cell lung cancer. N Engl J Med. 2017 Aug 31; 
377(9):849–61. [PMID: 28854088]
PULMONARY METASTASIS
Pulmonary metastasis results from the spread of an extra
-
pulmonary malignant tumor through vascular or lym
-
phatic channels or by direct extension. Metastases usually 
occur via the pulmonary artery and typically present as 
multiple nodules or masses on chest radiography. The 
radiographic differential diagnosis of multiple pulmonary 
nodules also includes pulmonary arteriovenous malforma
-
tion, infections (including abscesses, septic emboli, and 
atypical infections), sarcoidosis, rheumatoid nodules, and 
granulomatosis with polyangiitis. Metastases to the lungs 
are found in 20–55% of patients with various metastatic 
malignancies. Most are intraparenchymal. Carcinoma of 
the kidney, breast, rectum, colon, and cervix and malignant 
melanoma are the most likely primary tumors. Head and 
neck cancers with extensive or lower cervical nodal involve
-
ment have a 30% risk for distant metastasis; half of these 
metastases present in the lungs. Pulmonary metastases are 
common in patients with osteosarcomas and develop in 
approximately 20% of patients with soft tissue sarcomas.
Lymphangitic carcinomatosis
 denotes diffuse involve
-
ment of the pulmonary lymphatic network by primary or 
metastatic lung cancer, probably a result of extension of 
tumor from lung capillaries to the lymphatics. 
Tumor 
embolization
 from extrapulmonary cancer (renal cell car
-
cinoma, hepatocellular carcinoma, choriocarcinoma) is an 
uncommon route for tumor spread to the lungs. Metastatic 
cancer may also present as a malignant pleural effusion.
 
»
Symptoms are uncommon but include cough, hemoptysis 
and, in advanced cases, dyspnea and hypoxemia. Symp
-
toms are more often referable to the site of the primary 
tumor.
The diagnosis of metastatic cancer involving the lungs is 
usually established by identifying a primary tumor. Appro
-
priate studies should be ordered if there is a suspicion of 
any primary cancer, such as breast, thyroid, testis, colorectal, 
or prostate, for which specific treatment is available. If the 
history, physical examination, and initial studies fail to 
reveal the site of the primary tumor, attention is better

reveal the site of the primary tumor, attention is better 
focused on the lung, where tissue samples obtained by 
bronchoscopy, percutaneous needle biopsy, video-assisted 
thoracoscopic surgery (V ATS), or thoracotomy may estab
-
lish the histologic diagnosis and suggest the most likely 
primary cancer. Occasionally, cytologic studies of pleural 
fluid or pleural biopsy reveals the diagnosis.
To determine a primary diagnosis, immunohistochemi
-
cal staining should be done on the biopsy specimen. For 
example, prostate-specific antigen (PSA) and thyroglobu
-
lin staining are highly specific for prostate and thyroid 
cancer, respectively. Thyroid transcription factor-1 (TTF-1) 
and napsin-A are relatively specific for primary lung ade
-
nocarcinoma, while the former can be positive in cases of 
SCLC and thyroid carcinoma and the latter can be positive 
in papillary and clear cell renal cell carcinomas. An adeno
-
carcinoma that demonstrates negative TTF-1 and napsin-
A staining strongly suggests a nonpulmonary primary 
cancer. Positive estrogen receptor (ER) and progesterone 
receptor (PR) stains suggest primary breast cancer.
C. Imaging
Chest radiographs usually show multiple spherical densi
-
ties with sharp margins. The size of metastatic lesions var
-
ies from a few millimeters (miliary densities) to large 
masses. The lesions are usually bilateral, pleural or sub
-
pleural in location, and more common in lower lung zones. 
Cavitation suggests squamous cell tumor; calcification 
suggests osteosarcoma. Lymphangitic spread and solitary 
pulmonary nodule are less common radiographic presen
-
tations of pulmonary metastasis. Mammography should be 
considered in women to search for possible primary breast 
cancer. CT imaging of the chest, abdomen, and pelvis may 
reveal the site of a primary tumor and will help determine 
feasibility of surgical resection of the metastatic lung 
tumors. PET-CT scan is helpful in identifying the site of a 
primary cancer and identifying other areas of extrathoracic 
metastasis.
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»
Treatment
Once the diagnosis has been established, management 
consists of treatment of the primary neoplasm and any 
pulmonary complications. Surgical resection of a 
solitary
 
pulmonary nodule is often prudent in the patient with 
known current or previous extrapulmonary cancer. Local 
resection of one or more pulmonary metastases is feasible 
in a few carefully selected patients with various sarcomas 
and carcinomas (such as testis, colorectal, and kidney). 
Only about 15–25% of metastatic solid tumor patients have 
metastases limited to the lungs and are surgical candidates. 
Surgical resection should be considered only if the primary 
tumor is under control, if the patient has adequate cardio
-
pulmonary reserve to tolerate resection, if all metastatic 
tumor can be resected, if effective nonsurgical approaches 
are not available, and if there is no evidence of extratho
-
racic metastases that are not controlled or controllable. 
Unfavorable prognostic factors also include shorter 
disease-free interval from primary tumor treatment to 
presentation of metastases and a larger number of 
metastases. Retrospective data from the International 
Registry of Lung Metastases report an overall 5-year sur
-
vival rate of 36% and 10-year survival rate of 26% after 
complete resection of pulmonary metastases. Patients who 
are not surgical candidates but have solitary or limited 
metastatic disease to the lungs may be candidates for ste
-
reotactic radiotherapy, radioablation, or cryotherapy. For 
patients with unresectable progressive disease, chemo
-
therapy tailored to the primary tumor can be offered, and 
diligent attention to palliative care is essential (see Chapter 5).
Erhunmwunsee L et al. Preoperative evaluation and indications 
for pulmonary metastatectomy. Thorac Surg Clin. 2016 Feb; 
26(1):7–12. [PMID: 26611505]
Guerrera F et al. Surgery of colorectal cancer lung metastases: 
analysis of survival, recurrence and re-surgery. J Thorac Dis. 
2016 Jul;8(7):1764–71. [PMID: 27499967]
Petrella F et al. Pulmonary metastatectomy: an overview. J Thorac 
Dis. 2017 Oct;9(Suppl 12):S1291–8. [PMID: 29119017]
 
»
Unilateral, nonpleuritic chest pain and dyspnea.
 
»
Distant (more than 20 years earlier) history of 
exposure to asbestos.
 
»
Pleural effusion or pleural thickening or both on 
chest radiographs.
 
»
Malignant cells in pleural fluid or tissue biopsy.
 
»
Mesotheliomas are primary tumors arising from the surface 
lining of the pleura (80% of cases) or peritoneum (20% of 
cases). Numerous studies have confirmed the association of 
malignant pleural mesothelioma
 with exposure to asbestos. 
The lifetime risk to asbestos workers of developing malig
-
nant pleural mesothelioma is as high as 10%. The latent 
period between exposure and onset of symptoms ranges 
from 20 to 40 years. The clinician should inquire about 
asbestos exposure through mining, milling, manufacturing, 
shipyard work, insulation, brake linings, building construc
-
tion and demolition, roofing materials, and other asbestos 
products (pipes, textiles, paints, tiles, gaskets, panels).
 
»
The average interval between onset of symptoms and diagno
-
sis is 2–3 months; the median age at diagnosis is 72–74 years 
in Western countries. Symptoms include the insidious onset 
of shortness of breath, nonpleuritic chest pain, and weight 
loss. Physical findings include dullness to percussion, dimin
-
ished breath sounds and, in some cases, digital clubbing.
Pleural fluid is exudative and often hemorrhagic. Cytologic tests 
of pleural fluid are often negative. V ATS biopsy is usually 
necessary to obtain an adequate specimen for histologic diag
-
nosis. The histologic variants of malignant pleural mesotheli
-
oma are epithelial (50–60%), sarcomatoid (10%), and biphasic

-
-
oma are epithelial (50–60%), sarcomatoid (10%), and biphasic 
 
(30–40%). Since distinction from benign inflammatory condi
-
tions and metastatic adenocarcinoma may be difficult, immu
-
nohistochemical stains are important to confirm the diagnosis.
C. Imaging
Radiographic abnormalities consist of nodular, irregular, 
unilateral pleural thickening and varying degrees of unilat
-
eral pleural effusion. Sixty percent of patients have right-
sided disease, while only 5% have bilateral involvement. 
CT scans demonstrate the extent of pleural involvement. 
PET-CT is used to help differentiate benign from malig
-
nant pleural disease, improve staging accuracy, and iden
-
tify candidates for aggressive surgical approaches.
 
»
Malignant pleural mesothelioma progresses rapidly as the 
tumor spreads along the pleural surface to involve the peri
-
cardium, mediastinum, and contralateral pleura. The 
tumor may eventually extend beyond the thorax to involve 
abdominal lymph nodes and organs. Progressive pain and 
dyspnea are characteristic. Local invasion of thoracic struc
-
tures may cause superior vena cava syndrome, hoarseness, 
Horner syndrome, arrhythmias, and dysphagia.
 
»
Treatment
Chemotherapy is the mainstay of treatment (Tables 39–2 
and 39–3), with surgery included in multimodality treat
-
ment only if there is localized disease that can be com
-
pletely surgically resected with no evidence of mediastinal 
nodal involvement. The optimal surgical approach is still 
under debate. For localized disease, surgical options 
include pleurectomy and decortication (surgical stripping 
of the pleura and pericardium from apex of the lung to 
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diaphragm) or extrapleural pneumonectomy (a radical 
surgical procedure involving removal of the ipsilateral 
lung, parietal and visceral pleura, pericardium, and most of 
the hemidiaphragm). Limited nonrandomized data have 
shown that a trimodality approach for localized disease 
with extrapleural pneumonectomy, adjuvant radiation, and 
(neoadjuvant or adjuvant) chemotherapy can prolong sur
-
vival in highly selected patients. In advanced disease, pal
-
liative chemotherapy with cisplatin and pemetrexed can 
achieve response rates of 30–40%, can extend median 
overall survival to 12 months, and can improve quality of 
life. Adding bevacizumab (a monoclonal antibody to vas
-
cular endothelial growth factor [VEGF]) to cisplatin and 
pemetrexed has been shown to further improve overall 
survival. Drainage of pleural effusions, pleurodesis, radia
-
tion therapy, and even surgical resection may offer pallia
-
tive benefit to some patients.
 
»
Prognosis
Most patients die of respiratory failure and complications 
of local extension. Median survival time from diagnosis 
ranges from 7 months to 17 months. Five-year survival is 
5–10%. Tumors that are predominantly sarcomatoid are 
more resistant to therapy and have a worse prognosis, with 
median survivals less than 1 year. Poor prognostic features 
include poor performance status, non-epithelioid histology, 
male gender, nodal involvement, elevated lactate dehydro
-
genase, high white blood cell count, low hemoglobin, and 
high platelet count.
Baas P et al. ESMO Guidelines Committee. Malignant pleural 
mesothelioma: ESMO clinical practice guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep; 
26(Suppl 5):v31–9. [PMID: 26223247]
Meyerhoff RR et al. Impact of mesothelioma histologic subtype 
on outcomes in the Surveillance, Epidemiology, and End 
Results database. J Surg Res. 2015 Jun 1;196(1):23–32. [PMID: 
25791825]
Wald O et al. New concepts in the treatment of malignant pleural 
mesothelioma. Annu Rev Med. 2018 Jan 29;69:365–77. 
[PMID: 29029582]
Zalcman G et al; French Cooperative Thoracic Intergroup 
(IFCT). Bevacizumab for newly diagnosed pleural mesothe
-
lioma in the Mesothelioma Avastin Cisplatin Pemetrexed 
Study (MAPS): a randomised, controlled, open-label, phase 
 
3 trial. Lancet. 2016 Apr 2;387(10026):1405–14. Erratum in: 
Lancet. 2016 Apr 2;387(10026):e24. [PMID: 26719230]
h
E
p
A
TOBILIARY CANCERS
HEPATOCELLULAR CARCINOMA
 
»
Usually a complication of cirrhosis.
 
»
Characteristic CT and MRI features may obviate 
the need for a confirmatory biopsy.
 
»
Malignant neoplasms of the liver that arise from parenchy
-
mal cells are called hepatocellular carcinomas (accounting 
for 85% of liver cancers); those that originate in the ductu
-
lar cells are called cholangiocarcinomas (15% or less). Rare 
tumors of the liver include angiosarcoma and lymphoma.
Hepatocellular carcinomas are associated with cirrhosis 
in 85% of cases. In Africa and most of Asia, hepatitis B virus 
(HBV) infection is a major etiologic factor, and a family his
-
tory of hepatocellular carcinoma increases the risk synergis
-
tically. In the United States and other Western countries, 
incidence rates have risen rapidly (over twofold since 1978, 
with slowing of the rate increase since 2006 except in men 
ages 55–64), presumably because of the increasing preva
-
lence of cirrhosis caused by chronic hepatitis C virus (HCV) 
infection and nonalcoholic fatty liver disease (NAFLD). In 
Western countries, risk factors for hepatocellular carcinoma 
in patients known to have cirrhosis are male gender, age 
greater than 55 years (although there has been an increase in 
the number of younger cases), Hispanic or Asian ethnicity, 
family history in a first-degree relative, overweight, obesity 
(especially in early adulthood), alcohol use (especially in

(especially in early adulthood), alcohol use (especially in 
combination with obesity), tobacco use, diabetes mellitus, 
hypothyroidism (in women), a prolonged prothrombin time, 
a low platelet count, and an elevated serum transferrin 
saturation. The risk of hepatocellular carcinoma is higher in 
persons with a viral rather than nonviral cause of cirrhosis 
and may be increased in persons with autoimmune diseases. 
Other associations include high levels of HBV replication; 
HBV genotype C; hepatitis D coinfection; elevated serum 
ALT levels in persons with chronic hepatitis B (in whom 
antiviral therapy to suppress HBV replication appears to 
reduce the risk); HCV genotypes 1b and 3; lack of response 
to antiviral therapy for HCV infection; hemochromatosis 
(and possibly the C282Y carrier state); aflatoxin exposure 
(associated with mutation of the 
TP53
 gene); alpha-1-anti
-
protease (alpha-1-antitrypsin) deficiency; tyrosinemia; and 
radiation exposure. In patients with the metabolic syndrome 
and NAFLD, hepatocellular carcinoma may arise from a 
hepatocellular adenoma in the absence of cirrhosis. Evi
-
dence for an association with long-term use of oral contra
-
ceptives is inconclusive. While sulfonylurea and insulin use 
may increase the risk of hepatocellular carcinoma, consump
-
tion of coffee, vegetables, white meat, fish, and n-3 polyun
-
saturated fatty acids; aspirin use; and statin and metformin 
use in diabetic patients appear to be protective.
The fibrolamellar variant of hepatocellular carcinoma 
generally occurs in young women and is characterized by a 
distinctive histologic picture, absence of risk factors, 
unique genomic profiles, and indolent course. Vinyl chlo
-
ride exposure is associated with angiosarcoma of the liver. 
Hepatoblastoma, the most common malignant liver tumor 
in infants and young children, occurs rarely in adults.
 
»
The presence of a hepatocellular carcinoma may be unsus
-
pected until there is deterioration in the condition of a 
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cirrhotic patient who was formerly stable. Cachexia, weak
-
ness, and weight loss are associated symptoms. The sudden 
appearance of ascites, which may be bloody, suggests portal 
or hepatic vein thrombosis by tumor or bleeding from a 
necrotic tumor.
Physical examination may show tender enlargement of 
the liver, occasionally with a palpable mass. In Africa, the 
typical presentation in young patients is a rapidly expand
-
ing abdominal mass. Auscultation may reveal a bruit over 
the tumor or a friction rub when the tumor has extended 
to the surface of the liver.
Laboratory tests may reveal leukocytosis, as opposed to the 
leukopenia that is frequently encountered in cirrhotic 
patients. Anemia is common, but a normal or elevated 
hematocrit value may be found in up to one-third of 
patients owing to elaboration of erythropoietin by the 
tumor. Sudden and sustained elevation of the serum alka
-
line phosphatase in a patient who was formerly stable is a 
common finding. HBsAg is present in a majority of cases 
in endemic areas, whereas in the United States anti-HCV is 
found in up to 40% of cases. Alpha-fetoprotein levels are 
elevated in up to 70% of patients with hepatocellular carci
-
noma in Western countries (although the sensitivity is 
lower in blacks and levels are not elevated in patients with 
fibrolamellar hepatocellular carcinoma); however, mild 
elevations (10–200 ng/mL [10–200 mcg/L]) are also often 
seen in patients with chronic hepatitis. Serum levels of des-
gamma-carboxy prothrombin are elevated in up to 90% of 
patients with hepatocellular carcinoma, but they may also 
be elevated in patients with vitamin K deficiency, chronic 
hepatitis, and metastatic cancer. Cytologic study of ascitic 
fluid rarely reveals malignant cells.
C. Imaging
Multiphasic helical CT and MRI with contrast enhance
-
ment are the preferred imaging studies for determining the 
location and vascularity of the tumor; MRI may be more 
sensitive than CT, and imaging with gadoxetic acid increases 
sensitivity. Lesions smaller than 1 cm may be difficult to 
characterize. Arterial phase enhancement of the lesion fol
-
lowed by delayed hypointensity (“washout”) is most specific 
for hepatocellular carcinoma. Ultrasonography is less sensi
-
tive and more operator dependent but is used to screen for 
hepatic nodules in high-risk patients. Contrast-enhanced 
ultrasonography has a sensitivity and specificity approach
-
ing those of arterial phase helical CT but, unlike CT and 
MRI, cannot image the entire liver during the short duration 
of the arterial phase and is thus associated with false-
positive results. In selected cases, endoscopic ultrasonogra
-
phy (EUS) may be useful. PET is under study.
D. Liver Biopsy and Staging
Liver biopsy is diagnostic, although seeding of the needle 
tract by tumor is a potential risk (1–3%). For lesions 
smaller than 1 cm, ultrasonography may be repeated every 
3 months followed by further investigation of enlarging 
lesions. For lesions 1 cm or larger, biopsy can be deferred 
when characteristic arterial hypervascularity and delayed 
washout are demonstrated on either multiphasic helical CT 
or MRI with contrast enhancement (or both) or if surgical 
resection is planned. Staging in the TNM classification 
includes the following definitions: T0: no evidence of pri
-
mary tumor; T1a: solitary tumor less than or equal to 2 cm; 
T1b: solitary tumor more than 2 cm without vascular inva
-
sion; T2: solitary tumor more than 2 cm with vascular 
invasion or multiple tumors none more than 5 cm; 
 
T3: multiple tumors with at least one more than 5 cm; 
 
T4: single or multiple tumors of any size involving a major 
branch of the portal or hepatic vein or with direct invasion 
of adjacent organs other than the gallbladder or with 
perforation of the visceral peritoneum; N1, regional 
lymph node metastasis; M1, distant metastasis; F0, no to

lymph node metastasis; M1, distant metastasis; F0, no to 
moderate hepatic fibrosis; F1, severe hepatic fibrosis to cir
-
rhosis. The Barcelona Clinic Liver Cancer (BCLC) staging 
system is preferred and includes the Child-Pugh class, 
tumor stage, and liver function and has the advantage of 
linking overall stage with preferred treatment modalities 
and with an estimation of life expectancy.
 
»
Surveillance for the development of hepatocellular carcinoma 
is recommended in patients with chronic hepatitis B (begin
-
ning as early as age 20 in Africans, age 40 in Asians or those 
with a family history of hepatocellular carcinoma, and age 50 
in others) or cirrhosis caused by HCV , HBV , or alcohol. There 
is some evidence that surveillance for hepatocellular carci
-
noma leads to a survival advantage over clinical diagnosis, 
but only a minority of cases are detected by surveillance. The 
standard approach is ultrasonography and alpha-fetoprotein 
testing every 6 months, although the value of alpha-fetopro
-
tein screening has been questioned because of its low sensi
-
tivity. CT and MRI are considered too expensive for screening, 
but the sensitivity of ultrasonography for detecting early 
hepatocellular carcinoma is only 63%. The risk of hepatocel
-
lular carcinoma in a patient with cirrhosis is 3–5% a year, and 
patients with tumors detected by surveillance have a less 
advanced stage on average and greater likelihood that treat
-
ment will prolong survival than those not undergoing sur
-
veillance. In a population of patients with cirrhosis, over 60% 
of nodules smaller than 2 cm in diameter detected on a 
screening ultrasonography prove to be hepatocellular carci
-
noma. Mass vaccination programs against HBV in develop
-
ing countries are leading to reduced rates of hepatocellular 
carcinoma. Successful treatment of hepatitis B and of hepati
-
tis C in patients with cirrhosis also reduces the subsequent 
risk of hepatocellular carcinoma, and thus hepatocellular 
carcinoma is considered a preventable neoplasm. However, 
hepatocellular carcinoma may still occur after clearance of 
hepatitis B surface antigen or cure of HCV infection and may 
reduce the efficacy of treatment for HCV infection.
 
»
Treatment
Surgical resection of a solitary hepatocellular carcinoma 
may result in cure if liver function is preserved (Child-Pugh 
class A or possibly B) and portal vein thrombosis is not 
present. Laparoscopic liver resection has been performed in 
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selected cases. Treatment of underlying chronic viral hepa
-
titis, adjuvant chemotherapy, and adaptive immunotherapy 
may lower postsurgical recurrence rates. Liver transplanta
-
tion may be appropriate for small unresectable tumors in a 
patient with advanced cirrhosis, with reported 5-year sur
-
vival rates of up to 75%. The recurrence-free survival may 
be better for liver transplantation than for resection in 
patients with well-compensated cirrhosis and small tumors 
(one tumor less than 5 cm or three or fewer tumors 
 
each less than 3 cm in diameter [Milan criteria]) and in 
those with expanded (University of California, 
 
San Francisco) criteria of one tumor less than or equal to 
 
6.5 cm or three or fewer tumors less than or equal to 
 
4.5 cm. The Extended Toronto criteria include tumor dif
-
ferentiation, cancer-related symptoms, confinement of 
tumor to the liver, and absence of vascular invasion, without 
regard to tumor number or size, to determine candidacy for 
liver transplantation, and appear to predict outcomes as 
well as the Milan criteria. Patients with stage 2 hepatocel
-
lular carcinoma meeting the Milan criteria receive an addi
-
tional 28 points on their Model for End-Stage Liver Disease 
(MELD) score after 6 months on the waiting list (see Chap
-
ter 16), markedly increasing their chances of undergoing 
transplantation. However, liver transplantation is often 
impractical because of the donor organ shortage, and living 
donor liver transplantation may be considered in these 
cases. Patients with larger tumors (3–5 cm), a serum alpha-
fetoprotein level 1000 ng/mL (1000 mcg/L) or higher, or a 
MELD score 20 or more have poor posttransplantation 
survival. In patients with a serum alpha-fetoprotein level 
greater than 1000 ng/mL (1000 mcg/L), downstaging by 
locoregional therapy to an alpha-fetoprotein level less than 
500 ng/mL (500 mcg/L) improves survival following subse
-
quent liver transplantation. Chemotherapy, hormonal ther
-
apy with tamoxifen, and long-acting octreotide have not 
been shown to prolong life, but transarterial chemoemboli
-
zation (TACE), TACE with drug-eluting beads, transarterial 
chemoinfusion (TACI), and transarterial radioembolization 
(TARE) via the hepatic artery are palliative and may pro
-
long survival in patients with a large or multifocal tumor in 
the absence of extrahepatic spread. TACI and TARE are 
suitable for patients with portal vein thrombosis. TARE 
with yttrium-90 has been shown to result in a longer time 
to progression than TACE. Radiofrequency ablation of, 
cryotherapy of, microwave ablation of, or injection of abso
-
lute ethanol into tumors smaller than 2 cm may prolong 
survival in patients who are not candidates for resection 
and have tumors that are accessible; these interventions, as 
well as stereotactic body radiation therapy, may also provide 
a “bridge” to liver transplantation. Radiofrequency ablation 
is superior to ethanol injection for tumors larger than 2 cm 
in diameter (but is not effective for those larger than 5 cm) 
and can be performed after TACE in select cases. Cryoabla
-
tion may result in slower tumor progression than radiofre
-
quency ablation for tumors that are 3.1–4 cm in diameter. 
Microwave ablation is being used increasingly and allows 
shorter treatment times. Stereotactic body radiation therapy 
is also being used to treat unresectable hepatocellular carci
-
noma and may be effective in treating lesions larger than 
those treated with ablation techniques. Sorafenib (an oral 
multikinase inhibitor of Raf kinase, the VEGF receptor, and 
the platelet-derived growth factor receptor [and others]) 
prolongs median survival as well as the time to radiologic 
progression by 3 months in patients with advanced hepato
-
cellular carcinoma; sorafenib is standard care in these 
patients. Regorafenib is another oral multikinase inhibitor 
that provides a survival benefit for patients whose disease

-
that provides a survival benefit for patients whose disease 
progresses despite sorafenib therapy, and nivolumab is an 
immune checkpoint inhibitor that has been approved for 
advanced hepatocellular carcinoma. The modified Response 
Evaluation Criteria in Solid Tumors (mRECIST) are used to 
assess treatment response based on tumor shrinkage and 
viability after locoregional and antiangiogenic treatment. 
Meticulous efforts at palliative care are essential for patients 
in whom disease progresses despite treatment or in whom 
advanced tumors, vascular invasion, or extrahepatic spread 
are present. Severe pain may develop in such patients due to 
expansion of the liver capsule by the tumor and requires 
concerted efforts at pain management, including the use of 
opioids (see Chapter 5).
 
»
Prognosis
In the United States, overall 1- and 5-year survival rates for 
patients with hepatocellular carcinoma are 23% and 5%, 
respectively. Five-year survival rates rise to 56% for patients 
with localized resectable disease (T1, T2, selected T3 and 
T4; N0; M0) but are virtually nil for those with locally unre
-
sectable or advanced disease. In patients with HCV-related 
hepatocellular carcinoma, the serum alpha-fetoprotein level 
at the time of diagnosis of cancer has been reported to be an 
independent predictor of mortality. Some, but not all, stud
-
ies have reported an unexpectedly high rate of early tumor 
recurrence in patients who were cured of HCV infection 
with oral direct-acting antiviral agents, rather than inter
-
feron-based therapy. A serum alpha-fetoprotein level 
greater than or equal to 200 ng/mL (200 milli-international 
units/mL) or increases of greater than 15 ng/mL/month 
predict worse outcomes in patients awaiting liver 
transplantation. In patients who are not eligible for surgery, 
an elevated serum C-reactive protein level is associated with 
poor survival. Contrary to traditional opinion, the fibrola
-
mellar variant does not have a better prognosis than con
-
ventional hepatocellular carcinoma without cirrhosis.
 
»
All patients with hepatocellular carcinoma should be 
referred to a specialist.
 
»
•	
Complications of cirrhosis.
•	
•	
For surgery and other interventions.
Bruix J et al; RESORCE Investigators. Regorafenib for patients with 
hepatocellular carcinoma who progressed on sorafenib treat
-
ment (RESORCE): a randomised, double-blind, placebo-
 
controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064): 56–66. 
Erratum in: Lancet. 2017 Jan 7;389(10064):36. [PMID: 27932229]
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Kanwal F et al. Risk of hepatocellular cancer in HCV patients 
treated with direct-acting antiviral agents. Gastroenterology. 
2017 Oct;153(4):996–1005. [PMID: 28642197]
Mokdad AA et al. JAMA patient page. Treatment of liver cancer. 
JAMA. 2016 Jan 5;315(1):100. [PMID: 26746473]
Prenner SB et al. Hepatocellular carcinoma decreases the chance 
of successful hepatitis C virus therapy with direct-acting anti
-
virals. J Hepatol. 2017 Jun;66(6):1173–81. [PMID: 28161470]
Vitale A et al. Personalized treatment of patients with very early 
hepatocellular carcinoma. J Hepatol. 2017 Feb;66(2):412–23. 
[PMID: 27677712]
White DL et al. Incidence of hepatocellular carcinoma in all 50 
United States, from 2000 through 2012. Gastroenterology. 
2017 Mar;152(4):812–20. [PMID: 27889576]
CARCINOMA OF THE BILIARY TRACT
 
»
Presents with obstructive jaundice, usually pain
-
less, often with dilated biliary tract.
 
»
Pain is more common in gallbladder carcinoma 
than cholangiocarcinoma.
 
»
A dilated gallbladder may be palpable (Cour
-
voisier sign).
 
»
Diagnosis by cholangiography with biopsy and 
brushings for cytology.
 
»
Carcinoma of the gallbladder occurs in approximately 2% of 
all people operated on for biliary tract disease; the incidence 
may be decreasing in the United States. It is notoriously 
insidious, and the diagnosis is often made unexpectedly at 
surgery. Cholelithiasis (often large, symptomatic stones) is 
usually present. Other risk factors are chronic infection of 
the gallbladder with 
, gallbladder polyps 
over 1 cm in diameter (particularly with hypoecholic foci on 
EUS), mucosal calcification of the gallbladder (porcelain 
gallbladder), anomalous pancreaticobiliary ductal junction, 
and aflatoxin exposure. Genetic factors include 
K-ras
 and 
TP53
 mutations. Spread of the cancer—by direct extension 
into the liver or to the peritoneal surface—may be seen on 
initial presentation. The TNM classification includes the fol
-
lowing stages: Tis, carcinoma in situ; T1a, tumor invades 
lamina propria, and T1b, tumor invades muscle layer; T2, 
tumor invades perimuscular connective tissue with no 
extension beyond serosa (visceral peritoneum) (T2a) or into 
liver (T2b); T3, tumor perforates the serosa or directly 
invades the liver or adjacent organ or structure; T4, tumor 
invades the main portal vein or hepatic artery or invades two 
or more extrahepatic organs or structures; N1, metastasis to 
one to three regional lymph nodes; N2, metastasis to four or 
more regional lymph nodes; and M1, distant metastasis.
Carcinoma of the bile ducts (cholangiocarcinoma) 
accounts for 10–25% of all hepatobiliary malignancies and 
3% of all cancer deaths in the United States. It is more preva
-
lent in persons aged 50–70, with a slight male 
predominance, and more common in Asia. About 50% arise 
at the confluence of the hepatic ducts (perihilar, or so-called 
Klatskin, tumors), and 40% arise in the distal extrahepatic 
bile duct (the incidence of which has risen since 1990); the 
remainder are intrahepatic (the incidence of which rose 
dramatically from the 1970s to the early 2000s). Staging for 
perihilar cholangiocarcinoma is as follows: Tis, carcinoma in 
situ/high-grade dysplasia; T1, tumor is confined to bile duct; 
T2, tumor invades beyond the wall of the bile duct to sur
-
rounding adipose tissue (2a) or to the adjacent liver (2b); T3, 
tumor invades unilateral branches of the portal vein or 
hepatic artery; T4, tumor invades the main portal vein or its 
branches bilaterally, common hepatic artery, second-order 
biliary radicals, and contralateral portal vein or hepatic 
artery; N1, metastasis to one to three regional lymph nodes; 
N2, metastasis to one to four regional lymph nodes; M1, 
distant metastasis. Staging for intrahepatic cholangiocarci
-
noma is as follows: T1a, solitary tumor less than or equal to

-
noma is as follows: T1a, solitary tumor less than or equal to 
5 cm without vascular invasion; T1b, solitary tumor more 
than 5 cm without vascular invasion; T2, solitary tumor with 
intrahepatic vascular invasion or multiple tumors 5 cm or 
smaller with or without vascular invasion; T3, tumor perfo
-
rating the visceral peritoneum; T4, tumor invades adjacent 
organ (except gallbladder); N1, regional lymph node metas
-
tasis; and M1, distant metastasis. Additional staging is avail
-
able for distal bile duct tumors. Other staging systems 
consider the patient’s age, performance status, tumor extent 
and form, perineural invasion, vascular encasement, hepatic 
lobe atrophy, underlying liver disease, and peritoneal metasta
-
sis. The frequency of carcinoma in persons with a choledochal 
cyst has been reported to be over 14% at 20 years, and surgical 
excision is recommended. Most cases of cholangiocarcinoma 
are sporadic. There is an increased incidence of cholangiocar
-
cinoma in patients with bile duct adenoma; biliary papilloma
-
tosis; Caroli disease; a biliary-enteric anastomosis; ulcerative 
colitis, especially those with primary sclerosing cholangitis; 
biliary cirrhosis; diabetes mellitus; hyperthyroidism; chronic 
pancreatitis; heavy alcohol consumption; smoking; and past 
exposure to Thorotrast, a contrast agent. Aspirin use is associ
-
ated with a reduced risk of all types of cholangiocarcinoma, 
and in diabetic patients, metformin use is associated with a 
reduced risk of intrahepatic cholangiocarcinoma. In South
-
east Asia, hepatolithiasis, chronic typhoid carriage, and infec
-
tion of the bile ducts with helminths 
(Clonorchis sinensis, 
Opisthorchis viverrini)
 are associated with an increased risk of 
cholangiocarcinoma. Hepatitis C virus (and possibly hepati
-
tis B virus) infection, cirrhosis, HIV infection, nonalcoholic 
fatty liver disease, diabetes mellitus, obesity, and tobacco 
smoking are risk factors for intrahepatic cholangiocarci
-
noma. Mixed hepatocellular carcinoma-cholangiocarcinoma 
is a tumor that is being recognized increasingly.
 
»
Progressive jaundice is the most common and usually the first 
sign of obstruction of the extrahepatic biliary system. Pain in 
the right upper abdomen with radiation into the back is usu
-
ally present early in the course of gallbladder carcinoma but 
occurs later in the course of bile duct carcinoma. Anorexia 
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and weight loss are common and may be associated with fever 
and chills due to cholangitis. Rarely, hematemesis or melena 
results from erosion of tumor into a blood vessel (hemobilia). 
Fistula formation between the biliary system and adjacent 
organs may also occur. The course is usually one of rapid 
deterioration, with death occurring within a few months.
Physical examination reveals profound jaundice. Pruritus 
and skin excoriations are common. A palpable gallbladder 
with obstructive jaundice usually is said to signify malignant 
disease (Courvoisier sign); however, this clinical generaliza
-
tion has been proven to be accurate only about 50% of the 
time. Hepatomegaly due to hypertrophy of the unobstructed 
liver lobe is usually present and is associated with liver ten
-
derness. Ascites may occur with peritoneal implants.
With biliary obstruction, laboratory examination reveals 
predominantly conjugated hyperbilirubinemia, with total 
serum bilirubin values ranging from 5 to 30 mg/dL. There 
is usually concomitant elevation of the alkaline phospha
-
tase and serum cholesterol. AST is normal or minimally 
elevated. The serum CA 19-9 level is elevated in up to 85% 
of patients and may help distinguish cholangiocarcinoma 
from a benign biliary stricture (in the absence of cholangitis) 
but is neither sensitive nor specific.
C. Imaging
Ultrasonography and contrast-enhanced, triple-phase, heli
-
cal CT may show a gallbladder mass in gallbladder carci
-
noma and intrahepatic mass or biliary dilatation in 
carcinoma of the bile ducts. CT may also show involved 
regional lymph nodes and atrophy of a hepatic lobe because 
of vascular encasement with compensatory hypertrophy of 
the unaffected lobe. MRI with magnetic resonance cholan
-
giopancreatography (MRCP) and gadolinium enhancement 
permits visualization of the entire biliary tract and detection 
of vascular invasion and obviates the need for angiography 
and, in some cases, direct cholangiography; it is the imaging 
procedure of choice, but may understage malignant hilar 
strictures. The sensitivity and image quality can be increased 
with use of ferumoxide enhancement. The features of intra
-
hepatic cholangiocarcinoma on MRI appear to differ from 
those of hepatocellular carcinoma, with contrast washout in 
the latter but not the former. In indeterminate cases, PET 
can detect cholangiocarcinomas as small as 1 cm and lymph 
node and distant metastases, but false-positive results occur. 
The most helpful diagnostic studies before surgery are either 
endoscopic retrograde or percutaneous transhepatic cholan
-
giography with biopsy and cytologic specimens, although 
false-negative biopsy and cytology results are common. 
Digital image analysis and fluorescent in situ hybridization 
of cytologic specimens for polysomy improve sensitivity. 
EUS with FNA of tumors, peroral cholangioscopy, confocal 
laser endomicroscopy, and intraductal ultrasonography may 
confirm a diagnosis of cholangiocarcinoma in a patient with 
bile duct stricture and an otherwise indeterminate evalua
-
tion, but FNA can result in tumor seeding and is often 
avoided if the tumor is potentially resectable.
 
»
Treatment
In young and fit patients, curative surgery for gallbladder 
carcinoma may be attempted if the tumor is well localized. 
The 5-year survival rate for carcinoma of the gallbladder 
invading the lamina propria or muscularis (stage 1, T1a or 
1b, N0, M0) is as high as 85% with laparoscopic cholecys
-
tectomy but drops to 60%, even with a more extended open 
resection, if there is perimuscular invasion (T2). The role 
of radical surgery for T3 and T4 tumors is debatable. If the 
tumor is unresectable at laparotomy, biliary-enteric bypass 
(eg, Roux-en-Y hepaticojejunostomy) can be performed. 
Carcinoma of the bile ducts is curable by surgery in less 
than 10% of cases. If resection margins are negative, the

than 10% of cases. If resection margins are negative, the 
5-year survival rate may be as high as 47% for intrahepatic 
cholangiocarcinomas, 41% for hilar cholangiocarcinoma, 
and 37% for distal cholangiocarcinomas, but the periopera
-
tive mortality rate may be as high as 10%. Factors predict
-
ing shorter survival for intrahepatic cholangiocarcinoma 
include large tumor size, multiple tumors, lymph node 
metastasis, and vascular invasion. Adjuvant chemotherapy 
with capecitabine has been shown to result in superior 
overall survival compared with no adjuvant therapy. 
Palliation can be achieved by placement of a self-expand
-
able metal stent via an endoscopic or percutaneous trans
-
hepatic route. Covered metal stents may be more 
cost-effective than uncovered metal stents because of a 
longer duration of patency, but they are associated with a 
higher rate of stent migration and cholecystitis due to 
occlusion of the cystic duct and are not associated with 
longer survival. For perihilar tumors, insertion of a unilat
-
eral stent rather than bilateral stents may suffice. Plastic 
stents are less expensive initially, but not in the long term, 
because they are more prone to occlude than metal ones; 
they may be considered in patients expected to survive 
only a few months. Photodynamic therapy in combination 
with stent placement prolongs survival when compared 
with stent placement alone in patients with nonresectable 
cholangiocarcinoma. Endoscopic retrograde cholangio
-
pancreatography (ERCP)–directed radiofrequency abla
-
tion, TACE, and TARE are additional emerging options. 
Radiotherapy may relieve pain and contribute to biliary 
decompression. There is limited response to chemotherapy 
with gemcitabine alone, but the combination of cisplatin 
and gemcitabine or capecitabine and gemcitabine prolongs 
survival in patients with locally advanced or metastatic 
cholangiocarcinoma. Few patients survive for more than 
24 months. Although cholangiocarcinoma is generally 
considered to be a contraindication to liver transplantation 
because of rapid tumor recurrence, a 75% 5-year survival 
rate has been reported in patients with stage I and II peri
-
hilar cholangiocarcinoma undergoing chemoradiation and 
exploratory laparotomy followed by liver transplantation.
 
»
All patients with carcinoma of the biliary tract should be 
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»
•	
Biliary obstruction.
•	
Cholangitis.
Almadi MA et al. Plastic vs. self-expandable metal stents for pallia
-
tion in malignant biliary obstruction: a series of meta-analyses. 
Am J Gastroenterol. 2017 Feb;112(2):260–73. [PMID: 27845340]
Banales JM et al. Expert consensus document: cholangiocarci
-
noma: current knowledge and future perspectives consensus 
statement from the European Network for the Study of Chol
-
angiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 
2016 May;13(5):261–80. [PMID: 27095655]
Koshiol J et al. Association of aflatoxin and gallbladder cancer. 
Gastroenterology. 2017 Aug;153(2):488–94. [PMID: 28428144]
Sadeghi A et al. Diagnostic yield of EUS-guided FNA for malig
-
nant biliary stricture: a systematic review and meta-analysis. 
Gastrointest Endosc. 2016 Feb;83(2):290–8. [PMID: 26422979]
CARCINOMA OF THE PANCREAS & 
 
AMPULLA OF VATER
 
»
Obstructive jaundice (may be painless).
 
»
Enlarged gallbladder (may be painful).
 
»
Upper abdominal pain with radiation to back, 
weight loss, and thrombophlebitis are usually late 
 
»
Carcinoma is the most common neoplasm of the pancreas. 
About 75% are in the head and 25% in the body and tail of 
the organ. Pancreatic carcinomas account for 2% of all can
-
cers and 5% of cancer deaths. Ampullary carcinomas are 
much less common. Risk factors for pancreatic cancer 
include age, tobacco use (which is thought to cause 20–25% 
of cases), heavy alcohol use, obesity, chronic pancreatitis, 
diabetes mellitus, prior abdominal radiation, family history, 
and possibly gastric ulcer and exposure to arsenic and cad
-
mium. New-onset diabetes mellitus after age 45 years occa
-
sionally heralds the onset of pancreatic cancer. In diabetic 
patients, metformin use may reduce the risk of pancreatic 
cancer slightly, but insulin use and glucagon-like peptide-
1-based therapy (eg, sitagliptin) may increase the risk. 
About 7% of patients with pancreatic cancer have a family 
history of pancreatic cancer in a first-degree relative, com
-
pared with 0.6% of control subjects. In 5–10% of cases, 
pancreatic cancer occurs as part of a hereditary syndrome, 
including familial breast cancer (carriers of 
BRCA-2
 have a 
7% lifetime risk of pancreatic cancer), hereditary pancreati
-
tis (
PSS1
 mutation), familial atypical multiple mole mela
-
noma (
p16
/
CDKN2A
 mutation), Peutz-Jeghers syndrome 
(
STK11
/
LKB1
 mutation), ataxia-telangiectasia (
ATM
 muta
-
tion), and Lynch syndrome (hereditary nonpolyposis 
colorectal cancer [
MLH1
, 
MSH2
, 
MSH6
 mutations]). Neu
-
roendocrine tumors account for 1–2% of pancreatic neo
-
plasms and may be functional (producing gastrin, insulin, 
glucagon, vasoactive intestinal peptide, somatostatin, 
growth hormone–releasing hormone, adrenocorticotropic 
hormone, and others) or nonfunctional. Cystic neoplasms 
account for only 1% of pancreatic cancers, but they are 
important because pancreatic cysts are common and may 
be mistaken for pseudocysts. A cystic neoplasm should be 
suspected when a cystic lesion in the pancreas is found in 
the absence of a history of pancreatitis. At least 15% of all 
pancreatic cysts are neoplasms. Serous cystadenomas 
(which account for 32–39% of cystic pancreatic neoplasms 
and also occur in patients with von Hippel-Lindau disease) 
are benign. However, mucinous cystic neoplasms (defined 
by the presence of ovarian stroma and accounting for 
10–45% of cystic pancreatic neoplasms), intraductal papil
-
lary mucinous neoplasms (21–33% of cystic pancreatic 
neoplasms), solid pseudopapillary tumors (less than 5%, 
primarily in young women), and cystic islet cell tumors 
(3–5%) may be malignant, although their prognoses are 
better than the prognosis of pancreatic adenocarcinoma, 
unless the cystic neoplasm is at least locally advanced.
 
»

»
Pain is present in over 70% of cases and is often vague, 
diffuse, and located in the epigastrium or, when the lesion 
is in the tail, located in the left upper quadrant. Radiation 
of pain into the back is common and sometimes 
predominates. Sitting up and leaning forward may afford 
some relief, and this usually indicates that the lesion has 
spread beyond the pancreas and is inoperable. Diarrhea, 
perhaps due to maldigestion, is an occasional early symp
-
tom. Migratory thrombophlebitis is a rare sign. Weight loss 
is a common but late finding and may be associated with 
depression. Occasional patients (often aged 40 years or 
older) present with acute pancreatitis in the absence of an 
alternative cause. Jaundice is usually due to biliary obstruc
-
tion by a cancer in the pancreatic head. A palpable gall
-
bladder is also indicative of obstruction by a neoplasm 
(Courvoisier sign), but there are frequent exceptions. 
A hard, fixed, occasionally tender mass may be present. In 
advanced cases, a hard periumbilical (Sister Mary Joseph’s) 
nodule may be palpable.
There may be mild anemia. Glycosuria, hyperglycemia, 
and impaired glucose tolerance or true diabetes mellitus 
are found in 10–20% of cases. The serum amylase or lipase 
level is occasionally elevated. Liver biochemical tests may 
suggest obstructive jaundice. Steatorrhea in the absence of 
jaundice is uncommon. Occult blood in the stool is sugges
-
tive of carcinoma of the ampulla of Vater (the combination 
of biliary obstruction and bleeding may give the stools a 
distinctive silver appearance). CA 19-9, with a sensitivity of 
70% and a specificity of 87%, has not proven useful for 
early detection of pancreatic cancer; increased values are 
also found in acute and chronic pancreatitis and cholangitis. 
Plasma chromogranin A levels are elevated in 88–100% of 
patients with pancreatic neuroendocrine tumors (NETs).
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C. Imaging
Multiphase thin-cut helical CT is generally the initial diag
-
nostic procedure and detects a mass in over 80% of cases. 
CT identifies metastases, delineates the extent of the tumor, 
and allows percutaneous FNA for cytologic studies and 
tumor markers. MRI is an alternative to CT. Ultrasonography 
is not reliable because of interference by intestinal gas. PET 
is a sensitive technique for detecting pancreatic cancer and 
metastases, but PET-CT is not a routine staging procedure. 
Selective celiac and superior mesenteric arteriography may 
demonstrate vessel invasion by tumor, a finding that would 
preclude attempts at surgical resection, but it is used less 
commonly since the advent of multiphase helical CT. EUS 
is more sensitive than CT for detecting pancreatic cancer 
and equivalent to CT for determining nodal involvement 
and resectability. A normal EUS excludes pancreatic cancer. 
EUS may also be used to guide FNA for tissue diagnosis, 
tumor markers, and DNA analysis. ERCP may clarify an 
ambiguous CT or MRI study by delineating the pancreatic 
duct system or confirming an ampullary or biliary neo
-
plasm. MRCP appears to be at least as sensitive as ERCP in 
diagnosing pancreatic cancer. In some centers, pancreatos
-
copy or intraductal ultrasonography is used to evaluate 
filling defects in the pancreatic duct and assess resectability 
of intraductal papillary mucinous tumors. With obstruction 
of the splenic vein, splenomegaly or gastric varices are pres
-
ent, the latter detected by endoscopy, EUS, or angiography.
Cystic neoplasms can be distinguished by their appear
-
ance on CT, EUS, and ERCP and features of the cyst fluid on 
gross, cytologic, and genetic analysis. For example, serous 
cystadenomas may have a central scar or honeycomb 
appearance; mucinous cystadenomas are unilocular or mul
-
tilocular and contain mucin-rich fluid with high carcinoem
-
bryonic antigen levels (greater than 200 ng/mL [200 mcg/L]) 
and 
K-ras
 mutations; and intraductal papillary mucinous 
neoplasms are associated with a dilated pancreatic duct and 
extrusion of gelatinous material from the ampulla.
 
»
Staging
Staging of pancreatic cancer by the TNM classification 
includes the following definitions: Tis: carcinoma in situ; 
T1a: tumor limited to the pancreas, 0.5 cm or less in greatest 
dimension; T1b: tumor more than 0.5 cm and less than 1 cm; 
T1c: tumor 1–2 cm; T2: tumor limited to the pancreas, more 
than 2 cm and less than or equal to 4 cm in greatest dimen
-
sion; T3: tumor more than 4 cm in greatest dimension; T4: 
tumor involves the celiac axis, superior mesenteric artery, or 
common hepatic artery regardless of size; N1: metastasis to 
one to three regional lymph nodes; N2: metastasis to four or 
more regional lymph nodes; M1: distant metastasis.
 
»
Treatment
Abdominal exploration is usually necessary when cytologic 
diagnosis cannot be made or if resection is to be attempted, 
which includes up to 30% of patients with pancreatic carci
-
noma. In a patient with a localized mass in the head of the 
pancreas and without jaundice, laparoscopy may detect tiny 
peritoneal or liver metastases and thereby avoid resection in 
4–13% of patients. Radical pancreaticoduodenal (Whipple) 
resection is indicated for cancers strictly limited to the head 
of the pancreas, periampullary area, and duodenum (T1, 
N0, M0). Five-year survival rates are 20–25% in this group 
and as high as 40% in those with negative resection margins 
and without lymph node involvement. Preoperative endo
-
scopic decompression of an obstructed bile duct is often 
achieved with a plastic stent or short metal stent but does 
not reduce operative mortality and is associated with com
-
plications. The best surgical results are achieved at centers 
that specialize in the multidisciplinary treatment of pancre
-
atic cancer. Adjuvant chemotherapy with gemcitabine, 
5-fluorouracil, or gemcitabine with capecitabine is superior

-
5-fluorouracil, or gemcitabine with capecitabine is superior 
to no adjuvant therapy. Gemcitabine with capecitabine has 
been found to be superior to gemcitabine alone. The role of 
adjuvant chemoradiation is controversial but often used in 
the United States. Neoadjuvant chemotherapy with or with
-
out radiation is increasingly being used to downstage 
patients and in those with resectable cancer. Common che
-
motherapy regimens for this purpose include FOLFIRI
-
NOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) 
and gemcitabine with albumin-bound (nab)-paclitaxel. 
Chemoradiotherapy downstages about 30% of patients with 
locally advanced disease to allow resection. When resection 
is not feasible, endoscopic stenting of the bile duct is per
-
formed to relieve jaundice. A plastic stent is generally 
placed if the patient’s anticipated survival is less than 6 
months (or surgery is planned). A metal stent is preferred 
when anticipated survival is 6 months or greater. Whether 
covered metal stents designed to prevent tumor ingrowth 
offer an advantage over uncovered stents is uncertain 
because covered stents are associated with higher rates of 
migration and acute cholecystitis due to occlusion of the 
cystic duct. Surgical biliary bypass may be considered in 
patients expected to survive at least 6 months. Surgical duo
-
denal bypass may be considered in patients in whom duo
-
denal obstruction is expected to develop; alternatively, 
endoscopic placement of a self-expandable duodenal stent 
may be feasible. Chemoradiation may be used for palliation 
of unresectable cancer confined to the pancreas. Chemo
-
therapy has been disappointing in metastatic pancreatic 
cancer, although improved response rates have been 
reported with FOLFIRINOX and with the combination of 
gemcitabine and nab-paclitaxel. In patients who have 
received prior chemotherapy, 5-fluorouracil and leucovorin 
in combination with nanoliposomal irinotecan has resulted 
in improved survival compared with 5-fluorouracil and 
leucovorin alone. Celiac plexus nerve block (under CT or 
endoscopic ultrasound guidance) or thoracoscopic splanch
-
nicectomy may improve pain control.
Surgical resection is the treatment of choice for NETs, 
when feasible. Metastatic disease may be controlled with 
long-acting somatostatin analogs, interferon, chemotherapy, 
peptide-receptor radionuclide therapy, and chemoemboli
-
zation. For potentially neoplastic cystic lesions, there is a 
consensus that asymptomatic incidental pancreatic cysts 2 
cm or smaller are at low risk for harboring invasive carci
-
noma. The cysts may be monitored by imaging tests (MRI) in 
1 year and then every 2 years for 5 years and perhaps longer 
if no changes are observed, with EUS and FNA if a cyst 
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enlarges to 3 cm and another high-risk feature (dilated 
main pancreatic duct, presence of a solid component) 
develops. The optimal approach is uncertain, however, and 
other guidelines have been proposed.
Surgical resection is indicated for mucinous cystic neo
-
plasms, symptomatic serous cystadenomas, solid pseudo
-
papillary tumors (which have a 15% risk of malignant 
transformation), and cystic tumors larger than 2 cm in 
diameter that remain undefined after helical CT, EUS, and 
diagnostic aspiration. All intraductal papillary mucinous 
neoplasms of the main pancreatic duct should be resected, 
but those of branch ducts may be monitored with serial 
imaging if they (1) are asymptomatic and exhibit benign 
features; (2) have a diameter less than 3 cm (some authori
-
ties recommend a diameter 1.5 cm or smaller, but even 
lesions 3 cm or larger may be monitored in elderly persons 
with no other worrisome cyst features); and (3) lack non
-
enhancing mural nodules, a thick wall, an abrupt change in 
the caliber of the pancreatic duct with distal pancreatic 
atrophy, or possibly bile duct dilatation and gallbladder 
adenomyomatosis. Most such lesions with benign features 
remain stable on follow-up, but the risk of malignancy 
persists for at least 10 years. Moreover, the risk of pancre
-
atic ductal carcinoma and of nonpancreatic cancers may 
also be increased in this group of patients. In the absence 
of locally advanced disease, survival is higher for malignant 
cystic neoplasms than for adenocarcinoma. Endoscopic 
resection or ablation, with temporary placement of a pan
-
creatic duct stent, may be feasible for ampullary adenomas, 
but patients must be followed for recurrence.
 
»
Prognosis
Carcinoma of the pancreas, especially in the body or tail, 
has a poor prognosis; 80–85% of patients present with 
advanced unresectable disease, and reported 5-year sur
-
vival rates range from 2% to 5%. From 1980 to 2010, mor
-
tality from pancreatic cancer did not decrease, but it may 
now be starting to improve. Obesity may adversely affect 
mortality in Western countries. Metformin may improve 
survival in diabetic patients with pancreatic adenocarci
-
noma. Tumors of the ampulla have a better prognosis, with 
reported 5-year survival rates of 20–40% after resection; 
jaundice and lymph node involvement are adverse prog
-
nostic factors. In carefully selected patients, resection of 
cancer of the pancreatic head is feasible and results in rea
-
sonable survival. In persons with a family history of pan
-
creatic cancer in at least two first-degree relatives, or with 
a genetic syndrome associated with an increased risk of 
pancreatic cancer, screening with EUS and helical CT or 
MRI/MRCP should be considered beginning at age 40–45 
or 10 years before the age at which pancreatic cancer was 
first diagnosed in a family member.
 
»
All patients with carcinoma involving the pancreas and the 
ampulla of Vater should be referred to a specialist.
 
»
Patients who require surgery and other interventions 
should be hospitalized.
Crippa S et al. Active surveillance beyond 5 years is required for 
presumed branch-duct intraductal papillary mucinous neo
-
plasms undergoing non-operative management. Am J 
Gastroenterol. 2017 Jul;112(7):1153–61. [PMID: 28244498]
Fogel EL et al. A multidisciplinary approach to pancreas cancer 
in 2016: a review. Am J Gastroenterol. 2017 Apr;112(4):537–54. 
[PMID: 28139655]
Kamisawa T et al. Pancreatic cancer. Lancet. 2016 Jul 2; 
388(10039):73–85. [PMID: 26830752]
Koulouris AI et al. Pain in patients with pancreatic cancer: 
prevalence, mechanisms, management and future develop
-
ments. Dig Dis Sci. 2017 Apr;62(4):861–70. [PMID: 
28229252]
Neoptolemos JP et al; European Study Group for Pancreatic

-
28229252]
Neoptolemos JP et al; European Study Group for Pancreatic 
Cancer. Comparison of adjuvant gemcitabine and capecitabine 
with gemcitabine monotherapy in patients with resected pan
-
creatic cancer (ESPAC-4): a multicentre, open-label, ran
-
domised, phase 3 trial. Lancet. 2017 Mar 11; 
389(10073):1011–24. [PMID: 28129987]
ALIMENTARY TRACT CANCERS
ESOPHAGEAL CANCER
 
»
Progressive dysphagia to solid food.
 
»
Weight loss common.
 
»
 
»
Esophageal cancer usually develops in persons between 50 
and 70 years of age. There were an estimated 17,920 new 
cases of esophageal cancer in 2018. The overall ratio of 
men to women is 3:1. There are two histologic types: squa
-
mous cell carcinoma and adenocarcinoma. Squamous cell 
carcinoma is common in Eastern Europe and Asia while 
adenocarcinoma is more common in North America and 
most Western European countries. In the United States, 
squamous cell carcinoma
 is much more common in 
blacks than in whites. Most (90%) squamous cell carcino
-
mas occur in the distal two-thirds of the esophagus. 
Chronic alcohol and tobacco use are strongly associated 
with an increased risk of squamous cell carcinoma. 
Adeno
-
carcinoma
 is more common in whites. Its incidence is 
increasing dramatically, and it is now more common than 
squamous cell carcinoma in the United States. The major
-
ity of adenocarcinomas develop as a complication of Bar
-
rett metaplasia due to chronic gastroesophageal reflux. 
Thus, most adenocarcinomas arise in the distal third of the 
esophagus. Obesity also is strongly associated with 
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adenocarcinoma, even after controlling for gastroesopha
-
geal reflux.
 
»
The majority (50–60%) of patients with esophageal cancer 
present with advanced, incurable disease. While early 
symptoms are nonspecific and subtle, over 90% eventually 
have solid food dysphagia, which progresses over weeks to 
months. Odynophagia is sometimes present. Significant 
weight loss is common. Local tumor extension into the 
tracheobronchial tree may result in a tracheo-esophageal 
fistula, characterized by coughing on swallowing or by 
pneumonia. Chest or back pain suggests mediastinal exten
-
sion. Recurrent laryngeal nerve involvement may produce 
hoarseness. Physical examination is often unrevealing. The 
presence of supraclavicular or cervical lymphadenopathy 
or of hepatomegaly implies metastatic disease.
Laboratory findings are nonspecific. Anemia related to 
chronic disease or occult blood loss is common. Elevated 
aminotransferase or alkaline phosphatase concentrations 
suggest hepatic or bony metastases. Hypoalbuminemia 
may result from malnutrition.
C. Imaging
A barium esophagogram may be the first study obtained to 
evaluate dysphagia. The appearance of a polypoid, obstruc
-
tive, or ulcerative lesion is suggestive of carcinoma and 
requires endoscopic evaluation. However, even lesions 
believed to be benign by radiography warrant endoscopic 
evaluation. Chest radiographs may show adenopathy, a 
widened mediastinum, pulmonary or bony metastases, or 
signs of tracheo-esophageal fistula such as pneumonia.
D. Upper Endoscopy
Endoscopy with biopsy establishes the diagnosis of esopha
-
geal carcinoma with a high degree of reliability. In some 
cases, significant submucosal spread of the tumor may 
yield nondiagnostic mucosal biopsies. Repeat biopsy may 
be necessary.
 
»
Staging
After confirmation of the diagnosis of esophageal carci
-
noma, the stage of the disease should be determined since 
doing so influences the choice of therapy. Patients should 
undergo evaluation with CT of the chest and abdomen to 
look for evidence of pulmonary or hepatic metastases, 
lymphadenopathy, and local tumor extension. If there is no 
evidence of distant metastases or extensive local spread on 
CT, EUS with guided FNA biopsy of lymph nodes should 
be performed to evaluate the locoregional stage. EUS is 
superior to CT in demonstrating the level of local medias
-
tinal extension and local lymph node involvement. PET 
with fluorodeoxyglucose or integrated PET-CT imaging is 
indicated to look for regional or distant spread in patients 
thought to have localized disease after other diagnostic 
studies, prior to invasive surgery. Bronchoscopy is some
-
times required in esophageal cancers above the carina to 
exclude tracheobronchial extension. Laparoscopy to 
exclude occult peritoneal carcinomatosis should be consid
-
ered in patients with tumors at or near the gastroesopha
-
geal junction (see Gastric Adenocarcinoma).
 
»
Esophageal carcinoma must be distinguished from other 
causes of progressive dysphagia, including peptic stricture, 
achalasia, and adenocarcinoma of the gastric cardia with 
esophageal involvement. Benign-appearing peptic stric
-
tures should be biopsied at presentation to exclude occult 
 
»
Treatment
The approach to esophageal cancer depends on the tumor 
stage, tumor location, patient preference and functional 
status, and the expertise of the gastroenterologists, sur
-
geons, oncologists, and radiation oncologists. It is helpful 
to classify patients into two general categories: those with 
early stage (curable) disease and those with advanced stage 
(incurable) disease.
A. Therapy for “Curable” Disease
Superficial esophageal cancers confined to the epithelium 
(high-grade dysplasia or carcinoma in situ [Tis]), lamina 
propria (T1a), or submucosal (T1b) are increasingly rec
-

-
ognized in endoscopic screening and surveillance 
programs. Esophagectomy achieves high cure rates for 
superficial tumors but is associated with mortality (2%) 
and morbidity. If performed by experienced clinicians, 
endoscopic mucosal resection of Tis and T1a cancers 
achieves equivalent long-term survival with less morbid
-
ity (see Barrett Esophagus, Chapter 15). Patients with 
larger tumors or deeper tumors invasive to the submu
-
cosa (T1b) have higher rates of lymph node metastasis. 
For this reason, an esophagectomy is recommended for 
those with T1b tumors. Frequent posttreatment endo
-
scopic surveillance is required to ensure no residual or 
recurrent tumor.
1. Surgery with or without neoadjuvant chemoradiation 
therapy—
There are multiple surgical approaches to the 
resection of invasive (non-superficial) but potentially 
“curable” esophageal cancers (stage Ib, II, IIIA, or IIIB). 
Accepted techniques include en bloc transthoracic excision 
of the esophagus with extended lymph node dissection, 
transhiatal esophagogastrectomy (entailing laparotomy 
with cervical anastomosis), and minimally invasive esoph
-
agectomy techniques. Meta-analysis data suggest equiva
-
lent oncologic outcomes from minimally invasive 
esophagectomy and conventional open techniques, 
although there are fewer postoperative complications and 
shorter hospital stays with the laparoscopic approach. 
Removal of at least 15 lymph nodes is recommended for 
optimal surgical staging in patients who have not received 
neoadjuvant therapy; the optimal number of lymph nodes 
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after neoadjuvant therapy is not known though similar 
lymphadenectomy is recommended by expert guidelines.
Patients with stage I tumors have high cure rates with 
surgery alone and do not require radiation or chemotherapy. 
If regional lymph node metastases have occurred (stages 
IIB and III), the rate of cure with surgery alone is reduced 
to less than 20%. Meta-analysis of trials comparing neoad
-
juvant (preoperative) therapy followed by surgery with 
surgery alone suggests a 13% absolute improvement in 
2-year survival with combined therapy. Preoperative 
(neoadjuvant) chemoradiation therapy is recommended 
for stage IIA, IIB, and III tumors in fit patients. The 
preferred neoadjuvant chemotherapy regimen used with 
radiation is weekly carboplatin plus paclitaxel (Table 39–2). 
As an alternative, a combination of cisplatin plus 
5-fluorouracil may be used along with radiation. When 
radiation therapy is considered, techniques that are less 
toxic such as intensity-modulated radiation therapy 
(IMRT) or proton beam therapy may be considered. 
Perioperative chemotherapy without radiation is also appro
-
priate for tumors of the gastroesophageal junction based on 
the randomized, multicenter, phase III MAGIC trial.
2. Chemotherapy plus radiation therapy without 
surgery
—
Combined treatment with chemotherapy and 
radiation is superior to radiation alone and has achieved 
long-term survival rates in up to 25% of patients. 
Chemoradiation alone should be considered in patients 
with localized disease (stage II or IIIA) who are poor surgi
-
cal candidates due to serious medical illness or poor func
-
tional status (Eastern Cooperative Oncology Group score 
greater than 2). Chemoradiation alone as definitive, nonsur
-
gical therapy is more likely to achieve short-term and long-
term survival in patients with squamous cell carcinoma than 
in patients with adenocarcinoma. This is especially true for 
patients with cervical esophageal cancers, which appear 
similar biologically to head and neck cancers.
3. Supportive care during definitive therapy—
Patients 
with significant tumor obstruction may require local mea
-
sures such as esophageal stent placement or percutaneous 
gastric or jejunal tube placement to maintain adequate 
hydration and nutrition during neoadjuvant chemoradia
-
tion or chemotherapy. Multidisciplinary consultation is 
required to determine the optimal procedure. Consultation 
with a nutritionist also is appropriate to optimize nutrition 
perioperatively.
B. Therapy for Incurable Disease
More than half of patients have either locally extensive 
tumor spread (T4b) that is unresectable or distant metasta
-
ses (M1) (stage IIIC and stage IV). Surgery is not war
-
ranted in these patients. Since prolonged survival can be 
achieved in few patients, the primary goal is to provide 
relief from dysphagia and pain, optimize quality of life, and 
minimize treatment side effects. The optimal palliative 
approach depends on the presence or absence of metastatic 
disease, expected survival, patient preference, and institu
-
tional experience. Many patients with advanced disease 
may prefer concerted efforts at pain relief and care directed 
at symptom management (see Chapter 5).
1. Chemotherapy or chemoradiation—
Combined radia
-
tion therapy and chemotherapy may achieve palliation in 
two-thirds of patients but is associated with significant side 
effects. It should be considered for patients with locally 
advanced tumors without distant metastases (stage IIIC) 
who have good functional status and no significant medi
-
cal problems, in whom prolonged survival may be achieved. 
Improvement in dysphagia occurs within 2–4 weeks in 
almost 90% of patients.
Combination chemotherapy may be considered in 
those patients with metastatic disease who still have good 
functional status and expected survival of at least several 
months. Three-drug combinations commonly include a

months. Three-drug combinations commonly include a 
fluoropyrimidine (5-fluorouracil or capecitabine), a plati
-
num drug (cisplatin or oxaliplatin), and either epirubicin 
or a taxane (docetaxel or paclitaxel) (Table 39–2). For 
patients with poor functional status, single-agent therapy 
with a fluoropyrimidine, a taxane, or irinotecan may be 
used. In patients with metastatic distal esophageal and 
gastroesophageal junction adenocarcinomas positive for 
amplification of the 
HER2
 gene (approximately 15% of 
cases), addition of the monoclonal antibody trastuzumab 
(see Chapter 17) to chemotherapy is associated with pro
-
longed survival. In addition, ramucirumab, a monoclonal 
antibody targeting the VEGF receptor-2, demonstrated a 
survival advantage in patients with adenocarcinoma of the 
gastroesophageal junction after progression on first-line 
therapy when used both as monotherapy and in combina
-
tion with paclitaxel (Tables 39–2 and 39–3).
2. Local therapy for esophageal obstruction—
Patients 
with advanced esophageal cancer often have a poor func
-
tional and nutritional status. Radiation therapy alone to the 
area of esophageal obstruction may afford short-term relief 
of pain and dysphagia and may be suitable for patients with 
poor functional status or underlying medical problems. 
This can generally be performed in a short course over a few 
weeks or less but may be complicated by temporary worsen
-
ing of dysphagia and odynophagia. For patients with frank 
obstruction or near obstruction, local antitumor therapies 
may be preferred. Rapid palliation of dysphagia may be 
achieved by peroral placement of permanent expandable 
wire stents (alone or followed by radiation). Palliative feed
-
ing tube placement may be considered for hydration and 
nutrition in selected cases if the obstruction is not amenable 
or if it is refractory to stenting, radiation, or other local 
therapies. Stents are most commonly used because of their 
relative ease of placement. Although dysphagia and quality 
of life are improved, patients seldom can eat normally after 
stent placement. Complications occur in 20–40% and 
include perforation, migration, and tumor ingrowth.
 
»
Prognosis
The overall 5-year survival rate of esophageal carcinoma is 
less than 20%. Apart from distant metastasis (M1b), the 
two most important predictors of poor survival are adja
-
cent mediastinal spread (T4) and lymph node involvement. 
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Whereas cure may be achieved in patients with regional 
lymph node involvement (stages IIB and III), involvement 
of nodes outside the chest (M1a) is indicative of metastatic 
disease (stage IV) that is incurable. For those patients 
whose disease progresses despite chemotherapy, meticu
-
lous efforts at palliative care are essential (see Chapter 5).
 
»
•	
Patients should be referred to a gastroenterologist for 
evaluation and staging (endoscopy with biopsy, EUS) 
and palliative endoscopic antitumor therapy (stent).
•	
Patients with curable and resectable disease for whom 
neoadjuvant therapy may be appropriate (stage IIB or 
IIIA) should be referred to medical, radiation, and sur
-
gical oncologists for consideration of neoadjuvant che
-
motherapy, chemoradiotherapy, or surgical resection.
•	
Patients with metastatic disease should be referred to 
medical and radiation oncologists for consideration of 
palliative chemotherapy or chemoradiation.
•	
Patients with metastatic disease and obstructive tumors 
not amenable to or refractory to palliative radiation or 
stenting may require referral to an interventional radi
-
ologist, gastroenterologist, or surgeon for gastric or 
jejunal tube placement for liquid artificial nutrition. 
Early referral to palliative care services may improve 
symptom management in patients with advanced or 
metastatic disease.
 
»
Patients with high-grade esophageal obstruction with 
inability to manage oral secretions or maintain hydration 
should be admitted. Acute complications such as perfora
-
tion, bleeding, aspiration, or fistula also may require 
Best LM et al. Non-surgical versus surgical treatment for 
oesophageal cancer. Cochrane Database Syst Rev. 2016 Mar 29; 
3:CD011498. [PMID: 27021481]
Blum Murphy MA et al. Current concepts and future potential 
in neoadjuvant chemotherapy for esophageal cancer. Expert 
Rev Gastroenterol Hepatol. 2016 Mar;10(3):383–92. [PMID: 
26560689]
-
-
Doosti-Irani A et al. Complications of stent placement in 
patients with esophageal cancer: a systematic review and 
network meta-analysis. PLoS One. 2017 Oct 2; 
12(10):e0184784. [PMID: 28968416]
Glen P . The role of stents in the palliation of oesophageal cancer. 
BMJ Support Palliat Care. 2016 Mar;6(1):135–9. [PMID: 
25573667]
Janmaat VT et al. Palliative chemotherapy and targeted therapies 
for esophageal and gastroesophageal junction cancer. 
Cochrane Database Syst Rev. 2017 Nov 28;11:CD004063. 
[PMID: 29182797]
Klevebro F et al. A randomised clinical trial of neoadjuvant 
chemotherapy vs. neoadjuvant chemoradiotherapy for cancer 
of the oesophagus or gastro-oesophageal junction. Ann 
Oncol. 2016 Apr;27(4):660–7. [PMID: 26782957]
Le DT et al. Mismatch repair deficiency predicts response of 
solid tumors to PD-1 blockade. Science. 2017 Jul 28; 
357(6349):409–13. [PMID: 28596308] 
National Cancer Institute. Esophageal cancer treatment 
(PDQ®)—Health Professional Version. https://www.cancer 
.gov/types/esophageal/hp/esophageal-treatment-pdq
National Cancer Institute. SEER Cancer Statistics Factsheets: 
Esophageal Cancer, 2017. https://seer.cancer.gov/statfacts/
html/esoph.html
Vellayappan BA et al. Chemoradiotherapy versus chemoradio
-
therapy plus surgery for esophageal cancer. Cochrane Database 
Syst Rev. 2017 Aug 22;8:CD010511. [PMID: 28829911]
GASTRIC ADENOCARCINOMA
 
»
Dyspeptic symptoms with weight loss in patients 
over age 40 years.
 
»
Iron deficiency anemia: occult blood in stools.
 
»
Abnormality detected on upper gastrointestinal 
series or endoscopy.
 
»
Gastric adenocarcinoma remains the second most com
-
mon cause of cancer death worldwide. However, its inci
-

»
-
-
dence has declined rapidly over the last 70 years, especially 
in Western countries, which may be attributable to changes 
in diet (more fruits and vegetables), food refrigeration 
(allowing more fresh foods and reduced salted, smoked, 
and preserved foods), reduced toxic environmental expo
-
sures, and a decline in 
. The incidence of 
gastric cancer remains high (70/100,000) in Japan and 
many developing regions, including eastern Asia, Eastern 
Europe, Chile, Colombia, and Central America. In the 
United States, there were an estimated 26,240 new cases 
and 10,800 deaths in 2018. The incidence is higher in Asian 
Americans, Hispanics, African Americans, and American 
Indian/Alaska Natives.
There are two main histologic variants of gastric cancer: 
“intestinal-type” (which resembles intestinal cancers in 
forming glandular structures) and “diffuse” (which is 
poorly differentiated, has signet-ring cells, and lacks glan
-
dular formation). The incidence of 
intestinal-type gastric 
cancer
 has declined significantly, but it is still the more 
common type (70–80%); it occurs twice as often in men as 
women, primarily affects older people (mean age 63 years), 
and is more strongly associated with environmental factors. 
It is believed to arise through a gradual, multi-step progres
-
sion from inflammation (most commonly due to 
 
H pylori
), to atrophic gastritis, to intestinal metaplasia, and 
finally dysplasia or cancer. Chronic 
H pylori
 gastritis is the 
strong risk factor for gastric carcinoma, increasing the rela
-
tive risk 3.5- to 20-fold. It is estimated that 60–90% of cases 
of gastric carcinomas may be attributable to 
H pylori.
 
Other risk factors for intestinal-type gastric cancer include 
pernicious anemia, a history of partial gastric resection 
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more than 15 years previously, smoking, and diets that are 
high in nitrates or salt and low in vitamin C. 
Diffuse 
gastric cancer
 accounts for 20–30% of gastric cancer cases. 
In contrast to intestinal-type cancer, it affects men and 
women equally, occurs more commonly in young people, is 
not as strongly related to 
H pylori
 infection, and has a 
worse prognosis than intestinal-type cancer. Most diffuse 
gastric cancers are attributable to acquired or hereditary 
mutations in the genes regulating the E-cadherin cell adhe
-
sion protein. Hereditary diffuse gastric cancer accounts for 
1–3% of gastric cancers. The cancer may arise at a young 
age, is often multifocal and infiltrating with signet ring cell 
histology, and confers poor prognosis. Many of these fami
-
lies have a germline mutation of E-cadherin 
CDH1,
 which 
is inherited in an autosomal dominant pattern and carries 
a greater than 60% lifetime risk of gastric cancer. Prophy
-
lactic gastrectomy should be considered in patients known 
to carry this mutation.
In addition to the hereditary diffuse gastric cancer, 
there are other hereditary cancer predisposition syndromes 
that account for 3–5% of gastric cancers. These include 
Lynch syndrome, juvenile polyposis syndrome, Peutz-
Jeghers syndrome, and familial adenomatous polyposis. 
There are specific guidelines for how often screening 
endoscopies should be done for these syndromes (see 
Most gastric cancers arise in the body and antrum. 
These may occur in a variety of morphologic types: 
(1) polypoid or fungating intraluminal masses; (2) ulcerat
-
ing masses; (3) diffusely spreading (linitis plastica), in 
which the tumor spreads through the submucosa, resulting 
in a rigid, atonic stomach with thickened folds (prognosis 
dismal); and (4) superficially spreading or “early” gastric 
cancer—confined to the mucosa or submucosa (with or 
without lymph node metastases) and associated with a 
favorable prognosis. 
HER2
 amplification and overexpres
-
sion is seen in 10–25% of gastric adenocarcinoma cases 
and is commonly observed in intestinal histology and 
moderately differentiated disease. The prognostic signifi
-
cance of HER2 status is uncertain. Testing for microsatel
-
lite instability (MSI), deficiency in mismatch repair 
proteins (dMMR) and PD-L1 is recommended in advanced 
disease to identify tumors that may respond to immuno
-
therapy. For gastric adenocarcinoma, MSI-H/dMMR is 
found in 8–16% of cases.
In contrast to the dramatic decline in cancers of the 
distal stomach, a rise in incidence of tumors of the gastric 
cardia has been noted. These tumors have demographic 
and pathologic features that resemble Barrett-associated 
esophageal adenocarcinomas (see Esophageal Cancer).
 
»
Gastric carcinoma is generally asymptomatic until the 
disease is quite advanced. Symptoms are nonspecific and 
are determined in part by the location of the tumor. 
Dyspepsia, vague epigastric pain, anorexia, early satiety, 
and weight loss are the presenting symptoms in most 
patients. Patients may derive initial symptomatic relief 
from over-the-counter remedies, further delaying 
diagnosis. Ulcerating lesions can lead to acute gastrointes
-
tinal bleeding with hematemesis or melena. Pyloric 
obstruction results in postprandial vomiting. Lower esoph
-
ageal obstruction causes progressive dysphagia. Physical 
examination is rarely helpful. A gastric mass is palpated in 
less than 20% of patients. Signs of metastatic spread include 
a left supraclavicular lymph node (Virchow node), an umbil
-
ical nodule (Sister Mary Joseph nodule), a rigid rectal shelf 
(Blumer shelf), and ovarian metastases (Krukenberg 
tumor). Guaiac-positive stools may be detectable.
Iron deficiency anemia due to chronic blood loss or anemia 
of chronic disease is common. Liver test abnormalities,

of chronic disease is common. Liver test abnormalities, 
particularly elevation of alkaline phosphatase, may be pres
-
ent if there is metastasis to the liver. Circulating tumor 
markers do not have established clinical validity in screen
-
ing or diagnosis of gastric cancer. However, when checked 
serially, tumor markers can assist in monitoring treatment 
response.
Upper endoscopy should be obtained in all patients over 
age 60 years with new onset of epigastric symptoms 
(dyspepsia) and young patients with “alarm” symptoms 
(dysphagia, recurrent vomiting, significant weight loss), 
especially in immigrants from countries with a high preva
-
lence of gastric cancer. Endoscopy with biopsies of suspi
-
cious lesions is highly sensitive for detecting gastric 
carcinoma. It can be difficult to obtain adequate biopsy 
specimens in linitis plastica lesions.
D. Imaging
Once a gastric cancer is diagnosed, preoperative evaluation 
with CT of chest and abdomen (including pelvis in 
females) and EUS is indicated to delineate the local extent 
of the primary tumor as well as to evaluate for nodal or 
distant metastases. EUS is superior to CT in determining 
the depth of tumor penetration and is useful for evaluation 
of early gastric cancers that may be removed by endoscopic 
mucosal resection. PET or combined PET-CT imaging is 
recommended for detection of distant metastasis.
 
»
Screening
Because of its unproven efficacy and cost-effectiveness, 
screening for 
H pylori
 infection and treating it to prevent 
gastric cancer is not recommended for asymptomatic 
adults in the general population but may be considered in 
patients who have immigrated from regions with a high 
incidence of gastric cancer or who have a family history of 
gastric cancer. Because of the high incidence of gastric 
carcinoma in Japan, screening upper endoscopy is per
-
formed there to detect early gastric carcinoma. 
Approximately 40% of tumors detected by screening are 
early, with a 5-year survival rate of almost 90%. Screening 
is not recommended in the United States.
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»
Staging
Staging is defined according to the TNM system, in which 
T1 tumors invade the lamina propria or muscularis mucosa 
(T1a) or submucosa (T1b), T2 invade the muscularis pro
-
pria, T3 penetrate the subserosal connective tissue, and T4 
invade serosa or adjacent structures. Lymph nodes are 
graded as N0 if there is no involvement, and N1, N2, or N3 
if there are involvement of 1–2, 3–6, or more than 7 
regional nodes. M0 signifies the absence of metastatic dis
-
ease and MI, its presence. Sampling of at least 15 lymph 
nodes is recommended during surgical staging (see 
Curative Surgical Resection below). A staging laparoscopy 
prior to definitive surgery to exclude peritoneal carcinoma
-
tosis should be considered in patients with stage T1b or 
greater disease without radiographic evidence of distant 
metastases. Pathologic review should include (1) grade of 
tumor, (2) histologic subtype, (3) depth of invasion, 
 
(4) whether lymphatic or vascular invasion is present, and 
(5) if there is known metastatic disease, the status of HER2 
protein expression by immunohistochemistry or fluores
-
cent in situ hybridization or both.
 
»
Ulcerating gastric adenocarcinomas are distinguished 
from benign gastric ulcers by biopsies. Approximately 3% 
of gastric ulcers initially believed to be benign later prove 
to be malignant. All gastric ulcers identified at endoscopy 
should be biopsied to exclude malignancy. Ulcers that are 
suspicious for malignancy to the endoscopist or that have 
atypia or dysplasia on histologic examination warrant 
repeat endoscopy in 2–3 months to verify healing and 
exclude malignancy. Nonhealing ulcers should be consid
-
ered for resection. Infiltrative carcinoma with thickened 
gastric folds must be distinguished from lymphoma and 
other hypertrophic gastropathies.
 
»
Treatment
A. Curative Surgical Resection
Surgical resection is the only therapy with curative 
potential. Laparoscopic techniques achieve similar outcomes 
and lower overall complication rates as open gastrectomy. 
After preoperative staging, about two-thirds of patients 
will be found to have localized disease (ie, stages I–III). In 
Japan and in specialized centers in the United States, endo
-
scopic mucosal resection is performed in select patients 
with small (less than 1–2 cm), early (intramucosal or T1aN0) 
gastric cancers after careful staging with EUS. Approxi
-
mately 25% of patients undergoing surgery will be found to 
have locally unresectable tumors or peritoneal, hepatic, or 
distant lymph node metastases that are incurable. The 
remaining patients with confirmed localized disease should 
undergo radical surgical resection with curative intent. For 
adenocarcinoma localized to the distal two-thirds of the 
stomach, a subtotal gastrectomy should be performed. For 
proximal gastric cancer or diffusely infiltrating disease, 
total gastrectomy is necessary. The ultimate goal of surgery 
is obtaining negative surgical margins. Vitamin B
12
 supple
-
mentation is required after gastrectomy. For patients with 
localized gastric cancer that is resectable, current National 
Comprehensive Cancer Network (NCCN) treatment 
guidelines recommend gastrectomy with extended (D1), or 
modified regional (D2), lymph node dissection and sam
-
pling of 15 or more lymph nodes. D2 lymphadenectomy 
has been shown to improve disease-specific survival, but is 
associated with increased postoperative mortality.
B. Perioperative Chemotherapy or Chemoradiation
The use of perioperative chemotherapy or adjuvant chemo
-
radiation is associated with improved survival in patients 
with localized or locoregional gastric adenocarcinoma who 
undergo surgical resection. The choice of treatment 
depends on the location and extent of tumor, type of sur
-
gery, patient comorbidities and performance status, and 
institutional experience. Tumors arising in the gastro
-

-
-
esophageal junction may be treated following algorithms 
for esophageal primary tumors. Multidisciplinary treat
-
ment decision making involving the surgeon, radiation 
oncologist, and medical oncologist is imperative.
C. Palliative Modalities
Many patients will be found either preoperatively or at the 
time of surgical exploration to have advanced disease that 
is not amenable to “curative” surgery due to peritoneal or 
distant metastases or local invasion of other organs. In 
some of these cases, palliative resection of the tumor none
-
theless may be indicated to alleviate pain, bleeding, or 
obstruction. For patients with unresectable disease, a surgi
-
cal diversion with gastrojejunostomy may be indicated to 
prevent obstruction. Alternatively, unresected tumors may 
be treated with endoscopic laser or stent therapy, radiation 
therapy, or angiographic embolization to relieve bleeding 
or obstruction. Chemotherapy may be considered in 
patients with metastatic disease who still have good func
-
tional status and expected survival of at least several 
months. Multiple chemotherapy regimens have demon
-
strated activity in metastatic gastric adenocarcinoma 
(Table 39–2). Two-drug combination regimens are pre
-
ferred for first-line therapy, with most common regimens 
including a fluoropyrimidine or a taxane agent plus a plati
-
num agent. A three-drug combination of epirubicin or 
docetaxel plus cisplatin and 5-fluorouracil, or a modifica
-
tion thereof, may be appropriate for first-line treatment in 
medically fit patients. Addition of trastuzumab (a mono
-
clonal antibody against HER2 receptor) to standard che
-
motherapy prolonged survival in the subset (approximately 
15%) of patients with advanced gastric adenocarcinomas 
harboring amplification of the HER2. Trastuzumab is not 
recommended for combination with anthracyclines such as 
epirubicin due to risk for cardiotoxicity. Of note, addition 
of lapatinib, a dual tyrosine kinase inhibitor of HER2 and 
EGFR, to chemotherapy did not result in improvement in 
overall survival. After progression on first-line chemo
-
therapy, further chemotherapy treatments are associated 
with better overall survival than supportive care alone. 
Second-line treatments include ramucirumab, irinotecan, 
or paclitaxel (Tables 39–2 and 39–3). Ramucirumab is a 
monoclonal antibody targeting the VEGF receptor-2 and 
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can be used both as monotherapy and in combination with 
paclitaxel. In 2017, the FDA approved the immunothera
-
peutic agent pembrolizumab, a drug that targets lympho
-
cyte PD-L1, for second-line or subsequent therapy for 
MSI-H or dMMR cancers and for third-line or beyond 
therapy for PD-L1–positive adenocarcinomas. In Japan, 
nivolumab is approved for advanced gastric cancers after 
progression on standard therapies.
 
»
Prognosis
The 5-year survival of gastric carcinoma is approximately 
30%. However, 5-year survival in patients who undergo 
successful curative resection exceeds 45%. Survival is 
related to tumor stage, location, and histologic features. 
Stage I and stage II tumors resected for cure have a greater 
than 60% long-term survival. Patients with stage III tumors 
have a poor prognosis (less than 30% long-term survival) 
and should be considered for enrollment in clinical trials. 
Even with apparently localized disease, proximal tumors 
have a 5-year survival of less than 15%. For those whose 
disease progresses despite therapy, meticulous efforts at 
palliative care are essential (see Chapter 5). Diffuse-type 
tumors and tumors located in the proximal stomach have a 
worse prognosis.
 
»
•	
Patients with dysphagia, weight loss, protracted vomit
-
ing, iron deficiency anemia, melena, or new-onset of 
dyspepsia (especially if aged 55 years or older or associ
-
ated with other alarm symptoms) in whom gastric 
cancer is suspected should be referred for endoscopy.
•	
Patients should be referred to a surgeon for attempt at 
curative resection in stage I, II, or III cancer, including 
staging laparoscopy if indicated.
•	
Prior to surgery, patients should be referred to an 
oncologist to determine the role for perioperative 
chemotherapy or adjuvant chemoradiation or 
•	
Patients who have undergone gastrectomy require con
-
sultation with a nutritionist due to propensity for mal
-
nutrition and complications, such as dumping syndrome 
12
 deficiency, postoperatively.
•	
Patients with unresectable or metastatic disease should 
be referred to an oncologist for consideration of pallia
-
tive chemotherapy or chemoradiation. Early referral to 
palliative care services may also be considered for 
symptom management in patients with advanced and 
metastatic disease. 
 
»
Patients with protracted vomiting, inability to maintain 
hydration or nutrition, or acute bleeding.
Anandappa G et al. Emerging novel therapeutic agents in the 
treatment of patients with gastroesophageal and gastric ade
-
nocarcinoma. Hematol Oncol Clin North Am. 2017 Jun; 
31(3):529–44. [PMID: 28501092]
Kang YK et al. Nivolumab in patients with advanced gastric or 
gastro-oesophageal junction cancer refractory to, or intoler
-
ant of, at least two previous chemotherapy regimens 
 
(ONO-4538, ATTRACTION-2): randomized, double-blind, 
placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2; 
390(10111):2461–71. [PMID: 28993052]
Makris EA et al. Surgical considerations in the management of 
gastric adenocarcinoma. Surg Clin North Am. 2017 Apr; 
97(2):295–316. [PMID: 28325188]
Maron SB et al. Update on gastroesophageal adenocarcinoma 
targeted therapies. Hematol Oncol Clin North Am. 2017 Jun; 
31(3):511–27. [PMID: 28501091]
Stomach Cancer, 2017. https://seer.cancer.gov/statfacts/html/
stomach.html
National Cancer Institute. Stomach (Gastric) Cancer—Health 
Professional Version. https://www.cancer.gov/types/stomach/hp
Ngamruengphong S et al. Endoscopic management of early 
 
gastric adenocarcinoma and preinvasive gastric lesions. Surg 
Clin North Am. 2017 Apr;97(2):371–85. [PMID: 28325192]
Rugge M et al. Gastric cancer as preventable disease. Clin 
 
Gastroenterol Hepatol. 2017 Dec;15(12):1833–43. [PMID: 
28532700]
Spiegel D et al. Role of chemotherapy and radiation therapy

28532700]
Spiegel D et al. Role of chemotherapy and radiation therapy 
 
in the management of gastric adenocarcinoma. Surg Clin 
North Am. 2017 Apr;97(2):421–35. [PMID: 28325195]
GASTRIC LYMPHOMA
 
»
Symptoms of dyspepsia, weight loss, or anemia.
 
»
Variable abnormalities on upper gastrointestinal 
series or endoscopy including thickened folds, 
ulcer, mass or infiltrating lesions; diagnosis estab
-
lished by endoscopic biopsy.
 
»
Abdominal CT and EUS required for staging.
 
»
Gastric lymphomas may be primary (arising from the gastric 
mucosa) or may represent a site of secondary involvement in 
patients with nodal lymphomas. Distinguishing advanced 
primary gastric lymphoma with adjacent nodal spread from 
advanced nodal lymphoma with secondary gastric spread is 
essential because the prognosis and treatment of primary 
and secondary gastric lymphomas are different. Primary 
lymphoma is the second most common gastric malignancy, 
accounting for 3–5% of gastric cancers. More than 95% of 
these are non-Hodgkin B-cell lymphomas mainly consisting 
of either mucosa-associated lymphoid tissue (MALT)-type 
lymphoma and diffuse large B-cell lymphoma. Gastric T-cell 
lymphoma, which is associated with HTLV-1 infection, is 
rare and makes up 7% of primary gastric lymphomas.
H pylori
 is an important risk factor for 
the development of primary gastric lymphoma. Chronic 
H pylori
 causes an intense lymphocytic 
inflammatory response that may lead to the development 
of lymphoid follicles. Over 90% of low-grade primary gas
-
tric MALT-type lymphomas are associated with 
H pylori
 
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infection. It is hypothesized that chronic antigenic stimula
-
tion may result in a monoclonal lymphoproliferation that 
may culminate in low-grade or high-grade lymphoma.
 
»
Clinical Findings & Staging
The clinical presentation and endoscopic appearance of gas
-
tric lymphoma are similar to those of adenocarcinoma. Most 
patients have abdominal pain, weight loss, or bleeding. 
Patients with diffuse large B-cell lymphoma are more likely to 
have systemic symptoms and advanced tumor stage. At 
endoscopy, lymphoma may appear as an ulcer, mass, or dif
-
fusely infiltrating lesion. It tends to have horizontal infiltra
-
tion as opposed to the vertical extension seen in 
adenocarcinoma. The diagnosis is established with endo
-
scopic biopsy; FNA is not adequate. Since the disease can be 
multifocal, biopsies of both suspicious and normal-appearing 
areas are recommended. Biopsy specimens should be tested 
for 
H pylori
 and, if positive, for t(11;18) via PCR or FISH. EUS 
is the most sensitive test for determining the level of invasion 
and presence of perigastric lymphadenopathy and should be 
performed for accurate staging, if available. All patients 
should undergo staging with CT scanning of chest, abdomen, 
and pelvis. For patients with diffuse large B-cell lymphomas 
involving the stomach, combination PET-CT imaging, bone 
marrow biopsy with aspirate, tumor lysis laboratory tests, and 
hepatitis B and HIV serologies also may be required for stag
-
ing and treatment planning (see Chapter 13).
 
»
Treatment
Treatment of primary gastric lymphomas depends on the 
tumor histology, grade, and stage. Marginal B-cell lympho
-
mas of the MALT type that are low-grade and localized to 
the stomach wall (stage IE) or perigastric lymph nodes 
(stage IIE
1
) have an excellent prognosis. Patients with pri
-
mary gastric MALT-lymphoma should be tested for 
 
H pylori
 infection and treated if positive. Complete lym
-
phoma regression after successful 
H pylori
 eradication 
occurs in approximately 75% of cases of stage IE and 
approximately 55% with stage IIE low-grade lymphoma. 
However, 95% of cancers positive for t(11;18) do not 
respond to antibiotics. Remission may take as long as a 
year, and relapse occurs in about 2% of cases per year. 
Restaging with endoscopy and biopsy is recommended 
3 months after antibiotic treatment and 3–6 months fol
-
lowing radiation therapy. Ultimately, endoscopic surveil
-
lance after treatment is recommended every 3–6 months 
for 5 years to evaluate for recurrence.
In patients whose tumors harbor specific gene transloca
-
tions, including t(11;18) (API2-MALT1), t(1;14), or t(14;18), 
rates of remission after 
H pylori
 eradication are lower, and 
treatment with radiation may be required. Patients with 
localized marginal zone MALT-type lymphomas who either 
are not infected with 
H pylori
 or do not respond to eradica
-
tion therapy may be treated with radiation therapy or ritux
-
imab, if not a candidate for radiation. Many patients with 
minimal disease after successful 
H pylori
 eradication may be 
observed closely without further therapy.
The long-term survival of low-grade MALT lymphoma 
for stage I is over 90% and for stage II is 35–65%. Because 
of a low risk of perforation with either radiation therapy or 
chemotherapy, surgical resection is no longer recom
-
mended. Surgery for diffuse large B-cell lymphoma (but 
not MALT) has been associated with a better prognosis 
than conservative treatment. Diffuse large B-cell or other 
higher-grade lymphomas with secondary gastrointestinal 
involvement usually present at an advanced stage with 
widely disseminated disease and are treated according to 
stage and subtype of lymphoma (see Chapter 13).
Ikoma N et al. Multimodality treatment of gastric lymphoma. 
Surg Clin North Am. 2017 Apr;97(2):405–20. [PMID: 
28325194]
GASTRIC NEUROENDOCRINE TUMORS
Gastric NETs make up less than 1% of gastric neoplasms.

28325194]
Gastric NETs make up less than 1% of gastric neoplasms. 
They may occur sporadically or secondary to chronic 
hypergastrinemia that results in hyperplasia and transfor
-
mation of enterochromaffin cells in the gastric fundus. The 
majority of NETs are caused by hypergastrinemia and occur 
in association with either pernicious anemia (75%) (type 1) 
or Zollinger-Ellison syndrome (5%) (type 2). Type 1 tumors 
are associated with chronic atrophic gastritis, gastric achlor
-
hydria, and secondary hypergastrinemia. Initial diagnostic 
workup includes serum gastrin level, upper endoscopy, and 
EUS. Gastrin level should be obtained 1 week after the 
patient has stopped taking protein pump inhibitors. For 
low-grade tumors (ki-67 less than 3% or less than 
 
2 mitoses/10 HPF), somatostatin receptor–based imaging 
(somatostatin receptor scintigraphy or gallium-68 dotatate 
PET/CT) should be considered. For high-grade tumors 
 
(ki-67 greater than 20% or greater than 20 mitoses/10 HPF), 
PET/CT is preferred to evaluate the extent of disease.
For patients with hypergastrinemia (suspected of type 1 or 
type 2 carcinoid), serum vitamin B
12
 and intrinsic factor anti
-
body levels should be obtained to exclude pernicious anemia. 
Gastric NETs associated with Zollinger-Ellison syndrome 
occur almost exclusively in patients with multiple endocrine 
neoplasia type 1 (MEN 1), in which chromosomal loss of 
11q13 has been reported. Gastric NETs caused by hypergas
-
trinemia tend to be multifocal, be smaller than 1 cm, have a 
low potential for metastatic spread, and thus are unlikely to 
cause development of the carcinoid syndrome. Small lesions 
may be successfully treated with endoscopic resection fol
-
lowed by endoscopic surveillance every 6–12 months, or with 
observation. Antrectomy reduces serum gastrin levels and 
may lead to regression of small tumors. It can be considered in 
patients with type 1 gastric NETs to reduce recurrence risk 
and frequency of post-therapy monitoring. Octreotide ther
-
apy may be appropriate for patients with underlying gastri
-
noma and Zollinger-Ellison syndrome. Patients with tumors 
larger than 2 cm should undergo endoscopic or surgical resec
-
tion (see Small Intestinal Adenocarcinomas below).
Type 3 gastric NETs arise sporadically, independent of 
gastrin production, and account for up to 20% of gastric 
NETs. Most sporadic gastric NETs are solitary, larger than 
2 cm, and have a strong propensity for hepatic or pulmonary 
metastases and thus the carcinoid syndrome at initial 
presentation. CT or MRI should be obtained to evaluate for 
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metastatic disease. Localized sporadic NETs should be treated 
with partial or total gastrectomy and regional lymphadenec
-
tomy. Advanced, low-grade gastric NETs can be monitored 
with serial scans, if asymptomatic. Somatostatin analogs may 
provide symptomatic relief for patients with functional gas
-
tric NETs. Advanced high-grade gastric neuroendocrine 
carcinomas are treated in a fashion similar to SCLCs.
Corey B et al. Neuroendocrine tumors of the stomach. Surg Clin 
North Am. 2017 Apr;97(2):333–43. [PMID: 28325190]
National Comprehensive Cancer Network. Clinical Practice 
Guidelines in Oncology. Neuroendocrine tumors. Version 3. 
June 13, 2017. https://www.nccn.org/professionals/physician_
gls/pdf/neuroendocrine.pdf
GASTROINTESTINAL MESENCHYMAL 
TUMORS
Gastrointestinal mesenchymal tumors (which include stro
-
mal tumors, leiomyomas, and schwannomas) derive from 
mesenchymal stem cells and have an epithelioid or spindle 
cell histologic pattern, resembling smooth muscle. The 
most common stromal tumors are gastrointestinal stromal 
tumors (“GISTs”), which originate from interstitial cells of 
Cajal. GISTs occur throughout the gastrointestinal tract, but 
most commonly in the stomach (60%) and small intestine 
(30%). Approximately 85–90% of GISTs have mutations in 
KIT
. Other mesenchymal tumors, such as leiomyomas, 
which derive from smooth muscle cells, generally stain 
negative for CD117. Mesenchymal tumors may be discov
-
ered incidentally on imaging studies or endoscopy or may 
cause symptoms (most commonly bleeding, pain, or 
obstruction). At endoscopy, they appear as a submucosal 
mass that may have central umbilication or ulceration. EUS 
with guided FNA biopsy is the optimal study for diagnosing 
gastric mesenchymal tumors and distinguishing them from 
other submucosal lesions. Percutaneous biopsy may confer 
risk of bleeding or intra-abdominal seeding. CT of the 
abdomen and pelvis with contrast, MRI, and PET imaging 
are useful in the diagnosis and staging. PET imaging also 
may be useful to monitor response to treatment.
While almost all GISTs have malignant potential, the 
risk of developing metastasis is increased with tumor size 
greater than 2 cm, nongastric location, and mitotic index 
greater than 5 mitoses per 50 high-powered fields. It is dif
-
ficult to distinguish benign from malignant tumors by EUS 
appearance or by FNA. But, in general, lesions are more 
likely benign if they are smaller than 2 cm, have a smooth 
border, and have a homogeneous echo pattern on EUS. 
Resection settles the issue.
Surgery is recommended for all patients with tumors 
that are 2 cm or larger, increasing in size, have an EUS 
appearance suspicious for malignancy, or are symptomatic. 
The management of asymptomatic gastric lesions 2 cm or 
smaller in size depends on the EUS features. Tumors with 
high-risk EUS features can be surgically resected. If no 
high-risk features are noted, endoscopic surveillance can 
be performed. Because of the low but real long-term risk of 
malignancy, surgical resection should be considered in 
younger, otherwise healthy patients. However, other 
patients may be monitored with serial endoscopic ultraso
-
nographic examinations or, in select cases, endoscopic 
resections. After complete surgical resection, GISTs recur 
within 5 years in over half of patients. The majority of 
recurrences are within the first 3 years. Adjuvant therapy 
with the tyrosine kinase inhibitor imatinib delays recur
-
rence and prolongs survival. Adjuvant imatinib is recom
-
mended for all high-risk patients for at least 1 year, though 
the 5-year recurrence-free survival rate is significantly 
better following 3 years than 1 year of such therapy (65.6% 
vs 47.9%). After surgical resection, patients should have 
surveillance with history and physical examination and CT 
of the abdomen and pelvis every 3–6 months. Neoadjuvant 
therapy with imatinib may be considered for patients with

therapy with imatinib may be considered for patients with 
localized GIST tumors who are deemed to be at high risk 
for resection because of comorbidities, tumor size, or 
tumor location. A biopsy is required to confirm the diag
-
nosis of GIST prior to initiation of neoadjuvant imatinib.
Untreated metastatic GIST tumors are aggressive and 
carry a poor prognosis. Imatinib induces disease control in 
up to 85% of patients with metastatic disease with a pro
-
gression-free survival of 20–24 months and median overall 
survival of almost 5 years. Imatinib-resistant tumors may 
respond to high-dose imatinib or to sunitinib, another 
multi-targeted kinase inhibitor that is approved as second-
line therapy for metastatic GIST. For patients who have 
progressive disease after treatment with imatinib and suni
-
tinib, the multi-targeted kinase inhibitor regorafenib can 
Keung EZ et al. Management of gastrointestinal stromal tumors. 
Surg Clin North Am. 2017 Apr;97(2):437–52. [PMID: 28325196]
Lanke G et al. How best to manage gastrointestinal stromal 
tumor. World J Clin Oncol. 2017 Apr 10;8(2):135–44. [PMID: 
28439494]
Liu Y et al. Randomized clinical trials in gastrointestinal stromal 
tumors. Surg Oncol Clin N Am. 2017 Oct;26(4):545–57. 
[PMID: 28923219]
Nishida T et al. The standard diagnosis, treatment, and follow-
up of gastrointestinal stromal tumors based on guidelines. 
Gastric Cancer. 2016 Jan;19(1):3–14. [PMID: 26276366]
Standards of Practice Committee; Faulx A et al. The role of 
endosocopy in subepithelial lesions of the GI tract. 
Gastrointest Endosc. 2017 Jun;85(6):1117–32. [PMID: 
28385194]
Xiong H et al. Laparoscopic surgery versus open resection in 
patients with gastrointestinal stromal tumors: an updated 
systematic review and meta-analysis. Am J Surg. 2017 Sep; 
214(3):538–46. [PMID: 28412996]
MALIGNANCIES OF THE SMALL INTESTINE
1. Small Intestinal Adenocarcinomas
These are aggressive tumors that occur most commonly in 
the duodenum or proximal jejunum. The incidence is rare, 
with 10,470 new diagnoses estimated in 2018 in the United 
States. Overall, prognosis is poor, with 5-year survival of 
85% for localized disease, 75% for regional disease, and 
42% for distant disease (overall, 27% of patients are stage IV 
at diagnosis). The management of small intestinal adeno
-
carcinoma is extrapolated from data available for the 
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management of colon adenocarcinoma. The ampulla of 
Vater is the most common site of small bowel carcinoma. 
The incidence of ampullary carcinoma is increased more 
than 200-fold in patients with familial adenomatous 
polyposis. Periodic endoscopic surveillance to detect early 
ampullary neoplasms is therefore recommended. 
Ampullary carcinoma may present with jaundice due to 
bile duct obstruction or bleeding. Surgical resection of 
early lesions is curative in up to 40% of patients.
2. Small Intestinal Lymphomas
Lymphomas may arise primarily in the gastrointestinal 
tract or may involve it secondarily in patients with dissemi
-
nated disease. In Western countries, primary gastrointesti
-
nal lymphomas account for 5% of lymphomas and 20% of 
small bowel malignancies. They occur most commonly in 
the small intestine. There is an increased incidence of small 
intestinal lymphomas in patients with AIDS, Crohn dis
-
ease, and those receiving immunosuppressive therapy. The 
most common histologic subtype is non-Hodgkin extrano
-
dal marginal zone (MALT) B-cell lymphoma. Enteropathy-
associated T-cell lymphomas appear to be increasing in 
incidence in the United States. They are associated with the 
diagnosis of celiac disease. In the Middle East, lymphomas 
may arise in the setting of immunoproliferative small intes
-
tinal disease. Other types of intestinal lymphomas include 
primary intestinal follicular cell lymphoma, mantle cell 
lymphoma, and Burkitt lymphoma (see Chapter 13).
Presenting symptoms or signs of primary small bowel 
lymphoma include abdominal pain, weight loss, nausea 
and vomiting, distention, anemia, and occult blood in the 
stool. Fevers are unusual. Protein-losing enteropathy may 
result in hypoalbuminemia, but other signs of malabsorp
-
tion are unusual. Barium radiography or CT enterography 
helps localize the site of the lesion. The diagnosis requires 
endoscopic, percutaneous, or laparoscopic biopsy. Imaging 
and bone marrow biopsy are required to determine stage.
Treatment depends on the tumor histologic subtype 
and stage of disease (see Chapter 13). Surgical resection of 
primary intestinal lymphoma, if feasible, may be appropri
-
ate for localized tumors. In patients with limited disease 
(stage IE) in whom resection is performed with negative 
margins, the role of adjuvant chemotherapy is unclear. 
Locoregional radiation should be considered if surgical 
margins are positive. Patients with more extensive disease 
generally are treated according to the tumor histology.
3. Intestinal Neuroendocrine Tumors
 
»
Majority are asymptomatic and discovered 
incidentally at endoscopy or surgery.
 
»
Carcinoid syndrome occurs in less than 10%; 
hepatic metastases are generally present.
 
»
Risk of metastasis is related to tumor size and 
location.
 
»
Neuroendocrine tumors account for approximately one-
third of tumors arising in the small bowel. Gastrointestinal 
NETs most commonly occur in the small intestine (45%) 
but are also found in the rectum (20%), appendix (17%), 
and colon (11%), with the remainder occurring in the 
stomach (less than 10%; see Gastric Neuroendocrine 
Tumors above). Carcinoid tumors are well-differentiated 
tumors that may secrete a variety of hormones, including 
serotonin, somatostatin, gastrin, and substance P .
Small intestinal carcinoids most commonly arise in the 
distal ileum within 60 cm of the ileocecal valve. Up to 30% 
are multicentric. Although many carcinoids behave in an 
indolent fashion, the overall 5-year survival rates for 
patients with locoregional and metastatic small bowel car
-
cinoids are approximately 65% and 35%, respectively. The 
risk of metastatic spread increases when the tumor is 1 cm 
or larger and when it is larger than 2 cm with invasion 
beyond muscularis propria. Appendiceal carcinoids are 
identified in 0.3% of appendectomies, usually as an inci
-

-
dental finding. Almost 80% of these tumors are smaller 
than 1 cm, and 90% are smaller than 2 cm. However, in 
patients with appendiceal carcinoid tumors larger than 
2 cm, approximately 90% develop nodal and distant metas
-
tases; right hemicolectomy is recommended in these cases.
Rectal carcinoids are usually detected incidentally as 
submucosal nodules during proctoscopic examination and 
often locally excised by biopsy or snare polypectomy before 
the histologic diagnosis is known. Endorectal ultrasound is 
usually recommended to assess the size, presence and 
depth of invasion, and presence of lymph node metastases. 
Rectal carcinoids smaller than 1 cm virtually never metas
-
tasize and are treated effectively with local endoscopic or 
transanal excision. Larger tumors are associated with the 
development of metastasis in 10%. Hence, a more extensive 
cancer resection operation is warranted in fit patients with 
rectal carcinoid tumors larger than 1–2 cm or with high-
risk features (such as invasion of muscularis propria or 
evidence of nodal involvement), or both.
 
»
Most lesions smaller than 1–2 cm are asymptomatic and 
difficult to detect by endoscopy or imaging studies. 
Through local extension or metastasis to mesenteric lymph 
nodes, carcinoids engender a fibroblastic reaction with 
contraction and kinking of the bowel or encasement of 
mesenteric vessels. Small intestinal carcinoids may present 
with abdominal pain, bowel obstruction, bleeding, or 
bowel infarction. Appendiceal and rectal carcinoids usually 
are small and asymptomatic, but large lesions can cause 
bleeding, obstruction, or altered bowel habits. 
Carcinoid 
syndrome
 occurs in less than 10% of patients. More than 
90% of patients with carcinoid syndrome have hepatic 
metastases, usually from carcinoids of small bowel origin. 
About 10% of patients with carcinoid syndrome have pri
-
mary bronchial or ovarian tumors without hepatic 
metastases. Carcinoid syndrome is caused by tumor 
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secretion of hormonal mediators. The manifestations include 
facial flushing, edema of the head and neck (especially with 
bronchial carcinoid), abdominal cramps and diarrhea, bron
-
chospasm, cardiac lesions (pulmonary or tricuspid stenosis 
or regurgitation in 10–30%), and telangiectases.
Serum chromogranin A (CgA) is elevated in the majority of 
NETs, although its sensitivity for small, localized carcinoid 
tumors is unknown. CgA is elevated in almost 90% of 
patients with advanced small bowel carcinoid. Urinary 
5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin 
levels are also elevated in patients with metastatic carcinoid; 
however, these tests are less sensitive than CgA. There is 
increased urinary 5-HIAA in carcinoid syndrome; symp
-
tomatic patients usually excrete more than 25 mg of 5-HIAA 
per day in the urine. Because certain foods and medications 
can interfere with 5-HIAA levels, these should be withheld 
for 48 hours prior to a 24-hour urine collection.
C. Imaging
Abdominal CT may demonstrate a mesenteric mass with 
tethering of the bowel, lymphadenopathy, and hepatic 
metastasis. Abdominal CT or enterography may reveal kink
-
ing of the bowel, but because the lesion is extraluminal, the 
diagnosis may be overlooked for several years. Somatostatin 
receptor scintigraphy (OctreoScan) or gallium Ga-68 
DOTATATE PET scan are routinely used in staging and can 
help identify diseases that may benefit from treatment with 
somatostatin analogs. Most patients with carcinoid syn
-
drome have liver metastasis on abdominal imaging.
 
»
Treatment & Outcomes
Small intestinal carcinoids generally are indolent tumors with 
slow spread. Patients with disease confined to the small intes
-
tine should be treated with surgical excision. There is no 
proven role for adjuvant therapy after complete resection. 
Five-year survival rates for patients with stage I and II disease 
are 96% and 87%, respectively. In patients with resectable 
disease who have lymph node involvement (stage III), the 
5-year survival is 74%; however, by 25 years, less than 25% 
remain disease free. Even patients with metastatic disease 
may have an indolent course with a 5-year survival of 43%.
In patients with advanced disease, therapy historically 
has been deferred until the patient is symptomatic. Con
-
ventional cytotoxic chemotherapy agents do not achieve 
significant responses in carcinoid tumors and have not 
been associated with improved outcomes. Radiolabeled 
somatostatin analogs are used in Europe as another treat
-
ment modality for patients with somatostatin-receptor 
positive advanced carcinoid tumors. FDA approval is 
anticipated in the United States in 2018. In patients with 
metastatic disease, surgery should be directed toward 
palliation of obstructive symptoms or bleeding.
In patients with carcinoid syndrome, the somatostatin 
analog octreotide, which inhibits hormone secretion from 
the carcinoid tumor, can be administered subcutaneously 
three times a day or as a long-acting intramuscular depot 
formulation administered monthly. In 90% of patients this 
results in dramatic relief of symptoms of carcinoid syn
-
drome, including diarrhea or flushing, for a median period 
of 1 year. Thereafter, many patients stop responding to 
octreotide. In selected patients with refractory carcinoid 
syndrome, resection of hepatic metastases may provide 
dramatic improvement. Liver-directed therapy (chemoem
-
bolization, radioembolization, or surgical debulking) also 
may provide symptomatic improvement in some patients 
with hepatic metastases.
4. Small Intestine Sarcoma
Sarcomas constitute approximately 10% of small bowel 
neoplasms and are commonly found in the jejunum and 
ileum (and in a Meckel diverticulum, if present). Most arise 
from stromal tumors (GISTs) that stain positive for CD117; 
a minority arise from smooth muscle tumors (leiomyosar
-

-
comas) (see Gastrointestinal Mesenchymal Tumors above). 
Common symptoms of small intestine sarcoma include 
pain, weight loss, bleeding, and perforation. As the lesions 
tend to enlarge extraluminally, obstruction is rare.
Kaposi sarcoma was at one time a common complica
-
tion in AIDS, but the incidence is declining with antiretro
-
viral therapy. It can also occur in the setting of 
immunosuppression after organ transplant. It is caused by 
infection with human herpesvirus 8 (HHV8). Lesions may 
be present anywhere in the intestinal tract. Visceral involve
-
ment usually is associated with cutaneous disease. Most 
lesions are clinically silent; however, large lesions may be 
symptomatic. Widespread involvement may be best treated 
by systemic chemotherapy using single-agent therapy or 
combinations of pegylated-doxorubicin, paclitaxel, vincris
-
tine, bleomycin, or etoposide. Surgery or radiation may be 
indicated for isolated high-risk lesions.
Aparicio T et al. Small bowel adenocarcinoma. Gastroenterol 
Clin North Am. 2016 Sep;45(3):447–57. [PMID: 27546842]
Ecker BL et al. Efficacy of adjuvant chemotherapy for small 
bowel adenocarcinoma: a propensity score-matched analysis. 
Cancer. 2016 Mar 1;122(5):693–701. [PMID: 26717303]
Elli L et al. Use of enterosocopy for the detection of malignant 
and premalignant lesions of the small bowel in complicated 
celiac disease: a meta-analysis. Gastrointest Endosc. 
2017 Aug;86(2):264–73. [PMID: 28433612]
Kim JS et al. Imaging and screening of cancer of the small bowel. 
Radiol Clin North Am. 2017 Nov;55(6):1273–91. [PMID: 
28991566]
Small Intestine Cancer, 2017. https://seer.cancer.gov/statfacts/
html/smint.html
Pusceddu S et al. Update on medical treatment of small intesti
-
nal neuroendocrine tumors. Expert Rev Anticancer Ther. 
2016 Sep;16(9):969–76. [PMID: 27353232]
Rondonotti E et al. Neoplastic diseases of the small bowel. 
Gastrointest Endosc Clin N Am. 2017 Jan;27(1):93–112. 
[PMID: 27908521]
Y ao JC et al; RAD001 in Advanced Neuroendocrine Tumours, 
Fourth Trial (RADIANT-4) Study Group. Everolimus for the 
treatment of advanced, non-functional neuroendocrine 
tumours of the lung or gastrointestinal tract (RADIANT-4): a 
randomised, placebo-controlled, phase 3 study. Lancet. 
2016 Mar 5;387(10022):968–77. [PMID: 26703889]
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Zaaimi Y et al. Advanced small bowel adenocarcinoma: 
molecular characteristics and therapeutic perspectives. Clin 
Res Hepatol Gastroenterol. 2016 Apr;40(2):154–60. [PMID: 
26547136]
COLORECTAL CANCER
 
»
Personal or family history of adenomatous or 
serrated polyps or colorectal cancer are important 
 
»
Symptoms or signs depend on tumor location.
 
»
Proximal colon:
 fecal occult blood, anemia.
 
»
Distal colon:
 
change in bowel habits, 
 
»
Diagnosis established with colonoscopy.
 
»
Colorectal cancer is the second leading cause of death due 
to malignancy in the United States. Colorectal cancer will 
develop in approximately 4.2% of Americans and has a 
5-year survival rate of 65%. In 2018, there were an estimated 
140,250 new cases of colorectal cancer in the United States, 
with an estimated 50,630 deaths. Between 1996 and 2010, 
its mortality rate has decreased by 46%. During this same 
period, the percentage of patients 50 years or older who 
were screened for colorectal cancer increased to 66%. On 
average, new cases have been falling 3.2% each year over the 
last 10 years. The colorectal cancer mortality in adults aged 
20–54 years increased by 1% annually from 2004 to 2014, 
although the same trend was not observed in black patients.
Colorectal cancers are almost all adenocarcinomas, 
which tend to form bulky exophytic masses or annular con
-
stricting lesions. The majority of colorectal cancers are 
thought to arise from malignant transformation of an ade
-
nomatous polyp (tubular, tubulovillous, or villous ade
-
noma) or serrated polyp (hyperplastic polyp, traditional 
serrated adenoma, or sessile serrated adenoma). Polyps that 
are “advanced” (ie, polyps at least 1 cm in size, adenomas 
with villous features or high-grade dysplasia, or serrated 
polyps with dysplasia) are associated with a greater risk of 
cancer. Approximately 85% of sporadic colorectal cancers 
arise from adenomatous polyps and have loss of function of 
one or more tumor suppressor genes (eg, p53, APC, or 
DCC) due to a combination of spontaneous mutation of 
one allele combined with chromosomal instability and 
aneuploidy (abnormal DNA content) that leads to deletion 
and loss of heterozygosity of the other allele (eg, 5q, 17q, or 
18p deletion). Activation of oncogenes such as 
KRAS
 and 
BRAF
 is present in a subset of colorectal cancers with prog
-
nostic and therapeutic implications discussed further below.
Approximately 10–20% of colorectal cancers arise from 
serrated polyps, most of which have hypermethylation of 
CpG-rich promoter regions that leads to inactivation of 
the DNA mismatch repair gene 
MLH1,
 resulting in 
microsatellite instability, and activation of mutations of 
the 
BRAF
 gene. Serrated colon cancers have distinct clini
-
cal and pathologic characteristics, including diploid DNA 
content, predominance in the proximal colon, poor dif
-
ferentiation, and more favorable prognosis.
Up to 5% of colorectal cancers are caused by inherited 
germline mutations resulting in polyposis syndromes (eg, 
familial adenomatous polyposis) or hereditary non
-
polyposis colorectal cancer (HNPCC or Lynch syndrome). 
These conditions are discussed further in Chapter 15.
 
»
Risk Factors
A number of factors increase the risk of developing 
colorectal cancer. Recognition of these has impact on 
screening strategies. However, 75% of all cases occur in 
people with no known predisposing factors.
A. Age
The incidence of colorectal cancer rises sharply after age 
45 years, and 90% of cases occur in persons over the age of 
50 years with a median age of 68 years at the time of diag
-
nosis. For unknown reasons, its incidence is increasing 
among younger adults between the ages of 20 and 54.
B. Family History of Neoplasia
A family history of colorectal cancer is present in approxi
-
mately 20% of patients with colon cancer. Hereditary fac
-

-
-
tors are believed to contribute to 20–30% of colorectal 
cancers; however, the genes responsible for most of these 
cases have not yet been identified. (See Chapter 15 for dis
-
cussion of inherited polyposis syndromes.) Approximately 
6% of the Ashkenazi Jewish population has a missense 
mutation in the 
APC
 gene 
(APC I1307K)
 that confers a 
modestly increased lifetime risk of developing colorectal 
cancer (OR 1.4–1.9) but phenotypically resembles sporadic 
colorectal cancer rather than familial adenomatous polyp
-
osis. Genetic screening is available, and patients harboring 
the mutation merit intensive screening.
A family history of colorectal cancer or adenomatous 
polyps is one of the most important risk factors for colorec
-
tal cancer. The risk of colon cancer is proportionate to the 
number and age of affected first-degree family members 
with colon neoplasia. People with one first-degree family 
member with colorectal cancer have an increased risk 
approximately two times that of the general population; 
however, the risk is almost four times if the family member 
was younger than 45 years when the cancer was diagnosed. 
Patients with two first-degree relatives have a fourfold 
increase, or 25–30% lifetime, risk of developing colon 
cancer. First-degree relatives of patients with adenomatous 
polyps also have a twofold increased risk for colorectal neo
-
plasia, especially if they were younger than 60 years when 
the polyp was detected or if the polyp was 10 mm or larger.
C. Inflammatory Bowel Disease
The risk of adenocarcinoma of the colon begins to rise 
 
8 years after disease onset in patients with ulcerative colitis 
and Crohn colitis (see Chapter 15). For this reason, 
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initiation of surveillance with colonoscopy is recommended 
at 8–10 years after onset of inflammatory bowel disease 
symptoms.
D. Dietary and Lifestyle Factors and 
Chemoprevention in Colorectal Cancer Risk
In epidemiologic studies, diets rich in fats and red meat are 
associated with an increased risk of colorectal adenomas 
and cancer, whereas diets high in fruits, vegetables, and 
fiber are associated with a decreased risk. However, pro
-
spective studies have not shown a reduction in colon can
-
cer or recurrence of adenomatous polyps with diets that are 
low in fat; are high in fiber, fruits or vegetables; or that 
include calcium, folate, beta-carotene, or vitamin A, C, D, 
or E supplements.
Low-dose aspirin has been associated with a reduced 
risk of colorectal adenomas and cancer in multiple studies. 
A 2016 USPSTF systematic review of controlled trials 
concluded that prolonged regular use of low-dose aspirin 
(81 mg/day) is associated with a 40% reduction in colorec
-
tal cancer incidence after 10 years and a 33% reduction in 
colorectal cancer mortality after 20 years. Because long-
term aspirin use is associated with a low incidence of seri
-
ous complications (gastrointestinal hemorrhage, stroke), 
low-dose aspirin should not be routinely administered as 
a chemopreventive agent without other medical 
indications. Specifically, the Task Force recommends ini
-
tiation of low-dose aspirin in patients who are age 
50–59 years, who have a greater than 10% 10-year risk of 
cardiovascular disease events, who are not at increased 
risk for bleeding, who have a life expectancy of at least 
10 years, and who are willing to take the low-dose aspirin 
daily for at least 10 years (grade B recommendation). The 
Task Force states that the decision to initiate low-dose 
aspirin use for the primary prevention of colorectal cancer 
(and cardiovascular disease) in adults who are age 
60–69 years and who have a 10% or greater 10-year cardio
-
vascular disease risk should be an individual one. Persons 
who are not at increased risk for bleeding, have a life 
expectancy of at least 10 years, and are willing to take low-
dose aspirin daily for at least 10 years are more likely to 
benefit; persons who place a higher value on its potential 
benefits than its potential harms may choose to take low-
dose aspirin (grade C recommendation). Low-dose aspi
-
rin may also be considered in patients with a personal or 
family history of colorectal cancer or advanced adenomas; 
however, its administration does not obviate the need for 
colonoscopy screening and surveillance.
Retrospective analysis of randomized phase III trial 
data and a meta-analysis have shown that patients with 
higher levels of pre- and post-diagnosis physical activity 
experience reduced colorectal cancer–specific mortality 
and all-cause mortality. Maintaining a healthy body weight, 
a healthy diet, and a physically active lifestyle are recom
-
mended in colorectal cancer survivors.
E. Other Factors
The incidence and mortality of colon adenocarcinoma is 
higher in blacks than in whites. It is unclear whether this is 
due to genetic or socioeconomic factors (eg, diet or 
reduced access to medical care).
 
»
Adenocarcinomas grow slowly and may be present for 
several years before symptoms appear. However, some 
asymptomatic tumors may be detected by the presence of 
fecal occult blood (see Screening for Colorectal Neoplasms, 
below). Symptoms depend on the location of the carcinoma. 
Chronic blood loss from right-sided colonic cancers may 
cause iron deficiency anemia, manifested by fatigue and 
weakness. Obstruction, however, is uncommon because of 
the large diameter of the right colon and the liquid consis
-
tency of the fecal material. Lesions of the left colon often 
involve the bowel circumferentially. Because the left colon 
has a smaller diameter and the fecal matter is solid,

-
has a smaller diameter and the fecal matter is solid, 
obstructive symptoms may develop with colicky abdomi
-
nal pain and a change in bowel habits. Constipation may 
alternate with periods of increased frequency and loose 
stools. The stool may be streaked with blood, though 
marked bleeding is unusual. With rectal cancers, patients 
note tenesmus, urgency, and recurrent hematochezia. 
Weight loss is uncommon. Physical examination is usually 
normal except in advanced disease. A mass may be palpa
-
ble in the abdomen. The liver should be examined for 
hepatomegaly, suggesting metastatic spread. For cancers of 
the distal rectum, digital examination is necessary to deter
-
mine whether there is extension into the anal sphincter or 
fixation, suggesting extension to the pelvic floor.
A CBC is obtained to look for evidence of anemia. Elevated 
liver biochemical tests, particularly the serum alkaline 
phosphatase, are suspicious for metastatic disease. The 
serum carcinoembryonic antigen (CEA) should be mea
-
sured in all patients with proved colorectal cancer, but is 
not appropriate for screening. A preoperative CEA level 
greater than 5 ng/mL is a poor prognostic indicator. After 
complete surgical resection, CEA levels should normalize; 
persistently elevated levels suggest the presence of persis
-
tent disease and warrant further evaluation. The sensitivity 
of CEA for detection of recurrence ranges from 68% to 
82% and its specificity from 80% to 97%. For this reason, 
CEA is routinely monitored at the time of adjuvant therapy 
and during postoperative surveillance for patients who had 
elevated levels before resection.
C. Colonoscopy
Colonoscopy is the diagnostic procedure of choice in 
patients with a clinical history suggestive of colon cancer or 
in patients with an abnormality suspicious for cancer 
detected on radiographic imaging. Colonoscopy permits 
biopsy for pathologic confirmation of malignancy. In 
patients in whom the colonoscope is unable to reach the 
cecum (less than 5% of cases) or when a nearly obstructing 
tumor precludes passage of the colonoscope, CT colonog
-
raphy examination should be performed.
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D. Imaging
Chest, abdominal, and pelvic CT scans with contrast are 
required for preoperative staging. CT scans may demon
-
strate distal metastases but are less accurate in the determi
-
nation of the level of local tumor extension (T stage) or 
lymphatic spread (N stage). Intraoperative assessment of 
the liver by direct palpation and ultrasonography can be 
performed to detect hepatic metastases. For rectal cancers 
(generally defined as tumors arising 12 cm or less proximal 
to the anal verge), pelvic MRI or endorectal ultrasonogra
-
phy is required to determine the depth of penetration of 
the cancer through the rectal wall (T stage) and perirectal 
lymph nodes, informing decisions about preoperative 
(neoadjuvant) chemoradiotherapy and operative 
management. PET is not routinely used for staging or sur
-
veillance in colorectal cancers.
 
»
Staging
The TNM system is the commonly used classification to 
stage colorectal cancer. Staging is important not only 
because it correlates with the patient’s long-term survival 
but also because it is used to determine which patients 
should receive adjuvant therapy.
 
»
The nonspecific symptoms of colon cancer may be con
-
fused with those of irritable bowel syndrome, diverticular 
disease, ischemic colitis, inflammatory bowel disease, 
infectious colitis, and hemorrhoids. Neoplasm must be 
excluded in any patient over age 40 years who reports a 
change in bowel habits or hematochezia or who has an 
unexplained iron deficiency anemia or occult blood in 
stool samples.
 
»
Treatment
A. Surgery
Resection of the primary colonic or rectal cancer is the 
treatment of choice for almost all patients who have resect
-
able lesions and can tolerate general anesthesia. For colon 
cancer, multiple studies demonstrate that minimally inva
-
sive, laparoscopically assisted colectomy results in similar 
outcomes and rates of recurrence to open colectomy. 
Regional dissection of at least 12 lymph nodes should be 
performed to determine staging, which guides decisions 
about adjuvant therapy.
For rectal carcinoma, preoperative (neoadjuvant) 
chemoradiation with 5-fluorouracil is recommended in all 
node-positive tumors, and in T3 and greater tumors, due to 
increased risk of local recurrence (see below). After neoad
-
juvant therapy, the operative approach depends on the level 
of the tumor above the anal verge, the size and depth of 
penetration, and the patient’s overall condition. Clinical 
staging by endorectal ultrasound or MRI with endorectal 
coil is important in guiding the clinical approach. In care
-
fully selected patients with small, mobile (less than 4 cm), 
well-differentiated T1 or T2 rectal tumors that are less than 
8 cm from the anal verge, transanal excision may be 
considered. This approach avoids laparotomy and spares 
the rectum and anal sphincter, preserving normal bowel 
continence. All other patients will require either a low ante
-
rior resection with a colorectal anastomosis or an abdomi
-
noperineal resection with a colostomy, depending on how 
far above the anal verge the tumor is located and the extent 
of local tumor spread. Careful dissection of the entire 
mesorectum by either open or laparoscopic surgery reduces 
local recurrence to 5%. Although low anterior resections 
obviate a colostomy, they are associated with increased 
immediate postsurgical complications (eg, leak, dehis
-
cence, stricture) and defecatory complaints (eg, increased 
stool frequency, and incontinence). With unresectable 
rectal cancer, the patient may be palliated with a diverting 
colostomy or placement of an expandable wire stent. 
Pathology review of colorectal cancers should include test
-
ing for mismatch repair proteins for all patients younger 
than 70 years or with stage II disease. Tumors of patients 
with metastatic colorectal cancer should also be tested for 
extended 
RAS
 and 
BRAF
 mutations.

extended 
RAS
 and 
BRAF
B. Systemic Chemotherapy for Colon Cancer
Chemotherapy has been demonstrated to improve overall 
and tumor-free survival in select patients with colon cancer 
depending on stage (Table 39–2).
1. Stage I—
Because of the excellent 5-year survival rate 
(approximately 92%), no adjuvant therapy is recommended 
for stage I colon cancer. The 5-year survival rate of rectal 
cancer is approximately 87%.
2. Stage II (node-negative disease)—
The 5-year survival 
rate is approximately 87% for stage IIA disease and 63% for 
stage IIB disease. A significant survival benefit from adju
-
vant chemotherapy has not been demonstrated in most 
randomized clinical trials for stage II colon cancer (see 
discussion for stage III disease). However, otherwise 
healthy patients with stage II disease who are at higher risk 
for recurrence (perforation; obstruction; close or indeter
-
minate margins; poorly differentiated histology; lymphatic, 
vascular, or perineural invasion; T4 tumors; or fewer than 
12 lymph nodes sampled) may benefit from adjuvant che
-
motherapy. Patients whose tumors reveal microsatellite 
instability have a more favorable prognosis and do not 
benefit from 5-fluorouracil adjuvant therapy.
3. Stage III (node-positive disease)—
With surgical resec
-
tion alone, the expected 5-year survival rate is 30–50%. 
Postoperative adjuvant chemotherapy significantly 
increases disease-free survival as well as overall survival by 
up to 30% and is recommended for all fit patients 
(Table 39–2). Large, well-designed studies of adjuvant 
therapy for stage III colon cancer reported a higher rate of 
disease-free survival at 5 years for patients treated for 6 
months postoperatively with a combination of oxaliplatin, 
5-fluorouracil, and leucovorin (FOLFOX) (73.3%) than with 
5-fluorouracil and leucovorin (FL) alone (67.4%). Similar 
benefit was reported for patients treated with oxaliplatin and 
capecitabine (orally active fluoropyrimidine). The benefit of 
adding oxaliplatin to 5-fluorouracil has not been demon
-
strated in patients who are 70 years of age or older. 
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Randomized controlled trials comparing 3 months with 
6 months of adjuvant therapy have confirmed efficacy with 
3 months of therapy in patients with low-risk disease 
(T1-3, N1) with reduced risk of neuropathy; however, 
 
6 months of adjuvant chemotherapy is still recommended 
for high-risk disease (T4 or N2). The addition of a biologic 
agent (bevacizumab or cetuximab) to adjuvant chemo
-
therapy does not improve outcomes.
4. Stage IV (metastatic disease)—
Approximately 20% of 
patients have metastatic disease at the time of initial diag
-
nosis, and an additional 30% eventually develop metastasis. 
A subset of these patients has limited disease that is poten
-
tially curable with surgical resection. Resection of isolated 
liver metastases may result in long-term (over 5 years) 
survival in 35–55% of cases. For those with unresectable 
hepatic metastases, local ablative techniques (cryosurgery, 
radiofrequency or microwave coagulation, embolization, 
hepatic intra-arterial chemotherapy) may provide long-
term tumor control. A subset of patients who have isolated 
pulmonary metastases may undergo resection with poten
-
tial cure. The majority of patients with metastatic disease 
do not have resectable (curable) disease. In the absence of 
other treatment, the median survival is less than 12 months; 
however, with current therapies, median survival 
approaches 30 months. Tumor location has been found to 
have a potential prognostic importance: median survival 
rates are 33.3 months for patients with left-sided colon 
cancers compared to 19.4 months for those with right-
sided cancers.
The goals of therapy for patients with metastatic 
colorectal cancer are to slow tumor progression while 
maintaining a reasonable quality of life for as long as 
possible. Currently, either FOLFOX (the addition of 
oxaliplatin to 5-fluorouracil and folinic acid) or FOLFIRI 
(the addition of irinotecan to 5-fluorouracil and folinic 
acid) is the preferred first-line treatment regimen for fit 
patients. For convenience, oral capecitabine (instead of 
intravenous 5-fluorouracil and leucovorin) can be used in 
combination with oxaliplatin as it has similar efficacy to 
5-fluorouracil; however, combination with irinotecan is 
not recommended due to increased toxicity (diarrhea). 
Addition of a biologic agent to combination chemotherapy 
improves response rates and overall survival and is recom
-
mended in the first-line of treatment in suitable patients. 
Bevacizumab is a monoclonal antibody targeting VEGF. 
Combination therapy with bevacizumab and FOLFOX or 
FOLFIRI prolongs mean survival by 2–5 months compared 
with either regimen alone. Cetuximab and panitumumab 
are monoclonal antibodies targeting EGFR. Activating 
codon 12 and 13 
K-ras
 gene mutations downstream of 
EGFR are present in approximately 35% of patients with 
metastatic colorectal cancer and are a biomarker for nonre
-
sponse to cetuximab and panitumumab, for which reason 
the use of these agents is restricted to patients with tumors 
wild-type for 
K-ras.
 In stage IV patients with 
K-ras
 wild-
type tumors, the addition of panitumumab or cetuximab to 
FOLFOX or FOLFIRI prolongs survival by approximately 
 
4 months. Bevacizumab may cause serious side effects, 
including arterial thromboembolic events, bowel perforation, 
or serious bleeding, in up to 5% of patients. EGFR-targeted 
agents cause an acneiform rash in the majority of patients. 
Cetuximab is associated with severe infusion reactions in 
approximately 2–5%.
When disease progresses despite treatment either with 
FOLFOX or with FOLFIRI (often in conjunction with 
bevacizumab or an EGFR-targeted antibody), therapy is 
switched to the alternate regimen. The novel anti-
angiogenic agent, aflibercept, is FDA approved for second-
line treatment of colorectal cancer in combination with 
FOLFIRI. Palliative therapy with cetuximab or panitu
-
mumab can benefit patients with 
K-ras

-
K-ras
 wild-type tumors 
whose disease has progressed after first-line and second-
line chemotherapies. Both trifluridine/tipiracil and the 
multi-targeted kinase inhibitor regorafenib are FDA 
approved for patients with metastatic, refractory colorectal 
cancer after progression on standard regimens.
C. Neoadjuvant and Adjuvant Therapy 
 
for Rectal Cancer
Compared with colon cancer, rectal cancer has lower long-
term survival rates and significantly higher rates of local 
tumor recurrence with surgery alone (approximately 25%) 
attributed in part to the difficulty of achieving adequate 
surgical resection margins and to lack of serosal encase
-
ment of the rectum. When initial imaging studies suggest 
stage I disease, surgery may be performed first (see Surgery 
above). For stage II and III tumors by clinical staging 
(including endorectal ultrasound or pelvic MRI), preoper
-
ative chemoradiation with 5-fluorouracil or capecitabine as 
a radiation-sensitizing agent improves disease-free survival 
and decreases pelvic recurrence rate. Preoperative chemo
-
radiation has been shown to be superior to postoperative 
chemoradiation with lower local recurrence and toxicity 
rates in the randomized, phase III CAO/ARO/AIO-94 
trial. Following surgical resection with total mesorectal 
excision (see Surgery above), adjuvant 5-fluorouracil–
based therapy (generally with the FOLFOX regimen 
extrapolating from its benefit in patients with similarly-
staged colon cancers) is recommended for a total of 
approximately 6 months of perioperative therapy inclusive 
of neoadjuvant chemoradiation.
 
»
Follow-Up After Surgery
Patients who have undergone resections for cure are moni
-
tored closely to look for evidence of symptomatic or 
asymptomatic tumor recurrence that may be amenable to 
curative resection in a small number of patients. Patients 
should be evaluated every 3–6 months for 2 years and then 
every 6 months for a total of 5 years with history, physical 
examination, and laboratory surveillance, including serum 
CEA levels if baseline levels are elevated. The NCCN and 
ASCO guidelines recommend surveillance CT scans of 
chest, abdomen, and pelvis annually for up to 5 years post-
resection in high-risk stage II and all stage III patients. 
Patients who had a complete preoperative colonoscopy 
should undergo another colonoscopy 1 year after surgical 
resection. Patients who did not undergo full colonoscopy 
preoperatively also should undergo colonoscopy within 
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3–6 months postoperatively to exclude other synchronous 
colorectal neoplasms. If a colonoscopy does not detect new 
adenomatous polyps 1 year postoperatively, surveillance 
colonoscopy should be performed every 3–5 years thereaf
-
ter to look for metachronous polyps or cancer. Because of 
the high incidence of local tumor recurrence in patients 
with rectal cancer, proctoscopy surveillance of the low 
anterior resection anastomotic site may also be performed 
periodically. New onset of symptoms or a rising CEA war
-
rants investigation with chest, abdominal, and pelvic CT 
and colonoscopy to look for a new primary tumor or recur
-
rence, or metachronous metastatic disease that may be 
amenable to curative or palliative therapy. For patients with 
a rising CEA level with unrevealing CT imaging, a PET 
scan may be more sensitive for the detection of occult 
 
»
Prognosis
The stage of disease at presentation is the most important 
determinant of 5-year survival in colon cancer: stage I, 
greater than 90%; stage II, 70–85%; stage III with fewer 
than 4 positive lymph nodes, 67%; stage III with more than 
4 positive lymph nodes, 33%; and stage IV , 5–7%. For each 
stage, rectal cancers have a worse prognosis. For those 
patients whose disease progresses despite therapy, meticu
-
 
»
Screening for Colorectal Neoplasms
Colorectal cancer is ideal for screening because it is a com
-
mon disease that is fatal in almost 50% of cases and yet is 
curable if detected at an earlier stage. Furthermore, most 
cases arise from benign adenomatous or serrated polyps 
that progress over many years to cancer, and removal of 
these polyps has been shown to prevent the majority of 
cancers. Colorectal cancer screening is endorsed by the 
USPSTF, the Agency for Health Care Policy and Research, 
the American Cancer Society, and every professional gas
-
troenterology and colorectal surgery society. Although 
there is continued debate about the optimal cost-effective 
means of providing population screening, there is unani
-
mous consent that screening of some kind should be 
offered to every patient over the age of 50 years. Several 
analyses suggest that screening is cost-effective.
It is important for primary care providers to understand 
the relative merits of various options and to discuss them 
with their patients. Discussion and encouragement by the 
primary care provider are the most important factors in 
achieving patient compliance with screening programs. 
The 2016 USPSTF endorsed screening for colorectal can
-
cer with any of eight different strategies for average-risk 
adults aged 50–75 years. In the United States, the two most 
widely used strategies currently are colonoscopy every 
10 years or FIT testing annually.
Recommendations for screening from the 2016 USPSTF 
and 2008 US Multi-Society Task Force (USMSTF) are listed 
in Table 39–6. Screening is recommended for all men and 
women ages 50 through 75 years of age who are at average 
risk for cancer. Some guidelines recommend screening for 
African Americans beginning at age 45. The potential for 
harm from screening must be weighed against the likeli
-
hood of benefit, especially in elderly patients with comor
-
bid illnesses and shorter life expectancy. Although routine 
screening is not recommended in adults above age 75, it 
may be considered on a case-by-case basis in adults age 76 
through 85 years who have excellent health and functional 
status. In 2017, the USMSTF issued revised, simplified 
recommendations in which screening tests were placed 
into three tiers (Table 39–7). For average-risk patients, 
colonoscopy every 10 years or fecal immunochemical test
-
ing (FIT) testing is preferred (Tier 1). Tier 2 tests (CT 
colonography every 5 years, flexible sigmoidoscopy every 
 
5 years, or fecal FIT-fecal DNA testing every 3 years) and

-
 
5 years, or fecal FIT-fecal DNA testing every 3 years) and 
Tier 3 tests (colon capsule every 5 years) may be offered but 
are considered less suitable due to various disadvantages 
(discussed below). 
Patients with first-degree relatives with colorectal neo
-
plasms (cancer or adenomatous polyps) are at increased 
risk; earlier and more frequent screening may be recom
-
mended (preferably with colonoscopy) for these 
individuals. Recommendations for screening in families 
with inherited cancer syndromes or inflammatory bowel 
disease are provided in Chapter 15. For patients at average 
Table 39–6.
 
Recommendations for colorectal cancer 
screening,
1
 including the U.S. Preventive Services Task 
Force (2016) recommendations
2
 and the US Multi-
Society Task Force on Colorectal Cancer (2008) 
2
Average-risk individuals ≥ 50 years old
2
Annual fecal occult blood testing using higher sensitivity tests 
(Hemoccult SENSA)
Annual fecal immunochemical test (FIT)
Fecal DNA test (interval uncertain)
Flexible sigmoidoscopy every 5 years
Colonoscopy every 10 years
CT colonography every 5 years
Individuals with a family history of a first-degree member with 
colorectal neoplasia
3
Single first-degree relative with colorectal cancer diagnosed 
at age 60 years or older:
 Begin screening at age 40. 
Screening guidelines same as average-risk individual; 
however, preferred method is colonoscopy every 10 years.
Single first-degree relative with colorectal cancer or 
advanced adenoma diagnosed before age 60 years, or 
 
two first-degree relatives:
 Begin screening at age 40 or at 
age 10 years younger than age at diagnosis of the youngest 
affected relative, whichever is first in time. Recommended 
screening: colonoscopy every 5 years.
1
For recommendations for families with inherited polyposis syn
-
dromes or hereditary nonpolyposis colon cancer, see Chapter 15.
2
Joint Guideline from the American Cancer Society, the US 
 
Multi-Society Task Force on Colorectal Cancer, and the American 
College of Radiology. Gastroenterology 2008 May;134(5):1570-95; 
and US Preventive Services Task Force. Screening for Colorectal 
Cancer: US Preventive Services Task Force Recommendation 
Statement. JAMA. 2016 Jun 21;315(23):2564–75.
3
American College of Gastroenterology. Guidelines for Colorectal 
Cancer Screening. Am J Gastroenterol. 2009 Mar;104(3):739–50.
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risk for colorectal cancer, the recommendations of the 
USPSTF and USMSTF are discussed below.
Screening tests may be classified into two broad catego
-
ries: stool-based tests and examinations that visualize the 
structure of the colon by direct endoscopic inspection or 
radiographic imaging.
A. Stool-Based Tests
1. Fecal occult blood test—
Most colorectal cancers and 
some large adenomas result in increased chronic blood 
loss. A variety of tests for fecal occult blood are commer
-
cially available that have varying sensitivities and specifici
-
ties for colorectal neoplasia. These include guaiac-based 
tests (gFOBT) (eg, Hemoccult I and II and Hemoccult 
SENSA) that detect the pseudoperoxidase activity of heme 
or hemoglobin and fecal immunochemical tests (FIT) that 
detect human globin. In clinical trials, FIT have proven 
superior to gFOBT in sensitivity for detection of colorectal 
cancer and advanced adenomas with similar specificity. 
Because FIT are not affected by diet or medications and 
have superior accuracy, the USMSTF now recommends 
their use instead of gFOBT.
Several FIT kits are commercially available. These tests 
are highly specific for detecting human globin and therefore 
eliminate the need for pretest dietary restrictions. In 19 clini
-
cal studies, the pooled sensitivity and specificity of FIT for 
colorectal cancer in average-risk patients were 79% and 94%, 
respectively. The optimal interval (yearly or every 2 years) 
and number of stool samples (one or two) required for opti
-
mal FIT testing is as yet undetermined. Three randomized 
controlled trials comparing one-time colonoscopy with FIT 
testing for colorectal cancer screening are ongoing. Currently, 
annual testing of a single stool sample is recommended.
FIT testing is the preferred option for population-based 
screening in various European and Australian programs. In 
the United States, it is offered as the preferred option by many 
healthcare plans. For healthcare systems in which screening 
colonoscopy is readily available, FIT is a suitable option for 
patients seeking a noninvasive screening test who are willing 
to undertake annual fecal testing. Patients with a positive FIT 
test must undergo further evaluation with colonoscopy.
2. Multitarget DNA assay—
Stool DNA tests measure a 
variety of mutated genes and methylated gene markers 
from exfoliated tumor cells. A newer-generation assay 
(“Cologuard”) combines a fecal DNA panel with a FIT. In a 
prospective comparative trial conducted in persons at aver
-
age risk for colorectal cancer undergoing colonoscopy, the 
sensitivity for colorectal cancer for “Cologuard” was 92.3% 
vs 73.8% for FIT alone and the sensitivity for adenomas 
larger than 1 cm or serrated polyps for “Cologuard” was 
42.4% vs 23.8% for FIT alone. A positive stool DNA test 
requires colonoscopy evaluation. Compared with FIT test
-
ing alone, FIT-fecal DNA testing has disadvantages includ
-
ing higher cost, lower specificity, lower cost-effectiveness, 
cumbersome requirements for stool collection and mailing. 
Hence, the 2017 USMSTF relegated it to Tier 2, noting that 
it may be recommended in patients age 50–65 years who 
seek a noninvasive test with high-sensitivity, due to accept
-
able specificity in this age group.
B. Endoscopic Examinations of the Colon
1. Colonoscopy—
Colonoscopy permits examination of the 
entire colon. In addition to detecting early cancers, colo
-
noscopy allows removal of adenomatous polyps by biopsy 
or polypectomy, which is believed to reduce the risk of 
Table 39–7.
 
Revised recommendations for colorectal 
cancer screening for average-risk individuals from the 
US Multi-Society Task Force on Colorectal Cancer 
(2017).
1
Tier 1
2
Colonoscopy every 10 years, or
Fecal immunochemical test (FIT) every 1 year
Tier 2
3
CT colonography every 5 years, or
Flexible sigmoidoscopy every 5–10 years, or 
Fecal FIT-fecal DNA testing every 3 years
Tier 3
3

Tier 2
3
Tier 3
3
Colon capsule every 5 years
1
Screening of individuals considered to be at “average risk” for 
colorectal cancer is recommended beginning at 50 years of age, 
except in African-Americans for whom beginning at 45 years of age 
is supported by some limited data. Since the incidence of colorectal 
cancer is rising in persons under age 50 years, a thorough diagnos
-
tic evaluation is recommended for younger individuals with rectal 
bleeding. Colorectal screening can be discontinued at 75 years of 
age in persons who are up-to-date with screening and who have 
had consistently negative screening tests (especially prior negative 
colonoscopy), or in individuals who have life expectancies of less 
than 10 years. Conversely, in persons who have no prior screening, 
colorectal screening can be initiated and continued to 85 years of 
age, depending on health and life expectancy.
2
Colonoscopy and FIT are recommended as the cornerstones of 
colorectal cancer screening. In a sequential approach in which 
colonoscopy every 10 years is offered first, FIT done annually 
should be offered to patients who decline colonoscopy. “Tier 1” 
designation indicates that colonoscopy and FIT are recommended 
as the tests of choice even when multiple other options are avail
-
able. A risk-stratified approach is also considered appropriate with 
FIT screening in patient populations estimated to have a low 
prevalence of advanced colonic neoplasia and colonoscopy con
-
sidered more appropriate in patient populations estimated to have 
a high prevalence of colonic neoplasia.
3
Tier 2 and Tier 3 tests may be offered but are considered less suit
-
able due to various disadvantages (see text). 
Note:
 USMSTF screening recommendations vary for individuals 
considered to be at “high risk” for colorectal cancer: Specifically, for 
individuals with a family history of colorectal cancer or advanced 
adenoma in a first-degree relative at age < 60 years or with these 
findings in two first-degree relatives at any age, screening by colo
-
noscopy every 5 years is recommended, beginning 10 years before 
the age at diagnosis of the youngest relative or at age 40 years, 
whichever is earlier. Individuals with a single first-degree relative 
diagnosed with colorectal cancer or advanced adenoma at age 
> 60 years are recommended to undertake the “average-risk” 
screening options shown above but beginning at 40 years of age.
Modified, with permission, from Rex DK et al. Colorectal cancer 
screening: recommendations for physicians and patients from the 
U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 
2017 Jul;112(7):1016–30. By permission from Springer Nature.
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subsequent cancer. Over the past decade, there has been a 
dramatic increase in screening colonoscopy, with over 60% 
of US adults screened in the past 10 years. In asymptomatic 
individuals between 50 and 75 years of age undergoing 
screening colonoscopy, the prevalence of advanced colonic 
neoplasia is 4–11% and of colon cancer is 0.1–1%.
Although colonoscopy is believed to be the most sensi
-
tive test for detecting adenomas and cancer, it has several 
disadvantages. To allow adequate visualization of the entire 
colonic mucosa, it requires thorough bowel cleansing the 
evening and morning prior to the examination. To alleviate 
discomfort during the procedure, intravenous sedation is 
used for most patients, necessitating a companion to trans
-
port the patient home post-procedure. Serious complica
-
tions occur uncommonly; they include perforation (0.1%), 
bleeding (0.25%), and death (2.9/100,000).
The skill of the operator has a major impact upon the 
quality of the colonoscopy examination. In several studies, 
the rate of colorectal cancer within 3 years of a screening 
colonoscopy was 0.7–0.9%, ie, approximately 1 in 110 patients. 
This may be attributable to polyps and early cancers that 
were overlooked during the colonoscopy. Polyps that are 
small, flat, or located behind folds are easily missed, espe
-
cially if the bowel preparation is poor. Population-based 
case-control and cohort studies suggest that colonoscopy is 
associated with greater reduction in colorectal cancer inci
-
dence and mortality in the distal colon (80%) than the 
proximal colon (40–60%). This may be attributable to 
incomplete examination of the proximal colon, and differ
-
ences between the proximal and distal colon that include 
worse bowel preparation, suboptimal colonoscopic tech
-
nique, and a higher prevalence of serrated polyps and flat 
adenomas. To optimize diagnostic accuracy as well as 
patient safety and comfort, colonoscopy should be per
-
formed after optimal bowel preparation by a well-trained 
endoscopist who spends sufficient time (at least 7 minutes) 
carefully examining the colon (especially the proximal 
colon) while withdrawing the endoscope.
Use of a 60-cm flexible sig
-
moidoscope permits visualization of the rectosigmoid and 
descending colon. Adenomatous polyps are identified in 
10–20% and colorectal cancers in 1% of patients. The find
-
ing at sigmoidoscopy of an adenomatous polyp in the distal 
colon increases the likelihood at least twofold that an 
advanced neoplasm is present in the proximal colon. 
Therefore, patients with an adenomatous polyp of any size 
found during screening sigmoidoscopy should subse
-
quently undergo colonoscopy to evaluate the proximal 
colon. A 2012 US study of almost 155,000 participants 
randomized to sigmoidoscopy screening or usual care 
between 1993 and 2001 reported a 50% reduction in distal 
colorectal cancer mortality in the sigmoidoscopy group 
after 11 years median follow-up.
The chief disadvantage of screening with flexible sig
-
moidoscopy is that it requires some bowel cleansing, it 
may be associated with some discomfort (since intrave
-
nous sedation is not used), and it does not examine the 
proximal colon. The prevalence of proximal versus distal 
neoplasia is higher in persons older than age 65 years, in 
African Americans, and in women. For these reasons, the 
2017 USMSTF recommendations have placed flexible sig
-
moidoscopy among Tier 2 tests. If chosen, flexible sig
-
moidoscopy should be performed every 5–10 years.
C. Radiographic and Other Imaging of the Colon
1. CT colonography—
Using helical CT with computer-
assisted image reconstruction, two- and three-dimensional 
views can be generated of the colon lumen that simulate 
the view of colonoscopy (virtual colonoscopy). CT colo
-
nography requires a similar bowel cleansing regimen as 
colonoscopy as well as insufflation of air into the colon

-
colonoscopy as well as insufflation of air into the colon 
through a rectal tube, which may be associated with dis
-
comfort. Nonetheless, this examination is performed rap
-
idly and requires no sedation or intravenous contrast. 
Several large studies have compared the accuracy of virtual 
colonoscopy with colonoscopy for colorectal screening. 
Using current imaging software with multidetector helical 
scanners, the sensitivity is greater than 95% for the detec
-
tion of cancer and greater than 84–92% for the detection of 
polyps 10 mm or larger. CT colonography is less sensitive 
than colonoscopy for the detection of polyps smaller than 
1 cm, flat adenomas, and serrated polyps. 
Patients undergoing screening with CT colonography 
should be managed appropriately. If no polyps are found, 
the interval for repeat screening examination is uncertain; 
however, 5 years may be reasonable. All patients with 
polyps 10 mm or larger should be referred for colonoscopy 
with polypectomy because of the high prevalence (30%) of 
advanced pathology (cancer, high-grade dysplasia, or vil
-
lous features) within these polyps. The optimal manage
-
ment of patients with polyps less than 10 mm in size is 
controversial. The USMSTF currently recommends that 
colonoscopy with polypectomy be offered to patients with 
one or more 6–9 mm polyps. Patients who refuse or who 
have increased risk of carcinoma should undergo surveil
-
lance CT colonography in 3–5 years. At the present time, 
there is no consensus on the management of patients with 
polyps smaller than 6 mm; however, some radiologists 
choose not even to report these findings.
The chief disadvantages of CT colonography are the 
need for a bowel preparation, limited availability in many 
health care systems, a possible increased risk of neoplasia 
due to radiation exposure, and the potential for finding 
incidental extracolonic findings that may lead to further 
evaluations. The 2017 USMSTF has therefore classified this 
as a Tier 2 screening option (Table 39–7). CT colonography 
is an excellent screening option in patients who do not 
wish or are unsuitable for colonoscopy and in patients in 
whom colonoscopy could not be completed. 
2. Capsule colonoscopy—
Imaging of the colon can be 
accomplished by oral ingestion of a capsule that captures 
video images of the colon. Compared with colonoscopy, the 
colon capsule has reduced sensitivity for polyps greater than 
6 mm (64% vs 84%) and for colorectal cancers (74% vs 
100%). At present, it is approved by the FDA for evaluation 
in patients who are not suitable candidates for colonoscopy 
or in whom colonoscopy could not evaluate the proximal 
colon. In addition to its suboptimal sensitivity for neoplasia, 
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the main disadvantages of capsule colonoscopy are its cost, 
need for extensive bowel preparation, lack of reimburse
-
ment by most insurance carriers, and small risk of small 
bowel obstruction. For these reasons, the 2017 USMSTF 
recommendations classified it a Tier 3 screening test, suit
-
able for highly selected patients (Table 39–7).
3. Barium enema—
Double-contrast barium enema was 
previously used as a screening technique because it was 
widely available, relatively inexpensive, and safe. However, 
compared to CT colonography, it is more time-consuming 
and difficult to perform, less comfortable, and less accurate. 
It can no longer be recommended for routine screening.
 
»
•	
Patients with symptoms (change in bowel habits, hema
-
tochezia), signs (mass on abdominal examination or 
digital rectal examination [DRE]), or laboratory tests 
(iron deficiency anemia) suggestive of colorectal neo
-
plasia should be referred for colonoscopy.
•	
Patients with suspected colorectal cancer or adenoma
-
tous polyps of any size should be referred for 
•	
Virtually all patients with proven colorectal cancer 
should be referred to a surgeon for resection. Patients 
with clinical stage T3 or node-positive rectal tumors (or 
both) also should be referred to medical and radiation 
oncologists preoperatively for neoadjuvant therapy. 
Patients with stage II, III, or IV colorectal tumors 
should be referred to a medical oncologist.
 
»
•	
Patients with complications of colorectal cancer 
(obstruction, acute bleeding) requiring urgent evalua
-
tion and intervention.
•	
Patients with severe complications of chemotherapy.
•	
Patients with advanced metastatic disease requiring 
palliative care.
Inadomi J. Screening for colorectal neoplasia. N Engl J Med. 
2017 Jan 12;376(2):149–56. [PMID: 28076720]
issues for physicians and patients: a review. JAMA. 2016 Nov 22; 
316(20):2135–45. [PMID: 27893135]
National Institutes of Health. SEER cancer statistics factsheets: 
colon and rectum cancer, 2017. https://seer.cancer.gov/
statfacts/html/colorect.html
Overman MJ et al. Nivolumab in patients with metastatic DNA 
mismatch repair-deficient or microsatellite instability-high 
colorectal cancer (CheckMate 142): an open-label, 
multicenter, phase 2 study. Lancet Oncol. 2017 Sep;18(9): 
1182–91. [PMID: 28734759]
Rex DK et al. Colorectal cancer screening: recommendations for 
physicians and patients from the U.S. Multisociety Task Force 
on Colorectal Cancer. Gastroenterology. 2017 Jul;153(1): 
307–23. [PMID: 28600072]
-
statement by the US Multi-Society Task Force on Colorectal 
Cancer. Gastrointest Endosc. 2017 Jan;85(1):2–21.e3. [PMID: 
27769516]
Rusieki J et al. Colonoscopy surveillance after colorectal cancer 
resection. JAMA. 2017 Dec 19;318(23):2346–7. [PMID: 
29260211]
Siegel RL et al. Colorectal cancer incidence patterns in the 
United States, 1974–2013. J Natl Cancer Inst. 2017 Aug 1; 
109(8):djw322. [PMID: 28376186]
Siegel RL et al. Colorectal cancer mortality rates in adults aged 
20 to 54 years in the United States, 1970–2014. JAMA. 
2017 Aug 8;318(6):572–4. [PMID: 28787497]
Singal AG et al. Effect of colonoscopy outreach vs fecal immuno
-
chemical test outreach on colorectal cancer screening com
-
pletion: a randomized clinical trial. JAMA. 2017 Sep 5; 
318(9):806–15. [PMID: 28873161]
US Preventive Services Task Force; Bibbins-Domingo K et al. 
Screening for colorectal cancer: US Preventive Services Task 
Force recommendation statement. JAMA. 2016 Jun 21; 
315(23):2564–75. Erratum in: JAMA. 2016 Aug 2;316(5):545. 
[PMID: 27304597]
Venook AP et al. Effect of first-line chemotherapy combined 
with cetuximab or bevacizumab on overall survival in patients 
with 
KRAS

with 
KRAS
 wild-type advanced or metastatic colorectal 
cancer: a randomized clinical trial. JAMA. 2017 Jun 20; 
317(23):2392–401. [PMID: 28632865]
Wells K et al. Hereditary colorectal cancer syndromes. Surg Clin 
North Am. 2017 Jun;97(3):605–25. [PMID: 28501250]
CARCINOMA OF THE ANUS
The anal canal is lined from its proximal to distal extent by 
columnar, transitional, and non-keratinized squamous 
epithelium, which merges at the anal verge with the kera
-
tinized perianal skin. Tumors arising from the mucosa of 
the anal canal are relatively rare, comprising only 1–2% of 
all cancers of the anus and large intestine. Squamous can
-
cers make up the majority of anal cancers. Anal cancer is 
increased among people practicing receptive anal inter
-
course and those with a history of anorectal warts. In over 
80% of cases, HPV may be detected, suggesting that this 
virus is a major causal factor. In a large controlled trial, 
HPV vaccination of healthy men (16 to 26 years old) who 
have sex with men decreased the incidence of anal intraepi
-
thelial neoplasia by 50%. Women with anal cancer are at 
increased risk for cervical cancer (which may be due to a 
field effect of oncogenic HPV infection) and require gyne
-
cologic screening and monitoring. Anal cancer is increased 
in HIV-infected individuals, possibly due to interaction 
with HPV . HPV vaccine is recommended for boys and girls 
starting at age 11 or 12, for females aged 13 through 
26 years, and in men who have sex with men up to age 26 
who have not been previously vaccinated.
Bleeding, pain, and local tumor are the most common 
symptoms. The lesion is often confused with hemorrhoids 
or other common anal disorders. These tumors tend to 
become annular, invade the sphincter, and spread upward 
via the lymphatics into the perirectal mesenteric lymphatic 
nodes. CT or MRI scans of the abdomen and pelvis are 
required to identify regional lymphadenopathy or meta
-
static disease at diagnosis. PET imaging may be used in 
conjunction.
Treatment depends on the tumor location and histo
-
logic stage. Well-differentiated and small (less than 2 cm) 
superficial lesions of the perianal skin may be treated with 
wide local excision. Adenocarcinoma of the anal canal is 
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treated in similar fashion to rectal cancer (see above), com
-
monly by abdominoperineal resection with neoadjuvant 
chemoradiotherapy and adjuvant chemotherapy. Squa
-
mous cancer of the anal canal and large perianal tumors 
invading the sphincter or rectum are treated with com
-
bined-modality therapy that includes external radiation 
with simultaneous chemotherapy (5-fluorouracil plus 
mitomycin). Local control is achieved in approximately 
80% of patients. Radical surgery (abdominoperineal resec
-
tion) is reserved for patients who fail chemotherapy and 
radiation therapy. Metastatic disease is generally treated 
with 5-fluorouracil in combination with cisplatin. The 
5-year survival rate is 81% for localized tumors and 
approximately 30% for metastatic (stage IV) disease.
Alam NN et al. Systematic review of guidelines for the assess
-
ment and management of high-grade anal intraepithelial 
neoplasia (AIN II/III). Colorectal Dis. 2016 Feb;18(2):
 
135–46. [PMID: 26559167]
Kim DW et al. EGFR inhibitors in patients with advanced squa
-
mous cell anal carcinomas: a single-institution experience. 
Oncology. 2017;92(4):190–6. [PMID: 28152526]
Mensah FA et al. The human papillomavirus vaccine: current 
perspective and future role in prevention and treatment of 
anal intraepithelial neoplasia and anal cancer. Oncologist. 
2016 Apr;21(4):453–60. [PMID: 26961923]
Anal Cancer, 2017. https://seer.cancer.gov/statfacts/html/
anus.html
CANCERS OF T
h
E GENITOURINARY TRACT
PROSTATE CANCER
 
»
Prostatic induration on DRE or elevation of PSA.
 
»
Most often asymptomatic.
 
»
Rarely: systemic symptoms (weight loss, bone 
pain).
 
»
Prostatic cancer is the most common noncutaneous cancer 
detected in American men and the second leading cause of 
cancer-related death in men. In 2018 the United States, an 
estimated 164,690 new cases of prostate cancer were diag
-
nosed, and 29,430 deaths resulted. However, the clinical 
incidence of the disease does not match the prevalence 
noted at autopsy, where more than 40% of men over 
50 years of age are found to have prostatic carcinoma. Most 
such occult cancers are small and contained within the 
prostate gland; few are associated with regional or distant 
disease. The incidence of prostatic cancer increases with 
age. Whereas 30% of men aged 60–69 years will have the 
disease at autopsy, its incidence increases to 67% in men 
aged 80–89 years. Although the global prevalence of pros
-
tatic cancer at autopsy is relatively consistent, the clinical 
incidence varies considerably (high in North America and 
European countries, intermediate in South America, and 
low in the Far East). A 50-year-old American man has a 
lifetime risk of 40% for latent cancer, 16% for developing 
clinically apparent cancer, and a 2.9% risk of death due to 
prostatic cancer. African-American race, family history of 
prostatic cancer, and history of high dietary fat intake are 
risk factors for prostate cancer.
 
»
Prostate cancer may manifest as focal nodules or areas of 
induration within the prostate at the time of DRE. How
-
ever, currently most prostate cancers are detected because 
of elevations in serum PSA (not DRE findings).
Patients rarely present with signs of urinary retention or 
neurologic symptoms from epidural metastases and cord 
compression. Obstructive voiding symptoms are most 
often due to benign prostatic hyperplasia, which occurs in 
the same age group. Nevertheless, large or locally extensive 
prostatic cancers can cause obstructive voiding symptoms. 
Lymph node metastases can lead to lower extremity 
lymphedema. Because the axial skeleton is the most com
-
mon site of metastases, patients may present with back 
pain or pathologic fractures.

-
1. Serum tumor markers—
PSA is a glycoprotein produced 
only by cells, either benign or malignant, of the prostate 
gland. The serum level is typically low and correlates with 
the total volume of prostate tissue. Measurement of serum 
PSA is useful in detecting and staging prostate cancer, 
monitoring response to treatment, and identifying recur
-
rence before it becomes clinically evident. As a screening 
test, PSA will be elevated (greater than 4.0 ng/mL 
[4.0 mcg/L]) in 10–15% of men. Approximately 18–30% of 
men with intermediate degrees of elevation (4.1–10 ng/mL 
[4.1–10 mcg/L]) and between 50% and 70% of men with 
elevations greater than 10 ng/mL (10 mcg/L) will be found 
to have prostate cancer. Patients with intermediate levels of 
PSA usually have localized and therefore potentially cur
-
able cancers. Interestingly, approximately 20% of patients 
who undergo radical prostatectomy for localized prostate 
cancers have normal levels of PSA.
In untreated patients with prostate cancer, the level of 
PSA correlates with the volume and stage of disease. 
Whereas most organ-confined cancers are associated with 
PSA levels below 10 ng/mL (10 mcg/L), advanced disease 
(seminal vesicle invasion, lymph node involvement, or 
occult distant metastases) is more common in patients 
with PSA levels in excess of 40 ng/mL (40 mcg/L). 
Approximately 98% of patients with metastatic prostate 
cancer will have elevated PSA. However, there are rare 
cancers that are localized despite substantial elevations in 
PSA. Therefore, initial treatment decisions cannot be made 
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on the basis of PSA testing alone. A rising PSA after ther
-
apy is usually consistent with progressive disease, either 
locally recurrent or metastatic.
2. Miscellaneous laboratory testing—
Patients with uri
-
nary retention or with ureteral obstruction due to loco-
regionally advanced prostate cancers may present with 
elevations in blood urea nitrogen or serum creatinine. 
Patients with bony metastases may have elevations in 
serum alkaline phosphatase or calcium. Laboratory and 
clinical evidence of disseminated intravascular coagulation 
can occur in patients with advanced prostate cancers.
3. Prostate biopsy—
Transrectal ultrasound-guided biopsy 
is the standard method for detection of prostate cancer. The 
use of a spring-loaded, 18-gauge biopsy needle has allowed 
transrectal biopsy to be performed with minimal patient 
discomfort and morbidity. Local anesthesia is routinely used 
and increases the tolerability of the procedure. The specimen 
preserves glandular architecture and permits accurate grad
-
ing. Prostate biopsy specimens are taken from the apex, 
mid-portion, and base in men who have an abnormal DRE 
or an elevated serum PSA, or both. Extended-pattern biop
-
sies, including a total of at least 10 biopsies, are associated 
with improved cancer detection and risk stratification of 
patients with newly diagnosed disease. Patients with abnor
-
malities of the seminal vesicles can have these structures 
specifically biopsied to identify local tumor invasion.
C. Imaging
Transrectal ultrasonography
 has primarily been used for the 
staging of prostate carcinomas, where tumors typically appear 
as hypoechoic areas. In addition, transrectal ultrasound-
guided, rather than digitally guided, biopsy of the prostate is 
a more accurate way to evaluate suspicious lesions. Use of 
imaging should be tailored to the likelihood of advanced 
disease in newly diagnosed cases. Asymptomatic patients 
with well-differentiated to moderately differentiated cancers, 
thought to be localized to the prostate on DRE and transrectal 
ultrasound and associated with modest elevations of PSA (ie, 
less than 10 ng/mL [10 mcg/L]), need no further imaging.
MRI
 allows for evaluation of the prostate as well as 
regional lymph nodes. The positive predictive value for 
detection of both capsular penetration and seminal vesicle 
invasion is similar for transrectal ultrasound and MRI, 
although newer multi-parametric MRI techniques may 
better stage patients considering treatment or, alternatively, 
active surveillance. MRI-guided biopsy may improve not 
only overall cancer detection but discovery of clinically 
relevant disease, and its use in routine clinical practice has 
increased and continues to evolve. CT plays little role 
because of its inability to accurately identify or stage pros
-
tate cancers, but it can be used to detect regional lymphatic 
metastases and intra-abdominal metastases.
Conventional 
radionuclide (99-technetium) bone scans
 
are superior to conventional plain skeletal radiographs in 
detecting bony metastases. Most prostate cancer metastases 
are multiple and most commonly localized to the axial skel
-
eton. Men with more advanced local lesions, symptoms of 
metastases (eg, bone pain), high-grade disease, or elevations 
in PSA greater than 20 ng/mL (20 mcg/L) should undergo 
radionuclide bone scan. PET (eg, 
18
F-sodium fluoride [
18
F-
NaF] PET) and 
18
F-NaF PET/CT hybrid imaging appear to 
be more sensitive than conventional bone scans. A high fre
-
quency of abnormal scans with 
18
F-NaF PET/CT resulting 
from degenerative joint disease, however, has resulted in a 
reduced enthusiasm for their use. Cross-sectional imaging 
either by CT or MRI is usually indicated only in those 
patients in the latter group who have negative bone scans in 
an attempt to detect lymph node metastases. Patients found 
to have enlarged pelvic lymph nodes are candidates for FNA.

to have enlarged pelvic lymph nodes are candidates for FNA. 
PET imaging using fluciclovine (Axumin) has been approved 
for suspected cancer recurrence based on elevated PSA after 
prior treatment. Small molecules targeting PSMA (prostate-
specific membrane antigen) also show significant promise as 
next-generation imaging agents (eg, 
18
F-DCFBC (N-[N-
[(S)-1,3-dicarboxypropyl]carbamoyl]-4-
18
F-fluorobenzyl-L-
cysteine), a low-molecular-weight radiotracer that targets 
PSMA).
Intravenous urography and cystoscopy are not rou
-
tinely needed to evaluate patients with prostate cancer.
Despite application of modern, sophisticated tech
-
niques, understaging of prostate cancer occurs in at least 
20% of patients.
 
»
Screening for Prostate Cancer
Whether screening for prostate cancer results in a decrease 
in its mortality rate is controversial. The screening tests 
currently available include DRE, PSA testing, and transrec
-
tal ultrasound. Prostate cancer detection rates using DRE 
alone vary from 1.5% to 7%, but unfortunately, most of 
these cancers are advanced (stage T3 or greater). Transrec
-
tal ultrasound should not be used as a first-line screening 
tool because of its expense, low specificity (and therefore 
high biopsy rate), and minimal improvement in detection 
rate when compared with the combined use of DRE and 
PSA testing.
PSA testing increases the detection rate of prostate can
-
cers compared with DRE. Approximately 2–2.5% of men 
older than 50 years of age will be found to have prostate 
cancer using PSA testing compared with a rate of approxi
-
mately 1.5% using DRE alone. The sensitivity, specificity, 
and positive predictive value of PSA and DRE are listed in 
Table 39–8. PSA-detected cancers are more likely to be 
localized compared with those detected by DRE alone. The 
Prostate Cancer Prevention Trial provided data demon
-
strating a significant risk of prostate cancer even in men 
with PSA less than 4.0 ng/mL (4.0 mcg/L) (Table 39–9) and 
a web-based calculator has been developed to estimate the 
risk of harboring both prostate cancer and high-grade can
-
cer (http://myprostatecancerrisk.com).
To improve the performance of PSA as a screening test, 
several investigators have developed alternative methods 
for its use. These include establishment of age- and race-
specific reference ranges, measurement of free serum and 
protein-bound levels of PSA (
percent free PSA
), and cal
-
culation of changes in PSA over time (
PSA velocity
). Gen
-
erally, men with PSA free fractions exceeding 25% are 
unlikely to have prostate cancer, whereas those with free 
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fractions less than 10% have an approximately 50% chance 
of having prostate cancer. Newer tests, including the Pros
-
tate Health Index (PHI) and 4kscore (https://4kscore.com), 
may better identify not only men at greater risk for prostate 
cancer but those with more aggressive disease. The fre
-
quency of PSA testing also remains a matter of debate. The 
traditional yearly screening approach may not be the most 
efficient; rather, earlier PSA testing at younger age may 
allow less frequent testing later as well as provide informa
-
tion regarding PSA velocity. Studies from the Baltimore 
Longitudinal Study of Aging suggest that men with PSA 
above the age-based median when tested between 40 and 
60 years are at significantly increased risk for subsequent 
cancer detection over 25 years. Men with lower PSA 
(0.6 ng/mL [0.6 mcg/L] aged 40–50 and 0.71 ng/mL 
[0.71 mcg/L] aged 50–60) may require less frequent PSA 
tests. In addition, men with PSA velocity greater than 
0.35 ng/mL (0.35 mcg/L) per year measured 10–15 years 
before diagnosis had significantly worse cancer-specific 
survival compared with those with lower PSA velocity. The 
NCCN guidelines (https://www.nccn.org/professionals/
physician_gls/f_guidelines.asp) for prostate cancer early 
detection incorporate many of these factors (Figure 39–2). 
The European Association of Urology (EAU) recommends 
offering a baseline serum PSA to all men aged 40–45 years 
and subsequently initiating a risk-adapted strategy.
Two large, randomized trials question the benefit of 
screening men for prostate cancer. In the US Prostate, 
Lung, Colorectal, and Ovarian (PLCO) Cancer Screening 
Trial, no mortality benefit was observed after combined 
screening with PSA testing and DRE during 13-year 
follow-up. Although screening resulted in a 12% increase 
in prostate cancer detection, the cancer-specific mortality 
rate was similar in the screening and control arms (3.7 and 
3.4 deaths per 10,000 person-years, respectively). Similarly, 
in the European Randomized Study of Screening for Pros
-
tate Cancer (ERSPC) trial, the benefit of PSA screening was 
minimal with an absolute reduction of 1.28 prostate cancer 
deaths per 1000 men screened at 13-year follow-up. In 
2018, the USPSTF issued a revised (Grade C) recommen
-
dation for men aged 55 to 69 years that the decision to 
undergo periodic PSA–based screening should be an indi
-
vidual one. Before deciding about screening, men should 
discuss its potential benefits and harms with their clinician, 
incorporating their own values and preferences in the deci
-
sion. The revised recommendation acknowledges that, 
while screening offers some men a small potential benefit 
of reducing the chance of dying from prostate cancer, many 
other men will experience potential harms from screening. 
These include false-positive results that require additional 
testing and possible prostate biopsy; overdiagnosis and 
overtreatment; and treatment complications, such as 
incontinence and erectile dysfunction. In determining 
whether this service is appropriate in individual cases, the 
individual patient’s family history, race/ethnicity, comorbid 
medical conditions, values about the benefits and harms of 
screening and treatment-specific outcomes, and other 
health needs should be considered. Clinicians should not 
screen men who do not express a preference for screening. 
For men age 70 years and older, the USPSTF recommends 
against PSA-based screening (Grade D recommendation).
 
»
Staging
The majority of prostate cancers are adenocarcinomas. 
Most arise in the peripheral zone of the prostate, though a 
small percentage arise in the central (5–10%) and transi
-
tion zones (20%) of the gland. Pathologists utilize the 
Gleason grading system whereby a “primary” grade is 
applied to the architectural pattern of malignant glands 
occupying the largest area of the specimen and a

occupying the largest area of the specimen and a 
“secondary” grade is assigned to the next largest area of 
cancer. Grading is based on architectural rather than histo
-
logic criteria, and five “grades” are possible. Adding the 
score of the primary and secondary grades gives a Gleason 
score from 2 to 10. Gleason score correlates with tumor 
volume, pathologic stage, and prognosis. There are efforts 
to validate and disseminate a contemporary, simplified 
five-grade group system.
Table 39–8.
 
Screening for prostatic cancer: test 
performance.
Test
p
ositiv
e 
p
r
edictive 
Value
Abnormal PSA 
 
(> 4 ng/ mL 
[mcg/L])
0.67
0.97
0.43
Abnormal DRE
0.50
0.94
0.24
Abnormal PSA or 
DRE
0.84
0.92
0.28
and DRE
0.34
0.995
0.49
DRE, digital rectal examination; PSA, prostate-specific antigen.
Modified, with permission, from Kramer BS et al. Prostate cancer 
screening: what we know and what we need to know. Ann Intern 
Med. 1993 Nov 1;119(9):914–23. Copyright © 1993 American 
College of Physicians. All rights reserved.
Table 39–9.
 
Risk of prostate cancer in men with PSA 
 
≤ 4.0 ng/mL (or mcg/L).
p
SA Level (ng/mL 
[or mcg/L])
p
er
centage With 
p
r
ostate Cancer
p
er
h
igh-
Grade
1
 
p
r
≤ 0.5
6.6
12.5
0.6–1.0
10.1
10.0
1.1–2.0
17.0
11.8
2.1–3.0
23.9
19.1
3.1–4.0
26.9
25.0
1
High-grade cancer was defined as Gleason score ≥ 7.
Data from Thompson IM et al. Prevalence of prostate cancer 
among men with a prostate-specific antigen level ≤ 4.0 ng per 
milliliter. N Engl J Med. 2004 May 27;350(22):2239–46.
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»
Treatment
A. Active Surveillance
The optimal treatment for patients with clinically localized 
prostate cancers remains controversial. A survival benefit 
of treating localized prostate cancer has not been conclu
-
sively demonstrated. Patients need to be advised of all 
treatment options, including active surveillance, with the 
specific benefits, risks, and limitations. The goal of active 
surveillance is to avoid treatment in men who never expe
-
rience disease progression while recognizing and effec
-
tively treating men with evidence of progression. Treatment 
decisions are made based on stage and cancer grade 
(Gleason score) as well as the age and health of the patient. 
Given the observed significant migration to lower stage 
and grade resulting from screening using PSA testing, 
active surveillance alone may be appropriate management 
for selected patients. Such patients included are typically 
Discussion of risks and benefits
Assessment including: family history,
medications, prostate history, ethnicity
Baseline evaluation at age 40
DRE and PSA
PSA/uni00A0
≤ 
2.5 ng/mL
and PSAV/uni00A0
≤
/uni00A00.35
Annual screening with DRE and PSA
PSA < 0.6 ng/mL
PSA ≥ 0.6 ng/mL
Repeat PSA at age 45
Annual follow-up
PSA > 4.0 ng/mL
Consider biopsy
Transrectal ultrasound-guided biopsy
1
PSA 
≥ 
0.6 ng/mL
or family history
or African American
or taking 5-ARI
PSA 2.6-4.0 ng/mL
or
PSAV/uni00A0
≥
/uni00A00.35 when
≤ 
2.5 ng/mL
(Free PSA < 25%
or PSAV/uni00A0
≥
/uni00A00.75)
Begin annual
screening at age 50
Discontinue or reduce frequency of screening
Life expectancy < 10 years; PSA < 3.0 ng/mL
at age 75; PSA < 1.0 ng/mL at age 65
1
NCCN guidelines utilize PSA threshold of 
1.
0 ng/mL in men < 50 year
s,
 the 75th percentile range for this
age gr
oup; the median PSA 
va
lue for men 40–49 
ye
ars is 0.6 ng/mL. 
 
▲
Figure 39–2.
 
An algorithm for prostate cancer early detection. DRE, digital rectal examination; 5-ARI, 5-alpha-
reductase inhibitor; PSAV, PSA velocity (ng/mL/year) calculated on at least three consecutive values over at least an 
18- to 24-month. 
(Based on NCCN guidelines, data from the Baltimore Longitudinal Study on Aging, and Prostate Cancer 
Prevention Trial.)
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older with small volume, well-differentiated cancers. 
Depending on the age and health of the patient, some of 
these very low-volume, low-grade cancers may never 
become clinically relevant and can be monitored with 
active surveillance, which involves serial PSA levels, DREs, 
and periodic prostate biopsies to reassess grade and extent 
of cancer. Endpoints for intervention in patients on active 
surveillance, particularly PSA changes, have not been 
clearly defined and surveillance regimens remain an active 
area of research; nonetheless, they are increasingly accepted 
by patients and clinicians. Active surveillance, which is 
distinguished from mere observation, is featured promi
-
nently in the 2017 NCCN guidelines and may be the pre
-
ferred management in most men with very low risk 
prostate cancer. This approach is increasingly accepted and 
incorporated in routine clinical practice.
B. Radical Prostatectomy
During radical prostatectomy, the seminal vesicles, prostate, 
and ampullae of the vas deferens are removed. Refinements 
in technique have allowed preservation of urinary conti
-
nence in most patients and erectile function in selected 
patients. Radical prostatectomy can be performed via open 
retropubic, transperineal, or laparoscopic (with or without 
robotic assistance) surgery. Local recurrence is uncommon 
after radical prostatectomy and related to pathologic stage. 
Organ-confined cancers rarely recur; however, cancers with 
adverse pathologic features (capsular penetration, seminal 
vesicle invasion) are associated with higher local (10–25%) 
and distant (20–50%) relapse rates.
Ideal candidates for radical prostatectomy include 
healthy patients with stages T1 and T2 prostate cancers. 
Patients with advanced local tumors (T4) or lymph node 
metastases are rarely candidates for prostatectomy alone, 
although the surgery is sometimes used in combination 
with hormonal therapy and postoperative radiation ther
-
apy for select high-risk patients.
C. Radiation Therapy
Radiation can be delivered by a variety of techniques includ
-
ing use of external beam radiotherapy and transperineal 
implantation of radioisotopes. Morbidity is limited, and the 
survival of patients with localized cancers (T1, T2, and 
selected T3) approaches 65% at 10 years. As with surgery, the 
likelihood of local failure correlates with technique and can
-
cer characteristics. The likelihood of a positive prostate 
biopsy more than 18 months after radiation varies between 
20% and 60%. Patients with local recurrence are at an 
increased risk of cancer progression and cancer death com
-
pared with those who have negative biopsies. Ambiguous 
target definitions, inadequate radiation doses, and understag
-
ing of the cancer may be responsible for the failure noted in 
some series. Newer techniques of radiation (implantation, 
conformal therapy using three-dimensional reconstruction 
of CT-based tumor volumes, heavy particle, charged particle, 
and heavy charged particle) may improve local control rates. 
Three-dimensional conformal radiation
 delivers a higher 
dose because of improved targeting and appears to be associ
-
ated with greater efficacy as well as lower likelihood of 
adverse side effects compared with previous techniques. 
Brachytherapy
—the implantation of permanent or 
temporary radioactive sources (palladium, iodine, or iridium) 
into the prostate—can be used as monotherapy in those with 
low-grade or low-volume malignancies or combined with 
external beam radiation in patients with higher-grade or 
higher-volume disease. The PSA may rise after brachyther
-
apy because of prostate inflammation and necrosis. This 
transient elevation (PSA bounce) should not be mistaken for 
recurrence and may occur up to 20 months after treatment.
D. Cryosurgery
In cryosurgery, liquid nitrogen is circulated through small 
hollow-core needles inserted into the prostate under ultra
-

-
sound guidance. The freezing process results in tissue 
destruction. The positive biopsy rate after cryoablation 
ranges between 7% and 23%.
E. Localized Disease
Although selected patients may be candidates for active 
surveillance based on age or health and evidence of small-
volume or well-differentiated cancers, most men with an 
anticipated life expectancy of longer than 10 years should 
be considered for treatment. Newly introduced genomic 
tests may provide novel information to help guide treat
-
ment decisions. Both radiation therapy and radical prosta
-
tectomy result in acceptable levels of local control. A large, 
prospective, randomized trial compared active surveillance 
with radical prostatectomy in 695 men with clinically local
-
ized and well-differentiated to moderately differentiated 
cancers. Radical prostatectomy significantly reduced dis
-
ease-specific mortality, overall mortality, and risks of 
metastasis and local progression. The relative reduction in 
the risk of death at 23 years was 0.56 in the prostatectomy 
group, with the number needed to treat to avert one death 
(NNT) = 8 patients; the benefit was largest in men younger 
than age 65 years (relative risk [RR] = 0.45) and with 
intermediate-risk prostate cancer (RR = 0.38). Surgery also 
reduced the risk of metastases in older men (RR = 0.68).
F. Locally and Regionally Advanced Disease
Patients with advanced pathologic stage or positive surgical 
margins are at an increased risk for local and distant tumor 
relapse. Such patients are candidates for adjuvant therapy 
(radiation for positive margins and seminal vesicle inva
-
sion or androgen deprivation for lymph node metastases). 
Two randomized clinical trials (EORTC 22911 and SWOG 
8794) have demonstrated improved progression-free and 
metastasis-free survival with early radiotherapy in these 
men, and subsequent analysis of SWOG 8794 showed 
improved overall survival in men receiving adjuvant radia
-
tion therapy. Evidence suggests that salvage radiotherapy 
after radical prostatectomy, within 2 years of PSA relapse, 
increases prostate cancer-specific survival in men with 
shorter PSA doubling time (less than 6 months).
Those with locally extensive cancers, including seminal 
vesicle and bladder neck invasion, are at increased risk for 
both local and distant relapse despite conventional therapy. 
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A variety of investigational regimens are being tested in an 
effort to improve cancer outcomes in such patients. Combi
-
nation therapy (androgen deprivation combined with sur
-
gery or irradiation), newer forms of irradiation, and 
hormonal therapy alone are being tested, as is neoadjuvant 
and adjuvant chemotherapy. Neoadjuvant and adjuvant 
androgen deprivation therapy combined with external 
beam radiation therapy have demonstrated improved sur
-
vival compared with external beam radiation therapy alone.
G. Metastatic Disease
Since death due to prostate carcinoma is almost invariably 
the result of failure to control metastatic disease, research 
has emphasized efforts to improve control of distant dis
-
ease. Most prostate carcinomas are hormone dependent 
and approximately 70–80% of men with metastatic prostate 
carcinoma will respond to various forms of androgen depri
-
vation. 
Androgen deprivation therapy
 may be effected at 
several levels along the pituitary–gonadal axis using a variety 
of methods or agents (Table 39–10). Use of luteinizing hor
-
mone-releasing hormone (LHRH) agonists (leuprolide, gos
-
erelin) achieves androgen deprivation without orchiectomy 
and is the most common method of reducing testosterone 
levels. A single LHRH antagonist (degarelix) is FDA approved 
and has no short-term testosterone “flare” associated with 
LHRH agonists. Because of its rapid onset of action, 
ketocon
-
azole
 should be considered in patients with advanced pros
-
tate cancer who present with spinal cord compression, 
bilateral ureteral obstruction, or disseminated intravascular 
coagulation. Although testosterone is the major circulating 
androgen, the adrenal gland secretes the androgens dehydro
-
epiandrosterone, dehydroepiandrosterone sulfate, and andro
-
stenedione. Some investigators believe that suppressing both 
Table 39–10.
 
Androgen deprivation for prostatic cancer.
Level
Agent
Dose
Sequelae
Pituitary, hypothalamus
1–3 mg orally daily
Gynecomastia, hot flushes, thromboembolic 
disease, erectile dysfunction
L
h
R
h
 agonists
Leuprolide
Goserelin
Triptorelin
Histrelin
Daily subcutaneous injection
Monthly to quarterly depot injection
Monthly depot injection
Annual subcutaneous implant
Erectile dysfunction, hot flushes, gynecomastia, 
rarely anemia
L
h
R
h
 antagonist
Degarelix
240 mg subcutaneously initial dose, 
then 80 mg subcutaneously 
monthly
Hot flushes, weight gain, erectile dysfunction, 
increased liver tests
Adrenal
400 mg three times orally daily
Adrenal insufficiency, nausea, rash, ataxia
Aminoglutethimide
250 mg four times orally daily
20–40 mg orally daily
Gastrointestinal bleeding, fluid retention
CY
p
17a1 inhibitor
Abiraterone
1000 mg orally daily (with 
prednisone 5 mg orally twice daily)
Weight gain, fluid retention, hypokalemia, 
Testis
Orchiectomy
Gynecomastia, hot flushes, erectile dysfunction
Prostate cell
Flutamide
250 mg three times orally daily
No erectile dysfunction when used alone; nausea, 
diarrhea
Bicalutamide
50 mg orally daily
Liver, cardiac and pulmonary toxicity 
Enzalutamide
160 mg orally daily
Seizures, dizziness, asthenia
Cytotoxic 
 
chemotherapeutic 
agents
Bone marrow, skin, pulmonary, cardiac, 
gastrointestinal, hepatic toxicities possible
Docetaxel
75 mg/m
2
 intravenously once on 
day 1 of 21-day cycle (with 
 
prednisone 10 mg orally daily)
Cabazitaxel
20 mg/m
2
 
LHRH, luteinizing hormone-releasing hormone.
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testicular and adrenal androgens allows for a better initial and 
longer response than methods that only inhibit production of 
testicular androgens. In patients with untreated metastatic 
disease, 
complete androgen blockade,
 combining either oral 
abiraterone acetate 
plus 
 or 
docetaxel 
plus 
pred
-
nisone
 with use of an LHRH agonist/antagonist or orchiec
-
tomy, results in superior survival compared to LHRH agonist/
antagonist therapy alone. Nonsteroidal antiandrogen agents 
may be useful in the setting of the initial treatment of non-
metastatic (PSA only) disease. They act by competitively 
binding the receptor for dihydrotestosterone, the intracellular 
androgen responsible for prostate cell growth and develop
-
ment. A meta-analysis of trials comparing the use of either an 
LHRH agonist or orchiectomy alone or of either in combina
-
tion with an antiandrogen agent showed little benefit of com
-
bination therapy. However, patients at risk for disease-related 
symptoms (bone pain, obstructive voiding symptoms) due to 
the initial elevation of serum testosterone that accompanies 
the use of an LHRH agonist should receive antiandrogens 
initially. In addition to immediate side effects of androgen 
deprivation, including sexual dysfunction and hot flashes, the 
chronic suppression of testosterone leads to osteoporosis and 
risk of fractures, cardiovascular disease and diabetes mellitus, 
and decreased muscle and increased fat. 
 
can prevent osteoporosis associated with androgen depriva
-
tion, decrease bone pain from metastases, and reduce skeletal-
related events. 
Denosumab
, a RANK ligand inhibitor, is 
approved for the prevention of skeletal-related events in 
patients with bone metastases from prostate cancer and also 
appears to delay the development of these metastases in 
patients with castration-resistant prostate cancer.
Docetaxel
 is the first cytotoxic chemotherapy agent to 
improve survival in patients with castration-resistant pros
-
tate cancer, which is defined as progressing disease despite a 
suppressed (castrate level) of serum testosterone of less than 
50 ng/dL. It is also used in conjunction with initial androgen 
deprivation therapy for patients with untreated high-volume 
metastatic disease, where it also improves survival. 
 (which targets CYP17, a key enzyme in andro
-
gen synthesis) and 
enzalutamide
 (a potent androgen recep
-
tor antagonist) have both demonstrated improvement in 
survival in castration-resistant prostate cancer patients and 
can be used prior to or following docetaxel. 
Sipuleucel-T,
 an 
autologous cellular immunotherapy, is FDA approved in 
asymptomatic or minimally symptomatic men with meta
-
static castration-resistant prostate cancer. 
 is a 
second-line taxane chemotherapy used in men who have 
already received docetaxel. 
Radium-223 dichloride
 is 
approved for the treatment of men with castration-resistant, 
symptomatic bone metastases, with significant improve
-
ments in both overall survival and time to skeletal-related 
events (eg, fractures and spinal cord compression).
 
»
Prognosis
The likelihood of success of active surveillance or treat
-
ment can be predicted using risk assessment tools that 
usually combine stage, grade, PSA level, and number and 
extent of positive prostate biopsies. Several web-based tools 
are available (eg, https://www.mskcc.org/nomograms/
prostate). One of the most widely used is the 
Kattan 
nomogram;
 it incorporates cancer stage, grade, and PSA 
level to predict the likelihood that a patient will be disease-
free after radical prostatectomy or radiation therapy.
The University of California San Francisco 
CAPRA 
nomogram
 (https://urology.ucsf.edu/research/cancer/
prostate-cancer-risk-assessment-and-the-ucsf-capra-score) 
uses serum PSA, Gleason score, clinical stage, percent posi
-
tive biopsies, and patient age in a point system to risk

-
tive biopsies, and patient age in a point system to risk 
stratify and predict the likelihood of PSA recurrence 3 and 
5 years after radical prostatectomy (Tables 39–11 and 39–12) 
Table 39–11.
 
The UCSF Cancer of the Prostate Risk 
Assessment (CAPRA).
Variable
Level
p
oin
ts
PSA (ng/mL [or mcg/L]) at diagnosis
0–6
0
6.1–10
1
10.1–20
2
20.1–30
3
> 30
4
Gleason grade, primary/secondary
1–3/1–3
0
1–3/4–5
1
4–5/1–5
3
T stage
T1 or T2
0
T3a
1
% positive biopsies (biopsy cores positive 
divided by the number of biopsies 
obtained)
< 34%
0
≥ 34%
1
Age
< 50 years
0
≥ 50 years
1
Source: https://urology.ucsf.edu/research/cancer/prostate-cancer-
risk-assessment-and-the-ucsf-capra-score
Table 39–12.
 
CAPRA: Probability of freedom from 
 
PSA recurrence after radical prostatectomy by 
 
CAPRA point total.
CA
p
RA Score
3-Year Recurrence-
Free Survival (%) 
(95% CI)
5-Year Recurrence-
(95% CI)
0–1
91 (85–95)
85 (73–92)
2
89 (83–94)
81 (69–89)
3
81 (73–87)
66 (54–76)
4
81 (69–89)
59 (40–74)
5
69 (51–82)
60 (37–77)
6
54 (27–75)
34 (12–57)
7+
24 (9–43)
8 (0–28)
PSA, prostate-specific antigen.
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as well as metastasis and prostate cancer-specific and over
-
all survival. The CAPRA nomogram has been validated on 
large multicenter and international radical prostatectomy 
and radiation-treated cohorts.
The patterns of prostate cancer progression have been well 
defined. Small and well-differentiated cancers (Gleason 
grades 1 and 2) are usually confined within the prostate, 
whereas large-volume (greater than 4 mL) or poorly differen
-
tiated (Gleason grades 4 and 5) cancers are more often locally 
extensive or metastatic to regional lymph nodes or bone. 
Penetration of the prostate capsule by cancer is common and 
occurs along perineural spaces. Seminal vesicle invasion is 
associated with a high likelihood of regional or distant disease, 
and disease recurrence. The most common sites of lymph 
node metastases are the obturator and internal iliac lymph 
node chains and of distant metastases, the axial skeleton.
 
»
•	
Refer all patients to a urologist for management of 
localized disease or active surveillance.
•	
For metastatic disease, medical oncology should be 
consulted for consideration of systemic treatments.
•	
Active surveillance may be appropriate in selected patients 
with very low-volume, low-grade prostate cancer.
•	
Localized disease may be managed by active surveil
-
lance, surgery, or radiation therapy.
•	
Locally extensive, regionally advanced, and metastatic 
disease often require multimodal treatment strategies.
Barry MJ et al. Evaluating an elevated screening PSA test. JAMA. 
2015 Nov 17;314(19):2073–4. [PMID: 26575065]
Barry MJ et al. Prevention of prostate cancer morbidity and 
mortality: primary prevention and early detection. Med Clin 
North Am. 2017 Jul;101(4):787–806. [PMID: 28577627]
Beer TM et al; PREV AIL Investigators. Enzalutamide in meta
-
static prostate cancer before chemotherapy. N Engl J Med. 
2014 Jul 31;371(5):424–33. [PMID: 24881730]
Cooperberg MR et al. Trends in management for patients with 
localized prostate cancer, 1990–2013. JAMA. 2015 Jul 7; 
314(1):80–2. [PMID: 26151271]
Eggener SE et al. Prostate cancer screening. JAMA. 2015 Aug 25; 
314(8):825–6. [PMID: 26305653]
Filson CP et al. Expectant management for men with early stage 
prostate cancer. CA Cancer J Clin. 2015 Jul–Aug;65(4):265–82. 
[PMID: 25958817]
Fizazi K et al. Abiraterone in metastatic prostate cancer. N Engl 
J Med. 2017 Oct 26;377(17):1697–8. [PMID: 29083131]
Francini E et al. Prostate cancer: developing novel approaches to 
castration-sensitive disease. Cancer. 2017 Jan 1;123(1):29–42. 
[PMID: 27802360]
Hamdy FC et al; ProtecT Study Group. 10-year outcomes after 
monitoring, surgery, or radiotherapy for localized prostate 
cancer. N Engl J Med. 2016 Oct 13;375(15):1415–24. [PMID: 
27626136]
Jayadevappa R et al. Comparative effectiveness of prostate cancer 
treatments for patient-centered outcomes: a systematic review 
and meta-analysis (PRISMA Compliant). Medicine 
(Baltimore). 2017 May;96(18):e6790. [PMID: 28471976]
Litwin MS et al. The diagnosis and treatment of prostate cancer: 
a review. JAMA. 2017 Jun 27;317(24):2532–42. [PMID: 
28655021] National Cancer Institute. SEER Cancer Statistics 
Factsheets: Prostate Cancer, 2017. https://seer.cancer.gov/
statfacts/html/prost.html
Razmaria AA. JAMA patient page. Prostate cancer screening. 
JAMA. 2015 Nov 17;314(19):2096. [PMID: 26575077]
Rekoske BT et al. Immunotherapy for prostate cancer: false 
promises or true hope? Cancer. 2016 Dec 1;122(23):3598–607. 
[PMID: 27649312]
Ritch CR et al. Advances in the management of castration resis
-
tant prostate cancer. BMJ. 2016 Oct 17;355:i4405. [PMID: 
27754846]
Rosenkrantz AB et al. Prostate magnetic resonance imaging and 
magnetic resonance imaging targeted biopsy in patients with 
a prior negative biopsy: a consensus statement by AUA and 
SAR. J Urol. 2016 Dec;196(6):1613–8. [PMID: 27320841]
Sweeney CJ et al. Chemohormonal therapy in metastatic hor
-

-
mone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20; 
373(8):737–46. [PMID: 26244877]
Violette PD et al. Decision aids for localized prostate cancer treat
-
ment choice: systematic review and meta-analysis. CA Cancer 
J Clin. 2015 May–Jun;65(3):239–51. [PMID: 25772796]
BLADDER CANCER
 
»
Gross or microscopic hematuria.
 
»
 
»
Positive urinary cytology in most patients.
 
»
Filling defect within bladder noted on imaging.
 
»
Bladder cancer is the second most common urologic can
-
cer; it occurs more commonly in men than women (3.1:1), 
and the mean age at diagnosis is 73 years. Cigarette smok
-
ing and exposure to industrial dyes or solvents are risk 
factors for the disease and account for approximately 60% 
and 15% of new cases, respectively. In the United States, 
almost all primary bladder cancers (98%) are epithelial 
malignancies, usually urothelial cell carcinomas (90%). 
Adenocarcinomas and squamous cell cancers account for 
approximately 2% and 7%, respectively. The latter is often 
associated with schistosomiasis, vesical calculi, or pro
-
longed catheter use.
 
»
Hematuria—gross or microscopic, chronic or 
intermittent—is the presenting symptom in 85–90% of 
patients with bladder cancer. Irritative voiding symptoms 
(urinary frequency and urgency) occur in a small percent
-
age of patients as a result of the location or size of the 
cancer. Most patients with bladder cancer do not have signs 
of the disease because of its superficial nature. Abdominal 
masses detected on bimanual examination may be present 
in patients with large-volume or deeply infiltrating cancers. 
Hepatomegaly or palpable lymphadenopathy may be pres
-
ent in patients with metastatic disease, and lymphedema of 
the lower extremities results from locally advanced cancers 
or metastases to pelvic lymph nodes.
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Urinalysis reveals microscopic or gross hematuria in the 
majority of cases. On occasion, hematuria is accompanied 
by pyuria. Azotemia may be present in a small number of 
cases associated with ureteral obstruction. Anemia may 
occasionally be due to chronic blood loss or to bone mar
-
row metastases. Exfoliated cells from normal and abnormal 
urothelium can be readily detected in voided urine 
specimens. Cytology can be useful to detect the disease 
initially or to detect its recurrence. Cytology is sensitive in 
detecting cancers of higher grade and stage (80–90%), but 
less so in detecting superficial or well-differentiated lesions 
(50%). There are numerous urinary tumor markers under 
investigation for screening, assessing recurrence, progres
-
sion, prognosis, or response to therapy.
C. Imaging
Bladder cancers may be identified using ultrasound, CT, or 
MRI as masses within the bladder. However, the presence 
of cancer is confirmed by cystoscopy and biopsy, with 
imaging primarily used to evaluate the upper urinary tract 
and to stage more advanced lesions.
D. Cystourethroscopy and Biopsy
The diagnosis and staging of bladder cancers are made by 
cystoscopy and transurethral resection. If cystoscopy—
performed usually under local anesthesia—confirms the 
presence of bladder cancer, the patient is scheduled for 
transurethral resection under general or regional anesthe
-
sia. Random bladder and, on occasion, transurethral pros
-
tate biopsies are performed to detect occult disease in the 
bladder or elsewhere and potentially identify patients at 
greater risk for cancer recurrence and progression.
 
»
Pathology & Staging
Grading is based on cellular features: size, pleomorphism, 
mitotic rate, and hyperchromatism. Bladder cancer staging 
is based on the extent (depth) of bladder wall penetration 
and the presence of regional or distant metastases.
The natural history of bladder cancer is based on two 
separate but related processes: cancer recurrence within 
the bladder and progression to higher-stage disease. Both 
are correlated with cancer grade and stage.
 
»
Treatment
Patients with superficial cancers (Ta, T1) are treated with 
complete transurethral resection and selective use of intra
-
vesical chemotherapy. The subset of patients with carci
-
noma in situ and those undergoing resection of large, 
high-grade, recurrent Ta lesions or T1 cancers are good 
candidates for adjuvant intravesical therapy.
Patients with invasive (T2, T3) but still localized can
-
cers are at risk for both nodal metastases and progression 
and require radical cystectomy or the combination of che
-
motherapy and selective surgery or irradiation due to the 
much higher risk of progression compared with patients 
with lower-stage lesions.
For patients with muscle invasive (T2 or greater) urothe
-
lial cell carcinoma, neoadjuvant systemic chemotherapy 
prior to radical cystectomy is superior to radical cystectomy 
alone. This is particularly important for higher-stage or bulky 
tumors in order to improve their surgical resectability.
A. Intravesical Chemotherapy
Immunotherapeutic or chemotherapeutic agents delivered 
directly into the bladder via a urethral catheter can reduce 
the likelihood of recurrence in those who have undergone 
complete transurethral resection. Most agents are adminis
-
tered weekly for 6–12 weeks. Efficacy may be increased by 
prolonging contact time to 2 hours. The use of maintenance 
therapy after the initial induction regimen is beneficial. 
Common agents include thiotepa, mitomycin, doxorubicin, 
valrubicin, and BCG, the last being the only agent effective in 
reducing disease progression. Side effects of intravesical che
-
motherapy include irritative voiding symptoms and hemor
-
rhagic cystitis. Patients in whom symptoms or infection 
develop from BCG may require antituberculous therapy.

-
-
Although transurethral resection is the initial form of treat
-
ment for all bladder tumors since it is diagnostic, allows for 
proper staging, and controls superficial cancers, muscle-
infiltrating cancers require more aggressive treatment. 
Partial cystectomy is indicated in selected patients with soli
-
tary lesions or those with cancer in a bladder diverticulum. 
Radical cystectomy entails removal of the bladder, prostate, 
seminal vesicles, and surrounding fat and peritoneal attach
-
ments in men and the bladder, uterus, cervix, urethra, ante
-
rior vaginal vault, and usually the ovaries in women. Bilateral 
pelvic lymph node dissection is performed in all patients.
Urinary diversion can be performed using a conduit of 
small or large bowel. However, continent forms of diver
-
sion avoid the necessity of an external appliance and can be 
considered in a significant number of patients.
External beam radiotherapy delivered in fractions over a 
6- to 8-week period is generally well tolerated, but approxi
-
mately 10–15% of patients will develop bladder, bowel, or 
rectal complications. Local recurrence is common after 
radiotherapy alone (30–70%) and it is therefore combined 
with systemic chemotherapy in an effort to reduce the need 
for radical cystectomy or to treat patients who are poor 
candidates for radical cystectomy.
Metastatic disease is present in 15% of patients with newly 
diagnosed bladder cancer, and metastases develop within 
 
2 years in up to 40% of patients who were believed to have 
localized disease at the time of cystectomy or definitive 
radiotherapy. Cisplatin-based combination chemotherapy 
results in partial or complete responses in 15–45% of patients 
(see Table 39–2). The immune checkpoint inhibitor atezoli
-
zumab was approved for use in patients with bladder cancer 
who have progressed despite platinum chemotherapy.
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Combination chemotherapy has been used to decrease 
recurrence rates with both surgery and radiotherapy and to 
attempt bladder preservation in those treated with radiation. 
Neoadjuvant chemotherapy appears to benefit all patients 
with muscle-invasive disease prior to planned cystectomy. 
Chemotherapy should also be considered before surgery in 
those with bulky lesions or those suspected of having 
regional disease. Chemoradiation is best suited for those 
with T2 or limited T3 disease without ureteral obstruction. 
Alternatively, chemotherapy has been used after cystectomy 
in patients at high risk for recurrence, such as those who 
have lymph node involvement or local invasion.
E. Immunotherapy
Anti–PDL-1 immunotherapy with atezolizumab is associ
-
ated with response rates of 25–30% in locally advanced and 
metastatic bladder cancer. In many cases, however, the 
responses to therapy are durable. Atezolizumab was 
approved by the FDA in May 2016 for urothelial cancer. 
A tumor test for PDL-1 expression, Ventana PD-L1, was 
also approved; however, PDL-1 expression is not required 
for treatment with atezolizumab. Additional checkpoint 
inhibitors have also been approved, including the anti-PD-1 
agents pembrolizumab and nivolumab and the anti-PDL-1 
agents durvalumab and avelumab (Table 39–2).
 
»
Prognosis
The frequency of recurrence and progression are correlated 
with grade. Whereas progression may be noted in few low-
grade cancers (19–37%), it is common with poorly differ
-
entiated lesions (33–67%). Carcinoma in situ is most often 
found in association with papillary bladder cancers. Its 
presence identifies patients at increased risk for recurrence 
and progression.
At initial presentation, approximately 50–80% of bladder 
cancers are superficial: stage Ta, Tis, or T1. When properly 
treated, lymph node metastases and progression are uncom
-
mon in such patients and survival is excellent (81%). Five-
year survival of patients with T2 and T3 disease ranges from 
50% to 75% after radical cystectomy. Long-term survival for 
patients with metastatic disease at presentation is rare.
 
»
•	
Refer all patients to a urologist. Hematuria often 
deserves evaluation with both upper urinary tract 
imaging and cystoscopy, particularly in a high-risk 
group (eg, older men).
•	
Refer when histologic diagnosis and staging require 
endoscopic resection of cancer.
•	
Metastatic urothelial cancer should be managed by a 
medical oncologist.
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as second-line therapy for advanced urothelial carcinoma. N 
Engl J Med. 2017 Mar 16;376(11):1015–26. [PMID: 28212060]
Burger M et al. ICUD-EAU International Consultation on Blad
-
der Cancer 2012: non-muscle-invasive urothelial carcinoma 
of the bladder. Eur Urol. 2013 Jan;63(1):36–44. [PMID: 
22981672]
Donin NM et al. Immunotherapy for the treatment of urothelial 
carcinoma. J Urol. 2017 Jan;197(1):14–22. [PMID: 27460757]
Hautmann RE et al. ICUD-EAU International Consultation on 
Bladder Cancer 2012: urinary diversion. Eur Urol. 2013 Jan; 
63(1):67–80. [PMID: 22995974]
Johnson DC et al. Surgical advances in bladder cancer: at what 
cost? Urol Clin North Am. 2015 May;42(2):235–52. [PMID: 
25882565]
Jordan EJ et al. Targeted therapy in advanced bladder cancer: 
what have we learned? Urol Clin North Am. 2015 May; 
42(2):253–62. [PMID: 25882566]
Kamat AM et al. Bladder cancer. Lancet. 2016 Dec 3; 
388(10061):2796–810. Erratum in: Lancet. 2016 Dec 3; 
388(10061):2742. [PMID: 27345655]
Kamat AM et al. ICUD-EAU International Consultation on 
Bladder Cancer 2012: screening, diagnosis, and molecular 
markers. Eur Urol. 2013 Jan;63(1):4–15. [PMID: 23083902]
Lee CH et al. Role of imaging in the local staging of urothelial 
carcinoma of the bladder. AJR Am J Roentgenol. 2017 Jun; 
208(6):1193–205. [PMID: 28225635]
Lerner SP et al. Novel endoscopic diagnosis for bladder cancer.

Lerner SP et al. Novel endoscopic diagnosis for bladder cancer. 
Cancer. 2015 Jan 15;121(2):169–78. [PMID: 25132313]
Lucca I et al. Novel biomarkers to predict response and progno
-
sis in localized bladder cancer. Urol Clin North Am. 
2015 May;42(2):225–33. [PMID: 25882564]
Packiam VT et al. Non-muscle-invasive bladder cancer: intra
-
vesical treatments beyond Bacille Calmette-Guérin. Cancer. 
2017 Feb 1;123(3):390–400. [PMID: 28112819]
Razmaria AA. JAMA patient page. Bladder cancer. JAMA. 
2015 Nov 3;314(17):1886. [PMID: 26529173]
Sternberg CN et al. ICUD-EAU International Consultation on 
Bladder Cancer 2012: chemotherapy for urothelial carcinoma-
neoadjuvant and adjuvant settings. Eur Urol. 2013 Jan; 
63(1):58–66. [PMID: 22917984]
CANCERS OF THE URETER & RENAL PELVIS
Cancers of the ureter and renal pelvis are rare and occur 
more commonly in patients who have bladder cancer, 
Balkan nephropathy, or Lynch syndrome, who smoke, 
who were exposed to Thorotrast (a contrast agent with 
radioactive thorium in use until the 1960s), and who have 
a long history of analgesic abuse. The majority are urothe
-
lial cell carcinomas. Gross or microscopic hematuria is 
present in most patients; flank pain secondary to bleeding 
and obstruction occurs less commonly. As with bladder 
cancers, urinary cytology is often positive. The most 
common signs identified at the time of CT or intravenous 
urography include an intraluminal filling defect, unilat
-
eral nonvisualization of the collecting system, and hydro
-
nephrosis. Ureteral and renal pelvic tumors must be 
differentiated from calculi, blood clots, papillary necrosis, 
or inflammatory and infectious lesions. On occasion, 
upper urinary tract lesions are accessible for biopsy, ful
-
guration, or resection using a ureteroscope. Treatment is 
based on the site, size, grade, depth of penetration, and 
number of cancers present. Most are excised with laparo
-
scopic or open nephroureterectomy (renal pelvic and 
upper ureteral lesions) or segmental excision of the ureter 
(distal ureteral lesions). Endoscopic resection may be 
indicated in patients with limited renal function or focal, 
low-grade, cancers. Similar to urothelial bladder cancers, 
use of chemotherapy prior to surgery may improve 
outcomes.
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Aragon-Ching JB. Challenges and advances in the diagnosis, 
biology, and treatment of urothelial upper tract and bladder 
carcinomas. Urol Oncol. 2017 Jul;35(7):462–4. [PMID: 
28625477]
Gupta S et al. Systemic immunotherapy for urothelial cancer: 
current trends and future directions. Cancers (Basel). 
2017 Jan 27;9(2):15. [PMID: 28134806]
Porten S et al. Neoadjuvant chemotherapy improves survival of 
patients with upper tract urothelial carcinoma. Cancer. 
2014 Jun 15;120(12):1794–9. [PMID: 24633966]
Rouprêt M et al. European Association of Urology guidelines on 
upper urinary tract urothelial carcinoma: 2017 update. Eur 
Urol. 2018 Jan;73(1):111–22. [PMID: 28867446]
Seisen T et al. Oncologic outcomes of kidney-sparing surgery 
versus radical nephroureterectomy for upper tract urothelial 
carcinoma: a systematic review by the EAU Non-muscle 
Invasive Bladder Cancer Guidelines Panel. Eur Urol. 2016 Dec; 
70(6):1052–68. [PMID: 27477528]
Verges DP et al. Endoscopic treatment of upper tract urothelial 
carcinoma. Curr Urol Rep. 2017 Apr;18(4):31. [PMID: 
28251485]
RENAL CELL CARCINOMA
 
»
 
»
Flank pain or mass in some patients.
 
»
Systemic symptoms such as fever, weight loss may 
be prominent.
 
»
Solid renal mass on imaging.
 
»
Kidney (renal cell) and renal pelvis carcinomas account for 
3.8% of all adult cancers. In 2018 in the United States, it is 
estimated that approximately 65,340 cases of renal cell car
-
cinoma will be diagnosed and 14,970 deaths will result. 
Renal cell carcinoma has a peak incidence in the sixth 
decade of life and a male-to-female ratio of 2:1. It may be 
associated with a number of paraneoplastic syndromes.
The cause is unknown. Cigarette smoking is the only 
significant environmental risk factor that has been 
identified. Familial causes of renal cell carcinoma have 
been identified (von Hippel–Lindau syndrome, hereditary 
papillary renal cell carcinoma, hereditary leiomyoma-renal 
cell carcinoma, Birt-Hogg-Dubé syndrome) and there is an 
association with dialysis-related acquired cystic disease 
and specific genetic aberrations (eg, Xp11.2 translocation), 
but sporadic carcinomas are far more common.
Renal cell carcinoma originates from the proximal tubule 
cells. Various histologic cell types are recognized (clear cell, 
papillary, chromophobe, collecting duct and sarcomatoid).
 
»
Historically, 60% of patients presented with gross or micro
-
scopic hematuria. Flank pain or an abdominal mass was 
detected in approximately 30% of cases. The triad of flank 
pain, hematuria, and mass was found in only 10–15% of 
patients, and often a sign of advanced disease. Fever occurs 
as a paraneoplastic symptom. Symptoms of metastatic dis
-
ease (cough, bone pain) occur in 20–30% of patients at 
presentation. Because of the widespread use of ultrasound 
and CT scanning, renal tumors are frequently detected 
incidentally in individuals with no urologic symptoms. 
There has been profound stage migration toward lower 
stages of disease over the past 10 years, likely due to the 
increased use of abdominal imaging. However, population 
mortality rates remain stable.
Hematuria is present in 60% of patients. Erythrocytosis 
from increased erythropoietin production occurs in 5%, 
though anemia is more common; hypercalcemia may be 
present in up to 10% of patients. 
Stauffer syndrome
 is a 
reversible syndrome of hepatic dysfunction (with elevated 
liver tests) in the absence of metastatic disease.
C. Imaging
Solid renal masses are often first identified by abdominal 
ultrasonography or CT. CT and MRI scanning are the most 
valuable imaging tests for renal cell carcinoma. These scans 
confirm the character of the mass and further stage the 
lesion with respect to regional lymph nodes, renal vein, or

lesion with respect to regional lymph nodes, renal vein, or 
liver. CT and MRI also provide valuable information regard
-
ing the contralateral kidney (function, bilaterality of neo
-
plasm). Chest radiographs exclude pulmonary metastases, 
and bone scans should be performed for large tumors and in 
patients with bone pain or elevated serum alkaline phospha
-
tase levels. MRI and duplex Doppler ultrasonography are 
excellent methods of assessing the presence and extent of 
tumor thrombus within the renal vein or vena cava.
 
»
Solid lesions of the kidney are renal cell carcinoma until 
proved otherwise. Other solid masses include renal angio
-
myolipomas (fat density usually visible by CT), renal pelvis 
urothelial cancers (more central location, involvement of 
the collecting system, positive urinary cytology), renal 
oncocytomas (indistinguishable from renal cell carcinoma 
preoperatively), renal abscesses, and adrenal tumors 
(superoanterior to the kidney).
 
»
Treatment
Surgical extirpation is the primary treatment for localized 
renal cell carcinoma. Patients with a single kidney, bilateral 
lesions, or significant medical renal disease should be con
-
sidered for partial nephrectomy. Patients with a normal 
contralateral kidney and good renal function but a small 
cancer are also candidates for partial nephrectomy, while 
radical nephrectomy is indicated in patients with cancers 
larger than 7 cm and those in whom partial nephrectomy is 
not technically feasible. Radiofrequency and cryosurgical 
ablation are being studied; they likely yield equivalent 
short-term oncologic outcomes with reduced morbidity in 
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select patients. Surveillance in selected patients may be war
-
ranted, and percutaneous biopsy can provide information 
regarding histology and grade to help inform the decision.
No effective cytotoxic chemotherapy is available for 
metastatic renal cell carcinoma. Vinblastine yields short-
term partial response rates of 15%. Bevacizumab can pro
-
long time to progression in patients with metastatic disease 
(see Table 39–2). With biologic response modifiers, such as 
interferon-alpha and interleukin-2, partial response rates of 
15–20% and 15–35%, respectively, have been reported. 
Responders tend to have lower tumor burdens, metastatic 
disease confined to the lung, and a high-performance status. 
Patients with metastatic renal cell carcinoma and good per
-
formance status who have resectable primary tumors should 
undergo cytoreductive nephrectomy. Two randomized trials 
have shown a survival benefit of surgery followed by the use 
of systemic therapy—specifically, biologic response 
modifiers—compared with the use of systemic therapy alone.
Several targeted medications, specifically VEGF, 
Raf-kinase, and mTOR inhibitors, are effective (40–60% 
response rates) in patients with advanced kidney cancer 
(Table 39–2). These oral agents, which include sunitinib, 
pazopanib, cabozantinib, axitinib, and sorafenib, are gener
-
ally well tolerated and particularly active for clear cell 
carcinoma. The appropriate timing and combination of 
these agents, with and without surgery and cytokine ther
-
apy, remain to be determined. Sunitinib has been approved 
for adjuvant use after complete surgical resection in 
patients with adverse pathological features. The mTOR 
inhibitors everolimus and temsirolimus are approved for 
use in patients with prior anti-VEGF therapy, as is the 
combination of lenvatinib and everolimus. Nivolumab is an 
approved immunotherapy for treating metastatic disease 
that has progressed despite antiangiogenic therapy, and the 
combination with ipilimumab proved superior to sunitinib 
in previously untreated metastatic renal cell carcinoma. In 
2017, the FDA granted breakthrough therapy designation 
to the combination of the PD-L1 inhibitor avelumab with 
the VEGF inhibitor axitinib (Table 39–2).
 
»
Prognosis
After radical or partial nephrectomy, tumors confined to 
the renal capsule (T1–T2) demonstrate 5-year disease-free 
survivals of 90–100%. Tumors extending beyond the renal 
capsule (T3 or T4) and node-positive tumors have 50–60% 
and 0–15% 5-year disease-free survival, respectively. One 
subgroup of patients with nonlocalized disease has reason
-
able long-term survival, namely, those with solitary resect
-
able metastases. In this setting, radical nephrectomy with 
resection of the solitary metastasis results in 5-year disease-
free survival rates of 15–30%.
 
»
•	
Refer patients with solid renal masses or complex cysts 
to a urologist for further evaluation.
•	
Refer patients with renal cell carcinoma to a urologic 
surgeon for surgical excision.
•	
Refer patients with metastatic disease to an oncologist 
and urologist.
Dey S et al. Neoadjuvant targeted molecular therapy before renal 
surgery. Urol Clin North Am. 2017 May;44(2):289–303. 
[PMID: 28411920]
Haifler M et al. Current role of renal biopsy in urologic practice. 
Urol Clin North Am. 2017 May;44(2):203–11. [PMID: 
28411912]
Hammers HJ et al. Safety and efficacy of nivolumab in combi
-
nation with ipilimumab in metastatic renal cell carcinoma: 
the Checkmate 016 study. J Clin Oncol. 2017 Dec 
1;35(34):3851–8. [PMID: 28678668]
Johnson DB et al. Immune checkpoint inhibitors in challenging 
populations. Cancer. 2017 Jun 1;123(11):1904–11. [PMID: 
28241095]
Merrill SB. Postoperative surveillance for renal cell carcinoma. Urol 
Clin North Am. 2017 May;44(2):313–23. [PMID: 28411922]
Motzer RJ et al. Lenvatinib, everolimus, and the combination in

28241095]
Motzer RJ et al. Lenvatinib, everolimus, and the combination in 
patients with metastatic renal cell carcinoma: a randomised, 
phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov; 
16(15):1473–82. Erratum in: Lancet Oncol. 2016 Jul; 
17(7):e270. [PMID: 26482279]
Motzer RJ et al; CheckMate 025 Investigators. Nivolumab versus 
everolimus in advanced renal-cell carcinoma. N Engl J Med. 
2015 Nov 5;373(19):1803–13. [PMID: 26406148]
Kidney and Renal Pelvis Cancer, 2018. https://seer.cancer.
gov/statfacts/html/kidrp.html
Pierorazio PM et al. Management of renal masses and localized 
renal cancer: systematic review and meta-analysis. J Urol. 
2016 Oct;196(4):989–99. [PMID: 27157369]
Ravaud A et al; S-TRAC Investigators. Adjuvant sunitinib in 
high-risk renal-cell carcinoma after nephrectomy. N Engl 
 
J Med. 2016 Dec 8;375(23):2246–54. [PMID: 27718781]
Sun M et al. Risk assessment in small renal masses: a review 
article. Urol Clin North Am. 2017 May;44(2):189–202. 
[PMID: 28411911]
OTHER PRIMARY TUMORS OF THE KIDNEY
Oncocytomas account for 3–5% of renal tumors, are usu
-
ally benign, and are indistinguishable from renal cell carci
-
noma on preoperative imaging. These tumors are seen in 
other organs, including the adrenals, salivary glands, and 
thyroid and parathyroid glands.
Angiomyolipomas are rare benign tumors composed of 
fat, smooth muscle, and blood vessels. They are most com
-
monly seen in patients with tuberous sclerosis (often mul
-
tiple and bilateral) or in young to middle-aged women. 
CT scanning may identify the fat component, which is 
diagnostic for angiomyolipoma. Asymptomatic lesions less 
than 5 cm in diameter usually do not require intervention; 
large lesions can spontaneously bleed. Acute bleeding can 
be treated by angiographic embolization or, in rare cases, 
nephrectomy. Lesions over 5 cm are often prophylactically 
treated with angioembolization to reduce the risk of 
bleeding.
SECONDARY CANCERS OF THE KIDNEY
The kidney is not an infrequent site for metastatic 
 
disease. Of the solid tumors, lung cancer is the most com
-
mon (20%), followed by breast (10%), stomach (10%), and 
the contralateral kidney (10%). Lymphoma, both Hodgkin 
and non-Hodgkin, may also involve the kidney, although it 
tends to appear as a diffusely infiltrative process resulting in 
renal enlargement rather than a discrete mass.
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TESTICULAR CANCERS (
Germ Cell Tumors
)
 
»
Most common neoplasm in men aged 20–35 years.
 
»
Patient typically discovers a painless nodule.
 
»
Orchiectomy necessary for diagnosis.
 
»
Malignant tumors of the testis are rare, with approximately 
five to six cases per 100,000 males reported in the United 
States each year. Ninety to 95 percent of all primary testicu
-
lar tumors are germ cell tumors and can be divided into 
two major categories: 
nonseminomas,
 including embryo
-
nal cell carcinoma (20%), teratoma (5%), choriocarcinoma 
(less than 1%), and mixed cell types (40%); and 
seminomas
 
(35%). The lifetime probability of developing testicular 
cancer is 0.3% for an American male.
Approximately 5% of testicular cancers develop in a 
patient with a history of cryptorchism, with seminoma 
being the most common. However, 5–10% of these tumors 
occur in the contralateral, normally descended testis. The 
relative risk of development of malignancy is higher for the 
intra-abdominal testis (1:20) and lower for the inguinal 
testis (1:80). Placement of the cryptorchid testis into the 
scrotum (orchidopexy) does not alter its malignant poten
-
tial but does facilitate routine examination and cancer 
Testicular cancer is slightly more common on the right 
than the left, paralleling the increased incidence of cryptor
-
chidism on the right side. One to 2 percent of primary tes
-
ticular cancers are bilateral and up to 50% of these men have 
a history of unilateral or bilateral cryptorchidism. Primary 
bilateral testicular cancers may occur synchronously or 
asynchronously but tend to be of the same histology. Semi
-
noma is the most common histologic finding in bilateral 
primary
 testicular cancers, while malignant lymphoma is 
the most common bilateral testicular tumor overall.
 
»
The most common symptom of testicular cancer is painless 
enlargement of the testis. Sensations of heaviness are not 
unusual. Patients are usually the first to recognize an 
abnormality, yet typical delay in seeking medical attention 
ranges from 3 to 6 months. Acute testicular pain resulting 
from intratesticular hemorrhage occurs in approximately 
10% of cases. Ten percent of patients are asymptomatic at 
presentation, and 10% manifest symptoms relating to 
metastatic disease such as back pain (retroperitoneal 
metastases), cough (pulmonary metastases), or lower 
extremity edema (vena cava obstruction).
A discrete mass or diffuse testicular enlargement is noted 
in most cases. Secondary hydroceles may be present in 5–10% 
of cases. In advanced disease, supraclavicular adenopathy 
may be present, and abdominal examination may reveal a 
mass. Gynecomastia is seen in 5% of germ cell tumors.
Several serum markers are important in the diagnosis and 
monitoring of testicular carcinoma, including human cho
-
rionic gonadotropin (hCG), alpha-fetoprotein, and lactate 
dehydrogenase. Alpha-fetoprotein is never elevated with 
pure seminomas, and while hCG is occasionally elevated in 
seminomas, levels tend to be lower than those seen with 
nonseminomas. Lactate dehydrogenase may be elevated 
with either type of tumor. Liver tests may be elevated in the 
presence of hepatic metastases, and anemia may be present 
C. Imaging
Scrotal ultrasound can readily determine whether a mass is 
intratesticular or extratesticular. Once the diagnosis of 
testicular cancer has been established by inguinal orchiec
-
tomy, clinical staging of the disease is accomplished by 
chest, abdominal, and pelvic CT scanning.
 
»
Staging
Testicular cancer is staged using the TNM system created 
based on extent of cancer in the testis, status of regional 
lymph nodes, the presence of metastases in distant lymph 
nodes or other viscera, and serum levels of tumor markers.

nodes or other viscera, and serum levels of tumor markers. 
Based on these features, germ cell tumors can be grouped to 
assign an overall stage: stage I lesion is confined to the testis; 
stage II demonstrates regional lymph node involvement in the 
retroperitoneum; and stage III indicates distant metastasis.
 
»
An incorrect diagnosis is made at the initial examination in 
up to 25% of patients with testicular tumors. Scrotal ultra
-
sonography should be performed if any uncertainty exists 
with respect to the diagnosis. Although most intratesticu
-
lar masses are malignant, a benign lesion—epidermoid 
cyst—may rarely be seen. Epidermoid cysts are usually 
very small benign nodules located just underneath the 
tunica albuginea; occasionally, however, they can be large. 
Testicular lymphoma is discussed below.
 
»
Treatment
Inguinal exploration with early vascular control of the sper
-
matic cord structures is the initial intervention. If cancer 
cannot be excluded by examination of the testis, radical 
orchiectomy is warranted. Scrotal approaches and open tes
-
ticular biopsies should be avoided. Further therapy depends 
on the histology of the tumor as well as the clinical stage.
Up to 75% of clinical stage I 
nonseminomas
 are cured 
by orchiectomy alone. Selected patients who meet specific 
criteria may be offered surveillance after orchiectomy. 
These criteria are as follows: (1) cancer is confined within 
the tunica albuginea; (2) cancer does not demonstrate vas
-
cular invasion; (3) tumor markers normalize after orchiec
-
tomy; (4) radiographic imaging of the chest and abdomen 
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shows no evidence of disease; and (5) the patient is reliable. 
Patients most likely to experience relapse on a surveillance 
regimen include those with predominantly embryonal 
cancer and those with vascular or lymphatic invasion iden
-
tified in the orchiectomy specimen.
Stage IIa and IIb 
seminomas
 (retroperitoneal disease 
less than 2 cm diameter in IIa and 2–5 cm in IIb) are treated 
by radical orchiectomy and retroperitoneal irradiation. 
Retroperitoneal lymph node dissection is being studied as 
an alternative to radiation for stage IIa and IIb seminoma. 
Patients with clinical stage I disease are candidates for sur
-
veillance, single-agent carboplatin, or adjuvant radiother
-
apy. Seminomas of stage IIc (greater than 5-cm-diameter 
retroperitoneal nodes) and stage III receive primary chemo
-
therapy (etoposide and cisplatin or cisplatin, etoposide, and 
bleomycin) (Table 39–2). After chemotherapy, surgical 
resection of residual retroperitoneal nodes is warranted if 
the node is greater than 3 cm in diameter and positive on 
PET scan, since 40% will harbor residual carcinoma.
Postoperative active surveillance by the clinician and 
patient means patients are followed up every 2–6 months for 
the first 2 years and every 4–6 months in the third year. For 
nonseminomas, tumor markers are obtained at each visit, and 
chest radiographs and abdominal and pelvic CT scans are 
obtained every 4–6 months. For seminomas, serum tumor 
markers may be obtained (optional), chest imaging is obtained 
only as clinically indicated, and abdominal and pelvic CT 
scans are performed every 3–6 months. Follow-up continues 
beyond the initial 3 years; however, 80% of relapses will occur 
within the first 2 years. With rare exceptions, patients who 
relapse can be cured by chemotherapy or surgery. Alternatives 
to surveillance for clinical stage I nonseminoma include adju
-
vant chemotherapy (bleomycin, etoposide, cisplatin) (see 
Table 39–2) or retroperitoneal lymph node dissection.
Following orchiectomy, p atients with bulky retroperito
-
neal disease (greater than 5-cm nodes) or metastatic non
-
seminomas are treated with combination chemotherapy 
(cisplatin and etoposide or cisplatin, etoposide, and bleo
-
mycin) (Table 39–2). If tumor markers normalize and a 
residual mass greater than 1 cm persists on imaging studies, 
it is resected because 15–20% will harbor residual cancer 
and 40% will harbor teratomas. Even if patients have a com
-
plete response to chemotherapy, some clinicians advocate 
retroperitoneal lymphadenectomy since 10% of patients 
may harbor residual carcinoma and 10%, retroperitoneal 
teratoma. If tumor markers fail to normalize following pri
-
mary chemotherapy, salvage chemotherapy is required 
(cisplatin, etoposide, and ifosfamide).
 
»
Prognosis
The 5-year disease-free survival for patients with stage I 
 (includes all treatments) ranges from 96% to 
100%. For low-volume stage II disease, 90% 5-year disease-
free survival is expected. The 5-year disease-free survival rates 
for stage I and IIa 
seminomas
 (retroperitoneal disease less 
than 2 cm in diameter) treated by radical orchiectomy and 
retroperitoneal irradiation are 98% and 92–94%, respectively. 
Ninety-five percent of patients with stage III disease attain a 
complete response following orchiectomy and chemotherapy. 
Patients with bulky retroperitoneal or disseminated disease 
treated with primary chemotherapy followed by surgery have 
a 5-year disease-free survival rate of 55–80%.
 
»
Refer all patients with solid masses of the testis to a urologist 
or medical oncologist if metastatic disease is suspected.
Chovanec M et al. Management of stage I testicular germ cell 
tumours. Nat Rev Urol. 2016 Nov;13(11):663–73. [PMID: 
27618772]
Hanna NH et al. Testicular cancer—discoveries and updates. 
 
N Engl J Med. 2014 Nov 20;371(21):2005–16. Erratum in:

27618772]
 
N Engl J Med. 2014 Nov 20;371(21):2005–16. Erratum in: 
 
N Engl J Med. 2014 Dec 11;371(24):2342. [PMID: 25409373]
Verrill C et al; Members of the International Society of Urologi
-
cal Pathology Testicular Tumor Panel. Reporting and Staging 
of Testicular Germ Cell Tumors: The International Society of 
Urological Pathology (ISUP), Testicular Cancer Consultation 
Conference Recommendations. Am J Surg Pathol. 2017 Jun; 
41(6):e22–32. [PMID: 28368923]
Williamson SR et al; Members of the ISUP Testicular Tumour 
Panel. The World Health Organization 2016 classification of 
testicular germ cell tumours: a review and update from the 
International Society of Urological Pathology Testis 
Consultation Panel. Histopathology. 2017 Feb;70(3):335–46. 
[PMID: 27747907]
Y adav K. Retroperitoneal lymph node dissection: an update in 
testicular malignancies. Clin Transl Oncol. 2017 Jul;19(7):793–8. 
[PMID: 28150168]
SECONDARY CANCERS OF THE TESTIS
Secondary cancers of the testis are rare. In men over the age 
of 50 years, lymphoma is the most common. Overall, it is 
the most common secondary neoplasm of the testis, 
accounting for 5% of all testicular cancers. It may be seen 
in three clinical settings: (1) late manifestation of wide
-
spread lymphoma, (2) the initial presentation of clinically 
occult disease, and (3) primary extranodal disease. Radical 
orchiectomy is indicated to make the diagnosis. Prognosis 
is related to the stage of disease.
Metastasis to the testis is rare. The most common pri
-
mary site of origin is the prostate, followed by the lung, 
gastrointestinal tract, melanoma, and kidney.
 
º
CANCER COM
p
LICATIONS & 
EMERGENCIES
SPINAL CORD COMPRESSION
 
»
Complication of metastatic solid tumor, 
lymphoma, or plasma cell myeloma (formerly 
multiple myeloma).
 
»
Back pain is most common presenting symptom.
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»
Prompt diagnosis is essential because once a 
severe neurologic deficit develops, it is often 
irreversible.
 
»
Emergent treatment may prevent or potentially 
reverse paresis and urinary and bowel 
 
»
Cancers that cause spinal cord compression most commonly 
metastasize to the vertebral bodies, resulting in physical 
damage to the spinal cord from edema, hemorrhage, and 
pressure-induced ischemia to its vasculature. Persistent 
compression can result in irreversible changes to the myelin 
sheaths resulting in permanent neurologic impairment.
Prompt diagnosis and therapeutic intervention are 
essential, since the probability of reversing neurologic 
symptoms largely depends on the duration of symptoms. 
Patients who are treated promptly after symptoms appear 
may have partial or complete return of function and, 
depending on tumor sensitivity to specific treatment, may 
respond favorably to subsequent anticancer therapy.
 
»
Back pain at the level of the tumor mass occurs in over 80% 
of cases and may be aggravated by lying down, weight bear
-
ing, sneezing, or coughing; it usually precedes the develop
-
ment of neurologic symptoms or signs. Since involvement 
is usually epidural, a mixture of nerve root and spinal cord 
symptoms often develops. Progressive weakness and sen
-
sory changes commonly occur. Bowel and bladder symp
-
toms progressing to incontinence are late findings.
The initial findings of impending cord compression 
may be quite subtle, and there should be a high index of 
suspicion when back pain or weakness of the lower extrem
-
ities develops in a cancer patient.
B. Imaging
MRI is usually the initial imaging procedure of choice in a 
cancer patient with new-onset back pain. If the back pain 
symptom is nonspecific, a whole-body PET scan with 
18
F-2-deoxyglucose may be a useful screening procedure. 
Bone radiographs are neither sensitive nor specific for the 
evaluation of a cancer patient with back pain. When neu
-
rologic findings suggest spinal cord compression, an emer
-
gent MRI should be obtained; the MRI should survey the 
entire spine to define all areas of tumor involvement for 
treatment planning purposes.
 
»
Treatment
Patients with a known cancer diagnosis found to have epi
-
dural impingement of the spinal cord should be given cor
-
ticosteroids immediately. The initial dexamethasone dose is 
10–100 mg intravenously followed by 4–6 mg every 6 hours 
intravenously or orally. Patients without a known diagnosis 
of cancer should have emergent surgery to relieve the 
impingement and obtain a pathologic specimen; preopera
-
tive corticosteroids should not be given since they might 
induce a tumor response and compromise the pathology 
results. Patients with solid tumors who have a single area of 
compression and who are considered candidates for surgery 
are best treated first with surgical decompression followed 
by radiation therapy. Better outcomes (ie, improved ability 
to ambulate and improved bladder and bowel function) 
occur in patients who undergo surgery followed by radia
-
tion therapy than in those who receive radiation alone. If 
multiple vertebral body levels are involved with cancer, 
fractionated radiation therapy is the preferred treatment 
option. Corticosteroids are generally tapered toward the 
end of radiation therapy. A scoring system exists for 
patients presenting with spinal cord metastases to identify 
those with poor survival times who would be best managed 
with supportive care or single fraction palliative radiation.
George R et al. Interventions for the treatment of metastatic extra
-
dural spinal cord compression in adults. Cochrane Database 
Syst Rev. 2015 Sep 4;(9):CD006716. [PMID: 26337716]
Scott BJ. Neuro-oncologic emergencies. Semin Neurol. 
2015 Dec;35(6):675–82. [PMID: 26595868]
Sodji Q et al. Management of metastatic spinal cord compres
-

-
sion. South Med J. 2017 Sep;110(9):586–93. [PMID: 
28863223]
Spratt DE et al. An integrated multidisciplinary algorithm for the 
management of spinal metastases: an international Spine 
Oncology Consortium report. Lancet Oncol. 2017 Dec; 
18(12);e720–30. [PMID: 29208438]
MALIGNANT EFFUSIONS
 
»
Occur in pleural, pericardial, and peritoneal 
spaces.
 
»
Caused by direct neoplastic involvement of serous 
surface or obstruction of lymphatic drainage.
 
»
Half of undiagnosed effusions in patients not 
known to have cancer are malignant.
 
»
The development of an effusion in the pleural, pericardial, or 
peritoneal space may be the initial finding in a patient with 
cancer, or an effusion may appear during the course of disease 
progression. Direct involvement of the serous surface with 
tumor is the most frequent initiating cause of the accumula
-
tion of fluid. The most common malignancies causing pleural 
and pericardial effusions are lung and breast cancers; the 
most common malignancies associated with malignant asci
-
tes are ovarian, colorectal, stomach, and pancreatic cancers.
 
»
Patients with pleural and pericardial effusions complain of 
shortness of breath and orthopnea. Patients with ascites 
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complain of abdominal distention and discomfort. Cardiac 
tamponade causing pressure equalization in the chambers 
impairs both filling and cardiac output and can be life-
threatening. Signs of tamponade include tachycardia, muf
-
fled heart sounds, pulsus paradoxus, and hypotension. 
Signs of pleural effusions include decreased breath sounds, 
egophony, and percussion dullness.
Malignancy is confirmed as the cause of an effusion when 
analysis of the fluid specimen shows malignant cells in 
either the cytology or cell block specimen.
C. Imaging
The presence of effusions can be confirmed with radio
-
graphic studies or ultrasonography.
 
»
The differential diagnosis of a malignant exudative pleural 
or pericardial effusion includes nonmalignant processes, 
such as infection, pulmonary embolism, heart failure, and 
trauma.
The differential diagnosis of malignant ascites includes 
similar benign processes, such as heart failure, cirrhosis, 
peritonitis, and pancreatic ascites.
Bloody effusions are usually due to cancer, but a bloody 
pleural effusion can also be due to pulmonary embolism, 
trauma and, occasionally, infection. Chylous pleural or 
ascitic fluid is generally associated with obstruction of 
lymphatic drainage as might occur in lymphomas.
 
»
Treatment
In some cases, treatment of the underlying cancer with 
chemotherapy can cause regression of the effusions; how
-
ever, not uncommonly, the development of an effusion is 
an end-stage manifestation of the cancer. In this situation, 
decisions regarding management are in large part dictated 
by the patient’s symptoms and goals of care.
A. Pleural Effusion
A pleural effusion that is symptomatic may be managed 
initially with a 
large volume thoracentesis.
 With some 
patients, the effusion slowly reaccumulates, which allows 
for periodic thoracentesis when the patient becomes symp
-
tomatic. However, in many patients, the effusion reaccu
-
mulates quickly, causing rapid return of shortness of 
breath. For those patients, two other management options 
exist. 
Chest tube drainage followed by pleurodesis
 
involves placement of a chest tube that is connected to 
closed water seal drainage. After lung expansion is con
-
firmed on a chest radiograph, a sclerosing agent (such as 
talc slurry or doxycycline) is injected into the catheter. 
Patients should be premedicated with analgesics and 
placed in a variety of positions in order to distribute the 
agent throughout the pleural spaces. Occasionally, sponta
-
neous pleurodesis will occur with drainage ceasing and the 
chest tube can be removed. Pleurodesis will not be 
successful if the lung cannot be reexpanded. These patients 
are better managed with the second option of 
placement of 
an indwelling catheter
 that can be drained by a family 
member or a visiting nurse. This procedure may also be 
preferable for patients with short life expectancies or for 
those who do not respond to pleurodesis. Chest tube drain
-
age followed by pleurodesis or placement of an indwelling 
catheter have essentially equivalent outcomes in terms of 
cost, relief of symptoms, and other measures of quality of life.
B. Pericardial Effusion
Fluid may be removed by a needle aspiration or by place
-
ment of a catheter for more thorough drainage. As with 
pleural effusions, most pericardial effusions will reaccu
-
mulate. Management options for recurrent, symptomatic 
effusions include prolonged catheter drainage (for several 
days until drainage has decreased to 20–30 mL/day) or 
surgical intervention such as a pericardiotomy or 
pericardiectomy.
C. Malignant Ascites
Patients with malignant ascites not responsive to chemo
-
therapy are generally treated with repeated large-volume 
paracenteses. As the frequency of drainage to maintain 
comfort can compromise the patient’s quality of life, other 
alternatives include placement of a catheter or port so that

alternatives include placement of a catheter or port so that 
the patient, family member, or visiting nurse can drain fluid 
as needed at home. For patients with portal hypertension 
from large hepatic masses, diuretics (such as spironolac
-
tone 100 mg with furosemide 20–40 mg orally daily) may 
be useful to decrease the need for repeated paracentesis.
-
nelled peritoneal catheter placement for malignant ascites: a 
cost-minimization study. AJR Am J Roentgenol. 2015 Nov; 
Clive AO et al. Interventions for the management of malignant 
pleural effusions: a network meta-analysis. Cochrane Database 
Syst Rev. 2016 May 8;(5):CD010529. [PMID: 27155783]
Desai NR et al. Diagnosis and management of malignant pleural 
effusions: state of the art in 2017. J Thorac Dis. 2017 Sep; 
9(Suppl 10):S1111–22. [PMID: 29214068]
Virk SA et al. Systematic review of percutaneous interventions 
for malignant pericardial effusions. Heart. 2015 
Oct;101(20):1619–26. [PMID: 26180077]
 
»
Usually symptomatic and severe (15 mg/dL 
[3.75 mmol/L] or more).
 
»
Most common paraneoplastic endocrine 
syndrome; accounts for most inpatients with 
 
»
The neoplasm is clinically apparent in nearly all 
cases when hypercalcemia is detected.
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»
Hypercalcemia affects 20–30% of cancer patients at some 
point during their illness. The most common cancers causing 
hypercalcemia are myeloma, breast carcinoma, and NSCLC. 
Hypercalcemia is caused by one of three mechanisms: sys
-
temic effects of tumor-released proteins, direct osteolysis of 
bone by tumor, or vitamin D–mediated osteoabsorption.
 
»
Symptoms and signs of hypercalcemia can be subtle; more 
severe symptoms occur with higher levels of hypercalcemia 
and with a rapid rate at which the calcium level rises. Early 
symptoms typically include anorexia, nausea, fatigue, con
-
stipation, and polyuria; later findings may include muscu
-
lar weakness and hyporeflexia, confusion, psychosis, 
tremor, and lethargy.
Symptoms and signs are caused by free calcium; as calcium is 
bound by protein in the serum, the measured serum calcium 
will underestimate the free or ionized calcium in patients 
with low albumin levels. In the setting of hypoalbuminemia, 
the corrected serum calcium should be calculated by one of 
several available formulas (eg, corrected calcium = measured 
calcium – measured albumin + 4). Alternatively, the free ion
-
ized calcium can be measured. When the corrected serum 
calcium rises above 12 mg/dL (3 mmol/L), especially if the 
rise occurs rapidly, sudden death due to cardiac arrhythmia 
or asystole may occur. The presence of hypercalcemia does 
not invariably indicate a dismal prognosis, especially in 
patients with breast cancer, myeloma, or lymphoma.
In the absence of symptoms or signs of hypercalcemia, 
a laboratory finding of elevated serum calcium should be 
retested immediately to exclude the possibility of error.
C. ECG
Electrocardiography in hypercalcemia often shows a short
-
ening of the QT interval.
 
»
Treatment
Emergency management should begin with the initiation of 
intravenous fluids with 0.9% saline at 100–300 mL/h to 
ensure rehydration with brisk urinary output of the often 
volume-depleted patient. If kidney function is normal or 
only marginally impaired, a bisphosphonate should be 
given. Choices include pamidronate, 60–90 mg intrave
-
nously over 2–4 hours, zoledronic acid, 4 mg intravenously 
over 15 minutes, or ibandronate 2–4 mg intravenously over 
2 hours. Zoledronic acid is more potent than pamidronate 
and has the advantage of a shorter administration time as 
well as a longer duration of effect, but with repeated dosing, 
it is more often associated with the very uncommon but 
serious side effect of osteonecrosis of the jaw. Once hyper
-
calcemia is controlled, treatment directed at the cancer 
should be initiated if possible. However, hypercalcemia can 
occur in patients with cancers that are unresponsive to 
treatment. In the event that the hypercalcemia becomes 
refractory to repeated doses of bisphosphonates, other 
agents that can help control hypercalcemia (at least 
temporarily) include calcitonin and denosumab; corticoste
-
roids can be useful in patients with myeloma and lymphoma. 
Salmon calcitonin, 4–8 international units/kg given subcuta
-
neously or intramuscularly every 12 hours, can be used in 
patients with severe, symptomatic hypercalcemia; its onset of 
action is within hours but its hypocalcemic effect wanes in 
2–3 days. Denosumab, 120 mg given subcutaneously weekly 
for 4 weeks followed by monthly administration, is a choice 
for long-term management of bisphosphonate-refractory 
hypercalcemia or for patients with kidney dysfunction that 
precludes use of a bisphosphonate.
Goldner W . Cancer-related hypercalcemia. J Oncol Pract. 
2016 May;12(5):426–32. [PMID: 27170690]
Pi J et al. A review in the treatment of oncologic emergencies. 
 
J Oncol Pharm Pract. 2016 Aug;22(4):625–38. [PMID: 26447101]
HYPERURICEMIA & TUMOR LYSIS SYNDROME
 
»
Complication of treatment-associated tumor lysis

»
Complication of treatment-associated tumor lysis 
of hematologic and rapidly proliferating 
malignancies.
 
»
May be worsened by thiazide diuretics.
 
»
Rapid increase in serum uric acid can cause acute 
urate nephropathy from uric acid crystallization.
 
»
Reducing pre-chemotherapy serum uric acid is 
fundamental to preventing urate nephropathy.
 
»
Tumor lysis syndrome (TLS) is seen most commonly fol
-
lowing treatment of hematologic malignancies, such as 
acute lymphoblastic leukemia and Burkitt lymphoma. 
However, TLS can develop from any tumor highly sensitive 
to chemotherapy. TLS is caused by the massive release of 
cellular material including nucleic acids, proteins, phos
-
phorus, and potassium. If both the metabolism and excre
-
tion of these breakdown products are impaired, 
hyperuricemia, hyperphosphatemia, and hyperkalemia 
will develop abruptly. Acute kidney injury may then 
develop from the crystallization and deposition of uric acid 
and calcium phosphate within the renal tubules further 
exacerbating the hyperphosphatemia and hyperkalemia.
 
»
Symptoms of hyperphosphatemia include nausea and 
vomiting as well as seizures. Also, with high levels of phos
-
phorus, co-precipitation with calcium can cause renal 
tubule blockage, further exacerbating the kidney injury. 
Hyperkalemia, due to release of intracellular potassium 
and impaired kidney excretion, can cause arrhythmias and 
sudden death.
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»
Treatment
Prevention is the most important factor in the management 
of TLS. Aggressive hydration prior to initiation of chemo
-
therapy as well as during and after completion of the chemo
-
therapy helps keep urine flowing and facilitates excretion of 
uric acid and phosphorus. In addition, for patients at moder
-
ate risk for developing TLS, eg, those with intermediate-
grade lymphomas and acute leukemias, allopurinol should 
be given before starting chemotherapy at an oral dose of 
100 mg/m
2
 every 8 hours (maximum 800 mg/day) with dose 
reductions for impaired kidney function. Rasburicase 
0.1–0.2 mg/kg/day is given intravenously for 1–7 days to 
patients at high risk for developing TLS, eg, those with high-
grade lymphomas or acute leukemias with markedly ele
-
vated white blood cell counts (acute myeloid leukemia, white 
blood cell count greater than 50,000/mcL [50,000/10
9
/L]; 
acute lymphoblastic leukemia, white blood cell count greater 
than 100,000/mcL [100,000/10
9
/L]; or chronic lymphocytic 
leukemia with large lymph nodes [10 cm or larger] or nodes 
5 cm or larger accompanied by white blood cell counts 
greater than 25,000/mcL [25,000/10
9
/L] and treated with 
venetoclax; or in any patient in whom hyperuricemia devel
-
ops despite treatment with allopurinol). Rasburicase cannot 
be given to patients with known glucose 6-phosphate dehy
-
drogenase (G6PD) deficiency nor can it be given to pregnant 
or lactating women. Systemic bicarbonate infusions to alka
-
linize the urine is not routinely recommended unless there is 
accompanying metabolic acidosis. In addition to the hyper
-
uricemia, laboratory values should be monitored following 
initiation of chemotherapy; elevated potassium or phospho
-
rus levels need to be promptly managed.
 
»
Should urinary output drop, serum creatinine or potas
-
sium levels rise, or hyperphosphatemia persist, a nephrolo
-
gist should be immediately consulted to evaluate the need 
for dialysis.
Howard SC et al. Tumor lysis syndrome in the era of novel and 
targeted agents in patients with hematologic malignancies: a 
systematic review. Ann Hematol. 2016 Mar;95(4):563–73. 
[PMID: 26758269]
Chapters 30 and 31 provide more detailed discussions of 
infections in the immunocompromised patient.
 
»
In patients with neutropenia, infection is a medical 
 
»
Although sometimes attributable to other causes, 
the presence of fever, defined as a single tempera
-
ture greater than 38.3
°
C (101
°
F) or a temperature 
of greater than 38
°
C (100.4
°
F) for longer than 
 
1 hour, must be assumed to be due to an infection.
 
»
Many patients with disseminated neoplasms have increased 
susceptibility to infection. In some patients, this results from 
impaired defense mechanisms (eg, acute leukemia, Hodgkin 
lymphoma, plasma cell myeloma, chronic lymphocytic 
leukemia); in others, it results from the myelosuppressive 
and immunosuppressive effects of cancer chemotherapy or a 
combination of these factors. Complicating impaired defense 
mechanisms are the frequent presence of indwelling cathe
-
ters, impaired mucosal surfaces, and colonization with more 
virulent hospital-acquired pathogens.
The source of a neutropenic febrile episode is deter
-
mined in about 30% of cases through blood, urine, or 
sputum cultures. The bacterial organisms accounting for 
the majority of infections in cancer patients include gram-
positive bacteria (coagulase-negative 
Staphylococcus, 
Staphylococcus aureus, Streptococcus pneumoniae, Coryne
-
bacterium,
 and streptococci) and gram-negative bacteria 
(
Escherichia coli, Klebsiella, Pseudomonas, Enterobacter
). 
Gram-positive organism infections are more common, but 
gram-negative infections are more serious and life-
threatening. The risk of bacterial infections rises when the 
neutrophil count is below 500/mcL (0.5 × 10
9
/L); the risk

9
/L); the risk 
markedly increases when the count falls below 100/mcL 
(0.1 × 10
9
/L) or when there is a prolonged duration of neu
-
tropenia, typically greater than 7 days.
 
»
A thorough physical examination should be performed. 
Routine DREs are generally avoided unless symptoms sug
-
gest a rectal abscess or prostatitis. If a DRE is necessary, 
antibiotics should be administered first. Appropriate cultures 
(eg, blood, sputum, urine and, if indicated, cerebrospinal 
fluid) should always be obtained. Two sets of blood cultures 
should be drawn before starting antibiotics; if the patient has 
an indwelling catheter, one of the cultures should be drawn 
from the line. A chest radiograph should also be obtained.
 
»
Treatment
Empiric antibiotic therapy needs to be initiated within 
 
1 hour of presentation and following the collection of 
blood cultures in the febrile, neutropenic patient. The 
choice of antibiotics depends on a number of different fac
-
tors including the patient’s clinical status and any localizing 
source of infection. If the patient is clinically well, mono
-
therapy with an intravenous beta-lactam with anti-
 activity (cefepime, ceftazidime, imipenem/
cilastatin, piperacillin/tazobactam) should be started (see 
Infections in the Immunocompromised Patient, 
Chapter 30). If the patient is clinically ill with hypotension 
or hypoxia, an intravenous aminoglycoside or fluoroqui
-
nolone should be added for “double” gram-negative bacte
-
ria coverage. If there is a strong suspicion of a gram-positive 
organism, such as from 
S aureus
 catheter infection, intrave
-
nous vancomycin can be given empirically. Low-risk 
patients may be treated with oral antibiotics and even in 
the outpatient setting. The Infectious Diseases Society of 
America (IDSA) has published recommendations for such 
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antibiotic use. These patients must have an expected neu
-
tropenic timeframe of 7 days or less and have no comor
-
bidities or signs of hemodynamic instability, gastrointestinal 
symptoms, altered mental status, pulmonary problems 
(infiltrate, hypoxia, or underlying chronic obstructive pul
-
monary disease), or liver or kidney disease or impairment. 
A validated risk index, such as the Multinational Associa
-
tion for Supportive Care in Cancer (MASCC) score, may be 
used to assess a patient for appropriateness of outpatient 
management. If a patient is to be treated as an outpatient, he 
or she must also have good support at home and easy access 
to returning to the hospital if the clinical status worsens.
Antibiotics should be continued until the neutrophil 
count is rising and greater than 500/mcL (0.5 × 10
9
/L) for 
at least 1 day and the patient has been afebrile for 2 days. If 
an organism is identified through the cultures, the antibiot
-
ics should be adjusted to the antibiotic sensitivities of the 
isolate; treatment should be continued for the appropriate 
period of time and at least until the neutrophil count recov
-
ers and fever resolves.
For the neutropenic patient who is persistently febrile 
despite broad-spectrum antibiotics, an empiric antifungal 
drug should be added (amphotericin B, caspofungin, itra
-
conazole, voriconazole, or liposomal amphotericin B).
Krzyzanowska MK et al. Approach to evaluation of fever in 
ambulatory cancer patients receiving chemotherapy: a sys
-
tematic review. Cancer Treat Rev. 2016 Dec;51:35–45. [PMID: 
27842279]
Table 39–13.
 
Commonly used supportive care agents.
1
Agent
Usual Dose
Allopurinol (Xyloprim)
Prevent hyperuricemia from 
tumor lysis syndrome
600–800 mg/day orally
Delayed: rash
Dexrazoxane (Zinecard)
Prevent cardiomyopathy 
 
secondary to doxorubicin; 
anthracycline-induced 
 
injection site extravasation
10 times the doxorubicin dose 
 
intravenously before doxorubicin; 
1000 mg/m
2
 intravenously on days 
 
1 and 2, then 500 mg/m
2
 
intravenously on day 3
Delayed: myelosuppression, 
 
elevated transaminases
Leucovorin
Rescue after high-dose 
 
methotrexate; in combination 
with fluorouracil for colon 
cancer
10 mg/m
2
 intravenously or orally 
 
every 6 hours; 20 mg/m
2
 or 
 
200–500 mg/m
2
before fluorouracil; various doses
Acute: nausea, vomiting, 
 
diarrhea
Delayed: stomatitis, fatigue
Levoleucovorin (Fusilev)
 
cancer
7.5 mg intravenously every 6 hours for 
10 doses; 100 mg/m
2
before fluorouracil
Delayed: stomatitis, diarrhea
Mesna (Mesnex)
Prevent ifosfamide-induced 
 
hemorrhagic cystitis
20% of ifosfamide dose 
 
intravenously at 0, 4, and 8 hours; 
Delayed: fatigue
(
continued
)
 
º
p
RIMARY CANCER TREATMENT
SYSTEMIC CANCER THERAPY
Detailed guidelines from the NCCN for cancer treatment 
can be found at www.nccn.org.
Use of cytotoxic drugs, hormones, antihormones, and 
biologic agents has become a highly specialized and increas
-
ingly effective means of treating cancer, with therapy admin
-
istered and monitored by a medical oncologist or hematologist. 
Selection of specific drugs or protocols for various types of 
cancer is usually based on results of clinical trials. Increas
-
ingly, newer agents are being identified that target specific 
molecular pathways. Y et both initial and acquired drug resis
-
tance remains a challenge. Described mechanisms of drug 
resistance include impaired membrane transport of drugs,

-
resistance include impaired membrane transport of drugs, 
enhanced drug metabolism, mutated target proteins, and 
blockage of apoptosis due to mutations in cellular proteins 
(see Table 39–2 for suggested agents for various cancers).
TOXICITY & DOSE MODIFICATION OF 
CHEMOTHERAPEUTIC AGENTS
Use of chemotherapy to treat cancer is generally guided by 
results from clinical trials in individual tumor types. The 
complexity of treating cancer has increased over the last 
decade as more drugs, including those with novel mecha
-
nisms of action, have been approved by the US Food and 
Drug Administration (FDA) and introduced into general 
practice. Drug side effects and toxicities must be anticipated 
and carefully monitored. The short- and long-term toxicities 
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1
Agent
Usual Dose
Palifermin (Kepivance)
Prevent mucositis following 
60 mcg/kg/day intravenously for 3 days 
before and 3 days after 
Delayed: rash, fever, elevated 
serum amylase, erythema, 
edema
Pilocarpine (Salagen)
Radiation-induced xerostomia
5–10 mg orally three times a day
Acute: flushing, sweating, 
 
nausea, dizziness
Delayed: increased urinary 
 
frequency, rhinitis
Radium (Ra)-223 dichloride 
(Xofigo)
Symptomatic bone metastases
50 kilobecquerel/kg 
 
(1.35 microCurie/kg) 
 
intravenously every 4 weeks for 
 
6 cycles
 
diarrhea, peripheral edema
Rasburicase (Elitek)
3–6 mg intravenously once
Acute: hypersensitivity, 
nausea, vomiting, diarrhea, 
fever, headache
Delayed: rash, peripheral 
edema
Bone-Modifying Agents
Denosumab (Xgeva)
Osteolytic bone metastasis
120 mg subcutaneously every 
 
4 weeks
Delayed: hypocalcemia, 
 
hypophosphatemia, fatigue, 
osteonecrosis of the jaw
Pamidronate (Aredia)
Osteolytic bone metastasis, 
hypercalcemia of malignancy
90 mg intravenously every 
 
3–4 weeks; 60–90 mg 
 
intravenously, may repeat after 
 
7 days
Delayed: dyspnea, arthralgia, 
bone pain, osteonecrosis of 
the jaw, nephrotoxicity, 
hypocalcemia
Zoledronic acid (Zometa)
4 mg intravenously every 3–4 weeks; 
 
4 mg intravenously once, may repeat 
after 7 days
Growth Factors
Darbepoetin alfa (Aranesp)
Chemotherapy-induced anemia
2.25 mcg/kg subcutaneously weekly; 
 
500 mcg subcutaneously every 
 
3 weeks
Epoetin alfa (Epogen, Procrit)
40,000 units subcutaneously once 
weekly; 150 units/kg subcutaneously 
three times a week
Delayed: hypertension, 
thromboembolic events, 
increased risk of tumor 
progression or recurrence
Filgrastim (Neupogen)
Febrile neutropenia prophylaxis, 
mobilization of peripheral 
stem cells
5–10 mcg/kg/day subcutaneously or 
intravenously once daily, treat past 
nadir
Delayed: bone pain
Pegfilgrastim (Neulasta)
Febrile neutropenia prophylaxis
6 mg subcutaneously once per 
 
chemotherapy cycle
Sargramostim (Leukine)
Myeloid reconstitution following 
bone marrow transplant, 
blood stem cells
250 mcg/m
2
 intravenously daily until 
the absolute neutrophil count is 
 
> 1500 cells/mcL for 3 consecutive 
days
Acute: fever, rash, pruritus, 
 
injection site reaction, 
dyspnea
Delayed: asthenia, bone pain, 
mucositis, edema, 
arrhythmia
1
For amifostine, samarium, strontium, filgrastim-sndz, and tbo-filgrastim, see Table 39–13 in 
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of individual drugs are listed in Tables 39–3 and 39–13. 
Decisions on dose modifications for toxicities should be 
guided by the intent of therapy. In the palliative setting where 
the aim of therapy is to improve symptoms and quality of life, 
lowering doses to minimize toxicity is commonly done. 
However, when the goal of treatment is cure, dosing frequency 
and intensity should be maintained whenever possible.
A CBC including a differential count, with absolute neutro
-
phil count and platelet count, and liver and kidney tests should 
be obtained before the initiation of chemotherapy. In patients 
with normal CBCs as well as normal liver and kidney function, 
drugs are started at their full dose. When the intent of chemo
-
therapy is cure, including treatment in the adjuvant setting, 
every attempt should be made to schedule chemotherapy on 
time and at full dose. A CBC with differential may be checked at 
mid cycle (to determine the nadir of the absolute neutrophil and 
platelet counts), and liver and kidney function tests should be 
obtained immediately before the next cycle of chemotherapy.
Dose reductions may be necessary for patients with 
impaired kidney or liver function depending on the clear
-
ance mechanism of the drug. For patients receiving chemo
-
therapy for palliation, bone marrow toxicity can be managed 
with dose reductions or delaying the next treatment cycle. 
A schema for dose modification is shown in Table 39–14.
1. Bone Marrow Toxicity
A. Neutropenia
Granulocyte colony-stimulating factor (G-CSF), given as 
either daily subcutaneous injections (eg, filgrastim, 300 mcg 
or 480 mcg) or as a one-time dose (pegfilgrastim, 6 mg) 
beginning 24 hours after cytotoxic chemotherapy is com
-
pleted, reduces the duration and severity of granulocytope
-
nia following cytotoxic chemotherapy (Table 39–13). The 
American Society of Clinical Oncology and NCCN guide
-
lines recommend primary prophylaxis with G-CSF when 
there is at least a 20% risk of febrile neutropenia or when age, 
medical history, and disease characteristics put the patient at 
high risk for complications related to myelosuppression.
B. Anemia
Erythropoiesis-stimulating agents (ESAs) ameliorate the 
anemia and its associated symptoms caused by cancer che
-
motherapy but these drugs have untoward effects, including 
an increased risk of thromboembolism, and possibly a 
decreased survival due to cancer-related deaths as well as a 
shortened time to tumor progression. The NCCN recom
-
mends that these drugs should not be used when the intent 
Table 39–14.
 
A common scheme for dose modification 
of cancer chemotherapeutic agents.
Granulocyte 
p
latelet Count 
 
(/mcL)
Suggested Drug 
Dosage (% of Full 
Dose)
> 2000
> 100,000
100%
1000–2000
75,000–100,000
50%
< 2000
< 50,000
0%
of chemotherapy is curative. Administration of red blood 
cell transfusions is the alternative to managing symptom
-
atic anemia in such patients.
ESAs can be an option in cancer patients with symptom
-
atic anemia undergoing palliative treatment; patient prefer
-
ence is important in determining when to use ESAs or 
transfusions. When using ESAs, treatment should not be initi
-
ated until the hemoglobin is less than 10 g/dL (100 g/L) and 
the ESA held when the hemoglobin is greater than 12 g/dL 
(120 g/L). Epoetin alfa can be given subcutaneously at a dose 
of 40,000 units weekly or 150 units/kg three times weekly with 
a target hemoglobin of 11–12 g/dL (110–120 g/L). Darbepoetin 
alfa is given subcutaneously at a dose of 300–500 mcg every 
3 weeks or 2.25 mcg weekly with the same target hemoglobin 
(see Table 39–13). To have maximum therapeutic effect, 
patients need to be iron replete. Uncontrolled hypertension is 
a contraindication to the use of ESAs; blood pressure must be 
controlled prior to initiation of this therapy.
C. Thrombocytopenia
Drug management of chemotherapy-induced thrombocyto
-

-
penia is more limited. The only available drug, oprelvekin or 
recombinant interleukin-11, has modest activity in improv
-
ing chemotherapy-related thrombocytopenia; however, it is 
rarely used due to the side effects of fluid retention, heart 
failure, and arrhythmias. Two drugs that activate the throm
-
bopoietin receptor, romiplostim and eltrombopag, are FDA 
approved for use in idiopathic thrombocytopenia; while 
these agents have been used in selected cases of refractory 
chemotherapy-related thrombocytopenia with some reports 
of success, trials to date have not demonstrated efficacy in 
patients with chemotherapy-induced thrombocytopenia 
and neither agent is FDA approved for this indication.
2. Chemotherapy-Induced Nausea & Vomiting
A number of cytotoxic anticancer drugs can induce nausea 
and vomiting, which can be the most anticipated and stressful 
side effects for patients. Chemotherapy-induced nausea and 
vomiting is mediated in part by the stimulation of at least two 
central nervous system receptors, 5-hydroxytryptamine sub
-
type 3 (5HT
3
) and neurokinin subtype 1 (NK
1
). Chemotherapy-
induced nausea and vomiting can be anticipatory, occurring 
even before chemotherapy administration; acute, occurring 
within minutes to hours of chemotherapy administration; or 
delayed until the second day and lasting up to 7 days. Chemo
-
therapy drugs are classified into high, moderate, low, and 
minimal likelihoods of causing emesis (90%, 30–90%, 
10–30%, less than 10%, respectively). Highly emetogenic 
chemotherapy drugs include carmustine, cisplatin, cyclo
-
phosphamide (at doses over 1.5 g/m
2
), dacarbazine, mechlor
-
ethamine, and streptozocin, or a combination of regularly 
dosed anthracyclines and cyclophosphamide. Moderately 
emetogenic chemotherapy drugs include alemtuzumab, 
azacitadine, bendamustine, carboplatin, clofarabine, crizo
-
tinib, cyclophosphamide, cytarabine, daunomycin, doxorubi
-
cin, epirubicin, idarubicin, ifosfamide, irinotecan, mitotane, 
oxaliplatin, romidepsin, temozolomide, and vismodegib. Low 
emetogenic drugs include bortezomib, brentuximab, 
capecitabine, cabozantinib, dabrafenib, dasatinib, docetaxel, 
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erlotinib, etoposide, fludarabine, fluorouracil, gemcitabine, 
hydroxyurea, ipilimumab, ixabepilone, lenalidomide, metho
-
trexate, mitomycin, mitoxantrone, omacetaxine, paclitaxel, 
pemetrexed, pomalidomide, ponatinib, temsirolimus, tra
-
metinib, and topotecan. Drugs with minimal risk of emesis 
include bevacizumab, bleomycin, cetuximab, cladribine, 
decitabine, fludarabine, nivolumab, panitumumab, pembroli
-
zumab, rituximab, temsirolimus, trastuzumab, vinblastine, 
vincristine, and vinorelbine.
Major advances have occurred in the development of 
highly effective antiemetic drugs. Antagonists to the 5HT
3
-
receptor include ondansetron, granisetron, dolasetron, and 
palonosetron, as well as tropisetron and ramosetron 
(neither yet available in the United States). Ondansetron 
can be given either intravenously (8 mg or 0.15 mg/kg) or 
orally (24 mg once before highly emetogenic chemother
-
apy, 8 mg twice daily for moderately emetogenic chemo
-
therapy). Doses of 8 mg can be repeated parenterally or 
orally every 8 hours. Dosing of granisetron is 1 mg or 
0.01 mg/kg intravenously or 1–2 mg orally. Dolasetron is 
given once as an oral 100-mg dose. Palonosetron, a long-
acting 5HT
3
 with high affinity for the 5HT
3
-receptor, is 
given once at a dose of 0.25 mg intravenously, both for 
acute and delayed emesis. Where available, tropisetron is 
given at a dose of 5 mg either orally or intravenously and 
ramosetron, as a one-time 300-mcg dose intravenously. The 
efficacy of the 5HT
3
-blockers is improved by adding dexa
-
methasone 10 mg once intravenously, then 4 mg orally or 
intravenously every 6 hours. As a class of drugs, the 5HT
3
-
receptor antagonists have the potential to cause electrocar
-
diogram changes, including QT prolongation. Before using 
these agents, hypokalemia or hypomagnesemia should be 
corrected. In addition, clinicians should be cautious when 
using these agents in patients who are elderly, who have 
preexisting bradyarrhythmias or heart failure, or who are 
taking medications known to prolong the QT interval.
Aprepitant, fosaprepitant, and rolapitant are antagonists 
to the NK
1
 receptor. Aprepitant is given as a 125-mg oral 
dose followed by an 80-mg dose on the second and third 
day along with a 5HT
3
-receptor antagonist (such as ondan
-
setron or granisetron) and dexamethasone to increase its 
immediate and delayed protective effect for highly emeto
-
genic chemotherapy. Fosaprepitant, the intravenous for
-
mulation of aprepitant, can be given at a dose of 115 mg if 
followed by 2 days of aprepitant or at a dose of 150 mg if 
given alone. Rolapitant, a potent selective NK
1
 receptor 
antagonist, has a 7-day half-life; it is given as a one-time 
oral dose of 180 mg 1–2 hours before the start of moder
-
ately or highly emetogenic chemotherapy.
The first antiemetic combination treatment netupitant/
palonosetron (NEPA) is a single-dose capsule consisting of a 
combination of the new N-receptor antagonist, netupitant 
300 mg, and the 5HT
3
-receptor antagonist, palonosetron 5 mg.
Thus, for highly emetogenic chemotherapy (eg, cisplatin), 
patients should be offered a four-drug regimen (a 5HT
3
-
antagonist, dexamethasone, neurokinin-1 receptor antago
-
nist, and olanzapine), all given on the first day (and if used, 
aprepitant given again on the second and third days with 
decadron and olanzapine continued on days 2–4. For mod
-
erately emetogenic chemotherapy, standard regimens 
include both three-drug regimens (an NK
1
 receptor antago
-
nist, a 5HT
3
-antagonist, and dexamethasone) or a two-drug 
combination (5HT
3
-antagonist and dexamethasone). 
Palonosetron is the preferred 5HT
3
-blocker due to its greater 
affinity for the 5HT
3
-receptor and its longer half-life. For low 
emetogenic chemotherapy drugs, a single agent such as a 
5HT
3
-antagonist or prochlorperazine or dexamethasone can 
be given. A 25-mg suppository form of prochlorperazine

5HT
3
be given. A 25-mg suppository form of prochlorperazine 
may be used for patients unable to swallow oral medications. 
Other medications that are helpful for anticipatory or refrac
-
tory nausea and vomiting are olanzapine, 10 mg given orally 
once, or lorazepam, 0.5–1.0 mg given orally every 6–8 hours.
The importance of treating chemotherapy-induced nau
-
sea and vomiting expectantly and aggressively beginning 
with the first course of chemotherapy cannot be overem
-
phasized. Patients being treated in the clinic setting should 
always be given antiemetics for home use with written 
instructions as well as contact numbers to call for advice.
3. Gastrointestinal Toxicity
Untoward effects of cancer chemotherapy include damage to 
the more rapidly growing cells of the body such as the muco
-
sal lining from the mouth through the gastrointestinal tract. 
Oral symptoms range from mild mouth soreness to frank 
ulcerations. Not uncommonly, mouth ulcerations will have 
superimposed candida or herpes simplex infections. In addi
-
tion to receiving cytotoxic chemotherapy, a significant risk 
factor for development of oral mucositis is poor oral hygiene 
and existing caries or periodontal disease. Toxicity in the 
gastrointestinal tract usually manifests as diarrhea. 
Gastrointestinal symptoms can range from mild symptoms of 
loose stools to life-threatening diarrhea leading to dehydration 
and electrolyte imbalances. Drugs most commonly associated 
with causing mucositis in the mouth and the gastrointestinal 
tract are cytarabine, 5-fluorouracil, and methotrexate.
Patients undergoing treatment for head and neck can
-
cer with concurrent chemotherapy and radiation therapy 
have a very high risk of developing severe mucositis.
Preventive strategies for oral mucositis include pretreat
-
ment dental care, particularly for all head and neck cancer 
patients and any cancer patient with poor dental hygiene 
who will be receiving chemotherapy. For patients receiving 
fluorouracil, simple measures such as ice chips in the 
mouth for 30 minutes during infusion can reduce the inci
-
dence and severity of mucositis. Once mucositis is encoun
-
tered, superimposed fungal infections should be treated 
with topical antifungal medications (oral nystatin mouth 
suspensions, or clotrimazole troches) or systemic therapy 
(fluconazole 100–400 mg orally daily). Suspected herpetic 
infections can be treated with acyclovir (up to 800 mg 
orally five times daily) or valacyclovir (1 g orally twice 
daily). Mucositis may also be managed with mouthwashes; 
it is also important to provide adequate pain medication.
Other strategies for prevention of oral mucositis 
include the use of the recombinant keratinocyte growth 
factor inhibitor, palifermin. Prophylaxis with intravenous 
palifermin (60 mcg/kg/day) for patients receiving high-
dose chemotherapy can reduce the incidence and duration 
of mucositis (Table 39–13).
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Diarrhea is most associated with fluorouracil, 
capecitabine, and irinotecan as well as the tyrosine kinase 
inhibitors (dasatinib, imatinib, nilotinib, regorafenib, 
sorafenib, sunitinib) and epithelial growth factor inhibitors 
(cetuximab, erlotinib, panitumumab). Mild to moderate 
diarrhea can be managed with oral antidiarrheal medica
-
tion (loperamide, 4 mg initially followed by 2 mg every 
2–4 hours until bowel movements are formed). 
Occasionally, severe diarrhea will cause dehydration, elec
-
trolyte imbalances, and acute kidney injury; these patients 
require inpatient management with aggressive intravenous 
hydration and electrolyte replacement. Octreotide, 
100–150 mcg subcutaneously three times daily, can be useful.
4. Skin Toxicity
Dermatologic complications from cancer chemotherapy 
can include hyperpigmentation (busulfan, hydroxyurea, 
liposomal doxorubicin), alopecia, photosensitivity, nail 
changes, acral erythema, and generalized rashes. Acral 
erythema (hand-foot syndrome), most commonly associ
-
ated with administration of capecitabine, fluorouracil, and 
liposomal doxorubicin, manifests as painful palms or soles 
accompanied by erythema, progressing to blistering, des
-
quamation, and ulceration in its worst forms. Strategies for 
prevention of acral erythema include oral pyridoxine, 
200 mg daily, and applying cold packs to the extremities 
during chemotherapy administration. Agents targeting the 
epidermal growth factor pathway can cause an acne-like 
rash; the development of the rash may identify those who 
will respond to the drug. Inhibitors of the tyrosine kinase 
pathway are also associated with a high incidence of der
-
matologic complications, such as rash and acral erythema.
5. Miscellaneous Drug-Specific Toxicities
The toxicities of individual drugs are summarized in 
Tables 39–3 and 39–13; however, several of these warrant 
additional mention, since they occur with frequently admin
-
istered agents, and special measures are often indicated.
A. Hemorrhagic Cystitis Induced by 
Cyclophosphamide or Ifosfamide
Patients receiving cyclophosphamide must maintain a high 
fluid intake prior to and following the administration of the 
drug and be counseled to empty their bladders frequently. 
Early symptoms suggesting bladder toxicity include dysuria 
and increased frequency of urination. Should microscopic 
hematuria develop, it is advisable to stop the drug temporar
-
ily or switch to a different alkylating agent, to increase fluid 
intake, and to administer a urinary analgesic such as 
phenazopyridine. The neutralizing agent, mesna, can be 
used for patients in whom cystitis develops. With severe 
cystitis, large segments of bladder mucosa may be shed, 
resulting in prolonged gross hematuria. Such patients should 
be observed for signs of urinary obstruction and may 
require cystoscopy for removal of obstructing blood clots. 
The cyclophosphamide analog ifosfamide can cause severe 
hemorrhagic cystitis when used alone. However, when its 
use is followed by a series of doses of the neutralizing agent 
mesna, bladder toxicity can be prevented (Table 39–13).
B. Neuropathy Due to Vinca Alkaloids and Other 
Chemotherapy Drugs
Neuropathy is caused by a number of different chemo
-
therapy drugs, the most common being vincristine. The 
peripheral neuropathy can be sensory, motor, autonomic, 
or a combination of these types. In its mildest form, it con
-
sists of paresthesias of the fingers and toes. Occasionally, 
acute jaw or throat pain can develop as a form of trigeminal 
or glossopharyngeal neuralgia. With continued vincristine 
therapy, the paresthesias extend to the proximal interpha
-
langeal joints, hyporeflexia appears in the lower extremi
-
ties, and significant weakness can develop. Other drugs in 
the vinca alkaloid class as well as the taxane drugs 
(docetaxel and paclitaxel) and agents to treat myeloma 
(bortezomib and thalidomide) cause similar toxicity. The

(bortezomib and thalidomide) cause similar toxicity. The 
presence of neurologic symptoms is not in itself a reason to 
stop therapy; the severity of the symptoms must be bal
-
anced against the goals of therapy. Usually, though, the 
development of moderate to severe paresthesias or motor 
impairment results in the decision to discontinue the drug.
Constipation is the most common symptom of auto
-
nomic neuropathy associated with the vinca alkaloids. 
Patients receiving these drugs should be started on mild 
cathartics and other agents (Table 15–4); otherwise, severe 
impaction may result from an atonic bowel. More serious 
autonomic involvement can lead to acute intestinal obstruc
-
tion with signs indistinguishable from those of an acute 
abdomen. Bladder neuropathies are uncommon but may be 
severe. These two complications are absolute contraindica
-
tions to continued vincristine therapy.
C. Methotrexate Toxicity
Methotrexate, a folate antagonist, is a commonly used com
-
ponent of regimens to treat patients with leptomeningeal 
disease, acute lymphoblastic leukemia, and sarcomas. 
Methotrexate is almost entirely eliminated by the kidney. 
Methotrexate toxicity affects cells with rapid turnover, includ
-
ing the bone marrow and mucosa resulting in myelosuppres
-
sion and mucositis. Methotrexate can also damage the liver 
and kidney manifesting as elevated serum liver enzymes and 
creatinine. High-dose methotrexate, usually defined as a dose 
of 500 mg/m
2
 or more given over 4–36 hours, would be lethal 
without “rescue” of the normal tissues. Leucovorin, a form of 
folate, will reverse the toxic effects of methotrexate and is 
given until serum methotrexate levels are in the safe range 
(less than 0.05 mmol/L). It is crucial that high-dose metho
-
trexate and leucovorin are given precisely according to proto
-
col as deviations of the timing of methotrexate delivery or 
delay in rescue can result in patient death. The dose used in 
intrathecal therapy is 12 mg. Lower doses of methotrexate can 
be problematic in patients with kidney disease who cannot 
clear the drug normally or in patients with effusions in which 
the drug distributes itself and leaks out continuously, exposing 
normal tissue to the drug. In a patient with kidney disease or 
an effusion, prolonged rescue with leucovorin is necessary.
Vigorous hydration and bicarbonate loading can help 
prevent crystallization of high-dose methotrexate in the 
renal tubular epithelium and consequent nephrotoxicity. 
Daily monitoring of the serum creatinine is mandatory. 
 
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 CMDT 2019
If possible, drugs impairing methotrexate excretion, such 
as aspirin, nonsteroidal anti-inflammatory drugs, amioda
-
rone, omeprazole, penicillin, phenytoin, and sulfa, should 
be stopped before methotrexate administration.
D. Cardiotoxicity From Anthracyclines and 
 
Other Chemotherapy Drugs
A number of cancer chemotherapy drugs are associated with 
cardiovascular complications including traditional drugs 
such as anthracyclines as well as new targeted agents. The 
anthracycline drugs, including doxorubicin, daunomycin, 
epirubicin, and idarubicin, can produce acute (during 
administration), subacute (days to months following admin
-
istration), and delayed (years following administration) car
-
diac toxicity. The most feared complication is the delayed 
development of heart failure. Risk factors for this debilitating 
toxicity include the anthracycline cumulative dose, age over 
70, previous or concurrent irradiation of the chest, preexist
-
ing cardiac disease, and concurrent administration of che
-
motherapy drugs such as trastuzumab. The problem is 
greatest with doxorubicin because it is the most commonly 
administered anthracycline due to its major role in the treat
-
ment of lymphomas, sarcomas, breast cancer, and certain 
other solid tumors. Patients receiving anthracyclines should 
have a baseline multiple-gated radionuclide cardiac scan 
(MUGA) to calculate the left ventricular-ejection fraction 
(LVEF). If the LVEF is greater than 50%, anthracyclines can 
be administered; if the LVEF is less than 30%, these drugs 
should not be given. For patients with intermediate values, 
anthracyclines can be cautiously given, if necessary, at lower 
doses with LVEF monitoring between doses. Changes in 
cardiac dynamics occur in most patients by the time they 
have received a total dose of 300 mg/m
2
 of doxorubicin. In 
general, patients should not receive doses in excess of 
450 mg/m
2
; the dose should be lower if prior chest radio
-
therapy has been given. The appearance of a high resting 
pulse may herald the appearance of overt cardiac toxicity. 
Unfortunately, toxicity may be irreversible and frequently 
fatal at total dosage levels above 550 mg/m
2
. At lower doses 
(eg, 350 mg/m
2
), the symptoms and signs of cardiac failure 
generally respond well to medical therapy and discontinua
-
tion of the anthracycline. Doxorubicin and daunomycin have 
been formulated as liposomal products; these drugs, approved 
for use in patients with Kaposi sarcoma and sometimes in 
other cancers as a substitute for the conventional anthracy
-
clines, appear to have minimal potential for cardiac toxicity.
As molecular mechanisms for cancer have been increas
-
ingly delineated, therapies have been developed that better 
target these mechanisms. Therapies targeting oncogenesis 
pathways include (1) HER2 inhibitors (lapatinib, pertu
-
zumab, trastuzumab); (2) VEGF signaling pathway inhibi
-
tors (afilbercept, axitinib, bevacizumab, carozantinib, 
lenvatinib, pazopanib, ramucirumab, regorafenib, 
sorafenib, sunitinib, vandertanib); (3) multitargeted tyro
-
sine kinase inhibitors (dasatinib, nilotinib, ponatinib); 
(4) proteasome inhibitors (bortezomib, carfilzomib); and 
(5) immune checkpoint inhibitors (ipilimumab, nivolumab, 
pembrolizumab). Many of the pathways targeted by these 
drugs share a common biologic pathway in cardiac tissue. 
Untoward cardiac events are being increasingly reported 
with these agents, including arrhythmias, cardiac ischemia, 
myocarditis, thrombosis, and heart failure. It is important 
to carefully monitor patients on these drugs and aggres
-
sively manage any modifiable cardiac risk factors (smoking, 
hyperlipidemia, diabetes mellitus, sedentary lifestyle).
E. Cisplatin Nephrotoxicity and Neurotoxicity
Cisplatin is effective in treating testicular, bladder, head and 
neck, lung, and ovarian cancers. With cisplatin, the serious

neck, lung, and ovarian cancers. With cisplatin, the serious 
side effects of nephrotoxicity and neurotoxicity must be 
anticipated and aggressively managed. Patients must be 
vigorously hydrated prior to, during, and after cisplatin 
administration. Both kidney function and electrolytes must 
be monitored. Low serum magnesium, potassium, and 
sodium levels can develop. The neurotoxicity is usually 
manifested as a peripheral neuropathy of mixed sensorimo
-
tor type and may be associated with painful paresthesias. 
Development of neuropathy typically occurs after cumula
-
tive doses of 300 mg/m
2
. Ototoxicity is a potentially serious 
manifestation of neurotoxicity and can progress to deafness. 
Amifostine, given intravenously at a dose of 910 mg/m
2
 
over 15 minutes prior to cisplatin, is used to protect against 
nephrotoxicity and neuropathy. Use of amifostine does 
not appear to compromise its antineoplastic effect. The 
second-generation platinum analog, carboplatin, is non-
nephrotoxic, although it is myelosuppressive. In the setting 
of preexisting kidney disease or neuropathy, carboplatin is 
occasionally substituted for cisplatin.
F. Bleomycin Toxicity
See online text at www.accessmedicine.com/cmdt.
PROGNOSIS
Patients receiving chemotherapy for curative intent will often 
tolerate side effects with the knowledge that the treatment 
may result in eradication of their cancer. Patients receiving 
therapy for palliative intent often have their therapy tailored 
to improve quality of life while minimizing major side effects. 
A valuable sign of clinical improvement is the general well-
being of the patient. Although general well-being is a combi
-
nation of subjective (possibly partly a placebo effect) and 
objective factors, it nonetheless serves as a sign of clinical 
improvement along with improved appetite and weight gain 
and increased “performance status” (eg, ambulatory versus 
bedridden). Evaluation of factors such as activity status 
enables the clinician to judge whether the net effect of 
chemotherapy is worthwhile palliation (see Chapter 5).
Jordan K et al. Recent developments in the prevention of 
chemotherapy-induced nausea and vomiting (CINV): a 
comprehensive review. Ann Oncol. 2015 Jun;26(6):1081–90. 
[PMID: 25755107]
Moslehi JJ. Cardiovascular toxic effects of targeted cancer thera
-
pies. N Engl J Med. 2016 Oct;375(15):1457–67. [PMID: 
27732808]
induced nausea and vomiting. N Engl J Med. 2016 Apr 7; 
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ACUTE INTERMITTENT PORPHYRIA
 
»
Unexplained abdominal crisis, generally in young 
women.
 
»
Acute peripheral or central nervous system 
dysfunction; recurrent psychiatric illnesses.
 
»
Hyponatremia.
 
»
Porphobilinogen in the urine during an attack.
 
»
Though there are several different types of porphyrias, the 
one with the most serious consequences and the one that 
usually presents in adulthood is acute intermittent porphyria 
(AIP), which is inherited as an autosomal dominant condi
-
tion, though it remains clinically silent in most patients who 
carry a mutation in 
HMBS
. Clinical illness usually develops 
in women. Symptoms begin in the teens or 20s, but onset can 
begin after menopause in rare cases. The disorder is caused 
by partial deficiency of hydroxymethylbilane synthase 
activity, leading to increased excretion of aminolevulinic 
acid and porphobilinogen in the urine. The diagnosis may 
be elusive if not specifically considered. The characteristic 
abdominal pain may be due to abnormalities in autonomic 
innervation in the gut. In contrast to other forms of por
-
phyria, cutaneous photosensitivity is absent in AIP . Attacks 
are precipitated by numerous factors, including drugs and 
intercurrent infections. Harmful and relatively safe drugs for 
use in treatment are listed in Table 40–1. Hyponatremia may 
be seen, due in part to inappropriate release of antidiuretic 
hormone, although gastrointestinal loss of sodium in some 
patients may be a contributing factor.
 
»
Patients show intermittent abdominal pain of varying 
severity, and in some instances it may so simulate acute 
abdomen as to lead to exploratory laparotomy. Because 
the origin of the abdominal pain is neurologic, there is an 
absence of fever and leukocytosis. Complete recovery 
between attacks is usual. Any part of the nervous system 
may be involved, with evidence for autonomic and 
peripheral neuropathy. Peripheral neuropathy may be 
symmetric or asymmetric and mild or profound; in the 
latter instance, it can even lead to quadriplegia with respi
-
ratory paralysis. Other central nervous system manifesta
-
tions include seizures, altered consciousness, psychosis, 
and abnormalities of the basal ganglia. Hyponatremia 
may further cause or exacerbate central nervous system 
Often there is profound hyponatremia. The diagnosis can 
be confirmed by demonstrating an increased amount of 
porphobilinogen in the urine during an acute attack. 
Freshly voided urine is of normal color but may turn dark 
upon standing in light and air.
Most families have different mutations in 
HMBS
 caus
-
ing AIP . Mutations can be detected in 90% of patients and 
used for presymptomatic and prenatal diagnosis.
 
»
Avoidance of factors known to precipitate attacks of AIP—
especially drugs—can reduce morbidity. Sulfonamides and 
barbiturates are the most common culprits; others are 
listed in Table 40–1 and on the internet (www.drugs-
porphyria.org). Starvation diets or prolonged fasting also 
cause attacks and so must be avoided. Hormonal changes 
during pregnancy can precipitate crises.
 
»
Treatment
Treatment with a high-carbohydrate diet diminishes the 
number of attacks in some patients and is a reasonable 
empiric gesture considering its benignity. Acute attacks 
may be life-threatening and require prompt diagnosis, 
withdrawal of the inciting agent (if possible), and treat
-
ment with analgesics and intravenous glucose in saline and 
hematin. A minimum of 300 g of carbohydrate per day 40
Reed E. Pyeritz, MD, PhD 
Genetic & Genomic 
Disorders
CMDT19_Ch40_p1681-p1689.indd   1681
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Chapter 40
1682
 CMDT 2019
should be provided orally or intravenously. Electrolyte bal
-
ance requires close attention. Hematin therapy should be 
undertaken with full recognition of adverse consequences, 
especially phlebitis and coagulopathy. The intravenous 
dosage is up to 4 mg/kg once or twice daily. Liver trans
-
plantation may provide an option for patients with disease 
poorly controlled by medical therapy.
 
»
•	
For management of severe abdominal pain, seizures, or 
•	
For preventive management when a patient with por
-
phyria contemplates pregnancy.
•	
For genetic counseling and molecular diagnosis.
 
»
The patient should be hospitalized for an acute attack when 
accompanied by mental status changes, seizure, or 
Bissell DM et al. Porphyria. N Engl J Med. 2017 Aug 31; 
377(9):862–72. [PMID: 28854095]
Table 40–1.
 
Some of the “unsafe” and “probably safe” 
drugs used in the treatment of acute porphyrias.
Unsafe
p
r
obably Safe
Alcohol
Clonidine
Dapsone
Ergots
Estrogens, synthetic
Food additives
Glutethimide
Ketamine
Meprobamate
Pentazocine
Phenytoin
Rifampin
Succinimides
Tolazamide
Aspirin
Atropine
Beta-adrenergic blockers
Chloral hydrate
Diazepam
Digoxin
Hyoscine
Ibuprofen
Imipramine
Insulin
Lithium
Naproxen
Opioid analgesics
Penicillin and derivatives
Procaine
Thiouracil
Fontanellas A et al. Emerging therapies for  acute intermittent 
porphyria. Expert Rev Mol Med. 2016 Nov 2;18:e17. [PMID: 
27804912]
Pischik E et al. An update of clinical management of acute inter
-
mittent porphyria. Appl Clin Genet. 2015 Sep 1;8:201–14. 
[PMID: 26366103]
Singal AK et al. Liver transplantation in the management of 
porphyria. Hepatology. 2014 Sep;60(3):1082–9. [PMID: 
24700519]
Stein PE et al. Acute intermittent porphyria: fatal complications 
of treatment. Clin Med. 2012 Jun;12(3):293–4. [PMID: 
22783787]
DOWN SYNDROME
 
»
Typical craniofacial features (flat occiput, epican
-
thal folds, large tongue).
 
»
Intellectual disability.
 
»
Congenital heart disease (eg, atrioventricular 
canal defects) in 50% of patients.
 
»
Alzheimer dementia in early-to-mid adulthood.
 
»
Three copies of chromosome 21 (trisomy 21) or 
a chromosome rearrangement that results in 
three copies of a region of the long arm of chro
-
mosome 21.
 
»
Nearly 0.5% of all human conceptions are trisomic for 
chromosome 21. Because of increased fetal mortality, 
birth incidence of Down syndrome is 1 per 700, but varies 
from 1 per 1000 in young mothers to more than three 
times as frequent in women of advanced maternal age. The 
presence of a fetus with Down syndrome can be detected 
in many pregnancies in the first or early second trimester 
through screening maternal serum for alpha-fetoprotein 
and other biomarkers (“multiple marker screening”) and 
by detecting increased nuchal thickness and underdevel
-
opment of the nasal bone on ultrasonography. Prenatal 
diagnosis with high sensitivity and specificity can be 
achieved by assaying fetal DNA that is circulating in 
maternal blood. The chance of bearing a child with Down 
syndrome increases exponentially with the age of the 
mother at conception and begins a marked rise after age 35. 
By age 45 years, the odds of having an affected child are as 
high as 1 in 40. The risk of other conditions associated 
with trisomy also increases, because of the predisposition 
of older oocytes to nondisjunction during meiosis. There 
is little risk of trisomy associated with increased paternal

is little risk of trisomy associated with increased paternal 
age. However, older men do have an increased risk of 
fathering a child with a new autosomal dominant 
condition. Because there are so many distinct conditions, 
though, the chance of fathering an offspring with any 
given one is extremely small.
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CMDT 2019
 
»
Down syndrome is usually diagnosed at birth on the basis 
of the typical craniofacial features, hypotonia, and single 
palmar crease. Several serious problems that may be evi
-
dent at birth or may develop early in childhood include 
duodenal atresia, congenital heart disease (especially atrio
-
ventricular canal defects), and hematologic malignancy. 
The intestinal and cardiac anomalies usually respond to 
surgery. A transient neonatal leukemia generally responds 
to conservative management. The incidences of both acute 
lymphoblastic and myeloid leukemias are increased in 
childhood. Intelligence varies across a wide spectrum. 
Many people with Down syndrome do well in sheltered 
workshops and group homes, but few achieve full indepen
-
dence in adulthood. Other frequent complications include 
atlanto-axial instability, celiac disease, frequent infections 
due to immune deficiency, and hypothyroidism. An 
Alzheimer-like dementia usually becomes evident in the 
fourth or fifth decade. Patients with Down syndrome who 
survive childhood and who develop dementia have a 
reduced life expectancy; on average, they live to about age 
55 years.
Cytogenomic analysis should always be performed—even 
though most patients will have simple trisomy for chromo
-
some 21—to detect unbalanced translocations; such 
patients may have a parent with a balanced translocation, 
and there will be a substantial recurrence risk of Down 
syndrome in future offspring of that parent and potentially 
that parent's relatives.
 
»
Treatment
Duodenal atresia should be treated surgically. Congenital 
heart disease should be treated as in any other patient. 
Effective treatment does no long-term harm to neurode
-
velopment. As yet, no medical treatment has been proven 
to affect the neurodevelopmental or the neurodegenerative 
aspects. Based on the glutamatergic hypothesis for 
Alzheimer disease, studies have been initiated examining 
the potential benefit of the 
N
-methyl-D-aspartate receptor 
antagonist memantine.
 
»
•	
For comprehensive evaluation of infants to investigate 
congenital heart disease, hematologic malignancy, and 
duodenal atresia.
•	
For genetic counseling of the parents.
•	
For signs of dementia in an adult patient.
 
»
A young patient should be hospitalized for failure to thrive, 
regurgitation, or breathlessness.
Alsaied T et al. Does congenital heart disease affect neurodevelop
-
mental outcomes in children with Down syndrome? Congenit 
Heart Dis. 2016 Jan–Feb;11(1):26–33. [PMID: 26914309]
Badeau M et al. Genomics-based non-invasive prenatal testing 
for detection of fetal chromosomal aneuploidy in pregnant 
women. Cochrane Database Syst Rev. 2017 Nov 10; 
11:CD011767. [PMID: 29125628]
Lee P et al. The biology, pathogenesis and clinical aspects of 
acute lymphoblastic leukemia in children with Down 
syndrome. Leukemia. 2016 Sep;30(9):1816–23. [PMID: 
27285583]
Ross WT et al. Care of the adult patient with Down syndrome. 
South Med J. 2014 Nov;107(11):715–21. [PMID: 25365441]
FAMILIAL HYPERCHOLESTEROLEMIA
 
»
Elevated serum total cholesterol and LDL 
 
»
Autosomal dominant inheritance.
 
»
Mutation in 
LRL
, 
PCSK9
, or 
APOB.
 
»
Familial hypercholesterolemia (FH) is a group of autosomal 
dominant conditions that result in elevated low-density 
lipoprotein (LDL) levels in the blood. High LDL predis
-
poses to atherosclerosis, which in turn leads to premature 
myocardial infarction or stroke. The incidence of these seri
-
ous complications increases with age and when associated 
with the other common predispositions to atherosclerosis, 
such as smoking and hypertension. About 1 in 500 people 
in the United States have FH, and worldwide prevalence is 
about 10 million. Only about 15% of people with FH are

about 10 million. Only about 15% of people with FH are 
diagnosed and even fewer are treated effectively.
In the great majority of instances, the elevated LDL is 
inherited as an autosomal dominant trait; each child of an 
affected parent has a 50/50 chance of inheriting FH. In uncom
-
mon cases, both parents have a mutation in the LDL receptor 
and one-quarter of their children, on average, will inherit two 
mutant alleles and have homozygous FH, which is a much 
more serious disease with manifestations in childhood.
Mutations in the following genes can cause FH: 
 
(1)
 LDLR
, which encodes the LDL receptor located on the 
surface of cells and is responsible for moving LDL into the 
cell for metabolism; the most common mutant gene in FH; 
(2)
 APOB
, which encodes a component of LDL and muta
-
tions inhibit binding to the LDL receptor; (3)
 PCSK9
, which 
encodes a protein that normally reduces production of LDL 
receptors, so mutations actually protect from hypercholes
-
terolemia; and (4) 
ARH
, which requires mutations in both 
alleles (autosomal recessive inheritance) to cause FH.
 
»
Y ellow lipid deposits appear on tendons, especially the 
Achilles (tendon xanthoma).
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The total serum cholesterol is elevated with the LDL com
-
ponent particularly high. A detailed family history and 
genetic testing are recommended for individuals younger 
than 40 years whose LDL level is greater than 200 mg/mL 
and for individuals older than 40 years whose LDL level is 
greater than 250 mg/mL. DNA analysis for mutations in 
the genes that cause FH is readily available.
 
»
Treatment
Statins, usually at high doses, can reduce LDL levels, occa
-
sionally to acceptable levels. The earlier in life that treat
-
ment is begun, the better the outcome of reducing mortality 
from atherosclerosis. In homozygous FH, if high-dose 
statins do not reduce LDL sufficiently, then plasmaphoresis 
to reduce LDL is often needed. If these measures are not 
effective enough, treatment with an antibody that inhibits 
the product of the 
PCSK9
 gene can be a quite expensive 
adjunct to standard therapy.
At-risk relatives should be screened for FH by measur
-
ing LDL levels; identifying the mutation in the family and 
utilizing that for screening is being increasingly done.
 
»
•	
For genetic counseling of the patient, his or her parents, 
siblings, and offspring.
 
»
•	
For signs or symptoms of acute arterial occlusive 
events.
Louter L et al. Cascade screening for familial 
hypercholesterolemia: practical consequences. Atheroscler 
Suppl. 2017 Nov; 30:77–85. [PMID: 29096865]
Migliara G et al. Familial hypercholesterolemia: a systematic 
review of guidelines on genetic testing and patient 
management. Front Public Health. 2017 Sep 25;5:252. [PMID: 
28993804]
Rosenson RS. CETP inhibition improves the lipid profile but has 
no effect on clinical cardiovascular outcomes in high-risk 
patients. Evid Based Med. 2017 Oct;22(5):184–5. [PMID: 
28844064]
FRAGILE X MENTAL RETARDATION
 
»
Expanded trinucleotide repeat (more than 200) in 
the 
FMR1
 gene.
 
»
Males:
 mental retardation and autism; large testes 
after puberty.
 
»
Females:
 learning disabilities or mental retarda
-
tion; premature ovarian failure.
 
»
Late-onset tremor and ataxia in males and females 
with moderate trinucleotide repeat (55–200) 
expansion (premutation carriers).
 
»
This X-linked condition accounts for more cases of mental 
retardation in males than any condition except Down 
syndrome; about 1 in 4000 males is affected. The central 
nervous system phenotype includes autism spectrum, 
impulsivity and aggressiveness, and repetitive behaviors. 
The condition also affects intellectual function in females, 
although less severely and about 50% less frequently than in 
males. Affected (heterozygous) young women show no 
physical signs other than early menopause, but they may 
have learning difficulties, anxiety, sensory issues, or frank 
retardation. Affected males show macro-orchidism (enlarged 
testes) after puberty, large ears and a prominent jaw, a high-
pitched voice, autistic characteristics, and mental retardation. 
Some males show evidence of a mild connective tissue 
defect, with joint hypermobility and mitral valve prolapse.
Women who are premutation carriers (55–200 CGG 
repeats) are at increased risk for premature ovarian failure 
and mild cognitive abnormalities. Male and female premu
-
tation carriers are at risk for mood and anxiety disorders 
and the development of tremor and ataxia beyond middle 
age (fragile-X tremor-ataxia syndrome, FXTAS). Changes 
in the cerebellar white matter may be evident on MRI 
before symptoms appear. Because of the relatively high 
prevalence of premutation carriers in the general popula
-
tion (1/130–1/600), older people in whom any of these 
behavioral or neurologic problems develop should undergo 
testing of the 
FMR1
 locus.
The first marker for this condition was a small gap, or fragile 
site, evident near the tip of the long arm of the X chromosome.

FMR1
 locus.
site, evident near the tip of the long arm of the X chromosome. 
Subsequently, the condition was found to be due to expansion 
of a trinucleotide repeat (CGG) near a gene called 
FMR1
. All 
individuals have some CGG repeats in this location, but as the 
number increases beyond 52, the chances of further expan
-
sion during spermatogenesis or oogenesis increase.
Being born with one 
FMR1
 allele with 200 or more 
repeats results in mental retardation in most men, and in 
about 60% of women. The more repeats, the greater the 
likelihood that further expansion will occur during game
-
togenesis; this results in anticipation, in which the disorder 
can worsen from one generation to the next.
 
»
DNA diagnosis for the number of repeats has supplanted 
cytogenetic analysis for both clinical and prenatal diagnosis. 
This should be done on any male or female who has unex
-
plained mental retardation. Newborn screening based on 
hypermethylation of the 
FMR1
 gene is being considered as 
a means of early detection and intervention.
 
»
Treatment
Several treatments that address the imbalances in neuro
-
transmission have been developed based on the mouse 
model and are in clinical trials. Valproic acid may reduce 
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symptoms of hyperactivity and attention deficit, but stan
-
dard therapies should be tried first.
 
»
•	
For otherwise unexplained mental retardation or learn
-
ing difficulties in boys and girls.
•	
For otherwise unexplained tremor or ataxia in middle-
aged individuals.
•	
For premature ovarian failure.
•	
For genetic counseling.
Hagerman RJ et al. Fragile X syndrome. Nat Rev Dis Primers. 
2017 Sep 29;3:17065. [PMID: 28960184]
GAUCHER DISEASE
 
»
Deficiency of beta-glucocerebrosidase.
 
»
Anemia and thrombocytopenia.
 
»
Enlargement of the liver and spleen.
 
»
Pathologic fractures.
 
»
Gaucher disease has an autosomal recessive pattern of 
inheritance. A deficiency of beta-glucocerebrosidase causes 
an accumulation of sphingolipid within phagocytic cells 
throughout the body. Anemia and thrombocytopenia are 
common and may be symptomatic; both are due primarily to 
hypersplenism, but marrow infiltration with Gaucher cells 
may be a contributing factor. The abdomen can become pain
-
fully distended from enlargement of the liver and spleen. 
Cortical erosions of bones, especially the vertebrae and femur, 
are due to local infarctions, but the mechanism is unclear. 
Episodes of bone pain (termed “crises”) are reminiscent of 
those in sickle cell disease. A hip fracture in a patient of any 
age with a palpable spleen—especially in a Jewish person of 
Eastern European origin—suggests the possibility of Gaucher 
disease. Peripheral neuropathy may develop in patients.
Two uncommon forms of Gaucher disease, called type II 
and type III, involve neurologic accumulation of sphingolipid 
and a variety of neurologic problems. Type II is of infantile 
onset and has a poor prognosis. Heterozygotes for Gaucher 
disease are at increased risk for developing Parkinson disease.
Bone marrow aspirates reveal typical Gaucher cells, which 
have an eccentric nucleus and periodic acid–Schiff (PAS)-
positive inclusions, along with wrinkled cytoplasm and 
inclusion bodies of a fibrillar type. In addition, the serum 
acid phosphatase is elevated. Definitive diagnosis requires 
the demonstration of deficient glucocerebrosidase activity 
in leukocytes. Hundreds of mutations have been found to 
cause Gaucher disease and some are highly predictive of 
the neuronopathic forms. Thus, mutation detection, espe
-
cially in a young person, is of potential value. Only four 
mutations in glucocerebrosidase account for more than 
90% of the disease among Ashkenazi Jews, in whom the 
carrier frequency is 1:15.
 
»
Gaucher disease is the most common lysosomal storage 
disorder. Most clinical complications can be prevented by 
early institution of enzyme replacement therapy. Carrier 
screening, especially among Ashkenazi Jews, detects those 
couples at 25% risk of having an affected child. Prenatal 
diagnosis through mutation analysis is feasible. Because of 
an increased risk of malignancy, especially plasma cell 
myeloma and other hematologic cancers, regular screening 
of adults with Gaucher disease is warranted.
 
»
Treatment
A recombinant form of the enzyme glucocerebrosidase 
(imiglucerase) for intravenous administration on a regular 
basis reduces total body stores of glycolipid and improves 
orthopedic and hematologic manifestations. Unfortunately, 
the neurologic manifestations of types II and III have not 
improved with enzyme replacement therapy. The major draw
-
back is the exceptional cost of imiglucerase, which can exceed 
$300,000 per year for a severely affected adult patient. Eliglus
-
tat tartrate is an oral inhibitor of glucosylceramide synthase 
and reduces the compound that accumulates; while still quite 
expensive, this approach eliminates the need for frequent 
intravenous infusions. Early treatment of affected children 
normalizes growth and bone mineral density and improves

normalizes growth and bone mineral density and improves 
liver and spleen size, anemia, and thrombocytopenia. In 
adults with thrombocytopenia due to splenic sequestration, 
enzyme replacement often obviates the need for splenectomy.
Biegstraaten M et al. Management goals for type 1 Gaucher 
disease: an expert consensus document from the European 
working group on Gaucher disease. Blood Cells Mol Dis. 
2018 Feb;68:203–8. [PMID: 28274788]
Coutinho MF et al. Genetic substrate reduction therapy: a prom
-
ising approach for lysosomal storage disorders. Diseases. 
2016 Nov 9;4(4). pii: E33. [PMID: 28933412]
Roshan Lal T et al. The spectrum of neurological manifestations 
associated with Gaucher disease. Diseases. 2017 Mar 2;5(1). 
pii: E10. [PMID: 28933363]
DISORDERS OF HOMOCYSTEINE 
METABOLISM
 
»
Hyperhomocysteinemia: more vascular disease 
but lowering homocysteine levels is not helpful.
 
»
Homocystinuria: Marfan-like habitus, ectopia 
lentis, mental retardation, thromboses.
 
»
Elevated homocysteine in the urine or plasma.
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»
Patients with clinical and angiographic evidence of coro
-
nary artery disease and cerebrovascular and peripheral 
vascular diseases tend to have higher levels of plasma 
homocysteine than persons without these vascular diseases. 
Although this effect was initially thought to be due at least 
in part to heterozygotes for cystathionine beta-synthase 
deficiency (see below), there is little supporting evidence. 
Rather, an important factor leading to hyperhomocystein
-
emia is folate deficiency. Pyridoxine (vitamin B
6
) and 
vitamin B
12
 are also important in the metabolism of methio
-
nine, and deficiency of any of these vitamins can lead to 
accumulation of homocysteine. A number of genes influ
-
ence utilization of these vitamins and can predispose to 
deficiency. For example, having one—and especially two—
copy of an allele that causes thermolability of methylene 
tetrahydrofolate reductase predisposes people to elevated 
fasting homocysteine levels. Both nutritional and most 
genetic deficiencies of these vitamins can be corrected by 
dietary supplementation of folic acid and, if serum levels are 
low, vitamins B
6
 and B
12
. In the United States, cereal grains 
are fortified with folic acid. However, therapy with B vita
-
mins and folate lowers homocysteine levels significantly but 
does not reduce the risk of either venous thromboembolism 
or complications of coronary artery disease. The role of 
lowering homocysteine as primary prevention for cardio
-
vascular disease has received modest direct support in clini
-
cal trials. Hyperhomocysteinemia occurs with end-stage 
chronic kidney disease. In the general population, elevated 
homocysteine correlates with cognitive impairment.
 
»
Homocystinuria in its classic form is caused by cystathionine 
beta-synthase deficiency and exhibits autosomal recessive 
inheritance. This results in extreme elevations of plasma and 
urinary homocystine levels, a basis for diagnosis of this 
disorder. Homocystinuria is similar in certain superficial 
aspects to Marfan syndrome, since patients may have a similar 
body habitus and ectopia lentis is almost always present. 
However, mental retardation is often present in homocystin
-
uria, and the cardiovascular events are those of repeated 
venous and arterial thromboses whose precise cause remains 
obscure. Thus, the diagnosis should be suspected in patients in 
the second and third decades of life who have arterial or venous 
thromboses without other risk factors. Bone mineral density is 
reduced in untreated patients. Life expectancy is reduced, espe
-
cially in untreated and pyridoxine-unresponsive patients; myo
-
cardial infarction, stroke, and pulmonary embolism are the 
most common causes of death. This condition is diagnosed by 
newborn screening for hypermethioninemia; however, pyri
-
doxine-responsive infants may not be detected. In addition, 
homozygotes for a common mutant allele, p.I278T, show 
marked clinical variability, with some unaffected as adults.
Although many mutations have been identified in the cys
-
tathionine beta-synthase gene (
CBS
), amino acid analysis of 
plasma remains the most appropriate diagnostic test. 
Patients should be studied after they have been off folate or 
pyridoxine supplementation for at least 1 week. Relatively 
few laboratories currently provide highly reliable assays for 
homocysteine. Processing of the specimen is crucial to 
obtain accurate results. The plasma must be separated 
within 30 minutes; otherwise, blood cells release the amino 
acid and the measurement will then be artificially elevated.
 
»
About 50% of patients have a form of cystathionine beta-
synthase deficiency that improves biochemically and clini
-
cally through pharmacologic doses of pyridoxine 
(50–500 mg/day) and folate (5–10 mg/day). For these

-
(50–500 mg/day) and folate (5–10 mg/day). For these 
patients, treatment from infancy can prevent retardation 
and the other clinical problems. Patients who are pyridox
-
ine nonresponders must be treated with a dietary reduc
-
tion in methionine and supplementation of cysteine, also 
from infancy. The vitamin betaine is also useful in reduc
-
ing plasma methionine levels by facilitating a metabolic 
pathway that bypasses the defective enzyme.
 
»
Treatment
Patients with classic homocystinuria who have suffered 
venous thrombosis receive anticoagulation therapy, but 
there are no studies to support prophylactic use of warfarin 
or antiplatelet agents.
Kumar T et al. Homocystinuria: therapeutic approach. Clin 
Chim Acta. 2016 Jul 1;458:55–62. [PMID: 27059523]
Sacharow SJ et al. Homocystinuria Caused By Cystathionine 
Beta-Synthase Deficiency. In: Adam MP et al, editors. 
GeneReviews
®
 Seattle (W A): University of Washington, 
Seattle; 1993-2018. 2004 Jan 15 [updated 2017 May 18]. 
[PMID: 20301697]
Zeng R et al. The effect of folate fortification on folic acid-based 
homocysteine-lowering intervention and stroke risk: a 
meta-analysis. Public Health Nutr. 2015 Jun;18(8):1514–21. 
[PMID: 25323814]
KLINEFELTER SYNDROME
 
»
Males with hypergonadotropic hypogonadism 
and small testes.
 
»
47,XXY karyotype.
 
»
Boys with an extra X chromosome are normal in appear
-
ance before puberty; thereafter, they have disproportion
-
ately long legs and arms, sparse body hair, a female 
escutcheon, gynecomastia, and small testes. Infertility is 
due to azoospermia; the seminiferous tubules are hyalin
-
ized. The incidence is 1 in 660 newborn males, but the 
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diagnosis is often not made until a man is evaluated for 
inability to conceive. Intellectual disability is somewhat 
more common than in the general population. Many men 
with Klinefelter syndrome have language-based learning 
problems. However, their intelligence usually tests within 
the broad range of normal. As adults, detailed psychomet
-
ric testing may reveal a deficiency in executive skills. The 
risk of osteoporosis, breast cancer, and diabetes mellitus is 
much higher in men with Klinefelter syndrome than in 
46,XY men.
Low serum testosterone is common. The karyotype is typi
-
cally 47,XXY , but other sex chromosome anomalies cause 
variations of Klinefelter syndrome.
 
»
Screening for cancer (especially of the breast), deep venous 
thrombosis, and glucose intolerance are indicated.
 
»
Treatment
Treatment with testosterone after puberty is advisable but 
will not restore fertility. However, men with Klinefelter 
syndrome have had mature sperm aspirated from their 
testes and injected into oocytes, resulting in fertilization. 
After the blastocysts have been implanted into the uterus of 
a partner, conception has resulted. But men with Klinefelter 
syndrome do have an increased risk for aneuploidy in 
sperm, and therefore genomic analysis of a blastocyst 
should be considered before implantation.
Ross JL et al. Androgen treatment effects on motor function, 
cognition, and behavior in boys with  Klinefelter syndrome. 
 
J Pediatr. 2017 Jun;185:193–9. [PMID: 28285751]
Skakkebæk A et al. Quality of life in men with Klinefelter syn
-
drome: the impact of genotype, health, socioeconomics, and 
sexual function. Genet Med. 2018 Feb;20(2):214–22. [PMID: 
28726803]
MARFAN SYNDROME
 
»
Disproportionately tall stature, thoracic deformity, 
and joint laxity or contractures.
 
»
Ectopia lentis and myopia.
 
»
Aortic root dilation and dissection; mitral valve 
prolapse.
 
»
FBN1
, the gene encoding fibrillin-1.
 
»
Marfan syndrome, a systemic connective tissue disease, has 
an autosomal dominant pattern of inheritance. It is charac
-
terized by abnormalities of the skeletal, ocular, and cardio
-
vascular systems; spontaneous pneumothorax; dural 
ectasia; and striae atrophicae. Of most concern is disease of 
the ascending aorta, which begins as a dilated aortic root. 
Histology of the aorta shows diffuse medial degeneration. 
Mitral valve leaflets are also abnormal and mitral prolapse 
and regurgitation may be present, often with elongated 
chordae tendineae, which on occasion may rupture.
 
»
Affected patients are typically tall, with particularly long 
arms, legs, and digits (arachnodactyly). However, there can 
be wide variability in the clinical presentation. Commonly, 
scoliosis and anterior chest deformity, such as pectus exca
-
vatum, are found. Ectopia lentis is present in about half of 
patients; severe myopia is common and retinal detachment 
can occur. Mitral valve prolapse is seen in about 85% of 
patients. Aortic root dilation is common and leads to aortic 
regurgitation or dissection with rupture. To diagnose 
Marfan syndrome, people with an affected relative need 
features in at least two systems. People with no family his
-
tory need features in the skeletal system, two other systems, 
and one of the major criteria of ectopia lentis, dilation of 
the aortic root, or aortic dissection. Patients with homocys
-
tinuria due to cystathionine beta-synthase deficiency also 
have dislocated lenses, tall, disproportionate stature, and 
thoracic deformity. They tend to have below normal intel
-
ligence, stiff joints, and a predisposition to arterial and 
venous occlusive disease. Males with Klinefelter syndrome 
do not show the typical ocular or cardiovascular features of 
Marfan syndrome and are generally sporadic occurrences

Marfan syndrome and are generally sporadic occurrences 
in the family.
Mutations in the fibrillin gene (
FBN1
) on chromosome 15 
cause Marfan syndrome. Nonetheless, no simple labora
-
tory test is available to support the diagnosis in question
-
able cases because related conditions may also be due to 
defects in fibrillin. The nature of the 
FBN1
little predictive value in terms of prognosis. The pathogen
-
esis of Marfan syndrome involves aberrant regulation of 
transforming growth factor (TGF)-beta activity. Mutations 
in either of two receptors for TGF-beta (TGFBR1 and 
TGFBR2) can cause conditions that resemble Marfan syn
-
drome in terms of aortic aneurysm and dissection and 
autosomal dominant inheritance. Mutations in more than 
one dozen other genes can predispose adults to thoracic 
aortic aneurysm and dissection.
 
»
There is prenatal and presymptomatic diagnosis for 
patients in whom the molecular defect in 
FBN1
 has been 
found.
 
»
Treatment
Children with Marfan syndrome require regular ophthal
-
mologic surveillance to correct visual acuity and thus pre
-
vent amblyopia, and annual orthopedic consultation for 
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diagnosis of scoliosis at an early enough stage so that brac
-
ing might delay progression. Patients of all ages require 
echocardiography at least annually to monitor aortic root 
diameter and mitral valve function. Long-term beta-adrenergic 
blockade, titrated to individual tolerance but enough to 
produce a negative inotropic effect (atenolol, 1–2 mg/kg 
orally daily) retards the rate of aortic dilation. While inhi
-
bition of the TGF-beta signaling pathway through angio
-
tensin receptor blockade (ARB) in mice with Marfan 
syndrome is highly effective, ARB treatment in humans is 
no more effective than beta-adrenergic blockade. Calcium 
channel blockers, once used as a substitute for beta-
blockade, are detrimental to the aorta. Restriction from 
vigorous physical exertion protects from aortic dissection. 
Prophylactic replacement of the aortic root with a compos
-
ite graft when the diameter reaches 45–50 mm in an adult 
(normal: less than 40 mm) prolongs life. A procedure to 
resuspend the patient's native aortic valve and replace just 
the aneurysmal sinuses of Valsalva and ascending aorta 
avoids the need for lifelong anticoagulation. Women with 
Marfan syndrome are at heightened risk for aortic dissec
-
tion in the peripartum and postpartum periods. Having an 
aortic root dimension greater than 40 mm should prompt 
consideration for prophylactic, valve-sparing aortic repair 
before undertaking a pregnancy.
 
»
Prognosis
People with Marfan syndrome who are untreated com
-
monly die in the fourth or fifth decade from aortic dissec
-
tion or heart failure secondary to aortic or mitral 
regurgitation. However, because of earlier diagnosis, life
-
style modifications, beta-adrenergic blockade, and prophy
-
lactic aortic and mitral valve surgery, life expectancy has 
increased by several decades.
 
»
•	
For detailed ophthalmologic examination.
•	
For at least annual cardiologic evaluation.
•	
For moderate scoliosis.
•	
For pregnancy in a woman with Marfan syndrome.
•	
 
»
Any patient with Marfan syndrome in whom severe or 
unusual chest pain develops should be hospitalized to 
exclude pneumothorax and aortic dissection.
Bradley TJ et al. The expanding clinical spectrum of extracardio
-
vascular and cardiovascular manifestations of heritable tho
-
racic aortic aneurysm and dissection. Can J Cardiol. 2016 
Jan;32(1):86–99. [PMID: 26724513]
Price J et al. Long-term outcomes of aortic root operations for 
Marfan syndrome: a comparison of Bentall versus aortic 
valve-sparing procedures. J Thorac Cardiovasc Surg. 2016 
Feb;151(2):330–8. [PMID: 26704057]
Pyeritz RE. Etiology and pathogenesis of the Marfan syndrome: 
current understanding. Ann Cardiothorac Surg. 2017 
Nov;6(6):595–8. [PMID: 29270371]
Pyeritz RE. Evaluation of the adolescent or adult with some fea
-
tures of Marfan syndrome. Genet Med. 2012 Jan;14(1):171–7. 
[PMID: 22237449]
Pyeritz RE. Recent progress in understanding the natural and 
clinical histories of the Marfan syndrome. Trends Cardiovasc 
Med. 2016 Jul;26(5):423–8. [PMID: 26908026]
Roman MJ et al. Aortic complications associated with pregnancy 
in Marfan syndrome: the NHLBI National Registry of 
Genetically Triggered Thoracic Aortic Aneurysms and 
Cardiovascular Conditions (GenTAC). J Am Heart Assoc. 
2016 Aug 11;5(8):e004052. [PMID: 27515814]
HEREDITARY HEMORRHAGIC 
TELANGIECTASIA
 
»
Recurrent epistaxis.
 
»
Mucocutaneous telangiectases.
 
»
Visceral arteriovenous malformations (especially 
lung, liver, brain, bowel).
 
»
Hereditary hemorrhagic telangiectasia (HHT), formerly 
termed “Osler-Weber-Rendu syndrome, ” is an autosomal 
dominant disorder of development of the vasculature. 
Epistaxis may begin in childhood or later in adolescence. 
Punctate telangiectases of the lips, tongue, fingers, and skin 
generally appear in later childhood and adolescence.

generally appear in later childhood and adolescence. 
Arteriovenous malformations (AVMs) can occur at any age 
in the brain, lungs, and liver. Bleeding from the gastrointes
-
tinal tract is due to mucosal vascular malformations and 
usually is not a problem until mid-adult years or later. 
Pulmonary AVMs can cause hypoxemia (with peripheral 
cyanosis, dyspnea, and clubbing) and right-to-left shunting 
(with embolic stroke or brain abscess). The criteria for diag
-
nosis require presence of three of the following four features: 
 
(1) recurrent epistaxis, (2) visceral AVMs, (3) mucocutane
-
ous telangiectases, and (4) being the near relative of a clearly 
affected individual. Mutation analysis can be used for pres
-
ymptomatic diagnosis or exclusion of the worry of HHT.
MR or CT arteriography detects AVMs. Mutations in at 
least five genes can cause HHT. Three have been identified, 
and molecular analysis to identify them is available; these 
ENG, ALK1
, and 
SMAD4
 account for about 
87% of families with HHT. When the familial mutation is 
known, molecular testing is far more cost effective than 
repeated clinical screening of relatives who are at risk.
 
»
Embolization of pulmonary AVMs with wire coils or other 
occlusive devices reduces the risk of stroke and brain 
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abscess. Treatment of brain AVMs reduces the risk of hem
-
orrhagic stroke. All patients with HHT with evidence of a 
pulmonary shunt should practice routine endocarditis 
prophylaxis (see Table 33–5). All intravenous lines (except 
those for transfusion of red blood cells and radiographic 
contrast) should have an air-filter to prevent embolization 
of an air bubble. Prenatal diagnosis through mutation 
detection is possible.
 
»
Treatment
All patients in whom the diagnosis of HHT is considered 
should have an MRI of the brain with contrast. A contrast 
echocardiogram will detect most pulmonary AVMs when 
“bubbles” appear on the left side of the heart after 3–6 car
-
diac cycles. A positive contrast echocardiogram should be 
followed by a high-resolution CT angiogram for localiza
-
tion of pulmonary AVMs. Patients who have AVMs with a 
feeding artery of 1–2 mm diameter or greater should 
undergo embolization. After successful embolization of all 
treatable pulmonary AVMs, the CT angiogram should be 
repeated in 6 months and 3 years. A person with a negative 
contrast echocardiogram should have the test repeated 
every 5 years. Several studies suggest that treatment with 
anti-estrogenic agents (eg, tamoxifen), thalidomide or its 
relatives, or anti-vascular endothelial growth factor agents 
(eg, bevacizumab) can reduce epistaxis and gastrointestinal 
bleeding and improve hepatic shunting. However, two ran
-
domized, controlled clinical trials of intranasal bevaci
-
zumab therapy failed to show an improvement in 
epistaxis.
an evidence based review of surgical management. J Otolaryngol 
Head Neck Surg. 2016 Jan 12;45:3. [PMID: 26754744]
-
staxis duration in hereditary hemorrhagic telangiectasia: a 
Jackson SB et al. Gastrointestinal manifestations of hereditary 
hemorrhagic telangiectasia (HHT): a systematic review of the 
literature. Dig Dis Sci. 2017 Oct;62(10):2623–30. [PMID: 
28836046]
McDonald J, Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. 
In: Adam MP et al, editors. GeneReviews
®
 [Internet]. Seattle 
(W A): University of Washington, Seattle; 1993–2017. 
 
2000 Jun 26 [updated 2017 Feb 2]. [PMID: 20301525]
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Sports Medicine & 
Outpatient Orthopedics
41
C. Benjamin Ma, MD 
Musculoskeletal problems account for about 10–20% of 
outpatient primary care clinical visits. Orthopedic prob
-
lems can be classified as traumatic (ie, injury-related) or 
atraumatic (ie, degenerative or overuse syndromes) as well 
as acute or chronic. The history and physical examination 
are sufficient in most cases to establish the working 
diagnosis; the mechanism of injury is usually the most 
helpful part of the history in determining the diagnosis.
SHOULDER
1. Subacromial Impingement Syndrome
 
»
Shoulder pain with overhead motion.
 
»
Night pain with sleeping on shoulder.
 
»
Numbness and pain radiation below the elbow 
are usually due to cervical spine disease.
 
»
The shoulder is a ball and socket joint. The socket is very 
shallow, however, which enables this joint to have the most 
motion of any joint. The shoulder, therefore, relies heavily 
on the surrounding muscles and ligaments to provide 
stability. The subacromial impingement syndrome 
describes a collection of diagnoses that cause mechanical 
inflammation in the subacromial space. Causes of 
impingement syndrome can be related to muscle strength 
imbalances, poor scapula control, rotator cuff tears, 
subacromial bursitis, and bone spurs.
With any shoulder problem, it is important to establish 
the patient’s hand dominance, occupation, and recreational 
activities because shoulder injuries may present differently 
depending on the demands placed on the shoulder joint. For 
example, baseball pitchers with impingement syndrome may 
complain of pain while throwing. Alternatively, older adults 
with even full-thickness rotator cuff tears may not complain 
of any pain because the demands on the joint are low.
 
»
Subacromial impingement syndrome classically presents 
with one or more of the following: pain with overhead 
activities, nocturnal pain with sleeping on the shoulder, or 
pain on internal rotation (eg, putting on a jacket or bra). On 
inspection, there may be appreciable atrophy in the supraspi
-
natus or infraspinatus fossa. The patient with impingement 
syndrome can have mild scapula winging or “dyskinesis. ” 
The patient often has a rolled-forward shoulder posture or 
head-forward posture. On palpation, the patient can have 
tenderness over the anterolateral shoulder at the edge of the 
greater tuberosity. The patient may lack full active range of 
motion (Table 41–1) but should have preserved passive 
range of motion. Impingement symptoms can be elicited 
with the Neer and Hawkins impingement signs (Table 41–1).
B. Imaging
The following four radiographic views should be ordered to 
evaluate subacromial impingement syndrome: the anteropos
-
terior (AP) scapula, the AP acromioclavicular joint, the lateral 
scapula (scapular Y), and the axillary lateral. The AP scapula 
view can rule out glenohumeral joint arthritis. The AP acro
-
mioclavicular view evaluates the acromioclavicular joint for 
inferior spurs. The scapula Y view evaluates the acromial 
shape, and the axillary lateral view visualizes the glenohu
-
meral joint as well and for the presence of os acromiale.
MRI of the shoulder may demonstrate full- or partial-
thickness tears or tendinosis. Ultrasound evaluation may 
demonstrate thickening of the rotator cuff tendons and 
tendinosis. Tears may also be visualized on ultrasound, 
although it is more difficult to identify partial tears from 
small full thickness than on MRI.
 
»
Treatment
A. Conservative
The first-line treatment for impingement syndrome is usually 
a conservative approach with education, activity modifica
-
tion, and physical therapy exercises. Impingement syndrome 
can be caused by muscle weakness or tear. Rotator cuff muscle 
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Table 41–1.
 
Shoulder examination.
Maneuver
Check the patient’s posture and “SEADS” (
s
welling, 
e
rythema, 
a
trophy, 
d
eformity, 
s
urgical 
s
cars).
Palpation
Include important landmarks: acromioclavicular (AC) 
joint, long head of biceps tendon, coracoid, and 
greater tuberosity (supraspinatus insertion).
Range of motion testing
Check range of motion actively (patient performs) and 
passively (clinician performs).
Flexion
Move the arm forward as high as possible in the 
 
sagittal plane.
External rotation
Check with the patient’s elbow touching their body 
 
so that external rotation occurs predominantly at 
 
the glenohumeral joint.
(
continued
)
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Shoulder examination. (continued)
Maneuver
Internal rotation
The patient is asked to reach the thumbs as high as 
possible behind the spine on each side. The clinician 
can record the highest spinous process that the 
individual can reach on each side (iliac crest = L4, 
inferior angle of scapula = T8).
Rotator Cuff Strength Testing
Supraspinatus (open can) test
Perform resisted shoulder abduction at 90 degrees 
with slight forward flexion to around 45 degrees to 
test for supraspinatus tendon strength (“open can” 
test), or with shoulder abduction at 30 degrees and 
flexion to 30 degrees (“empty can” test).
The patient resists by externally rotating the arms with 
elbows at his or her side.
(
continued
)
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Maneuver
Internal rotation (lift-off test)
A positive “lift-off” test is the inability of the patient to 
hold his or her hand away from the body when 
reaching toward the small of the back. The clinician 
pushes the patient’s hand toward the back while the 
patient resists. A positive lift-off indicates 
subscapularis tendon insufficiency.
Internal rotation (belly-press test)
A positive “belly-press” test is the inability to hold the 
elbow in front of the trunk while pressing down 
with the hand on the belly. A positive belly press 
test indicates subscapularis tendon insufficiency.
Impingement Testing
Neer impingement sign
Perform by having the clinician flex the shoulder 
maximally in an overhead position. The test is 
positive when pain is reproduced with full passive 
shoulder flexion. Sensitivity is 79%; specificity is 53%.
(
continued
)
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strengthening can alleviate weakness or pain, unless the ten
-
dons are seriously compromised, which may cause more 
symptoms. Physical therapy is directed at rotator cuff muscle 
strengthening, scapula stabilization, and postural exercises. 
There is no strong evidence supporting the effectiveness of ice 
and NSAIDs as a prolonged therapy. In a Cochrane review, 
corticosteroid injections produced slightly better relief of 
symptoms in the short term when compared with placebo. 
Most patients respond well to conservative treatment.
B. Surgical
Procedures include arthroscopic acromioplasty with cora
-
coacromial ligament release, bursectomy, or debridement 
or repair of rotator cuff tears.
 
»
•	
Failure of conservative treatment over 3 months.
•	
Y oung and active patients with impingement due to 
full-thickness rotator cuff tears.
Hermans J et al. Does this patient with shoulder pain have rota
-
tor cuff disease? The Rational Clinical Examination system
-
atic review. JAMA. 2013 Aug 28;310(8):837–47. [PMID: 
23982370]
2. Rotator Cuff Tears
 
»
A common cause of shoulder impingement syn
-
drome after age 40.
 
»
Difficulty lifting the arm with limited active range 
of motion.
 
»
Weakness with resisted strength testing suggests 
full-thickness tears.
 
»
Tears can occur following trauma or can be more 
degenerative.
 
»
Rotator cuff tears can be caused by acute injuries related to 
falls on an outstretched arm or to pulling on the shoulder. 
It can also be related to chronic repetitive injuries with 
overhead movement and lifting. Partial rotator cuff tears 
are one of the most common reasons for impingement 
syndrome. Full-thickness rotator cuff tears are usually 
more symptomatic and may require surgical treatment. 
The most commonly torn tendon is the supraspinatus.
 
»
Most patients complain of weakness or pain with overhead 
movement. Night pain is also a common complaint. The 
clinical findings with rotator cuff tears include those of the 
impingement syndrome except that with full-thickness 
rotator cuff tears there may be more obvious weakness 
noted with light resistance testing of specific rotator cuff 
muscles. Supraspinatus tendon strength is tested with 
resisted shoulder abduction at 90 degrees with slight for
-
ward flexion to around 45 degrees (“open can” test). 
Infraspinatus/teres minor strength is tested with resisted 
shoulder external rotation with shoulder at 0 degrees 
abduction, elbow by side. Subscapularis strength is tested 
with the “lift-off ” or “belly-press” tests. The affected 
patient usually also has positive Neer and Hawkins 
impingement tests (Table 41–1).
B. Imaging
Recommended radiographs are similar to impingement 
syndrome: AP scapula (glenohumeral), axillary lateral, 
supraspinatus outlet, and AP acromioclavicular joint views. 
The AP scapula view is useful in visualizing rotator cuff 
tears because degenerative changes can appear between the 
acromion and greater tuberosity of the shoulder. Axillary 
lateral views show superior elevation of the humeral head 
in relation to the center of the glenoid. Supraspinatus outlet 
views allow evaluation of the shape of the acromion. 
 
Maneuver
Hawkins impingement sign
Perform with the shoulder forward flexed 90 degrees 
and the elbow flexed at 90 degrees. The shoulder is 
then maximally internally rotated to impinge the 
greater tuberosity on the undersurface of the 
acromion. The test is considered positive when the 
patient’s pain is reproduced by this maneuver. 
Sensitivity is 79%; specificity is 59%.
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High-grade acromial spurs are associated with a higher 
incidence of rotator cuff tears. The AP acromioclavicular 
joint view evaluates for the presence of acromioclavicular 
joint arthritis, which can mimic rotator cuff tears, and for 
spurs that can cause rotator cuff injuries.
MRI is the best method for visualizing rotator cuff 
tears. The MR arthrogram can show partial or small (less 
than 1 cm) rotator cuff tears. For patients who cannot 
undergo MRI testing or when postoperative artifacts limit 
MRI evaluations, ultrasonography can be helpful.
 
»
Treatment
Partial rotator cuff tears
 may heal with scarring. Most 
partial rotator cuff tears can be treated with physical ther
-
apy and scapular and rotator cuff muscle strengthening. 
However, research suggests that 40% of the partial-
thickness tears progress to full-thickness tears in 2 years. 
Physical therapy can strengthen the remaining muscles to 
compensate for loss of strength and can have high rate of 
success for chronic tears. Physical therapy is also an option 
for older sedentary patients. On the contrary, 
full-
thickness rotator cuff tears
 do not heal well and also have 
a tendency to increase in size with time. Forty-nine percent 
of the full-thickness tears get bigger on an average of 
2.8 years. When tears get larger, they are also associated 
with worsening pain. Fatty infiltration is a degenerative 
process where muscle is being replaced by fat following 
injury to the rotator cuff tendons. Fatty infiltration pro
-
gresses in full-thickness rotator cuff tears and it is a nega
-
tive prognostic factor for successful surgical treatment. 
Fatty infiltration is an irreversible process so operative 
interventions are usually performed when the degree of 
infiltration is low. 
Most young active patients with acute, 
full-thickness tears should be treated with operative 
fixation.
 Full-thickness subscapularis tendon tears should 
undergo surgical repair as untreated tears usually lead to 
premature osteoarthritis (OA) of the shoulder. Nonetheless, 
physical therapy is indicated for atraumatic degenerative 
rotator cuff tears and success can be as high as 70%.
 
»
•	
Y oung and active patients with full-thickness rotator 
cuff tears.
•	
Partial tears with greater than 50% involvement and 
with significant pain.
•	
Older and sedentary patients with full-thickness rotator 
cuff tears who have not responded to nonoperative 
•	
Full-thickness subscapularis tears.
Eljabu W et al. The natural history of rotator cuff tears: a system
-
atic review. Arch Orthop Trauma Surg. 2015 Aug;135(8): 
1055–61. [PMID: 25944157]
Gombera MM et al. Rotator cuff tear and glenohumeral 
instability: a systematic review. Clin Orthop Relat Res. 
2014 Aug;472(8):2448–56. [PMID: 24043432]
Keener JD et al. A prospective evaluation of survivorship of 
asymptomatic degenerative rotator cuff tears. J Bone Joint 
Surg Am. 2015 Jan 21;97(2):89–98. [PMID: 25609434]
3. Shoulder Dislocation & Instability
 
»
Most dislocations (95%) are in the anterior 
direction.
 
»
Pain and apprehension with an unstable shoulder 
that is abducted and externally rotated.
 
»
Acute shoulder dislocations should be reduced as 
quickly as possible, using manual relocation tech
-
niques if necessary.
 
»
The shoulder is a ball and socket joint, similar to the hip. 
However, the bony contours of the shoulder bones are much 
different than the hip. Overall, the joint has much less stabil
-
ity than the hip, allowing greater movement and action. 
Stabilizing the shoulder joint relies heavily on rotator cuff 
muscle strength and also scapular control. If patients have 
poor scapular control or weak rotator cuff tendons or tears, 
their shoulders are more likely to have instability. Ninety-five 
percent of the shoulder dislocations/instability occur in the

percent of the shoulder dislocations/instability occur in the 
anterior direction. Dislocations usually are caused by a fall on 
an outstretched and abducted arm. Patients complain of pain 
and feeling of instability when the arm is in the abducted and 
externally rotated position. Posterior dislocations are usually 
caused by falls from a height, epileptic seizures, or electric 
shocks. Traumatic shoulder dislocation can lead to instability. 
The rate of repeated dislocation is directly related to the 
patient’s age: patients aged 21 years or younger have a 
70–90% risk of redislocation, whereas patients aged 40 years 
or older have a much lower rate (20–30%). Other risks 
include male gender and patients with hyperlaxity. Ninety 
percent of young active individuals who had traumatic 
shoulder dislocation have labral injuries often described as 
Bankart lesions when the anterior inferior labrum is torn, 
which can lead to continued instability. Older patients (over 
age 55 years) are more likely to have rotator cuff tears or 
fractures following dislocation. Atraumatic shoulder disloca
-
tions are usually caused by intrinsic ligament laxity or repeti
-
tive microtrauma leading to joint instability. This is often 
seen in swimmers, gymnasts, and pitchers as well as other 
athletes involved in overhead and throwing sports.
 
»
For acute traumatic dislocations, patients usually have an 
obvious deformity with the humeral head dislocated 
anteriorly. The patient holds the shoulder and arm in an 
externally rotated position. The patient complains of acute 
pain and deformity that are improved with manual 
relocation of the shoulder. Reductions are usually 
performed in the emergency department. Even after 
reduction, the patient will continue to have limited range of 
motion and pain for 4–6 weeks, especially following a first-
time shoulder dislocation.
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Patients with recurrent dislocations can have less pain 
with subsequent dislocations. Posterior dislocations can be 
easily missed because the patient usually holds the shoul
-
der and arm in an internally rotated position, which makes 
the shoulder deformity less obvious. Patients complain of 
difficulty pushing open a door.
Atraumatic shoulder instability is usually well tolerated 
with activities of daily living. Patients usually complain of a 
“sliding” sensation during exercises or strenuous activities 
such as throwing. Such dislocations may be less symptom
-
atic and can often undergo spontaneous reduction of the 
shoulder with pain resolving within days after onset. The 
clinical examination for shoulder instability includes 
the apprehension test, the load and shift test, and the 
O’Brien test (Table 41–1). Most patients with persistent 
shoulder instability have preserved range of motion.
B. Imaging
Radiographs for acute dislocations should include a stan
-
dard trauma series of AP and axillary lateral scapula 
(glenohumeral) views to determine the relationship of the 
humerus and the glenoid and to rule out fractures. 
Orthogonal views are used to identify a posterior shoulder 
dislocation, which can be missed easily with one AP view 
of the shoulder. An axillary lateral view of the shoulder can 
be safely performed even in the acute setting of a patient 
with a painful shoulder dislocation. A scapula Y view in the 
acute setting is insufficient to diagnose dislocation. For 
chronic injuries or symptomatic instability, these recom
-
mended radiographic views are helpful to identify bony 
injuries and Hill-Sachs lesions (indented compression 
fractures at the posterior-superior part of the humeral head 
associated with anterior shoulder dislocation). MRI is 
commonly used to show soft tissue injuries to the labrum 
and to visualize associated rotator cuff tears. MRI arthro
-
grams better identify labral tears and ligamentous 
structures. Three-dimensional CT scans are being used to 
determine the significance of bone loss.
 
»
Treatment
For 
acute dislocations
, the shoulder should be reduced as 
soon as possible. The Stimson procedure is the least trau
-
matic method and is quite effective. The patient lies prone 
with the dislocated arm hanging off the examination table 
with a weight applied to the wrist to provide traction for 
20–30 minutes. Afterward, gentle medial mobilization can 
be applied manually to assist the reduction. The shoulder 
can also be reduced with axial “traction” on the arm with 
“counter-traction” along the trunk. The patient should be 
sedated and relaxed. The shoulder can then be gently inter
-
nally and externally rotated to guide it back into the socket.
Initial treatment of acute shoulder dislocations should 
include sling immobilization for 2–4 weeks along with 
pendulum exercises. Early physical therapy can be used to 
maintain range of motion and strengthening of rotator cuff 
muscles. Patients can also modify their activities to avoid 
active and risky sports. For patients with a traumatic inci
-
dent and unilateral shoulder dislocation, a Bankart lesion is 
commonly present. The risk of recurrence is dependent on 
the age of first shoulder dislocation. Y oung patients (less 
than 27 years of age) can have recurrence up to 70% 
whereas patients older than 40 years old have recurrences 
as low as 10%. However, once the patient has a second 
dislocation, the recurrence rate is extremely high, up to 
95%, regardless of age. Operative intervention is the only 
treatment that has been shown to decrease recurrence. 
Open and arthroscopic stabilization can have very similar 
outcomes. Repeat dislocation has been shown to increase 
the risk of arthritis and further bony deterioration.
The treatment of 
atraumatic shoulder instability
 is 
different than traumatic shoulder instability. Patients with 
chronic, recurrent shoulder dislocations should be man
-

 is 
-
aged with physical therapy and a regular maintenance 
program, consisting of scapular stabilization and postural 
and rotator cuff strengthening exercises. Activities may 
need to be modified. Surgical reconstructions are less suc
-
cessful for atraumatic shoulder instability than for trau
-
matic shoulder instability.
 
»
•	
Patients who are at risk for second dislocation, such as 
young patients, certain job holders (eg, police officers, 
firefighters, and rock climbers) to avoid recurrent dislo
-
cation or dislocation while at work.
•	
Patients who have not responded to conservative 
approach or who have chronic instability.
Chalmers PN et al. Do arthroscopic and open stabilization tech
-
niques restore equivalent stability to the shoulder in the set
-
ting of anterior glenohumeral instability? A systematic review 
of overlapping meta-analysis. Arthroscopy. 2015 Feb; 
31(2):355–63. [PMID: 25217207]
Olds M et al. Risk factors which predispose first-time traumatic 
anterior shoulder dislocations to recurrent instability in 
adults: a systematic review and meta-analysis. Br J Sports 
Med. 2015 Jul;49(14):913–22. [PMID: 25900943]
4. Adhesive Capsulitis (“Frozen Shoulder”)
 
»
Very painful shoulder triggered by minimal or no 
trauma.
 
»
Pain out of proportion to clinical findings during 
the inflammatory phase.
 
»
Stiffness during the “freezing” phase and resolu
-
tion during the “thawing” phase.
 
»
Adhesive capsulitis (“frozen shoulder”) is seen commonly 
in patients 40 to 65 years old. It is more commonly seen in 
women than men, especially in perimenopausal women or 
in patients with endocrine disorders, such as diabetes mel
-
litus or thyroid disease. There is higher incidence following 
breast cancer care (such as mastectomy). Adhesive capsuli
-
tis is a self-limiting but very debilitating disease.
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»
Patients usually present with a painful shoulder that has a 
limited range of motion with both passive and active 
movements. A useful clinical sign is limitation of move
-
ment of external rotation with the elbow by the side of the 
trunk (Table 41–1). Strength is usually normal but it can 
appear diminished when the patient is in pain.
There are three phases: the inflammatory phase, the 
freezing phase, and the thawing phase. During the inflam
-
matory phase, which usually lasts 4–6 months, patients 
complain of a very painful shoulder without obvious clini
-
cal findings to suggest trauma, fracture, or rotator cuff tear. 
During the “freezing” phase, which also usually lasts 
4–6 months, the shoulder becomes stiffer and stiffer even 
though the pain is improving. The “thawing” phase can 
take up to a year as the shoulder slowly regains its motion. 
The total duration of an idiopathic frozen shoulder is usu
-
ally about 24 months; it can be much longer for patients 
who have trauma or an endocrinopathy.
B. Imaging
Standard AP , axillary, and lateral glenohumeral radio
-
graphs are useful to rule out glenohumeral arthritis, which 
can also present with limited active and passive range of 
motion. Imaging can also rule out calcific tendinitis, which 
is an acute inflammatory process in which calcifications 
are visible in the soft tissue. However, adhesive capsulitis is 
usually a clinical diagnosis, and it does not need an exten
-
sive diagnostic workup.
 
»
Treatment
Adhesive capsulitis is caused by acute inflammation of 
the capsule followed by scarring and remodeling. During 
the acute “freezing” phase, NSAIDs and physical therapy 
are recommended to maintain motion. There is also evi
-
dence of short-term benefit from intra-articular corticoste
-
roid injection or oral prednisone. A randomized control 
trial showed that intra-articular corticosteroid injection 
provided better pain relief than NSAIDs in the first 
 
8 weeks. However, no difference was seen in range of motion 
or pain after 12 weeks, which is similar to other noncon
-
trolled studies. One study demonstrated improvement at 
 
6 weeks but not 12 weeks following 30 mg of daily predni
-
sone for 3 weeks. During the “freezing” phase, the shoulder 
is less painful but remains stiff. Anti-inflammatory medi
-
cation is not as helpful during the “thawing” phase as it is 
during the “freezing” phase, and the shoulder symptoms 
usually resolve with time. Surgical treatments, which are 
rarely indicated, include manipulation under anesthesia 
and arthroscopic release.
 
»
•	
When the patient does not respond after more than 
6 months of conservative treatment.
•	
When there is no progress or worsening range of 
motion over 3 months.
Page MJ et al. Manual therapy and exercise for adhesive 
capsulitis (frozen shoulder). Cochrane Database Syst Rev. 
2014 Aug 26;(8):CD011275. d[PMID: 25157702]
Ranalletta M et al. Corticosteroid injections accelerate pain relief 
and recovery of function compared with oral NSAIDs in 
patients with adhesive capsulitis: a randomized controlled 
trial. Am J Sports Med. 2016 Feb;44(2):474–81. [PMID: 
26657263]
SPINE PROBLEMS
1. Low Back Pain
 
»
Nerve root impingement is suspected when pain 
is leg-dominant rather than back-dominant.
 
»
Alarming symptoms include unexplained weight 
loss, failure to improve with treatment, severe 
pain for more than 6 weeks, night or rest pain.
 
»
Cauda equina syndrome is an emergency; often 
presents with bowel or bladder symptoms 
(or both).
 
»
Low back pain remains the most common cause of disabil
-
ity for patients under the age of 45 and is the second most 
common cause for primary care visits. The annual preva
-
lence of low back pain is 15–45%. Low back and neck pain 
is estimated to be the third-largest condition of health care

-
is estimated to be the third-largest condition of health care 
spending at $87.6 billion. Low back pain is the condition 
associated with the highest years lived with disability. 
Approximately 80% of episodes of low back pain resolve 
within 2 weeks and 90% resolve within 6 weeks. The exact 
cause of the low back pain is often difficult to diagnose; its 
cause is often multifactorial, although there are usually 
degenerative changes in the lumbar spine.
Alarming symptoms for back pain caused by cancer 
include unexplained weight loss, failure to improve with 
treatment, pain for more than 6 weeks, and pain at night 
or rest. History of cancer and age older than 50 years are 
other risk factors for malignancy. Alarming symptoms for 
infection include fever, rest pain, recent infection (urinary 
tract infection, cellulitis, pneumonia), or history of 
immunocompromise or injection drug use. The 
cauda 
equina syndrome
 is suggested by urinary retention or 
incontinence, saddle anesthesia, decreased anal sphincter 
tone or fecal incontinence, bilateral lower extremity 
weakness, and progressive neurologic deficits. Risk fac
-
tors for back pain due to vertebral fracture include use of 
corticosteroids, age over 70 years, history of osteoporosis, 
severe trauma, and presence of a contusion or abrasion. 
Back pain may also be the presenting symptom in other 
serious medical problems, including abdominal aortic 
aneurysm, peptic ulcer disease, kidney stones, or 
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»
The physical examination can be conducted with the 
patient in the standing, sitting, supine, and finally prone 
positions to avoid frequent repositioning of the patient. In 
the standing position, the patient’s posture can be observed. 
Commonly encountered spinal asymmetries include 
scoliosis, thoracic kyphosis, and lumbar hyperlordosis. The 
active range of motion of the lumbar spine can be assessed 
while standing. The common directions include flexion, 
extension, rotation, and lateral bending. The one-leg 
standing extension test assesses for pain as the patient 
stands on one leg while extending the spine. A positive test 
can be caused by pars interarticularis fractures (spondy
-
lolysis or spondylolisthesis) or facet joint arthritis.
With the patient sitting, motor strength, reflexes, and 
sensation can be tested (Table 41–2). The major muscles in 
the lower extremities are assessed for weakness by eliciting 
a resisted isometric contraction for about 5 seconds. 
Comparing the strength bilaterally to detect subtle muscle 
weakness is important. Similarly, sensory testing to light 
touch can be checked in specific dermatomes for corre
-
sponding nerve root function. Knee (femoral nerve L2–4), 
ankle (deep peroneal nerve L4–L5), and Babinski (sciatic 
nerve L5–S1) reflexes can be checked with the patient sitting.
In the supine position, the hip should be evaluated for 
range of motion, particularly internal rotation. The straight 
leg raise test puts traction and compression forces on the 
lower lumbar nerve roots.
Finally, in the prone position, the clinician can carefully 
palpate each vertebral level of the spine and sacroiliac joints 
for tenderness. A rectal examination is required if the cauda 
equina syndrome is suspected. Superficial skin tenderness 
to a light touch over the lumbar spine, overreaction to 
maneuvers in the regular back examination, low back pain 
on axial loading of spine in standing, inconsistency in the 
straight leg raise test or on the neurologic examination sug
-
gest nonorthopedic causes for the pain or malingering.
B. Imaging
In the absence of alarming “red flag” symptoms suggesting 
infection, malignancy, or cauda equina syndrome, most 
patients do not need diagnostic imaging, including radio
-
graphs, in the first 6 weeks. The Agency for Healthcare 
Research and Quality guidelines for obtaining lumbar 
radiographs are summarized in Table 41–3. Most clinicians 
obtain radiographs for new back pain in patients older than 
50 years. If done, radiographs of the lumbar spine should 
include AP and lateral views. Oblique views can be useful 
if the neuroforamina or bone lesions need to be visualized. 
MRI is the method of choice in the evaluation of symptoms 
not responding to conservative treatment or in the pres
-
ence of red flags of serious conditions.
C. Special Tests
Electromyography or nerve conduction studies may be 
useful in assessing patients with possible nerve root symp
-
toms lasting longer than 6 weeks; back pain may or may 
not also be present. These tests are usually not necessary if 
the diagnosis of radiculopathy is clear.
 
»
Treatment
Nonpharmacologic treatments are key in the management 
of low back pain. Education alone improves patient 
Table 41–2.
 
Neurologic testing of lumbosacral nerve 
Nerve 
Root
Motor
Reflex
Sensory Area
L1
Hip flexion
None
Groin
L2
None
Thigh
L3
Extension of 
knee
Knee jerk
Knee
L4
Dorsiflexion of 
ankle
Knee jerk
Medial calf
L5
first toe
Babinski reflex
First dorsal web 
space between 
first and 
 
second toes
S1
Plantar flexion 
 
of foot, knee 
flexors, or 
hamstrings
Ankle jerk
Lateral foot
S2
Knee flexors or 
Knee flexor
Back of the thigh
S2–S4
External anal 
sphincter
Anal reflex, 
 
rectal tone
Perianal area
Table 41–3.
 
AHRQ criteria for lumbar radiographs in 
patients with acute low back pain.

S2–S4
sphincter
 
Possible fracture
 
M
ajor trauma
 
M
inor trauma in patients > 50 years
 
L
ong-term corticosteroid use
 
> 70 y
ears
Possible tumor
 
or infection
 
> 50 y
ears
 
< 20 y
ears
 
H
istory of cancer
 
C
onstitutional symptoms
 
Rec
ent bacterial infection
 
I
njection drug use
 
Immunosuppression
 
Supine pain
 
Noc
turnal pain
AHRQ, Agency for Healthcare Research and Quality.
Reproduced, with permission, from Suarez-Almazor ME et al. Use 
of lumbar radiographs for the early diagnosis of low back pain. 
Proposed guidelines would increase utilization. JAMA. 1997 
Jun;277:1782-6. Copyright © 1997 American Medical Association. 
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satisfaction with recovery and recurrence. Patients require 
information and reassurance, especially when diagnostic 
procedures are not necessary. Discussion must include 
reviewing safe and effective methods of symptom control 
as well as how to decrease the risk of recurrence with 
proper lifting techniques, abdominal wall/core strengthen
-
ing, weight loss, and smoking cessation. Tai chi, mindful
-
ness-based stress reduction, and yoga have shown benefit 
for chronic low back pain patients. The effectiveness of 
exercise, psychological therapies, and multidisciplinary 
rehabilitation, have been shown to be modestly effective 
for acute low back pain (strength of evidence, low).
Physical therapy exercise programs can be tailored to 
the patient’s symptoms and pathology. A randomized con
-
trolled trial demonstrated that individualized physical 
therapy was clinically more beneficial than advice alone 
with sustained improvements at 6 months and 12 months. 
Strengthening and stabilization exercises effectively reduce 
pain and functional limitation compared with usual care. 
Heat and cold treatments have not shown any long-term 
benefits but may be used for symptomatic treatment. The 
efficacy of transcutaneous electrical nerve stimulation 
(TENS), back braces, and physical agents are unproven. 
Spinal manipulation, massage, and acupuncture does have 
limited, low evidence for chronic low back pain. Improve
-
ments in posture including chair ergonomics or standing 
desks, core stability strengthening, physical conditioning, 
and modifications of activities to decrease physical strain 
are keys for ongoing management. Radiofrequency dener
-
vation of facet joints, sacroiliac joints, or intervertebral 
disks, did not result in clinically important improvement in 
chronic low back even when combined with a standardized 
exercise program in randomized controlled trials. 
NSAIDs are effective in the early treatment of low back 
pain (see Chapter 20). Acetaminophen and oral corticoste
-
roids are relatively ineffective for chronic low back. There is 
limited evidence that muscle relaxants provide short-term 
relief; since these medications have addictive potential, they 
should be used with care. Muscle relaxants are best used if 
there is true muscle spasm that is painful rather than simply 
a protective response. Opioids alleviate pain in the short 
term, but have the usual side effects and concerns of long-
term opioid use (see Chapter 5). Treatment of more chronic 
neuropathic pain with alpha-2-delta ligands (eg, gabapentin), 
serotonin-norepinephrine reuptake inhibitors (eg, duloxetine), 
or tricyclic antidepressants (eg, nortriptyline) may be 
helpful. Epidural injections may reduce pain in the short 
term, and appear to reduce the need for surgery in some 
patients within a 1-year period but not longer.
Surgical indications for back surgery include cauda equina 
syndrome, ongoing morbidity with no response to more 
than 6 months of conservative treatment, cancer, infection, 
or severe spinal deformity. Prognosis is improved when 
there is an anatomic lesion that can be corrected and symp
-
toms are neurologic. Spinal surgery has limitations. Patient 
selection is very important and the specific surgery recom
-
mended should have very clear indications. Patients should 
understand that surgery can improve their pain but is 
unlikely to cure it. Surgery is not generally indicated for 
radiographic abnormalities alone when the patient is rela
-
tively asymptomatic. Depending on the surgery performed, 
possible complications include persistent pain; surgical site 
pain, especially if bone grafting is needed; infection; neuro
-
logic damage; non-union; cutaneous nerve damage; 
implant failure; deep venous thrombosis; and death.
 
»
•	
Patients with the cauda equina syndrome.
•	
Patients with cancer, infection, fracture, or severe spinal

»
•	
•	
Patients with cancer, infection, fracture, or severe spinal 
•	
Abdel Shaheed C et al. Efficacy, tolerability, and dose-dependent 
effects of opioid analgesics for low back pain: a systematic 
review and meta-analysis. JAMA Intern Med. 2016 Jul 1; 
176(7):958–68. [PMID: 27213267]
Bicket MC et al. Epidural injections in prevention of surgery for 
spinal pain: systematic review and meta-analysis of random
-
ized controlled trials. Spine J. 2015 Feb 1;15(2):348–62. 
[PMID: 25463400]
Chou R et al. Systemic pharmacologic therapies for low back 
pain: a systematic review for an American College of Physi
-
cians clinical practice guideline. Ann Intern Med. 2017 Apr 4; 
166(7):480–92. [PMID: 28192790]
Downie A et al. Red flags to screen for malignancy and fracture 
in patients with low back pain: systematic review. BMJ. 2013 
Dec 11;347:f7095. [PMID: 24335669]
Qaseem A et al. Noninvasive treatments for acute, subacute, and 
chronic low back pain: a clinical practice guideline from the 
American College of Physicians. Ann Intern Med. 2017 Apr 4; 
166(7):514–30. [PMID: 28192789]
2. Spinal Stenosis
 
»
Pain is usually worse with back extension and 
relieved by sitting.
 
»
Occurs in older patients.
 
»
May present with neurogenic claudication symp
-
toms with walking.
 
»
OA in the lumbar spine can cause narrowing of the spinal 
canal. A large disk herniation can also cause stenosis and 
compression of neural structures or the spinal artery 
resulting in “claudication” symptoms with ambulation. The 
condition usually affects patients aged 50 years or older.
 
»
Patients report pain that worsens with extension. They 
describe reproducible single or bilateral leg symptoms that 
are worse after walking several minutes and that are relieved 
by sitting (“neurogenic claudication”). On examination, 
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patients often exhibit limited extension of the lumbar 
spine, which may reproduce the symptoms radiating down 
the legs. A thorough neurovascular examination is recom
-
mended (Table 41–2).
 
»
Treatment
Exercises, usually flexion-based as demonstrated by a 
physical therapist, can help relieve symptoms. Physical 
therapy showed similar results as surgical decompression 
in a randomized trial, though there was a 57% crossover 
rate from physical therapy to surgery. Facet joint cortico
-
steroid injections can also reduce pain symptoms. A 2014 
randomized trial found a benefit overall from epidural 
injection at 6 weeks, but did not find a difference when 
patients received injections of corticosteroids plus lido
-
caine compared to lidocaine alone. The extended benefit of 
epidural lidocaine injection alone is not well studied, so 
present practice most likely will continue to include corti
-
costeroids. Epidural corticosteroid injections similarly 
showed only modest but significant improvement com
-
pared to gabapentin in patients with worse leg symptoms.
Surgical treatments for spinal stenosis include spinal 
decompression (widening the spinal canal or laminectomy), 
nerve root decompression (freeing a single nerve), and spinal 
fusion (joining the vertebra to eliminate motion and dimin
-
ish pain from the arthritic joints). In one multicenter ran
-
domized trial, subgroups initially improved significantly 
more with surgery than with nonoperative treatment. 
Variables associated with greater treatment effects included 
lower baseline disability scores, not smoking, neuroforami
-
nal stenosis, predominant leg pain rather than back pain, not 
lifting at work, and the presence of a neurologic deficit. 
However, long-term follow-up of the patients with symp
-
tomatic spinal stenosis who received surgery in the multi
-
center randomized trial showed less benefit of surgery between 
4 and 8 years, suggesting that the advantage of surgery for 
spinal stenosis diminishes over time. A Cochrane review of 24 
randomized controlled trials of treatments for lumbar spinal 
stenosis showed that various surgeries including decompres
-
sion plus fusion and interspinous process spacers were not 
superior to conventional spinal decompression surgery alone.
 
»
•	
If a patient exhibits radicular or claudication symptoms 
for longer than 12 weeks.
•	
MRI or CT confirmation of significant, symptomatic 
spinal stenosis.
Cohen SP et al. Epidural steroid injections compared with 
gabapentin for lumbosacral radicular pain: multicenter 
randomized double blind comparative efficacy study. BMJ. 
2015 Apr 16;350:h1748. [PMID: 25883095]
Friedly JL et al. A randomized trial of epidural glucocorticoid 
injections for spinal stenosis. N Engl J Med. 2014 Jul 3; 
371(1):11–21. Erratum in: N Engl J Med. 2014 Jul 24; 
371(4):390. [PMID: 24988555]
Lurie JD et al. Long-term outcomes of lumbar spinal stenosis: 
eight-year results of the Spine Patient Outcomes Research 
Trial (SPORT). Spine (Phila Pa 1976). 2015 Jan 15;40(2):
 
63–76. [PMID: 25569524]
Machado GC et al. Surgical options for lumbar spinal stenosis. 
Cochrane Database Syst Rev. 2016 Nov 1;11:CD012421. 
[PMID: 27801521]
3. Lumbar Disk Herniation
 
»
Pain with back flexion or prolonged sitting.
 
»
Radicular pain into the leg due to compression of 
neural structures.
 
»
Lower extremity numbness and weakness.
 
»
Lumbar disk herniation is usually due to bending or heavy 
loading (eg, lifting) with the back in flexion, causing her
-
niation or extrusion of disk contents (nucleus pulposus) 
into the spinal cord area. However, there may not be an 
inciting incident. Disk herniations usually occur from 
degenerative disk disease (dessication of the annulus 
fibrosis) in patients between 30 and 50 years old. The 
L5–S1 disk is affected in 90% of cases. Compression of

L5–S1 disk is affected in 90% of cases. Compression of 
neural structures, such as the sciatic nerve, causes radicular 
pain. Severe compression of the spinal cord can cause the 
cauda equina syndrome, a surgical emergency.
 
»
Discogenic pain typically is localized in the low back at the 
level of the affected disk and is worse with activity. 
“Sciatica” causes electric shock-like pain radiating down 
the posterior aspect of the leg often to below the knee. 
Symptoms usually worsen with back flexion such as bend
-
ing or sitting for long periods (eg, driving). A significant 
disk herniation can cause numbness and weakness, includ
-
ing weakness with plantar flexion of the foot (L5/S1) or 
dorsiflexion of the toes (L4/L5). The cauda equina syn
-
drome should be ruled out if the patient complains of 
perianal numbness or bowel or bladder incontinence.
B. Imaging
Plain radiographs are helpful to assess spinal alignment 
(scoliosis, lordosis), disk space narrowing, and OA changes. 
MRI is the best method to assess the level and morphology 
of the herniation and is recommended if surgery is planned.
 
»
Treatment
For an acute exacerbation of pain symptoms, bed rest is 
appropriate for up to 48 hours. Otherwise, first-line treat
-
ments include modified activities; NSAIDs and other 
analgesics; and physical therapy, including core stabiliza
-
tion and McKenzie exercises. Following nonsurgical treat
-
ment for a lumbar disk for over 1 year, the incidence of low 
back pain recurrence is at least 40% and is predicted by 
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longer time to initial resolution of pain. In a randomized 
trial, oral prednisone caused a modest improvement in 
function at 3 weeks, but there was no significant improve
-
ment in pain in patients with acute radiculopathy who 
were monitored for 1 year. The initial dose for oral predni
-
sone is approximately 1 mg/kg once daily with tapering 
doses over 10–15 days. Analgesics for neuropathic pain, 
such as the calcium channel alpha-2-delta ligands (ie, 
gabapentin, pregabalin) or tricyclic antidepressants, may 
be helpful (see Chapter 5). Epidural and transforaminal 
corticosteroid injections can be beneficial. A systematic 
review demonstrated strong evidence that fluoroscopic-
guided epidural injections gave short-term benefit (less 
than 6 months) in acute radicular pain for individuals. 
However, epidural injections have not shown any change in 
long-term surgery rates for disk herniations.
The severity of pain and disability as well as failure of 
conservative therapy were the most important reasons for 
surgery. A large trial has shown that patients who under
-
went surgery for a lumbar disk herniation achieved greater 
improvement than conservatively treated patients in all 
primary and secondary outcomes except return to work 
status after 4-year follow-up. Patients with sequestered frag
-
ments, symptom duration greater than 6 months, higher 
levels of low back pain, or who were neither working nor 
disabled at baseline showed greater surgical treatment 
effects. Microdiscectomy is the standard method of treat
-
ment with a low rate of complications and satisfactory 
results over 90% in the largest series. Minimally invasive 
techniques include percutaneous endoscopic discectomy, 
which involves using an endoscope to remove fragments of 
disk herniation fragments (interlaminar or transforaminal 
approaches) under local anesthesia, although results are less 
successful than microdiscectomy. Disk replacement surgery 
has shown benefits in short-term pain relief, disability, and 
quality of life compared with spine fusion surgery.
 
»
•	
Cauda equina syndrome.
•	
Progressive worsening of neurologic symptoms.
•	
Loss of motor function (sensory losses can be followed 
in the outpatient clinic).
Gadjradj PS et al. Management of symptomatic lumbar disk 
herniation: an international perspective. Spine (Phila Pa 
1976). 2017 Dec 1;42(23):1826–34. [PMID: 28632645]
Goldberg H et al. Oral steroids for acute radiculopathy due to a 
herniated lumbar disk: a randomized clinical trial. JAMA. 
2015 May 19;313(19):1915–23. [PMID: 25988461]
Kerr D et al. What are long-term predictors of outcomes for 
lumbar disc herniation? A randomized and observational 
study. Clin Orthop Relat Res. 2015 Jun;473(6):1920–30. 
[PMID: 25057116]
Kreiner DS et al; North American Spine Society. An evidence-
based clinical guideline for the diagnosis and treatment of 
lumbar disc herniation with radiculopathy. Spine J. 2014 
Jan;14(1):180–91. [PMID: 24239490]
Manchikanti L et al. Do epidural injections provide short- and 
long-term relief for lumbar disc herniation? A systematic 
review. Clin Orthop Relat Res. 2015 Jun;473(6):1940–56. 
[PMID: 24515404]
4. Neck Pain
 
»
Chronic neck pain is mostly caused by degenera
-
tive joint disease; whiplash often follows a 
traumatic neck injury.
 
»
Poor posture is often a factor for persistent neck 
pain.
 
»
Most neck pain, especially in older patients, is due to 
mechanical degeneration involving the cervical disks, facet 
joints, and ligamentous structures and may occur in the 
setting of degenerative changes at other sites. Pain can also 
come from the supporting neck musculature, which often 
acts to protect the underlying neck structures. 
Posture is a 
very important factor, especially in younger patients.
 
Many work-related neck symptoms are due to poor posture

Many work-related neck symptoms are due to poor posture 
and repetitive motions over time. Acute injuries can also 
occur secondary to trauma. Whiplash occurs from rapid 
flexion and extension of the neck and affects 15–40% of 
people in motor vehicle accidents; chronic pain develops in 
5–7%. Neck fractures are serious traumatic injuries acutely 
and can lead to OA in the long term. Ultimately, many 
degenerative conditions of the neck result in cervical canal 
stenosis or neural foraminal stenosis, sometimes affecting 
underlying neural structures.
Cervical radiculopathy can cause neurologic symptoms 
in the upper extremities usually involving the C5–C7 disks. 
Patients with neck pain may report associated headaches 
and shoulder pain. Both peripheral nerve entrapment and 
cervical radiculopathy, known as a “double crush” injury, 
may develop. Thoracic outlet syndrome, in which there is 
mechanical compression of the brachial plexus and neuro
-
vascular structures with overhead positioning of the arm, 
should be considered in the differential diagnosis of neck 
pain. Other causes of neck pain include rheumatoid 
arthritis, fibromyalgia, osteomyelitis, neoplasms, polymy
-
algia rheumatica, compression fractures, pain referred 
from visceral structures (eg, angina), and functional disor
-
ders. Amyotrophic lateral sclerosis, multiple sclerosis, 
syringomyelia, spinal cord tumors, and Parsonage-Turner 
syndrome can mimic myelopathy from cervical arthritis.
 
»
Neck pain may be limited to the posterior region or, 
depending on the level of the symptomatic joint, may radi
-
ate segmentally to the occiput, anterior chest, shoulder 
girdle, arm, forearm, and hand. It may be intensified by 
active or passive neck motions. The general distribution of 
pain and paresthesias corresponds roughly to the involved 
dermatome in the upper extremity.
The patient’s posture should be assessed, checking for 
shoulder rolled forward or head forward posture as well as 
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scoliosis in the thoracolumbar spine. Patients with disco
-
genic neck pain often complain of pain with flexion, which 
causes cervical disks to herniate posteriorly. Extension of 
the neck usually affects the neural foraminal and facet 
joints of the neck. Rotation and lateral flexion of the cervi
-
cal spine should be measured both to the left and the right. 
Limitation of cervical movements is the most common 
objective finding.
A detailed neurovascular examination of the upper 
extremities should be performed, including sensory input 
to light touch and temperature; motor strength testing, 
especially the hand intrinsic muscles (thumb extension 
strength [C6], opponens strength (thumb to pinky) [C7], 
and finger abductors and adductors strength [C8–T1]); 
and upper extremity reflexes (biceps, triceps, brachioradialis). 
True cervical radiculopathy symptoms should match an 
expected dermatomal or myotomal distribution. The 
Spurling test involves asking the patient to rotate and 
extend the neck to one side (Table 41–4). The clinician can 
apply a gentle axial load to the neck. Reproduction of the 
cervical radiculopathy symptoms is a positive sign of nerve 
root compression. Palpation of the neck is best performed 
with the patient in the supine position where the clinician 
can palpate each level of the cervical spine with the muscles 
of the neck relaxed.
B. Imaging and Special Tests
Radiographs of the cervical spine include the AP and lat
-
eral view of the cervical spine. The odontoid view is usually 
added to rule out traumatic fractures and congenital 
abnormalities. Oblique views of the cervical spine can 
provide further information about arthritis changes and 
assess the neural foramina for narrowing. Plain radio
-
graphs can be completely normal in patients who have 
suffered an acute cervical strain. Comparative reduction in 
height of the involved disk space and osteophytes are fre
-
quent findings when there are degenerative changes in the 
cervical spine. Loss of cervical lordosis is commonly seen 
but is nonspecific.
MRI is the best method to assess the cervical spine since 
the soft tissue structures (such as the disks, spinal cord, and 
nerve roots) can be evaluated. If the patient has signs of 
cervical radiculopathy with motor weakness, these more 
sensitive imaging modalities should be obtained urgently. 
CT scanning is the most useful method if bony abnormali
-
ties, such as fractures, are suspected.
EMG is useful in order to differentiate peripheral nerve 
entrapment syndromes from cervical radiculopathy.
 
»
Treatment
In the absence of trauma or evidence of infection, malig
-
nancy, neurologic findings, or systemic inflammation, the 
patient can be treated conservatively. More frequent obser
-
vation of individuals in whom very severe symptoms are 
present early on after an injury is recommended because 
high pain-related disability is a predictor of poor outcome 
at 1 year even if individuals decline care. Ergonomics 
should be assessed at work and home. A course of neck 
stretching, strengthening and postural exercises in physical 
therapy have demonstrated benefit in relieving symptoms. 
A soft cervical collar can be useful for short-term use (up 
to 1–2 weeks) in acute neck injuries. Chiropractic manual 
manipulation and mobilization can provide short-term 
benefit for mechanical neck pain. Although the rate of 
complications is low (5–10/million manipulations), care 
should be taken whenever there are neurologic symptoms 
present. Specific patients may respond to use of home cer
-
vical traction. NSAIDs are commonly used and opioids 
may be needed in cases of severe neck pain. Muscle relax
-
ants (eg, cyclobenzaprine 5–10 mg orally three times daily) 
can be used short term if there is muscle spasm or as a 
sedative to aid in sleeping. Acute radicular symptoms can 
be treated with neuropathic medications (eg, gabapentin

be treated with neuropathic medications (eg, gabapentin 
300–1200 mg orally three times daily), and a short course 
of oral prednisone (5–10 days) can be considered (starting 
at 1 mg/kg). Cervical foraminal or facet joint injections can 
also reduce symptoms. Surgeries are successful in reducing 
neurologic symptoms in 80–90% of cases, but are still con
-
sidered as treatments of last resort. Cervical disk arthro
-
plasty (replacement) has become more common as a 
treatment option. A meta-analysis of 18 randomized con
-
trolled trials showed that cervical disk arthroplasty was 
superior to anterior diskectomy and fusion for the treat
-
ment of symptomatic cervical disk disease, with better 
success and less reoperation rates.
 
»
•	
Patients with severe symptoms with motor weakness.
•	
Surgical decompression surgery if the symptoms are 
severe and there is identifiable, correctable pathology.
Table 41–4.
 
Spine: neck examination.
Maneuver
Check the patient’s posture in the standing 
position. Assess for cervical hyperlordosis, 
head forward posture, kyphosis, scoliosis, 
torticollis.
Palpation
Include important landmarks: spinous 
 
process, facet joints, paracervical muscles 
(sternocleidomastoid, scalene muscles).
Range of motion 
testing
Check range of motion in the cervical spine, 
especially with flexion and extension. 
Rotation and lateral bending are also 
helpful to assess symmetric motion or any 
restrictions. Pain and radicular symptoms 
can be exacerbated by range of motion 
testing.
Check motor strength, reflexes and 
dermatomal sensation in the upper (and 
lower if necessary) extremities.
Spurling test
Involves asking the patient to rotate and 
extend the neck to one side. The clinician 
can apply a gentle axial load to the neck. 
Reproduction of the cervical radiculopathy 
symptoms is a positive sign of nerve root 
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Iyer S et al. Cervical radiculopathy. Curr Rev Musculoskelet Med. 
2016 Sep;9(3):272–80. [PMID: 27250042]
Verhagen AP et al. Conservative interventions for treating work-
related complaints of the arm, neck or shoulder in adults. 
Cochrane Database Syst Rev. 2013 Dec 12;12:CD008742. 
[PMID: 24338903]
UPPER EXTREMITY
1. Lateral & Medial Epicondylosis
 
»
Tenderness over the lateral or medial epicondyle.
 
»
Diagnosis of tendinopathy is confirmed by pain 
with resisted strength testing and passive stretch
-
ing of the affected tendon and muscle unit.
 
»
Physical therapy and activity modification are 
more successful than anti-inflammatory 
 
»
Tendinopathy involving the wrist extensors, flexors, and 
pronators are very common complaints. The underlying 
mechanism is chronic repetitive overuse causing micro
-
trauma at the tendon insertion, although acute injuries can 
occur as well if the tendon is strained due to excessive 
loading. The traditional term “epicondylitis” is a misnomer 
because histologically tendinosis or degeneration in the 
tendon is seen rather than acute inflammation. Therefore, 
these entities should be referred to as “tendinopathy” or 
“tendinosis. ” Lateral epicondylosis involves the wrist exten
-
sors, especially the extensor carpi radialis brevis. This is 
usually caused be lifting with the wrist and the elbow 
extended. Medial epicondylosis involves the wrist flexors 
and most commonly the pronator teres tendon. Ulnar neu
-
ropathy and cervical radiculopathy should be considered 
in the differential diagnosis.
 
»
For lateral epicondylosis, the patient describes pain with 
the arm and wrist extended. For example, common com
-
plaints include pain while shaking hands, lifting objects, 
using a computer mouse, or hitting a backhand in tennis 
(“tennis elbow”). Medial epicondylosis presents with pain 
during motions in which the arm is repetitively pronated 
or the wrist is flexed. This is also known as “golfer’s elbow” 
due to the motion of turning the hands over during the golf 
swing. For either, tenderness directly over the epicondyle is 
present, especially over the posterior aspect where the ten
-
don insertion occurs. The proximal tendon and musculo
-
tendinous junction can also be sore. To confirm that the 
pain is due to tendinopathy, pain can be reproduced over 
the epicondyle with resisted wrist extension and third digit 
extension for lateral epicondylosis and resisted wrist pro
-
nation and wrist flexion for medial epicondylosis. The pain 
is also often reproduced with passive stretching of the 
affected muscle groups, which can be performed with the 
arm in extension. It is useful to check the ulnar nerve 
(located in a groove at the posteromedial elbow) for ten
-
derness as well as to perform a Spurling test for cervical 
radiculopathy.
B. Imaging
Radiographs are often normal, although a small traction 
spur may be present in chronic cases (enthesopathy). 
Diagnostic investigations are usually unnecessary, unless 
the patient does not improve after up to 3 months of con
-
servative treatment. At that point, a patient who demon
-
strates significant disability due to the pain should be 
assessed with an MRI or ultrasound. Ultrasound and MRI 
can visualize the tendon and confirm tendinosis or tears.
 
»
Treatment
Treatment is usually conservative, including patient educa
-
tion regarding activity modification and management of 
symptoms. Ice and NSAIDs can help with pain. The main
-
stay of treatment is physical therapy exercises. The most 
important steps are to begin a good stretching program 
followed by strengthening exercises, particularly eccentric 
ones. Counterforce elbow braces might provide some 
symptomatic relief, although there is no published evi
-
dence to support their use. If the patient has severe or long-

-
standing symptoms, injections can be considered. 
A randomized trial showed improvement with corticoste
-
roid injection at 1 month as well as evidence of decreased 
tendon thickness and Doppler changes but no improve
-
ment at 3 months. Treatments such as extracorporeal shock 
wave therapy and other injections have not shown clear 
long-term benefit. In a randomized controlled trial com
-
paring platelet-rich protein (PRP) injection to controls 
(n = 119), the PRP-treated patients reported 55.1% 
improvement in their pain scores at 12 weeks compared to 
47.4% in the active control group (
P
 = 0.163). At 24 weeks, 
the PRP-treated patients reported 71.5% improvement in 
their pain scores compared to 56.1% in the control group 
(
P
 = 0.019). Clinically significant improvement was 25% 
improvement of pain symptoms. The evidence suggests, 
however, that in most cases, PRP is a second-line treatment 
after physical therapy.
 
»
Patients not responding to 6 months of conservative treat
-
ment should be referred for an injection procedure (PRP or 
tenotomy), surgical debridement, or repair of the tendon.
Amin NH et al. Medial epicondylitis: evaluation and 
management. J Am Acad Orthop Surg. 2015 Jun;23(6):
 
348–55. [PMID: 26001427]
Mishra AK et al. Efficacy of platelet-rich plasma for chronic ten
-
nis elbow: a double-blind, prospective, multicenter, random
-
ized controlled trial of 230 patients. Am J Sports 
Med. 2014 Feb;42(2):463–71. [PMID: 23825183]
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Sirico F et al. Local corticosteroid versus autologous blood injec
-
tions in lateral epicondylitis: meta-analysis of randomized 
controlled trials. Eur J Phys Rehabil Med. 2017 Jun;53(3): 
483–91. [PMID: 27585054]
Sayegh ET et al. Does nonsurgical treatment improve longitudi
-
nal outcomes of lateral epicondylitis over no treatment? 
A meta-analysis. Clin Orthop Relat Res. 2015 Mar;473(3): 
1093–107. [PMID: 25352261]
2. Carpal Tunnel Syndrome
 
»
Pain, burning, and tingling in the distribution of 
the median nerve.
 
»
Initially, most bothersome during sleep.
 
»
Late weakness or atrophy of the thenar 
eminence.
 
»
Can be caused by repetitive wrist activities.
 
»
Commonly seen during pregnancy and in patients 
with diabetes mellitus or rheumatoid arthritis.
 
»
An entrapment neuropathy, carpal tunnel syndrome is a 
painful disorder caused by compression of the median 
nerve between the carpal ligament and other structures 
within the carpal tunnel. The contents of the tunnel can be 
compressed by synovitis of the tendon sheaths or carpal 
joints, recent or malhealed fractures, tumors, tissue infil
-
tration, and occasionally congenital syndromes (eg, muco
-
polysaccharidoses). The disorder may occur in fluid 
retention of pregnancy, in individuals with a history of 
repetitive use of the hands, or following injuries of the 
wrists. Carpal tunnel syndrome can also be a feature of 
many systemic diseases, such as rheumatoid arthritis and 
other rheumatic disorders (inflammatory tenosynovitis), 
myxedema, amyloidosis, sarcoidosis, leukemia, acromegaly, 
and hyperparathyroidism. There is a familial type of carpal 
tunnel syndrome in which no etiologic factor can be 
 
»
The initial symptoms are pain, burning, and tingling in the 
distribution of the median nerve (the palmar surfaces of 
the thumb, the index and long fingers, and the radial half 
of the ring finger). Aching pain may radiate proximally 
into the forearm and occasionally proximally to the shoul
-
der and over the neck and chest. Pain is exacerbated by 
manual activity, particularly by extremes of volar flexion or 
dorsiflexion of the wrist. It is most bothersome at night. 
Impairment of sensation in the median nerve distribution 
may or may not be demonstrable. Subtle disparity between 
the affected and opposite sides can be shown by testing for 
two-point discrimination or by requiring the patient to 
identify different textures of cloth by rubbing them between 
the tips of the thumb and the index finger. A Tinel or Pha
-
len sign may be positive. A 
Tinel sign
 is tingling or shock-
like pain on volar wrist percussion. The 
Phalen sign
 is pain 
or paresthesia in the distribution of the median nerve when 
the patient flexes both wrists to 90 degrees for 60 seconds. 
The 
carpal compression test
, in which numbness and 
tingling are induced by the direct application of pressure 
over the carpal tunnel, may be more sensitive and specific 
than the Tinel and Phalen tests. Muscle weakness or atro
-
phy, especially of the thenar eminence, can appear later 
than sensory disturbances as compression of the nerve 
worsens.
B. Imaging
Ultrasound can demonstrate flattening of the median 
nerve beneath the flexor retinaculum. Sensitivity of ultra
-
sound for carpal tunnel syndrome is variable but estimated 
between 54% and 98%.
Electromyography and nerve conduction studies show 
evidence of sensory conduction delay before motor delay, 
which can occur in severe cases.
 
»
Treatment
Treatment is directed toward relief of pressure on the 
median nerve. When a causative lesion is discovered, it 
should be treated appropriately. Otherwise, patients in 
whom carpal tunnel syndrome is suspected should modify 
their hand activities. The affected wrist can be splinted in 
the neutral position for up to 3 months, but a series of

the neutral position for up to 3 months, but a series of 
Cochrane reviews show limited evidence for splinting, 
therapeutic ultrasound, exercises, and ergonomic 
positioning. Oral corticosteroids or NSAIDs can also be 
tried. Methylprednisolone injections were found to have 
more effect at 10 weeks than placebo, but the benefits 
diminished by 1 year. A randomized, controlled trial 
showed both corticosteroid injection and surgery resolved 
symptoms but only decompressive surgery led to resolu
-
tion of neurophysiologic changes.
Compared to trigger finger management, which usu
-
ally includes injections, as many as 71% of patients with 
carpal tunnel directly undergo surgery without first 
getting injections. Carpal tunnel release surgery can be 
beneficial if the patient has a positive electrodiagnostic 
test, at least moderate symptoms, high clinical probability, 
unsuccessful nonoperative treatment, and symptoms last
-
ing longer than 12 months. Surgery can be done with an 
open approach or endoscopically, both yielding similar 
good improvements.
 
»
•	
If symptoms persist more than 3 months despite con
-
servative treatment, including the use of a wrist 
splint.
•	
If thenar muscle (eg, abductor pollicis brevis) weakness 
or atrophy develops.
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Andreu JL et al. Local injection versus surgery in carpal tunnel 
syndrome: neurophysiologic outcomes of a randomized clini
-
cal trial. Clin Neurophysiol. 2014 Jul;125(7):1479–84. [PMID: 
24321619]
Padua L et al. Carpal tunnel syndrome: clinical features, 
diagnosis, and management. Lancet Neurol. 2016 Nov; 
15(12):1273–84. [PMID: 27751557]
Sears ED et al. National utilization patterns of steroid injection 
and operative intervention for treatment of common hand 
conditions. J Hand Surg Am. 2016 Mar;41(3):367–73.e2. 
[PMID: 26774548]
Vasiliadis HS et al. Endoscopic release for carpal tunnel syn
-
drome. Cochrane Database Syst Rev. 2014 Jan 31;1:CD008265. 
[PMID: 24482073]
3. Dupuytren Contracture
 
»
Benign fibrosing disorder of the palmar fascia.
 
»
Contracture of one or more fingers can lead to 
limited hand function.
 
»
This relatively common disorder is characterized by hyper
-
plasia of the palmar fascia and related structures, with 
nodule formation and contracture of the palmar fascia. The 
cause is unknown, but the condition has a genetic predis
-
position and occurs primarily in white men over 50 years 
of age, particularly in those of Celtic descent. The inci
-
dence is higher among alcoholic patients and those with 
chronic systemic disorders (especially cirrhosis). It is also 
associated with systemic fibrosing syndrome, which 
includes plantar fibromatosis (10% of patients), Peyronie 
disease (1–2%), mediastinal and retroperitoneal fibrosis, 
and Riedel struma. The onset may be acute, but slowly 
progressive chronic disease is more common.
 
»
Dupuytren contracture manifests itself by nodular or cord-
like thickening of one or both hands, with the fourth and 
fifth fingers most commonly affected. The patient may 
complain of tightness of the involved digits, with inability 
to satisfactorily extend the fingers, and on occasion there is 
tenderness. The resulting cosmetic problems may be unap
-
pealing, but in general the contracture is well tolerated 
since it exaggerates the normal position of function of the 
hand.
 
»
Treatment
If the palmar nodule is growing rapidly, injections of triam
-
cinolone or collagenase into the nodule may be of benefit; 
the injection of collagenase 
 lyses 
collagen thereby disrupting the contracted cords. Surgical 
options include open fasciectomy, partial fasciectomy, or 
percutaneous needle aponeurotomy and are indicated in 
patients with significant flexion contractures. Recurrence 
is possible and there are more adverse events compared to 
nonoperative treatments. A multicenter study showed that 
collagenase injection and limited fasciectomy had similar 
improvements with contractures at the metacarpophalan
-
geal joints, while surgery had better results for contractures 
involving the proximal interphalangeal joints.
 
»
Referral can be considered when one or more digits are 
affected by severe contractures, which interfere with every
-
day activities and result in functional limitations.
Rodrigues JN et al. Surgery for Dupuytren’s contracture of the 
fingers. Cochrane Database Syst Rev. 2015 Dec 9; 
(12):CD010143. [PMID: 26648251]
Zhou C et al. Collagenase 
 versus lim
-
ited fasciectomy for Dupuytren’s contracture: outcomes from 
a multicenter propensity score matched study. Plast Reconstr 
Surg. 2015 Jul;136(1):87–97. [PMID: 25829153]
4. Bursitis
 
»
Often occurs around bony prominences where it 
is important to reduce friction.
 
»
Typically presents with local swelling that is 
painful acutely.
 
»
Septic bursitis can present without fever or 
systemic signs.
 
»
Inflammation of bursae—the synovium-like cellular mem
-
branes overlying bony prominences—may be secondary to 
trauma, infection, or arthritic conditions such as gout, rheu
-

»
-
-
matoid arthritis, or OA. Bursitis can result from infection. 
The two common sites are the olecranon (Figure 41–1) and 
prepatellar bursae; however, others include subdeltoid, 
ischial, trochanteric, and semimembranous-gastrocnemius 
(Baker cyst) bursae. The bursitis can be septic. Aseptic bur
-
sitis is usually afebrile.
 
»
Bursitis presents with focal tenderness and swelling and is 
less likely to affect range of motion of the adjacent joint. 
Olecranon or prepatellar bursitis, for example, causes an 
oval (or, if chronic, bulbous) swelling at the tip of the elbow 
or knee and does not affect joint motion. Tenderness, ery
-
thema and warmth, cellulitis, a report of trauma, or evi
-
dence of a skin lesion are more common in septic bursitis 
but can be present in aseptic bursitis as well. Patients with 
septic bursitis can be febrile but the absence of fever does 
not exclude infection; 
one-third of those with septic 
olecranon bursitis are afebrile
. A bursa can also become 
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symptomatic when it ruptures. This is particularly true for 
Baker cyst, whose rupture can cause calf pain and swelling 
that mimic thrombophlebitis.
B. Imaging
Imaging is unnecessary unless there is concern for osteo
-
myelitis, trauma or other underlying pathology. Ruptured 
Baker cysts are imaged easily by sonography or MRI. It 
may be important to exclude a deep venous thrombosis, 
which can be mimicked by a ruptured Baker cyst.
Acute swelling and redness at a bursal site calls for aspira
-
tion to rule out infection especially if the patient is either 
febrile (temperature more than 37.8
°
C) or has prebursal 
warmth (temperature difference greater than 2.2
°
C) or 
both. A bursal fluid white blood cell count of greater than 
1000/mcL indicates inflammation from infection, rheuma
-
toid arthritis, or gout. The bursal fluid of septic bursitis 
characteristically contains a purulent aspirate, fluid-to-
serum glucose ratio less than 50%, white cell count more 
than 3000 cells/mcL, polymorphonuclear cells more than 
50%, and a positive Gram stain for bacteria. Most cases are 
caused by 
 the Gram stain is positive 
in two-thirds.
 
»
Treatment
Bursitis caused by trauma responds to local heat, rest, 
NSAIDs, and local corticosteroid injections. Chronic, sta
-
ble olecranon bursa swelling usually does not require 
aspiration. Repetitive minor trauma to the olecranon bursa 
should be eliminated by avoiding resting the elbow on a 
hard surface or by wearing an elbow pad. For chronic asep
-
tic bursitis or when there are athletic or occupational 
demands, aspiration with intrabursal steroid injection can 
be performed. Aspiration of the olecranon bursa runs the 
risk of creating a chronic drainage site, which can be 
reduced by using a “zig-zag” approach with a small needle 
(25-gauge if possible) and pulling the skin over the bursa 
before introducing it. Applying a pressure bandage may 
also help prevent chronic drainage. Ultrasound-guided 
aspiration and injection can improve the accuracy of the 
procedures. Treatment of a ruptured Baker cyst includes 
rest, leg elevation, and possibly injection of triamcinolone, 
20–40 mg into the knee anteriorly (the knee compartment 
communicates with the cyst). However, corticosteroid 
injections in nonseptic bursitis have more complications 
and skin atrophy than simple symptomatic treatment.
Treatment for septic bursitis involves incision and 
drainage and antibiotics usually delivered intravenously.
 
»
•	
Surgical removal of the bursa is indicated only for cases 
in which repeated infections occur.
•	
Elective removal for persistent symptoms affecting 
activities of daily living can be considered.
Baumbach SF et al. Prepatellar and olecranon bursitis: literature 
review and development of a treatment algorithm. Arch 
Orthop Trauma Surg. 2014 Mar;134(3):359–70. [PMID: 
24305696]
Reilly D et al. Olecranon bursitis. J Shoulder Elbow Surg. 
2016 Jan;25(1):158–67. [PMID: 26577126]
HIP
1. Hip Fractures
 
»
Internal rotation of the hip is the best provocative 
diagnostic maneuver.
 
»
Hip fractures should be surgically repaired as soon 
as possible (within 24 hours).
 
»
Delayed treatment of hip fractures in older adults 
leads to increased complications and mortality.
 
»
Approximately 4% of the 7.9 million fractures that occur 
each year in the United States are hip fractures. There is a 
high mortality rate among older adult patients following 
 
▲
Figure 41–1.
 
Chronic aseptic olecranon bursitis 
without erythema or tenderness. 
Medicine,
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hip fracture, with death occurring in 8–9% within 30 days 
and in approximately 25–30% within 1 year. Osteoporosis, 
female sex, height greater than 5-foot 8-inches, and age 
over 50 years are risk factors for hip fracture. Hip fractures 
usually occur after a fall. High-velocity trauma is needed in 
younger patients. Stress fractures can occur in athletes or 
individuals with poor bone mineral density following 
repetitive loading activities.
 
»
Patients typically report pain in the groin, though pain 
radiating to the lateral hip, buttock, or knee can also com
-
monly occur. If a displaced fracture is present, the patient 
will not be able to bear weight and the leg may be externally 
rotated. Gentle logrolling of the leg with the patient supine 
helps rule out a fracture. Examination of the hip demon
-
strates pain with deep palpation in the area of the femoral 
triangle (similar to palpating the femoral artery). Provided 
the patient can tolerate it, the clinician can, with the patient 
supine, flex the hip to 90 degrees with the knee flexed to 
90 degrees. The leg can then be internally and externally 
rotated to assess the range of motion on both sides. Pain 
with internal rotation of the hip is the most sensitive test to 
identify intra-articular hip pathology. Hip flexion, exten
-
sion, abduction, and adduction strength can be tested.
Patients with hip stress fractures have less pain on physi
-
cal examination than described previously but typically have 
pain with weight bearing. The Trendelenburg test can be 
performed to examine for weakness or instability of the hip 
abductors, primarily the gluteus medius muscle; the patient 
balances first on one leg, raising the non-standing knee 
toward the chest. The clinician can stand behind the patient 
and observe for dropping of the pelvis and buttock on the 
non-stance side. Another functional test is asking the patient 
to hop or jump during the examination. If the patient has a 
compatible clinical history of pain and is unable or unwilling 
to hop, then a stress fracture should be ruled out. The back 
should be carefully examined in patients with hip com
-
plaints, including examining for signs for sciatica.
Following displaced hip fractures, a thorough medical 
evaluation and treatment should be pursued to maximize 
the patients’ ability to undergo operative intervention. 
Patients who are unable to get up by themselves may have 
been immobile for hours or even days following their falls. 
Thus, clinicians must exclude rhabdomyolysis, hypother
-
mia, deep venous thrombosis, pulmonary embolism, and 
other conditions that can occur with prolonged immobili
-
zation. Delay of operative intervention leads to an increased 
risk of perioperative morbidity and mortality.
B. Imaging
Useful radiographic views of the hip include AP views of the 
pelvis and bilateral hips and frog-leg-lateral views of the pain
-
ful hip. A CT scan or MRI may be necessary to identify the 
hip fracture pattern or to evaluate non-displaced fractures. 
Hip fractures are generally described by location, including 
femoral neck, intertrochanteric, or subtrochanteric.
 
»
Treatment
Almost all patients with a hip fracture will require surgery 
and may need to be admitted to the hospital for pain con
-
trol while they await surgery. 
Surgery is recommended 
within the first 24 hours
 because studies have shown that 
delaying surgery 48 hours results in at least twice the rate 
of major and minor medical complications, including 
pneumonia, pressure injuries (formerly pressure ulcers), 
and deep venous thrombosis. High-volume centers have 
multidisciplinary teams (including orthopedic surgeons, 
internists, social workers, and specialized physical thera
-
pists) to comanage these patients, which improves periop
-
erative medical care and expedites preoperative evaluation 
leading to reduced costs.

-
-
Stress fractures in active patients require a period of 
protected weight bearing and a gradual return to activities, 
although it may take 4–6 months before a return to normal 
activities. Femoral neck fractures are commonly treated 
with hemiarthroplasty or total hip replacement. This 
allows the patient to begin weight bearing immediately 
postoperatively. Peritrochanteric hip fractures are treated 
with open reduction internal fixation, where plate and 
screw construct or intramedullary devices are used. The 
choice of implant will depend on the fracture pattern. Since 
fracture fixation requires the fracture to proceed to union, 
the patient may need to have protected weight bearing dur
-
ing the early postoperative period. Dislocation, peripros
-
thetic fracture, and avascular necrosis of the hip are 
common complications after surgery. Patients should be 
mobilized as soon as possible postoperatively to avoid pul
-
monary complications and pressure injuries. Supervised 
physical therapy and rehabilitation are important for the 
patient to regain as much function as possible. Unfortu
-
nately, most patients following hip fractures will lose some 
degree of independence. Patients with hip fracture surgery 
when compared with elective total hip replacement have 
been shown to have higher risk of in-hospital mortality.
 
»
Bone density screening can identify patients at risk for 
osteopenia or osteoporosis, and treatment can be planned 
accordingly. There is strong evidence that bisphosphonates, 
denosumab, and teriparatide reduce fractures compared 
with placebo, with relative risk reductions of 0.60–0.80 for 
nonvertebral fractures. Nutrition (calcium and vitamin D 
intake) and bone health (bone densitometry, serum cal
-
cium and 25-OH vitamin D levels) should be reviewed with 
the patient (see Chapter 26). For patients with decreased 
mobility, systemic anticoagulation should be considered to 
avoid deep venous thrombosis (see Table 14–14). Fall pre
-
vention exercise programs are available for older adult 
patients at risk for falls and hip fractures. Hip protectors are 
uncomfortable and have less use in preventing fractures.
 
»
•	
All patients in whom hip fracture is suspected.
•	
All patients with hip fracture or in whom the diagnosis 
is uncertain after radiographs.
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Crandall CJ et al. Comparative effectiveness of pharmacologic 
treatments to prevent fractures: an updated systematic review. 
Ann Intern Med. 2014 Nov 18;161(10):711–23. [PMID: 
25199883]
Le Manach Y et al. Outcomes after hip fracture surgery compared 
with elective total hip replacement. JAMA. 2015 Sep 15; 
 
314(11):1159–66. [PMID: 26372585]
Swart E et al. Dedicated perioperative hip fracture comanage
-
ment programs are cost-effective in high-volume centers: an 
economic analysis. Clin Orthop Relat Res. 2016 Jan; 
474(1):222–33. [PMID: 26260393]
2. Hip Osteoarthritis
 
»
Pain deep in the groin on the affected side.
 
»
Swelling.
 
»
Degeneration of joint cartilage.
 
»
Loss of active and passive range of motion in 
severe OA.
 
»
In the United States, the prevalence of OA will grow as the 
number of persons over age 65 years doubles to more than 
70 million by 2030. Cartilage loss and OA symptoms are 
preceded by damage to the collagen-proteoglycan matrix. 
The etiology of OA is often multifactorial, including previ
-
ous trauma, prior high-impact activities, genetic factors, 
obesity, and rheumatologic or metabolic conditions. 
Femoroacetabular impingement, which affects younger 
active patients, is considered an early development of hip OA.
 
»
OA usually causes pain in the affected joint with loading of 
the joint or at the extremes of motion. Mechanical 
symptoms—such as swelling, grinding, catching, and 
locking—suggest internal derangement, which is indicated 
by damaged cartilage or bone fragments that affect the 
smooth range of motion expected at an articular joint. Pain 
can also produce the sensation of “buckling” or “giving 
way” due to muscle inhibition. As the joint degeneration 
becomes more advanced, the patient loses active range of 
motion and may lose passive range of motion as well.
Patients complain of pain deep in the groin on the 
affected side and have problems with weight-bearing 
activities such as walking, climbing stairs, and getting up 
from a chair. They may limp and develop a lurch during 
their gait, leaning toward the unaffected side as they walk 
to reduce pressure on the hip.
B. Imaging
An anterior-posterior weight-bearing radiograph of the 
pelvis with a lateral view of the symptomatic hip 
are preferred views for evaluation of hip OA. Joint space 
narrowing and sclerosis suggest early OA, while osteo
-
phytes near the femoral head or acetabulum and subchon
-
dral bone cysts are more advanced changes. The sensitivity 
of radiographic hip OA for hip pain localized to the groin 
was 36.7%, specificity 90.5%, positive predictive value 
6.0%, and negative predictive value 98.9%. However, not all 
patient with radiographic hip OA had hip or groin pain; 
the converse is also true because of the low sensitivity of 
the radiographs. After age 35, MRI of the hips already show 
labral changes in almost 70% of asymptomatic patients.
 
»
Treatment
Changes in the articular cartilage are irreversible. There
-
fore, a cure for the diseased joint is not possible, although 
symptoms or structural issues can be addressed to try to 
maintain activity level. Conservative treatment for patients 
with OA includes activity modification, proper footwear, 
therapeutic exercises, weight loss, and use of assistive 
devices (such as a cane). A 2014 randomized study found 
that physical therapy did not lead to greater improvement 
in pain or function compared with sham treatment in 
patients with hip OA. Analgesics may be effective in some 
cases. Corticosteroid injections can be considered for 
short-term relief of pain; however, hip injections are best 
performed under fluoroscopic, ultrasound, or CT guidance 
to ensure accurate injection in the joint.
Joint replacement surgeries are effective and cost-effective 
for patients with significant symptoms and functional limi

-
tations, providing improvements in pain, function, and 
quality of life. Minimally invasive surgeries and computer-
assisted navigation during operation are being investigated 
as methods to improve techniques (eg, accurate placement 
of the hardware implant) and to reduce complication rates.
Hip resurfacing surgery is a newer joint replacement 
technique. Rather than use a traditional artificial joint 
implant of the whole neck and femur, only the femoral 
head is removed and replaced. Evidence to date suggests 
that hip resurfacing is comparable to total hip replacement 
and is a viable alternative for younger patients. The cumu
-
lative survival rate of this implant at 10 years is estimated 
to be 94%. Concerns following resurfacing surgery include 
the risk of femoral neck fracture and collapse of the head. 
In a systematic review of national databases, the average 
time to revision was 3.0 years for metal-on-metal hip 
resurfacing versus 7.8 years for total hip arthroplasty. 
Dislocations were more frequent with total hip arthro
-
plasty than metal-on-metal hip resurfacing: 4.4 vs 0.9 per 
1000 person-years, respectively.
Guidelines recommend prophylaxis for venous 
thromboembolic disease for a minimum of 14 days after 
arthroplasty of the hip or knee using warfarin, low-
molecular-weight heparin, fondaparinux, aspirin, 
rivaroxaban, dabigatran, apixaban, or portable mechanical 
compression (see Table 14–14).
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»
Patients with sufficient disability, limited benefit from con
-
servative therapy, and evidence of severe OA can be 
referred for joint replacement surgery.
Bennell KL et al. Effect of physical therapy on pain and function 
in patients with hip osteoarthritis: a randomized clinical trial. 
JAMA. 2014 May 21;311(19):1987–97. [PMID: 24846036]
Kim C et al. Association of hip pain with radiographic evidence 
of hip osteoarthritis: diagnostic test study. BMJ. 2015 Dec 2; 
351:h5983. [PMID: 26631296]
Lieberman JR et al. Prevention of venous thromboembolic 
disease after total hip and knee arthroplasty. J Bone Joint Surg 
Am. 2013 Oct 2;95(19):1801–11. [PMID: 24088973]
Marshall DA et al. Hip resurfacing versus total hip arthroplasty: 
a systematic review comparing standardized outcomes. Clin 
Orthop Relat Res. 2014 Jul;472(7):2217–30. [PMID: 
24700446]
Nwachukwu BU et al. Arthroscopic versus open treatment of 
femoroacetabular impingement: a systematic review of 
medium- to long-term outcomes. Am J Sports Med. 2016 Apr; 
44(4):1062–8. [PMID: 26059179]
KNEE
1. Knee Pain
 
»
Effusion can occur with intra-articular pathology 
(eg, OA, meniscus and cruciate ligament tears).
 
»
Acute knee swelling (due to hemarthrosis) within 
2 hours may indicate ligament injuries or patellar 
dislocation or fracture.
 
»
The knee is the largest joint in the body and is susceptible 
to injury from trauma, inflammation, infection, and degen
-
erative changes. The knee is a hinge joint. The joint line 
exists between the femoral condyles and tibial plateaus. 
Separating and cushioning these bony surfaces is the lateral 
and medial meniscal cartilage, which functions as a shock 
absorber during weight bearing, protecting the articular 
cartilage. The patella is a large sesamoid bone anterior to 
the joint. It is embedded in the quadriceps tendon, and it 
articulates with the trochlear groove of the femur. Poor 
patellar tracking in the trochlear groove is a common 
source of knee pain especially when the cause is atraumatic 
in nature. The knee is stabilized by the collateral ligaments 
against varus (lateral collateral ligament) and valgus (medial 
collateral ligament) stresses. The tibia is limited in its ante
-
rior movement by the anterior cruciate ligament (ACL) and 
in its posterior movement by the posterior cruciate liga
-
ment (PCL). The bursae of the knee are located between the 
skin and bony prominences. They act to decrease friction of 
tendons and muscles as they move over adjacent bony 
structures. Excessive external pressure or friction can lead 
to swelling and pain of the bursae. The prepatellar bursae 
(located between the skin and patella), and the pes anserine 
bursa (which is medial and inferior to the patella, just below 
the tibial plateau) are most commonly affected. Joint fluid, 
when excessive due to synovitis or trauma, can track poste
-
riorly through a potential space, resulting in a popliteal cyst 
(also called a Baker cyst). Other structures that are suscep
-
tible to overuse injury and may cause knee pain following 
repetitive activity include the patellofemoral joint and the 
iliotibial band. OA of the knees is common after 50 years of 
age and can develop due to previous trauma, aging, activi
-
ties, alignment issues, and genetic predisposition.
 
»
Evaluation of knee pain should begin with general ques
-
tions regarding duration and rapidity of symptom onset 
and the mechanism of injury or aggravating symptoms. 
Overuse or degenerative problems can occur with stress or 
compression from sports, hobbies, or occupation. A his
-
tory of trauma, previous orthopedic problems with, or 
surgery to, the affected knee should also be specifically 
queried. Symptoms of infection (fever, recent bacterial 
infections, risk factors for sexually transmitted infections

infections, risk factors for sexually transmitted infections 
[such as gonorrhea] or other bacterial infections [such as 
staphylococcal infection]) should always be elicited.
Common symptom complaints include the following:
1.
 
Presence of grinding, clicking, or popping with bending 
may be indicative of OA or the patellofemoral syndrome.
2.
 
“Locking” or “catching” when walking suggests an 
internal derangement, such as meniscal injury or a 
loose body in the knee.
3.
 
Intra-articular swelling of the knee or an effusion indi
-
cates an internal derangement or a synovial pathology. 
Large swelling may cause a popliteal (Baker) cyst. 
Acute swelling within minutes to hours suggests a 
hemarthrosis, most likely due to an ACL injury, frac
-
ture, or patellar dislocation, especially if trauma is 
involved.
4.
 
Lateral “snapping” with flexion and extension of the 
knee may indicate inflammation of the iliotibial band.
5.
 
Pain that is worsened with bending and walking down
-
stairs suggests issues with the patellofemoral joint, usu
-
ally degenerative such as chondromalacia of the patella 
or OA.
6.
 
Pain that occurs when rising after prolonged sitting 
suggests a problem with tracking of the patella.
A careful history coupled with a physical examination 
that includes observation, palpation, and range of motion 
testing, as well as specific tests for particular anatomic 
structures is frequently sufficient to establish a diagnosis. 
When there is a knee joint effusion caused by increased 
fluid in the intra-articular space, physical examination will 
demonstrate swelling in the hollow or dimple around the 
patella and distention of the suprapatellar space.
Table 41–5 shows the differential diagnosis of knee 
pain, and Table 41–6 outlines possible diagnoses based on 
the location of pain.
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Laboratory testing of aspirated joint fluid, when indicated, 
can lead to a definitive diagnosis in most patients (see 
Tables 20–2 and 20–3).
C. Imaging
Knee pain is evaluated with plain (weight-bearing) radio
-
graphs and MRI most commonly, but CT and ultrasound 
are sometimes useful.
An acute hemarthrosis represents bloody swelling that 
usually occurs within the first 1–2 hours following trauma. 
In situations where the trauma may be activity-related and 
Table 41–5.
 
Differential diagnosis of knee pain.
Mechanical dysfunction or disruption
Internal derangement of the knee: injury to the menisci or 
ligaments
Degenerative changes caused by osteoarthritis
Dynamic dysfunction or misalignment of the patella
Fracture as a result of trauma
Intra-articular inflammation or increased pressure
ligaments
Inflammation or infection of the knee joint
Ruptured popliteal (Baker) cyst
Peri-articular inflammation
ligaments
Prepatellar or anserine bursitis
Ligamentous sprain
Table 41–6.
 
Location of common causes of knee pain.
Medial knee pain
Medial compartment osteoarthritis
Medial collateral ligament strain
Medial meniscal injury
Anserine bursitis (pain over the proximal medial tibial plateau)
Anterior knee pain
Patellofemoral syndrome (often bilateral)
Prepatellar bursitis (associated with swelling anterior to the 
patella)
“Jumper’s knee” (pain at the inferior pole of the patella)
Gout or other inflammatory disorder
Lateral knee pain
Lateral meniscal injury
Iliotibial band syndrome (pain superficially along the distal 
iliotibial band near lateral femoral condyle or lateral tibial 
insertion)
Lateral collateral ligament sprain (rare)
Posterior knee pain
Popliteal (Baker) cyst
Meniscal tears
Hamstring or calf tendinopathy
not a result of a fall or collision, the differential diagnosis 
most commonly includes ACL tear (responsible for more 
than 70% in adults), fracture (patella, tibial plateau, femo
-
ral supracondylar, growth plate [physeal]), and patellar 
dislocation. Meniscal tears are unlikely to cause large 
hemarthrosis.
2. Anterior Cruciate Ligament Injury
 
»
An injury involving an audible pop when the knee 
buckles.
 
»
Acute swelling immediately (or within 2 hours).
 
»
Instability occurs with lateral movement activities 
and going down stairs.
 
»
The anterior cruciate ligament (ACL) connects the poste
-
rior aspect of the lateral femoral condyle to the anterior 
aspect of the tibia. Its main function is to control anterior 
translation of the tibia on the femur. It also provides rota
-
tionally stability of the tibia on the femur. ACL tears are 
common with sporting injuries. They can result from both 
contact (valgus blow to the knee) and non-contact 
(jumping, pivoting, and deceleration) activities. The patient 
usually falls down following the injury, has acute swelling 
and difficulty with weight bearing and complains of insta
-
bility. ACL injuries are common in skiing, soccer, football, 
and basketball among young adolescents and middle-aged 
patients. Prepubertal and older patients usually sustain 
fractures instead of ligamentous injuries.
 
»
Acute ACL injuries usually lead to acute swelling of the knee, 
causing difficulty with motion. After the swelling has 
resolved, the patient can walk with a “stiff-knee” gait or 
quadriceps avoidance gait because of the instability. Patients 
describe symptoms of instability while performing side-to-
side maneuvers or descending stairs. Stability tests assess the 
amount of laxity of the knee while performing side-to-side 
maneuvers or descending stairs. The Lachman test (84–87% 
sensitivity and 93% specificity) is performed with the patient

sensitivity and 93% specificity) is performed with the patient 
lying supine and the knee flexed to 20–30 degrees 
(Table 41–7). The clinician grasps the distal femur from the 
lateral side and the proximal tibia with the other hand on 
the medial side. With the knee in neutral position, stabilize 
the femur, and pull the tibia anteriorly using a similar force 
to lifting a 10- to 15-pound weight. Excessive anterior trans
-
lation of the tibia compared with the other side indicates 
injury to the ACL. The anterior drawer test (48% sensitivity 
and 87% specificity) is performed with the patient lying 
supine and the knee flexed to 90 degrees (Table 41–7). The 
clinician stabilizes the patient’s foot by sitting on it and 
grasps the proximal tibia with both hands around the calf 
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and pulls anteriorly. A positive test finds ACL laxity com
-
pared with the unaffected side. The pivot shift test is used to 
determine the amount of rotational laxity of the knee 
(Table 41–7). The patient is examined while lying supine 
with the knee in full extension. It is then slowly flexed while 
applying internal rotation and a valgus stress. The clinician 
feels for a subluxation at 20–40 degrees of knee flexion. The 
patient must remain very relaxed to have a positive test.
Table 41–7.
 
Knee examination.
Maneuver
Examine for the alignment of the lower extremities (varus, 
 
valgus, knee recurvatum), ankle eversion and foot pronation, 
gait, SEADS.
Palpation
Include important landmarks: patellofemoral joint, medial and 
lateral joint lines (especially posterior aspects), pes anserine 
bursa, distal iliotibial band and Gerdy tubercle (iliotibial band 
insertion).
Check range of motion actively (patient performs) and passively 
(clinician performs), especially with flexion and extension of 
the knee normally 0–10 degrees of extension and 
120–150 degrees of flexion.
Knee strength testing
Test resisted knee extension and knee flexion strength manually.
Ligament Stress Testing
Lachman test
Performed with the patient lying supine, and the knee flexed to 
20–30 degrees. The examiner grasps the distal femur from the 
lateral side, and the proximal tibia with the other hand on the 
medial side. With the knee in neutral position, stabilize the 
femur, and pull the tibia anteriorly using a similar force to 
lifting a 10–15 pound weight. Excessive anterior translation of 
the tibia compared with the other side indicates injury to the 
anterior cruciate ligament.
Anterior drawer
Performed with the patient lying supine and the knee flexed to 
90 degrees. The clinician stabilizes the patient’s foot by sitting 
on it and grasps the proximal tibia with both hands around the 
calf and pulls anteriorly. A positive test finds anterior cruciate 
ligament laxity compared with the unaffected side.
(
continued
)
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Knee examination. (continued)
Maneuver
Valgus stress
Performed with the patient supine. The clinician should stand on 
the outside of the patient’s knee. With one hand, the clinician 
should hold the ankle while the other hand is supporting the 
leg at the level of the knee joint. A valgus stress is applied at 
the ankle to determine pain and laxity of the medial collateral 
ligament. The test should be performed at both 30 degrees 
and at 0 degrees of knee extension.
Varus stress
The patient is again placed supine. For the right knee, the 
clinician should be standing on the right side of the patient. 
The left hand of the examiner should be holding the ankle 
while the right hand is supporting the lateral thigh. A varus 
stress is applied at the ankle to determine pain and laxity of 
the lateral collateral ligament. The test should be performed at 
both 30 degrees and at 0 degrees of knee flexion.
(
continued
)
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Maneuver
Meniscal Signs
McMurray test
Performed with the patient lying supine. The clinician flexes the 
knee until the patient reports pain. For this test to be valid, it 
must be flexed pain-free beyond 90 degrees. The clinician 
externally rotates the patient’s foot and then extends the knee 
while palpating the medial knee for “click” in the medial 
compartment of the knee or pain reproducing pain from a 
meniscus injury. To test the lateral meniscus, the same 
maneuver is repeated while rotating the foot internally 
(53% sensitivity and 59–97% specificity).
Modified McMurray
Performed with the hip flexed to 90 degrees. The knee is then 
flexed maximally with internal or external rotation of the 
lower leg. The knee can then be rotated with the lower leg in 
internal or external rotation to capture the torn meniscus 
underneath the condyles. A positive test is pain over the joint 
line while the knee is being flexed and internally or externally 
rotated.
(
continued
)
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B. Imaging
Plain radiographs are usually negative in ACL tears but are 
useful to rule out fractures. A small avulsion injury can 
sometimes be seen over the lateral compartment of the 
knee (“Segond” fracture) and is pathognomonic of an ACL 
injury. An ACL injury that avulsed the tibial spine can be 
seen in radiographs. MRI is the best tool to diagnose ACL 
tears and associated articular and meniscal cartilage issues. 
It has greater than 95% sensitivity and specificity for 
ACL tears.
 
»
Treatment
Most young and active patients will require surgical recon
-
struction of the ACL. Some data suggest reconstruction 
within 5 months has better outcomes. However, a small 
randomized trial suggested that acute ACL injuries can be 
treated nonoperatively and delayed ACL reconstruction 
had similar outcomes to acute ACL reconstructions but 
patients for whom the reconstruction is delayed have more 
cartilage or meniscus problems at the time of surgery. 
Common surgical techniques use the patient’s own tissue, 
usually the patellar or hamstring tendons (autograft) or a 
cadaver graft (allograft) to arthroscopically reconstruct the 
torn ACL. Different patients groups experienced improved 
results with specific surgical graft choices. However, 
allografts do have a higher failure rate when compared with 
autografts. Recovery from surgery usually requires 
 
6 months.
Nonoperative treatments are usually reserved for older 
patients or those with a very sedentary lifestyle. Physical 
therapy can focus on hamstring strengthening and core sta
-
bility. An ACL brace can help stability. Longitudinal studies 
have demonstrated that nonoperative management of an 
ACL tear can lead to a higher incidence of meniscus tears.
 
»
•	
Almost all ACL tears should be referred to an orthope
-
dic surgeon for evaluation.
•	
Individuals with instability in the setting of a chronic 
ACL tear (greater than 6 months) should be considered 
for surgical reconstruction.
•	
Patients with an ACL tear and associated meniscus or 
articular injuries may benefit from surgery to address 
the other injuries.
Kaeding CC et al. Risk factors and predictors of subsequent ACL 
injury in either knee after ACL reconstruction: prospective 
analysis of 2488 primary ACL reconstructions from the Moon 
Cohort. Am J Sports Med. 2015 Jul;43(7):1583–90. [PMID: 
25899429]
Sanders JO et al. Treatment of anterior cruciate ligament 
injuries. J Am Acad Orthop Surg. 2016 Aug;24(8):e81–3. 
[PMID: 27355285]
Shea KG et al. The American Academy of Orthopaedic Surgeons 
evidence-based guideline on management of anterior cruciate 
ligament injuries. J Bone Joint Surg Am. 2015 Apr 15; 
97(8):672–4. [PMID: 25878313]
 
Maneuver
Thessaly test
Performed with the patient standing on one leg with knee 
slightly flexed. The patient is asked to twist the knee while 
standing on one leg. Pain can be elicited during twisting 
motion.
SEADS, swelling, erythema, atrophy, deformity, and (surgical) scars.
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3. Collateral Ligament Injury
 
»
Caused by a valgus or varus blow or stress to the 
knee.
 
»
Pain and instability in the affected area.
 
»
Limited range of motion.
 
»
The medial collateral ligament (MCL) is the most commonly 
injured ligament in the knee. It is usually injured with a val
-
gus stress to the partially flexed knee. It can also occur with a 
blow to the lateral leg. The MCL is commonly injured with 
acute ACL injuries. The lateral collateral ligament (LCL) is 
less commonly injured, but this can occur with a medial blow 
to the knee. Since both collateral ligaments are extra-articular, 
injuries to these ligaments may not lead to any intra-articular 
effusion. Affected patients may have difficulty walking ini
-
tially, but this can improve when the swelling decreases.
 
»
The main clinical findings for patients with collateral liga
-
ment injuries are pain along the course of the ligaments. The 
patient may have limited range of motion due to pain, espe
-
cially during the first 2 weeks following the injury. The best 
tests to assess the collateral ligaments are the varus and valgus 
stress tests. The sensitivity of the tests is as high as 86–96%.
The 
valgus stress test
 is performed with the patient 
supine (Table 41–7). The clinician should stand on the 
outside of the patient’s knee. With one hand, the clinician 
should hold the ankle while the other hand is supporting 
the leg at the level of the knee joint. A valgus stress is 
applied at the ankle to determine pain and laxity of the 
MCL. The test should be performed at both 30 degrees and 
at 0 degrees of knee extension.
For the 
varus stress test
, the patient is again placed supine 
(Table 41–7). For the right knee, the clinician should be stand
-
ing on the right side of the patient. The clinician’s left hand 
should be holding the ankle while the right hand is supporting 
the lateral thigh. A varus stress is applied at the ankle to deter
-
mine pain and laxity of the LCL. The test should be performed 
at both 30 degrees and at 0 degrees of knee flexion.
The test results can be graded from 1 to 3. Grade 1 is 
when the patient has pain with varus/valgus stress test but 
no instability. With grade 2 injuries, the patient has pain, 
and the knee shows instability at 30 degrees of knee flexion. 
In grade 3 injuries, the patient has marked instability but 
not much pain. The knee is often unstable at both 30 degrees 
and 0 degrees of knee flexion.
B. Imaging
Radiographs are usually nondiagnostic except for avulsion 
injuries. However, radiographs should be used to rule out 
fractures that can occur with collateral ligament injuries. 
Isolated MCL injuries usually do not require evaluation by 
MRI, but MRI should be used to evaluate possible associ
-
ated cruciate ligament injuries. LCL or posterolateral cor
-
ner injuries should have MRI evaluation to exclude 
associated injuries and to determine their significance.
 
»
Treatment
The majority of MCL injuries can be treated with protected 
weight bearing and physical therapy. For grade 1 and 2 
injuries, the patient can usually bear weight as tolerated 
with full range of motion. A hinged knee brace can be 
given to patients with grade 2 MCL tears to provide 
stability. Early physical therapy is recommended to protect 
range of motion and muscle strength. Grade 3 MCL inju
-
ries require long leg braces to provide stability. Patients can 
weight-bear, but only with the knee locked in extension 
with a brace. The motion can then be increased with the 
brace unlocked. Grade 3 injuries can take up to 6–8 weeks 
to heal. MCL injuries rarely need surgery. LCL injuries are 
less common but are usually associated with other ligament 
injuries (such as ACL and PCL). LCL injuries do not 
recover well with nonoperative treatment and usually

recover well with nonoperative treatment and usually 
require urgent surgical repair or reconstruction.
 
»
•	
Symptomatic instability with chronic MCL tears or 
acute MCL tears with other ligamentous injuries.
•	
LCL or posterolateral corner injuries require urgent 
surgical repair or reconstruction (within 1 week).
Devitt BM et al. Physical examination and imaging of the lateral 
collateral ligament and posterolateral corner of the knee. 
Sports Med Arthrosc Rev. 2015 Mar;23(1):10–6. [PMID: 
25545645]
Pacheco RJ et al. Posterolateral corner injuries of the knee: a seri
-
ous injury commonly missed. J Bone Joint Surg Br. 2011 Feb; 
93(2):194–7. [PMID: 21282758]
4. Posterior Cruciate Ligament Injury
 
»
Usually follows an anterior trauma to the tibia, 
such as a dashboard injury during a motor vehicle 
accident.
 
»
The knee may freely dislocate and reduce.
 
»
One-third of multi-ligament injuries involving the 
PCL have neurovascular injuries.
 
»
The posterior cruciate ligament (PCL) is the strongest liga
-
ment in the knee. PCL injuries usually represent significant 
trauma and are highly associated with multi-ligament 
injuries and knee dislocations. More than 70–90% of PCL 
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injuries have associated injuries to the posterolateral cor
-
ner, MCL, and ACL. Neurovascular injuries occur in up to 
one-third of all knee dislocations or PCL injuries. 
There 
should be high suspicion for neurovascular injuries and 
a thorough neurovascular examination of the limb 
 
»
Most patients with acute injuries have difficulty with 
ambulation. Patients with chronic PCL injuries can ambu
-
late without gross instability but may complain of subjec
-
tive “looseness” and often report pain and dysfunction, 
especially with bending. Clinical examinations of PCL 
injuries include the 
“sag sign”
; the patient is placed supine 
and both hips and knees are flexed to 90 degrees. Because 
of gravity, the posterior cruciate ligament-injured knee 
will have an obvious set-off at the anterior tibia that is 
“sagging” posteriorly. The PCL ligament can also be exam
-
ined using the 
posterior drawer test;
 the patient is placed 
supine with the knee flexed to 90 degrees. In a normal 
knee, the anterior tibia should be positioned about 10 mm 
anterior to the femoral condyle. The clinician can grasp 
the proximal tibia with both hands and push the tibia 
posteriorly. The movement, indicating laxity and possible 
tear of the PCL, is compared with the uninjured knee (90% 
sensitivity and 99% specificity). A PCL injury is some
-
times mistaken for an ACL injury during the anterior 
drawer test since the tibia is subluxed posteriorly in a 
sagged position and can be abnormally translated forward, 
yielding a false-positive test for an ACL injury. Pain, swell
-
ing, pallor, and numbness in the affected extremity may 
suggest a knee dislocation with possible injury to the pop
-
liteal artery.
B. Imaging
Radiographs are often nondiagnostic but are required to 
diagnose any fractures. MRI is used to diagnose PCL and 
other associated injuries.
 
»
Treatment
Isolated PCL injuries can be treated nonoperatively. Acute 
injuries are usually immobilized using a knee brace with 
the knee extension; the patient uses crutches for ambulation. 
Physical therapy can help achieve increased range of 
motion and improved ambulation. Many PCL injuries are 
associated with other injuries and may require operative 
reconstruction.
 
»
•	
The patient should be seen urgently within 1–2 weeks.
•	
If the lateral knee is also unstable with varus stress test
-
ing, the patient should be assessed for a posterolateral 
corner injury, which may require an urgent surgical 
•	
Isolated PCL tears may require surgery if the tear is 
complete (grade 3) and the patient is symptomatic.
LaPrade CM et al. Emerging updates on the posterior cruciate 
ligament: a review of the current literature. Am J Sports Med. 
2015 Dec;43(12):3077–92. [PMID: 25776184]
5. Meniscus Injuries
 
»
Patient may or may not report an injury.
 
»
Joint line pain and pain with deep squatting are 
the most sensitive signs.
 
»
Difficulty with knee extension suggests an internal 
derangement that should be evaluated urgently 
with MRI.
 
»
The menisci act as shock absorbers within the knee. 
Injuries to a meniscus can lead to pain, clicking, and locking 
sensation. Most meniscus injuries occur with acute injuries 
(usually in younger patients) or repeated microtrauma, 
such as squatting or twisting (usually in older patients).
 
»
The patient may have an antalgic (painful) gait and diffi
-
culty with squatting. He or she may complain of catching 
or locking of the meniscal fragment. Physical findings can 
include effusion or joint line tenderness. Patients can usu
-
ally point out the area of maximal tenderness along the 
joint line. Swelling usually occurs during the first 24 hours 
after the injury or later. Meniscus tears rarely lead to the

-
after the injury or later. Meniscus tears rarely lead to the 
immediate swelling that is commonly seen with fractures 
and ligament tears. Meniscus tears are commonly seen in 
arthritic knees. However, it is often unclear whether the 
pain is coming from the meniscus tear or the arthritis.
Provocative tests, including the 
McMurray
 
test,
 the 
modified McMurray test
, and the 
, can be 
performed to confirm the diagnosis (Table 41–7). Most 
symptomatic meniscus tears cause pain with deep squat
-
ting and when waddling (performing a “duck walk”).
B. Imaging
Radiographs are usually normal but may show joint space 
narrowing, early OA changes, or loose bodies. MRI of the 
knee is the best diagnostic tool for meniscal injuries (93% 
sensitivity and 95% specificity). High signal through the 
meniscus (bright on T2 images) represents a meniscal tear.
 
»
Treatment
Conservative treatment can be used for degenerative tears 
in older patients. The treatment is similar for patients with 
mild knee OA, including analgesics and physical therapy for 
strengthening and core stability. A randomized controlled 
trial showed that physical therapy compared to arthrosopic 
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partial meniscectomy had similar outcomes at 6 months. 
However, 30% of the patients who were assigned to physical 
therapy alone underwent surgery within 6 months.
Randomized studies have shown that arthroscopic sur
-
gery has no benefit over sham operations in patients who 
have degenerative meniscal tears, especially with imaging 
showing signs of osteoarthritis. Another randomized con
-
trolled trial found that patients with degenerative meniscus 
tears but no signs of arthritis on imaging treated conserva
-
tively with supervised exercise therapy had similar outcomes 
to those treated with arthroscopy with 2 year follow up. 
There is crossover between the groups; patients can be 
treated with supervised exercise therapy first, and if they do 
not respond to nonoperative treatment, they can undergo 
meniscus surgeries. Acute tears in young and active patients 
with clinical signs of internal derangement (catching and 
swelling) and without signs of arthritis on imaging or 
patients with acute mechanical locking with a displaced 
meniscus can be best treated arthroscopically with meniscus 
repair or debridement. There is also growing evidence that 
untreated meniscus root tears can lead to accelerated osteo
-
arthritic changes. Surgical treatment before cartilage break
-
down is recommended for acute meniscus root injuries.
 
»
•	
If the patient has symptoms of internal derangement 
suspected as meniscus injury. The patient should 
receive an MRI to confirm the injury.
•	
If the patient cannot extend the knee due to a mechani
-
cal block, the patient should be evaluated as soon as 
possible. Certain shaped tears on MRI, such as bucket 
handle tears, are amenable to meniscal repair surgery.
•	
If the patient has MRI confirmation of acute meniscus 
root injuries.
Bhatia S et al. Meniscal root tears: significance, diagnosis, and 
treatment. Am J Sports Med. 2014 Dec;42(12):3016–30. 
[PMID: 24623276]
Khan M et al. Arthroscopic surgery for degenerative tears of the 
meniscus: a systematic review and meta-analysis. CMAJ. 
2014 Oct 7;186(14):1057–64. [PMID: 25157057]
Kise NJ et al. Exercise therapy versus arthroscopic partial men
-
iscectomy for degenerative meniscal tear in middle aged 
patients: randomised controlled trial with two year follow-up. 
BMJ. 2016 Jul 20;354:i3740. [PMID: 27440192]
Sihvonen R et al; Finnish Degenerative Meniscal Lesion Study 
(FIDELITY) Group. Arthroscopic partial meniscectomy ver
-
sus sham surgery for a degenerative meniscal tear. N Engl 
 
J Med. 2013 Dec 26;369(26):2515–24. [PMID: 24369076]
6. Patellofemoral Pain
 
»
Pain experienced with bending activities (kneel
-
ing, squatting, climbing stairs).
 
»
Lateral deviation or tilting of the patella in relation 
to the femoral groove.
 
»
Patellofemoral pain, also known as anterior knee pain, 
chondromalacia, or “runner’s knee, ” describes any pain 
involving the patellofemoral joint. The pain affects any 
or all of the anterior knee structures, including the 
medial and lateral aspects of the patella as well as the 
quadriceps and patellar tendon insertions. The patella 
engages the femoral trochlear groove with approximately 
30 degrees of knee flexion. Forces on the patellofemoral 
joint increase up to three times body weight as the knee 
flexes to 90 degrees (eg, climbing stairs), and five times 
body weight when going into full knee flexion (eg, squat
-
ting). Abnormal patellar tracking during flexion can lead 
to abnormal articular cartilage wear and pain. When the 
patient has ligamentous hyperlaxity, the patella can sub
-
lux out of the groove, usually laterally. Patellofemoral 
pain is also associated with muscle strength and flexibil
-
ity imbalances as well as altered hip and ankle 
biomechanics.
 
»
Patients usually complain of pain in the anterior knee with

-
 
»
Patients usually complain of pain in the anterior knee with 
bending movements and less commonly in full extension. 
Pain from this condition is localized under the kneecap but 
can sometimes be referred to the posterior knee or over the 
medial or lateral inferior patella. Symptoms may begin 
after a trauma or after repetitive physical activity, such as 
running and jumping. When maltracking, palpable and 
sometimes audible crepitus can occur.
Intra-articular swelling usually does not occur unless 
there are articular cartilage defects or if OA changes 
develop. On physical examination, it is important to pal
-
pate the articular surfaces of the patella. For example, the 
clinician can use one hand to move the patella laterally, and 
use the fingertips of the other hand to palpate the lateral 
undersurface of patella. Patellar mobility can be assessed by 
medially and laterally deviating the patella (deviation by 
one-quarter of the diameter of the kneecap is consider 
normal; greater than one-half the diameter suggests exces
-
sive mobility). The 
apprehension sign
 suggests instability 
of the patellofemoral joint and is positive when the patient 
becomes apprehensive when the patella is deviated laterally. 
The 
patellar grind test
 is performed by grasping the knee 
superior to the patella and pushing it downward with the 
patient supine and the knee extended, pushing the patella 
inferiorly. The patient is asked to contract the quadriceps 
muscle to oppose this downward translation, with repro
-
duction of pain or grinding being the positive sign for 
chondromalacia of the patella. There are two common 
presentations: (1) patients whose ligaments and patella are 
too loose (hypermobility); (2) and patients who have soft 
tissues that are too tight leading to excessive pressure on 
the joint.
Evaluation of the quadriceps strength and hip stabiliz
-
ers can be accomplished by having the patient perform a 
one-leg squat without support. Patients who are weak may 
display poor balance, with dropping of the pelvis (similar 
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to a positive hip Trendelenburg sign) or excessive internal 
rotation of the knee medially. Normally, with a one-leg 
squat, the knee should align over the second metatarsal ray 
of the foot.
B. Imaging
Diagnostic imaging has limited use in younger patients and 
is more helpful in older patients to assess for OA or to 
evaluate patients who do not respond to conservative treat
-
ment. Radiographs may show lateral deviation or tilting of 
the patella in relation to the femoral groove. MRI may 
show thinning of the articular cartilage but is not clinically 
necessary, except prior to surgery or to exclude other 
pathology.
 
»
Treatment
For symptomatic relief, use of local modalities such as ice 
and anti-inflammatory medications can be beneficial. If 
the patient has signs of patellar hypermobility, physical 
therapy exercises are useful to strengthen the quadriceps 
(especially the vastus medialis obliquus muscle) to help 
stabilize the patella and improve tracking. There is consis
-
tent evidence that exercise therapy for patellofemoral pain 
syndrome may result in clinically important reduction in 
pain and improvement in functional ability. Lower quality 
research supports that hip and knee exercises are better 
than knee exercises alone. Strengthening the quadriceps 
and the posterolateral hip muscles such as the hip abduc
-
tors that control rotation at the knee should be recom
-
mended. Support for the patellofemoral joint can be 
provided by use of a patellar stabilizer brace or special 
taping techniques (McConnell taping). Correcting lower 
extremity alignment (with appropriate footwear or over-
the-counter orthotics) can help improve symptoms, espe
-
cially if the patient has pronation or high-arched feet. If the 
patient demonstrates tight peripatellar soft tissues, special 
focus should be put on stretching the hamstrings, iliotibial 
band, quadriceps, calves, and hip flexors.
Surgery is rarely needed and is considered a last resort for 
patellofemoral pain. Procedures performed include lateral 
release or patellar realignment surgery.
 
»
Patients with persistent symptoms despite a course of con
-
servative therapy.
Jin J. JAMA patient page. Running injuries. JAMA. 2014 Jul; 
312(2):202. [PMID: 25005669]
Khayambashi K et al. Posterolateral hip muscle strengthening 
versus quadriceps strengthening for patellofemoral pain: a 
comparative control trial. Arch Phys Med Rehabil. 2014 
May;95(5):900–7. [PMID: 24440362]
van der Heijden RA et al. Exercise for treating patellofemoral 
pain syndrome. Cochrane Database Syst Rev. 2015 Jan 20; 
1:CD010387. [PMID: 25603546]
7. Knee Osteoarthritis
 
»
 
»
Pain with bending or twisting activities.
 
»
Swelling.
 
»
severe OA.
 
»
70 million by 2030. The incidence of knee OA in the 
United States is 240 per 100,000 person-years.
Cartilage loss and OA symptoms are preceded by dam
-
age to the collagen-proteoglycan matrix. The etiology of 
OA is often multifactorial including previous trauma, prior 
high-impact activities, genetic factors, obesity, and rheu
-
matologic or metabolic conditions.
 
»
becomes more advanced, the patient loses active range of

As the condition worsens, patients with knee OA have 
an increasingly limited ability to walk. Symptoms include 
pain with bending or twisting activities, and going up and 
down stairs. Swelling, limping, and pain while sleeping are 
common complaints with OA, especially as it progresses.
B. Imaging
The most commonly recommended radiographs include 
bilateral weight-bearing 45-degree bent knee posteroante
-
rior, lateral, and patellofemoral joint views (Merchant 
view). Radiographic findings include diminished width of 
the articular cartilage causing joint space narrowing, sub
-
chondral sclerosis, presence of osteophytes, and cystic 
changes in the subchondral bone. MRI of the knee is most 
likely unnecessary unless other pathology is suspected, 
including ischemic osteonecrosis of the knee.
 
»
Treatment
Changes in the articular cartilage are irreversible. Therefore, 
a cure for the diseased joint is not possible, although 
CMDT19_Ch41_p1690-p1721.indd   1718

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CMDT 2019
maintain activity level. Conservative treatment for all patients 
with OA includes activity modification, therapeutic exer
-
cises, and weight loss. Lifestyle modifications also include 
proper footwear and avoidance of high-impact activities. 
Optimal exercise programs for knee OA should focus on 
improving aerobic capacity, quadriceps muscle strength, or 
lower extremity performance. Ideally, the program should be 
supervised and carried out three times a week.
Use of a cane in the hand opposite to the affected side is 
mechanically advantageous. Knee sleeves or braces provide 
some improvement in subjective pain symptoms most 
likely due to improvements in neuromuscular function. If 
patients have unicompartmental OA in the medial or lat
-
eral compartment, joint unloader braces are available to 
offload the degenerative compartment. Cushioning foot
-
wear and appropriate orthotics or shoe adjustments are 
useful for reducing impact to the lower extremities.
There are several oral and intra-articular pharmaco
-
logic options. Treatments that have been studied include 
oral acetaminophen, diclofenac, ibuprofen, naproxen, 
celecoxib, and intra-articular corticosteroids and hyal
-
uronic acid. All treatments except acetaminophen showed 
clinically significant improvement in pain. If a traditional 
NSAID is indicated, the choice should be based on cost, 
side-effect profile, and adherence. The cyclooxygenase 
(COX)-2 inhibitor celecoxib is no more effective than tra
-
ditional NSAIDs; it may offer short-term, but probably not 
long-term, advantage in preventing gastrointestinal com
-
plications. Due to its cost and potential cardiovascular risk, 
celecoxib should be reserved for carefully selected patients. 
Topical NSAIDs or capsaicin can be effective in the treat
-
ment of OA, since they avoid many of the traditional 
NSAID complications. Opioids can be used appropriately 
in patients with severe OA (see Chapter 5). Glucosamine 
and chondroitin sulfate are supplements that have been 
widely used and marketed for OA. Despite some initial 
promise, the best-controlled studies indicate these supple
-
ments are ineffective as analgesics in OA. However, they 
have minimal side effects and may be appropriate if the 
patient experiences subjective benefit.
Knee joint corticosteroid injections are options to help 
reduce pain and inflammation and can provide short-term 
pain relief, usually lasting about 6–12 weeks. 
Viscosupplementation by injections of hyaluronic acid–
based products is controversial. Because reviews suggest 
that viscosupplementation has a questionably clinically 
relevant effect size, and has an increased risk of adverse 
events, the American Academy of Orthopedic Surgeons 
has recommended that viscosupplementation should not 
be used in the treatment of knee OA. However, the 
American College of Rheumatology’s 2012 OA guidelines 
recommend the use of intra-articular hyaluronic acid 
injection for the treatment of OA of the knee in adults. 
Platelet-rich plasma injections contain high concentration 
of platelet-derived growth factors, which regulate some 
biologic processes in tissue repair. A meta-analysis of 10 
studies demonstrated that platelet-rich plasma injections 
reduced pain in patients with knee OA more efficiently 
than placebo and hyaluronic acid injections. However, 9 of 
the 10 studies had a high risk of bias, and the underlying 
mechanism of biologic healing is unknown. An FDA safety 
and efficacy study showed that leukocyte-poor PRP autolo
-
gous conditioned plasma improved overall Western Ontario 
and McMaster Universities Arthritis Index scores by 78% from 
the baseline score after 12 months, compared to 7% for the 
placebo group, though the sample size was small (30 patients).
Two randomized trials demonstrated that arthroscopy

Two randomized trials demonstrated that arthroscopy 
does not improve outcomes at 1 year over placebo or rou
-
tine conservative treatment of OA. Joint replacement sur
-
geries are effective and cost-effective for patients with 
significant symptoms or functional limitations, providing 
improvements in pain, function, and quality of life. The 
number of total knee arthroplasty procedures jumped 
162% from 1991 to 2010, along with an increase in compli
-
cations and hospital readmissions. Minimally invasive 
surgeries and computer-assisted navigation during opera
-
tion are being investigated as methods to improve tech
-
niques (eg, accurate placement of the hardware implant) 
and to reduce complication rates; however, major improve
-
ments have yet to be demonstrated.
Knee realignment surgery, such as high tibial osteotomy 
or partial knee replacement surgery, is indicated in patients 
younger than age 60 with unicompartmental OA, who 
would benefit from delaying total knee replacement. Knee 
joint replacement surgery has been very successful in 
improving outcomes for patient with end-stage OA. 
Long-term series describe more than 95% survival rate of 
the implant at 15 years.
 
»
-
Bannuru RR et al. Comparative effectiveness of pharmacologic 
interventions for knee osteoarthritis: a systematic review and 
network meta-analysis. Ann Intern Med. 2015 Jan 6; 
162(1):46–54. [PMID: 25560713]
Brosseau L et al. The Ottawa panel clinical practice guidelines 
for the management of knee osteoarthritis. Part two: 
strengthening exercise programs. Clin Rehabil. 2017 May; 
31(5): 596–611. [PMID: 28183213]
for the management of knee osteoarthritis. Part three: aerobic 
exercise programs. Clin Rehabil. 2017 May;31(5):612–24. 
[PMID: 28183194]
Juhl C et al. Impact of exercise type and dose on pain and dis
-
ability in knee osteoarthritis: a systematic review and meta-
regression analysis of randomized controlled trials. Arthritis 
Rheumatol. 2014 Mar;66(3):622–36. [PMID: 24574223]
Laudy AB et al. Efficacy of platelet-rich plasma injections in 
osteoarthritis of the knee: a systematic review and meta-
analysis. Br J Sports Med. 2015 May;49(10):657–72. [PMID: 
25416198]
Smith PA. Intra-articular autologous conditioned plasma injec
-
tions provide safe and efficacious treatment for knee osteoar
-
thritis: an FDA-sanctioned, randomized, double-blind, 
placebo-controlled clinical trial. Am J Sports Med. 2016 Apr; 
44(4):884–91. [PMID: 26831629]
CMDT19_Ch41_p1690-p1721.indd   1719

C
HAPTER
 4
1
1720
 CMDT 2019
ANKLE INJURIES
1. Inversion Ankle Sprains
 
»
Localized pain and swelling.
 
»
The majority of ankle injuries involve inversion 
injuries affecting the lateral ligaments.
 
»
Consider chronic ankle instability or associated 
injuries if pain persists for longer than 3 months 
following an ankle sprain.
 
»
Ankle sprains are the most common sports injuries seen in 
outpatient clinics. Patients usually report “turning the 
ankle” during a fall or after landing on an irregular surface 
such as a hole or an opponent’s foot. The most common 
mechanism of injury is an inversion and plantar flexion 
sprain, which injures the anterior talofibular ligament 
(ATF) ligament rather than the calcaneofibular ligament 
(CF) ligament. Other injuries that can occur with inversion 
ankle injuries are listed in Table 41–8. Women appear to 
sustain an inversion injury more frequently than men. Up 
to 43% of ankle sprains can still have problems at 6 months, 
even with physical therapy, which makes proper early 
treatment of ankle sprains important.
 
»
The usual symptoms following a sprain include localized 
pain and swelling over the lateral aspect of the ankle, dif
-
ficulty weight bearing, and limping. The patient’s ankle 
may feel unstable. On examination, there may be swelling 
or bruising over the lateral aspect of the ankle. The ante
-
rior, inferior aspect below the lateral malleolus is most 
often the point of maximal tenderness consistent with ATF 
and CF ligament injuries. The swelling may limit motion of 
the ankle. Special stress tests for the ankle include the 
anterior drawer test
; the clinician keeps the foot and ankle 
in the neutral position with the patient sitting, then uses 
one hand to fix the tibia and the other to hold the patient’s 
heel and draw the ankle forward. Normally, there may be 
approximately 3 mm of translation until an endpoint is felt. 
A positive test includes increased translation of one foot 
compared to the other with loss of the endpoint of the 
anterior talofibular ligament.
Another stress test is the 
subtalar tilt test,
 which is 
performed with the foot in the neutral position with the 
patient sitting. The clinician uses one hand to fix the tibia 
and the other to hold and invert the calcaneus. Normal 
inversion at the subtalar joint is approximately 30 degrees. 
A positive test consists of increased subtalar joint inversion 
greater than 10 degrees on the affected side with loss of 
endpoint for the calcaneofibular ligament. In order to 
grade the severity of ankle sprains, no laxity on stress tests 
is considered a grade 1 injury, laxity of the ATF ligament 
on anterior drawer testing but a negative tilt test is a grade 
2 injury, and both positive drawer and tilt tests signify a 
grade 3 injury.
B. Imaging
Routine ankle radiographic views include the AP , lateral, 
and oblique (mortise) views. Less common views 
requested include the calcaneal view and subtalar view. 
Ottawa Ankle Rules
 are clinical prediction rules to 
guide the need for radiographs and have a 97% sensitiv
-
ity and 99% negative predictive value. If the patient is 
unable to bear weight immediately in the office setting or 
emergency department for four steps, then the clinician 
should check for (1) bony tenderness at the posterior 
edge of the medial or lateral malleolus and (2) bony ten
-
derness over the navicular (medial midfoot) or at the 
base of the fifth metatarsal. If either malleoli demon
-
strates pain or deformity, then ankle radiographs should 
be obtained. If the foot has bony tenderness, obtain foot 
radiographs. An MRI is helpful when considering the 
associated injuries.
 
»
Treatment
Immediate treatment of an ankle sprain follows the MICE 
mnemonic: 
m
odified activities, 
i
ce, 
c
ompression, and 
e
le
-
vation. Subsequent treatment involves protected weight

»
Treatment
mnemonic: 
m
i
ce, 
c
e
le
-
vation. Subsequent treatment involves protected weight 
bearing with crutches and use of an ankle stabilizer brace, 
especially for grade 2 and 3 injuries. 
Early motion is essen
-
tial, and patients should be encouraged to do home 
exercises or physical therapy.
 Proprioception and balance 
exercises (eg, “wobble board”) are useful to restore func
-
tion to the ankle and prevent future ankle sprains. Regular 
use of an ankle support with activities can reduce the risk 
of lateral ankle sprains. Chronic instability can develop 
after acute ankle sprain in 10–20% of people and may 
require surgical stabilization with ligament reconstruction 
surgery.
Table 41–8.
 
Injuries associated with ankle sprains.
Ligaments
Subtalar joint sprain
Sinus tarsi syndrome
Syndesmotic sprain
Deltoid sprain
Lisfranc injury
Tendons
Posterior tibial tendon strain
Peroneal tendon subluxation
Bones
Osteochondral talus injury
Lateral talar process fracture
Posterior impingement (os trigonum)
Fracture at the base of the fifth metatarsal
Jones fracture
Salter fracture (fibula)
Ankle fractures
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CMDT 2019
 
»
•	
Ankle fractures.
•	
Recurrent ankle sprains or signs of chronic ligamentous 
ankle instability.
•	
No response after more than 3 months of conservative 
•	
Suspicion of associated injuries.
Brison RJ et al. Effect of early supervised physiotherapy on 
recovery from acute ankle sprain: randomised controlled 
trial. BMJ. 2016 Nov 16;355:i5650. [PMID: 27852621]
Czajka CM. Ankle sprains and instability. Med Clin North Am. 
2014 Mar;98(2):313–29. [PMID: 24559877]
Gribble PA et al. 2016 consensus statement of the International 
Ankle Consortium: prevalence, impact and long-term conse
-
quences of lateral ankle sprains. Br J Sports Med. 2016 Dec; 
50(24):1493–5. [PMID: 27259750]
2. Eversion (“High”) Ankle Sprains
 
»
Severe and prolonged pain.
 
»
 
»
Mild swelling.
 
»
Difficulty with weight bearing.
 
»
A syndesmotic injury or “high ankle” sprain involves the 
anterior 
tibio
fibular ligament in the anterolateral aspect of 
the ankle, superior to the anterior 
talo
fibular (ATF) 
ligament. The injury mechanism often involves the foot 
being turned out or externally rotated and everted (eg, 
when being tackled). This injury is commonly missed or 
misdiagnosed as an ATF ligament sprain on initial visit.
 
»
Symptoms of a high ankle sprain include severe and pro
-
longed pain over the anterior ankle at the anterior tibio
-
fibular ligament, worse with weight bearing. This is often 
more painful than the typical ankle sprain. The point of 
maximal tenderness involves the anterior tibiofibular liga
-
ment, which is higher than the ATF ligament. It is also 
important to palpate the proximal fibula to rule out any 
proximal syndesmotic ligament injury and associated 
fracture known as a “maisonneuve fracture. ” There is often 
some mild swelling in this area, and the patient may or may 
not have an ankle effusion. The patient usually has limited 
range of motion in all directions. To perform the 
external 
rotation stress test,
 the clinician fixes the tibia with one 
hand and grasps the foot in the other with the ankle in the 
neutral position. The ankle is then dorsiflexed and 
externally rotated, reproducing the patient’s pain. 
(
Note:
 The patient’s foot should have an intact neurovascu
-
lar examination before undertaking this test.)
B. Imaging
Radiographs of the ankle should include the AP , mortise, 
and lateral views. The mortise view may demonstrate loss 
of the normal overlap between the tibia and fibula, which 
should be at least 1–2 mm. Asymmetry in the joint space 
around the tibiotalar joint suggests disruption of the syn
-
desmotic ligaments. If there is proximal tenderness in the 
lower leg especially around the fibula, an AP and lateral 
view of the tibia and fibula should be obtained to rule out 
a proximal fibula fracture. Radiographs during an external 
rotation stress test may visualize instability at the distal 
tibiofibular joint. MRI is the best method to visualize 
injury to the tibiofibular ligament and to assess status of the 
other ligaments and the articular cartilage.
 
»
Treatment
Whereas most ankle sprains are treated with early motion 
and weight bearing, treatment for a high ankle sprain 
should be conservative with a cast or walking boot for 
4–6 weeks. Thereafter, protected weight bearing with 
crutches is recommended until the patient can walk pain-
free. Physical therapy can start early to regain range of 
motion and maintain strength with limited weight bearing 
initially.
 
»
If there is widening of the joint space and asymmetry at the 
tibiotalar joint, the patient should be referred urgently to a 
foot and ankle surgeon. Severe or prolonged persistent 
cases that do not heal may require internal fixation to avoid 
chronic instability at the tibiofibular joint. Screw fixation

chronic instability at the tibiofibular joint. Screw fixation 
remains the gold standard, although newer techniques with 
bioabsorbable constructs are emerging.
Magan A et al. Evaluation and management of injuries of the 
tibiofibular syndesmosis. Br Med Bull. 2014 Sep;111(1): 
101–15. [PMID: 25190761]
Van Heest TJ et al. Injuries to the ankle syndesmosis. J Bone 
Joint Surg Am. 2014 Apr 2;96(7):603–13. [PMID: 24695928]
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 CMDT 2019
Juno Obedin-Maliver, MD, MPH, MAS 
Patricia A. Robertson, MD 
Kevin L. Ard, MD, MPH 
Kenneth H. Mayer, MD 
Madeline B. Deutsch, MD, MPH 
Lesbian, Gay, Bisexual, & 
Transgender Health
42
World Health Organization (WHO) recognized this difi
-
ciency, stating that the limitation in available data “points 
to the fact that LGBT people often experience poorer 
health outcomes than the general population and face 
barriers to health care that profoundly affect their overall 
health and well-being. ”
Daniel H et al. Lesbian, gay, bisexual, and transgender health 
disparities. Ann Intern Med. 2015 Dec 15;163(12):963. 
[PMID: 26666793]
Gereige JD et al. The sexual health of women in Lebanon: are 
there differences by sexual orientation? LGBT Health. 
2018 Jan;5(1):45–53. [PMID: 29130791]
Institute of Medicine (US) Committee on Lesbian, Gay, Bisexual, 
and Transgender Health Issues and Research Gaps and 
Opportunities. The health of lesbian, gay, bisexual, and trans
-
gender people: building a foundation for better understanding. 
Washington, DC: National Academies Press (US); 2011. 
[PMID: 22013611]
Lunn MR et al. Sociodemographic characteristics and health 
outcomes among lesbian, gay, and bisexual U.S. adults using 
Healthy People 2020 leading health indicators. LGBT Health. 
2017 Aug;4(4):283–94. [PMID: 28727950]
Muller A et al. Making the invisible visible: a systematic review 
of sexual minority women’s health in Southern Africa. BMC 
Public Health. 2016 Apr 11;16:307. [PMID: 27066890]
Obedin-Maliver J et al. Lesbian, gay, bisexual, and transgender-
related content in undergraduate medical education. JAMA. 
2011 Sep 7;306(9):971–7. [PMID: 21900137]
World Health Organization. Improving the health and well-
being of lesbian gay, bisexual and transgender persons. 
Geneva, Switzerland: World Health Organization, 2013. 
Executive Board: 133rd Session: 4.
 
»
Importance of Asking & Knowing 
Patients’ Sexual Orientation
Having a sexual minority sexual orientation has been 
shown to be associated with health disparities. It is also 
central to individuals’ identities, social structures, and 
behaviors. For these reasons, asking and knowing about a 
patient’s sexual orientation correlates with better health 
and health care outcomes.
One study compared sexual minority women (women 
who identify as lesbian, gay, bisexual, or queer) with het
-
erosexual women; results found that sexual minority 
 
º
LESBIAN & BISEXUAL WOMEN’S HEALTH
Comprising roughly 4% of adult women in the United States, 
lesbian and bisexual women are considered a medically 
underserved population in the United States by the 
National Academy of Medicine. Furthermore, since 2016, 
lesbian and bisexual women—as sexual minorities—are 
considered a health disparity population by the US National 
Institutes of Health. Professional medical organizations, 
such as the American College of Physicians, have published 
position papers to educate and make recommendations on 
achieving equity for lesbian, gay, bisexual, and transgender 
(LGBT) individuals in the health care system. Barriers to 
care include both personal and structural. Personal barriers 
may include the patient’s experience of disrespectful behav
-
ior and discrimination by health care providers and staff 
members and feeling threatened or experiencing a refusal 
of treatment due to sexual orientation, which may cause 
delay or avoidance of care. Structural barriers may include 
social stigma and even abject violence, financial challenges 
caused by decreased prevalence of insurance coverage (eg, 
many employers do not provide same-sex partner benefits), 
and the lack of trained providers to care for lesbian and 
bisexual women. Even when lesbian and bisexual women 
do seek medical care, it may not be appropriately targeted 
to the unique issues of this underserved population and 
therefore less effective. In the United States, women in

therefore less effective. In the United States, women in 
same-sex couples are less likely to get nonurgent medical 
care when needed, see a specialist, and feel that doctors 
spent enough time with them. Lesbian and bisexual women 
in the United States are also less likely to have primary care 
providers. A study in Lebanon noted that significantly 
more sexual minority women reported having trouble 
accessing health care than heterosexual women, and a 
meta-analysis of southern African countries outlined the 
unique health challenges faced by sexual minority women, 
including social exclusion and invisibility, criminalization, 
and systematic homophobic sexual assault. There is a lack 
of systematic medical knowledge, however, about the care 
and understanding of lesbian and bisexual women. The 
CMDT19_Ch42_p1722-p1742.indd   1722

LESBIAN, GAY , BISEXUAL, & TRANSGENDER HEALTH
1723
 
CMDT 2019
women reported greater satisfaction with their health care 
provider when the clinician assessed or knew their sexual 
orientation. Furthermore, asking sexual minority women 
about their sexual orientation led to normalization of non
-
majority sexual orientation status and enhanced percep
-
tion of the doctor-patient relationship. Conversely, not 
inquiring, proposed by many clinicians to avoid offense, 
led to a feeling of silencing. Although many providers do 
not ask and are concerned that patients will not respond 
favorably to questions about sexual orientation, very high 
acceptability among patients has been demonstrated in a 
review of studies looking at patient acceptability of 
questions. In a study documenting the discordence between 
patient and provider perceptions, 78% of providers thought 
that patients (both sexual minority and sexual majority) 
would refuse to disclose their sexual identities, while only 
10% of patients reported that they would not disclose their 
sexual orientation. The degree of discordance, though, may 
not be the same across all groups; in one study in New Y ork 
City, 13% of lesbian women and 33% of bisexual women 
did not disclose their sexual orientation or same-sex 
behaviors to their health care providers. Nondisclosure of 
sexual orientation was related to poorer psychological well-
being at 1-year follow-up, independent of baseline psycho
-
logical well-being. Nondisclosure by lesbian and bisexual 
women was more likely if she was a member of an ethnic 
minority group, had low educational level, had children, 
had higher level of internalized homonegativity, and did 
not have a history of a medical condition. Rates for con
-
tinuing medical care were significantly decreased if there 
was a negative interaction with the clinician as perceived 
by sexual minority African-American female patients in 
one study: 34% of the patients did not see a doctor the next 
time they were ill. A solid therapeutic relationship can 
mitigate the difficulty in disclosure of sexual orientation.
Disclosure in the electronic medical record has been 
advocated in the United States by the Institute of Medicine 
and Joint Commission. However, there are risks for lesbian 
and bisexual women with having their sexual orientation 
documented in the medical record. Examples of such risks 
include loss of job (in 28 states in the United States a per
-
son can legally be fired on the basis of sexual orientation, 
and same-sex sexual relations are criminalized in over 
 
72 countries) and fear of discrimination within the medical 
system (where 18% of lesbian, gay, bisexual, transgender, 
and queer [LGBTQ] individuals avoid seeking health care 
given concerns about identity-based discrimination).
Disclosure goes beyond establishing rapport but directly 
enhances clinical interactions. In an experimental design, 
researchers randomly assigned LGB patients to read het
-
eronormative (wherein the assumption is heterosexuality) 
and nonheterosexual vignettes and then asked participants 
to indicate the level of health-related information they 
would disclose. Exposure to nonheterosexual health care 
vignettes positively correlated with more complete infor
-
mation disclosure. However, disclosure to health care pro
-
viders, despite having positive outcomes, can still be 
challenging. Facilitating meaningful disclosure is aided by 
establishing a strong therapeutic rapport with patients and 
critical self-assessment and modification of health care 
providers’ own heteronormative value systems and com
-
munication styles. Changing the culture of medicine to 
welcome lesbian and bisexual women in one’s medical 
practice and applying one’s knowledge about the specific 
health issues of this underserved population is essential to 
their achieving health equity.
Bjarnadottir RI et al. Patient perspectives on answering ques
-

-
tions about sexual orientation and gender identity: an integra
-
tive review. J Clin Nurs. 2017 Jul;26(13-14):1814–33. [PMID: 
27706875]
Cahill SR et al. Inclusion of sexual orientation and gender iden
-
tity in stage 3 meaningful use guidelines: a huge step forward 
for LGBT health. LGBT Health. 2016 Apr;3(2):100–2. [PMID: 
26698386]
Haider AH et al. Emergency department query for patient-
centered approaches to sexual orientation and gender identity: 
the EQUALITY study. JAMA Intern Med. 2017 Jun 1; 
177(6):819–28. [PMID: 28437523]
Li C et al. Predictors and consequences of negative patient-
provider interactions among a sample of African American 
sexual minority women. LGBT Health. 2015 Jun;2(2):140–6. 
[PMID: 26790120]
 
»
Methods of Identification of Sexual 
Orientation in Practice
How does a clinician identify the lesbian and bisexual 
women during an office visit? Some patients voluntarily self-
disclose their sexual orientation without prompting, some 
respond to intake forms, others to direct questioning, and 
some never disclose. How a clinician assesses sexual orienta
-
tion depends on practice type, specialty, care location, and 
population. One approach is to assess with questionnaires or 
patient portals on an electronic medical record prior to a 
first new patient encounter. A good question regarding sex
-
ual orientation to incorporate in the history form is
“Do you think of yourself as lesbian, gay, or homosexual? 
Straight or heterosexual? Bisexual? Something else, please 
describe. ” Having answer options such as “Don’t know” 
and “Choose not to answer” can also be included on the 
form. The Fenway Institute, which specializes in LGBT 
Health and Health Care, proposes using the following 
statement and follow-up questions:
“
I am going to ask you some questions about your sexual 
health and sexuality that I ask all my patients. The answers 
to these questions are important for me to know how to help 
keep you healthy. Like the rest of this visit, this information 
is strictly confidential.
”
Evidence suggests that most individuals are ready and 
willing to disclose to sensitive providers who make it clear 
the intent behind their questions. Additional questions 
“Do you have a partner or a spouse?” or “ Are you cur
-
rently in a relationship?”
“ Are you sexually active?”
“When was the last time you had sex?”
“What are the genders of your sexual partner (s)?”
“How many sexual partners have you had during the 
last year?”
“Do you have any desires regarding sexual intimacy that 
you would like to discuss?”
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 CMDT 2019
Rather than considering this a one-time intervention, it 
should rather be thought of as a process that is assessed 
over time and at critical junctures and changes in health 
status.
Part of identifying and serving lesbian and bisexual 
women is to create a welcoming clinical space where each 
person is cared for and respected for 
all
 of who they are—
including their sexual orientation. One exercise is to look 
at clinic materials (ie, signs, posters, brochures, magazines, 
intake forms etc.) and see if materials presume heterosex
-
ual sexual behavior interactions or identities. Often, 
materials discussing sex, family planning, conception, 
pregnancy, and birth presume heterosexual interactions. If 
so, find or create more inclusive materials to replace them.
The Association of American Medical Colleges (AAMC) 
has created a series of online videos that highlight history-
taking that includes assessments of sexual orientation, gen
-
der identity, and sexual practices: https://www.aamc.org/
initiatives/diversity/450606/clinicalvignettes.html. The 
AAMC has produced noteworthy videos about family coun
-
seling and coming out (https://www.aamc.org/initiatives/
diversity/450466/family-counseling.html), gender and sex
-
ual history taking (https://www.aamc.org/initiatives/
diversity/450468/gender-and-sexual-history1.html and 
https://www.aamc.org/initiatives/diversity/450470/
gender-and-sexual-history2.html), and ineffective history 
taking (https://www.aamc.org/initiatives/diversity/450472/
ineffective-history-taking.html).
National LGBT Cancer Network. Cultural competency in-person 
trainings and on-line materials, updated 2017. https://cancer-
network.org/programs/cultural-competency-training
National LGBT Education Center. Ten things: creating inclusive 
health care environments for LGBT people. July 2015. http://
www.lgbthealtheducation.org/wp-content/uploads/
Ten-Things-Brief-Final-WEB.pdf
For providers and staff training: https://www.lgbthealtheducation
 
.org
 
»
Understanding Differences Between 
Orientation, Identity, & Behaviors
Who are lesbian and bisexual women? Lesbian women 
are romantically, emotionally, and sexually attracted to, 
and/or engage sexually with other women. Bisexual 
women are romantically, emotionally, and sexually 
attracted to, and/or engage sexually with both men and 
women. These definitions, though, may obscure differ
-
ences between sexual orientation and sexual behaviors 
and also presume that there are only two genders. Also, 
for most people, the assumption is that the above state
-
ments refer to cisgender women, individuals whose gen
-
der identity as a woman is consistent with a female sex 
assigned at birth. However, transgender women (indi
-
viduals whose gender identity as a woman is different 
than their male sex assigned at birth) often have lesbian 
and bisexual identities and behavioral patterns as well. 
However, there is scant research on the experiences of 
transgender women who are lesbian and bisexual, so 
almost all of the data subsequently discussed presumes 
cisgender lesbian and bisexual women.
For lesbian and bisexual women, differences between 
identity and behavior are common. For example, among 
those who identify as lesbian women, 70% are sexually 
active exclusively with other women (women who have sex 
with women [WSW]), and 30% are sexually active with 
women and men (women who have sex with women and 
men [WSWM]). Assessment of behavior in addition to 
identity is critical to delineate patterns of risk and opportu
-
nities for intervention, such as counseling about preven
-
tion of an unintended pregnancy while understanding 
health modifying features like social support structures. In 
the United States, about 9% of women overall report ever 
having a same-sex partner, with 15% reporting this sexual 
activity in the 20- to 24-year-old cohort. Ten percent of 
self-identified lesbians have never been sexually active with

self-identified lesbians have never been sexually active with 
men (“lifetime lesbians”) and 90% of lesbians have been 
sexually active with men in the past (“adult lesbians”). 
Lesbian and bisexual women are diverse in age, ethnicity, 
location, income, and educational level. Of those women 
who currently identify as bisexual in orientation, they may 
be in a current sexual relationship with a man but have a 
history of being in sexual relationships with women, or 
they may have both male and female sexual partners con
-
currently. About 70% of lesbian women are in couple rela
-
tionships and 59% of bisexual women and 31% of lesbian 
women have children.
Part of appreciating and accurately assessing sexual 
orientation is delineating it from gender identity (a person’s 
internal sense of maleness, femaleness, or another gender) 
and from gender expression (how gender is presented 
using clothes and mannerisms, for example) and how this 
is yet again different from person’s sex assigned at birth 
(the physiologic, anatomic, and reproductive structures 
with which one was born).
Many transgender women have lesbian or bisexual 
sexual orientations. It is important to understand that sex
-
uality (including identity, attraction, and behaviors), like 
gender identity and gender expression, is a spectrum and 
may vary over time with age, cultural context, and region.
Structural barriers in communities also contribute to 
health disparities (eg, community norms, institutional 
policies). Living in communities with high levels of anti-
gay prejudice increases the risk of premature mortality for 
all sexual minorities, since LGBT people living in commu
-
nities with high levels of anti-gay prejudice experience a 
shorter life expectancy by 12 years with contributions of 
suicide, homicide/violence, and cardiovascular disease 
(CVD). To help decrease this all-cause mortality in lesbian 
and bisexual women, clinicians can educate themselves 
about health issues of this population and focus on preven
-
tion as well as advocate for community and institutional 
changes.
 
»
Health Disparities Affecting Lesbian & 
Bisexual Women
Health disparities exist across the life span for lesbian and 
bisexual women compared to heterosexual women. The 
following are increased among lesbian and bisexual 
women: childhood physical abuse in the home, childhood 
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sexual abuse, substance use including alcohol and tobacco, 
risk of chlamydial infection as teens and young adults, risk 
of sexual assault, prevalence of depression, rate of disabili
-
ties, body mass index (BMI), intimate partner violence, 
threats and violence outside the home, risk of asthma, and 
risk of CVD. It has been suggested that rates of human 
papillomavirus (HPV) are higher among lesbian and 
bisexual women due to decreased rates of HPV 
immunization. Sexual dysfunction for lesbian and bisexual 
women is at a rate lower than or equal to that of heterosexual 
women. A high risk of sexual dysfunction can be detected by 
a single question of “bother” regarding sexual function: “ Are 
you bothered by issues of sexual function?” Studies of elders 
in the Irish LGBT community reveal concerns about resi
-
dential care outside of their own home as well as respect by 
health professionals; similarly, there are concerns about 
home services for lesbian and bisexual women in Canada. 
Lesbian and bisexual women have fewer children available 
to help them as they age compared to heterosexual women. 
Therefore, it is critical that health care providers identify 
health decision makers for all patients including lesbian and 
bisexual women who may have more “family of choice” 
members versus “family of origin” members who may be 
estranged. This is especially important as same-sex marriage 
is not allowed in many countries and is still considered 
socially unacceptable in many areas of the United States. To 
avoid conflict during critical decision-making moments, the 
health decision maker needs to be identified on the medical 
record, after a private conversation with the patient. In one 
survey, only about 50% of same-sex couples who desired 
their partner to be the health decision maker had appropri
-
ate forms, and even if married, advance directives should be 
completed given past visitation denials. Many notable legal 
cases, including that of Sharon Kowalski and Karen Thomp
-
son, have documented the struggles that same-sex partners 
can face regarding visitation and appropriate recognition 
during end-of-life care or critical medical decision making 
when these documents have not been completed. Elder 
abuse screening also needs to be done, since the incidence is 
unknown but does occur.
Lawton A et al. End-of-Life and advance care planning consid
-
erations for lesbian, gay, bisexual and transgender patients 
#275. J Palliat Med. 2014 Jan;17(1):106–8. [PMID: 24351127]
Reiter PL et al. HPV infection among a population-based sample 
of sexual minority women from USA. Sex Transm Infect. 
2017 Feb;93(1):25–31. [PMID: 27165699]
 
»
Prevention of CVD
The risk of CVD is higher in sexual-minority women. 
Though many studies lack objective measures such as bio
-
markers, a systematic review demonstrated greater CVD 
among sexual minority women. Ultimately this outcome 
seemed most influenced by societal conditions (ie, cumula
-
tive minority stress) that exert negative effects on CVD 
risk. In one study, lesbian and bisexual women were 14% 
older in vascular terms than their chronological age, which 
was 6% greater than that of their heterosexual counterparts 
and the risk was not fully explained by excessive smoking 
or alcohol use. When the effect of five stressful life events 
(physical abuse, sexual abuse and forced sex, homelessness, 
school expulsion, death of a parent), was compared 
between LGB women and heterosexual women, higher 
cardiometabolic risk scores were found in LGB women, 
even after controlling for demographic factors, socioeco
-
nomic status, health behaviors, and self-reported illness. 
Although many studies report similar hypertension preva
-
lence among lesbian, bisexual, and heterosexual women, 
more recent work has described higher prevalence of 
hypertension among sexual minority women when com
-
pared with heterosexual counterparts.

-
-
The leading five modifiable risk factors for CVD are 
smoking, physical inactivity, obesity, elevated lipid levels, 
and diabetes. Three of these factors (smoking, physical 
inactivity, and obesity) have a higher prevalence in lesbian 
and bisexual women.
Caceres BA et al. A systematic review of cardiovascular disease 
in sexual minorities. Am J Public Health. 2017 Apr; 
107(4):e13–21. [PMID: 28207331]
Clark CJ et al. Disparities in long-term cardiovascular disease 
risk by sexual identity: The National Longitudinal Study of 
Adolescent to Adult Health. Prev Med. 2015 Jul;76:26–30. 
[PMID: 25849883]
Kinsky S et al. Risk of the metabolic syndrome in sexual 
minority women: results from the ESTHER study. J Womens 
Health (Larchmt). 2016 Aug;25(8):784–90. [PMID: 26885574]
 
»
Smoking
Cigarette smoking is more prevalent among lesbian and 
bisexual women than in heterosexual women. While esti
-
mates vary, the National Adult Tobacco Survey noted 22% 
of lesbian women and 32% of bisexual women smoke com
-
pared with 13% of heterosexual women. The National 
Health Interview Survey noted that lesbian and bisexual 
women are also heavier smokers. The tobacco industry’s 
well-documented targeted marketing to LGBT groups and 
the use of cigarette smoking to decrease social stress are 
probable factors. Significant racial and ethnic differences 
exist with Asian and Pacific Islander lesbian and bisexual 
women, who have four times higher odds of smoking than 
heterosexual Asian and Pacific Islander women. In high 
school, LGB adolescents reported a higher prevalence of 
daily cigarette use (22%) compared with heterosexual 
youth (11%). Protective factors against smoking behaviors 
for young LGB women included LGBT community con
-
nections. Another study demonstrated that though desire 
to quit did not differ between sexual minority women and 
their heterosexual counterparts, cessation attempts did dif
-
fer, suggesting that clinicians need to customize cessation 
interventions for sexual minority women.
Traditional smoking cessation programs and targeted 
LGBT programs are effective for LGBT people. A review of 
smoking cessation programs for LGBTI (Intersex) people 
found that with cultural modifications for LGBTI people, 
61% had quit at the end of interventions and this stabilized 
to 39% at 3–6 months. The LGBT community in Ireland 
has very high tobacco use and exposure to secondhand 
smoke. Attention should be paid to messaging about smok
-
ing warnings as not all messages are perceived as equally 
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effective by sexual minorities when compared with hetero
-
sexual people. Encourage patients to check with their com
-
munity or online resources for smoking cessation programs 
and encourage participation in LGBTQ tailored programs, 
if available.
Berger I et al. Smoking cessation programs for lesbian, gay, 
bisexual, transgender, and intersex people: a content-based 
systematic review. Nicotine Tob Res. 2017 Nov 7;19(12): 
1408–17. [PMID: 27613909]
Fallin A et al. Smoking characteristics among lesbian, gay, and 
bisexual adults. Prev Med. 2015 May;74:123–30. [PMID: 
25485860]
Gonzales G et al. Comparison of health and health risk factors 
between lesbian, gay, and bisexual adults and heterosexual 
adults in the United States: results from the National Health 
Interview Survey. JAMA Intern Med. 2016 Sep 1;176(9): 
1344–51. [PMID: 27367843]
Johnson SE et al. Tobacco product use among sexual minority 
adults. Am J Prev Med. 2016 Apr;50(4):e91–100. [PMID: 
26526162]
National LGBT Tobacco Control Network. http://www.lgbtto
-
bacco.org/index.php
Tuthill Z et al. Racial disparities in health and health behaviors 
among gay, lesbian, bisexual and heterosexual men and 
women in the BRFSS-SOP . Ethn Health. 2017 Dec 11:1–12. 
[PMID: 29226695]
 
»
Activity & Body Weight
Data regarding obesity and overweight prevalence in lesbi
-
ans and bisexual women are mixed. Many studies, though, 
including an analysis of over 60,000 women in the National 
Health Interview Survey find that being a sexual minority 
woman is associated with an elevated BMI compared to 
heterosexual women. The prevalence of obesity may not be 
uniform across racial and ethnic groups. The odds of obe
-
sity among lesbians in the following groups differed when 
compared with heterosexuals in the same racial group: 
Latina lesbians 1.39 (95% CI, 1.20, 1.61), Asian and Pacific 
Islander lesbians 1.22 (95% CI, 0.76, 1.94) vs American 
Indian/Alaska Native lesbians 2.06 (95% CI, 1.56, 2.70). 
Findings also differed between bisexual and lesbian women 
within racial and ethnic minority groups.
Obesity and overweight may start at a young age in 
lesbian and bisexual youth and they may conceptualize 
their weight differently than heterosexual peers. Among 
adolescents in the Massachusetts Y outh Risk Behavior 
Survey, lesbian and bisexual females were more likely to 
self-perceive as being of healthy weight or underweight 
despite being overweight or obese, and 33% engaged in 
hazardous weight control behaviors. A high school–based 
study (grades 9–12) in 22 Wisconsin schools revealed that 
sexual minority female youth, compared to their heterosexual 
counterparts, were less likely to participate in team sports, 
and in college, only one of three lesbian, bisexual, and 
queer women met national physical activity guidelines. 
Overweight and obesity may also develop as women age. 
When women were followed longitudinally, lesbian women 
were more at risk for developing obesity than heterosexual 
women. Studies of physical activity have found that while 
there may be greater physical activity and fitness among 
some sexual minority women, so is increased sedentary 
time. There have also been findings of differences in 
dietary patterns between lesbian, bisexual, and heterosex
-
ual women.
Studies about successful weight intervention programs 
for lesbian and bisexual women are emerging. A US Office 
on Women’s Health-funded study of a 12-session interven
-
tion program targeted to lesbian and bisexual women over 
60 years of age found the program to be efficacious with a 
3.7% decrease in waist circumference. Further, randomized 
interventions using mindfulness, healthy eating, and physi
-
cal activity in obese lesbian and bisexual women were 
effective in reducing low-density lipoprotein cholesterol 
and increasing healthy eating. Focus groups have identified 
themes related to weight for lesbian and bisexual women:

themes related to weight for lesbian and bisexual women: 
aging, physical and mental health status, community 
norms, subgroup differences, family and partner support, 
and awareness and tracking of diet and physical activity. 
Participants expressed feeling unprepared for age-related 
changes to their health and voiced interest in interventions 
addressing these issues. Findings from focus groups included 
(1) a preference for interventions focusing on promoting 
health and full life participation rather than on weight loss 
only, (2) cultural norms within the lesbian community that 
were accepting of larger body types, (3) an increased 
awareness in older age that the larger body size may 
exacerbate chronic health problems such as knee pain, and 
(4) the importance of social support and group structures 
in initiating and maintaining healthy behaviors.
Jackson CL et al. Sexual orientation identity disparities in health 
behaviors, outcomes, and services use among men and 
women in the United States: a cross-sectional study. BMC 
Public Health. 2016 Aug 17;16(1):807. [PMID: 27534616]
Tomisek A et al. Strong, healthy, energized: striving for a healthy 
weight in an older lesbian population. J Women Aging. 
2017 May–Jun;29(3):230–42. [PMID: 27484950]
Wood SM et al. Disparities in body mass index trajectories from 
adolescence to early adulthood for sexual minority women. 
 
J Adolesc Health. 2017 Dec;61(6):722–8. [PMID: 28935384]
VanKim NA et al. Dietary patterns during adulthood among 
lesbian, bisexual, and heterosexual women in the Nurses’ 
Health Study II. J Acad Nutr Diet. 2017 Mar;117(3):386–95. 
[PMID: 27889314]
VanKim NA et al. Physical activity and sedentary behaviors 
among lesbian, bisexual, and heterosexual women: findings 
from the Nurses’ Health Study II. J Womens Health (Larchmt). 
2017 Oct;26(10):1077–85. [PMID: 28816590]
 
»
Prevention of Pulmonary Disease
Pulmonary disease has not been rigorously studied in les
-
bians or bisexual women. However, with the increased 
prevalence of smoking in these communities compared to 
heterosexual women, there may be more acute respiratory 
illness, chronic pulmonary disease, and lung cancer—
especially with increasing age. Lesbian women have a 
higher prevalence of lifetime and current asthma, even 
when statistical models are used to correct for current and 
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past smoking and obesity, all of which are increased in 
lesbian and bisexual women. Overweight or obese lesbian 
and bisexual women are more than seven times more likely 
to report current asthma and three times more likely to 
report lifetime asthma than lesbian and bisexual women 
who are not overweight or obese.
Dai H et al. Sleep deprivation and chronic health conditions 
among sexual minority adults. Behav Sleep Med. 2017 Jun 28: 
1–15. [PMID: 28657361]
Fredriksen-Goldsen KI et al. Chronic health conditions and key 
health indicators among lesbian, gay, and bisexual older US 
adults, 2013–2014. Am J Public Health. 2017 Aug;107(8): 
1332–8. [PMID: 28700299]
Simoni JM et al. Disparities in physical health conditions among 
lesbian and bisexual women: a systematic review of 
population-based studies. J Homosex. 2017;64(1):32–44. 
[PMID: 27074088]
 
»
Prevention of Sexually Transmitted 
Sexually transmitted infections (STIs) occur in lesbian and 
bisexual women in all countries, but little population-
based data are available to delineate precise risks. Asking 
about sexual 
behaviors
 in addition to sexual 
identity
 is key 
to identifying STI risk and advising appropriate testing 
since risk may vary by specific sexual practice (eg, digital-
vaginal, vaginal-vaginal, digital-anal, oral-vaginal, oral-
anal contact) and the specific pathogen. WSW are noted by 
the Centers for Disease Control and Prevention (CDC) to 
have diverse sexual practices and that use of barrier protec
-
tion in examined studies (eg, use of gloves, dental dams) 
was ubiquitously low.
Chlamydial infections were higher in 14- to 24-year-old 
women who reported same-sex behavior when attending 
family planning clinics in the US Pacific Northwest com
-
pared to women who reported exclusively heterosexual 
behavior. Possible explanations for this observation include 
differences in these groups’ use of reproductive health care 
services, infrequent use of barrier methods to prevent STI 
transmission with female partners, trends toward higher-
risk behaviors, and different social network characteristics. 
Untreated chlamydial infection places a woman’s future 
fertility at risk due to potential tubal occlusion. Some 
women who have a chlamydial infection do not have 
symptoms. Secondary sequelae of chlamydia include intra-
abdominal abscesses, chronic pain, and the need for mul
-
tiple surgeries. Regardless of sexual orientation, the CDC 
recommends annual 
 (and 
Neisseria 
gonorrheae
) screening from the age of first sexual activity 
to the age of 25 years for all women.
It is important to ask lesbian and bisexual women about 
specific sexual practices, as some practices may carry a 
higher risk of STIs than others, although there has been 
little research on sexual practices and the risk of STIs in this 
population. Thus, inferences are drawn from heterosexual 
prevention of these infections. “Safer Sex Kits” have occa
-
sionally been distributed to WSW and WSWM to decrease 
the risk of STIs, but intervention effectiveness has not been 
studied. These kits often include dental dams to prevent 
transmission of bacteria and viruses from oral sex, but the 
efficacy of dental dams for this function has not been stud
-
ied. Female latex condoms and latex gloves may provide 
better protection against infectious transmission from oral 
sex since latex has been studied as a barrier for prevention 
of HIV and other STIs. Exchange of blood should be 
avoided as much as possible, especially in HIV-discordant 
lesbian couples, since viral genotype analysis has confirmed 
that HIV can be transmitted sexually between women. The 
clinician should encourage both partners in new lesbian 
couples to have HIV screening prior to sexual contact and 
recommend barrier protection for 6 months until the cou
-
ple is again screened to verify that their HIV status is still

-
ple is again screened to verify that their HIV status is still 
negative. If the couple is monogamous, barrier precautions 
do not need to be continued. However, lesbian and bisexual 
women may not follow this advice, since many feel they are 
at low risk for HIV , which may be correct, but data are 
lacking. About 20–50% of lesbian women use sexual aids 
(eg, vibrators, dildos, or other sexual toys); these should not 
be shared with partners and should be cleaned after use. 
The HPV can remain on these sexual aids for up to 24 hours 
after use, even after standard cleaning. Some lesbian and 
bisexual women are sex workers or have had sexual rela
-
tionships with high-risk male sexual partners (sometimes 
gay male friends) and are at increased risk for STIs. Current 
CDC guidelines recommend that all women should be 
tested once in their lifetime for HIV , and then repeated 
according to risk factors.
The herpes simplex virus (HSV) can be transmitted 
sexually between women. The same precautions regarding 
the transmission of HSV should be provided to lesbian, 
bisexual, and heterosexual women; there should be no 
sexual contact during any prodromal symptoms that may 
precede a genital herpes outbreak or during the blister 
stage of the outbreak. Suppression of lesions can usually be 
accomplished with antiviral medications, such as acyclovir 
or valacyclovir, if the lesions are recurrent (see Chapter 6).
There is evidence of HPV transmission between female 
sexual partners. Ten percent of lesbian women have never 
had sex with men, yet cervical dysplasia and cervical cancer 
develop in some of these women. All women need Papani
-
colaou smears, including lesbian women, according to 
timetables provided by professional society guidelines. The 
rate of HPV vaccination in lesbian women (8.5%) is less 
than in heterosexual women (28.4%) and bisexual women 
(33.2%), which contributes to health disparities. Adminis
-
tration of the HPV vaccine is critical to the prevention of 
cervical cancer. Despite recommendations that Papanico
-
laou testing be performed regardless of sexual orientation, 
Papanicolaou testing varies according to identity irrespec
-
tive of behavior. In a national probability sample of who 
underwent Papanicolaou testing, WSWM had the same 
odds of testing as WSM only, whereas women with lifetime 
female partners had lower odds of testing. Those who iden
-
tified as bisexual also had lower odds of testing.
 can be transmitted easily between 
female sexual partners. One study of women attending an 
STI clinic in the United States noted that 
 was 
the most common curable STI found in this population 
with a prevalence of 17% in WSW and 24% in WSWM.
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Bacterial vaginosis is common among women and 
according to the CDC, even more common among WSW . It 
is unknown whether bacterial vaginosis can be transmitted 
between women. A study from Australia found a 27% preva
-
lence of bacterial vaginosis in women and their female part
-
ners; risk factors for bacterial vaginosis were four or more 
lifetime female sexual partners, a female partner with bacte
-
rial vaginosis symptoms, and smoking at least 30 cigarettes 
weekly. Routine screening for bacterial vaginosis, though, is 
not currently recommended and testing should be based on 
symptoms. One approach for a WSW who has symptomatic 
bacterial vaginosis is to treat her and not her female sexual 
partner. If symptoms recur, her female sexual partner(s) 
should be evaluated and treated with consideration of re-
treating the index woman. This strategy may also be used for 
treatment of recurrent or hard to treat vulvovaginal candi
-
diasis, which technically is not considered to be sexually 
transmitted, but anecdotally, improvement has occurred 
with treatment of the index patient and female partner.
Agénor M et al. Sexual orientation and sexual health services 
utilization among women in the United States. Prev Med. 
2017 Feb;95:74–81. [PMID: 27932056]
Agénor M et al. Sexual orientation identity disparities in aware
-
ness and initiation of the human papillomavirus vaccine 
among U.S. women and girls: a national survey. Ann Intern 
Med. 2015 Jul 21;163(2):99–106. [PMID: 25961737]
Muzny C et al. Sexual partnership characteristics of African 
American women who have sex with women; impact on sex
-
ually transmitted infection risk. Sex Transm Dis. 2014 Oct; 
41(10):611–7. [PMID: 25211257]
 
»
Prevention of Substance Use
Substance use is higher in lesbian and bisexual women 
compared to heterosexual women and is especially well-
documented for cigarette smoking and alcohol use. A sec
-
ondary analysis of alcohol, tobacco, and other drug use 
among lesbian and bisexual women in the American 
College Health Association’s National College Health 
Assessment revealed that bisexual women had greater odds 
of using alcohol, tobacco, and marijuana than heterosexual 
women and lesbian women. In addition, bisexual women 
had greater odds of using all illicit drugs (except steroids) 
and misusing prescription drugs than heterosexual women. 
Furthermore, bisexual women had greater odds of using 
amphetamines other than methamphetamine, sedatives, 
and 3,4 methylenedioxymethamphetamine (MDMA; 
Ecstasy) when compared to lesbians. Lesbians had greater 
odds of using tobacco, marijuana, sedatives, hallucinogens, 
and other illicit drugs and misusing prescription drugs 
than heterosexual women.
Multiple interventions have been initiated to decrease 
alcohol and other substance use in lesbian and bisexual 
female youth. In Canada, there were significant lower odds 
of binge-drinking among lesbian and bisexual girls in 
schools with longer-established Gay-Straight Alliances. 
Recommendations for improving substance use treatment 
for sexual minority persons include providing interven
-
tionists with training in LGB cultural sensitivity. There has 
been no specific interventions outcomes research, however, 
comparing LGBT adapted materials with routine materials. 
Some LGBT clients in these programs find it hard to “come 
out” to a group that potentially includes members who may 
be homophobic. Sexual minority women, compared to 
heterosexual women, with lifetime alcohol use disorders 
are at heightened risk for concomitant psychiatric and drug 
use disorders, underscoring the need for substance abuse 
programs to provide access to individual counseling with 
mental health professionals.
Konishi C et al. Population-level evaluation of school-based 
interventions to prevent problem substance use among gay, 
lesbian and bisexual adolescents in Canada. Prev Med. 
2013 Dec;57(6):929–33. [PMID: 23850517]

Mereish EH et al. Intersecting identities and substance use prob
-
lems: sexual orientation, gender, race and lifetime substance 
use problems. J Stud Alcohol Drugs. 2014 Jan;75(1):179–88. 
[PMID: 24411810]
Mereish EH et al. Sexual orientation disparities in psychiatric 
and drug use disorders among a nationally representative 
sample of women with alcohol use disorders. Addict Behav. 
2015 Aug;47:80–5. [PMID: 25899096]
 
»
Cancer Risk, Prevention, & Treatment
Very little is known about the incidence and prevalence of 
various cancers in lesbians and bisexual women, since 
sexual orientation has not been routinely included in can
-
cer screening programs and cancer registries. However, 
emerging data suggest that sexual minority women may be 
at a higher risk for cancer-related mortality than hetero
-
sexual counterparts. Investigators from the Women’s 
Health Study compared sexual minority veterans and civil
-
ians to their heterosexual counterparts and found that 
sexual minority women veterans had a higher risk of can
-
cer-specific mortality. Information from the US National 
Health Interview Survey showed that lesbian and bisexual 
women have cancer risk factors, such as tobacco use, 
underscoring the need for vigilant screening. Since lesbian 
and bisexual women have barriers to accessing health care 
and may not see a clinician on an annual basis, any visit to 
a health care provider is an opportunity to check on cancer 
screening status (eg, colonoscopy, mammography). There 
is also recognition that upon receiving a cancer diagnosis, 
LGBT people face challenges in receiving equitable care 
throughout the cancer care continuum and may experience 
cancer differently and have different needs during their 
care; heterosexual and sexual minority cancer survivors in 
the UK reported receiving different care. The US National 
Cancer Care Network Guidelines do not address how sex
-
ual and gender minority status should be considered in 
site-specific guidelines. One qualitative study with sexual 
and gender minority breast cancer survivors underscored 
the challenges of disclosing sexual orientation during can
-
cer care and the importance of provider recognition that 
varying social networks are critical to positive experiences 
of care provision. The 2017 American Society for Clinical 
Oncology position statement recommends five action steps 
to enhance LGBT cancer care and reduce disparities: 
 
(1) patient education and support, (2) workforce 
development and diversity, (3) quality improvement 
strategies, (4) policy solutions, and (5) research strategies. 
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All providers need to consider whether their prevention, 
screening, diagnostic, treatment, and palliative approaches 
will be equitably experienced by lesbian and bisexual 
women.
Brown MT et al. Unmet support needs of sexual and gender 
minority breast cancer survivors. Support Care Cancer. 
2018 Apr;26(4):1189–96. [PMID: 29080921]
adults in the United States: results from the national health 
interview survey. JAMA Intern Med. 2016 Sep 1;176(9): 
Hudson J et al. Sexual and gender minority issues across NCCN 
Guidelines: results from a national survey. J Natl Compr Canc 
Netw. 2017 Nov;15(11):1379–82. [PMID: 29118229]
Hulbert-Williams NJ et al. The cancer care experiences of gay, 
lesbian and bisexual patients: a secondary analysis of data 
from the UK Cancer Patient Experience Survey. Eur J Cancer 
Care (Engl). 2017 Jul;26(4). [PMID: 28239936]
Obedin-Maliver J. Time to change: supporting sexual and gen
-
der minority people-an underserved, understudied cancer 
risk population. J Natl Compr Canc Netw. 2017 Nov; 
15(11):1305–8. [PMID: 29118223]
A. Breast Cancer
The literature has been mixed on whether lesbian and 
bisexual women have a slight increased risk of breast can
-
cer compared to heterosexual women. A 2013 systemic 
review found the few prevalence studies of breast cancer in 
lesbians unreliable; however, lesbians do have an increased 
prevalence of risk factors predisposing to breast cancer, 
including nulliparity, alcohol use, obesity, and smoking. 
The literature is also inconsistent regarding the rate of 
mammography screening in lesbian women; however, a 
study done in Massachusetts showed that bisexual women 
were less likely than heterosexual women and lesbian 
women to adhere to mammography screening guidelines. 
Lesbian and bisexual women who have breast cancer may 
not want reconstruction at the same rate as heterosexual 
women and often find that breast cancer support groups 
focus on issues for heterosexual women (such as attractive
-
ness to a male partner).
B. Cervical Cancer
Primary prevention of cervical cancer is essential. All 
females between the ages of 12 and 26 years should receive 
the HPV vaccine series even if they never have been or plan 
to be sexually active with men. HPV is transmitted sexually 
between lesbian or heterosexual partners. The rate of HPV 
immunization among lesbians is significantly less than for 
heterosexual women, which creates a health disparity that 
needs to be corrected. Papanicolaou smears should be part 
of lesbian and bisexual women’s health care at the same 
intervals as for heterosexual women. Lesbians and bisexual 
women, however, receive Papanicolaou smears at a lower 
rate than sexually active heterosexual women, in part 
because many of the Papanicolaou smears are done in 
reproductive health clinics; lesbians who are not sexually 
active may not access these clinics. In addition, some les
-
bian patients as well as their health care providers mistak
-
enly think that lesbians do not need Papanicolaou smears. 
All lesbians need Papanicolaou smears starting at the age of 21, 
consistent with recommendations for Papanicolaou smears 
for all women
.
C. Lung Cancer
Compared to heterosexual women, the rate of lung cancer 
is likely higher in lesbian and bisexual women due to their 
increased rate of smoking. The incidence and prevalence of 
lung cancer, however, has not been determined in this 
sexual minority population.
D. Endometrial and Ovarian Cancer
Endometrial and ovarian cancer are associated with nullipar
-

-
ity, which is more likely in sexual minority women. Obesity, 
a known risk factor for both cancers, appears to be more 
prevalent among sexual minority women. Conversely, the use 
of oral contraceptives, which is protective against the devel
-
opment of both of these cancers, is lower in lesbian women 
than in heterosexual women. Vigilance toward and education 
about presenting signs and symptoms (eg, postmenopausal 
bleeding, early satiety, unintended weight loss) are important 
to detect cancers as early as possible. Neither incidence nor 
prevalence of endometrial or ovarian cancer has been deter
-
mined in this sexual minority population.
Bazzi AR et al. Adherence to mammography screening guide
-
lines among transgender persons and sexual minority women. 
Am J Public Health. 2015 Nov;105(11):2356–8. [PMID: 
26378843]
 
»
Prevention of Violence
Compared to heterosexual women, lesbians and bisexual 
women have higher exposures to violence throughout their 
lifetimes. Lifetime prevalence of sexual assault may be as 
high as 85%. In a study of four countries in southern 
Africa, nearly one-third of lesbian and bisexual women 
experienced forced sex and assault including “corrective 
rape” by men as an attempt to change the women’s sexual 
orientation.
The CDC reports that 61% of bisexual women and 44% 
of lesbians experience rape, physical violence, and stalking 
by an intimate partner. These rates are higher than similar 
trauma in heterosexual women (35%). Additionally, 
approximately 20% of bisexual women compared with 10% 
of heterosexual women have been raped by an intimate 
partner in their lifetimes. The rate of stalking experienced 
by bisexual women is twice that of heterosexual women 
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and a higher percentage of bisexual women report being 
afraid of an intimate partner. Despite alarming rates for 
women of any identity, lesbian and bisexual women survi
-
vors of sexual assault and interpersonal violence may expe
-
rience unique difficulties when seeking assistance. These 
problems include a limited understanding of interpersonal 
violence in the relationships of lesbian and bisexual women, 
stigma, and systemic inequities (such as shelters unwel
-
come to this population and staff lacking cultural sensitiv
-
ity and appropriate training in working with lesbian and 
bisexual women). Barriers to preventing LGBTQ violence 
include stigma, systemic discrimination, and a lack of 
understanding of LGBTQ intimate partner violence.
Community violence is experienced more frequently by 
LGBT persons. In-depth interviews of 19 Flemish sexual 
minority victims of violence revealed the use of four coping 
strategies: (1) avoidance, (2) assertiveness and confronta
-
tion, (3) cognitive change, and (4) social support. Applying 
these coping skills and actively attaching meaning to nega
-
tive experiences, helped victims of anti-LGBT violence 
overcome fear, embarrassment, or depressive feelings. The 
presence of a supportive network was important in facili
-
tating the positive outcomes.
Calton JM et al. Barriers to help seeking for lesbian, gay, bisexual, 
transgender, and queer survivors of intimate partner violence. 
Trauma Violence Abuse. 2016 Dec;17(5):585–600. [PMID: 
25979872]
D’haese L et al. Coping with antigay violence: in-depth inter
-
views with Flemish LGB adults. J Sex Res. 2015;52(8):912–23. 
[PMID: 26010740]
Mellins CA et al. Sexual assault incidents among college under
-
graduates: prevalence and factors associated with risk. PLoS 
One. 2017 Nov 8;12(11):e0186471. Erratum in: PLoS One. 
2018 Jan 25;13(1):e0192129. [PMID: 29117226]
Sandfort T et al; Southern African Lesbian and Bisexual Women 
Research Team. Histories of forced sex and health outcomes 
among Southern African lesbian and bisexual women: a 
cross-sectional study. BMC Womens Health. 2015;15:22. 
[PMID: 25783653]
Walters ML et al. The National Intimate Partner and Sexual 
Violence Survey (NISVS): 2010 Findings on Victimization by 
Sexual Orientation. Atlanta, GA: National Center for Injury 
Prevention and Control, Centers for Disease Control and 
Prevention.  https://www.cdc.gov/violenceprevention/pdf/
nisvs_sofindings.pdf
 
»
Prevention of Mental Disorders
Lesbians and bisexual women, especially if they are African 
American, have an increased risk of depression. Many of the 
health disparities and health risks faced by lesbians and 
bisexual women, such as depression and cardiovascular risk, 
have been attributed to Meyer’s theory of minority stress. 
This theory proposes that individuals who identify as a sex
-
ual minority experience chronic, additive, and unique stresses 
stemming from living in social conditions that are character
-
ized by prejudice and discrimination. Therefore, rather than 
identifying mental health problems as synonymous with a 
sexual minority identity or stemming from in-born 
association with minority sexual orientation, minority stress 
causes mental health challenges that stem from societal dis
-
crimination and stigma borne by individuals with minority 
identities (and behaviors). A 2013 survey in Ireland of older 
LGBT people (aged 55 to 80+) revealed that 33% reported 
having experienced a mental health problem at some point in 
their lives. Approximately 11% were currently taking pre
-
scribed medications. An examination of lesbian and bisexual 
women veterans from the Behavioral Risk Factor Surveil
-
lance System found that sexual minority women veterans

-
-
lance System found that sexual minority women veterans 
were three times more likely than heterosexual women to 
experience “mental distress. ” Mortality risk from suicide is 
also elevated among women with same-sex partners. There is 
evidence from the National Epidemiologic Survey on Alcohol 
and Related Conditions–III that bisexual women had greater 
rates of specific psychiatric disorders than lesbians or hetero
-
sexual women. Resilience factors that are protective for men
-
tal distress and poorer mental health among lesbian, gay, 
bisexual, queer and questioning youth and adults in Israel 
included family support as well as other community-level 
factors, such as friends’ support, LGBT connectedness, and 
having a steady partner. How parents react to an adolescent’s 
“coming out” has a profound effect on their child’s health 
outcomes. For those adolescents whose parents were sup
-
portive, there was less homelessness, depression, substance 
use problems, and unprotected sex. Interventions for build
-
ing resilience can be important in achieving a reduction in 
anxiety and depression. There is some evidence that online 
friends can serve as a buffer and social support, especially for 
LGBT youth, although in-person social support appears to be 
more protective against victimization.
There is emerging evidence that being in a legally rec
-
ognized same-sex relationship, particularly in marriage, 
diminishes mental health differences between heterosexual 
and lesbian, gay, and bisexual persons. In contrast, psychi
-
atric disorders increased among lesbian, gay, and bisexual 
persons who live in states in the United States that enacted 
constitutional amendments to ban same-sex marriage 
compared to states that did not. One study examined the 
mental health of individuals living in states before (wave 1, 
2001–2002) and after (wave 2, 2004–2005) the enactment 
of same-sex marriage bans in 2004–2005. Among LGB 
respondents living in states that enacted the marriage bans, 
the National Epidemiologic Survey on Alcohol and Related 
Conditions (N = 34,653), revealed that there was a signifi
-
cantly increased prevalence of any mood disorder (36% 
increase), generalized anxiety disorder (248% increase), 
any alcohol use disorder (42% increase), and psychiatric 
comorbidity (36.3%) between wave 1 and wave 2 of the 
survey, suggesting that living in sociopolitical environ
-
ments that do not legally recognize same-sex relationships 
can have deleterious effects on mental health.
Kerridge BT et al. Prevalence, sociodemographic correlates and 
DSM-5 substance use disorders and other psychiatric disor
-
ders among sexual minorities in the United States. Drug 
Alcohol Depend. 2017 Jan 1;170:82–92. [PMID: 27883948]
Lyons A. Resilience in lesbians and gay men: a review and key 
findings from a nationwide Australian survey. Int Rev 
Psychiatry. 2015;27(5):435–43. [PMID: 26222668]
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McCann E et al. Lesbian, gay, bisexual and transgender older 
people in Ireland: mental health issues. Aging Ment Health. 
2013;17(3):358–65. [PMID: 23323710]
Wight RG et al. Same-sex marriage and psychological well-
being: findings from the California Health Interview Survey. 
Am J Public Health. 2013 Feb;103(2):339–46. [PMID: 
23237155]
Ybarra ML et al. Online social support as a buffer against online 
and offline peer and sexual victimization among U.S. LGBT 
and non-LGBT youth. Child Abuse Negl. 2015 Jan;39:123–36. 
[PMID: 25192961]
 
»
Family Planning
A. Pregnancy Prevention
Comprehensive family planning for lesbians and bisexual 
women is important to address during the potential repro
-
ductive decades spanning from young teens until mid-50s. 
The majority of lesbians have been sexually active with men 
at some point in their lives (85–90%), and 30% of self-
identified lesbians are currently active with men. Fewer 
lesbian youth use hormonal contraception than heterosex
-
ual female youth. However, on multiple surveys, one of the 
reasons that lesbians do not follow up for gynecologic care 
is the assumption by the clinician that they are heterosexual, 
and the (insensitive) advocacy of birth control in that 
assumptive atmosphere about their sexuality. But avoidance 
of unintended pregnancy is a lesbian issue. From multiple 
studies, the unintended pregnancy rate of female lesbian 
youth is higher than that of the comparison heterosexual 
female youth. Unintended pregnancy risk continues into 
adulthood with one sample from the Chicago Health and 
Life Experiences of Women (CHLEW) survey reporting 
24% of sexual minority women reporting having had unin
-
tended pregnancies. The reasons for disproportionate unin
-
tended pregnancy rates have not been fully elucidated but 
may involve discrimination and family rejection leading to 
higher-risk behaviors, increased alcohol and other sub
-
stance use, less birth control usage, and multiple sexual 
partners. Another reason may be attempts to prove one’s 
“straightness” through pregnancy. If it has been determined 
that the patient self-identifies as a lesbian and is having 
(penis-in-vagina) sex with men, one suggested question 
might be, “ Are you planning to get pregnant this year?” If 
the answer is no, this is an opportunity to explain that stud
-
ies show a higher unintended rate of pregnancy in lesbians 
and to review effective contraception options. It is also a 
good time to talk about protection from STIs when having 
sex with men (ie, discuss condoms). As with any person 
engaging in penis-in-vagina sex, experts recommend addi
-
tional contraceptives to condoms, which are only 80% reli
-
able in preventing pregnancy (typical use). Long-acting 
reversible contraceptives, which are not patient or sexual act 
dependent and function effectively despite alcohol or other 
substance use, are especially important to consider. Long-
acting reversible contraceptives such as an etonorgestrel 
subdermal implant in the arm (0.05% annual failure) or 
either the copper (0.8% annual failure) or levonorgestrel 
(0.2% annual failure) intrauterine devices are highly effec
-
tive and typical use is generally equivalent to ideal use.
Everett BG et al. Unintended pregnancy, depression, and 
hazardous drinking in a community-based sample of sexual 
minority women. J Womens Health (Larchmt). 2016 Sep; 
25(9):904–11. [PMID: 26977978]
B. Family Building
Family building should be discussed with all patients, 
regardless of sexual orientation or gender. Options include 
adoption (in some countries this option is not open to 
LGBT persons), co-parenting a partner’s child/children, 
biologic pregnancy, or stepparenting. Lesbians and bisex
-
ual women have many options to consider for conception 
and may ask the clinician for an opinion and to guide them 
to resources. Many lesbians decide to have inseminations

-
to resources. Many lesbians decide to have inseminations 
with an unknown donor (some donors sign a release so 
that the child may contact the donor when the child 
reaches 18 years old), and some lesbians decide to involve 
a known sperm donor. Most sperm banks are regulated in 
regard to the administration of medical history forms, the 
testing of sperm for STIs, and the performance of genetic 
screening. Known donors may have risk factors but are not 
routinely screened for them. It is important for women to 
be as informed as she can be about the legal implications of 
each option. In some states and countries, unless the 
insemination with a known donor takes place in the office 
of a physician and with legal provisions abdicating familial 
rights, the known donor has full legal rights as well as 
financial responsibilities for the offspring. A woman plan
-
ning a pregnancy should be encouraged to consult with a 
family attorney prior to conception, and if she is partnered, 
her partner needs to be aware of her legal rights and 
responsibilities. Even if they are married, some jurisdic
-
tions do not recognize same-sex marriage and may not 
recognize parentage rights of the couple over biologic 
rights of the donor. In some states in the United States, 
married same-sex female couples who conceive children 
with the use of donor sperm will go through adoption pro
-
cesses to have their full parental rights recognized. Not all 
US states support the rights of same-sex couples to adopt. 
In one study of 129 lesbian mothers with 77 index off
-
spring, 77.5% of the mothers were satisfied with the type of 
donor chosen (36% had chosen known sperm donors, 25% 
open-identity donors, and 39% unknown donors). Donor 
access and custody concerns were the primary themes 
mentioned by lesbian mothers regarding their (dis)satisfac
-
tion with the type of sperm donor they had selected.
Access to sperm banks and fertility treatment is not 
always available to lesbians who are “out. ” Even in countries 
where legislation affords lesbians access to reproductive 
technology, interactions with health professionals can 
result in homonegative experiences, as reported in the 
United Kingdom.
Some lesbians who are partnered decide to do “co–in 
vitro fertilization (IVF), ” which is also known as “reciprocal 
IVF” or “co-maternity” in which one partner provides an 
egg, it is fertilized in the laboratory with sperm of a known 
or unknown donor, and then the other partner carries the 
pregnancy. Many lesbians also engage in stimulating lacta
-
tion for the non-gestating mother with resources that 
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stemmed originally from the experiences of adoptive 
mothers. Health care providers should be willing to support 
patients in exploring these options. Many lesbians delay 
childbearing until later in life, and then the issues of fertility, 
pregnancy loss, and birth defects are increased. There have 
been many studies on the outcomes of children of lesbians, 
all of which have been positive when comparing them to 
children raised by heterosexual parents, despite the stigma 
the children experience of having same-sex parents. Using 
the 2011–2012 National Survey of Children’s Health data set 
from the United States, children with female same-sex par
-
ents and different-sex parents demonstrated no differences 
in outcomes (spouse-partner relationships, emotional dif
-
ficulties, coping behaviors, and learning behavior). There is 
very little about parenting experiences among women who 
identify as bisexual and how these findings might differ 
from experiences of lesbian women.
Bos HM et al. Same-sex and different-sex parent households and 
child health outcomes: findings from the national survey of 
children’s health. J Dev Behav Pediatr. 2016 Apr;37(3):179–87. 
[PMID: 27035692]
Gartrell NK et al. Satisfaction with known, open-identity, or 
unknown sperm donors: reports from lesbian mothers of 
17-year-old adolescents. Fertil Steril. 2015 Jan;103(1):242–8. 
[PMID: 25439795]
Manning WD et al. Child well-being in same-sex parent 
families: review of research prepared for American 
Sociological Association amicus brief. Popul Res Policy Rev. 
2014 Aug 1;33(4):485–502. [PMID: 25018575]
van Rijn-van Gelderen L et al. Dutch adolescents from lesbian-
parent families: how do they compare to peers with hetero
-
sexual parents and what is the impact of homophobic 
stigmatization? J Adolesc. 2015 Apr;40:65–73. [PMID: 
25658718]
 
º
GAY & BISEXUAL MEN’S HEALTH
Included in this section are the health issues of gay, bisex
-
ual, and other men who have sex with men (MSM). These 
men are a diverse group of individuals with unique health 
needs that stem from their sexual behavior and from the 
effects of societal stigma and discrimination. This section 
is devoted to the primary care of cisgender (that is, non-
transgender) MSM regardless of their sexual identity. Most 
health-related research focused on MSM categorizes men 
based on their sexual behavior as MSM, rather than their 
self-reported identification as gay, bisexual, or other 
identities. Although sexual identity is not always congruent 
with sexual behavior, identity is important to recognize in 
order to optimize health and health care. When a differ
-
ence on the basis of sexual identity (for example, gay- 
versus bisexual-identified men) with regard to health or 
health disparities is known, this is indicated.
 
»
Definitions & Concepts
Sexual orientation refers to a deep-seated sense of one’s 
sexuality that encompasses three dimensions: identity, 
behavior, and desire. Sexual identities include gay or 
homosexual (those who are predominantly attracted to 
and/or sexually active with members of the same sex), 
bisexual (those who are attracted to and/or sexually active 
with both men and women), and heterosexual or straight; 
however, several other terms may be used, and terminol
-
ogy may change over time. For example, the word “queer, ” 
historically a pejorative term, has been reclaimed by some 
as a positive descriptor of a nonheterosexual orientation.
The three dimensions of sexual orientation—identity, 
behavior, and desire—do not necessarily overlap. For 
example, less than 50% of MSM in one national, probability-
based survey identified as gay. MSM who identify as het
-
erosexual rather than as gay or bisexual may be more likely 
than their gay-identified counterparts to be married to 
women, foreign-born, of minority race, and of lower socio
-

-
-
economic status. The incomplete overlap of identity and 
behavior mean that clinicians cannot rely upon self-
reported identity to infer sexual behavior, and vice versa.
Sexual orientation may also change over time or be situ
-
ational (eg, emerge during periods of limited mobility 
without contact with women, such as during incarcera
-
tion). In addition, people may hide their sexual orientation 
from others, including clinicians, in order to avoid stigma 
and discrimination. Revealing one’s sexual orientation to 
others is called “coming out”; this process may occur at any 
point in life and may vary by context (for example, being 
“out” to family but not coworkers), although the average 
age at which men and boys come out has been declining 
and is currently estimated to be in the mid-teenage years.
 
»
Demographics
The size of the MSM population in the United States is not 
known with certainty due to variability in the definition of 
sexual orientation used in surveys and the possibility that 
some survey respondents do not disclose nonheterosexual 
orientations because of concerns about discrimination. 
Nevertheless, based on available data, it is estimated that 
2.2% of American adult men identify as gay, and an 
additional 1.4% of men identify as bisexual. The proportion 
of men who engage in sex with other men or experience 
sexual attraction to other men is estimated to be higher, 
with 7.3% and 6.2% of adult men reporting some same-sex 
attraction and sexual behavior, respectively, in one national 
survey.
 
»
Stigma & Discrimination
Although social acceptance of nonheterosexual orientations 
is increasing, gay, bisexual, and other MSM may still experi
-
ence stigma and discrimination based on their sexual orien
-
tation and/or gender expression, with significant impacts 
on health. In one national survey of LGBT Americans, dis
-
criminatory experiences were commonly reported: 39% of 
respondents endorsed experiences of rejection by family or 
friends, 30% had been physically attacked or threatened, 
23% had been treated poorly in public, and 21% reported 
being treated unfairly at work. These experiences may con
-
tribute to adverse health outcomes among MSM and other 
LGBT populations. One model for how this occurs centers 
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on the concept of minority stress. In this model, stressors 
such as experiences of prejudice, expectations of rejection, 
the cognitive burden of deciding whether to come out in 
different circumstances, and internalized homophobia lead 
to anxiety, depression, and maladaptive coping behaviors 
such as substance use disorders and risky sexual behavior. 
In adolescents, family rejection has been linked to increased 
risk of depression, homelessness, suicide attempts, illegal 
drug use, sexual risk-taking, and HIV/STI acquisition. 
Avoidance of—or delays in—seeking health care due to 
concerns about discrimination in medical settings may also 
contribute to adverse health outcomes in MSM.
Copen CE et al. Sexual behavior, sexual attraction, and sexual 
orientation among adults aged 18-44 in the United States: 
data from the 2011-2013 National Survey of Family Growth. 
Natl Health Stat Report. 2016 Jan 7;(88):1–14. [PMID: 
26766410]
Frost DM et al. Minority stress and physical health among sexual 
minority individuals. J Behav Med. 2015 Feb;38(1):1–8. 
[PMID: 23864353]
Pew Research Center. A survey of LGBT Americans: attitudes, 
experiences, and values in changing times, 2013. http://www
 
.pewsocialtrends.org/2013/06/13/a-survey-of-lgbt-americans
Xu F et al. Men who have sex with men in the United States: 
demographic and behavioral characteristics and prevalence of 
HIV and HSV-2 infection: results from National Health and 
Nutrition Examination Survey 2001–2006. Sex Transm Dis. 
2010 Jun;37(6):399–405. [PMID: 20473245]
 
»
Health Disparities
Gay, bisexual, and other MSM face health disparities stem
-
ming from the biologic aspects of their sexual behavior 
and/or from minority stress. Because of these disparities, 
MSM have been identified as a priority population for 
health-related research and improvement in health care by 
both the Institute of Medicine and the federal government’s 
Healthy People initiative. These health disparities are exac
-
erbated if young MSM have experienced early life trau
-
matic events, such as sexual abuse or familial rejection.
Opportunities. The health of lesbian, gay, bisexual, and 
transgender people: building a foundation for better 
understanding. Washington, DC: National Academies Press 
(US); 2011. [PMID: 22013611]
Office of Disease Prevention and Health Promotion (ODPHP). 
Healthy People 2020: lesbian, gay, bisexual, and transgender 
health. 2016. https://www.healthypeople.gov/2020/topics-
objectives/topic/lesbian-gay-bisexual-and-transgender-health
A. HIV and Other STIs
A difference in the burden of HIV infection is one of most 
well-described disparities affecting MSM. MSM account for 
70% of all new HIV infections in the United States, despite 
representing a small proportion of the country’s population. 
The high burden of HIV infection among MSM stems in 
part from the efficient transmission of the virus through 
receptive anal intercourse, which confers a higher risk of 
HIV infection than other sexual activities, such as 
penile-vaginal and oral intercourse. Role versatility can also 
uniquely potentiate HIV spread among MSM, since the 
same person can acquire HIV via receptive intercourse and 
become an efficient transmitter by engaging in insertive 
intercourse with HIV-uninfected partners. The origin of 
disparate HIV rates between MSM and other populations is 
not solely biologic in origin, however, as societal stigma and 
psychosocial problems also contribute to sexual risk behav
-
ior among MSM. MSM of color face an increased risk of 
HIV; the CDC estimates that the lifetime risk of HIV infec
-
tion is 1 in 2 for African American MSM and 1 in 4 for 
Latino MSM compared to 1 in 11 for white MSM. Racial and 
ethnic disparities in HIV infections among MSM do not

-
ethnic disparities in HIV infections among MSM do not 
appear to be due to differences in sexual behavior or sub
-
stance use but rather factors such as lack of access to medical 
care, lower rates of recent HIV testing among nonwhite 
MSM, and assortative mixing, (ie, being more likely to have 
sex with partners from one’s own racial or ethnic group).
Beyond HIV , some STIs are more common among MSM. 
In 2016, 58% of primary and secondary syphilis diagnoses 
occurred in MSM or men who have sex with both men and 
women. Syphilis is associated with a high risk of subsequent 
HIV acquisition in MSM and may serve as a marker for indi
-
viduals who could benefit from intensive HIV prevention 
efforts, such as preexposure prophylaxis (PrEP). In addition, 
an outbreak of ocular syphilis, occasionally resulting in 
blindness, was reported in 2016, with a majority of cases 
occurring in MSM. The incidence of gonorrhea among MSM 
exceeds that among men who have sex with women (MSW) 
and has increased. MSM also are more likely than MSW to be 
infected with antibiotic-resistant gonorrhea. Many gonococ
-
cal infections in MSM occur at extragenital sites, such as the 
pharynx or the rectum, where they may be asymptomatic, 
underscoring the importance of eliciting a comprehensive 
sexual history, including an inventory of potential anatomic 
exposures, in order to provide optimal health care to MSM.
MSM also face increased risks of viral hepatitis. 
Outbreaks of hepatitis A infection have been documented 
in MSM groups, likely due to anal sexual contact, including 
oral-anal exposure (“rimming”) as well as insertive and 
receptive practices. Likewise, hepatitis B appears to be 
more common among MSM than the general population; 
approximately 20% of MSM have evidence of either current 
or prior infection with hepatitis B by age 30. This high
-
lights the importance of universal vaccination for young 
MSM, preferably prior to the initiation of sexual contact. 
Finally, although hepatitis C is generally not efficiently 
transmitted via sexual contact, hepatitis C infection has 
been identified as a problem among HIV-infected MSM 
and is associated with condomless receptive anal sex, group 
sex, manual insertion of fingers into the rectum (“fisting”), 
and recent STIs, which make the rectal mucosa more sus
-
ceptible to hepatitis C acquisition.
HPV infection, which can cause anogenital warts, anal 
dysplasia, and anal cancer, is more common among MSM 
than MSW . A meta-analysis estimated the prevalence of the 
oncogenic HPV type 16 in the anal canal to be 35.4% 
among HIV-infected MSM and 12.5% among MSM with
-
out HIV . Correspondingly, anal cancer incidence is higher 
among HIV-infected versus HIV-uninfected MSM. 
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Studies are underway to determine the optimal frequency 
of screening for anal cellular atypia and follow-up high 
resolution anoscopy for sexually active MSM (see below).
Some enteric infections may be sexually transmitted 
among MSM engaging in anal sexual contact, especially 
oral-anal sexual contact, and should be considered in the 
differential diagnosis of gastrointestinal complaints. These 
infections include giardiasis, amebiasis, and shigellosis. In 
addition, 
Shigella
 infections are more likely to be antibiotic 
resistant among MSM than among other individuals.
Clusters of meningococcal disease among MSM in the 
United States and Europe have also been reported, most 
recently in 2016, prompting some jurisdictions to recom
-
mend meningococcal vaccination for all MSM. Intimate 
contact with multiple partners has been identified as a risk 
factor for infection in some of these outbreaks.
Centers for Disease Control and Prevention (CDC). HIV among 
African American gay and bisexual men. 2017. https://www
 
.cdc.gov/hiv/group/msm/bmsm.html
gay and bisexual men. 2017. http://www.cdc.gov/hiv/group/
msm/index.html
Nanduri S et al. Outbreak of serogroup C meningococcal disease 
primarily affecting men who have sex with men—Southern 
California, 2016. MMWR Morb Mortal Wkly Rep. 2016 Sep 9; 
65(35):939–40. [PMID: 27606798]
Nyitray AG et al. Incidence, duration, persistence, and factors 
associated with high-risk anal human papillomavirus persis
-
tence among HIV-negative men who have sex with men: a 
multinational study. Clin Infect Dis. 2016 Jun 1;62(11): 
1367–74. [PMID: 26962079]
Stall R et al. Association of co-occurring psychosocial health 
problems and increased vulnerability to HIV/AIDS among 
urban men who have sex with men. Am J Public Health. 
2003 Jun;93(6):939–42. [PMID: 12773359]
Vanhommerig JW et al; MOSAIC (MSM Observational Study of 
Acute Infection With Hepatitis C) Study Group. Risk factors 
for sexual transmission of hepatitis C virus among human 
immunodeficiency virus-infected men who have sex with 
men: a case-control study. Open Forum Infect Dis. 2015 Aug 6; 
2(3):ofv115. [PMID: 26634219]
B. Mental Health
Likely due to minority stress (ie, growing up in non-affirming 
societies), MSM experience mental health disorders more 
commonly than other men. Whether defined by self-reported 
identity as gay or bisexual or behaviorally by report of sexual 
activity with other men, MSM have a higher lifetime preva
-
lence of depression and anxiety disorders than men who 
identify as heterosexual and/or who report sexual activity only 
with women. Behaviorally bisexual men experience a higher 
burden of both depression and anxiety disorders, compared to 
men who engage in only homosexual behavior, in part 
because bisexual men may not have access to defined com
-
munities of choice, like self-identified gay men. The increased 
prevalence of mental health disorders among behaviorally 
bisexual men may also stem from dual stigmatization by both 
the heterosexual and gay male communities, as well as inter
-
nalized stigma. Among MSM overall, anti-gay violence, 
community alienation, and dissatisfaction with an idealized 
body image have all been associated with depression.
Bostwick WB et al. Dimensions of sexual orientation and the 
prevalence of mood and anxiety disorders in the United 
States. Am J Public Health. 2010 Mar;100(3):468–75. [PMID: 
19696380]
Mills TC et al. Distress and depression in men who have sex with 
men: the Urban Men’s Health Study. Am J Psychiatry. 2004 
Feb;161(2):278–85. Erratum in: Am J Psychiatry. 2004 Apr; 
161(4):776. [PMID: 14754777]
C. Substance Use
Compared to men with only female sexual partners, MSM 
are more likely to report lifetime recreational drug use; 
they are specifically more likely to have used cocaine, hal
-
lucinogens, inhalants, analgesics, and tranquilizers. In

-
lucinogens, inhalants, analgesics, and tranquilizers. In 
addition, men who identify as gay or bisexual are more 
likely to smoke cigarettes than those who identify as het
-
erosexual. Although it is not clear that MSM are more 
likely than others to use methamphetamines, methamphet
-
amine use in MSM communities has been linked to 
increased sexual risk behavior and transmission of 
hepatitis C, HIV , and other STIs. Consistent with the 
minority stress model, experiences of discrimination have 
been independently associated with substance use among 
MSM. Several studies have indicated that substance use 
programs that integrate support for minority sexual iden
-
tity for MSM can result in long-term successful outcomes.
25485860]
Hoenigl M et al. Clear links between starting methamphetamine 
and increasing sexual risk behavior: a cohort study among 
men who have sex with men. J Acquir Immune Defic Syndr. 
2016 Apr 15;71(5):551–7. [PMID: 26536321]
McCabe SE et al. The relationship between discrimination and 
substance use disorders among lesbian, gay, and bisexual 
adults in the United States. Am J Public Health. 2010 Oct; 
100(10):1946–52. [PMID: 20075317]
 
»
Clinical Care
Clinicians can take steps to address health disparities 
affecting gay, bisexual, and other MSM by making clinical 
environments welcoming, inquiring about social and sex
-
ual histories in an open and nonjudgmental manner, and 
providing preventive care that is concordant with clinical 
practice guidelines that have been developed for this 
A. Making Clinical Environments Welcoming to 
Gay, Bisexual, and Other MSM
Several simple steps can contribute to a friendlier care 
environment for MSM. These include incorporating 
LGBT-friendly imagery on posters and brochures, creating 
and prominently displaying a nondiscrimination statement 
that includes sexual orientation and gender identity, col
-
lecting information about sexual orientation and gender 
identity routinely from all patients, and avoiding assump
-
tions about heterosexuality throughout the patient care 
process. For example, when inquiring about relationship 
status, clinicians should ask male patients about “partners” 
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or “spouses” rather than “girlfriends” or “wives. ” Strategies 
to make clinic environments more welcoming to LGBT 
patients are described in the above section, Lesbian & 
Bisexual Women’s Health.
B. Obtaining Sexual History From Gay, 
Bisexual, and Other MSM
The core history and physical examination is not different 
for MSM in comparison to other patients. As with all ado
-
lescents or adults, a complete medical history for MSM 
should include a comprehensive sexual history. Key data to 
gather include sexual function and satisfaction, the num
-
ber of partners if the patient is sexually active, and the 
gender of the patient’s sexual partner(s). In addition, clini
-
cians should determine the types of sexual practices the 
patient engages in (for example, oral sex, insertive anal sex, 
and/or receptive anal sex); how often condoms are used, if 
at all, for the different sexual practices the patient engages 
in; and whether drugs or alcohol are consumed in conjunc
-
tion with sex. Clinicians should also establish whether 
there is a history of STIs because a positive history may 
have implications for medical follow-up and sexual risk 
assessment. For example, a recent diagnosis of syphilis 
would indicate the need for rapid plasma reagin titer moni
-
toring to ensure adequate treatment and would prompt 
consideration of PrEP due to the association of syphilis 
with HIV acquisition in MSM. Clinicians may wish to 
preface discussion of the patient’s sexual history with a 
statement indicating that this information is confidential 
and is important for optimal health care. For example, 
understanding the types of sex MSM engage in permits 
clinicians to recommend site-appropriate screening tests 
for gonorrhea and chlamydia.
Centers for Disease Control and Prevention (CDC). A guide to 
taking a sexual history. http://www.cdc.gov/std/treatment/
sexualhistory.pdf
Van Wagenen A. Ten things: creating inclusive health care envi
-
ronments for LGBT people. National LGBT Health Education 
Center. 2015. http://www.lgbthealtheducation.org/wp-content/
uploads/Ten-Things-Brief-Final-WEB.pdf
C. Preventive Care and Clinical Practice Guidelines
Clinicians can help address health disparities affecting 
MSM by following clinical practice guidelines that pertain 
to this population (Table 42–1). The CDC recommends 
that sexually active MSM undergo screening for HIV , 
syphilis, gonorrhea, and chlamydia annually and more 
often if the risk history warrants more frequent assessment. 
An HIV antibody-antigen assay is preferred for HIV 
screening because this test increases the sensitivity for 
detection of acute or recent HIV infection. Nucleic acid 
amplification testing (NAAT) provides optimal sensitivity 
for diagnosis of gonorrhea and chlamydia and can be per
-
formed on the oropharynx, rectum, urine, and urethra. 
Although oropharyngeal testing for chlamydia is not 
Table 42–1.
 
Clinical practice guidelines pertaining to the care of MSM.
Comments
Human papillomavirus (4- or 9-valent)
Up to age 26 years
Hepatitis A and B
Consider pre-vaccination serologic testing if the immunization history is uncertain; 
vaccinate if seronegative
Meningococcal
Recommended by some jurisdictions due to outbreaks of meningococcal disease 
among MSM
Preexposure prophylaxis (PrEP) for HIV
For MSM at high, ongoing risk of HIV infection (eg, condomless anal sex, recent STI 
diagnosis, HIV-infected sexual partner)
Postexposure prophylaxis (PEP) for HIV
Consists of 28 days of antiretroviral medication following a discrete exposure to HIV
Screening tests
HIV serology
At least annually, more often if high risk
Syphilis serology
Nucleic acid amplification test for gonorrhea and 
chlamydia
At least annually, more often if high risk; all potentially exposed sites (oropharynx,

chlamydia
At least annually, more often if high risk; all potentially exposed sites (oropharynx, 
urethra, rectum) should be screened, as indicated by the sexual history
Hepatitis C serology
Annually for HIV-infected MSM and HIV-uninfected MSM engaging in behaviors that 
might expose them to blood (for example, injection drug use or traumatic anal 
sexual practices)
Anal cytology
For HIV-infected MSM; the appropriateness of anal cytology for HIV-uninfected MSM 
 
is under study
Behavioral health (depression, substance use)
At the first clinical encounter, with follow-up screening for those who report behav
-
ioral health concerns
MSM, men who have sex with men; STI, sexually transmitted infection.
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recommended, MSM should otherwise be screened for 
these infections at any of the aforementioned sites that may 
have been exposed during sex, regardless of condom use. 
First-catch urine and urethral specimens for gonorrhea 
and chlamydia NAAT in men provide comparable accu
-
racy; thus, there is no advantage to the urethral swab for 
routine screening. Rectal swabs for NAAT can be 
self-collected.
CDC also recommends that MSM be screened for 
chronic hepatitis B infection at least once in their lives and 
that they be vaccinated against hepatitis A and B. Annual 
hepatitis C screening with a hepatitis C antibody test is 
recommended for HIV-infected MSM due to the elevated 
incidence of this infection in this population and the 
advent of well-tolerated, curative therapy.
Both CDC and the World Health Organization recom
-
mend PrEP for HIV with the fixed-dose combination of 
tenofovir disoproxil fumarate (TDF)-emtricitabine for 
MSM at high risk for HIV infection (see Chapter 31). 
Individuals at high risk include those who engage in con
-
domless anal sex outside of a monogamous relationship with 
an HIV-negative man; those who have recently been diag
-
nosed with a bacterial STI; and those whose sexual partners 
are HIV-infected. However, the utility of PrEP is likely low 
in the latter scenario if the relationship is monogamous and 
the HIV-infected partner is consistently virologically sup
-
pressed on antiretroviral therapy, because antiretroviral 
therapy significantly reduces the likelihood of HIV trans
-
mission through sexual contact. PrEP has been shown in 
randomized controlled trials to prevent HIV infection in 
MSM and is addressed in more detail in Chapter 31.
Clinicians who care for MSM should also be aware of 
postexposure prophylaxis (PEP), which consists of antiret
-
rovirals started within 72 hours of a discrete exposure to 
HIV and taken for 28 days, and either provide PEP them
-
selves or be able to rapidly link patients to PEP care (see 
Chapter 31).
While HPV immunization with the quadrivalent or 
nonavalent vaccines is recommended for all boys and 
young men up to age 21 years, vaccination is recom
-
mended for MSM up to age 26. The HIV Medicine 
Association (HIVMA) recommends routinely screening 
HIV-infected MSM for anal cancer with anal cytology; 
however, this approach has not yet been proven to be ben
-
eficial in a randomized controlled clinical trial. In addition, 
the optimal screening interval (ages at which to initiate and 
cease screening) and management of abnormal results are 
not clearly defined. Patients with abnormal anal cytology 
are typically referred for high-resolution anoscopy with 
biopsy. Colonoscopy performed for colon cancer screening 
is not considered a substitute for anal cytology or high-
resolution anoscopy because colonoscopy does not assess 
for cellular abnormalities in the anal canal. Anal cytology 
screening of HIV-negative MSM is not currently recom
-
mended in any national consensus guidelines, although 
some clinicians perform this screening due to the elevated 
risk of anal cancer in these men. Large prospective studies 
are underway in the United States and Australia to attempt 
to address the questions related to optimal timing of anal 
HPV screening for MSM.
Finally, clinicians should ensure that MSM are offered 
preventive care recommended for all individuals, including 
smoking cessation counseling and pharmacotherapy, 
screening for depression, and assessment for and counsel
-
ing about alcohol misuse. Some studies have found that 
behavioral health programs tailored specifically for MSM 
are more effective in promoting healthy behaviors than 
those that are not culturally sensitive.
Aberg JA et al. Primary care guidelines for the management of 
persons infected with HIV: 2013 update by the HIV Medicine 
Association of the Infectious Diseases Society of America. 
Clin Infect Dis. 2014 Jan;58(1):1–10. [PMID: 24343580]

guidelines for antiretroviral postexposure prophylaxis after 
sexual, injection-drug use, or other nonoccupational expo
-
sure to HIV—United States, 2016. MMWR Morb Mortal 
Wkly Rep. 2016 May 6;65(17):458. [PMID: 27149423]
Grant RM et al. Preexposure chemoprophylaxis for HIV preven
-
tion in men who have sex with men. N Engl J Med. 
2010 Dec 30;363(27):2587–99. [PMID: 21091279]
Jain S, Krakower DS, Mayer KH. The transition from postexpo
-
sure prophylaxis to preexposure prophylaxis: an emerging 
opportunity for biobehavioral HIV prevention. Clin Infect Dis. 
2015 Jun 1;60(Suppl 3):S200–4. [PMID: 25972505]
Reback CJ et al. Development of an evidence-based, gay-specific 
cognitive behavioral therapy intervention for methamphet
-
amine-abusing gay and bisexual men. Addict Behav. 
2014 Aug;39(8):1286–91. [PMID: 22169619]
Rodger AJ et al. Sexual activity without condoms and risk of 
HIV transmission in serodifferent couples when the HIV-
positive partner is using suppressive antiretroviral therapy. 
JAMA. 2016 Jul 12;316(2):171–81. Erratum in: JAMA. 
2016 Nov 15;316(19):2048. [PMID: 27404185]
 
º
TRANSGENDER HEALTH & 
DISEASE 
p
REVENTION
 
»
Terminology & Definitions
Transgender (abbr: “trans”) people have a gender identity 
that differs from the sex they were assigned at birth. 
Gender identity describes a person’s internal sense of 
gender. Sex refers to the sex assigned at birth typically by 
the attending medical provider, based on assessment of 
external genitalia as well as chromosomes and gonads. In 
everyday language “sex” and “gender” are used inter
-
changeably; however, in the context of transgender people 
the meanings differ. Gender expression describes the out
-
ward manner in which an individual expresses or displays 
gender, including choices in clothing and hairstyle, speech, 
and mannerisms. Gender identity and gender expression 
may differ; for example, a woman (transgender or non-
transgender) may have an androgynous appearance, or a 
man (transgender or non-transgender) may have a 
feminine form of self-expression. Transgender people who 
have a well documented and persistent gender identity 
 
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that differs from their sex assigned at birth and are experi
-
encing distress as a result of this mismatch, meet the diag
-
nostic criteria for gender dysphoria as described in the 
Diagnostic Statistical Manual,
 5th edition (
DSM-5
).
A transgender man is someone with a male gender 
identity and a female birth-assigned sex; a transgender 
woman is someone with a female gender identity and a 
male birth-assigned sex. A non-transgender person may be 
referred to as cisgender (latin root 
cis
 = near/next to) refers 
to people whose gender identity and birth sex are the same, 
ie, non-transgender. Non-binary, gender nonconforming, 
or genderqueer describes a person whose gender identity 
differs from that assigned at birth but may be more com
-
plex, fluid, multifaceted, or otherwise less clearly defined 
than purely male or female. Non-binary people may prefer 
neutral pronouns such as “they, ” “them, ” or “their. ” The 
term transsexual is an older term that has fallen out of 
favor and referred specifically to a transgender person who 
seeks medical interventions. Other related terms include 
cross dresser, which describes someone who may wear 
clothing of the opposite gender without a clear identifica
-
tion with that gender, and drag, which describes cross 
dressing for performance purposes. These identities share 
some commonalities with transgender people, but are dis
-
tinct in that they do not involve a core sense of gender 
dysphoria.
Sexual orientation, which describes sexual attraction 
and behaviors, is not directly related to gender identity. The 
sexual orientation of transgender people should be 
described based on the lived gender; a transgender woman 
attracted to other women would be a lesbian, and a trans
-
gender man attracted to other men would be a gay man.
 
»
Providing a Welcoming Clinic Atmosphere
Transgender people may avoid seeking care due to prior 
discrimination or disrespect in a clinic setting. One in three 
transgender people report delay in seeking care due to prior 
discrimination, and one in five report being refused medi
-
cal care due to their transgender identity. Providing a safe, 
welcoming and culturally appropriate clinic environment is 
essential to ensure that transgender people not only seek 
care but return for follow-up. Each patient should be 
approached as an individual including preferences of ter
-
minology, complex or novel gender identities, and differing 
desires for gender affirming treatments. Patients should not 
be expected to discuss their gender identity or transition 
unless it is relevant to the current visit. Training on trans
-
gender cultural sensitivity and health should be provided to 
all clinic staff and providers. Waiting areas should include 
transgender-themed posters, artwork, and magazines to 
indicate a message of inclusion. If gender neutral bath
-
rooms are not available, a clearly stated policy allowing the 
use of either bathroom should be posted.
Electronic medical record (EMR) systems should 
include functionality for the recording of gender identity, 
birth-assigned sex, as well as chosen name and pronoun in 
the case of a transgender person who has not changed their 
legal identity documents. Chosen name and pronoun func
-
tionality should be displayed in all banners, schedules, and 
other viewing screens. Transgender people can be identi
-
fied within the EMR for those whose entries for gender 
identity and birth sex differ. EMRs should also allow the 
tracking of an organ inventory since transgender people 
may have different organs tthan are typically associated 
with the sex under which they are registered in the system. 
An accurate organ inventory can drive decision support 
and other functionality for preventive health screening or 
examination templates.
Transgender people may seek any one of a number of 
gender affirming medical, surgical or related interventions.

gender affirming medical, surgical or related interventions. 
Based on research demonstrating positive effects on mul
-
tiple psychosocial measures, such interventions are recog
-
nized as medically necessary by the World Professional 
Association for Transgender Health (WPATH), an interna
-
tional, multidisciplinary professional organization that 
publishes widely recognized Standards of Care. Not all 
transgender people seek all interventions, and some may 
seek none; the current standard of care is to allow each 
transgender person to seek only those interventions they 
desire to affirm their own gender identity.
-
26698386]
Coleman E et al. Standards of Care for the Health of Transsexual, 
Transgender, and Gender-Nonconforming People, Version 7. 
Int J Transgenderism. 2012;13(4):165–232.
Deutsch MB et al. Electronic medical records and the transgen
-
der patient: recommendations from the World Professional 
Association for Transgender Health EMR Working Group. J 
Am Med Inform Assoc. 2013 Jul–Aug;20(4):700–3. [PMID: 
23631835]
Deutsch MB et al. Electronic health records and transgender 
patients—practical recommendations for the collection of 
gender identity data. J Gen Intern Med. 2015 Jun;30(6):843–7. 
[PMID: 25560316]
 
»
Medical Interventions
Gender affirming hormone therapy is the primary medical 
intervention sought by transgender people. Such treatment 
allows the acquisition of secondary sex characteristics 
more aligned with an individual’s gender identity. The 
WPATH Standards of Care recognize that hormone 
therapy is within the scope of practice for primary care 
providers. The Standards also permit medical providers to 
prescribe hormone therapy under an informed consent 
approach without a mental health assessment if the medi
-
cal provider feels comfortable making the diagnosis of 
gender dysphoria.
A. Feminizing Hormone Therapy
The goal of feminizing hormone therapy is the develop
-
ment of female secondary sex characteristics, and 
suppression/minimization of male secondary sex charac
-
teristics. The general approach of therapy is to obtain 
physiologic premenopausal female range estrogen and tes
-
tosterone levels through the combined use of an estrogen 
with an androgen blocker, and in some cases a progestagen. 
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Clinical endpoints include breast development (often max
-
imum Tanner stage 2/3), reduction of body hair, reduced 
muscle mass, and female redistribution of body fat.
The most commonly used estrogen is 17-beta estradiol, 
in pill, patch, or less commonly injected form. The choice 
of route is based to some degree on patient preference 
(Table 42–2). Transdermal estradiol has a well-established 
safety profile based on studies in menopausal cisgender 
women. Injected estradiol is the least studied route and can 
be associated with both supratherapeutic levels as well as 
cyclical levels over the dosing interval. Estrogens should be 
continued after gonadectomy without reduction in dose. 
There is no evidence to support discontinuation of estro
-
gen once a patient arrives at a menopausal age. Ethinyl 
estradiol should be avoided due to thrombogenicity and a 
lack of need for suppression of ovulation.
The most commonly used anti-androgen is spironolac
-
tone, a potassium-sparing diuretic that is frequently used 
for female hirsutism or adult acne. Spironolactone inhibits 
both the synthesis of and action of testosterone. In higher 
doses (100–200 mg orally daily), spironolactone can lead to 
suppression of androgen levels into the female physiologic 
range. Common side effects include orthostasis and 
polyuria. Monitoring should include periodic assessment 
of kidney function and serum potassium. Other options 
for those who cannot tolerate spironolactone include 
5-alpha-reductase inhibitors (finasteride, dutasteride), 
gonadotropin-releasing hormone (GnRH) analog, orchi
-
ectomy, or the use of a progestagen. After gonadectomy, 
anti-androgens can be discontinued.
No studies have been conducted on the role of proges
-
tagens in transgender women. Some believe there is benefit 
to breast development, mood, or libido, and there is no 
evidence to suggest any harm related to progestagens. 
Progestagens may be an effective anti-androgen, particu
-
larly cyproterone acetate, which is used widely outside the 
United States as the primary androgen blocker in feminiz
-
ing regimens. If used, progestagens should be initiated after 
at least several months of estrogen plus anti-androgen.
The primary risk associated with estrogen therapy is 
venous thromboembolism (VTE). However, when using 
17-beta estradiol at physiologic estrogen dosing, the risk is 
minimal. Prior studies showing 20- to 40-fold increased risk 
of VTE involved the use of ethinyl estradiol at doses of up 
to 200 mcg/day and did not control for tobacco use. More 
recent data found no increased risk of VTE in transgender 
Table 42–2.
 
Feminizing hormone therapy.
Dosage
Hormone Therapy
Initial, Low
1
Initial, Typical
Maximum, Typical
2
Comments
Estrogen
Estradiol oral/
sublingual
1 mg/day
2–4 mg/day
8 mg/day
If > 2 mg is recommend, dose should be 
divided and taken twice daily.
Estradiol 
50 mcg
100 mcg
100–400 mcg
Maximum available single patch dose is 
100 mcg. Frequency of change is brand 
and product dependent. Patients may 
find that more than 2 patches at a time 
are cumbersome.
Estradiol valerate, 
intramuscularly
3
< 20 mg every 
 
2 weeks
20 mg every 2 weeks
40 mg every 2 weeks
May divide dose into weekly injections for 
cyclical symptoms.
Estradiol cypionate, 
< 2 mg every 
 
2 weeks
2 mg every 2 weeks
5 mg every 2 weeks
p
r
ogestagen
Medroxyprogester
-
one acetate 
(Provera)
2.5 mg orally each 
night at bedtime
5–10 mg orally each 
Micronized 
progesterone
100–200 mg each night 
at bedtime
Androgen Blocker
50 mg orally twice 
daily
5 mg orally daily
1
Initial low dosing for those who desire (or require due to medical history) a low dose or slow upward titration.
2

1
2
Maximal effect does not necessarily require maximal dosing, as such maximal doses do not necessarily represent a target or ideal dose. 
Dose increases should be based on patient response and monitored hormone levels.
3
Available as standard U.S. Pharmacopia (USP) as well as compounded products.
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women using transdermal 17-beta estradiol. Thus, trans
-
dermal estradiol is the preferred route for those who smoke 
or with risk factors for or a personal history of VTE.
Asscheman H et al. A long-term follow-up study of mortality in 
transsexuals receiving treatment with cross-sex hormones. 
Eur J Endocrinol. 2011 Apr;164(4):635–42. [PMID: 21266549]
Canonico M et al. Hormone replacement therapy and risk of 
venous thromboembolism in postmenopausal women: 
systematic review and meta-analysis. BMJ. 2008 May 31; 
336(7655):1227–31. [PMID: 18495631]
Rosenthal SM. Approach to the patient: transgender youth: 
endocrine considerations. J Clin Endocrinol Metab. 
2014 Dec;99(12):4379–89. [PMID: 25140398]
Wierckx K et al. Clinical review: breast development in trans 
women receiving cross-sex hormones. J Sex Med. 2014 May; 
11(5):1240–7. [PMID: 24618412]
B. Masculinizing Hormone Therapy
The goal of masculinizing hormone therapy is the 
development of male secondary sex characteristics, and 
suppression/minimization of female secondary sex char
-
acteristics. The general approach involves the use of one 
of several forms of parenteral testosterone using an 
approach similar to that in hypogonadal or agonadal cis
-
gender men (Table 42–3). Blockade of estrogen is not 
needed.
Testosterone may be injected or applied as a topical gel 
or patch. Two studies support the use of subcutaneous 
(rather than intramuscular) injections, which allow the use 
of a smaller needle. The use of topical testosterone, or using 
a weekly (vs biweekly) injection interval can help maintain 
even hormone levels in those with cyclical mood symp
-
toms or pelvic cramping. Clinical endpoints include the 
development of facial hair, deepening of the voice, clitoral 
growth, male body fat redistribution and muscle growth, 
and induction of amenorrhea by 6 months.
Prior concerns of testosterone-induced hepatotoxicity 
were based on the use of oral methyltestosterone. There is 
no evidence to support a concern of hepatotoxicity in 
transgender men using parenteral testosterone.
Table 42–3.
 
Masculinizing hormone therapy.
Dosage
Androgen
1
2
Comment
Testosterone cypionate
3
20 mg/week 
 
50 mg/week 
100 mg/week 
For every 2-week dosing, 
double each dose.
Testosterone enthanate
3
20 mg/week intramuscu
-
larly/subcutaneously
50 mg/week 
Testosterone topical 
 
gel 1%
12.5–25 mg every 
morning
50 mg every morning
100 mg every morning
May come in pump or 
packet form.
 
gel 1.62%
4
20.25 mg every morning
40.5–60.75 mg every 
morning
103.25 mg every morning
Testosterone patch
1–2 mg every night
4 mg every night
8 mg every night
Patches come in 2-mg and 
4-mg size. For lower 
doses, may cut patch.
Testosterone cream
5
10 mg
50 mg
100 mg
Testosterone axillary 
 
gel 2%
30 mg every morning
60 mg every morning
morning
Comes in pump only; one 
pump = 30 mg.
undecanoate
6
N/A
750 mg intramuscularly, 
repeat in 4 weeks, then 
every 10 weeks ongoing
N/A
Requires participation in 
manufacturer 
monitored program.
6
1
Initial, low-dose regimen is recommended for genderqueer and non-binary persons.
2
Maximum dosing does not mean maximal effect. Furthermore, these dosage ranges do not necessarily represent a target or ideal dose. 
Dose increases should be based on patient response and monitored hormone levels. Some patients may require less than this amount, and 
some may require more.
3
4
Doses of less than 20.25 mg with 1.62% gel or less than 30 mg with 2% axillary gel may be difficult, since measuring one-half of a pump

4
Doses of less than 20.25 mg with 1.62% gel or less than 30 mg with 2% axillary gel may be difficult, since measuring one-half of a pump 
or packet can present a challenge. Patients requiring doses lower than 20.25 mg and whose insurance does not cover 1% gel may require 
prior authorization or an appeal.
5
Testosterone creams are prepared by individual compounding pharmacies. Specific absorption and activity varies and consultation with 
the individual compounding pharmacist is recommended.
6
Testosterone undecanoate has been associated with rare cases of pulmonary oil microembolism and anaphylaxis; in the United States, the 
drug is available only through the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program (https://www.aveedrems.com/AveedUI/
rems/preHome.action). All injections must be administered in an office or hospital setting by a trained and registered health care provider 
and monitored for 30 minutes afterward for adverse reactions.
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Common side effects of testosterone therapy in trans
-
gender men include acne and male pattern baldness, both 
of which can be approached as in cisgender men. Hemo
-
globin and hematocrit should be monitored, and if the 
levels are elevated, consider reducing testosterone dose or 
changing to a transdermal form or weekly injections to 
maintain more even levels. Polycystic ovarian syndrome 
and obesity have been found to be at an increased preva
-
lence in transgender men prior to beginning testosterone 
therapy. Testosterone is not contraindicated in the presence 
of these conditions; instead, related metabolic disorders 
can be managed concurrently.
Baba T et al. Distinctive features of female-to-male transsexualism 
and prevalence of gender identity disorder in Japan. J Sex Med. 
2011 Jun;8(6):1686–93. [PMID: 21477021]
Olson J et al. Subcutaneous testosterone: an effective delivery 
mechanism for masculinizing young transgender men. LGBT 
Health. 2014 Sep;1(3):165–7. [PMID: 26789709]
C. Monitoring Therapy
Hormone effects should be monitored both by clinical 
results as well as hormone levels, if available. Patients 
should be reminded that results may vary and can take up 
to 5 years to reach maximal effect; supraphysiologic hor
-
mone levels are not likely to enhance results but may incur 
risks. Note that reported laboratory reference range values 
may differ depending on the sex of registration of the 
patient; in general, clinicians should use the reference 
ranges driven by the current hormonal status of the patient. 
For example, female reference ranges will be included on 
automated laboratory reports of a transgender man taking 
testosterone while still legally registered as female. The 
interpreting clinician should use the male reference ranges 
for any tests run on this patient that have sexually 
dimorphic reference ranges. Tables 42–4 and 42–5 describe 
general monitoring recommendations, rationales, and 
“sex-specific” laboratory values that may require individu
-
alized interpretation.
D. Long-Term Health Outcomes
Well-designed, large, long-term studies of health out
-
comes in transgender people are lacking. The largest exist
-
ing study of mortality is in a retrospective cohort of 966 
transgender women and 365 transgender men who were 
treated with cross-sex hormones from the Netherlands, 
which did not control for a number of risk factors. All-
cause as well as cardiovascular, cerebrovascular, and other 
disease-specific mortality among transgender men did not 
differ from the general Dutch population of cisgender 
women. Among transgender women, all-cause mortality 
was 51% higher than cisgender men in the general Dutch 
population, with the overwhelming majority of the differ
-
ence due to HIV , drug overdose and suicide; a 64% 
increased risk (95% CI 43 to 87) in cardiovascular 
mortality was seen; however, no significant difference was 
seen for cerebrovascular mortality. It should be noted that 
this study did not control for tobacco use. Any decisions 
to provide hormone therapy should include a detailed 
informed consent discussion and consideration, including 
recognizing the significant risks of withholding treatment 
on psychological well being which can have negative 
impacts on physical health as well as suicidality or sub
-
stance abuse.
 
»
Surgical Interventions
A wide range of gender-affirming surgeries are available to 
transgender people. These include surgeries specific to 
Table 42–4.
 
Laboratory monitoring for feminizing hormone therapy.
Comments
Baseline
3 Months
1
6 Months
1
12 Months
1
Yearly
As needed
Blood urea nitrogen/
 
Creatinine/Potassium
Only if spironolactone is 
used
X
X
X
X
X
Lipids
X if clinically 
indicated
X
X
X
Hemoglobin A
1C
X
X
X
X
Estradiol
X
X
X

1
12 Months
1
Yearly
As needed
 
used
X
X
X
X
X
Lipids
indicated
X
X
X
1C
X
X
X
X
Estradiol
X
X
X
Total testosterone
X
X
X
X
Sex hormone binding 
globulin (SHBG)
2
X
X
X
X
Albumin
2
X
X
X
X
Prolactin
Only if symptomatic
X
1
In first year of therapy only.
2
Used to calculate bioavailable testosterone (http://www.issam.ch/freetesto.htm).
CMDT19_Ch42_p1722-p1742.indd   1740

1741
 
CMDT 2019
gender affirmation as well as procedures commonly per
-
formed in cisgender populations (Table 42–6).
 
»
Cancer Risk & Screening
Several retrospective studies have not identified an 
increased risk of cancer in transgender people compared to 
birth-sex matched controls. However, because of the 
numerous barriers to care as well as to identifying trans
-
gender people in clinical databases, underscreening and 
underreporting are likely. In general, an organ-based 
approach to screening should be taken. There are no modi
-
fications to screening recommendations (or recommenda
-
tions not to screen) for ovarian, uterine, or cervical cancer 
in transgender men. Breast cancer screening for transgen
-
der men who have not undergone mastectomy should be 
performed based on guidelines for cisgender women. The 
role of screening for breast cancer in transgender men who 
have undergone mastectomy is unknown and depends on 
the technique used as well as technical limitations on 
screening small amounts of residual breast tissue. In trans
-
gender women, breast cancer screening using guidelines for 
cisgender women is recommended, with the modifications 
starting at age 50 and only after a minimum of 5 years of 
lifetime estrogen exposure. Screening for prostate cancer in 
transgender women is complicated beyond the current 
debate over the utility of prostate cancer screening in 
cisgender men by the effects of feminizing hormones on 
prostatic hypertrophy and interpretation of tests of the PSA.
While screening transgender women for pituitary 
adenoma with serum prolactin levels has been done in 
the past, this is not recommended in asymptomatic 
patients since current guidelines for the management of 
incidental prolactinomas is watchful waiting. Prolactin 
screening should occur in transgender women with 
galactorrhea, visual disturbances, or a new headache 
pattern.
UCSF Center of Excellence for Transgender Health Guidelines 
for the Primary and Gender Affirming Care of Transgender 
and Gender Nonconforming People. http://transhealth.ucsf
 
.edu/trans?page=protocol
Wierckx K et al. Long-term evaluation of cross-sex hormone 
treatment in transsexual persons. J Sex Med. 2012 Oct; 
9(10):2641–51. [PMID: 22906135]
Wierckx K et al. Prevalence of cardiovascular disease and cancer 
during cross-sex hormone therapy in a large cohort of trans 
persons: a case-control study. Eur J Endocrinol. 2013 Sep 13; 
169(4):471–8. [PMID: 23904280]
 
»
HIV
Transgender women in the United States are 34 times more 
likely to be infected with HIV than the general population. 
This disparity is driven by a number of factors, including 
lack of both employment opportunities and legal 
Table 42–5.
 
Laboratory monitoring for masculinizing hormone therapy.
Comments
Baseline
3 Months
1
6 Months
1
12 Months
1
Yearly
As Needed
Lipids
No evidence
X
Based on USPSTF 
X
X
X
X
1c
 or fasting 
glucose
X
X
X
X
Estradiol
X
X
X
X
X
Albumin
2
X
X
X
X
Hemoglobin and hematocrit
X
X
X
X
X
X
1
2
Used to calculate bioavailable testosterone.
USPSTF, United States Preventive Services Task Force.
Table 42–6.
 
Procedural interventions for gender 
affirmation.
Surgeries specific to transgender populations
Feminizing vaginoplasty
Masculinizing phalloplasty, scrotoplasty
Metaoidioplasty (clitoral release/enlargement, may include 
urethral lengthening)
Masculinizing chest surgery (“top surgery”)
Facial feminization procedures
Reduction thyrochondroplasty (tracheal cartilage shave)
Voice surgery
Surgeries not specific to transgender populations
Augmentation mammoplasty
Hysterectomy, oophorectomy
Vaginectomy
Other interventions
Facial hair removal
Voice modification
Genital tucking and packing
Chest binding
CMDT19_Ch42_p1722-p1742.indd   1741

C
HA
p
TER
 4
2
1742
 CMDT 2019
protections in the workplace and elsewhere, all of which 
can result in survival transactional sex and sex work, and 
an association between unaffirmed gender identity and 
high-risk sexual behavior. Based on studies of hormonal 
contraception, gender-affirming hormone therapy is not 
believed to have negative interactions with antiretroviral 
medications, although direct studies are lacking. A sub
-
analysis of transgender women within a larger study of 
HIV PrEP with a daily fixed-dose combination of tenofovir 
disoproxil fumarate 300 mg and emtricitabine 200 mg sug
-
gested efficacy when taken as prescribed but demonstrated 
poor adherence in comparison to control MSM. Such find
-
ings support the notion that HIV services and programs 
targeting transgender populations should be developed 
and implemented distinctly from those targeting MSM, 
and that bundling of HIV care with gender-affirming care 
may improve HIV outcomes.
Baral SD et al. Worldwide burden of HIV in transgender women: 
a systematic review and meta-analysis. Lancet Infect Dis. 
2013 Mar;13(3):214–22. [PMID: 23260128]
Deutsch MB et al; iPrEx investigators. HIV pre-exposure pro
-
phylaxis in transgender women: a subgroup analysis of the 
iPrEx trial. Lancet HIV . 2015 Dec;2(12):e512–9. [PMID: 
26614965]
Poteat T et al. HIV risk and preventive interventions in transgen
-
der women sex workers. Lancet. 2015 Jan 17;385(9964): 
274–86. [PMID: 25059941]
Sevelius JM. Gender affirmation: a framework for conceptualizing 
risk behavior among transgender women of color. Sex Roles. 
2013 Jun 1;68(11–12):675–89. [PMID: 23729971]
CMDT19_Ch42_p1722-p1742.indd   1742

1743
 
CMDT 2019
A3243G
 mutation, 1222
(A)H7N7 influenza, 1426
(A)H7N9 influenza, 1426, 1427
AA (Alcoholics Anonymous), 1107
AA (secondary) amyloidosis, 434, 550. 
 
See also
 Amyloidosis
AAAS
 gene, 1181
Abacavir, 1363
t
, 1366, 1371. 
See also
 
Antiretroviral therapy
in combination regimens, 1371, 1372
t
, 
1373
t
. 
See also
 Epzicom; 
Triumeq; Trizivir
HLA-B-associated drug hypersensitivity 
and, 894
Abaloparatide, 1174
Abatacept, 852
ABCB4
 gene, 740
ABCD scores, 1005
ABCDE rule/features, 112
Abciximab, 375, 381, 568
t
. 
See also
 
Glycoprotein IIb/IIIa 
receptors, drugs blocking
Abdominal abscess/infection, 666, 1321
t
, 
1484
, 1484
t
, 1486
Abdominal aortic aneurysm, 5, 6
t
, 
 
492–494
Abdominal imaging, in poisoning/drug 
overdose, 1587
Abdominal pain/tenderness, 
589–591
, 
654. 
See also
 
specific cause
Abemaciclib, 770
Abetalipoproteinemia, vitamin E 
deficiency and, 1285
ABIC score, 710
Abiraterone, 1200, 1623
t
, 1662
t
, 1663
abl
 gene, 534, 535
Abnormal illness behaviors, 
1071–1072
Abnormal sleep behaviors, 
1103
Abnormal uterine bleeding (AUB)
endometrial carcinoma and, 777, 
 
778, 788
ovulatory, 776, 777
postmenopausal, 
778
estrogen replacement therapy and, 
778, 1211, 1212
premenopausal, 
776–778
in polycystic ovary syndrome, 795
ABO system, 552, 552–553
Abortion
anaerobic infection after, 1485
elective/induced, 
806
. 
See also
 
specific 
disorder
with IUD in place, 804
IUD insertion after, 804
recurrent, 
819
spontaneous, 
817–819
Abscesses, 161–163, 1322
t
, 1353, 1450
t
. 
See also
 
specific disorder
abdominal, 666, 1321
t
, 1484, 1484
t
anaerobic, 1321
t
t
anorectal/perianal, 665, 666, 667, 686
in bacterial rhinosinusitis, 227
brain, 217, 
1020–1021
, 1305, 1306, 
1321
t
, 1484, 1486
in Crohn disease, 665, 666, 667, 686
deep neck, 240, 241
in drug users, 1310
epidural, 217, 885, 1307
intravascular. 
See
 Septic 
thrombophlebitis
liver
amebic, 1528, 1529, 1529–1530, 
 
1530
t
pyogenic, 
729–730
lung, 
286–287
in coccidioidomycosis, 1553, 1554
in mycetoma, 1560
mycobacteria causing, 1488
myocardial, endocarditis and, 1465, 
1466
pancreatic, 744, 745
pelvic, 1484
perforated appendicitis and, 654, 655
peritonsillar, 
240
soft tissue/subcutaneous, 1450
t
, 1553, 
1554
in spinal tuberculosis, 886
staphylococcal, 753, 828, 1353, 
 
1454–1455, 1455
f
Absence (petit mal)/atypical absence 
seizures, 996
t
, 998. 
See also
 
Seizures
Absidia (Lichtheimia)
 infection, 228–229, 
1558–1559
Abstinence syndrome, 1112
Abuse. 
See also
 
specific type
 and Domestic 
violence; Violence
prevention of, 17
Acamprosate, 19, 709, 1108
Acanthamoeba keratitis, 186
Acanthocytes, 926
Acanthosis nigricans, 1222, 1224, 1224
f
Acarbose, 1230
t
, 1234, 1599
Accelerated idioventricular rhythm, 389, 
409
Accessory atrioventricular pathways, 399, 
400, 
400–401
ACE inhibitors. 
See
 Angiotensin-
converting enzyme (ACE) 
Acebutolol, 463
t
, 1594
Acetaminophen (paracetamol), 36, 82, 85, 
86
t
in analgesic nephropathy, 960
contraindications to in heat stroke, 
 
1566
with opioid analgesics, 88, 94
t
for osteoarthritis, 842
overdose/toxicity of, 700, 1584
t
, 1587
t
, 
1588–1589
, 1588
f
anion gap acidosis and, 1587, 1588
hepatotoxicity/liver failure and, 699, 
700, 711, 1588, 1588
f
Acetazolamide, 187, 207
t
, 1022, 1577, 1578
Acetoacetate, 919
Acetohexamide, 1229, 1230
t
Acetonitrile, cyanide poisoning and, 1596
Acetylcholine
aminoglycosides affecting, 1060
botulinum toxin affecting, 1059
in myasthenia gravis, 1058
in myasthenic syndrome, 1059
Acetylcholine receptor antibodies
in cancer-related neuropathy, 1022
Acetylcholinesterase inhibitors. 
See
 
Anticholinesterases
for acetaminophen overdose/toxicity, 
700, 1584
t
, 1587
t
, 1589
contrast media nephrotoxicity mediated 
by, 932, 1248
Achalasia, 617
t
, 
629–630
Achlorhydria, in pernicious anemia 
gastritis, 634
Acid-antisecretory agents, 591, 608, 621, 
631, 637, 639, 641. 
See also
 
Antacids; H
2
 receptor

t
, 
629–630
See also
 
2
 receptor 
blocking drugs; Proton pump 
Acid-base disorders, 906
t
, 
917–925
, 917
t
. 
See also
 Acidosis; Alkalosis
in kidney disease/renal failure, 906
t
, 
918, 919–920, 930, 939
f
, 941
mixed, 
917–918
step-by-step analysis and, 917
Acid-fast rods, treatment of infections 
caused by, 1319
t
Acidosis, 917, 917
t
. 
See also
 Ketoacidosis
anion gap, 917–918, 918, 918–922, 918
t
, 
920
t
. 
See also
 Anion gap/
anion gap acidosis
dilutional, 921
drowning and, 1570
hyporeninemic hypoaldosteronemic, 
920
t
, 921
t
, 
f
, 941. 
See also
 Renal tubular acidosis
lactic, 919, 1255
t
, 
1260–1261
. 
See also
 
metabolic, 917, 917
t
, 
918–922
. 
See also
 
in poisoning/drug overdose, 1587
renal tubular, 906
t
, 920–921, 920
t
, 921, 
922. 
See also
 Renal tubular 
acidosis
respiratory, 917, 917
t
, 
924
. 
See also
 
in respiratory failure, 329, 924
Index
NOTE: Page numbers in 
boldface
 type indicate a major discussion. A 
t
 following a page number indicates tabular material, 
 
and 
f
 following a page number indicates a figure. Drugs are listed under their generic names.
CMDT2019_Index_p1743-1884.indd   1743
23/07/18   6:42 PM

INDEX1744
 
CMDT 2019
in burn injury, 1572
in pancreatitis, 744, 745
smoke inhalation and, 316
Acute respiratory failure, 
329–331
, 329
t
. 
See also
 Acute respiratory 
distress syndrome; 
Acute retinal necrosis, 1377
Acute tubular necrosis, 926, 930
t
, 
932–934
rhabdomyolysis and, 866, 933
Acyclovir, 1379
t
for herpes simplex infections, 127, 181
t
, 
185, 238, 623, 837, 1298–1299, 
1346
t
, 1352, 1378, 1379
t
, 1380
for herpes zoster/ VZV infection, 129, 
186, 997, 1346
t
, 1353, 1379
t
, 
1384
nephrotoxicity of, 932
during pregnancy, 835, 837
Adalimumab, 665, 669–670, 673, 852. 
 
See also
 Anti-TNF agents
Adamantanes (amantadine and 
rimantadine), 1423, 1426
ADAMTS-13 (von Willebrand factor 
cleaving protease), 561, 561
t
Addiction (drug). 
See
 Drug addiction; 
Substance use disorders
Addison disease (primary adrenal 
insufficiency), 
1180–1184
. 
 
See also
 Adrenal insufficiency
acute adrenal crisis and, 1124, 1180, 
1181, 1183
congenital, 1181
drug-induced, 1181
hyperkalemia and, 907, 1180, 1182
hyponatremia and, 900, 1182
perioperative corticosteroid replacement 
and, 53
shock and, 505
t
, 509
Adductor canal, femoral artery disease 
and, 484–485
Adefovir, 702
Adenoma sebaceum, 1023
Adenomas. 
See
 
specific type or structure 
affected
Adenomatous polyposis coli gene. 
See
 
APC
 
gene
Adenomatous polyps, 678, 
678–679
colorectal cancer and, 678, 1649, 1653
familial, 
680
. 
See also
 Familial 
adenomatous polyposis
nonfamilial, 
678–679
screening tests for, 678–679, 679, 1653
Adenomyomatosis, biliary tract/
gallbladder, 733
t
, 734
Adenomyosis, uterine, 780
Adenopathy. 
See
 Lymphadenopathy
Adenosine, 393, 395
t
, 399
Adenosine deaminase, in tuberculosis, 
289, 323, 614, 716
Adenosine deaminase 2 mutation, 870
Adenosine triphosphatase, copper-
transporting 
(ATP7B)
 
mutation, 725, 726
Adenosylcobalamin, 517. 
See also
 
Vitamin B
12
Adenovirus infections, 
1428–1429
conjunctivitis/keratoconjunctivitis, 176, 
1429
diarrhea/gastroenteritis, 599
t
, 1429
Adherence/nonadherence, 1–2. 
See also
 
without ST-segment elevation 
(NSTEMI), 
378–383
, 380
f
, 
382
t
. 
See also
 
Non–ST-segment elevation 
syndromes
ST-segment elevation (STEMI), 27–29, 
28
t
, 29, 365, 378, 379, 382
t
, 
383–393
, 385
t
. 
See also
 
Acute fatty liver of pregnancy, 699, 712, 
838
Acute flaccid paralysis (AFP), 1397
coxsackievirus infection and, 1434
enterovirus 71 causing, 1435
in West Nile infection, 1401
Acute idiopathic polyneuropathy. 
See
 
Acute intermittent porphyria, 1049, 
 
1681–1682
, 1682
t
Acute interstitial pneumonia (AIP), 302
t
Acute kidney injury (acute renal failure), 
926, 
929–936
, 930
t
. 
See also
 
acute tubular necrosis causing, 926, 
930
t
, 
932–934
cardiorenal syndrome and, 
936
celecoxib causing, 85, 843
cirrhosis and (hepatorenal syndrome), 
616, 718
glomerulonephritis causing, 930
t
, 
 
935–936
GLP-1 receptor agonist use and, 1235
interstitial nephritis causing, 930
t
, 
 
934–935
intrinsic, 930
t
, 931, 934–935
pancreatitis and, 742
in plasma cell myeloma, 546, 547, 548, 
964
postoperative, 54, 54
t
postrenal, 930
t
, 931
prerenal, 930–931, 930
t
in tumor lysis syndrome, 1673
Acute leukemia, 
538–540
, 1612
t
Acute liver failure, 
699–701
. 
See also
 Liver 
(hepatic) failure
Acute lung injury
ARDS as, 
331–333
, 331
t
transfusion-related, 554
Acute lymphoblastic/lymphocytic 
leukemia (ALL), 538, 539, 
540, 1612
t
Acute motor axonal neuropathy (AMAN), 
1051
Acute motor and sensory axonal 
neuropathy (AMSAN), 1051
Acute mountain sickness (AMS), 1577
Acute myeloid leukemia (AML), 538, 539, 
540, 1612
t
Acute-on-chronic liver failure, 699
Acute pain, 82, 
82–83
. 
See also
 Pain; Pain 
Acute paralytic (adynamic) ileus, 
650–651
Acute-phase response, 1173
Acute promyelocytic leukemia (APL), 538
Acute radiation syndrome (radiation 
sickness), 1575
Acute renal failure. 
See
 Acute kidney 
injury

650–651
See
injury
Acute respiratory distress syndrome 
(ARDS), 
331–333
, 331
t
. 
 
See also
 Respiratory failure
acute gastric aspiration and, 317
Acidosis (
Cont
.):
rewarming, 1567
uremic, 918, 919–920
Acids, corrosive, 205, 1584, 
 
1589–1590
Aciduria, paradoxic, 923
 infections, 1318
t
Acitretin, 116, 209
t
Acne/acne vulgaris, 
134–136
, 134
f
antibiotics for, 106
t
, 135
inversa (hidradenitis suppurativa), 
 
162
rosacea and, 134, 136
steroid, 134
testosterone replacement therapy and, 
1203
Acoustic neuroma/neurinoma (vestibular 
schwannoma/eighth nerve 
tumors), 
224
, 1018
t
Acoustic trauma. 
See
 Noise trauma
Acquired immunodeficiency syndrome 
(AIDS). 
See
 HIV infection/
AIDS
Acral erythema, chemotherapy-induced, 
1679
Acral-lentiginous melanoma, 112
Acrocyanosis, 858
Acrodermatitis chronicum atrophicans, 
1507, 1508
t
Acromegaly, 
1126–1128
hirsutism/virilization and, 1206
hyperprolactinemia and, 1128, 1129
Acropachy, thyroid, 1142, 1148
ACTH. 
See
 Adrenocorticotropic hormone
Actinic dermatitis, 163, 164
Actinic (ultraviolet) keratitis, 
205
Actinic keratoses, 
125
, 152
Actinic prurigo, 163
Actinobacillus/Aggregatibacter 
actinomycetemcomitans
. 
 
See
 HACEK organisms
/
 
(actinomycosis), 1319
t
, 
 
1486
Actinomycetoma, 
1560
Activated charcoal, 1584–1585, 1585, 
 
1586
Activated protein C. 
See
 Protein C
Activities of daily living (ADLs)–
instrumental activities of daily 
living (IADLs), assessment of, 
55–56
Acupuncture, for migraine prophylaxis, 
991–992, 992
t
Acute adrenal crisis, 1124, 1180, 1181, 
1183
Acute angle-closure glaucoma/crisis. 
See
 
Glaucoma
Acute arterial limb occlusion, 
487–488
Acute cardiogenic liver injury, 728
Acute chest syndrome, 522
Acute colonic pseudo-obstruction 
 
(Ogilvie syndrome), 
651–652
Acute confusional state. 
See
 Delirium
Acute coronary syndromes, 365, 378. 
 
See also
 Myocardial infarction; 
syndromes
chest pain/discomfort in, 27–29, 28
t
risk assessment/management and, 
27–29, 382, 382
t
perioperative, 47–48, 48
f
CMDT2019_Index_p1743-1884.indd   1744

INDEX1745
 
CMDT 2019
colorectal cancer risk and, 1649
dementia and, 
57–60
, 1032, 1032
t
. 
 
See also
 Dementia
entropion/ectropion and, 175
glycemic targets and, 1245
t
hearing loss/presbyacusis and, 
70
, 218
perioperative neurologic assessment/
management and, 52
perioperative pulmonary assessment/
management and, 50
sleep affected by, 1101
testosterone levels and
in men, 1201
in women, 1215
vision impairment/presbyopia and, 
69–70
weight loss and, 37, 
67
Age-related hypogonadism, 1200, 1201
Age-related macular degeneration/
maculopathy, 
193–194
Agglutinins
cold, 
525–526
febrile, 1295
. 
See
Aggregatibacter aphrophilus
. 
See
 HACEK 
organisms
Aggression, 
1103–1105
. 
See also
 Violence
Aging. 
See
 Age/aging
Agitation, 59, 
73–74
, 1035. 
See also
 
Delirium
Agnosia
in dementia, 57
tumors causing, 1016
Agoraphobia, 1066, 1068
Agranulocytosis. 
See also
 Neutropenia
clozapine causing, 1027, 1084
mirtazapine causing, 1093
thiourea therapy causing, 1144
Agrin antibodies, 1058
Aid in dying (physician-assisted death), 
78–79, 78
t
AIDS. 
See
 HIV infection/AIDS
asthma and, 253
COPD and, 268, 270
Air travel
barotrauma and, 214
lower extremity edema/venous 
thromboembolism and, 33, 
34, 1579
medical safety/patient selection and, 
1578–1579
during pregnancy, 815
AIRE
 gene, 1220
Airway disorders, 
252–268
. 
See also
 
dyspnea and, 23–24, 24
t
by food/“café coronary, ” 
317
foreign body causing, 248–249
of lower airways, 252–253
occupational disorders and, 
319–320
during sleep (sleep apnea), 241, 242, 
327, 
328–329
, 1103
tracheostomy/cricothyrotomy for, 
 
248
of upper airways, 252
respiratory failure caused by, 329
t
stridor and, 243
thermal injury/smoke inhalation and, 
316, 1571
Adrenal nodules, incidentally discovered, 
1189, 1190, 
1194–1195
Adrenal tumors
amenorrhea caused by, 1209
cancer, 1184, 1186–1187, 1615
t
cortical
ACTH-secreting, 1184
aldosterone-secreting, 454, 1188, 
1189
cortisol-secreting, 1184
hirsutism/virilization caused by, 1206, 
1207
medullary. 
See
 Pheochromocytoma
in MEN, 1197
t
, 1198
Adrenal vein sampling, in aldosteronism, 
1189
Adrenocortical carcinoma, 1184, 
 
1186–1187, 1187
Adrenocortical deficiency/insufficiency. 
See
Adrenocorticosteroids. 
See
 Corticosteroids
Adrenocorticotropic hormone (ACTH), 
1119
adrenal tumor secreting, 1184, 1187
deficiency/suppression of, 1120, 1121, 
1122, 1180, 1181, 1182. 
See 
also
ectopic/hypersecretion of, 1184, 1185, 
1186, 1187
gastroenteropancreatic NETs secreting, 
1196
in hypercortisolism/Cushing syndrome, 
1184, 1185
pituitary adenoma secreting, 1184, 1186, 
1187
Adrenocorticotropic hormone (ACTH)-
independent/dependent 
Cushing syndrome, 1185
Adrenoleukodystrophy, 1180
Aducanumab, 1034
Adult Still disease, 
852–853
Adult T-cell deficiencies, 895
t
Adult T cell lymphoma/leukemia (ATL), 
1408, 1409
Adulthood ductopenia, idiopathic, 740
Advance care planning/advance directives, 
76
Adynamic bone disease, 940
Adynamic (paralytic) ileus, 
650–651
Aerobic training. 
See
 Exercise/activity
Aerodigestive tract. 
See also
 
specific 
structure
foreign bodies in, 
248–249
Aeromonas,
 diarrhea and, 599
t
, 603
Aerophagia, 598
Aerophobia, 1399
Aerosols, sniffing, 1114
Afatinib, 1620
t
, 1627
Affect, in schizophrenia/psychotic 
disorders, 1079
Aflatoxin exposure, hepatocellular 
carcinoma and, 1631
Aflibercept, 193, 194, 197, 1652
African American patients. 
See
 Black 
patients
African tick bite fever, 1437
t
, 1442
African trypanosomiasis, 
1510–1511
, 
1511
t
Age/aging. 
See also
 Older adults
anemia associated with, 513
breast cancer risk/prognosis and, 754, 
754
t
, 772
Adhesive capsulitis (frozen shoulder), 
1252, 
1696–1697
Adipose tissue. 
See
 Body fat
Adjustment disorders, 
1063–1064
with depressed mood, 1087
illness/hospitalization and, 1116, 1117, 
1118
suicide risk and, 1089
Adjuvant chemotherapy. 
See also

See
 Body fat
1063–1064
1118
See also
 
for bladder cancer, 1665
for breast cancer, 763, 765–766
in older women, 767
for colorectal cancer, 1651, 1652
for gastric adenocarcinoma, 1643
for lung cancer/mesothelioma, 1627, 
1631
Ado-trastuzumab emtansine, 770, 1619
t
. 
See also
 Trastuzumab
Adolescents
antidepressant use/suicide risk and, 
1090
glycemic targets in, 1245
t
immunization recommendations for, 
1325, 1470
Adoption, for lesbian and bisexual women, 
1731
ADPKD1
/
ADPKD2
 genes, 962
Adrenal adenoma, 1184, 1186, 1187
hyperaldosteronism caused by, 454, 
1188, 1189
t
, 1198
Adrenal carcinoma, 1184, 1186–1187, 
1187
Adrenal cortex
diseases of, 
1180–1189
. 
See also
 
specific 
disorder
in hypopituitarism, 1120
in HIV infection/AIDS, 1180, 1352
hyperplasia of, 1181, 1182, 1208
aldosteronism caused by, 454, 1188, 
1189
congenital, 1181, 1182
Cushing syndrome caused by, 1184
hirsutism/virilization and, 1181, 
1206, 1207
in MEN, 1198
hypoplasia of, congenital, 1120
tumors of. 
See
 Adrenal tumors
Adrenal crisis, 1124, 1180, 1181, 1183
Adrenal hemorrhage, 1180
Adrenal incidentalomas, 1189, 1190, 
1194–1195
Adrenal insufficiency, 1120, 1121, 1122, 
1180–1184
. 
See also
 Addison 
disease
1181, 1183
amenorrhea and, 1209
central, 1121
hypopituitarism/pituitary surgery and, 
1120, 1187
meningococcemia and (Waterhouse-
Friderichsen syndrome), 1180
and, 53
t
, 509
CMDT2019_Index_p1743-1884.indd   1745

INDEX1746
 
CMDT 2019
adrenal adenoma/hyperplasia secreting, 
454, 1188, 1189
drugs blocking receptors for. 
See also
 
in cardiomyopathy, 429
for heart failure, 388, 417
f
, 418–419, 
418
t
, 419
for hypertension, 461–462
t
, 471, 479
in hypertension, 454, 456, 471, 479
potassium balance and, 905, 1188
in primary aldosteronism, 454, 1188, 
1189
Aldosterone:plasma renin activity ratio, 
1188
Aldosteronism (hyperaldosteronism), 
1188–1189
glucocorticoid-remediable, 454, 906
t
hypertension and, 454, 456, 471, 479
saline-unresponsive metabolic alkalosis 
and, 923
Alectinib, 1620
t
, 1628
Alemtuzumab, 1038
t
, 1619
t
Alendronate, 1168, 1173, 1219. 
See also
 
Alfieri procedure, 352, 432
Alfuzosin, 207
t
, 986, 986
t
Alimentary hypoglycemia, functional, 
1265
Alimentary tract cancers, 
1638–1657
. 
 
See also
 
specific type or 
structure affected
Alirocumab, 10, 368, 1273
t
, 1274
Aliskiren/aliskiren-combinations, 465, 
466
t
ALK1
 gene, 1627, 1628, 1688
ALK
-rearranged lung cancer, 1628
Alkali administration. 
See
 Bicarbonate
Alkalies, caustic/corrosive, 205, 1584, 
1590
Alkaline phosphatase, 690, 690–691, 690
t
, 
1176, 1177, 1178
Alkalosis, 917, 917
t
contraction, 923
metabolic. 
See
 Metabolic alkalosis
posthypercapnia, 923, 924
respiratory. 
See
 Respiratory alkalosis
salicylate overdose/toxicity causing, 
1606
saline-responsive, 922–923, 922
t
, 923
saline-unresponsive, 922
t
, 923
Alkylating agents, 816
t
, 1616–1617
t
All-trans-retinoic acid, 538, 1622
t
. 
See also
 
Tretinoin
Allergens. 
See also
 Allergies/allergic 
disorders/reactions
asthma caused by. 
See
 Asthma, allergic
avoidance of. 
See
 Avoidance therapy
Allergic alveolitis, extrinsic 
(hypersensitivity 
pneumonitis), 
318–319
, 319
t
Allergic bronchopulmonary mycosis/
aspergillosis, 
275
, 893
t
, 1557, 
1558
Allergic conjunctivitis, 178
Allergic eye disease, 
178
Allergic rhinitis (hay fever), 
229–230
nasal polyps and, 229, 232
Allergic vasculitis, 171
t
Allergies/allergic disorders/reactions, 
 
890–897
, 893
t
anaphylactic, 
890–891
asthma and, 253, 255, 257, 264
to drugs. 
See
 Drug allergy
cirrhosis and, 708, 709, 710, 715, 716
hepatocellular carcinoma and, 710, 
1631
coma and, 1255
t
, 1581
complications associated with, 1107, 
1115
t
Cushing syndrome/hypercortisolism 
and, 1185
delirium caused by, 1106, 1110, 1115
t
depression and, 1088
differential diagnosis of, 1107
fatty liver and, 708, 709
folic acid deficiency and, 519
gastritis/dyspepsia and, 590, 591, 633
hepatitis and, 51, 708, 710
hyperosmolality caused by, 904, 905
hypertension and, 10, 453, 457
t
, 458
hyperuricemia/gout and, 844, 846
hypoglycemia and, 1111, 1246, 1261, 
1261
t
, 1266
hypophosphatemia and, 913
immunization recommendations in, 
1328
t
, 1331
t
ketoacidosis and, 919
in lesbian and bisexual women, 1728
lipid abnormalities and, 1269
liver disease and, 
708–710
Mallory-Weiss syndrome/tears and, 606, 
608, 624
management of, 19, 1107–1111, 
 
1109–1110
f
metabolic acidosis/osmolar gap and, 
905, 1107, 1586
methotrexate use and, 851
neuropathy and, 1049
pancreatitis and, 741, 742, 746, 747, 748
in panic disorder, 1066
platelet function affected by, 568
t
pregnancy and, 812–813, 1107
preventable disease/deaths and, 3
t
prevention of/screening tests for, 
18–19
, 
18
t
psychiatric/psychotic disorders and, 
1106–1107, 1107, 1108, 1110, 
1116
in PTSD, 1066
rhabdomyolysis and, 866
sleep-wake disorders and, 1102
suicide and, 1089, 1106
thiamine deficiency/supplement and, 
919, 1108, 1282–1283, 1581
Wernicke encephalopathy/Wernicke-
Korsakoff syndrome and, 709, 
1039, 1040, 1107, 1108
withdrawal and, 1106, 1108–1111, 
1109–1110
f
t
seizures caused by, 1002, 1106
Alcohol Use Disorder Identification Test 
(AUDIT), 18, 18
t
, 1106
Alcohol withdrawal syndrome, 1106
Alcoholic brain syndromes, chronic, 1107
Alcoholic (organic) hallucinosis, 
 
1106–1107, 1107, 1108, 1116
Alcoholic hepatitis.

t
, 1106
 
Alcoholic hepatitis. 
See
 Hepatitis
Alcoholic ketoacidosis, 919
Alcoholics Anonymous, 1107
Aldesleukin, 1623
t
. 
See also
 Interleukin-2
Aldicarb poisoning, 1605
Aldosterone. 
See also
 Aldosteronism; 
Airway management. 
See also
 Intubation
burn injury/smoke inhalation and, 316, 
1571
for coma, 1580
tracheostomy and cricothyrotomy in, 
248
Akathisia, 1030, 1085
Akinetic mutism (persistent vegetative 
state), 
1042
AL (primary) amyloidosis, 434, 435. 
 
See also
Al-Anon, 1107
Alanine aminotransferase (ALT), 690, 
690
t
. 
See also
 
specific disorder 
affecting
Albendazole
for ascariasis, 1541
for clonorchiasis/opisthorchiasis, 1537
for cutaneous larva migrans, 1546
for cysticercosis, 1539
for enterobiasis/pinworms, 1544
for filariasis, 1547
for giardiasis, 1534
for hookworm disease, 1542
for hydatid disease, 1540
for microsporidiosis, 1532
for strongyloidiasis, 1543
for toxocariasis, 1545
for trichinosis, 1545
for trichuriasis/whipworm, 1541
Albiglutide, 1230
t
, 1235. 
See also
 
Glucagon-like peptide 1 
(GLP-1) receptor agonists
Albinism, 166
Albinism-associated storage pool disease, 
567
Albumin, 690
t
. 
See also
 Hypoalbuminemia
ascitic fluid, 614. 
See also
 Serum-ascites 
albumin gradient
calcium levels and, 910, 911
in liver disease/jaundice, 690
t
, 715, 716, 
720, 720
t
in feminizing hormone therapy, 1740
t
in masculinizing hormone therapy, 
1741
t
in protein-losing enteropathy, 655
urinalysis measuring, 927, 954
Albuminuria, 927. 
See also
 
specific cause 
and
 Proteinuria
Albuterol
for asthma, 259, 262
t
, 263
t
for COPD, 271, 273
for cystic fibrosis, 276
for hyperkalemia, 909
t
Alcaftadine, 181
t
Alclometasone, 104
t
Alcohol-based antiseptics/hand sanitizers, 
1302, 1425
Alcohol use disorder (alcohol misuse/
alcoholism), 
18–19
, 
 
1105–1111
acute intoxication/poisoning, 905, 1106, 
1107, 1586, 1587
t
, 
1598–1599
aggressive/violent behavior and, 1104
amnestic syndrome and, 1116
anxiety self-treatment and, 1068
at-risk/risky drinking and, 18, 
 
1105–1106, 1107, 1107–1108
atrial fibrillation and, 402
breast cancer risk and, 754
cardiomyopathy and, 429
CMDT2019_Index_p1743-1884.indd   1746

INDEX1747
 
CMDT 2019
Amenorrhea, 
1208–1216
in anorexia nervosa, 1281
in hyperprolactinemia, 1128, 1209, 1210
hypothalamic, 1120, 1209, 1210
in polycystic ovary syndrome, 795, 
1206, 1209, 1210
premature, 1211
primary, 
1208–1210
secondary, 
1210–1216
. 
See also
 
Menopause; Pregnancy
in Turner syndrome, 1216, 1217
American trypanosomiasis (Chagas 
disease), 629, 
1512–1513
screening blood for, 553–554, 1513
American Urological Association (AUA) 
symptom index, 983, 984
t
Amifostine, 1680
Amikacin, 179
t
, 282, 285
t
, 1488
Amiloride/amiloride-HCTZ, 418, 461
t
, 
462
t
, 908, 1099, 1099
t
Aminocaproic acid, 569
t
, 571
Aminoglutethimide, 1662
t
myasthenia gravis and, 1058, 1060
nephrotoxicity/acute kidney injury and, 
932
neuromuscular transmission affected by, 
1060
ototoxicity of, 219
for pneumonia, 282
Aminophylline, lithium interactions and, 
1099
t
5-Aminosalicylic acid, 662, 668, 672, 675
Aminotransferase levels, 690, 690
t
, 728. 
See also
 
affecting
for arrhythmias, 393, 394
t
atrial fibrillation, 394
t
, 403, 406
supraventricular tachycardia, 389, 
392, 394
t
, 400
ventricular tachycardia/fibrillation, 
389, 394
t
, 410, 411
epididymitis and, 973
hyperthyroidism/Graves disease caused 
by, 1134, 1140, 1143, 1147
hyponatremia caused by, 900
hypothyroidism caused by, 1134
levothyroxine therapy and, 1138
ophthalmic effects of, 207
t
pregnancy and, 446
Amitriptyline, 1091
t
, 1094, 1610. 
See also
 
for dyspepsia, 591
for interstitial cystitis, 974
for migraine prophylaxis, 992
t
for neuropathic pain/diabetic 
neuropathy, 1048, 1249
Amlodipine/amlodipine combinations. 
 
See also
 Calcium channel 
blocking drugs
for angina, 374
for hypertension, 466
t
, 467
t
, 469
t
, 470
t
, 
471, 473
t
overdose/toxicity of, 207
t
, 466
t
, 471, 
473
t
, 1594
Ammonia, in liver failure/hepatic 
encephalopathy, 699, 700, 718
Amnestic syndrome, 1116. 
See also
 
Memory impairment
Amniocentesis, 813
Alteplase (tissue plasminogen activator/
tPA), 385
t
, 386. 
See also
 
Fibrinolytic therapy; 
Thrombolytic therapy
for acute arterial occlusion of limb, 488
for myocardial infarction, 385
t
, 386
for pulmonary embolism, 311–312, 585, 
587
t
for stroke, 1009
Altered mental status. 
See also
 Cognitive 
disorders
in HIV infection/AIDS, 1348
Alternaria,
 1561
Altitude-related illness, 
1575–1579
Aluminum preparations
for hyperphosphatemia, 914
osteomalacia caused by, 940, 1176
Alveolar hemorrhage syndromes, 
315–316
Alveolar hydatid disease, 1540
Alveolar hyperventilation, 
327
Alveolar hypoventilation, obesity and 
(Pickwickian syndrome), 
327
Alveolar proteinosis, 
304–305
Alveolitis, 300
extrinsic allergic (hypersensitivity 
318–319
, 319
t
Alvimopan, 651
Alzheimer disease, 57–60, 1032
t
. 
See also
 
Dementia
deaths attributable to, 2
t
neuroimaging in, 58, 1033
screening for, 58
seizures in, 999
treatment of, 59–60, 1034–1035
Alzheimer’s Association/Alzheimer’s 
Disease and Related Disorders 
Association, 59
Amanita
 mushroom poisoning, 699, 
 
1603–1604
Amantadine
for Huntington disease, 1028
influenza/influenza resistance and, 
1423, 1426
for neuroleptic malignant syndrome, 
1085
for Parkinson disease/parkinsonism, 
1025, 1085
Amatoxin mushroom poisoning, 699, 
1603–1604
Amaurosis fugax (“fleeting blindness”), 
196, 488, 1008, 1016
Ambiguous genitalia, 1182
Ambulatory blood pressure monitoring, 
451–453, 452
f
, 452
t
Ambulatory electrocardiographic 
monitoring, 32, 371, 413
Ambulatory esophageal pH monitoring. 
See
 Esophageal pH 
Amebiasis (entamoeba infection), 
 
1528–1530
, 1529
f
, 1530
t
extraintestinal/hepatic, 1528, 1529, 
1529–1530, 1530
t
in gay and bisexual men/MSM, 1734
intestinal, 599
t
, 600, 603, 1322
t
, 1528, 
1529, 1529
f
, 1530
t
ophthalmic effects of drugs used for, 
209
t
Amebic keratitis, 
186
Amebicides, 209
t
, 1529–1530, 1530
t
Ameboma, 1528, 1530
t
Amenavir, 1378
eosinophilic esophagitis and, 624–625

f
, 1530
t
209
t
186
t
t
t
in HIV infection/AIDS, 1341
household molds and, 1561
to insulin, 1247
testing for, 
892–894
in topical dermatologic therapy, 109
in topical ophthalmic therapy, 177, 
206
, 
206
f
Allergy testing, 
892–894
Allgrove (triple A) syndrome, 1181, 1182
Allodynia, 97
Alloimmunization
platelet transfusion and, 554
Rhesus, 552, 813, 814, 
815
transfusion graft-versus-host disease 
and, 554
hypersensitivity reaction to, 847, 894
for hyperuricemia/gout, 847
in cancer patients, 1674, 1675
t
in polycythemia, 531
in transplant patients, 847
urinary stones and, 976
ophthalmic effects of, 209
t
for tumor lysis syndrome, 1674, 1675
t
Almotriptan, 991
Alogliptin, 1231
t
, 1236, 1237
Alopecia, 
168–169
chemotherapy causing, 1679
Alosetron, 659
Alpha-adrenergic agonists
for retrograde ejaculation, 982
for Tourette syndrome, 1031
Alpha-adrenergic blocking drugs
for benign prostatic hyperplasia, 986, 
986
t
cataract surgery and, 191, 207
t
, 986
for hypertension, 471–475, 474
t
, 476
f
, 
481
t
, 482
pheochromocytoma/
pheochromocytoma surgery 
and, 1193
phosphodiesterase inhibitor interaction 
and, 980
ureteral stone expulsion and, 977
Alpha-1-antiprotease/antitrypsin
in COPD/emphysema, 268, 270, 272
in hepatocellular carcinoma, 1631
Alpha-delta storage pool disease, 566
Alpha-fetoprotein
in Down syndrome, 1682, 1683
in hepatocellular carcinoma, 1632, 1633
testicular tumors producing, 1669
Alpha-gal (galactose-alpha-1,3-galactose) 
hypersensitivity, 891
Alpha-globin gene/chain, 514, 514–515, 
514
t
, 515, 516
Alpha-glucosidase inhibitors, 1230
t
, 1234, 
1599
Alpha interferon. 
See
 Interferon-alpha
Alpha-melanocyte-stimulating hormone 
(alpha-MSH), 1180, 1181
5-Alpha-reductase inhibitors. 
See
 
Alpha-thalassemia syndromes, 514–515, 
514
t
, 515, 516
sickle cell disease and, 523
t
, 524
ALPL
 gene, 1177
Alprazolam, 1024, 1067
t
, 1068, 1598
Alprenolol, overdose/toxicity of, 1594
Alprostadil, 980, 1250
CMDT2019_Index_p1743-1884.indd   1747

INDEX1748
 
CMDT 2019
Andes virus, 1415
Andexanet, 1591
Androgen blockade/deprivation. 
See also
 
in cancer chemotherapy, 1623
t
complete, 1663
in feminizing hormone therapy, 1738, 
1738
t
for prostate cancer, 1662–1663, 1662
t
Androgen insensitivity/resistance, 1200, 
1209
Androgenetic (male pattern) alopecia, 
 
168
Androgenic steroids. 
See
 Anabolic steroids
Androgens. 
See also
 Antiandrogens; 
acne and, 134, 1206
for aplastic anemia, 527
deficiency of. 
See also
 Hypogonadism
pseudohermaphroditism/amenorrhea 
and, 1209
in women, 1123
excess of. 
See
 Hyperandrogenism
in male breast cancer, 775
replacement therapy with. 
See
 
Testosterone replacement 
therapy
Anejaculation, 979, 982–983, 1075. 
 
See also
 Erectile dysfunction/
impotence
Anemias, 
510–528
, 511
t
. 
See also
 
specific 
cause or type
in cancer chemotherapy, 1676
t
, 1677
of chronic disease, 512, 
513–514
classification of, 510, 511
t
in elderly, 513
in erythrovirus (parvovirus) infection, 
1430
in fish tapeworm infection, 517, 1538
in folic acid deficiency, 519
in kidney disease, 513, 926, 930, 939
f
, 
940–941
in malabsorption, 644
t
in myelodysplastic syndromes, 536
in myelofibrosis, 533
in myeloma, 547
of organ failure, 513
in paroxysmal nocturnal 
hemoglobinuria, 520
perioperative evaluation/management 
and, 51
during pregnancy, 510, 814, 
829
retinal/choroidal disease and, 198
sickle cell. 
See
 Sickle cell anemia/
syndromes
thiazolidinediones causing, 1234
in vitamin B
12
 deficiency, 517, 518
in Waldenström macroglobulinemia, 
549–550
Anergy testing. 
See
 Skin test anergy
Anesthesia/anesthetics
liver function and, 50–51
local, ophthalmic, precautions for use 
of, 
206
malignant hyperthermia caused by, 
1301–1302
Aneuploidy screening, 813
Aneurysms, 
492–497
. 
See also
 
specific type 
and artery involved and
 Aortic 
aneurysms; Intracranial 
aneurysm
inflammatory, 493
Amyloidosis, 
550–552
cardiac/cardiomyopathy and, 434, 435, 
551
dialysis-related (beta-2-microglobulin), 
550
hereditary (transthyretin/TTR), 434, 
435, 550
LECT2, 550
localized, 550
myeloma and, 547, 551, 964
nephrotic spectrum disorders and, 
 
551
neuropathy and, 551, 1050
primary (AL), 434, 435, 550
renal, 947
t
secondary (AA), 434, 550
senile, 550
systemic, 550, 551
Amyotrophic lateral sclerosis, 1046, 
 
1046–1047
Amyotrophy
diabetic, 1049, 1249
neuralgic, 1056
Anabolic steroids
abuse of, 1114, 1203
aggression/violence and, 1104, 1114
gynecomastia and, 1204
for HIV wasting, 1343
Anaerobic infections, 
286–287
, 1321
t
, 
1322
t
, 
1483–1485
, 1484
t
, 
1485
f
. 
See also
 
specific organ 
or structure involved
Anagrelide, 532
Anakinra, 846, 853
Anal dysplasia/cancer, 1354–1355, 1615
t
, 
1656–1657
in gay and bisexual men/MSM, 
 
1734–1735, 1735
t
, 1736
Anal fissures, 665, 666, 667, 686
Anal fistulas, 665, 666, 667, 686
Anal sphincter, fecal incontinence and, 
685
Anal syphilis, 684, 1494, 1498
f
Anal warts. 
See
 Venereal (genital) warts
Analgesia/analgesics. 
See
 
disorder and
 Pain 
Analgesic nephropathy, 960, 961
ureteral/renal pelvis cancer and, 1666
Analgesic rebound headache, 
993
Anaphylactoid reactions, 890
to radiocontrast media, 892
“red man syndrome” as, 892
Anaphylaxis/anaphylactic shock, 505
t
, 508, 
890–891
. 
See also
 
Anaphylactoid reactions
food causing, 891
insulin allergy causing, 1247
penicillin allergy causing, 1324
transfusion causing, 553
venom allergy causing, 892
Anaplasma capra/equi/phagocytophilum
 
(anaplasmosis), 1437
t
, 
 
1443–1444
coinfections and, 1443, 1508
Anasarca, 613
Anastrozole, 208
t
, 755, 766–767, 769, 769
t
, 
1623
t
. 
See also
 
for endometriosis, 791
for gynecomastia, 1205
Ancylostoma braziliense/caninum/
duodenale,
 1542, 1545
Amodiaquine, 1518
t
, 1519
with artesunate (ASAQ), 1518
t
, 1519, 
1519
t
, 1520
t
, 1522
with sulfadoxine-pyrimethamine 
(Fansidar), 1522, 1524
Amoxapine, 1091
t
Amoxicillin/amoxicillin-clavulanate, 1322
t

t
, 1519
t
, 1519, 
1519
t
, 1520
t
, 1522
t
t
for anaerobic infections, 286, 1483, 1484
for bacterial rhinosinusitis, 227, 1322
t
, 
1347
in 
H pylori
 eradication, 638, 638
t
, 639
for Lyme disease, 1508
t
, 1509
for peritonsillar abscess, 240
for pharyngitis, 1449
pneumococcal resistance and, 1453
for pneumonia, 279
t
, 281, 286, 1322
t
, 
1453
rash caused by, 1387
for rosacea, 137
for skin and soft tissue infections, 1450
abuse/overdose/toxicity of, 207
t
, 
1113
, 
1590–1591
during pregnancy, 813
for attention-deficit/hyperactivity 
disorder, 1100
Amphotericin B, 1561, 1561
t
. 
See also
 
for aspergillosis, 228–229, 1299, 1558
for blastomycosis, 1559
for candidiasis, 1551
for coccidioidomycosis, 1554
for cryptococcal meningitis, 1345
t
, 1557
for histoplasmosis, 1552
for leishmaniasis, 1514, 1515
for mucormycosis, 228–229, 1559
932, 1561
for ophthalmic disorders, 181
t
for paracoccidioidomycosis, 1560
for sporotrichosis, 1560
Ampicillin/ampicillin-sulbactam, 1321
t
allopurinol interactions and, 847
for anaerobic infections, 1483
for endocarditis/endocarditis 
prophylaxis, 1467
t
, 1468
for listeriosis, 1464
for meningitis, 1305
t
, 1321
t
t
, 281, 282, 1321
t
rash caused by, 239, 1324, 1387
for spontaneous bacterial peritonitis, 
615
for urinary tract infection, 834, 968
t
Amprenavir, 1369. 
See also
 Antiretroviral 
therapy
Ampulla of Vater, carcinoma of 
(ampullary/periampullary 
carcinoma), 
1636–1638
, 1647
Amputation
in acute arterial limb occlusion, 488
in peripheral artery aneurysms, 495
in tibial/pedal occlusive disease, 486
Amrinone, 509
Amyl nitrite, abuse of, 1114
Amylase
ascitic fluid, 614
in pancreatic enzyme supplements, 748
t
in pancreatitis, 742
pleural fluid, 323
Amyloid angiopathy, cerebral, 1010
Amyloid protein, 551, 1033, 1034. 
See also
 
CMDT2019_Index_p1743-1884.indd   1748

INDEX1749
 
CMDT 2019
in renal tubular acidosis, 906
t
, 920–921, 
920
t
, 921, 922
toxins causing, 919
Anisakiasis 
(Anisakis marina),
 589, 635
Ankle-brachial index (ABI/ABPI)
in aortoiliac occlusive disease, 483
in femoral/popliteal occlusive disease, 
485
in venous insufficiency/leg ulcers, 34, 
165, 166
Ankle injuries/sprains, 
1720–1721
, 1720
f
Ankylosing spondylitis, 
877–879
Annuloplasty, for tricuspid regurgitation, 
361
Anogenital/perianal pruritus, 
156–157
, 
156
f
, 686–687, 1543
Anogenital warts. 
See
 Venereal (genital) 
warts
Anorectal disorders, 
682–687
. 
See also
 
specific cause and
 Genital 
ulcers
anal cancer, 1354–1355, 1615
t
, 
 
1656–1657
bleeding in, 609. 
See also
 Rectal 
bleeding
in Crohn disease, 665, 666, 667
fecal incontinence and, 
685–686
fissures/abscesses/fistula, 665, 666, 667, 
686
hemorrhoids, 609, 
682–684
infections, 
684
lymphogranuloma venereum, 684, 1490
pruritus, 120, 156, 686–687
warts. 
See
Anorectal manometry, 596
Anorexia
in HIV infection/AIDS, 1343
nervosa, 
1280–1281
, 1282
Anorexia-cachexia syndrome, 77
Anorgasmia, 796, 797, 1075. 
See also
 
Orgasm, loss of
Anoscopy, 610, 685
Anosmia, 230–231, 1016, 1044. 
See also
 
Olfactory dysfunction
Anosognosia, 1016
Anovulation
abnormal uterine bleeding and, 776
infertility and, 798
in polycystic ovary syndrome, 795, 1206
Anserine (pes anserine) bursa/bursitis, 
1709
Antacids
antidepressant drug interactions and, 
1095
t
benzodiazepine interactions and, 1069
t
for GERD, 621, 631
for peptic ulcer disease, 637–638
Anterior chest wall syndrome, 372
Anterior cruciate ligament (ACL), 1709, 
1710, 
1710–1714
, 1711
t
Anterior drawer sign/test
ACL injury and, 1710–1711, 1711
t
ankle sprain and, 1720
Anterior hypopituitarism, 
1119–1123
Anterior interosseous syndrome, 
1052
Anterior ischemic optic neuropathy, 
199
, 
868
Anterior (patellofemoral) knee pain, 1709, 
1717–1718
Anterior talofibular ligament, in ankle 
sprains, 1720
for heart failure, 417
f
, 418
t
, 419, 423, 
465
infarct-related, 388, 392, 392–393
hyperkalemia caused by, 907, 908
for hypertension, 465–471, 468–470
t
, 
475, 476, 477, 478
for nephrotic syndrome/nephrotic 
spectrum disorders, 955, 957
perioperative kidney injury and, 49, 54
pregnancy and, 833
Angiotensin-converting enzyme (ACE) 
inhibitors, 465, 466–467
t
, 475
acute kidney injury/renal failure and, 
419
in black patients, 478
breastfeeding and, 816
t
for cardiomyopathy, 429, 433
f
, 434
in cardiovascular/heart disease 
prevention, 368, 475, 1251
chronic kidney disease and, 477–478, 
936, 939
diabetes/diabetic nephropathy and, 465, 
476, 477, 955, 958, 1248, 1251
f
, 418
t
, 419, 423, 
465
infarct-associated, 392, 392–393
hyperkalemia caused by, 465, 907, 908
for hypertension, 465, 466–467
t
, 475, 
476, 477–478, 478, 481
t
, 1251
hypoglycemia risk and, 1266
lithium interactions and, 1099, 1099
t
for myocardial infarction, 388, 392
pregnancy and, 445, 833
Angiotensin receptor-neprilysin inhibitor 
(ARNI), 417
f
, 418
t
, 419, 429
Angle closure, pupillary dilation and, 187, 
206
Angle-closure glaucoma. 
See
 Glaucoma
Angular cheilitis, 236, 236
f
, 1350
Anhedonia, 1087. 
See also
 Depression
Anhidrosis and asthenia (tropical), 139
Anicteric leptospirosis, 1504–1505
Anidulafungin, 1551, 1558, 1561, 1561
t
Aniline toxicity, 1603
Animal bites, 
1307–1308
. 
See also
 Insect 
bites/stings
anaerobic skin infections and, 1307, 
1485
poisonous snake, 1584
t
, 
1607–1608
rabies and, 1307, 1308, 1398, 1399, 1400
Anion gap/anion gap acidosis, 917–918, 
918, 918–922, 918
t
, 920
t
. 
See 
also
 Urinary anion gap
alcoholic ketoacidosis and, 919
decreased, 918
t
diabetic ketoacidosis and, 919, 1255, 
1257
increased, 918, 
918–920
, 918
t
, 921
lactic acidosis and, 919, 1260
normal, 918, 918
t
, 
920–921
, 920

t
1257
918–920
, 918
t
, 921
t
, 
920–921
, 920
t
, 922. 
See also
 Normal anion gap 
acidosis
with osmolar gap, 905
in poisoning/drug overdose, 919, 1587
with methanol or ethylene glycol, 
919, 1587, 1602, 1603
with salicylates, 919, 1606
in renal failure (uremic), 918, 919–920
in Kawasaki disease, 1446, 1447
mycotic, 1013
drug use and, 1311
ruptured, 492
Angiitis
with granulomatosis (Wegener 
granulomatosis). 
See
 
Granulomatosis, with 
primary, of central nervous system, 
876–877
Angina
intestinal (visceral artery insufficiency), 
490–491
Ludwig, 240, 241
pectoris, 365, 
368–377
, 373
f
, 376
t
, 377
t
. 
See also
 Coronary heart 
disease
alteration in before myocardial 
infarction, 372, 383
aortic valve disease and, 353–354
in apathetic hyperthyroidism, 1141, 
1148
chest pain/discomfort in, 27–28, 369, 
372, 383
chronic stable, 
368–377
, 373
f
, 376
t
, 
377
t
coronary vasospasm and, 368, 
 
377–378
drugs in management of, 372–375, 
373
f
with normal arteriogram, 
377–378
postinfarction, 375, 389
Prinzmetal (variant), 378
risk reduction and, 375
thiazolidinedione use and, 1233
unstable. 
See
 Acute coronary 
syndromes
Vincent (necrotizing ulcerative 
gingivitis), 
237
Angiodysplasias, 606, 609
Angioectasias, 606, 609
Angioedema, 
141–142
, 893
t
ACE inhibitors causing, 141, 142, 
 
465
hereditary, 141, 893
t
Angiofibroma, in MEN, 1197
t
Angiography/arteriography. 
See
 
specific 
type or disorder
Angiomas/angiomatosis
bacillary, 1353, 1483
in Sturge-Weber syndrome, 1023
Angiomyolipomas, of kidney, 1668
Angioplasty. 
See also
 Endovascular 
surgery/prostheses
carotid. 
See
 Carotid surgery
coronary. 
See
 Percutaneous coronary 
for renal artery stenosis/renal vascular 
hypertension, 944
Angiosarcoma, of liver, 1631
Angiotensin II receptor blocking agents, 
465–471, 468–470
t
, 475
for aortic regurgitation, 359
f
prevention, 475
chronic kidney disease and, 478, 936, 
939
476, 477, 955, 958
CMDT2019_Index_p1743-1884.indd   1749

INDEX1750
 
CMDT 2019
for ACS (NSTEMI/STEMI), 379, 380
f
, 
381, 387
for acute arterial limb occlusion, 487
1095
t
for antiphospholipid antibody 
syndrome, 830, 857
for atrial fibrillation/stroke prevention, 
402
t
, 403, 403–406, 404
t
, 405
t
in hyperthyroidism, 1148
in mitral stenosis, 347, 364
t
, 404, 405
for atrial flutter, 408
bleeding caused by, 207
t
, 310–311, 406, 
576
t
, 582, 585
t
, 
1591
bridging, 51, 363, 364
t
after cardiac valve replacement, 347, 
355, 356, 
363–365
, 364
t
classes of drugs in, 573–577, 575–576
t
for DVT/PE (venous thromboembolic 
disease), 309–311, 574, 
 
575–576
t
, 577–585, 578–579
t
, 
580
t
, 581
t
drug/patient selection and, 581–585, 
581
t
, 583
t
, 584
t
, 585
t
duration of, 309–310, 582–584, 585
t
, 
586
t
prevention and, 309, 575–576
t
, 
 
577–579, 577
t
, 578–579
t
, 579
t
treatment and, 309–311, 579–585, 
580
t
, 581
t
, 583
t
, 584
t
, 585
t
, 
586
t
in endocarditis, 364
t
, 1469
GI bleeding/peptic ulcer disease and, 
387, 640
for heart failure/cardiomyopathy, 421, 
429, 434
hematuria in patient taking, 966
heparin-induced thrombocytopenia 
and, 562–563, 563
t
for hepatic vein obstruction 
 
(Budd-Chiari syndrome), 727
for intracranial venous thrombosis, 1015
after joint replacement, 1708
in nephrotic syndrome/nephrotic 
spectrum disorders, 955
for noncirrhotic portal hypertension, 
729
overdose/toxicity/bleeding and, 207
t
, 
310–311, 406, 576
t
, 582, 585
t
, 
1591
for patent foramen ovale, 338–339
perioperative management of, 51–52, 
52
t
, 363, 364
t
, 405–406
for portal vein thrombosis, 729
in pregnancy, 363–364, 364
t
, 830
for pulmonary hypertension, 314, 444
for stroke, 1010
for superficial thrombophlebitis, 499
thrombocytopenia caused by, 562–563, 
563
t
, 565
t
for transient ischemic attacks, 1005
Anti-contactin associated protein-like 2 
antibody, 1021
Anticonvulsant therapy, 995–996
t
, 1001, 
1002
t
for glossopharyngeal neuralgia, 997
t
for myoclonus, 1030
nonadherence and, 1001, 1002
overdose/toxicity and, 995–996
t
, 
 
1591–1592
monitoring blood levels of, 1320
in neutropenic patient, 1299, 1300
for ophthalmic disorders, 179–181
t
for pelvic infection/PID, 793
perioperative, surgical site infections 
and, 
54
for pharyngitis, 239, 1322
t
, 1449
for pneumonia
anaerobic pneumonia, 286–287, 1484
community-acquired pneumonia, 
279
t
, 281–282, 1321
t
nosocomial pneumonia, 284–286, 
285
t
principles of use of, 
1317–1324
, 1318–
1320
t
, 1321
t
, 1322–1323
t
promptness of response to, 1317–1320
prophylactic. 
See
 Antimicrobial 
chemoprophylaxis
resistance to. 
See
 Drug resistance
routes of administration for, 
 
1323–1324
for septic shock, 509
susceptibility testing and, 1317
thrombocytopenia/platelet function 
and, 565
t
, 568
t
topical, 106
t
Antibodies. 
See
 Immunoglobulins
Antibody deficiency disease, 895
t
, 
 
896–897
Anti-CADM 140 antibody, 862
t
Anticardiolipin antibodies
in antiphospholipid antibody syndrome, 
830, 857
in DVT/PE (venous thromboembolic 
disease), 306
in SLE, 853
t
, 855, 855
t
Anti-Caspr2 antibody, 1021, 1022
Anti-CCP antibodies, 849, 878
Anticentromere antibody, 854
t
, 860
Anticholinergic agents. 
See also
 
specific 
disorder
for allergic disorders/rhinitis, 230
1095
t
for asthma, 260
t
, 263, 263
t
for COPD, 271
for irritable bowel syndrome, 658
for nausea and vomiting, 593
t
, 658, 1584
t
, 
1593
for Parkinson disease, 1027
Anticholinergic syndrome/effects, 1586, 
1593
antidepressants causing, 1091
t
, 1094, 
1609
antipsychotics causing, 1081, 1082
t
, 
1083
hallucinogens causing, 1601
Anticholinergic-type mushroom 
poisoning, 1593
Anticholinesterases/acetylcholinesterase 
inhibitors, 59, 1034, 1058, 
1584
t
, 
1605
Anticipatory anxiety, 1066
Anticoagulant, lupus. 
See
 Lupus 
anticoagulant
Anticoagulation therapy, 
573–588
. 
See also
 
specific agent or disorder and

1584
t
, 
1605
See
 Lupus 
573–588
. 
See also
 
Antiplatelet therapy; Direct-
acting oral anticoagulants; 
Anterior tibiofibular ligament, in ankle 
sprains, 1721
Anthracyclines, 1618
t
for breast cancer, 761, 765–766
heart failure/myocarditis and, 427
toxicity of, 427, 1618
t
, 1675
t
, 1680
Anthrax, 1319
t
, 
1461–1462
Anthrax vaccine, 1462
Anti-140 antibody, 862
t
Anti-155/140 antibody, 862, 862
t
Anti-adrenal antibodies, 1182
Anti-AMPA receptor antibody, 1021
Anti-amphiphysin antibody, 1021
t
1738
t
gynecomastia and, 1205
t
Antianginal drugs, 47, 372–375, 373
f
Antianxiety drugs, 1067–1069, 1067
t
, 
1069
t
. 
See also
 
Antiarrhythmic drugs, 393–396, 394–395
t
. 
See also
 
specific agent and 
specific arrhythmia
for arrhythmias in poisoning/drug 
overdose, 1582
in heart failure, 421
overdose/toxicity of, 394–395
t
, 396
Antibacterial agents. 
See
 Antibiotics; 
Antimicrobial therapy
Anti-beta-2-glycoprotein I antibodies
in antiphospholipid syndrome, 830, 857
in SLE, 855, 855
t
Antibiotic-associated/
 colitis/
diarrhea, 599
t
, 600, 603, 
 
659–662
, 1312
t
Antibiotic lock therapy, 1303
Antibiotics, 1317, 1318–1320
t
, 1321
t
, 
1322–1323
t
. 
See also
 
under 
Antimicrobial
for acne, 106
t
, 135
adverse reactions/toxicity and, 208
t
, 
1323
for asthma, 267
for bacteremia, 1456–1457, 1473–1474
for bite wounds, 1308
t
for bronchiectasis, 274–275
for burn injury, 1572
clinical response to, 1317
colitis/diarrhea 
(C difficile)
 associated 
with use of, 599
t
, 600, 603, 
659–662
, 1312
t
for COPD, 272, 273
cost of, 1324
for Crohn disease, 668
for diarrhea, 602, 1314
duration of treatment and, 1320
in fever management, 36, 1295, 1300
for gram-negative infections, 1318
t
, 
1318–1319
t
for gram-positive infections, 1318
t
, 
1319
t
hypersensitivity tests/desensitization 
and, 
1324–1325
for impetigo, 106–107
t
, 132, 1322
t
infection in cancer patient and, 
 
1674–1675
for irritable bowel syndrome, 659
for malaria, 1522–1523
CMDT2019_Index_p1743-1884.indd   1750

INDEX1751
 
CMDT 2019
Antiglaucoma agents, 183–184
t
, 187, 
 
188–189
Antigliadin antibodies, 646
Antiglobulin test. 
See
 Coombs test
Anti-glomerular basement membrane 
antibodies, in 
glomerulonephritis/
Goodpasture syndrome, 315, 
935, 946
t
, 948
f
, 
951–952
Anti-GQ1b antibodies, 1051
Anti-HAV , 692–693, 692
f
Anti-HBc, 694
f
, 695, 695
t
, 701
screening blood for, 553, 695
Anti-HBe, 694
f
, 695
t
Anti-HBs, 694
f
, 695, 695
t
Anti-HCV , 697, 697
f
, 703
in hepatocellular carcinoma, 1632
Anti-HDV , 698, 702
Anti-HEV , 698
Antihistamines. 
See also
 
abuse/overdose/side effects/toxicity of, 
229, 1114, 1593
for allergic eye disease, 178, 181
t
for allergic rhinitis, 229
1095
t
t
for insomnia, 1102
nefazodone interactions and, 1093
for pruritus, 103–109, 155
for scombroid poisoning, 1607
for urticaria, 142
Anti-HMG-CoA reductase, 862
t
, 863
Anti-Hu antibody, 1021
Antihyperglycemic agents. 
See
 
Antidiabetic agents
Antihypertensive drug therapy, 458–460, 
458
t
, 459
t
, 
460–478
, 461–
462
t
, 463–464
t
, 466–470
t
, 
472–474
t
, 474
t
, 476
f
, 477
t
. 
See 
also
 
specific class or agent
aldosterone receptor antagonists in, 
461–462
t
, 471
alpha-adrenoceptor antagonists in, 
 
471–475, 474
t
, 476
f
angiotensin II receptor blocking agents 
in, 465–471, 468–470
t
, 475
angiotensin-converting enzyme (ACE) 
inhibitors in, 465, 466–467
t
, 
475
in aortic dissection, 480
t
, 496–497
arteriolar dilators in, 474
t
, 475
beta-adrenergic blocking agents in, 
460–465, 463–464
t
, 475, 476
f
in black patients, 460, 465, 475, 477
t
, 
478
calcium channel blocking drugs in, 471, 
472–473
t
, 475, 476
f
cardiovascular/cardiac disease and, 
10–11, 373
f
, 455, 458, 459, 
459
t
, 465, 475
cocaine use and, 465
combination products in, 462
t
, 463
t
, 
464
t
, 466
t
, 467
t
, 468
t
, 469
t
, 
470
t
, 475–476, 476
f
demography and, 476, 477
t
depression caused by, 474
t
, 475, 
 
1088
developing regimen for, 475–476, 476
f
in chronic kidney disease, 941
clinical studies of, 1227–1228
combination regimens and, 1237, 1245
hospitalization/surgery and, 53, 1252
hypoglycemia and, 1228, 1261, 1262, 
1262
t
with insulin therapy, 1245
overdose/toxicity of, 209
t
, 1244
f
, 1584
t
, 
1599
during pregnancy, 831, 1253–1254
Antidiarrheal agents, 602, 605
for chemotherapy-associated diarrhea, 
1679
for fecal incontinence, 685
for microscopic colitis, 675
for short bowel syndrome, 649
for traveler’s diarrhea, 1316
for ulcerative colitis, 672
Anti-dipeptidyl-peptidase-like protein-6, 
1021
Antidiuretic hormone (ADH), 1119. 
 
See also
 Vasopressin
in diabetes insipidus/hypernatremia, 
1124
hyponatremia and, 899, 900
inappropriate secretion of (SIADH). 
 
See
 Syndrome of 
inappropriate ADH secretion
Antidotes, 
1584
, 1584
t
. 
See also
 
specific 
agent
Anti-double-stranded (anti-ds)-DNA, in 
lupus/SLE, 123, 854, 855
Anti-DPPX encephalitis, 1021
Antidromic reentrant tachycardia, 401
Anti-EGFR therapy. 
See
 EGFR (epidermal 
growth factor) mutations/
Antiemetics, 593–594, 594
t
, 1677
for chemotherapy-induced nausea and 
vomiting, 1678
for hyperemesis gravidarum, 817
Antiendomysial antibodies, 646
Antiepilepsy drugs. 
See
 Anticonvulsant 
therapy
Anti-factor V antibodies, 
572
Antifibrinolytics. 
See
 Fibrinolytic therapy; 
Antifolates. 
See also
 Methotrexate
for malaria, 1521–1522
Antifreeze. 
See
 Ethylene glycol
Antifungal agents, 107
t
, 
1561–1563
, 
 
1561–1562
t
. 
See also
 
specific 
agent or disorder
for candidiasis
esophageal, 623, 1346
t
, 1350, 1551
oral disease, 237, 1350
vulvovaginal, 781–782, 1551
in fever management, 36, 1300
in immunocompromised host, 1300
for invasive sinusitis, 228–229
in neutropenia, 1299
t
for skin disorders/topical, 107
t
, 119, 
 
120

t
t
, 119, 
 
120
Anti-GABA receptor antibodies, 1021
Antigen-antibody complexes. 
See
 Immune 
complexes
Antigenic drift/shift
influenza and, 1422
norovirus and, 1433
for personality disorders, 1078
for postherpetic neuralgia, 997
during pregnancy/teratogenicity and, 
834, 1001
for PTSD, 1066
for status epilepticus, 1002
for trigeminal neuralgia, 994, 995–996
t
Anti-CTLA-4 agents
hypophysitis caused by, 1119
thyroid disease caused by, 1141
Anti-CV2/CRMP5 antibody, 1021
Anti-D, 559, 560
f
Antidepressants, 1089–1095, 1091
t
, 1092
f
, 
1094
t
, 1095
t
. 
See also
 
specific 
type and agent
with antipsychotic agents, 1083, 1090, 
1095
for anxiety/panic disorder, 1067, 1068, 
1094
aripiprazole with, 1082, 1090
arrhythmias and, 1090, 1093, 1094
atypical, 1090–1093, 1091
t
t
bupropion augmenting, 1068, 1090
combination therapy and, 1094–1095
for dementia, 1034
dispensing, 1089, 1090
dose tapering and, 1095
drug interactions of, 1095
t
in elderly, 61
hypotension and, 1094, 1581
for irritable bowel syndrome, 658–659
lithium and, 1090, 1097
maintenance therapy with, 1095
t
monoamine oxidase inhibitors 
(MAOIs), 1091
t
, 1094, 1094
t
, 
1095
t
. 
See also
 Monoamine 
oxidase inhibitors
for neuropathic pain/painful diabetic 
neuropathy, 96
t
, 100
for OCD, 1070, 1090, 1093
overdose/toxicity of, 208
t
, 1090–1093, 
1091
t
, 1581, 
1609–1610
, 1609
f
for phobic disorders, 1068
during pregnancy, 1093
for premenstrual syndrome, 779
for psychotic depression, 1090
seizures and, 1094, 1583, 1583
t
, 1609
sexual dysfunction caused by, 
 
1092–1093, 1094
SNRIs, 1090–1093, 1091
t
. 
See also
 
Serotonin (serotonin-
selective) norepinephrine 
reuptake inhibitors
SSRIs, 1090–1093, 1091
t
. 
See also
 
Serotonin-selective reuptake 
stimulants as, 1094
suicide and, 1089, 1090, 1609
switching agents and, 1094–1095
for terminally ill/dying patient, 79–80
thyroid medication/liothyronine 
augmenting, 1090
tricyclic, 1091
t
, 1093–1094, 1095
t
. 
See 
also
 Tricyclic antidepressants
Antidiabetic agents, 1229–1237, 
 
1230–1231
t
, 1244–1245, 
1244
f
. 
See also
 
CMDT2019_Index_p1743-1884.indd   1751

INDEX1752
 
CMDT 2019
in febrile cancer patient, 1674–1675
in fever management, 36, 1295, 1300, 
1311
t
, 281, 284, 285
t
, 
1321
t
, 1555
for shock, 509
for skin and soft tissue infections, 
1450, 1450
t
and, 
1324–1325
monitoring blood levels in, 1320
principles of, 
1317–1324
, 1318–1320
t
, 
1321
t
t
See
routes of administration for, 1323–1324
thrombocytopenia caused by, 565
t
Antimicrotubule agents, 1618
t
Antimitochondrial antibodies, in primary 
biliary cholangitis/cirrhosis, 
721, 722
Antimitochondrial antibody-negative 
primary biliary cholangitis 
(autoimmune cholangitis), 
722
Antimonials, pentavalent, 1514–1515, 1515
Antimullerian hormone, in infertility 
workup, 798
Antimuscarinic agents, 66
Anti-
N
-methyl-D-aspartate (anti-
NNMDA) receptor-associated 
encephalitis, 1021, 1305
Anti-nAChR, in cancer-related 
neuropathy, 1022
Anti-native DNA antibody, 853
t
, 854
t
, 
855
t
Antineutrophil cytoplasmic antibody 
(ANCA), 854
t
in autoimmune hepatitis, 707
in eosinophilic granulomatosis with 
polyangiitis (Churg-Strauss 
syndrome), 946
t
, 948
f
in glomerulonephritis (pauci-immune), 
872, 935, 946
t
, 948
f
, 
950–951
in granulomatosis with polyangiitis 
(Wegener granulomatosis), 
854
t
, 871, 872, 946
t
, 948
f
, 950, 
951
in microscopic polyangiitis, 874
in primary sclerosing cholangitis, 740
Anti-NMDA receptor-associated 
Antinuclear antibody (ANA), 854
t
in glomerulonephritis, 948
f
854
t
in hyperthyroidism/Graves disease, 
1140, 1142
in lupus/SLE, 123, 853, 853
t
, 854, 854
t
, 
855
t
, 948
f
in polymyositis/dermatomyositis, 854
t
, 
862
in rheumatoid arthritis, 854
t
in scleroderma/CREST syndrome, 854
t
, 
860
in Sjögren syndrome, 854
t
, 865
severe disease, 1518
t
, 1519, 1520
t
, 
1521, 1522
treatment, 1518–1519, 1518
t
, 
 
1519–1523, 1520
t
uncomplicated falciparum, 
 
1518–1519, 1518
t
, 1519
t
, 
1520–1521, 1520
t
, 1521
rabies vaccine and, 1400
resistance to, 1518, 1519, 1520, 1520
t
, 
1521
for rheumatoid arthritis, 851
Anti-MDA5 antibody, 862
t
Antimetabolites, 1617–1618
t
Anti-Mi-2 antibody, 862, 862
t
Antimicrobial chemoprophylaxis. 
See also
 
for anthrax, 1462
for aspergillosis, 1299, 1558
in bronchiectasis, 274
for CMV infection, 199, 1390
in COPD, 272
for cystitis, 968
for endocarditis, 448, 833, 1466, 1466
t
, 
1467
t
. 
See also
 Endocarditis
for esophageal varices, 627
in fever management, 36
for group B streptococcal infection, in 
pregnancy, 814, 835, 1451
for herpes simplex infection, 127, 837, 
1378–1380, 1380
for high-altitude illness, 1578
for histoplasmosis, 1552–1553
for influenza, 1424–1425, 1426–1427
for MAC infections, 1361, 1488
for malaria, 1523–1524, 1523
t
. 
See also
 
Antimalarial agents
rabies vaccine and, 1399, 1400
for opportunistic infections, 1298–1299
for otitis media, 215
for plague, 1480
for 
 infection/pneumonia, 
1298–1299, 1361, 1362
t
, 1556
for Q fever, 1445
for relapsing fever, 1503
for rheumatic fever, 437, 1449
sexual violence (rape/sexual assault) 
and, 807–808, 808
615, 717
for surgical site infections, 
54
for toxoplasmosis, 1361, 1528
for traveler’s diarrhea, 816, 1316
for tuberculosis, 294–295
Antimicrobial therapy, 
1317–1325
, 
 
1318–1320
t
, 1321
t
, 
 
1322–1323
t
. 
See also
 
Antibiotics; Antimicrobial 
adverse reactions/toxicity and, 1323
cost of agents and, 1324
duration of, 1320
empiric, 1317, 1318–1320
t
in asthma, 267

t
for cancer-related infections, 
 
1674–1675
Antihypertensive drug therapy (
Cont.
):
in diabetes mellitus, 459, 460, 465, 471, 
476, 477
complication rate/diabetic 
nephropathy and, 955, 1248
diuretics in, 460, 461–462
t
, 475, 476
f
in elderly, 460, 465, 477
t
, 478
follow-up and, 478
goals of, 458–459, 459
t
, 479–480
heart disease/failure and, 10–11, 418, 
455
nonadherence and, 476, 479
patient selection for, 458, 458
t
peripheral sympathetic inhibitors in, 
474
t
, 475
and, 1193
in poisoning/drug overdose, 1582
for preeclampsia/eclampsia, 480
t
, 824
during pregnancy, 832–833
preoperative/perioperative, 49
in renal disease/failure, 477–478, 480
t
renin inhibitors in, 465, 466
t
resistant hypertension and, 477
t
stroke/stroke prevention and, 455–456, 
459, 479–480, 1011
sympatholytics in, 474
t
, 475, 1596
thresholds for, 458–459, 459
t
in urgencies/emergencies, 479–480, 
480
t
, 481
t
vasodilators in, 474
t
, 475
Anti-IgA antibodies, IgA deficiency and, 
896
Anti-IL-12/23 antibody, 665, 670
Anti-inflammatory drugs. 
See
 
Corticosteroids; Nonsteroidal 
anti-inflammatory drugs
Anti-insulin antibodies
in autoimmune/immunopathologic 
hypoglycemia, 1261, 1266
in diabetes, 1220, 1221
t
, 1242
insulin therapy causing, 1246–1247
Anti-insulin receptor antibodies
in diabetes/insulin resistance, 1222
in hypoglycemia, 1261, 
1266
Anti-integrins, 664–665, 670, 673
Anti-intrinsic factor antibodies, 634
Anti-Jo-1 antibody, 854
t
, 862, 862
t
Anti-leucine rich glioma inactivated 1 
Antileukocyte antibodies, transfusion-
related acute lung injury 
caused by, 554
Antileukotriene agents. 
See
 Leukotriene 
modifiers
Anti-LKM1 (liver-kidney microsome 
 
type 1 antibodies), 707
Anti-Ma2 antibody, 1021
Anti-MAG antibodies, in cancer-related 
Antimalarial agents, 208–209
t
, 1518–1519, 
1518
t
, 1519–1523, 1519
t
, 
1520
t
, 1523
t
G6PD deficiency and, 521, 1518, 1521
for lupus/SLE, 123, 855
for malaria, 1518
t
t
, 
1520
t
, 1523
t
chemoprophylaxis, 1523–1524, 
 
1523
t
non-falciparum, 1518, 1518
t
self-treatment, 1523
CMDT2019_Index_p1743-1884.indd   1752

INDEX1753
 
CMDT 2019
for gay and bisexual men/MSM, 
1735
t
, 1736
preexposure, 4, 1310, 1356–1358, 1357
t
1735
t
, 1736
pregnancy/newborn and, 836, 1358
progressive multifocal 
leukoencephalopathy 
incidence and, 1408
prophylactic, 4, 1310, 1356, 1356–1358, 
1357
t
syphilis and, 1501
toxicity and, 1366, 1374, 1374
f
, 1375
transmission prevention and, 1310, 
1356
tuberculosis outcomes and, 1365
Anti-Rh
o
 (D) antibody, 813, 814, 815
Anti-RNA polymerase III antibody, in 
scleroderma, 860
Anti-SAE antibody, 862
t
Anti-SCL-70 antibody, 854
t
Antiseizure medications. 
See
 
Anticonvulsant therapy
Anti-signal recognition particle (anti-SRP) 
antibody, 862, 862
t
Anti-SLA, 707
Anti-Smith (anti-Sm) antibody, 123, 853
t
, 
854, 854
t
, 855
t
Antisocial personality disorder, 1077, 
1077
t
, 1078
Antispasmodic agents, for irritable bowel 
syndrome, 658
Anti-SRP antibody, 862, 862
t
Anti-SS-A/Ro antibody, 854
t
in lupus/SLE, 123, 854
t
t
, 865
Anti-SS-B/La antibody, 854
t
t
t
, 865
Antistreptolysin O (ASO) titers, in 
postinfectious 
glomerulonephritis, 949
Antisynthetase syndrome/antibodies, 862, 
862
t
Antithrombin deficiency, DVT/PE (venous 
thromboembolic disease) and, 
306, 586
t
Antithrombotic therapy, 
573–587
. 
See also
 
Anticoagulation therapy; 
Antiplatelet therapy; 
for ACS (NSTEMI/STEMI), 379–381, 
384–385, 385
t
, 386–387, 388, 
392
for atrial fibrillation, 402
t
, 403–406, 
404
t
, 405
t
PCI and, 386
Antithymocyte globulin, 527, 527–528, 
537
Antithyroid (antithyroglobulin/
antithyroperoxidase) 
antibodies, 1131, 1135
t
. 
 
See also
 
specific disorder and
 
Thyroid testing
Anti-TNF agents. 
See also
 
specific agent
adverse effects of, 664, 1299
for ankylosing spondylitis, 878
histoplasmosis in patient taking, 
 
1552
for dementia-associated behavior 
problems, 59, 1035
for depression, 1090
dosage forms and patterns for, 1083
interactions and, 1083
intranasal administration of, 1083
long-acting(decanoate/enanthate) forms 
of, 1083
neuroleptic malignant syndrome caused 
by, 1084–1085, 1583, 1592
overdose/toxicity/side effects of, 1082
t
, 
1083–1086, 1084
t
, 
1592–1593
parkinsonism (reversible) caused by, 
1024, 1085
in pregnancy, 1084
for psychedelic/hallucinogen abuse/
toxicity, 1112
t
Antipyretic drugs, 36
contraindications to in heat stroke, 1566
Antiretroviral therapy (ART), 1362–1375, 
1363–1365
t
, 1367
t
, 1372–
1373
t
, 1374
f
. 
See also
 
specific 
agent
adherence and, 1, 1373, 1374
antituberculous drug interactions and, 
293, 1347, 1369
CD4 counts and, 1342, 1362, 1374
CMV disease control and, 199, 623, 
1388–1389, 1389, 1390
combinations/regimens for, 1362–1366, 
1371–1373, 1372–1373
t
alternative treatments, 1372–1373
t
, 
1375
choosing, 1366–1373, 1367
t
, 
 
1372–1373
t
constructing, 1371–1373, 1372–1373
t
, 
1375
fixed dose preparations and, 1366, 
1367
t
drug-drug interactions and, 1351
drug holidays/structured treatment 
interruptions and, 1374
drug resistance and, 702, 1373, 1374, 
1374–1375
gender-affirming hormone therapy and, 
1742
hepatitis B and, 1351
hepatitis C and, 697, 1351
HIV prognosis and, 1338, 1375
inflammatory reactions/immune 
reconstitution and, 1355–1356
initiation of, 1362–1365
Kaposi sarcoma and, 155, 1346
t
, 1354
lactic acidosis caused by, 919, 1351
lipid abnormalities/lipodystrophy/
lipoatrophy and, 1062, 1186, 
1355, 1366, 1369
monitoring, 1374–1375, 1374
f
myopathy caused by, 884, 1062, 1350
after needle stick, 1359
neuropathy caused by, 1349, 1368
opportunistic infection/malignancies 
and, 1365
oral contraceptive drug interaction and, 
800
postexposure, 4, 807–808, 808, 1310, 
1358
Antioxidants. 
See also
 Vitamin C; 
 
Vitamin E

and, 1365
800
1358
See also
 Vitamin C; 
 
Vitamin E
for age-related macular degeneration, 
193
in chemoprevention, 11
Antiparkinsonism drugs, 1025–1027, 1085
Anti-PD-1/PDL-1 agents
for bladder cancer, 1666
for Hodgkin lymphoma, 546
for lung cancer, 1627, 1628
for renal cell carcinoma, 1668
Antiphospholipid antibody syndrome/
antiphospholipid antibodies, 
586
t
, 
829–830
, 
856–857
DVT/PE (venous thromboembolic 
disease) and, 306, 584, 586
t
, 
830, 856–857
factor II antibodies and, 572
false-positive syphilis tests and, 853
t
, 
855, 857
livedo reticularis/racemosa and, 877
pregnancy loss and, 819, 829–830, 
 
856–857
SLE and, 853
t
, 855, 855
t
stroke and, 857, 1009
Antiplatelet antibody
heparin-associated, 562
in immune thrombocytopenia, 559
in posttransfusion purpura, 565
Antiplatelet therapy. 
See also
 
Aspirin
t
, 388, 392
for angina, 373
f
, 374–375
402
t
t
, 405
t
prevention, 368, 484
387, 640
perioperative discontinuation of, 381
for stroke/TIA, 1005–1006, 1010
t
for transient monocular visual loss, 196
Antiprotease/antitrypsin, alpha-1. 
See
 
Alpha-1-antiprotease/
antitrypsin
Antiproteinase-3 ANCA. 
See
 
Antineutrophil cytoplasmic 
antibody
Antipruritic agents, 103–109, 107–108
t
, 
155
Antipsychotic drugs, 1080–1086, 1081
t
, 
1082
t
, 1084
t
. 
See also
 
specific 
abnormal movements caused by, 1030
adherence/nonadherence issues and, 
1081, 1082, 1083
for aggressive/violent behavior, 
 
1104
for alcoholic hallucinosis, 1108
with antidepressants, 1083, 1090, 1095
atypical. 
See
 Atypical antipsychotics
for bipolar disease/mania, 1097
breast cancer and, 1084
catatonia caused by, 1085
clinical indications for, 1082–1083
for delirium, 62
delirium caused by, 1083
CMDT2019_Index_p1743-1884.indd   1753

INDEX1754
 
CMDT 2019
405, 405
t
, 406
disease), 575–576
t
, 578
t
, 580
t
, 
582
overdose/toxicity of, 406, 1591
perioperative management of, 52
t
, 406
Aplastic anemia, 
526–528
, 526
t
, 527
t
stem cell transplantation for, 527
thrombocytopenia and, 527, 556, 558
Aplastic crises, 515, 522, 1430
Apnea, sleep. 
See
 Sleep apnea hypopnea
Apnea test, 1042
Apneustic breathing, 1041
APOB
 mutation, 1683
ApoE genotyping, in Alzheimer disease, 
58, 1034
APOL1
 gene
in HIV-associated nephropathy, 958
in kidney disease/focal segmental 
glomerulosclerosis, 456, 936, 
953, 956
Apotransferrin, 510
Appendectomy, 654–655
in pregnant patient, 839
ulcerative colitis risk and, 671
Appendiceal carcinoids, 1196, 1647
Appendicitis, 
653–655
in pregnancy, 654, 
839
Appetite, genetic control of, 1278
Apprehension sign, 1717
Apraclonidine, 183
t
, 188–189, 1596
Apraxia, 57, 1016, 1033
Apremilast, 117, 880, 876
Aprepitant, 593, 594
t
, 1678
Aqua glycolic, 108
t
Aquaphor, 108
t
Aquaporin-4, in neuromyelitis optica, 
1037
Arachnodactyly, in Marfan syndrome, 
1687
Arbovirus encephalitides, 
1401–1402
Arcing (flash) burns, 1573
ARDS. 
See
 Acute respiratory distress 
syndrome
Arenaviruses, hemorrhagic fever caused 
by, 1412
Arg133Trp (PAX-4)
 mutation, 1221
Argatroban, 563, 563
t
Arginine vasopressin. 
See
Argyll Robertson pupils, 1500
ARH
Aripiprazole, 1081, 1081
t
, 1082, 1082
t
, 
1084
t
for aggressive/violent behavior, 1104
with antidepressants, 1082, 1090
for bipolar disease/mania, 1082, 1097
for depression, 1082
overdose/toxicity/side effects of, 207
t
, 
1082
t
, 1084
t
, 1592
Arm edema, in breast cancer/
postmastectomy, 758, 773–774
Armodafinil, 39, 1103
Arnold-Chiari malformation, 993, 
 
1045–1046
Aromatase inhibitors/inactivators (AIs)
adverse effects of, 208
t
, 767, 769, 769
t
, 
1623
t
t
for breast cancer treatment/
prevention, 755, 766–767, 769
chest pain/discomfort and, 29–30
drugs for management of, 1067–1069, 
1067
t
, 1069
t
hospitalization/illness and, 1116, 1117, 
1118
hyperventilation/respiratory alkalosis 
and, 327, 924, 925
palpitations in, 31, 32
pre- and postsurgical, 1116, 1117, 1118
Anxiolytic drugs, 1067–1069, 1067
t
, 1069
t
. 
See also
 
Aorta. 
See also
 
under Aortic
atherosclerotic/occlusive disease of, 
483–484
coarctation of, 
335–336
diseases affecting, pregnancy and, 
 
447–448
, 447
t
in Marfan syndrome, 447, 448, 1687, 
1688
traumatic injury of, 445
Aortic aneurysms
abdominal, 5, 6
t
, 
492–494
dissection and, 496–497
in syphilis, 494, 1499, 1500, 1500
f
thoracic, 
494–495
Aortic arch, coarctation of, 336
Aortic dissection, 
496–497
chest pain/discomfort in, 28, 372, 496
hypertension and, 456, 480
t
, 496, 
 
496–497
in pregnancy, 447–448
Aortic regurgitation, 343–345
t
, 
358–360
, 
359
t
. 
See also
 Valvular heart 
disease
hypertension and, 358
in Marfan syndrome, 358, 359, 1687
Aortic root disease/dilation
in aortic regurgitation, 358, 359
in aortic stenosis, 352, 355
in Marfan syndrome, 1687, 1688
Aortic sclerosis, 353
Aortic stenosis, 343–345
t
, 346
t
, 
352–357
, 
353
t
, 354
t
, 356
f
, 357
f
. 
See also
 
Valvular heart disease
Aortic valve
repair/replacement of, 354–357, 354
t
, 
356
f
, 357
f
, 359, 359
t
. 
See also
 
Valve replacement
in rheumatic fever/heart disease, 358, 
435
traumatic rupture of, 445
Aortoenteric fistula, 606–607
Aortoiliac occlusive disease, 
483–484
APACHE II, 742
Apallic state (persistent vegetative state), 
1042
Apathetic hyperthyroidism, 1141, 1148
Apathy, in dementia, 1033
APC
 gene, 678, 680, 1649
Aphasia. 
See also
 
dementia and, 57, 1032
t
nonfluent/agrammatic variant, 1032
t
semantic variant, 1032
t
stroke and, 1008
Aphthous ulcer, 
237–238
, 876, 1350
API2-MALT1
 gene translocation, 1645

t
t
t
237–238
, 876, 1350
Apical ballooning syndrome. 
See
 Stress 
Apicitis, petrous, 216–217
Apixaban, 575–576
t
, 578
t
, 580
t
, 582
Anti-TNF agents. (
Cont
.):
infection in patient taking, 664, 1297, 
1298
for inflammatory bowel disease, 663, 
664, 669–670, 673, 674
for psoriasis/psoriatic arthritis, 116, 880
for rheumatoid arthritis, 851–852
tuberculosis reactivation and, 664, 852, 
1299
Antitoxin
botulism, 1060, 1460
diphtheria, 1463
Anti-Tr antibody, 1021
Antitrypsin/antiprotease, alpha-1. 
See
 
Anti-tTG (transglutaminase/tissue 
transglutaminase) antibody
in autoimmune/Hashimoto thyroiditis, 
1132
in celiac disease/dermatitis 
herpetiformis, 131, 604–605, 
645–646
Antituberculous drugs, 291–295, 292
t
, 
293
t
antiretroviral drug interactions and, 
directly observed therapy (DOT) and, 
291, 292–293, 293, 294
for drug-resistant disease, 288, 289, 
289
t
, 293, 293–294, 295, 1347
for extrapulmonary disease, 294
in fixed dose combinations, 293
in HIV-negative persons, 292–293, 292
t
, 
293
t
in HIV-positive persons, 293, 1347, 
1359
in latent disease/chemoprophylactic, 
294–295
for MAC infections, 1487, 1488
monitoring therapy with, 294
during pregnancy/lactation, 293, 294, 
836
treatment of contacts and, 294, 295
for tuberculous pericarditis, 439
Anti-VEGF therapy. 
See also
 
193
cardiac toxicity and, 1680
for esophageal cancer, 1640
Antivenin
for black widow spider bites, 1608
for scorpion stings, 1608
for snake bites, 1584
t
, 1608
Antiviral agents, 181
t
, 208
t
, 1379
t
. 
See also
 
specific agent or infection
Anti-voltage-gated calcium channel 
Anti-voltage-gated potassium channel 
Anti-Y o antibody, 1021
Anti-Zic antibody, 1021
Anton syndrome, 1016
Anus. 
See also
 
under Anal
cancer of, 1354–1355, 1615
t
, 
1656–1657
 
1733–1734, 1735
t
, 1736
rectum protruding through 
 
(rectal prolapse), 683
Anxiety/anxiety disorders, 
1066–1069
CMDT2019_Index_p1743-1884.indd   1754

INDEX1755
 
CMDT 2019
leukemic, 889
Lyme. 
See
 Lyme disease
mutilans, 879
neck pain caused by, 1701, 1702
nongonococcal acute bacterial (septic), 
881–883
, 1311, 1321
t
pneumococcal, 1452
in polychondritis, 875
pseudoseptic, 882
psoriatic, 115, 
879–880
reactive. 
See
 Reactive arthritis
in rheumatic fever, 435, 436, 436
t
, 850
rheumatoid. 
See
 Rheumatoid arthritis
rubella and, 884, 1396
in sarcoidosis, 
887
septic. 
See
 Arthritis/arthralgia, 
nongonococcal acute bacterial
in SLE, 850, 853
t
, 854
staphylococcal, 881, 1321
t
in Still disease, 
852–853
streptococcal, 1451
tophaceous, 844, 845, 847
tuberculous, 
886–887
in ulcerative colitis, 881
viral, 
884
in Whipple disease, 647, 881
Arthritis-dermatitis syndromes, 
gonococcal infection and, 
1481, 1482
Arthrocentesis, 840. 
See also
 
specific 
disorder
Arthropathy, neurogenic. 
See
 Neurogenic 
arthropathy
Arthroplasty. 
See
 Joints, replacement of
Arthropods, skin lesions caused by, 
 
159–160
Artificial insemination, 799
for lesbian and bisexual women, 1731
Artificial nutrition. 
See
 Nutritional 
support
Artificial pancreas. 
See
 Closed loop 
systems
Artificial sweeteners, 1229
Artificial tears, 177, 865
Aryepiglottic folds, cancer of, 246–247
Arytenoid cartilage, contact ulcers/
granulomas of, 245
5-ASA, 662, 668, 672
ASAQ (artesunate-amodiaquine), 1518
t
, 
1519, 1519
t
, 1520
t
, 1522
Asbestosis (asbestos exposure), 318, 318
t
, 
320, 1624, 1630
 (ascariasis), 
1541
Ascites, 
612–614
, 613
t
. 
See also
 
specific 
cause
bacterial peritonitis and, 613, 613
t
, 
614–616, 717
in cirrhosis/liver disease, 612, 612–613, 
613, 613
t
, 614–616, 716–717, 
720, 720
t
malignant, 613, 613
t
, 
616
, 1672
neutrocytic, 613, 614, 615
Ascites albumin gradient, serum (SAAG), 
613
t
, 614, 728. 
See also
 Ascites
Ascitic fluid analysis, 613–614. 
See also
 
Paracentesis
Ascorbic acid. 
See
 Vitamin C
Asenapine, 1081, 1081
t
, 1082, 1084
t
Aseptic meningitis, 1304, 1304
t
. 
See also
 
coxsackieviruses causing, 1304, 1434
in respiratory alkalosis, 917, 917
t
, 924, 
925
in respiratory failure, 329, 330
ventilatory control and, 327
Arterial graft/prosthesis. 
See
 
Revascularization procedures
Arterial lines, infection and, 1302
Arterial occlusion
acute limb, 
487–488
atherosclerotic, 
483–491
. 
See also
 
Arterial thrombosis. 
See
 Thrombosis
Arteriography. 
See
 
specific type or disorder
Arteriolar dilators, 474
t
, 475. 
See also
 
Vasodilator therapy
Arteriovenous fistulae, spinal dural, 1015
Arteriovenous malformations
gastrointestinal (angioectasias), 606, 609
in hereditary hemorrhagic 
telangiectasia, 1688, 1689
intracranial, 1010, 1011, 
1013–1014
Arteritis. 
See also
 Polyarteritis
See
 Giant cell (temporal/
cranial) arteritis
in Kawasaki disease, 1446
Takayasu, 
869–870
Artesunate, 1518
t
t
, 1522
with amodiaquine (ASAQ), 1518
t
, 1519, 
1519
t
, 1520
t
, 1522
with mefloquine, 1519
t
, 1522
with pyronaridine, 1518
t
, 1519
t
, 1520, 
1522
(Fansidar), 1518
t
, 1519
t
, 1522
Arthritis/arthralgia. 
See also
 
specific 
disorder causing
in ankylosing spondylitis, 878
arthroplasty/joint replacement for, 843, 
1708, 1719. 
See also
 
specific 
joint
in Behçet syndrome, 876
calcium pyrophosphate deposition and, 
848
cancer-associated, 850, 889
in chikungunya fever, 884, 1419
chondroitin/glucosamine for, 843
in Crohn disease, 666, 881
crystal deposition, 
844–848
, 844
t
, 845
f
, 
846
t
degenerative, 
840–843
, 842
f
. 
See also
 
in diabetes, 1252
diagnosis/evaluation of, 840
884, 1430
extra-articular manifestations and, 840
glucosamine/chondroitin for, 843
gonococcal, 880, 
883–884
, 1321
t
, 1481, 
1482
gouty. 
See
 Gout/gouty arthritis
850, 871, 872
in hemophilia, 568
in hepatitis, 850, 884
of hip, 
1708–1709

, 1321
t
, 1481, 
1482
gouty. 
See
of hip, 
1708–1709
in HIV infection/AIDS, 884, 1349
infectious, 
881–884
, 1311
inflammatory intestinal diseases and, 
666, 
881
joint involvement pattern and, 840, 841
t
of knee, 881, 1709, 
1718–1719
Arousal (excitement) stage of sexual 
activity, 796, 797, 1075, 1076. 
See also
 Sexual dysfunction
Arrhythmias, 
393–414
, 394–395
t
. 
See also
 
specific type and
 
antidepressants causing, 1090, 1093, 
1094
in COPD, 269, 270, 273
in heart failure, 414, 416, 418, 421
in hypercalcemia, 912
in hypocalcemia, 910
in hypothermia/rewarming, 1567, 1567
f
myocardial infarction and, 383, 389–390
palpitations and, 30–32, 31
t
of, 49
in pheochromocytoma, 1191
in poisoning/drug overdose, 
 
1582–1583
, 1582
t
. 
See also
 
with antidepressants, 1090, 1093, 
1094
with antipsychotics, 1084, 1592
seizures differentiated from cerebral 
hypoperfusion caused by, 
1000
syncope and, 413–414
in tetralogy of Fallot, 341, 342
treatment of
catheter ablation for, 396, 400, 401, 
407, 409, 410, 432
pharmacologic, 393–396, 394–395
t
. 
See also
 Antiarrhythmic drugs
Arsenic poisoning, 1584
t
, 
1593
Arsenic trioxide, 538, 1622
t
Arsenical melanosis, 166, 1593
Artemether
t
, 1520
t
, 1522
with lumefantrine (Coartem/Riamet), 
1518
t
, 1519
t
, 1520
t
, 1522, 
1523
for schistosomiasis chemoprophylaxis, 
1536
Artemisinins (qinghaosu)/artemisinin 
derivatives/combinations 
(ACTs), 1518, 1518
t
, 1522, 
1523
Arterial aneurysms. 
See
 
Aneurysms
in acid-base disorders, 917, 917
t
in ARDS, 331, 332
in asthma/asthma exacerbation, 256, 
256
t
in carbon monoxide poisoning, 316, 
1595
COPD/home oxygen therapy and, 269, 
269
t
, 270, 271
t
in cystic fibrosis, 276
in drowning, 1570
in dyspnea evaluation, 25
in metabolic acidosis, 917, 917
t
, 921
in metabolic alkalosis, 917, 917
t
, 923
in methemoglobinemia, 1603
in 
 pneumonia, 1344, 
 
1555
in pulmonary embolism, 307
in pulmonary hypertension, 313
in respiratory acidosis, 917, 917
t
, 924
CMDT2019_Index_p1743-1884.indd   1755

INDEX1756
 
CMDT 2019
long-term control medications for, 
259, 260–261
t
NAEPP 3 guidelines for, 254
f
, 255
t
, 
257–259, 258
f
, 262
t
, 263
t
, 
265
t
, 266
t
pharmacologic, 254
f
, 255
t
, 258
f
, 259, 
259–267, 260–261
t
, 262–263, 
262
t
, 265
f
, 266
f
in pregnant patient, 833–834
quick relief medications for, 258
f
, 
259, 262–263
t
stepwise approach to, 254
f
, 255
t
, 257, 
258
f
, 264
triad, 232, 892
vaccinations for patients with, 264
zanamivir contraindications and, 1423, 
1425
Asthma action plan, 257
Astrocytoma, 1017
t
, 1615
t
Astroviruses, diarrhea/gastroenteritis 
caused by, 599
t
ASXL1
 mutation, 534, 537, 538
Asymmetric septal hypertrophy, 431, 432
At-risk/risky drinking, 18, 1105–1106, 
1107, 1107–1108. 
See also
 
Alcohol use disorder
Atactic breathing, 1041
Ataxia
fragile-X tremor-ataxia syndrome and, 
1684
Friedreich, 1049
VZV infection causing, 1383
Ataxia-telangiectasia 
(ATM)
 mutation
in breast cancer, 754
in chronic lymphocytic leukemia, 541
in pancreatic/periampullary carcinoma, 
1636
Atazanavir, 1364
t
, 1370, 1373
t
. 
See also
 
with cobicistat, 1364
t
, 1369, 1370, 1373
t
prophylactic/transmission to fetus/
newborn and, 1358
with ritonavir, 1358, 1370, 1371, 1373
t
Atelectasis
in bronchial obstruction, 253
mechanical ventilation and, 330
in right middle lobe syndrome, 299
Atenolol/atenolol-HCTZ, 463
t
, 446, 816
t
Atezolizumab, 1134, 1140, 1628, 1665, 
1666
Atherosclerosis, 
483–491
. 
See also
 
specific 
structure affected and
 
Cardiovascular disorders; 
Vascular disorders
acute limb occlusion and, 
487–488
aneurysms and, 
492–497
aortoiliac disease and, 
483–484
cerebrovascular occlusive disease and, 
488–490
, 489
f
. 
See also
 Stroke
cholesterol/lipoproteins in, 6
t
, 
 
1267–1268, 1269–1270
coronary artery/heart disease and, 
 
365–393
. 
See also
 Coronary 
in diabetes mellitus, 1250–1251, 1251
femoral/popliteal artery disease and, 
484–485
homocysteine/hyperhomocysteinemia 
and, 1686
hypertension and, 456
lipid-lowering therapy and. 
See
 
Lipid-lowering therapy
respiratory disease associated with 
sensitivity to, 253, 
892
Reye syndrome and, 1385
for rheumatic fever, 436
for stroke, 6
t
, 11
for transient ischemic attacks, 1006
Aspirin (NSAID) exacerbated respiratory 
disease, 253, 
892
Asplenia, immunization recommendations 
in, 1328
t
, 1333
t
Assisted reproductive technologies, 799, 
983
Astemizole, antidepressant drug 
interactions and, 1093, 1095
t
Astereognosis, 1016
Asterixis, 613, 718
Asthenozoospermia, 981
f
Asthma, 21, 22
t
, 
253–268
allergic, 253, 255, 257, 264
allergic bronchopulmonary mycosis/
aspergillosis and, 275, 1557, 
1558
aspirin triggering, 232, 253
“cardiac, ” 253, 257
catamenial, 253
classification/diagnosis of, 253–257, 
254
f
, 255
t
, 256
t
comorbid conditions and, 259
complications of, 257
COPD differentiated from, 257, 270
cough in, 21, 22
t
, 253, 254
differential diagnosis of, 257
drugs causing, 253, 321
t
exacerbations of
classification/assessment of severity/
control and, 254
f
, 255, 255
t
, 
256
t
, 257–259, 258
f
treatment of, 254
f
, 255
t
, 257, 
 
259–261, 262
t
, 263, 264–267, 
265
f
, 266
f
exercise-induced, 253, 254
f
, 256, 259, 
264
“functional, ” 257
lesbian and bisexual women and, 
 
1726–1727
NAEPP 3 diagnosis/management 
guidelines for, 254
f
, 255
t
, 
256
t
f
, 262
t
, 
263
t
, 265
t
, 266
t
occupational, 253, 319
during pregnancy, 
833–834
pulmonary function testing in, 254
f
, 
255
t
, 256–257, 256
t
, 265–267, 
265
f
, 266
f
severity/control of, 253–257, 254
f
, 255
t
, 
256
t
, 257
f
, 255
t
f
, 
259–264, 260–261
t
, 262
t
, 
264–267, 265
f
, 266
f
desensitization/immunotherapy in, 
258
f
, 261
t
, 264
in emergency department setting, 
 
267
for exacerbations, 254
f
, 255
t
, 257, 
t
265
f
, 266
f
inhalation therapy, 258
f
, 259, 260
t
,

258
f
, 261
t
, 264
 
267
f
, 255
t
, 257, 
t
265
f
, 266
f
f
, 259, 260
t
, 
261, 262–263
t
, 263
t
, 264, 265, 
267
in intensive care setting, 267
Aseptic meningitis (
Cont.
):
echoviruses causing, 1304, 1434
herpes simplex causing, 1304, 1378, 
1380
leptospiral, 1304, 1505
in Lyme disease, 1304, 1506, 1507
mumps/mumps vaccine and, 1304, 1395
in syphilis, 1497
Asfotase alfa, 1177
Asherman syndrome, 1210
Asparaginase 
Erwinia chrysanthemi,
 1622
t
Aspartate aminotransferase (AST), 690, 
690
t
. 
See also
 
affecting
Aspergilloma, 1557
Aspergillus/Aspergillus fumigatus
 
(aspergillosis), 
1557–1558
allergic bronchopulmonary, 
275
, 893
t
, 
1557, 1558
chemoprophylaxis for, 1299, 1558
in immunocompromised host/HIV 
infection/AIDS, 1299, 
 
1557–1558
invasive, 1299, 1557–1558, 1558
sinusitis and, 228–229, 1557, 1558
Aspiration, 
316–317
. 
See also
 Pneumonia, 
aspiration
enteral nutritional support and, 1291
of food/“café coronary, ” 
317
foreign body, 248–249, 
317
of gastric contents
acute (Mendelson syndrome), 
 
316–317
, 1302
chronic, 
317
of inert material, 
317
of toxic material/petroleum distillates, 
317
, 1605, 1606
Aspirin, 36, 85, 86
t
. 
See also
 Antiplatelet 
therapy; Salicylates
for ACS (NSTEMI/STEMI), 379, 380, 
384, 385
t
, 387, 388
f
, 374
cardiac valve replacement and, 356, 364, 
364
t
prevention, 6
t
, 11, 368, 459, 
484, 1251
for chemoprevention, 6
t
, 11, 368, 1650. 
See also
 
in colorectal cancer prevention, 6
t
, 1650
coronary stent thrombosis prevention 
and, 375
disease), 578
t
, 582
for essential thrombocytosis, 532
GI/diverticular bleeding associated 
with, 85, 610–611, 636, 843
for Kawasaki disease, 1446, 1447
nasal polyps and asthma as 
contraindication to, 232
with opioid analgesics, 94
t
overdose/toxicity of, 636, 640, 843, 1606
for pain management, 85, 86
t
in peptic ulcer disease, 636, 640, 843. 
See also
 Peptic ulcer disease, 
NSAID-induced
for pericarditis, 439
t
, 843
for polycythemia, 531
CMDT2019_Index_p1743-1884.indd   1756

INDEX1757
 
CMDT 2019
Atypical measles, 1381
t
Atypical mycobacteria. 
See
 
Nontuberculous (atypical) 
mycobacteria
Atypical nevi/mole, 
110–111
, 110
f
Atypical squamous cells of unknown 
significance (ASC-US), 783
t
, 
784
AUA symptom index, for benign prostatic 
hyperplasia, 983, 984
t
Audiology, 210–211
Audiovestibular disorders, 219, 
224
. 
See 
also
 Vertigo; Vestibular 
disorders
AUDIT (Alcohol Use Disorder 
Identification Test), 18, 18
t
, 
1106
Auditory canal. 
See
 Ear canal
Auer rods, 539
Augmentation mammoplasty. 
See
 Breast 
implants
Aura
in migraine headache, 990, 1000
pre-seizure, 999
Auricle, disorders of, 
211
Austin Flint murmur, 358
Austrian triad, 1452
Autism spectrum disorder, 
1101
fragile X mental retardation and, 1684
vaccines and, 1393
Autoimmune adenopathy, 250
Autoimmune cholangitis, 722
Autoimmune cytopenia, 896
Autoimmune disorders, 
848–867
. 
See also
 
specific disease
adrenal insufficiency/Addison disease 
and, 1180
breast implants and, 753
common variable immunodeficiency 
and, 896
diabetes and, 1220, 1220–1221, 1221
t
epilepsy and, 999
fever/FUO and, 1294, 1295
hearing loss in, 219
neurocognitive disorders/delirium 
caused by, 1115
t
Autoimmune hemolytic anemia, 
524–525
Autoimmune hepatitis, 
706–708
Autoimmune hypoglycemia, 
1265–1266
Autoimmune hypoparathyroidism, 1161
Autoimmune myocarditis, 425
t
, 426
Autoimmune neutropenia, 528
Autoimmune pancreatitis, 746, 747
Autoimmune paraneoplastic disorders, 
1021
Autoimmune polyendocrine syndrome 
(APS/autoimmune 
polyendocrinopathy-
candidiasis-ectodermal 
dystrophy [APECED]) , 1131, 
1161, 1180
Autoimmune regulatory 
(AIRE)
 gene, 
1220
Autoimmune thyroiditis, 1131, 1132, 
1132–1133, 1133, 1134. 
See 
also
 Thyroiditis
Autologous packed red blood cells, 552. 
See also
 Transfusion
Autologous serum eye drops, 177
Automatisms/postepileptic automatisms, 
998
lone, 403
in mitral regurgitation, 349, 350
f
in mitral stenosis, 347, 348
f
, 404, 405
in myocardial infarction, 389
prosthetic heart valves and, 364, 365
t
recurrent paroxysmal, 402, 407
reentry/preexcitation and, 400, 401
refractory, 407
transient, 404
treatment of, 394
t
, 402–407, 402
t
, 404
t
, 
405
t
Atrial flutter, 394
t
, 
407–408
reentry/preexcitation and, 401, 407
Atrial gallop. 
See
 Heart sounds
Atrial myxoma, 444–445, 445, 1295
Atrial (supraventricular) premature beats, 
389, 394
t
, 408
Atrial septal aneurysm, 337
Atrial septal defect, 
336–339
Atrial septal lipoma, 445
Atrial tachycardia, 
408
, 1141
Atrioventricular (heart) block, 
397–398
in atrial septal defect/patent foramen 
ovale, 337
in Lyme disease, 437, 1506, 1508
t
, 1509
in myocardial infarction, 389–390
t
, 1594
Atrioventricular (AV) dissociation, 398
Atrioventricular nodal reentrant 
tachycardia (AVNRT), 399, 
400
Atrioventricular pathways, accessory, 399, 
400, 
400–401
Atrioventricular reciprocating tachycardia 
(AVRT), 399
Atripla (tenofovir [TDF]/emtricitabine/
efavirenz), 1366, 1367
t
, 1368, 
1371, 1372
t
Atrophic gastritis, 634, 635
gastric tumors and, 1641, 1645
Atrophic urethritis, 65
Atrophic vaginitis, 65, 809, 809–810
Atrophie blanche, 33
Atropine
for calcium channel blocker overdose, 
1594
for cholinesterase inhibitor 
(anticholinesterase) 
poisoning, 1584
t
, 1605
for nerve agent exposure, 1595, 1605
overdose/toxicity of, 1584
t
, 
1593
Attention-deficit/hyperactivity disorder 
(ADHD), 1031, 
1100–1101
Atypical absence seizures, 998
Atypical antidepressants, 1090–1093, 
1091
t
. 
See also
 
Atypical antipsychotics, 1081. 
See also
 
Antipsychotic drugs
for dementia/dementia-associated 
behavior problems, 59, 1035
diabetes and, 1084, 1084
t
t
, 
t
Atypical (complement-mediated) 
hemolytic-uremic syndrome, 
561, 561
t
Atypical facial pain, 
997
Atypical major depression, 1087, 1090

t
561, 561
t
997
mesenteric vascular disease and, 
 
490–491, 
491
renal artery stenosis/renal vascular 
hypertension and, 944
tibial/pedal artery disease and, 
486–487
transient ischemic attacks and, 1004
visceral artery insufficiency and, 
 
490–491
Atherosclerotic cardiovascular disease 
(ASCVD). 
See
 Atherosclerosis; 
Coronary heart disease
Atherosclerotic cardiovascular disease risk 
calculator, 365
Athletes
cardiovascular screening of, 
448–450
, 
449
t
, 450
t
head injury/concussion in, 1044
sports medicine injuries and, 
 
1690–1721
sudden death of, 426, 449, 450
t
Athlete’s foot, 120
f
, 
121–122
, 121
f
, 145
Athletic hypertrophy, 431
Atlanta classification, revised, 742, 
 
743–744
ATM
 (ataxia-telangiectasia) mutation
1636
Atomoxetine, 1099
Atonic seizures (epileptic drop attacks), 
998. 
See also
 Seizures
Atopic dermatitis, 
113–114
. 
See also
 
Eczema
Atopic disease (atopy), 890. 
See also
 
 Allergies/
allergic disorders/reactions
allergic bronchopulmonary mycosis 
and, 275, 893
t
allergic rhinitis and, 229, 230
asthma and, 253, 257
Atopic keratoconjunctivitis, 178
Atorvastatin, 367
t
, 381–382, 1268, 1272, 
1273
t
. 
See also
 Statins
with amlodipine, 473
t
in HIV infection/AIDS, 1369
peripheral arterial disease and, 484
for malaria, with proguanil (Malarone), 
1518
t
, 1520
t
, 1522, 1523, 
1523
t
for 
 infection, 1345
t
, 1362
t
, 
1555
ATP7B
 mutation, 725, 726
Atrial fibrillation, 31, 
401–407
, 402
t
, 404
t
, 
405
t
. 
See also
 Arrhythmias
arterial emboli and, 402
anticoagulation and, 402
t
, 403, 
 
403–406, 404
t
, 405
t
limb occlusion and, 487
retinal artery occlusion and, 195
stroke and, 402, 402
t
, 404, 404–406, 
404
t
, 405
t
, 407, 1009
transient ischemic attacks and, 1004, 
1005
asymptomatic/“subclinical, ” 402
with bradyarrhythmia (“tachy-brady 
syndrome”), 397
catheter ablation of, 396, 407
in hyperthyroidism/thyrotoxicosis, 
1141, 1147–1148
CMDT2019_Index_p1743-1884.indd   1757

INDEX1758
 
CMDT 2019
B-raf/BRAF
 gene/mutations
GI cancer, 678, 682, 1649, 1651
hairy cell leukemia and, 542
lung cancer and, 1627, 1628
B-type natriuretic peptide (BNP/beta)
in aortic regurgitation, 358
in aortic stenosis, 354
in cardiac trauma, 445
in cardiomyopathy, 428, 434
in dyspnea, 24
in heart failure, 416
in myocarditis, 426, 427
recombinant. 
See
 Nesiritide
Babesia divergens/duncani/microti/
venatorum
 (babesiosis), 
 
1524–1525
, 1525
f
Bacillary angiomatosis, 1353, 1483
Bacillary dysentery (
Shigella
 dysentery/
gastroenteritis), 1313
t
, 1316, 
1319
t
, 1322
t
, 1476
Bacillus,
 1319
t
anthracis,
 1319
t
, 1461, 1462
cereus,
 599
t
, 600, 1312
t
, 1314
Bacillus Calmette-Guérin (BCG). 
See
 BCG
Bacitracin/bacitracin/polymyxin, 179
t
Back pain, 83, 
1697–1699
, 1698
t
, 
 
1700–1701. 
See also
 
specific 
cause
disk-related, 
1700–1701
spinal cord compression causing, 1671
spinal stenosis causing, 
1699–1700
Background (nonproliferative) retinopathy, 
197, 1247
Baclofen, 709, 994, 1039
Bacteremia. 
See also
 Sepsis/septic shock
anaerobic, 
1485
 causing, 1478
gram-negative, 
1473–1474
health care–associated, 1209, 1301, 
1302, 1303
in listeriosis, 1463
neutropenia and, 1299, 1473
osteomyelitis and, 885
salmonella, 1319
t
, 
1475
staphylococcal, 
1456–1457
transfusion and, 553
vibrios causing, 1319
t
, 1477–1478
Bacterial infections, 1318–1320
t
, 
 
1448–1490
. 
See also
 
specific 
type and
actinomycosis, 1319
t
, 
1486
diarrhea in, 599
t
, 600, 600–601, 
 
1311–1314, 1312–1313
t
drugs for. 
See
 Antibiotics; Antimicrobial 
therapy
endocarditis, 
1464–1469
, 1465
f
, 1466
t
, 
1467
t
gram-negative, 1318
t
, 1318–1319
t
, 
1469–1485
gram-positive, 1318
t
, 1319
t
, 
 
1448–1464
meningitis, 1304, 1305, 1305
t
, 1306, 
1321
t
mycobacterial, 1319
t
, 
1487–1490
nocardiosis, 1319
t
, 
1486–1488
peritonitis, 613, 
614–616
, 717
procalcitonin and, 
1485
prostatitis, 968
t
, 
970–972
, 971
t
Azacitidine, 537, 1617
t
Azarcon toxicity, 1597
t
for autoimmune hepatitis, 707
for granulomatosis with polyangiitis 
873
669, 673
for myasthenia gravis, 1059
for myasthenic syndrome, 1059
for neuromyelitis optica, 1037
for pemphigus, 147
thiopurine methyltransferase variants 
and, 707
Azelastine, 181
t
, 229. 
See also
 
Azidothymidine (AZT). 
See
 Zidovudine
Azilsartan/azilsartan with chlorthalidone, 
468
t
Azithromycin, 1321
t
, 1322
t
, 1323
t
. 
See also
 
Macrolides
for diarrhea, 602, 1314, 1316
for endocarditis prophylaxis, 1467
t
for gonococcal infections, 1482
for Lyme disease, 1509
for MAC infections, 1361, 1487, 1488
for ophthalmic disorders, 179
t
t
, 1449
t
t
, 
1322
t
, 1453, 1473
for syphilis, 1496
Azo compounds, 662
Azoospermia, 981
f
, 982, 1686
artificial insemination for, 799
Y chromosome microdeletions causing, 
982
Azotemia. 
See also
 
Kidney disease/injury
in hepatorenal syndrome, 717
hypercalcemia/hyperparathyroidism 
and, 1168
in hyperglycemic hyperosmolar state, 
1259
hypocalcemia/hyperphosphatemia/
hypoparathyroidism and, 1162
parenteral nutritional support and, 1293
t
t
, 931
t
Aztreonam, for pneumonia, 279
t
, 285
t
B19 parvovirus infection. 
See
 Erythrovirus 
(parvovirus) infection
B-cell lymphoma, 543, 543
t
, 544. 
See also
 
Lymphoma; Non-Hodgkin 
lymphoma
and, 896
Epstein-Barr virus and, 1388
gastric, 1644–1645
intestinal, 1647
B cells
defects in, common variable 
immunodeficiency and, 896
pancreatic
in diabetes, 1220
hypoglycemia caused by tumors of, 
1261–1264
, 1262
t
, 1263
t
. 
 
See also
 Insulinomas; Islet cell 
tumors
Automobile accidents

1261–1264
, 1262
t
, 1263
t
. 
 
See also
tumors
cardiac injury and, 445
prevention of injury caused by, 17
Automobile driving
distracted, accidents and, 17
by patients with dementia, 59–60
by patients with syncope/ventricular 
tachycardia/sudden cardiac 
arrest, 413
by suicidal patients, 1089
Autonomic dysfunction. 
See
 
Dysautonomia
Autonomic failure, pure, 1003
Autonomic neuropathy, 1003
cancer-related/chemotherapy-induced, 
1022, 1679
in diabetes, 1249–1250. 
See also
 
Diabetic neuropathy
dysautonomia and, 1003, 1048
in porphyria, 1049, 1681
Autonomic testing
in dysautonomia, 1003–1004
in syncope, 413
Autophony
patulous eustachian tube and, 214
in superior semicircular canal 
dehiscence, 224
Autopsy, 81
Autosomal dominant polycystic kidney 
disease, 
962–963
, 962
t
, 963
f
Autosomal recessive syndromes, in 
diabetes, 1222
AV dissociation, 398
AV nodal reentrant tachycardia (AVNRT), 
399, 400
AV reciprocating tachycardia (AVRT), 399
Avanafil, 979–980
Avascular necrosis of bone (osteonecrosis), 
890
corticosteroid use and, 890, 1218–1219
in HIV infection/AIDS, 1349
of jaw, bisphosphonate use and, 890, 
1173
Aveeno, 108
t
Avelumab, 1666, 1668
Avian influenza, 1422, 
1425–1427
. 
See also
 
Influenza
AVNRT (AV nodal reentrant tachycardia), 
399, 400
Avoidance therapy
for allergic rhinitis, 133, 230
for contact dermatitis, 133
Avoidant personality disorder, 1077
t
, 1078
AVRT (AV reciprocating tachycardia), 399
Axicabtagene, 544
Axillary lymph nodes, in breast cancer, 758
adjuvant/neoadjuvant therapy and, 768
dissection of, 764, 764
f
arm edema and, 773–774
evaluation of, 757, 757
f
prognosis/recurrence and, 765
t
, 772, 
772
t
, 773
Axitinib, 1141, 1620
t
, 1668
Axonal injury, diffuse, 1043
t
Axonal neuropathies, 1047, 1051. 
See also
 
 Guillain-
Barré syndrome; Neuropathies
in critically ill patient, 1050
plasma cell myeloma/paraproteinemias 
and, 1049
toxic, 1050
CMDT2019_Index_p1743-1884.indd   1758

INDEX1759
 
CMDT 2019
Bendroflumethiazide/bendroflumethiazide-
nadolol, 461
t
, 464
t
Bends, 1576
Benign mole, 
110–111
, 110
f
Benign paroxysmal positioning vertigo 
(BPPV), 221, 222–223
Benign prostatic hyperplasia, 
983–988
, 
984
t
, 985
f
, 986
t
urinary incontinence and, 65, 66
Benign recurrent lymphocytic (Mollaret) 
meningitis, 1378
Bentall procedure, 355
Benzalkonium, 1589
Benzalkonium-free eye drops, 189
Benznidazole, 1512–1513
Benzocaine toxicity, 1603
Benzodiazepines, 1067–1068, 1067
t
, 1069
t
. 
See also
 
for alcohol detoxification/withdrawal, 
19, 1108, 1110
with antipsychotic agents, 1083
for anxiety/panic disorder, 1067–1068, 
1067
t
, 1068
drug interactions of, 1069
t
for hallucinogen overdose/toxicity, 1602
for hypertensive emergencies, 480
t
overdose/toxicity of, 1068, 1584
t
, 
 
1598–1599
sleep cycle affected by, 1102
for sleep-wake disorders/insomnia, 
1067
t
, 1102
withdrawal from, 1068
Benzoyl peroxide, 106
t
, 135
Benzoylecgonine, 1590
Benztropine, 1085, 1592
Bepotastine, 181
t
Berger disease (IgA nephropathy), 946
t
, 
948
f
, 
949–950
Beriberi, 1049, 1282. 
See also
 Thiamine 
(vitamin B
1
), deficiency of
Bernard-Soulier syndrome, 566, 567
Berry aneurysms, 1011, 1013. 
See also
 
Intracranial aneurysm
Berylliosis, 320
Besifloxacin, 179
t
for asthma
exacerbation management and, 259, 
262–263
t
, 265
f
, 266
f
, 267
long-acting, 258
f
, 259, 260
t
in pregnant patient, 834
short-acting, 254
f
, 255
t
, 258
f
, 259, 
262
t
, 264, 265, 265
f
, 266
f
, 267
Beta-adrenergic blocking drugs
for ACS (NSTEMI/STEMI), 381, 
 
387–388, 392
for angina, 372–374, 373
f
for anxiety disorders, 1068
for aortic dissection, 496–497
for arrhythmias, 393, 421
atrial fibrillation, 389, 403, 1148
supraventricular tachycardia, 
 
389, 400
ventricular tachycardia, 410, 410–411
t
for cardiomyopathy, 429, 432, 433
f
, 434, 
446
depression caused by, 1088
for esophageal varices, 628
Basal cell carcinoma
of skin, 
151–152
, 151
f
eyelid involvement and, 175
of vulva, 789, 790
Basal cell nevus syndrome, 151
Basal energy expenditure (BEE), 1278, 
1289
Basedow disease, 1139–1140. 
See also
 
Graves disease; 
Basic life support, drowning and, 1570
Basilar artery migraine, 991
Basilar artery occlusion, 1007
t
, 1008
Basilar meningitis, in syphilis, 1497, 1500
Basilar skull fracture, 223, 1043
“Bath salts, ” 1590
Bathing, in dermatologic therapy, 103
Battered child/elderly. 
See
 Child abuse; 
Elder abuse/mistreatment
Battered woman. 
See
 Domestic violence
Batteries (disk/button), ingested, 1590
Battle sign, 1043
Baylisascaris procyonis,
 1545
Bazedoxifene, 1174
BCG, for bladder cancer, 1666
BCG vaccine, 295
tuberculin skin test affected by, 4, 290, 
295
tuberculosis blood tests/interferon 
gamma release assays and, 4, 
290, 291, 1344
bcl-2/BCL2
 expression, 543, 544
BCLC (Barcelona Clinic Liver Cancer) 
staging system, 1632
bcr/abl
 fusion gene, 534, 535, 540
Beau lines, 169
Becaplermin, 165, 1249
Becker muscular dystrophy, 1060, 1061
t
Beclomethasone, 229, 262
t
Bed rest. 
See also
 Immobility
for frostbite, 1569
hazards of, 62
hypercalcemia and, 1167
for lumbar disk herniation, 1700
Bedbugs, 159
Bedside Index for Severity in Acute 
Pancreatitis (BISAP), 742
Bedside tracheotomy, 248
Beef tapeworm 
(T saginata),
 
1538
Beer potomania, 901
Behavioral problems, in dementia, 59, 
1034–1035
Behavioral-variant frontotemporal 
dementia, 1032
t
Behçet syndrome, 
876
uveitis in, 189, 876
Bejel (endemic syphilis), 1503
Belching (eructation), 598
Belimumab, 855
Bell palsy, 
1054
, 1054
f
. 
See also
 Facial 
neuropathy/paralysis/palsy
herpes infection and, 225, 997, 1054, 
1378, 1380
Belladonna
MAOI interactions and, 1095
t
overdose/toxicity of, 1593
Belly-press test, 1693
t
, 1694
Benazepril/benazepril combinations, 
 
466
t
Bence Jones proteinuria (light chain in

1378, 1380
t
t
, 1694
 
466
t
Bence Jones proteinuria (light chain in 
urine), 546, 547, 927, 933, 964
Bendamustine, 1616
t
rhinosinusitis (sinusitis), 
226–228
, 
1322
t
vaginosis, 781, 781
f
, 782, 1309
Bacterial overgrowth, 
648–649
diarrhea and, 603, 604
f
, 605, 648
vitamin B
12
 deficiency and, 517, 648
Bacterial synergistic gangrene, 1485
Bacteriuria, during pregnancy, 834
 1318
t
, 1321
t
, 1484
abdominal sepsis caused by, 1321
t
fragilis,
 1484
melaninogenicus
. 
See
 
Prevotella/
BAD-1 protein, 1559
Bagassosis, 319
t
Baker (popliteal) cyst, 1705, 1706, 1709
BAL (British anti-Lewisite). 
 
See
 Dimercaprol)
Balance. 
See
 Falls; Vestibular disorders
Balanitis
candidal, 140
in chancroid, 1482
in reactive arthritis, 880, 880
f
Balanoposthitis, in diabetes, 1224
Baldness. 
See
 Alopecia
Balint syndrome, 1016
Balkan nephropathy, 1666
Balloon angioplasty, coronary. 
See
 
Percutaneous coronary 
Balloon expulsion test, 596
Balloon pump, intra-aortic (IABP), 390, 
391
Balloon tube tamponade, 627
Balloon valvuloplasty. 
See
 Valvuloplasty
Balsalazide, 662, 672
Bamboo spine, 878
Band keratopathy, 1165
Banding (band/variceal ligation)
for esophageal varices, 608, 624, 627, 
628, 729
for hemorrhoids, 683
Bankart lesion, 1695
Barbiturates. 
See
 Opioids/opioid 
analgesics; Sedative-hypnotics
Barcelona Clinic Liver Cancer (BCLC) 
BARD score, 713
Bariatric surgery, 13, 1279–1280
in diabetes, 1244
hypoglycemia after, 1265
in hypogonadism, 1203
Baritosis, 318
t
Barium enema, for cancer screening, 1656
Barium esophagography, 618, 619, 625, 
629, 630, 1639
Barotrauma, 
214
, 330, 1576
Barrett esophagus, 620, 1638
Bartholin duct cyst/abscess, 
783
, 783
f
Bartonella henselae/quintana
 
(bartonellosis), 
1483
bacillary angiomatosis caused by, 1353, 
1483
endocarditis caused by, 1468, 1483
in HIV infection/AIDS, 1353, 1361, 
1483
lymphadenitis/lymphadenopathy in, 
250, 503, 1483
pediculosis and, 158, 1483
Bart’s hemoglobin, 515
Bartter syndrome, 906
t
CMDT2019_Index_p1743-1884.indd   1759

INDEX1760
 
CMDT 2019
pancreatitis and, 735, 737, 738, 740, 741, 
742, 744
pre- and postcholecystectomy 
syndromes, 
735–736
pregnancy and, 
837–839
primary sclerosing cholangitis, 
739–741
strictures, 
738–739
Bilirubin levels, 688, 690
t
. 
See also
 
in liver disease/jaundice, 688, 690
t
, 709, 
720, 720
t
, 728
urine, 690
t
Bilirubinate, calcium, in gallstones, 732
Billowing mitral valve. 
See
 Mitral valve 
prolapse
Biloma, 738
Bimatoprost/bimatoprost combinations, 
184
t
Binge eating. 
See
 Bulimia nervosa
Biologic response modifiers, 1624
t
. 
See also
 
specific agent and disorder
infections in patient taking, 1298
Biologic therapies, for inflammatory bowel 
disease, 663–665
Biomarkers
in breast cancer, 762, 762–763, 772. 
 
See also
 Hormone receptor sites
cardiac. 
See
 Cardiac biomarkers/
enzymes
Bioprostheses, cardiac. 
See
 Valve 
Bioterrorism
anthrax and, 1461
botulinum toxin and, 1460
chemical warfare agents and
nerve agents, 
1595
, 1605
ricin, 
1595–1596
skin decontamination and, 1584, 
1595
/Q fever and, 1445
plague and, 1480
 and, 1436
smallpox/smallpox vaccine and, 1431
tularemia 
(Francisella tularensis)
 and, 
1479
Bipolar disorder, 1088, 1097–1099, 1099
t
. 
See also
 Depression; Mania
drug therapy/lithium for, 1088, 
 
1097–1099, 1099
t
pregnancy risks and, 1097, 1098
prognosis for, 1100
schizophrenia and, 1080, 1082
Bipolaris,
 1561
Bird-fancier’s lung, 319
t
Bird mites. 
See
 Mites
Birds
avian influenza and, 1425–1426, 1426
bird-fancier’s lung and, 319
t
histoplasmosis and, 1552
psittacosis (ornithosis) and, 1492
West Nile encephalitis and, 1401
Birt-Hogg-Dubé syndrome, 1667
Birth classes, 813
Birth control. 
See
 Contraception
Birth control pills. 
See
 Oral 
 
contraceptives
Bisacodyl/bisacodyl suppository, 597
t
BISAP (Bedside Index for Severity in 
Acute Pancreatitis), 742
in comatose patient, 1255
t
in diabetic ketoacidosis, 1255, 1255
t
in fluid management, 925
t
gastrointestinal loss of, acidosis caused 
by, 920, 920
t
t
lithium interactions and, 1099
t
t
, 918, 
921
t
, 922, 
922
t
, 923
in normal anion gap/renal tubular 
acidosis, 920, 921
t
, 924
t
, 924
for salicylate poisoning, 1606
for tricyclic antidepressant overdose, 
1581, 1582, 1610
for urinary alkalinization, 1585
urinary anion gap and, 920, 920
t
, 921
in metabolic alkalosis, 923
in renal tubular acidosis, 920
Bictegravir, 1365
t
, 1371. 
See also
 
Bicuspid aortic valve, 352, 353, 355, 358, 
359
Bier block, 1589
Bifascicular block, 398
 probiotic, 659
“Big gastrin, ” 1195
Bigeminy, 409
Biguanides, 1230
t
, 1599
Bile acid-binding resins, 1272–1274
Bile ducts. 
See also
 
under Biliary
carcinoma of. 
See
 Cholangiocarcinoma; 
Periampullary/ampullary 
carcinoma
stones in. 
See
 Choledocholithiasis
Bile salt binders, 605, 649, 658, 668
Bile salt malabsorption, 605, 649
Bilharziasis, 
1535–1536
. 
See also
 
Schistosoma
Biliary cholangitis
drugs/toxins causing, 711
primary (primary biliary cirrhosis), 707, 
721–723
Biliary obstruction
in choledocholithiasis/cholangitis, 736
jaundice caused by, 688–690, 689
t
, 691, 
737
in pregnant patient, 838
Biliary pancreatitis, 735, 737, 738, 740, 
741, 742, 744
Biliary sludge (microlithiasis), 732, 743
Biliary stricture, 
738–739
pancreatitis and, 738, 746
Biliary tract disease, 
731–741
, 733
t
. 
 
See also
 
carcinoma, 
1634–1636
cholecystitis, 
733–735
, 733
t
, 838
choledocholithiasis/cholangitis, 733
t
, 
736–738
cholelithiasis (gallstones), 
731–733
, 
733
t
, 838
dyspepsia and, 590
in fascioliasis, 1536
in HIV infection/AIDS, 1351
inflammation. 
See
 Cholangitis

t
, 
736–738
731–733
, 
733
t
, 838
See
nausea and vomiting in, 592, 592
t
Beta-adrenergic blocking drugs (
Cont
.):
for glaucoma/ocular hypertension, 183
t
, 
188
in heart failure, 387, 417
f
, 418
t
, 420, 421
for hypertension, 460–465, 463–464
t
, 
476
f
, 477, 481
t
, 482, 496–497
hypoglycemia and, 1246, 1266
for mitral valve prolapse, 352
overdose/toxicity of, 460–465, 1581, 
1593–1594
perioperative, 47, 48
t
and, 465, 1193
during pregnancy, 446
Beta-carotene, 11, 1285
Beta-catenin, 731
Beta-globin gene/chain/cluster region, 514, 
515, 522
Beta-glucan/beta-D-glucan levels, in 
1344, 1555
Beta-glucocerebrosidase deficiency, 1685
Beta-2-glycoprotein I antibodies
t
Beta-hCG. 
See
 Human chorionic 
Beta-hemolytic streptococci. 
See
 
specific 
type under Group
Beta-hydroxybutyrate/hydroxybutyric acid
in alcoholic ketoacidosis, 919
in diabetes/diabetic ketoacidosis, 919, 
1255, 1256
in insulinoma, 1262, 1262
t
3-Beta-hydroxysteroid dehydrogenase 
deficiency, 1209
Beta interferon. 
See
 Interferon-beta
Beta-lactam antibiotics, 279
t
, 281, 282, 615
Beta-natriuretic peptide. 
See
 B-type 
natriuretic peptide
Beta-thalassemia syndromes, 515, 
 
515–516, 515
t
, 516
t
, 524
Betaine, 1686
Betamethasone, 105
t
, 825
Beta-2-microglobulin amyloidosis, 550
Betaxolol/betaxolol combinations, 183
t
, 
188, 463
t
Bethesda assay, 568, 572
Bethesda criteria, 681, 682
Bethesda System
for Pap smear classification, 783
t
, 784
for thyroid nodules, 1150
Betrixaban, 575–576
t
, 578
t
Bevacizumab, 193, 194, 197, 1619
t
, 1652, 
1668
Bexarotene. 1119–1120, 1120
Bezlotoxumab, 661
Bezold-Jarisch reflex, 369
Bicalutamide, 1207–1208, 1623
t
, 1662
t
t
for acidosis
diabetic ketoacidosis, 1257
increased anion gap acidosis, 918, 921
lactic acidosis, 1261
normal anion gap/renal tubular 
acidosis, 922
in chronic kidney disease, 923, 941
CMDT2019_Index_p1743-1884.indd   1760

INDEX1761
 
CMDT 2019
disorders of, 
510–555
. 
See also
 
screening, 553–554
for dengue virus, 1414–1415
for hepatitis, 553, 554, 695, 697, 698
for HIV , 553, 554, 1340, 1359
for HTLV , 553, 1408
for West Nile virus, 553, 1401, 1402
in stool. 
See
 Dysentery; Fecal occult 
blood testing
transfusion of. 
See
in urine. 
See
 Hematuria; 
Blood alcohol level, 1106, 1598
Blood dyscrasias. 
See also
 Bleeding
retinal disorders associated with, 
198
Blood flukes, 
1535–1536
Blood gases. 
See
 Arterial blood gases; 
Venous blood gases
Blood glucose levels. 
See
 Glucose, blood 
levels of
Blood glucose meters, 1226
Blood loss. 
See
 Bleeding
Blood pressure. 
See also
 Hypertension; 
cardiovascular/heart disease and, 6
t
, 
10–11, 336, 369, 373
f
, 375, 
383, 390, 429
in hypertension, 451, 452
f
, 456
treatment goals/thresholds and, 10, 
458–459, 458
t
urgencies/emergencies, 451, 479, 
 
480
in hypotension/shock, 506, 508
measurement of, 
451–453
, 452
f
, 453
t
orthostatic changes in. 
See
 Orthostatic 
(postural) hypotension
in poisoning/drug overdose, 1581, 1582, 
1586
Blood pressure screening/hypertension 
assessment/diagnosis, 6
t
, 
10–11, 451–453, 452
f
, 453
t
Blood transfusion. 
See
Blood (compatibility) typing, 552
Blood urea nitrogen (BUN), 928, 928
t
in acute kidney injury, 930, 930–931, 
930
t
, 933, 935
in diabetic ketoacidosis, 1255
1259
monitoring, in feminizing hormone 
therapy, 1740
t
Blood urea nitrogen:creatinine ratio, 
 
928
930
t
, 935
Blood vessels. 
See
 
specific type and under 
Vascular
Blowout fracture, of orbital floor, 205
“Blue bloaters, ” 268, 269
t
Blue nevi, 
111
, 111
f
Blumer shelf, 1642
Blunt trauma. 
See
 Trauma
Blurred vision. 
See
 Visual impairment/loss
BMI (body mass index), 1277. 
See also
 
Obesity/overweight
BMPR1A
 gene, 681
Bocavirus, 1430
Boceprevir, 703
BODE index, 273
Body cavity (primary effusion) lymphoma, 
1391
cyclophosphamide/ifosfamide causing, 
1675
t
, 1679
neuropathies, chemotherapy-induced, 
1679
Bladder training, 66
Blalock shunt (classic/modified), 341
Blast cells, in myelodysplastic syndromes, 
536
Blastomycosis, 
1559
South American 
(paracoccidioidomycosis), 
1559–1560
Bleeding/blood loss, 
556–588
, 557
t
. 
 
See also
 
Coagulopathy; 
anticoagulation therapy and, 207
t
, 310–
311, 406, 576
t
, 582, 585
t
, 1591
in cirrhosis/liver disease, 
572–573
, 715
coagulation disorders causing, 
567–573
. 
See also
 Coagulopathy
in DIC, 564, 564
t
, 573
in essential thrombocytosis, 532
fibrinolytic therapy and, 386
See
 Gastrointestinal 
bleeding
iron deficiency and, 510, 511
t
perioperative risk evaluation/
management and, 46, 47
t
, 
51–52, 52
t
platelet/disorders and, 
556–567
, 557
t
in polycythemia vera, 530
during pregnancy, 557
t
, 820, 821, 
 
827–828
premenopausal/postmenopausal. 
See
 
rectal. 
See
 Rectal bleeding
retinal disorders and, 198
shock caused by, 505, 505
t
, 506, 507
vaginal. 
See
 Menstruation; Vaginal 
bleeding
Bleeding history, directed, 46, 47
t
, 51
Bleeding scans, 610
Bleomycin, 150, 1622
t
, 1670
Blepharitis, 118, 
175
Blepharospasm, 1029
Blinatumomab, 540
Blind loop syndrome, 517
Blindness. 
See also
 
disorders causing and
 
Visual impairment/loss
age-related macular degeneration 
causing, 193
cataract causing, 191
cortical, 1016
diabetic eye disease and, 197
“fleeting” (amaurosis fugax), 196, 488, 
1008
in giant cell arteritis, 868
glaucoma causing, 188
river (onchocerciasis), 
1547–1548
snow, 205
trachoma causing, 177
vitamin A deficiency and, 1285
Blister, burn, 1571
“Blister” cells, 521
Blistering (bullous) skin disorders, 104
t
, 
146–148
. 
See also
 
Bloating (abdominal), 598–599
Blood. 
See also
 Bleeding/blood loss
contaminated, 553
Bisexual health.

t
, 
146–148
. 
See also
 
Blood. 
See also
Bisexual health. 
See
 Gay and bisexual 
men/MSM; Lesbian and 
bisexual women
Bismuth compounds
for diarrhea, 602, 675
traveler’s diarrhea and, 602, 816, 1316
in 
H pylori
 eradication/peptic ulcer 
disease, 637–638, 638, 638
t
, 
639
salicylate overdose/toxicity and, 1606
Bisoprolol/bisoprolol-HCTZ, 418
t
, 420, 
429, 463
t
Bisphosphonates. 
See also
 
in breast cancer management, 767, 
 
768–769
and, 912, 1167, 1168, 1173
metabolic bone disorders/renal 
osteodystrophy and, 940
t
osteonecrosis of jaw and, 890, 1173
for osteoporosis, 11, 1172–1173, 1707
in androgen deprivation, 1663
corticosteroid use and, 263, 1219
for Paget disease of bone, 1179
for thyroid cancer bone metastases, 
1156
“Bite” cells, 521
Bites. 
See
 Animal bites; Human bite 
wounds; Insect bites
Bithionol, 1537
Bitot spots, 1285
Bitter almonds odor, in cyanide poisoning, 
1596
for ACS (NNSTEM/STEMI), 380
f
, 381
for heparin-induced thrombocytopenia, 
563, 563
t
Biventricular pacing (resynchronization). 
See also
 Pacemaker
for heart failure/cardiomyopathy, 417
f
, 
422, 429, 432
for mitral regurgitation, 350
f
, 351
Black eye, 205
in nasal trauma, 232
Black fever. 
See
 Visceral leishmaniasis
Black molds, 1561
Black patients
hypertension management and, 460, 
465, 475, 477
t
, 478
Kaposi sarcoma in, 154, 1354
sickle cell anemia/syndromes in, 522
Black plague, 1480
Black widow spider bite, 159, 425
t
, 
 
1608
Bladder
biopsy of, in bladder cancer, 1665
cancer of, 1612
t
, 1615
t
, 
1664–1666
thiazolidinedione use and, 1234
disorders/dysfunction of. 
See
 
specific 
type and
 Urinary incontinence
infection of. 
See
 Cystitis
neuropathic
chemotherapy-induced, 1679
in diabetes, 1250
painful (interstitial cystitis), 44, 
974
paraganglioma of, 1190
Bladder catheterization
for urinary incontinence, 67
urinary tract infection and, 968, 1301, 
1302, 1303
Bladder toxicity
CMDT2019_Index_p1743-1884.indd   1761

INDEX1762
 
CMDT 2019
GI cancer and, 678, 682, 1649, 1651
Brain
vasculitis of (primary angiitis of central 
nervous system), 
876–877
Zika virus affecting development of, 
1418
Brain abscess. 
See
 Abscesses
Brain death, 
1041–1042
organ donation and, 81, 1041
Brain edema. 
See
 Cerebral edema
Brain imaging. 
See
 Neuroimaging
Brain injury, traumatic, 1042, 1044
Brain natriuretic peptide. 
See
 B-type 
Brain stimulation
for depression, 1096
for idiopathic torsion dystonia, 1029
for OCD, 1070
for seizures, 1001
Brain tumors, 
1016–1020
, 1017–1018
t
, 
1019. 
See also
 Intracranial 
masses/tumors
Brainstem
herniation of, lumbar puncture and, 
1305, 1306
ischemia of, seizures differentiated 
from, 1000
lesions/tumors/infarction of, 1016, 
1017
t
coma/stupor caused by, 1041
vertigo caused by, 224
Bran, dietary (bran powder), 597
t
. 
See also
 
Fiber, dietary
Branch retinal artery occlusion, 
195–196
Branch retinal vein occlusion, 
194–195
, 
194
f
Branchial cleft cysts, 
249
Brandt-Daroff exercises, 223
Brazilian spotted fever, 1440
BRCA1/BRCA2
 genes
breast cancer and, 754, 754
t
, 771
in male, 775
ovarian cancer and, 794
pancreatic/periampullary carcinoma 
and, 1636
Breast, 
750–775
abscess of, 752, 
753
, 828
augmented, 
753
. 
See also
 Breast 
implants
benign disorders of, 
750–753
biopsy of
in breast mass evaluation, 750, 
 
758–760, 759
f
, 760
f
in fat necrosis, 752
in fibroadenoma, 751
in fibrocystic condition, 750, 751
mammographic localization, 760
stereotactic, 760
ultrasound-guided, 760
cancer of. 
See
 Breast cancer
density of, cancer risk/mammography 
and, 754, 755
examination of
in cancer follow-up, 773
in cancer screening/early detection/
mass evaluation, 15
t
, 756, 
757–758, 757
f
fat necrosis of, 
752
fibroadenoma of, 
751
in myeloma, 546, 547
in neutropenia, 528, 528
t
in primary myelofibrosis, 533
in thrombocytopenia
failure and, 
556–558
infiltration and, 
558
Bone marrow/stem cell transplantation. 
See also
 
adenovirus infection and, 1428–1429
aspergillosis after, 1299, 1557
CMV infection and, 1299
immunizations and, 
1325–1337
, 1333
t
infection and, 1297
Bone metastases, supportive care agents 
for, 1676
t
Bone-modifying agents, for 
chemotherapy-induced 
toxicity, 1676
t
Bone morphogenic receptor protein 1A 
(BMPR1A)
 gene, 681
Bone scanning
for breast cancer metastases, 758
for prostate cancer metastases, 1658
Borderline leprosy, 1489, 1490
Borderline personality disorder, 1077, 
1077
t
, 1078
Bordetella
 infection
bronchiseptica,
 1470
pertussis
, 1469–1470. 
See also
 Pertussis
Bornholm disease (epidemic pleurodynia), 
1434
Borrelia
 (borreliosis)
afzelii,
 1507
, 1319
t
, 1505. 
See also
 Lyme 
disease
garinii,
 1507
miyamotoi,
 1443
recurrentis,
 1319
t
relapsing fever caused by, 1319
t
, 1503
Borrelial lymphocytoma, 1506
Bortezomib, 209
t
, 548, 1619
t
, 1679
Bosentan, for scleroderma, 861
Bosutinib, 535, 1620
t
Botox. 
See
 Botulinum toxin therapy
Botulinum toxin, 1059, 1460
Botulinum toxin therapy
for achalasia, 629
for focal torsion dystonias, 1029
for migraine prophylaxis, 992, 992
t
for urinary incontinence, 66
Botulism, 
1059–1060
, 1312
t
, 
1460
Botulism antitoxin, 1060, 1460
Bouchard nodes, 841, 842
f
Bougie dilators. 
See
 Esophageal dilation
Boutonneuse fever, 1437
t
, 1442
Boutonnière deformity, 852
Bouveret syndrome, 732
Bovine spongiform encephalopathy 
(vCJD/mad cow disease), 
1406
Bowen disease, 
126
Brachial plexus
lesions/neuropathy of, 
1055–1058
in thoracic outlet syndromes, 887
Brachytherapy. 
See
 Radiation therapy
Bradycardia/bradyarrhythmias, 393, 
 
396–397
in myocardial infarction, 383, 389
persistent (sick sinus syndrome), 397
t
, 1594
BRAF/B-raf
Body fat, in obesity, 1277. 
See also
 
diabetes and, 1222, 1224

t
, 1594
See also
 
Body fluid precautions (universal). 
 
See
 Body substance isolation
Body lice, 158, 159. 
See also
 Lice
Body mass index (BMI), 1277. 
See also
 
Body substance isolation/universal 
precautions, 1302
hemorrhagic fevers and, 1413
HIV infection/AIDS prevention and, 
1358
monkeypox and, 1431
Body (core body) temperature
in burn injury, maintaining, 1572
elevated, 34–37. 
See also
 Fever; 
Hyperthermia
cholinergic urticaria caused by, 141
FUO and, 1295
in hyperthermia/heat exposure, 1565, 
1566
in hypothermia, 1566, 1567
maintenance of, 1564
normal, 35
Body water, 898, 899
t
. 
See also
 Fluid 
management/hydration
water deficit calculation and, 904
Body weight. 
See
 Weight
Boerhaave syndrome, 593
Boils (furunculosis), 
161–163
, 1322
t
, 
1353, 1450
t
, 1455
Bone
adynamic disease of, 940
avascular necrosis of (osteonecrosis). 
See
 Avascular necrosis of bone
in HIV infection/AIDS, 1349–1350
in hypercalcemia/hyperparathyroidism, 
939, 940, 940
f
, 1164
infections of, 
884–886
, 
1456
. 
See also
 
t
metabolic disease of. 
See
 Metabolic 
bone disease
in myeloma, 546, 547, 548
Paget disease of, 
1178–1179
pheochromocytoma/paraganglioma 
involving, 1194
SGLT2 inhibitor use affecting, 1237
in syphilis, 1499
tuberculosis of, 294, 
886
Bone alkaline phosphatase
in hypophosphatasia, 1176, 1177
in Paget disease, 1178
Bone density/bone density measurements/
bone densitometry, 
 
1171–1172
in hyperparathyroidism, 1164, 1166
in osteoporosis, 11, 810, 1171–1172, 
1707
SGLT2 inhibitor use and, 1237
Bone marrow
antipsychotic drug use and, 1084
in aplastic anemia, 526
in cancer chemotherapy, 
1677
in leukemia, 535, 538, 539, 541
in lymphoma, 544
methotrexate affecting, 851, 1679
in myelodysplastic syndromes, 536–537
CMDT2019_Index_p1743-1884.indd   1762

INDEX1763
 
CMDT 2019
in breast cancer, 757
in fibrocystic condition, 751
Breast surgery, 763–764, 764
f
. 
See also
 
Lumpectomy; Mastectomy
reconstruction/implants after, 753, 774
Breastfeeding. 
See
 Lactation
Breath tests
in bacterial overgrowth, 605, 648
for carbohydrate/lactose intolerance, 
650
in 
H pylori
 infection, 590, 634, 637
Breathing. 
See also
 
under Respiratory
in burn injury, 316, 1571
in coma/stupor, 1041, 1581
sleep-related disorders of, 241–242, 
327–329
, 1103. 
See also
 Sleep 
apnea hypopnea
Breathing exercises, for COPD, 272
Brentuximab, 545, 546, 1619
t
Bridging anticoagulation, 51, 363, 364
t
Brief psychotic disorders, 1079
Brigatinib, 1628
Brill-Zinsser disease, 1436, 1438
Brimonidine/brimonidine combinations
t
, 
184
t
, 188, 189
overdose/toxicity of, 1596
Brincidofovir, 1390, 1429, 1431
Brinzolamide/brinzolamide combinations, 
184
t
British anti-Lewisite (BAL). 
See
 
Dimercaprol
Brivaracetam, 995
t
Broca aphasia, 1008. 
See also
 Aphasia
Brodifacoum poisoning, 1591
“Broken heart syndrome, ” 430. 
See also
 
Stress cardiomyopathy
Bromfenac, 182
t
Bromocriptine. 
See also
 Dopamine 
agonists
for cocaine withdrawal, 1113
for diabetes, 1231
t
, 1237
for hyperprolactinemia/prolactinoma, 
1130
1085, 1584, 1592
for ovulation induction, 799
Brompheniramine, 229
Bronchi, foreign body in, 
248–249
Bronchial carcinoid tumors (bronchial 
adenomas), 
299
, 1195, 1196
Bronchial gland carcinoma, 1612
t
Bronchial obstruction, 252–253
Bronchial provocation testing, 256
Bronchiectasis, 
274–275
COPD differentiated from, 270
cystic fibrosis and, 274, 276
in measles, 1392
Bronchiolitis, 
277
adenoviruses causing, 1429
constrictive (obliterative/bronchiolitis 
obliterans), 277, 320
with organizing pneumonia (BOOP/
cryptogenic organizing 
pneumonia/pneumonitis/
COP), 277, 302
t
, 303
diffuse panbronchiolitis, 277
follicular, 277
metastatic, 758, 761, 768–772, 769
t
, 772, 
772
t
MRI in detection/evaluation of, 15, 756
nipple discharge in, 752, 752
t
, 757, 760
noninvasive, 761, 761
t
, 762
oral contraceptive use and, 802
Paget, 126, 126
f
, 757, 757
f
, 761
pain and, 757
and, 1636
pathologic types of, 760–761, 761
t
pregnancy affecting risk of, 754, 754
t
, 
774
pregnancy and, 754, 754
t
, 761–762, 774
prevention of, 755
prognosis for, 762, 772–773, 772
t
recurrence of, 762–763, 773
breast reconstruction/implants and, 
753, 773
self-examination in detection/evaluation 
of, 15
t
, 756
staging of, 760, 764, 764
f
, 772, 772
t
survivorship issues and, 773–774
treatment of, 1614
t
adjuvant systemic, 763, 764–767, 765
t
biomarkers/hormone receptor status 
and, 762, 763, 764, 766–767, 
768
bisphosphonates in, 767, 768–769
breast-conserving, 763–764, 764
f
chemotherapy in, 762, 775, 1614
t
adjuvant/neoadjuvant, 763, 
 
765–766, 767–768
palliative, 771
pregnancy and, 761–762
choice/timing of primary therapy 
and, 763
curative, 763–768, 764
f
, 765
t
endocrine therapy in, 762, 763, 764, 
766–767, 768, 769–770, 769
t
, 
775
follow-up, 773–774
mastectomy in, 764
neoadjuvant, 763, 767–768
palliative, 768–772, 769
t
during pregnancy/lactation, 
 
761–762
radiation therapy in, 763, 764, 
 
768–769
surgical resection, 763–764, 764
f
, 775. 
See also
 Lumpectomy; 
Mastectomy
targeted therapy in, 766–767, 
 
769–771, 769
t
“triple-negative, ” 762, 768, 771
ultrasonography in detection/evaluation 
of, 750, 756, 758, 759
f
, 760
Breast-conserving therapy, 763–764, 
 
764
f
local recurrence and, 773
for noninvasive (ductal/lobular) 
carcinoma, 762
during pregnancy, 761
with radiation, 763, 764
Breast implants, 
753
, 774
Breast milk. 
See
 Lactation
fibrocystic condition and. 
See
 
Fibrocystic breast condition
male
carcinoma of, 
774–775
disorders/enlargement of, 
 
1204–1205

753
, 774
See
 Lactation
See
 
male
774–775
 
1204–1205
, 1204
t
. 
See also
 
mass/lump in. 
See
 Breast cancer; Lump 
(breast)
nipple discharge and, 
752
, 752
t
, 760
phyllodes tumor of, 751
reconstruction of after mastectomy, 753, 
773, 774
self-examination of, 15
t
, 756
Breast cancer, 
753–775
, 1612
t
, 1614
t
anatomic locations of, 757, 757
f
arm edema and, 758, 773–774
bilateral, 762
biomarkers/gene expression profiling 
and, 762–763, 772
biopsy in diagnosis of, 758–760, 759
f
, 
760
f
breast reconstruction/implants and, 753, 
774
clinical examination in. 15
t
, 756, 
 
f
, 773
clinical findings in, 15
t
, 756–760, 757
f
, 
759
f
, 760
f
cytologic evaluation of, 758–759, 760
differential diagnosis of, 760
ductal
in situ, 761, 761
t
, 762
invasive/infiltrating, 761
t
early detection/screening for, 755–756
clinical findings and, 15
t
, 756–760, 
757
f
, 759
f
, 760
f
genetic testing and, 754
in lesbian and bisexual women, 1729
in transgender patients, 1741
estrogen replacement therapy and, 754, 
810, 1211, 1212, 1213
fibrocystic condition and, 750, 751, 754, 
754
t
genetic mutations in, 754, 754
t
. 
See also
 
 genes
gestational. 
See
 Breast cancer, in 
pregnancy
HER2 overexpression/
HER2
 gene in, 
761, 762
prognosis and, 762, 765
t
, 772
therapy and, 763, 764, 765, 766, 
 
767–768, 770
hypercalcemia and, 758, 1673
incidence/risk/mortality of, 753–755, 
754
t
in male, 774
inflammatory, 761
t
, 762
invasive, 761, 761
t
lobular
in situ, 761
t
, 762
t
in male, 
774–775
, 1205
mammography in detection/evaluation 
of, 14–15, 15
t
, 755, 755–756, 
758, 759
f
, 760
f
. 
See also
 
CMDT2019_Index_p1743-1884.indd   1763

INDEX1764
 
CMDT 2019
Bypass tracts (accessory AV pathways), 
399, 400, 
400–401
Byssinosis, 320
C3 glomerulopathies/glomerulonephritis, 
935, 
952–953
C282Y
 mutation, 710, 723, 724, 1631
c-
myc
 gene, 543
C-peptide
in factitious hypoglycemia, 1266
insulinoma secreting, 1195, 1262, 1262
t
C-reactive protein, coronary heart disease 
risk and, 1269
C-urea breath testing. 
See
 Urea breath 
testing
CA 15-3, in breast cancer, 758
CA 19-9
in cholangiocarcinoma, 740, 1635
1636
CA 27-29, in breast cancer, 758
CA 125, in ovarian tumors, 794
Cabazitaxel, 1618
t
, 1662
t
, 1663
Cabergoline, 208
t
, 799, 1127, 1129–1130, 
1187
Cabotegravir, 1371. 
See also
therapy
Cabozantinib, 1157, 1668
Cachexia
“cardiac, ” 38
diabetic neuropathic, 1249
in protein-energy malnutrition, 1276
in terminally ill/dying patient, 77
Cadherin cell adhesion protein, 1642
CADM 140 antibody, 862
t
Café au lait spots, 1023
“Café coronary”/food aspiration, 
317
Cafergot, 991
Caffeine, 
1113–1114
for migraine headache, 991
overdose/toxicity of, 1114, 
1608–1609
during pregnancy, 812, 813
Caffeinism, 1114
cagA
 gene, 633
Calabar swellings, 1549
Calcaneofibular ligament, ankle sprains 
and, 1720
Calcifediol, 1177
Calciferol, 1162
t
Calcific (degenerative) aortic stenosis, 
 
353
Calcinosis, in hypercalcemia/
hyperparathyroidism, 1165
Calciphylaxis, in hypercalcemia/
Calcipotriene, 116
Calcitonin (serum), in thyroid cancer, 
1154
Calcitonin/nasal calcitonin-salmon, 912, 
1174, 1673
Calcitriol (1,25-dihydroxycholecalciferol)
for hyperparathyroidism, 1168
for hypocalcemia/hypoparathyroidism/
tetany, 1162–1163, 1162
t
, 
1163
for hypophosphatemic osteomalacia, 
1177
for metabolic bone disorders/renal 
osteodystrophy, 940, 1168
after parathyroidectomy, 1169
Calcitriol ointment, for psoriasis, 116
Bufotenin, 1597
Bulbar palsy, progressive, 1046
Bulbar poliomyelitis, 1397, 1398
Bulimia nervosa, 
1281–1282
Bullectomy, 273
Bullous impetigo, 131–132, 131
f
, 1353
Bullous pemphigoid, 
148
Bullous (blistering) skin disorders, 104
t
, 
146–148
. 
See also
 
specific 
 
type
Bumetanide, 390, 418, 424, 461
t
, 482
Bundle branch block, 398
in atrial septal defect, 337
in myocardial infarction, 384, 390
ventricular tachycardia and, 410
Bunyaviruses
encephalitis caused by, 1401
hemorrhagic fevers caused by, 1412
Buprenorphine, 19, 89
t
, 90
t
, 96, 1112, 
 
1604
Bupropion, 1090–1093, 1091
t
for antidepressant drug augmentation, 
1068, 1090
for anxiety, 1068
for drug-induced sexual dysfunction, 
1092–1093
with naltrexone, for obesity, 1244, 1279
overdose/toxicity of, 1609, 1610
for smoking cessation, 7
Burkholderia
mallei
 (glanders), 1318
t
pseudomallei
 (melioidosis), 1318
t
Burkitt lymphoma, 543, 545, 1387
Burn dressings, 1572
Burn unit, 1571
Stevens Johnson syndrome/toxic 
epidermal necrolysis 
treatment and, 144, 173
Burning mouth syndrome, 
237
Burns, 
1570–1573
, 1571
f
chemical. 
See
 Chemical injury
electrical, 1571, 
1573–1574
infection and, 1298
smoke inhalation and, 316, 1571
survival/prolonged hospitalization and, 
1117, 1571
Bursa/bursitis, 
1705–1706
, 1706
f
. 
See also
 
specific type or joint 
 
affected
Buruli ulcer, 1488
“Bush teas, ” sinusoidal obstruction 
syndrome caused by, 727
Buspirone, 1067
t
, 1068
Busulfan, 1617
t
, 1679
Butane toxicity, 1601–1602
Butanediol, 1599
Butenafine, 107
t
Butoconazole, 782
Butterfly rash, in SLE, 853
t
, 854
Button batteries, ingested, 1590
Butyrolactone, gamma, 1599
Butyrophenones, 593, 1081. 
See also
 
Antipsychotic drugs; 
Bypass grafting. 
See
 Revascularization 
Bypass surgery, for obesity. 
See
 Bariatric 
surgery
Bronchiolitis (
Cont
.):
proliferative, 277
respiratory, 277
interstitial lung disease associated 
with (RB-ILD), 302
t
, 303
RSV , 1421
Bronchioloalveolar cell carcinoma

surgery
Cont
.):
t
, 303
RSV , 1421
Bronchioloalveolar cell carcinoma 
(adenocarcinoma in situ), 
1624
Bronchitis
chlamydial, 1492
chronic, 268, 269
t
, 272. 
See also
 Chronic 
obstructive pulmonary disease
industrial, 319
Bronchoalveolar lavage (BAL), 301, 304, 
305
Bronchoconstriction. 
See
. 
See also
 Asthma; 
Bronchospasm
for asthma
evaluation/classification and, 256
262–263
t
f
, 259, 260
t
, 263
f
, 255
t
, 258
f
, 259, 
262
t
, 263, 264
t
Bronchogenic carcinoma, 21, 26
t
, 
 
1624–1629
, 1626
f
. 
See also
 
Lung cancer
Bronchoprovocation testing. 
See
 Bronchial 
provocation testing
Bronchopulmonary mycosis/aspergillosis, 
allergic, 
275
, 893
t
, 1557, 1558
Bronchoscopy, 301, 1625
Bronchospasm/bronchoconstriction. 
 
See also
 Asthma
f
, 256, 259, 264
in pulmonary edema, 425
Brown recluse spider bites, 159, 1608
Brown-Séquard syndrome, 1045
Brown tumors of bone, in 
hyperparathyroidism, 1164
Bruce protocol, 370, 376
Brucella abortus/melitensis/suis
 
(brucellosis), 1318
t
, 
 
1478–1479
endocarditis caused by, 1468, 1479
Brudzinski sign, 1470
Brugada syndrome, 32, 449, 450
t
Brugia malayi/timori,
 1546
Bruxism, earache and, 218
Buboes
in lymphogranuloma venereum, 684, 
1490
in plague, 1480
Budd-Chiari syndrome (hepatic vein 
obstruction), 
726–728
Budesonide
for asthma, 259, 260
t
, 262
t
668, 672, 675
Buerger disease (thromboangiitis 
obliterans), 
491
Raynaud disease/phenomenon and, 491, 
858
CMDT2019_Index_p1743-1884.indd   1764

INDEX1765
 
CMDT 2019
HIV infection/AIDS and, 1338, 1339
t
, 
1345–1346
t
, 1354–1355
hypercalcemia associated with, 911, 
911
t
, 912, 1166, 
1672–1673
. 
See also
 Hypercalcemia
hyperuricemia associated with, 
 
1673–1674
, 1676
t
incidence/risk/mortality of, 2
t
, 1611, 
1612
t
infectious complications of, 1021, 1297, 
1298, 
1674–1675
in lesbian and bisexual women, 
 
1728–1729
neurocognitive disorders/delirium and, 
1115
t
neuropathies associated with, 1022, 
1050
, 1679
nonmetastatic neurologic complications 
of, 
1021–1022
, 1050
obesity and, 13
pain associated with, 82, 
83–84
. 
See also
 
Pain; Pain management
pericarditis/effusion associated with, 
437, 438, 439, 1671, 1672
periungual/subungual lesions, 169
pleural effusions in, 323, 323–324, 324
t
, 
1671, 1672
polymyositis/dermatomyositis and, 861, 
862, 889
prevention of, 11, 
14–17
, 15
t
, 1650
prognosis for, 1680
radiation exposure and, 1575, 1611
rheumatologic manifestations of, 
889
SIADH and, 901, 901
t
, 1625
smoking/smoking cessation and, 7, 14, 
1611
spinal cord compression and, 
 
1670–1671
staging of, 1612
transgender health and, 1741
treatment of, 1612, 1612–1616
t
, 
 
1616–1624
t
, 
1675–1680
, 
1675–1676
t
, 1677
t
. 
See also
 
Chemotherapy; Radiation 
therapy
tumor lysis syndrome and, 
1673–1674
, 
1676
t
Cancer pain, 82, 
83–84
. 
See also
 Pain; Pain 
Candesartan/candesartan-HCTZ, 418
t
, 
419, 468
t
, 992
t
Candida
 (candidiasis), 
1550–1551
albicans,
 1550
auris,
 1551
in diabetes, 1224, 1251
endocarditis in, 1550–1551, 1551
esophageal, 623, 1343–1344, 1346
t
, 
1350–1351, 1550, 1551
glabrata,
 1551, 1561
infection/AIDS, 236–237, 
236
f
, 623, 1343–1344, 1346
t
, 
1350, 1350–1351, 1353
invasive, 140, 1550, 1551
krusei,
 1551
mucocutaneous/mucosal, 
139–140
, 
140
f
, 1550
nail infection and, 140
non-albicans, 1551
oral (thrush). 
See
 Oral candidiasis
parapsilosis,
 1551
resistant strains of, 1551, 1561
1594
for hydrofluoric acid burns, 1589
tetany, 910, 1162
Calcium nephrolithiasis, 976–977
calcium supplementation and, 976, 
976–977, 1172
hypercalcemia/hypercalciuria/
hyperparathyroidism and, 
911, 976, 1165
in polycystic kidney disease, 963
Calcium polycarbophil, 597
t
. 
See also
 
Calcium pyrophosphate crystals, 845, 848. 
See also
 Calcium 
pyrophosphate deposition 
disease
Calcium pyrophosphate deposition disease 
(CPPD), 
848
Calcium-sensing receptor, 906
t
, 908, 910, 
911, 1167–1168
Caliciviruses, diarrhea/gastroenteritis 
caused by, 1313
t
California encephalitis, 1401
California flea rickettsiosis, 1437
t
Calorie requirements, in nutritional 
support, 1288–1289
Calorie restriction, in obesity 
management, 1278, 1279
Calreticulin 
(CALR)
 mutation, 529, 532, 
533
Calymmatobacterium (Donovania) 
granulomatis,
 1482
CAM (confusion assessment method), 
61–62
Cameron lesions, 640
Camphor/menthol preparations, 103, 
 
107
t
Campylobacter,
 1322
t
, 1361, 
1478
diarrhea/gastroenteritis caused by, 599
t
, 
600, 1312
t
, 1316, 1322
t
, 1478
Guillain-Barré syndrome and, 1051
fetus
 subsp 
fetus,
 1478
jejuni,
 599
t
, 1318
t
, 1478
Campylobacter-like organisms, 1478
Canagliflozin, 1231
t
, 1236, 1237, 1245
Canakinumab, 368, 846, 853
Cancer, 
1611–1680
. 
See also
 
and under Malignant
back pain and, 1697
complications of, 
1021–1022
, 
 
1670–1675
“consumptive hypothyroidism” and, 
1134
DIC in, 564
in Down syndrome, 1683
early detection/screening tests for, 
14–17, 15
t
. 
See also
 Cancer, 
prevention of
1728–1729
effusions associated with, 
1671–1672
emergencies associated with, 
 
1670–1675
Epstein-Barr virus infection and, 233, 
1387
etiology of, 1611, 1612
t
exfoliative dermatitis/erythroderma 
and, 125
fever/FUO and, 1294, 1295, 1674
Calcium
albumin levels and, 910, 911
dietary/supplementary, 1287

1387
t
and, 125
Calcium
1581, 1594
deficiency of in osteomalacia/rickets, 
1175, 1175
t
, 1176, 1176–1177
hypercalcemia caused by, 1167
hypercalciuria and, 911, 976
for hyperkalemia, 908, 909
t
for hypermagnesemia, 916
for hyperoxaluric calcium 
nephrolithiasis, 976–977
for hypertension, 458, 1287
for hypocalcemia/
hypoparathyroidism/tetany, 
910, 1162, 1163
osteodystrophy, 940
milk-alkali syndrome and, 911, 912
in nutritional support, 1290
for osteomalacia, 1177
for osteoporosis, 810, 1172, 1287
during pregnancy/lactation, 814, 815
urinary stone formation and, 976, 
disorders of concentration/metabolism 
of, 906
t
, 
908–912
, 910
t
, 911
t
. 
See also
 Hypercalcemia; 
in chronic kidney disease/renal 
osteodystrophy, 910, 939, 940, 
940
f
, 1164, 1166
in insulinoma diagnosis, 1264
magnesium balance and, 910, 911, 915, 
916
normal values for, 908
parathyroid hormone affecting, 910, 
912, 1161, 1164
phosphorus/phosphate metabolism and, 
910, 912, 913, 914
urinary excretion of. 
See
 Hypercalciuria
in urinary stones, 975, 976–977. 
See also
 
Calcium nephrolithiasis; 
Hypercalciuria
Calcium bilirubinate, in gallstones, 732
Calcium channel blocking drugs
for ACS (NSTEMI/STEMI), 381, 388, 
392
f
, 374
for arrhythmias, 393, 395
t
, 400, 403
for cardiomyopathy, 432
in diabetes, 476, 477
heart failure and, 421
for hypertension, 471, 472–473
t
, 475, 
476, 476
f
, 477, 478, 481
t
lower extremity edema and, 33
overdose/toxicity of, 374, 471, 1581, 
1594
and, 1193
for Raynaud phenomenon, 858, 860
Calcium disodium edetate (EDTA), 961, 
1600, 1601
Calcium gluconate. 
See also
 Calcium, 
dietary/supplementary
CMDT2019_Index_p1743-1884.indd   1765

INDEX1766
 
CMDT 2019
in angina management, 375
antihypertensive therapy and, 458, 459
t
in postinfarction management, 392
preoperative, 
46–49
, 47
t
, 48
f
Cardiac Risk Index, Revised (RCRI), 46, 
47
t
, 48
f
Cardiac rupture, 391, 445
Cardiac sarcoma, 445
Cardiac tamponade. 
See
 Tamponade
Cardiac transplantation
for cardiac amyloidosis, 435
f
, 422
Cardiac trauma, 
445–446
, 449
Cardiac tumors, 
444–445
Cardiac valves. 
See
 Prosthetic heart valves; 
Valve replacement; Valvular 
Cardiobacterium hominis
. 
See
 HACEK 
organisms
Cardioembolism, stroke/TIA and, 1004, 
1009
Cardiogenic liver injury, acute, 728
Cardiogenic pulmonary edema, 415, 
 
424–425
Cardiogenic shock, 383, 390–391, 426, 
505, 505
t
, 506, 508–509
Cardiomyopathy, 
427–435
, 428
t
, 433
f
adenovirus infection and, 1429
amyloidosis and, 434, 435, 551
catecholamine-induced. 
See
 
Cardiomyopathy, stress
congestive, 414
in diabetes, 429, 1250
dilated, 31, 414, 
427–430
, 428
t
heart failure and, 414, 428–430, 428
t
, 
433
f
, 434
heart murmurs in, 346
t
in hyperthyroidism, 429, 1141, 1148
hypertrophic, 414, 428
t
, 
431–433
, 433
f
ischemic, 414
mitral regurgitation and, 350
perioperative cardiac complications and, 
48
of pregnancy (peripartum 
cardiomyopathy), 432, 
446
, 
447
t
, 1129
restrictive, 414, 428
t
, 
434–435
constrictive pericarditis differentiated 
from, 434, 441, 442
sarcoidosis causing, 303, 304
stress (catecholamine-induced/
 
Tako-Tsubo syndrome), 383, 
428, 
430–431
, 1192
sudden death of athlete and, 426, 449, 
450
t
trastuzumab causing, 766
Cardiomyotomy, Heller, 630
Cardiopulmonary resuscitation
in electrical injury, 1573
in hypothermia, 1567
orders regarding, 76–77
Cardiorenal syndrome, 
936
Cardiotoxicity. 
See also
 Heart disease
anthracycline/chemotherapy and, 427, 
1680
dexrazoxane for, 427, 1675
t
antidepressants causing, 1094, 1609, 1609
f
Cardiovascular disorders. 
See also
 
under 
Cardiac; Coronary; Myocardial 
and
 Heart disease; Stroke
Carbon monoxide, diffusing capacity for 
(D
l
CO
)
in 
 pneumonia, 1344
in pulmonary hypertension, 444
Carbon monoxide poisoning, 316, 1584
t
, 
1587
t
, 
1594–1595
headache in, 41, 1595
smoke inhalation and, 316, 1594
Carbonic anhydrase inhibitors, 184
t
, 189, 
207
t
Carboplatin, 768, 1616
t
, 1628, 1670, 1680
Carboxyhemoglobin levels
1594–1595, 1595
in smoke inhalation, 316
Carbuncles, 
160–163
, 1450
t
, 1455, 1455
f
Carcinoembryonic antigen (CEA)
in breast cancer, 758
in colorectal cancer, 1650, 1652, 1653
in thyroid cancer, 1154
Carcinoid heart disease, 1196
Carcinoid syndrome, 299, 1196, 1645, 
1647–1648, 1648
Carcinoid tumors, 
1195–1197
, 1615
t
bronchial, 
299
gastric, 634–635, 1645
intestinal, 1195, 1647, 1648
t
, 1198
Carcinomatosis
lymphangitic, 1629
peritoneal, 616
Carcinomatous meningitis 
(leptomeningeal metastases), 
1019, 1305
Card agglutination test for trypanosomes 
(CATT), 1511
Cardiac amyloidosis, 434, 435, 551
Cardiac arrhythmias. 
See
“Cardiac asthma, ” 253, 257
Cardiac biomarkers/enzymes
in ACS (NSTEMI/STEMI)/chest pain, 
29, 379, 384
in trauma, 445
“Cardiac cachexia, ” 38
Cardiac catheterization
in ACS (NSTEMI/STEMI), 382, 382
t
, 
388–389
in cardiomyopathy, 428
t
, 429, 432
in pericarditis, 442
Cardiac cirrhosis, 715
Cardiac Disease in Pregnancy 
Investigation (CARPREG) 
scoring system, 446
Cardiac dysrhythmias. 
See
Cardiac friction rub. 
See
 Friction rubs
Cardiac glycosides. 
See
 Digitalis/digitalis 
glycosides/digoxin
Cardiac index, in shock, 505, 507
Cardiac murmurs. 
See
 Heart murmurs
Cardiac output
acute kidney injury and, 930
in aortic stenosis, 353, 353
t
in pregnancy, 833
in shock liver/cardiogenic liver injury, 728
Cardiac resynchronization therapy. 
 
See
 Resynchronization 
(biventricular pacing)

t
 
See
Cardiac risk assessment/reduction, 27–29, 
365, 366
f
, 367–368, 367
t
, 458, 
459
t
Candida
 (candidiasis) (
Cont
.):
tinea differentiated from, 120
in urine, 1550, 1551
vulvovaginal, 140, 781, 781
f
, 1550, 1551
in HIV infection/AIDS, 1346
t
, 1355
and, 1309
Candida
 antigen, for wart removal, 150
Candidal funguria (candiduria), 1550, 
1551
Candidatus R rioja,
 1437
t
, 1442
Candidemia, 1550, 1551
Candiduria, 1550, 1551
Canker sore (aphthous ulcer), 
237–238
, 
876, 1350
Cannabinoids/cannabidiol, 1112–1113
for nausea and vomiting, 97, 593–594, 
1344
for neuropathic pain, 100, 1048
toxicity/amphetamine-like reactions 
and, 1590, 1601–1602
, 1112–1113. 
See also
 
Cannabinoids/cannabidiol; 
Marijuana
Cannon A waves, 31
Capecitabine, 1617
t
for biliary tract carcinoma, 1635
for pancreatic/periampullary carcinoma, 
1637
toxicity of, 1679
Capillaria philippinensis
 (capillariasis), 603
Capillary angiomas, in Sturge-Weber 
syndrome, 1023
Caplan syndrome, 318
CAPRA nomogram, 1663–1664, 1663
t
Capsaicin, 107
t
, 129, 842, 1249, 1719
Capsule imaging/endoscopy/colonoscopy, 
610, 611, 666, 679, 1653, 
1654
t
, 1655–1656
Captopril/captopril-HCTZ
for heart failure, 388, 418
t
, 419, 471
t
, 471, 481
t
, 482
Carbamate poisoning, 1605
Carbamazepine, 995
t
, 1099. 
See also
 
for bipolar disease/mania, 1099
HLA-associated drug hypersensitivity 
and, 894
overdose/toxicity of, 995
t
, 1099, 1585
t
, 
1587
t
, 1592
pregnancy and, 834, 1099
for seizures, 995
t
Carbapenems, penicillin allergy and, 1324
Carbaryl poisoning, 1605
Carbidopa (carbidopa-levodopa/
carbidopa-levodopa-
entacapone), 1026, 1027
Carbohydrate deficient transferrin, 1107
Carbohydrates, dietary. 
See also
 
High-carbohydrate diet
in diabetes, 1228, 1229
for hypoglycemia, 1246, 1599
malabsorption of, 603
restriction of, 1278
Carbon dioxide. 
See also
 Arterial blood 
gases
increased production of, 329
t
Carbon dioxide laser therapy, 149–150, 
785
CMDT2019_Index_p1743-1884.indd   1766

INDEX1767
 
CMDT 2019
Catamenial asthma, 253
Catamenial pneumothorax, 326
Cataplexy, 1103
Cataract, 
191
diabetic, 1247
Cataract surgery, alpha blocking drugs 
and, 191, 207
t
, 986
Catastrophic antiphospholipid syndrome, 
857
Catatonia, 1079, 1080, 1083
antipsychotic-induced, 1085
malignant, 35
Catcher’s mitt hand, 888
O
(COMT) inhibitors, 
 
1026–1027
Catecholamines
in pheochromocytoma/paraganglioma, 
1190, 1191–1192, 1191
t
for shock, 508
in stress cardiomyopathy, 430–431
Catenin, beta, hepatocellular adenoma 
and, 731
Caterpillars, skin lesions caused by, 160
Cathartic abuse, in bulimia, 1282
Catheter ablation techniques, for 
arrhythmias, 396, 400, 401, 
407, 409, 410, 432. 
See also
 
Catheterization. 
See
 Bladder 
catheterization; Cardiac 
Catheters/intravenous lines
health care–associated infection and, 
1301, 1301–1302, 1302–1303, 
1303, 1321
t
, 1323–1324
for parenteral nutritional support, 1292
thrombophlebitis/septic phlebitis and, 
499, 1292, 1302, 1321
t
Cathinones, toxicity of, 1601–1602
CATT (card agglutination test for 
trypanosomes), 1511
Cauda equina syndrome, 1697, 1698, 
 
1700
Cauliflower ear (auricular hematoma), 
 
211
Caustic/corrosive agents
acids, 
1589–1590
alkalies, 205, 1584, 
1590
esophageal injury and, 1589, 1590
eye injury and, 205, 1584, 1589, 1590
inhalation injury and, 1589
skin injury and, 1584, 1589, 1590
Cavernoma, portal, 728, 729
Cavernous hemangioma of liver, 730
Cavernous sinus thrombosis, 227
CBS
 (cystathionine beta-synthase) gene, 
1686
CCKomas, 1195, 1196
CCP antibodies, 849, 878
CCR5 inhibitors, for HIV infection/AIDS, 
1370
CD markers. 
See also
 
specific marker
in leukemia, 539, 541, 542
CD3-positive T-cell large granular 
lymphoproliferative disorder, 
528
CD4 lymphopenia syndrome, idiopathic, 
1407
CD4 T cells, in HIV infection/AIDS, 1338, 
1341, 1341
f
, 1342
t
absolute count, 1342, 1342
t
Cardioverter defibrillator, implantable. 
 
See
 Implantable cardioverter 
defibrillator
Carditis, rheumatic, 435, 436
t
Carey-Coombs murmur, in rheumatic 
carditis, 435
Carfilzomib, 548, 1619
t
Cariprazine, 1081, 1081
t
, 1082
Carisoprodol, 1598
Carney complex/syndrome, 444, 1126, 
1199
l
-Carnitine, for valproic acid overdose/
toxicity, 1587
t
, 1592
Carotene/carotenoids
193
excess intake of, 1285
Carotid artery occlusive disease (carotid 
stenosis/insufficiency), 488, 
489, 489
f
headache in, 993
retinal artery occlusion/visual loss and, 
195, 196, 488
stroke/TIA and, 53, 488, 489, 489
f
, 1004, 
1006, 1007
t
, 1008
Carotid sinus hypersensitivity, 413
Carotid sinus massage/pressure, for 
paroxysmal supraventricular 
tachycardia, 399
Carotid surgery (angioplasty/
endarterectomy/stenting/
thromboendarterectomy), 
489, 1006
prophylactic/preoperative, 53, 489
196
Carpal compression test, 1704
Carpal spasm. 
See
 Trousseau sign
Carpal tunnel syndrome, 
1704–1705
in acromegaly, 1126, 1127
CARPREG (Cardiac Disease in Pregnancy 
Investigation) scoring system, 
446
Carteolol, 183
t
Carvallo sign, 361
for heart failure/cardiomyopathy, 387–
388, 392, 418
t
, 420, 429, 465
for hypertension, 460, 463
t
, 465, 475
Cascara, 597
t
Caspofungin, 623, 1551, 1558, 1561, 1562
t
, 
1563
Castleman disease, 1295, 1391
Castor beans, ricin in, 1595
Casts, urinary, 926, 927
t
, 930
t
. 
See also
 
specific type and specific disorder
Cat bites, 1307, 1308
cat-scratch disease and, 1483
rabies and, 1307, 1308, 1399, 1400
Cat exposure/feces
bacillary angiomatosis and, 1353
toxoplasmosis and, 813, 1525, 1527
Cat-flea typhus, 1442
Cat hookworm, cutaneous larva migrans 
caused by, 1545
Cat roundworm 
(T cati),
 toxocariasis/
visceral larva migrans caused 
by, 1545
Cat-scratch disease, 250, 503, 1483. 
 
See also
 
Bartonella henselae/
quintana
atherosclerotic (ASCVD). 
 
See
 Atherosclerosis; Coronary 

by, 1545
 
See also
 
quintana
 
See
in athletes, screening for, 
448–450
, 449
t
, 
450
t
in Chagas disease, 1512
chemoprevention in, 6
t
, 10, 11, 365, 
366
f
t
, 1268, 
1271–1275, 1272
t
, 1273
t
. 
See 
also
 Lipid-lowering therapy
chronic kidney disease/uremia and, 936, 
938–939, 938
t
cocaine abuse and, 378, 383, 427, 1113
coxibs (COX-2 inhibitors) and, 85, 633, 
636, 843
in diabetes, 1250–1251
glycemic control and, 1227
hypertension control and, 459, 465, 
477, 1228, 1251
tibial and pedal artery disease and, 486
drugs used in
t
t
thrombocytopenia and, 565
t
estrogen replacement therapy and, 810, 
1212
homocysteine/hyperhomocysteinemia/
homocystinuria and, 1686
911, 1165
hypertension and, 6
t
, 10–11, 373
f
, 455, 
458, 459, 459
t
, 465, 475
in hyperthyroidism, 415, 429, 1141, 
1147–1148, 1148
influenza and, 1423
in lesbian and bisexual women, 1725
lipid fractions/lipoproteins and, 6
t
, 10, 
365, 
1267–1268
, 1270
t
, 1509
t
NSAID use and, 85, 633, 636, 640, 843
and, 
46–49
, 47
t
, 48
f
1191, 1192
446–448
, 447
t
, 
833
prevention of, 
5–11
, 6
t
, 8–9
t
, 9
t
, 365, 
366
f
t
, 1268, 
1270–1275, 1272
t
, 1273
t
. 
See 
also
cholesterol screening and, 6
t
, 1267–
1268, 1269–1270
1725
lipid-lowering therapy and, 365, 366
f
, 
367
t
, 1268, 1270–1275, 1272
t
, 
1273
t
. 
See also
 Lipid-lowering 
therapy
risk factors for, 27–29, 365, 366
f
, 458, 
459
t
smoking/smoking cessation and, 6
t
, 
7–9, 8–9
t
, 9
t
, 365, 373
f
syphilis and, 1323
t
, 1493, 1494
t
, 
 
1499–1500, 1500
f
thiamine deficiency and, 1282
Cardioversion
for atrial fibrillation, 389, 403, 406, 1147
for supraventricular tachycardia, 400
for ventricular tachycardia, 389, 410
CMDT2019_Index_p1743-1884.indd   1767

INDEX1768
 
CMDT 2019
ophthalmic effects of drugs used in, 
207–208
t
primary angiitis, 
876–877
vertigo and, 220, 221
t
, 222, 
224
Central nervous system lymphoma 
(primary cerebral lymphoma), 
544–545, 1018
t
, 1019–1020, 
1348, 1354, 1527
Central neurogenic hyperventilation, 327, 
1041
Central pontine myelinolysis (cerebral 
osmotic demyelination), 902
Central retinal artery occlusion, 
195–196
, 
1008
Central retinal vein occlusion, 
194–195
, 
194
f
Central sleep apnea, 327, 1103
Central vein nutritional support (total 
parenteral nutrition/
hyperalimentation), 1289, 
1289
f
, 1291
acidosis caused by, 921, 1293
t
complications of, 1292
in Crohn disease, 668
patient monitoring during, 1292–1293
for ulcerative colitis, 673
Central venous catheters
infection and, 1289, 1292, 1302, 1303
in shock management, 507
Central venous pressure, in shock, 507
 (scorpion) stings, 1608
Cephalexin, 1322
t
t
for pharyngitis, 1322
t
, 1449
for skin and soft tissue infections, 1322
t
, 
1450, 1450
t
, 1455
for urinary tract infection, 834, 968, 
968
t
, 1322
t
Cephalosporins
penicillin allergy and, 1324
for pharyngitis, 239, 1449
615
Cephalothin, platelet function affected by, 
568
t
Ceratopic, 108
t
CeraVe, 108
t
Cercarial dermatitis, in schistosomiasis, 
1535
Cerclage, 818, 826
Cerebellar artery occlusion, 1008
Cerebellar degeneration, paraneoplastic, 
1021
Cerebellar hemangioblastoma, 1018
t
Cerebellar hemorrhage, 1011
Cerebellar tonsils, herniation of, 1018
Cerebellar tumors, 1016
Cerebral amyloid angiopathy, 1010
Cerebral aneurysm. 
See
aneurysm
Cerebral angiography/arteriography. 
 
See
Cerebral arteriovenous malformations, 
1010, 1011, 1013–1014
Cerebral artery occlusion, in stroke, 1008
Cerebral contusions/lacerations, 1043, 
1043
t
Cerebral edema
diabetic ketoacidosis treatment and, 
1256, 1258
t
t
Celecoxib, 85, 86
t
, 636, 843. 
See also
 
Coxibs
cardiovascular complications and, 85, 
633, 636, 843
for familial adenomatous polyposis, 680
kidney injury and, 85, 843
t
NSAID gastritis/ulcers and, 85, 633, 
636, 639, 640, 843
for osteoarthritis, 843, 1719
Celiac disease/sprue (gluten enteropathy), 
645–647
autoimmune/Hashimoto’s thyroiditis 
and, 1132
dermatitis herpetiformis and, 131, 
 
645
intestinal lymphoma and, 131, 1647
iron deficiency anemia and, 510, 511
microscopic colitis and, 675
tTG testing in, 604–605, 645–646
Cell-mediated (delayed/type IV) 
hypersensitivity, 
894–895
Cell surface antigens. 
See
 
under CD
Cellophane tape test, in enterobiasis/
pinworms, 1544
Cellular immunity, impaired, infections 
and, 1297
Cellulitis, 
145–146
, 145
f
, 1322
t
, 1450
t
of auricle, 211
of breast, 753, 828
eosinophilic (Well syndrome), 1430
erythrovirus (parvovirus) infection and, 
1430
in leg ulcers, 165–166
lymphangitis/lymphadenitis and, 145, 
503
lymphedema and, 504
necrotizing fasciitis/streptococcal 
gangrene differentiated from, 
146
non-clostridial crepitant, 1485
orbital, 
202–203
in bacterial rhinosinusitis, 202, 227
240
sublingual/submaxillary space (Ludwig 
angina), 240, 241
superficial (erysipelas), 
144–145
, 1322
t
, 
1449, 1450
f
, 1450
t
synergistic necrotizing, 1485
tinea pedis and, 121, 145
venous insufficiency/stasis and, 146, 
500, 500
f
vibrios causing, 1477–1478
Cenesthetic hallucinations, 1079. 
See also
 
Cenicriviroc, 740
Centor criteria, 238, 1448
Central cord syndrome, 1015, 1045
Central diabetes insipidus, 
1124–1126
. 
 
See also
 Diabetes insipidus
“Central fever, ” 35
Central nervous system disorders. 
See also
 
dysautonomia and, 1003
in HIV infection/AIDS, 1347–1349
1304–1307
, 1304
t
, 1305
t
. 
See 
also
 Encephalitis; Meningitis
1484
otitis media and, 217

1304–1307
, 1304
t
, 1305
t
. 
See 
also
1484
CD4 T cells, in HIV infection/AIDS 
(
Cont
.):
antiretroviral therapy initiation/
monitoring and, 1342, 1362, 
1374
CMV infection and, 198, 1388–1389, 
1390
immune reconstitution and, 1355
MAC infections and, 1342, 1488
opportunistic infection/course of 
disease and, 1338, 1341, 
1341
f
, 1360
t
percentage of, 1342, 1342
t
 pneumonia and, 1342, 
1344, 1361, 1554, 1556
CD8 T cells, in drug-induced 
hypersensitivity, 894
CD10 (common ALL antigen), 539
CD30, EBV-associated lymphoproliferative 
disease and, 1388
CD117, 1646, 1648
CDC73
 mutation, 1170
CDH-1
 mutation, 1642
CDK inhibition, for breast cancer, 770
CDKN1B
 gene, 1199
CDKN2A
 gene, 1636
CEBPA
 biallelic mutations, 538
Cecal carcinoids, 1196
Cecum, in colonic pseudo-obstruction 
(Ogilvie syndrome), 651, 652
Cefadroxil, for pharyngitis, 1449
Cefazolin, 1321
t
for bacteremia, 1456
prophylaxis, 1467, 1467
t
, 1468
for group B streptococcal infection 
prophylaxis in pregnancy, 
 
814
t
for osteomyelitis, 1456
for skin and soft tissue infections, 1450, 
1450
t
, 1455
Cefdinir, 1449, 1453
Cefepime, 279
t
, 282, 285
t
, 1305
t
, 1321
t
, 
1484
t
Cefixime, 1323
t
Cefotaxime, 279
t
, 281, 282, 615, 717, 
1508
t
, 1509
Cefoxitin, 1322
t
Cefpodoxime, 279
t
, 1322
t
, 1449, 1453
Ceftaroline, 1455
Ceftazidime, 179
t
, 285
t
, 1321
t
, 1484
t
Ceftriaxone, 1321
t
, 1322
t
, 1323
t
for anaerobic infections, 1321
t
, 1484, 
1484
t
for diarrhea, 1475, 1476
for endocarditis, 1467, 1468
t
, 1509
t
, 1321
t
, 1454
t
t
for 
 infections/typhoid fever, 
1475
615, 717
for syphilis, 1496, 1496
t
, 1501, 1502
for urinary tract infection, 968
t
, 1321
t
, 
1323
t
Cefuroxime/cefuroxime axetil, 1322
t
t
, 1509
CMDT2019_Index_p1743-1884.indd   1768

INDEX1769
 
CMDT 2019
Chagas disease (American 
trypanosomiasis), 629, 
 
1512–1513
Chagoma, 1512
Chalazion, 
175
Chalkstick fractures
bisphosphonates causing, 1173, 1174
in Paget disease of bone, 1178
Chancre
syphilitic, 684, 1493–1494, 1494
f
, 1494
t
, 
1496
trypanosomal, 1510
Chancroid, 
1482
Channelopathies, periodic paralysis, 
1062
Charcoal, activated, 1584–1585, 1585, 
1586
Charcot joint (neurogenic arthropathy), 
889
in diabetes, 889, 1248
in tabes dorsalis, 889, 1500, 1501
f
Charcot-Marie-Tooth disease, 1048
Charcot triad, 736
Checkpoint inhibitors
cardiotoxicity of, 1680
diabetes caused by, 1221
hypophysitis caused by, 1119, 1122
myalgia caused by, 863
thyroid disease and, 1132, 1134, 1140, 
1141
Chediak-Higashi syndrome, 567
Cheilitis, angular, 236, 236
f
, 1350
Cheiroarthropathy/cheiropathy, diabetic, 
860, 1252
Chelation therapy, 1584
t
. 
See also
 
specific 
type
for arsenic poisoning, 1593
for hemochromatosis/iron poisoning/
overload, 516, 523, 724, 
 
1587
t
for lead poisoning, 961, 1600–1601
for mercury poisoning, 1602
t
for Wilson disease, 726
Chemical injury
acids causing, 205–206, 
1589–1590
alkalies causing, 205–206, 
1590
of esophagus, 1589, 1590
of eye (conjunctivitis/keratitis), 
 
205–206
, 1589, 1590
of lung
acid inhalation and, 1589
aspiration and, 
317
occupational, 300
t
, 320
of skin, 1584, 1589, 1590
Chemical warfare agents. 
See also
 
1595
, 1605
ricin, 
1595–1596
skin decontamination after exposure to, 
1584, 1595
Chemiluminescence (CIA) assay, in 
syphilis, 1495, 1495
t
“Chemo brain, ” 773
Chemoprevention/chemoprophylaxis, 11
antibiotic/antimicrobial. 
See
 
Antimicrobial 
for cancer, 11, 14, 1650
Cervical intraepithelial neoplasia (CIN/
dysplasia of cervix), 
783–785
, 
783
t
, 784
f
HIV infection/AIDS and, 1355
HPV infection and, 4, 14, 15
t
, 16, 783, 
784, 784–785, 786
Cervical lymphadenopathy, reactive, 
250
Cervical radiculopathy, 1701, 1702
Cervical rib syndrome, 
1057
Cervical spine/disk disease, 
1055
, 
 
1056–1057
f
, 
1701–1703
, 
1702
t
. 
See also
 Spine
cervical spondylosis, 
1055
chest pain and, 372
herniation/protrusion, 
1055
, 1702
neck pain and, 
1055
, 1056–1057
f
, 
 
1701–1703
, 1702
t
vertigo and, 223
Cervical spondylosis, 
1055
Cervical vertigo, 223
Cervical warts, 782. 
See also
 Venereal 
(genital) warts
Cervicitis
chlamydial, 
1491
gonococcal, 1481, 1482
postgonococcal, 1491
Cervicofacial actinomycosis, 1486
Cervix (uterine)
anaerobic flora/infection of, 1484
biopsy of, 777, 784, 786
cancer of, 
785–787
, 1614
t
t
, 16
t
, 
148–149, 784–785, 786, 1656
preinvasive (carcinoma in situ/CIN), 
783–785
, 783
t
, 784
f
, 786
prevention of/screening for, 15
t
, 16, 
783
t
, 784
1729
conization of, 785, 786
dysplasia (CIN) of, 
783–785
, 783
t
, 
 
784
f
incompetent, 818
myoma of, 787
polyps of, 
782–783
stenosis of, 780
“strawberry, ” 781, 781
f
Cesarean delivery
in cardiac patient, 448, 833
placental disorders and, 827
for prevention of disease transmission
hepatitis B, 695
herpes genitalis, 837
HIV , 836, 1340, 1358
puerperal infection and, 828
Cestode infections, 
1538–1540
. 
See also
 
Cetaphil, 108
t
Cetirizine, 142, 229. 
See also
 
Cetuximab, 1619
t
, 1652, 1679
Cevimeline, 865
CFTR modulator drugs, 276
CFTR protein, 275
genetic/prenatal testing for, 276, 277
in pancreatitis, 741, 746, 747
CGG repeats, 1684
CH50. 
See
 Complement
CHADS
2
 Risk Score, 402
t
, 404, 404
t
, 407
CHA
2
DS
2
-V ASc Risk Score, 404, 404
t
, 407
head injury and, 1044
high-altitude (HACE), 
1577
hypernatremia treatment and, 904
in liver failure, 700
in stroke, 1008, 1009–1010
Cerebral hemorrhage. 
See
 Intracerebral 

t
, 407
1577
See
Cerebral hypoperfusion, arrhythmias 
causing, 1000
Cerebral infarction/ischemia, 488–490, 
489
f
, 
1007–1010
, 1007
t
. 
See 
also
 Stroke; Transient 
ischemic attacks
Cerebral injury, 1043, 1043
t
. 
See also
 Head 
injury
Cerebral ischemia. 
See
 Cerebral infarction/
ischemia; Stroke; Transient 
Cerebral lymphoma (primary central 
nervous system lymphoma), 
t
Cerebral metastases, 1018
Cerebral osmotic demyelination, 902
Cerebral salt wasting, 900, 902
Cerebral toxoplasmosis, 1019–1020, 1348, 
1526, 1527. 
See also
 
Cerebral vasoconstriction syndrome, 41
Cerebritis, lupus, 855
Cerebrospinal fluid analysis, 1304
t
, 1306. 
See also
 
in CNS infections, 1304
t
, 1306
in headache evaluation, 42
in herpetic encephalitis/meningitis, 
1304–1305, 1378
in Lyme disease, 1509
in meningococcal meningitis, 
 
1470–1471
in multiple sclerosis, 1036
in pneumococcal meningitis, 1454
in subarachnoid hemorrhage, 1012
in syphilis, 1360, 1497, 1501
in tuberculous meningitis, 
 
1488–1489
Cerebrospinal fluid leakage, in head injury, 
1043, 1044
Cerebrovascular accident. 
See
 Stroke
Cerebrovascular disorders
cancer-related, 1021
t
headache in, 40, 993–994
and, 1686
hypertensive, 455–456
occlusive, 
488–490
, 489
f
, 1007
t
. 
See also
 
Stroke; Transient ischemic 
attacks
Ceritinib, 1620
t
, 1628
Certolizumab, 664, 669–670, 852. 
See also
 
Anti-TNF agents
Cerumen impaction, 210, 
211
Ceruminous gland adenoma, 213
Cervical canal stenosis, 1701
Cervical cap, 
805
Cervical carcinoma. 
See
 Cervix (uterine), 
cancer of
Cervical discharge, in chlamydial 
infection, 1491
Cervical dystonia, 1029
CMDT2019_Index_p1743-1884.indd   1769

INDEX1770
 
CMDT 2019
Chloroquine, 208
t
, 209
t
, 1518
t
, 1519, 
1520
t
, 1523
t
for amebiasis, 1529, 1530
t
erythrovirus (parvovirus)-associated 
anemia and, 1430
for lupus, 123
t
t
, 1523
t
for chemoprophylaxis, 1519, 1523, 
1523
t
for non-falciparum malaria, 1518, 
1518
t
t
in pregnancy, 816
resistance to, 1518, 1519, 1520
t
for uncomplicated falciparum 
malaria, 1518, 1519, 1520
t
Chlorpheniramine, 229
Chlorpromazine, 1081
t
, 1082
t
. 
See also
 
overdose/toxicity of/side effects of, 207
t
, 
1082
t
, 1084, 1592
for serotonin syndrome, 1584, 1610
Chlorpropamide, 209
t
, 1229, 1230
t
Chlorthalidone/chlorthalidone 
combinations, 207
t
, 418, 460, 
461
t
, 463
t
, 468
t
, 474
t
Chokes, 1576
Cholangiocarcinoma, 1631, 1634, 1635
clonorchiasis/opisthorchiasis and, 1537, 
1634
primary sclerosing cholangitis and, 740, 
741
Cholangiography/
cholangiopancreatography, 
691. 
See also
 
in choledocholithiasis, 736, 737, 738
pancreatitis after, 691
Cholangiopathy, AIDS, 740, 1351, 1532
Cholangitis, 
736–738
autoimmune, 722
biliary stricture and, 738
choledocholithiasis and, 
736–738
IgG
4
-associated, 740
liver abscess and, 729, 730
primary biliary (primary biliary 
cirrhosis), 707, 
721–723
primary sclerosing, 
739–741
autoimmune hepatitis and, 707
cholangiocarcinoma and, 740, 741
in HIV infection/AIDS, 740, 1351
pyogenic, 737
3
), 1162
t
, 1172, 
1177. 
See also
 Vitamin D
Cholecystectomy
for cholecystitis, 735
for choledocholithiasis/cholangitis, 
736–737, 737, 738, 740
for cholelithiasis/gallstones, 732
pancreatitis and, 744
for precholecystectomy syndrome, 
 
735
in pregnant patient, 732, 838
symptom persistence after 
(postcholecystectomy 
syndrome), 
735–736
Cholecystitis, 
733–735
, 733
t
, 1321
t
acalculous, 733–734, 1293
t
, 1351
acute, 
733–735
, 733
t
choledocholithiasis (bile duct stones) 
and, 737
Chest tube drainage. 
See
 Tube 
thoracostomy
Chest wall
breast cancer recurrence in, 773
disorders of, 329
t
, 372, 631
Cheyne-Stokes respiration, 1041
Chickenpox. 
See
 Varicella
Chiggers, 159–160, 1439
Chikungunya fever, 884, 1381
t
, 
1419–1420
Chilblain (erythema pernio), 
1568
aggression/violence/impulse control 
disorders and, 1104
 
1724–1725
Munchausen syndrome and, 1071
PTSD and, 1066
Child-Pugh score for cirrhosis, 720, 720
t
hepatocellular carcinoma and, 1632
postoperative complications and, 51
variceal hemorrhage and, 628
Childbirth. 
See
 Labor and delivery
Childbirth preparation classes, 813
Children
t
1325
Chinese liver fluke infection, 1537
Chlamydia
 (chlamydial infections), 1320
t
, 
1323
t
, 
1490–1492
. 
See also
 
t
endocarditis, 1468
inclusion conjunctivitis, 177
keratoconjunctivitis, 177
in lesbian and bisexual women, 1727
screening for, 1309, 1491, 1727
 
1735–1736, 1735
t
 
1727
prenatal, 814, 1491
trachoma, 177
trachomatis,
 684, 1320
t
, 1323
t
, 1490, 
1490–1491
anorectal involvement and, 684
epididymitis, 973, 1323
t
lymphogranuloma venereum, 684, 
1490–1491
pelvic infection/PID, 792, 793, 1320
t
, 
1322
t
pregnancy and, 814, 
837
, 1491
and, 808, 1309
urethritis/cervicitis/urinary tract 
infection, 1309, 1320
t
, 1323
t
, 
1491
, 1490. 
See also
 
Chlamydia
pneumoniae,
 278
t
, 1320
t
, 1321
t
, 1322
t
, 
1490, 
1492
psittaci,
 1320
t
, 1490, 
1492
Chloasma (melasma), 166, 167
Chlorambucil, 209
t
, 541, 1617
t
Chloramphenicol, 179
t
, 208
t
, 1438, 1441, 
1442
Chlordiazepoxide, 1067
t
, 1110, 1598
Chloride
t
Chloride secretory agents, 597
Chlorofluorocarbon inhalers (CFCs), 262
t
, 
263
t

1442
t
Chloride
t
t
, 
263
t
Chemoprevention/chemoprophylaxis 
(
Cont
.):
for cardiovascular disease, 6
t
, 11, 365, 
366
f
t
, 1268, 
t
, 1273
t
. 
See 
also
for cluster headache, 993
disease), 309, 575–576
t
, 
 
t
, 578–579
t
, 579
t
for migraine headache, 991–992, 992
t
for stress gastritis, 632–633
Chemoradiation therapy
for breast cancer, 769
for laryngeal cancer, 247
for nasopharyngeal carcinoma, 233
1637
Chemoreceptor trigger zone, 591, 592
t
Chemotherapy (cancer), 1612, 
 
1612–1616
t
, 1616–1624
t
, 
1675–1680
, 1675–1676
t
, 
1677
t
. 
See also
 
specific agent 
and cancer type
anemia caused by, 1676
t
, 1677
bone marrow toxicity of, 
1677
fever and, 1321
t
, 1674
heart failure/myocarditis and, 427, 1680
hyperuricemia/tumor lysis syndrome 
and, 1673–1674, 1676
t
leukemia caused by, 538
nausea and vomiting caused by, 591, 
592
t
, 593, 
1677–1678
neuropathies caused by, 1679
neutropenia caused by, 528, 1676
t
, 1677
infections and, 1297, 1321
t
, 1674
ototoxicity and, 219
with radiation therapy. 
 
See
 Chemoradiation therapy
supportive agents/care and, 1675–1676
t
thrombocytopenia and, 
558
, 565
t
, 1677
thyroid disease and, 1134, 1140, 1141
toxicity/dose modification and, 209
t
, 
1675–1680
t
, 
1677
t
Chest pain/discomfort, 
27–30
, 28
t
. 
 
See also
 
in ACS, 378
in angina, 27–28, 369, 372
coronary vasospasm/normal 
arteriogram and, 368, 
 
377–378
diagnosis/differential diagnosis of, 
27–30, 28
t
, 372
esophageal/undetermined, 372, 630, 
631
in myocardial infarction/ST-segment 
elevation, 27–29, 28
t
, 378, 383
noncardiac/psychologic causes of, 
29–30, 631
palpitations and, 
30–32
, 31
t
in pericarditis, 28–29, 438
pleuritic, 28, 28
t
, 321–322
in pulmonary embolism, 29, 306
t
visceral sensitivity causing, 631
Chest pain observation units, 378
CMDT2019_Index_p1743-1884.indd   1770

INDEX1771
 
CMDT 2019
metabolic bone disorders of (renal 
osteodystrophy), 939–940, 
940
f
neurologic disorders/neuropathy and, 
941
pericarditis and (uremic pericarditis), 
437, 438, 439, 939
reversible causes of, 937, 938
t
stages of, 936–937, 937
t
surgery in patient with, 54
Chronic lymphocytic leukemia (CLL), 
540–542
, 1612
t
Chronic mountain sickness (Monge 
disease), 
1578
Chronic myeloid leukemia (CML), 530
t
, 
534–536
, 1612
t
, 1430
Chronic myelomonocytic leukemia 
(CMML), 536
Chronic noncancer pain (CNCP), 82, 
83
, 
1072–1075
, 1073
f
. 
See also
 
Chronic obstructive pulmonary disease 
(COPD), 
268–273
, 269
t
, 271
t
270, 1328
t
, 1331
t
pulmonary hypertension and, 313, 443, 
443
t
Chronic/chronic noncancer (CNCP) pain, 
82, 
83
, 
1072–1075
, 1073
f
Chronic pelvic pain. 
See
 Pelvic pain
Chronic prolymphocytic leukemia, 540
Chronic renal failure. 
See
 Chronic kidney 
disease
Chronic thromboembolic pulmonary 
hypertension, 312, 313, 314, 
443, 443
t
Chronic traumatic encephalopathy, 1044
Chronic venous insufficiency. 
See
 Venous 
insufficiency/stasis
Churg-Strauss syndrome. 
See
 Eosinophilic 
Chvostek sign
in hypocalcemia/hypoparathyroidism, 
910, 1161
t
Chylomicrons, 1269
Chylous ascites, 716
Chylous effusion, 322
CIA assay, in syphilis, 1495, 1495
t
Cicatricial (scarring) alopecia, 168
Ciclopirox, 107
t
Cidofovir, 198, 208
t
, 244, 1346
t
, 1379
t
, 
1431
Cigarette/cigar smoking. 
See
 Smoking
Ciguatera poisoning, 1607, 1607
t
Cilostazol, 484, 1006
Cimetidine, 621, 633, 637. 
See also
 H
2
 
receptor blocking drugs
1095
t
t
CYP 2C19/ulcer complications and, 640
 bites, 159
Cinacalcet, 912, 940, 1167–1168
Ciprofloxacin, 1321
t
. 
See also
 
for anaerobic infections, 1484
t
t
Chondromalacia (patellofemoral knee 
pain), 1709, 
1717–1718
Chorea
drug-induced, 1030
in Huntington disease, 1027–1028
in rheumatic fever (Sydenham), 435, 
436, 436
t
Chorioamnionitis, 
828–829
Choriocarcinoma, 
821–822
, 1141, 1614
t
, 
1669
Choriomeningitis, lymphocytic, 
 
1405–1406
Chorionic gonadotropin. 
See
 Human 
chorionic gonadotropin
Chorionic villus sampling, 813
Chorioretinitis, toxoplasmic, 190, 1526
Chromoendoscopy, in ulcerative colitis, 
674
Chromogranin A (CgA)
NETs secreting, 1195, 1648
in pheochromocytomas, 1190, 1192
Chronic alcoholic brain syndromes, 1107
Chronic benign neutropenia, 528
Chronic bronchitis. 
See
 Bronchitis
Chronic cutaneous lupus erythematosus, 
123
Chronic disease, anemia of, 512, 
513–514
Chronic fatigue syndrome, 
38–40
, 39
f
, 
888, 1444
Chronic inflammatory polyneuropathy, 
1051–1052
Chronic intestinal pseudo-obstruction, 
652–653
Chronic kidney disease (CKD), 926, 
 
936–945
, 937
t
, 938
f
, 938
t
, 
939
f
, 940
f
. 
See also
 Renal 
failure
acid-base disorders and, 941
alkalosis in alkali administration and, 
923
amyloidosis and, 550, 947
t
anemia in, 513, 926, 939
f
, 940–941
cardiorenal syndrome and, 936
cardiovascular disorders and, 936, 
 
t
coagulopathy of, 941
complications of, 938–943, 939
f
, 940
f
diabetes and, 941, 942, 947
t
, 954, 955, 
957–958, 1245
t
, 1247, 
 
1247–1248. 
See also
 Diabetic 
dietary management in, 942
drug/medication use and, 942
endocrine disorders and, 941–942
gout and, 844, 
964–965
heart failure and, 415, 938
t
, 939
and, 911, 912, 938
t
, 939
f
, 
1164, 1165
hyperkalemia and, 907, 907
t
, 938
t
, 939
f
, 
941
hypermagnesemia and, 916
hyperphosphatemia in, 914, 939
f
hypertension and, 454, 456, 477–478, 
937, 938–939, 938
t
, 939
f
hypocalcemia and, 910
hypoglycemia and, 941, 958
hypomagnesemia treatment and, 
 
916
hyponatremia in, 901

f
t
, 939
f
 
916
1328
t
, 1331
t
cholelithiasis/gallstones and, 732, 733, 
734
chronic, 733
t
, 734, 735
in HIV infection/AIDS, 734, 1351
parenteral nutritional support and, 
1293
t
838
xanthogranulomatous, 734
Cholecystokinin, tumors producing 
(CCKomas), 1195, 1196
Choledocholithiasis, 733
t
, 
736–738
, 745
Cholelithiasis (gallstones), 
731–733
, 733
t
cholecystitis and, 732, 733, 734
and, 736, 737
in Crohn disease, 666
pancreatitis and, 741, 743
during pregnancy, 732, 
838
in short bowel syndrome, 649
somatostatinomas and, 1196
Cholera, 1313
t
, 1319
t
, 
1477
Cholera vaccine, 1477
Cholestasis, 688, 689
t
hereditary/intrahepatic, 688, 689
t
, 
839
of pregnancy, 689
t
, 
838
, 
839
in primary biliary cholangitis/cirrhosis, 
721
Cholestatic jaundice, 688, 689
t
, 1084
Cholesteatoma, 216, 216
f
Cholesterol. 
See also
 
Hypercholesterolemia; 
Lipoproteins
antiretroviral therapy/protease 
inhibitors affecting, 1369
in cardiovascular/coronary heart 
disease, 6
t
, 10, 365, 
 
1267–1268, 1269–1270, 
 
t
, 1273
t
, 1683
in diabetes mellitus, 1227, 1251
dietary, 1271
estrogen replacement affecting, 810, 
1212, 1213
in familial hypercholesterolemia, 1683, 
1684
in gallstones, 732
lowering levels of. 
See
therapy
“normal”/reference values for, 
 
1267–1268
screening tests for, 6
t
, 10, 1267–1268, 
1269–1270
thiazolidinediones affecting, 1233
total, 1267, 1269
Cholesterol-lowering diet, 1271, 1287
Cholesterolosis of gallbladder, 733
t
, 734
Cholesteryl ester transfer protein 
inhibitors, 1271
for diarrhea, 605, 649, 658, 668
for lipid modification, 1272–1274, 1273
t
Choline magnesium salicylate, 86
t
Cholinergic rebound, 1094
Cholinergic syndrome, 1586
Cholinergic urticaria, 141
Cholinesterase inhibitors. 
See
 
Chondritis. 
See
 Polychondritis
Chondrocalcinosis, 848, 1166
Chondroitin/chondroitin plus glucosamine 
sulfate, 843, 1719
CMDT2019_Index_p1743-1884.indd   1771

INDEX1772
 
CMDT 2019
 (clonorchiasis), 
1537
, 
1634
Clopidogrel
f
, 
385, 386, 388, 392
f
, 374
cardiac valve replacement and, 356, 364
t
cardiovascular/heart disease prevention 
and, 368
and, 375, 388
636, 640
t
Clorazepate, 995
t
, 1067, 1067
t
Closed globe injury, 205
Closed loop systems, for glucose 
monitoring, 1227
 (clostridial infections), 1319
t
, 
1458–1460
, 1459
t
abdominal, 1484
bifermentans,
 1458
botulinum
 (botulism), 
1059–1060
, 
1312
t
, 
1460
difficile
, colitis/diarrhea and, 599
t
, 600, 
603, 659–662, 1302, 1312
t
histolyticum,
 1458
myonecrosis/gas gangrene, 1319
t
, 
1458
novyi,
 1458
perfringens,
 599
t
, 600, 1312
t
, 1314, 1458
ramosum,
 1458
tetani
, 1319
t
, 1459. 
See also
 Tetanus
Clothing (flame) burns, 1573
Clotrimazole, 107
t
, 1678
for candidiasis, 1353
mastitis, 140
oral, 237, 1350
vulvovaginal, 782, 1551
Clotting factors. 
See
 Coagulation factors
Clozapine, 1081, 1081
t
, 1082
t
, 1084, 1084
t
, 
1086. 
See also
 Antipsychotic 
drugs
agranulocytosis caused by, 1027, 1084
for antipsychotic-induced tardive 
dyskinesia, 1085
neuroleptic malignant syndrome and, 
1085
overdose/toxicity/side effects of, 1027, 
1082
t
t
Clubbed fingers (digital clubbing), 169, 
169
f
, 1625. 
See also
 
specific 
cause
Clue cells, 781, 781
f
Cluster headache, 
992–993
Clusters of differentiation. 
See
 CD markers
CMV immune globulin, 1390
CMV inclusion disease, 1388, 1389
Co– (reciprocal) in vitro fertilization/
co-maternity, 1731
Coagulase-negative staphylococci, 1321
t
, 
1457–1458
, 1464, 1468, 1469
Coagulation disorders. 
See
 Bleeding; 
Hypercoagulability
Coagulation factors. 
See also
 
under Factor
for anticoagulant overdose, 1591
deficiencies/defects of. 
See
 Bleeding; 
Coagulopathy
in liver disease, 572
in 
H pylori
t
, 639
for MAC infections, 1345
t
, 1361, 1487, 
1488
t
, 281, 1453, 1473
Classic (nonexertional) heat stroke, 1565
Claudication, 483. 
See also
 
jaw/masticatory, 868, 997
spinal stenosis and, 1699
Cleaning agents. 
See
 Caustic/corrosive 
agents
Clear liquid diet, 1286
Clemastine, 229
Clevidipine, 480, 480
t
, 481
t
, 482
Clicks. 
See
 Heart murmurs; Heart sounds
Climacteric, 1210. 
See also
 Menopause
t
, 135, 1322
t
for anaerobic infections, 286, 1322
t
, 
1483, 1484
for bacterial vaginosis, 782
t
for malaria, 1520
t
, 1522
for 
 infection, 1555
t
, 1449
t
, 
1353, 1450, 1450
t
, 1455
for toxoplasmosis, 1345
t
, 1527
Clinical Institute Withdrawal Assessment 
for Alcohol Revised 
(CIW A-Ar), 1109–1111, 
1109–1110
f
Clinically isolated syndrome (CIS), 1037
Clobazam, 995
t
Clobetasol, 105
t
Clocortolone, 105
t
Clofarabine, 1617
t
Clofazimine, 208
t
, 1490
Clofibrate, 1062, 1274
in infertility workup, 798
for male hypogonadism/infertility, 1123, 
1202
for ovulation induction, 795, 798–799, 
1123
Clomipramine, 1070, 1091
t
. 
See also
 
Clonal hematopoiesis of indeterminate 
potential (CHIP), 536
Clonazepam, 996
t
, 1067
t
. 
See also
 
for burning mouth syndrome, 237
overdose/toxicity of, 996
t
, 1598
for panic disorder/attacks, 1065, 1067
t
, 
1068
for seizures, 996
t
for sleep-wake disorders, 1103
Clonic seizures, 998. 
See also
 Seizures
Clonidine/clonidine combinations
1095
t
for diarrhea, 605, 1250
for heroin/opioid withdrawal, 1112
for hypertension, 474
t
, 475, 481
t
, 482
for menopausal symptoms, 809

1095
t
t
, 475, 481
t
, 482
overdose/toxicity of, 474
t
, 475, 481
t
, 
482, 
1596
Clonidine suppression testing, 1192
Ciprofloxacin (
Cont
.):
for cyclosporiasis, 1532
for diarrhea, 602, 1316, 1475, 1476
for external/malignant otitis, 212, 213
t
t
, 282, 285
t
, 1321
t
for rickettsial infections, 1439, 1442
for 
 infections/typhoid, 1475
615, 717
t
, 1321
t
Circulation assessment/support, in 
comatose patient, 1581
Circumcision, STD transmission risk and, 
1310, 1356, 1380
Cirrhosis, 
714–721
. 
See also
 Liver, 
disorders of
alcoholic liver disease/hepatitis and, 
708, 709, 710, 715, 716
ascites in, 612, 612–613, 716–717
biliary
primary (primary biliary cholangitis), 
707, 
721–723
secondary, 715
cardiac, 715
coagulopathy and, 572, 715
drugs/toxins causing, 712
esophageal varices/GI bleeding and, 
606, 626, 627, 628, 715
hemochromatosis and, 710, 715, 723, 
724
hepatopulmonary syndrome/
portopulmonary hypertension 
and, 719
hepatorenal syndrome and, 616, 
 
717–718
liver cancer and, 710, 714, 1631
methotrexate toxicity and, 851
nonalcoholic fatty liver disease and, 712, 
713, 714, 715, 1631
portal hypertension and, 606, 714, 715
spontaneous bacterial peritonitis and, 
viral hepatitis and, 696, 698, 702, 703, 
706, 1631
Cisapride, antidepressant interactions and, 
1093, 1095
t
Cisgender, 1737
gay and bisexual men, 1732
lesbian and bisexual women, 1724
Cisplatin, 1616
t
1628, 1631
for testicular cancer, 1670
toxicity of, 209
t
, 219, 1616
t
, 1678, 1680
Citalopram, 1090–1093, 1091
t
, 1609
for Alzheimer disease/dementia, 59, 
1034, 1035
Citrate, in hypocitraturic calcium 
nephrolithiasis, 977
CIW A-Ar, 1109–1111, 1109–1110
f
Cladophialophora,
 1561
Cladribine, 542, 1617
t
Clarithromycin. 
See also
 Macrolides
t
CMDT2019_Index_p1743-1884.indd   1772

INDEX1773
 
CMDT 2019
Colonography, CT (virtual colonoscopy), 
678, 1650, 1653, 1653
t
, 1654
t
, 
1655
in cancer screening/polyp 
identification/treatment, 
 
678–679, 1650, 1652–1653, 
1653
t
, 1654–1655, 1654
t
bleeding after, 609, 679
for colon decompression, 652
in diarrhea, 604
f
, 605
in GI bleeding, 609, 610, 611
in HNPCC/Lynch syndrome, 682
in ischemic colitis, 490, 609
surveillance, 679, 1652–1653
in ulcerative colitis, 671, 674
virtual, 678, 1650, 1653, 1653
t
, 1654
t
, 
1655
Colorado tick fever, 1401, 
1420
Colorectal cancer, 1612
t
, 1615
t
, 
 
1649–1656
, 1653
t
, 1654
t
aspirin/NSAIDs in prevention of, 6
t
, 
1650
chemotherapy for, 1651–1652
Crohn disease and, 667, 1649–1650
endometrial cancer and, 681, 788
familial adenomatous polyposis and, 
680, 1649
genetic/family risk factors and, 681, 
1649, 1654
GI bleeding and, 609, 1650
hamartomatous polyposis syndromes 
and, 680
hereditary, 
679–682
hereditary nonpolyposis (HNPCC/
Lynch syndrome), 
681–682
, 
1649. 
See also
 Lynch 
syndrome
incidence/risk/mortality of, 1612
t
, 1649, 
1649–1650, 1650, 1653
inflammatory bowel disease and, 667, 
674, 1649–1650
metastatic, 1652
nonfamilial adenomatous/serrated 
polyps and, 678, 1649
ovarian cancer and, 681, 682
and, 1636
polyps/polyposis and, 678, 1649, 1653
prevention of/screening for, 11, 15
t
, 16, 
1650, 1653–1656, 1653
t
, 
 
1654
t
primary sclerosing cholangitis and, 740
surgery/follow-up for, 1651, 1652–1653
ulcerative colitis and, 674, 1649–1650
Colorectal disease, 
655–682
. 
See also
 
Colostomy, 1651
Colostrum, 815
Colposcopy, 16, 777
t
, 784
Columbia-Suicide Severity Risk Scale, 
1089
Coma, 
1040–1042
, 1042
t
assessment/emergency management of, 
1040–1041, 1042
t
brain death differentiated from, 1042
diabetic/hyperglycemic, 1223, 1224, 
1254
, 1255
t
. 
See also
 Diabetic 
coma
hypoglycemic, 1246, 1255
t
, 1581
hypothermia and, 1042, 1567, 1581
myxedema, 1135, 1137
Coitus. 
See
 Sexual intercourse
Colchicine, 439, 616, 845, 846, 848
Cold (common cold/viral rhinosinusitis), 
225–226
, 1429
Cold, disorders caused by exposure to, 
1564
, 
1566–1569
. 
See also
 
livedo reticularis and, 877
Raynaud phenomenon and, 857–859, 
858
t
Cold agglutinin disease, 
525–526
Cold/fever sore (herpes simplex), 
 
126–127
, 126
f
. 
See also
 
Herpes simplex infection
Cold urticaria, 141
Cold water, facial contact with, for 
t
, 1237
for lipid modification, 1273
t
, 1274
Colestipol, 605, 649, 668, 1273
t
, 1274
Colistin, 285
t
Colitis. 
See also
 Diarrhea
amebic (intestinal amebiasis), 599
t
, 600, 
603, 1322
t
, 1528, 1529, 1529
f
, 
1530
t
antibiotic-associated/
C difficile,
 599
t
, 
600, 603, 
659–662
, 1312
t
CMV , 1389, 1390
collagenous, 675
Crohn, 665. 
See also
 Crohn disease
ischemic, 490, 609
lymphocytic, 675
microscopic, 603, 
675
postdysenteric, 1529
pseudomembranous, 660. 
See also
 
Colitis, antibiotic-associated
ulcerative. 
See
 Ulcerative colitis
Collagenomas, in MEN, 1197
t
Collateral ligaments of knee, 1709, 1712
t
, 
1715
Colloids, for fluid management/volume 
replacement, 507, 925
Cologuard screening, 1654
Colon
anaerobic flora of, 1484
biopsy of, in diarrhea, 605
t
, 1615
t
, 1650, 1651, 
1651–1652. 
See also
 
Colorectal cancer
carcinoid tumors, 1195, 1196, 
 
1647
dilation of. 
See also
 Megacolon
in acute colonic pseudo-obstruction 
(Ogilvie syndrome), 651, 
 
652
655–682
. 
See also
 
specific 
disorder
polyps of, 
678–682
. 
See also
 Polyps/
polyposis
Colon cutoff sign, 743
Colonic (gastrointestinal) CMV disease, 
1389, 1390
Colonic inertia (slow colonic transit), 595, 
595
t
Colonic pseudo-obstruction
acute (Ogilvie syndrome), 
651–652
chronic, 
652–653
Colonic transit time, 595, 595
t
, 596
transfusion of, 554–555. 
See also
 
Plasma/plasma fractions/

595
t
651–652
chronic, 
652–653
t
, 596
See also
 
components, Transfusion
Coagulopathy, 
567–573
. 
See also
 
specific 
type and
 Bleeding
of chronic kidney disease, 941
congenital disorders causing, 
567–571
, 
569
t
, 570
t
consumptive (DIC), 
563–565
, 564
t
, 
573
. 
See also
 Disseminated 
intravascular coagulation
of liver disease, 51, 
572–573
, 699, 719. 
See also
 Esophageal varices
Coal worker’s pneumoconiosis, 318, 318
t
Coarctation of aorta, 
335–336
, 353, 455
Coartem (artemether-lumefantrine/
Riamet), 1518
t
, 1519
t
, 1520
t
, 
1522, 1523
Cobalamins, 517. 
See also
 Vitamin B
12
Cobicistat. 
See also
 Antiretroviral therapy
with atazanavir, 1364
t
, 1369, 1370, 
1373
t
in combination regimens, 1372
t
, 1373
t
. 
See also
 Genvoya; Stribild; 
Symtuza
with darunavir, 1364
t
t
Cobimetinib, 1621
t
Cocaine/cocaine abuse, 
1113
, 
1590–1591
beta-blocker use and, 465
cardiac toxicity and, 378, 383, 427, 1113
epistaxis and, 231
granulomatosis with polyangiitis 
(Wegener granulomatosis) 
and, 873
levamisole-associated purpura and, 874
during pregnancy, 813, 1113
psychotic/violent behavior and, 1080, 
1104, 1113
pulmonary disorders caused by, 320, 
1113
rhabdomyolysis and, 866, 1590
Coccidioides immitis/posadasii
 
(coccidioidomycosis), 279
t
, 
1553–1554
Coccidiosis, 
1530–1533
Cochlear disorders, 210, 211, 218–219, 220
Cochlear implants, 70, 211
“Cochlear otosclerosis, ” 217
Cockcroft-Gault formula, 928
Codeine, 88, 94
t
, 605, 816
t
, 1604
Coffee grounds emesis/aspirate, 606, 610, 
632, 641
Cogan syndrome, 219
Cognitive ability, 57–58. 
See also
 Cognitive 
disorders
1212
Cognitive disorders, 57–60, 1031–1035, 
1032
t
, 1114–1116, 1115
t
. 
 
See also
 
Delirium; Dementia
chemotherapy causing (“chemo brain”), 
773
in elderly, 57, 57–58, 59, 1032, 1032
t
after head injury, 1044, 1115
t
hypothalamic damage and, 1121
mild impairment, 58, 1031
postoperative, 52
Cognitive reserve, 1032
Coin lesion. 
See
 Solitary pulmonary 
nodule
CMDT2019_Index_p1743-1884.indd   1773

INDEX1774
 
CMDT 2019
Congenital adrenal insufficiency, 1181
Congenital combined hypopituitarism, 
1119
Congenital cytomegalovirus (CMV) 
infection, 1388, 1389
Congenital gonadotropin deficiency, 1120
Congenital growth hormone deficiency, 
1119, 1120
Congenital heart disease, 
334–342
. 
 
See also
 
endocarditis/endocarditis prophylaxis 
and, 1464, 1466, 1466
t
pregnancy and, 446, 447
t
, 833
Congenital high-oxygen-affinity 
hemoglobin, 531
Congenital rubella syndrome, 1396
Congenital VZV syndrome, 835
Congestive heart failure. 
See
 Heart 
(cardiac) failure
Conivaptan, 903
Conization of cervix, 785, 786
Conjunctiva
foreign body of, 
203
, 204
f
lacerations of, 205
Conjunctivitis, 
176–178
, 176
t
. 
See also
 
Keratoconjunctivitis
adenovirus, 176, 1429
allergic, 178
bacterial, 
176–177
chemical, 
205–206
, 1589
coxsackievirus, 176, 1434
enterovirus 70, 176, 1435
gonococcal, 176–177, 1481, 1482
inclusion, 177, 837
in loiasis, 1549
viral, 
176
Conn syndrome, 1188, 1189
Connective tissue disorders. 
See also
 
mixed, 
864
t
Connexin-26
 mutation, 219
Consciousness
in head injury, 1043
in minimally conscious state, 1042
in seizures, 998
psychogenic nonepileptic/
pseudoepileptic, 1001
Constipation, 
73
, 
595–598
, 595
t
, 597
t
anogenital pruritus and, 156
fecal impaction and, 598
opioid-induced, 73, 97
palliation of, 
73
Constitutional delay in growth and 
puberty, 1209
Constrictive pericarditis. 
See
 Pericarditis
Consumptive coagulopathy, 
563–565
, 
564
t
, 
573
. 
See also
 
“Consumptive hypothyroidism, ” 1134
Contact dermatitis, 
132–133
, 133
f
allergic, 109, 132, 133
f
cellulitis differentiated from, 146
irritant, 132
Contact lenses, 174
corneal infections/ulcers/acanthamoeba 
keratitis and, 174, 185, 186
toxic/hypersensitivity reactions to 
cleaning solutions for, 206
Compression/entrapment neuropathy, 
1050, 1052–1054. 
See also
 
specific type or nerve affected 
and
 Neuropathies
Compression stockings
for leg ulcers, 165
for lower extremity edema/PE/DVT 
(venous thromboembolic 
disease), 34, 501, 586
for lymphedema, 504
for varicose veins, 498
Compromised host. 
See
 
Immunocompromised host
Compulsions, 1070. 
See also
 Obsessive-
compulsive disorder
Compulsive water drinking. 
See
 
Psychogenic polydipsia
Computed tomography (CT scans). 
See 
also
 
in angina/chest pain evaluation, 29, 371
in colorectal cancer screening, 678, 
1650, 1653, 1653
t
, 1654
t
, 1655
coronary heart disease risk and, 1269
in hyperparathyroidism, 1166
in hyperthyroidism, 1143
in lung cancer/cancer screening, 15
t
, 16, 
297
, 1625, 1626, 1626
f
, 1627
in pancreatitis, 743
in pericarditis/effusion, 439, 440, 442
1192
in pulmonary embolism, 307, 309, 310
f
radiation exposure/cancer risk and, 
1611
in renal artery stenosis, 944
Computed tomography angiography 
(CTA)
in angina/ACS/STEMI/chest pain 
evaluation, 29, 371
f
in renal artery stenosis/renal vascular 
Computed tomography colonography 
(virtual colonoscopy), 678, 
t
, 1654
t
, 1655
Computerized stereotactic guided core 
needle breast biopsy, 760
COMT inhibitors, 1026–1027
Concussion, 1042, 1043, 1043
t
labyrinthine, 223
Condoms
for contraception, 
805
in STD/HIV prevention. 
See
 Safer sex
Conduction block, intraventricular, 398
Conduction disturbances. 
See also
 
specific 
type and
in beta-blocker overdose/toxicity, 1594
in myocardial infarction, 28
t
, 389–390
Conduction velocity studies, 1047, 1048, 
1698
Conductive hearing loss, 210. 
See also
 
Hearing loss
Condylomas (condylomata)
acuminata. 
See
lata, 684, 1497, 1498
f
Confusion. 
See
 Delirium
Confusion assessment method (CAM), 
61–62
Congenital adrenal hyperplasia, 1181, 
1182, 1207, 1208

See
f
See
 Delirium
61–62
Congenital adrenal hypoplasia, 1120, 1181
Coma (
Cont.
):
in poisoning/drug overdose, 1255
t
, 
1580–1581
in stroke, 1008, 1018, 1040, 1255
t
Coma vigil (persistent vegetative state), 
1042
Combivir (zidovudine with lamivudine), 
1366
Comedones, 134, 135. 
See also
 Acne
Comfrey toxicity, 712, 727, 1597
t
Common ALL antigen, 539
Common cold (viral rhinosinusitis), 
 
225–226
, 1429
Common peroneal (fibular) nerve palsy, 
1053
Common variable immunodeficiency, 
895
t
, 
896–897
Commotio cordis, 449, 450
t
Community-acquired pneumonia, 278, 
278–283
, 278
t
, 279
t
, 1321
t
, 
1452. 
See also
 Pneumonia
chlamydial, 278
t
, 1321
t
, 1322
t
, 1492
in coccidioidomycosis, 279
t
, 1553
in HIV infection/AIDS, 280, 1344
Legionnaires, 278
t
, 1319
t
, 1321
t
, 1322
t
, 
1472–1473
Community-associated methicillin-
resistant 
S aureus
 (CA-MRSA) 
infections. 
See also
 
S aureus
 
(MRSA) infections
impetigo, 132
pneumonia, 279
t
, 280, 281
Compartment syndrome
in burn patient, 1572
in electrical injury, 1574
in frostbite, 1569
Compassionate death (physician-assisted 
death), 78–79, 78
t
Compatibility testing, for transfusion, 
 
552
Complement. 
See also
 
specific component
disorders of, 895
t
in glomerulopathies/
glomerulonephritis, 935, 948
f
, 
952
in gonococcal arthritis, 883
immunization recommendations in 
deficiencies and, 1328
t
, 1333
t
Complement-mediated hemolytic-uremic 
syndrome, 561, 561
t
Complera (tenofovir [TDF]/emtricitabine/
rilpivirine), 1366, 1367
t
, 1368, 
1372
t
Complete abortion, 818
Complete androgen blockade, 1663
Complete (third-degree) heart block, 389, 
390, 397, 398. 
See also
 
Atrioventricular (heart) 
 
block
Complex 15, 108
t
Complex regional pain syndrome (reflex 
sympathetic dystrophy), 
 
888–889
Compliance/noncompliance. 
See
 
Adherence/nonadherence
Compound nevi, 110, 110
f
Compression chambers/centers. 
 
See
 Hyperbaric oxygen 
therapy; Recompression
CMDT2019_Index_p1743-1884.indd   1774

INDEX1775
 
CMDT 2019
acute/ST-segment elevation infarction 
myocardial (STEMI), 27–29, 
28
t
, 365, 378, 379, 382
t
, 
 
383–393
, 385
t
angina pectoris (chronic stable) and, 
368–377
, 373
f
, 376
t
, 377
t
antihypertensive drug therapy and, 
10–11
aortic regurgitation and, 358
aortic stenosis and, 354, 355
aspirin/chemoprevention for, 6
t
, 11, 
365, 366
f
t
, 
1251, 1268, 1271–1275, 1272
t
, 
1273
t
. 
See also
therapy
t
, 10, 
365,1267–1268, 1269–1270
chronic kidney disease and, 939
in diabetes mellitus, 365, 365
f
, 368, 375, 
376, 383
1212
heart failure and, 414, 422
in HIV infection/AIDS, 1355
in, 1686
t
f
, 455, 
457, 458, 459
t
levothyroxine treatment and, 1137
lipid disorders and, 10, 365, 1267–1275
metabolic syndrome and, 365
myocardial hibernation/stunning and, 
365–367
and, 47–48, 48
f
in pregnancy, 
447–448
, 833
5–11
, 6
t
, 8–9
t
, 9
t
, 365, 
366
f
t
, 1268, 
t
, 1273
t
t
, 
 
f
, 
367–368, 367
t
, 1268, 
 
t
, 1273
t
. 
See 
also
revascularization procedures for, 373
f
, 
375–376, 385–386. 
See also
 
risk/risk stratification/reduction for, 5, 
10, 27–29, 365, 366
f
, 367–368, 
367
t
lipoproteins/lipid fractions and, 6
t
, 
10, 365, 367–368, 
1267–1268
sudden death and, 411
in athletes, 449
triglycerides in, 368, 1267, 1275
vasospasm and, 368, 
377–378
, 383
in women, 1270
Coronary reperfusion. 
See
 Reperfusion 
therapy; Revascularization 
Coronary sinus atrial septal defect, 
 
337
Coronary stents, 375, 385–386. 
See also
 
antiplatelet therapy and, 386
preoperative/perioperative risks and, 
47–48
thrombotic events and, 375
Coronary vasospasm, 368, 
377–378
, 
 
383
for emergency/postcoital contraception, 
804, 806
Copper-transporting adenosine 
triphosphatase, 725
Coprolalia, 1031
Cor pulmonale, 269, 270, 273, 415
Coral snake antivenom, 1608
Coral snake envenomation, 1607, 1608
Cord cavitation (syringomyelia), 
1045–1046
Corditis, polypoid, 245
“Core-binding factor” leukemias, 538
Core body temperature (CBT). 
See
 Body 
(core body) temperature
Core needle (large-needle) biopsy, of 
breast, 750, 758, 759–769, 
759
f
, 760
f
. 
See also
 Breast, 
biopsy of
Cornea
203
, 204
f
infection of, 176
t
. 
See also
 Keratitis; 
trauma to, 176
t
abrasions, 
203–204
chemical burns (conjunctivitis and 
keratitis), 
205–206
, 1589
lacerations, 205
ulcers of, 
178–185
, 185. 
See also
 
Keratitis
contact lens wear and, 185
in vitamin A deficiency, 1285
ultraviolet burns of (ultraviolet/actinic 
205
Corneal reflex, in coma/stupor, 1040
Corneoscleral lacerations, 205
t
, 
388–389
in angina, 371–372
normal findings and, 
377–378
Coronary angioplasty. 
See
 Percutaneous 
coronary intervention
Coronary arteries
365–393
. 
See also
 
in Kawasaki syndrome, 1446, 1447
447–448
, 833
of athlete, 449, 450
t
traumatic injury to, 445–446
vasospasm of, 368, 
377–378
, 383
Coronary artery bypass grafting (CABG), 
376. 
See also
for angina/ACS/STEMI, 376, 393
antiplatelet therapy/platelet function 
and, 568
t
for heart failure, 422
PCI compared with, 376
PCI for stenoses after, 375
prophylactic/preoperative, 47–48
Coronary artery disease (CAD). 
See
 
Coronary heart disease, 
365–393
. 
See also
 
Acute coronary syndromes; 
Angina; Myocardial infarction

See
 
365–393
. 
See also
 
acute coronary syndromes without 
ST-segment elevation 
(NSTEMI), 
378–383
, 380
f
, 382
t
Contact photosensitivity, 163, 164. 
See also
 
Photodermatitis
Contact ulcers, of arytenoid cartilage, 245
Contagious pustular dermatitis (orf), 1431
Continuous glucose monitoring systems, 
1226, 1227. 
See also
 Self-
monitoring of blood glucose
Continuous positive airway pressure 
(CPAP), for sleep apnea, 328
Continuous renal replacement therapy 
(continuous venovenous 
hemodiafiltration), for 
poisoning/drug overdose, 
1585, 1601
Continuous subcutaneous insulin infusion 
(CSII) pumps, 1240, 1243. 
See 
also
 Insulin infusion pumps
Contraception, 
800–807
, 801
t
, 802
t
, 804
t
. 
See also
 
specific method
emergency/postcoital, 
805–806
. 
See also
 
Emergency/postcoital 
contraception
fertility awareness and, 
805
sterilization for, 
806–807
Contraceptive foam/cream/film/sponge/
jelly/suppository, 
805
Contraceptive injections/implants, 803
Contraceptive-related hypertension, 802
Contraceptive transdermal patch, 803
Contraceptive vaginal ring, 803–804
Contraction alkalosis, 923
Contrast media
iodinated, for hyperthyroidism/Graves 
disease, 1144–1145
932, 1248
reactions to, 892
Contrast nephropathy, 932, 1248
Contusions
cerebral, 1043
t
of eye, 
205
myocardial, 445
Conversion disorder (functional 
neurologic symptom 
disorder), 1071
seizures and, 1000–1001, 1071
Convertase subtilisin kexin type 9 
(PCSK9) inhibitors, 10, 
 
367–368, 1274
Convulsions. 
See
 Seizures
Cooley anemia (thalassemia major), 515
Cooling
in heat exposure, 1565, 1566
for hyperthermia in poisoning/drug 
overdose, 1583
Coombs test/micro-Coombs test
in autoimmune hemolytic anemia, 525
in cold agglutinin disease, 526
550
CO-oximetry. 
See
 Pulse oximetry/
CO-oximetry
COPD. 
See
 Chronic obstructive 
pulmonary disease
Copeptin, in headache evaluation, 42
Copper
1293
t
in Wilson disease, 725, 726
Copper-containing IUD, 804
CMDT2019_Index_p1743-1884.indd   1775

INDEX1776
 
CMDT 2019
 (Q fever), 1437
t
, 
 
1444–1445
Coxsackievirus infections, 
1433–1434
CPR. 
See
 Cardiopulmonary resuscitation
“Crab yaws, ” 1502
Crabs (pubic lice), 158, 159. 
See also
 Lice
Crack cocaine. 
See
 Cocaine/cocaine abuse
CRAG (cryptococcal antigen) test, 1348, 
1556
Cramps (menstrual). 
See
 Dysmenorrhea
Cranial arteritis. 
See
Cranial nerve VIII (acoustic nerve) 
lesions. 
See
 Schwannoma, 
vestibular
Cranial nerve palsies. 
See also
 
brainstem lesions causing, 1016
in malignant external otitis, 213
ocular motor palsies and, 
201–202
, 201
f
in sarcoidosis, 1050
Cranial nerve tumors, 1018
t
Cranial neuropathies
glomus tumor causing, 218
in Lyme disease, 1050, 1506, 1507, 
1508
t
, 1509
Craniopharyngioma, 1017
t
, 1122, 1124
CRB-65, 282
Creatine (supplement), toxicity of, 1597
t
Creatine kinase-MB (CK-MB)
in ACS (NSTEMI/STEMI), 379, 384
in myocarditis, 426
Creatinine
in acute kidney injury, 929, 930, 
 
930–931, 930
t
, 933, 935
in chronic kidney disease, 938, 938
f
t
urinary
in Cushing syndrome diagnosis, 1185
in pheochromocytoma, 1192
ratio of to urinary protein, 927. 
See 
also
Creatinine:blood urea nitrogen ratio, 928
930
t
, 933, 935
Creatinine clearance, 928
ACE inhibitors and, 465
anticoagulation therapy and, 52
t
Creeping eruption, 
1545–1546
, 1545
f
Crescentic glomerulonephritis, 946
t
, 948
f
, 
951
CREST syndrome, 854
t
, 858, 859. 
See also
 
Cretinism, 1134, 1159. 
See also
 
Creutzfeldt-Jakob disease, 1025, 1030, 
1035, 1406–1407
Cricothyrotomy, 
248
Crigler-Najjar syndrome, 688
Crimean-Congo hemorrhagic fever, 1412, 
1413
Crisaborole, 106
t
Critical illness
community-acquired pneumonia and, 
282, 282–283
for Kawasaki disease, 1446–1447
for lichen planus, 154, 235
for lumbar disk herniation, 1701
for meningitis, 1306
for minimal change disease, 955–956, 
956
for multiple sclerosis, 1036
for muscular dystrophy, 1060
for nasal polyps, 232–233
for nausea and vomiting, 73, 593, 594
t
for ophthalmic disorders, 182–183
t
, 
206
osteoporosis and, 263, 1172, 1218
in pain management, 100
perioperative, 53, 1183
for 
 infection, 1344, 1555
for polyarteritis nodosa, 870
for polymyositis/dermatomyositis, 863
in pregnant patient, 825–826, 1218
for prostate cancer, 1662
t
in psoriasis/psoriatic arthritis, 116, 880
for pulmonary vasculitis, 315
for rheumatic fever/heart disease, 436
for rheumatoid arthritis, 850–851
for seborrheic dermatitis, 118, 1353
for skin disorders, 103, 104–106
t
for spinal stenosis, 1700
for spinal trauma/compression, 1045, 
1671
strongyloidiasis in patients taking, 1542
for sudden sensory hearing loss, 219
for Takayasu arteritis, 869
topical, 103, 104–106
t
Cortisol. 
See also
ACTH deficiency and, 1120, 1121
after adrenal carcinoma surgery, 1186
deficiency/insufficiency of, 1121, 1180, 
1181, 1352. 
See also
 Adrenal 
insufficiency
excess of, 
1184–1187
. 
See also
 Cushing 
syndrome
familial resistance to, 1185
Cortisol withdrawal syndrome, 1186
Corynebacterium
diphtheriae
, 1319
t
, 1462. 
See also
 
jeikeium,
 1319
t
Cosyntropin test
in adrenal insufficiency/Addison 
disease, 1121, 1181–1182
in hirsutism/virilization, 1207
Cough, 
20–23
, 21
t
, 22
t
. 
See also
 
specific 
cause
blood production and (hemoptysis), 
26–27
in COPD, 20, 21, 22, 268, 269
t
drugs causing, 321
t
headache associated with, 
993
in heart failure, 21, 415
Counterpulsation, extracorporeal, 376
Courvoisier law/sign, 1635, 1636
Cowden syndrome/disease, 681

t
t
993
COX-1/COX-2, aspirin/NSAIDs affecting, 
843
COX inhibitors. 
See
 Nonsteroidal 
 
Coxibs (COX-2 inhibitors), 633. 
See also
 
Celecoxib
Coronavirus, Middle East respiratory 
syndrome caused by, 
 
1427–1428
“Corrective rape, ” 1729
Corrigan pulse, 358
Corrosive agents. 
See
agents
Corti, organ of, hearing loss and, 210
Cortical blindness, 1016
Cortical stimulation, for seizures, 1001
Corticobasal degeneration, 1025
Corticosteroids, 103, 104–106
t
, 
 
1217–1219
, 1218
t
. 
See also
 
specific agent and disease
acne/folliculitis caused by, 134, 137
for ACTH/adrenal insufficiency/
Addison disease, 1122, 
 
1182–1183
for adhesive capsulitis (frozen 
shoulder), 1697
t
, 1217–1219
for allergic eye disease, 178
for ARDS, 332
for aspergillosis, 1558
for asthma, 255
t
, 258
f
, 259–263, 260
t
, 
262
t
, 263
t
f
, 
266
f
, 267
exacerbation management and, 254
f
, 
255
t
, 259, 261, 264, 265, 265
f
, 
266
f
, 267
inhaled, 258
f
, 259–261, 262
t
, 264
systemic, 255
t
, 258
f
, 260
t
, 261–263, 
263
t
f
, 266
f
, 267
for atopic dermatitis/eczema, 113–114, 
114
for autoimmune hemolytic anemia, 525
for Bell palsy, 1054, 1380
in cancer chemotherapy, 1624
t
for cancer-related hypercalcemia, 1673
for chronic inflammatory 
polyneuropathy, 1052
clinical use of, 1122, 
1217–1219
, 1218
t
Cushing syndrome caused by, 1183, 
1184
diabetes/insulin resistance and, 1223
for eosinophilic esophagitis, 625
for epicondylosis, 1703
in erythema multiforme/SJS/TEN, 144
for eustachian tube dysfunction, 214
for exfoliative dermatitis/erythroderma, 
125
for fetal lung maturity, 825–826
for giant cell arteritis, 196, 869
for gout, 845–846, 847
for herpes zoster/VZV infection, 129, 
1384
for immune thrombocytopenia, 559, 
560
f
for inflammatory bowel disease, 662–
663, 668–669, 672, 673–674
in interstitial lung disease, 303
for gout, 846, 847
for osteoarthritis, 843
for ischemic optic neuropathy, 199
CMDT2019_Index_p1743-1884.indd   1776

INDEX1777
 
CMDT 2019
Cyclophosphamide, 1616
t
. 
See also
 
Immunosuppressive 
 
therapy
for breast cancer, 765–766
t
315, 873
hemorrhagic cystitis caused by, 1679
interstitial cystitis caused by, 974
for lupus nephritis, 855, 953
for scleroderma, 860
Cycloserine (DCS), 1068
Cyclospora cayetanensis
 (cyclosporiasis), 
599
t
, 600, 603, 
1530–1533
adverse effects/toxicity of, 208
t
, 932
hyperkalemia caused by, 908
insulin secretion affected by, 1223
nefazodone interaction and, 1093
for ophthalmic disorders/dry eye, 177, 
183
t
, 865
for psoriasis, 116–117
for ulcerative colitis, 674
Cyclothymic disorders, 1088
CYP2C9 variants, warfarin and, 582
CYP2C19, 640
CYP17 (17-hydroxylase/P450c17) 
deficiency, 1200, 1209
CYP17a1 inhibitor, for prostate cancer, 
1662
t
CYP34A, in corticosteroid metabolism, 
1217
Cyproheptadine, 142, 1584, 1610. 
See also
 
Cystadenocarcinoma, of liver, 731
Cystadenoma
of liver, 731
pancreatic, 1636, 1637, 1638
Cystathionine beta-synthase 
(CBS)
 gene/
deficiency, 1686
Cystatin C, for GFR estimation, 928
Cystectomy, 1665
Cysteine, supplementary, 1686
Cystic fibrosis, 
275–277
1558
bronchiectasis and, 274, 276
genetic/prenatal testing for, 276, 277, 
 
813
pancreatitis and, 741, 746, 747
Cystic fibrosis transmembrane 
conductance regulator 
(CFTR) modulator drugs, 
 
276
(CFTR) protein, 275
genetic/prenatal testing of, 276, 277
Cystic hydatid disease, 1540
Cystic kidney disorders, 937
t
, 
 
961–964
, 962
t
. 
See also
 Renal 
cysts
Cystic medial necrosis, sudden death in 
athlete and, 449
Cysticercosis, 1538, 
1539
Cystine urinary stones, 975, 977
Cystinuria, 975
Cryptosporidium hominis/parvum
 
(cryptosporidiosis), 599
t
, 600, 
1352, 
1530–1533
Crystal deposition arthritis, 
844–848
, 
844
t
, 845
f
, 846
t
Crystalloids, for fluid management, 507, 
925, 1571–1572
CSF FTA-ABS test, 1501
CSF-VDRL test, 1360, 1500, 1501
CSF3R
 mutation, 529
CT. 
See
 Computed tomography
CT-FFR (fractional flow reserve), 371
CTLA-4 agents. 
See
 Anti-CTLA-4 agents
Cubital tunnel, ulnar nerve lesions and, 
1052, 1053
Cultural issues, end-of-life care/autopsy/
organ donation and, 77, 81
Culture-negative endocarditis, 1465–1466, 
1468, 1483
Culture-negative neutrocytic ascites, 615
Cultured allogeneic keratinocyte grafts, for 
burns, 1572
 infection, 1558–1559
Cupping/cup-disk ratio, in glaucoma, 188
Cupulolithiasis, 223
Curative efforts, withdrawal of, 76, 78
CURB-65, 282
Curettage. 
See
 D&C; Endocervical 
curettage; Endometrial biopsy
Curvularia,
 1561
Cushing disease, 1184, 1186. 
See also
 
muscle weakness in, 863
pituitary adenoma/pituitary surgery 
and, 1187
Cushing syndrome (hypercortisolism), 
1184–1187
amenorrhea in, 1209
hirsutism/virilization in, 1206
hypertension and, 454–455
Cutaneous anthrax, 1461, 1461–1462
Cutaneous (mucocutaneous) candidiasis, 
139–140
, 140
f
Cutaneous drug reactions. 
See
 Drug 
eruptions
Cutaneous innervation, 1056–1057
f
Cutaneous larva migrans, 
1545–1546
, 
1545
f
Cutaneous leishmaniasis, 1513, 
 
1513–1514, 1514, 1514
f
, 1515
Cutaneous lupus erythematosus, 
123–124
, 
171
t
Cutaneous T-cell lymphoma (mycosis 
fungoides), 
124
, 125
Cutaneous tests. 
See
 
 Skin 
tests
Cyanide antidotes, 1584
t
, 1596–1597
Cyanide poisoning, 1584
t
, 
1596–1597
Cyanogenic plants, 1596
Cyanokit, 1597
Cyberknife surgery, for pituitary tumor, 
1127
Cyclic citrullinated peptide (CCP) 
antibody, 849, 878
Cyclic thrombocytopenia, 
558
Cyclin dependent kinase inhibition, for 
breast cancer, 770
Cycling, in bipolar disorder, 1088, 1097
Cyclooxygenases. 
See
 COX-1/COX-2
Cyclooxygenase inhibitors. 
See
 Celecoxib; 
Coxibs; Nonsteroidal

See
See
Coxibs; Nonsteroidal 
 
diabetes management and, 1253
fever/health care–associated infection 
and, 1301, 1303
myopathy and, 1062
neuropathy and, 
1050
psychosis and, 1116
shock liver/cardiogenic liver injury and, 
728
stress gastritis and, 632, 632–633
Critical limb ischemia, 486
Crizotinib, 1621
t
, 1628
CroFab, 1608
Crohn disease, 662, 
665–671
. 
See also
 
arthritis in, 666, 881
colorectal/small intestine cancer and, 
667, 1649–1650
social support and, 665
vitamin B
12
 deficiency and, 517
Crohn’s and Colitis Foundation of 
America (CCFA), 665
Cromolyn
for allergic eye disease, 181
t
for allergic rhinitis, 230
for asthma, 258
f
, 260
t
, 264
Cross dresser, 1737
Crossmatching, in blood compatibility 
testing, 552
Cross-reactivity/sensitivity, in drug 
allergies, 1324
Cross-resistance, in antiretroviral therapy, 
1375
Crotalid antivenin (CroFab), 1608
Croup, 1421
Crowned dens syndrome, 848
Cruciate ligaments of knee, 1709, 
 
1710–1714
, 1711
t
, 
1715–1716
Crusted/weeping skin lesions, 103, 104
t
, 
131–133
. 
See also
 
Cryoglobulins/cryoglobulinemia, 
875
glomerulonephritis and, 875, 946
t
, 948
f
, 
952
hepatitis C and, 697, 706, 875, 952, 953
Raynaud phenomenon and, 858
Cryoprecipitate, 554–555, 564
Cryotherapy/cryosurgery. 
See also
 Liquid 
nitrogen
for CIN/cervical cancer, 785
for hepatocellular carcinoma, 1633
for prostate cancer, 1661
for wart removal/condylomata 
acuminata, 149, 782
Cryptococcal antigen (CRAG) test, 1348, 
1556
Cryptococcomas, 1556
Cryptococcus gattii/neoformans
 
(cryptococcosis/cryptococcal 
meningitis), 
1556–1557
in HIV infection/AIDS, 1020, 
 
1345–1346
t
, 1348–1349, 1556, 
1557
Cryptogenic organizing pneumonia/
pneumonitis (COP/
bronchiolitis obliterans with 
organizing pneumonia/
BOOP), 277, 302
t
, 303
Cryptogenic stroke/TIA, 338, 1006, 1009. 
See also
 Stroke
Cryptorchism, 1200, 
1204
pseudohermaphroditism and, 1209
testicular cancer and, 1200, 1204, 
 
1669
CMDT2019_Index_p1743-1884.indd   1777

INDEX1778
 
CMDT 2019
gastrointestinal, 
1584–1586
, 1585
t
, 
1589, 1590
skin, 
1584
, 1589, 1590, 1595
Decorticate (flexor) posturing, 1040, 
 
1041
De-efferented state (locked-in syndrome), 
1042
Deep brain stimulation
Deep breathing exercises, postoperative 
pulmonary complications 
 
and, 50
Deep neck infections, 
240–241
“Deep sulcus” sign, 326
Deep venous thrombosis, 33, 33
t
, 34. 
 
See also
 Venous 
thromboembolic disease
air travel and, 33, 34, 1579
306, 584, 586
t
, 830, 856–857
estrogen replacement/feminizing 
hormone therapy and, 810, 
1211, 1212, 1738–1739
872
hypercoagulability and, 306
joint replacement and, 1708
lower extremity edema and, 33, 33
t
, 34
prevention of, 309, 575–576
t
, 577–579, 
577
t
, 578–579
t
, 579
t
, 587
pulmonary embolism and, 305–306, 
308, 309
t
, 587. 
See also
 
Pulmonary venous 
recurrent, 582–584
risk/risk stratification for, 305–306, 
306
t
, 309
t
, 310
f
, 310
t
, 311, 
t
, 581, 581
t
treatment of, 309–312, 575–576
t
, 
 
579–587
anticoagulation, 309–311, 574, 
 
575–576
t
, 579–585, 580
t
, 581
t
, 
583
t
, 584
t
, 585
t
, 586
t
nonpharmacologic, 586–587
thrombolytic therapy, 586
venous insufficiency/stasis and, 33, 33
t
, 
34, 500, 501
Defecation, dyssynergic (pelvic floor 
dyssynergia), 595–596, 595
t
, 
596
Deferasirox, 209
t
, 724, 1559
Deferiprone, 724
Deferoxamine, 209
t
, 724, 1587
t
Defibrillation. 
See
 Cardioversion
Defibrillator cardioverter, implantable. 
 
See
Defibrillator vest, 411
Defibrotide, 727
Deflazacort, 1060
Degarelix, 1623
t
, 1662, 1662
t
Degenerative (calcific) aortic stenosis, 353
Degenerative joint disease, 
840–843
, 842
f
. 
See also
 Arthritis; 
Dapagliflozin, 1231
t
Dapivirine, 1424
Dapsone
t
G6PD deficiency and, 1298, 1361
and, 894
for leprosy, 1490
methemoglobinemia caused by, 1361, 
1603
for 
 infection, 1298, 1345
t
, 
1362
t
, 1555
for toxoplasmosis, 1361
Daptomycin, 1450, 1455, 1456, 1457, 1468
Daratumumab, 548, 551, 1619
t
Darbepoetin, 514, 527, 940–941, 1676
t
, 
1677
Darunavir, 1370, 1372
t
t
t
t
, 
1373, 1373
t
. 
See also
 Symtuza
with ritonavir, 1364
t
, 1370, 1371, 1372
t
, 
1373, 1373
t
Dasabuvir, 704
t
, 705, 1351
Dasatinib, 535, 540, 1621
t
, 1679
DASH diet, in hypertension/hypertension 
prevention, 457, 457
t
“Date-rape” drug (gamma-
hydroxybutyrate/GHB), 1185, 
1599
Datura stramonium,
 toxicity of, 1593
Daunorubicin/daunomycin, 546, 1618
t
, 
1680
Dawn phenomenon, 1243, 1243
t
DCC
 gene, 1649
DCCT, 1227, 1242
De Quervain (painful subacute) 
thyroiditis, 1131–1132, 1132, 
1133, 1134, 1140
Deafness. 
See
 Hearing loss
Death. 
See also
 End of life; Sudden death
Kübler-Ross’ patterns of emotions and, 
79
leading/preventable causes of, 2, 2
t
, 3
t
. 
See also
 Health maintenance/
disease prevention
patient expectations about, 74
physician-assisted, 78–79, 78
t
tasks after, 
81
Death certificate, 81
Death with dignity (physician-assisted 
t
Debridement, in burn care, 1572
Decadron, 1678
Decerebrate (extensor) posturing, 1040, 
1041
Decision making, medical
advance directives/end of life and, 76
older patient’s capacity/self-neglect and, 
58, 70–71
Decitabine, 537, 1617
t
Decompression sickness, 214, 
1575–1576
for bacterial rhinosinusitis, 227, 1347
for epistaxis, 231
for eustachian tube dysfunction/
barotrauma, 213, 214
t
, 1596
for viral rhinosinusitis (common cold), 
225
Decontamination
eye, 
1584
Cystitis, 43, 
967–969
, 968
t
, 1322
t
.

t
, 1596
225
eye, 
1584
967–969
, 968
t
, 1322
t
. 
See also
 
in female, 43, 834, 967–969
hemorrhagic. 
See
 Hemorrhagic cystitis
interstitial, 44, 
974
Cystocele, 791–792
Cystoscopy, 966
in benign prostatic hyperplasia, 984
in hematuria, 966
in interstitial cystitis, 974
Cystourethroscopy, in bladder cancer, 
1665
Cytarabine, 1617
t
, 1678
Cytolytic snake venom, 1607
Cytomegalovirus (CMV) disease, 
 
1388–1391
esophageal, 623
gastritis/diarrhea, 599
t
, 635, 1389, 1390
infection/AIDS, 198–199, 
1350, 1388–1389, 1389, 
 
1389–1390, 1390
mononucleosis, 1388, 1389
posttransplant, 1299, 1388, 1389–1390, 
1390
prevention of, 199, 1299
retinitis, 198–199, 1346
t
, 1350, 1362, 
1388, 1389, 1390
transfusion in transmission of, 554
Cytomegalovirus (CMV) immune 
globulin, 1390
Cytomegalovirus (CMV) inclusion disease, 
1388, 1389
Cytopenia
autoimmune, common variable 
methotrexate causing, 851
D&C, 777
t
D-cycloserine (DCS), for phobic disorders, 
1068
D-dimer fibrin
in DIC, 539, 564
disease), 34, 307, 309, 310
f
, 
583
D state sleep, 1101
Dabigatran, 574, 575–576
t
, 578
t
, 580
t
, 582
404, 405
t
, 406
disease), 574, 575–576
t
, 578
t
, 
580
t
, 582
after myocardial infarction, 388
t
, 406
prosthetic heart valves and, 404
Dabrafenib, 1621
t
, 1628
Dacarbazine, 1617
t
Daclatasvir, 704
t
, 705
Dacryocystitis, 
175–176
Dactinomycin, 1622
t
Dalbavancin, 1455
Dalfampridine, 1037
Dalfopristin/quinupristin, 1452
Dalteparin, 578
t
, 580
t
Danazol, 525, 551, 791
Dandruff, 118
Dantrolene, 1039, 1085, 1302, 1583–1584, 
1592
CMDT2019_Index_p1743-1884.indd   1778

INDEX1779
 
CMDT 2019
OCD and, 1070
oral contraceptive use and, 802, 1088
panic disorder and, 1066
Parkinson disease and, 1025
perimenopausal, estrogen replacement 
therapy and, 1212
phototherapy for, 1096
with postpartum onset, 1087–1088
during pregnancy/prenatal, 1087–1088, 
1093
in premenstrual dysphoric disorder, 
779, 1088
prognosis for, 1099
reserpine causing, 474
t
, 475, 1088
schizophrenic/psychotic disorders/
ideation and, 1079, 1087, 
1088, 1090
screening for
in gay and bisexual men/MSM, 1735
t
with seasonal onset, 1087, 1096
sleep-wake disorders and, 1101
somatic symptom disorder and, 1071
suicide and, 1089, 1118
in terminally ill/dying patient, 79–80
treatment of, 1089–1097, 1091
t
, 1092
f
, 
1095
t
. 
See also
 
bipolar disorder and, 1097–1099, 
1099
t
Dermacentor-borne-necrosis-erythema-
lymphadenopathy/scalp 
eschar neck 
lymphadenopathy/tick-borne 
lymphadenopathy, 1437
t
, 1442
Dermatitis. 
See also
 Skin disorders
actinic, 163, 164
atopic, 
113–114
. 
See also
 Eczema
cercarial, in schistosomiasis, 1535
contact. 
See
 Contact dermatitis
contagious pustular (orf), 1431
drugs causing (medicamentosa/drug 
eruption), 
170–173
, 171–172
t
, 
894
exfoliative (exfoliative erythroderma), 
124–125
, 171
t
herpetiformis, 
131
, 645
in HIV infection/AIDS, 1352–1354
in niacin deficiency, 1283
seborrheic. 
See
 Seborrheic dermatitis
stasis. 
See also
 Venous insufficiency/
stasis
leg ulcers and, 165, 165
f
vesiculobullous of palms and soles 
(pompholyx), 
129–130
, 130
f
Dermatographism, 142
Dermatologic disorders. 
See
 Dermatitis; 
Skin disorders
Dermatologic therapy, 
103–110
, 104–109
t
, 
209
t
Dermatomyositis, 854
t
, 
861–864
, 862
f
, 
862
t
cancer-related, 861, 862, 889, 1022
sine myositis, 861
Dermatopathic lymphadenopathy, 124
Dermatophytosis. 
See
 Tinea
Dermopathy
in Graves disease (pretibial myxedema), 
1140, 1142, 1148
nephrogenic fibrosing, 860
vitamin B
12
 deficiency and, 517, 1034
 folliculitis, 137, 138
Demyelination/demyelinating 
neuropathies/
polyneuropathies, 1047. 
 
See also
 
Neuropathies
chronic inflammatory, 
1051–1052
hyponatremia complications/treatment 
and, 902
optic neuritis and, 199–200
and, 1049
Dengue/dengue hemorrhagic fever, 
 
1413–1415
Dengue shock syndrome, 1414
Dengue vaccine/Dengvaxia, 1415
Denial
at-risk drinking and, 1107
of illness, 1116, 1117
Denosumab, 1173–1174
for cancer-related hypercalcemia, 912, 
1168, 1673
for chemotherapy-induced toxicity/bone 
metastases, 1676
t
for osteoporosis, 1173–1174
for prostate cancer, 1663
for thyroid cancer bone metastases, 1156
“Dense deposit disease, ” 952
Dental disorders
anaerobic pleuropulmonary infections 
and, 286, 1484
bisphosphonate use and, 890, 1173
deep neck infections and, 240
earache and, 218
facial pain caused by, 997
Dental procedures, endocarditis 
prophylaxis and, 1467
Dentatorubral-pallidoluysian atrophy, 
1028
Deoxyribonuclease, human (rhDNase), 
276
Dependency (drug), 98, 1105. 
See also
 
specific drug and
 Substance 
use disorders
Dependent personality disorder, 1077
t
Depigmentation disorders, 166, 167
Depression, 
60–61
, 1087, 1087–1088
adjustment disorder with, 1087
alcohol use and, 1088
with atypical features, 1087, 1090
bipolar disorder and, 1097–1099, 1099
t
complications of, 1089
in cyclothymic disorders, 1088
dementia and (pseudodementia), 57, 
1032–1033, 1116
differential diagnosis of, 1088–1089
dispensing medications and, 1089, 1090
drug-induced, 1088
dysthymia, 1087
ECT for, 1095–1096
in elderly, 
60–61
in gay and bisexual men/MSM, 1734, 
1735
t
hospitalization/illness and, 1088, 1116, 
1117, 1118
in lesbian and bisexual women, 1730
major depressive disorder, 60, 1087–1089
“Degenerative” mitral valve disease. 
 
See
 Mitral valve prolapse

t
1117, 1118
 
See
Degenerative motor neuron diseases. 
 
See
 Motor neuron diseases
Dehydration. 
See
 Volume status
Dehydroemetine, 1529, 1530
t
Dehydroepiandrosterone/
dehydroepiandrosterone 
sulfate (DHEA/DHEAS)
and, 1182, 1183
hirsutism/virilization and, 1207
in hypopituitarism and hypogonadism, 
1123
Dejerine-Sottas disease, 1048–1049
Delafloxacin, 1455
Delavirdine, 1363
t
, 1368. 
See also
 
Delayed adolescence/puberty. 
See
 Puberty
Delayed hypersensitivity, 
894–895
Delirium, 57, 
61–62
, 
73–74
, 1032, 1115
alcohol use disorder/withdrawal and, 
1106, 1110, 1115
t
antipsychotics causing, 1083
dementia and, 57, 58–59, 1032
in elderly, 57, 
61–62
at end of life/palliation of, 
73–74
hallucinogens causing, 1116
hospitalization/illness and, 61, 1116
lithium causing, 1098
urinary incontinence and, 65
Delirium tremens, 1106
Delivery (childbirth). 
See
 Labor and 
delivery
Delta agent (hepatitis D virus/HDV), 696, 
698
, 701–703. 
See also
 
Hepatitis D
Delta-globin gene/chain, 514, 515
“Delta” sleep, 1101
Delta
9
-tetrahydrocannabinol. 
See
 
Cannabinoids/cannabidiol
Delusions/delusional disorders, 1079
psychotic major depression, 1087
schizophrenia/psychotic disorders, 1079
Demeclocycline, for hyponatremia, 903
Dementia, 
57–60
, 
1031–1035
, 1032
t
, 
1115–1116. 
See also
 
behavioral problems and, 59, 1034–1035
behavioral variant frontotemporal, 
1032
t
cognitive impairment and, 59, 1033, 
1034, 1115–1116
in Creutzfeldt-Jakob disease, 1025, 1035, 
1406
delirium and, 57, 58–59, 1032
depression and (pseudodementia), 57, 
57–60
t
1212
frontotemporal, 1032
t
, 1034
hypertension and, 455–456
with Lewy bodies, 57, 1032
t
, 1034
rapidly progressive, 1035
screening for, 57–58, 1033
CMDT2019_Index_p1743-1884.indd   1779

INDEX1780
 
CMDT 2019
pregnancy and, 831, 832, 1226–1227, 
1245
t
heart disease in, 365, 365
f
, 368, 375, 
376, 383, 429, 1250–1251
hepatitis B vaccination in, 4, 696, 1328
t
, 
1332
t
HLA in, 1220
hospitalization/surgery and, 53, 1245
t
, 
1252–1253, 1253
t
hypertension and, 452
f
, 476, 477, 1224, 
1228, 1251
antihypertensive therapy for, 459, 
460, 465, 471, 476, 477, 1251
1328
t
, 1331
t
, 1332
t
infections and, 1242, 1251, 1298
insulin resistance and, 1221, 1222, 1223, 
1223
t
. 
See also
 Insulin 
resistance/insensitivity
ketones (urine/blood) in, 919, 1224
latent autoimmune of adulthood 
(LADA), 1221
lipid/lipoprotein abnormalities in, 1227, 
1251, 1269
maturity-onset of young (MODY), 
1221
t
, 1222
mitochondrial DNA mutations and, 
1222
nephrotic syndrome and. 
See
 Diabetic 
neurogenic arthropathy (Charcot joint) 
in, 889, 1248
neuropathy and. 
See
 Diabetic 
713, 714
occult, 
1265
ocular complications of, 188, 197–198, 
1247. 
See also
 Diabetic 
retinopathy
osteomyelitis in, 885
pancreatic disorders/cancer/pancreatitis 
and, 1222, 1223, 1241, 1636, 
1638
patient education (self-management 
training) in, 1242
and, 53
polycystic ovary syndrome and, 795, 
1206
prebreakfast hyperglycemia in, 1243, 
1243
t
during pregnancy, 814, 
831–832
, 831
t
, 
1245
t
, 1253–1254
prognosis for, 1254
screening for, 6
t
, 814, 831, 1269
secondary, 1222–1223, 1223
t
self/continuous-monitoring of blood 
glucose and, 831, 832, 
 
1226–1227
skin/mucous membrane disorders and, 
1224, 1251
statin use and, 1272
surgery in patients with, 53
surgical, 1241
treatment of, 1228–1241, 1230–1231
t
, 
1238
t
, 1241–1247, 1243
t
, 
1244
f
, 1245
t
. 
See also
 
Antidiabetic agents; Insulin 
therapy
in chronic kidney disease, 941, 942
blood glucose self/continuous-
monitoring in, 1226–1227
in pregnant patient, 831, 832, 1226
bone/joint complications in, 1252
cardiomyopathy and, 429, 1250
cardiovascular/vascular complications 
of, 1227, 1250–1251
tibial and pedal artery disease and, 
486
chronic kidney disease and, 941, 942, 
947
t
, 954, 955, 957–958, 
1245
t
, 1247, 1247–1248. 
See 
also
 Diabetic nephropathy
cirrhosis and, 714
classification and pathogenesis of, 
1220–1223, 1221
t
clinical trials in, 1227–1228
coma in. 
See
 Diabetic coma
complications of, 1247–1252, 1249
f
. 
See 
also
 
specific type or organ/
system affected
glycemic control and, 1227–1228
hypoglycemia and, 1227, 1228, 1246
insulin therapy and, 1246–1247
continuous glucose monitoring systems 
in, 1226–1227
t
diagnosis of/diagnostic examination in, 
6
t
, 1224–1226, 1225
t
, 
 
1241–1242
diuretic use and, 460, 1223
drugs/medications associated with, 
1223, 1223
t
emphysematous pyelonephritis in, 969
environmental factors in, 1221
epidemiologic considerations in, 1220, 
1221
t
erectile dysfunction in, 1250
estrogen replacement and, 1212
exercise and, 1222, 1240, 1242, 1244, 
1244
f
, 1246
foot disorders/foot care in, 1242, 1248, 
1249, 1249
f
, 1251
gastroparesis in, 653, 1249–1250, 1253
genetic factors in, 1220–1221, 1221, 
1221
t
gestational, 814, 831–832, 831
t
. 
See also
 
Diabetes mellitus, during 
pregnancy
glucagonoma and, 1196
glucose tolerance test in, 1224–1225, 
1225
t
in pregnant patient, 814, 831, 831
t
, 
832
glucosuria/glycosuria in, 1224
glycated hemoglobin (hemoglobin A
1c
) 
in, 1225, 1225
t
, 1227, 
 
1227–1228
glycemic control in. 
See also
 Glycemic 
control in diabetes; Insulin 
therapy, intensive
acceptable levels of, 1245–1246, 
 
1245
t
cardiovascular disease and, 1227
clinical studies in evaluation of, 
1227–1228
hospitalization/surgery and, 53, 
1245
t
, 1252–1253, 1253
t
Des-gamma-carboxy prothrombin, in 
hepatocellular carcinoma, 
1632

1227–1228
1245
t
t
1632
Descovy (tenofovir/emtricitabine), 1363
t
, 
1366, 1367
t
, 1372
t
, 1373, 1357
Desensitization therapy. 
See also
 
Immunotherapy
f
, 261
t
, 264
for drug/penicillin allergies, 1324, 
1324–1325
“Designer drugs, ” 1114
Desipramine, 96
t
, 100, 1091
t
, 1094, 1100, 
1249. 
See also
 Antidepressants
Desloratadine, 229
Desmoid tumors, 680
Desmopressin (DDAVP), 569, 569
t
, 571, 
1125
Desogestrel, 800, 801
t
Desonide, 104
t
Desoximetasone, 106
t
Desvenlafaxine, 1090–1093, 1091
t
Desynchronization sleep disorder, 1101
Detergent worker’s lung, 319
t
Detrusor muscle disorders, 65, 66, 67
Deutetrabenazine, 1028
DeVega annuloplasty, 361
Devic disease/syndrome (neuromyelitis 
optica), 199–200, 
1037–1038
Dexamethasone. 
See also
for fetal lung maturity, 825
for high-altitude illness, 1577, 1578
560
f
for meningitis, 1306, 1454
for multiple sclerosis, 1038
t
t
, 
1678
for ophthalmic disorders, 182
t
for spinal tumors/compression, 1020, 
1671
Dexamethasone suppression test, 1185
Dexlansoprazole, 608, 621, 633, 637, 639. 
See also
 Proton pump 
Dexmedetomidine, 1110–1111
Dexrazoxane, 427, 1675
t
Dextroamphetamine, 1094, 1103, 1113
Dextromethorphan, 1095
t
, 1601–1602, 
1604
Dextrose, 925
t
, 1002, 1040, 1581, 1599
Diabetes Control and Complications Trial 
(DCCT), 1227, 1242
Diabetes insipidus, 
1124–1126
craniopharyngioma and, 1122
hypernatremia and, 1124
1120, 1122, 1124, 1127, 1130
nephrogenic, 906
t
, 1125
and, 911, 912, 1165
in Wolfram syndrome, 1124, 1222
Diabetes insipidus, type 1 diabetes 
mellitus, optic atrophy, 
deafness (DIDMOAD), 1124, 
1222
Diabetes mellitus, 
1220–1261
. 
See also
 
under Diabetic
antipsychotic drug use and, 1084, 1084
t
blood/serum/plasma glucose levels in 
diagnosis of, 1224, 1224–1225, 
1225
t
CMDT2019_Index_p1743-1884.indd   1780

INDEX1781
 
CMDT 2019
Shigella,
 599
t
, 600, 1313
t
, 1316, 1319
t
, 
1322
t
, 1476
toxins causing, 599–600, 599
t
, 600, 
1312
t
, 1313
t
, 1314
traveler’s, 600, 1315, 
1316–1317
in typhoid fever, 1474
viral, 599
t
, 1313
t
, 
1432–1433
. 
See also
 
specific virus
Diastolic dysfunction/heart failure, 414. 
See also
 Heart (cardiac) failure
Diazepam, 1067
t
. 
See also
 Benzodiazepines
for alcohol withdrawal, 1108
for anxiety, 1067, 1067
t
, 1068
t
, 1598
for seizures, 1002, 1583
for spasticity, 1039
for vertigo, 222
Diazoxide, 1264
Dichuchwa (endemic syphilis), 1503
Diclofenac, 85, 86
t
, 182
t
, 842
Dicloxacillin, 228, 1322
t
, 1450
t
, 1455
Dicyclomine, 658
Didanosine (ddI), 1349, 1351, 1363
t
, 
1366–1368. 
See also
 
DIDMOAD, 1124, 1222
Diet/nutrition
acne and, 135
in acute tubular necrosis, 933
cancer risk and, 754, 1611, 1650
cardiovascular disease prevention/
management and, 6
t
, 373
f
cholelithiasis/gallstones and, 732
cholesterol/lipid-lowering, 1271, 1287
in cirrhosis, 716
consistency alterations and, 
1286
constipation and, 596
in diabetes, 831, 832, 1228, 1228–1229
in diarrhea control, 602
diverticular disease and, 676, 677
in end-of-life care, 77–78
gastric adenocarcinoma and, 1641
in GERD management, 621
gluten-free, 131, 646
in gout, 846
in heart failure management, 422
in hemochromatosis, 724
in hypertension/hypertension 
t
in hypertriglyceridemia, 1275
in irritable bowel syndrome, 656, 658
in kidney disease, 942
lactose-free, 598, 650
MAOI interactions and, 1094, 1094
t
Mediterranean, 1271
nutrient-restricting, 
1286–1287
nutrient-supplementing, 
1287–1288
in obesity, 1278–1279
in osteoporosis, 1172
in pancreatitis, 744, 745, 747
in porphyria, 1681
during pregnancy, 812, 
814–815
, 831, 
832
t
, 6
t
therapeutic, 
1286–1288
in ulcerative colitis, 672
urinary stone formation and, 975, 976
in Wilson disease, 726
Diet therapy, 
1286–1288
. 
See also
 Diet/
nutrition
in poisoning/drug overdose, 1586–1587, 
1586
t
in prenatal care, 813–814
preoperative evaluation and, 46
Diagnostic and Statistical Manual 
 
(DSM-5),
 1063
Dialysis, 942–943
amyloidosis and, 550
“gut” (repeat-dose charcoal), 1586
for heat stroke, 1566
hypercalcemia/hyperphosphatemia and, 
912, 914
t
immunization recommendations and, 
1328
t
, 1331
t
, 1332
t
iron deficiency and, 512
for kidney disease/injury, 934, 942–943
for poisoning/drug overdose, 1585, 
1585
t
, 1587
t
. 
See also
 
specific 
drug/toxin
renal cysts/renal cell carcinoma and, 
961, 1667
surgery in patient receiving, 54
3,4-Diaminopyridine, 1059
Diaphragm, respiratory failure caused by 
t
Diaphragm (contraceptive), 
805
DIAPPERS mnemonic, 65
Diarrhea, 
599–606
, 599
t
, 600
t
, 601
f
, 604
f
. 
See also
 
Colitis; Gastroenteritis
acute, 
599–603
, 599
t
, 601
f
, 
1311–1314
, 
1312–1313
t
in amebiasis. 
See
 Intestinal amebiasis
 599
t
, 
600, 603, 
659–662
, 1312
t
antibiotics for, 602
bacterial, 599
t
 
t
in bacterial overgrowth, 603, 604
f
, 605, 
648
bloody. 
See
 Dysentery
in cholera, 1313
t
, 1477
chronic, 600
t
, 603–606, 604
f
coccidial/microsporidial, 1530–1533
diabetic, 1250
drugs in management of, 602. 
See also
 
Antidiarrheal agents
E coli,
 599
t
, 600, 1312
t
, 1316, 
 
1476–1477
factitious, 600
t
fluid management in, 602, 925
t
hypokalemia caused by, 905
infection/AIDS, 600, 601, 604, 
1343, 1351–1352
infectious, 599
t
, 600, 600–601, 600
t
, 
603–604, 
1311–1314
, 
 
1312–1313
t
inflammatory, 599
t
, 600–601, 600
t
, 601, 
603, 604
f
, 1314. 
See also
 
Dysentery
in malabsorption, 600
t
, 603, 644
t

t
t
, 
603–604, 
1311–1314
, 
 
1312–1313
t
t
t
, 601, 
603, 604
f
, 1314. 
See also
 
Dysentery
t
, 603, 644
t
in measles, 1393
noninflammatory, 599
t
, 600, 600
t
, 1314
osmotic, 600
t
, 603, 604
f
secretory, 600
t
, 603
1227–1228
diet in, 1228, 1228–1229. 
See also
 
1245
t
t
in pregnant patient, 831, 1253–1254
steps in, 1241–1247, 1243
t
, 1244
f
, 
1245
t
transplantation in, 1241
type 1, 1220, 1220–1221, 1221
t
, 1223–
1224, 1227, 1237–1241, 1238
t
, 
1242–1243, 1243
t
idiopathic (type 1B), 1220, 1221
immune-mediated (type 1A), 1220, 
1220–1221, 1221
t
insulin therapy for, 1227, 1237–1241, 
1238
t
, 1242–1243, 1243
t
surgery in patient with, 1252, 1253
t
type 2, 1220, 1221–1222, 1224, 1224
f
, 
1243–1245
drugs for management of, 1229–1237, 
1230–1231
t
1244
f
. 
See also
 Antidiabetic 
agents
insulin therapy for, 1227–1228, 1237, 
1245
in nonobese patients, 1244
in obese patients, 1222, 1224, 1244
t
Diabetic amyotrophy, 1049, 1249
Diabetic cataracts, 1247
Diabetic cheiroarthropathy/cheiropathy, 
860, 1252
Diabetic coma, 1223, 
1254
, 1255
t
. 
See also
 
diabetic ketoacidosis and, 1223, 
 
1254–1258, 1255
t
hyperglycemic hyperosmolar state and, 
1223, 1224, 1255
t
, 1258–1260
lactic acidosis and, 1255
t
Diabetic diarrhea, 1250
Diabetic dyslipidemia, 1227, 1251, 1269
Diabetic ketoacidosis (DKA), 919, 1223, 
1254–1258
, 1255
t
anion gap acidosis and, 919, 1255, 
 
1257
coma caused by, 1223, 1254–1258, 1255
t
hypophosphatemia in, 914, 1255, 1257
insulin infusion pumps and, 1240
insulin needs during surgery and, 1252
insulin therapy for, 1256–1257, 1258
Diabetic maculopathy/macular edema, 197
Diabetic nephropathy, 947
t
, 953, 955, 
957–958
, 1247–1248
glycemic control and, 1227, 1228, 1248
Diabetic neuropathic cachexia, 1249
Diabetic neuropathy, 1049, 1248–1250, 
1249
f
and, 889, 1248
Diabetic retinopathy, 
197–198
, 1247
glycemic control and, 1227, 1228
during pregnancy, 197
Diabetic shin spots, 1251
Diagnostic/laboratory tests. 
See also
 
CMDT2019_Index_p1743-1884.indd   1781

INDEX1782
 
CMDT 2019
Dislocated shoulder, 
1695–1696
Disopyramide, 393, 394
t
, 432, 433
f
Disseminated intravascular coagulation 
(DIC), 
563–565
, 564
t
, 
573
in acute leukemia, 539
in cancer, 564, 1021
cryoprecipitate transfusions for, 
 
554–555, 564
in meningococcal infection, 1471
Distal muscular dystrophy, 1061
t
Distal renal tubular acidosis, 906
t
, 920, 
920
t
, 922. 
See also
 Renal 
tubular acidosis
nephrolithiasis/nephrocalcinosis/
urolithiasis and, 920
in tubulointerstitial disease, 960
Distal symmetric polyneuropathy, in 
diabetes, 1248–1249, 1249
f
Distributive shock, 505–506, 505
t
, 506, 
508
Disulfiram, 19, 1069
t
, 1095
t
, 1108
Diuretics. 
See also
 
abuse of in bulimia, 1282
for acute tubular necrosis, 933
adverse effects of, 207
t
, 460, 461–462
t
f
, 434
in chronic kidney disease, 460, 478, 
938–939
for cirrhotic ascites, 716
contraction alkalosis and, 923
gout/hyperuricemia and, 460, 846
for heart failure, 390, 417
f
, 418–419, 
 
423
for hypercalciuria, 976
for hyperkalemia, 907, 909
t
for hypertension, 460, 461–462
t
, 475, 
476
f
, 478, 480
t
, 481
t
, 482, 
938–939
hypokalemia caused by, 460, 905, 1287
lithium interactions and, 1098–1099, 
1099
t
for pericarditis, 442
for pulmonary edema, 424
for pulmonary hypertension, 444
for renal tubular acidosis, 922
for tricuspid regurgitation, 361
for tricuspid stenosis, 360
tubulointerstitial nephritis caused by, 
959
t
Diverticula
colonic, 
675–678
Zenker, 
626
Diverticular bleeding, 609, 610, 
678
Diverticulitis, 
676–678
Diverticulosis, 609, 675, 
676
Diving (underwater). 
See
 Scuba/deep sea 
diving
Dix-Hallpike testing, 221
Dizziness. 
See
 Vertigo; Vestibular disorders
D
l
CO
 (diffusing capacity for carbon 
monoxide), in 
 
pneumonia, 1344
DML, 108
t
DMP1
 mutations, 1176, 1177
DMPA, for contraceptive injection, 803
for antipsychotic overdose/toxicity, 
1085, 1592
t
for nausea and vomiting, 73
Diphenoxylate with atropine, 602, 605, 
668, 672, 1593. 
See also
 
Diphtheria, 1319
t
, 
1462–1463
neuropathy in, 1050, 1463
pharyngitis in, 239, 1449, 1463
prevention/immunization and, 4, 1327
t
, 
1328
t
, 1329
t
, 1463. 
See also
 
Tetanus and diphtheria 
toxoids and pertussis vaccines
Diphtheria antitoxin, 1463
Diphtheria toxoid, 1463. 
See also
 Tetanus 
and diphtheria toxoids and 
pertussis vaccines
 (fish tapeworm), 
517, 
1538
 (dog tapeworm), 
1538, 1540
Dipyridamole, 568
t
, 1006
Dipyridamole-thallium scintigraphy. 
 
See
 Myocardial perfusion 
scintigraphy
Direct-acting oral anticoagulants 
(DOACs/new/novel oral 
anticoagulants), 404–406, 
405
t
, 574, 575–576
t
, 580
t
, 582. 
See also
 
specific drug
347, 404–406, 405
t
for cardiomyopathy, 429
and, 388
disease), 309, 574, 575–576
t
, 
580
t
, 582
overdose/toxicity and, 405, 1591
perioperative management and, 51–52, 
52
t
, 405–406
during pregnancy, 364
switching to from warfarin, 404–405, 
576
t
switching to warfarin from, 576
t
Direct renin assay, in aldosteronism, 1188
Direct thrombin inhibitors, 381, 563, 563
t
Directed bleeding history, 46, 47
t
, 51
Directly observed therapy (DOT), for 
tuberculosis, 291, 292–293, 
293, 294
Discogenic disease. 
See
 Cervical spine/disk 
disease; Lumbar spine/disk 
disease; Sacral spine/disk 
disease
Discoid lupus erythematosus, 123, 854
Disease-modifying antirheumatic drugs 
(DMARDs), 850, 851–852
Disease prevention. 
See
 Health 
maintenance/disease 
Disk batteries, ingested, alkali injuries

See
 Health 
Disk batteries, ingested, alkali injuries 
caused by, 1590
Disk disease. 
See
disease
Dietary supplements
oral nutritional supplements, 67 1288
toxicity of, 
1597
, 1597
t
Diethylcarbamazine, 1547, 1549
Diethylene glycol toxicity, 1602
Diethylstilbestrol (DES), 1662
t
Dieulafoy lesion, 606
Difenacoum poisoning, 1591
Diffuse axonal injury, 1043
t
Diffuse esophageal spasm, 617
t
, 630, 631
Diffuse idiopathic skeletal hyperostosis 
(DISH), 878, 1252
Diffuse infiltrative lymphocytosis 
syndrome, 884
Diffuse interstitial pneumonias, 
301–303
, 
302
t
Diffuse parenchymal lung disease. 
See
 
Diffusing capacity for carbon monoxide 
(D
l
CO
), in 
 
Diflorasone, 105
t
Diflunisal, 86
t
Digestion, disorders of. 
See
 Malabsorption
Digital clubbing, 169, 169
f
, 1625. 
See also
 
Digital rectal examination. 
See
 Rectal 
Digitalis/digitalis glycosides/digoxin, 395
t
1095
t
for arrhythmias, 393–396, 395
t
, 403, 
1147–1148
t
for heart failure/cardiomyopathy, 390, 
420, 429, 434
t
, 905, 1582, 
1584
t
, 1587
t
, 
1597–1598
Digoxin-specific Fab antibody (digoxin 
immune Fab), 1582, 1584
t
, 
1587
t
, 1598
Dihydroartemisinin/dihydroartemisinin-
piperaquine, 1518
t
, 1518
t
, 
1519–1520, 1519
t
, 1520
t
, 
1522, 1524
Dihydroergotamine, 991, 993
Dilated cardiomyopathy. 
See
 
Dilation and curettage (D&C), 777
t
Diloxanide, 1529, 1530
t
Diltiazem. 
See also
for arrhythmias, 389, 395
t
, 400, 403
for hypertension, 471, 472
t
overdose/toxicity of, 472
t
, 1594
Dilutional acidosis, 921
Dimenhydrinate, 593
Dimercaprol (BAL), 1593, 1600, 1602
2,3-Dimercaptopropanesulfonic acid 
(DMPS/unithiol), 1593, 1602
Dimercaptosuccinic acid (DMSA). 
 
See
 Succimer
Dimethoate poisoning, 1605
Dimethyl fumarate, 1038
t
Dimethyltryptamine, 1112
Dipeptidyl peptidase 4 (DPP-4) inhibitors, 
1231
t
, 1235–1236, 1244
f
, 
 
1245
Diphenhydramine. 
See also
 Antihistamines
CMDT2019_Index_p1743-1884.indd   1782

INDEX1783
 
CMDT 2019
Drowning, 
1569–1570
Droxidopa, 1004
Drug abuse, 
18–19
, 1105, 
1111–1114
. 
See 
also
 Poisoning/drug overdose; 
Drug addiction, 98, 98–99. 
See also
 
specific 
drug and
 Substance use 
disorders
Drug allergy, 
891–892
, 
894–895
, 
 
1324–1325
, 1341. 
See also
 
Drug dependency, 98, 1105. 
See also
 
 Substance 
Drug eruptions, 
170–173
, 171–172
t
, 
 
894
Drug fever, 1301
Drug-induced disorders/side effects. 
 
See also
 specific disorder
abnormal movements, 
1030
asthma, 253, 321
t
constipation, 595
t
, 596
depression, 1088
dermatitis (dermatitis medicamentosa), 
170–173
, 171–172
t
, 
894
erythema multiforme/Stevens-Johnson 
syndrome/toxic epidermal 
necrolysis, 143, 144, 170, 172
t
exfoliative dermatitis/erythroderma, 
125, 171
t
headache (analgesic rebound/
medication overuse 
headache), 
993
HLA haplotypes and, 847, 894
hypoglycemia, 1227, 1229, 1245, 1246, 
1261
t
, 
1266
hyponatremia, 900, 901, 901
t
lichenoid/lichen planus-like, 153, 172
t
liver disease/failure, 699, 700, 
710–712
lung disease, 300
t
, 
320
, 321
t
lupus/SLE, 321
t
, 
856
nausea and vomiting, 592
t
neurocognitive disorders/delirium, 
58–59, 1115
t
ocular, 207–209
t
, 
209
ototoxicity, 219
photodermatitis, 163, 164
pigmentary changes, 167, 172
t
pityriasis rosea-like eruption, 117, 
 
172
t
porphyria, 130, 131, 1681, 1682
t
leukoencephalopathy, 665, 
1407, 1408
psychoses, 1080
pulmonary disorders, 300
t
, 
320
, 321
t
rhinitis (rhinitis medicamentosa), 225
SIADH, 901, 901
t
teratogenicity, 812
t
thrombocytopenia/platelet function, 
565
, 565
t
, 568
t
tubulointerstitial nephritis, 959
t
Drug-induced hypersensitivity reaction 
(drug reaction with 
eosinophilia and systemic 
symptoms), 170, 171, 171
t
, 
894–895
Drug overdose. 
See
 Poisoning/drug 
overdose
Drug reaction with eosinophilia and 
systemic symptoms (DRESS), 
170, 171, 171
t
, 711, 
894–895
Doripenem, 1484
t
Dornase alpha (rhDNase), 276
Dorzolamide/dorzolamide combinations, 
184
t
“Double crush” injury, 1701
“Double-effect” principle, 79
Double-hit lymphoma, 544
Double-stranded DNA antibodies, 123, 
854, 855
Down syndrome (trisomy 21), 813, 
 
1682–1683
Doxazosin
986
t
, 987
t
t
and, 1193
Doxepin, 103, 107
t
, 142, 156, 1091
t
. 
 
See also
Doxercalciferol, 1168
Doxorubicin, 154, 546, 765, 768, 1618
t
, 
1679, 1680
Doxycycline, 208
t
, 1322
t
, 1323
t
for acne, 135
t
for diarrhea, 602
for Lyme disease, 1508, 1508
t
, 1509
for malaria/malaria chemoprophylaxis, 
1518
t
, 1520
t
1523
t
t
, 281, 1322
t
, 1453
for rickettsial infections, 1438, 1439, 
1440, 1441, 1442, 1443, 1445
t
, 
1353, 1455
for syphilis, 1323
t
, 1496
t
t
, 
 
1323
t
for 
Wolbachia
 eradication, 1547, 
 
1548
Doxylamine, 593
DPP-4 inhibitors, 1231
t
f
, 
1245
Drawer sign/test
anterior
t
posterior, 1716
Dream sleep, 1101
DRESS (drug reaction with eosinophilia 
and systemic symptoms), 170, 
171, 171
t
, 711, 
894–895
Dressler syndrome (postmyocardial 
infarction/postcardiotomy 
pericarditis), 391–392, 
 
437–438, 438, 439
Drinking, at-risk/risky, 18, 1105–1106, 
See also
 
Driving (automobile). 
See
 Automobile 
driving
Dronabinol, 73, 593–594, 1343, 1344. 
 
See also
 Cannabinoids/
cannabidiol
Dronedarone, 393, 394
t
, 395
t
, 407
Drop attacks, epileptic (atonic seizures), 
998. 
See also
 Seizures
Droperidol, 1592
Drospirenone, 800, 801
t
, 1214
DMPS (2,3-dimercaptopropanesulfonic 
acid/unithiol), 1593, 1602
DMSA (dimercaptosuccinic acid/
succimer), 1593, 1601, 1602
DNA

998. 
See also
 Seizures
t
, 1214
DNA
double-stranded, antibodies to, 123, 
854, 855
hepatitis B virus, 694
f
, 695, 701, 702, 
703
HPV , testing for, 784, 1355
mitochondrial, mutations in
in diabetes, 1222
myopathies associated with, 
1062
native, antibodies to, 853
t
, 854
t
, 855
t
DNA analysis/diagnosis/probes
in cancer screening/polyp identification, 
678
in tuberculosis, 289, 289
t
, 1347
DNAR (do not attempt resuscitation) 
orders, 76–77
DNMT3A
 mutation, 537, 538
Do not/do not attempt resuscitation 
(DNR/DNAR) orders, 76–77
Dobrava-Belgrade virus, 1415
Dobutamine, 390, 508–509
Dobutamine stress echocardiography. 
See
 
Echocardiography/Doppler
Docetaxel, 1618
t
for breast cancer, 765–766, 770
neuropathy caused by, 1679
t
t
, 1663
Docusate sodium, 597
t
Dofetilide, 393, 394
t
, 395
t
, 406, 408
Dog bites, 1307
rabies and, 1307, 1308, 1398, 1400
Dog hookworm, 1542, 1545
Dog roundworm 
(T canis),
by, 1545
Dog tapeworm 
(D caninum),
 1538, 1540
Dolasetron, 593, 594
t
, 1678. 
See also
 
Antiemetics
Dolutegravir, 1365
t
, 1371, 1372
t
. 
See also
 
Antiretroviral therapy; Juluca; 
Triumeq
Domestic violence, 17, 1104, 1104–1105
elder abuse and, 17, 
70–71
, 70
t
intimate partner, 17, 1104, 1104–1105
lesbian and bisexual women and, 1725, 
1729–1730
Donepezil, 59, 1034
Donovan bodies, 1482
Dopamine/dopamine agonists
for GH-secreting tumors (acromegaly/
gigantism), 1127
for hypotension/shock, 390–391, 508
hypothyroidism and, 1136
for left ventricular (infarct-related) 
failure, 390
1085
Parkinson disease and, 1024, 1026
for prolactinoma/hyperprolactinemia, 
1129–1130
for restless legs, 1030
Dopamine antagonists, 593, 594
t
. 
See also
 
Doppler. 
See
 Echocardiography; 
DORAs, 1103
CMDT2019_Index_p1743-1884.indd   1783

INDEX1784
 
CMDT 2019
Dyssynergia, pelvic floor (dyssynergic 
defecation), 595–596, 595
t
, 
596
Dysthymia, 1087. 
See also
Dystonia
drug-induced, 1030, 1085
torsion
focal, 
1029
idiopathic, 
1028–1029
Dystrophin, 1060, 1061
t
Dysuria (painful urination), 
43–45
, 45
f
E-cadherin cell adhesion protein, 1642
E-cigarettes, 7, 813
E coli
. 
See
 
Ear, 
210–225
. 
See also
 
under Hearing
barotrauma affecting, 
214
cauliflower, 211
herpes zoster involving, 218, 1383
in HIV infection/AIDS, 
224–225
inner, 
218–224
middle, 
215–218
painful. 
See
 Earache
Ear canal, 
211–212
bony overgrowths (exostoses/osteomas) 
of, 
213
foreign body in, 
212
neoplasia of, 
213
pruritus of, 
213
Ear drops
for cerumen removal, 211
for external otitis, 212
ototoxic, perforated tympanic 
membrane and, 219
Earache (otalgia), 213, 
218
Early goal-directed therapy, for shock, 
507–508
Early menopause, 1210
East African trypanosomiasis, 1510, 1511, 
1511
t
Eastern (equine) encephalitis, 1401
Eastern subtype tick-borne encephalitis, 
1404
Eating disorders, 
1280–1282
. 
See also
 
Eaton-Lambert syndrome. 
See
 Lambert-
/Ebola viral disease (EVD), 
1409–1411
Ebola virus vaccine, 1411
Ebstein anomaly, 361
Ecchymosis
of eye (black eye), 205, 232
t
Echinacea purpurea,
 987
Echinocandins, 1551, 1561. 
See also
 
Echinococcus granulosus/multilocularis
 
(echinococcosis), 
1540
Echocardiography/Doppler. 
See also
 
in angina, 370
in aortic regurgitation, 345
t
, 358
in aortic stenosis, 345
t
, 354
for athlete screening, 448
in atrial fibrillation, 402
ovale, 338
t
, 429, 430–431, 
432, 434
in coarctation of aorta, 336
Duloxetine, 61, 1090–1093, 1091
t
neuropathy, 61, 96
t
, 99, 1048, 
1249
Dumping syndrome, 1265
Duncan disease, 1387
Duodenal disorders, 
631–644
, 638
t
. 
See 
also
 Peptic ulcer disease; 
Small intestine
Dupilumab, 114
Dupuytren contracture, 714, 
1705
Durable power of attorney for finance 
matters (DPOAF), 60
Durable Power of Attorney for Health 
Care (DPOA-HC), 76
Duroziez sign, 358
Durvalumab, 1628
Dutasteride, 987, 1738, 1738
t
Dwarf tapeworm 
(H nana),
 
1538
Dwarfism, 1120
Dying patient, care of. 
See
 End of life, 
provision of care at
Dysautonomia (autonomic dysfunction), 
1003–1004
in Guillain-Barré syndrome, 1003, 1051
neuropathy causing, 1003, 1048
Dysbarism, 214, 
1575–1576
Dysentery, 600, 601–602. 
See also
 
specific 
cause
t
, 600, 
603, 1322
t
f
, 
1530
t
bacillary 
(Shigella)
. 
See
 Bacillary 
dysentery
colitis after (postdysenteric colitis), 1529
reactive arthritis and, 880
Trichuris,
 1541
Dysequilibrium (imbalance). 
See
 Vertigo; 
Dysfunctional uterine bleeding. 
See
 
Abnormal uterine bleeding
Dysgeusia, 
237
Dyshidrosis/dyshidrotic eczema. 
 
See
 Pompholyx
Dyskeratosis congenita, 526, 556
Dyskinesia
levodopa-induced, 1025
tardive, 1030
Dyslipidemia. 
See
 Hyperlipidemia; Lipid 
disorders/lipids
Dysmenorrhea, 
779
, 790
IUD use and, 804
Dysmetabolic iron overload syndrome, 
713
Dysmotility. 
See
 Motility disorders
Dysnomia, 1016
Dysorgasmia. 
See
 Orgasm, loss of
Dyspareunia (painful intercourse), 796
Dyspepsia, 
589–591
, 633, 636, 637. 
 
See also
 
Dysphagia, 617, 617
t
, 619, 630, 1638. 
 
See also
 
Dysphonia, 
243
, 244, 247
Dysphoric disorder, premenstrual, 779, 
1088
Dysplastic nevi. 
See
 Atypical nevi/mole
Dyspnea, 20, 21, 
23–26
, 24
t
, 
72–73
. 
 
See also
 
in COPD, 268, 269
t
, 272, 273
palliation of, 25, 
72–73
, 273
Dysrhythmias. 
See
Drug resistance, 1301, 1317. 
See also
 
specific agent and specific 
disorder
in antiretroviral therapy, 702, 1373, 
1374, 1374–1375
in gonococcal infection, 1481–1482

See
See also
 
disorder
1301
in influenza, 1423–1424
in malaria, 1518, 1519, 1520, 1520
t
, 
1521
pharyngitis treatment and, 238
in pneumonia, 281, 283, 1453
in staphylococcal infections. 
See
 
S aureus
 
in tuberculosis, 288, 289, 289
t
, 295, 
1347
Drug susceptibility testing, 1317. 
See also
 
Drug resistance
in antiretroviral therapy, 1373, 
 
1374–1375
in nontuberculous mycobacterial 
infection, 296
t
, 1347
Drug tolerance, 97, 98, 1105, 1111, 1113. 
See also
disorders
“Drugs of abuse” toxicology screen, 1587
Drusen, 193, 200
Dry beriberi, 1282
Dry eye (keratoconjunctivitis sicca), 
 
177–178
in Sjögren syndrome, 864, 865
Dry mouth
Dry powder inhalers (DPIs), 259, 260
t
, 
261, 262
t
DSM-5 (Diagnostic and Statistical 
Manual),
 1063
Dual antiplatelet therapy. 
See also
 Aspirin; 
after coronary stent placement, 386
636, 640
Dual-chamber pacing, 398, 432. 
See also
 
Pacemaker
Dual energy x-ray absorptiometry (DXA)
in osteoporosis, 1171–1172
Dual orexin receptor antagonists 
(DORAs), 1103
Dubin-Johnson syndrome, 688, 689
t
Duchenne muscular dystrophy, 1060, 1061
t
Duct-centric chronic pancreatitis, 
idiopathic, 746
Ductal carcinoma in situ, 761, 761
t
, 762
Paget carcinoma and, 126, 126
f
, 761
Ductography, in nipple discharge/breast 
cancer, 752, 760
Ductopenia, idiopathic adulthood, 740
Ductoscopy, in nipple discharge/breast 
cancer, 752
Duke criteria (modified), for endocarditis, 
1466
Duke Treadmill Score, 376, 377
t
Dulaglutide, 1230
t
, 1235. 
See also
 
CMDT2019_Index_p1743-1884.indd   1784

INDEX1785
 
CMDT 2019
in hyperkalemia, 908
in hypertension, 457
in hypokalemia, 906
in hypothermia, 1567, 1567
f
in infectious myocarditis, 426
in mitral regurgitation, 344
t
in mitral stenosis, 344
t
in palpitations, 31–32, 31
t
, 32
in paroxysmal supraventricular 
in pericarditis/effusion, 439, 440
preoperative, 46
in pulmonary valve regurgitation, 362
in pulmonary valve stenosis, 335
in tetralogy of Fallot, 341
in tricuspid regurgitation, 344
t
, 361
in tricuspid stenosis, 344
t
, 360
in valvular heart disease, 344
t
in ventricular septal defect, 340
Electroconvulsive therapy (ECT), 
 
1095–1096
for catatonia, 1083
for depression, 1095–1096
1085
for schizophrenia/psychotic disorders, 
1083
Electroencephalogram (EEG)
in brain death determination, 1042
in epilepsy, 1000, 1002
pseudoepileptic seizure 
identification and, 1001, 1071
Electrolytes. 
See also
 
disorders of concentration of, 
899–916
, 
906
t
assessment of, 898–899
in nutritional support, 1293
t
replacement guidelines for, 925, 925
t
Electromyography
in back pain evaluation, 1698
in motor neuron disease, 1047
in muscular dystrophies, 1060
Electronic cigarettes, 7, 813
Electronic medical record systems
care of lesbian and bisexual women and, 
1723
care of transgender patients and, 1737
Electrophoresis. 
See
 Hemoglobin 
Electrophysiologic testing
in syncope evaluation, 413
Electrovaporization of prostate, 
transurethral, 988
Elephantiasis, 1546, 1546
f
Eletriptan, 991
Elevated intraocular pressure, 183–184
t
, 
187, 188–189, 1203
Eliglustat tartrate, 1685
Elotuzumab, 548, 1619
t
Elsberg syndrome, 1384
for aplastic anemia, 527, 558
for hepatic coagulopathy, 719
for myelodysplastic syndromes, 537
for thrombocytopenia, 558, 559, 560
f
, 1677
EGFR (epidermal growth factor) 
mutations/inhibitors
in breast cancer, 765
t
in colorectal cancer, 1652
in lung cancer, 1627, 1627–1628
Ehlers–Danlos syndrome, 573
mitral valve prolapse in, 351
pregnancy and, 447
storage pool disease and, 567
Ehrlichia canis/chaffeensis/ewingii/
 
muris
-like (ehrlichiosis), 
1381
t
, 1437
t
, 
1443–1444
EIA, in syphilis, 1495, 1495
t
EIF2AK3
 gene, 1222
Eighth nerve lesions. 
See
. 
See
Eisenmenger physiology/syndrome, 337, 
339, 340, 443
Ejaculate, for semen analysis. 
See
 Semen 
analysis
Ejaculation disturbances, 979, 982–983, 
1075. 
See also
 Erectile 
dysfunction/impotence
antidepressants causing, 1092–1093, 
1094
in infertility, 979, 981, 982
Ejaculatory duct obstruction, in infertility, 
983
Ejection clicks. 
See
 Heart murmurs; Heart 
sounds
Ejection fraction. 
See
 Left ventricular 
ejection fraction
Elafibranor, 713
Elapid (coral snake) envenomation, 1607, 
1608
Elbasvir, 704
t
, 705
Elbow
bursitis of (olecranon bursitis), 1705, 
1706, 1706
f
tennis or golf, 1703
ulnar nerve lesions and, 1052–1053
Elder abuse/mistreatment, 17, 
70–71
, 70
t
Elderly patients. 
See
 Geriatric medicine; 
Electrical alternans, 440
Electrical cardioversion. 
See
Electrical injury/burns, 1571, 
1573–1574
Electrocardiogram (ECG). 
See also
 
specific 
disorder
in ACS (NSTEMI/STEMI), 28, 28
t
, 29, 
379, 384
in angina, 369, 370, 371
antidepressants affecting, 1094, 1609, 
1609
f
antipsychotics affecting, 1083–1084
in aortic dissection, 496
in aortic regurgitation, 344
t
, 358
in aortic stenosis, 344
t
, 354
for athlete screening, 448, 449
ovale, 337–338
in cancer-related hypercalcemia, 912, 
1673
in cardiomyopathy, 428, 428
t
, 430, 432, 
434
in chest pain evaluation, 28
t
, 29

1673
t
, 430, 432, 
434
t
, 29
in mitral regurgitation, 345
t
, 349
in mitral stenosis, 345
t
, 347
in mitral valve prolapse, 351, 352
in myocardial infarction, 384
in pericarditis/effusion, 439, 440, 
 
441–442
preoperative, 49
in tetralogy of Fallot, 341–342
in tricuspid regurgitation, 345
t
, 361
in tricuspid stenosis, 345
t
, 360
in valvular heart disease, 345
t
Echolalia, 1031, 1079
Echopraxia, 1031
Echovirus infections, 
1434–1435
Eclampsia, 822, 823, 824, 916. 
See also
 
Preeclampsia-eclampsia
Econazole, 107
t
“Ecstasy, ” 900, 1114, 1583
t
, 1590
Ectasias, GI bleeding in, 606, 609
Ecthyma, 131
contagiosa (orf), 1431
Ectopia lentis, in Marfan syndrome, 1687
Ectopic pregnancy, 
819–821
appendicitis differentiated from, 654
hCG levels in, 811, 820
IUDs and, 804
minipill use and, 803
PID and, 792, 793, 819, 820
Ectropion, 175
Eculizumab, 520–521, 562, 1333
t
Eczema, 
113–114
dyshidrotic. 
See
 Pompholyx
herpeticum, 114, 1378, 1381
t
Edema. 
See also
 
arm, in breast cancer/postmastectomy, 
758, 773–774
in cirrhosis, 716–717
in filariasis, 1546, 1546
f
in heart failure, 415
lower extremity, 
32–34
, 33
t
t
in nephrotic syndrome, 954, 955
refeeding, 1277
Reinke, 245
thiazolidinediones causing, 1233
in venous insufficiency. 
See
 Venous 
Edetate calcium disodium, 961, 1600, 
 
1601
Edoxaban, 575–576
t
, 580
t
, 582
405, 405
t
, 406
t
, 580
t
, 582
t
EDTA (calcium disodium edetate), 961, 
1600, 1601
Efavirenz, 1363
t
, 1366, 1368, 1371, 1372
t
, 
1373. 
See also
therapy; Atripla
with lopinavir/r, 1370
pregnancy and, 836
Effusions. 
See
 Malignant effusions; 
Pericardial effusions; Pleural 
effusions
Efinaconazole, 107
t
, 170
Eflornithine, 795, 1207, 1511, 1511
t
CMDT2019_Index_p1743-1884.indd   1785

INDEX1786
 
CMDT 2019
physician-assisted death and, 78–79, 78
t
prognosis at, 74
provision of care at, 
74–81
. 
See also
 
advance care planning/advance 
directives and, 76
autopsy/organ donation and, 81
care of family and, 75, 75
t
clinician self-care and, 75–76
communicating with patient and, 
74–75, 75
t
cultural issues in, 77
decision-making and, 76
DNAR orders and, 76–77
ethical/legal issues and, 79
follow-up/grieving and, 81
in hospice/palliative care institution, 
77
nutrition/hydration needs and, 77–78
patient’s wishes regarding, 76, 76–77, 
77
psychologic/social/spiritual issues 
and, 79–80, 80
t
tasks after death and, 
81
withdrawal/withholding curative 
efforts and, 76, 78
End-stage renal disease (ESRD), 936, 937
t
, 
942–943. 
See also
 Chronic 
kidney disease; Renal failure
diabetic nephropathy and, 958, 1248
1328
t
, 1331
t
kidney transplantation for. 
See
 Kidney 
polycystic kidney disease and, 962
Endarterectomy, carotid. 
See
 Carotid 
surgery
Endemic flea-borne (murine) typhus, 
1437
t
, 
1438–1439
Endemic goiter, 
1159–1160
Endemic hemolytic-uremic syndrome, 
561, 562
Endemic syphilis, 
1503
infective, 1321
t
, 
1464–1469
, 1465
f
, 
1466
t
, 1467
t
1485
anticoagulation and, 364
t
, 1469
antimicrobial chemoprophylaxis and, 
1466, 1466
t
, 1467
t
telangiectasia, 1689
during pregnancy/delivery, 448, 
833
prosthetic heart valves and, 335, 
1466
t
in tetralogy of Fallot, 342
in bartonellosis, 1468, 1483
candidal, 1550–1551, 1551
Coxiella
/Q fever, 1444, 1445
in drug user, 1311, 1321
t
enterococcal, 1451, 1452, 1464, 1468, 
1469
HACEK organisms causing, 1464, 
1468
native valve, 1464, 1469
pneumococcal, 1452, 1453, 1467
prosthetic valve, 364
t
, 1464, 
 
1466–1467, 1468, 1469
t
, 
1373
t
. 
See also
 Atripla; 
Complera; Descovy; Genvoya; 
Odefsey; Stribild; Symtuza; 
Truvada
1742
for hepatitis B, 1351, 1366
Enalapril/enalapril-HCTZ, 418
t
, 419, 466
t
Enalaprilat, 481
t
, 482
Enasidenib, 539
Encainide, toxicity of, 396
Encephalitis, 1304–1305. 
See also
 
specific 
cause and
 
Meningoencephalitis
anti-DPPX, 1021
anti-NMDA receptor-associated, 1021, 
1305
arbovirus, 
1401–1402
cancer-related/autoimmune 
paraneoplastic, 1021, 1022, 
1305
in chikungunya fever, 1419
CMV , 1389
in coxsackievirus infection, 1434
herpes simplex, 1378, 1380
HHV-6 causing, 1391
inclusion body, 1392
limbic, 1021
measles and, 1392
Nipah virus causing, 1421
parkinsonism after, 1024
rabies, 1398–1401
rubella infection and, 1396
tick-borne, 1401, 
1403–1405
toxoplasmic, 1526, 1527
varicella zoster virus, 1383
Encephalitozoon/Encephalitozoon 
intestinalis,
 1531, 1532
Encephalomyelitis
in Lyme disease, 1507
alcohol use disorder and (chronic 
alcoholic brain syndromes), 
1107
bovine spongiform (vCJD/mad cow 
disease), 1406
in cancer, 1020
chronic traumatic, 1044
with fatty liver. 
See
 Reye syndrome
hepatic. 
See
 Hepatic encephalopathy
hypertensive, 456, 479
in influenza, 1423
lead, 1114, 1600
in Lyme disease, 1506–1507
melarsoprol causing, 1511
See
 Metabolic 
in Reye syndrome. 
See
spongiform (spongiosis/prion diseases), 
1406–1407
uremic, 941
Wernicke, 
1039–1040
, 1107, 1108, 1282
End of life
79
pain at, 82, 
84
Eluxadoline, 658
Elvitegravir, 1365
t
, 1371. 
See also
 
Antiretroviral therapy; 
Genvoya; Stribild
Embolectomy, 312, 1009, 1010
Embolism. 
See also
 Pulmonary venous 
thromboembolism; 
Thromboembolism; Venous 
acute arterial limb occlusion caused by, 
487, 488
arterial aneurysms and, 495

487, 488
in atrial fibrillation, 402, 402
t
, 403, 
t
, 405
t
in atrial flutter, 408
cerebrovascular occlusion/TIA/stroke 
and, 488, 489, 1004, 1009. 
 
See also
 Stroke
in endocarditis, 1465, 1466, 1468
gas, in decompression sickness, 1576
paradoxic, 338, 1004
Embolization
for GI bleeding, 608, 611, 624
tumor, in lung cancer, 1629
Embryo. 
See
 Fetus
Embryonal cell carcinoma, of testis, 1669
Emedastine, 181
t
cancer-related, 
1670–1675
hypertensive. 
See
 Hypertensive 
emergencies/urgencies
in-flight (air travel), 1578–1579
Emergency/postcoital contraception, 
 
805–806
IUD for, 804, 806
for sexual violence (rape/sexual assault) 
victim, 806, 807, 808
Emery-Dreifuss muscular dystrophy, 
 
1061
t
Emesis. 
See also
 Nausea and vomiting
for poisoning/drug overdose, 
 
1584–1585
Emetine, 1529, 1530
t
Emission, loss of (anejaculation), 979, 
982–983, 1075. 
See also
 
Erectile dysfunction/
impotence
Emollients, 103, 108–109
t
Empagliflozin, 1231
t
, 1236–1237, 1237, 
1245
Emphysema, 268, 269
t
, 273. 
See also
 
Chronic obstructive 
alpha-1-antiprotease/antitrypsin 
deficiency in, 268, 270, 272
panacinar bibasilar, 270
subcutaneous, 29, 326
Emphysematous pyelonephritis, 969
Empty can test, 1692
t
Empyema
anaerobes causing, 286, 1484
in hepatic hydrothorax, 717
middle ear, 215. 
See also
 Otitis, 
 
media
pleural, 322, 324, 324
t
, 1484
subdural, 1484
Emtricitabine, 1363
t
, 1366. 
See also
 
CMDT2019_Index_p1743-1884.indd   1786

INDEX1787
 
CMDT 2019
1291
in elderly/dementia/end-of-life care, 67, 
77
in pancreatitis, 745
for protein-energy malnutrition, 1277
Enteric (typhoid) fever, 
1474–1475
t
, 1321
t
 (enterobiasis/
pinworms), 156, 
1543–1544
Enterocele, 791–792
Enterococcus faecalis/faecium
 (enterococcal 
infection), 1318
t
, 1321
t
, 
1322
t
, 
1451–1452
drug resistance and, 1301, 1452
endocarditis, 1321
t
, 1451, 1452, 1464, 
1468, 1469
Enterocolitis. 
See also
 Diarrhea; 
in HIV infection/AIDS, 600, 1351–1352
salmonella, 599
t
, 600, 1313
t
, 1322
t
, 
 
1475
Enterocytozoon/Enterocytozoon bieneusi,
 
1530–1531, 1532
Enteropathy
AIDS, 1352
gluten-sensitive. 
See
 Celiac disease
protein-losing, 
655
. 
See also
 Protein-
losing enteropathy
Enteropathy-associated T cell lymphoma, 
1647
Enterostomies, tube, 1289, 1289
f
. 
See also
 
Enteral nutritional support
Enterovirus infections, 1381
t
, 
1433–1436
. 
See also
 
Enterovirus D68, 
1435
Enterovirus 70, 
1435
Enterovirus 71, 
1435
Enterovirus 72, 1436. 
See also
 Hepatitis A 
virus
Enterovirus EV-104A, 1435
Enthesopathy/enthesitis
in lateral/medial epicondylosis, 1703
Enthesophytes, in diffuse idiopathic 
skeletal hyperostosis, 878
Entrapment/compression neuropathy, 
See also
 
and
Entropion, 
175
Entry inhibitors, for HIV infection/AIDS, 
1365
t
, 1370. 
See also
 
Environmental emergencies, disorders 
caused by, 
1564–1579
. 
 
See also
 
Environmental factors
in asthma, 259
in diabetes, 1221
in lung disease, 300
t
, 
316–321
. 
See also
 
Environmental radiation exposure, 1575
Environmental tobacco smoke. 
See
 Passive 
smoking
Enzalutamide, 1623
t
, 1662
t
, 1663
Enzyme immunoassay (EIA), in syphilis, 
1495, 1495
t
Enzyme inhibitors, in cancer 
chemotherapy, 1618–1619
t
Endoscopy
identification/removal, 679, 
1654–1655. 
See also
 
Colonoscopy; Sigmoidoscopy
in diarrhea, 605
in dyspepsia, 590
in erosive/hemorrhagic gastritis 
(gastropathy), 632
in esophageal disorders, 617–618
Barrett esophagus, 620
bleeding varices, 608, 627
cancer, 1639
caustic/corrosive injury, 1589, 1590
esophagitis, 622, 623, 624, 625
GERD, 619, 622
Mallory-Weiss syndrome, 608, 624
motility disorders, 629, 630
stricture, 621
in gastric adenocarcinoma, 1642
in GI bleeding, 606, 607, 608, 610, 611, 
641–642
in 
H pylori
 detection/assessment, 634
in pancreatitis, 747–748
in peptic ulcer disease, 637, 641–642
in ulcerative colitis, 671
Endothelin receptor blockers (ERBs), for 
pulmonary hypertension, 314, 
444
Endotracheal intubation. 
See
Endovascular surgery/prostheses. 
See also
 
Stents/stent grafts
for acute arterial limb occlusion, 488
for aneurysm repair, 493, 494, 495
for aortic dissection, 497
for carotid occlusive disease, 488
for femoral/popliteal occlusive disease, 
485
for intestinal ischemia, 490
for peripheral arterial disease, 484
for tibial/pedal occlusive disease, 486
Endurance exercise. 
See
Enemas
barium, for cancer screening, 1656
for constipation, 597
t
Energy deficiency (protein-energy 
malnutrition), 
1276–1277
Energy requirements, in nutritional 
support, 1289–1290
Enfuvirtide, 1365
t
, 1370. 
See also
 
ENG
 gene, 1688
Enolase, neuron-specific, in Creutzfeldt-
Jakob disease, 1035
for ACS (NSTEMI), 380
f
, 381, 387
t
, 580
t
Entacapone (entacapone-levodopa-
carbidopa), 1026, 1026–1027
Entamoeba
, 1528, 1529. 
See also
 Amebiasis
dispar,
 1528, 1529
histolytica,
 599
t
, 603, 1322
t
, 1528, 1529
moshkovskii,
 1528

, 580
t
Entamoeba
See also
 Amebiasis
dispar,
 1528, 1529
 599
t
, 603, 1322
t
 1528
Entecavir, 702, 1351
Enteral nutritional support (tube 
feedings), 1288–1289, 1289
f
, 
1290–1291
, 1290
t
. 
See also
 
Nutritional support
staphylococcal, 1321
t
, 1456, 1464, 
1466, 1468, 1469
streptococcal, 1451, 1464, 1466–1467, 
1468, 1469
surgical management of, 1468
Libman-Sacks, 854
Endocervical curettage, 777
t
in CIN/cervical cancer, 784, 786
in endometrial carcinoma, 788
Endoclips, for GI bleeding, 608, 624
Endocrine disorders, 
1119–1219
. 
See also
 
specific gland and disorder
in chronic kidney disease, 941–942
in HIV infection/AIDS, 1352
in hyponatremia, 900
in infertility. 
See
t
and, 
53–54
Endocrine therapy. 
See
 Hormone therapy
Endoleaks, after aneurysm repair, 493
Endolymphatic hydrops (Ménière 
syndrome), 222
Endometrial ablation
for abnormal uterine bleeding, 777, 778
Endometrial biopsy, 777, 777
t
, 788
Endometrial carcinoma/cancer of uterus, 
788–789
, 1612
t
, 1614
t
abnormal premenopausal/
postmenopausal bleeding and, 
777, 778, 788
breast cancer risk and, 754, 754
t
estrogen replacement therapy and, 788, 
1212
HNPCC/Lynch syndrome and, 681, 
 
788
oral contraceptive use and, 788, 802
polycystic ovary syndrome and, 788
Endometrial curettage. 
See
 Endometrial 
biopsy
Endometrial hyperplasia
777, 778
endometrial carcinoma and, 788
estrogen replacement therapy and, 1211, 
1212
Endometriosis, 
790–791
, 798
pelvic pain and, 779, 780, 790, 791
Endometritis, 
792–793
. 
See also
 Pelvic 
inflammatory disease
amenorrhea and, 1210
postpartum, 
828–829
Endomyocardial biopsy, in infectious 
myocarditis, 426
Endomyometritis, 
828–829
Endomysial antibodies, 646
Endoscopic retrograde 
cholangiopancreatography 
(ERCP), 691
in biliary tract carcinoma, 1635
in pancreatitis/pancreatitis after, 691, 
737, 738, 747
Endoscopic ultrasonography (EUS), 691, 
736, 737, 747. 
See also
 
CMDT2019_Index_p1743-1884.indd   1787

INDEX1788
 
CMDT 2019
Erysipeloid, 145
Erythemas, 104
t
, 
141–146
. 
See also
 
specific 
type
acral, chemotherapy-induced, 1679
induratum, 161, 501
infectiosum, 1381
t
, 1430
144–146
, 145
f
marginatum, in rheumatic fever, 435, 
435–436, 436
t
migrans, 
144
, 144
f
, 1506, 1508–1509, 
1508
t
. 
See also
multiforme/herpes-associated erythema 
multiforme, 
142–144
, 143
f
, 
1378, 1380
nodosum, 
160–161
, 161
f
, 171
t
in coccidioidomycosis, 1553
leprosum, 1490
in sarcoidosis, 303, 304, 887
pernio (chilblain), 
1568
reactive, 
141–144
, 141
f
, 143
f
, 144
f
Erythrasma, 120, 156, 156
f
Erythrocytes/erythrocyte count. 
See also
 
under Red cell
in myeloproliferative neoplasms, 530, 
530
t
in pleural fluid, 322, 324
t
in urine. 
See
 Hematuria; Red cell 
 
casts
Erythrocytosis, testosterone replacement 
therapy and, 1203
Erythroderma, exfoliative, 
124–125
, 171
t
Erythrogenic toxin (pyrogenic 
erythrotoxin), 1448, 1451
Erythromelalgia, 532, 858, 889
Erythromycin. 
See also
t
, 135
for amebiasis, 1530
t
for gastroparesis, 653, 1250
for nonbacterial prostatitis, 972
t
Erythroplakia, 234, 
234–235
Erythropoiesis, iron-restricted, 513
Erythropoiesis-stimulating agents, 514, 
527, 537, 940–941, 1677. 
 
See also
 
Erythropoietin (epoetin alfa), 514, 527, 
1362, 1676
t
, 1677
Erythrotoxin, pyrogenic (erythrogenic 
toxin), 1448, 1451
Erythrovirus gene, 1430
Erythrovirus (parvovirus) infection, 
 
1429–1431
arthritis in, 850, 884, 1430
erythema infectiosum, 1381
t
, 1430
Eschar formation
in anthrax, 1461
in pressure injury, 68
in rickettsialpox, 1442
in scrub typhus, 1349
in tick typhus, 1442
Escharotomy, in burn care, 1572
Escherichia coli,
 1318
t
, 1321
t
, 1322
t
cystitis/urinary tract infection/
pyelonephritis caused by, 834, 
967, 969, 1318
t
, 1321
t
, 1322
t
diarrhea/gastroenteritis/food poisoning 
t
, 600, 1312
t
, 
1316, 
1476–1477
Epileptic drop attacks (atonic seizures), 
998. 
See also
 Seizures
Epileptic spasms, 998, 998–999
Epinastine, 181
t
Epinephrine
for anaphylaxis, 891
endoscopic injection of, 608, 624, 642
1190, 1191
Epirubicin, 546, 765, 1618
t
, 1643
Episodic vertigo, 222
Epistaxis, 
231–232
cocaine/cocaine abuse and, 231
t
Epithelial cell/renal tubular casts, 926, 927
t
Eplerenone, 388, 418–419, 418
t
, 419, 462
t
, 
471, 1189
Epley maneuver, 222–223
Epoetin, 514, 527, 940–941, 1362, 1676
t
, 
1677
Epoprostenol, 314, 444
Eprosartan, 468
t
Epstein-Barr virus, 
1386–1388
Burkitt lymphoma and, 1387
hemophagocytic lymphohistiocytosis 
and, 1388
mononucleosis caused by, 1381
t
, 
 
1386–1387
nasopharyngeal carcinoma and, 233, 
1387
thrombocytopenia and, 566
Eptifibatide, 375, 380–381, 380
f
, 568
t
Epzicom (abacavir with lamivudine), 1366, 
1367
t
, 1373
t
Equianalgesic dosing, 88
Equine encephalitis, 1401
Equine rabies antiserum, 1400
Erb (limb-girdle) muscular dystrophy, 863, 
1060, 1061
t
Erectile dysfunction/impotence, 
978–980
, 
1075, 1076–1077. 
See also
 
Sexual dysfunction
drugs causing, 979, 1083, 1092–1093, 
1094
endocrine causes/hypogonadism and, 
979, 1200
phosphodiesterase inhibitors/sildenafil 
and, 979–980, 1076, 1250
psychologic/psychogenic, 979, 1075, 
1076–1077
vascular disease and, 978–979
Erections, 978
loss of, 978–979. 
See also
 Erectile 
prolonged painful. 
See
 Priapism
Ergocalciferol (vitamin D
2
), 1162
t
, 1163, 
1177. 
See also
 Vitamin D
Ergotamine, 991, 993
Erlotinib, 1621
t
, 1627, 1679
Erosive esophagitis. 
See
 Esophagitis
Erosive gastritis. 
See
 Gastritis
Erosive skin disorders, 104
t
Ertapenem, 1321
t
, 1484
t
Eructation (belching), 598
Eruptive xanthoma. 1224, 1251, 1269, 
1269
f
Erysipelas, 
144–145
, 1322
t
, 1449, 1450
f

See
 Gastritis
t
t
, 1484
t
1269
f
144–145
, 1322
t
f
, 
1450
t
Enzyme-linked immunosorbent assay 
(ELISA). 
See also
 
specific 
disorder
in HIV infection/AIDS, 1342, 1342
t
Eosinophilic esophagitis, 617
t
, 
624–625
Eosinophilic fasciitis, 860
Eosinophilic folliculitis (itchy red bump 
syndrome), 137, 138, 1341
Eosinophilic granulomatosis with 
syndrome), 315
leukotriene modifiers for asthma and, 
264
pulmonary involvement in, 315
renal involvement in, 946
t
, 948
f
, 951
Eosinophilic pneumonia, 305
Eosinophilic pulmonary syndromes, 
305
, 
1546
Ependymoma, 1017
t
, 1020
Ephedrine (decongestant), overdose/
toxicity of, 207
t
, 1590
Ephedrine (“herbal ecstasy”), 1590
Ephelides (freckles), 
111
Epicondylosis (epicondylitis), lateral and 
medial, 
1703–1704
Epidemic keratoconjunctivitis, 176, 1434
Epidemic louse-borne typhus, 
1436–1438
, 
1437
t
Epidemic pleurodynia, 1434
Epidermal growth factor (EGFR) 
mutations/inhibitors. 
See
 
EGFR (epidermal growth 
factor) mutations/inhibitors
Epidermal inclusion cysts (EICs), 162, 
163
Epidermoid cyst, testicular, 1669
Epididymal obstruction, in infertility, 983
Epididymitis, 968
t
, 
973
, 1323
t
chlamydial, 973, 1323
t
in filariasis, 1546
gonococcal, 973, 1323
t
Epidural hemorrhage
cerebral, 1043, 1043
t
spinal, 1015
Epigastric pain. 
See
 Abdominal pain/
tenderness; Dyspepsia
Epiglottis, cancer of, 246–247
Epiglottis “thumb sign, ” 245
Epiglottitis (supraglottitis), 
245
, 1449, 
1472
Epilepsia partialis continua, 1030
Epilepsy, 995–996
t
, 
997–1002
. 
See also
 
Seizures
in autoimmune disorders, 999
classification/syndromes/types of, 
 
998–999
drug therapy for, 995–996
t
, 1001, 1002. 
See also
therapy
genetic, 999
immune, 999
management of, 1001
mesial temporal sclerosis and, 999
metabolic, 999
myoclonic ragged red fiber (MERRF), 
1062
myoclonus/myoclonic jerks and, 
 
1030
photosensitive, 1000
posttraumatic, 999, 1044
834
solitary seizure and, 1001–1002
structural causes of, 999
CMDT2019_Index_p1743-1884.indd   1788

INDEX1789
 
CMDT 2019
in estrogen replacement therapy, 809, 
1212, 1214
Estradiol vaginal tablets, 1214
Estrogen-progesterone therapy. 
See
 
Estrogen (hormone) 
replacement therapy
Estrogen receptor modulators, selective. 
See
 Selective estrogen receptor 
modulators
Estrogen (hormone) replacement therapy, 
1211–1216. 
See also
 Estrogens; 
Selective estrogen receptor 
agents used in, 1213–1215
for atrophic urethritis/vaginitis, 809, 
1211–1212, 1214
benefits of, 1211–1212
breast cancer/breast cancer risk and, 
754, 810, 1211, 1212, 1213
endometrial hyperplasia/carcinoma and, 
788, 1211, 1212
growth hormone replacement and, 1123
1168
hypertension and, 455
injections, 1214
lipid modification/heart disease and, 
810, 1212, 1213
nipple discharge and, 752
oral, 1212, 1213, 1214
osteoporosis and, 1172, 1211, 1212, 
1215
ovarian cancer risk and, 1213
postmenopausal bleeding and, 778, 
1211, 1212
with progestins (combined HRT), 809, 
1211, 1212, 1213, 1214
without progestins (unopposed HRT), 
809, 1211, 1212, 1212–1213, 
1214
risks/adverse effects of, 208
t
, 810, 
 
1212–1213
after surgical menopause, 810
transdermal, 809, 1211, 1212, 
 
1213–1214
in Turner syndrome, 1217
vaginal, 809, 1212, 1214
for vasomotor symptoms/hot flushes, 
809, 1212, 1214–1215
Estrogen vaginal creams/tablets, 809, 1214
Estrogens. 
See also
 Estrogen (hormone) 
for abnormal uterine bleeding, 777
breast cancer/breast cancer risk and, 754
1738
t
in fibrocystic breast condition, 750
in hypogonadotropic hypogonadism, 
1123, 1201
in menopause, 1210
in oral contraceptives, 801
t
receptors for
antagonists of, 1623
t
in breast cancer, 762, 763, 764, 765
t
, 
768
Estrone, in estrogen replacement therapy, 
809
Estropipate, 1214
Eszopiclone, 1067
t
, 1102
Etanercept, 116, 852. 
See also
 Anti-TNF 
agents
Esophagography, barium, 618, 619, 625, 
Esophagus
Barrett, 620, 1638
cancer of, 617
t
, 1614
t
, 
1638–1641
adenocarcinoma, 1638–1639
Barrett esophagus and, 620, 1638
dyspepsia and, 589
squamous cell, 1638
617–631
, 617
t
. 
See also
 
under Esophageal and
 
benign, 
624–629
chest pain and, 372, 630, 
631
corrosive/caustic injury, 1589, 1590
GERD, 
618–623
motility. 
See
 Esophageal motility 
disorders
in scleroderma, 860
249
“jackhammer, ” 631
rupture of
pleural effusion in, 324
t
vomiting and (Boerhaave syndrome), 
593
“sigmoid, ” 629
strictures of, 617
t
, 621
Espundia (mucocutaneous leishmaniasis), 
1513, 1514, 1515
Essential fatty acids, in nutritional support, 
1290
Essential hypertension, 453, 456. 
See also
 
Essential thrombocytosis, 530
t
, 
531–532
Essential (familial) tremor, 
1024
Essure, for tubal interruption, 807
Estazolam, 1067
t
Estimated glomerular filtration rate, 
 
927–928. 
See also
 Glomerular 
filtration rate
Estradiol/ethinyl estradiol
1214
1738
t
in feminizing hormone therapy, 
 
1740
t
1741
t
in oral contraceptives, 800
parenteral, 1214
in transdermal patch. 
See
 Estradiol 
transdermal systems
in vaginal rings
contraceptive, 803–804
for hormone replacement, 809, 1212, 
1214
Estradiol gels/mists, 1213
Estradiol injections, 1214
1738
t
Estradiol transdermal systems (skin 
patches)
for contraception, 803
for feminizing hormone therapy, 1738, 
1738
t
for hormone replacement therapy, 809, 
1211, 1212, 1213–1214
Estradiol vaginal ring
enterohemorrhagic (EHEC), 599
t
, 600, 
1312
t
enteroinvasive (EIEC), 599
t
, 1476
enterotoxigenic (ETEC), 599
t
, 600, 
1312
t
, 1316, 1476
fever/neutropenia/chemotherapy and, 
1321
t
, 1674
hemolytic-uremic syndrome caused by, 
561, 561
t
, 601, 1476
pneumonia caused by, 278
t
, 283

t
, 600, 
1312
t
1321
t
, 1674
561, 561
t
, 601, 1476
t
, 283
shiga-toxin–producing (STEC), 561, 
561
t
, 600, 601, 1312
t
, 1476
 O104:H4, 601, 1476
 O145, 561, 1476
 O157:H5, 599
t
 O157:H7, 561, 600, 1476
Escitalopram, 591, 1068, 1090–1093, 
1091
t
, 1211
Eslicarbazepine, 995
t
Esmolol
for arrhythmias, 389, 394
t
, 400, 403
for hypertension, 480, 480
t
, 481
t
, 482, 
497
Esomeprazole, 608, 621, 631, 633, 637, 
639, 641. 
See also
 Proton 
Esophageal clearance, in GERD, 619
Esophageal dilation, 621, 625, 630
Esophageal dysphagia, 617, 617
t
. 
See also
 
Dysphagia
Esophageal manometry, 618, 629, 630
Esophageal motility disorders, 618, 
 
629–631
chest pain in, 372, 630, 631
dysphagia in, 617, 617
t
, 630
Esophageal pH monitoring, 618, 619–620, 
622
Esophageal (Schatzki) rings, 617
t
, 
625
Esophageal spasm, diffuse, 617
t
, 630, 631
Esophageal sphincters
in achalasia, 629
artificial, 622
in GERD, 618–619, 622
in Zenker diverticulum, 626
Esophageal varices, 
626–629
cirrhosis and, 606, 626, 627, 628
GI bleeding from, 606, 608, 626–629
portal hypertension and, 606, 626–629, 
729
in primary biliary cirrhosis, 722
Esophageal webs, 
625
iron deficiency anemia and (Plummer-
Vinson syndrome), 511, 625
Esophagectomy, 630, 1639, 1639–1640
candidal, 623, 1346
t
, 1350–1351, 1550, 
1551
chest pain in, 372
CMV , 623
eosinophilic, 617
t
, 
624–625
erosive/reflux, 606, 618, 619, 620, 621, 
622. 
See also
 Gastroesophageal 
reflux disease
herpetic, 623, 1378, 1380
in HIV infection/AIDS, 623, 1350–1351, 
1378
623–624
pill-induced, 
624
stricture formation and, 621
Esophagogastric junction cancer, 1614
t
CMDT2019_Index_p1743-1884.indd   1789

INDEX1790
 
CMDT 2019
Exposure (cold). 
See
 Cold, disorders 
caused by exposure to
Exposure keratitis, 185
Extensively/extremely drug-resistant 
tuberculosis, 288, 295, 1347
Extensor (decerebrate) posturing, 1040, 
1041
External auditory canal. 
See
 Ear canal
External hordeolum (sty), 174
External otitis/malignant external otitis, 
212–213
, 212
f
External rotation, at shoulder, 1691
t
, 
1692
t
, 1694, 1697
External rotation stress test, in ankle 
sprain, 1721
Extracorporeal counterpulsation, 376
Extracorporeal membrane oxygenation 
(ECMO)
1594
for cardiomyopathy of pregnancy, 446
for hypotension in drug overdose, 
1581–1582
for systemic hypothermia, 1567
Extracorporeal shock wave lithotripsy. 
 
See
 Shock wave lithotripsy
Extramammary Paget disease, 126, 126
f
Extraocular movements. 
See
 Eye 
(extraocular) movements
Extrapyramidal disorders/effects
antidepressants and, 1085, 1092
antipsychotics and, 1081, 1082, 1082
t
, 
1084, 1592
Extrasystoles. 
See
 Atrial (supraventricular) 
premature beats; Ventricular 
premature beats
Extrauterine pregnancy. 
See
 Ectopic 
pregnancy
Extremities. 
See also
 Lower extremity; 
Upper extremity
acute arterial occlusion of, 
487–488
hypothermia of, 
1568–1569
Extrinsic allergic alveolitis 
318–319
, 
 
319
t
Exudates, pleural, 322, 323, 323
t
Eye, 
174–209
. 
See also
 
under Ocular; 
Optic; Visual
decontamination of, 
1584
, 1589, 
 
1590
174–209
. 
See also
 
specific 
type or cause and
 Visual 
impairment/loss
age-related macular degeneration, 
193–194
allergic, 
178
in Behçet syndrome, 189, 876
in blood dyscrasias, 
198
cataract, 
191
, 1247
chemical burns, 
205–206
, 1589
chlamydial, 177, 837
CMV infection, 198–199, 1346
t
, 
1350, 1362, 1388, 1389, 1390
in coma/stupor, 1040–1041
corneal ulcers, 
178–185
diabetes and, 188, 197–198, 1247. 
 
See also
 Diabetic retinopathy
drugs (systemic) causing, 207–209
t
, 
209
Exanthema subitum (roseola infantum), 
1381
t
, 1391
Exanthems, 1381–1382
t
. 
See also
 Rashes
drugs causing (dermatitis 
medicamentosa), 
170–173
, 
171–172
t
, 
894
Exchange transfusion. 
See
Excitement (arousal) stage of sexual 
See also
Executive dysfunction, 57, 1033
Exemestane, 755, 766–767, 769, 769
t
, 
1623
t
Exenatide, 1230
t
, 1234–1235, 1235, 1599. 
See also
 Glucagon-like peptide 
1 (GLP-1) receptor agonists
Exercise/activity
angina precipitated by, 369
bronchoconstriction/asthma 
precipitated by, 253, 254
f
, 256, 
259, 264
cancer risk and, 14, 1611
cardiovascular/heart disease prevention/
t
, 373
f
, 
1270–1271
for COPD, 272
in diabetes, 1222, 1240, 1242, 1244, 
1244
f
, 1246
in elderly, 57, 62–63
for fatigue/chronic fatigue syndrome, 40
in health maintenance, 
11–12
heart murmurs affected by, 346
t
heat exposure and, 1565
t
, 458
hyponatremia and, 900
lesbian and bisexual women and, 1726
for menopausal symptoms, 1211
in obesity/overweight, 12, 13, 
 
1278–1279
1726
for osteoporosis, 810, 1172
patellofemoral pain syndrome and, 
1717–1718
for peripheral arterial disease, 
 
483–484
in peripheral arterial disease, 484
for polycystic ovary syndrome, 795
reduced. 
See
 Bed rest; Immobility; 
Lifestyle, sedentary
Exercise challenge (bronchial provocation) 
testing, 256
Exercise-induced bronchoconstriction/
asthma, 253, 254
f
, 256, 259, 
264. 
See also
 Asthma
Exercise-induced hypoglycemia, 1240, 
1242, 1246
Exercise testing. 
See
 Stress/exercise testing
Exertional heat stroke, 1565
Exfoliative dermatitis/erythroderma, 
 
124–125
, 171
t
Existential challenges, for terminally 
 
ill/dying patient, 80, 80
t
Exophiala,
 1561
Exophthalmos, Graves. 
See
 Graves

124–125
, 171
t
 
t
 1561
See
 Graves 
ophthalmopathy/orbitopathy/
exophthalmos
Exostoses, 
213
Etelcalcetide, 1168
Eteplirsen, 1060
Ethacrynic acid, 461
t
Ethambutol, 208
t
, 292, 292
t
, 293, 293
t
, 
1487, 1488
in pregnancy, 293, 294, 836
Ethanol (ethyl alcohol). 
See also
 Alcohol 
use disorder; Ethanol 
blood levels of, 1106, 1598
for methanol or ethylene glycol 
t
, 1587
t
, 1603
Ethanol (ethyl alcohol) percutaneous 
injection, for thyroid nodules, 
1151
Ethanol-associated hypoglycemia, 1111, 
1246, 1261, 1261
t
, 1266
Ethanol intoxication/poisoning, 1106, 
1587
t
, 
1598–1599
. 
See also
 
905, 1107
Ethics
end-of-life care and, 79
principles of care and, 2
Ethinyl estradiol. 
See
 Estradiol/ethinyl 
estradiol; Estrogens
Ethmoiditis/ethmoid sinusitis, 226
Ethosuximide, 996
t
Ethyl alcohol. 
See
 Alcohol use disorder; 
Ethanol
Ethylene glycol poisoning, 1584
t
, 1587
t
, 
1602–1603
anion gap/osmolar gap in, 905, 919, 
1587, 1602
hemodialysis for, 1585
t
, 1587
t
, 1603
Ethylenediaminetetraacetic acid (EDTA), 
961, 1600, 1601
Ethynodiol diacetate, in oral 
contraceptives, 801
t
Etodolac, 86
t
, 633
Etonogestrel
in contraceptive vaginal ring, 803–804
in hormone replacement therapy, 1214
in implant, 779, 803
Etoposide/etoposide phosphate, 1618
t
, 
1628, 1670
Etravirine, 1364
t
, 1368–1369. 
See also
 
Etretinate, 209
t
, 1353–1354
ETV6
 mutation, 556
Eucerin, 108
t
Euglycemic insulin therapy. 
See
 High-dose 
insulin euglycemic therapy
Eumycetoma (maduromycosis), 
1560
European (Western) subtype tick-borne 
encephalitis, 1404
Eustachian tube, 
213–214
dysfunction of, 210, 
213–214
in HIV infection/AIDS, 224
patulous, 214
serous otitis media and, 
214
Euthyroid sick syndrome, 1136
Euvolemic hypernatremia, 904
Euvolemic hypotonic hyponatremia, 899
f
, 
900–901, 902
Evans syndrome, 524
Event recording, 393, 397, 407, 413, 1000
Everolimus, 770, 1264, 1621
t
, 1668
Eversion (high) ankle sprain, 
1721
Evolocumab, 10, 368, 1273
t
, 1274
CMDT2019_Index_p1743-1884.indd   1790

INDEX1791
 
CMDT 2019
Familial hypercholesterolemia, 
1683–1684
Familial hypocalcemia, 906
t
Familial hypocalciuric hypercalcemia, 
906
t
, 1167
Familial juvenile polyposis, 681
Familial Mediterranean fever, 
616
Familial partial lipodystrophy type I, 1186
Familial renal glycosuria, 1224
Familial (essential) tremor, 
1024
Family/significant others, of patient at end 
of life, 75, 75
t
, 81
Family building, for lesbian and bisexual 
women, 1731–1732
Family planning, 
800–807
, 801
t
, 802
t
, 
804
t
. 
See also
for lesbian and bisexual women, 
 
1731–1732
Famotidine, 621, 633, 637. 
See also
 H
2
 
Fanconi anemia/syndrome, 526, 556, 913, 
920, 964, 1224
Fanconi-like syndrome, 702
Fansidar (pyrimethamine-sulfadoxine), 
1518, 1518
t
, 1522, 1524
with amodiaquine, 1522
with artesunate, 1518
t
, 1519
t
, 1522
in pregnancy, 1524
resistance to, 1518, 1522
Far Eastern subtype tick-borne 
Farmer’s lung, 319
t
Fasciitis
eosinophilic, 860
necrotizing. 
See
 Necrotizing fasciitis
palmar, 889
Fasciola hepatica/gigantica
 (fascioliasis), 
1536–1537
Fasciolopsis buski,
 1537
Fasciotomy, in burn care, 1572
Fasting
insulinoma diagnosis and, 1263, 1263
t
porphyria and, 1681
Fasting hypoglycemia, 1261, 1261
t
, 1262. 
See also
 Hypoglycemia
Fat. 
See also
 Lipid disorders/lipids
body. 
See
 Body fat; Obesity/overweight
dietary, 1287. 
See also
 Lipid disorders/
lipids
in diabetes, 1228
lowering, 1271, 1287
intravenous. 
See
 Intravenous fat
Fat necrosis of breast, 
752
Fat-restricted diet, 1271, 1287
for pancreatitis, 744, 747
Fatal familial insomnia, 1406
Fatigue, 
38–40
, 39
f
, 
73
post-Q fever, 1444
Fatty acids, 3
t
, 1290
Fatty liver (hepatic steatosis)
alcoholic, 708, 709
with encephalopathy. 
See
 Reye 
syndrome
in hepatitis C, 698
nonalcoholic, 712, 713, 714, 1631
of pregnancy, 699, 712, 
838
Favipiravir, 1411
FBN1
 mutation, 1687
Febrile agglutinins, 1295
Febrile seizures, 1000
Ezetimibe, 367, 1273
t
, 1274
EZH2
 mutation, 537
Ezogabine, 995
t
Face. 
See also
 
under Facial
herpes zoster affecting, 225, 997, 1383. 
See also
 Ramsay Hunt 
syndrome
Facial neuropathy/paralysis/palsy, 
1054
, 
1054
f
herpes infection and, 225, 997, 1054
Lyme disease and, 1054, 1054
f
, 1506, 
1507, 1508
t
, 1509
Facial pain, 
994–997
Facioscapulohumeral muscular dystrophy, 
1061
t
Factitious disorders, 1071. 
See also
 
specific 
disorder
Factor II antibodies, 
572
Factor II deficiency, 571
Factor V antibodies, 
572
Factor V deficiency, 571
Factor V Leiden
disease) and, 306, 586
t
in noncirrhotic portal hypertension, 729
Factor VII deficiency, 571
acquired antibodies to, 567, 568, 569, 
571–572
in cryoprecipitate, 554
deficiency of
in hemophilia, 567–568
in von Willebrand disease, 570, 570
t
Factor VIII concentrate, 568–569, 569
t
, 
572
Factor IX
acquired antibodies to, 567, 568, 569
in hemophilia, 567, 568
Factor IX concentrate, 568–569, 569
t
Factor X deficiency, 571
Factor XI concentrate, 571
Factor XI deficiency, 569
t
, 
571
Factor XIII deficiency, 571
Factor concentrates, for hemophilia, 
 
568–569, 569
t
Factor inhibitors, in hemophilia, 569
Faget sign, 1416
Failed back surgical syndrome, 83
Fainting, 413. 
See also
 Syncope
Fallot
pentalogy of, 341
tetralogy of, 
341–342
pulmonary valve regurgitation after 
repair of, 362
Falls, in elderly, 
63–65
, 64
t
False vocal folds, cancer of, 246–247
Famciclovir, 1379
t
for herpes simplex infections, 127, 185, 
623, 1346
t
, 1352, 1379
t
186, 1346
t
t
, 1384
Familial adenomatous polyposis, 
680
, 
1649
Familial cortisol resistance, 1185
Familial Creutzfeldt-Jakob disease, 1406, 
1407
Familial hemiplegic migraine (FHM), 990
Familial hirsutism, 1206
Familial hyperaldosteronism, 1188
glaucoma, 176
t
, 
187
, 
188–189

1407
t
, 
187
, 
188–189
871
herpes simplex infection, 
185
, 1377, 
1378, 1380
herpes zoster infection, 128, 
186
, 
1353, 1383, 1384
in HIV infection/AIDS, 198–199, 
1350
inflammation, 176
t
. 
See also
 
Conjunctivitis; Uveitis
keratitis. 
See
 Keratitis
lids/lacrimal apparatus involvement 
and, 
174–176
management of, 179–184
t
, 
206–209
, 
206
f
. 
See also
 Ophthalmic 
ocular motor palsies, 
201–202
, 
 
201
f
in onchocerciasis (river blindness), 
1547–1548
optic disk swelling, 
200–201
optic neuritis, 
199–200
optic neuropathy (ischemic), 
199
, 868
orbital cellulitis, 
202–203
pinguecula/pterygium, 
178
refractive errors, 
174
retinal, 
192–193
, 192
f
, 
194–195
, 194
f
, 
195–196
, 
197–199
, 488, 1008. 
See also
 Retina
in rheumatoid arthritis, 849
thyroid (Graves ophthalmopathy), 
202
, 202
f
, 1140, 1142, 1143, 
1145, 1147
transient monocular visual loss, 
196
, 
488
traumatic, 
203–205
, 204
f
vitreous hemorrhage, 
193
dry (keratoconjunctivitis sicca), 
 
177–178
in diabetes patients, 197, 1247
203
, 204
f
in SLE, 854
in toxoplasmosis, 190, 1526
traumatic injury of, 
203–205
, 204
f
Eye drops, 179–184
t
. 
See also
autologous serum, 177
contaminated, 
206
preservative-free, 189, 206
systemic absorption/effects of, 
 
206–209
toxic and hypersensitivity reactions to, 
177, 
206
, 206
f
Eye (extraocular) movements
in ocular motor palsies, 201, 201
f
“Eye worm” 
(Loa loa),
 1548–1549
Eyelids
blepharitis affecting margins of, 175
174–176
seborrheic dermatitis affecting margins 
of, 118
tumors of, 
175
CMDT2019_Index_p1743-1884.indd   1791

INDEX1792
 
CMDT 2019
diverticular disease and, 676, 677, 1287
fecal incontinence and, 685
hemorrhoids and, 683
hypertension and, 457
irritable bowel syndrome and, 658, 1287
lipid-modifying effects of, 1271, 1287
Fiber laxatives, 596, 597
t
Fiberoptic bronchoscopy. 
See
 
Fibric acid derivatives (fibrates), for lipid 
modification, 1273
t
, 1274
Fibrillation. 
See
 Atrial fibrillation; 
Ventricular fibrillation
Fibrillin gene mutation, 1687
Fibrin D-dimer. 
See
 D-dimer fibrin
Fibrinogen. 
See also
 Cryoprecipitate
t
, 573
Fibrinolytic therapy. 
See also
 Thrombolytic 
therapy
after cardiac valve replacement, 364
t
, 
365
for myocardial infarction, 385, 385
t
, 
386–387
contraindications to without 
ST-segment elevation, 379, 
385
Fibroadenoma of breast, 
751
(phosphatonin), 913, 939, 
1176, 1177
Fibrocystic breast condition, 
750–751
breast cancer risk and, 750, 751, 754, 
754
t
nipple discharge in, 750, 752, 752
t
Fibroelastoma, valvular papillary, 445
Fibrogenesis imperfecta ossium, 1176
Fibroid tumor of uterus, 
787–788
Fibrolamellar hepatocellular carcinoma, 
1631, 1632
Fibromuscular dysplasia/hyperplasia
hypertension and, 454, 944
Fibromyalgia, 
888
Fibronectin, fetal, 825
Fibrosing cholestatic hepatitis, 702
Fibular (peroneal) nerve, common, injury 
to, 
1053
Fidaxomicin, 661
Field defects/loss. 
See
 Visual impairment/
loss
“Field treatment, ” for actinic keratoses, 125
Fifth disease (erythema infectiosum), 
1381
t
, 1430
Figurate (“shaped”) erythema, 104
t
, 
 
141–146
. 
See also
 
and
 Erythemas
Filariasis, 
1546–1549
, 1546
f
Filgrastim (G-CSF), 527, 529, 1362, 1676
t
, 
1677
Financial abuse, of elderly, 60
Financial planning, advance, for dementia 
patients, 60
Finasteride (5-alpha-reductase inhibitor)
for androgenetic alopecia, 168, 986
t
986–987, 986
t
, 987
1738
t
for hirsutism/virilization, 795, 1208
t
Fertilization, in vitro (IVF), 798, 799, 983
Fesoterodine, 66
Fetal alcohol syndrome, 812, 1107
Fetal fibronectin, 825
Fetal goiter, 1146
Fetal hemoglobin. 
See
 Hemoglobin F
Fetal lung maturity, corticosteroids for, 
825–826
Fetal-placental unit, in preeclampsia-
eclampsia, 823
t
, 824
Fetal testing, 813–814. 
See also
 
specific 
 Genetic testing
Fetal varicella infection, 835
Fetoprotein. 
See
 Alpha-fetoprotein
Fetotoxic drugs, 812
t
Fetus. 
See also
 Pregnancy
age of viability of, 806
chikungunya fever transmission to, 1419
CMV transmission to, 1388, 1389
dengue transmission to, 1414
hepatitis transmission/vaccine and, 694, 
695, 696, 837, 1228
t
herpes simplex transmission to, 837, 
1377–1378
HIV transmission to, 836, 1340, 1358
affecting, 1165, 1166–1167
malaria transmission to, 1516
rubella affecting, 1396
syphilis transmission to, 837, 1493, 1502
penicillin treatment in maternal 
disease and, 1496, 1502
thyroid disease affecting, 831. 
See also
 
Pregnancy, thyroid disease 
and
toxoplasmosis transmission to, 813, 
1526, 1526–1527
Zika virus infection affecting, 1418
Fever, 
34–37
. 
See also
 
specific disorder or 
cause
cancer-related, 1294, 1295, 1674
in critically ill patient, 1301, 1303
drug, 1301
in drug user, 1311
E coli
 causing, 1476
episodic, 1295
factitious (self-induced), 1295
in HIV infection/AIDS, 1294, 1295
in infectious disease, 
1294–1296
in malaria, 1516, 1518
in neutropenic patient, 529, 1294, 1295, 
1674
antimicrobial therapy and, 36, 529, 
1300, 1321
t
postoperative, 1301–1302
prolonged, 1295
recurrent, 1295
seizures and, 1000
severe, with thrombocytopenia, 1412
travel and, 1294, 1315
dengue causing, 1413, 1414
of unknown/undetermined origin 
(FUO), 35–36, 868, 
 
1294–1296
Fever/cold sore, 
126–127
, 126
f
. 
See also

1294–1296
126–127
, 126
f
. 
See also
 
Fexofenadine, 142, 229. 
See also
 
Fiber, dietary, 596, 597
t
, 1287
constipation and, 596, 597
t
diabetes and, 1228, 1287
Febuxostat, 847
Fecal antigen assay, in 
H pylori
590, 634, 637
Fecal DNA tests, in cancer screening/
polyp identification, 678, 
1653
t
Fecal immunochemical test (FIT). 
See also
 
Fecal occult blood testing
16, 678, 1653, 1653
t
, 1654, 
1654
t
in GI bleeding, 611, 612
Fecal impaction, 598
“overflow” fecal incontinence/diarrhea 
and, 598, 685
Fecal incontinence, 
685–686
Fecal microbiota transplant, 661–662
16, 678
t
, 1654
Fecal osmolality, 603
Feeding tubes, 1289, 1289
f
. 
See also
 
in elderly/dementia, 67, 77
Feet
atherosclerotic/occlusive disease and, 
486–487
in diabetes mellitus, 1242, 1248, 1249, 
1249
f
, 1251
immersion/trench, 
1568
tinea of, 120
f
, 
121–122
, 121
f
cellulitis and, 121, 145
vesiculobullous dermatitis of 
129–130
, 130
f
Felbamate, 995
t
, 1592
Felodipine, 471, 473
t
, 1594
Felty syndrome, 528, 529, 849
Female condom, 805, 1727
Female sexual dysfunction, 
796–797
Feminizing hormone therapy, for 
transgender patients, 
 
1737–1739, 1738
t
, 1740, 1740
t
Femoral arteries
aneurysms of, 495
484–485
, 488
Femoral cutaneous nerve, lateral, lesions 
of (meralgia paresthetica), 
1053
Femoral neck fracture, 1707. 
See also
 Hip 
fracture
atypical, bisphosphonate use causing, 
1173
Femoral neuropathy/nerve palsy, 
1053
Fenoldopam, 480
t
, 481
t
, 482
Fenoprofen, 86
t
Fentanyl (oral transmucosal/buccal/
transdermal), 88–96, 90
t
, 91
t
, 
1604
Fenthion poisoning, 1605
Ferric pyrophosphate citrate, 512
Ferriman-Gallwey scale, 1207
Ferritin, 510, 512
in anemia, 510, 511, 512, 513, 941
in hemochromatosis, 723, 724
Ferroportin, 510, 723
Ferrous sulfate, 512
Fertility awareness, contraception based 
on, 
805
CMDT2019_Index_p1743-1884.indd   1792

INDEX1793
 
CMDT 2019
Fluorouracil, 1618
t
t
, 1678, 1679
for wart removal, 150
Fluoxetine, 1090–1093, 1091
t
, 1609. 
 
See also
 Serotonin-selective 
t
lithium interaction and, 1099
t
Fluoxymesterone, 527
Fluphenazine, 1031, 1081, 1081
t
, 1082
t
, 
1083, 1249
Flupirtine, 1407
Flurandrenolide, 106
t
Flurazepam, 1067
t
, 1068, 1102
Flurbiprofen, 87
t
, 182
t
Flutamide, 795, 1187, 1207–1208, 1623
t
, 
1662
t
Fluticasone, 229, 260
t
, 262
t
, 271
Fluvastatin, 367
t
, 1273
t
. 
See also
 Statins
Fluvoxamine, 1090–1093, 1091
t
, 1609. 
 
See also
Flying. 
See
 Air travel
FMR1
 gene, 1684
Focal nodular hyperplasia of liver, 731
Focal segmental glomerulosclerosis, 947
t
, 
956
Focal (partial) seizures/epilepsy, 995–996
t
, 
998, 999, 1000. 
See also
 
Seizures
Focal torsion dystonia, 
1029
FODMAPS
celiac sensitivity and, 646
flatus and, 598, 599
irritable bowel syndrome and, 658
Folate. 
See
 Folic acid
Foley catheter
health care (hospital)–associated 
urinary tract infection and, 
968, 1301, 1302, 1303
Folic acid (folate), 519
antagonists/inhibition of synthesis of, 
1521–1522, 1617
t
. 
See also
 
deficiency of, 
518–519
, 519
t
in homocystinuria/
hyperhomocysteinemia, 1686
in pregnancy, 519, 519
t
, 829
thrombocytopenia and, 558
vitamin B
12
 deficiency and, 519
supplementary, 519
for hemoglobin H disease/
thalassemia, 516
for homocystinuria/
with methotrexate (leucovorin 
rescue), 851, 1675
t
in pregnancy, 519, 812, 814, 815, 829
for sickle cell anemia/syndromes, 523
Folinic acid (leucovorin)
with methotrexate, 851, 1675
t
, 1679
in toxoplasmosis, 1345
t
, 1361, 1527
Follicle-stimulating hormone (FSH), 1119
in amenorrhea, 1209, 1210
in hirsutism/virilization, 1206, 1207
in hypogonadism, 1120, 1121, 1200, 
1201
invasive disease, 1551
t
, 
1346
t
, 1557
for onychomycosis, 170
for tinea versicolor, 122
Flucytosine, 1345
t
, 1346
t
, 1557, 
 
1562
t
Fludarabine, 524, 1617
t
Fludrocortisone, 413, 922, 1004, 1182, 
1183, 1250
Fluid and electrolyte disorders, 
899–916
, 
906
t
. 
See also
 
specific 
electrolyte
management/replacement guidelines 
and, 
925
, 925
t
Fluid management/hydration, 
925
, 925
t
. 
See also
 
Water/fluid intake
in ARDS, 332
in burns, 1571–1572
in cholera, 1477
diabetes insipidus and, 1124, 1125
in diabetic ketoacidosis, 1256
in diarrhea/gastroenteritis, 602, 925
t
, 
1314, 1679
dilutional acidosis and, 921
in GI bleeding, 607
in hypercalcemia, 912, 1167, 1673
1259
in hypernatremia, 904
in hyponatremia, 902, 903
hypotension in poisoning/drug 
overdose and, 1581
in nutritional support, 1289
in pancreatitis, 744
in shock, 507
for tumor lysis syndrome/
hyperuricemia, 1674
urinary stone formation and, 975, 976, 
977
Fluid volume alterations
hyperosmolality with and without, 
 
904–905
metabolic alkalosis and, 922–923, 922
t
, 
923
Flukes, infections caused by, 
1535–1538
. 
See also
 
Flumazenil, 1581, 1584
t
, 1598
Flunisolide, 229, 262
t
Fluocinolone/fluocinolone implant, 105
t
, 
116, 197, 1148
Fluocinonide, 105
t
, 237–238, 1350
Fluorescein, contaminated, 206
Fluorescent treponemal antibody 
absorption test. 
See
 FTA-ABS 
test
Fluorometholone, 182
t
Fluoroquinolones, 208
t
, 1321
t
, 1322
t
t
t
, 
1322
t
Fine-needle aspiration biopsy/cytology
in breast lump, 758–759. 
See also
 Breast, 
biopsy of

t
, 1321
t
, 1322
t
t
t
, 
1322
t
See also
 Breast, 
biopsy of
in lung cancer, 1625
thyroid, 1133, 1135
t
, 1150, 1150–1151, 
1150
t
Fingernail disorders. 
See
 Nail disorders
Fingers. 
See also
 
under Hand
Raynaud phenomenon affecting, 858
thromboangiitis obliterans (Buerger 
disease) involving, 491
Fingolimod, 208
t
, 1038
t
Firearms, prevention of injury/death 
caused by, 17
First aid. 
See also
 Cardiopulmonary 
resuscitation
First-degree heart block, 389, 390, 397, 
398. 
See also
 Atrioventricular 
(heart) block
First-degree (superficial) burns, 1571
Fish oil. 
See
 Omega-3 fatty acids
Fish (seafood) poisoning, 
1607
, 1607
t
Fish tapeworm 
(D latum),
 517, 
1538
Fistula in ano, 686
Fistulas
in diverticulitis, 677
perianal, 665, 666, 667, 686
perilymphatic, 223
Fitz-Hugh and Curtis syndrome, 792
5q loss (5q–/del[5q]), 536, 537
Fixed drug eruptions, 170, 171
t
Flail leaflet, 351
Flame (clothing) burns, 1573
Flash (arcing) burns, 1573
Flatus, 598–599
Flaviviruses, encephalitis caused by, 1401, 
1404
Flea bites, 159
in plague transmission, 1480
in rickettsial disease transmission, 
1437
t
, 1438, 1439, 1442
Flea-borne endemic (murine) typhus, 
1437
t
, 
1438–1439
Flea rickettsiosis, California, 1437
t
Flecainide, 393, 394
t
, 396, 406
“Fleeting blindness” (amaurosis fugax), 
196, 488, 1008
Flexion, at shoulder, 1691
t
Flexor (decorticate) posturing, 1040, 1041
FLI1
Flibanserin, 797, 1076, 1215
Floppy iris/eye syndrome, 191, 986
“Floppy” mitral valve. 
See
prolapse
Flower cells, 1409
FLT3
 mutation, 538, 539
FLT3-ITD
 mutation, 538
FLT3
 kinase inhibitor, 539
Flu/flu shots. 
See
 Influenza; Influenza 
virus vaccine
Fluciclovine imaging, in prostate cancer, 
1658
Fluconazole, 1562
t
, 1678
for aspergillosis, 1299
cutaneous/mastitis/vulvovaginal, 140, 
781–782, 782, 1346
t
, 1551
endocarditis, 1551
t
funguria, 1551
CMDT2019_Index_p1743-1884.indd   1793

INDEX1794
 
CMDT 2019
Frozen shoulder, 1252, 
1696–1697
Fructosamine, in diabetes, 1226
FTA-ABS test, 1495, 1495
t
on cerebrospinal fluid (CSF FTA-ABS), 
1501
in HIV infection/AIDS, 1360
Fukuda test, 222
Full liquid diet, 1286
Full-thickness (third-degree) burns, 1571
Fulminant ulcerative colitis, 671, 673–674
Fulvestrant, 769, 769
t
, 770, 1623
t
Fumagillin, 1532
Functional alimentary hypoglycemia, 
1265
Functional (specific) antibody deficiency, 
897
“Functional” asthma, 257
Functional hypopituitarism, 1120, 1124
Functional neurologic symptom disorder 
(conversion disorder), 1071
Functional proteinuria, 926–927
Functional screening, 56
Fundoplication, 622, 630
Fungal infections, 
119–122
, 119
f
, 1353, 
1550–1563
. 
See also
 
specific 
type
drugs for, 107
t
, 
1561–1563
, 1561–1562
t
. 
See also
 Antifungal agents
keratitis, 
186
meningitis, 1304
t
myocarditis in, 425
t
of nails, 169, 170
opportunistic, 1297
superficial/skin/rashes, 
119–122
, 119
f
, 
1353. 
See also
 Tinea
systemic/invasive, 
1550–1563
sinusitis, 
228–229
Fungemia
in candidiasis, 1550, 1551
Funguria, candidal (candiduria), 1550, 
1551
Furazolidone, 1534
Furosemide. 
See also
 Diuretics; Loop 
diuretics
for heart failure, 390, 418
for hypertension, 460, 461
t
, 481
t
, 482
t
for pseudotumor cerebri, 1022
Furuncles/furunculosis, 
161–163
, 1322
t
, 
1353, 1450
t
, 1455
Fusarium,
 1560, 1561
Fusidic acid, 179
t
Fusion inhibitors/enfuvirtide, 1365
t
, 1370. 
See also
 Entry inhibitors
Fusobacteria/
Fusobacterium necrophorum,
 
1449, 1483, 1484
FXTAS (fragile-X tremor-ataxia 
syndrome), 1684
G20210A prothrombin mutation
in hepatic vein obstruction (Budd-
Chiari syndrome), 726
GA (tabun) poisoning, 1595, 1605
Gabapentin, 995
t
. 
See also
therapy
for essential tremor, 1024
Foscarnet, 1379
t
for CMV infection, 198, 623, 1346
t
, 
1379
t
for herpes simplex infections, 623, 
1346
t
, 1378, 1379
t
1379
t
, 1384
Fosfomycin, 969, 1322
t
Fosinopril/fosinopril-HCTZ, 467
t
Fosphenytoin, 1002
4kscore, in prostate cancer, 1659
14-3-3 protein, in Creutzfeldt-Jakob 
disease, 1035, 1406–1407
Fourth nerve palsy, 201
Foxglove, toxicity of, 1597
Fractional excretion, 898. 
See also
 
specific 
Fractional flow reserve, 371, 371–372
Fracture-dislocation, spinal, 1045
Fracture Risk Assessment Tool (FRAX), 
1171–1172, 1172
Fractures. 
See also
 
Bone
atypical, bisphosphonates causing, 1173
corticosteroid use and, 1218
in elderly, falls and, 64
1212
malabsorption and, 644
t
in metabolic bone disorders/renal 
osteodystrophy, 940, 1164
in osteomalacia, 1176
in osteoporosis, 11, 1170, 1707
Fragile X mental retardation, 
1684–1685
Fragile-X tremor-ataxia syndrome, 1684
Fragility fractures. 
See
 Fractures
Frailty, in elderly, 
56–57
Frambesia (yaws), 1319
t
, 
1502
Framingham score/projections, 13, 365
1479
Frataxin gene, in Friedreich ataxia, 1049
FRAX, 1171–1172, 1172
Freckles (ephelides), 
111
Free thyroxine assay (FT
4
), 1135
t
. 
See also
 
Thyroxine
in hypopituitarism, 1121, 1122
pregnancy and, 830, 831, 1143
in thyroid disorders, 1135
t
, 1145
Free thyroxine index (FT
4
I), 1142
Free triiodothyronine (FT
3
), 1135
t
Freons, toxicity of, 1605–1606
Fresh-frozen plasma, 554. 
See also
 Plasma/
plasma fractions/components
Fresh whole blood, 552. 
See also
 
Friction rubs
in pericarditis/effusion, 28, 391, 438, 
440
in pulmonary embolism, 306
t
Friedreich ataxia, 1049
Frontal lobe lesions, 1016
Frontal sinusitis, 226
Frontotemporal dementias, 1032
t
, 1034

440
t
t
, 1034
Frostbite, 1568, 
1568–1569
Frostnip, 
1568
Frovatriptan, 991
“Frozen globe, ” 227
Follicle-stimulating hormone (FSH) 
(
Cont
.):
for hypogonadism/infertility, 982, 1123, 
1203
in infertility workup, 798, 982
1206, 1207
recombinant, for ovulation induction, 
799, 1123
Folliculitis, 
137–138
, 138
f
, 1455
acne/steroid acne and, 134, 137
in HIV infection/AIDS, 134, 137, 138, 
1353
Follitropins, for infertility, 1123
Folstein Mini Mental State Exam (MMSE), 
1033
Fomepizole, 921, 1584
t
, 1587
t
, 1603
Fondaparinux, 574, 578
t
, 580
t
, 582
f
, 381
t
, 580
t
, 582
563
Food. 
See also
 Food poisoning
allergy/intolerance to, 589, 625, 
891
antimicrobial therapy and, 1323
aspiration of/“café coronary, ” 
317
t
withholding, in end-of-life care, 77–78
Food anaphylaxis, 891
Food poisoning, 600, 1314. 
See also
 
specific 
cause and
 Diarrhea
botulism, 
1059–1060
, 1460
 causing, 599
t
, 600
listeriosis and, 599
t
, 600, 1463
Salmonella,
 599
t
, 600, 1313
t
, 1322
t
, 
1475, 
1475
seafood contamination/toxicity and, 
1607
, 1607
t
Shiga-toxin producing 
E coli
 causing, 
600, 1312
t
, 1476
vibrios causing, 599
t
, 1313
t
, 1477
Foot. 
See
 Feet
Foramen ovale, patent, 
336–339
closure of, 1006
TIA/stroke and, 338, 1004, 1006, 1009
Forced expiratory volume in one second 
(FEV
1
). 
See
 Pulmonary 
Forced expiratory volume in one second/
forced vital capacity ratio 
(FEV
1
/FVC ratio). 
See
 
Pulmonary function tests
Forced vital capacity (FVC). 
See
 
aspiration of, 248–249, 
317
. 
See also
 
conjunctival/corneal, 
203
, 204
f
in ear canal, 
212
esophageal, 
249
intraocular, 
203
in trachea and bronchi, 
248–249
in upper aerodigestive tract, 
248–249
Formication, stimulant abuse and, 1080
Formoterol, 259, 260
t
, 271
Fosamprenavir/ritonavir, 1364
t
, 1370. 
See 
also
Fosaprepitant, 593, 594
t
, 1678
CMDT2019_Index_p1743-1884.indd   1794

INDEX1795
 
CMDT 2019
erosive/hemorrhagic, 606, 
632–633
H pylori,
 633–634, 1641
nonerosive/nonspecific, 
633–635
pernicious anemia, 634–635
phlegmonous/necrotizing, 635
stress, 632, 632–633
Gastroenteritis, 1322
t
. 
See also
 
specific 
cause and
 Diarrhea
acute, 
1311–1314
, 1312–1313
t
 599
t
, 600, 1312
t
, 1316, 
1476–1477
food-borne. 
See
in HIV infection/AIDS, 600, 601, 604, 
irritable bowel syndrome and, 656
t
, 600, 1313
t
, 1322
t
, 
1475
viral, 599
t
, 1313
t
, 
1432–1433
Gastroenteropancreatic neuroendocrine 
tumors (GEP-NETs), 
1195–
1197
, 1545–1546, 1647–1648. 
See also
 
Neuroendocrine tumors
in MEN, 1195, 1198, 1262, 1645
Gastroesophageal junction
dysfunction of, in GERD, 618–619
mucosal laceration of (Mallory-Weiss 
syndrome/tears), 593, 606, 
608, 
624
stricture at. 
See
 Esophagus, strictures of
Gastroesophageal reflux disease (GERD), 
618–623
chest pain in, 372, 631
chronic gastric aspiration and, 317
t
dyspepsia in, 589
erosive (reflux) esophagitis/GI bleeding 
and, 606, 618, 619, 620, 621, 
622
esophageal webs and rings and, 625
extraesophageal manifestations of, 619, 
622
heartburn in, 589, 617
into larynx (laryngopharyngeal reflux), 
244
Gastrointestinal adenocarcinoma
gastric, 635, 
1641–1644
small intestine, 667, 
1646–1647
Gastrointestinal bleeding, 
606–612
. 
 
See also
 
aneurysm repair and, 493
from angioectasias, 606, 609
anorectal disease causing, 609, 682, 683
antithrombotic therapy and, 387
aspirin/NSAIDs and, 85, 610–611, 843
in cirrhosis, 606, 715
colorectal cancer and, 609, 1650
in Crohn disease, 667
diverticular, 609, 610, 
678
in erosive esophagitis, 606
gastric cancer and, 606, 1642
in gastritis/gastropathy, 606, 632
from gastrointestinal/esophageal 
varices, 606, 608, 626–629
hemorrhoids causing, 609, 682, 683
Gas gangrene, 1319
t
, 
1458
Gases, sniffing, 1114
Gasoline, sniffing, 1114
sleeve, for obesity, 1280
Gastric acid/gastric contents
aspiration of. 
See also
 Aspiration
 
316–317
, 1302
chronic, 
317
hypersecretion of, in Zollinger-Ellison 
syndrome/gastrinoma, 643, 
1196
inhibition of secretion of. 
See
 Acid-
antisecretory agents; Antacids; 
H
2
 receptor blocking drugs; 
nosocomial pneumonia and, 283
reflux of. 
See
 Gastroesophageal reflux 
disease
Gastric cancer, 1615
t
, 
1641–1646
adenocarcinoma, 635, 
1641–1644
carcinoid tumors, 634–635, 1645
680
gastric ulcers and, 640
GI bleeding and, 606
H pylori
 infection and, 544, 634, 1641, 
1644–1645
HNPCC/Lynch syndrome and, 682
lymphoma, 544, 634, 
1644–1645
mesenchymal tumors, 
1646
neuroendocrine tumors, 
1645–1646
Gastric emptying
delayed. 
See also
 Gastroparesis
in GERD, 619
poisoning/drug overdose and, 
 
1584–1585
Gastric lavage, for poisoning/drug 
overdose, 1584–1585
Gastric outlet obstruction, 592, 
642
Gastric polyps, 680
Gastric surgery. 
See also
 Bariatric surgery
for adenocarcinoma, 1643
hypoglycemia after, 
1265
for mesenchymal tumors, 1646
for neuroendocrine tumors, 1645, 1646
for obesity, 1279–1280
Gastric ulcers. 
See
 Peptic ulcer disease
Gastric varices, noncirrhotic portal 
hypertension and, 728, 729
Gastrin, hypersecretion of
in gastrinoma/Zollinger-Ellison 
syndrome, 643, 644, 1195, 
1196. 
See also
 Gastrinoma
NETs/carcinoid tumors and, 1645
in pernicious anemia gastritis, 634
Gastrinoma (Zollinger-Ellison syndrome), 
643–644
in MEN, 643, 1195, 1198
peptic ulcer disease and, 635, 640, 643, 
1196
Gastritis, 
631–635

643–644
1196
631–635
. 
See also
 Gastropathy
alcoholic, 633
in anisakiasis, 635
atrophic, 634, 635
COX-2 inhibitor/NSAID, 85, 606, 633
for menopausal symptoms, 809, 1211
for neuropathic pain/neuropathies, 96
t
, 
99, 1048, 1249, 1349
t
, 1592
for phobic disorders, 1068–1069
t
for trigeminal neuralgia, 994
GAD65 (glutamic acid decarboxylase 65 ) 
antibodies, in diabetes, 1220, 
1221
t
, 1242
Gadolinium, nephrogenic (necrotizing) 
systemic fibrosis caused by, 
371, 931, 944
Gail 2 model, 754, 755
Gait/gait disorders
63–65
, 63
t
in syphilis, 1500
Galactomannan, in invasive aspergillosis, 
1558
Galactorrhea, 1128, 1129
Galactose-alpha-1,3-galactose (alpha-gal) 
Galantamine, 59, 1034
Gallavardin phenomenon, 353
carcinoma of, 734, 1634, 1635
cholesterolosis of, 733
t
gangrene of, 734
hydrops of, 734
porcelain, 733
t
, 734
stones in. 
See
 Cholelithiasis
strawberry, 734
Gallstone ileus, 732
Gallstones. 
See
Gamete intrafallopian transfer, 799
Gamma-butyrolactone, 1599
Gamma-globin gene/chain, 514, 515
Gamma globulin, intravenous. 
See
 
Intravenous immune globulin
Gamma-glutamyl transpeptidase (GGTP), 
690, 1107
Gamma-hydroxybutyrate (GBH), 1185, 
1599
Gamma interferon release assays. 
See
 
Interferon gamma release 
assays
Gamma knife radiosurgery, for pituitary 
tumor, 1127
Gamma4 (Bart’s) hemoglobin, 515
Gamolenic acid, 751
Ganciclovir, 181
t
, 1379
t
for CMV infection, 198, 623, 1299, 
1346
t
, 1379
t
, 1390
Ganciclovir intravitreal implant, 198
Ganglioneuromas, 1197
t
, 1199
Ganglioside antibodies, in Guillain-Barré 
syndrome, 1051
Gangrene
anaerobic infection and, 1485, 1485
f
bacterial synergistic, 1485
of feet, 486, 1251, 1485
f
of gallbladder, 734
gas, 1319
t
, 
1458
Gardner syndrome, 163
 infection (bacterial vaginosis), 
781, 781
f
, 782, 1309
Gas, gastrointestinal, 
598–599
Gas embolism, in decompression sickness, 
1576
CMDT2019_Index_p1743-1884.indd   1795

INDEX1796
 
CMDT 2019
Gender identity, 1724. 
See also
 Sexual 
orientation
differences from assigned sex and, 1075, 
1076, 1736–1737. 
See also
 
Transgender health/disease 
in gay and bisexual men/MSM, 1732, 
1734
in lesbian and bisexual women, 1724, 
1727, 1730–1731
sexual orientation/behavior differences 
and, 1724, 1732
STDs/STIs and, 1727
Gender nonconforming man/woman, 
1737. 
See also
 Transgender 
health/disease prevention
Gender reassignment surgery, 1076
Genderqueer, 1737. 
See also
Gene expression profiling, in breast 
cancer, 762–763, 772
Gene therapy
for hemophilia, 569
Generalized anxiety disorder (GAD), 
1066, 1067–1068
Generalized seizures/epilepsy, 995–996
t
, 
998–999, 999, 1000–1001
Genetic/genomic disorders, 906
t
, 
 
1681–1689
. 
See also
 
specific 
disorder
Genetic instability, in GI cancer, 678, 681, 
682, 1649
Genetic testing/counseling. 
See also
 
specific 
 Prenatal testing
in aldosteronism, 1188
for cancer susceptibility genes/cancer 
screening, 680, 754
for Down syndrome, 813, 1682, 1683
for Duchenne muscular dystrophy, 1060
for hemochromatosis, 724
for hyperparathyroidism, 1165
for hypophosphatemic rickets, 1176, 1177
for male infertility, 982
for pheochromocytoma/paraganglioma, 
1190
for recurrent abortion, 819
Genital herpes, 
126–127
, 1377. 
See also
 
anorectal involvement and, 684, 1377
during pregnancy/neonatal/congenital 
infection, 
837
, 1377–1378, 
1380
Genital reconstructive surgery, 1076
Genital ulcers, 1309
in granuloma inguinale, 1482
herpetic. 
See
 Genital herpes
1490
STDs causing, 1309
in syphilis (chancre), 1493–1494, 1494
f
, 
1494
t
Genital warts. 
See
Genitalia, ambiguous, 1182
Genitourinary disorders, 
965–988
. 
See also
 
specific cause or structure 
affected
benign prostatic hyperplasia, 
983–988
, 
984
t
, 985
f
, 986
t
small intestinal disease, 
644–655
, 
644
t
Kaposi sarcoma involving, 154, 1354, 
1648
obstruction of. 
See
 Intestinal 
Gastroparesis, 
652–653
in diabetes, 653, 1249–1250, 1253
vomiting and, 592, 593, 652, 653
Gastropathy, 
631–635
. 
See also
 Gastritis
632–633
portal hypertensive, 606, 632, 633. 
 
See also
 Portal hypertension
Gastrostomies, 1289. 
See also
 Enteral 
GATA1
Gatifloxacin, 179
t
, 185, 1266
Gaucher cells, 1685
Gaucher disease, 
1685
Gay and bisexual men/MSM, 
1732–1736
, 
1735
t
care environment and, 1734
clinical care and, 1734–1736, 1735
t
condyloma acuminata (warts) in, 684
definition and concepts and, 1732
demographics and, 1732
gonococcal infections/arthritis and, 883, 
1733, 1735
t
health disparities and, 1733–1734
hepatitis and, 694, 1733, 1735
t
history taking and, 1735
HIV infection/AIDS and, 1338, 1340, 
1356, 1733–1734
1328
t
, 1331
t
, 1332
t
, 1735
t
mental health and, 1734
preventive care/practice guidelines and, 
t
STDs/STD screening and, 1309, 
 
t
stigma/discrimination and, 1732–1733
substance use and, 1734
syphilis/syphilis testing and, 1359–1360, 
1493, 1496, 1501–1502, 1733, 
1735, 1735
t
GB (sarin) poisoning, 1595, 1605
GBL (gamma-butyrolactone), 1599
GD (soman) poisoning, 1595, 1605
Gefitinib, 1621
t
, 1627
Gemcitabine, 1618
t
, 1628, 1635, 1637
Gemfibrozil, 1273
t
, 1274, 1369
Gemifloxacin, 279
t
, 281, 282
Gender (sex), 1736
hypertension management and, 477
Gender affirming interventions, 1737, 
1737–1741
hormone therapy, 1076, 1737–1740, 
1738
t
, 1739
t
, 1740
t
, 1741
t
antiretroviral therapy and, 1742
feminizing, 1737–1739, 1738
t
, 1740, 
1740
t
long-term health outcomes and, 1740
masculinizing, 1739–1740, 1739
t
, 
1740, 1741
t
monitoring, 1740, 1740
t
, 1741
t

t
t
, 1740, 
1740
t
t
, 
1740, 1741
t
t
, 1741
t
surgery, 1076, 1740–1741, 1741
t
Gender dysphoria, 1075, 1076, 1737. 
 
See also
 Transgender health/
Gender expression, 1724, 1736
Gastrointestinal bleeding (
Cont
.):
hepatic encephalopathy and, 627, 718
telangiectasia, 606, 1688, 1689
iron deficiency and, 511
lower GI, 
609–611
608, 624
occult, 611, 
612
overt, 611
in peptic ulcer disease, 606, 
641–642
polyps/polypectomy and, 609, 679
in portal hypertension/portal 
hypertensive gastropathy, 606, 
633, 728, 729
small bowel, 
611
upper GI, 
606–609
Gastrointestinal carcinoids
small intestine, 1647, 1648
Gastrointestinal fluid losses, replacement 
guidelines for, 925
t
Gastrointestinal gas, 
598–599
Gastrointestinal lymphoma
gastric, 544, 634, 
1644–1645
1647
Gastrointestinal mesenchymal tumors, 
1646
Gastrointestinal stromal tumors (GISTs), 
1646, 1648
Gastrointestinal system, 
589–687
. 
See also
 
specific structure and under 
Intestinal
decontamination of, in poisoning/drug 
overdose, 
1584–1586
, 1585
t
589–687
. 
See also
 
specific 
disorder and cause
anorectal diseases, 
682–687
in anthrax, 1461, 1462
bleeding. 
See
bleeding
cancer, 
1638–1657
chemotherapy-induced, 
1678–1679
in CMV infection, 599
t
, 635, 1389, 
1390
colorectal diseases, 
655–682
73
, 
595–598
, 595
t
, 597
t
diarrhea, 
599–606
, 599
t
, 600
t
, 601
f
, 
604
f
. 
See also
 Diarrhea
t
t
dyspepsia, 
589–591
esophageal disorders, 
617–631
, 617
t
functional
dyspepsia, 589, 590, 591
irritable bowel syndrome, 656, 657
gastric and duodenal disorders, 
 
631–644
, 638
t
gastrointestinal gas, 
598–599
hiccups (singultus), 
594–595
in HIV infection/AIDS, 1350–1352
in hypercalcemia/
motility. 
See
nausea and vomiting, 
591–594
, 592
t
, 
594
t
. 
See also
 Nausea and 
vomiting
peritoneal disease, 
612–617
, 613
t
837–839
CMDT2019_Index_p1743-1884.indd   1796

INDEX1797
 
CMDT 2019
anti-glomerular basement membrane 
(anti-GBM), 315, 935, 946
t
, 
948
f
, 
951–952
C3, 935, 
952–953
crescentic, 946
t
, 948
f
, 951
cryoglobulin-associated, 875, 946
t
, 948
f
, 
952
t
, 948
f
, 951
in Goodpasture syndrome, 315, 935, 
946
t
, 948
f
, 
951–952
872, 873, 946
t
, 948
f
, 950, 951
in Henoch-Schönlein purpura, 875, 
946
t
, 
950
hepatitis C infection and, 946
t
, 952, 
953
IgA nephropathy, 946
t
, 948
f
, 
949–950
immune-complex, 935, 948
f
, 952
in lupus/SLE, 854, 855, 946
t
, 948
f
, 
 
953–954
membranoproliferative, 946
t
, 948
f
, 
 
952–953
in microscopic polyangiitis, 874, 948
f
, 951
monoclonal immunoglobulin-mediated, 
935
pauci-immune (ANCA-associated), 872, 
935, 946
t
, 948
f
, 
950–951
postinfectious, 946
t
, 948
f
, 
949
rapidly progressive, 945, 945
f
serologic testing in, 947
streptococcal infection and, 949, 1448
Glomerulonephropathies. 
See also
 
Glomerulonephritis; 
Nephropathy
t
, 952, 
953
t
, 948
f
, 
 
952–953
hepatitis C and, 946
t
, 952, 953
Glomerulopathies. 
See also
 
C3, 935, 
952–953
sickle cell, 964
Glomerulosclerosis
in diabetic nephropathy, 958
focal segmental, 947
t
, 
956
Glomus tumors (tympanicum/jugulare), 
218, 220
Glossitis, 
237
Glossodynia, 
237
Glossopharyngeal neuralgia, 218, 997, 
1679
Glottic (true vocal fold) cancer, 246–247
Glucagon
for beta-blocker overdose/toxicity, 1581, 
1594
contraindications to in 
pheochromocytoma, 1190
for hypoglycemia, 1246
impaired response to, 1246
tumors secreting, 1195, 1196
Glucagon emergency kit, 1246
Glucagon-like peptide 1 (GLP-1), 1234, 
1265
Glucagon-like peptide 1 (GLP-1) receptor 
agonists, 1230
t
, 1234–1235, 
1244
f
, 1245
adverse effects of, 1235, 1244
f
for hypoglycemia, 1265
for obesity, 1279
for polycystic ovary syndrome, 1208
Gibbus deformity, 886
Gigantism, 
1126–1128
Gilbert syndrome, 688, 689
t
Gilles de la Tourette syndrome, 
1030–1031
Gingivitis/gingivostomatitis. 
See also
 
Periodontal disease; 
 
herpes, 
238
in HIV infection/AIDS, 1350
necrotizing ulcerative, 
237
Ginkgo, toxicity of, 1597
t
Ginseng, 73, 1597
t
Gitelman syndrome, 906
t
Glanders, 1318
t
Glanzmann thrombasthenia, 566, 567
Glasgow alcoholic hepatitis score, 709
Glasgow Coma Scale, 1042, 1042
t
, 1044
Glatiramer, 1037, 1038
t
Glaucoma
acute angle-closure, 176
t
, 
187
antipsychotics precipitating, 1083
pupillary dilation and, 187, 206
chronic, 
188–189
angle-closure, 187
in diabetes mellitus, 188, 1247
neovascular (rubeotic), 194
normal-tension, 188
after retinal vein occlusion, 194
treatment of, 183–184
t
, 187, 188–189
Gleason grading system/score, 1659, 1663, 
1663
t
, 1664
Glecaprevir, 704
t
, 705
GLI-similar 3
Gliadin antibodies, 646
Glial tumors/mixed neuronal-glial tumors, 
1017
t
, 1018
Gliclazide, 1230
t
, 1232
Glimepiride, 1230
t
, 1232, 1237
Glioblastoma multiforme, 1017
t
, 1615
t
Gliomas
intracranial, 1016, 1017
t
, 1018–1019
spinal, 1020
Glipizide, 1230
t
GLIS3
Glitazones. 
See
 Thiazolidinediones
Global Registry of Acute Cardiac Events 
(GRACE) Risk Score, 29, 382, 
392
Globe index, 722
Globin gene/globin chain synthesis
in sickle cell syndromes, 522
in thalassemias, 514
Glomerular diseases, 937
t
, 
945–955
, 945
f
, 
946
t
, 947
t
, 948
f
. 
See also
 
Glomerular filtration rate/estimated 
glomerular filtration rate 
(GFR/eGFR), 927–928
923
hypertension management and, 
 
477–478
Glomerular hematuria, 927, 945, 945
f
, 947, 
949
Glomerular proteinuria, 927
Glomerulonephritis, 926, 930
t
, 
935–936
, 
946–954
, 946
t
, 947
t
, 948
f
acute kidney injury caused by, 930
t
, 
935–936
cancer, 
1657–1670
hematuria in,

f
, 947, 
949
t
, 
935–936
, 
946–954
, 946
t
, 947
t
, 948
f
t
, 
935–936
cancer, 
1657–1670
hematuria in, 
966–967
967–973
, 968
t
, 
1484–1485
interstitial cystitis, 44, 
974
male erectile/sexual dysfunction, 
 
978–980
male infertility, 
980–983
, 981
f
207
t
ulcers. 
See
 Genital ulcers
urinary incontinence, 
65–67
urinary stone disease, 
975–978
Genitourinary syndrome of menopause, 
44
Gentamicin, 1321
t
. 
See also
 
for endocarditis, 1321
t
, 1468
t
, 180
t
for pneumonia, 282, 285
t
t
Gentian violet, for candidal skin infection/
Genvoya (tenofovir/elvitegravir/cobicistat/
emtricitabine), 1366, 1367
t
, 
1371, 1372
t
, 1373
Geriatric Depression Scale, 61
Geriatric medicine/disorders, 
55–71
. 
See 
also
 Age/aging; Older adults
assessment of older adult and, 
55–57
, 
56
f
, 56
t
, 57
t
management of common problems and, 
57–71
. 
See also
 
specific 
problem
principles of care and, 
55
Germ cell tumors, testicular, 
1669–1670
. 
See also
 Testicular cancer
Germline mutations/testing
in GI cancer, 679, 681, 682, 1649
1190
in prion disease, 1406
Gerstmann syndrome, 1016
Gerstmann-Sträussler-Scheinker 
syndrome (GSS), 1406
Gestational diabetes, 814, 831–832, 831
t
. 
See also
 Diabetes mellitus
Gestational hyperthyroidism. 
See
 
Hyperthyroidism 
(thyrotoxicosis), during 
pregnancy
Gestational thrombocytopenia, 
566
Gestational trophoblastic disease, 
 
821–822
t
“Geste antagoniste, ” 1029
Gestodene, in oral contraceptives, 800
GHB (gamma-hydroxybutyrate), 1185, 
1599
Ghon complex, 290
Giant cell (temporal/cranial) arteritis, 195, 
196, 199, 
867–869
fever/FUO caused by, 868, 1295
Giant cell thyroiditis. 
See
 Subacute 
thyroiditis, painful
Giardia lamblia/intestinalis/duodenalis
 
(giardiasis), 599
t
, 600, 603, 
1533–1534
CMDT2019_Index_p1743-1884.indd   1797

INDEX1798
 
CMDT 2019
multinodular (nodular), 1140, 1146, 
1149–1152
, 1150
t
, 1198
substernal/retrosternal, 1160
Gold salts, 209
t
Goldman Risk Score, modified, 29
Golfer’s elbow, 1703
Golimumab, 664, 673, 852, 878. 
See also
 
Gonadal dysgenesis. 
See
 Turner syndrome
Gonadectomy, for gender dysphoria, 1076
Gonadotropin-releasing hormone 
(GnRH), in amenorrhea, 
1209, 1210
Gonadotropin-releasing hormone (GnRH) 
analogs. 
See also
 
for endometriosis, 780, 791
in feminizing hormone therapy, 1738
for hyperandrogenism, 1208
hypogonadism caused by, 1120
Gonadotropins. 
See also
gonadotropin; Human 
menopausal gonadotropins
deficiency of, 1120, 1121. 
See also
 
in infertility, 981
f
, 1120, 1123
for hypogonadotropic hypogonadism, 
982, 1123, 1203
Gonococcal infections/gonorrhea, 1318
t
, 
1321
t
, 1323
t
, 
1480–1482
anorectal involvement and, 684, 1481
arthritis and, 
883–884
, 1321
t
, 1481, 
1482
reactive arthritis differentiated from, 
880, 883, 1481
conjunctivitis, 176–177, 1481, 1482
diarrhea and, 599
t
disseminated, 1480, 1481, 1482
drug resistant, 1481–1482
epididymitis in, 973, 1323
t
in gay and bisexual men/MSM, 883, 
1733, 1735, 1735
t
, 1736
pelvic infection/PID, 792, 793, 1322
t
, 
1481, 1482
pharyngitis in, 1481, 1482
837
prevention and, 1481
in gay and bisexual men/MSM, 1733, 
1735, 1735
t
, 1736
prenatal, 814
in STD patients, 1309
urethritis and, 1309, 1323
t
, 1481
in women, 1480, 1481, 1482
Goodpasture syndrome, 315, 935, 946
t
, 
948
f
, 
951–952
Gordon syndrome, 454, 906
t
Goserelin, 769, 769
t
, 1623
t
t
Gottron papules, 862
Gottron sign, 862
Gout/gouty arthritis, 
844–848
, 844
t
, 845
f
, 
846
t
kidney disease and, 844, 
964–965
lead poisoning and, 845
nongonococcal/septic arthritis and, 882
rheumatoid arthritis differentiated from, 
845, 850
normal values for, 1225, 1225
t
in pregnancy, 814, 831, 831
t
, 832
Glucosidase inhibitors, 1230
t
Glucosuria/glycosuria, 1224
t
in diabetes, 1224
1255
t
, 1259
nondiabetic (renal), 1224
Glutamic acid decarboxylase 65 (GAD65) 
antibodies, diabetes, 1220, 
1221
t
, 1242
Glutathione reductase, in riboflavin 
deficiency, 1283
Gluten, in celiac disease/dermatitis 
herpetiformis, 131, 645
Gluten enteropathy. 
See
Gluten-free diet, 131, 646
Glyburide, 1229–1232, 1230
t
, 1253, 
 
1237
Glycated (glycosylated) hemoglobin. 
See
 
1
/A
1c
Glycemic control in diabetes
acceptable/target levels of, 1245–1246, 
1245
t
1245
t
t
complications rate and, clinical studies 
of, 1227–1228
estrogen replacement therapy affecting, 
1212
exercise/activity and, 1242, 1246
fructosamine measurements and, 1226
1c
) 
measurements and, 1225, 
1227, 1227–1228. 
See also
 
1
/A
1c
intensive insulin therapy for. 
See
 Insulin 
nephropathy and, 1227, 1228, 1248
neuropathy and, 1227
pregnancy and, 831, 832, 1245
t
retinopathy and, 1227, 1228
glucose and, 1226–1227
vascular disorders and, 1227
Glycemic index, 1229
Glycohemoglobins. 
See
 Hemoglobin A
1
/
A
1c
Glycoprotein Ib/IX, in Bernard-Soulier 
syndrome, 566
Glycoprotein IIb/IIIa receptors
drugs blocking
for ACS (NSTEMI/STEMI), 380–382, 
380
f
PCI and, 375
t
Glanzmann thrombasthenia and, 566
Glycosuria. 
See
 Glucosuria/glycosuria
Glycosylated (glycated) hemoglobin 
(hemoglobin A
1c
). 
See
 
1
/A
1c
Glycyrrhetinic/glycyrrhizinic acid, 
hypertension/aldosteronism 
and, 1189
Goiter, 1134
endemic, 
1159–1160
fetal, 1146

1c
). 
See
 
1
/A
1c
and, 1189
endemic, 
1159–1160
hyperthyroidism and, 1160
hypothyroidism/cretinism and, 1134, 
1159, 1160
Glucagon stimulation test, 1122
Glucagonoma syndrome, 1196
Glucagonomas, 1195, 1196
Glucan levels, in 
1344, 1555
Glucocerebrosidase deficiency, 1685
Glucocorticoid-remediable 
hyperaldosteronism, 454, 
906
t
, 1188. 
See also
 
Glucokinase gene defect, 1222
Glucosamine/glucosamine sulfate plus 
chondroitin, in osteoarthritis, 
843, 1719
Glucose. 
See also
 Glucose tolerance/
intolerance
ascitic fluid, 614, 615
blood levels of. 
See also
 Hyperglycemia; 
t
in diabetes, 1224, 1224–1225, 1225
t
, 
1245, 1245
t
control of. 
See
 Glycemic control in 
diabetes
1245
t
t
pregnancy and, 814, 831, 831
t
self/continuous-monitoring of, 
1226–1227
in pregnant patient, 831, 832, 
1226
in diabetic ketoacidosis, 919, 1255
1c
 levels and, 1225, 
1225
t
, 1227, 1227–1228
1255
t
, 1259
in hypoglycemia, 1261, 1265
t
, 1263, 
1264
monitoring/management
1741
t
of during surgery, 53, 1245
t
, 
 
t
t
prebreakfast hyperglycemia and, 
1243, 1243
t
t
cerebrospinal fluid, 1304
t
, 1306
fatal hypophosphatemia and, 913
for hypoglycemia, 1246, 1584
t
pleural fluid, 324
t
in urine. 
See
1039, 1108
Glucose-dependent insulinotropic 
polypeptide (GIP1), 1234
Glucose-6-phosphate dehydrogenase 
(G6PD) deficiency, 
521
antimalarial therapy and, 521, 1518, 
1521
dapsone therapy and, 1298, 1361
primaquine therapy and, 1518, 1521
sulfasalazine therapy and, 851
Glucose tolerance/intolerance, 1224–1225, 
1225
t
. 
See also
 Diabetes 
mellitus
in diabetes mellitus, 1224–1225, 1225
t
impaired, 1225, 1225
t
lithium affecting, 1098
CMDT2019_Index_p1743-1884.indd   1798

INDEX1799
 
CMDT 2019
GTP cyclohydrolase I gene mutation, 1029
Guaiac testing, 16, 1654. 
See also
 Fecal 
occult blood testing
Guanabenz, 475, 1596
Guanadrel, 475
Guanethidine, 475, 1095
t
Guanfacine, 474
t
, 475, 992
t
, 1031, 1596
Guanidine, 1059
Guarana, toxicity of, 1597
t
Guargum, 597
t
Guillain-Barré syndrome (acute idiopathic 
polyneuropathy), 1048, 
1051
chikungunya fever and, 1419
dysautonomia in, 1003, 1051
after herpes zoster, 1382
influenza vaccine and, 1424
poliomyelitis and, 1398
Zika virus infection and, 1418
Gum disease. 
See
 Gingivitis
Gummas
in endemic syphilis, 1503
in syphilis, 1493, 1494
t
, 1499, 1499
f
in yaws, 1502
Gun-related injury/death, prevention of, 
17
Gut dialysis (repeat-dose charcoal), 1586
Gynecologic disorders, 
776–810
. 
See also
 
diagnostic procedures used in, 777
t
Gynecomastia, 
1204–1205
, 1204
t
breast cancer and, 774, 775, 1205
testosterone replacement causing, 1201, 
1203
testosterone replacement for, 1205
Gyromitra
 (monomethylhydrazine) 
mushroom poisoning, 1604
H
1
 receptor blocking drugs. 
See
 
H
2
 receptor blocking drugs
for GERD, 621
for laryngopharyngeal reflux, 244
for peptic ulcer disease, 637, 638
t
for stress gastritis, 632
H1N1 influenza, 1422, 1423, 1425. 
See also
 
Influenza
H3N2 influenza, 1423, 1424. 
See also
 
Influenza
H5N1 influenza, 1426. 
See also
 
Influenza
H5N1 influenza virus vaccine, 1427
H7N2 influenza, 1426
H7N3 influenza, 1426
H7N7 influenza, 1426
H7N9 influenza, 1426
H7N9 influenza virus vaccine, 1427
H9N2 influenza, 1426
H63D
 mutation, 723, 724
H1069Q
 mutation, 725
H pylori
See
 
infection
“Habit cough, ” 22
HACEK organisms, 1464, 1468
Haemophilus,
 1318
t
, 1322
t
, 
1471–1472
aphrophilus
 
(Aggregatibacter 
aphrophilus)
. 
See
 HACEK 
organisms
ducreyi,
 1482
influenzae,
 278
t
, 1344, 1471–1472
hypercalcemia in, 911, 1167
masses in, 
249–251
nasal involvement in, 
232–234
neck masses, 
250
thyroiditis. 
See
 Subacute thyroiditis, 
painful
Graves dermopathy (pretibial myxedema), 
Graves disease, 1139–1140, 1143–1146, 
1148. 
See also
 
eye disease and, 
202
, 202
f
, 1140, 1142, 
1143, 1145, 1147
in pregnancy, 830–831, 1141, 1148
thyroid antibodies/TSH receptor 
antibody in, 1139
Graves ophthalmopathy/orbitopathy/
exophthalmos, 
202
, 202
f
, 
1140, 1142, 1143, 1145, 1147
Gray platelet syndrome, 567
Grazoprevir, 704
t
, 705
Greta (azarcon) toxicity, 1597
t
Grief reaction/grieving, 81, 1087
Grind (patellar) test, 1717
Grip (handgrip), heart murmurs affected 
by, 346
t
Grippe (summer), 1433
Griseofulvin, 170
Ground itch, 1542
Group A beta-hemolytic streptococcal 
infection, 1318
t
, 1322
t
, 
 
1450–1451
cellulitis, 145, 146, 1322
t
endocarditis, 1451, 1467
erysipelas, 144–145, 1322
t
f
, 
1450
t
glomerulonephritis and, 949, 1448
necrotizing fasciitis 146, 1451
pharyngitis, 238, 239, 239
f
, 1322
t
, 
1448–1449
. 
See also
 
pneumonia and empyema, 1451
rheumatic fever and, 240, 435, 436, 437, 
1448, 1449
scarlet fever, 1382
t
, 1448, 1451
skin infections, 
1449–1450
, 1450
f
, 1450
t
Group B streptococcal infection, 1318
t
, 
1321
t
, 1451
arthritis, 881
endocarditis, 1467
in pregnancy/neonate, 814, 
834–835
, 
1451
Group C streptococcal infection, 1318
t
, 
1467
Group D streptococcal infection, 1451
Group G streptococcal infection, 1318
t
, 
1467
Growth factors, 527, 529, 1676
t
, 1677. 
See 
also
 Filgrastim; Sargramostim
Growth hormone (GH/somatropin), 1119
deficiency of, 1119, 1120, 1121–1122, 
1122
excess of, 1126–1128
replacement therapy with, 1123, 1217, 
1343
tumors secreting, 1126–1128
prolactin cosecretion and, 1126, 1127, 
1128, 1129
Growth hormone–releasing hormone 
(GHRH), in acromegaly, 1126
Growth hormone stimulation tests, 1121–
1122
saturnine, 845
in transplant patient, 847

1128, 1129
1122
gp120, HIV vaccine development and, 
1359
GRACE score, 29, 382, 392
Gradenigo syndrome, 217
Graft enteric fistula, after aneurysm repair, 
493
Graft-versus-host disease, 554, 1388, 1391
Graham Steell murmur, 362
Gram-negative infections, 1318
t
, 1318–
1319
t
, 1321
t
, 1322
t
, 
1469–
1485
. 
See also
 
bacteremia and sepsis, 1321
t
, 
 
1473–1474
folliculitis, 137, 138
Gram-positive infections, 1318
t
, 1319
t
, 
1448–1464
. 
See also
 
specific 
agent
Gramicidin/neomycin/polymyxin B, 180
t
Granisetron, 593, 594
t
, 1678. 
See also
 
Granular urinary casts, 926, 927
t
Granulocyte colony-stimulating factor 
(G-CSF). 
See
 Filgrastim
Granulocyte count. 
See also
chemotherapy dosage modification and, 
1677
t
infections and, 1297
Granulocyte disorders, 895
t
Granulocyte macrophage colony-
stimulating factor (GM-CSF). 
See
 Sargramostim
Granulocytic anaplasmosis/ehrlichiosis, 
1437
t
, 1443
Lyme disease coinfection and, 1443, 
1508
Granulocytopenia. 
See
Granuloma. 
See also
 Granulomatosis; 
Granulomatous disorders
arytenoid cartilage, 245
hepatic, drugs/toxins causing, 711
inguinale, 
1482
lethal midline, 234
in sarcoidosis, 304
swimming pool, 1488
eosinophilic, with polyangiitis (Churg-
Strauss syndrome), 315
264
t
, 948
f
, 951
infantisepticum, 1463
with polyangiitis (Wegener 
granulomatosis), 315, 854
t
autoantibodies/ANCA in, 854
t
, 871, 
872, 946
t
, 948
f
microscopic polyangiitis and, 
 
872–873, 874
nose and paranasal sinus involvement 
in, 
233–234
, 871, 872
pulmonary involvement in, 315, 871, 
872
renal involvement in, 872, 946
t
, 948
f
, 
950, 951
rheumatoid arthritis and, 850, 871, 
872
Granulomatous disorders. 
See also
 
specific 
type and
 Granuloma; 
fever/FUO and, 1294
CMDT2019_Index_p1743-1884.indd   1799

INDEX1800
 
CMDT 2019
Headache, 
40–43
, 41
t
, 
990–994
, 992
t
. 
See 
also
 
 Migraine 
headache
acute, 
40–43
, 41
t
, 990
brain tumors causing, 40–41, 
993
, 1016
chronic, 990
in head injury, 
993
, 1044
primary, 990
secondary, 990
in subarachnoid hemorrhage, 41, 42, 
993–994
Health care (hospital)–associated 
1300–1303
anaerobic, 1484
t
 colitis, 
599
t
, 600, 603, 
659–662
burn injury and, 1572
candidiasis and, 1551
coagulase-negative staphylococci 
causing, 1457–1458
fever/FUO and, 1294, 1301, 1303
meningitis, 1302, 1305, 1306–1307
nasal vestibulitis, 228
pneumonia, 278, 278
t
, 
283–286
, 284
t
, 
285
t
, 1321
t
. 
See also
 
Pneumonia
scabies, 157–158
sinusitis/bacterial rhinosinusitis, 226, 
227
in transplant recipient, 1297
Health care–associated pneumonia, 278, 
278
t
, 
283–286
, 284
t
, 285
t
, 
1321
t
Health care environment
gay and bisexual men/MSM and, 1734
transgender patients and, 1737
Health care providers
herpes simplex transmission prevention 
and, 1380
HIV transmission prevention and, 
1358–1359
1328
t
, 1329
t
, 1330
t
, 1332
t
, 
1424
zoster transmission prevention and, 
1385
Health maintenance/disease prevention, 
1–19
, 2
t
, 3
t
. 
See also
 
specific 
disease
adherence and, 1–2
approach to patient and, 
1–2
gay and bisexual men/MSM and, 
 
t
immunization and, 3–5, 
1325–1337
, 
1326–1334
t
, 1335–1336
t
 
1724–1732
Hearing aids/hearing amplification, 70, 
211
Hearing evaluation, 70, 210–211
Hearing loss, 
70
, 
210–211
, 211
t
. 
See also
 
specific type and cause
autoimmune, 219
barotrauma causing, 214
cisplatin causing, 1680
conductive, 210, 211
diabetes and (maternally inherited 
diabetes and deafness), 1222
in elderly/presbyacusis, 
70
, 218
eustachian tube dysfunction and, 210
Hansen disease (leprosy), 1050, 1319
t
, 
1489–1490
Hantaan virus, 1415, 1416
Hantavirus pulmonary (cardiopulmonary) 
syndrome, 1415–1416
Hantaviruses, 
1415–1416
HAPS (harmless acute pancreatitis score), 
742
Haptoglobin, 519
Harm reduction model, 1107
Harmless acute pancreatitis score (HAPS), 
742
Harris–Benedict equation, 1289
Hartley-Dunhill operation, 1145
Hashimoto (autoimmune/lymphocytic) 
thyroiditis, 1131, 1132, 
 
See also
Hashitoxicosis (painless sporadic/silent 
thyroiditis), 1131, 1132, 1133
Hawkins impingement sign, 1690, 1694, 
1694
t
Hay fever. 
See
 Allergic rhinitis
HBcAg, 694
antibody to (anti-HBc), 694
f
, 695, 695
t
, 
701
HBeAg, 694
f
, 695, 695
t
, 701, 702
antibody to (anti-HBe), 694
f
HBeAg-negative chronic hepatitis B, 701, 
702
HBsAg, 694, 694
f
, 695, 695
t
, 701
antibody to (anti-HBs), 694
f
, 695, 695
t
hepatitis D coinfection and, 698
inactive carrier state, 701
maternal carrier state/transmission to 
newborn and, 694, 813, 
 
836–837
vaccination recommendations and, 
696, 816, 836
HCTZ. 
See
 Hydrochlorothiazide
HDAg, 698, 702
antibody to (anti-HDV), 698, 702
HDCV (human diploid cell) rabies 
vaccine, 1400
Head injury, 
1042–1045
, 1042
t
, 1043
t
coma/stupor and, 1042, 1042
t
, 1255
t
headache and, 
993
, 1044
hearing loss and, 219
intracranial hemorrhage and, 1011, 
1043, 1043
t
, 1044
1044, 1115
t
olfactory dysfunction and, 230
seizures and, 999, 1044
Head lice, 158, 158–159. 
See also
 Lice
Head and neck cancer, 1614
t
lymphoma, 
251
metastatic, 
250–251
squamous cell carcinoma of larynx, 
246–247
Head and neck infections
actinomycosis, 1486
1483
deep neck infections and, 
240–241
Lyme disease and, 
250
masses caused by, 
250
Head-up tilt table testing, in syncope, 413
 type b (Hib) 
vaccine, 1327
t
, 1328
t
, 1333
t
, 
1335
t
Hair

240–241
250
250
t
, 1328
t
, 1333
t
, 
1335
t
Hair
excess of. 
See
 Hirsutism
loss of, 
168–169
. 
See also
 Alopecia
Hair analysis, in toxicology screening, 
1105
Hair cells, hearing loss and, 210
Hairy cell leukemia, 527, 
542–543
, 889, 
1613
t
Hairy leukoplakia, 235, 235
f
, 1350
Hallucinations/hallucinosis. 
See also
 
alcoholic (organic), 1106–1107, 1107, 
1108, 1116
in narcolepsy, 1103
psychedelic drug use/hallucinogens and, 
1112, 1116, 1601–1602
in psychotic major depression, 1087
in schizophrenia/psychotic disorders, 
1079–1080
Hallucinogenic mushroom poisoning, 
1601–1602
Hallucinogens/psychedelics, 1112, 1116, 
1601–1602
Hallucinosis. 
See
 Hallucinations/
hallucinosis
Halo sign
in invasive aspergillosis, 1558
reverse, in mucormycosis, 1559
Halobetasol, 105
t
Halofantrine, 1518
t
, 1523
Haloperidol, 1081, 1081
t
, 1082
t
, 1083. 
 
See also
 Antipsychotic drugs
1095
t
for dementia, 59
for opioid-induced nausea and 
vomiting, 97
t
, 1082
t
, 1592
toxicity, 1112, 1602
Hamartoma, pulmonary, 297
Hamartomatous polyposis syndromes, 
680–681
Hamilton scale, 1089
Hamman-Rich syndrome (acute interstitial 
pneumonia/AIP), 302
t
HAMP
 gene, 723
Hampton hump, 307
Hand
complex regional pain syndrome and, 
888
in immersion syndrome, 1568
Hand eczema, vesiculobullous 
129–130
, 130
f
Hand-foot-mouth disease
coxsackieviruses causing, 1434
enterovirus 71 causing, 1434, 1435
Hand-foot syndrome, chemotherapy-
induced, 1679
Hand sanitizers, 1302, 1425, 1433
Hand washing, 1298, 1302, 1425, 1433
Handgrip, heart murmurs affected by, 346
t
CMDT2019_Index_p1743-1884.indd   1800

INDEX1801
 
CMDT 2019
chronic systolic, 418
cirrhosis and, 715
classification of, 414–415, 415
contraindicated treatments and, 421
coronary heart disease and, 414, 422
coronary revascularization in, 422
cough in, 21, 415
coxsackievirus causing, 1434
ejection fraction preserved in, 416, 423
ejection fraction reduced in, 416–422, 
417
f
, 418
t
hypertension and, 10–11, 414, 418, 455
in hyperthyroidism, 415, 1141, 1148
in hypothyroidism/myxedema, 415, 
1135
liver in, 
728
mitral regurgitation and, 349, 350
f
myocardial infarction and, 390, 415
myocarditis and, 426, 427
palliative care in, 417
f
, 422
and, 48–49
pleural effusion in, 323
in pregnancy/postpartum period 
(peripartum cardiomyopathy), 
432, 
446
, 447
t
, 448, 833
pulmonary hypertension and, 312–313, 
415, 416
refeeding in protein-energy 
malnutrition and, 1277
renin-angiotensin-aldosterone system 
in, 419–420, 423
reversible causes of, 418, 423
saxagliptin use and, 1236
shock and. 
See
 Cardiogenic shock
in SLE, 854
thiazolidinedione use and, 421, 1233
nonpharmacologic, 422, 423
pharmacologic, 417
f
, 418–422, 418
t
, 
423
in tricuspid regurgitation, 361
in tricuspid stenosis, 360
in ventricular septal defect, 339
Heart-lung transplant
for pulmonary hypertension, 314
Heart murmurs
in angina, 369
in aortic regurgitation, 343–344
t
, 358
in aortic stenosis, 343–344
t
, 346
t
, 353
ovale, 337
bedside maneuvers/interventions 
affecting, 346
t
in cardiomyopathy, 346
t
, 428, 432
in endocarditis, 1465
in mitral regurgitation, 343–344
t
, 346
t
, 
349
in mitral stenosis, 343–344
t
, 347
in mitral valve prolapse, 346
t
, 352
in myocardial infarction, 383, 391
in pulmonary valve stenosis, 334
in rheumatic carditis, 435
and, 1686
t
f
, 455, 
t
in hyperthyroidism, 415, 1141, 
 
1147–1148
hypertriglyceridemia and, 368, 1267, 
1275
in hypothyroidism, 415, 1135
1328
t
, 1331
t
influenza and, 1424
Kawasaki disease and, 1446, 1447
lipid disorders and, 10, 365, 1270
t
, 1509
445
myocarditis, 
425–435
, 425
t
neoplastic, 
444–445
pericardial disorders and, 
437–442
and, 
46–49
, 47
t
, 48
f
446–448
, 447
t
, 
833
5–11
, 6
t
, 8–9
t
, 9
t
, 365, 
366
f
t
t
, 1267–
f
, 
t
, 1268, 1270–
1275, 1272
t
, 1273
t
. 
See also
 
442–444
, 443
t
rate and rhythm disturbances, 
393–414
, 
394–395
t
. 
See also
 
rheumatic/rheumatic fever and, 
435–
437
, 436
t
f
, 367–368, 
367
t
, 458, 459
t
t
, 
1267–1268
in sarcoidosis, 303, 304
spondylitic, 878
surgery in patient with, 
46–49
, 47
t
, 48
f
445–446
valvular, 
342–365
, 343–345
t
, 346
t
. 
See 
also
 Valvular heart disease
Heart (cardiac) failure, 
414–425
, 417
f
, 
418
t
acute/pulmonary edema, 415, 
424–425
anthracyclines causing, 427
anticoagulation therapy in, 421, 429, 
434
in aortic stenosis, 353
arrhythmias in, 414, 416, 418, 421
asthma/wheezing caused by (“cardiac 
asthma”), 253, 257
beta-blocker therapy and, 387, 417
f
, 
418
t
, 420
cardiomyopathy and, 414, 428–430, 
428
t
, 433
f
, 434

f
, 
418
t
, 420
428
t
, 433
f
, 434
case management in, 422
chemotherapy-induced, 427, 1680
chronic kidney disease and, 415, 938
t
, 
939
in glomus tumors, 218
hereditary, 219
in HIV infection/AIDS, 225
long QT syndrome and, 412
neural, 210
ossicular chain disruption causing, 210, 
218
in otitis media, 214, 216
otosclerosis and, 210, 217
ototoxicity and, 219. 
See also
 Ototoxicity
sensory/sensorineural, 210, 211, 
 
218–219
sudden, 219
tinnitus and, 220
traumatic, 217, 218, 219
vertigo/vestibular disorders and, 221, 
222, 223, 224
vestibular schwannoma (acoustic 
neuroma) causing, 224
Heart. 
See also
 
under Cardiac; Coronary; 
Myocardial and
 
Heart disease
in athlete screening, 448, 449
t
t
in myocardial infarction, 383
“holiday, ” 402
myxedema, 1135
445–446
, 449
tumors of, 
444–445
Heart block. 
See
 Atrioventricular (heart) 
block
Heart disease, 
334–450
. 
See also
 
specific 
disorder
acute heart failure/pulmonary edema, 
415, 
424–425
anthracycline-induced, 427
t
t
, 11, 
365, 366
f
t
, 
t
, 
1273
t
. 
See also
therapy
448–450
, 449
t
, 
450
t
cardiomyopathies, 
425–435
, 428
t
, 
446
, 
447
t
t
, 10, 365, 
See
therapy
congenital, 
334–342
. 
See also
 Heart 
disease, pregnancy and
coronary (atherosclerotic CAD/
ischemic), 
365–393
. 
See also
 
t
f
, 368, 375, 
and, 448, 833, 1464, 1466
t
heart failure. 
See also
 Heart (cardiac) 
failure
CMDT2019_Index_p1743-1884.indd   1801

INDEX1802
 
CMDT 2019
GI bleeding and, 607
in anemias, 510
glycated/glycosylated. 
See
A
1
/A
1c
monitoring, in masculinizing hormone 
therapy, 1740, 1741
t
nephrotoxicity/acute tubular necrosis 
and, 933
in sickle cell syndromes, 522, 522–523, 
523
t
. 
See also
 Sickle cell 
anemia/syndromes
in thalassemias, 514, 515, 515
t
in sickle cell syndromes, 523
t
, 524
in thalassemia syndromes, 514, 515, 
515
t
1
/A
1c
 (glycated/glycosylated 
hemoglobin), 1225
t
in diabetes, 1225, 1225
t
acceptable levels of, 1245, 1245
t
diagnosis and, 1225, 1225
t
glycemic control and, 1225, 1227, 
1227–1228
t
pregnancy and, 832, 1245
t
, 1253
t
1741
t
2
t
, 524
in thalassemia syndromes, 515, 515
t
, 
516
Hemoglobin AS genotype (sickle cell 
trait), 
523–524
, 523
t
Hemoglobin electrophoresis
in prenatal care, 813
in sickle cell syndromes, 522–523
in thalassemias, 515, 515
t
, 516
Hemoglobin F (fetal hemoglobin)
523
t
, 524
515
t
, 516
Hemoglobin H/hemoglobin H disease, 
514
t
, 515, 516
Hemoglobin S, 522, 523, 523
t
Hemoglobin SC disease, retinopathy in, 
198
Hemoglobin SS, in pregnancy, 829
Hemoglobinemia, hemolytic anemia and, 
519–520
hemolytic anemia and, 520
paroxysmal nocturnal, 
520–521
Hemojuvelin, 723
Hemolymphatic trypanosomiasis, 1510, 
1511
Hemolytic anemias/hemolysis, 
519–520
, 
520
t
. 
See also
 
cause
autoimmune, 
524–525
in cold agglutinin disease, 525
in G6PD deficiency, 521
microangiopathic, 560, 561
in thalassemia, 514, 515, 516
Helminthic infections, 
1535–1549
. 
 
See also
 
cestodes causing, 
1538–1540
t
nematodes (roundworms) causing, 
1541–1549
trematodes (flukes) causing, 
1535–1538
Helper-inducer T cells. 
See
 CD4 T cells
Helvella
Hemagglutinin, influenza virus, 1422
Hemangioblastoma, cerebellar, 1018
t
Hemangioma, cavernous, of liver, 730
Hemarthroses, of knee, 1709, 1710
Hematemesis, 606
Hematin, 1682
Hematochezia, 606, 609, 610, 641
Hematocrit. 
See also
 
in anemia, 510
t
530
t
Hematogenous osteomyelitis, 885, 1456
Hematologic disorders, 
510–555
. 
See also
 
 Hemostasis 
disorders
anemias, 
510–528
, 511
t
blood transfusions and, 
552–555
leukemias/myeloproliferative 
neoplasms, 
529–543
, 529
t
, 
530
t
lymphomas, 
543–552
, 543
t
neutropenia, 
528–529
, 528
t
and, 46, 47
t
, 
51–52
, 52
t
in preeclampsia-eclampsia, 823
t
in SLE, 853
t
Hematoma
auricular (cauliflower ear), 211
perianal, 683
septal, 232
subdural. 
See
 Subdural hemorrhage/
hematoma
Hematopoiesis of indeterminate potential, 
clonal (CHIP), 536
Hematopoietic stimulating factors. 
See
 
Filgrastim; Growth factors; 
Sargramostim
Hematuria, 927, 
966–967
. 
See also
 
specific 
cause
in bladder cancer, 1664, 1665
in cystic/polycystic kidney disease, 
962–963
dysuria and, 43
glomerular, 927, 945, 945
f
, 947, 949
with hemoptysis, 26
after renal biopsy, 929
synpharyngitic, 950
Hemiplegic migraine, familial/sporadic, 
990
Hemobilia, 607, 1635
Hemochromatosis, 
723–725
, 1182, 1631
Hemodiafiltration, continuous 
venovenous, for poisoning/
drug overdose, 1585
Hemodialysis. 
See
 Dialysis
Hemodynamic status
atrial fibrillation management and, 
402–403
Heart murmurs (
Cont
.):
in tricuspid regurgitation, 343–344
t
, 361
in tricuspid stenosis, 343–344
t
, 360
in valvular heart disease, 343–344
t

402–403
Cont
.):
t
, 361
t
, 360
t
Heart rate and rhythm, disturbances of, 
393–414
, 394–395
t
. 
See also
 
HEART (History, Electrocardiogram, Age, 
Risk Factors, Troponin) Risk 
Score, 28, 29
Heart sounds
in aortic regurgitation, 343
t
in aortic stenosis, 343
t
, 353
in mitral regurgitation, 343
t
, 349
in mitral stenosis, 343
t
, 346–347
in myocardial infarction, 28, 28
t
, 383
t
in pulmonary valve stenosis, 334–335
in tricuspid regurgitation, 343
t
, 361
in tricuspid stenosis, 343
t
in valvular heart disease, 343
t
Heart transplantation
endocarditis prophylaxis and, 1466
t
f
, 422
Heart valves. 
See
Heartburn (pyrosis), 589, 617, 619
Heartland virus, 1412
Heat
disorders caused by exposure to, 
139
, 
1364
, 
1364–1366
. 
See also
 
Burns; Hyperthermia
measures for removal of, 36, 1566
Heat cramps, 1565
Heat exhaustion, 1565
Heat rash, 
139
Heat stroke, 1565, 1565–1566
Heat syncope/collapse, 1565
Heavy metals. 
See also
 
overdose/poisoning and, 1584
t
tubulointerstitial disease caused by, 960, 
961
Heberden nodes, 841, 842
f
Hedgehog pathway inhibitors, 151–152
Heimlich maneuver, 248
Heinz bodies, 521
Helical (spiral) CT. 
See
 Computed 
tomography
 infection, 1318
t
dyspepsia and, 590, 591
eradication therapy for, 591, 634, 
 
638–639, 638
t
, 639, 641
gastric cancer/lymphoma and, 544, 634, 
1641, 1644–1645
gastritis, 633–634, 1641
peptic ulcer disease and, 606, 634, 635, 
637, 638–639, 638
t
, 639, 
 
640
testing for, 634, 637, 639
gastric cancer and, 634, 1642, 1645
Heller cardiomyotomy, 630
HELLP syndrome, 564, 564–565, 823
CMDT2019_Index_p1743-1884.indd   1802

INDEX1803
 
CMDT 2019
pregnancy and, 695, 697, 699, 813, 
836–837
transfusion-associated, 553, 554, 694, 
695, 697, 706
in VZV infection, 1383
Hepatitis A, 
691–693
, 692
f
1735
t
prevention/immunization and, 4, 693, 
1327
t
, 1328
t
, 1332
t
. 
See also
 
Hepatitis A vaccine
screening for, in STD patients, 1309
Hepatitis A and B vaccine, 693
Hepatitis A immune globulin, 4, 693
Hepatitis A vaccine, 4, 692, 693, 1327
t
, 
1328
t
, 1332
t
, 1335
t
in gay and bisexual men/MSM, 1309, 
1328
t
, 1332
t
, 1735
t
, 1736
infection/AIDS, 693, 1328
t
during pregnancy, 816, 1328
t
for travelers, 693, 1332
t
Hepatitis A virus (HAV), 692, 692
f
antibody to, 692–693, 692
f
Hepatitis B, 
694–696
, 694
f
, 695
t
, 
701–703
acute, 
694–696
, 694
f
, 695
t
antiretroviral agents for, 1351
arthritis in, 884
cancer associated with, 694, 696, 702, 
703, 1631, 1632
chronic, 694, 696, 
701–703
cirrhosis and, 696, 702, 703, 1631
in gay and bisexual men/MSM, 694, 
1733, 1735
t
hepatitis D (delta agent) coinfection 
and, 696, 698, 702
HIV infection/AIDS and, 694, 1351
immune tolerant/immune clearance, 
701
inactive carrier state, 701, 702
newborn and, 694, 695, 
 
836–837
vaccination and, 696, 816, 837, 
 
1328
t
polyarteritis nodosa and, 870
pregnancy and, 695, 696, 813, 836–837
prevention/immunization/screening 
and, 4, 694, 695, 1327
t
, 1328
t
, 
1332
t
. 
See also
 Hepatitis B 
vaccine
in gay and bisexual men/MSM, 1328
t
, 
1332
t
, 1735
t
, 1736
reactivated, 701–702
transfusion/screening blood and, 553, 
554, 694, 695
Hepatitis B core antigen. 
See
 Anti-HBc; 
HBcAg
Hepatitis B e antigen. 
See
 Anti-HBe; 
HBeAg
Hepatitis B immune globulin, 695–696, 
837
Hepatitis B surface antigen. 
See
 Anti-HBs; 
HBsAg
Hepatitis B vaccine, 4, 694, 695, 696, 
1327
t
, 1328
t
, 1332
t
, 1335
t
in cancer prevention, 696, 1632
t
, 
1332
t
, 1733, 1735
t
, 1736
 
hyperkalemia caused by, 907
for intracranial venous thrombosis, 
1015
in pregnant patient, 364, 830
thrombocytopenia caused by, 
562–563
, 
563
t
Heparin-induced thrombocytopenia 
(HIT), 
562–563
, 563
t
Hepatic abscess
amebic, 1528, 1529, 1529–1530, 1530
t
pyogenic, 
729–730
Hepatic adenoma. 
See
 Hepatocellular 
adenoma
Hepatic amebiasis, 1528, 1529, 1529–1530, 
1530
t
Hepatic biopsy. 
See
 Liver, biopsy of
Hepatic coagulopathy, 51, 
572–573
, 699, 
719. 
See also
 Esophageal 
varices
Hepatic cysts, hydatid, 1540
Hepatic disease. 
See
 Liver, disorders of
Hepatic encephalopathy, 714–715, 
 
718–719
in acute liver failure, 699, 700
in cirrhosis, 714–715, 718–719, 720, 
720
t
GI bleeding/esophageal varices and, 
627, 718
protein-restricted diet for, 718, 1287
Hepatic failure. 
See
 Liver (hepatic) failure
in cirrhosis, 715
in nonalcoholic fatty liver disease, 709, 
713, 714
Hepatic hydrothorax, 717
Hepatic iminodiacetic acid (HIDA) scan, 
in cholecystitis, 734
Hepatic steatosis. 
See
 Fatty liver
Hepatic vein obstruction (Budd-Chiari 
726–728
Hepatitis. 
See also
 
alcoholic, 51, 708, 710
706–708
fibrosing cholestatic, 702
hypoxic, 728
ischemic, 728
viral. 
See also
 
acute, 
691–699
arthritis in, 850, 884
701–706
cirrhosis and, 696, 698, 702, 703, 706, 
1631
CMV , 1389
in drug users, 694, 697, 1311
1733, 1735
t
herpetic, 1378
in HIV infection/AIDS, 694, 697, 
1351
liver cancer and, 694, 696, 698, 702, 
703, 706, 1631, 1632
liver failure and, 696, 699, 700
Hemolytic crises, 522

1351
Hemolytic disease of newborn, 815
Hemolytic streptococcus. 
See
 
under Group
Hemolytic transfusion reactions, 552–553
Hemolytic-uremic syndrome, 560–562, 
561
t
, 601, 1476
Hemopericardium, 445
Hemophagocytosis, 566
lymphohistiocytosis (Epstein-Barr 
virus) and, 1388
Hemophilia A and B, 
567–570
, 569
t
, 
 
571–572
Hemophilia C (factor XI deficiency), 569
t
, 
571
Hemoptysis, 
26–27
in lung cancer, 26, 1625
in pulmonary embolism, 26, 27, 306
t
, 
309
t
Hemorrhage. 
See
 
affected and
 Bleeding
Hemorrhagic conjunctivitis
coxsackievirus infection and, 176, 1434
enterovirus 70 causing, 176, 1435
Hemorrhagic cystitis, 43
chemotherapy-induced, 1675
t
, 1679
Hemorrhagic fever with renal syndrome 
(HFRS), 1415
Hemorrhagic fevers, 
1409–1417
. 
See also
 
Hemorrhagic (erosive) gastritis. 
See
 
Gastritis
Hemorrhagic pleural effusion, 322
Hemorrhagic/hypovolemic shock, 505, 
505
t
, 506, 507
Hemorrhagic stroke, 1007
t
Hemorrhoidectomy, 683
Hemorrhoids, 609, 
682–684
fecal soiling/incontinence and, 685
pruritus ani caused by, 156
thrombosed, 683
Hemosiderin, 510, 723. 
See also
 
Hemosiderosis
idiopathic pulmonary, 315–316
transfusional, in thalassemia, 515–516
Hemostasis disorders, 
556–588
, 557
t
. 
See 
also
Hemosuccus pancreaticus, 607
Hemothorax, 322, 325
Hemotympanum, 214, 218
Henderson-Hasselbalch equation, 917
Henoch-Schönlein purpura, 
875
, 946
t
, 
950
HepA-HepB vaccine (hepatitis A and B 
vaccine), 693
Heparin/unfractionated/low-molecular 
weight heparin, 573–574, 
578
t
, 581–582
for ACS (NSTEMI/STEMI), 381, 387, 392
in bridging anticoagulation, 51, 364
t
cardiac valve replacement and, 363, 
364
t
, 365
coagulopathy/bleeding caused by, 311, 
574, 577
for DIC, 564, 564–565
disease), 309, 310, 311, 578
t
, 
580
t
, 581–582, 582
CMDT2019_Index_p1743-1884.indd   1803

INDEX1804
 
CMDT 2019
Herniation syndromes, 1016–1018
lumbar puncture and, 1305, 1306
Heroin abuse, 1111, 1604
Herpangina
coxsackievirus, 1433
enterovirus 71, 1433, 1435
Herpes-associated erythema multiforme, 
142–144
, 143
f
, 1378, 1380
Herpes genitalis. 
See
Herpes labialis (cold/fever sore), 
126–127
, 
126
f
. 
See also
 Herpes simplex 
infection
Herpes simplex infection, 
126–127
, 127
f
, 
1377–1380
, 1378
f
Bell palsy and, 1054, 1378, 1380
conjunctivitis, 176, 1377
dermatitis and (eczema herpeticum), 
114, 1378, 1381
t
disseminated/generalized, 114, 1352, 
1378, 1380
encephalitis, 1378, 1380
erythema multiforme associated with, 
142–144
, 143
f
esophagitis in, 623, 1378, 1380
eye involvement and, 
185
, 189, 1377, 
1378, 1380
gladiatorum, 127, 1377
HIV infection/AIDS/
immunocompromised host 
and, 623, 1298–1299, 1346
t
, 
1352–1353, 1377, 1380
185
, 1377, 1378, 1380
lesbian and bisexual women and, 1727
837
1380
retinitis, 199, 1377
stomatitis/gingivostomatitis in, 
238
in transplant patients, 1298–1299
treatment/prophylaxis/prevention and, 
127, 1378–1380, 1379
t
, 1380
type 1, 126, 1377
type 2, 126, 1377
vaccine development and, 1380
Herpes stomatitis/gingivostomatitis, 
238
Herpes zoster (shingles), 
128–129
, 128
f
, 
1381–1386
ear involvement in, 218, 1383
eye involvement and, 128, 
186
, 1353, 
1383, 1384
facial involvement/Ramsay Hunt 
syndrome/Bell palsy and, 225, 
997, 1054, 1383, 1384
infection/AIDS, 128, 129, 186, 
225, 1346
t
, 1353, 1383
neuralgia after, 128, 129, 
997
, 1384
pregnancy and, 835
prevention and, 4–5, 128, 1327
t
, 1353, 
1385–1386. 
See also
 Herpes 
zoster vaccine
Herpes zoster ophthalmicus, 128, 
186
, 
1383, 1384
Herpes zoster oticus, 218, 1383
Herpes zoster retinitis, 199
Herpes zoster vaccine (recombinant/live), 
4–5, 128, 997, 1327
t
, 1328
t
, 
1330
t
, 1385–1386
immunocompromised host/HIV 
infection/AIDS and, 1328
t
, 
1353, 1361, 1386
primary biliary cholangitis/cirrhosis 
and, 722
pyogenic abscess and, 730
Hepatocellular disease. 
See also
 Cirrhosis; 
Liver, disorders of
jaundice in, 688, 689
t
, 690, 737
Hepatocyte nuclear factor 1 alpha 
(HNF1alpha)
 mutation, 731, 
1222
Hepatojugular reflux, 415, 728
Hepatolenticular degeneration. 
See
 Wilson 
disease
Hepatopathy, ischemic, 728
Hepatopulmonary syndrome, 719
Hepatorenal syndrome, 615–616, 717–718
Hepatosplenic candidiasis, 1550
Hepatotoxicity, 
710–712
. 
See also
 
specific 
cause
of acetaminophen, 699, 700, 711, 1588, 
1588
f
of methotrexate, 851, 1679
in mushroom poisoning, 699, 1603, 
1604
of nevirapine, 1368
of statins, 1272
testosterone-induced, 1739
of thiazolidinediones, 1234
Hepcidin, 510, 941
in hemochromatosis, 723
Hepegivirus-1, 696
HER2
 gene. 
See also
 
Trastuzumab
in breast cancer, 761, 762
t
, 772
 
cardiotoxicity of chemotherapy 
targeting, 766, 1680
in gastric cancer, 1642, 1643
“Herbal ecstasy” (ephedrine), 1590
Herbal products, toxicity of, 
1597
, 1597
t
Herbicide poisoning (cholinesterase 
inhibitors), 1584
t
, 
1605
Herd immunity
enterovirus infection and, 1435
measles and, 1393
Hereditary cholestatic syndromes, 688, 
689
t
Hereditary colorectal cancer/polyposis 
679–682
, 1649. 
See also
 
Hereditary/genetic disorders, 906
t
, 
 
1681–1689
. 
See also
 
specific 
disorder
Hereditary hearing loss, 219
Hereditary hemorrhagic telangiectasia, 
573, 606, 
1688–1689
Hereditary motor and sensory neuropathy 
(HMSN), types I to IV , 
 
1048–1049
Hereditary nonpolyposis colon cancer. 
See
 
Lynch syndrome
Hereditary ovarian cancer syndrome, 794
Hermansky-Pudlak syndrome, 567
Hernias
hiatal, 618–619, 625
vaginal (pelvic organ prolapse), 
 
791–792
Herniated nucleus pulposus.

See
 
Hernias
 
791–792
Herniated nucleus pulposus. 
See
 Nucleus 
pulposus, herniation of
Hepatitis B vaccine (
Cont
.):
infection/AIDS, 694, 696, 
1328
t
, 1332
t
, 1361
for newborn/pregnant patient, 696, 816, 
837, 1328
t
and, 808
Hepatitis B virus (HBV), 694, 694
f
, 695
Hepatitis B virus DNA, 694
f
, 695, 701, 
702, 703
Hepatitis C, 
697–698
, 697
f
, 701, 
703–706
, 
704
t
acute, 
697–698
, 697
f
cancer associated with, 698, 706, 1631, 
1632
chronic, 698, 701, 
703–706
, 704
t
cirrhosis and, 696, 698, 706, 1631
cryoglobulinemia and, 697, 706, 875, 
952, 953
in gay and bisexual men/MSM, 697, 
1733, 1735
t
HIV infection/AIDS and, 697, 1351
immune thrombocytopenia and, 559
in pregnancy, 697, 813, 
837
prevention of/screening for, 698, 813
t
, 
1736
renal disease and, 946
t
, 952, 
953
thyroiditis/hypothyroidism and, 1135
554, 697, 698, 706
Hepatitis C virus (HCV), 696, 697, 697
f
, 
703–706
antibodies to, 697, 697
f
, 703. 
See also
 
Anti-HCV
Hepatitis C virus RNA, 697, 697
f
, 703
Hepatitis D, 696, 
698
, 
701–703
hepatitis B coinfection and, 696, 698, 
702, 1631
hepatocellular carcinoma and, 698, 
 
1631
Hepatitis D antigen. 
See
 Anti-HDV; 
 
HDAg
Hepatitis D virus (HDV/delta agent), 696, 
698
, 701–703
Hepatitis D virus RNA, 698
Hepatitis E, 
698–699
Hepatitis E vaccine, 699
Hepatitis E virus (HEV), 696, 698
antibody to (anti-HEV), 698
Hepatitis E virus RNA, 699
Hepatitis G virus (HGV/pegivirus), 696
Hepatobiliary cancers, 
1631–1638
. 
See also
 
Hepatobiliary CMV , 1389
Hepatoblastoma, 1631
Hepatocellular adenoma, 731
hepatocellular carcinoma arising from, 
1631
oral contraceptive use and, 731, 802
Hepatocellular carcinoma, 1612
t
, 1616
t
, 
1631–1634
cirrhosis and, 710, 714, 1631
hemochromatosis and, 723, 724, 1631
hepatitis/hepatitis vaccine and, 694, 696, 
698, 703, 706, 1631, 1632
nonalcoholic fatty liver disease and, 714, 
1631
CMDT2019_Index_p1743-1884.indd   1804

INDEX1805
 
CMDT 2019
prevention/chemoprophylaxis/
treatment and, 1345–1346
t
, 
1359–1361, 1360
t
, 1361–1362, 
1362
t
. 
See also
therapy
coronary heart disease in, 1355
counseling and, 1356
cryptococcosis/cryptococcal meningitis 
in, 1020, 1345–1346
t
, 
 
1348–1349, 1556, 1557
cryptosporidiosis and, 1352, 1361, 1531
dementia associated with, 1348
diarrhea/enterocolitis in, 600, 1343, 
1351–1352
differential diagnosis of, 1342–1343
drug use and, 1310, 1311, 1340, 1356
endocrinologic manifestations of, 1352
epidemiology of. 
See
AIDS, transmission of
erythrovirus (parvovirus) infection in, 
1430
esophagitis in, 623, 1350–1351, 1378
eustachian tube dysfunction/serous 
otitis media and, 224
eye disease associated with, 198–199, 
1350
folliculitis and, 134, 137, 138
fungal rashes in, 1353
gastrointestinal manifestations of, 
 
1350–1352
gastropathy in, 1352
gay and bisexual men/MSM and, 1338, 
1340, 1356, 1733–1734
gynecologic manifestations of, 1355
hairy leukoplakia in, 235, 235
f
, 1350
health care maintenance and, 
 
t
1362
t
hepatic disease/hepatitis in, 694, 697, 1351
vaccine recommendations and, 693, 
694, 696, 1328
t
, 1332
t
, 1361
herpes simplex infection and, 623, 
1298–1299, 1346
t
, 1352–1353, 
1377, 1378, 1380
herpes zoster/herpes zoster vaccine and, 
128, 129, 186, 199, 225, 1328
t
, 
1346
t
, 1353, 1361, 1386
histoplasmosis in, 1552, 1552–1553
Hodgkin disease in, 1354
home tests for, 1342
hyperkalemia in, 908
hyponatremia in, 900
immune thrombocytopenia in, 559
immunization recommendations in, 4, 
1325
, 1328
t
, 1361
incidence/prevalence of, 1340
infections in, 1297, 1338, 1339
t
, 1345–
1346
t
. 
See also
 
and
 Opportunistic infections
CD4 T cell levels and, 1338, 1341, 
1341
f
, 1342
t
inflammatory reactions (immune 
reconstitution syndromes) in, 
1355–1356
influenza vaccine and, 1328
t
intracranial tumors in, 
1019–1020
Kaposi sarcoma in, 154–155, 
 
1340–1341, 1346
t
, 1350, 1354
laboratory findings in, 1342, 1342
t
leishmaniasis and, 1514
Histiocytic necrotizing lymphadenitis 
(Kikuchi disease), 250
 (histoplasmosis), 
1552–1553
History, Electrocardiogram, Age, Risk 
Factors, Troponin (HEART) 
Risk Score, 28, 29
Histrelin, 1662
t
Histrionic (hysterical) personality 
disorder, 1077
t
HIV . 
See also
drug resistance and, 1373, 1374, 
 
1374–1375
drugs blocking entry of into cells (entry 
inhibitors), 1365
t
, 1370
screening blood for antibody to, 553, 
554, 1340, 1359
serologic tests in identification of. 
See
 
HIV testing
HIV antibody tests, 1342, 1342
t
. 
See also
 
HIV antigen tests, for blood screening, 
553, 554, 1340
HIV-associated dementia, 1348
HIV-associated nephropathy, 947
t
, 
 
958–959
HIV-immune complex disease, 958
HIV infection/AIDS, 
1338–1376
. 
See also
 
adherence to therapy and, 1, 1373, 1374
adrenal insufficiency and, 1180, 1352
anal dysplasia/cancer and, 1354–1355, 
1656
arthritis in, 884, 1349
autoimmunity/allergic reactions/
hypersensitivity in, 1341
bacillary angiomatosis/bartonellosis in, 
1353, 1361, 1483
biliary disease in, 1351
breastfeeding and, 1340
campylobacter/campylobacter-like 
organisms causing disease in, 
1361, 1478
cancer associated with, 1338, 1339
t
, 
1345–1346
t
candidiasis in, 1353
t
, 
1350–1351
oral (thrush), 236–237, 236
f
, 
 
1343–1344, 1350
vulvovaginal, 1346
t
, 1355
CD4 T cells in. 
See
 CD4 T cells
CDC definitions and, 1338, 1339
t
cerebral lymphoma in, 1019–1020, 
1348, 1354
cholangiopathy in, 740, 1351, 1532
CIN/cervical cancer in, 1355
clinical findings in, 1341–1342, 1341
f
, 
1342
t
CMV infections in, 635, 1388–1389, 
1390
esophagitis, 623
prophylaxis/treatment and, 199, 1390
t

f
, 
1342
t
1390
t
coccidial and microsporidial infection 
in, 1531, 1532
coccidioidomycosis in, 1553
complications of, 1343–1356. 
See also
 
infections in
safety (adverse effects/
contraindications/
precautions) and, 1334
t
, 1336
t
Herpesviruses, 
1377–1391
. 
See also
 
specific 
type
Herpetic whitlow, 1377, 1378
f
 flukes, 1538
Heterotopic pregnancy, 819. 
See also
 
Hexosaminidase deficiency, in juvenile 
spinal muscular atrophy, 1046
HFE
 gene/protein, 723, 724
Hiatal hernia, 618–619, 625
Hib vaccine, 1327
t
, 1328
t
, 1333
t
, 1335
t
Hibernation, myocardial, 365–367
Hiccups, 
594–595
HIDA scan, in cholecystitis, 734
Hidradenitis suppurativa (acne inversa), 
162
HIF2A
 mutations, 1199
High-altitude cerebral edema (HACE), 
1577
High-altitude illness, 
1576–1578
High-altitude pulmonary edema (HAPE), 
1577–1578
High (eversion) ankle sprain, 
1721
High-calcium diet, 1287
High-carbohydrate diet, 1271, 1681, 
 
1681–1682
High-density lipoproteins/cholesterol 
(HDL), 1267
cardiovascular/coronary heart disease 
and, 365, 1267, 1270
in diabetes, 1227, 1251
hormone replacement affecting, 1212, 
1215
raising levels of, 368, 1271, 1272, 1274
screening tests for, 1267, 1269, 1270
High-dose insulin euglycemic therapy, 
1581, 1594
High-fiber diet. 
See
 Fiber, dietary
High-oxygen-affinity hemoglobin, 
congenital, 531
High-potassium diet, 1287
High-sensitivity C-reactive protein 
(hs-CRP), coronary heart 
disease risk and, 1269
Hill-Sachs lesions, 1696
Hill sign, 358
Hip, 
1706–1709
arthritis of, 
1708–1709
back pain and, 1698
osteonecrosis of, 890
Hip fracture, 
1706–1708
atypical, bisphosphonate use and, 
 
1173
1212
in osteoporosis, 1170, 1707
Hip replacement
for arthritis, 843, 1708
for fracture, 1708
Hip resurfacing surgery, 1708
Hirschsprung disease, 1198
Hirsutism, 
1205–1208
in congenital adrenal hyperplasia, 1181, 
1206
Histamine, drugs blocking receptors for. 
See
 Antihistamines; H
2
 
CMDT2019_Index_p1743-1884.indd   1805

INDEX1806
 
CMDT 2019
Hives. 
See
 Urticaria
HJV
 gene, 723
HLA. 
See
 Human leukocyte antigen
HMBS
 mutation, 1681
HMG-CoA reductase antibody, 862
t
, 863
HMG-CoA reductase inhibitors. 
See
 
Statins
HNF1alpha
 mutation, 731
Hoagland sign, 1386
Hoarseness, 
243
, 243–244, 244
Hodgkin lymphoma, 543
t
, 
545–546
, 1613
t
Epstein-Barr virus and, 1387
fever/FUO and, 1295
in HIV infection/AIDS, 1354
of kidney, 1668
“Holiday heart, ” 402
Holmium laser enucleation of prostate 
(HoLEP), 985
f
Holosystolic murmurs. 
See
Holter monitoring. 
See
 Ambulatory 
Homans sign, 306
t
Home blood pressure monitoring, 10, 451, 
452
f
, 452
t
Home hemodialysis, 943
Home HIV tests, 1342
Home oxygen therapy, 270–271, 271
t
Homeobox protein 4, 1061
t
Homeostenosis. 
See
 Age/aging
Homocysteine, disorders of metabolism of, 
1685–1686
. 
See also
 
Homocystinuria; 
Homocystinuria, 1686
Homosexuality. 
See
 Gay and bisexual men/
MSM; Lesbian and bisexual 
women
Honey, infant botulism and, 1460
Hookworm disease, 
1541–1542
cutaneous larva migrans, 
1545–1546
, 
1545
f
Hordeolum, 
174
Hormone receptor sites, in breast cancer, 
762
t
, 772
treatment and, 762, 763, 764, 766–767, 
768
Hormone therapy. 
See also
 Estrogen 
(hormone) replacement 
therapy; Testosterone 
for abnormal premenopausal/
postmenopausal bleeding, 
 
777
for breast cancer, 762, 763, 764, 
 
t
in contraception, 
803–804
injections/implants, 
803
IUDs, 804
1731
oral contraceptives, 
800–803
, 801
t
, 
802
t
for endometriosis/pelvic pain, 779, 780, 
790–791
for erectile dysfunction, 979
gender-affirming, 1076, 1737–1740, 
1738
t
, 1739
t
, 1740
t
, 1741
t
T cells in. 
See
 CD4 T cells
toxoplasmosis in, 1019–1020, 1345
t
, 
1348, 1361, 1526, 1527, 1528
in transgender patients, 1741–1742
transmission of, 1338–1340
bites in, 1307, 1308
to fetus/newborn, 836, 1340, 1358
prevention of, 4, 1356–1361, 1357
t
, 
1360
t
, 1361
antiretroviral therapy and, 1310, 
1356
blood screening/blood treatment 
and, 553, 554, 1340, 1359
in health care settings, 1358–1359
postexposure prophylaxis and, 4, 
807–808, 808, 1310, 1358
preexposure prophylaxis and, 4, 
1310, 1356–1358, 1357
t
, 1733
testing/counseling and, 1356
vaccine for, 1359
sexual behavior and, 1338, 1356, 1733
and, 807–808, 808, 1309, 1310
transfusions and, 553, 554, 1340, 1359
treatment of, 1361–1375, 1363–1365
t
, 
1367
t
, 1372–1373
t
, 1374
f
adjunctive, 1362
antiretroviral therapy in, 1362–1375, 
1363–1365
t
, 1367
t
, 
 
1372–1373
t
, 1374
f
. 
See also
 
opportunistic infections/malignancies 
and, 1297, 1338, 1339
t
, 1345–
1346
t
, 1354–1355, 1359–1361, 
1360
t
, 1361–1362, 1362
t
pregnancy and, 1358
tuberculosis and, 1347
tuberculin skin test in, 291
t
, 1344, 1359
tuberculosis in. 
See
 Tuberculosis
vaccine development and, 1359
VZV infection/vaccine and, 128, 129, 
186, 199, 225, 1328
t
, 1330
t
, 
1346
t
weight loss in, 1343
Wernicke encephalopathy in, 1039
in women, 1340, 1356
xerosis in, 1353
yellow fever vaccine in, 1417
HIV integrase inhibitors. 
See
 Integrase 
HIV painful articular syndrome, 884
HIV rapid antibody tests, 1309, 1342, 
1342
t
HIV retinopathy, 198, 1350
HIV testing, 4, 1342, 1342
t
, 1356
in blood screening, 553, 554, 1340, 1359
gay and bisexual men/MSM and, 1356, 
t
in pregnant patient, 814, 836, 1358
after sexual violence (rape/sexual 
assault), 808, 1309, 1310
syphilis patients and, 1497, 1499, 1501
HIV viral load tests, 1342, 1342
t
. 
See also
 
monitoring and, 1362–1365, 
1374
for blood screening, 1340
HIV wasting syndrome, 1343

t
. 
See also
 
1374
HIV infection/AIDS (
Cont
.):
listeriosis in, 1464
lymphadenopathy in, 224, 249
lymphoma in, 1019–1020, 1340, 1345
t
, 
1347, 1348, 1354
MAC infections in, 296, 1342, 1345
t
, 
1361, 1488
malabsorption in, 1343, 1352
malaria in, 1517, 1522
meningitis in, 1020, 1348–1349, 1349
meningococcal vaccine in, 1328
t
, 1333
t
 
1349
mental status/cognitive changes in, 1348
MMR vaccine in, 1328
t
, 1329
t
, 1361, 
1393, 1396–1397
molluscum contagiosum in, 150, 1353, 
1431
myelopathies in, 1349
myopathy in, 884, 1350
nausea and vomiting in, 1343, 
 
1343–1344
needle-stick injury and, 1340, 
 
1358–1359
nephropathy in, 947
t
, 
958–959
neurologic manifestations of
central, 1347–1349
peripheral/neuropathy, 1349
nontuberculous mycobacterial infection 
in, 296, 1345
t
, 1347, 1487
oral lesions in, 1350
otitis in, 224–225
otologic manifestations of, 
224–225
pathophysiology of, 1340–1342, 1341
f
, 
1342
t
pneumonia in, 278
t
, 280, 287, 1344, 
1345
t
, 1554–1556. 
See also
 
infection/pneumonia
CD4 T cell count and, 1342, 1344, 
1361, 1554, 1556
pneumonitis in, 1347
in pregnancy, 814, 
836
, 1340, 1358
prevention of. 
See
 HIV infection/AIDS, 
transmission of, prevention of
prognosis of, 1338, 1375
leukoencephalopathy in, 1349, 
1407, 1408
psoriasis/psoriatic arthritis in, 884, 
1353–1354
pulmonary manifestations of, 278
t
, 287, 
1344–1347. 
See also
 HIV 
infection/AIDS, pneumonia 
in
reactive arthritis and, 884
 
198–199
, 1350, 1362
rheumatic manifestations of, 
884
, 
 
1349–1350
 infection in, 1361, 1475
screening for. 
See
 HIV testing
seborrheic dermatitis in, 1353
sinusitis in, 228, 229, 1347
skin disorders in, 1352–1354
spermicides/nonoxynol 9 and, 805, 1356
staphylococcal skin infections in, 1353
strongyloidiasis in, 1542
1495, 1497, 1499, 
1501–1502
, 
1733
CMDT2019_Index_p1743-1884.indd   1806

INDEX1807
 
CMDT 2019
recurrent respiratory (laryngeal) 
papillomas caused by, 244
screening for, 15
t
, 16, 784, 1354–1355
in vulvar carcinoma/VIN, 789
warts caused by, 148, 684, 782. 
See also
 
Venereal (genital) warts
Human papillomavirus (HPV) DNA, 
testing for, 784, 1355
Human papillomavirus (HPV) vaccine, 4, 
148–149, 684, 782, 784–785, 
786, 1327
t
, 1328
t
, 1330–1331
t
cancer prevention and, 4, 14, 148, 784–
785, 786, 1656
t
, 
1331
t
, 1736
infection/AIDS, 4, 1328
t
, 
1331
t
in lesbian and bisexual women, 1725, 
1727
t
, 1335
t
STD prevention and, 1309
Human papillomavirus (HPV) virus-like 
particle (VLP) vaccine, 4. 
See 
also
 Human papillomavirus 
(HPV) vaccine
Human parainfluenza viruses (HPIV), 1421
Human parechovirus infection (HPeV), 
1436
Human parvovirus B19 infection. 
See
 
Erythrovirus (parvovirus) 
infection
Human pegivirus (hepatitis G virus/
HGV), 696
Human rabies immune globulin, 1400
Human T cell lymphotropic/leukemia 
virus (HTLV-1/HTLV-2), 
1408–1409
adult T cell lymphoma/leukemia caused 
by, 1408–1409
myelopathy caused by, 
1039
, 1408, 1409
1408
“Humidifier” lung, 319
t
Humoral immunity. 
See also
 
Immunoglobulins
infections and, 896, 897, 1297
Hungry bone syndrome, 1161, 1169
Hunter canal, femoral artery disease and, 
485
Huntingtin gene, 1027
Huntington disease, 1025, 
1027–1028
Huntington disease-like (HDL) disorders, 
1028
Hürthle cell thyroid carcinoma, 1151, 
1153, 1158
Hutchinson sign, 1383, 1384
Hyalin, alcoholic, 709, 712
Hyaline casts, 927
t
Hyaluronic acid injections, for knee 
arthritis, 1719
Hydatid disease/cysts, 1540
Hydatidiform mole, 
821–822
hyperthyroidism and, 821, 1141
for heart failure/cardiomyopathy, 420, 
421, 429, 446
t
, 475, 481
t
, 482
pregnancy and, 446, 482, 824
Human bite wounds, 
1307–1308
Human chorionic gonadotropin (hCG)
in amenorrhea, pregnancy and, 1209, 
1210
in ectopic pregnancy, 811, 820
in gestational trophoblastic disease, 821, 
1141
hyperthyroidism during pregnancy and, 
821, 1141
1203
in ovulation induction, 799
pregnancy tests and, 811
in spontaneous abortion, 818
tumors producing, 1141, 1669
Human deoxyribonuclease (rhDNase), 276
Human diploid cell (HDCV) rabies 
Human granulocytic anaplasmosis/
ehrlichiosis, 1437
t
, 1443, 1508
Human growth hormone. 
See also
 Growth 
hormone
Human herpesvirus 1 and 2. 
See
 Herpes 
simplex infection
Human herpesvirus 3. 
See
 Varicella zoster 
virus
Human herpesvirus 4. 
See
 Epstein-Barr 
virus
Human herpesvirus 6, 237, 1381
t
, 
1391
Human herpesvirus 7, 1381
t
, 
1391
Human herpesvirus 8 (Kaposi sarcoma-
associated herpes virus), 154, 
1341, 
1391
Human herpesviruses, 
1377–1391
. 
 
See also
 
Human immunodeficiency virus. 
See
 HIV
Human insulin, 1238, 1238
t
. 
See also
 
Insulin therapy
Human interferons. 
See
 
specific type under 
Interferon
Human leukocyte antigen (HLA)
drug hypersensitivity and, 847, 894
platelet transfusions and, 554
in seronegative spondyloarthropathies, 
877, 878, 880, 881
Human menopausal gonadotropins 
(hMG), for ovulation 
induction, 799
Human metapneumovirus, 1421
Human monocytic ehrlichiosis, 1437
t
, 
1443
Human papillomavirus (HPV)
in anal cancer, 1354–1355, 1656
anorectal infection and, 684
in CIN/cervical cancer, 15
t
, 16, 783, 
784, 786, 1656
gay and bisexual men/MSM and, 1328
t
, 
1331
t
, 1733–1734, 1735
t
genital types of. 
See
warts
in laryngeal cancer, 246
1727
in nasal tumors (inverted papillomas), 
233
in oropharyngeal squamous cell 
carcinoma, 236
prevention of infection with, 4, 148–
149, 784–785, 1327
t
, 1328
t
, 
1330–1331
t
. 
See also
 Human 
papillomavirus (HPV) vaccine

233
t
, 1328
t
, 
1330–1331
t
. 
See also
 Human 
t
, 1740, 
1740
t
t
, 
1740, 1741
t
t
, 1741
t
for infertility, 981
f
, 982
for menopausal symptoms, 1211–1216
for osteoporosis, 1172
t
t
, 810, 
 
1212–1213
Horner syndrome (oculosympathetic 
paralysis)
in coma/stupor, 1040
headache and, 41, 992
in stroke, 1008
Hospice care, 77. 
See also
Hospital-acquired pneumonia, 278, 278
t
, 
283–286
, 284
t
, 285
t
Hospital-associated infections. 
See
 Health 
care (hospital)–associated 
Hospitalization
for alcohol use disorders/withdrawal, 
1108
for asthma, 261, 266
f
, 267
279
t
, 281–282, 282–283
for COPD, 272–273, 1116
delirium and, 61, 1116
diabetes management and, 53, 1245
t
, 
t
immobility/pressure injury and, 68–69, 
68
t
infections acquired during, 
1300–1303
. 
See also
 Health care 
(hospital)–associated 
for preeclampsia/eclampsia, 824
prolonged, 1117
psychiatric problems associated with, 
1116–1118
1080
for suicidal patients, 1089, 1090
for transient ischemic attack, 1005
for tuberculosis, 291–292
Host defenses, impaired. 
See
 
Hot environments, disorders caused by 
exposure to, 
1564
, 
1564–1566
Hot flushes
in menopause, 809, 1211, 1214–1215
niacin causing, 1272, 1284
Hot soaks, for wart removal, 150
Hot tub 
(Pseudomonas)
 folliculitis, 137, 
138
Household cleaning agents. 
See
 Caustic/
corrosive agents
Household molds, 
1561
Howell-Jolly bodies, 522
HPV-genotype–specific testing, 16
HPV/HPV vaccine. 
See
 Human 
papillomavirus; Human 
HTLV-1 associated myelopathy/tropical 
spastic paraparesis (HAM/
TSP), 1039, 1408, 1409
CMDT2019_Index_p1743-1884.indd   1807

INDEX1808
 
CMDT 2019
parathyroid hormone analogs 
contraindicated in, 1174
parathyroidectomy for, 1168–1169
Hypercalciuria, 976. 
See also
 Calcium 
nephrolithiasis
and, 912, 976, 1165
hypocalcemia/hypoparathyroidism and, 
911, 1162
hypomagnesemia and, 906
t
Hypercalciuric calcium nephrolithiasis, 
976
Hypercapnia. 
See
 Respiratory acidosis
Hypercarotenosis, 1285
Hyperchloremic normal anion gap 
acidosis, 918, 918
t
, 
920–921
, 
920
t
, 922. 
See also
 Normal 
1257–1258
parenteral nutritional support and, 921, 
1293
t
Hypercholesterolemia. 
See also
 
Cholesterol; Lipid disorders
clinical presentations in, 1269
familial, 
1683–1684
heart disease risk and, 365
in metabolic syndrome, 365, 453
t
t
, 1267–1268, 1269–1270
treatment of, 365, 366
f
t
, 
1268, 1270–1275, 1272
t
, 
1273
t
, 1684. 
See also
 
in antiphospholipid syndrome, 306, 584, 
586
t
, 830
t
Chiari syndrome), 726, 727
in noncirrhotic portal hypertension, 
728, 729
stroke and, 1009
Hypercortisolism, 
1184–1187
. 
See also
 
Hyperemesis gravidarum, 
816–817
gestational trophoblastic disease and, 
1141
thyroid disorders and, 817, 1141
Wernicke encephalopathy and, 1039
Hypereosinophilic syndromes, 893
t
Hypergastrinemia
Zollinger-Ellison syndrome 
(gastrinoma) and, 643, 644, 
1195, 1196
Hyperglycemia, 1220. 
See also
 Diabetes 
mellitus
antipsychotic drug use and, 1084, 
 
1084
t
calcium channel blocker overdose and, 
1594
coma caused by. 
See
in diabetic ketoacidosis, 919, 1255, 
1255
t
Hydroxymethylglutaryl-coenzyme A 
(HMG-CoA) reductase 
inhibitors. 
See
 Statins
17-Hydroxyprogesterone
in amenorrhea, 1209
3-beta-Hydroxysteroid dehydrogenase 
5-Hydroxytryptamine-3 receptor 
antagonists. 
See
 Serotonin 
5-HT
3
-receptor-blocking 
agents
Hydroxyurea, 523, 531, 532, 533, 1622
t
, 
1679
Hydroxyzine, 109, 142, 1067
t
, 1102. 
 
See also
Hymen, imperforate, 1209
Hymenolepis
diminuta
 (rodent tapeworm), 1538
nana
 (dwarf tapeworm), 
1538
Hyoscyamine, 658
Hyoscyamus niger,
Hyperactivity (attention-deficit/
hyperactivity disorder), 
 
1100–1101
Hyperacusis, 
220
Hyperadrenergic syndrome
in hypertensive emergency, 480
t
mitral valve prolapse and, 351, 352
Hyperaldosteronism. 
See
 Aldosteronism
Hyperalgesia, opioid-induced, 97
Hyperalimentation. 
See
 Central vein 
Hyperandrogenism
amenorrhea caused by, 1209, 1210
 
1206
Hyperbaric oxygen therapy
for carbon monoxide poisoning, 1584
t
, 
1587
t
, 1595
for dysbarism/decompression sickness, 
1576
Hyperbilirubinemia, 688, 689
t
. 
See also
 
Hypercalcemia, 906
t
, 
911–912
, 911
t
. 
See 
also
 Hyperparathyroidism
artefactual, 1166
bisphosphonate use causing, 1173
bisphosphonates for, 912, 1673
calcium/vitamin D excess and, 911, 
911
t
, 1163
cancer-related, 758, 911, 911
t
1625, 
1672–1673
differential diagnosis of, 1166–1167
hypercalciuria and, 912
hyperparathyroidism and, 911, 
 
1164–1170
hypocalciuric/familial hypocalciuric, 
906
t
, 911, 912, 1167
hypoparathyroidism/hypocalcemia 
treatment and, 912
hypophosphatemia and, 912
immobilization, 1167
in kidney injury/renal failure/dialysis 
patients, 911, 912, 938
t
in myeloma, 546, 547, 548, 964, 1167, 
1673
parathyroid carcinoma causing, 
 
1165
Hydration. 
See
 Fluid management/
hydration

t
1673
 
1165
See
hydration
Hydrocarbon toxicity/abuse, 317, 
 
1601–1602, 1605–1606
Hydrocele
in filariasis, 1546, 1547
in testicular cancer, 1669
in cryptococcosis, 1556, 1557
normal pressure, 1034
in subarachnoid hemorrhage, 
 
1012–1013
tumor causing, 1018
Hydrochlorothiazide, 460, 461
t
. 
See also
 
Diuretics; Thiazide diuretics
in combination products, 462
t
, 463
t
, 
464
t
, 466
t
, 467
t
, 468
t
, 469
t
, 
470
t
for heart failure, 418
t
Hydrocodone, 88, 91
t
, 94
t
Hydrocortisone, 103, 104
t
, 1122. 
See also
 
for acute adrenal crisis, 1183
after adrenal carcinoma surgery, 1186, 
1187
for adrenal insufficiency/Addison 
disease, 1122, 1182, 
 
1182–1183
664, 672, 673–674
for thyroid crisis/storm, 1148
topical, 103, 104
t
Hydrofluoric acid burns, 1589
Hydrofluoroalkane inhalers (HFAs), 260
t
, 
262
t
, 263
t
Hydrogen breath test, for carbohydrate/
lactose intolerance, 650
Hydrogen cyanide gas poisoning, 1596
Hydromorphone, 88, 91
t
, 1604
Hydronephrosis, in tubulointerstitial 
disease, 960, 961
Hydrophobia, 1399
Hydrops
endolymphatic (Ménière syndrome), 
222
fetalis, 514
t
, 515
Hydroquinone, 167
Hydrothorax, hepatic, 717
Hydroxocobalamin, for cyanide poisoning, 
1584
t
, 1597
Hydroxybutyrate/hydroxybutyric acid
beta
1255, 1256
t
gamma (GHB), 1185, 
1599
Hydroxychloroquine, 123, 208
t
, 209
t
, 851, 
855
5-Hydroxyindoleacetic acid (5-HIAA), in 
carcinoids, 1648
11-Hydroxylase/P450c11 deficiency, 1206, 
1209
17-Hydroxylase/P450c17 deficiency, 1200, 
1209
21-Hydroxylase/P450c21 deficiency, 1181, 
1182, 1206, 1207, 1208, 1209, 
1210
Hydroxymethylbilane synthase deficiency, 
1681
CMDT2019_Index_p1743-1884.indd   1808

INDEX1809
 
CMDT 2019
delayed, 
894–895
drug-induced, 170, 171, 171
t
, 
894–895
, 
1324–1325
. 
See also
 Drug 
allergy
immediate, 
890–892
myocarditis caused by, 425
t
, 427
to transfusions, 553
to ultraviolet radiation. 
See
 
visceral
chest pain/discomfort and, 631
Hypersensitivity pneumonitis, 
318–319
, 
319
t
Hypersomnias, 
1103
Hypertension, 
451–482
in adrenal hyperplasia, 454, 1181
aldosteronism and, 454, 456, 471, 1188
aortic dissection and, 456, 480
t
, 496, 
496–497
assessment/diagnosis/screening and, 6
t
, 
10–11, 456–457, 456
f
t
, 
478
cardiovascular/heart disease/heart 
failure and, 6
t
f
, 
455, 458, 459, 459
t
, 475
cerebrovascular disease and, 455–456
in coarctation of aorta, 336, 455
455–456
cystic kidney disease and, 962
t
, 963
dementia and, 455–456
diabetes/diabetic nephropathy and, 
452
f
, 459, 460, 465, 471, 476, 
477, 1224, 1228, 1251
t
, 478
epistaxis and, 231, 232
essential, 453, 456
etiology/classification of, 453–455, 453
t
exercise/activity in management of, 10, 
453, 457
t
, 458
fibromuscular dysplasia/renal artery 
stenosis and, 454, 944
gender considerations and, 477
genetic factors in, 453–454
in heart disease/failure, 6
t
, 10–11, 414, 
415, 455
insulin resistance/insensitivity and, 453
intracerebral hemorrhage and, 455, 456, 
480, 480
t
, 1010
intracranial. 
See
kidney disease/renal failure and, 454, 
456, 477–478, 480
t
, 937, 
 
t
, 939
f
malignant, 479. 
See also
management of, 10, 457–478
lifestyle modifications/
nonpharmacologic therapy 
and, 10, 457–458, 457
t
pharmacologic, 458–460, 458
t
, 459
t
, 
460–478
, 461–462
t
, 463–464
t
, 
466–470
t
, 472–474
t
, 474
t
, 
476
f
, 477
t
. 
See also
 
Antihypertensive drug therapy
458–459, 459
t
Hypernatremia, 
903–904
in diabetes insipidus, 1124
Hypernatremic dehydration, enteral 
nutritional support and, 1291
Hyperosmolality (hyperosmolar 
disorders), 
904–905
hyperglycemia and (hyperglycemic 
hyperosmolar state), 1223, 
1224, 1255
t
, 
1258–1260
hypernatremia and, 903, 904
Hyperosmolar nonketotic dehydration, 
parenteral nutritional support 
and, 1293
t
Hyperostosis, diffuse idiopathic skeletal 
Hyperoxaluric calcium nephrolithiasis, 
976–977
Hyperparathyroidism, 
1164–1170
. 
See also
 
asymptomatic, 1167, 1168–1169
bisphosphonate use and, 1173
bone changes and, 939, 940, 940
f
, 1164
chronic kidney disease and, 939, 939
f
, 
940, 940
f
, 1164
hypercalcemia and, 911, 1164–1170
hypercalciuria and, 912, 976, 1165
hypophosphatemia and, 914, 1165
in MEN, 1164, 1169, 1197
t
, 1198
in newborn, 1163
normocalcemic, 1165
pancreatitis and, 746, 1165, 1169
during pregnancy, 1165
after RAI treatment for 
hyperthyroidism, 1145
Hyperparathyroidism-jaw tumor 
syndrome, 1165
Hyperpathia. 
See also
 Thalamic syndrome
neuropathy causing, 1048
tumor causing, 1016
Hyperphosphatemia, 
914–915
, 915
t
hypercalcemia and, 912
in kidney disease, 914, 930, 939
f
bone disorders and, 939, 940, 940
f
hyperparathyroidism and, 1164
hypocalcemia/hypoparathyroidism 
and, 910
t
in tumor lysis syndrome, 1673, 1674
Hyperpigmentation, 166, 167. 
See also
 
Pigmented skin lesions
disease, 1181, 1182
antipsychotics causing, 1084
chemotherapy and, 1679
nail, 169
Hyperplastic polyps, 678
Hyperprolactinemia, 
1128–1130
, 1128
t
amenorrhea and, 1128, 1209, 1210
hypogonadotropic hypogonadism and, 
982, 1121, 1123, 1128, 1129, 
1201
infertility and, 798, 1128, 1129,

1128–1130
, 1128
t
1201
infertility and, 798, 1128, 1129, 
 
1129–1130
nipple discharge in, 752
Hyperreactio luteinalis, 1206
Hypersensitivity. 
See also
1223, 1223
t
drugs for, 1229–1237, 1230–1231
t
, 
1244–1245, 1244
f
. 
See also
 
therapy
hospitalization/surgery and, 53
t
, 
1258–1260
insulin deficiency/resistance and, 1223
1293
t
pentamidine-induced, 1266, 1555
prebreakfast, 1243, 1243
t
in pregnancy, 831, 832
t
Hyperglycemic coma. 
See
Hyperglycemic hyperosmolar state, 1223, 
1224, 1255
t
, 
1258–1260
Hyperhomocysteinemia, 306, 586
t
, 1686
Hyperinfection syndrome, in 
strongyloidiasis, 1542, 1543
Hyperinsulinemia
factitious, 1262, 1266
in insulin resistance syndrome, 1223
insulinoma causing, 1262, 1264
pentamidine causing, 1266
Hyperkalemia, 906
t
, 
907–908
, 907
t
, 909
t
and, 907, 1180, 1182
antihypertensive drug therapy and, 465, 
471, 478
1259
renal disorders/failure and, 907, 907
t
, 930
spurious/venipuncture technique and, 
907, 907
t
Hyperkalemic periodic paralysis, 906
t
, 
1062
Hyperketonemia. 
See
 Ketones/ketone 
bodies/ketonemia/ketonuria
Hyperkinetic seizures, 998
Hyperlactatemia, 1260. 
See also
 Lactic 
acidosis
Hyperlipidemia. 
See also
lipids
antipsychotics and, 1084, 1084
t
antiretroviral therapy causing, 1355, 1369
clinical presentation of, 1269
in diabetes, 1227, 1251, 1269
1212, 1213
spectrum disorders, 954, 955, 
957
treatment of. 
See
Hyperlordosis, lumbar, 1698
Hypermagnesemia, 
916
in acute tubular necrosis/kidney injury, 
916, 933
eclampsia/hypomagnesemia treatment 
and, 824, 916
915, 1161
Hypermetabolism, in burn injury, 1572
Hypermethioninemia screening, 1686
CMDT2019_Index_p1743-1884.indd   1809

INDEX1810
 
CMDT 2019
Hypervitaminosis A, 1285
Hypervolemic hypernatremia, 904
Hypervolemic hypotonic hyponatremia, 
899
f
, 901, 902
Hyphema, 205
Hypnagogic hallucinations, 1103. 
See also
 
Hypnosis, for menopausal symptoms, 1211
Hypnotic drugs. 
See
 Sedative-hypnotics
Hypoactive delirium, 61
Hypoactive sexual (hyposexual) desire 
disorder, 796, 797, 1076
Hypoadrenalism. 
See
ascites and, 613, 613
t
decreased anion gap in, 918
in nephrotic syndrome, 954, 957
after adrenalectomy, 1189
hyporeninemic, 920
t
, 921
Hypobaric hypoxia, 1577, 1578–1579
Hypocalcemia, 906
t
, 
910–911
, 910
t
, 1176, 
1176–1177. 
See also
 
acute (hypoparathyroid tetany), 910, 
1162, 1162–1163
congenital hypoparathyroidism/
pseudohypoparathyroidism 
causing, 1161, 1162
differential diagnosis of, 1162
familial, 906
t
hyper-/hypomagnesemia and, 910, 915, 
916
hypercalciuria and, 911, 1162
hyperphosphatemia and, 910
hypoalbuminemia and, 910, 911
hypoparathyroidism and, 910, 
 
1160–1163, 1162
t
hypophosphatemia and, 910
kidney disease/renal osteodystrophy 
and, 910, 939, 940, 940
f
in newborn, 1165
osteomalacia/rickets and, 1175, 1175
t
, 
1176, 1176–1177
in Paget disease of bone, 1179
after parathyroidectomy, 1161, 1169
postoperative, prophylaxis against, 1162
tetany and, 910, 1162
Hypocalciuria, 912
hypercalcemia and (hypocalciuric 
hypercalcemia), 906
t
, 911, 912
Hypocapnia. 
See
Hypochloremia, in respiratory acidosis, 
924
Hypochlorite solution, for skin 
decontamination, 1584
Hypocholesterolemic drugs. 
See
 Lipid-
lowering therapy
Hypochondriasis. 
See
 Somatic symptom 
disorders
Hypocitraturic calcium nephrolithiasis, 
977
Hypocomplementemia, in hepatitis 
C-related renal disease, 953
Hypocretin deficiency syndrome, 1103
Hypogammaglobulinemia, 541, 550, 896
Hypoglycemia, 
1261–1266
, 1261
t
alcohol-related, 1111, 1246, 1261, 1261
t
, 
1266
medication-induced, 1140–1141
muscle weakness and, 863
painful subacute (de Quervain) 
thyroiditis and, 1132, 1134, 
1140
periodic paralysis and, 1062, 1142, 1148
and, 53–54
pituitary tumor/hyperplasia causing, 
1141
postpartum/postpartum thyroiditis and, 
1131, 1140, 1141, 1148
during pregnancy, 830–831, 1141, 1142, 
1143, 1146–1147, 1148
hyperemesis gravidarum and, 817, 
1141
recombinant human thyroid-stimulating 
hormone (rhTSH) causing, 
1141, 1156
subclinical, 1142, 1148
thyroid carcinoma and, 1141, 1154
thyroid testing in, 1135
t
, 1139
t
, 
 
1142–1143
thyroiditis and, 1131, 1132, 1133, 1134, 
1146
TSH levels in, 1135
t
, 1139, 1139
t
, 1142, 
1143
Hypertonic hyponatremia, 899–900, 899
f
Hypertrichosis lanuginosa, 1206
Hypertriglyceridemia, 1267, 1269, 1272. 
See also
 Lipid disorders; 
diabetes and, 1224, 1227, 1269
estrogen replacement therapy causing, 
1213
in heart disease, 368, 1267, 1275
HIV infection/antiretroviral therapy 
and, 1369
pancreatitis and, 742, 744, 1275
Hypertrophic cardiomyopathy. 
See
 
Hypertrophic pulmonary 
osteoarthropathy, 850, 889
Hyperuricemia, 844, 844
t
, 845, 846
1673–1674
, 1676
t
in diabetes insipidus, 1125
in diabetes mellitus, 1252
in gout, 844, 844
t
, 845
kidney disease/acute tubular necrosis 
and, 844, 933, 938
t
, 964–965, 
1673
in myeloma, 547, 548, 964
urinary stone formation and, 844, 975, 
976, 977. 
See also
 Uric acid 
urinary stones
Hyperuricosuric calcium nephrolithiasis, 
976
Hyperventilation, 
327
in metabolic/lactic acidosis, 921, 1260
neurogenic, in coma/stupor, 327
respiratory alkalosis (hypocapnia) and, 
327, 924, 925
Hyperviscosity
in myeloma/myeloma kidney, 547, 964

327
549, 550
Hypertension (
Cont
.):
metabolic syndrome and, 365, 453
ocular. 
See
 Ocular hypertension
and, 49
in pheochromocytoma, 455, 456, 1190, 
1192
1582
portal. 
See
portopulmonary, 719
during pregnancy, 454, 455, 822–825, 
823
t
, 
832–833
. 
See also
 
t
pulmonary. 
See
 Pulmonary 
renal vascular, 454
resistant, 454, 477
t
, 
479
, 479
t
retinochoroidopathy/retinopathy in, 
198
, 456, 456
f
secondary, 453–455, 453
t
sleep apnea and, 328, 453
sodium restriction and, 10, 453, 457
t
, 
458
stroke and, 6
t
, 10–11, 455–456, 459, 
479–480, 1009, 1011
“white coat, ” 451, 452
f
, 479
Hypertension exacerbated in pregnancy, 
454
Hypertensive emergencies/urgencies, 
 
479–480
, 480
t
, 481
t
blood pressure in, 451, 479, 480
in pheochromocytoma, 455, 1190
Hypertensive encephalopathy, 456, 479
Hypertensive nephropathy, 479
Hyperthecosis. 
See
 Polycystic ovary 
syndrome
Hyperthermia, 
34–37
, 1564. 
See also
 
Fever; Heat; Serotonin 
syndrome
antipsychotics causing. 
See
 Neuroleptic 
malignant syndrome
malignant, 35, 1301–1302, 1584
1583–1584
Hyperthermia therapy, for benign 
prostatic hyperplasia, 988
Hyperthyroidism (thyrotoxicosis), 
 
1139–1149
, 1139
t
. 
See also
 
amiodarone-induced, 1134, 1140, 1143, 
1147
apathetic, 1141, 1148
autoimmune/Hashimoto thyroiditis 
and, 1131, 1133
cancer-related, 1141, 1154
cardiac disorders/failure and, 415, 429, 
eye disease associated with, 
202
, 202
f
, 
factitious, 1141
fetal, 831
1141
goiter/thyroid nodules and, 1140, 1146, 
1149, 1151, 1160
hypothyroidism after treatment for, 
1134
iodine-induced (Jod-Basedow disease/
phenomenon), 1140–1141, 
1143
CMDT2019_Index_p1743-1884.indd   1810

INDEX1811
 
CMDT 2019
mass lesions and, 1119–1120, 1123
postpartum pituitary necrosis/Sheehan 
syndrome and, 1120
Hypopnea, 327. 
See also
 Sleep apnea 
hypopnea
Hypoproteinemia, in nephrotic syndrome, 
955
Hypoprothrombinemia, 572
Hypopyon, 185, 190, 876
Hyporeninemic hypoaldosteronism, 920
t
, 
921
Hyposexual (hypoactive sexual) desire 
Hyposmia, 230–231. 
See also
 Olfactory 
antidepressants causing, 1094
in diabetes, 1223, 1250
dysautonomia (autonomic dysfunction) 
and, 1003, 1004
myocardial infarction and, 390–391
orthostatic (postural). 
See
palpitations and, 31
pheochromocytoma removal 
and, 1192, 1192–1193
1581–1582
in right ventricular infarction, 391
in shock, 505, 506, 507, 508
Hypotensive agents. 
See
 Antihypertensive 
drug therapy
Hypothalamic amenorrhea, 1120, 1209, 
1210
Hypothalamic disorders, 
1119–1130
amenorrhea and, 1120, 1209, 1210
982, 1120, 1121
hypopituitarism and, 1121. 
See also
 
coma in, 1042, 1567, 1581
of extremities, 
1568–1569
1581
sudden cardiac arrest and, 411, 1567
systemic (accidental), 
1566–1568
, 1566
f
Hypothyroidism, 1121, 1122, 
1134–1139
, 
1135
t
, 1136
t
amiodarone-induced, 1134
and, 1131, 1133, 1134
cardiac disorders/failure and, 415, 1135
congenital/fetal, 831, 1134, 1146–1147, 
1159
consumptive, 1134
cretinism and, 1134, 1159
fibromyalgia and, 888
goiter/thyroid nodules and, 1134, 1149, 
1159, 1160
hepatitis C and, 1135
after hyperthyroidism treatment/thyroid 
surgery, 1134, 1145, 1148
1136
and, 53
1259
hypomagnesemia and, 905, 915, 916
kidney injury/renal tubular acidosis 
and, 920, 922, 938
t
1293
t
Hypokalemic periodic paralysis, 906
t
, 
1062, 1142, 1148
Hypomagnesemia, 
915–916
, 915
t
hypercalciuria and, 906
t
910, 911, 915, 916, 1161, 1163
hypokalemia and, 905, 915, 916
1293
t
Hypomagnesemia-hypercalciuria 
syndrome, 906
t
Hypomania, 1079, 1088, 1097–1099, 
1099
t
. 
See also
 Bipolar 
disorder; Mania
Hyponatremia, 
899–903
, 899
f
, 901
t
and, 900, 1182
dilutional, heat exposure and, 1565
drugs causing, 900, 901, 901
t
1259
1121, 1122, 1127, 1130, 1186
in hypothyroidism/myxedema, 900, 
1137
MDMA causing, 900
polydipsia/beer potomania causing, 901, 
1080
in SIADH, 901, 901
t
, 902
in subarachnoid hemorrhage, 1013
Hypoparathyroidism, 
1160–1163
, 1162
t
. 
See also
 Hypocalcemia
congenital, 1161
hyper-/hypomagnesemia and, 915, 1161
hypocalcemia and, 910, 1161
during pregnancy, 1163
tetany and, 1162–1163
after thyroid surgery, 1145, 1146, 1148, 
1155, 1160–1161
Hypophosphatasia, 1176, 1177, 1177–1178
Hypophosphatemia, 906
t
, 
913–914
, 913
t
, 
1176, 1177
in diabetic ketoacidosis, 914, 1255, 1257
and, 912, 1165
hypercalciuria and, 912, 976
1259–1260
osteomalacia/rickets and, 906
t
, 1175
t
, 
1176, 1177
Hypophysitis, 1119, 1121, 1122
Hypopigmentation, 166, 167
Hypopituitarism, 
1119–1124
hypogonadism and, 982, 1120, 1121, 
1123
altered awareness of, 1246, 1262
1265–1266
chronic kidney disease/uremia and, 941, 
958

1119–1124
1123
1265–1266
958
coma caused by, 1246, 1255
t
, 1581
counterregulatory issues and, 1246
diabetes treatment and, 1227, 1228, 
1245
t
, 1246, 1599. 
See also
 
Hypoglycemia, insulin-
induced
drug-induced, 1227, 1229, 1245, 1246
exercise-induced, 1240, 1242, 1246
factitious, 1262, 
1266
fasting, 1261, 1261
t
, 1262
functional alimentary, 
1265
after gastric surgery, 
1265
glucagon response to, impaired, 1246
in hypopituitarism, 1121
immunopathologic, 1261, 1261
t
insulin-induced/intensive glycemic 
control and, 1227, 1228, 
1245
t
, 1246, 1599
insulin receptor antibodies causing, 
1261, 
1266
insulinoma causing, 1196, 1261–1264, 
1262
t
, 1263
t
noninsulinoma pancreatogenous 
hypoglycemia syndrome (islet 
cell hyperplasia) causing, 
 
1264
nonislet cell tumor, 
1264–1265
occult diabetes and, 1265
pancreatic B cell tumors causing, 
 
1261–1264
, 1262
t
, 1263
t
postprandial (reactive), 1261, 1261
t
Hypoglycemic drugs. 
See
agents
Hypoglycemic unawareness, 1246, 1262
and, 1180, 1181
age-related, 1200, 1201
female, 1121, 1129
amenorrhea in, 1121, 1129, 1209
premature (premature menopause/
ovarian failure), 808, 1209, 
1210, 1211
GH-secreting pituitary tumor causing, 
1126, 1127
hypergonadotropic (primary/testicular 
failure), 982, 1120, 1121, 1123, 
1199, 1199
t
, 1200, 1201
hypogonadotropic (secondary), 982, 
1119, 1120, 1121, 1123, 1124, 
1181, 1199, 1199
t
hyperprolactinemia and, 982, 1121, 
1123, 1128, 1129, 1201
isolated/congenital, 1119, 1120, 1124, 
1200
male, 981
f
, 982, 1121, 
1199–1204
, 1199
t
infertility and, 981
f
, 982
sexual dysfunction and, 979, 1200
osteoporosis and, 1171, 1172
Hypokalemia, 
905–907
, 905
t
, 906
t
aldosteronism and, 905, 1188, 1189
diabetic ketoacidosis and, 1257
diuretics causing, 460, 905, 1287
CMDT2019_Index_p1743-1884.indd   1811

INDEX1812
 
CMDT 2019
IIV vaccines, 1329
t
, 1334
t
, 1335
t
, 1424. 
See 
also
 Influenza virus vaccine
IL6/JAK/STAT pathway, hepatic adenoma 
and, 731
IL28B (IFNL3)
 gene, 697
Ileitis/ileocolitis, in Crohn disease, 665, 666
Ileum. 
See also
 Small intestine
resection of, short bowel syndrome and, 
649
Ileus
gallstone, 732
paralytic (acute/adynamic), 
650–651
Iliac arteries, atherosclerotic/occlusive 
disease of, 
483–484
Illicit drug use. 
See
disorders
Illness, psychiatric problems associated 
with, 1088, 
1116–1118
Illness behaviors, abnormal, 
1071–1072
Illusions, in schizophrenia/psychotic 
Iloperidone, 1081, 1081
t
, 1082
t
Iloprost, 314, 444
Imaging. 
See also
 
specific type and disorder
1575, 1611
Imatinib, 535, 536, 1621
t
, 1646, 1679
Imbalance. 
See
 Falls; Vertigo; Vestibular 
disorders
Imidazoles, 107
t
. 
See also
 
Imiglucerase, 1685
Imipenem, 279
t
, 282, 285
t
, 1321
t
, 1484
t
Imipramine, 208
t
, 1091
t
, 1094, 1103. 
See 
also
Imiquimod, 149
Immediate hypersensitivity, 
890–892
Immersion (trench) foot/hand, 
1568
Immobility
disease) and, 305, 309
t
62–63
pressure injury and, 68–69, 68
t
Immune alveolar hemorrhage, 315
Immune checkpoint inhibitors
1141
Immune complexes
glomerulonephritis and, 935, 948
f
, 952
HIV-associated glomerular disease and, 
958
membranous nephropathy and, 948
f
, 957
Immune globulin. 
See
 
Immune insulin resistance, 1222, 1247, 
1257
Immune reconstitution inflammatory 
syndromes (IRIS), 199, 
 
1355–1356
in cryptococcosis, 1556
Kaposi sarcoma, 154, 1354
leukoencephalopathy and, 
1407, 1408
t
t
Ibutilide, 393, 394
t
, 395
t
, 403, 406, 408
ICA-512 (tyrosine phosphatase IA2) 
1221
t
, 1242
ICA (islet cell antibodies), in diabetes, 
1220, 1221, 1221
t
, 1242
Icteric leptospirosis (Weil syndrome), 1505
Icterus. 
See
 Jaundice
Idarubicin, 546, 1618
t
Idarucizumab, 406, 1591
Idelalisib, 541, 1621
t
IDH1/IDH2
Idiopathic adulthood ductopenia, 740
Idiopathic brachial plexus neuropathy 
(neuralgic amyotrophy), 1056
Idiopathic bronchiolitis obliterans with 
organizing pneumonia. 
See
 
pneumonia/pneumonitis
Idiopathic CD4 lymphopenia syndrome, 
leukoencephalopathy in, 1407
Idiopathic crescentic glomerulonephritis. 
See
 Crescentic 
Idiopathic duct-centric chronic 
pancreatitis, 746
Idiopathic inflammatory myopathies, 854
t
, 
861–864
, 862
f
, 862
t
. 
See also
 
Dermatomyositis; 
Idiopathic interstitial pneumonias, 301, 
302
t
. 
See also
 Diffuse 
interstitial pneumonias
Idiopathic intracranial hypertension 
(pseudotumor cerebri), 41, 
994, 
1022–1023
Idiopathic midline destructive disease, 
 
234
Idiopathic polyneuropathy, acute. 
See
 
Idiopathic pulmonary fibrosis (IPF), 301, 
303, 303
f
Idiopathic pulmonary hemosiderosis, 
315–316
Idiopathic (primary) pulmonary 
hypertension, 312, 442–443, 
443
Idiopathic skeletal hyperostosis, diffuse 
Idiopathic torsion dystonia, 
1028–1029
Idioventricular rhythm, accelerated, 389, 
409
Idoxuridine, 1379
t
I
f
 channel blocker. 
See
 Ivabradine
IFNL3 (IL28B)
 gene, 697
Ifosfamide, 1616
t
, 1675
t
, 1679
IgA, selective deficiency of, 895
t
, 
896
IgA nephropathy (Berger disease), 946
t
, 
948
f
, 
949–950
IgA vasculitis, 946
t
IgE, in immediate hypersensitivity, 890, 
891
IgG, intravenous. 
See

, 1679
t
, 
896
t
, 
948
f
, 
949–950
t
891
See
 Intravenous immune 
globulin
IgG
4
-associated disease, 
865–866
cholangitis, 740
pancreatitis, 746, 747, 866
IgVH somatic mutation, 541
Hypothyroidism (
Cont
.):
postpartum thyroiditis and, 1131, 1134, 
1140
during pregnancy, 830, 1134
pubertal delay and, 1209
in subacute painful (de Quervain) 
thyroiditis, 1132, 1134, 1140
subclinical, 1136
thyroid testing in, 1135–1136, 1135
t
, 
1136
t
thyroiditis and, 1131, 1132, 1133, 1134
See
 Levothyroxine
TSH levels and, 1121, 1122, 1135–1136, 
1135
t
, 1136
t
, 1138
Hypotonic hyponatremia, 899
f
, 900–901
Hypoventilation
obesity and (Pickwickian syndrome), 
327
respiratory acidosis and, 924
sleep-related, 1103
Hypovolemic hypernatremia, 904
Hypovolemic hypotonic hyponatremia, 
899
f
, 900, 902
Hypovolemic/hemorrhagic shock, 505, 
505
t
, 506, 507
Hypoxemia. 
See
 Arterial blood gases
Hypoxia, hypobaric, 1577, 1578–1579
Hypoxia inducible factor 2A mutations, 
1199
Hypoxic hepatitis, 728
Hypoxis rooperi,
 for benign prostatic 
hyperplasia, 987
Hysterectomy. 
See also
 Oophorectomy
777–778, 778
for cervical carcinoma, 786
for endometrial carcinoma, 788
for endometriosis/pelvic pain, 780, 791
estrogen replacement therapy and, 809, 
1213
for fibroid tumors, 788
for gestational trophoblastic disease, 821
for morbidly adherent placenta/
bleeding, 827
for ovarian cancer, 794
for pelvic organ prolapse, 792
premature ovarian failure and, 808, 
1210
prophylactic, 682
Hysterical (histrionic) personality 
t
Hysterosalpingography, 777, 777
t
, 798
Hysteroscopy, 777, 777
t
, 788
123
I-MIBG scanning, in 
paraganglioma, 1192
131
I. 
See
 Radioactive iodine
131
I-MIBG therapy, in 
paraganglioma, 1194
Iatrogenic Creutzfeldt-Jakob disease, 1406, 
1407
Iatrogenic pneumothorax, 325
Ibandronate, 1173, 1673. 
See also
 
Ibritumomab tiuxetan, 544
Ibrutinib, 541, 550, 1621
t
Ibuprofen, 87
t
gastrointestinal effects of, 636
t
CMDT2019_Index_p1743-1884.indd   1812

INDEX1813
 
CMDT 2019
Immunotherapy. 
See also
 
Immunomodulating therapy
f
, 261
t
, 264
venom, 892
in wart removal, 150
Impedance plethysmography/testing
in esophageal disorders, 618, 619–620, 
622
in venous thrombosis/pulmonary 
embolism, 308
Imperforate hymen, 1209
Impetiginization, 132
Impetigo, 131, 
131–132
, 1322
t
, 1353, 1449
antibiotics for, 106–107
t
, 132, 1322
t
glomerulonephritis after, 949
Impingement syndrome (subacromial), 
1690–1694
, 1693–1694
t
Implantable cardioverter defibrillator
f
, 
for long QT syndrome, 412
postinfarction, 392
preoperative/prophylactic/surgery and, 
49
for ventricular fibrillation/sudden death, 
411
for ventricular tachycardia, 410
Impotence. 
See
impotence
Impulse conduction, disturbances of. 
See
 
Conduction disturbances
Impulse control disorders, 1104
In vitro fertilization (IVF), 798, 799, 983
Inactivated enhanced-potency polio 
vaccine (IPV/Salk vaccine), 
1398
pregnancy and, 816
Inactivated influenza vaccines (IIV), 
1329
t
, 1334
t
, 1335
t
, 1424. 
See 
also
Inactivated vaccines, 1325
Inborn errors of metabolism, seizures and, 
999
Incentive spirometry, postoperative 
pulmonary complications and, 
50
Incidentalomas
adrenal, 1189, 1190, 
1194–1195
thyroid, 1133, 1150
Inclusion body encephalitis, 1392
Inclusion body myositis, 863, 
1062
Inclusion conjunctivitis, 177, 837
Inclusion cysts, epidermal (EICs), 162, 
 
163
Inclusion disease, CMV , in newborn, 1388, 
1389
Incompetent cervix, 818
Incomplete abortion, 818
Incontinence. 
See
 Fecal incontinence; 
Urinary incontinence
Increased intracranial pressure. 
See
 
Intracranial hypertension
Incretins, 1230
t
, 1231
t
, 1234–1236, 
 
1279
Indapamide, 207
t
, 461
t
Indian tick typhus, 1437
t
Indigestion. 
See
 Dyspepsia
Indinavir, 1364
t
, 1369. 
See also
 
mucormycosis in, 228, 1559
t
 infections in, 278
t
, 1298, 
1344, 1345
t
, 1361, 1362, 
1362
t
, 
1554–1556
1407, 1408
pulmonary infiltrates/pneumonia in, 
278
t
, 280, 
287
, 1344, 
 
1554–1556
RSV infection in, 1421
scabies in, 157, 158
squamous cell carcinoma in, 152
t
, 
tuberculosis in, 290
yellow fever vaccine and, 1417
Immunodeficiency, 
895–897
, 895
t
. 
See 
also
 Immunocompromised 
host
in Epstein-Barr virus infection, 1387, 
1388
in HIV infection/AIDS, 1340–1341. 
See 
also
infections associated with, 896, 897, 
1296–1300
. 
See also
 
Opportunistic infections
Immunoglobulin-mediated 
glomerulonephritis, 935
Immunoglobulins. 
See also
 
under Ig and
 Antibodies
deficiencies of, 
895–897
, 895
t
, 1297
Immunologic disorders, 
890–897
, 893
t
, 
895
t
, 1115
t
. 
See also
allergic disorders/reactions; 
Atopic disease; Autoimmune 
disorders; Immunodeficiency
Immunomodulating therapy. 
See also
 
f
, 261
t
, 264
in cancer chemotherapy, 1619
t
669, 672–673
ophthalmic disorders/effects and, 183
t
, 
208
t
t
Immunopathologic hypoglycemia, 1261, 
1261
t
Immunoreactive insulin
in prebreakfast hyperglycemia, 1243
t
Immunosuppressive therapy. 
See also
 
Immunocompromised host; 
infections and, 1297. 
See also
 
for lupus nephritis/SLE, 855, 953
for neuromyelitis optica, 1037–1038
t
after transplant
CMV infection and, 1299, 1388, 1390

See also
 
t
1325, 1337
squamous cell carcinoma and, 152
Immune recovery uveitis, 199
Immune thrombocytopenia (ITP), 557, 
558–560
, 560
f
. 
See also
 
Immunity/immune response disorders, 
890–897
, 893
t
, 895
t
. 
See also
 
Allergies/allergic disorders/
reactions; Atopic disease; 
Autoimmune disorders; 
Hypersensitivity; 
Immunodeficiency
Immunizations (vaccines), 3–5, 
 
1325–1337
, 1326–1334
t
, 
1335–1336
t
. 
See also
 
specific 
type and disorder
active and passive immunity and, 1325
autism concerns and, 1393
recommended types/schedules for, 3–5, 
1325–1337
t
for adults, 
1325–1337
t
1328
t
, 1331
t
, 1332
t
, 1735
t
, 
1736
infection/AIDS, 4, 
1325
, 
1328
t
, 1361
for infants/children/adolescents, 
1325
1727, 1729
815–816
, 
1325
, 
1328
t
for travelers, 4, 1329
t
, 1332
t
, 1333
t
, 
1337
t
, 
1335–1336
t
, 
1337
Immunocompromised host, 
895–897
, 
895
t
. 
See also
AIDS; Immunodeficiency
aspergillosis in, 1299, 1557–1558
1353, 1483
bronchiectasis in, 274
cancer-related infection and, 1021, 1297, 
1298, 
1674–1675
CMV infections in, 198–199, 1350, 
1388–1389, 1389, 1389–1390
cryptococcosis in, 1020, 1345–1346
t
, 
diarrhea in, 600, 601, 604
1430
1300
herpes zoster and, 128, 129, 186, 199, 
225, 1328
t
, 1346
t
immunizations and, 4, 
1325
, 1328
t
, 
1361.
 See also
 specific vaccine
infections and, 896, 897, 
1296–1300
. 
See also
 Opportunistic 
infectious esophagitis in, 623–624
t
, 
1361
CMDT2019_Index_p1743-1884.indd   1813

INDEX1814
 
CMDT 2019
Infliximab, 116, 664, 669–670, 673, 674, 
852. 
See also
Influenza, 2
t
, 22, 
1422–1425
, 
1425–1427
avian, 1422, 
1425–1427
drug resistance and, 1423, 1423–1424, 
1426
neuraminidase inhibitors (oseltamivir/
zanamivir/peramivir) for, 
1379
t
, 1423–1424, 1425, 
 
1426
pneumonia and, 282, 1423, 1424
prevention of, 3, 1327
t
, 1328
t
, 1329
t
, 
1424–1425, 1426–1427. 
See 
also
seasonal, 
1422–1425
Influenza virus vaccine, 3, 1327
t
, 1328
t
, 
1424, 1427
in asthma patients, 264
avian influenza and, 1427
in cystic fibrosis, 277
infection/AIDS, 1328
t
in pneumonia prevention, 282
pregnancy and, 816, 1325, 1328
t
, 1329
t
, 
1424
t
, 
1335
t
, 1424
Infraclavicular lymph nodes, in breast 
cancer, 758
Infraspinatus tendon, 1694
Infundibular stenosis, 334
Infusion pumps, insulin. 
See
 Insulin 
infusion pumps
Ingrown nails, 169
Inhalation injury/smoke inhalation, 300
t
, 
316
corrosive acids and, 1589
cyanide poisoning and, 1596
Inhalational anthrax, 1461, 1462
Inhaled insulin, 1238
t
, 1240–1241
Inhalers
for asthma therapy, 259, 260
t
, 261, 262
t
, 
263
t
for COPD therapy, 271, 272, 273
Inherited (hereditary/genetic) disorders, 
1681–1689
. 
See also
 
specific 
disorder
electrolyte metabolism disturbances 
and, 906
t
Injection drug use. 
See also
disorders
febrile patient and, 1311
infections and, 
1310–1311
arthritis, 881, 1311
clostridial infection/wound botulism, 
1059, 1310, 1458, 1460, 1604
endocarditis, 1311, 1321
t
, 1464
hepatitis, 694, 697, 1311, 1332
t
HIV infection/AIDS, 1310, 1311, 
1340, 1356
osteomyelitis, 885, 1311
skin infections, 1310, 1485
tuberculosis, 1310–1311
Injury. 
See
 Trauma
Inkspot lentigines, 111
Inner ear, 
218–224
Innocent murmurs. 
See
Inotropic agents, 390, 425, 508. 
See also
 
Digitalis/digitalis glycosides/
digoxin
shock associated with. 
See
 Sepsis/septic 
shock
surgical site, 1302, 1303
antibiotic prophylaxis for, 
54
, 1303
566
transfusion in transmission of, 
553–554
travel/traveler’s diarrhea and, 
 
1314–1315
, 
1316–1317
tubulointerstitial nephritis caused by, 959
t
Infection control
infections and, 1302–1303
in immunocompromised host, 
 
1298–1299
influenza transmission and, 1425
viral diarrhea and, 1433
Infection (struvite) urinary stones, 975, 
977
Infectious diseases. 
See
 Infection
Infectious mononucleosis. 
See
 
Infective endocarditis. 
See
Inferior vena cava filters/interruption, 312, 
586–587
Infertility, 
797–800
, 
980–983
, 981
f
female, 
797–800
endometriosis and, 790, 798
pelvic infection/PID and, 792, 793
798
hyperprolactinemia and, 798, 1128, 
1129, 1129–1130
in hypopituitarism, 1123, 1124. 
See also
 
male, 797, 798, 
980–983
, 981
f
cryptorchism and, 1204
hypogonadism and, 981
f
in Klinefelter syndrome, 982, 1686, 
1687
marijuana use and, 1113
Inflammation. 
See also
 
specific type and 
structure/systems affected
anemia of, 513
in HIV infection/AIDS, 1355–1356
Inflammatory adenoma of liver, 731
Inflammatory bowel disease, 
662–675
. 
See 
also
 Crohn disease; Ulcerative 
colitis
arthritis and, 666, 
881
colorectal cancer and, 667, 674, 
 
1649–1650
diarrhea in, 603, 604
f
GI bleeding and, 609
primary sclerosing cholangitis and, 739, 
740, 741
social support for patient with, 665
Inflammatory breast carcinoma, 761. 
 
See also
Inflammatory eye disease, 176
t
. 
See also
 
Inflammatory myopathy, 854
t
, 
861–864
, 
862
f
, 862
t
, 1062. 
See also
 
Inflammatory pericarditis, acute, 
437–440
, 
438
t
. 
See also
 
and
Inflammatory polyneuropathy, chronic, 
1051–1052
Inflammatory skin nodules, 
160–163
. 
 
See also

437–440
, 
438
t
. 
See also
 
and
1051–1052
160–163
. 
 
See also
 
Indomethacin, 87
t
for gout, 845
t
ophthalmic disorders/effects and, 182
t
, 
209
t
in pain management, 87
t
for preterm labor, 826
Industrial bronchitis, 319
Inevitable abortion, 818
Infant. 
See
 Newborn
Infant botulism, 1460
Infarcts. 
See
 
Infection/infectious diseases, 
1294–1337
. 
See also
 
specific causative 
agent or system affected
and, 1180
anorectal, 
684
antimicrobial therapy and, 
1317–1325
, 
1318–1320
t
, 1321
t
, 
 
1322–1323
t
arthritis, 
881–884
bite wounds and, 
1307–1308
of bone. 
See
 Osteomyelitis
burn injury and, 1298, 1572
in cancer patients, 1021, 1297, 1298, 
1674–1675
. 
See also
 
diabetes and, 1242, 1251, 1298
t
t
, 
603–604, 
1311–1314
, 
 
1312–1313
t
in drug users, 
1310–1311
. 
See also
 
Injection drug use, infections 
and
erythema nodosum associated with, 160
erythemas, 
144–146
, 145
f
esophagitis caused by, 
623–624
fever/FUO and, 
1294–1296
gastritis caused by, 635
genitourinary, 
967–973
, 968
t
glomerulonephritis and, 946
t
, 948
f
, 
949
headache and, 40
health care–associated, 
1300–1303
immunization against, 
1325–1337
, 
1326–1334
t
t
. 
See 
also
 Immunizations
in immunocompromised host, 896, 897, 
1296–1300
. 
See also
 HIV 
infection/AIDS; 
insulin requirements and, 1242
185–186
myocarditis and, 
425–427
, 425
t
t
neuropathies associated with, 
1050
neutropenia and, 528, 529, 1299
opportunistic. 
See
834–837
prevention of/vaccine-preventable, 
3–5
, 
1325–1337
t
, 
1335–1336
t
, 
1391–1398
. 
See 
also
seizures and, 999
sexually transmitted, 
1308–1310
1727–1728
CMDT2019_Index_p1743-1884.indd   1814

INDEX1815
 
CMDT 2019
with oral antidiabetic agents, 1245
patient education/self-management and, 
1242
prebreakfast hyperglycemia and, 1243, 
1243
t
purified insulin and, 1238, 1246, 1247
in pregnant patient, 831, 832, 1226, 
1227
for type 1 diabetes, 1220, 1227, 1237–1241, 
1238
t
t
hospitalization/surgery and, 53, 1252, 
1253
t
for type 2 diabetes, 1227–1228, 1237, 
1245
1253
t
Insulinomas, 1195, 1196, 1261–1264, 
1262
t
, 1263
t
. 
See also
 Islet cell 
tumors
hypoglycemia caused by, 1196, 
 
1261–1264, 1262
t
, 1263
t
localization of, 1196, 1263–1264
in MEN, 1195, 1198, 1262, 1263
Insulinopenia, pentamidine-induced, 1266
Integrase inhibitors, 1365
t
, 1370–1371, 
t
Integrative pain management, 
100
Integrins, drugs targeting. 
See
 Anti-
integrins
Intensive care unit, patient in. 
See
 Critical 
illness
Intensive care unit psychosis, 1116
Intercostal neuritis, 372
Intercourse, sexual. 
See
Interdigital (toe web) tinea pedis, 121, 
121
f
, 145
Interferon, depression caused by, 1088
Interferon-alpha/interferon alfa, 208
t
, 
1379
t
, 1623
t
, 1668. 
See also
 
Peginterferon
Interferon-beta, for multiple sclerosis, 
1037, 1038
t
Interferon gamma release assays (IGRAs), 
4, 290–291
in HIV infection/AIDS, 1344, 1359
latent disease treatment and, 294
musculoskeletal disease and, 886
in pregnant patient, 836
Interleukin-1 (IL-1) inhibitors, 846, 
 
853
Interleukin-2 (IL-2), 1668
Interleukin-11 (IL-11), recombinant 
(oprelvekin), 1677
Interleukin-12/23 (IL-12/23) inhibitors, 
665, 670
Intermediate-acting insulin, 1238
t
, 1239. 
See also
 Insulin therapy; NPH 
insulin
Intermediate uveitis (pars planitis), 190. 
See also
 Uveitis
Intermittent claudication, 483
Internal hordeolum, 174
hip fracture and, 1707
at knee, 1718
low back pain and, 1698
at shoulder, 1690, 1692
t
, 1693
t
Interosseous nerve, anterior, lesion of, 
1052
GH deficiency/rhGH therapy and, 1120, 
1121, 1123
GH excess and, 1126, 1127, 1128
Insulin-like growth factor-2 (IGF-2), 
nonislet cell tumor 
hypoglycemia and, 1264, 1265
Insulin lispro, 1238, 1238–1239, 1238
t
, 
1240, 1242. 
See also
 Insulin 
therapy
in mixtures/combination therapy, 1238
t
, 
1240, 1242
in pregnancy, 831, 1254
Insulin pens, 1238, 1240
Insulin pumps. 
See
Insulin receptor antibodies
1266
Insulin resistance/insensitivity, 1223. 
See 
also
 Metabolic syndrome
acanthosis nigricans and, 1222, 1224, 
1224
f
in diabetes, 1221, 1222, 1223, 1223
t
drugs causing, 1223
hypertension and, 453
immune, 1222, 1247, 1257
lipid disorders and, 1227
713
obesity and, 1222, 1223
Insulin syringes and needles, 1240
Insulin therapy, 1227, 1227–1228, 1237–
1241, 1238
t
, 1244
f
administration methods/regimens for, 
1240–1241
allergy to, 1247
1095
t
anti-insulin antibodies and, 1246–1247
bioavailability and, 1238, 1238
t
chronic kidney disease and, 941
in closed loop system, 1227
complications of, 1246–1247
continuous subcutaneous infusion 
(CSII) pumps in, 1240, 1243. 
See also
 Insulin infusion 
pumps
for diabetic ketoacidosis, 1256–1257, 
1258
exercise affecting, 1240, 1242, 1246
factitious hypoglycemia and, 1262, 1266
with glucose. 
See
 High-dose insulin 
euglycemic therapy
hospitalization/surgery and, 53, 1252–
1253, 1253
t
for hyperglycemic hyperosmolar state, 
1259
t
hypoglycemia and, 1227, 1262, 1599
immunopathology of, 1246–1247
inhalation for administration of, 1238
t
, 
1240–1241
injection sites for, 1240, 1247
intensive, 1227–1228, 1242–1243, 1243
t
, 
1245, 1253–1254
lipodystrophy/lipoatrophy/
lipohypertrophy and, 1240, 
1247

t
, 
1240–1241
t
, 
1247
mixtures/combination therapy and, 
1238
t
, 1239–1240, 1242–1243
Insect bites/stings
allergic reactions to, 
892
t
scorpion stings, 425
t
, 
1608
skin lesions caused by, 159–160
spider bites, 159, 425
t
, 
1608
urticaria caused by, 141
Insecticide poisoning (cholinesterase 
t
, 
1605
Insemination, artificial, 799
Insomnia, 1035, 1067
t
, 
1101–1103
fatal familial, 1406
Instability. 
See also
 Falls; Gait/gait 
disorders; Genetic instability
shoulder, 
1695–1696
Insulin. 
See also
 Insulin therapy; 
Insulinoma
antibodies to (IAA)
t
, 1242
ectopic, 1265
immunoreactive, 1243
t
, 1266
insensitivity to. 
See
 Insulin resistance/
insensitivity
receptors for. 
See
 Insulin receptors
See
secretion of, 1220, 1229–1232, 1230
t
by tumors
B cell tumors/insulinomas, 1195, 
1196
nonislet cell tumors, 1264–1265
Insulin aspart, 1238, 1238–1239, 1238
t
, 
1240. 
See also
 Insulin 
 
therapy
t
, 
1240
Insulin degludec, 1238, 1238
t
, 1239, 1240, 
1242, 1243
t
. 
See also
 Insulin 
therapy
in mixtures/combination therapy, 1237, 
1238
t
, 1240, 1242
in pregnancy, 1254
Insulin detemir, 1238, 1238
t
1242, 1243
t
, 1245. 
See also
 
in pregnancy, 1239, 1254
Insulin gene, 1220
Insulin glargine, 1238, 1238
t
1242, 1243
t
. 
See also
 Insulin 
therapy
in combination therapy, 1237, 1240, 
1245
Insulin glulisine, 1238, 1238–1239, 1238
t
, 
1240, 1254. 
See also
 Insulin 
therapy
Insulin infusion pumps, 1240, 1243. 
See 
also
 Insulin therapy
continuous glucose monitoring and, 
1226
ketoacidosis and, 1240
during pregnancy, 1253
rapidly acting analogs used in, 
 
1239
Insulin-like growth factor-1 (IGF-1)
deficiency of, 1120, 1121
CMDT2019_Index_p1743-1884.indd   1815

INDEX1816
 
CMDT 2019
pelvic infection/PID and, 793, 804
Intrauterine insemination, 983
Intravascular abscesses (septic superficial 
thrombophlebitis). 
See
 Septic 
Intravascular ultrasound, in angina, 371
Intravenous antimicrobial therapy, 
 
1323–1324
Intravenous drug use. 
See
 Injection drug 
use
Intravenous fat
for antidepressant overdose, 1610
for beta-blocker overdose, 1594
1594
for hypotension in drug overdose/
toxicity, 1581
in nutritional support, 1292
Intravenous fluids. 
See
hydration
for cold agglutinin disease, 526
for common variable 
immunodeficiency, 897
for Guillain-Barré syndrome, 1051
560
f
for toxic epidermal necrolysis, 144
Intravenous lines. 
See
 Catheters/
intravenous lines
Intraventricular conduction block, 398
Intravesical chemotherapy, for bladder 
cancer, 1665
Intrinsic acute kidney injury, 930
t
, 931. 
 
See also
 
Intrinsic factor, in pernicious anemia/
Intubation. 
See also
 Airway management; 
Mechanical ventilation
for burn injuries/smoke inhalation, 316
in comatose patient, 1580
conversion to tracheotomy and, 248
infection and. 
See
 Ventilator-associated 
pneumonia
for respiratory failure, 330
Invasive fungal sinusitis, 
228–229
Invasive mole, 821
Invasive nematode (roundworm) 
1544–1546
Invasive/invasive fibrous (Riedel) 
thyroiditis, 1132, 1133–1134
Inverse pityriasis rosea, 117, 120
Inverse psoriasis, 115
Inversion ankle sprains, 1720–1721, 1720
t
Inverted papilloma, 233
Involved nodal radiotherapy (INRT), 544, 
546
Iodinated contrast agents, 1144–1145
Iodine
1159–1160
in goiter prevention/treatment, 1160
hyperthyroidism/Graves disease and, 
1140, 1140–1141, 1143, 1146
hypothyroidism and, 1134
restriction of in thyroid disease, 1146
thyroiditis and, 1131
hypertension and, 455, 456, 480, 480
t
, 
1010
Intracoronary stents. 
See
 Coronary stents
Intracranial abscess. 
See
masses
Intracranial aneurysm, 
1013
. 
See also
 
Stroke
intracerebral/subarachnoid hemorrhage 
and, 1010, 1011, 1012, 1013
Intracranial arteriovenous malformations, 
1010, 1011, 
1013–1014
Intracranial bleeding. 
See
hemorrhage; Subarachnoid 
in cryptococcal meningitis, 1557
headache and, 41, 994, 1022
idiopathic (pseudotumor cerebri), 41, 
994, 
1022–1023
in liver failure/hepatic encephalopathy, 
699, 700
optic disk swelling and (papilledema), 
200
in stroke, 1009–1010
tumors causing. 
See also
Intracranial masses/tumors, 
1016–1021
, 
1017–1018
t
, 1615
t
abscess causing, 
1020–1021
. 
See also
 
Abscesses
false localizing signs and, 1018
headache caused by, 40–41, 
993
, 1016
1019–1020
, 
1354
1019
ocular motor palsies and, 201
olfactory dysfunction caused by, 230
primary, 
1016–1019
t
seizures caused by, 999, 1016
Intracranial venous thrombosis, 
1015
. 
See 
also
 Stroke
Intracytoplasmic sperm injection (ICSI), 
798, 799, 983
Intradermal testing. 
See
 Skin testing
Intraepidermal squamous cell carcinoma 
(Bowen disease), 
126
Intrahepatic cholestasis, 688, 689
t
, 
839
Intrahepatic portosystemic shunts. 
See
 
Transvenous (transjugular) 
intrahepatic portosystemic 
shunts
Intraocular foreign body, 
203
Intraocular hypertension. 
See
 Ocular 
Intraocular inflammation, 176
t
. 
See also
 
Intraocular lenses, 174, 191
Intraocular pressure, elevated. 
See
 Elevated 
intraocular pressure
Intrathecal pumps, for pain management, 
100–101, 101
t

t
. 
See also
 
See
 Elevated 
t
Intrauterine devices (IUDs). 
See also
 
Copper-containing IUD; 
Levonorgestrel/progestin-
releasing IUD
804, 806
Interpersonal relationships, terminally ill/
dying patient and, 80, 80
t
Interstitial cystitis/painful bladder 
syndrome, 44, 
974
Interstitial lung disease, 
300–305
, 300
t
, 
302
t
. 
See also
 
diffuse pneumonias, 
301–303
, 302
t
drug-related, 300
t
, 321
t
443
t
t
Interstitial nephritis, 854, 926, 930
t
, 
934–
935
Intertrigo, 120, 
126
Interventional modalities, in pain 
management, 
100–101
, 101
t
Interventricular septum rupture, 391
Intervertebral disk disorders. 
See
 Cervical 
spine/disk disease; Lumbar 
spine/disk disease; Sacral 
spine/disk disease
Intestinal adenocarcinoma, 667, 
1646–
1647
Intestinal amebiasis, 599
t
t
, 
1528, 1529, 1529
f
, 1530
t
Intestinal angina (visceral artery 
490–491
Intestinal bacterial overgrowth. 
See
 
Intestinal carcinoids, 1647, 1648
Intestinal disorders. 
See
system, disorders of
Intestinal flukes, 
1537–1538
Intestinal inflammation, in irritable bowel 
syndrome, 656
Intestinal ischemia, 490
Intestinal lymphoma, 667, 
1647
Intestinal motility disorders. 
See
 Motility 
disorders
Intestinal nematode (roundworm) 
1541–1544
Intestinal obstruction. 
See also
 Motility 
disorders
(Ogilvie syndrome), 651–652
in Crohn disease, 666, 666–667, 670
gallstones causing, 732
in gastroparesis/chronic intestinal 
pseudo-obstruction, 
 
652–653
vomiting and, 592, 592
t
Intestinal sarcoma, 
1648
Intestinal schistosomiasis, 1535
Intestinal tuberculosis, 
655
Intimate partner (domestic) violence, 17, 
1104, 1104–1105
1729–1730
Intoxication. 
See
 
specific substance causing 
and
 Poisoning/drug overdose
Intra-abdominal sepsis. 
See
 Abscesses
Intra-aortic balloon pump (IABP), 390, 
391
Intracerebral hemorrhage, 1007
t
, 
 
1010–1011
, 1043, 1043
t
, 1044. 
See also
 Stroke
arteriovenous malformations causing, 
fibrinolytic therapy for myocardial 
infarction and, 386
CMDT2019_Index_p1743-1884.indd   1816

INDEX1817
 
CMDT 2019
for candidiasis, 237, 623, 1551
for mycetoma, 1560
for tinea infections, 120, 122
Ivabradine, 374, 397, 417
f
, 418
t
, 421, 429
Ivermectin
for loiasis, 1549
for onchocerciasis, 1548
for pediculosis, 158–159
for scabies, 158
for trichuriasis, 1541
Ixazomib, 548, 1619
t
J wave, 1567, 1567
f
“Jackhammer esophagus, ” 631
JAK2
 inhibitors, 116–117, 531, 533
JAK2
 mutation
in mesenteric vein occlusion, 491
in myeloproliferative disorders, 529, 
530, 531, 532, 533
Jakob-Creutzfeldt disease. 
See
 Creutzfeldt-
Jakob disease
Jamestown Canyon virus, 1401
Janeway lesions, 1465
Janus kinase. 
See
 
under JAK
Japanese encephalitis, 1401, 
1402–1403
Jarisch-Herxheimer reaction
leptospirosis treatment and, 1505
relapsing fever treatment and, 1503
syphilis treatment and, 1497
Jaundice (icterus), 
688–691
, 689
t
, 690
t
, 
737. 
See also
 
leptospirosis with (Weil syndrome), 
1505
obstructive, 688–690, 689
t
, 691, 737
travel and, 1315
Jaw
osteonecrosis of, bisphosphonate use 
and, 890, 1173
tumors of, hyperparathyroidism and, 
1165
Jaw (masticatory) claudication, 868, 997
JC virus (John Cunningham virus/JCV), 
leukoencephalopathy caused 
by, 665, 1407–1408
Jejunostomies, 1289. 
See also
 Enteral 
Jervell-Lange-Nielsen syndrome, 412
Jo-1 antibody, 854
t
, 862, 862
t
Jock itch, 
120–121
Jod-Basedow disease/phenomenon 
(iodine-induced 
hyperthyroidism), 1140–1141, 
1143. 
See also
 Graves disease; 
John Cunningham virus. 
See
 JC virus
Joint fluid examination, 840, 841
t
, 842
t
, 
882, 883, 886–887. 
See also
 
Irritable bowel syndrome, 595
t
, 603, 
 
656–659
Irritant contact dermatitis, 132
Irritative voiding symptoms, 967, 969, 983
Isavuconazole, 1558, 1562
t
Ischemia
brainstem, seizures differentiated from, 
1000
cerebrovascular, 488–490, 489
f
, 1007
t
. 
See also
critical limb, 486
intestinal/mesenteric, 490
myocardial. 
See
 Myocardial ischemia
ocular, 196, 199, 488
Ischemia testing, noninvasive, 
preoperative, 46–47, 48
f
Ischemic cardiomyopathy. 
See
 
Ischemic chest pain, 27–29, 28
t
, 378. 
See 
also
 Angina
Ischemic colitis, 490, 609
Ischemic heart disease. 
See also
 Angina, 
pectoris; Coronary heart 
disease; Myocardial ischemia
Ischemic hepatitis/hepatopathy, 728
Ischemic optic neuropathy, 
199
, 868
Islet cell antibodies (ICA), 1220, 1221, 
1221
t
, 1242
Islet cell tumors. 
See also
 Insulinoma
functioning carcinoma, 1264
hypoglycemia and, 
1261–1264
, 1262
t
, 
1263
t
Islet cells, pancreatic
hyperplasia of (noninsulinoma 
pancreatogenous hypoglycemia 
syndrome), 1264
neuroendocrine tumors arising in, 1195
transplantation of, 1241
Isolated 5q loss, 536, 537
Isolated hypogonadotropic hypogonadism, 
1120, 1124
Isoniazid (INH), 292, 292
t
, 293, 293
t
t
for chemotherapy toxicity, 1679
for MAC infections, 1487
t
, 292
t
, 1583
t
, 
1584
t
, 1599, 
1599–1600
, 1600
pyridoxine (vitamin B
6
) and, 293, 
294, 1284, 1584
t
, 1600
for tuberculosis, 292, 292
t
, 293, 293
t
, 
294–295
in combination agents, 293, 295
in HIV infection/AIDS, 294–295
in latent disease/prophylactic, 
 
294–295
resistance and, 288, 293, 294
Isopropanol, osmolar gap affected by, 919
Isoproterenol, 410, 1594
Isosorbide, 372, 390, 417
f
, 421, 424. 
 
See also
 Nitrates
Isospora belli
 (isosporiasis), 
1530–1533
Isotonic hyponatremia, 899–900, 899
f
Isotretinoin, 123, 135–136, 137, 209
t
Isradipine, 471, 473
t
, 1594
Itching. 
See
 Pruritus

See also
 Nitrates
1530–1533
f
t
t
, 1594
Itching. 
See
 Pruritus
Itchy red bump syndrome (eosinophilic 
folliculitis), 137, 138, 1341
Itraconazole, 1562
t
Jod-Basedow disease/phenomenon and, 
1140–1141
radioactive. 
See
 Radioactive iodine; 
Radioiodine thyroid scans and 
uptake
Iodine-123 MIBG scanning, 1192
Iodine-131 MIBG therapy, 1194
Iodized salt, goiter and, 1160
Iodochlorhydroxyquin, 209
t
Iodoquinol, 1529, 1530
t
Ionizing radiation, 1574. 
See also
 
under 
Radiation
Iontophoresis sweat test, 276
Iopanoic acid, 1144–1146, 1146, 1147
Ipilimumab, 1620
t
thyroid disease caused by, 1134, 1140
iPledge, 135
Ipodate sodium. 1144–1145, 1146, 1147, 
1148
Ipratropium
for allergic/vasomotor rhinitis, 230
for asthma, 263, 263
t
, 266
f
for COPD, 271, 272–273
t
Irbesartan/irbesartan-HCTZ, 468
t
Iridodialysis, 205
Iridotomy/iridectomy, 187, 187
f
, 189
Irinotecan, 1619
t
IRIS (immune reconstitution 
inflammatory syndromes), 
199, 1355–1356
1407, 1408
Iritis (anterior uveitis), 176
t
, 189, 190
Iron
accumulation of, in hemochromatosis, 
723–724
conjunctival/corneal foreign body of, 
203
deficiency of/iron deficiency anemia, 
510–513
, 511
t
anemia of inflammation and, 513
celiac disease and, 510, 511, 645
chronic disease/chronic kidney 
disease and, 940, 941
esophageal webs and (Plummer-
GI bleeding and, 511
in idiopathic pulmonary 
hemosiderosis, 316
during pregnancy, 510, 814–815, 
 
829
nutritional support requirements and, 
1290
t
, 1587
t
. 
See 
also
 Hemosiderosis
supplementary, 510, 512, 812, 814–815, 
829
See
 Iron, 
Iron overload. 
See also
 Hemochromatosis; 
dysmetabolic, 713
Iron-refractory iron deficiency anemia, 
511
Iron-restricted erythropoiesis, 513
CMDT2019_Index_p1743-1884.indd   1817

INDEX1818
 
CMDT 2019
metastatic disease of, 
1668
NSAIDs affecting, 843
in phosphate regulation, 912–913
polycystic, 
962–963
, 962
t
, 963
f
t
toxic drug effects on. 
See
 Nephrotoxicity
transplantation of. 
See
 Kidney 
Kidney disease/injury, 
926–965
, 945, 945
f
, 
946–954
, 946
t
, 948
f
. 
See also
 
under Renal and
 Nephritis; 
acid-base disorders in, 906
t
, 939
f
. 
See 
also
acute, 926, 
929–936
, 930
t
. 
See also
 
Acute kidney injury; Renal 
failure
923
aminoglycosides and, 932
in amyloidosis, 550, 947
t
assessment of, 
926–929
, 927
t
, 928
t
biopsy in, 
929
. 
See also
 
and
 Renal biopsy
cardiovascular disorders and, 936, 938–
939, 938
t
chronic, 
936–945
, 937
t
, 938
f
, 938
t
, 939
f
, 
940
f
. 
See also
disease
616, 717–718
cystic, 937
t
, 
961–964
, 962
t
. 
See also
 
Renal cysts
t
diabetes insipidus and. 
See
 Diabetes 
insipidus, nephrogenic
diabetes mellitus and, 941, 942, 947
t
, 
954, 955, 
957–958
, 1245
t
, 
1247, 1247–1248. 
See also
 
t
, 948
f
, 951
GFR in, 927–928
glomerular, 937
t
, 
945–955
, 945
f
, 946
t
, 
947
t
, 948
f
glucagon-like peptide 1 (GLP-1) 
receptor agonist use and, 
 
1235
in gout, 844, 
964–965
t
, 948
f
, 950, 951
hantaviruses causing (hemorrhagic fever 
with renal syndrome), 
 
1415–1416
hematuria in, 927, 945, 945
f
, 947, 949
Henoch-Schönlein purpura and, 875, 
946
t
, 
950
t
, 952, 
953
in HIV infection/AIDS, 947
t
, 
958–959
t
, 939
f
, 
1164, 1165
hypercalciuria and, 976
t
, 920, 922, 
938
t
, 939
f
, 941
hyperphosphatemia in, 914, 930, 939
f
Keratic precipitates, 190
Keratinocyte grafts, for burns, 1572
Keratitis. 
See also
 Cornea, ulcers of
chemical, 
205–206
, 1589
contact lens wear and, 174
exposure, 185
herpetic, 
185
185–186
. 
See also
 
specific 
type and causative agent
neurotrophic, 185
in onchocerciasis, 1548
ultraviolet (actinic), 
205
Keratoconjunctivitis. 
See also
 
atopic, 178
chlamydial, 177
epidemic, 176, 1434
sicca (dry eye), 
177–178
vernal, 178
Keratoderma blennorrhagicum, 880
Keratolytic agents, for wart removal, 149
Keratomalacia, in vitamin A deficiency, 
1285
Keratopathy, band, 1165
Keratoses
actinic, 
125
, 152
seborrheic, 
111
, 112
f
Kernig sign, 1470
Ketamine, 42, 100, 711, 1094
Ketoacidemia, in diabetic ketoacidosis, 
1256
Ketoacidosis
alcoholic, 919
diabetic, 919, 1223, 
1254–1258
, 1255
t
. 
See also
 Diabetic ketoacidosis
Ketoconazole, 107
t
, 1562
t
for candidiasis, 237, 1353
for Cushing syndrome, 1187
for prostate cancer, 1662, 1662
t
Ketones/ketone bodies/ketonemia/
ketonuria
t
1224, 1257–1258
Ketoprofen, 87
t
Ketorolac, 82, 87
t
, 182
t
Ketosis, in diabetes, 1220. 
See also
 Diabetic 
17-Ketosteroid reductase deficiency, 1200
Ketotifen, 182
t
Ki-67
in breast cancer, 762
in gastroenteropancreatic NETs, 1197
Kidney. 
See also
 
under Renal
biopsy of, 
929
. 
See also
 
and
calculus formation in. 
See
 
Nephrolithiasis; Urinary stone 
disease
cancer/tumors of, 961, 1612
t
, 1614
t
, 
1667–1668
cystic diseases of. 
See
 Renal cysts
926–965
. 
See also
 Kidney 
disease/injury
in gout, 844, 964–965
See

disease
t
, 1614
t
, 
1667–1668
See
926–965
. 
See also
 Kidney 
See
 Pyelonephritis
medullary cystic, 962
t
medullary sponge, 962
t
, 
963–964
Joints
Charcot. 
See
 Charcot joint
in decompression sickness, 1576
disorders/inflammation of. 
See also
 
degenerative/crystal-induced, 
840–
848
, 842
f
, 844
t
, 845
f
. 
See also
 
Arthritis; Osteoarthritis
881–884
palindromic, 
889–890
pattern of, 840, 841
t
in rheumatoid arthritis, 848–849, 
849
f
t
, 854
replacement of. 
See also
 
specific joint
infection and, 882, 1457–1458
for osteoarthritis, 843, 1708, 1719
thromboembolism prophylaxis and, 
1708
tuberculosis of, 
886–887
Jones criteria, 435, 436
t
Juluca (dolutegravir and rilpivirine), 1367
t
, 
1368, 1371. 
See also
 
Junctional nevi, 110
Juvenile polyposis, familial, 681
K-ras/KRAS
colorectal cancer and, 678, 1649, 1651, 
1652
gallbladder cancer and, 1634
and, 1637
K103N
 mutation, antiretroviral resistance 
and, 1373
Kala azar. 
See
Kallmann syndrome, 1119, 1120, 1200, 
1209
Kaolin pneumoconiosis, 318
t
Kaposi sarcoma, 
154–155
, 1340–1341, 
1346
t
, 1354
chemotherapy for, 154, 1346
t
cutaneous, 
154–155
, 1354
ear involvement in, 224
in HIV infection/AIDS, 154–155, 1340–
1341, 1346
t
, 1354
intestinal/visceral, 154, 1354, 1648
oral, 1350
pulmonary, 154, 1347
virus causing, 154, 1341, 
1391
Kaposi sarcoma-associated herpes virus 
(human herpesvirus 8), 154, 
1341, 
1391
Kaposi sarcoma–immune reconstitution 
inflammatory syndrome, 154, 
1354
Kasabach-Merritt syndrome, 730
Katayama syndrome, 1535
Kato-Katz test
for schistosomiasis, 1535–1536
Kattan nomogram, 1663
Kava, toxicity of, 1597
t
Kawasaki disease, 1382
t
, 
1445–1447
Kawasaki shock syndrome, 1446
Kayser-Fleischer ring, 725, 725
f
Kegel exercises, 66, 67, 685, 792
Kennedy syndrome, 1046
Kenya tick typhus, 1437
t
CMDT2019_Index_p1743-1884.indd   1818

INDEX1819
 
CMDT 2019
Lacrimal sac infection (dacryocystitis), 
175–176
LaCrosse encephalitis, 1401
Lactam antibiotics. 
See
 Beta-lactam 
Lactase deficiency, 
649–650
. 
See also
 
Lactose (milk) intolerance
Lactase enzyme replacement, 650
Lactate. 
See
 Lactic acid
Lactate dehydrogenase (LD/LDH)
pleural fluid, 322, 325
in 
in shock liver/cardiogenic liver injury, 
728
Lactation/breastfeeding, 
815
antituberculosis drug therapy during, 
294, 836
breast cancer and, 761
drug/medication avoidance and, 
815
, 
816
t
. 
See also
 
HIV infection/AIDS transmission and, 
1340
iron requirements/supplementation 
during, 510
lithium use and, 1098
mastitis/abscess and, 140, 753, 828
progestin minipill and, 803
radioactive iodine/radioisotope imaging 
and, 1143
suppression of, 
815
thyroid medication and, 1147
Lactic acid (lactate), 919, 1260, 1261. 
 
See also
 Lactic acidosis
Lactic acidosis, 919, 1255
t
, 
1260–1261
antiretroviral drugs causing, 919, 1351
diabetic coma and, 1255
t
in diabetic ketoacidosis, 919
metformin causing, 941, 1233, 1260, 
1599
Lactose-free diet, 598, 650
Lactose (milk) intolerance, 598, 603, 644
t
, 
649–650
, 1287
Lactulose
for constipation, 596, 597
t
, 658
for hepatic encephalopathy, 627, 718
Lacunar infarction, 
1006–1007
, 1007
t
. 
See 
also
 Stroke
LAIV influenza vaccine, 1329
t
, 1335
t
, 
1424
Lambert-Eaton myasthenic syndrome, 
1022, 
1059
Lamivudine (3TC), 1363
t
See 
also
t
, 
1373
t
. 
See also
 Epzicom; 
for hepatitis B, 702, 1351, 1366
resistance to, 702
with zidovudine, 1366
Lamotrigine, 834, 994, 995
t
, 1099, 1592
LAMP (loop-mediated isothermal 
amplification) tests
in filariasis, 1547
in malaria, 1517
in trypanosomiasis, 1511
Klinefelter syndrome, 982, 1200, 1201, 
1205, 
1686–1687
Knee, 
1709–1719
, 1710
t
, 1711–1714
f
arthritis of, 881, 1709, 
1718–1719
bursae/bursitis of, 1705
889
meniscal injuries and, 1713–1714
t
, 
1716–1717
Knee/patellofemoral pain, 
1709–1710
, 
1710
t
, 
1717–1718
Knee realignment surgery, 1719
Knee replacement, 843, 1719
in lichen planus, 153
in psoriasis, 115
KOH preparation, 119, 119
f
Koplik spots, 1392, 1392
f
, 1393
Korsakoff psychosis/syndrome, 
1040
, 
1107, 1108, 1282
Krukenberg tumor, 1642
Kübler-Ross, 79
Kugelberg-Welander syndrome, 1046
Kupffer cells, in cirrhosis, 715
Kuru, 1406
Kussmaul respirations, 24, 921
in pericarditis, 441
Kwashiorkor/kwashiorkor-like secondary 
protein-energy malnutrition, 
1276–1277
Kyphoplasty, in osteoporosis, 1174
Kyphosis, 1698
l
-carnitine, for valproic acid overdose/
t
La belle indifférence, 1071
La/SSB antibody, 854
t
t
t
, 865
Labetalol, 463
t
, 480, 480
t
, 481
t
, 482, 
 
496–497
in aortic dissection, 496–497
and, 1193
pregnancy and, 446, 824, 832
Labor and delivery
in acute fatty liver of pregnancy, 838
for cardiac patient, 448, 833
for diabetic patient, 1254
for HIV-positive patient, 836, 1340, 1358
induction after 41 weeks and, 814
in preeclampsia-eclampsia, 824
preparation classes for, 813
preterm, 813, 814, 
825–827
Laboratory tests. 
See
 Diagnostic/laboratory 
tests
Labral tears, 1695
Labyrinthine concussion, 223
Labyrinthine decompression sickness, 1576
Labyrinthitis, 222
Lacerations
t
ocular, 
205
scalp, 1044
Lachman test, 1710, 1711
t
Lac-Hydrin, 108
t
Lacosamide, 995
t
Lacrimal apparatus, disorders of, 
174–175
480
t
, 937, 938–939, 938
t
, 939
f
hyperuricemia and, 844, 933, 938
t
, 
 
964–965, 1673

t
t
174–175
480
t
t
, 939
f
t
, 
 
hypomagnesemia treatment and, 916
infection. 
See
t
, 931
lithium use and, 1098, 1601
mercury causing, 960, 1602
methotrexate and, 851, 1679
multisystem diseases and, 
964–965
in myeloma, 546, 547, 548, 
964
myoglobinuria/rhabdomyolysis and, 
866, 932–933
nephritic spectrum, 945, 945
f
, 
946–954
, 
946
t
, 948
f
nephrotic spectrum. 
See also
 Nephrotic 
syndrome
glomerular, 945, 945
f
, 947
t
, 
954–955
in primary renal disorders, 
955–957
from systemic disorders, 
957–959
941
NSAIDs causing, 843
and, 
54
, 54
t
t
proteinuria in, 926, 926–927, 945, 945
f
, 
954, 955, 957
proton pump inhibitors causing, 622, 
637
pruritus and, 155
in scleroderma, 860, 861
sickle cell syndromes and, 522, 
964
in SLE, 853
t
, 854, 855, 946
t
, 
953–954
in spontaneous bacterial peritonitis, 615
toxic drug effects and. 
See
 
Nephrotoxicity
in tuberculosis, 964
tubulointerstitial, 937
t
, 
959–961
, 959
t
urinalysis in, 926
Kidney stones. 
See
 Nephrolithiasis; 
Urinary stone disease
Kidney transplantation, 943
hypercalcemia after, 1164
for IgA nephropathy, 950
infections after, 1297
pancreas transplantation and, 1241
Kiesselbach plexus, 231
Kikuchi disease, 250
Killed vaccines, 1325
Killip classification, 383
Kimmelstiel-Wilson nodules, 958
Kinase inhibitors. 
See
 Tyrosine kinase 
Kindling, 1105, 1113
Kingella
 species. 
See
KIT
 mutations, 1646
Klatskin tumors, 1634, 1635
Klebsiella/Klebsiella pneumoniae,
 1318
t
, 
1321
t
, 1322
t
1321
t
t
, 283
urinary tract infection/pyelonephritis 
caused by, 969, 1321
t
, 1322
t
Kleine-Levin syndrome, 1103
CMDT2019_Index_p1743-1884.indd   1819

INDEX1820
 
CMDT 2019
Leiomyosarcoma
gastrointestinal, 1648. 
See also
 
Gastrointestinal mesenchymal 
tumor
of uterus, 787
Leishmania
 (leishmaniasis), 
1513–1515
, 
1514
f
recidivans, 1514
Leishmanin skin test, 1514
Lemierre syndrome, 241, 1449, 1483
Lenalidomide, 123, 533, 534, 537, 548, 
1619
t
Lens opacity. 
See
 Cataract
Lentigines, 
111
, 167
Lentigo maligna melanoma, 112
Lenvatinib, 1156, 1621
t
Lepromatous leprosy, 1050, 1489, 1490. 
See also
 Leprosy
Lepromin skin test, 1489
Leprosy (Hansen disease), 1050, 1319
t
, 
1489–1490
Leptin/leptin receptor, 1278
Leptomeningeal metastases 
(carcinomatous meningitis), 
1019, 1305
Leptospira/Leptospira interrogans
 
(leptospirosis), 1304, 1319
t
, 
1504–1505
Lesbian and bisexual women, 
1722–1732
activity/body weight issues and, 1725, 
1726
cancer risk/prevention/treatment and, 
1728–1729
cardiovascular disease/prevention and, 
1725
differences among sexual orientation/
identity/behavior and, 1724
family planning and, 1731–1732
health disparities and, 1724–1725
identification of sexual orientation and, 
1723–1724
learning patients’ sexual orientation 
and, 1722–1723
mental health and, 1730–1731
pulmonary disease prevention and, 
1726–1727
smoking hazards/cessation efforts and, 
1725–1726, 1728
STI prevention and, 1727–1728
substance use prevention and, 1728
violence and, 1725, 1729–1730
Lesbian, gay, bisexual, and transgender 
(LGBTQ) health issues, 
 
1722–1742
. 
See also
 Gay and 
bisexual men/MSM; Lesbian 
and bisexual women; 
Lesinurad, 847
Letermovir, 1299, 1390
Lethal midline granuloma, 234
Letrozole, 766–767, 769, 769
t
, 770, 791, 
799, 1623
t
Leucovorin (folinic acid)
t
, 1679
t
Leukemias, 
529–543
, 529
t
, 530
t
, 1612
t
. 
 
See also
 
acute, 
538–540
, 1612
t
. 
See also
 
specific 
type
adult T cell (ATL), 1408, 1409
aleukemic, 539
Lavage, gastric, for poisoning/drug 
Laxative abuse, 603, 1114
Laxatives, 73, 596–598, 597
t
, 658
LCHAD deficiency, acute fatty liver of 
pregnancy and, 838
LDLR
Lead encephalopathy, 1114, 1600
Lead nephropathy, 960, 961
Lead poisoning, 1114, 1584
t
, 
1600–1601
gout and, 845
961
LECT2 amyloidosis, 550
Ledipasvir, 698, 704
t
, 705, 837, 1351
LEEP (loop electrosurgical excision 
procedure), 785
Leflunomide, 851
Left ventricular aneurysm, 391, 446
Left ventricular (LV) apical ballooning 
syndrome. 
See
 Stress 
Left ventricular assist devices. 
See
 
Ventricular assist devices
Left ventricular ejection fraction
in aortic regurgitation, 359
t
, 354
in cardiomyopathy, 428, 429, 433
f
, 434
in heart failure
preserved, 416, 423
reduced, 416–422, 417
f
, 418
t
f
Left ventricular end-diastolic pressure, in 
dyspnea, 24, 24
t
Left ventricular (left heart) failure/
dysfunction, 414, 415. 
See also
 
Heart (cardiac) failure
myocardial infarction and, 390
and, 48–49
313, 443, 443
t
Left ventricular hypertrophy
aortic dissection and, 496
aortic stenosis and, 354
in athletes, 431, 449
t
, 431, 432. 
See 
also
 Cardiomyopathy
hypertensive, 456
Leg. 
See also
 
under Lower extremity
acute arterial occlusion of, 487–488
Leg ulcers
in polyarteritis nodosa, 870
in venous insufficiency/varicose veins/
lower extremity occlusive 
disease, 33, 34, 
164–166
, 165
f
, 
500, 501
Legal issues, in end-of-life care, 79
Legionella/Legionella pneumophila,
 278
t
, 
1319
t
, 1321
t
, 1322
t
, 1472–1473
Legionnaires disease (legionella 
pneumonia/legionellosis), 
278
t
, 1319
t
, 1321
t
, 1322
t
, 
1472–1473
Leiden mutation
t
Leiomyoma-renal cell carcinoma, 1667
Leiomyomas
gastrointestinal, 1646

t
, 
1472–1473
t
of uterus (fibroid tumor), 
787–788
Laninamivir, 1424
Lanreotide, 1127, 1196
Lansoprazole, 608, 621, 631, 633, 637, 639. 
See also
Lanthanum, for hyperphosphatemia, 914, 
940
Lapatinib, 770, 1621
t
, 1643
Large cell carcinoma of lung, 1624. 
 
See also
 Lung cancer
Large-needle (core needle) biopsy, for 
breast lump evaluation, 750, 
758, 759–760, 759
f
, 760
f
. 
See 
also
 Breast, biopsy of
Large-volume paracentesis. 
See
 
Large-volume thoracentesis. 
See
 
Laron syndrome/dwarfism, 1120
Laropiprant, 1274
Larva migrans
1545–1546
, 1545
f
ocular, 1545
visceral, 1545
Laryngeal carcinoma, 246, 
246–247
Laryngeal leukoplakia, 
246
Laryngeal nerve, recurrent
thyroid surgery and, 247, 1145–1146, 
1154–1155
vocal fold paralysis and, 247
Laryngeal papillomas, 244
Laryngectomy, 246, 247
Laryngitis, 
243–244
Laryngopharyngeal reflux, 
244
. 
See also
 
Gastroesophageal reflux 
disease
Laryngotracheitis, human parainfluenza 
virus causing, 1421
Larynx, 
243–248
. 
See also
 
under Laryngeal
masses of, 
245–247
papillomas of, 244
Laser-induced prostatectomy, 
transurethral (TULIP), 988
for benign prostatic hyperplasia, 985
f
, 
988
for glaucoma, 189
for hirsutism, 1207
for refractive errors, 174
acuminata, 149–150
Lasmiditan, for migraine headache, 42
Lassa fever, 1412, 1413
Latanoprost/latanoprost combinations, 
184
t
Late-onset preeclampsia-eclampsia, 824
Latent autoimmune diabetes mellitus of 
adulthood (LADA), 1221
Lateral collateral ligament, 1709, 1712
t
, 
1715
Lateral epicondylosis, 
1703–1704
Lateral femoral cutaneous nerve lesions 
(meralgia paresthetica), 
1053
Lateral medullary syndrome, 1008
Lateral meniscus, 1709, 1713–1714
t
, 
 
1716–1717
Lateral sclerosis, amyotrophic/primary, 
1046
 antivenom, 1608
Latrodectus mactans
 (black widow spider), 
159, 1608
CMDT2019_Index_p1743-1884.indd   1820

INDEX1821
 
CMDT 2019
in nonalcoholic fatty liver disease 
management, 713
in obesity prevention/management, 
13
pain behavior and, 1074
in peripheral arterial disease 
management, 483–484
sedentary
obesity and, 13, 1278
1726
operative cardiac risk and, 46
t
, 
11–12
Lifitegrast, 177
Lift-off test, 1693
t
, 1694
Light, pupillary reaction to. 
See
 Pupillary 
reactions
Light chains
in amyloidosis, 550, 551
in urine. 
See
 Bence Jones proteinuria
Light eruption, polymorphous (PMLE), 
163, 164
Light therapy. 
See
 Phototherapy
Lightning injuries, 1573
Ligneous (Riedel) thyroiditis, 1132, 
 
1133–1134
Liletta IUD, 804
Lille model/score, 710
Lily-of-the-valley, toxicity of, 1597
Limb. 
See
 Extremities
Limb-girdle (Erb) muscular dystrophy, 
863, 1060, 1061
t
Limb loss. 
See
 Amputation
Limbic encephalitis, 1021
Linaclotide, 597, 597
t
, 658
Linagliptin, 1231
t
Linear scleroderma, 860
Linezolid, 208
t
, 279
t
, 285
t
, 1452, 1455
Linitis plastica, 1642
Linoleic acid, in nutritional support, 1290
Liothyronine. 
See also
 Thyroid hormone
antidepressant drug augmentation and, 
1090
for myxedema coma, 1137
Lipase
in pancreatic enzyme supplements, 747, 
748
t
Lipedema, 500
Lipemia retinalis, 1224, 1269
Lipid-based amphotericin B, 1561, 1561
t
for candidal endocarditis, 1551
Lipid disorders/lipids, 
10
, 
1267–1275
. 
 
See also
 Fat; Lipoproteins
t
antiretroviral therapy and, 1062, 1186, 
1355, 1369
and, 6
t
, 10, 365, 1267–1268, 
1269–1270
cholesterol lowering and, 365, 366
f
, 
t
, 1268, 
 
1270–1275
, 1272
t
, 1273
t
. 
See 
also
clinical presentations in, 
1269
for hypothyroidism/myxedema, 
 
1122–1123, 1137–1138
myxedema crisis and, 1137
during pregnancy, 830, 1137, 1138
in thyroiditis, 1133
for thyroid cancer, 1155, 1156, 1157
thyroid nodule evaluation/treatment 
and, 1150
t
, 1151
after thyroidectomy, 1155
with triiodothyronine, 1137, 1138
Lewy body dementia, 57, 1032
t
, 1034. 
See 
also
 Dementia
Leydig cells/Leydig cell tumors/
hyperandrogenism in women caused by, 
1206
male hypogonadism and, 1200
LGBTQ health issues, 
1722–1742
. 
See also
 
Gay and bisexual men/MSM; 
Lesbian and bisexual women; 
Libido, loss of, 978, 1076. 
See also
 Sexual 
1094
in female, 796, 797, 1076
Libman-Sacks endocarditis, 854
Lice, 
158–159
relapsing fever transmission and, 1503
trench fever transmission and, 1483
typhus transmission and, 1436–1438, 
1437
t
Lichen planus, 
153–154
oral, 153, 234, 
235
vulvovaginal, 153
Lichen planus-like drug eruptions, 153, 
172
t
Lichen sclerosus, vulvar, 789, 797
Lichenoid drug eruptions, 153, 172
t
Lichtheimia (Absidia)
1558–1559
Licorice, hypertension/aldosteronism and, 
1189
Lid. 
See
 Eyelids
Liddle syndrome, 454, 906
t
Lidocaine/lidocaine patch
for arrhythmias, 389, 393, 394
t
t
, 100, 1249
Life expectancy
Alzheimer disease/dementia and, 60
assessment/prognosis of older adult 
and, 55, 56
f
, 56
t
, 57
t
prognosis at end of life and, 74
Life support
basic, in drowning, 1570
withdrawal/withholding, in end-of-life 
care, 76
Lifestyle
colorectal cancer risk and, 1650
modifications of
adherence and, 1
in constipation management, 596
in hypertension management, 10, 
457–458, 457
t
in incontinence management, 66–67
in menopausal symptom 
management, 809
aplastic anemia differentiated from, 527
chronic, 530
t
, 
534–536
, 
540–542
, 1612
t
. 
See also
 
t
t
, 
534–536
, 
540–542
, 1612
t
. 
See also
 
1430
hairy cell, 527, 
542–543
, 889, 1613
t
infection in, 539
rheumatologic manifestations of, 889
stem cell transplants for, 539, 540, 542
Leukemic arthritis, 889
Leukoagglutinin transfusion reactions, 
552, 553
Leukocyte count. 
See
 White blood cell 
count
Leukocyte-poor blood, 552, 553, 554. 
See 
also
Leukocytoclastic vasculitis, 889
Leukoencephalopathy, progressive 
multifocal. 
See
 Progressive 
multifocal 
leukoencephalopathy
Leukoplakia
hairy, 235, 235
f
, 1350
laryngeal, 
246
oral, 234–235, 
234
, 234
f
, 235
f
, 1350
Leukoreduced blood, 552, 553, 554. 
See 
also
Leukotriene modifiers
f
, 261
t
, 263–264
Leuprolide, 1623
t
for breast cancer, 769, 769
t
for infertility, 1123
t
Levalbuterol, 259, 262
t
Levamisole-associated purpura, 
874
Levetiracetam, 834, 995
t
, 996
t
, 1592
Levobunolol, 183
t
Levocabastine, 181
t
Levodopa (levodopa-carbidopa/
 
levodopa-carbidopa-
entacapone), 1025–1026, 
1026, 1027, 1069
t
, 1095
t
Levofloxacin, 1321
t
, 1322
t
. 
See also
 
for diarrhea, 602, 1316, 1476
for ophthalmic disorders, 180
t
t
, 281, 282, 285
t
, 
1321
t
for sinusitis in HIV infection/AIDS, 
1347
for typhoid fever, 1475
t
, 1321
t
Levoleucovorin rescue, 851, 1675
t
Levomilnacipran, 1090–1093, 1091
t
Levonorgestrel, 800, 801
t
, 806, 809, 1214
Levonorgestrel/progestin-releasing IUD 
(levonorgestrel intrauterine 
system), 804
777, 778
for endometriosis/pelvic pain, 780, 790
in estrogen replacement therapy, 1211, 
1215
Levorphanol, 92
t
Levothyroxine (thyroxine)
CMDT2019_Index_p1743-1884.indd   1821

INDEX1822
 
CMDT 2019
nonalcoholic fatty liver disease and, 
714, 1631
and, 722
cavernous hemangioma of, 730
691–731
. 
See also
 
specific 
disorder and under Hepatic
acute liver failure. 
See
 Liver (hepatic) 
failure
alcoholic, 
708–710
amebic abscess, 1528, 1529, 
 
t
ascites in, 612, 612–613, 613, 613
t
, 
614–616, 716–717, 720, 720
t
cirrhosis, 
714–721
in CMV infection, 1389
coagulopathy, 
572–573
, 699, 719
drug- and toxin-induced, 699, 700, 
710–712
. 
See also
 
Hepatotoxicity
606, 626–629
in fascioliasis, 1536–1537
in heart failure, 
728
hemochromatosis, 
723–725
hepatic vein obstruction (Budd-
Chiari syndrome), 
726–728
hepatitis. 
See
 Hepatitis
1328
t
, 1331
t
jaundice in, 
688–691
, 689
t
, 690
t
, 737
1604
neoplastic. 
See also
 Liver, cancer of
benign tumors, 
730–731
oral contraceptive use and, 731, 
802
nonalcoholic fatty liver disease, 690, 
712–714
, 1631. 
See also
 Fatty 
liver
noncirrhotic portal hypertension, 
728–729
1293
t
and, 
50–51
t
837–839
primary biliary cholangitis (biliary 
721–723
pyogenic abscess, 
729–730
statins causing, 1272
syphilis and, 1499
Wilson disease (hepatolenticular 
degeneration), 
725–726
, 725
f
fatty. 
See
fibrosis of. 
See
 Hepatic fibrosis
focal nodular hyperplasia of, 731
hydatid cyst of, 1540
nodular regenerative hyperplasia of, 
728–729
nutmeg, 728
passive congestion of, 613
t
, 728
shock, 728
transplantation of, 719–720. 
See also
 
specific disease and
 
Transplantation
for acute liver failure, 700, 701
1212, 1213
lowering. 
See
screening tests for levels of, 6
t
Liposomal amphotericin B, 1561, 1561
t
. 
See also
 Lipid-based 
amphotericin B
t
, 1557
5-Lipoxygenase inhibitor, 261
t
, 264
Liquid artificial nutrition (tube feedings). 
See
 Enteral nutritional 
support
Liquid diets, clear and full, 1286
Liquid nitrogen. 
See also
 Cryotherapy
for actinic keratoses, 125
Liraglutide, 713, 1231
t
, 1235, 1237, 1244, 
1245, 1279. 
See also
 
Lisinopril/lisinopril-HCTZ, 418
t
, 419, 
467
t
, 816
t
 (listeriosis), 1319
t
, 
1321
t
, 
1463–1464
diarrhea/food poisoning caused by, 
599
t
, 600, 1463
meningitis caused by, 1306, 1321
t
, 
1463–1464
Literacy (health), adherence and, 1
LITH
 gene, 732
Lithium, 1097–1099, 1099
t
antidepressant drug augmentation/
interaction and, 1090, 1095
t
for cluster headache prophylaxis, 993
t
, 1098–1099, 
1099
t
t
, 1098, 1583
t
, 
1585
t
, 1587
t
, 
1601
pregnancy/breastfeeding and, 816
t
, 1098
thyroid disorders and, 1098, 1145
Lithium-induced delirium, 1098
Lithotripsy
for cholelithiasis, 733
for urinary stone disease, 977–978, 978
Live attenuated influenza vaccine (LAIV), 
1329
t
, 1335
t
, 1424
Live attenuated vaccines, 1325, 1361
Livedo reticularis/livedo racemosa, 857, 
870, 
877
Liver
anesthesia/surgery affecting function of, 
50–51
biopsy of, 691
in alcoholic liver disease, 709
Chiari syndrome), 727
in nonalcoholic fatty liver disease, 713
in primary sclerosing cholangitis, 739
t
, 1616
t
, 
1631–1634

t
, 1616
t
, 
1631–1634
hepatitis/hepatitis vaccine and, 694, 
696, 698, 702, 703, 706, 1631, 
1632
Lipid disorders/lipids (
Cont
.):
t
1741
t
957
polycystic ovary syndrome and, 795
screening/treatment for, 6
t
, 
10
, 365, 
366
f
t
, 1267–
1268. 
See also
therapy
secondary conditions and, 
1268–1269
triglycerides and, 1267, 1269
Lipid emulsion, intravenous. 
See
 
Lipid fractions, coronary heart disease risk 
and, 6
t
, 10, 365, 
1267–1268
. 
See also
 Lipoproteins
Lipid-lowering therapy, 1267, 
1268
, 
 
1270–1275
, 1272
t
, 1273
t
, 1684
for cardiovascular/heart disease 
t
, 10, 365, 366
f
, 
t
, 1268, 
 
1270–1275
, 1272
t
, 1273
t
t
, 10, 
 
1269–1270
combination therapy and, 1274
in diabetes, 1251
diet and, 1271, 1287
in familial hypercholesterolemia, 
 
1684
high LDL cholesterol and, 365, 366
f
, 
t
, 1268, 1269, 
1270–1275
, 1272
t
, 1273
t
high triglycerides and, 368, 1272, 1273
t
, 
1275
in nephrotic syndrome, 955
pharmacologic, 
1270–1275
, 1272
t
, 
1273
t
. 
See also
 
and
 Statins
rhabdomyolysis/myopathy/myositis and, 
863, 866
selection of agents for, 1274
therapeutic effects of, 
1268
in women and older patients, 1270
Lipid-modifying diets, 1271, 1287
Lipiduria, 926
Lipoatrophy. 
See
 Lipodystrophy
Lipodermatosclerosis, 33
Lipodystrophy/lipoatrophy
familial partial, type I, 1186
and, 1062, 1186, 1366, 1369
at insulin injection sites, 1240, 1247
Lipohypertrophy, at insulin injection sites, 
1240
Lipoid nephrosis (minimal change 
disease), 947
t
, 
955–956
Lipoid pneumonia, 317
Lipomas
atrial septal, 445
epidermal inclusion cysts and, 162
t
. 
See
 Mites
Lipoproteins. 
See also
 
Cholesterol
coronary heart disease and, 6
t
, 1267–
1268, 1270
in diabetes, 1227
CMDT2019_Index_p1743-1884.indd   1822

INDEX1823
 
CMDT 2019
Low-carbohydrate diet, 1278
Low-cholesterol diet, 1271, 1287
Low-density lipoprotein receptor-related 
protein 4 antibodies, 1058
Low-density lipoproteins/cholesterol 
(LDL), 1267
antiretroviral therapy affecting, 1369
and, 10, 365, 1267, 1269, 
1270, 1683
diet affecting, 1271, 1287
1684
lowering levels of, 365, 366
f
, 367–368, 
367
t
1270–1275
, 
1272
t
, 1273
t
. 
See also
 
screening tests for, 10, 1267, 1269–1270, 
1270
xanthomas and, 1269, 1269
f
Low-fat diet, 1271, 1287
in pancreatitis, 744, 747
Low-protein diet. 
See
 Protein-restricted 
diet
Low-salt diet. 
See
 Sodium-restricted diet
Low-saturated-fat diet, 1271, 1287. 
See also
 
Low-fat diet
Low vision. 
See
Lower airway/respiratory tract disorders, 
252–253
. 
See also
 Pneumonia
asthma differentiated from, 257
smoke inhalation and, 
316
Lower extremity edema, 
32–34
, 33
t
venous insufficiency/leg ulcers and, 33, 
33
t
, 34, 165, 166, 500, 501
Lower GI bleeding, 
609–611
. 
See also
 
Gastrointestinal bleeding
Lower leg/foot arteries
acute occlusion of, 487–488
486–487
leg ulcers and, 33, 34, 
164–166
, 165
f
Lower motor neuron lesions. 
See
 Motor 
neuron diseases
Loxapine, 1081
t
, 1082
t
, 1083
Loxosceles laeta/reclusa
 (loxoscelism/
brown recluse spider), 159, 
1608
LRP4 antibodies, 1058
LSD, 1112, 
1601–1602
Lubiprostone, 73, 597, 597
t
, 658
Lubriderm, 108
t
Ludwig angina, 240, 241
Lues maligna, 1499
Lujo virus, 1412
Lumbar hyperlordosis, 1698
Lumbar plexus/nerve lesions, 
1057–1058
Lumbar puncture, 1306. 
See also
 
Cerebrospinal fluid analysis
in CNS infection/brain abscess, 1305, 
1306
headache and, 42, 993, 994
herniation syndromes and, 1305, 1306
neuroimaging and, 1306
in syphilis, 1497, 1498, 1501
Long QT syndrome, 31, 394
t
, 
412
. 
See also
 
QT interval, long
sudden death of athlete and, 449, 450
t
Long-term care facilities
norovirus infections and, 1433
scabies outbreaks and, 157–158
Loop diuretics. 
See also
 Diuretics; 
adverse effects of, 460, 461
t
in chronic kidney disease, 460, 939, 955
for heart failure, 418, 419
t
t
, 480
t
, 481
t
, 
482
Loop electrosurgical excision procedure 
(LEEP), 785
Loop-mediated isothermal amplification 
tests. 
See
 LAMP 
 
(loop-mediated isothermal 
Loperamide, 602, 605, 1314. 
See also
 
1679
for diabetic diarrhea, 1250
Lopinavir/r (lopinavir/ritonavir), 1358, 
1364
t
, 1370. 
See also
 
Loratadine, 142, 178, 229. 
See also
 
Lorazepam, 1067
t
. 
See also
 
for alcohol withdrawal, 1110, 1111
with antipsychotics, 1083
for anxiety/stress disorders, 1064, 1067–
1068, 1067
t
vomiting, 73, 1678
overdose/toxicity of, 1598
for seizures, 824, 1002, 1583
Lorcaserin, 13, 1244, 1279
Losartan/losartan-HCTZ, 418
t
, 465–471, 
468
t
Loteprednol, 177, 183
t
Louse-borne relapsing fever, 1503
Louse-borne typhus, epidemic, 
 
1436–1438
, 1437
t
Lovastatin, 367
t
, 1268, 1272, 1273
t
. 
 
See also
 Statins

t
, 465–471, 
468
t
t
 
1436–1438
, 1437
t
t
t
. 
 
See also
 Statins
protease inhibitor interactions and, 1369
for thyroid cancer, 1156
Low back pain, 83, 
1697–1699
, 1698
t
. 
See 
also
 Back pain
Low-calorie diets, 1278, 1279
biliary stricture after, 738
cholangiocarcinoma and, 1635
for cirrhosis/alcoholic liver disease, 
710, 713, 719–720, 720–721
esophageal varices and, 628
for hepatic coagulopathy, 572
 
(Budd-Chiari syndrome), 
 
727
for hepatocellular carcinoma, 
 
1633
for hepatopulmonary syndrome/
portopulmonary 
hypertension, 719
for hepatorenal syndrome, 718
in HIV infection/AIDS, 719, 1351
for mushroom poisoning, 1604
for nonalcoholic liver disease, 713
for primary biliary cholangitis, 722
for primary sclerosing cholangitis, 
740, 741
Liver biochemical tests, 
690–691
, 690
t
Liver cell adenoma. 
See
adenoma
Liver (hepatic) failure, 
699–701
, 1234
acetaminophen causing, 699, 700, 1588
didanosine causing, 1368
drugs/toxins causing, 699, 700, 711, 
1272, 1588
fatty liver of pregnancy and, 699, 838
1604
nefazodone causing, 1093
Liver flukes, 
1536–1537
Liver-kidney microsome type 1 antibodies 
(anti-LKM1), 707
Liver-kidney transplantation, for cirrhosis 
with kidney failure, 719–720
Lixisenatide, 1231
t
, 1235. 
See also
 
LKB1/STK11
 mutation, 1636
Loa loa
 (loiasis), 
1548–1549
Lobular carcinoma in situ, 761
t
, 762
Local anesthetics, ophthalmic, precautions 
for use of, 
206
Locked-in syndrome (de-efferented state), 
1042
Lodoxamide, 181
t
Loeys-Dietz syndrome, aortic disorders/
aneurysm in, pregnancy and, 
447
Löffler syndrome, 305
Loiasis, 1549
Lomitapide, 1273
t
Long-acting beta-agonists, 258
f
, 259, 260
t
, 
271
Long-acting insulin, 1238, 1238
t
, 1239. 
See 
also
t
, 
1240, 1242, 1245
Long-acting muscarinic agents, 260
t
, 263, 
271
Long-chain acyl coenzyme A 
dehydrogenase (LCHAD) 
deficiency, acute fatty liver of 
CMDT2019_Index_p1743-1884.indd   1823

INDEX1824
 
CMDT 2019
Luteinizing hormone-releasing hormone 
(LHRH) antagonist, 1623–
1624
t
t
Luteoma of pregnancy, 1206
Lyme disease (Lyme borreliosis), 1050, 
1319
t
, 
1505–1509
, 1508
t
arthritis in, 1506, 1507, 1508
t
, 1509
gonococcal/nongonococcal/
rheumatoid arthritis 
differentiated from, 850, 882, 
883
chronic (post-Lyme disease syndrome), 
1508, 1508
t
, 1509
erythema migrans in, 
144
, 144
f
, 1506, 
1508–1509, 1508
t
facial palsy and, 1054, 1054
f
, 1506, 1507, 
1509
head and neck manifestations of, 
250
myopericarditis in, 437, 1506, 1508
t
, 
1509
neurologic disorders/neuropathy 
associated with, 1050, 1506, 
1507
during pregnancy, 1508, 1509
serologic testing in, 1507–1508
Lyme urinary antigen test, 1507
Lymph nodes. 
See
 
specific nodes and
 
Lymphadenitis; 
Lymphadenectomy, selective (sentinel 
lymph node biopsy), 762, 764, 
764
f
, 768
Lymphadenitis, 
503–504
. 
See also
 
specific 
cause
histiocytic necrotizing (Kikuchi 
disease), 250
mycobacterial (tuberculous and 
nontuberculous), 
250
, 1487
Lymphadenopathy. 
See also
 
autoimmune, 250
dermatopathic, 124
HIV , 249
reactive cervical, 
250
tick-borne/Dermacentor-borne-
necrosis-erythema-
eschar neck lymphadenopathy, 
1437
t
, 1442
Lymphangitic carcinomatosis, 1629
Lymphangitis, 
503–504
, 1322
t
rickettsiosis associated with, 1437
t
, 1442
Lymphatic channel diseases, 
503–504
Lymphatic filariasis, 
1546–1547
, 1546
f
Lymphedema, 34, 
504
, 504
f
Lymphocytic choriomeningitis, 
 
1405–1406
Lymphocytic hypophysitis, 1119, 1121
Lymphocytic meningitis, benign recurrent 
(Mollaret meningitis), 1378
Lymphocytoma, borrelial, 1506
Lymphocytosis, 541
Lymphoepithelioma, nasopharyngeal, 233
Lymphogranuloma venereum, 684, 
 
1490–1491
Lymphohistiocytosis, hemophagocytic, 
1388
metastatic, 1629
myasthenic syndrome and, 1059
non–small cell (NSCLC), 1613
t
, 1624–
1625, 1625, 1627–1628. 
See 
also
 Non–small cell lung 
cancer
occupational exposures and, 
320
palliative therapy for, 1628, 1628–1629
paraneoplastic syndromes associated 
with, 1625
t
, 16, 
297
, 1627
pulmonary function testing in, 
 
1626–1627
SIADH in, 901, 1625
small cell (SCLC), 1614
t
, 1625, 1628, 
1628
t
. 
See also
 Small cell 
carcinoma of lung
smoking/smoking cessation and, 15
t
, 
16, 297, 320, 1611, 1624, 1627
solitary pulmonary nodule and, 297, 
298, 1629, 1630
squamous cell carcinoma, 1624, 1625, 
1626
f
staging of, 1625–1626, 1626
t
superior vena caval obstruction/
syndrome in, 502, 1625
treatment of, 1627–1629
Lung capacity, total (TLC). 
See
 Pulmonary 
Lung flukes 
(Paragonimus),
 1537
Lung injury, acute. 
See
 Acute lung injury
Lung transplantation. 
See also
 
for COPD, 273
Lung volume reduction surgery (LVRS), 
Lung volumes. 
See
 Pulmonary function 
tests
Lupus anticoagulants, 
573
, 855
830, 857
in SLE, 853
t
, 855, 855
t
Lupus cerebritis, 855
autoantibodies in, 123
123–124
, 171
t
systemic. 
See also
 Systemic lupus 
Lupus nephritis, 854, 855, 946
t
, 948
f
, 
 
953–954
Lupus panniculitis, 161
Lupus pernio, 303, 303
f
Lupus profundus, 854
Lurasidone, 1081, 1081
t
t
, 
1084
t
Luteinizing hormone (LH), 1119
in hypogonadism, 1120, 1121, 1199
t
, 
1200, 1201
1206, 1207
(LHRH) analogs, 1623
t
, 1662, 
1662
t
, 1663
Lumbar spine/disk disease
back pain and, 
1697–1699
, 1698
t
, 
1700–1701
disk herniation,

1206, 1207
t
, 1662, 
1662
t
, 1663
1697–1699
, 1698
t
, 
1700–1701
disk herniation, 
1700–1701
spinal stenosis, 
1699–1700
Lumbosacral plexus/nerve lesions, 
 
1057–1058
Lumbosacral spine disease. 
See also
 
anogenital pruritus in, 156
neurologic testing in, 1698, 1698
t
Lumefantrine-artemether (Coartem/
t
, 1519
t
, 1520
t
, 
1522, 1523
Lump (breast), 756, 757. 
See also
 Breast 
cancer
biopsy in evaluation of, 750, 758–760, 
759
f
, 760
f
fat necrosis causing, 752
fibroadenoma, 751
in fibrocystic condition, 750
removal of. 
See
 Lumpectomy
Lumpectomy, 763–764, 764
f
genetic mutations for breast cancer and, 
754
for phyllodes tumor, 751
radiation and, 763, 764
Lung. 
See also
 
under Pulmonary and 
Respiratory
abscess of, 
286–287
aspergilloma of, 1557
cancer of. 
See
collapse of. 
See
 Atelectasis
See
 Pulmonary fibrosis
neuroendocrine tumors of, 1198
radiation injury of, 
320–321
, 1624
toxic/chemical injury of
317
t
, 
320
Lung biopsy
in interstitial lung disease, 301
in mesothelioma, 1630
Lung cancer, 1612
t
, 
1624–1631
adenocarcinoma, 1624, 1629
asbestosis and, 318
bronchogenic carcinoma, 21, 26
t
, 
 
1624–1629
, 1626
f
and, 872
in HIV infection/AIDS, 1347
hypercalcemia and, 1625, 1673
t
, 1624, 
1629
inhaled insulin and, 1241
in situ, 1624
large cell, 1624
mesothelioma, 320, 445, 1614
t
, 
 
1630–1631
CMDT2019_Index_p1743-1884.indd   1824

INDEX1825
 
CMDT 2019
in prostate cancer, 1658
in thyroid cancer, 1154, 1158
Maisonneuve fracture, 1721
Major depressive disorder, 60, 1087–1089. 
See also
Malabsorption, 
644–650
, 644
t
. 
See also
 
specific disorder or cause
diarrhea caused by, 600
t
, 603, 644
t
in HIV infection/AIDS, 1343, 1352
Malar rash
in dermatomyositis, 861–862, 862
f
in SLE, 853
t
, 854
Malaria, 
1515–1524
, 1517
f
cerebral, 1516
congenital, 1516
drug resistance in, 1518, 1519, 1520, 
1520
t
, 1521
non-falciparum, 1518
during pregnancy, 815, 1516, 1524
prevention of, 1523–1524, 1523
t
. 
 
See also
 Antimalarial agents
self-treatment and, 1523
severe, 1516, 1518
t
t
, 1521, 
1522
treatment of, 1518–1523, 1518
t
, 1519
t
, 
1520
t
. 
See also
 Antimalarial 
agents
uncomplicated falciparum, 1518–1519, 
1518
t
, 1519
t
, 1520–1521, 
1520
t
, 1521
vaccine development and, 1523
Malarone (atovaquone-proguanil), 1518
t
, 
1520
t
, 1522, 1523, 1523
t
Malassezia furfur
folliculitis caused by, 137, 138
seborrheic dermatitis caused by, 1353
tinea versicolor caused by, 122
Malathion lotion, for pediculosis, 158
Malathion poisoning, 1605
Male breast
774–775
1204–1205
, 
1204
t
. 
See also
 Gynecomastia
Male pattern (androgenetic) alopecia, 168
Malignancy-related DIC, 564
Malignant ascites, 613, 613
t
, 
616
, 1672
Malignant catatonia, 35
Malignant effusions, 323, 323–324, 324
t
, 
1671–1672
. 
See also
 
specific 
type
Malignant external otitis, 
212–213
, 212
f
Malignant hypertension, 479. 
See also
 
Malignant hyperthermia, 35, 1301–1302, 
1584
Malignant melanoma. 
See
 Melanoma
Malignant pleural mesothelioma, 
 
1630–1631
Mallory hyalin, 709, 712
Mallory/Mallory-Denk bodies, 709
Mallory-Weiss syndrome/tears, 593, 606, 
608, 
624
Malnutrition. 
See also
disorders
neuropathy associated with, 1049
protein-energy, 
1276–1277
Malocclusion (dental), facial pain and, 
 
997
Macrolides. 
See also
 
specific agent and
 
t
, 281
pneumonia resistant to, 281
Macrophage activation syndrome, 853
Macroprolactin/macroprolactinemia/
macroprolactinoma, 1128, 
1129, 1130
Macropsia, 1016
Macular degeneration, age-related, 
 
193–194
Maculopathy/macular edema
age-related, 
193–194
diabetic, 197
Mad cow disease (vCJD/bovine 
spongiform encephalopathy), 
1406
Maddrey discriminant function index, 709
MADH4
 gene, 681
Maduromycosis (eumycetoma), 
1560
Magnesium
calcium balance/hypocalcemia and, 910, 
911, 915, 916
910, 1163
for hypomagnesemia, 916, 1163
nutritional support and, 1290
disorders of concentration of, 906
t
, 
915–917
, 915
t
. 
See also
 
Hypermagnesemia; 
normal values for, 915
potassium balance/hypokalemia and, 
905, 915, 916
Magnesium-ammonium-phosphate 
(struvite) urinary stones, 975, 
977
Magnesium/choline magnesium salicylate, 
86
t
, 87
t
Magnesium citrate, 596, 597
t
Magnesium hydroxide, 596, 597
t
Magnesium sulfate, 267, 824, 826, 916
Magnetic resonance angiography (MRA), 
in renal artery stenosis/renal 
vascular hypertension, 
 
944
Magnetic resonance cholangiography, 736, 
739
Magnetic resonance 
(MRCP), 691, 738, 739, 747
Magnetic resonance imaging (MRI). 
 
See also
 
Neuroimaging
in breast cancer evaluation/screening, 
15, 756, 758, 760
cardiac
in angina/chest pain, 371
t
, 429, 434
in liver disorders, 691, 1632
1192
Lymphoma, 
543–552
, 543
t
, 1612
t
, 1613
t
. 
See also
 Burkitt lymphoma;

1192
Lymphoma, 
543–552
, 543
t
, 1612
t
, 1613
t
. 
See also
 Burkitt lymphoma; 
Hodgkin lymphoma; 
 
Non-Hodgkin lymphoma
aggressive, 544–545
B-cell. 
See
 B-cell lymphoma
of breast, implants and, 753
classification of, 543, 543
t
and, 896
cutaneous T-cell (mycosis fungoides), 
124
, 125
“double-hit, ” 544
Epstein-Barr virus infection and, 1387, 
1388
follicular, 543, 544
1644–1645
head and neck, 
251
high-grade, 545
in HIV infection/AIDS, 1019–1020, 
1340, 1345
t
, 1347, 1348, 1354
indolent, 544
large cell (Richter syndrome), 540
lymphoblastic, 545
mantle cell, 544
marginal zone, 544, 1645, 1647
mucosa-associated lymphoid tissue. 
 
See
 MALT lymphoma
and, 234
pemphigus and, 146, 147
primary cerebral/central nervous 
system, 544–545, 1018
t
, 
 
1019–1020, 1348, 1354, 1527
primary effusion (body cavity), 1391
1647
small lymphocytic, 544
stem cell transplantation for, 544, 545, 
546
T-cell. 
See
 Human T cell lymphotropic/
leukemia virus; T-cell 
lymphoma
testicular, 1670
of thyroid, 1153, 1157, 1159
Lymphopenia, idiopathic CD4, progressive 
1407
Lymphoproliferative disorder
posttransplant, 1388
X-linked, Epstein-Barr infection and, 
1387
Lynch syndrome (hereditary nonpolyposis 
colon cancer/HNPCC), 
 
681–682
, 1649
endometrial carcinoma and, 681, 788
and, 1636
Lysergic acid diethylamide (LSD), 1112, 
1601–1602
Lyssavirus, 1399
M184V
 mutation, 1375
M918T
 mutation, 1159
M-protein, 547, 549
Ma huang, toxicity of, 1597
t
Macroglobulinemia, Waldenström. 
 
See
 Waldenström 
macroglobulinemia
CMDT2019_Index_p1743-1884.indd   1825

INDEX1826
 
CMDT 2019
complications of, 330
pneumonia and (ventilator-associated 
pneumonia), 278, 
283–286
, 
284
t
, 285
t
, 330, 1303
tracheotomy for, 248
withdrawal of, in end-of-life care, 78
Mechanic’s hands, 862
Meclizine, 222, 593
Meclofenamate, 87
t
Medial collateral ligament, 1709, 1712
t
, 
1715
Medial epicondylosis, 
1703–1704
Medial meniscus, 1709, 1713–1714
t
, 
1716–1717
Median nerve compression, in carpal 
tunnel syndrome, 1704
Mediastinal masses, 
299
Mediastinal widening, drug-induced, 321
t
Mediastinitis, in histoplasmosis, 1552
Mediator inhibitors. 
See
 Mast cell 
stabilizers/mediator inhibitors
Medical cannabis/marijuana. 
See
 
Marijuana
Medical imaging. 
See also
 
disorder
1575, 1611
Medical (or Physician) Orders for Life-
Sustaining Treatment 
(MOLST/POLST) forms, 76
Medical (or Physician) Orders for Scope of 
Treatment (MOST/POST) 
forms, 76
Medication-induced lung disease, 
32
, 300
t
Medication overuse headache, 
993
Medication reconciliation, for older 
patients, 69
Medications. 
See also
 
under Drug
adherence to regimen for, 1–2
use of during pregnancy, 446, 812, 812
t
Medicinal herbs, toxicity of, 
1597
, 1597
t
Mediterranean diet, 1271
Mediterranean fever, familial, 
616
Mediterranean spotted fever, 1437
t
, 1442
Medroxyprogesterone (DMPA)
for abnormal premenstrual/
777, 778
for contraceptive injection, 803
for feminizing hormone therapy, 1738
t
in hormone replacement therapy, 809, 
1214
for psychosexual disorders, 1076
Medullary cystic kidney, 962
t
Medullary sponge kidney, 962
t
, 
963–964
Medullary thyroid carcinoma, 1152
t
, 1153, 
1157, 1159, 1197
t
, 1198
Medulloblastoma, 1017
t
Mefenamic acid, 87
t
Mefloquine, 1518
t
, 1520–1521, 1520
t
, 
1523, 1523
t
with artesunate, 1519
t
, 1520–1521, 1522
Megacolon, toxic, 652, 673
Megaesophagus, 630
Megaloblastic anemia, 510, 511
t
. 
See also
 
subacute combined degeneration of 
spinal cord and, 1039
f
, 260
t
, 264
Mast cells, in allergic/pseudoallergic 
reactions, 890, 891, 892
Mastectomy, 751, 762, 764
arm edema after, 773–774
breast reconstruction/implants after, 
753, 774
cancer recurrence and, 773
transgender men and, 1741
partial. 
See
prophylactic, 754
Masticatory (jaw) claudication, 868, 997
Mastitis, puerperal, 140, 753, 
828
Mastocytosis, 893
t
Mastoiditis, 216
Match test, 21
Maternally inherited diabetes and deafness 
(MIDD), 1222
Maturity-onset diabetes of young 
(MODY), 1221
t
, 1222
Maxillary sinusitis, 226
Maximum laryngeal height, 21, 24, 24
t
May-Thurner syndrome, 33
Mayer-Rokitansky-Küster-Hauser 
syndrome, 1209
Mayo risk score, 722, 739
Maze procedure, 347
Mazzotti test, 1548
MC2R (melanocortin 2 receptor), 1181
McConnell taping, 1718
McCune-Albright syndrome, 1126, 1199
McDonald criteria, 1036
MCKD1/MCKD2
 genes, 963
McKenzie exercises, 1700
McMurray test, 1713
t
, 1716
MCV4 vaccine, 1335
t
, 1471. 
See also
 
Meningococcal vaccine
MDA5 antibody, 862
t
MDMA (methylenedioxymethamphet- 
amine), 900, 1114, 1583
t
, 1590
MDPV (methylenedioxypyrovalerone), 
1590
Meal replacement diets, 1278, 1279
Mean cell/corpuscular volume (MCV), 
510, 511
t
, 1107. 
See also 
Measles (rubeola), 1382
t
, 
1391–1394
atypical, 1381
t
prevention/immunization and, 3, 1327
t
, 
1328
t
, 1329
t
, 1392, 1393. 
See 
also
 MMR (measles-mumps-
rubella) vaccine
Measles encephalitis, 1392
Measles immune globulin, 1393
Measles-mumps-rubella vaccine. 
See
 
MMR (measles-mumps-
Measles-mumps-rubella-varicella vaccine 
(MMRV), 1385, 1393, 1395, 
1396
Mebendazole

for asthma, 256, 266
f
, 267
MALT lymphoma (MALToma)
gastric, 544, 634, 1644–1645
thyroid, 1153, 1157, 1159
Maltese crosses, 954
Mammographic localization biopsy, 760
Mammography, 14–15, 15
t
, 755, 755–756
breast biopsy and, 756, 760
in breast lump evaluation, 14–15, 15
t
, 
750, 755, 758, 759
f
, 760
f
digital, 15
pregnancy and, 761
Mammoplasty, augmentation. 
See
 Breast 
implants
Mania/manic episodes, 1087, 1088, 
 
t
. 
See also
 
Bipolar disorder
drug therapy/lithium for, 1097–1099, 
1099
t
ECT for, 1095
schizophrenia and, 1079, 1080
Manic-depressive disorder. 
See
 Bipolar 
disorder
Manic psychosis, 1079, 1080
Mannitol, 1099
t
, 1607
Manometry
anorectal, 596
esophageal, 618, 629, 630
Mansonella/Mansonella perstans,
 filariasis 
caused by, 1546, 1547
Mantle cell lymphoma, 544
Mantoux test, 290, 291
t
. 
See also
 
Tuberculin skin test
Maple bark stripper’s disease, 319
t
Maprotiline, 1091
t
Marasmus/marasmus-like secondary 
1276–1277
Maraviroc, 1365
t
, 1370. 
See also
 
Marfan syndrome, 573, 
1687–1688
aortic disorders (dissection/aneurysm/
regurgitation) in, 358, 359, 
1687, 1688
pregnancy and, 447, 448, 1688
mitral valve prolapse and, 351
sudden death of athlete and, 449
“Marginal blepharitis, ” 118, 175
Marginal zone lymphoma, 544, 1645, 
 
1647
Maribavir, 1390
Marijuana, 
1112–1113
for HIV infection/AIDS/wasting, 1343
1344
Marine-Lenhart syndrome, 1140
MARS, for hepatorenal syndrome, 718
Marshall scoring system, modified, 742
MASCC score, 36, 1675
Masculinizing hormone therapy, for 
transgender patients, 1739–
1740, 1739
t
, 1740, 1741
t
“Masked hypertension, ” 451
Mast cell stabilizers/mediator inhibitors. 
See also
 Cromolyn; 
t
CMDT2019_Index_p1743-1884.indd   1826

INDEX1827
 
CMDT 2019
Menorrhagia, 776, 777
iron deficiency anemia and, 510
Menstruation/menstrual cycle, 776. 
 
See also
 Vaginal bleeding
abnormalities of, in polycystic ovary 
syndrome, 795, 1206
asthma associated with (catamenial 
asthma), 253
cessation of, 808–809. 
See also
 
Amenorrhea; Menopause
failure to appear. 
See
 Amenorrhea
IUD affecting bleeding in, 804
pain associated with. 
See
pneumothorax associated with 
(catamenial pneumothorax), 
326
Mental disorders. 
See
 Psychiatric/
psychologic disorders
fragile X, 
1684–1685
Mental status, altered. 
See also
 Cognitive 
disorders
Mental stimulation, for dementia, 1034
Meperidine, 92
t
, 387, 1095
t
, 1604
Mephedrone toxicity, 1601–1602
Mepolizumab, 261
t
, 264
Meralgia paresthetica, 
1053
Mercaptopurine, 663, 669, 673, 708, 1617
t
Mercury poisoning, 960, 1112, 1584
t
, 
1602
Merlin gene, 1023
Meropenem, 279
t
, 282, 285
t
, 1321
t
, 1484
t
Meropenem-vaborbactam, 1317
MERRF syndrome, 1062
MERS/MERS-CoV , 
1427–1428
Mesalamine, 662, 668, 672
Mescaline, 1112, 1601–1602
Mesenchymal tumors, gastrointestinal, 
1646
Mesenteric vascular disease, 
 
490–491
Mesenteric vasculitis
in SLE, 854
Mesenteric vein occlusion, 
491
Mesial temporal sclerosis, epilepsy/
Mesna, 1675
t
, 1679
Mesoamerican nephropathy, 960, 961
Mesothelioma, 320, 445, 1614
t
, 
1630–1631
Metabolic acidosis, 917, 917
t
, 
918–922
. 
See also
 
specific type or cause
anion gap. 
See
 Anion gap/anion gap 
acidosis
t
, 
918, 919–920, 930, 941. 
See 
also
urolithiasis and, 920, 975
1293
t
1587, 1602, 1603
posthypocapnia, 921, 925
respiratory alkalosis and, 921, 925
carcinomatous (leptomeningeal 
metastases), 1019, 1305
chronic, 1304
cryptococcal, 1020, 1345–1346
t
, 
 
CSF analysis in, 1304
t
fungal, 1304
t
 causing, 1306, 1472
health care–associated, 1302, 1305, 
1306–1307
herpes simplex, 1304, 1378, 1380
 
1348–1349, 1349
in listeriosis, 1306, 1321
t
, 1463–1464
meningococcal, 1306, 1321
t
, 1349, 
1470–1471
in mumps, 1304, 1395
otogenic, 217
pneumococcal, 1306, 1321
t
, 
1454
in poliomyelitis (nonparalytic), 1397
See
 Meningococcal 
vaccine; Pneumococcal 
vaccine
purulent/bacterial, 1304, 1305, 1305
t
, 
1306, 1321
t
in syphilis, 1494
t
, 1497, 1500
1488–1489
West Nile, 1401
Meningococcal 
(Neisseria meningitidis)
 
infections, 1318
t
. 
See
 
1735
t
meningitis, 1306, 1321
t
, 1349, 
 
1470–1471
nasopharyngeal carriage and, 1471
resistance and, 1471
Meningococcal vaccine, 1327
t
, 1328
t
, 
1333
t
, 1335
t
, 1471
t
t
, 1333
t
, 
1349
Meningococcemia, 1382
t
, 1470
adrenal crisis and (Waterhouse-
Meningoencephalitis, 1304
t
. 
See also
 
Encephalitis; Meningitis
in trypanosomiasis, 1510, 1511, 1511
t
Meningovascular syphilis, 1494
t
, 1497, 
1500. 
See also
 Neurosyphilis
Meniscal cartilage, of knee, 1709, 1713–
1714
t
, 
1716–1717
Menopause/menopausal syndrome, 
808–
810
, 
1210–1216
early and premature, 808, 1209, 1210, 
1211
estrogen replacement therapy for. 
See
 
normal/typical, 1210, 1211
surgical, 808, 810
vaginal bleeding after. 
See

1211
See
 
See
 
Postmenopausal vaginal 
bleeding
Megestrol, 67, 769
t
, 1343
Meglitinide/meglitinide analogs, 1230
t
, 
1232
Meglumine antimonate, 1514–1515
Meibomian gland
abscess of (internal hordeolum), 174
inflammation of (blepharitis/chalazion) 
and, 175
Melancholic depression, 1087, 1090. 
See 
also
Melanocortin 2 receptor (MC2R), 1181
Melanocyte-stimulating hormone, alpha 
(alpha-MSH), in adrenal 
insufficiency/Addison disease, 
1180, 1181
Melanocytic nevi (normal moles), 110, 
110
f
Melanoma, 
111–113
, 112
f
, 1612
t
, 
 
1616
t
nevi and, 110, 112
and, 1636
Melanosis, arsenical, 166, 1593
Melarsoprol, 1511, 1511
t
MELAS syndrome, 1062, 1260
Melasma (chloasma), 166, 167
MELD/MELD-Na score, 720, 720
t
in alcoholic liver disease/cirrhosis, 709, 
710
hepatocellular carcinoma and, 1633
699, 700
Melena, 606, 610, 641
Melioidosis, 1318
t
Melody valve, 335, 342, 363
Meloxicam, 87
t
, 633
Melphalan, 1616
t
Memantine, 59, 1034, 1683
glomerulonephropathy, 946
t
, 
948
f
, 
952–953
t
, 952, 953
Membranous nephropathy, 947
t
, 
957
hepatitis and, 953
Memory impairment, 1116
in dementia/delirium, 57, 1033, 1115
ECT and, 1095
head injury and, 1043
MenACWY vaccine, 1327
t
, 1328
t
, 1333
t
, 
1335
t
. 
See also
vaccine
Menarche, 1208
failure of. 
See
MenB vaccine, 1327
t
, 1328
t
, 1333
t
, 1335
t
, 
1471. 
See also
vaccine
Mendelson syndrome, 
316–317
, 1302
Ménière syndrome (endolymphatic 
hydrops), 222
menin
 gene, 1198
Meningeal irritation, noninfectious, 1305
Meningeal leukemia, 539
Meningiomas, 1017
t
, 1018
Meningismus, 1305
Meningitis. 
See also
 Meningoencephalitis
aseptic/viral, 1304, 1304
t
. 
See also
 
 Aseptic 
benign recurrent lymphocytic 
(Mollaret), 1378
CMDT2019_Index_p1743-1884.indd   1827

INDEX1828
 
CMDT 2019
Methylprednisolone. 
See also
 
Addison disease, 1122, 1183
for alcoholic liver disease, 709
t
, 261, 263
t
668, 672, 673–674
for multiple sclerosis, 1037, 1038
t
for nausea and vomiting, 594
t
for thyroid eye disease, 1147
Methyltestosterone, oral, 1201, 1202, 1215
Methylxanthines. 
See
 Theophylline
Metipranolol, 183
t
Metoclopramide, 73, 591, 594
t
, 653, 991, 
1250, 1343–1344
Metolazone, 418, 419, 461
t
, 933
Metoprolol/metoprolol-HCTZ
for ACS/STEMI, 381, 387, 389
t
, 400, 403
for heart failure/cardiomyopathy, 418
t
, 
420, 429, 465
for hypertension, 463
t
, 465
and, 1193
Metritis, 
828–829
. 
See also
 Endometritis
Metronidazole, 1321
t
, 1322
t
t
for anaerobic infections, 286, 1321
t
, 
1484, 1484
t
for antibiotic-associated colitis, 661
for Crohn disease, 668, 670
for giardiasis, 1533–1534
in 
H pylori
t
, 639
for hepatic encephalopathy, 718
for 
 vaginitis 
(trichomoniasis), 782, 1534
Metrorrhagia, 776
Metyrapone, 1187
Metyrosine, 1194
Mexiletine, 393, 394
t
MHA-TP test, 1495
t
Mi-2 antibody, 862, 862
t
MIC (minimal inhibitory concentration), 
1317
Micafungin, 1551, 1561, 1562
t
Miconazole, 107
t
, 782, 1551
Micro-Coombs test. 
See
Microangiopathic hemolytic anemias, 560, 
561
Microangiopathy, thrombotic, 
560–562
Microbes. 
See
 Infection/infectious diseases
Microcephaly, Zika virus infection and, 
1418
Microglobulin, beta-2, amyloidosis and, 
550
Microlithiasis (biliary sludge), 732, 743
Microprolactinoma, 1128, 1129, 1130
Micropsia, 1016
Microsatellite instability, GI cancer, 678, 
681, 682, 1642
Microscopic colitis, 603, 
675
Microscopic polyangiitis, 
873–874
glomerulonephritis and, 874, 948
f
, 951
and, 872–873, 874
Microscopic urinalysis. 
See also
 Urinalysis
S aureus
 (MRSA) 
t
cellulitis, 146
community-acquired 132, 279
t
, 280, 281
furunculosis/carbuncles, 162
health care/hospital–associated, 1301, 
1303
in HIV infection/AIDS, 1353
mastitis, 828
nosocomial pneumonia, 283, 284
t
osteomyelitis, 1456
t
, 280, 281
skin/soft tissue infections, 1353, 1455, 
1455
f
Methicillin-susceptible 
S aureus
 (MSSA) 
infections, 146, 1318
t
, 1468
Methimazole
autoimmune hypoglycemia and, 1265
for hyperthyroidism/Graves disease, 
1144, 1147
pregnancy/lactation and, 830–831, 
1144, 1146, 1147
for solitary thyroid nodule/multinodular 
goiter, 1146
Methionine, in homocystinuria/
Methocarbamol, for black widow spider 
bites, 1608
Methotrexate, 1617
t
for ectopic pregnancy, 820
for elective abortion, 806
folinic acid/leucovorin/levoleucovorin 
rescue and, 851, 1675
t
, 1679
873
669
for psoriasis/psoriatic arthritis, 116, 
879–880
toxicity of, 851, 1617
t
, 1678, 1679–1680
Methscopolamine, 658
Methyl alcohol. 
See
 Methanol
Methyl salicylate, 1606. 
See also
 Salicylates
Methylcellulose, 597
t
. 
See also
 Fiber, 
dietary
Methylcobalamin, 517. 
See also
 Vitamin 
B
12
1095
t
t
, 475
t
t
, 475, 1596
pregnancy and, 446, 832
Methylene blue
1594
for hypotension in drug overdose, 1581
for methemoglobinemia, 1587
t
, 1603
Methylenedioxymethamphetamine. 
See
 
MDMA
Methylenedioxypyrovalerone (MDPV), 
1590
Methylnaltrexone, 73, 597–598, 598

1594
t
, 1603
See
 
MDMA
1590
Methylphenidate, 73, 1094, 1099, 1113
Metabolic alkalosis, 917, 917
t
, 
922–924
, 
922
t
. 
See also
 
respiratory acidosis and, 923, 924
t
, 923
t
, 923
Metabolic bone disease, 
1170–1179
. 
 
See also
 
in chronic kidney disease (renal 
940
f
coma/stupor caused by, 
1041
dysphagia and, 617
t
t
 
1049–1050
nutritional support and, 921, 1291, 
1292, 1293
t
cancer-related, 1020
Metabolic obesity, diabetes and, 1222, 
1223
Metabolic syndrome, 365, 453, 1223. 
See 
also
coronary heart disease and, 365
diabetes/insulin resistance and, 365, 
453, 1222, 1223
hypertension and, 365, 453
nonalcoholic fatty liver disease and, 712
obesity and, 13, 365, 453, 1278
Metanephrines, in pheochromocytoma/
paraganglioma, 1191–1192, 
1191
t
Metapneumovirus, human, 1421
Metaproterenol, for COPD, 271
Metered-dose inhalers (MDIs)
t
, 262
t
, 
263
t
, 265
f
, 266
f
Metformin
antipsychotic drug-related weight gain 
and, 1084
for diabetes, 1228, 1230
t
, 1232–1233, 
1237, 1244–1245, 1244
f
intensive therapy with, 1227–1228
for hirsutism/virilization, 1208
lactic acidosis and, 941, 1233, 1260, 1599
and, 1636, 1638
Methadone, 19, 88, 92
t
, 1112, 1604
Methamphetamine, 1113, 1590
Methanol poisoning, 1584
t
, 1587
t
, 
1602–
1603
ethanol for, 921, 1584
t
, 1587
t
t
, 1587
t
, 1603
Methazolamide, 207
t
Methcathinone, 1590
Methemoglobinemia, 1587
t
, 
1603
Methergine, antiretroviral therapy and, 
836
CMDT2019_Index_p1743-1884.indd   1828

INDEX1829
 
CMDT 2019
t
, 1329
t
, 
1361, 1393, 1396–1397
pregnancy and, 816, 1328
t
, 1329
t
, 1393, 
1396
t
, 
1335
t
, 1393
undervaccination and, 1392, 1393
MMRV (measles-mumps-rubella-varicella) 
vaccine, 1385, 1393, 1395, 
1396
MMSE (Mini Mental State Examination), 
1033
Mobility, limited/reduced. 
See
Mobitz type I (Wenckebach) 
atrioventricular block, 389, 
397, 398
Mobitz type II atrioventricular block, 390, 
397–398, 398
MoCA© (Montreal Cognitive 
Assessment), 58, 1033
Modafinil, 39, 73, 722, 1037, 1103
Model for End-Stage Liver Disease 
(MELD/MELD-Na) score, 
720, 720
t
710
699, 700
Modified Duke criteria, for endocarditis, 
1466
Modified Marshall scoring system, 742
Modified McMurray test, 1713
t
, 1716
Moexipril/moexipril HCTZ, 467
t
Mohs surgery, 151, 152, 175
Moisturizers (skin)/emollients, 103, 
 
108–109
t
Molar pregnancy, 
821–822
, 1141
Molds
household, 
1561
opportunistic infections caused by, 
1297, 
1560–1561
Mole, hydatidiform. 
See
 Hydatidiform 
mole
Mole (skin). 
See
 Nevi
Molecular adsorbent recirculating system 
(MARS), 718
Mollaret meningitis, 1378
Molluscum contagiosum, 
150
, 1353, 
 
1431
MOLST forms, 76
Mometasone, 105
t
, 229, 260
t
, 262
t
Mönckeberg medial calcific sclerosis, 486
Monge disease, 
1578
Monkeypox, 1431–1432
Monoamine oxidase inhibitors (MAOIs), 
1091
t
t
, 1095
t
t
, 1091
t
, 1094
for Parkinson disease, 1026
serotonin syndrome and, 1093
Monoclonal antibodies, in cancer 
chemotherapy, 1619–1620
t
. 
See also
 
Monoclonal gammopathy of unknown 
significance (MGUS), 
549
, 
1050
Monoclonal immunoglobulin-mediated 
Mipomersen, 1273
t
Mirabegron, 66
Mirena IUD, 804, 1215
Mirizzi syndrome, 734
Mirtazapine, 61, 73, 97, 1090–1093, 1091
t
Miscarriage (spontaneous abortion), 
 
817–819
Mismatch repair gene defects, 678, 681, 
682, 1642, 1649
Misoprostol, 637, 638
t
, 806, 818
Missed abortion, 818
Mistreatment (elder), 17, 
70–71
, 70
t
Mitchell-Riley syndrome, 1222
Mites
bird and rodent, 160
1437
t
, 1439, 1442
skin lesions and, 160
trombiculid, 159–160, 1439
Miticides, for scrub typhus prevention, 
1440
Mitiglinide, 1230
t
, 1232
Mitochondrial DNA mutations
myopathies associated with 
(mitochondrial myopathies), 
1062
Mitomycin, 1622
t
Mitotane, 1120, 1186–1187
Mitoxantrone, 546, 1038
t
, 1622
t
Mitral clip, 351
Mitral regurgitation/insufficiency, 343–
345
t
, 
348–351
, 350
f
. 
See also
 
interventions affecting murmur in, 346
t
mitral valve prolapse and, 349, 351, 352
in myocardial infarction, 349
Mitral stenosis, 343–345
t
, 
346–348
, 348
f
. 
See also
Mitral valve
degenerative disease of. 
See
prolapse
“parachute, ” 346
repair/replacement of, 347, 350–351, 
350
f
, 351, 352. 
See also
 Valve 
in rheumatic fever/heart disease, 346, 
348
f
, 435
Mitral valve prolapse (“floppy”/
myxomatous mitral valve), 31, 
351–352
t
, 
352
in Marfan syndrome, 351, 1687
mitral regurgitation and, 349, 351, 352
Mittelschmerz, appendicitis differentiated 
from, 654
Mixed acid-base disorders, 
917–918
Mixed connective tissue disease, 
864
Mixed phenotype acute leukemia, 538
Mixed sleep apnea, 327
MLH1
 gene
in colorectal cancer/HNPCC/Lynch 
syndrome, 678, 681, 682, 1649
1636
MLL
MLL
-PTD mutation, 538
MMR (measles-mumps-rubella) vaccine, 
3, 1327
t
, 1392, 1393, 1395, 
1396
Microsporidiosis, 
1530–1533
 skin infection, 119, 120
Microwave ablation
for benign prostatic hyperplasia, 988

3, 1327
t
1396
1530–1533
Micturition. 
See
 Voiding
Midazolam, 1002, 1067
t
, 1583
MIDD (maternally inherited diabetes and 
deafness), 1222
Middle ear, 
215–218
See
 Otitis, media
218
trauma to, 
217–218
Middle East respiratory syndrome/Middle 
East respiratory syndrome–
coronavirus (MERS/MERS-
CoV), 
1427–1428
Midline malignant reticulosis, 234
Midodrine, 413, 718, 1004, 1250
Midostaurin, for acute myeloid leukemia, 
539
Mifepristone (RU 486), 806, 1090
Miglitol, 1230
t
Migraine equivalent, 990
Migraine headache, 41, 41
t
, 
990–992
, 992
t
nausea and vomiting in, 41
t
, 592
t
TIA differentiated from, 1005
vertigo/dizziness and, 223
MIL77, for Ebola viral disease, 1411
Milan criteria, 1633
Mild cognitive impairment, 58, 1031
Miliaria (crystallina/profunda/pustulosa/
rubra), 
139
“Miliary” tuberculosis, 290
Milk-alkali syndrome, 911, 912
Milk intolerance. 
See
 Lactose (milk) 
Milk thistle (silymarin), for mushroom 
poisoning, 700, 1604
Milker’s nodules (paravaccinia), 1431
Miller Fisher syndrome, 1051, 1398
Milnacipran, 1090–1093, 1091
t
Milrinone, 425, 509
Miltefosine, 1515
Mineral oil/mineral oil enema, 597
t
Mineralocorticoid replacement therapy, 
1183
Mineralocorticoids. 
See also
 Aldosterone
apparent excess of, 454, 906
t
deficiency of, 907, 1181, 1352. 
See also
 
Minerals
metabolism of, chronic kidney disease/
renal osteodystrophy and, 
939–940, 940
f
“Mini-cog” screening, 58, 1033
Mini Mental State Examination, 1033
Minimal change disease, 947
t
, 
955–956
Minimal inhibitory concentration (MIC), 
1317
Minimally conscious state, 
1042
Minimally invasive coronary artery bypass 
surgery, 376
Minimally invasive prostate surgery, 988
Minipill (progestin), 802–803
Minnesota tube, 627
Minocycline, 135, 137, 208
t
, 1440, 1455
Minority stress, 1730, 1733, 1734
Minoxidil, 168, 474
t
, 475, 1207
Miotics, 183
t
CMDT2019_Index_p1743-1884.indd   1829

INDEX1830
 
CMDT 2019
Multibacillary (lepromatous) leprosy, 1050, 
1489, 1490. 
See also
 Leprosy
Multidrug resistance. 
See also
 Drug 
health care–associated infections and, 
1301
pneumonia, 283, 284
t
in tuberculosis, 288, 294, 295, 1347
Multinational Association for Supportive 
Care in Cancer (MASCC) 
score, 36, 1675
Multinodular (nodular) goiter, 
1149–1152
, 
1150
t
. 
See also
 Goiter; 
Thyroid nodules
toxic, 1140, 1146, 1150, 1151
Multiple endocrine neoplasia (MEN), 
1197–1199
, 1197
t
MEN 1 (Wermer syndrome), 1197
t
, 
1198
acromegaly in, 1126
adrenal adenoma/hyperplasia in, 
1197
t
, 1198
carcinoid tumors in, 1197
t
, 1198
gastrinoma/Zollinger-Ellison 
syndrome in, 643, 1195, 1198
gastroenteropancreatic NETs in, 1195, 
1198, 1262, 1645
hyperparathyroidism/parathyroid 
adenoma/hyperplasia in, 
1164, 1169, 1197
t
, 1198
insulinoma in, 1195, 1198, 1262, 1263
pituitary adenoma in, 1126, 1128, 
1197
t
, 1198
prolactinomas in, 1128
thyroid adenoma in, 1197
t
, 1198
MEN 2 (MEN 2A/Sipple syndrome), 
1197
t
, 
1198
1164, 1197
t
, 1198
medullary thyroid carcinoma in, 
1153, 1157, 1159, 1197
t
, 
 
1198
pheochromocytoma in, 1190, 1197
t
, 
1198
MEN 3 (MEN 2B), 1197
t
, 
1198–1199
t
t
MEN 4, 1197
t
, 
1199
parathyroid adenoma/hyperplasia in, 
1164, 1197
t
, 1199
1197
t
, 1199
Multiple gestation pregnancy, 799, 814, 
826, 1123
Multiple marker screening, 1682
Multiple myeloma. 
See
 Plasma cell 
myeloma
Multiple sclerosis, 
1036–1037
, 1038
t
trigeminal neuralgia and, 994
vertigo/hearing loss in, 224
Multisystem atrophy (Shy-Drager 
syndrome), 1003, 1025
Multisystem crisis, 1191
Multitarget DNA tests, in cancer/polyp 
screening, 678, 1654
Mumps, 
1394–1395
, 1394
f
in irritable bowel syndrome, 656
t
Motivational interview, at-risk drinking 
and, 1107
Motor conduction velocity studies. 
See
 
Conduction velocity studies
Motor neuron diseases, 
1046–1047
spasticity and, 1038–1039
spinal trauma and, 1045
Motor vehicle accidents. 
See
accidents
Mountain sickness
acute (AMS), 1577
chronic (Monge disease), 
1578
subacute, 
1578
Mouth. 
See
 Oral cavity
Movement disorders, 
1024–1031
. 
See also
 
drug-induced, 
1030
in Wilson disease, 725, 1030
Moxalactam, platelet function affected by, 
568
t
Moxifloxacin, 1322
t
for anaerobic infections, 1484, 1484
t
t
, 185
t
, 281, 282, 1453
MPL
 mutation, 529, 532, 533
MPSV4 vaccine, 1335
t
, 1471. 
See also
 
MRI. 
See
 Magnetic resonance imaging
MSH2/MSH6
 genes
in HNPCC/Lynch syndrome, 681
1636
mTOR inhibitors, 770, 1264, 1668
Mucocutaneous (mucosal) candidiasis, 
139–140
, 140
f
, 1550
Mucocutaneous herpes simplex, 126–127, 
127
f
, 1377
Mucocutaneous leishmaniasis (espundia), 
Mucocutaneous lymph node syndrome 
(Kawasaki disease), 1382
t
, 
1445–1447
Mucocutaneous syphilis, 1494
t
, 1497, 
1498
f
, 1499
Mucomimetics, for dry eye, 177
Mucormycosis/
Mucor
1558–1559
Mucosa-associated lymphoid tissue 
lymphoma. 
See
 MALT 
lymphoma
Mucosal biopsy
in celiac disease, 646
Mucosal protective agents, for peptic ulcer 
disease, 637–638
Mucositis, oral, chemotherapy-induced, 
1676
t
, 1678
Mucous membranes
diabetes mellitus affecting, 1251
leishmaniasis involving, 1513, 1514, 
1515
melanoma involving, 112
syphilis involving, 1494
t
, 1497, 1498
f
, 
1499
“Muddy brown (granular) casts, ” 926, 
 
927
t
MUGA scan, 370, 1680
Müllerian agenesis, 1209
Multi-gated acquisition (MUGA) scan, 
370, 1680
Monoclonal protein. 
See also
 Paraproteins
in plasma cell myeloma, 547, 964
549, 550

370, 1680
See also
549, 550
Monocular visual loss, transient, 
196
Monocytic ehrlichiosis, 1437
t
, 1443
Monomethylhydrazine mushroom 
poisoning, 1604
Mononeuritis (mononeuropathy) 
multiplex, 
1047–1052
. 
See 
also
in diabetes, 1249
in Lyme disease, 1050, 1506
polyarteritis nodosa and, 870, 1050
Mononeuropathies, 1048, 
1052–1054
. 
 
See also
in diabetes, 1249. 
See also
 Diabetic 
CMV , 1388, 1389
Epstein-Barr virus, 1381
t
, 
1386–1387
pharyngitis in, 238–239, 1386, 1387, 
1448–1449
Mononucleosis-like syndrome, 173, 1388, 
1389
Montelukast, 142, 230, 261
t
, 264
Montenegro (leishmanin) skin test, 1514
Montgomery-Asberg scale, 1089
Montreal Cognitive Assessment 
(MoCA©), 58, 1033
Mood disorders, 
1086–1100
. 
See also
 
Depression; Mania
dementia and, 1033, 1034–1035
Moraxella
/
278
t
, 1318
t
, 1322
t
, 
1472
Morbidly adherent placenta (placenta 
accreta/increta/percreta), 827
Morbilliform skin disorders, 104
t
Morganella,
 1319
t
Moricizine, toxicity of, 396
Morning sickness. 
See
 Vomiting, of 
pregnancy
Morphea, 860
Morphine, 88, 93
t
for dyspnea, 72
for myocardial infarction, 387
overdose/toxicity of, 93
t
, 207
t
, 1604
Mosaicism
Klinefelter syndrome and, 1200, 1687
premature menopause and, 1210
Turner syndrome and, 1216, 1217
Mosquitoes/mosquito control
dengue and, 1413, 1414
encephalitis and, 1401, 1402, 1403
filariasis and, 1546, 1547
hemorrhagic fever and, 1412
malaria and, 1516, 1523
yellow fever and, 1416
Zika virus infection and, 1417–1418, 
1418
Moths, skin lesions caused by, 160
Motility disorders. 
See also
 
esophageal. 
See
disorders
intestinal, 
650–653
. 
See also
constipation and, 595, 595
t
diarrhea and, 600
t
, 603
CMDT2019_Index_p1743-1884.indd   1830

INDEX1831
 
CMDT 2019
Myelin-associated glycoprotein (MAG), 
neuropathy and, 1050
Myelin oligodendrocyte glycoprotein, in 
neuromyelitis optica, 1037
Myelin protein 22/myelin protein zero 
genes, 1048
Myelinolysis, central pontine (cerebral 
Myelodysplastic syndromes, 
536–537
platelet function/thrombocytopenia 
and, 536, 537, 556–557, 558, 
568
t
stem cell transplantation for, 537
Myelofibrosis (primary/idiopathic), 530
t
, 
533–534
Myeloid growth factors. 
See
 Filgrastim; 
Growth factors; Sargramostim
Myeloid leukemia. 
See
 Acute myeloid 
leukemia; Chronic myeloid 
leukemia
Myeloma. 
See
 Plasma cell myeloma
Myeloma kidney, 964
Myelopathy. 
See also
 
in cervical spondylosis, 1055
epidural/subdural hemorrhage causing, 
1015
HIV , 1349
human T-cell leukemia virus (HTLV), 
1039
Myeloperoxidase ANCA (MPO-ANCA). 
See
 Antineutrophil 
cytoplasmic antibody
Myeloproliferative disorders, 
529–543
, 
529
t
, 530
t
. 
See also
 Leukemias
platelets affected in, 530, 530
t
, 531, 532, 
533, 535, 568
t
Myeloradiculopathy, in spinal dural 
arteriovenous fistulae, 1015
Myelosuppressive therapy, 531. 
See also
 
Chemotherapy; 
Immunomodulating therapy; 
Immunosuppressive therapy
Myerson sign, 1025
MYH9
Myocardial abscess, endocarditis and, 
1465, 1466
Myocardial contusions/hematomas, 445
Myocardial dysfunction, 390–392. 
See also
 
Myocardial hibernation, 365–367
Myocardial hypertrophy. 
See
 
Myocardial infarction/ST-segment 
elevation myocardial 
infarction (STEMI), 27–29, 
28
t
t
, 
 
383–393
, 385
t
. 
See also
 
accelerated idioventricular rhythm and, 
389, 409
antihypertensive therapy and, 480
t
arrhythmias associated with, 383
t
, 368, 
1251
biomarkers in, 379, 384
t
, 
383
clinical findings/diagnosis and, 383–384
cocaine abuse and, 378, 383, 1113
MYC
 translocations, 544
Mycetoma, 
1560
 (mycobacterial infections), 
1319
t
, 
1487–1490
abscessus,
 296, 297, 1487, 1488
avium
 complex (MAC), 296, 1319
t
, 
1345
t
, 1361, 1362
disseminated disease caused by, 296, 
1488
in HIV infection/AIDS, 296, 1342, 
1345
t
, 1361, 1362, 1488
pulmonary disease caused by, 1487
bovis
BCG vaccine made from, 290, 295
intestinal disease caused by, 655
chelonae/chelonei,
 296, 297, 1319
t
, 1487, 
1488
fortuitum,
t
, 1487, 1488
gordonae,
 1487
kansasii,
t
, 1487
leprae,
 1319
t
, 1489, 1490
lymphadenitis/adenitis, 
250
, 1487
malmoense,
 296
marinum,
 1488
t
nontuberculous (atypical). 
See also
 
Nontuberculous atypical 
in HIV infection/AIDS, 296, 1347
lymphadenitis/adenitis caused by, 
250
, 1487
pulmonary disease caused by, 
 
295–297
, 1347, 
1487
skin and soft tissue infections caused 
by, 
1487–1488
szulgai,
 1487
, 287–295, 289
t
, 1319
t
, 1488. 
See also
bone and joint disease caused by, 294, 
886–887
intestinal disease caused by, 
655
lymphadenitis caused by, 
250
, 1487
meningitis caused by, 
1488–1489
 
287–295
, 289
t
, 290
f
, 291
f
, 
292
t
, 293
t
resistant strains of, 288, 289, 289
t
, 
1347
ulcerans,
 1488
xenopi,
 296, 1487
for autoimmune hepatitis, 708
Mycoplasma,
 1320
t
genitalium,
 1309, 1491
 143, 278
t
, 1321
t
, 1322
t
Mycosis fungoides (cutaneous T-cell 
lymphoma), 
124
, 125
Mycotic aneurysms, 1013, 1311
Mycotic infections (mycoses), 
119–122
, 
119
f
, 1353, 
1550–1563
. 
See 
also
 Fungal infections
275
, 893
t
t
, 
1561–1563
t
. 
See also
119–122
, 119
f
,

. 
See 
also
275
, 893
t
t
, 
1561–1563
t
. 
See also
119–122
, 119
f
, 
1353. 
See also
 Tinea
228–229
, 
1550–1563
MYD88
 mutation, 550
t
, 
1328
t
, 1329
t
, 1395. 
See also
 
Mumps vaccine, 1395. 
See also
 MMR 
(measles-mumps-rubella) 
vaccine
Munchausen syndrome/Munchausen by 
proxy, 1071
Mupirocin, 106
t
, 138, 228, 1353
Mural thrombus, 392
Murine (flea-borne) typhus, 1437
t
, 
 
1438–1439
Murmurs. 
See
Murphy sign, 735
Murray Valley encephalitis, 1401
Muscarinic agents. 
See also
 
t
, 263, 263
t
in polymyositis/dermatomyositis, 
 
862–863
Muscle cysticercosis, 1539
Muscle-specific tyrosine kinase (MuSK) 
antibodies, 1058
Muscle wasting. 
See
 Wasting
Muscle weakness differential diagnosis of, 
863. 
See also
 Myopathies; 
Myositis; Paralysis
Muscles, disorders of. 
See
 Musculoskeletal 
disorders
Muscular dystrophies, 
1060
, 1061
t
Musculoskeletal disorders, 
1690–1721
. 
See 
also
 
 Arthritis
ankle injuries, 
1720–1721
, 1720
f
in cysticercosis, 1539
dysphagia in, 617
t
hip problems, 
1706–1709
knee problems, 
1709–1719
, 1710
t
, 
1711–1714
f
t
shoulder problems, 
1690–1697
, 
 
1691–1694
t
spine problems, 
1697–1703
, 1698
t
, 
1702
t
sports injuries and, 
1690–1721
in trichinosis, 1544
in tuberculosis, 294, 
886
upper extremity problems, 
1703–1706
, 
1706
f
Mushroom picker’s disease, 319
t
Mushroom poisoning, 
1603–1604
anticholinergic-type mushrooms and, 
1593
hallucinogenic mushrooms and, 
 
1601–1602
liver failure and, 699, 1603, 1604
MuSK antibodies, 1058
Musset sign, 358
Mutism
akinetic (persistent vegetative state), 
1042
1079
“Mutton-fat” keratic precipitates, 190
MUTYH
 mutation, 680
Myasthenia gravis, 
1058–1059
aminoglycoside use and, 1058, 1060
Myasthenic crisis, 1058
Myasthenic/Lambert-Eaton myasthenic 
syndrome, 1022, 
1059
CMDT2019_Index_p1743-1884.indd   1831

INDEX1832
 
CMDT 2019
NAEPP (National Asthma Education and 
Prevention Program), 254
f
, 
255
t
, 256
t
f
, 
262
t
, 263
t
, 265
t
, 266
t
Nafcillin, 568
t
, 1321
t
, 1450, 1468
NAFLD Fibrosis Score, 713
Naftifine, 107
t
Nail disorders, 
169–170
candidal infection, 140
hyperpigmentation, 169
pitting/stippling, 115, 115
f
, 169
in Raynaud phenomenon, 858
tinea unguium (onychomycosis), 169, 
170
Nailbed capillary pulsations (Quincke 
pulses), 358
Naldemedine, 598
Nalmefene, for opioid overdose, 1584
t
Naloxegol, 73
Naloxone, 19, 99, 1040, 1111, 1581, 1584
t
, 
1604
Naltrexone, 19, 709, 1108, 1112
with bupropion, 1244, 1279
NAP1 
 660, 661
Naphazoline, 1596
Naproxen, 87
t
, 209
t
, 636, 845
Napsin-A, 1629
Naratriptan, 991
Narcissistic personality disorder, 1077
t
Narcolepsy, 1103
Narcotic antagonists. 
See
 Opioid (narcotic) 
antagonists
Narcotics, 1111. 
See also
analgesics
Narrowband UVB (NB-UVB) therapy, 
116. 
See also
Nasal bleeding. 
See
 Epistaxis
Nasal CPAP , for sleep apnea, 328
Nasal polyps, 229, 
232–233
Nasal pyramid, fracture of, 232
Nasal septoplasty, for sleep apnea, 328
Nasal sinuses. 
See
 Paranasal sinuses
Nasal trauma, 
232
Nasal tumors, 
232–233
Nasal vestibulitis, 
228
Nasolacrimal duct obstruction, 175–176
Nasopharynx, malignant tumors of, 
233
Epstein-Barr virus and, 233, 1387
serous otitis media and, 214, 233
Natalizumab, 665, 1038
t
, 1407, 1408
Natamycin, 181
t
Nateglinide, 1230
t
, 1232, 1244
f
, 1245
hypoglycemia and, 1246, 1262
t
, 1266
National Asthma Education and 
Prevention Program 
(NAEPP), 254
f
, 255
t
, 256
t
, 
f
, 262
f
, 262
t
, 
263
t
, 265
t
, 266
t
National Surgical Quality Improvement 
Program (NSQIP) risk 
assessment tool, 46, 48
f
, 50
Native DNA, antibodies to, 853
t
, 854
t
, 
855
t
Natriuretic peptide, B-type (BNP/beta). 
See
 B-type natriuretic peptide
Natural killer cell lymphoma. 
See
 NK-cell 
lymphoma
Nausea and vomiting, 
73
, 
591–594
, 592
t
, 
594
t
. 
See also
 
chemotherapy-induced, 591, 592
t
, 593, 
1677–1678
Myoedema, percussion, 1399
Myoglobin/myoglobinuria
in ACS (NSTEMI/STEMI), 379
in kidney disease/injury/
rhabdomyolysis, 866, 
 
932–933
Myomas (leiomyomas/fibroid tumors), 
787–788
Myomectomy, 788
Myonecrosis, clostridial (gas gangrene), 
1319
t
, 
1458
Myopathies (myopathic disorders), 
 
1060–1062
, 1061
t
antiretroviral therapy causing, 884, 
1062, 1350
HIV , 884, 1350
inflammatory, 854
t
, 
861–864
, 862
f
, 
862
t
, 1062. 
See also
 
lipid-lowering therapy/statins causing, 
862
t
, 863, 866, 955, 1272
mitochondrial, 
1062
Myopathy, encephalopathy, lactic acidosis, 
and stroke-like episodes 
(MELAS), 1062, 1260
Myopericarditis. 
See also
/Lyme disease 
causing, 437, 1506, 1508
t
, 
1509
Myosin heavy chain, genes coding for, 
 
431
Myositis. 
See also
 Dermatomyositis; 
autoantibodies in, 854
t
, 862, 862
t
in HIV infection/AIDS, 884
inclusion body, 863, 
1062
statins causing, 862
t
, 863, 1272
Myotomy, 626, 630
per oral endoscopic (POEM), 630
Myotomy–myomectomy, 432
Myotonia/myotonic dystrophy, 
 
1060–1061
, 1061
t
congenita, 
1061
Myotonin-protein kinase, 1061
t
Myringotomy, 214, 215, 217
Myxedema, 
1134–1139
. 
See also
 
pretibial (Graves dermopathy), 1140, 
1142, 1148
Myxedema coma, 1135, 1137
Myxedema crisis, 1137
Myxedema heart, 1135
Myxedema madness, 1135, 1137
Myxoma, atrial, 444–445, 445, 1295
Myxomatous mitral valve. 
See
prolapse
N-methyl-D-aspartate (NMDA) receptor 
antibodies, encephalitis and, 
1021, 1305
N-receptor antagonist, 73, 1678
N-terminal proBNP (NT-proBNP)
Nabumetone, 87
t
Nadolol/nadolol-bendroflumethiazide, 
464
t
, 628
Myocardial infarction/ST-segment

t
464
t
, 628
infarction (STEMI) (
Cont
.):
coronary artery trauma and, 445
coronary vasospasm and, 383
diabetes and, 1228, 1250, 1251
fibrinolytic therapy for, 385, 385
t
, 386, 
386–387
heart failure and, 390, 415
hemodynamic status and, 384
ischemia after, 375, 389
mitral regurgitation and, 349
oral contraceptive use and, 800
painless, 383
perioperative, preoperative risk and, 
47–48, 48
f
pregnancy and, 447, 448
Q waves and, 28
t
, 384. 
See also
 Non-Q 
wave (non-ST elevation) 
reinfarction and, 384, 387
revascularization/reperfusion and, 
47–48, 375–376, 385–387, 393
risk/risk stratification/reduction for, 
365, 366
f
t
, 392
shock and, 383, 390–391
sudden death and, 383, 411
treatment of, 384–389, 385
t
, 392–393
ventricular fibrillation and, 383, 411
Myocardial ischemia, 
365–393
. 
See also
 
Angina; Coronary heart 
disease; Myocardial infarction
in ACS, 27–28, 378
chest pain/discomfort and, 27–29, 28
t
, 
378
hypertension management and, 480
t
preoperative testing for, 46–47, 48
f
vasospasm causing, 377–378
Myocardial perfusion scintigraphy
t
, 429, 432
Myocardial rupture, 391, 445
Myocardial sarcoidosis, 303, 304
Myocardial stunning, 365–367
Myocarditis, 
425–427
in African trypanosomiasis, 1510
clozapine causing, 1084
coxsackievirus, 1434
diphtheritic, 1463
drug-induced/toxic, 173, 425
t
, 427
425–427
, 425
t
noninfectious, 425
t
, 
427
pericarditis with, 438
sudden death of athlete and, 426, 449, 450
t
Myoclonic-atonic seizures, 998
Myoclonic epilepsy, ragged red fiber 
(MERRF) syndrome, 1062
Myoclonic seizures, 996
t
, 998. 
See also
 
Seizures
Myoclonus, 
1030
with opsoclonus, 1021–1022
palatal, tinnitus and, 220
CMDT2019_Index_p1743-1884.indd   1832

INDEX1833
 
CMDT 2019
struvite, 975, 977
uric acid, 844, 964–965, 977
Nephrolithotomy, 978
Nephropathia epidemica, 1415
analgesic, 960, 961
Balkan, 1666
contrast, 932, 1248
diabetic, 947
t
, 953, 955, 
957–958
, 
 
1247–1248
glycemic control and, 1227, 1228, 
1248
HIV-associated, 947
t
, 
958–959
hypertensive, 479
IgA (Berger disease), 946
t
, 948
f
, 
 
949–950
lead, 960, 961
membranous. 
See
 Membranous 
Mesoamerican, 960, 961
obstructive, 937
t
, 938
t
reflux, 960, 960–961
urate/uric acid, 844, 964–965
Nephrosclerosis, hypertension causing, 
456
Nephrosis
t
lipoid (minimal change disease), 947
t
, 
955–956
Nephrotic spectrum diseases
f
, 947
t
, 
954–955
. 
See also
 Nephrotic syndrome
955–957
957–959
Nephrotic syndrome, 926, 945, 945
f
, 954. 
See also
 
in amyloidosis, 551
t
in diabetes, 955, 1248. 
See also
 Diabetic 
focal segmental glomerulosclerosis and, 
947
t
, 
956
HIV-associated nephropathy and, 947
t
, 
958–959
lipid abnormalities and, 954, 955, 957
membranous nephropathy and, 947
t
, 
957
minimal change disease and, 947
t
, 
 
955–956
Nephrotoxicity. 
See also
 
of aminoglycosides, 932
of cisplatin, 1680
kidney injury/acute tubular necrosis 
and, 932–933, 938
t
of mercury, 960, 1602
of radiographic contrast media, 932, 
1248
Neprilysin inhibitor, 417
f
, 418
t
, 419, 429
Neratinib, 766
Nerve agents, for chemical warfare, 
1595
, 
1605
1584, 1595
Nerve biopsy, in polyarteritis nodosa, 
 
870
Nerve block, in pain management, 100, 
101
t
Nerve conduction velocity studies. 
See
 
Nervous system. 
See
 
under Neurologic
Nesiritide, 424–425
Neisseria
, 684, 1318
t
, 1321
t
, 1323
t
, 
1481. 
See also
 Gonococcal 
resistant strains of, 1481–1482
, 1318
t
, 1470. 
See also
 
(Neisseria 
meningitidis)
 infections
resistant strains of, 1471
Nelfinavir, 1364
t
, 1369. 
See also
 
Nelson syndrome, 1186, 1187
Nematode (roundworm) infections. 
 
See also
 
filariasis, 
1546–1549
, 1546
f
intestinal, 603, 
1541–1544
invasive, 
1544–1546
Neoadjuvant chemotherapy. 
See also
 
for bladder cancer, 1665, 1666
for breast cancer, 763
for colorectal cancer, 1652
for esophageal cancer, 1639–1640
1631
Neologisms, 1079
Neomycin/polymyxin B/gramicidin, 180
t
Neonate. 
See
 Newborn
Neoplasia. 
See
 Cancer
Neoplastic pericarditis/effusion, 437, 438, 
439, 1671, 1672
Neostigmine, 207
t
, 652, 1058
Neovascularization, in diabetes, 197, 1247
Nepafenac, 182
t
Nephrectomy, for renal cell carcinoma, 
1667, 1668
Nephritic spectrum glomerular diseases, 
945, 945
f
, 
946–954
, 946
t
, 948
f
. 
See also
 Glomerulonephritis
Nephritic syndrome, 945, 945
f
. 
See also
 
Nephritis. 
See also
t
interstitial, 854, 926, 930
t
, 
934–935
lupus, 854, 855, 946
t
, 948
f
, 
953–954
t
Nephrocalcinosis
1164
hypoparathyroidism treatment causing, 
1162
Nephrogenic diabetes insipidus. 
See
 
nephrogenic
Nephrogenic fibrosing dermopathy, 860
Nephrogenic (necrotizing) systemic 
fibrosis, 371, 931, 944
Nephrolithiasis (kidney stones), 975, 978. 
See also
 Urinary stone 
 
disease
calcium, 975, 976–977
cystine, 975, 977
hyperparathyroidism and, 975
probenecid use and, 847
in renal tubular acidosis, 920, 975
drugs for management of. 
See
 
in HIV infection/AIDS, 1343, 
 
1343–1344

See
 
1343–1344
in intestinal obstruction, 592, 592
t
in migraine headache, 41
t
, 592
t
opioid-induced, 97
73
in pregnancy, 592, 
816–817
, 837
821, 1141
Nearsightedness, management of, 174
Nebivolol, 418
t
, 460, 464
t
, 465, 475
Nebulizer therapy
t
, 262
t
, 263
t
, 265
f
, 
266
f
for COPD, 271, 272, 273
Necator americanus,
 1542
Necitumumab, 1620
t
Neck
infections of
1483
deep, 
240–241
250
masses in, 
249–251
. 
See also
 Head and 
neck cancer
congenital lesions in adults, 
249–250
infectious and inflammatory, 
250
lymphoma, 
251
250–251
thyroid. 
See
 Thyroid cancer; Thyroid 
nodules
Neck fractures/injury, 1701
cervical vertigo and, 223
head trauma and, 1043
Neck pain, 
1701–1703
, 1702
t
1055
f
, 1702
Necrobiosis lipoidica diabeticorum, 1251
Necrolysis, toxic epidermal, 
142–144
, 170, 
172
t
Necrosectomy, 745
Necrosis-erythema-lymphadenopathy, 
Dermacentor-borne/scalp 
t
, 1442
Necrotizing cellulitis, synergistic, 1485
Necrotizing fasciitis, 1485
staphylococcal, 1455
Necrotizing (phlegmonous) gastritis, 635
Necrotizing lymphadenitis, histiocytic 
Necrotizing pneumonia, 286
Necrotizing ulcerative gingivitis, 
237
t
f
, 260
t
, 264
Needle ablation of prostate, transurethral 
(TUNA), 985
f
, 988
Needle-stick injury, HIV infection/AIDS 
transmission and, 1340, 
 
1358–1359
Neer impingement sign, 1690, 1693
t
, 1694
Nefazodone, 1090–1093, 1091
t
Neglect/abuse, of elderly, 17, 
70–71
, 70
t
Negri/Negri-like bodies, 1399
Neighborhood reaction, 1304
t
, 1305
CMDT2019_Index_p1743-1884.indd   1833

INDEX1834
 
CMDT 2019
Neuromuscular/neuromuscular 
transmission disorders, 
1058–
1060
. 
See also
 
t
t
Neuromyelitis optica (Devic disease/
syndrome), 199–200, 
 
1037–1038
Neuron-specific enolase, in Creutzfeldt-
Neuronal/mixed neuronal-glial tumors, 
1017
t
Neuronal neuropathy, 1047. 
See also
 
Neuronitis, vestibular, 223
Neuronopathy, cancer-related, 1022
Neuropathic bladder
Neuropathic pain, 96, 96
t
, 99–100, 1048. 
See also
in diabetes, 1248, 1249
Neuropathies, 
1047–1058
. 
See also
 
specific 
acute motor axonal/acute motor and 
sensory axonal (AMAN/
AMSAN), 1051. 
See also
 
alcoholism and, 1049
in amyloidosis, 551, 1050
antiretroviral agents (didanosine/
stavudine) causing, 1349, 1368
autonomic. 
See
 Autonomic neuropathy
brachial plexus, 
1055–1058
1022, 
1050
, 1679
in chronic kidney disease/uremia, 941, 
1049
cisplatin-induced, 1680
in critically ill patient, 
1050
in cryoglobulinemia, 875
diabetic, 1049, 1248–1250, 1249
f
. 
See 
also
 Diabetic neuropathy
diphtheritic, 1050, 1463
entrapment/compression, 1050, 
 
1052–1054
facial, 
1054
, 1054
f
. 
See also
 Facial 
hereditary motor and sensory (HMSN), 
types I to IV , 1048–1049
infectious/inflammatory disease and, 
1050
inherited, 
1048–1049
in leprosy, 1050, 1489
in Lyme disease, 1050, 1506, 1507
metabolic/systemic disease and, 
 
1049–1050
nutritional, 1049. 
See also
 
specific 
nutrient
optic
inflammatory (optic neuritis), 
 
199–200
ischemic, 
199
, 868
in paraproteinemias, 1049–1050
peripheral, 
1047–1058
. 
See also
 
specific 
type
in polyarteritis nodosa, 870, 1050
sensorimotor/sensory, 1022
in stroke, 1008–1009, 1011, 1012, 1013, 
1014
in toxoplasmosis, 1527
in transient ischemic attacks, 1005
Neurokinin receptor antagonists, 73, 593, 
594
t
, 1678
Neurokinin receptors, in nausea and 
vomiting, 591, 1677
Neuroleptic malignant syndrome, 35, 36, 
1084–1085, 1583, 1592
Neuroleptics. 
See
Neurologic disorders, 
990–1062
. 
See also
 
1021–1022
in chronic kidney disease/uremia, 941
CMV causing, 1389
t
, 
 
dysautonomia and, 
1003–1004
, 1048
t
in herpes simplex infection, 1378
in high-altitude illness, 1577
911–912, 1164–1165
1304–1307
, 1304
t
, 1305
t
. 
See 
also
1484
in Lyme disease, 1050, 1506, 1508
t
, 
 
1509
measles causing, 1392
nausea and vomiting and, 592, 592
t
nonmetastatic complications of cancer, 
1021–1022
207–208
t
postoperative, 
52–53
t
primary angiitis and, 
876–877
t
SIADH caused by, 901, 901
t
in SLE, 853
t
, 854, 855
in syphilis, 1323
t
, 1360, 1494
t
, 1496
t
, 
1500–1501. 
See also
 
vertigo/vestibular disorders and, 220, 
221
t
, 222, 
224
vitamin B
12
 deficiency causing, 517, 
 
518
in VZV infection, 1383, 1384
Neurologic evaluation. 
See also
 
52–53
in spine disorders, 1698, 1698
t
Neuroma/neurinoma. 
See also
 
acoustic, 
224
, 1018
t
mucosal, in MEN, 1199
plexiform, 1023
Neuromodulatory therapy
for angina, 376
in pain management, 100–101, 101
t
Netupitant/netupitant-palonosetron 
(NEPA), 73, 593, 594
t
, 1678

t
t
, 1678
Neural hearing loss, 210. 
See also
 Hearing 
loss
Neuralgia
glossopharyngeal, 218, 997, 1679
postherpetic, 127, 129, 186, 
997
, 1384
trigeminal, 
994–997
Neuralgic amyotrophy, 1056
Neuraminidase, influenza virus, 1422
Neuraminidase inhibitors (oseltamivir/
zanamivir/peramivir), 1379
t
, 
1423–1424, 1425, 1426
Neuritis
intercostal, 372
optic, 
199–200
Neuroblastoma, 1615
t
Neurocognitive disorders, 
1114–1116
, 
1115
t
. 
See also
 Cognitive 
disorders; Delirium; 
Dementia
Neurocutaneous diseases, 
1023
Neurocysticercosis, 1539
Neurodegenerative disease. 
See
 Dementia
Neuroendocrine tumors (NETs). 
See also
 
diarrhea and, 605
gastric, 
1645–1646
gastrinoma differential diagnosis and, 
643–644
gastroenteropancreatic (GEP-NETs), 
1195–1197
, 1545–1546, 
1647–1648
1647–1648
lung, 1198
nonfunctioning, 1195
pancreatic, 1636, 1637
thymic, 1198
Neurofibromas, 1023
Neurofibromatosis, 
1023
type 1 (Recklinghausen disease), 1190, 
1195, 1199
type 2/vestibular schwannoma (eighth 
nerve tumors/acoustic 
neuroma), 224, 1018
t
NEUROG3
Neurogenic arthropathy (Charcot joint), 
889
in diabetes mellitus, 889, 1248
f
Neurogenic claudication, 1699
Neurogenic hyperventilation, 327, 1041
Neurogenic shock, 505
t
, 506
Neuroglycopenia, hypoglycemia and, 1246, 
1262
in brain abscess, 1021, 1306
in cerebrovascular occlusive disease, 
 
488
in coma, 1040
in dementia, 58, 1033–1034
in headache, 41, 41
t
, 42
in intracranial tumors, 1018
lumbar puncture and, 1306
in pituitary adenoma/hypopituitarism, 
1122, 1126
1080
CMDT2019_Index_p1743-1884.indd   1834

INDEX1835
 
CMDT 2019
in breast cancer, 752, 752
t
, 757, 760
in fibrocystic breast condition, 750, 752, 
752
t
in hyperprolactinemia, 752, 1129
Nisoldipine, 471, 473
t
, 1594
Nitazoxanide, 1532, 1534
Nithiodote, 1596–1597
Nitrates. 
See also
 Nitroglycerin
390
for angina, 372, 373
f
417
f
, 420, 421, 446
phosphodiesterase inhibitor/sildenafil 
contraindications and, 388, 
980, 1076
Nitrendipine, 475
Nitric oxide, in erection, 978, 979
Nitrites
for cyanide poisoning, 1584
t
, 1596, 1597
methemoglobinemia caused by, 1603
Nitrobenzene toxicity, 1603
Nitrofurantoin, 834, 968, 968
t
, 969, 1322
t
Nitrogen, liquid. 
See
 Liquid nitrogen
Nitrogen balance, nutritional support and, 
1293
Nitrogen mustards, 1616
t
Nitrogen oxide gases, 1603
Nitroglycerin. 
See also
 Nitrates
for ACS (NSTEMI/STEMI), 381, 387, 
388, 390
for angina, 369, 372, 373
f
for heart failure, 390, 421
t
, 
481
t
, 482
980, 1076
Nitroprusside
in aortic dissection, 497
t
, 481
t
, 482, 
497
pheochromocytoma surgery and, 1193
Nitrous oxide, subacute combined 
degeneration of spinal cord 
and, 1039
Nivolumab, 1620
t
for gastric adenocarcinoma, 1644
for lung cancer, 1628
Nizatidine, 621, 637. 
See also
 H
2
 receptor 
Njovera (endemic syphilis), 1503
NK-cell lymphoma, 234, 543, 543
t
, 1388
NK
1
 receptor antagonists, 73, 593, 594
t
, 
1678
NK
1
 receptors, in nausea and vomiting, 
591, 1677
NMDA receptors, encephalitis and, 1021, 
1305
NMO-IgG, in neuromyelitis optica, 1037
No-added-salt diet, 1286
hepatitis C transmission and, 837
herpes simplex infection and, 837
HIV transmission and, 836, 1340, 1358
hypercalcemia/hyperparathyroidism in, 
1163
hypocalcemia/hypoparathyroidism/
tetany in, 1165
1324
listeriosis in (granulomatosis 
infantisepticum), 1463
malaria in, 1516
parechovirus infection in, 1436
rabies vaccination in, 1400
syphilis in (congenital syphilis), 837, 
1493, 1502
Tdap vaccination and, 816
toxoplasmosis in, 813, 1526, 1526–1527
varicella in, 835
Zika virus infection/testing and, 1418
Nexplanon, 803
NF1/NF2
 genes, 1023
NF-kappa-B, 547
Niacin (vitamin B
3
)
1283–1284
for lipid modification, 368, 1271, 1272, 
1273
t
, 1274
side effects/toxicity of, 1272, 
1284
Niacinamide, 1239, 1283
for hypertension, 471, 473
t
, 480, 480
t
, 
481
t
, 482
overdose/toxicity of, 471, 473
t
, 481
t
, 
1594
and, 1193
Niclosamide, 1538
Nicotinamide, 1283, 1284
Nicotine/nicotine replacement therapy, 7, 
813. 
See also
 Smoking
Nifedipine. 
See also
t
, 481
t
, 482
t
, 481
t
, 
482, 1594
and, 1193
Nifurtimox, 1511, 1511
t
, 1512–1513
Night blindness, in vitamin A deficiency, 
1285
Nikolsky sign, 147
Nil disease (minimal change disease), 
947
t
, 
955–956
Nilotinib, 535, 1621
t
, 1679
Nilutamide, 1623
t
Nimodipine, 1012, 1594. 
See also
 Calcium 
channel blocking drugs
Nintedanib, 303
Nipah virus, 1421
Nipple, Paget disease of, 126, 126
f
, 757, 
757
f
, 761
Nipple dermatitis, candidal, 140
Nipple discharge, 
752
, 752
t
, 760
in thiamine deficiency, 1282
toxic, 
1050
vincristine-induced, 209
t
, 1618
t
, 1679
vitamin B
6
 causing, 517, 518, 1284

f
, 761
752
, 752
t
, 760
toxic, 
1050
t
, 1618
t
, 1679
vitamin B
6
Neuropsychological/neuropsychiatric 
assessment, in dementia, 1033
Neuroses, Sunday, 1066
Neurosyphilis, 1323
t
t
, 1496
t
, 
1500–1501
in HIV infection/AIDS, 1360, 1501
treatment/treatment failures and, 1323
t
, 
1496
t
, 1501
Neurotoxicity. 
See also
 Neurologic 
disorders
of snake venom, 1607
Neurotransmitters. 
See
 
Neurotrophic keratitis, 185
Neurotropic disease
viral, 
1398–1409
. 
See also
 
specific 
disorder
yellow fever vaccine-associated, 1417
Neutral protamine Hagedorn/isophane 
insulin. 
See
 NPH insulin
Neutrocytic ascites, 613, 614, 615
Neutrogena, 108
t
528–529
, 528
t
antibiotic prophylaxis/therapy in, 1299, 
1300
bacteremia and, 1299, 1473
cancer/chemotherapy and, 528, 1297, 
1321
t
, 1674, 1676
t
, 1677
fever/FUO and, 529, 1294, 1295, 1674
1300, 1321
t
infections and, 528, 529, 1297, 1299, 
1674
pulmonary infiltrates in, 287
Neutrophil count, 528. 
See also
 
Neutropenia
ascitic fluid, 613, 615
joint fluid, 840, 841
t
, 842
t
, 882, 883
Nevi, 
110–111
atypical (dysplastic), 
110–111
, 110
f
blue, 
111
, 111
f
melanocytic, 
110
, 110
f
melanoma and, 110, 112
Nevirapine, 1364
t
, 1368. 
See also
 
Nevus. 
See
 Nevi
New (novel) anticoagulants. 
See
 Direct-
acting oral anticoagulants
New World cutaneous leishmaniasis, 1513, 
1513–1514, 1514
f
, 1515
Newborn/infant
antiretroviral therapy for, 836, 1358
chikungunya fever in, 1419
chlamydial infection in, 837
CMV infection/inclusion disease in, 
1388, 1389
coxsackievirus infection in, 1434
dengue in, 1414
GH deficiency in, 1120
gonococcal infection in, 837
Graves disease in, 1145
group B streptococcal infection and, 
834–835, 1451
heart failure in, 1434
hemolytic disease of, 815
hepatitis B transmission/vaccine and, 
694, 695, 696, 837, 1228
t
CMDT2019_Index_p1743-1884.indd   1835

INDEX1836
 
CMDT 2019
790
gastrointestinal side effects (bleeding/
gastritis/gastropathy) and, 85, 
606, 633, 843
interstitial/tubulointerstitial nephritis 
caused by, 934, 959
t
t
, 
209
t
for osteoarthritis, 842–843, 843, 1719
in pain management, 85, 86–88
t
, 88
in peptic ulcer disease, 633, 635, 636, 
638
t
, 639–640, 843
t
, 843
pompholyx-like eruption caused by, 130
for psoriatic arthritis, 879
renal toxicity of, 843, 930
sensitivity to, 
892
for rheumatoid arthritis, 850
topical, 85, 106
t
, 842–843, 1719
Nonstreptococcal exudative pharyngitis, 
1429
Nontreponemal antibody tests, for 
syphilis, 1494–1495, 1495
t
Nontuberculous (atypical) mycobacteria 
(NTM), 
295–297
, 
1487–1488
in HIV infection/AIDS, 296, 1345
t
, 
1347, 1487
250
, 
1487
MAC infections. 
See
 
(mycobacterial infections), 
avium
 complex
295–297
, 
1347, 
1487
skin and soft tissue infections caused by, 
1487–1488
Norelgestromin, in transdermal 
contraceptive patch, 803
Norepinephrine
for hypotension/shock, 391, 508, 1581
1190, 1191
Norepinephrine reuptake inhibitors, with 
opioid agonists, 94–95
t
Norethindrone
777, 778
1213–1214, 1214
in oral contraceptives, 800, 801
t
with oral estrogens, 1214
in progestin minipill, 802–803
Norfloxacin, 180
t
, 615, 717, 968
t
. 
See also
 
Norgestimate, 801
t
, 1214
Norgestrel, in oral contraceptives, 801
t
Normal anion gap acidosis, 918, 918
t
, 
920–921
, 920
t
, 922
diabetic ketoacidosis and, 919
1293
t
Noninfectious meningeal irritation, 
 
1305
Noninsulinoma pancreatogenous 
cell hyperplasia), 1264
Noninsulinomas, 1196, 1263–1264
Noninvasive ischemia testing, 
f
Noninvasive positive-pressure ventilation 
(NIPPV)
Nonionizing radiation, 1574
Nonislet cell tumor hypoglycemia, 
 
1264–1265
Nonketotic hyperglycemic hyperosmolar 
coma (hyperglycemic 
1224, 1255
t
, 
1258–1260
Nonnucleoside polymerase inhibitors, 
704
t
, 705
Nonnucleoside reverse transcriptase 
inhibitors (NNRTIs), 1363–
1364
t
See also
 
293
resistance to, 1368, 1373
Nonoxynol-9, 805, 1310, 1356
Nonparalytic poliomyelitis, 1397
Nonproliferative retinopathy, 197, 1247
Non-Q wave (non-ST elevation) 
infarction, 384. 
See also
 
Myocardial infarction; 
 
syndromes
fibrinolytic/thrombolytic therapy 
contraindicated in, 379, 385
Non-rapid eye movement (non-REM) 
sleep, 1101
Nonscarring alopecia, 168
Nonseminomas, 1669, 1669–1670, 1670
Non-sexually transmitted epididymitis, 
968
t
, 973
Non-sexually transmitted treponematoses, 
1319
t
, 
1502–1503
Non–small cell lung cancer (NSCLC), 
1613
t
, 1624–1625, 1625. 
 
See also
 
1627–1628
t
, 1627
treatment of, 1627–1628
Nonspecific interstitial pneumonia (NSIP), 
302
t
, 303, 1347
Non–ST-segment elevation syndromes 
(NSTEMI), 
378–383
, 380
f
, 
382
t
, 389. 
See also
 Acute 
coronary syndromes
Nonsteroidal anti-inflammatory drug 
(NSAID) exacerbated 
respiratory disease, 
892
(NSAIDs), 82, 85, 86–88
t
. 
 
See also
 
acute kidney injury and, 843

t
. 
 
See also
 
633, 636, 640, 843
Nocardia asteroides/brasiliensis
 
(nocardiosis), 1319
t
, 
 
1486–1488
Nodular goiter. 
See
 Multinodular 
(nodular) goiter
Nodular malignant melanoma, 112
Nodular regenerative hyperplasia, 728–729
Nodules
milker’s (paravaccinia), 1431
pulmonary, 
297–299
, 1629, 1630
rheumatoid, 849, 849
f
in coal workers (Caplan syndrome), 
318
gouty tophi differentiated from, 845, 
850
skin, 104
t
. 
See also
 
inflammatory, 
160–163
violaceous to purple, 
153–155
subcutaneous. 
See
 Subcutaneous 
nodules
thyroid. 
See
 Thyroid nodules
vocal fold, 245
Noise trauma
hearing loss caused by, 211, 218
tympanic membrane perforation and, 
217
Non-ABCDE hepatitis, transfusion-
associated, 697
Nonadherence/adherence, 1–2
Nonalcoholic fatty liver disease (NAFLD), 
690, 
712–714
, 1631. 
See also
 
Fatty liver
Nonalcoholic steatohepatitis (NASH), 712, 
713, 713–714
Nonbacterial folliculitis, 137, 138
Nonbacterial prostatitis, 971
t
, 
972
Non-binary man/woman, 1737. 
See also
 
Noncancer pain, chronic (CNCP), 82, 
83
, 
1072–1075
, 1073
f
. 
See also
 
Noncardiac chest pain, 29–30, 
631
Noncirrhotic portal hypertension, 
 
728–729
Non-clostridial crepitant cellulitis, 1485
Noncompliance/compliance. 
See
 
Nonadherence/adherence
Nonconvulsive status epilepticus, 1002
Nondiabetic (renal) glycosuria, 1224
Nonepileptic seizure, psychogenic (PNES), 
1000–1001, 1071
Nonexertional (classic) heat stroke, 1565
Non-falciparum malaria, 1518, 1518
t
Nonfamilial adenomatous and serrated 
polyps, 
678–679
, 1649
Nongonococcal acute bacterial (septic) 
881–883
, 1311, 
1321
t
Non-group A streptococcal infections, 
1451
Non-Hodgkin lymphoma, 
543–545
, 543
t
, 
1345
t
, 1612
t
, 1613
t
. 
See also
 
Lymphoma
t
in HIV infection/AIDS, 1345
t
, 1347, 
1348, 1354
kidney involved in, 1668
small intestine, 1647
CMDT2019_Index_p1743-1884.indd   1836

INDEX1837
 
CMDT 2019
hypothalamic damage causing, 1121, 
1122
hypoventilation and (Pickwickian 
327
insulin resistance and, 1222, 1223
medical conditions/evaluation and, 
1278
medications for, 13, 1279–1280
metabolic, 1222, 1223
in metabolic syndrome, 13, 365, 453, 
1278
713
osteoarthritis and, 841, 842
t
, 
12–13
treatment of, 1278–1280. 
See also
 
weight gain in pregnancy and, 814
Obesity-hypoventilation syndrome 
327
Obeticholic acid, 722, 740
Obinutuzumab, 541, 1620
t
Obliterative portal venopathy, 729
Obsessions, 1070. 
See also
Obsessive-compulsive disorder (OCD), 
1069–1070
, 1090
Tourette syndrome and, 1031
Obsessive-compulsive disorder (OCD) 
spectrum, 1070
Obsessive-compulsive personality 
t
Obstetrics/obstetric disorders, 
811–839
. 
See also
 Pregnancy
208
t
Obstructive lung disease. 
See
 Airway 
disorders, obstruction; 
Obstructive nephropathy, 937
t
, 938
t
Obstructive shock, 505, 505
t
, 506
Obstructive sleep apnea hypopnea, 241, 
242, 327, 
328–329
, 1103
Obstructive uropathy, 931, 937
t
, 938
t
, 
 
960
Obstructive voiding symptoms, 983
Obturator sign, 654
Occipital lobe lesions, 1016
Occlusive dressings, for wart removal, 
 
149
Occlusive vascular disease. 
See also
 
specific 
vessel involved and
 
Occult diabetes, 
1265
Occult GI bleeding, 611, 
612
. 
See also
 
Fecal occult blood testing; 
Occupational asthma, 253, 319
Occupational pulmonary diseases, 300
t
, 
317–320
, 318
t
, 319
t
. 
See also
 
Occupational radiation exposure, 1575
OCD spectrum, 1070. 
See also
Ocrelizumab, 1037, 1038
t
lactic acidosis caused by, 919
myopathy associated with use of, 884
Nucleotide reverse transcriptase inhibitor, 
792, 1363
t
, 1366. 
See also
 
Nucleus pulposus herniation
cervical, 
1055
, 1702
lumbar/sacral, 1700–1701
Nursing (breastfeeding). 
See
 Lactation
Nursing homes
Nusinersen, 1047
Nutmeg liver, 728
Nutrients. 
See also
 Diet/nutrition; 
Nutritional disorders; 
diets restricting, 
1286–1287
diets supplementing, 
1287–1288
requirements for in nutritional support, 
1289–1290
See
 Diet/nutrition
Nutritional disorders, 
1276–1293
. 
See also
 
Eating disorders; 
Malnutrition; Obesity/
overweight
t
neuropathy associated with, 1049. 
 
See also
 
thrombocytopenia associated with, 
558
Nutritional support, 
1288–1293
, 1289
f
, 
1290
t
, 1292
t
, 1293
t
. 
See also
 
77
indications for, 
1288–1289
, 1289
f
methods for, 1288–1289, 1289
f
nutritional requirements and, 
 
1289–1290
patient monitoring during, 
1292–1293
in ulcerative colitis, 673
Nystagmus
in coma/stupor, 1041
in vertigo, 221–222, 223, 224
Nystatin, 237, 782, 1678
Obesity/overweight, 
1277–1280
bulimia nervosa and, 1282
definition of/measurements in, 
 
1277–1278
in diabetes, 1222, 1224, 1228, 1244
diet/eating behavior changes and, 
 
1278–1279
exercise/activity and, 12, 13, 1278–1279
genetic factors in, 1278
GERD and, 619, 621
GH deficiency and, 1120
in hypertension, 453, 457
t
, 458
1121, 1203

1278–1279
t
, 458
1121, 1203
renal disease/renal tubular acidosis and, 
906
t
t
, 921, 922, 
960
urinary anion gap in assessment of, 
920
t
, 921
Normal flora, 1457, 1484, 1486
Normal pressure hydrocephalus, 1034
Normetanephrine, in pheochromocytoma, 
1190, 1191, 1192
Normochloremic metabolic (increased 
anion gap) acidosis, 918, 
 
918–920
, 918
t
, 921
Normokalemic periodic paralysis, 1062
Noroviruses, 599
t
, 1313
t
, 1432–1433
North Asian tick typhus, 1442
Nortriptyline, 96
t
, 100, 1091
t
, 1094, 1249. 
See also
Norwalk virus, 1432–1433
Nose, 
225–234
. 
See also
 
under Nasal
233–234
, 871, 872
225–229
. 
See also
 
Rhinosinusitis; Sinusitis
234
, 303
f
232
tumors/granulomatous disease of, 
 
232–234
Nosebleed. 
See
 Epistaxis
Nosocomial infections. 
See
Nosocomial pneumonia, 278, 278
t
, 
 
283–286
, 284
t
, 285
t
Notch 1, in aortic stenosis, 353
Novel (new) anticoagulants. 
See
 Direct-
Novolin. 
See also
NPH insulin, 1238, 1238
t
1242–1243, 1245. 
See also
 
t
, 
1239–1240, 1242–1243, 1245
NPL insulin, 1238
t
, 1240. 
See also
 Insulin 
therapy
NPM1
NREM sleep, 1101
NS3/4A protease inhibitors, 704
t
, 705
NS5A inhibitors, 704
t
, 705
NS5B polymerase inhibitors, 704
t
, 705
NSQIP risk assessment tool, 46, 48
f
, 50
Nuclear bleeding scans, 610
Nuclear bone scanning. 
See
 Bone scanning
Nuclear factor-kappa B ligand (RANKL), 
547, 1174
Nuclear transcription factor mutations, 
1222
Nucleic acid amplification testing 
(NAAT-TB/NAAT-R)
in blood screening, 553
in STDs, 1309
t
Nucleic acid-binding protein, 1061
t
Nucleophosmin 1 
(NPM1)
Nucleoside polymerase inhibitors, 704
t
, 
705
Nucleoside reverse transcriptase inhibitors 
(NRTIs), 1363
t
, 1366–1368, 
1371. 
See also
therapy
for hepatitis B, 702
CMDT2019_Index_p1743-1884.indd   1837

INDEX1838
 
CMDT 2019
Omeprazole, 608, 621, 631, 632, 633, 637, 
639, 641, 843. 
See also
 Proton 
On-off phenomenon, 1026
Onabotulinum toxin A, 66
 (onchocerciasis/river 
blindness), 
1547–1548
Oncocytoma, of kidney, 1668
Ondansetron, 97, 593, 594
t
, 659, 1344, 
1678. 
See also
 Antiemetics
One-leg squat test, 1717–1718
One-leg standing extension test, 1698
Onycholysis, 169
Onychomycosis (tinea unguium), 169, 
170
Oophorectomy (salpingo-oophorectomy)/
ovarian ablation
in breast cancer prevention/treatment, 
754, 769
for hirsutism/virilization, 1207
premature ovarian failure and, 1210
surgical menopause and, 808, 810
Oophoritis, in mumps, 1394
Open-angle glaucoma. 
See
 Glaucoma
Open biopsy, for breast lump evaluation, 
759. 
See also
Open can test, 1692
t
, 1694
Open globe injury, 205
Open loop systems, in insulin therapy, 
1243. 
See also
 Continuous 
subcutaneous insulin infusion 
(CSII) pumps
Ophthalmia
neonatorum, 837
sympathetic, 190
Ophthalmic artery occlusion, 1008
Ophthalmic medications, 179–184
t
t
206
precautions for use of, 
206–209
systemic effects of, 
206–209
177, 
206
, 206
f
Ophthalmic SJS/TEN, 143
Ophthalmopathy, Graves, 
202
, 202
f
, 1140, 
1142, 1143, 1145, 1147
Ophthalmoplegia, in headache, 41, 991
Opiates. 
See also
 Opioids/opioid analgesics
overdose/abuse of, 19, 98, 
1111–1112
, 
1604–1605
Opioid (narcotic) antagonists, 1111–1112. 
See also
 Naloxone
for coma, 1581
for heroin/opioid overdose/withdrawal, 
1111–1112, 1581, 1584
t
, 1604
for opioid-induced constipation, 
 
597–598
Opioid epidemic, 98. 
See also
 Opioids/
opioid analgesics, abuse/
misuse/overdose of
Opioid-receptor antagonist laxatives, 
 
597–598
Opioid Risk Tool, 98
Opioids/opioid analgesics, 82, 88–99, 
89–95
t
. 
See also
 
specific 
 
agent
abuse/misuse/overdose of, 19, 98, 
 
1111–1112
, 1584
t
, 
1604–1605
limiting risk of, 98–99
for nausea and vomiting, 593, 594
t
, 
1678
t
, 
1082
t
t
, 1592
Olaparib, 771
Olaratumab, 1620
t
Old World cutaneous leishmaniasis, 1513, 
f
, 1515
Older adults. 
See also
 
affecting
abuse/mistreatment/neglect and, 17, 
70–71
, 70
t
advance directives and, 76
anemia in, 513
appendicitis in, 654
55–57
, 56
f
, 56
t
, 57
t
benzodiazepine use in, 1068
cholesterol screening in, 1270
delirium in, 57, 
61–62
, 
73–74
dementia in, 
57–60
t
. 
 
See also
 Dementia
depressed, 
60–61
. 
See also
dialysis in, 942, 943
drug use (pharmacotherapy/
polypharmacy) and, 
69
falls and, 63–64, 64
t
falls/gait disorders and, 
63–65
, 63
t
, 64
t
fever/FUO in, 1294
frail, 
56–57
functional assessment/screening for, 
55–56
t
hearing impairment in, 70, 218
hypertension and, 460, 465, 477
t
, 478
hypertrophic cardiomyopathy in, 431
immobility and, 
62–63
influenza vaccination in, 1424
pressure injury in, 
68–69
, 68
t
principles of care of, 
55
prognosis/life expectancy and, 55, 56
f
, 
56
t
, 57
t
, 74
self-neglect and, 
70–71
, 70
t
urinary incontinence and, 
65–67
values/preferences and, 55
vision impairment in, 
69–70
weight loss in, 37, 
67
Oleander, toxicity of, 1597–1598
Olecranon bursitis, 1705, 1706, 1706
f
Olestra, 603
Olfactory dysfunction, 
230–231
, 1016, 1044
in Kallmann syndrome, 1120
Oligodendroglioma, 1017
t
Oligomenorrhea, 776
Oligozoospermia, 981
f
, 982
982
Oliguria, 926, 931, 933. 
See also
 
specific 
cause
Olmesartan/olmesartan combinations, 
468
t
, 469
t
, 471
Olopatadine, 182
t
Olsalazine, 662
Omacetaxine mepesuccinate, 1622
t
Omalizumab, 142, 258
f
, 261
t

See also
 
specific 
cause
468
t
, 469
t
, 471
t
t
f
, 261
t
, 264
Ombitasvir, 704
t
, 705, 1351
Omega-3 fatty acids/fish oil, 3
t
, 568
t
, 
1273
t
, 1369
for ACTH-secreting tumor, 1186
for carcinoid syndrome, 1648
for diarrhea, 605, 1352, 1679
for dumping syndrome, 1265
for esophageal varices/GI bleeding, 608, 
627
for gastric/gastroenteropancreatic NETs, 
1196, 1645
for GH-secreting tumor/acromegaly/
gigantism, 1127
for sulfonylurea overdose/hypoglycemia, 
1584
t
, 1599
Ocular contusions, 
205
Ocular disease. 
See
 Eye, disorders of
Ocular examination. 
See
 Eye, examination 
of
Ocular hemorrhages, 205
vitreous, 
193
Ocular hypertension, 183–184
t
, 187, 188, 
188–189. 
See also
 Glaucoma
1203
Ocular lacerations, 
205
Ocular larva migrans, 1545
Ocular medications. 
See
Ocular melanoma, 112
Ocular motor palsies, 
201–202
, 201
f
Ocular movements. 
See
 Eye (extraocular) 
movements
Ocular myasthenia gravis, 1058
Ocular transient ischemic attack, 196, 488
Ocular trauma, 
203–205
, 204
f
Oculocephalic reflex, in coma/stupor, 1041
Oculomotor response, in coma/stupor, 
1041
Oculopharyngeal muscular dystrophy, 
1061
t
Oculosympathetic paralysis. 
See
 Horner 
syndrome
Oculovestibular reflex, in coma/stupor, 
1041
Oddi, sphincter of. 
See
 Sphincter of Oddi
Odefsey (tenofovir/emtricitabine/
t
, 1368, 
1372
t
Odontogenic infections. 
See also
 Dental 
disorders
deep neck infections and, 240, 241
Odor identification/discrimination/
threshold disorders, 230–231, 
1016, 1044
Odynophagia, 617, 1638
Ofatumumab, 1620
t
Ofloxacin, 180
t
, 602, 1316, 1322
t
. 
See also
 
Ogilvie syndrome, 
651–652
Oil of evening primrose (OEP), for 
fibrocystic condition, 751
Olanzapine, 1081, 1081–1082, 1081
t
, 
1082
t
, 1083, 1084, 1084
t
, 
1086. 
See also
drugs
with antidepressants, 1090
diabetes and, 1084
CMDT2019_Index_p1743-1884.indd   1838

INDEX1839
 
CMDT 2019
amyl nitrate affecting, 1114
loss of/orgasmic disorder/dysfunction, 
796, 797, 1075. 
See also
 Sexual 
1094
Oriental spotted fever, 1442
Orientia tsutsugamushi,
 1437
t
, 1439
Oritavancin, 1455
Orlistat, 1244, 1279
Ornithosis (psittacosis), 1320
t
, 
1492
Oromandibular dystonia, 1029
Oropharyngeal anthrax, 1461
Oropharyngeal cancer, 234, 236
Oropharyngeal dysphagia, 617, 617
t
. 
See 
also
 Dysphagia
Oropharyngeal secretions, aspiration of, 
anaerobic pleuropulmonary 
infection and, 286, 1322
t
, 
1484
Orthodromic reentrant tachycardia, 400–
401
Orthokeratology, 174
Orthopedics. 
See also
disorders
Orthophosphates, for hypercalciuria, 976
Orthopoxviruses, novel, 1432
falls and, 64, 64
t
heat syncope/collapse and, 1565
syncope and, 413
Orthostatic proteinuria, 926–927
Osborn wave, 1567, 1567
f
Oseltamivir, 225, 1379
t
, 1423, 1423–1424, 
1425, 1426
Osimertinib, 1621
t
, 1627–1628
Osler nodes, 1465, 1465
f
Osler sign, 456
Osler triad, 1452
Osler-Weber-Rendu syndrome (hereditary 
hemorrhagic telangiectasia), 
573, 606, 
1688–1689
fecal/stool, 603
serum, 898
in diabetes, 1223, 1224, 1255, 1259
urine, 904, 930
t
Osmolar/osmol gap, 898, 
904–905
, 1586
t
1586
t
alcohol toxicity and, 905, 1107, 1586
methanol or ethylene glycol toxicity 
and, 905, 1602, 1603
Osmolarity, 898
Osmostat, reset, 901
Osmotic demyelination, cerebral, 902
Osmotic diuretics, lithium interactions 
and, 1099
t
Osmotic gap, stool, 603, 604
f
Osmotic laxatives, 596, 597
t
, 658
Ospemifene, 1215
Ossicular disruption, hearing loss and, 
210, 218
Osteitis condensans ilii, 878
Osteitis deformans (Paget disease of bone), 
1178–1179
leukoplakia involving, 234–235, 
234
, 
234
f
, 235
f
, 1350
lichen planus involving, 153, 234, 
235
ulcerative lesions of, 
237–238
chemotherapy-induced, 1678
Oral contraceptives, 
800–803
, 801
t
, 802
t
t
breast cancer risk and, 754, 802
combination, 800–802, 801
t
contraindications/adverse effects of, 
800–802, 802, 802
t
depression associated with use of, 802, 
1088
drug interactions and, 800
806
788, 802
790
hepatocellular adenoma/liver tumors 
and, 731, 802
for hormone replacement therapy, 1214
melasma (chloasma) caused by, 166
nipple discharge caused by, 752
ovarian cancer risk and, 802
Oral glucose tolerance test. 
See
 Glucose 
tolerance/intolerance
Oral hypoglycemic agents. 
See
 
Oral nutritional supplements, 67, 1288, 
1343
Oral polio vaccine (OPV/Sabin vaccine), 
1398
Orbital abscess, bacterial rhinosinusitis 
and, 227
Orbital cellulitis, 
202–203
bacterial rhinosinusitis and, 202, 227
Orbital floor, blowout fracture of, 205
Orbitopathy, Graves. 
See
 Graves 
for intra-abdominal testes, 1204
t
, 1663
for testicular cancer, 1669, 1670
Orchiopexy/orchidopexy, 1204, 1669
Orchitis
mumps, 1394
Orexin receptor antagonists, dual 
Orf, 1431
Organ of Corti, hearing loss and, 210
Organ donation/transplantation, 81. 
See 
also
 
Organ preservation surgery, for laryngeal 
cancer, 247
Organic brain syndrome. 
See
 Cognitive 
Dementia
Organic (alcoholic) hallucinosis, 1106–
1107, 1107, 1108, 1116
Organophosphate poisoning, 1583
t
, 1584
t
, 
1605
Orgasm, 1075
management of, 99, 1584
t
pain management and, 98

Dementia
t
, 1584
t
, 
1605
t
addiction and, 98, 98–99
adverse effects/risks of, 98, 98–99
assessment of benefits of, 97
in combination products, 88, 94–95
t
constipation caused by, 73, 97
dependency and, 98, 98–99
dose limitations and, 98
for dyspnea, 25, 72
in end-of-life care, 84
nausea and vomiting caused by, 97, 
 
591
in pain management, 82, 83, 88–99, 
89–95
t
, 96
t
prescribing limitations and, 98–99
receptors for, in nausea and vomiting, 
591
shared decision-making approach to use 
of, 99
side effects/disadvantages of, 89–95
t
, 
97–99
tolerance and, 97, 98, 1111
withdrawal and, 1111–1112
Opisthorchis felineus/viverrini
 
(opisthorchiasis), 
1537
, 1634
Opium, tincture of, for diarrhea, 605, 668
Opportunistic infections, 896, 897, 
1296–
1300
. 
See also
 
anti-TNF agents/biologics and, 1298
1674–1675
fungi/molds causing, 1297, 
1560–1561
in HIV infection/AIDS, 1297, 1338, 
1339
t
, 1345–1346
t
antiretroviral therapy affecting, 1365
CD4 T cell counts and, 1338, 1341, 
1341
f
, 1342
t
prophylaxis/treatment of, 1298–1299
immunization recommendations and, 4, 
1325, 1328
t
prevention of, 1298–1299
in transplant recipients, 1297, 
 
1298–1299
treatment of, 1299–1300
Oprelvekin, 1677
Opsoclonus/myoclonus, 1021–1022
Optic atrophy, 200
Optic disk
crowded, 199, 200
drusen of, 200
in glaucoma, 188
swelling of, 
200–201
Optic neuritis, 
199–200
, 1037
199–200
ischemic, 
199
, 868
OPV (oral/Sabin polio vaccine), 1398
Oral allergy syndrome, 891
Oral candidiasis (thrush), 140
f
, 
236–237
, 
236
f
, 1343–1344, 1350
esophagitis and, 623, 1343–1344, 1550
Oral cavity, 
234–242
anaerobic flora of, pneumonia/lung 
abscess and, 286, 1484
cancer of, 234, 235–236, 235
f
, 1612
t
erythroplakia involving, 234, 
234–235
CMDT2019_Index_p1743-1884.indd   1839

INDEX1840
 
CMDT 2019
Ovulatory dysfunction AUB, 776, 777
Owl’s eye inclusions, 1390
Oxacillin, 1455, 1456, 1468
Oxalate, dietary, urinary stone formation 
and, 976, 976–977
Oxaliplatin, 1616
t
, 1651, 1652
Oxandrolone, 1343
Oxantel pamoate, for trichuriasis/
whipworm, 1541
Oxaprozin, 87
t
Oxazepam, 1067
t
, 1598
Oxcarbazepine, 834, 995
t
, 1099. 
See also
 
Oxiconazole, 107
t
Oximetry. 
See
Oxitriptan, 1030
Oxprenolol, overdose/toxicity of, 1594
Oxybutynin, 66
Oxycodone, 88, 93
t
, 94
t
, 816
t
, 1604
Oxycodone-naloxone, 1030
Oxygen, partial pressure of. 
See
 Arterial 
blood gases
Oxygen saturation. 
See
gases; Pulse oximetry
Oxygen therapy
for asthma exacerbation, 266
f
, 267
for carbon monoxide poisoning, 316, 
1584
t
, 1587
t
, 1595
for COPD, 270–271, 271
t
, 272, 273
for drowning, 1570
1576
for headache, 42, 993
home, 270–271, 271
t
hyperbaric. 
See
therapy
for methemoglobinemia, 1603
t
for respiratory failure, 329–330
for smoke inhalation, 316
Oxyhemoglobin saturation. 
See
 Arterial 
blood gases; Pulse oximetry
Oxymetazoline, 1596
Oxymorphone, 88, 93
t
, 94
t
Oxytocin, 1119
Oxyuriasis. 
See
 Pinworm infection
P2Y
12
 inhibitors, 374, 379, 381, 384–385, 
388
P16/CDKN2A
 mutations, 1636
P53
 mutations, 7. 
See also
 
TP53
 mutations
in colorectal cancer, 1649
P450 aromatase (P450arom) deficiency, 
1209
P450c11 deficiency, 1206, 1209
P450c17 deficiency, 1200, 1209
P450c21 deficiency, 1181, 1182, 1206, 
1207, 1208, 1209, 1210
Pacemaker, 398
for atrioventricular block, 390, 398
AV dissociation and, 398
f
, 422, 429, 432
f
, 351
for syncope, 413–414
Osteosclerosis, vertebral (rugger jersey 
spine), 1166
Ostium primum/secundum atrial septal 
defects, 337, 338
Otalgia (earache), 213, 
218
Otic barotrauma. 
See
 Barotrauma
Otic drops. 
See
 Ear drops
Otitis
external/malignant external, 
212–213
, 
212
f
 causing, 1318
t
, 1322
t
media, 1322
t
acute, 
215
, 215
f
chronic, 
215–216
complications of, 216–217
hearing loss and, 214, 216
in HIV infection/AIDS, 224–225
serous, 
214
nasopharyngeal carcinoma and, 
214, 233
Otoconia, 223
Otogenic meningitis, 217
Otosclerosis, 210, 
217
Ototoxicity, 219
cisplatin, 1680
Ottawa Ankle Rules, 1720
Ottawa subarachnoid hemorrhage clinical 
decision rule, 42
Ovarian ablation. 
See
Ovarian cancer/tumors, 
793–795
, 1614
t
 genes and, 794
dermatomyositis and, 862, 889
estrogen replacement therapy and, 1213
1207
HNPCC/Lynch syndrome and, 681, 682
palmar fasciitis and, 889
prevention of, 16
thyroid tissue in (struma ovarii), 1141
Ovarian cyst. 
See also
 Ovarian cancer/
tumors
in gestational trophoblastic disease, 821
Ovarian failure, 808, 1209, 1210, 1211. 
See 
also
 Amenorrhea; Menopause
Ovarian reserve, 798
Ovarian tumor antigen (CA 125), 794
Ovaries, polycystic. 
See
syndrome
Over-the-counter drugs, use/abuse of, 
1114
antihistamines and, 1114, 1593
stimulants and, 1590
Overflow incontinence
fecal, 598, 685
urinary, 66, 67
Overlap syndrome
biliary disease, 707
connective tissue disease, 
864
Overload proteinuria, 927
Overt GI bleeding, 611
Overweight. 
See
 Obesity/overweight
Ovulation
awareness of, contraception based on, 
805
evaluation of in infertility workup, 798
induction of, for infertility, 795, 798–
799, 1123
Osteitis fibrosa cystica, 940, 1164
Osteoarthritis, 
840–843
, 842
f
. 
See also

805
799, 1123
840–843
, 842
f
. 
See also
 
specific joint affected and
 
Arthritis
See also
 
specific 
joint
coagulase-negative staphylococcal 
infection and, 1457–1458
cervical/neck pain and, 1701, 1702
of hip, 
1708–1709
of knee, 1709, 
1718–1719
842, 850
t
Osteoarthropathy, hypertrophic 
pulmonary, 850, 889
Osteodystrophy, renal, 939–940, 940
f
, 
1164, 1166
Osteogenic sarcoma. 
See
 Osteosarcoma
Osteoma, 
213
Osteomalacia, 940, 
1175–1178
, 1175
t
hypophosphatemic, 906
t
, 1175
t
, 1176, 
1177
osteopenia/osteoporosis and, 1177
tumor-induced, 1176, 1177
Osteomyelitis, 
884–886
, 1321
t
, 
1456
acute pyogenic, 
884–886
bacterial rhinosinusitis and, 227
in drug users, 885, 1311
epidural/epidural abscess and, 885
in sickle cell syndromes, 522, 885
of skull base (malignant external otitis), 
212–213, 212
f
staphylococcal, 885, 1321
t
, 
1456
vertebral, 885, 1456
Osteonecrosis, 
890
1173
Osteopenia. 
See also
 Osteoporosis
Osteophytes, in diffuse idiopathic skeletal 
hyperostosis, 878
Osteoporosis, 
11
, 809, 810, 
1170–1175
, 
1170
t
circumscripta, 1179
corticosteroid therapy and, 263, 1172, 
1218
fractures/bone pain and, 11, 1170, 1707
osteomalacia with, 1177
prevention/treatment of, 
11
, 1172–1175
bisphosphonates in, 11, 1172–1173, 
1707
calcium in, 810, 1172, 1287
estrogen replacement therapy in, 
1211, 1212, 1215
exercise/activity and, 810, 1172
selective estrogen receptor 
modulators in, 1174, 1215
surgery and, 1174–1175
vitamin D in, 810, 1172
screening for, 11
Osteoprotegerin, 547
Osteosarcoma (osteogenic sarcoma), 1615
t
Paget disease of bone and, 1179
parathyroid hormone analogs and, 1174
CMDT2019_Index_p1743-1884.indd   1840

INDEX1841
 
CMDT 2019
Pancreatic secretory trypsin inhibitory 
(PSTI)
 gene, 746, 747
Pancreatic transcription factor mutations, 
1222
Pancreaticolithiasis, 747
Pancreatitis, 
741–748
acute, 
741–746
, 742
t
, 743
t
ascites in, 614, 615, 748
autoimmune, 746, 747
biliary/biliary stricture, 738, 746
choledocholithiasis and, 736, 737, 745
cholelithiasis/cholecystitis and, 741
chronic, 744, 
746–748
, 748
t
cystic fibrosis and, 741, 746, 747
diabetes/hyperglycemia and, 1223
receptor agonist use and, 1235
and, 746, 1165, 1169
hypertriglyceridemia and, 742, 744, 
1275
745, 910
necrotizing, 744, 745
and, 747, 748, 1636
t
post-ERCP , 737, 738, 838
sphincter of Oddi dysfunction and, 743
tropical, 746
tumefactive, 747
Pancreatitis activity scoring system 
(PASS), 743
Pancytopenia, 526, 527, 527
t
in aplastic anemia, 526, 527, 527
t
in leukemia, 539, 542
Panencephalitis, subacute sclerosing, 1030, 
1392
Panhypopituitarism, 1121, 1123
Panic disorder/attacks, 1066, 1068, 1090
chest pain/discomfort in, 29–30
seizures differentiated from, 1000
Panitumumab, 1620
t
Panniculitis
lupus, 161, 854
sclerosing, 146
Panobinostat, 548, 1622
t
Pantoprazole, 608, 621, 631, 633, 637, 639, 
641. 
See also
Panuveitis, 189. 
See also
 Uveitis
Papanicolaou smear (Pap smear), 783
t
, 
784
anal, 1354–1355
gay and bisexual men/MSM, 1734, 
1735
t
, 1736
in cancer screening, 15
t
, 16, 783
t
, 784, 
1355
in CIN, 783
t
, 784, 1355
in HIV infection/AIDS, 1354–1355, 
1355
in lesbian and bisexual women, 1727, 
1729
definition and scope of, 
72
at end of life, 
74–81
. 
See also
 End of life
hospice care and, 77
pain management and, 
84
. 
See also
 Pain 
symptom management and, 
72–74
PALM-COEIN system, 776
Palmar fasciitis, 889
Palms
tinea of, 
121–122
129–130
, 130
f
Palonosetron, 593, 594
t
, 1678. 
See also
 
Palpitations, 
30–32
, 31
t
. 
See also
 
specific 
cause
Palsies. 
See
 
 Paralysis/
palsies
Pamidronate, 1168, 1173, 1219, 1673, 
1676
t
. 
See also
 
Panacinar bibasilar emphysema, 270. 
See 
also
 Emphysema
 (ginseng), 73, 1597
t
Panbronchiolitis, diffuse, 277. 
See also
 
Bronchiolitis
Pancreas
artificial. 
See
 Closed loop systems
cancer of, 1264, 1612
t
, 1615
t
, 
 
1636–1638
pancreatitis and, 747, 748
741–748
. 
See also
 
under 
Pancreatic and
 Pancreatitis
diabetes/hyperglycemia and, 1222, 
1223, 1241, 1636, 1638. 
See 
also
diarrhea/malabsorption and, 603, 
604
f
, 605
t
divisum, 741
1261–1264
, 1262
t
, 1263
t
Pancreatectomy
islet transplantation after, 1241
Pancreatic abscess, 744, 745
Pancreatic ascites, 614, 615, 748
Pancreatic cystadenoma, 1636, 1637, 1638
Pancreatic duct
ascites caused by disruption of, 748
calculus formation in 
(pancreaticolithiasis), 747
Pancreatic duodenal homeobox (PDX1), 
in MODY , 1222
Pancreatic enzyme supplements, 747, 748
t
Pancreatic islets
pancreatogenous 
hypoglycemia syndrome), 
1264
tumors of. 
See
 Islet cell tumors
Pancreatic neuroendocrine tumors, 1264
Pancreatic polypeptide, neuroendocrine 
tumors secreting, 1198
Pancreatic pseudocysts, 742, 744, 745, 
 
748
cystic carcinoma and, 1636
infected (pancreatic abscess), 744, 745
Pacemaker syndrome, 398
Packed red blood cells, 552. 
See also
 
Paclitaxel, 765–766, 768, 1618
t

748
See also
 
t
, 1679
Padua Risk Score, 577, 577
t
Paecilomyces,
 1560, 1561
Paget carcinoma of breast, 126, 126
f
, 757, 
757
f
, 761
Paget disease, 
126
, 126
f
of bone, 
1178–1179
extramammary, 126
mammary. 
See
 Paget carcinoma of 
breast
Pain/pain disorders. 
See also
 
and
 Pain management
acute, 82, 
82–83
cancer, 82, 
83–84
chronic/chronic noncancer (CNCP), 82, 
83
, 
1072–1075
, 1073
f
dynamic, 82
at end of life, 82, 
84
neuropathic, 96, 96
t
See 
also
otic. 
See
 Earache
response to, in coma/stupor, 1040
static, 82
taxonomy of, 
82–84
“Pain contracts, ” 98
Pain management, 
82–102
. 
See also
 
acute pain and, 82
assessment scales and, 84–89, 84
t
back pain and, 1698–1699
barriers to good care and, 85
cancer pain and, 83–84
chronic pain and, 83, 97, 1074–1075
84
integrative, 
100
interventional, 
100–101
, 101
t
85–100
acetaminophen/NSAIDs/COX 
inhibitors, 85, 86–88
t
adjuvant, 100
for neuropathic pain, 96
t
, 99–100
opioids, 82, 83, 88–99, 89–95
t
, 96
t
prescription drug abuse and, 19, 98–99
Pain management specialists, 100–101
Painful bladder syndrome (interstitial 
cystitis), 44, 
974
Painful diabetic neuropathy, 1248, 1249
Painful intercourse (dyspareunia), 796
Painful subacute (de Quervain) thyroiditis, 
1131–1132, 1132, 1133, 1134, 
1140
Painless myocardial infarction, 383
Painless (silent) thyroiditis
postpartum, 1131, 1132, 1133
sporadic subacute (hashitoxicosis), 
1131, 1132, 1133
PAIR, for hydatid cysts, 1540
Palatal myoclonus, tinnitus and, 220
Palbociclib, 770, 1621
t
Palifermin, 1676
t
, 1678
Palilalia, 1031
Palindromic rheumatism, 
889–890
Paliperidone, 208
t
, 1081, 1081
t
, 1082, 
1084
t
Palivizumab, 1379
t
, 1422
Palliative care, 
72–81
CMDT2019_Index_p1743-1884.indd   1841

INDEX1842
 
CMDT 2019
phosphate balance/imbalances and, 913, 
914, 1165
recombinant human (rhPTH), 1163, 
1174
resistance to, in 
pseudohypoparathyroidism, 
1162
Parathyroid hormone (PTH) analogs, for 
osteoporosis, 1174
Parathyroid hormone-related protein 
(PTHrP)
in cancer-related hypercalcemia, 911, 
912, 1166
in hypophosphatemia, 914
Parathyroidectomy, 1168–1169
hypoparathyroidism/hypocalcemia after, 
1161, 1169
in MEN 1, 1169
Paravaccinia, 1431
Parechovirus infection, 
1436
Parenchymal lung disease. 
See
 Interstitial 
Parenteral fluids. 
See
hydration
Parenteral nutritional support, 1289, 
1289
f
, 
1291–1293
, 1292
t
, 
1293
t
. 
See also
support
acidosis and, 921, 1293
t
1292
Paresis (general), in syphilis, 1500
chemotherapy-induced, 1679, 1680
in diabetes, 1223
t
Paricalcitol, 1168
Parietal lobe lesions, 1016
Paris/Paris II criteria, 707, 722
Paritaprevir, 704
t
, 705, 1351
Parkinson disease/parkinsonism, 
 
1024–1027
drug-induced, 1024, 1030, 1085
Huntington disease and, 1028
Wilson disease and, 725, 1025
Parkland formula, 1572
Paromomycin
t
for cryptosporidiosis, 1532
for leishmaniasis, 1515
Paronychia, 140, 162, 162
f
Parotid glands. 
See also
 Salivary glands
in mumps, 1394, 1394
f
sialadenitis affecting, 242
tumors of, 243
Parotitis, 1394, 1395
Paroxetine, 1068, 1090–1093, 1091
t
, 1609. 
See also
Paroxysmal atrial fibrillation, recurrent, 
402, 407
Paranasal sinuses, 
225–234
233–234
, 871, 872
225–229
. 
See also
 
malignant tumors of, 
233
234
, 303
f
Paraneoplastic cerebellar degeneration, 1021
Paraneoplastic pemphigus, 146, 147
Paraneoplastic retinopathy, 1022
Paranodal demyelination, 1047
Paranoid delusions/paranoia
in alcoholic (organic) hallucinosis, 
1106–1107
1079
Paranoid personality disorder, 1077
t
Paraparesis, spastic
in cervical disk disease, 1055
tropical, HTLV-1 associated, 1408, 1409
Paraphilias, 1075, 1076
Paraplegia. 
See also
 Paralysis
after aneurysm repair, 494
after spinal trauma, 1045
Parapneumonic pleural effusion, 322, 323, 
324–325, 324
t
, 1452
Parapoxviruses, 1431
Paraproteins
in myeloma, 547, 964
neuropathy associated with, 1049–1050
549, 550
Parasitic infections, diarrhea in, 599
t
, 
603–604
Parasomnias, 
1103
Parathion poisoning, 1605
Parathyroid glands, 1164
autotransplantation of, after thyroid 
surgery, 1155, 1161
cryopreserved, transplantation of, 1163
1160–1170
. 
See also
 
Hyperparathyroidism; 
adenoma/hyperplasia, 1164, 1169
t
, 1198
resorptive hypercalciuria and, 976
carcinoma, 1164, 1165, 1169, 
 
1169–1170
ectopic, 1164
resection of. 
See
 Parathyroidectomy
thyroid surgery affecting, 1145, 1146, 
1148, 1155, 1160–1161
Parathyroid hormone (PTH). 
See also
 
bisphosphonates affecting, 1173
calcium balance/imbalance and, 910, 
911, 912, 1164, 1165
in hypercalciuria, 912, 976, 1162
910, 1161, 1162, 1163
magnesium imbalances and, 910, 915, 
1161
osteodystrophy, 939, 940, 
940
f
, 1164
Papaverine, for erectile dysfunction 
diagnosis/treatment, 980, 
1250
Papillary muscle dysfunction/rupture

1161
940
f
, 1164
1250
mitral stenosis and, 346
myocardial infarction and, 350, 391
Papillary renal cell carcinoma, 1667
Papilledema, 200
Papillitis, 200
Papillomas
intraductal, nipple discharge and, 752, 
752
t
inverted, 233
recurrent respiratory (laryngeal), 
244–
245
Papillomaviruses. 
See
 Human 
papillomavirus
PAPP-A , testing for, 813
Papular urticaria, 141
Papules, 104
t
, 
148–153
153–155
in ascites, 613–614, 615, 616, 1672
large-volume, 616
Paracetamol. 
See
 Acetaminophen
“Parachute mitral valve, ” 346
Paracoccidioides brasiliensis/lutzii
 
1559–1560
Paradoxic aciduria, 923
Paradoxic embolism, patent foramen 
ovale/TIA and, 338, 1004
Paradoxic sleep, 1101
Paradoxical pulse. 
See
 Pulsus paradoxus
Paraganglioma, 
1190–1194
, 1191
t
familial, 1190
malignant/metastatic, 1193, 1193–1194, 
1194
Paragonimus/Paragonimus kellicotti/
westermani
 (paragonimiasis), 
1537
Parainfluenza viruses, 1421
Paralysis/palsies. 
See also
 
acute flaccid, 1397
West Nile infection and, 1401
in conversion disorder, 1071
facial. 
See
 Bell palsy; Facial neuropathy/
paralysis/palsy
ocular motor, 
201–202
, 201
f
periodic. 
See
 Periodic paralysis
in poliomyelitis, 1397, 1398
progressive supranuclear, 1025
sleep, 1103
spinal cord infarction and, 1015
in tick-borne encephalitis, 1404
vocal fold, 
247–248
thyroid surgery and, 247, 248, 1145–
1146, 1148
Paralytic (adynamic) ileus, 
650–651
Paralytic shellfish poisoning, 1607, 1607
t
Paramalignant pleural effusion, 323, 324, 
324
t
Paramyxovirus respiratory infections, 
1420–1422
CMDT2019_Index_p1743-1884.indd   1842

INDEX1843
 
CMDT 2019
for actinomycosis, 1486
allergy to, 891, 1324, 1325
t
, 
1483, 1484, 1485
for endocarditis, 1466, 1467, 1467
t
, 
1468, 1485
for group B streptococcal prophylaxis in 
pregnancy, 814
t
, 1509
for meningitis, 1454
for non-sexually transmitted 
treponematoses, 1502
t
, 1449
t
pneumococcal resistance and, 1453, 
1454
for pneumonia, 286, 1322
t
, 1453
for rheumatic fever, 436, 437
for streptococcal skin infections, 1322
t
, 
1450
for syphilis. 
See
 Syphilis
Penicillin skin testing, 1324
Penile discharge. 
See
 Urethral discharge
Penile prostheses, 980, 1250
Pentalogy of Fallot, 341
for African trypanosomiasis, 1511, 
1511
t
blood glucose levels affected by (hyper-/
hypoglycemia), 1266, 1555
for 
t
, 
1362
t
, 1555
pneumothorax and, 326
Pentavalent antimonials, 1514–1515, 1515
Pentobarbital, 1002
Pentosan, 974
Pentostatin, 542, 1617
t
Pentoxifylline, 165, 709
Peptic stricture, 617
t
, 621
Peptic ulcer disease, 
635–642
, 638
t
abdominal pain/dyspepsia in, 589, 636
641–642
duodenal ulcers, 634, 635, 636, 637, 639
gastric cancer and, 640
gastric outlet obstruction and, 
642
gastric ulcers, 634, 635, 636, 637, 639
GI bleeding in, 606, 
641–642
H pylori
-associated, 606, 634, 635, 637, 
t
, 639
herpes simplex infection and, 1378
NSAID-induced, 633, 635, 636, 638
t
, 
639–640
pharmacologic/medical management of, 
637–641, 638
t
refractory, 640, 643
silent, 636
ulcer perforation and, 
642
(gastrinoma) and, 635, 640, 
643, 1196
Peptostreptococci, 1483, 1484
Per oral endoscopic myotomy (POEM), 
630
Peramivir, 1379
t
, 1423, 1423–1424, 1426
Perampanel, 995
t
PERC (Pulmonary Embolism Rule-Out 
Criteria), 309, 310
f
, 310
t
Percent free PSA, 1658
Perceptual distortions. 
See also
 Delirium
psychedelics causing, 1112
1079–1080
PE severity index (PESI), 581, 581
t
Peak expiratory flow (PEF), in asthma, 
254
f
, 255
t
t
, 264, 
265
f
, 266
f
Pedal arteries, atherosclerotic/occlusive 
486–487
Pediculosis (capitis/corporis/pubis), 
 
158–159
relapsing fever and, 1503
trench fever and, 1483
typhus and, 1436–1438, 1437
t
 var 
capitis
/var 
corporis
, 
158, 158–159. 
See also
 
Pediculosis
PEG score, 97
Pegaptanib, 193, 194, 197
Pegfilgrastim, 1676
t
, 1677
Peginterferon. 
See also
 Interferon-alpha/
interferon alfa
for hepatitis B, 702, 703
for hepatitis C, 698, 703, 704
for hepatitis D, 703
Pegivirus (hepatitis G virus/HGV), 696
Pegloticase, 847
Pegvisomant, 1127
Pelger-Huet abnormality, 536
Peliosis hepatis, 712, 802, 1483
Pellagra, 1196, 1283
Pelvic abscess, 1484
Pelvic appendicitis, 654
Pelvic floor dyssynergia, 595–596, 595
t
, 
596
Pelvic floor muscle (Kegel) exercises, 66, 
67, 685, 792
Pelvic inflammatory disease (PID)/pelvic 
792–793
, 1322
t
. 
See 
also
 Endometritis; Salpingitis
in actinomycosis, 1486
anaerobic, 792, 793, 1322
t
, 
1484–1485
chlamydial, 792, 793, 1320
t
, 1322
t
gonococcal, 792, 793, 1322
t
, 1481, 1482
IUDs and, 793, 804
828–829
Pelvic organ prolapse, 
791–792
in female, 
779–780
, 790, 791
in male, 971
t
, 972
Pembrolizumab, 1620
t
Pemetrexed, 1617
t
, 1628, 1631
Pemirolast, 181
t
Pemphigoid, bullous, 
148
Pemphigus, 
146–148
, 147
f
foliaceus/erythematosus, 146, 147
paraneoplastic, 146, 147
vulgaris/vegetans, 146, 147, 147
f
Pen injectors, insulin, 1238, 1240
Penbutolol, 464
t
Penciclovir. 
See also
 Famciclovir
Penetrating trauma. 
See
 Trauma
Penicillamine, 209
t
, 726

f
t
See also
See
 Trauma
t
, 726
Penicillin, 1322
t
, 1323
t
. 
See also
 
disorder 
used in
Paroxysmal nocturnal hemoglobinuria, 
520–521
Paroxysmal supraventricular tachycardia 
(PSVT), 
399–400
PARP inhibitors, 771
Pars planitis (intermediate uveitis), 190. 
See also
 Uveitis
Partial seizures. 
See
 Focal (partial) seizures
Partial-thickness burns, deep and 
superficial, 1571
Partner abuse (domestic violence), 17, 
1729–1730
Parvovirus B19 infection. 
See
Pasireotide, 1186, 1187
PASS, 743
Passive smoking (environmental tobacco 
smoke), health hazards of, 7
cancer, 7, 1624
COPD, 268, 270
 species, in animal bite 
infections, 1307
Patch pump, insulin (electronic/
mechanical), 1240
Patellar grind test, 1717
Patellar tracking disorders, knee pain and, 
1709, 1717
Patellofemoral pain/syndrome, 1709, 
1717–1718
Patent foramen ovale, 
336–339
Pathergy phenomenon, 876
Pathologic fractures. 
See
 Fractures
Patient-controlled analgesia (PCA), 82
Patient-delivered therapy, 1310
Patient Health Questionnaire-9 (PHQ-9), 
61, 1089
Patient-provider agreements (“pain 
contracts”), 98
Patient surrogate, 76, 78
Patient values/preferences, assessing in 
older adult, 55
Patiromer, 908
Patulous eustachian tube, 214
Paucibacillary (tuberculoid) leprosy, 1050, 
See also
 Leprosy
Pauci-immune (ANCA-associated) 
glomerulonephritis, 872, 935, 
946
t
, 
950–951
PAX-4 (Arg133Trp)
Pazopanib, 1621
t
, 1668
PCEC (purified chick embryo cell culture) 
rabies vaccine, 1400
PCP . 
See
 Phencyclidine
PCSK9
PCSK9 inhibitors, 10, 367–368, 1274
PCV13 vaccine, 1327
t
, 1328
t
, 1331
t
, 1334
t
, 
1336
t
. 
See also 
Pneumococcal 
vaccine
PD-1 (programmed cell-death-1) 
See
 Anti-PD-1/
PDL-1 agents
PDL-1 expression. 
See also
in bladder cancer, 1666
in gastric cancer, 1642
in lung cancer, 1627, 1628
PDX1, in MODY , 1222
CMDT2019_Index_p1743-1884.indd   1843

INDEX1844
 
CMDT 2019
Peroneal (fibular) nerve, common, injury 
to, 
1053
Peroxisome proliferator-activated receptor 
alpha (PPAR-alpha) agonists, 
1273
t
, 1274
gamma (PPAR-gamma), 
thiazolidinediones affecting, 
1233
Perphenazine, 1081, 1081
t
, 1082
t
, 1083
Persistent anovulation. 
See
 Polycystic 
ovary syndrome
Persistent vegetative state, 
1042
Personality disorders, 
1077–1078
, 1077
t
Perspiration. 
See
 Sweating
Pertussis (whooping cough), 20, 21, 
 
1469–1470
t
, 
1328
t
, 1329
t
See 
also
 Tetanus and diphtheria 
Pertussis vaccine, 1469. 
See also
 Tetanus 
Pertuzumab, 766, 767–768, 770, 1620
t
Pes anserine bursa/bursitis, 1709
PESI score, 581, 581
t
Pessaries, 67, 792
Pesticide poisoning (cholinesterase 
t
, 
1605
Pestiviruses, 1432
Petit mal (absence) seizures. 
See
 Absence 
(petit mal)/atypical absence 
seizures
Petroleum products, toxicity/abuse of, 317, 
1114, 
1605–1606
Petrous apicitis, 216–217
Peutz-Jeghers syndrome, 680–681, 1636
Peyronie disease, 979, 980, 1196
pH
in acid-base disorders, 917. 
See also
 
in diabetic ketoacidosis, 1255, 1256
esophageal, monitoring, 618, 619–620, 
622
in metabolic acidosis, 917, 921
in metabolic alkalosis, 917, 923
pharyngeal, monitoring, 244
in respiratory acidosis, 917, 924
in respiratory alkalosis, 917, 925
urine
manipulation of in poisoning/drug 
overdose, 1585
normal, 975
acidosis, 920, 920
t
, 921
stone disease and, 975, 976, 977
vaginal, 780
Phacoemulsification, 191
Phaeohyphomycosis, 1561
Phalen sign, 1704
Pharmaceuticals. 
See
 
under Drug
Pharmacogenetic tests, in medication 
reaction prediction, 171
Pharyngeal cancer, 1612
t
Pharyngeal dysphagia, 617. 
See also
 
Dysphagia
Pharyngitis, 
238–240
, 238
f
, 1322
t
antibiotics for, 239, 1322
t
, 1449
Perindopril/perindopril combinations, 
368, 467
t
Perinuclear ANCA (p-ANCA). 
See
 
antibody
Periodic limb movement disorder, 1030, 
1103
Periodic paralysis, 906
t
, 
1062
, 1142
Periodontal disease. 
See also
anaerobic, 286, 1483, 1484
Perioperative management. 
See
 
Preoperative evaluation/
perioperative management
Periorbitopathy, prostaglandin-associated, 
188
Peripartum cardiomyopathy, 432, 
446
, 
447
t
Peripartum depression, 1087–1088
Peripheral arterial disease, 
483–491
. 
 
See also
 
specific artery and
 
Peripheral artery aneurysms, 
495–496
Peripheral intravenous lines, infection and, 
1301, 1302–1303, 1323–1324
Peripheral nerve injury/tumor, 
mononeuropathy caused by, 
1052
Peripheral neuropathies, 
1047–1058
. 
See 
also
 
Peripheral pulses. 
See
 Pulses
See
 Vascular 
disorders
Peripheral vein nutritional support, 1289, 
1289
f
, 1291. 
See also
 
Peripheral vestibular disease, 220, 
 
221–222, 221
t
, 222–224
Perirectal abscess, in Crohn disease, 665, 
666, 667
Peristalsis, disorders of. 
See
 Motility 
disorders
Peritoneal carcinomatosis, 616
Peritoneal dialysis, 909
t
, 943. 
See also
 
Dialysis
Peritoneal diseases, 
612–617
, 613
t
. 
See 
also
 
 Ascites; 
nausea and vomiting in, 591, 592
Peritoneal mesothelioma, 1630–1631
Peritonitis, 1321
t
ascites and, 613, 717
bacterial/spontaneous bacterial, 613, 
614–616
, 717, 1321
t
dialysis and, 943
in familial Mediterranean fever, 616
peptic ulcer perforation and, 642
perforated appendicitis and, 654, 839
secondary, 615
Peritonsillar abscess/cellulitis, 
240
Peritrochanteric hip fracture, 1707. 
See 
also
 Hip fracture
Periungual lesions, malignant, 169
Periungual warts, 148
PERK
Permethrin, 157–158, 158
Pernicious anemia, 517

240
See 
also
PERK
gastric cancer and, 635
gastritis and, 634–635
Percussion myoedema, 1399
Percutaneous aspiration/injection/
reaspiration (PAIR), for 
hydatid cysts, 1540
Percutaneous balloon valvuloplasty. 
See
 
Valvuloplasty
Percutaneous coronary intervention (PCI), 
47–48, 375–376, 385–386
Percutaneous dilatational tracheotomy, 
248
Percutaneous transcatheter valve 
replacement. 
See
 
Transcatheter valve 
Percutaneous transhepatic 
cholangiography (PTC), 691, 
736
Percutaneous valvuloplasty. 
See
 
Perennial rhinitis, 229
Perforation
in appendicitis, 654, 654–655, 839
of colonic diverticula, 676
ulcer, 
642
Performance anxiety, 1066
Perfusion scans. 
See
scintigraphy; Ventilation-
perfusion scans
Periampullary/ampullary carcinoma, 
1636–1638
, 1647
Perianal abscesses and fistulas, 665, 666, 
667, 686
Perianal cellophane tape test, in 
enterobiasis/pinworms, 1544
Perianal disease. 
See
 
under Anal and
 
Anorectal disorders
Perianal hematoma, 683
Perianal pruritus. 
See
 Anogenital/perianal 
pruritus
Pericardial disease, 
437–442
in SLE, 854
tumors, 445. 
See also
 Mesothelioma
Pericardial effusions, 
440–441
. 
See also
 
malignant/neoplastic, 437, 438, 439, 
1671, 1672
in pericarditis, 28–29, 437, 439, 440
in pneumococcal pneumonia, 1452, 
1453
Pericardial friction rub. 
See
Pericardial “knock, ” 441
Pericardial tamponade. 
See
 Tamponade
acute inflammatory, 
437–440
, 438
t
chest pain in, 28–29, 438
constrictive, 
441–442
restrictive cardiomyopathy 
differentiated from, 434, 441, 
442
coxsackieviruses causing, 437, 1434
effusion/tamponade and, 28–29, 437, 
439, 440, 1671, 1672
pneumococcal, 1452, 1453
postmyocardial infarction/
postcardiotomy (Dressler 
syndrome), 391–392, 
 
Perichondritis, 211. 
See also
Perihepatitis, Fitz-Hugh and Curtis 
syndrome and, 792
Perihilar cholangiocarcinoma, 1634, 1635
Perilymphatic fistula, 223
CMDT2019_Index_p1743-1884.indd   1844

INDEX1845
 
CMDT 2019
Phytanic acid metabolism, in Refsum 
disease, 1049
Phytonadione, 572, 719. 
See also
 Vitamin 
K
Phytotherapy, for benign prostatic 
Pibrentasvir, 704
t
, 705
Pica, 511
Pickwickian syndrome (obesity-
hypoventilation syndrome), 
327
Piebaldism, 166
Pigmentary skin disorders, 
166–168
, 172
t
, 
1285. 
See also
 
Hyperpigmentation; 
Hypopigmentation; 
Pigmented basal cell carcinoma, 151
Pigmented skin lesions, 104
t
, 
110–113
. 
 
See also
 
Pill-induced esophagitis, 
624
Pilocarpine iontophoresis sweat test, 276
Pilocarpine/pilocarpine combinations, 
183
t
, 187, 189, 865, 1676
t
Pimavanserin, 1027
Pimecrolimus, 106
t
, 114
Pimozide, 1031
Pindolol, 464
t
, 1104
Pineal tumor, 1017
t
Pinguecula/pingueculitis, 
178
“Pink puffers, ” 268, 269
t
Pinta, 
1502–1503
Pinworm infection, 156, 
1543–1544
Pioglitazone, 1230
t
, 1233–1234, 1237, 
1244
f
, 1245, 1599. 
See also
 
Piperacillin-tazobactam, 279
t
, 282, 285
t
, 
1321
t
, 1484
t
Piperaquine, 1518
t
, 1519–1520
with dihydroartemisinin, 1518
t
, 
 
t
, 1520
t
, 
1522, 1524
Piracetam, 1030
Pirbuterol, 259, 262
t
Pirfenidone, 303
Piroxicam, 87
t
Pit viper envenomation, 1607, 1608
Pitavastatin, 367
t
, 1273
t
. 
See also
 Statins
Pitting (nail), 115, 115
f
, 169
Pituitary adenoma, 1017
t
, 1119
ACTH-secreting, 1184, 1186, 1187
diabetes insipidus and, 1124
GH-secreting (acromegaly/gigantism), 
1126–1128
hypopituitarism caused by, 1119
in MEN, 1126, 1128, 1197
t
, 1198
prolactin-secreting, 1126, 1128–1130
surgical resection/removal of, 1123, 
1127, 1127–1128, 1130
thyrotrophe (TSH-secreting), 1141
Pituitary apoplexy, 1122, 1127
Pituitary Cushing disease, 1186, 1187
Pituitary gland
destruction/necrosis of
adrenal crisis caused by, 1124
postpartum hemorrhage causing 
(Sheehan syndrome), 1120
1119–1130
acromegaly/gigantism, 
1126–1128
anterior hypopituitarism, 
1119–1123
. 
See also
 Hypopituitarism
for erectile dysfunction diagnosis/
treatment, 979–980, 1076, 
1092, 1250
nitrate/nitroglycerin contraindications 
and, 388, 980
t
Phospholipase A2 receptor, 957
Phosphorus/phosphate
calcium metabolism and, 910, 912, 913, 
914
in calcium nephrolithiasis/
hypercalciuria, 912, 976
deficiency of, 906
t
, 1175
t
,, 1176, 1177. 
See also
 Hypophosphatemia
for diabetic ketoacidosis, 914, 1257
for hyperglycemic hyperosmolar 
state, 1259–1260
for hypophosphatemia, 914, 1177
for osteomalacia/rickets, 1177
restriction of in chronic kidney 
disease, 940, 942
of, 906
t
, 
912–915
, 913
t
, 915
t
. 
See also
 Hyperphosphatemia; 
osteodystrophy, 914, 930, 
939
f
, 940, 1164
912, 1165
910
parathyroid hormone affecting, 913, 
1165
See
 Phosphaturia
Photoallergy, 163, 164. 
See also
 
Photochemotherapy. 
See
 Psoralen plus 
ultraviolet A (PUV A) therapy
Photodermatitis, 104
t
, 
163–164
, 172
t
Photoepilation, for hirsutism, 1207
Photophobia, in migraine headache, 41
t
Photopsia, in migraine headache, 990
Photosensitive epilepsy, 1000
Photosensitivity
contact, 163, 164. 
See also
 
drugs causing, 163, 164, 172
t
, 1084
Phototherapy, 116, 154, 1096, 1353–1354
Phototoxicity, 163–164
Photovaporization of prostate (PVP), 988
PHQ-9 (Patient Health Questionnaire-9), 
61, 1089
Phthirus pubis,
 158, 159
Phyllodes tumor of breast, 751
Physician-assisted death, 78–79, 78
t
Physician (or Medical) Orders for Life-
(POLST/MOLST) forms, 76
Physician (or Medical) Orders for Scope of 
Treatment (POST/MOST) 
forms, 76

t
forms, 76
Physiologic drug dependence, 98, 1105. 
See also
disorders
Physostigmine, 1584
t
, 1593, 1602
differential diagnosis of, 239, 1387, 
1448–1449
in diphtheria, 239, 1449, 1463
 1449, 1483
mononucleosis and, 238–239, 1386, 
1387, 1448–1449
nonstreptococcal exudative 
(adenovirus), 1429
streptococcal, 238, 239, 239
f
, 1322
t
, 
1448–1449
rheumatic fever and, 240, 435, 436, 
437, 1448, 1449
Pharyngoconjunctival fever, 1429
Pharynx, 
234–242
Phenacetin, in analgesic nephropathy, 960
Phenazopyridine, 44, 969, 1603
Phencyclidine (PCP), 1080, 1104, 
1112
, 
1601–1602
Phenelzine, 1091
t
Phenobarbital, 995
t
, 1002, 1067
t
, 1583, 
1585
t
Phenothiazines, 207
t
, 593, 1081, 1082
t
, 
1592. 
See also
drugs
Phenoxybenzamine, pheochromocytoma/
and, 1193
Phentermine/topiramate, 1244, 1279
Phentolamine, 480
t
, 1250
d
-Phenylalanine derivatives, 1230
t
, 1232
Phenylbutazone, 209
t
, 1099
t
Phenylephrine, for, 508
Phenylethylamine toxicity, 1601–1602
Phenytoin, 208
t
, 834, 995
t
, 1002, 1095
t
, 
1591
Pheochromocytoma, 
1190–1194
, 1191
t
beta-blocker use and, 465, 1193
hypertension in, 455, 456, 1190, 1192
1194
in MEN, 1190, 1197
t
, 1198
Pheochromocytomatosis, 1193
PHEX
 mutation, 1176, 1177
PHF6
Philadelphia chromosome, 529, 534, 538, 
540
Phimosis, in chancroid, 1482
Phlebectomy, 498
Phlebitis. 
See
 Thrombophlebitis
Phlebotomy
potassium levels affected by technique 
and, 907, 907
t
Phlegmon, 241, 666
Phlegmonous (necrotizing) gastritis, 635
Phobic disorders/phobias, 1066, 1068–
1069
Phonophobia, in migraine headache, 41
t
Phosphate. 
See
 Phosphorus/phosphate
Phosphate enema, 597
t
Phosphatonin (fibroblast growth 
factor-23), 913, 939, 1176, 
1177
Phosphaturia, hypophosphatemia and, 914
Phosphodiesterase inhibitors
for asthma, 264
for benign prostatic hyperplasia, 986
t
, 
987
CMDT2019_Index_p1743-1884.indd   1845

INDEX1846
 
CMDT 2019
in pneumonia, 281, 323, 324
t
in tuberculosis, 289, 323, 324
t
Pleural friction rub. 
See
Pleural/malignant pleural mesothelioma, 
1630–1631
Pleuritis/pleuritic chest pain, 28, 28
t
, 
 
321–322
Pleurodesis, for malignant pleural 
effusion, 1672
Pleurodynia, epidemic, 1434
Pleuropulmonary infection, anaerobic, 
278
t
, 283, 
286–287
, 
1484
Plexiform neuroma, 1023
Plexopathy (diabetic amyotrophy), 1049, 
1249
Plummer disease (toxic multinodular 
goiter), 1140, 1146, 1150, 1151
Plummer-Vinson syndrome, 511, 625
PML-RAR
-alpha fusion gene, 538
PMS2
 genes, 681
Pneumatic dilation. 
See
dilation
(Streptococcus pneumoniae)
 
t
, 1321
t
, 
1322
t
, 
1452–1454
brain abscess, 1321
t
drug resistance and, 238, 281, 1453, 1454
endocarditis, 1452, 1453, 1467
immunization against. 
See
 
t
, 
1454
otitis, 1322
t
pericarditis, 1452, 1453
pneumonia, 278
t
, 281, 1321
t
, 1322
t
, 
1344, 1424, 
1452–1454
Pneumococcal vaccine, 3, 282, 1327
t
, 
1328
t
, 1331
t
for asthma patients, 264
infection/AIDS, 282, 1328
t
, 
1331
t
in pneumonia prevention, 3, 282
t
t
, 1336
t
Pneumoconioses, 
317–318
, 318
t
 infection/
pneumonia (pneumocystosis), 
278
t
, 1298, 1344, 1345
t
, 1361, 
1362, 1362
t
, 
1554–1556
CD4 T cell count and, 1342, 1344, 1361, 
1554, 1556
pentamidine for, 1298, 1345
t
, 1362
t
, 
1555
pneumothorax and, 326, 1344, 1555
Pneumomediastinum, pneumothorax and, 
326
Pneumonia, 21, 21
t
, 
278–287
, 278
t
, 1321
t
, 
1322
t
. 
See also
 
and
 Pneumonitis
acute interstitial (AIP), 302
t
adenovirus, 1429
anaerobic, 278
t
, 283, 
286–287
, 1321
t
, 
1484
in aspergillosis, 1558
aspiration, 1322
t
. 
See also
in anaerobic infections, 286, 1322
t
, 
1484
drug use and, 1310
toxic materials and, 317, 1605
Platelet disorders, 
556–567
acquired, 
567
, 568
t
566–567
qualitative, 
566–567
, 568
t
quantitative. 
See also
 Thrombocytopenia
decreased platelet production 
causing, 
556–558
, 557
t
increased platelet destruction causing, 
557
t
, 
558–565
Platelet factor 4 (PF4)-heparin antibody, 
562
Platelet glycoprotein IIb/IIIa receptors. 
See
 
receptors
Platelet-inhibiting agents. 
See
therapy
Platelet-rich protein
for knee arthritis, 1719
Platelet transfusion, 
554
, 559, 560
f
. 
See 
also
contaminated blood and, 553
for DIC, 564
thrombotic microangiopathy and, 562
Platelets. 
See also
 Platelet count; Platelet 
disorders
aspirin/NSAIDs affecting function of, 
568
t
, 843
autoantibodies against. 
See
antibody
in Bernard-Soulier syndrome, 566, 567
in chronic kidney disease/uremia, 568
t
, 
941
drugs inhibiting. 
See
therapy
in Glanzmann thrombasthenia, 566, 567
530
t
, 531, 532, 533, 535, 568
t
sequestration of in spleen, 557
t
, 
566
in storage pool disease, 566
in von Willebrand disease, 570
Platinum analogs/platinum-based 
chemotherapy, 768, 1616
t
, 
1627. 
See also
 Cisplatin
Platypnea-orthodeoxia syndrome, 23, 337
Plecanatide, 597, 597
t
Plenadren, 1183
Plesiomonas,
 diarrhea caused by, 599
t
, 603
Plethysmography, impedance
622
Pleural biopsy, in tuberculosis, 289, 323
Pleural diseases, 
321–327
, 323
t
, 324
t
. 
See 
also
 Pulmonary disorders
occupational, 
320
t
Pleural effusions, 
322–325
, 323
t
, 324
t
, 325
f
drug-induced, 321
t
in lung cancer, 1625, 1671, 1672
malignant, 323, 323–324, 324
t
, 1671, 
1672
paramalignant, 323, 324, 324
t
parapneumonic, 322, 323, 324–325, 
324
t
, 1452, 1453
rheumatoid, 324
t

t
, 1671, 
1672
t
324
t
t
tuberculous, 289, 323, 324
t
Pleural fluid analysis, 322, 324
t
in lung cancer/mesothelioma, 323, 324
t
, 
1625, 1630
Pituitary gland, disorders of (
Cont
.):
diabetes insipidus and, 1120, 1122, 
1124–1126
. 
See also
 Diabetes 
insipidus
hyperprolactinemia, 
1128–1130
, 
1128
t
hyperplasia of, thyrotrophe, 1141
in thyroid disorders, 1136, 1141
tumors of, 1017
t
, 1119, 1124, 1209. 
See 
also
 Pituitary adenoma
Pituitary surgery/microsurgery, 1123, 
1127, 1127–1128, 1130, 1186
Pityriasis
rosea, 
117–118
, 117
f
, 172
t
rubra pilaris, 125
versicolor (tinea versicolor), 
122
Pityrosporum ovale
. 
See
 
Pivot shift test, ACL injury and, 1711
“Pizza-pie” retinopathy, 1389
PKD1
/
PKD2
 mutations, 962
PKR-like ER kinase mutation, 1222
PLA
2
R, 957
Placenta
morbidly adherent (placenta accreta/
increta/percreta), 827
previa, 827
Placental abruption, 827
Placental site trophoblastic tumor, 821
Plague, 1319
t
, 
1480
Plan B, 806
Plantar nerve compression, 1054
Plantar warts, 148
Plasma/plasma fractions/components, 
554–555
, 562, 564, 607, 1591. 
See also
Plasma cell leukemia, 547
Plasma cell myeloma, 
546–548
, 549, 1613
t
amyloidosis and, 547, 551, 964
hypercalcemia and, 546, 547, 964, 1167, 
1673
kidney involvement in, 546, 547, 548, 
927, 
964
“nonsecretory, ” 547
Plasma chromogranin A (CgA) screening 
test. 
See
 Chromogranin A
Plasma renin activity
disease, 1182
Plasmacytomas, 546, 547. 
See also
 Plasma 
, 1516–1524, 1517
f
, 1518
t
, 
1520
t
, 1523
t
. 
See also
 Malaria
falciparum,
 1516–1524, 1517
f
, 1518
t
, 
1519
t
, 1520
t
, 1523
t
knowlesi,
 1516
malariae,
 1516, 1517
f
, 1520
t
ovale,
f
, 1518
t
, 1520
t
, 
1523
t
vivax,
f
, 1518
t
, 1520
t
, 
1523
t
Platelet count
chemotherapy dose modification and, 
1677
t
cyclic oscillations of (cyclic 
thrombocytopenia), 
558
desired ranges for, 556, 557
t
530
t
, 531, 532, 533, 535
Platelet-derived growth factor 
(becaplermin) 165, 1249
CMDT2019_Index_p1743-1884.indd   1846

INDEX1847
 
CMDT 2019
Poliosis, in Vogt-Koyanagi-Harada 
syndrome, 190
f
Poliovirus vaccine, 1398
vaccine-associated disease and, 1398
Pollen-associated food allergy syndrome, 
891
POLST forms, 76
Poly (adenosine diphosphate-ribose) 
polymerase (PARP) inhibitors, 
771
Poly(A)-binding protein-2, 1061
t
Polyangiitis. 
See
 Granulomatosis, with 
polyangiitis; Microscopic 
Polyarteritis. 
See also
 Arteritis
glomerulonephritis in, 946
t
neuropathy associated with, 870, 1050
nodosa, 161, 
870–871
livedo reticularis/racemosa and, 870, 
877
Polyarthralgia/polyarthritis. 
See
 Arthritis/
arthralgia
Polycarbophil, 597
t
. 
See also
Polychondritis, relapsing, 211, 
875–876
Polycystic kidney disease, 
962–963
, 962
t
, 
963
f
Polycystic ovary syndrome (PCOS), 
 
795–796
, 1206, 1207, 1208
amenorrhea in, 795, 1206, 1209, 1210
hirsutism/virilization in, 795, 1206, 
1207, 1208
infertility and, 795, 798
Polycythemia/polycythemia vera, 
 
530–531
, 530
t
, 531
t
, 1613
t
hepatic vein obstruction/Budd-Chiari 
syndrome and, 726
Polydipsia/thirst
in diabetes insipidus, 1124, 1125
in diabetes mellitus, 1223, 1255
hyponatremia caused by, 901
psychogenic, 901, 1080
Polyendocrinopathy-candidiasis-
ectodermal dystrophy, 
autoimmune (APECED), 
1161, 1180
Polyethylene glycol/PEG 3350, 596, 597
t
, 
658, 1585
Polymenorrhea, 776
Polymerase chain reaction (PCR) testing
on cerebrospinal fluid, 1306
in Lyme disease, 1508
in syphilis, 1495–1496
Polymerase inhibitors, 705
Polymorphic reticulosis, 234
Polymorphonuclear neutrophil count. 
 
See
 Neutrophil count
Polymorphous light eruption (PMLE), 
163, 164
Polymyalgia rheumatica, 850, 863, 
 
867–869
Polymyositis, 854
t
, 
861–864
, 862
t
Polymyxin/bacitracin, 179
t
Polymyxin B/polymyxin B combinations, 
180
t
, 285
t
Polyneuropathies, 
1047–1052
. 
See also
 
acute idiopathic. 
See
 Guillain-Barré 
syndrome
cancer-related, 1022, 1050
community-acquired disease, 279
t
, 
281–282
, 1321
t
nosocomial disease, 284–286, 284
t
, 
285
t
in tularemia, 1479
usual interstitial (UIP), 301, 302
t
varicella zoster virus, 835, 1383
Pneumonia Severity Index (PSI), 282
Pneumonitis. 
See also
 Pneumonia
aspiration, 316–317, 1302, 1605
cryptogenic organizing (COP/
t
, 303
hydrocarbon/petroleum distillates/
solvents causing, 317, 1605, 
1606
318–319
, 319
t
interstitial, 300
t
, 321
t
, 1347
mercury causing, 1602
radiation, 
321
toxoplasmic, 1526
Pneumoplasty, reduction, for COPD, 273
Pneumothorax, 23, 24, 
325–327
in COPD, 270, 326
in 
 pneumonia, 326, 1344, 
1555
Pocapavir, 1398
Podagra, 844, 845
f
Podocyte-expressed thrombospondin 
type-1 domain-containing 7A 
(THSD7A), 957
Podophyllum resin (podophyllin/
podofilox), 149, 782
POEM, 630
Poison control centers, 1580
Poison ivy/oak/sumac, 132, 133
f
. 
See also
 
Poisoning/drug overdose, 
1580–1610
. 
 
See also
 
specific drug or agent
abdominal imaging in, 1587
anion gap in, 919, 1587. 
See also
 Anion 
gap/anion gap acidosis
antidotes for, 
1584
, 1584
t
arrhythmias in, 
1582–1583
, 1582
t
coma caused by, 1255
t
, 
1380–1381
diagnosis of, 
1586–1588
, 1586
t
, 1587
t
eye decontamination in, 
1584
, 1589, 
1590
gastrointestinal decontamination in, 
1584–1586
, 1585
t
hypertension in, 
1582
hyperthermia in, 
1583–1584
hypotension in, 
1581–1582
hypothermia in, 
1581
initial evaluation in, 
1580
laboratory tests in, 1586–1587, 1586
t
t
osmol gap in, 1586–1587, 1586
t
physical examination in, 1586
seizures in, 
1583
, 1583
t
skin decontamination in, 
1584
toxicology screen in, 1587, 1587
t
Poisonous mushrooms. 
See
 Mushroom 
poisoning
Poisonous snakes, 1584
t
, 
1607–1608
Poliomyelitis, 
1397–1398
. 
See also

, 1583
t
1584
t
See
 Mushroom 
poisoning
t
, 
1607–1608
1397–1398
. 
See also
 
Poliovirus vaccine
bronchial obstruction and, 253
bronchiolitis obliterans and (BOOP/
t
, 303
t
, 1321
t
, 1322
t
, 1492
t
, 1553
community-acquired, 
278–283
, 279
t
, 
1321
t
cryptococcal, 1556
t
, 303
t
diffuse interstitial, 
301–303
, 302
t
eosinophilic, 305
 causing, 278
t
, 283
t
, 
1344, 1472
herpes simplex, 1378
in histoplasmosis, 1552
hospitalized patient with, 279
t
, 281–282, 
282–283
idiopathic, 301, 302
t
infection/AIDS, 278
t
, 280, 
287, 1344, 1554–1556. 
See also
 
influenza and, 282, 1423, 1424
t
, 
 
283
t
, 1319
t
, 1321
t
, 1322
t
, 
1472–1473
in leptospirosis, 1505
lipoid, 317
in measles, 1392, 1393
t
, 
1472
t
, 1321
t
, 1322
t
necrotizing, 286
nonspecific interstitial (NSIP), 302
t
, 
303, 1347
nosocomial (hospital-acquired/
ventilator/health 
 
care–associated), 278, 278
t
, 
283–286
, 284
t
, 285
t
, 330, 
1303, 1321
t
plague, 1480
pleural effusion in (parapneumonic 
pleural effusion), 322, 323, 
t
, 1452
pneumococcal/streptococcal, 278
t
, 281, 
1321
t
, 1322
t
See
 
. 
See
 
postoperative, 49–50, 50
t
, 1321
t
t
, 
279
t
, 283, 284
t
RSV , 1421
staphylococcal, 278
t
, 279
t
, 280, 283, 
284
t
, 1321
t
treatment of, 1321
t
anaerobic infection, 286–287, 1321
t
, 
1484
CMDT2019_Index_p1743-1884.indd   1847

INDEX1848
 
CMDT 2019
Postexposure rabies immunization, 1399, 
1400
Postgonococcal urethritis/cervicitis, 1491. 
See also
 
Chlamydia
Postherpetic neuralgia, 127, 129, 186, 
997
, 
1384
Posthypercapnia alkalosis, 923, 924
Posthypocapnia acidosis, 921, 925
Postinfarction ischemia/angina, 375, 389
Postinfectious glomerulonephritis, 946
t
, 
948
f
, 
949
Postinfectious irritable bowel syndrome, 
656
Post-inflammatory hyperpigmentation, 
167
Post-kala azar dermal leishmaniasis, 1513
Post-laminectomy pain syndrome, 82
Post-Lyme disease syndrome, 1508, 1508
t
, 
1509
Postmenopausal osteoporosis. 
See
 
Postmenopausal vaginal bleeding, 
778
endometrial carcinoma and, 778, 788
Postmyocardial infarction/postcardiotomy 
pericarditis (Dressler 
 
Postnasal drip, 20, 21, 22, 22
t
Postoperative delirium, 52
Postoperative fever, 1301–1302
Postoperative hyponatremia. 
See
 
Postoperative ileus, 650, 651
Postoperative infection, 1302, 1303
prevention/antibiotic prophylaxis of, 
54
, 
1303
Postoperative meningitis, 1305
t
, 1321
t
Postpartum depression, 1087–1088
Postpartum hemorrhage, pituitary gland 
necrosis caused by (Sheehan 
syndrome), 1120
Postpartum infection
anaerobic, 1484–1485
chorioamnionitis/metritis, 
828–829
mastitis, 140, 753, 
828
Postpartum preeclampsia-eclampsia, 824
Postpartum psychosis, 1087–1088
Postpartum thyroiditis, 1131, 1132, 1133, 
1134, 1140, 1141, 1148
Postphlebitic syndrome, 33
Post-poliomyelitis syndrome, 1397
Postpolypectomy hemorrhage, 679
Postpolypectomy surveillance, 679
Postprandial (reactive) hypoglycemia, 
1261, 1261
t
, 
1265–1266
. 
See 
also
Postrenal acute kidney injury/azotemia, 
930
t
, 931. 
See also
 Acute 
kidney injury
Postsurgical anxiety states, 1116, 1117
Postsurgical meningitis, 1305
t
, 1321
t
Post-thrombotic syndrome, 498, 500, 579, 
586
Posttransfusion purpura (PTP), 
565–566
Posttransplant lymphoproliferative 
disorder, 1388
Posttraumatic epilepsy/seizure disorder, 
999, 1044
Posttraumatic headache, 
993
, 1044
Posttraumatic stress disorder (PTSD), 
1064–1065, 1105
Posttraumatic vertigo, 223
Porphobilinogen, in porphyria, 1681
Porphyria, 1049
acute intermittent, 1049, 
1681–1682
, 
1682
t
cutanea tarda, 
130–131
, 130
f
peripheral nerve involvement in, 1049
Portal cavernoma, 728, 729
Portal decompression, 627
Portal hypertension
ascites in, 612, 613, 613
t
cirrhosis and, 606, 714, 715
noncirrhotic, 
728–729
Portal hypertensive gastropathy, 606, 632, 
633. 
See also
 Portal 
Portal vein thrombosis, 728, 729
Portal venopathy, obliterative, 729
Portopulmonary hypertension, 719
Portosystemic shunts
emergency/surgical, 627, 628
transvenous (transjugular). 
See
 
shunts
Posaconazole, 1299, 1558, 1559, 1562
t
, 
1563
Positioning vertigo, benign paroxysmal 
Positive inotropic agents. 
See
 Inotropic 
agents
Positive-pressure ventilation. 
See
 
Noninvasive positive-pressure 
ventilation
Positron emission tomography (PET)
in angina, 371
in dementia, 1033
in gastroenteropancreatic NETs, 1196
in lung cancer, 1626
1192
in solitary pulmonary nodule, 298
“Post-capillary” pulmonary hypertension, 
313
Postcardiotomy/postmyocardial infarction 
 
Postcholecystectomy syndrome, 
 
735–736
Postcoital contraception, 
805–806
. 
See also
 
Postdysenteric colitis, 1529
Postencephalitic parkinsonism, 1024
Post-encephalitic syndrome, 1404
Postepileptic automatism, 998
Posterior cruciate ligament (PCL), 1709, 
1715–1716
Posterior drawer sign/test, 1716
Posterior ischemic optic neuropathy, 199

1715–1716
Postexposure antiretroviral prophylaxis, 4, 
807–808, 808, 1310, 1358, 
1359
for gay and bisexual men/MSM, 1735
t
, 
1736
Polyneuropathies (
Cont
.):
1051–1052
in critically ill patients, 
1050
in diabetes, 1049, 1248–1249, 1249
f
. 
See 
also
Polypectomy, colonoscopic, 679, 1654
GI bleeding after, 609, 679
Polyphagia with weight loss, in diabetes 
mellitus, 1223
Polypharmacy/pharmacotherapy
chronic pain and, 1073
69
t
psychiatric issues and, 1116–1117
Polypoid corditis, 245
Polyps/polyposis
adenomatous, 678. 
See also
 
Adenomatous polyps
familial, 
680
. 
See also
 Familial 
678–679
cervical, 
782–783
of colon, 
678–682
GI bleeding and, 609, 679
screening for, 678–679, 679, 1653
gastric, 680
hamartomatous, 
680–681
679–682
in HNPCC/Lynch syndrome, 
681–682
, 
1649
juvenile familial, 681
mucosal, 678
nasal, 229, 
232–233
serrated, 678, 1649
submucosal, 678
Polyradiculoneuropathy/polyradiculopathy
in Guillain-Barré syndrome, 1051
Polysomnography, 241, 328
Polystyrene sulfonate, for hyperkalemia, 
908, 909
t
Polysurgery (surgery proneness), 1116, 
1117
Polyuria. 
See also
 
in diabetes insipidus, 911, 1124, 1125
Pomalidomide, 534, 548, 1619
t
Pompholyx (vesiculobullous dermatitis of 
palms and soles), 
129–130
, 
130
f
Ponatinib, 535
Poncet disease, 887
Pontine hemorrhage, 1011
Pool (swimming pool) granuloma, 1488
Popliteal arteries
484–485
Popliteal (Baker) cyst, 1705, 1706, 1709
Porcelain gallbladder, 733
t
, 734
Pork, trichinosis and, 1544
Pork tapeworm 
(T solium),
 
1538
, 1539
CMDT2019_Index_p1743-1884.indd   1848

INDEX1849
 
CMDT 2019
air travel and, 1579
alcohol use during, 812–813, 1107
amenorrhea and, 1209, 1210
anemia during, 510, 814, 
829
antidepressant use during, 1093
antiphospholipid antibody syndrome 
and, 819, 
829–830
, 856–857
antipsychotic drug use during, 1084
appendicitis during, 654, 
839
asthma during, 
833–834
biliary tract disorders and, 
837–839
bleeding during, 557
t
, 820, 821, 
 
827–828
t
, 761–762, 
774
cardiomyopathy of (peripartum 
446
, 
447
t
 infection/testing 
and, 814, 
837
, 1491
cholelithiasis/cholecystitis during, 732, 
838
cholestasis of, 689
t
, 
838
, 
839
chorioamnionitis/metritis and, 
828–829
chronic kidney disease and, 941, 1253
CMV infection during, 1388, 1389, 1390
cocaine use and, 813, 1113
complications of
cardiovascular, 
446–448
, 447
t
, 
833
during first and second trimesters, 
816–822
gastrointestinal/hepatic/biliary, 
 
837–839
834–837
medical conditions, 
829–834
peripartum, 
828–829
during second and third trimesters, 
822–828
coxsackievirus infection during, 1434
dengue and, 1414
depression and (peripartum 
depression), 1087–1088, 1093
diabetes insipidus and, 1125
diabetes mellitus and, 814, 
831–832
, 
831
t
, 1245
t
 
811–812
drug/medication use/avoidance during, 
446, 812, 812–813, 812
t
. 
 
See also
 
ECT during, 1095
ectopic. 
See
 Ectopic pregnancy
endocarditis prophylaxis and, 448, 833
1430
fatty liver of (hepatic steatosis), 699, 
712, 
838
fever during, 35
folic acid deficiency/supplementation 
during, 519, 829
gastrointestinal disorders and, 
837–839
genital warts/wart removal and, 782
glucosuria and, 1224
gonorrhea and, 814, 
837
814, 
834–835
, 1451
growth hormone replacement during, 
1123
headache and, 41
heart disease and, 
446–448
, 447
t
, 
833
hemolytic disease of newborn and, 815
for paragonimiasis, 1537
for schistosomiasis, 1536
for tapeworm infections, 1538
Prazosin, 207
t
, 471–475, 474
t
, 986, 986
t
, 
1066
Prebreakfast hyperglycemia, 1243, 1243
t
Precholecystectomy syndrome, 
735
Prediabetes, 1225, 1265
Prednicarbate, 105
t
Prednisolone, 183
t
, 260
t
, 263
t
Prednisone. 
See also
 
for amiodarone-induced 
hyperthyroidism, 1147
t
, 261, 263
t
for erythema nodosum leprosum, 1490
873
560
f
668, 672
for minimal change disease, 956
for multiple sclerosis, 1037
for 
 infection, 1344, 1345
t
, 
1555
for polymyalgia rheumatica, 869
t
, 1663
for reversal reaction (leprosy), 1490
for SLE, 855
for Still disease, 853
Preeclampsia-eclampsia, 
822–825
, 823
t
, 
832
antihypertensive therapy in, 480
t
, 824
diabetes and, 1253
hypermagnesemia and, 824, 916
late-onset (postpartum), 824
in molar pregnancy, 821
Preexcitation syndromes, 31, 
400–401
Preexposure antiretroviral prophylaxis, 4, 
t
t
, 
1736
Preexposure rabies immunization, 1400
Pregabalin, 96
t
, 99, 995
t
, 1030, 1048, 1249
Pregnancy, 
811–839

t
t
, 
1736
t
, 99, 995
t
811–839
acne treatment and, 135
and, 1181
Postural hypotension. 
See
Postural tremor, drug-induced, 1030
Potassium
in acidosis, 907, 920, 922, 933
aldosterone/aldosteronism and, 905, 
1188
dietary/replacement, 906, 1287
for diabetic ketoacidosis, 1257
t
Graves disease and, 1140
state, 1259
hypertension and, 10, 453, 458
for hypocitraturic calcium 
for hypokalemia, 460, 905–906, 1287
for metabolic alkalosis, 923
disease, 941, 942
for uric acid calculi, 977
905–908
, 
905
t
, 906
t
, 907
t
. 
See also
 
Hyperkalemia; Hypokalemia
periodic paralysis and, 906
t
, 1062
magnesium imbalances and, 905, 915, 
916
t
venipuncture technique affecting, 907, 
907
t
Potassium channel blocking drugs, 393, 
1059, 1060
Potassium concentration gradient, 
transtubular (TTKG), 906
Potassium iodide, 1145, 1160
Potassium-sparing diuretics. 
See
 Diuretics
Potomania, beer, 901
Pott disease (spinal tuberculosis), 
886
Pott puffy tumor, 227
Pouchitis, 674
Poultry, avian influenza and, 1425–1426, 
1426
Powassan encephalitis/agent, 1401, 1404
Power of attorney, durable
for finance matters (DPOAF), 60
for health care, 76
Poxvirus infections, 
1431–1432
. 
See also
 
PPAR-alpha agonists, 1273
t
, 1274
PPAR-gamma, thiazolidinediones 
affecting, 1233
PPD (purified protein derivative) test, 290, 
291
t
, 1344, 1359. 
See also
 
PPSV23 vaccine, 1327
t
, 1328
t
, 1331
t
, 
1336
t
. 
See also 
vaccine
Prader-Willi syndrome, 1119, 1120, 1200
Pralidoxime, 1584
t
, 1595, 1605
Pramipexole, 1026, 1030
Pramlintide, 1231
t
, 1237, 1599
Pramoxine, 103, 108
t
, 156
Prasugrel, 379, 380
f
, 384–385, 392
Pravastatin, 367
t
, 382, 1268, 1270, 1272, 
1273
t
, 1369. 
See also
 Statins
Praziquantel
for intestinal flukes, 1538
CMDT2019_Index_p1743-1884.indd   1849

INDEX1850
 
CMDT 2019
Prehn sign, 973
Premature beats. 
See
 Atrial 
(supraventricular) premature 
beats; Ventricular premature 
beats
Premature ejaculation, 979, 1075. 
See also
 
impotence
Premature menopause/ovarian failure, 
808, 1209, 1210, 1211
Prematurity. 
See
 Preterm labor/birth
Premenopausal bleeding
abnormal, 
776–778
normal menstrual. 
See also
 
Menstruation; Vaginal 
bleeding
Premenstrual dysphoric disorder, 779, 
1088
Premenstrual syndrome/tension, 
 
778–779
Premixed insulins, 1238
t
, 1239–1240
Prenatal care, 
812–814
, 812
t
Prenatal depression, 1093
Prenatal testing/diagnosis. 
See also
 
specific 
Prenatal vitamins, 812, 814–815
Preoperative evaluation/perioperative 
46–54
. 
See also
 
specific type of disorder
antibiotic prophylaxis and, 
54
asymptomatic patient and, 
46
cardiovascular disorders and, 
46–49
, 
47
t
, 48
f
endocrine disorders and, 
53–54
hematologic disorders and, 46, 47
t
, 
51–52
, 52
t
kidney disease and, 
54
, 54
t
50–51
neurologic disorders and, 
52–53
ophthalmic effects of agents used in, 
207
t
pulmonary disorders and, 
49–50
, 50
t
Prepatellar bursae/bursitis, 1705, 1709
Prerenal acute kidney injury/azotemia, 
t
. 
See also
 Acute 
Presbyacusis (hearing impairment in 
elderly), 70, 218
Presbyopia (vision impairment in elderly), 
69–70
Prescription drug abuse, 19, 98–99. 
See 
also
 Substance use disorders
Preservatives/preservative-free eye drops, 
189, 206
toxic/hypersensitivity reactions and, 
177, 
206
, 206
f
Pressure injury (pressure ulcers), 
68–69
, 
68
t
Presurgical anxiety states, 1116
Preterm labor/birth, 813, 814, 
825–827
Pretibial myxedema (Graves dermopathy), 
Preventive care. 
See
Prevotella/Prevotella melaninogenica,
 
1319
t
, 1483, 1484
Priapism, 979
psychosis and, 1087–1088
pulmonary hypertension and, 444, 446, 
447
t
Q fever during, 1444, 1445
rabies vaccination and, 1400
radiation exposure during, 813
and, 1143, 1145
respiratory alkalosis and, 924
Rhesus alloimmunization (Rh 
incompatibility) and, 813, 814, 
815
. 
See also
 Rh
o
 (D) immune 
globulin
rubella exposure/vaccination and, 816, 
1328
t
, 1329
t
, 1393, 1396
scabies and, 157
screening tests in, 813–814
seizures and, 824, 
834
, 1001
sickle cell anemia and, 813, 829
smoking during, 812–813
STDs and, 
837
syphilis/syphilis testing and, 814, 
837
, 
1493, 1496, 1496
t
, 
1502
termination of
breast cancer and, 761, 774
by delivery. 
See also
 Labor and 
delivery
in acute fatty liver of pregnancy, 
838
by elective/induced abortion, 
806
heart disease and, 833
hypertension and, 833
by recurrent abortion, 
819
by spontaneous abortion, 
817–819
tetanus/diphtheria/pertussis 
immunization and, 816, 1325, 
1328
t
, 1329
t
, 1459, 1463, 1470
thrombocytopenia during, 559, 
566
thyroid cancer and, 1155
thyroid disease and, 
830–831
, 1131, 
1132, 1133, 1134, 1141, 1142, 
1143, 1155. 
See also
 
specific 
type
1141
thyroiditis during, 830, 831, 1131, 1132, 
1133, 1134, 1140, 1141, 1148
toxoplasmosis during, 813, 1526, 
 
1526–1527, 1527
815–816
, 
1316, 1579
trophoblastic disease and, 
821–822
, 
1141, 1614
t
tuberculosis and, 293, 294, 
836
of unknown location, 811
urinary tract infection during, 43, 
834
varicella (chickenpox) and, 
825
, 1328
t
, 
1330
t
, 1384, 1385
vomiting of, 592, 
816–817
, 837
821, 1141
von Willebrand disease and, 571
weight gain recommendations and, 814
yellow fever vaccination and, 1417
Zika virus infection and, 812, 815, 1418

821, 1141
Pregnancy-associated plasma protein-A 
(PAPP-A), testing for, 813
Pregnancy tests, 811. 
See also
 Human 
Pregnancy (
Cont
.):
hepatitis B/hepatitis B vaccination and, 
695, 696, 703, 813, 816, 
 
836–837
, 1328
t
hepatitis C and, 697, 
837
hepatitis E and, 699
herpes simplex/zoster during, 835, 
837
, 
1377–1378, 1380
HHV-6 or HHV-7 infection during, 
1391
HIV infection/AIDS and, 814, 
836
, 
1340, 1358
HPV vaccine and, 1328
t
, 1331
t
hyperaldosteronism during, 1189
during, 1165, 1166–1167
hypercortisolism and, 1185
hypertension and, 454, 455, 822–825, 
823
t
, 
832–833
. 
See also
 
hyperthyroidism during, 830–831, 1141, 
1142, 1143, 1146–1147, 1148
hypoparathyroidism during, 1163
hypothyroidism during, 1134
immunizations during, 
815–816
, 
1325
, 
1328
t
influenza/influenza vaccination and, 
816, 1325, 1328
t
, 1329
t
, 1424
iodine deficiency and, 1159
iron requirements/deficiency anemia 
during, 510, 814, 814–815, 
829
lactation and. 
See also
 Lactation
lesbian and bisexual women and, 1731–
1732
listeriosis during, 600, 1463, 1464
liver disorders and, 
837–839
luteoma of, 1206
Lyme disease and, 1508, 1509
lymphocytic choriomeningitis and, 
1405–1406
malaria and, 815, 1516, 1524
manifestations of, 811
measles and, 816, 1328
t
, 1329
t
, 1393
melasma/chloasma and, 166
meralgia paresthetica and, 1053
mitral stenosis and, 347
MMR vaccine and, 816, 1328
t
, 1329
t
, 
1393, 1396
molar (hydatidiform mole), 
821–822
, 
1141
multiple gestation, 799, 814, 827, 1123
nutrition in, 812, 
814–815
208
t
parathyroidectomy during, 1168
and, 1191
preeclampsia-eclampsia in, 822–825, 
823
t
, 832, 916
prenatal care and, 
812–814
, 812
t
preterm labor/birth and, 813, 814, 
 
825–827
See
prolactinoma/hyperprolactinemia in, 
1128, 1129
prosthetic heart valves and, 363–364, 
364
t
pseudohyperparathyroidism of, 
 
1166–1167
CMDT2019_Index_p1743-1884.indd   1850

INDEX1851
 
CMDT 2019
Proliferative retinopathy, 197, 1247
Promethazine, 593, 594
t
, 1592. 
See also
 
Pronator teres syndrome, 
1052
Pronouncement (death), 81
Propafenone, 393, 394
t
, 406
Propamidine, 180
t
Propanil toxicity, 1603
Prophylactic antibiotics. 
See
, 134, 1321
t
. 
See 
also
 Acne
Propofol, 1002, 1583
Propoxyphene, 1069
t
, 1604
Propranolol/propranolol-HCTZ, 464
t
. 
See 
also
 Beta-adrenergic blocking 
drugs
1095
t
for arrhythmias, 394
t
, 400, 403
for hypertension, 464
t
1143–1144, 1146, 1147, 1148
t
overdose/toxicity of, 1593, 1594
for thyroid nodules/goiter, 1146
for thyroiditis, 1146
Proprotein convertase subtilisin/kexin type 
9 (PCSK9) inhibitors, 10, 
Propylthiouracil, 830–831, 1144, 1146, 
1146–1147, 1147, 1148
Prosopagnosia, 1016
Prostacyclin/prostacyclin analogs, for 
444
Prostaglandin analogs, 184
t
, 188. 
See also
 
Prostaglandin-associated periorbitopathy, 
188
Prostaglandins
treatment, 980, 1250
Prostate cancer, 1612
t
, 1615
t
, 1633
t
, 1650
t
, 
1657–1664
, 1660
f
, 1662
t
breast cancer and, 774, 775
t
, 1657, 
1659
t
, 1663–1664, 1663
t
localized, 1661
locally/regionally advanced, 1661–1662
metastatic, 1662–1663, 1662
t
pathology/staging of, 1659
CAPRA score and, 1663–1664, 1663
t
t
, 1658–1659, 1659
t
, 
1660
f
surgery for, 1661
1201, 1203
Prostate gland
benign hyperplasia of, 
983–988
, 984
t
, 
985
f
, 986
t
. 
See also
 Benign 
prostatic hyperplasia
biopsy of, 1658, 1660
f
cancer of. 
See
 Prostate cancer
inflammation/infection of. 
See
 
ectopic pregnancy/viability and, 811, 820
in estrogen replacement therapy, 
 
1214–1215
1738
t
for obesity-hypoventilation syndrome, 
327
for preterm labor prevention, 826
receptors for, in breast cancer, 762, 763, 
764, 765
t
, 768, 772
topical, 1214–1215
Progestin minipill, 802–803
Progestin withdrawal test, 1210
777, 778
for endometriosis, 790
1211, 1213–1214, 1214, 
 
1214–1215
with estrogens, 809, 1211, 1212, 1213, 
1214
IUDs releasing, 1211, 1215
oral, 1214, 1214–1215
long-acting (contraceptive injections/
implants), 
803
t
Programmed cell-death-1 (PD-1) 
See
Progressive bulbar palsy, 1046
“Progressive massive pulmonary fibrosis, ” 
318
Progressive multifocal 
leukoencephalopathy (PML), 
1407–1408
drug-induced, 665, 1407, 1408
in HIV infection/AIDS, 1349, 1407, 
1408
Progressive spinal muscular atrophy, 1046
Progressive supranuclear palsy, 1025
Proguanil-atovaquone (Malarone), 1518
t
, 
1520
t
t
Proinsulin, in insulinoma, 1195, 1262, 
1262
t
PROKR2
 mutation, 1200
Prolactin (PRL), 1119
cardiomyopathy of pregnancy and, 1129
deficiency of, 1121
excess of, 
1128–1130
, 1128
t
. 
See also
 
in feminizing therapy/transgender 
woman, 1740
t
, 1741
1201
 
1129–1130
in psychogenic nonepileptic/
identification, 1001, 1071
tumors secreting, 1123, 1126, 
 
1128–1130
Prolactinoma, 1123, 1126, 1128–1130
GH cosecretion and, 1126, 1127, 1128, 
1129
 
1129–1130
in MEN, 1128
erectile dysfunction therapy causing, 
980, 1250
trazodone causing, 1094, 1102

1129
 
1129–1130
980, 1250
Prickly heat, 139
G6PD deficiency and, 1518, 1521
1518, 1518
t
t
, 
1521, 1523
t
for 
t
, 1555
Primary angiitis of central nervous system, 
876–877
Primary biliary cholangitis/cirrhosis, 707, 
721–723
Primary cerebral/central nervous system 
lymphoma, 544–545, 1018
t
, 
Primary effusion (body cavity) lymphoma, 
1391
Primary lateral sclerosis, 1046
Primary (idiopathic) pulmonary 
443
Primary sclerosing cholangitis, 
739–741
Primidone, 995
t
, 1024
Primrose oil (oil of evening primrose/
OEP), for fibrocystic 
condition, 751
Prinzmetal (variant) angina, 378
Prions (proteinaceous infectious particles)/
prion protein mutations, 
1035, 1406
Creutzfeldt-Jakob disease caused by, 
1025, 1030, 1035, 1406–1407
disorders caused by, 
1406–1407
Pritelivir, 1378
PRKAR1A
 mutation, 1186
PRNP
 gene, 1035
Pro-IGF-II, nonislet cell tumor 
hypoglycemia and, 1265
Probenecid, 847, 851, 1322
t
Probiotics, 596, 599, 659, 660, 673, 674
Procainamide, 389, 393, 394
t
, 400, 1095
t
Procalcitonin, 
1485
Procarbazine, 1095
t
, 1617
t
Prochlorperazine, 97, 593, 594
t
, 991, 1343, 
1592, 1678. 
See also
 
Proctitis, 684
anorectal bleeding and, 610
chlamydial, 684
in gonorrhea, 684, 1481
herpes simplex, 684, 1377, 1378, 1380
HPV/condylomata acuminata and, 684
1490
radiation, 610
in syphilis, 684
in ulcerative colitis, 671, 672
Proctoscopy, surveillance, in rectal cancer, 
1653
Proctosigmoiditis, in ulcerative colitis, 
671, 672
Proctosigmoidoscopy. 
See
 Sigmoidoscopy
Profunda femoris artery, atherosclerotic/
occlusive disease of, 485
Progestagen, in feminizing hormone 
therapy, 1738, 1738
t
Progesterone. 
See also
 Progestins
CMDT2019_Index_p1743-1884.indd   1851

INDEX1852
 
CMDT 2019
kidney disease/injury caused by, 622, 
637
levothyroxine therapy affected by, 1138
for NSAID gastritis/toxicity mitigation, 
85, 633, 639–640, 640, 843
for peptic ulcer disease, 608, 637, 638, 
638
t
, 639, 639–640, 641
for stress gastritis, 632, 633
for Zollinger-Ellison syndrome/
gastrinoma, 644, 1196
Protozoal infections, 
1510–1534
. 
See also
 
t
, 603–604
t
Protriptyline, 1091
t
Providencia,
 1319
t
Proximal renal tubular acidosis, 906
t
, 920, 
920
t
, 922. 
See also
 Renal 
tubulointerstitial disease and, 960
Prozone phenomenon, 1495, 1501
PrP[C]/PrP[Sc], in prion disease, 1406
PRSS1
 gene, 746
Prurigo, actinic, 163
Pruritus (itching), 104
t
, 
155–160
. 
See also
 
ani/anogenital/perianal, 120, 156, 
 
156–157
, 156
f
, 686–687
in chronic kidney disease/uremia, 155, 
937
in decompression sickness (skin bends), 
1576
drugs for, 103–109, 107–108
t
, 155
of ear canal, 
213
vulvae, 156
Pseudallescheria boydii,
 1560
Pseudoachalasia, 629
Pseudoallergic reactions, 
892
, 893
t
Pseudoaneurysm
femoral artery, 495
myocardial rupture and, 391
pancreatic, GI bleeding and, 607, 
 
744
Pseudobacteremia, 1302
Pseudobulbar palsy, 1046, 1047
Pseudo-Cushing syndrome, 1186
Pseudocysts
See
 Pancreatic pseudocysts
Pseudodementia (depression and 
dementia), 57, 1032–1033, 
1116
Pseudoephedrine. 
See also
 Decongestants
t
Pseudoepileptic seizures. 
See
 Psychogenic 
nonepileptic seizure
Pseudofolliculitis, 137, 138
Pseudogout, 845, 848
Pseudogynecomastia, 1204
Pseudohermaphroditism, 1209
Pseudohyperkalemia, 907
Pseudohyperparathyroidism of pregnancy, 
1166–1167
Pseudohyperphosphatemia, 915
t
Pseudohypoaldosteronism, types I and II, 
454, 906
t
Pseudohypoglycemia, 1226
Pseudohyponatremia, 900, 902
Pseudohypoparathyroidism, congenital, 
1162. 
See also
 
Protein-bound paclitaxel, 1618
t
. 
See also
 
Paclitaxel
Protein C deficiency/resistance
t
Protein-calorie undernutrition, 
1276–1277
Protein/creatinine urinary concentration, 
927. 
See also
Protein-energy malnutrition, 
1276–1277
Protein-losing enteropathy, 
655
intestinal lymphoma and, 1647
in Whipple disease, 647
Protein-restricted diet, 1287
for chronic kidney disease/nephrotic 
syndrome/nephrotic spectrum 
disorders, 942, 955, 1248, 
1287
for hepatic encephalopathy, 718, 1287
for urinary stones, 975, 976
Protein S deficiency
t
Proteinaceous infectious particles. 
See
 
Prions
Proteinase-3 ANCA (PR3-ANCA). 
See
 
antibody
Proteinuria, 926, 926–927. 
See also
 
specific 
cause
Bence Jones. 
See
 Bence Jones 
in nephritic syndrome/nephritic 
spectrum disease, 945, 945
f
f
, 
in preeclampsia-eclampsia, 822, 823
t
, 
824
Proteus/Proteus mirabilis/vulgaris,
 1319
t
, 
1322
t
Prothrombin (factor II), acquired 
antibodies to, 
572
Prothrombin mutation, DVT/PE (venous 
306, 596
t
Prothrombin time, 690
t
in anticoagulant overdose, 1591
in jaundice/liver disease, 709, 720, 
 
720
t
Proton beam radiosurgery, for pituitary 
adenoma, 1127
adverse effects of, 621–622, 637
antiplatelet therapy and, 640
atazanavir and, 1370
for Barrett esophagus, 620
clopidogrel interaction/
coadministration and, 640
for esophageal motility disorders, 631
after fibrinolytic therapy for STEMI, 
387
for GERD/esophagitis, 619, 621–622, 
622, 631
in 
H pylori
t
, 639
H pylori
 test results affected by, 634, 637

387
622, 631
in 
H pylori
t
, 639
H pylori
hypomagnesemia and, 916
Prostate Health Index (PHI), 1659
Prostate-specific antigen (PSA), 1657
in benign prostatic hyperplasia, 984, 
985
f
in prostate cancer, 1657–1658, 1661
in CAPRA assessment tool, 1663, 
1663
t
screening and, 15
t
, 1658, 1659
t
, 1660
f
Prostate-specific antigen (PSA) free 
fraction, 1658–1659
Prostate-specific antigen (PSA) velocity, in 
cancer screening, 1658, 1659, 
1660
f
Prostate-specific membrane antigen 
(PSMA), 1658
Prostatectomy
f
, 
986
t
, 987–988
open, 987–988
acute bacterial, 968
t
, 
970–971
, 971
t
chronic bacterial, 968
t
, 
971–972
, 971
t
gonococcal, 1309, 1481
nonbacterial, 971
t
, 
972
Prostatodynia, 971
t
, 
972–973
Prosthetic heart valves. 
See also
 Valve 
anticoagulation therapy and, 347, 355, 
356, 
363–365
, 364
t
infection and, 1457–1458, 
1468, 1469
endocarditis and, 1464, 1466–1467, 
1468. 
See also
t
, 1469
pregnant patient and, 347, 363–364, 
364
t
Prosthetic joints. 
See
Protamine, 574, 582
Protease, in pancreatic enzyme 
supplements, 748
t
Protease inhibitors, 1364
t
, 1369–1370. 
See 
also
boosted, 1369
oral contraceptive drug interaction 
and, 800
for hepatitis C, 703–704, 704
t
, 705
lipid abnormalities caused by, 1355, 
1369
resistance to, 1369
Proteasome inhibitors, 1619
t
, 1680
Protein
t
, 1306
dietary, 1287
chronic kidney disease/nephrotic 
disorders and, 942, 955, 1287
deficiency of (protein-energy 
1276–1277
restriction of. 
See
diet
pleural fluid, 322
urinary, 926, 926–927. 
See also
 
ratio of to urinary creatinine, 927
CMDT2019_Index_p1743-1884.indd   1852

INDEX1853
 
CMDT 2019
pulmonary hypertension, 
312–315
, 
442–444
, 443
t
t
thromboembolism, 
305–312
, 306
t
, 309
t
, 
310
f
, 310
t
, 311
t
. 
See also
 
vasculitis, 
315
Pulmonary cysts, hydatid, 1540
Pulmonary decompression sickness, 1576
Pulmonary disorders. 
See also
 
and under Respiratory and 
Breathing
acute respiratory distress syndrome 
(ARDS), 
331–333
, 331
t
airway disorders, 
252–277
in aspergillosis, 1557, 1558
aspirin (NSAID) sensitivity and, 253, 
892
in blastomycosis, 1559
chronic. 
See
 
circulatory, 
305–316
cocaine use/abuse and, 320, 1113
t
, 1553, 1554
in common variable immunodeficiency, 
896
t
drug-induced, 300
t
, 
320
, 321
t
environmental, 300
t
, 
316–321
eosinophilic, 
305
315, 871, 872
t
, 1318
t
hantaviruses causing, 1415–1416
in HIV infection/AIDS/
immunocompromised host, 
278
t
, 287, 1344–1347. 
See also
 
Pneumonia; Tuberculosis
270, 1328
t
, 1331
t
278–297
, 300
t
. 
See also
 
Pneumonia
t
, 283, 
286–287
, 
1484
 causing, 
1470
infiltrates in immunocompromised 
host and, 
287
mycobacterial
nontuberculous, 
295–297
, 1347, 
1487
287–295
, 289
t
, 290
f
, 
291
f
, 292
t
, 293
t
. 
See also
 
viral, 
1420–1428
influenza and, 282, 1423
interstitial (diffuse parenchymal), 
 
300–305
, 300
t
, 302
t
Kaposi sarcoma, 154, 1347
 
1726–1727
in measles, 1392–1393
1629–1630
Psychologic disorders. 
See
Psychologic drug dependence, 1105. 
See 
also
Psychopathic (antisocial) personality 
disorder, 1077, 1077
t
, 1078
Psychosexual disorders, 
1075–1077
sexual dysfunction and. 
See also
 Sexual 
Psychotic depression/psychotic major 
depression, 1079, 1087, 1090
Psychotic disorders (psychoses), 
1078–
1086
. 
See also
 Schizophrenia
alcohol withdrawal and (delirium 
tremens), 1106, 1110
alcoholic (organic) hallucinosis, 
 
brief/acute, 1079
delusions and, 1079
depression and, 1079, 1087, 1090
drug-induced/toxic, 1080
drug therapy for, 1080–1086, 1081
t
, 
1082
t
, 1084
t
. 
See also
 
in hypothyroidism (myxedema 
madness), 1135, 1137
intensive care unit, 1116
Korsakoff, 
1040
manic, 1079, 1080
phencyclidine use/abuse and, 1112
postpartum, 1087–1088
stimulant/cocaine abuse and, 1080, 
1104, 1113
suicide risk and, 1080, 1085, 1089
Psychotic resolution, 1080
Psychotropic agents. 
See also
 Antianxiety 
drugs; Antidepressants; 
t
Psyllium fiber, 597
t
. 
See also
PTEN multiple hamartoma syndrome 
(Cowden disease), 681
Pteroylmonoglutamic acid. 
See
 Folic acid
Pterygium, 178
PTF1A
Puberty
delayed/failure to enter, 1120, 1122, 
1209
hypogonadism and, 1120
Turner syndrome and, 1216
gynecomastia during, 1204, 1205
Pubic lice, 158, 159. 
See also
 Lice
Puerperal infections
chorioamnionitis and metritis, 
 
828–829
828
Puffer fish poisoning, 1607, 1607
t
Puffy tumor, Pott, 227
Pulmonary alveolar proteinosis, 
304–305
Pulmonary angiography, in pulmonary 
embolism, 307, 308, 309, 310
f
Pulmonary arterial hypertension, 312. 
See 
also
 Pulmonary hypertension
Pulmonary artery catheter, in shock 
management, 507
Pulmonary aspiration syndromes, 
316–
317
, 1302. 
See also
Pulmonary circulation disorders, 
305–316

See 
also
316–
317
, 1302. 
See also
305–316
alveolar hemorrhage syndromes, 
 
315–316
Pseudomembranous colitis, 660. 
See also
 
Pseudomonas aeruginosa,
 1319
t
, 1321
t
endocarditis and, 1469
1321
t
, 1674
malignant external otitis caused by, 212, 
212
f
, 213
t
, 279
t
, 283, 
284
t
, 1344
urinary tract infection caused by, 1321
t
Pseudo-obstruction, intestinal
651–652
chronic, 
652–653
Pseudo-papilledema, 200
Pseudoporphyria, 131
Pseudorheumatoid arthritis, 848
Pseudoseizures. 
See
Pseudoseptic arthritis, 882
Pseudothrombocytopenia, 
566
“Pseudothrombophlebitis, ” 33
Pseudotumor cerebri, 41, 994, 
1022–1023
Pseudoxanthoma elasticum, 516
PSI (Pneumonia Severity Index), 282
Psilocybin, 1112
Psittacosis (ornithosis), 1320
t
, 
1492
Psoas sign, 654
Psoralen plus ultraviolet A (PUV A) 
therapy, 116, 154, 167. 
See also
 
Phototherapy
Psoriasiform eruptions, 172
t
Psoriasis, 
115–117
, 115
f
in HIV infection/AIDS, 884, 1353–1354
Psoriatic arthritis, 115, 
879–880
, 884
Psoriatic spondylitis, 879
PSS1
PSTI
Psychedelic/hallucinogen drug abuse, 
1112
, 1116, 
1601–1602
Psychiatric/psychologic disorders, 
1063–
1118
. 
See also
 
chest pain/discomfort and, 29–30, 631
cognitive impairment/dementia and, 
1032–1033
eating disorders (anorexia/bulimia 
nervosa) and, 1280–1281
in elderly, urinary incontinence and, 65
fatigue/chronic fatigue and, 38, 39–40
hospitalization and illness and, 
 
1116–1118
hyponatremia and, 901
intentional drug/poison ingestion and, 
1580
irritable bowel syndrome and, 656, 657, 
659
 
1730–1731
palpitations and, 31, 32
t
“Psychogenic cough, ” 22
Psychogenic nonepileptic seizure (PNES/
pseudoepileptic seizure), 
Psychogenic polydipsia, 901, 1080
Psychologic challenges, for terminally 
 
ill/dying patient, 79–80
CMDT2019_Index_p1743-1884.indd   1853

INDEX1854
 
CMDT 2019
Pulmonic stenosis. 
See
 Pulmonary valve 
stenosis
Pulsatile tinnitus, 218, 220
Pulse oximetry/CO-oximetry. 
See also
 
in carbon monoxide poisoning, 1595
Pulses, in hypertension, 457
Pulsus paradoxus, 440
asthma exacerbation and, 256
t
Pupillary dilation, glaucoma and, 187, 206
Pupillary reactions, in coma/stupor, 1040
Pure autonomic failure, 1003
Pure red cell aplasia, in erythrovirus 
(parvovirus) infection, 1430
Purgatives, for constipation/preoperative 
bowel cleansing, 597
t
Purified chick embryo cell culture (PCEC) 
Purified insulin, 1238, 1246, 1247. 
See also
 
Purified protein derivative (PPD) test, 290, 
291
t
See also
 
Purine analogs, 1617
t
Purines, dietary, 846
t
in hyperuricemia/gout, 846, 846
t
in urinary stone formation, 976
Purpura
cancer-related, 889
in cryoglobulinemia, 875, 952
fulminans, 1391
Henoch-Schönlein, 
875
, 946
t
, 
950
levamisole-associated, 
874
posttransfusion, 565
thrombotic thrombocytopenic (TTP), 
560–562, 561
t
Purulent meningitis, 1304, 1305, 1305
t
, 
1306, 1321
t
Push enteroscopy, 610
Pustular skin disorders, 104
t
, 
134–139
. 
 
See also
 
Puumala virus, 1415
PUV A therapy. 
See
ultraviolet A (PUV A) 
 
therapy
Pyelonephritis, 43, 926, 968
t
, 
969–970
, 
1321
t
, 1322
t
Pygeum africanum,
Pylephlebitis
liver abscess and, 729
perforated appendicitis and, 654
portal vein, 728, 729
Pyoderma
in pediculosis, 158
in scabies, 158
Pyogenic (nongonococcal acute bacterial/
septic) arthritis, 
881–883
, 
1311, 1321
t
Pyogenic cholangitis, 737
Pyogenic hepatic abscess, 
729–730
Pyogenic osteomyelitis, acute, 
884–886
Pyrantel pamoate, 1541, 1544
Pyrazinamide/pyrazinamide combinations, 
292, 292
t
, 293, 293
t
, 294
Pyridostigmine, 1058
6
)
1284
homocystinuria/hyperhomocysteinemia 
and, 1686
pulmonary valve regurgitation and, 362
in scleroderma, 442, 859, 861
Pulmonary infarction, pleural effusion in, 
324
t
Pulmonary infiltrates. 
See also
 Pneumonia
t
infection/AIDS, 
287
, 1298, 
1347
Pulmonary nodules, 
297–299
Pulmonary osteoarthropathy, 
hypertrophic. 
See
 
osteoarthropathy
Pulmonary overinflation syndrome, 1576
Pulmonary radiation fibrosis, 
321
Pulmonary rehabilitation, for COPD, 272
Pulmonary-renal syndromes, 872, 874
Pulmonary thromboembolism. 
See
 
Pulmonary tuberculosis, 
287–295
, 289
t
, 
290
f
, 291
f
, 292
t
, 293
t
. 
See also
 
Pulmonary valve
repair/replacement of, 335, 362–363. 
See 
also
 Valve replacement
in rheumatic fever/heart disease, 435
Pulmonary valve regurgitation, 
362–363
Pulmonary valve stenosis, 
334–335
Pulmonary vasculitis, 
315
Pulmonary vein isolation, 407
Pulmonary venous hypertension, 313. 
See 
also
Pulmonary venous thromboembolism, 23, 
24, 
305–312
, 306
t
, 309
t
, 310
f
, 
310
t
, 311
t
. 
See also
 Deep 
venous thrombosis; Venous 
chest pain/discomfort in, 27, 28, 29, 
306
t
872
hemoptysis in, 26, 27, 306
t
, 309
t
t
, 577–579, 
577
t
, 578–579
t
, 579
t
, 586–587
pulmonary hypertension and, 312, 313, 
314, 443, 443
t
risk/risk stratification for, 27, 29, 305–
306, 306
t
, 309
t
, 310
f
, 310
t
, 
311, 577–579, 577
t
, 581, 581
t
septic, 1311, 1483
t
, 
 
579–587
anticoagulation in, 309–311, 574, 
575–576
t
t
, 581
t
, 
583
t
, 584
t
, 585
t
, 586
t
nonpharmacologic measures in, 312, 
586–587, 587
t
thrombolytic therapy in, 311–312, 
585–587, 587
t

575–576
t
t
, 581
t
, 
583
t
, 584
t
, 585
t
, 586
t
t
t
Pulmonary ventilation-perfusion scans. 
See
 Ventilation-perfusion 
scans
Pulmonic regurgitation. 
See
 Pulmonary 
valve regurgitation
Pulmonary disorders (
Cont
.):
297–299
. 
See also
 Lung 
cancer
t
in nocardiosis, 1486, 1487
t
, 
317–320
, 318
t
, 319
t
207
t
in paragonimiasis, 1537
perioperative evaluation/management/
risk and, 
49–50
, 50
t
pleural diseases and, 320, 
321–327
, 
323
t
, 324
t
443
t
radiation causing, 
320–321
respiratory failure, 
329–331
, 329
t
t
in SLE, 854
toxic. 
See
 Lung, toxic/chemical injury of
tropical pulmonary eosinophilia, 1546
ventilation control disorders and, 
 
327–329
Pulmonary edema, 
424–425
t
in heart failure (cardiogenic), 415, 
 
424–425
high-altitude (HAPE), 
1577–1578
t
noncardiac causes of, 424
t
transfusion-related (transfusion-related 
acute lung injury), 554
Pulmonary embolectomy, for pulmonary 
embolism, 312
Pulmonary embolism. 
See
 Pulmonary 
venous thromboembolism
Pulmonary Embolism Rule-Out Criteria 
(PERC), 309, 310
f
, 310
t
Pulmonary embolism severity index 
(PESI), 581, 581
t
t
idiopathic (IPF), 301, 303, 303
f
“progressive massive, ” 318
321
in asthma/asthma exacerbation, 254
f
, 
255
t
t
, 265–267, 
265
f
, 266
f
in COPD, 268–269, 269
t
in lung cancer, 1626–1627
preoperative, 50
Pulmonary heart disease (cor pulmonale), 
269, 270, 273, 415
Pulmonary hemosiderosis, idiopathic, 
315–316
Pulmonary hypertension, 
312–315
, 
 
442–444
, 443
t
. 
See also
 
drug and toxin, 442–443, 443
t
heart failure and, 312–313, 415, 416
in hyperthyroidism, 1141
in mitral stenosis, 346, 347
pregnancy and, 444, 446, 447
t
CMDT2019_Index_p1743-1884.indd   1854

INDEX1855
 
CMDT 2019
pericarditis caused by, 438
pneumonitis and, 
321
pulmonary fibrosis and, 
321
1671
558
for thyroid cancer, 1157
thyroid cancer and, 1149, 1152
vomiting and, 592
t
Radiculopathy, cervical, 1701, 1702
Radioactive iodine. 
See also
 Radioiodine 
thyroid scans and uptake
for goiter, 1146
1145, 1147
side effects/contraindications to, 1146, 
1156
Graves ophthalmopathy flares and, 
1147
pregnancy/pregnancy planning and, 
1143, 1145, 1146
for thyroid cancer, 1155–1156
for thyroid nodules/multinodular goiter, 
1146, 1151
Radiocontrast media. 
See
 Contrast media
for arrhythmias, 396, 400, 401, 407, 409, 
410, 432. 
See also
 
specific 
for Barrett epithelium, 620
for benign prostatic hyperplasia 
f
, 988
for cardiomyopathy, 432, 433
f
Radioiodine thyroid scans and uptake, 
1143. 
See also
 Radioactive 
iodine
1135
t
, 1143
in nodule evaluation, 1135
t
, 1150, 1150
t
in thyroid cancer, 1152
t
, 1154, 1158
Radioisotope thyroid uptake and imaging, 
1143. 
See also
Radionuclide angiography
t
, 429
Radiosurgery, stereotactic, for pituitary 
adenoma, 1127, 1130
Radiotherapy. 
See
Radium-223 dichloride, 1663, 1676
t
Radon, lung cancer and, 320, 1624
Raf-kinase inhibitors, 1633, 1668
Rage attacks, seizures differentiated from, 
1000
Ragged red fibers, in mitochondrial 
myopathies, 1062
Rai classification, 540–541
Raloxifene, 755, 1168, 1174, 1205, 1215
Raltegravir, 1365
t
, 1371–1373. 
See also
 
in combination regimens, 1359, 
 
1371–1373, 1372
t
prophylactic/postexposure, 1358, 1359
Ramelteon, 1067
t
, 1102–1103
Ramipril, 368, 418
t
, 419, 465, 467
t
Ramosetron, 1678. 
See also
Ramsay Hunt syndrome, 225, 1383, 1384
overdose/toxicity/side effects of, 208
t
, 
1082
t
, 1084
t
, 1592
Quinacrine, 123
Quinagolide, 1130
Quinapril/quinapril-HCTZ, 467
t
Quincke pulses, 358
Quinidine
1095
t
t
t
t
, 1521
overdose/toxicity of, 394
t
, 1519
Quinine, 209
t
, 1518–1519, 1518
t
, 1520
t
, 
1521, 1523
Quinsy (peritonsillar abscess), 
240
Quinupristin/dalfopristin, 1452
R 364D, tick typhus caused by, 1442
R waves. 
See also
 Electrocardiogram
Rabeprazole, 621, 631, 633, 637, 639. 
See 
also
 Proton pump inhibitors
Rabies, 
1398–1401
bite injuries and, 1307, 1308, 1398, 1400
Rabies antiserum, 1400
Rabies immune globulin, 1400
Rabies vaccine, 1400
in animal population, 1399, 1400
antimalarial drugs/chloroquine and, 
1400
postexposure, 1399, 1400
preexposure, 1400
Raccoon roundworm 
(Baylisascaris 
procyonis),
 1545
Raccoon sign, 1043
Racemose cysticercosis, 1539
Radial nerve lesions, 
1053
Radiation exposure/reactions, 
1574–1575
. 
See also
acute, 1575
cancer risk and, 1575, 1611
lung injury caused by, 
320–321
, 1624
myocarditis, 427
Radiation fibrosis, pulmonary, 
321
Radiation pneumonitis, 
321
Radiation proctitis, 610
Radiation syndrome, acute (radiation 
Radiation therapy, 1575. 
See also
 Radiation 
exposure/reactions
for breast cancer, 763, 764, 768–769
pregnancy and, 762
cancer risks and, 1575, 1611
with chemotherapy. 
See
 Chemoradiation 
therapy
for GH-secreting tumors/acromegaly/
gigantism, 1128
in gynecomastia, 1205

See
therapy
lung injury and, 
320–321
, 1624
isoniazid overdose/toxicity and, 293, 
294, 836, 1284, 1584
t
, 1600
1284
for vomiting during pregnancy, 593, 817
Pyrimethamine
for isosporiasis, 1532
for malaria, with sulfadoxine (Fansidar), 
1518, 1518
t
t
, 1519
t
, 1522
for toxoplasmosis, 1020, 1345
t
, 1348, 
1361, 1527
Pyrimidine analogs, 1617–1618
t
Pyrogenic erythrotoxin (erythrogenic 
Pyronaridine, 1518
t
, 1520
t
, 1519
t
, 1520, 
1522
Pyrophosphate (technetium-99m) 
scintigraphy, in myocardial 
infarction, 384
Pyrosis (heartburn), 589, 617, 619
Pyuria, 926
sterile, 964
Q fever, 1437
t
, 
1444–1445
Q fever vaccine, 1445
Q waves, in myocardial infarction, 28
t
, 
384, 391. 
See also
 Myocardial 
infarction; Non-Q wave 
(non-ST elevation) infarction
Qinghaosu/qinghaosu derivatives. 
See
 
Artemisinins
QRS complex, wide. 
See also
 
in poisoning/drug toxicity, 1582, 1582
t
antidepressants in, 1609, 1609
f
antipsychotics in, 1592
beta-adrenergic blockers in, 1594
QT interval. 
See also
long, 31, 394
t
, 
412
in poisoning/drug toxicity, 1582, 
1582
t
antidepressants in, 1090, 1093, 
1582, 1609, 1610
antipsychotics in, 1084, 1084
t
, 1592
quinine/quinidine in, 1519, 1521
ranolazine and, 374
t
short, in cancer-related hypercalcemia, 
912, 1673
Quad screen, 813
Quadriplegia after spinal trauma, 1045. 
See 
also
 Paralysis
Quality of life
assessment of for older adult, 55
decision-making at end of life and, 76
palliative care and, 72, 74, 76
Quantitative pilocarpine iontophoresis 
sweat test, 276
Quazepam, 1067
t
“Quebec beer-drinkers cardiomyopathy, ” 
427
Quebec platelet disorder, 567
Queensland tick typhus, 1437
t
, 1442
Quetiapine, 1081, 1081
t
t
, 
1084
t
. 
See also
drugs
for dementia, 1035
CMDT2019_Index_p1743-1884.indd   1855

INDEX1856
 
CMDT 2019
Rectal prolapse, 683
Rectal (Blumer) shelf, 1642
Rectal temperature. 
See
 Body (core body) 
temperature
Rectal ulcer, 609
Rectocele, 791–792
Rectovaginal fistulas, in Crohn disease, 
665, 666, 667
Rectum. 
See also
 
under Rectal
t
, 1615
t
1652. 
See also
 Colorectal 
cancer
655–682
. 
See also
 
gonococcal infection, 684, 1481
Recurrent abortion, 
819
Recurrent laryngeal nerve
1154–1155
Recurrent respiratory papillomatosis, 
 
244–245
Red blood cells. 
See
 
 and 
Erythrocytes
Red bugs, 159–160
Red cell aplasia, pure, in erythrovirus 
Red cell casts, 926, 927
t
Red cell count, in pleural fluid, 322, 324
t
Red cell transfusions, 
552–554
. 
See also
 
“Red man syndrome, ” 892, 893
t
Reductase inhibitors. 
See
 Finasteride
Reduction pneumoplasty, for COPD, 273
Reed-Sternberg cells, 545
Reentry
atrial fibrillation/flutter and, 400, 401, 
407
in supraventricular tachycardia, 399, 
400–401
in ventricular premature beats, 409
Refeeding
Refeeding edema, 1277
Reflex sympathetic dystrophy (complex 
regional pain syndrome), 
888–889
Reflux. 
See
 
Refractive errors, 
174
Refractive surgery, 174
Refractory ulcers, 640, 643
Refsum disease, 1049
Regional poison control centers, 1580
Regorafenib, 1621
t
, 1633, 1646, 1652, 1679
Regular insulin, 1238, 1238
t
, 1240, 1245. 
See also
for diabetic ketoacidosis, 1256
t
, 
1239–1240, 1245
Regurgitation, 591, 619, 629
Rehydration. 
See
hydration
Reinke edema, 245
Reiter syndrome. 
See
Relapsing fever, 1319
t
, 
1503–1504
Relapsing polychondritis, 211, 
875–876
Relapsing-remitting multiple sclerosis, 
1036
REM sleep, 1101
REM sleep behavior disorder, 1103
Rate control
for atrial fibrillation, 403, 406–407
Rathke cleft cyst, 1123, 1124
Rattlesnake envenomation, 1607, 1608
Rauwolfia derivatives, antidepressant drug 
interactions and, 1095
t
Raxibacumab, 1462
Raynaud disease, 858
Raynaud phenomenon, 
857–859
, 858
t
obliterans) and, 491, 858
scleroderma and, 858, 858
t
, 859–860
SLE and, 854, 858
RCRI (Revised Cardiac Risk Index), 46, 
47
t
, 48
f
Reactive arthritis (Reiter syndrome), 
 
880–881
, 880
f
, 884
Reactive cervical lymphadenopathy, 
250
Reactive (postprandial) hypoglycemia, 
1261, 1261
t
, 
1265–1266
. 
 
See also
Rebound headache, analgesic, 
993
Recall. 
See
 Memory
Reciprocal (co-) in vitro fertilization, 1731
Recklinghausen disease. 
See
 
Recombinant follicle-stimulating hormone 
(FSH), 799, 1123
Recombinant growth factors. 
See
 Growth 
factors
Recombinant human deoxyribonuclease 
(rhDNase), 276
Recombinant human growth hormone 
(rhGH), 1123
Recombinant human parathyroid hormone 
(rhPTH), 1163, 1174
Recombinant human thyroid-stimulating 
hormone (rhTSH), 1141, 1156
Recombinant influenza virus vaccines 
(RIV), 1329
t
, 1334
t
, 1424. 
See 
also
Recombinant tissue plasminogen activator. 
See
 Alteplase
Recombinant vesicular stomatitis Ebola 
virus vaccine, 1411
Recombinant zoster vaccine (RZV), 1327
t
, 
1328
t
, 1330
t
, 1361, 1386. 
See 
also
 Herpes zoster vaccine
Recompression. 
See also
 Hyperbaric 
214, 1576
Reconstructive surgery
after mastectomy, 753, 774
local recurrence and, 753, 773
vascular. 
See
Recrudescent epidemic typhus (Brill-
Zinsser disease), 1436, 1438
Recruitment, in cochlear dysfunction, 220
Rectal bleeding, 609. 
See also
 
See also
 
Rectal carcinoids, 1647
Rectal examination
in benign prostatic hyperplasia, 984, 985
f
cauda equina syndrome and, 1698
in prostate cancer screening/diagnosis, 
1657, 1658, 1659
t
, 1660
f
Ramucirumab, 1620
t
, 1640, 1643–1644
Range of motion
ankle disorders and, 1721
hip disorders and, 1707, 1708
knee disorders and, 1711
t
, 1715, 1718
neck pain and, 1702, 1702
t
shoulder disorders and, 1690, 1691
t
, 
1695, 1696, 1697
Ranibizumab, 193, 194, 197
Ranitidine, 73, 621, 633, 637. 
See also
 H
2
 
RANK/RANKL, 547, 1173, 1663
Ranke complex, 290
Ranolazine, for angina, 373
f
, 374
Ranson criteria, 742, 742
t
Rape/rape trauma syndrome, 807–808, 
1104. 
See also
 Sexual violence
emergency contraception and, 806
 
1729–1730
statutory, 807, 808
STD transmission and, 807–808, 
 
1309–1310
Rapid antigen/rapid antigen detection 
testing (RADT)
in community-acquired pneumonia, 
280
in pharyngitis, 239, 1448
Rapid cyclers, in bipolar disorder, 1088, 
1097
Rapid detoxification, 1112
Rapid eye movement (REM) sleep, 
 
1101
Rapid eye movement (REM) sleep 
behavior disorder, 1103
Rapid HIV antibody tests, 1309, 1342, 
1342
t
Rapid plasma reagin test. 
See
 RPR test
Rapid treponemal tests, 1495
Rapidly acting insulin analogs, 1238, 
1238–1239, 1238
t
, 1243
t
. 
 
See also
t
, 
1239–1240, 1242
in pumps, 1239
Rapidly progressive glomerulonephritis, 
945, 945
f
Rasagiline, 1026
Rasburicase, 1674, 1676
t
Rashes. 
See also
 
specific type or cause and
 
acute exanthems, 1381–1382
t
f
170–173
, 
171–172
t
, 
894
fungal, 1353
heat causing (miliaria), 
139
lamotrigine therapy and, 1099
penicillin/ampicillin use and, 239, 1324, 
1387
photodistributed (photodermatitis), 
104
t
, 
163–164
, 172
t
in SLE, 853
t
, 854
Rat-bite fever, 
1504
Rat poison, anticoagulant toxicity and, 
1591
CMDT2019_Index_p1743-1884.indd   1856

INDEX1857
 
CMDT 2019
Respiratory distress syndrome, acute. 
 
See
syndrome
Respiratory drugs, ophthalmic effects of, 
207
t
Respiratory failure, 
329–331
, 329
t
. 
See also
 
Acute respiratory distress 
syndrome
acidosis in, 329, 924
asthma and, 256, 256
t
, 257, 266
f
, 267
in COPD, 270
t
perioperative risk assessment/
management and, 49–50, 50
t
Respiratory papillomatosis, recurrent, 
244–245
Respiratory syncytial virus (RSV), 
 
1420–1422
Respiratory tract infection. 
See
 Pulmonary 
disorders, infections
Rest. 
See also
 Bed rest; Immobility
requirements for during pregnancy, 813
Restenosis, with PCI, 375–376
Restless legs syndrome, 
1030
Restlessness, terminal (terminal delirium), 
73–74
Restrictive cardiomyopathy. 
See
 
Resurfacing surgery, hip, 1708
Resuscitation. 
See
Resynchronization (biventricular pacing). 
See also
 Pacemaker
f
, 
f
, 351
ret
 oncogene, 1159, 1198–1199
Retapamulin, 107
t
See
 Mental retardation
Retention, urinary. 
See
 Urinary retention
Reteplase, 385
t
, 386
Reticulocytopenia, in anemia 
classification, 510, 511
t
Reticulocytosis, in anemia classification, 
510, 511
t
Reticulosis, polymorphic (midline 
malignant), 234
Retigabine, 208
t
Retina
detachment of, 
192–193
, 192
f
in hypertension, 198, 456, 456
f
systemic diseases and, 
197–199
. 
See also
 
Retinal arteries, in hypertension, 198, 456, 
456
f
Retinal artery occlusions, central and 
branch, 
195–196
, 488, 1008
Retinal neovascularization, 197
Retinal tears, 192
Retinal vasculitis, 190. 
See also
 Uveitis
Retinal vein occlusions, central and 
branch, 
194–195
, 194
f
Retinitis
in bartonellosis, 1483
CMV , 198–199, 1346
t
, 1350, 1362, 1388, 
1389, 1390
herpetic (acute retinal necrosis), 199, 
1377
Renal vascular hypertension, 454. 
See also
 
Renin activity
Renin-angiotensin-aldosterone system. 
See 
also
in hypertension, 465
inhibitors of. 
See
 Angiotensin II 
receptor blocking agents; 
enzyme (ACE) inhibitors; 
Renin inhibitors
Renin inhibitors. 
See also
enzyme (ACE) inhibitors
for heart failure, 419
for hypertension, 465, 466
t
, 475, 477
Repaglinide, 1230
t
f
, 1245, 1237
t
, 1266
Repeat-dose charcoal, 1586
Reperfusion therapy. 
See also
 
for myocardial infarction, 385–387, 393
fibrinolytic therapy, 385, 385
t
, 
 
386–387
percutaneous coronary intervention 
(PCI), 375–376, 385–386
Rescue angioplasty, 388
Rescue collapse, 1567
Reserpine, 474
t
, 475, 1028, 1095
t
t
, 475, 1088
Reset osmostat, 901
Residual volume (RV). 
See
 Pulmonary 
Resin T
3
/T
4
 uptake, in hyperthyroidism, 
1142, 1143
Resistance, microbial. 
See
Resistance testing. 
See also
 Drug 
susceptibility testing
in antiretroviral therapy, 1373, 1374–
1375
Reslizumab, 261
t
, 264
Resolution stage of sexual activity, 1075
Resource allocation, principles of care and, 
2
Respiration. 
See
 Breathing; Ventilation
Respiratory acidosis (hypercapnia), 917, 
917
t
, 
924
. 
See also
 
specific 
cause
in asthma, 256
metabolic alkalosis and, 923, 924
respiratory failure and, 329, 924
Respiratory alkalosis (hypocapnia), 917, 
917
t
, 
924–925
, 924
t
. 
See also
 
in hyperventilation syndromes, 327, 
924, 925
metabolic acidosis and, 921, 925
Respiratory bronchiolitis-associated 
interstitial lung disease 
(RB-ILD), 302
t
, 303

924, 925
t
, 303
Respiratory depression, opioid therapy/
pain relief and, 97–98
Respiratory disorders. 
See
 Pulmonary 
disorders
Remitting seronegative synovitis with 
non-pitting edema, 889
Remnant ablation (thyroid), 1155
Renal amyloidosis, 947
t
Renal angiography/arteriography, in renal 
artery stenosis/renal vascular 
Renal artery stenosis, 454, 930, 
944
Renal biopsy, 
929
. 
See also
 
specific 
 
disorder
in focal segmental glomerulosclerosis, 
956
in nephritic spectrum disorders, 947
spectrum disorders, 954–955, 
958
Renal calculi, 975, 978. 
See also
 
disease
Renal cell carcinoma, 961, 1612
t
, 1614
t
, 
1667–1668
Renal colic/pain, urinary stones causing, 
975, 976
Renal cysts, 937
t
, 
961–964
, 962
t
acquired, 962
t
in autosomal dominant polycystic 
kidney disease, 
962–963
, 962
t
, 
963
f
complex, 961
infected, 963
in medullary cystic kidney, 962
t
in medullary sponge kidney, 962
t
, 
 
963–964
simple/solitary, 
961–962
, 962
t
Renal disorders. 
See
 Kidney disease/injury
Renal failure. 
See also
 Acute kidney injury; 
Chronic kidney disease; 
Kidney disease/injury; Uremia
929–936
, 930
t
chronic, 926, 
936–945
, 937
t
, 938
f
, 938
t
, 
939
f
, 940
f
in cystic kidney disease, 962
t
dialysis for. 
See
 Dialysis
1328
t
, 1331
t
t
postoperative, 54
transplantation for. 
See
 Kidney 
Renal (nondiabetic) glycosuria, 1224
Renal imaging, in dysuria evaluation, 44
Renal osteodystrophy, 939–940, 940
f
, 
1164, 1166
Renal pelvis, cancer of, 1612
t
, 
1666–1667
, 
1667
Renal salt wasting, 900, 920, 921, 1013
Renal transplantation. 
See
 Kidney 
Renal tubular acidosis, 906
t
, 920–921, 
920
t
, 921, 922
hyperkalemia and, 907, 933
hypokalemia and, 920, 922
urinary anion gap in, 920
t
, 921
Renal tubular cell casts, 926, 927
t
Renal tubular necrosis 866, 926, 930
t
, 
932–934
CMDT2019_Index_p1743-1884.indd   1857

INDEX1858
 
CMDT 2019
Rhinitis
allergic (hay fever), 
229–230
medicamentosa, 225
nasopharyngeal/paranasal sinus cancer 
and, 233
perennial, 229
vasomotor, 229
Rhinocerebral mucormycosis, 228–229, 
1559
Rhinosinusitis
acute bacterial, 
226–228
, 1322
t
. 
See also
 
Sinusitis
nasopharyngeal/paranasal sinus 
cancer and, 233
orbital cellulitis and, 202, 227
acute viral (common cold), 
225–226
, 
1429
Rhizopus
 infection, 228–229, 1558–1559
Rhodococcus equi,
 pneumonia caused by, 
1344
Riamet (artemether-lumefantrine/
Coartem), 1518
t
, 1519
t
, 1520
t
, 
1522, 1523
Ribavirin, 1379
t
for hemorrhagic fevers, 1413
for hepatitis C, 703, 704, 705, 1351
for RSV infection, 1379
t
, 1422
Ribociclib, 770
Riboflavin (vitamin B
2
)
1283
t
Rice water stool, 1477
Richter syndrome, 540
Ricin 
(Ricinus communis),
 
1595–1596
Rickets, 
1175–1178
hypophosphatemic (vitamin 
D-resistant), 906
t
, 1176, 1177
vitamin D-dependent, 1176
 (rickettsial diseases), 1320
t
, 
1436–1445
, 1437
t
. 
See also
 
364D,
 1442
aeschlimannii,
 1441, 1442
africae,
 1437
t
, 1442
akari,
 1437
t
, 1442
australis,
 1437
t
, 1442
conorii,
 1437
t
, 1442
felis,
 1437
t
, 1442
helvetica,
 1442
japonica,
 1442
lymphangitis-associated, 1437
t
, 1442
massiliae,
 1440, 1441, 1442
monacensis,
 1442
t
parkeri,
 1440, 1442
phillipi,
 1440
prowazekii,
 1436, 1437
t
raoultii,
 1437
t
, 1442
rickettsii,
 1437
t
, 1440
sibirica,
 1437
t
, 1442
mongolitimonae,
 1437
t
, 1441, 1442
slovaca,
 1437
t
typhi,
 1437
t
, 1438
XY99, 1441
Rickettsial fever (tick typhus), 1437
t
, 
 
1442
Rickettsialpox, 1437
t
, 
1442
Rickettsiosis
California flea, 1437
t
t
, 1442
spotted fever, 1441, 1442
Rh
o
 (D) immune globulin, 806, 813, 814, 
815, 818, 820
Rh incompatibility, 552, 813, 814. 
See also
 
Rh
o
 (D) immune globulin
Rh typing
compatibility testing for transfusion 
and, 552
during pregnancy, 813, 814, 815
Rhabdomyolysis, 
866–867
acute tubular necrosis and, 866, 933
in cocaine abuse, 866, 1590
statins causing, 863, 866, 1272, 862
t
, 
863, 866, 955, 1272
Rhabdomyoma, cardiac, 445
rhDNase, 276
Rhegmatogenous retinal detachment, 192
incompatibility), 552, 813, 
814. 
See also
 Rh
o
 (D) immune 
globulin
Rheumatic carditis/rheumatic valvulitis, 
426
t
, 435
and, 1464, 1466
t
Rheumatic fever, 
435–437
, 436
t
arthritis in, 435, 436, 436
t
gonococcal arthritis and, 883
nongonococcal/septic arthritis and, 
882
rheumatoid arthritis and, 850
streptococcal infection and, 240, 435, 
436, 437, 1448, 1449
Rheumatic heart disease, 435–437, 436
t
t
Rheumatism, palindromic, 
889–890
848–852
, 849
f
in coal workers (Caplan syndrome), 318
CPPD and (pseudorheumatoid 
arthritis), 848, 850
differential diagnosis of, 850
ankylosing spondylitis and, 878
gouty/tophaceous arthritis and, 845, 
850
and, 850, 871, 872
850, 882
osteoarthritis and, 842, 850
viral arthritis and, 850
neuropathies associated with, 1050
Rheumatoid factor, 849, 854
t
cryoglobulinemia and, 875, 952
t
, 
862
in rheumatoid arthritis, 849, 854
t
t
, 865
Rheumatoid nodules, 849
850
Rheumatoid pleural effusion, 324
t
Rheumatologic disorders, 
840–848
. 
 
See also
 
t
cancer and, 
889
t
HIV infection/AIDS and, 
884
, 
 
1349–1350
209
t
Retinochoroiditis, toxoplasmic, 190, 1526
Retinochoroidopathy, hypertensive, 
198
, 
456, 456
f
Retinoic acid, 538, 1622
t
. 
See also
 
Tretinoin
Retinoids. 
See also

209
t
198
, 
456, 456
f
t
. 
See also
 
Tretinoin
See also
 
Vitamin A
t
for psoriasis, 116
diabetic, 
197–198
, 1247
HIV , 198, 1350
hypertensive, 198, 456, 456
f
paraneoplastic, 1022
“pizza-pie, ” 1389
sickle cell, 198, 522
in West Nile virus, 1401
Retrobulbar optic neuritis, 200
Retrocecal appendicitis, 654
Retrograde ejaculation, 979, 981, 982, 
1075. 
See also
 Erectile 
Retroileal appendicitis, 654
Retropharyngeal abscess, 1449
Revascularization procedures/bypass 
grafting. 
See also
 
for acute arterial limb occlusion, 
 
487–488
for aortoiliac occlusive disease, 484
coronary. 
See also
 
therapy
for angina/ACS/STEMI, 373
f
, 
 
375–376, 385–386, 393
emergent, traumatic injury and, 
 
445–446
485
Reversal reactions, in leprosy, 1490
Reverse transcriptase inhibitors. 
See
 
Nonnucleoside reverse 
transcriptase inhibitors; 
Nucleoside reverse 
Nucleotide reverse 
transcriptase inhibitor
Revised Atlanta classification, 742, 
 
743–744
Revised Cardiac Risk Index (RCRI), 46, 
47
t
, 48
f
Rewarming
for frostbite, 1568–1569
for frostnip/chilblain, 1568
for immersion syndrome, 1568
for systemic hypothermia, 1567–1568, 
1581
Rewarming shock, 1567
Reye syndrome, 712, 1423
aspirin use and, 1385
VZV infection/vaccine and, 1383–1384, 
1385
Reynolds pentad, 736
RFX6
CMDT2019_Index_p1743-1884.indd   1858

INDEX1859
 
CMDT 2019
Rosacea, 136, 
136–137
acne and, 134, 136
Rose spots, 1474
Rosemont criteria, 747
Roseola infantum (exanthema subitum), 
1381
t
, 1391
Rosiglitazone, 1230
t
1599. 
See also
 
pulmonary valve regurgitation after, 363
pulmonary valve stenosis after, 334
Rosuvastatin, 367
t
, 459, 1268, 1272, 1273
t
, 
1369. 
See also
 Statins
Rotation. 
See
 External rotation; Internal 
rotation
Rotator cuff tears, 1692–1693
t
, 
1694–1695
impingement syndrome and, 1690, 1694
shoulder dislocation and, 1695
Rotavirus vaccines, 1432
Rotaviruses, 599
t
, 1313
t
, 1432, 1433
Roth spots, 198, 1465
Rotigotine, 1026, 1030
Rotor syndrome, 689
t
Rotterdam Criteria, 795
Rotterdam score, 727
Rouleaux formation
549
Roundworm infections, 
1541–1549
. 
See 
also
 
1546–1549
, 1546
f
1541–1544
invasive, 
1544–1546
Royal Free Hospital score, 720
RPR test, 1494–1495, 1495
t
in HIV infection/AIDS, 1359, 1360
RS3PE (remitting seronegative synovitis 
with non-pitting edema), 889
RTS,S vaccine, 1523
RU 486. 
See
 Mifepristone
Rubber band ligation. 
See
 Banding
Rubella, 1382
t
, 
1395–1397
arthritis and, 884, 1396
during pregnancy/congenital, 1396
t
, 
1328
t
, 1329
t
, 1396–1397. 
See 
also
Rubella virus vaccine. 
See also
 MMR 
vaccine
Rubeola. 
See
 Measles
Rufinamide, 995
t
Rugger jersey spine, 1166
Rule of nines, 103, 1571, 1571
f
Rumination, 591
Runner’s knee (patellofemoral pain), 1709, 
1717–1718
RUNX1/RUNX1T1
 mutation/protein, 537, 
538
Russell viper venom clotting time, 855, 857
Rust ring, 203
Ruxolitinib, 531, 534
Ruzasvir, 705
S stage sleep, 1101
Sabin-Feldman dye test, in toxoplasmosis, 
1526
Sabin vaccine (oral/OPV polio vaccine), 
1398
with fosamprenavir, 1370
for hepatitis C, 705, 1351
with indinavir, 1369
with lopinavir (lopinavir/r), 1358, 1364
t
, 
1370
for protease inhibitor boosting, 1369
oral contraceptive drug interactions 
and, 800
with saquinavir, 1369
with tipranavir, 1364
t
, 1370
Rituximab, 1620
t
(Wegener granulomatosis), 873
560
f
for leukemia, 541, 541–542, 543
for non-Hodgkin lymphoma, 544, 1345
t
by, 1407, 1408
for rheumatoid arthritis, 852
for thrombotic microangiopathies, 562
for Waldenström macroglobulinemia, 
550
RIV vaccines, 1329
t
, 1334
t
, 1424. 
See also
 
Influenza virus vaccine
Rivaroxaban, 575–576
t
, 578
t
, 580
t
, 582
404–405, 405
t
, 406
prevention, 368, 374–375
and, 388
t
, 578
t
, 580
t
, 
582
t
, 406
Rivastigmine, 59, 1027, 1034
River blindness (onchocerciasis), 
 
1547–1548
Rizatriptan, 991
RNA
hepatitis C virus, 697, 697
f
, 703
hepatitis D virus, 698
hepatitis E virus, 699
Ro/SSA antibody, 854
t
t
t
, 865
Rocky Mountain spotted fever (RMSF), 
1382
t
, 1437
t
, 
1440–1442
, 
1441
f
Rodent tapeworm 
(H diminuta),
 1538
Rodenticide poisoning, anticoagulant 
toxicity and, 1591
Roflumilast, 272
Rolapitant, 593, 594
t
, 1678
Romaña sign, 1512
Romberg testing, 221
Romiplostim, 537, 558, 559, 560
f
, 1677
Ropinirole, 1026, 1030
ROS-1
 mutation, 1627
ROS1
 rearranged lung cancer, 1627, 1628
Riedel thyroiditis/struma, 1132, 
 
1133–1134
Rifabutin, 208
t
, 1345
t
, 1347
antiretroviral agent interactions and,

ROS-1
ROS1
 
1133–1134
t
, 1345
t
, 1347
antiretroviral agent interactions and, 
293, 1347
Rifampin, 292, 292
t
, 293, 293
t
293, 1347, 1368
t
for nasal vestibulitis, 228
t
, 293, 293
t
, 
295
in combination agents, 292
t
, 293, 295
in HIV infection/AIDS, 293, 295, 
1347
in latent disease/prophylactic, 295
resistance and, 288, 294
Rifapentine/rifapentine-isoniazid, 292
t
, 
295
Rifaximin
for bloating/flatulence, 599
for diarrhea, 602, 1316
Rift Valley fever, 1412, 1413
Right middle lobe syndrome, 
299
Right ventricular (right heart) failure, 414, 
415. 
See also
failure
Right ventricular infarction, 391
Rigidity, in Parkinson disease, 1025
Rilonacept, 846
Rilpivirine, 1364
t
, 1368. 
See also
 
Complera; Juluca; Odefsey
Riluzole, 1046
Rimantadine, influenza/influenza 
resistance and, 1423, 1426
Ring shadow sign, 961
Ring X chromosome, in Turner syndrome, 
1216
Rinne test, 210
Riociguat, 444
Risedronate, 1173. 
See also
 
Risky drinking. 
See
 At-risk/risky drinking
Risperidone, 1081, 1081
t
, 1082
t
, 1083, 
1084
t
. 
See also
drugs
for delirium at end of life, 74
t
, 
1082
t
, 1084
t
, 1592
Ritonavir, 1364
t
, 1369. 
See also
 
with atazanavir, 1358, 1370, 1371, 1373
t
t
, 
1373, 1373
t
t
, 1370, 1371, 
1372
t
, 1373
CMDT2019_Index_p1743-1884.indd   1859

INDEX1860
 
CMDT 2019
Schistosoma guineensis/haematobium/
intercalatum/japonicum/
mansoni/mekongi
 
(schistosomiasis), 
1535–1536
Schizoaffective disorders, 1079
Schizoid personality disorder, 1077
t
Schizophrenia/schizophrenia spectrum 
disorders, 
1078–1086
. 
See also
 
Psychotic disorders
depression and, 1079, 1087, 1088
differential diagnosis of, 1080
t
, 
1082
t
, 1084
t
. 
See also
 
ECT for, 1083
positive and negative symptoms in, 1079
antipsychotics affecting, 1081, 1082, 
1083
suicidality and, 1080, 1085, 1089
Schizophreniform disorders, 1079
Schizotypal personality disorder, 1077
t
, 
1078
Schneiderian papillomas, 233
Schwannoma
vestibular (acoustic neuroma/
neurinoma/eighth nerve 
tumor), 
224
, 1018
t
Sciatic nerve palsy, 
1053
Sciatica. 
See also
 Back pain
SCL-70 (scleroderma) antibody, 854
t
, 
 
860
Sclera, lacerations of, 205
Scleritis, in granulomatosis with 
polyangiitis (Wegener 
granulomatosis), 871, 871
f
Scleroderma (systemic sclerosis), 854
t
, 
859–861
t
, 860
limited (CREST syndrome), 854
t
, 858, 
859
linear, 860
pulmonary hypertension in, 442, 859, 
861
Raynaud phenomenon and, 858, 858
t
, 
859–860
Scleroderma (anti-SCL-70) antibody, 854
t
, 
860
Scleroderma renal crisis, 860
Scleromyxedema, 860
Sclerotherapy
627
Scoliosis, 1698
Marfan syndrome and, 1687, 1688
neck pain and, 1702
Scombroid poisoning, 1607, 1607
t
Scopolamine, 73, 593, 1593
Scorpion stings, 425
t
, 
1608
Scotomas, in migraine headache, 990
“Screamer’s nodules, ” 245
Screening tests. 
See
 
 Genetic testing; 
Prenatal testing
Scrofula, 1487
Scrotal mass. 
See
Scrotal pruritus, 156
Scrotal swelling, in filariasis, 1546, 
 
1547
Scrub typhus, 1437
t
, 
1439–1440
enteric (typhoid) fever and, 
1474–1475
in HIV infection/AIDS, 1361, 1475
paratyphi,
 1474
typhi,
 1474
typhimurium,
 1474
Salpingitis, 
792–793
. 
See also
 Pelvic 
Salpingo-oophorectomy. 
See
 
Oophorectomy
Salt restriction. 
See
 Sodium-restricted 
 
diet
Salt tablets, contraindications to in heat 
exposure syndromes, 1565, 
1566
Salt wasting
in adrenal hyperplasia, 1181, 1182
cerebral, 900, 902
renal, 900, 920, 921, 1013
 toxicity, 1601–1602
Same-sex marriage, mental health and, 
1730
Samter triad, 232, 892
SAPE (sentinel acute pancreatitis event), 
746
Saphenous vein
superficial thrombophlebitis of, 499
varicose, 497, 498
Sapovirus, diarrhea caused by, 599
t
Saquinavir/ritonavir, 1364
t
, 1369. 
See also
 
Sarcocystis bovihominis/suihominis
 
(sarcocystosis), 
1530–1533
Sarcoidosis, 
234
, 
303–304
arthritis in, 
887
hypercalcemia/hypercalciuria in, 911, 
1167
and, 
234
, 303
f
pulmonary involvement and, 
303–304
Sarcoma. 
See
 
 infection, 125, 
157–158
, 
157
f
Sargramostim (GM-CSF), 527, 529, 1362, 
1676
t
Sarin (GB) poisoning, 1595, 1605
Satellite vesicopustules, candidal, 140
Saturday night palsy, 1052
Saturnine gout, 845
Saw palmetto, 987
Saxagliptin, 1231
t
Saxitoxin, 1607
t
Scabies, 125, 
157–158
, 157
f
Scaling skin disorders, 104
t
, 
113–126
. 
 
See also
 
Scalp
injuries of, 1044
in pediculosis, 158, 158–159
psoriasis of, 116
Scalp eschar neck lymphadenopathy/tick-
borne lymphadenopathy/
Dermacentor-borne-necrosis-
erythema-lymphadenopathy, 
1437
t
, 1442
“Scalp vein sign, ” 1178
Scarlet fever (scarletina), 1382
t
Scarring (cicatricial) alopecias, 168
Scedosporium apiospermum/prolificans,
 
1560, 1561
Schatzki rings, 617
t
, 
625
Schirmer test, 865
Saccular (berry) aneurysm, 1011, 1013. 
See 
also
 Intracranial aneurysm
Sacral plexus/nerve lesions, 
1057–1058
Sacral spine/disk disease. 
See also

t
, 
625
See 
also
1057–1058
See also
 Spine
1697–1699
, 1698
t
Sacroiliac joint/sacroiliitis
psoriatic spondylitis and, 879
Sacubitril/valsartan, 418
t
, 419–420, 429
Saddle nose deformity
872
nasal trauma and, 232
SAE antibodies, 862
t
Safer sex, 4
contraception and, 805
for genital herpes prevention, 127, 1380
for gonorrhea prevention, 1481
for HIV infection/AIDS prevention, 
1356, 1361
 
1727–1728
for syphilis prevention, 1496
Safinamide, 1026
“Sag sign, ” 1716
Salbutamol, 207
t
Salicylates. 
See also
 Aspirin
t
, 919, 921, 
1585
t
, 1587
t
, 
1606
t
, 843
Salicylic acid preparations, for wart 
removal, 149
Saline, 925
t
. 
See also
hydration; Sodium
Saline breast prostheses. 
See
 Breast 
implants
Saline infusion sonohysterography, 
 
776–777, 777, 777
t
Saline purgatives. 
See
 Purgatives
Saline-responsive metabolic alkalosis, 
922–923, 922
t
, 923
Saline-unresponsive metabolic alkalosis, 
922
t
, 923
Salivary glands, 
242–243
infiltrative disorders of, 
243
inflammatory disorders of
acute, 
242
chronic, 
243
f
tumors of, 
243
Salivary stones (sialolithiasis), 
242
Salk vaccine (inactivated/IPV polio 
vaccine), 1398
t
Salmon calcitonin. 
See
 Calcitonin
 subsp 
enterica
 
(salmonellosis), 1319
t
, 1322
t
, 
1474–1475
bacteremia and, 1319
t
, 
1475
choleraesuis,
 1474
diarrhea/enterocolitis/gastroenteritis 
and, 599
t
, 600, 1313
t
, 1322
t
, 
1475
drug resistance and, 1475
CMDT2019_Index_p1743-1884.indd   1860

INDEX1861
 
CMDT 2019
Senna, 597
t
Sensorimotor peripheral neuropathy. 
 
See
Sensory conduction velocity studies. 
See
 
Sensory/sensorineural hearing loss, 210, 
211, 
218–219
, 225. 
See also
 
Sensory neuronopathy, cancer-related, 
1022
Sentinel acute pancreatitis event (SAPE), 
746
Sentinel loop, 743
Sentinel lymph node biopsy, in breast 
cancer, 762, 764, 764
f
, 768
Sentinel pile, 686
Seoul hantavirus, 1415
Sepsis/septic shock, 505
t
, 506, 507, 508, 
509. 
See also
 Bacteremia; 
Infection/infectious diseases
bleeding and, 557
t
catheter-related, 1292, 1302, 1303, 1321
t
contaminated blood transfusion 
causing, 553
E coli
t
early goal-directed therapy of, 507–508
gram-negative, 1321
t
, 
1473–1474
in pyelonephritis, 969
thrombocytopenia and, 557
t
, 
566
t
Septal hematoma, 232
Septal hypertrophy, asymmetric, 431, 432
Septic (nongonococcal acute bacterial) 
881–883
, 1311, 
1321
t
Septic bursitis, 1705, 1706
Septic thrombophlebitis, 499, 1302, 1321
t
anaerobic infections and, 1484
catheter-associated infection and, 499, 
1292, 1302, 1321
t
CNS, 1484
sigmoid sinus/otitis media and, 
 
217
Septic transfusion reaction, 553
Septo-optic dysplasia, 1119
Septoplasty, nasal, for sleep apnea, 328
Sequential organ failure assessment 
(SOFA) score
in liver failure, 699
Sequoiosis, 319
t
Serine protease 1 
(PRSS1)
 gene, 746
Serine protease inhibitor 
(SPINK1)
 gene, 
746
Serine protease inhibitors. 
See
 Protease 
Serine threonine kinase gene, 681
Seronegative spondyloarthropathies, 850, 
877–881
. 
See also
 
Seronegative synovitis, remitting, with 
Serotonin 5-HT
3
 receptors, 591, 593, 
 
1677
3
-receptor-blocking agents, 
73, 593, 594
t
, 659, 991, 1027, 
1678. 
See also
 Serotonin-
selective reuptake inhibitors
1583
, 
1583
t
, 1604
posttraumatic, 999
during pregnancy, 824, 
834
psychogenic nonepileptic 
(pseudoepileptic), 1000–1001, 
1071
schizophrenia/psychotic disorders 
differentiated from, 1080
secondary generalization of, 998
serial, 998
solitary, 1001–1002
surgical management of, 1001
theophylline use and, 1608, 1609
TIA differentiated from, 1000, 1005
tonic, 998
tonic-clonic, 998
vagal nerve stimulation for, 1001
vascular disorders and, 999
Selective estrogen receptor modulators 
(SERMs). 
See also
 Tamoxifen
755
t
as estrogen replacement alternative, 
1215
for osteoporosis, 1174, 1215
Selective immunoglobulin A deficiency, 
895
t
, 
896
Selective serotonin reuptake inhibitors. 
See
 
Selegiline/selegiline transdermal, 1026, 
1091
t
, 1094
Selenium sulfide lotion, 122
Self-care
assessment of ability to manage, 55–56
asthma management and, 257
clinician, providing end-of-life care and, 
75–76
diabetes management and, 1242
Self-examination, breast, 15
t
, 756
Self-harm, intentional. 
See
 Suicide
Self-monitoring of blood glucose
in diabetes, 1226–1227
1243, 1243
t
in pregnant patient, 831, 832
in functional alimentary hypoglycemia 
diagnosis, 1265
in insulinoma diagnosis, 1262, 1262–
1263
Self neglect, in elderly, 
70–71
, 70
t
Self-treatment, malaria prophylaxis and, 
1523
Semaglutide, 1231
t
, 1235. 
See also
 
Semen analysis, in infertility workup, 798, 
981
f
, 982
Semicircular canal dehiscence, 
 
223–224
Seminal emission, loss of (anejaculation), 
979, 982–983, 1075. 
See also
 
impotence
Seminomas, 1669, 1670
SEN-V virus, 696–697
Sengstaken-Blakemore tube, 627
Senile freckles (lentigines), 
111

See also
 
impotence
111
Scuba/deep sea diving, barotrauma/
dysbarism/decompression 
sickness and, 214, 1576
Scurf, 118, 118
f
Scurvy, 1284
SDH
 (succinate dehydrogenase) mutations, 
1190, 1194
Seafood intake, preventable disease/deaths 
and, 3
t
Seafood poisonings, 
1607
, 1607
t
Seasonal affective disorder, 1087, 1096
Seasonal influenza. 
See also
 Influenza
Seborrheic dermatitis, 113, 117, 
118–119
, 
118
f
, 1353
Seborrheic keratoses, 
111
, 112
f
Second-degree heart block, 389, 397, 398. 
See also
Second-degree (superficial 
 
partial-thickness) burns, 1571
Second-hand smoke. 
See
 Passive smoking
Second impact syndrome, 1044
Secretin stimulation test, 747
Secukinumab, 878–879, 880
Sedative-hypnotics, 1067
t
antidepressant drugs and, 1090, 1091
t
, 
1094, 1095
t
overdose/toxicity of, 
1598–1599
sleep cycle affected by, 1067
t
, 1102
Sedentary lifestyle. 
See
 Lifestyle
Segmental demyelination, 1047
Segmental myoclonus, 1030
Segond fracture, 1714
Seizures, 995–996
t
, 
997–1002
. 
See also
 
 Epilepsy; 
Status epilepticus
absence (petit mal)/atypical absence, 
996
t
, 998
alcohol withdrawal, 1002, 1106
antidepressant use/overdose and, 1094, 
1583, 1583
t
, 1609
antipsychotic use and, 1084
atonic (epileptic drop attacks), 998
awareness and, 998
classification of, 998–999
clonic, 998
congenital/perinatal injury and, 999
deep brain/cortical stimulation for, 
 
1001
differential diagnosis of, 1000–1001
t
See also
therapy
fever and, 1000
flumazenil use and, 1581, 1598
focal (partial), 995–996
t
generalized, 995–996
t
, 998–999, 999, 
1000–1001
910, 1162
infection/infectious diseases and, 999, 
1000
intracranial tumors causing, 999, 1016
motor, 998, 998–999
myoclonic, 996
t
, 998
myoclonic-atonic, 998
1115
t
nonmotor, 998
panic disorder differentiated from, 1000
CMDT2019_Index_p1743-1884.indd   1861

INDEX1862
 
CMDT 2019
 
1724–1725, 1729–1730
STDs and, 807–808, 1309–1310
Sexually transmitted diseases (STDs), 
1308–1310
. 
See also
 
specific 
disease
epididymitis, 968
t
, 973
gay and bisexual men/MSM and, 1309, 
1733–1734
HIV testing in patients with, 1309
 
1727–1728
837
See
 Safer sex
and, 807–808, 1309–1310
syphilis/syphilis testing and, 1496
Zika virus infection as, 815, 1418
Sézary cells, 124
Sézary syndrome, 124, 125
SF3B1
SFTS (severe fever with thrombocytopenia 
syndrome virus), 1412
SGLT2
 gene, 1224
SGLT2 inhibitors, 1231
t
, 1236–1237, 
1244
f
, 1245
Shagreen patches, 1023
Shared epitope, 848
Shaver disease, 318
t
Shawl sign, 862
Sheehan syndrome, 1120
Sheep liver fluke, 1536–1537
Shellfish, paralytic, 1607, 1607
t
Shift work sleep disorder, 1103
E coli,
 600, 1312
t
, 
1476
561, 561
t
, 601, 1476
Shigella dysenteriae/flexneri/sonnei
 
(shigellosis/bacillary 
dysentery), 599
t
, 600, 1313
t
, 
1316, 1319
t
, 1322
t
, 
1476
Shin spots, diabetic, 1251
Shingles. 
See
 Herpes zoster
Shiny corner sign, 878
Shock, 
505–509
, 505
t
anaphylactic. 
See
 Anaphylaxis/
anaphylactic shock
cardiogenic, 383, 390–391, 505, 505
t
, 
506, 508–509
dengue, 1414
distributive, 505–506, 505
t
, 506, 508
in heat stroke, 1565–1566
hypovolemic/hemorrhagic, 505, 505
t
, 
506, 507
Kawasaki, 1446
in myocardial infarction, 383, 390–391
neurogenic, 505
t
, 506
obstructive, 505, 505
t
, 506
and, 1102, 1192–1193
septic. 
See
vasodilatory (distributive), 505–506, 
505
t
, 506, 508
Shock liver, 728
Shock wave lithotripsy, 977–978, 978
Sexual arousal disorders, 796, 797, 1075, 
1076. 
See also
 Sexual 
Sexual assault. 
See
Sexual behavior/practices. 
See also
 Gay 
and bisexual men/MSM; 
Sexually transmitted diseases; 
anal cancer and, 1354–1355, 1656
in gay and bisexual men/MSM, 1732
hepatitis/hepatitis vaccination and, 694, 
697
HIV infection/AIDS and, 1338, 1356, 
1733
1358
preexposure prophylaxis and, 4, 1310, 
1356–1358, 1357
t
1727
sexual orientation/identity differences 
syphilis and, 1493
Zika virus transmission and, 815, 1418
Sexual desire disorders, 796, 797
drugs causing, 979
antidepressants, 1092–1093, 1094
antipsychotics, 1083
in female, 
796–797
in male, 
978–980
. 
See also
 Erectile 
psychologic/psychosexual, 979, 
 
1075–1076, 1076–1077
Sexual identity. 
See
 Gender identity
Sexual intercourse
emergency contraception and, 
805–806
. 
See also
 Emergency/postcoital 
1338, 1339
t
, 1356, 1733
postexposure prophylaxis and, 4, 1358
t
painful (dyspareunia), 796, 797
timing of, infertility and, 981, 982
unlawful (statutory rape), 807
Sexual minority. 
See
bisexual women; Minority 
stress; Transgender health/
Sexual orientation. 
See also
 Gender 
identity
gay and bisexual men/MSM and, 1732
 
1722–1724
methods of identification of, 1723–1724
sexual identity/behavior differences and, 
1724, 1732, 1737
of transgender people, 1737
Sexual pain disorders, 796, 797
Sexual violence (rape/sexual assault), 
 
807–808
, 1104
emergency contraception and, 806, 807, 
808
gamma-hydroxybutyrate (“date rape” 
drug) use and, 1599
Serotonin-selective reuptake inhibitors

807–808
, 1104
808
Serotonin-selective reuptake inhibitors 
(SSRIs), 1090–1093, 1091
t
for anxiety/stress disorders, 1064, 1067, 
1068
for depression, 61, 1090–1093, 1091
t
for hot flushes/menopausal symptoms, 
809, 1211
MAOI interaction and, 1095
t
t
, 1091
t
, 1583
for panic disorder, 1068
t
serotonin syndrome caused by, 35, 1093
sexual side effects of, 1092–1093
Serotonin (serotonin-selective) 
norepinephrine reuptake 
inhibitors (SNRIs/SSNRIs), 
1090–1093, 1091
t
for anxiety/stress disorders, 1067, 1068
for depression, 1090–1093, 1091
t
t
t
, 99
t
, 1091
t
Serotonin syndrome, 35, 1093, 1583, 1609, 
1610
Serous otitis media, 
214
nasopharyngeal carcinoma and, 214, 233
Serrated polyps/adenomas, 678, 
678–679
, 
1649, 1653
Serratia,
 1319
t
Sertaconazole, 107
t
Sertoli cell tumors, gynecomastia and, 1205
Sertraline, 659, 1066, 1090, 1090–1093, 
1091
t
, 1609. 
See also
 
Serum-ascites albumin gradient (SAAG), 
613
t
, 614, 728. 
See also
 Ascites
Serum eye drops, 177
Serum osmolality, 898
Serum sickness/serum-sickness-like 
syndromes, 893
t
urticarial vasculitis in, 141
Sevelamer, for hyperphosphatemia, 914, 
940
Severe fever with thrombocytopenia 
syndrome virus (SFTS), 1412
Sex. 
See
 Gender
Sex chromosomes. 
See
 X chromosome; Y 
Sex hormone binding globulin, 
monitoring, in feminizing 
hormone therapy, 1740
t
Sex steroid replacement therapy. 
See
 
replacement therapy; 
therapy
CMDT2019_Index_p1743-1884.indd   1862

INDEX1863
 
CMDT 2019
in chronic venous insufficiency, 500, 
500
f
1584
for caustic/corrosive burns, 1584, 
1589, 1590
nerve agents and, 1584, 1595
disorders of. 
See
 
 Skin 
cancer; Skin disorders
hardening of. 
See
 Scleroderma
preoperative preparation of, 1303
Skin bends, 1576
Skin cancer. 
See also
 
basal cell carcinoma, 
151–152
, 151
f
melanoma, 
111–113
, 112
f
, 1612
t
, 1616
t
squamous cell carcinoma, 
152–153
, 
152
f
sun avoidance and, 14
Skin disorders, 
103–173
, 104
t
. 
See also
 
under Cutaneous and
 
anaerobic infections, 
1485
, 1485
f
anthrax, 1461, 1461–1462
arthropod infestations, 
159–160
blistering (bullous), 104
t
, 
146–148
cancer. 
See
 Skin cancer
candidal, 139–140
in Chagas disease (chagoma), 1512
chemotherapy causing, 
1679
medicamentosa/drug 
170–173
, 171–172
t
, 
894
in electrical burns, 1573
epidermal inclusion cysts, 162, 
163
erosive, 104
t
erythemas, 104
t
, 
141–146
in frostbite, 1568, 1569
in frostnip/chilblain, 1568
fungal infections, 
119–122
, 119
f
, 1353. 
See also
 Tinea
gonococcal arthritis and, 883, 1481, 
1482
946
t
, 950
in leishmaniasis, 1513, 1513–1514, 1514, 
1514
f
, 1515
in leprosy, 1489, 1490
in Lyme disease, 1506, 1507
morbilliform, 104
t
mycobacterial infections, 
1487–1488
in nocardiosis, 1487
nodules, 104
t
160–163
153–155
papules, 104
t
, 
148–153
153–155
in paracoccidioidomycosis, 1559, 1560
photodermatitis, 104
t
, 
163–164
, 172
t
pigmentary, 
166–168
, 172
t
, 1285. 
See 
also
 Hyperpigmentation; 
Hypopigmentation
Silent thyroiditis. 
See
 Painless (silent) 
thyroiditis
Silibinin/silymarin, for mushroom 
Silicone gel breast implants. 
See
 Breast 
implants
Silicosis, 318, 318
t
Silo-filler’s disease, 320
Silodosin, 207
t
, 986
t
Silymarin/silibinin, for mushroom 
Simeprevir, 704
t
, 705, 1351
Simple partial seizures, 998. 
See also
 
Seizures
Simple/solitary renal cysts, 
961–962
, 962
t
Simtuzumab, 740
Simultagnosia, 1016
Simvastatin, 367, 367
t
, 1272, 1273
t
, 1274. 
See also
 Statins
Sin Nombre virus, 1415
“Singer’s nodules, ” 245
Single photon emission computed 
tomography (SPECT)
in dementia, 1033–1034
Singultus (hiccups), 
594–595
Sinoatrial exit block (sick sinus syndrome), 
397
Sinonasal inflammatory disease, 
233–234
Sinus arrest (sick sinus syndrome), 397
Sinus arrhythmia, 
396–397
. 
See also
 
Bradycardia; Tachycardia
Sinus venosus atrial septal defect, 337
Sinuses. 
See
Sinusitis, 
225–226
, 
226–228
, 1322
t
in aspergillosis, 228–229, 1557, 1558
226–228
. 
See also
 
Rhinosinusitis, acute bacterial
 causing, 1322
t
in HIV infection/AIDS, 228, 229, 1347
hospital-associated, 226, 227
invasive fungal, 
228–229
in mucormycosis, 228, 1559
and, 233
viral (common cold), 
225–226
, 1429
Sinusoidal obstruction syndrome, 712, 727
Sipple syndrome. 
See
 Multiple endocrine 
neoplasia (MEN), MEN 2
Sipuleucel-T, 1623
t
, 1663
Sirolimus, insulin resistance and, 1223
Sister Joseph/Sister Mary Joseph nodule, 
1636, 1642
Sitagliptin, 1231
t
, 1236, 1237, 1599, 1636
Siti (endemic syphilis), 1503
Sixth disease (exanthema subitum), 1381
t
, 
1391
Sixth nerve palsy, 201
Sjögren syndrome, 854
t
, 
864–865
Skeletal hyperostosis, diffuse idiopathic 
Skeletal system disorders. 
See
 Bone; 
Musculoskeletal disorders
Skin
anaerobic flora/infection of,

t
, 
864–865
See
 Bone; 
Skin
anaerobic flora/infection of, 
1485
, 1485
f
biopsy of, in polyarteritis nodosa, 870
in breast cancer, 757, 757
f
caustic/corrosive injuries of, 1584, 1589, 
1590
Short-acting beta agonists
for asthma, 254
f
, 255
t
, 258
f
, 259, 262
t
, 
264, 265, 265
f
, 266
f
, 267
Short-acting insulin, 1238–1239, 1238
t
. 
See also
in mixtures, 1239–1240
Short-acting muscarinic agents, 263, 263
t
Short bowel syndrome, 
649
Short-lasting neuralgiform headache 
attacks with conjunctival 
injection and tearing, 993
Short stature
Shortness of breath. 
See
 Dyspnea
Shoulder, 
1690–1697
, 1691–1694
t
dislocated/unstable, 
1695–1696
frozen (adhesive capsulitis), 1252, 
1696–1697
rotator cuff tears and, 1692–1693
t
, 
1694–1695
subacromial impingement syndrome 
and, 
1690–1694
t
Shoulder-hand syndrome, 888, 889
Shoulder stability/instability, 
1695–1696
atraumatic dislocation and, 1695, 1696
SHOX
 gene, 1217
Shunt procedures, portosystemic. 
See
 
Shy-Drager syndrome (multisystem 
atrophy), 1003, 1025
Sialadenitis, 
242
Sialolithiasis, 
242
Siberian/Siberian Asian tick typhus, 1437
t
, 
1442
Siberian type tick-borne encephalitis, 1404
Sick role, 1074
Sick sinus syndrome, 397
Sickle cell anemia/syndromes, 
522–524
, 523
t
osteomyelitis and, 522, 885
in pregnancy, 813, 829
renal dysfunction and, 522, 964
testing for, 813
Sickle cell glomerulopathy, 964
Sickle cell retinopathy, 198, 522
Sickle cell trait, 
523–524
, 523
t
Sickle thalassemia, 523
t
, 
524
Sideroblasts, ringed, 536, 557
Siderosis, 318
t
“Sigmoid esophagus, ” 629
Sigmoid sinus thrombosis, 217
in antibiotic-associated colitis, 660
identification/treatment, 679, 
680, 1653, 1653
t
, 1654
t
, 1655
in GI bleeding, 610
Signal recognition particle (SRP) antibody, 
862, 862
t
Significant others. 
See
 Family/significant 
others
Sildenafil. 
See also
 Phosphodiesterase 
1092, 1250
and, 388, 980, 1076
t
in women, 797
CMDT2019_Index_p1743-1884.indd   1863

INDEX1864
 
CMDT 2019
and, 6
t
, 7–9, 8–9
t
, 9
t
, 365, 
373
f
, 1270
in COPD, 268, 270
Crohn disease and, 665
environmental exposure and. 
See
 
Passive smoking
Graves ophthalmopathy flares and, 1145
hypertension and, 453, 458
laryngeal leukoplakia and, 246
 
pancreatitis and, 746
pneumothorax and, 325, 326
postoperative pulmonary complications 
and, 50
during pregnancy, 812–813
t
, 6
t
, 7, 
14, 1611
disease) and, 491
ulcerative colitis and, 671
vocal fold changes and, 245
Smoldering myeloma, 548
Snake bites, 425
t
, 1584
t
, 
1607–1608
Sneddon syndrome, 877
Sniffing (solvents/gases), 
1114
1605–1606
Snoring, 
241–242
in sleep apnea hypopnea, 241, 242, 328
“Snow blindness, ” 205
Social challenges, for terminally ill/dying 
patient, 80, 80
t
Social phobias, 1066, 1068, 1069
Sodium
dietary, 1286
t
, 458, 
1286
t
See
diet
899–904
, 
899
f
, 901
t
. 
See also
 
Hypernatremia; 
t
. 
See also
 
Saline
fractional excretion of, in acute kidney 
injury, 930
t
, 931
in hyponatremia treatment, 900, 
 
902–903
Sodium bicarbonate. 
See
Sodium channel blocking drugs, 393, 394
t
Sodium deficit, calculation of, 903
Sodium-glucose cotransporter 
(SGLT2)
 
gene, 1224
Sodium-glucose cotransporter (SGLT2) 
inhibitors, 1231
t
1244
f
, 1245
Sodium ipodate. 
See
 Ipodate sodium
Sodium nitrite, for cyanide poisoning, 
1584
t
Sodium nitroprusside. 
See
 Nitroprusside
Sodium oxybate. 
See
 Gamma-
hydroxybutyrate
Sodium phosphate enema, 597
t
Sleep panic attacks, 1066
Sleep paralysis, 1103
Sleep-related hypoventilation, 1103
Sleep-wake disorders, 
1101–1103
Sleepiness, excessive, 
1103
Sleeping sickness, 
1510–1511
, 1511
t
Sleeve gastrectomy, 1280
Slow colonic transit, 595, 595
t
Sm antibody, 123, 853
t
, 854, 854
t
SMAD4
 mutation, 1688
Small bowel bleeding, 
611
. 
See also
 
Small cell carcinoma of lung (SCLC), 
1614
t
, 1625. 
See also
 Lung 
cancer
with, 1625
t
treatment of, 1628, 1628
t
Small intestine. 
See also
 
under Intestinal
adenocarcinomas in, 667, 
1646–1647
bacterial overgrowth in, 
648–649
. 
See 
also
 Bacterial overgrowth
biopsy of, in celiac disease, 646
bleeding from, 
611
carcinoid tumors in, 1195, 1647, 1648
644–655
, 644
t
appendicitis, 
653–655
malabsorption, 
644–650
, 644
t
malignant tumors, 
1646–1649
motility disorders, 
650–653
. 
See also
 
protein-losing enteropathy, 
655
655
680
lymphomas in, 667, 
1647
neuroendocrine tumors in, 
 
1647–1648
649
sarcomas in, 
1648
Small intestine push enteroscopy, 610
Small intestine transplantation, for short 
bowel syndrome, 649
Small lymphocytic lymphoma, 544
Smallpox (variola), 1382
t
, 1431
Smallpox (variola) vaccine, 1431
Smell disorders. 
See
 Olfactory dysfunction
Smith antibody, 123, 853
t
, 854, 854
t
, 855
t
SMN
 (survival motor neuron) genes, 1046, 
1047
Smoke inhalation, 300
t
, 
316
burn injuries and, 316, 1571
carbon monoxide poisoning and, 316, 
1594
Smoking/tobacco use/smoking cessation, 
6
t
, 7–9, 8–9
t
, 9
t
, 1611
cancer and, 7, 14, 1611. 
See also
 
specific 
type
bladder cancer, 1664
laryngeal cancer, 246
lung cancer, 15
t

t
, 9
t
, 1611
See also
 
specific 
type
t
, 16, 297, 320, 1611, 
1624, 1627
renal cell carcinoma and, 1667
ureteral/renal pelvis, 1666
Skin disorders (
Cont
.):
pigmented lesions, 104
t
, 
110–113
pruritus (itching) and, 104
t
, 
155–160
. 
See also
 
Pruritus
pustular, 104
t
, 
134–139
in sarcoidosis, 30
f
, 303
scaling, 104
t
, 
113–126
in schistosomiasis, 1535
in sporotrichosis, 1560
staphylococcal infections, 1353, 1450
t
, 
1454–1455
, 1455
f
streptococcal infections, 
1449–1450
, 
1450
f
, 1450
t
t
f
. 
See also
 
Chancre; Gummas
treatment of, 
103–110
, 104–109
t
ophthalmic effects of drugs in, 209
t
ulcers, 104
t
, 
164–166
, 165
f
in diabetes, 1248, 1249, 1249
f
, 1251
mycobacterial, 1488
in paracoccidioidomycosis, 1559, 
1560
in polyarteritis, 870
pressure (pressure injury), 68–69, 68
t
venous insufficiency/varicose veins/
disease and, 33, 34, 
164–166
, 
165
f
, 500, 501. 
See also
 
Venous insufficiency/stasis
in uremia, 155, 937
vesicular, 104
t
, 
126–131
weeping/crusted, 104
t
, 
131–133
drying agents for, 103
Skin grafts, for burns, 1572
Skin test anergy
in HIV infection/AIDS, 1342
tuberculin skin test and, 290, 1344
Skin testing, 892–894. 
See also specific 
disorder
in asthma, 257
for drug allergies, 891, 1324
Skull base tumors, vocal fold paralysis 
caused by, 247
Skull fracture, 1043, 1044. 
See also
 Head 
injury
Skyla IUD, 804
Slapped cheek fever, 884
SLC11A3
 mutation, 723
Sleep, 1101
abnormal behaviors during 
(parasomnias), 
1103
breathing disorders and, 241–242, 
 
327–329
, 1103. 
See also
 Sleep 
1101–1103
drugs for, 1067
t
Sleep apnea hypopnea, 241, 242, 327, 
 
328–329, 1103
hypertension and, 328, 453
in obesity-hypoventilation syndrome, 
327
obstructive, 241, 242, 327, 
328–329
, 
1103
pulmonary hypertension and, 313, 443
1203
Sleep attacks, 1103
Sleep hygiene, 1102
CMDT2019_Index_p1743-1884.indd   1864

INDEX1865
 
CMDT 2019
See
 Vertebral osteomyelitis
lumbar disk herniation, 
1700–1701
1055
, 
1701–1703
, 
1702
t
t
stenosis, 
1699–1700
tuberculosis (Pott disease), 
886
tumors. 
See
 Spinal cord, lesions/
tumors of
SPINK1
 gene, 746
Spinocerebellar degeneration, 1038
Spiral (helical) CT. 
See
 Computed 
Spiramycin, 1527
Spirillum minus,
 1504
Spiritual challenges, for terminally ill/
dying patient, 80, 80
t
Spirochetal infections, 1319
t
, 
1493–1509
. 
See also
 
anaerobic, 1483, 1484
meningitis caused by, 1304
t
t
non-sexually transmitted, 1319
t
syphilis, 1319
t
, 1323
t
, 
1493–1502
, 1494
t
Spirometry. 
See also
 
incentive, postoperative pulmonary 
complications and, 50
Spironolactone/spironolactone-HCTZ
for adrenal hyperplasia, 1189
1738
t
for heart failure, 388, 418–419, 418
t
, 
419, 423
for hirsutism/virilization, 795, 1207
for hypertension, 461
t
, 462
t
, 471, 476
f
t
Spirulina, toxicity of, 1597
t
Spleen, platelet sequestration in, 557
t
, 
566
Splenic vein thrombosis, 728, 729
Splinter hemorrhages, in endocarditis, 
1465, 1465
f
Spondylitic heart disease, 878
ankylosing, 
877–879
psoriatic, 879
Spondyloarthropathies, seronegative, 850, 
877–881
. 
See also
 
Spondylosis, cervical, 
1055
Spongiform encephalopathies/spongiosis 
(prion diseases), 
1406–1407
Spontaneous abortion, 
817–819
Spontaneous bacterial peritonitis, 613, 
614–616
, 717
Spontaneous pneumothorax, 23, 
325–327
. 
See also
 Pneumothorax
Spoon nails, 169
Sporadic Creutzfeldt-Jakob disease, 1406, 
1407
Sporadic thyroiditis, painless/silent 
subacute (hashitoxicosis), 
 (sporotrichosis), 
1560
Sports medicine, 
1690–1721
. 
See also
 
Spotted fever rickettsiosis, 1441, 1442
Spotted fevers, 1437
t
, 
1440–1442
, 1441
f
Spousal abuse (domestic violence), 17, 
1729–1730
South African tick fever, 1437
t
South American blastomycosis, 
1559–1560
Southern tick-associated rash illness 
(STARI), 1506
Spasmodic torticollis, 1029
Spastic paraparesis
Spasticity, 
1038–1039
Specific (functional) antibody deficiency, 
897
Sperm analysis, in infertility workup, 798, 
981
f
, 982
Spermatogenesis, 981, 982
hormone therapy affecting, 1124, 1202
Spermicides, 805
HIV infection/AIDS and, 805, 1356
use with condom and, 805
SPF (sun protective factor), 109
Sphenoid sinusitis, 226
Sphincter of Oddi dysfunction, 735–736, 
743, 744
Sphincterotomy
biliary, 735, 737, 744, 745
pancreatic, 744, 745, 748
Sphingolipids, in Gaucher disease, 1685
Spider bites, 159, 425
t
, 
1608
cavitation of (syringomyelia), 
1045–1046
compression of, 1020, 1045, 
1670–1671
dural arteriovenous fistulae of, 1015
epidural/subdural hemorrhage and, 
1015
in HIV infection/AIDS (HIV 
myelopathy), 1349
infarction of, 1015
lesions/tumors of, 1018
t
, 
1020
cord compression by, 1020, 
 
1670–1671
syringomyelia and, 1045, 1046
subacute combined degeneration of, 
1039
1045
vascular diseases/vasculitis of, 
876–877
, 
1015–1016
Spinal cord stimulation, for angina, 376
Spinal dural arteriovenous fistulae, 1015
Spinal muscular atrophy, 1046, 1047
Spinal poliomyelitis, 1397
Spinal (neurogenic) shock, 505
t
, 506
Spinal stenosis, 
1699–1700
Spinal surgery
for back pain, 1699
for lumbar disc herniation, 1701
for neck pain, 1055, 1702
Spinal tumors. 
See
tumors of
Spine. 
See also
 Spinal cord
bamboo, 878
disorders of, 1056–1057
f
, 
1697–1703
, 
1698
t
, 1702
t

See
tumors of
Spine. 
See also
f
, 
1697–1703
, 
1698
t
, 1702
t
1697–1699
, 1698
t
, 
See also
 Back pain
cervical disk herniation, 
1055
fractures, 1045, 1170, 1697
Sodium polystyrene sulfonate, 908, 909
t
Sodium-restricted diet, 1286–1287
for chronic kidney disease, 938, 942
for heart failure/cardiomyopathy, 422
for hypertension, 10, 453, 457
t
, 458, 
1286
Sodium stibogluconate (antimony), 
 
1514–1515
Sodium sulfacetamide. 
See
 Sulfacetamide
Sodium thiosulfate, for cyanide poisoning, 
1584
t
SOFA score
Sofosbuvir, 698, 704
t
, 705, 837, 1351, 1418
Soft diet, 1286
Soft tissue infections. 
See also
1485
, 1485
f
mycobacterial, 
1487–1488
staphylococcal, 1450
t
, 
1454–1455
, 1455
f
streptococcal, 1450
t
Soft tissue sarcoma, 1616
t
Solar lentigines, 167
Soles of feet
f
, 
121–122
, 121
f
129–130
, 130
f
Solitary pulmonary nodule, 
297–299
, 
1629, 1630
Solitary/simple renal cysts, 
961–962
, 962
t
Solitary seizures, 1001–1002
Solitary thyroid nodule, toxic (thyroid 
adenoma), 1140, 1146, 1197
t
, 
1198
Soluble liver antigen antibodies, 707
Solvents, toxicity/abuse of, 
1114
, 
 
1601–1602, 
1605–1606
Soman (GD) poisoning, 1595, 1605
Somatic cough syndrome, 22
Somatic symptom (somatization) disorders 
(abnormal illness behaviors), 
1071–1072
Somatostatin/somatostatin analogs, 627, 
1127, 1195, 1196, 1648
Somatostatin receptor scintigraphy
in Zollinger-Ellison syndrome/
gastrinoma, 643
Somatostatinomas, 1195, 1196
Somatropin. 
See
 Growth hormone
Somnolence, excessive, 
1103
Somogyi effect, 1243, 1243
t
SONIC staging system, 718
Sonidegib, 151
Sonography. 
See
Sonohysterography, 776–777, 777
t
Sorafenib, 1141, 1413, 1622
t
, 1633, 1668, 
1679
Sorbitol, 596, 597
t
, 603, 658
Sore throat. 
See
 Pharyngitis
Sorivudine, 1384
Sotalol, 393, 395
t
for atrial arrhythmias/fibrillation, 394
t
, 
395
t
, 406, 446
for ventricular tachycardia, 394
t
, 395
t
CMDT2019_Index_p1743-1884.indd   1865

INDEX1866
 
CMDT 2019
Statutory rape, 807
Stauffer syndrome, 1667
Stavudine (d4T), 1349, 1351, 1355, 1363
t
, 
1366. 
See also
therapy
Steatohepatitis, nonalcoholic (NASH), 712, 
Steatorrhea, 644
t
. 
See also
somatostatinoma and, 1196
Steatosis, hepatic. 
See
Stein-Leventhal syndrome. 
See
Stem cell transplantation. 
See
 Bone 
marrow/stem cell 
“STEMI equivalent, ” 384
Stensen duct
calculus formation in, 242
mumps and, 1394
Stent thrombosis, 375
Stents/stent grafts (“covered stents”). 
See 
also
 Endovascular surgery/
prostheses
in aneurysm repair, 493
carotid, 489
coronary. 
See
 Coronary stents; 
Stereotactic guided core needle biopsies, in 
breast cancer, 760
Stereotactic radiosurgery
for lung cancer, 1627
for pituitary adenoma, 1127, 1130
Stereotypy, stimulant abuse and, 1080, 
1113
Sterile pyuria, 964
Sterility. 
See
 Infertility
Sterilization, for birth control, 
806–807
Steroid acne, 134
Steroid-resistant nephrotic syndrome, 956
Steroidogenic enzyme defects
Steroids. 
See
 Anabolic steroids; 
Stevens-Johnson syndrome, 
142–144
, 
143
f
, 170, 172
t
herpes simplex infection and, 143, 1378
Stevens-Johnson syndrome/toxic 
epidermal necrolysis (SJS/
TEN) overlap, 143, 170, 172
t
Stibogluconate (antimony), 1514–1515
Still disease, 
852–853
, 882
Stimson procedure, 1696
Stimulant laxatives, 596–597, 597
t
Stimulants
abuse of, 
1113
aggressive/violent/psychotic behavior 
and, 1104
kindling and, 1105, 1113
OTC medications and, 1590
for depression, 1094
for narcolepsy, 1103
Stings. 
See
 Insect bites/stings
diarrhea/food poisoning/gastroenteritis, 
599
t
, 600, 1313
t
, 1314
t
, 1456, 1464, 1466, 
1468, 1469
epidermidis,
 1457
1321
t
, 1674
folliculitis and, 138, 1353, 1455
furunculosis/carbuncles and, 161, 162, 
1322
t
, 1353, 1455, 1455
f
haemolyticus,
 1457
hominis,
 1457
impetigo, 131–132, 1353
mastitis, 753, 828
meningitis, 1321
t
methicillin-resistant. 
See
 Methicillin-
resistant 
S aureus
 (MRSA) 
methicillin-susceptible (MSSA), 146, 
1318
t
osteomyelitis, 885, 1321
t
, 
1456
t
, 279
t
, 280, 283, 284
t
, 
1321
t
saccharolyticus,
 1457
saprophyticus,
 1322
t
, 1457
septic thrombophlebitis, 499, 1321
t
of skin and soft tissues, 1353, 1450
t
, 
1454–1455
, 1455
f
toxic shock syndrome, 
1457
, 1457
f
warneri,
 1457
Starvation (protein-energy malnutrition), 
1276–1277
Stasis dermatitis, 33. 
See also
 Venous 
f
Statins (HMG-CoA reductase inhibitors), 
1271–1272, 1272
t
, 1273
t
in aortic stenosis, 355
hepatotoxicity of, 1272
high-, moderate, low-intensity, 365, 
366
f
t
, 1272, 
1272
t
for lipid modification/cardiovascular/
heart disease prevention, 6
t
, 
10, 365, 366
f
t
, 
373
f
, 1268, 1269–1270, 1271–
1272, 1272
t
, 1273
t
, 1683. 
See 
also
ACS and, 381–382
t
, 10, 365, 
1269–1270
1684
heart failure and, 421–422
hypertension and, 459
in women/older patients, 1270
t
perioperative, 47
rhabdomyolysis/myopathy/myositis 
caused by, 862
t
, 863, 866, 955, 
1272
Statoconia, detached, 223
Status epilepticus, 998, 1001, 1002
alcohol withdrawal and, 1002
nonconvulsive, 1002
in theophylline overdose, 1608, 1609
tonic-clonic, 1002
Sprains, ankle, 
1720–1721
, 1720
t
Sprue, celiac. 
See

1720–1721
, 1720
t
See
Spurling test, 1702, 1702
t
Sputum/sputum examination
blood found on (hemoptysis), 
26–27
infection, 296, 1347
in pneumonia, 280, 281, 283, 287
in tuberculosis, 288–289, 289
t
SQSTM1
 mutations, 1178
of anus, 1354–1355, 1656
of bladder, 1664
cervical, 786
of ear canal, 213
of esophagus, 1638
intraepidermal (Bowen disease), 
126
of larynx, 
246–247
leukoplakia and, 246
of lung, 1624, 1625, 1626
f
nasopharyngeal/sinus, 233
oral, 234, 235, 235
f
of skin, 
152–153
, 152
f
of vulva, 789
Squamous intraepithelial lesions, high or 
low (HSIL/LSIL), 783
t
, 784
“Square-root” sign, 442
Squaric acid dibutylester, 150
Squatting, heart murmurs affected by, 346
t
SRP antibody, 862, 862
t
SRSF2
SRY
 gene, 1200
SS-A/Ro antibody, 854
t
t
t
, 865
SS-B/La antibody, 854
t
t
t
, 865
St. Louis encephalitis, 1401
ST segment changes. 
See also
 
t
, 29, 
379, 382
t
, 384. 
See also
 
in stress cardiomyopathy, 430
ST-segment elevation myocardial 
28
t
t
, 
383–
393
, 385
t
. 
See also
Staggers, 1576
Standing, heart murmurs affected by, 346
t
Stannosis, 318
t
 (staphylococcal infections), 
753, 828, 1318
t
, 1321
t
, 1322
t
abscesses, 1353
arthritis, 881, 1321
t
atopic dermatitis and, 114
aureus,
 1321
t
, 1322
t
, 1450
t
, 
1454–1458
, 
1455
f
, 1457
f
bacteremia, 
1456–1457
carrier state and, 1454–1455
nasal vestibulitis and, 228
surgical site infection and, 1303
t
coagulase-negative, 
1457–1458
, 1464, 
1468, 1469
cohnii,
 1457
cystitis/pyelonephritis, 969, 1322
t
CMDT2019_Index_p1743-1884.indd   1866

INDEX1867
 
CMDT 2019
risk factors in, 5
spinal cord vascular disease and, 
 
1015–1016
subarachnoid hemorrhage causing, 
1007
t
Stroke (heat), 1565, 1565–1566
Stromal tumors (gastrointestinal stromal 
tumors/GISTs), 1646
Strongyloides fuelleborni/stercoralis
 
(strongyloidiasis), 603, 
 
1542–1543
“Stroop test, ” 718
Struma ovarii, 1141
Struvite urinary stones, 975, 977
Strychnine poisoning, 1583
t
Stunning, myocardial, 365–367
Stupor, 
1040–1042
. 
See also
 Coma
Sturge-Weber syndrome, 
1023
Sty (external hordeolum), 174
Subacromial impingement syndrome, 
1690–1694
t
Subacute combined degeneration of spinal 
cord, 
1039
Subacute cutaneous lupus erythematosus 
(SCLE), 123
Subacute mountain sickness, 
1578
Subacute sclerosing panencephalitis, 1030, 
1392
Subacute thyroiditis, 1132, 1133, 1134, 
1140, 1142–1143
painful (de Quervain), 1131–1132, 
1132, 1133, 1134, 1140
painless (silent), 1132
sporadic (hashitoxicosis), 1131, 1132, 
1133
Subarachnoid hemorrhage, 1007
t
, 
 
1011–1013
. 
See also
 Stroke
arteriovenous malformations/fistulae 
causing
intracranial, 1011, 1013, 1014
head injury and, 1011
headache in, 41, 42, 993–994, 1012
hypertension and, 480
hypopituitarism and, 1120
intracranial aneurysms causing, 1010, 
1011
Subareolar abscess, 752, 753
Subclavian steal syndrome, 1004
Subcutaneous insulin infusion, 
continuous, 1240, 1243. 
See 
also
in erythema nodosum, 160, 161
f
in loiasis (Calabar swellings), 1549
in nocardiosis, 1486
t
318
850
Subdural hemorrhage/hematoma
t
, 1044
falls in elderly and, 64
viridans, 1318
t
, 1321
t
, 1451
endocarditis caused by, 1321
t
, 1451, 
1464, 1466–1467, 1469
Streptokinase, 311, 385
t
, 386–387. 
See also
 
Streptomycin, 208
t
, 292
t
, 293, 294, 1479, 
1480. 
See also
 
Stress (psychiatric/psychologic)
adjustment disorders and, 1063–1064
depression and, 1087
suicide and, 1089
trauma and, 
1064–1065
. 
See also
 
Posttraumatic stress disorder
Stress cardiomyopathy (Tako-Tsubo 
syndrome/catecholamine-
induced cardiomyopathy), 
383, 428, 
430–431
, 1192
Stress echocardiography. 
See
 
Stress fractures. 
See
 Fractures
Stress gastritis/ulcers, 632, 632–633
Stress incontinence, 66, 66–67
Stress/exercise testing
in angina/chest pain evaluation, 29, 370, 
376, 377
t
in athlete screening, 449
electrocardiography, 370
preoperative, 47–48
Striae distensae, 1186
Stribild (tenofovir/emtricitabine/
elvitegravir/cobicistat), 1366, 
1367
t
t
Stridor, 
243
in vocal fold paralysis, 248
Stroke, 488–490, 
1006–1016
, 1007
t
857, 1009
1010, 1011
t
, 11
atrial fibrillation and, 402, 402
t
, 404, 
404–406, 404
t
, 405
t
, 407
carotid intervention causing, 489
carotid occlusion causing, 53, 488, 489, 
489
f
, 1004, 1006, 1007
t
, 1008
cerebral infarct/ischemia causing, 488–
490, 489
f
, 
1007–1010
, 1007
t
cerebrovascular occlusive disease 
causing, 488, 489
coma caused by, 1008, 1018, 1040, 1255
t
cryptogenic, 338, 1006, 1009
in endocarditis, 1009, 1465
1211, 1212, 1213
hemorrhagic, 1007
t
t
, 10–11, 455, 456, 
459, 479–480, 480, 480
t
, 1009, 
1011
intracranial aneurysm causing, 1010
ischemic (infarcts), 488–490, 489
f
, 
1007–1010
, 1007
t
lacunar infarct causing, 
1006–1007
, 1007
t
NSAID use and, 843
patent foramen ovale and, 338, 1006, 
1009
postoperative, 52–53

f
, 
1007–1010
, 1007
t
1006–1007
, 1007
t
1009
5–11
, 6
t
, 8–9
t
, 9
t
, 1010
Stippling (nail), 169
in psoriasis, 115, 115
f
STK11/LKB1
Stomach disorders, 
631–644
, 638
t
. 
See also
 
under Gastric and 
Gastrointestinal and
 Gastritis
cancer, 1615
t
, 
1641–1646
. 
See also
 
Gastric cancer
herpes, 
238
ulcerative (aphthous ulcers), 
237–238
, 
876, 1350
Stool. 
See also under Fecal
analysis of
identification, 1654
in diarrhea, 601–602, 601
f
, 604
f
, 605, 
660
blood in. 
See
rice water, 1477
Stool osmolality, 603
Stool softeners/surfactants, 597
t
Storage pool disease, 566, 567
Straight leg raise test, 1698
Strawberry cervix, 781, 781
f
Strawberry gallbladder, 734
Strength testing
knee ligaments, 1711–1712
t
shoulder/rotator cuff, 1692–1693
t
Strep throat. 
See
 Pharyngitis, streptococcal
Streptobacillary fever, 1504
Streptobacillus moniliformis,
 1504
 (streptococcal infections), 
1318
t
, 1321
t
, 1322
t
, 
 
1448–1451
, 1450
f
, 1450
t
arthritis, 1451
t
t
drug resistance and, 238, 281, 1453
empyema, 1451
endocarditis, 1451, 1464, 1466–1467, 
1468, 1469
erysipelas, 
144–145
, 1322
t
f
, 
1450
t
gallolyticus (bovis),
 1451, 1468
glomerulonephritis after, 949, 1448
group A. 
See
 Group A beta-hemolytic 
streptococcal infection
group B. 
See
 Group B streptococcal 
infection
impetigo, 131–132, 1322
t
, 1449
necrotizing fasciitis, 1451
non-group A, 
1451
t
pharyngitis. 
See
 Pharyngitis, 
t
, 281, 1321
t
, 1322
t
, 
1451
, 278
t
, 281, 1318
t
, 
 
1452–1454
. 
See also
 
pneumoniae)
pyogenes
. 
See
1448, 1449
of skin, 
1449–1450
, 1450
f
, 1450
t
toxic shock syndrome caused by, 
 
1451
CMDT2019_Index_p1743-1884.indd   1867

INDEX1868
 
CMDT 2019
accessory atrioventricular pathways 
causing, 399, 400, 
400–401
catheter ablation of, 396, 400, 401
palpitations in, 30, 31
paroxysmal (PSVT), 
399–400
postinfarction, 389
treatment/prevention of, 394
t
, 395
t
Suramin, 1511, 1511
t
Surfer’s ear, 213
Surgery. 
See also
 
antibiotic prophylaxis and, 54
anticoagulation therapy and, 51–52, 52
t
, 
363, 364
t
anxiety before/after, 1116, 1117
bowel cleansing before, 597
t
diabetes/insulin therapy and, 
 
t
fever after, 1301–1302
gender affirming, 1076, 1740–1741, 
1741
t
ileus after, 650, 651
liver function and, 
50–51
meningitis after, 1305
t
patient evaluation/management and, 
46–49
, 47
t
, 48
f
. 
See also
 
Surgery proneness (polysurgery), 1116, 
1117
Surgical menopause, 808, 810
Surgical site infection, 1302, 1303
54
, 
1303
Surrogate, for medical decision making, 
76, 78
Surveillance. 
See
 Watchful waiting/
surveillance
Surveillance colonoscopy, 679, 1652–1653
Survival motor neuron 
(SMN)
 genes, 1046, 
1047
Susceptibility testing. 
See
 Drug resistance; 
Drug susceptibility testing
Suvorexant, 1067
t
, 1103
Swallowing disorders. 
See
 Dysphagia; 
Odynophagia
Swan-neck deformity, 852
Sweat chloride test, 276
Sweating, fluid loss replacement guidelines 
and, 925
t
Sweeteners, artificial, 1229
Swimmer’s ear, 212
Swimmer’s itch, 1535
Swimming pool granuloma, 1488
Swine influenza (pandemic H1N1), 1422. 
See also
 Influenza
Sycosis, 
137–138
, 138
f
Sydenham chorea, 435, 436, 436
t
Sympathetic inhibitors, peripheral, 474
t
, 
475
Sympathetic ophthalmia, 190
Sympatholytic agents, 474
t
, 475, 481
t
, 
1596
Sympatholytic syndrome, 1586
Sympathomimetic agents, 183
t
, 207
t
, 208
t
, 
1095
t
Sympathomimetic syndrome, 1586
Symptom evaluation/management, 
20–45
. 
See also
 
specific symptom
Symtuza (tenofovir [TAF]/emtricitabine/
darunavir/cobicistat), 1367
t
, 
1370. 
See also
therapy
physician-assisted (physician-assisted 
t
schizophrenia/psychotic disorders/
antipsychotic drug use and, 
1080, 1085
Sulconazole, 107
t
Sulfacetamide, 137, 180
t
Sulfadiazine, 1020, 1345
t
, 1527
Sulfadoxine-pyrimethamine (Fansidar), 
1518, 1518
t
t
, 1519
t
, 1522
Sulfamethoxazole-trimethoprim. 
See
 
Sulfasalazine, 662, 851
Sulfonamides, ophthalmic effects of, 208
t
Sulfonylureas, 1229–1232, 1230
t
, 1244
f
, 
1245. 
See also
 
hypoglycemia and, 1229, 1245, 1246, 
1262, 1262
t
, 1266, 1599
t
overdose/toxicity of, 1229, 1244
f
, 1584
t
, 
1599
Sulfur-sodium sulfacetamide. 
 
See
Sulindac, 88
t
, 680
Sumatriptan, 42, 208
t
, 991, 993
Summer grippe, 1433
Sun exposure. 
See
 Ultraviolet light/
sunlight
Sun protective factor (SPF), 109
Sunday neuroses, 1066
“Sundowning, ” 1115
Sunitinib, 1141, 1156, 1194, 1622
t
, 1646, 
1668, 1679
Sunscreens, 109. 
See also
sunlight
in cancer prevention, 14, 109
for lupus/SLE, 125, 855
photodermatitis and, 164
Superficial (first-degree) burns, 1571
Superficial spreading melanoma, 112
Superficial venous thrombophlebitis, 
499
Superior semicircular canal dehiscence, 
223–224
Superior vena cava sinus venosus defect, 
337
Superior vena caval obstruction/syndrome, 
502–503
, 1625
Superwarfarins, poisoning caused by, 1591
Supplements. 
See
 Dietary supplements
Suppurative sialadenitis, 242
Supraclavicular lymph nodes, in breast 
cancer, 757, 758
Supraglottic carcinoma, 246–247
Supraglottitis (epiglottitis), 
245
, 1449, 1472
Supranuclear palsy, progressive, 1025
Supraspinatus tendon, 1692
t
, 1694
Supratentorial mass lesion, coma/stupor 
caused by, 1041
Supraventricular beats
aberrantly conducted, differentiation of

t
, 1694
aberrantly conducted, differentiation of 
from ventricular beats, 410
premature. 
See
Supraventricular tachycardia, 393. 
See also
 
Tachycardia/tachyarrhythmia
Suberosis, 319
t
Submandibular glands. 
See also
 Salivary 
glands
Submersion injury (drowning), 
1569–1570
Subscapularis tendon, 1693
t
, 1694, 1695
Substance use disorders, 
18–19
, 
 
1105–1114
. 
See also
 
specific 
type and
 Injection drug use; 
Poisoning/drug overdose
aggressive/violent behavior and, 
 
1104–1105
autism spectrum disorder and, 1101
1735
t
hallucinations/hallucinosis caused by, 
1116, 1601–1602
HIV infection/AIDS and, 1310, 1311, 
1340, 1356
1310–1311
caused by withdrawal and, 
1115
t
pain management and, 19, 98–99
pregnancy and, 812–813
prescription drug, 19, 98–99
18–19
, 
18
t
t
septic arthritis and, 881, 1311
toxicology screen in, 1105, 1587
Subtalar tilt test, 1720
Subtentorial lesions. 
See also
 Brainstem
Subungual lesions, malignant, 169
Succimer (dimercaptosuccinic acid/
DMSA), 1593, 1601, 1602
Succinate dehydrogenase 
(SDH)
 
mutations, 1190, 1194
t
t
Succussion splash, 592
Sucralfate, 283, 331, 633, 637
Sudden death (sudden cardiac death/
sudden cardiac arrest), 
411
of athlete, 426
cardiomyopathy and, 426, 449
driving recommendations and, 413
myocardial infarction and, 383, 411
myocarditis causing, 426
ventricular fibrillation causing, 383, 
411
ventricular premature beats and, 409
ventricular tachycardia and, 409, 411
Sudden sensory hearing loss, 219
Suicide, 1089
acetaminophen overdose/liver failure 
and, 699
alcohol use disorder and, 1089, 1106
antidepressant overdose and, 1089, 
1090, 1609
carbon monoxide poisoning and, 1595
t
gender dysphoria and, 1072
hospitalization/illness and, 1118
in older adults, 60
personality disorders and, 1078
CMDT2019_Index_p1743-1884.indd   1868

INDEX1869
 
CMDT 2019
gastric, 1644
and, 234
tacrolimus/pimecrolimus and, 114
T cell-mediated (delayed/type IV) 
T cell tolerance genes, 1220
T-DM1 ado-trastuzumab emtansine. 
 
767–768, 770. 
See also
 
T helper cells. 
See
 CD4 T cells
T lymphocytes
and, 897
in delayed hypersensitivity, 894
in HIV infection/AIDS. 
See
 CD4 T cells
T pallidum
 particle agglutination (TPPA) 
test, 1495
t
T score, 1171, 1172
T waves. 
See also
Tabes dorsalis, 1500
in, 889, 1500, 1501
f
Tabun (GA) poisoning, 1595, 1605
TACE/TACI/TARE, 1633, 1635
Tâche noire, in tick typhus, 1442
“Tachy-brady syndrome, ” 397
Tachycardia/tachyarrhythmia, 
396–397
. 
See also
accessory pathways causing, 399, 400, 
400–401
antidromic reentrant, 401
atrial, 
408
AV nodal reentrant (AVNRT), 399, 400
AV reciprocating (AVRT), 399
in hyperthyroidism, 1141, 1147
in myocardial infarction, 383, 389, 409, 
410
orthodromic reentrant, 400–401
palpitations in, 30, 31, 32, 410
paroxysmal, 
399–400
in poisoning/drug overdose, 1582, 
 
1582
t
See
 
under 
Supraventricular
t
, 395
t
, 410–411
See
 
under Ventricular
Tachypnea, in pulmonary embolism, 306, 
306
t
Tacrolimus, 106
t
for anogenital pruritus, 156
for atopic dermatitis/eczema, 114
t
, 
208
t
Tadalafil. 
See also
t
, 
987
1092, 1250
t
neurosyphilis and, 1323
t
, 1496
t
, 1501
pregnancy and, 1496, 1496
t
, 1502
837
, 1493, 1496, 
1496
t
, 
1502
prevention of/screening for, 1493, 
 
1494–1496, 1495
t
. 
See also
 
Syphilis, serologic tests for
primary, 1323
t
, 
1493–1497
, 1494
f
, 
1494
t
, 1495
t
, 1496
t
public health measures in management 
of, 1497
secondary, 1323
t
t
, 1495
t
, 
1496
t
, 1497–1498, 1498
f
serologic tests for, 1494–1496, 1495
t
. 
See 
also
 
specific test
anticardiolipin/antiphospholipid 
antibody/lupus anticoagulant 
affecting, 853
t
, 855, 857
 
1359–1360, 1496, 1735, 1735
t
HIV infection/AIDS and, 1359–1360, 
1495, 1501
in neurosyphilis, 1360
in pregnant patient, 814, 837, 1496, 
1502
tertiary (late), 1493, 1494
t
, 1495
t
, 1496
t
, 
1499–1500
, 1499
f
, 1500
f
treatment of, 1319
t
, 1323
t
, 1496–1497, 
1496
t
failures and, 1497
nontreponemal antibody titers and, 
1495
uveitis in, 190
Syringobulbia, 1045
Syringomyelia, 
1045–1046
and, 889
Systemic fibrosing syndrome, 1705
Systemic fibrosis, nephrogenic 
(necrotizing), 371, 931, 944
Systemic hypertension. 
See
 Hypertension
Systemic inflammatory response 
syndrome (SIRS), 506
in pancreatitis, 742, 744
Systemic lupus erythematosus (SLE), 
 
853–856
, 853
t
, 854
t
, 855
t
arthritis in, 850, 853
t
, 854
autoantibodies in, 123, 853, 853
t
, 
 
854–855, 854
t
, 855
t
drugs and, 321
t
, 
856
lupus anticoagulant/antiphospholipid 
antibody syndrome and, 853
t
, 
855, 855
t
renal involvement in, 853
t
, 854, 855, 
946
t
, 
953–954
skin lesions in (cutaneous lupus), 
 
123–124, 171
t
, 855
Systemic sclerosis. 
See
T315I
 mutation, 535
T372R/YY1
 mutation, 1262
T790M
 mutation, 1627, 1628
T-cell gene rearrangement test, 124, 543, 
543
t
, 545
T-cell lymphoma, 543, 543
t
, 545. 
See also
 
lymphoma
adult (ATL), 1408, 1409
cutaneous (mycosis fungoides), 
124
, 125

543
t
, 545
t
, 545. 
See also
 
lymphoma
124
, 125
enteropathy-associated, 1647
Syncope/near syncope, 
412–414
cardiogenic, 413
heat, 1565
postmicturition, 413
reflex, 413
vasodepressor/vasovagal, 413
Syndesmophytes
in psoriatic spondylitis, 879
Syndrome of apparent mineralocorticoid 
excess, 454, 906
t
Syndrome of inappropriate ADH secretion 
(SIADH), 901, 901
t
, 902, 1625
Syndrome X, 378. 
See also
 Insulin 
resistance/insensitivity; 
Metabolic syndrome
Synergistic necrotizing cellulitis, 1485
Synovial fluid examination, 840, 841
t
, 
842
t
, 882, 883, 886–887. 
See 
also
 
Synovitis, remitting seronegative, with 
Synpharyngitic hematuria, 950
Syphilis, 1319
t
, 1323
t
, 
1493–1502
, 1494
t
anorectal involvement and, 684, 1494, 
1498
f
aortic aneurysms and, 494, 1499, 1500, 
1500
f
cerebrospinal fluid examination in, 
1360, 1497
condyloma lata in, 684, 1497, 1498
f
congenital, 837, 1493, 1502
contact treatment and, 1497
course/prognosis of, 
1493
drug therapy for, 1496–1497, 1496
t
. 
See 
also
 Syphilis, penicillin for
Jarisch-Herxheimer reaction and, 
1497
for neurosyphilis, 1323
t
, 1496
t
early (infectious), 1323
t
, 1493, 1496
t
endemic, 
1503
follow-up care in, 1497
in gay and bisexual men/MSM, 1359–
1360, 1493, 1496, 1501–1502, 
1733, 1735
t
gummatous, 1493, 1494
t
f
1501–1502
, 
1733
latent, 1323
t
t
, 
1498–1499
early, 1323
t
t
, 1498
late, 1496
t
, 1498–1499
meningovascular/meningitis, 1494
t
, 
1497, 1500. 
See also
 
mucocutaneous, 1494
t
f
, 
1499
natural history of, 
1493
f
neurologic involvement in, 1323
t
, 1360, 
1494
t
, 1496
t
, 1500–1501. 
See 
also
penicillin for, 1323
t
, 1496, 1496
t
CMDT2019_Index_p1743-1884.indd   1869

INDEX1870
 
CMDT 2019
Teratoma, testicular, 1669
Teratozoospermia, 981
f
Terazosin, 207
t
t
, 973, 986, 
986
t
Terbinafine, 107
t
, 120, 121, 122, 170, 1560, 
1562
t
Terbutaline, 826
Terconazole, 782
Teres minor, 1694
Terfenadine, antidepressant drug 
t
Teriflunomide, 1038
t
Teriparatide, 1173, 1174, 1219
Terlipressin, 627
Terminal deoxynucleotidyl transferase 
(TdT), 539
Terminal illness. 
See
 End of life
Terminal restlessness/delirium, 73–74
Terrorism. 
See
 Bioterrorism
Testes
1199–1204
, 1199
t
. 
See also
 
under Testicular and
 
examination of in hypogonadism/
infertility, 981–982, 981
f
masses/tumors of. 
See
in mumps, 1394
undescended (cryptorchism), 1200, 
1204
Testicular cancer, 1614
t
, 
1668–1669
cryptorchism and, 1200, 1204, 1669
t
secondary/metastatic, 
1670
Testicular dysgenesis, 1200
Testicular failure (hypergonadotropic/
primary hypogonadism), 982, 
1120, 1121, 1123, 1199, 1199
t
, 
1200, 1201. 
See also
 
Testicular lymphoma, 1670
Testicular torsion, 973
Testis. 
See
 Testes
Testosterone. 
See also
 Androgens; 
therapy
deficiency of, 982, 1121, 1199–1204. 
See 
also
and, 1209
excess of. 
See
in infertility, 982
insensitivity/resistance to. 
See
 Androgen 
insensitivity/resistance
1739–1740, 1739
t
 
1740
t
1740, 1741
t
normal values for, 1200
Testosterone buccal tablets, 1202
Testosterone cypionate, 1202, 1739
t
Testosterone deficiency syndrome, 1200
Testosterone enanthate, 1203, 1739
t
Testosterone gels, 1201–1202, 1739
t
nasal, 1202
Testosterone pellets, 1202
Tdap vaccine, 4, 1327
t
, 1328
t
, 1329
t
, 1336
t
, 
1459, 1459
t
, 1463, 1470. 
See 
also
 Tetanus 
 
See also
 
Tears, artificial, 177, 865
Technetium-99m scintigraphy
for thyroid scanning, 1135
t
, 1143
Technosphere inhaled insulin, 1238
t
, 
1240–1241
Tedizolid, 1455
Teduglutide, 649
Teeth, disorders of. 
See
 Dental disorders
TEL-AML1
 translocation, 538
Telangiectasia
hereditary hemorrhagic, 573, 606, 
1688–1689
Telangiectatic focal nodular hyperplasia of 
liver, 731
Telaprevir, 703
Telavancin, 1455
Telbivudine, 702, 703
Telmisartan/telmisartan combinations, 
459, 469
t
Telogen effluvium, 168
Temazepam, 1067
t
, 1102
Temozolomide, 1018, 1124, 1130, 1194, 
1617
t
Temperature. 
See
temperature; Fever
Temporal (giant cell/cranial) arteritis. 
See
 
Giant cell (temporal/cranial) 
arteritis
Temporal lobe herniation, 1016–1018
Temporal lobe lesions, 1016
Temporal sclerosis, mesial, epilepsy/
Temporomandibular joint dysfunction
facial pain and, 997
Temsirolimus, 1622
t
Tendinopathy (tendinosis), upper 
extremity (lateral and medial 
epicondylosis), 
1703–1704
Tendinous xanthoma, 1269
Tenecteplase (TNK-t-PA), 385
t
, 386, 587
t
Tennis elbow, 1703
Tenofovir (TDF/TAF), 702, 1363
t
, 1366, 
1371. 
See also
therapy
t
, 
1373
t
. 
See also
 Atripla; 
Truvada
1742
for hepatitis B, 702, 703, 1351, 1366
postexposure, 1358, 1359
preexposure, 1356–1357, 1357
t
Tenosynovitis
in gonococcal arthritis, 883, 1481
in tuberculosis, 886
Tension pneumothorax, 325, 326
Tension-type headache, 
992
Teratogenic drugs, 812
t
. 
See also
 
specific 
agent
Taenia
saginata
 (beef tapeworm), 
1538
solium
 (pork tapeworm), 
1538
, 1539
Tafenoquine, 1518
Tafluprost/tafluprost combinations, 184
t

992
t
. 
See also
 
specific 
agent
Taenia
saginata
1538
solium
1538
, 1539
t
Takayasu arteritis, 
869–870
Tako-Tsubo syndrome (stress/
catecholamine-induced 
cardiomyopathy), 383, 428, 
430–431
, 1192
Talazoparib, 771
Talcosis (talc exposure), 318
t
, 320
Talcott rules, 36
Tall stature
GH excess causing, 1126
in Klinefelter syndrome, 1200, 1686
in Marfan syndrome, 1687
Talofibular ligament, ankle sprains 
involving, 1720
Tamm-Horsfall urinary mucoprotein, 926
Tamoxifen, 766, 769, 769
t
, 1623
t
adverse effects/risks of, 208
t
, 766, 769
t
for breast cancer, 755, 766, 769, 769
t
, 
775
for GH-secreting tumor/acromegaly, 
1127
for Riedel thyroiditis/struma, 1133
Tamponade, 
440–441
cancer-related, 1672
infarct-related, 390
in pericarditis/effusion, 28–29, 437, 439, 
440, 1672
in traumatic cardiac injury, 445
Tamponade (balloon tube), 627
TAMs (thymidine analog mutations), in 
antiretroviral resistance, 1375
Tamsulosin, 207
t
, 977, 981, 986, 986
t
Tap water enema, 597
t
Tapentadol, 94
t
, 95
t
Tapeworm infections, 
1538–1540
invasive, 
1539–1540
noninvasive, 
1538–1539
vitamin B
12
 deficiency in, 517, 1538
Tar shampoo, 116, 118
Tardive dyskinesia, 1030
Tardive dystonia, 1085
Targeted therapy, in cancer treatment, 
1619–1622
t
. 
See also
 
specific 
type of cancer
Tarsal tunnel syndrome, 
1053–1054
Tau protein
in Creutzfeldt-Jakob disease, 1035, 1407
in dementia, 1034, 1035
in head injury and, 1044
Tavaborole, 107
t
, 170
tax
 gene, 1408
Taxanes, 1618
t
for breast cancer, 761–762, 765–766
Tay-Sachs disease, screening for, 813
TcdA/TcdB toxins, in antibiotic-
associated/
 colitis, 
660
TCF7L2
 gene, 1221
TCu380A IUD, 804
Td vaccine, 4, 1327
t
, 1328
t
, 1336
t
, 1459, 
1459
t
. 
See also
 Tetanus and 
diphtheria toxoids and 
CMDT2019_Index_p1743-1884.indd   1870

INDEX1871
 
CMDT 2019
Thioridazine, overdose/toxicity of, 208
t
, 
1592
Thiosulfate, for cyanide poisoning, 1584
t
, 
1596–1597
Thiothixene, 1081
t
, 1082
t
Thioureas, 1144, 1146, 1147, 1148
Third-degree (full-thickness) burns, 1571
Third-degree (complete) heart block, 389, 
See also
 
Atrioventricular (heart) block
Third nerve palsy, 201, 201
f
Third-trimester bleeding, 
827–828
Thirst. 
See
 Polydipsia
Thoracentesis, 322. 
See also
 Pleural fluid 
analysis
in malignant pleural effusion, 323, 1672
in parapneumonic pleural effusion, 325
in pneumonia, 281, 1453
Thoracic actinomycosis, 1486
Thoracic aortic aneurysms, 
494–495
Thoracic carcinoid, in MEN, 1197
t
Thoracic kyphosis, 1698
Thoracic outlet syndromes, 
887
chest pain and, 372, 631
neck pain and, 887, 1701
Thoracic spine disease, chest pain and, 
372, 631
Thoracoscopic surgery, video-assisted. 
See
 
Video-assisted thoracoscopic 
surgery
Thoracostomy, tube. 
See
 Tube 
Thoracotomy, in lung cancer, 1629
Thorotrast exposure, ureteral/renal pelvis 
cancer and, 1666
Thought content, in schizophrenia/
psychotic disorders, 1079
Threatened abortion, 818
“3” sign, in coarctation of aorta, 336
“Thrifty” 
(LITH)
 gene, 732
Throat, 
234–242
Throat culture, in pharyngitis, 239, 1448
Thrombasthenia, Glanzmann, 566, 567
Thrombin inhibitors. 
See
 Direct thrombin 
Thromboangiitis obliterans (Buerger 
disease), 
491
Raynaud disease/phenomenon an, 491, 
858
Thrombocytopenia, 
556–566
, 557
t
, 560
f
, 
565
t
. 
See also
 
amegakaryocytic, 556, 557
aplastic anemia and, 527, 556, 558
with autoimmune hemolytic anemia 
(Evans syndrome), 524
in cancer chemotherapy/irradiation, 
558
, 565
t
, 1677
cyclic, 
558
decreased platelet production causing, 
556–558
, 557
t
DIC and, 563–565, 564
t
drug-induced/related, 
565
, 565
t
, 568
t
gestational, 
566
heparin-induced (HIT), 
562–563
, 563
t
immune (ITP), 557, 
558–560
, 560
f
557
t
, 
558–565
infection/sepsis-related, 557
t
, 
566
nutritional deficiencies and, 
558
platelet sequestration and, 557
t
, 
566
Tetrodotoxin, 1607
t
TFR2
 (transferrin receptor 2) mutation, 
723
TGFBR1/TGFBR2 receptor mutations, 
1687
Thalamic stimulation, 1024, 1027, 1029
Thalamic syndrome, 1008, 1016
Thalassemias, 
514–517
, 514
t
, 515
t
iron deficiency differentiated from, 512, 
516
prenatal screening for, 813
sickle, 523
t
, 
524
for cancer chemotherapy, 1619
t
for plasma cell myeloma, 548
for primary myelofibrosis, 533, 534
Thallium-201 scintigraphy
in thyroid cancer, 1158
f
, 261
t
, 264
for COPD, 271–272, 273
t
overdose/toxicity of, 1583
t
, 1585
t
, 1587
t
, 
1608–1609
Therapeutic abortion, 
806
Therapeutic diets. 
See also
Thermal injury. 
See
 Burns
Thermoregulation, 1564
Thessaly test, 1714
t
, 1716
Thiabendazole, 1543, 1546
Thiamine (vitamin B
1
)
for coma, 1040, 1581
1282–1283
alcohol use/alcoholic ketoacidosis 
and, 919, 1282–1283, 1581
neuropathy associated with, 1282
1039, 1107, 1108, 1282
Thiazide diuretics. 
See also
 Diuretics
t
t
chronic kidney disease and, 460, 
 
938–939, 955
for hyperkalemia, 907
t
, 475, 476
f
, 
938–939
1099
t
Thiazolidinediones, 1230
t
, 1233–1234
heart failure and, 421, 1233
with metformin, 1233
t
, 1233, 1233–
1234, 1599
Thienopyridines, platelet function affected

t
t
1234, 1599
Thienopyridines, platelet function affected 
by, 568
t
Thiopurine methyltransferase variants, 
azathioprine/mercaptopurine 
therapy and, 707
Thiopurines, 663, 669, 672–673. 
See also
 
Azathioprine; Mercaptopurine
Testosterone replacement therapy, 
 
1201–1203
gynecomastia caused by, 1201, 1203
for hypogonadism, 1201–1203
for Klinefelter syndrome, 1687
for osteoporosis, 1172, 1215
in women, 809–810, 1215
Testosterone undecanoate, 1202, 1739
t
TET2
Tetanospasmin, 1459
Tetanus, 1319
t
, 
1458–1460
, 1459
t
t
, 
1328
t
, 1329
t
, 1459, 1459
t
. 
See 
also
Tetanus-diphtheria 5-component acellular 
pertussis (Tdap) vaccine, 4, 
1327
t
, 1328
t
, 1329
t
, 1336
t
, 
1459, 1459
t
See 
also
Tetanus-diphtheria toxoid (Td vaccine), 4, 
1327
t
, 1328
t
, 1336
t
, 1459, 
1459
t
. 
See also
Tetanus and diphtheria toxoids and 
pertussis vaccines (DTaP/
Tdap/Td vaccines), 4, 1327
t
, 
1328
t
, 1329
t
t
, 
1463, 1469–1470
bite wounds and, 1308
booster and, 4, 1327
t
, 1328
t
, 1329
t
, 
1459, 1463, 1470
frostbite and, 1569
t
, 1361
t
, 1329
t
, 
t
, 1336
t
Tdap replacing Td and, 4, 1459, 1470
Tetanus immune globulin, 1459, 1459
t
Tetany
910, 1162, 1162–1163
t
in respiratory alkalosis, 924–925
Tetrabenazine, 1028, 1031
t
t
in 
H pylori
 eradication, 638
t
, 639
ophthalmic effects of, 208
t
t
, 1501
for 
Vibrio
 infections, 1478
Tetrahydrocannabinol. 
See
Tetrahydrozoline, 1596
Tetralogy of Fallot, 
341–342
CMDT2019_Index_p1743-1884.indd   1871

INDEX1872
 
CMDT 2019
Thyroid antibodies. 
See
 Antithyroid 
(antithyroglobulin/
Thyroid cancer, 1152–1159, 1152
t
, 1155
t
, 
1612
t
, 1615
t
anaplastic/undifferentiated, 1152
t
, 1153, 
1156, 1159
differentiated, 1152, 1153, 1154–1156
fine-needle aspiration biopsy and, 
1135
t
t
follicular, 1152
t
, 1153, 1154, 1158–1159
follow-up care and, 1157–1158
functioning, 1141
hyperthyroidism and, 1141, 1154
lymphoma, 1153, 1157, 1159
medullary, 1152
t
, 1153, 1157, 1159, 
1197
t
metastatic, 1153, 1154, 1155–1156, 1156
microcarcinoma/microscopic/
micropapillary, 1153, 1155
papillary/mixed papillary-follicular, 
1152–1153, 1152
t
, 1153, 1154, 
1158
pregnancy and, 1155
radiation exposure and, 1149, 1152
staging of, 1155, 1155
t
thyroid nodules and, 1149, 1153
thyroid surgery for, 1154–1155
radioactive iodine therapy after, 1155
t
, 1153–1154
Thyroid crisis/storm, 1142, 1148
perioperative, 53–54
during pregnancy, 830, 1141
Thyroid cysts, 1150, 1151
Thyroid eye disease, 
202
, 202
f
Thyroid gland
biopsy of, 1133, 1135
t
1150
t
disorders of, 1131–1160. 
See also
 
Hyperthyroidism; 
Hypothyroidism; Thyroiditis
202
, 202
f
, 
heart disease and, 415, 1135, 1141, 
1147–1148
See
 Thyroid cancer; 
and, 53–54
830–831
, 1131, 
1143
1141
thyroid testing in. 
See
 Thyroid 
 
testing
enlarged. 
See
 Goiter
examination of, 1141
infection of (infectious/suppurative 
thyroiditis), 1132, 1133
nodular. 
See
 Multinodular (nodular) 
goiter; Thyroid cancer; 
Thyroid hormone. 
See also
 Thyroxine; 
Triiodothyronine
Thrombophilia, 583, 584, 585
t
, 586
t
. 
See 
also
 Thromboembolism; 
Thrombosis; Venous 
Thrombophlebitis. 
See also
 Deep venous 
thrombosis; Thrombosis
oral contraceptive use and, 800–802
septic. 
See
 Septic thrombophlebitis
of superficial veins, 
499
varicosities and, 498, 499
Thrombopoietin receptor agonists, 558, 
560
f
. 
See also
 Eltrombopag; 
Thrombosis. 
See also
487, 488
in aneurysms, 493, 495
85–87, 306, 584, 586
t
, 830, 
856–857
cavernous sinus, 227
of deep veins. 
See
in DIC, 564, 565, 573
drugs in management of, 
573–587
. 
See 
also
 Anticoagulation therapy
(Wegener granulomatosis), 872
hemorrhoidal, 683
in heparin-induced thrombocytopenia, 
562, 563
in hyperhomocysteinemia/
homocystinuria, 306, 586
t
, 
1686
intracranial, 
1015
. 
See also
 Stroke
in polycythemia, 530, 531
sigmoid sinus, 217
stent, 375
venous. 
See
 Venous thromboembolic 
disease
venous sinus, 1021
Thrombotic microangiopathy, 
560–562
Thrombotic thrombocytopenic purpura 
(TTP), 560–562, 561
t
Thrush. 
See
THSD7A, 957
“Thumb sign, ” 245
“Thunderclap headache, ” 41, 1012
Thymic neuroendocrine tumors, in MEN, 
1198
Thymidine analog mutations (TAMs), in 
Thymoma, myasthenia gravis and, 1058, 
1059
Thyroglobulin
antibodies to. 
See
in thyroid cancer, 1153, 1157
Thyroglossal duct cysts, 
249–250
Thyroid acropachy, 1142, 1148
Thyroid adenoma, toxic
t
, 1198
multiple (toxic multinodular goiter), 
1140, 1146, 1150, 1151
solitary (toxic solitary thyroid nodule), 
1140, 1146
Thrombocytopenia (
Cont
.):
platelet transfusion for, 554

t
, 1198
1140, 1146
Cont
.):
posttransfusion purpura (PTP) and, 
565–566
with severe fever, 1412
thrombotic microangiopathy and, 561, 
561
t
von Willebrand disease type 2B and, 
566, 571
Thrombocytopenia-absent radius 
syndrome, 556
Thrombocytosis
essential, 530
t
, 
531–532
reactive, 532
Thromboembolectomy
pulmonary, 312
for stroke, 1009, 1010
Thromboembolism. 
See also
 Embolism; 
487, 488
t
t
, 403, 
t
, 405
t
573–587
. 
See 
also
therapy and, 810, 1211, 1212, 
1738–1739
872
t
, 
1686
in myocardial infarction, 391
prosthetic heart valves and, 362–365, 
364
t
See
t
Thromboendarterectomy
carotid. 
See
485
Thrombolysis in Myocardial Infarction 
(TIMI) Risk Score, 28, 29, 
382, 392
Thrombolytic therapy. 
See also
 Fibrinolytic 
therapy
 
488
disease), 311–312, 585–587, 
587
t
for hepatic vein obstruction (Budd-
for retinal artery occlusion, 195
blood pressure and, 480
CMDT2019_Index_p1743-1884.indd   1872

INDEX1873
 
CMDT 2019
Tic douloureux (trigeminal neuralgia), 
994–997
Ticagrelor, 374, 379, 380, 384–385, 392
proton pump interaction/
Ticarcillin, platelet function affected by, 
568
t
Tick bite fever, African, 1437
t
, 1442
Tick-borne encephalitis (TBE), 1401, 
1403–1405
erythema-lymphadenopathy/
scalp eschar neck 
lymphadenopathy (TIBOLA/
DEBONEL/SENLAT), 1437
t
, 
1442
Tick-borne relapsing fever, 1503
Tick fever, Colorado, 1401, 
1420
Tick typhus, 1437
t
, 
1442
Ticks
in babesiosis transmission, 1524, 1525
in hemorrhagic fever transmission, 1412
in Lyme disease transmission, 1506, 
1508
removal of, 160
1437
t
, 1440, 1441, 1442, 1443
skin lesions caused by, 159, 1442
Ticlopidine, 568
t
. 
See also
therapy
Tics, in Tourette syndrome, 1031
Tietze syndrome, 372
Tigecycline, 1455
Tilt table testing, 413
TIMI score, 28, 29, 382, 392
Timolol/timolol combinations, 183
t
, 184
t
, 
464
t
Tincture of opium, for diarrhea, 605, 668
Tinea
corporis/circinata, 117, 
119–120
, 120
f
cruris, 
120–121
manuum, 
121–122
pedis, 120
f
, 
121–122
, 145
profunda, 162
unguium (onychomycosis), 169, 
170
versicolor (pityriasis versicolor), 117, 
122
Tinel sign, 1704
Tinidazole, 782, 1529, 1530
t
, 1533–1534, 
1534
Tinnitus, 
220
in glomus tumors, 218, 220
Tioconazole, 782
Tiotropium, 260
t
, 271
Tipiracil/trifluridine, 1622
t
, 1652
Tipranavir/ritonavir, 1364
t
, 1370. 
See also
 
Tirofiban, 375, 380–381, 380
f
, 568
t
Tisagenlecleucel, 540
Tissue plasminogen activator (tPA/
alteplase), 385
t
, 386. 
See also
 
t
, 386
587
t
Thyroid testing, 1135
t
in goiter, 1160
in heart failure, 415–416
in hyperthyroidism, 1135
t
, 1139
t
, 
 
1142–1143
in hypothyroidism, 1135–1136, 1135
t
, 
1136
t
pregnancy and, 830, 1143
in thyroid cancer, 1135
t
in thyroid nodules, 1135
t
in thyroiditis, 1132, 1135
t
Thyroid transcription factor-1 (TTF-1), 
1629
Thyroidectomy. 
See
 Thyroid surgery/
thyroidectomy
Thyroiditis, 
1131–1134
Hashimoto/autoimmune, 1131, 1132, 
1132–1133, 1133, 1134
1131, 1132, 1133, 1134, 1140, 
1146
hypothyroidism and, 1131, 1132, 1133, 
1134
infectious (suppurative), 1132, 1133
lymphocytic, 1131, 1132
postpartum, 1131, 1133
1133
pregnancy/postpartum, 830, 831, 1131, 
1132, 1133, 1134, 1140, 1141, 
1148
Riedel, 1132, 1133–1134
subacute. 
See
 Subacute thyroiditis
subclinical, 1131
thyroid antibodies in, 1131, 1132
in Turner syndrome, 1131, 1216
Thyroperoxidase, antibodies against. 
See
 
Antithyroid 
Thyrotoxic cardiomyopathy, 429, 1141
Thyrotoxic hypokalemic periodic 
paralysis, 1062, 1142, 1148
Thyrotoxicosis, 
1139–1149
, 1139
t
. 
See also
 
factitia, 1141
Thyrotrophe pituitary adenoma/
hyperplasia, 1141
Thyroxine (T
4
), 1135
t
, 1136
t
, 1139
t
. 
See 
also
 
free. 
See
 Free thyroxine assay
levothyroxine replacement and, 1123, 
1137, 1137–1138, 1138
uptake of (resin). 
See
 Resin T
3
/T
4
 uptake
Thyroxine index, free (FT
4
I). 
See
 Free 
thyroxine index
Thyroxine-withdrawal stimulated 
131
I 
therapy, 1156
Tiagabine, 996
t
, 1592
Tibial artery, atherosclerotic/occlusive 
486–487
Tibial nerve, entrapment of (tarsal tunnel 
1053–1054
Tibiofibular ligament, in ankle sprains, 
1721
Tibolone, 1215
Tic cough, 22
1090
excess/deficiency of. 
See
 
exogenous, excess ingestion of

1721
1090
See
 
exogenous, excess ingestion of 
(thyrotoxicosis factitia), 1141
See
 
Levothyroxine
Thyroid incidentalomas, 1133, 1150
Thyroid nodules, 
1149–1152
, 1150
t
. 
See 
also
 Goiter; Thyroid cancer
biopsy of, 1150–1151, 1150
t
functioning (toxic multinodular goiter/
Plummer disease), 1140, 1146, 
1150, 1151
incidentally discovered, 1133, 1150
solitary toxic (thyroid adenoma), 1140, 
1146, 1197
t
, 1198
thyroid cancer and, 1149, 1153
t
Thyroid radioactive iodine uptake and 
scan. 
See
 Radioiodine thyroid 
scans and uptake
Thyroid remnant ablation, 1155
Thyroid-stimulating hormone (TSH/
thyrotropin), 1119, 1135
t
deficiency of, 1120
in euthyroid sick syndrome, 1136
t
t
, 
1142
amiodarone-induced, 1140, 1143
pregnancy and, 830, 831, 1141, 1143
in hypothyroidism, 1121, 1122, 1135–
1136, 1135
t
, 1136
t
, 1138
pregnancy and, 830, 1137
pituitary disease and, 1121, 1141
pregnancy and, 830, 831, 1137, 1141, 
1143
recombinant human (rhTSH)
hyperthyroidism and, 1141, 1156
reference/normal values for, 1135–1136
suppression of, for thyroid cancer, 1155, 
1157
in thyroid nodules, 1149–1150, 1151
Thyroid-stimulating immunoglobulins/
TSH receptor antibodies (TSI/
TSHrAb), 1135
t
, 1139, 1142, 
1143
Thyroid storm. 
See
 Thyroid crisis/storm
Thyroid surgery/thyroidectomy
for goiter, 1146, 1160
1145–1146, 1146, 1147
hypocalcemia after, 1162
hypoparathyroidism after, 1145, 1146, 
hypothyroidism after, 1134, 1146, 1148
during pregnancy, 1147, 1155
for thyroid cancer, 1154–1155
radioactive iodine treatment and, 
1155
for thyroid nodules, 1146, 1151
vocal fold paralysis/recurrent laryngeal 
nerve damage and, 247, 248, 
1145–1146, 1148, 1154–1155
CMDT2019_Index_p1743-1884.indd   1873

INDEX1874
 
CMDT 2019
Trachoma, 177
Tractional retinal detachment, 192
“Trait” thalassemias, 514, 514
t
, 515, 516
Tramadol, 95
t
, 96
t
, 1604
Trametinib, 1628
Trandolapril/trandolapril with verapamil, 
418
t
, 467
t
Tranquilizers. 
See
 
Trans fatty acids, preventable disease/
deaths and, 3
t
Transannular patch, for tetralogy of Fallot, 
341, 342
Transarterial chemoembolization (TACE)/
chemoinfusion (TACI)/
radioembolization (TARE), 
1633, 1635
Transbronchial lung biopsy. 
See
 Lung 
biopsy
Transcatheter valve replacement, 355, 
356–357, 357
f
in aortic stenosis, 355, 356–357, 357
f
in mitral regurgitation, 351
in tricuspid stenosis, 360, 362
Transcranial magnetic stimulation, 992, 
993, 1096
Transdermal contraceptive patch, 803
Transdermal testosterone, 1202, 1739
t
Transesophageal echocardiography. 
See
 
Transferrin
in anemia, 512, 513
carbohydrate deficient, 1107
Transferrin receptor 2 
(TFR2)
 mutation, 
723
Transformation zone, in CIN, 783
Transforming growth factor beta (TGF-
beta), Marfan syndrome and, 
1687
Transfusion (blood/blood products), 
 
552–555
. 
See also
 
specific 
component and disorder
acute lung injury caused by, 554
for chemotherapy-associated anemia, 
1677
for DIC, 554–555, 564
disease transmission and, 553–554
dengue, 1414–1415
donor screening programs and, 
 
553–554
hepatitis, 553, 554, 694, 695, 697, 706
HIV , 553, 554, 1340, 1359
HTLV , 553, 1408
West Nile virus, 553, 1401, 1402
1430
for fluid management/volume 
replacement, 507
for GI bleeding/variceal hemorrhage, 
607
graft-versus-host disease caused by, 554
preoperative, 51
purpura associated with, 565–566
Transfusion graft-versus-host disease, 
 
554
Transfusion reactions
Total parenteral nutrition. 
See
Total protein. 
See
 Protein
Tourette syndrome, 
1030–1031
Toxic adenoma
1140, 1146
Toxic epidermal necrolysis, 
142–144
, 170, 
172
t
Toxic lung injury. 
See
 Lung, toxic/chemical 
injury of
Toxic megacolon, 652, 673
Toxic-mold syndrome, 1561
Toxic multinodular goiter, 1140, 1146, 
1150, 1151. 
See also
 
Multinodular (nodular) goiter
Toxic neuropathies, 
1050
Toxic psychosis, 1080
Toxic shock syndrome
diaphragm/cervical cap use and, 805, 
1457
1457
, 1457
f
Toxic solitary thyroid nodule (toxic 
adenoma), 1140, 1146
Toxicology consultation (regional poison 
control center), 1580
Toxicology screen, 1105, 1587, 1587
t
opioid pain management and, 98
in poisoning/drug overdose, 1587, 1587
t
Toxicosis, T
3
, 1142
Toxins, 660. 
See also
overdose
anion gap affected by, 919
in diarrhea/food poisoning/
gastroenteritis, 599–600, 599
t
, 
600, 1312
t
, 1313
t
, 1314
liver disease caused by, 
710–712
. 
See 
also
 Hepatotoxicity
osmolar/osmol gap affected by, 1586–
1587, 1586
t
See
 Toxicology screen
Toxocara canis/cati
 (toxocariasis), 
1545
Toxoplasma/Toxoplasma gondii
 
(toxoplasmosis), 
1525–1528
eye disease caused by, 190, 1526
infection/AIDS, 1019–1020, 
1345
t
, 1348, 1361, 1526, 1527, 
1528
during pregnancy/congenital, 813, 1526, 
TP53
See also
 
P53
 mutations
hepatocellular carcinoma and, 1631
in myelodysplastic syndromes, 537
TPPA test, 1495, 1495
t
Trabeculectomy/laser trabeculoplasty, 189
Trace elements, in nutritional support, 1290
Trachea
248–249
obstruction of, 252
stenosis of, 252
Tracheal intubation. 
See
 Intubation; 
Tracheostomy/tracheotomy, 
248
. 
See also

Trachea
248–249
See
248
. 
See also
 
for deep neck infections, 241
for obstructive sleep apnea, 328–329
Tissue transglutaminase. 
See
 
Transglutaminase
Tizanidine, 1039, 1596
TMPRSS6
 gene, 511
TNM staging classification, 1612. 
See also
 
specific type of cancer
Tobacco use. 
See
 Smoking
Tobramycin, 180
t
, 181
t
, 282, 285
t
, 1321
t
. 
See also
 Aminoglycosides
Tocilizumab, 852, 869
Tocolytics, 208
t
, 826
Toe-brachial index, in femoral/popliteal 
occlusive disease, 485
Toe web (interdigital) tinea pedis, 121, 
121
f
, 145
Toenails, disorders of. 
See
Toes, thromboangiitis obliterans (Buerger 
Tofacitinib, 116–117, 851
Togaviruses, encephalitis caused by, 1401
Tolazamide, 1229, 1230
t
Tolazoline, clonidine overdose and, 1596
Tolbutamide, 1229, 1230
t
Tolcapone, 1026
Tolerance (drug), 97, 98, 1105, 1111, 1113. 
See also
disorders
Tolmetin, 88
t
Tolterodine, 66
Toluene toxicity/abuse, 919, 1114, 
 
1601–1602
Tolvaptan, 903
Tonal tinnitus, 220
Tongue disorders (glossitis/glossodynia), 
237
Tonic-clonic seizures, 998. 
See also
 
Seizures
Tonic-clonic status epilepticus, 1002
Tonic seizures, 998. 
See also
 Seizures
Tonicity, 898
Tonsillectomy/quinsy tonsillectomy, 240
Tonsillitis, 
238–240
, 238
f
. 
See also
 
Tooth disorders. 
See
Tophus (tophi)/tophaceous arthritis, 844, 
845, 847, 1252
Topiramate, 996
t
for alcohol use disorder, 19
t
t
, 1592
with phentermine, 1244, 1279
pregnancy and, 834
t
Topoisomerase inhibitors, 1618–1619
t
Topotecan, 1619
t
Toremifene, 769
t
, 1623
t
Torsades de pointes, 409, 412
in hypomagnesemia, 916
t
, 
1609, 1610
Torsemide, 418, 461
t
Torsion dystonia
focal, 
1029
1028–1029
Torticollis, 1029, 1085
Total body water. 
See
 Body water
Total lung capacity (TLC). 
See
 Pulmonary 
CMDT2019_Index_p1743-1884.indd   1874

INDEX1875
 
CMDT 2019
caused by, 1044, 1115
t
ocular, 
203–205
, 204
f
pneumothorax and, 325
17
seizures caused by, 999
and, 808
spinal, 
1045
stressor-related disorders and, 
 
1064–1065
subarachnoid hemorrhage and, 1011
vertigo caused by, 223
245
Traumatic brain injury, 1042, 1044
pituitary insufficiency and, 1120
Traumatic encephalopathy, chronic, 1044
Travel. 
See also
 Air travel
dengue and, 1413
Ebola viral disease and, 1411
fever/FUO and, 1294, 1315
hepatitis A and, 692, 693, 1332
t
hepatitis E and, 698
1329
t
, 1332
t
, 1333
t
, 
1337
infectious disease/diarrhea and, 
 
1314–1315
, 1315, 
1316–1317
malaria and, 1516, 1519, 1523–1524, 
1523
t
815–816
Traveler’s diarrhea, 600, 816, 1315, 
 
1316–1317
Traveler’s thrombosis, 1579
Travoprost/travoprost combinations, 184
t
Trazodone, 1090–1093, 1091
t
, 1609. 
See 
also
for insomnia, 1035, 1066, 1102
priapism caused by, 1094, 1102
Treatment refusal/withdrawal, 76, 78
Trematode (fluke) infections, 
1535–1538
. 
See also
 
Tremelimumab
Tremor
essential (familial), 
1024
1684
in Parkinson disease, 1025
Trench fever, 1483
Trench (immersion) foot/hand, 
1568
Trench mouth (necrotizing ulcerative 
237
Trendelenburg test, 1707
Treponema
non-sexually transmitted diseases 
t
pallidum
, 684, 1319
t
, 1323
t
, 1493, 1494. 
See also
 Syphilis
carateum,
 1502
endemicum,
 1503
pertenue,
 1319
t
, 1502
Treponemal antibody tests, 1495
Treprostinil, for pulmonary hypertension, 
314, 444
Tretinoin, 135, 209
t
, 1622
t
. 
See also
 
Triad asthma (Samter triad), 232, 892
immunization in recipients and, 
 
1325–1337
, 1333
t
, 
1337
infections following, 1297, 1298–1299. 
See also
adenoviruses causing, 1428–1429
aspergillosis, 1299, 1557
CMV causing, 1299, 1388, 
 
fungal, 1297, 1299
lymphocytic choriomeningitis virus 
causing, 1405, 1406
pneumonia/
Pneumocystis,
 287, 1298, 
1555, 1556
rabies causing, 1399
RSV , 1421
toxoplasmosis, 1526
lymphoproliferative disorder after, 1388
organ donation for, 81
squamous cell carcinoma after, 152
Transsexual, 1737. 
See also
Transthyretin (TTR) amyloidosis, 434, 
 
550
Transtubular potassium concentration 
gradient (TTKG), 906
Transudates, pleural, 322, 323, 323
t
Transurethral electrovaporization of 
prostate, 988
Transurethral incision of prostate (TUIP), 
985
f
, 986
t
, 987
Transurethral laser-induced prostatectomy 
(TULIP), 988
Transurethral needle ablation of prostate 
f
, 988
Transurethral resection of prostate 
(TURP), 985
f
, 986
t
, 987
Transurethral resection syndrome, 987
Transvenous (transjugular) intrahepatic 
portosystemic shunts (TIPS), 
627, 716–717
for cirrhotic ascites, 716–717
627, 628, 729
 
Tranylcypromine, 1091
t
Trastuzumab, 1620
t
for breast cancer, 761–762, 764, 765, 
766, 767–768, 770, 1620
t
toxicity of, 766, 1620
t
, 1680
Trastuzumab emtansine, 770
Trauma
auricular (traumatic auricular 
hematoma), 211
cardiac injury and, 
445–446
, 449
888
corneal, 176
t
, 
203–204
t
head injury and, 
1042–1045
, 1042
t
, 
1043
t
. 
See also
 Head injury
993
, 1044
hearing loss associated with, 217, 218, 
219
meningitis and, 1305
t
, 1321
t
middle ear, 
217–218
nasal, 
232
compatibility testing in prevention of, 
552

993
, 1044
219
t
, 1321
t
217–218
nasal, 
232
552
contaminated blood causing, 553
hemolytic, 552–553
hypersensitivity reactions, 553
leukoagglutinin, 552, 553
Transfusion-related acute lung injury 
(TRALI), 554
Transgender health/disease prevention, 
1075, 1076, 
1736–1742
, 1738
t
, 
1739
t
, 1740
t
, 1741
t
cancer risk/screening and, 1741
care environment and, 1737
feminizing therapy and, 1737–1739, 
1738
t
t
HIV infection/AIDS and, 1741–1742
hormone therapy in, 1076, 1737–1740, 
1738
t
, 1739
t
, 1740
t
, 1741
t
t
, 1741
t
masculinizing therapy and, 1739–1740, 
1739
t
t
medical interventions and, 1737–1740, 
1738
t
, 1739
t
, 1740
t
, 1741
t
STD screening and, 1309
surgical interventions and, 1076, 
 
1740–1741, 1741
t
terminology/definitions and, 1736–1737
Transgender man/woman, 1724, 1736, 
1737. 
See also
Transglutaminase/tissue transglutaminase 
(tTG)
1132
645–646
Transient autoimmune thyroiditis, 
postpartum. 
See
 Thyroiditis, 
pregnancy/postpartum
Transient ischemic attacks, 488–490, 489
f
, 
1004–1006
atrial fibrillation and, 1004, 1005
carotid, 488, 489, 489
f
, 1004, 1006
cerebrovascular occlusion/embolization 
and, 488, 489, 489
f
, 1004
ocular, 196, 488
patent foramen ovale and, 338, 1004, 
1006
seizures differentiated from, 1000, 1005
strokes/stroke risk and, 1004
vertebrobasilar, 1004
Transient monocular visual loss, 
196
, 488
Transjugular intrahepatic portosystemic 
shunts. 
See
 Transvenous 
(transjugular) intrahepatic 
portosystemic shunts
Transketolase activity coefficient, in 
thiamine deficiency, 1283
Translocational hyponatremia, 900, 902
Transmembrane serine protease 6 
(TMPRSS6)
 gene, 511
Transmissible spongiform 
encephalopathies (prion 
diseases), 
1406–1407
Transplantation. 
See also
 
organ and
 
hyperkalemia and, 908
hyperuricemia/gout and, 847
CMDT2019_Index_p1743-1884.indd   1875

INDEX1876
 
CMDT 2019
Trypanosoma
 (trypanosomiasis)
African, 
1510–1511
, 1511
t
American (Chagas disease), 629, 
 
1512–1513
brucei gambiense/rhodesiense,
 1510
cruzi,
 1512
Trypsinogen mutations, 746, 747
Tsutsugamushi fever (scrub typhus), 1437
t
, 
1439–1440
TT virus (TTV), 696
TT677
 mutation
TTF-1 (thyroid transcription factor-1), 
1629
TTR (hereditary/wild-type) amyloidosis, 
434, 435, 550
Tubal ligation/sterilization, 807
Tubal pregnancy, 819. 
See also
 Ectopic 
pregnancy
Tube enterostomies, 1289, 1289
f
. 
See also
 
Tube feedings. 
See
support
Tube thoracostomy (chest tube drainage)
for anaerobic pleuropulmonary disease, 
287, 1484
for empyema/parapneumonic pleural 
effusion, 325
for hemothorax, 325
for malignant pleural effusion, 1672
for pneumonia, 1453
for pneumothorax, 326
Tuberculin skin test, 290, 291
t
BCG vaccine affecting, 4, 290, 295
in HIV infection/AIDS, 291
t
in intestinal tuberculosis, 655
in musculoskeletal tuberculosis, 886
in pregnancy, 836
in tuberculous meningitis, 1489
Tuberculoid leprosy, 1050, 1489, 1490. 
See 
also
 Leprosy
Tuberculoma, meningeal, 1488
Tuberculosis, 
287–295
, 289
t
, 290
f
, 291
f
, 
292
t
, 293
t
, 1319
t
, 1488
active, 288
and, 1180
blood tests/interferon gamma release 
assays in identification of, 4, 
290–291
bone and joint infection in, 294, 
 
886–887
drug-resistant/multidrug resistant/
extensively drug-resistant, 
288, 289, 289
t
, 294, 295, 1347
in drug users, 1310–1311
extrapulmonary, 294. 
See also
 
specific 
type or site
in HIV infection/AIDS, 290, 293, 
 
1344–1347, 1359
antiretroviral therapy affecting 
outcome and, 1365
chemoprophylaxis/prevention and, 
1359
Trimethobenzamide, 594
t
. 
See also
 
Trimethoprim, 908, 1345
t
, 1555
Trimethoprim/polymyxin B, 180
t
Trimethoprim-sulfamethoxazole, 1322
t
for malaria, 1522
for nocardiosis, 1487
for 
 infection, 1298, 1344, 
1345
t
, 1362
t
, 1555
t
, 
1353, 1450
t
, 1455
615, 717
t
, 1348, 1361, 1527
for urinary tract infection, 968, 968
t
, 
969, 1322
t
Trimipramine, 1091
t
Trinucleotide repeats
in fragile X mental retardation, 1684
in Friedreich ataxia, 1049
in Huntington disease, 1027
Triple A (Allgrove) syndrome, 1181, 1182
“Triple-negative” breast cancer, 762, 768, 
771
Triple therapy, after myocardial infarction, 
388
Triptans, 208
t
, 991, 1095
t
Triptorelin, 1623
t
, 1662
t
Trismus
in cervicofacial actinomycosis, 1486
in tetanus, 1459
Trisomy 21 (Down syndrome), 813, 
 
1682–1683
Triumeq (abacavir/lamivudine/
dolutegravir), 1367
t
, 1371, 
1372
t
, 1373
Trizivir (abacavir/lamivudine/zidovudine), 
1366, 1367
t
Troglitazone, 1234
Trombiculid mites, 159–160, 1439
Tropheryma whipplei,
 647, 1468
Trophoblastic disease. 
See
 Gestational 
trophoblastic disease
Tropical anhidrosis and asthenia, 139
Tropical pancreatitis, 746
Tropical pulmonary eosinophilia, 1546
Tropical spastic paraparesis, HTLV-1 
associated, 1408, 1409
Tropisetron, 1678. 
See also
Troponins
Trousseau sign (carpal spasm)
910, 1161
t
Trousseau syndrome, 564
True vocal fold (glottic) cancer, 246–247
Truvada (tenofovir [TDF] with 
t
t
, 
1373, 1373
t
postexposure/after needle stick, 1359

t
t
, 
1373, 1373
t
preexposure, 4, 1310, 1356, 1357
t
with raltegravir, 1359, 1371
Triamcinolone, 105
t
, 123, 136, 262
t
, 843. 
See also
Triamterene, 418, 462
t
t
Triazenes, 1617
t
Triazolam, 1067
t
, 1068, 1102, 1598
Tribendimidine, 1537
Trichinella/Trichinella spiralis
 (trichinosis/
trichinellosis), 
1544–1545
Trichloroethylene toxicity, 1601–1602, 
1605–1606
Trichoderma longibrachiatum,
 1560
 vaginitis 
(trichomoniasis), 781, 781
f
, 
782, 1309, 
1534
and, 1309
Trichophyton/Trichophyton rubrum,
 119, 
121, 170
Trichosporon,
 1560
Trichotillomania, 168
Trichuris
 dysentery syndrome, 1541
 (trichuriasis/
whipworm), 
1541
Triclabendazole, 1536–1537
Tricuspid regurgitation, 343–345
t
, 
 
361–362
. 
See also
 Valvular 
Tricuspid stenosis, 343–345
t
, 
360–361
. 
See 
also
Tricuspid valve
repair/replacement of, 360, 361–362. 
See 
also
Tricyclic antidepressants, 1091
t
, 1093–
1094, 1095
t
. 
See also
 
neuropathy, 100, 1048, 1249
t
, 1091
t
, 1094, 
1581, 1582, 1593, 
1609–1610
, 
1609
f
arrhythmias and, 1094, 1582, 1610
t
, 1609
Trientine, 726
Trifluoperazine, 1081, 1081
t
, 1082
t
Trifluridine/trifluridine-tipiracil, 181
t
, 
1378, 1379
t
, 1622
t
, 1652
Trigeminal autonomic cephalgias, 993
Trigeminal neuralgia (tic douloureux), 
994–997
Trigeminy, 409
Triglycerides, 1267, 1269, 1272. 
See also
 
lowering levels of, 368, 1272, 1273
t
, 
1275
. 
See also
therapy
screening for, 1267, 1269
3
), 1135
t
, 1136
t
, 1139
t
. 
See also
 
See
 Resin T
3
/T
4
 uptake
3
) toxicosis, 1142
CMDT2019_Index_p1743-1884.indd   1876

INDEX1877
 
CMDT 2019
t
, 1143, 1150, 
1150
t
, 1154, 1157
in varicose veins, 498
Ultraviolet (actinic) keratitis, 
205
Ultraviolet light/sunlight
atypical nevi and, 110
basal cell carcinoma and, 151
cancer/cancer prevention and, 14
corneal burns (ultraviolet/actinic 
keratitis) and, 
205
herpes simplex recurrence and, 126, 127
hyperpigmentation and, 167
lupus/SLE and, 123, 855
photodermatitis and, 163–164
porphyria cutanea tarda and, 131
with psoralen. 
See
rosacea and, 137
sunscreens and, 14, 109
therapeutic. 
See
vitamin D and, 1175, 1177
Uncinate (temporal lobe) lesions, 1016
Undernutrition. 
See
 Malnutrition; 
Nutritional disorders
Underwater diving. 
See
diving
Undescended testes. 
See
 Cryptorchism
Unicuspid aortic valve, 352
United Kingdom Prospective Diabetes 
Study (UKPDS), 1227–1228
Unithiol (DMPS), 1593, 1602
Universal precautions. 
See
 Body substance 
isolation/universal 
precautions
Unlawful sexual intercourse (statutory 
rape), 807
Unoprostone, 184
t
Unstable angina. 
See
syndromes
“Up and Go Test, ” 63
Upper airway/respiratory tract disorders, 
252
foreign body, 248–249
obstruction, 252
obstructive sleep apnea hypopnea, 241, 
242, 327, 328
thermal injury/smoke inhalation, 316, 
1571
Upper endoscopy. 
See
 Endoscopy
Upper extremity disorders, 
1703–1706
, 
1706
f
. 
See also
 Shoulder
Upper GI bleeding, 
606–609
. 
See also
 
Upper motor neuron lesions. 
See
 Motor 
Upper respiratory tract disorders. 
See
 
Upper airway/respiratory tract 
disorders
Uprifosbuvir, 705
Urate lowering therapy, 846–847
Urate (uric acid) nephropathy, 844, 
 
964–965
Urates/urate crystals, 844, 844
t
, 845, 965. 
See also
 Uric acid
Urea, 109
t
, 904, 1099
t
Urea breath testing, in 
H pylori
Urea clearance, 928
Typhoid fever, 
1474–1475
Typhoid vaccine, 1475
Typhus, 1382
t
, 
1436–1440
, 1437
t
. 
See also
 
Tyrosine kinase inhibitors, 1620–1622
t
for gastrointestinal mesenchymal 
tumors, 1646
for leukemia, 535, 540, 541
for lung cancer, 1627–1628
thyroid disorders and, 1134, 1141
toxicity of, 1620–1622
t
, 1679, 1680
Tyrosine phosphatase IA2 (ICA-512) 
1221
t
, 1242
U-Lactin, 108
t
U2AF1
“Ugly duckling sign, ” 112
UK-PBC score, 722
UKPDS, 1227–1228
Ulcer perforation, 
642
Ulcerative colitis, 662, 
671–675
, 671
t
. 
See 
also
 Inflammatory bowel 
disease
arthritis and, 881
colorectal cancer and, 674, 1649–1650
fulminant, 671, 673–674
GI bleeding and, 671
740, 741
Ulcerative stomatitis. 
See
 Stomatitis, 
ulcerative
Ulcers. 
See also
amebic, 1529, 1529
f
anal fissures, 665, 666, 667, 686
aphthous, 
237–238
, 876, 1350
Buruli, 1488
contact, of arytenoid cartilage, 245
corneal, 
178–185
. 
See also
 Keratitis
genital/genitourinary. 
See
intraoral, 
237–238
skin. 
See
 Skin disorders, ulcers
Ulipristal, 806
Ulnar nerve lesions, 
1052–1053
Ultrarapid detoxification, 1112
Ultrasonography (Doppler/duplex)
in acute arterial limb occlusion, 487
in aneurysm evaluation, 492, 495
in breast lump detection/evaluation, 
750, 756, 758, 759
f
, 760
in cerebrovascular occlusive disease, 488
disease), 33
t
, 308
in ectopic pregnancy, 820
endoscopic (EUS), 691, 736, 737, 747
in femoral/popliteal occlusive disease, 485
in heart disease. 
See
 Echocardiography/
Doppler
intravascular, in angina, 371
in liver disease, 691
during pregnancy, 812, 813, 814, 820

See
Doppler
in prostate cancer, 1658, 1660
f
drug-resistant disease and, 1347
drug use and, 1310–1311
intestinal involvement and, 655
treatment of, 1347
655
latent, 288, 290, 294–295, 836
testing for, 290–291, 291
t
meningitis and, 
1488–1489
musculoskeletal involvement and, 294, 
886
pericarditis and, 437, 438
pleural effusion in, 289, 323, 324
t
836
primary, 288, 289–290, 290
f
progressive primary, 288
287–295
, 289
t
, 290
f
, 291
f
, 
292
t
, 293
t
reactivation, 288
anti-TNF agents and, 664, 852, 1299
renal manifestations of, 964
reporting requirements and, 291
silicosis and, 318
skin test for. 
See
 Tuberculin skin test
spinal (Pott disease), 
886
treatment of, 291–295, 292
t
, 293
t
. 
See 
also
 Antituberculous drugs
adherence/nonadherence and, 291, 
1347
Tuberculous arthritis, 
886–887
Tuberculous lymphadenitis, 
250
, 1487
Tuberculous meningitis, 
1488–1489
Tuberous sclerosis, 
1023
, 1668
Tubo-ovarian abscess, 654, 793, 1484
Tubular acidosis. 
See
acidosis
Tubular necrosis, acute. 
See
 Acute tubular 
necrosis
Tubular proteinuria, 927
Tubulointerstitial diseases, 937
t
, 
959–961
, 
959
t
Tubulointerstitial nephritis-uveitis, 959
t
Tularemia, 
1479
Tumefactive chronic pancreatitis, 747
Tumor embolization, in lung cancer, 1629
Tumor lysis syndrome (TLS), 
1673–1674
, 
1676
t
Tumor necrosis factor (TNF/cachectin)
agents inhibiting. 
See
in inflammatory bowel disease, 664
“Tumor plop, ” 444
Tungiasis 
(Tunga penetrans),
 160
Tuning fork tests, 210
Turcot syndrome, 680. 
See also
 Familial 
Turner syndrome (gonadal dysgenesis), 
1131, 1200, 1209, 
1216–1217
, 
1216
t
Twinrix (hepatitis A and B vaccine), 693
Tympanic membrane
in acute otitis media, 215, 215
f
cerumen removal and, 211
in chronic otitis media, 216
in eustachian tube dysfunction, 213
in external otitis, 212
ototoxic ear drops and, 219
perforation/rupture of, 214, 215, 
 
217–218, 217
f
in serous otitis media, 214
underwater diving and, 214
Tympanocentesis, 215
CMDT2019_Index_p1743-1884.indd   1877

INDEX1878
 
CMDT 2019
Urokinase, 311, 587
t
. 
See also
 
Urolithiasis. 
See
 Nephrolithiasis; Urinary 
stone disease
Urologic disorders, 
965–988
. 
See also
 
Genitourinary disorders
Uropathy, obstructive, 931, 937
t
, 938
t
, 960
Urosepsis. 
See also
 Urinary tract infection
Urothelial cell carcinomas
bladder, 1612
t
, 1615
t
, 
1664–1666
ureter/renal pelvis, 1612
t
, 
1666–1667
, 
1667
Ursodeoxycholic acid, 713, 722, 733, 740, 
839
Urticaria, 
141–142
, 141
f
, 159, 172
t
Urticating hairs, skin lesions caused by, 
160
Ustekinumab, 116, 665, 670, 880
Usual interstitial pneumonia (UIP), 301, 
302
t
Uterine bleeding. 
See
 Menstruation; 
Uterine tubes, interruption/ligation of, 807
Uterus
amenorrhea in disorders of, 1209, 1210
cancer of. 
See
 Endometrial carcinoma
gravid. 
See
 Pregnancy
leiomyoma (fibroid tumor) of, 
787–788
perforation of by IUD, 805
peripartum infection of, 828–829
UVB therapy. 
See also
Uveitis, 176
t
, 
189–191
, 190
f
in ankylosing spondylitis, 189, 878
anterior (iritis), 176
t
, 189, 190
herpetic, 189, 1377, 1380
immune recovery, 199
posterior, 189, 190
in reactive arthritis, 880
toxoplasmic, 190, 1526
tubulointerstitial nephritis and, 959
t
Uvulopalatopharyngoplasty, 242, 328
V1/V2 vasopressin receptors, 1125
V2 vasopressin receptor antagonists, 903
V617F
 mutation. 
See also
 
JAK2
 mutation
V-go insulin patch pump, 1240
Vaborbactam-meropenem, 1317
vacA
 gene, 633
Vaccine-associated poliomyelitis, 1398
Vaccine-preventable infections, 
 
1325–1337
t
, 
1335–1336
t
, 
1391–1398
. 
 
See also
 
Vaccines. 
See
 
Vaccinia, 1431
Vaccinia immunization, monkeypox 
prevention and, 1432
Vacuum erection device, 980, 1250
Vagal nerve. 
See
 Vagus nerve
Vagal nerve stimulation, 1001, 1096
Vagina. 
See also
 
under Vaginal and
 
Vaginitis/vulvovaginitis
Urinary anion gap, 920
t
, 921. 
See also
 
Anion gap/anion gap acidosis
Urinary antigen testing
in pneumonia, 280
Urinary bladder. 
See
 Bladder
Urinary calculi. 
See
 Urinary stone disease
Urinary casts, 926, 927
t
, 930
t
Urinary catheter. 
See
 Foley catheter
Urinary disorders. 
See
 Genitourinary 
disorders
Urinary incontinence, 
65–67
benign prostatic hyperplasia and, 65, 66
65–67
estrogen replacement therapy and, 1214
Urinary retention
in prostatitis, 970
Urinary schistosomiasis, 1535
Urinary stone disease, 
975–978
. 
See also
 
specific type of stone and
 
Crohn disease and, 666
Urinary tract infection, 43–45, 45
f
, 1321
t
, 
1322
t
. 
See also
 Cystitis; 
candidal, 1550, 1551
dysuria and, 43–45, 45
f
E coli
 causing, 834, 967, 969, 1318
t
, 
1321
t
, 1322
t
health care (hospital)–associated, 968, 
1301, 1302, 1303
incontinence and, 65
during pregnancy, 43, 
834
struvite calculi and, 977
Urinary tract obstruction
kidney injury and, 931, 937
t
, 938
t
stones causing, 975, 977, 978
tubulointerstitial disease caused by, 960
Urinary urgency, 43, 44, 65, 66
Urination. 
See
 Voiding
Urine
acidification of, in poisoning/drug 
alkalinization of
for cystine calculi, 977
in poisoning/drug overdose, 1585
for salicylate toxicity, 1606
candida in, 1550, 1551
evaluation of. 
See
ketones in. 
See
 Ketones/ketone bodies/
ketonemia/ketonuria
pH of
acidosis, 920
t
, 921
protein in. 
See

pH of
t
, 921
See
Urine culture, in dysuria evaluation, 44
Urine drug testing, 98, 1105
Urine osmolality, 904, 930
t
Urine protein-to-creatinine ratio, 927. 
 
See also
Urofollitropins, for infertility, 1123
Urea nitrogen. 
See
 Blood urea nitrogen
Ureaplasma urealyticum,
 880, 1491
Uremia/uremic syndrome, 929, 937, 939
f
. 
See also
 Hemolytic-uremic 
syndrome; Kidney disease/
injury; Renal failure
t
neuropathy associated with, 941, 1049
pericarditis and, 437, 438, 439, 939
platelet function affected in, 568
t
pruritus in, 155, 937
Uremic acidosis, 918, 919–920
Uremic encephalopathy, 941
Uremic fetor, 937
Ureter, cancer of, 
1666–1667
Ureteral stones, 975, 977–978. 
See also
 
Ureterosigmoidostomy, normal anion gap 
acidosis and, 920
Urethral discharge, STDs causing, 1309, 
1481, 1491
Urethral implant, 988
Urethral incompetence/obstruction, 
incontinence and, 66, 66–67, 
67
Urethral injection/suppository, 980, 1250
Urethritis, 1309, 1323
t
chlamydial, 1309, 1320
t
, 1323
t
, 
1491
gonococcal, 1309, 1323
t
, 1481
 causing, 1309, 1534
Urethrocele, 791–792
Urge incontinence, 43, 44, 65, 66
Urgencies, hypertensive. 
See
emergencies
Uric acid. 
See also
 Hyperuricemia
calcium nephrolithiasis and, 976
diuretics affecting, 460, 846
t
, 845, 846–847
kidney disease and, 844, 933, 938
t
, 
 
964–965, 977, 1673
reducing levels of, 846–847
tumor lysis syndrome and, 1673, 1674, 
1676
t
uric acid nephrolithiasis/nephropathy 
and, 844, 847, 964–965, 975, 
977
Uric acid crystals. 
See
 Urates/urate 
 
crystals
Uric acid (urate) nephropathy, 844, 
 
964–965
Uric acid urinary stones (calculi), 844, 
964–965, 975, 977
Uricase, 847
Uricosuric drugs, 847
Uridine diphosphate (UDP) 
 
glucuronosyltransferase, 
hyperbilirubinemia and, 688
Urinalysis, 926. 
See also
 
for drug detection, 1105
in dysuria evaluation, 43–44
in fluid and electrolyte disorders, 898
in glomerulonephritis/nephritic 
spectrum disorders, 947
in hematuria evaluation, 927, 966
in nephrotic spectrum disorders, 954
in proteinuria evaluation, 926, 927
CMDT2019_Index_p1743-1884.indd   1878

INDEX1879
 
CMDT 2019
Variant Creutzfeldt-Jakob disease, 1406, 
1407. 
See also
Varicella (chickenpox), 
1381–1386
, 1382
t
, 
1383
f
during pregnancy/congenital, 
835
, 1384
prevention/immunization and, 1327
t
, 
1328
t
, 1330
t
, 1385. 
See also
 
Varicella vaccine
reactivation of, 1382. 
See also
 Herpes 
zoster
Varicella vaccine (V AR), 816, 1327
t
, 1328
t
, 
1330
t
, 1334
t
, 1336
t
, 1385
Varicella-zoster immune globulin, 835, 
1385
Varicella zoster virus (VZV), 1381. 
See 
also
 Herpes zoster; Varicella
Bell palsy caused by, 1054
giant cell arteritis and, 868
immunization and. 
See
 Herpes zoster 
vaccine; Varicella vaccine
835
See also
 Herpes 
zoster
Varicocele, 798, 981–982, 981
f
, 982
Varicose veins (varicosities/varices), 
 
497–499
, 500, 501
f
See
Variola (smallpox), 1382
t
, 1431
Variola (smallpox) vaccine, 1431
Varus stress test, 1712
t
, 1715
Vas deferens
absence of, in cystic fibrosis/infertility, 
276
obstruction of, in infertility, 983
Vasa previa, 827
Vascular dementia, 57, 1032
t
. 
See also
 
Dementia
Vascular disorders (vascular occlusion/
anomalies), 
483–503
. 
See also
 
specific type or vessel affected 
and
 Vasculitis
arterial aneurysms, 
492–497
483–491
erectile dysfunction and, 978–979
GI bleeding and, 606, 609
glomerulonephritis and, 935
Budd-Chiari syndrome, 
726–728
sinusoidal obstruction syndrome, 
712, 727
and, 306, 586
t
, 1686
kidney disease and, 935, 937
t
nonatherosclerotic, 
491
t
pulmonary hypertension and, 312, 
 
442–443, 443
t
renal vascular hypertension and, 454
spinal cord, 
1015–1016
venous, 
497–503
vertigo caused by, 
224
anticoagulation after, 347, 355, 356, 
363–365
, 364
t
for aortic regurgitation, 359, 359
t
for aortic stenosis, 354–357, 354
t
, 356
f
, 
357
f
for endocarditis, 1468
for mitral regurgitation, 350–351, 350
f
for mitral stenosis, 347
for mitral valve prolapse, 351, 352
in pregnant patient, 363–364, 364
t
for pulmonary valve regurgitation, 
 
362–363
for pulmonary valve stenosis, 335
for tricuspid regurgitation, 361–362
Valves, cardiac. 
See
Valvular heart disease, 
342–365
, 343–345
t
, 
346
t
. 
See also
 
anticoagulation management for 
prosthetic valves and, 347, 
355, 356, 
363–365
, 364
t
congenital, in adults, 
334–342
and, 1466, 1466
t
. 
See also
 
and, 49, 363–365, 364
t
pregnancy and, 347, 363–364, 364
t
, 
 
447
t
rheumatic fever/rheumatic heart disease 
and, 435
Valvular papillary fibroelastoma, 445
Valvular rupture, 445
Valvulitis, rheumatic, 435
for aortic stenosis, 355
Vancomycin, 1321
t
for bacteremia, 1456, 1456–1457
t
, 1466, 1467, 
 
1468
for group B streptococcus prophylaxis 
in pregnancy, 814
t
, 1321
t
, 1454
t
, 285
t
, 1321
t
, 1453
“red man syndrome” caused by, 892, 
893
t
1450
t
, 1455
for superficial/septic thrombophlebitis, 
499, 1321
t
Vandetanib, 1156, 1157
Vanicream, 109
t
, 113
Vardenafil. 
See also
1092, 1250

499, 1321
t
t
, 113
See also
1092, 1250
t
Varenicline, 7, 270
Variant (Prinzmetal) angina, 378
Vaginal atrophy. 
See
 Atrophic vaginitis
in endometrial carcinoma, 777, 778, 788
normal menstrual, 776. 
See also
 
Menstruation
778
t
, 820, 821
premenopausal abnormal, 
776–778
Vaginal cones, 67
Vaginal discharge, 780, 1309. 
See also
 
Vaginal dryness. 
See
Vaginal estrogen, 809, 1212, 1214
Vaginal gels, progesterone, 1215
Vaginal hernias (pelvic organ prolapse), 
791–792
Vaginal ring
for estrogen replacement therapy, 1212, 
1214
Vaginal testosterone, 1215
Vaginal warts, 782. 
See also
 Venereal 
Vaginismus, 796, 797
Vaginitis/vulvovaginitis, 
780–782
. 
See also
 
atrophic. 
See
gonococcal, 1481
 causing 
f
, 
782, 1309, 
1534
in lesbian and bisexual women and, 
1727
Vaginosis, bacterial, 781, 781
f
, 782, 1309
Vagus nerve
stimulation of. 
See
 Vagal nerve 
Valacyclovir, 1379
t
238, 623, 1346
t
t
t
t
, 
1384
Valganciclovir, 198, 623, 1299, 1346
t
, 
1379
t
, 1390
Valgus stress test, 1711, 1712
t
, 1715
Valproic acid/valproate, 996
t
, 1097
t
t
t
, 1587
t
, 
 
1592
t
, 1587
t
pregnancy/breastfeeding/teratogenicity 
and, 816
t
, 834, 1097
t
, 1002
t
for paroxysmal supraventricular 
Valsartan/valsartan combinations
for heart failure/cardiomyopathy, 388, 
418
t
, 419, 471
with sacubitril, 418
t
for hypertension, 469
t
, 470
t
, 471
Valve replacement. 
See also
 Prosthetic 
heart valves
CMDT2019_Index_p1743-1884.indd   1879

INDEX1880
 
CMDT 2019
fever and, 1301
t
, 
1686
1015
. 
See also
 Stroke
t
, 34
t
, 577–579, 
577
t
, 578–579
t
, 579
t
, 586–587
recurrent, 582–584, 585
t
risk/risk stratification and, 27, 29, 
 
305–306, 306
t
, 309
t
, 310
f
, 
310
t
, 311, 577–579, 577
t
, 
 
581, 581
t
t
, 
 
579–587
575–576
t
t
, 581
t
, 
583
t
, 584
t
, 585
t
, 586
t
nonpharmacologic therapy in, 312, 
t
t
Venous ultrasonography, in DVT/PE 
t
, 308
Venovenous hemodiafiltration, 
continuous, for poisoning/
Ventilation
disorders of control of, 
327–329
. 
 
See also
 Hyperventilation; 
mechanical. 
See
 Mechanical ventilation
327–329
, 1103
Ventilation-perfusion scans
in COPD, 269
t
in pulmonary embolism, 307–308, 309, 
311
t
Ventilator-associated pneumonia, 278, 
283–286
, 284
t
, 285
t
, 330, 
1303
Ventricular aneurysm, 391, 446
Ventricular arrhythmias. 
See also
 
specific 
type
catheter ablation of, 396, 409, 410, 432
differentiation of from aberrantly 
conducted supraventricular 
beats, 410
1582
t
, 1592
for cardiogenic shock, 391
f
, 
422, 429
Ventricular dysfunction/failure. 
See
 Heart 
Ventricular fibrillation, 394
t
, 
411
catheter ablation of, 396
in myocardial infarction, 383, 389, 411
sudden death caused by, 383, 
411
, 449
Vena cava filters/interruption, 312, 586–
587
Vena cava obstruction of, 
502–503
, 1669
Venereal Disease Research Laboratory test. 
See
 VDRL test
Venereal infections. 
See
 Sexually 
transmitted diseases
Venereal (genital) warts, 148–150, 149
f
, 
782
anal cancer and, 1354, 1656
anorectal involvement and, 148, 149
f
, 
684
cervical/vaginal/vulvar, 
782
HPV vaccination in prevention of, 4, 
148–149, 782
Venetoclax, 541, 1623
t
, 1674
Venezuelan equine encephalitis, 1401
Venipuncture technique, potassium levels 
affected by, 907, 907
t
Venlafaxine, 1090, 1090–1093, 1091
t
for anxiety/panic disorder, 1068
t
t
, 99–100, 1048
t
, 1609
disease), 308
in superior vena caval obstruction, 502
Venomous insect bites/stings. 
See
 Insect 
Venomous snake bites, 425
t
, 1584
t
, 
1607–
1608
Veno-occlusive disease, hepatic
726–728
sinusoidal obstruction syndrome, 712, 
727
Venous blood gases, 25, 917
Venous catheterization. 
See
Venous disease, 
497–503
. 
See also
 
specific 
type
Venous insufficiency/stasis, 
500–502
, 
 
500
f
cellulitis and, 146, 500, 500
f
disease) and, 33, 33
t
, 34, 
 
305–306
164–166
, 165
f
, 
500, 501
t
, 34, 
500
varicose veins and, 498, 500, 501
f
Venous pressure
in lower extremity, 33
in shock, 506
Venous reflux
in varicose veins, 497, 498
in venous insufficiency, 500, 501
Venous sinus thrombosis, 1021
Venous thromboembolic disease. 
See also
 
Deep venous thrombosis; 
t
chest pain/discomfort and, 27, 28, 29, 
306
t

t
306
t
DVT/PE and, 305–306, 308, 309
t
Vascular endothelial growth factor 
(VEGF) inhibitors. 
See
 Anti-
VEGF therapy
Vascular reconstruction. 
See
 
Vasculitis, 
867–877
, 867
t
. 
See also
 
specific 
disorder
allergic, 171
t
brain and spinal cord involvement and 
(primary angiitis of central 
876–877
315
retinal, 190. 
See also
 Uveitis
urticarial, 141
Vasculopathy. 
See
 Vascular disorders
Vasectomy, 807
Vasoactive drug therapy
treatment, 979–980, 1250
Vasoactive intestinal polypeptide, tumors 
secreting (VIPoma), 1195, 
1196
Vasodepressor syncope, 413
Vasodilator therapy, 474
t
, 475, 481
t
Vasodilatory (distributive) shock, 505–506, 
505
t
, 506, 508
Vasomotor disorders
in menopause (hot flushes), 809, 1211, 
1214–1215
rhinitis, 229
syncope and (“common faint”), 413
Vaso-occlusive episodes, 522, 524
Vasopressin, 508, 1119, 1124. 
See also
 
Antidiuretic hormone; 
Desmopressin
Vasopressin antagonists, 903
Vasopressin challenge test, 1125
Vasopressin V1/V2 receptors, 1125
Vasopressinase-induced diabetes insipidus, 
1125
Vasospasm. 
See also
 Vasomotor disorders
coronary, 368, 
377–378
, 383
subarachnoid hemorrhage and, 
 
1012
Vasovagal hypotension, syncope and 
(“common faint”), 413
Vater, ampulla of. 
See
 Ampulla of Vater
VDRL test, 1494–1495, 1495
t
on cerebrospinal fluid (CSF-VDRL), 
1360, 1500, 1501
victim, 808
Vedolizumab, 664–665, 670, 673
Vegetarians/vegans, vitamin B
12
in, 517
Vegetative state, persistent, 
1042
VEGF inhibitors. 
See
 Anti-VEGF therapy
VEGF Trap-Eye. 
See
 Aflibercept
Veins
deep, thrombosis of. 
See
497–503
. 
See also
 
specific 
type
superficial, thrombophlebitis involving, 
499
varicose. 
See
 Varicose veins
Velpatasvir, 704
t
, 705
Vemurafenib, 543, 1622
t
CMDT2019_Index_p1743-1884.indd   1880

INDEX1881
 
CMDT 2019
phencyclidine use/abuse and, 1080, 
1104
17
sexual. 
See
VIPomas, 1195, 1196
Viral diseases, 
1377–1436
. 
See also
 
specific 
type and virus
884
conjunctivitis, 
176
dermatitides, in HIV infection/AIDS, 
1352–1353
t
, 1313
t
, 
1432–1433
drug therapy for, 1379
t
. 
See also
 
Antiviral agents
exanthematous, 1381–1382
t
, 
1429–1432
hemorrhagic fevers, 
1409–1417
See
 Hepatitis
See
 Aseptic meningitis
myocarditis in, 425, 425
t
, 426
neurotropic, 
1398–1409
pericarditis, 437, 438
respiratory, 
1420–1428
rhinosinusitis (common cold), 
225–226
, 
1429
transfusion-associated, 553–554
t
vaccine-preventable, 
1391–1398
Viral load tests. 
See
 HIV viral load tests
Virchow node, 1642
Virchow triad, 305–306
Viridans streptococci, 1318
t
, 1321
t
, 1451
t
, 1451, 
Virilization, 
1205–1208
Virtual colonoscopy, 678, 1650, 1653, 
1653
t
, 1654
t
, 1655
Viruses. 
See
 Viral diseases
Visceral artery insufficiency, 
490–491
Visceral hypersensitivity (heightened 
visceral nociception)
Visceral larva migrans, 1545
Visceral leishmaniasis (kala azar), 1513, 
1514, 1514–1515
Viscerotropic disease
leishmaniasis, 1513. 
See also
 Visceral 
Viscocanalostomy, 189
Viscosupplementation, for knee arthritis, 
1719
Vision, impaired/blurred. 
See
 Visual 
Vismodegib, 151
Visual acuity, reduced. 
See
 Visual 
Visual field defects/loss. 
See
 Visual 
Visual impairment/loss. 
See also
 
specific 
cause and
in age-related macular degeneration, 
193–194
in carotid territory occlusion, 195, 196, 
488
in cataract, 191, 1247
in diabetes, 197, 1247. 
See also
 Diabetic 
in elderly (presbyopia), 
69–70
in giant cell arteritis, 196
in labyrinthitis, 222
migrainous, 223
in multiple sclerosis, 224
in perilymphatic fistula, 223
peripheral causes of, 220, 221–222, 221
t
, 
222–224
dehiscence, 223–224
traumatic, 223
vascular compromise causing, 
224
in vestibular neuronitis, 223
Very-low-calorie diets, 1279
Very-low-density lipoproteins/cholesterol 
(VLDL), 1267, 1269, 1272. 
See 
also
 Cholesterol; Triglycerides
Vesicants, skin decontamination after 
exposure to, 1584
Vesicopustules, candidal, satellite, 140
Vesicoureteral reflux, 960, 960–961
Vesicular dermatoses, 104
t
, 
126–131
. 
See 
also
 
Vesiculobullous dermatitis of palms and 
soles. 
See
 Pompholyx
Vestibular disorders (vestibulopathy), 
220–224, 221
t
. 
See also
 
Vertigo
autoimmune hearing loss and, 219
central, 220, 221
t
, 222, 
224
nausea and vomiting caused by, 73, 591, 
592
t
neuronitis, 223
peripheral, 220, 221–222, 221
t
, 222–224
schwannoma. 
See
Vestibulitis
nasal, 
228
vulvar, 796
Vibrio,
 1319
t
, 
1477–1478
alginolyticus,
 1477, 1478
cholerae
, 599
t
, 1313
t
, 1319
t
, 1477. 
See 
also
 Cholera
599
t
, 1313
t
, 1477
parahaemolyticus,
 599
t
, 1313
t
, 1477, 
1478
vulnificus,
 1477, 1478
Vidarabine, 1378
Video-assisted thoracoscopic surgery 
(V ATS)
in lung cancer, 1629
Videoesophagography, 618
Vienna Prediction Model, 583
Vigabatrin, 208
t
, 996
t
, 1592
Vilanterol/fluticasone, 260
t
Vilazodone, 1090–1093, 1091
t
Vildagliptin, 1231
t
, 1236
Vinblastine, 154, 1618
t
, 1668
Vinca alkaloids, 1618
t
, 1679
Vincent angina (necrotizing ulcerative 
237
Vincristine, 209
t
, 1618
t
, 1679
Vinorelbine, 1618
t
, 1628
Vinyl chloride, angiosarcoma of liver and, 
1631
Violaceous to purple papules/nodules, 
153–155
Violence, 
1103–1105
. 
See also
 Domestic 
violence; Rape
anabolic steroid use and, 1104, 1114

t
, 1628
1631
153–155
Violence, 
1103–1105
. 
See also
 Domestic 
 
Ventricular gallop. 
See
Ventricular hypertrophy
t
, 431, 432. 
See 
also
Ventricular premature beats (ventricular 
extrasystoles/PVCs), 394
t
, 
409
catheter ablation of, 396, 409
t
Ventricular rate control. 
See
 Rate control
Ventricular septal aneurysm, 340
Ventricular septal defect, 
339–340
Ventricular tachycardia, 31, 393, 
409–411
. 
See also
 Torsades de pointes
catheter ablation of, 396, 410
beats, 410
in myocardial infarction, 389, 409, 410
nonsustained/sustained, 409
palpitations in, 30, 31, 410
in poisoning/drug overdose, 1582, 1582
t
polymorphic, 410, 411
sudden death and, 409, 411, 449, 450
t
t
, 410–411
Ventriculography, radionuclide, 429
Verapamil/verapamil combinations. 
See 
also
for arrhythmias, 395
t
, 400, 403, 408
f
, 434
for hypertension, 467
t
, 471, 472
t
t
t
, 1594
Verbigeration, 1079
Vernal keratoconjunctivitis, 178
Verner–Morrison syndrome, 1191, 1196
Vero cell rabies vaccine, 1400
Verrucae (warts), 
148–150
, 149
f
. 
See also
 
Vertebrae. 
See
 Spinal cord; Spine
Vertebral artery occlusion, 1008
Vertebral fracture
back pain caused by, 1697
in osteoporosis, 1170
Vertebral osteomyelitis, 885, 1311, 1456
Vertebral tuberculosis, 886
Vertebrobasilar insufficiency/obstruction
stroke/TIA caused by, 1004, 1007
t
, 1008
224
Vertebroplasty, in osteoporosis, 1174
Vertigo, 
220–224
, 221
t
in audiovestibular disorders, 219, 
224
with and without auditory symptoms, 
221
t
benign paroxysmal positioning (BPPV), 
221, 222–223
central causes of, 220, 221
t
, 222, 
224
cervical, 223
in endolymphatic hydrops (Ménière 
CMDT2019_Index_p1743-1884.indd   1881

INDEX1882
 
CMDT 2019
laryngopharyngeal reflux causing, 244
in vocal fold paralysis, 247
Voiding
increased. 
See
 Polyuria
involuntary. 
See
painful (dysuria), 
43–45
, 45
f
Voiding symptoms, irritative/obstructive, 
967, 969, 983
Volume reduction surgery, for COPD, 273
Volume replacement. 
See
 Fluid 
Volume status (depletion/overload). 
See 
also
 Fluid and electrolyte 
disorders; Fluid management/
hydration
diarrhea and, 602
hyper-/hyponatremia and, 899
f
, 900–
901, 904
hypercalcemia and, 911, 912
t
, 
923
pregnancy and, 829, 833
venous insufficiency and, 33
weight change reflecting, 898
Volutrauma, 330. 
See also
Vomiting. 
See also
 
in food poisoning, 1314
73
of pregnancy, 592, 
816–817
, 837
821, 1141
Vomiting center, 591
von Hippel-Lindau syndrome, 1190, 1199
1636
renal cell carcinoma in, 1667
von Recklinghausen disease. 
See
 
von Willebrand disease, 569
t
, 
570–571
, 
570
t
type 2B, 
566
, 570, 570
t
, 571
von Willebrand factor, 554, 566, 570, 570
t
von Willebrand factor cleaving protease 
(vWFCP/ADAMTS-13), 561, 
561
t
von Willebrand factor concentrate, 569
t
, 
571
Vorapaxar, 374
Voriconazole, 1562
t
, 1563
for candidiasis, 623, 1551
t
Vorinostat, 537
Vortioxetine, 1090–1093, 1091
t
Voxilaprevir, 704
t
, 705
VSL#3 probiotic, 659, 674
Vulvar carcinoma, 
789–790
Vulvar dystrophy, 789
Vulvar intraepithelial neoplasia (VIN), 
789, 790
Vulvar vestibulitis, 796
Vulvar warts, 782. 
See also
 Venereal 
Vulvodynia, 796, 797
Vulvovaginal atrophy. 
See
 Atrophic 
vaginitis
in osteomalacia/rickets, 940, 1175, 
1175
t
in osteoporosis, 1171
hypercalcemia and, 911, 911
t
, 912, 
1167
for hyperparathyroidism, 940, 1165, 
1168
910, 1162–1163, 1162
t
, 1163
osteodystrophy, 939, 940
in hypercalciuria, 976
hypophosphatemia/hypophosphatemic 
rickets and, 906
t
t
overproduction of, in hypercalcemia, 
911
phosphate balance/imbalances and, 913
Vitamin D
2
. 
See
 Ergocalciferol
Vitamin D
3
. 
See
 Cholecalciferol
Vitamin D analogs, 116, 1168. 
See also
 
Vitamin D
Vitamin D-dependent rickets, 1176
Vitamin D-resistant (hypophosphatemic) 
rickets, 906
t
Vitamin E
for Alzheimer disease, 1034, 1285
1038
, 
1285
1286
Vitamin K, 572
572
Vitamin K antagonist. 
See
 Warfarin
Vitamin K epoxide reductase complex 
(VKORC1), 572
Vitamins. 
See also
 
specific vitamin
disorders of metabolism of, 
1282–1286
t
prenatal, 812, 814–815
supplemental, in HIV infection/AIDS, 
1361
Vitiligo, 122, 166, 167, 167
f
Vitreous hemorrhage, 
193
VKORC1
 gene, 582
VLP vaccine, 4. 
See also
 Human 
papillomavirus (HPV) 
 
vaccine
Vocal fold cysts, 245
Vocal fold dysfunction syndrome, 252
Vocal fold nodules, 245
Vocal fold polyps, 245
Vocal folds
cancer of, 246–247
in hoarseness, 243
leukoplakia of, 246
paralysis of, 
247–248
thyroid surgery and, 247, 248, 
 
1145–1146, 1148
traumatic lesions of, 
245
Voglibose, 1230
t
, 1234
Vogt-Koyanagi-Harada syndrome, 
 
189–190, 190
f
Voice, abnormal, 
243
Visual impairment/loss (
Cont
.):
in glaucoma, 187, 188
in headache, 41
in HIV infection/AIDS, 198, 1350
in intracranial mass lesions, 1016

f
243
Cont
.):
in ischemic optic neuropathy, 199, 868
in methanol intoxication, 1602
onchocerciasis causing (river blindness), 
1547–1548
in optic neuritis, 200
refractive errors causing, 174
in retinal artery occlusion, 195–196, 488
in retinal detachment, 192
in retinal vein occlusion, 194–195
in SJS/TEN, 143
in stroke, 1008, 1011
in trachoma, 177
transient monocular, 
196
, 488
in vitreous hemorrhage, 193
Visuospatial impairment, 1033
Vital capacity, forced (FVC). 
See
 
Vitamin A
1285
t
, 
1285
Vitamin B
1
. 
See
 Thiamine
Vitamin B
2
. 
See
 Riboflavin
Vitamin B
3
. 
See
 Niacin
Vitamin B
6
 (pyridoxine)
1284
and, 1686
t
, 1600
1284
Vitamin B
12
 (cobalamin), 517
517–518
, 517
t
. 
See also
 
in bacterial overgrowth, 517, 648
in Crohn disease, 517, 666
dementia and, 517, 1034
fish tapeworm infection and, 517, 
1538
homocystinuria/
hyperhomocysteinemia and, 
1686
neuropathy and, 517, 518
in pernicious anemia gastritis, 517, 
634
short bowel syndrome/ileal resection 
and, 517, 649
spinal cord degeneration and, 1039
normal values for, 518
supplemental, 518, 649, 1039, 1686
Vitamin C (ascorbic acid)
1284
1285
Vitamin D
deficiency of/resistance to, 1175, 1177
940
f
, 1175
in hyperparathyroidism, 1164, 1165
multiple sclerosis and, 1036
CMDT2019_Index_p1743-1884.indd   1882

INDEX1883
 
CMDT 2019
Well syndrome, 1430
Wells criteria/“Wells prediction rule, ” 34, 
309, 309
t
Wenckebach (Mobitz type I) 
397, 398
Werdnig-Hoffmann disease, 1046
Wermer syndrome. 
See
neoplasia (MEN), MEN 1
Wernicke aphasia, 1008. 
See also
 Aphasia
Wernicke encephalopathy, 
1039–1040
, 
Wernicke-Korsakoff syndrome, 709, 
 
1039–1040, 1107, 1108, 1282
West African trypanosomiasis, 1510, 1511, 
1511
t
West Nile virus/fever/encephalitis, 
 
1401–1402
screening blood for, 553, 1401, 1402
Westermark sign, 307
Western blot assay, in HIV infection/
AIDS, 1342, 1342
t
Western (equine) encephalitis, 1401
Wet beriberi, 1282
WFS1
Wharton duct, calculus formation in, 242
Wheals. 
See
 Urticaria
Wheat procedure, 355, 359
Wheezes
in asthma, 254–255, 256
t
in heart failure (“cardiac asthma”), 253
Whiplash injuries, 1045, 1701
Whipple disease, 
647–648
, 881
Whipple triad, 1262
Whipworm infections (trichuriasis), 
1541
Whispered voice test, 70, 210
White blood cell count (leukocyte count)
t
, 1306
1677, 1677
t
t
, 842
t
, 882, 883
in myeloproliferative neoplasms, 530
t
, 
535
pleural fluid, 322, 324
t
White cell casts, 926, 927
t
“White coat” hypertension, 451, 452
f
, 479
Whitlow, herpetic, 1377, 1378
f
Whole blood. 
See
 Fresh whole blood
Whole bowel irrigation, for poisoning/
Whooping cough. 
See
 Pertussis
Wickham striae, 153
Wide QRS complex. 
See
 QRS complex, 
wide
Wild-type TTR amyloidosis, 434, 550
725–726
, 725
f
, 
1025, 
1030
Winter acute respiratory disease, 1430
Winterbottom sign, 1510
Wiskott-Aldrich syndrome, 556, 567
Withdrawal. 
See also
 
specific substance
t
Withdrawal response, in coma/stupor, 
1040
Withdrawal/withholding of curative effort, 
in terminally ill/dying patient, 
76, 78
Wolbachia
 eradication, 1547, 1548
replacement of/requirements for, 925, 
925
t
, 1289
restriction of
for chronic kidney disease, 942
for hyponatremia, 902, 903
977
Water shifts, hyperosmolality with and 
without, 
904–905
Waterhouse-Friderichsen syndrome, 1180
WDHA, 1196
Weakness/muscle weakness. 
See also
 
Myopathies; Myositis; 
Paralysis
differential diagnosis of, 863
“Wearing off effect, ” with levodopa, 1026
Web space (interdigital) tinea pedis, 121, 
121
f
, 145
Weber test, 210
Webs, esophageal. 
See
 Esophageal webs
Weeping/crusted skin lesions, 104
t
, 
 
131–133
. 
See also
 
Wegener granulomatosis. 
See
 
Weight
changes in. 
See also
 Weight gain; Weight 
loss
water balance and, 898, 925
exercise/activity in maintenance/
reduction of, 12, 13
1726
normal, 12
Weight gain. 
See also
 Obesity
drugs causing
antipsychotic agents, 1084, 1084
t
sulfonylureas, 1229, 1245
thiazolidinediones, 1234
prevention of, exercise/activity and, 12, 
13
smoking cessation and, 7
Weight loss (involuntary/unintended), 
37–38
. 
See also
 
specific 
 Weight reduction
cachexia and, 1249
in elderly, 37, 
67
t
in diabetes, 1228, 1244, 1244
f
diet and, 1278–1279
in hypertension management/
prevention, 457
t
, 458
for hypogonadism, 1203
in obesity, 13–14, 1278–1279
for obesity-hypoventilation syndrome 
(Pickwickian syndrome), 327
for sleep apnea/snoring, 241, 328
Weil syndrome, 1505

Vulvovaginal candidiasis, 140, 781, 781
f
, 
1550, 1551
t
, 1355
and, 1309
Vulvovaginitis. 
See
 Vaginitis
VX poisoning, 1595, 1605
VZV syndrome, congenital, 835
Waldenström macroglobulinemia, 
 
549–550
, 1613
t
Warfarin (vitamin K antagonist), 574, 
578
t
, 582, 583
t
, 584
t
syndrome, 857
347, 404, 404–405, 405, 1148
t
363–364, 364
t
coronary stents/STEMI and, 388, 392
disease), 309, 311, 578
t
, 582, 
583
t
, 584
t
in heart failure/cardiomyopathy, 421, 
429
563
1015
overdose/toxicity of, 1591
perioperative management of, 51, 52
t
pregnancy and, 363–364, 446
switching to from DOAC, 576
t
switching to DOAC from, 404–405, 
576
t
vitamin K epoxide reductase complex 
(VKORC1) and, 582
Warts (verrucae), 
148–150
, 149
f
. 
See also
 
Washout time, 1095
Wasting
t
Watchful waiting/surveillance
for benign prostatic hyperplasia, 984–
985, 985
f
, 986
t
after orchiectomy for testicular cancer, 
1669–1670, 1670
for prostate cancer, 1660–1661, 1661
for thyroid microcarcinoma, 1155
Water, body. 
See
 Body water
Water deficit, calculation of, 904
Water-hammer pulse, 358
Water/fluid intake. 
See also
 Fluid 
disorders of/inappropriate. 
See also
 
genetic disorders and, 906
t
hypernatremia caused by, 903, 904
hyponatremia caused by, 899, 902, 
903, 1080
1080
CMDT2019_Index_p1743-1884.indd   1883

INDEX1884
 
CMDT 2019
myopathy caused by, 1062, 1350
for prevention of HIV transmission
to fetus/newborn, 836, 1358
Zika virus, 
1417–1419
pregnancy and, 812, 815, 1418
screening blood for, 553
Zika virus vaccine/vaccine development, 
1418
Zileuton, 258
f
, 261
t
, 264
Zinc
1290, 1293
t
toxicity of, 1597
t
Zinc transporter 8 (ZnT8) antibodies, in 
diabetes, 1220, 1221
t
, 1242
Ziprasidone, 1081, 1081
t
t
, 
1084, 1084
t
t
, 
1084
t
, 1592
Zirconium cyclosilicate, for hyperkalemia, 
908
Ziv-aflibercept, 1623
t
ZMapp, for Ebola viral disease, 1411
ZnT8 antibodies, in diabetes, 1220, 1221
t
, 
1242
Zoledronate/zoledronic acid, 1156, 1168, 
1173, 1179, 1673, 1676
t
. 
See 
also
 Bisphosphonates
Zollinger-Ellison syndrome (gastrinoma), 
643–644
, 1195, 1196, 1198
1196
Zolmitriptan, 208
t
, 991, 993
Zolpidem, 1067
t
, 1094, 1102, 1598
Zonisamide, 208
t
, 996
t
, 1592
Zoster ophthalmicus, 128, 
186
, 1383
Zoster oticus, 218, 1383
Zoster retinitis, 199
Zoster sine herpete, 1384
Zoster vaccine live (ZVL), 1327
t
, 1328
t
, 
1330
t
, 1334
t
, 1385–1386, 
1386. 
See also
vaccine
Zoster vaccine recombinant (RZV), 1327
t
, 
1328
t
, 1330
t
 
See also
 
vaccine
Zygote intrafallopian transfer, 799
Xanthogranulomatous cholecystitis, 734
Xanthomas
eruptive, 1269, 1269
f
in diabetes, 1224, 1251, 1269
f
in familial hypercholesterolemia, 1683
tendinous, 1269
Xerosis, 1285, 1353
Xerostomia
pilocarpine for, 865, 1676
t
radiation induced, 1676
t
XO gonadal dysgenesis, 1216–1217. 
See 
also
XO/XX Turner syndrome, 1216, 1217
XO/XY Turner syndrome, 1217
Xp–, in Turner syndrome, 1217
Xp11.2 translocation, in renal cell 
carcinoma, 1667
Xq, in Turner syndrome, 1216, 1217
XX karyotype, in Turner syndrome, 1216, 
1217
XY gonadal dysgenesis/XY mosaicism, 
1200, 1217. 
See also
 Turner 
syndrome
XY karyotype, amenorrhea and, 1209
Y chromosome microdeletions, 982
Y aws (frambesia), 1319
t
, 
1502
Y ellow fever, 
1416–1417
Y ellow fever virus vaccine, 1337, 1417
Yersinia
enterocolitica,
 599
t
, 600, 1313
t
pestis,
 1319
t
, 1480
Y ohimbine, toxicity of, 1597
t
Yttrium-90 ibritumomab tiuxetan, 544
YY1/T372R
Z score, 1171
Zafirlukast, 261
t
, 264
Zaire ebolavirus,
 1410, 1411
Zaleplon, 1067
t
, 1102, 1598
Zanamivir, 1379
t
, 1423, 1423–1424, 1424, 
1425, 1426
ZAP-70, 541
ZEBOV vaccine, 1411
Zenker diverticulum, 
626
Zeta-associated protein (ZAP-70), 541
Zidovudine (AZT), 1363
t
, 1366. 
See also
 
with lamivudine, 1366
with lamivudine and abacavir. 
 
See
 Trizivir
Wolcott-Rallison syndrome, 1222
Wolff-Parkinson-White (WPW) pattern/
syndrome, 31, 400, 401
t
Wolfram syndrome, 1124, 1222
Wood alcohol. 
See
 Methanol
Woody (Riedel) thyroiditis, 1132, 1133–
1134
Word-finding difficulty, 1033
Wound botulism, 1059, 1310, 1460, 1604
Wound care
for bite wounds, 1307–1308
rabies and, 1400
for burn injuries, 1572
for lymphangitis/lymphadenitis, 503–
504
for pressure injuries, 68, 68
t
tetanus prophylaxis/treatment and, 
1459, 1459–1460, 1459
t
Wound infections
clostridial
botulism, 1059, 1310, 1460, 1604
t
, 
1458
tetanus, 1319
t
, 
1458–1460
, 1459
t
. 
See 
also
 Tetanus
antibiotic prophylaxis of, 
54
, 1303
Wrestlers, epidemic herpes in (herpes 
gladiatorum), 127, 1377
Wrist, in carpal tunnel syndrome, 
 
1704–1705
Writer’s cramp, 1029
Wuchereria bancrofti,
 1546, 1547
X chromosome
fragile site on, 1684
in Klinefelter syndrome, 1200, 1686, 
1687
X chromosome mosaicism

 1546, 1547
1687
X-inactive-specific transcriptase (XIST), in 
Klinefelter syndrome, 1201
X-linked adrenoleukodystrophy, 1180
X-linked hypophosphatemic rickets, 1177
X-linked lymphoproliferative disorder, 
1387
Xanthine oxidase inhibitors, 847
CMDT2019_Index_p1743-1884.indd   1884

Contemporary Cancer Research 
J ac A. Nickoloff, SERIES EDITOR 
Cancer Diagnostics: Current and Future Trends, edited by Robert N. Nakamura, Wayne 
W. Grody, James T. Wu, and Raymond B. Nagle, 2004 
Brain Tumors, edited by Francis Ali-Osman, 2005 
Cancer Gene Therapy, edited by David T. Curiel and Joanne T. Douglas, 2004 
DNA Damage and Repair, Volume 3: Advances from Phage to Humans, edited by Jac A. 
Nickoloff and Merl F. Hoekstra, 2001 
Prostate Cancer: Biology, Genetics, and the New Therapeutics, edited by Leland W. K. 
Chung, William B. Isaacs, and Jonathan W. Simons, 2001 
Chemokines and Cancer, edited by Barrett J. Rollins, 1999 
Breast Cancer: Moleuclar Genetics, Pathogens , and Therapeutics , edited by Anne M. 
Bowcock, 1999 
DNA Damage and Repair, Volume 1: DNA Repair in Prokaryotes and Lower Eukaryotes, 
edited by Jac A. Nickoloff and Merl F. Hoekstra, 1998 
DNA Damage and Repair, Volume 2: DNA Repair in Higher Eukaryotes, edited by Jac 
A. Nickoloff and Merl F. Hoekstra, 1998

Cancer Diagnostics 
Current and Future Trends 
Edited by 
Robert M. Nakamura, MD 
Scripps Clinic, La Jolla, CA 
Wayne W. Grody, MD, PhD 
UCLA School of Medicine, Los Angeles, CA 
James T. Wu, PhD 
ARUP Labs, Salt Lake City, UT 
Raymond B. Nagle, MD, PhD 
Arizona Cancer Cent er, Tucson, AZ 
* Springer Science+ Business Media, LLC

© 2004 Springer Science+Business Media New York 
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Library of Congress Cataloging in Publication Data 
Cancer diagnostics : current and fu ture trends 1 edited by Robert M. 
Nakamura ... [et al.]. 
p. ; cm. --(Contemporary cancer research) 
Includes bibliographical references and index. 
ISBN 978-1-61737-399-2 ISBN 978-1-59259-791-8 (eBook) 
DOI 10.1007/978-1-59259-791-8 
1. Cancer--Diagnosis. 2. Cancer--Molecular diagnosis. 
[DNLM: 1. Neop1asms--diagnosis. 2. Laboratory Techniques and 
Procedures. 3. Tumor Markers, Biological--diagnostic use. QZ 241 C2152 
2004] 1. Nakamura, Robert M., 1927- II. Series. 
RC270.C345 2004 
616. 99'4075--dc22 
2003026932

Preface 
In the past, many tumor marker laboratory tests have not been sensitive enough for 
the very early detection of cancer. However , many of them have nonetheles s proved 
useful in monitoring therapy, following the course of the tumor , and predicting prog ­
nosis . Today, cancer may be viewed as a genetic disease with various specific chromo­
somal and nucleotide aberrations, such as mutations , deletions, gene amplification, 
gene rearrangements, and translocations occurring during the transformation of a nor­
mal cell into a malignant cell. 
The considerable advances in technology during the past several years have greatly 
enhanced our ability to detect human cancers in the very early stages of tumor forma­
tion. These technol ogies include: (1) nucl eotide molecular assays (genomics); (2) 
proteomics (multiplex protein measurements); (3) DNA microarrays; and (4) bio­
informatics . Many of these technologies are already helping in the integration and use 
of multiple biomarkers for tumors. Although the individual biomarkers may reveal 
only limited information, the use of multiple biomarke rs can help markedly elevate the 
diagnostic capabilities for early detection of tumor s. 
Nucleic acid molecular tests are unusual in that the tests do not measure any physi ­
ological state and can be performed on fresh, frozen, or archival biological tissue speci ­
mens. Many of the molecular tests may be specific to one disease. The modern 
approach to the diagnosis and understanding of cancer has been characterized by the 
use of molecular and protein profiling. With the help of bioinforma tics, artificial intel ­
ligence, and neural networks, even more accurate and sensitive diagnosti c tests for 
cancer will surely be developed. 
Cancer Diagnostics: Current and Future Trends is concerned primarily with those 
clinical laboratory tests that may already, or in the near future, help in the early detec­
tion, evaluation, and prediction of human tumor s for specific therapeutic decisions. It 
should be of high intere st and value to physicians who diagno se and treat cancer pa­
tients, and to clinical laboratory scientists and pathologists who are intere sted in diag­
nostic clinical laboratory tests for cance r and their future evaluation. 
v Robert M. Nakamura, MD 
]ames T. Wu, PhD 
Raymond B. Nagle, MD, PhD

Contents 
Preface ................. .......................... ........................... ............. ................................ v 
Contributors ............... ............. ............................................... ................... .......... ix 
PART I: INTRODUCTION 
1 General Considerations in the Use and Application of Laboratory Tests 
for the Evaluation of Cancer 
Robert M. Nakamura and Wayne W. Grody .............. ................... ................ 3 
2 New Insights and Future Advances in Cancer Diagnostics: 
Limitations of Conventional Tumor Markers 
Yasushi Kasahara and Yutaka Tsukada .......... ............ ............................ ..... 15 
3 The Changing Role of the Pathologist in the Management 
of the Cancer Patient 
Raymond B. Nagle ........................ .................................................................... 27 
PART II: S EROLOGICAL TuMOR MARK ERS 
4 Types of Circulating Tumor Markers 
and Their Clinical Applications 
James T. Wu ........................................................................................................ 35 
5 Identification of Risk Factors for Earl y Neoplasm 
James T. Wu .................................... ............... ............................. ........................ 53 
6 Emerging Circulating Tumor Markers 
James T. Wu ................... ................................................... ........................ .......... 65 
7 Prostate Cancer Markers: From Disco very to the Clinic 
Judith A. Finlay, Stephen D. Mikolajczyk, Thomas M. Pribyl, 
R. Bruce Wallace, and Harry G. Rittenhouse .......................................... 85 
8 Serum Tumor Marker Test Profile in Testicular 
Germ-Cell Tumors 
Frank f. Liu, Robert M. Nakamura, C. Howard Tseng, 
and Kevin S. Liu ....................... .................................................................. . 129 
9 Autoantibodies, Autoimmunity, and Cancers: 
Mark ers for Identification of Early Stages of Tumors 
Robert M. Nakamura and Eng M. Tan ............... ...................................... ... 169 
PART III: CELLULAR TuMOR MARKERS 
10 MHC Tetramers: A Tool for Direct Ex Vivo Detection 
and Enumeration of Tumor-Specific Cytotoxi c T Lympho cytes 
Jennie C. C. Chang, Ferdynand Kos, Charles T. Nugent, 
and Kristine Kuus-R eichel ........................................................................ 185 
Vll

viii 
11 New Applications of Flow Cytometry in Cancer Diagnosis 
and Therapy Cont ents 
Sophie Song and Faramarz Naeim ............................................................... 199 
12 Mol ecular Diagnostics in Neopl astic Hem atopatholog y 
Daniel A . Arber .............................................................................................. .. 233 
13 HER2 and Topoisomerase Ila in Breast Carcinoma 
Kenneth f. Bloom ................................... ........................ .................................. 261 
14 Study of Sentinel Lymph Nodes in the Staging 
of Malignant Neoplasms 
Alice A. Roberts and Alistair J. Cochran ................. .................................. 285 
15 A Marker for Early Diagnosis of Lung Cancer: The Heterogene ous Nucl ear 
Ribonucl eoprotein A2/Bl (hnRNP A2/Bl) 
Jordi Tauler, Alfredo Martinez , and James L. Mulshin e ................ ......... 307 
PART IV: MOLECULAR AND GENETIC TUMO R M A RKERS 
16 M o lecular Techniqu es in Can cer Diagnosis and Man a gem ent 
JeffreyS . Ross, Karen Gray, Rebecca Mosher, and James Stec .............. 325 
17 DNA Repair Defects in Cancer 
Ramune Reliene and Robert H. Schiestl ........................ ............................. 361 
18 Chrom osomal and Molecular Cytogenetic Assays 
for Evaluation of Human Tum ors 
Peter C. Hu, Vicki L. Hopwood, and Armand B. Glassman ........... ........ 379 
19 Microsatellite Alterations as Diagnostic and Prognostic 
Molecular Markers in Patient s With Canc er 
Bret Taba ck and Dav eS. B. Hoon ................................................. ......... ...... 395 
20 Recent Advances in Mol ecular Classification and Prognosis 
of C olore ctal Canc er 
Tsung- Teh Wu and Asif Rashid ............. ............................ .......................... 429 
21 Genetic Counselin g for Hereditary Cancer Predispo sition Testing 
Joyc e L. Seldon and Patricia A. Gan z ................ ............. ..................... ....... 453 
22 Diagnosis of At axia-Te lan gi ectasia : ATM Mutations Assoc iated 
With Ca ncer 
Midori Mitsui, Shar eef A. Nahas, Helen H. Chun, 
and Richard A. Gatti ........................ ................................ .......................... 473 
Index ................................. ............................ ....................... .............. .............. .. 489

Contributors 
DANIEL A. ARBER, MD • Departmen of Pathology , Stanford University Medical Center, 
Stanford , CA 
KENNETH J . BLOOM, MD • Senior Medical Director, US Labs , Irvine, CA 
JENNIE C. C. CHANG, PhD • Beckman Coulter Inc., San Diego, CA 
HELEN H. CHUN, PhD • Division of Molecular Pathology, Department of Pathology and 
Laboratory Medicine, The David Geffen School of Medicine at UCLA , Los Angele s, CA 
ALISTAIR J. COCHRAN, MD, FRCP • Departments of Pathology and Laboratory Medicin e 
and Surgery, The David Geffen School of Medicine at UCLA, Los Angeles, CA 
JuorTH A. FINLA Y, PhD • Hybritech Inc., A Subsidiary of Beckman Coulter 
Inc. San Diego, CA 
PATRICIA A. GANz, MD • Department of Hematology and Oncology and School of Public 
Health , Department of Health Services and Medicine and The David Geffen School 
of Medicine at UCLA, Los Angeles, CA 
RICHARD A. GAm, MD • Division of Molecular Pathology, Department of Pathology and 
Laboratory Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, CA 
ARMAND B. GLASSMAN, MD • Department of Pathology and Laboratory Medicine, 
The University of Texas MD Anderson Cancer Center, Houston, TX 
KAREN GRAY, PhD • Millennium Pharmaceuticals Inc., Cambridge, MA 
WAYNE W. GRODY, MD, PhD • Divisions of Medical Genetics and Molecular Pathology , 
Departm ents of Pathology and Laboratory Medicine, Pediatrics, and Human 
Genetics , The David Geffen School of Medicine at UCLA, Los Ange les, CA 
DAVES. B. HooN, PhD • Department of Molecular Oncology, John Wayne Cancer 
Institute, Santa Monica, CA 
VICKI L. HoPwooD, MS • Cytogenetic Technology Program, MD Anderson Cancer 
Center , The University of Texas, Houston, TX 
P ETER C. Hu , MS • Cytogenetic and Medical Technology Programs, MD Anderson 
Cancer Center, The Universi ty of Texas, Houston, TX 
Y ASUSHI KAsAHARA, PhD, DMSc • Department of Clinical Pathology, Schoo l of Medicine , 
Showa Univ ersity , Tokyo, Japan 
FERDYNAND Kos, PhD • Beckman Coulter Inc., San Diego, CA 
KRISTINE Kuus-REICHEL, PhD • Beckman Coulter Inc., San Diego, CA 
FRANK J. Liu, MD • F. J. Medical Consultation Services, Sugar Land , TX 
KEVIN S. LIU, MD • Department of Fami ly Medicine, Scott & White Clinics (Waco 
Clinic), Texas A&M University College of M edicine, Waco , TX 
ALFREDO MARTiNEZ, PhD • Cell and Cancer Biology Branch , National Cancer Institute , 
Bethesda, MD 
STEPHEN D. MIKOLAJCZYK, MS • Hybritech Inc., A Subsidiary of Beckman Coulter Inc. 
San Diego, CA 
MrooRI Mrrsur, PhD • Division of Molecular Pathlogy , Department of Pathology and 
Laboratory Medicine, The David Geffen School of Medicine at UCLA , Los Angeles, CA 
ix

X Contributors 
REBECCA MosHER, MD • Millennium Pharmaceuticals Inc., Cambridge, MA 
JAMES L. MuLSHINE, MD • Cell and Cancer Biology Branch, National Cancer Institute, 
FARAMARZ NAEIM, MD • Department of Pathology and Laboratory Medicine, UCLA 
Medical Center, Los Angeles , CA 
RAYMOND B. NAGLE, MD, PhD • Department of Pathology, Arizona Cancer Center, 
Tucson, AZ 
SHAREEF A. NAHAS, MS • Division of Molecular Pathlogy, Department of Pathology 
and Laboratory Medicine, The David Geffen School of Medicine at UCLA, Los 
Angeles, CA 
RoBERT M. NAKAMURA, MD • Department of Pathology, Scripps Clinic , La Jolla , CA 
CHARLES T. NuGENT, PhD • Beckman Coulter Inc., San Diego, CA 
THOMAS M. PRIBYL, PhD • Hybritech Inc., A Subsidiary of Beckman Coulter, Inc., 
AsrF RASHID, MD, PhD • Department of Pathology , The University of Texas MD 
Anderson Cancer Center , Houston, TX 
RAMUNE RELIENE, PhD • Department of Pathology and Laboratory Medicine, The 
David Geffen School of Medicine at UCLA, Los Angeles, CA 
HARRY G. RJITENHOUSE, PhD • Hybritech Inc., A Subsidiary of Beckman Coulter , Inc., 
ALICE A. RoBERTS, MD, PhD • Department of Pathology and Laboratory Medicine , 
The David Geffen School of Medicine at UCLA , Los Angeles , CA 
JEFF REY S. Ross, MD • Department of Pathology and Laboratory Medicine, Albany 
Medical College, Albany, NY and Millennium Pharmaceuticals Inc., Cambridg e, MA 
RoBERT H. ScHIESTL, PhD • Departments of Pathology, Environmental Health, and 
Radiation Oncology, UCLA Schools of Medicine and Public Health , Los Angeles , CA 
JoYCE L. SELDO N, MS CGc • Jonsson Comprehensive Cancer Center , University of California , 
Los Angeles, CA 
SoPHIE SoN G, MD, PhD • Department of Pathology and Laboratory Medicine, 
JAMES STEC • Millennium Pharmaceuticals Inc., Cambridge , MA 
BRET TABACK, MD • Department of Molecular Oncology , John Wayne Cancer Institute , 
Santa Monica , CA 
ENG M. TAN, MD • W. M. Keck Autoimmune Disease Center, Department of Mole cular 
and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 
JoRDI T AULER, PhD • Cell and Cancer Biolo gy Branch, National Cancer Institute, 
C. HowARD TsENG, MD, PhD • College of Medicine , Chung Shan Medical University , 
Taichung , Taiwan 
YuTAK A TsuKADA, MD, PhD • Hachioji Main Labs , SRL Inc., Tokyo , Japan 
R. BRUCE WALLACE, PhD • Hybritech Inc., A Subsidiary of Beckman Coulter, Inc., 
San Diego , CA 
JAMES T. Wu, MD • ARUP Labs, Universi ty of Utah, Salt Lake City, UT 
T suNc-TEH Wu , MD, PhD • Department of Pathology, The University of Texas MD 
Anderson Cancer Center, Houston, TX

1 
General Considerations in the Use and Application 
of Laboratory Tests for the Evaluation of Cancer 
Robert M. Nakamura and Wayne W. Grody 
1. INTRODUCTION 
Cancer Diagnostics is concerned with diagno stic tests for the detection and evaluation of 
human tumors. A cancer cell is the result of malignant transformation of a normal cell ( 1 ). 
Cancer cells are associated with significant growth dysregulation. The identification of a 
universal tumor-specific epitope or marker has remained elusive. In the past, many types of 
tumor markers have been characterized The serological and serum tumor marker s have 
included enzymes, proteins, hormones, mucin, and blood group substances ( 1 ). Many cur­
rent tumor marker tests are useful primarily for prediction of prognosis and monitoring 
therapy of previously diagnosed cancers. However, significant research efforts have been 
directed to finding laboratory tests that may be useful for screening or early detection of 
tumors. One useful organ-specific marker has been the prostate specific antigen (PSA) test 
which has been useful for helping the clinician in the decision to proceed to prostatic biopsy 
for the diagnosi s of cancer vs prostatic hyperplasia (2). 
Within recent years, there has been a revolutionary development of molecular patholo gy 
tests for the diagnosis and evaluation of cancer. Many of these molecular tests can specifi ­
cally characterize the type of tumor. Many have demonstrated that they can be useful for the 
early diagnosis of certain cancers and even the predict ion of those that are heredit ary ( 3- 5 ). 
Following completion of the sequencing phase of the human genome project, there has 
been an emphasis on the study of human protein s as drug targets, combining the newer 
efforts of proteomics and pharmacogenomics. The study of proteins will undoubt edly 
become a central component in diagnostics ( 6 ). Currently, several comprehensive approaches 
to the identification of protein markers in cancer are being develop ed (7,8), building on 
advances in two-dimension al electrophoresis, mass spectrometry, and chip-based technolo­
gies, including tissue and antibody arrays. Through the use of serum proteomic patterns, 
Petricoin et al. ( 8) identified 50 ovarian cancers in a masked set that included 18 stage I 
cases. The 50 cases were compared to 66 cases of nonmalignant disease, of which 63 were 
noncancer patients. The results yielded a sensitivity of 100%, specificity of 95% and a posi­
tive predictive value of 94%, far exceeding any other existent general screening test for 
malignancy. 
From: Cancer Diagno stics: Current and Future Trend s 
Edited by: R. M. Na kamu ra, W. W. Grody, J. T. Wu, and R. B. Nagle© Humana Press Inc., Totowa , NJ 
3

4 Nakamura and Grady 
In this chapter, to set the stage for the remaining contributors in this volume, there will be 
a brief discussion of the modern concepts of cancer and general discussion of the character­
istics of various clinical laboratory tests. 
2. MODERN CONCEPTS OF CANCER 
Most cancers are caused by the combined interaction of genetic factors, lifestyle, and 
environmental exposures (9,10) . Over the past several years, cancer research efforts have 
made extensive progress in the definition of the molecular basis for malignant transforma­
tion and proliferation of cells. 
Today, cancer may be viewed as a genetic disease with its various specific chromosomal 
and nucleotide aberrations ( 1 ,4, 11 ). The multiple genetic changes include mutations, dele­
tions, gene amplifications, gene rearrangements, and translocations during the transforma­
tion of a normal cell into a malignant one. 
Researchers have made significant advances in the study of mutations in DNA sequences 
that lead to amplification or suppression of oncogenes or to the deletion of tumor suppressor 
genes encoding regulatory proteins that normally suppress cellular proliferation (1,4). The 
mutations in cancer can be either germline mutations -which are inherited and associated 
with specific familial cancer syndromes-or somatic acquired mutations. The somatic muta­
tions are sporadic and are the most frequent abnormalities associated with tumor formation 
and progression ( J 2,13 ). 
Environmental influences that cause oncogenic mutations include radiation , ultraviolet 
light exposure, and chemical carcinogens. Also, infectious agents, such as the human papil­
loma virus (HPV) or the Epstein-Barr virus (EBV), can promote malignancy through inter­
action with the host genome (9,10,14,15). A genetic susceptibility to cancer can result from 
mutations that alter the normal cellular regulatory or DNA repair mechanisms. 
Most cancers are the result of multiple events involving multiple genes. Certain genetic 
mutations precede tumor formation, and other mutations evolve during tumor progression 
( 16-20). Fearon and Vogelstein (21) document evidence that the pathogenesis of colon can­
cer is a multi-step process. Colorectal carcinomas may arise from a pre-existing benign 
adenoma. The colorectal tumors have mutational events that result in activation of oncogenes 
and inactivation of tumor suppressor genes. Thus, many carcinomas require at least five 
genetic alterations in a multi-step process. The nature and progression of the tumor is influ­
enced by the total accumulation of changes rather than the sequenc e of events. 
3. REASONS FOR REQUESTING CLINICAL LABORATORY TESTS 
There are several indications for physicians requesting a clinical laboratory test (22,23 ). 
These indicators are listed in Table 1. 
In general, clinical laboratory tests are commonly ordered for diagnosis of diseases, moni­
toring therapy , and predictions of prognosis. The most frequent and important tests requested 
are those used to influence therapeutic decisions and to monitor the course of therapy. 
A laboratory test that may not be useful and necessary for medical care today may never­
theless be important in the future when a new therapeutic drug or modality is discovered. For 
example, tests for a variety of oncogenes and anti-oncogenes (i.e., tumor suppr esso r genes, 
such as p53) will probably be very important tests in the future much as testing for HER-2/ 
neu oncogene amplification has become (23,24). A mutation in the ras oncogene or a dele-

Laboratory Tests for the Evaluation of Cancer 5 
Table 1 
Uses and Reasons for Requesting a Laboratory Test Diagnosis 
I. Assessment of prognosis and severity 
2. Monitoring course of disease or response to therapy 
3. Genetic classification 
4. Screening of defined populations, i.e., high risk 
5. Establishment of baseline values for assessment of future change 
6. Risk assessment 
7. Clinical research studies 
tion of p53 is often involved in tumor formation. Investigators are developing anticancer 
agents which can block the induction of tumors by mutated ras genes (24,25). When such 
agents become generally available, many laboratories will need to institute assays to detect 
ras oncogene mutations in order to determine which patients would be candidates for these 
specific gene-targeted therapies. 
The value of a laboratory test depends on its ability to answer a specific clinical question 
for patient management (26). The clinical value of a new test should be determined by how 
well it outperforms currently available tests and whether this performance can be economi­
cally justified. The cost effectiveness of the new laboratory test in clinical practice should be 
determined (27,28). 
The predictive value of a test result is not a real measure of its clinical value, especially 
when it is used in the later stages of a diagnostic workup (29). The clinical value can be 
determined by the amount of useful information for patient management provided by the test 
result. Thus, a useful laboratory test ordered by the physician will be needed for and applied 
to a medical and therapeutic decision based upon the results. Many clinicians today are 
aware of an aphorism which states, "Before ordering a laboratory test, decide what you will 
do if the results are normal or abnormal. If both answers are the same, the test is not neces­
sary" (22). 
4. SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUE 
OF LA BORA TORY TESTS 
There are several characteristics used to describe laboratory tests. It is critical for the 
clinician to have some information on the sensitivity and specificity of the laboratory test 
being ordered ( 30-34 ). Sensitivity can be defined as "positivity in disease" or the probabil­
ity of a test being positive in patients who actually have the disease. Specificity concerns the 
ability of the test to distinguish the patients who have the disease from the patients who do 
not have the disease . 
Positive predictive value (PPV) is the likelihood that the patient has the disease if the 
test is positive. Negative predictive value (NPV) is the likelihood that the patient does not 
have the disease if the test result is negative. There are important issues that should be 
emphasized ( 31 ): 
I. Positive and negative results must be well defined so they can be compared. 
2. The disease in question must be defined clearly and have relevance to decisions made in practice. 
3. The calculation of specificity should be done using well-defined reference groups:

6 Nakamura and Grady 
Table 2 
Immunological and Serologic Methods 
Methods 
Immunofluorescence 
Enzyme immunoas say (EIA) 
Double immunodiffusion (ID) 
Counterimmunoelectrophoresis (CIE) 
Particle agglutination 
Immunoblotting (IB) Use 
Sensitive assay for screening 
Requires precipitin reaction; high 
specificity but not very sensitive 
procedure 
Increased sensitivity and speed as 
compared with ID 
More sensitive than ID 
Very sensitive and allows detection of 
antibodies to soluble and insoluble 
antigens. 
a. A group that has been carefully selected to exclude the specific disease in question , or 
b. A "healthy" group defined by the absence of any major illness. 
4. If the test is used to screen a population for the specific disease, then the prevalence of the 
disease must be considered. 
5. If the test is used to distinguish options on the differential diagnosis of two different diseases, 
then the relative prevalence of these two conditions is more important than the prevalence of 
either condition in the population as a whole. 
None of the current immunological or serologic tumor marker assays approach the I 00% 
specificity and sensitivity of an ideal assay ( 1 ). Table 2lists commonly used immunochemi­
cal and serologic testing methods. 
Immunofluorescence assays, enzyme immunoassays, immunoblotting assays, and chemi­
luminescence assays involve a primary antibody-antigen reaction and are sensitive. Such 
primary antigen-antibody assays are 1000 times more sensitive than secondary antigen-anti­
body assays , such as immunodiffusion, counterimmunoelectrophoresis (CIE), and particle 
agglutination assays ( 35 ). As a general rule, highly sensitive tests useful for exclusion of 
disease have low diagnostic specificity, whereas the less sensitive assays may offer greater 
diagnostic specificity. Sensitivity and specificity are inversely related and have much to do 
with the cutoff level or upper limit of the normal reference range . In many assays for a 
particular tumor marker, the cutoff level is commonly set at the 95th percentile of the 
so-called "normal population" that is not known to have the cancer. However, there is often 
an overlap between the cancer patients and normal population, patients with benign tumors, 
and patients with diseases other than cancer. 
Often there are reports of new tumor markers stating that the difference between the mean 
of the tumor population and that of the normal population is significant. However, if the 
difference in the mean of the two populations is five- to ten-fold, the marker may be useful 
and show promise. If the mean of the population of normal and cancer patients shows only 
2 -to 2.5-fold difference, then when patients with other diseases are examined, there usually 
will be considerable overlap and the test will not demonstrate good sensitivity and specificity.

Laboratory Tests for the Evaluation of Cancer 7 
5. DIAGNOSTIC TESTING VS EVALUATIVE TESTING 
Ward (36,37) has emphasized that clinical laboratory tests may be categorized as diag­
nostic or evaluative. The usefulness of a new diagnostic test is determined by how the test 
categorizes diseased persons as diseased and unaffected persons as unaffected based on com­
parison with a gold standard indicator of disease. For a diagnostic test to be useful it must be 
able to demonstrate high sensitivity and specificity on the differences between individual 
patients. Good diagnostic tests should give reproducible results over time. Evaluative tests 
are used to measure and assess changes in disease activity over time and to determine indexes 
of change ( 38). The evaluative tests are used to compare the current status of a patient with 
his or her status at a previous point in time to determine if there is improvement or disease 
progression. The value and accuracy of an evaluative test is determined by how it monitors 
changes in disease activity. The test should be compared with changes in an accepted gold 
standard measurement of disease activity. An example of a useful evaluative test would be to 
determine the serum level of the acute phase inflammatory C-reactive protein in rheumatic 
fever or rheumatoid arthritis. The C-reacti ve protein levels parallel the inflammatory activity 
during the course of the disease ( 39,40 ). 
6. ASSESSING NEW EVALUATIVE LABORATORY TESTS 
Before a new laboratory test is recommended to be incorporated in clinical practice , the 
following points should be considered ( 36): 
1. The test should be standardized so that findings of the test in clinical research studies can be 
reproduced and applied in a nonresearch setting. 
2. Test results should available in a timely manner for good patient care and clinical decision­
making. 
3. The new test should be more valid or sensitive to change when compared to evaluative tests 
already in use. 
4. The new test should be compared with existing tests by randomi zed trials to determine cost 
effectiveness (41 ). 
7. CUTOFF VALUES (REFERENCE RANGES) AND MULTIPLICITY 
OF LABORATORY TESTS 
Each clinical laboratory must define and establish cutoff values between a normal and 
abnormal result. The assignment of the cutoff values will determine the proportion of false­
positive and false-negative results (42). For example, does the "normal reference range" 
include 95, 97.5, or 99% ofthe so-called normal population? Are age-related refer ence ranges 
assigned? 
For many clinical laboratory tests, the cutoff is set to include only 95% of the normal 
population, therefore allowing a 5% false-positive rate. Thus, if someone without the specific 
disease has one test performed, there is a 5% chance the result will be outside of the refer­
ence range. When multiple tests are performed, with a cutoff to include 95% of the normal 
population , then the likelihood of obtaining a false-positive result rises dramatically with the 
number of tests performed. The likelihood of one abnormal result with five tests is 22% 
( 34,43 ). Therefore, abnormal results must be interpreted with caution if multiple tests have 
been performed.

8 Nakamura and Grady 
8. NUCLEIC ACID MOLECULAR MARKERS FOR CANCER 
Nucleic acid-based molecular tests are unusual as the tests do not measure any physio­
logical state and can be performed on fresh, frozen, or archival biologic tissue specimens. 
Many of the molecular tests may be specific to one disease . The modern approach to diagno­
sis and understanding of cancer has been with the use of molecular profiling ( 45-47) . Under 
this technology, an additional category of testing exists besides the usual diagnostic, evalu­
ative, and prognostic tests for cancer. The molecular tests are used to determine the risk of 
future disease in an individual who is healthy at the time of testing. In the cancer field , such 
tests have become prominent in the setting of familial cancer syndromes. 
Most of the heritable familial cancer syndrome genes have multiple possible mutations, 
many of which are quite rare or even unique to one family.Thorough laboratory testing may 
require direct sequencing of the gene to attain the highest accuracy and sensitivity of mutation 
detection and allow individuals to make critical diagnostic and therapeutic decisions ( 3,4 ). 
Molecular techniques have provided many basic tools that will allow successful detec­
tion, specific diagnoses, and rapid treatment of cancers. Through the use of molecular tests, 
it will also be possible to reliably differentiate similar cancers from one another. 
DNA microassay techniques are now used for a comprehensive detection of many cancer­
associated mutations, or for gene expression in an effort to fingerprint various cancers for 
diagnosis and therapeutic evaluation (7,48,49). 
9. EXAMPLES OF MOLECULAR MARKERS FOR EARLY DETECTION 
OF CANCERS 
Several researchers have reported on the use of a new generation of panels of molecular 
tests for the early detection of tumors of the pancreas and lung, colorectal tumors, liver 
carcinoma, and head and neck tumors. These molecular techniques may provide a new 
approach to cancer screening, diagnosis and therapy in the future. The molecular assays 
have been applied to DNA extracted from stool, serum, and body fluids for detecting various 
types of cancer. 
9.1. Circulating Serum/Plasma Tumor DNA 
Small amounts of free DNA circulate in both normal and diseased human plasma 
(50-52). However, increased concentrations of DNA are present in plasma of cancer patients. 
In cancer patients, mutations of oncogenes (i.e., ras gene) and tumor suppressor genes (p53), 
and microsatellite alterations have been detected. Plasma DNA analysis may become a use­
ful noninvasive diagnostic approach for detection and evaluation of many different types of 
cancer (53,54) . 
9.2. Colorectal Carcinoma 
Molecular assays on DNA extracted from stool specimens have been reported for detec­
tion of colorectal cancers (55- 57). The reported incidence of k-ras mutations is between 7 
and 80% (58), and 40% (58,59). The mutations in k-ras codons12 and 13 were present in 53 
and 89% of colon cancers , respectively (60,59). The application of k-ras and p53 mutation 
gene analyses in the feces was only able to detect 57.7% of patient s with colorectal cancer 
(61 ).Therefore, the study of other genes involved in colorectal carcinogenesis was found to 

Laboratory Tests for the Evaluation of Cancer 9 
Gocke et al. (62) have reported thatp53 and APC (adenomatous polyposis coli) mutations 
are detectable in the plasma and serum of patients with colorectal cancer or adenomas. 
The following panel of molecular markers detecting gene mutations in DNA extracted 
from stool specimens was reported to be useful for early detection of colorectal carcinoma 
(56). These panels included assays for APC, k-ras, p53, and Bat 26 as described below. 
Adenomatous polyposis coli gene (APC) plays a role in cell adhesion and migration. In a 
mutated form, the protein f)-catenin accumulates in high levels and stimulates cell growth. 
k-ras is involved in signal transduction from activated transmembrane receptors to protein 
kinases. Wildtype p53 genes will initiate cell cycle arrest and DNA repair. Mutated forms 
lead to decrease or absence of p53 function. Thus, the damaged cells do not repair their DNA 
properly and produce more damaged cells. Bat-26 is a marker of microsatellite instability 
(MSI). In the normal genome, tandem repeats of 1 to 6 nucleotide (microsatellites), are scattered 
and fixed in number. With errors in the DNA mismatch repair mechanism, the microsatellites 
are expanded in repeat number. Ten to 15% of colon cancers have MSI (62,63). 
9.3. Pancreatic Carcinoma 
Pancreatic cancers are difficult to detect early. The serological tumor markers, such as 
CEA and CA-19-9, have not been sensitive enough to screen patients for pancreatic cancers 
at an early stage ( 1 ). Molecular markers have been reported to show promise of early detec­
tion of pancreatic cancers by serum and stool analysis. Pancreatic cancers are known to have 
a high incidence (over 90%) of k-ras gene mutations (64,65). 
A potential noninvasive source of DNA in pancreatic cancer patients is the serum (64-66). 
Also, k-ras mutations have been detected in stool, in pancreatic duct secretions, and pancre­
atic cytology smears (67). Mulcahy et al. (66) found k-ras mutations in the DNA from plasma 
of 17 of 24 patients with pancreatic cancer. They also noted that plasma DNA alterations 
were found 5 to 14 mo before clinical diagnosis of pancreatic cancer in four patients. 
9.4. Cervical Carcinoma 
Recently, the FDA's Microbiology Device Panel made recommendations to the FDA (68) 
that HPV molecular testing should be added to the Pap smear for primary screening of high­
grade cervical disease or cancer in women over 30 yr of age. The current primary screening 
tool for cervical cancer is the Pap smear and is not performed on approximately one-third of 
the eligible women. The sensitivity of the Pap has been estimated to be 35-81% (68). If 
both the Pap smear and HPV test are negative, the negative predictive value of the combined 
test is virtually 100%. HPV tests can be used as a follow-up of ASCUS Pap (abnormal 
squamous cells of undetermined origin). A negative HPV test on an ASCUS follow-up would 
indicate that the patient does not have a carcinoma or a significant dysplasia (69,70). 
The oncogenic proteins E6 and E7 of HPV types 16, 18, 31, and 33 bind to tumor suppres­
sor genes p53 and RB, respectively (71, 72 ). The process results in impaired tumor-suppres­
sor gene function, involving DNA repair, decreased apoptosis, mutations, and eventual 
virus-induced cervical carcinogenesis. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
ISSUES WITH MOLECULAR TESTS 
Molecular genetic and oncology tests can provide unique information not available by 
any other clinical method. However, many of the tests are often "home brew" and the perfor-

10 Nakamura and Grady 
mance and quality assurance issues are mainly the responsibilities of the individual clinical 
laboratory (5,73,74). 
The recommendations and guidelines regarding quality control and assurance issues have 
been defined for all clinical laboratories performing DNA testing. The procedures are 
described in detail in the laboratory inspection checklists and guidelines for molecular 
pathology and molecular genetics, published by the College of American Pathologists, 
American College of Medical Genetics and the National Committee on Clinical Laboratory 
Standards (NCCLS) (5). 
Each laboratory should conduct the various quality control and quality assurance proce­
dures recommended. In addition, for each molecular assay, the clinical laboratory should 
perform a clinical validation study or literature review and determine the medical utility and 
usefulness. The guidelines as recommended by CLIA-88 (Clinical Laboratory Improvement 
Ammendments) should be followed. Proficiency testing procedures as defined by CLIA-88 
must be implemented (75). 
11. ETHICAL ISSUES IN MOLECULAR TESTS 
There are certain unique ethical issues raised by molecular tests, especially those pertain­
ing to testing for genetic diseases by virtue of their predictive nature and the implications of 
positive findings for insurability, employment, and other family members. Although not 
widespread, there have been instances of adverse effects and discrimination as a result of 
genetic testing, even for recessive mutations (4, 76-78).lnformation in the medical record is 
legally recognized as private and confidential ( 3, 76). Pathologists, clinicians, and health 
care workers should not disclose confidential information to others without the patient's 
consent, actual or implied. With current information technology and the numerous person­
nel with legitimate access to medical records in electronic form, there has been a perceived 
need for new regulations and technology to provide greater security of the data and maintain 
confidentiality. Laboratories performing molecular testing have a heightened role to play in 
ensuring their appropriate use, confidentiality, and meaningful reporting. Because this area 
of clinical laboratory testing is so new and complex, many primary care physicians are not 
comfortable with result interpretation, and inaccurate, potentially harmful, misinformation 
may be conveyed to patients even when the analytic portion of the test was performed impec­
cably (79). Molecular testing laboratories must therefore be highly cognizant of the pre- and 
post-analytic aspects of these tests, to ensure their proper use and enhance their clinical 
utility. 
12. SUMMARY 
The clinical laboratory should clearly state the immunochemical or immunological test 
procedure performed, along with the definition of reference range to include the cutoff value 
and what percent of the normal population is included in the reference range. 
The clinical interpretation of the specific laboratory test can be influenced by many fac­
tors, including the sensitivity and specificity of the test, the clinical setting in which the test 
was requested, the reason the test was request ed, and the number of tests performed. The 
clinician should order the test on the basis of "what question does he or she want answered?" 
and, what he will do or recommend when the results of the clinical laboratory are normal or 
definitely abnormal. The test request is not necessary or definit ely nece ssary for patient care

Laboratory Tests for the Evaluation of Cancer 11 
if the physician will not change his clinical care or recommendation if the results are either 
normal or definitely abnormal. 
The newer approach for laboratory tests in the diagnosis and management of cancer will 
likely be panel testing at the genetic and protein levels, since cancer is now known to result 
from multiple genetic abnormalities accumulating over a long period of time. Data will be 
accumulated on specific types of tumor panel assays, which will become available for "fin­
gerprint analysis" of specific types of tumors. 
The assay panels may include specific gene loci and sequences, oncogenes and suppres­
sor gene products, mini-satellite instability analysis, chromosome analysis, etc. Such panels 
or "microassays" will be analyzed by a sophisticated software program with access to a large 
database for early detection and diagnosis, evaluation and therapeutic management of the 
cancer patients. 
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2 
New Insights and Future Advances in Cancer Diagnostics 
Yasushi Kasahara and Yutaka Tsukada 
Tumor markers for malignant diseases can be divided into various stages, namely screen­
ing, diagnostic, monitoring and prognosis, and in the foreseeable future, preventive testing . 
Neither conventional serological tumor markers, spanning from carcinoembryonic antigen 
(CEA) (1) to prostate-specific antigen (PSA) (2), nor the genomic markers ( 3) reported in 
the past 20 yr, have risen to our expectations with regard to early diagnostic or early disease 
detection. 
There are currently about 50 serological tumor makers available ( 4 ), some are used for 
diagnostic purposes in European countries and in Japan. In the United States, however , the 
application of tumor markers is restricted to monitoring or prognosis rather than diagnosis, 
except for PSA and nuclear matrix protein (NMP) (5), owing to insufficient sensitivity for 
early stage detection. Even CA19-9 (6) and CA125 (7) were just approved as diagnostic 
markers in 2002 for the Medicare reimbursement system. 
Relentless efforts have been exerted to find better ways to diagnose cancer. The logistic 
regression model using multiple makers has been used to improve the sensitivity and accu­
racy of diagnosis, with only limited success. The proteomics assay (8) especially matrix­
assisted laser desorption/ ionization (MALDI) (9) is expected to serve as a new tool for the 
enhancement of multiple m arker assays and for the discovery of new markers. 
The simultaneous detection of large numbers of targets such as in proteomics ( 10) on 
micro chips ( 11) as well as in DNNRNA array will help shed light on the disease proces s of 
cancer, but the advantages and efficacies of this technique for diagnostic application will 
need to be assessed. 
Malignant transformations are associated with the mutation or genetic alternation of 
oncogenes (3) or suppressor genes (12). Suppressor gene alternation is detected in a broader 
spectrum of cancers than oncogene alternation. More than one gene alternation is required to 
transform a cell into a cancer cell regardless of whether it is a germ line cell or a somatic cell. 
In cancer cells , oncogenes mostly involved in growth signal transaction are upregulated 
from transcriptional stage to phenotypic activity, while suppressor genes involved in DNA 
repair and genomic integrity are downregulated . Oncogenes are known to be tumor associ­
ated rather than tumor specific, in the same way that tumor mark ers are known to be tumor­
associated antigens. From the point of view of clinical application, genomic markers may 
not be as attractive as anticipated. 
From : Cance r Diagn ostics: Curr ent and Future Tre nds 
Edited by: R. M. Naka mura, W. W. Grody , ). T. Wu, and R. B. N agle© Hum ana Press Inc., Totowa, Nj 
15

16 
Table 1 
Tissue Specificity and Overall Sensitivity/Specificity 
of Typical Serological Markers 
Serological markers Primary type tumor Other tumors 
CEA" Colorectal Pancreatic, kidney , 
stomach 
a-Fetoprotein" Hepati c Cell Testicular, ovarian 
sec Cervical SCC (Head & Neck, 
Lung) 
PSA Prostate 85%/80% 
CA 19-9" Pancreatic Gastric , colorectal 
CA 125 Ovarian Cervical75 %/75% 
CA 15-31> Breast Renal Cell, 
Cervical 
CA 72-41> Gastric Ovarian, Colorectal 
°Carcinoembryonic protein. 
bCarbohydr ate antigens defined by monoclonal antibody. Kasahara and Tsukada 
Overall sensitivity/ 
specificity 
65%/65% 
80%/70 % 
50%/85% 
80%/70% 
45%/90 % 
50%/90% 
On the other hand, through molecular research findings, it has been possible to gain some 
insight on the molecular pathways that allow malignant growth for some types of cancer. 
Numerous target cancer drugs are currently under development ( 13 ). In pharmacogenomics, 
a diagnosis is required to identify the cause of cancer for each patient, and new molecular 
markers are selected for more accurate treatment with fewer side effects when using target 
cancer drugs instead of conventional cancer drugs. Because each targeting drug requires a 
specific assay, this field offers interesting prospects of expansion. 
Through the advancement of PC-aided graphic imaging technology for cancer diagnos­
tics, it is now possible to detect tumors of less than 10 mm in diameter and determine the 
exact location of the cancer ( 14 ). Medical imaging technology is the most feasible method 
for the screening or diagnosis of the early stage of cancer and it will likely soon replace 
serological markers on solid tumors. 
It is worth considering imaging technology not only with conventional tracer reagent but 
also with new tumor markers ( 15 ). In the near future, imaging technology is likely to become 
more cost effective and sensitive, and to detect disease at the earliest stage possible. Cancer 
diagnosis for prevention or possible risk prediction is the ultimate goal. 
2. ADVANTAGES AND LIMITATIONS OF CONVENTIONAL TUMOR 
MAKERS IN SERUM 
The development of tumor specific epitopes or molecules has been elusive in spite of 
research efforts in science and medicine . Table 1 shows the overall characteristics of popular 
tumor markers in serum ( 16-25 ), selected among over 100 markers reported in the past 50 yr 
(4). CEA ( 1) was identified from tumor tissue of colorectal cancer patients through serologi­
cal adsorption using adjacent normal tissue, a technique similar to the subtraction method 
using gene cloning. 
In terms of sensitivity and specificity at the cutoff point of each marker, CEA is not 
adequate for diagnostic purposes ( 16). The a-fetoprotein has a higher sensitivity than CEA 
with 80%, but its specificity is lower because of the positivity of benign diseases (18).

~ ~ 
>-+-' s 
:;::::; 
'(j) 
c 
(!) 
(/) 80 
60 
40 
20 
0 Standard Classification 
early~stage of Disease - pr ogress ---+- CEA 
(Colorectal Ca.) 
-o- sec 
(Cervical Ca.) 
----.- PSA 
(Prost ate Ca.) 
-t- CA125 
(Ovarian Ca.) 
···~· · CA19-9 
(Pancrea tic Ca.) 
--e -CA 15-3 
(Breast Ca.) 
Fig. l. Relation between sensitivity and disea se progression for typical tumor marker s. 17 
CA 19-9 , the first tumor marker to be defined by monoclonal antibody, recognizes the 
sugar chain as specific epitope, not as a whole molecule (6). This specific epitope is present 
on a wider variety of molecules . It shows about 85% sensitivity and 70% specificity for 
pancreatic cancer (22). PSA has the highest detection sensitivity with 85% and 85% speci­
ficity, and is currently the best serum marker for prostatic cancer (21 ). CA 15- 3 and CA 72-4 
both have low sensitivity and high specificity (24,25). 
Even typical markers shown here are not sensitive or specific enough for diagnostic and 
screening purposes. PSA, the most sensitive marker, is highly organ specific, squamous cell 
carcinoma (SCC) is rather tissue specific (20), and all other marker s are less organ specific. 
Figure 1 shows the brief relation between detection sensitivity and the stage of disea ses at 
standard classifications for various markers. Most markers increase in serum concentration 
with the size of the tumor, and the detection sensitivity percent is proportional to the 
advancement of the tumor. If specific tumor markers without the cutoff value were devel­
oped in the near future, more sensitive detection methodology would be required to detect 
the earliest stage of disease. 
Only PSA shows a relatively better sensitivity at the early stage (26,27). PSA is elevated 
in serum even in tumors of less than 1 em in diameter (21) . NMP bladder cancer marker 
using urine as specimen has the same sensitivity as PSA at the early stage (28,29). 
To improve diagnostic sensitivity and accuracy, an algorithm based on a combination of 
multiple markers has been applied to various tumors , some achieved improvement on detec­
tion sensitivity; however, decisive results have not been obtained ( 30). 
The search for a more sensitive and reliable method is now turning to proteomics analysis 
( 10,31 ), which allows for the simultaneous measurement of hundreds of test parameters in 
serum on a chip . However, only two reports have shown proteomic assays as a promising tool 
for cancer diagnostics. 
An assay based on mass spectrometry, surface-enhanced laser desorption/ionization 
(SELDI), was able to detect ovarian cancer at 100% sensitivity with 95% specificity, includ­
ing all 18 cases of stage I patients as shown by cluster pattern analysis ( 32 ). SELDI assay 
showed 93% sensitivity for all breast cancer cases at 91% specificity using 3 makers se-

18 Kasahara and Tsukada 
lected from among 147 markers ( 10). SELDI is a promising method for the discovery of new 
biological markers. However, further data using serum as specimen must be collected to 
assess the value of this technology for practical applications in the future. The sensitivity of 
existing markers at the early stage of diseases is inadequate for diagnostic or screening , but 
acceptable for monitoring of cancer or prognosis. Following the discovery of PSA 15 yr ago, 
no other adequate marker has been reported, and therefore we need to look into new genomic 
related markers as suitable tumor marker candidates. Only in vitro diagnostics using 
biomarkers can predict the risk of cancer prior to its onset, not imaging diagnostics . 
3. NUCLEIC ACID MOLECULE DETERMINATION AS TUMOR MARKERS 
Molecular science and gene analysis have contributed to the understanding of cancer 
biology ( 33 ). A single gene defect, developing several hereditary tumors has been reported, 
and more than hundreds of oncogenes and suppressor genes have been identified (3). 
Thus, too much has been expected of gene markers for cancer diagnostics; the develop­
ment of most cancers involves a complex series of steps ( 34 ), and the genes themselves do 
not reflect any physiological state in the body . A recent study on identical twins has revealed 
that cancer is weakly influenced by genetic makeup . That means nurture is more important 
than nature's encoding ( 35 ). The possible targets of nucleic acid determination with regards 
to cancer so far are as follows: 
• Oncogenes/suppressor genes mutation. 
• Inactivation of suppressor genes through methylation on CpG island or instability of promoter 
region. 
• mRNA profile of somatic cell. 
• Microsatellite mutation (instability). 
• Telomere stability and telomerase activity. 
Most oncogenes related with intracellular signal-transduction pathways cause cancer by 
overexpression as a result of mutation, especially in the case of ras-related genes. However, 
oncogenes or oncogene profiles for cancer diagnostics have proven inadequate for clinical 
application in spite of intensive investigation. 
The mutation of MIC, KRASIKRAF, Her2/EGFR, BCL-2 and other genes is found in a 
certain percentage of various malignancies ( 36,37). The combination of oncogenes with con­
ventional tumor markers, such as K-ras mutation with CA19-9 for colorectal and pancreatic 
cancer improves detection sensitivity and prognostic value ( 38 ). The mutation of suppressor 
genes such as p53 and BR is more common in overall cancers than that of oncogenes. 
Table 2 shows the suppressor genes that might be important for possible application on 
cancer testing ( 3,39-45). These can be divided into categories according to function of tran­
scription related activity (40), cell-cycle controller , and DNA repair (45,46) . Those func­
tions require normal cells to prevent disturbing factors such as mismatch accumulation, 
abnormal cell growth, and cell transformation. 
The loss-of-function of singl e suppressor genes in germline mutations such as p53, RB, 
BLM causes hereditary cancer. Mutations of ELM (44) and BRCA1/BRCA2 cause colon (42), 
breast, and ovarian cancer respectively resulting from a defect in DNA repair . PETEN 
mutation (46), a lack of activity reducing the amount of kinas e Akt product, is found in 
various cancers. KLF6 gene ( 41) of transcription factor is mutated in 77% of primary prostate 
cancers.

I Table 2 
Important Tumor Suppressor Genes Causing Cancer 
Genes Function Type of cancer 
p53 Cell-cycle response Colon, various 
p27 Cell-cycle inhibitor Breast 
RB Cell-cycle inhibitor Lung, AML 
BRCA DNA stability Breast , ovarian 
PTEN Signal transduction Various, systemic 
RARb2 Retinoic acid receptor Colon, APL 
KLF6 Transcription factor Gastric 
RUNX3 Transcription related Gastric 
EZH2 Transcription repressor Prostate 
Blm DNA repair Bowel, colon 
Mutation or deletion of suppressor gene 
Mutation or deletion of transcription factor, 
specific to suppressor gene 
Stability (micro satellite) of promoter sequence 
Methylation of promoter GpC site to suppressor gene, 
or its transcription factor 
Fig. 2. Impact of inactivation or silencing of suppr essor gene on tumor. 19 
t 
I 
Various factors trigger the inactivation of suppresser genes. Figure 2 shows various fac­
tors for the inactivation of suppressor genes that are sleeping or switched off with methyla­
tion on the CpG island within the promoter region (47), other than the existing concepts of 
deletion or mutation of suppresso r genes. Current research reveals the importance of the 
silencing of suppressor gene by promoter methylation on tumors. 
DNMT1/DNMT3b encoded methyltransferase is a key molecul e responsible for the 
methylation of suppressor genes ( 43 ). RERb2, retinoic acid receptor gene silenced by 
methylation (48), which causes acute promyelocytic leukemia (APL) or acute myeloid leuk­
emia (AML), has been confirm ed in experimental models. In addition, cases of colon, lung, 
lym-phoma, and breast cancer with a high percentage of methylation have been reported . 
Tumor suppressor genes play a crucia l role in anticancer defense. Suppressor gene somatic 
cells have , in principle, the same potential to inform on risk of cancer onset and early stages 
of cancer than oncogenes .

20 Kasahara and Tsukada 
However, whether methylation for genes silenced by the methyletransferase expression 
product of DNMT1/DNMT2 is specific to the suppressor gene locus or to global genes 
remains to be solved, and how many genes are involved in the methylation of suppressor 
genes in cancer in addition to DNMTl/ DNMT3b also remains unclear (43). 
Microarray applied on gene expression profile uses tissue or cell as specimen. To improve 
prognosis and classification of prostate cancer, Saravana et a!., analyzed thousands of genes 
using transcription profile, from normal adjacent prostate to metastatic cancer for over 700 
clinical specimens. 
The expression of hepsin and pim-1 transcript screen showed the correlation with clinical 
outcome reflecting the progression of the disease ( 49 ). In a subsequent study, they identified 
enhancer of zeste homolog 2 (EZH2) as a candidate of most specific markers for prostatic 
cancer with regard to the metastatic and lethal progression of the disease (50, 51). In addi­
tion, gene-expression analysis of solid tumors between primary tumors and metastases 
showed a set of genes associated with metastasis and metastatic cells being present in pri­
mary tumors. 
Prostasin, a potential serum marker for ovarian cancer was also identified through 
microarray technology (51). The transcription profile-method using microarray is a useful 
tool for the discovery of new markers. This technology, although more complicated than 
routine diagnostic application, provides more precise data and should be used in conjunction 
with pathological diagnosis. 
The somatic mutation of microsatelllite instability is comparable to a molecular clock 
showing tumor cell divisions through changes in diversity (53). Current reports show that 
microsatellite diversity is detected even in the serum of cancer patients using PCR amplifi­
cation of DNA. 
Microsatellite mutation in serum is detected in 71% of patients with small cell lung can­
cer (53) as well as colon, head, and neck cancers (54), among others. DNA analysis of 
microsatellite instability in serum, detected 71% of hepatocellular carcinoma in cancer 
patients with an a-fetoprotein serum concentration of less than cutoff level, and overall 
hepatocellular carcinoma at 100% sensitivity and 81% specificity when using the profile of 
19 marker DNAs (55). Thus, microsatellite instability is a unique potential marker in serum 
for nonorgan specific cancer, offering the possibility of detecting the early stage of events in 
cancer. Telomerase activity has been detected in over 90% of human cancers from tissue 
specimen (56,57) and normal germ cells but not in normal adjacent tumor tissues and is 
associated with more aggressive tumor behavior. 
Telomerase activity measured by telomeric repeat amplification protocol was positive in 
81% of colocectal cancers and in 70% of gastric cancers (58,59); another study detected 
positive telomerase activity in 93% of overall breast cancers (60), including 68% of primary 
tumors and 95% of advanced stage tumors, among surgically resected samples. 
Telomerase detection in body fluids, such as ascites, bronchial washings, and urine has 
also been demonstrated in various cancers (61 ). Telomerase enzyme activity was detected in 
94.7% of bladder cancers using bladder washes as specimen. Telomerase activity in cancer 
has no organ specificity, but detection sensitivity and specificity is high compared with other 
tumor markers in serum. 
4. PHARMACOGENOMIC TESTING OF CANCER FOR TARGETING DRUGS 
Current advancements in pharmacogenomics are anticipated to lead toward a tailored can­
cer therapy targeting specific molecules that cause particular tumors ( 12). Target drugs pro-

Limitations of Conventional Tumor Markers 21 
Table 3 
Target Drugs to Specific Genes for Cancer Therapy 
Drug Target Gene Function Cancer 
Herceptin HER-2 Monoclonal antibody Breast 
to HER-2 protein TK 
inactivation 
Gleevec bcr/abl Tyrosine kinase Leukemia 
Inhibitor 
Ires sa EGFR Tyrosinekinase Lung 
Inhibitor 
bevacizumab VEGF Monoclonal antibody Breast, 
to VEGF for anti- Colorectal 
angiogenesis 
CCI-779 PETN/mTOR-S6 mTOR/S6 kinase Prostate, Brain 
Inhibitor in PTEN-
deficient tumo r 
vide for accurate treatment, offering a judicious, and cost-effective alternative to conven­
tional drugs; they ensure that the optimum dose of the right drug is given to the right patient 
with fewer adverse effects . Each new target drug needs a specific test to identify the 
pharmacogenomic background of the patient prior to dose administration. For instance, 
Herceptin, a breast cancer drug already on the market, is restricted to patients with an 
overexpression of HER-2/neu . Patients who carry an overexpressed HER-2/neu receptor 
protein, about 20% of all cancer patients, must be differentiated from others for therapy (62). 
Table 3 shows a number of target drugs and their brief characteristics. Gleevec is an Food 
amd Drug Administration (FDA)-approved drug (63,64). Bcr-Abl tyrosine kinase inhibitor 
is about 90% effective in the early stage of chronic myelogenous leukemia (CML) caused by 
Bcr-Abl tyrosine kinase abnormality. Iressa (65,66), EGFR tyrosine kinese inhibitor, has 
only been approved for nonsmalllung cell cancer in Japan. 
Both avastin (67), a monoclonal antibody to VEGF protein, and CCI-779 (68,69), an 
inhibitor to mTOR-S6 kinase signal transaction in PTEN-deficient tumors , are in clinical 
trial stage. The next target drug should focus on the genes associated with the invasion or 
metastasis of cancer. Pharmacogenomics might thus provide the chance to develop new mo­
lecular marker testing methods that will provide detailed information on the functioning 
mechanism of targeting drugs. All targeting drugs listed in the table require a new cancer 
testing approach that characterizes the tumor of each patient with molecular markers, thereby 
reducing side effects and avoiding the unnecessary use of expensive drugs (70) . 
5. IMPACT OF IMAGING DIAGNOSTICS ON CANCER IN RELATION 
WITH TUMOR MARKERS 
Tumor biomarkers have improved with time for prognosis and monitoring purpo ses 
mainly , but for earlier detection and risk assessment their development have not yet reached 
a level adequate for clinical applications. In the past two decade s, noninvasive imagin g tech­
nology based on various platforms for cancer diagnostics has made significant advances 
with the surrounding computer-aided technologies, not only for clinical applications but 
also for basic research ( 13).

22 Kasahara and Tsukada 
In the case of lung cancer, early detection is needed to improve prognosis because most 
cancers are metastasized when first detected by biomarkers or by cytological assessment of 
sputum . Mass screening for lung cancer with low-dose X-ray spiral computerized tomogra­
phy (CT) in mobile units was performed on 5483 individuals from the general population in 
Japan (1 3 ). The detection rate with CT was 0.48%, including cancers of less then 10 mm in 
diameter, whereas that of standard mass screenings done previously in the same area were 
0.03-0 .05%, I 0 times less sensitive. This high-resolution CT also constitutes an excellent 
tool for confirmatory discrimination of subtypes of small peripheral lung peripheral adeno­
carcinomas (71 ). Magnetic resonance imaging (MRI) on preoperative local staging of 
patients with pancreatic cancer was applied to discriminate resectability. MRI results showed 
98% sensitivity, 92% specificity, and 96% accuracy in patients with suspected pancreatic 
tumor (72). MRI-guided intervention is now expanding to diagnosis and treatment of pros­
tate cancer, as in the case of fiber-guided endoscopy for colorectal or gastric cancer. 
A recently developed method, optical coherence tomography (OCT) combined with opti­
cal fiber may differentiate flat malignant from inflammatory lesions, without requiring 
biopsy. Ultrasonography with improved resolution is now a common screening tool for the 
physical check-up of healthy individuals. 
Ultrasonography used as a second-line test to serum CA125 shows an increased detection 
sensitivity in ovarian cancer (73 ), similar to the combination of occult blood testing with 
fiber endoscope in colorectal cancer. 
Positron emission tomography (PET), which produces images by detecting the radiation 
given off by tracer molecules, has improved in terms of sensitivity; its applications have also 
been expanded through the development of new tracers responding to specific targets. PET 
using tracers responding to target genes are being adapted to gene expression study in 
experimental animals (14). PET imaging of HSVJ-tk expression using thymidine analog 
called FIAU labeled with radioisotope was used in a clinical gene-therapy trial. 
Imaging technologies in diagnostics of cancer have acquired a strong position in relation 
to molecular and biomarkers in serum or tissue. Advancements in imaging technology will 
soon lead to the development of a downsized and more cost-effective system with higher 
resolution that will be easier to use. Without additional improvement, most tumor markers 
could serve as supplemental tools to imaging diagnosis in the near future. The development 
of tumor markers as possible tracers with the intervention of imaging analysis, a form of 
functional molecular imaging analysis, and the development of new primary test markers 
prior to the application of imaging diagnostics, are promising paths to explore for cancer 
testing. However, imaging technologies are limited in the sense that they cannot predict 
cancer risk or provide information on the aggravation of the disease (74 ). 
6.SUMMARY 
New biomarkers in serum that make up for the limitations of conventional tumor markers 
need to be improved both in terms of organ specificity and detection sensitivity at the early 
stage of disease. The proteomics assay, especially that based on SELDI, and the gene 
expression assay are considered promising tools for the discovery of new biomarkers. The 
development of new biomarkers that reflect both aggravation and metastasis of tumors is 
highly desirable. 
Compared with phenotypic biomarkers , oncogenes/suppressor genes are not very specific 
in cancer somatic cells, in spite of initial expectations, and they are not likely to become

Limitations of Conventional Tumor Markers 23 
mainstream in routine cancer diagnostics. Further studies on suppressor gene silencing as a 
result of methylation of the promoter region and microsatellite instability need to be evalu­
ated as possible markers to a broad spectrum of cancers. 
Telomerase activity expressed in somatic cancer cells and associated with aggressive 
tumor behavior , is the most specific marker. Telomerase activity measured by telomeric 
repeat has been detected in over 90% of tissue specimen in solid tumors and body fluids. If 
greater detection sensitivity for telomerase activity is achieved, serum rather than tissue will 
be used as specimen. The early stage detection of solid tumors in routine screening is thus 
foreseeable with telomerase activity combined with imaging analysis . 
Pharmacogenomic testing for targeting cancer drugs is the most promising emerging rou­
tine diagnostics tool. In contrast to conventional cancer drugs, new targeting drugs require 
corresponding molecular testing to select the right dose for the right patient with fewer 
adverse effects and effective cost containment. 
Imaging technologies based on various platforms have progre ssed significantly with the 
aid of computer-aided technologies. Imaging diagnostics can detect as little as 10 mm in 
diameter of solid tumor in addition to showing localization . Most conventional tumor mark­
ers for diagnostics are likely to disappear in the future. The development of new biomarkers 
either for primary testing prior to imaging diagnostics or for specific tracers of imaging 
analysis is one option worth investigating for early cancer diagnostics. Only in vitro diag­
nostics using biomarkers can predict the risk of cancer prior to its onset, not imaging diag­
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3 
The Changing Role of the Pathologist 
in the Management of the Cancer Patient 
Raymond B. Nagle 
1.1. The Difficult Diagnosis 
The experienced surgical pathologist routinely uses paraffin embedded tissue stained with 
hematoxylin and eosin (H&E) to establish the correct cancer diagnosis . A number of cir­
cumstances arise, however, in which the H&E slide is insufficient to establish the correct 
diagnosis. This occurs in approx 4-10% of all tumors and is usually owing to the fact that the 
tumors are undifferentiated and the cell of origin remains elusive. These undifferentiated 
tumors tend to fall into three categories: 
1. The large cell undifferentiated tumor. 
2. The small cell undifferentiated tumor. 
3. The spindle cell undifferentiated tumor. 
A second circumstance is the tumor presents as a metastasis with an uncertain origin. 
Often these tumors are poorly differentiated adenocarcinomas in which the organ of origin 
cannot be ascertained from the histological pattern of the metasta sis. Approximately 20% of 
all cancer patients present with metastasis. Studies have revealed that in as many as 4% of 
these patients the primary cancer is never found, even with complete autopsy examination. 
2. CURRENT USE OF IMMUNOHISTOCHEMICAL 
MARKERS OF CELL LINEAGE 
Beginning in the 1980s, antibodies specific to various cell linage proteins that could be 
used in immunohistochemical applications became available to the pathologist. It was found 
that all epithelial neoplasms expressed cytoskeleton proteins of the cytokeratin family . It 
was discovered that there were 20 such proteins, and exact combinations of these proteins 
were expressed with great fidelity in various cell lines ( 1 ). These findings were adapted for 
diagnostic use, allowing many undifferentiated tumors to be clearly diagnosed as carcinomas 
after demonstrating that they expressed cytokeratins. Shortly thereafter , other proteins were 
discovered that also were cell lineage specific. Over the years this has evolved and now there 
are a great number of antibodies that are useful in classifying undifferentiated neoplasms or 
in defining the site of origin of metastatic neoplasms. 
Examples of the use of such antibodies for identifying large cell undifferentiated neo­
plasms (2-4) or neoplasms of uncertain origin is shown in Fig. I. Antibodic;rs useful in the 
From : Cancer Diagn ostics: Current and Future Trend s 
Edit ed b y: R. M. Naka mur a, W. W. Grody, J. T. Wu, and R. B. Nagle © Humana Press Inc., Totow a, NJ 
27

28 
Cytokeratin Renal Cell Carcinoma-- CD10 (+) 
Thyroid Carcinoma-- Thyroglobulin(+), TTF-1 (+) 
Mesothelioma-- Calretinin (+), CK 5/6 (+), Thrombomodulin (+) 
Ovarian -ER/PR(+/-) 
Endometrial -ER/PR(+/-) 
(-)t Breast Carcinoma --ER/PR (+/-), mammoglobin (+), BRST-2 (+) 
! Colo rectal carcinoma --CK7 (-), CK20 (+) 
Hepatocellular carcinoma-- CK7 (-), CK20 (-), 
CEA canaliculi pattern, alpha fetoprotein 
Lung adenocarcinoma --CK7 (+), CK20 (-), TTF-1 (+) 
Melanoma-- S-100 (+), Melan A(+/-), Tyrosinase(+/-), HMB45 (+/-) 
Hematolymphoma -CD45 T-Cell --CD3 (+), CDS (+) (c B-Cell-- CD20 (+), lgH&L(+) 
(-) Plasmacytoma-- CD38 (+), CD138 (+) 
Hodgkins Lymphoma--CD15(+), CD30 (+) 
Anaplastic Lymphoma --CD 30(+), Alk-1 (+), CD15 (-) 
Seminoma (dysgerminoma) --PLAP (+) 
Fig. 1. Large cell undifferentiated or neoplasms of unknown origin. 
Cytokeratin Merkle cell carcinoma-- CK7 (-), CK20 (+), Neurofilament (+), TTF-1 (-) 
Small cell lung carcinoma- -CK7 (+), CK20 (-), TTF-1 (+) 
T-Cell Lymphoma-- CD3 (+),CDS(+) 
-B-Cell Lymphoma-- CD20 (+), lgG H&L (+) 
PNET --Vimentin (+), CD99 (+), BCL-2 (+), NSE (+/-) 
~ Embryonal Rhabdomyosarcoma --CD 56 (+) Desmin (+), 
SMS actin(+), MyoD1 (+) 
Ewing Sarcoma --Vimentin (+), CD99 (+), BCL-2 (-), 
Neuroblastoma-- CD56 (+), Chromagranin (+/-), BCL-2 (-) 
Fig. 2. Small cell undifferentiated neoplasm. Nagle 
differential diagnosis of small cell undifferentiated neoplasms (5-8) are shown in Fig. 2 and 
those used for poorly differentiated spindle cell neoplasms (9-11) are shown in Fig. 3. Using 
an algorithm approach to tumor diagnosis, which utilizes a few relatively inexpensive 
immunohistochemical tests, has resulted in better patient care and reduced cost. Use of these 
markers has also better categorized tumors so that clinical drug trials and other studies are on 
a firmer basis in terms of the tumor classification.

Changing Role of the Pathologist 29 
Vimentin <+-Spindle cell squamous carcinoma-- HMW CK (+) 
Cytokeratin Monophasic synovial sarcoma-- CK (+), NSE (+/-), S-100 (-) 
Desmoplastic melanoma-- S-100 (+), Melan A(+/-), Tyrosinase(+/-), 
HMB 45 (+/-), NSE (+) 
Vimentin (+) Nerve sheath tumor-- S-100 (+), HMB 45 (-), NSE (+/-) 
Rhabdomyosarcoma-- Desmin (+), SMS actin(+), MyoD1 (+) 
GIST tumor --CD117 (+) 
Fig. 3. Poorly differentiated spindle cell neoplasms. 
3. TECHNOLOGICAL ADVANCES 
This effort to establish cell lineage specific marker reagents was enhanced by two techno­
logical developments: First, the discovery by Kohler and Milstein that monoclonal antibod­
ies could be made by fusing specifically immunized murine spleen cells with murine 
myeloma cells resulting in a cell line producing a specific antibody that could be grown in 
tissue culture. This resulted in the production of specific monoclonal antibodies that were 
easily made in great quantity and could be sent around the world to various laboratories 
enabling the establishment of standardized immunohistochemical testing. Unfortunately, the 
majority of these antibodies were made against conformational epitopes, which were often 
denatured during standard formalin fixation of clinical specimens. A second major techno­
logic advancement was the discovery of heat antigen retrieval in which cross-linking by 
formalin was reversed by exposing the tissue to various protocols of steam or boiling. This 
enabled many monoclonal antibodies that were previously only used on fresh frozen tissue 
to be used in archival, formalin fixed, paraffin-embedded tissue. 
The impact of cloning the human genome has resulted in the ability to predict amino acid 
sequences for any human protein. Peptides can be synthesized or constructed and recombi­
nant proteins can be made in bacterial plasmids that can be used as immuogens . This has 
resulted in monoclonal antibodies (MAbs) specific for every human gene product now being 
possible. With the advent of microarray analysis, gene expression for a variety of human 
tumors is being determined. These studies will undoubtedly result in a new set of targets and 
generation of MAbs with greater specificity and clinical relevance. 
4. PREDICTIVE MARKERS 
In general, antibody markers have been used to confirm or rule out a diagnosis in the 
context of comparing immunohistochemical results with morpholog y and clinical informa­
tion. They were used, therefore, as adjuncts to conventional pathologic diagnosis. The new 
challenge presented to pathologists is the use of immunohistochemistry to detect therap eutic 
protein targets. The current thinkin g in medical oncology is to move away from general 
cytotoxic agents to customized therapy, where certain target proteins expressed in the indi­
vidual patient are being treated with protein-specific agents. These target proteins have been 
shown to function in strategic signaling pathways or other fundamentally important bio-

30 Nagle 
chemical pathways in various cancers and have been chosen as targets for therapy. Drugs 
specifically interacting with targeted proteins would block these pathways and lead to the 
selective killing of tumor cells. The quantification of the amount of target present in the 
tumor is therefore used to predict therapeutic response. 
The great advantage of detecting these targets by immunohistochemistry rests in the abil­
ity to directly associate the target with the malignant cells. A sample of current protein target 
molecules for which there are already drugs available is shown in Table 1. The drug devel­
opment industry is moving very rapidly and has presented the field with a great challenge in 
developing tests for these targets. Only one of these target detection reagents, HER-2/neu, has 
Premarket Approval (PMA) status as a diagnostic reagent (Table I). 
Currently, there are a few approved as In Vitro Diagnostic (IVD) status but most of these 
are being currently used as Analytic Specific Reagents (ASR) . The need for standardization 
of these tests is great, because unlike the previous diagnostic immunohistochemical tests 
that were correlated with morphology and clinical histories, these tests are "stand alone" 
tests. For example, the level of HER-2/neu growth factor receptor expression in a breast 
cancer predicts whether the patient might respond to HerceptinR , independent of the mor­
phology or other pathologic features. Detection of HER-2/neu expression is an independent 
test and therefore test standardization needs to be rigidly controlled. 
Currently, there is a great deal of confusion as to how one measures these protein levels , 
and whether or not this can be quantitated using digital imaging and image analysis. One of 
the technological developments that may be import ant in this regard is the widespread use of 
immunohistochemical automation that better ensures run to run consistency (12). There is 
increasing pressure on pathology labs to quantitate these results so that the therapeutic trials 
and testing of the new reagents are on a more sound basis. The College of American 
Pathology is currently proposing a plan for testing and qualifying laboratories performing 
these predictive tests. 
5. CHALLENGES FOR PREDICTIVE TESTS 
The "stand alone" predictive test raises a numb er of new challenges for pathologists. The 
first challenge is to have proper positive controls. The use of a series of cell lines with known 
levels of protein expression is an attractive solution. Cell lines however, are not equivalent 
to tissue sections and their use requires stringent control of their culture, fixation, and meth od 
used for their attachment to glass slides. 
Perhaps the most important barrier to the study of predictive protein markers is the effect 
of cross-linking or precipitating fixatives routinely applied by pathology laboratori es. The 
conformation of certain protein epitopes is adverse ly affected by formalin fixation and is 
dependant on time, temperature, and the buffering system used in the original processing of 
the tissue. These procedures are not standardized and until this problem is addressed the full 
potential of protein target detection by immunohistochemical assays will not be realized . 
Even if these test procedures can be standardized there is still the question of whether the 
results can be quantified. Predictive markers such as the estrogen and progesterone receptors 
and Her-2/neu are currently being investigated to determine whether modem optical meth­
ods can be used to obtain clinically relevant quantif ication. It is likely that as neoplasms 
progress or respond to a given therapeutic regimen they will evolve into cell clones using 
different survival strate gies and therefore change their phenotype. This will require 
resampling and rephenotyping the neoplasm to enable the therapist to adjust customized

Changing Role of the Pathologist 
Table 1 
Drug Targets Now in Use and the Statues of Their Detection Testsa 
Target 
Estrogen Receptor 
HER-2/neu 
EGFR 
CD20 
CD 52 ASR 
Class I 
X 
X 
X 
Progesterone Receptors X 
Androgen receptor X 
Asparagine synthase 
(low levels cause sensitivity) X 
Thymidylate synthase 
(low level s cause sensitivity) X 
Dihydrofolate reductase 
GAR transformylase X 
Mismatch repair abnormal cells X 
Thymidine phosphorylase 
(high levels casues activation of the agent) 
CDll7 X 
Adenosine deaminase X 
Somatostatin Receptor X 
Topoisomerase I X 
Topoisomerase II X 
RAR X 
COX- 2 X 
DNA polymeras e X 
RXR X 
IL2 receptor X 
Ribonucleotide reductase X IVD 
Class 2 
X 
X 
X PMA 
Class 3 
X 
0Protein targets for which there are therapeutic drugs currently in use or in clinical trial. 
Notes : The table indicates the current levels at which existing reagents are approved . 
Class !-Analytic specific reage nt (ASR). 
Class 2-In vitro diagnostic (IVD) . 
Class 3-Premarket approva l (PMA). 31 
therapy that would be the most appropriate for the patient. Resampling most likely will be 
restricted to small samples such as needle aspirates or perhaps even circulating tumor cells. 
The analysis of this type if specimen again will present new challenges to the pathologist 
and may require the use of more sensitive methods of individual cell analysis including the 
use of the new fluorescent probes and laser microscopy. Undoubtedly, these developments 
will improve cancer patient care. On the other hand , they will create technolo gical chal­
lenges for pathology laboratorie s and health care provid ers who will demand that these new 
tests are accurate and cost effective.

32 Nagle 
I. Moll R, Franke WW, Schiller DL. 1982 . The catalog of human cytokeratins: Patterns of expres­
sion in normal epithelium, tumors, and cultured cells. Cell 31: 11-24. 
2. Linder J. 1990. Immunohistochemistry in surgical pathology: the case of the undifferentiated 
malignant neoplasm. Clin. Lab. Med . 10:59-76. 
3. Jaramillo M, Rangel C, Grogan T. 2000. Immunohistochemistry in leukemias and lymphomas, 
in: Methods in Molecular Medicine , vol 55, Hematologic Malignancies: Methods and Tech­
niques. Humana Press: Totowa, NJ, pp. 301-319. 
4. Orchard GE. 2000. Comparison of immunohistochemical labeling of melanocyte differentiation 
antibodies melan-A, tyrosinase and HMB-45 with NKIC3 and S I 00 protein in the evaluation of 
benign naevi and malignant melanoma. Histochem. J. 32:4 75--481. 
5. Hasegawa T, Hirose T, Ayala AG, et al. 2001 . Adult neuroblastoma of the retroperitoneum and 
abdomen Am. J. Surg. Path. 25:918-925 . 
6. Stevenson A, Chatten J, Bertoni F, et al. 1994. CD99 (p30/32MIC2) neuroectodermal/Ewing's 
sarcoma antigen as an immunohistochemical marker: review of more than 600 tumors and the 
literature experience. Appl. Immunohistochem. 2:231-240. 
7. Folpe AL, Patterson K, Gown AM. 1997. Antineuroblastoma Antibody NB-84 Also Identifies a 
Significant Subset of Other Small Blue Round Cell Tumors. Immunohistochem. 4:239-245. 
8. Hess E, Cohen C, DeRose PB, Yost BA, Costa MJ. 1997 . Nonspecificity of p30/32MIC2 
Immunolocalization with the 013 Monoclonal Antibody in the Diagnosis of Ewing ' s Sarcoma: 
Application of an Algorithmic Immunohistochemical Analysis. Immunohistochem. 5:94-103. 
9. Shipley WR, Hammer RD, Lennington WF, Macon WR. 1997 . Paraffin Immunohistochemical 
Detection of CD56 , a Useful Marker for Neural Cell Adhesion Molecule (NCAM), in Normal 
and Neoplastic Fixed Tissues. Immunohistochem . 5:87-93 . 
I 0. Thompson LOR, Wieneke JA, Miettinen M and Heffner DK. 2002. Spindle Cell (Sarcomatoid) 
Carcinomas of the Larynx. Am. J. Surg. Pathol. 2:153-170. 
11. Boyle JL, Haupt HM, Stern J, Multhaupt HAB. 2002. Tyrosinase Expression in Malignant Mela­
noma, Desmoplastic Melanoma, and Peripheral Nerve Tumors. Arch. Pathol. Lab. Med. 
126:153-170. 
12. Grogan TM, Rangel C, Rimsza L, et al. 1995. Automated Double-Labeled Immunohistochemis­
try and in situ Hybridi zation in Diagnostic Pathology. Advances in Pathol and Lab Med. vol. 8. 
Mosby: Year Book, Inc. 79-99.

1. INTRODUCTION 4 
Types of Circulating Tumor Markers 
James T. Wu 
1.1. Enzymes, Serum Proteins, and Hormones 
It was during the 1950s and 1960s when we began to realize that the concentration of 
many molecules circulating in the blood reflected tumor cell activity. Because blood could 
be sampled repeatedly, these circulating molecules were used to monitor the success of can­
cer treatment in patients, which allowed for the adjustment of therapeutic regiment from 
time to time. These molecules included enzymes , isoenzymes, serum proteins , and hormones 
that could be found in normal blood circulation ( 1 ). 
During this time there were only a limited number of circulatin g molecules used as tumor 
markers for the manag ement of cancer patients. These markers included norepinephrine for 
pheochromocytoma, tryptophan hyroxyindole acetic acid for carcinoid tumors, serum prote­
ins for multiple myeloma, hormones for various endocrine tumors and several glycolytic 
enzymes (2). All these molecules were also detectable in normal blood circulation . The blood 
concentration of these molecule s was sufficiently high that it could be detected without the 
use of a sensitive immunoassay . Although it was realized that these ubiquitous serum mol­
ecules were not specific to canc er, their levels often reflected tumor progres sion and paral­
leled the clinical status of the patient. They were therefore clinicall y useful for monitoring 
the success of therapy but not for diagnosis. Among these circulating molecules, several 
enzymes had been frequently used (Table 1) (3). Many of these enzymes may complement 
currently used tumor markers in terms of improved sensitivity and specificity when used 
together in a multiple mark er panel. 
Although total enzyme activity was being used for monitorin g cancer therapy, isoenzym es 
were also found useful as circulating tumor mark ers (Table 2). Because many isoenzymes 
are tissue specific, their detection at elevated level s may be useful to suggest the tissue site 
of the tumor , such as elevated bone alkaline phosphatase isoenzyme for bone cancer . 
Unfortunat ely, most serum proteins and enzyme s exhibited low sensitivity and specificity 
when used as tumor mark ers. As illustrated in the study of breast cancer by Coombes et al. 
( 3 ), most serum proteins and enzymes were elevated only in patients with advanced meta­
static disease. Most of these molecules could not detect cancer at an early stage. Even at the 
advanc ed stage, only 8 of the 21 markers were elevated in slightly over half the patients. In 
From: Cancer Diagnostics: Current and Fut ure Trends 
Edited by: R. M. N akamura , W. W. Gr ody, J. T. Wu, and R. B. N agl e© Hurnan a Press Inc., Toto wa, NJ 
35

36 
Table 1 
Enzyme as Tumor Marker 
Enzyme 
Prostatic acid phosphatase 
Lactate dehydrogenase 
5'-Nucleotide 
phosphodiesterase 
Sialyltransferase 
Fucosyltransferase 
Urinary ary !sulfatase 
Thymidine kinase 
Terminal deoxynucleotidyl 
transferase 
Table 2 Associated malignant disease 
Prostate carcinoma at a late stage 
Acute leukemia; malignant lymphoma; germ cell 
tumors; metastatic colon, breast, and lung cancers 
Lung cancer; liver metastases 
Nonspecific 
Multiple malignant tumors 
Myeloid leukemia 
Hodgkins lymphoma, certain leukemias, and small 
cell carcinoma of the lung 
Lymphoblastic cancer 
Most Frequently Used Serum Isoenzyme as Tumor Marker 
Isoenzyme 
CK-BB 
Typc-2 Macro-CK 
(oligomeric mitochondrial CK 
Type 1 macro CK (complex 
between CK-BB and IgG 
Mitochondrial CK-IgA complex 
Galactosyltransferase 112 
Placental ALP (PLAP)" 
(Regan isoenzyme) 
Bone ALP 
LD-1 
LD-4 and LD-5 isoenzymes Associated malignant diseases 
Adenocarcinoma of the prostate, lung, and 
stomach, not very specific 
Metastatic liver cancer and various carcinomas 
Various neoplastic disease s 
Detected in various carcinomas. Appears to 
be a prognosticator for patients with 
advanced tumors 
Ovarian, liver, and esophageal cancers 
Advanced colorectal cancer, not very 
specific placental-like ALP 
The highest frequency was found in germ ­
cell tumors (e.g. seminomas) and ovarian 
cancers, not very specific 
Osteosarcoma , bone metastase s 
Testicular germ cell tumors (seminomas, 
yolk sac tumo r) 
Elevated in most cancers at advanced stage 
0The placental-like isozyme has different bioche mical and immuno chemical propertie s 
compared to the placental ALP. However, there is 98% hom ology in amino acid sequence 
betwee n these two enzymes . Wu

Circulating Tumor Markers and Their Clinical Applications 
Table 3 
Some Commonly-Known Carcinoembryonic Proteins 
Carcinoembryonic 
proteins 
CEA 
AFP 
ALP 
IgGT 
5'NDPase -V 
POA Comments 
For cancers of the gastrointestinal tract 
Hepatoma and yoc sac tumors 
Multiple isoenzymes of ALP can be detected in cancer tissue 
It is the hepatoma-specific y-glutamyltranspeptidase 
migrating in the a1-globulin region that can be found in 
cancer and fetal liver cells 
The specificity and sensitivity of 5'-nucleiotide 
phosphodiesterase isoenzyme- V makes it better than 
CEA for metastatic breast cancer 
Pancreatic oncofetal antigen measurement is us eful both as 
a diagnostic test and for monitoring the clinical course of 
pancreatic cancer 37 
all probability, the low sensitivity and specificity of these enzymes and protein markers 
limited their clinical usefulness for cancer management . The types of tumor markers used in 
the early days differ dramatically in terms of specificity and sensitivity from tumor markers 
used in recent years. These enzymes, serum proteins, and hormon es were known from their 
normal physiologic functions. They all play specific roles in normal metabolism and there­
fore can be detected under normal conditions. However, monitoring these molecules in can­
cer patients may still allow us to relate their elevated concentrations to the molecular basis of 
malignant growth. Their measurement may also provide clues to the location of tumors such 
as elevated 5'-nuclotidase is usually associated to the tumor in the liver. 
The measurement of enzyme concentration in physiological fluid may also aid in the 
prognosis of specific types of cancer. For example, lactate dehydrogenase (LDH) in perito­
neal fluid was found to be a reliable biochemical marker related to prognosis in patients with 
ovarian carcinoma. Peritoneal fluid LDH appeared to have prognostic value owing to its 
correlation with advanced stage, poor histologic type, higher grade, and positive abdominal 
cytology of serous ovarian cancer ( 4 ). 
2. CARCINOEMBRYONIC PROTEINS 
Carcinoembryonic proteins are proteins that can be detected in high concentration in the 
fetal tissue, are absent in the normal adult tissue but reappear in an elevated concentration in 
tumor tissue. Originally, they were called fetal tumor antigens and were latter changed to 
carcinoembrionic proteins because they are not necessarily immunogenic. A list of 
carcinoembryonic proteins is shown in Table 3. Placental alkaline phosphatase (the Regan 
isoenzyme) could be one of the earliest, if not the first, carcinoembryonic protein identified 
(6). This is an enzyme normally produc ed by the syncytiotrophoblast s in the placenta after 
the 12th wk of pregnancy but is also found elevated in advanced colorectal cancer. In the late 
1970s, it was the discovery of carcinoembrionic antigen (CEA) in colorectal carcinoma and 
the development of a sensitive radioimmunoassay for quantifying plasma CEA by Thomson

38 Wu 
et al. (7) that provoked the beginning of a new era of tumor marker investigations and appli­
cations. The discovery of CEA also initiated an intensive search for additional 
carcinoembryonic proteins and tumor-specific markers. Even though the results were disap­
pointing we learn many valuable lessons about how to utilize tumor markers in the manage­
ment of cancer patients. 
The expression of carcinoembryonic protein associated with tumorigensis suggests that 
these proteins may be related specifically to the events of cancer development . Unfortu­
nately, none of these carcinoembryonic proteins were later found to be tumor specific, 
although their specificity and sensitivity were improved over the enzymes and serum pro­
teins used as tumor marker. The serum concentration of these carcinoembryonic proteins 
correlates well with tumor activity. Because of their insufficient sensitivity and specificity, 
they are not recommended for cancer screening, or for diagnosis. They are most frequently 
used to monitor the success of treatment for cancer patients. However , their appearance in 
blood circulation is usually several months before any clinical symptom. They are also use­
ful for detecting recurrence for cancer patients postoperatively. 
Unlike enzymes and hormones, many of these carcinoembryonic proteins, such as CEA 
and a-fetoprotein (AFP), do not have clearly defined physiological functions. Most of these 
molecules are present in nano- and picogram concentrations in the blood circulation. Quanti­
fication of their concentrations circulating in the blood for patient management requires 
the sensitivity of a radioimmunoassay or enzyme immunoassays. Again, unlike enzymes, 
these newly discovered tumor markers are usually associated with cancers of higher inci­
dence, such as with epithelial cell-derived carcinomas. 
3. MONOCLONAL-DEFINED TUMOR MARKERS 
Monoclonal-defined tumor markers are related to epitopes defined by monoclonal anti­
bodies. Note that these monoclonal kits recognize only the epitope , not the entire molecule 
and that the same epitope may appear in different molecules. Currentl y, they are frequently 
used in the management of cancer patients. The development of monoclonal-defined tumor 
markers was originally an attempt to improve the specificity and sensitivity of tumor marker 
of carcinoembryonic proteins such as CEA. It was thought that replacing polyclonal with 
monoclonal antibody in the assay eliminated the cross-reaction between various tumor mark­
ers because of the sharing of some epitopes between tumor markers. It was hoped that the 
use of monoclonal antibodies (MAbs) would lead us to the identification of tumor-specific 
markers (or tumor-specific epitopes). Although none of the epitopes identified turned out to 
be tumor-sp ecific, the overall specificity and sensitivity of the monoclonal kits have been 
improved when compared to polyclonal kits. 
Several monoclonal tumor marker kits have become available commercially in recent 
years (Table 4). These monoclonal antibodies have provided a greater degree of specificity 
and sensitivity than the polyclonal CEA assay in the management of patients with breast , 
ovarian, and pancreatic carcinomas. However, they are still limit ed in their clinical utilities. 
The major functions of these monoclonal tumor markers are still limited in the monitoring of 
treatment and detection of recurrence. They are not recommended for screening or for diag­
nosis. As a result, when a malignant disease is associated with a monoclonal kit, it is under­
stood that the monoclonal tumor marker is only the major marker associated with the 
malignancy and is not necessarily specific for the malignant disease. In fact, almost all mono­
clonal tumor markers can be found in all carcinomas though in varying concentrations.

Table 4 
Monoclonal Antibody Defined Tumor Markers 
Monoclonal kit 
CA 125 
Hybri-BREScan (CA 549)0 orCA 15-3 
Hybri-CMark (CA 195)0 orCA 19-9 
CA 72-4 
CEA 
°From Hybritech (San Diego, CA) Associated major malignant disease 
Ovarian carcinoma 
Breast carcinoma 
Pancreatic carcinoma 
Gastric carcinoma 
MAbs are used, 
specificity has been changed 39 
Because the monoclonal antibody recognizes only the epitope, not the entire molecule, 
monoclonal tumor marker assays may react with different molecules as long as they both 
express the same epitope. For example, the antigen purified from the cell membrane for CA 
19-9 is a ganglioside, whereas the molecule circulating in the patients' sera is a glycoprotein, 
However, because both molecules express the CA 19-9 epitope, consequently, these two 
different molecules are both CA 19-9 positive. Listed below are some more detail descrip­
tions of these monoclonal-defined tumor markers 
3.1. CA 15-3 
TheCA 15-3 monoclonal tumor marker is best for monitoring patients with breast carci­
noma during treatment and for the detection of recurrence. Elevated CA 15-3 is usually not 
detectable in benign breast tumors. Elevated CA 15-3 appears in blood circulation most 
frequently after metastases. The epitope associated with the tumor marker CA 15-3 is found 
on the polymorphic epithelial mucin (PEM) antigen and also in the milk fat globule mem­
brane. Two MAbs, MAb 115D8 and MAb DF3, measure the tumor marker CA 15-3 in a 
sandwich format. However, only MAb DF3 is specific for the CA 15-3 epitope, whereas 
MAb 115D8 is only used to catch the tumor marker in the serum. The epitope recognized by 
DF3 MAb appears as tandem repeats in the serum tumor-marker molecule. CA 549, CA 
M26, and CA M29 are all epitopes present on the circulating molecule. 
3.2. CA 125 
CA 125 is the best monoclonal tumor marker for serous ovarian carcinoma and is not 
elevated in mucinous ovarian tumor. Althou gh not specific for ovarian cancer, elevated CA 
125 appears early at benign stages and has the potential for screening ovarian cancer at early 
stages. The epitope corresponding to tumor marker CA 125 is present in a large molecular 
weight, mucin-like glycoprotein complex that can be found in sera from patients with ova­
rian cancer. This epitope recognized by MAb OC 125 is considered a peptide in nature 
because of its sensitivity to protease and its relative stability to glycosidases. 
3.3. CA 19-9 
CA 19-9 is the best monoclonal tumor marker for monitoring patients with pancreatic 
carcinoma . This epitope, identified by MAb 19-9, was produced by a hybridoma prepared 
from spleen cells of a mouse immunized with a human colon carcinoma cell line, designed 
to replace polyclonal CEA to improve both specificity and sensitivity of polyclonal CEA.

40 Wu 
However, it turned out that the resultant CA 19-9 was better for pancreatic cancer, although 
it was still reactive with colon cancer. The mucin glycoprotein, expressing CA 19-9 in the 
serum, has a MW of= 5 x 106. The epitope is also shared by glycolipids in the cell mem­
brane (8). CA 19-9 is one of the gastrointestinal cancer-associated antigens defined by MAbs, 
which includes CA 50 and sialyl-Lewisx (CSLEX-1). Patients with Lewis negative antigens 
(Lea"Leb·) will not express elevated CA 19-9 regardless of how advanced their pancreatic 
cancer is. 
3.4. CA 19-5 
This epitope identified by MAb CC3C-195 is very similar to CA 19-9 (9). CA 195 also 
reacts with both Lea and sialyl-Lea epitopes ( 10). MAb CC3C-195 binds with higher affinity 
with the sialylated Lea blood group antigen than the nonsialylated counterpart. 
3.5. CA 50 
The epitope defined by the CA 50 assay is similar to the epitope of CA 19-9 and CA 195 
but lacks a fucose residue, the same epitope found in Lewis negative (Le a-b-) individuals 
( 11 ). Assays for CA 19-9, CA 195, and CA 50 all produce elevated levels of activity in sera 
from many patients with colon and pancreatic cancers. 
4. BLOOD GROUP SUBSTANCES 
It is interesting to note that many blood group substances are closely related to many 
tumor markers currently used for cancer patient management. For example, an integral part 
of the CEA molecule is its blood group substance. CEA from entodermally derived adeno­
carcinoma is found to be an incomplete blood group substance of the ABO system. The 
deficient antigens have tumor-specific activity resulting from the unmasking of a structural 
sequence that is cryptic in normal situations. Holburn et al. and Ball JP et al. ( 12-14) have 
demonstrated that the A, B, Le, and Leb and H detected in CEA preparations were consis­
tent with the patients' blood group and not the result of contaminations. In addition, gly­
colipid extracts from various human cancer tissues and cell lines show various blood group 
antigenicities and represent a tumor-associated epitope (carbohydrate epitope) owing to ab­
errant glycosylation ( 13 ). lgM antibodies to T antigen, an immediate precursor of blood 
groups M and N expressed in about 90% of carcinomas, are present in severely depressed 
levels in patients with breast, lung, or gastrointestinal (GI) cancers. 
Many of the tumor-associated antigens are carbohydrate in nature. It appears that the 
accumulation of sugar chains, such as sialyi-Lea and sialyl-LeX, is the major carbohydrate 
alteration associated with malignant transformation . The first monoclonal antibody made against 
such cancer altered blood group antigens with gastrointestinal cancer specificity is CA 19-9. 
CA 19-9 is a carbohydrate moiety with the sugar sequence containing a sialylated Lea-active 
pentasaccharide directed against epitopes on a monosialoganglioside from colorectal cancer 
cell lines and against mucin molecules in the serum of gastrointestinal carcinoma patients 
( 15 ). Most of these carbohydrate antigens in epithelial tumors are derived from the Lewis 
blood group-related antigens. Lewis blood group antigen (Le) specificities have been found 
to reside in glycosphingolipids and glycoprotein molecules on the surface of erythrocytes, 
epithelial and endothelial cells, as well as in bound or free glycoprotein oligosaccharides 
secreted into various body fluids, such as saliva, ovarian-cyst fluid, urine, and milk. Co-expres­
sion and an increase in Lewis blood group-antigen-active glycolipids have been found in 
human adenocarcinoma. Le and Leb carbohydrate determinants coexist in both glycolipid

Table 5 
Glycosyl Transferases as Tumor Markers 
Glycosyltransferase* 
Galactosyl­
transferases 
Sialyl­
Fucosyl­
transferases Donor 
substrate 
UDP-Gal 
CMP-NeuAc 
GDP-Fuc Associated diseases 
malignant 
Isoenzyme II is sensitive 
for pancreatic cancer 
Elevated in various 
carcinomas 
Early stage of gastric cancer, 
malignant endometrial 
tissue and various 
metastatic carcinomas ( 44) 41 
and glycoprotein forms in the same cells. The distribution of the Lea and Leb activities in the 
glycoprotein fraction corresponded well with that in glycolipids (Table 5). 
Altered blood group antigens (or their carbohydrate epitopes) are frequently 
overexpressed in malignant tissues. Overexpression of altered blood group antigens is usu­
ally related to the process of tumor progression and is associated with poor prognosis. This 
overexpression is nonspecific and can be found in most carcinomas of varying degrees of 
advancement. During neoplastic transformation and neoplastic growth , blood group antigen 
expression in the glycoprotein and glycolipid antigens of tissues changes profoundly. Neo­
plastic cells may "lose" or "acquire" new antigens expressed or not expressed, respectively, 
by their normal counterparts. 
Many of these malignancy associated blood group antigens relating to blood groups A, B, 
H, and Lewis antigens and their precursors are results of incomplete biosynthesis of the 
major blood group antigens. These precursor-like substances accumulated frequently in 
tumor cells (16). For example, blood group A, B, and H antigens are deficient in many 
human adenocarcinomas. Loss of antigen expression has been found in bladder cancer, cor­
relating with invasiveness. Modifications of these glycoproteins were also found through 
fucosylation and sialylation, affecting expression of blood group antigens and resulting in 
the production of most of the known tumor-associated carbohydrate antigens. Typical 
examples of tumor-associated antigens in gastrointestinal and colorectal lesions are 
fucosylated mono- and multimeric LeX, LeY, and sialylated LeX and Le3 structures. The 
expression of blood group ABH antigen of the oncodevelopmental type was discovered in 
colonic epithelia and tumors ( 17). Conceivably , monoclonal antibodies against these altered 
carbohydrate epitopes may prove useful for identification and establishment of tumor marker 
immunoassays. Many MAbs directed to individual types of structures have been used as 
probes for the detection of these antigens as tumor-associated markers. An increased synthe­
sis of one type of antigen and decreased formation of another type seems to be frequently 
associated with carcinogenesis in breast, lung, and ovarian cancer (1 8). 
4.1. Glycosyltransferases 
Because of the association of blood group substances with tumor markers, the enzymes 
that catalyze the addition of specific sugar residues from an activated donor substrate to 
glycoproteins, namely glycosyltransferases, also reflect tumor cell activity and could be used 
as tumor marker (18). Past observations suggest that celJ-type specific glycosylation

42 
Table 6 
Nmps Found in Various Human Tumors* 
Tumor Type 
Prostate 
Colon 
Breast 
Cervix 
Bladder 
Osteosarcoma 
*Modif ied from ref. 19. Name/Designation of Altered NMP 
PC-I 
CC 1-6, NC 1-4 
NM200.4;NMBc 1-6; NMBC W-Z 
C 1-11; N 12-15 
p69;pl86;p200 
NMP 22 (NuMA) 
No formal designation Wu 
sequences can result from the regulated expression of glycosyltransferase genes. The specificity 
of the enzymes for their donor and acceptor substrates constitutes the primary basis for de­
termining the structures of the sugar chains produced by a cell. Changes in terminal 
glycosylation during development, differentiation, and oncogenic transformation are 
determined by these enzyme activities. Therefore, the activity of glycosyltransferases, which 
appear in the tumor tissue, determine the type of carbohydrate tumor markers eventually 
detected in cancer patients. In other words, the changes in glycolipid or glycoprotein 
glycosylation in transformed cells correspond to quantitative or qualitative changes in the 
expression of the relevant glycosyltransferases . It has been estimated that 100 or more 
glycosyltransferases are required for the synthesis of known carbohydrate structures on 
glycoproteins and glycolipids, and most of these are involved in elaborating the highly 
diverse terminal sequences found in mucinous glycoproteins. These enzymes are grouped 
into families based on the type of sugar they transfer. Several of the glycosyltransferases 
appear to associate specifically with certain tumor activity and have been used as tumor 
markers (Table 5). Serum fucosyltransferase has been found to respond to therapy designed 
for colon cancer patients with metastases. Galactosyltransferase has been determined useful 
for differentiating between benign and malignant pancreatic carcinoma. 
5. NUCLEAR MATRIX PROTEINS 
Nuclear matrix proteins (NMPs) were originally thought to be primarily an architectural 
protein network responsible for maintaining nuclear shape but now are known as a dynamic 
family of proteins that has a vital role in such fundamental cell processes as steroid hormone 
binding, gene transcription, and protein translation (Table 6). In the past, NMP was not 
expected to be released from the nucleus of tumor cells in quantities sufficient to be measured 
by conventional immunological techniques. Initially NMPs did not receive much attention 
as tumor markers. It was thought that only through the shedding of cell surface antigens or 
active secretion of cellular products would they be detectable in the extracellular space and 
blood circulation. Because these views have been revised, one would expect to see increas­
ing reports of new NMPs for tumor diagnosis. 
NMPs have been viewed as a potential target for diagnostic tests in cancer patients and for 
anticancer therapies. NMPs have been suggested as biomarkers of neoplastic disease in 
serum, body fluids, and tissue (19). It is interesting to note that many NMPs found in the 
tumor were not detectable in normal tissue (20) NMPs can be released to the blood circula-

Circulating Tumor Markers and Their Clinical Applications 43 
tion upon cell death. NMP was also detectable in urine, and the NMP22 urine assay has been 
used as a screening test for recurrent disease in patients with a history of transitional cell 
carcinoma (TCC) of the bladder. The sensitivity ofthe test was almost 100% in patients with 
invasive TCC. The NMP22 assay may repre sent a useful alternative or adjunct to cystos­
copy and cytology for disease surveillance in patients with TCC (21 ). A new NMP , namely 
BLCA-4, was found to be sensitive (96.4%) and specific (100%) marker for bladder cancer. 
A urine-based immunoassay has been developed and can be used for bladder cancer diagno­
sis (22). A cervical tumor-associated nuclear matrix antigen, NMP179, was found useful for 
early detection of high and low-grade cervical intraepithelial neopla sia. The NMP179 assay 
detected squamous-intraepitheliallesions with high accuracy (96.7%). The assay was 79.3% 
sensitive for the detection of low and high-grade cervical intraepithelial neoplasia (grades 
1-3), with a specificity of70.4 %. NMP179 may be an effective marker for the early detection 
of preneoplastic-squamous intraepithelial lesions of the cervix and may be useful as an 
adjunctive tool for better management of cervical intraepithelial neoplasia (23 ). 
The NMP22 test kit is marketed by Matritech (Newton, Mass). Several new NMPs have 
been developed by Matritech for colon, breast (NMP66), and prostate cancer. Although 
the initial results are promising, further studies are needed to confirm the clinical utilities of 
the NMPs. Recently urinary NMP22 levels were found to be useful in the diagnosis of upper 
urinary tract cancer in patients with a tubeless cutaneous ureterostom y but had no diagnostic 
value in patient s with urinary diversion using a bowel segment (24). 
6. CELL-SPECIFIC MARKERS 
Currently, the most popular monoclonal -defined tumor markers, such as CA 15-3, CA 
125, and CA 199 are used for monitoring of therapy and detection of recurrence of epithelial 
cell-derived carcinomas. However, tumors are heterogeneous in their cell composition. Many 
solid tumors may contain malignant cells other than epithelial cell. In these cases, tumors 
may not be detected if only tumor markers specific for epithelial cell are used. Measuring 
these tumor markers of different cell-specificity is not only important in increasing the 
sensitivity of tumor detection but also provide information leadi ng for the design of 
appropriate therapeutic strategy. 
6.1. sec 
Squamous cell has been found in tumors such as cervical cancer, lung cancer , head and 
neck cancer, and esophageal carcinoma. The tumor marker specifically associated with squa­
mous cell is squamous carcinoma antigen (SCC antigen), which is a subfraction ofT A-4. 
T A-4 was purified from squamous cell carcinoma tissue of the uterine cervix , which is also 
a glycoprotein with a molecular weight of approx 48 kDa. Elevated serum SCC has been 
detected in patients with cervical, lung, head and neck, and esophageal cancer. Howeve r, 
elevated serum sec can also be detected in benign diseases, including pulmonary benign 
diseases, ovarian cystoma, uterin e myoma, endometriosis, hepatitis , and cirrhosis. The fre­
quency and the serum levels of sec in these benign diseases were low (24,25), with few 
cases exceed ing 5 ng/mL. In cervical squamous cell carcinoma (CSCC) SCC appears to 
increase with the advance of clinical stages of the cancer. sec was highest in patients with 
recurrence malignant diseases. A decline of serum SCC was observed in patients responding 
to chemotherapy. SCC complements CEA in the detection of CSCC: a combination of SCC 
and CEA raised the sensitivity for CSCC compared to the single antigen test (26).

44 Wu 
6.2. CgA 
Two cell-specific tumor markers can be found in tumors containing neuroendocrine cells: 
chromogranin A (CgA) and neuron-specific enlonase (NSE). CgA is an acidic glycoprotein 
with a molecular weight of 68 kDa. CgA is present in a variety of polypeptide secret ing 
endocrine cells that possess secretory granules, such as neuroendocrine cells. Although 
serum CgA is a well-known marker for the neuroendocrine cell, it is rarely used. Resulting 
from the lack of commercial assay kits in the United States in the past, serum CgA rarely has 
been measured for the diagnosi s and management of patients with neuroendocrine tumors 
such as neuroblastoma, pheochromocytoma, small cell lung carcinoma, and carcinoid-like 
tumors. CgA has been found to be more stable and thus more easily manageable marker than 
plasma and urinary catecholamines, which were traditionally used , for the diagnosis and 
management of pheochromocytoma (27). 
Neuroendocrine cells, in general, have not been found in nonendocrine carcinomas, nor 
has serum CgA been detected in carcinomas except in those tumor s whose normal counter­
parts contain neuroendocrine cells, such as the prostate tumors (28). However , elevated 
serum CgA can frequently be detected in carcinomas at more advanced stages (27). 
6.3. NSE 
Neuron specific enolase is a glycolytic enzyme normally present in neurons , peripheral 
nerve tissues, and neuroendocrine tissues, especially in the cells of the amine precur sor 
uptake decarboxylation (APUD) system. NSE is a dimer and possesses either aG or -yG two 
monomers with a molecular weight of approx 95 kDa, which are expressed preferentially in 
neurons and neuroendocrin e cells and APUD cells. NSE is found at high levels in tumors of 
neuroendocrine origin such as small cell carcinoma of the lung and neuroblastoma (29). 
Highly elevated serum NSE is also associated with advanced cancer. Repeated measure­
ments of NSE during treatment can help with the evaluation of its effectiveness and the 
prediction of a possible relapse. Most importantly, elevated serum NSE has been found in 
78% of patients with SCLC but only 17% of patients with other solid malignant tumor s (29 ). 
Importantly, moderately increased serum levels of NSE have also been found in a small 
percentage of patients with pneumonia ( 30 ). 
7. ASSOCIATION WITH METASTASIS 
It is recognized that tumor metastasis is associated with an unfa vorab le outcome, and is 
the major cause of death in cancer patients. Because the entire process of metastasis is known, 
markers associated with individual events of metastasis can be identifi ed. These markers are 
then used to identify patients at high risk and predict prognosis ( 31 ). 
The process of metastases can be roughly divided into several major stages (32). In order 
for tumor cells at the primary site to metastasize, the process involves the digestion of the 
basement membrane, expression of specific receptors, expression of adhesion molecules, 
cellular adhesion, and cell migration. The cell components and products associated with 
these processes, such as proteolytic enzymes and their receptors, cell adhesion molecules, 
and various polypeptide growt h factors, are all candidates for markers of metastas is. More­
over, a family of tumor cell-derived motility-inducing cytokines, fibron ectin, collagen ( 33 ), 
and laminin in the extracell ular matrix are also potentially useful markers. When tumor cells 
are ready to spread, there may also be a release of type IV collagen , glycoproteins, and

Circulating Tumor Markers and Their Clinical Applications 45 
proteoglycans from the basement membranes when they are hydrolyzed by proteolytic 
enzymes derived from tumor cells (34). 
7.1. Protease 
Among all markers identified with metastasis, the most clinically useful tumor marker is 
probably the protease. Following transformation by oncogenes, proteases may be found in 
cells that are not present in normal parental cells. For example, a single major extracellular 
matrix metalloprotease was secreted by human bronchial epithelial cells after being trans­
formed by H-ras oncogene (34).These secreted extracellular matrix metalloproteases repre­
sent a group of type IV collagenase, coded by a newly recognized gene family, associated 
with their metastatic potential. In addition, elevated levels of cathepsin D and urokinase­
type plasminogen activator (uP A) found in the tumor tissue of a breast cancer patient was 
related to a higher risk for the development of metastasis and a reduced prospect of overall­
survival. Studies with tumor tissues or tumor cell lines also suggested that tumor invasion 
and metastasis were associated with elevated levels of proteases. 
Four different classes of proteases are known to be correlated with malignancy: 
1. Serine prote ases (e.g., uP A and plasmin). 
2. Cysteinyl proteases (e.g., cathepsin B and L). 
3. Aspartyl proteinases (e.g., cathepsin D). 
4. Metalloproteases (e.g., gelatinases, collagenases, stromelysins). 
The ability of tumor cell derived pro teases to dissolve structures in the immediate vicinity 
of the cell is the first step of metastasis. Degradation of the surrounding extracellular matrix 
is necessary to allow the migration of tumor cells away from their primary site. These pro­
teases assist active tumor cells in the penetration of basement membranes and interstitial 
stroma during the transition from in situ to invasive carcinoma . Proteases may also act 
directly and indirectly in the role of plasminogen activators in tissue degradation in neopla­
sia. The plasmin can activate proenzyme forms of other proteases or may directly degrade 
the extracellular matrix including the basement membrane ( 35) Increasing evidence has sug­
gested that proteases may serve as prognostic factors in solid tumors, especially in breast 
cancer, to predict the outcome ofthe disease. Both uP A and cathepsin D, measured in extracts 
of breast cancer tissues, have a major impact on the prediction of relapse and overall survival 
time for the cancer patient. Wolf et al. ( 36) reported that the stromelysin 3 gene, which 
encodes a putative matrix metalloproteinase, is expressed in all invasive breast carcinomas. 
8. NONSPECIFIC TUMOR MARKERS 
Two criteria, namely specificity and sensitivity, are often employed to evaluate the clini­
cal utility of a tumor marker. Few tumor markers discovered today have a desirable specific­
ity and sensitivity. On the other hand , there are several nonspecific markers that are clinically 
useful for monitoring disease during treatment and for detecting recurrence. Although these 
tumor markers are detectable nonspecifically in a large variety of cancers, their concentra­
tions are nevertheless sensitive to changes of the tumor activity. Many of these nonspecific 
tumor markers are inexpensive and simple to measure , and are therefore useful for monitor­
ing therapy and detecting recurrence for patients with a known diagnosis. For example , Lipid 
associated sialic acid in the plasma (LASA-P) can be quantified with a simple, rapid, and 
inexpensive calorimetric procedure and its serum concentration closely parallels the serum

46 Wu 
concentrations of many tumor markers of higher specificity. Nonspecific tumor markers 
could also be useful in multiple marker formats to improve both the sensitivity and specific­
ity of individual tumor marker assays. 
Serum tissue polypeptide specific antigen (TPS), despite its nonspecificity, has been shown 
to be complementary to CA 15-3 in the management of breast cancer. The addition ofTPS to 
CA 15-3 not only increases the sensitivity of CA 15-3 from 28.6% up to 44.4% in the overall 
population, and from 71.9% to 87.6% in patients with metastases but also increased the 
overall sensitivity by 12.7% during postsurgical follow-up (37). Changes in the TPS level 
showed the strongest association with clinical response after the first course of 
chemotherapy. TPA and TPS were better indicators of disease progression than CA 15-3 in 
breast cancer patients treated with chemotherapy ( 38 ). 
8.1. Proliferation Marker 
Despite its nonspecificity, proliferation markers have been widely used clinically in cancer 
patient management because the deregulated cell proliferation is one of the major factors 
contributing to tumor growth. The overall rate of proliferation may be indirectly related to 
the clinical outcome of many types of tumors. Because the cell cycle is the major mechanism 
controlling cell proliferation, expression of these proliferation markers is usually related to 
various phases of cell cycle progression. There are several proliferation markers that have 
demonstrated clinical utility. 
8.2. Ki-67 
Ki-67 is identified by MIB-1 MAb utilizing immunohistochemistry. MIB-1, recognizes 
proliferating cells in all phases of the cell cycle except G0• Ki-67 works well in formalin­
fixed paraffin-embedded sections with appropriate antigen retrieval. Ki-67 antigen 
expression generally correlates well with mitotic activity. The Ki-67 antigen was expressed 
in S phase cells although not in G1 cells in human mitogen-stimulated peripheral blood lym­
phocytes entering the first cell cycle. The monoclonal antibody (mAb) Ki-67 has been used 
for about 10 yr, mainly to monitor proliferating cells in tissue sections, but to date little is 
known about the proteins it recognizes. The new monoclonal Ki-S3 and Ki-SS antibodies 
detect proliferating cells in frozen and paraffin-embedded tissues. They recognize proteins 
with the same molecular mass as Ki-67 in Western blot. In immunoprecipitation experi­
ments, the measurement of Ki-67 (as MIB-1 proliferation index) has proven useful in 
predicting the clinical outcome of the neuroendocrine tumors of the pancreas. The index also 
appeared useful for determining the prognosis for the survival of an individual ( 39 ). Soluble 
Ki-67 was not detectable in blood circulation. The failure of Ki-67 detection is likely to the 
result of its instability in blood circulation. 
8.3. PCNA 
Proliferating cell nuclear antigen (PCNA) is a 36-kD nuclear protein present in highest 
amounts during the S phase. PClO, a MAb against PCNA, is used to stain PCNA in paraffin­
fixed tissue ( 40 ). 
8.4. CYFRA 21-1 
CYFRA 21-1 is the serum fragments of cytokeratin 19, which has been widely assessed as 
a serum marker of several malignancies. Assay for CYFRA 21-1 is commercially available. 
Cytokeratins are proteins of the intermediate filament family and a main component of the

Circulating Tumor Markers and Their Clinical Applications 47 
cell cytoskeleton. Cytokeraton is composed of different types of filaments with different 
sizes; actin, intermediate filaments, myosine, and microtubules. At present, 20 cytokeratins 
have been described, and all are proteins restricted only to epithelial cells. 
CYFRA 21-1 appears to be a useful marker for non-small cell lung cancer (NSCLC), 
especially the squamous type with a sensitivity of 55%. Increased levels correlate with the 
severity of the disease ( 4 1). In a group of squamous-cell lung cancer patients at different 
stages of disease, measurement of CYFRA 21-1 and SCC have showed significant prognostic 
value for clinical stages. A significant relationship between marker level and survival was 
observed for CYFRA 21-1 as well as SCC levels. In a multivariate analysis, CYFRA 21-1 
and/or TPS remained significant predictors of survival (42). The Combination of 
proliferation markers with other tumor markers appears most effective. Combination of 
CYFRA 21-1 and NMP22 help determine the need for cystoscopy in patients with bladder 
cancer ( 43 ). 
8.5. TKl 
Cytosolic thymidine kinase 1 (TKl) is one of the enzymes involved in DNA replication. 
TKl is activated at late G1 of cell cycle, and its activity correlates with cell proliferation. A 
polyclonal anti-TKI antibody against a synthetic peptide from the C-terminus of human 
TKl is available. TKl is located in the cytoplasm of cells, and is strongly expressed in the 
cells in S+G 2 period, raised at late G1 and decreased during mitosis (44). 
8.6. Mitosin 
Mitosin is a 350 kD nuclear phosphoprotein involved in cell division. It is expressed in 
the late G1, S, G2, and M phases of the cell cycle but is absent in G0• Presently, only the 
immunohistochemical method has been used for its detection in formalin-fixed, paraffin­
embedded tumors. Mitosin has been determined useful in node-negative breast cancer (45). 
8.7. LASA-P 
Sialic acids (N-acetylneuraminic acids) are the acylated derivatives of neuraminic acid 
and are the terminal residues at the nonreducing end of the carbohydrate chains in many 
glycoproteins, glycolipids, and proteoglycans. Sialoglycoproteins on the tumor cell surface 
have a long history of being associated with invasiveness and metastases (46). LASA-P is 
found elevated in a variety of malignant diseases, such as in the breast, or in those dis­
eases associated with the gastrointestinal tract and the lung-leukemia, lymphoma, 
Hodgkin's disease, and melanoma-but also in nonmalignant inflammatory diseases. 
Apparently LASA-P is not specific to any specific type of tumor and is used in conjunction 
with other tumor markers for increased levels of sensitivity and specificity (47,48). This lack 
of tumor specificity substantially limits its use as a tumor marker for diagnosis; however, it 
compares favorably with the most widely used tumor markers for following a patient's 
response to therapy and for the early detection of recurrent disease (49). The sensitivity of 
LASA-P assay for various cancers was reported to range from 77 to 97%. 
9. ECTOPIC TUMOR MARKER 
It is important to note that most ectopic tumor markers are related to metastasis. The term 
"ectopic tumor marker" is used to describe markers that are unexpectedly or ectopically 
produced by certain tumors and that have no apparent association with the parent tissue of 
these tumors. Their appearance may also be related to the genetic control of protein

48 
Table 7 
Some Known Ectopic Tumor Markers 
Ectopic marker 
AFP (> 1000 ng/mL) 
Calcitonin 
Chromogranin A 
ACTH 
Free a-HCG subunit 
f31 subunit of HCG 
A subunit of the 
glycoprotein 
tropic hormones 
Thyroglobulin Ectopic appearance 
GI tumor and gallbladder carcinoma, renal, breast, 
ovarian carcinomas (50) 
Carcinoma of lung, islet cell, carcinoid, breast and 
medullary carcinoma of the lung and ovary , 
pheochromocytoma 
Endocrine tumors ( medullary thyroid Ca. anterior 
pituitary adenoma, pancreatic islet-cell Ca.) 
Pancreatic and oat-cell carcinoma 
Colorectal , pancreatic, and brochogenic carcinoma 
Nontrophblstic cancers (For endocrine tumors 
(medullary thyroid Ca., anterior pituitary 
adenoma, pancreatic islet-cell ca 
Metastatic gastric carcinoid 
Differentiated thyroid carcinoma Wu 
expression; the same theory explains why carcinoembryonic proteins appear in tumors. Both 
carcinoembryonic proteins and ectopic markers have identical features in common; both are 
expressed at fetal tissues, and both expressions are suppressed during normal growth or cell 
differentiation and re-expressed after the transformation of normal cells into tumor cells. 
Similar to carcinoembryonic proteins, ectopic markers are detectable in malignant tumors 
because the malignant tumor contains the same genetic composition as its parent fetal 
tissue. It is the result of de-repression or loss of genetic control in the tumor that accounts for 
the re-appearance of carcinoembryonic proteins and ectopic markers. We believe that the 
appearance of ectopic markers may occur further on in the passage of tumor progression (at 
a later stage, after multiple mutations). In other words, there-expression of the ectopic mark­
ers in the tumor cell requires a greater loss of genetic control, a loss that occurs, for example, 
during advanced malignant disease or metastasis. Because of the close association of ectopic 
tumor markers with metastasis, the detection of ectopic makers would suggest a poor prog­
nosis. 
The elevation of serum concentrations of AFP found in neoplasms, such as colon , ova­
rian, pancreatic, and breast carcinomas, is a typical example of an ectopic marker (Table 7). 
The serum concentration of the ectopic AFP may be highly elevated at the thousandth nano­
gram range. As expected, the fetal cells of these AFP-producing, nonhepatic tumors are also 
capable of producing AFP. Note that in most cases , these nonhepatic tumors do not synthe­
size AFP. Ectopic AFP production usually occurs in rapidly growing and poorly differenti­
ated tumors, such as tumors having regional or distant metastases, although liver function 
tests may be normal. Ectopic markers are frequently found in polypeptide hormones. In fact, 
many of these ectopic hormones in the serum even precede clinical recognition of the tumor. 
Their quantification may also be useful in monitoring responses to therapy. Detection of 
ectopic AFP has been found to be a useful preoperative tumor marker for differentiating

Circulating Tumor Markers and Their Clinical Applications 49 
between the patient with primary gallbladder carcinoma and the patient with gallbladder 
hydrops. Gallbladder carcinoma is rarely diagnosed before surgery, which sometimes 
inhibits operative planning . 
tO. SUMMARY 
All molecules appearing in the blood circulation can be used as tumor markers providing 
their concentrations correlate with certain aspects of tumor activity. The serum or plasma 
concentration of any molecule that correlates with malignant transformation, tumor cell pro­
liferation, tumor size, and metastasis can be used as a tumor marker for cancer management. 
Circulating tumor markers can be divided into various groups based on their differences in 
clinical application. 
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5 
Identification of Risk Factors for Early Neoplasm 
James T. Wu 
1. INFLAMMATION MARKER 
Inflammation, especially chronic inflammation, is a significant factor in the development 
of solid tumor malignancies (2). Several inflammation markers, including interleukin 6 
(IL-6), C-reactive protein (CRP), and amyloid protein, can be detected in the blood circula­
tion and serve as risk factors for early neoplasm . CRP is nonspecific but is the most sensitive 
marker of inflammation. IL-6, IL-l, and tumor necrosis factor alpha induce the synthesis of 
CRP in hepatocytes. Its role as a predictor of survival has been shown in multiple myeloma, 
melanoma, lymphoma, ovarian, renal, pancreatic, and gastrointestinal tumors (3). Chronic 
infection by viruses, bacteria, parasites, chemical irritants, nondigestible particles, or nonin­
fectious sources all may result in chronic inflammation, a major risk factor for cancer. The 
longer inflammation persists, the higher the risk of associated carcinogenesis. It is well 
known that during the phagocytosis of bacteria or virus-infected cells, a powerful mixture of 
oxidants such as nitric oxide (NO), 02 and H202 are released. These oxidants from infection 
may cause oxidative damage to DNA, leading to mutations and eventually carcinogenesis (4). 
In addition to reactive oxygen species, inflammatory cells and cytokines are also found in 
tumors, which mediate the inflammatory pathway (e.g., NF-KB and COX-2) and are likely 
to contribute to tumor growth and progression. They increase cell cycling, cause the loss of 
tumor suppressor function, and stimulate oncogene expression, all of which may lead to 
malignancy. For example , both hereditary and sporadic forms of chronic pancreatitis are 
associated with an increased risk of developing pancreatic cancer. The combined increase in 
genomic damage and cellular proliferation, both of which are seen with inflammation, 
strongly favors the malignant transformation of pancreatic cells (4,5). Ulcerative colitis and 
colonic Crohn' s disease (known collectively as inflammatory bowel disease [IBD]) are both 
associated with increased risk for colorectal cancer (6). The genetic alterations found in 
ulcerative colitis associated colorectal cancer involve many of the same targets found in 
sporadic colorectal tumors and include multiple sites of allelic deletion, microsatellite insta­
bilities, and mutations of APC, p53, k-ras as well as msh2 and other genes. The progression 
of dysplasia to carcinoma is generally accompanied by an accumulation of these mutations 
and the similarities in the biology of colorectal cancer associated with ulcerative colitis and 
sporadic colorectal cancer appear to outweigh their differences (7). 
From: Callcfl· Diag11ostics: C11rre1lf a11d Future Tre11d s 
Edited by: R. M. Na kamura, W. W. Grod y, ). T. Wu, and R. B. Nagle © Hum ana P ress Inc., Totow a, NJ 
53

54 
Table 1 
Associations of Various Known Pathogens With Cancer 
Pathogen 
Helicobacter pylori (bacteria) 
Helicobacter pylori 
Schistosoma haematobium (parasite) 
HTLV -I (virus) 
HTLV-11 
HBV 
HHV-8 
EBV 
EBV 
EBV 
HPV 
HIV Malignancy 
Mucosal-associated lymphoid tissue 
Bladder cancer 
Adult T -cell leukemia/lymphoma 
Hairy cell leukemia 
Hepatoma 
Kaposi's sarcoma 
Lymphoproliferati ve disorders 
Nasopharyngeal carcinoma 
Burkitt's lymphoma 
Anogenital carcinoma, cervical cancer, 
head and neck carcinoma 
Abbr: HIV, human immunodeficiency virus; HTL V, human T -cell leukemia/lymphoma 
virus; HHV, human herpes virus; EBV, Epstein-Bar virus; HBV, hepatitis B virus; HPV, 
human papilloma virus. 
2. BACTERIAL AND VIRUS INFECTION Wu 
There is a well-known link between bacterial or virus infection and cancer risk (Table 1). 
The key determinants of this risk are bacterial and virus infection-induced inflammation. 
This risk, however can be identified by direct detection of bacteria or virus in the blood 
circulation, which may also serve as an early marker for early neoplasm. It has been recently 
recognized that viruses and other pathogens play an important role in the etiology of human 
cancers (8). In other words, the bacterial and virus infections themselves are considered to 
be risk factors for cancer. Table I lists the associations of various know pathogens with 
cancer. 
The most well known link between virus and cancer is the link between human 
papillomavirus (HPV) and cervical cancer. DNA of specific HPV types has been found in 
almost all cervical cancer biopsies (9). Current screening protocols are based on the use of 
Pap smears. In fact, high-risk HPV genotypes are also found to be responsible for other 
anogenital cancers, and squamous-cell carcinoma of the head and neck ( 10 ). The screening 
of high-ri sk HPV can be performed by the detection of viral DNA and cellular proteins (viral 
onocoproteins) by cytological and coloscopic analysis. The identification of specific types of 
HPV as causative agents for cancer of the cervix and its precursor lesions led to the develop­
ment of a new method for cancer screening and early diagnosis. HPV genomes and viral 
oncoproteins should present convenient markers for a transient of persistent infection. The 
detection of high-risk HPV markers should be followed by a careful clinical investigation 
and repeated testing for HPV persistence . Because HPV is the cause of essentially all cervi­
cal cancers, testing for HPV is the most effective scree ning method with inconclusive Pap 
tests (high sensitivity and high negative predictive value) and a negative predictive value 
approaching lOO% for Pap smear plus HPV testing (9).

Identification of Risk Factors for Early Neoplasm 55 
The association of Helicobacter pylori infection with the development of gastric cancer is 
well recognized as well ( 11 ). The key pathophysiologic event in H. pylori infection is the 
initiation and continuance of an inflammatory response. Oxidative and nitrosative stress 
associated with H. pylori-caused inflammation plays an important role in gastric carcino­
genesis as a mediator of carcinogenic compound formation, DNA damage, and cell prolif­
eration ( 12). H. pylori infection is identified by histologic examination , the rapid urease test, 
and serologic evaluation. Stool cultures for H. pylori or a direct detection of H. pylori anti­
gen in stools by PCR are expensive, tedious, and exhibit low sensitivity. A more sensitive 
enzyme immunoassay (EIA) has been developed to detect H. pylori antigen ( 13 ). 
Cancer remains a significant burden for human immunodeficiency virus-infected indi­
viduals. The discovery of a high incidence of Kaposi's sarcoma in patients with acquired 
immune deficiency syndrome (AIDS) is now believed to be caused by Kaposi's-sarcoma­
associated herpesvirus/human herpesvirus 8. AIDS-lymphoma is known to be associated 
with Epstein-Barr virus (EBV) and/or KSHV infection. AIDS-related malignancies also 
include HPV-related cancer. The FDA considers human papillomavirus (HPV) to be a pri­
mary screening tool for cervical cancer (14). 
It has been reported that hepatocellular carcinoma (HCC) , a major type of primary liver 
cancer, is etiologically linked to viral factors such as chronic infections with the hepatitis B 
virus (HBV). In addition, about 5% of HCC patients have the hepatitis C virus (HCV) infec­
tion (15). Recently, associations between infection with HPV-16 and 18, anal and perianal 
skin cancer (16), as well as between EBV and oral squamous cell carcinoma (OSCC) have 
been reported ( 17). 
In addition to the detection of viral or bacterial genomes by PCR, the detection of 
antipathogen antibodies in the blood by serologic tests such as enzyme -linked 
immunosorbent assay (ELISA) has also been proposed. The presence of these antibodies in 
the blood indicates an infection eradicated long before the cancer began to evolve. The stag­
ing of the disease, as well as follow up of therapy can be monitored by differentially deter­
mining the concentrations of IgM and IgG antibodies. 
3.80HDG 
DNA lesions caused by oxidative stress appear to be early risk factors for cancer. Oxida­
tive stress is a potential mutagen leading to the accumulation of frameshift mutations and 
may contribute to microsatellite instability in human DNA in the setting of chronic inflam­
mation ( 18). Oxidants generated during normal metabolism can react with DNA and cause 
damage. The body continuously repairs its own DNA, but any oxidative lesion that is not 
repaired can lead to mutations, increasing the risk of cancer ( 19). Human 8-0xoguanine­
DNA-glycosylase (h0GG1) is a major enzyme for repair of 8-0H-G lesion in human cells 
and 8-hydroxyguanine (8-0H-G), the most abundant product of oxidative damage, is the site 
of frequent muta genic lesion s of DNA produced by oxidative damage. As a result, 8-hy­
droxy deoxyguanine (8-0HdG) became a biomarker of generalized , cellular oxidative stress. 
The measurement of 8-0HdG in the urine appears to be an indicator of generalized, cellular 
oxidative stress. Musarrat et al., (20) also found a statistically significant 9.76 -fold higher 
level of 8-0HdG in malignant breast tissue with invasive ductal carcinoma compared with 
normal breast tissue. They believ ed that the accumulation of 8-0HdG in DNA has a predic­
tive significance for breast cancer risk assessment and is conceivably a major contributor in 
the development of breast neoplasia.

56 Wu 
4. HOMOCYSTEINE 
It was found recently that homocysteine, a well-known risk factor for cardiovascular dis­
eases, is also a risk factor for malignant diseases (21,22). Elevated serum or plasma 
homocysteine can be found in most cancer patients. Several biochemical changes, including 
folate deficiency, oxidative stress, aberrant DNA methylation, and production of homocys­
teine thiolactone have been identified in association with hyperhomocysteinemia. All of the 
events mentioned above may lead to carcinogensis and eventually cancer. Conceivably 
plasma or serum homocysteine can be treated as a risk factor for early neoplasm. 
As suggested by Ziegler et al. (23 ), circulating homocysteine may be an especially accu­
rate indicator of inadequate folate, an integratory measurement of insufficient folate in tis­
sues, or a biomarker of disruption of one carbon metabolism. Higher levels of plasma 
homocysteine were also detected in head and neck squamous cell carcinoma (24). There was 
also a report concerning the association of methylenetetrahydrofolate reductase polymor­
phism C677T and dietary folate; both have an impact on homocystene level, with the risk of 
cervical dysplasia. A polymorphic variant (TT) has been linked to reduced levels of plasma 
folate, aberrant DNA methylation in leucocytes, and increased risk of colorectal cancer 
(CRC) under conditions of low folate intake. Serum homocysteine has been strongly and 
significantly predictive of invasive cervical cancer risk (25) . As a result, maintaining 
adequate folate and pyridoxine status and lower levels of homocysteine will reduce the risk 
of pancreatic cancer. 
5. PSA, CA 125, CA 19-9, AND CEA 
The use of serum tumor markers for the early detection of cancer is not suggested because 
of their low sensitivity and low positive predictive value. It has been the experience of inves­
tigators that most circulating tumor markers currently being used are elevated only when 
tumors begin to metastasize. However, when a panel of three serum tumor markers was 
used, such as OVX1, CA-125 -II, and macrophage-colony stimulating factor (M-CSF) the 
sensitivity was significantly greater than that of the CA-125-ll assay alone in patients with 
primary ovarian epithelial tumors of different histotypes including early -stage , potentially 
curable diseases (26). When a single marker, CA-125-11, was used, it could only distinguish 
invasive Stage I tumors from apparently healthy women. 
Multiple serum markers have been analyzed in women with early stage epithelial, 
interleukin -6 (IL-6), IL-10, lipid -associated sialic acid (LSA), M-CSF , OVX1 , T AG72 (CA 
72-4), tumor necrosis factor (TNF), and tissue polypeptide antigen (TPA). The serial mea­
surement of complementary serum markers can improve the use of marker screening for 
epithelial ovarian cancer. This approach improves the sensitivity , specificity , and positive 
predictive value of serum markers CA 125 and OVX 1. A procedure that measures comple­
mentary serum markers over time can be used as a primary screenin g technique followed by 
transvaginal ultrasonography. This procedur e can provide a cost-effective means of early 
detection and can significantly decrease the probability of surgical intervention for false­
positive test results (27). 
In Taiwan, a study screened a total of 41,495 asymptomatic individuals for cancer by 
measuring multiple tumor markers (28). The purpose of the screening was to find cancer 
among asymptomatic individuals. Included in the panel of tumor markers for screening were 
a-fetoprotein (AFP), CA 125, CA 15-3, CA 19-9, CEA, and prostate -specific antigen (PSA).

Identification of Risk Factors for Early Neoplasm 57 
We detected elevated tumor markers in 3070 of asymptomatic individuals. However, only 
384 of the 3070 individuals with elevated levels of tumor markers returned for a more detail 
examination by oncologists. Among these 384 individuals, 131 of them (34.1%) were found 
to have a tumor. The good news was that some of the tumors detected were discovered at the 
benign stage. In particular, for individuals having elevated CA 125, 16 had benign ovarian 
tumors and only five individuals were found to have malignant ovarian cancer (9% ). Appar­
ently, the sensitivity of tumor detection was increased when multiple tumor marker s were 
monitored. Many tumors would have gone undetected had we not measured multiple tumor 
markers. Therefore, we believe that screening with multiple tumor markers not only helps 
detect tumors but also may detect tumors at an early stage. 
6.COX2 
Cyclooxygenase (COX) enzymes catalyze the first step in the conversion of arachidonic 
acid to prostaglandins. There are two isoforms, COX-1 and COX-2; both are glycoproteins 
and sit on the nuclear membrane. Both COX isoforms are normally absent in most cells but 
can be transiently up-regulated in response to growth factors and cytokines. Recently it was 
found that COX-2 appears to play an emerging role in inflammation and carcinogenesis. 
Overexpression of COX-2 inhibits apoptosis, which could predispose to cancer (29 ). 
Moreover, prostaglandins are believed to be important in the promotional phase of 
tumorigensis. As a key regulator y enzyme in the synthesis of prostaglandins, COX-2 con­
ceivably plays an importa nt role in the early development of tumori genesis and may serve as 
an early tumor marker. 
Although the COX-2 reactivity was higher in transit ional and adenocarcinomas as well as 
in squamous cell carcinoma , COX-2 reactivity can also be detected in the nonmalignant 
urothelium, mainly in areas of regenerative atypical, dysplasia or squamous metaplasia ( 30 ). 
COX-2 mRNA is highly elevated in most human colorectal cancers but is also found in a 
subset of adenomas. Non-neoplastic mucosa adjacent to the colon tumor also expresses 
COX-2 (31). COX-2 can be found expressed in polyps 2 mm and larger , suggesting an 
early role for the enzyme in the development of the polyp. Expression of COX-2 may occur 
earlier than K-ras following the mutation of the tumor suppressor adenomatouys polyposis 
coli (APC) in the development of familial adenomatous polyposis and the majority of spo­
radic colorectal cancers. 
COX-2, also a marker of inflammation and can be induced by H. pylori infection through 
the activation of nuclear factor-KB (NF-KB) . NF-KB is an oxidant-sensitive transcripti on 
regulator. In gastric cancer cells, expression of mRNA and protein for COX-2 was inhibited 
by antioxidants glutathione (GSH), N-acetylcysteine (NAC), and NF-KB inhibitor , 
pyrrolidine dithiocarbamate (PDTC) ( 32). 
7. TGF-a AND TGF-al 
Cytokines, growt h factors, and hormones are the primary driving force for most biologi­
cal reactions. The elevation of cytokines is likely an early event in tumorigensis ( 33 ). The 
measurement of cytokines such as TGF-a and TGF-al can be potentially useful for the 
early detection of tumors. TGF-a/EGFR autocrine signaling plays an important role in squa­
mous cell carcinoma of the head and neck (SCCHN), and upregulation of TGF-a and EGFR 
have been suggested to be an early event in SCCHN carcinogenesis ( 34 ). Expression of

58 Wu 
Table 2 
Circulating Oncoproteins That Could be Used as Early Markers 
Cancer Corresponding Genes 
Colorectal APC, ras, DCC 
Stomach tpr-met, ras 
Breast ras, c-erbB-2 
Endometrial ras 
Pancreatic cancer in melanoma-prone families pl6 1NK4 
Adapted from ref. 69. 
TGF-a1 levels was found higher in low grade and early stage of bladder transitional cell 
carcinoma than in high grade and advanced stage tumors. It is suggested that TGF-a 1 
expression might be specific to early stage human bladder cancer ( 35 ). 
8. C-ERBB-2, RAS (P21), AND IGF-1 
The linear path from cytokine and growth factor to membrane receptor and eventually 
DNA replication is the most important cascade in growth regulation. A large number of 
extracellular signals are transmitted through signaling transduction pathways via G proteins 
(RAS protein), leading to diverse biological consequences (Table 2). G protein behaves as a 
sorting point, capable of interacting with different effectors and connects to distinct signal­
ing pathways (33). Consequently, receptors such as c-erbB-2 and RAS protein are crucial 
regulators of cell growth in eukaryotic cells. There are several ras genes, including k-ras, 
H-ras and N-ras. The ras genes give rise to a family of related proteins with a molecular 
weight of 21 kDa (hence p21) that have strong transforming potential. The ras gene family is 
one of the most commonly mutated genes in both solid tumors and hematological neoplasm. 
Among them, the k-ras gene is most prone to mutation ( 33 ). 
8.1. C-erbB-2 
C-erhB-2 gene alterations have been detected in mammary tumors as early as stage 1 or 11 
and in ductal carcinomas in situ ( 36 ), suggesting that overexpression of c-erbB-2 oncoprotein 
(pl85) and the appearance of the serum ectodomain of the c-erbB-2 oncoprotein may also be 
an early event in carcinogenesis. Expression of p 185 has been found to be significantly 
higher in preneoplastic lesions (95.8% of cases) than in colorectal cancer; therefore, it was 
also suggested that pl85 overexpression might be associated with the early stages of 
colorectal cancer. 
8.2. Ras Protein 
As we know now, one of the best characterized tumor-related genes is k-ras, which 
somatically mutates in several types of sporadic human cancers. Because mutations of this 
gene occur exclusively in three hot spots (codons 12, 13, and 61), and are frequently detected 
and well characterized in colorectal, pancreas, and lung cancers, molecular diagnosis and 
susceptibility (risk) assessment targeting k-ras mutations are being developed. Clinical 
samples used for molecular diagnosis and risk assessment include stool and lavage fluid, 
pancreatic and duodenal juices for colorectal cancers, and pancreas and sputum for lung

Identification of Risk Factors for Early Neoplasm 59 
cancers. Molecular analysis has begun to show promise in assessing susceptibility to, or risk 
of developing sporadic cancers ( 37). 
Several studies have suggested that the activation of p21 could also be an early event of 
carcinogenesis. The early mutation of ras gene and early expression of p21 have been 
observed in mucinous ovarian tumors, gastric carcinomas and in endometrial carcinomas 
(38-40). 
8.3. IGF-1 
The insulin-like growth factors (IGFs) are a ubiquitous family of growth factors involved 
in normal cell growth and development. They are also implicated in numerous pathological 
states, including malignancy. IGF-I receptor (IGF-IR), a cell-surface tyrosine kinase recep­
tor with a 70% homology to the insulin receptor, may be overexpressed owing to mutations 
in tumor suppression gene products (such as p53) and WT-1 or growth factors (such as 
bFGF and PDGF). This family of growth factors, especially the IGF-1, may present an excel­
lent target for new therapeutic agents in the treatment of cancer and other disorders of exces­
sive cellular proliferation ( 41). Stattin et al. ( 42) in their study of prostate cancer found a 
strong association between the increase of prostate cancer and men with elevated plasma 
IGF-1. This association was particularly strong in younger men, suggesting that circulating 
IGF-I may be specifically involved in the early pathogenesis of prostate cancer. 
Measurement of serum levels of IGF-1 and the calculation of IGF-1/PSA ratios were also 
found by Djavan et al. ( 43) to significantly improve the detection of prostate cancer over the 
use of PSA alone . They suggested that the increase in IGF-1 levels (i.e., the IGF-1/PSA 
ratio) not only was associated with an increased risk of prostate cancer but might also be a 
useful tool for its early detection. 
9. P53 AND P53 AB 
9.1. p53 Mutant Protein 
p53 is a suppressor gene. Wild type p53 protein suppresses cell growth and plays a crucial 
role in maintaining genomic stability in both normal and tumor cells. A mutation of the p53 
gene and the appearance of mutated p53 proteins seem to play an important role in early 
tumorigenesis. Several reports have indicated that p53 protein can be used as an early marker. 
CagA( +) H. pylori infection, for example, is associated with an early, higher prevalence of 
p53 mutations in gastric adenocarcinoma (44). The p53 protein has been detected in esoph ­
ageal precancerous lesions. Wang et al. (45) suggested that accumulation of p53 protein 
might be an early biomarker for identifying high-risk subjects for esophageal cancer. The 
p53 protein was found in patients with early stage laryngeal carcinoma by Narayana et al. 
(46) and in patients with early gastric cancer (47). 
In colorectal tumors, the mutation of the p53 suppressor gene appears earlier in the 
adenoma-carcinoma sequence than the k-ras mutation. The p53 gene seems to play a more 
important role than the k-ras mutation in the early stages of colorectal tumorigenesis (48). 
The detection of p53 gene alterations is also possible in sputum samples by PCR-SSCP­
silver stain for early diagnosis of lung cancer (49). Additionally, overexpression of the p53 
mutant protein was found in early stage diseases of squamous cell carcinoma of the cervix 
and in HPV 16118 positive tumors (50). Detection of micrometastasis ofthe regional lymph 
nodes of ovarian cancer by immunohistochemical staining of p53 protein is also possible in 
predicting the prognosis of patients with stage I or II epithelial ovarian cancer (51) .

60 Wu 
9.2. p53Ab 
Mutated p53 protein induced anti-p53 antibodies (p53 Ab) in sera of patients with various 
types of malignant neoplastic disease. Measureming (p53 Ab) in blood circulation appears 
to be another marker of potential use for early cancer detection. The finding of antibody 
against p53 in the sera of individuals who are at high risk of cancer, such as asbestos exposed 
workers or heavy smokers, indicates that measuring antibody against p53 has promising 
potential in the early detection of cancer (52). Similar findings have also been reported for 
esophageal cancer (53). The detection of serum p53 Ab is also useful in the early diagnosis 
of superficial colorectal cancer (54). 
9.3. VEGF 
Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific mitogen; a 
potent angiogenic factor specific for vascular endothelial cells. Detection of VEGF in serum 
is usually related to tumor metastasis, in which new blood vessels are formed to obtain 
nutrients for tumor growth. However, Giatromanolaki et al. (55) found that VEGF could be 
an early marker that may appear at the early-stage of NSCL cancer (including squamous cell 
carcinomas and adenocarcinomas). They found that the expression ofVEGF occurred before 
the appearance of other markers, such as p53, bcl-2, epidermal growth factor receptor, and 
c-erbB-2 oncoprotein in NSCL cancer. It was suggested by Kuroi et al. (56) that VEGF 
could be used to determine the risk of carcinogenesis, screen for early cancer, distinguish 
benign from malignant disease, and distinguish between different types of malignancies. 
VEGF expression may stimulate tumor cell proliferation in the early stages of cervical can­
cer, and may be responsible for cervical tumorigenesis (57). 
10. CELL-FREE DNA 
"Cell-free DNA" or circulating plasma DNA is not a marker by itself. However, it carries 
identical mutations as the DNA from the tumor of the same patient. In other words, cell­
free DNA is the perfect specimen to be used for early detection of tumorigenesis. It is impor­
tant that the procedure for obtaining cell-free DNA is noninvasive. The sampling of plasma 
or serum can be performed in asymptomatic individuals and can be performed as frequently 
as required. The detection of microsatelite instability , DNA hypermethylation, and k-ras 
mutations has been performed successfully with cell-free DNA obtained from cancer 
patients. The study of plasma DNA with the detection of genetic abnormalities associated 
with specific cancers has produced promising results. Taback et al. (58) have discovered the 
presence of circulating microsatellite alterations in the serum from patients with early stage 
breast cancer. 
Blood tests for circulating tumor genetic markers are likely to provide valuable prognos­
tic information. Assays of genetic alterations in circulating plasma DNA may be developed 
as a useful addition to conventional techniques for the diagnosis of lung cancer (59). 
Circulating tumor DNA appears to shed early on in the disease process. Consequently, the 
detection of genetic alteration in cell-free DNA holds significant promise for early detection 
of breast cancer (60). The possibility that cell-free plasma or serum DNA may become a 
useful diagnostic tool for early and potentially curable cancers has also been suggested by 
Chen and colleagues (61 ). The possibility of early diagnosis was also proposed by Nunes et al. 
(62) for head and neck squamous cell carcinomas. It is important to note that the detection of

Identification of Risk Factors for Early Neoplasm 61 
specific losses of heterozygosity (LOH), microsatellite instability (MT), and promoter hyper­
methylation was made possible using circulating, cell-free DNA in breast cancer patients 
with small or even in situ lesions. Genetic alterations were found in plasma or serum DNA 
from patients with various cancers. Early tumor detection by noninvasive screening proce­
dures appears feasible by measuring microsatellite instability (allele shifts) and loss of het­
erozygosity in plasma DNA (63). Detection of p53 mutations in plasma DNA have been 
reported as a likely prognostic factor and an early marker to indicate recurrence or distant 
metastasis (64). 
11. DNA AND PROTEIN ARRAY (ANTIBODY ARRAY) 
As discussed above, the advantages of measuring multiple tumor markers for improving 
both the sensitivity and specificity for early risk detection of cancer are apparent. Through 
the development of high-throughput technology, such as genomics and proteomics in recent 
years, the simultaneous measurement of multiple genes and proteins in a single sample is 
now possible. The new technology will certainly aid in the screening of high-risk individu­
als. In particular, the protein array (or antibody array), a branch ofproteomics , is useful for 
the measurement of several known markers at the same time . 
Using a high-throughput proteomic classification system , Adam et al. (65) provided an 
accurate and innovative approach for the early detection/diagnosis of prostate cancer. A 
protein biochip surface enhanced laser desorption/ionization mass spectrometry approach 
coupled with an artificial intelligence learning algorithm was used to generate protein profil­
ing with proteomic patterns that differentiate prostate cancer from noncancer cohorts. Feroze­
Merzoug et al. (66) also has measured the gene expression patterns (both mRNA and protein 
expression profiling) to differentiate between normal prostate and prostate tumor, and 
between tumors at different stages. 
Petricoin et al. (67) detected proteomic patterns in serum to distinguish neoplastic from 
nonneoplastic diseases within the ovary and for the detection of early-stage ovarian cancer. 
They generated proteomic spectra by mass spectroscopy (surface-enhanced laser desorption 
and ionisation that completely discriminated cancer from noncancer). Their result yielded a 
sensitivity of 100%, specificity of 95%, and positive predictive value of 94%. This proves 
that it is possible to use a prospective population-based assessment of proteomic pattern 
technology in serum as a screening tool for all stages of ovarian cancer in high-risk and 
general populations. 
Cancer is a complex genetic disease. It is generally believed that the accumulation of 
multiple gene mutations leads to the development of cancer ( 1 ). In addition to inherited 
mutations, additional mutations have to be acquired for the development of a cancer. At 
early stages of tumorigenesis, there may be only a few mutations present. The detection of 
phenotypes corresponding to these early mutations in the circulation makes the detection of 
early neoplasm possible at a curable stage. Recently it was found that several risk factors 
might also lead to tumorigensis, which can be eliminated with diet adjustment and life style 
changes. Most of these risk factors related to inflammation and oxidative stress may also be 
detected in the blood circulation or urine. The measurement of all of these mutant pheno­
types and risk factors in the circulation may help to identify individuals at risk for cancer , or

62 Wu 
to detect early tumors at benign stage. In this chapter, we identify risk markers and 
biomarkers during the preclinical stage in order to offer opportunities for early intervention. 
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Identification of Risk Factors for Early Neoplasm 63 
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2489-2495 . 
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IGF-1/PSA ratio for prostate cancer detection. Urology 54:603-606. 
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and p53 gene mutations in gastric adenocarcinoma. Carcinogenesis 23:419-424. 
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esophageal precancerous lesions: a possible early biomarker for carcinogenesis. Cancer Res. 
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47. Narayana A, Vaughan ATM, Gunaratne A. 1998. Is p53 an independent prognostic factor in 
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early gastric cancer. Cancer 75:1454 -1459. 
49. Hosaka S, Aoki Y, Akamatsu T, Nakamura N, Hosaka N, Kiyosawa K. 2002. Detection of genetic 
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Chern. 41:1410-1413.

6 
Emerging Circulating Tumor Markers 
James T. Wu 
Current tumor markers are limited in their clinical utilities. They are only useful for moni­
toring cancer patients during treatment and for detecting recurrence. Because of the lack of 
specificity and sensitivity, currently used tumor markers are not recommended for screening 
or diagnosis. Therefore, new tumor markers are being sought to improve the sensitivity for 
cancer detection and to improve the specificity for diagnosis. In this chapter we introduce 
several new tumor markers to complement currently used tumor markers. These new tumor 
markers may provide specificity and improved sensitivity for cancer management. Recently 
the importance of using tumor markers for target therapy, prognosis , and early detection has 
been emphasized ( 1 ). Therefore, there is a need to discover new circulating tumor markers 
for use in these areas. Introduced in this chapter are several new tumor markers that appear 
to have improved clinical utilities. In addition, a new group of circulating tumor markers are 
also described in this chapter relating to the signal transduction pathway, cell cycle, 
apoptosis, angiogenesis, and adhesion. This addition is largely owing to the recent change of 
emphasis on tumor markers . Instead of stressing diagnosis, monitoring and early detection 
of recurrence, the emphasis is placed at early tumor detection , prognosis, and target therapy. 
Note that these new tumor markers are also detectable in blood circulation. Because their 
appearance in the circulation are associated with various stages of growth regulation of cells, 
their detection could be correlated with prognosis and to be detectable in early neoplasm, 
and to be identifiable as target for target therapy . As will be shown below, these new mark­
ers involve not only oncoproteins and mutated suppressor proteins but also enzymes and 
various factors. Although not yet fully verified, these new tumor markers described here 
should greatly improve the use of circulating tumor markers in cancer management. 
2. CELL-SPECIFIC TUMOR MARKERS 
Tumors are heterogeneous in their composition of cells. Carcinomas, although made of 
malignant cell mainly derived from epithelial cell, also contain other cells in the tumor. Both 
neuroendocrine and squamous cell have been found in carcinomas (2,3 ), which may also 
proliferate and progress to malignancy. Both neuroendocrine and squamous cells can be 
detected with the measurement of specific tumor markers including squamous cell carci­
noma-as sociated antig en (SCC antigen), chromogranin A (CgA), and neuron-sp ecific eno­
lase (NSE). Their detection is also important for the designing of proper therapeutic strategy. 
From : Cance r Diagno stics: Current an d Future Trmd s 
Edited by: R. M. Nakamura, W. W. G rody, ). T. Wu, and R. B. N agle© Human a Press Inc., Totowa , NJ 
65

66 Wu 
2.1. SCC Antigen 
Elevated serum SCC antigen has been detected in tumors containing squamous cell, which 
include cervical cancer, lung cancer, head and neck cancer, and esophageal carcinoma. SCC 
antigen, a subfraction ofT A-4 purified from squamous cell carcinoma tissue of the uterine 
cervix, is also a glycoprotein with a molecular weight of approx 48 kDa. Although elevated 
serum sec can also be found in benign disease including pulmonary benign diseases, ova­
rian cystoma, uterine myoma, endometriosis, hepatitis, and cirrhosis, the frequency and the 
serum levels of SCC in these benign diseases, however, were low (4). Few of these benign 
diseases containing sec exceeded 5 ng/mL. sec appears to increase with the advance of 
clinical stage. SCC antigen is highest in patients with recurrent malignant diseases. Decline 
of serum sec was observed in patients who respond to chemotherapy. 
2.2. CgA and NSE 
Both CgA and NSE are markers for neuroendocrine cells. They are useful for the diagno­
sis and management of patients with carcinoid-like tumors and neuroendocrine tumors such 
as neuroblastoma, pheochromocytoma, and small cell lung carcinoma (5). 
Chromogranin A (CgA) is an acidic glycoprotein with a molecular weight of 68 kDa. 
CgA is present in a variety of polypeptide-secreting endocrine cells that possess secretory 
granules, such as in neuroendocrine cells. CgA is a more stable and thus more easily man­
ageable marker than plasma and urinary catecholamines traditionally used for the diagnosis 
and management of pheochromocytoma (6). 
Neuroendocrine cells, in general, have not been found in nonendocrine carcinomas. Serum 
CgA has not been detected in carcinomas except in those tumors whose normal counterparts 
contain neuroendocrine cells, such as the prostate (7). However, elevated serum CgA can 
frequently be detected in carcinomas at more advanced stage (6). Recently, it was found that 
in patients with prostate cancer undergoing hormonal serum, CgA may rise several months 
earlier than PSA when patients developed resistance (8). Neuron-specific enolase (NSE) is a 
glycolytic enzyme normally present in neurons, peripheral nerve tissues, and neuroendo­
crine tissues, especially in the cells of the amine precursor uptake decarboxylation (APUD) 
system. The dimers of aG and yG, two monomers with a molecular weight of approx 
95 kDa, are expressed preferentially in neurons and neuroendocrine cells and APUD cells. 
NSE is a useful marker for small cell lung cancer (SCLC) (9) and elevated levels have been 
found in 78% of patients with SCLC but only 17% of patients with other solid malignant 
tumors (9). As a marker of neuroendocrine cell, NSE appears to be less sensitive in many 
neuroendocrine tumors than that of CgA. 
3. HOMOCYSTEINE 
Homocysteine (Hey) is a sulfur-containing amino acid detected in blood circulation. Cur­
rent procedures employed for the measurement of plasma homocysteine measure the total 
concentration of homocysteine (tHey), which includes albumin bound, mixed disulfide link­
ages, and the free reduced form of homocysteine. 
tHey is a well-known risk factor for cardiovascular diseases but has been found recently 
as a risk factor for cancer ( 10,11) and can be used as a tumor marker monitoring treatment of 
cancer patients. It was found that the rapid proliferation rate of tumor cells would cause an 
elevation of circulating concentration of tHey. Therefore , in blood circulation, the level of

Emerging Circulating Tumor Markers 67 
tHey will reflect tumor activity. Current assays available for tHey measurement are too 
expensive for use as a monitoring tool. However, new less expensive enzymatic methods 
will soon be available allowing the use of serum or plasma tHey to monitor cancer patients 
during treatment. It should be noted that the level of serum or plasma tHey change s with the 
type of drugs that affect folate status. Wu and colleagues (II) and Geisler et al. ( I2) have 
found that circulating tHey could fluctuate in cancer patients during chemotherapy. Geisler 
suggested the use of circulating tHey as a responsive indicator of leucovorin (LV) pharma­
codynamics. It is important to know that measurement of tHey has advantages over cur­
rently used monoclonal defined tumor markers such as CA 15-3, CA 125, and CA 19-9. 
Using cell tissue culture, we have found that the concentration of tHey reflected cell death 
but not these monoclonal-defined tumor markers. The concentration of monoclonal anti­
body-defined tumor markers continued to rise even when cells started dying , but the level of 
serum tHey declined responding to the death of tumor cells ( 10). 
4. CELL-FREE DNA 
There are two types of DNA present in the circulating blood; blood lymphocyte DNA and 
so-called cell-free circulating DNA. Cell-free DNA can be detected in either plasma or 
serum. The greatest advantage of cell-free circulating DNA is its easy sampling . Sampling 
cell-free DNA is a non-invasive procedure, and it can be performed frequently. Unlike DNA 
from tissue biopsies, cell-free DNA allows use for screening and monitoring. Cell-free cir­
culating DNA has the potential of replacing invasive and laborious tissue biopsy for detect­
ing DNA mutations. 
Cell-free DNA is elevated in cancer patients ( I3 ). The clinical utility of quantifying cell­
free DNA has not been established although elevated plasma cell-free DNA from cancer 
patients exhibited all the characteristics of the tumor DNA in the same cancer patient such as 
microsatellite instability, hypermethylation, and the presence of specific oncogene , tumor 
suppressor gene (I 4 ). 
Castells et al. (15) have concluded that analyzing k-ras in cell-free plasma DNA is a 
highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implica­
tions in patients with pancreatic carcinoma. Detection of k-ras mutation in circulating plasma 
DNA has also been reported by de Kok et al. ( I6) to assess tumor burden in patients with 
neoplastic disease and as a tumor marker in consecutive testing after surgery or chemo­
therapy for detecting recurrence. The fact that small tumors of grade 1 or in situ carcinomas 
of breast could present DNA alterations in the plasma/serum at an early stage by Chen eta!. 
(17) suggest that cell-free plasma or serum DNA may become a useful diagnostic tool for 
early and potentially curable cancer. The possibility for early diagnosis of head and neck 
squamous cell carcinomas was also supported by Nunes eta!. ( I8). Assaying genetic alter­
ations in circulating cell-free plasma DNA was also believed to be a useful addition to con­
ventional markers for the diagno sis of lung cancer , because there is no satisfactory tumor 
marker for cancer of lung. 
Conceivably one should be able to sample cell-free DNA in an asymptomatic popul ation 
to measure early mutations to detect early neoplasm. One can also meas ure mutations in 
cell-free DNA to predict progno sis and to identify target for target therapy. Detecting residual 
tumor should also be possible with cell-free DNA to determine the success of therapy 
including surgery. In addition, coupled with specific PCR, detection of tumor-specific muta-

68 Wu 
tions in cell-free DNA can be treated as having a new tumor marker of high specificity 
for tumor. It is believed that a combined measurement of the cell-free DNA with currently 
used tumor markers will improve the sensitivity and specificity for cancer management. 
5. INFLAMMATION MARKER 
Inflammation plays a major part in tumorigenesis ( 19,20). Among many markers for 
inflammation, C-reactive protein (CRP) is the most sensitive and can be frequently detected 
in the blood circulation of various cancer patients (21,22). Fluctuation of serum CRP can 
also be found in serial specimens from cancer patients undergoing treatment. It appears that 
a combination of CRP with currently used tumor markers will improve the sensitivity of 
tumor detection . 
5.1. CRP 
CRP is an acute phase globulin with a molecular weight of approx 105 kD. In tumor, CRP 
is synthesized only by hepatocytes upon stimulation by interleukins from activated mono­
cytes and macrophages at the inflammation site. CRP is the most dynamic and easily mea­
sured among acute phase reactants. Appearance of elevated cytokines, and acute phase 
proteins such as CRP in circulation has been observed in many cancer patients (22-24). In 
colon cancer, a preoperative serum CRP was found to be an indicator of the malignant 
potential of the tumor as well as a predictor of the prognosis (24 ). Serum level of CRP also 
appears to have prognostic value and is useful to help make treatment decision . One study 
found that patients with elevated pretreatment serum CRP would benefit from cytoreductive 
surgery, and those in whom serum CRP decreased to within normal limits would expect 
longer survival when surgery is combined with postoperative immunotherapy (21 ). 
Cancers of the liver, nasopharyngeal, and gastric carcinomas, commonly prevailing in 
Asia countries, were found to be associated with high percentages of elevated serum CRP. 
The percent of elevation of serum CRP in leukemia and lymphoma was comparable to that 
found in carcinomas. In breast cancer, a 70% elevation was found with elevated serum CRP, 
a 97.5% elevation was found in liver cancer, 88.5 % in nasopharygeal carcinoma, 90.3% in 
gastric carcinoma, 58.1 % in colon carcinoma, 82.6 % in lymphoma, and 73.5 % in leukemia 
(Wu JT, et al., unpublished data). Individuals with elevated serum CRP should be treated to 
reduce inflammation to avoid risk for cancer. 
5.2. COX-2 
Cyclooxygenase-2 (COX -2) is one of two COX enzymes catal yzing the first step in the 
conversion of arachidonic acid to prostaglandin. A detailed description of COX -2 can be 
found in Chapter 14. COX-2 is a marker of inflammation and could be a new tumor marker 
for early detection of tumorigensis . 
6. PROTEINASES AND THEIR INHIBITOR 
6.1. MMP-2 and 9 
Matrix metalloproteinas es (MMPs) are zinc-dependent endopeptidases implicated in can­
cer invasion and metastasis. MMPs are capable of degr ading most components of the extra­
cellular matrix such as collagen s, elastins, laminin s, fibronectins , and the protein core of 
prodeoglycans. MMP activity is a hallmark of tumor metastasis. Because the degradation 
and penetration of extracellular matrices, particularly basement membranes, are critical for

Emerging Circulating Tumor Markers 69 
cancer cell metastasis, MMP-2 and MMP-9 are unique in their ability to cleave the helical 
domains of type IV collagen (type IV collagenases), a principle structural component of the 
basement membrane. Consequently, these enzymes have been implicated in tumor cell inva­
sion and metastasis, as well as angiogenesis and other normal cellular scenarios involving 
basement membrane remodeling . 
Elevated MMP-2 and MMP-9 have been found in many human cancers such as breast, 
colon, prostate, and ovarian and have been associated with increased metastatic potential. 
They may be secreted by tumor cell themselves or secreted by host cells within the tumor 
stroma (25). 
6.2. TIMP 
Because MMPs are all produced as latent proenzymes from tumor cells, they undergo 
proteolytic cleavage of an amino terminal domain during activation. The net activity of 
MMPs is determined by the amount of proenzyme expressed, the extent to which the proen­
zyme is activated, and the local concentration of specific tissue inhibitors of MMPs (MMPI). 
Four different tissue inhibitors of metalloproteinases (TIMP) exist. They are TIMP-1, TIMP-2, 
TIMP-3, and TIMP -4 (6). They regulate the MMPs activity in the extracellular space. It is 
conceivable that the imbalance between MMPs and TIMPs determines the invasive potential 
in cancer cells. During tumor invasion, the balance between MMPs and TIMPs is often 
shifted in favor of the proteases. Studies have shown an inverse correlation between TIMP 
levels and the invasive potential of murine and human tumor cells (27). Increased levels of 
TIMP-1 were found in patients with advanced cancer (28) and correlated with the level of 
invasion in malignant melanomas (29). 
7. ASSOCIATION WITH SIGNAL TRANSDUCTION PATHWAY 
The signal transduction pathway is the major biological pathway controlling cell growth 
(I). Many of the proteins involved in these multiple pathways are oncoproteins that can be 
used as tumor markers, specifically related to target identification , prognosis, and early 
detection. Described below are several well-studied new tumor markers 
7.1. TGF-{31 
All activities relating to cell growth start with the interaction of cytokines or growth fac­
tors with their receptors (I). Transforming growth factor-B (TGF-B I), a cytokine, is believed 
to play a dual role in carcinogenesis. It is a multifunctional peptide that controls the prolif­
eration, differentiation, and other functions in many cell types. Several inhibitory as well as 
stimulating activities were found to be associated with TGF-[3. TGF -[31 is expressed higher 
in low grade and stage of bladder transitional cell carcinoma than in the high grade and stage 
tumors suggesting that TGF-[31 expression may be specific to early stage human bladder 
cancer. However, serum TGF-f3llevels were significantly elevated in patients with invasive 
bladder cancer compared to healthy controls TGF-[3 ( 30), In addition, elevated TGF-[31 has 
been found in about 20% of liver cancer patients. Some patients with elevated TGF -[31 did 
not show elevation of serum AFP ( 31). Elevated TGF-[31 has also been detected in cervical 
cancer (32) and in ovarian carcinoma (33). Plasma TGF-B levels were markedly elevated in 
men with prostate cancer metastatic to regional lymph nodes and bone ( 34 ). Pretreatment 
TGF-[31 levels were a significant prognostic factor for survival and local control. The pre­
treatment TGF-[31 levels refle ct tumor burden and are a significant prognostic factor for 
survival ( 32 ).

70 Wu 
7.2. TNF-a 
Tumor necrosis factor-a (TNF-a), a cytokine, belongs to the family including TNF-f3 or 
lymphotoxin. TNF-a is produced mainly by monocytes and/or macrophages, whereas TNF-f3 
is a product of lymphoid cells. TNF-a and TNF-f3 are grouped among the major inflamma­
tory cytokines. They are produced at the sites of inflammation by infiltrating mononuclear 
cells. Serum TNF-a levels were detected in 36.5% of patients with pancreatic cancer patients 
with metastasis. Patients with metastatic disease had significantly higher positive serum 
TNF-a rate compared to those with nonmetastatic disease. Serum TNF-a levels were found 
to inversely correlated with body weight, body mass index, hematocrit, hemoglobin, and 
serum protein and albumin levels ( 35 ). 
7.3. C-erbB2 Oncoprotein (p185) 
The importance ofthe interaction between growth factors and their receptors is first illus­
trated in c-erbB-2 oncoprotein (pl85). The protein encoded by c-erbB-2 gene is a 185 kDa 
transmembrane receptor; also a glycoprotein having intracellular, transmembrane, and 
extracellular domains ( 36). The c-erbB-2 protein shows structural and functional homology 
with the epidermal growth factor receptor (EGFR). The cytosolic tyrosine-kinase domain of 
these two receptors differs only at the ectodomain of the molecule. 
This transmembrane receptor is presumably involved in the regulation of cell growth and 
cell transformation through signal transduction pathway. The oncoprotein sits in the cell 
membrane and transmits signals by interacting with growth factor outside the cell mem­
brane, which activates its cytosolic tyrosine kinase , and passes the message (signal) via a 
specific pathway to the nucleus to initiate biosynthesis. Overexpression of pl85 has been 
found in breast, ovarian, gastric, endometrial carcinoma, NSCL adenocarcinoma and pros­
tate cancer . Both amplification and overexpression of c-erbB-2 oncoprotein was associated 
with poor prognosis and with short survival and recurrence ( 37,38). 
The ectodomain of the c-erbB-2 oncoprotein can be proteolytically cleaved from the intact 
receptor and released as soluble molecule ( 38,39 ). In blood circulation, only the ectodomain 
of the c-erbB-2 protein exist (38). There is no pl85 molecule present in the serum. Because 
c-erbB-2 gene alterations have been detected in mammary tumors as early as in stage I or II 
and also in ductal carcinomas in situ suggesting that the overexpression of c-erbB-2 
oncoprotein and the appearance of serum ectodomain may be an early event in tumorigen­
esis ( 40 ). In other words, serum ectodomain could be used as an early marker to detect tumor 
at benign stage, especially for breast and ovarian cancers. 
The first successful example of "target therapy" was the treatment of women with meta­
static breast cancer with Herceptin , a humani zed monoclonal antibody against the 
ectodomain of c-erbB2 oncoprotein. Detecting the overexpression of c-erbB -2 oncoprotein 
has been used to identify women with metastatic breast cancer for Herceptin treatment (41 ). 
Overexpression of c-erbB2 protein could also be used to define a subgroup of breast cancer 
patients with estrogen receptor-positive primary tumors , who are less likely to respond to the 
endocrine therapy . 
7.4. EGFR 
Epidermal growth factor receptor (EGFR) is another important receptor that has been 
used as one of the risk factors in tumor tissue cytosol for breast cancer. EGFR belongs to 
class I subfamily, which include the products of the erbB2/n eu, erbB3, and erbB4 gene s.

Emerging Circulating Tumor Markers 71 
EGFR is also a transmembrane glycoprotein with tyrosine kinase activity, which transmits 
the mitogenic action of the EGF family of growth factors including EGF, TGFj3l, and 
amphiregulin. 
Overexpression of the EGFR has been reported in a number of human malignancies, 
including cancer of the breast, brain, bladder, head, and medulloblastomas. High levels of 
expression of this receptor also have been associated with poor survival in some of these 
patients. Like c-erbB-2, the ligand-induced activation of cells also acts primarily via recep­
tors on the cell surface. EGFR may also form a suitable target for monoclonal antibody­
directed therapy (42). The fact that this receptor is not found in normal tissue also makes it 
an attractive candidate for various anti-tumor strategies. 
7.5. IGF-1 and IGF-1R (IGFBP-3) 
The insulin-like growth factors (IGFs) are a ubiquitous family of growth factors, binding 
proteins, and receptors that are involved in normal cell growth and development. High serum 
concentrations of IGFl are associated with an increased risk of breast, prostate, colorectal, 
and lung cancers. Because IGF 1 is the major mediator of the effects of the growth hormone, 
it has a strong influence on cell proliferation and differentiation and is a potent inhibitor of 
apoptosis ( 43 ). Measurement of the level of circulating IGF-l and IGF binding protein-3 
appears to be most useful for cancer management. Plasma levels ofiGF-I and IGFBP-3 were 
found as predictors of advanced-stage prostate cancer ( 44 ). This family of growth factors, 
especially the IGF-1 receptor, is also an excellent target for new therapeutic agents in the 
treatment of cancer and other disorders of excessive cellular proliferation ( 45 ). 
Risk for prostate cancer is increased in men with elevated plasma IGF-I. This association 
was particularly strong in younger men in this study , suggesting that circulating IGF-I may 
be specifically involved in the early pathogenesis of prostate cancer ( 46). Significantly higher 
IGF-I and intact IGFBP-3 levels were found in carcinoma of the prostate (CaP) vs benign 
prostate hyperplasia (BPH). IGF-1 and IGFBP-3 (intact and total) correlated significantly 
and inversely with free PSA in BPH, but not in CaP. Increases in IGF-1 and intact IGFBP-3 
levels were positively associated with the presence of CaP in one group of patients with low 
to moderately elevated PSA and that their measurements in relation to PSA might help 
improve diagnostic discrimination between BPH and prostate cancer (47). 
7.6. IL-2R 
Interleukin-2 (IL-2), is a lymphokine , secreted by T lymphocytes upon antigen stimula­
tion for normal immune responsiveness. Even though it is secreted exclusively by T cells, 
IL-2 stimulates all lymphoid cells to proliferate and differentiat e via binding to its receptor 
(IL-2R). IL-2R is a transmembrane receptor with extracellular, membrane, and cytosolic 
domains ( 48). Three forms of the receptor are recognized with different affinity for IL-2 
binding. The high affinity receptor is a hetero -trimer composed of a , 13, and y ( c )-polypep­
tide chains. The 55 kDa a-chain, also known as the T-cell activation (Tac) antigen or CD-25, 
is a unique subunit of the high affinity IL-2 receptor (IL-2R a), which is readily shed from 
the cell surface. 
A rising serum soluble IL-2R (siL-2R) level in serial samples from patients with hairy 
cell leukemia indicates increased risk of relapse (49,50) . In all stages of melanoma the mean 
values of siL-2R were significantly higher than in normal control s and correlated with the 
disease progression. In patients with head and neck cancer, high serum concentrations of

72 Wu 
siL-2Ra at diagnosis were highly correlated with a shorter survival. In addition, patients 
who had low serum siL-2R concentrations at diagnosis were less likely to develop distant 
metastasis. Serum siL-2R acould be considered an independent serum biomarker (51). 
Levels of serum slL-2R in the patients with stage III and IV breast cancer were signifi­
cantly higher than in normal controls, and patients with stage I and II breast cancer. Serum 
levels ofiL-2R in patients with distant metastasis were also significantly higher than patients 
without distant metastasis (52) . siL-2Ra showed the strongest correlation with the tumor 
burden in non-Hodgkin's lymphoma (NHL) (53). 
7.7. Ras Protein (ras p21 or p2Fa 5) 
Ras protein is a crucial regulator of cell growth in eukaryotic cells. It is activated most 
frequently by receptors along the signal transduction pathways with various functions. There 
are several ras genes including k-ras, H-ras, and N-ras. The ras genes give rise to a family 
of related proteins with a molecular weight of 21 kDa (hence p21) that have strong trans­
forming potential. Ras gene family is one of the most commonly mutated genes in both solid 
tumors and hematological neoplasm, and k-ras gene is the most prone to mutation (54). 
At least a third of tumors contain mutated ras genes, therefore, 30% of human cancers, 
including the common colon, bladder, and pancreatic cancer are caused by the presence of 
activated ras protein. Mutant, constitutively activated forms of ras proteins, are frequently 
found in cancer. In leukemia and solid tumors, aberrant ras signaling can be induced directly 
by ras gene mutation or indirectly by altering genes that associate with ras or its signaling 
pathways. 
Because k-ras gene is most prone to mutation, elevation of k-ras protein or ras p2 1 are 
frequently observed in various cancers including 30 to 50% of colorectal carcinoma (55), 
prostate carcinoma (56), NSCLC (30 to 50%) (57), gastric carcinoma (58), endometrial car­
cinoma (59), ovarian carcinoma (60), duodenal adenocarcinomas (61), and 90 to 95% in 
pancreatic carcinoma. 
7.8. C-Myc 
At the end of the signal transduction pathway the signal needs to enter the nuclei to 
activate the transcription factor in the nuclei. C-myc is one of the more important transcrip­
tion factors located in the nucleus that is also a nuclear oncogene. There are three character­
ized member s of the myc gene family including c-myc, N-myc , and L-myc. Their coded 
proteins are myc oncoproteins that act as sequence-specific transcription factors that regu­
late a variety of genes important in normal cellular growth and differentiation processes. 
Aberrant expression of all three memb ers of the myc gene family has been implicated in 
the development of a wide variety of tumors. The best characterized member of the family is 
the c-myc gene, which was originally isolated by virtue of its homology to the v-myc 
oncogene carried by avian myelocytomatosis virus. The protein product of the three myc 
genes are closely related to each other (62). All these myc proteins modulate cell prolifera­
tion by functioning as transcription factors. 
Overexpression of any one of the myc famil y me mber is a feature of over 95% of SCLC 
cell lines and in SCLC tumor specimens (63). There is ample evidence that the elevated myc 
gene expression is associated with cell proliferation and can help induce a transformed phe­
notype. Approximat ely 70% of colon carcinomas and adenomatous polyps also over express 
the c-myc gene (64).

Emerging Circulating Tumor Markers 73 
8. ASSOCIATION WITH CELL CYCLE 
Regarding cell growth, the cell cycle represents the most important biological process 
controlling cell proliferation. Many oncogenes and suppressor genes encode proteins oper­
ating throughout the cell cycle, leading eventually to uncontrolled cell growth. For example, 
some cyclins behave like oncoproteins whereas certain cell cycle inhibitors behave as pro­
teins encoded by tumor suppressor genes . Products of the tumor suppressor gene may sup­
press cell growth by interacting with the cyclins and negatively regulating progression 
through the cell cycle. Mutations in the cyclin gene have been found in a variety of cancers. 
8.1. Cyclin Dl 
Cyclin D 1 is a protooncogene that plays a critical role in G1 progression of the cell cycle. 
Overexpression of the cyclin D 1 locus was found in many human cancers as a result of gene 
amplification or translocations (65). Cyclin D1 is also the most frequently overexpressed in 
tumor. Because there is evidence that cell cycle derangement becomes worse as tumors 
progress to a more malignant state, the detection or measurement of cell cycle proteins has 
been used to determine a patient's prognosis. Amplification of Cyclin Dl gene has been 
observed in carcinomas of the breast, and head and neck, and translocated in parathyroid 
adenomas and centrocytic lymphomas (65). More than one-third of human breast cancers 
may contain excessive levels of cyclin D 1, which accumulate through the deregulated ex­
pression of cyclin D 1 without an apparent increase in gene copy number, indicating the 
prognostic significance of cyclin D 1 protein. 
Overexpression of cyclin Dl also occurs in most invasive ductal cancers of the breast, 
which can distinguish invasive breast caners from nonmalignant lesions. Abnormal 
coexpression of cyclin D1 and p53 protein contributes to the development of endometrial 
carcinoma (66). 
8.2. Cyclin E 
Cyclin E is another G1 cyclin which can be severely expressed in many tumor cells. 
Altered expression of cyclin E protein (as oncogene) occurs in most of the breast tumor and 
increases with increase of grade and stage of the tumor. Alteration of cyclin E was also 
observed in other types of solid tumors as well as leukemia . It appears that cyclin Eprotein 
(not cyclin D protein) is the most consistent marker for determining the prognosis of early­
stage node-negative ductal carcinomas. In breast cancer, the alteration in cyclin E expres­
sion becomes progressively worse with increasing stage and grade of the tumor, suggesting 
its potential as a new prognostic marker. Cyclin E alteration is reported as a more consistent 
event then c-erb B2 overexpression in breast cancer (67). Cyclin E protein overexpression 
was also found associated with p53 alteration and it was suggested that a simultaneous 
overexpression of both cyclin E and p53 is related to poor prognosis (66,68). According to 
Gong et al. (69) the expression of cyclin £usually peaked at the time of cell entrance to S 
phase. Cyclin E will accumulate up to certain critical level before the initiation of DNA 
replication. 
8.3. Cyclin-Dependent Kinase Inhibitor 
The cell cycle is regulated by cyclin-dependent kinases (CDKs). Complexes ofCDKs and 
their partner cyclins drive the cell through the cell cycle. Each complex phosphorylates a 
distinct set of proteins at a particular check-point or phase of the cycle. In addition, there are

74 Wu 
inhibitors for CDKs. Normal control of cellular growth requires a balance between the acti­
vators (cyclins) and the inhibitors of the CDKs. Several inhibitors of CDK can also be used 
as tumor markers. The several most common inhibitors of CDKs are listed below. 
8.3.1. p16 
Mutation of pl6 has been reported in several malignancies. Alteration in the pl6 gene 
and its mutant protein have been found in several tumor cell lines and tumors, which include 
squamous cell carcinoma of the head and neck, esophageal squamous cell carcinoma, 
NSCLC, familial melanoma kindreds, primary bladder carcinoma, acute adult T-cellleuke­
mia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia (70). 
8.3.2. p27 
Although mutation in p27 is rare, reduced expression of p27 correlates with poor survival 
in cohorts of breast and colorectal carcinoma patients have been reported (71 ). High cyclin E 
and low p27 expression is associated with about 20% survival among all women tested and 
approx 30% survival in the node-negative subgroup. 
Other cyclin dependent kinase inhibitors involving in mali gnanci es include p21 in NSCLC 
and pancreatic adenocarcinoma, and p15 in leukemia, melanoma and metastatic lung cancer, 
and p57 in sarcomas and Wilms' tumors. Additional studies are needed in the future will 
verify their clinical utilities as tumor markers. 
9. ASSOCIATION WITH APOPTOSIS 
As cell cycle controls the cell proliferation the process of apoptosis regulates the number 
of cells. There are several proteins involved in apoptosis including Bcl-2, p53 protein, sF as, 
and sFasL. 
9.1. Bcl-2 Protein 
The Bcl-2 protein is an intracellular, integral membrane protein found primarily in the 
nuclear envelope, endoplasmic reticulum, and outer mitochondri al membrane. Bcl-2 may 
contribute to tumorigenesis by blocking apoptosis and prolonging cell survival without nec­
essarily affecting the rate of cell proliferation. Overexpression of Bcl-2 not only may pro­
mote neoplastic transformation but may also confer resistance of tumor (such as in ovarian 
carcinoma) to chemotherapy by enabling cells to avoid apoptosis. Bcl-2 expression has been 
demonstrated in solid tumors, including NSCLC, thyroid, prostate, colon, uterine cervix, 
bladder, and breast. Bcl-2 expression is usually associated with a survival advantage for 
tumor (72). 
In certain cancers, Bcl-2 protein is strongly associated with a good prognosis, and with 
several favorable prognostic features such as lack of p53 protein expression (inversely re­
lated to p53 expression) in cancer of the breast, lung , and ovarian carcinoma (73 ). 
9.2. p53 Mutant Protein 
p53 is a suppressor gene. Wild-type p53 protein suppresses cell growth and plays a cru­
cial role in maintaining genomic stability in both normal and tumor cells. The p53 tumor 
suppressor protein induces cell-cycle arrest , or cell death by triggering apoptosis in response 
to DNA -dama ging agents, such as radiation and many of the chemotherapeutics used in 
cancer therap y. Mutation of p53 gene (through mis-sense point mutation or allelic loss)

Emerging Circulating Tumor Markers 75 
causes functional inactivation of the gene, which appears to be the commonest genetic alter­
ation encountered in human malignancy. More than 50% of human cancers contain p53 
mutation including breast, bladder, esophageal, gastric, head and neck, hepatocellular, 
laryngeal, lung, ovarian, pancreatic, prostate, thyroid and chronic myelogenus leukemia, 
glioblastoma, B-cell lymphoma, melanoma, neuroblastoma, nephroblastomas, and sarco­
mas (most commonly occurring cancers). Detection of p53 mutant proteins has been shown 
to be associated with aggressive tumor phenotypes while normal cells, in contrast, typically 
have undetectable concentrations of mutant p53 protein. Consequently mutant p53 protein is 
the single most important predictive indicator for recurrence and death for breast cancer 
patients. 
Several reports have indicated that p53 protein may be used as an early tumor marker. 
Mutant p53 protein was detected in esophageal precancerous lesions. Wang et al. (74) sug­
gested that accumulation of p53 protein might be a promising early biomarker for identify­
ing high-risk subjects for esophageal cancer. Mutant p53 protein was also found in patients 
with early stage laryngeal carcinoma by Narayana et al. (75 ), and mutant p53 protein 
overexpression was found in patients with early gastric cancer (76). 
9.3. P53 Autoantibody (p53 Ab) 
Certain cancer patients with elevated circulating concentration of mutated p53 protein 
(released from dying tumor cells) may mount a humoral immune response producing anti­
body against mutant protein p53 (p53 Ab). Serum antibodies against the p53 mutant protein 
have been found in about 20% of patients with breast, lung, and lymphoreticular cancers 
(77). p53-Abs are found predominantly in human cancer patients with a specificity of 96%. 
Such antibodies are predominantly associated with p53 gene missense mutations and p53 
accumulation in the tumor, but the sensitivity of such detection is only 30%. The clinical 
value of these antibodies remains subject to debate, but consistent results have been observed 
in breast, colon, lung, oral, and gastric cancers, and in children with B-lymphomas in which 
they have been associated with high-grade tumors and poor survival. 
9.4. sFas 
Fas (A po-l, CD95) is a cell-surface receptor, a member of the tumor necrosis factor/nerve 
growth factor receptor superfamily. Fas exists in two forms, transmembrane and soluble 
form. Cell-surface Fas is widely expressed in normal and malignant cells. The soluble form 
of Fas (sF as) lacks the transmembrane domain of the full-length Fas, which has five variants 
produced via alternative mRNA splicing. sFas inhibits Pas-mediated apoptosis by neutraliz­
ing FasL (78). Binding of sFas with cell-surface Fas will prevent signal transduction by Fas. 
Serum sFas levels are elevated in patients with leukemia, colon cancer, breast cancer, and 
bladder cancer. The suppression of apoptosis contributes to carcinogenesis, as well as to a 
resistance to chemotherapy and radiotherapy. sFas may be a useful tumor marker in that it 
may reflect cancer status. A decrease in serum sFas levels has been found to occur after 
surgical resection in breast cancer. 
Elevated sFas can also be detected in bladder carcinoma, gastric carcinoma, hepatoma, 
osteosarcoma (79 ), gynecological malignancies (ovarian, cervical, endometrial), T-and 
B-cellleukemia, lymphoma and non- Hodgkin's lymphoma (80). They are usually associ­
ated with poor prognosis .

76 Wu 
9.5. sFasL 
It is likely that soluble forms ofFas ligand (sFasL) are derived from the membrane bound 
FasL after the cleavage by a metalloproteinase(s) . FasL belongs to the growing tumor necro­
sis factor family. FasL induces apoptosis by binding to its receptor , Fas. FasL is predomi­
nantly expressed in activated T cells and natural killer cells, whereas Fas is ubiquitously 
expressed in various cells. 
Patients with Ta bladder carcinoma with a low level of serum sFasL (less than the median 
value) had a longer postoperative tumor-free interval than patients with a high sFasL level 
(greater than the median value) in the 5-yr follow-up. Elevated serum sFasL level s may be 
associated with a greater risk of disease progression and recurrence in patients with bladder 
carcinoma (81). There was an apparent inverse correlation between the level of serum sFasL 
and antiautologous tumor cytotoxic activity. Therefore, the level of serum sFasL correlates 
with both disease progression and increase in the tumor grade. An elevated serum sFasL 
level predicted early recunence in patients with Ta bladder carcinoma. 
The sFasL levels are also significantly increased in patients with gastric carcinoma in a 
manner reflective of the disease stages such as the depth of tumor invasion , lymph node 
metastasis, and distant metastasis . Patients with high sFasL level s had a worse prognosis 
than those with low levels. It was found that sFasL concentrations could be a prognostic 
tumor marker for the assessment of the progression of advanced gastric carcinoma. 
10. ASSOCIATION WITH ANGIOGENESIS 
10.1. Angiogenic Factor 
Angiogenesis, the development of new blood vessels from pre-existing vasculature, is a 
prerequisite for tumor growth and metastasis. Several potential regulators of angiogenesis 
have been identified, including vascular endothelial growth factor (VEGF), acidic fibroblast 
growth factor (aFGF), basic fibroblast growth factor (bFGF), transforming growth factor-a 
(TGF -a, TGF-j3, hepatocyte growth factor/scatter factor (HGF/SF), tumor necrosis factor-a 
(TNF -a), and angiogenin. Only those factors that have been studied in detail are presented 
here. 
10.1.1. bFGF 
Basic fibroblast growth factor is produced by a wide variety of normal and malignant 
cells and has been shown to be a potent inducer of angiogenesis. Elevated bFGF concentra­
tion in serum and urine has been found in many cancers in addition to breast, head and neck 
cancer, and myoloma (82). 
The serum levels of bFGF and VEGF were found to be significantly high er in patients 
with renal cancer compared to healthy subjects. bFGF and VEGF values were significantly 
higher in patients with disseminat ed cancer compared to those with undisseminated cancer. 
Elevated serum levels of VEGF, bFGF, and IL-8 were strongly correlated with a poor over­
all and progression-free survival , respectively (83). 
10.1.2. VEGF 
Vascular endothelial growth factor is an endothelial cell-spec ific mitogen. VEGF is potent 
angiogenic factor specific for vascular endothelial cells and, unlik e bFGF, freely diffusible. 
VEGF has anti-apoptotic, mito genic, and permeability-increasing activities specific for vas­
cular endothelium. VEGF plays a pivotal role in the development of neovasc ularization in

Emerging Circulating Tumor Markers 77 
both physiological and pathological processes, e.g., developmental and reproductive angio­
genesis, proliferative retinopathies, and cancers. Several solid tumors produce ample 
amounts ofVEGF, which stimulates proliferation and migration of endothelial cells, thereby 
inducing neovascularization by a paracrine mechanism. Measurements of circulating VEGF 
have diagnostic and prognostic value not only in malignancies but also in cardiovascular 
failures and inflammatory diseases. 
Elevated VEGF can be detected in various cancers including colon (84-88). VEGF can be 
measured to determine the risk of cancer development, screen for early tumor detection, 
distinguish benign from malignant disease, and distinguish between different types of 
malignancies. In patients with established malignancies VEGF can be used to determine 
prognosis, predict the response to therapy, and monitor the clinical course (89). The study of 
multiple angiogenic factors in melanoma cell lines demonstrated the importance of measur­
ing VEGF, bFGF, IL-8, and platelet-derived endothelial cell growth factor simultaneously. 
Apparently, a unique expression pattern associated with each cell line and multiple angio­
genic factors are involved in the promotion of angiogenesis in the most angiogenic mela­
noma lines , whereas angiogenesis in the least angiogenic melanoma lines was possibly 
promoted solely by VEGF. 
It is important to note that inhibiting a single angiogenic factor may not be effective in the 
prevention of angiogenesis. To achieve an efficient anti-angiogenic treatment of melanoma 
therefore, may require identification and blocking of common functional features of several 
angiogenic factors (90 ). Combining VEGF with p53 status resulted in better prognostic pre­
diction. The results significantly correlated with a worse outcome for patients with estrogen 
receptor-positive tumors receiving adjuvant tamoxifen . Combining VEGF and p53 determi­
nations also provided additional prognostic information in terms of relapse-free survival and 
overall survival in breast cancer (86). 
11. ASSOCIATION WITH ADHESION 
Cellular adhesion molecules are implicated in tumor progression and metastasis. They 
exist in both soluble and membrane bound forms. All soluble biologically active forms of 
adhesion molecules including E-cadherin, CD 44, L-selectin, E-selectin, VCAM-1, and 
ICAM-1 can be found in vivo and in vitro. Adhesion molecules also help disguise tumor 
cells to look and act like normal lymphocytes. This disguise allows tumor cells to avoid 
immune attack in the blood circulation to be able to spread throughout the body via lym­
phatic and blood vessel. These molecules appear to be useful tumor markers for predicting 
prognosis. 
11.1. E-Cadherin 
E-cadherin, a distant member of the immunoglobulin superfamily, is important in main­
taining homophilic cell-cell adhesion in epithelial tissues. Loss of normal E-cadherin con­
tributes to progression in breast cancer and other solid tumor s by increasing proliferation, 
invasion, and/or metastasis (9 1 ). Therefore E-cadherin behaves as a therapeutic agent capable 
of suppressing tumor invasion and/or metastasis. 
Soluble fragments of E-cadherin molecule, on the other hand , have been reported to 
increase in the sera in 67% of patients with gastric cancer. Serum soluble E-cadherin is 
regarded as a potential valid prognostic marker for gastric cancer (92).

78 Wu 
11.2. CD 44 
CD44 is a tightly regulated cell adhesion molecule present on leukocytes and implicated 
in their attachment to endothelium during an inflammatory immune response. CD44 is a 
transmembrane glycoprotein involving in the cell-cell and cell-substrate interactions . 
Ectodomain of CD44 can shed from the cell surface and release as a soluble molecule. High 
serum levels of CD44 have been demonstrated in some solid tumors such as advanced gas­
tric and colon cancer. Serum CD44 concentration is correlated with tumor metastasis. 
Elevated soluble CD 44 has been detected in a variety of cancers including ovarian carci­
noma (93), non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia (94). Soluble 
CD44 can be used for monitoring therapy in patients with low grade NHL and CLL who 
have received interferon-a (IFN-a). 
11.3. ICAM-1 
Intercellular adhesion molecule-] (JCAM-1, CA 54) belongs to the immunoglobulin gene 
superfamily and is the ligand for the 132-integrins, and the leucocyte function associated 
antigen- I. The expression of ICAM-1 on the cell surface can be induced by several cytokines 
such as IFN-y, TNF-aand also by lipopolysaccharid, oxygen radicals, and hypoxia. 
ICAM-lis involved in metastatic spread. It has been shown that ICAM-1, both cell sur­
face bound form and soluble form, increased in a variety of carcinoma cell lines, including 
those of the stomach, colon, liver, lung, and pancreas. Elevated siCAM-1 has also been 
detected in breast (95) and gastric carcinomas, (96), and in Hodgkin disease (97). Elevated 
levels of siCAM-1 in serum have been shown to be associated with poor prognosis in 
Hodgkin disease and non-Hodgkin lymphomas. High serum siCAM-1 levels were signifi­
cantly associated with advanced stage and poor response to therapy (98). 
11.4. VCAM-1 
Vascular cell adhesion molecule 1 (V CAM -1) is expressed on endothelial cells as a result 
of VEGF stimulation. In early breast cancer serum VCAM-1 correlated closely with the 
microvessel density in tumors. Women who developed early recurrence had higher preop­
erative levels of serum VCAM-1. Serum VCAM-1 levels rose in women with advanced 
breast cancer whose disease progressed; but remained unchanged or fell in women with 
advanced breast cancer whose disease remained stable or showed a partial response to hor­
monal therapy. Women with lymph node-positive and high-grade tumors had higher levels 
of serum VCAM-1 than women with lymph node-negative and low-grade tumors. Serum 
VCAM-1 is a surrogate marker of angiogenesis in breast cancer and its measurement may 
help in the assessment of anti-angiogenic drugs (99). 
12. MISCELLANEOUS 
There are a few promising tumor markers, which do not fit into the categories listed above. 
12.1. LPA 
The plasma level of total lysophosphatidic acid (LPA) has been shown to be a new, poten­
tial biomarker for ovarian cancer and other gynecological cancers. Total LPA is composed 
of different LPA species with distinct fatty acid chains. Because lysophosphatidylinositol 
(LPI) co-migrates with LPA, ratio of LPA/LPI has been analyzed and compared with dis­
ease status. Results suggested that increased LPA/LPI species with unsaturated fatty acid 
chains might be associated with late-stage or recurrent ovarian cancer (99).

Emerging Circulating Tumor Markers 79 
12.2. Telomere and Telomerase 
Telomerase activity is a potential new tumor marker. Telomeres are the specialized DNA/ 
protein structures located at the end of eukaryotic chromosomes consisting of small, 
tandemly repeated DNA sequences (TTAGGG). The telomeres shorten with each round of 
DNA replication, and cells stop dividing when telomeres reach a critical length. Telomerase 
is a ribonucleoprotein, which is also called telomerase reverse transcriptase. The telomerase 
enzyme acts as a reverse transcriptase that uses part of human telomerase-associated RNA 
(hTR) (on which the TTAGGG repeats at the ends of chromosome can be synthesized) as a 
template for telomeric repeat synthesis ( 100). Most somatic cells switch off the activity of 
telomerase after birth. By contrast, many cancer cells reactivate telomerase. The telomerase 
rebuilds chromosomes' ends (telomeres) and allows tumor cells to replicate indefinitely. 
Telomerase has been detected in a majority of tumor cells ( 101) . The presence of telomerase 
activity is correlated with poor clinical outcome in cancer patients. For example, telomerase 
activity is strongly associated with prostate cancer but not benign prostatic hyperplasia (BPH) 
or the normal gland (102). Similarly significant levels of telomerase activation frequently 
occurred in ovarian and pancreatic cancer but rarely in premalignant and benign lesions 
( 103,104). 
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7 
Prostate Cancer Markers 
From Discovery to the Clinic 
R. Bruce Wallace, and Harry G. Rittenhouse 
In 1936 prostatic acid phosphatase (PAP) became the key serum marker for monitoring 
prostate cancer (PCa) treatment ( 1-3 ). Approximately 50 yr later, prostate-specific antigen 
(PSA) emerged as the most useful serum marker for PCa management followed a few years 
later by the watershed application for early detection. In spite of the many tumor marker 
candidates proposed and studied for over 50 yr, these two prostate proteins remained the 
most clinically requested PCa serum tests (Table 1). With the accumulation of human 
genome sequence knowledge and extraordinary methodological advances in gene arrays and 
proteomics, new PCa molecular tests appear to be on the horizon. Although the biological 
rationale for a marker's function may not be known when research is initiated, marker can­
didates with biological basis for their function, will likely be the most useful. Therefore, the 
biological function of a marker is an important factor to consider when assessing the poten­
tial of new markers. Table 2 and Fig. 1 illustrate PCa markers catagorized by biological 
activity. What are the clinical utilities and deficiencies for PSA today and what are the fea­
tures of PAP and PSA, which contribute to the long standing utility ofthese markers? These 
properties will be important when assessing the potential of new markers for PCa. 
1.1. Current Practice of PCa Diagnosis 
Following Food and Drug Administration(FDA) approval of PSA for monitoring PCa 
relapse in 1986, PSA has surpassed PAP as a clinical test for PCa. After radical prostatec­
tomy (RP), it was hypothesized that PSA would drop to undetectable concentrations. Patients 
usually exhibit serum PSA of less than 0.1 ng/mL after surgically disrupted PSA is cleared 
from the body. Concentrations of PSA above 0.1 ng/mL signal "biochemical relapse" fol­
lowed by clinical relapse. Studies using ultrasensitive PSA detection have shown that the 
"biological zero" (the lowest level of PSA which can be attained after RP) is less than 0.008 
ng/mL ( 4 ). Among other ramifications, this result indicates that nonprostate sources of PSA 
do not contribute to blood PSA concentrations, including the periurethral glands, which 
express PSA (4). 
Apparently the PSA from periurethral glands leaks directly into the urinary tract con­
founding the use of urine as a specimen source for clinical testing (5,6). The availability of 
ultrasensitive PSA assays require a three month postoperative period before PSA testing to 
From : Canc er Diagnos tics: Current and Future Trends 
Edited by: R. M. Nakamura , W. W. G rody, J. T. Wu, and R. B. Nagl e © Humana Press Inc., Totowa , Nj 
85

86 Finlay et al. 
Table 1 
Milestones for PAP and PSA 
1936 
1970s 
1972 
1976 
1978 
1981 
1986 
1990 
1990 
1994 
1995 
1998 
2000 PAP discovered 
Immunoa ssay for PAP 
y-Seminoprotein (ySP) identified as forensic marker for semen 
p30 Identified as forensic marker for semen 
PSA discovered as potential PCa marker 
First immunoassa y for PSA 
FDA approval of PSA to monitor PCa relapse 
ySP, p30, and PSA reported as identical 30K protein 
PSA forms (free/complex) discovered in blood 
FDA approval of PSA for early detection of PCa 
FDA approval of complex PSA (cPSA) for monitoring 
FDA approval of FPSA for use with total PSA to increase specificity for 
PCa detection 
Identifi cation of molecular forms of FPSA in serum, BPS A, proPS A 
Apoptotic 
index Diet or Drugs-----------, 
l 
Apoptosis Stimulato rs 
(inhibi t cancer) 
red wine polypheno ls 
bisphosphonates 
exisu lind t______,_ decrease serum 
celecoxib r-r PSA Hormonal Metabo lic Pathway 
Apoptos is Inhibitors 
(stimu late cancer) AMACR 
Androgen Receptor 
5 alpha reduc tase 
survivin 
bcl2 
caveolin -1 
Angiogenesis/ 
Tumor Enhancemen t 
FGF 
VEGF 
PSMA (ectopic) Proteolytic Cascade of 
Activation Events 
Heps in' 
TMPRSS2' 
hK2 
PSA 
hK11 
PSMA' (peptidase) 
CathepsinB/S tefin A 
•type tl transmembran e proteins 
Fig. 1. Current and potential markers for PCa with a biolo gical basis for their use. Selected current 
and potential future PCa markers are categorized into indic ated groups on the basis of biological 
activity. A canc er ma rker, which is linked to a biological process, may have more potential for utility . 
For details and references see Table 2.

Prostate Cancer Markers: From Discovery to the Clinic 
Table 2 
Classification of Future and Current PCa Markers by Biological Activity 
Biological 
function/effect 
Apoptosis inhibitors 
Apoptosis stimulators 
( chemoprevention) 
Factors involved in 
hormonal or 
metabolic pathways 
Angiogenesis/tumor 
enhancement 
proteolytic cascade 
of activation events 
Tumor suppressor 
genes/proteins 
Oncogenes/ 
oncoproteins Example markers 
survivin 
bcl-2 
caveolin-1 
red wine polyphenols 
Bisphosphonates 
Exisulind 
Celecoxib 
a-methylacyl-CoA racemase 
(AMACR) 
androgen receptor 
5-a reductases 
fibroblast growth factor (FGF) 
vascular endothelial growth factor 
(VEGF) 
prostate-specific membrane antigen 
(PSMA) (ectopic expression) 
Hepsin 
transmembrane protease receptor 
speract/scavenger 
family 2 (TMPRSS2) 
human kallikrein 2 (hK2) 
Prostate-specific Antigen (PSA) 
human kallikrein 11 (hKll) 
PSMA (77,205,292) cathepsin B/ 
stefin A 
p53 
c-erbB-2 (equivalent to HER-2/neu) 
ras 
myc Ref. 
(230,284) 
(284) 
(146) 
(285) 
(286) 
(287) 
(288) 
(72) 
(289,290) 
(291) 
(269,270) 
( 119,268,269) 
(77,205,292) 
(91,124) 
(293) 
(40,197,198) 
(29,40,53) 
(294) (295) 
(266,267,296) 
(212 ,215,216,218) 
(297) 
(297) 87 
allow clearance of residual preoperative PSA (7). With the advent of the ultrasound-guided 
sextant biopsy as an outpatient procedure in the late 1980s, the paradigm to use PSA for 
biopsy decisions began to emerge (8-10). Clinical studies ofPSA in the early 1990s led to 
the first tumor marker approved by the US FDA for early cancer detection. One of the most 
compelling facts leading to the use ofPSA in conjunction with digital rectal exam (DRE) for 
early detection of PCa was the superior predictive value of PSA over DRE ( 11-14 ). 
The relatively high positive predictive value of approx 25% for men with PSA greater 
than 4.0 ng/mL has led to an unprecedented number of PCas detected in the last 10 yr. This 
has resulted in a significant migration to lower clinical stage at diagnosis and has signi­
ficantly reduced the number of patients presenting with PSA concentrations higher than 
10 ng/mL. Recent studies have indicated that the cancer mortality for PC a is decreasing

88 Finlay et al. 
slightly ( 15-19). The combination of PSA testing with sextant biopsy has revolutionized the 
detection of PCa (20-22) . Monitoring PCa patients with PSA following treatment has 
become the gold standard to detect cancer relapse. 
The rise in the use of PSA has essentially eclipsed the use of PAP. Is there still a clinical 
role for PAP? Some studies have indicated that PAP may be a more accurate indicator of 
micrometastatic disease than PSA and should be used for monitoring patients after radiation 
treatment (23 ). A study at Walter Reed Medical center showed that PAP testing significantly 
added prognostic information and was an independent predictor of recurrence (24). The use 
of neural net analysis or other algorithm approaches may benefit from the inclusion of PAP. 
Nevertheless PAP has been completely surpassed by PSA and is infrequently used (25 ). 
PAP has the potential to regain importance in PCa as a therapy target. Recent studies have 
identified T -cell epitopes from PAP leading to its potential use for directing immunotherapy 
in advanced PCa (26-28). 
Although PSA has been in routine use for well over 10 yr and the analyte has completed 
a standardization process (29) differences between PSA assays from different manufacturers 
still exist ( 30 ). Furthermore, the issues of standardization will only get more complicated as 
multiple markers come into use. For instance , if a certain cutpoint is recommended for 
%FPSA with two assays from one manufacturer, will this cutpoint still be valid if a different 
manufacturer's PSA assay is used in the denominator? This depends on how close the two 
PSA assays correlate. These types of standardization and correlation issues will become 
more important as more markers are used and become available from a variety of manufac­
turers. 
1.2. Current Unmet Clinical Need 
What are the unmet diagnostic needs and current dilemmas of the frequent and multiple 
uses of PSA? Although valuable nomograms to predict organ-confined disease using PSA 
have been developed, ( 31) PSA is not related to tumor volume nor does it accurately predict 
aggressive PCa in the "diagnostic gray zone" from 4-10 ng/mL ( 32-34 ). Currently, no blood 
test can definitively tell how aggressively a man, who has been diagnosed with apparently 
localized PC a should be treated ( 35 ). It is well known that most PC a patients will die with 
the disease and not from it ( 36). The potential for over treatment exists along with the possi­
bility of dying from the cancer in the absence of proper treatment ( 36). 
A blood test is needed to significantly aid in the management of localized PC a. The detec­
tion of cancer cells in blood is being examined to detect micrometastatic disease . Reverse 
transcriptase polymerase chain reaction (RT -PCR) of PSA for the detection of cells express­
ing PSA mRNA in blood of PCa patients has been demonstrated in a number of studies. 
However, most studies, including a large consortium study, have concluded that the method 
does not provide significant information for clinical staging and can not be used for therapy 
decisions ( 37-39 ). The current failure of the test for staging may be the lack of discrimina­
tion between normal prostate cells and cancer cells. Both cells will express mRNA for PSA 
and be detected, leading to confusing results. In addition, the test does not discriminate 
between different types of prostate cancer cells , such as cells with high vs low metastatic 
potential. Quantitative RT-PCR may enhance this technique; knowing the number of circu­
lating PSA containing cells may be crucial. In men with low PSA concentrations, for 
example, below 2 ng/mL , the test works well in screening populations to indicate which men 
will have a low probability of prostate cancer. However, marker( s) to increase cancer speci-

Prostate Cancer Markers: From Discovery to the Clinic 89 
ficity in the 2-10 ng/mL range are needed (40-42). Using the standard 4.0 ng/mL "cut-off," 
the goal of the primary value PSA is to spare biopsies for the majority of men with lower 
cancer risk. For every 100 men going into the clinic for PC a screening about 80-85 men will 
have PSA values lower than 4.0 ng/mL and are not routinely biopsied. Nevertheless, the 
15-20 remaining men with PSA greater than 4 ng/mL are candidates for biopsy even though 
greater than 60% of these men do not have clinical prostate cancer. This results in a large 
number of biopsies and many millions of dollars in medical expense. Various methods to 
enhance PSA specificity are currently in use including factoring the size of the prostate 
gland (PSA density), rate of increase of PSA with time (PSA velocity), and age specific 
cutoffs for PSA (35,40-43). 
Perhaps the most practical and frequent method to increase cancer specificity is to mea­
sure uncomplexed or free PSA (FPSA) and use the free to total PSA ratio (40,43-46). FPSA 
in serum is higher in benign prostatic hyperplasia (BPH), resulting from the higher concen­
trations of inactive PSA in the BPH tissues (47). FPSA has been shown to reduce 20% of 
unnecessary biopsies ( 45 ), only missing 5% of the cancers (they tend to be theJess aggres­
sive cancers). 
However, the clinical diagnostic challenge of detecting PCa in men with mod erately 
elevated PSA concentrations may be growing. PSA may have created its own clinical 
dilemma. For more than 10 yr, millions of men have been screened with PSA. In 2001 about 
16-25 million PSA tests were done in the United States ( 48,49). A significant portion of these 
men will have PSA in the 4-10 ng/mL range. Some of these men will be biopsy positive for 
cancer, but the majority will be biopsy negative . The biopsy-negative men will likel y con­
tinue to have a PSA greater than 4 unless benign prostatic hyperplasia (BPH) therapy is 
undertaken and reduces the PSA. This group with elevated PSA will be screened again for 
PCa. Even if no cancer develops in the interim period, their PSA will likely remain high 
owing to the chronic benign prostate condition that led to the original elevation . As this pool 
of men with suspicious PSA concentrations resulting from benign disease increases, repeat 
biopsies become a serious challenge to the patient and the physician. Total PSA is not help­
ful in this situation. FPSA is useful for a minor portion of the patients but when to do a repeat 
biopsy has not been clearly established. No satisfactory marker is available to select the 
appropriate patients for biopsy in men who have PSA 4-10 ng/mL, a previous negative 
biopsy and a %FPSA of 10-25%. New markers could be helpful for this ever-growing patient 
group. 
Although the combination of PSA and biopsy is a practical method to detect early PCa in 
men with PSA greater than 4.0 ng/mL, a significant number of men missed by this procedure 
are becoming more evident. The initial norm al range limit of 4.0 for PSA was determined in 
1986 in a small population of 4 72 men without a history of prostate disease (50). Later 
studies containing larger and more clinically relevant populations to define the optimum 
"cutoff' value combining both sensitivity and specificity for cancer detection fluctuated 
between 2.8 and 4.0 (11,13,51). The screening study of 6630 men aged 50-74 led to FDA 
approval of PSA for early detection and assessed the efficacy of the 4.0 cutoff and derived an 
upper limit of 3.9 in the 50-54 age group (52). Consequently >4.0 ng/mL has been used most 
frequently for recomm ending biopsy. 
Recently a number of studies have focused on the 2.5-4.0 ng/mL range resulting in a 
growing consensus that as many as 40% of PCa patients have PSA below 4.0 (53). FPSA 
can help select some of these patients but the majority will be undetected unless biopsy of

90 Finlay et al. 
this group of men is completed (53). The problem is that more men with benign prostate 
disease without clinical PCa are in the 2-4 ng/mL PSA range. More specific and sensitive 
markers are needed to justify routine biopsy of men in this lower PSA range. 
Although PSA is the gold standard for detection of PCa relap se after therapy and before 
clinical symptoms develop, there remains uncertainty regarding the concentration of PSA 
that should be used to initiate further treatments ( 16,54,55 ). The availability of ultrasensitive 
methods that detect less than 0.05 ng/mL PSA can lead to anguish for the patient whereas 
appropriate secondary treatment protocols are often given only after the PSA reaches con­
centrations higher than 0.1 ng/mL (55). Markers, which provide information about the 
velocity of the clinical relapse, would augment the current test. 
PSA is not a tumor-specific marker, which limit s its usefulness for PCa detection. How­
ever, PSA does accurately reflect the integrity of the prostate and this key property may 
expand the clinical applications. More evidence is accumulating that S-a-reductase inhibitor 
drugs like finasteride (Proscar) diminish symptoms for some BPH patients by decrea sing the 
size of the prostate (56,57). Patients with PSA values greater than 1.8 are more likely to 
respond to Proscar and decreases in PSA with duration of treatment may be a positive indi­
cator of drug efficacy( 56-58). 
Proscar treatment may also complicate PSA testing for PCa. PSA levels in serum drop 
approx 50% with continued Proscar treatment (59). A correction method has been used that 
multiplies the observed PSA value by 2. Although a group of men will show a 50% mean 
reduction of serum PSA , there is significant variation from individual to individual (60). In 
contrast , the free to total PSA ratio does not change significantly with Proscar treatment and 
may provide a superior method to detect cancer in men treated with Proscar (61 ). The recent 
report from the Prostate Cancer Prevention trial with a study cohort of almost 19,000 men 
has demonstrated that Proscar prevents or delays prostate cancer (62). This striking result 
has enormous ramifications and will likely lead to millions of men taking Proscar or related 
drugs in the near future. The current diagnostic algorithm using PSA for PCa detection will 
need to be reexamined and alternative diagnostic algorithms may be needed. 
A growing number of drugs requir e specific laboratory tests to guide their use. For 
example, before a woman receives Herceptin therapy for breast cancer a test must be run on 
the breast cancer tissue to determine if it contains significant expression of the human epi­
dermal growth factor receptor (HER2); the protein product of the HER-2/neu oncogene. The 
therapeutic efficacy depends upon a significantly elevated concentration of the protein. A 
test specifically coupled to therapy is referred to as a theranostic. The theranostic use of PSA 
and of new markers for therapy selection and for monitoring treatment course is likely to 
increa se in the future. Prostate markers, which may be predicti ve of "prostate health"(i .e., 
smaller volumes and architecturally intact prostates may be valuable to monitor 
chemopreventive trials and individual dietary regimens). The effect of several drugs and 
herbal treatments on serum PSA has already been documented (Table 3). Man y epidemio ­
logical studies point to a significant positive association between saturated fat intake and 
PCa risk (63-69). Conversely, certain trace minerals and antio xidants corre late with 
decreased incidenc e of PC a, indicating some cancers may have been chemoprevented or at 
least chemode layed (63- 70). Several of the dietary antioxidants correlat ing with decreased 
PCa incidence including lycopene have been recently reported to decrease PSA concentra­

tion (71 ). Markers that can be used to guide positive dietary effects on overall prostate health 
would be valuable to resolve the complex and often confusing results from the many studies

Prostate Cancer Markers: From Discovery to the Clinic 91 
Table 3 
Drugs, Herbal Treatments, and Dietary Factors 
That May Effect Serum PSA Concentration 
Drug or herbal Effect on serum PSA 
treatment Dosage Use concentration Ref. (s) 
Lycopene chemo- decreases approx 20% (71) 
prevention? 
PC-SPES treat PCA decreases 50% (68) 
Finasteride 1 mg/d decrease or greater 
(Propecia) baldness, decreases by (298) 
chemo- approx 50% 
Finasteride 5 mg/d treat BPH decreases by (299) 
(Proscar) approx 50% 
Dutasteride 0.5 mg/d treat BPH , decreases by (291) 
Saw palmetto treat BPH no effect (67) 
cernitin , treat BPH no effect (300) 
saw palmetto, 
B-sitosterol 
and vitamin E 
Exisulind treat PCA PSA inhibited the rise (287) 
progression ofPSA 
after Radical 
prostatectomy 
Docetaxel treat hormone significant (301) 
refractory PCA decrease 
inPSA 
to date. Biomarkers which signal fatty acid metabolic pathway activities may also be useful 
in this regard (e.g., the recently reported overexpression of the a-methylacyl-CoA racemase 
(AMACR) gene in prostate tumor s) (72). 
1.3. PC a Markers for Bone Metastases 
An exciting and emerging research focus on the cellular and molecular mechanisms that 
lead to the specific targeting of PCa cells to bone with subsequent osteoblastic lesions may 
reveal an entirely new set of PCa markers (73,74). For several years, bone specific alkaline 
phosphatase and other bone matrix derived components have been investigated as more spe­
cific markers than total alkaline phosphatase for assessment of PCa metastasis (75). An 
intriguing hypothesis that PCa cells mimic osteoblast cells and acquire "bone-like" properties 
in order to effectively succeed in bone metastasis, has stimulated investigations of the ectopic 
expression of bone proteins in PCa cells (75, 76). PCa cells have now been re ported to 
secrete several bone extracellular matrix proteins including osteopontin, osteocalcin, and 
bone sialoprotein (75, 76). Future methodologies that allow the specific and practical capture 
of prostate cells in blood or urine may provide the targets for selective probes of bone-

92 Finlay eta!. 
associated proteins to estimate metastatic potential and provide valuable clinical staging 
information. 
1.4. Special Properties of PAP and PSA That Have Contributed to Their Prevalent 
Clinical Diagnostic Use 
Both PAP and PSA are secretory proteins produced by the prostate. The level of PAP is 
more than 200-fold higher in prostate than other tissues (41 ). PSA is highly localized to the 
prostate and is expressed more than 1 million-fold higher in prostate tissue and seminal 
plasma (40,41) than in blood. Two key shared properties are the secretory nature and pros­
tate tissue localization. Secretory proteins are more likely to leak into the blood in a rela­
tively intact form than cytosolic or membrane bound proteins. Prostate-specific membrane 
antigen (PSMA), which is highly enriched in prostate and up regulated in hormonally resis­
tant PCa, is a good target for antibody-labeled imaging (ProstaScintR) and a potential target 
for antibody therapy (77). PSMA has also been investigated as a serum marker, but studies 
have not revealed significant sensitivity or specificity for PCa (78, 79) over and above that of 
PSA. One possible explanation is the transmembrane property of PSMA. Unless the extra­
cellular portion of a transmembrane protein is released into blood, as is the case for Her-2/ 
neu in breast cancer (80) and possibly CA125 in ovarian cancer (81), these types of proteins 
are not consistently released into the blood in an easily measurable form. The tissue enrich­
ment and localization of a protein appears to play a major role in the utility of some markers. 
The significantly greater clinical utility of PSA may result from its increased prostate speci­
ficity over PAP. 
Today the role for PAP has all but disappeared. The abundance of PSA in the prostate and 
seminal plasma and its extreme compartmentalization away from the blood is an important 
property for clinical utility. Elevations of PSA usually signal a significant disturbance of the 
prostate. The prostate compartmentalization of PSA model can now be used to partially 
explain the relative increase of uncomplexed or FPSA in benign prostate disease compared 
with PCa (82). A distinct enzymatically inactive PSA form, benign PSA (BPSA), is associ­
ated with nodular hyperplasia in the prostate transitional zone , which is characteristic of 
BPH. BPSA is released as one of the forms of FPSA in blood (82,83 ). 
A similar paradigm exists for troponin I which is compartmentalized to the heart muscle 
and appears in the blood if muscle damage occurs (84-86). Unlike the troponin I model, 
perturbations of the prostate can occur by multiple mechanisms and diseases, including pros­
tatitis (87), chronic BPH, and even vigorous bicycle riding before blood draw (88,89), as 
well as PCa. The multiple mechanisms leading to PSA elevations hinder its diagnostic accuracy. 
1.5. The Search for New PCa Markers 
The search for new markers with powerful tools like gene arrays and protein chips may 
identify candidate markers that are more specific to prostate tumors compared with normal 
prostate tissue (90-105). It may be important to determine if the genomic and proteomic 
approaches would have identified either PAP or PSA. Both of these genes are not 
overexpressed in cancer, which probably rules out the gene array methodologies . In theory , 
the proteomics approach would identify both protein markers. However, proteomic testing 
of serum using two-dimensional (2D)-gel electrophoresis or mass spectrometry techniques 
like surface enhanced laser desorption/ionization (SELDI) will detect the abundant serum 
proteins before the detection of minor amounts of tumor protein s ( 106). Tumor markers like

1936 1 
PAP Discovered 
1990 
Discovery: FPSA 
helps discriminate 
PCa from BPH 
I 
-~l. 1994 
FDA Approval of 
PSA forPCa 
Detection 
1995 
cPSA for PCa 
Monitoring 1956 
Radioimmune Assay 
Methodology 
1986 
FDA Approva l of 
PSA for monitoring 
PCa recurrence 
1998 
FDA Approval FPSA 1978 
PSA Discovered as 
PCa Marker 
1980's 
Transrectal Ultrasound guided 
prostate biopsies/prostate volume 
(outpatient procedure) 
Future : 
Multi-analyte molecular 
profiling/Algorithms, 
Neural Net Analysis 93 
Fig. 2. Milestones in PCa testin g. Some important events and dates in PCa testing are shown . As 
illustrated here it can take a long time for a marker to move from discovery and use in research labs 
to routine clinical practice. The adoption rate for markers that are completely new in methodolo gy or 
concept can be expected to take longer to adopt to routine clinical practice than markers that are a 
variation on what is already accepted practice as is seen here for PSA and FPSA. 
CA 125, CEA, or PSA are usually present at picomolar concentrations, therefore the ability 
of a proteomic approach to detect these markers in the presence of the abundant serum pro­
teins sets a limit on the usefulness of these approaches ( 107). For a particular methodology 
the technic al approach may fail to identify proteins derived from the tumor and detect instead 
host-response proteins (e.g., haptoglobin) that are elevated owing to the presence of the 
tumor ( 108,109 ). 
The discovery technologies available today may lead to significant improvements in PCa 
diagnostics. Some of the diagnostic gaps for PSA may close in the near future. Will new 
markers replace PSA as rapidly and completely as PSA replaced PAP? This is unlikely 
because of the millions of patients tested with PSA and the enormous clinical experience 
using this marker. The PSA database will probably continue to be used as a referenc e assay 
even if superior markers are discovered. If a methodology provides a superior result from 
previous methodologies, the adoption rate often takes years for a test to be incorporated 
into standard clinical laboratory testing (Fig. 2).

94 Finlay et al. 
For instance, urologists began to use PSA to screen patients for PCa in clinical research 
studies long before the clinical trial data was obtained to gain FDA approval. The adoption 
rate of approx 15 yr for PSA use in PCA early detection is relatively rapid for a new marker. 
On the other hand, a related test like FPSA may have a faster adoption rate because the 
testing paradigm already exists. It is likely that new markers will be developed to comple­
ment and augment PSA to cover the significant unmet clinical needs, e.g., an accurate serum 
test to predict cancer aggressiveness. In addition, remember that the development and prac­
tical application of new markers is a formidable time-consuming and costly process. It should 
be expected that the immediate future will see improved use ofPSA, as we are learning more 
about the relationship of serum PSA elevations and clinical parameters. Perhaps the nearest 
term advance will be specific assays of PSA forms in serum to get all the pieces, benign as 
well as malignant, of the PSA puzzle. 
2. SPECIMEN SOURCES FOR PCA 
Throughout the process of using markers to detect, stage, and monitor PCa, several differ­
ent sources of specimens can be used. Serum and plasma are the most convenient specimens 
because they are easy to prepare and can be stored frozen for many years. Although storage 
is not important for clinical lab testing, it can be important when conducting research to 
determine if a test is useful. Stored clinical samples with good clinical histories are easier to 
use than creating a protocol where fresh samples from eligible patients are collected. PSA 
and FPSA are examples of markers detected primarily in serum or plasma. Serum is gener­
ally thought of as a better sample than plasma because it contains fewer proteins and is less 
likely to develop precipitates that will interfere in assays, especially upon freeze thaw. Nev­
ertheless , plasma is being promoted over serum as a sample for many clinical tests because 
it can be prepared more quickly ( 1 10). Additionally, some analytes may be more stable in 
plasma than serum. 
Whole blood will be needed for most nucleic acid based tests. This may change how 
research is done on markers. Whole blood is not easily stored like serum or plasma so a test 
that requires whole blood must be tested in a prospective trial. This limits the ability of 
researchers to test a marker and later bring it into routine use in the clinic. The use of retro­
spective studies and archived samples makes it easier and less expensive to evaluate a marker 
in the research stage. In fact, our current selection of markers may be biased by this. As new 
tests are evaluated it will be important to take sample type into consideration and find new 
ways of circumventing the problems of using whole blood, cell-based assays, and labile 
analytes so useful clinical tests are not overlooked. 
Whole blood is not routinely used for PCa testing . In the future, it may be used more 
frequently as new techniques, such as cell-based assays and nucleic acid testing (NAT) come 
into greater use. For example, MHC-tetramer detection of PC aT cell receptors and circulat­
ing cell-based PCa tests currently utilize whole blood. Epithelial cancer cells found in bone 
marrow, as well as cells isolated from whole blood have been used in an attempt to detect 
micro metastases in PCa (Ill). Cell-based assays that detect markers on known circulating 
cancer cells in either blood or bone marrow could be useful in clinical decision making but 
so far these types of tests are not commonly used in PCa. Prostate biopsy cores and prostate 
tissue from prostates removed after radical prostatectomy can be examined by immunohisto­
logical or in situ hybridization methods. Portions of the tissue and cores may also be homog­
enized and the resulting proteins or nucleic acids extracted for assay by molecular methods.

Prostate Cancer Markers: From Discovery to the Clinic 95 
Cancer specific groups of cells can be isolated by laser capture microdissection (LCM) 
and analyzed by a variety of molecul;1r methods ( 112,113 ). This is a powerful research 
application and greatly reduces the significant variability of cell types in dissected tumor 
tissue. The molecular testing of biopsy cores and tissue obtained after radical prostatectomy 
are not yet routinely used for clinical tests but research progress (90,91,114) indicates that 
significant tests for staging and therapeutic decisions are on the horizon. 
Prostatic and seminal fluids can be obtained from the prostate and seminal vesicles 
respectively ( 115 ). These fluids may be valuable sources of cancer related prostate-secreted 
proteins and even cancer cells. Cells, proteins, and nucleic acids from both glands are poten­
tially valuable specimen sources for key clinical diagnostic information about the pathologi­
cal state of these glands, especially with respect to the pathology and metastatic potential of 
PCa. Currently, no test has successfully utilized these fluids for PCa diagnostics although 
attempts are in progress ( 116). 
At first glance, urine appears to be the most accessible clinical specimen for urological 
cancers. Because it passes through the prostate on its way out of the body it might be expected 
to yield important diagnostic information about PCa. For example, Fluorescence in situ 
hybridization (FISH) of cells obtained from urine has recently been developed and marketed 
as a test for bladder cancer (117). Unfortunately, several factors lead to the severe limita­
tions for using urine as a valid specimen for PCa testing (40). Analyte instability in stored 
urine, variability of shed cells from prostate, and the necessity to correct for volume change 
(creatinine index), as well as diurnal variation in analytes, contribute to the multiple chal­
lenges for urine analysis of tumor markers. Consequently, urine clinical assays for PCa are 
not in use. However, the shedding of PCa cells into the urinary tract does make this speci­
men potentially valuable if cells can be induced to be released from the prostate gland. It 
appears that molecular techniques on nucleic acids and/or proteins combined with cell-based 
assays may allow for more diagnostic utility from fluids associated with the prostate, includ­
ing urine and proteomic techniques . 
3. TYPES OF MARKERS 
3.1. Nucleic Acids 
3.1.1. Methods for Discovery 
The search for nucleic acid disease-associated genes and markers fall into several 
approaches : linkage-association, subtractive hybridization/differential display libraries, 
RT-PCR, chip-based (microarray) gene expression profiling, and in vitro perturbation of 
gene expression. To a large extent, each of these methods has been enhanced through devel­
opments associated with the genome sequencing efforts, including single nucleotide poly­
morphisms (SNPs) (for linkage) and higher gene/coding sequence content for chips 
(microarray). In addition, the relative ease that a laboratory can now perform quantitative 
RT-PCR has helped both to validate gene expression data as well as provide a platform to 
perform the diagnostic and investigative analyses. 
Some of the most detailed insights in the search for new markers have recently come from 
the use of DNA microarrays to analyze tumor tissue . When used in conjunction with laser 
capture microdissection, which can effectively isolate a relatively homogenous set of can­
cerous cells from the surrounding normal tissue, microarray analysis can elucidate a more 
discrete pattern of gene expression changes associated with PCa (90).

96 Finlay et al. 
Through these studies, a variety of genes are cataloged as either up regulated or down 
regulated in PCa. The total number of gene expression changes and their magnitudes are 
variable, and depend upon the stage and grade of the tumor, tumor tissue sample, sample 
heterogeneity, density of sequences on the chip, and even the assay itself. Given these differ­
ences, a twofold or greater change in expression either up or down, can be detected in any­
where from 5 to over 400 genes. Therefore, results from microarray experiments require 
extensive follow-up validation by more quantitative and standardized methods-usually 
either by RT-PCR or Northern blot. 
3.1.2. Potential Nucleic Acid Markers for Use in PCa 
Results from microarray analyses have detected a wide variety of prostate tumor and 
metastasis-associated genes. For instance, transcriptional up-regulation has been noted for 
hepsin, pim-1, PSMA, c-myc, ras,fas and bcl-2, whereas transcriptional down-regulation 
has been documented for PTEN, CD44, Nkx3 .1, p27, GST family, caveolin 1, E-cadherin 
(90,91, 95,114,11 8-122). Microarray expression validation efforts are both ongoing and time 
consuming, thus the following section highlights some of these genes and trends. 
3.1.3. Hepsin 
Hepsin has recently emerged as one of the most exciting up-regulated genes in PCa. The 
hepsin protein is a membrane-bound serine protease first identified by Leytus et al ( 123 ). 
The gene was cloned from a liver eDNA library ( 124). Microarray analyses have revealed 
that the expression of hepsin mRNA is barely detectable in normal prostate tissue, but 
increases between 30 and 40 fold in PCa tissue (90,91,1 14). 
A similar dramatic increase is observed at the protein level, and initial immunohistochemi ­
cal staining of tumor tissue sections localizes the protein to the transformed cells. Real-time 
quantitative PCR shows a strong overexpression in prostate cancer tissue that may be useful 
to assess PC a aggressiveness ( 125 ). The expression of hepsin by liver tissue ( 123) may pose 
problems for diagnostic use in plasma but the detection and localization of hepsin presents 
intriguing opportunities for both cancer detection and possibly therapeutics . 
3.1.4. Melanoma Antigen Encoding Gene Family 
The melanoma antigen encoding genes (MAGEs) are a collection of cell-surface antigens 
that expressed in a variety of tumors and tumor-types. Microarray and RT-PCR analyses 
have been performed using a set of nested primers that specifically amplify the MAGE-l, 
-2, -3/6, - 4, and -12 genes from the MAGE-A family (126). Expression of these genes is 
absent from normal prostate and bone marrow samples. In contrast, a heterogeneous 
expression of MAGE genes was detected both in prostate tumor tissue and in bone marrow 
aspirates (containing metastatic prostate tumor cells). These data suggest that although there 
is no single consensus pattern of MAGE gene expression , the ability to detect MAGE gene 
products (and perhaps even a specific subset) in a biopsy might be highly predicti ve of 
cancer or metastasis. 
3.1.5. Telomeras e 
Telomerase is a ribonucleoprotein complex responsible for the maintenance of the telom­
ere length of chromosomes. The presence of active telomera se in normal adult cells and 
tissue is highly debated. It is present at low levels in some cells in the normal state, although 
in cancer and tumorigenesis, telomerase is up regulated and its activity associated with

Prostate Cancer Markers: From Discovery to the Clini c 97 
immortality of the transformed cells. Measurement of telomerase by enzyme activity utiliz­
ing the telomerase repeat amplification protocol (TRAP) assay or with RT -PCR for the RNA 
component oftelomerase has yielded variable results, most likely resulting from the unstable 
nature of the RNA component of the molecule. Nevertheless, positive correlations exist 
between telomerase and detection ofPCa (127-129). 
Further studies examining tumor samples by RT -PCR for mRNA of the catalytic subunit 
of telomerase (hTERT), have demonstrated better reliability and sensitivity, and a positive 
association between detection of hTERT mRNA and PCa has been noted (130). 
3.1.6. 003 (PCA3) 
The transcript for 003 was first identified through differential display analysis of tumor 
vs normal prostate tissue. The expression of this gene is limited to the prostate and is nor­
mally expressed at low levels ( 131). Northern blot analysis reveals that expression of this 
gene is dramatically increased in prostate tumor tissue compared with normal prostate tis­
sue. OD3 with another prostate-specific gene overexpressed in PCa may represent a distinct 
class of prostate-specific genes that lack protein coding capacity ( 13 2). Combination analy­
sis ofDD3 and hTERT expression by real time quantitative RT-PCR in tumor samples dem­
onstrated an average of a 34-fold increase over normal tissue for OD3 and a sixfold increase 
for hTERT ( 133 ). Although D03 might prove to be a more sensitive marker to reveal the 
early stages of PCa (owing to its tissue specificity), the relationship between hTERT and 
tumor stage is significant ( 133 ). In 003 and hTERT, a practical PCa test will require avail­
able PCa cells captured from blood or induced by prostate massage into the urine. Saad et al. 
observed a high clinical specificity and moderate sensitivity for cancer detection utilizing 
nucleic acid sequence-based amplification (NASBA) for detection of the relative expression 
of the PSA and D03 genes in shed cells in first morning voided urine following a vigorous 
DRE ( 134 ). This study demonstrates the potential of molecular tests utilizing urine if the 
prostate can be manipulated to release cancer cells into the urinary tract. 
3.1.7. Prostate-Specific Membrane Antigen (PSMA) 
Markers to discriminate aggressive PCa from less aggressive cancers prior to therapy are 
an important unmet clinical need in the management of PCa. Many labs have attempted to 
detect circulating PCa cells in the blood of PCa patients by RT -PCR ( 135-137). PSMA has 
been a mRNA target in addition to PSA and hK2. The use of these analytes to detect meta­
static cancer or discriminate more aggressive PCas before radical prostatectomy has pro­
duced mediocre and conflicting results. It is not surprising that PSMA does not work well as 
an RT -PCR analyte since both prostatic and non-prostatic tissues express it. Nevertheless, 
the results with PSA and hK2 have not been more useful clinically ( 137) even though these 
analytes are more prostate specific. The data from studies using telomerase and/or DD3 (see 
Section 3.1.6 .) are relatively compelling, and when combined with new markers entering 
the field (hepsin, EZH2, MAGE , for example), current attempts to develop real time quanti­
tative RT-PCR assays may enable the formation of a clinically useful test. Nevertheless , at 
this time the use of RT -PCR assays to aid in detection, staging, or the aggressiveness of PCa 
is far from being incorporated into standard clinical practice. 
3.1.8. Enhancer of Zeste Homolog 2 (EZH2) 
In a recent report, Varambally et al. ( 138) described up-regulation of the EZH2 mRNA 
specifically associated with metastatic PCa. This mRNA product of a known regulatory gene

98 Finlay et al. 
was discovered through gene expression profiling among several genes up regulated in meta­
static prostate tissue. When mRN A levels of EZH2 were decreased by transfecting cells with 
interfering RNA in vitro, cell proliferation was reduced. Conversely, when mRNA levels for 
gene were increased by transfection of the EZH2 gene into prostate cells, cell proliferation 
was enhanced. Thus, there is a link between the regulation of EZH2 mRNA and the tumor 
proliferative phenotype. Furthermore, EZH2 may represent a new marker for the progres­
sion ofPCa (138). 
3.1.9. Hereditary Breast Cancer Genes BRCAl and 2 
Epidemiological studies show evidence of predisposition of PCa in men who have muta­
tions in BRCA 1 or 2 ( 139) but further studies indicate that BRCA genes or their protein 
products may only be peripherally involved in PCa (140,141) . There is a possibility that the 
link may be the result of a gene distal to BRCA1 ( 142). Because of all the unknowns, it is 
unlikely that BRCA genes or their protein products will be used for PCa diagnosis and moni­
toring soon. 
3.1.9.1. PROMOTER HYPERMETHYLATION 
Microarray analyses have revealed decreased expression for CD44, E-cadherin, androgen 
and estrogen receptors, caveolin-1 and glutathione-S-transferase, among others in PCa tis­
sue when compared with normal tissue. RT-PCR and immunohistochemical staining have 
confirmed these findings. Transcriptional silencing of genes is often accompanied by an 
increase in the methylation of the DNA in or near the 5' end of the gene (in the regulatory 
regions containing CpG islands). Experiments using methyl-sensitive restriction enzymes, 
genomic PCR amplification, and genome sequencing have demonstrated an increase in the 
methylation of promoter regions of these genes ( 143-146). Although there is general agree­
ment that methylation of these genes accompany the progression of PCa, the absolute level, 
heterogeneity, lack of tissue specificity, and occasionally inconsistent correlation between 
methylation status and expression (147-149), decreases the potential of this methodology 
for use as a robust clinical test for PCa. 
3.1.9.2. LINKAGE MAPPING AND POLYMORPHISMS 
A volume of data exists in which linkage studies have been performed to determine the 
probable location of PCa disease genes. PCa, like most other cancers, is a complex and 
multifactorial disease, thus the search for the specific genes related to PCa is difficult. Evi­
dence exists for PCa susceptibility loci on chromosome 1-CAPB in 1p36, HPC1 in 1q25-
q25, PCAP in 1q42-q43; chromosome 17-HPC2/ELAC2 in 17pll; chromosome 20-HPC20 
in 20q 13 and X chromosome-HPCX in Xq27 -q28 (150-156). The use of SNPs to saturate 
these loci is currently used and should accelerate the identification of the specific disease­
related gene(s) contained within these large chromosomal regions. 
Polymorphisms and mutations have been identified in several genes believed to be 
involved in pathways associated with the development of PCa, including the androgen and 
vitamin D receptors, ribonuclease L, S-a-reductase II, and isoforms of cytochrome P 
(1 05,157-160 ). The weak association data highlight the fact that none of these polymor­
phisms represent a highly penetrant allele for PCa susceptibility. The combined result of 
these analyses indicates that PCa involves several distinct loci with no single major gene 
accounting for a major proportion of susceptibility to the disease. Thus, the search for a 
detection or diagnostic marker may result in the use of a combination of involved genes.

Prostate Cancer Markers: From Discovery to the Clinic 99 
Recently, a polymorphism has been found in the hK2 gene that correlates with prostate can­
cer risk ( 161 ). This polymorphism is even more interesting because elevated serum concen­
trations of hK2 have previously been shown to correlate with increased prostate cancer risk. 
A combination of the gene polymorphism data along with hK2 serum concentration data 
was able to segregate a group of patients with a approx 14-fold higher risk of having prostate 
cancer in the above study. 
3.1.9.3. HPCl 
Hereditary forms of prostate cancer account for approx 10% of clinical prostate cancers. 
The most intensive effort has been focused on chromosome 1, and it has been proposed to 
contain at least three subchromosomal regions (HPCl, PCAP, CAPB) harboring putative 
PCa susceptibility gene(s). Nevertheless, one susceptibility gene, ELAC2/HPC2 at chromo­
some 17, has been identified. Yet, it seems to have a questionable role in PC a predisposi­
tion (151). 
3.1.9.4. THE RNASE L GENE (2',5'-0LIGOISOADENYLATE-SYNTHETASE DEPENDENT) 
The RNase L gene codes for an enzyme that destroys RNA and may induce apoptosis in 
a novel way. Variants in the RNase L gene are enriched in families with mutant HPCl that 
include more than two affected members and may also be associated with younger age at disease 
onset. This suggests a possible modifying role in cancer predisposition. The impact that 
the RN ase L sequence variants have on PC a burden at the population level seems small 
(105,153). Although the association of RNase L variants with mutations in the HPCl is a 
provocative finding, the number of patients with the mutations is too small to be clinically 
useful at this time. However, if the gene(s) within HPC 1 are further defined, the association 
ofthese identified genes with RNase L may be stronger, leading to a role for RNase Land an 
identified HPC 1 gene in PCa management. 
In addition to HPC l(lq24-q25), PCa susceptibility loci reported so far include PCAP 
(lq42-q43), HPCX (Xq27-q28), CAPB (lp36), HPC20 (20q13), HPC2/ELAC2 (17pll), 
and 16q23. PCa aggressiveness loci have also been reported (5q31-q33, 7q32 and 19ql2). 
Further complicating the process is the existence of polymorphisms in several genes associ­
ated with PCa including, AR, PSA, SRD5A2, VDR, and CYP isoforms. These polymor­
phisms are not thought to be highly penetrant alleles in families at high risk for PCa. It is 
clear that PCa etiology involves several genetic loci with no major gene accounting for a 
large proportion of susceptibility to the disease. At this time, it is too early to predict if these 
or any other genes may become important tests for predicting people who will get the dis­
ease as well as those likely to have disease with a worse prognosis. 
3.2. Proteins 
3.2.1. Kallikrein Biochemistry 
PSA is a single-chain glycoprotein with a polypeptide backbone of approx 26 kDa con­
sisting of 237 amino acid residues. The apparent mass of PSA is approx 33 kDa, as deter­
mined both by gel filtration and by sodium dodecylsulfate-polyacrylamide gel 
electrophoresis (SDS-PAGE). These techniques overestimate the true mass of glycoproteins 
owing to the presence of the carbohydrate moiety. The true mass of PSA as determined by 
mass spectrometry is approx 28.4 kDa. PSA is a serine protease with chymotrypsin-like 
hydrolytic activity toward the carboxy-terminal side of selective tyrosine and leucine resi­
dues ( 162 ). The biological function of PSA is believed to be liquefaction of the seminal clot

100 Finlay et al. 
formed by semenogelin I and II, and fibronectin in freshly ejaculated semen ( 163), which 
aids in sperm motility and may have a role in fertility. These and other biochemical proper­
ties of PSA have been extensively reviewed (40,164). 
3.2.2. Current PSA Assays and Cancer Detection 
The measurement of serum PSA is widely used for the screening and early detection of 
PCa ( 11,164-166). The first clinical investigations of serum PSA established that values 
above 4 ng/mL were significantly correlated with an increased risk of PCa. Later it was 
discovered that serum contained two distinct forms of PSA: one form that was covalently 
attached to the serum protease inhibitor a.l-antichymotrypsin (complexed PSA), and a sec­
ond form that was present as the free "noncomplexed" form (FPSA) (167,168). The devel­
opment of immunoassays to measure these two forms of serum PSA has improved the 
discrimination of PCa from benign disease, such as BPH. A higher ratio of FPSA correlates 
with a lower risk ofPCa (45,169). In addition to free and total assays, an assay for complexed 
PSA has been developed. Because complexed PSA is the counterpart to FPSA in serum, it is 
not surprising that its ratio with total PSA performs comparably with FPSA. Although vari­
ous advantages of this assay may be a consideration for some laboratories, the most recent 
and comprehensive multi-site clinical study comparing complexed PSA to FPSA and total 
PSA concludes that cPSA detects PCa equivalently to total PSA, and less well than ratios of 
free or complexed PSA (cPSA) with total PSA ( 170). 
3.2.3. Molecular Forms of PSA That Improve Prostate Disease Discrimination 
The primary shortcoming of PSA as a serum marker of PCa is that PSA is also released 
into the serum as a result of benign prostate diseases such as BPH and prostatitis. This defi­
ciency is compounded by the fact that benign conditions are far more prevalent than cancer. 
Prostates become enlarged as a result of BPH and higher volume prostates are associated 
with elevated serum PSA. The finding of free and complexed forms of PSA, and the finding 
that a higher FPSA was more positively associated with benign disease was the first signal 
that an understanding of the molecular forms of FPSA might add value to PSA as a diagnos­
tic tool. Only the free form of PSA appears to be a candidate for a more detailed molecular 
characterization. This is a result of the single PSA form and the relative homogeneity of 
PSA-ACT. Only enzymatically active PSA can form a complex with protease inhibitors 
such as ACT, and thus it is expected that this PSA is relatively homogeneous. Peter et a!. 
confirmed this hypothesis by analyzing PSA that was chemically released from the PSA-ACT 
complex and found that there were no structural differences from seminal plasma PSA ( 171 ). 
The only hypothesis involving the PSA-ACT itself as a cancer marker, refers to the potential 
for intrinsic ACT complex formation in cancer tissues ( 172). There has been little experi­
mental evidence, however, to support this hypothesis because almost all of the PSA in tis­
sues is found in the free form (83,173). This suggests that PSA-ACT is formed almost 
exclusively in the blood as native PSA released from the prostate reacts with serum protease 
However, FPSA (enzymatically inactive PSA) can result from any number of processes. 
These include PSA containing internal peptide bond cleavages that are known to be present 
in seminal plasma PSA ( 40 ). In addition, PSA is expressed as the zymogen or precursor that 
is enzymatically inactive. The third molecular form of FPSA is a mature, intact, nonclipped 
form of PSA that does not form a complex with ACT (82).

Prostate Cancer Markers: From Discovery to the Clinic 101 
Therefore, the term "molecular forms of PSA" has expanded beyond reference to free and 
complexed PSA only. In recent years, there have been significant advances in the molecular 
characterization of FPSA to understand the mechanisms leading to the elevation of serum 
FPSA with benign disease. These efforts are directed toward a better discrimination of benign 
from cancerous conditions (82). Implicit in FPSA forms research is the hypothesis that PSA 
is expressed as a homogeneous, enzymatically active protein, but that the tissue environment 
associated with benign or cancerous conditions plays a role in rendering the PSA inactive, 
possibly as a result of the action of disease-specific proteases. Understanding the disease­
associated nature of FPSA may lead to better serum markers to discriminate cancer from 
benign disease. 
3.2.4. ProP SA for Cancer Detection 
The first molecular form of FPSA characterized in serum is the zymogen, or precursor 
form ofPSA. Paradoxically, this FPSA form was found to be associated with cancer and not 
benign disease ( 174,175 ). This contradiction can be explained by the fact that FPSA is actu­
ally a mixture of these distinct forms and has a statistical association with benign disease. It 
is also important to note that the correlation with benign disease is not absolute. For instance, 
men with greater than 25% FPSA have a 92% probability of benign disease, but still have an 
8% chance of cancer (53). BPH and cancer are co-existing diseases and therefore cancer can 
occur in men with advanced BPH. The discovery that pPSA was present in serum was the 
first indication that FPSA might also be comprised of cancer-associated forms of PSA and 
that this could potentially explain cancer patients with high % FPSA. In fact, preliminary 
studies have shown that pPSA is significantly elevated in PCa patients with high % 
FPSA (176). 
Although the presence of proPS A in serum was initially controversial (177, 178 ), several 
studies have now confirmed the presence ofpPSA forms in serum ( 174,175,179-181). Over­
all pPSA represents about a third of the FPSA in cancer serum, although the pPSA itself is 
composed of three major pPSA subforms (Fig. 3). PSA is normally secreted from prostate 
luminal epithelial cells as pPSA, an inactive proenzyme containing a seven amino acid pro­
leader peptide (APLILSR) attached to theN-terminus of the PSA protein ( 182,183 ). Studies 
reported that pPSA was present in several truncated pPSA forms, containing from one to 
five amino acids in the pro-leader peptide instead of the usual seven amino acids 
( 174,175 ,179,180). Three research immunoassays have been recently developed to measure 
the pPSA forms with both seven and five amino acid pro-leader peptides ([-5, -7]pPSA), the 
pPSA with the four amino acid pro-peptide ([-4]pPSA, and the two amino acid pro-peptide 
([-2]pPSA) ( 176). 
A rationale for the apparent enrichment of truncated pPSA forms is that more truncated 
forms of pPSA are more resistant to activation than the intact pPSA ( 175). Thus, the trun­
cated pPSA forms are more stable as pPSA forms, and not rapidly converted to mature PSA. 
Studies have shown that cumulatively, the pPSA formed as a percentage of FPSA, is supe­
rior to PSA, FPSA, or complexed PSA in predicting PCa, particularly in the range between 
2.5 and 4 ng/mL where the standard PSA assays are largely ineffective ( 176) . Among the 
pPSA forms, [-2]pPSA appears to be the most cancer associated , and also correlated with 
aggressive cancer. A number of studies are underway to explore the diagnostic properties of 
the pPSA forms.

102 Finlay et al. 
3.2.9. Benign PSA (BPSA) in Benign Prostate Disease 
The first evidence that PSA in BPH contained more enzymatically inactive species was 
demonstrated by Chen et al. (47). In this study ofBPH tissues, the PSA mixture contained a 
higher level of internal peptide bond cleavages. A study of BPH tissue by Mikolajczyk eta!. 
identified a distinct degraded form ofPSA termed benign PSA (BPSA) because it was present 
at lower levels in cancer tissue from the same prostate ( 83 ). BPSA is characterized by two 
internal peptide bond cleavages at residues Lys 145 and Lys 182. Studies with specific immu­
noassays for BPSA have shown that BPSA represents about a third of the FPSA in serum 
(82) (Fig. 3). 
Serum BPSA alone would not be expected to provide specific discrimination of PC a from 
BPH, because PCa and BPH frequently coexist. The ratio of BPSA (more BPH associated) 
and pPSA (more cancer associated) has shown some significant promise in discriminating 
cancer from BPH ( 176). Thus, it is not only the % FPSA but the relative proportion of the 
FPSA subforms that offers the most potential to improve cancer detection. 
Studies are underway to evaluate BPSA as a biomarker for clinical BPH. In preliminary 
studies of men undergoing drug treatment for BPH, early changes in BPSA levels may sig­
nal eventual drug response (unpublished results). Thus, BPSA may have several potential 
applications in the study of cancer and BPH. One striking characteristic of BPSA is that it is 
secreted into seminal plasma, apparently as an indicator of BPH. In normal pooled seminal 
plasma of healthy men, BPSA is present on average at 5-8% of the total PSA, while in older 
men the BPSA can represent more than 30% of the total seminal plasma PSA ( 82 ). This wide 
range of BPSA levels in the seminal plasma may represent corresponding levels of BPSA in 
the prostate. Therefore, BPSA in seminal plasma may represent a direct marker of biochemi­
cal changes in the prostate and provide a means to monitor some aspects of drug therapy. 
3.2.5 . In PSA the Third Component of FPSA in Serum 
BPSA and pPSA forms make up a substantial percentage of FPSA in serum but there is a 
third form designated as intact nonnative PSA (inPSA) (see Fig. 3). This form of FPSA has 
been observed in seminal plasma where a significant amount of PSA is intact, mature PSA 
but has been altered to prevent complex formation with exogenous ACT ( 184). Such forms 
have also been observed with the PSA expressed by LNCaP cells (185). The definition of 
inPSA in this section is defined as FPSA that is not pPSA or BPSA. Prevailing evidence 
suggests that inPSA represents mostly intact, nonnative (and thus inactive) PSA, though the 
presence of some minor percentage of PSA forms with internal cleavages such as Lysine 
145 alone can not be completely ruled out. It is likely that inPSA contains PSA with missing 
N-terminal amino acids, which are also inactive. 
An alternate approach to measuring intact forms of PSA has also been reported by 
Nurmikko ( 186). This assay detects intact PSA (PSA-I), which is defined as PSA that is not 
clipped at Lys145. PSA-1 would include both inPSA and pPSA. The FPSA forms not mea­
sured by this assay would include PSA forms clipped at Lys145 such as BPSA. Although the 
assay of PSA-1 has both overlapping and distinct features compared to specific BPSA and 
pPSA assays, a common theme is emerging for studies of molecular forms of FPSA to en­
hance the discrimination BPH from cancer. The exact role of inPSA as a member of the triad 
of PSA forms in FPSA (Fig. 3) has not been established. The relationship of inPSA with 
pPSA and BPSA in the discrimination of cancer from BPH is complex and awaits further 
experimental and statistical analysis.

Prostate Cancer Markers: From Discovery to the Clinic 103 
Free PSA Proportions 
proPSA Proportions 
Fig. 3. FPSA is composed of three disease-associated forms of PSA . The pie chart shows typical 
mean proportion s of these PSA forms in PCa serum containing 4-10 ng/mL total PSA. All FPSA 
forms are enzymatically inactive and do not complex with ACT. BPSA , "benign PSA ," is associated 
with BPH. ProPS A (pPSA) indicate s precursor forms of PSA, which are associated with PCa. pPSA 
is composed of native pPSA ([-7]pPSA) and truncated forms, [-5]pPSA, [-4]pPSA and [-2]pPSA. 
The [-2]pPSA form is most associated with cancer. The inPSA (intact, non-native PSA) in serum 
appears to correlate with cancer independently from pPSA. The measurement of these free forms of 
PSA significantly improves cancer detection over free, complexed, or total PSA, especially in the 
total PSA range below 4 ng/mL. 
3.2.6. Human Kallikrein 2 (hK2) 
Although PSA is the predominant tissue kallikrein in the prostate, a second tissue kal­
likrein called human kallikrein 2, hK2, has also been the subject of much investigation. PSA 
and hK2 share many properties, such as high amino acid sequence identity, prostate local­
ization, androgen regulation , and gene expression but have other biochemical properties 
distinct from one another (40). PSA and hK2 differ most in their enzymatic properti es. HK2 
displays the trypsin-lik e specificity common to most members of the tissue kallikrein family 
of proteases, while PSA is anomalous with chymotrypsin-like activity. HK2 is a much more 
active protease than PSA, with about 20,000 times more activity on its synthetic substrates 
than is PSA on its synthetic substrate. 
HK2 appears to be more highly expressed by PCa cells than by normal prostate epithe­
lium, as judged by immunostaining. In contrast to PSA, hK2 immunostaining increa ses with 
increasing Gleason grade, and hK2 has been proposed to be a potentially better candidate 
marker for cancer aggressiveness ( 187). HK2 exhibits other potentially cancer-inducing 
properties such as the ability to activate single chain urokinas e plasminogen activator (uP A), 
and to inactivate plasminogen activator inhibitor-! (PAI-l), the major inhibitor of uPA 
( 188, 189). Although the examination of PCa tissues showed that less than 1% of the PSA is 
comple xed to inhibitors such as ACT, cancer tissues were found to contain about 10% of the 
hK2 as a novel complex with an intracellular serine protease inhibitor called protease inhibi­
tor-6 ( 190 ). Curiously, the ma jor complex of hK2 in serum is with ACT even though ACT is 
an inhibitor of chymotrypsin-like proteases. However, preliminary data indicat e the con­
centration of hK2-A CT in serum is at the most only 5-20% of the free hK2 (191.192), 
almost the inver se of the typical PSA to PSA -ACT ratio. The minor protease-inhibitor com­
plex formation ofhK2 in serum may reflect a rapid inactivation ofhK2 in tissu e. Preliminary

104 Finlay et al. 
studies ofhK2-ACT in serum have not revealed a diagnostic role for this complexed form of 
hK2. The tissue, hK2-PI-6 complex has not been detected at measurable levels in serum but 
appears to have several interesting properties in prostate tissues (193 ). 
3.2.7. Clinical Studies With hK2 
Several immunoassays specific for hK2 have now been developed (191,194-196). Con­
centrations of serum hK2 are typically less than 100 pg/mL and represent 1 to 2% of serum 
PSA concentration. However, the hK2 levels are not directly proportional to PSA and they 
do improve the discrimination of cancer in combination with total PSA and FPSA ( 197,198 ). 
HK2 also appears to serve as a better marker for aggressiveness ( 199) and has been shown to 
correlate with extra-capsular extension of the cancer. It is in the area of aggressiveness , or 
correlation with stage, or grade of the cancer that hK2 appears to have the most distinctive 
diagnostic properties compared to PSA. It seems unlikely that hK2 will survive as a stand­
alone diagnostic marker because it does not significantly improve cancer detection over % 
FPSA, the current standard for cancer detection. With PSA and other PSA forms combined 
with the appropriate mathematical algorithms, hK2 may find clinical utility in both the 
improved detection of cancer and the discrimination of more aggressive forms of cancer. 
3.2.9.5. OTH ER HUMAN KALLIKREI NS AND CANCER 
Until recently, only three members of the human kallikrein family had been identified: 
hKl, hK2, and hK3 (PSA). This was in contrast to the extensive kallikrein families in rats 
(approx 20 genes or pseudogenes) and mice (24 genes or pseudogenes) (200). The next 
member of the human kallikrein family to be identified was prostase, hK4, though many 
other potential candidate kallikreins were under investigation (201 ). All 15 kallikrein genes 
of the human KLK family are clustered in the gene locus 19ql3.4. The most successful 
effort to discover and elucidate the many members of this family was mounted by the 
Diamandis laboratory, and these findings have been comprehensively reviewed by Y ousef 
et al. (202 ). Genes representing 15 members of the human kallikrein family have been iden­
tified and their protein transcripts have been at least partially characterized. 
Within this family of 15 human kallikreins only hK2, hK3(PSA), and hK4 appear to be 
predominantly prostate localized, though hKlO, hK12, hK13, and hK15 are significantly 
expressed in the prostate. Utilizing PCR amplification technology, almost all of these kal­
likreins can be found at some level of expression in several tissues throughout the body, 
including breast, ovary, testis, salivary gland, and pancreas. The tissue localization of these 
kallikreins and the diversity of function in multiple disease processes is an exciting field that 
is only beginning to emerge (202). 
PSA and hK2 have been studied fairly extensively ( 40) as the first kallikreins determined 
to be localized to the prostate, but hK4 has yet to receive significant attention as a serum 
marker. Biochemically, hK4 appears to be similar to hK2 and could potentially serve some 
of the putative functions ascribed to hK2, such as the activation of proPS A (203 ). Specific 
and sensitive immunoassays for kallikreins hK4 to hK15 are currently being developed and 
it is too early to assess potential roles in PCa . However, each of these prostate localized 
kallikreins could offer both therapeutic as well as diagnostic value as our understanding of 
their role in the prostate increases. Even tissue kallikreins that are not exclusive to the prostate 
may turn out to have positive diagnostic value once their role in the prostate is identified.

Prostate Cancer Markers: From Discovery to the Clinic 105 
3.2.8. Prostate-Specific Membrane Antigen 
Prostate-specific membrane antigen (PSMA) is a type II membrane bound protein abun­
dant in prostate tissue, but it is not prostate specific because it can also be found in kidney 
(41), small intestine, and brain (204). Antibodies to this protein have been used to make an 
FDA approved, in vivo, imaging agent (Prosta-ScintR) that is currently in use in the clinic 
(205) primarily for predicting durable complete response in postoperative patients. Never­
theless, PSMA has not attained wide spread in vitro clinical use probably because it is not 
sufficiently prostate specific. A novel protein-biochip immunoassay has been reported to 
detect significantly higher PSMA in men with PCa than men with BPH, but paradoxically 
the normal group of men over 50 yr of age had higher ng/mL concentrations of PSMA than 
the BPH men (79). Interestingly this assay detects hundreds of ng/mL of PSMA in patient 
sera. Further studies to detect the prostate form of the protein, if it exists, are needed to 
evaluate its utility as a serum PCa marker. 
PSMA is currently being used in a number of experimental gene and immunotherapy 
trials for PCa (206,207). If these therapies are successful, theranostic (rather than diagnos­
tic) tests for PSMA may become more prevalent as the therapy would be followed at the 
molecular level. 
Interestingly PSMA has been found to be ectopically expressed on the neovasculature of 
renal cell (208), breast and bladder (209) carcinoma . Neovasculature associated PSMA may 
be a target for the detection of angiogenesis. 
3.2.9. HER-2/neu 
As a result of the success of HER2/neu antibody (Herceptin) treatment for breast cancer, 
the association of this oncogene with PCa has been further explored (210,211 ). Analysis of 
biopsies by HER-2/neu immunohistochemistry added additional prognostic information to 
traditional metrics during radiation therapy for PCa (212). Although a clinical trial using an 
antibody against HER-2/neu has begun (213), it is still unknown how useful this type of 
therapy will be for PCa nor is it yet known how to interpret HER2/neu marker data from 
immunohistochemistry, fluorescence, or colorimetric in situ hybridization (F/CISH) (214-218). 
3.2.10. Telomerase 
Telomerase can be studied with both nucleic acid based as well as protein based tests 
primarily because the enzyme has a nucleic acid subunit. Most normal, noncancerous cells 
do not contain the ribonucleoenzyme telomerase but cancerous cells often do (219 ). There­
fore, telomerase is currently being examined for use as a cancer marker and a therapeutic 
target. The human telomerase enzyme requires a protein subunit: telomerase reverse tran­
scriptase (hTRT), and an RNA subunit (hTR) for activity (130). Therefore, assays to detect 
telomerase may be directed at the protein portion of the enzyme, the RNA portion of the 
enzyme, or both at once in the form of enzymatic activity assays because both properly 
folded RNA and protein are required for activity. 
Multiple studies are underway to investigate telomerase as a therapeutic target for PCa 
(219-222). Straub et al. attempted to use telomerase activity to aid in early planning of 
adjuvant therapy for PCa but found that telomerase was not more sensitive than conven­
tional histolo gy or PSA -RT-PCR (223). Several groups are at the early stages of investigat­
ing the potential of telomerase as a marker for PC a. Ruijter and colleagues have looked at the

106 Finlay et al. 
cytological and histological changes of the enzyme with PCa (224) and Sakr et al. have 
looked at changes in telomerase between high grade prostatic intraepithelial neoplasia 
(HGPIN) and PCa (225). Study of the HGPIN to PCa progression is important because it is 
well known that a finding of HGPIN upon biopsy confers increased risk of finding PCa in 
that patient in later prostate biopsies. 
In general, many strong correlations exist between cancer and telomerase. However tech­
nical hurdles to develop robust telomerase assays have hindered rapid progress for definitive 
evaluations (226). Conceptually , telomerase is an attractive candidate tumor marker but 
much work is yet to be done before the parameters for practical use are established. 
3.2.11. Survivin 
Survivin is a new tumor antigen identified on the basis of spontaneous cytotoxic T lym­
phocyte (CTL) responses in cancer patients (227). Survivin has been shown to be an 
antiapoptosis protein and is overexpressed in most human cancers (228) so it has potential 
utility as a cancer marker. Survivin is a member of the inhibitor of apoptosis protein (lAP) 
family (229) and has homology in one baculovirus lAP repeat (230). No other homologies 
were found between survivin and other known proteins, and survivin has little sequence 
homology to the other well-known anti-apoptosis protein bcl-2. Xing and colleagues have 
examined prostate tissue sections from patients who had under gone prostatectomy for treat­
ment of PCa. Apoptosis could not be detected in neuroendocrine cells of the prostates but 
they found cells in both benign and malignant areas of the glands that overexpressed surviv­
ing (231 ). Nevertheless, they were unable to find an association between survivin positivity 
and PCa progression. 
3.2.12. Insulin-Like Growth Factors and Their Binding Proteins 
Numerous growth factors may be involved in PCa (Table 4), but insulin-like growth fac­
tors (IGFs) and their receptors, or binding proteins (IGFBPs) have historically been studied 
for possible in vitro diagnostic utility and as therapeutic targets (232 ). Measurement of serum 
or plasma IGFs and IGFBPs have been show to predict prostate cancer risk (233,234) . 
Recently it has been shown that IGFs and IGFBPs have limited utility as screening markers 
(235) for PCa. The cleavage of IGFBP3 by PSA has been reproduced in vitro, neverthe­
less the cleaved binding protein fragments that result could not be used successfully as 
markers (236). Several labs are currently exploring the ways IGFs and their binding proteins 
can be used as markers for prostate cancer (237 -239). Recently , Latif et al. have examined 
the relationship between IGF-1, IGFBP-3, PSA, and C-reactive protein and have concluded 
that the modulations in IGF-1 and IGFBP-3 are owing to systemic inflammatory response 
not prostate cancer stage (240). In summary, there is much research activity on the use of 
IGFs and IGFBPs as prostate cancer markers , but more research will need to be completed 
before the utility of these markers can be determined. 
3.2.13. Matrix Metalloproteases and Their Tissue Inhibitors 
Matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) have been consid­
ered promising therapeutic targets for cancer for some time (241). It was logical to attempt 
to use either of these proteins as diagnostic markers for prostate or other cancers. Indeed 
there is research evidence that these markers may be useful as immunohistochemical (242) 
or DNA probe tests on tumor tissue (243) or that TIMP-1 may find use in the future as a 
plasma test for PCa metastases (244 ).

Table 4 
Peptide Growth Factor Families 
Name Acronym 
Transforming TGF-[3 
growth 
factor-[3 
Fibroblast FGFs 
growth 
factors 
Insulin-like IGFs 
growth 
factors 
Neuropeptide s: not applicable 
serotonin , 
somatostatin Relation to PCa References 
mRNA decreased (302) 
in PCa tissue 
angiogenesis factors (269,270) 
for PCa 
may predict the risk (235) 
of developing 
advanced- PCa 
Utility for screening 
prostate limited 
serotonin is expre ssed (303,304) 
higher in benign 
and cancerous 
tissue than lymph 
node metastases 
Somatostatin receptor 
mRNA is up-regulated 
in PCa tissue when 
compared to 
BPH tissue 107 
3.2.14. Urokinas e-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type-1 
The association of urokinase -type plasminogen activator (uPA) with PCa meta stases has 
been well studied and recently reviewed (245 ). It appears that metastases are mediated by 
pericellular plasminogen activation. Biochemical studies have shown that prostate localized 
kallikrein proteases hK2 and hK4 can activate pro-uP A as well as inactivate (by complexing 
with it) PAI-l (189,203) in vitro. The use of uP A and PAI-l as markers is not as evolved. 
Plasminogen activator and its receptor were found to be more highly expressed in high grade 
PCa tumors (246) and the uPA gene is sometimes amplified in hormone refractory PCa 
(247). Data from an immunoassay for both forms when combined with prostate volume 
indicated that increased serum concentrations were associated with overall survival (248). 
Nevertheless , the methods need to be characterized before uP A and PAI-l can be used suc­
cessfully as markers to test for PCa metastases or prognosis. 
3.2.15. Circulating Autoantibodie s to PSA 
Circulating antibodies to tumor antigens (autoantibodies) may be earlier and more sensi­
tive markers for cancer detection than direct measurement of circulating cancer antigens 
themselves (249). A small amount of tumor antigen can provoke an immune response, gen­
erating circulating antibodies that are at a higher concentration than the original antigen. 
However, a major obstacle to formulating immunoassays for the detection of autoantibodies 
to cancer antigens has been the putative low affinity and low titer of autoantibodies. For an

108 Finlay et al. 
assay to be successful there must be a clear demonstration of detection of the anti-tumor 
antigen specifically without nonspecific signal generated by other proteins in serum or 
plasma that might raise the background of the assay. For example, rheumatoid factor has a 
similar structure to human immunoglobin (Ig). Rheumatoid factor might substitute for anti­
gen and give a signal in autoantibody assays without anti-tumor autoantibody being present. 
This type of interference would confound anti-tumor antigen immunoassays. 
A few researchers have begun to generate assays for circulating antibodies to tumor anti­
gens, but no immunoassays for these analytes has yet made it to routine clinical practice 
similar to established immunoassays for cancer associated antigens. However, the potential 
use of circulating cancer antigen antibodies is being explored and preliminary qualitative 
assays have been established. Experimental use of these type of assays has been explored in 
breast cancer and has recently been reviewed (249). The autoantibodies may circulate free or 
bound to antigen. Although the use of circulating antibodies to breast cancer antigens is still 
controversial it appears to have potential in the area of screening. 
Circulating antibodies to PSA have been assayed by two separate groups as a potential 
way of monitoring PCa immunotherapy with recombinant vaccinia virus expressing PSA. 
Sanda et al. made a qualitative Western blot assay for PSA antibodies by reacting patient 
sera with nitrocellulose that had been blotted with purified PSA. They measured the sera for 
response to both IgG and IgM. Interestingly, they found that most of the patients had anti­
PSA antibodies before the immunotherapy had begun. Only one patient out of six had any 
change in anti-PSA antibody status over the course of the therapy (250). Eder and colleagues 
have used an enzyme linked immunosorbent assay (ELISA) to measure presence of anti­
PSA IgG and IgM in patients undergoing experimental therapy. Out of 33 patients, only one 
developed low concentrations of anti-PSA IgG (251 ). 
Although the early results for using anti-PSA antibody immunoassays do not appear overly 
successful, these publications do not include detail about the analytical characteristics of the 
assays. It is possible that the anti-PSA assays will be more successful once they are fully 
developed and demonstrate low nonspecific signal in the presence of common serum or 
plasma Ig-like molecules and can specifically and sensitively measure circulating human Ig 
molecules directed against PSA. If this type of assay can be constructed, as new therapies for 
PCa evolve , these assays may be used in different monitoring situations and find more use. 
3.2.16. Polycomb Group Protein Enhancer of Zeste Homolog 2 
Recently the gene encoding the EZH2 protein, a repressor of gene transcription, has been 
found to be up regulated in advanced prostate tumors (138). Consequently, EZH2 may be a 
tissue marker for PCa aggressiveness. Modulation of EZH2 in PCa may cause subsequent 
changes in the regulation of many genes. Increased expression of EZH2 as measured by 
immunohistochemistry increased with tissue pathology type. It was lowest in benign pros­
tate tissue, but expression increased in cancerous tissue and in metastatic tissue . Researchers 
showed that patients with clinically localized PC a that have higher expression of EZH2 also 
had a greater risk of recurrence of their cancer after prostatectomy. 
3.2.17. Caveolin-1 
The role of caveolin-1 in androgen-independent PC a, has recently been reviewed ( 146 ). 
Caveolin-1 is a major structural protein in caveolae, which are membrane microdomains that 
have a role in signal transduction and membrane transport. Experiments in animals and cell 
lines indicate that the caveolin-1 gene is anti-apoptotic. Caveolin-1 expression progressively

Prostate Cancer Markers: From Discovery to the Clinic 109 
increases in primary cancer, metastatic cancer, and hormone resistant cancer (after androgen 
ablation therapy). The role of caveolin-1 in PCa is not straightforward because although the 
protein appears to be increased in more aggressive cancer, the promoter of the gene is 
more highly methylated in PCa tissue than in adjacent normal tissue ( 147), which would be 
expected to decrease transcription of the gene in PCa. Caveolin-1 has been found in the 
serum of stage-D cancer patients (252). Cumulative data indicate that the caveolin-1 gene and 
protein plays an important role in the progression of PCa. Caveolin-1 gene has also been 
found in serum, albeit in extreme disease circumstances, this protein and gene has potential 
to become an important PCa marker in the future. 
3.2.18. Neuroendocrine Markers and PCa 
Neuroendocrine cells exist in the normal prostate but not much is known about their func­
tion. It is thought that these cells are important in growth, differentiation, and homeostasis of 
normal prostate tissue. Some neuroendocrine differentiation is found in 30-100% of PC a and 
markedly neuroendocrine-like tumors are associated with poor prognosis (253 ). Several neu­
roendocrine markers can currently be measured in the serum of PCa patients: neuron-spe­
cific enolase (NSE), chromogranins A and B, and pancreastatin (a breakdown product of 
chromogranin A). Increases in serum or tissue neuroendocrine markers generally correlate 
with androgen independent cancer or poor prognosis. Which neuroendocrine markers will 
be the most successful at predicting poor prognosis is yet to be determined. 
3.3. Cellular Markers 
3.3.1. T-Cell Markers 
Now that the components of an effective immune response are better defined, this knowl­
edge is used to design new therapies for PCa, involving the patient's immune system (254). 
If the patient's dysfunctional immune system can be manipulated by therapeutic agents it 
may be possible to specifically redirect PCa cells with curative effect (255 ). These new 
therapies for PCa will change how and what markers will be used during treatment of dis­
ease. For example, Eaton et al., in a recent clinical trial, immunized hormone refractory PCa 
patients with several allogenic PCa cell lines (256). They monitored the therapy with PSA, 
intracellular cytokines, and specific humoral and cell-mediated assays. More than four dif­
ferent assays were needed to monitor this trial. One standard for PCa; PSA, one routinely 
used for immunotherapy: intracellular cytokines, and several assays derived specifically for 
this trial. Similarly, Heiser and colleagues treated patients with autologous dendritic cells 
transfected with PSA mRNA (257). They analyzed the patients post therapy for production 
of PSA specific T cells , PSA, and circulating tumor cells. It is clear that as immunotherapy 
trials for PCa continue many assays will be needed to monitor them. It is too early to know 
if serum or plasma PSA is a useful marker for PCa immunotherapy. It is also too early to 
know which other assays will become most useful. What is known is that clinical trials for 
several types of novel PC a therapies have already begun to stimulate research into a myriad 
of methods and antigens to be explored for their efficacy in aiding clinical decision-making. 
3.3.2 . Major Histocompatability Complex Tetramers 
Major histocompatability complex (MHC) tetramers are a relatively new reagent (258) 
(see Chapter 10) that can be used to enumerate T-cells specific for a particular peptide. 
Vonderheide et al. (259) have used MHC tetramers with a peptide found in telomerase 
reverse transcriptase to show increased numbers of specific T -cells after immunization of

110 Finlay et al. 
PCa patients with autologous dendritic cells pulsed with the same telomerase peptide. As the 
numbers of immunotherapy trials increase, the use of MHC tetramers to follow these trials is 
expected to increase as well. 
3.3.3. Circulating Tumor Cells 
The detection and characterization of rare circulating tumor cells in blood has potential 
for PCa management. Moreno et al. have initiated studies to assess whether detection of 
circulating tumor cells will aid in PCa management ( 111 ). They captured potential cancer 
cells with an antibody to an epithelial cell adhesion molecule and detected them with multi­
parameter flow cytometry and CD45 (leukocyte marker to identify nonepithelial cells), and 
cytokeratin (epithelial cell marker) antibodies. They detected increased numbers of cells in 
men with localized PCa and in men with metastatic disease. Men with more slowly progress­
ing disease had lower numbers of cells in their blood than men with rapidly progressing 
disease. They also observed that the number of circulating cancer cells fluctuated more than 
serum PSA during chemotherapy suggesting that measurement of circulating tumor cells 
may add value when monitoring for treatment response. Nevertheless, previous studies have 
not shown much additional information gained over conventional histology in examining 
either pelvic lymph nodes (260) or bone marrow (261) by cytokeratin immunohistochemis­
try. However, a recent study has shown that PSA RT-PCR of blood cells can help prognos­
ticate hormone refractory prostate cancer and allow for separation of patients into groups for 
phase III clinical trials (262). Eventually, cell-based assays may provide the greatest diag­
nostic utility because the cancer cell is directly measured and characterized as opposed to the 
"surrogate" serum markers currently used. Advances in technology to make this type of 
assay easier, practical, and robust will require significant resource and future studies. 
3.3.4. Angiogenesis and Blood Vessel Growth 
Angiogenesis or growth of new blood vessels around tumors is thought to be essential for 
their continued growth and eventual metastasis. Increased microvessel density was shown to 
be associated with PC a previously (263 ). More recently, the protein endoglin (CD 105) was 
found to be expressed on immature blood vessels and immunohistochemical studies indi­
cated endoglin was prognostic for survival (264 ). There are recent well-designed studies 
describing the relationship of the angiogenesis related proteins; p53, vascular endothelial 
growth factor (VEGF), thrombospondin 1 (TSP-1) (265-270) . TSP-1 is a p53-dependent 
inhibitor of tumor angiogenesis. VEGF mediates angiogenesis during tumor progression. 
These markers are associated with other markers in the angiogenesis process. Angiogenesis 
is critically important in tumor progression, thus any of these proteins may be important 
markers for PCa staging. Presently, most studies have examined the qualitative levels of 
microvessel density and associated markers by immunohistochemistry in PCa specimens 
obtained as paraffin embedded tissue after radical prostatectomy. They could be developed 
as prognostic indicators but they may need to be explored in other formats to become more 
useful to urologists making clinical decisions regarding therapy. For example, if these mark­
ers are found to be prognostic at the biopsy stage they might yield important information 
about outcomes before radical prostatectomy is performed. In the future, perhaps the tech­
nique of laser capture microdissection may allow these types of markers to be used in a more 
quantitative way, thus increasing their utility ( 112,113). In addition to VEGF associated 
angiogenesis markers, the following markers have also been found to have significant asso -

Prostate Cancer Markers: From Discovery to the Clinic 111 
ciations with PCa at the immunohistochemical level: cyclooxygenase-2 (271), MUCI (48), 
hyaluronic acid and hyaluronidase (272), and endoglin (CD lOS) (264). 
Although angiogenic markers are not routinely used in the clinic at this time, a recent 
study reports how these markers could be used for therapeutic monitoring. Bok et al. have 
shown that an ELISA for urine VEGF can be predictive of survival for hormone refractory 
patients who were undergoing therapy with a growth factor antagonist (269). 
4. MULTIANALYTE TESTS 
4.1. The Proteomics of PCA Markers 
4.1.1. Proteomic Challenges 
Proteomics is a large and growing multidisciplinary field (273 ), and the search for PCa 
markers is representative of many of these applications. This section does not review the 
many proteomic technologies because they have been extensively reviewed (274 ), but rather 
describes some approaches, findings, and future challenges as they apply to PCa. 
As with genomic approaches, the search for PCa protein markers usually attempts to iden­
tify new proteins or proteins that increase or decrease in men with cancer. In the latter case, 
findings from genomic and proteomic technologies are not necessarily correlated. For 
instance , the mRNA expression of hK2 can range from I 0-50% of PSA (275) while the 
actual levels of hK2 protein in prostate tissues, seminal plasma, and serum are typically only 
1-2% of the PSA levels (40). Thus, whereas hK2 mRNA may be expressed at significant 
levels, the protein may be less abundant because it is degraded rapidly . Aside from expres­
sion levels, proteins are affected by posttranslational modification, turnover rates, solubility, 
membrane association, and other factors such as complex formation. Gene expression alone 
does not always provide the relevant information for the identification of suitable protein 
biomarkers. 
The comparison between PSA and hK2 as protein cancer markers illustrates another 
important challenge for proteomics; protein concentration. PSA is present at mg/mL levels 
in the prostate, and must be detected at ng/mL in the serum to be clinically useful. Levels of 
hK2 are typically present at less than 0.1 ng/mL in the serum, which is already challenging 
for the well-established and sensitive immunoassay technologies. Ideally, any proteomic 
technology should be capable of detecting and quantifying proteins in the ng/mL range while 
in the presence of other proteins of at least 1000-fold higher concentrations ( 106). 
4.1.2. Separation, Enrichment, and Detection of Proteins 
Investigational proteomics may be split into two categories: proteins in the tissue, and 
proteins in the blood. At the tissue level , these technologies are not unlike some aspects of 
the genomic technologies . One of the more useful techniques in discriminating tissue-spe­
cific genes and proteins is laser capture microdissection (LCM) ( 1 12). The ability to isolate 
small numbers of cells based on their common morphology greatly enhances the specificity 
of subsequent findings. More material is needed for protein identification because no com­
parable amplification techniques are available for protein enhancement such as PCR for 
genes. Conceptually, the study of tissues may be better suited for the discovery and identifi­
cation of new cancer-related proteins. Once identified in tissue studies, antibodies can be 
developed, and sensitive immunoassays or other technologies developed to measure poten­
tially low levels of the protein in the blood.

112 Finlay et al. 
In tissues and especially in blood there is a need to enrich for the proteins of interest. 
Given that blood contains more than 50 mg/mL protein, and cancer related analytes would 
likely be present at ng/mL to pg/mL levels, a means of enriching blood samples for tumor­
derived proteins is essential. For many years, 2D electrophoresis has been the standard for 
separating blood components, and more recently combined with mass spectrometry to iden­
tify the proteins. A wide number of studies have been undertaken utilizing 2D gels to iden­
tify new PCa markers, with mixed results (276). In order to identify new proteins present at 
less than approx 1 ug/mL in the blood it is still necessary to apply classical protein separa­
tion technology prior to loading on 2D gels. 
Another recent approach has been the use of chemically modified protein chips, a deriva­
tive of gene array chip technology. In the case of protein chips, the matrix typically contains 
ionic, hydrophobic, or metal binding sites. Blood or serum is incubated with the matrix and, 
after washing, bound proteins are analyzed by matrix-assisted laser desorption-induced mass 
spectrometry (MALDI-MS). A chip technology termed surface-enhanced laser desorption/ 
ionization (SELDI) (Ciphergen Biotechnologies, Palo Alto, CA), coupled with MALDI-MS 
has received some prominence by automating this approach. Only a minor subset of blood 
proteins are theoretically bound to any given chip chemistry, although the diagnostic effi­
cacy of one type of chip over another must be tested empirically. Many studies continue in 
this area (276), though the translation from the finding of a new MS peak to the identifica­
tion of that peak as a novel cancer-associated protein or useful tumor marker has yet to be 
realized. An interesting second-generation approach to the SELDI technology is the use of 
antibodies to bind specific components from the serum. This approach was used success­
fully to measure PSMA in serum where standard immunoassay techniques had been unsuc­
cessful (79 ). 
4.1.3. Protein Profiling 
Genomic approaches are typically dependent on cells and their genomic components , 
whether from RT -PCR of circulating ce11s or from the study of neoplastic tissues directly. In 
these cases, the cellular genesis of the signal is clear. In proteomic approaches utilizing 
protein profiling the signal (protein or peptide) may not derive from neoplastic cells or tis­
sue, and the proteins in theory do not even need to be identified. Protein profiling depends on 
specific patterns of proteins that increase or decrease in cancer serum compared to benign 
serum, and depends on sophisticated algorithms to interpret these patterns. Results from 
such controlled studies can be impressive, with sensitivity and specificity greater than 90% 
(277). 
It remains to be seen if protein-profiling approaches can survive the rigors of diagnostic 
screening demands if it turns out that none of the proteins that make up the profile are tissue 
or tumor-specific. In blood at least, the issue of protein concentration becomes an issue even 
with SELDI technology. It is probable that tumors as large as a cubic centimeter could not 
contribute more than ng/mL serum concentrations of any diagnostic protein (107). Many 
interfering serum proteins are at concentrations more than 1000 times higher, thus technol­
ogy may necessarily be selecting for response proteins to the tumor and not from the tumor 
itself ( 106). In some cases the most highly correlated serum proteins with cancer have been 
acute phase or inflammatory proteins such as thioredoxin and haptoglobin. Protein profiling 
does have one unique advantage in that it relies on a pattern of several proteins, which should 
minimize the effects of aberrant induction of a single component. Utilizing protein profiling,

Prostate Cancer Markers: From Discovery to the Clinic 113 
the paradigm has clearly shifted from identifying unique tumor associated proteins, to iden­
tifying protein patterns resulting from any number of biochemical processes ancillary to the 
tumor. Once the proteins are identified, a multiplex assay format may provide clinical labs 
with a practical way to offer these tests. Many challenges remain. 
4.2. Methodologies for Multiple Markers 
Through the explosion of new potential markers discovered through genomics and 
proteomics, the use of multiple markers to increase specificity will become more common. 
A simple example of the use of multiple markers is the ratio of FPSA to PSA or % FPSA. 
The use of% FPSA is already frequently used in the clinic. When the assay result for FPSA 
is used along with the assay result for total PSA it allows urologists to eliminate 20% of 
unnecessary biopsies while only missing 5% of cancers, which also tend to be low stage and 
grade ( 45 ). Percent FPSA is used as a simple ratio of the FPSA assay result divided by the 
total PSA assay result. More complicated, informatics type analysis methods have been pro­
posed but none are used commonly in the clinic. 
There are several problems in PCa treatment where multiple markers and clinical param ­
eters are known to be individually predictive of outcome but if combined these parameters 
might be even more predictive . Several groups have explored two methods , multivariate 
logistic regression (MLR) and artificial neural networks (ANN ), where data can be com­
bined. For example, O'Dowd and colleagues constructed a multivariate logistic regression 
algorithm including patients' age, initial biopsy diagnosis, total PSA, and free/total PSA that 
could predict the likelihood of cancer on the repeated biopsy with an accuracy of 70% (278 ). 
Others have used ANN to improve prediction of cancer on biopsy by 20-22% over % FPSA 
(279) or to improve the prediction over standard cutoffs (280) . Several studies have com­
pared ANN and MLR and neither method appears to be better than the other in general 
(281,282 ). Selection between ANN, logistic regression , or other techniques will depend upon 
what data is being input, what the actual data distributions look like and exactly what type of 
clinical questions need to be answered (283). 
5.SUMMARY 
Currently, PSA and FPSA are the only PCa markers widely used in the clinic. These 
assays have established a paradigm for use of markers for PCa management. Novel kal­
likrein or PSA forms immunoassays may be the first new markers implemented if it can be 
shown that they add a significant amount of additional diagnostic information over and above 
that provided by PSA and FPSA. 
New therapies for PCa will stimulate the development of assays for clinical assessments. 
The successful therapies will determine which assays are used for clinical research, diagnos­
tic, or theranostic purposes. 
New markers , specimen sources, and techniques will be realized as good clinical value is 
shown with ability for implementation. It is a long road from noting a correlation of a 
biomarker to a PCa clinical parameter, to perfecting a technique, and elucidating a method 
robust enough for clinical or pathology labs to run the test to give urologists clear decision 
points . 
It is our speculation that the world of PC a markers will expand from single analyte serum 
based immunoassays for PSA to a variety of molecular diagnostic techniques using multiple 
analytes of either proteins and/or nucleic acids, that utilize a variety of sample types includ -

114 Finlay et al. 
ing cells, tissues, and fluids. The data from the multiple analytes and samples will be com­
bined with bioinformatic output to provide urologists with practical algorithmic results for 
spanning a variety of clinical decision points across the PCa treatment continuum from pre­
vention through treatment of metastatic disease with experimental therapies. 
ACKNOWLEDGMENTS 
The authors wish to thank Susan Keenan and Sherrie Green for their expert technical and 
informational assistance in the preparation of this manuscript. 
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8 
Serum Tumor Marker Test Profile 
in Testicular Germ-Cell Tumors 
Frank J. Liu, Robert M. Nakamura, C. Howard Tseng, 
and Kevin S. Liu 
1.1. Histologic Classification of Testicular Cancer 
The primary testicular cancers are classi fied as testicular germ-cell tumors and non-g erm­
cell tumors of the testis. The testicular germ-cell tumors constitute approx 90 to 95% of all 
testicular cancers, whereas the incidence of non-germ-cell tumors of testes is usually less 
than 10% ( 1). The testicular germ -cell tumors include seminoma, embryonal carcinoma, 
and teratoma with or without malignant transformation, choriocarcinoma, and yolk sac tumor 
(also known as endodermal sinus tumor , or embryonal adenocarcinoma of the prepubertal 
testis) (1). 
1.1.1. Histopathologic Classification of Testicular Germ-Cell Tumors 
Histopathologic classifications of neoplasia and clinical staging evaluations of cancer have 
provided an important clinical basis for therapeutic decision-making (I ). Surgical patholo gy 
diagnoses of the surgically removed tumor tissu e provide the most accurate skills of identi­
fying and classifying a tumor and predicting and estimating its possible occurrence of local 
extent or metastasis into other organ systems (I). There is a close relationship between serum 
tumor markers and histologic types of testicular germ-cell tumors; therefore, while applying 
the serum tumor marker tests, it is necessary to understand the interrelationship between the 
histologic types of testicular germ -cell tumors and the serum tumor markers (I). The follow­
ing four histologic classifications are listed for understanding the association of the histo­
logic types of testicular germ -cell tumors with each serum tumor marker that is clinically 
useful for the manag ement of patients with testicular germ-cell tumors. 
1.1.1.1. REVIS ED WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION 
OF GERM-CELL TUMOR OF THE TESTIS 
The WHO classification of testicular germ-cell tumors categorizes the tumors into three 
main groups: 
I. Precursor lesion. 
2. Tumors of one histologic type including seminoma, spermatic seminoma, embryonal carcinoma, 
yolk sac tumor , polyembryoma, trophoblastic tumor s (choriocarcinoma: pure , mixed or placen­
tal-site implantation tumor), teratoma (mature teratoma , immature teratom a, and teratom a with 
malignant areas). 
From : Canc er Diagnostic s: Current and Future Trmd s 
Edited by: R. M. Na kam ura, W. W. Grody, J. T. Wu, and R. B. Nagle © Humana Press Inc., Totowa, NJ 
129

130 Liu et al. 
3. Tumors of more than one histologic type (2). 
Relative frequency of histologic types oftesticular germ-cell tumors are 35-70% for semi­
noma, 3-6% for embryonal carcinoma, 3% for teratoma in adults, and 38% for childhood, 
l% for choriocarcinoma, and 60% for mixed tumors of more than one histologic type (2). 
The majority of cases being the mixed tumor reflect the pluripotential nature of testicular 
germ-cell tumors (1,2). The occurrence of different histologic types in the metastatic site 
compared to the primary tumor is evidence of the pluripotential nature of testicular germ­
cell tumors, and in particular nonseminomatous tumors, more than half of which display 
different morphologies in primary vs metastatic sites, although pure choriocarcinoma 
invariably spreads unaltered ( 1,2). For example, postmortem studies indicate that 30 to 45% 
of patients dying with seminoma in the primary tumor had nonseminomatous metastases; 
this is another evidence to reflect this nature ( 1,2). 
1.1.1.2. DIXON AND MOORE PATHOLOGICAL CLASSIFICATION OF TESTICULAR GERM-CELL TUMORS 
Based on the clinical and pathological characters of testicular germ-cell tumors, Dixon 
and Moore classified testicular germ-cell tumors into five histopathological groups: group I, 
pure seminoma; group II, embryonal carcinoma, pure, or with seminoma; group III, ter­
atoma, pure, or with seminoma; group IV, teratoma, with either embryonal carcinoma or 
choriocarcinoma or both, and with or without seminoma; and group V, choriocarcinoma, 
pure, or with embryonal carcinoma or seminoma or both (3). 
In the group of 166 patients with stage I, II, and III testicular germ-cell tumors at the 
University of Texas MD Anderson Cancer Center (UTMDACC), 18 (11%) patients had 
group I, pure seminoma; 67 (40%) had group II, embryonal carcinoma, pure, or with semi­
noma; 2 (1 %) had group III, teratoma, pure, or with seminoma; 63 (38%) had group IV, 
teratoma, with either embryonal carcinoma or choriocarcinoma or both, and with or without 
seminoma; and 16 ( 1 0%) had group V, choriocarcinoma, pure, or with embryonal carcinoma 
or seminoma or both (4,5). 
1.1.1.3. BROAD CLASSIFICATION OF TESTICULAR GERM-CELL TUMORS 
Testicular germ-cell tumors are broadly classified pathologically into two groups, as pure 
seminoma and nonseminomatous testicular germ-cell tumors ( 1,6). The nonseminomatous 
testicular germ-cell tumors are further classified as embryonal carcinoma, teratoma, and 
choriocarcinoma ( 1,6). Nonseminomatous testicular germ-cell tumors are often mixtures of 
more than one histologic type, sometimes including seminoma (1,6). The classification is 
important, convenient, and significant for the management and treatment of patients, because 
each histological type should have different treatments and has its specific biological behav­
ior, clinical outcome, and special association with different tumor markers ( 1,6). Most clini­
cal studies for tumor markers have classified the patients into these two groups and analyzed 
the impact of the use of tumor markers on each histologic morphology ( 1,6). 
1.1.1.4. CLASSIFICATION OF PREPUBERTAL TESTICULAR TUMORS 
Seminoma and choriocarcinoma are extremely rare in children, therefore, adult classifi­
cation for testicular tumors are not adequate for children (7). The section on urology of the 
Academy of Pediatrics has developed the classification of prepubertal testis tumors (7). It 
categorizes child testicular tumors as: 
I. Germ-cell tumors that include yolk sac tumor , teratoma, teratocarcinoma, and seminoma. 
2. Gonadal stromal tumors.

Marker Test Profile in Testis Cancer 131 
3. Gondablastoma. 
4. Tumors of supporting tissues (fibroma, leiomyoma, and hemangioma). 
5. Lymphomas and leukemia. 
6. Tumor-like lesion (epidermoid cyst, hyperplasic nodule attributable to congenital adrenal 
hyperplasia) . 
7. Secondary tumors. 
8. Tumors of adnexa (7). 
There is a difference of incidence of testicular germ-cell tumors between children and 
adults; only 60-75% of children's testicular tumors are germ-cell tumors, whereas 95% 
of all testicular tumors in adults are germ-cell tumors (1, 7 ). Another difference between 
adults and children is that the children have the higher incidence of benign tumors. Overall, 
the yolk sac carcinoma is the most common prepubertal testicular tumor (7). This tumor is 
also known as an endodermal sinus tumor, orchidoblastoma, embryonal carcinoma , infantile 
adenocarcinoma of the testis, and a testicular adenocarcinoma with clear cells (7). 
1.2. Incidence of Testicular Cancer 
The American Cancer Society (ASC) estimated that about 7600 new cases of testicular 
cancer were diagnosed in the year 2003 in the United States and an estimated 400 men died 
of testicular cancer in the year 2003 (8). Testicular cancer is relatively rare when compared 
to the leading cancer types for the estimated new cancer cases in 2003 in the United States. 
Leading tyes of cancers include prostate, lung and bronchus, colon and rectum, urinary blad­
der, melanoma of skin, non-Hodgkin's lymphoma, leukemia, kidney, oral cavity , liver, 
esophagus, and pancreatic cancer as estimated by the ASC (8). 
1.2.1. Age-Specific Incid ence 
Testicular cancer is relatively rare, however, it represents the most common malignancy 
in men in the 15-to 35-yr-old age group and the second most common malignancy from age 
35 to 40 in the United States ( 1). Although testicular cancer may be seen at any age, it 
usually occurs in three distinct age groups: infants and children between 0 and 10 yr, young 
adults between the age of 20 and 40 yr, and older adults over the age of 60 yr ( 1 ). 
1.2.2. Histologic Types and Age Distribution 
Different histologic types tend to occur at different age groups. Seminoma is the most 
common histologic type overall with a peak incidence between the age of 35 and 39 yr, 
however, it is rare under the age of 10 yr and above the age of 60 yr ( 1,9). Choriocarcinoma 
constitutes only 1- 2 % of testicular germ-cell tumors and is extremely rare in infancy but 
occurs more often between the ages of20 and 30 yr (1,2,9). Embryonal carcinoma and tera­
tocarcinoma are present predominantly in the age group of 25 to 35 yr ( 1,9). Yolk sac carci­
nomas are the predominant lesion of infancy and children, but are frequently found in 
combination with other histologic elements in adults (1,7). Histologically, benign pure ter­
atoma occurs most often in the pediatric age but frequently appears in combination with 
other elements in adults (1,7,9). 
1.3. Survival Improvement of Testicular Germ-Cell Tumor Patients 
There have been improvements during the past three decades in survival of patients with 
testicular germ-cell tumors ( 1,9). The survival of patients with testicular germ-cell tumors in 
the 1970s was only 10% with survival rates improving to 90% in the 1990s (1,9). The

132 Liu et al. 
advances in survival have resulted from combinations of accurate and sensitive imaging 
diagnostic techniques such as computed tomography (CT) scans and X-ray examinations; 
the successful integration of multimodal therapies including effective platinum-based com­
bination chemotherapy regimens accompanied by improved and effective antimicrobial treat­
ments with advanced general supportive therapy; improved radiation treatment, newly 
modified surgical procedures; and development and availability of clinically useful and rela­
tively specific serum tumor marker tests in testicular germ-cell tumors ( 1,6,9). A decrease in 
morbidity and mortality as a result of all these advances has resulted in an overall survival 
for patients with all stages of testicular germ-cell tumors of well over 80% and of almost 
100% for patients with low stages of disease ( 1,9). The overall 5-yr survival rates for all 
stages of disease for testicular germ-cell tumors are higher than that for any other cancers 
( 1,9). The modern approach to this disease with the above improved and effective 
multimodalities exemplifies the requirement of an effective cooperation and collaboration 
among the surgeon, oncologist, radiation therapist, radiologist, and clinical laboratory phy­
sician and scientist ( 1, 9,10 ). 
1.4. Advancements of Serum Tumor Marker Tests for Testicular Germ-Cell Tumors 
Research and development of serum tumor marker tests for testicular germ-cell tumors 
during the past four decades has resulted in better understanding of the biomolecular and 
clinical characteristics of current serum tumor markers; which help aid and confirm the 
diagnosis, facilitate case finding at the higher risk population, staging improvement, assist 
differential diagnosis of histologic types, prognostic prediction with outcome estimation, 
monitoring the response of the patients toward therapy, and early detection of recurrence 
(1, 9-11 ). These advancements allow careful follow-up with intervention and modification 
of therapy earlier in the course of disease, resulting in the survival improvement ( 1,9-11 ). 
1.4.1. Serum a-Fetoprotein , Serum Human Chorionic Gonadotropin, 
and Serum Lactate Dehydrogenase 
Accumulated clinical data show that serum a-fetoprotein (AFP), serum human chorionic 
gonadotropin (HCG), and serum lactate dehydrogenase (LD) are well-established tumor 
markers integral to the successful management of patients with testicular germ-cell tumors 
( 11 ). Based on detailed review of published reports on germ-cell tumor markers followed by 
critical appraisal by a multi-specialty group of experts and finally validation of the draft 
guidelines by specialists in medical oncology, seven medical societies and organizations 
including the Association of Clinical Biochemists in Ireland (ACBI), the American Joint 
Committee on Cancer (AJCC), the European Association of Urology (EAU), the European 
Group on Tumor Markers (EGTM), the European Society of Medical Oncology (ESMO), 
the National Academy of Clinical Biochemistry (NACB), and the Scottish Intercollegiate 
Guideline Network (SIGN) have individually developed "Practice Guidelines for Tumor 
Marker use in Germ-cell Tumors" (1 I). These reports, presenting guidelines for tumor 
marker usage in germ-cell tumors, provide useful and comprehensive summaries of relevant 
literatures ( 11 ). Except for the ACBI and the AJCC guidelines, the other five organizations' 
guidelines recommend the three tumor-marker profiles of serum AFP, serum HCG, and 
serum LD as the gold standard for the management of testicular germ-cell tumor patients 
( 11 ). The ACBI guideline recommends only serum AFP and serum HCG without including 
serum LD for staging , prognosis , detecting recurrence , and monitoring therapy only ( 11 ).

Marker Test Profile in Testis Cancer 133 
The AJCC guidelines suggest the use of serum AFP and serum HCG without serum LD and 
indicate the markers are useful for staging and prognosis only ( 11 ). 
1.4.2. Serum Lactate Dehydrogenase Isoenzyme 1 
Studies have shown that the predominant and most important isoenzyme fraction of serum 
LD; which is associated with testicular germ-cell tumors, is the lactate dehydrogenase iso­
enzyme 1 (LD-1) (4,5,12-20). Total serum LD is a highly nonspecific test (5,14). Serum 
LD-1 test is a more sensitive and specific test as a tumor marker than total serum LD for 
testicular germ-cell tumors ( 4,5,12-20 ). Serum LD-1 is a useful adjuvant tumor marker for 
diagnosis, staging, monitoring the response to therapy, detection of recurrence, and prog­
nostic estimation for patients with testicular germ-cell tumors ( 4,5,12-20 ). 
2. STAGING SYSTEMS OF TESTICULAR GERM-CELL TUMORS 
Most testicular germ-cell cancers metastasize first along the lymphatic channels to the 
lymph nodes in the retroperitoneum, along the aorta and inferior vena cava ( 1,6,9). Embryo­
logically, the testicles develop within the abdominal cavity of the fetus and therefore derive 
their blood and lymph vessels from retroperitoneal, not the scrotal sources (1,6,9) . Blood 
borne metastases usually are a late event and the lungs are the most common metastatic 
organs ( 1,6,9). At later stages , the tumors may metastasize to visceral organs; liver, brain, 
bone, or other organs ( 1,6,9). Brain involvement is often not recognized at the early stage 
( 1,9). The stage of cancer at the time of diagnosis defines the extent of cancer involvement in 
a particular patient ( 1,6,9). Clinical staging is performed preoperatively , whereas pathologic 
staging allows post-surgical assessment of the tumor size and location ( 1,6,9,10). Disease 
staging dictates the treatment protocol ( 1,6,9). Early stage disease, with the cancer confined 
to the organ of cancer origin, is effectively treated by surgery with or without adjuvant 
therapy including additional post-surgical treatments with cytotoxic drug administration and/ 
or radiation therapy ( 1,6,9,10) Pre-operative chemotherapy may be given to reduce the tumor 
size prior to the surgery ( 1 ,6,9 ). Regional extension of the cancer may determine the surgical 
treatment along with adjuvant radiation therapy or chemotherapy (1,6,9). Patients with 
metastases to distant organs require systemic treatment with cytotoxic agents (1,6,9,45). In 
testicular germ-cell tumors, the clinical staging is usually assessed following the orchiectomy 
with pathological confirmation of the histologic diagnosis. The patient is evaluated on the 
basis of noninvasive diagnostic procedures and techniques including physical examination , 
radiologic, and other diagnostic imaging techniques, such as chest X-ray, CT of abdomen, 
pelvis, brain or chest, laborator y studies including serum tumor marker tests (1,9). Patho­
logic staging systems are based on surgical procedures, including retroperitoneal lymph node 
dissection , supraclavicular lymph node biopsy, and occasionally more invasive surgery. To 
determine the extent of the disease , detectable masses are dissected for cytoreductive opera­
tions for pathological examination ( 1,6,9). 
Clinical studies of serum tumor markers at different medical centers often examine the 
extent of the disease in patients with testicular germ-cell tumors and correlate the clinical 
significance of the tumor marker status with the prognostic outcome and treatment modality 
decision. Therefore, it is relevant to be familiar with commonly used staging systems used 
by different institutions that reported their studies on the tumor marker on testicular germ­
cell tumor patients ( 1,9,10).

134 Liu et al. 
Almost all current commonly used staging systems divide patients into three groups: stage I 
or A includes those with tumor confined to the testis, stage II orB includes those with tumor 
metastasis in the retroperitoneum, and stage III or C includes those with tumor gone beyond 
the retroperitoneum (10). 
2.1. Skinner and Water Reed Pathological Staging System 
Skinner staging systems for testicular germ-cell tumors divide the disease into stage A, 
stage B, and stage C. Stage A includes those with tumor confined to testis ( 10). Stage B 
includes those with metastasis in retroperitoneum lymph nodes only; further divided into: 
stage B 1 with less than six positive nodes and nodes less than 2 em; stage B2 with more than 
six positive nodes or any node greater than 2 em and stage B3 with bulk disease, greater than 
five em ( 10). Stage C has disease beyond retroperitoneum ( 10). Walter Reed staging systems 
are similar to the Skinner staging systems ( 10). They use stage I for stage A, stage II for 
stage B, stage IIA for stage B 1, stage liB for stage B2, stage IIC for stage B3 and stage III for 
stage C in the Skinner staging systems ( 10). 
2.2. University of Texas MD Anderson 
Cancer Center Clinical Staging System 
Clinical staging at the University of Texas MD Anderson Cancer Center (UTMDACC) is 
done according to the following criteria based on the method of Samuels and associates: 
stage I patients had disease confined to the testes; stage IIA patients had microscopic evi­
dence of metastasis in retroperitoneal lymph nodes; and stage liB patients had gross evi­
dence of metastasis in retroperitoneal lymph nodes; and stage IIC patients had extracapsular 
involvement of retroperitoneal lymph nodes (21,22). Stage lilA patients had metastatic dis­
ease confined to supraclavicular nodes; stage IIIB-1 patients had gynecomastia with or with­
out elevation of serum AFP and serum HCG, but had no gross tumor detectable; stage IIIB-2 
patients had minimal pulmonary disease, with total size of metastatic lung masses less than 
40 cm3; stage IIIB-3 patients had advanced pulmonary disease with any mediastinal or hilar 
mass, and neoplastic pleural effusion or intrapulmonary masses greater than 40 cm 3; stage 
IIIB-4 patients had advanced abdominal mass and ureteral displacement with obstructive 
uropathy (21,22). Stage IIIB-5 patients had visceral disease (excluding the lungs) with 
metastasis to visceral organs such as the liver, gastrointestinal tract, brain, and inferior vena 
cava (21,22). One difference from the other staging system is that the advanced abdominal 
disease is classified as a very advanced disease as stage IIIB-4 (21,22). 
2.3. International Germ-Cell Consensus Classification 
The International Germ-Cell Collaboratory Group (IGCCC) developed a new staging clas­
sification of independent prognostic variables to predict survival for patients with metastatic 
testicular germ-cell tumors following analysis of a large population of over 5000 patients 
designated as the International Germ-cell Consensus Classification (IGCCC) (23 ). The prog­
nostic variables in the IGCCC staging system included the number of metastatic sites as well 
as concentrations of three serum tumor markers including serum LD, serum AFP, and serum 
HCG (23 ). This staging system has three new features compared with previous classification 
systems: first, patients with seminoma have a better prognosis than patients with 
nonseminomatous germ-cell tumor; second, that patients with distant extrapulmonary 
metastases have a poor prognosis ; and third, it includes three serum tumor markers of serum

Marker Test Profile in Testis Cancer 135 
LD, serum AFP, and serum HCG. The IGCCC separated patients into three categories based 
on the prognostic variables including the pretreatment concentrations of three serum tumor 
markers that contribute to the classification of metastatic germ-cell tumors as having good 
prognosis disease, intermediate prognosis disease, or poor prognosis disease (23 ). The stag­
ing system has been supported by many studies. The IGCCC recommends oncologists use 
serum LD, serum AFP, and serum HCG as the "gold standard" in the staging of patients 
together with sites of metastases for patients with metastatic testicular germ-cell tumors 
(23 ). Treatment strategy may be based on three categories of patients with metastatic testicu­
lar germ-cell tumors. Patients with a good prognosis receive the standard regimen with less 
toxicity and fewer side effects, whereas patients with poor prognoses receive more intensive 
chemotherapy to obtain a chance of cure even with the risk of higher toxicity (24). 
2.4. The International Union Against Cancer TNM Staging System 
The fifth edition of the International Union against Cancer (UICC) TNM Staging System 
includes the prognostic value of the pretreatment marker concentrations of serum LD, serum 
AFP, and serum HCG established by the International Germ-cell Collaboratory Group . 
Additionally the conditions ofT (primary tumor), N (lymph node metastasis), and M (dis­
tant metastasis) in the staging of patients with metastatic testicular germ-cell tumors (25) are 
included. It appears that the IGCCC was the bone frame of the fifth edition of the TNM 
staging classification (23,25). Using these criteria, the patients are grouped into three stages. 
Pretreatment marker concentrations contribute to the classification of patients with meta­
static germ-cell tumors as having low-, intermediate-, or high-risk subgroups similar as in 
the IGCCC (25 ). 
3. BIOMOLECULAR AND CLINICAL CHARACTERISTICS 
OF TUMOR MARKERS 
Understanding the biomolecular and clinical characteristics of each clinical useful serum 
tumor marker is essential for appropriate use of the tumor marker tests to gain the best ben­
efits for patients and reach the maximum effective treatment outcome. The biomolecular and 
clinical characteristics of the four clinically useful tumor markers including serum AFP, 
serum HCG, serum LD and, serum LD-1 isoenzyme are shown below. Although there are 
other tumor markers that have been reported to be elevated in some patients with testicular 
germ-cell tumors, these tumor markers did not provide significant clinical decision making 
information and are not recommended for clinical use for the management of patients. 
3.1. Biomolecular and Clinical Characteristics of AFP 
AFP is an oncofetal protein. AFP was the first tumor associated antigen to be used as a 
tumor marker in the clinical management of human malignancies. AFP is a glycoprotein 
with molecular weight of 61,000 to 70,000 Da, similar to albumin chemically and physically 
with a single polypeptide chain with interior regions homologous with human albumin. It 
has an isoelectric point of 4.8 and migrates as a homogeneous a-globulin on electrophoresis 
in an alkaline media. Chemically, it consists of 95% protein and 5% carbohydrate. AFP is 
synthesized in the liver , yolk sac, and gastrointestinal tract of the fetus and is a normal 
component of serum protein in human fetus older than 6 wk. The peak fetal serum AFP 
concentrations may reach 3-4 mg/dL by wk 12 to 15 of gestation. The predominant fetal 
serum protein serves many functions in fetus, as albumin does in the postnatal period. At

136 Liu et al. 
birth, serum AFP declines to 30 [tg/mL. At 1 yr of age, serum AFP decreases to normal adult 
value. The normal serum AFP range in adult is 2-10 ng/mL. Each laboratory should study, 
evaluate, and establish its own reference value independently , depending on the individual 
assay kit. The biological circulating metabolic half-life of serum AFP is 5 d. Using the sen­
sitive and specific RIA or EIA assays, elevated serum AFP may be observed in a wide vari­
ety of both malignant and benign disorders. Serum AFP elevations have been reported in the 
following malignant disorders: hepatoma, testicular, and ovarian germ-cell tumors , malig­
nant mixed Mullerian tumor of the ovary, gastric cancer, pancreatic carcinoma, male breast 
cancer, renal cell carcinoma, colonic carcinoma, and bronchogenic carcinoma. Increased 
serum AFP concentrations have been reported in benign conditions with viral hepatitis, 
chronic active hepatitis, postnecrotic and primary biliary cirrhosis, tyrosinemia, ataxia 
telangiectasia , and normal and abnormal pregnancy (26-44 ). 
3.2. Biomolecular and Clinical Characteristics of HCG 
Measurement of elevated HCG in serum or urine has been used to diagnose pregnancy. 
HCG is a glycoprotein with molecular weight of 45,000 Da with branched carbohydrate side 
chains that terminate with sialic acid. HCG is normally compos ed of two dissimilar sub­
units, a and j3 polypeptide subunits. The a subunit of HCG has a molecular weight of 15,000-
20,000 Da and is identical to and indistinguishable from that of pituitary hormones, including 
luteinizing hormone (LH), thyroid stimulation hormone (TSH), and follicular stimulation 
hormone (FSH). a-Subunit serves only as a carrier for the j3-subunit chain. The j3-subunit of 
HCG, which has molecular weight of 25,000 -30,000 Dais a biologically active component. 
The j3-subunit or C-terminal part of the j3-subunit of HCG is structurally and antigenically 
distinct from that of the three pituitary hormones and therefore is specific immunogenically. 
During pregnancy, HCG is synthesized and secreted by the syncytiotrophoblastic cells of 
normal placenta. HCG is also secreted by various malignant neoplasms. HCG is normally 
absent or present in minimal amounts in the sera of nonpregnant women. The circulating 
half-life of serum HCG is between 24 and 36 h. The availability of sensitive and specific 
immunoassays for serum HCG using antibody against the j3-subunit of HCG that do not 
crossreact with pituitary hormones including LH, TSH, and FSH has improved the diagnosis 
and management of normal and abnormal pregnancy, trophoblastic disease, and various 
malignant diseases. Malignant diseases with increa sed serum HCG are testicular and ova­
rian germ-cell tumors, breast cancer, melanoma, gastrointestinal tract cancer, hepatoma, 
pancreatic carcinoma, sarcoma, lung cancer, renal cancer, multiple myeloma , and other 
hematopoietic malignancies ( 39,40,45-60 ). 
3.3. Biomolecular and Clinical Characteristics of LD 
LD is a ubiquitous cellular enzyme with molecular weight of 134,000 Da. It is present in 
the cytoplasm of all the cells and tissues in human body. It is a zinc containing enzyme that 
is part of the glycolytic pathway (61 ). It is particularly abundant in smooth , cardiac, and 
skeletal muscle s; liver, kidney , and brain ( 14,61 ). Serum LD test is a highly nonspecific test; 
an abnormal elevation in serum can be caused by damage to any organs or by prolif eration of 
any tissues (61 ). Therefore , elevations of total serum LD do not provide clinicall y specific 
diagnostic information without the correlation of additional clinical and/or laboratory test 
findings (61 ). Elevations of total serum LD may be seen in myocardial injury, pneumocytis 
carinii pneumonia , toxic or ischemic liver injury , megaloblastic anemia, hemoly tic anemia ,

Marker Test Profile in Testis Cancer 137 
sepsis, or other causes of shock causing multiple organs damages and cardiopulmonary arrest, 
skeletal muscle injury, renal cortical infarct, and advanced malignant diseases including lym­
phoma, leukemia, multiple myeloma, renal cell carcinoma, ovarian dysgerminoma and tes­
ticular germ-cell tumors (5,14,61). Total serum LD concentrations have been used as one of 
the three tumor marker profiles for testicular germ-cell tumors and reported to be a clinically 
useful tumor marker in diagnosis; monitoring the patient's clinical course, in staging , and 
for prognostic prediction for patients ( 11,23,25 ). However, because of its low specificity, 
serum LD test results must be correlated with other clinical and laboratory findings for diag­
nosis and management of the patient (4,5,61 ). 
3.4. Biomolecular and Clinical Characteristics of LD-1 
LD appears in serum and is present in tissues as five distinct isoenzymes that are tetram­
ers of two active subunits, H designated for heart and M designated for muscle . These five 
isoenzymes are represented by LD-1 (HHHH ), LD-2 (HHHM ), LD-3 (HHMM), LD-4 
(HMMM), and LD-5 (MMMM) (14, 61). They can be separated by electrophoretic tech­
nique on the basis of their mobility (14,61). LD-1 is the fastest anodally migrating isoen­
zyme and LD-5 is the slowest (14). Relative percentage of these five isoenzym es in the 
serum and various tissues is different and is useful in differential diagnosis of elevated 
total serum LD ( 14,61 ). The half-lives of LD isoenzymes are different for each LD isoen­
zymes (61) The half-life for LD-1 is approx 4--4 112 d, whereas that ofLD-5 is from 4 to 6 h 
(61). The LD isoenzymes are present in many human tissues with various percent of distri­
butions (14,61). Heart, kidney, brain, and erythrocytes have abundant LD-1, whereas liver, 
skeletal muscle and skin show the highest activity of LD-5 ( 14,61 ). 
Elevation of serum LD-1 is observed in patients following myocardial infarction, renal 
infarction, hemolytic anemia, and megaloblastic anemia (14,61). An increase in serum 
LD-5 is observed in diseases associated with hepatic cell or skeletal muscle damage ( 14,61 ). 
Three different types of LD isoenzyme patterns have been observed in a variety of malig­
nancies. An elevated LD-5 to LD-1 ratio has been noted in malignant prostatic tumor , pros­
tatic fluids, and in the serum of patients with prostatic carcinoma ( 14,61). A general increase 
in LD-2 , LD-3, and LD-4 isoenzymes has been observed in the serum of patients with leuke­
mia, malignant lymphoma, metastatic carcinoma, neuroblastoma, and oral cancer (14,61). 
Serum LD-1 isoenzymes have been found elevated in the serum of patients with osteosar­
coma and germ-cell tumors of the testis and the ovaries ( 14,61). If further identification of 
the source of the abnormal incre ase of total serum LD is indicated, electro phor etic separa­
tion of the five isoenzymes and the isoenzyme patterns may provide more specific clinical 
information, if alternative clinical and laborator y means cannot help differentiate the cause 
of abnormality (14,61). 
4. ASSOCIATION OF TUMOR MARKERS AND HISTOLOGIC TYPES 
OF TESTICULAR GERM-CELL TUMORS 
4.1. Demonstration of Tumor Markers in Testicular Germ-Cell Tumor Tissu es 
of Specific Histological Type 
Various tumor markers have been shown to be present in the tumor cells or the cytosol of 
tumor tissues of specific histologic types of testicular germ-cell tumors using immunohis­
tochemical stainin g (12,62 -68).

138 Liu et al. 
4.1.1. AFP in Testicular Germ-Cell Tumor Tissues of Various Histologic Types 
Utilizing indirect immunoperoxidase technique, AFP was shown positive in the tumor 
tissue of 13 of 15 cases of yolk sac tumors, in 3 of 11 cases of teratoma , and in 3 of 14 cases 
of embryonal carcinoma (62). Another study using an immunop eroxidase technique shows 
that AFP positivity was not found in the tumor tissue of 30 patients with seminoma; how­
ever, AFP was positive in 12 cases with endodermal sinus tumor elements, and additionally, 
in solid cell clusters in embryonal carcinoma areas , arising as a component of a mixed germ­
cell tumor (63 ). The same study also shows AFP-positivity in 54% of 37 cases with 
nonseminomatous tumors (63). Simultaneous measurements of AFP concentrations in the 
peripheral serum and tumor cytosol of 40 patients with nonseminomatous testicular cancer 
show that serum AFP levels were normal in 13 of these 40 patients but AFP levels were 
elevated in 7 (54%) of 13 tumor cytosols from these 13 patient s with normal serum AFP 
levels, indicating that tumor cytosols are more likely to have elevated levels of AFP than are 
sera in patients with testicular tumors (64). 
4.1.2. HCG in Testicular Germ-Cell Tumor Tissues of Various Histologic Types 
The use of immunop erox idase technique to localize HCG to spec ific histologic types of 
testicular germ-cell cancers, HCG was positive for syncytiotrophoblasts in 14 of 15 cases of 
nonseminomatous testicular germ-cell tumors, and for syncytiotrophoblasts in two of two 
cases of choriocarcinoma (62). Another study using an immunoperoxidase technique shows 
HCG-positivit y in 51% of 37 nonseminomatous tumors (63 ). The same study shows that the 
HCG was localized in syncytiotrophoblastic-like giant cells, occurr ing in chor io­
carcinomatous elements and as single cells in embryonal carcinomas, teratocarcinomas, and 
yolk sac tumors ( 63 ). In the tumor tissues of 30 patients with seminomas, only one case of 
HCG positive giant cells was observed (63 ). The status of immunohistochemical expression 
of HCG was examined in 45 seminoma tumor tissues and immunohistochemical expression 
of HCG was observed in syncytiotrophoblastic giant cells in 11 tumors and a few mono­
nuclear seminoma cells in 36 tumors (65). HCG positivity is also seen in mononuclear 
embryonal carcinoma cells (66). Simultaneous measurements of HCG in the peripheral 
serum and tumor cytosol of 40 patients with nonseminomatous testicular cancers show that 
serum HCG levels were normal in 16 of 40 patients but HCG levels were elevated in 13 of 16 
(81 %) tumor cytosols from these patients with normal serum HCG levels. These findings 
indicate that tumor cytosols are more likely to have elevated levels of HCG than are sera in 
patients with testicular germ -cell tumors ( 64 ). 
4.1.3. LD-1 in Testicular Germ -Cell Tumor Tissues of Various Histologic Types 
Elevated LD-1 isoenzyme pattern was demonstrated in both the tumor tissue and the serum 
of patients with seminoma and dysgerminoma as reported by Zondag in 1964 ( 12). Using 
antiserum to LD-1 , Murakami and Said determined immunohistochemical pattern of local­
ization of LD-1 in the tumor tissues in several histopatho logic types of testicular germ -cell 
tumors. LD I was found to be positive in the tumor tissues of all 29 seminomas and terato­
carcinomas and four of seven embryonal carcinomas (67). These results suggest that elevated 
serum LD 1 found in patients with testicular germ-ce ll tumor s is synthesized and secreted 
into the circulation directly from the tumor cells as evidence of the association of serum LD-1 
levels with the testicular germ-cell tumor. In addition, the levels of serum LD-1 may be 
related to the tumor burden (67).

Marker Test Profile in Testis Cancer 139 
In addition , a study of LD isoenzyme patterns in both the tumor tissues and the serum of 
children with yolk sac tumors showed an elevated LD-1 in both the tumor tissue s and the 
serum of the patients. On the basis of these findings, it is easy to assume that increased 
LD-1 in the serum of patient s with yolk sac tumors is derived from tumor tissues , suggesting 
that serum LD-1 is useful as a tumor marker for yolk sac tumors, although it is not specific, 
and associated with other histologic types of testicular germ-cell tumors (68). 
4.2. Abnormal Serum Tumor-Marker Concentrations in Patients With Different 
Histologic Types 
4.2.1. Association of Serum AFP and Histopathol ogy of Testicular Germ-Cell Tumor 
Highly elevated serum AFP concentrations are present in patients with tumors containing 
endodermal sinus (yolk sac) tumor elements irrespective of the location of the neoplasm or 
presence or absence of metastatic disease (69,70). There is good correlation between the 
presence and quantity of endodermal sinus (yolk sac) tumor elements within the primary 
tumor or its metastases and elevated levels of serum AFP (69, 70). All patients with tumors 
composed of pure seminoma or dysgerminoma , and teratoma have normal serum AFP levels 
(69). Slight elevations of serum AFP up to 60 ng/mg are observed in a few patients with 
testicular tumors composed of pure embryonal carcinoma, whereas patients with tumors 
composed of or containing endodermal sinus (yolk sac) tumor elements have serum AFP 
levels measured up to 1 OOs or 1 OOOs of ng/mL. Serum AFP would be elevated only in patients 
with active disease (69). Serum AFP in all patients with gonadal tumors of non germ-cell 
origin is normal (69). Serum AFP is a useful tumor marker for nonseminomatou s testicular 
germ-cell tumors. Serum AFP was elevated in 67% of patients with advanced nonsemi­
nomatous germ-cell testicular tumors (71 ). 
4.2.2. Association of Serum HCG and Histopathology of Testicular Germ-Cell Tumor 
Elevated serum HCG is correlated and relatively specific to choriocarcinoma (39,40, 
70-72). In one report on patients with advanced nonseminomatous testicular germ -cell 
tumors, patients with choriocarcinoma always have elevated HCG (72). However , serum 
HCG elevations are also observed in seminoma, and all other histolo gic subtypes of 
nonseminomatous testicular germ-cell tumors ( 39,40,65,66). The frequency of elevated 
serum HCG measured by immunoassays has been estimated to be 15% for seminoma, 50% 
for embryonal carcinoma, 42% for teratocarcinoma , and 100% for chor iocarcinoma (39,40). 
4.2.3. Association of Serum LD-1 and Histopathology of Testicular Germ-Cell Tumor 
Elevated serum LD-1 has been shown in patients with seminomas ( 12,13). Serial determi ­
nations of serum LD-1 in eight children with yolk sac tumors show seven had elevated serum 
LD-1 and one without serum LD-1 abnormality had early stage of disease (68). Abnormal 
levels of serum LD-1 activity have been observed in 34 of 42 patients (81%) with stage III 
testicular germ-cell malignancy ( 14). Serum LD-1 elevation occurred in 4 of 6 patients (67%) 
with group 1-pure seminoma , 17 of 21 patients (81 %) with group 11-embryona l carcinoma, 
pure, or with seminoma, 8 of 10 patients (80%) with group IV -teratoma with either embryo­
nal carcinoma or choriocarcinoma or both , and all (100%) of the five patients with group 
V -choriocarcinoma, pure or with embryonal carcinoma or seminoma, or both ( 14 ). In another 
group of 166 patients with stage I, stage II, and stage III testicular germ-cell tumors, abnor­
mal serum LD-1 was observed in 11 of 18 patients (61 %) with group I-pure seminoma; 39 of

140 Liu eta!. 
67 patients (58%) with group II-embryonal carcinoma, pure, or with seminoma; I of 2 
patients (50%) with group III-teratoma, pure, or with seminoma; 29 of 63 patients (46%) 
with group IV -teratoma, with either embryonal carcinoma or choriocarcinoma or both, and 
with or without seminoma; and 8 of 16 patients (50%) with group V -choriocarcinoma, pure, 
or with embryonal carcinoma or seminoma or both (4,5). 
4.3. Summary: Association of Tumor Markers and Histological Types 
Based on the findings of the association of tumor markers both in tumor tissues and in the 
serum with the histologic types of testicular germ-cell tumors, the relationship between the 
tumor markers and the histologic types of testicular germ-cell tumors is summarized below. 
Pure seminoma is associated with serum-HCG, serum-LD, and serum-LD 1 and must not 
have elevated serum AFP. If a patient, diagnosed by a surgical pathologist to have a pure 
seminoma, has elevated serum AFP; he must have nonseminomatous germ-cell components 
either in the primary tumor undetected and/or in undetected metastatic sites. Further studies 
with step sectioning of the tumor tissue or other means would usually find the 
nonseminomatous germ-cell tumor components; therefore, treatment has to be modified and 
treated the same as for the nonseminomatous germ-cell tumors. The embryonal carcinoma 
or mixed germ-cell tumor containing the embryonal components may have elevation of 
serum AFP, serum HCG, serum LD, and serum LD-1, yolk sac tumor is associated with 
increased serum AFP, serum LD, and serum LD-1, whereas choriocarcinoma is associated 
with serum HCG, serum LD, and serum LD-1. Mature teratoma does not have good tumor 
markers. 
5. CLINICAL ROLE AND SIGNIFICANCE OF TUMOR MARKERS 
The serum tumor-marker test profile of serum AFP, serum HCG, serum LD, and serum 
LD-1 play a significant role in diagnosis, staging, estimation of prognosis, monitoring the 
clinical course, and detection of recurrence of the patients with testicular germ-cell tumors 
(4,5, 11-20). Clinical role and significance of serum tumor markers for testicular germ-cell 
tumors are discussed below. 
5.1. Diagnostic Purposes 
Ideally, serum tumor marker tests for testicular germ-cell tumors should have the diag­
nostic ability to detect and diagnose all patients with testicular germ-cell cancers in all age 
groups of men and have the ability of providing a negative test result in all men without 
testicular germ-cell tumors, but may have other benign or malignant disorders and condi­
tions. Unfortunately, like other currently available serum tumor marker tests, none of the 
four serum tumor marker tests for testicular germ-cell tumors possesses these characteristics 
of making a diagnosis easily. Therefore, the clinical usage of these serum tumor-marker 
tests, though very valuable in the management of testicular germ-cell cancer patients, is of 
limited value and may have greater value in other certain applications. 
5.1.1. Screening for General Asymptomatic Population: Not Recommended 
Because of insufficient clinical diagnostic sensitivity and clinical diagnostic specificity, 
all four currently available serum tumor marker tests may produce a significant degree of 
false-positive and false-negative test rates, which leads to the inability of these serum tumor 
marker tests to be used independently for cancer screening in the asymptomatic general

Marker Test Profile in Testis Cancer 141 
population or as the sole criterion for making or ruling out a diagnosis of testicular germ-cell 
tumors ( 11,7 3 ). Therefore, they are not recommended as screening tools to independently 
detect and diagnose testicular germ-cell cancers for the general asymptomatic population of 
men. None of the seven published "Practice Guidelines for Tumor Marker Use in Germ-Cell 
Tumors" recommends that the three tumor-marker tests including serum AFP, serum HCG, 
and serum LD be used as screening tools for general asymptomatic populations ( 11 ). The 
same principle can be applied to serum LD-1 tumor marker test, because of its similar lim­
ited clinical diagnostic sensitivity and specificity (4,5,14,15). However, an increasing 
understanding of cancer biology based on advances in basic sciences and technolo gy has led 
to proper uses of these serum tumor-marke r tests in correlation with clinical findings, other 
laboratory findings, and diagnostic imaging findings. This in turn, has provided a positive 
impact in the areas of cancer diagnosis and management, including case findings on symp­
tomatic or high-risk individuals, diagnosis in patients with cancer, staging of diseases, cor­
rection of histopathological types and selecting the therapeutic modality, monitorin g the 
clinical course of patients, and estimation of progno sis and outcome ( 11,73 ). 
5.1.2. Case Findings on Symptomatic Patients or High-Risk Individuals 
Cancer screening using only serum tumor-marker tests should not be performed on the 
asymptomatic general population but can be done for symptomatic and high-risk individuals 
in conjunction with other diagnostic means ( 11,73 ). For example , serum total PSA is now 
considered the best screening tumor-marker test for prostate cancer for high-risk age popu­
lations and symptomatic individuals ( 11,73 ). It is accepted as an important component in the 
diagnostic algorithm used in early detection of prostate cancer in combination with the digi­
tal rectal examination (73 ). The serum PSA screening program detects cancer at the earlier 
stages (73 ). There is increasing evidence of its success in efficacy of radical prostatectomy 
and to reduce prostate cancer mortality rates (73 ). Serum AFP is also used as a screening tool 
for primary hepatoma in China , because of high incidence of hepatoma in that country (73 ). 
Ovarian cancer is often discovered and diagnosed at the advanced stage, therefore the use of 
serum CA 125 as a scree ning tool to detect ovarian cancer is being studied for early detec­
tion of ovarian cancer for the high-risk population (73 ). Serum tumor-marker tests fortes­
ticular germ-cell tumors may be used in combination with physical examination (palpitation 
of the scrotum) and ultrasound examination for detection of the scrotal mass for case find­
ings in the high-risk population, particularly in patient s with symptoms and signs suggest ive 
of testicular germ-cell tumors ( 11 ). Five of the seven published "Practice Guidelines for 
Tumor Marker Use in Germ-Cell Tumors" including those by the EAU, EGTM, ESMO, 
NACB and SIGN, recommend the use of serum AFP , serum HCG, and serum LD for detec­
tion purposes ( 11 ). Serum LD- 1, which reports similar diagnostic specificity for testicular 
germ-cell tumors as serum AFP and serum HCG, can be used for this purpose (4,5,12-20). 
5.1.3. Diagnosis in Patients With Cancer 
The serum tumor-marker tests for testicular germ-cell tumors cannot be used as the sole 
criterion to make a diagnosis of testicular germ-cell cancer resulting from the lack of accept­
able clini cal diagnostic specificity . Serum AFP, serum HCG, serum LD, and serum LD-1 are 
not spec ific for testicular germ -cell cancers, and they may be elevated in benign and malig ­
nant conditions other than testicular germ-cell tumors (see Section 3.). However, in patients

nant conditions other than testicular germ-cell tumors (see Section 3.). However, in patients 
with suspicion of testicular germ-cell tumors, the serum tumor -marker tests, particularly

142 Liu et al. 
serum AFP, and serum HCG are specific and only rarely do patients with elevations of these 
tumor markers not have testicular germ-cell tumors (6,45). A young male patient with a hard 
mass in one of his testicles with an elevation of either or both serum AFP and serum HCG is 
highly suggestive of testicular germ-cell cancer and most likely has a testicular germ-cell 
tumor. Rarely, this young man will be ruled out for that disease (6,45 ). Serum LD-1 eleva­
tions also have the similar ability to provide this degree of relative diagnostic specificity 
(4,5,12-20). 
Although serum tumor-marker tests for testicular germ-cell tumors cannot be used inde­
pendently to make a diagnosis of testicular germ-cell tumor, they can serve as a confirma­
tory aid in the diagnosis of symptomatic patients ( 11 ). As an adjuvant in cancer diagnosis, 
these serum tumor-marker tests offer an opportunity to provide an early diagnosis ( 11 ). In 
early diagnosis, when the cancer is still localized to the testis, patients can receive curative 
treatment earlier and easier. Normal serum tumor-marker test results must not be used to 
rule out a diagnosis of testicular germ-cell cancer, because a portion of patients with cancer 
do not have elevation of serum tumor markers (6,45). Surgical exploration and histopatho­
logical examination and diagnosis remain the most insured method of diagnosis (6). Five of 
the seven published "Practice Guidelines for Tumor Marker Use in Germ-Cell Tumors" 
including those by the EAU, EGTM, ESMO, NACB and SIGN, recommend the use of serum 
AFP, serum HCG, and serum LD for the purpose of diagnosis in testicular germ-cell tumors 
( l1 ). To improve the clinical diagnostic sensitivity and diagnostic specificity, use of mul­
tiple serum tumor-marker tests is observed and recommended for all cancer markers (73). 
5.1.3.1. TUMOR-MARKER PROFILE OF SERUM AFP AND SERUM HCG 
The tumor-marker test profile of serum AFP and serum HCG has been shown to be the 
best tumor-marker system in human oncology, even though serum AFP and serum HCG are 
also elevated in the circulation of patients with other malignant and benign disorders ( 6,45 ). 
Simultaneous assay of both serum AFP and serum HCG for patients with nonseminomatous 
germ-cell tumors has shown to increase clinical diagnostic sensitivity (40). Serum AFP was 
abnormal in only 58% of patients with nonseminomatous germ-cell tumors and serum HCG 
was positive in 77% of the same group of patients. If both serum AFP and serum HCG were 
used together, 91% of these patients showed either serum AFP or serum HCG or both eleva­
tions (40). Combined use of both serum AFP and serum HCG increases the clinical diagnos­
tic sensitivity and when both markers are positive for a patient, the diagnostic specificity is 
also increased because rare disorders in men cause increase of both serum AFP and serum 
HCG concurrently (6,45). 
5.1.3.2. TUMOR-MARK ER PROFILE OF SERUM AFP, SERUM HCG, AND SERUM LD 
A study of 62 patients with advanced nonseminomatous testicular germ-cell tumors by 
measurements of serum HCG, serum AFP, serum LD, and serum carcinoembryonic antigen 
(CEA) shows that serum CEA was determined not a useful tumor marker for testicular germ­
cell tumors (71 ). Serum HCG was elevated in 64% of the patients, serum AFP elevation was 
observed in 67% , and serum LD was increased in 62% (71 ). Either serum HCG or serum 
AFP was elevated in 86% of the patients (71). We examined and recalculated the data 
included in the study and found that 41 patients had simultaneous assays of all the three 
tumor markers of serum HCG, serum AFP, and serum LD. Of these 41 patients, 16 (39%) 
had all the three markers , serum HCG, serum AFP , and serum LD elevations, 5 (12%) had 
both serum HCG and serum AFP increases, 2 (5%) had both serum HCG and serum LD 
abnormalities, 4 (I 0%) had both serum AFP and serum LD elevations, 3 (7%) had elevation

Marker Test Profile in Testis Cancer 143 
of serum HCG only, 5 ( 12%) had an increase of serum AFP on! y, and 3 (7%) had a serum LD 
abnormality only (71 ). Addition of serum LD to the serum tumor-marker test profile of 
serum HCG and serum AFP has increased the clinical diagnostic sensitivity of 7% (71). 
Combined use of all three marker tests shows that at least one of these three tumor markers 
was elevated in 91% of patients (71 ). There is still 9% of patients with diseases that have 
normal serum tumor-marker levels (71 ). Another prospective study of 80 patients with tes­
ticular germ-cell cancers by simultaneous and serial determinations of serum LD, serum 
AFP, and serum HCG shows serum LD elevation in 78% of the stage III patients, serum AFP 
abnormality in 78.6%, and serum HCG elevation in 76.2% (74) Serum HCG and serum AFP 
concentrations were always elevated in the presence of elevated serum LD levels except in 
one patient when serum LD was the only elevated tumor marker, in which case changes of 
serum LD values correlated with clinical disease (74). These two reports indicate that addi­
tion of total serum LD test as a tumor-marker test to the profile of serum AFP and serum 
HCG improves clinical diagnostic sensitivity (71,74). 
5.1.3.3 . TUMOR -MA RKER PROFILE OF SERUM AFP , SERUM HCG, AND SERUM LD-1 
Simultaneous measurements of serum AFP and serum HCG and serum LD-1 were done 
in 166 patients with stage T, stage IT, and stage III testicular germ-cell tumors to evaluate the 
clinical usefulness of serum LD-1 levels as an additional tumor-marker test ( 4,5 ). Serum 
AFP level was elevated in 90 of 166 patients (54%), serum HCG level was increa sed in 101 
of 166 patients (61% ), and serum LD-1 level was abnormal in 88 of 166 patients (53%) ( 4,5 ). 
Of these 166 patients, 35 (21%) had elevations of all three tumor markers , 30 (18%) had 
elevations of both serum AFP and serum HCG levels, 13 (8%) had elevations of both serum AFP 
and serum LD-1 values, 25 (15%) had an increase of both serum HCG and serum LD-1 con­
centrations, 12 (7%) had elevations of serum AFP only, 11 (7%) had elevation of serum 
HCG only, and 15 (9%) had elevation of serum LD-1 only ( 4,5 ). At least one of these three 
tumor markers was elevated in 141 (85%) of the 166 patients (4,5) . Adding serum LD-1 to 
the tumor-marker test profile of serum AFP and serum HCG increased the clinical diagnos­
tic sensitivity from 76 to 85% (4,5). Fifteen of these 166 patients (9%) who did not have 
either serum AFP or serum HCG abnormality benefited from having serum LD-1 as a tumor 
marker for management and treatment (4,5). Serum LD-1 is a useful tumor-marker test for 
testicular germ-cell cancers ( 4,5,12-20 ). The addition of serum LD-1 to the test profile of 
serum AFP and serum HCG not only has increased the diagnostic sensitivity but has 
increased the clinical diagnostic specificity when multiple tumor markers are elevated in one 
patient (4,5,12-20). Serum LD-1 is a useful tumor marker for testicular germ-cell tumors 
(4,5,12-20). In another group of 18 patients with pure seminomatous testicular germ-cell 
tumors, 10 patients (55%) had elevation s of serum HCG and 11 patients (61%) had elevation 
of serum LD-1 (5). When these two serum tumor-marker tests were used together, 9 (50%) 
had elevations of both serum HCG and serum LD-1 , 1 patient (5%) had only serum HCG 
elevation, and 2 (10%) had only serum LD-1 abnormality (5). At least one of these two 
serum tumor-marker tests would be elevated in 13 of the 18 patients (65%) (5). Therefore, 
the combined use of serum LD-1 and serum HCG as the tumor-marker test profile has 
increased the clinical diagnostic sensitivity for seminoma ( 5 ). 
5.1.3.4. TUMOR-M ARKER PROFILE OF SERUM AFP , SERUM HCG , SERUM LD, AND SERUM LD-1 
Fifty-eight patients, with histologically confirmed testicular germ-c ell tumors, were evalu ­

ated with simultaneous assays of all the four tumor markers including serum AFP, serum 
HCG, serum LD, and serum LD-1 (15). Postsur gically, 21 of these 58 patients had no evi-

144 Liu et al. 
dence of diseases, whereas 37 had evidence of disease. Of these patients, 19 had stage II and 
18 had stage III diseases ( 15). Serum HCG, serum LD, and serum LD-1 (except serum AFP) 
were all within the normal limits in the 21 patients who had no evidence of diseases ( 15 ). 
However, 2 of the 21 disease-free patients had elevated serum AFP immediately after the 
surgery ( 15 ). The elevated serum AFP values in these two patients declined to normal level 
in the follow-up ( 15 ). In this study, the serum LD-1 abnormality was defined in three crite­
ria; serum LD-1 absolute value expressed in absolute enzyme activity as U/L, greater than 
the upper limit of reference values; serum LD-1/total serum LD ratio greater than 0.25; and 
the third abnormality defined as serum LD-1/serum LD-2 ration greater than 0.8 ( 15 ). Of the 
37 patients with stage II and stage III testicular germ-cell tumors, 21 (57%) had elevations of 
serum LD, 14 (38%) had elevations of serum AFP, 25 (67%) had elevations of serum HCG, 
and 22 (60%) had serum LD-1 abnormality (15). Twenty of the 22 patients with serum LD-1 
abnormality had elevated serum LD-1 absolute value ( 15 ). The elevation of serum LD-1 
absolute values overlapped significantly with the elevated serum LD ( 15 ). Twenty of 21 
patients with elevated serum LD had elevated serum LD-1 absolute values ( 15 ). Of the 20 
patients with elevated serum LD-1, absolute values also included most patients with elevated 
serum LD-1/serum LD ratios and elevated serum LD-1/serum LD-2 ratios (15). Of the 37 
patients with stage II and stage III testicular germ-cell tumors, 9 had seminoma and 28 had 
nonseminomatous germ-cell tumors ( 15). Serum HCG level was elevated in 6 of 9 patients 
(67%) with seminoma and serum LD-1 value was elevated in 7 of 9 patients (78%) with 
seminomas (15 ). Further analysis shows that 5 of 9 (56%) patients with seminoma had 
elevations of both the serum HCG level and the serum LD-1 value, 1 of 9 patients ( 11%) had 
elevation of serum HCG only, and 2 of 9 patients (22%) had serum LD-1 elevation only ( 15 ). 
When the two serum tumor-marker tests were used simultaneously, the clinical diagnostic 
sensitivity increased to 8 of9 (88%) patients from 67% for serum HCG and 78% for serum 
LD-1 (15 ). In the group of 28 patients with nonseminomatous germ-cell tumor, 19 patients 
(68%) had serum HCG elevations, 14 (50%) had serum AFP elevations and 13 (46%) had 
serum LD-1 elevations ( 15 ). Of these 28 patients, 7 (25%) had elevations of all the serum 
AFP, serum HCG, and serum LD-1, 3 (11 %) had elevations both serum AFP and serum 
HCG, 2 (7%) had elevations of both serum AFP and serum LD-1, 2 (7%) had elevations of 
both serum HCG and serum LD-1, 2 (7%) had elevations of serum AFP only, 7 (25%) had 
elevations of serum HCG only, and 2 (7%) had elevations of serum LD-1 only ( 15 ). When 
all serum tumor-marker tests were assayed simultaneously, the clinical diagnostic sensitiv­
ity increased to 25 of 28 patients (89%) from the range of 46 to 68% when a simple serum 
tumor-marker test was used ( 15 ). 
5.1.4 . Summary of the Role of Tumor-Marker Test for Diagnostic Purposes 
In summary, the currently available serum tumor-marker tests for testicular germ-cell 
tumors should include serum AFP, serum HCG, serum LD, and serum LD-1. The serum 
tumor-marker tests should not be used in screening the general asymptomatic population 
for the purpose of making or ruling out a diagnosis of testicular germ-cell tumors. The serum 
tumor-marker tests may be applied for case findings on symptomatic patients and high-risk 
individuals. When they are utilized for diagnosis, they should not be used as the only crite­
rion or utilized independently to make a diagnosis because of potential false positive test 
results or rule out a diagnosis because the test results are negative because of high false­

negative results. They should be used as a confirmatory aid in diagnosis in patients with

Marker Test Profile in Testis Cancer 145 
disease. Finally , when used for diagnostic purposes, simultaneous assays of multiple tumor­
marker tests are the current recommended practice to enhance both clinical diagnostic sensi­
tivity and specificity. 
5.2. Tumor Markers and Stage of Diseases 
Serum tumor-marker tests for testicular germ-cell tumors play a useful clinical role of 
improving staging accuracy, although the clinical role of serum tumor markers in staging is 
limited ( 1 ,6, 11, 19,39,45-47). Despite the limitations, serum tumor-marker tests are helpful 
in staging and should be adopted as one of several modalities used for evaluation of the 
patient's extent of disease more accurately (1,6,11,19,39,45-47) . 
5.2.1. Correlation of Frequency of Serum Tumor-Marker Abnormality With Stages of Diseases 
A significant relationship is suggested between stage of disea se and frequency of serum 
tumor-marker elevations in patients with testicular germ-cell tumors ( 5, 6, 14,39 , 70, 7 4). The 
frequency of serum AFP elevations in patients with nonseminomatou s testicular germ-cell 
tumors conela tes with the advance of disease stages ( 39). Only 2 of 11 of patients (18%) 
with stage I disease had elevated serum AFP, while 11 of 19 (58%) stage II patients and 42 
of 48 (87%) stage III patients with nonseminomatous testicular germ-cell tumors had abnor­
mal serum AFP ( 39 ). Frequency of elevations of serum AFP and/or serum HCG tests 
increases as the stage of disease increases (70). 
Serum LD and serum LD-1 were elevated more frequently with increasing tumor burden 
and increasing clinical staging ( 4,5, 14,74 ). The clinical values of serum tumor-marker tests 
for staging of patients with testicular germ-cell tumors are limited ; because approx 60% of 
patients with microscopica lly positive lymph nodes in the retroperitoneum had normal pre­
operative serum tumor-marker levels and 45% of patients with grossly positive lymph nodes 
in the retroperitoneum also had normal preoperative serum tumor marker values. Addition­
ally, 10% of patients with bulky retroperitoneal node diseases or distant metastatic disease 
had norm al preoperativ e serum tumor-marker levels (45). When the three serum tumor­
marker tests including serum AFP , serum HCG, and serum LD-1 were assayed simulta­
neously, 50% of stage I testicular germ-cell tumor patients, 30% of stage II testicular 
germ-cell tumor patients, and 10% of stage III testicular germ-cell patients had normal serum 
tumor-marker test results of all the three tumor markers ( 4 ). Therefore , norm al serum tumor­
marker test results do not indicate the absence of diseases (4,6,14, 45). 
5.2.2. Correcting Clinical Staging Error and Impl ement ing the Proper Therapy 
Despite the fact that the clinical role of serum tumor markers tests is of limited value in 
staging patients with testicular germ-cell tumors, they are of some value in patient stagi ng 
( 1,11,19,39 ,40,46,47) . The significant impact of serum tumor-marker tests in the staging of 
patients with nonseminomatous testicular germ-cell tumors has been the reduction of clini­
cal staging errors, especia lly in the cases of understaging of the patients with non­
seminoma tous testicular germ-cell tumors (1,11 ,19,39,40,46 ,47). 
Serial measurements of both serum AFP and serum HCG postoperatively following 
orchiectomy have corrected and reduced the staging errors ranging from 28 to 59%, to 9 to 
50% in clinical stage I patients with nonseminom atous testicular germ -cell tumors 
( 39,40,46, 47). Persistent increase s of serum AFP and/or serum HCG above the normal meta­
bolic decay curve after orchiectomy in clinical stage I patients always indicate that the 
patients have actually stage II disease or stage III disease ( 39,40,46,47). The clinical impli-

146 Liu et al. 
cation of conecting the clinical stage I error is important in selecting patients to receive 
adjuvant chemotherapy or other proper treatment modalities pertaining to the patient' s true 
disease stage ( 1,9). Similarly, persistently elevated serum AFP and/or serum HCG following 
a successful retroperitoneal lymph node dissection for patients with clinical stage II diseases 
indicate that patients have stage III disease ( 47). These patients identified to have erroneous 
understaging can then receive proper and more intensive therapeutic regimens (47). All seven 
published "Practice Guidelines for Tumor Marker Use in Germ-Cell Tumors" established by 
the ACBI, AJCC, EAU, EGTM, ESMO, NACB , and the SIGN recommend that both serum 
AFP and serum HCG are helpful in the staging of nonseminomatous germ-cell tumors ( 11 ). 
However, only five of the seven guidelines including those publi shed by the EAU , EGTM, 
ESMO, NACB , and the SIGN also recommend that the total serum LD test is a useful serum 
tumor marker for staging ( 11 ). 
Serial measurements of serum LD-1 tumor-marker test following orchiectomy in patients 
with clinical stage I nonseminomatous germ-cell tumors have also been reported to detect 2 
of 10 patients originally classified as clinical stage I nonseminom atous germ-cell tumor of 
havin g pathological stage II diseases by evidence of persistent elevation of serum LD-1 
postoperatively ( 19). 
Normal serum tumor-marker values or normal serum tumor-marker concentrations 
that fall at the normal decay rate during the postoperative period do not assure absence of 
residual diseases or disseminated disease (47). A negative serum tumor-marker te st result 
must not be used to rule out the presence of residual disease or the diagno sis of testicular germ ­
cell tumor (6,45). 
5.3. Correction of Histopathological Diagnosis Error and Selecting the Right 
Therapeutic Modality 
Serum AFP and serum HCG tumor markers are closely related to the histopathological 
classification oftesticular germ-cell tumors ( 1,62,63 ,65,69-71, 75, 76). The broad classifica­
tion of testicular germ-cell tumors into two groups as pure seminoma and nonseminomatous 
testicular germ-cell tumors has impacted choice of treatment mod alities and other clinical 
management strategies for patients with testicular germ-cell tumors ( 1,6). Treatment 
modalities for pure seminoma and nonseminomatous testicular germ-cell tumor are differ­
ent based on their biological nature (1,6,9,45). Usually, seminoma is sensi tive to radiation 
therapy, therefore patients with stage I seminoma undergo conventional therapy for pure semi­
noma with orchiectomy and subsequent radiation therapy. The treatment of choice of for 
patients with nonseminomatous tumors receive chemother apy after orchiectomy ( 1,6,9,45 ). 
Studie s have confirmed that pure seminoma does not produce AFP and only occa siona lly 
produces HCG. The majority of choriocarc inoma patients show elevated serum HCG. The 
adult type of embryonal carcinoma synthesizes AFP only or both AFP and HCG , pure endo­
dermal sinus tumor produces only the AFP and mature teratoma does not produce any mark­
ers ( 1,2,62,63,65,66 ,70-72). 
Surgical diagnosis of testicular germ-cell tumors often shows a tumor containing two or 
more histopathological types within the primary tumor mass or one histopathological type in 
the primary tumor while another histopathological component may be found in the meta ­
static site, reflecting the pluripotential origin of the testicular germ-cell tumor ( 1,2). The 
nonseminomatous germ-cell cancers may contain a seminomatous component in addition to 
an embryonic component ( 1 ). If a patient with a histopathological diagnosis of a pure semi-

Marker Test Profile in Testis Cancer 147 
noma shows an elevated serum AFP, this patient must have nonseminomatous germ-cell 
cancer component undetected during surgical pathological examination (1,6,10,11, 75,76) . 
Because a surgical pathological diagnosis is based on one or two small parts of tumor tissue 
sampled from the entire tumor mass, the nonseminomatous tissue component may not be 
included in tissue taken from the tumor for morphological diagnosis at the initial examination 
( 1,6). More sectioning of the primary tumor submitted for morphological examination often 
reveals the presence of nonseminomatous germ-cell neoplasm ( 1 ). In many cases , the initial 
diagnosis of pure seminoma from institutions with little experience in diagnosing testicular 
germ-cell tumors, made a misdiagnosis of embryonal carcinoma as a pure seminoma (6). 
Elev ated serum AFP level helps correct the missing histological diagnosis of nonsemi­
nomatous germ-cell tumors (1,6,10,11,75,76). This corrected diagnosis helps to select the 
proper therapy resulting in the better outcome. Seminoma is a radiation sensitive cancer, 
although the nonseminomatous testicular germ-cell carcinoma is more susceptible to che­
motherapy ( 1,6). However , only four of the seven "Practice Guidelines for Tumor Marker 
Use in Germ-Cell Tumors" including those publi shed by the EAU, EGTM, ESMO, and 
NACB recommend that elevated serum AFP be used for the differential diagnosis of histo­
pathology for nonseminomatous testicular germ-cell tumors ( 11 ). 
5.4. Monitoring the Clinical Course of Patients 
The most important role of serum tumor-marker tests is observing the changes of disea se 
activities and serving as a guide to further therapeutic strategy for patients with 
nonseminomatous testicular germ-cell tumors (4-6,11,14,45,69). Serial serum tumor­
marker test profiles before, during, and after treatment in patients with testicular germ-ce ll 
cancers have been useful for determining the efficacy of surgery, the response of patients to 
postoperative radiotherapy and/or chemotherapy, for predicting prognosis , and for early 
detection of disease recurrence (4-6, 11, 14,20 ,45,52,69 , 77). 
5.4.1. Assessin g the Response of Patients to Therapy 
The greatest values and impact of serum AFP and serum HCG in the management and 
treatment of patients with nonseminomatous testicular germ-cell tumors is monitoring the 
clinical course of patients after surgery, after a completion of chemotherapy and/or radio­
therapy, and during the therapy (6,11,45,52,69 ,77). After successful and complete surgical 
removal of a tumor from stage I patients with preoperatively increased serum AFP and/or 
serum HCG, the serum AFP and/or serum HCG levels decline to normal according to the 
theoretical decay half-life of the tumor markers (52, 77). However, negative serum AFP and/ 
or serum HCG results after chemotherapy do not necessarily mean that the patient is disease 
free, because serum AFP and/or serum HCG values often return to normal before the tumor 
cells are completely eradicated (45,52). Therefore, normal serum AFP and serum HCG val­
ues after therapy must not be a signa l to stop planned chemotherapy (45,47,52). Durin g 
chemotherapy, sustained and elevated serum AFP and/or serum HCG values indicate persis­
tent disease and continuous escalation of serum AFP and/or serum HCG concentrations 
accompany progression of the disease, suggesting that the current chemotherapy is ineffec­
tive and alternative treatments should be considered (45,47,52,69). 
Studies of total serum LD as a tumor-marker test for stage B and stage C testicu lar germ ­
cell tumor patients show that serum LD has similar clinical characteristics in monitoring and 
evaluation of the clinical course of patients as serum AFP and serum HCG ( 11,71,74,78). 
Serial determinations of total serum LD reflect that decreasing disease activity is accompa-

148 Liu et al. 
nied by the decline of the initially increased total serum LD; and when the patients are resis­
tant to therapy or have progression in disease activity, the stationary or progressive disease 
activity is associated with sustained or progressively increasing levels of total serum LD 
(78). As reported by Lieskovsky and Skinner , all patients with persistent elevations of total 
serum LD after treatment have either died or experienced progression of diseases (78). Serum 
LD tests provide a similar clinical role as serum AFP and/or serum HCG does in monitoring 
the clinical course of patients with testicular germ-cell tumors (78 ). In addition, a portion of 
patients with diseases have normal total serum LD values emphasizing false negative results 
cannot be used to rule out the presence of a residual diseases (74, 78). Six of the seven pub­
lished "Practice Guidelines for Tumor Marker Use in Germ-Cell Tumors" including those 
developed by the ACBI, EAU, EGTM, ESMO, NACB, and SIGN recommend that two tumor 
markers of serum AFP and serum HCG be used in the monitoring of the clinical course of 
diseases for testicular germ-cell tumors (II). Five of these six guidelines established by the 
EAU, EGTM, ESMO, NACB, and SIGN also suggest that serum LD test is a useful 
serum tumor marker for monitoring the disease course of the testicular germ-cell tumor 
patients (II). 
Studies of serum LD-1 tumor-marker test for testicular germ -cell tumors have shown that 
the serum LD-1 test is a useful tumor marker for monitoring the clinical course of patients 
(4,5,I4). Serial measurements of serum LD-1 in patients with testicular germ-cell tumors 
have clinical value in monitoring the patients' disease activity in relation to their response to 
therapy ( 4, 5, I4). Again, there are patients who have active disea se and normal concentra­
tions of serum LD-1 indicating that there are also false negative results of serum LD-1 in 
patients with active diseases (4,5,I4) . 
5.4.2. Detection of Recurrent Disease or Metastatic Diseases 
Serum AFP and serum HCG test profiles are indispensable in testicular germ-cell cancer 
patients for detecting disease recurrence and metastasis (45,47,52 ,69,79). Serial meas ure­
ments of serum AFP and serum HCG in testicular germ-cell cancer patients on surveillance 
predict disease recurrence several months earlier than do radiographic or other diagnostic 
methods (9,45,52) . A retrospective study proposed that more frequent monitoring to ensure 
detection of all recurrences at a minimal disease state is necessary (80). Serial and simulta­
neous determinations of serum AFP , serum HCG , and serum LD for follow-up purposes 
show that the earliest indicator of recurrence was the elevated serum tumor-marker levels 
for patients with nonseminomatous testicular germ-cell tumors in those cases that serum 
tumor -marker test results detect the recurrence of the disease; whereas the earliest indicator 
of disease recurrence for patients with pure seminomas is the radiologic change (8I ). Early 
detection of recurrence should not rely only on serum tumor-marker levels because not all 
the patients with disease or recurrence had elevated tumor markers (8I ). Six of the seven 
current "Practice Guidelines for Tumor Marker Use in Germ-Cell Tumors" including those 
established by the ACBI , EAU, EGTM, ESMO, NACB , and SIGN, have recommended that 
serum AFP and serum HCG be used in detecting the recurrence of diseases, whereas five of 
these six guidelines also include total serum LD test in addition to serum AFP and serum 
HCG as a useful tumor marker for detection of recurrence (II). Serum LD-1 tests were 
elevated in 11 of 21 patients with testicular germ-cell tumors at the time of relapse of the 
disease (20 ). Seven of these 11 patients had elevations of serum LD-1 with a median time of 
2 mo ranging from 1.4 mo to 4.5 mo preceding other means of detection or evidence of

Marker Test Profile in Testis Cancer 149 
relapse of the disease (20). Serum LD-1 tests as a serum tumor-marker test for testicular 
germ-cell tumors can help detect the relapse of the cancer earlier in some cases complemen­
tary to serum AFP and serum HCG, and diagnostic imaging techniques (20 ). 
5.4.3. Transient Rise in Tumor Marker 
Some patients with advanced testicular germ-cell cancers with bulky tumor masses, have 
an acute transient increase of serum AFP and/or serum HCG during the initial induction 
phase of chemotherapy, even though radiographic and other evidence shows that the tumor 
is responding to the therapy and reducing in size (82-85 ). This discordance between the 
serum AFP and/or serum HCG values and disease status by imaging results from tumor 
cytolysis followed by release of AFP and/or HCG into the circulation (47). This phenom­
enon is called "paradoxical elevation" of serum tumor markers or marker surge. A paradoxi­
cal elevation of serum tumor marker requires definite radiologic or other diagnostic imaging 
evidence of reduction in tumor masses followed by the decline of serum tumor marker con­
centration; even if the serum tumor marker level may or may not rebound at a later date. This 
condition should not be considered as an adverse prognostic factor indicating a progre ssion 
of disease because of the sudden escalation of the serum tumor-marker levels . Frequent 
monitoring of the serum tumor-marker level is required to observe the patient's disease 
activity in either cure or recurrence. 
5.5. Estimation of Prognosis and Predicting the Outcome 
Pretreatment serum tumor marker concentrations and patterns of serum tumor marker 
level changes during and after treatments in patients with testicular germ-cell tumors are of 
value in estimating the prognosis and predicting the outcome (11,14 ,16,17,23,25, 
49,50,70, 74, 77,84,86-105). 
5.5.1. Pretreatment Serum Tumor-Marker Levels 
Initial concentrations of the four serum tumor markers of serum AFP , serum HCG, serum 
LD, and serum LD-1 before the treatment have prognostic values for patients with testicular 
germ -cell tumor, particularly in patients with advanced stages of diseases . 
5.5.1.1. PRETREATMENT SERUM AFP , SERUM HCG , AND SERUM LD VALU ES 
AS PROGNOSTIC PREDICTOR 
Pretreatment serum AFP and serum HCG values are independent prognostic variables for 
patients with advanced nonseminomatous testicular germ-cell tumors (11,23,25,70 ,86-96). 
Serum AFP greater than 500 ng/mL and/or serum HCG greater than 10,000 mL U/mL are 
considered to have unfavorable prognosis (86). The genitourinary consensus conference of 
the 1990 European Organization for Research on Treatment of Cancer (EORTC) reported 
that seven of the eight larger studies summarized that the pretreatment serum HCG value 
was a significant prognostic factor and four of the eight studies considered that serum AFP 
greater than 500 ng/mL predicted a poor prognosis (87). It is best to use serum tumor marker 
values together with a clinical staging system (88,89). For example, a favorable minimum 
lung presentation may be unfavorable with high serum tumor marker values and an unfavor­
able advanced abdominal presentation may actually be favorable if both serum AFP and 
serum HCG values are low (88,89). Using different cutoff values of serum AFP and/or serum 
HCG, many investigators report that pretreatment concentrations of these two serum tumor 
maker levels can provide the prognostic values as well (70,90-95). The pretreatment serum 
LD levels have been reported useful prognostic predictor for metastatic testicular germ-cell

150 Liu et al. 
tumors (74,96). In a study of 43 patients with testicular germ-cell tumors with normal total 
serum LD levels prior to therapy; mean survival time was 15.5 mo; while another group of 
26 patients who had pretreatment elevated total serum LD levels had a shorter mean survival 
time of 9.2 mo (74). Serial determinations of total serum LD in 44 patients with non 
seminomatous germ-cell tumors of the testis show that a poor prognosis was associated with 
abnormal elevations of total serum LD, whereas 92% of patients with normal total serum LD 
level had a survival time longer than 5 yr, no patient with elevated total serum LD had a 
survival time longer than 4 yr suggesting that the initial total serum LD concentrations are of 
prognostic value. This difference was especially significant in patients with advanced stages 
of disease (96). Serial measurements of total serum LD are of value as prognostic indicator 
and when elevated, might be utilized as a guide for response to therapy (96). 
The prognostic significance of the pretherapy serum AFP, serum HCG, and serum LD 
levels for patients with metastatic testicular germ-cell tumors discussed above has been con­
firmed by studies of the International Germ-cell cancer Collaborative Group (IGCCCG) that 
developed the International germ-cell consensus classification system (IGCCC) (23 ). Pre­
treatment marker concentrations are included as one of variables for classification of meta­
static germ-cell tumors into three categories; good, intermediate, or poor prognosis 
( 11,23,25). The UICC TNM staging system stratifies the three serum tumor marker values 
into four categories designed as SO, S 1, S2, and S3 (25 ). The SO category has all three serum 
marker levels within normal limits; Sl:Serum LD is <1.5 x ULR (upper limits of reference 
values) and serum HCG is <5000 miU/mL and serum AFP is <1000 ng/mL; S2:serum LD is 
1.5-10 x ULR or serum HCG is 5000-50,000 miU/mL or serum AFP is 1000-10,000 ng/mL; 
and S3: serum LD is> 10 x ULR or serum HCG is >50,000 miU/mL or serum AFP is> 10,000 
ng/mL (25 ). The international classification included only two cutoff points to predict the 
outcome of patients with metastatic testicular germ-cell tumors (25 ). Low levels of the serum 
tumor markers, the SO and S I categories, for patients with metastatic testicular germ-cell 
tumors indicate a standard risk for death of tumor (25 ). High levels of the serum tumor 
markers, the S2 and S3 categories, indicate two levels of increased risk (25). The IGCCC 
incorporates the SO into the S 1 with cutoff points of the three serum tumor markers being 
separated as S 1, S2, and S3 categories. S 1 is designated as a good prognosis marker level, S2 
as an intermediate prognosis marker level, and S3 as a poor prognosis marker level (23 ). All 
the seven "Practice Guidelines for Tumor Marker Use in Germ-Cell Tumors" developed by 
the ACBI, AJCC, EAU, EGTM, ESMO, NACB, and SIGN recommend that serum AFP and 
serum HCG are useful markers for prognosis ( 11 ). Only five of the seven guidelines suggest 
that serum LD can be used in prognosis evaluation ( 11 ). 
5.5.1.2. PRETREATMENT SERUM LD-1 vALUES AS PROGNOSTIC PREDICTOR 
Pretreatment serum LD-1 concentrations can also provide some prognostic values and are 
useful in predicting the clinical outcome of patients (14, 16, 17). 
In a study of 42 patients with advanced testicular germ-cell cancers, abnormal levels of 
serum LD-1 were observed in 34 patients (81%) with stage III germ-cell malignancy of the 
testis ( 14). All (100%) of the 8 patients with pretreatment normal serum LD-1 levels 
responded to the therapy and achieved complete remission and remained free of disease with 
serum LD-1 values remained normal ( 14). Only 16 patients (47%) with pretreatment elevated 
serum LD-1 achieved complete remission and remained free of diseases with return of the

serum LD-1 achieved complete remission and remained free of diseases with return of the 
abnormal serum LD-1 levels to normal. A total of 18 (53%) patients either did not respond to

Marker Test Profile in Testis Cancer 151 
therapy or achieved partial remission and complete remission during the disease course fol­
lowed by recurrent diseases with sustained, progressive or recurrent elevations of serum 
LD-1 ( /4 ). Interestingly, 14 patients with metastatic diseases to the liver had elevated serum 
LD-1 instead of serum LD-5 elevations. Logically, metastatic disease to the liver should 
result in the increase of the LD-5 isoenzyme secondary to damage of the liver parenchyma 
( 14 ). This observation suggests that testicular germ-cell tumors synthesize predominantly 
the LD-1 isoenzyme and release into the circulation ( 14 ). 
Eighty-one patients with metastatic testicular germ-cell tumors were monitored with all 
four serum tumor markers including serum LD-1 , serum LD, serum HCG, and serum AFP 
according to the criteria set by the IGCCCG for serum LD, serum AFP, and serum HCG 
( 16). Forty-two of 81 patients (52%) had an increased serum LD-1 and 41 of these 42 patients 
also had an elevated total serum LD level ( 16). However, an additional 8 patients had an 
increased total serum LD with a normal serum LD-llevel (16). A total of 39 patients with 
normal serum LD-1 concentrations had the best survival ( 16 ). This favorable survival was 
not related to whether total serum LD was normal (31 patients) or total serum LD was 
elevated (8 patients) ( 16 ). Serum LD-1 provided better prognostic information for the meta ­
static testicular germ-cell tumor patients than total serum-LD levels ( 16). These results indi­
cate that pretherapy serum LD-1 is better than total serum LD to predict the survival of 
patients with metastatic testicular germ-cell tumors. Accordingly, if the increase of total 
serum LD is not a result of the increase of serum LD-1, the prognostic implication of elevated 
total serum LD may not be grave because elevation of total serum LD is not caused by the 
elevation of serum LD-1 (16). The results of this study suggest that serum LD-1 offers a 
greater difference in survival between the subgroups of patients with the best and the worst 
survival than the IGCCCG classification ( 16). Overall, serum LD, serum HCG, and the prog ­
nostic classification of the IGCCCG study also showed predictive value for the survival, 
although serum AFP did not provide prediction for survival ( 16). 
The IGCCC staging system , which includes the prognostic variables of serum LD, serum 
AFP, and serum HCG, indicates that these three serum tumor markers could predict the 
death of patients with metastatic testicular genn-cell tumors from tumors (23 ). In a study of 
44 patients with metastatic germ-cell tumors, serum LD-1 levels using univariate analysis 
were shown to be a better predictor than criteria established by the international classifica­
tion for the other three serum tumor markers ( 17). In this evaluation , serum LD-I levels 
greater than the upper limit of reference value are considered to be abnormally elevated ( 17). 
A total of I 00% of patients with a normal serum LD-1 had the survival rate of 5 yr; 81% of 
patients with a normal total serum LD had the survival rate of 5 yr; 75% of patients with a 
normal serum AFP had the survival duration of 5 yr, and 77% of patients with a normal 
serum HCG had the survival duration of 5 yr (17). An elevated serum LD-1 had a predictive 
value of 46% for death from tumors in 5-yr; an elevated total serum LD had the predic­
tive value of 46% for death from tumor in 5-yr; an elevated serum AFP had the predictive 
value of 25% for death from tumors in 5 yr; and an elevated serum HCG had the predicti ve 
value of 40% for death from tumor in 5-yr ( 17). Of the patients who died of tumor, 100% had 
an elevated serum LD-1; 46% had an elevated total serum LD; 9% had an elevated serum 
AFP; and 18% had an elevated serum HCG ( 17). Of the patients who did not die of tumors , 
61% had a normal serum LD-1 ; 81% had a normal total serum LD, 94% had a normal serum

61% had a normal serum LD-1 ; 81% had a normal total serum LD, 94% had a normal serum 
AFP; and 94% had a normal serum HCG. Thes e data indicate that an increased value of

152 Liu et al. 
serum LD-1 classified more patients to a subgroup having an impaired survival than of serum 
LD, serum AFP, and serum HCG ( 17). 
The prognostic value of pretreatment serum LD-1 was evaluated in 110 patients with 
testicular seminoma clinical stage I diseases followed with surveillance after orchiectomy 
( 106). The patients with elevated serum LD-1 and those with normal serum LD-1 had a 
similar relapse or free survival ( 106). Elevated serum LD-1 did not predict a relapse during 
follow-up with surveillance in clinical stage I seminoma patients (106). The pretreatment 
serum LD-1 values do not provide a prognostic value for patients with seminoma in the early 
stage of disease ( 106). 
5.5.2. Serum Tumor-Marker Decline Rate (Marker Half-Lives) 
The clearance rates of a biological substance in the circulation are usually expressed as 
metabolic half-lives ( 37,48). The rate at which the serum tumor-marker values decrease 
after surgical removal of the tumor, during or after chemotherapy or radiation therapy , is 
designated as the actual half-life (AHL), marker decline, or marker half-life (MHL) 
(77,84,95,97 -105). The metabolic clearance rates of serum AFP and/or serum HCG have 
been reported to be a significant prognostic factor for nonseminomatous testicular germ-cell 
tumor patients (77,84,95,97-105) . The MHL of serum AFP and serum HCG is a useful 
prognostic factor in postoperative follow-up studies for patients with clinical stage I testicu­
lar germ-cell tumor patients (77, 97,98 ). Following orchiectomy in patients with clinical stage 
I testicular germ-cell tumors, an increased or prolonged MHL of serum AFP and/or serum 
HCG usually indicates a residual active tumor after surgical resection (77,97,98). The MHL 
of AFP may be more sensitive than serial monitoring of AFP in detecting preclinical recur­
rence after surgical resection of AFP-secreting tumors (77,97,98). A normal MHL may sug­
gest that surgical removal of the tumor is complete, but not all patients with normal MHL are 
completely free of a residual active tumor, because patients may still have the germ-cell 
tumor component of other histological subtypes (77). Therefore, abnormally prolonged MHL 
of serum tumor markers postoperatively is a significant prognostic variable indicating the 
presence of a residual cancer that requires further treatments (77,97,98). 
Many studies have indicated that the MHL of serum AFP and serum HCG during the 
initial phase of chemotherapy is a prognostic indicator reflecting tumor burden and predict­
ing the clinical outcome and dividing the patients between good prognosis and bad progno­
sis, which in turn can help make therapeutic decisions (77,84,95,97,99-105). These studies 
usually use 3 or 3.5 d as cutoffs for MHL of serum HCG and 7 d for serum AFP as the upper 
limit of the reference values for the MHL (77,84,95,97,99-105). When MHL of serum HCG 
is equal to or less than 3 or 3.5 d, it is considered normal AHL, normal MHL , or satisfactory 
marker decline (77,84,95,97,99-105). If the MHL of serum HCG is longer than 3 or 3.5 d, 
the MHL is prolonged, abnormal, increased AHL, prolonged, abnormal, increased MHL, or 
an unsatisfactory marker decline (77,84,95,97,99-105). The same parameters are applied to 
estimation of MHL of serum AFP using the cutoff of 7 d (77,84 ,95, 97,99-105). Prolonged, 
increased , or abnormal MHL, or a prolonged, abnormal; or increased AHL or unsatisfactory 
marker decline during the initial phase of chemotherapy, reflects ineffective chemotherapy 
indicating the presence of residual disease. It is recommended that patients require alterna­
tive and more intensive therapy if an acute transient rise of the serum tumor marker resulting 
from tumor cytolysis can be ruled out (77,84, 95,97,99-105). A normal MHL usually indi­
cates that the therapy is effective; disease activity is reducing; patients are responding to

cates that the therapy is effective; disease activity is reducing; patients are responding to 
treatments, and have a better prognosis with greater chance of achieving complete remission

Marker Test Profile in Testis Cancer 153 
and cure (77,84,95,97,99-105) . Studies using the similar principle but a modified criteria of 
serum HCG in patients with disseminated testicular germ-cell tumors and elevated serum 
HCG value during the first cycle of chemotherapy show that the ratio of d 22 serum HCG 
value to d I serum HCG value below 1:200 was highly predictive of a complete response, a 
ratio above this level suggested an incomplete response ( 49,50 ). Although a significantly 
prolonged MHL likely suggests failure to therapy and the presence of chemotherapy resis­
tant cells, many patients with a normal MHL fail to respond to the treatment (47). 
The prognostic value of the MHL of serum AFP and serum HCG has been debated and 
controversial. Several reports indicated that only the MHL of serum AFP is a useful prog­
nostic predictor, but the MHL of serum HCG did not discriminate between patients remain­
ing well or those who relapsed after chemotherapy nor did the prolonged MHL of serum 
HCG half-life adversely affect event-free survival and overall survival (107,108). A few 
reports argued that the MHL patterns of serum AFP or serum HCG did not predict the out­
come of chemotherapy with certainty; evaluation of the MHL of serum AFP and serum HCG 
during the initial chemotherapy did not predict patients at higher risk of progression and also 
was a poor guide to long-term prognosis; and MHL patterns were inaccurate parameters for 
the prediction of treatment failure (94, 109-111 ). In response to arguments regarding dis­
crepant results on the prognostic significance of the MHL of serum AFP and serum HCG 
during the early phase of chemotherapy in testicular germ-cell tumor patients, one of the 
groups that initially published favorable results on this subject (100-102) re-evaluated the 
prognostic values of the MHL of serum AFP and serum HCG together with IGCCC staging 
system developed by the IGCCCG and studied both the patients with normal MHL and with 
prolonged MHL regarding their prognostic significance ( 105) . They evaluated 189 germ­
cell cancer patients with elevated levels of serum AFP and serum HCG treated with plati­
num-based chemotherapy (105). Based on the IGCCC criteria, the patients were classified 
into three groups: as good prognosis disease, intermediate prognosis disease, or poor prog­
nosis disease groups and patients were separated into two groups as having normal MHL; 
and prolonged MHL (105). The IGCCC staging classification and the MHL status of the 
patients were correlated with response, event-free survival , and overall survival ( 105). 
Patients with normal MHL had statistically significant better complete response (CR) rates 
and better event-free and better overall survival (p < 0.0001) ( 105). Ninety two percent of 
patients with normal MHL and 62% of patients with a prolonged MHL achieved CR; 91% of 
patients with normal MHL and 69% of patients with a prolonged MHL had 2-yr event-free 
survival; and 95% of patients with normal MHL and 72% of patients with a prolonged MHL 
had 2-yr overall survival ( 105). MHL was still a significant variable for all three end-points 
when adjusted for the IGCCC staging groups (p < 0.01) with outcome difference s most 
pronounced in the poor -prognosis disease group ( 105). The authors concluded that the MHL 
of serum AFP and serum HCG during chemotherapy has prognostic value independent of 
the IGCCC prognosis staging and may play a significant role in the management of poor­
prognosis disease patients (1 05). 
6. RECOMMENDED PROCEDURES FOR MEASUREMENTS OF SERUM 
TUMOR-MARKER TESTS AND INTERPRETATION 
OF TUMOR-MARKER TEST RESULTS 
The following test-ordering procedures and interpretation guidelines of the serum tumor­
marker test results are recommended based on the knowledge of biomolecular and clinical 
characteristics, interrelationship between the histologic subtype s of testicular germ-cell tu-

154 Liu et al. 
mars, and the clinical role and significance of the serum tumor markers for the testicular 
germ-cell cancers. These recommendations may be applied when using the serum tumor­
marker tests in daily practice. 
6.1. Uses of Multiple Markers to Improve the Diagnostic Sensitivity 
and the Diagnostic Specificity Both at the Time of Diagnosis and During Monitoring 
It is generally recommended that multiple marker tests be determined for improving both 
the clinical diagnostic sensitivity and specificity (73 ). To improve the clinical diagnostic 
sensitivity and specificity, it is recommended that all four serum tumor-marker tests include 
serum AFP, serum HCG, serum LD, and serum LD-1 be tested at time of diagnosis and 
during monitoring for testicular germ-cell tumors. None of these tumor -maker tests have 
perfect clinical diagnostic sensitivity or specificity, and heterogeneous expressions of tumor 
markers by cancer cells of the same histologic type will maximize the clinical diagnostic 
sensitivity and specificity. 
It is generally thought that only initially elevated tumor markers prior to surgery be 
selected for monitoring recurrence (73). However, both serum AFP and serum HCG should 
be tested regularly at various intervals dependant upon the histology, stage, and postorchid­
ectomy treatment chosen regardless of the serum tumor-marker level as markers may be 
normal at presentation (6,11 ,81 ). The reason for this is as follows : one serum tumor marker 
may be initially elevated and the other tumor marker normal, later during the course of 
disease the elevated serum tumor marker may return to normal and the other initially normal 
serum tumor marker may rise (6,81 ). This type of discordant expression of the serum tumor 
marker not only provides useful information regarding the tumor activity but also may reflect 
the different histologic subtypes or tumor cell populations in relation to the tumor-marker 
production (1,6,11,81). Therefore, both serum AFP and serum HCG tumor-marker tests 
should be included in the follow-up studies for detection of recurrence and monitoring the 
response to the therapy, even if the initial serum tumor-marker level is normal (6,81). A 
study with simultaneous and serial measurements of serum AFP, serum HCG, and serum LD 
in 794 patients with germ -cell tumors shows that 123 of 754 patients developed a first recur­
rence with recorded serum tumor-m arker test results (81). Of these123 patients with first 
recurrence, 79 (64%) had elevated serum tumor markers at the time of diagnosis and 76 
(62%) had elevated tumor markers at the time of first recurrence (81). An elevated serum 
tumor-marker level was present at first recurrence in 58 of 79 patient s (73%) with initially 
positive serum tumor markers at the time of diagnosis and also in 18 of 44 patients ( 41%) 
with initially negative serum tumor markers at the time of diagnosis (81). In 84 of 123 
patients (68% ), the same marker pattern with positive or negativ e results was present at the 
time of diagnosis and at first recurrence, 78% in seminoma and 64% in nonseminomatous 
germ-cell tumors (81 ). Thirty patients developed a second recurrence, 27 of these patients 
(90%) had the same marker pattern as at first recurrence (81 ). These data indicate that serum 
tumor-marker evaluation in follow-up monitoring of patients should include all the serum 
tumor markers regardless of serum tumor-marker levels at time of diagnosis (81 ). Therefore, 
all the serum tumor markers for testicular germ-cell tumors should be included for both 
diagnosis and monitorin g (6,11,81).

Marker Test Profile in Testis Cancer 155 
6.2. Serial Determinations of Serum Tumor Markers Are Mandatory to Monitor 
the Response of Patients to Therapy and Detection of Recurrence 
The development of effecti ve and curativ e chemotherapy combined with improved surgi­
cal techniques and radiation therapy may predict the potential of tumor recurrence shortly 
after therapy renders not only the pretreatment serum tumor-marker measurements neces­
sary but also posttreatment determinations of serum tumor markers mandatory for monitor­
ing the disease course, estimation of effectiveness of therapy, detection of tumor recurrence, 
and prognostic prediction with serial determinations of several serum tumor-marker tests 
(1,9-11 ). 
Follow-up monitoring schedules are decided based on different stages of disease , type of 
treatments involved, monitoring purposes, and the histology, and postorchidectomy treat­
ment chosen ( 11 ). There are variations among the follow-up schedules at different institu­
tions even in the same category of the monitoring ( 11 ). Several protocols and testing 
frequency schedules have been developed and used by different medical centers over the 
years (2,6,9 -11,45). However, there is no single one thought to be optimal. 
6.2.1. Tumor-Mark er Tests Should Be Ordered Before and After Surgery 
Both serum AFP and serum HCG should be tested before and after orchiectomy and retro­
peritoneal lymph node dissection (6). However, even if all marker levels are normal , the 
diagnosis of malignancy should not be ruled out (6,47). When one or both of the serum AFP 
and serum HCG are elevated before surgery, the elevated serum tumor markers can be mea­
sured daily for 1- 2 wk following orchiectomy or retroperitoneal lymph node dissection to 
calculate the metabolic decline rate of the serum tumor marker (6). After the initial daily 
measurements of the serum tumor markers, both serum tumor markers should be determined 
regularly at an interval of one month for at least 2 yr until the patient has been free of disease 
(6). Usually , testicular germ-cell tumors relapse within first 2 yr after orchiectomy (6). 
Should the serum tumor marker's MHL be prolonged, incomplete removal of the tumo r is 
indicated suggesting that the patient has higher stage of disease and requires further investi­
gation and treatment with chemotherapy or other treatment modalit y (6). The cutoff normal 
MHL of serum HCG is 3 d and normal MHL for serum AFP is 7 d ( 11 ). The return of serum 
tumor-marker levels to normal according to the rate of the normal MHL does not nece ssari ly 
mean that the patient is completely free of tumor ( 47). The patient should still be monitored 
with serum tumor-marker measu rements and radio graphic examination, chest X-ray, and 
CT scan of abdomen and pelvis and/or sonogram regularly (6,11,45 ,47). The serum LD and 
serum LD-1 determinations are also recommended to impro ve the diagnostic sensitivity and 
regularly tested weekly for the first 2 mo and monthly thereafter for the first year and bi­
monthly for the second year until the patient is tumor-free (4,5,14,20) . 
6.2.2. Serial Determinations of Serum Tumor Markers for Patients With Advanced Disease 
and Receiving Chemotherapy in Monitoring 
It has been discu ssed previously that the first 6 wk can predict the potential for relapse 
when the MHL is prolonged (77,84,95,97,99-105). For calculating the MHL , weekly mea­
surements of elevated serum HCG and/or serum AFP are recommended during chemot herapy 
( 11, 77,84,95,97,99 -105). Generally, after the completion of chemother apy, serum tumor

156 Liu eta!. 
markers including serum AFP, serum HCG , serum LD, and serum LD-1 levels can be deter­
mined monthly for the first year and every 2 mo for the second year after the patient appears 
to be free of disease (II ,45 ). If further monitoring is indicated, serum tumor marker s may be 
tested every 2 or 3 mo during the third year, and then every 6 mo up to 5 yr (II). There is no 
optimal follow-up protocol agreed upon by all the guidelines ( I1 ). 
6.2.3. Role of Serum Tumor Markers on Surveillanc e 
Protocols for Stage I Testicular Germ-Cell Tumor 
Approximately 30% of clinical stage I patient s with nonseminomatous germ-cell tumors 
would develop progression of diseases without retroperitoneal lymph node dissection, 
because the stage of disease of these patients is originally understaged and disease is not 
confined to the testis only (9, 10 ). Before the availability of the effective and curative chemo­
therapy for advanced testicular germ cell, almost all clinical stage I testicular germ-cell tumor 
patients underwent retroperitoneal lymph node dissection routinely for fear of progression 
of diseases (9,10). Obviously , 70% of clinical stage I patients, who have their cancer truly 
confined to the testis and have pathologically negative lymph node s, receive no benefit from 
routine retroperitoneal lymph node dissection (9, /O).lns tead, these patients with true stage I 
diseases suffered from the side effects of anejaculation and infertilit y caused by the full 
bilateral retroperitoneal lymph node dissection (9,IO). 
After effective chemotherapy had become available, several investigators doubted the 
clinical efficiency of the role of routine retroperitoneal lymph node dissection for 
nonseminomatous germ -celJ tumor patients with early stage of disea se (9, 10). To keep these 
70% of patients from getting the unnec essary operation, careful observation procedures were 
designed and studied by several large medical cente rs reservin g effective and curative che­
motherapy and retroperitoneal lymph node dissection for the 30% of patients who later 
developed clinical manifestation of disease progre ssion (9, 10 ). The results of many studies 
were reported from the mid-1980 s to the mid-1990 s ( 10). The study concluded that 25 to 
35% of patients developed metastasis on surveillance protocols. Overall surviva l of the 
patients on surveillance is 98%, similar to primary retroperiton eal lymph node dissection; 
50 to 75% of cancer relapses appears in the retroperitoneum with the rest occurring in the 
lung or other organs suggesting the necessity of the inclusion of CT scan of abdomen and 
pelvis in follow-up observation protocols. Many patients with late recurrenc e at 6 yr and 9 yr 
respectively have been observed indicating that long term follow-up is required (9,10). Sev­
eral surveillance protocols have been developed with variations; despite the fact the optimal 
follow-up observation protocol has not been determined (2,9-11). Three different surveil­
lance protocols are listed below for reference. 
The surveillance protocol for testicular germ-cell tumor stage I patients developed by 
Steele and Richie, suggests that patients have physical examination , serum tumor markers, 
CT scan of abdomen and pelvis, and chest X-rays every 4 mo for the first 3 yr and have 
physical examination, CT scan abdomen and pelvi s, and chest X-ray every 6 mo for the next 
4 yr. In this protocol, serum tumor markers are not includ ed during the last 4 yr of observa ­
tion (2). 
The protocol used by Richie et a!. recommends that patients have physical examinat ion, 
chest X-ray, and serum tumor-marker tests every month for the first year, every 2 mo for the 
second year and every 3 to 6 mo per year after the second year. CT scan of abdomen and 
pelvis for evaluation of the retroperitoneum should be done every 2 to 3 mo for the first 2 yr

Marker Test Profile in Testis Cancer 157 
and at least every 6 mo after the second year (9). Observation duration of 5 yr or even 10 yr 
is recommended following orchiectomy (9). 
Skinner and Skinner design and recommend their surveillance protocol as follows: patients 
have serum tumor markers of serum AFP and serum HCG together with chest X-ray and 
physical examination every month for the first year and CT scan of abdomen and pelvis 
every 3 mo. For the second year, patients have chest X-ray, serum tumor markers, physical 
examination every 2 mo, and CT scan of abdomen and pelvis every 4 mo. From years 3 to 5, 
patients should have chest X-ray, serum tumor markers, physical examination every 3 mo 
and CT scan of abdomen and pelvis every 6 mo. Patients should have chest X-ray, serum 
tumor markers, physical examination every 6 mo, CT of abdomen and pelvis every year for 
yr 6 and thereafter ( 10). 
Serum tumor markers play an important role on the surveillance studies (2,9-11 ). How ­
ever, the serum tumor markers mentioned in the surveillance protocols often include serum 
AFP and serum HCG only; it is recommended that the serum tumor-marker test profile 
should add serum LD and serum LD-1 in order to increase the clinical diagnostic sensitivity 
of detecting the progression of diseases. 
6.3. Be Aware of Limitations of Tumor-Marker Tests 
The serum tumor-marker tests for testicular germ-cell tumors have limitations in both 
clinical diagnostic sensitivity and specificity and in the analytical accuracy, precision, sensi­
tivity, and specificity . Awareness of the limitations in both areas should raise caution in 
interpreting the test results, which might give erroneous information regarding diagnosis, 
prognosis, assessment of therapeutic effectiveness , and lead to ineffective treatment of the 
patients with unnecessary toxic agents or tissue damage resulting from unjustified surgical 
removal of normal organ or nonneoplastic tissue. 
6.3.1. Limitations of the Diagnostic Sensitivity and the Diagnostic Specificity 
Serum tumor-marker tests for testicular germ-cell tumors have a high false-negative test 
results in patients with early stage of diseases and approx 10% of patients with advanced 
diseases have false-negative test results (6,45). All four serum tumor markers are also 
elevated in benign and malignant disorders other than testicular germ-cell tumors that are 
considered to be false-positive results for testicular germ-cell tumors. Although serum tumor 
markers, when applied in the population of patients with high incidence of testicular germ­
cell tumors, had no false-positive results in one study ( 39 ), the possibility of encountering 
false-positive results in patients with testicular germ-cell cancer is not impossible 
(39,112,113). 
6.3.1.1. FALSE-NEGATIV E REsULTS IN PATI ENTS WITH DISEASES WHo Do Nor HAvE ABNORMAL 
SERUM TuMOR-MARKER TEsT RESULTS 
Although the use of serum tumor marker has reduced the understaging of patients with 
clinical stage I diseases from 4 7 to 37%, 37% of patients with stage II or higher do not have 
elevations of serum tumor markers ( 39 ). This false-negative test result makes the marker test 
unable to correctly diagnose testicular germ-cell tumors ( 39 ). Another study of patients with 
testicular germ-cell tumors shows a falsely negative incidence of 38% in patients found to 
have retroperitoneal metastases at lymphadenectomy ( 114). Serum tumor-marker levels dur­
ing chemotherapy are often normal even in the presence of residual tumor ( 114 ). Resulting 
from false-negative test results , the serum tumor-marker tests have a limited role in the early

158 Liu et al. 
detection of residual disease in patients treated systematically with prophylactic chemo­
therapy ( 114). To cope with this problem of false-negative marker results, efforts should 
focus on using other diagnostic tool such as CT scan of abdomen and pelvis to detect the 
residual mass and followed by a retroperitoneal lymph node dissection to confirm the pres­
ence of viable caner cells in the retroperitoneum ( 114 ). The findings indicate that a meticu­
lous retroperitoneal lymphadenectomy is the most important and effective mean in deciding 
the use of adjuvant chemotherapy ( 114 ). 
6.3.1.2. FALSE-POSITIVE TEST RESULTS DUE TO OTH ER DISORDERS 
It may not be difficult to recognize other disorders with elevation of these serum tumor 
markers in patients without testicular germ-cell cancers. However, it may be confusing when 
patients with testicular germ-cell cancers are complicated with another disorder that causes 
the serum tumor-marker elevation. This type of serum tumor-marker elevations , if not inter­
preted carefully, may be misused as a sign to indicate the progression of the germ-cell cancer 
activity resulting in implementing unnecessary and harmful therapy to the patients ( 112,113 ). 
Nine patients with testicular germ-cell cancers that had serum AFP elevation without pro­
gression or recurrence of the testicular germ-cell cancers were reported (112). The elevated 
serum AFP was caused by liver damage secondary to medication by chemotherapy, anes­
thetics, or antiepiletics ( 112 ). These patients do not have any clinical or surgical evidence of 
testicular germ-cell cancer activity ( 112). Another 11 patients with disseminated testicular 
cancer had elevation of serum AFP during induction chemotherapy of the V AB-6 regimen 
( 113 ). However , these patients had elevations of the markers of liver damage including serum 
AST, ALT, and serum LD ( 113). The elevations of the liver markers and serum AFP were 
induced by liver damage caused by the VAB-6 regimen, immediately after the end of induc­
tion chemotherapy ( 113 ). Similar to the acute transient elevation of serum tumor markers 
resulting form cytolysis secondary to the effective chemotherapy (82-85), the elevation of 
serum AFP in patients with germ-cell tumors produced by liver dysfunction should not be 
interpreted as progression of cancer activity ( 112,113 ). These elevations must be interpreted 
with caution to avoid unnecessary treatments. Whenever the elevation of serum AFP is sus­
pected as a result of liver damage, it is recommended to review the serum tumor markers of 
serum HCG and serum LD-1 concentration. Serum HCG and serum LD-1 are not associated 
with the liver damage, therefore they may somewhat be useful for differential diagnosis. 
6.3.1.3. NEVER UsE THE SERUM TuMOR-MARKER T EST R ESULTS AS THE O N LY CRIT ERIA TO MAKE 
oR RuLE OuT A DIAGNOSIS 
Serum AFP, serum HCG, serum LD, and serum LD-1 tests can be negative in a substan­
tial number of patients with testicula r germ-cell tumors; for patients with seminoma, the 
incidence of positive serum tumor-marker elevation is much lower than that of 
nonseminomatous testicular germ -cell tumors (5,6,14,39,40,45). In seminoma, only serum 
HCG, serum LD, and/or serum LD-1 may be elevated, and only 10% to 50% of patients with 
seminoma will have elevations of serum tumor markers (5,6,14,15 ,39,40,45,65). This high 
degree of false-negative rates of serum tumor marker tests leads to the inability of serum 
tumor-marker tests to be used to rule out a diagnosis of testicular germ-cell tumor 
(5,6,14,15,39,40,45,65). The four serum tumor-marker tests including serum AFP, serum 
HCG, serum LD, and serum LD-1 for testicular germ-cell tumors are associated with a vari­
ety of other malignant diseases and benign disorders or conditions. Therefore, the serum 
tumor-marker positive results can be a false-po sitive for germ-cell tumors. Because of the

Marker Test Profile in Testis Cancer 159 
possibility of false positivity of the tests, the serum tumor-marker tests must not be used as 
the sole criterion for making a diagnosis of testicular germ tumor. The bottom line is to 
never rely on the result of a single test to make any clinical decision regarding diagno sis and 
treatment modality. This issue can never be over-emphasized. 
6.3.2. Consideration of Analytical Limitations 
If the tumor-marker results do not match the clinical conditions of the patients , review 
potentially inaccurate analytical variables that may be causing the discordant test results. 
Always investigate the sources of errors during the test procedure s including the pre-anal yti­
cal phase, analytical, and post-analytical errors. 
6.3.2.1. PAY A ITENTION TO TH E AN ALYTICAL P E RFOR MANCE CHARA CTE RISTICS OF THE ASSAY KIT 
The keys to providing efficient and effective monitoring, evaluating patient response to 
therapy, early detection of the cancer recurrence and metastasis, and detection of a minimal 
residual disease by the serum tumor-marker test rely on analytically and clinically valid 
sensitivity (or detection limit), reliable assay precision and accuracy of each of serum tumor 
markers. Detection limit (DL) is the lowest or smallest detectable tumor-marke r concentra­
tion or minimum amount of a tumor marker that can be distingui shed from the zero concen­
tration or value ( 115 ). A clinically and analytically valid DL should be able to separate 
patients with detectable and undetectable concentrations of the tumor markers ( 115 ). Test 
results may be falsely detectable or falsely undetectable owing to a poorly establi shed DL 
that is inaccurate and/or imprecise . Both condition s may lead to an incorrect diagnosi s and 
mismanagem ent of patients with testicular germ-c ell cancers. A persistent and truly elevated 
marker level above the low upper limits of normal reference value indicates that there is still 
residual cancer, which would alert further nece ssary treatment , wher eas a falsel y detectable 
level will cause unnecessary procedures and therapy, causing a damaging outcome of the 
patient. Similarly, a falsely undetectable elevated tumor marker concentration will miss 
detection of a recurrent disease or a residual cancer delaying the necessary therapy and may 
result in progr ession of the disease into advanced and/or terminall y refractory stage. The 
import ance of establishing an analytically and clinically valid DL or evaluating and con­
firmin g the DL of the comm ercial tumor-mark er test kits cannot be overemphasiz ed ( 115 ). It 
is important to know the reliable assay precision and accuracy of the serum tumor-marker 
tests to correctly interpret that the scope of changes between serial-measurement results 
truly reflects changes of the patient 's disease activity instead of analytical variation s due to 
assay imprecision (115 ). 
6.3.2.2. WHEN ORDERIN G S E RIAL TESTIN G, B E C ER TAIN EACH T EsT I s D o NE 
BY U siNG THE SAME AssAY KIT 
Serum AFP and serum HCF are usually measured by immun oassays. Each different com ­
mercial immunoassay kit or methodology may generate different results on the same serum 
sample, even though all the kits are designed for the same tumor mark er (73 ). Orderin g from 
the same laborat ory consistently guarantees a more consistent performance (7 3 ). In some 
instances, the same laboratory may switch from one assay kit to another assa y kit for some 
reason. Should this happen , the practition ers should alway s inquire if the test result is incon­
sistent with the previous test result on the same patient. It is important to ensur e that any 
marker concentration change observed during the monitoring proces s is truly owin g to the 
change of tumor burden or other disease activity and not to the result of test methodological 
variability (7 3 ).

160 Liu et al. 
6.3.2.3. HETEROPHILIC ANTIBODY-INDUCED FALSELY ELEVATED RESULTS 
Falsely elevated serum HCG resulting from human anti-mouse IgG or heterophilic anti­
bodies has been reported in a number of women treated with unnecessary chemotherapy 
and/or surgery with a suspected diagnosis of trophoblastic disease or postgestational chorio­
carcinoma ( 116). These women suffered from adverse side effects from unnecessary chemo­
therapy and/or surgery ( 116 ). The falsely elevated test results may occur in any immunoassay 
using animal anti-human lgG antibody in the assay systems, when the assay systems are 
designed to block heterophilic antibodies insufficiently to produce an analytical accuracy 
( 116). A case report of a young man with elevated serum HCG and a testicular mass by 
palpation , was suspected to have testicular cancer ( 117). After the surgical removal of one of 
a testicle , his abnormal serum HCG did not decline ( 117). This patient had a heterophilic 
antibody that had caused a falsely elevated serum HCG result and the testicular mass was 
found to be a benign cyst rather than malignancy ( 117). The patient's serum was reassayed 
on another immunoassay instrument and bovine serum added to the patient's sample with 
reassay by the original method ( 117) . Addition of bovine serum to the patient's serum had a 
dramatic effect showing that his serum HCG was normal ( 117). The heterophilic antibody­
induced false test result by immunoassays was documented in the literature more than two 
decades ago, it has been still causing problems by producing false laboratory results in some 
immunoassay systems as described above ( 118 ). This fact indicates that the pathological 
diagnosis of the tissue still remains the best, and only certain, method of diagnosis ( 1,6,45). 
It is always important to keep in mind that possible assay errors could occur , particularly 
when patient's clinical status does not match the tumor-marker test result. 
6.3.2.4. BE AwARE THAT Low TEsT RESULTS INCONSI S T ENT WITH PATIENT's CoNDITION MAY BE 
CAUSED BY A HOOK EFFECT 
When the test result of a sandwich immunoassay for serum AFP and/or serum HCG is too 
low to be consistent with the patient's clinical advanced disease status, suspect errors that 
may be caused by a hook effect (73 ). The sample should be retested and measurement of the 
tumor marker be repeated with a 10-fold diluted serum sample (73 ). It is not uncommon with 
a sandwich immunoassay, that when the concentration of the serum sample exceeds the 
assay dynamic range (73). 
7. DISCUSSION 
Serum tumor-marker tests for testicular germ-cell tumor are the best tumor-marker sys­
tem in modern medical oncology (6,45). The serum tumor-marker tests have provided excel­
lent clinical values in diagnosis; significantly reduce staging errors, prognostic prediction , 
better defined the histopathological typing, monitored the response of the treatment and 
detection of the recurrent disease, and avoided unnecessary procedures and treatment and 
implemented appropriate therapy in patients (1,4-6, 11-20,23 ,25,39,40,45-47,74-77,84, 
86-105). Additionally, the development of effective and curative chemotherapy, more sen­
sitive imaging techniques , improved surgical procedures, advances in microbiology , antibi­
otics therapy, and technically improved general supportive therapy and management have 
contributed to the improvement of survival for patients with testicular germ-cell tumors 
( 1,9-11,23,25). 
The clinical value of serum tumor markers of serum AFP, serum HCG, and serum LD has 
been well established and documented (11 ). These three serum tumor markers are now

Marker Test Profile in Testis Cancer 161 
included in the IGCCC staging system, the fifth edition of the UICC TNM staging system, 
and the staging system of the American Joint Committee on Cancer (AJCC) as prognostic 
variables, and also listed in the five of seven published "Practice Guidelines for Tumor 
Marker Use in Germ-Cell Tumors" for several different clinical functions ( 11,23,25 ). Serum 
LD-1 test as a tumor marker for testicular germ-cell cancer is a useful adjuvant tumor-marker 
test for testicular germ-cell tumors (4,5,12-20). Addition of serum LD-1 to the marker test 
profile of serum AFP, serum HCG, and serum LD, not only has increased the clinical diag­
nostic sensitivity and specificity, but also demonstrated its clinical value in prognostic esti­
mation, staging, monitoring the response of the patient toward the therapy, and early 
detection of recurrent diseases (4,5,12-20). Serum LD-1 has also shown that it is more spe­
cific than serum LD in diagnosis and prognostic prediction ( 16,17 ). Some patients with 
elevated values of serum LD combined with a normal value of serum LD-1 had survival 
similar to that overall for patients with a normal serum LD-1, and did not show inferior 
survival caused by elevated serum LD ( 16). The prognostic value of serum LD-1 surpassed 
that of serum LD, serum HCG, or serum AFP (4,5,12-20,119) . 
Univariate analyses of patients with metastatic testicular germ-cell tumor show both the 
IGCCC and serum LD I highly and significantly predicted survival ( 16). In this evaluation, 
serum LD-1 was categorized into three prognostic subgroups : patients with serum LD-1 
< 1.0 x upper limit of reference value (ULR) had a good prognosis, those with serum LD-1 
1.0-10 x ULR had an intermediate prognosis and those with serum LD-1 >10 x ULR had a 
poor prognosis. Using these criteria, serum LD-1 predicted the survival as well as IGCCC 
staging ( 16 ). A recent study, based on 81 patients with metastatic testicular germ-cell tumors 
from two different medical centers using multivariate analysis, examined whether the 
IGCCC, serum LD-1, main histology (seminoma vs nonseminomatous testicular germ-cell 
tumors), serum LD, serum AFP, serum HCG, treatment center, and other prognostic factors, 
and combinations of these variables predict the survival for patients with metastatic testicu­
lar germ-cell tumors (119 ). The results showed that the addition of serum LD-1 in three 
stratified levels, to the IGCCC staging system improved the efficiency of the IGCCC in the 
survival prediction. Addition of the IGCCC to a model consisting of only serum LD-1 in 
three stratified levels also enhanced the ability to predict the survival more accurately ( 119). 
Adding the other prognostic variables such as the third TNM classification, treatment center, 
and serum HCG to the IGCCC, the prognostic value of the system was not improved ( 119 ). 
The study concluded the combination of the IGCCC and serum LD-1 in three categories to 
form a new model of staging system is a significant improvement for the prognostic staging 
classification ( 119). This new prognostic model provides a better survival prediction than 
either the IGCCC or serum LD-1 alone ( 119 ). One of the limitations of this study is that it 
analyzed a small number of patients ( 119). Further studies with larger number of patients are 
necessary because serum LD-1 appears to be a useful tumor marker for testicular germ-cell 
tumors ( 119) . 
Testicular germ-cell cancer is one of the few currently curable malignancies; it will 
continue to be the most curable solid cancer in men ( 1, 9,10 ). The serum tumor-marker test 
profile of serum AFP , serum HCG, serum LD, and serum LD-1 has contributed greatly to the 
management and treatment of patients with testicular germ-cell cancer ( 4,5, 11-20, 119). The 
serum tumor-marker test profile will continue to provide clinically important and useful

serum tumor-marker test profile will continue to provide clinically important and useful 
information offering the benefit of maintaining the excellent cure rate of this disease ( 1,4,5 , 
9-20,119).

162 Liu et al. 
Molecular diagnostic testing for testicular germ-cell tumors is still in the early stage of 
development ( 1, 120-124). Molecular diagnostics appears to be promising , although clinical 
application has not been established. Using reverse transcription-polymerase chain reaction 
(RT-PCR), the expression of melanoma antigen (MAGE) has been shown in testicular can­
cer (120). MAGE 1-3 genes were found in both seminomas and nonseminomatous germ­
cell tumors with various incidences ranging from 30 to 91.7% with more frequent presence 
in seminomas suggesting MAGE genes might be useful tumor markers for molecular staging 
of testicular germ-cell tumors particularly for seminoma (1 20 ). Wilms' tumor associated 
gene WTJ was also demonstrated in some testicular cancers ( 120 ). This gene was frequently 
expressed in patients of advanced stage of diseases, but less frequently in the low stage 
patients suggesting that WTl gene may be a tumor marker for high stage testicular germ-cell 
tumors ( 120). Investigation of proto-oncogenes in testicular germ-cell tumors shows N-myc 
expression in 94% of seminomas and 83% of embryonal carcinomas ( 1 ). Immature teratoma 
has a high level of c-erbB-1 expression ( 1). c-Ki-ras or N-ras was seen in all histologic 
subgroups of testicular germ-cell tumors and also normal testis which suggests a switch of 
proto-oncogene expression during differentiation ( 1 ). Expression of c-kit proto-oncogenes 
has been reported in seminoma but not in nonseminomatous testicular germ-cell tumors ( 1 ). 
Studies of p53 in testicular germ-cell tumors have shown controversial results by 
immunostaining suggesting a positive role of p53 in detecting the aggressiveness of the 
tumor but negative results using denaturant gel electrophoresis and single-strand conforma­
tion polymorphism ( 1 ). Chromosomal abnormalities have been described in testicular germ­
cell tumors, usually chromosome 1 and chromosome 12 abnormalities (121-123). The 
rearrangements in both the short and long arms of chromosome 1 have been reported ( 121 ). 
The testicular germ-cell tumors have characteristic chromosomal abnormalities with a high 
copy number of the short arms of chromosome 12, 12p, with or without an isochromosome 
12p ( 122,123 ). Correspondently, the gene locus for the H subunits of LD is localized to the 
short arms of the chromosome 12, 12p ( 124 ), whereas the gene locus for the M subunits of 
LD is localized to the short arms of chromosome 11, llp (124). Becuase LD-1 isoenzyme is 
a homogeneous tetramer of the H subunits of LD consisting of all four H subunits ( 14,61 ), 
the positive relationship between the elevated serum LD-1 and the high copy number the 
short arms of chromosome 12p in testicular germ-cell tumor reflects the molecular biology 
of this tumor ( 124 ). The high copy number of chromosome 12p in testicular germ-cell tumors 
is the cause ofthe predominant elevation of serum LD-1 in patients with testicular germ-cell 
tumors (124 ). 
Using multiple serum tumor marker tests for patients with testicular germ-cell tumors, 
there are still approx 30-50% of stage I patients with testicular germ-cell tumors and 10% of 
advanced stage patients have no elevation of anyone of these serum tumor markers 
(4,5,11,14,15,39,40,45, 71,114). The search for new sensitive and specific serum tumor mark­
ers for improving clinical diagnostic sensitivity and specificity is an important responsibility 
of the medical scientists and researchers. 
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9 
Autoantibodies, Autoimmunity, and Cancers 
Markers for Identification of Early Stages of Tumors 
Robert M. Nakamura and Eng M. Tan 
There is a significant association between neoplastic cancers and autoimmune diseases. 
Many autoimm une phenomena have been observed in cancers. Conversely, cancers have 
been diagnosed with increased frequency in autoimmune diseases (1-4). 
Several studies have shown a relationship between rheumatic diseases, autoimmune phe­
nomena, and cancers ( 1-6). Patients with malignant diseases may develop autoimmune phe­
nomena and rheumatic diseases resulting from generations of autoantibodies to various 
autoantigens, oncoproteins , tumor suppressor genes, proliferation assoc iated antigens, 
onconeural antigens, cancer/testes antigens, mRNA -binding proteins, and rheumatic disease ­
associated antigens (1-4 ). 
1.1. Autoantibodies as Predictors of Disease 
Autoantibodies are markers of disease activity and under certain circumstances should be 
able to help define the nature of the disease and provide markers to classify the disease , i.e. 
type I diabetes may be autoimmune or not autoimmune based on the existence of the specific 
disease-associated antibodies (7). Addition ally, they should have the ability to predict the 
presence of the specific disease. The goal is to prevent the manifestations of the disease in 
high-risk patients. 
Autoimmun e diseases, which affect 5% of the population, may be prevented by avoiding 
environmental factors that trigger the disease or by use of therapy that modulates the 
destructive pathogenesis. Screening populations for susceptibility to autoimmune disease 
may be feasible at this time. Similarly, the testing for autoantibodies may be used to screen 
populations for persons who may be at increased risk of manifesting clinically significant 
cancers. 
1.2. Autoantibodies and Cancers 
In a study of liver diseases that develop into hepatocellular carcinoma , Imai et a!. (8) 
found that one-third of patients with chronic hepatitis and/or liver cirrhosis demonstrated 
increasing titers and changing specificities of anti-nuclear antibodies (ANA) at or before 
transition to development of hepa tocellular carcinom a. It should be emphasized that sudden 
changes in titers and alterations of antibody specificities of the ANA are seen infrequentl y in 
classical systemic rheumatic diseases. 
From: Canc er Diagnos tics: Current and Future Trends 
Edited by: R. M. Nakamura, W. W. Grody, j. T. Wu, and R. B. Nagle © Human a Press Inc., Totowa , Nj 
169

170 Nakamura and Tan 
There have been reports that antibodies to certain oncoproteins and tumor suppressor 
gene antigens, such as p53, are detected before the diagnosis of the cancer or in the early 
stages of the malignant disease (9). Tan et al. (3,10-12) have observed that antibodies against 
aberrantly expressed tumor antigens (such as p62, CENP-F, and p53, for example) appear 
before tumors are detected by conventional diagnostic tests. In this chapter, the use of spe­
cific autoantibody assays for serological screening and use as a diagnostic tool for the early 
detection of cancers is described. 
2. AUTOIMMUNITY AND TUMOR IMMUNITY 
2.1. Autoimmunity 
The body is normally endowed with immune mechanisms that distinguish "self' from 
"non-self." There are several pathways and alterations of control mechanisms underlying 
self-recognition that result in an autoimmune response (13,14). The autoimmune response 
with similar antibodies can also be found in patients with various cancers. In addition, anti­
bodies with specificities unique to the cancerous process have been observed; such antibod­
ies may be involved in the immune surveillance that recognizes the neoepitopes on tumors 
as foreign (15-17). 
Autoimmunity can be pathologic and induce immunological injury of the host with dis­
eases, such as systemic lupus erythematosus. However, currently, it is known that autoim­
mune responses are not rare, and self-antigens may elicit a "natural autoimmunity" of the 
host without an accompanying autoimmune disease. Some of these benign autoimmune 
responses may serve a regulatory function within the immune network of the host ( 13,14 ). 
The association of cancers and autoimmunity has been described with increased frequency 
during the last two decades (1-6, 18). Also, autoantibodies have been observed in sera of 
patients with epithelial and hematologic malignancies ( 19 ). Through the use of immunofluo­
rescent assays, elevated titers of ANA have been seen in 27% of cancer patients (19). 
The incidence of autoantibodies to normal tissue constituents was studied in 250 cancer 
patients (20). Utilizing indirect immunofluorescent microscopy methods, Tannenberg et al. 
(20) observed the presence of autoantibody in 15% of 250 patients with malignant disease as 
compared with 24% of patients with general non-neoplastic disease and 8% in normal blood 
donors. In patients with lymphoma or leukemia , the incidence of anti-smooth muscle anti­
bodies was 15% compared with 4% in the control population. There was no increase of anti­
smooth muscle antibodies in patients with other malignant tumors. 
In contrast to the above observations, Swiss et al. (21) studied 164 patients with various 
malignant diseases, the authors did not observe an increased incidence of ANA in malignant 
conditions. The patients' sera were analyzed for ssDNA, dsDNA, poly(I), poly (G), cardio­
lipin, histones, RNP , Sm, SS-A/Ro, and SS-B/La by the enzyme-linked immunosorbent assay 
(ELISA) technique. We acknowledge that a limited number of autoantibody specificities 
were examined and these antibodies are largely seen within the rheumatic disease group of 
patients. It is widely known that cancer patients have different autoantibodies from rheu­
matic disease patients . 
2.2. Identifications of Specific Immune Responses in Cancers 
During the past decade new techniques have been developed to identify various 
oncoproteins and glycoproteins. A methodology called the serological identification of anti-

Autoantibodies, Autoimmunity, and Cancers 171 
gens by recombinant expression cloning (SEREX), which is a modification of immuno­
screening eDNA expression libraries ( 13 ), was used to identify more than 400 autoantigens 
( 15, 16). The antibodies to a given antigen were usually confined to patients with the same 
tumor type. Sahin et al. (1 5,16) have observed that human tumors elicit multiple specific 
immune responses in the autologous host and help provide diagnostic and therapeutic 
approaches to human cancer. The challenge has been to find ways to harness the autoim­
mune response to eliminate tumor cells by the use of immunostimulants or by vaccination 
with tumor-specific antigens. 
3. RHEUMATIC SYNDROMES ASSOCIATED WITH CANCERS 
An extensive search for occult or hidden malignancy in most rheumatic syndromes is not 
recommended unless accompanied by specific "clues" or findings suggestive of malig­
nancy (5,6). 
There is a definite association of cancers or malignancies with certain rheumatic syn­
dromes, such as rheumatoid arthritis or Sjogren's syndrome with monoclonal gammopathy 
and Lambert-Eaton myasthenic syndrome (paraneoplastic rheumatic disorder). Certain long­
standing rheumatic syndromes may behave like "premalignant conditions." The cancer may 
emerge because of immune dysregulation. 
The relative risk of cancer is increased in long standing rheumatoid arthritis, Sjogren's 
syndrome, dermatomyositis, systemic sclerosis, systemic lupus erythematosus, and tempo­
ral arteritis (5,6). However, the risk of cancer is not increased in polymyositis and 
polymyalgia rheumatica (5). Rheumatoid arthritis with monoclonal gammopathy carries a 
high risk for development of cancer (6). Sjogren's syndrome associated with monoclonal anti­
body isotype 17-109 is present in all patients undergoing development of malignancy (22 ). 
Cancer-associated rheumatic disorders may be classified as, paraneoplastic syndrome 
induced by mediators from a distant tumor, host-altered immune surveillance system result­
ing in both the rheumatic and neoplastic diseases , and rheumatic disorder which arises as an 
adverse reaction to anti-cancer therapy (5,6). Cancer-associated rheumatic syndromes occur 
at a distance from the primary tumor or metastasis and are induced by the malignancy through 
hormones, protein mediators, antibodies, and cytotoxic lymphocytes (5,6). 
These cancer-associated rheumatic disorders may precede, appear concomitantly with, or 
follow the clinical diagnosis of cancer. It should be noted that patients who are already 
diagnosed with a malignant disease might develop a systemic rheumatic autoimmune dis­
ease after chemotherapy treatm ent ( 4 ). Treatment of malignancies with immunomodulating 
agents may induce autoimmunity and autoimmune disease . Interferon treatment of myeloprolif­
erative disorders, such as chronic myelogenous leukemia, can often develop rheumatic symp­
toms and trigger the development of autoimmunity. The rheumatic syndromes after 
chemotherapy have been observed in patients with breast cancer , ovarian cancer, and non­
Hodgkin's lymphoma. 
4. PARANEOPLASTIC SYNDROMES 
Paraneoplastic syndromes are organ/tis sue disorders associated with cancer. The autoim­
mune response in paraneopl astic syndromes is triggered by specific antigens and often affects 
the nervous system. These paraneoplastic neurological degenerati ve (PND) syndromes are 
associated with lung, breast, and ovarian cancers (23-28).

172 Nakamura and Tan 
The PND syndromes with symptoms related to disorders of the nervous system show 
antoantibodies that react with nuclear and cytoplasmic components in neuronal cells. The 
associated malignant tumor may have aberrant expression of neuronal type tissues . The neu­
rological disorders include sensory neuropathy, opsoclonus myoclonus ataxia, cerebellar 
degeneration, and brain stem encephalitis. 
Anti-Hu/anti-neuronal nuclear antibody-! (ANNA-l) antibodies have been detected in 
90% of patients with small cell lung cancer (SCLC). The Hu antibody has been associated 
with encephalomyelitis, sensory neuropathy, and cerebellar degeneration. The Hu antigens 
are 35-40 kDa proteins and expressed in neurons . The Hu antigens constitute a family of 
RNA binding proteins with an RNA recognition motif of 80 amino acids (24,25). 
Anti- Yo/anti-Purkinje cell antibody (PCA) is an autoantibody that reacts with an 
onconeural antigen in the cytoplasm of Purkinje cells in the malignant cells of breast and 
gynecological cancers. The Yo antibody is associated with the development of cerebellar 
degeneration with clinical symptoms of ataxia and dysphagia (23-25,29). There are three 
types of Yo antigen and their corresponding genes are clones. 
Antibody to Ri/ANNA-2 protein antibody toRi has been observed in sera of patients with 
breast, SCLC, gynecological , and other cancers (23-28). The antibody toRi binds neuron­
specific RNA nuclear proteins with molecular weight of 55-80 kDa. Clinical features 
observed in patients with anti-Ri are cerebellar degeneration and myoclonus. The genes 
encoding two Ri proteins have been cloned, sequenced, and called neuronal onconeural 
ventral nervous system antigen Nova-/ and Nova -2 by Darnell and colleagues (25,30). 
Amphiphysin is a vesicle-associated protein on the synaptic terminal that binds the vesicle 
core protein adaptor AP2 and dynamin (25 ). Antibodies to amphiphysin may prevent the 
release of neurotransmitters at the synaptic junction. The antibody may occur in patients 
with breast, lung, and other neoplasms (25,31 ). The clinical disorders associated with anti­
amphiphysin are stiff man syndrome with diffuse muscle rigidity and less frequently , 
encephalomyelitis. 
Lambert-Eaton syndrome is a neuromuscular syndrome initiated by immune response 
against neuron-like components of the tumor cells. There is high frequency of calcium-chan­
nel antibodies found in patients with Lambert-Eaton syndrome. These antibodies react with 
voltage gated calcium channels (VOCC) (23-28 ,32-34 ). The VOCC antibodies are found in 
small cell lung cancer (SCLC) and cause a paraneoplastic disorder. The VOCC of the P/Q 
type is present at the presynaptic cholinergic-synapse and in Purkinje cells of the cerebellum 
(32,33). Clinical symptoms may improve if the patient's IgO is removed and replaced by 
plasma exchange treatment ( 34 ). The autoantibodies to Tr antigen have been observed in 
sera of patients with Hodgkin's disease associated paraneoplastic cerebellar degeneration 
(PCD) . The Tr antibody reacts with the cytoplasm and proximal dendrites of the Purkinje 
cells of the human cerebellum in a pattern similar to the Yo antibodies ( 35 ). 
Cancer-associated retinopathy (CAR) is rare and is associated with SCLC, melanoma, or 
gynecologic tumors. The symptoms include impaired visual changes, night blindness, pho­
tosensitivity, and the symptoms often precede the diagnosis of cancer (24,25). Serum anti­
bodies that react with retinal photoreceptor layer or ganglion cells have been observed. 
Antibodies to recoverin, a photoreceptor protein, have been characterized in some cases of 
CAR (36). Also, patients with CAR develop autoantibodies to a enolase. A small percentage 
of healthy subjects without evident tumor or visual symptoms may have serum antibodies 
against a enolase (37).

Autoantibodies, Autoimmunity, and Cancers 173 
5. AUTOANTIBODIES TO ONCOPROTEINS 
Oncoproteins are encoded by oncogenes and/or tumor suppressor genes and participate in 
the regulation of cell growth and differentiation. Mutations of the oncogenes or abnormal 
overexpression of the oncoproteins are involved in the genesis and initiation of malignant 
tumors (3,4,38). 
5.1. Autoantibodies to L-myc, c-myc, and c-myb Proteins 
The L-myc gene is a human oncogene with structural homology to c-myc and c-myb (39). 
The L-myc protein is overexpressed in 10--40% of tumors with neuroendocrine characteris­
tics. The L-myc gene is important in normal development of the brain, kidney, and lungs, and 
in combination with c-myc and c-myb plays a role in differentiation and proliferation (39,40). 
Because L-myc oncogene product is a nuclear protein, antibodies to L-myc could be con­
sidered as anti-nuclear antibodies. Antibodies to L-myc were observed in 10% (7 /70) of lung 
cancer patients. Of the lung tumors, there were five non-small cell lung carcinomas, two 
adenocarcinomas, two squamous cell carcinomas, and one large cell carcinoma (39). C-myc 
oncogene product is another nuclear protein involved in cell proliferation. Ben-Mahrez et al. 
(40) have shown the presence of antibodies to c-myc in patients with cancers of various 
types, including colorectal, breast, and ovarian cancers. C-myc antibodies were found in 
patients with African Burkitt's lymphoma in Ghana and also in normal Ghanians. Thus, 
c-myc antibodies may reflect an autoimmune phenomenon prevalent in the endemic region 
of Ghana (41 ). 
The c-myb gene is a normal cellular gene homologous to the avian myeloblastosis virus 
oncogene . The human c-myb gene product is a 80 kD nuclear protein associated with the 
chromatin and nuclear matrix (42). C-myb antibodies were found in many types of cancers. 
However, the c-myb antibodies were also observed in normal controls (healthy volunteers). 
The percentage of positive sera varied depending upon the cancer type, and breast cancer 
patients showed a frequency of 43% seropositivity for anti c-myb antibodies; however, the 
control patients had an incidence of 24% positivity (42). 
The antibodies to L-myc was detected only in sera of cancer patients (39). The antibodies 
to c-myc and c-myb are not specific for cancer and have been found in healthy patients and 
patients with systemic lupus erythematosus (40-44) . 
5.2. Autoantibody to HER-2/neu Protein 
HER-2/neu is a proto-oncogene that encodes a transmembrane tyrosine kinase human 
epidermal growth factor receptor protein ( 45 ). Overexpression of HER-2/neu protein is seen 
in 20-33 % of breast cancers ( 46,45) and at a lower frequency in other solid tumors, such as 
ovarian cancers. The HER-2/neu protein consists of three domains, an extracellular receptor 
binding site, a lipophilic transmembrane segment, and an intracellular segment with tyrosine 
kinase activity. The HER-2/neu receptor has an important role in cellular growth . Disis et al. 
(46) studied the antibody response to HER-2/neu in 107 newly diagnosed breast cancer 
patients. The sera was analyzed for the presence of HER-2/neu specific antibodies with a 
capture enzyme-linked immunosorbent assay (ELISA) and verified by a Western blot assay. 
Serum HER-2/neu antibodies correlated with the presence of breast cancer. The HER-2/neu 
antibodies at titers of I I 100 or greater were detected in 12 of 107 ( 11%) breast cancer patients 
vs none of 200 (0%) normal controls. Titers of greater than 1/5000 were detected in 5/107 
(5%). A total of 20% (9/44) patients with HER-2/neu positive breast cancers demonstrated

174 Nakamura and Tan 
serum antibodies to HER-2/neu. A total of 5% of patients with HER-2/neu negative breast 
tumors had the antibodies present in their sera ( 46 ). Ward et al. ( 45) studied 57 patients with 
colorectal cancers in various stages for the presence of serum HER-2/neu antibody titer of 
11100 or greater as compared to zero titer in the control population . The HER-2/neu anti­
body response detected in the serum of patients with colorectal cancer was primarily IgG 
and lgA. 
The data suggest that detection of antibody to HER-2/neu in cancer patients may be use­
ful, since the antibody was seen in the early stages of breast cancer patients. 
5.3. Autoantibodies ras Proteins 
The ras oncogenes are cancer-related genes that can be activated by specific point muta­
tion and found in many different types of cancer (47). Three ras genes have been identified 
as H-ras-1, k-ras-2, and N-ras. The ras genes encode a highly conserved group of 21,000 
M.W. proteins (47). 
Mutated ras proteins have been associated with malignant transformation of many human 
cancers. The ras mutations have been seen in 45% of colon adenocarcinomas. 
In a study of 160 colon cancer patients, Takahashi et al. (47) detected IgA antibodies in 
32% of the patients reactive with mutated p21 ras-Dl2 protein and only in one of 40 
so-called normal patients. Thus, the data suggest that the presence of antibody to the ras 
protein is highly correlated with the presence of colon cancer. The major antibody response 
to the p21 ras protein was an IgA response to epitopes located in the non-mutated carboxy 
terminus segment rather than to the mutated segments of the mutated rasprotein. 
5.4. Autoantibodies to Abl and Bcr Proteins 
Formation of an aberrant Abl-Bcr protein is the hallmark marker of Philadelphia chromo­
some (ph)-positive leukemia. Abl and Bcr are intracellular molecules that are biologically 
important in many cell function s (48). Talpaz et al. (48) studied cases of Philadelphia chro­
mosome-positive leukemia , Philadelphia chromosome-negative leukemia , and normal 
patients. A positive antibody response was observed in the above three groups, including 
healthy individuals and Philadelphia chromosome-negative cases of leukemia. Thus, it 
appears that serum assays for antibodies to Abl and Bcr proteins do not have a significant 
correlation to the leukemia group with a positive Philadelphia chromosome. 
6. AUTOANTIBODIES TO TUMOR SUPPRESSOR PROTEINS 
6.1. p53 Antibodies in Cancer Patients 
The tumor suppressor gene p53 is a phosphoprotein in the nucleus of normal cells. The 
p53 has certain properties that can activate genes involved in cell-cycle regulation and can 
arrest cell-cycle progression and allow damaged DNA to be repaired (9). 
In various types of cancers, an incidence of 50% mutations in the p53 gene have been 
observed (9). Approximately 30 to 40% of cancer patients with p53 mutations will develop 
p53 antibodies. The specificity of serum assay for p53 antibodies in cancer is 96% (9,49,50 ). 
The p53 mutations are the most frequent genetic event in human cancers. The most common 
mutations of p53 in human cancers are miss ense point mutations within the coding sequences 
of the gene (9,50,5 1). These mutant p53 proteins are usually inactive and have increased 
stability and accumulate in the nucleus of neoplas tic cells. The half-life of the mutant p53 
protein is several hours as compared with a 20 min half-life for the wild type of p53 protein.

Autoantibodies, Autoimmunity, and Cancers 175 
The p53 mutations have been found in cancers of the colon, stomach, breast, lung, brain, 
and esophagus (52). There is a positive correlation between the frequency ofp53 mutations 
in certain types of cancer (9). However, there are three types of cancers, hepatoma, testicular 
carcinoma, and melanoma that are devoid of p53 mutations and are also negative for anti­
bodies to the p53 protein (53-55). 
Esophageal and oral cancers have a high rate of p53 mutations and a high frequency of 
antibodies. The one exception is gliomatous tumor of brain that has a low incidence of p53 
antibodies despite a high frequency of p53 mutations (9,56). Rainnov et al. (56) found p53 
mutations in 24 to 60 glioblastomas and none of the patients demonstrated p53 serum anti­
bodies. The blood-brain barrier may inhibit the induction of the humoral immune response 
to p53. 
The specificity analysis of the p53 antibodies has revealed that antibody reacts with amino 
and carboxy terminal regions away from the central regions of p53 containing the mutations 
(9,50,57). As seen in many autoimmune diseases, the p53 antibodies are equally reactive 
with the wild type and mutated forms of p53 proteins . The mutated forrns of p53 have a 
longer half-life than the wild type and demonstrate an increased expression. 
The mutated forms of p53 with overexpression and aberrant localization in the nucleus 
and cytoplasm help trigger the autoimmune response. The antibody response to p53 is mainly 
of IgGl and IgG2 subclasses and some patients show an lgM antibody response (9). No 
IgG3 or IgG4 isotypes of p53 antibody was detected in the patients. 
The detection of serum p53 antibodies can be useful for early detection of cancer in high­
risk patients. Anti-p53 antibodies were found in sera of workers exposed to vinyl chloride, 
who developed angiosarcoma of the liver and in the sera of heavy smokers who developed 
lung cancer (57). In these individuals exposed to vinyl chloride, serum anti-p53 antibodies 
were detected before the diagnosis of the malignant disease. Anti-p53 antibodies in serum 
have been detected several month s before clinical diagnosis of cancers in heavy smokers and 
in patients with chronic obstructive pulmonary diseases (58,59). Cawley et al. (60) have 
studied patients with Barrett's esophagus and esophageal carcinoma and found that the pres­
ence of serum p53 antibodies may pre-date the clinical diagnosis of cancer. Thus, the data 
suggest that anti-p53 antibodies are found in sera of patients with cancer. The antibodies to 
p53 are generated in association with p53 gene missense mutation. It has a specificity of 
96% and is useful as a marker for the early detection of carcinoma in patients who are at high 
risk for developing malignancy. 
6.2. Antibody to Retinoblastoma Suppressor Protein 
The retinoblastoma (RB) gene product Rb is a cell-cycle regulator protein. The 
overexpression of Rb leads to hypermethylation of the cellular DNA and modulates DkA 
replication in the cell cycle (61 ). The inactivating mutation of the RB gene is seen in a 
variety of tumors (61,62). 
Matsumoto et al. ( 62) published the first report describing the presence of RB antibodies 
in several patients with small cell carcinoma and non-small cell carcinoma of the lung. The 
presence of antibody reactive with an RB fusion protein was not detected in 30 normal pa­
tients . The usefulness and significance of antibodies to RB suppressor protein needs to be stud­
ied further.

176 Nakamura and Tan 
7. AUTOANTIBODIES TO PROLIFERATION-ASSOCIATED ANTIGENS 
Cancer patients may develop antibodies reactive with antigens that are involved in cell­
cycle regulation. Antibodies to nuclear and cytoplasmic antigens associated with splicing 
processes and ribosome biosynthesis have been reported ( 3,4 ). 
Covini et al. ( 63) reported that antibodies to the nuclear protein cyclin B 1 (protein 
expressed in the Sand G2 phases of the cell cycle) have been found in 15% (151100) of 
patients with hepatocellular carcinoma (HCC). In the same study, no antibodies were 
detected to cyclin Dl and E and only one patient had antibodies to cyclin A. Anti-cyclin 
B 1 was also detected in the sera of patients with chronic active hepatitis and cirrhosis. 
A novel nuclear protein called SG2NA (S/G2 nuclear antigen) was found to be expressed 
inS and G2 phase cells (64,65). The SG2NA antigen was characterized from sera obtained 
from a patient with lung cancer. The SG2NA is involved in regulating nuclear function 
associated with cell cycles. CENP-F , also known as P330, is a cell cycle-associated nuclear 
antigen that is expressed in low amounts in GO/G I cells and accumulates in the nuclear 
matrix during the S phase with a maximal expression in G2/M cells (66,67) . CENP-F is 
associated with the centromeres and the nuclear matrix. 
Anti-CENP-F antibodies were found to be associated with cancer (67,68). The most com­
mon tumors were breast and lung cancers. Autoimmunity to CENP-F is not associated with 
systemic rheumatic diseases. The antibodies to CENP-F were present in rare cases of chronic 
liver disease, and chronic rejection of renal allografts and Crohn's disease (69). Thus, it 
appears that autoimmunity to CENP-F may be related to events of altered or abnormal cells 
proliferation. 
Antibodies to antigens associated with splicing processes and ribosomal biosynthesis have 
been found in cancer patients ( 3, 70,71 ). When the eukaryotic cells divide, the nucleoli dis­
perse before mitosis and reform in the daughter cells at the sites of ribosomal RNA gene 
clusters called nucleolus organizer regions (NOR) (70). 
Tightly bound to NOR during mitosis is the hUBF (human upstream binding factor) , a 
critical factor in the regulation of RNA transcription. Imai and co-workers (71-73) have 
found that sera from patients with hepatocellular carcinoma have antibodies that bind 
NOR-90/hUBF, the U3-RNP associated fibrillarin, DNA topoisomerase II, and other pro­
teins that are involved in the ribosomal biosynthesis. 
8. AUTOIMMUNE RESPONSES TO mRNA-BINDING PROTEINS P62 
AND KOC IN DIFFERENT TYPES OF CANCER 
8.1. p62 and KOC Antigens 
In hepatocellular carcinoma (HCC), autoantibodies to intracellular antigens are detected 
in 30 to 40% of patients ( 10-12). Further studies ( 8,11) have shown that when patients with 
chronic hepatitis or liver cirrhosis develop HCC, patients develop new autoantibodies with 
different immuno-specificities. 
In 1999, Zhang et al. (10) described a putative cancer antigen called p62. p62 is a 62-kD 
protein containing two types of RNA-binding motifs, the consensus sequence RNA-binding 
domain (CS-RBD) and four hn RNP K homology (KH) domains. 
The koc gene was identified by Mueller-Pillasch et al. (74) and the protein they called 
hKOC was observed to be overexpressed in pancreatic cancer. Additional experiments have

Autoantibodies, Autoimmunity, and Cancers 177 
shown that koc gene and overexpression of the messenger RNA were present in a variety of 
other cancers besides cancer of the pancreas. 
Nielsen et al. (75) reported three IGF-11 mRNA-binding protein s, which they called 
IMP -1, IMP-2 , and IMP-3. They demonstrated that IMP-1, 2 and 3 were able to bind IGF-11 
mRNA and alter the translatability of IGF-11 mRNA. 
Several proteins of this family bind to and alter the expression of insulin-like growth 
factor II (KG F-IT) messenger RNA. IGF-II has been implicated as a secondary oncogene and 
its overexpression has been demonstrated in cytoplasm of cells of many different types of 
cancer. Studies by Tan and colleagues ( 10-12 ) have shown that p62 (a splice variant of 
IMP2) is overexpressed in the cancer nodules of hepatocellular carcinoma (HCC). In addi­
tion, p62 mRNA was found in fetal livers and not detected in normal adult livers (76) and 
immunohistochemical assay on liver sections confirmed protein expression in fetus but not 
in adult tissue. Thus, p62 is developmentally regulated, expressed in fetal, but not in adult 
liver and aberrantly expressed in HCC. The p62 protein is cytoplasmic in location and 
autoantibodies were found in 21% of a cohort of HCC patients. The reported evidence shows 
that IGF-II may play an important role in carcinogenesis. 
8.2. Autoantibody Responses to p62 and KOC 
Zhang et al. ( 12) have demonstrated that with use of recombinant polypeptide antigens, 
autoantibodies to both p62 and KOC antigens can be detected. They studied sera from 777 
patients with ten different types of cancers. Autoantibodies to p62 were found in 11.6% and 
to KOC in 12.2% and cumulatively to both antigens in 20.5% with significant differen ces 
from control populations consisting of normal subjects and patients with autoimmune dis­
eases without cancer. 
The types of cancers and number of patients studied in each group are: breast (98), 
colo rectal ( 65 ), esophageal ( 119 ), gastric (135 ), hepatocellular (75 ), lung ( 84 ), lymphoma 
(72), pharyngeal (56), ovarian (33), and uterine (40). 
The control groups studied for the presence of p62 band KOC autoantibodies include 82 
normal patients and 139 patients with autoimmune diseases. The p values for the group of 
norm al patients as compared to the cancer patients was less than 0.05. The autoimmune 
disease group included patients with systemic lupus erythematosus (SLE) (62), rheumatoid 
arthritis (57), and Sjogren's syndrome (20). The p value was less than 0.01 in the compari­
son of the autoimmune group with the patients with cancer. 
The above data demonstr ates that tests for autoantibodies to p62 and KOC will be helpful 
tumor markers to identify patients with a wide variety of cancers. 
9. ANTI-CANCER/TESTIS ANTIGEN ANTIBODIES 
Cancer/testes antigens refer to a large group of antigens that are expressed in various 
tumors (77-79). Both specific cellular and humoral immune recognition of human tumor 
antigens have been reported. Seven cancer/testes antigens have been identified and belong 
to the following gene families: MAGE, GAGE, BAGE, SSX, ESO, SCP, and CIT (77-79). 
Antibodies to MAGE and tyrosinase antigens first recognized by cytotoxic T lympho­
cytes (CTL) have been detected in melanoma patients (78). A low frequency of 5% of anti­
MAGE- I and SSX2 was found in the sera of patients with melanoma, ovarian, or lung cancer 
(79 ). NY -ES0-1, a cancer-testes (CT) antigen has been identified by autologous antibody

178 Nakamura and Tan 
Table 1 
The Percentage of Positive Hsp27 Serum Antibodies 
in Various Cancers 
Ovarian cancer 50% 17/34 
Endometrial cancer 38.2% 13/34 
Cervical and uterine cancers 30% 3/10 
Vaginal and vulvar cancers 60% 3/5 
(77). In a study of 234 cancer patients, Stockert et al. (79) reported that the frequency of 
NY-ES0-1 antibody was 9.4% in melanoma patients and 12.5% in ovarian cancer patients, 
lung cancer ( 42% ), and breast cancer (71% ). 
10. AUTOANTIBODIES TO HSP-27 (HEAT SHOCK PROTEIN) 
AND CATHEPSIN DIN CANCERS 
Korneeva eta!. (80) found that autoantibodies to Hsp 27 were found to be associated with 
cancers of the female genital tract. Antibodies to the Hsp 27 were detected in only 1 in 29 
(3.4%) healthy control subjects and 1 in 23 (4.3%) women with benign lesions. In contrast, 
39 of 96 (40.6%) women with gynecologic cancers had positive antibody for Hsp27 
(p = 0.004 vs benign) (Table I). 
Besides the finding of the presence of antibodies to the Hsp27, there was no relationship 
between antibodies to the other shock proteins Hsp-60, Hsp-70, and Hsp90 and gynecologi ­
cal cancers. 
Bosscher et al. ( 81) determined the presence of circulating pro and mature forms of cathe­
psin D and antibodies reactive to the cathepsin D enzyme by a Western immunoblot and 
quantitated by an enzyme immunoassay. Specific immunoreactivity with the 34 kDa and 
52 kDa Cathepsin D forms were analyzed by Western blot on 40 patients with endometrial 
cancer and 15 normal patients. The circulating pro form of cathepsin D was detected in 31 of 
40 endometrial cancer patients tested and none of the healthy controls. Serum IgG autoanti­
bodies reactive with cathepsin D were demonstrated in 29 of 31 patients who also had circu­
lating procathepsin D. The normal control patients did not have evidence of anti-cathepsin D 
antibodies. 
ll.SUMMARY 
Malignant diseases are commonly associated with induction of autoimmunity, which 
results in the generation of numerous autoantibodies against a wide variety of autoantigens. 
Specific autoimmune features and rheumatic manifestations are associated with a signifi­
cant number of patients with cancer. The association between autoimmunity and cancer may 
result from a number of factors that include genetic, environmental, hormonal, and immuno­
logic factors. Many of the autoantibodies are highly specific for various cancers and include 
autoantibodies to p53, p62, KOC, L-myc, and ras oncogenes. Studies of antibodies to p53, 
p62, and KOC have shown that the specific autoantibodies have been detected in the sera of 
patients several months before the clinical diagnosis of malignancy. 
The studies on humoral immune responses to tumor-associated autoantigens have shown 
that antibodies can be useful reagents to identify aberrant cellular mechanisms involved in 
tumor formation. The autoantibodies to p53 have a specificity of 96% with a prevalence of

Autoantibodies, Autoimmunity, and Cancers 179 
30 to 40% of cancer patients with p53 gene mutations. The general incidence of p53 gene 
mutations in cancer patients is 50%. The incidence of autoantibodies to p62 and KOC anti­
gens were studied in 777 patients with 10 different types of cancer. Autoantibodies to p62 
were found in 11.6% and to KOC in 12.2% and cumulatively in 20.5% of the cancer patients 
studied. 
A recent study of 546 cancer sera used a multiple array of six antigens, which included 
p62, KOC, and p53 antigen (3). They observed that 45% of the sera were positive for 
antibody to any one of the six antigens, as compared with 12% when a single antigen was 
utilized. 
In the future, one can hope that a panel array of several antigens to detect various specific 
autoantibodies may be useful for the early detection of cancer in patients who are in a high­
risk population. 
The autoantibodies have been useful to provide insight into mechanisms and pathways 
associated with cell transformation, regulation of growth factors, and tumorigenesis. 
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43. Yamamoto A, Shimizu E, Takeuchi E, eta!. 1999. Infrequent presence of anti-c-Myc antibodies 
and absence of c-myc oncoprotein in sera from lung cancer patients. Oncology 56:129-133 . 
44. Yamauchi T, Naoe T, Kurosawa Y, Shiku H, Yamada K. 1990. Autoantibodies to c-myc nuclear 
protein products in autoimmune disease. Immunology 69:117-120. 
45. Ward RL, Hawkins NJ, Coomber D, Disis ML. 1999. Antibody immunity to the HER-2/neu 
oncogenic protein in patients with colorectal cancer. Hum. Immunol. 60:510-515. 
46. Disis ML, Pupa SM, Gralow JR, Dittadi R, Menard S, Cheever MA. 1997 . High-titer HER-2/neu 
protein-specific antibody can be detected in patients with early-stage breast cancer. Clin Oncol. 
15:3363 -3367. 
47. Takahashi M, Chen W, Byrd D, ct a!. 1995 . Antibody to ras proteins in patients with colon 
cancer. Clin . Cancer Res. 1:1071-1077. 
48. Talpaz M, Qiu X, Cheng K, et a!. 2000. Autoantibodies to Abl and Bcr proteins . Leukemia 
14:1661-1666. 
49. Angelopoulou K, Diamandis EP, Sutherland DJ, Kellen JA, Bunting PS. 1994. Prevalence of 
serum antibodies against the p53 tumor suppressor gene protein in various cancers. Int. J. Cancer 
58:480-487. 
50. Lubin R, Schlichtholz B, Bengoufa D, et al. 1993 . Analysis of p53 antibodies in patients with 
various cancers define B-cell epitopes of human p53: distribution on primary structure and expo­
sure on protein surface. Cancer Res. 53:5872-5876 . 
51. von Brevern MC, Hollstein MC, Cawley HM, et al. 1996. Circulating anti-p53 antibodies in 
esophageal cancer patients are found predominantly in individuals with p53 core domain muta­
tions in their tumor s. Cancer Res. 56:4917-4921. 
52. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. 1994. Mutations in the p53 tumo r suppres­
sor gene: clues to cancer etiology and molecular pathogeneis. Cancer Res. 54:4855 -4878. 
53. Fleischhacker M, Strohmeyer T, Imai Y, Slamon DJ, Koeffler HP. 1994 . Mutati ons of the p53 
gene are not detectable in human testicular tumors. Mod. Pathol. 7:435-439. 
54. Peng HQ, Hogg D, Malkin D, et al. 1993. Mutations of the p53 gene do not occur in testis cancer. 
Cancer Res. 53:3574 -3578. 
55. Lubbe J, Reichel M, Burg G, Kleihues P. 1994. Absence of p53 gene mutations in cutaneous 
melanoma. J. Invest. Derma to!. 102:819-821. 
56. Rainov NO, Dobberstein KU, Fittkau M, et al. 1995. Absen ce of p53 antibodies in sera from 
glioma patients. Clin. Cancer Res. 1:775 -781. 
57. Trivers GE, Cawley HL, DeBen edetti VM, et al. 1995. Anti-p53 antibodies in sera of workers 
occupationally exposed to vinyl chloride. J. Nat! Cancer Inst. 87:1400-1407. 
58. Trivers GE, DeBenede tti VM, Cawley HL, eta!. 1996. Anti-p53 antibodies in sera from patients 
with chronic obstructive pulmonary disease can predate a diagnosis of cancer. Clin. Cancer Res. 
2:1767-1775. 
59. Lubin R, Zalcman G, Bouchet L, et al. 1995. Serum p53 antibodies as early markers of lung 
cancer. Nat. Med. 1:701 -702. 
60. Cawley HM, Meltzer SJ, DeBenedetti V, et al. 1998. Anti -p53 antibodies in patients with 
Barrett's esophagus or esophageal carcinoma can predate cancer diagnosis. Gastroenterology 
115:19-27 .

182 Nakamura and Tan 
61. Pradhan S and Kim OD. 2002. The retinoblastoma gene product interacts with maintenance 
human DNA (cytosine-5) methyltransferase and modulates its activity. EMBO J. 21:779-788. 
62. Matsumoto S, Teramoto H, Nakamoto M, Igishi T, Kawasaki H, Shimizu E. 2001. Presence of 
antibodies against retinoblastoma tumor suppressor protein in patients with lung cancer. Int. J. 
Oncol. 19:1035-1039. 
63. Covini 0, Chan EKL, Nishioka M, Morshed SA, Reed SI, Tan EM. 1997. Immune response to 
cyclin B1 in hepatocellular carcinoma. Hepatology 25:75-80. 
64. Landberg 0 , Tan EM. 1994. Characterization of a DNA-binding nuclear autoantigen mainly 
associated with S phase and 02 cells. Exp. Cell. Res. 212:255-261. 
65. Muro Y, Chan EK, Landberg 0, Tan EM. 1995. A cell-cycle nuclear autoantigen containing 
WD-40 motifs expressed mainly in S and 02 phase cells . Biochem. Biophys . Res. Commun. 
207:1029-1037. 
66. Casiano CA, Landberg 0, Ochs RL, Tan EM. 1993. Autoantibodies to a novel cell cycle-regu­
lated protein that accumulates in the nuclear matrix during S phase and is localized in the kineto­
chores and spindle midzone during mitoses. J. Cell Sci. 106(Pt 4): 1045-1056. 
67. Landberg 0, Erlanson M, Roos 0, Tan EM, Casiano CA. 1996. Nuclear autoantigen p330d/ 
CENP-F: a marker for cell proliferation in human malignancies . Cytometry 25:90-98. 
68. Rattner JB, Rees J, Whitehead CM, et a!. 1997 . High frequency of neoplasia in patients with 
autoantibodies to centromere protein CENP-F . Clin. Invest. Med. 20:308-319. 
69. Casiano CA, Humbel RL, Peebles C, Covini 0 , Tan EM. 1995. Autoimmunity to the cell cycle­
dependent centromere protein p330d/CENP-F in disorders associated with cell proliferation. 
J. Autoimmun. 8:575-586. 
70. Chan EK, Imai H, Hamel JC, Tan EM. 1991. Human autoantibody to RNA polymerase I tran­
scription factor hUBF. Molecular identity of nucleolus organizer region autoantigen NOR-90 
and ribosomal RNA transcription upstream binding factor. J. Exp. Med. 174:1239 -1244. 
71. Imai H, Chan EK, Kiyosawa K, Fu XD, Tan EM. 1993 . Novel nuclear autoantigen with splicing 
factor motifs identified with antibody from hepatocellular carcinoma. J. Clin. Invest. 92: 
2419-2426. 
72. Imai H, Fritzler MJ, Neri R, Bombardieri S, Tan EM, Chan EK. 1994 . Immunocytochemical char­
acterization of human NOR-90 (upstream binding factor) and associated antigens reactive with 
autoimmune sera. Two MR forms of NOR-90/hUBF autoantigen s. Mol. Bioi. Rep. 19:115 -124. 
73. Imai H, Furuta K, Landberg 0, Kiyosawa K, Liu LF, Tan EM. 1995. Autoantibod y to DNA 
topoisomerase II in primary liver cancer. Clin. Cancer Res. 1:417-424. 
74. Muller-Pillasch F, Lacher U, Wallrapp C, et al. 1997. Cloning of a gene highly overexpressed in 
cancer coding for a novel KH-domain containing protein. Oncogene 14:2729-2733. 
75. Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC. 1999. A 
family of insulin-like growth factor II mRNA-b inding proteins represses translation in late 
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Protein p62 in Liver Cancer and Liver Cirrhosis. Am. J. Path. 159:945 -953. 
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78. Jager E, Chen YT, Drijfhout , JW, et al. 1998 . Simultaneous humoral and cellular immune 
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79. Stockert E, Jager E, Chen YT, et al. 1998. A survey of the humoral immune response of cancer 
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80. Korn eeva I, Bongiovanni AM, Oirotra M, Caputo TA, Witkin SS. 2000. Serum antibodies to the 
27-kd heat shock protein in women with gynecologic cancers. Am. J. Obstet. Oynecol. 183:18. 
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psin D autoantibodies in endometrial cancer patients. Oynecol. On col. 81:138-143.

10 
MHC Tetramers 
A Tool for Direct Ex Vivo Detection and Enumeration 
of Tumor-Specific Cytotoxic T Lymphocytes 
Jennie C. C. Chang, Ferdynand Kos, Charles T. Nu~ent, 
and Kristine Kuus-Retchel 
Recent advances in our understanding of the immune mechanisms at work in cancer vac­
cine therapy and our ability to precisely measure patient immune responses in association 
with cancer therapy have expanded the potential of cancer vaccines and immunotherapy to a 
new level. The emerging fields of genomics, proteomics, immunomics , and bioinformatics 
have provided new tools and allowed the accelerated discovery of cancer associated anti­
gens and specific peptides already proved useful in the development of effective cancer 
immunotherapies. It is critical that we measure the effectiveness of potential immunothera­
pies to quickly determin e if a new therapy has clinical potential and if individual patients are 
responding to specific therapies. In this chapter, we review the role of the measurement of 
antigen-specific T cells, using major histocompatibility complex (MHC) tetramer technol­
ogy, in management of cancer vaccine therapy and cancer immunotherapy. 
2. TUMOR ANTIGENS 
Therapeutic cancer vaccines have been an area of intense research in recent years, as 
reflected by the number of clinical trials using tumor-associated antigens (T AAs). Although 
tumor cells or tumor lysates are the basis of vaccines in some cases, in the majorit y of cases, 
predetermined T AAs are used. T AAs are defined as antigens or antigenic determinants that 
are either specifically expressed or overexpressed by tumor cells. As candidates for thera­
peutic vaccines, T AAs not only need to be recogni zed by the immune system, but also to be 
immunogenic (i.e., to elicit an immun e response). In this section, methods used to identify 
T AAs by cellular, serologic, and molecular approaches are described . 
2.1. T-Cell-D efined Tumor Antigens 
Many TAAs including MAGE-l (1), MAGE-3 (2), tyrosinase (3) gplOO (4,5), MART-I 
(6)and HER-2/neu (7) were derived using immunology -based assays, where CDS + tumor 
infiltr ating lymphocyte (TIL) cell lines/clones were used to define T AA. In these studies, 
TILs associated with clinical respons iveness and demonstrated tumor cell killing were used 
to identify target cells transfected with eDNA derived from tumor cells, or for reactivity 
with peptides eluted from MHC class I on tumor cells. Most of the molecular identification 
From: Ca11cer Diagnos tics: Current and Future Trends 
Edited by: R. M. Nakamura, W . W. Grod y, J. T. Wu, and R. B. Nag le© Humana Press Inc., Toto wa, NJ 
185

186 Chang et al. 
and characterization of tumor antigens has been done in association with melanoma, owing 
to the difficulty of establishing tumor-specific T-cell lines or clones from other types of 
cancer. Isolation of sufficient quantities of tumor-specific peptide s from human lymphocyt e 
antigen (HLA) class I alleles for sequencing is also technically demanding, owing to the 
large number of peptides represented on the cell surface that are bound to MHC molecules 
(up to 2000 by HLA class I alone) (5). 
Effort has been placed on defining the role of MHC !-restricted CDS+ T cells in cell­
mediated immunity against tumors. Evidence also suggests that CD4+ T cells may play a 
role in tumor immunity . CD4+ T cells are known to provide "help" for cos+ T cells, not only 
through cytokine production, but also by activation of antigen-presenting cells that effec­
tively stimulate CDS+ T cells (8). Moreover, melanoma and breast cancer cell lines have 
been shown to express MHC class II molecules upon induction by cytokines such as inter­
feron-y (IFN-y) and tumor necrosis factor-a (TNF-a) (9). In humans , CD4+ T cells reacting 
with tumor cells are an important subset of a TIL population ( 10,11 ). There are data that 
demonstrate the presence of MHC class II epitopes in proteins , such as tyrosina se, gp 1 00, 
MAGE-l, MAGE-3, MART -1, and NY-ES0 -1 (12-14), all originally defined as antigens 
recognized by CDS+ T cells. 
2.2. Classification ofT-Cell-Defined Tumor Antigens 
Recently , Renkvist et al. (15) compiled a comprehensive list ofT-cell-defined human 
tumor antigens and their epitopes. The list is posted at the internet website 
(www.istitutotumori.mi.it). This list consists of both cos+ and CD4 + T-cell-defined cancer 
antigens divided into the following class es: 
1. Tissue-specific antigens, such as the melanocyte-specific antigens and the prostate-specific 
antigens. Many of the melanocyte-lineage antigens are involved in the biosynthesis of melanin. 
Similarly , prostate antigens in this category are also specifically expressed in prostate tissue. 
2. Antigens such as MAGE proteins that are expressed only in tumor s but are not tissue-specific 
(i.e., they are expresse d by histologically different human tumor s). These antigens are now called 
cancer/testis antigens since they are also expressed in testis or embryonic/fetal tissues (16). 
Expression of MAGE proteins in tumors appears to result from transcriptional activation of the 
MAGE genes by nonspecifi c demethylation of the cell's genomic DNA ( 17). 
3. Oncogenes, such as HER-2/n eu and telomerase reverse transcriptase (hTRT), are expressed in 
many normal tissues and in many types of tumor s, with higher expression levels in the latter. 
4. Tumor-specific mutated or fusion gene products . Ma ny antige ns in this category are expressed 
only in the individual tumor where they were defined, thus precludin g them from extensive 
clinical development. A recent ly disco vered TAA that falls into this last category was from a 
lung carcinoma patient with long survival (18). Using HLA class I tetramers , high frequencies 
(0.1 to 0.4%) of peripheral blood CDS + T cells recognized the unique T AA (a mutat ed sequence 
in malic enzyme) in this patient over a span of 10 yr. Interestingly, the frequency of the TAA 
spec ific cos+ cells doubled within 2 wk after intradermal inoculation of lethall y irradiated 
autologous tumor cells , which demonstrated the immunogenicity of this specific peptide. 
2.3. Tumor Antigens Defined by Serology 
In addition to T cells, serum antibodies in cancer patients have been used to identify 
cance r antigens. One strategy was to make eDNA libraries from poly(A)+ RNA isolated 
from fresh tumor biopsi es. The eDNA libraries were cloned into phage particles and used to 
screen for antibodies in patient serum. This strateg y identified sp 100, Ran GTPase acti vat-

Major Histocompatibility Complex Tetramers 187 
ing protein in breast cancer patients (19) and TEGT from patients with brain tumors (20). 
TEGT was overexpressed in 8 of 12 astrocytomas compared to normal human brain tissues. 
TEGT is a conserved gene developmentally regulated in the testis (21) and thus belongs to 
the cancer/testis antigen group described above. 
As research on T AAs accumulated, tumor antigens initially defined by T -cell responses 
such as MAGE-l and tyrosinase were also detected by the serological approach (22). In fact, 
for several TAAs, including p53, MAGE, HER-2/neu , and NY-ES0-1 , both T-cell mediated 
and antibody responses were detected in the same cancer patients (23,24), suggesting an 
integrated immune response against tumor may exist that involves both CD4+ T cells, CDS+ 
T cells, and B cells. Passive immunotherapy such as administration of the humani zed anti­
HER2/neu antibody (Herceptin; Genentech, Inc.) has proven effective in clinical trials in 
patients with metastatic breast cancer. Vaccines that include HER- 2/neu pep tides are 
currently being tested in the clinic. These vaccines are based on peptides derived from 
HER-2/neu that were recognized by TILS derived from breast, ovarian, and pancreatic cancer 
patients . 
2.4. Molecular Approaches to Tumor Antigen Discovery 
Most T AAs identified by T -cell based assays were obtained from melanomas, resulting 
from the technical challenges of obtaining functionally relevant T -cell lines/clones in other 
cancers. Therefore, to identify T AAs in less well-characterized cancers, molecular tech­
niques including eDNA library substraction, Serial analysis of gene expression (SAGE), and 
in silica transcriptomics have also been used to search for genes that are preferentially 
expressed in neoplastic cells. Using a method that coupled eDNA library subtraction with 
eDNA microarray, Wang et al. (25) reported the discovery of a new gene product (L552S) in 
lung adenocarcinoma. L552S is overexpressed in lung adenocarcinoma tumors with half of 
lung adenocarcinoma tumors expressing more than tenfold the levels compared to normal 
tissues. To identify T AAs for diagnosis or immunotherapy purposes, genes derived by 
molecular approaches need to be tested by immunological assays to determine their antige­
nicity . In the study by Wang et al., antibodies to L552S were detected in patients' pleural 
effusions, thus demonstrating the immuno genicity of L552S. However, in order to consider 
this antigen as a vaccine component to stimulate T-cell-mediated immunity, the presence of 
T-cell-specific epitopes needs to be established. 
Another effort to identify T AAs with molecular approaches was recent ly reported by 
Argani et al. (26). In this study , a group of SAGE libraries composed of four pancreatic 
cancer cell lines and two primary pancreatic adenocarcinomas were compared to a group 
composed of short-term cultures of normal tissues, including pancreatic duct epithelial cells, 
colon epithelium, and microvascular endothelial cells. SAGE is a recently describ ed tech­
nique (27,28) in which cellular mRNA transcript s are converted to eDNA and then cleaved 
by restriction enzymes into small (14 bp) fragments, also known as tags. These tags are 
concatenated and sequenced as one long fragment of DNA to give digital information that 
correlates with the expression level of a particular gene. Each 14 bp tag uniquely identifies a 
specific gene transcript because it corresponds to a defined sequence near the transcript's 
3'terminus. SAGE, creating a large database that is available on line (www .ncbi.nlm .nih.gov / 
SAGE), has now analyzed a large number of norm al and neoplastic tissues. Through com­
parative data analysis, Argani et al. identified a new and previously unsuspected marker for 
pancreatic carcinoma, prostate stem cell antigen (PSCA). PCSA is a cell-surface protein that

188 Chang et al. 
has shown promise as a target for immunotherapy of advanced cancers of the prostate (29), 
thus raising the possibility that PCSA is a rational immune target in pancreatic cancers that 
overexpress PSCA. 
2.5. Epitope Discovery 
Through the abundance of gene products that are either specific to or overexpressed in 
cancer cells, a major challenge is to determine the antigenic epitopes that provide good vac­
cine candidates. Peptide libraries have been a major tool for this purpose. As bioinformatics 
began to become a discipline in biological sciences, several new tools are available to move 
from sequence to epitope discovery and vaccine design. Two of these programs, EpiMer and 
EpiMatrix, are computer-driven pattern-matching algorithms that identify T-cell epitopes. 
Conservatrix, BlastiMer, and Patent-Blast permit the analysis to find homology with previ­
ously patented epitopes ( 30 ). Recently, a non-cell-based and/or algorithm-based technology 
was made available. The Epitope Discovery System (iTopra Beckman Coulter) utilizes a 
novel technology that provides biopharmaceutical vaccine researchers with the tools to bet­
ter understand the mechanism of action for the selected protein. Characterization of peptide 
MHC binding is performed in vitro using a process capable of high throughput to identify 
promising epitope candidates and evaluate them for binding affinity and rate of dissociation. 
This new system has the ability to shorten the route to clinical development by allowing a 
systematic ranking of these candidate epitopes for subsequent functional studies. Tools that 
facilitate epitope discovery enable researchers to move quickly to vaccine design. However, 
the decisive test to determine the disease relevance of a T AA still resides in functional as­
says, patient testing, and clinical responses . 
3. METHODS TO MONITOR T-CELL RESPONSES IN CANCER PATIENTS 
A primary concern among investigators monitoring T-cell responses in cancer patients is 
to accurately define the magnitude and functional potential of cancer antigen-specific T cells. 
Several methods are currently available and in use as tools to monitor T-cell responses in 
cancer patients and healthy controls. This section will give a brief description of each method, 
outline what information each method can reveal, and consequently the information which it 
cannot. The remainder of this section will summarize how some of these methods have been 
used in tandem to monitor cancer antigen-specific T cells in cancer patients. 
3.1. Limiting Dilution Analysis 
Historically , the most common method used to assess antigen specificity, effector func­
tion, and frequency of cancer antigen-specific cells is limiting dilution analysis (LDA), where 
titrated numbers of PEL are incubated with the antigen of interest ( 31 ). Over time, the T -cell 
precursors able to respond to antigen will proliferate and expand to numbers sufficient for 
detection. Theoretically, this method gives every antigen-specific T-cell precursor an equal 
chance of proliferation and expansion, in contrast to general or "bulk" expansion ofT cells, 
which occasionally result in cultures that are monoclonal or of limited diversity, and obscure 
the true composition of the original population . 
The two methods commonly used for measuring the antigen-specific response in LDA are: 
1. Measurement ofT -cell expansion in response to incubation with antigen , and 
2. Measurement ofT -cell lysis of target cells expressing the antigen of interest.

Major Histocompatibility Complex Tetramers 189 
In the first approach, after culture of the T cells with antigen , radio labeled nucleotides are 
added into the cultures for a short time prior to harvesting the assay. The amount of radioac­
tive isotope incorporated into the cells represents the amount of DNA synthesized within the 
culture, and therefore the amount of proliferat ion that cells have undergone in response to 
antigenic stimulation. The second approach is to determine the lytic potential ofT cells. In 
this approach, after culture of T cells and antigen, the T cells are coincubated with target 
cells previously labeled with 51Chromium CS1Cr). Targets may be autologous tumor cells 
that naturally express the antigen of interest, or MHC-matched cell lines that express the 
antigen following peptide pulsing, recombinant DNA transfection, or viral infection . Tar­
gets lysed by cytotoxic T lymphocyte (CTL) release 51Cr into the supernatant, and the amount 
of 51Cr in the supernatant correlates with the magnitude of lytic activity ( 32). Alternatively, 
fluorometric and colorimetric readout systems can be used instead of radiolabeling for 
detection of lytic activity ( 33-35 ). Lytic analyses can be carried out with "bulk" T -cell cul­
tures if information concerning the frequency of antigen-specific T cells is not required. 
The strength of LOA is its reliance on statistical analysis and Poisson distribution . 
Through a series of calculations, the investigator may determine the original frequency of 
the antigen-specific T-cell precursors that are able to respond to cancer antigen(s). A weak­
ness of this approach is that T -cell frequency may be altered following in vitro expansion, as 
some antigen-specific T cells are incapable of expansion or unable to expand to levels suffi­
cient for detection. In addition, this procedure is technically challenging, requires prolonged 
culture in vitro, and results are highly operator-dependent. 
3.2. Enzyme-Linked Immunospot Assay 
In addition to lytic activity and proliferation, CDS + T cells secrete cytokines in response 
to antigen stimulation ( 36 ). Secretion of cytokinesis a primary function of CDS+ T cells, and 
in some cases, may be the primary effector function necessary for a successful immune 
response to some pathogens. Enzyme-linked immunospot (ELISPOT) was developed from 
the principle of enzyme-linked immunosorb ent assay (ELISA)-based analysis, where supe r­
natant from cultured cells of interest is incubated with plate-bound antibody that binds the 
cytokine of interest, followed by incub ation with an additional cytokine-specific Ab that 
will allow detection of the specific cytokine ( 37,38). In ELI SPOT, purified T cells are directly 
incubated in Ab-coated wells together with antigen for a pre-determined amount of time, 
usually 6-4S h. T cells able to recognize the antigen will releas e cytokines bound by the 
antibody coating the well. After the predetermined incubation time, cells are washed away, 
and a secondary enzyme-labeled antibody plus chromogenic substrate are added to each 
well. Production of cytokine is determin ed by visually enumerating the colored spots left 
behind by cells able to secre te lymphokin e in response to antigenic stimulation. The limit s of 
detection using this approach have been reported to be lower than ELISA performed on 
culture supernatants, and allows for single-cell resolution of effector function. This proce­
dure requir es that an investigator conside r which cytokine(s) to test. ELISPOT does not give 
absolute enumeration ofT cells able to respond to antigen -only those able to secrete the 
cytokine of interest will be detected. 
3.3. Intracellular Cytokine Analysis 
Another method to detect lymp hokine production is the intracellular cytokine cytometry 
(ICC) assay. Both ICC and ELISPOT detect whether a certain cytokine may be produced by

190 Chang et al. 
cells following a determined period of in vitro stimulation. In contrast to ELISPOT , ICC 
uses flow cytometry to detect cytokine production intracellularly , and therefore measures 
the cell's potential to make the cytokine of interest ( 39 ). During the latter part of the stimu­
lation period, secretion of extracellular proteins is chemically blocked, thus proteins nor­
mally secreted, such as cytokines, accumulate inside the cell. Following stimulation , cells 
are collected , fixed, and permeabilized prior to intracellular staining. In addition to measur­
ing cytokine production, ICC analysis has the capability to measure cell surface expression 
of activation and effector proteins that further characterize the T cells. As with ELISPOT, 
ICC will not detect antigen-specific T cells unable to produc e the cytokine of interest. 
3.4. Major Histocompatability Complex Tetramer-Based Detection 
of Antigen-Specific T Cells 
The assays described thus far have an absolute requirement for in vitro stimulation to 
carry out functional assessment. ELlS POT and ICC require a minimum of 6 h of stimulation 
before cells are harvested and processed, and LOA requires significantly more time, as cells 
must physically expand in numbers prior to assessment of function. In recent years, flow 
cytometric analysis of tetramer-stained cells has been used in experime nts to enumerate 
T cells. Tetramer-based detection ofT cells capitalizes on the observation that multimeric 
MHC/peptide (the primary ligand forT-cell antigen receptor) coupled with a fluorescent dye, 
allow detection and enumeration of antigen-specific T cells ex vivo, and in contrast to the 
other methods described above, do not require in vitro stimulation and manipulation (40). 
MHC tetramers are complexes of four MHC molecules, associated with a specific anti­
genic peptide and a fluorochrome. MHC tetramer specificity is conveyed in two ways: First, 
the four MHC molecules comprising the tetrame ric complex are specific for the subject's 
human leukocyte antigen (HLA), and second, the peptide bound to the MHC molecules is 
antigen-specific. Therefore, tetramers directly enumerate the number of CDS+ T cells able to 
interact with the antigen of intere st in the patient's peripheral blood. By design, MHC tet­
ramers enumerate all peptide-specific CDS+ T cells, regardless of functionality. MHC tet­
ramers enable accurate quantitative analysis of antigen-specific responses, even of extreme ly 
rare events that may comprise 0.01% of peripheral blood mononuclear cells (PBMCs) (41 ). 
The primary strength of tetramer-based analyses is that direct enumeration of antigenic pep­
tide/MHC a11ele-specific T cells can be performed directly from patient blood samples. In 
addition, tetramer-positive cells can be sorted by flow cytometry, expanded in vitro, and 
used to gather additional information on phenotype and functionality. Increasingly, tetramer­
based analysis is coupled with other assays to simultaneously assess frequency and function. 
In contras t to tetramer-positive T cells that respond to pathog ens, cancer-reactive T cells 
may be of lower avidity. This phenomenon is a result of immunological tolerance mecha­
nisms invoked against "self' epitopes , some of which are presented by tumor cells in asso­
ciation with their MHC comp lexes. Therefore , some cancer-reactive, tetramer-positive 
T cells may be of lower fluore scent intensity when analyzed by flow cytometry. 
3.5. Comparison of Methods Used to Evaluate Cancer-Specific T-Cells 
Lytic and proliferation assays, performed as stand-alone or coup led with LDA, had been 
the methods of choice for evaluating the functional capacity of cancer-specific T cells from 
patient samples. However, newer assays, such as ELISPOT, ICC, and tetramer, have some 
distinct advantages over the older assays . The advent of tetramer technology provides inves-

Major Histocompatibility Complex Tetramers 191 
tigators the ability to easily and rapidly enumerate T cells specific for a known antigen and 
MHC allele combination . In addition, costaining samples with antibodies specific for vari­
ous activation and adhesion markers yields additional information about the antigen-specific 
T -cell population. As mentioned above, tetramer staining does not yield information about 
the functional capacity ofT cells. On the contrary, ELISPOT, and ICC assays both measure 
the functional capacity ofT cells, but require significantly more time and technical expertise 
to perform (42). Separately, each of these methods has definite strengths and weaknesses. 
Therefore, in an increasing number of cancer immune monitoring studies, investigators are 
using cytokine and tetramer assays in tandem. 
Several published studies have dealt with direct comparison of various cytokine-based 
assays as well as a comparison of cytokine-based with tetramer-based analysis. In some 
studies, the frequency estimates given by tetramer staining exceeded those afforded by 
ELISPOT (43,44). These results could have arisen from two possibilities: 
1. Some MHC/peptide combinations used to produce tetramers tend to give higher backgrounds. 
In some alleles, this can be overcome by mutation of the CD8 binding region of the MHC mol­
ecule (45). 
2. ELISPOT analysis readily detects functional memory or effector T cells, or "primed " cells, but 
not naive cells, or cells requiring additional stimulation not afforded by the ELISPOT protocol. 
Tetramers are able to detect primed cells, as well as additional cells that may be considered non­
functional, naive, or anergic. 
To date, the most well-characterized cancer antigens and concordant immune responses 
include melanocyte/melanoma differentiation antigens MelanA/Mart-1, tyrosinase and 
gp100; cancer-testis antigens NY-ES0-1, CAMEL and MAGE-AlO; and PRJ, an antigen 
associated with CML (46-50). Tetramer-positive lymphocytes have been detected in patient 
blood samples for most of these antigens. For the most part, ELISPOT and tetramer-binding 
studies have been in general alignment when assessing antigen-specific T-cell frequencies, 
but results are dependent on the type of cancer and cancer antigen being monitored (51,52). 
A major challenge in the field of immune monitoring of cancer patients is the ability to 
detect antigen-specific T cells where only few exist. Tcells specific for some cancer-specific 
antigens (MAGE-3) may be at a frequency that is detectable only if several rounds of in vitro 
stimulation are first performed, as shown by Coulie et al. (53). In their study, multiple im­
munizations with MAGE antigen (MAGE-3.Al peptide) raised an oligoclonal response that 
required in vitro expansion. Emerging technologies such as quantitative reverse transcrip­
tion polymerse chain reaction analysis (qRT-PCR) are capable of specifically detecting T 
cells (by virtue of TCR expression) from small sample volumes, and will be a useful tool for 
cancer immune monitoring in the future (42,54). However, not all cancer-specific responses 
have been difficult to detect, for example, T cells specific for Melan-A/MART -1 can be 
detected in the peripheral blood of non-vaccinated and even normal individuals (55). 
Although many methods are available to enumerate and discern the functional capability 
of cancer antigen-specific T cells, functional, antigen-specific T cells specific for various 
cancer antigens can be found in detectable (and sometimes high) frequencies in the periph­
eral blood, tumors, and tumor-involved nodes of cancer patients. However, the presence of 
tumor antigen-specific T cells may not correlate with a successful immune response to the 
tumor in question. Some reasons for this include the presence of antigen-specific but non­
functional T cells or the presence ofT cells that are not reactive to the appropriate tumor 
antigen.

192 Chang et al. 
4. USE OF MAJOR HISTOCOMPATABILITY COMPLEX TETRAMERS 
IN CANCER PATIENT MANAGEMENT 
Recent developments in the molecular identification of tumor-associated antigens recog­
nized by the immune system have renewed enthusiasm in the application of immunothera ­
pies to treat cancer. A number of different vaccine strategies for cancer immunotherapy have 
been tested, including both nonspecific and tumor antigen-specific approaches (56-60). 
T-cell-based tumor-specific vaccines with purposes ranging from the induction of protective 
immunity to the activation ofT-cell-mediated responses currently represent the most viable 
approach. It is generally agreed that MHC class !-restricted cos + T cells constitute the pri­
mary effector component of the adaptive immunity against pathogens and tumors. 
The development of MHC tetramer technology has offered an easy and direct approach 
for ex vivo analysis of tumor antigen-specific COS+ T-cell responses in cancer patients. We 
are at the beginning stages of using tetramers to analyze T cells in patients, but this powerful 
technology may become, in the future, as useful as specific monoclonal antibodies in the 
studies of immunity. What are the potential utilities of MHC tetramers in cancer patient 
management? In this section we attempt to briefly review representative data in this field as 
well as to speculate and predict future applications. 
4.1. Use of Tetramers in the Monitoring of Tumor Antigen-Specific T Cells 
in Nonvaccinated Cancer Patients 
Cutaneous melanoma, one of the most immunogenic tumors, has served as the major 
model in the studies of tumor immunotherapy. A number of antigens expressed on mela­
noma cells have been identified (61 ). Most of them, including Melan-A/MART-1, tyrosi­
nase and gplOO are normal differentiation antigens, also present on normal melanocytes. 
Other antigens, such as MAGE, seem to be primarily expressed on tumor cells. Specific 
amino acid peptide sequences from melanoma-associated antigens bind to MHC Class I 
molecules, especially HLA-A2, and form epitopes recognizable by specific TCRs on cos+ 
CTLs. In some clinical trials, the inclusion of these peptides in vaccines can induce specific 
CTL responses in cancer patients. 
In monitoring the immune responses of cancer patients, tetramers have been a useful tool 
to enumerate antigen-specific cos+ T cells ex vivo in samples ofPBMCs, metastatic lymph 
nodes, and tumor infiltrating lymphocytes from HLA-A2 melanoma patients (62-65 ). Stain­
ing of tumor-infiltrating lymphocytes and cells from metastatic lymph nodes with Melan-N 
MART-1 tetramers showed relatively high levels of specific COS+ T cells in most patients 
(63,64). In contrast, tetramer-positive T cells were not detectable in normal lymph nodes. 
These observations indicate that Melan-A/MART-1-specific COS+ T cells accumulate in 
tumor inflammatory infiltrates as well as in metastatic lymph nodes, where tumor-associated 
antigens are present. Future development of techniques to stain tissue sections with tetram­
ers may facilitate the analysis of distribution and interactions between antigen-specific CTLs 
and tumor cells in situ. 
Tetramers have been used in studies of tolerance induction by tumors. Lee et al. have 
shown that MART-1- or tyrosinase-specific T cells are selectively rendered anergic in vivo 
and unable to control melanoma growth (62). These T cells were functionally unresponsive 
in vitro (i.e., they were unable to lyse melanoma target cells or to secrete cytokines in response 
to mitogens).

Major Histocompatibility Complex Tetramers 193 
MHC class I tetramers along with peptides they carry are specific ligands for their cog­
nate TCRs. Tetramer binding toT cells ex vivo can be detected with high sensitivity using 
flow cytometric analysis. Its lower detection limit reaches 0.01 % in peripheral blood lym­
phocytes in whole blood assays. Nonspecific binding is low and can be eliminated by apply­
ing exclusion staining using monoclonal antibodies to non- T-celllineage markers, followed 
by appropriate gating strategies in flow cytometric analysis. Antigen-specific T cells can be 
precisely enumerated without the need of using more complicated and labor-intensive assays 
such as LOA, ELISPOT, intracellular cytokine (IFN-y, TNF-a, MIP-1) staining, or 
51Cr-release cytotoxicity assay (55,66). Tetramer staining can be combined with some func­
tional assays, such as, IFN-y production or cytotoxicity assays. In general, these combined 
assays are more difficult to perform and often generate less consistent results. For example, 
to detect IFN-y production either by secretion or by intracellular assays, T cells need to be 
activated. Activation ofT cells leads to significant downregulation of surface TCRs, thus 
compromises the detection of IFN-y-producing T cells by tetramers unless the assay is accu­
rately timed . 
4.2. Use of Tetramers in the Monitoring of Tumor Antigen-Specific T Cells 
in Vaccinated Cancer Patients 
It is generally accepted that cancer immunotherapy may be limited in its effects as an 
adjuvant treatment to the conventional therapies and in the management of minimal residual 
disease following surgical resection of the primary tumor load (67). Nevertheless , adjuvant 
therapies improve survival and further understanding of antitumor immune responses pro­
vide additional advantages to cancer treatment protocols. 
It has been shown in some clinical studies that vaccination of cancer patients with pep­
tides derived from tumor antigens leads to the stimulation of cos+ T cells and, in some cases 
induces clinical responses. For example, Valmori et al. (68) showed that immunization of 
melanoma patients with Melan-A peptide selected high-avidity T -cell clones exhibiting 
increased tumor reactivity. The number of circulating Melan-A tetramer-positive Cos+ 
T cells increased after vaccination and remained at the stable level of 1.1%- 2. 3% of total 
circulating cos + T cells. Coulie et al. (53) observed a monoclonal 100-fold expansion of 
MAGE-3-specific cos+ T cells in a melanoma patient vaccinated with a MAGE-3 peptide 
presented by HLA-Al. This patient also exhibited a partial rejection of a large metasta sis 
after vaccination. In a study by Fong et al. (69), advanced colon and lung cancer patients 
were treated with Flt3 ligand injections to expand their dendritic cells in vivo , after which 
the dendritic cells were isolated from the blood, loaded with peptide derived from 
carcinoembryonic antigen (CEA), and injected back into the patients. Clinical response in 2 
of 12 patients was found to correlate with the expansion of tetramer -positive cos + T cells 
shown to recognize tumor cells expressing endogenous CEA. Molldrem et al. (50), in stud­
ies ofT cells specific for PRJ peptide derived from proteinase of chronic myelogenous 
leukemia cells , found a strong correlation between the presence of PR 1-specific T cells and 
clinical responses in patients after the IFN -y and bone marrow transplant therapy. PR !-spe­
cific T cells were identified with PR1-HLA -A*0201 tetramers in this study. In addition, 
investi gators observed that PRl-specifi c T cells were not detect ed in chemotherapy-treated 
or untreated patients. 
In addition to their use in monitoring T-cell responses in patients, MHC tetramers offer an 
excellent tool for the isolation of tumor-specific C08+ T cells from heterologous popula-

194 Chang et al. 
tions of cells such as PBMCs, tumor-infiltrating lymphocytes, or cultured cells (70). The 
isolated tumor-specific T cells can then be activated and expanded ex vivo for transfer to 
cancer patients by adoptive immunotherapy. Undoubtedly, tetramers would also be of value 
in tracking adoptively transferred T cells to define any correlations between their number, 
activity, or distribution with disease progression. 
Further use of tetramers may be monitoring of CDS+ T-cell repertoire during conven­
tional cancer therapies. Conventional cancer therapies often exert immunosuppressive effects 
that may not be desirable in terms of the overall therapeutic efficacy; therefore, information 
on status of antigen-specific T cells may provide new insights on how to balance anticancer 
effects of chemotherapeutics with their suppressive effects on anticancer immunity. 
S.SUMMARY 
Recent scientific advances allowed investigators to identify T AAs associated with indi­
vidual cancers at an accelerated rate. The association of TAAs identified through cellular, 
serologic, or molecular approaches with specific cancer cells has been confirmed. Cancer 
vaccines that contain these T AAs can specifically boost the immune response of patients to 
the relevant tumor antigens. In spite of these advances, the identification of the breadth of 
tumor-associated peptides in different cancers remains a challenge . In addition , the question 
of whether or not the measurement of immune responses to tumor peptides will correlate 
with clinical outcome remains unknown. Clinical trials are now underway to answer these 
questions. 
MHC tetramer analysis, which enumerates antigen-specific T cells, provides researchers 
with data that reflect the status of an individual's immune response to specific tumor anti­
gens, whether naturally induced or stimulated through administration of cancer vaccines . 
These data will allow investigators to monitor the specific immune response in patients in 
response to immune therapies and provide early evidence of the effectiveness of therapies. A 
recent review, published by the Society for Biologic Therapy, recommends the use of MHC 
tetramer analysis combined with a measurement of immune function such as Elispot or 
intracellular cytokine for measurement of the immune status of patients undergoing cancer 
vaccine therapy (42). 
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1. INTRODUCTION 11 
New Applications of Flow Cytometry 
in Cancer Diagnosis and Therapy 
Sophie Song and Faramarz N aeim 
1.1. Overview of Clinical Flow Cytometry 
Over the past two decades, clinical flow cytometry has evol ved from a highly specialized 
research tool to an integral component of clinical practice (1-4). This progress has been 
driven by several critical factors including the emergence of new classifications (5-14) of 
hematopoietic and lymphoid malignancies, the development of diagnostic consensus 
( 15-21), and advancement of several technological components (22-25 ). These technical 
advancements include new instrumentation and software, availability of high quality flu oro­
chromes and monoclonal antibodies, improved gating strategies , routine use of multiparam­
eter approaches, and increased emphasis on clinicopathologic correlations. 
Flow cytometry is a well-recognized powerful method of immunophenotyping in clinical 
diagnosis and management of hematopoietic and lymphoid malignancies. Just as immuno­
histochemistry revolutionized modern diagnostic pathology, many physicians predict that 
flow cytometry represents "the future of pathology." This statement refle cts the powerful 
and versatile clinical role of flow cytometry in the context of clinicopathologic correlations. 
Neverthel ess, this new era of flow cytometry does impose an unavoidable chall enge upon 
pathologists in their routine practice . 
This chapter will review the current applications of flow cytometry in cancer diagnosis 
and therapy, with a special focus on discussion of future trends in this field through introduc­
ing innovative and advanced technological approaches. 
1.2. Practical Highlights of Basic Principles 
Sever al outstanding reference books are available for a comprehensive understandin g of 
the fundamental principles and technical details in clinical t1ow cytometry (26-29). To pro­
vide a basis of understanding for clinicians and pathologists who are not used to instrumen­
tations and software of flow cytometers for their clinical data interpretation, a few practical 
highlight s are discussed in this section . 
1.2.1. Concepts of Flow Cytom etry, Cell Population , and Gatin g 
As the term implies, t1ow cytom etry measure s cell (or particl e) propertie s obtained when 
a stream of single cell (or particle) suspension passes through a set of optical detectors. Flow 
From : Ca11cer Diag11os tics: Curre11t a11d Futu re Tre11ds 
Edited by: R. M. Nakamur a, W. W. Grody, J. T. Wu, and R. B. Nagle© Hum ana Press Inc., Totowa , NJ 
199

200 
FSC u 
(/) 
(/) Song and Naeim 
CD45 
Fig. 1. Schematics of pattern recognition of hematopoietic cell clusters by flow cytometry using a 
combination of gating strategies. The diagram on the left shows cell population distribution using 
forward scatter (FSC) vs side scatter (SSC) gating. The diagram on the right represents cell popula­
tion distribution using CD45 SSC gating. G,granulocytes; M, monocytes; P, plasma cells; L, lympho­
cytes; B,blasts; E,erythroid precursors . 
cytometer recognizes particles that include cells, intracellular ultrastructures and macromol­
ecules, isolated nuclei, debris, cell aggregates, or microsphere beads, to name a few. 
To make any data analysis meaningful, specific instructions are given to the cytometer for 
delineating monodisperse cell populations, which under most circumstances are the target of 
analysis. A cell population of interest simply indicates a group of cells sharing identical 
characteristics creating a tendency of specific monodisperse clustering using multiparam­
eter analysis. The use of multiparameter analysis is critical because this approach enables a 
multidimensional correlation between parameters, which results in significantly increased 
sensitivity and specificity for detecting target populations. This explains why major clinical 
flow cytometry laboratories quickly adopted the use of four-color and six-parameter (com­
bination of two light scatter and four fluorescence colors) immunophenotyping in their rou­
tine diagnostic practice when cytometers with this type of analytic capacity became 
commercially available. 
Gating is setting a population of cells in an electronic window. Gating strategies have 
been dramatically improved over the past several years, and some methods have been 
accepted as the standard by experts ( 1,2,4,22,23,28). For example, the preferred gating strat­
egy of human peripheral blood and bone marrow is to use CD45 vs side scatter (22,23) (Fig. I). 
Both the sensitivity and specificity of immunophenotyping can be significantly improved 
when a combination of two or more gating strategies is used to complement each other. 
Proper gating is such a critical step in data analysis and interpretation that pathologists often 
offer advice to even the best-trained flow cytometry technologists. 
1.2.2. Fluorochromes, Fluorescence, and Compensation 
The availability of various fluorochromes and high-quality fluorochrome-conjugated 
monoclonal antibodies (MAbs) has enabled multiparameter immunophenotyping. Each fluo­
rochrome has a discrete spectral pattern of light excitation and emission, therefore the use of 
multicolor assays results in emission spectral overlap of fluorochromes. This overlap is a 
spillover phenomenon of fluorescence from one fluorochrome to its neighbor fluorochrome .

Flow Cytometry in Cancer Diagnosis and Therapy 201 
Compensation is the subtraction of this fluorescence spillover. Although compensation is 
easily understood conceptually, it remains one of the most challenging technical aspects in 
data acquisition when multicolor immunophenotyping is applied. The use of new tandem 
fluorochromes and the most recent emergence of software compensation ( 30) have contrib­
uted to the simplification of the procedure. Several recent publications have addressed this 
technical challenge by providing guidance for the standardization of this complex process 
(26,31-34). 
1.3. Critical Role of Quality Assurance and Quality Control 
Flow cytometry is a unique modern technology because its ultimate clinical utility relies 
on a highly sophisticated process involving a combination of both objective discrimination 
and artistic manipulation. Because of its increasing popularity and widespread use in routine 
clinical practice, the critical value of quality assurance and quality control of flow cytometry 
cannot be overemphasized. Although enormous efforts have been made to establish stan­
dards in this area by experts from Europe, the United States, and Canada ( 15-18,26 ,35-4 0), 
the intra- and interlaboratory reproducibility is yet to be established ( 41-43) in two major 
areas: (1) the methods used for assessment of antigen expression and (2) the criteria 
employed for interpretation and reporting of results ( 1,4 ). It is important for pathologists to 
identify this issue of quality assurance and quality control with a sense of urgency and pro­
fessional obligation. 
2. MODERN UTILITY OF FLOW CYTOMETRY IN DIAGNOSIS, 
CLASSIFICATION, PROGNOSTIC STRATIFICATION, AND MONITORING 
OF PREMALIGNANT AND MALIGNANT DISORDERS 
2.1. Advantage and Limitations of Flow Cytometry in Modern Cancer Diagnosis 
Immunophenotyping by flow cytometry is well recognized as an important diagnostic 
tool in hematopoietic and lymphoid malignancies in the context of clinicopathologic corre­
lations, including clinical, morphologic, cytogenetic, molecular genetic, and immunohis­
tochemical. Immunophenotyping by multiparametric flow cytometry is the only technique 
that permits simultaneous quantitative measurements of multiple characters in individual 
cells, thereby providing rapid , objective, and sensitive multivariable analysis of single-cell 
based cell populations (from single digit number to millions of cells). 
Flow cytometry provides relatively fast service. It is able to acquire and analyze tens of 
thousands of cells in less than a few minutes. The time between receiving specimens and report­
ing results by pathologists is not more than a few hours, much faster than the conventional 
cytogenetic and molecular pathology services. In addition, the ability of acquiring and ana­
lyzing a large number of cells, makes it possible to detect rare events, such as minimal residual 
disease, where abnormal cells can be one in 105 cells (or I0-5) or less. 
The major limitation of flow cytometry is its dependence on other clinicopathologic find­
ings, especially clinical history , morphologic examination, immunohistochemical study, 
cytogenetic, and molecular genetic analysis. Immunophenotyping by flow cytometry alone 
may not be efficient for achieving a proper pathologic diagnosis. A practical example of this 
argument is that flow cytometric immunophenotyping does not distinguish a lesion in the 
mediastinum , where normal thymic tissue, and lymphoblastic lymphoma/leukemia are all 
among potential differential diagno ses yet may share an identical immunophenotype.

202 Song and Naeim 
As a result of recent technological advances in the field, some cytometrists are optimistic 
in clinical flow cytometry being used in a complete high-throughput and automated format. 
In fact, some commercial and large academic flow cytometry laboratories have already 
started practicing high-throughput flow cytometry by ordering a universal large panel of 
antibodies on high volume specimens without special emphasis on clinical and morphologi­
cal correlations. Often in this type of high-throughput practice, the decision for proper gat­
ing, which is in fact a medical judgment, is left in the hands of flow cytometry technologists . 
It is important for pathologists to be aware of this issue and to identify the importance of 
their roles in data analysis and interpretation, in order to provide high quality flow cytometry 
service, which ultimately leads to high quality patient care. 
Flow cytometry can provide clinically meaningful and accurate information, only if con­
sidered in the context of clinicopathologic correlations . Therefore, despite the rapid techno­
logical advances in the field, it is difficult to argue that the practice of clinical flow cytometry 
will adapt a completely automated high-throughput format independent of clinicopathologic 
correlations in the future. 
2.2. Acute Leukemias 
The new World Health Organization (WHO) classification (44,45) provides a guideline 
for the immunophenotyping of acute leukemias by flow cytometry. It is best achieved 
through the following sequential events: 
1. Review of clinical history, morphologic evaluation, and panel selection. 
2. Enumeration, lineage identification, maturation, and phenotypic aberration assessment of 
leukemic population . 
3. Phenotypic characterization of pathologic subpopulations. 
4. Additional clinicopathologic correlations, including immunohistochemistry, cytochemistry, 
cytogenetics, and molecular genetics. 
Immunophenotypic features of leukemic/lymphomatous cells are considered as reflec­
tions of normal cells undergoing maturation arrest. However, accumulating new evidence 
has demonstrated aberrant immunophenotype of the pathologic cells displaying expression 
of cross-lineage and/or asynchronous antigens, ectopic phenotypes , as well as abnormal dif­
ferentiation pathways among others ( 1,46-50). The clinical relevance of aberrant expression 
and specific phenotype relies on its connection to prognostically relevant genotypic mark­
ers, because they appear to be important for identifying entities with distinct prognoses and 
clinical behavior (51). Recent studies have focused on addressing associations between spe­
cific immunophenotypes of leukemic cells and prognostically relevant genotypic markers. 
The majority of the recent findings are summarized thoroughly in a review by Hrusak and 
Porwit-MacDonald (52). 
2.2.1. Acute Lymphoblastic Leukemia/Lymphoma 
2.2.1.1. PRECURSOR B-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (B-ALL) LINEAGE 
B-lineage ALLs are characterized by expression of cytoplasmic CD22 and CD79a as well 
as membrane CD 19. In addition, it is important to assess the maturation stage of leukemic 
cells using CD34, TdT, CDlO, CD20, cytoplasmic heavy chain (IgM), and surface light 
chains (K or A). The detection of intracellular TdT is highly specific for ALL if a B-lineage 
process is confirmed. If TdT is negative , attention should be directed toward Burkitt leuke­
mia/lymphoma and other types of lymphomas, such as rare leukemic present ation of mantle

Flow Cytometry in Cancer Diagnosis and Therapy 
Table 1 
B-Lineage ALL Immunophenotypic Groups 
Type Characteristic immunophenotypic feature s 
Early precursor HLA-DR, TdT, CD34, cytoplasmic CD22, CD79a and often 
CD19 
Precursor B HLA-DR , TdT, COlO , ±CD34, cytoplasmic CD22, CD79a 
and often CD20 
Pre-B HLA-DR, cytoplasmic Ig heavy chain f.-l, ±TdT, COlO, CD19, 
CD20, CD22, and CD79a 
B (Burkitt type) HLA-DR, CD19, CD20, CD22, CD79a, surface Ig, and ±CDIO 
Table 2 
T-Lineage ALL Immunophenotypic Groups 
Type 
Early precursor 
Immature thymocyte 
Intermediate thymocyte 
Mature thymocyte Characteristic immunophenotypic features 
CD7, TdT, and CD34 
CD7, TdT, cytoplasmic CD3, C02, CDS, and CD38 
CD7, TdT, CD38, CDla, C02 , CD3, CDS, CD4 , 
and CD8 
CD7, CD38 , C02, CD3, CDS, CD4 or CD8 and ±TdT 203 
cell lymphoma (53). CD34 is expressed in about 50% of the B-lineage ALL cases. The 
B-lineage ALLs are divided into four immunophenotypic groups (see Table 1). 
Less than half of the precursor B-ALL patients demonstrate aberrant expre ssion of 
myeloid markers such as CD13 and CD33 (54-57). Although recent large clinical trial stud­
ies have not proven the clinical utility of the aberrant expression of myeloid antigens 
(54,58,59), the expression may predict an MLL gene rearrangem ent (54,60) . 
In B-lineage ALL, the genotypic marker t(l2:21) (TEL/AMLl) is found to be generally 
associated with a very good prognosis in pediatric patients (61-65,71). The characteristic 
immunophenotype in this group is low or absent CD9 , CD20, and CD45 , but high CDIO 
(61,65). The pediatric patients with t(12;21) also show more frequent expression of CDI3 
and/or CD33 (53). In the contrary, a poor prognosis is linked to t(9;22) (BCR/ABL) and 
t(4;11) (MLL/AF4) genotypic markers, with specific immunophenotypes being CD34 +f 
CD3S+ in t(9;22) (66) vs NG2+/CDI5+/CD10- in llq23 translocations, respectively (62,67 -70). 
2.2.1.2. PRE CURSOR T-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (T-LINEAG E ALL) 
The T-lineage ALLs are divided into four immunophenotypes (see Table 2) (72). 
The expression of CD3 (cytoplasmic or membrane) is the most helpful marker for linea ge 
specificity. In almost 100% of the patients, CD7 is expressed on leukemic cells. The expres­
sion of CD7 is by no means specific, it is also found in about 20% AML patients (73). 
Myeloid antigens, such as CD 13 and CD33 are frequently identified in T -lineage ALL, 
althou gh their clinical significance is unclear (54-58}. 
In T-lineag e ALL, it is more challenging to understand the connection between a given 
phenotype and prognostically relevant genotypic marke rs, because no cytogenetic or mo­
lecular genetic abnormality can be identified in most adult and pediatric cases (74, 75 ). Most

204 Song and Naeim 
recent trials have suggested that T-lineage ALL of intermediate differentiation (defined as 
expression of COla or combined with double positivity for CD4 and CDS) seems to be 
associated with a more favorable prognosis (76-78). Previous indications regarding the 
association of C02 and CD 10 expression with a more favorable outcome have not been 
proven in recent trials (76). A recent study described a new specific translocation t(5;14) 
(q35;q32), found in about 22% of pediatric T-ALL patients (79). According to the study, this 
translocation is associated with the HoxllL2 gene expression, which is reportedly in con­
nection with the intermediate T-ALL phenotype (52). 
2.2.2. Acute Myeloid Leukemia 
2.2.2.1. DIAGNOSIS AN D CLASSIFICATION 
According to the new WHO classification, acute myeloid leukemia (AML) has four major 
clinical and biological categories ( 44,45 ): 
I. AML with recurrent genetic abnormalities. 
2. AML with multilineage dysplasia. 
3. AML with myelodysplastic syndromes (MDS), therapy related. 
4. AML, not otherwise categorized . 
This new system of classification emphasizes the critical value of clinicopathologic cor­
relation using all available morphologic, genetic, and clinical data, in recognizing unique 
disease entities that are clinically and biologically meaningful. Based on the WHO criteria, 
the blast threshold for diagnosis of AML has also been set at :::::20 %. 
In addition to myeloperoxidase (MPO) as the lineage specific marker in AML ( 44 ), sev­
eral other myeloid antigens including CD13, CD33, CD117 are expressed in approx 65-90% 
or more of AML cases ( 80-83). Practical challenges arise in enumeration and 
immunophenotypic characterization of leukemic cells in AML cases, owing to the widely 
recognized differentiation heterogeneity of these leukemic cells (2,3,15,84). 
To achieve accurate enumeration and phenotypic assessment of the leukemic cells, spe­
cial attention should be devoted to the selection of proper gating strategies in the context of 
clinicopathological correlations. The standard gating method of CD45 vs side scatter is ad­
equate in majority of the AML cases ( 4 ), but a combination of several gating methods, such 
as forward vs side light scatter , as well as light scatter vs CD13, or CD33 , or CD34 , needs to 
be conducted to improve the sensitivity and specificity of leukemic cell detection. For 
example, blast cells in general express low intensity CD45, but in some cases of ALL, as 
well as acute monocytic and myelomonocytic leukemias, they may show high intensity CD45 
expression (Fig. 2). Therefore, proper gating should allow detection of target populations 
including myeloblasts and their equivalents, and are exemplified by abnormal promyelocytes 
in acute promyelocytic leukemia (APL), as well as monoblasts and promonocytes in acute 
myelomonocytic leukemia. 
A fundamental strategy in data analysis and interpretation is the recognition of antigen 
expression patterns, including lineage specific markers, maturation molecules , aberrant an­
tigens , as well as antigen expression intensities. This strategy is more valuable when the 
genotypic-immunophenotypic association becomes the focus of investigation as implicated 
in the new WHO classification system of AML (45) and published in the updated review 
(52) as mentioned earlier.

u 
VI 
VI 
u 
VI 
VI 
FSC M 
M 
0 u 
M 
M 
0 u 
CD7 .... 
Ci u 
.... ..... 
0 u 205 
CD64 
Fig. 2. Bone marrow flow cytometric analysis on a patient with acute myelomonocytic leukemia . 
When the gated population only represents CD45 dim cells (upper row) no CD14 positi ve cluster is 
detected. But, when the gate is expanded to also include CD45 strongly positive cells (lower row), 
there is clearly a population of CD14 positive cells , indicating the presence of a monocytic compo­
nent. In certain leukemias, such as acute monocytic and myelomonocytic types as well as occasional 
cases of acute lymphoblastic leukemias, blasts and immature forms partially or totally show strong 
expression of CD45. 
2.2.2.2. GENOTYPic-IMMUNOPHENOTYPIC AssociATIONs 
Recently , efforts have been made on addressing the associatiOn between 
immunophenotypes and prognostically significant genotypic markers. Although conflicting 
results still exist, abnormal phenotypes have been detected in all AML cases carrying spe­
cific translocations discussed below (52,85) (Table 3). 
2.2.2.2.1. AML With t(8;21) (AMLl/ETO) 
This translocation involves the AMLJ gene on chromosome 21 q22 and ETO gene on chro­
mosome 8q22 (86). It is found in approx 7% of AMLs (52) including both adult and child­
hood cases, with a relatively higher incidence in younger patients . AML with this genotype 
is generally associated with a higher sensitivity to therapy and a better outcom e ( 4 ). The 
leukemic cells demonstrate characteristic immunophenotype expressing high-inten sity MPO, 
CD13, and usually low-intensity CD33. Expression of CD15, CD34, CD65 , CD117, and 
HLA-DR is identified in high proportion of the cases. In addition, lymphoid lineage markers 
CD 19 and/or CD 56 are frequently expressed. The expression of CD 56 has been associated 
with a worse prognosis in some studies (87). 
2.2.2.2.2 . AML With t(l5; 17) (PMLIRARa) and Variants 
Acute promyelocytic leukemia (APL) constitutes about 5-15% of all AML cases (52), 
revealing distinct morphologic, genetic, and immunophenotypic findings (Fig. 3). The 
t(l5;17) translocation is characteristically present in APL, involving the PML gene on chro­
mosome 15 and the retinoic acid receptor alpha (RARa) gene on chromosome 17. About 
10% of cases of APL present as microgranular variants with altered underlying genotypes

Table 3 
Phenotypic and Genotypic Correlations in Acute Leukemia 
Type Immunophenotype Chromosomes Genes Comments 
ALL Early precursor B, CD 10-, t(4;ll)(q2l; q23) AF4/AML 50% of ALLs in infants 6-7% of all ALLs 
plus CD Js+ and/or CD65+ 
Precursor B phenotype CD J3+ t(l2;23)(p 13;q22) TEL/AMLl Undetected by routine karyotype 25% 
and/or CD33+ of childhood ALLs 
Precursor B phenotype plus CD9+ t(9;22)(q34;q 11) BCRJABL 25% of adult and 5% of childhood ALLs 
B phenotype,CD10± t(S; 14 )(q24;q32) MYC/IGH Burkitt leukemia/lymphoma African type 
surface Ig+, and TdT t(2;8)(p 11 ;q24) IGK/MYC EB V -associated 
t(8;22)(q24;qll) MYC/IGL 
Early precursor B, CD 10-t(l;l9)(q23;pl3) E2A/PBX1 About 5% of ALLs 
cytoplasmic IgM-, and surface lg-
Precursor B phenotype t(l7;19)(q21;pl3) E2A/HLF Rare 
N T-lineage, CD1a+, CD2+, CDS+, t(S; 14)(q35;q32) RanBP17/CTIP2 Approximately 20% of T-ALLs in children 
0 Q) cDr,cDs+ and adolescents 
AML CD34+, CDl3+, CDJS+, CD33+, t(8;21)( q22;q22) AMLl/ETO AML-M2 of FAB classification 
MPQ+, CD191ow±, and CDS6± About 7% of AMLs 
CD13+, CD33+, MPO+, HLA-DR·, t( 15; 17)( q22;q21) PML/RARa Acute promyelocytic leukemia 
CD3410w or CD34·, CD IS±, AML-M3 of FAB classification 
rare CD2+, and rare CD56+ 5-15% of AMLs 
CDJ3+, CD33+, CD14+, CDJS+, t(l6; 16)(pl3;q22) CBF~/MYHll Acute myelomonocytic leukemia 
CDlJb+, CD34+, CD1J7+, AML-M4eo of FAB classification 
CD4+, CD2+, and TdP 6-1 0% of AMLs 
CD4P, CD42+, CD6P, CDJ3±, t(l ;22)(p 13;q 13) OTT/MAL Acute mcgakaryoblastic leukemia 
CD33±, CD34± AML-M7 ofF AB classification 
About and HLA-DR± 
20% of all infant AMLs 
CDJ3+, CDlS+, CD33+, CD34+, t(9;22) BCR/ABL AML-Ml/M2 of FAB classification 
CD1J7+, HLA-DR+, About I% of AML 
plus B cell-associated markers

Flow Cytometry in Cancer Diagnosis and Therapy 207 
t(15:17) 
Fig. 3. Multiparameter studies in a patient with acute promyelocytic leukemia (APL). The 
bone marrow clot section (A) and smear (B) demonstrate numerous promyelocytes, some of 
which contain multiple Auer rods (arrows). The diagrams of flow cytometric results show that the 
gated promyelocytes express CD13 and CD33, but are negative for HLA-DR and CD14 . The FISH 
analysis demonstrates t(15; 17) characteristic for APL. Color figure available for viewing at 
www.humanapress.com. 
involving the RARa gene (88,89). APL demonstrates highly specific scatter and 
immunophenotypic features, with expression of CD13, CD33, MPO, variable CD15, but 
absence of HLA-DR and CD34 (90-93 ). Variable expression of CD34 is occasionally 
observed in microgranular variant APL (88,94,95) , although CD2 is often expressed in this 
variant (94). Several studies including recent results have suggested a link between CD56 
expression in APL and a worse prognosis (96). The overall sensitivity and specificity of 
immunophenotyping in the diagnosis of t(15; 17) is over 90% (93 ). The clinical significance 
of the diagnosis of APL with t(l5;17) is reflected by its sensitivity to treatment using all 
trans retinoic acid. 
2.2.2.2.3. AML With inv(l6) or t(16;16) (CBFBIMYHll) 
The myelomonocytic subtype of AML is often associated with inversion or translocation 
of chromosome 16 involving the CBF{3/MYHJJ gene, found in approx 6-10% of all AML 
(52). This chromosome abnormality has been associated with a more favorable clinical out­
come. The immunophenotype is complex yet characteristic, revealing constant maturation 
asynchrony and presence of both immature and differentiating blast subsets. The majority

208 Song and Naeim 
of the cases express CD4 (low-intensity), CD lib, CD13, CD 14, CD15, CD33 , CD34, CD64, 
CD65, CD117, and HLA-DR (97-99) . Expression of C02 is found in about 40% of the 
cases (99, 100 ), CD7 is less frequently expressed (1 01 ). 
2.2.2.2.4. AML With llq23 (MLL) 
Genetic alterations of chromosome band llq23 are predominantly identified in 
myelomonocytic and/or monocytic subtypes of AML, with involvement of the MLL gene. The 
leukemic cells display characteristic immunophenotypic features, expressing myelomonocytic­
associated markers including CD4 (low-intensity), CDllb, CD13, CD14, CD15, CD33, CD64, 
as well as CD56 (102-104). 
2.2.2 .2.5 AML With Aberrations of Chromosomes 5 and 7 
The aberrations of chromosome 5 and 7, such as -5/del(5q), -7 /del(7q), are mostly associ­
ated with AML secondary to myelodysplastic syndrome and/or AML of the elderly (52, 
1 37-140). High incidence of CD34 expression has been suggested in AML with aberrations 
of chromosomes 5 and 7 ( 141-143). Expression of CD14 is observed more often in cases 
with aberration of chromosome 5 than in cases with aberrations of chromosome 7 (52). 
T-cell related antigens such as C02 or CD7 are more commonly expressed in AML cases 
with aberrations of chromosome 5 (97). Expressions of TdT and CD7 are suggestive of 
multiple drug resistant phenotypes in adult AML cases with aberrations of chromosomes 5 
and 7 (144). 
2.2.3. The Quandary of Biphenotypic Leukemia 
The continuous advancement of immunophenotypic techniques along with the expansion 
of cells markers for the evaluation of the blast cells in acute leukemias have led to a growing 
incidence of leukemias that share features of more than one specific cell type. These leuke­
mias are frequently referred to as "biphenotypic" leukemias. Biphenotypic leukemias are 
primarily characterized by differentiation-associated antigens, and because most of these 
antigens are neither tumor-specific nor lineage-restricted, there is a significant overlap in 
their expression in myeloid and lymphoid leukemias. A scoring system originally proposed 
by Catovsky and associates in 1991 ( 135, 136), has been adopted by WHO as criteria ( 44) for 
the inclusion of biphenotypic leukemias (Table 4). According to this scoring system, a given 
lineage is defined if the total score for that lineage-associated marker is greater than 2. The 
most definitive lineage-associated markers are cytoplasmic CD22 and cytoplamic IgM and 
cytoplasmic CD79a for B lymphoblasts, cytoplasmic CD3 for T lymphoblasts and 
myeloperoxidase for myeloblasts. In general, the majority of acute leukemias that show ab­
errant antigenic expressions fall into either ALL or AML subtypes without being considered 
biphenotypic: These leukemias are divided into two major immunophenotypic groups: AMLs 
expressing lymphoid-associated markers, and ALLs expressing myeloid-associated markers. 
2.2.4. Minimal Residual Disease 
2.2.4.1. PROGNOSTIC SIGNI FICANCE 
It is well established that early response to therapy is one of the most important prognostic 
factors in acute leukemia . A small percentage of leukemic cells (approx 1-5% of the total 
marrow nucleated cells) can be detected by morphological examination alone, which pro­
vides useful information in stratification of patients achieving complete clinical remission 
(CR). However, many of these patients once diagnosed as CR eventually relapse, owing to 
the persistence of a very low percentage of leukemic cells (minimal residual disease, MRD) 
that are not detected by the conventional morphological examination ( 105-107) .

Table 4 
The Proposed Scoring System for Lineage Association* 
Score B-cell T-cell Myeloid 
2 cytCD22 CD3 (m/cyt) MPO 
cytCD79a ant-TCR 
cylgM 
CDlO CD2 CD13 
CD19 CDS CD33 
CD20 CDS CD65 
CDIO CD117 
0.5 TdT TdT CD14 
CD24 CD7 CD15 
CDla CD64 
*Adapted from ref. 44. 
Note : According to the proposed scoring system, criteria for acute biphenotypic 
leukemia are> 2 points from two separate lineages. 209 
The applicability and utilization of variable sensitive and specific techniques in the past 
decade, has allowed many investigations focusing on the clinical relevance of MRD. Inves­
tigation of MRD is a valuable tool for predicting impending relapses before clinical and 
hematologic presentations, defining risk groups, and establishing patient-specific treatment 
modalities in acute leukemia patients (46-49,105-115).1t is even suggested in a recent study 
that MRD level is the most powerful independent prognostic factor in acute leukemia, fol­
lowed by cytogenetics and number of cycles to achieve CR ( 114 ). 
2.2.4.2. DETEC TION METHODS 
Among these various technological approaches, both the PCR based molecular technique 
and immunophenotyping by multiparameter flow cytometry are the most commonly used 
methods. These two methods have shown improved sensitivity for the identification of leu­
kemic cells when compared with in situ hybridization (FISH) analysis, which demonstrates 
high specificity but low sensitivity (at best 1/1000 cells or I0- 3) in identifying leukemic cells 
( 1 I6). Using PCR based molecular technology, about 25-30% of ALL and AML cases can 
be monitored through detection of the gene fusion products, and about 90% of ALL can be 
followed up by B-or T-cell gene rearrangement studies (2,46,47,109-112,ll7). As com­
parison, the multiparametric immunophenotyping approach for MRD detection can be 
applied in about 90% ALLs and 80% AMLs ( 4, I 06, II4, I 15 ). The sensitivity of this method 
can reach one leukemic cell among 105 normal cells (l0- 5) (106). Additional large studies, 
especially in AML cases, are being conducted. However, the present available data support 
multi parametric immunophenotyping as a valuable tool in the evaluation of MRD levels in 
acute leukemia patients. 
2.2.4.3. STRATEGIC APPROACH BY fLOW CYTOMETRY 
The strategic approach in the detection of MRD by multi parametric immunophenotyping 
is identification of aberrant phenotypes through pattern recognition, which differentiates the 
leukemic population from the normal hematopoietic precursors in bone marrow. As men-

210 Song and Naeim 
tioned in Subheading 2.2., the concept of aberrant phenotype is now expanded to include 
expression of cross-lineage antigen, asynchronous antigen, ectopic antigen, altered differen­
tiation pathways, as well as abnormal antigen intensity and light-scatter pattern. 
Despite its clinical utility, MRD detection by flow cytometric immunophenotyping has 
two major pitfalls that would influence its sensitivity, specificity, and applicability 
( 67, 68,118-121 ). First, the absence of well-established antibodies against leukemia-specific 
antigens, such as BCR/ ABL and PMLIRARa fusion proteins. Second, the presence of phe­
notypic changes occurring at relapse. Although it is not uncommon for leukemic cells to 
display phenotypic changes at relapse (approx 20-70% according to various studies) 
(1 06,118-123 ), changes influencing aberrant phenotypes are less frequent ( approx 16%) 
( 106, 122 ), and at least one of the aberrances detected at the original diagnosis remained 
stable at relapse ( 106,122). The practical approach in dealing with these pitfalls is a careful 
examination of leukemic populations and subpopulations by selecting a combination of 
multiple aberrant phenotypic parameters. 
2.3. Myelodysplastic Syndrome 
Myelodysplastic syndrome (MDS) represents a group of heterogeneous clonal abnormali­
ties of bone marrow hematopoietic precursors. According to the new WHO classification 
( 124), MDS is divided into six subgroups: refractory anemia (RA), refractory anemia with 
ringed sideroblasts (RARS), refractory anemia with multilineage dysplasia (RAMD), 
refractory anemia with excess blasts (RAEB), unclassifiable MDS, and MDS associated 
with isolated del (5q) chromosome abnormality. Several factors including the percentage of 
blasts, cytogenetic abnormalities and cytopenia were found to be prognostically important, 
as suggested by the International Prognosis Scoring System ( 125 ). 
The diagnosis of MDS is primarily based on clinical history, morphologic findings, and 
cytogenetic studies. Although several studies of MDS using flow cytometric 
immunophenotyping have been published, their clinicopathologic significance including 
outcome prediction of MDS is yet to be well defined (126 -131). However, recent techno­
logical advances including multiparametric and pattern-recognition-based approaches in 
flow cytometric immmunophenotyping, have enabled phenotypic qualitative and quantita­
tive evaluation in hematopoietic precursors and their subpopulations in MDS ( 132-134 ). A 
recent large multicenter prospective study ( 134 ), has demonstrated significant correlation 
between the expression of aberrant phenotypes in MDS and diagnosis, prognostic scores, as 
well as cytogenetic risk factors. For example, the results of this study show that the presence 
of a myeloid subpopulation with CD36 expression on CD45 1ow or CD45hi gh/side scatterhigh 
cells is indicative of a poor prognosis, whereas CD71 expression is associated with a good 
prognosis (134 ). 
Utilizing emerging new evidence, the clinical role of multiparametric immuno­
phenotyping by flow cytometry in MDS, is being expanded from excluding other caus es of 
cytopenia and providing blast numeration to a useful tool for diagnostic and prognostic char­
acterization of MDS. 
2.4. Lymphoproliferative Malignancies and Plasma Cell Disorders 
In the past 10 yr, flow cytometric immunophenotyping has gradually gained its popularity 
and recognition in the diagnosis and monitoring oflymphoproliferativ e malignancies as well 
as plasma cell disorders (2,145 -152), a field that has historicall y relied on immunohis-

Flow Cytometry in Cancer Diagnosis and Therapy 211 
tochemical analysis as the key or even sole ancillary studies. Flow cytometry is now consid­
ered a useful tool for distinguishing benign from malignant lymphoid proliferation, estab­
lishing B-or T-cell lineage and assisting the differential diagnosis of lymphoproliferative 
disorders ( 150, 151). 
The new WHO classification (44) has provided an updated guideline for the diagnosis of 
lymphoproliferative and plasma cell malignancies. The flow cytometric immunophenotyping 
of lymphoid malignancies, is best achieved using multiparametric analysis that once again 
stresses clinicopathologic correlations including clinical history , morphologic (tissue sec­
tions, touch imprints, smears), cytogenetic, molecular genetic, and immunohistochemical 
findings. An updated understanding of phenotypic and genotypic correlations in non­
Hodgkin' s lymphoma is summarized in Table S (152a). The correlation with immunohis­
tochemical studies is of special interest because flow cytometry and immunohistochemistry 
can be relatively complimentary in lymphoid tissue immunophenotyping. 
2.4.1. B-Cell Neoplasm 
2.4.1.1. B-CHRONIC LYMPHOCYTIC LEU KEMIA/SM ALL LYMPHOCYTI C LYMPHOMA (CLL /SLL) 
B-chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most 
common adult leukemia in North America and Europe, and its nodal presentation is a com­
mon type of non-Hodgkin's lymphoma (6,153,154). CLL/SLL usually has a distinct 
immunophenotype expressing CDS, CD19, CD21, CD23, CD43, and CD20 10w, often lack­
ing COlO, FMC7, and CD103 (6,149,155, 156). The expression of slg is usually low, which 
is oflgM or IgD isotype when detectable (6). When atypical phenotypes are present , such as 
CDS+fCD23 -or CDS -!CD23+, other types of B-celllymphoma need to be excluded. 
Although the independent prognostic utility of specific antigen phenotype is controver­
sial (154,157-160), significant correlations do exist between genotypic markers of more 
aggressive clinical course (e.g., involving chromosomes 17 and 12) and atypical morphol­
ogy as well as phenotype (CD2Qhi gh, slghigh, CD22+, and/or CD23 -) ( 158,161-162c) . In addi­
tion, several recent studies have suggested an association between CD38 expression (in > 
30% of CLL/SLL) and a germline mutation of the Ig gene variable segment, indicating a 
poor prognosis ( 163,164 ). It has also been suggested that expression of Zap70 in CLL/SLL 
cases is associated with a worse prognosis ( 164a, 164b ). 
2.4.1.2. MANTLE CELL LYMPHOMA 
Mantle cell lymphoma is a clinically aggressive entity, and is characterized by t(ll;l4) 
involving the BCLl (cyclin 01) and IgH genes (165). The distinct immunophenotype is 
usually illustrated by CD4Shi gh, slg+ (lgD+ > lgM+/IgD+, A+ > K+), CDS+, CD43+, but 
COlle-, CD23 -, CD34 -, TdT ( 159, 165-168). In addition, pan B markers are usually strongly 
expressed, including CD19, CD20, CD22, and CD79a (166,169). Most of the mantle cell 
lymphomas lack CD 10, although some reports have suggested otherwise ( 167,170 ,171 ). The 
availability and applicability of antibodies against BCL-1 antigen have marked a turning 
point for the diagnosis of mantle cell lymphoma. Expression of BCL-1 protein has been 
detected using immunohistochemical studies (172 -174), although it has also been demon­
strated in recent studies using flow cytometric analysis ( 175 ). The identification of the BCL-1 
protein is critical in differentiating blastoid variant mantle cell lymphoma from 
prolymphocytic leukemia and B-lineage lymphoblastic lymphoma, as well as distinguishing 
atypical mantle cell lymphoma (CDS -/CD23+) from atypical CLL/SLL (CDS- or Co23 -).

212 Song and Naeim 
2.4.1.3. fOLLICULAR LYMPHOMA 
Follicular lymphoma is a common type of non-Hodgkins' lymphoma in North America 
and Europe. Most of the follicular lymphomas have an indolent course and patient s usually 
present with advanced stage of disease. Occasionally, it can present a leukemic phase espe­
cially in the later phases of the disease. The immunophenotype of follicular lymphoma in­
cludes strong expression of major pan B antigens and slg, with coexpression of CD 10 at 
variable intensities in 70-96% of the cases (29 ). The expression of CD23 10w to modera te is seen 
in a minority of follicular lymphoma cases. Virtually all follicular lymphoma cases lack 
CDS, BCL-1, CD 11 c, and CD 103 (29 ). BCL-6 is often helpful in identifying the follicular 
center origin of the neoplastic cells. BCL-2 is strongly expressed in subgroups of follicular 
lymphomas, although it is not specific because it is also expressed in other B-celllympho­
mas and leukemias as well as normal T-cells ( 176). 
2.4.1.4. MARGINAL ZONE LYMPHOMA 
Marginal zone lymphoma (MZL) includes marginal zone lymphoma of muco sa-associ ­
ated lymphoid tissue (MALT) type, nodal marginal zone lymphom a with/without monocy ­
toid B-cells, and splenic marginal zone lymphoma. The immunophenotypic features of MZL 
are rather unique, because they lack CDS, CDlO, CD23, and CD43 in more than 90% of 
cases (2, 170,1 72, 176-178), in addition to absence of BCL-1. It is important to note that very 
rare cases of MZL have been reported positive for CDS or CD103 (178). 
2.4.1.5. HAIRY CELL LEUKEMIA 
Although it is rarely enco untered in general practice ( 179), hairy cell leukemia (HCL) is 
important as proper treatment has enabled a durable remission in a large proportion of 
patients (153, 179,18 0 ). The immunophenotypic characters include increas ed forward scat­
ter resulted from an increase in cell size and strong expression of major B-cell antigens 
including CD19, CD20, CD22, and slg. The unique immunophenotypic features include 
strong expression ofCDllc, CDI03, and FMC7 , where the concomitant strong expression of 
COlle and CD103 is highly specific for HCL in the setting of a monoclonal B-cell prolifera­
tion ( 155,181-183 ). Expression of CD2S is found in approx 70-80% of the cases and is of 
low to moderate intensity (182) (Fig. 4 ). 
2.4.1.6. BURKITT LYM PHOMA 
It is an aggressive form of lymphoma with good response to modern chemotherapy. 
Immunoph enotyping is important in assessment of differentiation. The typical 
immunophenotypic features of Burkitt lymphoma are reflected by uniform and strong ex­
pression of CD19, CD20, CD4S, and immunoglobulin light chains, with CD 1 oiow expression 
found in majority of the cases (29) (Fig. S). Rare cases have been report ed as CDS + ( 184). In 
the event of one or more "blast"-associa ted immature antigens, such as CD34 and/or TdT, 
plus CD I Ohigh and slg-, the diagnosis of precursor B-celllymphoblastic lymphoma/leukemia 
should be confirmed in the absenc e of the characteristic MYC translocation s (Table S). 
2.4.1.7. PLASMA CEL L MYELOMA 
Immunophenotyping of plasma cell myeloma by multiparametric flow cytometry is an 
attractive approach for diagnostic and prognostic evaluati on of the disease. It allows dis­
crimination between myelomatous plasma cells and normal plasma cells (185-189) based 
upon the distinct phenotypi c aberrations that occur in more than 90% of the myelomat ous 
plasma cells (190). The normal plasma cells are defined as CD38hi gh, CDJ38hi gh, CDS6-,

I[') 
N 
0 u 
CD103 N 
N 
0 u 213 
c: ~ 
FMC? 
Fig. 4. Bone marrow flow cytometric studies on a patient with hairy cell leukemia. The leukemia 
cells characteristically coexpress CD25 and CD103 . They are also strong ly positive for CD22 and 
FMC7. 
en .---"!~--., .... 
Q u 
0 
N 
Q u CDS 
Kappa CD10 
Lambda 
Fig. 5. Flow cytometric analysis on a lymph node biopsy sample from a patient with Burkitt 
lymphoma. The gated lymph oid cells express CDIO and CD19, and are Kappa light chain restricted. 
The neoplastic cells in Burkitt lymphoma are negative for TdT (not shown). 
CD45 1 0w, CD20- , CD28 -, CD33-, and CDI17 -(190-192). The most frequent aberrant phe­
notypic features consist of CD19 -, strong expression of CD56, and decreased intensity of 
CD38. In addition, aberrant express ion of CDlO, CD20, CD22, CD28, CD117, and CD33 or 
other myelomonocytic markers are identified in neoplastic plasma cells. Although the prog­
nostic utility of myeloma immunophenotyping is yet to be defined, recent inve stigations 
have indicated that about 35% abnormal plasma cells are present in monoclonal gammopathy, 
whereas nearly all plasma cells are abnormal in plasma cell myeloma ( 191 ). Furthermore, it 
was suggested in a recent study that the presence of at least 30% normal plasma cells post 
therapy correlates with a significantly longer progression-free survival ( 190). 
2.4.2. T-Cell Neoplasm 
2.4.2.l.T -CELL LARGE GRANULAR LYMPHO CYTIC (T-LGL) LEUKEMIA 
T-LGL is one of the two most common forms of matur e T-celll eukemias in North America 
( 153, 179). Morphologically, LGL is characteristic, and is phenotypically divided into T-

Table 5 
Phenotypic and Genotypic Correlations in Non-Hodgkin Lymphomas 
Type Immunophenotype Chromosome s Genes Frequency (%) 
B-celllymphoma 
Follicular CDI9+, CD20+, CD22 +, t(l4;18)(q32;q31 ) lgH/BCL2 90 
COlo+, BCL2+, BCL6+, 
cos-, cow-, co43-
Burkitt B phenotype , CD Wt, t(8; l4)(q24 ;q32) MYC/IGH 75 
sJg+, TdT, BCL2 - t(2;8)(p 11 ;q24) lGK/MYC 16 
t(8;22)(q24;qll) MYC /IGL 9 
Mantle cell CDJ9+ , CD20+, CDS+, t(11;14)(ql3;q32) CCNDl/IgH 70 
FMCr, CD43+, BCLP 
N ColO-, CD23 -, BCL-6-
'-' Lymphoplasmacytic CD19+ , CD20+, CD22+, t(9; l4)(pl3;q32) PAX5/IGH 50 >!::. 
CD79a+, cos -, CDIO -, 
CD23-, CD43± 
Diffuse large cell CD19+ , CD20+, CD22+, 3q27 BCL6 40 
CD79a+, CDS±, CDJO± 
Marginal zone CD19+, CD2o+, CD79a+, t( 11; 18)( q21 ;q21) AP12/MLT 40 
CD43±, CD lie±, cos-
cow -, co23 -
Small lymphocytic CDI9+, CD23+, cos+ del(l3q14) 50 
CD20low, CD22 low 
CD79a 1ow, CDIO-, FMC7-
T -cell lymphoma 
Anaplastic CD30+, ALK+ , EMN t(2;5)(p23;q3S ) NPM/ALK 35 
Large cell C02+, CD4 +, CD43+, 
TIA-J+ , granzyme B+

<D In 
0 
£2 .:~·'./ . <D • .• 
,_. .. . . :'. 
0 .... 
(.) -. .. 
·.t~: .. t'•' -:Q'r~ -. . 
CD3 215 
Fig. 6. The large granular lymphocytes are of two major types: natural killer (NK) cell and cyto­
toxic T cell. Both types express CD16 and or CD56, but NK cells are CD3-negative (left) and T cells 
are CD3-positive (right). 
and NK-subtypes (Fig. 6) demonstrating strong correlations with clinical presentation, 
therapy, and prognosis (149). The T-LGL is usuall y a very low-grade leukemia, although its 
NK counterpart has a much more aggressive clini cal course. 
Immunophenotyping ofT- LGL reveal s mature T -celllymphoproliferation , with expre ssion 
of pan T markers including C02, CD3, CDS , and CD7, as well as CD8+/CD4- profil e and 
TCR gene rearrangement. Occasional loss of a panT antigen can be present. Usually, one or 
more NK-associated antigens , such as CD16, CDS6 , CDS7, are present with the expression 
of CDS7 being most commonly reported (29). It has been sugge sted that CDS6+ T-LGL is 
associated with a more aggressive clinical course, although it is not definitive ( 194-196). 
The NK-LGL shares the CD2 , CD7, CD8 antigen profile with the T-LGL , but does not 
express T-specific antigens such as CD3, CDS , and TCR. Howev er, the NK-LGL cannot be 
differentiated from benign NK lymphoproliferation by immunophenotypic featur es. 
2.4.2.2. SEZARY SYNDROME/MYCOSIS FUNGOIDES 
Mycosis fungoides (MF) is a malignant cutaneous T-cell lymphoma, and Sezary syn­
drome (SS) is defined when MF neoplastic cells are present in peripheral blood. MF/SS and 
T-LGL together represent the most prevalent forms of matur e T-cell leukemia in North 
America ( 153,179 ). Morphologically, MF/SS neoplastic cells demonstrate distinct features. 
These cells display abnorm al T-cell phenotyp e, with expression of CD4 +/CD8 -profil e in 
most cases, and CD4+JCD8+ or CD4 -JCD8+ in less than 10% of the cases (29). In addition , 
partial or total loss of CD7 is usually present (156, 197-199 ), which by itself, is not a defini­
tive indication of MF/SS nor a clonal/neoplastic T-cell population , because it can also be 
observed in reactive T lymphocytosis (200). 
2.4.3. CD4+ CDS6 + Ma lignancies 
CD4 + CDS6 + malignancies represent rare hematopoietic neoplasms (201- 203,205), which 
were recently linked to plasmacytoid dendritic cells or type 2 dendritic cells (DC2), in the 
absence of B-, T-, and myeloid lineage marker s (204,205). Although they are uncommon , 
the topic warrant s special attention , because the CD4+ CDS6+ malignancies display distinct 
clinical behavior, morphologic, and immunophenotypic chara cteristics, including specific 
immunophenotypic-prognostic associations. These lesions typically present as cutan eous 
nodule s associated with lymphadenopathy and/or splenomegaly. Cytopenia is frequent , with 
circulating malignant cells often detect ed. Massi ve bone marrow involvement is seen in more 
than 80% of the cases studied (205 ). According to th e new WHO classification , these tumors 
are referred to as blastic natural killer (NK) lymphoma/leukemia ( 44 ).

216 Song and Naeim 
In addition to CD4 and CD 56 expression, the neoplastic cells may also express CD36, CD38, 
CD45 10w, CD45RA, CD68, CD123, and HLA-DR. They are negative forCD16 , CD57, CD116, 
and CD 117 (205 ). The disease is rapidly fatal without chemotherapy . However, as indicated in 
a recent multicentric study (205), complete remission was observed in 78% of patients after 
polychemotherapy, although most patients relapsed in less than 2 yr. 
2.4.4. Minimal Residual Disease 
Although current data support multiparametric immunophenotyping as a valuable tool in 
the evaluation of minimal residual disease (MRD) in acute leukemia patients, its clinical 
utility in evaluation of MRD in lymphoid malignancies has not been well defined. Several 
recent large studies have addressed this issue, by exploring phenotypic aberrancies and vari­
ables in chronic B-cell lymphoproliferative disorders , which has set up a preliminary basis 
for the design of multiparametric panels used in the MRD investigations (206-209). The 
largest study series (467 patients) has indicated that the incidence of aberrant phenotypes 
ranges from 80-100% in B-cel1 chronic lymphoproliferative disorders, and most of the cases 
studied (90%) display four or more phenotypic aberrancies (206). Using the dilutional 
method, this study demonstrated a sensitivity limit of J0-4 to I0-5 in MRD monitoring . 
2.5. DNA Ploidy Analysis and Simultaneous S-Phase Assessment 
2.5.1. Traditional Approach 
Analysis of DNA content in malignant tissues is among the earliest clinical applications 
of flow cytometry. It contains DNA ploidy categorization and calculation of S-phasc fraction 
(SPF) according to the standardized or generally accepted terminology. The practical utility 
of DNA content analysis relies on its prognostic relevance, which has been the subject of 
many large trial studies, as well as reviews in the past decade, and has been best addressed in 
breast, bladder , prostate , colorectal, and hematopoietic malignancies (19 1,210-214 ). 
The results from these large trial studies are inconsistent regarding the correlations 
between prognosis and DNA ploidy or SFP, which are reflections of suboptimal study design 
and more importantly, significant interlaboratory variability as demonstrated in a recent CAP 
proficiency survey (215 ). The technical variable factors are demonstrated in specimen prepa­
ration, gating, plus software choices as well as debris and aggregation modeling. 
2.5.2. Recent Developments 
2.5.2.1. USE OF FLUORO CHROME-CONJUGATED TUMOR-SPECIFIC ANTI GENS 
Recently, multiparametric analysis and software compensation have introduced combined 
use of multiple fluorochrome-conjugated tumor specific antigens (i.e., FITC-conjugated 
CKS, 6, 8, 17, and 18) with assessment of DNA ploidy that enables not only clear separation 
of tumor vs background cells, but also detection of intratumor heterogeneity (216-219). 
2.5.2.2. SiMULTANEOUS SPECIFIC ANTIGENS AND SPF 
AssESSM ENT IN LIVING CELLS: DRAQ5 
The development of a novel DNA dye DRAQS has enabled rapid simultaneous detection 
of specific surface or nuclear antigens and SPF in both living and fixed cells (220-222). 
DRAQS demonstrates a high affinity for DNA and a high capacity to rapidly enter living 
cells or stain fixed cells. It shows special characteristics of excitation, which include optimal 
excitation by red-light at 647 nm as well as suboptimal excitation at 488 nm, 568 nm, and 
633 nm lines, and then yields a deep red emission spectrum with extension into the low

Flow Cytometry in Cancer Diagnosis and Therapy 217 
infra-red region. Because of these spectral features, DRAQ5 can be used in combination 
with FITC- and PE-labeled markers without the need for compensation. This offers a clear 
advantage over the traditional DNA dye such as propidium iodide, beause DRAQ5 can 
greatly reduce emission overlap with ultraviolet (UV)-excitable and visible range fluoro­
chromes if the optimal excitation 647 nm is used. 
A recent investigation has identified a significant correlation between Ki67 staining and 
the SFP using simultaneous quantification of Ki67 MAb and DNA content analysis to evalu­
ate the proliferative activity of breast cancer (223 ). The unique characteristics of DRAQ5 in 
both living and fixed cells permit the incorporation of cellular DNA content analysi s into a 
variety of multiparametric analyses including simultaneous evaluation of the SPF and cycle­
specific proteins, proliferation markers, as well as various surface and nuclear antigens. 
3. APPLICATIONS OF FLOW CYTOMETRY IN MONITORING CANCER 
BIOTHERAPY 
Conventional cytotoxic therapy of malignant neoplasm is often associated with signifi­
cant morbidity, mainly attributed by the lack of specificity to malignant cells and hence 
traumatic insult on the normal counterparts. In the past decade, enormous efforts have been 
undertaken to develop methods or strategies for more specific and targeted therapies of 
malignant diseases by not only using MAbs (224 ,225) directed against tumor cells, but also 
stimulating immunological rejection of tumors through antigen-specific immune responses 
(226,227). Strategies of the latter including tumor vaccines, gene-modified tumors, tumor 
antigen-encoding viral vectors, protein and peptide antigen, as well as dendritic cell-loaded 
antigen, are currently being investigated in clinical trials. Multiparametric analysis by flow 
cytometry is of special value in monitoring both phenotypic and functional characteristics of 
the antigen-specific immune responses, as suggested in recent reviews and results of a work­
shop sponsored by the Society for Biological Therapy (226-228) . 
3.1. Monoclonal Antibody Therapy of Hematological Malignancies 
Becaus e of the understanding of lineage-specific antigens in hematological malignancies 
and the relative accessibility of the malignant cells in blood and bone marrow, leukemias or 
lymphomas have provided successful testing grounds for the use of MAb therapy (224). 
Recent technological advancements, especially the development of human or chimeric mono­
clonal antibodies, have significantly overcome the toxicities associated with host immune 
respons es to rodent-derived MAbs. The first humanized MAb for the treatment of hemato­
logical malignancies, rituximab (anti-CD20 MAb) was approved about 6 yr ago, and has 
revolutionized the treatment of NHL (229,23 0). Currently, a range of MAbs is available in 
clinical studies and therapies , including anti-CD22, anti-CD33 , anti-CD45, anti-CD52 , and 
anti-tyrosine kinase STI571. Furthermore, protein engineering to combine MAbs with other 
biological active molecules such as radioisotopes, toxins, chemotherapy, and cytokines, has 
enabled a new spectrum of agents for clinical activity (224 ). As the antigen expression inten­
sity in hematological malignan cies becomes important for decision-making in relation to the 
MAb therapy, information obtained using flow cytometric analysis such as the number of 
antigen receptor sites per molecule is of special clini cal utility (231 ). Flow cytometric analy­
sis functions as a critical tool in the monitoring of MAb therapy by providing qualitative as 
well as quantitative measures of targeted markers.

218 
3.2. Measurement of In Vitro Antigen-Specific Immune Responses 
3.2.1. Peptide Major Histocompatibility Complex Tetramers Song and Naeim 
By applying this emerging technology to multiparametric analysis, one can detect anti­
gen-specific T cells that bind specifically, stably, and avidly, to soluble fluorochrome-labeled 
multimeric major histocompatability complex (MHC) peptide complexes, by gating on ens+ 
T-cells and looking for expression of antigen-specific TeRs (224,232). Several recent stud­
ies have demonstrated the utility of flow cytometric analysis using peptide MHC tetramers 
to quantify ens+ T cells that are specific for tumor antigens or control antigens used in 
immunotherapy protocols (233-235 ). Although the clinical relevance of tetramer-based 
analyses needs to be established by more large prospective trials, there is clear promise for 
the application of tetramers as a "front-line" clinical immune monitoring system (228). 
3.2.2. Intracellar Cytokines 
Evaluation of the T-cell immune status has evolved from enumeration ofen4+ and ens+ 
T cells to identification of functional T-cell subsets, because the latter has become increas­
ingly critical in the monitoring of immunotherapy. Previous studies using murine models 
(236) have set up the basis for accessing functional immune responses in humans by charac­
terizing the cytokine secretion pattern ofT cells in peripheral blood, lymph nodes, or other 
tissues. The understanding of the cytokine secretion pattern of a given T-cell subset, requires 
simultaneous collection of multidimensional data including soluble cytokines, cytokine-pro­
ducing cells, surface receptors, and other functional parameters. Multiparametric analysis by 
flow cytometry provides a perfect setting for this type of multidimensional studies (237,238 ). 
Recent studies with serial analysis of intracellular cytokine induction have demonstrated 
its correlation with clinical outcome. For example, Maraveyas et al. (239) suggested a pos­
sible association of the induction of intracellular TL-2 with improved survival in a study of 
stage IV malignant melanoma . In an anti-idiotype vaccine study in ovarian cancer patients 
by Reinartz et al. (240 ), the generation of antigen-specific antibodies and prolonged survival 
were found to correlate with an altered cytokine profile from secretion of IL-2 and IFN-a to 
T helper 2 type cytokines. 
4. THE FUTURE 
There is an emerging trend of combining flow cytometry with other techniques. The com­
bination of flow cytometry and molecular biological techniques is particularly powerful, and 
can be considered two complementary cornerstones of the 21st-century diagnostic pathol­
ogy. It offers the opportunity to study heterogeneous populations of cells with varying 
immunophenotypic and at the same time, genotypic features (241). This approach can be 
applied in a wide spectrum of analyses, including but not limited to gene products, TeR 
gene rearrangements, steroid hormone receptors, oncogene products, multidrug resistance 
gene products, minimal residual disease, gene therapy, cellular based FISH, and t1ow karyo­
typing. 
As an example, the detection of TeR gene rearrangement by t1ow cytometry using MAbs 
directed against the TeR VB chain families is now possible in clinical practice, with a fast 
and easy approach owing to the availability of a commercial testing kit (Figs. 7 and S). These 
reagents are useful indicators for the detection of possible clonal expansion of T cells in 
T -cell neoplasms, where no other markers of clonal expansion are currently available . Recent 
studies have established reference ranges for TeR VB repertoire in healthy controls (242), as

~ 
0 
~ 101 
w 
0.. 
FITC-LOG V/322 
(4.7%) 
V/314 
(3.4%) 219 
Fig. 7. Triple staining of TCR V~ in whole blood with Vj3 MAbs conjugated using only two 
fluorochromes (with permission and Courtesy of Beckman Coulter, INC.). In any given vial of the IO 
Test Beta Mark Kit (by Beckman Coulter, INC), there are three precalibrated and mixed Vj3 MAbs, 
each of which is labeled using either FITC, or PE, or FITC + PE. As shown here, the mAb mixture in 
this vial includes Vj314-FITC, Vj3ll-PE, and Vj322-FITC+PE . Simultaneous detection of the TCR 
Vj3 and T -cell subset antigens can be achieved using multiparametric analysis. 
tube H tube A 
tube F 
tubeD 
Fig. 8. TCR Vj3 repertoire coverage by IO Test Beta Mark (with permission and Courtesy of 
Beckman Coulter, INC.). This diagram shows the mean percentage of the Vj3 domains covered by the 
Vj3 MAb mixture in each vial of the IO Test Beta Mark kit. About 70% of the T-cell repertoire is 
addressed using a total of 24 Vj3 MAbs included in this kit.

220 Song and Naeim 
well as validated the use of the Vi) antibody panel covering up to 70% of the Vi) domains in 
T-ALL samples and T -cell lines (243 ). 
Technological advances in the field of flow cytometry continue to provide opportunities 
for expansion of clinical applications in cancer diagnosis and therapy using multi parametric 
analysis. The commercial availability of high speed (244) and three laser machines, plus 
advanced reagents and software compensation programs, has marked an era of multi-multi­
color immunophenotyping (245 ), likely introduced in practice of routine clinical flow 
cytometry in the not too distant future. This future of "high-throughput flow cytometry" can 
be a successful practice , only if the emphasis on clinico-pathologic correlation continues to 
dominate the center stage of clinical flow cytometry. 
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12 
Molecular Diagnostics in Neoplastic Hematopathology 
Daniel A. Arber 
Neoplastic hematopathology was one of the first areas of medicine to use genetic-related 
testing for diagnostic purposes. The discovery and characterization of the Philadelphia chro­
mosome in chro nic myelogenous leukemia (1,2) is viewed by many as the beginnin g of the 
diagnostic era of cytogenetics and becam e a defining feature in the evaluation of patients 
with chronic myeloproliferative disorders. The discovery of rearrangements of immunoglo­
bulin genes in lymphocytes and their use as clonal markers in lymphoid proliferations intro­
duced the molecular genetic tool of Southern blot analysis to lymp homa diagnosis ( 3,4 ). 
Since these early discoveries, many other genetic changes have been associated with 
hematolo gic malignancies. The detection of these recurring abnorma lities , and the charac­
terization of the molecular events involved, have resulted in revised disease classifications 
and therapies directed against genetically defined disease groups. In addition to the expan ­
sion of knowledge of genetic abnormalities, the methodology to detect these changes has 
rapidly advanced. Currently, Southern blot analysis is less commonly performed , being 
replaced by the polymerase chain reaction (PCR), reverse-transcriptase PCR (RT -PCR), 
"real-time " quantitative PCR, and fluoresc ence in situ hybridization (FISH) . This chapter 
will review the major molecular genetic changes of leukemia and lymphom a, as well as the 
various issues related to methodology and testing. 
2. ROLE OF CYTOGENETICS AND MOLECULAR DIAGNOSTICS IN THE 
CLASSIFICATION OF LYMPHOMA AND LEUKEMIA 
The applications of molecular genetic studies in neoplastic hematopatho logy include 
determination of clonality, identification of abnormalities associated with a specific disease 
subtype, determination of changes of prognostic significance , and detection of residual dis­
ease. The routine evaluation of samp les for lymphoma does not usually includ e karyotype 
analysis and most lymphoma cases are diagnosed without molecular genetic testing. Such 
testing may be performed when the differential diagno sis of reactive vs neoplastic cannot be 
resolved by morphologic or immunophenotypic studies, or when the question of subtyping 
of lymphoma cannot be resolved by more commonly used method s. Molecular studies are 
more often performed to monitor for minimal residual disease in lymphoma patients. 
In chronic leukemias , molecular studies are helpful in confirming a neoplastic over a 
reactive process and in subclas sifying the proce ss. These studies are not usually necessary to 
make a diagnosis of acute leukemi a, but add significant information about prognosis in acute 
From : Canc er Diagnostics: Current and Future Trends 
Edited by: R. M. Nak amur a, W. W. G rady , J. T. Wu, and R. B. Nag le © Hum ana Press Inc., Totow a, NJ 
233

234 Arber 
leukemia. For this reason, karyotype analysis, supplemented by appropriate molecular test­
ing, is recommended for acute leukemias. Some of these methods are also useful in the 
monitoring of residual disease. 
3. GENERAL DIAGNOSTIC APPROACHES 
3.1. Primary Diagnosis 
In the primary diagnosis of acute leukemia, the molecular genetic alterations of the leuke­
mia are primarily of prognostic importance, and karyotype analysis is usually an acceptable 
first line of testing. However, some karyotype abnormalities may be cryptic and will be 
missed by standard karyotype analysis. In addition, the detection of some abnormalities will 
result in different leukemia therapy and require more rapid detection. When cryptic or thera­
peutically significant abnormalities are suspected, RT-PCR or FISH based assays are com­
monly employed. When a chronic myeloproliferative disorder is suspected, detection of the 
Philadelphia chromosome has both diagnostic and therapeutic implications. Although this 
abnormality is usually detected by karyotype analysis, a cryptic t(9;22) may only be 
detectable by RT-PCR or FISH assays. 
In the primary diagnosis of malignant lymphoma, karyotype analysis is not usually 
performed, and molecular studies are not necessary in the majority of cases. Molecular 
genetic studies are useful in two settings in the diagnosis of lymphoma. First, when the 
differential diagnosis is between a reactive condition, malignant lymphoma and another neo­
plasm, B-cell and/or T-cell-associated gene rearrangement studies are useful. Detection of a 
disease-associated gene fusion product by PCR or FISH may be helpful, but is not necessary 
to confirm the presence of a clonal lymphoid neoplasm. Possible exceptions in follicular 
lymphomas and plasma cell disorders will be discussed in more detail below. The second 
major use of molecular studies in lymphoma is in subclassification, especially the lympho­
mas of small B-lymphocytes. The molecular detection of tumor cell infection by specific 
viruses is helpful in the classification of a small group of malignant lymphomas. 
3.2. Residual Disease Testing 
Molecular diagnostic testing is commonly used to monitor patients for disease recurrence. 
Although Southern blot and standard karyotype analyses can detect only 5% or more cells, 
some PCR-based tests can detect tumor burdens as low as 0.001%. Such a detection level is 
associated with disease relapse in some malignancies, but others require higher levels of 
molecular abnormalities associated with relapse. FISH analysis is less sensitive in the detec­
tion of residual disease, because many tests will not reliably detect a tumor burden below 
5%. However, recently described FISH methods have reported detection levels that rival 
PCR-based tests (5). 
For minimal residual disease testing, there are marked differences in the level of detection 
based on the PCR methodology utilized. For leukemias, most PCR testing uses RT-PCR 
directed against a specific fusion product and low levels of this fusion can be detected. Be­
cause some of these methods may be too sensitive for clinical use, quantitative PCR (Q­
PCR) methods are used to quantify the level of the fusion product. Q-PCR methods have 
been proven clinically useful in early studies. For many leukemias without balanced cytoge­
netic abnormalities, however, PCR-based testing cannot be performed, and less sensitive 
FISH methods are used to monitor for residual disease.

Molecular Hematopathology 235 
Balanced translocations also occur in certain malignant lymphomas and can be monitored 
similar to leukemias. However, the only molecular markers available for most malignant 
lymphomas are T-or B-cell gene rearrangements. This is also true for some acute lympho­
blastic leukemias. Southern blot analysis for these gene rearrangements is not sufficiently 
sensitive for residual disease testing, and PCR testing is typically performed. Most PCR­
based B-and T -cell gene rearrangement studies, however, use relatively nonspecific prim­
ers, termed consensus primers, that weaken the level of detection of these assays to levels of 
0.1-1%. To increase the detection of B-or T -cell gene rearrangements, some investigators 
have developed more sensitive PCR primers based on the exact sequence of a given patient's 
gene rearrangement (6, 7). Although these methods detect low levels of residual disea se, as 
low as 0.001%, they are not routinely offered in most diagno stic laboratories. Less labor 
intensive and patient specific methods have been reported that may allow for the sensitive 
detection of low-level disease in patients with lymphoid malignancies. These methods may 
become available in the future (8). 
4. MOLECULAR DIAGNOSTICS OF LEUKEMIA 
A large number of recurring balanced and unbalanced cytogenetic abnormalities occur in 
leukemia. Many of these are unique to specific disease types, and several categories of 
molecular abnormalities are now recognized . The detection of these genetic changes in 
leukemia is required for the diagnosis of some diseases, particularly chronic myelogenous 
leukemia and provides significant prognostic information for the acute leukemia s. Detailed 
recent reviews of the biology and clinical significance of some of these abnormalities have 
been recently published (9-11 ). 
4.1. Acute Myeloid Leukemia 
The recently published World Health Organization (WHO) classification of acute myeloid 
leukemia (AML) includes four categories with recurring cytogenetic abnormalities ( 12 ). The 
detection of these abnorma lities by karyotype or molecular genetic analysis is required for 
diagnosis of these disease types, and cases with these abnormalities are considered as acute 
leukemias without regard to the blast cell count. These include acute promyelocytic leuke­
mia with t(15;17)(q22;q21) or PMURARa and variants; AML with t(8;21)(q22;q22) or 
AMLJIETO; AML with inv (16) (p13q22)/t(16;16)(p13;q22) or CBF{3/MYHII and AML 
with 11q23 (MLL) abnormalities. These are some of the most common recurring genetic 
abnormalities, but other genetic changes of significance may also be present in AML and 
myelodysplasia (Table 1). The genetic changes of leukemia result in a variety of mecha­
nisms related to the development of disease, and some of the basic mechanism s will be 
discu ssed. Figure 1 provides a simp lified overview of how some fusion products affect 
hematopoiesis. 
4.1.1. Acute Promyelocytic Leukemia 
Acute prom yelocytic leukemi a results from abnormalities of the RARa gene, locat ed on 
chromosome l7q21 (13). RARa is a nuclear hormone receptor that binds to specific DNA 
sequences referred to as retinoic acid responsive elements in a heterodimeric complex with 
retinoid -X receptors (RXRa). The RARa/RXRa complexes can repress transcripti on through 
a variety of mechanisms, but norm al physiologic concentrations of retinoic acid in the body 
control this activity, allowing for normal activation of gene trans cription. In most cases of

236 
Table 1 
Some of the Common Cytogenetic/Molecular Genetic Abnormalities 
in Acute Myeloid Leukemia and Myelodysplasia 
Translocation 
inv(3)/t(3;3)(q21 ;q26) 
t(3;21 )(q26 ;q22) 
t(3;5)(q25;q34) 
t(8;21 )( q22;q22) 
t(6;9)(p23;q34) 
t(7;11)(p15;pl5) 
t(l5; 17)(q22;q21) 
t( II ; I 7)( q23 ;q21) 
t(ll ; I 7)( q 13 ;q2l) 
t(5;17)(q3l;q21) 
inv( 16)/t(l6; 16)(p 13;q22) 
t(9; 11 )(P22;q23) 
Other II q23 abnormalities 
t(l ;22)(p 13;q 13) 
Normal Involved genes 
Ribophorin 1/EVII 
EVIl , EAP or MDSIIAMLJ 
NPM/MLFJ 
AMLJIETO 
DEK!CAN 
NUP98/HOXA9 
PMURARa 
PLZFIRARa 
NuMA!RARa 
NPMIRARa 
CBF{3/MYH 11 
AF9/MLL 
MLL 
OTT/MAL 
Transactivation 
Domain 
Fusion Protein 
~' 
Leu kern ia --- ) DNA Binding Site )( Most common disease type 
Myelodysplasia 
Myelodysplasia Myelodysplasia, M2, M6 
M2 
MI,M2,M4 
M2,M4 
M3 
M3 
M3 
M3 
M4Eo 
MS 
M4,M5 
M7 
.. 
Target gene 
Target gene Arber 
Fig. 1. Overview of how some acute leukemia fusion products affect normal hematopoiesis. In 
many cases, the normal gene products bind specific areas of DNA. Once bound , the normal 
transactivation domains cause transcription of adjacent target genes involved in hematopoiesis. 
Abnormal fusion products may alter this process by many mechanisms, including altering DNA 
binding and loss of the normal transactivation domain . Color image available for viewing at 
www .humanapress.com. 
acute promyelocytic leukemia, the RARa gene fuses with the PML gene on chromosome 
15q22 . As a result of this fusion, physiologic levels of retinoic acid are no longer sufficient 
to control the effects of RARa and gene transcription is blocked . Therapeutic strategies that

Molecular Hematopathology 237 
include all-trans retinoic acid (A TRA) provide pharmacologic concentrations of retinoic 
acid allowing for the return of normal transcription. Acute promyelocytic leukemia has a 
generally good prognosis. 
The t( 15; 17) is usually detectable by karyotype analysis at diagnosis . Molecular detection 
of PMLIRARa is usually performed by RT-PCR or FISH analysis. Three different isoforms 
of the fusion may occur and RT-PCR assays should be designed to detect them all. They 
vary by differences in breakpoints within the PML gene. Breaks in intron 6 are termed bcr-1, 
long, or L forms; breaks in exon 6 are termed bcr-2, variable, or V-forms; and breaks in 
intron 3 are termed bcr-3, short, or S-forms. Some differences in clinical presentation occur 
with the different forms, including an association between the microgranular variant and the 
S-form, and V-form disease may have a lower disease-free survival (14). However, most 
laboratories do not distinguish between the different breakpoint types. 
The PMLIRARa RT-PCR test has been shown useful in early detection of residual disease 
in acute promyelocytic leukemia, and as a predictor of relapse of that disease (15 ). Most 
assays for PMURARa detect one translocated cell in 10,000-100 ,000 cells . However , this 
test appears less useful when more sensitive assays detecting one abnormal cell in one mil­
lion are used. This ultra-sensitive test will be positive in patients that are in long term remis­
sion and do not appear clinically relevant ( 16). This suggests that serial quantitative assays 
may be useful to follow patients with very low levels of disease. 
Although PMLIRARa is the most common fusion in this disease, other translocations of 
RARa on chromosome 17 with PLZF at 1lq23, NuMA at 1lql3, NPM at 5q35 and STAT 5b 
at 17qll may occur (17). Cases that lack an RARa translocation or have a translocation 
involving PLZF or STAT 5b, do not respond to all-trans-retinoic acid and require a different 
therapeutic approach (13, 18 ). 
4.1.2. CBF Leukemias 
The disruption of normal transcription factor activity is a common event in abnormalities 
associated with acute leukemias . The core binding factor (CBF) is a complex that includes 
elements encoded by theAMLl (akaRUNX1or CBFa2) gene on chromosome 21q22 and the 
CBF{3 gene at l6q22. Recurring translocations of these genes are some of the most common 
in acute leukemia ( 19,20). The CBF is critical in normal hematopoietic developm ent and 
translocations involving these genes result in disruption of hematopoiesis by a variety of 
mechanisms. 
The t(8;21 )(q22;q22) results in an AMLJ IETO (aka AML1/MTG8) fusion that eliminates 
the transcriptional activating domain of the CBF (21,22). This abnormality is associated 
with a distinct type of AML that represents a subgroup of M2 AMLs in the French-Ameri ­
can-British (FAB) classification and a specific type of AML in the WHO classification. 
Another distinct type of AML that commonly has admixed abnormal eosinophils, termed 
M4Eo in the FAB classification , is associated with inv(l6)(pl3q22)/t(l6;16)(pl3;q22). 
These abnormalities result in a fusion of the CBF{3 and MYH 11 genes of chromosome 16 
(23 ). The MYH 11 gene encodes the smooth muscle myosin heavy chain (SMMHC). 
Although this fusion does not effect the transcriptional activating domain of the CBF, it still 
acts as a suppressor of AMLJ function and may sequester AML1 from transcriptionally active 
sites. Both of these leukemia types respond well to high-dose chemotherapy. 
The CBF is also involved in other leukemias. The AMLJ gene is associated with chromo­
some 3 translocations that involve the EV1 1 and MDS1 genes, in association with myelodys -

238 Arber 
plasia and blast transformation of chronic myelogenous leukemia. In addition, AMLJ is dis­
rupted in the t(12;21)(p13;q22) of pediatric acute lymphoblastic leukemia. This results in a 
fusion with the TEL gene (see Section 4.2.2.). 
Most of the translocations that involve the CBF proteins can be detected by karyotype 
analysis, but the inv(l6) of CBFf3/MYH11 may be missed and the t(12;21) of TELIAMLJ is 
not usually detectable by routine karyotype. For these abnormalities, molecular studies are 
often needed at the time of the original diagnosis. RT-PCR and FISH assays are most com­
monly performed. For residual disease detection, RT -PCR for AMLJ I ETO and CBFf31 MYH 11 
must be interpreted with caution . It appears that other genetic aberrations, which may not be 
detectable by karyotype analysis, are necessar y for these types of leukemia to develop (24 ). 
In patients that have been treated for AML with t(8;21) or AML with inv(l6)/t( 16; 16), stan­
dard qualitative PCR testing may detect low levels of these fusions during remission that 
may not correlate with relapse of the disease (25,26 ). These PCR tests suggest that the fusion 
products may persist indefinitely and that qualitative PCR for AMLJ IETO and CBFf3/ MYH 11 
is not clinically useful for residual disease testing. It is assumed, however, that new methods 
for quantitative PCR will be of clinical significance , by showin g that an increasin g number 
of cells with AMLJIETO or CBF{3/MYHJJ over time correlates with relapse of disease. 
4.1.3. MLL Leukemias 
AML with 11q23 (MLL) abnormalities is a specific subtype of AMLin the WHO classi­
fication confering a generally poor prognosis . However, this category represents a heterog­
enous group of diseases with as many as 40 different translocation partners reported with the 
MLL gene. In addition, abnormalities that are not associated with balanced translocations 
may occur with MLL. 
MLL is a large, 90 kb gene that contains 36 exons and codes for a 431 kDa protein (27,28). 
The protein contains AT -hooks, which are known to regulate transcription by inducing 
changes in DNA conformation permitting the association of transcription factors with 
regulatory regions of DNA . These AT-hooks recognize specific DNA structures. Other 
regions of MLL are capable of repressing transcription from reporter constructs, mediate 
homodimerization, mediate interactions with nuclear proteins , contain transcriptional acti­
vating activity , and are involved with ATP-dependent chromatin remodeling. 
Although there are numerous translocation partners with MLL, the most common in AML 
are chromosomes 6q27 (AF6 gene), 9p22 (AF9) , 19pl3.3 (ENL) , 19pl3.1 (ELL), 19pl3.3 
(EEN), 16pl3 (CBP) and 22q13 (p300). The t(4;11), involving the AF4 gene, is more com­
mon in infant acute lymphoblastic leukemia (ALL) and adult therapy-related ALL. MLL 
abnormalities are also common in therapy -related AML, particularly after therapy with 
topoisomerase II inhibitors. Partial tandem duplications of MLL also occur in AML and are 
more common in patients with normal karyotypes (29,30). In general , the presence of MLL 
translocations and partial tandem duplication s indicates an unfavorabl e prognosis , but the 
t(9; 11) in childhood AML has been shown to confer a good prognosis ( 31 ). 
Karyotype analysis may not detect abnormalities of llq23, and this method cannot detect 
the partial tandem duplications of the MLL gene. Because of the multitude of potential M LL 
translocation partners , the PCR -based tests are of limited value. Most laboratories use FISH­
based testing for MLL translocations , but this method will not detect the internal tandem 
duplications. RT-PCR for MLL internal tandem duplications is not performed in most labo­
ratories, and reports of such duplications in healthy donors ( 32) suggests that only a quanti­
tative assay for this abnormalit y would be useful as a diagnostic test.

Molecular Hematopathology 239 
4.1.4. Nucleoporin Protein Fusions 
Nucleoporins represent one of several components of nuclear pore complexes; structures 
that allow macromolecules to move in and out of the cell nuclear. A number of chromosomal 
rearrangements in de novo AML, therapy-related AML , and myelodysplasia involve 
nucleoporins (11). The most commonly involved genes are NUP98 , on chromosome llpl5, 
and CAN (aka NUP214) on chromosome 9q34. It appears that nucleoporin fusion proteins 
act as aberrant transcription factors as well as altering nuclear transport by binding to soluble 
transport factors. NUP98 usually fuses with homeobox genes , including HOXA9 (on chro­
mosome 7p15), PMXJ (lq24), and HOXD13 (2q31) but other gene fusions have been 
described. CAN commonly fuses with the DEK gene in t(6;9)(p23;q34) a de novo AML type 
associated with erythroid hyperplasia, dysplasia and bone marrow basophilia ( 3 3). Although 
RT-PCR or FISH can be performed to test for all of these abnormalities, such testing is not 
offered in most molecular diagnostic laboratories . 
4.1.5. Receptor Tyrosine Kinase Abnormalities 
The receptor tyrosine kinases are cell surface transmembrane enzymes that are involved 
in ligand binding and signal transduction ( 34 ). Genes that encode receptor tyrosine kinases 
include c-kit , PDGFRf3, c-fms , and FLT-3. Mutations, internal duplications, and tyrosine 
kinase fusion proteins involving these genes occur in several different leukemia types. One 
tyrosine kinase gene of possible interest is c-kit, because c-kit protein is often expressed in 
AML. This gene is mutated in gastrointestinal stromal tumors and mast cell disease , but is 
infrequently mutated in AML. FLT-3 (aka STKJ and flk2), however, is another tyrosine 
kinase gene that frequently undergoes length mutations of the juxtamembrane or point muta­
tions in the second tyrosine kinase domain ( 35,36 ). The FLT -3 protein is expressed in early 
hematopoietic progenitor cells and is involved in early stem cell survival and myeloid differ­
entiation. Internal length or point mutations occur in 20-27% of adult AMLs and are most 
common in AMLs with normal cytogenetics. These mutations are associated with decreased 
disease free survival in adult AML. Because of the relatively high frequency and clinical 
significance of these mutations in AML, FLT-3 mutation testing will become more common 
in the future (37). 
4.2. Acute Lymphoblastic Leukemia 
Similar to AML, a wide variety of genetic abnormalities occur in acute lymphoblastic 
leukemia (ALL). The most common abnormalities will be described and some of the more 
common aberrations are listed in Table 2. 
4.2.1. ALL With t(9;22) 
The Philadelphia chromosome (Ph), or t(9;22)(q34;q 11), is a me mber of the nonreceptor 
protein tyrosine kinase family that results from a fusion of the ABL gene on chromosome 9 
and the BCR gene on chromosome 22. 
Three BCRIABL variants may occur (38-40) , but the p190 (aka p185) variant is most 
commonly associated with ALL. These leukemias are usually of precursor B-cell lineage, 
but they also usually show aberrant expression of the myeloid -associated antigens CD 13 and 
CD33 . Ph+ ALL represents less than 5% of pediatric ALLs and 20--25% of adult ALLs. A 
number of adult Ph+ ALL cases will demonstrate the p21 0 variant, rather than p 190, and 
both types of Ph+ ALL in adults are generally considered to have a poor prognosis. Details of 
the various t(9;22) fusions and their detection methods are discussed below for chronic my­
elogenous leukemia .

240 
Table 2 
Some of the Common Cytogenetic/Molecular Genetic 
Abnormalities in Acute Lymphoblastic Leukemia 
Precursor 8 
ALL (Ll/L2) 
BALL (L3) 
TALL (Ll!L2) Translocation 
t(9;22)(q34;qll) 
t(12;2l)(p 13;q22) 
t(l; 19)(q23;p 13) 
t(17;19)(q22;pl3) 
t(4; 11)(q21 ;q23) 
Other llq23 
abnormalities 
t(8; 14 )( q24;q32) 
t(2;8)(p 12;q24) 
t(8;22)( q24;q 11) 
1q32 abnormalities 
t(8;14)(q24;q11) 
t(l1;14)(p15;ql1) 
t(ll ;l4)(pl3;q 11) 
t(l0;14)(q24;ql 1) 
del 9(p21) 
t( 1 ;7)(p34 ;q34) Involved genes 
BCRIABL 
TEUAMLI 
E2AIPBX 
E2AIHLF 
AF4/MLL 
MLL 
IgHIMYC 
lgK!MYC 
lgAJMYC 
TALI 
TCRa/MYC 
TCRDIRBTNJ 
TCROJRBTN2 
TCRb!HOXJJ 
pl6 and pl5 
TCRfJJLCK 
4.2.2. ALL With t(12;21) Arber 
The t(l2;2l)(pl3;q22) results from a fusion of the CBF gene AMLJ on chromosome 21 
and the TEL (aka ETV6) gene on chromosome 12 (41,42). TEL is normally a transcriptional 
repressor and the TELIAMLI fusion redirects this repressor function to AMLI targets. This 
genetic abnormality is the most common recurring defect in pediatric ALL , present in 
20-25% of cases (43), but is uncommon in adult ALL. The defect was only recently identi­
fied, because it is not easily detected by routine karyotype analysis , and requires molecular 
studies. This type of ALL is considered to have a good prognosis, but very late relapses may 
occur. Both FISH and RT-PCR methods can detect this abnormality (44) and several reports 
using quantitative PCR have shown that this is a reliable method of following patients for 
residual disease ( 45,46 ). 
4.2.3. ALL With £2A Translocations 
Several translocations involving the E2A gene on chromosome 19q23 occur in ALL. 
Although these are more common in childhood leukemia (5-6% of pediatric ALLs), they may 
occur at any age (47). These translocations commonly occur in cytoplasmic J.L-positive, pre­
BALL and are associated with a poor prognosis. E2A is a helix-loop-helix protein coding

Molecular Hematopathology 241 
gene involved in B-cell development (48,49) and commonly fuses with the PBXJ gene on 
chromosome l q23, which is a homeodomain-containing HOX cofactor. This fusion encodes 
a chimeric transcription factor that causes inappropriate expression of genes critical for cell 
growth and differentiation . E2A less commonly fuses with the HLF gene on chromosome 
17q21-22, and this fusion activates antiapoptotic pathways (50). Karyotype, FISH, or 
RT-PCR can detect both abnormalities, but these molecular studies are often not offered by 
diagnostic laboratories. 
4.2.4. ALL With MLL Translocations 
MLL translocations in ALL are most common in cases of infant ALL and therapy-related 
ALL, and usually show a unique pro-B (COlO-negative) immunophenotype with aberrant 
expression of the myeloid-associated antigens CD15 and CD65 (27,51). The majority of 
MLL-associated ALLs demonstrate the t(4;11), involving the AF4 gene. 
4.2.5. Other Abnormalities in ALL 
The mature B-cell ALLs (FAB L3) are also termed Burkitt cell leukemia because they are 
leukemic presentations of Burkitt or Burkitt-lik e lymphoma. They are associated with trans­
locations that involve the c-myc gene on chromosome 8q24 . The features of this disease are 
described below with other lymphomas. 
T -cell ALL is less common than precursor and mature B-cell ALL, but many recurring 
genetic abnormalities have been reported. The more common of these abnormalities are 
listed in Table 2. These abnormalities are not routinely tested in most molecular diagno stic 
laboratories. 
4.3. Chronic Myeloproliferative Disorders 
4.3.1. Chronic Myelogenous Leukemia 
The detection of the Philadelphia chromosome is considered definitional for chronic my­
elogenous leukemia, and is useful in the exclusion of other chronic myeloproliferativ e disor­
ders and reactive hyperplasias. The BCRIABL fusion of t(9;22)(q34;q 11), may result in three 
different sized variants (38-40). The p190 (aka p185) results from what is termed an ela2 
junction, and is commonly associated with precursor B-cell ALL, as discussed above. The 
p210 variant is typically formed from a splicing of b2a2, b3a2, or a mixture of the two, and 
is often associated with chronic myelogenous leukemia. A less common variant, p230, is 
formed from an e 19a2 junction and is associated with a rare neutrophilic type of chronic 
myelogenous leukemia. The BCRIABL fusion product results in unregulated tyrosine kinase 
activity and activates a number of pathways including, but not limited to, Ras, Jun-kinase , 
and PI-3. This results in an increase in cell proliferation and a decrease in apoptosis. A 
recently introduced tyrosine kinase inhibitor originally identified as STI571 and now mar­
keted as Gleevec (Novartis, Hanover , NJ) blocks the tyrosine kinase activity of this fusion. 
This drug results in hematologic and morphologic remissions in many patients and a cytoge ­
netic remission in some patients. 
Although karyotype analysis remains the first line test for identification of the Philadel­
phia chromosome, a small subset of cases will have cryptic translocations that cannot be 
detected without FISH or RT -PCR. In addition, karyotype analysis may be suboptimal for 
evaluation of residual disease after bone marrow transplantation or Gleevec therapy. Because 
low levels of BCRIABL may remain in terminally differentiated cells after therapy, qualita­
tive RT -PCR assays are also of limited value. For this reason, many laboratories now offer

242 Arber 
quantitative RT-PCR for BCRIABL. These tests commonly detect the pl90 and p210 vari­
ants, and many laboratories do not offer testing for the less common p230 variant. 
4.3.2. Other Chronic Myeloproliferative Disord ers 
The majority of other chronic myeloproliferative disorders do not have recurring bal­
anced cytogenetic abnormalities, but the lack of detection of BCRIABL is often needed for 
the diagnosis of these diseases by excluding chronic myelogenous leukemia. A recurring 
balanced translocation occurs in a rare subtype of chronic myelomonocytic leukemia associ­
ated with an increase in eosinophils (52,53). The t(5;12)(q31;pl2) results in a TEUPDGF{3R 
fusion with tyrosine kinase activity similar to chronic myelogenou s leukemia. Testing for 
this translocation is not offered in most molecular diagnostic laboratories. 
5. MOLECULAR DIAGNOSTICS OF LYMPHOMA 
Gene rearrangements and recurring translocation s may be studied in lymphoma. Although 
these tests are not needed for most cases, they can be useful in the diagnosis of clonalit y as 
well as disease subclassification. These studies are usually not performed until after evalua­
tion of the tissu e morphology and immunophenotyping (54), and those results usually direct 
which molecular studies are appropriate. The most common aberrations in lymphoma are 
listed in Table 3. 
5.1. B-Cell Lymphoma 
5.1.1. Immunoglobulin Heavy- and Light -Chain Gene Rearrangements 
The detection of B-cell associated gene rearrangements is the most global means of 
detecting clonality in B-cell proliferations. The majority of malignant lymphomas are B-cell 
neoplasms. Rearrangement of the IgH gene on chromosome region 14q32 occurs in all nor­
mal developing B lymphocytes (55-57). This chromosomal region contains over 100 vari­
able (V) regions, 30 diversity (D), and 6 joining (J) regions (Fig. 2). When the B cell 
undergoes IgH gene rearrangement, one V, one D, and one J region move into close proxim­
ity of each other, with a wide diversity of possible VDJ combinations. Additional diversity is 
created by the random addition of so-called N-nucleotides between V, D, and J segments by 
terminal deoxynucleotidyl transferase. Because each normal B cell undergoes a relatively 
unique rearrangement, differences among each cell indicate a polyclonal B-cell population. 
Following rearrangement of the IgH gene, the immuno globulin K-light chain region of chro­
mosome 2p 11 rearranges in a similar fashion with the exception that it does not contain 
diversity (D) regions. If this rearrangement is not productive in either allele (approximately 
one-third of cases), the K-light-chain constant region locus is deleted and the immunoglobu­
lin A.-light-chain region on chromosome 22q11 undergoes rearrangement. Because mature 
B-cell lymphomas are clonal neoplasms, lgH and K-light- chain gene rearrangem ents are 
detectable in essentia lly all cases. The precursor B-cell malignancies (lymphoblastic lym­
phomas, and leukemia) , however , do not undergo the complete lymphocyte maturati on pro­
cess and may not undergo K-light chain gene rearrangement. Because A.-light-chain 
rearrangements do not always occur, and when present, occur later in B-cell development, 
this region is not usually evaluated as a diagnostic test for clonality. 
Immunoglobulin heavy and K-light-chain gene rearrangements are detected by Southern 
blot analysis or by use of PCR, with most laboratories now using PCR as the primary method. 
The use of PCR for the detection of lgH gene rearrangements allows for the use of smaller

Molecular Hematopathology 
5"-Table 3 
Common Molecular Genetic Abnormalities Associated 
With Non-Hodgkin's Lymphoma 
Most common disease 
Gene studied Chromosomal site associations 
Immunoglobulin heavy- 14q32 B-cell neoplasms 
Chain (lgH) 
rearrangements 
Immunoglobulin 2pll B-cell neoplasms 
light K-chain (/gK:) 
JH/BCL-1 t(11;14)(ql3;q32) Mantle cell lymphoma 
JH/BCL-2 t(l4; 18)(q32;q21) Follicular lymphoma, 
some diffu se large B-cell 
lymphomas 
PAX-5/IgH t(9; 14 )(p 13;q32) Lymphoplasmacytic lymphoma 
AP/2/MLT t(ll;l8)(q2l;q21) Extranodal marginal zone 
lymphoma 
BCL-6 translocations t(3;n)(q27;n) Some diffuse large B-cell 
lymphomas 
C-MYC translocations t(8;n)(q24;n) Burkitt 's lymphom a 
T-cell receptor a-
chain (TCRa) 
rearrangements 14qll T -cell neoplasms 
T -cell receptor y- 7q15 T -cell neoplasms 
chain (TCRy) 
NPM!ALK t(2;5)(p23 ;q35) Anaplastic large cell lymphoma 
v 0 
,.-"'---., 
- 3' 
0 /J rearrangement 
D J 
5'-- 3' 
D 
5'-243 
Fig. 2. Overview of the events of B-and T -cell associated gene rearrangements. Various variable 
(V), diversity (D) (if present) and joinin g (J) regions rearrange to form a specific YOJ or VJ segment 
for each lymphoid cell. Detection of the same VDJ or VJ rearrangement in a large population of cells 
is one means of determining monoclonality of a lymphoid proliferation. Color image available for 
viewing at www .humanapress.com.

244 Arber 
L < I>R II I R Ill 
50 bp 
Fig. 3. The VDJ rearrangement of the immunoglobulin heavy-chain gene (lgH) is the target of IgH 
PCR testing. The variable regions of each rearranged gene can be divided into three framework (FR) 
regions. PCR testing with primers directed against FRill and the JH (FRIV) regions give the smallest 
product and are the single most reliable test for this gene rearrangement. Assays directed against the 
FRI region are more likely to detect a higher percentage of IgH rearrangements, but the size of the 
PCR product and the large number of FRI primers needed for this assay limit its diagnostic use. Color 
image available for viewing at www.humanapress.com . 
amounts of DNA and DNA from paraffin-embedded tissue. This method uses consensus 
primer pairs that anneal to the V and J regions of the rearranged chromosome 14 (58). Cer­
tain nucleotide sequences are similar among the different V and J regions, and the consensus 
primers are made to anneal to these sequences even if they are not a perfect match. Because 
different, polyclonal rearrangements result in slightly different sized PCR products, a smear 
or ladder is observed on the gel in polyclonal specimens and one or two discrete bands are 
observed with a clonal proliferation. Capillary electrophoresis instruments are useful for 
DNA separation and replaced the use of gels in the evaluation of PCR products in many 
laboratories. Using this instrumentation, amplification products can be separated at the one 
base pair level, and polyclonal samples may show a range of peaks with no single dominate 
peak, compared to a dominate peak when a clonal population is present. 
The primers with the highest detection rate for the IgH gene rearrangements are directed 
against a region termed framework (FR) III of the various V H genes (Fig. 3 ). FRIII directed 
primers detect 60-70% of clonal B-cell malignancies (59). The addition of other framework 
regions, particularly FRII primers, increase the detection rate of this test. Framework I is 
composed of multiple families of regions that require multiple PCR reactions to detect reli­
ably. Based on the location of FRI, a combination of primers should detect the highest per­
centage of B-cell clones, but the products are often too large to reliably detect in 
paraffin-embedded tissues. Therefore, a combination of primers is more suitable for all speci­
men types and will detect 70-90% of B-cell neoplasms, depending on the type of disease. 
Somatic mutations of the lgH gene of some mature B disorders, especially follicular lym­
phomas and plasma cell malignancies, alter the sequence of the region amplified by the 
primers so that primer hybridization is suboptimal or does not occur, resulting in false nega­
tive PCR results (58). Because of these frequent somatic mutations, a negative IgH PCR 
result does not exclude the presence of a monoclonal B cell proliferation. In addition, con­
sensus primers are not a perfect match to the sequence being amplified and result in less 
efficient amplification. This results in lower sensitivity of detection, and impacts on the use 
of consensus IgH primers in the detection of minimal residual disease. Most tests that em­
ploy consensus primers for lgH gene rearrangements can detect only down to a level of one 
clonal cell in 100 polyclonal cells . 
PCR tests directed against rearrangement of the K-light-chain gene (lgK) or the K deleting 
segment are also useful in the detection of B-cell clonality in mature B-cell proliferations ,

Molecular Hematopathology 245 
and are reported to successfully detect clonality in up to 50% of B-celllymphomas (60,61 ). 
Although this method does not detect as many B-cell neoplasms as the lgH PCR test, 1gK 
PCR is useful as a second-line test.1gK PCR testing also uses consensus primers and this test 
suffers from the same minimal residual disease detection limitations of the standard lgH test. 
Several studies have cloned and sequenced the specific gene rearrangements in B-cell 
lymphomas and created primers specific for the individual patient's disease (6, 7). Although 
this approach is time consuming and expensive , it allows for detection of very low levels of 
disease (in the range of 1 abnormal cell in 100,000 cells), which would presumably result in 
earlier treatment of the disease. However, this approach has limitations because patient spe­
cific primers cannot be developed in all cases, some tumors have more than one clone, and 
all clones may not be detectable by the very specific primers developed. 
5.1.2. Specific Disease Types 
Specific cytogenetic trans locations are also associated with some types of malignant lym­
phoma. Unlike the translocations of acute leukemia, many of the more common lymphoma 
translocations do not involve large introns and are reliably amplified at the DNA level. There­
fore, PCR tests for these are performed on paraffin-embedded tissues. 
5.1.2.1. B-CELL SMALL LYMPHOCY TIC LYMPHOMA/ 
CHRONIC LYMPHOCYTIC LEUKEMIA 
Molecular studies are not always necessary for the diagnosis of B-cell small lymphocytic 
lymphoma/chronic lymphocytic leukemia (CLL), although all cases show lgH gene rear­
rangements, and they are usually detectable by PCR analysis. Characteristic cytogenetic 
abnormalities in CLL include deletions of 13ql4 , llq22-23, 17p13 and 6q21 , and trisomy 
12, with 13q deletions having the best prognosis and 17p deletions the worst (62). Trisomy 
12, originally thought common in CLL, is more often associated with atypical features or 
cases undergoing transformation to a higher-grade process. Because the genetic abnormali­
ties in CLL do not represent recurring balanced translocation s, they cannot be routinely 
diagnosed using PCR. Deletions and trisomies are often evaluated by FISH analysis. 
Recently, there has been interest in dividing cases of CLL into two groups based on IgH 
variable region gene mutations . Lack of mutation of this gene is associated with more ag­
gressive disease in CLL (63,64 ). Despite its clinical significance, IgH variable region gene 
mutation analysis is not offered in many diagnostic laboratories owing to its complexity. 
This test requires PCR amplification of the lgH gene rearrangement , usually requiring use of 
FRI directed primers. From this PCR product, the variable region of the monoclonal popula ­
tion is sequenced and the degree of mutation in the sequence is compared to a database. 
FISH analysis may become available in additional laboratories in the future. 
5.1.2.2. LYMPHOPLASMACYT! C LYM PHOMA 
The t(9;14)(pl3;q32) was originally reported to be detected in approximately half of 
lymphoplasmacytic lymphoma s (65) but is probably much less frequent than originally 
thought. This translocation involves the PAX-5 gene on chromosome 9 and the lgH gene 
on chromosome 14. The site of the translocation on chromosome 14 differs from the region 
involved in the JH/BCL-1 and JH!BCL-2 translocations, occurring 3' to the constant region 
of the IgH locus in the switch 1-l region. PAX-5 normally encodes a B-cell specific transcrip ­
tion factor known as B-cell-specific activator protein (BSAP) that is involved in the control 
of B-cell proliferation and differenti ation (66). Involvement of this gene may result in the 
plasmacytoid differentiation of these tumors . PAX-511gH translocations have also been

246 Arber 
reported in rare cases of marginal zone lymphoma and diffuse large B-cell lymphoma 
(65,67). Southern blot analysis, RT-PCR, or FISH may be used to detect PAX-5 rearrange­
ments. However, this lymphoma type is less common than other types with recurring trans­
locations and these methods are not offered in most diagnostic laboratories at this time. 
5.1.2.3. MARGINAL ZONE LYMPHOMAS 
The t(ll; 18)(q21 ;q21) is detected in approximately one-third of marginal zone lympho­
mas by classic karyotype analysis (68,69). Recently, this translocation has been shown to 
involve the apoptosis inhibitor gene (AP/2) on chromosome 11 and the MLT gene (also 
known as MALTJ) on chromosome 18 (70). AP/2/MLT translocations appear specific for 
only the nonsplenic, extranodal marginal zone lymphomas, occurring in approx 40% of 
gastric and lung marginal zone lymphomas, but not detected in splenic marginal zone 
lymphomas and the primary nodal marginal zone lymphomas previously termed monocy­
toid B-celllymphomas (71-74). In addition, the extranodal marginal zone lymphomas with 
increased large cells or evidence of large cell transformation do not demonstrate this 
translocation, even in the accompanying low-grade component. The presence of t(ll; 18) in 
gastric marginal zone lymphoma is associated with a lack of response to Helicobacter pylori 
therapy (75). 
Multiple breakpoint sites are described for AP/2/MLT, and RT-PCR or FISH analyses are 
usually needed to detect this abnormality. Because most of these tumors are now diagnosed 
based on small tissue biopsies without saved frozen tissue, FISH analysis on paraffin 
embedded tissue may be the most optimal means of detecting this translocation . 
In addition to the relatively common AP12/MLT translocation and the less common 
PAX-51/gH translocation in marginal zone lymphoma, trisomy 3 and t(l;l4)(q21-22;q32) 
have been reported. The t( 1; 14) results in a fusion or the BCL-10 gene and the IgH gene. 
Although this abnormality appears to occur in less than 10% of marginal zone lymphomas, 
overexpression of nuclear BCL-10 protein is associated with both t(l ;14) and t(ll; 18)-po si­
tive marginal zone lymphomas. 
5.1.2.4 . fOLLICULAR LYMPHOMA 
As a result of somatic hypermutation of the lgH gene in follicular center cells, only 
35-50% of follicular lymphomas will have a detectable lgH rearrangement by PCR analy sis 
using a single primer set (59,76,77). Because these mutations do not affect the overall gene 
rearrangement, virtually all follicular lymphomas will show a rearrangement by Southern 
blot analysis. Despite the relatively high false-negative rate for lgH gene rearrangement by 
PCR analysis, most (70-80%) follicular lymphomas will demonstrate t(l4;18)(q32;q21) 
involving the IgH gene on chromosome 14 and the BCL-2 gene on chromosome 18 (Fig. 4) 
(78), and 70-90% of these translocations are detectable by PCR analysis (79,80) . Over 
expression ofbcl-2 protein, which results from this translocation , is associated with a loss of 
apoptosis. This translocation is detectable by either Southern blot or by PCR (JH/BCL-2) analy­
sis (79). Most translocations involve the major breakpoint region (MBR) of BCL- 2, but 
5-10 % involve a minor cluster region (MCR) that requires the use of different PCR primers 
and Southern blot probes to detect (80-82). More recently described minor translocation 
clusters (including 3'BCL2 and 5'MCR) appear to be involved in most of the remaining 
cases, but are not routinely tested (83). Although most JH/BCL-2 translocations can be 
detected from paraffin-embedded tissues, some breakpoints result in PCR products that are 
very large and may not be detectable after fixation (84).

Tgl-1 18q21 
5'-D-0-1 -
t( 14;18) (q32;q2 1) 
bc/-2 lJH 
5'-MBR MCR 
19kb 
-j -3' 
MBR bcl-2 
-3' 247 
14q32 
-3' 
Fig. 4. The t(l4;18) of follicular lymphoma most commonly results in a 5' juxtaposition of the 
major breakpoint region (MBR) of the BCL-2 gene on chromosome 18 to a position adjacent to the 
joining (J) region of the immunoglobulin heavy chain (lgH) gene on chromosome 14. Color image 
available for viewing at www.humanapress.com. 
The t(l4;18) has also been reported to be detected by JH/BCL-2 PCR analysis in normal 
peripheral blood and in reactive lymph nodes (85-87), These reports suggest that this trans­
location can occur in small numbers of cells without the development of malignant lym­
phoma. Nonnested PCR tests for JH/BCL-2 that do not amplify over 45 cycles do not usually 
produce these "false positive" results (88). Detection of t(l4;18) by molecular methods is 
not necessary for the diagnosis of most cases of follicular lymphoma. However, such testing 
may be valuable in the detection of minimal residual disease, such as in bone marrow aspi­
rate material following chemotherapy, or bone marrow transplantation for follicular lym­
phoma. 
5.1.2.5. MANTL E C E LL LYMPHOM A 
The t(l1 ;14)(ql3;q32), which involves the lgH gene of chromosome 14 and the BCL-11 
PRAD1 gene of chromosome 11, is present in the majority of mantle cell lymphoma cases 
( 89,90). The BCL -1 gene encodes a cell cycle protein (termed cyclin D 1, PRAD 1 or BCL -1) 
and overexpression is associated with the aggressive behavior of this tumor. Detection of 
such overexpression has been useful in further defining this disease . The major translocation 
cluster (MTC) region is involved in 40-50 % of cases, but the remaining translocations 
involve a multitude of different sites that are not easily detectable by PCR analy sis (91). 
Methods for detection of BCL-1 mRNA are described that detected over 95% of cases of 
mantle cell lymphoma, and the mRNA expression presumably occurs with translocations 
that involve the MTC as well as other breakpoints (92, 93 ). This method requires a quantita­
tive reverse transcriptase PCR procedure that is not readily available in most laboratories. 
Mantle cell lymphomas also demonstrate nuclear overexpression of BCL-1/cyclin D1 pro-

248 Arber 
tein, related to the translocation involving BCL-1/PRAD1. Detection of cyclin D1 by 
immunohistochemistry is a more sensitive test for mantle cell lymphoma than direct PCR 
(94). Weak expression of BCL-1 protein has been described in other lymphoid tumors, 
including hairy cell leukemia (95 ). FISH detection oft( 11; 14) is performed by some labora­
tories and is a more sensitive method for the detection of this abnormality than the direct 
PCR test performed in most laboratories (96). 
5.1.2.6. DIFFUSE LARG E B-CELL LYMPHOMA 
The t(l4; 18)( q32;q21), identical to the translocations of follicular lymphomas , is identi­
fied in 17-38% of diffuse large B-celllymphoma with detection methods identical to those 
described above (59, 97-99). A number of studies have suggested that the presence oft( 14; 18) 
in large cell lymphoma is a poor prognostic indicator (98,99), which appears to contradict 
the findings of gene array studies (see below). In both follicular lymphomas and diffuse 
large B-celllymphomas, detection of this translocation does not correlate with BCL-2 pro­
tein expression. 
Many diffuse large B-celllymphomas, including some with t(l4;18), have abnormalities 
involving the BCL-6/LAZJgene on chromosome region 3q27 ( 100-104). Translocations 
involving BCL-6 involve the IgH region of 14q32, the K-light chain region of 2pl1, or the 
A.-light chain region of 22q 11. Trans locations involving chromosomes 1, 9, 11, and 12 have 
also been reported with BCL-6 in diffuse large B-celllymphoma . Rearrangements of BCL-6 
have also been reported to occur in other types of B-celllymphoma, particularly follicular 
lymphomas, and marginal zone lymphomas. The clinical significance of the detection of 
BCL-6 rearrangements in large cell lymphoma is controversial (98, 105 ). PCR based detec­
tion methods are limited by the large number of translocations that occur with this gene, the 
high frequency of somatic mutations of the gene, and because the translocations usually 
occur within an intron adjacent to the coding exons of the gene ( 104,106 ). As a result, long 
range PCR, RT-PCR or FISH methods are needed. Most methods require fresh or frozen 
tissue , but FISH analysis may be performed on paraffin-embedded tissue. Recently, the quan­
titative detection of BCL-6 RNA has been shown to have prognostic significance, and may 
become more common in the future (107). 
Although BCL-6 expression and t( 14; 18) are both markers of a possible germinal center 
cell origin in diffuse large B-celllymphoma, gene array studies are better suited for identify­
ing germinal center cell phenotypes than a single molecular or immunohistochemical assay 
(108,109) . These methods have identified three gene-expression subgroups of diffuse large 
B-celllymphoma. The germinal center B-cell-like lymphomas express genes characteristic 
of normal germinal centers. Detection of c-rel amplification and t(14; 18) are the most spe­
cific abnormalities in the germinal center B-cell-like group, but in contrast to previous stud­
ies on the prognostic significance of t(l4; 18), this lymphoma group is reported to be 
associated with a more favorable prognosis. The activated B-cell-like group expresses genes 
characteristic of mitogenically activated peripheral blood B cells , and are associated with a 
worse prognosis. Type 3 lymphomas do not express either germinal center or activated 
B-cell genes at a high level. Although these subgroups are prognostically significant, gene 
array methods are not currently available for diagnostic use. 
5.1.2.7. B URKITT /BURKITT-LYMPHOM A 
Burkitt's lymphoma is usually associated with trans locations involving the c-MYC gene 
of chromo some region 8q24, particularly the t(8;14)(q24;q32) identified in approx 80% of 
cases (110,111). The remaining cases demonstrate t(8;22)(q24;q11) or t(2;8)(pll;q24). The

Molecular Hematopathology 249 
site of translocation differs between endemic and sporadic Burkitt's lymphoma (J 12-115). 
In endemic disease, the t(8; 14) occurs up to 300 kb 5' from the coding region of the c-myc 
gene, although sporadic Burkitt's characteristically involves a translocation within the actual 
c-myc gene. These translocations may also occur in the Burkitt-like lymphomas and in a 
small number of diffuse large B-celllymphomas. Variations in these translocations , includ­
ing translocations involving the constant regions rather than joining regions of l4q32, make 
them poor targets for detection by routine PCR. Southern blot analysis for c-myc is the most 
commonly used method of detecting this abnormality. FISH studies may also be performed 
and can be used on paraffin-embedded tissues . 
5.2. T-Cell Lymphoma 
5.2.1. T-Cell Receptor Gene Rearrangements 
The T-cell receptor (TCR) genes undergo VDJ or VJ rearrangements similar to the immu­
noglobulin heavy and K-light chain genes in the sequential order of TCR() (chromosome 
14qll), TCRy (7q I 5), TCR~ (7q34) and TCRa (14qll) (56,116,117). Approximately 95% 
of circulating T cells are of the a/~ type, but a small population of y/() T cells do not unde rgo 
TCR(3 and TCRa rearrangements. Southern blot analysis of the TCR(3 chains will detect over 
90% ofT -cell malignancies but may not detect gene rearrangements in malignancies of y/o T 
cells or natural killer cells. The DNA may be hybridized with probes directed against the 
TCR(3 constant region (C~) or with a cocktail of probes directed against TCR(3 joining regions 
1 and 2 (J~1 and 2). 
PCR-based assays forT -cell clonality are usually directed against either TCR(3 or TCRy. 
Because of the complexity of the TCR~ locus, PCR for these rearrangements requires a large 
number of primers ( 118). The TCRy region is less complex with only four V region families 
containing 11 genes and five J region genes. Because the TCRy locus is consistently rear­
ranged prior to the TCRI3locus, PCR analysis with primers directed against the Vyl-8, Vy9, 
Vy 10 and Vy 11, coupled with a multiplex of J region primers will detect over 90% of clonal 
T cell neoplasms ( 119-121 ). Because it is a PCR based test directed against genomic DNA, 
TCRy PCR can be performed on paraffin-embedded tissue. In addition, TCRy rearrange­
ments can be detected in lymphomas of y/o T cells, that may not demonstrate evidence of 
clonality on Southern blotting for TCR(3. In contrast to the PCR for lgH gene rearrange­
ments , if all of the TCRy variable and joining regions sequences are covered by the PCR 
reactions, this test will result in very few false negative reactions when compared to South­
ern blot analysis. 
5.2.2. Specific Disease Types 
The t(2;5)(p23;q35) is the only recurring translocation that is routinely tested in mature 
T-celllymphomas. It is the most common cytogenetic abnormality in noncutaneous forms of 
anaplastic large cell lymphoma . Anaplastic large cell lymphoma , as it is defined in the REAL 
and WHO classifications, is a T -cell or null-cell lymphoma (12, 122 ). The t(2;5)(p 23 ;q35) 
results in a fusion transcript of the nucleolar phosphoprotein (NPM) gene of chromosome 5 
and the anaplastic lymphoma kinase (ALK) gene of chromosome 2 ( 123,124 ). Other reported 
ALK gene fusion partners are TPM3 at lq21, TFG at 3q21, ATJC at 2q35 , CTLC at 17q23, 
and MSN at Xq 11-12 (125, 126). The t(2;5) fusion product can be detected by rever se tran­
scriptase PCR by amplifying a fairly small eDNA fragment ( 127). Because the fusion prod­
uct is small, it may also be d etected in paraffin sections . The abnormality may also be 
detect ed by FISH analysis , which is a more sensitive test than RT-PCR (128). This translo-

250 Arber 
cation results in expression of the ALK protein, which is not normally expressed in lym­
phoid cells. ALK expression can be detected by immunohistochemistry ( 129 ), and in the 
right morphologic setting, ALK expression correlates well with FISH or other detection of 
t(2;5) (128). ALK expression has been shown to correlate with improved survival in this 
disease, compared to ALK-negative anaplastic large cell lymphoma ( 128, 130). ALK expres­
sion may be nuclear, cytoplasmic, or both, and translocations involving the ALK gene, other 
than t(2;5), that are described in anaplastic large cell lymphoma are also associated with 
ALK-immunoreactivity (131,132). The improved survival of ALK-positive lymphomas is 
independent of the translocation partner ( 132). Because all ALK translocations, including 
many NPMIALK translocations, are not detectable by RT-PCR analysis and the protein 
expression has such clinical relevance, ALK immunohistochemistry is the preferred test for 
this disease. The RT -PCR test may still have utility in monitoring for minimal residual 
disease. 
T -cell pro lymphocytic leukemia is associated with cytogenetic abnormalities of chromo­
some regions 14q, 8q, and llq. The most common abnormality is inv (14)(qllq32). Chro­
mosome 8 abnormalities include iso(8q) or trisomy 8 ( 133 ). Chromosome 11 abnormalities 
include llq23 abnormalities that do not appear to involve the MLL gene. Several reports 
have identified the combined cytogenetic abnormality of isochromosome 7q and trisomy 8 
in hepatosplenic yb T cell lymphoma (134 ). None of these abnormalities are routinely 
screened for diagnostic purposes, and FISH analysis is the best method for detecting many 
of the changes. 
5.3. Viruses in Lymphoma 
Several lymphoma types are associated with clonal viral integration of the lymphoma 
cells. Detection of the associated virus is often helpful in the classification of the neoplastic 
process. 
5.3.1. B-Cell Lymphomas 
The Epstein-Barr virus (EBV) is associated with Burkitt's lymphoma and the large B 
cells oflymphomatoid granulomatosis ( 135, 136). Molecular detection of EBV RNA is seen 
in 90% of endemic cases of Burkitt's lymphoma compared to a frequency of 20-30% in 
sporadic cases. EBV-positive Burkitt's lymphoma, however, is usually negative for EBV 
latent membrane protein (LMP) by immunohistochemistry and the in situ hybridization test 
for EBER is the preferred method for detecting EBV in this disease. 
Hepatitis Cis reported to be associated with a variety of types of B-celllymphomas ( 137). 
Most of the reported cases occur in patients with mixed cryoglobulinemia, a disease with a 
known association with lymphoplasmacytic lymphoma. Because most studies of this virus 
in lymphoma use serologic or PCR methodologies, definite infection of the lymphoma cells 
with the virus has not been demonstrated for most cases. 
Infection with Kaposi sarcoma herpes virus/human herpes virus-8 (KSHV/HHV-8) is 
associated with primary effusion lymphomas, plasmablastic lymphoma, and multicentric 
Castleman's disease (138). KSHV/HHV-8 is usually detected by direct PCR, but recently 
described antibodies directed against the latent nuclear antigen of KSHV, are suitable for 
use in paraffin section and may offer an alternative to the PCR test. Detection of KSHV I 
HHV8 is particularly useful in the rare primary effusion lymphomas, a disease with pleo­
morphic cells that do not usually immunoreact with T-or B-cell antibodies.

Molecular Hematopathology 251 
5.3.2. T-Cell Lymphomas 
There is a strong association between HTL V -1 infection and adult T -cell leukemia/lym­
phoma (ATLL) ( 139). Clonal integration of the virus occurs in almost all ATLL patients, but 
in situ hybridization studies for this virus are difficult to perform and not routinely offered. 
The virus may be detectable by serologic studies or PCR analysis. 
Nasal type NK/T cell lymphoma has a high association with clonal EBV in the tumor cells 
( 135 ). In situ hybridization detection of the virus in cells may be diagnostically useful in the 
small biopsy specimens obtained to evaluate for this disease. Because many of these cases 
are true NK neoplasms, they will not demonstrate T -cell receptor gene rearrangements, and 
the detection of EBV by in situ hybridization in the tumor cells is often the only diagnostic 
molecular test that is helpful. These tumors will usually not express EBV LMP by immuno­
histochemistry. 
5.3.3. Classical Hodgkin's Disease 
The Epstein-Barr virus is detectable in the neoplastic cells of approx 40% of cases of 
classical Hodgkin's disease (135 ). The virus is commonly detected in cases of the mixed 
cellularity type, and may be detected by either in situ hybridization or EBV-LMP-1 immu­
nohistochemistry. 
6. FUTURE DIRECTIONS IN MOLECULAR DIAGNOSTICS 
OF HEMATOPOIETIC NEOPLASMS 
The rapid expansion in new technologies for molecular analysis creates an overwhelming 
potential for future testing ( 140 ). Only some of these potential methods will be summarized. 
6.1. Protein Expression 
The overexpression of some proteins resulting from molecular genetic gene fusions can 
be detected by immunohistochemi stry ( 141 ). Several examples of the use of aberrant protein 
expression have been described and include cyclin Dl protein in mantle cell lymphoma and 
ALK protein in anaplastic large cell lymphoma . These immunohistochemical tests are cost­
effective and reliable surrogates for molecular events, and more examples of clinically use­
ful immunohistochemical markers will become clear in the future. One example is the 
expression ofT AL-l protein as a marker ofT -cell lymphoblastic leukemia and lymphoma. 
6.2. Karyotype Analysis and FISH 
Advances in FISH analysis should allow for the detection of lower levels of genetic 
abnormalities. In addition, spectral karyotyping (SKY), a method of specifically labeling all 
chromosomes in 24 colors for analysis, should increase the ability to identify translocations 
and other cryptic aberrations ( 142) . 
Comparative genomic hybridization (CGH) is a research tool that evaluates the binding of 
tumor DNA to normal chromosomes to determine loss or gains of genetic material (143). A 
similar technology employs CGH methods on DNA arrays. These methods allow for the 
evaluation of all areas of the genome, in contrast to only specific regions studied by PCR. 
The diagnostic applications of CGH are still unclear. 
6.3. Gene Array Technology 
Gene array analysis offers the ability to identify biologic disease subtypes that may corre­
late with prognosis and even response to specific chemotherapeutic agents. As mentioned

252 Arber 
previously, the early work using gene arrays in diffuse large B-celll ymphoma has identified 
prognosticall y significant subgroups (I 08, I 09) and there are similar studies using this meth­
odology in acute leukemia (144,I45). The role of this methodology in diagno sis re main s 
uncle ar, but these method s appear more suited to compliment existing diagno stic method s, 
rather than to replace them. The large amount of data that can be generated from these arrays 
also limits their use, and smaller, more specific arrays that are more disease specific may be 
needed before they come into routine use. 
6.4. Quantitative PCR and RT-PCR 
Because a variety of tumor-a ssociated molecular genetic changes may remain at low lev­
els after treatment without clinical relevanc e, the serial quantification of these signals may 
be of prognostic importance. Therefore, the various methods of "real-time ," quantitative 
PCR are of interest ( I46). This methodology is rapidly entering the diagnostic laboratory. 
One issue that relates to quantitative PCR that still needs to be resolved is consistency in 
reporting quantitative values between laboratorie s. In addition, clinical studies are need ed 
for most diseases to determine the optimal timetable for residual disease testin g as well as 
guidelines for the level of molecular diseas e that constitutes a significant risk for relapse . 
Such levels may vary by disease type. Such studies are underwa y and many of these ques­
tions should be resolved in the near future . 
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13 
HER2 and Topoisomerase Ila in Breast Carcinoma 
Kenneth J. Bloom 
In order for the human breast to develop and function appropriatel y, the cells of the breast 
must communicate with each other in a precise and coordinated fashion. A major mecha­
nism of communication is signal transduction; a process where external signaling molecules, 
or ligands, alter the behavior of a cell by affect ing the transcription of various genes. Behav­
ior of the cell is modified primarily by phosphorylating or dephosphorylating a series of 
transmembrane, intracellular, and adaptor proteins possessing enzymatic activity. The enzy­
matic activity of one protein turns on the enzymatic activity of the next protein in the path­
way resulting in signal propagation ( 1 ). Not all proteins are capable of interacting directly 
with each other, therefore adaptor proteins may be necessary to serve as a bridge. Signal 
transduction molecules include Shk adaptor proteins, which when phosphorylat ed, create 
docking sites for SH-2 domain containing molecules, such as, Grb2, PLC-y, STAT , and 
focal adhesion kinases. 
When the amino acid tyrosine serves as the substrate for phosphorylation, the resulting 
protein is known as a tyrosine kinase. There are approx 100 known protein tyrosine kinase 
genes, 58 of which encode transmembrane receptors (RTK) (2,3 ). All RTKs have a common 
structure consisting of an extracellular binding domain, a transmembrane a-helix and an 
intrac ellular domain, which possesses intrinsic tyrosine kinase activity. RTKs show diversity, 
predominantly in their external binding domain s and can be categorized into 20 subfamilies. 
One of these families, the epidermal growth factor receptor (EGFR) family, is composed of 
EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 ( 4,5 ). 
1.1. HER2 Signaling 
Three things are necessary to elicit a signal from the EGFR family of receptors: a ligand , 
a receptor , and a dimerization partner (6, 7). Ligands of the EGFR family include EGF , TGF-a, 
and amphiregulin , which are specific for EGFR , heparin-binding EGF , epiregulin , and 
betacellulin, binding EGFR and HER4, and the neuregulins, which bind HER3 and HER4 
(8). Ther e are no known ligands for HER2. After a ligand binds to a receptor, that receptor 
must dimerize with another member of the EGFR family to trigg er phosphorylation . It may 
dimerize with a like member of the family, which is known as hom odimerization , or it may 
dimerize with a different member of the family , which is known as heterodimeriz ation (9, 10 ). 
From : Cance r Diag nostics: Current nnd Futu re Trends 
Edited by: R. M. Nakam ura, W. W. Grady , ). T. Wu, and R. B. Nagle <D Human a Press Inc., Totowa , NJ 
261

262 Bloom 
When HER2 is available, it is the preferred dimerization partner of the other family mem­
bers ( 11 ). Moreover, HER2 heterodimers are stable and their signals are more potent than 
other receptor combinations ( 1, 7). The specific tyrosine residue on the intracellular portion 
of the phosphorylated receptor depends on the combination of ligand and dimer pair ( 12 ). 
Because there are four family members, ten dimer pair combinations are possible. Signifi­
cant intracellular crosstalk with other signaling pathways and the variety of different ligands 
allow for significant diversity in signaling. Major pathways activated include the Ras/MAPK 
pathway, PBK/Akt pathway, STAT pathway and PLC-y pathway (13-15). The end result is 
induction of the activated cell to proliferate, survive, gain increased motility, and induce 
growth of new blood vessels. 
Factors that influence the ability of a signal to induce changes in a target cell include the 
strength and length of time the signal stays activated before it is turned off. Not allligand­
dimer pair combinations show the same ability to propagate an intracellular signal. For 
example, the signaling strength of a HER2/HER3 dimer activated by heregulin is signifi­
cantly stronger than that activated by EGF ( 16). Signaling is eventually inactivated by 
endocytosis ( 17). The receptor remains transiently activated after endocytosis , although the 
specific pathway activated may change once the receptor loses its association with the mem­
brane. The process of endocytosis varies depending on the ligand, dimerization pair, and 
cellular pH. EGF occupied homodimers are rapidly endocytosed and undergo lysosomal 
degradation, thus terminating the signal. In contrast , EGF heterodimers containing HER2 
show enhanced signaling as EGF is dissociated from the receptor in the early endosomes, 
allowing the receptor to recycle back to the cell surface. 
1.2. HER2 Distribution 
The 185 KD HER2 protein is encoded by the HER2 gene located on chromosome 17q 
( 4,18 ). This gene shares homology to the rat gene neu and is thus sometimes referred to as 
HER-2/neu (19). In breast carcinoma, there is a tight association between the number of 
copies of the HER2 gene, the amount of HER2 mRNA and the number of HER2 receptors 
(20-23 ). Occasional tumors may show an increased number of receptors with a normal 
complement of HER2 genes, the purported single copy over -expressers. It has been sug­
gested that many of these tumors represent stromal rich carcinomas and that the stromal 
elements dilute the determination of the HER2 gene copy number. Although this may be true 
for determinations performed by Southern Blot, it should not be a factor in the determination 
of gene copy number by fluorescent in situ hybridization (FISH) analysis. 
Limited studies have looked at the distribution of the EGFR family and few have specifi ­
cally addressed the distribution of HER2 protein. Scanning laser microscopy has shown that 
HER2 protein is randomly distributed along the cell membrane, although there is a prefer­
ence towards the basal and lateral portions of the cell. The HER2 molecules cluster in groups 
of approx 1000 receptors that increase in size as protein synthesis is upregulated (24 ). Even­
tually, these clusters coalesce and give the appearance of complete membrane staining with 
an anti-HER2 antibody. There are approx 20,000 HER2 receptors expressed on the surface 
of benign breast epithelial cells, but the absolute number varies with age and menstrual 
status as well as a number of less well- defined factors (25 ). Most breast carcinomas express 
more receptors than benign breast epithelial cells (26). HER2 protein is synthesized and 
transported in the cytoplasm and after activation , is degraded through a process of endocyto­
sis. Therefore, it is not unusual to find evidence of HER2 in the cytoplasm of tumor cells.

HER2 and Topoisomerase Ila in Breast Carcinoma 263 
2. TESTING METHODS 
2.1. Protein Overexpression 
Robertson et al. attempted to define the range of HER2 expression in breast tissue by 
evaluating expression as a cont inuous variable in 123 invasive breast carcinomas utilizing 
radioimmunohistochemistry (rlHC) (27). BT474 cells, which express 730,000 receptors, 
were also radiolabeled and used as a control along with nine reduction mammoplasty speci­
mens. The staining intensity of cells obtained from the reduction mammoplasty specimens 
ranged from 1.4% to 4.2% (10,220-30,600 receptors) of the BT474 control cell line, with a 
mean of 2. 7% ( 17,520 receptors). Ninety-one percent of the carcinomas overexpressed HER2 
protein relative to the mammoplasty specimens and showed a bimodal distribution , with one 
peak ranging up to 332,880 receptors and the second peak beginning at 770,880 receptors. 
Five percent of the cases underexpressed HER2 protein. 
Eppenberger-Castori et al. evaluated the expression ofHER2 protein as a continuous vari­
able in 3208 fresh/frozen invasive breast carcinomas by enzyme immunoassay using cytosol 
preparations. A bimodal distribution pattern was observed, although significant overlap was 
present between the two peaks (28). 
Bloom et al. evaluated the immunohistochemical expression of HER2 protein as a con­
tinuous variable in 500 consecutive cases of invasive breast cancer utilizing the 
HercepTest™ kit and image analysis (29). The intensity of HER2 expression was deter­
mined from immunostained slides by assessing six distinct regions of tumor and then calcu­
lating the average staining inten sity. When plotted as a continuous variable the average 
staining intensity reveal ed a bimodal distribution with all tumors in the second peak reveal ing 
amplification of the HER2 gene. The consistency of this bimodal distribution pattern can be 
used to validate assays that assess HER2 protein expression. 
2.1.1. Biology of HER2 Over expressi on 
Differences in the definition of HER2 overexpression have plagued the literature. When 
overexpression is defined as an increased numb er of HER2 receptors compared to normal 
breast epithelial cells, most breast carcinomas are classified as showing overexpression. In 
practic e, overexpression has been assessed by immunohistochemistry. The large variety of 
antibodies, fixation methods , antigen retrieval techniques , and scoring systems have all con­
tributed to the lack of a standardized definition of HER overexpression. The advent of 
trastuzumab necessitated the development of a standardized assay so that patients could 
enroll in clinical trials. Preclinical data had suggested that only tumor cells expressing more 
than several hundred thousand HER2 receptors respond to trastu zumab. 
The number of HER2 receptors on a cell's surface is dependent on the balanc e of protein 
synthesis vs destruction. Gene amplification is the most common mechanism of increa sed 
protein synthesis in breast carcinomas but other mechanisms, including posttranscriptional 
events, reduced destruction of receptors, increased recycling of receptors to the cell surface, 
and receptor mutations are possible. Unlike EGFR, in which constitutively activated muta­
tions are common, no known mutations of HER2 exist in humans ( 5 ). Data on posttranscrip­
tional factors is limited. Tubbs et al. studied a series of 144 formalin-fixed paraffin-embedded 
(FFPE) invasiv e breast carcinomas and could not identify increased mRNA in tumor s show ­
ing significant overexpression by IHC without amplification of the HER2 gene (30). Slamon 
et al. also assessed the relationship betw een HER2 gene amplification , mRNA expression, 
and protein expression on a series of invasive breast carcinomas (22). All testing was per-

264 Bloom 
formed on well-preserved frozen tumor samples in which DNA, mRNA, and protein were 
all optimally preserved. Approximately 97% of the cases demonstrated a direct relationship 
between the level ofHER2 gene amplification (assessed by Southern blot), the expression of 
HER2 mRNA (assessed by Northern blot) and the expression of HER2 protein (assessed by 
Western blot and immunohistochemistry). However, 3% of the tumors showed markedly 
increased expression of HER2 mRNA and protein despite a normal complement of HER2 
genes. The difference between these two studies may be related to the use of FFPE rather 
than frozen tissue, or the determination of gene amplification by FISH analysis rather than 
Southern blot. 
2.1.2. Immunohistochemistry 
Most immunohistochemical stains routinely performed in clinical practice are qualitative, 
meaning they are performed to detect the presence or absence of a specific protein. Because 
the goal is merely detection, it is common to vary the conditions of the assay, such as the 
concentration of antibody, time of incubation, and antigen retrieval method, in order to 
enhance staining. HER2 is expressed on all breast carcinoma cells, therefore a qualitative 
HER2 assay is unwarranted. Instead, a quantitative assay that correlates the pattern and in­
tensity of immunostaining with the number of HER2 receptors is required . To achieve this 
goal, a standardized assay in terms of tissue handling, antibody, reagents, conditions, anti­
gen retrieval method, and scoring was developed. 
2.1.2.1. STANDARDIZING THE IHC ASSAY 
The original trastuzumab clinical trials used an IHC method to screen a large number of 
FFPE tissue blocks to select appropriate patients. This assay, known as the clinical trial 
assay (CTA), was a labor-intensive IHC assay that initially used an antibody directed against 
the same extracellular domain epitope as trastuzumab, known as 4D5. However, the anti­
body was switched during the study to CB 11, which is directed against an epitope on the 
intracellular domain of HER2. The CT A also defined a scoring system to semiquantitatively 
assess the immunohistochemical stain that ranged from 0 to 3+, and only patients whose 
tumors were scored as 2+ or 3+ were enrolled in the clinical trials. Cell-line data helped 
define the relationship between the number of HER2 receptors and the IHC staining pattern 
(Table 1 ). Although all of the samples in the original clinical trials were paraffin-embedded, 
the specific fixative used length of fixation. Storage condition of the tissue blocks was largely 
unknown. 
The results of the clinical trials allowed trastuzumab to receive FDA approval; however, 
the FDA required that prior to treatment, the patient's tumor be tested for overexpression of 
HER2 protein. A commercial standardized immunohistochemical assay known as 
HercepTest™ was approved explicitly for this purpose. The intent of the HercepTest™ kit 
was to create a reproducible, easy to perform assay that would mirror the CT A. Standardiza­
tion is the key attribute of the HercepTest™ kit. The assay specifies pre-analytic issues such 
as the fixative, the length of fixation, the antigen retrieval method, a predilute polyclonal 
antibody with all of its epitopes located on the intracellular domain of HER2, and the scoring 
method. 
The HercepTest™ scoring system is identical to that created to assign eligibility for the 
trastuzumab clinical trials (Fig. 1). It looks at the completeness and intensity of the mem­
brane stain. A score of zero shows no appreciable membrane staining or light partial staining 
in less than 10% of the cells; a score of 1 + shows light partial membrane staining in more

HER2 and Topoisomerase Ila in Breast Carcinoma 265 
Table 1 
Correlation of HER-2 Receptors and Amplification Status 
IHC Number of Gene 
score Assessment Cell line Pattern receptor s copies 
0 Neg MDA-231 No staining or 21,600 ± 2.4 ± 0.2 
membrane 6,700 
staining in less 
than I 0% of the 
tumor cells 
Neg MDA-175 Faint or barely 92,400 ± 3.0± 0.4 
perceptible 12,000 
partial mem-
brane staining 
in more than 
10% of 
2 Pos MDA-361 Weak to moderate 500,000 ± 
complete mem - 100,000 
10% of 
3 Pos SK-BR-3 Strong complete 2,390 ,000 ± 15.3 ± 3.9 
membrane 130,000 
staining in 
more than 
10% of 
than 10% of the cells. Complete membrane staining, if present , is not seen in more than 10% 
of the cells; a score of 2+ shows light to moderate complete membrane staining in more than 
10% of the cells and a score of 3+ shows strong complete membrane staining in more than 
10% of the tumor cells. 
Initially , the HercepTestTM kit created a lot of controversy with reports stating that the kit 
was too sensitive or not sensitive enough ( 31 ). Unfo rtunately, the majority of these studies 
changed the conditions specified in the kit, most commonly by changing the fixative and/or 
the antigen retrieval method (32). Use of alcohol based fixatives or microwave-antigen re­
trieval have both been associated with significantly amplifying the strength of the HER2 
immunostain leading to frequent false positive results. In a study of differen t HER2 antibod­
ies, Press et a!. reported a significant variation in detection rates by IHC using a large tissue 
block containing multiple breast tumors ( 33 ). 
Data from the NSABP B31 study highlights some of the problems in clinical practice 
( 34 ). The B31 trial is comparing adjuvant chemotherapy versus adjuvant chemotherapy plus 
trastuzu mab in patients whose tumor showed 3+ overexpression of HER2 by IHC or ampli­
fication of the HER2 gene. Review of the first 104 specimens enro lled in the trial revealed 
significant discrepancies between the assessment at the submitting laboratory and reanalysis 
at the central NSABP laboratory. Large volume laboratories that used the HercepTest™ kit 
showed 96% concordance; smaller laboratori es, however, achieved only 81% concordance

266 Bloom 
Fig. 1. Examples of breast carcinomas stained with the HercepTest™ kit. Top Left, 0+; no appre­
ciable membrane staining is seen. Top right, 1+; partial membrane staining is seen in more than 10% 
of the invasive tumor cells. No complete membrane staining is noted. Bottom left, 2+; moderate 
membrane staining is seen with complete membrane staining in more than 10% of the invasive tumor 
cells. Note the visible nucleoli. Bottom Left, 3+; strong complete membrane staining is seen in almost 
all of the invasive tumor cells. 
Fig. 2. Examples of in situ hybridization. The image on the left shows a breast carcinoma without 
evidence of HER2 gene amplification. The red signal represents the HER2 gene and the green signal 
represents a centromere probe to chromosome 17. There are equal numbers of HER2 and chromo­
some 17 signals. The middle image reveals numerous red signals representing amplifi cation of the 
HER2 gene . Two copies of chromosome 17 (green signals) are seen in most cells. The image on the 
right is an example of chromogenic in situ hybridization . The increase number of signals represents 
amplification of the HER2 gene.

HER2 and Topoisomerase Ila in Breast Carcinoma 267 
and those laboratories not using HercepTest™ or CB 11 showed only 50% concordance. 
Following these results, the NSABP required that submitted blocks be tested in certified 
laboratories, either large volume laboratories, or laboratories showing strong concordance 
between their IHC results and FISH results. Additional testing of 240 blocks at the certified 
laboratories revealed 98% concordance. Most of the certified laboratories were reference 
laboratories that cannot control tissue fixation or storage, it has therefore been suggested 
that preanalytical issues may not be a major cause of interlaboratory variability (at least in 
cases assessed as 3+ ). Results from the United Kingdom National External Quality Assess­
ment Scheme for Immunohistochemistry (UK NEQAS-ICC) also suggested that the lack of 
reproducibility of HER2 scoring between laboratories is likely not the result of tumor 
heterogeneity or preanalytic issues but rather the result of how the scoring system is 
applied (35). 
Although tumors assessed as 3+ by an experienced laboratory will likely have amplifica­
tion of the HER2 gene, it is less clear that tumors assessed as 0 or 1 +will lack gene amplifi­
cation. Mass et al. analyzed a subset of 0 and 1 + tumors for the presence of HER2 gene 
amplification and found that 7 of 207 (3%) tumors assessed as 0+ and 2 of 28 (7%) tumors 
assessed as 1 + were amplified by FISH ( 36 ). How this relates to current IHC testing is 
unclear, because the CT A is no longer used and all testing was performed on archival speci­
mens with unknown fixation and storage conditions. Bloom et al., prospectively studied 175 
consecutive invasive breast carcinomas scored as 0 or 1 + with the HercepTest™ kit and 
showed that 4 of the 175 (2.4%) tumors showed amplification of the HER2 gene ( 37). How­
ever, all four cases showed only borderline amplification and three of the four cases were 
assessed as 1 +/2+ showing moderate to strong immunostaining in the majority of the tumor 
cells but failed to show complete membrane staining in more than 10% of cells. LeBeau 
showed 0 of 22 (0%); Couturier, 1 of 88 (1.1 %); Jimenez, 0 of 21 (0%); Ridolfi, 1 of 56 
(1.8%); and Tsuda, 0 of 165 (0%) tumors scored as 0 or 1+ with the HercepTest™ kit when 
amplified by FISH (38-42). 
2.1.2.2. IHC ScoRING METHODS 
Initially, the HercepTest™ scoring system seems straightforward but many of the terms 
are ambiguous and have caused confusion. The assessment of signal strength as weak to 
moderate, or strong is the only difference between a 2+ and 3+ score. Similarly, determining 
if circumferential staining is present in 10% of the tumor cells is subject to observer varia­
tion. HER2 expression, when present, is preferentially located to the basal and lateral aspect 
of the cell, therefore if a cell is cut tangentially it may give the appearance of circumferential 
staining. To achieve better correlation with gene amplification, most pathologists now 
require strong, complete membrane staining in the majority of the invasive tumor cells before 
scoring an IHC stain as 3+. 
2.1.2.3. PATHOLOGISTS' INTERPRETATION 
Before assessing a HER2 immunostain, the pathologist should perform a standard check-
list including: 
1. Are the pre-analytical conditions of the assay met? 
2. Is a validated assay used? 
3. Is the positive control positive? 
4. Is the negative control negative? 
5. Is there no significant staining in normal ductal or lobular units?

268 Bloom 
Table 2 
Correlation Between IHC and FISH Based on Method of IHC Scoring 
Path 2 3 4 5 6 7 8 9 lO 
Manual 42% 61% 59% 83% 64% 65% 92% 76% 88% 83% 
Image 94% 91% 90% 94% 95% 91% 95% 95% 94% 92% 
Note: Correlation between IHC and FISH determined manually and with the aid of com-
puterized image analysis in each of 10 pathologists. 
Although these seem obvious, they are frequently ignored. For example, the use of an 
alcohol-based fixative invalidates the HercepTest™ . This does not mean that the IHC assay 
will not produce a clean immunostain, it means the relationship between the staining pattern, 
and intensity and receptor copy number will be unknown. Another common problem is over­
fixation. Laboratories that formalin fix breast specimens from the time they are received on 
Friday afternoon until the tissue is processed early Monday morning violate the specifica­
tions in the HercepTest™ guidelines and may lead to false negative results. Similarly , stor­
ing unstained slides at room temperature may diminish HER2 immunoreactivity (43). 
Even if the positive and negative controls stain as expected, careful review of the patient's 
slide must be performed. If staining is observed in benign epithelial elements, the stain should 
be repeated . The pathologist should also have knowledge of HER2 expression in various 
grades and types of breast cancer. Only 1-2% of well differentiated infiltrating ductal carci­
nomas and classic lobular carcinomas will overexpress HER2 as opposed to approx 30% of 
metastatic breast carcinomas and 20% of high grade infiltrating carcinomas ( 44 ). An 
immunostain assessed as 3+ in a tubular carcinoma should be repeated and if positive should 
be verified with another methodology, such as FISH. There are several artifacts that may 
cause false positive staining and must be avoided, including edge artifact, crush artifact, and 
tissue retraction. Because all three of these artifacts are present in core-needle biopsies, great 
caution must be used when interpreting these specimens. 
The assessment of a HER2 immunostain begins with the selection of a well preserved 
tissue block which minimizes known artifacts and contains a rim of normal breast tissue. 
The presence of normal breast tissue allows the observer to make sure significant staining is 
not present in benign elements. Review of the slide should begin with the x4 or x 10 objec­
tive to assess the uniformity and intensity of the stain. A uniform staining pattern with a 
distinct membranous pattern giving a "chicken-wire" appearance, should be assessed as 3+. 
If a chicken-wire pattern is not clearly present, the observer should move up to the x20 and 
x40 objectives. These objectives can serve as an aid to define weak, moderate, and strong 
staining . A chicken-wire pattern visible on x4 or x 10 equates to strong staining, on x20, 
moderate staining and on x40 weak staining. To avoid tangential sectioning, a nucleolus 
should be visible in any cell assessed as showing circumferential staining. This is possible 
because virtually all breast carcinomas that overexpress HER2 have visible nucleoli. A strong 
1 + immunostain typically reveals a partial membrane stain with an intense granular appear­
ance. The slide may look brown on lower power examination but a true chicken-wire pattern 
will not be present. Although interobserver variability is relatively low with tumors assessed 
as 0 and 3+, it may be significant in 2+ tumors.

HER2 and Topoisomerase Ila in Breast Carcinoma 269 
2.1.2.4. UsE OF IMAGE ANALYSIS 
Although the human eye is excellent at distingui shing morphological characteristics , it is 
not adept at distinguishing shades of color. The immunohistochemical assessment of HER2 
is largely dependent on the intensity of the stain, therefore image analysis may be a valuable 
tool to minimize interpathologist interpretation. Bloom et al. compared agreement among 10 
pathologists in the assessment of 130 HER2 stained slides ( 45) (Table 2). Each pathologist 
scored the slides utilizing standard light microscopy according to the HercepTest™ guide­
lines with the aid of an image analyzer. The result s were compared to the gene amplification 
status as assessed by FISH analysis. Although the experience of the pathologists varied, the 
concordance ranged from as low as 42% to as high as 92% on routine assessment. All of the 
pathologists achieved similar concordance, ranging from 90 to 95%, and even the most 
experienced pathologist showed improvement with the aid of the image analyzer. When the 
receiver operating characteristic (ROC) curves with conventional microscopy were analyzed 
for each of the ten pathologists, they had significantly different shapes, arguing that the 
variability was not just owing to differences in applying intensity thresholds but was related 
to some thing more fundamental in how the cases were scored. The ROC curves gene rated 
for each of the pathologists when using image analysis appeared similar. Other studies, using 
a variety of different image analysis systems, have also shown improved and more consis­
tent HER2 scoring ( 46,47). 
2.2. HER2 Gene 
There is a direct correlation between high level s of HER2 overexpression and amplifica ­
tion of the HER2 gene in carcinomas of the breast. The HER2 gene is located on chromo­
some 17 at 17 q 12. Several techniques have been employed to assess the HER2 gene including 
Southern Blotting techniques, FISH, chromogenic in situ hybridization (CISH), and poly­
merase chain reaction (PCR) techniques . Chromosome 17 frequently shows polysomy in 
breast carcinomas, therefore many of these assays include a reference probe for chromo­
some 17 so observers can differentiate between amplification of the gene and aneusomy of 
chromosome 17. 
2.2.1. HER2 Amplicon 
Amplification of the HER2 gene is not specific to HER2. The region of the chromosome 
that is amplifie d, known as the amplicon, is variable and usually involves other genes as 
well. The variability of the HER2-containing amplicon has been demonstrated in breast can­
cer cells lines as well as patient samples ( 48 ). In addition to HER2, the minimal amplicon 
also includes GRB7, a signaling protein involved in migration and invasion, MLN64 (thought 
to be involved in cholesterol transport) , NEUROD2 , PNMT, ZNFN 1A3, and EST 48582. 
Additional genes may occasionally be coamplified with HER2 but it is unclear if these 
genes are located on the same amplicon. These include genes like THRa, RARa, 
topoisomerase 11-a, MLN50 , MLN51, and TRAF4. The increased responsiveness ofHER2-
amplified tumors to anthracycline therapy may be limited to those tumors in which the 
topoisomerase 11-a gene, which is located telomeric to HER2, is co-am plified (49,50). The 
variably sized amplicon has implications in probe design as well in assessing the prognostic 
and predictive significance of the FISH result.

270 Bloom 
2.2.2. FISH 
Similar to IHC, FISH testing can be performed on FFPE tissue samples (51), but since 
DNA is less subject to tissue fixation and processing than protein, FISH has been advoca ted 
as a more robust testing method to assess HER2 status. The process of FISH testin g utilizes 
protease digestion to isolate the tumor nuclei, which are then heated to uncoil the DNA, 
flooded with a digoxigenin labeled probe, and cooled to allow the HER2 probe to anneal 
with the specific region of DNA . Following hybridization, the probe is visualized by apply­
ing fluorescent-labeled antibodies directed against the digoxigenin. In an optimally prepared 
specimen, detection of gene amplification is straight forward, although there is no accepted 
standard for evaluating a slide. Some scoring systems count only the HER2 signals, whereas 
others report the ratio of HER2 signals to a centromeric signal for chromosome 17 (Fig. 2). 
Since the HER2 gene is located on chromosome 17, the ratio allows the pathologist to differ­
entiate aneusomy of chromosome 17 from true gene amplification. Studies comparing the 
two methods are highly correlative (52). Slides prepared from FFPE blocks are generally 
between four and six microns in thickness, and thus do not represent complete nuclei. Initial 
reports in the literature suggested enumerating 60 cells, 15 cells from four different areas of 
the tumor would accurately detect gene amplification. Other reports suggested that enumer ­
ating as few as 20 cells will give identical results (53). 
One of the main advantages of FISH is that the pathologist knows when the assay has 
failed, because signals will not be detected; however, FISH, like any stain ing technique , is 
subject to variations in fixation, processing, storage , and detection. Even when hybridization 
is achieved, the intensity of the signals may be weak and the pathologist may underestimate 
the number of gene copies present. Furthermore, as the pathologist screens the slide, the 
intensity of the signal weakens as the slide is fluoresced. 
FISH is an excellent technique but has two main difficulties in clinical practice. The most 
important limitation is the difficulty in guaranteeing that the invasive tumor cells have been 
observed. Identifying the invasive tumor on a 4',6-diamidino-2-phenylindole (DAPI) stained 
section can be challenging if the section is not completely composed of tumor. In many 
institutions this is complicated by assigning a cytogenetic technician to evaluate the FISH 
slides, who may not be qualified to evaluate if a DAPI stained cell is carcinoma or invasive. 
Although matching the hematoxylin and eosin (H&E) stained section to the FISH slide is 
essential prior to evaluation, occasionally the sections are not similar, especially with needle 
core biop sies. In many institutions, the tumor is identified on the originally reviewed H&E 
sectio n and the FISH slide is later cut with sections for ER, PR, KI-67 , and ploidy, once the 
diagnosis of invasiv e carcinoma is established . In these cases, the section remov ed for FISH 
analysis may be up to 200 fl. away from the original H&E slide, and the circled area may not 
be representative of the tumor in the deeper section. Care must be taken to ensure that the 
H&E section used to select the invasive tumor and the FISH slide are step sections. A second 
limitation is background fluorescence, which is usually the result of either incomplet e pro­
tease digestion or over -digestion. To the untrained pathologist, this fluorescence may look 
similar to coalescence of HER2 gene signals seen in tumors with amplification. However, in 
tumors showing real amplification, the individual nature of the signal s can be observed on 
fine focus. 
2.3. Other Test s Including CISH, PCR, ELISA, and SERUM 
Southern and slot blotting were the first gene-based HER2 detection methods used in

Southern and slot blotting were the first gene-based HER2 detection methods used in 
breast cancer specimens. These methods require fresh or frozen tissue but can be signifi -

HER2 and Topoisomerase lla in Breast Carcinoma 271 
cantly hampered when the amount of tumor relative to the adjacent benign breast tissue and 
inflammatory cells is low, causing dilution of the tumor DNA. Chromogenic in situ hybrid­
ization or CISH has all of the advantages of IHC (routine microscope, lower cost, familiarity) 
and FISH (built-in internal control, subjective scoring, more robust DNA target), but is not 
FDA approved for selecting patients for trastuzumab therapy. The probes are identical for 
both CISH and FISH, however the HER2 gene is detected using a conventional peroxidase 
reaction, which is less sensitive than the fluorescence detection used in FISH (54). Tanner et al. 
studied 157 invasive breast carcinomas by CISH and identified 27 tumors with amplification 
of the HER2 gene, all of which were also amplified by FISH (55). Ten additional cases 
displayed HER2 gene amplification by FISH but not by CISH. This raised concern that 
CISH may not be able to detect tumors showing borderline amplification, although it is 
unknown if this subset of patients would respond to trastuzumab therapy. Tubbs et al., have 
reported excellent results with an alternative bright field testing method called gold-facili­
tated autometallographic in situ hybridization or GOLDFISH (56). This technique is being 
developed but has shown excellent interpathologist reproducibility. PCR techniques, includ­
ing differential, competitive, and real-time PCR, have predominantly been used to detect 
HER2 mRNA in peripheral blood and bone marrow samples (30,57,58) . Although it has 
correlated better with gene amplification status than IHC levels, it failed to predict survival 
in a study of 365 breast cancer patients (59). The advent of laser capture microscopy and the 
acceptance of real-time PCR as a routine and reproducible laboratory technique, may increase 
the use of real time PCR to assess HER2 status. 
ELISA-based measurements of HER2 protein in tumor cytosols, uniformly correlate with 
disease outcome (28,60-64). The ELISA technique is made from fresh tissue samples to 
avoid the potential antigen damage associated with fixation, embedding, and uncontrolled 
storage. However, tumors are being discovered at a smaller size, precluding ELISA testing 
because insufficient tumor tissue is available to produce a cytosol. 
Serum HER2 testing is a simple ELISA test that measures the extracellular domain (ECD) 
of the HER2 protein circulating in the serum. The ECD is a 100-110 protein released into 
the serum by specific metalloproteinases (65). The level of detectable ECD protein corre­
lates more to tumor burden than to the overexpression of HER2 in the tumor. As such, it is 
not surprising that many studies have failed to find a correlation between ECD levels and 
HER2 status as determined by FISH or IHC. The ease of a serum measurement is attractive 
and studies assessing how to best utilize the ECD protein measurement are ongoing. At this 
time however, ELISA is not recommended for selecting patients for trastuzumab therapy, 
although ELISA testing is an FDA approved method for the follow-up and monitoring of 
patient with metastatic breast carcinoma. 
3. SIGNIFICANCE OF HER2 ALTERATIONS 
3.1. HER2 as a Prognostic Factor 
HER2 is an important prognostic factor in both node negative and node positive breast 
carcinomas. The prognostic significance of HER2 has been evaluated in more than 25,000 
patients, encompassing 80 studies (28,59,60,66-100). Endpoints have included metastasis 
free survival, disease free survival, and overall survival rates. All of the studies assessing 
gene amplification were predictive of outcome by univariate analysis although 10% of the 
studies utilizing IHC were not. By multivariate analysis , 71% of the studies revealed that 
HER2 status was independent of all other prognostic variables, including tumor size, grade,

272 Bloom 
lymph nodes status, ER status, and vascular invasion in predicting an adverse prognostic 
significance. After analyzing the eight negative studies, five used immunohistochemistry 
(IHC) on FFPE tissues, two used Southern analysis, and one used a real time PCR technique. 
3.2. HER2 as a Predictive Factor of Response to Therapy 
Since its launch in 1998, trastuzumab, a monoclonal IgG 1 class humanized murine anti­
body has become a major therapeutic option for patients with HER2 positive metastatic 
breast cancer and is currently being evaluated for use in the adjuvant and nco-adjuvant set­
ting (101-104). Developed by Genentech Corporation (South San Francisco, CA, USA), 
trastuzumab received FDA approval based on the results of the phase III pivot trial which 
showed that the addition of trastuzumab to chemotherapy (anthracycline plus cyclophospha­
mide or taxane) was associated with a longer time to disease progression (median , 7.4 vs 4.6 
mo; p < 0.001), a higher rate of objective response (50 vs 32%; p < 0.001), a longer duration 
of response (median 9.1 vs 6.1 mo; p < 0.001 ), a lower rate of death at I yr (22 vs 33%; p = 
0.008), longer survival (median survival 25.1 vs 20.3 mo; p = 0.01) , and a 20% reduction in 
the risk of death ( 105 ). Despite its dramatic benefits, significant cardiac dysfunction occurred 
more frequently in patients treated with anthracycline and cyclophosphamide plus 
trastuzumab compared to patients treated with anthracycline and cyclophosphamide alone 
(27 vs 8% ). Cardiac toxicity still remains a limiting factor of trastuzumab use (106 ). 
The best method to identify patients who will respond to trastuzumab therapy has been a 
source of controversy. It has been suggested that FISH is more predictive of response than 
IHC but this is based on results of FISH testing performed retrospectively in patients that 
were already screened as either 2+ or 3+ by IHC. FISH assessment has not been tested 
prospectively and FISH results do not appear to outperform IHC when 3+ and 2+ tumors are 
evaluated independently. In the phase III clinical trial, the relative risk reduction of both 
time to progression and overall survival was similar, with virtually identical confidence inter­
vals, in patients assessed as 3+ by IHC and assessed as amplified by FISH (Tables 3 and 4). 
In this series , FISH testing did not identify a subset of 2+ patients that benefited from 
trastuzumab therapy ; however the number of patients treated was too small to achieve statis­
tical significance. In a trial where trastuzumab was used as a first line single agent, the 
response rate in Ill patients with 3+ IHC staining was 35% while the response rate for 2+ 
tumors was 0%; the response rate in patients with and without HER2 gene amplification was 
34% and 7% respectively ( 107). When trastuzumab was used in advanced metastatic breast 
cancer patients as a third or fourth line therapy , the response rate in 222 patients with 3+ 
staining was 18% and the response rate for 2+ patients was 6%; the response rate in patients 
with and without HER2 gene amplification was 19% and 0%, respectively ( 108). As seen by 
the above response rates, HER2 testing is best suited to identifying patients who are unlikely 
to respond to therapy rather than identifying those patients that will respond . Although the 
superiority of FISH over IHC remains controversial , most pathology laboratories are cur­
rently either screening all breast carcinomas with IHC and triaging selected tumors for FISH 
testing or using FISH as the only method for HER2 testing. 
Besides predicting response to trastuzumab, HER2 status is also predictive of response to 
hormon al therapy ( 109-113 ). Preclinical data shows that transfection of the HER -2 gene 
into HER2 negative , estrogen dependent cell lines leads to estrogen independence. Many 
studies have shown an inverse relationship between HER2 status and hormonal status in

studies have shown an inverse relationship between HER2 status and hormonal status in 
breast carcinoma (72, 91, 94,114 , I 1 5). These studies were limited by the assessment ofHER2

HER2 and Topoisomerase lla in Breast Carcinoma 
Table 3 
Trastuzumab + Chemo vs Chemo: Time to Progression 
Subgroup Relative risk 95% CI No. of patients 
IHC 3+ 0.42 0.33-0.55 349 
IHC2+ 0.82 0.54-1.24 120 
FISH+ 0.44 0.34-0.57 325 
FISH- 0.66 0.45-0.99 126 
Note: Data from the phase III clinical trial showing identical relative risk 
reduction and confidence intervals (CI) for both 3+ and FISH+ patients. 
Table 4 
Trastuzumab + Chemo vs Chemo: Overall Survival 
Subgroup Relative risk 95% Cl No. of patients 
IHC 3+ 0.70 0.54-0.92 349 
IHC2+ 1.09 0.71-1.58 120 
FISH+ 0.69 0.53-0.91 325 
FISH- 1.07 0.70-1.63 126 
reduction and confidence intervals (CI) for both 3+ and FISH+ patients . 273 
and hormonal status as dichotomous variables, but a recent study assessed HER2 and hor­
monal status as continuous variables and confirmed that HER2-positive tumors are more 
often associated with a negative hormonal status than HER2-negative tumors. Furthermore, 
even in hormone receptor positive tumors, the expression of HER2 appears to be inversely 
related to the expression ofER and PR ( 116). Many studies have shown that HER2-positive 
tumors are specifically resistant to tamoxifen therapy and some have suggested that HER2 
expression may actually have an adverse effect on outcome in tamoxifen treated patients 
compared to untreated patients ( 60, 95, 98, 99, 117). Other studies, including large intergroup 
studies in the United States have not confirmed this finding ( 118). In postmenopausal women, 
there is a suggestion that aromatase inhibitors may be able to overcome the tamoxifen resis­
tance seen in ER-positive HER2-positive tumors ( 119). 
HER2 protein overexpression has also been linked to resistance in patients treated with 
cytoxan, methotrexate , 5-fluorouracil (CMF) adjuvant chemotherapy, as well as taxane and 
cisplatin-based regimens (86,120-122). Menard et al., however, showed that CMF chemo­
therapy overcomes the poor outcome ascribed to HER2 overexpressing tumors treated by 
radical mastectomy alone (123 ). Cell lines expressing HER2 show increased resistance to 
paclitaxel , and clinical data suggests that HER2-positive patients receiving paclita xel con­
taining regimens without concomitant trastuzumab have a reduced respons e rate and a shorter 
duration of response than HER2 negative patients ( 122). Other studies suggest that taxanes 
may provide sensitivity to HER2 overexpressing tumors. When the HER2 gene is trans ­
fected into MCF-7 cells, they acquire resistance to cisplatin ( 124 ). However , when com­
bined with trastuzumab in HER2-positive patients, both paclitaxel and cisplatin show 
significant activity. Pegram et al. showed a 24% response rate and a 48% clinical benefit in

274 Bloom 
chemoresistant patients treated with trastuzumab and cisplatin ( 125). Several studies have 
shown a 50-60% objective response rate in patients treated with a combination of 
trastuzumab and taxanes ( 105). 
HER2 overexpression has also been associated with enhanced response rates to 
anthracycline-containing chemotherapy regimens in some, but not all studies. Retrospective 
analysis of the data generated from the CALGB 8541 study provided evidence that HER2 
overexpression was associated with increased responsiveness to high dose CAF chemo­
therapy (87). In this study, lymph node positive patients were randomized to receive one of 
three doses of CAF . At 3-yr follow-up, significant improvements in disease free and overall 
survival were seen in HER2-positive patients receiving high-dose CAF therapy . The NSAPB 
B-11 trial also provided evidence that HER2-positive patients benefit from anthracyline 
based therapy (1 26 ). Node-positive, ERIPR-negative patients were randomized to receive 
melphalan, doxorubicin and 5-fluorouracil or melphalan, and 5-fluorouracil alone. Patients 
whose tumors overexpressed HER2 showed significant improvement s in disease-free sur­
vival with the anthracycline containing regimens. The SWOG study S8814 compared 
tamoxifen alone vs tamoxifen plus CAF chemotherapy in ER positive patients (127). In 
contrast to HER2-negative patients, those patients whose tumor overexpress ed HER2 pro­
tein showed significantly improved benefit from chemoendocrine therapy. In summary, al­
though strong trends have been presented in published studies; including resistance to 
tamoxifen and sensitivity to anthracycline regimens for HER2-po sitive tumors, more studies 
are needed using appropriate control arms to confirm these important associations. 
4. TOPOISOMERASE Ila 
Topoisomerase Ila is a key enzyme in DNA replication and is the target of anthracycline 
chemotherapy. Although there appears to be an association between HER2 overexpression 
and benefit from anthracycline chemotherapy, it is not clear if this benefit is restricted to 
those patients with a concurrent topoisomerase Ila amplification . The relationship between 
HER2 amplification and topoisomerase Ila amplification; including whether they are part of 
the same amplicon, is currently the subject of investigation. Unlike HER2, there is not a tight 
correlation between gene amplification and protein expression. 
4.1. Topoisomerase II a Amplicon 
The topoisomerase Ila gene is located on chromosome 17, telomeric to HER2. In theory, 
if HER2 and topoisomerase Ila were part of the same amplicon, the copy number of both 
genes should be identical, but this is frequently not the case . To date, all tumors showing 
amplification of the topoisomerase Ila gene have also shown amplification of the HER2 
gene, but the converse is not true. Topoisomerase Ila amplification is evident in 40-45 % of 
breast carcinomas with HER2 amplification but 30-40% show topoi somerase Ila deletion 
by FISH. Som e of the discrepan cies may be explained by the design and relative size of the 
FISH probes used to assess the genes. Mapping of the HER2-containin g amplicon , using a 
series of overlapping FISH probes, reveals occasional skip areas possibly explaining the 
differences in HER2 and topoisomerase Ila copy numbers . There have been relatively few 
studi es attempting to determine if topoisomera se Ila and HER2 are part of the same 
amplicon. Jarvinen et al. utilized fiber FISH to address this problem (128). Fiber FISH is a 
technique used to map closely located genes, usually in normal DNA , but in this case the 
DNA fibers were prepared from malignant cells. HER2 -topoisomerase Ila tandem repeats

HER2 and Topoisomerase Ila in Breast Carcinoma 275 
were expected to be seen if the two genes were indeed part of the same amplicon; but instead 
HER2-HER2-HER2 and topoisomerase Ila-topoisomerase Ila-topoisomerase Ila repeats 
were seen in separate DNA fibers, arguing that HER2 and topoisomerase Ila are part of 
different amplicons . To explain this finding, it has been suggested that the HER2 amplicon 
is created first and its telomeric end occurs at a breakpoint located between the HER2 and 
topoisomerase Ila genes. This breakpoint then serves as a starting point for a secondary 
amplicon housing the topoisomerase Ila gene. It is unclear how HER2 amplification leads to 
an interstitial deletion but it is likely to involve the DNA repair proces s ( 129,130 ). The same 
phenomenon of interstitial deletions occurs following other amplifications such as cyclin D 1 
amplification ( 131,132 ). Heterogeneity in topoi somerase II a gene expression has been iden­
tified in breast carcinomas with some cells showing amplification and adjacent cells show­
ing deletion. This coupled with the fact that all breast carcinomas with topoisomerase Ila 
amplification also reveal HER2 amplification , implies that the HER2 amplification takes 
place before or concurrent with the topoisomerase Ila aberration and supports the hypoth­
esis that the chromosomal breakpoint of the HER2 amplicon is located between the HER2 
and topoisomerase Ila. genes. 
4.2. Topoisomerase Ila. and Response to Therapy 
There are several arguments that HER2 by itself does not predict responsiveness to 
anthracycline therapy. First, there is no known interaction between topoisomerase lla. 
inhibit ors and either the extracellular or intracellular domains of the HER2 protein. Pegram 
et al. induced HER2 protein overexpression in both mouse and human cells in vitro and did 
not see any alterations in the cell's responsiveness to topoisomerase II a inhibitor s. ( 133,134 ). 
Jarvinen et al. showed that topoisomerase Ila amplified cell lines were associated with 
increased topoisomerase Ila. protein expression and a significantly increased sensitivity to 
doxorubicin therapy, whereas cell lines with topoisomerase Ila. gene deletion revealed 
decreased protein expression and decreased sensitivity to doxorubicin therapy. Other in vitro 
studies also demonstrated that the sensitiv ity of topoisomerase Ila. inhibitors is directly 
related to the level of topoisomerase Ila. protein (135-1 38). Harris et al. found that 
topoisomerase lla. activity may be related to the expression level of HER2 even when gene 
amplification is not present (139). Topoisomerase Ila.levels were increased in unamplified 
cell lines when HER2 was activated by transfection of a chimeric receptor. The addition of 
trastuzumab downregulated both the HER2 and topoisomerase IIa. activity levels in these cells. 
In summary, there is a close interaction between HER2 and topoi somerase II a expression 
levels in breast cancer. In approx 40% of breast carcinomas, HER2 gene amplification is 
associated with topoisomerase lla. amplification. However, even without gene amplifica­
tion, HER2 activity appears to influence topoisom erase IIa expression and enhance respon­
siveness to anthracycline therapy. 
5. CONCLUSION 
HER2 is an important protein in breast carcinoma serving as prognostic marker in both 
node positive and node negative patients and as a predictive marker to trastuzumab therap y. 
Several options are available to assess HER2 status includin g IHC, FISH, CISH, and quan­
titative PCR. Currently, IHC and FISH are the only FDA approved method s and are the most 
widely used techniques for assessing HER2 status. Both techni ques provide excellent results 
when performed in skilled laboratori es according to the manufacturer's guidelines. Should

276 Bloom 
further studies confirm the associations between HER2 and hormonal and/or anthracyline 
therapy it would seem likely that HER2 testing, which achieved standard of care status in the 
American Society of Clinical Oncology breast cancer clinical practice guidelines in 2001 
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14 
Study of Sentinel Lymph Nodes in the Staging 
Alice A. Roberts and Alistair J. Cochran 
Surgeons have long appreciated the significance oflymph node metastases to cancer prog­
nosis. As far back as the 6th century, Actus of Amida observed that "malignant phlegmons" 
develop in the armpits of advanced breast cancer patients ( 1 ). The impor tance of lymph node 
metastases was recognized early on, and this naturally led to investigations of the underlying 
physiology. In 1622, Aselius demonstrated lymphatic drainage into lacteals of a postpran­
dial dog, thus laying the groundwork for centuries of attempts to map lymphatic pathway s. 
The most common approach was to inject dye into peripheral sites and dissect adjacent 
tissues looking for colored lymphatics. Various dyes, including India ink and mercury , were 
utilized to map lymphatic drainage in human cadavers and research animals. In the mid-20th 
century, radioisotopes were employed as markers of lymph drainage; some early experi­
ments in humans employed radioactive colloid gold (2), and later the less active technetium-
99 (TC-99) came into use ( 3 ). Peri tumoral injections of radiocolloid are now used in sentinel 
node biopsy to visualize draining nodes preoperatively by lymphoscintigraphy and intraop­
eratively using a handheld Geiger counter . The presence of lymph node metastases overrides 
all other prognostic factors for solid tumors and the surgical approach is usually altered by 
the presence of metastatic tumor in a lymph node. Staging for most solid tumors depends on 
knowing the tumor status of the draining lymph nodes . As the surgeon Moynihan aptly stated, 
"surgery of malignant disease is not the surgery of organs; it is the anatomy of the lymphatic 
system" (4). 
2. REGIONAL NODE DISSECTION 
Many patients with solid tumors are staged by screening regional lymph nodes, such as 
the ipsilateral axillary nodes in breast cancer. The role of tumor-positive lymph node s in 
the staging of solid neoplasms is widely accepted; however, the therapeutic value of com­
plete excision of draining lymph nodes remains somewhat controversial. Some contend that 
there is no therapeutic value in treating such patients because nodal involvement reflects 
aggressive disease that has already spread beyond local nodes ( 5 ). Regional lymphad enec ­
tomy is not likely to alter cancer progression in individuals with aggressive tumor s that have 
already metastasized extensively and systematically nor will it benefit individuals with node­
negative disease. It is clear that the only likely survival benefit of regional node dissection is 
to patient s with metastases that are absolutely or substantially limited to the primar y drain-
From: Cancer Diagnos tics: Current and Futu re Trend s 
Edited by: R. M. Nakamura , W. W. Grody, J. T. Wu, and R. B. Na gle© Humana Press Inc., Totowa , NJ 
285

286 Roberts and Cochran 
ing lymph node group, for example, individuals who are node-positive but do not have sub­
stantial distant metastatic deposits (there is evidence that distant micrometastases may lie 
dormant for many years) . These patients typically have moderate grade malignancies and no 
clinically detectable tumor metastases. 
Regional node dissection may be associated with significant side effects and financial 
costs . Patients have had debilitating, even fatal, complications stemming from inadequate 
lymphatic drainage after regional node dissections (6). One way to reduce both morbidity 
and cost of node dissection is to remove only the one to several nodes that are most likely to 
contain metastatic tumor. These nodes can be subjected to close pathologic scrutiny by evalu­
ating multiple tissue levels for hematoxylin and eosin (H&E) staining and ancillary tests, 
such as immunohistochemistry and molecular analyses. 
3. SENTINEL LYMPH NODE DISSECTION 
The idea of a primary draining node or "sentinel lymph node" (SLN) has occurred to a 
range of investigators. Cabanas, for example, used the term "sentinel" to describe a lymph 
node at the superficial epigastric venous plexus that received primary lymphatic drainage 
from the penis (7). Cabanas conceived of the SLN as an anatomically fixed lymph node that 
was the primary drainage node and thus the first site of tumor metastases. Other investiga­
tors had difficulty confirming Cabanas' anatomically designated SLN, and some individuals 
with bilateral negative anatomically defined SLN developed subsequent metastatic penile 
carcinoma (8). Morton and Cochran et al. at UCLA took the SLN concept a critical step 
further by reasoning that because lymphatic anatomy and drainage patterns differ between 
individuals, the SLN is unlikely to be anatomically fixed. The Morton-Cochran concept of 
the SLN is physiologic rather than anatomic, thus the SLN must be identified individually 
for each patient. SLN dissection (SLND) was subsequently developed using perioperative 
lymphatic mapping as a means to identify the regional lymph node(s), the primary draining 
nodes with the highest probability of early metastasis. The SLND technique involves 
peritumoral injection of radioisotope and/or dye markers that drain into the lymphatics. In 
cases using radioisotope, the most radioactive lymph node is visualized by lympho­
scintigraphy and localized intraoperatively by a hand-held Geiger counter. If peritumoral 
dye injections are done, the surgeon traces the lymphatics by dissection looking for blue­
colored nodes. By this method, the earliest draining node(s) or SLN, considered "high risk" 
lymph nodes for metastases, can be selectively removed and subjected to extensive 
pathologic analysis (beyond what is feasible for an entire regional node dissection). 
Morton et al. initially developed a feline model to demonstrate the feasibility of intraop­
erative lymphatic mapping (9), and then conducted trials to evaluate the extent that SLN 
tumor status predicts for the tumor status of the remaining regional nodes in patients with 
thick melanomas ( 3 ). Initially, intraoperative frozen sections were subjected to rapid immu­
nohistochemical analysis to evaluate the tumor status of the SLN. It was thought that once 
the technique was validated, the decision to perform a completion node dissection would be 
based on the results of the intraoperative frozen section. In the earliest cases, the intraopera­
tive SLN biopsy was followed by complete regional lymphadenectomy until it became clear 
that SLN tumor status reliably predicts the tumor status of the entire node bed ( 10 ). This first 
study of the "physiologic" SLN in humans demonstrated clearly that absence of tumor in the 
non-SLN was reliably predicted by a tumor-free SLN, thus raising the possibility of sparing

Sentinel Lymph Nodes for Staging Malignancy 287 
node-negative patients the potentially harmful side effects of regional node dissection. 
Oncologists and surgeons have now developed an interest in the oncologic and surgical 
implications of tumor-draining SLN in a wide range of different malignancies . 
4. CLINICAL SIGNIFICANCE OF SENTINEL LYMPH NODE METASTASES 
SLND is a minimally invasive staging technique established for staging and management 
of clinically node-negative melanoma patients with primaries of up to intermediate thick­
ness, viewed by many as the standard of care for these patients ( 11 ). SLND spares clinically 
node-negative cancer patients with tumor-free SLN the more invasive and morbid technique 
of regional lymph node dissection. Breast cancer staging also increasingly relies on SLND, 
sparing these patients a full axillary node dissection. SLND remains an investigative staging 
technique for other solid neoplasms. The development of ancillary techniques, such as 
immunohistochemistry and molecular analysis, has increased the frequency of detection of 
"positive" SLN resulting from the detection of smaller tumor deposits and singly dispersed 
tumor cells. The clinical significance of such minute tumor deposits and single tumor cells 
in SLN is an area of intense investigation, and the results are critical to interpreting the 
results of SLND. 
4.1. Melanoma 
Tumor involvement of the SLN is the most significant negative predictive factor for a 
patient with apparently localized melanoma, and is associated with a 40% decrease in 5-yr 
survival. Melanoma is more difficult to manage when regional nodes contain tumor, and 
20-30% of patients with clinically negative nodes have occult metastases on microscopic 
examination. The likelihood of SLN metastases increases with increasing thickness and 
ulceration of the primary melanoma; however, SLN status is the most important predictor of 
outcome in clinically node-negative melanoma patients, and nodal metastases outweigh all 
other risk factors. Melanoma thickness and ulceration are important prognosticators for SLN­
negative patients but are much less predictive in SLN-positive patients (10,12). SLND is 
thus a highly useful staging and prognostic technique for clinically node-negative melano­
mas and has dramatically fewer side effects than more extensive regional lymph node dis­
section. 
4.2. Breast Cancer 
The lymphatics that drain from the breast to the lymph nodes of the ipsilateral axilla are 
the primary route for breast cancer metastasis, and axillary lymph node status is the most 
important predictor of recurrence and survival in breast cancer. Internal mammary nodes 
are harder to access surgically and are less frequently the site of metastases. These nodes are 
utilized less for staging breast cancer. Axillary SLNs have been localized by isosulfan blue 
dye mapping (13, 14 ), by radioisotope localization (15 ), and by a combination of both 
approaches, which is generally considered to be the superior method ( 13-16). Mapping using 
combined blue dye and radioisotope is accurate , the rate of detection of metastases compar­
ing favorably to complete axillary lymph node dissection (ALND) ( 17-21 ). Prospective stud­
ies have shown that most breast cancer patients remain disease free as long as three years 
after a negative SLN biopsy, indicating a low false-negative rate for axillary SLND (22). A 
meta-analysis by Miltenburg et al. determined that SLN biopsy is as effective as ALND for 
staging axillary lymph nodes in breast cancers (23 ).

288 Roberts and Cochran 
Some authors have questioned the value of lymphoscintigraphy in breast SLND, main­
taining that it does not increase the detection rate of axillary sentinel nodes and that a nega­
tive scan does not preclude identification of an axillary sentinel node intraoperatively (24 ). 
Although axillary SLND may have prognostic power, it may be critically lacking in sensitiv­
ity if the localization technique excludes the internal mammary SLN. The prognostic signifi­
cance of axillary and internal mammary nodes is similar and taken together the different 
node groups provide information that is cumulative , suggesting that there is utility in assess­
ing internal mammary SLN (IMSLN) (25). However, in most series, the incidence of iso­
lated breast cancer metastases to IMSLN has been very low, and IMSLN sampling by the 
traditional surgical method has been associated with increased mortality, supporting the view 
that TMSLN sampling has no additive value to axillary SLN staging and may actually harm the 
patient (26 ). In a series of 700 breast cancer cases from the H. Lee Moffitt Cancer Center at 
UCLA, no cases of isolated metastases to IMSLN were identified ( 17). Likewise , in a multi­
center validation study by Krag et al., only 1 of 443 patients (0.3%) had isolated drainage to 
an IMSLN ( 15 ). Using a different approach, Ogawa et al. performed lymphatic mapping by 
lymphoscintigraphy and thoracoscopy on 49 breast cancer patients and found SLN among 
the internal mammary nodes in 15 cases (31%) (27). Of 11 patients who underwent thoraco­
scopic biopsies, 2 had tumor metastases, only one of which was limited to the IMSLN, an 
incidence of 1% (27). The thoroscopic approach may address some concerns regarding 
increased morbidity in IMSLN biopsy, making this approach more clinically viable. If the 
internal mammary pathway harbors tumor-draining SLN, additional surgery may be neces­
sary to biopsy these nodes, though many believe that tumor in the internal mammary nodes 
is controllable by customary radiotherapy. Furthermore, the therapeutic value of both com­
plete axillary dissection (and axillary SLND) has not been established, and axillary lym­
phatic staging may be sufficient to predict prognosis for most patients. At present , IMSLN 
biopsy remains a controversial and investigational procedure . 
5. A TEAM APPROACH TO SENTINEL LYMPH NODE DETECTION 
Successful outcome in SLND for melanoma and breast cancers depends on an effective 
collaboration between surgeon , nuclear medicine specialist, and pathologist, all of whom 
have worked together to master the technique (28,29). During the surgical learning phase, 
completion dissection of the entire node basin must be performed (regardless of the tumor 
status of the SLN until all participants demonstrate acceptable performance of the technique. 
Diagnostic accuracy in SLND depends on optimal site, type, timing, and dosage of marker 
injection, as well as good pre-operative lymphoscintographic imaging and interpretation. 
The surgeon carefully dissects the lymph node bed identified by lymphoscintigraphy . Fol­
lowing the signpost offered by the blue colored afferent lymphatic(s), the bluest and most 
radioactive (by Geiger counter) lymph node(s) are identified, carefully dissected out, and 
removed. It should be remembered that often, only a part of the SLN may be blue colored. 
Many patients may have more than one SLN, and 98% of positive axillary SLN are found 
by removing nodes with enhanced radioactivity although this may be only 10% of the hottest 
lymph node identified (30). SLN radioactivity may be relatively limited, especially in the 
presence of a relatively high tumor burden that can limit radioisotope uptake. In fact, if the 
SLN is replaced by tumor, lymph flow will be deviated and another node (that may be tumor­
free) may appear to be the SLN. Great caution is required in managing lymph node groups

Sentinel Lymph Nodes for Staging Malignancy 289 
where there is relatively abundant tumor present. In fact, the SLND technique is not intended 
for this class of patients. 
The radioisotope used for SLND must be short-lived with limited tissue penetration, as is 
Technetium-99m (t112 = 6 h). Trained early-read assessment of the preoperative 
lymphoscintogram by a radiologist is critical. If a lymphoscintogram is performed hours 
before surgery, a second peri tumoral injection of radioisotope will usually not be required. 
The surgeon uses the lymphoscintogram to select an optimal skin incision site and dissec ts 
into the underlying soft tissue looking for blue colored lymphatics and node(s) . At UCLA, 
the SLN is identified as the most radioactive node by hand-held Geiger counter and is sec­
ondarily assessed for visible blue coloration. However, if a second, blue lymph node is seen, 
it will also be removed and analyzed as a SLN. 
6. PATHOLOGIC PROCESSING OF SENTINEL LYMPH NODES 
Although Morton et al. initially developed the SLN approach using intraoperative frozen 
sections, identification of small metastatic foci and single tumor cells is more accurate in 
permanent sections owing to superior fixation and staining, and higher certainty of complete 
nodal sections ( 10). Facing ofthe frozen section block and subsequent refacing of the forma­
lin-fixed, paraffin-embedded material can result in loss of diagnostic tissue. Instead, the 
pathologist may do intraoperative touch imprint s of the cut face of the bisected SLN. A 
recent report supports the utility of intraoperative touch imprints of SLN for detection of 
breast cancer metastases ( 31 }, although others are less enthusiastic about this approach. SLN 
are processed somewhat differently for melanoma and breast cancer cases owing to differ­
ences in the kinetics of extension of these two tumors within the lymph node. In both types 
of cases, the SLN specimen is handled with care. If an intact rim of perinodal fat is present 
around each dissected node, it may be possible to detect tumor emboli within afferent lym­
phatics and assess extra-nodal spread. 
6.1. Melanoma 
Melanoma SLND is usuall y performed at the time of wide local resection of cutaneous 
melanoma. Surgeons submit each SLN in an individual container of 10% formalin and label 
it with the node color and level of radioactivity (cpm) . The pathologi st records the number 
and dimensions of the SLN(s) and notes the surgeo n's description-color (blue) and coun ts 
( cpm) -of each node. If there is more than one node, and one is blue-colored and selectively 
radioactive, this is noted, and the node is submitted separately for SLN workup. In mela­
noma cases, additional nodes that are neither blue nor more radioa ctive than the background 
are considered incidental nonsentinel nodes; however, these nodes are also submitt ed indi­
vidually for SLN workup. 
Because melanomas typicall y metastasize to the subcaps ular space first, particularly along 
the longest meridian of the node, the pathologist bisects the SLN through its longest circum­
ference and evaluates both cut surfaces for tumor (using a hand lens or dissecting micro­
scope), as well as foci of blue coloration (32). Node halves are placed cut face down into 
cassettes and formalin-fixed for 24-48 h. After processing, paraffin-embedded blocks are 
sectioned at 2 to 4 ~--tM interval s with minimal preparatory facing off of the block. Ten sec­
tions are cut from each half of the node (a total of 20 sections and used for H&E staining and 
immunohistochemical staining with antibodi es to S-100, HMB-45, and Melan-A/MART-1;

290 Roberts and Cochran 
ctions 
H E 
1 
H&E 
NEG 
P RE 
SP 
H E 
Fig. 1. Histopathologic analysis of melanoma sentinel lymph nodes. SLN are bisected, then for­
malin-fixed for 24 to 48 h, processed by histology, and ultimately embedded in paraffin. The tissue 
blocks are sectioned at 2-4 f!M intervals, including I 0 sections from each half of the SLN for hema­
toxylin and eosin (H&E) staining, as well as immunohistochemical staining with antibodies to S 100, 
HMB45, and MARTl!M elanA. Color image available for viewing at www.humanapress.com. 
Fig. 1). It is critical that the lymph node capsule is present in its entirety on sections or the 
entire sentinel node package may need to be repeated. 
6.2. Breast Cancer 
There are several approaches to the pathologic examination of SLN draining breast can­
cers. The College of American Pathologists' Surgical Pathology Committee, recommends 
submission of the entire (bisected) SLN for preparation of serial sections that will be alter­
nately used for three H&E stained slides and three cytokeratin immunostained slides ( 33 ). 
Examination of at least three levels of a bisected or multi-se ctioned SLN (50 to 100 ~M 
intervals) can detect betwee n 70 and 90% of SLN (34). Turner et al. of the John Wayne 
Cancer Institute (Santa Monica) have recommended cytokeratin immunostaining of two lev­
els of the paraffin block to detect breast cancer metastases ( 35 ). 
At UCLA, breast surgeons typically send the pathologist fibroadipose tissue that contains 
from one to three lymph nodes. The pathologist dissects all lymph nodes from the breast 
SLN specimen and records their individual dimensions and color in the surgical pathology 
report . Serial -sections of the SLN are cut at 2-mm intervals along the long axis and the entire 
node is submitted. If there is more than one SLN, they are submitted in separate cassettes for 
SLN workup. Six serial histologic sections are prepared for H&E stains (serial no. 1, 3, and 
5) and for possible cytokeratin staining (serial no. 2, 4, and 6). The three H&E sections are 
examined first, and if no diagnostic cancer is detected on the H&E sections , pan-cytokeratin 
(kerAE 1,3) immunostaining is done on serial sections no. 2 and 4. Serial section no. 6 is 
used for an immunostaining negative control.

Sentinel Lymph Nodes for Staging Malignancy 291 
Fig. 2. Sentinel lymph node with subcapsular melanoma micrometasta sis. In this case, a capsular 
lymphatic micrometastasis from a cutaneous nevoid melanoma is visible on the H&E stain and on 
immunostaining for SlOO, MARTI, and HMB45 markers . There is also strong immunostaining of 
metastatic melanoma with HMB45 in addition to the other immunomarkers. The strong HMB45 
positivity is consistent with the malignant nature of the melanocytic cells. Color image available for 
viewing at www .humanapress.com. 
7. MICROSCOPIC ANALYSIS OF SENTINEL LYMPH NODES 
7.1. Melanoma 
There is no doubt that histopathologic analysis of SLN is an acquired skill, and melanoma 
metastases , other than large multicellular colonies, may be difficult to see on H&E staining. 
Small melanoma metastases and micrometastases are typically found within the subcapsular 
sinus (Fig. 2), although they have on occasion been identified primarily in the internal nodal 
sinuses. As the metastases grow, they may expand into the lymph node parenchyma and/or 
through the capsule. The pathologist first scans the H&E slide at low power ( x40- l 00) and 
assesses the different nodal compartments with particular focus on the subcapsular sinus.

292 Roberts and Cochran 
Lymphatics within the perilymphatic tissue are also evaluated. Sequential high power (x400) 
fields are then scanned for single or clustered atypical cells that are suspicious for tumor 
cells. The entire node is carefully examined because melanoma metastases can occasionally 
be confined to the lymphoid parenchyma and/or the central nodal sinuses. Extracapsular 
invasion by tumor worsens the prognosis and is recorded if present ( 36). If metastases are 
detected, the pathologist records the number of tumor foci and the dimension of the largest 
focus, using image analysis or a micrometer (37). 
7.2. Breast Cancer 
H&E slides from breast SLN are examined at both low and high power, analogou s to the 
approach for melanoma SLN. Breast cancer metastases frequent the intranodal sinuses (more 
than the subcapsular sinus), although large metastases may displace part or all of the node. 
H&E staining alone is insufficient to detect metastases from lobular carcinomas, which may 
present as scattered small cells within the lymph node parenchyma. SLND is sometimes 
performed for ductal-carcinoma-in situ (DCIS), and 10-15% of patients with DCIS may 
have undetected, associated microinvasive DCIS and regional lymph nodes meta stases ( 38, 
39). We have observed that SLN metastases in patients with DCIS do occur and may be quite 
large with areas that recapitulate the DCIS morphology seen in the breast. 
8. IMMUNOHISTOCHEMICAL ANALYSIS OF SLN 
8.1. Melanoma 
Scattered, single tumor cells inapparent on H&E stained sections may be visualized using 
immunohistochemistry targeting melanoma markers, such as SlOO, HMB45, or MelanA/ 
MARTI. The immunoreactive single tumor cells may be seen clustering near a metastatic 
colony of melanoma cells first detected on the H&E stained slide. Immunohistochemistry 
plays a crucial role in the detection of micrometastases by highlighting individual cells and 
small clusters of melanoma cells, thereby improving the sensitivity of SLN analysis. When a 
node metastasis is first observed in immunostained sections, the pathologist should review 
the H&E sectio ns with guidance from the immunostained sections and try to retrosp ective ly 
identify the tumor cells. The proportion of SLN in which tumor is identified initially in the 
H&E sections increases with experience, but immunohistochemical analysis is still requir ed 
to maximize the sensitivity for micrometastases and to confirm the diagnosis of melanoma 
as the primary. 
In addition to SIOO, HMB45, and MelanA/M ARTl, antibodies to tyrosinase and glyco­
protein-100 may be used as markers for melanoma (40,41), as well as combined antibody 
cocktails. S 100 stains 100% of melanomas, whereas the other epitopes are absent from 5-
15% of melanomas. However, SIOO also stains cells in the node that are not melanocytic , 
including dendritic leukocytes of the paracortex . Separation of dendritic cells with reduced 
dendrites from small (nevocytic) melanoma cells can be difficult. It is therefo re essential to 
use a combination of single immunomarkers, such asS I 00, HMB45, and MelanA/M ART 1. 
8.2. Breast Cancer 
Cytokeratin immunost aining is helpful for detecting micrometastases and discriminating 
"atypical" but benign cells, such as activated histiocytes or reactive endothelial cells, from 
true metastases. If metastatic breast cancer is first observed on cytokeratin stains, morpho-

Sentinel Lymph Nodes for Staging Malignancy 293 
Fig. 3. Sentinel lymph node with trabecular nevus. In this case, a trabecular nevus is visible on an 
H&E stain and on immunostaining for MARTI and HMB45 markers (S 100 not shown). There is 
positive immunostaining of metastatic melanoma with MARTI. Weak to absent staining with 
HMB45, as is characteristic for benign capsular nevi. Color image available for viewing at 
logic comparison is made to corresponding cells in the H&E sections of the SLN and to the 
cytology of the primary tumor. 
9. PITFALLS IN THE MICROSCOPIC DIAGNOSIS 
OF SENTINEL LYMPH NODES 
The major pitfalls in the microscopic evaluation of sentinel nodes for melanoma occur 
from errors in reading immunostained sections. Discrimination of the pigment in 
melanophages from immunopositive cells is aided by antibody visualization with 
aminoethylcarbazole (red) rather than diaminobenzidine (brown). Additional potentialS 100-
positive distractors include reactive dendritic cells, (Fig. 2B) capsular and capsular or trabe­
cular nevi (Fig. 3), histiocytes, intranodal and perinodal nerves , and ganglion cells. 
Nonspecific HMB-45 immunostaining of calcified trabeculae in inguinal or pelvic lymph 
nodes may be recognized by its acellular chunky appearance. 
Discrimination of benign cells from metastatic melanoma requires consideration of nodal 
architecture and cytologic features of the cells of interest. Nevocytes within lymph nodes are 
typically found in a different compartment (intracapsular and intratrabecular) from meta ­
static melanoma cells (initially subcapsular, later subcapsular, and intraparenchymal). 
Benign nevocytes commonly appear as layered small polygonal or spindled cells around 
capsular vessels or within trabeculae (Fig. 3 ), as opposed to usually larger melanoma cells 
that occur individually and in small aggregates within the subcapsular sinus (Fig. 2). 
Capsular/trabecular nevocytes have a low nuclear to cytoplasmic ratio and lack prominent 
nucleoli. Histiocytes and macrophages have small , kidney bean -shaped nuclei with small 
nucleoli, although reactive histiocytes and endothelial cells may have a more alarming cyto­
logic appearance. Paracortical dendritic cells characteristically have elongated cell processes, 
although these may be reduced in frequency, complexity, and length as a result of tumor ­
released immune suppressive factors ( 42-44 ). Suspicious features for melanoma cells 
include large size, high nuclear to cytoplasmic ratio, prominent nucleoli, mitotic figures, and

294 Roberts and Cochran 
the presence of fine punctate melanin granules (as opposed to the coarse granules of melanin 
seen in melanophages). 
False positive interpretations of SLN removed for breast cancer can result from weak 
cytokeratin staining of fibroblastic reticular cells, particularly when antibodies directed at 
low-molecular keratins are used. The reticular cells may be distinguished by their mesh-like 
arrangement and benign cytologic features ( 45 ). In comparison to the multiple markers used 
for melanoma, cytokeratin immunostaining is not as specific for breast cancer, and meta­
static carcinoma from other primaries may need to be excluded. 
10. APPLICATION OF THE SENTINEL LYMPH NODE APPROACH 
TO OTHER SOLID MALIGNANCIES 
10.1. Gastric Cancer 
Lymphatic mapping for gastric carcinoma is of interest in countrie s such as Japan where 
the incidence of this disease is relatively high . The use of SLND for gastric tumors has 
potential advantages for identi fying nodal metastases, because diagnostic imaging is usually 
insufficient to detect lymph node metastases of gastric cancers. The complex natur e of the 
gastrointestinal lymphatics raises the concern that selective SLND might miss skip 
metastases, reportedly common in gastric cancers. Because of these concerns, the SLND 
approach to gastric cancer is still in its validation stage, although the results are promising 
enough to warrant larger trials (46). On average, two to four SLN are identified in surgeries 
where lymphatic mapping is done for gastric cancers (47). 
Hiratsuka et al. performed intraoperative SLN biopsy in gastric cancer patients by admin­
istering intraoperative, peritumoral injections of green dye, followed by gastrectomy, and 
extensive lymphadenectomy (48). In all but 1 of 74 patients, they were able to detect a SLN 
(an average of 2.6 SLN per patient), and the SLN tumor status predicted overall lymph node 
status in 90% of cases. In a different approach, Ichikura et al. performed intra-operative 
lymphatic mappin g in 62 patients via endoscopic dye injection into the gastric submucosa 
adjacent to the tumor ( 49 ). In most cases, green-stained lymph nodes were identified within 
5 min, occasionally localiz ed in the contralat eral side from the primary tumor and even 
outside the perigastric area (49). The unpredictable drainage of some gastric carcinomas 
highlights the complexity of the gastric lymphatics and the importance of functional lym­
phatic mapping in identifying the nodes that truly drain a gastric carcinoma. At present, the 
goal is increase d detection of lymph node meta stases from gastric cancer rather than mini ­
mization of the area of lymph node dissection (47). Lymphatic mapping may assist in the 
staging of gastric cancer by increasing the rate of lymph node detection and by identif ying 
a subset of draining lymph nodes that warrant close pathologic scrutiny rather than a single 
sentinel node. Given the complex lymphatic drainage of the stomach, all dye-colored nodes 
detected may not be "sentinel" nodes by conventional standards. 
10.2. Colorectal Cancer 
Regional nodal metastasis is the most significant risk factor for local and distant 
metastases from colorectal cancer (50). Although 55% of patients with colorectal cancer 
present with node-neg ative locali zed disease, up to 30% develop metastases follo wing colec ­
tomy (50). Special pathologic procedures, such as pinning and stretching of the resected 
bowel and the application of fat dissolving chemicals are undertaken to increase the number

Sentinel Lymph Nodes for Staging Malignancy 295 
of nodes identified in colectomy specimens. SLN analysis of colorectal cancers has been 
controversial, reflecting concerns regarding the possibility of "skip metastases," metastases 
in second or third echelon nodes with apparent sparing of first echelon nodes. However, 
reliance on anatomical considerations, such as physical proximity to tumor, has been proven 
unreliable by lymphoscintographic studies. 
The most common approach to intraoperative SLN mapping for colorectal cancer has 
been to inject isosulfan blue subserosally around the tumor. Saha et a!. report a multicenter 
trial of SLND on 203 patients with colorectal cancer to determine accuracy, upstaging, skip 
metastasis, and aberrant drainage (51). Blue dye was injected subserosally around the tumor 
and one to four blue staining nodes were marked as SLN for detailed histological analysis 
(51). SLN mapping was successful in 98% of patients with an average of 1.7 SLN per patient; 
37% of the patients had positive SLN, 63% were negative, and skip metastases were seen in 
only 8 (4%) of the patients (51). Occult micrometastases not visible on H&E staining, but 
detected by immunohistochemistry, were found in 14% of patients. In 5% of the patients, 
unusual lymphatic drainage resulted in a change in the extent of the lymphadenectomy (51). 
In an alternative approach, Wong et al. performed ex vivo mapping of colorectal carci­
noma in 26 patients following resection of a bowel segment containing a primary tumor 
(52). Within 30 min of removal, the specimens were delivered to pathology, grossly evalu­
ated, and opened longitudinally on the antimesenteric border. Isosulfan blue was injected 
submucosally around the primary tumor. The injection site was massaged for a few minutes, 
and the mesenteric fat dissected to look for blue-stained (sentinel) nodes (52). One to six 
blue -stained nodes were identified as SLN in 24 of 26 specimens, and of 14 specimens with 
negative SLN, one had metastases in other dissected nodes; four patients with negative 
mesenteric nodes on H&E staining were upstaged by cytokeratin immunohistochemistry (52). 
Focused analysis of SLN with multiple serial sections for H&E and immunohisto­
chemistry can detect nodal metastases missed on conventional H&E screening, as well as 
identify SLN in unexpected locations. For example , Wood et al. successfully removed intra­
operatively identified SLN from 97 of 100 consecutive patients undergoing colectomy, and 
the SLN accurately reflected the status of the nodal basin in 92 (95%) of them (53). Unex­
pected lymphatic drainage that altered the operative approach was found in eight patients , 
and 18 patients were upstaged by identification of occult nodal micrometastases missed on 
routine H&E staining but detected on multiple sections or by cytokeratin immunostaining 
(53). The results indicate that increased sensitivity for detecting lymphatic metastases is 
provided by the SLND technique . In another study of 55 patients, the SLN was successfully 
identified intraoperatively in 45 cases (82%) and the SLN status correctly predicted regional 
nodal status in 44 (98%) cases (54). Cytokeratin immunohistochemistry was critical to diag­
nosing tumor deposits in 6 of 14 positive SLN, and there was a 3% false-negative rate because 
of one case that had a negative SLN and a small pericolonic non-SLN replaced by tumor that 
was likely the true SLN (54). 
SLND for colorectal cancer permits selection of high-risk lymph nodes for ancillary stud­
ies such as immunohistochemistry and molecular analysis that would not be feasible on the 
large number of nodes typically obtained from a colectomy specimen . Bilchik et al. injected 
isosulfan blue peritumorally during 100 colectomies, and SLN were identified in 97% of 
cases (55). All mesenteric node s identified were examined by H&E staining; however, mul­

tiple serial sections of SLN were prepared for H&E staining and cytokeratin immunostaining,

296 Roberts and Cochran 
and in some cases RT-PCR analysis was done. Metastases were found in 26% of patients by 
H&E staining and immunohistochemistry and the remaining 74% had occult nodal 
micrometastases detected by immunohistochemistry or RT -PCR analysis (55). In eight cases, 
aberrant lymphatic drainage was discovered that required changes in the operative approach . 
Cytokeratin mRNA was detected in 12 of26 patients (46%) that were negative on H&E and 
cytokeratin immunostaining (55). Focused examination of SLN with the use of immunohis­
tochemistry and RT-PCR analysis identified or raised the possibility of micrometastatic 
colon cancer in a significant number of patients that would have been node-negative on 
conventional lymph node analysis by H&E staining alone. 
10.3. Gynecologic Cancers 
Lymph node metastases constitute the most important prognostic factor in squamous cell 
carcinoma (SCC) of the vulva (56, 57). The standard of care for SCC of the vulva with greater 
than 1 mm invasion has long been bilateral ilioinguinal node dissection, a procedure associ­
ated with high morbidity and frequent recurrences (58). Efforts to limit morbidity have 
included more superficial inguinal resections; however, deep inguinal or femoral node 
metastases have been reported in cases with negative superficial nodes (59). Intraopera­
tive lymphatic mapping has been done with isosulfan blue dye (60), radioisotope (61 ), and a 
combination of both ( 62 ). These attempts have been moderately successful at localizing the 
SLN draining vulvar carcinoma, and preliminary studies have had very low false-negative 
rates for metastases (60). 
Pilot studies of SLND for cervical carcinoma have also yielded preliminary but promising 
results. The lymphatic drainage from the cervix is not always readily predictable, suggesting 
a role for dynamic lymphatic mapping in improving the detection rate of lymph node 
metastases. Medl et a!. performed paracervical injections of isosulfan blue in three patients 
and identified disease-positive SLN either at the iliac artery or in the obturator space; all 
other pelvic lymph nodes removed were negative (63). Verheijen et al. reported localization 
of SLN as far as the common iliac level in 6 of 10 patients with early stage cervical cancer by 
a combined radioisotope and blue dye labeling technique (64). O'Boyle eta!. identified SLN 
in 12 of 20 patients with cervical cancer by the use of isosulfan blue, and reported more 
reliable detection where the tumor was <4 em in greatest dimension (65). 
Burke et al. attempted lymphatic mapping for advanced endometrial cancers by intraop­
erative injection of isosulfan blue dye into the subserosa! myometrium at three distinct sites 
(66). After 10 min, blue lymph nodes were observed in paraaortic, common iliac and pelvic 
sites, underscoring the complexity of uterine lymphatic drainage. Holub et al. have reported 
successful detection (83.3%) of SLN in early stage endometrial cancer based on intraopera­
tive application of blue dye to several points on the uterine serosal surface (67). 
10.4. Genitourinary Cancers 
SLN mapping has been investigated for the staging of prostate cancer. Wawroschek et al. 
localized SLN in 11 cases of prostate cancer via transrectal prostatic injection of techne­
tium-99m colloid 1 d prior to pelvic lymphadenectomy (68) . SLN were identified by 
lymphoscintigraphy and intraoperative use of a Geiger counter. Three of four patients had 
metastases in SLN only, two had positive SLN outside of the standard pelvic lymphadenec­
tomy area, and one had positive non-SLN associated with negative SLN (68). In a larger 
study , Vogt et a!. used 1ymphoscintigraphy and intraoperative probe measurement for the

Sentinel Lymph Nodes for Staging Malignancy 297 
identification of SLN in 117 patients with prostate cancer. SLN were detected in 114 of 117 
cases with an average of four SLN per patient, 25 of 28 patients with lymph node metastases 
had positive SLN, and 15 of these 25 had metastases limited to the SLN (69). 
Cabanas (7) and Fowler (70) used anatomic landmarks to identify SLN draining penile 
cancer; however, several subsequent studies of this anatomy-dependent approach had unac­
ceptable false-negative rates (71, 72 ). Larger series have had more success with intraopera­
tive lymphatic mapping for penile carcinoma. For example, Valdes-Olmos et al. reported a 
sensitivity of 89% and a negative predictive value of 96% for detection of SLN metastases 
by combined lymphoscintigraphy and blue dye technique; bilateral inguinal drainage was 
identified in 81% of cases (73 ). In another study , combined radioisotope and dye was used to 
detect SLN metastases with a reported sensitivity of 80%, although on clinical follow-up the 
false-negative rate was unacceptably high (22%) (74). 
Lymphatic mapping of bladder cancers may be facilitated by the tentatively easy accessi­
bility of the bladder mucosa via cystoscopy. In one study, 13 patients with bladder cancer 
received preoperative, peritumoral injections of radioisotope and dye (via cystoscopy), 
locali zing SLN in 11 of the patients (75 ). Four of the patients had positive SLN and no other 
positive lymph nodes, and three of the positive SLN were located outside the obturator 
fossa (75). 
11. REVERSE TRANSCRIPT ASE-POL YMERASE CHAIN REACTION ANALYSIS 
11.1. Melanoma 
Reverse transcriptase-polymerase chain reaction (RT -PCR) is an extremely sensitive 
method for amplifying small amounts of mRNA that can detect one positive cell in a back­
ground of 106 or 107 negative cells. It is potentially a more sensitive, but less specific tech­
nique than immunohistochemistry for detecting SLN metastases. The RT-PCR technique 
requires sacrifi ce of tissue that will be unavailabl e for histologic analysis. The lower speci ­
ficity is the result of the limited specificity of tumor markers. In the absence of morphologic 
data, it cannot be determined that the mRNA signal derives from malignant cells. 
The application ofthe RT-PCR technique to the analysis of melanoma SLN is the subject 
of much ongoing study. In a recent report, Boi et al. describe the analysis of 88 melanoma 
SLN from 74 patients by RT-PCR to detect tyrosinase mRNA in fresh tissue: 40 were posi­
tive by tyrosin ase RT-PCR, 28 of which were negative by H&E staining and by 
immunostaining for S 100, HMB-45, and tyrosinase (76). The frequency of detection of occult 
metastases by tyrosinase PCR alone was relatively high in this study (31% ), therefore at 
least some of the tyrosine RT-PCR-positive SLN may have contained true meta stase s, but it 
is not clear how to distinguish these from false-positives. 
To estimate the false positive rate for SLN RT-PCR studies, Gutzmer eta!. compared the 
results of tyrosin ase and HMB45 RT-PCR studies on SLN from melanoma patients to con­
trol studies on lymph nodes from nonmelanoma patients (77). All node s were initially ana­
lyzed by preparation of multiple sections for H&E staining and immunostaining for HMB45 
and MARTI (77). Fourteen of 39 melanoma SLN were positive on tyrosinase RT-PCR; only 
8 of the 14 were positive on H&E and/or immun ostaining, and HMB -45 PCR was positive in 
only 3 of the 14, indicating suboptimal sensitivity with this primer (77). Analyses of 29 non­
melanoma lymph nodes yielded four positive on tyrosinase-RT-PCR and negative on all

298 Roberts and Cochran 
other measures, indicating that tyrosinase-PCR may have insufficient specificity for deter­
mining tumor status of the SLN (77). The false positive rate for tyrosinase-RT-PCR may be 
underestimated because two melanoma SLN-containing nevi were excluded from PCR 
analysis, presumably because a positive RT-PCR signal would be difficult to interpret in 
those cases . 
Bostick et al. tested multiple markers (MAGE3 , MARTI, and tyrosinase mRNAs) in 
RT-PCR analysis of SLN from 72 melanoma patients in parallel with H&E staining and 
immunohistochemistry, for melanoma metastases (78). Sixteen of 17 patients with H&E­
and/or IHC-positive SLN expressed two or more mRNA markers by RT-PCR; however, 
20 of 55 patients with histopathologically negative SLN also expressed two or more mRNA 
markers (78). Patients with histopathologically melanoma-free SLN who were RT-PCR­
positive by multiple markers had increased risk of recurrence compared to individuals who 
were positive for one or none of the mRNA markers (78). These results suggest that H&E 
staining and immunohistochemistry alone may fail to detect a subgroup of clinically signifi­
cant melanoma micrometastases positive for multiple melanoma markers on RT -PCR analysis. 
In another study, Bonin et al. investigated multiple RT-PCR targets for melanoma SLN, 
including MAGEl, MAGE3 , melanocyte inhibitory antigen (MIA), and MelanA/MARTl 
mRNAs (79). They used a sensitive RT-PCR method to amplify mRNAs from a central, 
longitudinal cut of archived formalin-fixed, paraffin-embedded SLN specimens, and stained 
additional sections with H&E and antibodies for S 100 and HMB45 proteins (79). From 47 
SLN, 10 were positive on H&E and immunostaining, as well as by tyrosinase RT-PCR, and, 
of the remaining 37, only 2 were negative on H&E and immunostaining but positive on 
tyrosinase RT-PCR (79). A higher proportion of the SLN that were negative on H&E and 
immunohistochemical stains were PCR-positive for MART-1 (76%) and MIA (62%), than 
for MAGEl (38%), MAGE3 (19%) mRNAs, or tyrosinase (5%) , suggesting that the former 
targets might yield a greater number of false-positive results (79 ). In this study, overall results 
showed no correlation between tumor stage and positivity for a particular marker mRNA or 
the number of positive marker mRNAs (79). 
In a larger study, an Italian group performed tyrosinase RT-PCR on 448 SLN from 308 
patients, and the results were positive in 149 (48%) of these cases , in comparison to only 58 
cases (17%) exhibiting SLN metastases revealed histologically (H&E and/or 
immunostaining) (80). The RT-PCR results correlated strongly with tumor thickness of 
primary melanoma and with the clinical stage (80). However, 18 of the 149 RT-PCR-posi­
tive cases had intracapsular aggregates of nevus cells, and are therefore possible false-posi­
tives. Both nodal nevi and schwann cells associated with nodal nerves are potential sources 
of a nonspecific tyrosinase mRNA signal that may yield a false-positive result. Indeed, nodal 
melanocytic nevi have been shown to occur at a higher rate in melanoma patients than in 
patients with breast cancer (81), indicating an increased potential for false-positive results 
from melanoma SLN assessed by tyrosinase PCR. 
Analyses of SLN by RT-PCR are difficult to validate because the RT-PCR technique 
requires wholesale RNA isolation from a piece of tissue and thus precludes morphologic 
assessment of that tissue. This problem can be partially addressed by taking alternate sec­
tions for RT-PCR and immunohistologic analysis, but there may still be no morphologic 
correlate for positive in vitro RT-PCR results, and in situ hybridization techniques are not 
sufficiently sensitive. In situ RT-PCR is an alternative approach that offers simultaneous 
mRNA detection and morphologic detail. The in situ RT-PCR technique for tyrosinase has

Sentinel Lymph Nodes for Staging Malignancy 299 
been successfully applied to melanoma tissue cultures (82). However, in situ RT-PCR for 
melanoma markers on formalin-fixed, paraffin-embedded SLN specimens have yielded 
lower, (and less consistent) signals ( 83 ). 
11.2. Breast Cancer 
RT-PCR has been applied to the analysis of axillary SLN draining breast cancers with 
mixed results. Several previous studies report a higher incidence of positive SLN detected 
by RT-PCR for cytokeratin or other markers, as compared to routine histologic and/or 
immunohistochemical analyses (84-86). However, several of these studies have shown poor 
concordance between positive immunostaining results and RT -PCR, in part because of false­
negative RT-PCR results (84,86). The use of multiple markers may eliminate some of these 
false-negative RT-PCR results. Indeed, one study demonstrated a significantly higher sensi­
tivity for detection of metastases in RT-PCR studies that targeted multiple breast tumor 
markers (95.6%) than in individual studies with any single marker (78.8-83.6%) (85). The 
expression of at least two of three markers (maspin, cytokeratin 19, or mammaglobin I) 
resulted in the highest concordance with positivity on H&E stains or cytokeratin-19 
immunostains (85). 
12. CLINICAL SIGNIFICANCE OF LYMPH NODE MICROMETAST ASES 
With the advent of sensitive screening techniques, including SLND and molecular analy­
ses, for detecting lymph node metastases, a need for clinical data establishing the prognostic 
relevance of small tumor deposits or micrometastases has been recognized The RT-PCR 
technique offers an increased sensitivity for detecting SLN metastases, which successfully 
distinguishes true metastases from false positives. The appropriate therapy for patients with 
SLN that are PCR-positive only has not been clearly established. In order to understand the 
prognostic implications of micrometastases, accurate information regarding size and num­
bers of micrometastases must be combined with long-term clinical follow-up data. 
12.1. Melanoma 
The recent American Joint Committee on Cancer (AJCC) Cancer Staging Manual (6th 
ed.) defines nodal micrometastases as those detectable only by microscopy and not clini­
cally or radiographically, i.e., occult metastases (87,88). According to the AJCC guidelines, 
metastatic tumor to a local node constitutes stage III. Subclassifications within this category 
are largely based on the number of positive nodes and whether they are clinically detected. 
Some classification schemes for melanoma have taken into account the percent of the node 
cross-section involved by tumor (Cochran et al., unpublished data), whereas others are based 
on the micrometer diameter of nodal metastases, which has been linked to prognosis in some 
studies ( 37). In contrast to prior editions, size of individual melanoma metastases is not a 
consideration in the new AJCC staging guidelines for melanoma; although, the AJCC rec­
ommends that extent of tumor involvement in SLN be measured and recorded in the pathol­
ogy report (88). 
Currently, there is ongoing investigation into the clinical significance of patients with 
occult micrometastatic melanoma in locoregional nodes, sentinel and non-sentinel, detected 
by serial H&E stained sections, immunohistochemistry and/or RT-PCR. The available evi­
dence indicates that these techniques identify occult (clinically and radiographically unap­
parent) nodal metastases with increased frequency over conventional screening. Although

300 Roberts and Cochran 
the impact of these occult melanoma metastases on disease progression is still under 
investigation, their presence has been linked to other negative prognostic factors, and some 
investigators have found evidence that micrometastases detected by RT-PCR may be clini­
cally relevant. 
Gershenwald et al., of the MD Anderson Cancer Center (University of Texas), have 
observed that 8 of 10 archived SLN-negative melanoma cases with later nodal recurrences 
had micrometastases that were retrospectively identified by additional serial sectioning or 
immunohistochemistry (89). Similarly, Blaheta et al. have reported nodal recurrences in 6 of 
20 patients who were positive by tyrosinase RT-PCR (but negative on serial H&E sections 
and immunohistochemistry for HMB-45 or SlOO) during a median follow-up of34 mo (90). 
Blaheta et al. have also reported significantly higher tumor thickness in melanoma patients 
with nodal micrometastases identified exclusively by RT-PCR as compared to patients with 
negative results by RT-PCR (91). 
In an ongoing investigation with a large series of melanoma patients, Li et al. found that 
H&E staining combined with S 100 immunostaining-detected metastatic disease in 52 of 233 
(22%) of patients tested; whereas, 114 of 181 (63%) of patients with immunohistologically 
negative nodes had positive tyrosinase RT-PCR results (82). Importantly, PCR-positive and 
PCR-negative patient groups differed significantly in Breslow thickness, Clark level , and 
the presence of ulceration of the primary tumor; all of which are factors that have been 
shown to correlate with recurrence and survival (82). Hochberg et al. report that tyrosinase 
and MIA expression were sensitive indicators of melanoma SLN micrometastases that were 
negative on routine histopathologic examination and that positive MART-I PCR in SLN 
was negatively correlated with overall survival (92). 
The above results imply that micrometastases identified by PCR alone could have clinical 
relevance, but long-term follow-up is necessary to establish real differences in recurrence 
and overall survival. The ongoing national, multicenter Sunbelt Melanoma Trial is investi­
gating the utility of lymph node dissection and interferon therapy for patients who have SLN 
metastases detected only by PCR (93 ). 
12.2. Breast Cancer 
In the case of breast cancer nodal micrometastases, data indicate a lack of clinical signifi­
cance for tumor deposits under 2 mm (94). However, the prognostic significance of small 
tumor deposits in lymph nodes remains controversial. Some authors have suggested that 
tumor cell colonies of any size are clinically significant, whereas single cell tumor metastases 
are not (95). The tumor -node-metastasis (TNM) staging guidelines from the Union Interna­
tional Contra Ia Cancrum (UICC) define "isolated tumor cells " as single tumor cells or cell 
clusters under 0.2 mm in size (96). The 2002 AJCC guidelines have also adopted the "0.2 mm 
or less" size cutoff for "isolated tumor cells" and classifies them as pNO(itc) (97). Breast 
tumor metastases that measure between 0.2 mm and 2.0 mm are considered "micro­
metastases" and are classified as pN1 (mcm) (97). The AJCC recommends that the prognos­
tic relevan ce of isolated tumor cells become validated befor e adjuvant therapy is given to 
patients classified as pNO (itc) with otherwise good prognostic factors (97). 
The measurement of the micrometer diameter of nodal metastases has prognostic signifi­
cance ( 37) but may be confounded by variety in lymph node size and nodal enlargement 
resulting from factors other than tumor (98). The College of American Pathologists has 
taken the position that the prognostic and predicti ve value of micrometastases identified

Sentinel Lymph Nodes for Staging Malignancy 301 
using immunohistochemistry in SLN is still unproven; they do not recommend basing thera­
peutic decisions for breast cancer on such findings until their clinical significance has been 
demonstrated (99). 
Immunohistochemical analysis is critical for detecting occult micrometastases. The 
median size of micrometastases detected on cytokeratin immunohistochemistry is approx 
0.1 mm, compared to 1.0 mm for H&E staining (45). Based on an analysis of 120 patients 
(from a series of 1680 primary operable breast cancers) who had metastatic breast cancer to 
a single node, de Mascarel et al. determined that nodal metastases detected on serial H&E 
sectioning predict both recurrence and survival; whereas, immunohistochemically detected 
micrometastases predicted only recurrence for infiltrating ductal carcinomas and had no 
prognostic significance for infiltrating lobular carcinomas ( 100). However, a recent review 
of the literature by Dowlatshahi et al. identified survival differences in breast cancer patients 
with micrometastases in studies involving relatively large patient populations (ranging from 
147 to 921) and a follow-up of at least 6 yr (95 ). The literature review suggested that occult 
metastases detected by immunohistochemistry do have important prognostic implications, 
although they noted differences between authors in size parameters defining micrometas­
tases , indicating a need to follow standard criteria (95 ). 
The prognostic significance of SLN micrometastases may depend upon factors other than 
their size, such as the extent of down-regulation of the immune system by the primary tumor. 
Sentinel nodes in particular may exhibit features of immune suppression, such as reduction 
in dendritic cell number and arborization. For example , Cochran et al. have demonstrated 
significant reductions in total paracortical area of melanoma draining SLN, and in the den­
sity of paracortical interdigitating dendritic cells, of which almost all lacked the complex 
dendrites associated with active antigen presentation (42,43). These morphologic changes 
may reflect the action of tumor generated immunosuppressive factors released by the pri­
mary melanoma and may act against immune surveillance, facilitating expansion of the pri­
mary tumor and the establishment of early metastases. 
13. CONCLUSION 
The past 10 yr have seen the technique of sentinel lymph node analysis validated as a low 
morbidity alternative to regional node dissection for staging in cases of melanoma and breast 
cancer. The SLND technique has worked well for detecting early melanoma metastases in 
clinically node-negative patients, particularly those with tumors of intermediate thickness. 
Likewise, in breast cancer studies of axillary SLN biopsies show excellent correlation with 
the status of the remaining axillary node bed. Two factors have contributed to the success of 
the SLND technique; the ability to identify the primary tumor-draining node(s) (SLN) using 
dynamic lymphoscintigraphy and radio-guided surgery and intensive, focused pathologic 
examination of SLN by multiple levels and immunohistochemistry. In particular, immuno­
histochemical markers permit detection of nodal metastases easily missed on routine H&E 
slides, thereby increasing the sensitivity for detection of micrometastatic disease. 
The development of sensitive ancillary techniques for tumor detection, such as RT-PCR, 
has given us the capacity to detect smaller and smaller metastatic deposits in SLN. The use 
of molecular techniques in SLN analysis is still investigative, and the establishment of pro­
tocols with adequate sensitivity and specificity for the detection of tumor metastases is chal­
lenging. It is, however, likely that these techniques will become an important part of the 
assessment of SLN in the near future. At present, immunohistochemical stains provide the

302 Roberts and Cochran 
advantage of a morphologic reference to weed out false positives, whereas RT-PCR does 
not. The use of in situ PCR has theoretic potential; however, the procedure is technically 
demanding and may not be commercially viable in its present form . 
The clinical significance of single tumor deposits less than 0.2 em in SLN is undeter­
mined, and some authors distinguish between "single tumor cells " or clusters less than 
0.02 em and "micrometastases" considered as those clusters between 0.02 em and 0.2 em. 
Basic tumor biology, however, suggests that the presence of any tumor cells in a tissue is a 
significant finding and that the biological significance of the finding increases as tumor size 
and organization increase . Once a tumor deposit is recognized, it necessitates a clinical deci­
sion, therefore distinctions between metastases that are clinicall y significant and those that 
are too small to warrant additional treatment must be based on data from clinical trials. 
Ultimately, the surgeon has to decide whether a completion node dissection is necessary, 
and the oncologist has to decide whether adjuvant chemotherapy and/or radiation therapy 
are indicated. Before the clinical data are in, one possible approach may be to incorporate 
characteristics of the primary tumor that are known to affect prognosis, such as tumor size, 
depth of invasion, and/or ulceration, into treatment decisions for cancer patients with SLN 
that contain very small tumor deposits or are positive by PCR alone . 
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15 
A Marker for Early Diagnosis of Lung Cancer 
The Heterogeneous Nuclear Ribonucleoprotein A2/Bl (hnRNP A2/Bl) 
Jordi Tauler, Alfredo Martinez, and James L. Mulshine 
Lung cancer is the most important leading cause of cancer death. In the United States 
alone, 169,000 new cases were identified in 2002 ( 1) and lung cancer is responsible for more 
than 1 million deaths worldwide (2). Lung cancer has a lower incidence than other types of 
cancer (breast, colon, prostate, and cervical) but is more lethal. Throughout most of the 
world, 5-yr survival is less than 10%. Even with smoking cessation, the risk of lung cancer 
remains elevated because the injury in the airway tissue cannot be reversed (3). One of the 
reasons for such high mortality is the late detection of lung cancer , which in most cases 
occurs after metastatic dissemination. In those cases, the benefits of chemotherapy are mod­
est. The classical diagnostic imaging technology, chest X-ray, is not sensitive enough to 
provide a reliable early diagnosis oflung cancer. One approach to improve early detection is 
looking for specific molecular markers that may be tools for a better understanding of the 
initial steps of carcinogenesis. 
1.1. The Link Between Cancer and hnRNP A2/B1 
To find specific markers, we developed a panel of monoclonal antibodies against whole­
cell lysates of a nonsmall-cell lung carcinoma (NSCLC) cell line. These antibodies were 
used to screen a sputum specimen archive collected at the Johns Hopkins University. The 
archive contains sputum samples from a high-risk cohort, obtained on a yearly basis. Fol­
low-up was established in order to determine the development of lung cancer for up to 8 yr. 
The screening, by immunocytochemical analysis, was focused on the bronchial epithelial 
exfoliated cells recovered in sputum samples. One of the mouse monoclonal antibodies, 
703D4, was able to predict with a 90% accuracy (20 of 22 detected true positive cases) those 
individuals who would progress to invasive tumors within 2 yr ( 4 ). The antigen recognized 
by 703D4 antibody was characterized by a combination of high-performance liquid chroma­
tography (HPLC) and immunoprecipitation techniques. A single 31 kDa protein was obtained 
and identified as heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B 1 ( 5 ). 
Additional independent clinical trials have been performed with 703D4. In 1997, two 
prospective studies were conducted: a multicenter collaboration by the Lung Cancer Early 
Detection Working Group (LCEDWG) in stage I resected , disease-free patients, and a Chi­
nese industrial mining population, Yunnan Tin Corp. These two studies predicted patient 
outcome with an accuracy of 67 and 69%, respectivley, in the first year of follow-up (6). 
From : Ca11c er Diagno stics: Current and Future Trend s 
Edited by: R. M. Nak amura , W. W. Grody, ]. T. Wu, and R. B. Nagl e© Hum ana Press Inc., Totowa , N] 
307

308 Tauler, Martinez, and Mulshine 
Analyzing bronchial lavages from patients with metaplastic bronchial epithelial cells or 
tumor cells, it has been shown that 95% of the specimens had overexpression of hnRNP 
A2/B 1. Moreover, in 80 specimens reported as morphologically normal, 41 revealed hnRNP 
A2/B 1 overexpression. In 33 of those cases, a lung cancer was found within 1 yr (7). In the 
five clinical trials reported, after analyzing from high risk cohorts , totaling about 800 indi­
viduals, the overall sensitivity and specificity were both around 80%. 
A previously reported randomized chemoprevention trial using retinoid acid, utilized 
archival bronchial biopsy specimens from chronic smokers and were analyzed with 70304. 
In both normal and abnormal bronchial epithelium, hnRNP A2/B 1 overexpression was 
reported in 40% of the samples. No significant correlation between retinoid treatment and 
hnRNP A2/B 1 overexpression was found but a frequent overexpression of hnRNP A2/B 1 in 
central airways of chronic smokers was reported. This pattern of expression was comparable 
to a previous study showing overexpression of hnRNP A2/B 1 in the morphologically nor­
mal airways surrounding a primary lung cancer (8,9). The results from the prospective stud­
ies suggest a strong association between overexpression of hnRNP A2/B 1 and the 
development of lung cancer. This association has been confirmed with studies of bronchial 
lavages showing that hnRNP A2/B 1 overexpression is a common feature in established lung 
tumors (7). 
The study of the correlation between hnRNP A2/B I overexpression and molecular alter­
ations has demonstrated that morphologically normal cells with hnRNP A2/B 1 
overexpression show the same pattern of genetic alterations in microsatellite alterations 
(MA) and loss of heterozygosity (LOH) than similarly positive dysplastic or metaplastic 
cells. This observation suggests that these cells could be clonally derived and that hnRNP 
A2/B 1 status is more informative than morphological criteria alone. Moreover , subcellular 
localization of hnRNP A2/B 1 overexpression is also informative; cells with cytoplasmic 
hnRNP A2/B 1 overexpression appear to present a higher number of genetic alterations . The 
subcellular localization varied in different cell clusters of the same case as shown in Fig. 1 
( 10). Another study reported similar results, looking for the association between neoplastic 
clonal expansion in NSCLC and overexpression of hnRNP A2/B 1. The conclusion was that 
lung cancer cells undergoing clonal expansion frequently upregulate hnRNP A2/B 1 ( 11 ). 
These phenotypically normal cells with upregulation of hnRNP A2/B 1 could be interpreted 
as precursors of a future tumor. This result is important because it shows the potential origin 
of the clonal expansion and could be detected early by monitoring hnRNP A2/B 1 
overexpression. 
During mammalian lung development, hnRNP A2/B 1 expression is found in the earliest 
lung buds. As lung development progresses, the pattern of expression changes with detected 
expression now noted in cuboidal epithelial cells of the distal primitive alveoli. At this stage 
in lung development, hnRNP A2/B 1 expression in the proximal conducting airways 
decreases and disappears completely in the adult organ. Overexpression of hnRNP A2/B 1 at 
critical periods of lung development was comparable to the expression levels found in lung 
cancers and preneoplastic lesions . Thus , these data were consistent with the hypothesis that 
hnRNP A2/B 1 is an oncodevelopmental protein ( 12 ). 
The expression of hnRNP A2/B 1 was also analyzed in breast cancer by immunohis­
tochemistry. Overexpression was detected in 56.5% of primary invasive breast cancers, 
whereas it was only expressed in 9. 7% specimens of normal breast tissue. By Northern analy-

A Marker for Early Diagnosis of Lung Cancer 309 
Fig. 1. Cross-section of a small bronchiole in human lung stained for hnRNP A2/B I. Normal­
appearing bronchial epithelial cells (short arrows) are devoid of hnRNP A2/B I expression, whereas 
the hyperplastic cells (long arrows) show cytoplasmic hnRNP A2/B 1 immunoreactivity. Some of the 
cells located between the normal and hyperplastic cells display nuclear localization of hnRNP A2/B 1 
(arrowheads). Reproduced with permission from ref. 10. Color figure available for viewing at 
sis, a higher level of hnRNP A2/B 1 was found on breast cancer cells compared to normal 
cells. Interestingly, exposure of breast cancer cells to retinoids may reduce hnRNP A2/B 1 
expression, and regulate the translocation of hnRNP A2/B I from the nucleus to the cyto­
plasm as shown in Fig. 2 ( 13 ). This retinoid-related translocation of hnRNP A2/B 1 could be 
significant given the strong correlation between subcellular localization and malignity as 
previously described by Man et al. ( 10). Overexpression ofhnRNP A2/Bl has been detected 
in pancreatic tissue from smokers and in pancreatic tumor cells ( 14 ). Moreover, comparing 
the gene-expression profiles between adenocarcinoma metastas es of multiple tumor types 
and unmatched primary adenocarcinomas, eight genes were up-regulated in metastasis. Four 
of the genes were components of the translation machinery and hnRNP A/B was included in 
this group ( 15 }, establishing yet another link between this protein family and cancer progres­
sion. 
There is strong evidence supporting hnRNP A2/B 1 overexpression as an early marker for 
lung cancer, and with less data for cancers of other organs such as breast and pancreas. 
Despite these promising results, the molecular mechanism linking this overexpression and 
cancer remains largely unknown. 
2. hnRNPS: TRANSMITTING THE INFORMATION 
There has been an explosion of information in biological literature recently regarding the 
role of hnRNP A2/B 1 and related family members in a host of functions from splice regula­
tion, transcriptional regulation to shuttlin g dynamics. Much of this work has been performed 
in other nonneoplastic disease conditions. To understand the potential link between hnRNP 
and tumor biology , we will review hnRNP biology .

310 Tauler, Martinez, and Mulshine 
Fig. 2. Confocal microscopy of breast cancer cell line MDA-MB-231 stained for hnRNP A2/B 1 
(green, A,D,G) and counterstained with DAPI (blue B,E,H). Untreated cells (A-C) show inten se 
nuclear expression. After 24 h of retinoid ( 13cRA) exposure (D-F), hnRNP A2/B 1 has been translo­
cated from the nucleus to the cytoplasm. Treatment with HPR resulted in a partial translocation of 
hnRNP A2/B 1 expression (G-1). Reproduced with permission from ref. 13. Color figure available 
for viewing at www.humanapress.com. 
2.1. The World of hnRNP Proteins 
Over the past few years, it has become evident that properly translating an mRNA into 
a specific protein requires more information than the coding sequence alone. This informa ­
tion should cover other aspects, such as nuclear export, subcellular localization, translation 
and stability, and could be provided through specific RNA-binding proteins. 
The hnRNPs were initially described as an important group of chromatin -associated RNA­
binding proteins, but they play a major role in the interpretation and transmission of this 
information as well. The hnRNPs are a complex group of proteins with 20 major proteins

A Marker for Early Diagnosis of Lung Cancer 311 
Table 1 
Structure and Possible Functions of hnRNP Proteins 
hnRNP Domain 
proteins kDa structure Possible functions References 
mRNA splicing, (47,66-68) 
Al 34 2xRBD, RGG mRNA export, (69) 
Telomere biogenesis (70) 
mRNA splicing, (50,56,60) 
A2/Bl 36/38 2xRBD , RGG mRNA localization, (37,39) 
mRNA stability (33) 
Telomere biogenesis (42,43) 
Cl/C2 41143 lxRBD mRNA splicing, (16) 
mRNA stability (71) 
Telomere biogenesis , (72) 
D (AUF -I) 44-48 2xRBD, RGG mRNA stability (73) 
Recombination (74) 
El/E2 38-39 3xKH mRNA stability, (75) 
Translational control (71,76) 
F 53 3xRBD mRNA splicing (76) 
H/H'(DSEF -1) 56 3xRBD mRNA splicing, (77,78) 
Polyadenylation (79) 
mRNA splicing, (80, 81) 
I (PTB) 59 4xRBD Polyadenylation (82) 
mRNA localization , (83) 
K 62 3xKH, RGG Transcription , (84,85) 
Translational regulation (86-88) 
L 68 4xRBD mRNA export, (89) 
mRNA stability (90) 
Q 55-70 3xRBD, RGG mRNA splicing (91) 
u 120 RGG Nuclear retention (16) 
Abbr: RBD , RNA -bindin g domain ; RGG ; arginine-glycin e-glycine-rich domain 
identified and many of them having several isoforms. In addition , some less abundant pro­
teins have also been classified as hnRNPs. The more abundant hnRNP proteins and their 
functions are summarized in Table I. 
The hnRNP proteins play a role in a wide range of functions such as mRNA splicing, 
mRNA export, mRNA subcellular localization, telomere biogenesis, mRNA stability, trans­
lational control, transcription, polyadenylation, and nuclear retention. Most hnRNP proteins 
contain one or more RNA -binding motifs and have RNA-binding specificity, but can also 
recognize DNA.

312 Tauler, Martinez, and Mulshine 
Many of the most abundant hnRNP proteins are localized in the nucleus but they shuttle 
between the nucleus and the cytoplasm. There is no evidence for an established and defined 
composition of the hnRNPs associated with pre-mRNAs. Most likely, there is a unique 
combination of hnRNPs for each pre-mRNA. This unique combination is not stable during 
the RNA maturation process and changes through the export of the pre-mRNA from the 
nucleus to the cytoplasm. HnRNP proteins are part of the pathway of gene expression, 
involved with transcription complex formation through the final mature mRNA found in the 
cytoplasm (16,I7). 
2.2. Structure and Function of hnRNP A2/B1 
The hnRNP A2/B 1 protein is the most abundant major hnRNP protein that binds to pre­
mRNA and is involved in biogenesis of mRNA. HnRNP A2/B 1 is a member of the hnRNP 
AlB family which has three different genes: AI, A2/BI, and A3 (18,I9). A common origin 
for the AI and A2 genes by duplication from an ancestral gene that could also be shared for 
A3 has been suggested. The hnRNP A2/BI gene is divided in 12 exons and 11 introns. 
HnRNP A2 is the more abundant isoform and results from an alternative splicing that elimi­
nates ex on 2; hnRNP B 1 contains the 12 exons but it accounts only for 2-5% of total A2/B 1 
transcripts (20 ). An additional isoform, less abundant than B 1 and known as BOis generated 
by the elimination of exon 9. The hnRNP A2/B 1 protein has a molecular mass of 31 kDa. 
The three genes (AI, A2/BI, andAJ) are alternatively spliced and generate different isoforms 
that share a common modular structure with a highly conserved N-terminal domain, and a 
more divergent , glycine-rich C-terminal domain, also known as arginine-glycine-glycine 
(RGG) domain. TheN-terminal domain has two RNA-binding domains (RBD), arranged in 
tandem, also named RNA recognition motif (RRM) . This modular structure has been referred 
to as 2xRBD-Gly (Fig. 3). 
The RBD domains are responsible for RNA-binding interactions but some cooperation of 
the RGG domain has also been reported (21). The RGG domain has other important func­
tions such as protein-protein interactions and the ability to promote RNA annealing. Methy­
lated residues are found only in the RGG domain. Inhibition of the methylation of these 
residues results in a shift from nuclear to cytoplasmatic localization, as shown by 
immunoblotting and immunocytochemistry (22). A 29 amino acid sequence, called M9, in 
the RGG domain mediates rapid shuttling between nucleus and cytoplasm. This particular 
sequence acts both as nuclear localization determinant and as nuclear export sequence (23 ). 
It is likely that promoters of hnRNP A l and hnRNP A2/B 1 are coregulated to ensure the 
observed coordinate expression of these products in different cell types and tissues (24). We 
will describe the most relevant functions reported for hnRNP A2/B 1 and focus on the rela­
tionships of these functions and potential links with growth regulation and carcinogenesis. 
The nature of the regulation of hnRNP A2/B 1 is poorly understood. The hnRNP A I has a 
short 5'UTR that starts with a pyrimidine tract similar to the one found in mRNAs encoded 
by terminal oligo-pyrimidine (TOP) genes. These genes code for ribosomal proteins and 
other proteins related in the production and function of translational machinery . Analyzing 
the structural features of this pyrimidine tract and the translation behavior of hnRNP A I, this 
hnRNP could be included in the class of TOP genes, suggesting a role for hnRNP AI. This 
motif may also apply to hnRNP I but it does not appear relevant to hnRNP A2/B 1 and hnRNP 
Cl/C2. Despite the important similarities between hnRNP Al and hnRNP A2/Bl, it seems 
that there are important differences to their translational regulation (25). A recent study

A Marker for Early Diagnosis of Lung Cancer 313 
R60 1 RBD 2 RGG 
hnRNP A2/Bl mRNA 
hnRNP A2 (341 u) I 
hnRNP B 1 (353 u) 
hnRNP BOb (313 u) 
hnRNP BOa (301 u) 
Fig. 3. The coding sequence of hnRNP A2/B 1 is divided into 12 exons . A very short first exon, 2 
aa. is present in all isoforms. Exon 2, a 12 aa mini-exon, is spliced in the most abundant isofor m, 
hnRNP A2, and also in the rare isoform, hnRNP BOa. Exon 9 is spliced in isoforms hnRNP BOa and 
hnRNP BOb. RNA-binding domains (RBD) expand from exon 3 to exon 6: RBDl in exon 3 and 4; 
RBD2 in exon 5 and part of exon 6. Arginine-glycine-glycine (RGG) domain, expand along the 
N-terminal domain, from exon 6 to exon 12. hnRNP A2 is the most abundant isoform 
(80-98% ), however, the relative expression of the different isoforms vary with age and tissue types 
(92-94). Color image available for viewing at www.humanapress.com. 
reported that Sam68, a nuclear RNA-binding protein, binds a specific nucleotide motif, 
UAAA, in hnRNP A2/B 1 suggesting a possible role of Sam68 in the posttranscriptional 
regulation of these genes (26). Sam68 is a substrate for Src-family tyrosine kinas es during 
mitosis and is a member of the signal transduction and activation of RNA metabolism 
(STAR) family. This family comprises mediator proteins connecting RNA metabolism with 
signal transduction pathways (27-29). 
A previous result suggested that nuclear DEAF-1-related (NUDR), a nuclear Drosophila 
Deformed epidermal autoregulatory factor (DEAF-I) -related protein, may regulate the 
expression in vivo of hnRNP A2/B 1, acting as a transcriptional repressor. Thus, the down 
regulation of NUDR could explain the overexpression of hnRNP A2/B 1 in some cancers 
( 30 ). However, other studies showed a down-regulation of hnRNP A2/B 1 in human lung and 
breast carcinoma cells under hypoxic conditions as shown in Fig. 4. This down-regulation of 
hnRNP A2/B 1 is not mediated by the transcription factor hypoxia inducible factor 1, HIF- 1 
(31 ). Moreov er, in brain tumors, the binding of hnRNP A2/Bl with the 3'UTR of glucose 
transporter 1 (Glut 1) mRNA in a region called AU-rich response element (AURE) has been 
demonstrated. That interaction of hnRNP A2/B I, which also forms a complex with hnRNP 
Lin vivo, with the AURE of Glut 1 mRNA is critical for the regulation of Glut I expression. 
Hypoxia and hypoglycemia decrease polysomallevels of hnRNP A2 and hnRNP L resulting 
in an increase of Glut 1 mRNA stability ( 32,33 ). Nevertheless, some recent data suggest that

314 Tauler, Martinez, and Mulshine 
«l ·x Hypoxia 0 § ~ ~ ~ 
0 C\J ..q- a:> z C\J ..q-«l 
X Hypoxia 0 
E ~ ~ ~ .... 
0 C\J ..q- a:> z C\J ..q-
hnRNP A2/B1 -
AM-
288 rRNA-
H157 MCF7 
Fig. 4. Down-regulation of hnRNP A2/B 1 under hypoxic conditions in H 157 (lung cancer cell 
line) and MCF 7 (breast cancer cell line). hnRNP A2/B l expression levels were maintained after 
24 h but an important decrease was revealed after 48 h of treatment. Northern blots were probed with 
hnRNP A2/B 1 and, subsequently , with adrenomedullin, a previously reported hypoxia-inducible 
gene. Adrenomedullin levels were elevated in both cell lines after 24 h. Ethidium bromide staining of 
28S RNA was used to assess for equal loading and RNA integrity (95). Reproduced with permission 
from ref. 31. 
p VHL, a tumor-supressor gene, down-regulates hnRNP A2/B 1 expression in renal clear cell 
carcinomas, through a mechanism involving ubiquitination and targeting to proteasome deg­
radation ( 34 ). p VHL regulates protein turnover of HIF-1, a transcription factor for hypoxia­
inducible genes. The absence of pVHL in renal clear cells is associated with a hypoxic 
phenotype with cells expressing increased levels of vascular endothelial growth factor 
(VEGF) and Glut 1 ( 35,36). This suggests increased levels of both Glut 1 and hnRNP A2/B 1 
in renal clear cells, associated with reduced levels of the tumor suppressor gene, p VHL. In 
contrast, in brain tumors, the relation between Glut 1 and hnRNP A2/B 1 is inversely related 
under hypoxic conditions. The reports of Garayoa et al. and Hamilton et al. suggest the down 
regulation of hnRNP A2/B 1 under hypoxia conditions, in lung, breast, and brain tumors. 
Because hypoxia is an inherent condition in solid tumors it seems likely that hnRNP A2/B 1 
downregulation could play an important role in the survival of these tumors, mainly by 
allowing expression of tumor-survival genes. If this hypothesis proves true, we could envi­
sion hnRNP A2/B 1 as a tumor-suppressor gene product. The up-regulation observed in 
tumors may reflect an adaptive response from the cell attempting to counteract the carcino­
genesis process . 
Another function of hnRNP A2/B 1 is the regulation of cytopla smatic mRNA transport. A 
21 nucleotide segment called hnRNP A2 response element (A2RE) has been defined in the 
myelin basic protein mRNA. This sequence, recognized by hnRNP A2/B 1, is necessary and 
sufficient for cytoplasmatic transport of the mRNA of this protein. Mutations in the A2RE 
abolish binding of hnRNP A2/B 1 and block the transport of myelin basic protein mRNA to 
the cytoplasm ( 37). The A2RE can interact with either of the two RRM domains of hnRNP 
A2/B 1 acting in cis. This A2RE might be present in a variety of different mRNA s trans­
ported by hnRNP A2/B 1 ( 38 ). However, the distribution of the cytoplasmatic pool of hnRNP

A Marker for Early Diagnosis of Lung Cancer 315 
A2 is microtubule dependent. The M9 domain drives the translocation to the nucleus, but in 
the absence of M9 domain and in the presence of intact microtubules, proteins containing the 
second of the RRMs were concentrated in the distal processes of oligodendrocytes ( 39 ). 
There is strong evidence supporting the shifting of hnRNP A2/B 1 from nucleus to cyto­
plasm, suggesting the involvement of hnRNP A2/B 1 in mRNA transport. Recently, it has 
been suggested that hnRNP A2/B 1 interaction with actin may be central to the mechanism 
for transferring pre-mRNA from the nucleus to the cytoplasm (40). 
hnRNP A2/B 1 also binds single stranded telomeric repeats (TT AGGG )n found at the end 
of the chromosome. This interaction protects the telomeres from nuclease degradation and 
sustains telomerase activity (41). The hnRNP Bland hnRNP BOb bind telomeric repeats in 
a tandem fashion with more affinity, in vitro, than hnRNP A2 (42). A model has been pro­
posed in which telomerase binding to hnRNPs would promote telomere access (43). If 
hnRNP A2/B 1 is playing an important role in the regulation of the changes in telomere 
length its expression might alter the balance of telomere length regulation. Given the impor­
tance of telomere length regulation in controlling cell division ( 44,45 ), changes in the ex pres­
sion of hnRNP A2/B 1 might also influence cell life span or even immortality of cancer cells. 
Alternative splicing of pre-mRNAs from a single gene is predicted to occur in the major­
ity of human genes (46). Like other hnRNP proteins, hnRNP A2/B 1 is involved in regulation 
of alternative splicing and in mRNA transport. A seminal study demonstrating how hnRNP 
A2/B 1 could regulate 5' splice-site selection was one of the early observations suggesting 
the importance of this class of molecules (20). Increased levels of serine/arginine-rich 
proteins (SR proteins) results in the selection ofintron-proximal5' sites when a pre-mRNA 
contains two or more 5' alternative splicing sites, but increased levels of hnRNP A2/B 1 
promotes the selection of intron-distal 5' sites. hnRNP Al binds pre-mRNA more strongly 
than hnRNP A2/B 1. In contrast, hnRNP A2/B 1 has an order of magnitude stronger 
splice-site switching activity than hnRNP A 1, but this regulation is not specific of target 
sequence (47,48). 
Although there are a significant number of papers showing the important role of hnRNP 
A 1 in alternative splicing, this function had not been extensively studied for hnRNP A2/B 1. 
However, recent reports have changed this situation. First, hnRNP A2/B 1 may control alter­
native splicing of hnRNP AI mRNA. Different intronic regions, or control elements, flank­
ing the alternative exon 7b have been implicated in production of the A1 and AlB mRNA 
splice isoforms. These regions are; CEla and CEld, which are down stream of exon 7 and 
CE4m and CE4p located downstream of ex on 7b respectively . Differ ent hnRNP AlB bind­
ing sites are present in these regions. Some of them match the consensus for hnRNP Al, 
UAGRR(A/U), which is similar to the sequence of the telomere repeats (TT AGGG) recog­
nized by hnRNP A2/B 1 as previously described. These control elements promoting alterna­
tive splicing in the hnRNP A1 pre-mRNA are organized in groups adjacent to AlB binding 
sites. CEla and CE4 may be bound by hnRNP A1 to promote skipping of exon 7b in vivo 
and distal 5' splice site selection in vitro (47,49). However, the distal 5' splice selection is 
conserved in an extract prepared from mouse cells that are severely deficient in hnRNP A1 
proteins. It has been shown that hnRNP A2 compensates the hnRNP Al deficiency and 
controls, the alternative splicing ofhnRNP Al (50). hnRNP A1 also plays an important role 
in alternative splicing of several proteins such as CD44 (51). If hnRNP A2/B 1 potentially 
regulates alternative splicing of hnRNP Al, hnRNP A2/B 1 may indirectly and potentially

regulates alternative splicing of hnRNP Al, hnRNP A2/B 1 may indirectly and potentially 
influence the alternative splicing of CD44. Becaus e splice variants of CD44 have been

316 Tauler, Martinez, and Mulshine 
implicated in tumorigenesis and tumor progression (52,53), a link between hnRNP A2/Bl 
and regulation of tumor progression could be established by this pathway. 
Second, the alternative splicing of protein 4.1 R in ex on 16 (El6) is required during eryth­
ropoiesis for the establishment of proper mechanical integrity of the erythrocyte membrane 
(54,55). A highly conserved 42-nucleotide exonic element (CE 16) has been characterized in 
exon E16. This element interacts with hnRNP NB proteins and regulates the alternative 
splicing of exon E16. Binding of hnRNP A/B to CE 16 skips E16 in early erthyroid progeni­
tors. If hnRNP NB proteins are depleted from nuclear extracts, E16 inclusion increases 
significantly, whereas repletion with recombinant hnRNP A/B restores E16 silencing. More­
over, downregulation of hnRNP A/B expression temporally correlates with the inclusion of 
E16 during erythropoiesis, suggesting that it could be the functional switch for E16 expres­
sion (56). A similar mechanism has been reported in the human immunodeficiency virus 
type 1 (HIV -1 ). The splicing of HIV -1 mRN A is a complex process and it could be repressed 
by exonic splicing silencers (ESS). Interaction of hnRNP proteins with ESS could regulate 
HIV-1 pre-mRNA splicing (57,58). 
Hou and colleagues have recently shown the relationship between changes in expression 
levels of hnRNP A2/Bl and developmental processes (56). This could be linked to previ­
ously described results regarding the role of hnRNP A2/B 1 as an oncodevelopmental protein 
( 12). If hnRNP A2/Bl expression is altered, developmental pathways could potentially be 
activated in differentiated cells by a modified alternative splicing. These changes might be 
related to tumorigenesis. 
Third, hnRNP AI and A2 show a decreased expression in senescent fibroblasts (59). The 
constitutive decrease of the ratio hnRNP A I or A2 to SF2/ ASF is accompanied by an increase 
of one of the INK4a mRNA isoforms, pl6JNK4a, whereas overexpression of hnRNP A 1 or 
A2 appears to increase the steady state mRNA levels of both isoforms: p14ARF and 
p16JNK4a. If the ratio hnRNP AI or A2 to SF2/ASF increases, the isoform pl4ARF is 
preferentially chosen (60). These proteins, pl4ARF and pl6JNK4a , are both cell growth 
inhibitors. pl4ARF participates in stabilizing p53 protein levels and pl6/NK4a is involved 
in the pRb pathway (61,62). Given the role of pl4ARF and pl6INK4a in the control of cell 
proliferation, changes in the expression of p 14ARF and p 161N K 4a modulated by changes in 
the expression of hnRNP A2/B 1 could modify pathways of cell proliferation control. 
Since the characterization of hnRNP A2/B 1, its strong correlation with lung cancer has 
been widely reported. A role as a marker for this disease seems to be clearly characterized. 
However, analyzing the structure and function of hnRNP A2/B 1 there is not a definitive link 
between hnRNP A2/B 1 and cancer promotion and progression. The search for such a mecha­
nism could be exceedingly complex but still may lead to a fundamental contribution in 
understanding the nature of the cancer process. 
3. FUTURE DIRECTIONS 
Spiral computed tomography (CT) is highly sensitive and has been very promising in 
pilot clinical trials screening high-risk populations in which very small primary lung cancers 
(less than 1 em in diameter) are frequently detected ( 63 ). Because spiral CT services are so 
widely available and cost of these exams are becoming so affordable, this technology is 
likely to supercede biomarker-based early lung cancer detection. However, biomarkers such 
as hnRNP A2/B 1 provide superb tools to evaluate the mechanistic complexity of lung can ­
cer. In these cases, the small size of the tumor may allow different approaches to manage the

A Marker for Early Diagnosis of Lung Cancer 317 
disease, ranging from less invasive surgical interventions to targeted drug delivery (64,65). 
In addition, these biomarkers may inform the downstream clinical management of 
CT -detected lung cancer. The integrated development of these techniques to detect and 
manage early lung cancer may contribute to the eventual reduction in lung cancer mortality. 
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16 
Molecular Techniques in Cancer Diagnosis 
and Management 
JeffreyS. Ross, Karen Gray, Rebecca Mosher, and James Stec 
The introduction of targeted therapeutics into clinical oncology practice has create d 
opportunities for further development of molecular diagnostics to serve cancer patients. The 
approvals of Herceptin™ for the treatment of HER-2/n eu overexpressing breast cancer and 
Gleevac 1M for the treatment of chronic myelogenous leukemia featuring a bcr/abl transloca­
tion and gastrointestinal stromal tumors with selective c-kit oncog ene activating mutations 
have brought an expanded role to the diagnostic laboratory and for the testing of patients to 
determine their eligibility to receive these new therapies ( 1,2). The molecular diagn ostics 
industry is in a state of rapid evolution, technological development, and novel clinical appli ­
cations (3-5). As seen in Table 1, the in vitro diagnostics industry is now believed to consist 
of a $33 billion market of which molecular diagnostics is currently less than 3%. 
This modest market is in contrast to the worldwide pharmaceuticals industry belie ved to 
encompass more than $1 trillion. Gene-based and molecular diagnostics testing is currently 
listed at only one billion dollar s in worldwide sales, but is growing at a 30-50% rate. It is 
thought that as many as 1500 genes and 5000 proteins could become test targets. From an 
economic viewpoint, nonmolecular types of tests average $26.34 per test charge whereas 
molecular diagnostics tests average $113.04. In Table 2, the oncology molecular diagnostics 
industry is organized by the test or biomarker target, these being DNA , RNA, and protein. 
From this list, it can be seen that the evolving test menu combines a strategy of new applica­
tions for well established test platforms like in situ hybridization (ISH) and immuno ­
histochemistry (IHC) and the emerge nce of entirely new technolo gies. In addition, a varie ty 
of enabling technologies such as laser capture microdissection (LCM) and tissue microarrays 
(TMA) have accelerated the rate of biomarker discovery, validation, and introduction into 
clinical practice. 
2. DNA TARGETS FOR ONCOLOGY MOLECULAR DIAGNOSTICS 
The inher ent stability of DNA and its resistance to degradation even after tissue fixation 
and paraffin embedding has made it the most durable target for molecular diagnostic appli ­
cations . The DNA from human chromosomes has been used to demonstrate the presence of 
deletions, translocations, gains or losses of whole chromosomes, and a variety of other subtle 
defects associated with the diagn osis of cancer and disease outcome (6, 7). The introdu ction 
From : Cancer Diagno stics: Current a nd Future Trend s 
Edited by: R. M. Nakamura , W. W . Grody, J. T. Wu, and R. B. Nagle © Humana Press Inc., Totowa , NJ 
325

326 Ross et al. 
Table 1 
The World-Wide In Vitro Diagnostics Industry 
Clinical pathology Anatomic pathology Molecular diagnostics 
Market size $26 billion $6 billion $1 billion 
Growth rate >5% 5-10% 30-50% 
Margins Low Medium High 
and development of the polymerase chain reaction (PCR) has enabled more sophisticated 
techniques for detecting minute amounts of abnormal DNA in human tumors and relating 
these findings not only to patient outcome but selection of the therapy (8). 
2.1. Routine Metaphase Cytogenetics 
Metaphase cytogenetics is arguably the first molecular diagnostic test applied to the field 
of cancer diagnostics. Ironically, the discovery of the Philadelphia chromosome, the small 
acrocentric chromosome resulting from the 9/22 (bcr!abl) translocation first reported in the 
early 1950s also became one of the first gene-based targets in the new era of directed oncol­
ogy (2). The approval of the tyrosine kinase inhibitor STI-471 or GleevacTM as a direct 
inhibitor of the activated bcr/abl gene brought cytogenetics into the modem era of targeted 
therapeutics. In cancer patients, cytogenetics is predominately utilized for the classification 
of leukemia and lymphoma with significantly fewer applications for the evaluation of 
patients with solid tumors . Technical advancements, including trypsin banding and subse­
quently the introduction of fluorescence in situ hybridization (FISH), chromosomal bar 
codes, multi-color banding, spectral karyotyping, and comparative genomic hybridization 
(CGH) have added numerous important applications for cancer diagnostics (6 ). 
2.2. Interphase Cytogenetics: In Situ Hybridization for DNA Targets 
2.2.1. Fluorescence In Situ Hybridization 
2.2.1.1. ANEUSOMIES 
The detection of chromosomal gains and losses or aneusomies using complementary 
probes for the centromeres of the human chromosomes by FISH during interphase evalua­
tion of whole cells and tissue sections has been used in a variety of research and clinical 
applications (9). FISH-based aneusomy detection using urinary cytology samples has out­
performed conventional cytology and achieved significant clinical use for the evaluation of 
patients with recurrent urothelial carcinoma ( 10). 
2.2.1.2. TRANSLOCATIONS 
Although not sensitive enough to detect small chromosomal changes such as point muta­
tions, the FISH technique proved to be an excellent method for detecting specific chromo­
somal translocations. The FISH method for detection of the bcr/abl translocation can be 
performed on blood and bone marrow cells to detect chronic myelogenous leukemia (CML) 
with greater sensitivity and speed than conventional cytogenetics ( 11 ). FISH has also been 
used as a method of subclassifying soft tissue sarcomas (Table 3), which has led to major 
reconsideration of the derivation of both round cell and spindle cell lesions ( 12).

w 
N 
'-! Table 2 
Summary of Molecular Diagnostic Techniques in Oncology 
Target 
DNA Methods 
Routine 
cytogenetics 
ISH, FISH 
and CISH 
CGH 
CGH arrays 
SNPs 
PCR 
sequencing 
Southern blot Testing samples 
Blood 
Fresh tissues 
Blood 
Paraffin blocks 
Blood 
Blood 
Blood 
Blood 
Fresh tissues Current clinical examples 
Classification 
• Leukemia 
• Lymphoma 
• Sarcomas 
Bcr/abl translocation in CML 
HER-2/neu amplification 
N-myc amplification 
Sarcoma translocations 
HPV genotyping in gynecologic cytology 
Uncommon familial cancer 
predisposition 
Prediction of metabolism and toxicity 
of anti-cancer drugs 
Common familial cancer predisposition 
• BRCAJ,2 and others 
Tumor suppressor gene mutations 
• p53 and others 
Oncogene activating mutations 
• cKit in GIST 
Gene rearrangements in lymphoma 
Minimal residual disease after BMT 
High-risk HPV detection 
N-myc gene amplification 
in neuroblastoma Future status 
Limited by low 
sensitivity and resolution 
Selected growth . Limited by 
low resolution 
Continued development 
Major bioinformatics challenges 
Continued discovery of new 
applications 
Limited by low throughput 
Little further utility due to 
dilutional effects and lack of 
automation 

Table 
2 
(continued) Summary 
of 
Molecular 
Diagnostic 
Techniques 
in 
Oncology Target 
Methods 
Te
sting 
sa
mple
s 
Current 
clinical 
examples Micro-satellite 
Fresh 
tissu
es 
Colorectal 
cancer 
predisposition instability 
Urine 
Resection 
margin 
status Urothelial 
carcinoma 
metastasi
s RNA 
Transc
ript
ional 
Blood 
Pharmaco
genom
ic 
disco
very profiling 
Bone 
marrow Northern 
blot 
Fresh 
tiss
ue
s RT-PCR 
Blood 
Minimal 
residual disease after 
BMT Bone 
marrow 
Micrometastasis 
detection 
in w 
Fresh 
tissues 
sentinel 
lymp
h 
node
s N 
(?Paraffin 
blocks) 
Oncogene 
activation Oo 
CpG 
island 
hyperme
thyl
ation to 
detect 
prostate 
cancer TS/DPD 
levels 
to 
predict 
5-FU 
response ISH, 
FISH 
Blood 
(after 
ce
ll 
Melastatin 
detection 
for 
melanoma and 
CISH 
capture 
assays) 
prognosis Bone 
mar
row Fresh 
tiss
ues Protein 
Western 
blot 
Blood 20-PAGE 
Blood Bone 
marr
ow Fr
es
h 
tissues MALDI-TOF 
Blood Bone 
marrow Body 
fluids 
Future 
sta
tu
s Growth 
potential 
for 
selected clinical 
sit
uat
ions 
discovery of 
new 
s Substantial 
gro
wth Substantial 
grow
th Limited 
growth Limi
ted

SELDI 
Blood 
Detection 
of 
early 
stage 
ovarian 
cancer IHC 
Bone 
marrow 
Immunophenotyping 
of 
lymphoma 
Enormous 
potential 
if 
technique Fresh 
tissue
s 
Solid 
tumor 
classification 
can 
be 
standardized 
and ER/PR 
status 
in 
breast 
cancer 
reproducibility 
improved HER-2/neu 
status 
in 
breast 
cancer BioAssays 
PCR-based 
Fresh 
tissues 
Telomerase 
TRAP 
assay 
Limited Urine ligand-receptor 
Fresh 
tissues 
Hormone 
recepto
r (ER/PR) 
Limited assays 
Others Truncated 
Blood 
Familial polyposis 
(APC) 
detection 
Limited protein 
assays 
Bone 
marrow General 
enabling 
techniques Laser 
capture 
Fresh 
tissues 
Biomarker 
discovery micro-
Paraffin 
blocks w 
dissection N 
Tissue 
Fresh 
tissues 
Biomarker 
di
scovery (.0 
microarrays 
Paraffin 
blocks Quantitative 
Tissu
e sections 
Biomarker 
validation digital 
image 
Quantification 
of 
ISH 
and 
IHC analysis Micro-capillary 
Blood 
High 
throughput 
se
quencing 
Substantial 
potential electro-
Body 
fluids 
• Microsatellite 
instability phoresis 
Tissue-derived 
High 
throu
ghput 
proteomics fluids lmmuno-
Blood 
Detection 
of 
cancer 
in 
blood 
Unknown 
potential magnetic 
Bone 
marrow 
Pharmacogenomic testing cell 
capture 
Body 
fluids 
Pharmacodynamic 
testing assays

330 
Table 3 
Common Sarcoma Translocations (simplified) 
11:22 
2:13 
9:22 
X:l8 
12:14 
12:16 
2.2.1.3. GENE AMPLIFICATION DETECTION Tumor phenotype 
Ewings sarcoma and primitive 
neuroectodermal tumors 
Alveolar rhabdomyosarcoma 
Chondrosarcoma 
Synovial sarcoma 
Smooth muscle tumors 
Myxoid liposarcoma Ross et al. 
The most significant application of the FISH technique in cancer diagnostics has been for 
the detection of amplification of the HER-2/neu gene for the selection of patients to receive 
the humanized anti-HER-2/neu monoclonal antibody, Herceptin™ (13,14) . The FISH test 
(Fig. 1) for gene amplification is performed on 5 [!ill thick formalin-fixed paraffin-embed­
ded tissue sections similar to the competing immunohistochemical technique (see Section 4.5). 
Approximately, 85% of published studies have linked HER-2/neu gene amplification or pro­
tein overexpression with adverse outcome in breast cancer and the prediction of therapeutic 
benefit with HerceptinTM (1 3,14 ). The new chromogenic in situ hybridization test (CISH) 
will be discussed in Section 2.2.2. 
Other examples of FISH detection of gene amplifications in clinical practice include the 
prediction of disease aggressiveness and therapy selection for patients with neuroblastoma 
featuring amplification of the N-myc gene ( 15 ). Additional clinically significant gene ampli­
fication tests include the topoisomerase Ila gene for the prediction of anthracycline chemo­
therapy response ( 16) and the cyclin D gene as a predictor of outcome in breast cancer ( 17 ). 
2.2.2. Chromogenic In Situ Hybridization 
In situ hybridization using nonfluorescence probes has also become clinicaJiy useful for 
the management of patients with cancer and precancer syndromes. In contrast with other 
radiolabeled and fluorophore-labeled probes (Table 4), CISH has many advantages includ­
ing, relative ease of use, production of permanent slides, simplicity in slide scoring, and 
potential for automation and high throughput 
2.2.2.1. HER-2/NEU GEN E AMPLIHCATION DETECTIO N 
Similar to the FISH, the CISH technique has the advantages of using a sample with a built 
in internal control, a robust DNA target less likely to degrade after tissue processing, and the 
opportunity for a more objective scoring system when compared to immunohistochemistry 
( 18,19). In addition, the CISH method does not require a relatively expensive fluorescence 
microscope and produces slides that are easily stored and can be reviewed without Joss of 
signal over time. With further refinement employing signal amplification strategies, there is 
significant potential for the CISH method to eventually become the preferred method of 
detection of HER-2/neu gene amplification.

Molecular Techniques in Cancer Diagnosis and Management 331 
Fig. 1. HER-2/neu testing in breast cancer. Lower : Immunohistochemistry using HerceptestTM 
system (Dako , Corp.) with continuous membranous 3+ positive immunostaining for HER-2/neu pro­
tein. Middle: HER-2/neu gene amplification detected by FISH (Ventana Inform™ System). Upper: 
HER-2/neu gene amplification detected by CISH (Zymed System). Color figure available for view­
ing at www. humanapress.com.

w w N Table 4 
In situ Hybridization Comparison 
Sensitivity Ease of use 
Automation available 
Slide Scoring 
Microscope Requirements 
Signal amplification 
mRNA applications 
Current clinical 
applications FISH 
Fluorescence in situ 
hybridization Intermediate Intermediate Yes 
Difficult 
Fluorescence Limited use 
but complicate 
slide scoring 
Excellent for gene 
amplification scoring 
Limited to none 
Cytogenetics 
CGH and CGH arrays 
HER-2/neu gene 
Melastatin light-chain 
restriction in lymphoma 
/myeloma diagnosis CISH 
Chromogenic in situ 
hybridization Lowest Easiest Yes 
Easiest Routine 
Can increase sensitivity, 
Subjective, may require 
digital image analysis 
Yes 
Viral detection (HPV, others) 
amplification RISH 
Radiolabeled in situ 
hybridization Highest 
Most cumbersome No 
Most difficult 
Routine with dark field condenser 
Not generally required 
Autoradiographic grain 
counting most accurate 
Yes None

Molecular Techniques in Cancer Diagnosis and Management 333 
2.2.2.2. HUMAN PAPILLOMA VIRUS DETECTION 
CISH has been used to identif y high-risk types of human papilloma virus (HPV) in gyne ­
cologic cytology specimens (20-22). Using a cocktail of probes designed to detect the HPV 
genotypes associated with high risk for progression of low grade to high-grade cervical 
lesions, CISH has compared favorably with the established hybrid capture technique for 
detecting HPV (20-22). Large-scale studies are necessary to determine whether this method 
can equal or surpass the hybrid capture method for the wide scale screening of atypical 
gynecologic cytology specimens to determine which patients need clinical follow-up. 
2.2.3. Comparative Genomic Hybridization 
The FISH technology has been used to perform comparative genomic hybridization 
(CGH) where DNA extracted from malignant tumors can be comparatively hybridized 
against normal or reference DNA samples to discover chromosomal gains and losses of 
DNA segments in the neoplasm s (23,24 ). The CGH technology has uncovered numerous 
genetic defects in tumors that had previously been undetected by conventional cytogenetics 
(23,24 ). Clinical applications of CGH have been limited by lack of resolution. More recen tly, 
a technique of CGH combined with analysis of arrays containing artificial human chromo­
somes derived from bacteria or yeast (25-28) has significantly enhanced the precision, sensi­
tivity, and utility of CGH for mapping of tumor-specific genetic alterations (see Section 3.1.). 
2.2.4. Single Nucleotide Polymorphism Detection 
More than I million genetic markers known as single nucleotide polymorphi sms (SNPs) 
have recently become available for genotyping and phenotyping studies (29-32). SNPs are 
the most common type of genetic difference between individu als and provide a tool to sur­
vey the genome. With the intense competition to find disease associated genes, companies 
are turning to faster, more efficient means of interrogating the genome such as multiplexing 
using reverse transcriptase-pol ymerase chain reaction (RT -PCR), mass spectrometry (MS), 
arrays, or F ACs-based fuorescent bead methods. Hundreds of thousands of gene-associated 
SNP candidates have been identified and uncovered numerous loci that appear to have sig­
nificant potential to generate clinically useful data for patient man agement. Novel genotyping 
strategies are emerg ing on a regular basis using a variety of techniques, including oligo­
nucleotide genomic arrays (29,30), gel and flow cytometry, classic gene sequencing, MS 
( 31), and microarray or gene chips ( 32) all designed to increase the rate of data generation 
and analysis. In oncology, the SNP technology has focused on three areas of clinical applica­
tions: detecting the predisposition for cancer , the prediction of toxic responses and therapeu­
tic benefits for anti-cancer drugs. 
2.2.4.1. CANCER PREDISPO SITION TESTING 
SNP genotyping and gene sequencing have uncovered a variety of familiar cancer predis­
position syndromes based on single and multiple gene variances ( 32-34 ). Genotyping has 
been introduced widely for the detection of familial cancers of the breast, ovary, colon, 
melanoma , and multiple endocrine neoplasia ( 32-34 ). 
2.2.4.2. PREDI CTION OF DRUG TOXICITY 
One of the earliest appl ications of SNP genotyping in cancer management was the discov­
ery of variations in drug metabolism assoc iated with genomic variations in drug metaboliz­
ing enzymes such as the cytochrome p450 and conjugating enzyme systems (35). Known 
alternatively as pharmacogenetics and toxicogenomics, the wide potential clinical value of

334 Ross et al. 
Table 5 
Tumor Suppressor Genes 
Gene name Designation Location Disease association 
Adenomatous APC 5q21 Familial polyposis coli 
Polyposis Coli 
Breast cancer I BRCAl 17q21 Familial breast cancer 
Breast cancer 2 BRCA2 13ql2 Familial breast cancer 
E-cadherin CD HI 16q22 Familial stomach cancer 
Lobular breast cancer 
Prognosis in epithelial cance rs 
Cyclin-dependent CDK NlC 1 6q22 Beckwith- Wiedemann syndrome 
kinase Wilms tumor 
inhibitor lC Rhabdomyosarcom a 
p16 CDKN2A II p15 Familial melanoma 
Cyclin-dependent Bladder cancer 
kinase Other epithelial tumors 
inhibitor 2A 
(MTS l ; INK4A) 
Mitogen-a ctivated MAP 2K4 17pl1 Pancreatic, breast, colorectal cancer 
protein 
kinase 4 
Multiple endocrine MEN! llq13 Pituitary adenoma 
neoplasia Parathyroid adenoma 
type I Islet cell carcinoma 
Carc inoids 
Heredi tary non- hMSH 2 2p22 Colorectal cancer 
polyposis Ovarian cancer 
colorectal Endometrial cancer 
cancer type I 
Hereditary non- hMLHI 3p21 Colorectal cancer 
colorectal Endom etrial cancer 
Neurofibromatosis NFI 17ql1 Neurofibromas 
type 1 Gliomas 
Pheochromocytomas 
Acute myelogenous leukemia 
Neurofib romatosis NF2 22q12 Schwannomas 
type II Menin giomas 
Ependym omas 
Phosphatase and PTEN 10q23 Cow den's syndrome 
ten sin Gliomas 
homol og Prostate cancer 
Endometrial cance r 
Retinobla stoma RBI 13ql4 Retinoblastoma 
Small cell lung cancer 
Breast cancer 

Molecular Techniques in Cancer Diagnosis and Management 
Table 5 (continued) 
Gene name Designation 
Serineffhreonine STKll 
Kinase 11 
TP 53 p53 
Tuberous TSCl 
sclerosis 1 (KIAA023) 
Tuberous TSC2 
sclerosis 2 
Von-Hippel Lindau VHL 
Wilms tumor I WTl Location Disea se association 
19pl3 Peutz-Jehgers syndrome 
17p13 Li Fraumeni syndrome 
Inactive in >50% of human malignancie s 
9q34 Hamartomas 
Renal cell carcinoma 
Angiomyuliopma 
16pl3 Hamartomas 
Angiomyolipoma 
3p26 Hemangiomas 
Pheochromocytoma 
llp13 Genitour inary dysplasia 
Familial Wilms tumor 335 
this approach will be uncovered as more candidate polymorphisms can be associated with 
drug toxicities . 
2.2.4.3. PREDIC TION OF DRUG EFFI CACY-PHARMA COG ENOMI CS 
The application of genomic strategies to predict anticancer drug efficacy and employ the 
technology in drug discovery, development, and clinical trials encompasses the field of 
pharmacogenomics ( 36-38). Pharmacogenomics can utilize germ line SNPs and multigenetic 
polymorphisms to predict drug response as well as the direct profiling of tumors for expres­
sion of genes associated with drug efficacy and resistance. 
2.3. Polymerase Chain Reaction and Direct Sequencing 
The PCR technique is likely the single most important technical advance in the field of 
cancer molecular diagnostics (39). PCR approaches to DNA have yielded a variety of mo­
lecular diagnostic assays recently eclipsed by the applications of the mRNA assessment by 
real time PCR (see Section 2.3.1.). 
2.3.1. Tumor Suppressor Gene Mutation Detection 
PCR-based gene sequencing techniques have enhanced the ability to detect point muta­
tions in tumor suppressor genes such as TP53 (40). TP53 mutation analysis has been used 
for the management of urinary bladder cancer, detection of lung and colorectal cancer , mo­
lecular assessment of resected margins, and monitoring effectiveness of anti-p53 gene thera ­
pies ( 41-44 ). A list of tumor suppressor genes sequenced by PCR for clinical use is shown in 
Table 5. PCR technologies are also widely used to assist in the direct sequencing of genomic 
DNA from family members with familial cancer syndromes; such as detection of the BRCAJ 
and BRCA2 gene mutations and predisposition for breast cancer as well as some of the other 
syndromes listed in Table 5 (45).

336 Ross et al. 
2.3.2. Oncogene Activation 
PCR strategies have similarly been used to detect oncogene activation associated with 
point mutations in a variety of malignancies. For example, the PCR technique has been used 
to detect ras oncogene point mutations for the diagnosis of pancreatic cancer in limited 
clinical samples, as well as predict adverse outcome in a variety of solid tumors (46). 
Recently, PCR -based direct sequencing has been employed to detect specific therapy­
responsive mutations in the c-kit oncogene in GleevacTM_treated gastrointestinal stromal 
tumors (GISTs). Although virtually all GISTs overexpress the c-kit protein, it has been shown 
that a minority of point mutations in the c-kit gene can produce GleevacTM resistant tumors 
( 47). Recently, resistance or relapse in CML to Gleevac™ therapy has also shown to involve 
point mutations in the abl oncogene making the kinase less inhibited by the drug. 
2.3.3. Gene Rearrangements 
PCR methods have been developed to detect clonal gene rearrangements characteristic of 
malignant lymphoid neoplasms and for the detection of recurrent disease after therapy 
(48,49) . The RT-PCR method has become the preferred method for detecting successf ul 
engraftment after bone marrow transplantation and the presence of minimal residual disease 
in long term follow-up of lymphoma and leukemia patients in clinical remission (48,49) . 
2.3.4. HPV Detection 
In addition to the ISH and outdated South ern and dot blot methods, PCR-based testing 
and the hybrid capture assay have been widely used to detect high risk HPV genotypes in 
gynecologic cytology specimens (50-53). Although the hybrid capture technique is the most 
widely employed, clinicians continue to express concern regarding the value of HPV detec­
tion in the management of their patients with atypical cytology reports (53). 
2.4. Southern Blot 
The introduction of southern blot technology to clinical practice represented one of the 
earliest applications of the emerging field of molecular diagnostics in the 1980s. Southern 
blot continues to be used in many laborat ories for the detection of clonal gene rearr ange­
ments in patients with malignant lymphoid neoplasms (48,49) . Southern blotting is also 
occasionally used for detection of gene amplifications and remain s a major protocol test for 
the clinical management of children with diagnosed neuroblastoma ( 15 ). The relatively cum­
bersome natur e of the assay and potential for the target DNA to be diluted by adjacent stro­
mal, endothe lial, and inflammato ry cell DNA has limited the u se of southern blotting for the 
evaluation of solid tumors. 
2.5. Microsatellite Instability 
Microsatellite DNA sequences consist of 4-25 tandemly repeated nucleotide units scat­
tered throughout the human genome (54-57). The role of microsatellites in cellular homeo­
stasis is unknown. Using PCR and sequencing strateg ies, abnormalities in microsatellites 
have been associated with a variety of cancer predisposition syndromes (52) and have been 
used as a strategy for the early detection of mali gnancy including assessm ent of patients 
with recurrent urothelial neoplasia (58). MS includin g both the matrix -assisted desorption 
and electrospray-ionization methods has recentl y been introduced to measure microsatellite 
instability (MSI) (59). MSI is also associated with promoter gene hyper methylation which 
will be discuss ed in Section 3.

Molecular Techniques in Cancer Diagnosis and Management 337 
3. RNA TARGETS FOR ONCOLOGY MOLECULAR DIAGNOSTICS 
The measurement of gene expression by detecting absolute and relative mRNA levels has 
become a major approach to cancer molecular diagnostics ( 3-5,32,37). The determination of 
mRNA expression for both novel and known genes by transcriptional profiling using 
genomic microarrays, RT -PCR, and in situ hybridization has found both direct clinical 
applications and major roles in drug discovery and development (60,61 ). 
3.1. Transcriptional Profiling and Genomic Microarrays 
The development of printed and spotted genomic microarrays has allowed for the rapid 
screening and accumulation of new information concerning SNPs , gene mutation, and mRN A 
expression in human malignancies (62-69). Transcriptional profiling by hybridizing labeled 
probes derived from disease specimens to arrayed oligo or cDNAs gives a picture of the 
transcriptome or mRNA levels of known and novel genes in a neoplasm often compared to 
the gene expression status of a reference sample. Reference samples can include cell lines, 
normal tissues, and cancer precursor lesions (62-69). Biochip and microarray technologies 
have contributed to the industrialization of the genomic and proteomic discover y process 
and the development of personalized medicine ( 32 ). Table 6lists the major types of arrays or 
biochips and their associated fluorescent, radioisotope, or MS (67) reporter systems in current 
use or in development for oncology molecular diagnostics. Each of these techniques have 
the ability to generate hundreds of thousands of data points requiring sophisticated and com­
plex information systems necessary for accurate and useful data analysis (see Section 6.6.). 
3.1.1. eDNA Microarrays 
eDNA microarrays were introduced in the mid-1990s (70) and have achieved widespread 
use for the expression profiling of human clinical samples and in drug and biomarker target 
discovery. Using sequence verified eDNA clones, robotic printing, either tluorescent or 
radioisotope-based signal detection, and usually either glass slide or nylon membrane 
hybridization surfaces (Fig. 2), this technique has generated a wealth of new information in 
subtyping leukemia/lymphoma, solid tumor classification, pharmacogenomics, and drug and 
biomarker target discovery (62-69). In addition, oligonucleotid e-based eDNA Microarrays 
produced by companies like Affymetrix, Inc. have been used extensively to map the human 
gene trascriptome. 
3.1.2. Oligonucleotide Microarrays 
Oligonucleotide arrays have been extensively used for transcriptional profiling and detec­
tion of SNPs and individual gene point mutations. This method originally employed photo­
lithography techniques to apply the large number of oligonucleotides on the glass and nylon 
surfaces (62). Often there is redundancy so that a single gene is represented by more than 20 
oligonucleotides spanning its entire length that reduces the rate of false-negatives ( 62 ). This 
approach has been used to profile differences in gene expression between samples from 
human tumors and reference test tissues when compared similar to eDNA-based microarra ys. 
Oligonucleotide arrays are well regarded for their automated , high-throughput genome wide 
analysis of SNPS and other clinically relevant DNA polymorphisms (71 ). 
3.1.3. Comparative Genomic Hybridization (CGH) Microarrays 
In DNA array-based CGH (array-CGH) the original CGH techniqu e applied to metaphase 
chromosomes has been replaced by spots of either cloned cON A or bacterial artificial human

Table 6 
Types of Microarrays in Oncology Molecular Diagnostics 
eDNA microarray Oligonucleotide CGH-BAC /YAC Tissue 
Feature (spotted arrays) microarrays microarra ys microarra ys 
Target type Double-stranded eDNA 16-24 bp oligonucleotides DNA fragment arrays Paraffin sectio n 
and made from tumor mRNA in situ synthesis or printing Bacterial/yeast artificial arrays 
technology PCR products from eDNA Up to 240,000 oligos/chip chromosomes Frozen section arrays 
clones Probe redundanc y I OObp to 1 OOkb 
Competitive hybridization decreases false-positives 5000 spots 
1Mb resoluti on 
Types of Glass slides Glass slides Glass slides 
array Silicon Silicon 
surfaces Nylon membranes Nylon membranes 
Gels 
Beads 
Signal Fluo rophores Fluorophores Fluorophores Fluorophore s 
w Detection Radioisotopes Typi cally single color Chromage ns w 
Oo Systems Typically dual color Radi oisotopes 
Technical Printing inaccuracies Greater density, but limit ed Limited resolution Tumor heterogeneity 
limitations False hybridizations by cross-hybridization errors Formalin-based 
protein and RNA 
degradation 
Automation Robot printing Robot printin g Fluore scence micro scopy Image analysis 
capability Laser scanning Laser scanning Digital imaging 
Clinical Leukemia/lymphoma Gene re-sequencing High-resolution Currently used for 
applications classifica tion SNP discovery cytogenetics for gains research purposes 
Solid tumor classification Tumor classification and losse s only 
Carcinoma of unknown SNP prediction of toxicity Tumor classification 
primary site Drug selection New primary tumor 
Drug selection vs metastasis 
Drug Drug target selection Drug target selection Drug target discovery Drug target valida-
lion 
discov ery and Pharmacogenomics Pharmacogenomics Pharmacogenomic 
development discovery discovery target validation 
applications Biomarker discovery Biomarker discovery Biomarker validation

Molecular Techniques in Cancer Diagnosis and Management 339 
Fig. 2. eDNA microarrays . eDNA Microarra ys with each circle representing a distinct eDNA. 
Probes are genera ted from isolated RNA(s) by labeling with fluorescent or radioactive nucleotides 
for detection of spec ific hybridization. Top: Fluorophore -based detection comparin g Cy3-or Cy5-
labeled probes from normal and disease specimens . After hybridization , fluorescent intensiti es on 
scanned imag es are quantified, corrected for background noise, and normali zed. Bottom: Radio-iso­
tope detection with a [35S]-nucle otide labeled from a single specimen. The intensity of the densito ­
metric signal is equivalent to the relative abundance. Color figure available for viewing at www. 
humanapress.com. 
chromosomes (BAC) or yeast artificial human chro mosom es (YAC) (72). More recently, 
the CGH technique has been applied to eDNA genomic microarrays allowing for sensitive 
detection of single gene copy losses and gains in tumor samples compared with correspond­
ing normal tissues (73 ). The resolution of array-CGH is significantly greater when com-

340 Ross et al. 
pared to metaphase CGH. It is possible that array-CGH will allow the original cytogenetic 
level of resolution to reach a molecular level (72,73 ). The technique can be automated 
and will increase the throughput of comparing tumors to normal tissues for far more subtle 
gains and losses of genetic material on an industrial scale; opening the door to the individ­
ualization of patient therapies targeting the specific genetic alterations existing in their 
tumors (72,73). 
3.1.4. Tissue Microarrays and Target Validation 
Tissue microarrays (TMA) allow a high-throughput testing of multiple characterized tu­
mors samples often with known clinical status and follow-up on a single microscopic glass 
slide (74-78). TMA can facilitate the discovery of biomarkers and drug targets by allowing 
for rapid assessment of disease association , as well as improvements in efficiency and pro­
ductivity by conserving reagents and reducing hands-on time. Patient population studies as 
large as 600 cases can be assessed by ISH and IHC on a single microscopic slide. New 
digital image analysis hardware and software has been specifically designed to facilitate 
TMA analysis allowing for individual core slide scoring to be performed in a semi-auto­
mated manner. 
3.1.5. Data Analysis and Data Display 
Each DNA microarray produces tens of thousands of measurements that require signifi­
cant computer-based data analysis to determine biologically relevant patterns . It is critical to 
have systems in place that efficiently combine association , functional, and gene expression 
data to assess a gene's potential as a disease marker or drug target. Four techniques have 
emerged as the predominant method of DNA microarray data analysis: hierarchical cluster­
ing, self-organizing maps, multidimensional scaling, and pathway associations (79,80) . 
Originally described in 1997, the arrangement of hybridization data into a cluster order based 
on color-coded intensities, provided clues as to which genes were signaling in groups (81-86). 
Typically, genes whose expression was significantly greater than that of the reference sample 
are depicted with increasing intensity on the red scale and those with less gene expression 
than the reference sample displayed in increasing green signals (81). In hierarchical cluster­
ing, the algorithm groups genes in the array based on similarities in their patterns of gene 
expression. Typically , genes featuring the most similar patterns of expression are grouped 
next to each other in the vertical axis and patient samples with similar clinical or disease 
outcome features are arranged along the horizontal axis (Fig. 3). The grouping of similar 
gene expression samples with similar disease outcome samples is known as a dendrogram. 
Cluster analysis of genes can be performed in both a supervised and unsupervised manner. 
In supervised analysis, the bioinformatics system uses machine learning after the computer 
is provided with an initial batch of categorized data known as the learning set. In unsuper­
vised analysis, the computer attempts to perform the clustering without exposure to a set of 
previous training cases . 
3.1.6 . Tran scriptional Profiling and Pharmacogenomics 
Hierarchical clustering of transcriptional profiling data from clinical sample s known to 
have responded or been resistant to a single agent or combination of anti-cancer drugs is a 
fundamental component of modern pharmacogenomics (35,36,87-91). Using a predomi­
nantly eDNA microarray approach, several groups have now reported on their success at 
discovering gene expression that can be linked to resistance and responsiveness to standard

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Fig. 3. Breast cancer eDNA microarray results evaluated by hierarchical gene cluster analysis for 
defining specific gene expression signatures.Hierarchical clustering algorithm allows the clustering 
of individual tumor profiles on the basis of their similarities to their co-expression with the estrogen 
receptor a gene. Each row represent s a tumor and each column a single gene . A group of specimens 
featuring a similar gene expression signature is identified by the rectangular box. Color figure avail­
able for viewing at www.humanapress.com. 
of care chemotherapy (85,86). In the next several years, the ability of this approach to per­
sonalize the treatment of newly diagnosed cancer patients with individualized selection and 
dosage of chemotherapeutic agents will be tested on a large scale. 
3.2. Northern Analysis 
Northern blotting was the first mRNA detection method used to test gene expression pat­
terns in human cancer. Currently, Northern analysis is limited to a research role, and is not 
widely used for clinical assessment of human samples. The technique is cumbersome, slow, 
and similar to Southern blotting, at risk for the loss of sensitivity as a result of dilution of the 
target malignant cell mRNA levels by surrounding nonneoplastic tissues.

342 Ross et al. 
3.3. Differential Display 
Prior to the development of high-throughput microarray technologies, the differential dis­
play of mRNA was used. Differential display is a technique in which mRNA expression 
levels in a cell population are reverse transcribed and then amplified by many separate PCR 
reactions. This robust and relatively simple procedure allows identification of genes that are 
differentially expressed in different cell populations and is particularly useful for the discov­
ery of biomarkers (92). Differential display is not currently used for direct clinical testing. 
3.4. Serial Analysis of Gene Expression 
Serial analysis of gene expression (SAGE) is a direct and quantitative measure of gene 
expression based on the isolation and sequencing of unique sequence SAGE tags (93 ). The 
sequence data are then analyzed to identify the presence and level of gene expression and are 
combined to form a SAGE library. Similar to differential display , the SAGE method is cur­
rently applied to discovery biomarkers. 
3.5. Reverse Transcriptase-Polymerase Change Reaction 
The introduction of the real-time RT-PCR technique has allowed a rapid growth in gene 
expression studies for both hematologic malignancies and solid tumors (94 ). In multiplex 
RT-PCR, housekeeping and gene specific oligonucleotide primers and dye conjugated­
probes are added to eDNA produced from RNA isolated from clinical samples and a quanti­
tative level of mRNA expression is obtained by normalizing the amplification cycle time for 
the target gene against that of a housekeeping gene (94 ). A variety of commercial closed 
system RT-PCR technologies are used for clinical applications, predominantly the 
TaqMan™ method by ABI, Inc. and the Lightcycler™ by Roche Instruments, Inc. are the 
two most favored instruments. RT-PCR applications generally focus on the enhanced sensi­
tivity associated with PCR-based strategies owing to the ability to detect RNA over a 7-log 
range. 
3.5.1. Leukemia and Lymphoma Diagnosis and Management 
RT-PCR techniques have found their first clinical applications in the field of leukemia 
and lymphoma management (95-98). RT-PCR can be used to detect the presence of non­
Hodgkin's lymphoma in minute tissue samples (96,98), as well as the recurrence of the 
disease after bone marrow transplantation (97). Although the sensitivity ofPCR-based meth­
ods to detect recurrent lymphoma has caused significant concern as to the specificity for 
clinically significant vs molecular derived disease relapse, most major cancer centers employ 
the technique on a regular basis to follow their patients particularly after they have received 
intensive treatment and bone marrow transplantation . 
3.5.2. Solid Tumor Classification 
The RT -PCR technique has also been extensively employed to evolve and revise the clas­
sification of solid tumors. RT-PCR has been used to detect disease-specific DNA transloca­
tions in sarcomas (99,100) and mRNA expression tumor-specific biomarkers drug target 
genes such as HER-2/neu (101) and PSMA (102,103). 
3.5.3. Micrometastasis Detection, Sentinel Lymph Nodes, and Resection Margin Status 
Recently, RT-PCR methods have been used to detect minute amounts of tumor-derived 
mRNA in lymph node samples and resection margin biopsies from patients suffering from a

Molecular Techniques in Cancer Diagnosis and Management 343 
ISO 
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Fig. 4. Micrometastasis detection of breast cancer in a sentinel axillary lymph node biops y. Top 
panel: Real time PCR (TaqMan TM detection of cytokeratin 19 mRN A after 25 cycles of amplification 
(dark curve) normalized to internal control dye (light curve). Bottom panel left: hematoxylin and 
eosin stained section of one-half of the same lymph node showing no evidence of tumor cells. Bottom 
panel right: immunohistochemical stain for cytokertain 19 demonstates a single aggre gate of two 
malignant cells beneath the surface in the subcapsular sinusoid. Color figure available for viewing at 
variety of solid tumors (104-110) . This RT-PCR approach has been compared with serial 
tissue sections and immunohistochemistry (Ill, 112) for the detection of micrometatsases 
(Fig. 4) in sentinel lymph node biopsies. The methods designed to enhance the diagnosis of 
micrometastasis are currently controversial. It is not certain if lymph node samples reveal 
malignant cells on routine microscopy, but abnormal mRNA expression detected by 
RT-PCR are clinically different from lymph nodes that do not contain RT-PCR derived 
aberrant messages ( 113 ). Long -term clinical follow -up and treatment related follow-up will 
be needed to determine whether this ultrasensitive method of detecting tumor cells in lymph 
nodes or at microscopically negative surgical resection margins can guide therapy decisions 
and improve patient outcomes

344 Ross eta!. 
3.5.4. Rare Event Detection in Peripheral Blood and Body Fluids 
Detection of rare circulating tumor cells in peripheral blood and body fluids by RT -PCR 
has been used as a method for the diagnosis of early stage cancer and monitoring therapeutic 
response ( 114-116 ). A substantial number of malignant tumors have been detected by 
RT-PCR in peripheral blood samples including carcinomas of the breast, lung, pancreas, 
colon, prostate, and melanoma ( 114-116). Peripheral blood based RT-PCR detection of cir­
culating prostate cancer cells has been extensively studied, and although the RT-PCR based 
detection of PSA mRNA in blood samples is highly sensitive, concern remains as to the 
specificity of this method for the diagnosis of initial or recurrent carcinoma ( 117, I 18 ). 
3.5.5. Gene Methylation Status 
RT-PCR based measurement CpG island promoter gene hypermethylation in peripheral 
blood is an indicator for the existence of cancer ( 119-121 ). Detection of CpG island 
hypermethylation of the glutathione-S-transferase-Jt gene appears to be a tumor specific 
event in prostate cancer and shows significant promise as a blood-based test to improve on 
the specificity of the diagnosis of prostate cancer compared with serum PSA screening 
( 122-124). Gene methylation has also been studied in a wide variety of cancers as a prog­
nostic factor (125-128). Finally, methylation enzymes have recently emerged as a target of 
cancer therapeutics ( 129). 
3.5.6. Pharmacogenomics 
The RT-PCR technique has enabled the introduction of pharmacogenomics into clinical 
practice. Reflecting that the vast majority of human tumors are stored after formalin-fixation 
as paraffin blocks, strategies have been designed to amplify mRNA targets extracted from 
paraffin. Most notable is Taqman 1M RT-PCR quantitation of thymidylate synthase and 
dihydropyrimidine dehydrogenase mRNAs extracted from paraffin-embedded tissues is a 
predictor of response of colorectal cancer to 5-fluorouracil-based therapy ( 1 30). 
3.6. ISH, FISH, and CISH for mRNA Detection 
In situ hybridization techniques have been applied to detect cell- specific mRNA levels in 
tissue sections, aspirates, and smears of various human malignancies as well as to detect 
viral DNAs associated with infections and other biomarkers .. 
3.6.1. Melastatin 
Melastatin is a calcium channel -related gene associated with the development of the nevo­
melanocytic system. The expression of melastatin mRNA has been associated with normal 
neva! cells, melanocytic proliferations, and a substantial percentage of in situ and invasive 
malignant melanomas ( 131 ). Loss of expression of melastatin mRNA (Fig. 5) in either focally 
or diffuse patterns have been detected in malignant melanomas and linked to adverse clini­
cal outcome, independent of all known melanoma prognostic factors including tumor thick ­
ness (132 ). Melastatin testing has been introduced to guide follow-up diagnostic and 
therapeutic decisions such as sentinel lymph node biopsies based on the melastatin expres­
sion profile of the primary tumor. 
3.6.2. Other Uses 
In situ hybridiz ation has also been used to detect K and 'A light -chain mRNA expression in 
lymphoid infiltrates. Notoriously difficult to demonstrate in paraffin-based immunohis­
tochemistry , restriction of expression of light chain of mRN A has been demonstrated by the

Molecular Techniques in Cancer Diagnosis and Management 345 
Fig. 5. Melastatin expression loss in malignant melanoma . Top panel: dark field view with radio­
isotope-labeled probe showing melastatin expression loss in lower center of the microscopic field 
(arrow). Bottom panel: chromogenic ISH with digoxigenin -labeled probe showing melastatin loss in 
foci of tumor cells the cente r of the melanoma nodule (arrow). Color figure available for viewing at 
ISH method and correlated with other factors indicative of a clonal B cell malignant popula ­
tion ( 133). 
4. PROTEIN-BASED TARGETS FOR ONCOLOGY MOLECULAR DIAGNOSTICS 
The field of proteomics has emerged as a complementary strategy to genomics for both 
oncology drug discovery and molecular diagnostics ( 134-138 ). Proteomics is a systematic 
analysis and documentation of the proteins present in a biological sample. This includes

346 Ross et al. 
measurements of post-translational modification, up-/down-regulation of proteins and 
absence of expression . The technique requires sophisticated instrumentation for protein sepa­
ration and identification, and documentation in a standardized, easily retrievable, compara­
tive format. Sequencing the human genome had a finite end-point; in contrast, the proteome 
is highly dynamic with endless possible variations. Current estimates for the human genome 
are between 35,000-50 ,000 genes, but with the fact that many genes exhibit splice variants 
and that most proteins are post-translationally modified, it is estimated that at least I million 
different proteins exist. With this degree of complexity, the goal of scientists is not to simply 
catalog protein components under static conditions but to understand how changes in the 
proteomes contribute to physiological function, disease, as well as to associated proteins 
with pathways and networks ( 134-138). In the clinic, mass spectroscopy proteomic 
approaches to analyze blood and body fluids have been used to detect the existence of cancer 
( 139, 140 ), predict responses to anti-cancer drugs ( 141 ), and discover novel targets for can­
cer therapeutics ( 142). 
4.1. Western Analysis 
Despite its major role in the development of clinical assays and validation of protein 
targets for therapeutics and diagnostic purposes, gel electrophoresis and immunoblotting is 
not commonly used as a specific diagnostic platform for oncology patients. 
4.2. Two-Dimensional Gel Electrophoresis (2DGE) 
Two-dimensional gel electrophoresis (2DGE) is a technique that has been available for 
more than two decades and used to characterize complex mixtures of proteins first by charge 
(isoelectric focusing) and then by molecular size (SDS-gel electrophoresis) ( 135). The sepa­
rated proteins can be imaged and quantified after detection with organic dyes (Coomassie 
blue) metal reduction (silver stain), fluorophores, metal chelators (Sypro Ruby-fluorescent 
metal chelator), or radiolabels. 2DGE has been used for identification of novel proteins in 
protein mixtures, as well as a method for purification of individual proteins prior to spectros­
copy ( 135). The technique is challenging, somewhat cumbersome, and requires substantial 
user expertise. It is predominately done in research laboratories and pharmaceutical compa­
nies as "discovery" for the search of novel proteins biomarkers, or pathway regulators that 
will lead to a better understanding of novel disease mechanisms. Two-dimensional gel elec­
trophoresis also serves generally as an enabling tool to better resolve complex protein mix­
tures to prepare them for identification and sequencing by MS ( 135 ). 
4.3. Matrix-Assisted Laser Desorption/Ionization Time of Flight 
Mass spectroscopy has evolved as a major method of analysis of the proteome. Matrix­
assisted laser desorption/ionization time of flight (MALDI- TOP) instruments have been 
developed to characterize proteins and peptides obtained from 2DE samples and character­
ization of peptide sequences, and by inference, gene sequences (143-145). MALDI-TOP is 
a form of comparative MS in which fragmentation patterns in peptides obtained from an 
electron bombardment arc compared to databases of known amino acid sequences. The 
MALDI- TOP instruments analyze crystalline protein substrates after laser pulsation followed 
by energy transfer desorption and gas-phase matrix ion production (143-145). Both nega­
tive and positive molecular ions are detected by the MALDI-TOP system. MALDI-TOP has 
been used in a variety of biologic and clinical applications including protein and peptide

Molecular Techniques in Cancer Diagnosis and Management 347 
analysis, nucleic acid sequencing , and drug target discovery (146,147). The MALDI-TOF 
technique is a major method of genotyping patient samples for the detection of clinically 
important SNPs and polymorphisms (148). 
4.4. Surface-Enhanced Laser Desorption and Ionization Time of Flight Mass 
Spectroscopy 
Surface-enhanced laser desorption and ionization (SELDI) is a form of mass spectros­
copy in which surface-enhanced affinity capture, desorption, and release are performed 
(149,150). This technique separates proteins according to their mass and electrical charge 
generating a spectrum of mass/charge peaks or amplitudes for 15,000 or more proteins or 
peptid es in a single analysis. The height of the peak represents the relative abundance of a 
protein in the sample. The speed and cost effectiveness of SELDI-time of flight (TOF) is 
ideal for profiling serum or bodily fluids for disease-specific patterns. 
The most successful application of SELDI is a surface extraction technique in which the 
extraction, presentation, and structural modification or amplification of the sample is per­
formed using a surface protein-chip array ( 149,150). SELDI proteomic arrays allow for 
detecti on of minute amounts of proteins and peptides in complex protein mixtures such as 
serum and body fluids. The arrays use covalent linkage of antibodies , receptors , enzymes, 
ligands, and lectins, as well as DNA and RNA. After protein-chip purification on the SELDI 
surface, TOF-MS with laser desorption is performed to characterize the peptides present in 
the unknown sample. Substantial infomatics analysis is then required to evaluate the presence 
and amount of various peptide s. The technique can be highly sensitive for the detection of 
low concentration peptides, that has caused concern as to possible decreases in specific ity. 
The SELDI technique has been applied to a wide variety of cancer in varying clinical 
situations (151). Recently, the SELDI proteomics array method has been combined with a 
self-learning bioinfomatic system and successfully detected peptide patterns characteristic 
of early stage ovarian cancer ( 152). Although further validation of this approach must be 
performed on larger groups of patients, the SELDI-TOF technique shows great promise as a 
potential method of developing new disease markers capable of detecting cancers at early 
stages. 
4.5. Immunohistochemistry 
Immunohistochemistry (IHC) has served as a cornerstone of paraffin -based testin g of 
solid tumors for diagnosis, prognosis, prediction of drug response, and validation of new 
drug and biomarker targets (153,154). The detection ofHER -2/neu protein in breast cancer 
sample s by IHC linked to use of the drug, Herceptin™ significantly increased awareness in 
the limitations of the technique especially when a semi-quantitative imperfect scoring sys­
tem is used (13, 14,155,156 ). Pre-analytic issues, including fixation, tissue proces sing, and 
antigen retrieval can greatly impact the final results of the procedures ( 157-160 ). Imag e 
analysis instruments show promise for quantifying results and reducing interobserver and 
intraobser ver variations in slide scoring after staining (161) Proper standards , controls , and 
protocols must be adhered to whether IHC is performed manually or on automated instru­
ments (157-160). Nonetheless, owing to the wide availability of antibodies, the familiarity 
ofthe procedure in most pathology laboratories and the adaptability to fixed paraffin embed­
ded tissues; it is likely that the role of IHC in oncology molecular diagnostics will continue 
for the near future.

348 
Table 7 
Protein-Based Arrays 
Type of array 
eDNA clone arrays 
Protein microarrays 
Antibody microarrays 
Aptamer microarrays 
Microfluidic arrays 
4.6. Protein Arrays Utility 
Drug development 
Serum diagnostics 
Antibody screening 
Unknown 
Cancer screening Current status 
Research 
Research 
Clinical trials 
In development 
In development Ross et al. 
A variety of protein arrays (Table 7) have recently been designed to facilitate biomarker 
discovery and clinical molecular diagnostics ( 162 ). 
4.7. Enzyme Immunoassays 
Advances in enzyme-based serum immunodiagnostics have included increased sensitiv­
ity, expansion of automated methods, and the discovery of new shed glyocproteins allowing 
for closer monitoring of epithelial malignancies ( 163,164 ). Furthermore, a number of inven­
tive technologies have recently been introduced to allow multiplex ELISA based determina­
tion of up to 18 analytes in the same assay (i.e., antibody arrays or beads). Multiplexing may 
allow assessment of the phenotypic and physiological context that the target is expressed, by 
comparing with known clinical markers (e.g., PSA, CA125). Correlation with known physi­
ological parameters will help establish the rules which a specific target gene or protein oper­
ates in normal and disease systems, what the most effective therapy may be, and what 
happens with therapy. 
4.8. Truncated Protein Assays 
Recently, assays have been designed to detect truncated proteins as indicators of both 
germ line and somatic genetic defects in various forms of cancer. An example of this 
approach is the clinically available peripheral blood-based truncated protein assay for the 
diagnosis of familial polyposis coli ( 165). A fecal digital version of the truncated APC pro­
tein assay has recently shown promise as a screening test for the detection of larger high-risk 
colonic adenomas and cancers ( 166). 
5. BIOASSA YS 
5.1. Ligand-Receptor Assays 
Ligand-binding assays have largely been replaced by direct immunoassays on tissue sec­
tions and cytosols and protein extracts of tumor tissues ( 167). The advantages of 
immunolocalization assays as currently used for determining estrogen receptor status in 
patients with breast cancer must be weighed against the risk of false positive results when 
compared with biochemical functional assays such as the dextran-charcoal radiolabeled 
estradiol binding technique ( 167). The inherent advantages of confirming both the measure­
ments of the presence of immunodetectable protein and of the functional status of a cancer-

() bp 
74 bp 
8 bp 
62 p 
5 p 
so bp 
6 bp 
(lnf nal 'untrol) 349 
Fig. 6. Telomerase detection in urinary cytologic specimens. using the telomeric repeat amplifica­
tion protocol (TRAP) method correlate to the presence of malignant cells. Lanes I, 2, 3 and 4 contain 
fluids with malign ant cells from different patients that show a ladder of base-pairs indicatin g the 
presence of telomerase activity. Lanes 5, 6, 7, and 8 are patient fluid s that were negative for malig­
nant cells and show no base-pair ladder. Lane 9 is the control cell line known to be positive for 
telomerase activity and lane 10 is the telomerase negative control fluid . 
related cell receptor may achieve increasing importance in the era of targeted cancer thera­
peutics ( 168). 
5.2. PCR-Based Ligand-Receptor Assays 
Although a variety ofPCR-based bioassays have been developed, the test that has achieved 
the most widespread use in clinical applications is the telomere amplification protocol or 
TRAP procedure for determining telomerase activity ( 169). This technique (Fig. 6) has been 
used in early detection strategies in several clinical settings, most notable for the surveillance 
of patients with recurrent urothelial carcinoma ( 170-172 ). This technique appears to be more 
sensitive for detecting low-grade bladder tumor s than conventional cytology, but has been 
criticized for its loss of specificity resulting from the relatively frequent finding of false­
positive tests (173 ). New slide direct measurements using both ISH and IHC have recently 
introduced, but have not had widespread evaluation as to their clinical utility ( 170-172). 
6. GENERAL ENABLING TECHNOLOGIES 
6.1. Tissue Microarrays 
Tissue microarrays (TMAs) have been described previously (173 -77). TMAs are facili­
tating drug discovery and development by industrializing the assessment of mRNA and pro­
tein target expression in large numbers of clinical defined human and animal samples 
( 173-174) . TMAs are also used to validate disea se specific association of novel tumor 
biomarkers, prognostic and predictive factors ( 178) (Fig. 7).

350 Ross et al. 
Fig. 7. Tissue microarray. A series of blocks from a set of patients with prostate cancer have been 
bored at 1. 2 mm and transferred to a recipient block to form the tissue microarray . Sections from the 
recipient block can now be used to study a variety of biomarkers using immunohistochemistry and in 
situ hybridization. Color figure available for viewing at www.humanapress.com. 
6.2. Single Cell Analysis and Laser Capture Microdissection 
The discovery of laser microdissection allowed for determining individual cell and tissue 
specific expression of DNA, RNA, and protein for both clinical and research samples ( 179). 
Prior to this discovery, the major method of separating complex cell and tissue mixtures for 
individual cell or group analysis was performed using a fluorescence-based cell sorter (flow 
cytometry) . Laser microdissection includes the techniques oflaser-assisted microdissection, 
laser catapault microdissection, and laser capture microdissection (LCM) ( 179). Easily 
applied to both frozen and paraffin sections, LCM features microscopic selection of indi­
vidual cells or minute tissue areas to be detached from the surrounding sample or, alter­
nately, the undesired components can be eliminated and the remaining cells of interest 
obtained for molecular analysis ( 180). LCM has enabled the genomic profiling of small 
tissue biopsies by preventing the dilution of mRNA signals of the desired (i.e., tumor) cells 
by large numbers of benign stromal and inflammatory cells (181,182). Subcomponents of 
individual tissues can be separately selected and the mRNA extracted from this minute 
material amplified by PCR-based strategies (Fig. 8). LCM has had a major impact in 
proteomics-based discovery where the ability to sample minute tissue areas and profile the 
proteins by two-dimensional gel electrophoresis and MALDI mass spectroscopy has 
enhanced novel peptide identification, post-translational gene modifications, and protein­
protein interaction studies (183-185). Similarly, LCM has been combined with eDNA 
microarray profiling to elucidate novel gene expression pathways in isolated populations 
from diseases such as prostate cancer ( 186).

Molecular Techniques in Cancer Diagnosis and Management 351 
8 
c 
J 
I I 
Fig. 8. Laser capture microdissection . On the left are serial pictures of artery showing intact speci­
men (A), of specimen after capture of smooth muscle (B), and the isolated small muscle cells (C). On 
the right are the bioanalyzer run (A) and densitometric scans (B, C) showing that high quality mRNA 
is obtained by extraction from 10,000 captures of artery smooth muscle as evidenced by the strong 
28S and 18S ribosomal RNA bands. 
6.3. Digital Image Analysis 
Computer-assisted digital image analysis has been an enabling system for quantitative 
data accumulation for a wide variety of molecular technologies, including genomic, 
proteomic, and tissue microarrays. Image analysis has also continued to be applied to the 
scoring of slides obtained from ISH and IHC procedures (187,188). Recently, image analy­
sis has been used to improve accuracy and reproducibility of the scoring of slides stained 
with antibodies to HER-2/neu protein ( 189-191 ). By employing cells lines of known HER-2/ 
neu protein expression with digital image analysis, it is anticipated that more reliable assess-

352 Ross et al. 
ment breast cancer specimens can be performed on archival formalin-fixed material and 
allow an improved selection of patients for potential HerceptinTM_based therapies. 
6.4. Microcapillary Electrophoresis 
Microcapillary fluidic technologies including electrophoresis have enabled the develop­
ment of high-throughput approaches to proteomics (137-142,192,193). These methods are 
currently allowing for rapid miniaturized and point of care approaches to molecular diagnos­
tics for cancer and show significant potential to create simplified, closed systems for genomic 
and proteomic profiling ( 192). 
6.5. Immunomagnetic Bead Peripheral Blood Cell Capture 
The immunomagnetic bead cell capture system (1 94,195) has enabled the collection of 
small numbers of cancer cells from peripheral blood, bone marrow and body fluids ( 196-198). 
Although still limited by the small numbers of cells captured in most clinical situations and 
the resulting minute amounts of DNA, RNA, and protein recovered for molecular analysis, 
this method combined with the latest , highly sensitive genomic and proteomic strategies 
shows promise as a method of performing drug response monitoring and pharmacogenomics 
to individualize therapy for cancer patients. 
6.6. Bioinformatics 
The wealth of data generated by the emerging high throughput genomic and proteomic 
biochips is totally dependent on the bioinformatics system chosen to evaluate the data 
( 199-201). Microarray technologies are having a major impact in cancer disease under­
standing, biomarker, and drug development, but continue to struggle with limitations cre­
ated by a current lack of data comparability (202). The pathway to clinical use for all new 
molecular diagnostics-based assays will require a sophisticated and robust bioinformatics 
platform that can support both the early method validation and the subsequent clinical trials 
required for regulatory and commercial success. 
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17 
DNA Repair Defects in Cancer 
Ramune Reliene and Robert H. Schiestl 
Cancer is the second leading cause of death in the United State s, exceeded only by heart 
disease. In the United States, one of every four deaths is from cancer ( 1 ). It has been estab ­
lished that cancer is a genetic disease. Carcinogenesis can be promoted by a single dominant 
mutation leading to expression of an oncogene. Alternatively, according to the two-step 
mutation model proposed by Knudson in 1971 (2 ), cancer may arise when a recessi ve muta­
tion in a tumor suppressor gene is expressed ( 3,4 ). In familial cancers, this occurs when an 
inherited mutation is followed by a loss of heteroz ygos ity event removing the wildtype (Wt) 
allele of the gene. In sporadic cancers, a somatic mutation occurs in one allele followed by 
loss of heterozygosity of the second allele of a tumor suppressor gene . In a more complex 
model of tumorig enesis, cancer risk is enhanced by a deficiency in DNA repair. Loss of 
DNA repair function leads to accumulation of a high frequency of mutations, including 
tumor-promoting mutations. Such mutations can occur as point mutations or as result of 
large- scale chromosomal rearrangements, such as chromosomal deletions, duplications, and 
transloca tions. Cancer formation can be initiated by these event s, if the deleted chromo­
somal region encodes a tumor suppressor gene or if an amplified region encodes an oncogene. 
In fact, the genomic instability resulting in loss and gain of whole chromosomes or large 
portions thereof has been observed in the majority of tumors (5). Such rearrangements can 
lead to gene disruptions that inactivate a tumor suppressor gene or alter the function of a 
proto-oncogene. DNA is subject to continuous damage by noxious exogenous chemical and 
physical agents or oxygen radicals produced by the normal cellular metaboli sm. About 
10,000 oxidative lesions are formed in our genome in each cell every day (6). In addition, 
some chemical bonds in DNA undergo spontaneous hydrolysis. The cell responds to DNA 
damage by inducing cell-cycle arrest and DNA repair or, when damage is too severe to be 
repaired, undergoes cellular death by apoptosis. There are four pathways for DNA repair, 
such as base excision repair (BER), nucleotide excision repair (NER), mismatch repair 
(MMR) and double-stand-break (DSB) repair (7,8). DSBs are repaired by either 
nonhomologous end-joining (NHEJ) or homologous recombination (HR) (7,9-11 ). Several 
inherited syndromes associa ted with a markedly elevated inciden ce of cancer involv e genes 
that are essential in DNA repair (Table 1). These includ e xeroderma pigmentosum (XP), 
hereditary non polyposis colorectal cancer (HNPCC), ataxia telangi ectasia (AT), Nijm egen 
From : Cancer Diagnostics: Current and Future Trends 
Edited by: R. M. Nakam ura, W. W. Grad y, J. T. Wu, and R. B. Nagle © Human a Press Inc., Totowa, NJ 
361

w 0\ N Table 1 
DNA Repair Deficiency is Associated With Carcinogenesis 
DNA repair 
deficiency Nucleotide­excision 
Mismatch DNA damage 
check point 
and DSB 
repair 
Other: DNA helicases Genes affected 
XPA-XPG, XPV MSH,MLH 
ATM, Trp53, 
NBS, FA, 
BRCAJ, BRCA2 BLM, WRN Syndromes Xeroderma pigmentosum, Cockayne's, trichothiodys­trophy 
Hereditary nonpolyposis colorectal cancer 
Ataxia telangiectasia, Li-Fraumeni, 
Nijmegen breakage, Fanconi's anemia 
Werner's, Bloom's Common types 
of cancer 
Skin Colorectal, endometrial, 
gastric 
Lympoid, breast, 
ovarian, various 
carcinomas, squamous 
cell sarcoma 
WRN-primarily sarcomas, also various 
types of carcinomas 
Bloom-lymphoid, various types of 
carcinomas, including 
Wilms tumor, 
osteosarcoma References 17-19, 21 
28-31, 33, 34 
47, 48, 55, 56, 61, 
70-72, 85-87 
79-81

DNA Repair and Cancer 363 
breakage syndrome (NBS), Li-Fraumeni syndrome , Bloom's syndrome, Werner's syndrome, 
and Fanconi's anemia. 
1.1. Base Excision Repair 
BER eliminates single damaged or inappropriate base residues by the action of special­
ized DNA glycosylases and AP endonucleases (7,12). After removal of the damaged base by 
a DNA glycosylase, incision by AP endonuclease, and excision of damaged nucleotide by 
exonuclease, the resulting gap is filled by DNA synthesis and ligation seals the remaining 
single stranded break. Apparently, absence of any of the DNA glycosylases results in small 
or moderate changes in spontaneous mutation frequencies, that may have an effect on the 
long-term integrity of the genome. 
1.2. Nucleotide Excision Repair 
The role of nucleotide excision repair (NER) in cancer first came to light through the 
study of inherited disease xeroderma pigmentosum (XP) ( 13 ). Patients with this autosomal 
recessive disease are very sensitive to ultraviolet (UV)-Iight that causes prominent pigmen­
tation in the sun-exposed areas. Additionally, patients have greater than 2000-fold increased 
risk of developing skin cancer ( 14 ). The incidence of XP varies from I in 250,000 in Europe 
and the United States to as high as 1 in 40,000 in Japan (15,16). Defects in any of seven 
genes, designated XPA-XPG, give rise to this disease. XP heterozygotes are at no higher risk 
for neoplasia than the general population ( 17). Deficiency in some of the XP genes may also 
lead to a combination of XP and Cockayne's syndromes or XP and trichothiodystrophy. 
Cockayne's syndrome and trichothiodystrophy alone do not show evidence of increased 
cancer, but are associated with congenital neurological degeneration and skeletal abnormali­
ties (18). 
NER is the most flexible of all DNA repair mechanisms because of its ability to eliminate 
numerous structurally unrelated DNA lesions caused by many exogenous mutagens. This 
repair removes the major UV -induced photoproducts such as cyclobutane pyrimidine dimers, 
as well as other DNA adducts, including polycyclic aromatic hydrocarbons, and cisplatin 
lesions (19,20). NER excises damage within oligomers that are 25 to 32 nucleotides long 
(7, 18,21). The NER process involves the action of about 20-30 proteins in successive steps 
of damage recognition, local opening of the DNA double helix around the injury, and inci­
sion of the damaged strand on both sides of the lesion. After excision of the damage-contain­
ing oligonucleotide, the resulting gap is filled by DNA repair synthesis, followed by strand 
ligation. 
1.3. Mismatch Repair 
The role of MMR in cancer came with the discovery of a group of patients with colon 
cancer that exhibited alterations of poly(A) or poly (A C) tracts in their genomes (22,23 ). Such 
dispersed repetitive sequences consisting of 10--50 tandem repeats of 1-6 base pairs were 
termed microsatellites. Alterations in the length of such microsatellite sequences gave rise to 
the term microsatellite instability (MSI). The link between MSI and MMR deficiency has 
been suggested when MSI was observed in bacteria with defects in the mismatch- repair 
genes mutS or mutL (24) and in the yeast homologues of either mutS or mutL (25 ). In humans, 
homologues of the E. coli mutS, MSH (26), and homologues of the mutL, termed MLH or 
PMS (27), were identified and their mutant forms were found in kindred with hereditary

364 Reliene and Schiestl 
nonpolyposis colorectal cancer (28-31 ). MSI occurs in approx 15% of sporadic (nonfamilial) 
colorectal cancers and in most cancer patients with hereditary nonpolyposis colorectal can­
cer (22,23,32). About 10% of endometrial and gastric cancer cases contain defects in MMR 
( 33 ). Patients heterozygous for a mutation in a MMR gene are prone to cancer (29,34 ). MMR 
enzymes repair mismatches of nucleotides that occur when DNA polymerase inserts the 
wrong base in newly synthesized DNA. Incorrectly paired nucleotides are excised from the 
mismatched strand and new DNA is synthesized (7). 
1.4. DNA Double-Strand Break Sensing and Repair 
Chromosomal double-strand breaks (DSBs) can be formed by oxygen free-radicals, ion­
izing radiation, DNA replication or topoisomerase failure. DNA DSBs are repaired by either 
nonhomologous end-joining (NHEJ) or homologous recombination (HR) (7,9-11 ). During 
NHEJ, the ends of broken DNA are often modified by the addition or deletion of several 
nucleotides prior to relegation. Impaired rejoining of DSBs may result in large-scale genomic 
rearrangements, including chromosomal translocations, inversions and deletions , the alter­
ations observed in many tumor cells (35-38). In HR events, the homologous sequences pro­
vide a template for the repair. The original sequence is restored when HR occurs from allelic 
sequences on the sister chromatid or homologous chromosome. HR is usually a precise type 
of DNA repair when recombination occurs between homologs . Repetitive DNA sequences 
comprising about 25% of mammalian genome (39) provide an alternative template for HR. 
This type of HR is not cell-cycle dependent but may lead to deletions, duplications , and 
translocation s, events that have deleterious consequences for genome integrity and are asso­
ciated with carcinogenesis. As an example, HR between Alu elements (40) resulting in tan­
dem duplication in the ALL-I gene is associated with acute myeloid leukemia ( 41 ). Therefore, 
HR may serve as a mechanism for both DNA repair and chromosomal instability depending 
on the template used. 
Genes involved in signaling and repair of DNA DSBs include ATM, NBS, Trp53, BRCAJ 
and BRCA2, FANC, WRN and ELM (38,42 -44) . Mutations in these genes give rise to cancer­
prone syndromes, such as AT, Nijmegen breakage (NBS), Li-Fraumeni (Trp53) , Fanconi's 
anemia (FA), Werner's (WRN) and Bloom 's (BLM) syndromes. Most of these disorders , 
such as AT, NBS, BRCA mutation-associated breast cancer, FA, and BLM syndrome are 
associated with marked sensitivity to ionizing radiation ( 45) and/or DNA cross-links, both 
known to strongly induce DNA strand breaks . Consequently, cells from these patients dis­
play elevated frequencies of chromosomal aberrations. 
AT is an autosomal recess ive disorder characterized by early onset progressive cerebellar 
ataxia, ocular telangiectasia (dilation of blood capillaries), immunod eficiency, sterility , and 
cancer predisposition (46-48). This pleitropic disord er occurs in 1 of about 300,000 births 
(49,50). Approximately 10% of the AT patients develop cancers and there is a 250-fold 
increased risk for lymphom as and a 70-fold excess risk for leukemias (51). Other types of 
tumors include gastr ic, liver, pancreatic, ovarian , breast, and salivary gland cancers (52). AT 
arises from a mutation of the ATM gene (53, 54) that encodes a serine/threonine kinase 
involved in sensing of DNA damage and transcriptional activation of numerous downstream 
effectors resultin g in cell cycle arrest followed by DNA repair. 
Nijmegen breakage syndrome (NBS) patients share the phenotype of AT patients , such as 
immunodeficiency, radiosensitivity, and predisposition to lymphoid malignan cies, but lack 
both ataxia and telangiectasia (55,56). The NBS syndrome is caused by a recessive mutation

DNA Repair and Cancer 365 
in the NBS1 gene (57,58). NBS 1 protein together with RAD50 and MREll form the RAD50/ 
MREll/NBSl protein complex, which has diverse functions, including recombination, 
telomere maintenance and S-phase checkpoint response to DSBs (59,60). 
Li-Fraumeni syndrome (61,62) is a dominantly inherited disorder (only one inherited 
allele is mutant) caused by a mutation in the tumor suppressor gene Trp53. Tumorigenesis in 
Li-Fraumeni patients is associated with the loss of the remaining functional allele and nearly 
100% of patients develop cancer (63 ). Some patients develop multiple primary cancers (64 ). 
A variety oftumors, such as breast, brain, leukemia, lymphoma, lung carcinoma, and adeno­
carcinoma usually appear in children and young adults. The p53 protein is a downstream 
regulator of the ATM DNA damage response pathway. This pathway plays a role in main­
taining genomic integrity by suppressing excessive HR (65-67). Aneuploidy often observed 
in tumors from p53 deficient mice suggests that the functional p53 protein prevents chromo­
somal loss (68,69). 
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 show an autoso­
mal dominant inheritance pattern, although tumors appear when somatic mutation occurs to 
alter the second allele. Individuals carrying mutations in BRCA genes primarily develop 
breast and ovarian cancers (70, 71 ). Mutations in the BRCA 1 gene are found in about 70% of 
families with inherited breast and ovarian cancers and 20% of the families with only breast 
cancer (72). Mutations in one allele of BRCA2 are associated with up to 85% risk of breast 
cancer and 15% risk of ovarian cancer (72). BRCA2 mutations are the most common muta­
tions identified in hereditary pancreatic cancer (73 ). Both BRCA1 and BRCA2 mutant cells 
are deficient in homologous recombination (74, 75) see Section 2.6. The role of BRCA pro­
teins in DSB repair might be implemented via its interaction with HR protein RAD51 
(70, 71, 76) and cell-cycle checkpoint response to ionizing radiation (77). BRCAl appears to 
interact with a protein complex RAD50/MRE11/NBS1 (78), the repair complex linked to 
both NHEJ and HR. 
Several cancer prone autosomal recessive syndromes are caused by mutations in RECQ 
helicase genes (79-81), such as Bloom's (BLM), Werner's (WRN) and Rothmund-Thomson 
(RecQL4) syndromes. The tumor spectrum for Bloom's syndrome patients is extremely 
diverse ( 82 ). This includes the type of cancers that are seen in the general population, such as 
leukemia , various types of carcinomas and lymphomas , and cancers that are rare in the gen­
eral population, such as Wilms tumor and osteosarcoma. Werner and Rothmund-Thomson 
patients develop primarily sarcomas. Werner's syndrome is an adult progeria syndrome that 
manifests into age-related traits after puberty, including osteoporosis, calcification of soft 
tissue, atherosclerosis, cataracts, and diabetes mellitus (83 ). Evidence suggests that BLM 
protein plays a role in repairing DNA damage via interaction with RAD51 (84). WRN pro­
tein interacts with several proteins involved in DNA repair , including the Ku70/Ku80 
heterodimer, DNA topoisomerase I, and p53 (83). 
Mutations in one of eight FANC genes give rise to Fanconi's anemia (FA), an autosomal­
recessive disorder associated with aplastic anemia resulting from progressive loss of bone 
marrow stem cells and elevated risk of acute myeloid leukemia (15,000-fold) and squamous 
cell sarcoma (85-87). The prevalence of the disease is about 1 in 200,000. The most charac­
teristic phenotype of FA deficient cells is hypersensitivity to DNA cross-linking agents , 
such as mitomycin C or diepoxybutane ( 88 ). The biochemical function of FANC proteins is 
not fully understood. The finding that the FANCD2 colocalizes with BRCAl into irradia­
tion-induced foci in the nucleus offers a hint in supporting the role of FANC in DNA repair

366 Reliene and Schiestl 
Table 2 
Assays for DNA Repair Deficiency and Chromosomal Rearrangement 
DNA repair deficiency Assay 
NER Host-cell reactivation 
MMR Microsatellite instability 
DSB Single-cell electrophoresis 
or comet 
DNA strand rejoining capacity 
Chromosomal and extrachro­
mosomal plasmid 
Cytogenetic assays: 
Chromosome banding 
Multicolor FISH (M-FISH) 
Spektral karyotyping (SKY) Ref. 
93 
97 
98, 101, 104 
115, 116 
117, 118, 123, 129-131 
105 
108 
109 
(89). Observation that BRCA2 restored resistance to mitomycin C in fibroblasts derived 
from FANCB and FANCDI patients and that both patients have biallelic inactivation muta­
tions of BRCA2 linked the FANC genes with BRCAI and BRCA2 in a common pathway 
(90 ). Human homologs of RAD54 harbor somatic mutation in some human cancers (91, 92 ). 
2. ASSAYS FOR DNA REPAIR DEFICIENCY 
Assays developed to assess the capacity of DNA repair in the different pathways or 
resultant chromosomal rearrangements are summarized in Table 2. 
2.1. Host-Cell Reactivation Assay 
Athas et al. developed a host-cell reactivation assay to measure NER capacity in response 
to UV irradiation and chemical-induced DNA damage (93). For this assay , damaged, 
nonreplicating plasmid DNA harboring the chloramphenicol acetyltransferase (cat) reporter 
gene is introduced into unexposed host lymphocytes by transient transfection. Efficiency of 
NER of the damaged bacterial cat gene is monitored proportionally as a function of reacti­
vated CAT enzyme activity following a 40 h repair/expression incubation period. The assay 
was validated by its ability to discriminate XP cells in severe (complementation groups A 
and D) and moderate (complementation group C) NER deficiencies. The host reactivation 
assay has been used to demonstrate reduced NER efficiency in basal cell carcinoma patients 
(94,95). The reduced DNA repair of UV-induced DNA damage contributed to the risk of 
sunlight-induced skin carcinogenesis in basal cell carcinoma. This assay allows indirect 
measurement ofthe extent and efficiency of overall cellular repair of DNA but is less suitable 
for evaluating the repair of strand breaks, as they reduce plasmid transfer frequencies (96). 
2.2. Detection of Microsatellite Instability 
Microsatellite instability (MSI) is a characteristic of colon cancers with underlying muta­
tions in DNA MMR genes (22,23,32). The MSI detection assay is based on PCR amplifica­
tion from 5 to I 0 microsatellite markers, poly( A) or poly (AC) tracks, and analysis of 
amplification products by denaturing polyacrylamide gel electrophoresis (PAGE) (97) (see 
also Chapter 19) High-frequency MSI is defined as appearance of new alleles for two or

DNA Repair and Cancer 367 
more of five microsatellite markers. MSI observed for one of five markers is reported as 
low-frequency MSI. If low-frequency MSI is observed, additional markers, up to a maxi­
mum of ten, are tested. Instability of between I and 3 out of 10 loci assayed is defined as 
low-frequency MSI, whereas instability at 4 or more loci is defined as high-frequencyMSI. 
High-frequency MSI has been found in most cases of hereditary nonpolyposis colorectal 
cancer ( 32). The MSI assay is routinely used in clinical molecular diagnostic laboratories. 
Determination of MSI requires the presence of instability in the markers used. This method 
does not detect gross chromosomal alterations including large deletions, duplication s, and 
trans locations . 
2.3. Comet Assay 
Single-cell gel electrophoresis or comet assay is a rapid and sensitive fluorescent 
microscopic method to examine DNA damage and repair at the individual cell level 
(www.cometas say.com). It can be applied to proliferating as well as nonproliferating cells. 
In this assay, single cells are embedded in a thin layer of agarose on a microscope slide and 
lysed to remove cytoplasm and the majority of nuclear protein s. The released DNA is sub­
jected to gel electrophoresis. If breaks are present , relaxed DNA loops and/or DNA frag­
ments migrate into the gel, forming an image resembling a tail when viewed by fluorescence 
microscopy. The relative tail intensity and length is proportional to the frequency of DNA 
breaks. The alkaline comet assay for measuring DNA strand break s induced by genoto xic 
agents was developed by Singh et al. in 1988 (98). The alkaline comet assay, and further 
developments thereof detects various other forms of DNA damage , such as oxidative DNA 
base damage and DNA-DNA/DNA -protein/DNA-drug cross-linking , and DNA repair in 
virtually any eukaryotic cell (99-104). By determining the removal (repair) of DNA damage 
over time, the comet assay can be used in the clinic as a diagnostic tool for monitoring DNA 
repair capacity, which may be us ed to diagno se DNA repair defici ency syndrome s. The 
classical comet assay combined with fluorescent in situ hybridizat ion facilitates identifi ca­
tion of DNA damag e at particul ar gen es or chrom osomes. Specifi c oligonucl eotide prob es 
labeled with the fluorescent tags are hybridized to the region of interest to evaluat e gene/ 
chromo some specific DNA damage induction or repair. The comet assay has many impor­
tant applications ranging from clinical investigations and molecular epidemiology to 
biomonitoring and nutritional toxicology. 
2.4. Cytogenetic Assays 
Chromo somal rearrangements formed because of improper DSB repair, can be detected 
by cytog enetic techniques (see also Chapter 18) Chromo some analy sis is one of the most 
commonly performed diagnostic genetic tests in oncology , pren atal, and reproducti ve 
medicine. 
The analysi s typically involve s identification of chromosomes based on size, morphol­
ogy, and alternating light and dark band patterns ( 105) . Such a systemic examina tion of the 
karyotype allows identification of numerical chromosomal abnormalities (gain or loss of 
whole chrom osome) and certain structural rearrangements (translocations, inversion s, dele­
tions , insertions). Classical cytogenetic methods detect prim arily ex chan ge aberrations 
betw een chromo somes in mitotic cells. Prep aration of metaphase chromosomes require s suc­
cessful culturing of cells, which is difficult to achieve for some types of cells. In addition, it 
can produce artificial chromosom e abnormalitie s. The development of fluor escence in situ

368 Reliene and Schiestl 
hybridization (FISH) techniques specific for distinct chromosomal regions has greatly 
advanced this methodology to allow measurement of intrachromosomal aberrations. In addi­
tion, the technique is no longer restricted to the analysis of mitotic cells. The locus-specific 
or whole chromosome-specific "painting" with fluorescently labeled probes allows visual­
ization of chromosomal regions or individual chromosomes in metaphase or interphase cells 
and the identification of both numerical and structural chromosomal aberrations with high 
sensitivity and specificity ( 106,107). Using a series of dye combinations or fluorochromes, 
each chromosome can be differentially labeled and detected. The multicolor chromosome 
painting provides the means to examine the entire genome in a single experiment. The 
multicolor FISH test is often referred to as either multiplex-FISH (M-FISH) ( 108) or spectral 
karyotyping (SKY) ( 109). The two methods differ in the way they acquire and process the 
chromosome images. M-FISH is based on the use of fluorochrome-specific optical filters 
( 108), whereas SKY is based on the spectral signature of each fluorochrome in the probe 
cocktail (109). Chromosome painting has developed into a versatile research tool for chro­
mosomal analysis in clinical and cancer cytogenetics ( 106, 110). This technique allows iden­
tification of the structurally abnormal chromosomes (marker chromosomes), cryptic 
translocations, and complex rearrangements (109,111-113), which cannot be identified by 
chromosome banding technology alone. Combination of chromosomal painting with a con­
ventional chromosome banding technology would greatly improve the diagnostics of clini­
cal specimen. However, the multicolor FISH tests require advanced microscopy equipment 
and a specialized software computer and are, therefore, limited to a few selected clinical 
cytogenetic laboratories. Further development and maybe automatization of this technology 
may increase its availability for most cytogenetic labs. 
2.5. Assays for Chromosomal Double-Strand Break Rejoining Capacity 
An assay with the ability to detect correct rejoining of radiation-induced DSBs would 
provide a useful tool to predict radiosensitivity and, hence, cancer predisposition in humans. 
Certain individuals cannot tolerate conventional dose of radiotherapy, thus determining 
radiosensitivity in cancer patients is a prerequisite prior to subjecting them to radiotherapy. 
The colony survival assay in which percentage of survival of irradiated cells is measured 
allows determination of radiosensitivity of lymphoblastoid cells from patient blood ( 114). 
By using this assay, elevated radiosensitivity has been identified in cells from AT and FA 
patients ( 45) (see also Chapter 22). 
There are several cellular assays available to monitor rejoining of the radiation -induced 
DSBs. A conventional fraction of DNA radioactivity released (FAR) assay ( 115) is designed 
to measure total rejoining. In this assay, cells are irradiated to induce DSB and allowed to 
repair. The DNA from 14C-thymidine-labeled cells is then separated by pulsed-field gel elec­
trophoresis (PFGE). The fraction of radioactivity released from the plug is measured by 
liquid scintillation counting of the sliced gel. An induction curve for FAR versus irradiation 
dose is used to obtain relative numbers of DSBs after repair. 
Correct rejoining of radiation-induced DSBs can be monitored by measuring reconstitu ­
tion of an original size Not 1 fragment on chromosome 21 (116). Following cell irradiation 
and DNA repair, DNA is digested with a restriction enzyme Notl, separated by PFGE and 
hybridized with single-copy DNA probes to Notl restriction fragments (3.2, 2 and 1.2 
megabase pair fragments of chromosome 21). DSB induction and joining of correct ends are 
estimated by comparison of the intact full size band with a smear of broken or misrejoined

DNA Repair and Cancer 369 
restriction fragments. The misrejoining frequency can be assessed by comparing results from 
this technique with results from a conventional FAR assay ( 116 ). A limitation of the assay is 
its requirement of rather high radiation doses. 
2.6. Plasmid Assays for Double-Strand Break Repair by NHEJ and HR 
A number of plasmid-based assays allow measurement of distinct pathways of DNA DSB 
repair, such as NHEJ and HR. DSB repair by HR can be measured utilizing the rare-cutting 
I-Scel endonuclease ( 117). The assay determines 1-Scel-induced DSB repair efficiency by 
HR between tandem repeats of an inactivated bacterial antibiotic resistance gene or marker 
gene, such as CAT, luciferase, or GFP genes (118). The assay is implemented by transfec­
tion of two plasmids. One plasmid contains a substrate for HR (e.g., two copies of a gene) 
where one copy is inactivated by introducing the 18 base pair recognition sequence for 
1-Scel endonuclease. The second copy is made inactive by other means. Chromosomal or 
extrachromosomal DSB repair can be examined. When the HR substrate is integrated into a 
chromosome by stable transfection, repair of chromosomal DSBs induced by l-Scel is mea­
sured . Upon transient plasmid transfection, repair of DSBs within a plasmid (e.g., extrachro­
mosomal DNA), is monitored. A second plasmid containing the 1-Scel expression cassette is 
transiently transfected into the cells. I-Scel endonuclease generates a DSB at an 1-Scel site, 
which leads to HR between the tandem repeats and results in reconstitution of antibiotic 
resistance or a marker gene. The frequency of HR is assessed by the number of clones being 
able to grow on antibiotic containing media or by the expression of a fluorescent marker 
gene, respectively. The use of a fluorescent marker gene rather than antibiotic resistance 
gene is favorable, since it eliminates the need for colony formation, which might take a long 
time and cannot be used for primary cells. Reduced repair of I-Scel breaks has been observed 
in a number of cell lines deficient in recombination associated genes, such as RAD51, RAD54, 
XRCC2, XRCC3, BRCA1, and BRCA2 (74,75,119-122). 
Extrachromosomal HR recombination can be assessed using a transient luciferase expres­
sion assay in which HR between fragments of the luciferase gene in plasmid DNA restores a 
functionalluciferase gene (123). 
Chromosomal NHEJ can be examined by estimating efficiency of colony form ation on a 
selective media following random stable integration of a linearized plasmid bearing an intact 
antibiotic resistance gene ( 118,124-126). Extrachromosomal DNA rejoining capacity can 
be measured by using a luciferase reporter system, in which a linearized plasmid transfected 
into a cell will express the luciferase gene, once NHEJ and recircularization of the plasmid 
occurs ( 127,128 ). 
Recently, several plasmid assays were developed based on recon stitution of genes encod­
ing fluorescent proteins. Transient transfection and F ACS analysis is carried out on trans­
fected cells to estimate repair efficiency. These assays are sensitive and rapid to perform and 
may soon be adapted for a broad application in human cells for prognostic and diagnostic 
purposes. Additionally, the requirement for the cells to grow up into colonies will be elimi­
nated. The rapid dual fluoresc ence (RDF) assay determines the correct rejoining of DSBs 
induced by a restriction enzyme (129 ). The plasmid contains the genes for yellow fluores­
cent (YFP) and green fluorescent proteins (GFP), where the GFP gene is digested at a unique 
restriction site prior to transfection. Plasmid DNA will express YFP but not GFP unless 
correct repair of the DSB has taken place. A plasmid designed to measure HR capacity in 
human cancer cells (130) contains an intact , emission-shifted, blue variant of GFP (BFP)

370 Reliene and Schiestl 
with a 300 nucleotide stretch of homology to an inactive copy ofGFP. HR between two GFP 
sequences creates a functional GFP, whereas in the absence of HR only functional BFP is 
present. 
A plasmid system has been developed as a rapid assay to measure the efficiency and the 
proficiency of both, NHEJ or HR, after transient transfection ( 131 ). Two constructs allow 
the independent expression and simultaneous detection of the GFP protein, as a marker of 
transfection, expressed constitutively in the cells that have incorporated the DNA. The YFP 
protein, as a marker of recombination can only be expressed if the restriction enzyme intro­
duces DSBs in the vector. The substrates are linearized by restriction digestion to create a 
DSB, and transiently transfected into cells. For analysis of DSB repair by NHEJ a plasmid is 
linearized at a multicloning site located between the promoter and YFP structural gene. 
Rejoining of the DNA termini reconstitutes the original promoter-gene sequence and the 
recombination marker can be expressed. For analysis of DSB repair by HR, a second plas­
mid is linearized at the multiple cloning site located in the intervening sequence of a dupli­
cation-deletion in the YFP gene. Deletion of the duplicated sequence by HR reconstitutes the 
intact sequence of the YFP gene and allows its expression. In both assays, the recombination 
efficiency is determined as the number of recombinants as a fraction of the number of 
transfectants. Finally, one can sequence through the junctions of the NHEJ events to deter­
mine the pathway of the NHEJ event, such as the occurrence and extent of microhomology. 
With this plasmid system it was determined that Ku86 mutation reduced NHEJ to about 30% 
(I 3 I) and a deficiency in Wrn resulted in a significantly increased length of ON A deletions 
during NHEJ ( 132). 
3. ASSAYS FOR GENOMICS AND PROTEOMICS 
With the recent success in the sequencing of the human genome (approx 30 to 35,000 
genes) and the explosion of information in the field of genetics, it seems that the importance 
of genetics in public health will become more important than ever. Interindividual differ­
ences in cancer predisposition occur ( 133 ). Therefore, it is prudent to employ large-scale 
screening methods based on the sequence of the human genome to investigate such 
interindividual differences. Advances in automation and bioinformatics gave rise to a new 
discipline of biology termed genomics; a systematic approach to conduct global and com­
prehensive studies about genes and genomes. A full biological description of the molecular 
processes going on in the transition from normal to neoplastic growth is currently underway. 
Large-scale screening assays that can be used for cancer research include determination of 
the entire gene expression profile that is the entirety of the expression levels of all human 
genes , and the proteome that is the entirety of all proteins in a cell ( 134 ). 
The gene expression profile is established by using RNA isolated from normal or cancer 
cells, reverse transcribed into eDNA, labeled with different dyes, and hybridized to probes 
immobilized on glass or plastic slides in discrete spots, so that the position of each spot is 
assigned. The competitive hybridization of two differently labeled cON As hybridized to the 
discrete probes makes examination of differences in expression patterns possible. This analy­
sis has been shown to have great potential for molecular diagnosis of cancer. Two types of 
diffuse large B-cell lymphomas in patients exhibiting vastly different survival rates after 
treatment that cannot be characterized by currently available micro- or macroscopical patho­
logical examinations were classified by different gene expression patterns (135 ). Further­
more, studies of primary breast tumors from patients with BRCAJ mutations and patients

DNA Repair and Cancer 371 
with BRCA2 mutations identified 176 genes differently expressed between the two different 
tumor genotypes ( 136). 
Cellular functions are carried out by proteins . Proteomics cannot only characterize the 
expression levels of all proteins but also protein modifications that may regulate their func­
tions. Proteins are separated by two-dimensional electrophoresis and after isolation of spe­
cific protein spots from the gel, mass spectrometry is used to unequivocally identify the 
specific proteins. With this method, unique membrane proteins with potential roles in clini­
cal cancer were discovered in breast cancer cells ( 137). 
In summary, both gene expression profiling and proteomics are novel evolving technolo­
gies, but by further extension, the current studies indicate that both technologies might also 
be useful to determine cancer predisposition in people and establishing profiles as molecular 
markers of predisposition. 
This work was supported by grants from the National Institute of Environmental Health 
Sciences, NIH ROl No. ES09519 as well as National Cancer Institute, NIH ROl No. 
CA82473, as well as funding from the UCLA Center for Occupational and Environmental 
Health (to RHS), and a post graduate research fellowship of the UC Toxic Substances 
Research and Teaching Program (to RR). 
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18 
Chromosomal and Molecular Cytogenetic Assays 
for Evaluation of Human Tumors 
Peter C. Hu, Vicki L. Hopwood, and Armand B. Glassman 
1. INTRODUCTION: HISTORY OF CANCER CYTOGENETICS 
1.1. Pre-Hypotonic Era and Techniques 
In the Magnificent History of Genetics, written by Dr. Hsu ( 1 ), the time before 1952 was 
characterized as the "Dark Ages" of cytogenetics . Actually, the study of chromo somes started 
earlier in the 19th century. Walther Flemming discovered lampbrush chromosomes, 
described them in 1882, and coined the term "mitosis" (2 ). Balbiani communicated the struc­
ture of the polytene chromosomes in 1881 (3). Wilhelm Waldeyer-Artz coined the term 
"chromosome" in 1888 (4). Using grasshopper testes , Walter Sutton published The Chromo­
some Theory of Heredity in 1903 (5). Boveri, working with chromosomes of sea urchins in 
culture, theorized that chromosome changes were the cause of neoplasia (6). 
Early in the 1920s, it was believed that the chromosome number of man was 48. This 
number was derived by Painter ( 1) by using thin slices of testes taken from executed prison­
ers. Subsequently, tissue culturing techniques, mitotic arrestants, and more sophisticated 
study of chromosomes demonstrated that this number was incorrect. 
1.2. Post-Hypotonic Era and Techniques 
In 1952, T.C. Hsu reported the use of low-salt-concentrate solutions, which resulted in a 
better spread of chromosomes ( 1 ). In 1956, Tjio and Levan used these techniques to identify 
the correct chromosome number of man as 46 (7). Chromosomes were still stained without 
the benefit of banding differentiation until 1968 when Caspersson introduced Giemsal 
Trypsin/G-banding (G-banding) (8). Despite the fact that chromosome banding was not yet 
available, Nowell and Hungerford described the first consistent chromosomal abnormality 
associated with a human neoplasm, the Philadelphia chromosome (9 ). The Philadelphia chro­
mosome was thought to be chromosome 22. This abnormality was a consistently demon­
strated aberration associated with chronic myelogenous leukemia . At the time, chromosomes 
were classified by size and their centromere location. It was thought that what we now know 
as chromosome 22 was smaller than what we now know as chromosome 21. After Q-and 
G-banding, it became possible to distinguish chromosomes of similar size and shape by their 
distinctive banding patterns. Additional refinements of banding techniques included high­
resolution banding introduced by Yunis in 1976 (10). GTG remains the standard for chro­
mosome banding analysis. It is used as the initial screening technique for karyotypic 
From: Ca11cer Diag nosti cs: Current and Futur e Trm ds 
Edited by : R. M. Nakamura, W. W. G rody, ). T. Wu, and R. B. Nagle © Hum ana Press Inc., Toto wa, Nj 
379

380 Hu, Hopwood, and Glassman 
abnormalities in a variety of cancers and constitutional disorders. This technique permits a 
general survey of the genome. 
1.3. Molecular Cytogenetics Era and Techniques 
The era of molecular cytogenetics has begun. The use of DNA probes is incorporated into 
cytogenetic practice to determine loss, gain, or rearrangement of specific genes. It has pro­
vided increased resolution and sensitivity of analysis . In 1986, Gray and Pinkel ( 11) discov­
ered that blocking DNA could be used to suppress interspersed repetitive DNA sequences 
and this largely eliminated nonspecific signals and permitted better fluorescence in situ 
hybridization (FISH) . From 1991 to 1999, a series of advances occurred, including compara­
tive genomic hybridization (CGH) by Kallioniemi ( 12), spectral karyotyping (SKY) by 
Schrock (1 3 ), MFISH by Speicher, Ballard, Ward (1 4 ), Rx Fish by Muller, Rocci and 
Ferguson-Smith in 1997 ( 15 ), and M-banding in 1999. All resulted in the expanded applica­
tion of FISH technique. The techniques of CGH, RXFISH, SKY, MFISH, and M-banding 
are FISH techniques for screening and evaluating the entire genome. These methods comple­
ment and enhance our ability to determine chromosomal aberrations in GTG karyotyping. 
They have provided an increased ability to detect and describe complex chromosomal 
changes that are characteristic of neoplastic cells and help bridge the gap between molecular 
and classic cytogenetics. 
2. CYTOGENETIC EVALUATION OF LEUKEMIAS 
2.1. The Myeloid Leukemias 
2.1.1. Acute Myelogenous Leukemia 
Between 40 and 50% of patients presenting with acute myelogenous leukemias (AML) 
have an abnormal karyotype when examined by conventional method s. Additional informa­
tion regarding cryptic translocations and subtle molecular genetic changes can be detected 
by using FISH, polymerase chain reaction (PCR), real-time PCR (RT-PCR), quantitative 
PCR, and gene sequencing. These techniques are useful for the initial diagnosis, following 
response to therapy, evaluation of minimal residual disease and recurrence. Conventional 
karyotyping is limited in its utilization to the characterization of chromosomal change s noted 
if the cells undergo metaphase in tissue culture. The use of molecular cytogenetic changes 
(i.e., locus-specific FISH and PCR), permit evaluation of cells that are in interphase and 
various other phases of the cell cycle. 
To perform conventional karyotyping, a minimum of 20 metaphases are analyzed. 
Clonality requires that two of the metaphases have the same karyotypic make-up . If a patient 
has two out of 20 metaphases with trisomy chromosome 8 and is a male, his karyotype 
would be 47,XY,+8[2]/46,XY[l8] to describe his 20 metaphases. On the other hand , changes 
that are associated with deletions of all or part of a chromosome require that three metaph ases 
have the abnormality before clonality is declared. Exceptio ns to this are if the patient had a 
known chromosomal abnorm ality (i.e., translocation 9:22 ft(9;22)l, was treated), and has 
one out of 20 metaphases with the t(9:22); that one metaphase with the translocation would 
be reported because of the obvious historical clinical data and clinical significance. Cells 
unable to undergo mitosis and having no metapha ses cannot be characterized by conven­
tional karyotyping and the techniques of FISH and or PCR must be used to evaluate chromo­
somal abnormalities. Tissue culture of bone marrow, peripheral blood, or lymph node

CMC Assays for Evaluation of Human Tumors 381 
specimens requires from 24 to 72 h for growth prior to harvesting to obtain metaphases. 
Mitogens (e.g., lipopolysaccharide [LPS] for B cells and phytohemagglutinin [PHA] for 
T cells) can be used to increase the yield of metaphases. There is good correlation (>90%) 
for conventional karyotyping and molecular techniques for assessi ng the known abnormali­
ties of t(9:22), t(8:21), inv(l6), t(15: 17) and deletions of llq23. Each week at the University 
Texas MD Anderson Cancer Center a leukemia profile meeting is held. At this meeting 
patient clinical information, pertinent hematopathology, flow cytometry, molecular diag­
nostics, and cytogenetic findings including FISH are integrated, discussed, and correlated. 
Chromosomal changes seen in AML include changes in number and structure. Structural 
abnormalities include translocations (t); deletions (del); additions (add); and occasionally 
other changes such as inversions (inv); homogenously staining regions (hsr); double min­
utes (dm), and ring (r) alterations to the chromosomes. Unidentified chromosomes are clas­
sified as markers (mar). Because the diploid karyotypic state is either 46,XX (for female s) or 
46,XY (for males) any other numerical changes are considered either hyperdiploid (>46 
chromosomes) or hypodiploid (<46 chromosomes). A pseudodiploid state exists where the 
chromosome number remains 46 but there is some structural chromosome abnormality such 
as at, del, or add. An example of this would be 46,XY,t(9 ;22)(q34; ql1.2), which is a 
pseudodiploid clone. Frequent chromosomal changes include the trisomy state, represented 
as a plus sign. For instance , a patient with a myeloproliferative disorder with a trisomy 8 
would be 46,XX,+8. Various chromosomes may be added or deleted in whole or part. Loss of a 
chromosome is represented by a minus sign, so monosomy 7 would be represented as 45,XY, 
-7. Partial loss of a chromosome, for instance , a deletion of part of the q arm of chromosome 5 
would be represented as 46,X X,de l(5)(q31q 35) (16). 
Cytogenetic changes that relate to the French American British (FAB) classification of 
AMLs include the t(8:21 )(q22;q22) associated with M2; t(15; 17)(q22;q 11.2-12) present in 
M3; inv(l6) seen with M4Eo ( 17); and t(9;ll)(p22;q23) and other llq23 deletions or trans­
locations that are noted in M5. Alterations of 3q especially translocations or inversion s of 3q 
have been associated with thrombocytosis , platelet abnormalities and M7. 
The prognosis of AML has been clinically associated with karyotypic abnormalities . In 
general, t(8;21), t(15;17), and inv(16) are considered favorable cytogenetic changes and 
responsive to chemotherapy. Cytogenetic changes involving loss of part or all of chromo­
somes 5 and 7, as well as trisomie s 8, are considered of poor prognostic significance. Karyo­
types that are diploid or have insufficient metaphases for cytogenetic diagnosis are 
considered of intermediate predictive value. 
Other cytogenetic abnormalities that are seen in AML include: trisomy 8, monosomy 7, 
deletion of7q, monosomy 5, and deletion of Sq. Each of these occurs approx 10% of the time 
in patients with karyotypic abnormalities of AML. Deletion of 20q is seen in 5% or less of 
the patients with AML. llq23 deletions and translocations involving llq23 have been 
reported in various types of AML. Often llq23 abnormalities are part of more complex 
karyotypic abnormalities. The use of karyotype s for evaluating and assisting morphology 
and in use for prognosis is ongoing and expanding, particularly through the use of locus 
specific probes applied with FISH or spectral karyotyping (SKY). Favorable vs unfa vorab le 
karyotypes may result in alteration or selection of specific chemotherapeutic protocols 
depending upon the institution.

382 Hu, Hopwood, and Glassman 
2.1.2. Myelodysplastic Syndromes and Therapeutic Myelodysplastic Syndromes 
Myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia 
(CMML) are undergoing continued evolution in terms of classification, diagnosis, and treat­
ment. Approximately 40 to 50 ±% of MDS cases have recognizable cytogenetic abnormali­
ties. Despite this, specific clonal karyotypic abnormalities are not as well recognized as in 
the AMLs. A significant percentage of MDS patients evolve into AML and many of the 
chromosomal changes are similar to those seen in AML. MDS abnormalities include partial 
chromosome deletions, additions , and losses of entire chromosomes. No specific transloca­
tions are specified. Less than 50% of the cases with refractory anemia or refractory anemia 
with ringed sideroblasts show clonal abnormalities. More than 50% of the cases with high­
grade refractory anemia with excess blasts or refractory anemia with excess blasts in transi­
tion show clonal abnormalities (18). 
In a study from UTMDACC, our CMML population showed abnormal karyotypes in 34% 
of the patients. Reports in the literature indicate abnormalities in 30 to 40% of CMML. 
Karyotype abnormalities have failed to show significant independent correlation with sur­
vival in CMML. 
Therapeutic myelodysplastic syndrome (tMDS) is of increasing importance and occurs 
primarily in patients previously treated with alkalizing chemotherapeutic agents and/or ion­
izing radiation and topoisomerase inhibitors. Overall, these patients may account for as many 
as 10 to 15% of all cases of MDS and leukemia. The number of these patients may continue 
to increase as patients following therapy are living longer. tMDS usually occur between 
2 and 6 yr post-therapy. The karyotypic changes seen include monosomy 5 and 7 and dele­
tion of 5q and 7q as well as 11q23 abnormalities. 11q23 abnormalities are thought to be 
specifically related to prior treatment with topoisomerase inhibitors. 
2.1.3 Myeloproliferative Syndromes 
The chronic myelogenous proliferative syndromes are represented primarily by chronic 
myelogenous leukemia (CML). 
Nowell and Hungerford described a shortened G-group chromosome associated with CML 
in 1960. This was the first chromosomal abnormality to be recognized as a recurring aberra­
tion in a human cancer. Subsequently, this "Philadelphia" chromosome was identified as 
chromosome 22 and was the result of a reciprocal genetic exchange between chromosome 
22 and chromosome 9. The genes involved include the abl gene in the region of chromosome 
9q34 and the breakpoint cluster region (bcr) gene in the region of chromosome 2q11.2. 
Approximately 95% of the patients with CML that meet morphological and clinical criteria 
of the disease have the t(9;22)( q34;q 11.2). Cytogenetics can aid in the initial diagnosis of 
CML, in the response to therapy, and in looking for minimal residual disease. Increased 
analytical sensitivity can come from the use of FISH techniques to identify the Philadelphia 
chromosome, particularly in looking for minimal residual disease or CML recurrence in the 
bone marrow. 
CML in its early chronic phase usually presents with t(9;22) as a single chromosomal 
change. As the disease progresses and enters a more accelerated phase or blast crisis there 
may be additional chromosomal alterations. The most common alterations include an addi­
tional Philadelphia chromosome [trisomy der(22)t(9;22)], trisomy 8, isochromosome 17q 
[i(17)(q 10)], and trisomy 19. These so-called "clonal evolutionary changes" can also occur in 
combinations and are associated with a poorer prognosis for patients.

CMC Assays for Evaluation of Human Tumors 383 
It should be noted that t(9;22)(q34;q 11.2) can also be seen in up to 30%of ALL in adults 
and about 5% of childhood ALL. Essentially, many of the ALLs are associated with a differ­
ent breakpoint region and a protein of approx 185-190 kDa as a result of the fusion gene end 
product. In the CML, the fusion gene produces a protein of approx 210 kDa. The molecular 
genetic changes depend upon varying breakpoint regions and are described in other chap­
ters. Occasionally, variant translocations are seen that involve the chromosomes 9 and 22 
and an additional third or more chromosomes. It is thought that in the three-way variant 
translocations that the chromosome breaks occurred simultaneously and that material is trans­
located from the 9q region to the 22q region, the 22q region subsequently is transferred to 
the third chromosome, and the third chromosome then translocates back to the 9q34 
breakpoint region. These derivative t(9;22) rearrangements can occur as either two or three 
step rearrangements . In approx 3% ofthe cases, a Philadelphia chromosome (der(22)t(9;22)) 
can not be identified by conventional cytogenetic techniques , but is identified by FISH. 
Even greater analytical sensitivity can be obtained by molecular diagnostic techniques such 
as real time quantitative PCR, especially when looking for minimal residual disease ( 19 ). 
2.2. The Lymphoid Leukemias 
2.2.1. Acute Lymphocytic Leukemia 
Acute lymphocytic leukemias (ALLs) are observed in adults and children. The majority 
of ALLs are of B-cell derivation. The most common leukemia subtype in children is ALL 
which accounts for approx 75% of the cases of childhood leukemia. Characterization of the 
chromosomal abnormalities in childhood leukemia is in some ways of greater significance 
than in adults. The number of chromosomes and type of translocation has a significant prog­
nostic value. For instance, in childhood leukemia the modal number of chromosomes is 
classified into five subtypes. The first subtype is karyotypes that are hyperdiploid with greater 
than 50 chromosomes, including those that are near-tetraploid; a second category of hyper­
diploid karyotypes that have between 47 and 50 chromosomes; a third group is the 
pseudodiploid karyotype with 46 chromosomes that have structural or numerical abnormali­
ties; a fourth is the diploid karyotype with 46 apparently normal chromosomes; the fifth 
subtype is the hypodiploid karyotype with fewer than 46 chromosomes. The ploidy state is 
predictive of clinical outcome. Patients that are hyperdiploid with 51 plus chromosomes 
have a more favorable prognosis and a higher cure rate than other categories. The hyperdip­
loid 51 plus chromosome numbers represent about 25 to 30 percent of children presenting 
with ALL. Near triploidy (69-81 chromosomes) cases of childhood ALL are extremely rare, 
whereas about 3% of adult ALL cases present with this pattern. The near tetraploidy range 
occurs in 1 to 2% of childhood and adult cases and there appears to be a preponderance of 
T -cell ALLs in this group. Of those patients that present with a hyperdiploid count the median 
modal number of chromosomes is 55. This hyperdiploid state occurs, in 25 to 30% of chil­
dren but only about ten to 20% of adult ALL. Approximately 10 to 15% of both childhood 
and adult ALL are diploid (20). 
Three categories of hypodiploid ALL are recognized . These include chromosome counts 
of 41-45, 30-40, and less than 30 chromosomes. Hypodiploidy with a modal number of 45 
chromosomes occurs in 7-9% of both child and adult ALL. The hypodiploid state is associ­
ated with a poorer prognosis especially in childhood ALL. 
Translocation t(9;22)(q34;q 11.2) occurs in approx 20 to 30%of adult ALL and is associ­
ated with a poor prognosis. Childhood ALL with t(9;22) occurs in less than 5% of cases.

384 Hu, Hopwood, and Glassman 
Translocation 9;22 ALL carries a poor prognosis both in adults and children. Translocation 
t( I; 19)( q23;p 13.3) occurs in approx 3 to 6% of childhood and adult ALL. This translocation 
tends to be associated with ALL of the pre-B cell type. llq23 abnormalities involve the 
MLL (myeloid-lymphoid leukemia or mixed lineage leukemia) gene and are seen in approx 
50 to 60% of the ALL cases in children younger than one year of age. Translocations with 
llq23 have been reported with chromosome 4q21, 9p22, 1 Op 12, and 19p 13.3 among others. 
Translocations of t(11; 19)(q23;p13.3) and t(6; 11)(q27;q23) have been reported in cases of 
acute myelomonocytic and monocytic leukemia as well. 
Other less common abnormalities include deletions of 6q, 9p additions and deletions, 12p 
deletions, and or translocations. 
Burkitt's lymphoma, a type of B-cell ALL, is associated with three recognized transloca­
tions involving chromosome 8 and either the heavy-chain immunoglobulin gene , or the K-or 
A.-light-chain genes. These. trans locations are t(8; 14 )(q24;q32), t(2;8)(p 1 1 ;q24 ), and 
t(8;22)(q24;q 11) (21 ). T -cell leukemias represent about fifteen percent of all childhood ALL 
and are associated with chromosomal abnormalities in T-cell receptor regions. These include 
the T -cell receptor for a and 6 at chromosome 14q 11.2, T -cell receptor 13 at chromosome 
7q35, and T-cell receptor y at chromosome 7p15. 
2.2.2. Chronic Lymphocytic Leukemia (CLL) 
CLL is the most common type of leukemia found in adults. More than 90% of the CLL 
patients have a proliferation of B-cell lymphocytes, and the remainder have T-cell CLL. 
Clonal aberrations in B-cell CLL are seen in approx 30% of cases by conventional cytoge­
netics. Additional chromosomal abnormalities can be observed with the use of FTSH. Some 
of the more common chromosomal abnormalities include trisomy 12 found in approx 15 to 
20% of cases, deletions of 6q, particularly in those patients progressing to prolymphocytic 
leukemia (PLL), and deletion of 13q, which seems to have a poor prognosis in CLL, lym­
phomas and multiple myeloma (22). 
3. CYTOGENETIC EVALUATION OF LYMPHOMAS 
3.1. Non-Hodgkin's Lymphoma 
Non-Hodgkins lymphoma (NHL) comprises a diverse group of lymphomas made up of 
B-or T-celllymphocytes. Definitive diagnosis of B or T components requires flow cytometry 
and molecular diagnostic techniques (i.e., PCR). Obtaining good growth and the low prolif­
erative index of lymphomas require consideration for the use of mitogenic stimulation (i.e., 
LPS or PHA) and/or molecular techniques such as FISH and PCR. 
The more common translocations seen on cytogenetic evaluation include t(2;5)(p23;q35) 
in anaplastic large cell lymphoma (ALCL), which are often of the T-cell type, although they 
have also been reported in B-celllymphomas. Translocation t(14;18)(q32;q21.3) is consid­
ered to be the cytogenetic hallmark of follicular cell lymphomas. Translocation 
t(11; 14)(q 13;q32) seen in approx 8 to 10% of adult lymphoma cases is associated with mantle 
cell lymphoma. In addition to these changes, there are also numerical changes, particularly 
trisomy 12, trisomy 7, and trisomy 3. Structural changes including the deletion of 6q and 13q 
abnormalities also are useful in the diagnosis and prognosis of lymphomas (23 ). Multiple 
myeloma has been associated with translocation t( 11; 14) and carries a poorer prognosis with 
deletion l3q.

CMC Assays for Evaluation of Human Tumors 385 
No specific useful conventional cytogenetic information is available for Hodgkin's 
lymphoma. 
4. THE CYTOGENETIC EVALUATIONS OF SOLID TUMORS 
4.1. Epithelial Tumors 
In the field of clinical applied sciences, human cytogenetics is relatively new compared to 
other techniques. It was not until the mid-1950s that human chromosomes were clearly iden­
tified through the works of Hsu and others ( 1, 7). Nowell described thePhiladelphia 
chromosme, the first chromosomal abnormality associated with human malignancy in 1960 
(9). The debate of whether or not these chromosomal changes precede the development of 
malignancy or if they occur as secondary changes resulting from the development of malig­
nancies, has been going on for years (24). 
For most of the hematopoietic cancers, initiation begins with the activation of an oncogene 
followed by the loss of a suppressor gene. Although little is known about the activation of 
solid tissue and organ tumors (STOT), the majority of these cases are the result of the loss of 
suppressor genes associated with the activation of an oncogene (24 ). Part of the reason for 
the lack of knowledge comes from the difficulty of culturing solid tumors. However, recent 
culturing techniques have yielded successful analyzable karyotypes that show increasing 
varieties of chromosomal abnormalities for STOT compared to hematological malignancies. 
Thyroid adenomas, colorectal adenomas, and salivary gland adenomas are perhaps the 
three most studied epithelial tumors . Over 60% of salivary gland adenomas have changes 
involving chromosomes 3, 8, and 12 (25). However, abnormalities involving chromosomes 
8 and 12 have not been reported in the same tumor. Therefore, it is expected that rearrange­
ments involving these two chromosomes have different pathways. Rearrangements of chro­
mosome 10q and 11q have been associated with thyroid carcinomas (26). 
Colorectal adenomas have been shown to have aberrations involving extra copies of chro­
mosomes 8 and 13. Colorectal carcinomas generally have complex karyotypes. Genes located 
on chromosome 5 and 20 have shown to be involved with this particular cancer. Molecular 
studies have revealed specific genes associated with patients of familial or inherited associ­
ated polyposis and hereditary nonpolypopsis colorectal cancer (HNPCC). In addition, on the 
short arm of chromosome 3 lies a gene that is associated with HNPCC. The gene locus for 
familial adenomatous polyposis (FAP) has been mapped to the locus 5q21 and has been 
subsequently cloned (24 ). 
Within the malignant epithelial neoplasms, certain chromosomal changes have been 
reported for specific types. Deletions of the 3p region have been described in small cell and 
nonsmall cell undifferentiated lung epithelial carcinomas. For a hepatoblastoma, trisomy 20 
has been identified in 78% of tumors. It has been known since the early 1990s that epithelial 
carcinomas involving the tongue, uterus corpus, ovary, breast, colorectal, and kidney have 
aberrations of chromosome 1, suggesting secondary changes in tumor progression (27). 
4.2. Connective Tissue Tumors 
Two of the more studied benign mysenchymal tumors are leiomyomas and lipomas. Both 
show a variety of chromosomal changes. Within the group of lipomas, rearrangements 
involving translocations of chromosome 12 and 1, 2, 3, and 21 have been reported. Likewise 
for leiomyomas, chromosome rearrangements of 12 and chromosome 1, 6, and 14 have been

386 Hu, Hopwood, and Glassman 
identified (28). Both types of tumors also show deletions of 13q. Other consistent changes 
found in uterine leiomyomas included deletion of 7q, trisomy 12, monosomy 22, and ring 
chromosomes (29). 
Sarcomas are generally difficult to classify morphologically especially when poorly dif­
ferentiated or undifferentiated. In the pediatric population, the lack of differentiation often 
results in confusion and misdiagnosis. However, among these sarcomas, clinically significant 
cytogenetics findings have been reported: clear cell sarcoma +8, t(12:22)(q 13;q 12), alveolar 
rhabdomyosarcoma. t(2: 13)(q35;q 14), Ewing's sarcoma t(11 ;22)(q21 ;q 11), synovial sar­
coma t(X;18)(p12.2;q12.2), Askin's tumor t(l1;22)(q21;q13), extraskeletal myxoid chond­
rosarcoma t(9;22)(q22;q11), and malignant mesothelioma del(3)(p13p23) (30,31). 
Cytogenetic findings of the specific chromosomal changes in these sarcomas have 
revealed potential candidate regions and location of genes, which allowed further studies 
into molecular cloning of these regions. Translocation breakpoints involving 
t(12;16)(q13;pll), t(12;22)(q13;q12), t(ll;22)(q2l;q13), t(2;13)(q35;q14), and others have 
been characterized (32). 
4.3. Neurological Tumors 
The etiology of primary tumors of the nervous system remains unknown. The potential 
causes may include immunological disorders, environmental influences, viral inductions, 
genetic factors, hormonal factors, prior radiation therapy, and mutation. Today, two of the 
leading hypotheses for spontaneous neoplasms are viral and chemically induced mutagen­
esis. With the advance of molecular techniques, researchers have changed their focus from 
phenotypic characteristics to the understanding of events on the genotypic level. The discov­
eries of oncogenes, tumor suppressor genes, and mismatch repairs have expanded our knowl­
edge of the pathogenesis of brain neoplasms. For benign neurogenic neoplasms, the two 
most studied are meningioma and neurofibroma. Monosomy 22 was the first chromosomal 
aberration discovered in solid tumors. This abnormality is found in meningiomas, which 
have their origins from the meninges. In one study this abnormality was reported in 270 out 
of 300 cases ( 33 ). 
In children, the most common primary malignant brain tumor is medulloblastoma, which 
often displays the cytogenetic abnormality of isochromsome 17q. Eigner et al. in 1990 dem ­
onstrated 48% of tumors with clonal changes and showed a loss of alleles for loci on chro­
mosome 17q through molecular studies ( 34 ). 
The most common intraocular tumor of childhood is the retinoblastoma. This particular 
tumor occurs in both hereditary and spontaneous forms. A deletion of 13q is recognized by 
conventional cytogenetics in 5-10% of the patients . Molecular studies revealed submicro­
scopic deletions of the RB 1 gene exist in all patients. The RB 1 gene, when lost in homozy­
gous forms, leads to the initiation of retinoblastoma formation ( 35 ). 
Neuroblastoma is the most commonly found extracranial tumor in children. This tumor 
originates from the neural crest cells and demonstrates a consistent cytogenetic abnormality 
of deleted 1p. Through molecular studies, it has been shown to be involved with the ampli­
fication of the NMYC oncogene. The karyotypes of these patients have also proven to be a 
reliable prognostic indicator. Near diploid or tetraploid karyotypes generally leads to a poor 
prognosis while near triploid karyotypes will have an excellent prognosis ( 36).

CMC Assays for Evaluation of Human Tumors 387 
4.4. Germ-Cell Tumors 
Germ-cell tumors consist of a group of heterogeneous neoplasms located in different but 
restricted anatomical locations. There are three groups of germ cell tumors in the testis. 
Group I is comprised of teratomas and yolk sac tumors of infants, group II contains semino­
mas and nonseminomas of adolescents and adults, and group III consists of spermatocytic 
seminomas of the elderly. These groups are characterized epidemiologically, by chromo­
somal constitution and histological appearance. Proper categorization of these groups is cru­
cial because they may require different methods of treatment. It has been established that 
isochromosome 12 or i(l2)(p10) has been the consistent cytogenetic abnormality in testicu­
lar germ-cell tumors. Moreover, these markers often exist in multiple copies. They have also 
been identified in the subtypes such as seminoma, teratoma, embryonal carcinoma, com­
bined or mixed testes germ-cell neoplasms, dysgerminoma, and immature teratoma. These 
findings suggest that although their histology is different, some of the origins such as semi­
nomas and non-seminomatous tumors might be the same ( 37). 
5. TECHNIQUES 
5.1. Bone Marrow Culture Set-Up 
The purpose of culturing bone marrow cells is to identify chromosomal aberrations among 
hematopoietic cells. When a bone marrow aspirate is performed, approx 0.5-3.0 mL of early 
aspirate is collected in a sodium-heparinized glass tube. Sodium heparin is the anticoagulant 
of choice for collection purposes. Lithium heparin, EDT A, and other types of anticoagulants 
may be toxic to cells and have been shown to impair culture growth ( 38 ). If the sample is 
clotted, perform a white blood cell (WBC) count immediately. If the count is sufficient, 
proceed with culture set up. If the cell count is insufficient, try breaking up the clot mechani­
cally and/or warm the sample in a water bath to 37°C to dissolve the clot, which may be 
caused by the presence of cold auto-agglutinins. 
If bone marrow samples are not available, peripheral blood containing a minimum of30% 
blasts may be substituted for culture. Lower percentages of blasts have shown to yield poor 
to no growth when using peripheral blood. Approximately 5.0 mL of blood is needed for 
culture. The blood should be collected in a green-top tube containing sodium heparin. Blood 
may be transported at ambient room temperature, but avoid extreme temperatures. They 
may also be stored at 4 °C but never frozen as cell viability is lost. 
Lymph node biopsies should be collected in a sterile container with media. If media is not 
available, normal saline solution without preservatives may be substituted. The amount of 
specimen should be l em of tissue if possible. The tissue must be minced to release indi­
vidual cells for culture. 
Aseptic technique must be followed when performing bone marrow culturing. This is 
performed under a laminar flow hood. The procedure starts by performing a cell count utiliz­
ing an automated cell counter. We are only interested in the WBCs, thus red blood cell 
(RBC) lysing reagents such as Zapoglobin (Coulter Beckman) may be used. Otherwise, the 
cell count would be falsely increased from the interference ofthe RBCs. For optimal growth, 
the WBC count should be 1-4 million per 1 mL or 10-40 million per 10-mL culture. Cul­
tures may also be set up in different time intervals such as 24, 48, and 72 h. For example, for 
a bone marrow suspected of having CML, both 24 and 48 h cultures are set up.

388 Hu, Hopwood, and Glassman 
Successful growth must provide proper media, physical, and chemical environments. 
Physical environmental factors such as temperatures, pH, and osmotic pressure are mea­
sured to provide proper environment. Chemicals such as vitamins, carbohydrates, and buff­
ered salts are also added. If powdered media is used dissolve in water and sterilize before 
culturing. Serum is an essential part of a growth medium. Generally, 10-40% of the medium 
is serum. Fetal calf (bovine) serum is the most widely used. However, each batch of serum 
must be tested as they have been shown to exhibit different growth potentials and possibly 
may be toxic to specific cells. 
The harvesting procedure consists of three phases: (1) arresting the cells from dividing, 
(2) swelling of the cells, and (3) fixing the cells so they can be dropped onto the slides. 
The mitotic arresting reagent colcemid (deacetylmethyl colchicine), a synthetic form of 
Colchicine (naturally occurring, extracted from the autumn crocus) is the most widely used 
mitotic inhibitor. It prevents the formation of the spindle apparatus so that dividing cells will 
not enter anaphase thereby causing an accumulation of metaphases. However, the higher the 
concentration of colcemid in the culture, the shorter the chromosomes will become (39). 
Generally, 0.1 mL of colcemid is added for every 10 mL of culture for 15-20 min. Certain 
studies, such as hypermetaphase studies require colcemid to be added for up to 24 h. 
The spindle apparatus is not present because of the presence of colcemid; the chromo­
somes are suspended in the cytoplasmic membrane. The introduction of hypotonic solution 
causes the cells to swell, through a concentration gradient of fluids entering through the semi 
permeable cell membrane. Presently, the most widely used hypotonic solution is 0.075 M 
KCL. The hypotonic step usually takes 25-30 min. It is added after the colcemid step. The 
cells are still alive at this stage , thus during the waiting period, cultures are stored in a 37°C 
incubator for optimal recovery. 
After the hypotonic stage, the culture is centrifuged. The revolutions per minute (RPM) 
and time may vary from lab to lab but generally around 1200 rpm for 7 min. After centrifu­
gation, the supernatant (hypotonic solution) is removed and the fixative can be added. The 
fixative solution contains a 3:1 methanol and glacial acetic acid mixed in that order. Metha­
nol removes excess water from the cell membrane causing shrinkage and hardening of the 
cell wall, while acetic acid precipitates nucleic acids and dissolves nuclear histones. The 
fixative is added to the culture up to the 10-mL mark for 20 min. Subsequent washes with 
fixative may be performed to washout debris. 
When making the cell suspension for slide preparation, it is crucial not to over or under 
dilute. Either condition may cause poor spreading of chromosomes. Humidity and tempera­
ture can also affect the spreading . As the drop of fixative containing cells hits the micro­
scope slide, the drying action of the fixative causes the cell membrane to pull apart , exposing, 
and spreading the chromosomes. 
5.2. Culturing of Solid Tumors 
Samples for solid tumor studies should be collected with sterile techniques, which need 
to be maintained throughout the entire culturing process . The sample size is generally around 
1 cm3 if possible. It is transported in media but normal saline without preservatives may be 
substituted. This tissue can be minced or cells released by addin g collagenase. Collected 
specimens should be kept at room temperature . There are two main categories of long-term 
cultures; self-terminating and continuous. The self-terminating usually contains tissues from 
lymph nodes, skin, and gonads . The continous is further divided into two categories: (1) 
malignant tumors and (2) cell types that must be transformed to create continuous cell lines.

CMC Assays for Evaluation of Human Tumors 389 
There are many types of media used for long-term culture growth. They can be divided 
into three main types: growth medium (GM); maintenance medium (MM); and complete 
medium (CM). The main differences are CM contains all the necessary supplements and 
sera while GM contains the same as complete but with increased serum by 10-20%, and 
MM contains lower levels of serum with increased pH. New samples should be cultured in 
more than one type of media, and the media that requires the least amount of nutrients to 
sustain growth should be chosen . 
Various types of factors may be added to promote growth. Fetal bovine calf serum is 
commonly used because of its ability to generate good result s. Other media enhancements 
include: horse or bovine serum, epidermal growth factor, platelet derived growth factor, 
bovine pituitary extract, and fibroblast growth factor. These factors can be used in conjunc­
tion with fetal bovine calf serum. 
Mammalian cells generally require an artificial substrate to adhere to for growth . Glass 
and polystyrene (type of plastic ) culture vessels are suitable choices because of their nega­
tively charged surfaces, which will attract the positively charged cells ( 40). 
The dispersion of solid tissues prior to set-up is important. They may be dispersed in the 
following ways: physical cutting; exposed to enzymes such as pronase, collagenase, or 
trypsin; and chemically by soaking in a bath containing balanced salt solution (BSS) that is 
free of Ca++ and Mg++. When considering the use of enzymes it should be noted that collage­
nase has been shown to cause the least amount of damage to the cells ( 40 ). 
The incubation time for long term cultures is 5-7 d at 37°C in 5% C0 2. They shou ld be 
checked for contamination after 24-48 h. Media should be changed twice per week. This is 
done by replacing one- to two-thirds of fresh media to the cultur e. If the cell line is a fast 
growing type, subculturing is done every 2- 3 d. Sub-culturing can be done either with 
enzymes such as pronase or trypsin to promote cellular detachments from the flask , or by 
mechanical scraping . Primary cultures must be washed to remove any serum, which might 
interfere with the actions of the enzymes. For most cell lines, they are ready to be harve sted 
after 6- 9 d. 
5.3. Giemsa Banding 
There are many techniques to view chromosome banding under a microscope . The giemsa 
banding technique is often used in the routine cytogenetic laboratory. Banded chromosomes 
have helped the precision of cytogenetic diagnosi s by: differentiating member s of the D 
group chromosomes (e.g., between the G and Y group, the C and X group, and structural 
abnormalities). Giemsa is a comp lex of stains that specifically binds the phosphate group of 
the DNA. Giemsa or G-positive bands on a chromosome represent condensed chromatin 
made from the interactions of protein and DNA (4l) .lt has been suggested in the literature 
that these regions of the chromosome are late in replicating and gene poor.The exact mecha­
nism of binding between Giemsa and DNA is not yet known. 
There are additional steps prior to treatment with Giemsa. Aged or heated slides are rec­
ommended for achieving sharp banding patterns. A proteolytic enzyme, trypsin, must first 
treat chromosomes. Trypsin works by attacking specific peptide bonds in protein molecules 
that have carboxyl group s donated by certain amino acids (arginine and lysine). The length 
of trypsin expos ure depends on the type of the brand being used, pH, temperature, and con­
centration. The time in trypsin may range from 30 s up to 5 min for old slides. The pH is 
between 7.2 and 7 .4. After the slide is treated by trypsin, it is dipped into an antitrypsin bath 
such as fetal bovine serum, then quickly dipped into a Gurr's buffer bath (pH 7.2). Gurr's

390 Hu, Hopwood, and Glassman 
buffer tablets (Biomedical Specialties, Santa Monica, CA) can be used for convenience. 
Each tablet is mixed with 1000 mL (1 L) of water. Once the slide is in the Giemsa bath, the 
time may vary from 1 to 10 min. Afterwards, wash the slide with water to remove any 
excess dye. The slide is air-dried and ready for view under microscope. 
Troubleshooting tips include: under-trypsinized chromosomes may appear to have little 
contrast or indistinct bands. Over-trypsinized chromosomes may have a ghost-like or gray­
ish white appearance. 
5.4. Fluorescent In Situ Hybridization Technique 
Fluorescent in situ hybridization (FISH) is the most commonly used molecular cytoge­
netic technique. In conjunction with classical cytogenetic karyotypic analysis, FISH has 
demonstrated both specificity and reliability (42). FISH can be performed on various types 
of specimens; bone marrow or blood smears, directly fixed cells, and formalin-fixed tissues. 
It is often performed on conventionally prepared cytogenetic microscopic slides. The 
FISHtechnique was first detailed by researchers in 1969 (43). They stated that single­
stranded DNA would anneal to its complementary DNA sequence, thereby tagging a spe­
cific chromosomal region with a DNA probe it would be recognized by its complementary 
DNA sequence within an interphase nucleus or on a metaphase chromosome. The DNA 
probe and its target DNA must first be denatured by heating in a solution containing 
formamide. 
Because both ofthese highly repetitive nucleic acid sequences must be in single-stranded 
conformation. Aged cytogenetic slides are recommended for FISH. They can be aged natu­
rally or artificially by means of incubation at 37°C in 2X standard saline citrate (SSC). They 
can be stored in a desiccated chamber at room temperature. The aging process is completed 
so that DNA can be "hardened" and survive through the harsh conditions of hybridization. 
Pretreatment of the slide with pepsin, proteinase K, or RNase helps reduce unwanted protein 
and cytoplasmic debris that might interfere with the probe from reaching its target. 
For DNA to reanneal in its double-stranded form, the probe must be hybridized to the 
target DNA. In this cocktail of mixtures, excess repetitive sequence DNA is added to block 
off any nonspecific binding. Hybridization often takes 2-18 h at 37°C, and any excess 
repetitive sequence DNA is washed away by formamide-saline citrate solutions. To view the 
probe , a fluorescent tag is attached. This can be chemically modified by adding hapten mol­
ecules, such as biotin or digoxigenin, so that they can be indirectly fluorescently labeled 
using immunocytochemical techniques ( 44 ). Using a fluorochrome of a complementary color 
then counterstains the target DNA. A fluorescent microscope equipped with filters specific 
for the fluorochrome label and the counter stain is used to detect the probe. Utilizing imag­
ing systems, we can capture the images and enhance or increase the sensitivity of the probe 
via software programs. Fluorescent dyes fade under light, so proper storage must be consid­
ered when not in use. 
There are three types of probes used for cytogenetics FISH studies. First, are a-satellite 
DNA probes . These probes are designed to specifically recognize repetitive DNA sequences 
such as telomeric sequences or centromers. They give out bright signals and are very useful 
in identification of chromosomes in interphase nuclei. The second type is the unique 
sequence probe, which hybridizes a single copy of DNA sequences in a specific gene region 
on a chromosome. Another term associated with this is the cosmid probe. They are often

CMC Assays for Evaluation of Human Tumors 391 
used to identify microdeletion syndromes. The third type of probe is the whole chromosome 
paint (WCP). WCP probes are comprised of a combination of unique sequence probes that 
recognize the entire length of genetic material of a particular chromosome. Both homologs 
are usually painted and fluoresce brightly. They are useful in derivative studies. WCP FISH 
probes can only be used on metaphase preparations. Locus specific and satellite probes may 
be used on interphase as well as metaphase preparations. 
6. CONCLUSION 
Conventional cytogenetics has been used for many years in the diagnosis, treatment, prog­
nosis, and follow-up of myeloproliferative disorders, myelodysplastic disorders , lympho­
mas, and lymphocytic leukemias. Molecular techniques such as FISH, SKY, CGH, and others 
are complementary in evaluation of these disorders. They are useful when nonrandom pat­
terns are identified. Because of the karyotype complexity in solid tumors, conventional cyto­
genetics and molecular cytogenetics are still in the developmental stages of clinical 
applicability. Conventional cytogenetics has demonstrated its usefulness in terms of diagno­
sis, treatment approaches, and as an assessment for minimal residual disease for myelopro­
liferative and lymphoproliferative diseases. FISH and other molecular techniques help 
enhance the overall sensitivity and specificity. Although we have moved towards the under­
standing of solid tumors through cytogenetics with their recurrent chromosomal findings, 
future studies on these abnormalities are crucial for better understanding of human tumori­
genesis. 
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392 Hu, Hopwood, and Glassman 
14. Speicher MR, Ballard SG, Ward DC. 1996. Karyotyping human chromosomes by combinatorial 
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Harbor, NY, pp. 767-775.

19 
Microsatellite Alterations as Diagnostic and Prognostic 
Molecular Markers in Patients With Cancer 
Bret Taback and Dave S. B. Hoon 
Identification of specific genetic alterations associated with tumor initiation and progres­
sion offers a unique opportunity to develop nucleic acid based assays for cancer detection. 
Polymerase chain reaction (PCR) provides a highly sensitive and specific technique for the 
detection of these genetic changes in a limited amount of tissue. Recent findings of circulat­
ing nucleic acids in the plasma and serum from patients with a variety of malignancies pro­
vide a minimally invasive approach that may prove clinically useful for cancer screening, 
diagnosis, subclinical disease surveillance, and monitoring response to therapy . 
1.2. History 
Recent advances in tumor genetics have documented a variety of genetic alterations dur­
ing cancer initiation and progression. These mutations, whether inherited or acquired, can 
result in inactivation of tumor suppressor genes and/or activation of protooncogenes. Con­
tinued accumulation of these genetic abnormalities results in cellular transformation, uncon­
trolled proliferation, and subsequently a phenotype with the ability for invasion and 
metastasis. An additional genetic mechanism associated with neoplastic transformation is 
aberrant hypermethylation of CpG islands in gene promoter regions, which results in tran­
scriptional silencing of genes that regulate cell growth. However, one of the most frequent 
genetic changes identified in cancer is allelic imbalance manifested as loss of heterozygosity 
(LOH). The demonstration of LOH on multiple chromosomes across a number of different 
tumor types suggests the involvement of many putative tumor suppressor genes in carcino­
genesis. In 1971, Knudson evaluated the presentation and distribution of retinoblastomas 
among inherited and noninherited cases and hypothesized that cancer could arise in as few 
as two mutational events (I). Many believe the first stage requires the acquisition of a minor 
initial mutational event (such as a base insertion, substitution or deletion) that "knocks out" 
one allele and is followed by a second alteration, usually LOH of the corresponding allele on 
the other chromosome; the combination of these two events leads to complete loss of genetic 
expressiOn. 
Historically, cytogenetic studies were performed on tumor tissue to characterize gross 
chromosomal aberrations . These karyotypic analyses provide a genome-wide assessment of 
changes in absolute chromosome number and in chromosome structure , including deletions, 
amplifications, translocations, and inversions. At best, these studies are gross assessments of 
From: Cance r Diagnostics: Current and Futur e Tre nds 
Edited by: R. M. Naka mur a, W. W. G rody, J. T. Wu, and R. B. N agle© Hum ana Press Inc., Totowa, NJ 
395

396 Taback and Hoon 
regional alterations and are limited to the evaluation of tumor cells that are actively dividing. 
Comparative genomic hybridization (CGH) can detect changes in DNA sequence copy 
number across the entire genome. Minimal amount of tissue is needed, metaph ase cells are 
not required, and results can often be obtained rapidly (2). Unfortunately, the technique has 
limited sensitivity for detecting minimal deletions at present. Fluorescent in situ hybridiza­
tion (FISH) technique hybridizes fluorescent genetic probes to chromosomes in nuclei of 
metaphase or interphase cells ( 3). It requires a minimal amount of tissue or cells and can be 
performed on paraffin-embedded tumors for a rapid detection of chromosomal alterations, 
but is often problematic in reproducibility and sensitivity. These techniques have contributed 
significant insight into our understanding of cancer biology through tumor genetics ( 4,5 ). 
LOH analysis of microsatellite markers has provided investigators with a highly specific 
and focused assessment of regional chromosomal losses. LOH analysis can localize discrete 
regions of potential tumor suppressor genes. Simple sequence tandem repeats (STRs) of 
repetitive base pairs have been identified throughout the human genome (6). These so called 
microsatellites demonstrate polymorphism characterized by high variability in length among 
individuals (7). PCR primers that border a specific microsatellite region can be created and 
when amplified can be used to evaluate any loss at that particular chromosome loci. After 
post-PCR electrophoresis to separate fragment lengths, examination of band patterns for 
similarly amplified DNA primer sequences among individuals allows novel application of 
this technology for paternity testing as well as for forensics to establish identity . This 
approach has also been applied to cancer genetics. When compared to the electrophoresis 
band pattern of normal DNA, the pattern of tumor DNA may show a diminution of band 
intensity (allelic imbalance) and/or a shift in band position (microsatellite instability). 
There is compelling evidence to suggest that carcinogenesis is the clonal expansion of 
genetically altered cells and therefore DNA polymerase chain reaction (PCR)-based assays 
may provide a highly sensitive method to detect early-stage cancers. The relative stabi lity of 
DNA makes this assay system readily accessible and facile. Exponential amplification of a 
DNA target from a minimal amount of tissue or body fluids through routine PCR techniques 
offers a unique opportunity to assess tumor -specific genetic alterations that may serve as 
useful molecular surrogates of subclinical disease presence. This approach can characte rize 
tumors and may aide in diagnosi s when histopathologic assessment is inconclu sive. The 
molecular pathogenesis for colon, melanoma, and cervical cancers has been established based 
on the identification of genetic events during various stages of tumor development (8-10). 
Likewise, because genetic alterations demonstrate stability durin g disease progressio n, 
nucl eic acid PCR affords the opportunity to identify occult lymph node and systemic 
metastases associated with primary tumors containing this same genetic profile ( 10-13 ). 
Tumor-associated genetic alterations such as k-ras have provided unique molecular mark ers 
to look for colorectal cancer in stool specimens, lung cancer in bronchi al lavage fluid , pan­
creatic cancer in biliary secretions, and occult metastasis in tumor-draining lymph nodes 
( 14-19). Allelic imbalance has provided a genetic basis to explain the clinical phenomenon 
of field cancerization in head and neck tumors by demonstrating shared nucleic acid alter ­
ations in adjacent yet histologically different tissue s from hyperplasia, dyplasia, carcinoma 
in situ, and invasive lesions (20). These findings suggest that molecular analysis of suspi­

cious or high-risk lesions may be used to identif y very early cancers and determine patient 
risk for local recurrence (21-25).

MA as Molecular Markers in Patients With Cancer 397 
Recently, specific genetic alterations in primary tumors have demonstrated promise as 
molecular predictors of prognosis and determinants of response to therapy for carcinomas of 
different organs (26-40). However, examination of a primary tumor specimen may be of 
limited value because it is a static assessment of prior genetic events. It does not reflect the 
ongoing acquisition of genetic alterations throughout disease progression. Characterization 
of these additional aberrations may serve as supplementary predictors of patient outcome 
and/or more importantly treatment response ( 10,12,25,41 ). 
Circulating nucleic acids in the plasma and serum of cancer patients have been shown to 
harbor genetic alterations identical to those characterized in autologous primary tumors, 
which suggests their role as potential surrogate markers of disease ( 42-69 ). Our group and 
other investigators have speculated on the potential prognostic utility of circulating 
microsatellite marker alterations detected in the plasma/serum from cancer patients (70-75 ). 
Examination of blood specimens for genetic markers is a minimally invasive, facile, and 
logistically practical approach for the detection and monitoring of cancer. There is substan­
tial interest in circulating nucleic acids for cancer screening, diagnosis, prognosis, surveil­
lance of occult disease progression, identifying potential therapeutic targets, and monitoring 
response to therapy. 
1.3. Historical Aspects 
The identification of circulating nucleic acids was first described by Mandel and Metais 
in 1948 (76). Unfortunately, application in the field of cancer dod not occur until30 yr later 
when circulating "free" DNA was demonstrated to be elevated in patients with cancer. Dur­
ing the interim, indirect tests such as antibody fixation, or hapten-inhibition, arid direct mea­
surements, including immunoprecipitation or counterimmunoelectrophoresis , had limited 
sensitivity for DNA and therefore resulted in debate regarding the presence, pathology, and 
etiology of free DNA in plasma/serum (77-86) . As a consequence, interest in this field was 
limited to illnesses where circulating DNA was assumed to have clinical importance, such as 
in chronic inflammatory states, particularly systemic lupus, rheumatoid arthritis, and other 
collagen-vascular disorders (80,82,85,87-89). In 1977, Leon et al. used a highly sensitive 
radioimmunoassay to demonstrate markedly elevated nanogram levels of DNA in cancer 
patients compared to normal controls (mean concentration : 180 ng/mL vs 13 ng/mL, respec­
tively) (42,90) . Serum DNA levels were twice as high in patients with metastatic disease 
compared to patients without metastasis, implying that circulating free DNA may be used to 
monitor disease progression. Patients with a decreasing absolute serum DNA concentration 
after radiation therapy tended to have a better tumor response and clinical outcome. This 
was the first study to demonstrate the potential clinical utility of circulating DNA in cancer, 
but the application did not gain acceptance until 1989 when Stroun, Anker, and colleagues 
suggested that this circulating DNA originated from tumor cells (44,45). Their theory was 
confirmed in 1994 when two separate investigators identified k-ras and N-ras gene muta­
tions in the plasma from patients with acute myelogenous leukemia (AML) and pancreatic 
cancer, respectively (47,48). Currently, tumor-specific genetic alterations identified in both 
plasma and serum from cancer patients include oncogene mutations and amplifications, 
genetic rearrangements, microsatellite variations, allelic loss of tumor suppressor and 
metastasis inhibitor genes, tumor-associated viral DNA, and hypermethylation of gene pro­
moter CpG islands.

398 Taback and Hoon 
This chapter will discuss microsatellite alterations, particularly LOH, as potential diag­
nostic and prognostic markers in epithelial cancers. Emphasis is placed on those investiga­
tions that established a precedent for tumor analysis and on subsequent studies of circulating 
nucleic acids in plasma and serum as molecular markers of disease. Highlights will focus on 
genetic markers identified in epithelial malignancies, which may demonstrate clinical utility 
when detected in serum and plasma. 
2. TECHNIQUE 
Many of the historical methods for DNA extraction, quantitation, and assessment were 
time-consuming, lacked specificity and sensitivity , and were associated with exposure to 
potentially hazardous radioactive and toxic organic solvents (90,91) . Utilizing current com­
mercially available kits, quality DNA can be rapidly and efficiently extracted from plasma 
and serum (92). Newer blood collection tubes, isolation methods and post PCR semi-auto­
mated analysis systems permit high-throughput, batch processing of samples in less time 
and with reduced chance for technical error, producing consistent results. 
2.1. Blood Collection 
Consistently reliable and reproducible results require strict adherence to standard operat­
ing procedures (SOPs) and the application of good laboratory practice (GLP). during sample 
collection, processing, storage, DNA isolation, PCR set-up, and analysis. When collecting 
blood samples for PCR analysis during venipuncture, it is important to discard the first 
1- 2 mL of blood in a separate vacutainer tube to avoid contamination from the skin plug. 
However, if blood for PCR is drawn during other blood work then these tubes can be col­
lected last in sequence and therefore the aforementioned step is not necessary. For plasma 
assessment, blood is collected into sodium citrate or ethylenediamine tetraacetic acid 
(EDT A) tubes; tubes containing heparin should be avoided because heparin may impede 
PCR. For serum assessment, blood is collected in additive-free tubes kept at room tempera­
ture to permit coagulation; after centrifugation, the supernatant is collected and stored at 
-20°C to -80°C until utilized. Collected whole blood should not be exposed to excessive 
refrigeration or heat because temperature-induced cell lysis will contaminate the specimen 
with normal lymphocyte DNA. 
There is no consensus as to whether serum or plasma is preferable for circulating nucleic 
acid analysis. Plasma is centrifuged unclotted blood. In one study of specimens from patients 
with breast cancer, the incidence of LOH was higher in serum than in plasma; however, 
serum and plasma were assessed from different cohorts of patients and were not matched for 
stage of disease (60). Furthermore, a more sensitive detection method was used when evalu­
ating serum. However , higher concentrations of genomic DNA have been shown to be 
present in serum vs plasma (93 ). This finding may confound comparison of results for serum 
and plasma. Likewise, heating collected blood samples or storing them for prolonged peri­
ods at room temperature prior to DNA extraction may lead to increased DNA yields by 
lysing white blood cells and/or circulating tumor cells. We assessed DNA content in paired 
serum and plasma samples from ten patients with stage IV melanoma. Thirty milliliters of 
blood was collected from each patient; 10 mL was processed immediately for serum, 10 mL 
was processed immediately for plasma, and 10 mL was incubated overnight at 37°C and 
then processed for serum. In each instance, DNA was isolated from 800 ~-tL of serum or

MA as Molecular Markers in Patients With Cancer 
1100 
-9000 
E ....... 
Ol c 7000 
c 
.Q 
~ 5000 
1:: 
<ll 3000 (.) c 
0 u 1000 
·1000 
0 -1-
Plasma • • 
I • 
• 
I -• 
I 
Serum Serum overnight 
Type of Samples 399 
Fig. 1. DNA concentration in plasma, serum, and serum collected overnight. Blood was obtained 
from ten advanced stage IV melanoma patients and equivalent volume s were processed immediately 
for plasma and serum or after incubation for 24 hat room temperature (serum overnight) DNA was 
isolated from 800 ~--tL of plasma/serum. Quantification using the Picogreen assay was as follows: 
plasma (median 259 ng/mL; range: 83-604 ng/mL), serum (median 1056 ng/mL; range : 411-2821 
ng/mL) and serum overnight (median 4783 ng/mL; range: 1709-11054 ng/mL). Horizontal bars rep­
resent median DNA concentrations. 
plasma and quantitated using the Picogreen assay (Molecular Probes). In all cases, the con­
centration of DNA obtained from serum was greater than for the corresponding plasma. 
More interestingly, serum collected from blood samples incubated overnight demonstrated 
the most DNA (Fig. 1). Therefore, blood samples collected for multicenter trials and during 
serial bleeds from patients should be obtained in a uniform fashion. 
2.2. Blood Processing and Storage 
To enhance preservation of serum samples and avoid potential for contamination, we use 
CORVAC serum separator tubes (Sherwood-Davis & Geck) for blood collection. A self­
contained gel is dispersed along the sidewalls of each tube. Immediately after blood collec­
tion, the tube is centrifuged at room temperature, creating a physical gel barrier between the 
two compartments (clotted blood and serum). This ensures a more reliable transport by pre­
venting ongoing contamination ofthe serum with any genomic DNA released by cell lysis. 
We then filter the serum through a 13-mm serum filter (Fish er Scientific) to remove any 
potential contaminating cells and/or other debris; the serum is then placed in aliquots and 
cryopreserved at -30°C until analysis. From a 12.5-mL draw CORY AC serum separator 
vacutainer tube we can reliably collect approx 4 mL of quality serum. Peripheral blood lym­
phocytes collected from each patient in a conventional 4.5-mL sodium citrate vacutainer 
tube provide genomic DNA -to serve as a control for each individual. Lymphocytes were 
lysed in a commercially available buffered solution and DNA isolated using DNAzol (Mo­
lecular Research Center). In addition, we spot whole -blood collected from each patient onto 
FTA blood cards (Fitzco, Minneapolis , MN), which can be refrigerated at 4°C for future 
genomic DNA extraction.

400 Taback and Hoon 
2.2.1. DNA Isolation 
There are a variety of commercially available kits for DNA isolation from serum and 
plasma, none of which have demonstrated consistently improved yield or purity (92). The 
traditional organic extraction method using SDS and proteina se K digestion followed by 
phenol-chloroform remains the "gold standard" for DNA isolation (91,94). However, this 
technique is cumbersome, time-consuming, requires a larger volume of starting plasmal 
serum, and involves exposure to highly toxic/corro sive agents. In contrast, pre-made reagents 
and packaged spin columns from commercially available kits substantially reduce prepara­
tion and processing time, eliminate exposure to potentially harmful organic reagents, and 
facilitat e collection of DNA directly suitable for PCR. We have previously demonstrated the 
efficiency of the QIAmp DNA Blood Mini Kit (Qiagen) for high through-put processing of 
a large number of blood samples for rapid LOH analysis (73 ). However , there are limitations 
with this approach when isolating small amounts of DNA. 
Because of the assortment of isolation kits and methods for extrac tion, the quantity and 
quality of DNA obtained may vary between investigators and labor atories. These differ­
ences are increased by the lack of any standardiz ed protocol for isolating circulating nucleic 
acids prior to PCR. Many investigators do not quantitate their starting DNA concentrations 
but instead choose to use a constant volume. This can be problematic when interpreting 
results and performing assays on multiple marker s. 
2.3. DNA Quantitation 
Total DNA in serum from cancer patients can range from nano grams to micro grams per 
milliliter; the amount of DNA circulating in plasma is substantiall y less (42-45,84,90,95). 
Among normal healthy donor volunteers, free serum DNA concentrations are usually less 
than 200 ng/mL and most often below 50 ng/mL; free DNA in plasma is lower or not detect­
able (42,84,96). We have utilized the PicoGreen dsDNA Quantitation Kit (Molecular Probes, 
Eugene, OR) to quantify double-stranded DNA (dsDNA) in plasm a and serum after extrac­
tion. This highly sensitive fluorescent nucleic acid stain can quantitate DNA down to a level 
of 25 pg/mL. The intensity of fluorescence is read using a standard spectrofluorometer in a 
multi-well plate format, without interference from contaminating RNA and single-stranded 
DNA. Final concentrations are extrapolated from standard curve concentrations. Using this 
method we found dsDNA amounts of 9-79 ng/mL in serum from 25 healthy volunteers . In a 
second set of normal controls, 17 of 18 plasma specime ns had undetectable DNA levels. 
Overall, quantification of DNA levels in plasma/serum is important; however range can vary 
in normal individuals, cancer patients, and non-cancer patients with benign disease. Mea­
surement of DNA levels as sole markers of malignancy can prove challenging . 
2.4. Loss of Heterozygosity Analysis 
For LOH assessment, post-PCR products are separated by polyacrylamide-gel electro ­
phoresis (PAGE) and analyzed for signal intensit y using densitometric software (Fig. 2). 
Allelic band intensity can be detected by autoradiographs of 32P-labeled forward 
microsatellite PCR primers. Fluorescent dye-labeled primers avoid radioactivity exposure 
and allow effortl ess and more precise analysis using a laser gel scanner. Recently we have 
begun using capillary array electrophore sis (CAE) for post-PCR product band sepa ration 
and analysis (Fig. 3). This automated high-throughput technolog y affords a simple user 
interface and permits greater resolution than conventional slab gel electrophoresi s. Incorpo-

MA as Molecular Markers in Patients With Cancer 401 
Fig. 2. Post-PCR gel electrophoresis demonstrating LOH for microsatellite marker D3S 1293 in a 
patient's melanoma tumor CD and plasma sample (P) compared to paired lymphocyte DNA (N). 
ration of internal size standards for each sample can distinguish between fragment lengths 
that differ by a single base pair. Pool-plexing samples prior to a run allows for greater 
throughput and efficiency (Fig. 4 ). Regardless of the post- PCR separation procedure selected, 
allelic imbalance in the test sample must be evaluated by comparison with the individual's 
genomic DNA (from normal tissue or lymphocytes) run in parallel for each microsatellite 
marker assessed. LOH is calculated as a relative reduction in the signal intensity of one 
allele in tumor DNA compared to the corresponding allele in normal control DNA. The 
allelic ratio is calculated as (Tl/T2) /(Nl/N2) , where Tl and T2 are the signal intensities in 
the two alleles in the tumor DNA , and Nl and N2 are the corresponding alleles in normal 
DNA. It has been suggested that LOH be defined if the allelic ratio is less than 50-80 % (97). 
However, studies in the literature have reported positive LOH for allelic loss anywhere from 
25-80%. Standardization of plasma/serum analysis for LOH need s to be addressed for fu­
ture validation among laboratories . 
Variations in sample procurement, DNA extraction, primer design, buffers, PCR cycling 
conditions, and post-PCR product analysis can affect consistency among results. Attention 
to technique and the use of separate designated rooms for tissue processing , DNA extrac­
tion, PCR set-up, and post-PCR analysis is encouraged to prevent cross-contamination. 
Optimized PCR conditions must be established prior to evaluating tissue/body fluid samples 
to ensure accurate and reliable results. Positive and negative control s must be incorporated 
in each PCR run; if their respective results are not obtained, the assay should be considered 
invalid and repeated for verification. Highly polymorphic mark ers should be chos en for 
microsatellite analysis, to ensure a significant number of informative events. For LOH analy­
sis, control DNA should be obtained from patients' autolo gous peripheral blood lympho­
cytes or histologically confirmed normal tissue. Control DNA should be run in parallel with 
the patient 's test sample for every PCR experiment ; this DNA serves as a reference for the 
comparison of test sample band patterns and intensity.

loj::.. 
0 
N A Lymphocyte 
,_ 
--_, 
'""' -
~5000 -B 
20000 
·-
' I 
~ '·-
..... Tumor 
LOH 
• c 
-
.,.. 
.... 
I 
-~'""' " 
.... 
... Plasma 
LOH 
tU 1U 111 
Fig. 3. Capillary array electrophoresis demonstrating LOH for microsatellite marker Dl2Sl657 in a patient's melanoma tumor (A) and plasma 
sample (B) compared to paired lympho cyte DNA (C).

MA as Molecular Markers in Patients With Cancer 403 
1!.::.• 111541, Fragnent Data 
Blue: Tumor DNA Green: Tumor DNA 
2'..000 Black: PBL DNA Black: PBL DNA 
LOH 1: D95157; 9p23-21 LOH 2: D125393; 12p23-22 
20:~ Hele 1..,._ 
.. llele2 Allele 1..,._ 
i 1$X» Allele 2..,._ 
§ 
'" 
.. . . 
14() 100 lBO 
"" 100 200 220 
240 
!!000 lt-oH1 
~ '\l ...... \tli}J~ A AA .Al Jt J~ .._0~ 
? 
7 • 19 20 22 2 
('~~Y• . Kl 
Fig. 4. Pool-multiplex microsatellite marker analysis by capillary array electrophoresis. Simulta­
neous demonstration of LOH for microsatellite marker D9Sl57 (left-side of figure) and Dl2S393 
(right-side of figure). from a patients serum sample. Numbered peaks represent map marker. 
3. CLINICAL UTILITY OF A MOLECULAR MARKER 
3.1. Sensitivity and Specificity 
For any diagnostic test to achieve clinical application it must have a high degree of sensi­
tivity and specificity. Sensitivity is the ability of a test to detect a true positive result when 
the disease is present and is measured as: [(number of true positive cases)/(number of true 
positives cases+ number of false negative cases)] x 100%. Specificity is the ability of a test 
to detect a true negative result when there is no disease present and is measured as: [(number 
of true negative cases)/(number of true negative cases +number of false positive cases)] x 
100%. A highly sensitive assay identifies disease presence and excludes a false-negative 
result, whereas a highly specific assay confirms the presence of disease and rules out the 
possibility of other causes (i.e., a false-positive result). All diagnostic tests have a sensitivity 
and a specificity, however, the higher the sensitivity of a test the greater the risk of making a 
false-positive error and similarly, the higher the specificity of a test the greater the risk of 
committing a false-negative error. Thus, sensitivity and specificity are inversely related. In 
theory, it is better to have a false-negative result than a false-positive result because the 
former merely fails to identify the patient as having the disease whereas the latter 
misclassifies and inaccurately labels the patient with a disease (regarded as a dual error). 
Therefore, it is more favorable to have a test biased towards greater specificity while sacri­
ficing some degree of sensitivity. Dilution studies that mix serially decreasing amounts of 
mutated DNA in normal genomic DNA can establish an assay's sensitivity. Evaluation of a

404 Taback and Hoon 
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0.9 .. ··· ----
0.8 ,. ,. ,. 
0.7 ,. ,. B i:' ; 
0.6 ; 
~ / 
/ 
1/) 0.5 / 
s::: / 
Q) 0.4 / 
(/) / 
0.3 
0.2 
0.1 
0 
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 
1-Specificity 
Fig. 5. Representative ROC curves demonstrating a poor (A, 0.5), good (B, 0.7), and excellent 
(C, 0.9) test results. 
significant number of samples from healthy donor subjects (and possibly from patients with 
benign processes) are used to confirm specificity. 
3.2. Receiver Operating Characteristic Curve 
Receiver operating characteristic (ROC) curves are useful for evaluating the clinical util­
ity of a diagnostic test based on a molecular marker (98). A ROC curve is a graph that 
represents sensitivity vs !-specificity, also known as the false positive rate) of a particular 
test. The test is assessed in two cohorts, such as patients with a disease and normal or 
noncancer control subjects. The area under the ROC (AUROC) curve indicates the tests' 
ability to discriminate between the two groups. The greater the AUROC curve the better the 
diagnostic test. Although there are no established guidelines, generally, an AUROC curve of 
less than 0.7 is associated with a poor test, an area of0.7 to 0.8 is a marginally useful test, 0.8 
to 0.9 is a good test, and those tests with an area greater than 0.9 are excellent (Fig. 5). 
4. TUMOR SYSTEMS 
4.1. Breast 
Microsatellite analysis has demonstrated areas of common deletion in breast cancers on 
chromosome arms I p, I q, 2p, 3p, 4p, 8p, llq, 13q, 14p, 16q, 17p, 18q, and 22q (99-107). 
Because lymph node metastasis is the single most important prognostic factor in breast can­
cer, studies of primary tumors have attempted to demonstrate allelic imbalances associated 
with this event. This would identify putative tumor suppressor genes involved in cancer 
progression and could establish predictive molecular markers to evaluate primary tumors. 
Identifying LOH profiles that predict for metastasis would provide valuable prognostic 
information without the need for a diagnostic lymph node dissection. Large patient studies 
have reported that tumors demonstrating LOH of chromosomes llp, llq 13q, 17p, and 22q 
are associated with increased incidence of lymph node metastasis ( 108,109 ). Furthermore, 
LOH at loci 1 p34, 3p25, 8p22, 13q 12, 17p 13, and 22q 13 has been correlated with postopera-

MA as Molecular Markers in Patients With Cancer 405 
tive recurrence and poorer prognosis ( 30, II 0). However, in multivariate analysis only 13q 
LOH and 17p LOH were independently predictive of outcome. 
Many of these LOH events have been identified in early (ductal and lobular carcinoma in 
situ) and preneoplastic (hyperplasia and atypia) lesions (104,106,111). Additionally, LOH 
has been identified in morphologically normal terminal duct lobular units adjacent to can­
cers as well as in stromal cells distant from tumors (I 06, I12 ). These findings suggest that 
early genetic alterations in breast tumors are heterogenous and do not follow conventional 
progression models described in colon cancer and melanoma (8,9,1 13 ). Therefore , it is doubt­
ful that a particular marker(s) will be useful as diagnostic screening tool. Alternatively , 
assessing body fluids for circulating nucleic acids that are tumor associated and patient spe­
cific may serve as a valuable surrogate for disease progression. Circulating DNA with LOH 
has been detected in the serum and plasma from breast cancer patients (60,62,69, II4, JI5 ). 
We have correlated tumor-specific DNA microsatellites in serum with advancing AJCC stage 
of breast cancer (65). We postulated that this method may provide a novel approach for 
monitoring tumor-associated genetic changes in the blood of brea st cancer patients and 
that plasma/serum analysis for LOH may be of clinical utility in detecting subclinical dis­
ease progression. In a follow-up study we assessed microsatell ite alterations in the serum of 
56 patients with early-stage breast cancer (69). As expected, the incidence of circulating 
microsatellites for LOH was higher in patients with AJCC stage II disease (27%) than in 
patients with stage I disease (17% ). Additionally , the presence of circulating LOH was asso­
ciated with primary tumors that had increase d proliferation indice s as characterized by an 
increased diploid index, elevated MIB-1 fraction, and abnormal ploidy. This study included 
five patients with DCIS; LOH was not detected in serum from these patients. 
The literature reports a 27-66% incidence of plasma LOH in breast cancer, reflecting a 
very heterogeneous population of tumors, many of which were relativel y large and advanced 
( 60,62, 114,115 ). During our preliminary investigations, we evaluated paired plasma and 
serum from patients and found greater yields of free DNA in serum using Picogreen assay. 
Presently, most studies in breast cancer have not assessed or demonstrated any correlation 
betw een LOH and clinical , pathologic , or outcome parameters . However, Silva et al. found 
a significant correlation between plasma DNA alterations and invasive ductal histology, 
three or more lymph nodes positive for metastasis, and a high proliferative index (62). In a 
follow-up study, they showed that the preoperative presence of plasma LOH was signifi­
cantly associated with a worse disease-free survival rate (75). 
The relative paucity of reports identifying circulating DNA in the plasma/serum of breast 
cancer patients partially reflects difficulty with at least some aspect of this techniqu e ( II4 ). 
Chen et al. demonstrated that they could improve detection of circulating LOH by assessing 
serum instead of plasma and by the addition of laser fluorescence and an automatic sequence r 
in place of radioactive autoradio grap hy ( 48 vs 21 %, respectively) (60 ). Although they report 
a higher detection rate, all of the tumors were one centimeter or greater , and more than half 
were associated with lymph node involvement or unknown lymp h node status, indicating 
more advanced disease. This technique may prove more sensitive than conventio nal densito­
metric analysis of standard gels, but additional direct comparisons are required. 
Recent ly we have identified circulating microsatellite alterations in the bone marrow of

Recent ly we have identified circulating microsatellite alterations in the bone marrow of 
patients with early-stage breast cancer ( 116). The incidence was greater than that found in 
paired serum samples from the same patients. Bone marrow may be preferable to blood 
becau se the lower flow and less turbulent environment may permit pooling of tumor DNA.

406 Taback and Hoon 
Moreover, bone is the most frequent site of breast cancer metastasis and early detection may 
identify those patients at increased risk for relapse. Bone marrow analysis for LOH may be 
an important surrogate marker for systemic metastasis. These findings may corroborate the 
reported association between circulating tumor cells in bone marrow and worse prognosis 
( 117). Larger studies are needed with well-defined patient populations and long-term fol­
low-up. 
4.2. Melanoma 
Melanoma is characterized by significant increasing genetic instability with advancing 
stage ( 118-120). The most frequent genetic alteration in melanoma is allelic imbalance 
( 121-128). This occurs commonly at certain chromosome loci in a nonrandom manner, sug­
gesting the involvement of putative tumor suppressor and metastasis inhibitory genes. LOH 
at chromosomes 9p21 and 1 Oq23 .3 occurs in regions of recognized tumor suppressor genes 
p16/CDKN2A and PTENIMMAC1, respectively, and is frequently identified in tumors of all 
thickness, implicating an early potential role in the development and progression of primary 
melanomas (124,129). In contrast, LOH on chromosome 6q and the distal arm of lp occurs 
more frequently in thicker primary tumors and metastases ( 13,124,130,131 ). 
The demonstration of additional LOH events in systemic metastases suggests that genetic 
alterations continue to occur throughout disease progression and might serve as supplemen­
tal predictors of patient outcome. In an allelotypic analysis of 47 melanomas, Healy and 
colleagues found frequent 3p and lOg LOH in thin lesions; by comparison, 6q, llq, and 17p 
LOH were predominant in thicker tumors ( 123). LOH at 9p was most frequent and appeared 
in all tumor sizes. Melanoma appears to follow a tumor genetic progression model in which 
early LOH at 9p is followed by LOH at lOg, 3p, 6q, and later by LOH at llq, 17p, and lp 
(9,118). To date, no molecular marker identified in primary melanomas has consistently 
shown independent prognostic utility. There is more convincing evidence to suggest that the 
frequency of LOH may be more predictive of patient outcome in melanoma and other can­
cers ( 41,96, 124,132 ). Careful scrutiny is warranted when reviewing frequency of allelic loss 
and patient outcome data because LOH increases with tumor size and other more aggressive 
histopathologic features; this must be considered in any statistical analysis. 
We initially demonstrated the presence of circulating microsatellite markers in the plasma 
of melanoma patients and showed a significant concordance with genetic alterations in paired 
melanoma tumor tissues (58). This early study evaluated ten microsatellite markers corre­
sponding to six chromosome arms (lp, 3p, 6q, 9p, lOg, and llq) that were associated with 
frequent LOH in melanoma tumors. Increased LOH frequency was significantly associated 
with advanced AJCC stage, but follow-up was too short for outcome correlations. In a sec­
ond study, we evaluated preoperative plasma from 57 patients undergoing surgical resection 
of all clinically apparent disease. Again, LOH presence correlated significantly with stage of 
disease (74). At a median follow-up of 21 mo, the presence of LOH was associated with a 
statistically significant reduction in overall survival of patients with stage III and IV mela­
noma. This correlation was particularly significant for the expression of microsatellite marker 
D1S228 alone or in combination with D9S 157. Similarly, poorer prognosis has been ascribed 
to ovarian, gastrointestinal stromal tumors, adenocarcinomas of the colon, hematologic ma­
lignancies, and neuroblastomas that show LOH at these sites ( 35,38,40, 133,134 ). These two 
markers correspond to recognized tumor suppressor gene regions retinoblastoma (RB) and 
pl6 1NK4a, which play an integral role in cell cycle and differentiation (135,136). In addition,

Melanoma Patients 
AJCC Stage Ill 
(n=27) 
SN Positive Only 
(n=11) Multiple Nodes Positive 
(n=16) 
3 LOH (+) 
(27%) 8 LOH (·) 
(73%) 14 LOH (+) 
(88%) 2LOH(-) 
(13%) 407 
Fig. 6. Plasma LOH analysis relative to nodal tumor burden in same stage (III) melanoma patients 
undergoing sentinel lymph node (SLN) dissection followed by completion lymphadene ctomy . First 
tier segregates patients according to lymph node involvement by H&E and IHC (for SLN) and sec­
ond tier according to pre-operative plasma LOH status.+, plasma sample positive for LOH; -,plasma 
sample negative for LOH 
when we evaluated the presence of lymph node involvement in stage III melanoma patients 
we found a correlation with plasma LOH and the number of lymph node metastases (Fig. 6). 
These results provide evidence that circulating nucleic acids demonstrating LOH not only 
correspond to subclinical tumor burden but also may have prognostic significance . 
Recently, we have assessed the role of LOH as a molecular determinant of response to 
therapy. In this pilot study we retrospectively assessed serum collected from advanced mela­
noma patients at the time of enrollment onto a biochemotherapy protocol ( 137). Because 
treatment with this regimen can be toxic and its outcome uncertain , we examined whether 
molecular analysis of serum could differentiate between responders and nonresponders to 
biochemotherapy ( 138). At a median follow-up of 13 mo, we found an overall response rate 
of 56% (23 of 41 patients) LOH was present in serum from 12 of 41 (29%) patients and there 
was a significant association between biochemotherapy response rate and the absence of 
LOH . Only 2 of 23 (9% ). responders demonstrated LOH, vs 10 of 18 (56%) nonresponders 
(multivariate analysis, p = 0.003). Furthermore , serum LOH was a statistically significant 
independent predictor of disease progression (p = 0.003) . Current AJCC staging criteria do 
not consider treatment outcome ( 139 ). Assessment of serum for molecular determinants pro­
vides a novel approach for evaluating prognosis and treatment response. Molecular diagnos­
tics may improve risk stratification and identification of those patients most likely to benefit 
from a particular therapy. 
4.3. Gastrointestinal 
The presence of microsatellite alterations, including LOH and instability, has been we11 
described for esophageal , gastric, colorectal, pancreatic, and hepatic tumors. Some of the 
earliest investigations of a molecular pathogenesis for cancer were described in colorectal 
cancers ( 140-145) . Vogelstein et al. established a genetic tumor progression model for 
colorectal cancer by characterizing the frequency of allelic deletions on chromosome Sq

408 Taback and Hoon 
(APC region), 17 and 18q, as well as the presence of k-ras mutation in advancing histologic 
stages of polyps and a set of invasive cancers (8). Their findings identified the following 
temporal relationship : k-ras mutations occurred early during colorectal cancer development, 
with most presenting in adenomas larger than 1 em, whereas 5q alterations became more 
prominent in larger adenomas often with some degree of dysplasia. This was followed by 
LOH of 18q in larger adenomas and finally by 17p LOH in invasive colorectal cancers. In a 
follow-up study , the same group showed that stage II and III colorectal cancer patients with 
18q LOH in their primary tumors had a much worse 5 yr overall survival than same stage 
patients whose tumors did not contain this loss ( 32 ). 
The frequency of these tumor-specific genetic alterations led to their assessment in blood 
(plasma/serum) as unique molecular markers of disease . Hibi et al. performed a comprehen­
sive assessment of 44 colorectal cancers and paired serum samples for LOH and 
microsatellite instability (MST) using a panel of microsatellite markers mapped to chromo­
somes l8q, 17p, and 8p as well as mutational analysis for p53 and k-ras (70 ). Although 31 
(70%) and 15 (34%) of 44 tumors had LOH and microsatellite instability, respectively , 
neither could be identified in the paired serum samples. In contrast, k-ras mutations were 
detected in the serum from 3 ( 19%) of 16 patients with positive tumors, and p53 mutations 
were detected in 7 (70%) of 10 patients with this alteration in their primary tumor. Kolble et 
al. successfully demonstrated LOH and MSI in 7 (26%) and 13 (48%) of 27 serum samples, 
respectively, from patients with colorectal cancer (59). LOH was most frequently dem­
onstrated in serum from patients with extensive lymph node involvement or systemic 
metastasis, but no associations could be shown between tumor stage and patient outcome. 
These discouraging findings in plasma/serum have led many investigators to examine other 
sources, such as stool specimens, for the presence of tumor associated genetic markers that 
could be used for colorectal cancer diagnosis ( 14,146, 147). 
k-ras mutation is under intense investigation because of its high frequency in gastrointes­
tinal cancers ( 148). Approximately 50% of colorectal and 90% of pancreatic tumors have 
k-ras mutations. Unlike other gene mutations, k-ras occurs most often at a single codon(12) 
which allows for a highly simplified and thus practical approach for developing a gene­
based detection assay. Published series have identified circulating k-ras mutations in 
19-86% of plasma/serum from colorectal cancer patients (52,53,70). However , further 
refinement s in specificity and sensitivity of the various assays are needed before this 
approach is uniformly accepted. 
k-ras mutations may be more valuable for the diagnosis of pancreatic cancer. Although 
this disease represents only 2% of all new cancer cases in the United States each year, 80% 
of patients will die within 1 yr. Pancreatic cancer frequently develops and spreads without 
symptoms, making it difficult to diagnose and assess. Mutated k-ras has been detected in 
pancreatic secretions, biliary fluid, and duodenal juices from patients with pancreatic cancer 
( 16,149, 150). Unfortunately, similar genetic aberrations in patients with chronic pancreatitis 
have limited the clinical application of this assay as a diagnostic marker for cancer 
(151-154) . Assessing plasma/serum has been propo sed as an alternative becau se DNA lev­
els are lower in blood than in pancreatic secretions; circulating levels of this DNA mutation 
are higher in patients with cancer vs those with chronic pancreatitis (43,155) . A review of 
the literature by Sorenson found a 53% overall incidence of k-ras mutation in plasma/serum 
from 144 patients ( 156 ). He also noted an overall false-positive rate of only 2.5% in plasma/

from 144 patients ( 156 ). He also noted an overall false-positive rate of only 2.5% in plasma/ 
serum from normal healthy individuals, patients with nonmalignant pancreatic lesions, those

MA as Molecular Markers in Patients With Cancer 409 
with acute and chronic pancreatitis, and patients with non-k-ras mutant colorectal and pan­
creatic cancers. However, the sensitivity of detection was lower for blood than enteric secre­
tions; thus, most patients whose serum contained k-ras mutation already had metastatic 
disease. Theodor et al., identified k-ras mutations in the serum from 14 (70%) of 20 patients 
diagnosed with pancreatic cancer and was able to improve the assay sensitivity to 95% by 
combining it with an elevated CA19-9 level ( 155 ). Further studies are needed to evaluate the 
combination of markers, but the rarity of pancreatic cancer and the lack of disease- specific 
risk factors make any prospective marker investigation study unlikely. A more practical 
application would be as an aide in the diagnostic work-up of patients with a pancreatic mass 
or as a surrogate marker for monitoring subclinical disease progression. 
4.4. Urologic 
There are no proven tumor markers for urologic malignancie s, except PSA for prostate 
cancer. Because symptom presentation is often subtle, molecular diagnostics would not only 
provide insight into the tumor's origin but might facilitate early detection. Urologic tumor 
types have been differentiate d by uniqu e alterations of chromosomal profile patterns. Initial 
studies were based on differences in cytogenetics ( 3, 157, 158). Microsatellite markers that 
map chromosome regions with greater detail provide a precise tool for accurately assessing 
allelic imbalances. These markers can potentially distinguish between tumor types that are 
morphologically similar but have different biologic behaviors and treatments, such as lesions 
in the aerodigestive tract or in the collect ing ducts of the kidney (20,21, 159-161 ). 
Among renal cell carcinomas, of which clear cell histolo gy accounts for the majority, 
LOH is a frequent event. In particular, 3p LOH occurs with a frequency of over 95%; most 
genetic aberrations present at the von Rippel-Lindau tumor suppressor gene site locus 
3p25-26 (162-164). In contrast to renal clear cell carcinomas, which arise in the proximal 
collecting tubules of the kidney, those tumors arising from the distal collecting duct s display 
a different pattern of LOH with frequent allelic loss on chromosome arms lq, 6p, 8p, 13q, 
and 21 q ( 36,165 ). These results imply that proximal and distal renal cancers arise from dis­
tinct tumor genetic pathways and microsatellite analysis may facilitate their diagnosis as 
well as provide unique tumor -specific marker s for plasma/serum/urine surveillance. 
Based on 3p LOH frequency in renal cancers, Goessl et al. evaluated four microsatellite 
markers on this chromosome for LOH and MSI in the plasma of 40 patients with clear cell 
carcinoma (54). LOH for at least one microsatellite marker was detected in plasma DNA 
from 25 (63%) patients, and 14 (35%) demon strated LOH at more than one locus. MSl 
occurred in only one patient's tumor and another patient's plasma sample. No correlation 
with plasma LOH and tumor stage was found and outcome data was not evaluated . Although 
LOH specificity may be low for cance r screening, it may be useful for patient follow-up 
when combined with other microsatellite marker s such as those found on chromosome 9 and 
17 ( 166, 767). von Knobloch and colleagues used multipl e fluorescent microsat ellite mark­
ers and an automated laser sequencer to identify LOH in the serum of 20 (87% ). of 23 patients 
with renal cell carcinoma, with 85% specificity ( 168). Most frequent serum LOH detected 
was for 3p and 5q chromosomal region s. Although no association was found with tumor 
grade , this is the first study to correlate serum LOH with disease stage in kidney cancer 
patients. This same group evaluated serum and urine specimens from 39 patients with tran­
sitional cell carcinoma of the bladder cancer ( 169). Serum LOH was present in 33 (85%)

sitional cell carcinoma of the bladder cancer ( 169). Serum LOH was present in 33 (85%) 
patients, and the most frequent alteration occurred on chromosome 8p. LOH on 8p was also

410 Taback and Hoon 
the most frequent alteration in urine, but the incidence of LOH in urine was only 36%. There 
were no clinical correlations. The disparity may reflect differences in the stability and/or 
clearance of free DNA in blood vs urine. 
Cairns et al. found frequent LOH on chromosome 9p in bladder tumors and Mao et al. 
demonstrated that identical microsatellite aberrations could be detected in the urine from 
patients with bladder cancer (170, 171). In a study of 20 patients with suspicious bladder 
lesions 19 demonstrated microsatellite alterations in their urine as compared to 50% of 
patients with abnormal cytologies suggesting the potential role of microsatellite analysis for 
bladder cancer screening (51,172). Utting et al. analyzed tumors, plasma, serum, and urine 
from 44 patients with bladder cancer for six microsatellite markers on three chromosomes: 
4, 9, and 17 ( 173). The incidence of microsatellite alterations detected was as follows: tumor 
(27% ), plasma (50%), serum (44% ), and urine (54%). However, assay specificity for 
correctly identifying LOH for any of the body fluids evaluated was only 24-28%. The 
inconsistent results suggest that the presence of tumor DNA from these sources is highly 
variable. Clinically relevant microsatellite analysis of various body fluids to detect urologic 
malignancies or follow tumor progression will require specific tumor markers that are stable 
and obtained from a reliable source ( 174). 
4.5. Gynecologic 
Ovarian cancer may go relatively unnoticed until considerable clinical symptoms become 
evident, at which time the disease is already advanced, and patient prognosis is poor. In 
addition, the pathogenesis for many of these tumors remains unknown (175,176). A number 
of investigators have attempted to delineate the molecular events associated with ovarian carci­
noma to: 
1. Elucidate a tumor genetic cancer progression model. 
2. Identify potential precursor lesions of invasive cancer. 
3. Better characterize biologic behavior of morphologically similar tumor types. 
4. Identify molecular markers of disease progression and potential targets for therap y. 
It is becoming evident that diverse tumorigenic pathways for various ovarian cancers can 
be demonstrated by molecular genetics and that these findings may provide early detection 
markers ( 177-181 ). Cliby and colleagues performed a comprehensive allelotypic analysis of 
37 epithelial ovarian cancers using 70 polymorphic microsatellite markers and showed a 
high frequency ofLOH for the following chromosome arms: 5q (43%); 6p (62%); 6q (57%); 
7p (36%); 8p (40%); 9q (54%); 13q (56%); 14q (47%); 15q (36%); 17p (81%); 17q (76%); 
18q (43%); 2lq (36%); and 22q (71 %) (180). Moreover , they showed a significantly in­
creased frequency of LOH for chromosome arms 6p, 13q, 17p, and 17q in high-grade as 
compared to low-grade tumors. Dodson et al. employed LOH analysis to explore whether 
genetic differences could be used to discriminate between low-grade, high-grade, and bor­
derline epithelial ovarian cancers ( 179 ). They found that LOH on chromosome arms 13q and 
15q was significantly more frequent in high -grade tumors, LOH on 3p was more frequent in 
low-grade tumors, and LOH on 6p, 17p, and 17q was lost with equal frequency regardless of 
grade. The findings suggest that LOH during tumorigenesi s occurs initially on chromosomes 
6 and 17 and then on 13q and 15q. How ever, in this study, allelic loss was infrequent for 
low-grade and borderline tumors, and no common genetic events could be identified between 
borderline and invasiv e tumors. Thes e findings are in agreement with other investigators

Table 1 
ROC Curve Analysis of DNA Concentration in Patients With Cancer, 
Nonneoplastic Disease, and Healthy Donors 
DNA Concentration (ng/mL) 
Patient No. of Median Range (1 0-90 ROC curve 
characteristics patients plasma percentile) results 
Healthy 44 7 0-20 > 0.9 Nonneoplastic 164 16 7-71 
disease 
Cancer 122 59 10-844 > 0.74 
Adapted from ref. 96. 411 
who reported an increased frequency of LOH from more mitotically active tumors 
(69,111,178). To date no study has successfully divided different histologic tumor types 
based on characteristic LOH profile expression panels. 
Iwabuchi et al. used CGH, LOH, and MSI analysis to evaluate various ovarian cancers for 
genetic changes ( 181 ). They found a high rate of DNA-sequence copy number abnormalities 
in high-grade ovarian cancers as compared to low-grade tumors. Increased copy number 
abnormalities at 3q25-26 and 20q 13 were most frequent in low-grade tumors whereas 
increased copy number abnormalities at 8q24 were more likely to occur in high-grade tumors. 
Tumors demonstrating many copy number abnormalities were associated with decreased 
patient survival. One of the first studies to demonstrate the presence oftumor-specific genetic 
alterations in body fluids of ovarian cancer patients was by Hickey and colleagues (61 ). In 
their preliminary series, they found LOH in 17 (85%) of 20 patients' serum samples and 12 
(63%) of 19 peritoneal fluid samples. Interestingly, they observed these findings in few 
early-stage patients using a select panel of six microsatel-lite markers on four chromosome 
arms. This provided an incentive for future investigations to evaluate circulating DNA mark­
ers as a diagnostic test for ovarian cancer. 
The largest study of circulating DNA microsatellites for LOH as a diagnostic test for 
ovarian cancer was recently reported by Chang et al. (96). Plasma was analyzed from 330 
patients as follows: 54 with ovarian cancer, 68 with other non-ovarian cancers, 164 with 
nonneoplastic diseases and 44 healthy normal control donors. DNA was isolated using the 
QIAamp DNA Blood Kit; in most cases, 200 ~-tL of plasma was quantitated with Picogreen. 
Results are summarized in Table 1. Digital single nucleotide polymorphism (SNP) PCR was 
performed to assess allelic imbalance in the plasma samples from 54 patients with ovarian 
cancer and 31 patients with nonneoplastic disease . All plasma samples had DNA concentra­
tions greater than 50 ng/mL. The median number of informative markers per patient was 
four. When a cut-off level of 0 .6 for allelic proportion was used to define imbalance, the 
results demonstrated a sensitivity of 87% for stage 1/II and 95% for stage III/TV ovarian 
cancer patients. The AUROC curve was 0.95 when utilizing allelic imbalance to differenti­
ate between 54 patients with ovarian cancer and 31 control patients with nonneoplastic dis­
ease. In contrast , the AUROC curve was 0.76 when plasma DNA concentration was used as 
a discriminant. Interestingly , the AUROC curve was 0.78 for CA 125. The AUROC curve

412 Taback and Hoon 
increased to 0.84 when CA 125 was combined with plasma DNA concentration and used to 
evaluate serum from 45 patients with ovarian cancer and 18 patients with nonneoplastic 
diseases. The authors concluded that the sensitivity and specificity were too low for plasma 
DNA concentration alone to serve as a useful screening tool for ovarian cancer, but assess­
ment of allelic imbalance using digital SNP analysis might show promise. Digital SNP tech­
nology is costly and rigorous to perform. Certain technical issues need to be resolved and 
validated prior to widespread acceptance of this approach. 
Cervical cancer is one of the most frequent gynecologic malignancies worldwide ( 182 ). 
Detailed molecular analysis has identified human papilloma virus (HPV) types 16 and 18 as 
most commonly associated with cervical cancer. After HPV DNA integration into the host 
genome, the specific expression of viral oncogenes E6 and E7, most often from HPV types 
16 and 18, leads to genomic instability and subsequent neoplastic transformation of the cer­
vical epithelial cell. Although HPV infection is causally related to the development of cervi­
cal cancer, most women with HPV infection will not develop a malignancy (183-186 ). To 
further elucidate specific genetic events associated with cervical cancer, Kersemaekers and 
colleagues assessed 67 stage IB and IIA cervical cancers with 81 micro satellite markers 
( 37). Although LOH occurred frequently on chromosomes 3p, 4p, 6p, 6q, 11 q, 17p, and 18q, 
only 18q LOH correlated significantly with decreased overall survival. Correlations with 
other known clinical and pathologic prognostic parameters were not significant. The same 
group evaluated ten patients with cervical intraepithelial neoplasia (CIN) and synchronous 
invasive carcinomas and lymph node metastasis to chronicle the genetic events associated 
with cancer progression ( 10). They found frequent LOH on chromosome arms 3p, 6p, and 
11 q for CIN lesions, with additional LOH at 6q, 17p, and l8q for the corresponding invasive 
component. Lymph node metastasis was associated with additional LOH on chromosome X. 
Mitra et al. found LOH on chromosomes lq, 3q, 5q, 10q, 11p, and 18p in 26-42% of cervical 
cancers (187). LOH was most frequent on chromosomes 4q (46%) and 5p (53%). These 
authors identified a potential tumor suppressor gene site at locus 5p 15 and suggested its role 
as a potential marker for progression of precancerous cervical lesions (188). Interestingly, 
HPV status did not correlate with any of the sites showing frequent LOH. In a comprehen­
sive allelotypic analysis of cervix tumors, Mullokandov et al. reported a 39-43% incidenc e 
of LOH for 3p, 6p, and 18q ( 189 ). No pattern of LOH could be identified and no correlation 
with HPV status could be demonstrated. It appears that 3p LOH is an early event in cervical 
carcinoma, most often preceded by HPV infection, whereas lp LOH occurs later during 
tumor progression and is most often noted in metastatic lesions ( 190-19 2). The genetic 
alterations that develop betw een these two anchoring events remain far from resolved. 
The Pap smear remains the standard for diagnosis of cervical cancer, but its analysis is 
subjective. In an attempt to improve the diagnostic efficacy of cervical cytology, Rha et al. 
used nine microsatellite mark ers to evaluate Pap smears from 21 patients ( 193 ). 
Microsatellite alterations were detected in smears from 16 (76%) patients. Howe ver, only 11 
(85%) of 13 invasive squamous cell cancers and 5 (63%) of 8 earlier CIN lesions were iden­
tified, suggesting inferior sensitivity. In contrast, genetic alterations were detected in two 
cytologically normal Pap smears . Outcomes were not available but one may speculate a role 
for microsatellite analysis when the Pap smear is suspicious but not diagnostic. Recently this 
group assessed plasma HPV-16 and HPV-18 E7 DNA levels in patients with cervical cancer

group assessed plasma HPV-16 and HPV-18 E7 DNA levels in patients with cervical cancer 
(194). HPV DNA was identified in only 11 (6.9%) of 175 cases of invasive cancer and 
I (1.8%) of 57 patients with pre-invasiv e disease. A similarly low incidence of HPV DNA

MA as Molecular Markers in Patients With Cancer 413 
has been found in the pretreatment serum of cervical cancer patients ( 195). These findings 
demonstrate the limited diagno stic utility of this blood assay. Its role as a potential marker 
for recurrent disease will require further evaluation. 
4.6. Lung 
The identification of circulating DNA in plasma/serum for LOH was first reported in lung 
cancer in 1996, in the same journal issue as that for head and neck cancers ( 49,50 ). Because 
lung cancer is one of the most frequent cancer diagnoses and remains the leading cause of 
cancer death worldwide, numerous reports have focused on the potential clinical utility of 
prominent genetic changes in this disease. Lung cancer is associated with a significant degree 
of genomic instability of which the most frequently reported events include LOH and MSI; 
both have been identified in patients' plasma samples ( 196,197) . 
In their original report Chen et al. used three markers corresponding to chromosomes 6, 
21, and X to detect microsatellite alterations (LOH or MSI) in 16 (76%) tumor specimens 
and 15 (71%) plasma samples from 21 patients with small cell lung cancer (SCLC), with 
excellent concordance (49). Using those same markers in 43 patients with SCLC, Bruhn et 
al. found that the incidence of microsatellite alterations was 19% in tumor s and 25% in 
plasma samples, but concordance between tumor and plasma was only 40% ( 196). Differ­
ences between the two studies are attributed to different techniques and degrees of clinical 
tumor burden. 
Sanchez-Cespedes et al. used four microsatellite markers that map to chromosome 3p to 
evaluate serum from 22 patients with non-SCLC. Serum spec imens from 6 patients 
(28%) contained alterations, and in four patients these were identical to those in the primary 
tumor for at least one of the markers assessed (57). No clinical correlations were made in 
this study. 
Gonzalez et al. utilized the same three microsat ellite markers as Chen and others in con­
junction with an assessment for TP53 mutations in the plasma of 35 SCLC patients (66). 
They found concordance for at least one molecul ar marker in 71% of cases. Although no 
difference in survival was demonstrated with respect to the presence or absence of plasma 
alterations, those patients with plasma TP53 mutation and microsa tellite alterations dem­
onstrated a significantly reduced overall survival rate as compared to other patients. In less 
than one-half of all of the cases, a correlation was found between regression or progression 
of the tumor and the loss or persistence of the plasma DNA abnormality, respecti vely. Chro­
mosomal alterations including allelic imbalance and mutations such as k-ras and TP53 occur 
more frequently in lung cancers from smokers than non-smokers, and therefore may repre­
sent a potential screening tool in this high-risk population ( 198-200) . LOH on chromosomes 
3p, 6q, 9p, 16p 17p, l9p, and k-ras mutations were demonstrated more often in adenocarci­
nomas from smokers than nonsmokers, however clinical correlations with patient outcome 
are inconsistent and Jacking (31,201 ). 
Others have assessed sputum and bronchoalveolar lavage fluid for genetic changes asso­
ciated with lung cancers but in general assay sensitivities were low and sample sizes were 
small ( 15,170 ). Radiographic imaging, fiberoptic bronchoscopic examination, and cytologic 
sputum analysis have shown limited effectiveness for early cancer diagnosis and their rou­
tine use has yet to demonstrate a survival advantage. The field of molecular diagnostics 
offers promise, but highly specific markers with improved sensitivity must be demonstrated 
in large-scale clinical trials.

414 Taback and Hoon 
4.7. Head and Neck 
The first report to document circulating microsatellite alterations in serum was assessed 
in patients with head and neck cancer (50). This group had previously demonstrated 
microsatellite alterations in lung and bladder tumors and found similar alterations in corre­
sponding sputum and urine samples, respectively, leading to speculation that shed tumor­
associated free DNA may serve as "clonal markers for cancer detection" ( 170). This theory 
was tested by screening serum samples from 21 head and neck squamous cell cancer patients 
with a panel of 12 microsatellite markers. These markers mapped to chromosome sites 3p, 
9p, and 17p which were likely to harbor tumor suppressor genes and to two chromosomes 
regions on 14 and 21 which demonstrated a high propensity for MSI in primary tumors (50). 
Microsatellite alterations were found in 18 (86%) primary tumors and 6 (29%) serum 
samples. All alterations in serum were also identified in the corresponding primary tumor. 
More relevant was the statistically significant association between the presence of serum 
tumor DNA and poor outcome. It must be noted that many patients had advanced disease, 
which may have contributed to the favorable clinical correlations. Additionally, almost one­
half of the patients with no detectable serum alterations had advanced disease. Thus, the 
assay's sensitivity was limited . 
Microsatellite markers have been used in the field of head and neck cancer to characterize 
site of origin for unknown primary aerodigestive tract tumors (21), to establish a genetic 
basis for field cancerization (22,202,203), to assess occult primary and recurrent oral malig­
nancies (202), and to differentiate between various salivary gland tumors (159). These reports 
demonstrate the vast potential clinical applicability for microsatellite analyses. However, 
although primary head and neck squamous cell carcinoma (HNSCC) is associated with a 
number of genetic alterations (with greater than 70% ofLOH noted on chromosome 9p; 50% 
LOH on chromosomes 3, llq, 13q, and 17p; and greater than 35% LOH on chromosomes 4, 
6p, 8, 14q, and 19q), few evaluations have shown prognostic significance (204,205) . A study 
that used 20 microsatellite markers to assess LOH at 14q in 73 primary HNSCC demonstrated 
an incidence of LOH of 40% for at least one loci (39). Among 53 patients with known 
clinical outcome, those with primary tumors showing LOH for any one marker, had a three­
fold higher risk of death than patients whose primary tumors retained heterozygosity at 14q. 
Again, most patients (79%) had stage III/IV disease; the fact that no specific marker had 
particular prognostic significance may merely reflect the overall genomic instability associ­
ated with more progressive disease. 
Molecular markers may serve as indicators of more advanced disease and/or aggressive 
tumors that are not appreciated by current staging criteria. The detection of increasing 
amounts of circulating DNA alterations may serve as a surrogate marker of subclinical tumor 
burden and/or as a minimally invasive procedure for monitoring the increasing tumor insta­
bility that is associated with progression . The identification of those genetic aberrations that 
occur in premalignant head and neck lesions and have greater predicti ve value as a stratifica­
tion factor for those morphologically similar lesions at increased risk for progression may be 
more informative. This has been demonstrated in leukoplakic lesions that express deletions 
at 3p14 and 9p21 (24,25,2 06,20 7). 
4.8. Nasopharyngeal 
Nasopharyngeal carcinoma (NPC), relatively uncommon in the Western world, is one of 
the most frequent malignancies in Southeast Asia; it is endemic in China and Hong Kong.

MA as Molecular Markers in Patients With Cancer 415 
The detection of markedly elevated circulating levels of Epstein-Barr virus (EBV) antibody 
titers in almost all patients with NPC led to the presumption of a viral etiology (208,209). 
The identification of EBV DNA in NPC tumors confirmed the association; however, the 
demonstration of identical EBV DNA terminal repeat sequences among common primary 
tumors, carcinomas in situ and dyplastic lesions suggests clonal progression from an infected 
progenitor cell (210). Although EBV infection is an early event in NPC development, the 
fact that most viral transforming genes are not expressed in these tumors suggests that other 
genetic changes, such as loss oftumor suppressor genes, are required for tumorgenesis (211 ). 
Genetic aberrations demonstrated in NPC include LOH on chromosomes 3, 5, 6, 9, 11, 14, 
16, and 17; the most frequent sites of LOH (i.e., greater than 30%) are on chromosomes 3p, 
9p, llq, 13q, and 14q (212,213). These losses identified by CGH have been further delin­
eated by microsatellite analysis. 
LOH of 3p is one of the most frequent genetic events in NPC and in one investigation it 
was reported in 100% of informative cases, most frequently at loci 3p 14 and 3p25 (RAF-1 
locus) (214) . However , only half of the tumors were informative for any one marker. In 
contrast, EBV DNA was identified in all36 tumors. The findings demonstrat e limitat ions of 
LOH analysis compared to analysis based on gene amplification. LOH assesses for allelic 
loss, which is more difficult to evaluate among a background of normal wild-type DNA than 
a chromosomal gain, particularly when the gain is a heterotopic fragment. Allelic analysis 
can be confounded by contamination from normal DNA as well as its relati ve 
"uninformativity" for any given marker in any particular patient. 
LOH has also been described distally on the short arm of chromosome 3 in the VHL 
region, but mutations of this gene in NPC appear infrequent (215 ,216). Likewise, frequent 
LOH has been described on chromosome 9. In one study , up to 61% (11 of 18 cases) of 
tumors demonstrated an allelic deletion when assessed with a panel of 21 microsatellite 
markers (217) . Many of these deletions included the p15 and pl6 tumor suppressor gene 
regions and were hi-allelic. Failure to find significant point mutations suggests that homozy­
gous genetic deletions may be the dominant mech anism for NPC development (218). Addi­
tionally, LOH on chromosome 11 occurs frequently in NPC; one study report ed a 54% 
incidence among 52 primary tumors (219). Two separate sites of frequent major chromo­
some deletions were identified: llq13.2-22 and l1q22-24. Genes PYGM , cyclin D1, FOLRJ 
and the proto-oncogene JNT-2 reside in the llq13 region, wherea s theATM gene is found in 
the 11q22-23 region . Recently , 14q LOH has been shown to occur quite frequently (74%) 
(220). These findings were confirmed by another group that evaluated a series of 60 patients 
and found 78% LOH on 13q and 80% LOH on 14q. LOH at 3q31-q32 correlated with a 
lower level of EBV infection , whereas LOH at 14q was associated with more poorly differ­
entiated tumors (221 ). 
A recent study performed a comprehensive allelotyping of 27 microdissected NPC pri­
mary tumors. Allelic losses were greater than 80% on 3p, 9p, 9q, llq, and 14q, greater than 
70% on 11q and 12q, greater than 50% on 13q and 16q, but only 35-50% on 1p, 5q and 12p. 
Similar findings have been reported by Miturangur a et al. with the additional demonstration 
ofLOH at 3q, 6p, 19q,and 22q between 35 and 50% (222). Despite these findings, the unique 
association ofEBV DNA in almost all tumors makes this a highl y desirable molecular marker 
for this disease. Miturangura et al. successfully identif ied circulating EBV DNA in the serum 
from 13 (31%) of 42 NPC patient s (56). In this pilot trial, no prominent correlations could be

from 13 (31%) of 42 NPC patient s (56). In this pilot trial, no prominent correlations could be 
demonstrated with clinical data or tumor pathology. Lo et al. used a highly sensitive quanti-

416 Taback and Hoon 
tative PCR technique to detect EBV DNA in the plasma from 55 (96%) of 57 patients (72). 
The median copy number ofEBV DNA was 47,047/mL in patients with stage III/IV disease 
and only 5918/mL in patients with stage 1111 disease . Seven of the 15 patients who received 
radiotherapy had complete remission of their disease and plasma EBV DNA levels became 
undetectable; six of the remaining eight patients with persistently elevated EBV DNA copy 
levels (75%) demonstrated residual or progressive disease. In a follow-up study , the same 
investigators showed that a rise in circulating EBV DNA predicted disease recurrence 
whereas a persistently undetectable level correlated with clinical remissions. 
Lo et a!. speculated that an initial rise in free EBV DNA after the initiation of radio­
therapy most likely reflected tumor lysis (223 ). The "decay rate" of this circulating EBV 
DNA was assessed in serial bleeds from patients undergoing treatment. The median half-life 
was determined to be 3.8 d. In a larger study, evaluating 170 NPC patients undergoing radio­
therapy alone, this group found that elevated post-treatment EBV plasma DNA levels were 
more significantly associated with recurrence than elevated pretreatment levels: relative risk 
ratio 11.9 (95% confidence interval [CI] = 5.53 to 25.43) vs 2.5 (95% CI = 1.14 to 5.70), 
respectively (224). Because of the uniqueness of this disease, its associated highly specific 
DNA marker, the homogenous treatment regimen, and the logistics of performing serial 
blood assessments, these studies remain pivotal in the assessment of plasma kinetics of 
tumor-associated circulating nucleic acid markers (225-232 ). 
5. PITFALLS AND CONSIDERATIONS 
Current advances in molecular oncology have transformed microsatellite marker evalua­
tions into a powerful tool for the identification of genes associated with malignancy. 
Microsatellite analysis has been used to diagnose cancer, evaluate recurrence, assess 
response to therapy, and predict outcome. Many early studies evaluated primary tumor tis­
sue. However , the usefulness of this specimen is limited by genotypic heterogeneity among 
tumor cells and by infiltration with normal cells including lymphocytes and macrophages. 
More importantly, assessment of primary tumors cannot reflect the ongoing tumor alter­
ations that characterize progression and metastasis. By contrast, assessment of plasma/serum 
for circulating tumor DNA is a minimally invasive approach that is logistically practical for 
serial genetic analysis and may prove clinically relevant because it is dynamic rather than 
static in nature. 
Microsatellite analysis can detect chromosomal alterations, but marker selection has been 
too inconsistent to allow clinically relevant application across various patient populations. 
Moreover, LOH results are affected by the primer sequences selected, the labeling technique 
used, and the purity and quality of the commercially prepared marker product. PCR must be 
optimized on test samples prior to a definitive analysis. Care must be taken to avoid DNA 
contamination and to follow strictly established standard operating techniques that include 
separate designated areas for tissue/body fluid sample processing, DNA extraction, pre-PCR 
set-up, and PCR thermocycling. Methodologies for post PCR product analysis include stan­
dard gel electrophoresis followed by autoradiography of radioisotope or nonradioisotope 
products with densitometric analysis or laser scanning of fluorescently labeled products. 
Recently, CAE using an automated sequencer has been employed for fluorescent 
microsatellite analysis. This is extremely accurate for high-throughput evaluation of mul­
tiple samples. Results are shown as peaks instead of bands, and the area under the peak 
represents post-PCR product amount. LOH is calculated from the ratios of peak height s.

MA as Molecular Markers in Patients With Cancer 417 
However, a multicenter trial found no superiority in sensitivity with this technique as com­
pared to conventional gel analysis (233 ). Other approachs for screening LOH now include 
single nucleotide polymorphism analysis (SNPs). 
Currently, no standard exists for defining LOH. A positive LOH result has been described 
for allelic ratios of 25-80%; this wide range reflects contamination of tumor DNA with 
normal DNA. A variety of methods have been proposed for extracting DNA from body 
fluids and tissues (92,234-237). Laser capture microdissection (LCM), which permits selec­
tive extraction of single cells from a tumor specimen, can avoid contamination of tissue 
specimens, but cannot be used for serum and plasma (238). LOH assessment of DNA from 
blood depends on the method of blood processing . Some laboratories allow the plasmal 
serum to sit at room temperature while others heat the sample before processing; both tech­
niques appear to enrich circulating DNA levels and may affect the purity of results. 
Microsatellite analysis requires the comparison of tumor DNA to each patient's normal 
genomic DNA. For tissue and body fluid analyse s, we recommend peripheral blood lympho­
cytes, which can be readily collected and proce ssed for DNA. Retrospective tissue analysis 
often uses morphologically normal tissue from the tumor spec imen , but adjacent normal­
appearing tissue may contain genetic alterations identical to those in the tumor ( 112 ). We 
therefore suggest utilizing normal-appearing tissue furthest from the tumor, preferably with 
a mixed cell type to enhance the chance of having a predominance of normal DNA. 
Ideally, a tumor marker should be highly selective for occult tumor , highly specific for 
cancer, closely correlated with extent of disease, stable in plasma/ serum, and easy to assess. 
Because tumor initiation and progression is associated with a variety of different gene tic 
alterations that are not consistent for most tumor types, assessing multiple markers may 
improve results. The multimark er approach also accommodates the heterogeneity that exists 
within a tumor and among tumor lesions from the same patient. Protein markers are stable, 
easy to detect, and can be readily quantitated , but their limited sensitivity and specificity are 
suboptimal for screening and early diagnosis. mRNA markers are more sensitive and spe­
cific, but mRNA is relatively unstable and often require fresh/frozen tissue. Assay efficien­
cies can vary with specific primer sets, and false positives may result from the presence of 
pseudogenes, illegitimate expression, and/or contaminating RNA and DNA sequences (239 ). 
More importantly, specificity is affected by any change in the expression or the abundance 
of gene transcription . Sources of these changes include tumor heterogeneity, cytokines, 
growth factors, hormones, and the tumor microenvironment. DNA-based methods are highly 
specific for tumor cell detection, however DNA PCR amplification is less sensitive than 
RT-PCR because of a lower copy number per cell (73). Variations in clonal selection and 
deletion may affect results in a similar fashion as for mRNA assays. 
Assessment of circulating genetic markers provides an appealing approach for monitor­
ing subclinical disease progression and response to treatment in cancer patients. These 
molecular surrogates may eventually be used to screen high-ri sk populations for cancer and 
to develop novel therapeutics more patient specific. Serial assess ment of blood and/or body 
fluids for tumor-specifi c molecular genet ic alterations may provide valuable prognostic 
information that is less static and more practical than standard tumor analyses. We do not 
understand the mechanisms that elevate level s of circulating nucleic acids in cancer 
patients -is DNA released from tumor cells under going apoptosis, necrosis or is there a

418 Taback and Hoon 
means for active release? (45, 71,240-242). Additionally, we do not know whether certain 
chromosome loci DNA may be more efficient in "surviving" in blood and for how long. Nor 
do we know whether free tumor DNA is from circulating tumor cells, the primary tumor site, 
occult subclinical lesions, or metastasis. Further translational studies will help answer these 
questions and should firmly establish the role of these circulating DNA markers in cancer 
From the Gonda (Goldschmied) Research Laboratories of the John Wayne Cancer Insti­
tute. Supported in part by the California Breast Cancer Research Program Grant 7WB-0021, 
NCI PO 1 CA29605 and PO 1 CA 12582, Department of Defense DAMD-17 -03-1-0261, the Ben 
B. and Joyce E. Eisenberg Foundation (Los Angeles), Rachel Goodman Cancer Research 
Grant and the Fashion Footwear Association of New York. We wish to thank Ms. Gwen 
Berry for outstanding editorial assistance. We apologize to studies not cited in this review 
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20 
Recent Advances in Molecular Classification 
and Prognosis of Colorectal Cancer 
Tsung- Teh Wu and As if Rashid 
Colorectal cancer is the fourth most common cancer and the second most common cause 
of cancer death in the United States, with approx 130,000 new cases and 55,000 deaths per 
year ( 1 ). It is currently believed that most colorectal cancers arise from pre-existing precur ­
sor lesions (adenoma and dysplasia), but a small percentage of colorectal cancers can arise 
de novo without identifiable precursor lesions (2-8). A majorit y of the colorectal cancers are 
sporadic and only 5 to 10% of colorectal cancers are associated with inherited syndromes . 
The molecular pathogenesis of colorectal cancer, including genetic and epigenetic alter­
ations has been extensively studied in the past two decades and is among one of the best­
under stood hum an neoplasms . Although inherited forms of colorectal cancer constitute a 
minority of all colorectal cancers, the identification of underlying genetic defects responsible 
for the inherited syndrome has been instrumental for our under stand ing of the pathogenesis 
of colorectal neopla sia. 
Three major molecular pathways have been characterized in colorecta l cancers (Fig. 1). 
The conventional pathway invol ves accumulation of alterations of multiple tumor suppres­
sor genes including adenomatous polyposis coli (APC), deleted in colorectal cancer (DCC), 
delet ed in pancreatic cancer 4 (DPC4), and p53 and oncogenes including k-ras, and {3-cat enin 
in the adenoma-carcinoma sequence accounts for a majority of colorectal cancer (9, 10). 
Approximately 15% of sporadic colorectal cancers arise through a second distinct pathway 
involvin g "DNA mismatch repair genes" that is also responsible for the hereditary 
nonpolyposis colorectal cancer (HNPCC) syndrome. Mutations of the DNA repair genes 
(hMLH-1, hMSH-2 , and hMSH-6) cause insertions or deletions ofnucleotides in the unstable 
repeated sequences such as microsatellites ( 11-14). This subset of colorect al cancers has 
unusual pathologic features such as poor differentiation, medullary or mucinous histologic 
type, and prominent lymphoid inflammatory response ( 15-17). In addition to the genetic 
alterations described above , inactivation of tumor suppressor genes by promoter 
hypermethylation is a frequent epigenetic alteration in human cancer ( 18). In colorectal can­
cer, it has been shown that methylation of CpG islands is a common molecular defect in 
color ectal cancer ( 19,20 ). "DNA methylator pathway" is the third novel pathway character ­
ized by methylation of multiple CpG islands in a subset of colorecta l carcinomas , includin g 
genes known to be important in tumorigenesis such as the p16 tumor suppressor gene and 
hMLH1 mismatch repair gene. 
From : Cance r Diagnos tics: Current and Futur e Trends 
Edited by: R. M. Nakamura , W. W. Grod y, j. T. Wu, and R. B. Nag le © Hum ana P ress Inc., Totowa , Nj 
429

430 Wu and Rashid 
A Conventional pathway 
APC mutation Ear1y genetiC Late genet1c alteration 
5q LOH / aHerat10n ~ all• Hp, 18q LOH /. ~ / r-- K-ras mutation ---, ~erations of p53, DCC, DPC4 
'---Norm___,'' 1-1 ACF 1-1 Ado•~• I j r-----~ 
B DNA Mismatch Repair pathway 
Normal 1---1 ACF 
C DNA Methylator pathway 
Normal . . . Frameshift mutations of Alteration of DNA mismatch repa1r genes TGF~RII Ba 
~hMLH1, hMSH2, hMSHB)~ IGFII,R x, r-----, 
1--- Serr~:n:d:~oma + 
. Hyperplastic polyp 
CpG island methylation of tumor suppresor 
and associated genes 
(p16, p14, MGMT, COX2, hMLH1) ~ 
Adenoma 
Serrated adenoma 
Hyperplastic polyp 
Fig. 1. Schematic summary of genetic alterations involved in the three major pathways of 
colorectal tumorigene sis. Aberrant crypt foci (ACF) are the earliest precursors lesion. Sequential 
accumulation of alterations in multiple tumor suppressor genes and oncogenes occur in conventional 
pathway (A). A total of 15 to 20% of sporadic colorectal cancer have MSI-H genotype owing to 
inactivation of DNA mismatch repair genes. These tumors frequently have mutations in the tumor 
suppressor genes with short nucleotide repeats (B). Inactivation of gene function by DNA 
hypermethylation in tumor-specific (type C) genes including methylation of hMLHJ gene plays an 
important role in DNA methylator pathway (C). In addition to adenomas, serrated adenomas and 
hyperplastic polyps are also precursor lesions in DNA mismatch repair and DNA methylator path­
ways following the hyperplastic polyp-serrated adenoma-carcinoma sequence. 
1.1. Conventional Pathway 
The standard pathogenic pathway is the adenoma-carcinoma sequence, first described by 
Morson, and Hill and colleagues plays an important role in the majority of colorectal carci­
noma (21 ,22 ). Fearon and Vogelstein described sequential stepwise involvement of multiple 
tumor suppressor genes and oncogenes in the adenoma-carcinoma sequence (9). In this 
model, a combination of multiple genetic alterations is required for the ultimate development 
of colorectal cancer and the presence of a single genetic alteration is not sufficient for malig­
nant transformation. 
1.1.1. Tumor Suppressor Genes in Conventional Pathway 
Multiple tumor suppressor genes are involved in the development of colorectal cancers as 
evidenced by frequent chromosomal allelic losses of 1 p, 5q (APC) , 8p, l7p (p53), 18q (DCC), 
and 22q (9,23-25 ). The earliest genetic change occurs in the APC gene. APC is a tumor 
suppressor gene located on chromosome 5q21 and was first identified through its involve­
ment in familial adenomatous polyposis (FAP) syndrome (26-29). APC gene has been

Molecular Classification and Prognosis of CRC 431 
regarded as a "gatekeeper" gene and plays a critical role in colorectal carcinogenesis. The 
inactivation of APC gene in colorectal neoplasm follows the Knudson's two-hit hypothesis. 
Allelic loss of chromosome 5q is present in 40-50% of sporadic colorectal adenomas and 
carcinomas, and somatic mutation of APC gene can be identified in up to 70% of sporadic 
colorectal cancer by sensitive in vitro synthesizing protein assay ( 30,31 ). The identification 
of APC mutation in dysplastic aberrant crypt foci, the earliest morphologic colorectal 
precursor lesion , further supports the critical function of APC gene in the colorectal patho­
genesis (32). The function of APC gene has been recently characterized. APC gene product 
interacts with GSK-3~ and ~-catenin, and is an essential component in the Wnt pathwa y. APC 
gene also play an important role in cell adhesion through interaction with Cadherins ( 37). 
In contrast to APC gene, alterations of other tumor suppressor genes occur in the later 
stages of colorectal carcinogenesis. Mutations of p53 gene and allelic loss of chromosome 
17p occur in up to 75% of colorectal cancers , but rarely in adenomas (38-41). The p53 
protein can function as a transcription factor and is involved in the cell cycle regulation and 
programmed cell death. The presence of frequent p53 alterations in carcinoma but not in 
adenomas suggests that p53 may play an important role in progres sion of adenoma into 
carcinoma (39,40). 
Allelic loss of chromosomal 18q occurs in 70% of sporadic colorectal cancers and is less 
frequent in adenomas ( 10). DCC, DPC4 (SMAD4 ) and JV-18(SMAD2) genes are present on 
chromosome 18q. A candidate tumor suppressor gene designated DCC that belongs to the 
neural cell adhesion molecule (N-CAM) family has been identified (42). Only a minority of 
colorectal cancers demonstrated somatic mutations of DCC in limited mutation analysis of 
the whole gene, but the protein expression is frequently reduced or absent in colorectal can­
cers. The presence of allelic loss and loss of protein expression supports the role of DCC in 
colorectal carcinogenesis. Another tumor suppressor gene, DPC4 (SMAD4), first identified 
in pancreatic adenocarcinoma is also located in chromosome 18q. SMAD4 is a downstream 
mediator of the TGF~ signal pathway. Mutation of DPC4 gene has been identified in 16% of 
colorectal cancer ( 43) and DPC4 protein expression is absent in 8% of colorectal cancer 
(44) . Although the tumor suppressor gene in chromosome 18q involved in colorectal ca ncer 
remains unclear , the presence of chromosomal 18q allelic loss appears to predict a worse 
outcome especially in stage II colorectal cancer (45,46). 
1.1.2. Oncogenes in Conventional Pathway 
Among the oncogenes, k-ras is the most frequently mutated in colorectal adenomas and 
cancer. Activation mutation of k-ras oncogene has been detected in 50% of colorectal can­
cers and large (> 1 em) adenomas, but is less frequent (approx 10%) in smaller ( < 1 em) 
adenomas (9,10). The majority of k-ras mutations are present at codo ns 12 and 13, and less 
frequently at codon 61. The role of aberrant crypt and hyperplastic polyps in the develop­
ment of colorectal cancer is controversial but k-ras mutations have been frequently detected 
in aberrant crypt foci and hyperplastic polyps supporting the clonal nature of these lesions 
( 32,47) . The presence of k-ras mutations in colorectal adenomas and cancers are associated 
with a polypoid growth pattern rather than a flat growth pattern, but the significance of these 
findings is unclear (48). 
In addition to k-ras , other oncogenes such as Her-2/neu, myc, myb, and trk are infre­
quently involved in the colorectal carcinogenesis. ~-catenin is also an oncogene and inter­
acts with APC gene in the APCI {3-catenin pathway. Mutations of {3-catenin gene have been

432 Wu and Rashid 
reported in up to 50% of colorectal cancers lacking APC gene mutations, and in small 
colorectal adenomas ( 49,50 ). 
1.2. DNA Mismatch Repair Pathway 
Microsatellites are tandem repeat mono, di, tri, or tetranucleotides that are present through­
out the human genome. The functions of microsatellites are not known but have been postu­
lated to act as promoter sites for recombination or DNA topoisomerase binding sites (51-53) . 
Microsatellite instability (MSI) is characterized by alterations of microsatellites owing to 
defective mismatch repair mechanisms and has been observed in a subset (15%) of sporadic 
colorectal cancer. Colorectal carcinoma can be classified into microsatellite stable (MSS), 
microsatellite instability-low (MSI-L), and microsatellite instability-high (MSI-H). The cri­
terion for MSI-H varies with each study, but colorectal cancers with instability in more than 
40% of microsatellite markers are generally regarded as MSI-H. The National Cancer Insti­
tute (NCI) standardized the criteria for classification of MSS, MSI-L, and MSI-H in a con­
sensus conference. The conference proposed a panel comprising of five microsatellite makers 
including two mononucleotide markers (BAT 25 and BAT26) and three dinucleotide mark­
ers (D2S 123, D5S346 , and Dl7S250). Colorectal cancers with instability in two or more of 
these five markers are classified as MSI-H (54). 
In contrast to the conventional pathway, colorectal cancer with MSI-H tends to have less 
frequent l8q allelic loss or alterations of p53 and k-ras genes compared to colorectal cancer 
with MSS (55,56). Mutations of {3-catenin are more common in MSI-H colorectal cancer 
( 49,57,58 ). In addition, a distinct set of tumor suppressor genes containing short mononucle­
otide repeats in the encoding region such as transforming growth factor f3 receptor type II 
(TGFf3RIJ), insulin growth factor 2 receptor (IGFl/R) and BAX genes are frequently mu­
tated in MSI-H colorectal cancer (59-61 ). Most mutations in these genes are small deletions 
or insertions that result in frameshifts and result from mismatch repair gene defects during 
the DNA synthetic phase of the cell cycle. Interesting, not all mononucleotide repeats are 
subjected to the same rate of mutation in MSI-H colorectal cancer, a mononucleotide repeat 
with poly(G) tract is more prone to mutation than poly(A) tract (62). 
1.2.1. Mismatch Repair Genes and Microsatellite Instability 
The human mismatch repair (MMR) gene family consists of several genes homologues to 
Escherichia coli MMR genes: hMLHJ, hMSH2, hMSH3, hMSH6, hPMSJ, and hPMS2 
(63-68). In contrast, to HNPCC patients that have similar frequency of alterations of hMLHJ 
and hMLH2, more than 95% of the sporadic MSI-H colorectal cancers are owing to the 
inactivation of hMLH 1 in the majority (80 to 95%) of patients, and inactivation of hMSH2 
in a smaller subset (5 to 20%) of patients (69,70). The inactivation of hMLHJ, hMSH2 and 
hMSH6 in MSI-H colorectal cancer can be evaluated by the absence of protein expression 
in tumor cells by immunohistochemical stains (Fig. 2). The majority (95%) of the MSI-H 
colorectal cancer demonstrate absence of either hMLHJ or hMSH2 expression in the tumor 
cells (63,69). 
In the majority of patients with sporadic colorectal carcinoma the loss of hMLHl protein 
expression results from promoter methylation of the hMLHJ gene rather than mutations 
(70-73 ). No methylation of hMSH2 gene promoter has been reported, but allelic loss or 
somatic mutation have been reported in colorectal cancer with absent hMSH2 protein 
expression (70). Two other MMR genes, hMSH3 and hMSH6 are not directly responsible for

Molecular Classification and Prognosis of CRC 
• • • • 
' ' •! • ., . . ~ •· . . · .. 433 
Fig. 2. Immunohistochemical stain of hMLHJ and histological features of sporadic MSI-H 
colorectal cancer. The tumor cells show absence of hMLHJ nuclear expression in contrast to normal 
colonic crypt epithelium (arrow) with positive staining (A). In a high power view from panel A, the 
tumor cells (arrowheads) are negative for hMLH I staining, but the infiltrating lympho cytes (arrow­
heads) demon strate nuclear hMLHl expression (B). Histological characteristics ofMSI-H colorectal 
cancer include poor differentiation with solid growth pattern (C), mucinous differentiation with abun­
dant extracellular mucin pool formation (D) prominent intratumor lymphocyti c infiltrates (E), and 
Crohn's-like lymphoid response (arrows) at the tumor invadin g front (F). 
MSI-H phenotype but are associa ted with somatic slippage-related frameshift mutations in 
MSI-H tumors, and probably secondary to inactivation of hMLHJ or hMSH2 genes (74,75). 
The involvement of MMR genes in the MSI-L colorectal cancer is not clear. Germ-line 
mutation of hMSH6 gene has been reported in small subset of HNPCC families, and some of

434 Wu and Rashid 
tumors in these families have MSI-L phenotype (14, 76, 77). However, hMSH6 mutations 
appear to play a minor if any role in the pathogenesis of sporadic MSI-L colorectal cancer (78). 
1.2.2. Histological Characteristics of Sporadic Colorectal Cancer With Microsatellite Instability 
There are several distinct clinicopathological features of sporadic MSI-H colorectal can­
cers as compared with MSS colorectal cancers. Clinically, MSI-H cancers are more likely to 
present at a more advanced local stage, be proximally located, and have a better stage-spe­
cific survival after surgical and adjuvant therapies ( 11, 12,79-84 ). Histologically, character­
istics of MSI-H cancers include exophytic growth pattern, large tumor size, poor 
differentiation, mucinous differentiation, Crohn's-like lymphoid response, and intratumoral 
lymphocytic infiltrate (15-17) (Fig. 2). Sporadic colorectal cancers with these features 
should warrant genetic testing to confirm the MSI-H genotype. A frequent association with 
contiguous serrated adenomas in sporadic MSI-H colorectal cancer, in contrast to the tradi­
tional adenomas seen in HNPCC colorectal cancer has also been reported (85 ). However, no 
single clinicopathological feature mentioned above can sensitively predict MSI-H genotype 
or be used to select colorectal cancer for microsatellite instability testing ( 17). Immunohis­
tochemical stains for the MMR proteins (hMLH 1, hMSH2, and hMSH6) expression can be 
used as an adjunct for the microsatellite instability testing. The absence of MMR protein 
expression typically correlated well with MSI-H, and presence of protein expression with 
MSS or MSI-L as predicted by microsatellite instability testing using the five NCI markers. 
1.3. DNA Methylator Pathway 
Epigenetic alterations have been extensively studied in colorectal cancers in the last two 
decades. The emphasis of epigenetic changes has switched from global hypomethylation to 
hypermethylation of tumor specific genes in neoplasm. Inactivation of gene function by 
methylation of promoter region in the DNA methylator pathway overlaps closely with the 
genetic alterations observed in both the conventional and DNA mismatch repair pathways. 
Methylation of CpG islands present in the promoter region can silence tumor suppressor 
genes in the absence of mutations or chromosomal loss that are typically seen in the conven­
tional pathway. 
1.3.1. DNA Methylation and CpC Islands 
CpG islands are 0.5- to 2-kb regions rich in cytosine-guanine dinucleotides and are present 
in the 5' region of approximately half of all human genes (86). DNA methylation in CpG 
islands is essential for mammalian development (87). In neoplasia, CpG island methylation 
(CIM) is also an important mechanism for suppression of transcription of genes (87,88). 
Methylation of CpG islands is a molecular defect common in colorectal cancer ( 19). Genes 
with methylation can be classified as type A (age-related methylation) or type C (tumor­
specific methylation) (89). The methylation of type A genes in colonic mucosa increases 
with increasing age and include ER, IGF2, MYOD1, N33, PAX6, and CSPG2 (89-92). The 
methylation of type C genes includingp16, p14, MGMT, COX-2 , and hMLH1 is tumor spe­
cific and responsible for the carcinogenesis of sporadic colorectal cancer. Inactivation of tumor 
suppressor genes such as APC (18% of colorectal cancer) and p16 (28-55 % of colorectal 
cancer) by DNA methylation is a new model of inactivation in addition to the mutations of 
the gene and chromosomal allelic loss that accounts for the "two hit hypothesis" proposed 
by Kundson (93 ). There is also a close association between the methylation of MGMT, a 
ubiquitous DNA repair enzyme, and mutation of k-ras gene in colorectal cancer (94). Inac-

CIMP 
Case No. 
MINT-1 
MINT-2 
MINT-31 
p16 
hMLH1 Pos Neg 
Low Neg High Cont Cont 
1 2 3 RKO :e ~ ~ ~ ~ 
u M u M u M u M --·-----u 
HL-60 ~ 
--.. -----
HL-60 ~ ------HL-60 ~ -----
HL-60 ~ __ ... ---M 435 
Fig. 3. CpG island methylator phenotype (CIMP) in colorectal cancer. Colorectal cancers are 
classified as CIMP+ if multiple loci are methylated (CIMP-high), or CIMP- if none (CIMP-negative) 
or only one locus was methylated (CIMP-low). Methylation status of tumor is determined by methy­
lation -specific PCR (MSP) at MINTI, MINT2, MINT3/, p/6 and hMLHJ using primers for methy­
lated (M) and unmethylated (U) alleles of bisulfite-treated DNA. RKO , a colon cancer cell line used 
as a positive control; dH20, samples without DNA used as negati ve control for MINT I ; HL-60, a 
promyelocytic cell line used as negative control for MINT2, MINTJJ , pl6, and hMLHJ. 
tivation of MGMTby methylation also appears to precede k-ras mutation in small adenomas 
and underscores the role of DNA methylation in the early colorectal carcinogenesis (94 ). As 
discussed in the previous section , inactivation of MMR gene, hMLH 1, by DNA methylation 
is responsible for the majority of the sporadic MSI-H colorectal cancer. An association 
between methylation of MGMT and MSI-L colorectal cancer has been recently described 
in addition to the association to K-ras mutation (95). 
1.3.2 . Methylator Phenotyp e in Colorectal Cancer 
A major subset (approx 50%) of colorectal cancer, including sporadic MSI-H colorectal 
cancers have methylation of multiple CpG islands termed CpG island methylator phenotype 
(CIMP) (Fig. 3). CIMP positive (CIMP+) colorectal cancers have methylation of genes 
known to be important in tumorigenesis , such as the p16 tumor suppressor gene, hMLH1 
mismatch repair gene, and THBS1 (19). Approximately 75% of he MSI-H colorectal cancer 
also have CIMP+ phenotype owing to the presence of methylation of hMLH 1 gene (19 ). 
This CIMP phenotype can be observed in colorectal adenomas and aberrant crypt foci, the

436 Wu and Rashid 
Fig. 4. Precursor lesions of colorectal cancer. Aberrant crypt foci are the earliest morpholog ic 
precursor lesion and can be subclassified into dysplastic (insert) or heteroplastic with hyperplastic 
features (A). Hyperplastic polyp with classic saw-tooth pattern (B) a large hyperpla stic polyp or 
hyperplastic polyps from patients with hyperplastic polyposis can be a precursor lesion for colorectal 
cancer. Serrated adenoma is distinct from hyperplastic polyp by the presence of epithelial dysplasia 
with saw-tooth architecture (C). The classic precursor lesion, adenoma is characteri zed by the pres­
ence of dysplastic epithelium with tubular architecture (D). 
putative earliest lesion for colorectal cancers indicating the importance of DNA methylation 
pathway in early colorectal carcinogenesis ( 19,96 ,97). In addition, CIMP+ adenomas and 
carcinomas have a distinct genetic profile with frequent mutation of the k-ras gene, but 
uncommon p53 mutation (20). 
2. PRECURSOR LESIONS 
The molecular alterations present in the precursor lesion in the adenoma-carcinoma 
sequence of colorectal cancer have been extensively analyzed, especially for the conven­
tional pathway. In addition to the classic adenoma, other colorectal precursor lesions includ­
ing aberrant crypt foci, hyperplastic polyp, and serrated adenoma (polyp with mixed 
hyperplastic and adenomatous features) have also been extensively studied (Fig. 4). An 
alternative pathway of colorectal carcinogenesis with a hyperplastic polyp-serrated adenoma­
adenocarcinoma sequence has been proposed (98-105).

Molecular Classification and Prognosis of CRC 437 
2.1. Aberrant Crypt Foci: The Earliest Precursors Lesion 
Aberrant crypt foci (ACFs) are the earliest morphological precursor lesions for colorectal 
cancer defined by the distinct macroscopic appearance in colonic mucosa stained with dyes, 
such as methylene blue. ACFs are phenotypically diverse lesions and can be subclassified 
into dysplastic and heteroplastic (hyperplastic) ( 106). Dysplastic ACFs have histological 
features of adenoma and are more common in familial adenomatous polyposis (FAP) patients 
than in sporadic colorectal cancer patients. ACFs , especially dysplastic ones are considered 
precursors of colorectal cancer ( 106-111). 
Molecular alterations involving colorectal cancers have been evaluated in ACFs. Muta­
tions of APC gene have been identified in up to I 00% of dysplastic ACFs from FAP patients 
but not from sporadic colorectal cancers ( 110,111). In contrast, heteroplastic ACFs have 
frequent k-ras (up to 82%) mutations but no APC or {3-catenin mutations ( 106,110,111 ). 
Microsatellite instability is present in 100% of ACFs from HNPCC patients ( 112 ), but less 
frequently (3-23%) in ACFs from sporadic colorectal cancers (97,113,114). An increased 
p16 protein expression has been reported in ACFs (115). DNA methylation ofpl6, hMLH1 
and MGMT genes and other CpG islands (MINT31, MINTl and MINT3) is present in 34% 
of ACFs and is more frequent in sporadic ACFs (53%) than ACFs from FAP patients (11 %) 
(96). Furthermore, methylation is more common in dysplastic ACFs from sporadic patients 
(75%) than in FAP patients (8% ), but no difference is present in heteroplastic ACFs between 
these two groups of patients (96). 
2.2. Hyperplastic Polyps 
Hyperplastic polyps (HPs) are morphologically regarded as non-neoplastic lesions, and 
their roles as precursor lesions remain controversial. However, recent genetic analyses of 
HPs have shown that at least a subset of HPs, especially in patients with hyperplastic poly­
posis, are precursors of colorectal cancer (98,116-119). 
Genetic alterations typically seen in colorectal cancers such as k-ras mutation , chromo­
somal allelic loss of lp, and microsatellite instability can occur in HPs (32,98,120-123). The 
genotype appears to be different among HPs in hyperplastic polyposis (more than 20 HPs), 
multiple HPs (5-20 HPs) and large HPs (HPs more than 1 em in size), with frequent chromo­
somal allelic loss lp in HPs from hyperplastic polyposis (98). Patients with a large HP in the 
right colon or hyperplastic polyposis have increas ed risk of colorectal cancer (98, 116-119 ). 
No DNA methylation of the CpG islands that are commonly methylated in colorectal carci­
nomas is present in sporadic HPs, but frequent concordant methylation of multiple loci is 
present in 43% of large HPs and HPs from hyperplastic polyposi s ( 124 ). A putative anti­
adhesion gene HPP 1/TPEF on chromosome 2q32 -q33 identified from hyperplastic polyps 
can be inactivated by methylation in 63% of the HPs (125 ). 
2.3. Serrated Adenomas 
Serrated adenoma (SA) is an uncommon variant of colorectal adenoma, characterized by 
the saw-toothed architectural features of hyperplastic polyp, but with the presence of 
unequivocal epithelial dysplasia (126, 127). The role of serrated adenomas in colorectal car­
cinogenesis is not established, but it has been report ed that intramucosal carcinoma occurs in 
11% of serrated adenomas and that colorectal cancer is common in patients with serrated 
adenomatosis (127,128). The close morphological resemblance between HP and SA, fre-

438 Wu and Rashid 
quent occurrence of SA in hyperplastic polyposis, and adenocarcinoma arising in the setting 
of colorectal hyperplastic polyps or serrated adenomas, especially in patients with hyper­
plastic polyposis, or serrated adenomatous polyposis has propelled a hyperplastic polyp­
serrated adenoma-adenocarcinoma sequence as an alternative pathway of colorectal 
carcinogenesis (98-105 ,116-118,126 ,129,130). 
SA has been reported to have a lower frequency of APC gene mutation than in sporadic 
tubular adenomas (131 ). Other studies have shown heterogeneity of genetic alterations in 
serrated adenomas, including k-ras mutations, p53 gene mutations and MSI (98, 100,130, 
132,133). The frequency of k-ras gene mutations has been reported to be as high as 58%, 
i.e., higher than in tubular adenomas ( 133 ). Overexpression of p53 protein of the type asso­
ciated with p53 gene mutation (100%, II of II) and mutation of p53 (47%, 9 of 19) have 
been demonstrated in serrated adenomas in one study by Hiyoma et al ( 133 ). However, other 
studies have shown low rate of k-ras mutation and p53 overexpression ( 134,135 ). The devel­
opment of microsatellite instability in serrated adenoma may have a role in the pathogenesis 
of colorectal carcinomas (98,100,124,130). Jass and colleagues, have proposed that SA can 
be implicated in MSI-H and MSI-L colorectal cancers ( 129,130,136). 
Concordant CpG island methylation has been described in SAs in patients with multiple 
hyperplastic polyps and/or right-sided hyperplastic polyposis ( 124). Recent data has shown 
that concordant methylation (CIMP+) is also more frequent in sporadic serrated adenomas 
(68%) than in tubular adenomas (18%) indicating that CpG island methylation is common in 
sporadic serrated adenomas and may play an important role in their pathogenesis ( 137). 
2.4. Adenomas 
The majority of the colorectal cancers follow the adenoma-adenocarcinoma sequence. 
Adenomas are well-recognized precursor lesions for colorectal cancers irrespective of their 
underlying molecular pathway or genetic defects (21,22). Mutations of the gatekeeper gene, 
APC, allelic loss of chromosome Sq, and k-ras oncogenes mutations (20-70%) are frequently 
present in adenomas ( 138-146). Alterations frequently seen in the later stage of colorectal 
cancer development such as p53 mutation (5-26% ), 18q allelic loss (2-7%) are less fre­
quently seen in adenomas (145,146,149,150). MSI-H is frequently seen in adenomas from 
HNPCC patients (60-95% ), but only occasionally in sporadic adenomas (3-7%) 
( 151-155). Methylation at multiple loci (CIMP+) is present in 25-50% of sporadic colorectal 
adenomas ( 19,20,97). CIMP+ phenotype is more common in adenomas with villous histology, 
a characteristic associated with frequent predisposition to invasive colorectal cancer (97). 
3. FAMILIAL COLORECT AL CANCER 
Colorectal cancer can arise in inherited syndromes including familial adenomatous poly­
posis (PAP), hereditary nonpolyposis colorectal cancer syndrome (HNPCC), juvenile poly­
posis (JPS), Peutz-Jegher syndrome (PJS), and hyperplastic polyposis and account for 5-10% 
of colorectal cancers. 
3.1. Familial Adenomatous Polyposis Syndrome 
Familial adenomatous polyposis syndrome (PAP) affecting approx 1 in l 0,000 individu­
als, is an autosomal dominantly inherited disease with hundreds of colorectal polyps and 
germline mutation of the APC gene on the long arm of chromosome 5 (26-29 ). If left

Molecular Classification and Prognosis of CRC 439 
untreated, more than 85% of the FAP patients will have colorectal cancer by the age of 45 yr. 
Gardner syndrome is categorized by colonic polyps and with various extracolonic manifes­
tations such as osteoma, epidermoid cysts, and desmoid tumors. 
In FAP patients, two-thirds of the APC mutations are small insertions or deletions that 
cause frameshifts in the coding region, and the remaining one-third are single base substitu­
tions that result in stop codons. The location of the mutations can affect the clinical pheno­
type. Patients with attenuated FAP have APC mutations at the extreme 5' and 3' end of the 
gene (156-158). The location of the germline APC mutation also appear to have influe nce 
on the second APC hit in colorectal polyps in FAP patients: germline APC mutations within 
a small region ( codons 1194-1392) have predominantly allelic loss in colorectal adenomas 
as compared to other FAP patients that frequently have truncating mutations ( 159). 
APC gene polymorphism in Il307K allele is associated with increased risk of colorectal 
cancer in Ashkenazi Jews ( 160,161 ). This allele is found in 6% of Ashkenazi Jews lacking a 
family history and 28% with a family history of colorectal cancer ( 160). The Il307K allele 
contains an adenosine rich sequence A3 T A 4 at nucleotide 3920 that changes to A8, and cre­
ates a small hypermutable region in APC gene ( 160) with frequent insertion mutation at this 
A8 sequence (162). 
3.2. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) 
HNPCC is an autosomal dominant disorder caused by a germline mutation in MMR genes 
and accounts for 3-6% of colorectal cancers ( 163,164) . The inactivation of MMR genes 
results in high frequency of microsatellite instability (MSI-H) similar to the sporadic MSI-H 
colorectal cancer. More than 90% of the HNPCC patients have mutations in hMLH I and 
hMSH2 genes ( 165 ). Somatic frameshift mutation in hMSH3 and hMSH6 have been shown 
to occur in 53 and 33% of colorectal cancer in HNPCC patients secondary to germline inac­
tivation of hMLH1 or hMSH2 genes (61). DNA hypermethylation in hMLH1 promo ter fre­
quently seen in sporadic MSI-H colorectal cancers is infrequently detected in 46% of 
colorectal cancers in HNPCC patients (70). Simil ar to sporadic MSI-H colorectal cancers, 
mutations of TGF{3Rll are frequent in colorectal cancers from HNPCC patients, but muta­
tions of BAX gene are more frequent in colorectal cancers of HNPCC patients (55%) than in 
sporadic MSI-H colorectal cancers (13%) (55). 
3.3. Juvenile Polyposis Syndrome 
Juvenile polyposis syndrome (JPS) is an autosomal dominantly inherited syndrom e char­
acterized by multiple gastrointest inal hamartomatous polyps with increased risk of colorectal 
cancers ( 166-168). The underlying genetic altera tions are heterogeneo us for JPS with 
approximately half of the JPS families having disease-specific germline mutations. Muta­
tions of the SMAD4 ( DPC4) gene on chromosome 18q21.1 have been identified in a subset 
(up to 50%) of the JPS (169-173). In addition, a small subset of JPS has been linked to 
chromosome 10q22-23 with germline mutations of bone morphogenetic protein receptor lA 
(BMPR1A) or PTEN genes ( 174-179). 
IPS can be a component of Cowden syndrom e (CD) and Bannayan-Riley-Ruvalcaba syn­
drome (BRRS) ( 175, 176). Germline mutations of PTEN gene have identifi ed in some fami­
lies of CD and BRRS (180,181). Som atic mutation of PTEN gene are present in up to 19% 
sporadic colorectal cancer, and more frequently (60%) in MSI-H colorectal cancer ( 182, 183).

440 Wu and Rashid 
3.4. Peutz-Jegher Syndrome 
Peutz-Jegher syndrome (PJS) is an autosomal dominant disease characterized by gas­
trointestinal hamartomatous polyps with an arborizing smooth muscle in the lamina propria, 
mucocutaneous pigmentation, and increased risk of colon, pancreas, stomach, and breast 
cancers (184). The PIS gene, STK1 1 (LKB1) gene, is located on chromosome 19p (185-187). 
Germline mutations of STK1 1 can be identified in half of the PJS families. No somatic mu­
tation of STK1 1 has been identified in sporadic colorectal cancer ( 188,1 89). 
3.5. Hyperplastic Polyposis 
Hyperplastic polyposis is characterized by patients with numerous hyperplastic polyps 
(HPs) and increased risk of colorectal cancer (98,1 17-119). Patients with hyperplastic 
polyposis can be familial and are characterized by multiple large HPs or with serrated polyposis 
with multiple serrated adenomas (98, 116,119 ). The genetic basis of hyperplastic polyposis 
remains unclear. Somatic genetic alterations in HPs in patients with hyperplastic polypo­
sis have been discussed previously (see Section 2.2.). 
4. PROGNOSTIC IMPLICATION OF MOLECULAR MARKERS 
IN COLORECTAL CANCER 
Molecular alterations involving the pathogenesis of colorectal cancer, such as chromo­
somal allelic loss of 18q, 17p, 1 p and 8p; altered level of expression of DCC (deleted in 
colorectal cancer), p53 and p27Kipl and high level of microsatellite instability have been 
reported as prognostic markers in colorectal cancers ( 11 ,45, 79-84,190-195 ). Postoperative 
adjuvant chemotherapy can improve the outcome in stage III (Dukes'stage C) colon cancer 
( 196,197) . The benefit of postoperative chemotherapy for stage II (Duckes' stage liB) is 
uncertain and molecular markers such as chromosomal allelic loss in the conventional path­
way and microsatellite instability in the DNA mutator pathway may help in stratifying stage 
II colon-cancer patients with or without further treatment. 
4.1. 18q Chromosomal Allelic Loss as a Prognostic Marker 
Chromosomal allelic loss of 18q is frequently detected in up to 70% of colorectal cancers, 
and indicates a poor prognosis in colorectal cancers ( 10,1 1,45,190-195). In the initial study 
series of Jen et al., the 5-yr survival rate is 93% in patients with stage II colorectal cancer 
with no 18q loss and 54% in those with 18q loss, indicating the prognostic value of chromo­
some 18q loss in patients with stage II colorectal cancers ( 45 ). Several subsequent studies 
further confirm that 18q loss is a prognostic maker in colorectal cancers ( 11,45,190-195), 
except for the study by Carethers and colleagues (198). The loss of expression of DCC (a 
tumor suppressor gene on chromosome 18q21.1) , similar to loss of 18q can predict a worse 
survival in patients with stage TT or stage ITT colorectal cancers (46). The second tumor sup­
pressor gene on chromosome 18q21, DPC4, is altered in up to 33% of colorectal cancers, 
and loss of DPC4 expression can correlate with presence of metastatic disease at presenta­
tion ( 43,44 ). 
The prognostic value of 18q loss appears to be applicable to post-operative adjuvant che­
motherapy. In a large retrospective study analyzing 319 patients by W atababe and colleagues 
have shown that retention of chromosome 18q in microsatellite-stable cancers can predict a 
better outcome after post-operative adjuvant chemotherapy with fluorouracil-based regimens 
for stage III colon cancer ( 199).

Molecular Classification and Prognosis of CRC 441 
4.2. Microsatellite Instability Phenotype With Favorable Outcome 
Colorectal cancers with high levels of microsatellite instability (MSI-H) tend to have a 
better prognosis and metastasize less often than compared to microsatellite stable colorectal 
cancers (79-84,200,201 ). In a large series of population based studies of 607 patients by 
Gryfe and colleagues, 17% of the colorectal cancers were MSI-H and were associated with a 
significant survival advantage as compared to microsatellite stable colorectal cancers (84). 
A similar result was shown by Samowitz and colleagues in another population based study 
(200). In addition, patients with MSI-H colorectal cancers tend to have better prognosi s after 
postoperative adjuvant chemotherapy (202-204) . 
The reason MSI-H colorectal cancers have a better prognosis is unknown. Transforming 
growth factor j3 (TGFj3) is a potent inhibitor of epithelial cell growth. MSI-H colorectal 
cancers have a high rate (up to 90%) of mutations in the TGFf3 Rll gene (205 ). The presence 
of mutation of TGF/3 RII gene in colorectal cancers with MSI-H appears to predict a better 
outcome after postoperative adjuvant chemotherapy in stage III colorectal cancers ( 199) . 
MSI-H colorectal cancers tend to carry a higher number of activated cytotoxic intraepithelial 
lymphocyt es as compared to MSI-L or micro satellite stable colorectal cancers (206) , sug­
gesting a local cytotoxic immune response may be responsible for the better outcome for 
MSI-H cancers (207). In addition, tumor infiltrating lymphocytes against frameshift-muta­
tion-derived peptides resulting from the common frame shift mutation TGFf3 RII gene have 
been identified in peripheral blood from patients with MSI-H colorectal cancers (208-210). 
5. CONCLUSIONS 
The molecular genetics of familial colorectal cancers, includin g juvenile polyposis and 
Peutz-Jeghler's syndrome have been identified in the past decade. The molecular pathogen­
esis of sporadic colorectal cancers has three major pathways: the conventional pathway 
involving accumulation of alterations of tumor suppressor genes and oncogenes, DNA mis­
match repair pathway, and DNA methylator pathway. Through the advance of molecular 
analysis, the precursor lesions for colorectal cancer have expanded from classic adenomas 
and currently include hyperplastic polyps and aberrant crypt foci; the earliest morpholo gical 
precursor lesion. Althou gh, prognostic molecular makers are still limited for colorectal can­
cers, with the recent advances in gene expression profiling more prognostic molecular mark­
ers can be identified for both therapeutic and early detection purpose. 
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21 
Genetic Counseling for Hereditary Cancer 
Predisposition Testing 
Joyce L. Seldon and Patricia A. Ganz 
All cancer is "genetic" in that the uncontrolled proliferation of cells is the result of numer­
ous genetic mutations, however, we currently estimate that only 5-10 % of all cancer arises 
in individuals with an inherited susceptibility to cancer. The malignant transformation of a 
cell is not the result of one mutation, but rather a complex process resulting from numerous 
molecular mutations associated with gene-environment interactions. The rapid advancement 
of molecular biology has recognized that these molecular mutations fall into at least three 
distinct categories: oncogenes, tumor suppressor genes, and DNA mismatch repair genes. 
Lifetime cancer risks for individuals with an inherited predisposition can be high for certain 
hereditary syndromes. It is critical to identify high-risk individuals and families to provide 
targeted cancer screening and prevention counseling. Effective cancer screening and sur­
veillance may aid in the diagnosis of cancer at its earliest stages when prognosis and treat­
ment options are more favorable. Chemoprevention, prophylactic surgery, lifestyle 
modifications, and other therapies may reduce the risk of developing cancer for those with a 
hereditary predisposition. 
As new discoveries are made, the field of cancer genetics will grow to encompass new 
findings in gene-gene interaction s and gene -environment interactions . New discoveries will 
also aid in our understanding of cellular processes, such as genes that affect the metabolism 
of hormones and other environmental agents, or how an individual may respond to specific 
therapies. This chapter will review genetic counseling issues involved with hereditary can­
cer predisposition testing. Because cancer genetic counseling is frequently requested for 
families with the most common hereditary neoplasms of breast , ovary, and colon , we will 
discuss these associated syndromes in detail. 
2. FEATURES OF HEREDITARY CANCER SYNDROMES 
Over 200 hereditary syndromes with cancer as a component have been describ ed (Table 1) 
( 1 ). Most hereditary cancer syndromes follow an autosomal domin ant pattern of inheritance 
with incomplete penetrance and variable expressivity. Penetrance refers to the proportion of 
individuals with a mutant allele (heterozygot es) who will expr ess the associated trait or phe­
notype. A condition (most commonly inherited in an autosomal dominant manner) is said to 
have reduced or incomplete penetrance if clinical symptoms are not always present in indi-
From: Cancer Diagno stics: Current and Future Trends 
Edited by : R. M. Na kam ura, W. W. Gr ody, J. T. Wu, and R. B. Nagle © Hum ana Pre ss Inc., Totowa , NJ 
453

>!::. ~ Table 1 
Selected Inherited Cancer Syndromes 
Syndrome Hereditary breast and 
ovarian cancer syndrome 
Hereditary nonpolyposis colon cancer 
Ataxia telangectasia 
Li Fraumeni syndrome 
Cowden syndrome 
Peutz-Jeghers syndrome 
Basal cell nevus 
Syndrome (Gorlin syndrome) 
Familial adenomatous polyposis 
Multiple endocrine neoplasia, type 1 
Multiple endocrine neoplasia, type 2 Features and associated cancers 
Early onset breast cancer, ovarian cancer, and male breast cancer. 
Early onset colon cancer, uterine, ovarian, stomach, breast, and other 
GI/GU cancers. 
Neurologic degeneration, cerebellar ataxia, telangiectasia, immuno­
deficiency, sensitivity to ionizing radiation, leukemia, 
and lymphomas; breast cancer in heterozygotes. 
Sarcoma, breast cancer, brain, adrenocortical tumors, and leukemia 
Breast cancer, thyroid cancer, hamartomas, cerebellar gangliocytomas, 
macrocephaly, and mucocutaneous lesions 
Melanin spots of lips, buccal mucosa, and digits, GI hamartomatous 
polyps (especially in the jejunum), colon, breast, cervical, ovarian, 
testicular, and pancreatic cancer 
Multiple basal cell cancers, medulloblastoma, ovarian carcinomas, 
fibrosarcomas, jaw cysts, palmar/plantar pits, congenital skeletal 
anomalies, odontogenic keratocysts, or polyostocitc bone cyst. 
Colon cancer, bile duct, thyroid, small intestine. Also associated with 
Gardner and Turcot syndrome. 
Tumors of the parathyroid glands, pancreatic islets, and pituitary 
glands. Increased risk for parathyroid carcinomas, pancreatic islet 
cell tumors, and carcinoid tumors. 
Medullary thyroid carcinomas (MTC), pheochromocytomas, 
and benign parathyroid tumors. Inheritance Gene 
Autosomal dominant BRCAJ, BRCA2 
Autosomal dominant hMLHI, hMSH2, hPMSJ, 
hPMS2,MSH6 
Autosomal recessive ATM 
Autosomal dominant p53 
Autosomal dominant MMACJ, PTEN 
Autosomal dominant STK/1 
Autosomal dominant PTC 
Autosomal dominant APC 
Autosomal dominant MEN/ 
Autosomal dominant RET

Cancer Genetic Counseling 
Table 2 
Cardinal Features of Hereditary Cancer Syndromes 
1. Multiple affected family members (usually two or more) with the same type 
of cancer or cancers that are known to be related in certain syndromes 
(i.e., colon, ovarian, and uterine cancer are related types of cancers in 
HNPCC families) 
2. Multiple generations of related affected individuals (i.e., mother, daughter , 
and maternal aunt) 
3. Younger age of onset than is typical for type of cancer (i.e., <50 yr for 
breast and colon cancer) 
4. Presence of rare cancers (i.e., breast cancer in male s) 
5. Excess of multifocal or bilateral cancers (i.e., synchronous and 
metasynchronous colon cancer is found in HNPCC) 
6. Multiple primary cancers in the same individual (i.e., breast and ovarian 
cancer primaries in the same woman) 
7. Physical findings that may suggest a hereditary syndrome (i.e., gastrointe s­
tinal hamartomatou s polyps and excessive melanin deposits on the skin 
are possible characteristics of Peutz -Jeghers' syndrome) 455 
viduals who have the disease-causing mutation. In hereditary cancer syndromes, the pen­
etrance is usually not 100% because the phenotype is not always present in individuals who 
have the disease causing mutation(s). Variable expressivity refers to the extent that the phe­
notype is expressed. Variations in the clinical features of a hereditary cancer syndrome (e.g., 
type of cancer, pathologic features of a tumor, or age of onset) are observed between family 
members with the same deleterious mutation (intrafamilial variable expressivity) and 
between families with the same deleterious mutation (interfamilial variable expressivity). 
The interpretation of family history is important in determining whether to suspect a pos­
sible hereditary cancer syndrome. Features of a family history , such as early age at diagnosis 
and multiple affected individual s demonstrating autosomal dominant inheritan ce are some 
of the "red flags" for a possible hereditary syndrome (Table 2). These concepts are impor­
tant when providing cancer genetic counseling because an individual does not inherit can­
cer, but rather an increased risk for cancer or an inherited predisposition to cancer. 
3. GENETIC COUNSELING 
Genetic counseling is the process of communicating genetic , medical , and scientific 
knowl edge into underst andable and practical information for the patient so an educated and 
fully informed choice about testing c an be made . Health care providers should also be pre­
pared to discuss all possible consequences of testing and options for the medical and psycho­
logical management of the patient post-testing. The American Societ y of Clinical Oncology , 
the Nation al Soci ety of Genetic Counselors, the American Society of Human Genetics , and 
the National Action Plan on Breast Cancer have all issued position papers on cancer genet ic 
suscep tibility testing (2- 5 ). Cancer susceptibility testing should only be performed after 
comprehensive genetic counseling and informed consent. Genetic coun seling should be pro­
vided before, during, and after susceptibility testing.

456 Seldon and Ganz 
3.1. Family History 
Because hereditary cancer syndromes only occur in a small proportion of the population, 
the key to identifying a family at risk for a hereditary cancer syndrome is taking an adequate 
family history. The gathering of family history should be represented in a pedigree struc­
ture using standard nomenclature (6). At a minimum, the initial family history should include 
the current age or age at death, medical history, cause of death (if applicable), and cancer 
history of all first- and second-degree relatives of the patient, not just affected relatives. The 
pedigree should be extended, as appropriate, to more distant relatives. Important features to 
identify are the number of cancer cases in the family, type of primary cancer, multiple pri­
mary cancers, age of onset/diagnosis, degree of relationship, location/laterality of cancer, 
bilateral disease in paired organs, rare cancers, possible environmental exposures, and pos­
sible cancer risk reducing procedures or interventions (e.g., oophorectomy, hysterectomy). 
Ethnicity and the presence of consanguinity are also important to document in the pedigree. 
Family histories can often be inaccurately reported by patients (7), therefore, confirmation 
of cancer history by medical records, pathology reports, death certificates, and autopsy 
reports should be obtained whenever possible. It is important to note that a family history of 
cancer is dynamic and can change over time; therefore, it must be updated periodically. 
Unaffected relatives can develop cancer in the interim between visits to a healthcare pro­
vider and change the risk assessment of the pedigree. 
3.2. Risk Assessment 
The following aspects of the family history can identify average-risk, moderate-risk, and 
high-risk individuals: 
1. Number of affected relatives.Most inherited cancer syndromes will have multiple affected indi­
viduals (on the same side of the family) with the same type of cancer or cancers that are known 
to be related. The more family members with cancer, the more likely there is an inherited sus­
ceptibility. Small families might be difficult to assess. 
2. Ratio of affected to unaffected relatives. It is important not to neglect unaffected relatives. A 
65-yr-old patient with a history of breast cancer at 39 might seem significant until you learn that 
she has five older sisters with no cancer history. In assessing autosomal dominant patterns of 
inheritance , it is important to recognize the ratio of affected relatives to unaffected relatives. 
Again, small families will be difficult to assess. 
3. Closeness of biological relationship of affected relatives. Family history should include affected 
individuals who are at least first or second degree relatives. Keep in mind that most hereditary 
cancer syndromes are not fully penetrant, so unaffected obligate carriers are always a possibil­
ity. Additionally, some syndromes predominantly affect females (i.e., BRCA 1/2), so males are 
sometimes unaffected obligate carriers. 
4. Ages at cancer diagnoses. Most hereditary cancer syndromes typically have earlier ages of onset 
for specific tumors than their sporadic counterparts. 
5. Presence of bilateral/multifocal or multiple primary cancers. Affected individuals with an inher­
ited susceptibility frequently present with bilateral or multifocal cancers. These same individu­
als are also at risk for second primary cancers associated with the hereditary syndrome. 
6. Case(s) of rare cancer. The familial clustering of cancers that rarely occur in the general popula­
tion are difficult to explain by chance alone. Rare cancers such as male breast cancer and child­
hood adrenal gland tumors are "flags" for certain hereditary cancer syndromes and a careful 
family history should be obtained and assessed.

Cancer Genetic Counseling 457 
3.3. Informed Consent: Risks, Benefits, and Limitations of Testing 
The complexities and special nature of hereditary cancer susceptibility testing requires 
adequate informed consent and genetic counseling. In the process of offering cancer predis­
position testing to a patient or family, both the healthcare provid er and the individual being 
tested must be prepared to not only deal with the medical aspects oftesting, but also with the 
psychological , legal, and social consequences of testing. Proper informed consent should 
include discussion of basic principles of cancer biology; basic genetic concepts such as 
inheritance, genes, mutations, patterns of inheritance, variable expre ssion of genes, hetero­
geneity, polymorphisms, and penetrance of genes. Additionall y, implications of a positive, 
negative, or ambiguous result and informative testing; limitations; possible benefit s of test­
ing; genetic risk to relatives and transmission of mutation to offspring should be discussed. 
Accuracy of testing, costs, risk of psychological distress and strain on family relationships, 
risk of employment/insurance discrimination and stigmatization, confidentiality and sharing 
of results should be discussed along with the limitations of medical surveillance, screening, 
prophylactic surgery, chemoprevention, and alternatives to testing . 
3.4. Interpretation of Results 
Whenever possible, informative genetic cancer susceptibility testing should begin with an 
affected relative at high risk to carry a hereditary mutation (Fig. 1). A positive test result 
means that the patient has an increased likelihood of developing cancer associated with del­
eterious mutations in a particular gene. It allows for informative testing of other affected and 
unaffected relatives who may be at risk for carrying the familial mutation based on the inher­
itance of the syndrome. 
Negative test results can be difficult to interpret and to convey to patients. A negative test 
result in an affected individual from a high risk family has the following interpretations: 
false negative (individual is really positive for a mutation in tested gene, but the mutation 
was either not tested for or undetectable using particular lab method) ; a different (untested) 
gene(s) is responsible; the familial clustering is actually sporadic and the result of a chance 
event; or this is a family with a hereditary cancer syndrome, but the patient initiall y tested is 
a sporadic case (phenocopy). Therefore, testing of an unaffected individual is most informa­
tive in the context of a known mutation; however , this is not always possible. A negative test 
result in an unaffected individual is only a "true negative" if a mutation is known in the 
family. A negative test result in an unaffected individual from a family with no known 
hereditary mutation is considered "uninformative." What this means is that a negative result 
does not allow the health care professional to reassure the patient that his/her chances of 
developing cancer are the same as the general population because a mutation has not been 
previously identified . The patient may still have an inherit ed susceptibility because of an 
alteration in the gene tested or because of an alteration in a different gene that was not tested. 
Of course, it is also possible that the patient does not have an inherited susceptibility at all. 
The patient has learned little about his/her cancer after the test is performed and a negative 
result does not mean that the patient should stop close cancer screening procedures or give 
up actions and behaviors that reduce cancer risk. 
Ambiguous test results are a challenge associated with cancer predisposition testing. The 
most common example is a DNA sequence variant of undetermined clinical significance

458 Seldon and Ganz 
Ashkenazi Jewish Ancestry 
111:1 
30 yr 11:1 
53 yr 1:1 
Breast cancer dx at 39 yr 
40% chance for 
BRCA1/BRCA2 
111:2 111:3 
24 yr 27 yr 
20% chance for 
BRCA1/BRCA2 11:2 
55 yr 1:2 
Died at 4 7 yr with metastases 
Breast cancer dx at 45 yr 
111:4 
25 yr 11:3 
57 yr 
TAH-BSO at 30 years 
due to endometriosis 
Fig. 1. Cancer genetic susceptibility flow diagram 
(VUS). For some VUS, there will be published scientific reports of an increased risk for 
cancer associated with this particular alteration, although for others there are no published 
scientific reports. Therefore, it is difficult to interpret whether there is an increased risk for 
cancer. In the future, as more is discovered about these genes, new information may clarify 
the risk for cancer associated with these particular alterations . Follow-up studies such as 
linkage analysis or testing the parents of a patient or other affected relatives may provide 
some useful data in interpreting the VUS (8). Individualized management options should be 
discussed with the patient as well as encouragement to continue high-risk cancer screening 
procedures and actions and behaviors to reduce cancer risk. 
4. BREAST AND OVARIAN CANCER: BRCAl AND BRCA2 
4.1. Background 
An estimated 5-10 % of breast and ovarian cancers have an inherited component (9-12). 
Familial breast and ovarian cancer is characterized by breast cancer diagnosis at less than 
50 yr of age, bilateral breast and ovarian tumors, multiple affected related individuals within 
a family, multiple affected generations, and a strong association with male breast cancer. 
In 1994 and 1995, the BRCA1 and BRCA2 genes, respectively, were isolated by positional 
cloning methods (13-15). BRCA1 and BRCA2 have autosomal dominant inheritance with

Cancer Genetic Counseling 459 
incomplete penetrance and variable expressivity. The BRCA1 and BRCA2 genes account 
for an estimated 84% of hereditary breast and ovarian cancers ( 16, 17). Over 400 different 
deleterious BRCA1 and BRCA2 mutations have been identified (18). However , the exist­
ence of other breast and ovarian cancer susceptibility genes (BRCA3, BRCA4) is suspected 
by the identification of a high incidence of breast/ovarian cancer within families that do 
not show linkage to either BRCA1 or BRCA2 (17,19-25). Additionally , other low­
penetrance genes are being studied and may have clinical significance (26,27). 
4.2. Ashkenazi Jewish Population 
After the finding of a BRCAl (185delAG frameshift) mutation in several Ashkenazi Jew­
ish breast/ovarian families, a study was conducted in 858 Ashkenazim (unselected for can­
cer history) and 815 control subjects (unselected for ethnic origin) . The investigators found 
that almost 1% of the Ashkenazi Jewish population carried this mutation as compared to 
none of the controls, suggesting that in 100 women of Ashkenazi descent may be at an 
increased risk of developing breast/ovarian cancer (28). Further studies confirmed a recur­
rent BRCA2 mutation (6174delT) at an increased carrier frequency among the Ashkenazi 
Jewish population (29,30) . Subsequent large-scale population studies found that over 2% of 
Ashkenazi Jews carry BRCAI or BRCA2 mutations (185delAG, 5382insC, and 6174delT) 
that confer increased risks for breast, ovarian, and prostate cancer (31,32). Many studies 
have confirmed the higher prevalence of these founder mutation s among early onset breast 
and ovarian cancer patients (33-39). Therefore , Ashkenazi Jewish ancestry is a risk factor 
when evaluating a family history of breast and ovarian cancer. 
4.3. Risk of Cancer in Mutation Carriers 
There is little doubt that women who carry a mutation for either BRCAl or BRCA2 are at 
significantly increased risk of developing breast and ovarian cancer. However, estimates 
regarding the degree of risk for these women are still being refined. It is import ant for the 
healthcare provider and the patient to remember that hereditary cancer susceptibilit y testing 
cannot determine, with absolute certainty, whether or not an individual will develop cancer. 
It cannot predict what kind of cancer a patient may or may not develop or when a patient 
might develop cancer. Cancer risk may vary depending on the specific mutation identified 
and other modifying factors. According to several different studies, the lifetime risk of breast 
cancer for a BRCA 1 or BRCA2 carrier ranges from approx 56 to 87% ( 16,17,32,40-42 ). The 
risk for ovarian cancer ranges from approx 16-63% for BRCAI carriers and as high as 27% 
for BRCA2 carriers ( 16,17,32,40 -42). 
Additionally, there are other associated risks for mutation carriers . BRCAl/2 carriers with 
diagnosis of a first primary breast cancer are at an approx 40-65% lifetime risk for a second 
primary contralateral or ipsilateral breast cancer (41,43,44). Male breast cancer has also 
been associated with BRCA 1/2 mutations ( 17, 18,45,46). Studies have reported that BRCA 1/ 
2 mutation carriers are at statistically increased risks for the following cancers: pancreatic, 
uterine body , cervix, prostate, colon, liver, stomach, fallopian tube, melanoma, gallbladder, 
and bile duct (43,44,47) . 
4.4. Probability of Detecting a BRCAl/2 Mutation 
Several models exist for predicting the likelihood of detecting BRCA 112 mutations given 
a certain family history and ethnic background (48-52). These models may be useful in 
identifying families who are likel y to carry a predisposing mutation in BRCAl or BRCA2.

460 
Table 3 
Modeled Probabilities of BRCAl/2 Mutation in Women 
With Early Onset Breast Cancer (<50 yr) 
First- or Second-
First- or Second- degree Patient Patient 
degree relative relative with with ovarian with breast 
with breast ovarian cancer or bilateral cancer 
cancer <50 (any age) breast cancer <40 
• 
• 
• Seldon and Ganz 
ofBRCAl/2 
orBRCA2 
mutation 
25% 
40% 
51% 
76% 
35% 
35% 
71% 
71% 
35% 
59% 
71% 
89% 
Note: Based on analysis of women with at least I first- or second-degree relative with ova­
rian cancer or breast cancer before 50 yr of age. Adapted from ref. 48. 
Table 3 presents the modeled probability of carrying a BRCAl or BRCA2 mutation in 
women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or 
second-degree relative with either diagnosis (48). 
Figure 2 illustrates an example of a clinical risk assessment for a patient. This example 
illustrates a three-generati on pedigree with two affected women with breast cancer. Indi­
vidual III: 1 is a 30-yr-old female who presented for genetic counseling because she was 
concerned about her risk for breast/ovarian cancer and was considering prophylactic surger­
ies. We calculate her risk of being positive for a BRCA1/BRCA2 mutation by first calculat­
ing her mother's risk (because the data apply to affected women, not unaffected women). We 
find that her mother, individual II: 1, is alive at 53 yr of age with a previous diagnosis of breast 
cancer at 39 yr of age. Our patient's maternal grandmother died at 4 7 yr of age from breast 
cancer diagnosed at 45 years of age. The famil y is of Ashkenazi Jewish ancestry. Looking at 
Table 3 we see that individual II: 1 fits two risk factors ("first- or seco nd-degree relative with 
breast cancer <50" and "Patient with breast cancer <40") from this modeled probability, 
which gives her a 40% chance of carrying a gene for BRCA1 or BRCA2. Therefor e, given 
Mendelian autosomal dominant inheritance for BRCA l/BRCA2, individual III: l has an 
approx 20% risk of carrying a gene for BRCAl/BRCA2 (one-half of her mother's risk of 
40% ). Risk calculations, however, are not the only factors to discuss with this patient. The 
patient seeking genetic counseling should also have a complete discussion of the risks, ben­
efits, and limitations of cancer genetic susceptibility t esting as well as inform ed consent and 
a discussion of who in her family should have testing first (informative testing).

111:1 
30 yr 11:1 
53 yr 
24 yr 27 yr 
55 yr Died at 47 yr with metastases 
111:4 
25 yr 11:3 
57 yr 
due to endometriosis 461 
Fig. 2. A three-generation pedigree with breast cancer. Individual III: 1 is the initial patient seek­
ing genetic testing because she is concerned about her risk for breast and ovarian cancer and is con­
sidering prophylactic surgery. Note that testing should be done on an affected individual first, if 
possible, to establish informative testing for unaffected family members. The ideal individual to test 
first in this pedigree would be II: 1 because she is still alive and a first degree relative to the initial 
patient. Also note that the modeled probability of detecting a BRCAI or BRCA2 mutation (using 
Table 3) in individual II: 1 is 40%. Therefore, the a priori chance of detecting a BRCA l or BRCA2 
mutation in her daughter is 20% (112 of her mother's risk given autosomal dominant inheritance). If 
individual II: 1 tests positive for a mutation in either BRCA1 or BRCA2, then the chance that either 
III: I or her sister, III:2, are positive for the same mutation is 50% each. Additionally, a positive test 
result in II: 1 would mean that the chances for II:2, II:3, III:3, and III:4 to test positive for the same 
mutation would be 50%, 50%, 25%, and 25%, respectively. 
4.5. Medical Management Options 
The medical management of a woman with BRCAI/2 mutation is challenging and often 
requires a multi-disciplinary approach. The need for shared decision-making between health 
care providers and the patient is critical. Patients should weigh the risks, benefits, and limi­
tations of all management options carefully. In 1997, a task force reported on the recom­
mendations for follow-up care in BRCAI/2 carriers (53). Breast cancer surveillance options 
include: monthly self-breast examinations (starting at 18 yr of age), annual or semiannual

462 Seldon and Ganz 
clinical breast exams starting at age 25, and annual mammography beginning at age 25-
35 yr (or 10 yr younger than the youngest diagnosis in the family). Ovarian cancer screening 
options include: annual or semiannual transvaginal ultrasound with color Doppler and 
CA-125 blood levels (53). 
Prophylactic mastectomy and oophorectomy are options that should be addressed with 
BRCA 1/2 mutation carriers. Prophylactic mastectomy has been associated with a 90% or 
greater reduction in the incidence of breast cancer among women with a family history of 
breast cancer and women who carry BRCAl/2 mutations (54,55). Data regarding prophylac­
tic oophorectomy has been shown to reduce the risk for ovarian cancer by as much as 95% 
and the risk of breast cancer by as much as 50% in BRCAl/2 carriers (56-58). It should be 
emphasized to patients considering a surgical option that although prophylactic mastectomy 
and oophorectomy may reduce the risk of breast and ovarian cancer, the risk is never zero. 
Chemoprevention using tamoxifen or oral contraceptives is another option for patients to 
consider. In a matched case-control study, BRCAl/2 mutation carriers who used tamoxifen 
for 2 to 4 yr reduced their risk of developing a contralateral breast cancer by 75% (59). The 
Breast Cancer Prevention Trial (BCPT) reported a 49% reduction in risk for invasive breast 
cancer and a 50% reduction in risk for noninvasive breast cancer in women at increased risk 
for breast cancer who took tamoxifen, a nonsteroidal anti-estrogen (60). BRCAl/2 analysis 
from the BCPT trial has reported a 62% reduction in breast cancer incidence resulting from 
tamoxifen among women with BRCA2 mutations, which is consistent with the reduction in 
incidence as a result of tamoxifen of ER positive tumors. In contrast , the data suggested that 
there is no risk reduction in breast cancer incidence in BRCAl carriers, which is consistent 
with the lack of effect of tamoxifen on ER negative tumors (61 ). 
The salutary effects of oral contraceptives in reducing ovarian cancer risk in the general 
population appear to extend to BRCA 112 mutation carriers. A multicenter case-control study 
reported that the use of oral contraceptives was associated with a significant reduction in the 
risk of ovarian cancer among female carriers ofBRCAl/2 mutations. The risk reduction was 
approx 20% for up to 3 yr of use and 60% for more than 6 yr of use (62). In contrast, a 
population-based case-control in Israel did not find clear evidence of a protective effect of 
oral-contraceptive use among women who had a founder mutation in BRCAl/2 (63). 
5. HEREDITARY NONPOL YPOSIS COLORECT AL CANCER (HNPCC) 
5.1. Background 
Colorectal cancer is the third most common cancer in men and women. It is estimated that 
it will affect approx 135,400 individuals per year in the United States and is responsible for 
10% of cancer mortality (64). An estimated 5% of colon cancer can be attributed to highly 
penetrant autosomal dominant susceptibility syndromes (65,66). The most common syn­
drome is hereditary nonpolypo sis colon cancer syndrome (HNPCC), which is also known as 
Lynch syndrome. The rare familial adenomatous polyposis (FAP) syndrome also constitutes 
a small percent of inherited colon cancers. Studies of these syndromes have provided unique 
insights into both inherited and sporadic forms of human tumors. The HNPCC syndrome is 
characterized by early onset colon cancer (average onset is approx 44 yr of age) with a 
proximal predominance (approx 70% are proximal to the splenic flecture), multiple syn­
chronous and metachronous colorectal cancers, and other associated cancers such as breast, 
ovarian carcinoma, stomach, small bowel, urinary tract (ureter and renal pelvis carcinoma),

Table 4 
Clinical Criteria for HNPCC and MSI 
Amsterdam criteria for HNPCC (70) 
1. Three or more family members with colorectal cancer. One family member 
should be a first degree relative of the other two family members. 
2. Families with familial adenomatous polyposis excluded. 
3. At least two successive generations represented. 
4. At least one individual younger than 50 yr at diagnosis. 
Bethesda Criteria for MSI Testing ( 81) 
1. Individuals with cancer in families that meet the Amsterdam criteria. 
2. Individuals with two HNPCC-related cancers, including synchronous and 
metachronous colorectal cancers or extracolonic cancers. 
3. Individuals with colorectal cancer and a first-degree relative with colorectal 
cancer and/or HNPCC-related extracolonic cancer and/or a colorectal 
adenoma; one of the cancers diagnosed at less than 45 yr, and the 
adenoma diagnosed at less than 40 yr. 
4. Individuals with: 
a. colorectal or endometrial cancer diagnosed <45 
b. right-sided colorectal cancer with an undifferentiated pattern (solid/ 
cribriform) on histopa thology or signet-ring-cell-type diagnosed <45 yr 
c. adenomas diagnosed <40 yr 463 
endometrial , and pancreatic carcinoma (67-69). In 1991, the International Collaborative 
Group on HNPCC met in Amsterdam and put forth a list of clinical criteria (Table 4) for the 
diagnosis of HNPCC (70). Limitations of the Amsterdam criteria are that they are too 
restrictive in that certain featur es of HNPCC such as proximal colon cancer, multiple syn­
chronous and metachronous colon cancers, and other malignancies besides colon cancer are 
not considered. Additionally, small pedigr ees are not likely to meet the criteria. 
HNPCC shows genetic heterogeneity and the syndrome is associated with mutations in 
the MSH2 gene on chromosome 2p22-21 (71,72) , the MLHJ gene on chromosome 3p21 
(73,74), the hpmsl gene on chromosome 2q31-33 (75), and the PMS 2 gene on chromosome 
7p22 (75), and MSH6 on chromosome 2p16 (76). Thus far, all genes linked with HNPCC 
have been DNA mismatch repair (MMR) genes. The majority of germline mutations have 
been foun d in the MSH2 and MLHJ genes (77,78) . For many HNPCC families, a locus has 
yet to be discovered. The heterozygous phenotype is apparently norm al. However, when the 
normal MMR allele is inactivated by a somatic mutation, the tissue develops a hypermutable 
phenotype (see Subheading 5.2.), which then accelerates the carcinogenic multi-step process . 
5.2. Microsatellite Instability (MSI) 
Microsatellites are repetitive DNA sequences that naturally occur and are highly variable 
from one individual to another. Microsatellite instability (MSI) refers to the hypermutable 
phenotype of an expanded or contracted pattern of microsatellites found in tumor tissues. 
MSI is infrequently found in sporad ic colon cancers (10-15%) (79), but is common in 
HNPCC kindreds (92%) (77) and in young patients less that 35 yr of age (58%) ( 80 ). Testing

464 Seldon and Ganz 
for MSI can be used to identify families at high risk for HNPCC. In 1997, the Bethesda 
criteria (Table 4) were established for testing colorectal tumors for MSI (81). MSI testing 
can serve as a surrogate functional marker for defective MMR function, however, it is not a 
direct indicator of HNPCC (because MSI does occur in sporadic tumor tissue), nor is it 
indicative of specific mutations in a particular mismatch repair gene. 
5.3. Risks of Cancer in Mutation Carriers 
The lifetime risks of cancer in HNPCC mutation carriers are approximated as follows: 
colorectal (78%), endometrial (43%), stomach (19%), biliary tract (18%), urinary tract 
(10%), and ovarian (9%) (82). There is an increased risk for cancer at several other 
extracolonic sites such as small bowel, pancreas, and renal pelvis, and possibly breast 
(68,83). These risks are based on gene positive HNPCC families and may be subject to 
ascertainment bias. Estimates regarding the degree of risk for these HNPCC families are still 
being refined. 
Figure 3 illustrates a three-generation pedigree affected with HNPCC related cancers and 
some of the complexity involved in hereditary cancer testing. Individual III: 1 is the initial 
patient seeking genetic counseling because of his concern about his family history of colon 
cancer. His father died when the patient was a young boy and the patient is concerned because 
he is getting close to the age his father was when diagnosed with colon cancer. The family 
does not meet the Amsterdam Criteria, but it does meet the Bethesda criteria. In doing the 
risk assessment, the healthcare provider should note the following: there are few family 
members in the first and third generation; the individuals in the third generation are some­
what young; the history does include HNPCC related cancers in multiple affected individu­
als in multiple generations; and the affected aunt (11:3) has had uterine cancer and her 
treatment included an oophorectomy (reduced the risk for an ovarian cancer primary) and 
she has not had any colon cancer screening. One could test the patient (Ill: 1) directly for a 
germline mutation. This is likely to be uninformative. One could test the patient's deceased 
father's (II: I) tumor tissue for MSI, but insurance is not likely to cover the cost of testing in 
a family member and it is not certain whether or not tumor tissue will be available and 
reliable. One could recommend testing commence with the patient's aunt (II:3) with either 
MSI testing on the uterine tumor or direct DNA analysis for the possible germline mutation. 
For this patient, this involves contacting a family member he barely knows and he is not sure 
how she will react to hearing the information and request for testing. Additionally, the test­
ing has a potential impact on many family members including the patient's siblings, uncle, 
aunt, and numerous cousins (including a sister and female cousins possible at risk for HNPCC 
related cancers such as uterine and ovarian cancer). Regardless of the testing that may or 
may not be done, the patient and his siblings are at increased risk for colorectal cancer and 
should be adhering to high-risk screening recommendations. 
5.4. Medical Management Options 
For HNPCC carriers , an expert task force recommends colonoscopy every 1-3 yr begin­
ning at age 20-25 yr (84 ). It should be noted that colonoscopy as opposed to flexible sigmoi­
doscopy is recommended owing to the characteristic right-sided colon cancers in HNPCC 
that the sigmoidoscopy would not detect. For women specifically, the task force recom­
mended annual endometrial cancer screening with transvaginal ultrasound and/or endome-

Irish/English Ancestry 
/' 111:1 
35 yr 1:1 
Died CRC 60's 
Age of dx unknown, but 
thought to be "young". 
11:1 
Died 43 due to 
metastatic disease 
CRC dx at41 
0 
33 yr 31 yr 111:4 
22 yr 
TAH-BSO=Transabdominal Hysterectomy & 
Bilateral Salpingo Oophorectomy 
CRC=Colorectal Cancer 1 :2 
Died 75 stroke 
11:2 
50 yr 
111:5 111:6 
18 yr 37 yr 11:3 
57 yr 
Uterine Ca dx at 45, T AH-BSO , 
no CRC screc nin2: 
111:7 111:8 
34 yr 29 yr 465 
Fig. 3. A three-generation pedigr ee with colon and uterine cancer. Individual III: 1 is the initial 
patient seeking genetic counseling because of his concern about his family history of colon cancer. 
The family does not meet the Amsterdam Criteria, but it does meet the Bethesda criteria. Note that 
the family history is small; the individuals in the third generation are somewhat young; the history 
does include HNPCC related cancers in multiple affected individuals in multiple generations; and 
that the affected aunt (II:3) has had uterine cancer and that her treatment included an oophorectomy 
(redu ced the risk for an ovarian cancer primary) and that she has not had any colon cancer screening . 
There are differ ent ways to approach testing this family for HNPCC , which illustr ates some of the 
complex ity of hereditary susceptibility testing. One could test the patient (Ill: 1) directly for a germline 
mutation. One could test the patient 's deceased father 's (II: I) tumor tissue for MSI. One could rec­
ommend testing commence with the patient's aunt (II:3) with either MSI testing on the uterine tumor 
or DNA analysis for the possible germline mutation. 
trial biopsy beginning at 25-35 yr of age. Additionally, even though there is no recommen­
dation at this time for or against these surgeries for HNPCC mutation carriers, prophylactic 
subtotal colectomy , hysterectomy , and oophorectomy should be discus sed as options for the 
patient ( 84 ).

466 
6. FAMILIAL ADENOMATOUS POLYPOSIS (FAP) 
6.1. Background Seldon and Ganz 
Familial adenomatous polyposis (PAP), also known as Gardner syndrome, is a rare colon 
cancer syndrome that accounts for less than 1% of colon cancer cases. F AP is an autosomal 
dominant condition with clinical heterogeneity expected to demonstrate complete pen­
etrance. Classically, it is characterized by the progressive development of greater than 100 
adenomatous colorectal polyps, some of which will inevitably progress to cancer. Most of 
these polyps are usually less than five millimeters in diameter and so thickly grown that they 
carpet the entire surface of the colon. The clinical diagnosis ofF AP is based on the finding 
of 100 or more colorectal adenomas (85). Up to one-third ofFAP cases result from de novo 
germline mutations in the APC gene. Other features of PAP and its variants include jaw and 
sebaceous cysts, osteomata, a retinal lesion known as congenital hypertrophy of the retinal 
pigment (CHRPE), desmoid tumors, and cancers of the ampulla of Vater, bile duct, thyroid, 
and small intestine ( 1 ). There is also an attenuated form of FAP that is characterized by a 
fewer number of colorectal adenomas and a later age of onset of colorectal cancer (86). 
The gene responsible for FAP, known as the adenomatous polyposis coli gene (APC on 
chromosome 5q, has been identified and characterized (87-90). A study of 79 unrelated 
patients with PAP searched for germline mutations in the APC gene. A total of 67% carried 
germline mutations and of the mutations found, 92% resulted in the truncation of the APC 
protein (91 ). All affected individuals should be tested for mutations in the APC gene and 
appropriate relatives should consider testing given the high risk of colon cancer and the early 
age of onset. 
6.2. Medical Management Options 
For F AP carriers, annual flexible sigmoidoscopy beginning at age 10-11 is recommended. 
Once polyps are detected by endoscopy, counseling regarding prophylactic colectomy should 
commence. Surveillance for extracolonic neoplasms, specifically gastrointestinal tract 
adenomatous polyps is also recommended. For APC negative individuals, flexible sig­
moidoscopy at age 18, 25, and 35 is recommended. If no polyps are detected, then conven­
tional colon cancer screening with colonoscopy every 3-5 yr starting at age 50 is 
recommended (92). 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been experimentally shown to pro­
mote apoptosis and to inhibit angiogenesis, two mechanisms that facilitate the suppression 
of malignant tumor growth (93 ). A number of epidemiologic (nonrandomized) studies have 
found that long-term users of aspirin or other NSAIDs have a lower risk of colorectal 
adenomatous polyps and colorectal cancer than nonusers (93 ). More specifically, random­
ized clinical trials have established that two nonsteroidal anti-inflammatory drugs, su1indac 
(94-96) and celecoxib (a selective cyclooxygenase-2 inhibitor) (97,98), suppress 
adenomatous polyps and cause regression of existing polyps in patients with PAP. With 
regard to FDA approval, celecoxib was evaluated in a randomized, double-blind, placebo­
controlled trial in 83 PAP patients (97). Analysis showed a significant reduction in a surro­
gate endpoint-colorectal polyp counts-observed after 6 mo of therapy with celecoxib. 
The tolerability of celecoxib treatment in F AP patients was consistent with labeled adverse 
events for the drug. In December 1999, celecoxib (Celebrex) was granted accelerated FDA 
approval for the reduction in the number of colorectal polyps in PAP patients, as an adjunct to 
usual care (e.g., endoscopic surveillance or surgery).

Cancer Genetic Counseling 467 
7.SUMMARY 
It is critical that healthcare providers appreciate the complexities and special nature of 
genetic testing in order to accurately and responsibly interpret results for patients and their 
families . Further research is essential to fully understand the function of these genes and to 
develop effective prevention strategies and therapies. Although preventive surgical 
treatments may be effective in reducing the risk of some organ confined cancers, these inter­
ventions are extreme and may have both physical and psychological sequelae. As individuals 
with hereditary predisposition genes are detected earlier in the cancer process , it is important 
to include them in chemoprevention trials that may prevent the progression/development of 
disease . This becomes extremely important given the variable penetrance of these mutations. 
The Division of Cancer Prevention at the NCI currently supports a number of studies in 
high-risk and genetically susceptible populations , and when possible, health care providers 
should refer suitable participants to these studies. The NCI also maintains a website for 
information about hereditary cancer predisposition testing and a directory of healthcare pro­
fessionals who provide cancer genetic counseling. 
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inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342(26) : 1946-1952.

1. INTRODUCTION 22 
Diagnosis of Ataxia- Telangiectasia 
ATM Mutations Associated With Cancer 
Midori Mitsui, Shareef A. Nahas, Helen H. Chun, 
and Richard A. Gatti 
Prior to cancer therapy, it should be determined whether an underlying hereditary disor­
der might exist. A diagnosis of Ataxia-telangiectasia (A-T) shou ld be considered in every 
child that develops a malignancy before 5 yr of age becau se A-T patients are unusually 
sensitive to radiation and conventional doses of radiotherapy can lead to deva statin g clinical 
consequences . 
1.2. Early Diagnosis of A-T 
Once A-T is suspected, confi rming the diagnosis clinically can be difficult in young chil­
dren because most of the signs and symptoms do not manifest fully until much later: (1) 
the onset of ataxia can be subtle in a child just learning to walk, (2) dysarthria is difficult to 
assess until speec h patterns are well established, (3) detecting ocular apraxia requires the 
cooperation of the patient, (4) telangiectasias usually do not appear until severa l years after 
the onset of ataxia, (5) cerebellar atrophy may not be obvious on magnetic resonance imag­
ing (MRI) studies until 7 or 8 yr of age, and (6) hereditary patterns may not yet be appreci ­
ated in a young family. Additionally , although the serum a-fetoprotein (AFP) is elevated in 
most A-T patient s, 5-10% of A-T patients have normal level s. AFP can also remain above 
the normal labor atory range in normal infant s until about 18 mo of age, further limitin g the 
diagnostic value of this test. Karyotyping, with spec ial attention to translocations involving 
chromosomes 7 and 14, can be useful; however, harvesting metaphases from A-T cells is 
techni cally difficult because these lymphoc ytes do not respond well to most mitogens. Nev­
erthel ess, an astute parent will often notice even mild neuro logical symptoms, if present, 
and, when asked, will volunteer enough information to allow the oncologist to either rule out 
A-T or prompt a neurological consultation. 
Despite the need for a rapid solution to this problem, a laboratory confirmation of A-T 
currently take 2-3 mo because both immunoblotting and radiosen sitivity testing depend upon 
first establishing a lymphobl astoid cell line (LCL) (Table 1). Faster methods are under 
developm ent. 
From: Cancer Diagnostics: Current and Future Trends 
Edited b y: R. M. Naka mur a, W . W. Grady, J. T. Wu, and R. B. Nagle © Human a Press Inc., Totow a, NJ 
473

474 
Table 1 
Laboratory Confirmation of Clinical A-T 
Laboratory procedure 
I. a-fetoproteina (after 2 yr of age) 
2. Immunological statusa (immunoglobulins; T and B cells) 
3. Karyotypinga (technically difficult with A-T cells) 
4. Radiosensitivity testing 
Radioresistant DNA synthesis (RDS) 
Colony Survival Assayu (CSA) 
Chromatid breaks 
5. Western blots (for ATM protein in nuclear lysates of LCLs)a 
6. Deficient phosphorylation of ATM substrates 
7. Mutation detection 
If known from a prior affected*a 
If unknown-Haplotyping (compare to database of affected haplotypes)a.b 
Protein truncation test (uses mRNA) 
SSCP , CSGE, DOV AM, or REF 
Automated sequencing (including interpretation of data) 
dHPLC (heteroduplex detection; misses homozygotes) 
8. Haplotyping , to establish linkage to llq23.1 (requires a prior affected)a 
a Available in clinical laboratories. 
bDepends upon genetic homogeneity/inbreeding of ethnic population. 
1.3. A-T Syndrome Mitsui et al. 
False 
negative (%) 
5 
approx 30 
approx 10 
<J? 
approx 10 
approx 15 
<I 
approx I 
<I 
approx 20 
approx 20 
approx 15 
approx 10 
25 
A-T is primarily an early onset, and relentlessly progressive cerebellar ataxia transmitted 
as an autosomal recessive disorder ( 1-5 ). It occurs in approx 1 per 40,000 live births in the 
United States . This frequency varies considerably from country to country depending upon the 
frequency of cousin-to-cousin matings. 
Infants appear normal and walk at a normal age (1 yr), begin to stagger by age 3, and 
generally require a wheelchair by age 10. Oculocutaneous telangiectasias appear several 
years after onset of neurological symptoms. Ocular apraxia and dysarthria become apparent 
early and are hallmarks of the disease. Frequent sinopulmonary infections are common. Can­
cer, usually lymphoid, occurs in one-third of A-T patients. 
There is presently no treatment for A-T, although some of the secondary symptoms, such 
as drooling, are amenable to supportive therapy. Patients that do not die of early incurable 
cancers or overwhelming infections, sometimes survive into their 40s and even 50s. 
When infections are seen , they are usually sinopulmonary and are usually the result of, 
not opportunistic infections, but conventional ones-unlike that of other immunodeficiency 
disorders. Almost half of A-T patients die with pulmonary failure and an associated pneu­
monia. In this regard, A TM protein is quite prominent in the bronchial epithelial cells of 
normal tissue; perhaps the absence of this protein in the lungs of A-T patients plays an 
important role in the development of the chronic cough and poor oxygenation that precede 
the irreversible pulmonary failure of many A-T patients. Poor swallowing coordination and 
excessive drooling in some patients can also lead to frequent aspiration pneumonia. This 
late-stage syndrome is initially responsive to steroids although eventually even these become 
ineffective. The T-cell system is abnormal, usually in subtle ways. T-cell responses to viral 
antigens and to histocompatibility antigens are often impaired to various degrees (6, 7).

Diagnosis of Ataxia- Telangiectasia 475 
T-cell responses to various mitogens are often subnormal, although this is not a consistent 
finding and should not influence the diagnosis of new patients (8,9). CD45-RA+ (na'ive) 
memory cells are below normal levels in the peripheral blood of most A-T patients (1 0 ). 
High natural killer (NK) cell levels have been observed in many A-T patients, although 
some studies report normal levels (7). Patients are often allergic when skin tested. Because 
these findings are not common to all A-T patients, they are assumed secondary effects, per­
haps of inappropriate cell signaling. 
The most consistent immune defects of A-T patients are those of IgA, IgE, IgG2, or IgG4 
deficiencies (3, 7). In general, approximately one-third of A-T patients do not manifest any 
obvious immunodeficiency, nor do they have increased infection s. Antigenic challenge of 
patients with polyvalent pneumococcal polysaccharide vaccine reveals a generally poor IgG 
response ( 11 ). A consistent finding is the inappropriate rejoining of V(D)J regions in A-T 
cells ( 12,13 ). The thymus is dystrophic, with poor corticomedullary differentiation , and no 
Hassall's corpuscles (14,15). This probably reflects a perturbation in the maturation of 
T cells, as they try to rearrange the T -cell receptor (TCR) genes-a form of nonhomologous 
recombination . A similar situation probably arises during the differentiation of B cells. 
Interestingly, the severe humoral deficienci es observed in A-T patients (TgA, IgE and IgG2 
are deficient in over 80% of patients) correlate loosely with the physical distance between 
the heavy chain variable genes in the V(D)J region and those in the heavy chain constant 
regions ( 16). Conversely, other mechanisms might also influence the immune development 
and function of A-T cells. ATM protein phosphor ylates many important substrates. ATM 
protein appear s, in general, in the nucleus of replicating cells but in the cytoplasm of differ­
entiating cells . ATM protein plays a role in apoptosis, which could be pivotal to negative 
selection in the thymus (and in the central nervous system). Lim et al. (17) suggested that 
13-adaptins and movement of vesicles may be abnormal in A-T cells and may play a role in 
the secretion of immunoglobulin molecules. Studies by Rivero-Carmena et al. ( 18) suggest 
that membrane function ofT cells from A-T patients is intact. Regueiro et al. (7) exhaustively 
reviewed the immunological literature of A-T. 
2. CANCER RISK 
2.1. ATM Homozygotes 
The ATM gene plays a major role in oncogen esis (19-22). These patients develop new 
cases of cancer at approx 100 times the age-specific population rate (23 ). Most canc ers (85% 
for patients under 20 yr) involv e the lymphoid system, either as lymphomas or leukemias; 
lymphomas are more common . A charact eristic T-cellleukemi a (T-proliferative lympho­
cytic leukemia) occurs in older A-T patients in which TCL-1 is upregulated (24 ). Younger 
A-T patients typically develop a T -acute lymphocytic leukemia. In patients over 20 yr, 
appro ximately half of the canc ers are nonlymphoid, occurring in the following order of 
decreasing frequency: stomach , breast , medullobl astoma, basal cell carcinoma , ovarian 
dysgerminoma, hepatoma , and uterine leiom yoma (23 ). Homog yous Atm_ ,_ knockout mice 
develop thymi c lymphomas; by 5 rna of age, v irtually all of these mice have such tumor s (25 ). 
2.2. ATM Hetero zygote 
A TM mutations and loss of heterozygosit y across the 11 q22- 23 re gion have been 
reported in association with breast , prostate and ovarian canc er, head and neck cancer , 
lymphoma, and leukemia (26-29). Howev er, on closer inspection several caveats become 
apparent. First, A TM mutations for some human cancers are somatic, not inherit ed. Thus ,

476 Mitsui et al. 
such individuals would not be at an increased risk for cancer, at least with regard to the ATM 
gene (30). Although it is clear that the ATM gene and protein are involved in the pathogen­
esis, only about one-third ofT-PLL and chronic lymphocytic leukemia (CLL) patients were 
genomic ATM heterozygotes (31-33). Two mechanisms are implicated in such patients: a 
'second hit' to disable the remaining normal allele, or a dominant negative mutation, whereby 
the abnormal allele interferes with the functions of the normal allele, such as by blocking its 
access to a substrate (see below). 
When members of A-T families were studied for breast cancer incidence, a three to eight 
fold increase was found in almost every study (34-38). Paradoxically, when large breast 
cancer cohorts were screened for A TM mutations, the incidence of A TM mutations has 
seldom been higher than that in the control populations ( 39-46). Rare allelic variants are 
seen in certain populations and make such studies difficult to interpret. For example, 
Vorechovsky eta!. ( 47) screened 81 breast cancer patients and found 3 mutations and 5 rare 
variants. When FitzGerald et al. ( 43) used the protein truncation test (PTT) to screen 401 late 
onset breast cancer patients and 200 controls, only 2 A TM mutations were found in each 
group, with no significant difference between them. However, because PTT did not detect 
missense mutations, attention subsequently focused on the relevance of rare variants and 
missense mutations, rather than truncating mutations. 
Only about 10% of mutations in A-T patients are of the missense type, whereas >85% of 
ATM mutations associated with breast cancer (and not A-T) have been of the missense type. 
This prompted the hypothesis that perhaps the phenotypes are different for nonsense and 
missense ATM mutations (48) (i.e., perhaps certain missense changes have dominant nega­
tive effects that cause cancer but not the A-T syndrome). Most enzymes have two comple­
mentary functions: they bind specifically and then they catalyze generically. If a mutation 
interferes with one function but not the other, the defective molecule can actually create 
additional harm by keeping its natural substrates 'in complex' indefinitely. In this way, a 
single defective copy of a gene that normally functions in a recessive way for null alleles 
(those not producing any protein), would now function in a dominant way. This would fur­
ther suggest that defective proteins should be immediately targeted for destruction. Table 2 
summarizes the expected phenotypes that might be present from having two types of A-T 
carriers in the general population, A TMnonsense/wt and A TMmissen se/wt. This concept would 
also necessitate a reanalysis of cancer risks based on epidemiological studies, using different 
frequencies for each type of heterozygote. Current evidence suggests that the frequency of 
ATM missense mutations in the general population may be as high as 5-8%, and these do 
not generally appear to cause A-T. Accumulating data suggests that ATM missense muta­
tions may play a more significant role in some A-T cancers, such as breast cancer, than in 
others, such as childhood leukemia, in which the mutation spectrum seems to resemble that 
of A-T patients (49). 
Two large ongoing NIH-funded epidemiological studies are addressing the above issue. 
The IMECAT (International Molecular Epidemiology Consortium for Ataxia Telangiecta­
sia) study is evaluating the cancer risk of A-T relatives in eight countries, encompassing 600 
A-T families; the cancer epidemiology is being collected in parallel. The A TM mutation 
carriers in each family are being distinguished from noncarriers by haplotyping. The types 
of ATM mutations in each family are also being determined to later assess cancer-causing 
ATM mutations. A second independent study, WECARE (Women's Environment, Cancer,

ATM mutations. A second independent study, WECARE (Women's Environment, Cancer, 
and Radiation Epidemiology), is using denaturing high performance liquid chromatography

Table 2 
Phenotype/genotype Relationships for A TM Mutations 
Genotype 
ATMwt!wt 
A TMtrunc/trunc 
ATMmis/mis 
A TMmis/trunc 
A TMtrunc/wt 
ATMmi s/wt Phenotype 
Normal 
Ataxia-telangiectasia/cancer susceptibility 
Ataxia-telangiectasia/cancer susceptibility? 
Cancer susceptibility? 
Cancer susceptibility/neurological symptoms? 477 
( dHPLC) to identify the frequency and types of A TM mutations in over 2500 breast cancer 
patients from Europe, Australia, and the US (50). 
In addition, studies are underway to test the functional status of DNA changes (rare vari­
ants) in the ATM gene to distinguish mutations from polymorphism s, such as: 2546delSRI, 
S707P, P1054R , IVS10-6T>G, and 7271T>G. Scott et al. (51) have recently demonstrated 
that 2546deiSRI and S2592C have dominant interfering effects on ATM function. In follow­
up studies, Spring et al. (52) have further tested the dominant negative model of cancer risk 
by creating knock-in mice carrying the delSRI mutation. The de!SRI- 1-(i.e., homozygous) 
mice manifested a high frequency of tumors, as do ATM- 1-knockout mice (25 ). Most inter­
estingly, the de!SRJ+I -(i.e., heterozygous) mice also manifested an increased incidence of 
tumors, as compared to controls. This was different than the cancer risk of the heterozygous 
A TM knockout mice, in which the incidence of tumors did not differ from that of normal 
mice of the same genetic background (25). Thus , some ATM mutation s increase the risk of 
cancer even when in a heterozygous state (53). 
2.3. Radiosensitivity testing 
Cells from patients with A-T are typically sensitive to gamma ray radiation. The colony 
survival assay (CSA) was established as a diagnostic test, taking advantage of this character ­
istic radiosensitivity (54, 55). From a 5 mL heparinized whole blood sample, peripheral blood 
lymphocytes are immortalized by Epstein-Barr virus transformation and maintained in 15% 
fetal bovine serum (FBS) and incubated in 5% C0 2 at 37°C. This provides enough cells in 
the laboratory for testing both radiosensitivity, immunoblotting , kina se function, and muta ­
tion detection -an important issue when multipl e assays must be pe rformed on very small 
patients. 
CSA begins by plating 200 and 100 cells/well in duplicate 96-well plates. The plates are 
then exposed to ionizing radiation (IR) at a dose of 1 Gy (Fig. 1 ). After incubation for 
10-13 d at 37°C, the surviving cells are stained with vital dye (tetrazolium-based colorim et­
ric assay), followed by another 2-4 h incubation. 
The wells of each plate are then scored under a microscope for the formation of viable cell 
colonies (stained dark blue): "positive" (survival) is defined as >32 cells/well (indicating at 
least five cell divisions); "negative" signifies no colony formation in that well. Colony ­
forming efficiency (CFE) is calculated by comparing the ratio of negative wells to posi­
tive wells. The survival fraction (SF) is calculated by dividing the CFE of irradiated plates 
by the CFE of unirradiated control plates. An LCL with a SF of <21% is considered radi-

478 
Non-irradiated 
control Mitsui et al. 
~ Irradiat ed 
into 96 well plates 200 cells per well 0 count cells and put.ri~~~~~~~~~~~~~~~~f' 
LCLof 
unknown patient ~ 
I stain with MIT dye 
for 2-4 hours 
count the wells with positive colonies 
and calculate F% I 00 cell per well 
200 cells per well 
100 cells per well 
I 00 cells per well 
Fig. 1. Colony survival assay (CSA). For each test, a normal LCL and known A-T LCL are in­
cluded as controls. The number of positive wells per plate is scored (>32 cells/well = a positive 
well).Colony forming efficiency , CFE, is calculated for irradiated plates (CFEi) and non-irradiated 
plates (CFEc). Survival fraction percentage (SF%) = CFEi/CFEc (54). Color image available for 
viewing at www.humanapress.com. 
osensitive, while LCLs with a SF of >37% is considered radionormal. A SF between 21 and 
36% is considered as intermediate radiosensitivity. A-T LCLs typically fall in the radiosen­
sitive range. An LCL with intermediate radiosensitivity is non-diagnostic and requires fur­
ther testing. Roughly, 7% of A-T LCLs fall within this range; when such cells are retested 
across a range of radiation exposure rates (0.5 to 2 Gy), they are almost always radiosensi­
tive at higher exposures (Fig. 2) (55). A-T patients with intermediate radiosensitivity typi­
cally have mutations that fall within the functional domains of the A TM gene; the reason for 
this remains unclear (55). There is also suggestive evidence that such patients may have a 
slower progression of neurological symptoms (56). 
The CSA is a useful test for confirming an early clinical diagnosis of A-T. However, this 
assay is also abnormal in other chromosomal instability and immunodeficiency disorders 
(5). CSA sensitivity is >99%; specificity is approx 90%. Therefore, it is important to com­
bine CSA data with other diagnostic testing (57). 
2.3.1. Immunoblotting 
Recently, immunoblotting or western blot analysis has been adapted as a diagnostic test 
for A-T to detect ATM protein levels from nuclear lysates of LCLs (57-60) (Fig. 3). The

100~ --------------------------------------------~ 
60 
~ 0 
c 
0 ;: u ca ... u.. 
iii > 
~ 
::1 40 en 
0.5Gy -- Normal 
--- oonal 
-e-A -T 
-b--A ·T 
Intermediate range 
1Gy 
Dose (Gy) 1.5Gy 2Gy Normal 
range 
(>37%) 
A-T range 
(<21%) 479 
Fig. 2. Dose-response followup CSA testing for intermediate radiosensitivity. Four doses of irra­
diation are used : 0.5, 1.0, 1.5, and 2.0 Gy. Curves shown are for two normal and two A-T LCLs . Bar 
depi cts CSA ranges when only one gray is used. Color image available for viewing at 
www .humanapress.com . 
protein is 370 kDa in size and contains 3056 amino acids (aa). At least 5 million 
lymphoblastoid cells are necessary for immunoblotting. Anti-A TM antisera are used to de­
tect ATM protein, which is visualized by enhanced chemiluminescence , and is semi-quanti ­
tated by densitometry. ATM protein levels are compared to normal protein from a non-A-T 
patient, and are semi-quantitatively scored over a range of 0-100%: <5%, undetectable; 5-
15%, low; 16-75%, intermediate ; and >75%, normal protein levels. Patients with A-T typi­
cally have <5% protein levels. Heterozygotes typically have intermediate levels (57). An 
LCL with intermediate protein levels is not diagnostically conclusive; however, this is rarely 
encountered. The sensitivity and specificity of immunoblotting for A-T diagnosis are >99%.

480 Mitsui et al. 
2 3 -' 5 6 7 
T:\1 
Mrell 
%AM: 100 0 0 76 67 78 0 
Fig. 3. Immunoblot analysis of nuclear lysates from 5 million LCLs , for evaluating ATM protein 
levels. Percentages below indicate densitometry readings for upper blot. Antibody to Mre 11 is used 
as a loading control (lower blot). Lane 1, normal control; lane 2, A-T control; lanes 3 and 7, newly­
diagnosed A-T samples; lanes 4-6, not A-T patients. 
Occasionally, we encounter a sample with normal ATM protein levels and radiosensitiv­
ity. The recommended followup testing would be: functional assessment of ATM protein 
(i.e., kinase activity on a p53 substrate), ATM mutation screening, and immunoblotting for 
deficiency of other proteins . The Ligase IV deficiency syndrome was discovered in this way 
(61 ). Because Mrell deficiency manifests an early onset ataxia similar to A-T, our labora­
tory uses an antibody to Mre 11 protein as a loading control in A TM testing. However, to 
date, only three families with Mrell deficiency (also known as A-T Like Deficiency, ATLD) 
have been described (62,63 ). 
2.3.2. ATM Protein Kinase Activity: A Functional Assay 
Examining the protein kinase activity of ATM often helps the interpretation of an interme­
diate ATM protein level or CSA. Generally, cells from A-T patients do not have kinase func­
tion. However , rare patients have been described with near normal levels of ATM protein 
and greatly reduced kinase activity (64-66). 
ATM phosphorylates many substrates involved in cell cycle control, DNA damage repair, 
and oxidative stress responses, for example, p53, MDM2, NBSl, BRCAl, CHEK1, SMCl, 
H2AX, and FANC D2 (67). ATM is activated by autophosphorylation after DNA double­
strand breakage events and chromatin changes , such as those produced by IR and radiomimetic 
agents (68). 
An ATM kinase test can be performed as an ex vivo assay on LCLs, examining p53 serine 
15 (Serl5) as the phosphorylation target of ATM protein, or as an in vitro assay, by adding 
p53 and 32P-ATP. In the former assay, cells are exposed to 2 Gy of irradiation and lysed 15 
to 60 min after IR (57). Phosphorylation of p53 by the ATM homologue, ATR , occurs after 
1 hr, so ATM-specific phosphorylation of Ser15 is controlled by time of harvest after IR. 
Whole cell 1ysates for irradiated and unirradiated control and A-T LCLs are prepared and 
analyzed by immunoblot analysis, using a p53 phosphoserine 15 antibody to identify ATM­
specific phosphorylated p53. Typically, A-T cells have no inducible kinase activity follow­
ing IR (Fig. 4). Normal cells phosphorylate p53 Ser15 immediately after exposure. 
Similar assays using different A TM substrates may be used to further evaluate A TM pro­
tein kinase activity. Many phosphoserine-specific antibodies to ATM phosphorylation QS 
sites are commercially available, allowing considerable flexibility in choosing a phosphory­
lation target.

Diagnosis of Ataxia- Telangiectasia 481 
c::: c::: 
r-r-
eo:: (;; c::: I I 
E E -~ ~ r-I I r... :... r-== == 0 0 I I 0 0 z z ~ ~ z z 
p53 eriS 
Den itometry quantitation: 100% 0% 100% 
Fig. 4. A TM protein kinase assay, using p53 as substrate. LCLs were exposed to 2 Gy ionizing 
radiation (IR) to induce ATM kinase activity. Whole cell lysates were prepared, blotted , and 
immunoblots developed with antibody to phosphorylated Serine 15 ofp53. Positive bands are seen in 
lanes 2 and 6. Induced ATM kinase activity is semi-quantitated by densitometry. Lanes 1 and 2, 
normal control; lanes 3 and 4, A-T cells; lanes 5 and 6, newly-diagnosed non-A-T sample. 
2.4. ATM Mutations 
Identifying mutations in the ATM gene has been difficult owing to its large size (69-74). 
The gene extends over 150,000 nucleotides of genomic DNA, includes 66 exons, and has an 
open reading frame (ORF) of 9168 nucleotides . Most A-T patients are compound heterozy­
gotes; they inherit a different mutation from each parent. Mutations in A-T patient s are 
present throughout the ATM gene. Approximately 85% are nonsense mutations (many 
resulting from aberrant splicing) , 10% are missense, and 3% are large genomic deletions or 
pseudoexon insertions. The latter are not detected by PCR-based methods, especially when 
present in heterozygous form. A compilation of almost 400 unique mutations is contained in 
the ATM Mutation Database (www.benaroyaresearch.org/bri_investigators/atm.htm). 
Although mRNA is present in virtually all A-T patients, mature truncated proteins are not 
detected. This is probably because of instablility; however, the role of nonsense-mediated 
mRNA decay (NMD) in A-T cells is being evaluated. Missense mutations have been associ­
ated with an increased risk for malignancy, particularly breast cancer (as discussed above). 
The first method used to screen the large A TM gene for mutations is the Protein Trunca­
tion Test (PTT) (71). PTT detects about 70% of ATM mutations (72-74). If PTT does not 
identify both mutations, Single Strand Conformation Polymorphism (SSCP) (75, 76) is per­
formed, using RNA/eDNA as the starting template . This detects almost all types of muta­
tions but involves screening of more fragments. Large genomic deletions are analyzed by 
loss of heterozygosity (LOH) on the gDNA, using several microsatellite and single nucle­
otide polymorphism (SNP) markers (77,78). 
Other methods have been developed for mutation screening. These include: Conforma­
tion sensitive gel electrophoresis (CSGE), restriction endonuclease fingerprinting (REF), 
detection of virtually all mutations (DOV AM) (79), denaturing high performance liquid chro­
matography (dHPLC) (50,80), high-density oligonucleotide arrays, and direct sequencing. 
None of these methods is 100% efficient owing to several limitations. The large size of the 
gene makes direct sequencing difficult. Certain regions of the gene are usually not included 
in the screening, such as deep introns, promoter, and untranslated regions, becau se they

482 Mitsui et al. 
SPAT 3.2 SPAT4.3 SPAT5.3 SPAT6.1 SPAT7.3 
S1819 133 133 131 141 133 131 133 133 131 131 
NS22 161 161 165 163 171 159 161 161 163 163 
S2179 141 141 139 139 143 143 141 141 139 139 
S1818 154 154 160 156 144 160 154 154 158 158 
[A) [A] [6) [B) [C) [2) [A) [A) [D) [D) 
SPAT8.3 SPAT9.4 SPAT 10.3 SPAT11.4 SPAT12 
S1819 137 141 137 141 133 139 131 131 131 131 
NS22 163 151 163 163 165 173 169 161 161 161 
S2179 139 139 137 141 137 143 143 147 147 147 
S1818 152 152 158 160 160 152 164 158 158 158 
[5] [E) [F) [G) [H) [I) [J) [K) [K) [K) 
SPAT13 SPAT14 SPAT16 SPAT18 SPAT 19.3 
S1819 133 135 137 131 147 147 137 133 135 141 
NS22 167 173 163 161 163 163 163 163 159 163 
S2179 143 141 143 139 137 137 141 141 143 141 
S1818 160 160 160 154 154 154 160 162 160 158 
[L) [M] [S] [T) [N) [N) [U) [V] [3] [OJ 
SPAT20.3 SPAT22.3 SPAT23 SPAT24.3 SPAT27.3 
S1819 131 127 135 135 133 139 133 133 131 131 
NS22 165 163 175 175 165 173 161 161 165 165 
S2179 139 139 143 143 137 141 141 141 139 139 
S1818 160 154 164 164 160 158 154 154 160 160 
[6) [P) [Q) [Q) [H) [R) [A) [A) [6) (6) 
Fig. 5. Haplotypes of probands from 20 Spanish A-T families. Recurring haplotypes are color shaded. 
Note that 65% of families show recurring haplotypes. Haplotypes are assigned numbers instead of 
letters whenever the haplotype has also been observed in other countries. Mutations have been defined 
for each haplotype. Color image available for viewing at www.humanapress.com . 
yield very few mutations and DNA changes are difficult to interpret. Finally, heterozygous 
large genomic deletions are "masked" by the second allele when DNA fragments are ampli­
fied by PCR. 
In ethnically homogeneous populations, standardized haplotyping is especially efficient 
for identifying founder mutations (Fig. 5) (78 ). Four highly polymorphic microsatellite mark­
ers are used to construct the haplotypes. This finding simplifies mutation screening in these 
populations because in almost all cases identical mutations are carried by identical 
haplotypes. For example, in Costa Rica, four founder haplotypes accounted for 85% of the 
affected chromosomes (Table 3) (81 ); in Brazil and Spain, 65% of the A-T patients carried at 
least one founder haplotype with a mutation already identified (78,82) (Fig. 5). Our labora ­
tory has established a haplotype-mutation database for many ethnic populations, and we use 
this approach as the first step in mutation screening. 
Many founder effect mutations have been identified in international studies (Table 3). 
Only about a dozen mut ations have been obse rved with> 1% g lobal frequency . These recur ­
ring mutations appear to be ancestrally related (77) rather than independent mutational events 
(hot spots) (78); some ATM mutations appear to be thousands of years old (77). Taken 
together these dozen recurring mutations account for about one-third of all A TM mutations 
in A-T patients, the other mutations being of very low frequency.

Diagnosis of Ataxia-Telangiectasia 483 
Table 3 
ATM Mutations in Ethnic Populations 
Population (haplotype) Mutation Frequency (% alleles) 
Costa Rican 
A 5908C>T 56 
c 7449G>A 13 
D 4507C>T 9 
B IVS63del17kb 7 
Polish 
B 6095G>A 11 
A IVS53-2A>C 9 
E 5546delT 5 
c 7010delGT 3 
D 5932G>T 3 
Italian 
A 7517del4 20 
B 3576G>A 7 
Sl 3894insT Sardinia (>95) 
United Kingdom 
FM7 5762ins137 7 
FMlO 7636del9 6 
N African Jews 103C>T >99 
Amish 1563delAG >99 
Japanese 
A 7883del5 28 
B IVS33+2T>A 22 
Norwegian 3245ATC>TGAT 55 
Spanish 
6 8977C>T 18 
A 9010del28 15 
H 2413C>T 5 
Brazilian 
2 IVS28+ 17lldel3450 15 
7913G>A 9 
1 3802delG 9 
5 8264delA T AAG 7 
T IVSl I-2A>G 4 
Hispanic American 
H 103C>T 6 
M 1348delG 6 
J IVS20-579delAAGT 6 
Turkish 
A 3576G>A 17 
G 6188G>A 7 
H IVS4 4-IG>T 7 
B 5554insC 4 
D 1563delAG 4 
E 9170G>C 4 
F IVS21+1G>A 4

484 Mitsui et a!. 
3.SUMMARY 
Much has been learned about A-T within the past two decades. Perhaps the most progress 
has been made in the areas of early diagnosis and prenatal testing, as well as in under stand­
ing the role of ATM protein in cell signaling, DNA repair, and oxidative stress. A TM muta­
tions have been identified in over 600 families, as well as in non-A-T patients with various 
types of cancers. Surprisingly , the spectra of mutations for breast cancer and for A-T pa­
tients are quite different. Radiosensitivity (RS) studies of A-T have led to the discover y of 
other hereditary RS disorders , such as NBS, Mre 1 1 deficiency , Ligase IV deficiency, Fan coni 
anemia, and X-linked agammaglobulinemia. Mostly, the RS disorders also manife st immu­
node ficiency and cancer susceptibility (5). Despite these advances, major questions remain 
unanswered: 
1. How does A TM deficiency lead to cerebellar degeneration and ataxia? 
2. What is the mechanism by which ATM deficienc y results in RS? 
3. How can the relentle ssly progressive neurological degeneration be treated? 
1. Boder E and Sedgwick RP. 1958. Ataxia-telangiectasia: a familial syndrome of progressive cer­
ebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection . Pediatrics 
21 :526-554. 
2. Gatti RA, Boder E, Vinters, HV, Sparkes S, Norman A, Lange K. 1991. Ataxia-telangiectasia: an 
interdisciplinary approach to pathogenesis. Medicine 70:99-117. 
3. Gatti RA. 2002. Ataxia-telangi ectas ia, in: The Genetic Basis of Human Cancer, Voge lstein B 
and Kinzler KW, eds., McGraw-Hill: New York, pp. 239-266. 
4. Perlman S, Beeker -Catania S, Galti RA. 2003. Ataxia -Telangiectasia Diagnosis and Treatment. 
Sem. Pediat. Neurol. 10:173-182. 
5. Gatti RA. 200l.The inherited basis of human radiose nsitivity. Acta Oncologica 40:702-711. 
6. Yarchoan R, Kurman CC, Nels on DL. Defecti ve specific antiinflucnza virus antibody produc­
tion in vitro by lymphocytes from patients with ataxia-telangiectasia, in: Ataxia-Telangiectas ia: 
Genetics, Neurop atholo gy, and Immunolo gy of a Degenerative Disease of Childhood , Gatti RA 
and Swift M, eds., Alan R. Liss, Inc: New York, pp. 315-329. 
7. Regueiro JR, Porras 0, Lavin M, and Gatti RA. 2000 . Ataxia- Telangiectasia; a primary immuno­
deficiency revisited. Immunol. Allergy Clin. N. A mer. 20:177-206. 
8. Gatti RA, Bick M, Tam CF, et al. 1982. Ataxia-telangiect asia: a multi parame ter analysis of eight 
families . Clin . Tmmun ol. lmmun opath. 23:50 1-516. 
9. Woods CG and Taylor AMR. 1992. Ataxia telangi ectasia in the British Isles : the clinical and 
laboratory features of70 affected individuals. Quart . J. Med . New. 298:169-179. 
10. Paganelli R, ScalaE, Scarselli E, et al. 1992. Selective deficiency of CD4+/CD45RA + lympho­
cytes in patients with ataxia-telangiectasia. J. Clin. Immunol. 12:84-91. 
11. Sanal 0, Ersoy F, YelL, et al. 1999. Impaired IgG antibody production to pheumococcal polysac­
charides in patients with ataxia-telangeictasia. J. Clin. Immunol. 19:326-334 . 
12. Yuille MR, Colgnet LJ, Abraham SM, et al. 1998. ATM is usually rearranged in T -cell 
prolymphocytic leukemia. Onco gene 16:789 -796. 
13. Pan-Hammarstrom Q, Dai S, and Zhao Y, et al. 2003 . ATM is not required in somati c 
hype rmutation of VH, but is involved in the introduction of mutations in the switch u region. 
J. Immunol. 170:3707-3716. 
14. Peterson RDA, Kelly WD, Good RA. 1964. Ataxia-telangiectasia: its association with a defec ­
tive thymus, imm unological -deficiency disease , and malignancy. Lancet I: 1189. 
15. Amromin GO, Boder E, Teplitz R. 1979. Ataxi a-telangiectasia with a 32 year survival. A clinico­
pathological report. J. Neurop ath. Exp. Neurol. 38:621-64 3.

Diagnosis of Ataxia- Telangiectasia 485 
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17. Lim D-S, Kirsch D, Can man CE, eta!. 1998. A TM binds to beta-adaptin in cytoplasmic vesicles. 
Proc . Nat!. Acad.Sci. USA 95:10,146 -10,151. 
18. Rivero-Carmena ME, Porras 0, Pelaez B, Pacheco-Castro A, Gatti RA, Regueiro JR. 2000. 
Membrane and transmembrane signaling in Herpesvirus saimiri-translformed human CD4+ and 
CD8+ T cells is ATM-independent. Int. Immunol. 12:927-935. 
19. Gatti RA and Good RA. 1971. Occurrence of malignancy in immunodeficiency diseases. Cancer 
28:89-98 
20. Spector BD, Filipovich AH, Perry GS, Kersey JH. 1982. Epidemiology of cancer in ataxia­
telangiectasia, in: Ataxia-Telangiectasia-Cellular and Molecular Link Between Cancer, Neu­
ropathology and Immune Deficiency, Bridges BA and Harnd en DG, eds., John Wiley: London, 
pp. I 03-107. 
21. Morrell D, Cromartie E, and Swift M. 1986. Mortality and cancer incidence in 263 patients with 
ataxia-telangiectasia. J. Nat!. Cancer Inst. 77:89-92. 
22. Taylor AMR, Metcalfe JA, Thick J, Mak Y-F. 1996. Leukemia and lymphoma in ataxia telang­
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23. Su Y and Swift M. 2000. Mortality rates among carriers of ataxia -telangeictasia mutant alleles . 
Ann. Intern . Med. 133:770 -778. 
24. Chun HH, Castellvi-Bel S, Wang Z, eta!. 2002. TCL-1, MTCP-1 and TML-1 gene expression 
profile in non-leukemic proliferations associated with ataxia-telangiectasia. Int. J. Cancer 
97:726-731 . 
25. Barlow C, Hirotsune S, Paylor R, eta!. 1996 . Atm-deficient mice: a paradigm of ataxia telang­
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26. Koike M, Takeuchi S PartS, eta!. 1999 . Overian cancer: loss of heterozygosity frequently occurs 
in the A TM gene, but structural alterations do not occur in this gene. Oncology 56: 160-163. 
27. Laake K Odegard A, Andersen TI, et al. 1997. Loss of heterozygosity at 11 q23.1 in breast carci­
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18:175-180 . 
28. Lu Y, Condie A, Bennett JD, Fry MJ, Yuille MR, Shipley J. 2001 . Disruption of the ATM gene 
in breast cancer. Cancer Genet. Cytogenet. 126:97 -101. 
29. Carter SL, Negrini M, Baffa R, et al. 1994 . Loss of heterozygosity at 11 q22-q23 in breast cancer. 
Cancer Res. 54: 6270 -6274 . 
30. Stilgenbauer S, Schaffner C, Litterst A, et al. 1997 . Evidence for ATM as a tumor suppressor 
gene in T-prolymphocytic leukemia. Nat. Medicine 3:1155-1161. 
31. Bullrich F, Tasio D, Kitada S, et al. 1999. ATM mutations in B-cell chronic lymphocytic leuke­
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32. V orechovsky I, Luo L, Dyer MJS, et al. 1997 . Clustering of missen se mutations in the ataxia ­
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34. Swift M, Reitnauer PJ, Morrell D, Chase CL. 1987. Breast and other cancers in families with 
ataxia-telangiectasia . N. Engl. J. Med. 316:1289-1294. 
35. Swift A, Morrell D, Massey RB, Chase CL. 1991. Incidence of cancer in 161 families affected 
by ataxia-tel angiectasia. N. Engl. J. Med . 325: 1831-1836. 
36. Easton DF. 1994. Cancer risks in A-T heterozygotes . Int. J. Radiat. Bioi. 66:S 177- S 182. 
37. Athma P, Rappaport R, Swift M. 1996. Molecular genotypin g shows that ataxia -telangie ctasia 
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38. Olsen JH, Hahnemann J M, Borr esen-Dale A-L, et a!. 200 I. Cancer in patients with ataxia ­
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39. Chen J, Birksholtz GC, Lindblom P, Rubio C, Lindbl om A. 1998. The role of ataxia-telangiecta­

sia heterozygotes in familial breast cancer. Cancer Res. 58:1376 -1379.

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40. Bay J-0, Grancho M, Pernin D, et a!. 1998. No evidence for constitutional A TM mutation in 
breast/gastric cancer families. Int. J. On col. 12: 1385-1390. 
41. Vorechovsky I, Rasia D, Luo L, et a!. 1996. The A TM gene and susecptibility to breast cancer : 
analysis of 38 breast tumors reveals no evidence for mutation. Cane Res. 56:2726-2732. 
42. Stoppa-Lyonnet D, Soulier J, Lauge A, et al. 1998. ATM and breast cancer. Blood 91: 
3920-3926. 
43. FitzGerald MG, Bean JM, Hegde SR, et al. 1997. Heterozygous ATM mutations do not contrib­
ute to early onset of breast cancer. Nat. Genet. 15:307 -310. 
44. Broeks A, Floore AN, Urbanus JHM, et al. 2000. Classical ATM germline mutations contribute 
to breast cancer susceptibility. Amer. J. Hum. Genet. 66:494-500. 
45. Chevenix- Trench G, Spurdle AB, Gatei M, eta!. 2002. Dominant negative ATM mutations in 
breast cancer families . J. Nat. Cancer Inst. 94:205-215. 
46. Thor stenson YR, Roxas A, Kroiss R, et al. 2003. Contributions of A TM mutations to familial 
breast and overian cancer. Cancer Res. 63:3325-3333. 
47. Vorechovsky I, Luo L, Lindblom A, et al. 1996. ATM mutations in cancer families. Cancer Res. 
56:4130-4133. 
48. Gatti RA, Tward A, Concannon P. 1999. Cancer risk in ATM heterozygotes: a model of pheno­
typic and mechanistic differences between missense and truncating mutations . Mol. Genet. 
Metabol. 69:419-423 . 
49. Vorechovsky I, Luo L, Dyer MJS, et al. 1997. Clustering of missense mutations in the ataxia­
telangiectasia gene in a sporadic T-cellleukaemia . Nature Genet. 17:96-100. 
50. Bernstein JL, Teraoka S, Haile RW, et al. 2003. Designing and implementing quality control for 
multi-center screening of mutations in the ATM gene among women with breast cancer. Hum . 
Mut. 21: 542-550 . 
51. Scott SP, Bendix R, Chen P, Clark R, Dark T, Lavin MF. 2002. Missense mutations but not 
allelic variants alter the function of ATM by dominant interference in patients with breast cancer. 
Proc. Nat!. Acad. Sci. USA 99:925-30. 
52. Spring KF, Ahangari SP, Scott P, et al. 2002. Mice heterozygous for mutation in Atm, the gene 
involved in ataxia- telangiectasia, have heightened susceptibility to cancer. Nat. Genet. 32: 
185-190. 
53. Concannon P. 2002 . ATM heterozygosity and cancer risk. Nat. Genet. 32:89-90. 
54. Huo YK, Wang Z, Hong J-H, et al. 1994. Radiosensitivity of ataxia-telangiect asia, X-linked 
agammaglobulinemia and related syndromes. Cancer Res. 54: 2544-2547. 
55. Sun X, Beeker-Catania SG, Chun HH, et al. 2002 . Early diagnosis of ataxia-telangiectasia using 
radiosensitivity testing . J. Pediat. 140:732-735 . 
56. McConville CM, Stankovic T, Byrd PJ, et al. 1996 . AMR. Mutations associated with variant 
phenotypes in ataxia-telangiectasia. Am. J. Hum. Genet. 59:320 -330. 
57. Chun HH, Sun X, Nahas SA, et al. 2003. Improved diagnostic testing for ataxia-telangiectasia by 
immunoblotting of nuclear lysates for ATM protein expression and PI-3 kinase activity. Mol. 
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58. Fukao T, Kaneko H, Birrell G, et al. 1999. ATM is upregulated during the mitogenic response in 
peripheral blood mononuclear cells . Blood 94:1998 -2006. 
59. Beeker-Catania S, ChenG, Hwang M J, et al. 2000. Ataxia-telangiectasia: Phenotype/genotype 
studies of ATM protein expression, mutations, and radiosensitivity. Mol. Genet. Metab. 
70:122-133 . 
60. Gilad S, Chessa L, Khosravi R, et a!. 1998. Genotype-phenotype relationships in ataxia-telang ­
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61. O'Driscoll M, Cerosaletti KM, Girard P-M, et al. 2001. DNA ligase IV mutations identified in 
patients exhibiting developal delay and immunodeficiency. Mol. Cell. 8:1175-1185. 
62. Stewart GS, Maser RS, Stankovic T, et al. 1999. The DNA double-strand break repair gene 
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identified in a transcript protected from nonsese-mediated mRNA decay . Hum. Molec . Genet. 
10:1155-1162. 
64. Stankovic T, Kidd AMJ, Sutcliffe A, et al. 1998. ATM mutations and phenotype s in ataxia­
telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, 
lymphoma, and breast cancer. Am. J. Hum. Genet. 62:334-345. 
65. Stewart GS, Last JIK, Stakovic T, et al. 2001. Residual ataxia telanigiectasia mutated protein 
function in cells from A-T patients, with 5762ins137 and 7271T>G mutations, showing a less 
severe phenotype. J. Bioi. Chem . 276:30103-30141. 
66. Saviozzi S, Saluto A, Taylor AMR, et al. 2002. A late onset variant of ataxia-telangiectasia with 
a compound heterozygous genotype, A8030G/748linsA. J. Med. Genet. 39:57-61. 
67. Shiloh Y. 2003. ATM and related protein kinases : safeguarding genome integrit y. Nat. Rev. 
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68. Bakkenist CJ and Kastan MB. 2003. DNA damage activates A TM through intermolecular 
autophosphorylation and dimer dissociation. Nature 421:499-506. 
69. Savitsky K, Bar-Shira A, Gilad S, et al. 1995. A single ataxia-telangiecta sia gene with a product 
similar to Pl-3 kinase. Science 268:1749-1753. 
70. Platzer M, Rotman G, Bauer D, Savitsky K, Shiloh Y, Rosenthal A. 1997. Ataxia-telangiectasi a 
locus: analysis of 184 kb DNA provides evidence for mosaic genomic structure and complex 
transcriptional regulation of the ATM gene. Genome Res. 7:592-605 . 
71. Te1atar M, Wang Z, Udar N, et al. 1996. Ataxia-telangiectasia: mutations in A TM eDNA detected 
by protein-truncation screening. Am. J. Hum. Genet. 59:40-44 . 
72. Concannon P and Gatti RA. 1997. Diversity of ATM gene mutations detected in patients with 
ataxia-telangiectasia. Hum . Mut. 10:100-107 . 
73. Telatar M, Teraoka S, Wang Z, eta!. 1998. Ataxia-telangiectasia: identification and detection of 
founder-effect mutations in the A TM gene in ethnic populations. Am. J. Hum. Genet. 62:86 -97. 
7 4. Teraoka S, Telatar M, Beeker-Catania S, et al. 1999. Splicing defects in the ataxia -telangiectasia 
gene, ATM: underlying mutations and phenotypic consequences. Am. J. Hum. Genet. 64: 
1617-1631. 
75. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. 1989. Detection of polymorphisms of 
human DNA by gel electrophoresi s as single-strand conformation polymorphism. Proc. Nat!. 
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76. Castellvi-Bel S, Sheikhavandi S, Telatar M, et al. 1999. New mutations, polymorphisms, and 
rare variants in the ATM gene detected by a novel SSCP strateg y. Hum. Mut. 14:156 -162. 
77. Campbell C, Mitui M, Eng L, Coutinho G, Thorstenson Y, Gatti RA. 2003. ATM mutations on 
distinct SNP and STR haplotype s in ataxia-telangiectasia patients of differing ethnicities reveal 
ancestral founder effects. Hum. Mut. 21:80-85 . 
78. Mitui M, Campbell C, Coutinho G, et al. 2003. Independent mutational events are rare in the 
ATM gene: haplotype prescreening enhances mutational detection rate. Hum. Mut. 22:43-50. 
79. Buzin CH, Gatti RA, Nguyen VQ, et al. 2003. Comprehensive scanning of the ATM gene with 
DOVAM-S. Hum. Mut. 21:123-131. 
80. Thorstenson YR, Shen P, Tusher VG, et al. 2001. Global analysis of ATM polymorphi sm reveals 
significant functional constrait. Am. J. Hum. Genet. 69:396-412 . 
81. Telatar M, Wang Z, Castellvi-Bel S, eta!. 1998 . A model for ATM heterozygo te identification in 
a large population: Four founder -effect ATM mutations identify most of Costa Rican patients 
with ataxia Telangiectasia. Mol. Genet. Metab.64:36-43. 
82. Coutinho G, Mitui M, Campbell C, et al. 2004. Five haplotyp es account for fifty-five percent of 
A TM mutations in Brazilian patients with ataxia -telangiectasia : seven new mutations. Am. J. 
Med. Genet. In press.

A 
Aberrant crypt foci (ACFs) described, 
437 
Abl-Bcr proteins and Philadelphia 
chromosome leukemia, 17 4 
Acquired Immunodeficiency Syn­
drome (AIDS) and Karposi' s sar­
coma, 55 
Acute lymphoblastic leukemia/lym­
phoma (ALLs) 
B-lineage, 202-203, 241 (See also 
Burkitt's lymphoma) 
described, 383-384 
genetic abnormalities in, 239-241, 
383 
hypodiploid, 383 
phenotypic/ genotypic correla­
tions, 206 
T-lineage,203-204,241 
Acute myeloid leukemia (AML) 
chromosome changes in, 381 
c-kit protein in, 239 
diagnosis, 204, 235, 380-381 
gene fusion products, 205-208, 
237-238 
genetic alterations in, 208, 238, 381 
prognosis, 381 
suppressor genes in, 19 
WHO classification, 204, 235 
Acute promyelocytic leukemia (APL) 
described, 205, 235-237 
residual disease, detection of, 237 
translocations in, 205-208 
Adenocarcinoma 
and COX2, 57 
duodenal and ras mutations, 72 
gastric and p53, 59 
genetic upregulation in metastasis, 309 
489 Index 
1552S and, 187 
and Lewis blood group antigens, 40, 41 
and LOH abnormalities, 413 
NSCL and c-erbB-2 oncoprotein, 70 
Adenomas described, 385-387,438 
Adenomatous polyposis coli (APC) 
as molecular marker, 9, 429-431, 434, 
437,438-439 
gene in colorectal cancer, 430-431 
Adenomatous polyps , 72 
Adhesion, association with, 77-78 
a-Fetoprotein (AFP). See also individual 
cancer by name 
characteristics of, 135-136,141,142-143 
and disease stage , 145 
half life of, 152, 153 
in neoplasms , 48 
physiologic function of, 38 
sensitivity I specificity of, 16, 56-57, 
132 
Allelic band intensity , detecting, 400,401 
Allelic imbalance, assessing, 411 
ALLs. See Acute lymphoblastic leuke-
mia/lymphoma (ALLs) 
Amino acid sequences, predicting, 29 
Amphiphysin described, 172 
Amplicon defined, 269 
Anaplastic lymphoma kinase (ALK) 
protein expression, detecting, 250 
Aneusomies and FISH detection , 326 
Angiogenesis, 76-77, 110, 466 
ANNA-l antibody, 172 
ANNA-2 protein antibody, 172 
Anthracycline therapy, 274, 275 
Antibodies and neoplasm diagnosi s, 
27-28,29 
Antigens, 40, 188 
Antigen-sp ecific immun e responses, 
measurement of, 218

490 
Anti-nuclear antibodies (ANAs), 169 
Anti-Yo/anti-Purkinje cell antibody 
(PCA), 172 
Apoptosis 
association with, 74-76 
inducing, 76, 99,466 
inhibition of, 57, 71, 75 
Artificial neural networks (ANN), 113 
Ashkenazi Jews 
and APC polymorphisms, 439 
breastcancerand,459,460 
Assays. See individual assay by name 
Ataxia telangiectasia (A-T) 
breast cancer and, 476 
cytogenetics in, 473-47 4 
described, 364, 454, 473-475 
and DNA repair problems, 361, 364 
a-Fetoprotein (AFP) and, 473 
immune defects in, 475 
probands, haplotypes of, 482 
proteins, truncated and, 481 
T -cell leukemia and, 47 4-475 
Ataxia-telangiectasia mutated (ATM) 
gene mutations and cancer risk, 
475-477,480,481-483 
mutation Database url, 481 
protein kinase activity assay, 
480-481 
Autoantibodies, 169-170 
Autoimmune diseases, 169 
Autoimmunity, 170 
Avastatin, 21 
B 
Basal cell nevus syndrome described, 
454 
Basic fibroblast growth factor (bFGF) 
described, 76 
Bat-26 as molecular marker, 9 
B-cells 
clones, detecting, 244-245 
lymphornas,214,242-249,384,476 
B-cell small lymphocytic lymphoma/ 
chronic lymphocytic leukemia 
(CLL), 245, 384, 476 
Bel-l protein, 211 Index 
Bcl-2 protein, 74, 246 
Benign prostate hyperplasia (BPH) 
cancer and, 101 
finasteride and, 90 
and FPSA, 89, 92 
Benign PSA, 102 
Bevacizumab in cancer therapy, 21 
Bioinformatics described, 352 
and antigen expression, 41 
diagnosis and FISH, 95 
and EGFR, 71 
ligand-receptor assays, PCR based, 
349 
and LOH abnormalities, 409, 410 
NMP marker in, 17,43 
p16 gene mutations and, 74 
PSMA and, 105 
and ras mutations, 72 
sPas levels and, 75 
and SLN mapping, 297 
telomerase activity in, 20 
Bladder transitional cell carcinoma and 
TGF-[3, 69 
BLCA-4, sensitivity of, 43 
Blm gene, 19 
Blood 
antigens as tumor markers, 40-42 
chromosomal aberrations, detecting, 
387-388,397 
collection technique, 398-399 
gating strategy for, 200 
Lewis blood group antigens, 40, 41 
and nucleic acid based testing, 94 
PCR sampling technique, 398-399 
processing/ storage technique, 
399-400 
rare event detection in, 344 
Bloom's syndrome and DNA repair 
problems,363,364,365 
AML, flow cytometry diagram, 205 
culture setup technique, 387-388 
and LOH detection, 405 
Bone metastases, 91-92

Index 
Brain tumors 
EGFRand, 71 
and hnRNP A2/B1 overexpression, 
313,314 
medulloblastoma, 71, 386 
neuroblastoma, 330, 386 
andp53, 175 
retinoblastoma, 18, 19, 175, 386 
BRCA1/BRCA2 gene 
detection of, 335 
gene mutations in, 365,459-461 
and hereditary cancer, 18, 19, 
458-459 
and prostate cancer diagnosis, 98 
AFP serum levels in, 48, 136 
and anti-CENP-F antibodies , 176 
antigen expression and, 41 
in Ashkenazi Jews, 459,460 
A-T and,476 
autoantibody assays in, 108 
eDNA microarra y of, 341 
and c-erbB-2 oncoprotein, 70 
and CRP,68 
cyclin D1 and, 73 
and cyclin E, 73 
described, 458-459 
detection of, 335, 343,461 
E-Cadherin , 77 
and EGFR, 70-71 
gene amplification in, 263 
genetic causes of, 18, 19, 454, 475 
HER-2/neu antibodies in, 173 
HercepTe st kit, 264, 265, 266 
and hnRNP A2/B1 expres sion, 
308-309,310,313 
IGF and, 71 
and LOH, 398, 404-406, 473 
lymph node micrometastasis in, 
300-301 
microsatellite instability (MSI), 60, 
405 
and monoclonal-defined tumors, 38, 
39 
mutation carriers and cancer risk, 
459 and NMP assays,43 
patient management, medical , 
461-462 
and PNDs, 171 
PSMA and, 105 491 
and rheumatic syndromes, develop-
ment of, 171 
RT-PCR and, 299 
and sPas levels , 75 
sialoglycoproteins and tumor me-
tastasis, 47 
in situ hybridization, 266 
and SLNs, 287-288, 290-293 
staging and SLND, 287 
tamoxifen in therapy, 462 
telomerase activit y in, 20 
and topoisomera se Ila 275 
VCAM-1, 78 
Breast Cancer Prevention Trial (BCPT), 
462 
Bronchogenic carcinoma, 136 
Burkitt's lymphoma. See also Acute 
lymphoblastic leukemia/l ym­
phoma (ALLs), B lineage 
described, 212, 214 
c genetic abnormalities in, 248-249, 
384 
CA 15-3 serological tumor marke r, 16, 
17,39,46 
CA 19-5 serological tumor marker, 40 
CA 19-9 serological tumor marker, 16, 
39-40 ,56-57 
CA 50 serological tumor marke r, 40 
CA 72-4 serological tumor marker, 16, 
17 
CA 125 serological tumor marker , 16, 
39,56-57 
Canc er 
aggres siveness, predicting , 94 
antigens, most w ell-char acterized , 
191 
benign, 136 
cells, development of, 3, 53-55 , 361, 
362,396

492 
detection of (See also Molecular 
markers in cancer detection) 
DNA arrays in, 61, 95, 340 
general discussion, 175, 370 
immunologic methods, 6, 27, 138 
metastatic I recurrent, 148-149 
molecular profiling in, 8 
p53 gene mutations in, 8-9, 18, 
59-60,61,75 
proteins arrays and, 61, 348 
serologic methods, 6, 16 
TRAP, 349 
drug targeting, 20-21, 31 
hereditary syndromes, features of, 
19,453-455 
immune responses, identification of, 
170-171 
modern concepts of, 4 
mutation in, 361 
predisposition testing 
described, 333, 453 
flow diagram for, 458 
and genetic counseling, 455 
informed consent in, 457 
results, interpreting, 457-458 
risk assessment, 456 
and rheumatic disease, 169 
specificity, increasing, 89 
tissues and hK2, 103 
Cancer-associated retinopathy (CAR), 
172 
Cancer-testis antigens, 177-178 
Capillary electrophoresis, 244, 400, 402, 
403,416 
Carcinoembryonic antigen (CEA) 
blood group substance in, 40 
identification of, 16, 37-38 
sensitivity I specificity of, 16, 56-57 
Carcinoembryonic proteins, 37-38 
Cathepsin D, 178 
Caveolin-1, 108-109 
CBF leukemia. See Core binding factor 
(CBF) leukemia 
CCI-779, 21 
CD4+ CD56+ malignancies described, 
215--216 CD44 
alternative splicing regulation, 
315-316 
described, 78 Index 
eDNA microarrays described, 337, 338, 
339,341 
Celecoxib and FAP, 466 
Cell cycle, 73-74 
Cell-free DNA and tumorigenesis 
detection, 60-61, 67-68 
Cells 
growth, 173, 389 
lineage specific marker reagents, 
establishing, 29 
single, analysis of, 350-351 
tumor, 110, 289 
Cell-specific tumor markers, 43-44, 
65-66 
CENP-F antigen described, 176 
C-erbB-2 gene 
in teratoma, 162 
and tumorigenesis, 58, 70 
Cervical cancer 
and Hsp-27 antibodies, 178 
and LOH abnormalities, 412-413 
molecular markers for, 9 
molecular pathogenesis of, 396 
and sec, 43 
and SLNs, 296 
Cervical intraepithelial neoplasia 
(CIN), 43, 412 
Cervical squamous cell carcinoma 
(CSCC),43 
Chemotherapy 
and anthracycline therapy, 274 
resistance and trastuzumab therapy, 
273-274 
and rheumatic syndromes, develop­
and tumor marker decline, 152-153, 
155-156,160 
Children 
neuroblastoma,330,386

Index 
and HCG, 139 
incid ence of, 130, 131 
and LDH, 139, 140 
management of, 146 
Chromogenic in situ hybridization 
(CISH),271,330,332,337-340 
Chromogranin A (CgA), 44, 66 
18q chromosomal allelic loss and prog­
nosis, 440 
Chromosomes 
aberrations, identifying , 387-388, 
397,416 
Giemsa banding, 379, 389-390 
metaphase, preparation of, 367 
Chronic lymphocytic leuk emia (CLL) , 
245,384,476 
Chronic myelogenous leukemia (CML), 
241-242,382,383 
Circulating serum/plasma tumor DNA 
described, 8 
Cisplatin, 274 
c-kit protein in AML, 239 
Clinical trial assay (CTA) described, 264 
Cloning and amino acid sequence pre-
diction, 29 
C-myb gene described, 173, 431 
C-myc. See Myc family genes 
Cockayne' s syndrome, 363 
Colchicine and mitosis inhibition, 388 
Colon cancer 
AFP serum levels in, 48 
family pedigree showing, 465 
genetic causes of, 18, 19, 454 
and ICAM-1, 78 
and NMP assays, 43 
and sFas levels, 75 
and VEGF, 77 
Colony survival assay described, 368, 
477-478 ,479 
Colorectal cancer. See also H ereditary 
nonpolyposis colorecta l cancer 
(HNPCC) 
AFP and, 136 
APC gene in, 430-431 493 
classification , 385, 432, 434, 435 
conventional pathway in, 429-432 
and COX2 , 57 
and CRP , 68 
development of, 434 
DNA Methylator pathway in, 
434-436 
DNA Mismatch Repair pathwa y 
in,432-434 
familial, 438-440 
HER-2/neu protein, 431 
and IGF, 71 
and inflammation, 53 
methylation phenotype, 435-436 
microsatellite mutation in, 20, 433, 
441 
molecular markers in, 8-9,396 , 
440-441 
molecular pathogenesis of, 396, 
429-430 
Myc family genes, 72,431 
and p53 mutations, 59, 431 
and ras mutations, 72, 408, 435 
risk factors for, 294 
and SLNs, 294-296 
Comet assay described, 367 
Comparative genomic hybridization 
(CGH) described, 251, 333, 396 
Compensa tion defined, 201 
Computerized tomography (CT) 
and molecular markers, 22, 316 
testicular tumors and, 132 
Connective tissue tumors described, 
385-386 
Conventional pathway in colorectal 
cancer, 429-432 
Core binding factor (CBF) leuk emia, 
237-238 
Counterimmunoelectrophoresis (CIE) , 
6 
Cowde n syndrome described, 454 
COX2 . See Cyclooxygenase (COX2) 
CpG islands (CIMP)and DNA meth yla-
tion, 434-435 , 438 
C-reactive protein (CRP), 53, 68

494 
CRP. See C-reactive protein (CRP) 
CT. See Computerized tomography 
(CT) 
Cyclin D1, 73 
Cyclin-dependent kinase inhibitors 
(CDKs), 73-74 
Cyclin E, 73 
Cyclooxygenase (COX2), 57, 68 
CYFRA-21 described, 46-47 
assays described, 367-368 
in A-T, 473-474 
history of, 379-380 
interphase, routine described, 326, 
330,333,335 
in leukemia, 234-242, 251, 326, 380 
metaphase, routine described, 326 
molecular, 380 
Cytokeratin family and epithelial neo­
plasms, 27 
Cytokines 
detection of, 189, 218 
and tumorigenesis, 57-58, 69, 70 
Cytosolic thymidine kinase (TK1), 47 
D 
DD3,97 
Dendrogram defined, 340 
Diagnostic accuracy, improving, 17, 18 
Diagnostics testing, world market for, 
325,326 
Diagnostic testing described, 7 
Digital image analysis described, 
351-352 
Dixon-Moore pathological classification, 
testicular germ cell cancers, 130 
DNA 
arrays and cancer detection, 61, 95,340 
changes, testing functional status of, 
477 
double-stranded breaks (DSBs), 
364-366,367,368-369 
isolation technique, 400 
methylation 
CpG islands (CIMP) and, 434-435, 
438 Index 
transcriptional silencing of genes, 
98,395 
molecular diagnostic techniques in, 
327-328 
oncology molecular diagnostics, tar-
gets for, 325-336 
ploidy analysis described, 216 
quantitation of, 400 
repairs 
deficiency, assays for, 366-370 
issues and cancer, 361,363-365,429 
mechanisms, 361, 362,364-366 
sequence variants of undetermined 
significance (VUS), 457-458 
serum levels and metastatic disease, 
397,399 
DNA Methylator pathway in colorectal 
cancer, 434-436 
DNA Mismatch Repair pathway in 
colorectal cancer, 432-434 
DNMT encoded methyltransferase and 
suppressor genes, 19 
Double immunodiffusion (DI), 6 
Doxorubicin therapy, 275 
DRAQ5 described, 216-217 
Drugs 
efficacy, predicting, 335 
NSAIDs, 466 
targets, detection tests, 20-21, 31 
toxicity, testing, 333, 335 
Duodenal adenocarcinoma and ras 
mutations, 72 
Dysgerminoma, 138, 139 
E 
E-Cadherin, 77, 98 
Ectopic tumor markers, 47-49 
Effector functions, 188 
Embryonal carcinoma 
and AFP, 138, 139 
HCG and, 138, 139 
incidence of, 130, 131 
LDH and, 138, 139, 140 
Endocytosis described, 262 

Index 
c-erbB-2 oncoprotein and, 70 
mapping of, 296 
Enhancer of zone homolog 2 (EZH2) 
gene 
and hereditary cancer, 19 
and prostate cancer diagnosis, 97-98, 
108 
Enzyme immunoassay (EIA) in cancer 
detection, 6, 348 
(ELISA) described, 189, 271 
Enzyme-linked immunospot assay 
(ELISPOT), 189, 190, 191 
Enzymes, 35-37, 476 
Epidermal growth factor (EGFR), 
70-71,261 
Epithelial tumors described, 385 
Epitope Discovery System described, 188 
Epitopes 
discovery of, 188 
software aids for, 188 
and tumor markers, 38-39 
Epstein-Barr virus (EBV) 
and Hodgkin's disease, 251 
lymphomas, association with, 55, 250 
NPCs and, 415, 416 
Esophageal cancer 
p53 and, 59 
and sec, 43, 74 
Evaluative testing described, 7 
EZH2 gene. See Enhancer of zone 
homolog 2 (EZH2) gene 
F 
Familial Adenomatous Polyposis Syn­
drome (FAP), 438-439,454, 462, 
466 
Familial colorectal cancer, 438-440 
Family history and cancer diagnosis, 
455,456 
Fanconi's anemia, 363,364, 365 
Fetal tumor antigens. See 
Carcinoembryonic proteins Finasteride, 90, 91 
Flow cytometry . See also 
applications, 217-218 
described, 199-201 
and MRD detection, 209-210 
quality issues in, 201 
Fluorescence-activated cell sorter 
(FACS) analysis and double­
stranded breaks (DSBs), 369 
Fluorescence in situ hybridization 
(FISH) 
advantages/limitations, 270, 332 
aneusomies and, 326 495 
and bladder cancer diagnosis , 95 
gene amplification, detecting , 330 
genetic abnormalities, detecting , 245, 
270,326,368,390-391,396 
leukemic cells , identification of, 209, 
234,241,380 
translocations, detecting, 326 
and trastuzumab therapy, 272 
Follicular lymphoma 
described, 212 
genetic abnormalities in, 246-247, 
248,384 
Fraction of DNA radioactivity released 
(FAR) assay described, 368 
Free Prostate Specific Antigen (FPSA). 
See also Prostate Specific Antigen 
(PSA) 
benign prostate hyperplasia (BPH), 
89,92 
and cancer specificity, measuring, 
89,92, 100,101 
serum components, 102-103 
Fusion gene products, 186, 205-208, 
236-238 
G 
Gardner syndrome. See Familial 
Adenomatous Polyposis Syn­
drome (FAP) 
Gastric canc er 
and c-erbB-2 oncoprotein, 70

496 
E-Cadherin, 77 
ras mutations and, 72 
and sPas levels, 75 
SLNs and, 294 
Gastrointestinal cancer. See also indi-
vidual cancer by name 
k-ras mutations in, 72, 408 
and LOH abnormalities, 407-409 
sialoglycoproteins and tumor 
metastasis, 47 
Gating defined, 200 
Genes 
abnormalities, detecting, 243, 408 
(See also specific technique by 
name) 
amplification, detecting, 330 
array technology described, 
251-252 
cluster analysis of, 340 
expression profile, establishing, 370 
markers in cancer diagnostics, 18 
methylation status, measuring, 344 
mutations, 74, 244, 246, 482 
(See also individual cancer 
or gene by name) 
rearrangements, detection of, 
242-243,336 
transcription, suppression of, 434 
transcriptional silencing of and DNA 
methylation, 98, 395 
Genetic counseling described, 
455-458 
Genitourinary cancer. See also individual 
and SLN mapping, 296-297 
Genomics assays, 370 
Germ cell tumors described, 387 
(See also individual tumor by name) 
Gleevec in cancer therapy, 21, 241, 325, 
326 
Glycotransferases, 41-42 
Gold-facilitated autometallographic in 
situ hybridization (GOLDFISH), 
271 Index 
Gynecological cancers, 296, 410-413. 
See also individual cancer by name 
H 
Hairy cell leukemia, 71, 212 
Haplotyping and founder mutations, 
identifying, 482 
Head and neck cancer. See also Squa­
mous cell carcinoma, 
SCCHN(head and neck SCC) 
ATM mutation in, 475 
and cyclin D1, 73 
field canceri zation in, 396 
and IL-2, 71-72 
and LOH abnormalities, 414, 475 
microsatellite mutation in, 20 
and sec, 43, 56 
Heat antigen retrieval and formalin 
cross-linking reversal, 29 
Heat Shock Protein (Hsp-27), 178 
Heliobacter pylori, 54, 55, 59 
Hematopoiesis, disruption of, 200, 237 
Hepatitis-C, 250 
Hepatocellular carcinoma (HCC) 
and anti-nuclear antibodies (ANAs), 
169 
and mRNA binding proteins, 
176-177 
p62 overexpression and, 177 
and proliferation-associated anti­
gens, 176 
virus pathogens and, 55 
Hepatoma,75, 141 
Hepsin, 96 
HER-2/neu protein. See also Herceptin 
in colorectal cancer, 431 
described, 173-174 
and gene amplification detection, 
330-331 
HER2 protein 
detection methods, 271 
distribution, 262, 263 
immunostain, interpreting, 267-269 
overexpression in, 263-270 
as prognostic factor, 271-274

Index 
receptors amplification status, 265 
signaling, 261-262 
topoisomerase Ila copy numbers, 
275 
HercepTest kit 
alcohol fixatives and, 268 
and breast cancer, 264, 265, 266 
scoring methods in, 267 
Herceptin in cancer therapy , 21, 70, 90, 
105,325,330 
Hereditary nonpolyposis colorectal 
cancer (HNPCC). See also 
Colorectal cancer 
described, 462-463 
and DNA repair problems , 361, 429 
mutation carri ers, risk factors, 464 
patient managem ent, medica l, 
464-465 
Heterodimerization defined , 261 
Heterogenous nuclear ribonucleopro­
tein. See hnRNP A2/B1 
High-grade prostatic intraepithelial 
neoplasia (HGPIN), 106 
hnRNP A2/B1 
and 703D4, 308 
alternative splicing regulation, 315 
biology, 309-312 
and cancer, 307-309, 310, 313, 314 
coding sequence, 313 
and E16 silencing, 316 
and mRNA transport, regulation of, 
314,315 
overexpression of, 308, 309, 313 
structure/function of, 312-316 
hnRNP proteins, structure /function, 
311 
Hodgkin's disease, 78, 251 
Homocysteine (Hey), 56, 66-6 7 
Homodim erization defined, 261 
Hormones as tumor markers, 35-37 
Host-cell reactivation assay described, 
366 
HPC1 and prostate cancer diagnosis, 99 
HPV . See Human papillomavirus 
(HPV) 
Hsp-27. See Heat Shock Protein (Hsp-
27) 497 
hUBF. See Human upstream binding 
factor (hUBF) 
Human chorionic gonadotrophin 
(HCG) 
characteristics of, 136, 141, 142 
as tumor marker, 132, 142-144, 
152-153 
Human immunodeficiency virus type 1 
(HIV-1) and E16 silencing, 316 
Human papillomavirus (HPV), 54,333, 
336 
Human upstream binding factor 
(hUBF) and RNA transcription, 
176 
Hybridization data, arrangement of, 
340 
8 Hydroxy deox yguanidine (SOH DG) 
as biomarker, 55 
Hyperhomocysteinemia, 56 
Hyperplastic polyp s (HPs), 437, 440 
I 
Identity, establishing cytogenetically, 
396 
Immune responses, most well charac­
terized, 191 
Immune suppression and sentinel 
nodes, 301 
Immunoblotting (IB) in cancer detec­
tion, 6, 478-480 
Immunofluorescence in cancer detec­
tion, 6 
Immunoglobulin heavy (IgH) gene 
arrangements, 242, 244, 246 
Immunoglobulin light (IgK) gene ar­
rangements, 242, 244-245 
Immunohistochemistry (IHC), 30, 264, 
347 
Immunologic methods of cancer detec­
tion, 6, 27, 138 
Immunomagnetic bead peripheral 
blood cell capture described , 352 
Immunophenotyping. See also Flow 
cytometry 
advantages/limita tions, 201-202 
and biphenotypic leuk emia , 208

498 
and diagnosis, 200 
Inflammation, 53, 68 
Inhibitor of apoptosis protein (lAP) 
family described, 106 
In situ hybridization 
breast cancer and, 266 
mRNA detection, 344-345,350 
Insulin-like growth factors (IGFs) 
binding proteins (IGFBPs), 106, 177 
described, 71, 106 
and malignancy, 59, 71 
Intercellular adhesion molecule-1 
(ICAM-1) 
and metastasis, 78 
Interleukin-2 (IL-2) 
described, 71-72 
International Germ Cell Consensus 
Classification System (IGCCC) 
described, 134-135 
metastatic germ cell tumors, classify­
ing, 150, 161 
International Molecular Epidemiology 
Consortium for Ataxia Telang­
iectasia (IMECAT), 476 
International Union Against Cancer 
(UICC) TNM staging system, 135 
Intracellular cytokine cytometry (ICC), 
189-190, 191 
Iressa in cancer therapy, 21 
Isoenzymes as tumor markers, 35,36 
J 
Juvenile Polyposis Syndrome (JPS), 439 
K 
Kallikrein, 99-100, 103-104 
Karposi' s sarcoma, 55, 250 
Karyotype analysis. See Cytogenetics 
Ki-67 described , 46 
Kidney cancer and LOH abnormalities, 
409 
KLF6 gene and hereditary cancer, 18, 19 
Knudson's two-hit hypothe sis, 431, 434 
KOC antigen, 176-177 
k-ras mutations 
and cell-free DNA, 67 
in gastrointestinal cancers, 72, 408 L incidence of, 8, 58, 431 
and pancreatic cancer, 9 
in SAs, 438 Index 
L552S and adenocarcinoma, 187 
Laboratory tests, 4-7 
Lactate dehydrogenase (LDH) 
characteristics of, 136-137, 142-144 
in choriocarcinoma, 139, 140 
and disease stage, 145, 147-148 
in dysgerminoma , 138 
in embryonal carcinoma, 138, 139, 140 
LD-1, 137, 138, 139, 141, 142, 150-152 
in ovarian carcinoma, 37 
in seminoma, 138, 139 
in teratoma, 138, 139, 140 
in testicular cancer, 132, 133 
in yolk sac tumors, 139 
Lambert-Eaton syndrome, 172 
Laser capture microdissection (LCM) 
and angiogenesis , 110 
cancer cells, isolating, 95, 111, 
350-351 
Leiomyomas described, 385-386 
Leucoverin (LV) and tHey , 67 
Leukemia. See also individual leukemia 
by name 
acute 
diagnosis of, 234 
gene fusion products, 236 
ATM mutations in, 475 
and autoimmunity , 170 
biphenotypic , 208 
and CD44, 78 
cell detection, 204, 209 
and CRP, 68 
cytogenetic evaluation of, 234-242, 
251,380-384 
lineage association scoring system , 
209,211 
LOH in, 475 
and metaphase cytogenetics , 326 
MLL abnormalities, 238 
T-cell and A-T, 474-475

Index 
Lewis blood group antigen, 40, 41 
Li-Fraumeni syndrome 
described, 365, 454 
and DNA repair problems, 363 
Ligand-receptor assays described, 
348-349 
Limiting dilution analysis (LDA), 
188-189, 190 
Linkage mapping, 98-99 
Lipid-associated sialic acid in the 
plasma (LASA-P) described, 47 
Lipomas described, 385-386 
Liver cancer 
and CRP, 68 
LD-1levels and, 151-152 
and TGF-[3, 69 
Loss of heterozygosity (LOH). See also 
individual cancer by name 
analysis of, 400-403 
described, 395-398 
metastasis in, 406 
microsatellite markers, analysis, 396 
PCR photo in melanoma, 401 
Lung cancer 
and anti-CENP-F antibodies, 176 
deaths from, 307 
and hnRNP A2/B1 overexpression, 313 
ICAM-1 and, 78 
and IGF, 71 
imaging technologies and, 22 
MAGE antibodies and, 177-178 
and p53 mutations, 59 
PNDs and, 171 
and sec, 43 
sialoglycoproteins and tumor me­
Lung development, mammalian and 
hnRNP A2/B1, 308 
Lymph nodes 
biopsy samples of, 387 
mapping,285,286,288,295 
metastases and cancer progression, 
285,396 
micrometastasis in, 299-301, 302 Lymphomas 
and autoimmunity, 170 
B-cell 
CLL, 245, 384, 476 
described , 214 
detection of, 242-249 
diffuse large, 248 
and CRP, 68 
cytogenetic evaluation of, 326, 
384-385 
diagnosis of, 234, 242-251 499 
and Epstein-Barr virus (EBV), 55, 250 
Hepatitis-C and, 250 
LOH in, 475 
mantle cell, 211, 214, 247-248, 384 
RT-PCR testing, 342 
T-cell 
described, 214 
gene rearrangements in, 243, 
249-250 
translocations in, 235 
viruses associated with, 250 
Lymphoplasmacytic leukemia , 245-246 
Lymphoscintigraphy, value of, 288 
Lynch syndrome. See Hereditary 
non polyposis colorectal cancer 
(HNPCC) 
Lysophosphatidic acid (LPA), 78 
Lytic activity, detecting, 189 
M 
Magnetic resonance imaging (MRI) , 22 
Major histocompatibility (MHC) tet-
ramers 
applications , 192-194 
described, 190, 194 
peptide binding, characterization of, 
188 
and prostate cancer diagnosis , 
109-110 
specificity, conveyance of, 190 
MALDI- TOF, 346-347 
Mantle cell lymphoma 
described, 211, 214 
genetic abnormalities in, 247-248,384

500 
Marginal zone lymphoma (MZL) 
genetic abnormalities in, 246, 248 
Matrix-assisted laser desorption/ion­
ization time of flight (MALDI­
TOF) described, 346-347 
Matrix metalloproteinases (MMPs) 
described, 68, 106-107 
regulation of, 69 
and tumor metastasis, 68-69 
MDS. See Myelodysplastic syndrome 
(MDS) 
Medulloblastoma, 71,386 
Melanoma 
cells 
benign vs metastatic, 293 
suspicious features of, 293-294 
DNA content, assessing technique, 
398-399 
and IL-2, 71 
and LOH abnormalities , 406-407 
lymph node micrometasta sis in, 
299-300 
melastatin loss in, 345 
metastases, detecting, 301 
microsatellite markers in, 406 
p53 gene mutations , 431 
pathologic processing of SLNs, 
289-290 
and RT-PCR, 297-299 
and the SLN, 287 
SLN analysis, 291-292 
and TAAs, 186 
Melanoma antigen encoding genes 
(MAGE) 
antibodies to and melanoma, 
177-178 
expression of, 186, 191 
and prostate cancer diagnosis, 96, 
162 
Melastatin described, 344, 345 
MEN1 I MEN2, 454 
Metaphases, obtaining, 381 
Metastasis 
and cellular adhesion mole cules, 77 Index 
and cytokeratin immunostaining, 
292 
first site of, 286 
foci, identifying , 289 
indications of, 107 
LOH and,406 
lymph node, 285, 299-301, 302, 396 
nodal, 295, 300 
process of, 44-45 
prostate cancer, 91-92, 107 
rejection of, 193 
sialoglycoproteins and, 47 
skip, 295 
and tumor markers, 47, 56, 91-92 
MHL. See Tumor markers, half-lives of 
Microarrays in molecular diagnosis, 
338. See also individual microarray 
by name 
Microcapillary electrophoresis de­
scribed, 352 
Micrometastatic disease, detecting , 88 
Microsatellite instability (MSI) 
and breast cancer, 60, 405 
and colorectal cancer, 20, 433,441 
described, 336, 363,432, 463-464 
detection of, 366-367, 416 
markers of, 9, 55, 437 
mismatch repair gene and, 432-434 
mutation in, 20, 406, 433, 441 
in SAs,438 
Minimal residual disease (MRD) , 
208-209,216 
Mismatch repair described, 363-364 
Mitosin described, 47 
Molecular markers in cancer detection 
adenomatous polyposis coli (APC), 
9,429-431,434,437,438-439 
described , 8-9, 403-404, 408 
ethical issues with , 10 
imaging diagnostics, 21-22, 316 
nonspecific, 45-47 
nucleic acid, 8, 18-20, 95-99 
predictive, 29-31 
quality issues with, 9-10 
Molecular profiling in cancer detection , 
8

Index 
Monoclonal antibodies (mAb) 
and hematological malignancies, 
217, 219 
immunophenotyping ot 200-201 
making,29 
astumormarker,38-40,67 
Morton-Cochran concept of SLN, 286 
mRNA 
binding proteins and cancer, 176-177 
detection ot 344-345, 350 
differential display of, 342 
markers,298,417 
transport , regulation ot 314, 315 
Multiple endocrine neoplasia I/2 
(MEN1 / MEN2),454 
Multivariate logistic regression (MLR), 
113 
Myc family genes 
and adenomatous polyps , 72 
autoantibodies to, 173 
Burkitt's lymphoma and, 248-249 
in colorectal cancer, 72, 431 
described, 72 
in neuroblastoma, 330 
Mycosis fungoids (MF) described, 215 
Myelodysplastic syndrome (MDS), 210, 
382 
Myelomas, multipl e, 384 
N 
Nasopharyng eal cancers (NPCs), 68, 
414-416. See also individual cancer 
by name 
Negative predictive value (NPV) de­
fined, 5 
Neoplasia , classification of, 129 
Neoplasms 
and amphiphysin, 172 
and autoimmune diseases, 169 
c-reactive protein (CRP), 53 
diagnosis and antibodies, 27-28, 29 
epithelial and cytoske leton proteins, 
27 
a -Fetoprotein (AFP) in, 48 
formation and mutagenesis , 386 
and HCG, 136 
and SAGE, 187 501 
small cell undifferentiated, 28 
spindle celC poorly differentiated, 29 
T-cells in, 213, 214 
transformation ot 395 
Neoplastic hematopathology 
molecular genetics studies and, 
233-244 
and the Philadelphia chromosome, 
233 
Neuroblastoma , 330, 386 
Neurological tumors described , 386 
Neuron specific enolase (NSE), 44, 66 
Nijmegen breakage syndrome (NBS), 
363-365 
Nodal micrometastasis defined , 299 
Non-Hodgkin's Lymphoma 
cytogenetic evaluation ot 384-385 
genetic abnormalities in, 243 
phenotypic / genotypic correlation s, 
214 
and rheumatic syndro mes, develop­
and RT-PCR , 342 
Nonsmall cell lung cancer (NSCLC) 
and hnRNP A2/B1, 307, 308 
markers for, 47 
Nonsteroidal anti-inflammator y drugs 
(NSAID s) and apoptosis I angio­
genesis, 466 
Northern analysis described, 341 
NSABP B31 study, 265, 267 
NSAIDs and apoptosis/ angiogenesis, 
466 
NSCL adenocarcinoma and c-erbB -2 
oncoprotein, 70 
Nuclear matrix protein (NMP), 15, 17, 
42-43 
Nucleic acid molecular markers , 8, 
18-20, 95-99 
Nucleic acid sequence based amplifica­
tion (NASBA), 97 
Nucl eic acid testing (NAT), 94 
N ucleosporin protein fusions de­
scribed, 239

502 
Nucleotide excision repair (NER) 
described, 363 
0 
Oligonucleotides microarrays 
described, 337, 338 
Oncogenes, 15,336 
Oncology, 327-329 
Oncoproteins as early markers, 58, 70 
Oophorectomy, 462 
Optical coherence tomography (OCT), 
22 
Osteosarcoma, 75 
Ovarian cancer 
and antigen expression , 41 
CA 125 and, 141 
c-erbB-2 oncoprotein in, 70 
detection of, 61 
epithelial markers, improving, 56 
and LOH abnormalities, 410-412, 
475 
LPA and, 78 
and MAGE antibodies, 177-178 
monoclonal-defined tumors and, 38, 
39 
sFas levels and, 75 
Oxidative stress and cancer develop­
ment, 55 
p 
p16 gene, 74 
p21 gene, 58-59 
p27 gene, 19, 74 
p53 gene 
and angiogenesis, 110 
autoantibody (Ab), 75, 174-175, 
178-179 and colorectal cancer, 59, 431 
described, 74-75, 365 Index 
and laboratory testing, 4-5, 162 
and LOH abnormalities, 408 
mutations in cancer detection, 8-9, 
18,59-60,61,75 
in SAs,438 
p62 antigen, 176-177 
p185. See c-erbB-2 
P330 antigen described, 176 
Paclitaxel resistance and trastuzumab 
therapy, 273-274 
Pancreatic cancer 
AFP and, 48, 136 
detection of, 9, 336 
development of, 53 
309 
k-ras mutations in, 9 
molecular markers in, 396 
39-40 
MRI and,22 
and mRNA binding proteins, 177 
and ras mutations, 72, 408-409 
Pap smear, sensitivity of, 412 
Paradoxical deviation defined, 149 
Paraneoplastic syndromes (PND), 
171-172 
Particle agglutination in cancer detec­
tion, 6 
Pathogens, known and cancer develop-
ment, 54,55 
Pathological diagnosis, basis of, 147 
Pathologists, 27-31, 202 
Patients, 147-149,460 
P AX-5 gene and lymphoplasmacytic 
leukemia, 245-246 
PCA. See Anti-Yo/anti-Purkinje cell 
antibody (PCA) 
PCNA. See Proliferating cell nuclear 
antigen (PCNA) 
PCR. See Polymerase chain reaction 
(PCR) 
Penile cancer and SLN mapping, 297

Index 
Peptide growth factor families, 107 
Peptide libraries and vaccine develop­
ment, 188 
PET, 22 
Peutz-Jegher Syndrome (PJS), 440,454 
Pheochromocytoma,44 
Philadelphia chromosome 
described, 239, 241 
discovery of, 379, 382 
leukemia and Abl-Bcr proteins, 174 
neoplastic hematopathology and, 
233 
Placental alkaline phosphatase, history 
of, 37 
Plasma cell disorders and 
immunophenotyping, 210-211 
Plasma cell myeloma described, 
212-213,214 
Plasmid assays for DSB repair, 369-370 
Polymerase chain reaction (PCR) 
blood sampling technique, 398-399 
and direct sequencing, 335-336 
genetic abnormalities, detecting, 395 
and heparin, 398 
ligand-receptor assays, 349 
LOH, photo of in melanoma, 401 
Polymorphisms and prostate cancer 
diagnosis, 98-99 
Positive predictive value (PPV) de­
fined,5 
Positron emission technology (PET), 22 
PPV. See Positive predictive value 
(PPV) defined 
Precursor lesions, 436-438 
Predisposition testing 
Prognosis, predicting, 149-153, 161, 397 
Proliferating cell nuclear antigen 
(PCNA), 46 
Proliferation markers, 46 503 
Promoter hypermethylation and pros-
tate cancer diagnosis, 98 
Prophylactic mastectomy, 462 
ProPSA and cancer detection, 101 
Prostaglandins and tumorigenesis, 57 
Prostate cancer 
benign, 102 
classification/ prognosis of, 20 
diagnosis of 
2DGE,92 
artificial neural networks (ANN), 
113 
BRCA1/BRCA2 gene, 98 
CD44, 98 
DD3, 97 
E-Cadherin, 98 
EZH2 gene, 97-98, 108 
general discussion, 85-88, 93 
Hepsin, 96 
HPC1 and, 99 
kallikrein biochemistry and, 
99-100 
linkage mapping, 98-99 
MAGE, 96, 162 
MHC tetramers, 109-110 
MLR and, 113 
NASBA and, 97 
polymorphisms in, 98-99 
promoter hypermethylation, 98 
and protein arrays, 61 
proteinsin,99-109, 112-113 
SELDI, 92, 112 
TRAP, 97 
genetic causes of, 18, 19, 475 
and IGF, 59, 71 
immunotherapy, monitoring, 108 
management of, 88 
markers 
for bone metastases, 91-92 
classification of, 87 
multiple, methodologies for, 113 
neuroendocrine, 109 
nucleic acid, 96 
proteomics of, 111-113

504 
search for, 92-94 
and MRI, 22 
NMP assays and, 43 
specimen sources for, 94-95 
testing milestones, 93 
Prostate Cancer Prevention Trial, 90 
Prostate gland and human kallikreins, 
104 
Prostate Specific Antigen (PSA). See 
also Free Prostate Specific Antigen 
(FPSA) 
and cancer diagnosis, 3, 15, 56-57, 
85,87-88,92 
circulating autoantibodies to, 
107-108 
concentration, 90, 91 
Finasteride and, 90, 91 
in PSA, 102 
intact forms, measuring, 102 
limitations of, 100 
primary value, goal of, 89 
and prostate integrity, 90 
sensitivity I specificity of, 16, 17, 
100-101 
serum, measurement of, 100 
(PSMA), 92, 97, 105 
Prostate stem cell antigen (PSCA), 
187-188 
Prostatic acid phosphate (PAP) , 85, 86, 
88,92 
Prostatin described, 20 
Protease as tumor marker , 45 
Proteins 
arrays and cancer dete ction, 61, 348 
markers , 3, 417 
328-329,345-348 
and prostate cancer diagno sis, 
99-109,112-113 
RAS, 58-59, 72, 174 (See also k-ras 
mutations) 
therapeutic targets , predic ting, 29 
truncated , 348, 481 
Protein Truncation Test (PTT), 481 Index 
Proteomics assays, 370 
PSA-ACT as cancer marker, 100 
PTEN mutation and hereditary cancer, 
18,19,439 
PTT (Protein Truncation Test), 481 
Q 
Q-PCR, 234,252,380 
R 
Radioisotopes and lymph drainage , 
mapping, 285 
Radiolabelled in situ hybridization 
(RISH), 332 
RARa gene, 235-236,237 
RARb2 gene, 19 
RAS protein . See also k-ras mutations; 
autoantibodies of, 174 
point mutations, detecting, 336 
and tumorigenesis, 58-59, 72 
RB gene. See Retinoblastoma 
Receiver operating characteristic (ROC) 
curves, 404, 411 
Receptor tyrosine kinases described, 
239 
Regional node dissection, 285-286 
Renal cell cancer 
and hnRNP A2/B1 regulation , 314 
and LOH abnormalities, 409 
Retinoblastoma 
antibodies to, 175 
in children, 386 
and hereditar y cancer, 18, 19 
Retinoic acid receptor (RARb 2) gene, 19 
Rheumatic syndromes, 169, 171 
RNA , molecular diagnostic techniques 
in,328,337-345 
RNAse L gene and prostate cancer di-
agnosis , 99 
RNA trans cription , regulation of, 176 
ROC curves, 404 
Rothmund-Thomson (RecQL4) syn-
drome,365

Index 
RT-PCR 
described, 342 
leukemia testing, 234, 238, 252, 342, 
380 
micrometastases, detection of, 
342-343 
Philadelphia chromosome and, 241 
and PSA, 88 
in situ, 298-299, 302 
SLNDs, detection of, 342-343 
and SLNs, 298, 301 
telomerase activity, measuring, 97 
tumor classification and, 342 
and tumor markers, validating, 95 
tyrosinase , 298, 299, 300 
RUNX3 gene and hereditary cancer, 
19 
s 
Sam68 described, 313 
Sarcoma,55,75,250,330,386 
Saturated fats and prostate cancer, 90 sec antigen as tumor marker, 66 
Schistosoma haematobium, 54 
Seminoma 
AFP and, 139 
detection of, 148, 154, 162 
LDH and, 138, 139 
Sensitivity defined, 5, 6, 403 
Sentinel lymph node dissection (SLND) 
described, 286-287 
detection of by RT-PCR, 342-343 
diagnostic accuracy in, 288-289, 301 
plasma analysis, melanoma , 407 
Sentinel lymph nodes (SLN) 
analysis 
immunohistochemical, 292-293 
microscopic, 291-292, 293-294 
axillary, localization of, 286 
breastcancerand,287-288 ,290-293 
described, 286 
internal mammary (IMSLN), 288 
mapping , 296-297 Morton-Cochran concept, 286 
pathologic processing of, 289-291 
prognostic significance of, 301 
Sequence variants of undetermined 
Serial analysis of gene expression 
(SAGE), 187, 342 505 
Serological identification of antigens by 
recombinant expression cloning 
(SEREX), 171 
Serological tumor markers, 16-17, 39-40, 
56-57 
Serologic methods of cancer detection , 
6, 16 
Serrated adenomas , 437-438 
Serum 
applications as tumor markers, 35-37 
Serum tissue polypeptide specific anti-
gen (TPS), 46 
Sezary syndrome described, 215 
sPas described, 75 
sFasL described, 76 
SG2NA antigen described , 176 
Sialic acids described, 47 
Sialoglycoproteins and tumor metasta-
sis, 47 
Signal transduction described, 261, 262 
Signal transduction pathway, associa­
tion with, 69-72 
Single nucleotide polymorphism detec­
tion (SNPs), 333, 335, 417 
Single Strand Conformation Polymor­
phism (SSCP) , 481 
Skinner staging systems for testicular 
germ cell cancers, 134, 157 
SLN. See Sentinel lymph nodes (SLN) 
SLND. See Sentinel lymph node dissec­
tion (SLND) 
Small cell lung cancer (SCLC), 172, 413 
SNPs. See Single nucleotide polymor­
phism detection (SNPs) 
Solid tissue and organ tumors (STOT), 
activation of, 385 
Southern blotting described, 336 
Specificity defined , 5, 6, 403

506 
Spectral karyotyping described, 251 
S-phase fraction (SPF) described, 216-217 
Squamous cell carcinoma (SCC) 
described, 43 
head and neck SCC (SCCHN) (See 
also head and neck cancer) 
and cell-free DNA, 60-61, 67 
cytokine levels and, 57 
and LOH abnormalities, 414 
sensitivity/specificity of, 16,17 
Stomach cancer, 78 
Suppressor genes, 18-19,20 
Surface-enhanced laser desorption/ 
ionization (SELDI) 
and cancer detection, 17-18, 347 
and prostate cancer diagnosis, 92, 112 
Survivin described, 106 
T 
T A-4, isolation of, 43 
Tamoxifen in breast cancer therapy, 
462 
T -cell large granular lymphocytic leu­
kemia (T-LDL) described, 213-215 
T-cells 
antigen-specific, measuring, 185, 218 
in A-T, 474-475 
CD8+, isolation of, 193-194 
enumerating, 109, 190-191, 192-194 
lymphomas,214,243,249-250 
markers and prostate cancer diagno-
sis, 109 
neoplasmsin,213,214 
responses, monitoring, 188-191 
tumor antigens defined by, 185-186 
TCRs and MAGE ligands, 193 
Tdt, detection of, 202 
Technetium-99 and lymph drainage, 
mapping, 285, 289 
Telomerase activity 
in cancer, 20 
as tumor marker, 79,96-97, 105-106 
Telomerase repeat amplification proto­
col (TRAP), 97, 349 
Telomeres, 79, 315 Teratoma 
c-erbB-2 gene in, 162 
described, 387 
Testicular cancer, 129-131 
Testicular germ cell cancers 
and AFP, 138 Index 
Dixon-Moore pathological classifica­
tion, 130 
HCG and, 138 
histologic types and tumor markers, 
137-140 
monitoring of, 156 
nonseminatous, detection of, 148, 154 
prepubescent, classification of, 
130-131 
prognosis/ outcome, 131-132 
staging systems of, 133-135 
TGF and tumorigenesis, 57-58 
Theranostic defined, 90 
Therapeutic myelodysplastic syndrome 
(tMDS) described, 382 
Thrombospondin and angiogenesis, 
110 
Tissue inhibitors of metalloproteases 
(TIMPs), 69, 106-107 
Tissue microarrays (TMA) described, 
338,340,349-350 
TKl. See Cytosolic thymidine kinase 
(TK1) 
Topoisomerase Ila 
amplicon, 274-275 
and anthracycline chemotherapy, 274 
copy numbers vs HER2, 275 
TP53 mutation analysis, 335 
Transcriptions 
profiling and genetic microarrays, 
337,339-341 
repressing, 235 
Transforming growth factor~ (TGF-~), 
69 
Transient transfection assays, 369 
Transitional cell carcinoma (TCC), 43

Index 
Translocations, 326 
Transmembrane receptors, encoding, 261 
Trastumuzab 
FDA approval of, 264 
NSABP B31 study, 265,267 
in therapy, 272, 273 
Trichothiodystrophy, 363 
T-screening in asymptomatic patients, 
140-141 
Tumor-associated antigens (TAAs), 185 
Tumor markers 
blood group antigens as, 40-42 
cell-specific, 43-44, 65-66 
characteristics of, 3, 17, 135-137,417 
clinical applications, 140-145, 160 
decline and chemotherapy , 152-153 , 
155-156, 160 
ectopic described, 47-49 
epitopes and, 38-39 
half-lives of, 152-153 
human chorionic gonadotrophin 
(HCG) as, 132, 142-144, 152-153 
isoenzymes as, 35, 36 
lysophosphatidic acid (LP A) as, 78 
and metastasis, 47, 56, 91-92 
monoclonal-defined, 38-40 , 67 
multiple and diagnostic sensitivity, 
154,298 sec antigen as, 66 
serological, 16-17,39-40, 56-57 
serum,35-37, 132,153-160 
stages of, 15, 145-146 
telomerase activity as, 79, 96-97, 
105-106 
types of, 95-111 
usage guidelines, 132-133, 146,148, 150 
validating, 85, 95 
Tumor necrosis factor-a (TNF-a) 70, 76 
Tumor node metastasis (TNM) guide­
lines, 300 
Tumors 
antigens 
discovery of, molecular ap­
proaches, 187-188 
serologically defined, 186-187 
in children, incidence, 131 
classification and RT-PCR, 342 development of, 53 
gene amplification in, 267 
Gleevec resistant, 336 
isolated cells defined, 300 507 
node bed status, predicting, 286-287 
solid 
culturing of, 388-389 
described, 385-387 
suppressor genes in 
detection, 335, 430-431 
inactivation of, 434 
listing of, 334-335 
tolerance induction by, 192 
Tumor specific antigens, fluorochrome­
conjugated, 216 
Tumor-specific mutated products, 186 
Two-dimensional gel electrophoresis 
(2DGE), 92 
(2DGE) described, 346 
Tyrosine kinase described, 261 
u 
Urine as specimen for cancer testing, 95 
Urokinase-type plasminogen activator 
(uPA), 107 
Urological cancers , 349, 409-410 . See 
also individual cancer by name 
Uterine cancer , family pedigree show­
ing, 465 
UTMDACC cervical cancer staging 
systems for testicular germ cell 
cancers, 134 
v 
Vaginal cancer and Hsp-27 antibodies, 178 
Vascular cell adhesion molecule-1 
(VCAM-1), 78 
(VEGF) 
described, 60, 76-77 
hnRNP A2/B1 and, 314 
Vinyl chloride and serum anti-p53 anti­
bodies , 175 
Voltage-gated calcium channels 
(VGCC), 172

508 
w 
Walter staging systems for testicular 
germ cell cancers, 134 
Werner 's syndrome, 363, 364, 365 
Western blot analysis described, 346, 
478-480 
WHO classification 
acute leukemias, 202, 208 
acute myeloid leukemia (AML), 204, 
235 
myelodysplastic syndrome (MDS), 210 
testicular cancer, 129-130 
Women and tumor marker analysis, 56 Index 
X 
Xeroderma pigmentosa (XP), 361, 363 
y 
Yolk sac tumors 
andAFP, 138, 139 
described , 387 
incidence of, 131 
and LDH, 139 
z 
Zymogen and cancer , 101